PMID- 10573464
TI  - Extrapontine myelinolysis with involvement of the hippocampus in three children
      with severe hypernatremia.
AB  - Central pontine myelinolysis is a disorder of unknown etiology linked to overly
      aggressive correction of hyponatremia. In addition to the typical location of
      demyelination with preservation of neurons and axon cylinders in the basis
      pontis, similar lesions have been described in extrapontine locations. Central
      pontine myelinolysis and extrapontine myelinolysis usually occur together, and
      are identified at autopsy rather than in life because symptoms of extrapontine
      myelinolysis are often masked in the critically ill patient. Central pontine
      myelinolysis is described in children, usually in the clinical setting of
      hyponatremic dehydration. Extrapontine myelinolysis has not been described in
      children previously. We report three children with severe hypernatremia and
      extrapontine myelinolysis involving various combinations of thalamus, basal
      ganglia, external and extreme capsules, and cerebellar vermis. All three had
      additional involvement of the hippocampus seen on T2-weighted magnetic resonance
      imaging. None of the three had detectable pontine lesions. Clinical features of
      the three cases were dehydration in a 28-month-old girl, respiratory syncytial
      virus bronchiolitis in a 14-month-old girl, and acute respiratory failure due to
      anaphylaxis after consumption of walnuts in a 3-year-old boy. Peak sodium values
      in each child were 195, 168, and 177 mmol/L, respectively; each received
      aggressive treatment for hypernatremia. We believe this to be the first report of
      extrapontine myelinolysis in children, the first report of extrapontine
      myelinolysis without central pontine myelinolysis in children, and the first
      report in children of hippocampal formation involvement. The pathogenesis of the
      central and extrapontine myelinolysis complex in children is more complicated
      than previously believed, and might differ significantly from that of adults.

PMID- 10573465
TI  - Diagnosis and follow-up of a case of peroxisomal disorder with peroxisomal
      mosaicism.
AB  - Peroxisomal disorder phenotypes are the result of mutations that cause defective
      peroxisomal assembly or alterations in the import mechanism of peroxisomal
      proteins that lead to multiple peroxisomal dysfunctions, or the result of a
      peroxisomal enzymatic deficiency with a single peroxisomal dysfunction. With
      complementation analysis, 16 groups have been found. Assignment of the genetic
      defect has been described for some of the complementation groups. We describe the
      clinical evolution and follow-up over 10 years of a patient who belongs to
      complementation group 4, although he showed a milder clinical course. It has been
      found in fibroblasts different peroxisome populations, normal processing and
      expression of beta-oxidation PTS1 and PTS2 proteins, abnormal ALD protein
      distribution and normal plasmalogen biosynthesis; abnormal beta-oxidation
      metabolites have also been detected in serum. Ultrastructural studies in liver
      showed peroxisomal mosaicism as in fibroblasts. It has been taken into account
      that peroxisomal mosaicism may lead to variability in peroxisomal diagnostic
      parameters, making difficult the final diagnosis in these patients.

PMID- 10573466
TI  - Patterns of pregnancy loss, perinatal mortality, and postneonatal childhood
      deaths in families of girls with Rett syndrome.
AB  - Rett syndrome is a neurodevelopmental disorder that occurs predominantly in girls
      and results in severe physical and intellectual handicap. A popular genetic
      mechanism is an X-linked dominant disorder, lethal in males. A case control study
      design was used to investigate fetal wastage as indicated by reported miscarriage
      and stillbirth prevalence, and the prevalence and cause of reported neonatal and
      other childhood deaths. There was no disturbance in the sibling sex ratio when
      case and control families were compared. In the parental generation and in the
      proband generation miscarriages were reported in similar proportions in case and
      control families. The reported stillbirth rates in case families was almost
      double that in control families and reported perinatal loss was more common on
      the maternal side in case families than in control families. Stillbirths and
      neonatal deaths affected slightly more boys in the parental and proband
      generations of case families (19 of 30) than in control families (10 of 21).
      Childhood deaths also occurred a little more commonly in Rett syndrome families.
      Sudden infant death syndrome was reported in three siblings of Rett syndrome
      probands but in no control siblings. Confirmation of this pattern of perinatal
      loss and infant mortality could indicate an alternative expression of the Rett
      syndrome gene.

PMID- 10573467
TI  - Seizures in Chiari I malformation: a clinical and electroencephalographic study.
AB  - Seven subjects with Chiari I malformations and seizures (four males, three
      females; age range 11 years, 7 months to 36 years; mean, 22.28 +/- 7.58 years;
      median, 21) were identified in four different centers from among a group of 10
      patients. Our aim was to analyze clinical and electroencephalographic
      characteristics of seizures in this etiologically homogeneous group of patients.
      Most of the seizures were of the complex partial type, and paroxysmal
      abnormalities were mainly localized over the frontal and temporal regions. The
      course of the epilepsy was rather benign, with complete control of seizures in
      four patients and an important reduction in frequency in the remaining three
      subjects. Other cortical alterations are not usually associated with the typical
      abnormalities of the posterior fossa in Chiari I malformation; thus, it is
      possible to hypothesize that cerebral microdysgenesis or, alternatively, a
      cerebellar dysfunction could underlie epileptogenesis in these patients.

PMID- 10573468
TI  - Ischemic stroke and migraine in childhood: coincidence or causal relation?
AB  - Although migraine is an accepted cause of cerebral infarction in adults, this
      association is less well recognized in children. We present two children with
      migraine and cerebral infarction, which we regard as migrainous stroke, though
      neither patient fulfills all criteria of the International Headache Society for
      the diagnosis of migrainous infarction. Review of the literature concerning
      examples of migraine-associated stroke in childhood suggests that these criteria
      are too restrictive to comprise the majority of migrainous strokes, especially in
      this age group.

PMID- 10573469
TI  - Atypical nonketotic hyperglycinemia with normal cerebrospinal fluid to plasma
      glycine ratio.
AB  - The diagnosis of nonketotic hyperglycinemia is considered to depend upon the
      presence of increased cerebrospinal fluid glycine and an increased cerebrospinal
      fluid to plasma glycine ratio. We studied two siblings who have the neurologic
      and peripheral biochemical features of the atypical variant of nonketotic
      hyperglycinemia but have normal cerebrospinal fluid glycine and cerebrospinal
      fluid to plasma glycine ratios. The proband had reduced liver glycine cleavage
      system activity of 17% and 21% of mean normal values, confirmed in two
      independent laboratories. Her lymphoblast glycine cleavage system activity was
      normal. Nonketotic hyperglycinemia can be present in the absence of increased
      cerebrospinal fluid glycine. Measurement of liver glycine cleavage system
      activity is indicated when nonketotic hyperglycinemia is suggested by clinical
      features and peripheral glycine levels but cerebrospinal fluid glycine is normal.

PMID- 10573470
TI  - Congenital intramedullary tumor with neonatal manifestations.
AB  - The authors report on a 45-day-old boy with a congenital intramedullary tumor
      with clinical manifestations since birth. Neurologic examination disclosed severe
      bilateral lower-limb hypotonia and diplegia, with exacerbated deep tendon
      reflexes and clonus associated with severe pain at manipulation. Further
      evaluation of this patient included screening for infections, computed
      tomographic scan, myelography, and somatosensory evoked potentials. The definite
      diagnosis was a solid holocord astrocytoma. This report discusses a rare disorder
      in the neonatal period and makes other medical practitioners aware of this
      diagnosis. Previously published literature is also reviewed.

PMID- 10573471
TI  - Medication cost reduction in children on the ketogenic diet: data from a
      prospective study.
AB  - In a prospective study of the efficacy of the ketogenic diet in children with
      severe, refractory epilepsy, data were collected on medication changes over 1
      year. Cost reductions in medications were calculated over the first year and
      estimated for a second year. Fifty-seven percent of the children stayed on the
      diet for 1 year, and 74% of these children had their number of medications
      reduced. Forty-eight percent of children who stayed on the diet were on no
      medications at 12 months follow-up. Daily medication costs were reduced by nearly
      70%.

PMID- 10573472
TI  - Expression of the myotonic dystrophy locus-associated homeodomain protein in
      congenital myotonic dystrophy.
AB  - DM locus-associated homeodomain protein (DMAHP), a newly recognized homeodomain
      protein, is a candidate flanking gene and expressed in various tissues. We
      examined the expression of the DMAHP in tissues from a congenital myotonic
      dystrophy patient in comparison to that of control tissues by using
      semiquantitative reverse transcriptase-polymerase chain reaction. Reduced
      expression of DMAHP was observed in tissues from the patient with congenital
      myotonic dystrophy. This finding supports that reduced expression of DMAHP is
      related to the CTG repeat expansion.

PMID- 10573473
TI  - Anomalous ependyma inducing split cord and meningomyelocele?
AB  - The case is that of a female fetus of 17 to 18 weeks' gestation with major
      defects of the central nervous system: (1) The thoracic vertebrae demonstrated
      rachischisis, with segmental diplomyelia; the duplicated cords were dissimilar in
      size and lay side by side within a single meningeal sheath lacking a dividing
      septum or spur. Cranially to the divided cord lay an unsplit segment of "open
      cord" lacking the posterior elements and exposing the centrally placed ependyma
      of the central canal flanked by glial and epidermal lining, respectively; it
      could be regarded as an example of a meningomyelocele. (2) Heterotopic massed
      ependymal cells, some of which were actively proliferating, were associated with
      the choroid plexus in the brain. Minor anomalies included cerebellar heterotopia
      and the malpositioning of dorsal root ganglia outside the meningeal sheath.
      Because the ependyma is such a powerful inducer of the development of neighboring
      tissue, the findings could be united by a common pathogenic theme, viz
      problematic ependymal development and migration within both the brain and spinal
      cord. The causative agent responsible for these abnormalities remains
      unidentified, but the balance of evidence suggests that its effect was felt
      during the second week of postconceptual age.

PMID- 10573474
TI  - Chronic inflammatory demyelinating polyneuropathy and myasthenia gravis.

PMID- 10573475
TI  - Mitochondrial DNA mutations are where to look.

PMID- 10573476
TI  - Auditory hallucinations in migraine without psychosis.

PMID- 10573477
TI  - Single high-dose immunoglobulin therapy for childhood Guillain-Barre syndrome.

PMID- 10573478
TI  - Melatonin to treat fragmented sleep needs study.

PMID- 10573479
TI  - Subaortic stenosis: still more questions than answers.

PMID- 10573480
TI  - Pacing for vasovagal syncope.

PMID- 10573482
TI  - Taming platelets in coronary stenting: ticlopidine out, clopidogrel in?

PMID- 10573483
TI  - Should we ever treat the echo rather than the patient?

PMID- 10573484
TI  - Images in Cardiology: thrombosis of an aortic valve prosthesis.

PMID- 10573485
TI  - Improving quality of life in patients with angina.

PMID- 10573486
TI  - Non-cardiac chest pain: assessment and management.

PMID- 10573487
TI  - Early and late effects of radiation treatment for prevention of coronary
      restenosis: a critical appraisal.

PMID- 10573488
TI  - Can the surface electrocardiogram be used to predict myocardial viability?
AB  - OBJECTIVE: To investigate whether QRS morphology on the surface ECG can be used
      to predict myocardial viability. DESIGN: ECGs of 58 patients with left
      ventricular impairment undergoing positron emission tomography (PET) were
      studied. (13)N-Ammonia (NH(3)) and (18)F-fluorodeoxyglucose (FDG) were the
      perfusion and the metabolic markers, respectively. The myocardium is scarred when
      the uptake of both markers is reduced (matched defect). Reduced NH(3) uptake with
      persistent FDG uptake (mismatched defect) represents hibernating myocardium.
      First, the relation between pathological Q waves and myocardial scarring was
      investigated. Second, the significance of QR and QS complexes in predicting
      hibernating myocardium was determined. RESULTS: As a marker of matched PET
      defects, Q waves were specific (79%) but not sensitive (41%), with a 77% positive
      predictive accuracy and a poor (43%) negative predictive accuracy. The mean size
      of the matched PET defect associated with Q waves was 20% of the left ventricle.
      This was not significantly different from the size of the matched PET defects
      associated with no Q waves (18%). Among the regions associated with Q waves on
      the ECG, there were 16 regions with QR pattern (group A) and 23 regions with QS
      pattern (group B). The incidence of mismatched PET defects was 19% of group A and
      30% of group B (NS). CONCLUSIONS: Q waves are specific but not sensitive markers
      of matched defects representing scarred myocardium. Q waves followed by R waves
      are not more likely to be associated with hibernating myocardium than QS
      complexes.

PMID- 10573489
TI  - Images in Cardiology: left main coronary artery lesion detected by
      transoesophageal echocardiography before cardioversion.

PMID- 10573490
TI  - Dobutamine echocardiography predicts functional outcome after revascularisation
      in patients with dysfunctional myocardium irrespective of the perfusion pattern
      on resting thallium-201 imaging.
AB  - OBJECTIVE: To evaluate whether the predictive value of dobutamine
      echocardiography for assessing contractile reserve was altered by differing
      patterns of regional myocardial perfusion. PATIENTS: 31 consecutive patients with
      symptomatic congestive heart failure (left ventricular ejection fraction < 35%)
      caused by coronary artery disease. SETTING: A district general hospital. METHODS:
      Thallium-201 perfusion imaging and low dose dobutamine (5-15 microg/kg/min)
      echocardiography were performed and resting echocardiography was repeated three
      months after revascularisation. Perfusion pattern and systolic wall thickening
      were compared using a 12 segment left ventricular model. RESULTS: Of the 273
      severely dysfunctional segments, 106 (39%) showed a normal perfusion and 167
      (61%) an abnormal pattern. After revascularisation, recovery occurred in 71 of
      the segments with a normal perfusion pattern, and in these a dobutamine response
      was observed in 61 (86%); recovery also occurred in 56 segments with a mild to
      moderate abnormality of perfusion, and in these a dobutamine response was seen in
      46 (81%) (NS). After revascularisation, the positive and negative predictive
      values for recovery of dysfunctional segments, where the majority were abnormally
      perfused, were 88% and 86%, respectively. Systolic wall thickening score indices
      improved from (mean (SD)) 3.21 (0.58) to 2. 6 (0.66) (p < 0.001) after
      revascularisation in dobutamine responsive patients (n = 24) compared with
      patients who did not show a dobutamine response (2.86 (0.65) and 3.13 (0.56), p =
      0.61, respectively). CONCLUSIONS: Dobutamine echocardiography predicted
      improvement of dysfunctional myocardium after revascularisation irrespective of
      the resting perfusion pattern seen.

PMID- 10573491
TI  - Long term outcome after out-of-hospital cardiac arrest with physician staffed
      emergency medical services: the Utstein style applied to a midsized
      urban/suburban area.
AB  - OBJECTIVE: To test the effect of a physician staffed advanced cardiac life
      support (ALS) system on patient outcome following out-of-hospital cardiac arrest.
      DESIGN: Observational study. SETTING: Two tier basic life support (BLS) and
      physician staffed ALS services in the midsized urban/suburban area of Heidelberg,
      Germany. PATIENTS: All patients suffering out-of-hospital cardiac arrest of
      cardiac aetiology between January 1992 and December 1994 and who were covered by
      ALS services. INTERVENTIONS: Physician staffed ALS services. MAIN OUTCOME
      MEASURES: Return of spontaneous circulation, hospital discharge, and one year
      survival, according to the Utstein style. RESULTS: Of 330 000 inhabitants, 755
      suffered from cardiac arrest covered by the Heidelberg ALS services. In 512
      patients, cardiopulmonary resuscitation had been initiated. Of 338 patients with
      cardiac aetiology, return of spontaneous circulation was achieved in 164 patients
      (49%), 48 (14%) were discharged alive, and 40 (12%) were alive one year later;
      most of these patients showed good neurological outcome. Thus, 4.85 patients with
      cardiac aetiology were saved by the ALS services and discharged alive per 100 000
      inhabitants a year. Ventricular fibrillation or tachycardia was detected in 106
      patients (31%), other cardiac rhythms in 40 (12%), and asystole in 192 (57%).
      Hospital discharge rates (and one year survival) in these subgroups were 34.0%
      (29.2%), 12.5% (7.5%), and 3.6% (3.1%), respectively. Discharge rates increased
      if cardiac arrest was witnessed (bystander, 20.0%; BLS/ALS personnel, 21.4%; non
      witnessed arrest, 3.3%; p < 0.01), and if the time period between the alarm and
      the arrival of the ALS unit was four minutes or less (</= 4 minutes, 30.6%; 4-8
      minutes, 10.4%; > 8 minutes, 8. 1%; p < 0.001). In 69 patients with bystander
      witnessed cardiac arrest with ventricular fibrillation, the discharge rate was
      37.7%; 21 patients were alive after one year. CONCLUSIONS: A two tier BLS and
      physician staffed ALS system is associated with good long term outcome of
      patients suffering from out-of-hospital cardiac arrest of cardiac aetiology in a
      midsized urban/suburban area. Further studies, however, are required to assess
      whether having a physician in the ALS unit is an independent determinant for
      improved long term outcome.

PMID- 10573492
TI  - Seasonal variations in out of hospital cardiopulmonary arrest.
AB  - OBJECTIVE: To determine whether there are seasonal variations in survival
      following out of hospital cardiopulmonary arrest. DESIGN: Prospective cohort
      study using the Heartstart (Scotland) database. SETTING: All of Scotland.
      PATIENTS: 10 890 people who suffered out of hospital cardiopulmonary arrest in
      the summer or winter between December 1988 and August 1997 inclusive.
      INTERVENTION: Univariate comparisons of 5406 arrests occurring in summer with
      5484 in winter, in terms of patient characteristics, management, and survival
      using chi(2) and Mann-Whitney U tests. Multivariate analysis of the association
      between season and survival following adjustment for case mix. MAIN OUTCOMES
      MEASURES: Survival to discharge from hospital, survival pre-admission, in
      hospital survival. RESULTS: Only 6% of people who arrested in winter survived to
      discharge, compared to 8% of those who arrested in summer (odds ratio 0.77, p <
      0.001). People who arrested in winter had a poorer risk profile in that they were
      older, more likely to arrest at home, less likely to have a witness, and less
      likely to receive defibrillation. However, after adjustment for case mix, people
      who arrested in winter were still 19% less likely to survive compared to those
      who arrested in summer. Deaths pre-admission were significantly higher in winter
      (odds ratio 1.18, p < 0.05) but in-hospital deaths were not. CONCLUSIONS: People
      who suffer cardiopulmonary arrest in winter have a significantly lower likelihood
      of surviving. This is, in part, caused by the higher frequency of a number of
      recognised risk factors. However, their prognosis remains poorer even after
      adjustment for these factors.

PMID- 10573493
TI  - Coronary revascularisation for postischaemic heart failure: how myocardial
      viability affects survival.
AB  - OBJECTIVE: To assess the impact of revascularisation of viable myocardium on
      survival in patients with postischaemic heart failure. METHODS: 35 patients (mean
      (SD) age 58 (7) years) with severe heart failure (New York Heart Association
      (NYHA) functional class > or = III), mean left ventricular ejection fraction
      (LVEF) 24 (7)% (range 10-35%), and limited exercise capacity (peak oxygen
      consumption (VO(2)) 15 (4) ml/kg/min) were studied. 21/35 patients had no angina.
      Myocardial viability was assessed with quantitative positron emission tomography
      and the glucose analogue (18)F-fluorodeoxyglucose (FDG) (viable segment = FDG
      uptake > or = 0.25 micromol/min/g) in all patients before coronary artery bypass
      grafting. Patients were divided into two groups: group 1, > or = 8 viable
      dysfunctional segments (mean 12 (2), range 8-15); and group 2, < 8 viable
      dysfunctional segments (mean 3.5 (3), range 0-7). The two groups were comparable
      for age, sex, NYHA class, LVEF, and peak VO(2). RESULTS: Two patients died
      perioperatively and seven patients died during follow up (mean 33 (14) months).
      All deaths were from cardiac causes. Kaplan-Meyer survival analysis showed 86%
      survival for group 1 patients versus 57% for group 2 (p = 0.03). Analysis by Cox
      proportional hazard model revealed three independent factors for cardiac event
      free survival: presence of > or = 8 viable segments (p = 0.006); preoperative
      LVEF (p = 0.002); and patient age (p = 0.01). CONCLUSION: Revascularisation for
      postischaemic heart failure can be associated with good survival, which is
      critically dependent upon the amount of viable myocardium.

PMID- 10573494
TI  - Effect of cholesterol lowering treatment on positive exercise tests in patients
      with hypercholesterolaemia and normal coronary angiograms.
AB  - AIM: To assess the impact of cholesterol lowering on positive exercise stress
      tests in hypercholesterolaemic patients with normal coronary angiograms. METHODS:
      43 non-diabetic patients aged 43-61 years, with total serum cholesterol
      concentrations of more than 7.75 mmol/l, positive exercise tests, and normal
      coronary angiograms, were started on the American Heart Association step 1 diet.
      After 12 weeks these patients were randomly assigned to treatment for another 16
      weeks with the diet alone (diet group, n = 20) or with the diet plus lovastatin
      or simvastatin (statin group, n = 23). After this 28 week run in period, statins
      were withdrawn and lipid profile tests and exercise tests were done and repeated
      20 weeks later. RESULTS: At week 28, the statin group but not the diet group had
      significant reductions from baseline (week 12) in plasma total cholesterol (p <
      0.0001), low density lipoprotein (p < 0.0001), and triglyceride (p < 0.0001). The
      number of patients with positive exercise tests decreased from 23 to three in the
      statin group and from 20 to 15 in the diet group (p = 0.01). After the final 20
      weeks without statins, lipid profiles returned to baseline levels in all 17
      patients remaining in the statin group, and exercise tests were again positive in
      15 of these patients. CONCLUSIONS: In hypercholesterolaemic patients with normal
      coronary arteries, cholesterol lowering treatment reduces myocardial ischaemia,
      as shown by the beneficial effects on exercise testing.

PMID- 10573495
TI  - Transhepatic approach for cardiac catheterisation in children: initial
      experience.
AB  - AIM: To assess initial experience of cardiac catheterisation in children by the
      transhepatic approach where conventional venous access is impossible. PATIENTS
      AND METHODS: Percutaneous transhepatic cardiac catheterisation was performed on
      six occasions in five children (three male) aged 4 to 36 months (mean 17 months).
      All children had documented femoral venous occlusion and all but one had
      occlusion of the superior vena cava. Ultrasound was used in five of the six
      procedures to help identify a large hepatic vein. A 4 F or 5 F sheath was
      introduced into the vein using the Seldinger technique. In the fourth patient,
      hepatic venous access was obtained immediately without the assistance of
      ultrasound. RESULTS: Percutaneous transhepatic catheterisation was successfully
      performed at all six attempts. Total procedure time ranged from 120 to 200
      minutes (mean 138 minutes) and screening time from 14 to 22 minutes (mean 16.8
      minutes). A serious complication was encountered in only one patient who had a
      retroperitoneal bleed after administration of thrombolysis for loss of femoral
      arterial pulse. CONCLUSIONS: The percutaneous transhepatic technique can provide
      a safe alternative approach for cardiac catheterisation in children with multiple
      venous occlusion. The procedure can be performed very simply using the Seldinger
      technique and equipment normally used for conventional venous cannulation for
      cardiac catheterisation.

PMID- 10573496
TI  - Images in Cardiology: radiological findings in total anomalous pulmonary venous
      connection.

PMID- 10573497
TI  - Left ventricular function in adults with mild pulmonary insufficiency late after
      Fallot repair.
AB  - OBJECTIVE: To assess left ventricular function in adult Fallot patients with
      residual pulmonary regurgitation. SETTING: The radiology department of a tertiary
      referral centre. PATIENTS: 14 patients with chronic pulmonary regurgitation and
      right ventricular volume overload after repair of tetralogy of Fallot and 10
      healthy subjects were studied using magnetic resonance imaging. MAIN OUTCOME
      MEASURES: Biventricular volumes, global biventricular function, and regional left
      ventricular function were assessed in all subjects. RESULTS: The amount of
      pulmonary regurgitation in patients (mean (SD)) was 25 (18)% of forward flow and
      correlated significantly with right ventricular enlargement (p < 0.05). Left
      ventricular end diastolic volume was decreased in patients (78 (11) v 88 (10)
      ml/m(2); p < 0.05), ejection fraction was not significantly altered (59 (5)% v 55
      (7)%; NS). No significant correlation was found between pulmonary regurgitation
      and left ventricular function. Overall left ventricular end diastolic wall
      thickness was significantly lower in patients (5.06 (0.72) v 6.06 (1.06) mm; p <
      0. 05), predominantly in the free wall. At the apical level, left ventricular
      systolic wall thickening was 20% higher in Fallot patients (p < 0.05). Left
      ventricular shape was normal. CONCLUSIONS: Adult Fallot patients with mild
      chronic pulmonary regurgitation and subsequent right ventricular enlargement
      showed a normal left ventricular shape and global function. Although the left
      ventricular free wall had reduced wall thickness, compensatory hypercontractility
      of the apex may contribute to preserved global function.

PMID- 10573498
TI  - Total cavopulmonary and atriopulmonary connections are associated with reduced
      heart rate variability.
AB  - AIM: To determine whether cavopulmonary connections are associated with
      abnormalities of heart rate variability. METHODS: Heart rate variability was
      studied by 24 hour Holter monitoring in 39 patients (mean (SD) age 12.2 (4.1)
      years) who underwent cavopulmonary connection operations (partial in 12, total in
      13, and atriopulmonary in 14). Two control groups were used: 18 healthy children
      (11.1 (2.5) years) and 16 patients (11.7 (4.3) years) undergoing cardiovascular
      surgery for biventricular repair of congenital heart disease. All patients were
      in sinus rhythm and had normal left ventricular function. Four time domain
      indices were calculated: mean duration of RR intervals (RR), standard deviation
      of all RR intervals (SD), square root of the mean squared differences of
      successive RR intervals (r-MSSD), and percentage differences of successive RR
      intervals of > 50 ms duration (pNN50). Four frequency domain indices were
      calculated: total power (TP), low frequency (LF), high frequency (HF), and the
      LF:HF ratio. RESULTS: Heart rate variability indices were identical in the two
      control groups. Significantly reduced heart rate variability was found in
      patients with total cavopulmonary connections and atriopulmonary connections
      compared with the two control groups. In patients with partial cavopulmonary
      connections, heart rate variability was reduced compared with healthy controls.
      No differences in heart rate variability could be related to clinical status (New
      York Heart Association functional class), number of surgical interventions, or
      presence of right atrial enlargement. CONCLUSIONS: Patients with cavopulmonary
      connections have significantly reduced heart rate variability and a particularly
      low vagal drive.

PMID- 10573499
TI  - Natural history and surgical outcomes for isolated discrete subaortic stenosis in
      children.
AB  - OBJECTIVE: To document the natural history and surgical outcomes for discrete
      subaortic stenosis in children. DESIGN: Retrospective review. SETTING: Tertiary
      care paediatric cardiology centres. PATIENTS: 92 children diagnosed between 1985
      and 1998. MAIN OUTCOME MEASURES: Echocardiographic left ventricular outflow
      gradient (echograd), and aortic insufficiency (AI). RESULTS: The mean (SEM) age
      at diagnosis was 5.3 (0.4) years; the mean echograd was 30 (2) mm Hg, with AI in
      22% (19/87) of patients. The echograd and incidence of AI increased to 35 (3) mm
      Hg and 53% (36/68) (p < 0.05) 3.6 (0.3) years later. The echograd at diagnosis
      predicted echograd progression and appearance of AI. 42 patients underwent
      surgery 2.2 (0.4) years after diagnosis. Preoperatively echograd and AI incidence
      increased to 58 (6) mm Hg and 76% (19/25) (p < 0.05). The echograd was 26 (4) mm
      Hg 3.7 (0.4) years postoperatively, with AI in 82% (31/38) of patients. Surgical
      morbidities included complete heart block, need for prosthetic valves, and
      iatrogenic ventricular septal defects. Eight patients underwent reoperation for
      recurrent subaortic stenosis. The age at diagnosis of 44 patients followed
      medically and 42 patients operated on did not differ (5.5 (0.6) v 5. 0 (0.6)
      years, p < 0.05). However, the echograd at diagnosis in the former was less (21
      (2) v 40 (5) mm Hg, p < 0.05) and did not increase (23 (2) mm Hg) despite longer
      follow up (4.1 (0.4) v 2.2 (0. 4) years, p < 0.05). The incidence of AI at
      diagnosis and at last medical follow up was also less (14% (6/44) v 34% (13/38);
      40% (17/43) v 76% (19/25), p < 0.05). CONCLUSIONS: Many children with mild
      subaortic stenosis exhibit little progression of obstruction or AI and need not
      undergo immediate surgery. Others with more severe subaortic stenosis may
      progress precipitously and will benefit from early resection despite risks of
      surgical morbidity and recurrence.

PMID- 10573500
TI  - Long term follow up of prosthetic valve endocarditis: what characteristics
      identify patients who were treated successfully with antibiotics alone?
AB  - OBJECTIVE: To identify predictors for the safe use of antibiotic treatment
      without reoperation in patients with prosthetic valve endocarditis. SETTING:
      Retrospective study in a tertiary care centre. SUBJECTS AND DESIGN: All 49
      episodes of definite prosthetic valve endocarditis (Duke criteria) diagnosed at
      one institution between 1980 to 1997 were analysed. Ten episodes (20%) were
      treated with antibiotics only (antibiotic group) and 39 episodes (80%) with
      combined antibiotic and surgical treatment (surgery group). The analysis included
      detailed study of hospital records and data on long term follow up which were
      obtained in all patients by a questionnaire or telephone contact with physician
      or patient. The length of follow up (mean (SD)) was 41 (32) months in the
      antibiotic group and 45 (24) months in the surgery group (NS). Long term survival
      was estimated by the Kaplan-Meier method and compared by the log-rank test.
      RESULTS: There was no significant difference in age, history of previous
      endocarditis, number of previous heart operations, vegetations, emboli, type of
      prosthesis, or percentage of early prosthetic valve endocarditis and positive
      blood cultures between the two groups. In the antibiotic group, there were more
      enterococcal (50%; p = 0.005) and in the surgery group more staphylococcal
      infections (55%; p = 0.048). Annular abscesses (p < 0. 0001) and aortoventricular
      dehiscence (p = 0.02) were more common in the surgery group. No patient in the
      antibiotic group had heart failure. Long term follow up showed no significant
      difference between the surgery and antibiotic groups regarding late mortality
      (14% v 18%) and five year rates of recurrent endocarditis (14% v 16%), event
      related mortality (14% v 3%, log-rank test), and the need for reoperation (14% v
      19%; log-rank test). The only patient with conservatively treated staphylococcal
      prosthetic valve endocarditis died after reoperation for recurrence. CONCLUSIONS:
      Haemodynamically stable patients with non-staphylococcal prosthetic valve
      endocarditis who are carefully supervised can be treated with antibiotics alone
      without an increased rate of reinfection, reoperation, or death.

PMID- 10573501
TI  - Cardiac pacing for severe childhood neurally mediated syncope with reflex anoxic
      seizures.
AB  - OBJECTIVE: To determine whether permanent cardiac pacing could prevent syncope
      and seizures in children with frequent severe neurally mediated syncope, and if
      so whether dual chamber pacing was superior to single chamber ventricular pacing.
      METHODS: Dual chamber pacemakers were implanted into 12 children (eight male,
      four female) aged 2-14 years (median 2.8 years) with frequent episodes of reflex
      anoxic seizures and a recorded prolonged asystole during an attack. The pacemaker
      was programmed to sensing only (ODO), single chamber ventricular pacing with
      hysteresis (VVI), and dual chamber pacing with rate drop response (DDD) for four
      month periods, with each patient allocated to one of the six possible sequences
      of these modes, according to chronological order of pacemaker implantation. The
      parent and patient were blinded to the pacemaker mode and asked to record all
      episodes of syncope or presyncope ("near miss" events). The doctor analysing the
      results was blinded to the patient and pacemaker mode. RESULTS: One patient was
      withdrawn from the study after the pacemaker was removed because of infection. In
      the remaining children, both dual chamber and single chamber pacing significantly
      reduced the number of syncopal episodes compared with sensing only (p = 0.0078
      for both). VVI was as effective as DDD for preventing syncope, but DDD was
      superior to VVI in reducing near miss events (p = 0.016). CONCLUSIONS: Permanent
      pacing is an effective treatment for children with severe neurally mediated
      syncope and reflex anoxic seizures. VVI is as effective as DDD in preventing
      syncope and seizures, but DDD is superior in preventing overall symptoms.

PMID- 10573502
TI  - External cardioversion of atrial fibrillation: role of paddle position on
      technical efficacy and energy requirements.
AB  - AIM: To define the effect of defibrillator paddle position on technical success
      and dc shock energy requirements of external cardioversion of atrial
      fibrillation. METHODS: 301 patients (mean (SD) age 62 (11) years) with stable
      atrial fibrillation were randomly assigned to elective external cardioversion
      using anterolateral paddle position (ventricular apex-right infraclavicular area;
      group AL (151 patients)) or anteroposterior paddle position (sternal body-angle
      of the left scapula; group AP (150 patients)). A step up protocol was used,
      delivering a 3 J/kg body weight dc shock, then a 4 J/kg shock (maximum 360 J),
      and finally a second 4 J/kg shock using the alternative paddle location. RESULTS:
      The two groups were comparable for the all clinical variables evaluated. The
      cumulative percentage of patients successfully converted to sinus rhythm was 58%
      in group AL and 67% in group AP with low energy dc shock (NS); this rose to 76%
      in group AL and to 87% in group AP with high energy dc shock (p = 0.013). Thirty
      seven patients in group AL and 19 in group AP experienced dc shock with the
      alternative paddle position; atrial fibrillation persisted in 10/37 in group AL
      and in 10/19 in group AP. Mean dc shock energy requirements were lower for group
      AP patients than for group AL patients, at 383 (235) v 451 (287) J, p = 0.025.
      Arrhythmia duration was the only factor that affected the technical success of
      external cardioversion (successful: 281 patients, 80 (109) days; unsuccessful: 20
      patients, 193 (229) days; p < 0.0001). The success rate was lower if atrial
      fibrillation persisted for > 6 months: 29 of 37 (78%) v 252 of 264 (95%); p =
      0.0001. CONCLUSIONS: An anteroposterior defibrillator paddle position is superior
      to an anterolateral location with regard to technical success in external
      cardioversion of stable atrial fibrillation, and permits lower dc shock energy
      requirements. Arrhythmia duration is the only clinical variable that can limit
      the restoration of sinus rhythm.

PMID- 10573503
TI  - Decreased amplitude of left ventricular posterior wall motion with notch movement
      to determine the left posterior septal accessory pathway in Wolff-Parkinson-White
      syndrome.
AB  - OBJECTIVE: To determine preoperatively, by analysing asynchronous left
      ventricular wall motion, whether to approach through the right ventricle or the
      left ventricle when carrying out catheter ablation of the accessory pathway in
      Wolff-Parkinson-White syndrome, especially in patients with the pathway located
      on the septum. METHODS: 73 patients with manifest Wolff-Parkinson-White syndrome
      who underwent successful catheter ablation were studied. Location of accessory
      pathway was classified as right ventricular side: right anterior paraseptum,
      right anterior, right lateral, right posterior, anterior septum, midseptum, right
      posterior septum; left ventricular side: left posterior septum, left posterior,
      left lateral, left anterior. Asynchronous systolic wall motion was analysed by
      cross sectional echocardiography. RESULTS: Echocardiography showed that the
      amplitude of left ventricular posterior systolic wall motion was reduced when the
      pathway was located on the left ventricular side as opposed to the right
      ventricular side (mean (SD), 11.1 (1.7) v 12.9 (1.1) mm, p < 0.001), especially
      in patients with left posterior septal accessory pathway (9.7 (0.8) mm). There
      were no overlapping values between the left posterior septal accessory pathway
      and the right ventricular side accessory pathway. Posterior wall notch motion was
      observed in all patients with a left posterior septal accessory pathway (9/9),
      but not at all in patients with pathways located on the right ventricular side of
      the septum. In patients with a septal accessory pathway, an ECG algorithm
      provided poor information (relatively low sensitivity, specificity, and
      predictive value) for determining whether the subsite faced either the left (left
      posterior septum) or the right ventricle (anterior septum, midseptum, right
      posterior septum). CONCLUSIONS: Decreased amplitude of left ventricular posterior
      wall motion with notch movement is an important finding for accessory pathways
      located on the left posterior septum. These findings provided clinically useful
      information for determining whether to approach catheter ablation from the right
      or the left ventricle.

PMID- 10573504
TI  - Inhibition of nitric oxide synthesis improves left ventricular contractility in
      neonatal pigs late after cardiopulmonary bypass.
AB  - BACKGROUND: Following neonatal open heart surgery a nadir occurs in left
      ventricular function six to 12 hours after cardiopulmonary bypass. Although
      initiated by intraoperative events, little is known about the mechanisms
      involved. OBJECTIVE: To evaluate the involvement of nitric oxide in this late
      phase dysfunction in piglets. DESIGN: Piglets aged 2 to 3 weeks (4-5 kg)
      underwent cardiopulmonary bypass (1 h) and cardioplegic arrest (0.5 h) and then
      remained ventilated with inotropic support. Twelve hours after bypass, while
      receiving dobutamine (5 microg/kg/min), the left ventricular response to non
      selective nitric oxide synthase inhibition (l-N(G)-monomethylarginine (l-NMMA))
      was evaluated using load dependent and load independent indices (E(es), the slope
      of the end systolic pressure-volume relation; M(w), the slope of the stroke work
      end diastolic volume relation; [dP/dt(max)](edv), the slope of the dP/dt(max)-end
      diastolic volume relation), derived from left ventricular pressure-volume loops
      generated by conductance and microtip pressure catheters. RESULTS: 10 pigs
      received 7.5 mg l-NMMA intravenously and six of these received two additional
      doses (37.5 mg and 75 mg). E(es) (mean (SD)) increased with all three doses, from
      54.9 (40.1) mm Hg/ml (control) to 86.3 (69.5) at 7.5 mg, 117.9 (65.1) at 37.5 mg,
      and 119 (80.4) at 75 mg (p < 0.05). At the two highest doses, [dP/dt(max)](edv)
      increased from 260.8 (209.3) (control) to 470.5 (22.8) at 37.5 mg and 474.1
      (296.6) at 75 mg (p < 0.05); and end diastolic pressure decreased from 16.5 (5.6)
      mm Hg (control) to 11.3 (5.0) at 37.5 mg and 11.4 (4.9) at 75 mg (p < 0. 05).
      CONCLUSIONS: In neonatal pigs 12 hours after cardiopulmonary bypass with
      ischaemic arrest, low dose l-NMMA improved left ventricular function, implying
      that there is a net deleterious cardiac action of nitric oxide at this time.

PMID- 10573505
TI  - Physical activity is a major contributor to the ultra low frequency components of
      heart rate variability.
AB  - OBJECTIVE: To investigate the link between changes in level of physical activity
      and the pattern of heart rate variability during long term ambulatory monitoring.
      DESIGN: Heart rate variability was measured simultaneously with a quantitative
      indicator of muscle activity by electromyography (EMG) in five men and five women
      while they did activities typical of daily life or while they rested for 2-3
      hours. Spectral and cross spectral analyses were performed on both variables with
      standard fast Fourier transform. RESULTS: There was a marked reduction in
      spectral power in the ultra low frequency band (< 0.003 Hz) on going from active
      to rest conditions for both heart rate variability (men 6187 (1801) v 410 (89)
      ms(2)/Hz; women 4056 (1161) v 2094 (801), mean (SEM); p < 0.01) and EMG (p <
      0.001). Cross spectral analysis showed a strong positive gain between the EMG and
      heart rate variability signal that was virtually eliminated in the resting
      condition (p < 0.01). A sex-by-condition effect (p = 0.06) was noted with a
      reduction in total spectral power for heart rate variability during rest in men,
      while it increased slightly in women. CONCLUSIONS: There is a quantitative link
      between muscle activation and heart rate variability in the lowest frequency
      band. Voluntary restriction of physical activity in healthy young subjects caused
      marked reduction in spectral power in the lowest frequency band which is often
      used to assess patient prognosis. The findings strongly suggest that studies of
      ambulatory heart rate variability should always include an indication of physical
      activity patterns.

PMID- 10573506
TI  - Aortic balloon dilatation for congenital aortic stenosis: report of 90 cases
      (1986-98).
AB  - OBJECTIVE: To review 12 years of experience of balloon aortic valvoplasty in
      childhood. DESIGN: Early and mid-term clinical and instrumental evaluation of 104
      consecutive balloon aortic valvoplasties performed from 1986 to 1998. SETTING: A
      tertiary referral centre for congenital heart disease. PATIENTS: 90 patients with
      congenital aortic stenosis: 20 neonates (group 1), 16 infants (group 2), and 54
      children (group 3). INTERVENTIONS: Balloon aortic valvotomy. MAIN OUTCOME
      MEASURES: Doppler and peak to peak aortic gradient before and after valvoplasty,
      degree of aortic regurgitation before and after valvoplasty, early and late
      mortality, need for repeat intervention or surgery. RESULTS: Balloon aortic
      valvoplasty produced a gradient reduction of > 50% in 59 patients, 12 having a
      residual peak to peak gradient of > 50 mm Hg. Early mortality included three
      procedure related and six procedure unrelated deaths. There were no
      intraprocedural deaths. Grade III aortic regurgitation occurred in 20 patients.
      Five non-lethal complications occurred. At a mean follow up of 5.1 (group 1), 5.7
      (group 2), and 7.6 years (group 3), survival was 75%, 88%, and 96%, respectively.
      Redilatation was performed in three patients in group 1, one in group 2, and 10
      in group 3. Surgery was necessary for six in group 1, one in group 2, and eight
      in group 3. Freedom from events at last follow up was 50%, 75%, and 64%,
      respectively. There was a residual maximum Doppler gradient of < 30 mm Hg in 22
      patients and > 60 mm Hg in 23; 50 patients have mild to moderate aortic
      regurgitation. CONCLUSIONS: Balloon aortic valvoplasty is effective and
      repeatable and offers good palliation for congenital aortic stenosis in
      childhood.

PMID- 10573507
TI  - A young man with a heavy heart.
AB  - A 34 year old man presented with acute chest pain. His ECG was very abnormal but
      stable and he was treated with opiate analgesia. When his condition did not
      improve, chest radiography and cardiac ultrasound were performed. Both revealed
      metal dense deposits in the heart. On questioning, the patient revealed that he
      had self injected with mercury 15 years before. Self injection of elemental
      mercury is rare but well described and normally used by those who are suicidally
      depressed or who seek to improve sexual or athletic performance. Intravenous
      mercury may be deposited in the right heart and can result in ECG abnormalities,
      which may later be mistaken for changes due to coronary or other cardiac disease
      and result in inappropriate medication and hospitalisation.

PMID- 10573509
TI  - Microanatomy of the human liver-exploring the hidden interfaces.

PMID- 10573510
TI  - Expression of MUC1 and MUC2 mucin antigens in intrahepatic bile duct tumors: its
      relationship with a new morphological classification of cholangiocarcinoma.
AB  - Our previous immunohistochemical study on intrahepatic bile duct tumors showed
      that invasive cholangiocarcinoma (ICC) with a poor outcome expressed MUC1 mucin
      but was negative for MUC2 mucin, whereas bile duct cystadenocarcinoma (BDCC) with
      a favorable outcome was MUC1 negative and MUC2 positive. In the present study,
      ICC was further subdivided into 2 subtypes: intraductal growth type and/or
      periductal infiltrating type (ICC-IP) and mass forming type (ICC-M). The survival
      of patients with BDCC or ICC-IP is significantly better than that of patients
      with ICC-M. We examined these subtypes (ICC-IP and ICC-M) and BDCC for their
      expression of MUC1 mucins of different glycoforms. ICC-M showed significantly
      higher MUC1 expression rates (90%, 95%, and 85% positive rates as measured with
      the DF3, MY.1E12, and MUC1-Glycoprotein antibodies, respectively) than BDCC and
      ICC-IP (14% and 33%, 58% and 58%, and 0% and 50% positive respectively, as
      measured by the same antibodies). In contrast, BDCC (86% positive) and ICC-IP
      (67% positive) showed significantly higher MUC2 expression rates than ICC-M (25%
      positive) as measured with the anti-MRP antibody. Thus, the immunohistochemical
      staining pattern of ICC-IP resembled the pattern of BDCC more than they resembled
      ICC-M. In general, MUC1 expression is associated with poor patient outcome,
      irrespective of the glycosylation status. In particular, high expression of more
      sialylated forms of MUC1 mucins was correlated with poor survival. In contrast,
      expression of non-sialylated MUC2 mucin is a favorable prognostic indicator.
      These results suggest that ICC-IP is a different entity from ICC-M. This
      reclassification may have value in determining prognosis and treatment method.

PMID- 10573511
TI  - Independent predictors of liver fibrosis in patients with nonalcoholic
      steatohepatitis.
AB  - Nonalcoholic steatohepatitis (NASH) may present with increased hepatic fibrosis
      progressing to end-stage liver disease. No factors that determine increasing
      fibrosis and histologically advanced disease have been recognized, thus, liver
      biopsy is recommended in all patients for diagnosis and prognosis. Our aim was to
      identify independent predictors of severe hepatic fibrosis in patients with NASH.
      One hundred and forty-four patients were studied. All patients underwent liver
      biopsy. Clinical and biochemical variables were examined with univariate and
      multivariate analysis. Thirty-seven (26%) patients had no abnormal fibrosis, 53
      (37%) had mild fibrosis, 15 (10%) had moderate fibrosis, 14 (10%) had bridging
      fibrosis, and 25 (17%) had cirrhosis. In multivariate analysis, older age (P =.
      001), obesity (P =.002), diabetes mellitus (P =.009), and aspartate
      transaminase/alanine transaminase (AST/ALT) ratio greater than 1 (P =.03) were
      significant predictors of severe liver fibrosis (bridging/cirrhosis). Body mass
      index (P =.003) was the only independent predictor of the degree of fat
      infiltration. Increased transferrin saturation correlated positively with the
      severity of fibrosis (P =.02) in univariate analysis, and there was a trend for
      more female patients among those with more advanced fibrosis (P =. 09). However,
      iron studies or gender were not significant when controlled for age, obesity,
      diabetes, and AST/ALT ratio. In conclusion, older age, obesity, and presence of
      diabetes mellitus help identify those NASH patients who might have severe liver
      fibrosis. This is the subgroup of patients with NASH who would be expected to
      derive the most benefit from having a liver biopsy and considering
      investigational therapies.

PMID- 10573512
TI  - Cognitive impairment in alcoholic and nonalcoholic cirrhotic patients.
AB  - Cognitive impairment is common in patients with advanced liver disease. It has
      been suggested that patients with alcoholic liver disease (ALD) have more
      impaired cognition than nonalcoholics. The objective of this study was to
      characterize any differences in cognitive functions between alcoholic cirrhotic
      patients and non-alcoholic cirrhotic patients of similar age, education, and
      severity of liver disease. We assessed cognitive functions in 117 patients with
      alcoholic cirrhosis and 163 patients with nonalcoholic cirrhosis using a brief
      battery of neuropsychological tests. In addition, all patients had standard
      psychiatric examinations to assess the effect of the disease severity,
      alcoholism, anxiety, and depression on the test scores. The study showed a higher
      proportion of patients with cognitive impairment in the alcoholic group.
      Alcoholics performed poorly in tests of memory and motor speed compared with
      nonalcoholics, despite similar premorbid IQ and education. Because patients with
      alcoholic cirrhosis had more severe liver disease (Child-Pugh score 8.5 +/- 2.2
      vs. 7.6 +/- 2.2, P =.03) than nonalcoholics, the results were reanalyzed after
      adjusting for the linear effects of Child-Pugh score on cognitive test scores. We
      also used two-way analysis of variance to examine the interaction between Child
      class and alcoholism. Finally, the test scores were compared within each Child
      class. These analyses revealed no primary or interaction effect of alcoholism and
      confirmed that the differences in the test scores observed in alcoholics reflect
      the greater severity of their liver disease. The severity of cognitive impairment
      is similar in both alcoholic and non-alcoholic cirrhotic patients when adjusted
      for the severity of liver disease.

PMID- 10573513
TI  - Regional cerebral blood flow during mechanical hyperventilation in patients with
      fulminant hepatic failure.
AB  - Hyperventilation is frequently used to prevent or postpone the development of
      cerebral edema and intracranial hypertension in patients with fulminant hepatic
      failure (FHF). The influence of such therapy on regional cerebral blood flow
      (rCBF) remains, however, unknown. In this study the CBF-distribution pattern was
      determined within the first 12 hours after development of hepatic encephalopathy
      (HE) stage 4 before and during hyperventilation. Ten consecutive patients (median
      age 48 [range 33-57] years) with FHF and 9 healthy controls (median age 54 [24
      58] years) had rCBF determined by single photon emission computed tomography
      (SPECT) using intravenous injection of 133Xenon. For determination of high
      resolution CBF pattern, the patients were also studied with 99mTc-hexa
      methylpropyleneamine oxime (HMPAO) in the hyperventilation condition. There was
      no significant difference in the rCBF distribution pattern during
      normoventilation as compared with hyperventilation. The anterior to posterior
      (AP) ratio was significantly lower in patients as compared with healthy controls.
      After hepatic recovery and disappearance of HE, 3 patients had restored normal
      rCBF distribution pattern as compared with healthy controls. We conclude that in
      sedated patients with FHF, a relatively lower rCBF is found in the frontal
      regions and in the basal ganglia as compared with posterior regions. This rCBF
      distribution pattern was not aggravated during hyperventilation. It is speculated
      that this change of rCBF in patients with FHF may render the frontal brain
      regions more susceptible to hypoxia. The relative frontal rCBF decrease was shown
      to be reversible with hepatic recovery and alleviation of HE.

PMID- 10573514
TI  - Pediatric and adult forms of type I autoimmune hepatitis in Argentina: evidence
      for differential genetic predisposition.
AB  - The aim of this study was to compare major histocompatibility complex (MHC) class
      II susceptibility to type 1 autoimmune hepatitis (AH) between children and adults
      of the same ethnic group. HLA-DRB1, HLA-DRB3, HLA-DQA1, and HLA-DQB1 gene
      subtypes were examined by high resolution oligonucleotide typing in 122 pediatric
      (PAH) and 84 adult (AAH) patients and in 208 controls. In children, HLA-DRB1*1301
      was the primary susceptibility allele (66.4% patients vs. 10.6% controls,
      relative risk [RR] = 16.3, Pc < 10(-24)) whereas HLA-DRB1*1302, which differs
      from HLA-DRB1*1301 by only 1 amino acid, appeared to be protective. The exclusion
      of individuals with HLA-DRB1*1301 from control and pediatric patients allowed us
      to find a secondary association of PAH with HLA-DRB1*0301. Possession of HLA
      DRB1*1301, however, was associated with a lower therapeutic response rate.
      Analysis of peptide binding pocket residues indicated that Tyr 10, Ser 11, Ser
      13, and Val 86 in the class II beta chain were present in 85% of patients
      compared with 37% of controls, suggesting that a high proportion of AH
      susceptibility is attributable to these residues (etiologic fraction [EF] = 76%).
      In contrast to the class II associations in children, AAH was associated with HLA
      DRB1*0405 (RR = 10.4, Pc <.005) but not with HLA-DRB1*1301 or HLA-DRB1*0301. In
      addition, HLA-DR4 with the class I gene, HLA-A11, appeared synergistic in
      predisposing AAH patients to develop extra-hepatic autoimmune (AI) manifestations
      (odds ratio [OR] = 104.9, Pc < 10(-4)). Concomitant differences in autoantibody
      profiles were also observed in PAH versus AAH: smooth muscle antibodies (SMA)
      were most prevalent in PAH but antinuclear antibodies were most prevalent in AAH
      (P =.003). This study therefore reveals that different HLA-DRB1 allotypes confer
      susceptibility to AH in children and adults and raises the possibility that PAH
      and AAH may be triggered by different factors.

PMID- 10573515
TI  - Ursodeoxycholic acid as adjunctive therapy for problematic type 1 autoimmune
      hepatitis: a randomized placebo-controlled treatment trial.
AB  - To evaluate the efficacy of ursodeoxycholic acid as adjunctive therapy in type 1
      autoimmune hepatitis, 37 patients who had experienced treatment failure, repeated
      relapse, or incomplete response were randomized to ursodeoxycholic acid (13-15
      mg/kg daily) or placebo for 6 months in addition to their usual corticosteroid
      schedule. Serum aspartate transaminase (70% vs. 31%, P =.04) and alkaline
      phosphatase (47% vs. 7%, P =.02) levels improved more commonly in the 21 patients
      randomized to ursodeoxycholic acid. Mean serum levels, however, were similar
      before and after the treatment period. The frequency of dose reduction or
      corticosteroid withdrawal was comparable in both groups (29% versus 31%, P >.9),
      and clinical improvement (48% vs. 44%, P >.9) or its absence (52% vs. 56%, P >.9)
      occurred as commonly in patients receiving ursodeoxycholic acid or placebo. The
      modified histological activity score (3.5 +/- 0.8 vs. 3. 5 +/- 0.9) and the
      modified fibrosis score (2.4 +/- 0.4 vs. 2.4 +/- 0.4) were similar before and
      after treatment with ursodeoxycholic acid and no different than after placebo
      therapy. We conclude that ursodeoxycholic acid can improve certain laboratory
      tests in problematic patients with type 1 autoimmune hepatitis when administered
      adjunctively for 6 months. Short-term therapy, however, does not facilitate
      reduction in the dose of corticosteroids or its withdrawal, affect clinical
      outcome, or reduce histological activity.

PMID- 10573516
TI  - Autonomic dysfunction and hyperdynamic circulation in cirrhosis with ascites.
AB  - Patients with advanced cirrhosis frequently show hemodynamic abnormalities.
      Autonomic dysfunction (AD) is also common and, owing to the importance of
      autonomic function in cardiovascular homeostasis, it may be involved in the
      pathogenesis of the hyperdynamic circulation. We, therefore, evaluated the
      hemodynamic status and autonomic function in 30 patients with cirrhosis, most of
      them with an advanced stage of the disease. Autonomic function was assessed with
      7 cardiovascular tests exploring the vagal or sympathetic function. Each test was
      scored from 1 to 3 (normal, borderline, altered). Cardiac index (CI) was measured
      by an echocardiogram. Twenty-four (80%) patients showed an AD, this being
      definite in 14 (47%) patients. A vagal dysfunction (VD) was found in 19 patients
      (63%), this being definite in 11 patients (37%), and a sympathetic dysfunction
      (SD) in 7 patients (definite in 3 [10%] patients). The patients with AD showed a
      faster heart rate (P =.021), lower indicized peripheral vascular resistance (P
      =.013), and increased CI (P =.004) than patients without AD whereas mean arterial
      pressure did not differ. Similar results were seen by grouping patients according
      to the VD. AD score was directly correlated with heart rate (r = 0.53; P =.002)
      and CI (r = 0.45; P =. 016), and inversely correlated with peripheral vascular
      resistance (r = 0.46; P =.013). Even closer correlations were found with vagal
      score. AD (mainly VD) may be involved in the pathogenesis of the hyperdynamic
      circulatory syndrome of patients with advanced cirrhosis.

PMID- 10573517
TI  - Wedged hepatic venous pressure adequately reflects portal pressure in hepatitis C
      virus-related cirrhosis.
AB  - Wedged hepatic venous pressure (WHVP) is equivalent to portal venous pressure in
      patients with alcoholic liver diseases. However, it may underestimate portal
      pressure in nonalcoholics, which is important because hepatitis C virus (HCV)
      infection is a frequent cause of chronic liver disease. We investigated the
      agreement between directly measured portal pressure and WHVP in alcoholic and HCV
      related liver diseases. Seventy-one patients with liver disease resulting from
      HCV infection (n = 32), alcohol (n = 25), or both (n = 14) underwent simultaneous
      measurements of WHVP (by hepatic vein catheterization) and portal pressure (by
      direct puncture). In 9 patients, measurements were repeated 20 minutes after
      acute iv propranolol administration. WHVP showed an excellent agreement with
      portal pressure in patients with cirrhosis resulting from either HCV, alcohol or
      both (intraclass correlation coefficient: 0.94, 0.93, and 0.97, respectively; P
      <.001). A discrepancy of >/=5 mm Hg was observed in 7 cases. WHVP underestimated
      portal pressure in only 1 case and exceeded portal pressure by >/=5 mm Hg in 6
      patients. The WHVP response to propranolol closely and significantly correlated
      with changes in portal pressure (intraclass correlation coefficient: 0.87; P
      <.004). The simple and safe measurement of WHVP accurately reflects portal
      pressure in alcoholic and HCV-related liver disease. This technique also allows
      us to accurately assess the portal pressure response to propranolol in both
      alcoholic and HCV-related cirrhosis.

PMID- 10573519
TI  - Lipopolysaccharide potentiates the effect of hepatocyte growth factor on
      hepatocyte replication in rats by augmenting AP-1 activity.
AB  - The liver regenerates by replication of differentiated hepatocytes after damage
      or removal of part of the liver. Although several growth factors and signaling
      pathways are activated during regeneration, it is unclear as to which of these
      are essential for hepatocyte replication. We show here that low- (1 mg/kg) and
      high- (10 mg/kg) dose hepatocyte growth factor (HGF) induced replication of 2.1%
      and 11.1% of hepatocytes in rats, respectively. Lipopolysaccharide (LPS), an
      inducer of the acute phase response, augmented hepatocyte replication in response
      to low- and high-dose HGF by 4- and 2-fold, respectively. HGF alone induced
      moderate levels of c-Jun-N-terminal kinase (JNK) and p44/p42 mitogen-activated
      protein kinase (MAPK), resulting in moderate levels of AP-1-DNA binding activity.
      The combination of LPS + HGF increased JNK and AP-1-DNA binding activity more
      than levels seen with LPS or HGF alone. The activation of Stat3 that was observed
      after administration of LPS + HGF, but not HGF alone, could contribute to
      increased transcription of AP-1 components. Because phosphorylation of the c-Jun
      component of AP-1 by JNK increases its ability to activate transcription, the AP
      1 in hepatocytes from animals treated with LPS + HGF may be more active than in
      rats treated with LPS or HGF alone. LPS may contribute to hepatocyte replication
      by potentiating the effect of HGF on the activation of both AP-1-DNA binding and
      transcriptional activity.

PMID- 10573518
TI  - Cholangiocarcinomas express Fas ligand and disable the Fas receptor.
AB  - Cholangiocarcinoma is a highly-malignant adenocarcinoma originating from
      cholangiocytes. Current concepts support escape from immune surveillance using
      aberrant expression of Fas ligand (FasL) and dysregulation of receptor (FasR)
      signaling as a potential mechanism for tumor progression. Our aims were to
      determine if altered expression of FasR and FasL or changes in expression of
      FLICE inhibitor (I-FLICE) allow cholangiocarcinoma cells to escape immune
      surveillance. Human cholangiocarcinoma cell lines were evaluated for the
      functional expression of FasR and FasL by (1) quantitating apoptosis after
      incubation of cells with agonistic antibodies and (2) an in vitro cell death
      assay involving coculture of cholangiocarcinoma cells with Fas-sensitive
      thymocytes. I-FLICE antisense treatment was performed by stable transfection with
      complementary DNA (cDNA) for I-FLICE in the reverse orientation. We found that
      normal cholangiocytes in vivo express FasL. Human cholangiocarcinoma cell lines
      express both FasL and FasR and I-FLICE. FasL expressed by cholangiocarcinomas in
      vitro induced lymphocyte cell death (70% after 24 hours). Despite the expression
      of FasR, exposure of the cells to agonistic antibodies (500 ng/mL) induced only
      minimal apoptosis in the Jurkat cells. Antisense treatment of cholangiocarcinomas
      in vitro with I-FLICE reduced protein expression of I-FLICE by 90% to 95% and
      increased Fas-mediated apoptosis 2-fold. We concluded that cholangiocarcinomas
      escape immune surveillance either by disabling FasR signaling through the
      expression of I-FLICE and/or increased FasL expression to induce apoptosis of
      invading T cells. Reduction of I-FLICE expression in cholangiocarcinoma cells
      restored Fas-mediated apoptosis. Therapeutic maneuvers to inhibit expression of I
      FLICE may aid in the treatment of cholangiocarcinoma.

PMID- 10573520
TI  - Role for tumor necrosis factor alpha receptor 1 and interleukin-1 receptor in the
      suppression of mouse hepatocyte apoptosis by the peroxisome proliferator
      nafenopin.
AB  - Peroxisome proliferators (PPs) cause rodent liver enlargement and tumors. In
      vitro, PPs induce rat and mouse hepatocyte DNA synthesis and suppress apoptosis,
      a response mimicked by exogenous tumor necrosis factor alpha (TNFalpha). Here, we
      determine the role of TNF receptor 1 (TNFR1), TNF receptor 2 (TNFR2), and nuclear
      factor kappa beta (NFkappaB) in the response of mouse hepatocytes to the PP,
      nafenopin. Nafenopin (50 micromol/L) induced DNA synthesis as measured by
      bromodeoxyuridine (BrdU) incorporation, suppressed cell death as measured by
      Hoechst 33258 staining, induced peroxisomal beta-oxidation as measured by cyanide
      insensitive palmitoyl CoA oxidation (PCO) and caused activation of nuclear factor
      kappa beta (NFkappaB) as determined by electrophoretic mobility gel shift assay
      (EMSA). The induction of DNA synthesis and the suppression of apoptosis in
      response to nafenopin was abrogated completely by blocking antibodies to TNFR1
      but not to TNFR2. In contrast, the induction of peroxisomal beta-oxidation by
      nafenopin was not blocked by the anti-TNFR1 antibody. Next, we evaluated the
      response of hepatocytes to interleukin-1 (IL-1), another proinflammatory
      cytokine. IL-1alpha (2.5 ng/mL) and, to a lesser extent, IL-1beta (5 ng/mL),
      shared the ability of TNFalpha to induce DNA synthesis and suppress apoptosis. In
      addition, anti-IL-1 receptor, type 1/p80 (IL-1R) antibodies were able to abrogate
      the response to nafenopin. IL-1alpha was still able to perturb hepatocyte growth
      in the presence of the anti-TNFR1 antibody suggesting that IL-1alpha acts
      independently rather than by elaborating TNFalpha. In summary, these data provide
      additional evidence for a role for hepatic cytokines in the perturbation of
      hepatocyte growth by PPs such as nafenopin.

PMID- 10573521
TI  - The canals of Hering and hepatic stem cells in humans.
AB  - Small, extraportal, hepatic parenchymal cells, positive for biliary-type
      cytokeratins, may represent hepatic stem cells, canals of Hering (CoH), and/or
      ductal plate remnants. We evaluated these cells 3 dimensionally in normal human
      liver and massive necrosis. Tissues from normal human livers and from 1 liver
      with acetaminophen-induced massive necrosis were serially sectioned,
      immunostained for cytokeratin 19 (CK19), and sequentially photographed. Images
      were examined to determine 3-dimensional relationships among CK19-positive cells.
      Immunostains for other hepatocyte and progenitor cell markers were examined. In
      normal livers, intraparenchymal CK19-positive cells lined up as linear arrays in
      sequential levels. One hundred of 106 (94.3%) defined, complete arrays within
      levels examined, most having 1 terminus at a bile duct, the other in the lobule,
      beyond the limiting plate. In massive necrosis, there were 767 individual CK19
      positive cells or clusters around a single portal tract, 747 (97.4%) of which
      were spatially related forming arborizing networks connected to the interlobular
      bile duct by single tributaries. C-kit was positive in normal CoH. CK19 co
      expressed with HepPar1, c-kit, and alpha-fetoprotein (AFP) in parenchymal cells
      in massive necrosis. Small, extraportal, biliary-type parenchymal cells represent
      cross-sections of the CoH that radiate from the portal tract, usually extending
      past the limiting plate into the proximate third of the hepatic lobule. The 3
      dimensional structure of ductular reactions in massive necrosis suggests that
      these reactions are proliferations of the cells lining the CoH. Therefore, the
      CoH consist of, or harbor, facultative hepatic stem cells in humans.

PMID- 10573522
TI  - Intention-to-treat analysis of surgical treatment for early hepatocellular
      carcinoma: resection versus transplantation.
AB  - Liver transplantation is proposed as the best therapy for early hepatocellular
      carcinoma in cirrhotic patients. However, the confrontation with the results
      obtained by surgical resection has never been done on an intention-to-treat
      basis. Between 1989 and 1997, 164 out of 1,265 patients with hepatocellular
      carcinoma were evaluated for surgery. Seventy-seven (48 men, mean 61 years of
      age, 74 Child-Pugh class A, size 33 +/- 18 mm) were resected (first line option)
      and 87 (65 men, mean 55 years of age, 50 Child-Pugh class B/C, size 24 +/- 14 mm)
      were selected for transplantation. The 1-, 3-, and 5-year "intention-to-treat"
      survival was 85%, 62%, and 51% for resection and 84%, 69%, and 69% for
      transplantation (8 drop-outs on waiting list). Bilirubin and clinically relevant
      portal hypertension were independent survival predictors after resection.
      Thereby, the 5-year survival of the best candidates (absence of clinically
      relevant portal hypertension, n = 35) was 74%, whereas it was 25% for the worst
      candidates (portal hypertension and bilirubin >/=1 mg/dL, n = 27) (P <.00001).
      The variable "drop-out on waiting list" was the sole survival predictor after
      transplantation. The 2-year survival rate of patients evaluated for
      transplantation was 84% in the 1989 to 1995 period (mean waiting time, 62 days;
      no drop-outs) and 54% during 1996 to 1997 (mean waiting time, 162 days; 8 drop
      outs)(P <.003). This outcome was significantly lower than that of the best
      candidates for resection (P =.002). In conclusion, a proper selection of
      candidates for resection promotes better results than transplantation, in which
      the results are significantly hampered by the growing incidence of drop-outs
      because of the increasing waiting time.

PMID- 10573523
TI  - Interleukin-11 reduces T-cell-dependent experimental liver injury in mice.
AB  - Recombinant human interleukin-11 (rhIL-11) is a multifunctional cytokine that can
      reduce inflammation through the downregulation of multiple pro-inflammatory
      mediators from activated macrophages. rhIL-11 also inhibits production of several
      immunostimulatory cytokines such as IL-12 and interferon gamma (IFN-gamma) and
      has shown biological activity in multiple animal models of inflammatory disease
      consistent with immunomodulatory effects on macrophages and T cells. To further
      elucidate the anti-inflammatory activity of rhIL-11 in vivo, the effect of rhIL
      11 in a model of Concanavalin A (Con-A)-induced T-cell-mediated hepatotoxicity
      was examined. Administration of a single dose of rhIL-11 before Con-A
      administration reduced centrilobular liver necrosis and enhanced survival. A dose
      dependent reduction in serum levels of liver enzymes, tumor necrosis factor alpha
      (TNF-alpha), and IFN-gamma corresponded with this amelioration of liver damage.
      No significant change in infiltrating lymphocyte populations in the liver was
      observed following rhIL-11 treatment. Taken together, these results indicate that
      rhIL-11 ameliorates T-cell-mediated hepatic injury and suggests its therapeutic
      potential to treat inflammatory liver disease.

PMID- 10573524
TI  - Requirement for interleukin-12 in the pathogenesis of warm hepatic
      ischemia/reperfusion injury in mice.
AB  - Hepatic ischemia and reperfusion causes neutrophil-dependent liver injury.
      Although the mechanisms of ischemia/reperfusion-induced liver neutrophil
      recruitment are somewhat understood, less is known regarding the early events
      that initiate the inflammatory injury. Using a murine model of partial hepatic
      ischemia and reperfusion, we evaluated the role of endogenous interleukin (IL)-12
      in this inflammatory response. Hepatic ischemia for 90 minutes and reperfusion
      for up to 4 hours resulted in hepatocyte expression of IL-12. By 8 hours of
      reperfusion there were large increases in serum levels of interferon-gamma
      (IFNgamma) and tumor necrosis factor-alpha (TNFalpha). In addition, hepatic
      ischemia/reperfusion caused significant increases in liver neutrophil
      recruitment, hepatocellular injury, and liver edema, as defined by liver
      myeloperoxidase content, serum alanine aminotransferase, and liver wet to dry
      weight ratios, respectively. In mice treated with neutralizing antibody to IL-12
      and in mice deficient in the IL-12 p40 gene, ischemia/reperfusion-induced
      increases in IFNgamma and TNFalpha were greatly diminished. These conditions also
      caused significant reductions in liver myeloperoxidase content and attenuated the
      parameters of liver injury. The data suggest that IL-12 is required for the full
      induction of injury after hepatic ischemia and reperfusion.

PMID- 10573525
TI  - Kupffer cell-independent acute hepatocellular oxidative stress and decreased bile
      formation in post-cold-ischemic rat liver.
AB  - The purpose of this study was to examine distribution and time history of
      oxidative stress during the hyperacute period of reperfusion in the liver grafts
      undergoing cold ischemia and to investigate roles of Kupffer cells as a potential
      oxidant source. Rat livers were harvested at 4 degrees C in University of
      Wisconsin solution and followed by reperfusion with Krebs-Henseleit buffer under
      monitoring bile excretion. To investigate oxidative changes, laser-confocal
      microfluorography was performed in reperfused livers preloaded with
      dichlorodihydrofluorescein diacetate succinimidyl ester, a fluorescence precursor
      sensing intracellular hydroperoxide generation. Livers undergoing the 16-hour
      cold storage displayed an impaired recovery of bile acid-dependent bile output
      concurrent with a marked increase in hydroperoxide generation in hepatocytes,
      which occurred as early as 5 minutes after the onset of reperfusion, whereas the
      status of lobular perfusion was well maintained. Pretreatment with liposome
      encapsulated dichloromethylene diphosphonate, a Kupffer cell-depleting reagent,
      did neither alter the reperfusion-induced periportal oxidative changes nor
      improve the recovery of bile output in the graft. On the other hand, EPCK, a
      hepatotropic antioxidant composed of vitamin E phosphate ester bound to vitamin
      C, not only diminished the oxidative changes but also improved the reduction of
      bile acid-dependent bile output. Furthermore, the reagent was capable of
      inhibiting H(2)O(2)-induced oxidative stress in cultured hepatocytes. These
      results suggest that hepatocytes constitute a major site of the oxidative insult
      triggered through Kupffer cell-independent mechanisms and serve as an important
      cellular component to be protected by antioxidant therapeutics.

PMID- 10573526
TI  - Prostaglandin E(1) protects against liver injury induced by Escherichia coli
      infection via a dominant Th2-like response of liver T cells in mice.
AB  - Prostaglandin E series (PGEs) are known to protect against lipopolysaccharide
      (LPS)-induced liver injury by down-regulating the production of inflammatory
      cytokines. We show here a novel mechanism whereby prostaglandin E(1) protects
      mice against liver injury after Escherichia coli infection. Prostaglandin E(1)
      administration suppressed circulating interleukin 12 (IL-12) levels but increased
      the IL-10 production after E. coli challenge. Furthermore, prostaglandin E(1)
      alpha-cyclodextrin (PGE(1)) shifted the Th1/Th2 balance of CD3(intermediate) IL
      2Rbeta(+) T cells in the liver to a dominant Th2-like response. Neutralization of
      endogenous IL-4 by administration of anti-IL-4 monoclonal antibody (mAb)
      diminished the inhibitory effect of prostaglandin E(1) on liver injury after E.
      coli challenge. These results suggested that the Th2-like response of liver T
      cells may be at least partly involved in the mechanism whereby prostaglandin E(1)
      protects against E. coli-induced liver injury.

PMID- 10573527
TI  - Differential role of ethanol and acetaldehyde in the induction of oxidative
      stress in HEP G2 cells: effect on transcription factors AP-1 and NF-kappaB.
AB  - The oxidative metabolism of ethanol by the cytochrome P450 2E1 (CYP2E1) has been
      recognized to contribute to the ethanol-induced deleterious effects through the
      induction of oxidative stress. This study compared the effect of ethanol and
      acetaldehyde in the induction of oxidative stress and activation of transcription
      factors nuclear factor-kappaB (NF-kappaB) and activating protein 1 (AP-1) in
      HepG2 cells, which do not express CYP2E1, and HepG2 cells transfected with CYP2E1
      (E47 cells). Neither ethanol (80 mmol/L) nor acetaldehyde (25-200 micromol/L)
      caused oxidative stress in HepG2 cells, an effect that was independent of
      blocking reduced glutathione (GSH) synthesis with buthionine-L-sulfoximine (BSO).
      However, BSO preincubation caused an overproduction of peroxides and activation
      of NF-kappaB and AP-1 in E47 cells even in the absence of ethanol. Furthermore,
      the incubation of E47 cells with ethanol (80 mmol/L for up to 5 days) depleted
      cellular GSH stores in both cytosol and mitochondria, reflecting the induction of
      oxidative stress. Ethanol activated NF-kappaB and AP-1 in E47 cells, an effect
      that was prevented by 4-methylpyrazole, potentiated by cyanamide, and attenuated
      by trolox C. Interestingly, however, despite the inability of acetaldehyde to
      induce oxidative stress in HepG2, acetaldehyde activated NF-kappaB and AP-1; in
      contrast, ethanol failed to activate these transcription factors in HepG2. Thus,
      our findings indicate that activation of NF-kappaB and AP-1 by ethanol and
      acetaldehyde occurs through distinct mechanisms. CYP2E1 is indispensable in the
      induction of oxidative stress from ethanol, whereas the activation of NF-kappaB
      and AP-1 by acetaldehyde is independent of oxidative stress.

PMID- 10573528
TI  - Protective effect of liver ischemic preconditioning on liver and lung injury
      induced by hepatic ischemia-reperfusion in the rat.
AB  - This study evaluates whether preconditioning could modulate the injurious effects
      of tumor necrosis factor (TNF) on liver and lung following hepatic ischemia
      reperfusion (I/R) by inhibiting hepatic postischemic TNF release. The inhibition
      of hepatic TNF release from Kupffer cells with gadolinium chloride (GdCl(3))
      previous to ischemia maintained TNF at control levels, attenuating the increases
      in transaminases, vascular permeability, and edema associated with hepatic I/R
      injury. TNF addition reverted this beneficial effect, indicating the implication
      of the TNF released mainly from Kupffer cells in hepatic I/R injury.
      Preconditioning prevented hepatic TNF increases, thus attenuating the liver
      injury, while TNF addition abolished the benefits of preconditioning. Inhibition
      of nitric oxide (NO) synthesis abolished the effect of preconditioning, whereas
      GdCl(3) addition avoided the injurious effect of NO inhibition. In addition, NO
      administration before I/R offered similar results to those found in
      preconditioning, while TNF addition abolished the benefits of NO. Thus, the
      effect of preconditioning on TNF release after hepatic I/R is mediated by NO.
      Inhibition of hepatic TNF release from Kupffer cells with GdCl(3) prevented both
      the increase in plasma TNF and the injurious effect in lung seen after hepatic
      I/R, and these effects were reverted with TNF addition. Preconditioning resulting
      in reduced hepatic TNF levels prevented the systemic TNF release, thus reducing
      the lung damage following hepatic I/R. However, TNF addition abolished the
      protective effect of preconditioning on lung injury. These findings indicate that
      preconditioning attenuates hepatic postischemic TNF release from Kupffer cells,
      thus probably reducing the liver and lung injury following hepatic I/R, and that
      this effect of preconditioning is mediated by NO.

PMID- 10573529
TI  - The transforming growth factor beta(1)-inducible transcription factor TIEG1,
      mediates apoptosis through oxidative stress.
AB  - Transforming growth factor beta(1) (TGF-beta(1))-inducible transcription factors
      have recently elicited interest because of their critical role in the regulation
      of cell proliferation, differentiation, and apoptosis. We have previously
      reported that the TGF-beta(1)-inducible transcription factor, TIEG1, induces
      apoptosis in a pancreas-derived cell line. However, the mechanisms underlying the
      apoptotic effects of this transcription factor remain to be defined. In this
      study, using the TGF-beta(1)-sensitive Hep 3B cell line, we have defined the
      mechanistic sequence of events that characterize TIEG1-mediated apoptosis and
      compared these events with the changes observed during TGF-beta(1)-induced
      apoptosis. Both TGF-beta(1)- and TIEG1-induced cell death were accompanied by an
      increase in the generation of reactive oxygen species and a loss of the
      mitochondrial membrane potential preceding the morphological changes of
      apoptosis. In contrast, increases in caspase 3-like activity and glutathione
      (GSH) depletion occurred later in the apoptotic process, concurrent with the
      morphological features of apoptosis. The antioxidant, trolox, decreased the
      formation of reactive oxygen species and apoptosis. These results demonstrate
      that similar to TGF-beta(1), TIEG1 induces apoptosis by a mechanism involving the
      formation of reactive oxygen species.

PMID- 10573530
TI  - Phase I and phase II drug-metabolizing enzymes are expressed and heterogeneously
      distributed in the biliary epithelium.
AB  - Tissue expression of drug-metabolizing enzymes influences susceptibility to drugs
      and carcinogens. Because the biliary epithelium, exposed to bile-borne chemicals,
      may give rise to drug-induced cholangiopathies and to cholangiocarcinomas, we
      determined the pattern of expression of drug-metabolizing enzymes in this
      epithelium. We first demonstrated by blot analyses that biliary epithelial cells
      (BEC) isolated from human gallbladders display cytochrome P450 (CYP) 1A, 2E1, and
      3A, microsomal epoxide hydrolase (mEH), alpha, mu, and pi glutathione S
      transferase (GST), transcripts and proteins. We also identified CYP-associated
      steroid 6beta-hydroxylase activity in BEC. CYP and mEH expression was 5- to 20
      fold lower in BEC than in autologous hepatocytes, and further differed by a
      higher ratio of CYP3A5/CYP3A4, and by CYP1A1 predominance over CYP1A2. alphaGST
      was highly expressed in both hepatocytes and BEC, while piGST was restricted to
      BEC. In approximately 50% of individuals, muGST was expressed in hepatocytes and
      at lower levels in BEC. By using the same antibodies as those used in
      immunoblots, we could show by immunohistochemistry that CYP2E1, CYP3A, mEH,
      alpha, mu, and piGST immunoreactivities are expressed and display a heterogeneous
      distribution in the epithelium lining the entire biliary tract except for small
      intrahepatic bile ducts that were devoid of CYP3A and alphaGST
      immunoreactivities. In conclusion, BEC contribute to phase II, and although to a
      lesser extent than hepatocytes, to phase I biotransformation. The distribution of
      drug-metabolizing enzymes in BEC suggest that they are heterogeneous in their
      ability to generate and detoxicate reactive metabolites, which may contribute to
      specific distributions of cholangiopathies.

PMID- 10573531
TI  - The human multidrug resistance protein 2 gene: functional characterization of the
      5'-flanking region and expression in hepatic cells.
AB  - The human multidrug resistance protein 2 (MRP2), also termed as the canalicular
      multispecific organic anion transporter (cMOAT), is a member of the adenosine
      triphosphate-binding cassette transporter superfamily. In the liver, MRP2
      mediates the multispecific efflux of various types of organic anions, including
      glucuronate, sulfate, and glutathione conjugates, across the canalicular
      hepatocyte membrane to the bile. To investigate how the MRP2 gene is expressed in
      liver cells, the 5'-flanking region of the human MRP2 gene was isolated from a
      human placental genomic library. Sequence analysis of the MRP2 promoter showed a
      number of consensus binding sites for both ubiquitous and liver-enriched
      transcription factors. Transfection of human hepatic HepG2 cells with a series of
      5'-deleted promoter luciferase constructs identified a putative silencer element
      localized in the -1,659/-491 region and a liver-specific positive regulatory
      element localized in the -491/-258 region. This latter region contained the liver
      abundant transcription factor CCAAT-enhancer binding protein beta (C/EBPbeta).
      The transcriptional activity of the promoter construct containing a mutation in
      the C/EBPbeta binding site was significantly decreased in HepG2 cells. This study
      suggests that C/EBPbeta (-356 to -343) may regulate the liver expression of the
      MRP2 gene.

PMID- 10573532
TI  - Evolution of hepatitis C virus quasispecies in patients with severe cholestatic
      hepatitis after liver transplantation.
AB  - Evolution of hepatitis C quasispecies may be one mechanism by which fibrosing
      cholestatic hepatitis develops after liver transplantation. In this study, we
      compared changes in quasispecies complexity and/or divergence in (1) hepatitis C
      infected immunosuppressed transplant recipients and in immunocompetent controls;
      (2) transplant recipients with mild recurrence, and in those with the most severe
      form of posttransplantation recurrence. Quasispecies were measured in 12
      hepatitis C-infected patients pretransplantation and posttransplantation (6 with
      mild and 6 with severe recurrence), and in 5 immunocompetent patients with
      similar follow-up, and characterized by heteroduplex mobility and sequence
      analysis of the hypervariable region. Although the number of variants
      (complexity) did not change with time in either group, there was a qualitative
      change in the variants with time (divergence) in immunocompromised, but not in
      immunocompetent patients. These changes were most marked with severe recurrence,
      and preceded the development of severe disease. Phylogenetic analysis confirmed
      that most posttransplantation variants were unrelated to those detected
      pretransplantation. These observations suggest that in the absence of immune
      suppression, there is minor evolution of quasispecies. With immune suppression,
      divergence of quasispecies is enhanced, resulting in selection/emergence of many
      new variants, particularly in those with fibrosing cholestatic hepatitis. Thus,
      quasispecies may influence disease progression in immune suppressed populations.

PMID- 10573533
TI  - Living-related liver transplantation for patients with fulminant and subfulminant
      hepatic failure.
AB  - The prognosis for patients with fulminant (FHF) or subfulminant hepatic failure
      (SFHF) has improved since the introduction of liver transplantation. However, the
      death rate of patients awaiting liver transplantation is high, possibly because
      of the difficulty in obtaining grafts in a timely manner, given the relative
      shortage of cadaveric donors. Between June 1990 and June 1999, 106 patients
      underwent living-related liver transplantation (LRLT) at Shinshu University
      Hospital. Among them, 8 patients had FHF and 6 had SFHF; these 14 patients are
      the subjects of this report. The graft volumes (GV) ranged from 231 mL to 625 mL,
      corresponding to 35% to 105% of the recipients' standard liver volume (SLV). The
      postoperative courses of all donors were uneventful. Following liver
      transplantation, all grafts functioned favorably, with normalization of serum
      total bilirubin within 3 to 5 days and normalization of coagulation profiles
      within 4 to 7 days. Thirteen of the 14 recipients are still alive. The actuarial
      6-month, 1-year, and 5-year survival rates were 100%, 90%, and 90%, respectively.
      In the present study, when the ratio of the GV to the recipient's SLV was more
      than 35%, the graft was able to support the patient's metabolic demand after
      liver transplantation for FHF or SFHF. Because of the urgent nature of liver
      transplantation in this clinical condition, concerns over informed consent may be
      even greater than for elective LRLT. Nevertheless, the high success rate and low
      donor risk may justify this option for pediatric patients, as well as for a
      limited population of adult patients suffering from FHF or SFHF.

PMID- 10573534
TI  - Kupffer cell-induced oxidant stress during hepatic ischemia-reperfusion: does the
      controversy continue?

PMID- 10573535
TI  - The cholesterol-lowering action of plant stanol esters.
AB  - Plant sterols and stanols derived from wood pulp and vegetable oils lower total
      and LDL cholesterol by inhibiting cholesterol absorption from the intestine in
      humans. Plant stanols are virtually unabsorbable, which makes them more ideal
      hypocholesterolemic agents than plant sterols. The esterification of plant
      stanols has allowed their incorporation into various foods such as margarine
      without changing the taste and texture of those foods. Plant stanol esters at a
      level of 2-3 g/d have been shown to reduce LDL cholesterol by 10-15% without side
      effects. Plant stanol esters appear to be a helpful dietary adjunct to a prudent
      diet to lower cholesterol.

PMID- 10573536
TI  - Blood concentration of coenzyme Q(10) increases in rats when esterified forms are
      administered.
AB  - Coenzyme Q levels decrease during aging in most tissues and in the target organs
      of a number of diseases. The uptake of this lipid into the blood and other
      tissues was investigated in 6-wk-old male Sprague-Dawley rats after 3 wk of
      dietary supplementation. In addition to the natural form of coenzyme Q(10),
      acetylated and succinylated forms were also administered. Coenzyme Q(10) was
      taken up into the blood, but uptake was significantly greater in rats given the
      succinylated ( approximately 40%), and particularly, the acetylated forms (
      approximately 70%). All three forms increased significantly the total coenzyme Q
      concentration in both the liver ( approximately 100%) and spleen ( approximately
      130%). Coenzyme Q(10) and its esterified forms were not taken up into kidney,
      heart, muscle or brain. Intraportal and intraperitoneal administration of
      succinylated coenzyme Q(10) gave results similar to those obtained in the dietary
      experiments. Uptake of the dietary coenzyme Q(10) into the liver and spleen did
      not down-regulate the endogenous synthesis, i.e., the amounts of isolated
      coenzyme Q(9) did not change in these tissues. Thus, esterification of coenzyme Q
      increases the uptake of dietary lipid into the blood; however, the derivatization
      does not contribute to the elevation of coenzyme Q levels in various organs.

PMID- 10573537
TI  - Consumption of casein instead of soybean protein produces a transient rise in the
      concentration of sphingomyelin in VLDL in rats.
AB  - In rats fed cholesterol-rich diets, dietary casein vs. soybean protein raises
      VLDL cholesterol concentrations. Because sphingomyelin may be an essential,
      structural component of VLDL, we tested whether casein feeding would raise VLDL
      sphingomyelin. Rats were fed cholesterol-rich semipurified diets containing
      either soybean protein (35 g/100 g) or casein for up to 21 d. Consistent with
      previous work, casein consumption increased hepatic and VLDL cholesterol
      concentrations. Dietary casein also significantly raised the amount of
      sphingomyelin in the VLDL fraction, but this effect was transient. Casein feeding
      transiently lowered LDL- and HDL-2-sphingomyelin concentrations. We suggest that
      an increase in hepatic VLDL secretion after casein consumption imposed an
      increased demand for sphingomyelin in the liver. The activity of key enzymes of
      sphingomyelin synthesis, i.e., serine palmitoyltransferase,
      phosphatidylcholine:ceramide phosphocholinetransferase and
      phosphatidylethanolamine:ceramide phosphoethanolaminetransferase and
      sphingomyelin degradation, i.e., acid sphingomyelinase, were enhanced and
      depressed, respectively, by casein consumption. Again these effects were
      transient. Thus, these data indicate that the extra sphingomyelin needed after
      short-term casein feeding came about through enhanced rates of biosynthesis and
      reduced rates of degradation in the liver. In addition, plasma transfer of
      sphingomyelin from HDL-2 to VLDL might have contributed to the increase in VLDL
      sphingomyelin in the casein-fed rats. This study shows that dietary casein vs.
      soybean protein transiently influences sphingomyelin metabolism in rats.

PMID- 10573538
TI  - Dietary fat during pregnancy and lactation increases milk fat and insulin-like
      growth factor I concentrations and improves neonatal growth rates in swine.
AB  - Primiparous (n = 24) and multiparous (n = 24) sows were used to examine the
      effects of supplemental dietary fat and induction of parturition (d 112) on
      colostrum and milk composition and suckling piglet growth. Sows were assigned to
      one of eight treatments on d 90 of gestation that included variables such as
      parity (1 vs. >/=3), dietary fat (0 vs. 10%), and farrowing (natural vs.
      induction via lutalyse on d 112). Piglets suckling fat-supplemented dams grew up
      to 25% faster than control pigs nursing unsupplemented sows (250 vs. 200 g/d; P <
      0.01). Improved growth was correlated with elevated milk fat and insulin-like
      growth factor (IGF) concentrations associated with fat supplementation. Dietary
      fat elevated milk fat concentration at 48 and 72 h postfarrowing by 21.6 and
      22.6%, respectively (P < 0.05). Compared with nonfat-fed controls, multiparous
      sows fed 10% fat showed a more consistent rise in milk fat concentration, with
      26% and 41% elevations for induced or naturally farrowing sows, respectively, vs.
      a 19% reduction or a 1% elevation in induced or naturally farrowing gilts (P <
      0.01). The concentration of milk IGF-I tended to be lower in gilts than in
      multiparous sows (P < 0.2, 95.7 vs. 117.4 microg/L), and levels were particularly
      low in milk from induced gilts receiving no additional dietary fat (44.7
      microg/L). However, fat supplementation elevated IGF-I to levels (110.6 microg/L)
      exceeding those measured in unsupplemented, naturally farrowing control sows and
      gilts (95.8 microg/L). In conclusion, supplemental dietary fat elevates milk fat
      in multiparous sows more than primiparous gilts regardless of farrowing treatment
      (induced vs. natural farrowing) and improves piglet growth throughout lactation
      irrespective of parity or farrowing treatment. The potential of supplemental
      dietary fat to reverse the reductions in milk IGF-I observed in first-parity
      females and in dams induced to farrow merits further investigation.

PMID- 10573539
TI  - Supplementation of Jurkat T cells with green tea extract decreases oxidative
      damage due to iron treatment.
AB  - Regular tea consumption has been associated with a reduced risk of cancer. As
      demonstrated in vitro, green tea contains catechins with antioxidant properties.
      We evaluated the effect of the supplementation of the Jurkat T-cell line with
      green tea extract on oxidative damage. Cells grown in medium with or without
      green tea extract (10 mg/L) were treated with Fe(2+) (100 micromol/L) as an
      oxidative stimulus for 2 h. Cell membrane lipid peroxidation was evaluated by
      fatty acids pattern analysis and malondialdehyde production in alpha-linolenic
      acid-loaded cells. Furthermore, oxidative DNA damage (single strand breaks) was
      detected in cells by the Comet assay and quantified as relative tail moment
      (RTM). Supplementation with green tea extract significantly decreased
      malondialdehyde production (1.6 +/- 0.3 vs. 0.6 +/- 0.1 nmol/mg protein, P <
      0.05) and DNA damage (0.32 +/- 0.07 vs. 0.12 +/- 0.04 RTM, P < 0.05) after Fe(2+)
      oxidative treatment. In control cells, there was no effect on membrane
      distribution of (n-3) fatty acids due to Fe(2+) treatment. Cell enrichment with
      alpha-linolenic acid increased total membrane (n-3) fatty acids. However, the
      oxidative treatment did not modify the distribution of polyunsaturated fatty
      acids. It is likely that the observed protective effects can be attributed to
      epigallocatechin gallate, which is present mainly (670 g/kg) in green tea
      extract; however, we cannot exclude contributions by other catechins. These data
      support a protective effect of green tea against oxidative damage.

PMID- 10573540
TI  - Conjugated linoleic acid-enriched butter fat alters mammary gland morphogenesis
      and reduces cancer risk in rats.
AB  - Conjugated linoleic acid (CLA) is a potent cancer preventive agent in animal
      models. To date, all of the in vivo work with CLA has been done with a commercial
      free fatty acid preparation containing a mixture of c9,t11-, t10,c12- and c11,t13
      isomers, although CLA in food is predominantly (80-90%) the c9,t11-isomer present
      in triacylglycerols. The objective of this study was to determine whether a high
      CLA butter fat has biological activities similar to those of the mixture of free
      fatty acid CLA isomers. The following four different endpoints were evaluated in
      rat mammary gland: 1) digitized image analysis of epithelial mass in mammary
      whole mount; 2) terminal end bud (TEB) density; 3) proliferative activity of TEB
      cells as determined by proliferating cell nuclear antigen immunohistochemistry;
      and 4) mammary cancer prevention bioassay in the methylnitrosourea model. It
      should be noted that TEB cells are the target cells for mammary chemical
      carcinogenesis. Feeding butter fat CLA to rats during the time of pubescent
      mammary gland development reduced mammary epithelial mass by 22%, decreased the
      size of the TEB population by 30%, suppressed the proliferation of TEB cells by
      30% and inhibited mammary tumor yield by 53% (P < 0.05). Furthermore, all of the
      above variables responded with the same magnitude of change to both butter fat
      CLA and the mixture of CLA isomers at the level of CLA (0.8%) present in the
      diet. Interestingly, there appeared to be some selectivity in the uptake or
      incorporation of c9,t11-CLA over t10,c12-CLA in the tissues of rats given the
      mixture of CLA isomers. Rats consuming the CLA-enriched butter fat also
      consistently accumulated more total CLA in the mammary gland and other tissues
      (four- to sixfold increases) compared with those consuming free fatty acid CLA
      (threefold increases) at the same dietary level of intake. We hypothesize that
      the availability of vaccenic acid (t11-18:1) in butter fat may serve as the
      precursor for the endogenous synthesis of CLA via the Delta9-desaturase reaction.
      Further studies will be conducted to investigate other attributes of this novel
      dairy product.

PMID- 10573541
TI  - Activation of chick tendon lysyl oxidase in response to dietary copper.
AB  - Lysyl oxidase (EC 1.4.3.13), a cuproenzyme, can account for 10-30% of the copper
      present in connective tissue. Herein, we assess the extent to which tissue copper
      concentrations and lysyl oxidase activity are related because the functional
      activity of lysyl oxidase and the copper content of chick tendon are both related
      to dietary copper intake. Chicks (1-d old) were fed diets (basal copper
      concentration, 0.4 microg/g diet) to which copper was added from 0 to 16 microg/g
      diet. Liver and plasma copper levels tended to normalize in chickens that
      consumed from 1 to 4 microg copper/g of diet, whereas tendon copper
      concentrations suggested an unusual accumulation of copper in chickens that
      consumed 16 microg copper/g diet. The molecular weight of lysyl oxidase was also
      estimated using matrix-assisted laser desorption ionization/time-of-flight/mass
      spectrometry (MALDI/TOF/MS). A novel aspect of these measurements was estimation
      of protein mass directly from the surface of chick tendons and aortae. Whether
      copper deficiency (0 added copper) or copper supplementation (16 microg copper/g
      of diet) caused changes in the molecular weight of protein(s) in tendon
      corresponding to lysyl oxidase was addressed. The average molecular weight of the
      peak corresponding to lysyl oxidase in tendon and aorta from copper-deficient
      birds was 28,386 Da +/- 86, whereas the average molecular weight of corresponding
      protein in tendon from copper-supplemented birds was 28,639 Da +/- 122. We
      propose that the shift in molecular weight is due in part to copper binding and
      the formation of lysyl tyrosyl quinone, the cofactor at the active site of lysyl
      oxidase.

PMID- 10573542
TI  - Copper deficiency alters rat dopamine beta-monooxygenase mRNA and activity.
AB  - Dopamine beta-monooxygenase (DBM), a cuproenzyme, converts dopamine to
      norepinephrine in selected cells. Studies were conducted in albino rats to
      resolve the known paradox of DBM after copper deficiency in which metabolite
      analyses of tissues suggest lower activity, whereas direct assay of homogenates
      suggests enhanced activity. After 4 wk of postweanling copper deficiency, male
      Holtzman rats exhibited 1.4-fold higher adrenal DBM activity and 1. 8-fold higher
      adrenal DBM mRNA levels than copper-adequate rats. Mixing experiments did not
      support the existence of endogenous activators or inhibitors. Adrenal
      catecholamine content indicated lower norepinephrine, higher dopamine and
      unaffected epinephrine content in copper-deficient compared with copper-adequate
      rats. Studies in 22-d-old male Sprague-Dawley offspring of dams started on copper
      deficiency at d 7 of gestation indicated similar results for adrenal DBM mRNA, a
      1.75-fold increase compared with copper-adequate pups. Adrenal dopamine content
      was higher in female copper-deficient offspring compared with controls, but
      norepinephrine was not lower. Medulla oblongata/pons DBM mRNA concentration was
      higher in 22-d-old copper-deficient female but not male rats compared with
      controls. Six weeks of copper repletion to the 22-d-old rats restored adrenal DBM
      mRNA levels to control values. Enzyme assay and RNA results are consistent with
      enhanced formation of DBM in adrenal gland and noradrenergic cell bodies of
      copper-deficient rats. The molecular signal may not be solely lower
      norepinephrine content because adrenal DBM mRNA changes were evident in both
      nutritional models, whereas the norepinephrine content was altered only in the
      postnatal model.

PMID- 10573543
TI  - Insulin receptor at the mouse hepatocyte nucleus after a glucose meal induces
      dephosphorylation of a 30-kDa transcription factor and a concomitant increase in
      malic enzyme gene expression.
AB  - Insulin receptor translocation to the nucleus may represent a mechanism for
      activation of transcription factors controlling lipogenic gene expression in the
      mouse hepatocyte. Insulin stimulation was achieved in vivo by oral glucose
      feeding of mice deprived of food for 24 h. Hepatocytes were fractionated after
      the glucose meal and nuclei were purified. Insulin receptor levels and
      phosphorylation state in nuclei were assessed by immunoassay. Insulin receptor
      significantly increased from basal levels in hepatocyte nuclei within 15 min of
      the glucose meal. Immunoassay using antiphosphotyrosine indicated that
      phosphorylation of nuclear insulin receptor increased, whereas phosphorylation of
      a 30-kDa DNA-binding protein significantly decreased within 15 min of the glucose
      meal. Glucose treatment significantly increased expression of malic enzyme within
      the time frame of insulin receptor translocation to the nucleus. Nuclear protein
      binding to an insulin response element (IRE) within the malic enzyme gene
      promoter significantly increased within 15 min of the glucose meal. When cell
      nuclei were isolated from mice that had been deprived of food and treated in
      vitro with purified, activated insulin receptor, changes were observed in DNA
      binding protein phosphorylation and IRE-binding in the absence of cytoplasmic
      insulin signaling. In vitro incubation of nuclei with activated insulin receptor
      significantly decreased phosphorylation of a 30-kDa DNA-binding protein compared
      with basal levels. Increased binding of nuclear proteins to malic enzyme IRE was
      observed upon stimulation of isolated nuclei with activated insulin receptor.
      These results suggest that nuclear insulin receptors induce malic enzyme gene
      expression by regulating phosphorylation of IRE transcription factors.

PMID- 10573544
TI  - beta-carotene does not change markers of enzymatic and nonenzymatic antioxidant
      activity in human blood.
AB  - In vitamin A-replete populations, increased concentrations of serum carotenoids
      have been associated with a decreased risk of degenerative diseases. The
      mechanism of action of carotenoids in determining antioxidant activity is largely
      unknown. The aim of the study was to examine the effect of carotenoid
      supplementation and spinach intake on erythrocyte enzyme antioxidant activities,
      serum or plasma nonenzymatic antioxidant concentrations, and concentrations of
      oxidatively damaged amino acids in plasma. Subjects received for 3 wk a basic
      diet (n = 10), a basic diet with a carotenoid supplement (n = 12) or with a
      spinach product (n = 12 per group), i.e., whole-leaf, minced, liquefied or
      liquefied spinach plus added dietary fiber. After 3 wk of dietary intervention,
      changes in serum or plasma concentrations of ascorbic acid, alpha-tocopherol,
      FRAP (ferric reducing ability of plasma) and uric acid and erythrocyte enzyme
      activities were assessed, and differences among experimental groups were tested.
      Consumption of spinach resulted in greater (P < 0.01) erythrocyte glutathione
      reductase activity and lower (P < 0.05) erythrocyte catalase activity and serum
      alpha-tocopherol concentration compared with the control group. Consumption of
      the carotenoid supplement led to lower alpha-tocopherol responses (P = 0.02)
      compared with the basic diet only. Our data suggest that the short-term changes
      in erythrocyte glutathione reductase activity and serum alpha-tocopherol
      concentration can be attributed to an increased carotenoid (lutein and
      zeaxanthin) intake, but beta-carotene is unlikely to be a causative factor. Lower
      erythrocyte catalase activity after intervention with spinach products may be
      related to other constituents in spinach such as flavonoids.

PMID- 10573545
TI  - Some dietary fibers reduce the absorption of carotenoids in women.
AB  - Dietary fiber may be partly responsible for the lower bioavailability of
      carotenoids from food than from purified supplements. Due to the lack of detailed
      information available, we investigated the effects of different kinds of dietary
      fiber on the absorption of carotenoids and alpha-tocopherol. Six healthy young
      women received an antioxidant mixture consisting of beta-carotene, lycopene,
      lutein, canthaxanthin and alpha-tocopherol together with a standard meal. The
      meal did not contain additional dietary fiber or was enriched with pectin, guar,
      alginate, cellulose or wheat bran (0. 15 g. kg body weight(-1)). The increases in
      plasma carotenoid and alpha-tocopherol concentrations were followed over 24 h,
      and the areas-under-curves (AUC(24h)) were calculated. The mean AUC(24h) of beta
      carotene was significantly (P < 0.05) reduced by the water-soluble fibers pectin,
      guar and alginate with a mean decrease of 33-43%. All tested fibers significantly
      reduced the AUC(24h) of lycopene and lutein by 40-74% (P < 0.05). The dietary
      fiber effect on the AUC(24h) of canthaxanthin was almost significant (P = 0.059)
      and there was no effect on the AUC(24h) of alpha-tocopherol. We conclude that the
      bioavailability of beta-carotene, lycopene and lutein given within a mixed
      supplement is markedly reduced by different kinds of dietary fiber.

PMID- 10573546
TI  - Extra-virgin olive oil increases the resistance of LDL to oxidation more than
      refined olive oil in free-living men with peripheral vascular disease.
AB  - Patients with peripheral vascular disease (Fontaine stage II) are characterized
      by ischemia of the lower extremities, atherosclerosis and alteration of blood
      coagulation and fibrinolysis. A randomized, two-period, crossover design was used
      to compare the effects of extra-virgin (VO) and refined olive (RO) oils on plasma
      lipids and lipoprotein composition and LDL oxidation susceptibility in free
      living men with peripheral vascular disease. The oils differed in their
      antioxidant profile (alpha-tocopherol: 300 vs. 200 mg/kg; phenolic compounds 800
      vs. 60) and concentration but not in their fatty acid composition. Subjects were
      randomly assigned to two groups. The first group (n = 12) received VO with which
      to freely cook all meals for 3 mo, followed by a 3-mo wash-out period; they then
      received RO for the final 3 mo. The second group (n = 12) consumed the oils in
      the opposite order. Energy, fat, polyunsaturated fatty acids (PUFA) and alpha
      tocopherol intakes were not different when patients consumed the two oils.
      Profiles of the major fatty acids in plasma and LDL were not different after
      consumption of VO and RO. The slope of the line for LDL oxidation vs. the line
      for copper concentration was significantly higher after the intake of RO than
      after the intake of VO. Total LDL taken up by macrophages was significantly
      greater when the men consumed RO rather than VO. We suggest that antioxidants
      present in VO may protect LDL against oxidation more than does RO in men with
      peripheral vascular disease.

PMID- 10573547
TI  - Postprandial triacylglycerols from dietary virgin olive oil are selectively
      cleared in humans.
AB  - The aims of the present study were to evaluate the effect of a meal rich in
      virgin olive oil on triacylglycerol composition of human postprandial
      triacylglycerol-rich lipoproteins (fraction Sf > 400), and to assess the role of
      the triacylglycerol molecular species concentration and polarity on lipoprotein
      clearance. Fasting (0 h) and postprandial blood samples were collected hourly for
      7 h from eight healthy normolipidemic subjects after the ingestion of the meal.
      Plasma and lipoprotein triacylglycerol concentrations increased quickly over
      fasting values and peaked twice at 2 and 6 h during the 7-h postprandial period.
      The triacylglycerols in the lipoprotein fraction at 2 h generally reflected the
      composition of the olive oil, however, the proportions of the individualmolecular
      species were altered by the processes leading to their formation. Among the major
      triacylglycerols, the proportion of triolein (OOO; 43.6%) decreased (P < 0.05),
      palmitoyl-dioleoyl-glycerol (POO; 31. 1%) and stearoyl-dioleoyl-glycerol (SOO;
      2.1%) were maintained and linoleoyl-dioleoyl-glycerol (LOO; 11.4%) and palmitoyl
      oleoyl-linoleoyl-glycerol (POL; 4.6%) significantly increased (P < 0.05) compared
      with the composition of the triacylglycerols in the olive oil. Smaller amounts of
      endogenous triacylglycerol (0.8%), mainly constituted of the saturated myristic
      (14:0)and palmitic (16:0) fatty acids, were also identified. Analysis of total
      fatty acids suggested the presence of molecular species composed of long-chain
      polyunsaturated fatty acids of the (n-3) family, docosapentaenoic acid, [22:5(n
      3)] and docosahexaenoic acid (DHA), [22:6(n-3)] and of the (n-6) family
      [arachidonic acid, [20:4(n-6)]. The fastest conversion of lipoproteins to
      remnants occurred from 2 to 4 h and was directly related to the concentration of
      the triacylglycerols in the lipoprotein particle (r = 0.9969, P < 0.05) and not
      with its polarity (r = 0.1769, P > 0.05). The rates of clearance were
      significantly different among the major triacylglycerols (OOO, POO, OOL and POL)
      (P < 0.05) and among the latter ones and PLL (palmitoyl-dilinoleoyl-glycerol, POS
      (palmitoyl-oleoyl-stearoyl-glycerol) and OLL (oleoyl-dilinoleoyl-glycerol) (P <
      0.01). OOO was removed faster and was followed by POO, OOL, POL, PPO (dipalmitoyl
      oleoyl-glycerol), SOO, PLL, POS and OLL.

PMID- 10573548
TI  - Simultaneous vitamin A administration at routine immunization contact enhances
      antibody response to diphtheria vaccine in infants younger than six months.
AB  - A randomized, double-blind, placebo-controlled trial was conducted to evaluate
      the effect of simultaneous vitamin A supplementation and diphtheria, pertussis
      and tetanus (DPT) vaccination on the antibody levels. Infants aged 6-17 wk (n =
      56) were randomly given 15 mg oral vitamin A or placebo at the time of their DPT
      immunization. Three such doses were given at monthly intervals. Immunoglobulin
      (Ig) G antibodies to diphtheria, pertussis and tetanus were assayed on enrollment
      and 1 mo after the third dose. Baseline antibody concentrations to diphtheria,
      pertussis and tetanus did not differ between the vitamin A-supplemented and
      placebo-treated groups. The postdose antibody to diphtheria level was
      significantly greater in the vitamin A than in the placebo-treated group. The
      geometric mean +/- SEM antibody levels (mg/L) were 22.9 +/- 1.2 and 11.0 +/- 1.3
      in the vitamin A and placebo groups, respectively (P = 0.029). The
      postsupplementation concentrations of antibodies to pertussis and tetanus did not
      differ between the two groups. These results suggest that antibody response to
      diphtheria vaccination was potentiated by simultaneous vitamin A administration
      and DPT immunization.

PMID- 10573549
TI  - Early childhood nutrition, education and fertility milestones in Guatemala.
AB  - Data on fertility milestones were collected in 1994 and linked to information
      collected in a trial conducted in eastern Guatemala between 1969 and 1977, to
      examine whether early childhood nutrition was associated with the timing of
      fertility milestones. In the original trial, two pairs of villages were randomly
      allocated to receive either a high energy, high protein supplement (Atole) or a
      low energy, no-protein supplement (Fresco). Mean age at follow-up was 23.47 y (n
      = 240). About 62% of women had experienced first birth (median age at first birth
      = 19.83 y). The median intervals from menarche to first intercourse and from
      first intercourse to first birth were 5.67 and 0.95 y; they were 1.68 and 0.06 y
      shorter, respectively, for the Atole group than for the Fresco group. Women who
      had received Atole in utero and/or during early childhood experienced earlier
      milestones even after adjusting for socioeconomic status (SES), education and age
      at the prior event. Median age at first birth was 1.17 y earlier for the Atole
      group. Better growth during early childhood (not severely stunted) led to earlier
      milestones (median age at first birth was 1.04 y earlier), primarily among women
      with illiterate fathers. Completion of primary school significantly delayed
      fertility milestones; the median age at first birth was 4.27 y later for those
      who completed primary school compared with those who did not (P < 0.05). In sum,
      improved nutrition during early childhood results in earlier fertility
      milestones, but the effects of schooling in delaying fertility milestones are
      greater in magnitude. Intervention programs that improve early childhood
      nutrition should be accompanied by investments in education that ensure that
      girls complete primary school.

PMID- 10573550
TI  - Integration of vitamin A supplementation with the expanded program on
      immunization does not affect seroconversion to oral poliovirus vaccine in
      infants.
AB  - Childhood immunization programs may provide infrastructure for delivering vitamin
      A supplements to infants in developing countries. The effect of giving vitamin A,
      an immune enhancer, on antibody responses to trivalent oral poliovirus vaccine
      (TOPV) is unknown. A randomized, double-blind, placebo-controlled clinical trial
      was conducted to determine the effect of giving vitamin A simultaneously with
      TOPV on antibody responses to poliovirus. Infants (n = 467) received oral vitamin
      A, 15 mg retinol equivalent (RE), 7.5 mg RE or placebo with TOPV at 6, 10 and 14
      wk of age. Antibody responses to poliovirus types 1, 2 and 3 were measured by a
      microvirus neutralization assay at enrollment and at 9 mo of age. Seroconversion
      rates to poliovirus types 1, 2 and 3 ranged from 98 to 100% in the three
      treatment groups, and there were no differences in mean antibody titers to
      poliovirus types 1, 2 and 3 among treatment groups. This study demonstrates that
      oral vitamin A does not affect antibody responses to poliovirus vaccine when
      integrated with the Expanded Program on Immunization.

PMID- 10573551
TI  - Adipose tissue triacylglycerols of rats are modulated differently by dietary
      isomeric octadecenoic acids from coriander oil and high oleic sunflower oil.
AB  - Earlier feeding studies of rats revealed that petroselinic acid [18:1(n-12)] from
      triacylglycerols of coriander (Coriandrum sativum) oil is extensively
      incorporated into the lipids of heart and liver and metabolized via beta
      oxidation and chain elongation. We report here the composition and stereospecific
      distribution of acyl moieties, particularly isomeric octadecenoyl moieties, in
      adipose tissue triacylglycerols of male weaned Wistar rats fed diets containing,
      in addition to 20 g corn oil/kg feed, 120 g coriander oil per kg feed at a level
      of 63 g 18:1(n-12) moieties/100 g acyl moieties of the oil for 10 wk. For
      comparison, a group of rats was fed a similar corn oil-containing isocaloric diet
      with large proportions of oleoyl moieties [18:1(n-9)] from high oleic sunflower
      oil [72 g 18:1(n-9)/100 g acyl moieties of the oil]. The composition of the
      triacylglycerols of epididymal, subcutaneous and perirenal adipose tissues was
      very similar for each feeding group, broadly reflecting the composition of the
      dietary oils. Feeding coriander oil, compared with high oleic sunflower oil, led
      to extensive incorporation of 18:1(n-12) into the triacylglycerols of the adipose
      tissues with a concomitant significantly and dramatically lower 18:1(n-9)
      concentration and, as a consequence, to the generation of triacylglycerol species
      containing 18:1(n-12) moieties. Petroselinoyl moieties from coriander oil were
      esterified predominantly at the sn-1,3 positions of the adipose tissue
      triacylglycerols; 18:1(n-9) moieties from high oleic sunflower oil were fairly
      evenly distributed between the sn-1,3 and sn-2 positions. We suggest that
      acyltransferases involved in the biosynthesis of adipose tissue triacylglycerols
      direct 18:1(n-12) moieties preferentially to sn-1,3-positions.

PMID- 10573552
TI  - Intestinal microorganisms do not supply associated gnotobiotic rats with
      conjugated linoleic acid.
AB  - Conjugated linoleic acid (CLA) is produced from linoleic acid (LA) by bacteria in
      the rumen of herbivores. CLA enters the human diet mainly via milk fat and fatty
      beef; it acts as an effective anticarcinogen and exhibits other important
      physiological effects. The objective of the current study was to investigate the
      capability of a LA-conjugating bacterial community isolated from a human
      volunteer and associated with germ-free rats to supply the host with CLA.
      Gnotobiotic rats were fed a diet enriched with esterified LA in the form of
      sunflower-seed oil. The control group was fed the same diet and remained germ
      free. Bacterial cell counts, in vitro LA-conjugation activities, and CLA
      concentration in feces and in the contents of various intestinal segments were
      determined. After 10 wk, various tissues were analyzed for CLA concentrations. LA
      conjugation activity was found only in feces, cecum and colon content samples
      from associated rats, but CLA accumulation in various body tissues did not differ
      significantly between the two groups. The ratio of CLA to LA in feces and in
      cecal and colonic contents did not differ between groups, indicating that the
      microorganisms in the cecum and the colon do not synthesize substantial amounts
      of CLA in vivo and therefore, do not contribute to the CLA supplementation of the
      host.

PMID- 10573553
TI  - Net hepatic gluconeogenic amino acid uptake in response to peripheral versus
      portal amino acid infusion in conscious dogs.
AB  - These studies were conducted to determine the effect of route of gluconeogenic
      amino acid delivery on the hepatic uptake of the amino acids. After a sampling
      period with no experimental intervention (basal period), conscious dogs deprived
      of food for 42 h received somatostatin, intraportal infusions of insulin (3-fold
      basal) and glucagon (basal), and a peripheral infusion of glucose to increase the
      hepatic glucose load 1.5-fold basal for 240 min. A mixture of alanine, glutamate,
      glutamine, glycine, serine and threonine was infused intraportally at 7.6
      micromol. kg(-1). min(-1) (PorAA group, n = 6) or peripherally at 8.1 micromol.
      kg(-1). min(-1) (PerAA, n = 6), to match the hepatic load of gluconeogenic amino
      acids in PorAA. During the infusion period, there were no differences in PerAA
      and PorAA, respectively, with regard to arterial plasma insulin (144 +/- 18 and
      162 +/- 18 pmol/L), glucagon (51 +/- 8 and 47 +/- 11 ng/L), hepatic glucose load
      (199.8 +/- 22.2 and 210.9 +/- 16.6 micromol. kg(-1). min(-1)), net hepatic
      glucose uptake (2.8 +/- 2.2 and 2.2 +/- 1.7 micromol. kg(-1). min(-1)), hepatic
      load of amino acids (68 +/- 14 and 62 +/- 7 micromol. kg(-1). min(-1)), or net
      hepatic glycogen synthesis (11.1 +/- 2.2 and 8.9 +/- 2.2 micromol. kg(-1). min(
      1)). The net hepatic uptake of glutamine (2.1 +/- 0.4 vs. 0.8 +/- 0.3 micromol.
      kg(-1). min(-1)) and the net hepatic fractional extractions of glutamine (0.11 +/
      0.02 vs. 0.05 +/- 0.02) and serine (0.41 +/- 0.03 vs. 0.34 +/- 0.02) were
      greater in PorAA than in PerAA (P < 0.05). We speculate that one or more of the
      amino acids in the mixture causes enhancement of the net hepatic uptake and
      fractional extraction of glutamine, and perhaps other gluconeogenic amino acids,
      during intraportal amino acid delivery.

PMID- 10573554
TI  - High dietary protein and taurine increase cysteine desulfhydration in kittens.
AB  - The objective of this study was to determine the effect of dietary protein and
      taurine on cysteine desulfhydration in various kitten tissues. Cysteine
      desulfhydration was assessed in liver, kidney, skeletal muscle, heart, spleen,
      brain and jejunum of kittens fed one of the following diets for 5 wk: 20%
      protein, 0% taurine diet (LP0T); 20% protein, 0.15% taurine diet (LPNT); 60%
      protein, 0% taurine diet (HP0T); and 60% protein, 0.15% taurine diet (HPNT). Cats
      fed LP0T and HP0T had been fed a taurine-free diet for 10 wk before the 5-wk
      experiment. The activity of cysteine desulfhydration was determined by measuring
      the production of H(2)(35)S from (35)S-cysteine in the presence and absence of
      alpha-ketoglutarate (alphaKG) in the incubation medium. Liver and kidney had the
      highest total activities among the tissues tested (P < 0.01). Total hepatic
      desulfhydration activities [micromol H(2)S/(min. kg body wt)] in cats fed LP0T,
      LPNT, HP0T and HPNT were (mean +/- SEM) 117 +/- 6, 135 +/- 10, 137 +/- 10 and 190
      +/- 9, respectively. Dietary taurine had a significant effect on activity when
      expressed per gram liver (P < 0.01), per gram protein (P < 0.05) and per kilogram
      body weight (P < 0.001). Dietary protein had a significant effect (P < 0.001)
      only when activity was expressed relative to body weight because of the
      significant effect of protein on relative liver weight. The direct pathway via
      cysteine desulfhydrase appears to be the major route of cysteine desulfhydration
      in kitten liver because the values obtained in the absence of alphaKG were 81-88%
      of those obtained in the presence of alphaKG.

PMID- 10573555
TI  - Prolonged intake of fructo-oligosaccharides induces a short-term elevation of
      lactic acid-producing bacteria and a persistent increase in cecal butyrate in
      rats.
AB  - While the prebiotic effects of fructo-oligosaccharides (FOS), short-chain
      polymers of fructose, have been thoroughly described after 2-3 wk of ingestion,
      effects after intake for several months are unknown. We tested the hypothesis
      that these effects would differ after ingestion for short and long periods in
      rats. Rats were fed a basal low-fiber diet (Basal) or the same diet containing 9
      g/100 g of FOS for 2, 8 or 27 wk, and cecal contents were collected at the end of
      each time period. Cecal short-chain fatty acid concentration was higher in rats
      fed FOS than in those fed Basal, and this effect persisted over time: 83.8 +/-
      4.1 vs. 62.4 +/- 6.5 micromol/g at 2 wk and 103.5 +/- 5.8 vs. 73.2 +/- 7.4
      micromol/g at 27 wk (P < 0.05). The molar butyrate ratio was higher in rats fed
      FOS regardless of the time period (14.8 +/- 0.6% vs. 6.7 +/- 1.1% at 27 wk, P <
      0.05). Lactate concentration in rats fed FOS was elevated after 2 wk and then
      decreased: 63.5 +/- 21.6 micromol/g at 2 wk vs. 8.8 +/- 3.3 micromol/g at 8 wk (P
      < 0.05). After 2 wk, FOS increased the concentrations of total lactic acid
      producing bacteria, and Lactobacillus sp. (P < 0.05), without modifying total
      anaerobes. However, most of these effects were abolished after 8 and 27 wk of FOS
      consumption. In the long term, the FOS-induced increase in intestinal lactic acid
      producing bacteria was lost, but the butyrogenic properties of FOS were
      maintained.

PMID- 10573556
TI  - Boron stimulates yeast (Saccharomyces cerevisiae) growth.
AB  - Boron is required for the growth of vascular plants and embryonic development in
      fish. The molecular basis of boron's essentiality, however, remains unknown for
      both. The objective of this study was to determine whether yeast (Saccharomyces
      cerevisiae) could be used as a model for the evaluation of intracellular boron
      trafficking. Three experiments were conducted to assess the effect of boron
      supplementation on yeast growth. Cultures were grown in low boron media
      containing 0.04 micromol B/L. After 24 h, a new flask was inoculated with this
      culture; it was allowed to reach early log phase growth (9 h) and was then
      divided between two flasks. One flask was supplemented with ultrapure boric acid
      to achieve a concentration of 185 micromol B/L (+B); the other was supplemented
      with an equivalent volume of ultrapure water (NB). Boron significantly stimulated
      cell growth rate into the stationary phase of growth. Yeast cell boron
      concentrations decreased in both treatments over the course of the experiment,
      but analysis by inductively coupled plasma-mass spectrometry (ICPMS) did not
      detect differences in cellular concentration between the boron supplemented (B)
      and nonsupplemented (NB) groups. Ethanol concentrations did not differ between
      the two treatments, demonstrating that boron-stimulated growth was not a
      secondary effect of alcohol dehydrogenase inhibition. The demonstration of boron
      dependent growth stimulation in yeast suggests that Saccharomyces cerevisiae can
      be used as a model system for the study of intracellular boron trafficking.

PMID- 10573557
TI  - Single versus multiple deficiencies of methionine, zinc, riboflavin, vitamin B-6
      and choline elicit surprising growth responses in young chicks.
AB  - A soy-protein isolate diet that was deficient in methionine (Met), zinc (Zn),
      riboflavin, vitamin B-6 and choline for chick growth (Assay 1) was used to study
      individual or multiple deficiencies of several of these nutrients. In all cases,
      adding all three deficient nutrients together resulted in growth responses that
      were superior to those resulting from supplementation with any pairs of deficient
      nutrients. In Assay 2, single addition of Zn but not of methionine or riboflavin
      produced a growth response, but the combination of either Zn and Met or Zn and
      riboflavin resulted in growth responses that were greater than the response
      elicited by Zn alone. Assay 3 involved individual or multiple deficiencies of
      choline, riboflavin and vitamin B-6, and individual additions suggested that
      choline was first limiting. Choline + riboflavin supplementation, however,
      produced marked growth and gain:food responses that were far greater than those
      resulting from supplemental choline or riboflavin alone. Moreover, the growth
      response to a combination of choline + pyridoxine (PN) was also greater than that
      obtained from any of the three nutrients fed alone; even PN + riboflavin (in the
      absence of choline) produced responses greater than those observed with the
      unsupplemented negative-control diet. In Assay 4, chicks responded to individual
      additions of riboflavin, PN or Met, and in Assay 5, to either riboflavin or PN;
      all two-way combinations resulted in growth rates that were far greater than
      those occurring with any single addition. The data from these experiments show
      that unlike the situation with three deficient amino acids, the expected
      responses to first-, second- and third-limiting B-vitamins or deficient vitamins
      combined with deficient levels of Zn or Met do not follow the expected pattern of
      response to first-, further response to first- and second- and an even further
      response to first-, second- and third-limiting nutrients.

PMID- 10573558
TI  - Vitamin A antagonizes the action of vitamin D in rats.
AB  - Interactions between vitamin A and vitamin D have been suggested for several
      decades but have not been established. In particular, vitamin A has been proposed
      to intensify the severity of the bone mineralization disease, rickets and inhibit
      the ability of vitamin D to cure this disease. To investigate this hypothesis,
      weanling Holtzman rats were fed a 1.2% calcium, 0.1% phosphorus diet and 15.5 ng
      ergocalciferol (vitamin D(2)) every 3 d for 21 d in the presence of increasing
      amounts of retinyl acetate (0 microg to 8621 microg/d). The increasing amounts of
      retinyl acetate produced a progressive and significant decrease in total bone ash
      (P < 0.001) and an increase in epiphyseal plate width (P < 0.001). The same
      experiment conducted with increasing amounts of vitamin D(2) (0 to 645 ng/d)
      indicated that the antagonism by retinyl acetate could be demonstrated at all
      vitamin D(2) dosages. To further investigate this antagonistic relationship,
      weanling Holtzman rats were fed a 0. 47% calcium, 0.3% phosphorus diet and 15.5
      ng vitamin D(2) every 3 d for 33 d in the presence of increasing retinyl acetate
      (0 to 3448 microg/d). In the absence of retinyl acetate, these rats maintained a
      normal serum calcium level (2.34 mmol/L). Increasing retinyl acetate, however,
      eliminated the ability of vitamin D(2) to elevate the level of serum calcium
      (1.35 mmol/L). These results illustrated in vivo antagonism of vitamin D(2)
      action on intestine and bone by retinyl acetate.

PMID- 10573559
TI  - Bifidobacterium animalis protects intestine from damage induced by zinc
      deficiency in rats.
AB  - We investigated the potential beneficial effects of Bifidobacterium animalis on
      intestinal damage using zinc-deficient (ZD) rats as a model for intestinal
      alterations. The ZD rats were fed diets containing 1 mg Zn/kg for 20 (ZD(20)) or
      40 (ZD(40)) d to induce damage that differed in severity. Subgroups of these
      rats, the ZD(20) + B and ZD(40) + B groups, received a suspension of B. animalis
      (3.5 x 10(8) colony forming units) daily for the last 10 d. Another subgroup, the
      ZD(40) + B + 7 d group, was fed the ZD diet for 7 d after the B. animalis
      treatment period. Zinc deficiency induced ulcerations, edema, inflammatory cell
      infiltration and dilatation of blood vessels in duodenum, jejunum and ileum, with
      increasing severity between 20 and 40 d of zinc deficiency. The mucosa of the
      ZD(20) + B group was well preserved, and most of the morphologic alterations
      induced by zinc deficiency were normalized in the ZD(40) + B group. The high
      fecal concentrations of B. animalis in the ZD(40) + B and ZD(40) + B + 7 d groups
      indicate that these bifidobacteria survived passage through the gastrointestinal
      tract and proliferated. Electron microscopy confirmed the elevated numbers of
      bifidobacteria in cecum. Treatment with B. animalis resulted in greater
      epithelial cell proliferation and disaccharidase activities in the ZD(40) + B
      group compared with the ZD(40) group. These findings indicate that B. animalis
      can protect the intestine from alterations induced by zinc deficiency, suggesting
      that this bacterium may play a role in intestinal mucosal defense.

PMID- 10573560
TI  - Plasma carotenoids are biomarkers of long-term high vegetable intake in women
      with breast cancer.
AB  - We investigated predictors of change in plasma carotenoids from baseline to 3 y
      and examined plasma carotenoid concentrations at 1 and 3 y in response to a high
      vegetable diet. Participants were 56 women diagnosed with breast cancer and
      enrolled in a randomized feasibility study for a trial examining the effect of a
      diet high in vegetables and fruits on the risk of breast cancer recurrence.
      Independent t test analysis revealed that the intervention group had
      significantly higher vegetable and fruit servings and fiber at 12 mo and
      significantly higher vegetable servings at 36 mo compared with the control group
      (P < 0.05). Energy intake from fat was significantly lower in the intervention
      group at 12 and 36 mo. The intervention group had significantly higher
      consumption of beta-carotene, alpha-carotene, lutein and beta-cryptoxanthin at 12
      mo (P < 0.05). beta-Carotene, alpha-carotene and lutein intakes also were
      significantly higher at 36 mo (P < 0.05). At 36 mo, the intervention group had
      significantly higher plasma concentrations of alpha-carotene and beta-carotene
      compared with the control group. Repeated-measures ANOVA revealed that the
      intervention group had significantly increased (P < 0.05 with Bonferroni
      correction) plasma beta-carotene, alpha-carotene, lutein and lycopene
      concentrations at 12 and 36 mo compared with baseline. Baseline carotenoid
      concentrations were significantly inversely predictive (P < 0.05) of plasma
      carotenoid change. In addition, change in body mass index (BMI) and plasma
      cholesterol concentrations were predictive of plasma carotenoid change from
      baseline to 3 y. Results of this study demonstrate that change in plasma
      carotenoid concentrations is associated with change in BMI, change in plasma
      cholesterol and baseline carotenoid concentrations. Plasma carotenoid response
      can be an indicator of long-term high vegetable intake for women at risk of
      breast cancer recurrence.

PMID- 10573561
TI  - Growth hormone improves body mass recovery with refeeding after chronic
      undernutrition-induced muscle atrophy in aging male rats.
AB  - The effects of growth hormone (GH) administration and refeeding after chronic
      undernutrition (UN) were investigated in Fischer 344 male rats aging into
      senescence (24.5 mo of age) during UN initiated at 12.5 mo of age that produced
      muscle atrophy and a 50% decrease in body mass. Muscle mass, protein, myosin
      heavy-chain (MHC) composition and circulating testosterone levels were measured
      and compared to controls with free access to food. Within 9 wk, refeeding + GH
      restored body mass to control levels, whereas it was still decreased with
      refeeding alone. By 24.5 mo of age, refeeding alone restored body mass, while
      addition of GH resulted in overshoot. UN uniformly decreased mass of the
      gastrocnemius, extensor digitorum longus, soleus and diaphragm muscles to 50-60%
      of controls. Refeeding and refeeding + GH restored these losses with some
      overshoot of gastrocnemius muscle suggesting hypertrophy. UN more than doubled
      slow Type I MHC composition and approximately halved fast Type IIB and IIX MHC in
      the deep gastrocnemius muscle while it increased Type IIA MHC in the diaphragm.
      Refeeding and refeeding + GH reversed these shifts. MHC shifts in the extensor
      digitorum longus and soleus muscles were not statistically significant, whereas
      UN increased fast Type IIA MHC followed by decrease with refeeding + GH. UN
      decreased testosterone levels to nearly zero followed by restoration with
      refeeding and refeeding + GH. We conclude that the phenotype of mixed-MHC muscles
      such as the gastrocnemius and diaphragm are most affected by chronic UN, which is
      reversible with refeeding and refeeding + GH. These alterations were associated
      with changes in circulating testosterone, which may be a key regulatory element
      in these processes.

PMID- 10573562
TI  - Review of animal models in carotenoid research.
AB  - Foods containing provitamin A carotenoids are the primary source of vitamin A in
      many countries, despite the poor bioavailability of carotenoids. In addition,
      epidemiologic studies suggest that dietary intake of carotenoids influences the
      risk for certain types of cancer, cardiovascular disease and other chronic
      diseases. Although it would be ideal to use humans directly to answer critical
      questions regarding carotenoid absorption, metabolism and effects on disease
      progression, appropriate animal models offer many advantages. This paper will
      review recent progress in the development of animal models with which to study
      this class of nutrients. Each potential model has strengths and weaknesses. Like
      humans, gerbils, ferrets and preruminant calves all absorb beta-carotene (betaC)
      intact, but only gerbils and calves convert betaC to vitamin A with efficiency
      similar to that of humans. Mice and rats efficiently convert betaC to vitamin A
      but absorb carotenoids intact only when they are provided in the diet at
      supraphysiologic levels. Mice, rats and ferrets can be used to study cancer,
      whereas primates and gerbils are probably more appropriate for studies on
      biomarkers of heart disease. No one animal model completely mimics human
      absorption and metabolism of carotenoids; thus the best model must be chosen with
      consideration of the specific application being studied, characteristics of the
      model, and the available funding and facilities.

PMID- 10573563
TI  - Cupric oxide should not be used as a copper supplement for either animals or
      humans.

PMID- 10573564
TI  - AHA science advisory: monounsaturated fatty acids and risk of cardiovascular
      disease.

PMID- 10573566
TI  - Ontogeny of eyeblink conditioning using a visual conditional stimulus.
AB  - The developmental emergence of associative learning in rodents is determined by
      interactions among sensory, motor, and associative systems that are engaged in a
      particular experimental preparation (Carter & Stanton, 1996; Hunt & Campbell,
      1997; Rudy, 1992). In fear conditioning, chemosensory, auditory, and visual cues
      emerge successively as effective conditional stimuli (CS) during postnatal
      ontogeny. In the present study, we begin to examine the generality of this
      principle of sensory system development for eyeblink conditioning, a form of
      associative learning that develops substantially later than conditioned fear
      (Carter & Stanton, 1996). We asked whether the developmental emergence of
      eyeblink conditioning to a visual CS occurs at an age that is the same or
      different from conditioning to an auditory CS. In Experiment 1, rat pups were
      trained on postnatal Day 17 or 24 with experimental parameters (and design) that
      were identical to our previous studies of eyeblink conditioning except that
      presentation of a light rather than a tone served as the CS. The outcome was also
      identical: no eyeblink conditioning on Day 17 and strong conditioning on Day 24.
      In Experiment 2, conditioning to tone versus light was directly compared by means
      of a discrimination learning design on postnatal Days 19, 21, 23, and 31. There
      was no evidence for differential development of auditory versus visual eyeblink
      conditioning. The difference between this outcome and previous ones involving
      conditioned fear (Hunt & Campbell, 1997; Rudy, 1992) suggests that principles
      concerning sensory maturation and learning may be different for early- versus
      late-developing associative systems.

PMID- 10573567
TI  - Effects of unilateral suckling on nursing behavior and c-fos activity in the
      caudal periaqueductal gray in rats.
AB  - In rats, suckling elicits kyphosis-the bilaterally symmetrical, upright,
      humpbacked nursing posture-and maximal expression of the immediate early gene c
      fos in a region of the caudal periaqueductal gray (cPAG) that mediates the
      sensorimotor integration of kyphosis. We determined the effects of prepartum
      unilateral nipple removal on nursing behavior and c-fos expression during a 60
      min mother-litter interaction on Day 7 postpartum. Compared with dams suckled by
      6 pups bilaterally, dams suckled unilaterally displayed essentially normal
      maternal behaviors, including kyphosis. Unilaterally suckled dams, however,
      showed an increase in the abnormal prone nursing posture, a decrease in
      proportion of kyphotic nursing of total time over pups, and a 20% higher
      contralateral/ipsilateral ratio of cPAG neurons expressing c-fos. These results
      are consistent with an incompletely lateralized neural pathway conveying suckling
      stimulation to the cPAG and provide a mechanism whereby kyphosis is elicited by
      unilateral suckling when pups initiate nursing from their supine dam.

PMID- 10573568
TI  - Decreases in the response latency to priming over the first year of life.
AB  - We previously reported that the latency of responding to a memory prime in a
      reactivation procedure decreases between 3 and 6 months of age. The present study
      extended this analysis through the first year of life. In this study, 6-, 9-, and
      12-month-olds learned an operant task. One week after they had forgotten it,
      infants were exposed to a component of the original event as a memory prime and
      were tested after different delays for evidence of retention. Although the
      interval between the original event and priming increased linearly with age-from
      3 weeks at 6 months to 9 weeks at 12 months, the latency of responding after
      priming decreased linearly with age-from 1 hr at 6 months to 0-1 s at 12 months.
      The latency of responding after priming was not task-specific; at 6 months, it
      was identical in two different tasks. These results provide additional evidence
      that priming in reactivation studies with infants is the same automatic,
      perceptual identification phenomenon as repetition priming in studies with
      adults.

PMID- 10573569
TI  - Role of an enriched environment on the restoration of behavioral deficits in
      Lurcher mutant mice.
AB  - Lurcher mutant mice, characterized by massive degeneration of the cerebellar
      cortex, and normal littermate controls were reared from birth either in standard
      conditions or in an enriched environment. The effects of this manipulation on
      motor functions, landmark water maze learning, exploration, and anxiety were
      evaluated at 3 months of age. Under standard conditions, Lurcher mutants were
      impaired in comparison to controls on tests of sensorimotor function and had
      altered exploratory tendencies. The enriched housing improved the motor
      coordination of Lurcher mutants and decreased the number of trials before
      reaching criterion in the landmark water maze. In addition to its effects in
      Lurcher mutants, enriched rearing also increased some behavioral abilities in
      normal mice. It is hypothesized that enriched housing altered brain morphology or
      neurochemistry in both normal and cerebellar-damaged animals.

PMID- 10573570
TI  - Effects of stimulus preexposure on the generalization of conditioned taste
      aversions in infant rats.
AB  - Generalization of a conditioned taste aversion in infant rats and how this is
      affected by stimulus preexposure was investigated in a series of experiments. In
      Experiment 1 generalization of a conditioned aversion between two tastes (sweet
      and salty) was found, and the effect of tastes preexposure was a reduction in
      generalization (Experiment 2). However, when these tastes were combined with a
      common taste (acid) that was less (Experiment 3) or more intense (Experiment 3b),
      the effect of stimulus preexposure was a stronger generalization of the
      conditioned aversion. In this case, a reduction on generalization was again
      observed by increasing the number of preexposure trials to the taste compounds
      (Experiment 4). In all cases the generalization levels were directly related to
      the effect of stimulus preexposure on the acquisition rate of conditioning. It
      can be concluded that, with the appropriate parameters, a reduction of
      generalization of a conditioned taste aversion can be obtained after taste
      exposure in preweanling rats.

PMID- 10573571
TI  - Memory enhancement in aged rats: the differential outcomes effect.
AB  - Aged (23 months) and young (3 months) rats were trained on an operant Matching-To
      Position (MTP) task that had either (a) specific outcomes (reinforcers)
      correlated (differential groups), or (b) outcomes uncorrelated (nondifferential
      groups) for each correct sample-choice sequence. The traditional version of MTP
      uses a common outcome and is thought to assess spatial working memory. Aged rats
      are impaired on the traditional version of MTP. However, aged animals trained
      with the Differential Outcomes Procedure (DOP) did not display the typical age
      related decline in spatial working memory. Differences in choice accuracy between
      old and young rats reached significance only if the subjects were trained with a
      nondifferential outcomes procedure (NOP)-similar to when a common outcome is
      used. These data demonstrate that employing behavioral procedures to tap intact
      cognitive functions is an effective means of enhancing spatial working memory in
      normal as well as aged subjects.

PMID- 10573572
TI  - The influences of sex, rearing environment, and neonatal choline dietary
      supplementation on spatial and nonspatial learning and memory in adult rats.
AB  - The potential facilitative effects of early environmental enrichment and
      perinatal choline chloride dietary supplementation on male and female adult rats'
      learning and memory were examined using a "stimulus-elicited investigative," and
      a social/observational learning-cued spatial memory paradigm. Male and female
      animals were either maintained in a standard lighted colony (SC) or were given
      supplementary exposure to a complex environment (EC) for 2 hr daily from 24-90
      days of age. In each case, half of the animals were exposed to the choline
      supplementation both prenatally and postnatally for 24 days. In one paradigm, the
      90-day-old EC rats were found to be significantly more responsive than SC rats to
      each change in the spatial relationships of objects contained in an open field.
      Neither sex nor early diet of the animals were much of a factor in the
      investigative behavior observed. In the second paradigm, the effects of the
      perinatal choline diet did interact with those of sex and postnatal environment
      to alter the impact of social/observational experience on the acquisition and
      memory of place in the water maze. The choline-treated EC males were the most
      influenced by their experience seeing a demonstrator swim to a platform location.
      The present study provides some further insight into the scope of the long-term
      functional enhancements produced by perinatal choline supplementation and EC in
      male and female animals and relates these effects to common modifications to
      targets of cholinergic basal forebrain systems.

PMID- 10573573
TI  - The behavioral response to novelty is altered in rats neonatally exposed to
      cocaine.
AB  - It has recently been suggested that the effects of in utero cocaine exposure may
      result in subtle deficits related to a challenging environment, including
      exposure to novelty or stress. This study used a neonatal drug-exposure model to
      examine the behavioral response to a novel environment in rodents. Subjects were
      artificially reared (AR) from postnatal Days 4-10. There were four treatment
      groups; AR 40 mg/kg/day cocaine, AR 20 mg/kg/day cocaine, AR control group
      receiving no drug, and a normally reared control. In Experiment 1, subjects were
      tested for their preference of maternal home-cage or clean wood-chip odors in a T
      maze on postnatal Day 15. Subjects from all treatment groups preferred the
      maternal odor. In Experiment 2, subjects were habituated to four familiar odors
      and tested with a novel odor in an open field (postnatal Days 16-21). Neonatal
      exposure to 20 mg/kg/day cocaine led to an overall increase in exploratory
      behavior during testing, whereas 40 mg/kg/day did not, supporting the hypothesis
      that developmental exposure to cocaine at some doses may alter the offspring's
      response to a changing environment.

PMID- 10573574
TI  - Prognostic value of internal tandem duplication of the FLT3 gene in childhood
      acute myelogenous leukemia.
AB  - BACKGROUND: Recently, an internal tandem duplication of the FLT3 gene (FLT3/ITD)
      was found in 20% of adult cases of acute myelogenous leukemia (AML), and this
      length abnormality was suggested to be associated with leukemic progression.
      PROCEDURE: We examined the mRNA expression of the FLT3 gene by using reverse
      transcription-polymerase chain reaction (RT-PCR) in 64 children with AML, and
      further abnormal transcripts were cloned and sequenced. RESULTS: An unexpected
      longer product was found in seven patients (11%) by RT-PCR of the FLT3 gene.
      Sequence analysis of these abnormal products revealed the presence of tandemly
      duplicated fragments in all seven patients. Three factors were identified to be
      associated with high incidence of FLT3/ITD; older patients (> or = 10 years) (P =
      0.049), high WBC count (> or = 50,000/microl) at presentation (P = 0.002), and M3
      in FAB subtypes (P = 0.002). Induction failure was observed in 3 (43%) of 7
      patients with FLT3/ITD. Only FLT3/ITD was identified as a significant risk factor
      for induction failure by univariate analysis (P = 0.013), although it was not
      significant by multivariate analysis (P = 0.11). The Kaplan-Meier estimate of
      event-free survival rate at 5 years was 14% for patients with FLT3/ITD, which was
      significantly lower in comparison with 69% for patients without FLT3/ITD (P =
      0.003). This finding was also identified by multivariate analysis (P = 0.01).
      CONCLUSIONS: In this study, FLT3/ITD was observed in 11% of childhood AML and
      identified to be associated with poor prognosis. A large prospective study with
      uniform treatment is necessary to confirm our results.

PMID- 10573575
TI  - Clinically critical impact of molecular genetic studies in pediatric solid
      tumors.
AB  - BACKGROUND: Standard cytogenetic techniques are time-consuming and often not
      informative with solid tumors. In contrast, the reverse transcriptase-polymerase
      chain reaction (RT-PCR) is a readily available technique that can rapidly detect
      tumor-specific chromosomal rearrangements, even in small biopsy specimens. We
      present cases depicting the importance of including molecular diagnostic studies
      in the routine evaluation of pediatric solid tumors. PROCEDURE: We used RT-PCR to
      detect chimeric transcripts specific for major pediatric solid tumors, including
      peripheral primitive neuroectodermal tumor (pPNET), alveolar rhabdomyosarcoma
      (ARMS), and desmoplastic small round-cell tumor (DSRCT). We reviewed six recent
      cases in which the initial diagnosis was changed by the results of RT-PCR.
      RESULTS: Highly unusual or nonspecific clinical and/or histopathologic findings
      led to the initial diagnoses of neuroblastoma in three patients and DSRCT,
      leukemia, and carcinoma in one patient each. The final diagnoses after RT-PCR
      studies were pPNET in three patients, ARMS in two patients, and DSRCT in one
      patient. RT-PCR results led to early corrections in the diagnosis in two
      patients, but four patients received treatment not considered optimal for the
      neoplasms ultimately diagnosed, including three who, despite presenting with
      localized tumors that have a >70% cure rate with standard therapy, have died or
      are dying of disease. CONCLUSIONS: Molecular genetic studies on solid tumors can
      clarify the diagnosis in seemingly straightforward as well as in overtly
      problematic cases. These diagnostic distinctions are now critical as disease
      specific and risk-directed therapies have emerged.

PMID- 10573576
TI  - Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency:
      analysis of 19 patients from the BFM trials.
AB  - BACKGROUND: Non-Hodgkin lymphomas (NHL) represent an important complication of
      primary immunodeficiency (ID), posing new therapeutic challenges in this patient
      population. This study analyzes clinical data and therapy results of pediatric
      patients with primary ID and NHL in three consecutive NHL-BFM trials. PROCEDURE:
      Retrospective analysis of children with primary ID and NHL, treated according to
      protocol NHL-BFM, was performed regarding clinical presentation, diagnostic
      features, therapy, and outcome. RESULTS: From October, 1986, to April, 1997, 19
      of 1,413 newly diagnosed patients with NHL were registered as suffering from
      primary ID. Age at diagnosis of NHL was lower in patients with ID. Six patients
      suffered from humoral ID, 13 patients from combined ID (ataxia teleangiectasia n
      = 3; Nijmegen breakage syndrome n = 4; PNP deficiency n = 1; IL2 receptor defect
      n = 1, other combined ID n = 4). Thirteen lymphomas were of B-cell and six of T
      cell-lineage. Four of thirteen patients with combined ID were diagnosed with T
      NHL, nine with B-NHL. Two of six patients with humoral ID presented with T-NHL
      and four with B-NHL. NHL entities differed significantly between ID and non-ID
      patients (P < or = 0.01): centroblastic and immunoblastic lymphomas (31.6% vs.
      8.1%), anaplastic large cell lymphoma (26.3% vs. 10.7%), Burkitt lymphoma and B
      ALL (21% vs. 47. 8%). Seventeen patients received polychemotherapy. Therapy
      related toxicity was increased in ID- compared to non-ID-patients. Three patients
      died of sepsis; three died of tumor progression; one patient relapsed; one died
      of BMT-related toxicity; one died of second malignancy. Ten patients are in first
      continuous remission after a median follow-up of 4 years. CONCLUSIONS: Curative
      treatment of NHL in the presence of primary ID is possible and should be
      attempted.

PMID- 10573577
TI  - Motor performance of children during treatment for acute lymphoblastic leukemia.
AB  - BACKGROUND: Daily life motor skills of children with acute lymphoblastic leukemia
      (ALL) were studied during treatment using the Movement Assessment Battery for
      Children (Movement ABC). In addition, the possible relation with vincristine
      treatment was investigated. PROCEDURE: Seventeen children treated for ALL, aged 4
      12 years, were compared to an age- and sex-matched control group. RESULTS: The
      leukemia group performed more poorly than the control group on both fine and
      gross motor skills. In looking at the number of children with ALL who scored in
      the clinical range of the different subtests, problems in balance skills were
      found to be most pronounced at the end of induction therapy. Remarkably, half a
      year after reinduction therapy, problems with balance had decreased, whereas the
      number of children with fine motor problems had increased. CONCLUSIONS: A
      relation between the gross motor problems and vincristine neurotoxicity seems
      plausible based on a descriptive analysis of the data, but this was not supported
      statistically.

PMID- 10573578
TI  - Renal medullary carcinoma: prolonged remission with chemotherapy,
      immunohistochemical characterisation and evidence of bcr/abl rearrangement.
AB  - BACKGROUND: Renal medullary carcinoma (RMC), an extremely rare tumour of the
      kidney, carries a dismal prognosis, with no reports to date of significant
      response to chemotherapy or radiotherapy. A case of this tumour in a male child,
      who showed a dramatic response to chemotherapy, is described. PROCEDURE: A
      detailed histological evaluation of the tumour and cytogenetic analysis using
      fluorescent in situ hybridisation (FISH) was carried out. The child was treated
      with multiagent chemotherapy, followed by abdominal radiotherapy. RESULTS: A
      detailed histopathological and immunohistochemical portrait of this tumour is
      described, and FISH studies confirmed the presence of a bcr/abl rearrangement.
      The child obtained complete radiological remission following chemotherapy,
      although he later relapsed and died of progressive disease despite further
      attempts at treatment with chemotherapy. CONCLUSIONS: Although there are no
      previous reports of response of this tumour to chemotherapy, this case
      illustrates that treatment of this disease is justified. The responses of other
      cases to similar drug regimens would be of interest to confirm whether the
      encouraging response described for this case could be reproduced. Cytogenetic
      analysis of other cases of RMC may clarify whether the abnormalities seen in this
      case are typical.

PMID- 10573579
TI  - Tolerance of half-body irradiation as systemic therapy for patients with locally
      advanced breast cancer.
AB  - BACKGROUND: Locally advanced breast cancer (LABC) is one of the main causes of
      cancer death among women in Bulgaria. In 1988, when this study started, there was
      still controversy about the role of chemotherapy in controlling systemic disease.
      There were encouraging results from the Radiation Therapy Oncology Group (RTOG)
      82-06 study suggesting that half-body irradiation (HBI) should be used earlier in
      the disease course to prevent the development of metastases. There were many
      patients with LABC requiring treatment, but there was a problem with obtaining
      the drugs needed; they were expensive and not consistently available. PROCEDURE:
      Taking into account the medical contraindications to chemo-therapy treatment, its
      toxicity, and the possibility of chemoresistance, we initiated this study to look
      at the effects of HBI given as two fractions of 4 Gy to the upper and then lower
      parts of the body, after surgery and before local radiotherapy. RESULTS: The
      acute tolerance of this regimen in 36 patients with LABC was as good as it was in
      4 additional LABC patients with M1 disease, and hematologic recovery was
      satisfactory. CONCLUSIONS: We conclude that systemic treatment with HBI is
      tolerable. It therefore may be a convenient and cost-effective treatment for
      LABC, although better treatments are still needed.

PMID- 10573580
TI  - Another way.

PMID- 10573581
TI  - Dosimetry and growth hormone deficiency following cranial irradiation of
      childhood brain tumors.
AB  - BACKGROUND: Dosimetry of the hypothalamus-pituitary (HP) region could allow
      prediction of the risk of growth hormone deficiency (GHD) following cranial
      irradiation. PROCEDURE: Nineteen children (15 boys) with a median age of 6.3
      years (range 1.7-16.5) at the time of irradiation of a brain tumor not involving
      the HP axis were followed for 1.2-6.3 years (median 3.4) from radiotherapy (RT).
      The dose to a standardized anatomical model including the HP region was
      calculated from dose-volume histograms of 10% to 100% in steps of 10% of the HP
      model based on data from a computer-based treatment planning system. If GHD was
      suspected from insulin-like growth factor-I, serum insulin-like growth factor
      binding protein-3, and/or height velocity measurements, an arginine stimulation
      test was performed. GHD was defined by a peak GH <15mU/liter. RESULTS: Ten
      patients developed GHD 10-26 months from irradiation. Cox regression analysis
      identified the 90% dose-volume of the HP box as the strongest predictor of
      development of GHD (P = 0.03). The median dose to the 90% dose-volume of the HP
      region was 37.5 Gy (range 2. 3-55.3). The cumulated risk of GHD 2.5 years after
      radiotherapy for children receiving more than and less than 37.5 Gy to the HP
      region was 87% and 33%, respectively (P = 0.036). CONCLUSIONS: Dosimetry of a
      defined HP volume provides the opportunity to 1) calculate the exact dose
      delivered to this region, 2) predict the risk of GHD and, 3) in the future revise
      the treatment planning and thus reduce the risk of endocrine adverse effects.

PMID- 10573582
TI  - Radiotherapy of central nervous system tumors in young children: benefits and
      pitfalls.
AB  - BACKGROUND: The prognosis for young children suffering from brain tumors is, as
      many authors report, generally poor. The probability of late complications in
      young children is also high, and their quality of life is significantly worse
      than that of older children. This study presents the experience of one center in
      management of central nervous system tumors in children in aged 1-3 years with
      radiation therapy. PROCEDURE: From 1981 to 1990, 52 children (aged 1-3 years)
      with CNS tumors were treated at the First Radiotherapy Department in the Center
      of Oncology in Warsaw, Poland. These patients represented 18% of the total number
      of 293 children with brain and spine tumors treated in this period. The radiation
      treatment policy for young children was similar to that applied to older
      children, but total doses and doses per fraction were lower and did not exceed 50
      Gy to the tumor site and 30 Gy to the CNS axis. RESULTS: Overall 5-year survival
      was 52%, and disease-free survival was 50%. These results were similar to those
      obtained in older children (53% and 50%, respectively). Serious mental
      retardation (IQ < 70) was observed in 30% of young children in comparison to 7%
      of older patients, but in 62% these symptoms were noted even before the start of
      radiotherapy. CONCLUSIONS: The results obtained in this series did not confirm
      the hypothesis of more aggressive biology of CNS tumors in younger children. The
      proportion of children with serious psychological disturbances in this group is
      apparently high, although in most cases these symptoms were observed before the
      start of radiotherapy and were a result of tumor mass effects.

PMID- 10573583
TI  - Management of respiratory distress in children and adolescents with cancer.

PMID- 10573585
TI  - William osler of bond head, canada

PMID- 10573584
TI  - Intrapulmonary lymph nodes in children versus lung metastases.

PMID- 10573586
TI  - Long-term survival of a stage 4 neuroblastoma patient despite persistent bone
      marrow disease following autologous bone marrow transplantation.

PMID- 10573587
TI  - Pleuropulmonary blastoma: survival after intraocular recurrence.

PMID- 10573588
TI  - Congenital hepatoblastoma and schizencephaly in an infant with Beckwith-Wiedemann
      syndrome.

PMID- 10573589
TI  - Vertebra plana as a manifestation of Ewing sarcoma in a child.

PMID- 10573591
TI  - Letter to the editor: Authors' reply

PMID- 10573590
TI  - Fungal infection from Fusarium spp. in children with refractory hematologic
      malignancies.

PMID- 10573592
TI  - Management of systemic Fusarium infection in children with leukemia.

PMID- 10573593
TI  - The diagnosis and treatment of occupational diseases: integrating clinical
      practice with prevention.

PMID- 10573594
TI  - Medical examination for asbestos-related disease.
AB  - There are millions of workers whose exposure to asbestos dust prior to the
      implementation of asbestos regulation and improved control measures places them
      at risk of asbestos-related disease today. In addition, workers are still being
      exposed to significant amounts of asbestos, when asbestos materials in place are
      disturbed during renovation, repair, or demolition. Given the continued presence
      of asbestos-containing materials in industrial, commercial, and residential
      settings throughout the U.S., a sizeable population remains at risk of asbestos
      related disease. This article reviews the health effects associated with exposure
      to asbestos and delineates the steps necessary for the comprehensive screening
      and clinical assessment for asbestos-related disease, in order to assist
      physicians in identifying and preventing illness associated with exposure to
      asbestos among their patients.

PMID- 10573595
TI  - Clinical evaluation and management of lead-exposed construction workers.
AB  - An estimated one million construction workers are currently occupationally
      exposed to lead. Until 1993, construction workers were not offered the
      protections of OSHA's 1978 standard for lead exposure in industrial activities.
      Preventing exposure to lead in the construction setting presents many challenges,
      given the rapidly and frequently changing work environment. This article reviews
      the adverse effects of lead on human health and presents an approach to the
      diagnosis, management, and prevention of lead-related illness. The medical
      aspects of the 1993 OSHA standard for lead in construction are described.

PMID- 10573596
TI  - The diagnosis and management of solvent-related disorders.
AB  - Millions of workers in the United States are recurrently exposed to solvents
      throughout their working lives. Members of this class of compounds share the
      ability to dissolve waxes, fats, and oils as their common characteristic. This
      review offers the health practitioner a practical approach to the diagnosis,
      management, and prevention of solvent-related disorders that result from
      exposures to these compounds in the workplace. A description of commonly used
      solvents is provided, along with a brief review of the literature that documents
      their acute and chronic effects on health.

PMID- 10573597
TI  - Clinical evaluation and management of work-related carpal tunnel syndrome.
AB  - Carpal tunnel syndrome (CTS) is a clinical entity characterized by pain,
      paresthesias, and numbness in the distribution of the median nerve with weakness
      and atrophy of the thenar muscles in advanced cases. It is universally accepted
      that CTS is the clinical concomitant of compression of the median nerve as it
      passes through the carpal canal. It is reported to be the most common of the
      entrapment neuropathies. Increasing evidence suggests that occupational factors,
      including forceful use of the hands, repetitive use of the hands, and hand-arm
      vibration, are etiologic for CTS. When occurring as a result of occupational
      exposures, the term "work-related carpal tunnel syndrome" is applied. Clinical
      approaches to the diagnosis and treatment of work-related CTS are described in
      this paper. Particular attention is paid to the clinical features and
      pathophysiology of CTS, the epidemiology of work-related CTS, ascertainment of
      work-relatedness in the clinical setting, treatment including both work and non
      work interventions, and control of occupational ergonomic risk factors that may
      contribute to the illness.

PMID- 10573598
TI  - Evaluation and management of chronic work-related musculoskeletal disorders of
      the distal upper extremity.
AB  - This clinical review will describe the epidemiology, clinical presentation, and
      management of the following work-related musculoskeletal disorders (WMSDs) of the
      distal upper extremity: deQuervain's disease, extensor and flexor forearm
      tendinitis/tendinosis, lateral and medial epicondylitis, cubital tunnel syndrome,
      and hand-arm vibration syndrome (HAVS). These conditions were selected for review
      either because they were among the most common WMSDs among patients attending the
      New York State Occupational Health Clinics (NYSOHC) network, or because there is
      strong evidence for work-relatedness in the clinical literature. Work-related
      carpal tunnel syndrome is discussed in an accompanying paper. In an attempt to
      provide evidence-based treatment recommendations, literature searches on the
      treatment of each condition were conducted via Medline for the years 1985-1999.
      There was a dearth of studies evaluating the efficacy of specific clinical
      treatments and ergonomic interventions for WMSDs. Therefore, many of the
      treatment recommendations presented here are based on a consensus of experienced
      public health-oriented occupational medicine physicians from the NYSOHC network
      after review of the pertinent literature. A summary table of the clinical
      features of the disorders is presented as a reference resource.

PMID- 10573599
TI  - Evaluation and management of occupational low back disorders.
AB  - This clinical practice review of occupational low back disorders describes work
      related risk factors, occupational history, physical evaluation, clinical tests,
      diagnosis, care, and prevention. It is part of a quality assurance (QA) and
      quality improvement (QI) effort to establish exemplary occupational practice
      standards. It emphasizes the involvement of occupational medicine physicians in
      exposure assessment, care of injured workers, and disease prevention. Important
      occupational risk factors such as lifting, awkward body posture and vibration, in
      addition to psychosocial, socio-economic and other factors are summarized. The
      focus is on mechanical back disorders. Return-to-work, rehabilitation and
      prevention strategies are discussed as part of integrated disability management
      involving the injured worker, the primary care provider, employers and other
      relevant parties.

PMID- 10573600
TI  - Occupational hearing loss.
AB  - Hearing loss is a significant and unfortunately common occupational malady. Over
      the past several decades both the Occupational Safety and Health Administration
      (OSHA) and the National Institute for Occupational Safety and Health (NIOSH) have
      initiated efforts to better understand and to limit the occurrence of
      occupational hearing loss, particularly as it relates to excessive noise
      exposure. This paper briefly addresses the pathophysiology of noise-induced
      hearing loss and then describes the occupational and non-occupational factors
      which influence a worker's risk of hearing loss. The primary foci of this
      discussion are the clinical evaluation, diagnosis, and management of occupational
      hearing loss. Issues of prevention, OSHA-mandated hearing conservation efforts
      and compensation are reviewed.

PMID- 10573601
TI  - Clinical evaluation, management, and prevention of work-related asthma.
AB  - Work-related asthma (WRA) is asthma that is attributable to, or is made worse by,
      environmental exposures in the workplace. WRA has become the most prevalent
      occupational lung disease in developed countries, is more common than is
      generally recognized, and can be severe and disabling. Identification of
      workplace exposures causing and/or aggravating the asthma, and appropriate
      control or cessation of these exposures can often lead to reduction or even
      complete elimination of symptoms and disability. This depends on timely
      recognition and diagnosis of WRA. In this review, the diagnostic evaluation has
      been organized in a stepwise fashion to make it more practical for primary care
      physicians as well as physicians specializing in occupational diseases and
      asthma. WRA merits more widespread attention among clinicians, labor and
      management health and safety specialists, researchers, health care organizations,
      public health policy makers, industrial hygienists, and others interested in
      disease prevention.

PMID- 10573602
TI  - Medical evaluation for respirator use.
AB  - The purpose of a respirator is to prevent the inhalation of harmful airborne
      substances or to provide a source of respirable air when breathing in oxygen
      deficient atmospheres. For a physician to recommend the use of respirator,
      general background information on respiratory-protective devices is required. The
      first part of this clinical practice review describes the general aspects of
      industrial hygiene, respirators and a respirator-certification program. The
      second part addresses matters related to medical certification for respirator
      use. Medical certification for respirators is an important part of the activities
      of the occupational physician. To determine whether a worker is able to tolerate
      the added strain of a respiratory protective device is a complex process in which
      factors such as fitness for work, health of the individual, characteristics of
      the work itself, and the properties, type, and requirements of the respiratory
      protective device, have to be considered. Medical certification is of utmost
      importance for respirator use, and it should be viewed as an element in a
      comprehensive respiratory protection program. A comprehensive program is the key
      element in affording the workers' effective respiratory protection once the
      initial steps of the hierarchy of methods of hazard control have proved
      insufficient or infeasible. As a result, the need for the industrial
      hygiene/safety officer, the worker, the employer and the medical professional to
      work as a team is much more than in any other field of occupational medicine--a
      necessary requirement for making the right decision.

PMID- 10573604
TI  - Development of P2X receptor clusters on smooth muscle cells in relation to nerve
      varicosities in the rat urinary bladder.
AB  - Postnatal development of the distribution of different isoforms of purinergic
      (P2X) receptors on smooth muscle cells in relation to the development of the
      innervation of the cells by nerve varicosities in the rat urinary bladder has
      been determined with immunofluorescence and confocal microscopy. Antibodies
      against the extracellular domains of the P2X(1) to P2X(6) receptors were used to
      detect the receptors in the bladder. Several other antibodies were used to
      identify sympathetic varicosities and Schwann cells. At one day postnatal (D1)
      there were few strings of varicosities denoting isolated axons, with most axons
      confined to large nerve trunks. Small size clusters of P2X(1) to P2X(6) receptor
      subtypes (about 0.4 microm diameter) were observed in the muscle which were
      independent of each other, and sometimes juxtaposed to the rare isolated
      varicosity strings. At D4 large numbers of strings of varicosities could be
      discerned throughout the detrusor. Most of these clouds of small P2X(1) to P2X(6)
      receptor clusters in their immediate vicinity. Some of these were colocalised
      with the varicosities, which were of parasympathetic origin as they failed to
      counter-stain with antibodies to tyrosine hydroxylase. Up to D14 there was a
      gradual coalescence of many of the isolated P2X(1-6) small receptor clusters so
      that they became colocalized, often at varicosities. Most of the varicosities in
      isolated strings possessed receptor clusters at this time. By D21 it was rare to
      find varicosity strings in the detrusor that were not either in close
      juxtaposition with P2X small receptor clusters or possessing such clusters in
      colocalization. However, large numbers of small P2X receptor clusters, many of
      which consisted of a mixture of isoforms, could be found spatially unrelated to
      nerve varicosities throughout the detrusor muscle. In the adult, single axons
      were either coextensive with one or more isoforms of P2X receptor clusters or
      these were immediately juxtaposed to the axons so that is was rare to find a
      varicosity that did not possess a receptor cluster. However, different
      combinations of colocalized P2X receptor isoforms could still be discerned in
      small clusters unrelated to varicosities. These observations are discussed in
      relation to the mechanism of formation of the receptor clusters and their
      migration beneath parasympathetic varicosities during development.

PMID- 10573605
TI  - Abortive synaptogenesis as a factor in the inner hair cell degeneration in the
      Bronx Waltzer (bv) mutant mouse.
AB  - The Bronx Waltzer (vb) mutation in the mouse results in the degeneration of most
      but not all of the primary auditory receptors, the inner hair cells, and their
      afferent neurons. We analyzed the ultrastructure of 94 inner hair cells in the
      intact postnatal mutant mouse and in neonatal cochleas in culture to understand
      the pathogenesis of hair cell death and to detect factors that may prevent it.
      The vb spiral neurons of the Bronx Waltzer display two distinctive features: some
      of them continue to divide mitotically for at least seven postnatal days, and the
      type I radial fibers that innervate inner hair cells display a deficiency in
      immunoexpression of GAD. The growing endings of spiral neurons converge around
      the inner hair cells or, in their absence, invade the outer hair cell region.
      Their profuse sprouting among inner spiral sulcus cells contributes to the
      characteristic ultrastructural picture of the bv cochlea. During the first three
      days after birth, 40% of the inner hair cells appear normal and innervated, 40%
      are mostly denervated and degenerating, and 20% are immature, with minimal or no
      neuronal appositions. However, in mutants 6 days and older only a few inner hair
      cells survive, and these show either normal or superfluous afferent innervation
      and axosomatic GABAergic efferent innervation. Degeneration of inner hair cells
      begins with a distention of the nuclear envelope and the ribosomal endoplasmic
      reticulum. The outer nuclear membrane eventually breaks, and exudate fills the
      cell interior. The cellular edema leads to cell death. We propose that success or
      failure in synaptic acquisition is a decisive factor in the survival or decline
      of the mutant inner hair cells. We also suggest that the developmental delay in
      maturation of the spiral ganglion neurons (type I) and the failure in their
      synaptogenesis may be caused by an impairment in neurotrophin (NT3/BDNF)
      synthesis by their mutant receptor cells.

PMID- 10573606
TI  - A light and electron microscopic study of the CB1 cannabinoid receptor in the
      primate spinal cord.
AB  - The distribution of cannabinoid receptors was studied in the monkey spinal cord
      by immunocytochemistry and electron microscopy, using an antibody to the CB1
      brain cannabinoid receptor. Large numbers of labelled neurons were observed in
      all portions of the grey matter of the spinal cord. These included small diameter
      9-16 microm neurons in the dorsal horn, larger (40-60 microm) neurons in the
      intermediate grey, and very large (60-100 microm), motor neurons in the ventral
      horn. Reaction product was observed in dendrites postsynaptic to unlabelled axon
      terminals. Since cannabinoid receptor activation decreases neuronal excitability
      by several mechanisms, including inhibition of voltage dependent calcium
      channels, the dense staining of CB1 in dorsal horn neurons suggests that CB1
      could reduce calcium influx through such channels in these neurons. This, in
      turn, could decrease calcium-dependent changes in synaptic transmission and
      decrease sensitisation to nociceptive stimuli in these neurons. Similarly, the
      dense staining of CB1 in ventral horn cells suggests that cannabinoid receptors
      could limit calcium influx through voltage dependent calcium channels in these
      neurons, and could be significant in terms of neuroprotection to these neurons.

PMID- 10573607
TI  - Development of neuromuscular junctions on small mesenteric arteries of the rat.
AB  - This ultrastructural study has investigated the development of the innervation of
      second order mesenteric arteries from the ileum region of the rat intestine,
      particularly, the time course of the formation of the plexus of varicose axons
      around the arteries, and the formation of autonomic neuromuscular junctions. The
      time points studied were postnatal days-2, -4, -8 and -13. This study has
      revealed that the formation of neuromuscular junctions with mature structural
      characteristics occurred at;2 weeks postnatal. The plexus of varicose axons
      developed predominantly between day-4 and day-13, which agrees with previous
      light microscopy studies of catecholamine containing nerves around similar
      vessels. At day-2 and day-4, the axons lacked varicosities and were mainly
      contained in large bundles located in the outer region of the adventitia. The
      medio-adventitial border consisted of a dense layer of extracellular matrix and
      fibroblasts. By day-8, there were more axons and most were distributed in smaller
      bundles. Some had grown through the adventitia to lie at the medio-adventitial
      border and axon varicosities were also observed. Some varicosities had formed
      rudimentary neuromuscular contacts. By day-13, there were significantly more
      contacting varicosities compared to day-8. They were structurally more mature,
      being twice the size with three times the number of synaptic vesicles and
      consistently contained a mitochondrion. Conversely, the neuromuscular contact
      areas were similar at both time points. Some organisation of the synaptic
      vesicles associated with the prejunctional membrane, was evident in varicosities
      at day-8 but there were no presynaptic membrane specialisations similar to the
      putative neurotransmitter release sites found at mature skeletal neuromuscular
      junctions. The aggregation of small vesicles at the prejunctional membrane was
      more pronounced in neuromuscular junctions at day-13 with some having presynaptic
      membrane specialisations. Comparison of the structure of developing autonomic
      neuromuscular junctions with that of skeletal neuromuscular junctions has
      revealed a number of similarities.

PMID- 10573608
TI  - Co-localization of Shaker A-type K+ channel (Kv1.4) and AMPA-glutamate receptor
      (GluR4) immunoreactivities to dendrites of OFF-bipolar cells of goldfish retina.
AB  - Immunocytochemical methods were used to determine the comparative distribution of
      Shaker Kv1.4 and Shal Kv4.2 A-type voltage-gated K(+) channels and AMPA-type
      GluR4 glutamate receptors in the goldfish retina. Kv1.4-immunoreactivity (IR) was
      restricted to a very narrow band of bright puncta and filamentous processes in
      the outer plexiform layer (OPL), whereas GluR4-IR was found in radial processes
      of Muller cells in addition to a narrow band in the OPL. Kv4.2-IR was most
      prominent over cell bodies of horizontal cell, amacrine cells and ganglion cells,
      with very weak labeling over the synaptic terminal of cone photoreceptors. Double
      label experiments revealed complete co-localization of Kv1.4-IR and GluR4-IR in
      the OPL and showed that the Kv1.4 puncta in the OPL appeared enclosed by the
      Kv4.2-IR cone terminals. Electron microscopical immunocytochemistry showed that
      Kv1.4-IR and GluR4-IR were restricted to the dendrites of OFF-bipolar cells that
      innervated cone photoreceptor terminals and thin processes that coursed between
      the rod and cone terminals in the OPL. These data are consistent with other
      studies demonstrating the selective clustering of A-type voltage-gated K(+)
      channels and ionotropic glutamate receptors. However, they differ from mammalian
      preparations in which Shal-like Kv4.2 rather than Shaker-like Kv1.4 co-localize
      postsynaptically with glutamate receptors.

PMID- 10573609
TI  - Binding patterns of lectins with GalNAc specificity in the mouse dorsal root
      ganglia and spinal cord.
AB  - To localize membrane glycoconjugates in neurons of the mouse spinal cord and
      dorsal root ganglia (DRG), cryostat sections of newborn (P0), 7 day-old (P7),
      P14, P21 and P31 animals were stained with ten FITC-conjugated plant lectins, the
      majority of them recognizing N-acetyl-D-galactosamine (GalNAc) terminal sugar
      residues. In the dorsal root ganglia of P0 animals, the different lectins showed
      distinct patterns of labeling in either cells of the nervous system, including
      neurons, or other structures such as nerves or blood vessels. Moreover, some of
      these lectins showed important changes in their pattern of labeling during
      postnatal development. This was especially relevant for lectins that label a
      subpopulation of small-sized cells that have been previously identified as the
      nociceptive cells of the DRG. Enzymatic digestion of sections with neuraminidase
      removes sialic acid from the carbohydrate chains of glycoconjugates thus exposing
      novel sugar residues. When this treatment was applied to DRG sections from
      postnatal animals the pattern of lectin staining was either changed or eliminated
      and heterogeneous subsets of glycoconjugates normally masked by this sugar were
      exposed. In the spinal cord of PO animals, none of the lectins labeled cells in
      the central gray matter. However, after the enzymatic digestion of sections with
      neuraminidase, spinal cord motoneurons and some other cells were labeled by two
      of the lectins suggesting that GalNAc residues present in these cells are
      normally masked by terminal sialic acid. Altogether, these results show important
      changes in the temporal and spatial expression of glycoconjugates that may be
      relevant for the postnatal development of the CNS and PNS of mice.

PMID- 10573610
TI  - [Domestic violence in Caracas: social and cultural predictors].
AB  - The article gives an account of the results of a research intended to know
      violence reported by individual between couples and towards children and also to
      establish the importance of social (sex, income, education, civil status, work
      status, gun license, alcohol abuse, attraction to violent TV programs) and
      cultural (social norms about aggression between couples and children punishment,
      and capacity to express anger and handle conflicts in a non-violent ways)
      predictors in such behavior. The information is based on a survey applied to
      Caracas Metropolitan Area (CMA) inhabitants between 18 and 70 years of age (n =
      1,297) selected by probabilistic, biphasic, and tetra-stage sampling, and at
      random following the Politz method. The instrument was a questionnaire with on
      scale answers Likert type. The information was treated with multi-varying
      statistical analysis, using the association technique between two variables by
      means of the Chi-square test, with conditional independence log-linear for three
      variables. The results suggest relatively low violence levels between couples and
      towards children. Regarding children, women tend to be more violent with them,
      most probably explained by factors relating income and unemployment. It was found
      that the bigger the accord with the norm to discipline children with physical
      violence, the bigger the frequency of violent behavior towards them. On the
      contrary, the bigger the conviction to be skilled in handling situations without
      violence, the lesser the frequency of violent behavior. Regarding violence
      between couples no association was found with the sex variable, but one can
      certainly talk about violent couples, which is related to the way of coupling,
      unemployment, and lack of formal education. From the norm point of view, a
      relationship between belief in the norms and violent behavior is observed,
      although these norms and attitudes are measured by the ability of the couple of
      control himself/herself and act in a non-violent way.

PMID- 10573611
TI  - [The scientific videotape with digital processing in surgery. The new
      opportunities offered surgery for videotape recording and postprocessing with the
      use of information and digital technologies].
AB  - The facility of the tape recording of a surgical operation, by means of simple
      manageable apparatuses and at low costs, especially in comparison with the former
      cinematography, makes it possible for all surgeons to record their own operative
      activity. Therefore at present the demonstration in video of surgical
      interventions is very common, but very often the video-tapes show surgical events
      only in straight chronological succession, as for facts of chronicle news. The
      simplification of the otherwise sophisticated digital technology of informatics
      elaboration of images makes more convenient and advisable to assemble the more
      meaningful sequences for a final product of higher scientific value. The digital
      technology gives at the best its contribution during the phase of post-production
      of the video-tape, where the surgeon himself can assemble an end product of more
      value because aimed to a scientific and rational communication. Thanks to such an
      elaboration the video-tape can aim not simply to become a good documentary, but
      also to achieve an educational purpose or becomes a truly scientific film. The
      initial video will be recorded following a specific project, the script,
      foreseeing and programming what has to be demonstrated of the surgical operation,
      establishing therefore in advance the most important steps of the intervention.
      The sequences recorded will then be assembled not necessarily in a chronological
      succession but integrating the moving images with static pictures, as drawings,
      schemes, tables, aside the picture-in picture technique, and besides the vocal
      descriptive comment. The cinema language has accustomed us to a series of
      passages among the different sequences as fading, cross-over, "flash-back",
      aiming to stimulate the psychological associative powers and encourage those
      critical. The video-tape can be opportunely shortened, paying attention to show
      only the essential phases of the operation for demonstrate only the core of the
      problem and utilize at the best the physiological period of active attention of
      the observer. The informatic digital elaboration has become so easy that the
      surgeon himself can be able to elaborate personally on his personal computer,
      with professional and scientific attitude, the sequences of his surgical activity
      in a product of more general value. His personal engagement also in the phase of
      post-production gives him the possibility to demonstrate uprightly with images
      the complex surgical experience of science, skill and ability to communicate,
      perhaps better than he is able to do with words.

PMID- 10573612
TI  - [Hurthle-cell thyroid neoplasms: a clinical enigma].
AB  - Hurthle cell neoplasms represent a pathological entity whose diagnosis and
      therapy are still not defined. These neoplasms constitute from 1.5% to 10% of all
      thyroid tumors. Hurthle cell nodule is clinically indistinguishable from other
      nodular thyroid diseases and histologic features of the tumors do not always
      allow us to distinguish benign nodules from malignant ones. The authors,
      analyzing a segment of their own experience (335 surgical thyroid diseases),
      observed nine cases of Hurthle cell adenomas (0.03%). Because of concomitant
      presence of heterolobar thyroid disease, seven cases were treated with a total
      thyroidectomy, and two cases were treated with a lobo-isthmectomy. In a long-term
      follow-up study, there were not signs of Hurthle cells neoplastic disease. The
      authors suggest that the treatment of choice for patients with "surely benign"
      Hurthle cell nodule is lobo-isthmectomy. For malignant Hurthle cell tumors, total
      thyroidectomy is the most rational treatment associated with cervical
      lymphadenectomy in presence of metastatic nodes. In all cases, a long-term
      periodical check-up proves to be the best solution, also for patients treated for
      benign pathological Hurthle cell.

PMID- 10573613
TI  - [Drainage in thyroid surgery].
AB  - Bleeding represents a rare complication of thyroid surgery but when it occurs it
      may be life-threatening. To prevent this complication drainage is widely used.
      However no study has demonstrated the drains' value and recent reports have
      questioned its benefits. Therefore we have analyzed our experience of a 10 year
      period in which 1.217 thyroidectomies were performed by the same surgical team
      and prophylactic routine drainage was always adopted. In 13 patients (1.06%) a
      benign hematoma occurred with spontaneous remission. In 6 patients the bleeding
      was severe and compressive hematoma occurred; it required surgical re
      exploration. Such a complication is unusual in the neck surgery (0.49% in the
      authors' series) performed by experienced surgeons and when life-threatening
      hematomas do occur they depend on various uncontrolled factors and drainage is
      often not helpful. Otherwise a meticulous haemostatic technique is necessary and
      patients should be observed very closely during the few first hours following
      surgery on the thyroid gland. Therefore on the basis of the analysis of their
      series, although it is not always possible to prove the benefit of the drainage,
      the authors suggest its indication in the neck surgery, as in other fields with
      dead space, to remove blood and secretions reducing postoperative complications.
      They have never observed wound infections and patients were discharged within 72
      hours.

PMID- 10573614
TI  - [The subrenal abdominal aortic aneurysm. An examination of case histories and
      comments].
AB  - The purpose of the search has stayed that of verify the evolution of the approach
      to the patient carrier of MA and of the treatment pre-intra-post-operatorio. The
      study has stayed effected on sheltered patients in our Institute from the January
      1988 to the January 1997. They are about to be examined the data regarding 282
      patients of which 215 cases in election and 67 in urgency. The analysis of the
      data has shown that the sex masculine are stricken more than female one with a
      relationship of 8.4: 1; the range more stricken the inclusive one in 65-79 years,
      the mortality in election has stayed almost unchanged while that in urgency has
      suffered a clean decrement. The amelioration of the diagnostics techniques of the
      preparation preoperative of the technical anesthesiologic and surgical has
      allowed to get good person results in election and above all in urgency. From the
      comparison with the world literature result that the incidence of the MA is in
      increase in the population, but we have not given univocal for define the entity
      of this pathology, common datum is the small badger of mortality. In conclusion
      the MA stays a serious pathology, diagnosed for case burdened from the mortality
      still elevated (40%).

PMID- 10573615
TI  - [The radical treatment of hepatic hydatidosis with deep and multiple locations.
      The role of new technologies particularly in the case of multiple locations].
AB  - Advanced technologies (intraoperative ultrasonography, CT scan, argon coagulator
      ...) have changed the surgical approach of liver hydatid disease, allowing even
      multiple or deeply located cysts to be detected and treated successfully. Authors
      report a series of 4 patients with single (3) or multiple (1) unilocular hepatic
      cysts; and 1 patient with thoraco-pulmonary hydatid recurrent disease. Treatments
      of choice and surgical techniques are described. No infective compliances
      occurred. The mean period of hospitalization was 19 days (ranging between 10 days
      and 4 weeks). The longest hospitalization was observed in a patient with a post
      operative biliary fistula at low out put. Total cysto-pericystectomy is
      emphasized as the gold standard procedure in the treatment of non complicated
      unilocular hydatid cysts of the liver. Modern means of investigation and
      technical equipment make it feasible and safe even in unfavorable localizations,
      allowing radical removal of the cysts preserving in the meantime all the
      surrounding liver parenchyma.

PMID- 10573616
TI  - [The preoperative staging of rectal neoplasms: the clinical exam and diagnostic
      imaging].
AB  - The management of rectal cancer remains an important clinical problem. Although
      there was been great progress in surgical management, the survival of patients
      with locally advanced disease has not improved significantly during the past
      decades. Preoperative staging and evaluation of the risk of recurrence may help
      in the choice of operation. It is difficult for clinicians to quantify reliably
      with digital examination the degree of fixation of the tumor, and they usually
      cannot distinguish nodal metastases except in advanced cases. The more frequent
      overstaging of small tumors within one quadrant of the rectum is a major drawback
      of digital examination. Computed tomography and magnetic resonance seems to
      underestimate the extension of rectal tumors, but both can be helpful in
      selecting patients with advanced tumors for whom preoperative adjuvant treatment
      is being considered. Endoluminal ultrasound is superior in staging tumors
      confined to the rectal wall, but is not the ideal tool for staging: the results
      are examiner dependent, the field of vision in depth is limited, and stricturing
      tumors cannot be passed by the ultrasound transducer. Imaging diagnostic
      attendibility confirms the preeminent role of intraoperative exploration in the
      assessment of neoplastic diffusion in order to plan a correct surgical treatment.

PMID- 10573617
TI  - [The integrated radiosurgical treatment of rectal cancer].
AB  - The value of radio-surgical protocols in the treatment of advanced rectal cancer
      has been studied retrospectively. 21 patients operated between 1986 and 1990
      fulfilling some criteria were considered for this study. They were 9 men and 12
      women with rectal cancer Duke's stage B2-C; 16 were treated with preoperative
      radiotherapy (30-35 Gy), 5 were treated with postoperative radiotherapy (40-60
      Gy). The operative procedures were 12 anterior resections and 9 Miles operations.
      The 5 years results were: a) cancer free survival 52%; 2 patients alive with
      relapse; 2 patients with non cancer related death (DIC, radiation enteritis); d)
      cancer related deaths 28%; e) local recurrence was observed (3 pts) only in
      association with metastatic disease; f) no isolated local recurrence was
      observed. Preoperative radiotherapy with 30-35 Gy is judged the preferred
      protocol for decreasing the rate of isolated local recurrence and for increasing
      the survival rate. Omental flap transposition plays an important role in the
      radio-surgical treatment of advanced rectal cancer.

PMID- 10573618
TI  - [Perioperative changes in the plasma levels of fibrinogen and D-dimer during
      laparoscopic cholecystectomy: the preliminary results of a prospective randomized
      clinical study].
AB  - AIM: Considering that laparoscopic procedure is associated with increased
      resistance to lower-limb venous return and subsequent stasis, with possible
      implications in terms of thromboembolic complications, the aim of our study was
      to investigate prospectively the coagulative-fibrinolytic profile, in
      laparoscopic and open cholecystectomy, in patients randomly alloted to receive or
      not preoperative heparin. METHODS: We prospectively analyzed 36 patients (20
      laparoscopic and 16 open) and we randomly divided the patients in two groups:
      Group-A (28 patients--16 laparoscopic and 12 open) didn't take any preoperative
      thromboprophylaxis, Group-B (8 patients--4 laparoscopic and 4 open) took
      preoperative subcutaneous heparin. We took blood venous samples before surgery,
      at time 0 and + 30 min., at the end and 1 and 24 hours postoperatively. The
      following parameters were assessed: prothrombin time, partial thromboplastin
      time, fibrinogen and D-dimer. We statistically analyzed the differences by ANOVA
      test. RESULTS: In Group A, fibrinogen and D-dimer were significantly higher (p <
      0.0001 and p = 0.0266) in open group as compared with laparoscopic one and we
      observed significant time-depending changes of fibrinogen's concentration (p =
      0.0168). In Group B we obtained a higher fibrinogen's value in laparoscopic group
      than in conventional one, with a significant difference (p = 0.0283); also, the
      sampling-time affected the result in a very significant meaning (p = 0.0041).
      Comparing fibrinogen levels between Groups A and B, we observed lower values in
      heparin-treated group than in the other one (p < 0.0001), while in laparoscopic
      surgery there was not a significant difference between two groups of treatment.
      CONCLUSIONS: Our preliminary data suggest that, perioperatively (besides a
      smaller laparoscopic acute-phase response) the coagulative-fibrinolytic changes
      are lower in laparoscopic cholecystectomy than in open one and heparin treatment
      significantly reduces these changes in open surgery but doesn't seem to affect
      laparoscopic group. Our results seem to show another possible advantage of the
      laparoscopic surgical procedures over the traditional ones.

PMID- 10573619
TI  - [Experimental research on the use of deferoxamine in the prevention of renal
      damage from acute ischemia].
AB  - Oxygen free-radical reperfusion products play a critical role in postischemic
      tissues injury. In this study we used deferoxamine, an iron ligand that seems to
      inhibit hydroxyl radicals production, in renal normothermic acute ischemia in the
      rat. Our results demonstrated a significant protective effect of deferoxamine on
      kidneys subjected to normothermic acute ischemia.

PMID- 10573620
TI  - [Parathyroid cysts: comments apropos a case].
AB  - A case of non-functioning parathyroid cyst is reported, in which the preoperative
      diagnosis was missed. A careful review of the pertinent literature allows to
      outline the correct approach to this rare pathology as for the diagnosis and the
      treatment; as well, to enlight the current controversies about the
      physiopathology and the pathology.

PMID- 10573621
TI  - [Primary non-Hodgkin's lymphoma of the stomach (a rare case of extensive spread
      to the entire organ)].
AB  - Primary gastric lymphoma is the most frequent extra nodal primary site for non
      Hodgkin's lymphoma (NHL) and is itself uncommon. Moreover, a massive infiltration
      of all stomach (from cardias to antrum) simulating a linitis plastica, it's rare.
      We present a case report of this atypical presentation of primary gastric NHL in
      a 73 year old females. The patient came to our observation complaining of
      dyspepsia, epigastric pain and vomiting from 7 months associated with weight loss
      and asthenia. Physical examination revealed an epigastric palpable mass. Computed
      tomographic findings has been necessary to confirm that the massive infiltration
      of gastric wall (from cardias to pylorus) was ascribed to lymphoma. Dawson's
      criteria was respected to define primary gastric NHL and was performed a total
      gastrectomy with systematic lymphadenectomy. The histopathological evidences have
      confirmed clinical diagnosis of primary gastric NHL. Preoperative diagnosis to
      clarify the nature of lesions (primary or not) and accurate staging of neoplasm
      before the operation are indispensable for a correct therapeutic approach; in
      according to the Ann Arbor classification modified by Musshoff our cases was
      stage IIE and radical gastrectomy with systematic lymphadenectomy was performed.
      Surgical resection is generally considered to have a definitive role in the
      treatment of primary gastric lymphoma specially for the stage IE and IIE.

PMID- 10573622
TI  - [An acute superior mediastinal syndrome with critical tracheal stenosis due to
      benign multinodular goiter complicated by intracystic hemorrhage].
AB  - Large benign goiter with a cervical and intrathoracic retrotracheal location is
      uncommon, but troublesome, since it affects the upper mediastinum and usually
      causes dyspnea, dysphagia or vascular obstruction; on the other hand, a large
      mediastinal cyst of thyroid origin complicated by a massive, spontaneous
      hemorrhage is an exceptional event, implicating vital prognosis through an acute
      tracheal compression. A 45-year-old-man presented all these complications of a
      previously neglected nodular-cystic goiter, causing an acute respiratory
      distress. An emergency diagnosis and consequent surgery, in delayed urgency, were
      performed. This case is presented because of its rarity. Its clinic management is
      discussed, in the framework of the existing literature.

PMID- 10573623
TI  - [Myelolipoma of the adrenal gland].
AB  - Adrenal myelolipomas are rare, nonfunctioning, benign neoplasms of the adrenal
      gland. The authors describe their experience of a case and they report the review
      of the literature. They illustrate what's etiopathogenetic theories, modern
      diagnostic technology "of imaging" and different surgical approaches need to be
      adapted to the excision of the adrenal myelolipomas.

PMID- 10573624
TI  - [Serous cysts of the transverse mesocolon: a review of the literature in the
      light of 2 cases brought to our notice].
AB  - Mesenteric cyst is one of the rarest tumours, with about 820 cases reported since
      1507. Ultrasound and TC are the most valuable modalities for diagnosis of
      mesenteric cyst. Surgical resection is the treatment of choice. The authors
      report two cases of mesenteric cyst of the transverse mesocolon preoperatively
      diagnosed by ultrasonography and computed tomography (CT). A surgical enucleation
      was performed.

PMID- 10573625
TI  - [The ASL and hospitals: a model of emerging management].
AB  - The authors analysed the advantages and drawbacks of the legislative rules in the
      Italian medical services. They underline the impediments to the improvement in
      the quality and efficiency of both the organizing models and the control system
      of administration. The authors consider a new trend in the administration system
      taking place in the most innovative and dynamic units and they analyze the
      efficacy and speediness of diffusion of this new system. The new model could be
      extended to the ASL and Hospital as a possible improvement of the present
      situation. The article is structured in two main parts; in the first one the
      legal changing, that took place in the last year, in the organization of the
      national medical system is critically examined; the second one summarized the
      most significant innovation brought by the new administrative system of ASL and
      hospital.

PMID- 10573626
TI  - Physician-scientists: are they needed?

PMID- 10573627
TI  - Chimeric virus-like particles of the human papillomavirus type 16 (HPV 16) as a
      prophylactic and therapeutic vaccine.
AB  - Infection by certain human papillomaviruses (HPV), most notably HPV types 16 and
      18, is the major risk factor for cervical cancer. Worldwide, this disease
      represents the second most frequent malignant tumor in women; thus, there is
      urgent need for efficient therapy and prevention. The natural history of cervical
      cancer and its precursors (cervical intraepithelial neoplasias), as well as
      animal experiments, strongly suggest that the immune system controls both the
      primary infection (by neutralizing antibodies directed against the major
      structural protein L1) and the progression of the disease (via cytotoxic T cells
      specific for the viral oncoproteins expressed in transformed cells, e.g., E7). By
      the expression of an HPV 16 L1E7 fusion protein, we have generated chimeric virus
      like particles (CVLP). Immunization of mice with CVLPs induces neutralizing
      antibodies directed against L1 virus-like particles (devoid of the E7 portion)
      and E7-specific T cells as measured in vitro. Vaccinated animals are protected
      against tumor growth following inoculation of syngeneic HPV 16-transformed cells.
      In addition, we observed a therapeutic effect of vaccination on pre-existing
      tumors. This data allowed us to conclude that CVLPs are suitable for prevention
      and therapy of HPV infection. A vaccine based on HPV 16 L1E7 CVLPs is currently
      under development.

PMID- 10573628
TI  - Renal effects of experimental obstructive jaundice: morphological and functional
      assessment.
AB  - BACKGROUND: The pathophysiology of renal impairments occurring in obstructive
      jaundice has been extensively studied, but the underlying mechanism of these
      derangements remains unclear. The aim of the present study was to investigate the
      time-related morphological and functional changes occurring in the kidneys of
      rats undergoing obstructive jaundice. METHODS: Histological examination, renal
      function assessment and determination of (Na + K)-ATPase activity were performed
      in the kidneys of rats 7, 14, and 21 days following bile duct ligation (BDL) or
      sham operation (sham). RESULTS: Glomerular filtration rate was unaffected by BDL
      throughout the period of the study. Tubular effects occurred at days 7 and 14,
      being more marked at day 7, and consisted of an increase of about twice in the
      fractional excretion of sodium and chloride, paralleled by a decreased proximal
      and distal tubular reabsorption of sodium of about 50 and 40%, respectively.
      Natriuresis was consistent with augmentation of osmolar clearance but it was not
      associated with changes in the activity of renal (Na+ + K+)-ATPase. The ability
      to dilute urine was impaired at days 14 and 21 after BDL. Additionally, these
      effects were accompanied by decreased tubulointerstitial fibrosis and
      vasodilation of inner medullary capillaries. At day 21, the parameters of tubular
      function in BDL and sham groups were not significantly different. CONCLUSIONS:
      These data support the view that raised natriuresis taking place in the initial 2
      weeks following BDL is due mainly to tubular effects. The contribution of
      hemodynamic, paracrine and humoral mediators is discussed.

PMID- 10573629
TI  - Progesterone reduces immobility in rats forced to swim.
AB  - BACKGROUND: Among its behavioral actions, progesterone reduces anxiety in several
      species including humans; however, any antidepressant-like properties remain to
      be explored. METHODS: In the present study, Wistar rats received injections
      (i.p.) of progesterone (0.20-3.0 mg/kg) 24 and 2 h before being submitted to the
      forced swim, a test in which antidepressants regularly reduce immobility and
      exert few or no actions on locomotor activity. In order to discard the cumulative
      effects of progesterone and a possible effect from the repetition of the swimming
      test, all animals received one of several progesterone doses in a different
      sequence following a completely randomized experimental intrasubject design.
      RESULTS: Ovariectomy did not modify immobility in the forced swim test as
      compared to control tests practiced before surgery. A dose of 0.80 mg/kg strongly
      reduced the total time of immobility in forced swim test (p < 0.001), but did not
      modify locomotor activity. In a drug-free control test applied 1 week after the
      last injection of progesterone, immobility returned to the higher values observed
      in the control tests. CONCLUSIONS: From these results, it is concluded that
      progesterone may possess some anti-depressant-like activity.

PMID- 10573630
TI  - Vascular alpha 1D-adrenoceptor function is maintained during congestive heart
      failure after myocardial infarction in the rat.
AB  - BACKGROUND: During congestive heart failure, desensitization of beta
      adrenoceptors is related to a lower adrenergic responsiveness in the heart;
      little is known about alpha 1-adrenoceptors in the vasculature under this
      condition. We evaluated alpha 1D-adrenoceptor response in aorta and carotid
      arteries in a model of congestive heart failure (CHF) post-myocardial infarction.
      METHODS: Noradrenaline-elicited contraction was determined in endothelium-denuded
      arterial rings from young (10-week-old) Wistar rats in the absence and presence
      of the alpha 1D-adrenoceptor antagonist BMY 7378 (8-(2-(4-(2-methoxyphenyl)-1
      piperazinyl) ethyl)-8-azaspiro(4,5)decane-7,9-dione dihydrochloride) in sham
      operated rats and in rats that developed CHF 4 weeks or 7 months after myocardial
      infarction. RESULTS: In the thoracic aorta, BMY 7378 displaced noradrenaline
      effect to the right with pA2 values of: sham, 8.58 +/- 0.12; CHF, 8.36 +/- 0.13,
      and sham, 8.56 +/- 0.10; CHF, 7.99 +/- 0.13 at 4 weeks and 7 months after
      myocardial infarction, respectively. While in carotid arteries, the pA2 values
      were: sham, 8.43 +/- 0.19; CHF, 8.81 +/- 0.19, and sham, 8.35 +/- 0.18; CHF, 8.29
      +/- 0.08 at 4 weeks and 7 months after myocardial infarction, respectively. When
      adult (7-month-old) rats were subjected to myocardial infarction, CHF was not
      installed and pA2 values were similar and high in both sham and infarcted rats.
      CONCLUSIONS: These results indicate that alpha 1D-adrenoceptors remained as the
      main receptors involved in contraction in aorta and carotid arteries,
      irrespective of CHF duration.

PMID- 10573631
TI  - Detection of a factor released by L5178Y lymphoblasts that inhibits mouse
      macrophage-activation induced by lipopolysaccharides.
AB  - BACKGROUND: Several factors inhibit cellular immune response by deactivating
      macrophages, but very few, such as those described here, prevent macrophage
      activation. METHODS: Ascites liquid from 12-day-old BALB/c mice bearing 5178Y
      lymphoma tumors was collected, and cell-free ascites liquid (CFAL) was separated
      from lymphoblasts. The supernatant (S1) was obtained from the homogenized and
      centrifuged lymphoblasts. Then, macrophage cultures containing 0.2 x 10(6) cells
      from lymphoma-bearing or healthy mice were added to 10 microL of CFAL or S1, plus
      5 micrograms of lipopolysaccharides (LPS)/mL, 40 U interferon-gamma or a blend of
      both. Macrophages were incubated with CFAL or S1 prior to or after adding the
      activators to investigate whether any of the previously mentioned lymphoma
      fractions inhibited macrophage activation or whether they deactivated them. The
      effect of CFAL or S1 was estimated as the diminution of the amount of nitric
      oxide released by the experimental macrophage cultures with respect to controls
      (activated macrophages treated with none of the lymphoma fractions). RESULTS:
      LPS, IFN-gamma, and the LPS/gamma blend activated macrophages from both lymphoma
      bearing and healthy mice. None of the lymphoma fractions deactivated macrophages.
      CFAL, but not S1, inhibited the macrophage activation, i.e., the percentage of
      inhibition of nitric oxide releasing 76.7% and 78.1% in macrophages from healthy
      and lymphoma-bearing mice, respectively. In addition, CFAL was unable to inhibit
      the macrophage-activation effect of IFN-gamma or the LPS/IFN-gamma blend.
      CONCLUSIONS: Mouse L5178Y lymphoma releases a factor that in vitro inhibits the
      macrophage activation induced by LPS, but not by IFN-gamma controls.

PMID- 10573632
TI  - Usefulness of insulin-like growth factor binding protein-3 levels to determine
      acromegaly activity and effectiveness of transsphenoidal pituitary surgery.
AB  - BACKGROUND: Several series reported in the literature concerning the results of
      the treatment of acromegaly have been difficult to evaluate because the
      indicators are inaccurate. METHODS: We investigated the usefulness of insulin
      like growth factor binding protein-3 (IGFBP) levels to determine disease activity
      after surgical treatment of acromegaly in 13 patients with confirmed somatotroph
      adenoma. RESULTS: Before surgery, all 13 non-treated patients had elevated serum
      levels of IGFBP-3 as well as total and free IGF-I. In addition, there was no
      overlap with the normal controls (p < 0.001). IGFBP-3 levels correlated
      significantly (0.91, p < 0.001) with GH suppressibility by glucose after surgery.
      CONCLUSIONS: These data confirm that IGFBP-3 is a better indicator of acromegalic
      activity than either total or free IGF-I. There was a high correlation with GH
      suppressibility by glucose after surgery; both free and total IGF-I could be
      considered sensitive markers only for diagnosis of active acromegaly but not for
      efficacy of surgery.

PMID- 10573633
TI  - Rocuronium administration in children during isoflurane anesthesia: neuromuscular
      effects.
AB  - BACKGROUND: The time-course of the effect of rocuronium during isoflurane
      anesthesia in children has rarely been evaluated. Forty-five children, aged 2-14
      years, ASA 1, undergoing elective surgery and receiving isoflurane anesthesia,
      were studied. METHODS: Patients randomly received a dose of 400, 600, or 800
      micrograms/kg of rocuronium. The first response to the control height (T1:T0) was
      fitted to time in order to obtain times to onset of action (TOA) including time
      to 90 (B90) and 99.9% (B100) of relaxation and to spontaneous recovery of 10
      (T10), 25 (T25), 50 (T50), 75 (T75), and 90% (T90) of neuromuscular function
      (NMF). Each time was compared among groups. Linear regression analysis between
      the TOA or the times to spontaneous recovery of NMF (TSRNMF) and age or weight
      were also performed. RESULTS: The TOA were similar among the three groups while
      TSRNF in children receiving 600 or 800 micrograms/kg were longer (p < 0.05) than
      children receiving 400 micrograms/kg. The T10 and T25 were related to age (p =
      0.05), whereas T10, T50, T75, and T90 were related to weight (p < 0.01). These
      relationships were stronger in males than females. CONCLUSIONS: Maximal
      relaxation was reached in all children receiving 600 or 800 micrograms/kg of
      rocuronium. The TSRNMF were mainly related to the weight of the children, and
      gender affected each relationship. Widely variable responses were observed with
      all three doses.

PMID- 10573634
TI  - Comparative bioavailability evaluation of two cyclosporine oral formulations in
      healthy Mexican volunteers.
AB  - BACKGROUND: The use of conventional cyclosporine (Sandimmune) requires great
      care, as this drug exhibits a narrow therapeutic index and wide interindividual
      variability in its pharmacokinetics. Recently, a new microemulsion formulation
      (Neoral) was developed. With this formulation, cyclosporine is absorbed at the
      small intestine without the presence of bile. Therefore, the objective of this
      study was to compare the bioavailability of cyclosporine after the administration
      of conventional and microemulsion formulations in healthy Mexican volunteers in
      order to approach the optimal dosage regimen of microemulsion in the Mexican
      population. METHODS: The trial was conducted using 23 healthy volunteers
      according to a randomized crossover design. Volunteers received one 7.5-mg/kg
      dose as each formulation, with a 1-week washout period between treatments. Blood
      samples of 0.5 mL were obtained according to the following schedule: 0, 0.5, 1,
      2, 3, 4, 5, 6, 8, 12, and 24 h after medication. RESULTS: These indicated that
      Cmax and AUC0-24 values were higher with the microemulsion than with the
      conventional formulation. CONCLUSIONS: The microemulsion had a better absorption
      profile than the conventional formulation, because plasma levels with the
      conventional formulation demonstrated oscillations rather than reflecting an
      erratic absorption. Lower doses of the microemulsion are required to obtain Cmax
      values similar to those obtained with conventional cyclosporine.

PMID- 10573635
TI  - Predictive and prenatal diagnosis of Huntington's disease: attitudes of Mexican
      neurologists, psychiatrists, and psychologists.
AB  - BACKGROUND: Huntington's disease (HD) is a hereditary disease of the central
      nervous system. Its molecular diagnosis has allowed predictive and prenatal
      diagnosis to be done, and it is now a model for the study of the ethical, legal,
      and social problems arising from the diagnosis of such diseases. METHODS: This
      study explores the knowledge and attitudes of a group of Mexican specialists
      regarding the disease and its diagnosis. A self-administered, 30-item multiple
      choice questionnaire was completed anonymously by neurologists, psychiatrists,
      and psychologists. RESULTS: Fifty-five percent of the professionals had
      experience with HD patients, 59% claimed to know the hereditary risks, and 20%
      answered incorrectly concerning the risks. Neurologists had the most exposure to
      HD; 74% acknowledged the existence of predictive diagnosis, although only 10%
      knew the international guidelines for testing. Eighty-six percent of the
      participants recommended predictive diagnosis, the reasons being: 55%, if the
      patients considered having offspring; 41%, for the patient's professional
      reasons; 6%, if a treatment was available, and 12% did not answer. In cases in
      which the patient wanted to have offspring, 38% thought that this should be
      avoided. Thirty-six percent of the subjects considered prenatal diagnosis
      justified in a couple with a carrier, and 51% justified abortion for affected
      fetuses. CONCLUSIONS: Genetic counseling and predictive diagnosis in Mexico must
      be the responsibility of genetics units and specialists who are aware of
      inheritance risks and of guidelines for HD programs. The number of patients
      requiring such attention is increasing rapidly.

PMID- 10573636
TI  - Epidemiological and biological characteristics of methicillin-resistant
      staphylococcal infections in a Mexican hospital.
AB  - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) has spread
      worldwide since 1960. However, there is little information concerning methicillin
      resistant coagulase-negative staphylococci (MRCNS) infections. METHODS: In order
      to study the clinical and epidemiological characteristics of methicillin
      resistant staphylococci (MRS) infections and to determine the relationship
      between MRS and both synergistic hemolysis (SH) and slime production (SP), a
      laboratory-based survey and non-matched case-control study were carried out at a
      tertiary-care center in Mexico City. In regard to patients, from May 1991 to
      October 1992, 46 cases of MRS infection and 86 patients (controls) infected by
      methicillin-susceptible staphylococci (MSS) were included. Clinical and
      epidemiologic variables were analyzed. The isolates were identified and tested
      for antimicrobial susceptibility by standard methods. An MIC of oxacillin > or =
      8 micrograms/mL was defined as an MRS. RESULTS: During the study, 94 nosocomial
      staphylococcal infections were diagnosed: S. aureus, 35 and CNS, 59; 43 (45.7%)
      by MRS (rate of MRS infections was 1.12 per 100 in-patients); 2 MRSA; 41 MRCNS,
      and only 19 were symptomatic. Three infections were community-acquired, including
      one MRSA and two MRCNS. After multivariate analysis, the significant risk factors
      were previous antimicrobial therapy (p = 0.013) and catheter-related (p = 0.009)
      and urinary-tract source (p = 0.0001). Forty-nine percent of MRS showed SH while
      only 15% of MSS (p < 0.001) showed SH, especially in 10/10 MR-S. hemolyticus.
      Additionally, 48% of MRCNS showed SP, as did 18% of MSCNS (p = 0.019),
      particularly in 15/20 MR-S. epidermidis. Of all MRS isolates, 38% showed a
      homogeneous phenotype, a trait associated with multi-drug resistance (p < 0.01)
      and SH (p < 0.001). CONCLUSIONS: CNS predominated as the cause of MRS infections
      in our setting. The homogenous phenotype was associated with SH and multi-drug
      resistance.

PMID- 10573637
TI  - Improved serological response to human diploid cell rabies vaccine when given
      simultaneously with antirabies hyperimmune globulin.
AB  - BACKGROUND: The prevention of rabies in Mexico continues to be an important goal
      for the health sector. Although the prevalence of this disease continues to fall,
      between 1990 and 1995 a total of 238 cases were registered (an average of 40
      cases annually), with a mean annual incidence of 0.04 cases per 100,000
      inhabitants and a mortality of almost 100%, so that it is important to rely on
      highly effective vaccines with few side effects. The objective of this work was
      to evaluate seroconversion and tolerance to the human diploid cell antirabies
      vaccine administered to individuals with a history of exposure to rabies, to
      compare these results with those reported in the literature for the Fuenzalida
      vaccine, a rabies vaccine produced in the brain tissue of suckling mice, and to
      find the role antirabies hyperimmune gamma globulin plays in the concentration of
      post-vaccination antibody concentrations. METHODS: An analytical transverse study
      was carried out in 40 children and adults with a history of rabies exposure who
      were given a complete, five-dose intramuscular schedule of the human diploid cell
      rabies vaccine. Subjects were followed daily, and local and systemic signs and
      symptoms were recorded. Two blood samples (at baseline and at the end of the
      vaccination schedule) were taken and antibody titers against rabies glycoprotein,
      using the ELISA technique, were measured. RESULTS: Adverse side effects produced
      by the human diploid cell antirabies vaccine, such as frequency of pain,
      erythema, itching, and regional adenopathy were fewer than those reported in the
      literature for the Fuenzalida vaccine (p < 0.05), and of induration and local
      pain (p < 0.05) in relation to the latter vaccine. All patients seroconverted,
      producing geometric mean antibody titers of 6.22 IU/mL, an arithmetic mean titer
      of 9.66 IU/mL with a SD of 9.1 IU/mL. The level of tolerance to the diploid cell
      vaccine was good and its adverse effects were minimal and fewer than those
      reported for the Fuenzalida rabies vaccine. Patients receiving the diploid cell
      vaccine plus antirabies hyperimmune gamma globulin developed higher antibody
      titers (measured by ELISA test) at the end of the vaccination schedule than those
      only receiving the vaccine. CONCLUSIONS: These results are important in order to
      achieve an adequate and opportune level of protection provided by prophylactic
      vaccines to patients with exposure to rabies.

PMID- 10573638
TI  - Bone marrow transplantation in a child with hemophagocytic lymphohistiocytosis
      using a less toxic conditioning regimen.
AB  - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare non-neoplastic,
      frequently fatal disease of childhood. HLA-matched bone marrow transplantation
      (BMT) can bring about long-term remission and an eventual cure. METHODS: We
      report on the beneficial effect of BMT in a 2-month-old male using a less
      intensive conditioning regimen. The regimen included busulfan at 4 mg/kg/day
      (total dose 16 mg/kg), etoposide at 300 mg/m2/day (total dose 900 mg/m2), and
      cyclophosphamide at 50 mg/kg/day (total dose 150 mg/kg). Prophylaxis for graft
      vs.-host disease included methotrexate and cyclosporine. RESULTS: An absolute
      neutrophil count of 500 microL was noticed on + day 12 (engraftment day). At
      present, i.e., 400 days after the procedure, the patient is asymptomatic, his
      physical examination is normal, and a slightly increased level of gamma-glutamyl
      transpeptidase (GGT) and alkaline phosphatase are the only laboratory
      abnormalities. CONCLUSIONS: In this case, the conditioning regimen was adequate
      for the eradication of the disease and allowed persistent engraftment without
      significant toxicity. The results in our patient suggest that a less toxic
      regimen is feasible and permits rapid engraftment without compromising the
      effectiveness of chemotherapy.

PMID- 10573639
TI  - Animal rights in the 1990s: a different species, but you're still the prey.

PMID- 10573640
TI  - Descending thoracic and thoracoabdominal aneurysm.
AB  - The low incidence of permanent spinal cord injury in our most recent cohort
      (Group II) of patients suggests that serial sacrifice of intersegmental vessels,
      careful monitoring of spinal cord function are effective in preventing paraplegia
      after descending thoracic and thoracoabdominal aneurysm operations. Updated
      anesthetic and postoperative care minimized overall mortality risk. (Ref. 9.)

PMID- 10573641
TI  - Surgical treatment of transposition of the great arteries.
AB  - BACKGROUND: With regard to risk of the failure of systemic right ventricle after
      physiological correction of transposition of great arteries, anatomic repair is a
      current method of choice. OBJECTIVE OF STUDY: Analysis of results of surgical
      correction of transposition of great arteries performed between 1992 and October
      1998. METHOD: A total of 111 patients were operated on for transposition of the
      great arteries. In the 1st group of patients (n = 21, mean age was 135 +/- 55
      days), physiological correction according to Senning was performed. Patients of
      the 2nd group (n = 90, mean age was 15.4 +/- 21.6 days) underwent anatomic
      repair. RESULTS: Early mortality was 6% (7 patients). Mean follow-up is 2.95
      years (1.9 SD) ranging from 0.2 years to 6.1 years. Actuarial 1-month survival in
      the whole cohort (n = 111) is 94%, and it remains unchanged at 1, 2, 3, 4, 5, and
      6 years of follow-up. Patients, who underwent surgery after 1997, show
      significantly better survival compared to those operated before 1997 (p =
      0.0997). Thus, a date of operation (before 1997) is the only significant risk
      factor for death. Survival in patients operated after 1997 (n = 40) is 98%. All
      patients belonging to the 2nd group are in functional group NYHA 1. CONCLUSION:
      Anatomic repair of transposition of the great arteries is a method of choice for
      treatment of this congenital heart defect. Left ventricle becomes systemic
      ventricle, which is essential in view of long-term performance. Psychomotor
      development of children, who underwent ASO, is comparable with that of healthy
      population. (Tab. 3, Fig. 3, Ref. 18.)

PMID- 10573642
TI  - [Tracheal stenosis and its treatment].
AB  - A group of 89 patients suffering from tracheostenosis was studied in the period
      from January 1990 to January 1999. Surgical procedure on trachea was performed in
      63 patients with postintubation (posttracheostomic) stenosis, in 6 patients with
      direct tracheal trauma, in 9 with tracheoesophageal fistula, in 7 with malignant
      stenosis, in 3 with postinflammatory subglottic stenosis. In the treatment of
      tracheal stenosis a set of methods was used ranging from laser and tracheal
      endoproteses, through cartilage implantation and plastic reconstruction of
      tracheal defects to extensive segmental resections. In a group of 50 patients
      with segmental resection in 43 (%) of them the result was good, in 2 (4%) of them
      satisfying, in 4 (8%) of them temporary brace (on T-cannule) persists, 1 patient
      died in postoperative period (2%). In a group of 39 patients with combined
      conservative treatment in 18 patients good results were reached (43.8%), in 6
      satisfying (15.4%), in 13 of them temporary brace (on T-cannule) persists (33.3%)
      and 2 died in postoperative period (5.1%). In conclusion the results of this work
      suggest that the most frequent indication for surgical treatment is
      postintubation (postracheostomy) stenosis and that segmental trachea resection
      has priority in the treatment of tracheal stenoses. (Tab. 2, Ref. 18.)

PMID- 10573643
TI  - [Biochemical markers of perioperative myocardial infarct in non-cardiac surgery].
AB  - Perioperative myocardial infarction as well as other major cardiac events induced
      by myocardial ischemia during and after a more complex or long-lasting operation
      represents a permanent threat for a successful outcome. High number of cardiac
      ischemic events especially following major vascular surgery and in elder subjects
      requires early, sensitive and specific diagnostic markers. This review paper
      presents conventional as well as novel biochemical methods fulfilling the above
      mentioned criteria. Until now used estimations of traditional enzyme activities
      (aspartate aminotransferase and lactate dehydrogenase) are either entirely
      discarded or subsequently lose their importance (i.e. activities of total
      creatine kinase and its MB-isoenzyme) an instead modern methods that estimate the
      amounts of specific cardiac proteins--troponins T and I, constituents of
      myocardial contractile apparatus--released from ischemized heart are used.
      Patient's monitoring by means of these cardiac markers allows an early, rapid and
      reliable estimation of perioperative myocardial infarction enabling possible to
      arrange an immediate effective treatment. Recently the myocardial regulatory
      protein troponin I is considered the most specific cardiac marker the plasma
      level of which does not increase in acute damage and chronic diseases of skeletal
      muscles, nor in chronic renal failure. (Ref. 52.)

PMID- 10573644
TI  - [Surgical treatment of abdominal aortic aneurysms in severe ischemic coronary
      disease].
AB  - BACKGROUND: The abdominal aortic aneurysm (AAA) is one of the most serious
      problems of vascular surgery and general medicine, as well. Endovascular methods
      of treatment have been developing very rapidly, however, the conventional
      treatment of the AAA still predominates. The results of operative treatment have
      been influenced besides the delayed diagnostics of the AAA resulting in a high
      rate of ruptured AAA by the high comorbidity of the AAA patients population. The
      accentuation of the proper preoperative and perioperative management of patients
      could therefore significantly influence the results of the surgery. MAIN PURPOSE
      AND STARTING POINTS: Striking difference between the mortality of elective and
      emergent surgery of AAA has been unchanged despite the intensive effort of many
      centers. One of the main factors of mortality is the concomitant serious coronary
      heart disease (CHD), predominantly the acute myocardial infarction (MI). The
      paper analyses the possibilities to improve the results of AAA surgery by means
      of the patients selection and effective preparation before the elective surgery.
      The risk factors and concomitant diseases of patients suffering from the AAA, the
      elective and emergent surgery ratio and the operative mortality are referred. The
      results of surgical treatment before and after accepting the modern CHD
      management algorithm are compared. METHODS: The present study is a retrospective
      analysis of the data of 343 consecutive patients with AAA operated on during the
      20-years period from 1 January 1979 to 31 December 1998. The 1st group of 249
      patients operated on during the 18-years period from 1. January 1979 to 31
      December 1996 was not subjected to special attention concerning the CHD and was
      compared with the 2nd group of 93 patients operated on from 1 January 1997 to 31
      December 1998. In this group of patients special attention was focused on the
      improvement of surgical techniques, intensive care and comprehensive diagnostics,
      evaluation and proper management of the concomitant CHD. RESULTS: The mortality
      rate of the elective surgery in the 1st group was 5.5%, in the 2nd group
      decreased to 3.6%, the difference was not statistically significant. Evident
      improvement of the results was apparent in emergency operations for ruptured AAA.
      The mortality rate in the 1st group of 76% dropped to 40% in the 2nd group (p <
      0.05). The improved policy in the management has lead to statistically
      significant decrease of the MI incidence in the perioperative period (87.2% to
      28.5%, p < 0.001). CONCLUSION: The improved diagnostics, selection of patients
      with special concern to the CHD and management of the patients before surgery,
      improved surgical techniques and intensive care lead to evident improvement of
      the results in the surgical management of the AAA. This fact is confirmed by
      improved results of the 2nd group of patients because of improved CHD management
      algorithm. (Tab. 5, Fig. 1, Ref. 35.)

PMID- 10573645
TI  - [Preoperative levels of CEA and survival in patients with surgical treatment of
      colorectal carcinoma].
AB  - From the 1st January 1986 until the 31st December 1995 397 patients were operated
      on at the IInd Surgical Clinic of Medical Faculty, Comenius University in
      Bratislava because of colorectal cancer. Of them 325 patients were operated on
      electively and 72 patients were operated on as emergency cases. The authors
      analysed average survival time and the relationship between survival and
      preoperative level of CEA. The average survival time, without dividing into
      stages was 37.3 months, not involving patients with perioperative lethality of
      43.1 months. 5 years survival without dividing into stages was 36.8%. Average
      survival of patients without dividing into stages with increased preoperative
      level of CEA was 28.7 months, in patients without increased level of CEA it was
      42.5 months. 5-years survival in patients with normal preoperative level of CEA
      was 60.5%, in patients with increased level of CEA it was 35.7%. There was
      highest difference when dividing to subgroups based upon the stage of the disease
      between groups with stage pT4N0M0 and pT1-4N1-3M0. The positiveness or
      negativeness of the preoperative level of CE supports the staging of disease and
      supposes a significant difference in 5-years survival in patients especially in
      the mentioned stages. Although this difference is obvious, it is not possible to
      suppose individual prognosis of patients and the necessity of an adjuvant
      therapy. (Tab. 2, Ref. 31.)

PMID- 10573646
TI  - [Pedal bypass in the treatment of arterial occlusive disease of the lower
      extremities in diabetics].
AB  - BACKGROUND: The increase of the number of diabetics in the population and
      prolongation of their survival increases also the number of patients suffering
      from diabetic foot syndrome. Terminal complication of diabetic foot syndrome is
      diabetic gangrene, which is the cause of 50% of major amputations performed in
      Slovak republic. The problem of major amputations is not only medical, but also
      economic one. Adequate treatment can reduce the number of amputations by 50%. One
      of the possibilities to improve the prognosis of a diabetic suffering from
      obliterative macroangiopathy is the treatment by distal bypass, because with the
      regard to the characteristic distribution of the lesions to leg arteries is the
      classic vessel surgery (aortofemoral and femoropopliteal/femorocrural bypasses)
      inefficient. After the introduction of this treatment at our department
      preliminary results and some prognostic factors of the surgery success were
      evaluated. AIM OF THE STUDY: To evaluate the efficiency of pedal bypass as a
      method of treatment for peripheral obliterative atherosclerosis in diabetics and
      to determine the predictive value of paraclinical investigations and angiography.
      METHODS: Retrospective analysis of clinical, paraclinical and functional
      parameters of patients in whom pedal bypass was indicated, focused on the
      analysis of angiography. RESULTS: Of the 142 patients hospitalised with diabetic
      foot complications 32 were indicated for pedal bypass. All the patients were in
      the IV stage according to Fontain, the range of gangrene reached in average 2.7
      grades of Wagners scale. Early success--i.e. functional artery reconstruction
      after hospital discharge was achieved in 18 patients (56%). Positive criteria for
      early success of the surgery involve short interval from gangrene development and
      serum albumin level above 26 g/l as an indicator of the nutritional state.
      Favourable angiographic criteria were: passage free arteries of dorsum pedis
      (ADP, ATP, a. plantaris, ATA) in the length of 10 cm free from focal stenoses,
      presence of numerous collaterals of legs and dorsum pedis, opacification of
      metatarsal and digital arteries. CONCLUSION: Pedal bypass is an efficient method
      of treatment for obliterative processes of lower extremities in diabetics with
      involvement of leg arteries. On the basis of our results this procedure can be
      recommended after careful preoperative staging and analysis of angiography as the
      method of treatment. It is necessary to perform the operation as soon as possible
      regarding the worsened nutritional and healing potential of the organism in the
      case of gangrene. Providing the surgery is properly indicated and performed it
      significantly improves the life quality of the patient. (Tab. 5, Fig. 1, Ref.
      22.)

PMID- 10573647
TI  - [Concurrent cavernous and venous cerebral angiomas].
AB  - Presence of venous angioma (VA) in a close vicinity of cavernous angioma (CA) of
      the brain enhances the risk of bleeding from CA. However, VA drains the venous
      blood from surrounding brain tissue and should be left in place during surgical
      removal of CA. Coincidence of CA and VA was found in 6 of 44 patients operated on
      for 45 CA during a six years period (1993-1998). Coincidental VA were found more
      often with the CA located in the deep structures of the brain, in the thalamus
      and the brainstem (5 of 15 cases) than with the superficial CA (1 of 30 cases).
      The most valuable diagnostic method was T1 weighted MR imaging with contrast
      enhancement, less reliable was nonenhanced T1 or proton density weighted imaging.
      Finding of the VA may positively influence the decision making concerning the
      indication for surgery and the selection of the most appropriate surgical
      tactics. (Tab. 1, Fig. 2, Ref. 15.)

PMID- 10573648
TI  - [Laparoscopic appendectomy in acute appendicitis].
AB  - Laparoscopic appendectomy has not yet become a stable part of surgical
      armamentary as has laparoscopic cholecystectomy. The authors on the basis of
      their own experience show its benefit for the surgeon and for the patient. The
      conversion rate (7.7%) in the study group is comparable with literature data. The
      indication for operation was always periappendical mass, in combination with
      retroceocal position of the appendix. Minimum complication rate in the study
      group (one case of subfebrile fever in 5 days), very good overview in operation
      field with the possibility to treat also another pathologic findings concern the
      authors together with short hospital stay a clear advantages of laparoscopic
      appendectomy. On the basis of this experience their advocate the routine use of
      this operation. (Ref. 19.)

PMID- 10573649
TI  - [Laparoscopic vagotomy in the treatment of recurrent duodenal ulcer].
AB  - The paper represents our results of laparoscopic vagotomies. In 1993 was the
      first successful laparoscopic vagotomy in Slovakia performed, at the 1st
      Department of Surgery, Faculty Hospital, Bratislava. From this time 10 operations
      with front superselective and dorsal truncal vagotomy were performed.
      Effectiveness of vagotomy was controlled after 12 months by examination of the
      gastric acidity. Decrease of gastric acidity in average above 61% was reached.
      Laparoscopic vagotomy, despite dominant conservative treatment of peptic ulcer,
      is the method of choice, if the conservative treatment is unsuccessful. (Fig. 3,
      Ref. 6.)

PMID- 10573650
TI  - [Diagnosis of colorectal carcinoma].
AB  - The authors analyzed a group of 207 patients operated on for colorectal carcinoma
      at the 1st Department of Surgery, Medical Faculty of Comenius University, in the
      years 1994-1998. They detected a high number of patients in stages C and D
      according to Dukes' classification--53.1% and a high percentage of patients with
      liver metastases (42%). The number of urgent operations in this five year follow
      up increases gradually, which signalizes no improvement in early diagnostics of
      colorectal carcinoma. The first symptom of this disease was in 37% of cases bowel
      obstruction (ileus) or another complication of the underlying disease. It is
      clear from this analysis, that the early diagnostics of colorectal carcinoma is
      not improving. The authors also analyse the possibilities of improving this
      situation and the new possibilities of early diagnostics of colorectal carcinoma.
      (Tab. 2, Ref. 13.)

PMID- 10573651
TI  - [Aortoesophageal fistulae as a cause of fatal hemorrhage].
AB  - Aortoesophageal fistula is a rare cause of upper gastrointestinal bleeding,
      ranging from 0 to 2.3% in literature. The authors studied a group of 266 patients
      with upper gastrointestinal bleeding during the period of three years (1996
      1998). According to two patient cases and the data from literature diagnostic
      methods, causes of aortoesophageal fistulas are analysed and the necessity of
      urgent closure of the fistulas is stressed. (Tab. 2, Fig. 2, Ref. 15.)

PMID- 10573652
TI  - Hepatitis G virus (HGV) infection & its pathogenic significance in patients of
      cirrhosis.
AB  - In the present study the hepatitis G virus (HGV) infection and its pathogenic
      significance in patients of cirrhosis were assessed using reverse transcription
      plus nested polymerase chain reaction (RT-PCR). Serum samples were collected from
      a total of 50 patients of histologically proven non-alcoholic cirrhosis and from
      a control group consisting of 50 healthy voluntary blood donors. HGV RNA was
      detected by RT-PCR using primer sequences located in the conserved NS3 helicase
      region of HGV genome. Serological evaluation for markers of chronic infection
      with HBV (HBsAg, IgG anti-HBc, HBeAg) and HCV (anti-HCV) was carried out using
      commercially available kits. HBV DNA and HCV RNA were also tested by PCR in those
      samples that were found to be non-B, non-C by serological assays. Serological
      evidence of exposure to HBV was found in 31 (62%) and to HCV in 15 (30%)
      patients. HGV RNA was detected in 6 (12%) cirrhosis patients and in 2 (4%)
      healthy blood donors but the difference between the two groups was not
      statistically significant. Of the 6 HGV positive patients, 2 were coinfected with
      HBV, 1 with HCV, while the remaining 3 belonged to non-B, non-C category. No
      significant difference was observed in the clinical and biochemical profiles of
      HGV-positive and HGV-negative patients except that a history of blood transfusion
      was significantly (P < 0.005) more common in the former. The findings indicate
      that the HGV infection is commonly observed in both cirrhosis patients as well as
      healthy blood donors. A significant association of the virus with blood
      transfusion is indicative of a parenteral route of transmission. The observations
      of this study also suggest that the pathogenic role of HGV in the causation of
      liver disease may be insignificant.

PMID- 10573653
TI  - Prevalence of enterotoxin gene (stn) among different serovars of Salmonella.
AB  - The prevalence of Salmonella enterotoxin (stn) gene among different Salmonella
      serovars by using polymerase chain reaction (PCR) and its status of expression on
      the Chinese hamster ovary (CHO) cells were investigated. All the 26 strains of
      Salmonella enterica such as serovars Typhimurium, Enteritidis, Dublin, Typhi,
      Newport, Weltevreden, Gallinarum, etc. investigated in this study were found to
      carry stn gene as examined by the PCR and gene probe. However, only a limited
      number of stn positive strains (34.6%) were found to express phenotypically the
      Salmonella enterotoxin (Stn) as tested by the CHO cell assay. The strains of S.
      bongori were found to be negative for Stn production both genotypically and
      phenotypically.

PMID- 10573654
TI  - Dot-ELISA for detection of Salmonella enterotoxin.
AB  - Nineteen strains of Salmonella enterica belonging to seven serovars and two
      strains of S. bongori were investigated for enterotoxin production by the Chinese
      hamster ovary (CHO) cell assay and Dot-ELISA. All the 19 strains were found to
      carry stn gene when tested by polymerase chain reaction (PCR) using specific
      primers for stn sequence. Thirteen strains (68.42%) were found to produce
      Salmonella enterotoxin (Stn) when tested by the CHO cell assay. Dot-ELISA could
      detect Stn in 16 strains (84.21%). Dot-ELISA may be preferred over other assays
      due to its low cost and simplicity in performance.

PMID- 10573655
TI  - Occurrence of haemolytic & cytotoxic Aeromonas species in domestic water supplies
      in Chennai.
AB  - A study on the occurrence of Aeromonas species in the domestic water supplies in
      Chennai showed that as much as 37.9 per cent of the water samples analyzed from
      various sources harbored Aeromonas spp. Majority of the isolates belonged to
      Aeromonas sobria (13.7%), A. caviae (11.6%) and A. hydrophila (9.5%). Among the
      37 metropolitan water samples analyzed, 11 samples yielded Aeromonas spp.
      inclusive of three isolates of A. hydrophila, four of A. sobria and two isolates
      each of A. caviae and A. jandaei. From a total of 28 bore well water samples
      analyzed, Aeromonas spp. were recovered from 15 samples, comprising five isolates
      of A. hydrophila, six of A. sobria and four isolates of A. caviae. Aeromonas spp.
      inclusive of one isolate of A. hydrophila, five of A. caviae, three of A. sobria
      and one isolate of A. veronii were isolated from 10 of the 30 water packets of
      various commercial brands sold in Chennai. Of a total of 36 isolates obtained, 32
      (89%) produced beta-haemolysin with the titres ranging from 2-32 and 20 isolates
      (56%) were cytotoxic to vero cell monolayers. All the Aeromonas isolates were
      resistant to ampicillin and polymyxin B. All A. hydrophila and A. caviae isolates
      were also resistant to cephalothin and erythromycin and 83.3 per cent of
      Aeromonas isolates were resistant to erythromycin. Aeromonads resistant to
      tetracycline, gentamycin, co-trimoxazole and nalidixic acid appear to be
      emerging. The study revealed that Aeromonas spp. occur in the potable and
      domestic water supplies and even in the chlorinated water supplies in Chennai
      city, which are potentially enteropathogenic and hence may be hazardous to public
      health. In view of these findings drinking and domestic water quality standards
      need to be re-evaluated.

PMID- 10573656
TI  - Fifteen year follow up of trial of BCG vaccines in south India for tuberculosis
      prevention. Tuberculosis Research Centre (ICMR), Chennai.
AB  - A large scale community-based double blind randomized controlled trial was
      carried out in Chingleput district of south India to evaluate the protective
      effect of BCG against bacillary forms of pulmonary tuberculosis. From among
      366,625 individuals registered, 281,161 persons were vaccinated with BCG or
      placebo by random allocation. Two strains of BCG were used, the French and
      Danish, with a high dose (0.1 mg/0.1 ml) and a low dose (0.01 mg/0.1 ml) in each
      strain. The entire population was followed up for 15 years by means of resurveys
      every 30 months, and selective follow up every 10 months and continuous passive
      case finding. There were 560 cases (189, 191 and 180 from the high dose, low dose
      and placebo groups respectively) arising over 15 years, among 109,873 persons who
      were tuberculin negative and had a normal chest X-ray at intake. This represents
      a small fraction of the total incidence of 2.6 per 1000 person-years most of
      which came from those who were initially tuberculin positive. The incidence rates
      in the three "vaccination" groups were similar confirming the complete lack of
      protective efficacy, seen at the end of 7 1/2 years. BCG offered no overall
      protection in adults and a low level of overall protection (27%; 95% C.I. -8 to
      50%) in children. This lack of protection could not be explained by
      methodological flaws, or the influence of prior sensitisation by non specific
      sensitivity, or because most of the cases arose as a result of exogenous re
      infection. The findings at 15 years show that in this population with high
      infection rates and high nonspecific sensitivity, BCG did not offer any
      protection against adult forms of bacillary pulmonary tuberculosis.

PMID- 10573657
TI  - Trophic effects of vanadium on beta-cells of STZ-induced insulin dependent
      diabetic rats & evidence for long-term relief of diabetes mellitus.
AB  - The effects of one year combined vanadium and insulin treatment (VIT) on blood
      glucose levels of insulin dependent diabetic (IDD) rats were studied. Rats made
      diabetic by an i.v. injection of 55-60 mg/kg streptozotocin (STZ), divided into
      two groups and treated with a low dose of NPH insulin (2-4 U/rat) for two months
      to survive from hyperglycaemic shock. In group A, hyperglycaemia ameliorated
      during one year by increasing the daily dose of insulin to 8.2 +/- 0.4 U/100 g
      (IT) and in group B by switching over to hydrated vanadium solution (1 mg/ml
      vanadyl oxide sulphate pentahydrate in drinking water; VIT). The results of the
      study indicated that one year VIT regenerated new beta-cells, and relieved
      diabetes both during treatment and after withdrawal. However, one year IT showed
      no trophic effects on the destroyed beta-cells, hence no improvement in the
      glycaemic status of the animal was seen after withdrawal. The action of VIT was
      such that in group B normoglycaemeia persisted in 90 per cent of diabetic rats
      two weeks after insulin withdrawal. But in the same group, 45 days after combined
      vanadium and insulin withdrawal blood glucose was normal in 60 per cent of the
      rats, it was between 250-300 mg/dl in 18 per cent and between 350-400 mg/dl in 24
      per cent of the rats. In conclusion it appears that long term VIT regenerates
      pancreatic beta-cells of IDD rats and possibly by improving their secretory
      functions it relieves diabetes mellitus.

PMID- 10573658
TI  - Scientific facts behind creatine monohydrate as sport nutrition supplement.
AB  - Currently, strong efforts are being made toward demonstrating possible risks of
      using pure creatine monohydrate (Cr.H2O). In this article, scientific facts and
      considerations are presented, which support such concern. A further attempt is
      made to pursue the concept of possible risks of uncontrolled supplementation in
      athletes with pure Cr.H2O. The problem is viewed from the scientific evidence
      that a highly conservative mechanism of homeostatic feed-back inhibitory self
      regulation of Cr biosynthesis in the body has been evolutionary developed. It is
      shown that numerous features characteristic to Cr biosynthesis, metabolism, and
      regulation allow to interpret its stimulatory action in the body as endocrine
      hormone-like. Based on this assumption, a practical approach for detecting
      altered links in Cr metabolism and biosynthesis under conditions of pure Cr.H2O
      overdosing, is suggested. Strategic considerations regarding early diagnosis,
      prognosis, and correction of the down-regulated endogenous Cr biosynthesis in
      athletes on continuous pure Cr.H2O supplementation, are discussed. As a high
      efficient and safe alternative to pure Cr.H2O, a complex nutrition supplement
      formula for elite athletes is proposed, which exploits natural alpha
      ketoglutarate as a vehicle for delivering exogenous low molecular biologically
      active compounds, including Cr.

PMID- 10573659
TI  - Oral creatine supplementation improves multiple sprint performance in elite ice
      hockey players.
AB  - BACKGROUND: The purpose of this study was to assess the effect of oral creatine
      monohydrate supplementation on multiple sprint cycle and skating performance in
      ice-hockey players. METHODS:  PARTICIPANTS: sixteen elite ice-hockey players were
      selected as subjects. EXPERIMENTAL DESIGN: subjects were randomly assigned to
      either a creatine (Cr) (n = 8) or a placebo (P) group (n = 8) in a double blind
      design. After familiarization and baseline tests, subjects loaded with 5 g of
      creatine monohydrate or placebo (glucose) four times per day for 5 days, after
      which a maintenance dose of 5 g per day for 10 weeks was administered. At
      baseline, and after 10 days and 10 weeks of supplementation, subjects performed
      i) a cycle test involving 5 all-out sprints of 15 sec duration separated by 15
      sec recovery with the resistance set at 0.075 body mass (kg), and ii) 6 timed 80
      m skating sprints with the sprints initiated every 30 sec and a split time taken
      at 47 m. RESULTS: A two-way ANOVA demonstrated no significant change in any of
      the variables in the P group over the period of study. However, in the Cr group,
      average mean power output over the 5 sprints was significantly higher at 10 days
      (1074 +/- 241 W) and 10 weeks (1025 +/- 216 W) than at baseline (890 +/- 172 W),
      (p < 0.01). Average peak power output over the 5 sprints improved significantly
      from baseline (1294 +/- 311 W) to 10 days (1572 +/- 463 W), (p < 0.01). Average
      on-ice sprint performance to 47 m was significantly faster at 10 days (6.88 +/-
      0.21 sec) and 10 weeks (6.96 +/- 0.19 sec) than at baseline (7.17 +/- 0.27 sec),
      (p < 0.005). CONCLUSIONS: This study demonstrates that creatine supplementation
      has an ergogenic effect in elite ice-hockey players.

PMID- 10573660
TI  - Changes in metabolism and urinary excretion of antipyrine induced by aerobic
      conditioning.
AB  - BACKGROUND: Physical conditioning has been reported to increase liver oxidative
      metabolism determined by antipyrine clearance. The purpose of this investigation
      was to study effects of aerobic conditioning on the different metabolic pathways
      of antipyrine by comparing the production clearances of antipyrine metabolites.
      METHODS:  PARTICIPANT: volunteers not engaged in the systematic practice of any
      sport (n = 14) were compared with aerobically-conditioned subjects (n = 14) (long
      distance runners, defined as men running > 80 km/week). INTERVENTIONS: antipyrine
      was administered orally. Saliva samples were collected under basal conditions and
      at 8, 16, 24, 32 and 40 hrs following antipyrine administration. Urine was
      collected for 24 hrs after antipyrine ingestion. MEASURES: endurance performance
      was expressed by the maximal oxygen uptake (VO2max), the ventilatory threshold
      and the 4 mM.l-1 lactate threshold (OBLA). Antipyrine pharmacokinetic parameters
      (antipyrine clearance and half-live) were obtained from saliva samples by the
      standard multiple-sample method. RESULTS: VO2max, ventilatory threshold and OBLA
      were higher in trained than in control subjects (+32%, +16% and +74%,
      respectively). Salivary antipyrine clearance was higher, whether or not this
      variable was corrected for weight (+26% and +38%, respectively), and antipyrine
      half-life was significantly reduced (-31%) in runners. There was no significant
      change with training in the renal clearance of antipyrine or in the norantipyrine
      (NORA) formation clearance but significant increases were observed in
      hydroxymethylantipyrine (HMA) and 4-hydroxyantipyrine (OHA) formation clearances
      (+42 and +37%, respectively). CONCLUSIONS: The findings indicate that aerobic
      conditioning leads to increased disposition of antipyrine and that the main
      metabolic pathways of the compound are changed differently.

PMID- 10573661
TI  - Reproducibility of the oxygen uptake efficiency slope in normal healthy subjects.
AB  - BACKGROUND: To elucidate the intertest agreement of the oxygen uptake efficiency
      slope (OUES) in comparison with those of the maximal oxygen uptake (VO2max) and
      the ventilatory anaerobic threshold (VAT). METHODS:  EXPERIMENTAL DESIGN: A
      comparative study. SETTING: Institutional practice. A total of 19 healthy
      volunteers underwent two sessions of maximal exercise testing with an interval of
      no more than 7 days. The testing was conducted on a cycle ergometer with the work
      rate increased by either 20, 30, or 40 Watts (W)/min so that the subject would
      reach exhaustion within 9 to 12 min of exercise. VAT was defined as the level of
      oxygen uptake (VO2) at which either an increase in the ventilatory equivalent for
      oxygen without a concomitant increase in the ventilatory equivalent for carbon
      dioxide or a change in the slope of the linear relationship between carbon
      dioxide production (VCO2) and VO2 occurred. OUES was determined by the following
      equation: VO2 = a log VE + b, where VE was minute ventilation and "a" was the
      OUES. Intertest reproducibility was assessed by coefficient of repeatability
      (COR). RESULTS: The intertest reproducibility of VO2max and OUES were excellent
      (COR = 570 ml/min [16%] and 740 [20%], respectively). VAT showed poor agreement
      between the two tests (COR = 650 ml/min [31%]). CONCLUSIONS: Results show that
      OUES is reproducible and reliable, supporting the clinical usefulness of this
      index.

PMID- 10573662
TI  - The validity of ratings of perceived exertion for cross-modal regulation of
      swimming intensity.
AB  - BACKGROUND: This study examined the use of Borg's category Ratings of Perceived
      Exertion (RPE) scale for prescribing and self-regulating swimming intensity.
      Subjects were males and females (n = 19) ages nineteen to fifty-eight who
      regularly swam for fitness. EXPERIMENTAL DESIGNS: Subjects completed six trials.
      Each trial was separated by a minimum of forty-eight hours. Mean cycle ergometry
      heart rates at estimated RPE-overall 12 and 16 were compared to mean swimming
      heart rates at produced RPE-overall 12 and 16. Also, mean arm ergometry heart
      rates at estimated RPE-arms 12 and 16 were compared to mean swimming heart rates
      at produced RPE-arms 12 and 16. Cycling and arm ergometry anchor trials
      familiarized subjects with testing protocol and Borg's scale prior to estimation
      and production trials. Comparisons were made using a one-way ANOVA (alpha 0.05).
      RESULTS: Mean cycling heart rate at RPE-overall 16 was not significantly
      different from mean swimming heart rate at RPE-overall 16. Mean swimming heart
      rate was significantly greater than cycling heart rate at RPE-overall 12. Mean
      swimming heart rates at RPE-arms 12 and 16 were significantly greater than arm
      ergometry heart rates at RPE-arms 12 and 16. CONCLUSIONS: Results suggest that
      RPE-overall 16 may be useful in prescribing a higher exercise intensity for
      swimmers. However, adjustments from RPE-overall 12 are needed for establishing a
      lower intensity. Additionally, arm ergometry-based RPEs may require adjustments
      to be effective in prescribing and regulating swimming intensity. Results suggest
      that cycling and arm ergometry anchored RPE responses should be used with
      discretion when prescribing and regulating swimming intensity.

PMID- 10573663
TI  - A new predictive equation to calculate resting metabolic rate in athletes.
AB  - BACKGROUND: The purposes of the present study were: 1) to examine the accuracy
      and precision of seven published equations for predicting resting metabolic rate
      (RMR) in male athletes and 2) to develop a population-specific equation. SETTING:
      The study occurred during a non-intensive training period. The measurements were
      performed at the Human Physiology laboratory. PARTICIPANTS: Fifty-one male
      athletes (22 waterpolo, 12 judo, 17 karate) who exercised regularly at least
      three hours per day. MEASURES: RMR was measured (mRMR) using indirect calorimetry
      (ventilated hood system). Besides, mRMR was compared with values predicted (pRMR)
      using equations of FAO/WHO/UNU, Harris and Benedict, Mifflin et al., Owen et al.,
      Cunningham, Robertson and Reid, Fleisch. Statistical analyses. mRMR was compared
      with pRMR by means of Student's paired "t" tests, linear regression analysis and
      the Bland-Altman test. Relationships between mRMR and the different predictive
      variables were evaluated by Pearson correlation coefficients. The best subset was
      used to develop the predictive equation for RMR. RESULTS: mRMR was significantly
      underestimated by six of the seven equations in this sample of athletes. Only the
      Cunningham equation overestimated (+59 kcal/d) the actual RMR. Bland-Altman 95%
      limits of agreement were wide (+/- 200-300 kcal/d) for all equations. RMR
      correlated best with body surface area (r = 0.88), body weight (r = 0.84) and
      height (r = 0.81). The best-fit equation for the entire data included both weight
      and height and it was given by: RMR (kcal/d) = -857 + 9.0 (Wt in kg) + 11.7 (Ht
      in cm) (R2 = 0.78; SEE = 91 kcal/d; 95% IC: -226, 228). CONCLUSIONS: For an
      individual resting metabolic rate evaluation, the use of indirect calorimetry is
      recommended. In conditions where this technique cannot be used, our developed
      equation can predict the RMR of athletes better than any of the currently
      available prediction equations.

PMID- 10573664
TI  - The effects of slow- and fast-rhythm classical music on progressive cycling to
      voluntary physical exhaustion.
AB  - BACKGROUND: To investigate, based on the parallel information processing model
      and arousal hypothesis, whether musical tempo and its manipulation during
      exercise affect the maximal workload (watts) achieved during progressive cycling.
      METHODS:  DESIGN: repeated measures experiment that involved one control and four
      treatment conditions. SETTINGS: the experiment was performed in a controlled
      laboratory environment. PARTICIPANTS: twenty-four male and female volunteers,
      recruited from among a University population, were tested. INTERVENTION: the data
      collection proceeded in five counterbalanced test-sessions that included control
      (C), slow music (SM), fast music (FM) slow to fast music (SFM) and fast to slow
      music (FSM) interventions. In the last two conditions, musical tempo was changed
      when the participant's maximal HR reserve has reached 70%. In all test-sessions,
      participants started to cycle at 50 watts and then the workload was increased in
      increments of 25 watts every minute until self-declared exhaustion. Maximal
      ergometer cycling was defined as the workload at the last completed minute of
      exercise. MEASURES: workload, HR, and postexperimental ratings of test-session
      preferences were the dependent measures. RESULTS: Significantly higher workload
      was accomplished in the SFM condition. No between-session differences were seen
      in HR. The results also yielded significantly better "efficiency", in terms of
      workload/HR reserve ratio, in the SFM session. PARTICIPANTS preferred the FM and
      SFM sessions more than the other sessions. CONCLUSIONS: Switching to FM during
      progressive exercise results in the accomplishment of more work without
      proportional changes in HR. These effects may be due to distraction from fatigue
      and are, apparently, dependent on the attention capturing strength of the
      distracting stimulus.

PMID- 10573665
TI  - Exercise-induced muscle damage: absence of adaptive effect after a single session
      of eccentric isokinetic heavy resistance exercise.
AB  - BACKGROUND: Unaccustomed eccentric exercise induces muscle damage. A single
      session of eccentric exercise can induce an "adaptive effect" protecting
      exercised muscles during several weeks. Our aim was to verify this phenomenon in
      isokinetic exercise. Tested hypothesis was: the progressive muscle rise in
      tension due to isokinetic eccentric actions would be insufficient to induce the
      adaptive effect. METHODS:  EXPERIMENTAL DESIGN: prospective study. SETTING:
      general community. PARTICIPANTS: six healthy and moderately active (untrained)
      males (29.1 yr +/- 1.5 SEM). INTERVENTIONS: subjects performed two isokinetic
      eccentric exercises (EE1 and EE2) of the quadriceps femoris of both legs (120
      degrees.s-1; 8 sets of 15 repetitions) separated by 4 weeks. MEASURES: type I
      serum myosin heavy chains (MHC) and creatine kinase concentrations (CK), and rate
      of perceived soreness (DOMS) were collected before each exercise and on days 1,
      2, 4, 6 and 9. RESULTS: Both exercises induced significant (p < 0.01) increases
      in MHC and CK concentrations, and DOMS score. There was no significant difference
      between EE1 and EE2, at any measurement time for any parameter. Mean peak values
      (SEM) were respectively (EE1; EE2): MHC (microU.l-1): 308 (192); 285 (191). CK
      (U.l-1): 1217 (760); 1297 (1039). DOMS score: 2.67 (0.52); 2.33 (0.52).
      CONCLUSIONS: The first session of eccentric isokinetic exercise (EE1) had no
      adaptive effect against muscle damage when an identical session was performed 4
      weeks later (EE2). Muscle adaptation could have resulted in increased work
      production (+10.2%; p < 0.05; from EE1 to EE2).

PMID- 10573666
TI  - The effect of physical activity and fitness on specific antibody production in
      college students.
AB  - BACKGROUND: The purpose of this study was to determine the effect of moderate
      physical activity/fitness on the immune response to a defined antigen, in
      particular, the hemagglutinin-inhibition response to the H1 (A/Texas/36/91) and
      H3 (A/Johannesburg/33/94) components of the 1995-96 Influenza virus vaccine.
      METHODS: Sixty-seven volunteers 18-30 years of age (mean 21.1 + 2.3) participated
      in the study. Physical activity was assessed using the Stanford 7-Day Recall
      Questionnaire, physical fitness (VO2max) was predicted based on graded submaximal
      cycle ergometry. Participants were divided into six groups (lower-active/fit,
      moderate active/fit, and higher active/fit), based on their scores on the 7-Day
      Recall Questionnaire or predicted VO2max, respectively. Plasma samples were
      collected prior to, one, two, four, and six weeks post vaccination. A total of
      four separate repeated measures ANOVA were utilized to evaluate the effect of
      physical fitness and physical activity on the immune response to the H1 and H3
      components of the vaccine. RESULTS: As expected, for both antigens, titers
      significantly increased after vaccination, with the highest titers found on week
      four (H1) and week six (H3), respectively. However, for both antigens, there was
      no difference between groups and no significant interaction. CONCLUSIONS: The
      results of this study showed no significant effect of physical fitness or
      physical activity on the production of specific antibody in the range of physical
      fitness and physical activity found within this group of college students.

PMID- 10573667
TI  - Immune responses to exercise in children treated for cancer.
AB  - BACKGROUND: Children treated for cancer commonly benefit physiologically from
      moderate aerobic training, but it is less clear if impairment of the immune
      system secondary to chemotherapy reduces the immunological tolerance of exercise
      relative to normal children. METHODS:  EXPERIMENTAL DESIGN: a case series.
      SETTING: hospital laboratory. PARTICIPANTS: six children aged 13-14 yr,
      successfully treated for acute lymphoblastic leukaemia and other types of
      neoplasms, were compared with 11 normal volunteer children. INTERVENTIONS: three
      of the sample underwent 12 weeks training at 70-85% of maximal heart rate; the
      remaining three provided initial and final test data only. MEASURES: mood state
      (Piers-Harris test), anthropometric data, maximal oxygen intake, response to 30
      min exercise challenges at anaerobic threshold, and standard immune measures
      (differential count, cytolytic activity, and mitogen-induced lymphocyte
      proliferation) at rest, during and following submaximal exercise. RESULTS: A low
      maximal oxygen intake, excess of body fat, and high anxiety scores all improved
      with training. Children who were still receiving chemotherapy showed low resting
      CD3+, CD4+, CD8+, CD19+ and CD25+ counts and reduced PHA-induced proliferation.
      Acute exercise and training caused further impairment of immune responses,
      although changes remained insufficient to cause concern for health. CONCLUSIONS:
      Exercise therapy is beneficial following treatment of cancer, but should be
      prescribed individually, with a careful monitoring of immune responses.

PMID- 10573668
TI  - Tennis elbow, natural course and relationship with physical activities: an
      inquiry among physicians.
AB  - BACKGROUND: The main purposes of the study were to answer the following two
      questions: is a restrictive therapeutic management in case of tennis elbow (TE)
      better or worse than a regular therapeutic approach and do racket sports and
      other physical activities influence the risk to get TE and to what extent.
      METHODS:  DESIGN: Cross-sectional study by means of a postal questionnaire. The
      impression was verified that physicians are reserved about medical interventions
      when treating themselves for tennis elbow. The frequency of therapeutic measures
      and their results were compared with data reported in literature. Physical
      activities of physicians who had TE were compared with those of physicians who
      never had TE. SETTING: Physicians who attended postgraduate courses on diagnosis
      and treatment in orthopedic medicine from 1984 to 1992. PARTICIPANT: 72
      physicians who had TE and 266 with no history of TE. MEASURE: The study is based
      on self-assessment of therapeutic approaches and their results, reported physical
      activities at the onset of TE and at the moment of the inquiry. By a team of
      experts the grade of grasping and/or dorsiflexion of the physical activities was
      classified. RESULTS: Compared with patients in general practice, physicians
      treating themselves for TE were more restrictive to use NSAID's, ointments or
      local steroid injections or to consult a specialist. No-one was treated with
      surgery and no-one interrupted her/his work because of TE. In all but two of the
      72 cases the TE resolved within two years. The odds ratio for TE for playing
      racket sports versus not playing racket sports was 2.8 (95% confidence interval
      1.64-4.82). The odds ratio for activities with low-grade grasping and/or
      dorsiflexion versus "no sports or hobbies" was 0.11 (0.02-0.50). CONCLUSIONS:
      Absence from work and therapeutic measures for TE are (in physicians) not
      necessary for a good result on the long term. Playing racket sports increases the
      risk to get TE by a factor of 2.8. Performing weekly activities with low grade
      grasping and/or dorsiflexion of the wrist may have a protective effect against
      developing tennis elbow.

PMID- 10573669
TI  - A new thermoplastic splint for proximal interphalangeal joint flexion
      contractures.
AB  - BACKGROUND: Aim of this technical note is to describe the fabrication procedure
      of a new thermoplastic static-progressive hand-based splint for PIP joint flexion
      contractures, and report its effects in the treatment of a small group of
      sportsmen. METHODS: The serial-static splint consists of a short metacarpal
      gauntlet base, with a hole for the thumb and a dorsal finger gutter that extends
      to the distal extremity. A low-temperature thermoplastic material, two loop
      fastener straps, three small pieces of self-adhesive hook fastener and cooling
      spray are required. The orthosis has been tested on four professional volleyball
      players (3 females and 1 male), aged 18-24 years, suffering from PIP joint
      flexion contractures after traumatic hand injuries occurred 2 to 3 months before.
      Patients wore the splint for 1 hour followed by 1 hour of rest (6 times per day),
      for 2 to 3 weeks. During the resting periods patients performed a few sets of
      active ROM exercises at their PIP joint. RESULTS: This new splint design
      demonstrated to be effective in early recovery of complete PIP joint extension
      and subjects resumed soon their sports activity. CONCLUSIONS: Our device is easy
      to fabricate and to use and comfortable for patients.

PMID- 10573670
TI  - Comparison of two abdominal training devices with an abdominal crunch using
      strength and EMG measurements.
AB  - BACKGROUND: The purpose of this study was to compare the training effects of the
      Ab-Flex (F), Ab-Roller (R) and standard crunch (C) on EMG production, isometric
      maximum voluntary contraction (MVC), and isokinetic average peak torque at 30
      degrees/sec (ISO) of the abdominal muscles. It was hypothesized that the training
      devices would have similar value in a strength training program. METHODS: 
      EXPERIMENTAL DESIGN: this was a prospective study involving 18 training sessions
      of progressively increasing repetitions. SETTING: Neuromuscular Research
      Laboratory, University of Pittsburgh. SUBJECTS: thirty-two subjects volunteered
      for this study, but only 26 completed the training. Each subject participated in
      recreational activity, but had not performed any abdominal training prior to
      starting this study. Each subject was randomly assigned to either the control
      group or one of the treatment groups. INTERVENTIONS: there were three
      interventions: two training devices (Ab-Flex and Ab-Roller) and the standard
      crunch, considered a control group. MEASURES: the pretest consisted of skin fold
      measurements (%), EMG activity (V) during the three interventions, and peak
      torque (Nm) plus EMG during the MVC and ISO tasks. The 18 training sessions over
      three weeks consisted of three sets of exercise with increasing repetitions from
      10 to 20, by 2, every three sessions. The difference in pretest/posttest scores
      were compared using a One-way ANOVA on the mean differences (Mdiff) for each of:
      MVC, ISO (peak torque), and EMG for upper rectus (UR), lower rectus (LR),
      internal oblique (IO), and external oblique (EO). A T-Test was used to detect
      significance for the body fat measures. RESULTS: Mean differences (Mdiff) were
      normally distributed about zero for both MVC and ISO (MVC = -0.55, ISO = 4.57).
      The analysis by group showed no difference (p = 0.596) on the reported means (Nm)
      -3.16 (C), 5.84 (F) and -4.83 (R). The change associated to the treatment during
      MVC was only 4% (eta = 0.04). For the ISO the Mdiff (Nm) were 1.39 (C), 13.66 (F)
      and -2.06 (R) which were not significant (p = 0.127). The Ab-Flex was the only
      group to have a 95% confidence interval above zero, increasing by an average of
      16.5%. There were no significant differences for the EMG activity for Mdiff or
      between group scores. CONCLUSIONS: No significant differences were found with
      this study. These results would suggest that using these devices does not add
      significantly to overall abdominal strength development, or reduction of body
      fat. A suggestion could be made that certain devices influence muscles
      differently.

PMID- 10573671
TI  - Cardiovascular adaptation during action pistol shooting.
AB  - BACKGROUND: Action Pistol Shooting, implies high degree of physical and
      psychological stress, however cardiovascular adaptation during competition has
      not been studied so far. METHODS: We studied six healthy males athletes, during
      the Italian National Dynamic Pistol Shooting Championship. ECG was monitored and
      blood pressure (BP) manually measured along the match. RESULTS: Mean heart rate
      (HR) was close to 100 bpm per minute in all but one shooters. Marked tachycardia,
      above 180 beats per minute was recorded in four shooters, during "field course"
      stages. In two cases the heart rate under stress reached about 200 bpm, for the
      occurrence of paroxysmal atrial arrhythmias. BP behavior was different among the
      six shooters with mean systolic values ranging between 140 and 170 mmHg and
      maximal systolic values between 160 e 240 mmHg. CONCLUSIONS: Action Pistol
      Shooting induces acute elevation of HR and BP, which may reach abnormal values
      and can be associated with impaired performance and score. Further study is
      warranted in shooters undergoing combat-like tournaments to evaluate unperceived
      cardiovascular stress and their coping capability.

PMID- 10573672
TI  - Living for a cure.

PMID- 10573674
TI  - Adverse events of Kytril Injection questioned.

PMID- 10573673
TI  - Chemotherapy administration continuing-education opportunities will prevent
      errors.

PMID- 10573675
TI  - Internet services provide peer support.

PMID- 10573676
TI  - Travel is a large factor with remote facilities.

PMID- 10573677
TI  - Communication and planning play a vital role in care.

PMID- 10573678
TI  - A model nurse practitioner-managed smoking cessation clinic.
AB  - PURPOSE/OBJECTIVES: To describe an intensive nurse practitioner (NP)-managed
      smoking cessation clinic that evolved from a primary-care quality-management
      initiative. DATA SOURCE: Published articles, abstracts, books, clinical
      experience, and clinical data. DATA SYNTHESIS: Smoking continues to be the
      leading cause of preventable deaths in the United States and accounts for 87% of
      all lung cancers. Although smoking is responsible for nearly 30% of all cancer
      deaths, smoking prevalence rates remain stagnant in adults and are continuing to
      increase in adolescents. Twenty-five percent of all Americans smoke. An NP
      managed clinic was developed within a large teaching hospital located in the
      southeastern United States based on the Agency for Health Care Policy and
      Research guideline for smoking cessation. The clinic provided effective smoking
      cessation interventions that can be replicated by experienced nurses with a
      smoking cessation background. All nurses have opportunities to assist patients to
      stop smoking through brief counseling and minimum interventions. CONCLUSIONS:
      Nurses can effectively manage an intensive smoking cessation clinic that is
      utilized by the interdisciplinary team to treat referrals. Cessation rates were
      high because therapies combined intensive behavioral sessions and pharmacologic
      approaches rather than either single modality. IMPLICATIONS FOR NURSING PRACTICE:
      Nurses can replicate this practice in a variety of healthcare settings.
      Innovations in clinical practice often facilitate research studies to further
      define effective approaches for smoking cessation. Nurses need to identify and
      target smoking as the serious health problem it is and conduct much-needed
      research on cessation approaches within the inpatient and outpatient settings.

PMID- 10573679
TI  - Management of thromboembolism in patients with cancer.
AB  - PURPOSE/OBJECTIVES: To review the phenomenon of thromboembolism in patients with
      cancer, discuss treatment options for deep vein thrombosis (DVT), and describe
      oncology nurses' role. DATA SOURCES: Published articles, abstracts, professional
      communications, drug manufacturer information, and personal clinical experience.
      DATA SYNTHESIS: The incidence of DVT in patients with cancer can be as high as
      15%. The cause of thromboembolism is multifactorial and includes tumor type,
      alterations in coagulation, specific chemotherapy agents, and clinical
      considerations. Although these patients traditionally have been treated with
      standard unfractionated heparin (UFH) therapy, low molecular weight heparin
      (LMWH) has been studied extensively and is an acceptable alternative treatment.
      LMWH should be followed by a period of oral anticoagulants, although some
      patients may benefit from long-term heparin therapy. Oncology nurses are
      qualified to identify patients who are at risk for DVT and, in expanded roles,
      may manage patients on anticoagulant therapy successfully. CONCLUSIONS: LMWH
      followed by a course of oral anticoagulant therapy is an alternative way to treat
      DVT. Treatment with LMWH is less expensive than traditional UFH and has a
      preferred side effect profile. IMPLICATIONS FOR NURSING PRACTICE: All oncology
      nurses should be aware of the different risk factors for DVT in patients with
      cancer and current clinical management should DVT occur. Oncology nurses in
      expanded roles or advanced practice nurses may choose to manage DVT with LMWH
      followed by oral anticoagulant therapy. Some patients may require long-term
      treatment with heparin therapy rather than oral anticoagulants.

PMID- 10573680
TI  - School-age children's and adolescents' adjustment when a parent has cancer.
AB  - PURPOSE/OBJECTIVES: To describe school-age children's and adolescents' adjustment
      to parental cancer. DESIGN: Retrospective population control. SETTING: Screening
      cancer registries identified subjects at four Midwestern hospitals, including
      urban and rural settings of community and tertiary hospitals. All families were
      interviewed at home one time. SAMPLE: A convenience sample of 116 school-age
      children (6-10 years) and adolescents (11-18 years) living in the home of a
      parent with cancer. METHODS: Data were collected using two forms of the Child
      Behavior Checklist and an investigator-developed demographic form. The ill
      parent, the partner, and the adolescent rated the adjustment. This study's data
      were compared with population data, and comparisons were made among raters and
      with the existing literature. MAIN RESEARCH VARIABLES: School-age children's and
      adolescents' adjustment. FINDINGS: School-age children and adolescents of a
      parent with cancer have significantly more behavioral problems than were
      expected. The significant agreement among raters is of a modest magnitude but as
      strong as rater agreement reported in the literature. CONCLUSIONS: Most school
      age children and adolescents of a parent with cancer are well-adjusted, but a
      significant subset of youngsters is at risk for behavioral problems. IMPLICATIONS
      FOR NURSING PRACTICE: Nurses need to assess ill parents' concerns about their
      youngsters, provide information to parents, adolescents, and school-age children,
      and institute appropriate referrals.

PMID- 10573681
TI  - Comparison of subjective sleep quality in patients with cancer and healthy
      subjects.
AB  - PURPOSE/OBJECTIVES: To compare the subjective sleep quality of a group of
      patients with cancer undergoing treatment and a normative sample of healthy
      comparison subjects. DESIGN: Secondary analysis of data from a single time point
      in a repeated measures descriptive-correlational study. SAMPLE/SETTING:
      Convenience sample of 15 patients with cancer receiving antineoplastic therapy
      and admitted to a tertiary university medical center for fever or neutropenia and
      52 healthy comparison subjects without sleep disturbances. Although both groups
      were of similar age, a higher percentage of men comprised the comparison group.
      METHODS: Patients completed the Pittsburgh Sleep Quality Index (PSQI) on the
      first day of hospitalization to reflect their perceptions of sleep for the month
      prior to hospitalization. Healthy comparison subject scores on the PSQI were
      obtained from a published report outlining psychometric properties of the PSQI
      (Buysse, Reynolds, Monk, Berman, & Kupfer, 1989). MAIN RESEARCH VARIABLES: Sleep
      latency, sleep duration, sleep efficiency, sleep disturbances, medication use,
      daytime dysfunction, and global sleep quality. FINDINGS: Patients with cancer
      reported significantly poorer overall sleep quality accompanied by more daytime
      dysfunction. The incidence of specific sleep disturbances, such as snoring and
      dyspnea, was not different between the groups. CONCLUSIONS: This small sample of
      patients reported significantly poorer sleep quality than an historical
      comparison group. Specific sleep disturbances commonly seen in the general
      population were not problematic for the patients with cancer. Limited sample size
      and use of an historical comparison group need to be considered in interpreting
      and applying these findings. Additional research is needed to further
      characterize the nature of sleep problems in patients with cancer. IMPLICATIONS
      FOR NURSING PRACTICE: Nurses need to assess sleep in their patients, including
      its impact on quality of life and functional status.

PMID- 10573682
TI  - Use of routine and breakthrough analgesia in home care.
AB  - PURPOSE/OBJECTIVES: To describe current use of routine analgesics in home care
      and the treatment of breakthrough pain. DESIGN: Descriptive, companion study.
      SETTING: Homecare agencies in southern California. SAMPLE: Convenience sample of
      369 patients with cancer participating in a pain-education study. METHODS: Data
      regarding breakthrough pain were derived from the homecare medical records and
      patient interviews. MAIN RESEARCH VARIABLES: Analgesic medications prescribed and
      used for treatment of routine and breakthrough cancer pain. FINDINGS: Results
      demonstrate discrepancy between recommended pain management in clinical practice
      guidelines and the actual practice of pain management at home. Deficiencies were
      found in medications prescribed as well as in actual use by patients.
      CONCLUSIONS: Optimum relief of cancer pain is contingent on adequate treatment of
      routine and breakthrough pain, including greater use of recommended analgesics in
      adequate doses and clinical care consistent with clinical practice guidelines.
      IMPLICATIONS FOR NURSING PRACTICE: Breakthrough pain is a common problem
      affecting the quality of life of patients with cancer. Improved management of
      breakthrough pain is contingent on accurate pain assessment, optimum use of
      analgesics, and patient education. Nurses should address the important topic of
      breakthrough pain as new analgesic drugs and methods of delivery become
      available.

PMID- 10573683
TI  - The influence of daytime inactivity and nighttime restlessness on cancer-related
      fatigue.
AB  - PURPOSE/OBJECTIVES: To identify indicators involving circadian activity/rest
      cycles associated with higher levels of cancer-related fatigue (CRF) during the
      first three chemotherapy cycles after surgery for stage I/II breast cancer.
      DESIGN: Prospective, descriptive, repeated measures. SETTING: Midwestern oncology
      clinics and subjects' homes. SAMPLE: 72 women, ages 33-69 and free of unstable
      chronic illnesses, entered the study. Complete data were obtained from 30-47
      subjects at each time. METHODS: CRF was measured using the Piper Fatigue Scale at
      the start and midpoint of each chemotherapy cycle. Circadian activity/rest
      indicators were obtained using Mini-Motionlogger wrist actigraphs for 96 hours at
      the start of each treatment and for 72 hours at the midpoint of each chemotherapy
      cycle. MAIN RESEARCH VARIABLES: Fatigue and circadian activity/rest indicators.
      FINDINGS: Women who were less active and had increased night awakenings reported
      higher CRF levels at all three cycle midpoints, with the strongest association
      being number of night awakenings. During the third chemotherapy cycle, women who
      were less active during the day, took more naps, and spent more time resting
      during a 24-hour period experienced higher CRF. CONCLUSIONS: Women whose sleep is
      disrupted at cycle midpoints are at risk for CRF. The cumulative effects of less
      daytime activity, more daytime sleep, and night awakenings are associated with
      higher CRF levels. IMPLICATIONS FOR NURSING PRACTICE: Assessment of CRF and night
      awakenings at the midpoints of each chemotherapy cycle and development of nursing
      interventions to promote daytime activity and nighttime rest are key to managing
      fatigue and preventing loss of biologic rhythmicity.

PMID- 10573684
TI  - A multidisciplinary healthcare delivery model for women with breast cancer:
      patient satisfaction and physical and psychosocial adjustment.
AB  - PURPOSE/OBJECTIVES: To compare satisfaction with health and healthcare and
      physical and psychosocial adjustment of women who received their medical-oncology
      consultation in the hospital with that of women who received their consultation
      as part of a multidisciplinary outpatient clinic. DESIGN: Descriptive,
      correlational. SETTING: A large tertiary medical center in the Midwestern United
      States. SAMPLE: 55 of 66 women with newly diagnosed breast cancer who received
      their medical-oncology consult in the hospital and 66 of 102 women with newly
      diagnosed breast cancer who received their consult in the multidisciplinary
      outpatient clinic. Median participant age was 62 years in the hospital
      consultation group and 61 years in the outpatient group. METHODS: Participants
      completed the Cancer Rehabilitation Evaluation System-Short Form and a researcher
      designed satisfaction questionnaire. MAIN RESEARCH VARIABLES: Satisfaction with
      care and physical and psychosocial adjustment. FINDINGS: Women in the
      multidisciplinary outpatient clinic group reported significantly higher levels of
      physical function (p = 0.003) and satisfaction with their health (p < 0.01),
      physician (p < 0.001), and nursing care (p = 0.004) than women in the hospital
      group. CONCLUSIONS: This study demonstrated the positive benefits of a
      multidisciplinary team approach in which a concerted effort is placed on
      providing information and psychosocial support in the outpatient clinic setting.
      IMPLICATIONS FOR NURSING PRACTICE: These findings point to the benefits of
      establishing a multidisciplinary clinic in the outpatient setting.

PMID- 10573685
TI  - Nurses' attitudes toward death and caring for dying patients.
AB  - PURPOSE/OBJECTIVES: To examine possible relationships among the demographic
      variables of nurses and their attitudes toward death and caring for dying
      patients. DESIGN: Descriptive. SETTING: A private hospital and Visiting Nurses
      Association office in an ethnically diverse metropolitan area in the Midwest.
      SAMPLE: 403 nurses, predominantly female (90%) and Caucasian (70%), with a mean
      age of 41.8 years. METHODS: Participants completed the Frommelt Attitude Toward
      Care of the Dying Scale, the Death Attitude Profile-Revised (DAP-R), and a
      demographic questionnaire. MAIN RESEARCH VARIABLES: Attitudes toward death and
      caring for dying people. FINDINGS: DAP-R scores were related to sex, religious
      affiliation, and current contact with terminally ill patients. Frommelt scale
      scores (e.g., showing acceptance of death) were positively related to current
      contact with dying patients, negatively correlated with two DAP-R subscales (Fear
      of Death and Death Avoidance), and positively correlated with two other DAP-R
      subscales (Approach Acceptance and Neutral Acceptance). CONCLUSIONS: Nurses'
      attitudes toward death and their current contact with terminally ill patients
      were predictive of their attitudes toward caring for terminally ill patients.
      IMPLICATIONS FOR NURSING PRACTICE: Professionals who are responsible for
      designing educational programs focused on nurses' attitudes toward caring for
      terminally ill patients may want to include an assessment of death attitudes and
      interventions aimed at decreasing negative attitudes and increasing positive
      attitudes toward death in such programs.

PMID- 10573686
TI  - Peptide-formation on cysteine-containing peptide scaffolds.
AB  - Monomeric cysteine residues attached to cysteine-containing peptides by disulfide
      bonds can be activated by carbonyldiimidazole. If two monomeric cysteine
      residues, attached to a 'scaffold' peptide Gly-Cys-Glyn-Cys-Glu10, (n = 0, 1, 2,
      3) are activated, they react to form the dipeptide Cys-Cys. in 25-65% yield.
      Similarly, the activation of a cysteine residue attached to the 'scaffold'
      peptide Gly-Cys-Gly-Glu10 in the presence of Arg5 leads to the formation of Cys
      Arg5 in 50% yield. The significance of these results for prebiotic chemistry is
      discussed.

PMID- 10573687
TI  - Silica, alumina and clay catalyzed peptide bond formation: enhanced efficiency of
      alumina catalyst.
AB  - Catalytic efficiencies of clay (hectorite), silica and alumina were tested in
      peptide bond formation reactions of glycine (Gly), alanine (Ala), proline (Pro),
      valine (Val) and leucine (Leu). The reactions were performed as drying/wetting
      (hectorite) and temperature fluctuation (silica and alumina) experiments at 85
      degrees C. The reactivity of amino acids decreased in order Gly > Ala > Pro
      approximately Val approximately Leu. The highest catalytic efficiency was
      observed for alumina, the only catalyst producing oligopeptides in all
      investigated reaction systems. The peptide bond formation on alumina is probably
      catalyzed by the same sites and via similar reaction mechanisms as some alumina
      catalyzed dehydration reactions used in industrial chemistry.

PMID- 10573688
TI  - Mutual amino acid catalysis in salt-induced peptide formation supports this
      mechanism's role in prebiotic peptide evolution.
AB  - The presence of some amino acids and dipeptides under the conditions of the salt
      induced peptide formation reaction (aqueous solution at 85 degrees C, Cu(II) and
      NaCl) has been found to catalyze the formation of homopeptides of other amino
      acids, which are otherwise produced only in traces or not at all by this
      reaction. The condensation of Val, Leu and Lys to form their homodipeptides can
      occur to a considerable extent due to catalytic effects of other amino acids and
      related compounds, among which glycine, histidine, diglycine and diketopiperazine
      exhibit the most remarkable activity. These findings also lead to a modification
      of the table of amino acid sequences preferentially formed by the salt-induced
      peptide formation (SIPF) reaction, previously used for a comparison with the
      sequence preferences in membrane proteins of primitive organisms.

PMID- 10573689
TI  - Relative reactivity of ribosyl 2'-OH vs. 3'-OH in concentrated aqueous solutions
      of phosphoimidazolide activated nucleotides.
AB  - Phosphoimidazolide activated ribomononucleotides (*pN, see structure) are useful
      substrates for the non-enzymatic synthesis of oligonucleotides. In the presence
      of metal ions, aqueous solutions of *pN yield primarily the two internucleotide
      linked (pN2' pN and pN3' pN) and the pyrophosphate-linked (N5' ppN) dimers. Small
      amounts of cyclic dimers and higher oligomers are also produced. In this study
      the relative reactivity of 2'-OH vs. 3'-OH was determined from the ratio of the
      yields of pN2' pN vs. pN3' pN. Experiments were performed at 23 degrees C in the
      range 7.2 < or = pH < or = 8.4 with substrates that differ in nucleobase
      (guanosine (G), cytidine (C), uridine (U), and adenosine (A)) and leaving group
      (imidazole (Im), 2-methylimidazole (2-MeIm) and 2,4-dimethylimidazole (2,4
      diMeIm)). Two metal ions (Mg2+ or Mn2+) were employed as catalysts. The
      conditions used here, i.e. a substrate concentration in the range 0.1 M to 1.0 M
      and metal ion concentration in the range 0.05 M to 0.2 M, favor base-stacking
      interactions. The ratio pN2' pN: pN3' pN = 2'-5': 3'-5' was found independent of
      nucleobase and typically varied between 2 to 3 indicating that the 2'-OH is about
      2 to 3 times more reactive than the 3'-OH. *pN with Im, compared to 2-MeIm and
      2,4-diMeIm leaving group, produce lower yields of internucleotide linked dimers,
      and a higher pN2' pN: pN3' pN ratio. Trends in the data, observed with all three
      leaving groups, suggest an increase in pN2' pN: pN3' pN ratio with decreasing
      substrate concentration (up to 5.47 with 0.051 M ImpG). The observations are in
      accord with earlier studies reporting a relative reactivity 2'-5': 3'-5' = 6 to 9
      obtained with Im as the leaving group, in dilute nucleotide solutions and under
      conditions that disfavor stacking. It is speculated that the concentration
      induced change in the relative reactivity is the result of self-association via
      base-stacking that enhances selectively the proximity of the 3'-OH of one
      molecule to the reactive P-N bond of an other molecule. The implication of these
      conclusions for oligomerization/ligation reactions is discussed.

PMID- 10573690
TI  - Carboxylic and dicarboxylic acids extracted from crushed magnesium oxide single
      crystals.
AB  - Carboxylic and dicarboxylic acids (glycolic, oxalic, malonic and succinic) have
      been extracted with tetrahydrofuran (THF) and H2O from large synthetic MgO
      crystals, crushed to a medium fine powder. The extracts were characterized by
      infrared spectroscopy and 1H-NMR. The THF extracts were derivatized with tert
      butyldimethylsilyl (t-BDMS) for GC-MS analysis. A single crystal separated from
      the extract was used for an x-ray structure analysis, giving the monoclinic unit
      cell, space group P21/c with ao = 5.543 A, bo = 8.845 A, co = 5.086 A, and beta =
      91.9 degrees, consistent with beta-succinic acid, HOOC(CH2)COOH. The amount of
      extracted acids is estimated to be of the order of 0.1 to 0.5 mg g-1 MgO. The MgO
      crystals from which these organic acids were extracted grew from the 2860 degrees
      C hot melt, saturated with CO/CO2 and H2O, thereby incorporating small amounts of
      the gaseous components to form a solid solution (ss) with MgO. Upon cooling, the
      ss becomes supersaturated, causing solute carbon and other solute species to
      segregate not only to the surface but also internally, to dislocations and
      subgrain boundaries. The organic acids extracted from the MgO crystals after
      crushing appear to derive from these segregated solutes that formed C-C, C-H and
      C-O bonds along dislocations and other defects in the MgO structure, leading to
      entities that can generically be described as (HxCyOz)n-. The processes
      underlying the formation of these precursors are fundamental in nature and
      expected to be operational in any minerals, preferentially those with dense
      structures, that crystallized in H2O-CO2-laden environments. This opens the
      possibility that common magmatic and metamorphic rocks when weathering at the
      surface of a tectonically active planet like Earth may be an important source of
      abiogenically formed complex organic compounds.

PMID- 10573691
TI  - Prebiotic formation of ADP and ATP from AMP, calcium phosphates and cyanate in
      aqueous solution.
AB  - Adenosine-5'-triphosphate was synthesized by the phosphorylation of adenosine-5'
      diphosphate in aqueous solution containing cyanate as a condensing reagent and
      insoluble calcium phosphate produced from phosphate and calcium chloride. In a
      similar manner, adenosine-5'-diphosphate was synthesized from adenosine-5'
      monophosphate. When the experiment was carried out in the conditions of 4 degrees
      C and pH 5.75, the formation of adenosine-5'-diphosphate and adenosine-5'
      triphosphate from adenosine-5'-monophosphate was observed in the yields of 19 and
      7%, respectively. The other nucleoside-5'-triphosphates were also produced from
      their respective diphosphates.

PMID- 10573693
TI  - [HLA-G: a tolerance molecule implicated in the escape of tumors from
      immunosurveillance].
AB  - To define rational anti-tumor immunotherapy strategies, the reasons for the
      frequent lack of efficacy of the immune response to developing tumors must be
      elucidated. One hypothesis involves expression by tumor cells of molecules with
      local immuno-suppressive effects. HLA-G is known to be involved in tolerance of
      the fetus by the maternal immune system. We studied HLA-G expression in primary
      and metastatic melanomas (ex vivo biopsies and cell lines). We found a high level
      of HLA-G transcription and expression at the surface of the cells. A variety of
      patterns of HLA-G isoform transcription and protein expression were seen. The
      ability of HLA-G to inhibit the cytotoxic effect of two immunocompetent cell
      types involved in the antitumor response, namely natural killer cells (NK) and T
      cells, suggests that HLA-G may help tumors evade the immune system.

PMID- 10573692
TI  - Survival of life on asteroids, comets and other small bodies.
AB  - The ability of living organisms to survive on the smaller bodies in our solar
      system is examined. The three most significant sterilizing effects include
      ionizing radiation, prolonged extreme vacuum, and relentless thermal
      inactivation. Each could be effectively lethal, and even more so in combination,
      if organisms at some time resided in the surfaces of airless small bodies located
      near or in the inner solar system. Deep within volatile-rich bodies, certain
      environments theoretically might provide protection of dormant organisms against
      these sterilizing factors. Sterility of surface materials to tens or hundreds of
      centimeters of depth appears inevitable, and to greater depths for bodies which
      have resided for long periods sunward of about 2 A.U.

PMID- 10573694
TI  - [A therapeutic Trojan horse: intracellular antibodies].
AB  - Intracellular immunization is a novel therapeutic approach based on intracellular
      expression of recombinant antibody fragments, either Fab or single chain Fv (scFv
      generated by the assembly of the VH with the VL region), targeted to the desired
      cell compartment (cytosol, nucleus, endoplasmic reticulum ...) using appropriate
      targeting sequences. Due to their exquisite specificity, these intracellular
      antibodies can be used to neutralize or modulate the functional activity of the
      target molecule. Intracellular immunization strategies currently under
      investigation in the field of oncology are directed against mutated oncogenic
      molecules such as ErbB-2, p21ras, and p53, as well as against apoptosis
      inhibiting molecules such as Bcl-2. The first Phase I clinical trials on
      intracellular immunization are under way in the United States.

PMID- 10573695
TI  - [Skin cultures in the treatment of burns].

PMID- 10573696
TI  - [Developing a rational strategy for new antibacterial agents].

PMID- 10573697
TI  - [Contribution of direct bacteriologic examinations to the diagnosis of early
      materno-fetal bacterial infection: the Lille experience].
AB  - A prospective study was conducted in 3056 live-born infants delivered at the
      Jeanneade-Flandre maternity hospital of the Lille Teaching Hospital between
      January and August 1997. Clinical, laboratory test, and microbiological test
      findings were compared. A cohort of 1003 infants who remained in the maternity
      ward but were considered at increased risk of maternofetal infection (MFI) based
      on history and/or obstetrical criteria and/or neonatal criteria underwent routine
      collection of specimens including gastric fluid, auricular and anal swabs,
      amniotic fluid, and placental fragments. Microscopic examination of gastric fluid
      smears, the first result available to the clinician, was found to have 27.5%
      sensitivity (983 samples). Positive predictive value (PPV) was only 17.8% because
      of a high rate of colonization (16.8%), defined as absence of clinical symptoms
      and three peripheral specimens positive for the same organism. However, negative
      predictive value (NPV) was as high as 99.8% as a result of high sensitivity
      (97.8%) in the infected neonates. The gastric fluid smear was positive in 30% and
      35% of neonates born to mothers with hyperpyrexia during early and late labor,
      respectively, and in 42% of neonates born to mothers with a history of group B
      streptococcus carriage during the pregnancy. Forty-two per cent of neonates with
      a history of fetal tachycardia had a positive gastric fluid smear. Diagnostic
      criteria for infection were three peripheral specimens positive for the same
      organism, C-reactive protein elevation, and/or one or more clinical signs
      suggestive of infection, and/or a positive central specimen (blood, CSF). The
      infection rate in infants who remained in the maternity ward was 1.6%. The most
      common causative organisms were group B streptococci. These findings illustrate
      the useful contribution of gastric fluid smears to the early diagnosis of MFI and
      confirm the predominant role of group B streptococci.

PMID- 10573698
TI  - Evaluation of IS6110 as amplification target for direct tuberculosis diagnosis.
AB  - We describe in the present study an evaluation of the IS6110 repetitive element
      in the rapid diagnosis of pulmonary and extrapulmonary tuberculosis by polymerase
      chain reaction (PCR). A pair of oligonucleotide primers was designed to amplify a
      201-bp DNA fragment of IS6110. The amplified DNA was detected by ethidium bromide
      stained agarose gel electrophoresis and confirmed by Sal I digestion and Southern
      blot hybridization with a 32P-labeled probe. To detect the presence of
      amplification inhibitors, an internal control DNA that used the same primers as
      for the target sequence was added to each PCR reaction. PCR results were compared
      with the results of acid fast stained smears, cultures, and clinical data in 102
      sputum and 41 extrapulmonary specimens. With the exception of four samples, M.
      tuberculosis was detected by PCR in all smear- and culture-positive cases and in
      all smear-negative, culture positive cases. Additionally, PCR was able to detect
      6 cases that were smear and culture negative but clinically strongly suspected of
      tuberculosis. The final PCR sensitivity and specificity were 93.1% and 95.18%,
      respectively. One M. tuberculosis strain isolated from a sputum was found to lack
      IS6110. This study shows that (1) PCR diagnosis based on IS6110 reached the best
      sensitivity and specificity but must be considered carefully since some M.
      tuberculosis strains lack IS6110; and (2) PCR must be interpreted in conjunction
      with clinical and radiological data when it is discordant with conventional
      methods results.

PMID- 10573699
TI  - [Immunoblot applied to the diagnosis of congenital toxoplasmosis].
AB  - Western blot was evaluated for the neonatal diagnosis of congenital toxoplasmosis
      based on a comparison of antibody profiles between serum samples obtained from
      the mother at delivery and from the neonate. Passively transferred antibodies can
      be distinguished from antibodies produced by the neonate, thus allowing early
      postdelivery diagnosis of congenital toxoplasmosis before the results of other
      tests are available. This method was developed at the Parasitology-Mycology
      laboratory of the Pitie-Salpetriere Teaching Hospital, Paris, France, then
      evaluated in a retrospective study of 52 mother-infant pairs. The diagnosis of
      congenital toxoplasmosis was ruled out in 34 cases, confirmed in ten cases, and
      doubtful in 8 cases. Sensitivity was higher than with conventional serological
      tests. Antibody profile differences were found between mothers and affected
      infants; these differences usually involved IgGs (8 of 9 cases). Importantly, in
      two cases Western blot would have provided the diagnosis of congenital
      toxoplasmosis two months before the secondary elevation in IgM titers in one case
      and three weeks before the result of mouse placenta inoculation in another case.
      In conclusion, Western blot deserves to be used to complement established methods
      (serology and direct demonstration of the parasite by gene amplification, cell
      cultures, and mouse inoculations) as a means of rapidly (within 24 hours of
      receipt of the specimen) providing clinicians with information relevant to
      treatment decisions.

PMID- 10573700
TI  - [Molecular epidemiology of strains of Staphylococcus aureus resistant to
      methicillin, sensitive to aminoglycosides].
AB  - Twenty methicillin-resistant Staphylococcus aureus (MRSA) isolates surprisingly
      susceptible to all aminoglycosides, macrolides, sulfonamides and tetracycline
      were recovered from 20 elderly patients (mean age, 77) hospitalized in 4
      neighbouring facilities between 1996 and 1998. Molecular typing of the isolates
      performed by restriction fragment length polymorphism of the coagulase gene (PCR
      RFLP) and pulsed-field gel electrophoresis (PFGE) of Sma I macrorestriction
      fragments of total DNA, demonstrated the existence of distinct bacterial clones.
      Epidemic spreading was demonstrated for at least 2 clones, while others were
      responsible for sporadic cases. Most of the isolates of this study appeared to be
      genetically related to strains of MRSA resistant to aminoglycosides and
      macrolides included as controls, suggesting that multiresistant MRSA may have
      evolved recently in a manner that resulted in greater susceptibility to certain
      antibiotics.

PMID- 10573701
TI  - [HLA-C allele recognition using DNA sequencing].
AB  - The HLA-C locus was sequenced in 106 normal unrelated members of the French CEPH
      families. Following generic PCR amplification, exons 2 and 3 were amplified
      separately then sequenced using the ALF Expres sequencer. The Sequi Typer program
      was used for data analysis. Of the 72 alleles identified to date, 20 were
      recognized in the panel studied. Results were compared to those provided by the
      lymphocytotoxicity test, which had a 13.5% error rate and failed to reach the
      level of specific recognition. Sequencing preceded by amplification allowed
      immediate unambiguous allele assignment in 96% of cases. In four cases, a
      complementary method was required to resolve ambiguities. Reproducibility was
      high. The sequencing strategy described herein is a significant advance and may
      be particularly valuable for achieving perfect donor/recipient matching for
      allogeneic stem cell transplants.

PMID- 10573702
TI  - [Impact of methicillin resistance in S. aureus].
AB  - The prevalence of methicillin resistance among Staphylococcus aureus strains and
      the incidence of clinical infections due to methicillin-resistant S. aureus
      (MRSA) are disturbingly high in France. Evaluations of the negative impact of
      methicillin-resistance in S. aureus are needed to establish priorities for
      infection control programs. Whether methicillin resistance independently affects
      the frequency of S. aureus infections remains unclear. It follows that the impact
      of methicillin resistance in terms of morbidity, mortality, economic costs, and
      ecology should be assessed using both infection-free patients and patients
      infected with susceptible strains as controls. There is abundant direct and
      indirect evidence that morbidity related to MRSA is at least as high as that
      related to methicillin-susceptible S. aureus (MSSA). Whether MRSA strains are
      more virulent than MSSA strains is controversial. Serious MRSA infections are
      associated with significant mortality and account for a very large part of the
      overall infection-related mortality rate. Opinion remains divided as to whether
      multiple-drug resistant S. aureus strains are associated with higher mortality
      rates than other S. aureus strains. The economic cost of MRSA infections is huge
      and considerably higher than that of MSSA infections. The heavy glycopeptide use
      related to the high prevalence of MRSA infections has generated problems in the
      management of patients with enterococcal infections and may in the near future
      result in a pandemic of glycopeptide-resistant MRSA infections. The development
      of programs designed to control the clonal dissemination of MRSA strains is a top
      priority from both a medical and an economic viewpoint.

PMID- 10573703
TI  - [New immunosuppressive agents].
AB  - Over the last few years, improved knowledge of the immunological mechanisms
      underlying transplant rejection have resulted in the development of new
      immunosuppressive agents capable of selectively blocking various steps of the
      immune response. It is anticipated that these agents will prove useful in the
      treatment of autoimmune disease and graft-versus-host disease. Neoral is a
      cyclosporin microemulsion characterized by better and more consistent absorption
      as compared to the conventional galenic form. Tacrolimus shares with cyclosporin
      an ability to inhibit calcineurin and may have similar indications. Rapamycin and
      RAD are two related molecules that inhibit signal transduction by cytokines to T
      cells, although they have not yet been proved clinically effective in large
      studies of solid organ transplant recipients. Mycophenolate mofetil selectively
      inhibits purine synthesis and lymphocyte proliferation; it is easy to use and has
      been found effective in a number of autoimmune disorders. Further clinical work
      is needed to determine the therapeutic indications for each of these new drugs.
      Elucidation of their mechanisms of action may help to identify drug combinations
      providing both enhanced efficacy and improved safety.

PMID- 10573704
TI  - [Biliary diffusion of tazocillin in man].
AB  - The objective of this study was to determine the extent of biliary excretion of
      tazocillin, a combination of piperacillin and tazobactam administered as an
      intravenous infusion in a dose of 4 g of piperacillin and 0.5 g of tazobactam. In
      10 patients, piperacillin and tazobactam levels were determined in serum, main
      bile duct bile, gallbladder bile, and gallbladder wall specimens harvested during
      a cholecystectomy procedure 1 h after completion of a tazocillin infusion. In
      five other patients, piperacillin and tazobactam levels were determined in bile
      collected from a main bile duct T-tube during 12 h following a tazocillin
      infusion given seven days after cholecystectomy. HPLC was used to assay both
      compounds. Piperacillin and tazobactam levels in the intraoperative specimens
      were as follows: 69.1 +/- 13.8 and 9.9 +/- 1.7 micrograms/ml, respectively, in
      the serum; 630 +/- 133 and 11.9 +/- 2.2 micrograms/ml, respectively, in the main
      bile duct bile; 342 +/- 114 and 7.7 +/- 2.3 micrograms/ml, respectively, in the
      gallbladder bile; and 49.3 +/- 20.2 and 2.9 +/- 0.6 micrograms/g, respectively,
      in the gallbladder wall. In the T-tube bile specimens, peak piperacillin and
      tazobactam levels were 358 +/- 281 and 9.9 +/- 3.3 micrograms/ml, respectively,
      after 1 h; total biliary excretion over 12 hours was 28.3 +/- 18.0 mg and 1.0 +/-
      0.5 mg, i.e., 0.7 +/- 0.4% and 0.2 +/- 0.1% of the dose, respectively. The levels
      of piperacillin and tazobactam found in bile and gallbladder wall specimens in
      this study suggest that tazocillin may prove valuable for the prevention and
      treatment of biliary infections.

PMID- 10573705
TI  - [Antibiogram Committee of the French Society for Microbiology. Official Statement
      1999].

PMID- 10573706
TI  - Thrombolysis for acute ischemic stroke.
AB  - Data generated from randomized controlled trials in the last decade have shown
      that acute intervention can improve neurologic outcome in patients with ischemic
      stroke. This article reviews recent studies of systemic and intra-arterial
      thrombolysis for cerebrovascular disease in detail. Important considerations for
      treating patients with thrombolysis are explored, and theoretic and practical
      differences in the approach to patients with anterior and posterior circulation
      disease are highlighted.

PMID- 10573707
TI  - The National Institutes of Health Stroke Scale and its importance in acute stroke
      management.
AB  - The National Institutes of Health (NIH) stroke scale is a standardized neurologic
      examination developed to quantitate the patient's deficits in clinical trials for
      new stroke therapies. It is used on admission to determine patient eligibility
      for thrombolytic therapy, throughout the acute hospital stay, and at 3 months to
      assess neurologic recovery. The NIH stroke scale scores correlates with initial
      infarct volume, cerebral perfusion, and functional outcome.

PMID- 10573709
TI  - Acute stroke medical management.
AB  - The average length of hospital stay for acute stroke has been declining gradually
      in the United States. Medical care traditionally given in the acute setting often
      is continued in a rehabilitation unit or skilled nursing facility. This article
      outlines the necessary knowledge base for specialists in rehabilitation regarding
      acute stroke medical care and management.

PMID- 10573708
TI  - Guidelines for acute stroke treatment centers.
AB  - This article provides a description of the clinical infrastructure of a stroke
      center, including staffing requirements, technical capabilities, and recommended
      clinical protocols. These recommendations have been developed to assist in
      establishing new acute stroke centers that can deliver quality care and to aid in
      evaluating the relative strengths and weaknesses of existing stroke centers.

PMID- 10573710
TI  - Stroke prevention.
AB  - This article reviews the causes of stroke and emphasizes the underlying vascular
      pathology. The risk factors associated with the pathologic processes are
      examined, with emphasis on the beneficial impact on stroke risk through the risk
      factor modification. Risk factor modification is a powerful tool in stroke
      prevention and can lead to a marked decrease in the burden of stroke. The
      majority of strokes could be eliminated with an organized prevention strategy.

PMID- 10573711
TI  - Management of stroke risk factors during the process of rehabilitation. Secondary
      stroke prevention.
AB  - Epidemiologic and prospective cohort studies have shown a strong correlation
      between risk factors and stroke morbidity and mortality. The reduction or control
      of risk factors, on the other hand, can reduce stroke morbidity and mortality.
      Rehabilitation professionals involved in comprehensive rehabilitation of stroke
      patients may include the management of risk factors in the scope of their
      practice and thus contribute to longer life expectancy and improved quality of
      life of these patients. Decreasing disability, improving quality of life, and
      prolonging life are chief goals of the rehabilitation process. This article
      reviews the rationale for risk management and stresses the value of aerobic and
      conditioning exercises and is intended to supplement the article on stroke
      prevention co-authored by Daryl Gress and Vineeta Singh.

PMID- 10573712
TI  - The prevention and management of complications after stroke.
AB  - Medical, neurologic, and psychiatric complications can interfere with optimal
      recovery after stroke and increase the cost of care. Ideally, preventing these
      complications would be the best and most cost-effective treatment. This article
      reviews the clinical implications and management strategies for venous
      thromboembolism, spasticity, and depression after stroke.

PMID- 10573713
TI  - Stroke recovery. Lessons from functional MR imaging and other methods of human
      brain mapping.
AB  - The mechanisms underlying patient recovery after stroke remain incompletely
      understood. Human brain mapping methods such as functional MR imaging provide
      insights into stroke recovery mechanisms. After a unilateral brain insult,
      lasting changes take place in both hemispheres and along the rim of a cortical
      infarct. Such information may be of value in the design of therapies targeting
      stroke recovery.

PMID- 10573714
TI  - Stroke. Neurologic and functional recovery the Copenhagen Stroke Study.
AB  - Neurologic and functional recovery is dependent on a large variety of factors
      such as initial stroke severity, body temperature and blood glucose in the acute
      phase of stroke, stroke in progression, and treatment and rehabilitation on a
      dedicated stroke unit. The most important factor for recovery remains the initial
      severity of the stroke. In unselected patients 19% of the strokes are very
      severe, 14% are severe, 26% are moderate, and 41% are mild. In survivors,
      neurologic impairment after completed rehabilitation is still severe or very
      severe in 11%, moderate in 11%, mild in 47%, and 31% have achieved normal
      neurologic function. The ability to perform basic activities of daily living
      initially is reduced in three out of four patients with stroke. Most often
      affected is the ability to transfer, dress, and walk. After completed
      rehabilitation the group with moderate and severe disability is reduced from 50%
      to 25%, and the group with mild or no disability is increased from 50% to 75%.
      The prognosis of patients with mild or moderate stroke generally is excellent.
      Patients with severe stroke have a very variable recovery. Although the prognosis
      of patients with the most severe stroke is generally poor, one third of the
      survivors in this group are able to be discharged back to their own homes with no
      or only mild disability, if rehabilitated on a dedicated stroke unit. Functional
      recovery generally was completed within 3 months of stroke onset. Patients with
      mild stroke, however, recover within 2 months, patients with moderate stroke
      within 3 months, patients with severe stroke within 4 months, and patients with
      the most severe strokes have their functional recovery within 5 months from
      onset. Functional recovery is preceded by neurologic recovery by a mean of 2
      weeks.

PMID- 10573715
TI  - Aphasia management considered in the context of the World Health Organization
      model of disablements.
AB  - Approaches to the management of individuals with aphasia are numerous,
      heterogeneous, and individualized. Treatment varies with the unique constellation
      of symptoms, goals, and residual abilities of each patient. This article
      considers aphasia management within the context of the World Health Organization
      model of disablements.

PMID- 10573716
TI  - Advances in the management of dysphagia caused by stroke.
AB  - This article reviews the advancements that have occurred, primarily in the last
      decade, in the management and treatment of swallowing disorders related to
      stroke. An overview of swallowing physiology is given, and interventions, both
      indirect and direct, are explored. Expanding knowledge, applying techniques from
      other scientific disciplines, and developing new technologies provide hope for
      stroke patients who experience dysphagia.

PMID- 10573717
TI  - Impact of Health Care Financing Administration changes on stroke rehabilitation.
AB  - This article reviews the early influences of Medicare on the delivery of
      rehabilitation services, and discusses the changes in payment for hospital-based
      rehabilitation in the 1997 Balanced Budget Act. Among these changes is a
      prospective payment system for rehabilitation hospitals and units. This article
      also addresses Health Care Financing Administration's efforts to comply with this
      portion of the Act. Finally, some of the impacts that might result from these
      payment policies are discussed.

PMID- 10573718
TI  - Status of functional outcomes for stroke survivors.
AB  - In the past, it has taken several years to accumulate a sufficient number of
      subjects in the community-based studies to arrive at generalized conclusions.
      With an ongoing database, such as resides at CFAR-UDSMR, it is possible to
      collect a large number of cases within a relatively short period of time.
      Further, it is relatively easy to perform continuous monitoring in order to
      determine trends that may be occurring as a result of the changing scenes in
      health care delivery. It has been possible to uncover patterns of scoring the
      functional status of patients that reveal a consistent picture of an underlying
      biology of disability and predictable characteristics in patients' courses
      through the rehabilitation process. Newer analytic methods have allowed one to
      predict expected recovery patterns. This new information will allow one to better
      measure and manage outcomes, to improve the quality of care, to improve cost
      effectiveness, and to better manage financial risk. These are the tools necessary
      for clinicians to incorporate into practice, as expectations with respect to
      outcomes and reimbursement for health care are changing. All of the marks
      associated with FIM and UDSMR belong to the Uniform Data System for Medical
      Rehabilitation, a division of UB Foundation Activities, Inc.

PMID- 10573719
TI  - Returning to life. Stroke survivor community and Internet resources.
AB  - Returning to the community can be as traumatic an experience to the stroke
      survivor as experiencing the stroke itself. Smoothing the transition between the
      hospital and home can be accomplished through many support services and
      organizations offered through the community. This article explores the many
      resources readily available to the stroke survivor.

PMID- 10573720
TI  - [Mammary cancerology and gynecology. 35th Congress of the American Society of
      Clinical Oncology (ASCO) Atlanta (United States), May 1999].

PMID- 10573721
TI  - [Minocylcine: Hyde or Jekyl?].

PMID- 10573722
TI  - [Bimonthly 5-fluorouracil in elderly patients with metastatic colorectal cancer.
      Study of 50 patients].
AB  - PURPOSE: Recent advances in the management of colorectal cancer have improved the
      quality of life and the survival of patients treated with chemotherapy. In order
      to define the contribution of chemotherapy in elderly patients, we studied the
      tolerance and the efficacy of first-line chemotherapy in patients with metastatic
      colorectal cancer. METHODS: Patients aged over 75 years received, as outpatient
      therapy, a bimonthly 48 h leucovorin and fluorouracil regimen. Evaluation was
      assessed every six cycles (i.e., three months). RESULTS: Fifty patients were
      studied: 28 males and 22 females, aged between 75 to 87 years, 37 with colon
      cancer and 13 with rectal cancer. Among 45 patients capable of being evaluated,
      the response rate was 44%, with six complete responses (13%) and 14 partial
      responses (31%). Eighteen patients had stable disease (40%) and seven patients
      progressive disease (16%). Median progression-free survival was 8.8 months and
      median survival 16.4 months. Grade 3 to 4 toxicity occurred in 20% of the
      patients. Performance status improved in 56% of the patients. CONCLUSION: The
      bimonthly regimen is well tolerated in elderly patients and appears to prolong
      survival as well in younger patients.

PMID- 10573723
TI  - [Systemic reaction induced my minocycline treatment: a report of four patients
      and a review of the literature].
AB  - We report four cases of the side effects of minocycline seen during the last two
      years in our department. There was one case of drug-related lupus and three cases
      of hypersensitivity reactions, including one eosinophilic pneumopathy with
      pericarditis, one nephropathy and one severe, pseudo-infectious episode of high
      fever, rash, lympadenopathy, hepatitis and eosinophilia. Minocycline is a
      tetracycline agent widely used for acne therapy in France and all over the world.
      During the last few years, there has been an increasing number of reports
      concerning systemic adverse reactions to minocycline, with on the one hand auto
      immune disorders (lupus, autoimmune hepatitis, vascularitis with ANCA), occurring
      after a prolonged course of therapy and reported recently in the last few years,
      and on the other hand, hypersensitivity reactions (eosinophilic pneumopathies,
      hepatitis, nephropathies, myocarditis, serum sickness or pseudo-infectious
      reactions), occurring precociously in the course of therapy, and potentially
      severe. Although these side effects are uncommon in the context of the high
      number of patients who have been prescribed the drug, the first-line antibiotic
      therapy in acne must probably be reconsidered.

PMID- 10573724
TI  - [Pathology of large vessel vasculitides].
AB  - INTRODUCTION: Vasculitides can be classified according to the size of the
      involved vessels. The pathological patterns of large vessel vasculitides are
      presented here. CURRENT KNOWLEDGE AND KEY POINTS: They concern Buerger's disease,
      temporal arteritis, Takayasu's disease, Behcet's disease, infectious arteritides,
      rheumatologic and miscellaneous diseases. Buerger's disease is a thrombotic
      arteriopathy with no arterial wall involvement. Temporal arteritis and Takayasu's
      disease belong to the group of giant cell arteritides. In temporal arteritis, the
      inflammation is prominent in the internal part of the media and is aggressive for
      the arterial wall. In Takayasu's disease, the external part of the media is
      prominently involved. The fibrous thickening of the arterial wall with stenosis
      is characteristic. Behcet's disease can involve the large arteries with a risk of
      arterial rupture. Infectious arteritides are not unfrequent in vascular surgery
      and in previous arterial lesions. Rheumatologic diseases can result in aortitis
      with aortic incompetence. FUTURE PROSPECTS AND PROJECTS: These diseases have
      pathological characteristics which contribute to diagnosis. However, a clearcut
      classification of vasculitides will come from the precise knowledge of their
      etiology.

PMID- 10573726
TI  - [Neurologic complications of chemotherapy].
AB  - INTRODUCTION: Neurotoxicity can be induced by the synergistic or additive effects
      of cytotoxic treatments, and nervous system exposure is related to routes and
      doses. CURRENT KNOWLEDGE AND KEY POINTS: The improvements in treating systemic
      malignancy have been accompanied by reports of neurologic toxicity, which has an
      important impact on the quality of life and may even limit the use of the
      treatment. PERSPECTIVES AND FUTURE PROJECTS: It demands out a continuous clinical
      evaluation to detect their appearance. When neurological complications are
      diagnosed later, they are rarely reversible. Neuroprotective agents are still
      being evaluated.

PMID- 10573725
TI  - [Infections associated with pets].
AB  - INTRODUCTION: Domestic pets can transmit numerous infections, including
      bacterial, parasitic, fungal, and viral diseases. This paper reports the
      epidemiologic, clinical, therapeutic and prophylactic data of these zoonoses.
      CURRENT KNOWLEDGE AND KEY POINTS: The routes of transmission are various. Bites
      and scratches are the most common health hazards and result in localized
      infections. Pasteurellosis, various aerobic and anaerobic infections, and cat
      scratch disease are predominant. Bites are treated by cleaning the wound, rabies
      and tetanus prophylaxis, and the appropriate use of antibiotics. Other infections
      are transmitted through cutaneous, mucous, digestive or respiratory routes, by
      direct contact with the pets, excreta, or by arthropods. The most common are
      gastrointestinal (campylobacter, salmonella, yersinia, parasites, etc),
      dermatologic (dermatophytoses, scabies, cutaneous larva migraines, etc.),
      respiratory (psittacosis, etc.), and multisystemic (toxoplasmosis, toxocariasis,
      leishmaniosis). Certain people are at high risk for diverse diseases: small
      children (toxocariasis, helminthiasis), pregnant women (toxoplasmosis), and
      immunodeficient patients (cryptosporidiosis, salmonellosis, systemic
      pasteurellosis). These infectious diseases can be partly prevented by avoiding
      contact with diseased animals, and by washing the hands following exposure to
      pets or pet-derived excreta. Specific vaccines for humans and pets, as well as
      worming pets regularly, form an important part of the prevention. Veterinarians
      must discourage the keeping of wild or exotic animals as pets. FUTURE PROSPECTS
      AND PROJECTS: National health survey institutions and new communication systems
      can improve our knowledge about the real epidemiology of pet-transmitted
      zoonoses.

PMID- 10573727
TI  - [Treatment of chronic postinfectious fatigue: randomized double-blind study of
      two doses of sulbutiamine (400-600 mg/day) versus placebo].
AB  - PURPOSE: Chronic fatigue remains a medical mystery and a therapeutic failure. The
      subgroup of chronic fatigue postinfectious fatigue (CPIF) is an interesting one
      since it is quite frequent in general practice. METHODS: We studied sulbutiamine
      (Su), isobutyryl-thiamine disulfide in this context. We included 326 general
      practice patients suffering from CPIF: they received randomly either Su, 400 mg
      daily (n = 106), or Su, 600 mg daily (n = 111), or placebo (n = 109) for 28 days
      in a double-blind, parallel-group study. 315 patients completed the study.
      RESULTS: The evaluation of fatigue, by multiple means including mainly MFI, a
      validated multidimensional fatigue scale, showed overall no significant
      difference between the groups. On the 7th day, however, women receiving Su, 600
      mg had less fatigue (P < 0.01), but the figures were quite diverse and no
      persistent effect was noted at the 28th day. CONCLUSION: Thus, we showed for the
      first time that a high level general-practice study of fatigue is feasible using
      specific tools. Whether the effect observed after 1 week in women represents a
      true finding needs additional research. Further studies are in progress in order
      to characterize better the potential usefulness of Su in chronic fatigue.

PMID- 10573728
TI  - [Muscle infarction. An unknown complication of diabetes mellitus].
AB  - INTRODUCTION: Diabetic muscle infarction (MI) is a rare and little-known
      complication of diabetes mellitus. CASE REPORT: We report a case of relapsing MI
      in which magnetic resonance imaging (MRI) suggested the diagnosis. A 53-year-old
      man with multi-complicated type II diabetes mellitus was admitted to our unit for
      illness and deep tumefaction of the right thigh. Because of unconclusive MRI, a
      muscular biopsy of the lesion was performed and MI confirmed. Three months after,
      a left relapse of MI occurred. Immediate treatment with immobilization and
      heparinotherapy permitted a rapid recovery. CONCLUSION: About 70 previously
      reported cases are reviewed. The mean age at presentation was about 40 years. MI
      was usually seen in patients with long-standing diabetes with multiple end organ
      microvascular complications. Homo- or heterolateral recurrences are reported in
      almost half of the patients. MRI is the best imaging technique for suggesting the
      diagnosis.

PMID- 10573729
TI  - [Lymphocytic colitis and Gougerot-Sjogren syndrome. Report of two cases].
AB  - INTRODUCTION: Microscopic colitis describes a subset of patients with chronic
      watery diarrhea of unknown origin, and normal endoscopic findings and microscopic
      evidence of an inflammatory infiltrate in the colonic mucosa. We report two cases
      associated with sicca syndrome. EXEGESIS: A 56-year-old woman and a 76-year-old
      man presented with a history of lymphocytic colitis associated with sicca
      syndrome. Drugs or infectious agents were not implicated in the cause of
      lymphocytic colitis, suggesting that sicca syndrome may be involved in the
      pathogenesis of microscopic colitis. CONCLUSION: These cases suggest that sicca
      syndrome should be detected in patients with lymphocytic colitis.

PMID- 10573730
TI  - [Respiratory syncytial virus pneumonia in four immunocompromised adults].
AB  - INTRODUCTION: In hematologic malignancies, respiratory syncytial viral infections
      can be explained by neutropenia, and cellular and humoral immunodepression, and
      may cause severe respiratory infections. EXEGESIS: Four patients with hematologic
      malignancies developed a severe respiratory syncytial virus infection. Three of
      them had previously received autologous bone marrow transplantation (ABMT).
      Progress was favorable for three patients. One patient died of acute respiratory
      failure. CONCLUSION: When such patients present with respiratory symptoms,
      especially during the winter months, they should be screened for RSV.
      Bronchoalveolar lavage allowed quick and accurate diagnosis by
      immunofluorescence. Treatment with nebulized ribavirin is controversial. Its use
      may be interesting in patients with high-risk factors (intensive chemotherapy,
      ABMT, diffuse pneumonia with hypoxemia).

PMID- 10573731
TI  - [Autoimmune hepatitis and lupus syndrome associated with minocycline].
AB  - INTRODUCTION: Among several adverse effects following treatment with minocycline,
      certain cases of autoimmune hepatitis, associated with lupus erythematosus, have
      been described. The possibility of hepatic damage, although rare, is important to
      keep in mind because of its delicate diagnostic. EXEGESIS: We report one case of
      autoimmune hepatitis following treatment with minocycline for acne, in a 25-year
      old woman. This autoimmune hepatitis was associated with induced lupus syndrome.
      Usual causes of hepatitis were eliminated. Evolution was spontaneously favorable
      upon minocycline treatment interruption, with the disappearance of clinical
      symptoms and normalization of hepatic and immunologic biological values.
      CONCLUSION: The possibility of hepatic damage and lupus syndrome, following
      treatment with minocycline, should be recalled and verified in cases of long-term
      prescription. This observation stresses the difficulties of anamnesis in internal
      medicine. For those who know how to listen cautiously and rigorously, anamnesis
      may prove more helpful than many complementary examinations.

PMID- 10573732
TI  - [Psychoimmunology: a questionable model?].
AB  - INTRODUCTION: The concept of "psychoimmunology" that had long been supported by
      clinical observation and common sense, has acquired a sound scientific basis in
      the last two decades. The discovery of neuro-mediators and cytokines and their
      receptors shared by the central nervous system and the immune system has prompted
      research work using reliable methodologies to study the relationship between a
      'hard' scientific field, such as immunology, and a 'soft' one, such as the
      behavioral sciences. CURRENT KNOWLEDGE AND KEY POINTS: The complexity of the
      studies on stress and immunity lies upon the choice of immunological measurements
      and the development of reproducible stress protocols. Models of stress in
      experimental animals may address acute versus chronic stress, and individual
      versus social stress. In humans, typical situations such as academic exams, and
      care given to patients with dementia, for instance, have been chosen to study
      large groups of subjects. The development of self-questionnaires for a reliable
      evaluation of stress and its consequences has led to more accurate measurements
      of psychosocial events. In animals, acute stress usually drives the immune
      response towards a Th2, grossly 'immunosuppressive,' profile. In humans, acute
      stress associates an endocrine response (characterized by glucocorticoid
      secretion and hyperprolectinemia) with an immunosuppression. Chronic stress is
      more likely to induce a range of effects, depending on the capacity of the
      subject to cope with stress, and on his/her social environment. Among the
      numerous mediators of the hypothalamo-pituitary cascade, Corticotropin Releasing
      Hormone is a key factor in the stress-immunity relationship. Several studies in
      humans have demonstrated the influence of stress on the susceptibility to
      infections (including HIV infection) and on survival in malignant diseases. In
      autoimmune diseases, a high prevalence of depression, as well as a particular
      sensitivity to stressful events, seem to modify the course of conditions such as
      systemic lupus erythematosus, rhumatoid arthritis or Sjogren's disease. The
      relationship between stress and diseases is based on the pathogenic model which
      involves the following chain of events: stressor, reaction to stress, neuro
      endocrine changes, abnormalities of the immune response, and occurrence (or
      aggravation) of a disease. The evolution from health to disease could be
      associated, at least partially, with a 'passive' immunosuppressive mode of
      response, mediated by the pituitary-adrenal axis, typically the opposite of an
      'active,' immunostimulant mode of response, mediated by adrenergic stimulation.
      FUTURE PROSPECTS AND PROJECTS: Concept-related problems still remain to be
      solved: adaptation to stress ('coping'), is both genetically and socially
      mediated; the significance and interpretation of stress-related abnormalities and
      their precise involvement in the pathogenesis of diseases may be ambiguous.
      However, available epidemiological and pathophysiological evidence is currently
      sufficient to allow physicians in their everyday practice to take stress and
      depression into account in order to markedly improve the prognosis of many
      diseases related to immune responses. Prospective studies of neuropsychological
      intervention, using either pharmacologic or behavioral approaches, should be made
      to provide the necessary rational to a psychoimmunological management of
      patients.

PMID- 10573733
TI  - [Hammer, did you say hammer?].

PMID- 10573734
TI  - [Interstitial pneumopathy induced by fluoxetine].

PMID- 10573735
TI  - [Pneumocystis pneumonia complicated by infectious mononucleosis: an infrequent
      association].

PMID- 10573736
TI  - [Aspiration pneumonia from Pasteurella multocida].

PMID- 10573737
TI  - [Anatomy of thoracic outlet syndrome].

PMID- 10573738
TI  - [Clinical aspects of thoracic outlet syndrome].

PMID- 10573739
TI  - [Tridimensional scanner in thoracic outlet syndrome].

PMID- 10573740
TI  - [Exploration of the thoracic outlet syndrome: contribution of MRI].

PMID- 10573741
TI  - [Thoracic outlet syndromes: the viewpoint of the rheumatologist].

PMID- 10573742
TI  - [Thoracic outlet syndromes: the viewpoint of the angiologist].

PMID- 10573743
TI  - [Neurophysiological explorations of thoracic outlet syndrome].

PMID- 10573744
TI  - [Rehabilitation in thoracic outlet syndrome].

PMID- 10573745
TI  - [Criticisms of the Peet gymnastics. Proposal of a new exercise program for the
      patient].

PMID- 10573746
TI  - [Surgery of thoracic outlet syndromes].

PMID- 10573747
TI  - [Scientific and ethical in vivo human experimentation].

PMID- 10573748
TI  - [Non-small-cell bronchial cancers: long-term survival after single drug
      chemotherapy with vinorelbine].
AB  - We studied a cohort of 120 patients with inoperable non-small-cell lung cancer
      treated with vinorelbin at the dose of 25-30 mg/m2/week in a single drug
      chemotherapy regimen. Surgery was contraindicated due to staging or to
      concomitant morbidity. Twenty patients survived 18 months or more. One survivor
      responded exceptionally, surviving 120 months. The mean dose intensity of
      Vinorelbine in long-term survivors was 21 mg/m2/week. Objective response was
      found at multivariate analysis to be a prognostic factor for survival beyond 18
      months. Weight loss (< 5 kg) was an unfavorable prognostic factor in patients
      with metastases.

PMID- 10573749
TI  - [Computerized tomography imaging of round atelectasis. Study of a series of 21
      patients].
AB  - AIM: To show and compare to literature CT findings in round atelectasis. MATERIAL
      AND METHODS: It is a retrospective review of the clinical and radiological files
      of 21 patients (17 men; 4 women; Mean age: 62), having asbestos exposure (6/21)
      or pleural history (13/21) and in whom the diagnosis of round atelectasis was
      performed from 1988 to 1998. This diagnosis was based on the presence of the
      classical radiological triad: round mass abutting to pleurae, converging
      bronchovascular markings and pleural thickening adjacent to the mass associated
      at a one year follow up or three years radiological and clinical follow up or the
      association with three minors radiological signs. RESULTS: The 25 round
      atelectasis, 4 bilateral, were localized in the lower lobes (22/25) or upper
      lobes (3/25) at right (17/25) or left (8/25) side. Minor signs were found as in
      literature as followed: air bronchograms and centrally indistinct margin (25/25,
      diffused pleural thickening or pleural plaques (19/25), acute angles with the
      pleura (18/25), fissures displacement (18/25), main stem bronchus displacement
      (13/25), calcifications within the plaque (10/25), calcifications within the mass
      (10/25). A mean of 6.7 signs was found for each lesion. CONCLUSION: More than the
      major signs of round atelectasis the air bronchogram, the centrally indistinct
      margin and the presence of one sign of retraction were very frequent. The mean
      number of signs was 6.7 for every lesion.

PMID- 10573750
TI  - [Mediastinitis caused by Klebsiella pneumoniae with a pharyngeal portal].
AB  - We report a case of Klebsiella pneumoniae medisatinitis secondary to a
      retrophyarygeal abscess in a 40-year-old patient. The patient was treated with
      antibiotics and pleural drainage. Surgery was not necessary and the clinical
      course was favorable. We recall the pathophysiological and clinical aspects of
      this now uncommon condition and discuss the prognosis and therapeutic options.

PMID- 10573751
TI  - [Diagnostic imaging of tracheobronchial tuberculosis. Apropos of a case].
AB  - We report a new case of tracheo-bronchial tuberculosis. Diagnosis was suggested
      on CT examination first and then confirmed by endoscopy and bacteriological
      examinations. We discuss the possible mechanisms of stenosis. We present the
      radiological features of tracheo-bronchial tuberculosis, mainly helical CT
      features and we discuss and illustrate differential diagnosis. We emphasize the
      role of 3 D and multiplanar reconstructed CT images that may help visualizing the
      stenosis at different levels, its craniocaudal extent as well as the boundaries
      between the stenosis and surrounding tissues. Moreover helical CT appears
      superior to bronchofibroscopy in diagnosing peribronchial infiltration.

PMID- 10573752
TI  - [Unusual diagnosis of cavitating pulmonary opacity].
AB  - The authors reported a case of Hodgkin disease with excavated lung localisation
      discovered during a systematic detection in the occupational medicine framework.
      This observation raised the differential diagnosis problems mainly with
      tuberculosis in endemic countries.

PMID- 10573753
TI  - [Small-cell bronchogenic cancer one year after excision of 2 synchronous non
      small-cell bronchogenic cancers].

PMID- 10573754
TI  - [Severe acute asthma in the emergency room: amelioration of decreased peak flow
      rate is interpreted with difficulty].
AB  - We report a severe acute asthma case whose course was marked by persistent
      hypoxemia whereas proximal flows were normalized. This discordance reveals a
      ventilation/perfusion mismatch. This data suggests that care must be taken in
      interpreting the peak flow improvement during acute severe asthma management.

PMID- 10573755
TI  - [The Cleopatra project].

PMID- 10573756
TI  - Epidemiology of complementary and alternative practices in rheumatology.
AB  - The increasing prevalence of complementary and alternative medicine usage by the
      general population and rheumatic patients worldwide is reviewed. The many
      potential concerns about this type of therapy are addressed, ranging from
      toxicity issues to changes in behavioral attitudes. Finally, the authors
      speculate on some major socioeconomic outcomes associated with these therapies.

PMID- 10573757
TI  - Quackery: the National Council Against Health Fraud perspective.
AB  - Quackery is the promotion of false and unproven health schemes for a profit. It
      is rooted in the traditions of marketplace. Scientific thinking and standards of
      conduct underlie professionalism and consumer protection law. At the present
      time, commercialism has overwhelmed professionalism in the marketing of
      alternative remedies. Neither patients nor legitimate businesses that adhere to
      the standards of science and consumer protection are well served by a double
      standard.

PMID- 10573758
TI  - Talking with patients about alternative and complementary medicine.
AB  - The growing use of alternative and complementary therapies in the United States
      as well as other parts of the world is a trend that the responsible
      rheumatologist cannot ignore. With chronic musculoskeletal conditions being the
      leading indication for the use of alternative and complementary therapies,
      rheumatologists must become experts on talking to patients and advising them
      about the use or avoidance of such therapies. Currently, there is a growing body
      of literature on the safety and efficacy of the multiple alternative and
      complementary therapies available. Much of this information is reliable and of
      high methologic quality; however, much of it is not. With an increase in the
      budget of the Office of Alternative Medicine from $20 to $50 million in 1999 and
      the status of the office changing to an independent center, an important step has
      been taken to try to assure improved research in the near future to validate or
      disprove many of the current alternative and complementary therapies. In the
      meantime, our patients are using these therapies and are likely to continue to do
      so, with or without our guidance. We must get beyond the "don't ask, don't tell"
      approach that characterizes many physicians' attitudes toward the subject of
      alternative and complementary therapies. Although all discussions need not end in
      agreement, they are still opportunities for shared decision making and
      "relationship-centered care." Ultimately, we should not be concerned with
      practicing what is perceived to be traditional versus alternative and
      complementary medicine or biomedicine versus naturalistic medicine but only with
      what is truly "good" medicine.

PMID- 10573759
TI  - Why I would want to use complementary and alternative therapy: a patient's
      perspective.
AB  - People are increasingly turning to complementary therapy as an adjunct to
      traditional care, but a large percentage do not share that information with their
      physician. People with rheumatic disease use alternative and complementary
      therapies for many reasons, and they use a wide variety of therapies. Chronic
      diseases are among the most difficult to treat with traditional Western
      medications that attack symptoms, while more alternative and complementary
      therapies offer relief through other means. Everyone involved--medical doctor,
      patient, and complementary practitioner--needs to know about the entire treatment
      regimen and handle it with the patient's overall, long-term health and quality of
      life in mind. Organizations such as the Arthritis Foundation and professional
      holistic groups can partner to increase knowledge and further enhance quality of
      life for people with rheumatic disease.

PMID- 10573760
TI  - Why I would not recommend complementary or alternative therapies: a physician's
      perspective.
AB  - The use of complementary or alternative therapies by patients with rheumatic
      diseases is widespread and under-reported by patient to physician. The most
      commonly used forms of therapy are herbal/nutrient supplements, chiropractic,
      homeopathy, and acupuncture. The use of these therapies for treatment of
      rheumatic disease is not substantiated by review of the available medical
      literature. Furthermore, these therapies are expensive and potentially toxic.
      Incorporation of these treatments into the therapeutic armamentarium of the
      rheumatologist cannot be recommended until they are shown to be effective, safe,
      and affordable.

PMID- 10573761
TI  - Why I would recommend complementary or alternative therapies: a physician's
      perspective.
AB  - The successes of science and technology have created new health challenges. The
      use of various complementary therapies by patients reflects a response to one of
      those challenges, which is the need we all have to tell our stories, find
      meaning, and seek healing relationships. Although several alternative medical
      systems are conceptually incompatible with conventional medicine, the therapeutic
      modalities associated with them can be evaluated by standard clinical
      investigative approaches. These approaches, however, are intrinsically more
      difficult to apply in some cases because of the nature of objectivity and
      reductionism in complex, relationship-centered therapy, and because it is hard to
      study something that, by design, works slowly, mildly, and individually.

PMID- 10573762
TI  - Hope helps: placebos and alternative medicine in rheumatology.
AB  - Most clinicians recognize that emphatic listening is not always enough for
      patients and that many are comforted by a more tangible sign of help. Pills
      provide a comforting ritual, and although words should be more important than
      pills, placebos, rightly given, remind physicians and nurses that we are treating
      human beings even as they reassure patients that doctors are more than vending
      machines of techniques. For the physician, there should be no split between
      mainstream and complementary alternatives, for the benefits of empathy and
      communication may sometimes prove as great as those from pills and portions.

PMID- 10573763
TI  - Antibiotics for the treatment of rheumatologic syndromes.
AB  - Design of rational therapy depends on knowledge of the causes of the disease,
      which is knowledge often lacking in rheumatology. There have been theories of
      infectious causes of many rheumatologic diseases but no proof. The seductive
      possibility of an infectious etiology has led to the use of antibiotics for
      treating these diseases. This article reviews the effectiveness of antibiotics
      against rheumatologic syndromes, including rheumatoid arthritis and Lyme disease.

PMID- 10573764
TI  - The role of spa therapy in various rheumatic diseases.
AB  - Spa therapy seems to have a role in the treatment of a broad range of joint
      diseases. It cannot substitute for conventional therapy but can complement it.
      The improvement reported in some of the studies is of short duration, lasting for
      months. It should be considered for patients suffering from various types of
      inflammatory arthritides or noninflammatory arthritides who are symptomatic,
      despite accepted medical therapy and conservative physiotherapy, if they can
      afford the expense. The patients should be told that the effectiveness and
      success of this therapy cannot be predicted in advance. Because we have no way to
      date, of curing most rheumatic diseases, clinical trials of alternative
      therapeutic methods are justified. These methods may alleviate patient suffering
      and are almost totally devoid of serious adverse effects. No studies have been
      reported that evaluate their cost-effectiveness.

PMID- 10573765
TI  - Topical agents in the treatment of rheumatic disorders.
AB  - Topical drug delivery may be the optimal route for the treatment of localized
      musculoskeletal disorders because higher drug concentrations can be achieved at
      the sites of clinical significance. The rationale for the use of topical
      salicylates and other nonsteroidal anti-inflammatory drugs (NSAIDs) in the
      treatment of soft-tissue rheumatic complaints and osteoarthritis is reviewed.
      Topical capsaicin offers another potentially beneficial therapy for the treatment
      of osteoarthritis of selected joints. Although there are extensive, uncontrolled
      experiences with DMSO that suggests its effectiveness in the treatment of
      musculoskeletal disorders, controlled trials yield conflicting results. The basis
      for the use of physical modalities such as phonophoresis and iontophoresis to
      improve topical drug efficacy is summarized.

PMID- 10573766
TI  - Venoms, copper, and zinc in the treatment of arthritis.
AB  - This article discusses the use of venoms, copper, and zinc in the treatment of
      arthritis. The author examines the history and effectiveness of viper, bee, and
      ant venoms in order to determine whether these natural ingredients in anti
      inflammatory medications help relieve a patient's symptoms. Copper and zinc
      studies may offer therapeutic benefits, but there is still no solid consensus on
      the potential role of these elements in treating arthritis.

PMID- 10573767
TI  - Trace elements in the treatment of rheumatic conditions.
AB  - The role of trace metallic elements (copper, selenium, zinc, gold) in chronic
      inflammatory states is of great interest because many of them are co-factors in
      metabolic processes involving articular tissues and immune system function.
      Deficiencies of several of these have been documented in patients with rheumatoid
      arthritis. Other than for the clinically approved gold compounds, there exists
      only inconsistent evidence for a therapeutic role of trace metallic elements in
      the management of rheumatoid arthritis.

PMID- 10573768
TI  - Diets, dietary supplements, and nutritional therapies in rheumatic diseases.
AB  - Rheumatoid arthritis and many other systemic rheumatic diseases remain illnesses
      of unknown cause for which current therapy is often inadequate. This leads
      patients to seek questionable remedies, prominent among which are dietary
      manipulations. Is there a role for dietary modifications in the routine therapy
      for patients with rheumatic diseases? This article discusses the relationships
      between diets, fasting, elemental nutrition, vitamins, minerals, and foods for
      rheumatic diseases. Known scientific-based evidence for the use, safety, and
      efficacy of diets and dietary-related practices subscribed by patients with
      rheumatic diseases are presented. Studies that link diet with arthritis offer the
      possibility of identifying new therapeutic approaches for selected patients and
      of developing new insights to disease pathogenesis. Dietary therapy for
      arthritis, however, is still being investigated.

PMID- 10573769
TI  - Natural pressure-volume curves and conventional cystometry.
AB  - Conventional cystometry using high non-physiological filling rates creates an
      artificial condition with continuous pressure rise. Controlled Slow Cystometry
      (CSC), using a defined rate-unit calculated after body weight (hour-diuresis
      unit, HD), has enabled systematic studies of bladder reaction to natural filling.
      Physiological filling rate is up to 15 HD. At low physiological filling rate (<
      2.4 HD in cats) the pressure-volume curve is flat. Pressure rise is rate
      dependent, not volume-dependent and can occur at any time during filling, as the
      need of the body to excrete urine at high rate is not coordinated with bladder
      filling. Thus, in an individual cat and human there are numerous variations in
      natural pressure-volume curves.

PMID- 10573771
TI  - Visco-elastic properties of isolated detrusor smooth muscle.
AB  - The generation of force by the contractile apparatus and the modulation of that
      force by the intra- and extracellular matrix are the initial steps in the
      production of bladder wall tension. The biomechanical components contributing to
      the observed rise in bladder wall tension may be studied in isolated detrusor
      tissue and attempts can be made to isolate these. The problem is to determine
      whether clinically observed alterations in detrusor function are due to changes
      in the contractile apparatus or in the surrounding matrix. This review discusses
      the viscoelastic properties of detrusor muscle, concentrates upon the influence
      of bladder outflow obstruction on the mechanical properties of the detrusor in an
      attempt to understand changes in contractile function.

PMID- 10573770
TI  - In vitro responses of detrusor smooth muscle to stretch and relaxation.
AB  - In vitro studies subjecting detrusor smooth muscle to stretch and relaxation
      support the concept that bladder tonus and accommodation result from physical
      properties of the bladder wall and are not dependent upon neural activity. The
      properties of automaticity, hysteresis and length/tension relationships of smooth
      muscle seen clinically and in vivo are also seen in vitro.

PMID- 10573772
TI  - Behaviour of the human bladder during natural filling: the Newcastle experience
      of ambulatory monitoring and conventional artificial filling cystometry.
AB  - Conventional Artificial Filling Cystometry (CMG) is the Gold Standard
      investigation of detrusor function although the findings are limited by the
      constraints of rapid rates of filling with artificial filling media in conditions
      of restricted mobility and the clinical environment. Recent advances in
      technology have allowed the use of ambulatory monitoring (AM) of detrusor
      function during which the bladder fills at natural rates with urine whilst the
      patient is able to exercise and perform normal daily activities outside the
      clinical environment. Comparative studies of CMG and AM in the Department of
      Urology at the Freeman Hospital, Newcastle-upon-Tyne in recent years have shown
      interesting differences in the results obtained between the techniques. During AM
      the bladder pressure rise on filling is seen to be lower and associated with a
      greater incidence of spontaneous phasic detrusor activity than during CMG, whilst
      detrusor contraction pressures during the voiding phase following natural
      filling, are generally seen to be higher than during CMG. Several groups of
      patients, including men with neuropathic bladder disorder, chronic retention of
      urine and bladder outflow obstruction together with a group of asymptomatic
      healthy volunteers have been studied and the results presented.

PMID- 10573773
TI  - Blood supply to the bladder during filling.
AB  - Amongst other features of bladder physiology, the mechanics of cyclic filling and
      emptying make the blood supply of the bladder unique with respect to other organs
      of the body. Blood vessels are required to lengthen and shorten, whilst
      maintaining sufficient perfusion of the smooth muscle. Interruption of the blood
      supply may result in ischaemia and, ultimately reperfusion, resulting in bladder
      pathologies. The blood flow is also likely to be affected by factors such as
      increased intra-abdominal pressure. In this article, several features of the
      blood supply to the bladder- and also the urethra--are discussed.

PMID- 10573774
TI  - Structural changes in the rat bladder after acute outlet obstruction.
AB  - The urinary bladder of adult female rats was subjected to complete outlet
      obstruction for periods of up to 24 h. Within 2 h the obstruction led to a rise
      in intravesical pressure to about 80 mmH2O. Subsequently, the pressure remained
      high but declined slightly. After 24 h of complete obstruction the bladder was
      maximally distended, but its volume was similar to that of a control bladder
      fully distended, indicating that overstretch (or overdistension) occurs only to a
      very limited degree. After 6 h of obstruction there was congestion of all the
      intramural blood vessels and extravasation of red blood cells from some vessels
      of the mucosa. At 12 h and 24 h the extravasation was very substantial and there
      was also infiltration of erythrocytes in the muscle layer. Ultrastructurally,
      there were several damaged nerve endings (but no changes in the nerve trunks)
      and, occasionally, damaged muscle cells. Removal of the obstruction after 24 h
      was followed by resorption of the extravasate, partly by phagocytosis by muscle
      cells, a process which lasted 4-6 days, and by 7 days damaged varicosities and
      muscle cells became uncommon. We conclude that the changes observed in the
      bladder wall following complete obstruction are caused more by haemorrhage and
      ischaemia than by overstretch and that the changes are reversed when outlet
      conditions are normalized.

PMID- 10573775
TI  - Roles of the lamina propria and the detrusor in tension transfer during bladder
      filling.
AB  - In this study, structural changes within the lamina propria and detrusor layers
      were analysed during development as a function of bladder filling. Second-, third
      and full-term foetal bovine bladders were filled to 0%, 25%, 50%, 75% and 100%
      of their total capacity and snap frozen. The bladders were analysed
      histochemically and the relative thicknesses of the lamina propria and detrusor
      were measured. In all gestational stages examined, the total thickness of the
      bladder wall decreased during bladder filling. The lamina propria of the full
      term bladder thinned at a consistently faster rate than did the detrusor. The
      lamina propria of second and third trimester bladders followed the same thinning
      pattern, except when the bladders were filled from 25% to 50% of their
      capacities. At these gestational stages, the detrusor thinned at a faster rate
      than the lamina propria. Our results demonstrate that the detrusor layer carries
      tension only during a specific portion of the filling cycle and only during the
      second and third trimesters. We conclude that the lamina propria acts as the
      capacitance layer, while the detrusor functions as the "limiting" or "girding"
      layer to prevent over-distension of the bladder wall.

PMID- 10573776
TI  - Myosin light chain phosphorylation at resting level and the composition of myosin
      isoforms in the bladder body and urethra.
AB  - Bladder filling depends upon the coordinated control of a storage chamber, the
      bladder body, and its outlet, the bladder base and urethra. Bladder emptying
      results from development of force in the bladder body and relaxation of the
      outlet. Muscle strips from bladder body reveal phasic characteristics, whereas
      the strips from urethral wall are tonic. To determine whether the compositions of
      myosin heavy chain (MHC) isoforms and the level of myosin light chain (MLC)
      phosphorylation contribute to the regional variation in the contractile states of
      the bladder smooth muscle, we analyzed the levels of MLC phosphorylation and the
      expression of myosin isoforms in smooth muscle tissues from different regions of
      the urinary bladder. Strips of bladder from the dome, mid body, base of the
      bladder and urethra were removed and analyzed for the levels of MLC
      phosphorylation at the resting tone. The expression of MHC isoforms that differ
      in the C-terminus (SM1 and SM2) and in the N-terminal region (SM-A and SM-B),
      formed by alternative splicing of the pre-mRNA at either the 3' end or the 5'
      end, respectively, was analyzed. The expression of these isoforms was
      characterized at the mRNA and protein levels using reverse transcriptase
      polymerase chain reaction (RT-PCR), SDS-PAGE, and Western blotting. The levels of
      MLC phosphorylation were 35.5 +/- 4.6, 24.7 +/- 2.2, 13.6 +/- 2.1, and 12.8 +/-
      2.7 for dome, mid bladder body, base and urethra respectively. Almost 100% of the
      MHC mRNA in the dome, mid bladder body, and base contains a 7-amino acid insert
      near the ATP-binding region, whereas the MHC in the urethral smooth muscle is
      only 81% inserted. Prior studies have shown that inserted myosin has a two-fold
      higher actin-activated ATPase activity compared to the myosin isoform that lacks
      the insert, and the maximum velocity of shortening of smooth muscle containing
      this insert is high compared to muscle that do not contain the insert. The
      expression of SM1 and SM2 were not significantly different. Our data suggests the
      presence of a high degree of inserted myosin and LC20 phosphorylation in the
      bladder dome and mid-body helps to facilitate rapid force development and
      emptying. Non-inserted myosin and the low level of MLC phosphorylation in the
      urethra may contribute to slowly or non-cycling myosin cross bridges and the
      maintenance of a tonic or contracted state during bladder filling.

PMID- 10573777
TI  - Whole bladder mechanics during filling.
AB  - In addition to molecular and cellular properties, elemental and whole bladder
      properties are important to the function of the bladder during filling. The
      bladder pressure volume filling relation is dependent on all aspects of bladder
      tissue. Elemental mechanics properties include elasticity, viscoelasticity, and
      plastic deformation of bladder tissue. Whole bladder properties include bladder
      shape, mass, and distension. This paper reviews work on mathematical model aimed
      at determining the effect of whole bladder properties on bladder filling
      mechanics and outlines directions for the future.

PMID- 10573778
TI  - Metabolic aspects of urinary bladder filling.
AB  - Urinary bladder compliance allows the bladder to fill to near capacity without a
      large increase in intravesical pressure. Bladder compliance is composed of two
      interrelated factors: passive characteristics of the connective tissue elements
      of the bladder, and active properties of the smooth muscle elements. The tension
      generated by the smooth muscle elements can significantly affect bladder
      compliance. This study utilized an in-vitro whole-bladder model in rabbits to
      determine the effects of hypoxia, alterations in calcium concentrations, and
      muscarinic agonists and antagonists on bladder capacity and compliance. The
      urinary bladder was excised together with a short segment of proximal urethra. A
      catheter was inserted into the bladder via the dome and the urethra was canulated
      with a saline-filled tube. The bladder was mounted in an isolated bath containing
      Tyrode's buffer. The catheter was connected to a pressure transducer to monitor
      the intravesical pressure and connected to a saline-filled i.v. bag. The weight
      of the saline bag was continually monitored. The height of the saline bag was set
      to 80 mmH2O above the baseline intravesical pressure. Bladder filling was started
      by opening the bladder to the saline reservoir. Intravesical pressure, rate of
      pressure increase, rate of volume increase, and maximal volume were digitally
      recorded. The bladder filling was repeated while the whole bladder was subjected
      to hypoxia, high calcium concentration, the presence of EGTA, carbachol, atropine
      and tetrodotoxin, respectively. Results are summarized as follows: (a) control
      bladder filling was biphasic, there was an initial rapid rise in intravesical
      pressure followed by a slower linear rise to the pre-set pressure; (b) hypoxia
      significantly decreased the initial rate of the rise in intravesical pressure,
      increased the rate of bladder filling, and significantly increased final bladder
      volume; (c) incubation of the bladder in the presence of EGTA also significantly
      decreased the initial rate of intravesical pressure rise, increased the rate of
      filling and also significantly increased the final bladder volume; (d) high
      concentrations of calcium increased the initial rate of rise in intravesical
      pressure; (e) carbachol significantly increased the rate of intravesical pressure
      rise, decreased the rate of bladder filling, and significantly decreased final
      bladder volume; (f) atropine and tetrodotoxin (TTX) had no effects on bladder
      filling. In summary, alterations in muscle tone had significant effects on
      bladder capacity and compliance.

PMID- 10573779
TI  - Changes in bladder tone during filling: pharmacological aspects.
AB  - The mechanism by which the bladder maintains a low pressure during filling has
      not yet been established. Myogenic and neural factors have been suggested,
      although their relative importance has not been settled. There is an ongoing
      thoracolumbar sympathetic outflow to the lower urinary tract during filling, and
      noradrenaline, released from adrenergic nerves and acting through stimulation of
      beta-adrenoceptors (beta 2 and beta 3), may relax the bladder, due to a relative
      dominance of beta- over alpha-adrenoceptors in the detrusor. Non-adrenergic, non
      cholinergic mediators, such as nitric oxide and vasoactive intestinal polypeptide
      have been suggested to relax the detrusor during filling; there is no compelling
      evidence to support these proposals. Unidentified relaxant factors may be
      released from the bladder. Their existence and possible importance need to be
      further documented. Although it is widely accepted that there is no sacral
      parasympathetic outflow to the bladder during filling, antimuscarinic drugs
      increase, and anticholinesterase inhibitors decrease bladder capacity, suggesting
      an ongoing acetylcholine (ACh) mediated stimulation of detrusor tone. If this is
      correct, agents inhibiting ACh release should be expected to contribute to
      bladder relaxation during filling. Inhibition of ACh release can be obtained by
      stimulation of various receptors on cholinergic nerves, including alpha 2
      adrenoceptors, receptors for neuropeptide Y and galanin, or by antagonism of
      neuronal 5-HT4 receptors. Whether any of these mechanisms is of importance for
      bladder relaxation during filling, or whether they can be targets for
      pharmacological therapeutic interventions, remains to be established.

PMID- 10573780
TI  - Activation of pelvic afferent nerves from the rat bladder during filling.
AB  - This short paper has reviewed current information on the physiology of bladder
      mechanoreceptors. Afferents in the bladder mucosa appear to be sensitive to
      distension but not to contraction of the viscus, and are also sensitive to the
      chemical composition of the bladder contents. Evidence is provided that suggest
      that Neurokinin A is released from primary afferent endings in the submucosa and
      is involved in both the normal response to distension, and the sensitization
      process. The results suggest that the low threshold mechanoreceptors are
      polymodal, and are modulated by various mediators, including some peptides that
      may originate from the sensory endings themselves, and that these mediators may
      be active during normal filling.

PMID- 10573781
TI  - Definitions of subtypes of enuresis.
AB  - Enuresis is a disease of complex pathogenicity. Most monosymptomatic bedwetters
      have either normal bladder function and capacity and large urine production at
      night-time, or slightly increased micturition frequency during the day, normal
      circadian rhythm and small bladder capacity at night-time. In some studies,
      patients who failed to become dry when using alarm treatment had normal bladder
      function and capacity with large urine production at night. This same group of
      patients showed an excellent response to desmopressin treatment. Recent studies
      have also looked at the possible relationship of natriuresis or calciuria in
      monosymptomatic enuresis. The molecular genetic aspects of enuresis are
      attracting increased attention. Studies have substantiated the involvement of
      numerous loci on certain chromosomes; in excess of 10 chromosomes are thought to
      be involved. Rare enuresis subtypes include night-time natriuretics with or
      without polyuria, calciuria and airway obstruction-induced bedwetting. The role
      of bladder dysfunction in monosymptomatic bedwetting remains undetermined.

PMID- 10573782
TI  - Subtypes in monosymptomatic nocturnal enuresis. II.
AB  - Lasting cure rates in monosymptomatic nocturnal enuresis (MNE), using the alarm,
      imipramine or desmopressin, have been quoted as 43%, 17% and 22%, respectively.
      The low cure rates in addition to the number of different treatments indicate
      insufficient knowledge of MNE. Only research on arginine vasopressin (AVP) levels
      and nocturnal enuresis is unique in attempting to find a group within the MNE
      population that could benefit from substitution therapy with desmopressin. AVP
      levels are restored or amplified during desmopressin treatment. However, low
      nocturnal AVP production with high nocturnal urine output may be indicative of a
      disturbance in circadian rhythm. Pre-clinical data suggest a role for melatonin
      in the regulation of endogenous AVP and in the regulation of the sleep/wake
      cycle.

PMID- 10573783
TI  - IERC strategy for characterising nocturnal enuresis. International Enuresis
      Research Center.

PMID- 10573784
TI  - Locus coeruleus function in enuresis.
AB  - There are four neuronal networks projecting to many areas of the brain. All
      networks relate closely to arousal and sleep function. Among the four networks,
      the noradrenaline projection network, originating from the locus coeruleus (LC),
      is the system most typically responsible for arousal. This study shows that the
      LC is activated by the stimulation of bladder distension only while the patient
      is in deep sleep, not in light sleep. This finding corresponds with the mechanism
      of enuresis type I in our classification of enuresis, based on overnight
      simultaneous monitoring using electroencephalography and cystometry. The
      importance of arousal and sleep systems in the pathogenesis of enuresis is also
      discussed.

PMID- 10573786
TI  - Sleep arousal function in enuretic males.
AB  - Enuretic children are described as difficult to arouse from sleep. This paper
      reports on the clinical implications of auditory sleep arousal thresholds in 15
      enuretic and 18 control subjects (7-12-year-old males). All children were studied
      in a sleep laboratory for four consecutive nights using standard polysomnographic
      recording techniques. Sleep was undisturbed for the first two nights and waking
      thresholds were measured on the following two nights. Enuretic children were
      found to wet most frequently in the first two-thirds of the night. Arousal
      attempts were successful in 39.7% of controls and 9.3% attempts were successful
      in enuretics. The results of this study suggest that enuretic males were more
      difficult to arouse than age-matched controls. The elevated arousal thresholds
      may have been the result of delayed maturation. Therefore, treatment programs
      that rely on awakening should be cognizant of these features.

PMID- 10573785
TI  - Sleep disturbance and bladder dysfunction in enuretic children with treatment
      failure: fact or fiction?
AB  - To document the occurrence of sleep disturbance and bladder dysfunction in
      enuretic children, 25 children (21 boys, 4 girls, mean age 9.9 years) with
      monosymptomatic nocturnal enuresis were studied. All children had significant
      enuretic symptoms (> 4 wet nights per week) which persisted after treatment
      failure. The investigation protocol included cystometry during the day,
      simultaneous polysomnographic and cystometric monitoring during the night and
      recording of diurnal and nocturnal urine output. None of the patients had
      nocturnal polyuria. According to the presence or absence of sleep disturbance
      and/or bladder dysfunction, five different patterns could be recognized. These
      patterns were grouped as having normal and abnormal daytime urodynamics. In
      conclusion, sleep disturbances and bladder dysfunction are common among enuretic
      children, especially those who fail to respond to treatment.

PMID- 10573787
TI  - Enuretic sleep: a polysomnographic study.

PMID- 10573788
TI  - Sleep studies based on electroencephalogram energy analysis.
AB  - Current sleep studies use the manual polysomnographic technique or frequency
      analysis when investigating the mechanisms behind the incomplete transition from
      sleep to consciousness. Ten control subjects and 11 primary monosymptomatic
      enuretics were studied in a sleep laboratory for three consecutive nights (23.00
      07.00 h). The results showed no significant differences in sleeping pattern
      between enuretics and controls. Enuretics spent more time in stage 3 sleep than
      controls on recovery nights, indicating greater depth of sleep. No differences in
      sleep architecture were noted between the groups on baseline nights, although
      enuretics showed a shorter total sleep period than controls on the recovery
      night. Increased delta waves exhibited in the enuretic group are indicative of a
      greater depth of sleep. Moreover, electroencephalogram readings showed an
      impaired arousal in enuretics, which suggests that sleep may be a part of the
      pathology of enuresis.

PMID- 10573789
TI  - Effects of water balance, diet and antidiuretic-hormone administration on the
      renal excretion of water.
AB  - Enuresis is the result of multifactorial processes. Enuretic patients often
      exhibit an abnormal diurnal rhythm of plasma vasopressin in addition to high
      nocturnal urine production. Renal function is considered to be a core factor in
      influencing the volume of fluid delivered to the bladder. Animal studies have
      suggested that the amount of fluid delivered to the bladder is dependent upon the
      state of hydration and/or the amount of protein present in the animal's diet. The
      state of hydration, or diuresis, may also influence the permeability of the
      terminal collecting ducts to water and urea and the hydro-osmotic response of the
      kidney to desmopressin. Multiple agents, including vasopressin, glucagon,
      calcitonin, parathyroid hormone, beta-adrenergic agonist, insulin, angiotensin
      II, prostaglandins and calcium and magnesium ions influence sodium transport in
      the thick ascending limb, indicating that all of these factors may potentially
      play a role in enuresis.

PMID- 10573790
TI  - Pathophysiology and treatment of enuresis in adults.
AB  - Monosymptomatic nocturnal enuresis (MNE) in children is partly the result of
      inadequate reduction in the rate of urine output at night. This nocturnal
      polyuria is due to the lack of a rise in the anti-diuretic hormone, arginine
      vasopressin (AVP), and can be reduced or eliminated by treatment with
      desmopressin at bedtime. Since there is a 1% incidence of MNE among adults, this
      study investigated the circadian pattern of solute and water balance in nine
      young adult enuretics before and during desmopressin therapy and compared the
      results with nine-age- and sex-matched, healthy controls. Before treatment,
      enuretics and controls had similar total fluid intake, urine output, urine
      osmolality, plasma osmolality, plasma total protein, mean arterial pressure and
      plasma AVP. The circadian pattern of fluid intake was also normal in enuretics.
      This abnormality could not be attributed to a deficiency of plasma AVP or an
      increase in solute excretion, since both variables were similar to controls.
      Rather, their nocturnal polyuria appeared to be due to a marked nocturnal
      reduction in renal sensitivity to the antidiuretic effect of vasopressin. In
      seven enuretics, restudied during treatment with desmopressin (10-30 micrograms
      o.d.), circadian urine output was normal and enuresis was absent. These results
      indicate that: (i) The circadian pattern of urine output in healthy adults is
      largely due to a nocturnal decrease in solute excretion rather than a rise in
      plasma AVP; (ii) The subset of adults with persistent MNE also have nocturnal
      polyuria as a result of insensitivity to the antidiuretic action of AVP; (iii)
      These defects can be corrected by treatment with desmopressin.

PMID- 10573792
TI  - Sodium regulating hormones in enuresis.

PMID- 10573791
TI  - Defect of osmoregulatory renal function in nocturnal enuresis.
AB  - Renal function was studied in 62 children with primary nocturnal enuresis (PNE)
      and in 20 healthy children aged 6-15 years. During the night, children with PNE
      exhibited an increase in diuresis, free water reabsorption and solute excretion
      (including sodium and magnesium) in comparison to controls. Intranasal
      administration of Adiuretin-SD (10.5-24.5 micrograms) in the evening reduced
      diuresis and ion excretion to normal levels. During the treatment, 61% of the
      children became completely dry and, in 24% of the children, the number of wet
      nights was reduced by 50%. It is suggested that in the pathogenesis of PNE, the
      decrease in ion reabsorption in the thick ascending Henle's loop--resulting in a
      greater load of tubular fluid in the collecting ducts, an elevation of diuresis
      and increases in free water reabsorption and solute excretion--plays the leading
      role in disturbing renal function. Treatment of PNE with desmopressin is
      pathogenically justified, as it eliminates the principal defect of renal tubular
      function.

PMID- 10573793
TI  - Circadian variation of plasma arginine vasopressin concentration, or arginine
      vasopressin in enuresis.
AB  - The objective of these studies was to determine a relationship between primary
      nocturnal enuresis and arginine vasopressin (AVP) secretion. The first study
      compared 24-h AVP secretion profiles of enuretic (n = 9) and non-enuretic
      children (n = 8). Blood samples were collected at 1-h intervals for 24 h. In the
      second study, nocturnal AVP secretion in group A (n = 40)--with low urinary
      osmotic pressure (UOP) and large nocturnal urine output (NUO)--was compared with
      that in group D (n = 11) with normal UOP and small NUO. Plasma AVP levels were
      measured at 30-min intervals, immediately after falling asleep until 06.00 the
      following morning. The results of the first study showed that the plasma AVP
      level was significantly lower (p < 0.05-0.001) in the enuretic group between
      23.00 and 04.00. The second study showed that group A had significantly lower AVP
      levels (p < 0.05-0.001) than group D throughout the night. The mean AVP level
      during night sleep was 0.64 +/- 0.23 pg/ml in group A and 1.43 +/- 0.66 pg/ml in
      group D. The results of the first study suggest that decreased nocturnal AVP
      secretion is a cause of bedwetting. However, the results of the second study
      suggest that nocturnal enuresis cannot be explained by a decrease in nocturnal
      AVP secretion alone.

PMID- 10573794
TI  - Fluid deprivation in enuresis--effect on urine output and plasma arginine
      vasopressin.
AB  - Desmopressin responders tend to have a large volume of urine production at night,
      in contrast to desmopressin refractory patients who often produce normal volumes
      of urine. Controls and adolescent/adult primary monosymptomatic nocturnal
      enuretics were included in a study measuring urine volume and plasma vasopressin
      levels before and during a 24-hour water deprivation test. The results indicate a
      significantly higher urine production in desmopressin responders when compared
      with controls and non-responders. Before fluid deprivation, only the nocturnal
      polyuric patients showed a urine osmolality significantly lower than that of
      controls and desmopressin non-responders. A significant decrease in the clearance
      of osmols was evident in the desmopressin refractory group from day to night. All
      three groups showed a significant increase in plasma vasopressin during fluid
      deprivation, with polyuric, desmopressin-responding patients showing a lower
      increase that the non-responders and controls. Plasma vasopressin levels were
      normal in adolescent and adult enuretics regardless of their response to
      desmopressin. Moreover, response to fluid deprivation in both polyuric and
      enuretic patients resulted in a significant decrease in urine output from the
      first to the second night.

PMID- 10573795
TI  - Osmoregulation and desmopressin pharmacokinetics in enuretic children.

PMID- 10573796
TI  - A clinical and pharmacological model for explaining response to desmopressin.

PMID- 10573797
TI  - Enuresis treatment in the US.
AB  - A retrospective review of new patients assessed for incontinence at The Center
      for Kidney and Bladder Problems in Children, The Children's Hospital, Greenville,
      South Carolina, USA, was conducted to determine the causes of day and night
      wetting and the treatment outcomes. One hundred and twenty-seven new patients
      were assessed. Invasive, diagnostic studies were carried out to establish a
      diagnosis and determine a treatment protocol in only 28% of patients. Improvement
      was noted in 51% of patients.

PMID- 10573798
TI  - Enuresis treatment in the UK.
AB  - The Enuresis Resource and Information Centre (ERIC) is a UK-based charity that
      works with parents, carers, professionals, and children with nocturnal enuresis
      (NE). The charity has recently commissioned York University's centre for reviews
      and dissemination to undertake a detailed analysis of studies that measure the
      effectiveness of the most common psychological and pharmacological treatments for
      NE. This included reviewing 960 research articles from around the world. The
      resulting review will direct thinking in the UK towards the most effective
      treatment approaches. A brief summary presented at conferences in addition to
      data from ERIC's own clinical practice database shows the distribution and type
      of enuresis clinic currently being run within the UK.

PMID- 10573799
TI  - Enuresis treatment in France.
AB  - The aim of this study was to describe the current management of nocturnal
      enuresis (NE) in France. A survey was carried out among 3803 schoolchildren (5-10
      years of age) and treatments proposed by French experts were also noted. The
      prevalence of NE was 9.2%. Sixty-six percent of mothers of children with moderate
      to severe NE consulted a doctor; 20% of these doctors did not prescribe
      treatment, and the majority offered advice on lifestyle and diet in the first
      instance. The treatments proposed consisted of drugs rather than alarm therapy.
      The opinions of the experts varied widely, indicating a need for a consensus
      about the management of NE in France.

PMID- 10573800
TI  - Desmopressin treatment: current status.
AB  - Desmopressin has a proven pharmacological effect in most enuretic patients,
      although a clinical response is not seen in all patients. Numerous questions
      about the current treatment status of desmopressin include the specific anti
      enuretic effect of desmopressin, the effect of desmopressin on sleep and the use
      of desmopressin as a possible cure for enuresis. The Swedish Enuresis Trial has
      produced some very positive results on the long-term use of desmopressin, showing
      a 61% response rate (> 50% reduction in wet nights). Desmopressin has proven to
      be highly effective when used in combination with other treatments, including the
      alarm and oxybutinin, and after urotherapy. It is suggested that imipramine
      should not be used to treat enuresis unless the patient has attention deficit
      hyperactivity disorder. Bladder instability is also an important factor to
      consider when selecting treatment for enuresis. Bladder dysfunction (detrusor
      overactivity) can be the cause of lack of clinical response to either
      desmopressin or alarm treatment; in such cases, following a cystometrogram,
      patients should be treated with detrusor-relaxing drugs, and urotherapy should be
      considered as the first treatment option. The most effective treatment for
      enuresis is the treatment chosen by the patient and their families. Desmopressin
      and urotherapy have had promising results, with desmopressin acting as a bridge
      until spontaneous or treatment-induced remission occurs.

PMID- 10573801
TI  - Alarm treatment: analyses of response and relapse.
AB  - With focus on relapse, this article reports the results of treating nocturnal
      enuresis (NE) with an alarm. The frequency of wet nights/week was used as an
      indicator for the patients' predisposition for alarm treatment and thus the
      efficiency of the alarm. This article concludes that patients with the highest
      frequency of NE will obtain the best results when treated with an alarm.
      Furthermore, these patients find themselves in a better situation than children
      with lower frequency NE receiving the same treatment.

PMID- 10573802
TI  - Molecular genetics of nocturnal enuresis: linkage to a locus on chromosome 22.
AB  - The aim of this study was to investigate linkage of nocturnal enuresis to a locus
      on chromosome 22 in 35 German families and to analyse associations with the
      clinical phenotype. One hundred and sixty-seven enuretic children aged 5-11 years
      were examined using a somatic, psychiatric and psychological diagnostic protocol;
      a detailed pedigree over three generations was also compiled. Forty-two children
      (mean age: 8.11 years) were selected for further molecular genetic examination.
      EDTA blood samples were taken from the patients and 130 relatives, and
      polymorphisms of the microsatellite markers D22S446, D22S156 and D22S257 on
      chromosome 22 were analysed. Positive linkage was found in 11 families of 14
      children, indicating that 39.3% of families were compatible with linkage to the
      markers on chromosome 22. The phenotype included primary nocturnal enuresis and
      combined day and night wetting. The results for chromosome 22, as with previous
      loci for nocturnal enuresis on chromosomes 8, 12 and 13, support the hypothesis
      for genetic and clinical heterogeneity.

PMID- 10573803
TI  - [The electrosurgical treatment of endometrial cysts in the mare].
AB  - A minimally invasive technique for the removal of endometrial cysts is described.
      Intraluminal cysts hinder the migration of the embryo through the uterus in early
      pregnancy and in a later stage hinder placenta development and hence diminish the
      chance of successful pregnancy. Cysts can also give rise to false-positive
      results in early pregnancy tests. Endometrial cysts located in the lumen can be
      removed surgically from the standing mare. After placement of the endoscope, a
      wire is placed, via the biopsy channel, around the base of cyst, which is then
      cut through by cauterization. The cyst is removed with the help of forceps. Five
      barren mares with multiple cysts were treated in this way during the anoestrous
      period for October to February. Three of these mares became pregnant during the
      next oestrus period.

PMID- 10573805
TI  - [Examination using homeopathy].

PMID- 10573804
TI  - [The ferret. Part 2. Veterinary medical information].
AB  - This series of articles on the ferret provide a practical handout for companion
      animal practitioners. Aspects concerning the housing, nutrition, and reproduction
      of ferrets are briefly described, followed by a more detailed description of
      diagnostic procedures such as blood collection, anaesthesia, small surgical
      procedures, preventive veterinary care, and hospitalization. Frequently seen
      clinical problems with their differential diagnosis are discussed, and the cause,
      clinical symptoms, diagnosis, therapy and, if applicable, prevention and control
      of these disorders are briefly described.

PMID- 10573806
TI  - Clinical assessment of acid-base status. Strong ion difference theory.
AB  - The traditional approach to evaluating acid-base balance uses the Henderson
      Hasselbalch equation to categorize four primary acid-base disturbances:
      respiratory acidosis (increased PCO2), respiratory alkalosis (decreased PCO2),
      metabolic acidosis (decreased extracellular base excess), or metabolic alkalosis
      (increased extracellular base excess). The anion gap is calculated to detect the
      presence of unidentified anions in plasma. This approach works well clinically
      and is recommended for use whenever serum total protein, albumin, and phosphate
      concentrations are approximately normal; however, when their concentrations are
      markedly abnormal, the Henderson-Hasselbalch equation frequently provides
      erroneous conclusions as to the cause of an acid-base disturbance. Moreover, the
      Henderson-Hasselbalch approach is more descriptive than mechanistic. The new
      approach to evaluating acid-base balance uses the simplified strong ion model to
      categorize eight primary acid-base disturbances: respiratory acidosis (increased
      PCO2), respiratory alkalosis (decreased PCO2), strong ion acidosis (decreased
      [SID+]) or strong ion alkalosis (increased [SID+]), nonvolatile buffer ion
      acidosis (increased [ATOT]) or nonvolatile buffer ion alkalosis (decreased
      [ATOT]), and temperature acidosis (increased body temperature) or temperature
      alkalosis (decreased body temperature). The strong ion gap is calculated to
      detect the presence of unidentified anions in plasma. This simplified strong ion
      approach works well clinically and is recommended for use whenever serum total
      protein, albumin, and phosphate concentrations are markedly abnormal. The
      simplified strong ion approach is mechanistic and is therefore well suited for
      describing the cause of any acid-base disturbance. The new approach should
      therefore be valuable in a clinical setting and in research studies investigating
      acid-base balance. The presence of unmeasured strong ions in plasma or serum
      (such as lactate, ketoacids, and uremic anions) is best detected by calculating
      the SIG. The AG, actual bicarbonate concentration, and standard bicarbonate
      concentration all ignore the effects that changes in plasma protein and phosphate
      concentration have on plasma pH, thereby inevitably leading to inaccuracies in
      estimating the unmeasured strong ion concentration in plasma.

PMID- 10573807
TI  - Metabolic acidosis in calves.
AB  - In neonatal calves metabolic acidosis is a common sequela to diarrhea-induced
      dehydration and endotoxemia in the aftermath of gram-negative bacterial
      infections. Without treatment, metabolic acidosis is a prime factor in the death
      of many of these calves. This article begins with a general discussion about the
      causes and recognition of metabolic acidosis. The remaining sections detail the
      subjective and objective methods available to assess the severity of acidosis and
      treatment options for this metabolic condition.

PMID- 10573808
TI  - Oral electrolyte therapy.
AB  - Diarrhea is a common condition in neonatal calves and can be caused by a wide
      variety of infections and noxious agents. Oral electrolyte therapy is a simple
      and economical method of treating diarrheic calves. Oral electrolyte solutions
      can correct dehydration and acidosis, and they may also have a role in preventing
      or alleviating mucosal damage. Indications, the principles of administration, and
      choosing an electrolyte product are discussed with examples.

PMID- 10573809
TI  - Intravenous fluid therapy of calves.
AB  - Dehydration in neonatal calves with diarrhea is a common cause of death. Severely
      dehydrated calves that are unable to suckle need intravenous fluids for effective
      resuscitation. This article gives an overview of the principles of intravenous
      fluid therapy for dehydrated calves including the types of fluids commonly used
      and methods of fluid administration. Practical on-farm options for simple
      clinical assessment and treatment of dehydration and acidosis in calves are also
      discussed in this article.

PMID- 10573810
TI  - A practitioner's views on fluid therapy in calves.
AB  - This article is aimed to persuade most bovine practitioners that FET is a
      therapeutic tool that can easily be used under field conditions, and that by
      following the right protocol, one can provide a cost-effective treatment for the
      farmer, a rewarding experience for us, and a boost for our professional image.
      Based on the excellent current publications, the scheme of work to put FET into
      practice is presented. Controversial decisions must be made (such as oral vs.
      parenteral fluids, removing milk from diet vs. continued feeding, oral fluids
      with bicarbonate vs. those with metabolizable bases, and so forth). Practicality,
      economy, and owner compliance are critical components of a successful protocol.
      This work protocol is based on the current literature, considers controversial
      subjects, such as route of administration, alkalinizing agents, and fasting,
      employs simple yet effective techniques, and is successful in a high percentage
      of cases.

PMID- 10573811
TI  - Fluid therapy in mature cattle.
AB  - Fluid therapy is practical and beneficial when properly administered to cattle.
      Mature cattle are more frequently alkalotic than acidotic, so nonalkalizing
      solutions are usually indicated. Exceptions include cattle with choke,
      carbohydrate engorgement, diabetes mellitus, and occasionally, renal disease,
      diarrhea, and fatty liver/ketosis. Many dehydrated cattle need supplemental
      potassium and calcium as well as sodium, chloride, and water. Intravenous
      administration is indicated in patients with obstructive gastrointestinal disease
      and those with severe dehydration. Oral or intraruminal administration is less
      expensive and, often, very effective.

PMID- 10573812
TI  - Hypertonic saline.
AB  - A key feature in the successful resuscitation of dehydrated or endotoxemic
      ruminants is the total amount of sodium administered. Administration of small
      volumes of HS and HSD offer major advantages over large volumes of isotonic
      saline because HS and HSD do not require intravenous catheterization or periodic
      monitoring, and are therefore suitable for use in the field. Hypertonic saline
      and HSD exert their beneficial effect by rapidly increasing preload and
      transiently decreasing afterload. Contrary to early reports, HS and HSD decrease
      cardiac contractility and do not activate a pulmonary reflex. The osmolality of
      HS and HSD should be 2400 mOsm/L (7.2% NaCl solution, 8 times normal plasma
      osmolality). Use of HS and HSD solutions of different osmolality to 2400 mOsm/L
      should be avoided at all costs, as too low a tonicity removes the main advantages
      of HS (low cost, decreased infusion time), whereas too high a tonicity may cause
      rapid vasodilation and decreased cardiac contractility, resulting in death. Rapid
      administration (> 1 mL/kg-1/min-1) of HS (2400 mOsm/L) should be avoided, as the
      induced hypotension may be fatal when coupled with a transient decrease in
      cardiac contractility. For treating dehydrated adult ruminants, HS (2400 mOsm/L,
      4-5 mL/kg i.v. over 4-5 minutes) should be administered through the jugular vein
      and the cow allowed to drink water. This means that 2 L of HS should be
      administered to adult cattle. HSD should be administered in conjunction with
      isotonic oral electrolyte solutions to all calves 8% or more dehydrated (eyes
      recessed > or = 4 mm into the orbit, cervical skin tent duration > 6 seconds) or
      calves with reduced cardiac output (fetlock temperature < 29 degrees C when
      housed at 10-24 degrees C). For treating dehydrated calves, HSD (2400 mOsm/L NaCl
      in 6% dextran-70, 4-5 mL/kg i.v. over 4-5 minutes) should be administered through
      the jugular vein and the calf allowed to suckle an isotonic oral electrolyte
      solution. This means that 120-200 mL of HSD of HSD should be administered to a
      calf. HSD should be routinely administered to severely depressed or comatose
      calves, as HSD provides the fastest method of resuscitation while rapidly
      reversing the effects of hyperkalemia.

PMID- 10573813
TI  - Treatment of sodium balance disorders. Water intoxication and salt toxicity.
AB  - Electrolyte disorders are commonly identified in food animal medicine. Some of
      these electrolyte disturbances require that the veterinarian be aware of the
      potential for causing harm during routine fluid therapy. Hyponatremia (water
      intoxication) and hypernatremia (salt toxicity) are two such disorders. Both
      create osmolar disturbances that effect changes in the brain's osmolar state.
      During fluid resuscitation it is possible to cause iatrogenic central nervous
      system damage in these cases. It is important to recognize those cases where
      sodium imbalance may complicate routine therapy, understand the underlying
      mechanisms for osmolar changes in the plasma and brain, and know the appropriate
      steps to take for safe correction of the sodium disturbance.

PMID- 10573814
TI  - Treatment of potassium balance disorders.
AB  - Potassium is the predominant intracellular cation and is critical for the
      maintenance of resting cellular membrane potential. Abnormalities of potassium
      balance can manifest as skeletal and cardiac muscle dysfunction. Abnormalities of
      potassium concentration in plasma can result from changes in external potassium
      balance (intake vs. excretion) or internal balance (intracellular to
      extracellular). Hyperkalemia can result from renal failure, uroperitoneum, or
      severe dehydration and acidosis in calves with diarrhea. Hypokalemia occurs due
      to reduced forage intake, when increased gastrointestinal losses occur as with
      diarrhea, due to increased renal losses as with metabolic alkalosis or exogenous
      corticosteroid administration which promote kaliuresis, or with redistribution of
      potassium into the intracellular compartment with alkalosis or in association
      with insulin-mediated glucose uptake. Aggressive intravenous and oral therapy are
      often necessary to correct potassium balance disorders, in addition to therapy
      aimed at correcting any underlying disorder contributing to the potassium
      imbalance.

PMID- 10573815
TI  - Treatment of calcium, phosphorus, and magnesium balance disorders.
AB  - In food animal practice, the majority of the calcium, phosphorus, and magnesium
      balance disorders are due to low blood concentrations of one or more of these
      minerals. The purpose of this article is to review methods that can be used to
      restore normal blood concentrations of these minerals. Low plasma calcium is
      often accompanied by changes in plasma phosphorus and magnesium. Initial
      discussions will consider each mineral separately, followed by pros and cons of
      combined therapies. In all cases the doses of the treatments described in this
      article are those appropriate for the 600-kg cow.

PMID- 10573816
TI  - Use of blood and blood products.
AB  - It is sometimes necessary for the practitioner to transfuse the ruminant with
      whole blood or plasma. These techniques are often difficult to perform in
      practice, are time-consuming, expensive, and stressful to the animal. Acute loss
      of 20% to 25% of the blood volume will result in marked clinical signs of anemia,
      including tachycardia and maniacal behavior. The PCV is only a useful tool with
      which to monitor acute blood loss after intravascular equilibration with other
      fluid compartments has occurred. An acutely developing PCV of 15% or less may
      require transfusion. Chronic anemia with PCV of 7% to 12% can be tolerated
      without transfusion if the animal is not stressed and no further decline in
      erythrocyte mass occurs. Seventy-five percent of transfused bovine erythrocytes
      are destroyed within 48 hours of transfusion. A transfusion rate of 10 to 20
      mL/kg recipient weight is necessary to result in any appreciable increase in PCV.
      A nonpregnant donor can contribute 10 to 15 mL of blood/kg body weight at 2- to 4
      week intervals. Sodium citrate is an effective anticoagulant, but acid citrate
      dextrose should be used if blood is to be stored for more than a few hours. Blood
      should not be stored more than 2 weeks prior to administration. Heparin is an
      unsuitable anticoagulant because the quantity of heparin required for clot-free
      blood collection will lead to coagulation defects in the recipient. Blood cross
      matching is only rarely performed in the ruminant. In field situations, it is
      advisable to inject 200 mL of donor blood into the adult recipient and wait 10
      minutes. If no reaction occurs, the rest of the blood can probably be safely
      administered as long as volume overload problems do not develop. Adverse
      reactions are most commonly seen in very young animals or pregnant cattle. Signs
      of blood or plasma transfusion reaction include hiccoughing, tachycardia,
      tachypnea, sweating, muscle tremors, pruritus, salivation, cough, dyspnea, fever,
      lacrimation, hematuria, hemoglobinuria, collapse, apnea, and opisthotonos.
      Intravenous epinephrine HCl 1:1000 can be administered (0.2 to 0.5 mL)
      intravenously or (4 to 5 mL) intramuscularly (preferable) if clinical signs are
      severe. Pretreatment with antipyretics and slowing the administration rate may
      decrease the febrile response. Blood or plasma administered too rapidly will also
      result in signs of cardiovascular overload, acute heart failure, and pulmonary
      hypertension and edema. Furosemide and slower administration of blood or plasma
      should alleviate this problem. Administration rates have been suggested starting
      from 10 mL/kg/hr; faster rates may be necessary in peracute hemorrhage. Plasma
      should be administered when failure of absorption of passive maternal antibody
      has occurred or when protein-loosing enteropathy or nephropathy results in a
      total protein of less than 3 g/dL or less than 1.5 g albumin/dL. Plasma can be
      stored at household freezer temperatures (-15 to -20 degrees C) for a year;
      coagulation factors will be destroyed after 2 to 4 months when stored in this
      manner. To maintain viability of coagulation factors, plasma must be stored at 
      80 degrees C for less than 12 months. When administering plasma, a blood donor
      set with a built-in filter should always be used. When bovine plasma is thawed,
      precipitants form in the plasma and infusion of these microaggregates may result
      in fatal reactions in the recipient.

PMID- 10573817
TI  - Oral electrolyte replacement solutions.

PMID- 10573818
TI  - Parenteral electrolyte replacement solutions.

PMID- 10573819
TI  - [The role of estradiol metabolites in prevention of cardiovascular diseases by
      hormone substitution in postmenopause].
AB  - Postmenopausal estrogen replacement therapy has shown to reduce cardiovascular
      disease by direct and indirect estradiol-mediated effects on the cardiovascular
      system. Recently, evidence is growing that estradiol metabolites may also have
      beneficial actions. In the present review the existing experimental data for
      vascular effects of estradiol metabolites are summarized. The results of our own
      experiments in addition to those of other groups indicate that estradiol
      metabolites, especially catechol estrogens, exert beneficial effects on the
      vascular system and perhaps may play a physiologic role in the cardiovascular
      system. Reference to clinical-pharmacological aspects for the use of estradiol
      metabolites for prevention and treatment of cardiovascular diseases is presented.

PMID- 10573821
TI  - [Breast-saving therapy and primary reconstruction with latissimus dorsi flap
      combined with radiotherapy].
AB  - OBJECTIVE: The use of latissimus-dorsi-flap with postoperative radiotherapy is
      method of choice in primary reconstruction of breast cancer. The efforts of
      radiotherapy on flap healing, cosmetic results and formation of edema in the arm
      were studied in 30 patients. MATERIALS AND METHODS: 30 patients were followed in
      three to six months intervals clinically and sonographically (ATL-Ultramark 9,
      HDI). RESULTS: The most frequent symptom was a moderate edema. No healing
      problems or interference with cosmetic results were observed. Blood flow in the
      thoraco-dorsal vessels showed unchanged pre- and postoperatively. CONCLUSIONS:
      The complains might be the consequence of the combination of surgical dissection
      of the axilla, radiotherapy and possible additional factors such as trauma and
      overstress for example. Cosmetic result and healing seems to be impaired by 50 to
      60 gy.

PMID- 10573820
TI  - [Value of p53, urokinase plasminogen activator, PAI-1 and Ki-67 in vulvar
      carcinoma].
AB  - OBJECTIVE: The present study was to measure new prognostic factors including the
      plasminogen activator urokinase and the plasminogen inhibitor PAI-1, as well as
      p53 and Ki-67, a marker of proliferation and to compare the clinical value of
      these in relation to the classic histopathological prognostic factors. MATERIAL
      AND METHODS: The patient collective included 45 patients with vulvar carcinoma,
      both primary tumors and recurrences. RESULTS: Highly significant correlations
      were found for tumor diameter and thickness. According to Kaplan-Meier
      estimations, the influence of thickness on the prognosis had a p-value of 0.048,
      while the influence of diameter had a p-value of 0.029. The variable grading was
      also significantly associated to the probability of survival (p = 0.01). There
      was no statistically significant correlation between p53 and the parameters
      grading, degree of keratinization and Ki-67 color index. The correlation between
      p53 and PAI-1 as well as between UPA and PAI-1 was highly significant. According
      to the Kaplan-Meier estimations, Ki-67, UPA and PAI-1 had no influence on
      survival in our group of patients. CONCLUSIONS: For p53, the median value could
      be used as a divider with the median survival of patients with a p53 below 122
      pg/mg protein being 151 months and with a p53 above 122 pg/mg being only 61
      months. The corresponding p-value was significant at 0.0201.

PMID- 10573822
TI  - [Value of fetal lung maturity assessment in maternal diabetes].
AB  - OBJECTIVE: Results of antepartal fetal lung maturity (FLM) testing in diabetics
      were compared to control patients. We analysed 274 patients by phospholipid
      profile and 219 by phosphatidylglycerol (PG), consisting of 73, respectively 54
      diabetic and 201, resp. 165 normal control subjects. MATERIAL AND METHODS:
      Phospholipid concentration increased exponentially with gestational age (rreg =
      0.44 for diabetic and 0.57 for normal control patients). There was no significant
      difference between both groups. Measurement of PG showed a trend towards lung
      immaturity in diabetic infants for preterm and term gestations, which did not
      reach significance (chi-square [chi 2] test 0.07, resp. 0.06). RESULTS: Diabetic
      and non-diabetic pregnancies did not differ significantly in FLM and RDS
      frequency. Both methods show a high rate of falsely immature results. Antepartal
      FLM testing by measurement of phospholipids and PG does not play a role in
      clinical management of diabetic patients.

PMID- 10573823
TI  - [Determination of reference ranges and effect of maternal and fetal factors on
      insulin and C-peptide level in umbilical cord blood].
AB  - OBJECTIVE: The risks of pregnancy caused by maternal diabetes are well known.
      Patients with unrecognized gestational diabetes mellitus (GDM) represent a
      special problem. The aim of our study was to find out, whether the determination
      of insulin and C-peptide in cord blood serum offers a valuable tool for
      retrospective analysis. MATERIAL AND METHODS: In 600 paired serum samples from
      maternal venous blood and neonatal cord blood insulin and C-peptide were
      determined radioimmunologically. A reference group consisting of 338 mothers and
      their newborns was established by exclusion of all patients with known pregnancy
      complications. RESULTS: Positive correlations could be identified between fetal
      insulin and fetal C-peptide, as well as correlations of these parameters with
      birth weight and body length, with maternal values of insulin, C-peptide, body
      mass index, weight, and weight gain during pregnancy respectively. Increased
      levels of cord serum insulin were found in complicated pregnancies as well as in
      patients with previous pregnancy losses, preterm deliveries or stillbirths.
      CONCLUSIONS: Cord serum insulin and C-peptide were found to be useful parameters
      for immediate postnatal identification of impaired glucose tolerance during the
      course of pregnancy.

PMID- 10573824
TI  - [Effect of long-term hormone substitution therapy on serum TSH level in
      postmenopausal women].
AB  - OBJECTIVE: Dysfunction's of the thyroid gland are one of the most important
      endocrinological diseases. We report serum TSH levels in postmenopausal women
      before and during long-term hormone replacement therapy. MATERIAL AND METHODS:
      107 postmenopausal patients participated in this study. Criteria for inclusion
      were: no known thyroid dysfunction and request for hormone replacement. Before
      starting therapy TSH serum levels were measured in each patient. If basal levels
      were within normal range TSH serum levels were reported over 4 years of hormone
      replacement therapy. RESULTS: More than 10% of the postmenopausal women showed
      pathological TSH-levels without clinical symptoms requiring further diagnostic.
      During subsequent treatment cycles (4 years) serum TSH in euthyroid patients did
      not show significant changes. Women using hormone replacement therapy developed
      no new manifestation of thyroid disease. CONCLUSION: In euthyroid women using
      long-term hormone replacement therapy are no changes in thyroid function caused
      by hormone replacement therapy to expect.

PMID- 10573825
TI  - The effect of melatonin application on lipid peroxidation during cyclophosphamide
      therapy in female rats.
AB  - OBJECTIVE: Our purpose was to investigate whether melatonin has any protective
      effect against lipid peroxidation induced by cyclophosphamide. MATERIAL AND
      METHODS: We used an animal model to study the effect of melatonin. Fifteen female
      Wistar rats (180-200 gram in weight) were randomly assigned to three different
      groups. Group 1 (n = 5) received saline injections as a control. Group 2 (n = 5)
      received cyclophosphamide. Group 3 (n = 5) received cyclophosphamide + melatonin.
      The animals were sacrificed two hours after cyclophosphamide administration and
      blood samples were taken and used for assaying superoxide dismutase (SOD)
      activity, glutathione peroxidase (GP) activity for the antioxidative enzymes, and
      malondialdehyde (MDA) level as an index of lipid peroxidation. RESULTS: MDA
      levels were more increased in the second group compared with the control group (p
      < 0.01). In the third group, they were significantly lower than in the second
      group (p < 0.05). SOD and GP activities were found to be decreased significantly
      in the second group compared with the control group (p < 0.05 and p < 0.01,
      respectively). They were found to be elevated in the third group compared with
      the second group (p > 0.05 and p < 0.05, respectively). CONCLUSIONS: The above
      results suggest that melatonin has a protective role in cyclophosphamide induced
      lipid peroxidation in rats. Besides scavenging the highly toxic free radicals,
      melatonin also stimulates the antioxidant enzyme activity of GP.

PMID- 10573826
TI  - [Hepatocellular carcinoma as a rare cause of excessive rise in alpha-fetoprotein
      in pregnancy].
AB  - OBJECTIVE: Elevation of alphafetoprotein in pregnancy warrants a thorough
      diagnostic workup. In most cases, no pathologic result in the fetus will be
      obtained. CASE REPORT: A case report is presented on a hepatocellular carcinoma
      (HCC) during pregnancy, in which a massive increase of alpha-fetoprotein (AFP)
      was found during a routine screening for neural tube defects in the 17th week of
      gestation. The amniocentesis revealed a normal AFP value in the amniotic fluid.
      Liver sonography in the 21st week of gestation showed a 5 cm tumor, which was
      interpreted as nodular focal hyperplasia. In the control sonography in the 32nd
      week of gestation, there was a growth to 12 cm. The subsequently performed
      magnetic resonance imaging (MRI) and fine needle aspiration led to the diagnosis
      of a HCC. Delivery was performed in the 34th week of gestation by cesarean
      section followed by surgical therapy of the HCC. CONCLUSIONS: Unexplained cases
      of alphafetoproteinelevation in pregnancy can be caused by maternal disease and
      should prompt a directed amnamnestic and diagnostic search for maternal causes.
      Nuclear magnetic resonance beyond the first trimester of gestation can help to
      clarify the diagnosis in liver tumors.

PMID- 10573827
TI  - [Optimizing performance documentation in gynecology--assistance from the
      internet].
AB  - The documentation of operations in the field of gynecology and obstetrics is
      regulated by social laws in Germany. Only by optimal encoding of diagnoses and
      procedures an efficient cashing with the health insurance's can be achieved. This
      requires profound knowledge of the invoice modalities and usually support by
      computer systems. The Internet offers in this respect some assistance, which in
      the following is pointed out and evaluated critically.

PMID- 10573828
TI  - An approach to an objective background subtraction for elemental mapping with
      core-edges down to 50 eV: description, evaluation and application.
AB  - To image the distribution of a specific element in a specimen with an energy
      filtering TEM, the element-unspecific background under the core-edge has to be
      subtracted. The most commonly used procedure is the three-window power-law method
      leading to considerable systematic errors for low-energy core-edges. Here a new
      method is described which can be considered as a generalized difference method.
      Characteristic examples for element detection in biological specimens using this
      method are shown. The background under the core-edge can be described by one or
      two pre-edge windows as a polynome of third order. This function can be deduced
      from specimen areas that are not known to contain the element or from a second
      specimen used as a standard. Control experiments showed that background
      subtraction for on-overlapping core-edges in the low-loss region (50-200 eV)
      needs two pre-edge images, whereas at higher-energy losses (> 300 eV) only one
      pre-edge image is necessary. With the method described, objective elemental
      mapping becomes possible even for edges at 50-100 eV. This was proven for the
      M2,3-edge of iron at 60 eV. The detection of phosphorous was possible with a
      signal-to-noise ratio five times higher than when using the three-window method.
      Preliminary data showed that it should be possible to detect calcium with only
      one image before the edge.

PMID- 10573829
TI  - 6,7,8,9-Tetrahydro-3-methyl-1H-pyrano-[4,3-b]quinolin-1-one.
AB  - The condensation reaction of 4-amino-6-methyl-2-pyrone with 1
      cyclohexenecarboxaldehyde and a catalytic amount of (S)-(+)-10-camphorsulfonic
      acid in toluene at 358 K gave a 1:2.5 ratio of the title compound, (1)
      (C13H13NO2), and 7,8,9,10-tetrahydro-1H-pyrano[4,3-c]isoquinoline-1-one, (2). The
      formation of (2) presumably proceeds through an intermediate imine. Both (1) and
      (2) show inhibitory activities against acetylcholinesterase and human aldose
      reductase. Of the three linear-fused rings of (1), both ring A and ring B are
      planar and the angle between these planes is 0.46 (13) degrees. While the two C
      atoms of cyclohexane ring C attached to its common atoms with ring B are in the
      plane of the latter, as expected, the remaining two C atoms of ring C are out of
      this plane, by 0.342 (4) and -0.402 (3) A, respectively.

PMID- 10573830
TI  - A boron-containing estrogen mimic.
AB  - A prototype of a new class of 2,3,1-benzodiazaborine-based estrogen mimics is
      described. 1,2-Dihydro-1,6-dihydroxy-2-(2-methoxy-6-pyridyl)-2,3,1-benzodiazabor
      ine, (6), was obtained as a crystalline monohydrate (C13H12BN3O3.H2O) after
      regioselective BBr3-mediated O-demethylation of the condensation product formed
      from 2-formyl-4-methoxybenzeneboronic acid and 2-hydrazino-6-methoxypyridine. As
      intended by design, the solid-state structure of (6) features an intramolecular
      hydrogen-bond association between the donor B--OH group and the acceptor pyridine
      ring N, a connection which constitutes an additional 'virtual' six-membered ring,
      thereby providing for an overall topography closely matching that of a
      tetracyclic steroid. Specifically, prototype (6) can be viewed as a boron
      containing mimic of the O17-methyl ether derivatives of dihydroequilenin or
      estradiol.

PMID- 10573831
TI  - Core elements of developmental epidemiologically based prevention research.
AB  - In the early 1990's, important progress was documented in prevention research on
      mental and behavioral disorders, with recommendations for a prevention research
      agenda. One of the earliest implementation efforts was the workshop, "A
      Scientific Structure for the Emerging Field of Prevention Research," sponsored by
      the National Institute of Mental Health and The Johns Hopkins University
      Prevention Research Center, and held in Baltimore, Maryland, in December of 1994.
      The purpose of the workshop was to merge three perspectives from the
      traditionally disparate areas of epidemiology, life course development, and
      intervention trials technology into an integrated, interdisciplinary effort that
      would define a scientific structure enabling rapid advancement in prevention
      science. As a consequence of that workshop, the papers were written that are
      contained in this and the next special issue on prevention of the American
      Journal of Community Psychology. This first paper is a description of the salient
      features of developmental epidemiologically-based prevention research. Beyond the
      above three perspectives, we discuss the role of developmental and intervention
      theories; measurement of implementation, mediators, and moderators, including
      multi-stage sampling and measurement; the central role of multilevel growth
      modeling; concepts of attributable risk and prevented fraction; proximal/distal
      modeling and effect sizes; and partnerships between researchers and communities.

PMID- 10573832
TI  - Description and immediate impacts of a preventive intervention for conduct
      problems.
AB  - A population-based randomized intervention trial for the prevention of conduct
      problems (i.e., oppositional defiant disorder and conduct disorder) is described.
      The LIFT (Linking the Interests of Families and Teachers) intervention was
      designed for all first- and fifth-grade elementary school boys and girls and
      their families living in at-risk neighborhoods characterized by high rates of
      juvenile delinquency. The 10-week intervention strategy was carefully targeted at
      proximal and malleable antecedents in three social domains that were identified
      by a developmental model of conduct problems. From 12 elementary schools, 671
      first and fifth graders and their families participated either in the theory
      based universal preventive intervention or in a control condition. The
      intervention consisted of parent training, a classroom-based social skills
      program, a playground behavioral program, and systematic communication between
      teachers and parents. A multiple measure assessment strategy was used to evaluate
      participant satisfaction and participation, fidelity of implementation, and the
      immediate impacts of the program on targeted antecedents.

PMID- 10573833
TI  - Pathways of economic influence on adolescent adjustment.
AB  - An important part of a science aimed at the prevention of human dysfunction
      involves the development of empirically based models that identify processes of
      risk for or protection from emotional distress or behavioral problems over time.
      The present study developed and evaluated such a model that proposed two pathways
      through which family economic pressure was expected to influence change in
      adolescent internalizing symptoms (depression and anxiety) during the period from
      the eighth to the tenth grades. A total of 377 rural families in a midwestern
      state provided data for the analyses. The results were generally consistent with
      the conceptual model in that family economic pressure increased adolescent
      perceptions of family economic hardship, which, in turn, reduced the adolescent's
      sense of control or mastery over time. Lowered mastery was associated with
      increases in emotional distress. Also consistent with the model, prior levels of
      mastery appeared to reduce the magnitude of economic stress experienced by the
      adolescent, whereas prior emotional distress intensified the economic stress
      process. Although gender differences were found in these processes, the overall
      pattern of results suggests that girls and boys are both at risk for
      internalizing problems when families experience economic pressure. Implications
      of the findings for the development of effective preventive interventions with
      financially stressed families in rural areas are discussed.

PMID- 10573834
TI  - A developmental approach to prevention research: configural antecedents of early
      parenthood.
AB  - A developmental framework emphasizing the combined impact of correlated
      constraints within and without the individual was applied to a prospective
      longitudinal study of early parenthood. The purpose was to use a person-approach
      to the analysis of longitudinal data to clarify risk for early parenthood and to
      generate hypotheses about potentially useful intervention strategies. Respondents
      were 475 youth who were assessed annually from seventh grade through the end of
      high school and, again, at ages 20 and 24. The risk patterns associated with
      parenthood were the same for both sexes. Individuals with a middle-school
      configuration of low socioeconomic status, high aggression, low academic skills,
      low popularity, and prior grade failure were most likely to become parents by
      early adulthood. Risk for early parenthood increased substantially for
      respondents who dropped out of school early, regardless of their initial risk
      status.

PMID- 10573835
TI  - The application of latent curve analysis to testing developmental theories in
      intervention research.
AB  - The effectiveness of a prevention or intervention program has traditionally been
      assessed using time-specific comparisons of mean levels between the treatment and
      the control groups. However, many times the behavior targeted by the intervention
      is naturally developing over time, and the goal of the treatment is to alter this
      natural or normative developmental trajectory. Examining time-specific mean
      levels can be both limiting and potentially misleading when the behavior of
      interest is developing systematically over time. It is argued here that there are
      both theoretical and statistical advantages associated with recasting
      intervention treatment effects in terms of normative and altered developmental
      trajectories. The recently developed technique of latent curve (LC) analysis is
      reviewed and extended to a true experimental design setting in which subjects are
      randomly assigned to a treatment intervention or a control condition. LC models
      are applied to both artificially generated and real intervention data sets to
      evaluate the efficacy of an intervention program. Not only do the LC models
      provide a more comprehensive understanding of the treatment and control group
      developmental processes compared to more traditional fixed-effects models, but LC
      models have greater statistical power to detect a given treatment effect.
      Finally, the LC models are modified to allow for the computation of specific
      power estimates under a variety of conditions and assumptions that can provide
      much needed information for the planning and design of more powerful but cost
      efficient intervention programs for the future.

PMID- 10573836
TI  - Concepts in imaging and microscopy. Exploring biological structure and function
      with confocal microscopy.
AB  - Confocal microscopy is providing new and exciting opportunities for imaging cell
      structure and physiology in thick biological specimens, in three dimensions, and
      in time. The utility of confocal microscopy relies on its fundamental capacity to
      reject out-of-focus light, thus providing sharp, high-contrast images of cells
      and subcellular structures within thick samples. Computer controlled focusing and
      image-capturing features allow for the collection of through-focus series of
      optical sections that may be used to reconstruct a volume of tissue, yielding
      information on the 3-D structure and relationships of cells. Tissues and cells
      may also be imaged in two or three spatial dimensions over time. The resultant
      digital data, which encode the image, are highly amenable to processing,
      manipulation and quantitative analyses. In conjunction with a growing variety of
      vital fluorescent probes, confocal microscopy is yielding new information about
      the spatiotemporal dynamics of cell morphology and physiology in living tissues
      and organisms. Here we use mammalian brain tissue to illustrate some of the ways
      in which multidimensional confocal fluorescence imaging can enhance studies of
      biological structure and function.

PMID- 10573837
TI  - An endogenous SCP-related peptide modulates ciliary beating in the gills of a
      venerid clam, Mercenaria mercenaria.
AB  - The activities of both the lateral and frontal cilia of Mercenaria mercenaria
      were unaffected, either by the two endogenous SCP-related peptides AMSFYFPRMamide
      and YFAFPRQamide, or by FMRFamide (all at 10(-6) M). Dopamine (DA) inhibited the
      lateral cilia; the mean EC50 was 2 x 10(-6) M. The peptide YFAFPRQamide--but
      neither AMSFYFPRMamide nor FMRFamide--antagonized the inhibition induced by DA;
      this effect was dependent on both time and dose. At a DA concentration of 5 x 10(
      7) M, the effect of YFAFPRQamide appeared within 20 min and became maximal within
      40-60 min; the mean EC50 at these times was 4.7 x 10(-11) M. If the concentration
      of DA was increased to 10(-6) M, the maximal effect of the peptide was delayed to
      50 min, and the mean EC50 increased to 1.1 x 10(-7) M. Particle transport by the
      frontal cilia was inhibited by 5-hydroxytryptamine (5HT); the mean EC50 was 5.7 x
      10(-7) M. Again, only YFAFPRQamide had an antagonistic effect on the 5HT-induced
      inhibition. At a 5HT concentration of 10(-6) M, the effects of YFAFPRQamide did
      not appear until 45 min; the mean EC50 was 10(-6) M. When radioimmunoassayed with
      an SCP antiserum, the elution profile of a gill extract overlapped those of the
      SCP-related peptides that had previously been identified in extracts of whole
      animals. These data suggest that all three SCP analogs occur in the gill.
      Immunohistochemistry of the gill, carried out with a monoclonal antibody raised
      to SCPB, stained many varicose neuronal fibers. Most of these were associated
      with the gill musculature, but a sparse innervation of the filaments underlying
      the cilia was also observed. Some fluorescent nerve cell bodies were also seen in
      the gill tissue. Our results are consistent with the hypothesis that YFAFPRQamide
      modulates branchial activities--muscular as well as ciliary--that are associated
      with feeding.

PMID- 10573838
TI  - Ovigerous-hair stripping substance (OHSS) in an estuarine crab: purification,
      preliminary characterization, and appearance of the activity in the developing
      embryos.
AB  - Ovigerous-hair stripping substance (OHSS) is an active factor in crab hatch water
      (i.e., filtered medium into which zoea larvae have been released). This factor
      participates in stripping off the egg attachment structures (i.e., egg case,
      funiculus, and the coat investing ovigerous hairs) that remain attached to the
      female's ovigerous hairs after larval release. Thus this activity prepares the
      hairs for the next clutch of embryos. OHSS activity of an estuarine crab, Sesarma
      haematocheir, eluted as a single peak on molecular-sieve chromatography, but this
      peak still showed two protein bands at 32 kDa and 30 kDa on SDS-PAGE. The two
      protein bands stained with a polyclonal antiserum raised to the active fractions
      from molecular-sieve chromatography. Moreover, antibodies purified from this
      polyclonal OHSS antiserum also recognized both the 32-kDa and 30-kDa bands. OHSS
      immunoreactivity and biological activity were associated with the attachment
      structures that remained connected to the ovigerous hairs after hatching. In
      developing embryos, both protein bands could be stained immunochemically at least
      10 days before hatching. But OHSS biological activity appeared only 3 days before
      hatching. The immunoreactive protein bands were not observed in the zoea, but
      OHSS bioreactivity was present, though greatly reduced. The 32-kDa protein, at
      least, is probably an active OHSS, and the 30-kDa protein band may also be OHSS
      related. The OHSS appears to be produced and stored by the developing embryo.
      Upon hatching, most of the material may be trapped by the remnant structures, and
      the remainder is released into the ambient water.

PMID- 10573839
TI  - Origin of insulin receptor-like tyrosine kinases in marine sponges.
AB  - One autapomorphic character restricted to all Metazoa including Porifera
      [sponges] is the existence of transmembrane receptor tyrosine kinases (RTKs). In
      this study we screened for molecules from one subfamily within the superfamily of
      the insulin receptors. The subfamily includes the insulin receptors (InsR), the
      insulin-like growth factor I receptors, and the InsR-related receptors--all found
      in vertebrates--as well as the InsR-homolog from Drosophila melanogaster. cDNAs
      encoding putative InsRs were isolated from the hexactinellid sponge
      Aphrocallistes vastus, the demosponge Suberites domuncula, and the calcareous
      sponge Sycon raphanus. Phylogenetic analyses of the catalytic domains of the
      putative RTKs showed that the sponge polypeptides must be grouped with the InsRs.
      The relationships revealed that all sponge sequences fall into one branch of this
      group, whereas related sequences from mammals (human, mouse, and rat), insects
      and molluscs, and polypeptides from one cephalochordate, fall together into a
      second branch. We have concluded that (i) the InsR-like molecules evolved in
      sponges prior to the "Cambrian Explosion" and contributed to the rapid appearance
      of the higher metazoan phyla; (ii) the sponges constitute a monophyletic taxon,
      and (iii) epidermal growth factor (EGF)-like domains are present in sponges,
      which allows the insertion of this domain into potential receptor and matrix
      molecules.

PMID- 10573840
TI  - A new approach for measuring real-time calcium pumping and SR function in muscle
      fibers.

PMID- 10573841
TI  - Responses of retinal Muller cells to neurotransmitter candidates: a comparative
      survey.

PMID- 10573842
TI  - Sharpening of directional auditory input in the descending octaval nucleus of the
      toadfish, Opsanus tau.

PMID- 10573843
TI  - Temperature effects on first-year growth of cultured oyster toadfish, Opsanus
      tau.

PMID- 10573844
TI  - Squid axoplasm supports the retrograde axonal transport of herpes simplex virus.

PMID- 10573845
TI  - Messenger RNAs for kinesins and dynein are located in neural processes.

PMID- 10573846
TI  - Dynamic confocal imaging of interphase and mitotic microtubules in the fission
      yeast, S. pombe.

PMID- 10573847
TI  - Dynamic confocal imaging of mitochondria in swimming Tetrahymena and of
      microtubule poleward flux in Xenopus extract spindles.

PMID- 10573848
TI  - Effects of alpha-bungarotoxin on development of the sea urchin Arbacia
      punctulata.

PMID- 10573849
TI  - Leukotriene B4 as calcium agonist for nuclear envelope breakdown: an
      enzymological survey of endomembranes of mitotic cells.

PMID- 10573850
TI  - Intense concanavalin A staining and apoptosis of peripheral flagellated cells in
      larvae of the marine sponge Microciona prolifera: significance in relation to
      morphogenesis.

PMID- 10573851
TI  - Biosynthesis of tyrosine O-sulfate by cell proteoglycan from the marine sponge,
      Microciona prolifera.

PMID- 10573852
TI  - Substituted cyclodextrin as a model for a squid enzyme that hydrolyzes the nerve
      gas soman.

PMID- 10573853
TI  - Effects of green tea polyphenols on lens photooxidative stress.

PMID- 10573854
TI  - Decline of a horseshoe crab population on Cape Cod.

PMID- 10573855
TI  - The free reducing oligosaccharides of angico branco (Anadenanthera colubrina) gum
      exudate: an aid for structural assignments in the heteropolysaccharide.
AB  - A novel method is described for the determination of sequential side-chain
      structures in the complex, high-arabinose polysaccharide of the gum exudate of
      angico branco (Anadenanthera colubrina), using as basis the structurally similar
      reducing oligosaccharides present in small quantities. Of the ten detected, eight
      were characterized as disaccharides (2, 3, and 9), linear trisaccharides (1 and
      4), branched pentasaccharides (5 and 6), and a doubly branched heptasaccharide
      (8). The oligosaccharides are substituents of the polysaccharide, which has a (1-
      >3)-linked beta-D-galactopyranosyl main chain, and with two exceptions they had 6
      O-substituted galactopyranosyl reducing ends, probably corresponding to its main
      chain units. Characterization was effected through their 1D and 2D NMR
      correlation spectra, which were better resolved and more readily interpretable
      than those of the polysaccharide. These spectral data were supported by
      monosaccharide composition and rotation values. Controlled Smith degradations and
      methylation analyses were carried out when it was necessary. These data were
      confirmed by field-desorption MS.

PMID- 10573856
TI  - Immobilized 4-aminophenyl 1-thio-beta-D-galactofuranoside as a matrix for
      affinity purification of an exo-beta-D-galactofuranosidase.
AB  - An alternative and fast method for the purification of an exo-beta-D
      galactofuranosidase has been developed using a 4-aminophenyl 1-thio-beta-D
      galactofuranoside affinity chromatography system and specific elution with 10 mM
      D-galactono-1,4-lactone in a salt gradient. A concentrated culture medium from
      Penicillium fellutanum was chromatographed on DEAE-Sepharose CL 6B followed by
      chromatography on the affinity column, yielding two separate peaks of enzyme
      activity when elution was performed with 10 mM D-galactono-1,4-lactone in a 100
      500 mM NaCl salt gradient. Both peaks behaved as a single 70 kDa protein, as
      detected by SDS-PAGE. Antibodies elicited against a mixture of the single bands
      excised from the gel were capable of immunoprecipitating 0.2 units out of 0.26
      total units of the enzyme from a crude extract. The glycoprotein nature of the
      exo-beta-D-galactofuranosidase was ascertained through binding to Concanavalin A
      Sepharose as well as by specific reaction with Schiff reagent in Western blots.
      The purified enzyme has an optimum acidic pH (between 3 and 6), and Km and Vmax
      values of 0.311 mM and 17 mumol h-1 microgram-1 respectively, when 4-nitrophenyl
      beta-D-galactofuranoside was employed as the substrate.

PMID- 10573857
TI  - Enzymatic synthesis of alpha-L-fucosyl-N-acetyllactosamines and 3'-O-alpha-L
      fucosyllactose utilizing alpha-L-fucosidases.
AB  - An alpha-L-fucosidase from porcine liver produced alpha-L-Fuc-(1-->2)-beta-D-Gal
      (1-->4)-D-GlcNAc (2'-O-alpha-L-fucosyl-N-acetyllactosamine, 1) together with its
      isomers alpha-L-Fuc-(1-->3)-beta-D-Gal-(1-->4)-D-GlcNAc (2) and alpha-L-Fuc-(1-
      >6)-beta-D-Gal-(1-->4)-D-GlcNAc (3) through a transglycosylation reaction from p
      nitrophenyl alpha-L-fucopyranoside and beta-D-Gal-(1-->4)-D-GlcNAc. The enzyme
      formed the trisaccharides 1-3 in 13% overall yield based on the donor, and in the
      ratio of 40:37:23. In contrast, transglycosylation by Alcaligenes sp. alpha-L
      fucosidase led to the regioselective synthesis of trisaccharides containing a (1-
      >3)-linked alpha-L-fucosyl residue. When beta-D-Gal-(1-->4)-D-GlcNAc and lactose
      were acceptors, the enzyme formed regioselectively compound 2 and alpha-L-Fuc-(1-
      >3)-beta-D-Gal-(1-->4)-D-Glc (3'-O-alpha-L-fucosyllactose, 4), respectively, in
      54 and 34% yields, based on the donor.

PMID- 10573859
TI  - The structure of the specific capsular polysaccharide of Rhodococcus equi
      serotype 4.
AB  - The specific capsular polysaccharide produced by Rhodococcus equi serotype 4 was
      found to be a high-molecular-weight acidic polymer composed of D-glucose, D
      mannose, pyruvic acid and a previously unidentified 5-amino-3,5
      dideoxynonulosonic (rhodaminic) acid in the proportions 2:1:1:1. Structural
      analysis, employing a combination of microanalytical methods, nuclear magnetic
      resonance spectroscopy, and mass spectrometric techniques, established that the
      polysaccharide consisted of linear repeating tetrasaccharide units having the
      sequence of residues shown below. In the native polysaccharide, the rhodaminic
      acid residues were present as their acetamido derivatives (RhoANAc) and carried 1
      carboxyethylidene groups that bridged the O-7 and O-9 positions. Treatment of the
      capsular polysaccharide with dilute acetic acid and/or anhydrous hydrogen
      fluoride under hydrolytic/solvolytic conditions, resulted in the formation of
      four different oligosaccharide species. The 1H and 13C NMR resonances of these
      oligosaccharide fragments and of the native serotype 4 capsular polysaccharides
      were fully assigned by homo- and heteronuclear chemical shift correlation
      methods.

PMID- 10573858
TI  - Structural studies of the O-antigen polysaccharide from the enteroinvasive
      Escherichia coli O173.
AB  - The structure of the O-antigen polysaccharide (PS) from Escherichia coli O173 has
      been investigated. Sugar and methylation analyses, electrospray ionisation mass
      spectrometry together with 1H, 31P and 13C NMR spectroscopy were the main methods
      used. The structure of the pentasaccharide repeating unit of the PS was found to
      be: [formula: see text] By treatment with 48% HF the phosphoric diester linkage
      was cleaved together with the glycosidic linkage of the fucosyl group, rendering
      a tetrasaccharide with the structure: alpha-D-Glcp-(1-->2)-beta-D-Glcp-(1-->3)
      beta-D-GlcpNAc-(1-->3)-D-Glc.

PMID- 10573860
TI  - Structural analysis of three sulfated oligosaccharides isolated from human milk.
AB  - The structures of two sulfated octasaccharides and one sulfated nonasaccharide
      isolated from human milk have been investigated. Using 13C and 1H NMR
      spectroscopy and ESMS, the following structures 1-3 were established: [formula:
      see text].

PMID- 10573861
TI  - The structure of the core part of Proteus vulgaris OX2 lipopolysaccharide.
AB  - The identity of a novel structural component, an open-chain acetalic linkage, in
      the core part of the lipopolysaccharide (LPS) from Proteus vulgaris serotype OX2
      has been determined by extensive NMR spectroscopic analysis of fragments isolated
      after mild acid hydrolysis of the intact LPS. The open-chain N
      acetylgalactosamine fragment is substituted in the 4-position by non
      stoichiometric amounts of a beta-galactopyranose residue and the overall
      structure of the core is as follows: [formula: see text] All sugars except the N
      acetylgalactosamine are in the pyranose form, alpha-Hep refers to L-glycero-alpha
      D-manno-heptopyranose and alpha-DDHep to D-glycero-alpha-D-manno-heptopyranose.
      Bold italics indicate non-stoichiometric substituents.

PMID- 10573862
TI  - Preparation of chitooligosaccharides from chitosan by a complex enzyme.
AB  - Chitosan of 24% degree of acetylation was depolymerized by a mixture of
      cellulase, alpha amylase, and proteinase to give the title oligosaccharides. The
      removal of products by membrane separation permitted yield maximization of
      products having degree of polymerization in the 3-10 range.

PMID- 10573863
TI  - Evolutionary adaptations of cochlear function in Jamaican mormoopid bats.
AB  - Mormoopid bat species have their echolocation system adapted to different hunting
      strategies. To study the corresponding mechanical properties of their inner ear,
      we measured distortion-product otoacoustic emissions to assess cochlear
      sensitivity and tuning. Mormoops blainvillii, Pteronotus macleayii and P.
      quadridens use frequency-modulated echolocation signals, sometimes preceded by a
      short narrowband signal component. Their distortion-product otoacoustic emission
      threshold curves are most sensitive between 30 and 50 kHz and show no adaptation
      to the narrowband echolocation components. In contrast, the constant-frequency
      bat P. parnellii always uses long constant-frequency call components. Its inner
      ear is maximally sensitive at 62 kHz, the echo-frequency of the dominant constant
      frequency component, and pronounced insensitivities at 61 and 93 kHz (CF2 and CF3
      call frequency) are the major evolutionary change in comparison to its relatives.
      Furthermore, in P. parnellii, the optimum cochlear frequency separation is
      minimal at 62 and 93 kHz, associated with enhanced cochlear tuning, while for the
      other mormoopids there is no indication of enhanced tuning. The phylogeny of
      mormoopids, assessed by mitochondrial DNA analysis, shows a close relationship
      between the Pteronotus species. This suggests that major cochlear redesign,
      associated with the acquisition of echolocation-call specific cochlear processing
      in P. parnellii, has occurred within a relatively short evolutionary time scale.

PMID- 10573864
TI  - Tuning breadth and sex-specific sensitivity in chemosensory neurons of male and
      female Uca pugnax.
AB  - Chemosensory neurons of female fiddler crabs (genus Uca) display greater
      sensitivity to mixtures of food-related stimuli than do neurons in males. This
      phenomenon represents an interesting contrast to other sex-specific systems,
      which tend to be in response to cues associated with mating and parental care.
      This study examined the responses of chemosensory neurons in males and females to
      ten individual stimuli to determine if sex-specific responses were restricted to
      a few key compounds, or if the heightened sensitivity of females was broadly
      distributed. Neurons in males and females responded well to all stimuli, and
      although fiddler crabs are primarily herbivorous, highly efficacious
      physiological stimulants included amino acids and amines as well as carbohydrates
      most closely associated with plant material. The chemosensory neurons are
      characterized by broad tuning and relatively high response thresholds, when
      compared to other crustaceans. Most importantly, the investigations revealed a
      robust pattern in which female neurons displayed elevated responses to all
      stimuli. Tuning breadth was not shown to be sex-specific, nor were there
      detectable differences in over-all response profiles. The most likely explanation
      for these patterns is that the broad sex-specificity in Uca is produced via
      fundamental alterations in cellular properties associated with chemosensory
      transduction.

PMID- 10573865
TI  - Frequency discrimination of brief tonal steps as a function of frequency in the
      lesser bulldog bat.
AB  - In a two-alternative, forced-choice task lesser bulldog bats were trained to
      distinguish between a pure tone pulse and a pulse composed of a series of brief
      tonal steps oscillating between two different frequencies. The tone-step pulse
      gradually approximates the pure tone pulse as the frequency difference between
      the steps becomes progressively smaller. Frequency difference limens for the
      brief tonal frequency steps were determined for a broad range of ultrasonic
      frequencies. The variation in tone-step difference limens with frequency appears
      to be correlated to the frequency structure of the bat's short-constant
      frequency/frequency-modulated echolocation sound. There was a marked decline in
      the value of the relative frequency difference limens (Weber ratio) over a fairly
      narrow range of frequencies above the constant frequency and a sharp increase in
      threshold above this range. The relative thresholds for frequency discrimination
      were small and uniform over the frequency range of the frequency-modulated sweep
      and increased for frequencies below the frequency-modulated sweep. Thus, the most
      accurate frequency-discrimination abilities occur over a narrow frequency range
      around the frequency of the constant-frequency component of returning echoes.
      Frequency discrimination over the range of frequencies of the frequency-modulated
      component is relatively good.

PMID- 10573866
TI  - Central complex substructures are required for the maintenance of locomotor
      activity in Drosophila melanogaster.
AB  - In Drosophila melanogaster, former studies based on structural brain mutants have
      suggested that the central complex is a higher control center of locomotor
      behavior. Continuing this investigation we studied the effect of the central
      complex on the temporal structure of spontaneous locomotor activity in the time
      domain of a few hours. In an attempt to dissect the internal circuitry of the
      central complex we perturbed a putative local neuronal network connecting the
      four neuropil regions of the central complex, the protocerebral bridge, the fan
      shape body, the noduli and the ellipsoid body. Two independent and non-invasive
      methods were applied: mutations affecting the neuroarchitecture of the
      protocerebral bridge, and the targeted expression of tetanus toxin in small
      subsets of central complex neurons using the binary enhancer trap P[GAL4] system.
      All groups of flies with a disturbed component of this network exhibited a common
      phenotype: a drastic decrease in locomotor activity. While locomotor activity was
      still clustered in bouts and these were initiated at the normal rate, their
      duration was reduced. This finding suggests that the bridge and some of its
      neural connections to the other neuropil regions of the central complex are
      required for the maintenance but not the initiation of walking.

PMID- 10573867
TI  - Circadian rhythms in light-evoked responses of the fly's compound eye, and the
      effects of neuromodulators 5-HT and the peptide PDF.
AB  - Two sets of wide-field neurons extend neurites into the fly's optic lamina, where
      monopolar cells receive photoreceptor input. They exhibit immunoreactivity to
      antibodies raised against either 5-hydroxytryptamine or the crustacean peptide
      PDH, respectively. Both are proposed whole-field neuromodulators of vision,
      apparently regulating a circadian rhythm of monopolar cell size. Seeking
      functional correlates, we have re-examined the electroretinogram for circadian
      rhythmicity, and for responses to locally injected 5-hydroxytryptamine and
      peptide. Long-term electroretinogram recordings from Calliphora entrained to a
      light/dark cycle and then transferred to constant darkness, uncovered a gradual,
      modest increase during the subjective night in the electroretinogram's ON- and
      OFF-transients, from the lamina's monopolar cells. Five to twenty nl of 5
      hydroxytryptamine (10(-3) mol.1(-1)) injected into the head haemolymph strongly
      enhanced the electroretinogram transients, an action reversed by 5
      hydroxytryptamine antagonists. Injected into the eye, 5-hydroxytryptamine (10(-4)
      mol.1(-1)) had the opposite effect; the rapid onset there suggests direct action,
      whilst the opposing effect from haemolymph injection suggests a different
      receptor site. Pigment-dispersing hormone (2.2 x 10(-5) mol.1(-1)) injected into
      the haemolymph increased the electroretinogram transients along a biphasic
      course, with a slow partial recovery; injected into the eye, it lacked effect.

PMID- 10573868
TI  - Apamin-sensitive, small-conductance, calcium-activated potassium channels mediate
      cholinergic inhibition of chick auditory hair cells.
AB  - Acetylcholine released from efferent neurons in the cochlea causes inhibition of
      mechanosensory hair cells due to the activation of calcium-dependent potassium
      channels. Hair cells are known to have large-conductance, "BK"-type potassium
      channels associated with the afferent synapse, but these channels have different
      properties than those activated by acetylcholine. Whole-cell (tight-seal) and
      cell-attached patch-clamp recordings were made from short (outer) hair cells
      isolated from the chicken basilar papilla (cochlea equivalent). The peptides
      apamin and charybdotoxin were used to distinguish the calcium-activated potassium
      channels involved in the acetylcholine response from the BK-type channels
      associated with the afferent synapse. Differential toxin blockade of these
      potassium currents provides definitive evidence that ACh activates apamin
      sensitive, "SK"-type potassium channels, but does not activate carybdotoxin
      sensitive BK channels. This conclusion is supported by tentative identification
      of small-conductance, calcium-sensitive but voltage-insensitive potassium
      channels in cell-attached patches. The distinction between these channel types is
      important for understanding the segregation of opposing afferent and efferent
      synaptic activity in the hair cell, both of which depend on calcium influx. These
      different calcium-activated potassium channels serve as sensitive indicators for
      functionally significant calcium influx in the hair cell.

PMID- 10573869
TI  - Temporally patterned pulse trains affect duration tuning characteristics of bat
      inferior collicular neurons.
AB  - This study examines the effect of temporally patterned pulse trains on duration
      tuning characteristics of inferior collicular neurons of the big brown bat.
      Eptesicus fuscus, under free-field stimulation conditions. Using a 50% difference
      between maximal and minimal responses as a criterion, the duration tuning
      characteristics of inferior collicular neurons determined with pulse trains of
      different pulse durations are described as band-pass, long-pass, short-pass, and
      all-pass. Each band-pass neuron discharged maximally to a specific pulse duration
      that was at least 50% larger than the neuron's responses to a long- and a short
      duration pulse. In contrast, each long- or short-pass neuron discharged maximally
      to a range of long- or short-duration pulses that were at least 50% larger than
      the minimal responses. The number of impulses of an all-pass neuron never
      differed by more than 50%. When pulse trains were delivered at different pulse
      repetition rates, the number of short-pass and band-pass neurons progressively
      increased with increasing pulse repetition rates. The slope of the duration
      tuning curves also became sharper when determined with pulse trains at high pulse
      repetition rates. Possible mechanisms underlying these findings are discussed.

PMID- 10573870
TI  - GABAergic inhibition shapes frequency tuning and modifies response properties in
      the auditory midbrain of the leopard frog.
AB  - The functional role of GABAergic inhibition in shaping the frequency tuning of 96
      neurons in the torus semicircularis of the leopard frog, Rana pipiens, was
      studied using microiontophoresis of the GABAA receptor antagonist, bicuculline
      methiodide. Bicuculline application abolished, or reduced in size, the inhibitory
      tuning curves of 72 neurons. In each case, there was a concommitant broadening of
      the excitatory tuning curve such that frequency-intensity combinations that were
      inhibitory under control conditions, became excitatory during disinhibition with
      bicuculline methiodide. These effects were observed irrespective of the
      excitatory tuning curve configuration prior to bicuculline methiodide
      application. Results indicate an important role for GABA-mediated inhibition in
      shaping the frequency selectivity of neurons in the torus semicircularis of the
      leopard frog. Bicuculline application also affected several other response
      properties of neurons in the leopard frog torus. Disinhibition with bicuculline
      methiodide increased both the spontaneous firing rate (18 cells) and stimulus
      evoked discharge rate (81 cells) of torus neurons, decreased the minimum
      excitatory threshold for 18 cells, and altered the temporal discharge pattern of
      47 neurons. Additional roles for GABAergic inhibition in monaural signal analysis
      are discussed.

PMID- 10573871
TI  - Reactions to a black professional: motivated inhibition and activation of
      conflicting stereotypes.
AB  - The motivation to form a particular impression of an individual can prompt the
      inhibition of applicable stereotypes that contradict one's desired impression and
      the activation and application of stereotypes that support it. Participants,
      especially those high in prejudice, inhibited the Black stereotype when motivated
      to esteem a Black individual (because he had praised them). Participants
      motivated to esteem a Black doctor also activated the doctor stereotype. In
      contrast, participants motivated to disparage a Black doctor (because he had
      criticized them) inhibited the doctor stereotype. Participants motivated to
      disparage a Black individual also applied the Black stereotype to him, rating him
      as relatively incompetent. All these effects were driven by the self-protective
      motives of recipients of feedback from Black evaluators; detached observers
      showed no such effects.

PMID- 10573872
TI  - Stereotypes and terror management: evidence that mortality salience enhances
      stereotypic thinking and preferences.
AB  - If stereotypes function to protect people against death-related concerns, then
      mortality salience should increase stereotypic thinking and preferences for
      stereotype-confirming individuals. Study 1 demonstrated that mortality salience
      increased stereotyping of Germans. In Study 2, it increased participants'
      tendency to generate more explanations for stereotype-inconsistent than
      stereotype-consistent gender role behavior. In Study 3, mortality salience
      increased participants' liking for a stereotype-consistent African American and
      decreased their liking for a stereotype-inconsistent African American; control
      participants exhibited the opposite preference. Study 4 replicated this pattern
      with evaluations of stereotype-confirming or stereotype-disconfirming men and
      women. Study 5 showed that, among participants high in need for closure,
      mortality salience led to decreased liking for a stereotype-inconsistent gay man.

PMID- 10573873
TI  - Accentuation and sensitization effects in the categorization of multifaceted
      stimuli.
AB  - Categorization affects perceptions in ways that are assumed to underlie social
      stereotypes. Research on categorization, however, has focused either on very
      simple stimuli or on judgmental tasks that focus attention only on single
      dimensions. To more fully understand the role of categorization in social
      perception, it is important to examine its effects in the case of multifaceted
      stimuli and holistic judgments. In 3 studies, participants formed an impression
      of a focal category of multifaceted stimuli either by itself or in the context of
      another category. They then judged the typicality of exemplars to the focal
      category. Results showed that categorization in the presence of a context
      produced both accentuation and sensitization effects: Participants accentuated
      between-category differences on relevant dimensions, and they were less sensitive
      to exemplar differences on irrelevant dimensions.

PMID- 10573874
TI  - Commitment, pro-relationship behavior, and trust in close relationships.
AB  - The present work advances and tests an interdependence-based model of the
      associations among commitment, pro-relationship behavior, and trust. Findings
      from two longitudinal studies revealed good support for model predictions.
      Commitment-inspired acts such as accommodation and willingness to sacrifice
      provide diagnostic information regarding a partner's pro-relationship motives.
      Individuals come to trust their partners when they perceive that their partners
      have enacted pro-relationship behaviors, departing from their direct self
      interest for the good of the relationship. The results of mediation analyses are
      consistent with a model of mutual cyclical growth in which (a) dependence
      promotes strong commitment, (b) commitment promotes pro-relationship acts, (c)
      pro-relationship acts are perceived by the partner, (d) the perception of pro
      relationship acts enhances the partner's trust, and (e) trust increases the
      partner's willingness to become dependent on the relationship. Auxiliary analyses
      revealed that self-reported attachment style does not account for substantial
      variance beyond the features of interdependence that form the basis for the
      present model.

PMID- 10573875
TI  - The impact of stereotype-incongruent information on perceived group variability
      and stereotype change.
AB  - Three experiments showed increases in the perceived variability of social groups
      after perceivers received stereotype-incongruent information about group members.
      In Experiment 1, participants generated flatter distributions after exposure to
      incongruent information, compared with equally deviant congruent information, in
      the form of typical verbal materials. Experiment 2 indicated similar changes in
      dispersion after the presentation of numeric information about a single group
      member. In Experiment 3, the authors manipulated cognitive load at encoding or at
      the time group judgments were requested. Under conditions of cognitive
      constraint, stereotype-incongruent information ceased to promote more dispersed
      group representations. These results are consistent with the idea that
      incongruent information triggers more deliberative and comprehensive retrieval
      and generation of exemplars. The authors discuss the implications of these
      findings for stereotype change.

PMID- 10573876
TI  - Group entitativity and group perception: associations between physical features
      and psychological judgment.
AB  - Two experiments tested whether the perceived entitativity of groups (i.e.,
      cohesiveness) influences judgments about those groups, in terms of both their
      observable physical properties and underlying psychological traits. Entitativity
      was manipulated with groups whose members were similar or dissimilar in skin
      color. Experiment 1 demonstrated that beliefs about entitativity elicited more
      accurate judgments of skin color for entitative than nonentitative social groups,
      although memory for individual members of entitative groups was relatively
      impoverished. Experiment 2 revealed that entitative groups were viewed as not
      only physically similar but also psychologically homogeneous and elicited strong
      negative trait and behavioral judgments. Together, these findings suggest that
      physical properties (e.g., similarity) can create perceptions of psychological
      "groupness" that have important consequences for group perception.

PMID- 10573877
TI  - Feminized management and backlash toward agentic women: the hidden costs to women
      of a kinder, gentler image of middle managers.
AB  - Women who display masculine, agentic traits are viewed as violating prescriptions
      of feminine niceness (L. A. Rudman, 1998). By legitimizing niceness as an
      employment criterion, "feminization" of management (requiring both agentic and
      communal traits for managers) may unintentionally promote discrimination against
      competent women. Participants made hiring recommendations for a feminized or
      masculine managerial job. Agentic female job applicants were viewed as less
      socially skilled than agentic males, but this perception only resulted in hiring
      discrimination for the feminized, not the masculine, job. Communal applicants
      (regardless of sex) invariably received low hiring ratings. Thus, women must
      present themselves as agentic to be hireable, but may therefore be seen as
      interpersonally deficient. Ironically, the feminization of management may
      legitimize discrimination against competent, agentic women.

PMID- 10573878
TI  - Social presence effects in the Stroop task: further evidence for an attentional
      view of social facilitation.
AB  - In contrast with R. B. Zajonc's (1965) classic view about social facilitation
      inhibition (SFI) effects, it was found that the presence of relatively
      unpredictable audiences and forced social comparison with a slightly superior
      coactor both facilitated performance in the Stroop task while inhibiting
      automatic verbal processing. Not only do these findings reveal that social
      presence can help inhibit the emission of dominant responses, providing further
      support for an attentional view of SFI effects, but they also demonstrate the
      power of social situations over what has been thought to be invariant automatic
      processing. As such, they are inconsistent with the view reiterated in more than
      500 articles on Stroop interference over the past 60 years and suggest that more
      attention should be paid to the situations in which cognition takes place.

PMID- 10573879
TI  - Why ruminators are poor problem solvers: clues from the phenomenology of
      dysphoric rumination.
AB  - The phenomenology of dysphoric rumination and its consequences for problem
      solving were explored in 3 studies. In Study 1, self-focused rumination, compared
      with distraction, led dysphoric participants to rate their own biggest problems
      as severe and unsolvable and to report a reduced likelihood of actually
      implementing their solutions. Clues into the mechanisms behind these findings
      were explored in Study 2. The results showed that dysphoric ruminative thought is
      characterized by a focus on personal problems combined with a negative tone, self
      criticism, and self-blame for problems as well as reduced self-confidence,
      optimism, and perceived control. Finally, Study 3 revealed a direct relationship
      between the negatively biased content of ruminative thoughts and reduced
      willingness to solve one's problems. Implications of these findings for the
      consequences of self-focused rumination are discussed.

PMID- 10573880
TI  - Explaining the gender difference in depressive symptoms.
AB  - It was hypothesized that women are more vulnerable to depressive symptoms than
      men because they are more likely to experience chronic negative circumstances (or
      strain), to have a low sense of mastery, and to engage in ruminative coping. The
      hypotheses were tested in a 2-wave study of approximately 1,100 community-based
      adults who were 25 to 75 years old. Chronic strain, low mastery, and rumination
      were each more common in women than in men and mediated the gender difference in
      depressive symptoms. Rumination amplified the effects of mastery and, to some
      extent, chronic strain on depressive symptoms. In addition, chronic strain and
      rumination had reciprocal effects on each other over time, and low mastery also
      contributed to more rumination. Finally, depressive symptoms contributed to more
      rumination and less mastery over time.

PMID- 10573881
TI  - Interactive effects of personality and mood on emotion-congruent memory and
      judgment.
AB  - Prior research on emotion congruency has tended to focus on either the effects of
      mood states or of personality traits on cognition. The aim of the present
      research was to explore when and how personality traits and mood states interact
      to influence emotion-congruent memory and judgment. In Study 1, participants
      filled out measures of personality and natural mood and then completed a series
      of memory and judgment tasks. The same procedure was used in Study 2, except a
      positive or negative mood state was induced prior to completion of the cognitive
      tasks. Extraversion and positive affectivity were related to retrieval of
      positive memories and the tendency to make positive judgments. Neuroticism and
      negative affectivity were related to retrieval of negative memories and the
      tendency to make negative judgments. In addition, several significant personality
      by mood interaction effects on memory and judgment were obtained in Study 2,
      which suggests that personality and mood effects on cognition are not independent
      of one another. Discussion focuses on integrating mood-congruency theories with
      personality theories and specifying the conditions under which mood by trait
      interaction effects effects emerge.

PMID- 10573882
TI  - The role of neuroticism in daily stress and coping.
AB  - The authors examined the influence of neuroticism (N) on the occurrence of
      different types of daily events, primary and secondary appraisals of those
      events, use of specific coping strategies, and end-of-day negative mood. College
      students completed questionnaires at the end of every day for 14 consecutive
      days. When reporting their most stressful event of each day, high-N individuals,
      compared with low-N individuals, reported more interpersonal stressors and had
      more negative primary and secondary appraisals and reacted with more distress in
      response to increasingly negative primary and secondary appraisals. Compared with
      low-N individuals, high-N individuals used less-adaptive coping strategies (e.g.,
      hostile reaction) and reacted with more distress in response to some types of
      coping strategies. The appraisal findings, in particular, help to explain the
      chronic negative affectivity associated with neuroticism.

PMID- 10573883
TI  - Auditory hazard from airbag noise exposure.
AB  - Airbag deployment includes very intense acoustic stimulation, yet almost no tests
      of auditory hazard have been done with real ears. Therefore 32 anesthetized cats,
      positioned at the driver and passenger locations in a pickup truck, were exposed
      in pairs to one airbag deployment (electrically initiated). Hearing was tested at
      1, 2, 4, 8, and 16 kHz by evoked-response audiometry just before exposure,
      immediately after and at 1 month and 6 months. Exposure conditions included doors
      open, compartment closed, and closed compartment sealed with tape: seven
      exposures to passenger bag only and nine to driver and passenger bags. Peak
      pressures ranged from 167 to 173 dB with unweighted energies as high as 4000 J/m2
      (or 8 hr LEQA = 95.5 dB). The immediate threshold shift averaged 60 dB at 4.0 kHz
      that resolved to an average permanent shift of 37 dB. By extrapolation, these
      data from cats may indicate that susceptible human ears risk permanent hearing
      loss from airbag noise.

PMID- 10573884
TI  - Cochlear generation of intermodulation distortion revealed by DPOAE frequency
      functions in normal and impaired ears.
AB  - Distortion product otoacoustic emission (DPOAE) frequency functions were measured
      in normal-hearing and hearing-impaired ears. A fixed-f2/swept-f1 paradigm was
      used with f2 fixed at half-octave intervals from 1 to 8 kHz. L1 was always 10 dB
      greater than L2, and L2 was varied from 65 to 10 dB SPL in 5-dB steps. The
      responses were quantified by the frequency and amplitude of the peak response.
      Peak responses were closer to f2 in higher frequency regions and for lower
      intensity stimulation. Results from hearing-impaired subjects suggest that
      audiometric thresholds at the distortion product frequency, fdp, in addition to
      hearing status at f2, can affect DPOAE results. Results are discussed in terms of
      several manifestations of a second resonance model, as well as a dual source
      model for the generation of DPOAEs as measured in the ear canal of humans. It
      appears that a dual source model accounts for the data better than second filter
      models.

PMID- 10573885
TI  - A possible neurophysiological basis of the octave enlargement effect.
AB  - Although the physical octave is defined as a simple ratio of 2:1, listeners
      prefer slightly greater octave ratios. Ohgushi [J. Acoust. Soc. Am. 73, 1694-1700
      (1983)] suggested that a temporal model for octave matching would predict this
      octave enlargement effect because, in response to pure tones, auditory-nerve
      interspike intervals are slightly larger than the stimulus period. In an effort
      to test Ohgushi's hypothesis, auditory-nerve single-unit responses to pure-tone
      stimuli were collected from Dial-anesthetized cats. It was found that although
      interspike interval distributions show clear phase-locking to the stimulus,
      intervals systematically deviate from integer multiples of the stimulus period.
      Due to refractory effects, intervals smaller than 5 msec are slightly larger than
      the stimulus period and deviate most for small intervals. On the other hand,
      first-order intervals are smaller than the stimulus period for stimulus
      frequencies less than 500 Hz. It is shown that this deviation is the combined
      effect of phase-locking and multiple spikes within one stimulus period. A model
      for octave matching was implemented which compares frequency estimates of two
      tones based on their interspike interval distributions. The model quantitatively
      predicts the octave enlargement effect. These results are consistent with the
      idea that musical pitch is derived from auditory-nerve interspike interval
      distributions.

PMID- 10573886
TI  - Contrast enhancement improves the representation of /epsilon/-like vowels in the
      hearing-impaired auditory nerve.
AB  - This study examines the neural representation of the vowel /epsilon/ in the
      auditory nerve of acoustically traumatized cats and asks whether spectral
      modifications of the vowel can restore a normal neural representation. Four
      variants of /epsilon/, which differed primarily in the frequency of the second
      formant (F2), were used as stimuli. Normally, the rate-place code provides a
      robust representation of F2 for these vowels, in the sense that rate changes
      encode changes in F2 frequency [Conley and Keilson, J. Acoust. Soc. Am. 98, 3223
      (1995)]. This representation is lost after acoustic trauma [Miller et al., J.
      Acoust. Soc. Am. 105, 311 (1999)]. Here it is shown that an improved
      representation of the F2 frequency can be gained by a form of high-frequency
      emphasis that is determined by both the hearing-loss profile and the spectral
      envelope of the vowel. Essentially, the vowel was high-pass filtered so that the
      F2 and F3 peaks were amplified without amplifying frequencies in the trough
      between F1 and F2. This modification improved the quality of the rate and
      temporal tonotopic representations of the vowel and restored sensitivity to the
      F2 frequency. Although a completely normal representation was not restored, this
      method shows promise as an approach to hearing-aid signal processing.

PMID- 10573887
TI  - Quantifying the distortion products generated by amplitude-modulated noise.
AB  - When sinusoidal amplitude modulation (SAM) is applied to noise or tone carriers,
      the stimuli can generate audible distortion products in the region of the
      modulation frequency. As a result, when bandpass-filtered SAM noise is used to
      investigate temporal processing, a band of unmodulated noise is typically
      positioned at the modulation frequency to mask any distortion products. This
      study was designed to investigate the distortion products for bandpass noise
      carriers, and so reduce ambiguity about the form of this distortion and its role
      in perception. The distortion consists of two distortion-noise bands and a
      distortion tone at the modulation frequency. In the first two experiments, the
      level and phase of the distortion tone are measured using two different
      experimental paradigms. In the third experiment, modulation-frequency difference
      limens are measured for filtered SAM noise and it is shown that performance
      deteriorates markedly when the distortion tone is canceled. In a fourth
      experiment, masked threshold is measured at low frequencies for bands of high
      frequency, unmodulated noise with the same levels and spectra as the SAM noises
      in the earlier experiments. The results confirm that unmodulated noise also
      produces quadratic distortion which may explain some aspects of earlier reports
      on remote masking.

PMID- 10573888
TI  - Spectro-temporal modulation transfer functions and speech intelligibility.
AB  - Detection thresholds for spectral and temporal modulations are measured using
      broadband spectra with sinusoidally rippled profiles that drift up or down the
      log-frequency axis at constant velocities. Spectro-temporal modulation transfer
      functions (MTFs) are derived as a function of ripple peak density (omega
      cycles/octave) and drifting velocity (omega Hz). The MTFs exhibit a low-pass
      function with respect to both dimensions, with 50% bandwidths of about 16 Hz and
      2 cycles/octave. The data replicate (as special cases) previously measured purely
      temporal MTFs (omega = 0) [Viemeister, J. Acoust. Soc. Am. 66, 1364-1380 (1979)]
      and purely spectral MTFs (omega = 0) [Green, in Auditory Frequency Selectivity
      (Plenum, Cambridge, 1986), pp. 351-359]. A computational auditory model is
      presented that exhibits spectro-temporal MTFs consistent with the salient trends
      in the data. The model is used to demonstrate the potential relevance of these
      MTFs to the assessment of speech intelligibility in noise and reverberant
      conditions.

PMID- 10573889
TI  - Within-channel cues in comodulation masking release (CMR): experiments and model
      predictions using a modulation-filterbank model.
AB  - Experiments and model calculations were performed to study the influence of
      within-channel cues versus across-channel cues in comodulation masking release
      (CMR). A class of CMR experiments is considered that are characterized by a
      single (unmodulated or modulated) bandpass noise masker with variable bandwidth
      centered at the signal frequency. A modulation-filterbank model suggested by Dau
      et al. [J. Acoust. Soc. Am. 102, 2892-2905 (1997)] was employed to quantitatively
      predict the experimental data. Effects of varying masker bandwidth, center
      frequency, modulator bandwidth, modulator type, and signal duration on CMR were
      examined. In addition, the effect of band limiting the noise before or after
      modulation was shown to influence the CMR in the same way as a systematic
      variation of the modulation depth. It is demonstrated that a single-channel
      analysis, which analyzes only the information from one peripheral channel,
      quantitatively accounts for the CMR in most cases, indicating that an across
      channel process is generally not necessary for simulating results from this class
      of CMR experiments. True across-channel processes may be found in another class
      of CMR experiments.

PMID- 10573890
TI  - Evidence against an effect of grouping by spectral regularity on the perception
      of virtual pitch.
AB  - Two experiments investigated the role of the regularity of the frequency spacing
      of harmonics, as a separate factor from harmonicity, on the perception of the
      virtual pitch of a harmonic series. The first experiment compared the shifts
      produced by mistuning the 3rd, 4th, and 5th harmonics in the pitch of two
      harmonic series: the odd-H and the all-H tones. The odd-H tone contained odd
      harmonics 1 to 11, plus the 4th harmonic; the all-H tone contained harmonics 1 to
      12. Both tones had a fundamental frequency of 155 Hz. Pitch shifts produced by
      mistuning the 3rd harmonic, but not the 4th and 5th harmonics, were found to be
      significantly larger for the odd-H tone than for the all-H tone. This finding was
      consistent with the idea that grouping by spectral regularity affects pitch
      perception since an odd harmonic made a larger contribution than an adjacent even
      harmonic to the pitch of the odd-H tone. However, an alternative explanation was
      that the 3rd mistuned harmonic produced larger pitch shifts within the odd-H tone
      than the 4th mistuned harmonic because of differences in the partial masking of
      these harmonics by adjacent harmonics. The second experiment tested these
      explanations by measuring pitch shifts for a modified all-H tone in which each
      mistuned odd harmonic was tested in the presence of the 4th harmonic, but in the
      absence of its other even-numbered neighbor. The results showed that, for all
      mistuned harmonics, pitch shifts for the modified all-H tone were not
      significantly different from those for the odd-H tone. These findings suggest
      that the harmonic relations among frequency components, rather than the
      regularity of their frequency spacing, is the primary factor for the perception
      of the virtual pitch of complex sounds.

PMID- 10573891
TI  - Intrinsic envelope fluctuations and modulation-detection thresholds for narrow
      band noise carriers.
AB  - A model is presented which calculates the intrinsic envelope power of a bandpass
      noise carrier within the passband of a hypothetical modulation filter tuned to a
      specific modulation frequency. Model predictions are compared to experimentally
      obtained amplitude modulation (AM) detection thresholds. In experiment 1,
      thresholds for modulation rates of 5, 25, and 100 Hz imposed on a bandpass
      Gaussian noise carrier with a fixed upper cutoff frequency of 6 kHz and a
      bandwidth in the range from 1 to 6000 Hz were obtained. In experiment 2, three
      noises with different spectra of the intrinsic fluctuations served as the
      carrier: Gaussian noise, multiplied noise, and low-noise noise. In each case, the
      carrier was spectrally centered at 5 kHz and had a bandwidth of 50 Hz. The AM
      detection thresholds were obtained for modulation frequencies of 10, 20, 30, 50,
      70, and 100 Hz. The intrinsic envelope power of the carrier at the output of the
      modulation filter tuned to the signal modulation frequency appears to provide a
      good estimate for AM detection threshold. The results are compared with
      predictions on the basis of the more complex auditory processing model by Dau et
      al.

PMID- 10573892
TI  - Inter-relationship between different psychoacoustic measures assumed to be
      related to the cochlear active mechanism.
AB  - The active mechanism in the cochlea is thought to depend on the integrity of the
      outer hair cells (OHCs). Cochlear hearing loss is usually associated with damage
      to both inner hair cells (IHCs) and OHCs, with the latter resulting in a
      reduction in or complete loss of the function of the active mechanism. It is
      believed that the active mechanism contributes to the sharpness of tuning on the
      basilar membrane (BM) and is also responsible for compressive input-output
      functions on the BM. Hence, one would expect a close relationship between
      measures of sharpness of tuning and measures of compression. This idea was tested
      by comparing three different measures of the status of the active mechanism, at
      center frequencies of 2, 4, and 6 kHz, using subjects with normal hearing, with
      unilateral or highly asymmetric cochlear hearing loss, and with bilateral loss.
      The first measure, HLOHC, was an indirect measure of the amount of the hearing
      loss attributable to OHC damage; this was based on loudness matches between the
      two ears of subjects with unilateral hearing loss and was derived using a
      loudness model. The second measure was the equivalent rectangular bandwidth (ERB)
      of the auditory filter, which was estimated using the notched-noise method. The
      third measure was based on the slopes of growth-of-masking functions obtained in
      forward masking. The ratio of slopes for a masker centered well below the signal
      frequency and a masker centered at the signal frequency gives a measure of BM
      compression at the place corresponding to the signal frequency; a ratio close to
      1 indicates little or no compression, while ratios less than 1 indicate that
      compression is occurring at the signal place. Generally, the results showed the
      expected pattern. The ERB tended to increase with increasing HLOHC. The ratio of
      the forward-masking slopes increased from about 0.3 to about 1 as HLOHC increased
      from 0 to 55 dB. The ratio of the slopes was highly correlated with the ERB (r =
      0.92), indicating that the sharpness of the auditory filter decreases as the
      compression on the BM decreases.

PMID- 10573893
TI  - Different auditory filter bandwidth estimates based on profile analysis, notched
      noise, and hybrid tasks.
AB  - Auditory filter bandwidths were estimated in three experiments. The first
      experiment was a profile-analysis experiment. The stimuli were composed of
      sinusoidal components ranging in frequency from 200 to 5000 Hz. The standard
      stimulus was the sum of equal-amplitude tones, and the signal stimulus had a
      power spectrum that varied up-down ... up-down. The number of components ranged
      from four to 60. Interval-by-interval level randomization prevented the change in
      level of a single component from reliably indicating the change from standard to
      signal. The second experiment was a notched-noise experiment in which the 1000-Hz
      tone to be detected was added to a noise with a notch arithmetically centered at
      1000 Hz. Detection thresholds were estimated both in the presence of and in the
      absence of level randomization. In the third, hybrid, experiment a 1000-Hz tone
      was to be detected, and the masker was composed of equal-amplitude sinusoidal
      components ranging in frequency from 200 to 5000 Hz. For this experiment,
      thresholds were estimated both in the presence and absence of level variation.
      For both the notched-noise and hybrid experiments, only modest effects of level
      randomization were obtained. A variant of Durlach et al.'s channel model
      ["Towards a model for discrimination of broadband signals," J. Acoust. Soc. Am.
      80, 63-72 (1986)] was used to estimate auditory filter bandwidths for all three
      experiments. When a two-parameter roex(p,r) filter weighting function was used to
      fit the data, bandwidth estimates were approximately two to three times as large
      for the two detection tasks than for the profile-analysis task.

PMID- 10573894
TI  - Age differences in backward masking.
AB  - The present study was designed to assess the effects of age on the time course of
      backward masking. In experiment 1, thresholds for detecting a 10-ms, 500-Hz
      sinusoidal signal were measured as a function of the temporal separation between
      the signal and a 50-ms broadband masker. Subjects were younger (18-24) and older
      (over age 65) adults with normal hearing (thresholds less than 20 dB HL) for
      frequencies of 4 kHz and below. Younger subjects exhibited less overall masking
      and steeper recovery functions than did the older adults. Masked thresholds for
      younger participants approached unmasked thresholds for signal-masker delays
      greater than 6-8 ms. In contrast, older adults exhibited significant masking even
      at the longest delay tested (20 ms). In experiment 2, signal duration was
      decreased to 5 ms for a separate group of younger adults. Although overall
      thresholds were elevated for the shorter signal duration, the slope of the
      backward masking recovery function was not different from that observed for
      younger adults in experiment 1. The results suggest that age, independent of
      hearing loss, affects the temporal course of backward masking.

PMID- 10573895
TI  - Ripple depth and density resolution of rippled noise.
AB  - Depth resolution of spectral ripples was measured in normal humans using a phase
      reversal test. The principle of the test was to find the lowest ripple depth at
      which an interchange of peak and trough position (the phase reversal) in the
      rippled spectrum is detectable. Using this test, ripple-depth thresholds were
      measured as a function of ripple density of octave-band rippled noise at center
      frequencies from 0.5 to 8 kHz. The ripple-depth threshold in the power domain was
      around 0.2 at low ripple densities of 4-5 relative units (center-frequency-to
      ripple-spacing ratio) or 3-3.5 ripples/oct. The threshold increased with the
      ripple density increase. It reached the highest possible level of 1.0 at ripple
      density from 7.5 relative units at 0.5 kHz center frequency to 14.3 relative
      units at 8 kHz (5.2 to 10.0 ripple/oct, respectively). The interrelation between
      the ripple depth threshold and ripple density can be satisfactorily described by
      transfer of the signal by frequency-tuned auditory filters.

PMID- 10573896
TI  - Memory for pitch versus memory for loudness.
AB  - The decays of pitch traces and loudness traces in short-term auditory memory were
      compared in forced-choice discrimination experiments. The two stimuli presented
      on each trial were separated by a variable delay (D); they consisted of pure
      tones, series of resolved harmonics, or series of unresolved harmonics mixed with
      lowpass noise. A roving procedure was employed in order to minimize the influence
      of context coding. During an initial phase of each experiment, frequency and
      intensity discrimination thresholds [P(C) = 0.80] were measured with an adaptive
      staircase method while D was fixed at 0.5 s. The corresponding physical
      differences (in cents or dB) were then constantly presented at four values of D:
      0.5, 2, 5, and 10 s. In the case of intensity discrimination, performance (d')
      markedly decreased when D increased from 0.5 to 2 s, but was not further reduced
      when D was longer. In the case of frequency discrimination, the decline of
      performance as a function of D was significantly less abrupt. This divergence
      suggests that pitch and loudness are processed in separate modules of auditory
      memory.

PMID- 10573897
TI  - Identification and localization of sound sources in the median sagittal plane.
AB  - The ability of human listeners to identify broadband noises differing in spectral
      structure was studied for multiple sound-source locations in the median sagittal
      plane. The purpose of the study was to understand how sound identification is
      affected by spectral variations caused by directionally dependent head-related
      transfer functions. It was found that listeners could accurately identify noises
      with different spectral peaks and valleys when the source location was fixed.
      Listeners could also identify noises when the source location was roved in the
      median sagittal plane when the relevant spectral features were at low frequency.
      Listeners failed to identify noises with roved location when the spectral
      structure was at high frequency, presumably because the spectral structure was
      confused with the spectral variations caused by different locations. Parallel
      experiments on sound localization showed that listeners can localize noises that
      they cannot identify. The combination of identification and localization
      experiments leads to the conclusion that listeners cannot compensate for
      directionally dependent filtering by their own heads when they try to identify
      sounds.

PMID- 10573898
TI  - Variations in the feedback of hearing aids.
AB  - Variations in the loop response of hearing aids caused by jaw movements,
      variations in acoustics outside the ear, and variations of vent size have been
      identified. Behind The Ear (BTE) and In The Ear Canal (ITEC) hearing aids were
      considered. The largest variations among the variations of the acoustics outside
      the ear, except when the hearing aid was partly removed, were found with the ITEC
      when a telephone set was placed by the ear. The variations of the loop response
      caused by changes in vent size were compared with the variations of a theoretical
      model of the feedback path. The theoretical model was also used to compare the
      feedback of different designs of the vent that gives the same acoustic impedance
      at low frequencies. The calculated feedback was less with the short vents (12 mm)
      than the long vents (24 mm).

PMID- 10573899
TI  - A model of facial biomechanics for speech production.
AB  - Modeling the peripheral speech motor system can advance the understanding of
      speech motor control and audiovisual speech perception. A 3-D physical model of
      the human face is presented. The model represents the soft tissue biomechanics
      with a multilayer deformable mesh. The mesh is controlled by a set of modeled
      facial muscles which uses a standard Hill-type representation of muscle dynamics.
      In a test of the model, recorded intramuscular electromyography (EMG) was used to
      activate the modeled muscles and the kinematics of the mesh was compared with 3-D
      kinematics recorded with OPTOTRAK. Overall, there was a good match between the
      recorded data and the model's movements. Animations of the model are provided as
      MPEG movies.

PMID- 10573900
TI  - The effect of partially restored hearing on speech production of postlingually
      deafened adults with multichannel cochlear implants.
AB  - The effect of auditory feedback on speech production was investigated in five
      postlingually deafened adults implanted with the 22-channel Nucleus device.
      Changes in speech production were measured before implant and 1, 6, and 24 months
      postimplant. Acoustic measurements included: F1 and F2 of vowels in word-in
      isolation and word-in-sentence context, voice-onset-time (VOT), spectral range of
      sibilants, fundamental frequency (F0) of word-in-isolation and word-in-sentence
      context, and word and sentence duration. Perceptual ratings of speech quality
      were done by ten listeners. The significant changes after cochlear implantation
      included: a decrease of F0, word and sentence duration, and F1 values, and an
      increase of voiced plosives' voicing lead (from positive to negative VOT values)
      and fricatives' spectral range. Significant changes occurred until 2 years
      postimplant when most measured values fell within Hebrew norms. Listeners were
      found to be sensitive to the acoustic changes in the speech from preimplant to 1,
      6, and 24 months postimplant. Results suggest that when hearing is restored in
      postlingually deafened adults, calibration of speech is not immediate and occurs
      over time depending on the age-at-onset of deafness, years of deafness, and
      perception skills. The results also concur with hypothesis that the observed
      changes of some speech parameters are an indirect consequence of intentional
      changes in other articulatory parameters.

PMID- 10573901
TI  - Three-dimensional tongue surface reconstruction: practical considerations for
      ultrasound data.
AB  - This paper discusses methods for reconstructing the tongue from sparse data sets.
      Sixty ultrasound slices already have been used to reconstruct three-dimensional
      (3D) tongue surface shapes [Stone and Lundberg, J. Acoust. Soc. Am. 99, 3728-3737
      (1996)]. To reconstruct 3D surfaces, particularly in motion, collecting 60 slices
      would be impractical, and possibly unnecessary. The goal of this study was to
      select a sparse set of slices that would best reconstruct the 18 measured speech
      sounds. First a coronal sparse set was calculated from 3D surface
      reconstructions. Selection of contours was globally optimized using coarse to
      fine search. Sparse and dense reconstructions were compared using maximum error,
      standard deviation error, and surface coverage. For all speech sounds, maximum
      error was less than 1.5 mm, standard deviation error was less than 0.32 mm, and
      average reconstruction coverage was 80%. To generalize the method across
      subjects, optimal slice locations were calculated from only the midsagittal
      contour. Six midsagittal points were optimized to reconstruct the midsagittal
      contour. Corresponding coronal slices were then used to reconstruct 3D surfaces.
      For data collection planning, a midsagittal sample can be collected first and
      optimal coronal slices can be determined from it. Errors and reconstruction
      coverage from the midsagittal source set were comparable to the optimized coronal
      sparse set. These sparse surfaces reconstructed static 3D surfaces, and should be
      usable for motion sequences as well.

PMID- 10573902
TI  - Perception of coarticulatory nasalization by speakers of English and Thai:
      evidence for partial compensation.
AB  - The conditions under which listeners do and do not compensate for coarticulatory
      vowel nasalization were examined through a series of experiments of listeners'
      perception of naturally produced American English oral and nasal vowels spliced
      into three contexts: oral (C_C), nasal (N_N), and isolation. Two perceptual
      paradigms, a rating task in which listeners judged the relative nasality of
      stimulus pairs and a 4IAX discrimination task in which listeners judged vowel
      similarity, were used with two listener groups, native English speakers and
      native Thai speakers. Thai and English speakers were chosen because their
      languages differ in the temporal extent of anticipatory vowel nasalization.
      Listeners' responses were highly context dependent. For both perceptual paradigms
      and both language groups, listeners were less accurate at judging vowels in nasal
      than in non-nasal (oral or isolation) contexts; nasal vowels in nasal contexts
      were the most difficult to judge. Response patterns were generally consistent
      with the hypothesis that, given an appropriate and detectable nasal consonant
      context, listeners compensate for contextual vowel nasalization and attribute the
      acoustic effects of the nasal context to their coarticulatory source. However,
      the results also indicated that listeners do not hear nasal vowels in nasal
      contexts as oral; listeners retained some sensitivity to vowel nasalization in
      all contexts, indicating partial compensation for coarticulatory vowel
      nasalization. Moreover, there were small but systematic differences between the
      native Thai- and native English-speaking groups. These differences are as
      expected if perceptual compensation is partial and the extent of compensation is
      linked to patterns of coarticulatory nasalization in the listeners' native
      language.

PMID- 10573903
TI  - Continuous assessment of time-varying speech quality.
AB  - This paper addresses the question of whether subjects are able to assess the
      perceived time-varying quality of speech material continuously. A method is
      introduced which is characterized by a subjective continuous rating of the
      perceived speech quality by moving a slider along a graphical scale. The
      usability of this method is illustrated with an experiment in which different
      sequences of sentences were degraded in quality with a Modulated Noise Reference
      Unit. The modulation depth was varied with time and the subject's task was to
      assess the perceived quality. The results indicate that subjects can monitor
      speech quality variations very accurately with a delay of approximately 1 s. An
      objective speech quality measure based on an auditory processing model was
      applied to predict the subjective speech quality results. The speech quality
      measure qC was modified to allow for time-dependent objective measurement of the
      speech quality. The averaged subjective response data could be modeled by the
      scale transformed and low-pass filtered measure qC(t) with a high degree of
      accuracy.

PMID- 10573904
TI  - Effects of categorization and discrimination training on auditory perceptual
      space.
AB  - Psychophysical phenomena such as categorical perception and the perceptual magnet
      effect indicate that our auditory perceptual spaces are warped for some stimuli.
      This paper investigates the effects of two different kinds of training on
      auditory perceptual space. It is first shown that categorization training using
      nonspeech stimuli, in which subjects learn to identify stimuli within a
      particular frequency range as members of the same category, can lead to a
      decrease in sensitivity to stimuli in that category. This phenomenon is an
      example of acquired similarity and apparently has not been previously
      demonstrated for a category-relevant dimension. Discrimination training with the
      same set of stimuli was shown to have the opposite effect: subjects became more
      sensitive to differences in the stimuli presented during training. Further
      experiments investigated some of the conditions that are necessary to generate
      the acquired similarity found in the first experiment. The results of these
      experiments are used to evaluate two neural network models of the perceptual
      magnet effect. These models, in combination with our experimental results, are
      used to generate an experimentally testable prediction concerning changes in the
      brain's auditory maps under different training conditions.

PMID- 10573905
TI  - Integrality of nasalization and F1. II. Basic sensitivity and phonetic labeling
      measure distinct sensory and decision-rule interactions.
AB  - In vowel perception, nasalization and height (the inverse of the first formant,
      F1) interact. This paper asks whether the interaction results from a sensory
      process, decision mechanism, or both. Two experiments used vowels varying in
      height, degree of nasalization, and three other stimulus parameters: the
      frequency region of F1, the location of the nasal pole/zero complex relative to
      F1, and whether a consonant following the vowel was oral or nasal. A fixed
      classification experiment, designed to estimate basic sensitivity between
      stimuli, measured accuracy for discriminating stimuli differing in F1, in
      nasalization, and on both dimensions. A configuration derived by a
      multidimensional scaling analysis revealed a perceptual interaction that was
      stronger for stimuli in which the nasal pole/zero complex was below rather than
      above the oral pole, and that was present before both nasal and oral consonants.
      Phonetic identification experiments, designed to measure trading relations
      between the two dimensions, required listeners to identify height and
      nasalization in vowels varying in both. Judgments of nasalization depended on F1
      as well as on nasalization, whereas judgments of height depended primarily on F1,
      and on nasalization more when the nasal complex was below than above the oral
      pole. This pattern was interpreted as a decision-rule interaction that is
      distinct from the interaction in basic sensitivity. Final consonant nasality had
      little effect in the classification experiment; in the identification experiment,
      nasal judgments were more likely when the following consonant was nasal.

PMID- 10573906
TI  - The influence of early reflections on the identification and lateralization of
      vowels.
AB  - Sound coming directly from a source is often accompanied by reflections arriving
      from different directions. However, the "precedence effect" occurs when listeners
      judge such a source's direction: information in the direct, first-arriving sound
      tends to govern the direction heard for the overall sound. This paper asks
      whether the spectral envelope of the direct sound has a similar, dominant
      influence on the spectral envelope perceived for the whole sound. A continuum
      between two vowels was produced and then a "two-part" filter distorted each step.
      The beginning of this filter's unit-sample response simulated a direct sound with
      no distortion of the spectral envelope. The second part simulated a reflection
      pattern that distorted the spectral envelope. The reflections' frequency response
      was designed to give the spectral envelope of one of the continuum's end-points
      to the other end-point. Listeners' identifications showed that the reflections in
      two-part filters had a substantial influence because sounds tended to be
      identified as the positive vowel of the reflection pattern. This effect was not
      reduced when the interaural delays of the reflections and the direct sound were
      substantially different. Also, when the reflections were caused to precede the
      direct sound, the effects were much the same. By contrast, in measurements of
      lateralization the precedence effect was obtained. Here, the lateral position of
      the whole sound was largely governed by the interaural delay of the direct sound,
      and was hardly affected by the interaural delay of the reflections.

PMID- 10573907
TI  - Vowel formant discrimination: towards more ordinary listening conditions.
AB  - Thresholds for formant frequency discrimination have been established using
      optimal listening conditions. In normal conversation, the ability to discriminate
      formant frequency is probably substantially degraded. The purpose of the present
      study was to change the listening procedures in several substantial ways from
      optimal towards more ordinary listening conditions, including a higher level of
      stimulus uncertainty, increased levels of phonetic context, and with the addition
      of a sentence identification task. Four vowels synthesized from a female talker
      were presented in isolation, or in the phonetic context of /bVd/ syllables, three
      word phrases, or nine-word sentences. In the first experiment, formant resolution
      was estimated under medium stimulus uncertainty for three levels of phonetic
      context. Some undesirable training effects were obtained and led to the design of
      a new protocol for the second experiment to reduce this problem and to manipulate
      both length of phonetic context and level of difficulty in the simultaneous
      sentence identification task. Similar results were obtained in both experiments.
      The effect of phonetic context on formant discrimination is reduced as context
      lengthens such that no difference was found between vowels embedded in the phrase
      or sentence contexts. The addition of a challenging sentence identification task
      to the discrimination task did not degrade performance further and a stable
      pattern for formant discrimination in sentences emerged. This norm for the
      resolution of vowel formants under these more ordinary listening conditions was
      shown to be nearly a constant at 0.28 barks. Analysis of vowel spaces from 16
      American English talkers determined that the closest vowels, on average, were
      0.56 barks apart, that is, a factor of 2 larger than the norm obtained in these
      vowel formant discrimination tasks.

PMID- 10573908
TI  - Waveform interactions and the segregation of concurrent vowels.
AB  - Two experiments investigated the effects of small values of fundamental frequency
      difference (delta F0) on the identification of concurrent vowels. As delta F0's
      get smaller, mechanisms that exploit them must necessarily fail, and the pattern
      of breakdown may tell which mechanisms are used by the auditory system. Small
      delta F0's also present a methodological difficulty. If the stimulus is shorter
      than the beat period, its spectrum depends on which part of the beat pattern is
      sampled. A different starting phase might produce a different experimental
      outcome, and the experiment may lack generality. The first experiment explored
      the effects of delta F0's as small as 0.4%. The smallest delta F0 conditions were
      synthesized with several starting phases obtained by gating successive segments
      of the beat pattern. An improvement in identification was demonstrated for delta
      F0's as small as 0.4% for all segments. Differences between segments (or starting
      phase) were also observed, but when averaged over vowel pairs they were of small
      magnitude compared to delta F0 effects. The nature of delta F0-induced waveform
      interactions and the factors that affect them are discussed in detail in a
      tutorial section, and the hypothesis that the improvement in identification is
      the result of such interactions (beat hypothesis) is examined. It is unlikely
      that this hypothesis can account for the effects observed. The reduced benefit of
      delta F0 for identification at smaller delta F0's more likely reflects the
      breakdown of the same F0-guided segregation mechanism that operates at larger
      delta F0's.

PMID- 10573909
TI  - Native Italian speakers' perception and production of English vowels.
AB  - This study examined the production and perception of English vowels by highly
      experienced native Italian speakers of English. The subjects were selected on the
      basis of the age at which they arrived in Canada and began to learn English, and
      how much they continued to use Italian. Vowel production accuracy was assessed
      through an intelligibility test in which native English-speaking listeners
      attempted to identify vowels spoken by the native Italian subjects. Vowel
      perception was assessed using a categorial discrimination test. The later in life
      the native Italian subjects began to learn English, the less accurately they
      produced and perceived English vowels. Neither of two groups of early
      Italian/English bilinguals differed significantly from native speakers of English
      either for production or perception. This finding is consistent with the
      hypothesis of the speech learning model [Flege, in Speech Perception and
      Linguistic Experience: Theoretical and Methodological Issues (York, Timonium, MD,
      1995)] that early bilinguals establish new categories for vowels found in the
      second language (L2). The significant correlation observed to exist between the
      measures of L2 vowel production and perception is consistent with another
      hypothesis of the speech learning model, viz., that the accuracy with which L2
      vowels are produced is limited by how accurately they are perceived.

PMID- 10573910
TI  - Environmental constraints on sound transmission by humpback whales.
AB  - Singing humpback whales in Hawaii produce a variety of sounds at high source
      levels (ca. 185 dB re: 1 microPa), in coastal waters 15-500 m deep. These sounds
      are attenuated and distorted as they propagate away from a singer, limiting the
      utilizable range of the sounds. In the current study, simulations based on normal
      mode theory were used to investigate how the effects of shallow-water propagation
      constrain humpback whales' use of sound. It is shown that humpbacks can greatly
      affect transmission range by adjusting their positions and sounds in response to
      environmental factors. Source depth, in particular, is shown to be a major
      determinant of which frequencies propagate the farthest. A preliminary analysis
      of range-dependent distortion suggests that spectral cues can potentially provide
      listening whales with information about how far a sound has traveled.

PMID- 10573911
TI  - Free-field audiogram of the Japanese macaque (Macaca fuscata).
AB  - The audiograms of three Japanese macaques and seven humans were determined in a
      free-field environment using loudspeakers. The monkeys and humans were tested
      using tones ranging from 8 Hz to 40 kHz and 4 Hz to 22.4 kHz, respectively. At a
      level of 60 dB sound pressure level the monkeys were able to hear tones extending
      from 28 Hz to 37 kHz with their best sensitivity of 1 dB occurring at 4 kHz. The
      human 60-dB hearing range extended from 31 Hz to 17.6 kHz with a best sensitivity
      of -10 dB at 2 and 4 kHz. These results indicate that the Japanese macaque has
      low-frequency hearing equal to that of humans and better than that indicated by
      previous audiograms obtained using headphones.

PMID- 10573912
TI  - Shock wave-inertial microbubble interaction: a theoretical study based on the
      Gilmore formulation for bubble dynamics.
AB  - The Gilmore formulation for bubble dynamics coupled with zeroth-order gas
      diffusion were used to investigate theoretically the cavitation activity produced
      by a modified XL-1 lithotripter [J. Acoust. Soc. Am. 105, 1997-2009 (1999)]. The
      model calculation confirms many of the basic features in bubble dynamics observed
      experimentally, in particular the strong secondary shock wave emission generated
      by in situ lithotripter shock wave-inertial microbubble interaction. In addition,
      shock wave-inertial microbubble interaction produced by a Dornier HM-3, the most
      commonly used clinical lithotripter, was evaluated. It was shown that the forced
      collapse of inertial microbubbles with strong secondary shock wave emission could
      be produced consistently, provided that an appropriate preceding shock wave and
      interpulse delay were used. Further, it was demonstrated that truncation of the
      tensile stress of the lithotripter shock wave could significantly reduce the
      large expansion of the bubble following shock wave-inertial microbubble
      interaction, which may alleviate the risk for vascular injury during shock wave
      exposure.

PMID- 10573913
TI  - Time delay spectrometry for hydrophone calibrations below 1 MHz.
AB  - Knowing the response of miniature ultrasonic hydrophones at frequencies below 1
      MHz is important for assessing the accuracy of acoustic pressure pulse
      measurements in medical ultrasound applications. Therefore, a time delay
      spectrometry (TDS) system was developed as an efficient means to measure
      hydrophone sensitivity in this frequency range. In TDS a swept-frequency signal
      is transmitted. A tracking receiver distinguishes arrivals with different
      propagation delays by their frequency offset relative to the signal being
      transmitted, thus eliminating spurious signals such as those reflected from the
      water surface or tank walls. Two piezoelectric ceramic source transducers were
      used: a standard planar disk and a disk with varying thickness to broaden the
      thickness-resonance. This latter design was preferred for its more uniform
      response without significant sensitivity loss. TDS is not an absolute method, but
      it was demonstrated to provide efficient, accurate calibrations via comparison
      with a reference hydrophone using a substitution technique.

PMID- 10573915
TI  - 'I think I can ... I thought I could ... I did'

PMID- 10573914
TI  - Intelligibility of 1/3-octave speech: greater contribution of frequencies outside
      than inside the nominal passband.
AB  - We reported previously that "everyday" sentences were highly intelligible when
      limited to a 1/3-octave passband centered at 1,500 Hz and having transition-band
      slopes of approximately 100 dB/octave. The present study determined the relative
      contributions to intelligibility made by the passband (PB) and the transition
      bands (TBs) by partitioning the same bandpass sentences using 2,000-order FIR
      filtering. Intelligibility scores were: PB with both TBs, 92%; deletion of both
      TBs (leaving only the 1/3-octave PB with nearly vertical slopes), 24%; deletion
      of the PB (leaving both TBs separated by a 1/3-octave gap), 83%. These and other
      results indicate a remarkable ability to compensate for severe spectral tilt and
      the consequent importance of considering frequencies outside the nominal passband
      in interpreting studies using filtered speech.

PMID- 10573916
TI  - Cardiac care.

PMID- 10573917
TI  - Staving off cynicism.

PMID- 10573918
TI  - Cancer awareness.

PMID- 10573919
TI  - Battling cancer in Nebraska.

PMID- 10573920
TI  - Battling cancer in Utah.

PMID- 10573921
TI  - More to it than smokeless.

PMID- 10573922
TI  - From south of the border.

PMID- 10573923
TI  - Extraction vs. nonextraction.

PMID- 10573924
TI  - Extraction vs. nonextraction. A second opinion.

PMID- 10573925
TI  - Extraction vs. nonextraction. And a third.

PMID- 10573926
TI  - Evidence-based dentistry.

PMID- 10573927
TI  - Evidence-based dentistry. Liked the letter.

PMID- 10573928
TI  - Form follows function.

PMID- 10573929
TI  - Self-interest vs. societal good.

PMID- 10573930
TI  - Digital radiography.

PMID- 10573931
TI  - Radiographic hysteria?

PMID- 10573932
TI  - Digital radiography. A note from industry.

PMID- 10573933
TI  - Battling drug resistance.

PMID- 10573934
TI  - Acrylic fingernails pose infection control risk.

PMID- 10573935
TI  - Vegetables may be good for your bones.

PMID- 10573936
TI  - Dental office planning.
AB  - BACKGROUND: A properly planned dental office can contribute directly to the
      success of your practice. Critical steps in creating a successful dental office
      environment are developing a design program, determining the size and cost of
      your facility, selecting a location and assembling the appropriate professionals
      to help with planning and construction. PRACTICE IMPLICATIONS: Planning a dental
      office is a multifaceted and complex task. For optimal results, you need to
      completely understand the design and construction process, as no other business
      activity will demand a greater investment of your time and money.

PMID- 10573937
TI  - Design for treatment.
AB  - BACKGROUND: The majority of treatment room configurations typically revolve
      around the dentist. However, a design based on the relationships among the
      dentist, patient, staff members and dental equipment results in a more
      functionally appropriate design. PRACTICE IMPLICATIONS: As the dental practice's
      primary production space, the treatment room should be designed as efficiently as
      possible. Ideally planned operatories will benefit your practice by allowing you
      to produce as much as you choose, while decreasing your stress level.

PMID- 10573938
TI  - Interior design for dentistry.
AB  - BACKGROUND: In the increasingly complex, competitive and stressful field of
      dentistry, effectively designed dental offices can offer significant benefits.
      Esthetic, functional and life-cycle cost issues to be considered when developing
      your interior design scheme include color, finishes, lighting, furnishings, art
      and accessories. PRACTICE IMPLICATIONS: An appropriately designed dental office
      serves as a valuable marketing tool for your practice, as well as a safe and
      enjoyable work environment. Qualified interior design professionals can help you
      make design decisions that can yield optimum results within your budget.

PMID- 10573939
TI  - Assessing fluoride levels of carbonated soft drinks.
AB  - BACKGROUND: Dental fluorosis occurs as a result of excessive total fluoride
      intake during tooth development. Some children may receive substantial intake
      from soft drinks, but few studies have reported fluoride levels in soft drinks.
      The authors examined the fluoride concentrations of 332 soft drinks. METHODS:
      Soft drinks were purchased from Iowa grocery stores. To identify production
      sites, the authors recorded product details and batch numbers. After
      decarbonating the drinks, the authors assayed samples for fluoride content using
      a fluoride ion-specific electrode, and reported the results in parts per million,
      or ppm, using appropriate standards and duplicate assessments. Descriptive
      statistics were used to summarize the findings. RESULTS: The fluoride levels of
      the products ranged from 0.02 to 1.28 ppm, with a mean level of 0.72 ppm.
      Fluoride levels exceeded 0.60 ppm for 71 percent of the products. Results varied
      substantially by production site, even within the same company and for the same
      product. There were no substantial differences between flavors or between diet
      and regular soft drinks. CONCLUSIONS: The majority of soft drinks had fluoride
      levels exceeding 0.60 ppm. Variation in fluoride levels probably is due largely
      to the different water sources used in production. CLINICAL IMPLICATIONS: With no
      fluoride levels marked on the soft drink products or easily available from the
      manufacturers, it is not possible for clinicians or consumers to directly
      estimate fluoride ingestion from carbonated beverages. Therefore, to reduce the
      risk of dental fluorosis, dental and medical practitioners should be cautious
      about prescribing dietary fluoride supplements to preschool-aged children in
      nonfluoridated areas who consume large quantities of carbonated soft drinks.

PMID- 10573940
TI  - Chewing tobacco use and dental caries among U.S. men.
AB  - BACKGROUND: Chewing tobacco has high levels of sugars and may be cariogenic, but
      few studies have investigated such an association. This study examined the
      relationship between chewing tobacco use and dental caries among U.S. adult men.
      METHODS: Participants in the Third National Health and Nutrition Examination
      Survey conducted from 1988 to 1994 were interviewed about tobacco use and
      examined by dentists. The authors included in their analysis dentate men 18 years
      of age or older. They calculated the mean number of decayed or filled permanent
      teeth, or DFT, and decayed or filled coronal tooth surfaces, or DFS, as well as
      the mean number and percentage of decayed or filled root surfaces, or RDFS, and
      decayed root surfaces, or RDS, by tobacco-use status. They used multiple logistic
      regression to examine the association between chewing tobacco use and root
      surface caries. RESULTS: Men who currently used only chewing tobacco had a higher
      adjusted mean number of DFT than did those who currently used only snuff, only
      cigarettes or more than one form of tobacco or who never used tobacco. Mean DFS
      also was higher among chewing tobacco users than among those who used only snuff,
      only cigarettes or more than one form of tobacco. Chewing tobacco users had a
      higher mean RDFS and RDS than did the users of other forms of tobacco or
      nonusers. Current users of chewing tobacco were more than four times as likely as
      those who never used tobacco to have one or more RDFS or RDS, with a dose
      response relationship between number of packages used per week and odds of having
      root-surface caries. CONCLUSIONS: In addition to its established role as a
      carcinogen, chewing tobacco may be a risk factor in the development of root
      surface caries and, to a lesser extent, coronal caries. This may be due to high
      sugar content, increased gingival recession and enhanced collagenase activity.
      CLINICAL IMPLICATIONS: Interventions by dentists and other members of the oral
      health care team to prevent tobacco use and help users quit can reduce the risk
      of developing oral and systemic disease.

PMID- 10573941
TI  - Recalcitrant oral ulcers caused by calcium channel blockers: diagnosis and
      treatment considerations.
AB  - BACKGROUND: Oral ulcers often pose a dilemma in diagnosis and treatment. Patients
      seen routinely in dental practices are frequently receiving multiple medications.
      The authors discuss the pathogenesis, clinical appearance and treatment of drug
      induced oral ulcers. CASE DESCRIPTIONS: Two patients with recalcitrant painful
      oral ulcers caused by calcium channel blockers are described. These ulcers failed
      to heal despite repeated interventions, including surgery, laser ablation, and
      topical and systemic steroid therapy. Results of the histopathologic examinations
      were nonspecific. The patients were in a great deal of pain because of the
      initial failure to recognize the cause of these ulcers. CLINICAL IMPLICATIONS: A
      careful medical history, including a detailed list of medications received, is
      critical in identifying drug-induced oral ulcerations, especially when the ulcer
      is resistant to treatment and of indeterminate cause. To date, calcium channel
      blockers have not been reported to cause oral ulcerations.

PMID- 10573942
TI  - The role of orthognathic surgery in the treatment of severe dentoalveolar
      extrusion.
AB  - BACKGROUND: When mandibular molars are not replaced after extraction, the long
      term problem of inadequate interarch space for either a fixed or removable
      prosthesis can occur. In the past, practitioners needed to decide whether to
      shorten the teeth, extract the supererupted maxillary molars to recapture space
      or leave the area unrestored. The authors present another option. CASE
      DESCRIPTION: A 61-year-old man was referred to a periodontist by his general
      dentist for placement of mandibular implants in the posterior sextant. Extreme
      supereruption of the maxillary dentoalveolar segment prevented restoration of the
      opposing edentulous area. An oral and maxillofacial surgeon performed a segmental
      osteotomy of the posterior right maxilla to gain needed interarch space. After
      the osteotomy was stabilized, the periodontist placed implants that were
      subsequently restored with a fixed prosthesis. CLINICAL IMPLICATIONS: The role of
      orthognathic surgery in treatment planning should not be overlooked in the
      comprehensive management of severe extrusion. It offers patients the opportunity
      to gain both function and esthetics that might otherwise be impossible.

PMID- 10573943
TI  - Quickly and easily temporizing a broken tooth.

PMID- 10573944
TI  - What legal issues are involved in terminating employment?

PMID- 10573945
TI  - Improving treatment plan acceptance using staff-driven diagnostic data
      collection.

PMID- 10573946
TI  - Building a better mousetrap: toward an understanding of osteoporosis.

PMID- 10573947
TI  - Trends in untreated caries in permanent teeth of children 6 to 18 years old.
AB  - BACKGROUND: This article is the first in a series of three that focus on recent
      changes in the caries status of children and adolescents in the United States.
      METHODS: This study is based on analyses of data regarding untreated carious
      permanent teeth among children 6 to 18 years of age from the first and third
      National Health and Nutrition Examination Surveys, or NHANES I and NHANES III.
      The NHANES is periodically conducted by the National Center for Health Statistics
      of the Centers for Disease Control and Prevention. RESULTS: Overall, the number
      of carious permanent teeth among children 6 to 18 years old decreased from 1.43,
      as measured in NHANES I, to 0.33, as measured in NHANES III. The number of
      carious permanent teeth in children 6 to 18 years old also decreased across four
      demographic variables: age, sex, race and poverty level. CONCLUSIONS: The number
      of untreated carious permanent teeth among children has declined dramatically.
      Since the 1970s, the absolute difference in untreated caries between
      disadvantaged children and the rest of the child population has narrowed
      substantially. PRACTICE IMPLICATIONS: The reduction in untreated caries, the
      major oral disease among children, has been dramatic in all subgroups of
      children. This may reinforce the already apparent shift from restorative to
      preventive dental services.

PMID- 10573948
TI  - The private lives of professionals.

PMID- 10573949
TI  - Dental unit waterlines: approaching the year 2000. ADA Council on Scientific
      Affairs.
AB  - BACKGROUND: This article discusses biofilm formation in dental unit waterlines
      and its resulting potential health effects. It also provides a review of ongoing
      research and available means to reduce microbial contamination in dental unit
      water. METHODS: An expert panel was convened by the American Dental Association
      Board of Trustees to discuss the implications of biofilms in dentistry. This
      report summarizes the panel's conclusions. CONCLUSIONS: The dental profession
      must continue its awareness of the presence of high levels of opportunistic
      microorganisms in dental unit water. Despite the lack of evidence of adverse
      health effects related to these microorganisms, they have the potential to
      overload the defense systems of immunocompromised patients and occupationally
      exposed dental staff members. Steps should be taken to improve dental unit water
      quality; contact of a patient's open wound, mucous membrane or body cavity with
      water of poor microbiological quality simply is inconsistent with patient
      expectations of modern dentistry. Efforts should continue to evaluate the health
      implications of biofilms in dentistry as new technology, research and data become
      available.

PMID- 10573950
TI  - Tobacco settlement dollars should reach root of problem.
AB  - Arkansas' share of the 1998 settlement between states and the tobacco industry
      amounts to about $1.62 billion over 25 years. How that money will be spent could
      be partially decided by the house tobacco settlement task force when it hears
      from health experts and others during meetings Nov. 2-4.

PMID- 10573951
TI  - Influenza vaccine update.

PMID- 10573952
TI  - A call for the judicious use of antibiotics.
AB  - In the United States alone, more than one-fifth of antibiotic prescriptions
      written are for viral illnesses. Due to the increasing resistance rates among
      commonly encountered bacteria, it is imperative that physicians re-examine their
      prescription writing habits. Physician and patient re-education, better use of
      diagnostic testing, the use of narrow spectrum antibiotic agents and shorter
      course therapy are essential for this to occur. The future health of Arkansas
      residents is dependent upon changes being implemented before it is too late.

PMID- 10573953
TI  - The waves of the electrocardiogram: Part 2. The QRS complex.

PMID- 10573954
TI  - Doctors not required to provide deaf with interpreters in all cases.

PMID- 10573955
TI  - [Guidelines for cleaning and disinfection/sterilization of endoscopes].
AB  - Endoscopy is a diagnostic and therapeutic method which is being increasingly used
      in various fields of medicine, especially in minimal invasive surgery. During the
      endoscopic procedure, endoscopes are contaminated with patient's microbial flora.
      After each procedure and before the next patient, endoscope should be reprocessed
      in a way to be safe from post-procedural infection. Endoscopes are divided in two
      categories (the borders between them are not always clear-cut): high-risk
      category endoscopes which enter the sterile tissue, and medium-risk category
      which come in contact with mucosal surface. High-risk endoscopes should be
      sterilized or high-level disinfected, and medium-risk should be high-level
      disinfected. The first and the most important step in endoscope reprocessing is
      thorough manual cleaning of all parts of dismantled endoscope and of all channels
      in water and (enzymatic) detergent. The second step is disinfection of endoscope
      fully immersed in 2% glutaraldehyde for 20 minutes at room temperature. The third
      step is thorough rinsing in sterile water or tap water followed by 70% ethanol,
      depending on the next endoscopic procedure. Steps 2-4 can be done in the machine.
      During endoscopy as well as during endoscope reprocessing, strict preventive
      measures should be followed for health care workers protection.

PMID- 10573956
TI  - [Personal experience with ultrasonic diagnosis of hypertrophic pyloric stenosis
      in infants].
AB  - Until wide use of ultrasound in diagnostic procedures took its part, the only
      relevant procedures to diagnose Infantile Hypertrophic Pyloric Stenosis (IHPS)
      were clinical examination and X-ray of gastroduodenal tract. Use of diagnostic
      ultrasound avoids harmful effects of X-rays on immature children's tissues.
      Reliability of the procedure is very high. In the period between July 1993 and
      January 1999 we diagnosed 12 cases of IHPS in our Hospital by ultrasound
      examinations. Eleven patients were males between five and eight weeks of age, and
      one female was six weeks old. In six of them the finding was confirmed by
      radiological examination (on surgeon's request), in one neither radiological
      examination not surgery was performed, and five were operated on the basis of
      only ultrasound finding. In eleven operated patients ultrasound finding is proven
      by surgery.

PMID- 10573957
TI  - [Occurrence of nonspecific symptoms of irritation in workers exposed to latex].
AB  - The study included 17 female workers employed in latex glove rubber manufacturing
      plants. The mean age was 42 years and the mean duration of employment 19 years.
      Subjects were predominantly nonsmokers. A control group of 17 nonexposed workers
      was also studied. Chronic respiratory symptoms and diseases as well as acute work
      related symptoms were recorded for these workers. Ventilatory capacity was
      measured by recording maximum expiratory flow-volume (MEFV) curves on which
      forced vital capacity (FVC), one second forced expiratory volume (FEV1) and
      maximum expiratory flow at 50% and the last 25% of the vital capacity (FEF50,
      FEF25) were read. Skin prick tests were performed with three types of latex
      (original material-latex 1, extract from gloves-latex 2, and extract of latex
      company Epypharm-latex 3). The prevalence of chronic respiratory symptoms was
      greater among latex workers (varying from 5.9% for occupational asthma to 58.8%
      for dyspnea) than among control workers (0%). There was a high prevalence of
      acute work-related symptoms, particularly for eye irritation (76.5%), dryness of
      the nose (70.6%), throat burning (70.6%), dryness of the throat (64.7%) and cough
      (58.8%). Measured ventilatory capacity data in latex workers were significantly
      lower in comparison to control, particularly for FEF25 (75.1 +/- 19.5%). Among
      latex gloves making workers one had positive skin reaction to latex 3 along with
      the symptoms of occupational asthma. Our data indicate that employment in latex
      making gloves may be associated with the development of occupational asthma, in
      addition to frequent nonspecific respiratory findings.

PMID- 10573958
TI  - [Sertraline in the treatment of premenstrual dysphoric disorder].
AB  - About 75% of women in reproductive age have some premenstrual changes. It is
      estimated that 2% to 10% of women experience symptoms severe enough to interfere
      with their professional or social activities and they meet the DSM-IV criteria
      for PMDD, premenstrual dysphoric disorder. Benzodiazepines and antidepressants
      have been shown to be effective treatments for PMDD; GnRH agonists are the second
      choice. New findings support the opinion that intermittent dosing of some
      antidepressants, e.g. selective serotonin reuptake inhibitors, is equivalent in
      efficacy to continuous drug treatment. The aim of the present study was to
      analyze the characteristics of premenstrual symptoms. In addition, the authors
      wanted to estimate the efficacy of intermittent sertraline dosing in the
      treatment of women with premenstrual dysphoric disorder. The study involved women
      employed in Vrapce Psychiatric Hospital. One hundred and thirty seven of them
      were examined for the presence of premenstrual symptoms. Seven women with PMDD
      were included in the treatment with sertraline. Symptoms were monitored with
      daily reports using the Calendar of Premenstrual Experiences (COPE). Six women
      completed the study. In three of them, sertraline given during the luteal phase
      produced significant improvements of premenstrual symptoms.

PMID- 10573959
TI  - [Endoscopic hernioplasty].
AB  - Development of the endoscopic surgery has made operations of the groin hernia by
      endoscopic technique possible. In spite of some dilemmas, the endoscopic
      hernioplasty takes place in the surgery. The advantages of this procedure are
      less recurrences, less postoperative pain, shorter hospital stay, quicker
      recovery and return to everyday activities, and better cosmetic effect. The
      benefit of this method is particularly visible after procedures on bilateral and
      recurrent hernias. In this review, we described surgical technique of endoscopic
      hernioplasty, possible complications, as well anatomical and pathophysiological
      basis important for the endoscopic approach.

PMID- 10573960
TI  - [Low-renin hypertension and inherited mineralocorticoid diseases].
AB  - Liddle's syndrome, apparent mineralocorticoid excess (AME) and glucocorticoid
      remediable aldosteronism (GRA) are inherited diseases characterized by
      hypertension and low plasma renin activity. Constitutive activation of distal
      renal epithelial sodium channel (Liddle's syndrome), defect in 11 beta
      hydroxysteroid dehydrogenase activity (AME) and unequal crossing over, fusing
      regulatory sequences of 11 beta-hydroxylase gene to coding sequences of
      aldosterone synthase gene and forming a new chimeric gene (GRA), cause apparent
      or real mineralocorticoid excess. This diseases are often being unrecognized and
      classified as essential hypertension, especially in patients with normal serum
      potassium level. Family history of hypertension and characteristic serum and
      urine++ steroid profile direct us to diagnosis, and genetic analysis will confirm
      it.

PMID- 10573961
TI  - [Development of beta-lactam antibiotic resistance in gram-negative bacteria and
      the impact of resistance on therapy].
AB  - Bacterial resistance to antibiotic is the inevitable consequence of the
      utilization of antimicrobial agents all over the world, particularly in developed
      countries. It is particularly evident with beta-lactam agents because they are
      among most frequently prescribed drugs. The resistance is mainly attributable to
      production of various types of beta-lactamases but other mechanisms like
      alterations in PBP molecules or in outer membrane proteins can play a significant
      role. Increased resistance can be seen among fastidious gram-negative bacteria
      like Haemophilus influenzae or Moraxella catarrhalis. The percentage of M.
      catarrhalis isolates producing beta-lactamases has increased to over 90%. Among
      Enterobacteriaceae E. coli and Klebsiella pneumoniae pose a very serious problem
      because of the production of extended-spectrum beta-lactamases which confer
      resistance to third generation cephalosporins. The percentage of ampicillin
      resistant E. coli among hospital isolates has rosen to 78% in U.S.A. nowadays.
      Recently, the emergence of E. coli strain resistant to combination of amoxycillin
      and clavulanate, due to hyperproduction of TEM-1 beta-lactamase, was observed.
      Inducible beta-lactamases mediate beta-lactam resistance in Pseudomonas
      aeruginosa which often develops during therapy of P. aeruginosa infections.
      Imipenem resistance is increasingly prevalent among P. aeruginosa isolates
      nowadays, but can be detected in K. pneumoniae due to the production of novel
      beta-lactamases and changes in outer membrane proteins.

PMID- 10573962
TI  - [50 years' of use of liver biopsy in clinical diagnosis in Zagreb].
AB  - The author presents his clinical experience and that of his collaborators with
      the use of liver biopsy as a useful diagnostic method. This paper is written on
      the occasion of the 50th anniversary of the introduction of this method into
      clinical practice in Croatia.

PMID- 10573963
TI  - [The role of Dr. Vladimir Cepulic in Croatian orthopedics].
AB  - Professor B. Spisic is rightly referred to as founder of the Croatian
      orthopaedics and rehabilitation. Based on the principles formulated by Prof. B.
      Spisic the next generations of Croatian orthopaedists gave their contribution to
      the remarkable building of the orthopaedics. The First World War gave a strong
      impetus to the development of orthopaedics, as well as medical and social
      rehabilitation in Croatia. Dr. V. Cepulic was among the first who, as early as
      1915, joined Dr. B. Spisic. Their close and fruitful collaboration was disrupted
      by Dr. V. Cepulic's long absence because of illness. Later on, Dr. V. Cepulic
      became a famous Croatian physiologist. Owing to his contribution in fighting
      tuberculosis in Croatia, as well as his merits for the Croatian Medical
      Association, he is among the most prominent Croatian doctors. On this occasion,
      the memory of his place in the history of Croatian orthopaedics, that is less
      known, is refreshed.

PMID- 10573964
TI  - [Reintegration of health services in the Danube area of the Croatian health care
      system: introduction of laparoscopic surgery in the Vukovar General Hospital].
AB  - After six years of occupation, in the second half of 1997 started the
      reintegration of the Danube region in the Croatian health care system.
      Introducing of the laparoscopic surgery in Vukovar General Hospital has been
      presented in this article. A part of the laparoscopic equipment and reusable
      instruments was a gift of the Croatian Institute for Health Insurance, and some
      equipment and instruments were bought. Until now, 170,000 HRK has been spent for
      laparoscopic surgery. The first laparoscopic operations--laparoscopic
      cholecystectomies in our hospital were performed on June 25, 1998. From October
      1, 1998, laparoscopic operations have been regularly done. Until December 24,
      1998, laparoscopic cholecystectomies, hernioplasties, appendectomies and
      diagnostic laparoscopies were performed. The total number of laparoscopically
      operated patients is 23. We did not have serious intra or postoperative
      complications. On November 20-21, the 10th postgraduate course on laparoscopic
      cholecystectomy was organized in our hospital. In a relatively short time and
      specific circumstances, laparoscopic surgery has become a standard surgical
      method in Vukovar General Hospital.

PMID- 10573966
TI  - Bone and tissue banking: the need and scope in India.

PMID- 10573965
TI  - [Privatization of primary health care].

PMID- 10573967
TI  - Caesarean section on the rise.

PMID- 10573968
TI  - Age- and height-specific reference limits of blood pressure of Indian children.
AB  - BACKGROUND: Blood pressure in childhood is the most powerful predictor of
      hypertension in adults. Norms for blood pressure in children are based on the age
      and height-specific distribution of blood pressure in a reference sample of
      healthy children. METHODS: We performed a cross-sectional survey of school
      children in the age group 5 to 14 years in south Delhi and studied the
      distribution of systolic and diastolic blood pressure in 8293 children (4623 boys
      and 3670 girls). Blood pressure was measured in all children with a mercury
      column sphygmomanometer using a standardized technique. The first and the fourth
      Korotkoff sounds were taken as indicative of the systolic and the diastolic blood
      pressure, respectively. Height percentiles were computed for the study sample for
      every one-year sex-pooled group. Multiple linear regression was then performed
      for every one-year group in order to estimate the 90th and 95th percentiles of
      systolic and diastolic blood pressure according to percentiles of height.
      RESULTS: Age and height, but not gender, emerged as the principal determinants of
      systolic and diastolic blood pressure in multivariable linear regression
      analyses. Age- and height-specific 90th and 95th percentile values of systolic
      and diastolic blood pressure were estimated, which enabled us to categorize
      children into 'normal', 'high normal' and 'high' blood pressure groups.
      CONCLUSIONS: We present age- and height-specific reference values for blood
      pressure of Indian children based on a large study sample. The use of these
      standards should aid the identification of children with high blood pressure.

PMID- 10573969
TI  - A high rate of caesarean sections in an affluent section of Chennai: is it cause
      for concern?
AB  - BACKGROUND: While rising Caesarean section rates have been the subject of much
      attention and debate worldwide, there is not much information available on this
      rate and its potential adverse impact in India. METHODS: Our survey was a
      standard Expanded Programme on Immunization 30-cluster design, carried out in an
      urban educated, middle/upper class population in Chennai. Mothers of 210 children
      aged 12-36 months were interviewed and data collected on immunization and breast
      feeding practices. Since the mode of delivery was one of the questions, we could
      generate population-based data on the Caesarean section rate and its influence on
      breast-feeding. RESULTS: Of the 210 babies, 95 (45%, 95% confidence interval:
      39.1-51.3) had been delivered by Caesarean section. Two hundred and six of 210
      babies (98%) had been breast-fed at some time. However, babies born by Caesarean
      section tended to be started late on breast-feeds were given prelacteal feeds
      more often, and colostrum less often when compared to babies delivered vaginally
      (all statistically significant). CONCLUSIONS: Our study revealed a very high rate
      of Caesarean section in the selected metropolitan population. On purely
      scientific grounds, a rate of 40% to 50% is extremely difficult to justify.
      Though not conclusive, the data also suggest that Caesarean section may be
      adversely affecting some aspects of breast-feeding. There is a need for more data
      and audits on Caesarean section rates in India, and a wider debate on its
      potential adverse impact on the health of mothers and newborns.

PMID- 10573970
TI  - Detection of antibodies to HIV in saliva.
AB  - BACKGROUND: Saliva has been recommended as an alternative non-invasive specimen
      for detection of antibodies to human immunodeficiency virus (HIV) because of the
      inherent disadvantages of using serum for such testing. METHODS: In a double
      blind study, paired serum and saliva specimens were collected from 100 known HIV
      antibody seropositive and 100 seronegative individuals. The serum was tested in
      the conventional way while saliva was tested after modifying the routinely used
      serum enzyme-linked immunosorbent assay so as to detect antibodies to HIV from
      saliva. RESULTS: The sensitivity of saliva for HIV antibody detection using the
      modified test protocol was found to be 95% by GENELAVIA MIXT ELISA and 97% by
      DETECT-HIV ELISA, while the specificity for both was 100%. Identical results were
      obtained even after 7 months of storage of the saliva at 4 degrees C without any
      preservatives. CONCLUSION: Saliva is a safe and cost-effective alternative to
      serum for HIV antibody detection for most surveillance purposes but not for
      diagnostic purposes.

PMID- 10573971
TI  - Mechanisms of resistance to fluoroquinolones.
AB  - Fluoroquinolones have some of the properties of an 'ideal' anti-microbial agent.
      Because of their potent broad spectrum activity and absence of transferable
      mechanism of resistance or inactivating enzymes, it was hoped that clinical
      resistance to this useful group of drugs would not occur. However, over the
      years, due to intense selective pressure and relative lack of potency of the
      available quinolones against some strains, bacteria have evolved at least two
      mechanisms of resistance: (i) alteration of molecular targets, and (ii) reduction
      of drug accumulation. DNA gyrase and topoisomerase IV are the two molecular
      targets of fluoroquinolones. Mutations in specified regions (quinolone resistance
      determining region) in genes coding for the gyrase and/or topoisomerase leads to
      clinical resistance. An efflux pump effective in pumping out hydrophilic
      quinolones has been described. Newer fluoroquinolones which recognize both
      molecular targets and have improved pharmacokinetic properties offer hope of
      higher potency, thereby reducing the probability of development of resistance.

PMID- 10573972
TI  - Fibre works, but not wonders.

PMID- 10573973
TI  - Oral antibiotics can be used safely for the initial treatment of neutropenic
      fever.

PMID- 10573974
TI  - Approach to a patient with polyarthritis.

PMID- 10573975
TI  - Approach to a child with short stature.

PMID- 10573976
TI  - Survival analysis: an introduction.

PMID- 10573977
TI  - Evolving a strategy for control of sexually transmitted diseases in a developing
      country.

PMID- 10573978
TI  - Health care and the war.

PMID- 10573979
TI  - Elections to the Maharashtra Medical Council 1999.

PMID- 10573980
TI  - Current indications for hormone replacement therapy.

PMID- 10573981
TI  - Netilmicin resistance in Staphylococcus aureus.

PMID- 10573982
TI  - Low-dose urography with indigenous low osomolar contrast media.

PMID- 10573983
TI  - Blood transfusion: does it cause leucocytosis and relative lymphocytopenia?

PMID- 10573984
TI  - Visual evoked response (VER) in ocular ethambutol toxicity.

PMID- 10573985
TI  - Hospital Infection Control Committee.

PMID- 10573986
TI  - [Current aspects of the pathogenesis and clinical characteristics of
      otosclerosis: possibilities of drug therapy].
AB  - Otosclerosis is a multifactorial disease. A number of theories on the
      pathogenesis of this disease have been established in the last decades. It is
      important to review recent data on the pathogenesis of otosclerosis as it is a
      severe inner ear disease leading to deafness in the majority of cases. Surgical
      therapy is not always successful or feasible. In this review, authors describe
      the most relevant genetic, infective, immunological, inflammatory factors, as
      well as the impaired bone metabolism underlying the pathogenesis of otosclerosis.
      It is likely that genetic predisposition associated with morbilli infection may
      lead to bone resorption in the stapes and cochlea followed by spongiosis,
      fibrosis and sclerosis. It has been suggested that immunological mechanisms play
      a central role in the development of the disease. Some authors consider
      otosclerosis as autoimmune disorder based on the presence of several
      autoantibodies. Apart from classical diagnostic methods, such as audiometry and X
      ray, novel radiological techniques including CT, MRI or radionuclide scan are
      helpful in the localization of otosclerosis. As surgery is sometimes
      contraindicated or unsuccessful, drug therapy including the use of anti
      osteoporotic on non-steroidal antiinflammatory drugs may be administered,
      especially in the early phase of the disease.

PMID- 10573987
TI  - [Analysis of T-cell receptor gamma-gene rearrangement in lymphoproliferative
      disorders using polymerase chain reaction].
AB  - T-cell non-Hodgkin's lymphomas (NHL) exhibit a clonal T-cell receptor (TCR) gamma
      gene rearrangement as a result of sequential assembly of their variable (V gamma)
      and joining (J gamma) region segments. The analysis of the TCR gamma gene
      rearrangements may help to differentiate reactive lymphoproliferations from T
      cell NHLs. The aim of this study was to reveal the usefulness of polymerase chain
      reaction (PCR) analysis of the TCR gamma gene rearrangement in the diagnosis of T
      cell NHLs using native and formol-paraffin embedded tissues. The PCR
      amplification of the TCR gamma gene was performed by the V gamma specific sense
      and J gamma specific antisense primer pairs. The PCR products were evaluated by
      polyacrilamide gel electrophoresis containing ethidium bromide. The PCR analysis
      of the TCR gamma gene rearrangements has been performed in 95 lymphoproliferative
      disorders. The PCR analysis of the TCR gamma gene showed clonal gene
      rearrangement in 22 cases out of the 39 T-cell NHLs and in one case out of the 12
      O-cell anaplastic large cell lymphoma but no clonal rearrangements were detected
      in any of the 15 reactive lymphoproliferations or 13 B-cell NHLs. Thus, clonal
      TCR gamma gene rearrangements was detected by PCR in 58.2% of T-cell NHLs but no
      clonal TCR gamma gene rearrangements were shown in any of reactive
      lymphoproliferations of B-cell NHLs. These studied showed that the PCR
      amplification of the TCR gamma gene can be a powerful tool in the diagnosis of T
      cell NHLs.

PMID- 10573988
TI  - [The role of endoscopic ligation in the management of esophageal varices and
      rupture].
AB  - In the last two decades sclerotherapy has became one of the most widespread
      procedures in the palliative therapy of esophageal varicosity and rupture. Beside
      many of its advantages, there are high numbers of local and general
      complications. The new ligation method is very effective, but less invasive and
      free from side effects. The single shot method in spite of using overtube is
      slower, unpleasant and not free from risks. The new six shooter system, which
      uses 6 rubber-bands eliminates these disadvantages. This technique was introduced
      the first time in Hungary by the authors. They performed ligations between June
      1997 and June 1999 on 39 random patients, 55 times. 41 times due to rupture of
      varices, 8 times in no-bleeding periods for eradication of varices, 6 times for
      prophylaxis. The average age was 51 (27-75), 32 men and 7 women participating.
      The cause of esophageal varicosity was thrombosis of vena portae in 1 patient and
      cirrhosis in others. The background of the cirrhosis was alcohol in all cases
      except for one which was due to alcohol and hepatitis C in addition. Altogether
      346 rubber-bands were applied. The average ligation was 6.3 (3-17) per patient
      and 4.5 (3-6) per session. The 41 ruptures of the 32 patients were treated with
      80 units of blood, not including one patient given 29 units of blood who had
      mortal haemorrhage. It means 2.5 units of blood per patient and 2 units per varix
      rupture. After ligation patients had no complaints except for retrosternal
      discomfort in some patients. There were no complications observed. The mortality
      rate was 5 out of 32 one patient died due to bleeding. The follow up of the
      ligation was carried out by endoscopy and in the 4 dead patients by pathological
      procedures. The ligation method which was applied by the authors is effective,
      faster and has less complications in varix irradications than sclerotherapy. The
      prophylactic therapy of high risk patients and other therapeutic indications can
      contribute to its wider utilization.

PMID- 10573989
TI  - [Abdominal actinomycosis presenting as a malignant tumor--report of a case and
      review of the literature].
AB  - Actinomyces israelii is a normal inhabitant in the gastrointestinal tract of
      humans, it rarely causes disease. Abdominal involvement occurs in only 20 percent
      of all cases and can mimic malignant diseases, tuberculosis and inflammatory
      bowel disease. A case of a 36 years old female patient with abdominal
      actinomycosis and review of the literature is reported. Symptoms was presented as
      an acute abdomen associated with painful epigastric and left subcostal mass. The
      pathologic process infiltrated the retroperitoneal space simulated sarcoma or
      lymphoma. Diagnosis was established only at the second laparotomy, when
      histologic examination of the removed lymph node disclosed actinomycosis. The
      patient is completely free of symptoms 6 month after the second operation.

PMID- 10573990
TI  - [Certain characteristics of renaissance science].

PMID- 10573991
TI  - [Imaging of the heart on Hungarian medical medals].

PMID- 10573992
TI  - [Home childbirth].

PMID- 10573993
TI  - [Complications of central venous catheterization].

PMID- 10573994
TI  - [Psychosomatic rehabilitation].

PMID- 10573995
TI  - [Psychosomatic rehabilitation. Self-image, rehabilitative concepts,
      psychotherapeutic approaches, need vs. demand issues].
AB  - To provide optimal medical care for patients with psychosomatic disorders,
      rehabilitation and acute medicine should be viewed as separate but related parts
      of one overall health care concept. Psychosomatic rehabilitation now plays a
      major role in the care of chronically ill patients beyond the framework of
      traditional medical psychotherapy. The self image and rehabilitative concepts of
      this field are strongly influenced by two cornerstones of psychotherapy:
      psychodynamics and behavioral science. In the past the main factors used to
      define requirements for inpatient care were the capacity of existing facilities
      and the degree of their utilization; what was and still is lacking is an expert
      assessment of real demand. By offering programs for a broad spectrum of chronic
      disorders, the field of psychosomatic rehabilitation has achieved impressive
      therapeutic results at moderate cost; this assertion is substantiated by numerous
      analyses of the health care system. However, the high quality standard in the
      field of psychosomatic rehabilitation is currently endangered by politically
      motivated economic measures and the accompanying reduction of therapy time. If
      this counterproductive trend is not halted, the inevitable outcome will be
      suboptimal--in particular for chronically ill patients. In conclusion,
      possibilities are outlined for improved networking among professionals in
      psychosomatic rehabilitation.

PMID- 10573996
TI  - [Current trends in medical rehabilitation and their significance for the field of
      psychosomatic rehabilitation].
AB  - At present the process of serious restructuring can be observed in the system of
      medical rehabilitation in Germany. This paper focuses on recently initiated
      innovations and their consequences for psychosomatic rehabilitation. The
      patient's access to a psychosomatic rehabilitation system is analysed and
      examined to what extent innovations increase early detection of patients with
      psychosomatic disorders. Regarding the structure of psychosomatic rehabilitative
      offers, the initiated innovations such as an increase of flexibility, better
      transition and improvement of inpatient rehabilitative offers are described and
      discussed. Finally, the development of quality improvement programs and
      rehabilitation research in the field of psychosomatic rehabilitation is
      presented. Although many changes have taken place up to now, further relevant
      modifications in psychosomatic rehabilitation are predicted by the authors.

PMID- 10573997
TI  - [Medical and legal aspects of differentiation of inpatient psychotherapeutic
      treatment from psychosomatic rehabilitation].
AB  - In the field of psychotherapeutic and psychosomatic medicine inpatient treatment
      is indicated in cases of instability of patients, comorbidity with severe organic
      disease, not yet clearly diagnosed and potentially dangerous symptoms, lack of
      understanding the nature of the psychosomatic illness and of motivation for
      psychotherapy and sometimes organizational reasons or the necessity to remove the
      patient from his private or professional conflicts. To differentiate between
      hospital treatment and psychosomatic rehabilitation is more difficult than in
      other medical settings. Medical and legal aspects of this indication problem are
      presented as well as solutions in way of networks of treatment processes.

PMID- 10573998
TI  - [Quality assurance in the field of psychosomatic rehabilitation].
AB  - Since the mid 1990s, the statutory pension insurance agencies have developed and
      begun to implement a broad program for quality management in the field of medical
      rehabilitation. A total of 942 rehabilitation clinics from all areas of
      indication, including the field of psychosomatic rehabilitation, are currently
      participating in the program. In its first program point, the 5-point program
      deals with the collection and analysis of structural and conceptual aspects.
      Program point 2 deals with the documentation of therapy plans for the primary
      treatment groups; in program point 3, clinical documentations are used for a
      quality screening (peer review procedure), and in point four, patient
      satisfaction and treatment results will be evaluated by patient interviews. The
      analysis of inadequacies performed within these program points will be returned
      to the clinics by means of an information system. Thus, the clinics receive
      information on the conditions in their own clinics against the backdrop of
      results from clinics with similar structures. The quality problems which are
      identified, will be dealt with in the framework of quality circles (program point
      5). This article describes and discusses the specifications of the quality
      assurance program for the field of psychosomatic rehabilitation.

PMID- 10573999
TI  - [Analysis of premature termination in inpatient psychosomatic rehabilitation
      based on epidemiologic data from two hospital companies].
AB  - Premature termination of inpatient psychotherapy can have multiple, mostly
      negative, effects for patients, therapists, clinics, insurance companies, and
      employers, but research regarding inpatient settings is still deficient. The
      analysis of two sets of data of four different rehabilitation clinics from two
      different hospital companies (2699 and 2215 patients, respectively), aimed at
      possible predictors and outcomes of premature termination. We found ratios of
      premature termination of 8.3% and 14.7%, respectively. Especially young patients
      under 30 years of age and patients with eating and personality disorders were
      more likely to terminate inpatient treatment prematurely. Treatment outcome as
      rated by therapists was in significantly fewer cases among premature terminators
      than among successful terminators improved. The results seem to indicate, that
      assignment to inpatient psychotherapy can be optimized. For a better
      understanding of the process of premature termination more theory guided
      prospective and followup studies are necessary.

PMID- 10574000
TI  - [Development of a questionnaire for a standard follow-up assessment procedure for
      inpatient psychosomatic rehabilitation].
AB  - The paper establishes a follow-up assessment procedure for inpatient
      psychotherapy. It is suited for more than one theoretical approach or specific
      disorder. Using data from a larger follow-up-study, those items are identified
      that show substantial correlations with health and resource oriented
      questionnaires. In a second analysis, items are selected that predict therapeutic
      effects on parameters of health-behavior. This pool of items has to be completed
      by items constructed by plausibility criteria.

PMID- 10574001
TI  - [Long-term outcomes of psychosomatic rehabilitation].
AB  - According to the latest state of research psychosomatic rehabilitation can be
      considered as effective and efficient. Several program-evaluation studies
      document process and outcomes of over 4000 psychosomatic patients in
      rehabilitation clinics so far. The majority of patients in all studies show
      positive therapy outcomes, which also can be demonstrated in follow-up
      investigations. Those positive results cover disease and disorder related aspects
      as well as cost relevant facets. This paper presents one of those program
      evaluation studies which reports the outcomes of a one year and a five year
      follow-up respectively. It focuses on the outcomes of those subjects which
      participated in both inquiries. In addition to single criteria the construction
      of a multiple outcome criterion is discussed.

PMID- 10574002
TI  - [Success of psychosomatic rehabilitation as a function of treatment length].
AB  - Clinical practice, effect studies, the time structure of psychotherapeutic
      processes and treatment outcome data show that the legally provided treatment
      time of no more than 3 weeks for inpatient medical rehabilitation is usually not
      sufficient to achieve satisfactory and long-term stable psychotherapeutic
      improvement. In an evaluation study in a psychosomatic rehabilitation clinic the
      change in symptoms of 266 inpatients was recorded using the German version of the
      CES-D scale (ADS-L) and the Symptom Check List SCL90R. Values obtained after 21
      days of treatment were compared with data obtained on discharge after an average
      of 45 days. Multiple patient characteristics, therapy parameters and process
      aspects were studied empirically in order to select patient groups which show
      sufficient effects after a 3 weeks treatment. Irrespective of patient
      characteristics, therapeutic experience, clinically significant and long-term
      stable effects were only achieved after treatment periods exceeding 3 weeks.

PMID- 10574003
TI  - [Cost-benefit aspects in psychosomatic rehabilitation].
AB  - The active participation of patients in their healing process and early
      behavioral rehabilitation both cause a considerable and steady improvement of
      psychosomatic diseases. The results of a multicenter study show that patients
      become less ill, have shorter diseases and that their consumption of drugs
      decreases considerably following an inpatient behavior therapy. These changes
      also have an economical significance: Employers have to spend considerably less
      continued payments and health insurers have reduced expenses for medical
      treatments. The inpatient medical rehabilitation of psychosomatic disorders can
      cause a reduction of illness related costs of up to 2.5 billion DM annually.

PMID- 10574004
TI  - [Work and vocational integration of psychosomatic patients--utilization and
      indications for a workload tryout program].
AB  - The effect of a professional workload test was assessed in a longitudinal study
      with 80 patients psychosomatic rehabilitation during and following their. In a
      second study indication criteria were tested with 358 consecutive patients.
      Participants in the workload program show an improvement of their work ability
      and job performance according to self-appraisal, superior appraisal and medical
      assessment. Work ability was still maintained 7 months after treatment. Patients
      with lasting work disability and unemployment not only show negative work-related
      attitudes, but also elevated psychological symptoms and a reduced quality of
      life. The program participants show high levels of psychological strain but also
      a stronger disposition to change the professional situation. Negative work
      related and psychological consequences of lasting disability and unemployment
      deserve more attention in inpatient psychosomatic treatment.

PMID- 10574005
TI  - [Psychosomatic disease in female teachers. Social context, contents and
      perspectives of inpatient treatment with a goal of rehabilitation and return to
      work].
AB  - Despite the considerable consequences, school teachers treated in psychosomatic
      in-patient settings, have not yet been the subject of investigations. Whether,
      for whom and which kind of job related treatment can be helpful for teachers
      returning to work can only be discussed if the specific stress and the social
      situation of teachers as public officials ("Beamtenstatus") are taken into
      consideration. On this point of view a systematic evaluation of 63
      psychosomatically ill teachers consecutively admitted in a psychosomatic hospital
      was performed. The average age was 50, suffering mostly from depression or/and
      tinnitus. Most teachers rated job related stress as influencing their
      symptomatologies. A program focusing on discrepancies between personal ideals
      versus real situations in school, problems in social interactions and time
      management, should be a valuable part of the teachers' psychosomatic inpatient
      treatment. This approach was affected by a strong desire for early retirement in
      about half of the teachers.

PMID- 10574006
TI  - [Patient satisfaction with outpatient preparation prior to inpatient
      psychosomatic rehabilitation].
AB  - Patients often show lack of motivation prior to an inpatient behavioral therapy.
      On the other hand patients have problems to transfer the clinical experience into
      every day life after discharge. The test program "preparation and follow-up of
      psychosomatic inpatients" of the Psychosomatic Clinic Bad Durkheim tries to solve
      these problems by selected interventions. This pilot program is evaluated in a
      field study with an experimental and a control group. The control group receives
      the regular inpatient treatment program. The experimental group additional
      outpatient interventions. The article presents a part of the total evaluation:
      acceptance of prestationary information. This was examined with an especially
      developed assessment questionnaire and a discharge questionnaire. The data
      clearly show a considerable patient' acceptance of these offers and their
      positive consequences on the individual therapy. The acceptance of the
      prestationary information meetings is thereby quite irrespective of the patient's
      age, gender, school education, and diagnosis.

PMID- 10574007
TI  - [Results of a 1-year follow-up study of neighborhood ambulatory aftercare after
      inpatient psychosomatic rehabilitation].
AB  - Attention has been repeatedly drawn to the necessity to support patients after
      psychosomatic rehabilitation with their transfer of skills acquired during their
      stay at the interface between their inpatient treatment and their reintegration
      into everyday life. The authors' concept of the outpatient aftercare was already
      introduced in an earlier paper. This article presents the results of the one-year
      follow-up. A comparison with a control group revealed a further reduction of
      patients' depression. In contrast to the control group, the reduction in fear and
      discomfort already achieved during inpatient rehabilitation remained stable. At
      the same time the ability to cope with everyday life was expanded. Compared with
      the control group the participants of the aftercare could reduce the absence from
      work, days spent in hospital and visits to the doctor more than twice as much.
      Methodological problems of the design of the study are critically discussed.

PMID- 10574008
TI  - [Descriptive epidemiology of malignant tumors in children].
AB  - The object of this study is to present the descriptive epidemiology of cancer in
      children at the world and national levels. The international and national
      literature published on cancer in children was comprehensively reviewed, with
      emphasis on reports treating epidemiological aspects of time, place and person.
      For practical reasons and with the aim of integrating the information, only the
      more relevant publications were included. Incidence and child mortality were
      analyzed. Overall incidence is between 100 and 150 (annual rates = cases x 10(6)
      children). Specific incidence varies according to the type of cancer, the region
      and the country. The Latin American pattern of neoplasms is constituted by
      leukemias, lymphomas, and central nervous system tumors (CNST); in the
      Northamerican/European pattern the CNST appear in second place and in the African
      pattern, lymphomas show predominance. Incidence is higher among the younger than
      5 year olds, from urban environments, and there is a 1% annual increase of cancer
      in Northamerican children. Child mortality has diminished remarkably, mainly in
      developed countries, whereas in developing or underdeveloped countries, incidence
      remains stable or shows a slight fall. The incidence of cancer in children is
      greater in developed countries, but in underdeveloped countries it may be
      underestimated. These countries have not managed to reduce the incidence of child
      mortality caused by cancer, as have the United States or Great Britain. Further
      studies on the epidemiology of cancer in children are necessary, since many data
      remain unknown.

PMID- 10574009
TI  - Urinary tract infection: detection of Escherichia coli antigens in human urine
      with an ELIEDA immunoenzymatic assay.
AB  - Escherichia coli is the most common causative agent of urinary tract infection
      (UTI), and diagnosing this infection usually relies on bacteriologic methods.
      Nevertheless, screening methods can be useful for a rapid presumptive diagnosis
      even though some of these screening methods have low sensitivity or are
      expensive. To investigate a possible new alternative approach, an antigen-based
      immunoassay--enzyme-linked immunoelectrodiffusion assay (ELIEDA)--was
      standardized for screening for this bacterial infection. Combining counter
      immunoelectrophoresis with an immunoenzymatic assay, the ELIEDA requires
      concentrated urine specimens, a cellulose acetate membrane, polyclonal antibodies
      to E. coli raised in rabbits, and peroxidase-labeled sheep antibodies to rabbit
      immunoglobulin G (IgG). This ELIEDA technique was evaluated using 244 urine
      specimens, 76 of them with E. coli, 47 with heterologous bacteria, and 121
      without bacteria. In comparison to bacteriologic methods, the sensitivity,
      specificity, and positive and negative predictive values for the ELIEDA were
      93.4%, 98.2%, 95.9%, and 97.1%, respectively. The data obtained suggest that this
      assay is useful for routine diagnostic screening for UTI caused by E. coli. In
      addition, since the ELIEDA stained membranes can be stored, this assay makes
      retrospective studies possible.

PMID- 10574010
TI  - [Risk factors of low birth weight. Provincial Gynecologic-Obstetric Hospital of
      Sancti Spiritus, Cuba].
AB  - The objective of this work was to identify some risk factors that women could
      present during pregnancy and that are associated with low birthweight (less than
      2,500 g). A study was performed during 1994 with 378 cases and 649 controls at
      the Provincial Obstetric-Gynecologic Hospital of Sancti Spiritus, Cuba. The data
      were obtained from clinical histories, the registry of births, and personal
      interviews with mothers. A bivariate analysis was carried out and possible
      confounding factors were controlled utilizing dichotomous logistic regression,
      using the Epi Info 5 and SPSS software programs. With the final multivariate
      model, the following risk factors for low birthweight were identified as
      significant: hypertension during pregnancy, infrequent checkups during pregnancy,
      previous abortions, a period of less than 2 years since the last birth, and a
      maternal weight increase of less than 8 kg. Priority should be given to these
      last three variables in order to maintain the high standards of the maternal and
      child health program of Sancti Spiritus Province, Cuba.

PMID- 10574011
TI  - [Infectious and parasitic diseases in Brazil: a decade of transition].
AB  - Brazil has been undergoing a period of epidemiological and demographic
      transition, which has included an improvement in the quality of death certificate
      registrations and major changes in the patterns of mortality from infectious and
      parasitic diseases. This article outlines the changes in the mortality patterns
      that were observed in the country and in its states during the decade of the
      1980s. We used data from the Ministry of Health Mortality Information System,
      classified according to the International Classification of Diseases, 9th
      Revision. Our analysis showed important changes in mortality patterns in Brazil.
      Mortality from infectious diseases decreased by 41% among men and by 44% among
      women. While these types of changes were especially noticeable in the states of
      the North and Northeast, these states still have the highest mortality rates in
      the country. The changes particularly affected the extreme limits of the age
      continuum, most especially children under 1 year of age. Within the group of
      infectious and parasitic diseases, we also assessed the mortality due to
      intestinal infectious diseases, tuberculosis, and septicemia. We found that in
      the 1980s there was a major decrease in the rates of mortality due to intestinal
      infectious diseases and to tuberculosis. However, there was an increase in the
      risk of death from septicemia during the decade. In conclusion, we find that the
      rate of mortality caused by infectious and parasitic diseases remains high in
      Brazil. Therefore, Brazilian health authorities still need to give priority
      attention to this cause of death.

PMID- 10574012
TI  - Seroprevalence of Trypanosoma cruzi infection in three rural communities in
      Guatemala.
AB  - A systematic, house-based serological survey for Trypanosoma cruzi seroreactivity
      was conducted in three contiguous communities in Olopa municipality, Chiquimula
      Department, Guatemala. Blood samples from a total of 292 individuals in 63
      households were examined by enzyme-linked immunosorbent assay. The seropositive
      rate ranged from 0% to 20.8% for the three communities, with a mean of 15.1%. Log
      linear models showed that seroprevalence was significantly related to age (P <
      0.005) but not to sex. However, when the age group with the lowest prevalence (1
      9 years) was excluded from the analysis, age was not a significant factor (P =
      0.55). Data from a stratified sample collected at the same time were combined
      with those of the systematic sample to analyze the relationship between
      seropositivity and possible explanatory variables. Log-linear models, based on
      586 individuals in 129 households from the two surveys, revealed a significant
      positive association between seropositivity and thatched roofs (P = 0.01).

PMID- 10574013
TI  - [Milk fluoridation program in Codegua, Chile: evaluation after 3 years].
AB  - A study was done in 1994 to determine the effectiveness of the fluoridated dairy
      products that the Chilean National Program for Supplementary Feeding had been
      distributing to reduce the high prevalence of children's dental caries in rural
      areas of that country. For the study, the prevalence of caries was assessed in
      two rural communities of the Sixth Region of Chile. Children in the study
      community of Codegua had received fluoridated dairy products, while children in
      the control community of La Punta had received nonfluoridated dairy products.
      Three years after the program began in Codegua, the community showed a
      significant improvement in the indices of prevalence of caries. Over that time
      period, the prevalence of caries among children 3 to 6 years old declined between
      40% and 60%. Among children 3 years old, the proportion of them without a history
      of caries increased by 74%, from 40.7% to 70.8%. Among 4-year-olds, that
      proportion rose by 71%, from 33.3% to 56.9%. Similar to results obtained
      elsewhere with programs to fluoridate drinking water, the outcomes in Codegua
      were achieved without any other steps by the National Program for Supplementary
      Feeding, such as motivational campaigns for mothers or educational efforts to
      encourage consumption of the program's food products.

PMID- 10574014
TI  - [An information and epidemiologic surveillance system for Venezuelan equine
      encephalitis in the region of the Americas].
AB  - It is difficult to collect precise data on every epizootic and to document the
      direct and indirect effects of each one. This situation makes it impossible to
      assess the damage that Venezuelan equine encephalitis (VEE) causes in the Region
      of the Americas, as well as to identify new encephalitis strains, wild
      reservoirs, types of vectors in each enzootic cycle, and the period of immunity
      that the TC-83 vaccine provides. This all shows that, in order to improve
      prevention and control activities, it is essential to have a standard information
      and epidemiological surveillance system that involves the official public health
      and animal health services. This text describes general aspects of VEE and the
      epidemiological features to consider in order to increase the predictive ability
      of epidemiological surveillance programs and to reduce the negative socioeconomic
      effects of the disease. The piece also describes laboratory diagnostic procedures
      to confirm suspected encephalitis cases. Finally, the text describes the
      characteristics and structure of an information system that will generate useful
      data to investigate enzootic foci and areas at risk, make forecasts on outbreaks
      and epidemics, detect encephalitides quickly, and guide prevention and control
      measures.

PMID- 10574015
TI  - Thermostability of vaccines.

PMID- 10574016
TI  - Ischemic disease in women. Introduction.

PMID- 10574018
TI  - Heart rupture after acute myocardial infarction. It is more frequent in women?

PMID- 10574017
TI  - Atherogenesis and cardiovascular disease in women.

PMID- 10574019
TI  - The gender paradox.

PMID- 10574020
TI  - Thrombolytic therapy for women in myocardial infarction. Different prognosis?

PMID- 10574021
TI  - Coronary bypass surgery in women.

PMID- 10574022
TI  - Coronary risk reduction in the menopausal woman.

PMID- 10574023
TI  - [Radiology update 1999: gastrointestinal tract].

PMID- 10574024
TI  - [Therapy of abdominal aortic aneurysm: results with aortic stents].

PMID- 10574025
TI  - [Digital full field mammography: physical principles and clinical aspects].

PMID- 10574026
TI  - [Evaluating the diagnostic quality of mammography film-screen systems: a
      comparative study].

PMID- 10574027
TI  - [Wandering spleen: detection with ultrasound, CT, MR(A) and 99mTc scintigraphy
      with altered erythrocytes].

PMID- 10574028
TI  - [Diagnostic imaging of tumors of the head-neck area].

PMID- 10574029
TI  - [Diagnostic imaging of lung embolism].

PMID- 10574030
TI  - [A linear quadratic offset filter for contrast improvement in digital
      reconstruction of radiography imaging for virtual simulation in radiotherapy].

PMID- 10574031
TI  - [Tracheobronchial amyloidosis as the cause of a middle lobe syndrome].

PMID- 10574032
TI  - [Why talk about alcohol?].

PMID- 10574033
TI  - [Assessment and diagnosis of alcohol problems in general practice].
AB  - Problem drinkers and alcoholics are not easily identified in primary health care
      settings or among hospitalised patients. An early detection can be the basis of a
      better therapeutic approach for these patients. Clinical interviewing is an
      important phase during the detection process. Every patient should be asked about
      alcohol consumption. Standardised questionnaires, clinical examination and
      laboratory tests are also useful for screening and contribute to diagnosis. The
      screening must be organised in a progressive and opportunistic way.

PMID- 10574034
TI  - [Brief intervention: specific counseling of patients with problem alcohol
      consumption].
AB  - This article describes brief interventions for individuals with levels of alcohol
      consumption associated with increased morbidity and mortality but without severe
      dependence on alcohol. Brief interventions are described and the results of major
      studies evaluating their efficacy are reported. Data from the medical literature
      offer convincing evidence on the efficacy of these interventions to reduce
      alcohol consumption. Consecutive to a reduction of the level of alcohol
      consumption, further research also demonstrated a beneficial effect of brief
      interventions in terms of absenteeism at work, days hospitalized, and mortality.
      Evidence of the efficacy of brief interventions for "high-risk drinkers" justify
      their implementation in medical practice. In Switzerland, the national programme
      on handling alcohol "handle with care?" will offer workshops to primary care
      physicians about the practice of brief interventions.

PMID- 10574035
TI  - [Ambulatory management of alcohol withdrawal syndrome].
AB  - The alcohol withdrawal syndrome occurs in the hours or days after the cessation
      of alcohol drinking in an alcohol dependent patient. The alcohol withdrawal
      syndrome is produced by the emergence of the biological mechanism of neurological
      tolerance to ethanol. The clinical manifestations of the alcohol withdrawal
      syndrome are due to the hyperexcitability of the central nervous system:
      agitation, excitability, tremor, convulsions, status epilepticus, delirium,
      sympathetic hyperactivity. Usually benign, the alcohol withdrawal syndrome is
      frequently manageable on an ambulatory basis, as long as no clinical counter
      indication is present such as a serious previous alcohol withdrawal syndrome,
      previous withdrawal convulsions, a significant medical or psychiatric
      comorbidity, a high level of alcohol consumption, a pregnancy, or the lack of an
      effective familial or social support. The ambulatory management of the alcohol
      withdrawal syndrome requires frequently the use of a sedative drug.
      Benzodiazepines used orally for a duration of 3 to 5 days are actually considered
      a first choice. Inability to work and drive is frequently present for several
      days.

PMID- 10574036
TI  - [Alcohol problems in general practice--the value of biological markers].
AB  - The daily practice of primary care physicians includes the frequent encounter
      with patients suffering from alcohol problems. Among these are the identification
      and treatment of the alcohol dependent patient, but also the identification of
      and counseling for the excessive alcohol drinker. Biological indicators such as
      the new marker Carbohydrate-Deficient Transferrin (CDT), can be of some help in
      the field. They may be used as case finding tools for suspected excessive alcohol
      drinking or dependence, but also as a monitoring tool for the patient under
      treatment. The markers may be used in this way as a bio-feedback and/or as a
      compliance assessment instrument.

PMID- 10574037
TI  - [Alcoholism from the systemic viewpoint].
AB  - In this paper we attempt to view the phenomenon alcohol abuse and dependence
      within the family or partnership and to describe the important impact of
      alcoholism on social relation. Understating the role of alcohol in the familial
      structure may help to draw conclusions for competence and effectiveness of
      individual or familial psychotherapeutic interventions.

PMID- 10574038
TI  - [Identification and treatment of psychiatric comorbidity associated with
      alcoholism].
AB  - The importance of psychiatric comorbidity has been recently recognized. It may
      help to understand why a similar chronic disease has several clinical
      presentations. Concurrent psychiatric disorders associated with alcohol
      dependence worsen the prognosis for the patient. Depression and anxiety are
      frequently the consequence of chronic alcohol consumption; however, these
      disorders have been clearly identified, also as the primary disorder, which may
      be complicated secondarily by alcohol dependence. Therefore, the evaluation of
      concurrent psychiatric disorders is important because it allows for better
      therapeutic strategies, adjusted to specific problems of the patient. Cognitivo
      behavioural therapies are thus more effective if they are combined with a
      specific approach to concurrent disorders.

PMID- 10574039
TI  - [Multidisciplinary team and coordination of treatment network].
AB  - Because of the adverse consequences of alcohol dependence on somatic,
      psychological and social functions, treatment of alcoholics always requires a
      multidisciplinary approach. It is a good example of a treatment network. Despite
      the numerous difficulties encountered in such a multidisciplinary approach, its
      beneficial effect, its efficacy and even its rewards are tremendously important.
      The alcohol treatment network of our region should permit such multidisciplinary
      therapies. Two clinical presentations are used to illustrate its virtues, but
      also some open questions.

PMID- 10574041
TI  - [Personal benefit or consideration for the community?].

PMID- 10574040
TI  - [Alcoholism: cognitive-behavioral therapy].
AB  - Cognito-behavioral therapy of alcohol dependence is based mainly on the aspect of
      enhancing social integration and conditioning. Clinical applications are thus
      focused on behavioral modifications, including social learning and coping skills.
      This approach may be individual or based on group therapy; specific programs may
      be adjusted to the severity of neuropsychological impairment and/or to the
      motivation of the patient.

PMID- 10574042
TI  - [Quality assurance of prehospital emergency care].

PMID- 10574043
TI  - [Smoking among adolescents].

PMID- 10574044
TI  - [Time of crisis is time of possibilities--securing the recruitment with the help
      of the listed patients' system].

PMID- 10574045
TI  - [Prolonged follow-up of patients following kidney transplantation; comment].

PMID- 10574046
TI  - [Hepatitis A is now endemic among Norwegian drug addicts].

PMID- 10574047
TI  - [Surveillance of hepatitis A by molecular epidemiologic studies].
AB  - Hepatitis A virus was studied by molecular epidemiology in connection with an
      outbreak of hepatitis A associated with intravenous drug users (IVDU) in Norway.
      Hepatitis A virus was characterised by sequencing 114 of 1,242 notified cases of
      hepatitis A from January 1995 to July 1998. One hepatitis A variant (IVDU variant
      I) was detected among IVDU during an outbreak of hepatitis A, as well as among 19
      out of 49 cases with no apparent association to this outbreak. During the autumn
      of 1997, a new variant (IVDU variant II) was detected in the IVDU communities.
      Genotyping of virus from imported cases associated with travel to endemic
      regions, revealed that they were distinct from the two other IVDU variants.
      Hepatitis A has disseminated among IVDU over years; this indicates that hepatitis
      A is endemic in these communities. At the turn of the year 1997/98, there was a
      smaller outbreak of hepatitis A among homosexual men in Oslo, distinguished by
      genotyping from the outbreaks in the IVDU communities. By molecular epidemiology
      we have been able to identify individual outbreaks of hepatitis A and distinguish
      them from the IVDU outbreak.

PMID- 10574048
TI  - [Sick-listed persons think job adjustments might reduce sick-leave].
AB  - In the 1990's, improving the follow-up of sick-listed patients with a focus on
      job adjustments has been a priority in Norwegian social policy. In a study of
      1,000 consecutive sick-listed patients (14 days or more) with a musculoskeletal
      or mental disorder as primary diagnosis, we asked 499 randomly selected sick
      listed patients about their opinion on whether adjustments in their job situation
      might reduce their need for sick-leave in the current episode or in the future.
      161 useful questionnaires were returned. Nearly 30% replied that job adjustments
      might bring down his or her current sick-leave, and 40% thought that job
      adjustments might reduce future needs for sick-leaves. One in four were of the
      opinion that they might return to work immediately if job adjustments were made.
      Among those who knew about job adjustments which had in fact been implemented at
      their place of work, there were no significant differences in the estimates of
      potential reductions by age, sex, diagnosis or occupation, with the exception
      that young women who worked in places where such adjustments had been made, had
      little belief in the potential of such adjustments. We may conclude that in the
      sick-listed patients' own opinion, job adjustments have a considerable potential
      for cutting down the number of working days lost by sickness. The Norwegian
      "active sick-leave" scheme is suitable and might be used more.

PMID- 10574049
TI  - [Work ability and gender--physicians' assessment of sick-listed patients].
AB  - Medical assessments might be influenced by the patient's gender and work
      situation. This article explorers the relationship between physicians'
      assessments of work ability in sick-listed patients, and gender of the sick
      listed and the physicians. We conducted a questionnaire survey among 52 primary
      care physicians and 442 of their sick-listed full-time employed patients in Aust
      Agder county. The relationship between physician assessment of the patients' work
      ability and gender were analysed by full/part-time sick-leave, new/extended sick
      leave, patient's workload, and the physician's gender. Multivariate analyses were
      done in two-level logistic regression models. 60% of sick-listed women were
      assessed as having "very much" or "much" reduced work ability, against 71% of
      sick-listed men (p < 0.01). Women received part-time sickness certification more
      often than men, 27% vs. 11% (p < 0.001). These relationships were only found for
      extended sick-leaves, and were significant also after adjustment for physician's
      gender and patient work-load. Male physicians assessed work ability as more
      reduced among sick-listed men than among sick-listed women. Primary care
      physicians assessed work ability as less reduced among women than men. Women more
      often received part-time sickness certification. Possibly, the physicians' gender
      influenced their assessment of work ability, but this should be confirmed by more
      studies.

PMID- 10574050
TI  - [Occupational skin problems among dental personnel].
AB  - Occupational dermatological problems are common among dental health personnel. We
      conducted a questionnaire survey to investigate the frequency of occupational
      dermatological problems among dental health personnel in Hordaland county,
      Norway. 333 of 394 employees (85%) answered the questionnaire. 148 of 333
      respondents (44%) reported skin complaints. The proportion of respondents with
      skin complaints was lower among those with more than 20 years experience in
      dental health care. Hands were almost always involved. Use of gloves were
      reported to be the main cause of skin problems, especially the use of powdered
      gloves. Other frequently reported causes were soaps and methacrylates. Skin
      complaints from methacrylates occurred more often among employees wearing gloves
      most past of the working day. 3% of the respondents reported test-proven rubber
      allergy and 1% a methacrylate allergy. Our study confirm that occupational
      dermatological problems among dental health personnel are frequent. Irritant
      reactions are probably much more common than allergy. The most important
      allergens causing allergic contact dermatitis are rubber and methacrylates.
      Dental personnel should use non-powdered non-latex gloves and use non-touch
      techniques while handling methacrylates.

PMID- 10574051
TI  - [Children and adolescents with Down syndrome in Sor-Trondelag 1978-97].
AB  - Ultrasound examination offered to nearly all pregnant women in Norway may lead to
      the identification of fetuses with Down's syndrome. This may lead to termination
      of pregnancies and to a reduction in the prevalence of live-borns with Down's
      syndrome. In a retrospective study of hospital records we have examined the
      prevalence of Down's syndrome, associated malformations and diseases during the
      last 20 years. 68 children and adolescents with Down's syndrome were identified.
      43 were born 1988-97 (1.16 per 1,000 births) and 25 1978-87 (0.8 per 1,000
      births; p = 0.13). Congenital heart defects were diagnosed in 33 children (49%).
      Five children (7.4%) had died by the end of 1997, four with a cardiovascular
      defect. Four children had moved out of the region. Among 59 persons alive at the
      time of study, 11 (19%) were treated for hypothyroidism, 26 (44%) had been
      hospitalised because of infections, and 14 (20%) suffered from problems with
      sleep obstruction. 23 (39%) had impairments in hearing and 30 (51%) in vision.
      Ten children (18%) had a weight-for-height above the 97.5 percentile of standard
      growth charts for Norwegian children. Serum concentration of zink was below
      reference values in 15 children. We conclude that the prevalence of livebirths
      with Down's syndrome was not reduced in 1988-97 compared to 1978-87. Children
      with Down's syndrome have a wide range of somatic disorders and need close and
      systematic medical follow-up.

PMID- 10574052
TI  - [Quality revision of air ambulance services].
AB  - The 14 anaesthesiologist-manned ambulance helicopters in Norway are
      administratively placed under the head of the nearest anaesthetic department.
      Routines for quality assurance vary considerably. In 1995, a total of 6,850
      patients were treated by air ambulance anaesthesiologists. An enquiry to all 14
      air ambulance services revealed that approximately two thirds of all medical
      records were reviewed for quality assurance purposes. Only half of the reviewers
      based their work on written treatment procedures in addition to their own sense
      of good clinical practice. A review of all 162 medical records for one year at
      one air ambulance base indicates that a thorough review of one third of all
      records would identify all major areas of improvement. The selection of records
      has to be based on local experience concerning both patients and personnel. When
      areas of improvement are identified, the quality assurance process can be
      simplified without increasing the risk of not addressing serious problems.

PMID- 10574053
TI  - [How to enforce the prohibition of sales of tobacco to minors?].
AB  - The introduction in 1996 of a ban on the sale of tobacco to persons under the age
      of 18 in Norway does not seem to have reduced the extent of smoking among minors.
      One reason may be that Norway's 20,000 tobacconists have not respected the age
      limit. A representative sample of households was randomly selected from a
      database containing all telephone numbers in Norway. Of the 6,135 households
      contacted, 2,054 households contained young people aged 13 to 20 years. Of these,
      1,011 persons participated in the telephone survey. 75% of the tobacco smoked by
      13-17-year-olds is bought by the minors themselves or by other minors. 70% of
      smokers under the age of 18 report not being asked how old they were when they
      bought or tried to buy tobacco. Only 48% had been denied purchase of tobacco
      during the last three months. The systematic anti-smoking efforts being
      instituted in the schools would be much more effective if they were backed up by
      the tobacconists through effective enforcement of the 18-year age limit for the
      purchase of tobacco.

PMID- 10574054
TI  - [How to reduce illegal sales of tobacco to minors?].
AB  - Of the tobacco consumed by young people between the ages of 13 and 17 in Norway,
      75% is bought by minors. The Ministry of Health has requested the tobacconist's
      trade association to improve the enforcement of the 18-year age limit for the
      purchase of tobacco. After identifying 122 scientific articles through searches
      in Medline and Sociological Abstracts, we have reviewed the scientific literature
      on the effects of compliance-enhancing measures designed by the authorities in
      other countries. Four types of measures, including sanctions against tobacconist,
      have been used to improve age limit compliance. Voluntary agreements lead to
      higher tobacconist compliance; however, 20% of them still sell tobacco to minors.
      This is enough for young people not to report changes in availability or changes
      in smoking habits. Frequent spot tests, threats of fines or the revoking of
      licence have led to fewer young smokers. We conclude that the present Norwegian
      efforts at increasing tobacconist compliance are unlikely to lead to fewer
      smokers among minors.

PMID- 10574055
TI  - [Information technology and medical record routines in hospitals in the health
      care region 2].
AB  - Structure, standard and efficient methods in paper medical records are important
      for a successful implementation of computerised medical records. We have
      conducted a survey among 26 somatic hospitals in a Norwegian region regarding
      present routines and use of information technology in patients records. The
      hospitals use six different patient administration systems, six laboratory, six
      radiology, and approximately 20 different specialist systems. 16 hospitals use
      three different electronic journal/documentation systems. Ten hospitals use the
      Word word processor for patient records. The full potential of word processing is
      not utilised. Digital dictation is seldom used; few hospitals have 24-hours
      service for documentation, and information technology is not used for
      documentation in nursing care. Four hospitals use microfilm. The survey shows
      that improvement is needed in order to achieve coordinated and effective use of
      information technology and manual routines in hospital medical records.

PMID- 10574056
TI  - [Specialized positions, time allocation and clinical research at the Haukeland
      hospital].
AB  - An aim for Norwegian health care is to improve clinical medical research. Special
      positions for junior doctors are designated for research, quality control
      projects or subspecialization. In addition, four hours per week for all doctors
      at Haukeland University Hospital have recently been allocated to theoretical
      study. A questionnaire was sent to the heads of all 27 departments of Haukeland
      University Hospital to survey the use of these opportunities for medical
      research. There were 27 junior doctor positions for clinical research in 12
      different departments, constituting 4% of all positions for doctors at the
      hospital. 15 departments, including several large ones, did not have any junior
      doctor positions for clinical research. For 15 of the 27 positions, approximately
      50% of the working time was used for research with the goal of publishing in
      international referee-based journals. Four positions were used for clinical
      subspecialization, and eight positions were used entirely for routine clinical
      work. 14 department heads would give high priority to a new position for clinical
      research. Only 11 department heads claimed that the hours scheduled for
      theoretical work had improved research to some degree. There was general
      agreement that other aspects of department organisation was more important for
      promotion of research. Clinical research positions for junior doctors should be
      used for research, but even in an ambitious university hospital they are not
      fully used for such work. Most of the department heads have a clear ambition to
      improve the conditions for research in their departments.

PMID- 10574057
TI  - [A man with anemia, pulmonary infiltrates and increased liver enzymes].

PMID- 10574058
TI  - [Cardiovascular disease after kidney transplantation].
AB  - Norwegian renal transplant recipients have a high prevalence of cardiovascular
      disease. In this group of patients cardiovascular disease causes three out of
      four deaths. Well-known risk factors such as hypertension, dyslipidemia, impaired
      glucose tolerance and diabetes mellitus are common in renal transplant
      recipients, but these factors cannot fully explain the high cardiovascular
      morbidity and mortality. Atherosclerotic disease and left ventricular hypertrophy
      are highly prevalent in uremic patients before transplantation.
      Hyperhomocysteinemia, elevated levels of advanced glycosylated end products, and
      immunosuppressive medication may also accelerate the atherosclerotic process.
      Until results from controlled trials on the effect of lipid-lowering therapy in
      renal transplant recipients are available, treatment decisions must be based on
      studies in non-transplanted patients. Every patient should be treated
      individually with the overall risk pattern taken into account.

PMID- 10574059
TI  - [Cutaneous complications after organ transplantation].
AB  - Organ transplant recipients may develop cutaneous complications related to long
      term immunosuppressive drug treatment (prednisolone, azathioprine, cyclosporine).
      These complications are either related to the immunosuppression per se, such as
      common warts, dermatophytosis, premalignant lesions, and skin cancer, or drug
      specific effects, such as acne, rosacea, and hypertrichosis. Organ transplant
      recipients have a markedly increased risk of developing skin cancer, especially
      squamous cell carcinoma, but also basal cell carcinoma, Kaposi's sarcoma and
      malignant melanoma. Patients should be encouraged to avoid sun exposure, a well
      known risk factor for skin cancer, and to use sun protection measures. Patients
      with skin lesions suspected to be malignant should be referred to a
      dermatologist. Close dermatological follow-up of patients diagnosed with post
      transplant skin cancer is essential.

PMID- 10574060
TI  - [Cancer in organ transplanted patients].
AB  - The risk of cancer in organ transplant recipients is three to five times higher
      than in the general population. The increased risk seems to be related to the
      total amount of immunosuppressive agents received. Organ transplant recipients do
      not have a significantly higher risk of developing the most common types of
      cancer, such as cancer of the breast, lungs, prostate or the uterine body. Non
      melanoma skin cancers constitute well over 50% of all cancers in transplant
      recipients. Some forms of cancer, such as lymphomas, cancer of the cervix and
      Kaposi's sarcoma, are associated with viral infections. Organ transplant
      recipients should be regularly examined for cancer and avoid high exposure to
      ultraviolet light, an important aetiological risk factor for non-melanoma skin
      cancer. With the increasing number of new immunosuppressive drugs now being
      introduced, it is important to monitor their long-term side effects, including
      cancer.

PMID- 10574061
TI  - [Medicine and art].

PMID- 10574062
TI  - [The action for correct fees--storm in a glass of water?].

PMID- 10574063
TI  - [Misleading and incorrect about the Norwegian Migraine Society and drug
      industry].

PMID- 10574064
TI  - [Head asymmetry in children].

PMID- 10574065
TI  - [Occupational medicine and epidemiology].

PMID- 10574066
TI  - Studies on the transmission of Theileria annulata to cattle by the tick Hyalomma
      lusitanicum.
AB  - The role of the ixodid tick Hyalomma lusitanicum Koch 1844 as a vector of
      Mediterranean or tropical theileriosis (caused by the protozoan parasite
      Theileria annulata Dschunkowsky et Luhs 1904) in southern Spain was studied.
      Hyalomma lusitanicum was the most common tick, and the only species of the genus
      Hyalomma L., found on T. annulata-infected cattle from the theileriosis enzootic
      area studied (province of Cadiz, southern Spain). Likewise, we found that all
      sera of the cattle previously considered as suspected of theileriosis by clinical
      signs, tested for T. annulata antibodies, were positive and all blood samples of
      these suspected cattle examined had infected erythrocytes. Partially fed H.
      lusitanicum adults were collected in the field on T. annulata-infected cattle in
      this enzootic area and fed on an uninfected calf in an experimental farm free of
      theileriosis and ticks. At approximately 3 weeks post-tick feeding on the calf,
      this became positive for T. annulata antibodies and T. annulata merozoites were
      found in erythrocytes from blood smears. These results show the ability of H.
      lusitanicum to transmit the protozoan parasite T. annulata to susceptible cattle
      and indicate that H. lusitanicum is probably an important vector of T. annulata
      in the enzootic area surveyed.

PMID- 10574067
TI  - A case of an embryo transfer calf infected with bovine leukemia virus from the
      recipient cow.
AB  - A case was discovered where the embryo transfer (ET) calf had been infected with
      bovine leukemia virus (BLV) from the recipient cow. The embryo was transferred
      from the BLV-uninfected donor cow to the recipient cow. However, the BLV test had
      not been performed to the recipient cow before ET was performed. The ET calf was
      raised in a calf hatch from birth to 1-month old and was given the recipient
      cow's colostrum and milk artificially. The ET calf was raised with the two other
      calves from a 1-month old to a 6-month old. The BLV test was performed to the ET
      calf by agar gel precipitation (AGP) and passive haemagglutination (PHA) assay
      when the ET calf was 6 months old. Because the ET calf was positive, the BLV test
      was performed to the recipient cow, the two other calves raised with the ET calf
      and the two dams of the two other calves. Because the recipient cow only was
      positive at the time of the first test, we judged that the ET calf had been
      infected with BLV from the recipient cow. The importance of the BLV test being
      carried out on the recipient cow for the prevention of enzootic bovine leukemia
      in a case of ET was recognised.

PMID- 10574068
TI  - Initial lung lesions in two calves experimentally infected with Haemophilus
      somnus.
AB  - The initial lung lesions in two calves intrabronchially inoculated with
      Haemophilus somnus are described. The animals were euthanized within 7 h after
      challenge. The in situ location of H. somnus and accompanying lesions were
      examined by light microscopy, immunohistochemistry and transmission electron
      microscopy (TEM). Inoculation with H. somnus resulted in the development of acute
      pulmonary lesions within 3.5 h. H. somnus antigen was demonstrated only within
      the luminal spaces of the airways and in one area of bronchio-associated lymphoid
      tissue (BALT). As observed by TEM, the bacteria were phagocytized by both
      neutrophils and alveolar macrophages. Antigen was never demonstrated in the
      pulmonary intravascular macrophages.

PMID- 10574069
TI  - Patterns of seroconversion to Aujeszky's disease virus in unvaccinated
      chronically infected Swedish weaner pig-producing herds.
AB  - This study was carried out in nine unvaccinated Swedish weaner pig-producing
      herds, ranging in size from 20 to 134 breeding animals, which had experienced a
      previous outbreak of Aujeszky's disease (AD) and in which seropositive sows were
      still present. The objective was to quantify the seroconversion rate to
      Aujeszky's disease virus (ADV) in breeding animals and to find out whether
      unvaccinated herds could become free from ADV by using only seronegative animals
      for replacement. Serum samples were initially obtained from all adult pigs in the
      herds. Animals testing negative, as well as replacement animals, were
      subsequently tested every second or third month and the herds were followed for
      10-28 months. The herd owners were advised to keep seropositive and seronegative
      animals separate whenever possible and to implement sanitary measures against the
      reintroduction of the virus into the herds. All herds experienced long
      consecutive periods (> or = 4 months, median 9 months) without seroconversion.
      Three herds became free from ADV during the serological study; in two of these
      herds no seroconversion was observed. In those seven herds where seroconversion
      occurred, between 9 and 86% of the susceptible pigs became infected. The
      reinfection was indicative of the reactivation of latent virus in all herds but
      two, where the reintroduction of the virus was most likely. The pattern of
      seroconversion was either sporadic, involving not more than three animals at a
      time, or epidemic, involving a large proportion of the susceptible animals in the
      herd. Severe clinical outbreaks hit the two largest herds and these only became
      ADV-free after the conclusion of the study when vaccine was used, which reduced
      the incidence of seroconversion to zero. The results from the present study show
      that it is possible for smaller herds to achieve freedom from ADV without any
      radical control methods, provided that only ADV-free replacement animals are used
      and the virus is not reintroduced. Moreover, the finding that long periods can
      elapse without transmission suggests that when infection is discovered in a herd,
      the risk of massive spread is not necessarily imminent.

PMID- 10574070
TI  - Infections with Mycoplasma hyopneumoniae and Actinobacillus pleuropneumoniae in
      fattening pigs. Influence of piglet production systems and influence on
      production parameters.
AB  - Two hundred and sixty-four feeder pigs from an age-segregated herd (A-pigs) and
      264 feeder pigs from a continuous production system (C-pigs) were transferred
      into identical but separate rooms in a fattening herd employing all-in all-out
      production. On arrival, none of the A-pigs and 39% of the C-pigs were
      seropositive to Mycoplasma hyopneumoniae (M. hyo). At slaughter 30% of the A-pigs
      and 99% of the C-pigs were seropositive to M. hyo. Pigs with acute swine enzootic
      pneumonia (SEP) at slaughter and pigs that seroconverted to M. hyo late in the
      rearing period showed a lower growth rate compared with pigs with chronic SEP or
      pigs that seroconverted to M. hyo early or not at all. No A-pigs and 12% of the C
      pigs were seropositive to Actinobacillus pleuropneumoniae 2 (A. pp 2) at arrival
      to the fattening herd. At slaughter, 10% of the A-pigs and 13% of the C-pigs were
      seropositive to A. pp 2. On arrival, the prevalence of pigs seropositive to A. pp
      3 was lower among A-pigs than C-pigs. During the fattening period the situation
      was reversed. The prevalence of pleuritis at slaughter was low (2.7-4.2%) and
      there were no associations between pleuritis at slaughter and developments of
      antibodies to A. pp 2 or 3. However, pigs with pleuritis developed antibodies to
      M. hyo to a greater extent than pigs without pleuritis. Pigs with pleuropneumonia
      at slaughter and pigs that seroconverted to A. pp 2 or 3 had, during certain
      periods of the rearing, higher growth rates compared with pigs without
      pleuropneumonia or pigs that did not seroconvert to A. pp 2 or 3.

PMID- 10574071
TI  - Serological survey for antibodies against selected infectious agents among fallow
      deer (Dama dama) in central Italy.
AB  - Sera were collected from 224 fallow deer (Dama dama) in reserves in central
      Italy. Samples were tested for antibodies against Chlamydia spp., Brucella spp.
      and Coxiella spp. with the complement fixation (CF) test. Indirect
      immunofluorescence was used to test for antibodies against Borrelia spp. and
      agglutination tests were conducted for Leptospira interrogans antibodies. Enzyme
      linked immunosorbent assay (ELISA) tests were used to detect antibodies against
      bovine herpesvirus-1 (BHV-1) and bovine viral diarrhoea virus (BVDV). All samples
      were negative for antibodies against Brucella spp., L. interrogans, Coxiella spp.
      and BHV-1. Four samples (1.8%) had antibodies against Chlamydia spp., nine (4%)
      against Borrelia spp. and 10 (4.5%) against BVDV. These results indicate that
      fallow deer in central Italy have a low rate of exposure to pathogens typical of
      domestic livestock.

PMID- 10574072
TI  - Comparison of agar gel immunodiffusion test, enzyme-linked immunosorbent assay
      and western blotting for the detection of BLV antibodies.
AB  - An indirect enzyme-linked immunosorbent assay (ELISA) for the diagnosis of bovine
      leukaemia virus (BLV) infection was developed and compared with the agar gel
      immunodiffusion test (AGIDT). Western blotting (WB) was used as confirmatory
      test. ELISA and AGIDT had specificities that were comparable with that of WB,
      however, ELISA showed a higher sensitivity than AGIDT. The ELISA was useful for
      screening a large number of samples, whereas WB was important for detecting the
      antibody response against the individual BLV-proteins. Different types of
      positive serological reactions were discerned in WB, that correlated with
      reactions of sera in AGIDT and ELISA. The most important antigen in WB and ELISA
      was the BLV protein p24, whereas the BLV glycoproteins gp51 and gp30 were of
      special importance in AGIDT. The relevance of repeatedly testing the antibody
      response in BLV-infected herds for control and eradication programmes using
      assays with higher sensitivity than AGIDT was demonstrated.

PMID- 10574073
TI  - Phenotypical characterization of peripheral blood leucocytes in the newborn calf.
AB  - The present study was undertaken to establish reference values for the
      composition of blood leucocyte populations in neonatal calves by differential
      leucocyte counts and immunophenotyping. Neonatal calves 1 h post partum (p.p.)
      were found to have a very high absolute number of granulocytes while the number
      of peripheral blood mononuclear cells was lower than in calves aged 3-9 weeks.
      The relative numbers of T cell subpopulations were similar in newborn and older
      calves, but newborn calves had lower percentages of B cells and MHC class II
      positive cells. Within the first 4 h of life the relative numbers of CD2+, CD6+,
      and CD8+ T cells declined in colostrum-fed as well as in colostrum-deprived
      calves. In contrast, the percentage of MHC class II positive cells and monocytes
      increased from 1 h to 4 h p.p. particularly in colostrum-fed calves. Although
      there is some evidence for immaturity of lymphocytes in neonatal calves, the
      immune system of these animals seems to be fully present at birth.

PMID- 10574074
TI  - Longitudinal study on the susceptibility to bacteriophages of Staphylococcus
      aureus strains isolated from dairy farms in Trinidad.
AB  - A 6-month longitudinal study was conducted on 30 dairy cows in early lactation
      and their human handlers on six farms across Trinidad. Weekly samples of bulk
      milk, composite milk and anterior nares and hand swabs from human handlers were
      collected and cultured for Staphylococcus aureus on Baird-Parker agar (BPA). The
      susceptibility of S. aureus strains to bacteriophages and the relatedness of
      strains isolated over the study period were determined. Sixty-three (51.2%) of
      123 strains of S. aureus from bulk milk were typable compared with 111 (57.3%) of
      194 and 82 (61.7%) of 133 strains isolated from composite milk and human
      handlers, respectively. The differences were not statistically significant (P >
      0.05; chi 2). Bovine phage 42D lysed 3.3% (4 of 123), 16.5% (32 of 194) and 12.0%
      (16 of 133) of S. aureus strains isolated from bulk milk, composite milk and
      human handlers, respectively. The differences were statistically significant (P <
      0.001; chi 2). Amongst bulk milk isolates of S. aureus, 35 (31.8%) of 110
      exhibited relatedness in 11 groups based on their phage patterns and groups. The
      mean maximum interval between the first and last detection of related S. aureus
      strains in a group was 11.5 +/- 7.3 weeks. Amongst composite milk strains of S.
      aureus, 23 (46.0%) of 50, 25 (62.5%) of 40 and 22 (53.7%) of 41 exhibited
      relatedness on farms IB 2, IB 27 and IC 23, respectively, but the differences
      were not statistically significant (P > 0.05; chi 2). On farm IB 2, five groups
      of related strains of S. aureus were detected with a mean maximum interval of
      detection of 18.2 +/- 8.5 weeks compared to farm IB 27 where five groups of
      related strains were also observed but with an interval of 13.8 +/- 8.2 weeks. On
      farm IC 23, a total of seven groups of related S. aureus strains were detected
      with a mean interval of 8.0 +/- 5.5 weeks. For human strains of S. aureus from
      farm IB 2, nine (56.3%) of 16 strains isolated from anterior nares exhibited
      relatedness in three groups with a mean maximum interval of 13.3 +/- 4.7 weeks
      compared to four (25.0%) of 16 hand swab isolates which exhibited relatedness in
      two groups with mean interval of detection of 11.0 +/- 1.4 weeks. The differences
      were not statistically significant (P > 0.05; chi 2). On farm IB 27, for anterior
      nares isolates, eight (72.7%) of 11 exhibited relatedness in two groups with a
      mean maximum interval of detection of 20.5 +/- 2.1 weeks compared to hand swab
      isolates, with six (50.0%) of 12 showing relatedness in two groups and a mean
      interval of 10.5 +/- 2.1 weeks. It was concluded that dairy cows and their human
      handlers carried particular strains of S. aureus at various sites for extended
      periods, which served as continuous sources of contamination of milk and may play
      a significant role in the occurrence of subclinical mastitis, with an obvious
      economic impact.

PMID- 10574075
TI  - The temporal organization of affective and non-affective speech in patients with
      right-hemisphere infarcts.
AB  - To evaluate the right hemisphere's role in encoding speech prosody, an acoustic
      investigation of timing characteristics was undertaken in speakers with and
      without focal right-hemisphere damage (RHD) following cerebrovascular accident.
      Utterances varying along different prosodic dimensions (emphasis, emotion) were
      elicited from each speaker using a story completion paradigm, and measures of
      utterance rate and vowel duration were computed. Results demonstrated parallelism
      in how RHD and healthy individuals encoded the temporal correlates of emphasis in
      most experimental conditions. Differences in how RHD speakers employed temporal
      cues to specify some aspects of prosodic meaning (especially emotional content)
      were observed and corresponded to a reduction in the perceptibility of prosodic
      meanings when conveyed by the RHD speakers. Findings indicate that RHD
      individuals are most disturbed when expressing prosodic representations that vary
      in a graded (rather than categorical) manner in the speech signal (Blonder,
      Pickering, Heath et al., 1995; Pell, 1999a).

PMID- 10574076
TI  - A comparison of egocentric and allocentric spatial memory in medial temporal lobe
      and Korsakoff amnesics.
AB  - Two patients with medial temporal lobe damage, seven Korsakoff amnesics and
      fourteen healthy control subjects were tested on three conditions of a spatial
      memory test ('short delay', 'allocentric' and 'egocentric'). The task required
      subjects to recall the position of a single spot of light presented on a board
      after various delays. The 'short delay' condition tested memory over very short,
      unfilled intervals. The other two conditions used longer, filled delays. The
      allocentric condition required subjects to move to a different place around the
      board before recalling the position of the light. In the egocentric condition
      stimuli were presented in darkness, which eliminated allocentric cues. The
      Korsakoff amnesics were impaired at all delays of the short delay tasks,
      suggesting poor encoding. On the allocentric and egocentric tasks the Korsakoff
      amnesics showed a comparable impairment in the two conditions, which worsened
      with delay. This accelerated forgetting suggested that the Korsakoff amnesics
      also had impaired memory for allocentric and egocentric information. The patients
      with medial temporal lobe damage were unimpaired in the 'short delay' condition
      suggesting intact encoding and short-term memory of spatial information. However,
      they were impaired in the allocentric condition and showed accelerated loss of
      allocentric spatial information. In the egocentric condition, while the
      performance of one patient was impaired, the performance of the other was as good
      as controls. This result suggests that, in contrast to allocentric spatial
      memory, which is sensitive to medial temporal lobe damage, an intact medial
      temporal lobe need not be necessary for successful performance on an egocentric
      spatial memory task.

PMID- 10574077
TI  - A calculation and number processing battery for clinical application in
      illiterates and semi-literates.
AB  - Ten simple tasks assessing counting, number processing, elementary calculation
      and quantity estimation were proposed to 122 normal Brazilian adults aged between
      18 and 58 years with 0, 1, 2, 3 or 4 years of education. Tasks such as counting
      the number of elements in small sets were almost perfectly mastered by these
      illiterate or semi-literate normal subjects; however in other tasks (e.g. those
      assessing knowledge of the correspondence between numbers and banknotes) a
      sizeable proportion of the sample showed errors. The pattern of errors was
      analysed to identify difficulty factors. A strong gender effect with better
      performance in men than women was observed, which was even greater than the
      expected effect of educational level. Results in normals allowed to propose cut
      off scores for neuropsychological assessment in brain-damaged patients with very
      low levels of education, which were tested in a small sample of illiterate or
      semi-literate patients with cerebrovascular accident. It is argued that the
      relatively neglected area of neuropsychological assessment in illiterates is of
      great practical and theoretical interest.

PMID- 10574078
TI  - Influence of perceptual factors on line bisection.
AB  - In the present study we investigated whether masking/perceptual factors may
      influence line bisection performance in normal subjects. We carried out two
      experiments. In Experiment 1 the stimuli consisted of a line flanked at each end
      by: (1) parallel arrows, (2) oblique arrows, (3) or oblique geometrical figures.
      Of the two pairs of labels, one pair converged on the line and appeared to mask
      the flanked portion of the line. The results showed the presence of a bisection
      bias in the direction opposite to location of masking labels. In Experiment 2 we
      examined if orientation factors might have contributed to the observed bisection
      bias. The stimuli consisted of a line flanked by only one pair of oblique
      geometrical figures. The results showed that bisection bias was always in the
      direction opposite to label location, independently of the direction pointed out
      by oblique figures. These findings suggest that masking/perceptual factors may
      influence bisection performance in normal subjects.

PMID- 10574079
TI  - Naming people ignoring semantics in a patient with left frontal damage.
AB  - Studies about proper name anomia generally assume that persons' names are harder
      to recall than other semantic information one knows about them and that name
      retrieval is not possible without biographical knowledge. We describe a patient,
      SB, who, after a left frontal haemorrhage, was unable to recall any biographical
      information about people she could name. Moreover, she had a normal score in an
      Object Picture Naming Test, but gave confabulatory answers in a Semantic
      Questionnaire involving the same items. The role of frontal function in producing
      this pattern of impairment is discussed, together with the possible existence of
      a direct route from visual perception to proper name retrieval.

PMID- 10574080
TI  - Delusions in Alzheimer's disease: spet evidence of right hemispheric dysfunction.
AB  - Delusional thinking and related behaviours are common symptoms in Alzheimer's
      disease (AD). The aim of the study was to determine if any consistent cerebral
      image pattern can be identified using Tc99m-hexamethylpropyleneamine (HMPAO) SPET
      in AD patients with and without delusions. 18 AD patients with delusion and 15 AD
      patients without delusion underwent neuropsychological testing and regional
      cerebral blood flow imaging using Tc99m-HMPAO SPET. The reconstructed data was
      compared using regions of interest drawn over each cerebral lobe and a
      statistical parametric mapping (SPM) approach. The neuropsychological testing
      showed that there was no difference in the profiles of the deluded and non
      deluded AD patients. The imaging results showed a significant degree of image
      asymmetry. This took the form of a right hemisphere hypoperfusion mainly in the
      right frontal and limbic regions. The results do not indicate a specific focal
      site of hypoperfusion in the patients with delusion. They do, however, indicate
      that delusions in AD may be associated with areas of hypoperfusion in the right
      anterior hemisphere.

PMID- 10574081
TI  - Specificity of memory deficits after right or left temporal lobectomy.
AB  - An impairment of verbal memory has consistently been associated with resection of
      the left dominant temporal lobe, whereas non-verbal memory deficits have been
      less reliably observed following resection of the right temporal lobe. Such a
      dissociation may be due to material-specific differences of processing between
      verbal and non-verbal information. Alternatively, the influence of the left and
      right limbic structures may vary according to the stage of memory processing. The
      aim of the study was to test these hypotheses by comparing verbal and spatial
      learning in patients with left or right temporal lobe resection for intractable
      epilepsy, using verbal and visuospatial memory tasks with the same design:
      control of encoding, multiple trial learning, free and cued recall, short and
      long delays. The results showed: (1) a similar pattern of learning and recall in
      the two groups; (2) a higher performance in spatial learning for patients with
      left temporal lobe resection and in verbal learning for patients with right
      temporal lobe resection; (3) material-specific effects characterized by a higher
      sensitivity to cues in the verbal domain and a better retention of information
      during delays in the spatial domain. These results suggest parallel processing of
      the two temporal lobes at the various memory stages, rather than an interaction
      between memory stage and side of the lesion similar to that already proposed for
      the frontal lobes. They also confirm a double dissociation between verbal/spatial
      information processing and side of temporal lobe resection.

PMID- 10574082
TI  - Age-related slowing of control processes: evidence from a response coordination
      task.
AB  - Normal aging is associated with slowing of performance mostly due to a slowed
      functioning of central response-related processes. In this paper we set out to
      discover whether slowing occurs also when the process controlling the
      coordination of responses is engaged by the task. To this end, we compared the
      mean-reaction time performance of two groups of subjects (young vs. elderly) in
      single- and dual-task experimental paradigm. The response coordination process is
      required only by the dual-task paradigm. The results indicate that, in the dual
      task situation, the elderly are markedly slower than young subjects. The eventual
      relevance of information-processing speed in determining the cognitive
      performance of the elderly is considered in the discussion of the results.

PMID- 10574083
TI  - Visually guided exploration in Huntington disease.
AB  - We compared 24 patients in various stages of Huntington disease (HD) with 26
      control patients free from cerebral disorders using a simple visual saccadic
      tracking test. The two groups were well matched in regard to age, sex, verbal IQ
      and years of schooling. Test results differed widely. On a time versus error
      plot, sensitivity (96%) and specificity (100%) were high and the results did not
      depend on age, education, or disease duration, although an influence of disease
      stage could be observed. This study shows that a simple saccadic tracking task
      may be useful in detecting visuomotor disturbances in HD.

PMID- 10574084
TI  - Evaluation of culture enrichment procedures for use with Salmonella detection
      immunoassay.
AB  - To design efficient culture strategies for use with immunoassays to detect
      Salmonella in food, the growth of these organisms was investigated according to
      the Bacteriological Analytical Manual (BAM) and enrichment-immunoassay (EI)
      culture procedures. The cultures were further evaluated using a commercial enzyme
      linked immunosorbent assay (ELISA) kit. The BAM procedure includes pre-enrichment
      in nutrient broth (NB) for 16 h followed by selective enrichment in either
      Rappaport-Vassiliadis (RV) or tetrathionate brilliant green (TBG) broth for 16 h.
      The EI procedure includes pre-enrichment in NB for 4 h, selective enrichment in
      RV for 16 h and post-enrichment in NB for 4 h. The effects of different
      incubation times for pre- and post-enrichment, and different culture media for
      selective enrichment (TBG and RV) and post-enrichment in NB and Brain Heart
      Infusion broth (BHI) on the growth of the bacteria and ELISA titers in the EI
      procedure were also investigated. Salmonella enteritidis and S. typhimurium
      inoculated at different initial concentrations between 0.1 and 35 CFU/ml grew to
      similar concentrations of 10(7) to 10(8) colony forming unit (CFU)/ml in pure
      culture and generally 2 to 4 fold lower concentrations (P<0.05) in mixed culture
      using spiked chicken rinse. In the BAM procedure, the concentration of Salmonella
      cultured in RV was higher (P<0.01) than that in TBG. The cultures in TBG showed
      positive results for ELISA, but those in RV were generally negative. In the EI
      procedure, the ELISA titers from cultures post-enriched in NB or BHI were higher
      (P<0.01) when TBG, as compared to RV, was used for selective enrichment. Post
      enrichment in BHI yielded higher numbers of Salmonella and higher ELISA titers
      than those in NB (P<0.05) for post-enrichment. This study demonstrated that in
      both culture procedures small numbers of Salmonella could be increased to at
      least 10(7) CFU/ml which is detectable by most ELISAs, and that the type of the
      culture media used may have a significant impact on ELISA results.

PMID- 10574085
TI  - Thermal inactivation of Alicyclobacillus acidoterrestris spores under different
      temperature, soluble solids and pH conditions for the design of fruit processes.
AB  - Alicyclobacillus acidoterrestris, a thermoacidophilic, non-pathogenic and spore
      forming bacterium has been detected in several spoiled commercial pasteurised
      fruit juices. A. acidoterrestris spores, besides being resistant to the
      pasteurisation treatment conditions normally applied to acidic fruit products,
      can germinate and grow causing spoilage. Therefore, this microorganism was
      suggested as the target to be used in the design of adequate pasteurisation
      processes. The objectives of this work were to investigate the influence of
      temperature (T: 85-97 degrees C), total soluble solids (SS: 5-60 degrees Brix or
      % by weight) and pH (2.5-6.0) on D-values (decimal reduction time) of
      Alicyclobacillus acidoterrestris (type strain, NCIMB 13137) spores, and to fit a
      model using response surface methodology. A central composite face-centred
      experimental design was used, and the response, D-value determined in malt
      extract broth, ranged between 0.498+/-0.045 and 94.9+/-6.7 min. Within the factor
      ranges studied, temperature was the parameter that most affected the D-value.
      Following this was the SS and, lastly, the pH value. A linear decrease in D-value
      was observed with decreasing SS and pH, and a non-linear decrease in D-value was
      noticed with increasing temperature. A second order polynomial was successfully
      fitted to the data (R2 = 0.98). In general, D-values measured in real fruit
      systems, such as orange, apple and grape juices, blackcurrant concentrates,
      cupuacu (exotic fruit) extract and orange juice drink, were higher than those
      predicted by the malt extract broth model. This result emphasises the importance
      of experimental validation of any model-derived process.

PMID- 10574086
TI  - Exopolysaccharide-producing lactic acid bacteria strains from traditional Thai
      fermented foods: isolation, identification and exopolysaccharide
      characterization.
AB  - Lactic Acid Bacteria (LAB) isolated from various traditional Thai fermented foods
      were screened for exopolysaccharides (EPS) production. From 104 isolates, two rod
      shaped and five coccal-shaped LAB were able to produce EPS from sucrose on solid
      media. However, only the cocci were capable of producing EPS in liquid media and
      these were identified as Pediococcus pentosaceus. Pediococcus pentosaceus strains
      AP-1 and AP-3 produced EPS in high yield. In liquid media containing sucrose as
      carbon source, the amount of EPS produced by AP-1 and AP-3 strains was 6.0 and
      2.5 g/L, respectively. The isolated and purified EPSs were chemically
      characterized. On the basis of sugar composition, methylation analysis and
      nuclear magnetic resonance spectroscopy, both the EPSs were shown to belong to
      the same dextran class. In particular, both EPSs differed from linear dextran by
      branching through 3,6-di-Osubstituted alpha-D-glucopyranosyl residues. The EPS
      from P. pentosaceus AP-3 was characterized by a relatively higher degree of
      branching and by a higher molecular weight than that from P. pentosaceus AP-1.

PMID- 10574087
TI  - Detection of Salmonella enteritidis by reverse transcription-polymerase chain
      reaction (PCR).
AB  - A reverse transcription-polymerase chain reaction (RT-PCR) method was developed
      for detecting mRNA from the sefA gene of Salmonella enteritidis. Detection of
      target mRNA was examined from cells grown in buffered peptone water at different
      temperatures (37, 25 and 15 degrees C) and pH (5.5, 7.2 and 8.5). The results
      revealed that the levels of transcription of the sefA gene differed depending
      upon the physiological state of the cells. This affected the sensitivity of the
      RT-PCR assay. When the assay was evaluated for the detection of S. enteritidis
      PT4 in artificially contaminated minced beef and whole egg samples, an enrichment
      step was used (buffered peptone water, pH 7.2, 37 degrees C, 16 h) to increase
      the sensitivity of the assay. In the presence of the normal background flora of
      each food type, it was possible to detect ten cells of S. enteritidis PT4 after a
      16-h enrichment using the RT-PCR assay, with a total testing time of 28 h. Unlike
      the PCR test for the sefA gene that was tested in parallel, the RT-PCR assay did
      not detect nonviable (heat-inactivated) S. enteritidis PT4 cells. The results
      supported the usefulness of RT-PCR as a method for the detection of viable
      microorganisms.

PMID- 10574088
TI  - Improvement of the hygienic performance of the hindquarters skinning operations
      at a beef packing plant.
AB  - The hindquarters skinning operations in a commercial beef carcasses dressing
      process were modified, and for short trial periods reorganized for the purpose of
      reducing the numbers of bacteria deposited on the carcasses. During performance
      of modified or reorganized operations, samples were obtained from randomly
      selected carcasses, by swabbing specified sites related to opening cuts, rump
      skinning or flank skinning operations, randomly selected sites along the lines of
      the opening cuts, randomly selected sites on the skinned hindquarters of
      carcasses, or randomly selected sites on carcass sides leaving the dressing
      process. For each form of the hindquarters skinning operations, a set of 25
      samples of each type was collected, with a single sample being obtained from each
      selected carcass or side. Aerobic counts, coliforms and Escherichia coli were
      enumerated in each sample, and a log mean value was estimated for each set of 25
      counts on the assumption of a log normal distribution of the counts. The data
      indicated that the log numbers of total aerobes, coliforms and E. coli that were
      deposited on carcasses during the modified hindquarters skinning operations were
      generally about 0.5, 1.0 and 1.0 log unit less, respectively, than the log
      numbers that had been deposited on the carcasses during the unmodified
      operations. Reorganization of the modified operations gave further small but
      consistent reductions in the numbers of bacteria. It, therefore, appears that
      changes to dressing procedures which are guided by appropriate microbiological
      data can produce consistent reductions in the microbiological contamination of
      carcasses.

PMID- 10574089
TI  - Establishment of conditions for green table olive fermentation at low
      temperature.
AB  - Four Lactobacillus plantarum strains were isolated from table olive cold
      fermentation brines. Their specific growth rate and acidification in MRS broth
      and in green table olive brines were studied by means of a mixed 2 pH (4.5 and
      5.0) x 3 salt (3, 4 and 5%, w/v, NaCl) x 3 incubation temperature (9, 12 and 15
      degrees C) levels factorial design. In MRS broth, the greatest effect (linear) on
      acidification was due to temperature. In brine, the effects were considerably
      less, pH (linear) being the most important for specific growth rate, and
      temperature (linear) for acidification. In both media, an initial pH of 5.0 led
      to good acidification at 12-15 degrees C. The effectiveness of the conditions
      found (initial pH of 5.0; 3%,w/v, NaCl; and incubation at 12 degrees C) was
      confirmed in simulated green olive fermentations with three of the strains, which
      proved especially robust. Behaviour in terms of growth and acidification rates
      was similar for these strains, and comparable to that observed in traditional
      processes, although mannitol and sucrose were not metabolised and fructose was
      only partially used. This leads to the possibility of obtaining normal
      fermentation processes of table olives in cold regions when appropriate initial
      conditions and starter cultures are used.

PMID- 10574090
TI  - Growth and enumeration of the meat spoilage bacterium Brochothrix thermosphacta.
AB  - Brochothrix thermosphacta is a common meat spoilage bacterium. The morphology of
      this bacterium changes from coccobacilli and short rods to chains during growth,
      which may give a false estimation in numbers using some enumeration techniques.
      Methods for the quantification of this bacterium have been compared.
      Turbidimetric readings showed good agreement with cell dry weight indicating that
      the former provides a good measure of the change in cell mass during growth. The
      turbidimetric method also correlated well with bacterial numbers determined by
      plate counts, flow cytometry and manual counts (by microscope) over a limited
      range of 10(7)-10(9) cells/ml. Flow cytometry and manual counts gave a linear
      relationship over a wider range of 10(5)-10(9) cells/ml. The sensitivity of
      analysis, growth rates and lag time attained using these methods were also
      compared. As a consequence of changes in bacterial cell size during growth,
      turbidimetry over-estimated the growth rate. The plate count method proved unable
      to detect the difference between bacteria existing as chains or single cells. The
      sensitivity of analysis and the calculated growth related parameters were similar
      for flow cytometry and manual counts. This suggests that flow cytometry is
      capable of counting individual cells in a chain. Further investigation showed
      that passage of B. thermosphacta cells through the flow cytometer resulted in the
      breakage of chains into single cells. The reliability, low error and rapidity of
      this technique make it attractive for bacterial enumeration, something which has
      been demonstrated using B. thermosphacta, a bacterium which exhibits complex
      morphologies.

PMID- 10574091
TI  - Two-dimensional profiles of fumonisin B1 production by Fusarium moniliforme and
      Fusarium proliferatum in relation to environmental factors and potential for
      modelling toxin formation in maize grain.
AB  - This study has examined in detail the effect of temperature (7-37 degrees C) and
      water availability (water activity, a(w), 0.89-0.97) on fumonisin B1 (FB1)
      production by an isolate of Fusarium moniliforme and F. proliferatum on
      irradiated maize grain after incubation for 28 days. The optimum conditions for
      F. moniliforme and F. proliferatum were 30 degrees C at 0.97 a(w) and 15 degrees
      C at 0.97 a(w), respectively. The maximum concentrations were 2861 mg kg(-1) and
      17,628 mg kg(-1) dry wt. maize grain, respectively. At marginal a(w)/temperature
      conditions for growth (e.g. 0.89-0.91 a(w)) no FB1 was detected (<0.1 mg kg(-1)).
      A high variability was found between replicates for F. moniliforme, but not for
      F. proliferatum. These data were used to construct two-dimensional diagrams of
      all the a(w) x temperature conditions favourable for FB1 production for the first
      time. The data were also subjected to a polynomical regression, which
      demonstrated that there was a very good fit for the 15-30 degrees C range of
      temperature and at 0.97 a(w). However, at marginal environmental conditions this
      was not possible. This suggests that it may be possible to predict within a
      limited environmental range the potential for significant FB1 production.

PMID- 10574092
TI  - Behaviour of L. monocytogenes in an artificially made biofilm of a nisin
      producing strain of Lactococcus lactis.
AB  - The survival of Listeria monocytogenes in a binary biofilm with a bacteriocin
      producer (Lactococcus lactis CNRZ 150) was investigated. Two situations were
      simulated: in the first, L. monocytogenes was deposited on a 1-day biofilm of
      Lactococcus lactis (deferred adhesion); in the second, L. monocytogenes was
      simultaneously mixed with Lact. lactis (simultaneous adhesion). Biofilms were
      cultivated in tryptic soy broth supplemented with 6 g l(-1) of yeast extract (TSB
      YE) and L. monocytogenes counts were followed for 48 h, both in co-culture with
      Lact. lactis and in pure culture. The influence of the mode of inoculation of L.
      monocytogenes (deferred or simultaneous adhesion) into the Lact. lactis biofilm,
      the size of the L. monocytogenes inoculum and the replacement of the culture
      medium at 20-24 h on the survival of L. monocytogenes was studied. Results showed
      that the antilisterial activity of the Lact. lactis started within the first 6 h
      of the deposition of L. monocytogenes. The log cycle reduction rate in number of
      L. monocytogenes in the mixed biofilm (compared to the pure biofilm) was greatly
      dependent on the inoculum size: when the smallest inoculum was used to colonise
      stainless steel coupons (10(6)-10(7) CFU ml(-1)), the log cycle reduction was
      greater and L. monocytogenes was not detected after t = 10 h (simultaneous
      adhesion) and t = 24 h (deferred adhesion) in the adherent population as well as
      in the planktonic population. On the other hand, in the case of a greater supply
      of L. monocytogenes (10(8) CFU ml(-1)), the results showed that the early
      reduction of L. monocytogenes counts was relatively slow and was followed by a
      stabilisation of the population, leading to the establishment of a great number
      of resident cells in the biofilm (10(5) to 106 CFU cm(-2)). This population level
      was maintained during the 48 h of experimentation and replacement of the culture
      media with fresh medium at t = 22 h (simultaneous adhesion) or t = 24 h (deferred
      adhesion) did not modify the level of the population of L. monocytogenes within
      the biofilm.

PMID- 10574093
TI  - The production of 'Kpaye'--a fermented condiment from Prosopis africana (Guill
      and Perr) Taub. Seeds.
AB  - 'Kpaye', a fermented condiment from Prosopis africana seeds was produced using
      the traditional method. Bacillus subtilis, Bacillus licheniformis and Bacillus
      pumilus were consistently isolated in the fermentations lasting 120 h.
      'Kpaye'production involved a rise in pH, moisture content and total free amino
      acids while titratable acidity and reducing sugar decreased gradually after 24 h
      and 72 h of fermentation respectively.

PMID- 10574094
TI  - Prevalence of Campylobacter spp. in poultry and poultry meat in Germany.
AB  - Of 509 samples from poultry flocks, 209 isolates (41.1%) were Campylobacter
      positive. The number of positive cases in broiler carcasses was 45.9%. Of 52
      pheasants investigated, 25.9% were Campylobacter positive. Campylobacter jejuni
      was isolated from 86 (42.0%) poultry flock samples, 47 (43%) broiler samples and
      15 (28%) wild pheasant samples. C. coli was found at a rate of 1.2% in poultry
      flocks, 13% in broilers and 21% in pheasants.

PMID- 10574096
TI  - Bibliography of food microbiology.

PMID- 10574095
TI  - Detection and quantification of Salmonella in pure cultures using 5'-nuclease
      polymerase chain reaction.
AB  - Advances in detection and quantification assays based on nucleic acids
      conceivably will revolutionize the ability to quickly and specifically detect and
      quantify microorganisms in foods. Among these assays, the polymerase chain
      reaction (PCR) assay and the TaqMan PCR Detection System (Perkin-Elmer) probably
      are among the most promising. Since a 5'-nuclease PCR renders possible the
      automated and direct detection and quantification of PCR products (Holland et
      al., 1991. Proc. Natl. Acad. Sci. USA 88, 7276-7280), microorganisms in foods can
      be detected and quantified indirectly within a few hours through analysis of the
      microbial DNA or RNA sequences present. In the present report we have adapted a
      5'-nuclease-based kit for the quantification of Salmonella.

PMID- 10574097
TI  - Laparoscopic splenectomy for haematological diseases: review of current concepts
      and opinions.
AB  - Laparoscopic splenectomy is now currently used by most surgeons in the treatment
      of many haematological diseases. The operative technique varies depending on the
      surgeon, but results are usually comparable among published series. We have
      reviewed 104 papers about laparoscopic splenectomy for haematological diseases
      and paid particular attention to surgical aspects and early postoperative
      results. We searched MEDLINE from January 1989 to April 1998, and of the 104
      papers that we found 41 fulfilled our criteria of large series published in peer
      reviewed journals that had been cited often. They usually compared laparoscopic
      and open splenectomy and focused on common problems (such as accessory spleens)
      and technical aspects (such as bleeding). Laparoscopic splenectomy is reported by
      most authors to be as safe and effective as open splenectomy for haematological
      diseases. It also has several advantages over the open approach, such as shorter
      and less complicated postoperative stay with better cosmetic results and more
      rapid return to full activities.

PMID- 10574098
TI  - Early thoracoscopy for the evacuation of undrained haemothorax.
AB  - OBJECTIVE: To evaluate the accuracy of radiological tests and the outcome after
      thoracoscopic evacuation of retained haemothorax. DESIGN: Prospective study.
      SETTING: Academic trauma centre, USA. SUBJECTS: Of 703 patients with thoracic
      injuries, 58 (8%) were evaluated for and 15 (2%) were found to have, retained
      haemothorax. INTERVENTIONS: Plain chest radiographs (CXR) and thoracic computed
      tomograms (CT) 48 hours after admission, and thoracoscopic evacuation within 3-6
      days of admission. MAIN OUTCOME MEASURES: Accuracy of radiological tests,
      morbidity, and mortality. RESULTS: 12 patients underwent early thoracoscopy with
      minimal morbidity, no mortality, and appreciable clinical and radiological
      improvement. Three patients who were not operated on developed empyemas. CXR was
      inaccurate in predicting the need for thoracoscopy. CT was the only test that
      predicted the need for evacuation of haemothoraces. CONCLUSION: Thoracoscopic
      evacuation of retained haemothorax is safe and effective. The success of the
      procedure is assured by early intervention in appropriately selected patients. CT
      is the ultimate test on which to base decision-making.

PMID- 10574099
TI  - A review of serious injury and death from gunshot wounds in Sweden: 1987 to 1994.
AB  - OBJECTIVE: To evaluate the incidence, range and causes of injury, medical
      consequences, and mortality of patients with gunshot wounds (GSW) in Sweden.
      DESIGN: Retrospective case study. SETTING: The Swedish Hospital National
      Discharge Register (SNHDR). SUBJECTS: 1559 patients with gunshot wounds, in all
      2394 episodes treated in Swedish hospitals from 1987-1994. INTERVENTIONS:
      Statistical analysis of the Register. MAIN OUTCOME MEASURES: Incidence of GSW in
      Sweden, mortality, range of injuries and medical consequences. RESULTS: From 1987
      to 1994 a total of 1559 people were admitted to Swedish hospitals with GSW, which
      corresponds to 2.3 injuries/100000 population/year. In all, 2394 episodes were
      treated in hospitals. There were 1373 men (88%) and 186 women (12%), with a
      median age of 29 years (range 1-92). Of these, 990 were recorded as accidents
      (63%), 257 as suicides (16%), 174 as attempted murder (11%), and 138 as of
      "unknown cause" (9%). The annual incidence of GSW in Sweden was relatively
      constant during this period. The total number of deaths in our series of patients
      was 111 (7%), including 74 suicides, 16 accidents, 14 homicides, and 7 of
      "unknown cause". Among these, 53% had a head injury, 11% thoracic, and 8%
      abdominal injuries. Compared with other countries in the world, the incidence of
      GSW in Sweden is comparable with New Zealand and Finland, but lower than in the
      USA. Injuries to extremities were most common, followed by injuries to the head
      and neck. Thirty percent of all those admitted to hospital required more than one
      week in hospital. CONCLUSIONS: The incidence of GSW is low in Sweden, and they
      are mainly caused by accidents or attempted suicide. Injuries to the extremities
      were most common, followed by injuries to the head and neck. Two thirds of the
      patients left hospital within a week. Seven percent of patients treated for GSW
      in hospital died.

PMID- 10574100
TI  - Blunt injuries of the stomach.
AB  - OBJECTIVE: To evaluate the results of surgical treatment of patients with blunt
      injuries of the stomach. DESIGN: Retrospective study. SETTING: Two general
      hospitals, Greece. SUBJECTS: 10 patients operated on for blunt trauma to the
      stomach during a 10 year period. MAIN OUTCOME MEASURES: Hospital mortality and
      morbidity. RESULTS: All patients were victims of motor vehicle accidents and
      presented with clinical signs warranting early laparotomy. There were 6 full
      thickness, and 2 partial thickness gastric injuries located in the anterior wall.
      All injuries could be managed with simple surgical techniques without resections.
      Two patients bled to death on the operating table from associated injuries. All
      but one of the survivors had postoperative complications with a mean (SD)
      duration of hospital stay of 18(8) days (range 10-30). CONCLUSIONS: Blunt gastric
      injury is usually diagnosed at laparotomy for associated injuries but may
      occasionally be suspected from specific clinical findings. In most cases the
      injury is on the anterior wall. Simple repair is usually sufficient and the
      prognosis depends on the severity of the associated injuries.

PMID- 10574101
TI  - Carcinoma of the hypopharynx and the cervical oesophagus: a surgical challenge.
AB  - OBJECTIVE: To report our results after reconstruction of the upper digestive
      tract for locally advanced carcinoma of the hypopharynx and cervical oesophagus.
      DESIGN: Open study. SETTING: Teaching University hospital, Germany. SUBJECTS: Of
      the 517 patients who presented with carcinoma of the oesophagus between September
      1985 and March 1997, 16 had a locally advanced tumour of the hypopharynx and 25
      of the cervical oesophagus. INTERVENTIONS: Free jejunal grafts were used after
      circular resection in all patients with carcinoma of the hypopharynx, and for the
      3 with oesophageal carcinoma in whom we obtained adequate resection margins. In
      the remainder stomach was used in 21 and colon in 1. MAIN OUTCOME MEASURES:
      Morbidity and mortality. RESULTS: After jejunal grafting 1 patient died within 30
      days and 2 died in hospital. After gastric or colonic reconstruction 2 patients
      died within 30 days and 4 in hospital. There was 1 anastomotic leak, 1 transplant
      became necrotic and had to be replaced, in 2 patients the recurrent nerve was
      damaged, 1 patient developed a wound infection and 1 a cardiac infarction. After
      gastric or colonic replacement 7 patients had paralysed recurrent laryngeal
      nerves, there was 6 anastomotic leaks, 1 chylous leak, 1 haemorrhage, and in 1
      the transplant necrosed. CONCLUSION: Despite the fact that we compared tumours in
      different sites, these results suggest that the jejunal graft is safer for upper
      oesophageal and hypopharyngeal reconstruction.

PMID- 10574102
TI  - HLA-DR expression in acute pancreatitis.
AB  - OBJECTIVE: To investigate the role of the monocyte/macrophage system in acute
      pancreatitis DESIGN: Prospective clinical study SETTING: University clinic,
      Germany SUBJECT: 37 consecutive patients who presented with acute pancreatitis.
      MAIN OUTCOME MEASURE: Correlation between function of monocytes measured by HLA
      DR expression and outcome RESULTS: Patients were divided into three groups
      according to outcome: those with severe pancreatitis who died (n = 10), those
      with severe pancreatitis who survived (n = 15), and those with mild pancreatitis
      who survived (n = 12). There was a clear and significant difference between those
      with severe and those with mild disease. HLA-DR expression was initially
      depressed in both groups, but after the third day of treatment it started to
      recover significantly in those with mild disease (p < 0.05). The difference was
      also significant from day 7 onwards between those with severe disease who died
      and those with severe disease who survived (p < 0.05). CONCLUSION: Monocyte
      function as measured by HLA-DR expression (CD14+DR+) is reduced in patients with
      acute pancreatitis and does not recover in patients who are going to die (median
      < 20 relative antigen density units; RU).

PMID- 10574103
TI  - Complications after surgery for necrotising pancreatitis: risk factors and
      prognosis.
AB  - OBJECTIVE: To evaluate risk factors, results of treatment, and prognostic
      influence of complications on survival from acute necrotising pancreatitis.
      DESIGN: Retrospective study of prospectively collected data. SETTING: Tertiary
      referral centre, Austria. SUBJECTS: 100 consecutive patients operated on for
      necrotising pancreatitis confirmed by dynamic angio-computed tomography from 1988
      1997. INTERVENTIONS: 77 patients were operated on acutely followed by open
      management, and in 23 the operations were delayed. MAIN OUTCOME MEASURES:
      Morbidity, mortality, factors predisposing to complications, prognostic effect of
      complications on survival. RESULTS: Acute operations, alcoholic origin, APACHE II
      scores of > or = 10 on admission, and organ dysfunction on admission were
      independent factors that predisposed patients to complications. Colonic necrosis
      (n = 17) bleeding (n = 12) and intestinal fistulisation (n = 10) predominated.
      The overall mortality of complicated pancreatic necrosis was higher among
      patients admitted with surgical complications than in those who were not, but not
      significantly so (12/33 compared with 7/44 p = 0.06). Colonic necrosis (mortality
      53%, relative risk: 2.45, p = 0.01), however, seemed to be of prognostic
      relevance. CONCLUSIONS: Complications are common in severe necrotising
      pancreatitis leading to organ dysfunction and need for acute operations. Colonic
      necrosis is an independent prognostic factor for survival.

PMID- 10574104
TI  - Closure of burst abdomen after major gastrointestinal operations--comparison of
      different surgical techniques and later development of incisional hernia.
AB  - OBJECTIVE: To find out the incidence of incisional hernia in patients who had
      resuture of a burst abdomen and to compare different methods of wound closure and
      the development of incisional hernia. DESIGN: Retrospective study. SETTING:
      University hospital, Norway. SUBJECTS: 78 adults patients who had their burst
      abdomens resutured between January 1986 and December 1995. INTERVENTIONS: Five
      different methods were used to close the burst abdomen: interrupted or continuous
      sutures with or without retention sutures, or retention sutures alone. MAIN
      OUTCOME MEASURE: Incisional hernia after at least one year follow-up. RESULTS:
      Postoperative mortality was 14% (11/78), and 53 patients were followed up for at
      least a year. Incisional hernias developed in 43% (23/53) of the patients. When
      interrupted sutures were used (with or without retention sutures) 34% (13/38) of
      patients developed incisional hernias compared with 6/10 when the wound was
      closed with a continuous suture. Retention sutures did not reduce the incidence
      of incisional hernia. CONCLUSIONS: Incisional hernia is a common complication
      after resuture of a burst abdomen. We found no significant differences in the
      incidence of incisional hernias when continuous and interrupted techniques were
      compared. Retention sutures do not reduce the incidence of incisional hernias.
      There is still a need for refinements of the technique of closure of a burst
      abdomen.

PMID- 10574105
TI  - Perioperative functional activity of the alternative pathway of complement in
      patients with colonic cancer.
AB  - OBJECTIVE: To investigate the functional capacity of the alternative pathway of
      complement in patients with cancer of the colon before, during, and after
      operation. DESIGN: Prospective study. SETTING: One university and two district
      hospitals, Denmark. SUBJECTS: 28 patients having elective or emergency operations
      for colonic cancer. INTERVENTIONS: Measurements of C3b fixing capacity of the
      alternative complement pathway in serum before, during, and after operation. MAIN
      OUTCOME MEASUREMENTS: The functional capacity of the alternative pathway of
      complement, and changes during operation. RESULTS: The functional capacity of the
      alternative pathway in patients with cancer of the colon was above normal (p <
      0.0001 for both men and women), and the capacity remained unchanged during
      operation despite dilution of serum peroperatively. CONCLUSION: The alternative
      pathway seems to be the only immunological variable that has so far been shown to
      have increased functional capacity in patients with cancer, and that remains
      unaltered (mean value) during operation. The importance of retaining normal
      function of the alternative complement pathway in the prevention of postoperative
      infective complications and recurrence of cancer has not yet been elucidated.

PMID- 10574106
TI  - Ultrasound scans done by surgeons for patients with acute abdominal pain: a
      prospective study.
AB  - OBJECTIVE: To evaluate the routine use of abdominal ultrasonography (US) in
      patients admitted to the surgical emergency unit with acute abdominal pain.
      DESIGN: Prospective study with a three-step evaluation of patients over a 12
      month period. SETTING: University hospital, Switzerland. SUBJECTS: 496 patients
      (male/female = 234/262; mean age 45 years) who presented with acute abdominal
      pain. INTERVENTIONS: Every patient underwent routine investigations and had an
      abdominal US by the attending surgeon. MAIN OUTCOME MEASURES: Clinical diagnosis,
      post-ultrasonography diagnosis and final diagnosis. RESULTS: US improved the
      correct diagnostic rate from 348 (70%) to 414 (83%). The diagnostic accuracy for
      acute appendicitis and biliary tract disease improved after US from 455 (92%) to
      488 (98%) and from 463 (93%) to 490 (99%), respectively; the corresponding
      sensitivities and specificities were 91% and 99% and 94% and 99%. CONCLUSIONS:
      Ultrasonography should be part of routine surgical investigation and should be
      mastered and used by surgeons.

PMID- 10574107
TI  - Preoperative high dose methylprednisolone improves patients outcome after
      abdominal surgery.
AB  - OBJECTIVE: To assess the effect of preoperative high dose methylprednisolone on
      stress response and outcome. DESIGN: Randomised, placebo-controlled, double-blind
      study. SETTING: University hospital, Germany. SUBJECTS: 20 patients listed for
      abdominal surgery of whom 10 had major intra-abdominal interventions and 10 had
      incisional hernias repaired. INTERVENTIONS: Methylprednisolone 30 mg/kg (100 ml)
      was given by slow intravenous infusion 90-60 minutes before operation. The
      control group received the same volume of sodium chloride. MAIN OUTCOME MEASURES:
      Speed of convalescence, degree of fatigue, amount of pain, consumption of
      analgesics, breathing capacity, and hospital stay, as well as humoral and
      cellular mediators of the stress response. RESULTS: Methylprednisolone
      significantly improved criteria of postoperative recovery, fatigue by 47%, (day
      1), convalescence by about 45% (days 1-3), and breathing capacity (FEV1) between
      47% and 29% (days 5, 7) (p < 0.05, ANOVA), and led to a significant reduction of
      median hospital stay of 4.5 days. C-reactive protein concentration was
      significantly decreased (by 46% on day 3) and T-cell activation was suppressed
      (day 1). CONCLUSION: Outcome of the patients after conventional abdominal surgery
      is substantially improved by preoperative high dose methylprednisolone. This
      effect is more pronounced in patients having major operations.

PMID- 10574108
TI  - Pulmonary dynamics of radiolabelled erythrocytes and leucocytes in early gram
      negative sepsis in pigs.
AB  - OBJECTIVE: To study the pulmonary dynamics of erythrocytes and leucocytes in vivo
      in early experimental sepsis. DESIGN: Open, experimental study. SETTING: Academic
      research laboratory, Sweden. MATERIAL: 10 adolescent domestic pigs.
      INTERVENTIONS: Technetium (99mTc) labelling of erythrocytes (n = 5), and indium
      (111In) labelling of autologous leucocytes (n = 10). Sepsis was induced by
      endotoxin (n = 4) or live Escherichia coli (n = 3), given intravenously. MAJOR
      OUTCOME MEASURES: Regional pulmonary scintigraphy, central haemodynamics, and gas
      exchange followed for 180 minutes. RESULTS: Septic animals developed arterial
      hypoxia, pulmonary hypertension, and systemic hypotension. They also had an early
      increase in mean (SD) regional pulmonary erythrocyte and leucocyte counts [+10.3
      (7.7)% and +12.0 (3.5)%, respectively] with a simultaneous maximum 27-32 minutes
      after the start of the septic insult. CONCLUSIONS: The immediate sepsis-induced
      pulmonary accumulation of leucocytes as detected by external scintigraphy can be
      ascribed at least in part to a simultaneous sepsis-induced increase in pulmonary
      blood volume.

PMID- 10574109
TI  - Influence of growth factors erythropoietin and granulocyte macrophage colony
      stimulating factor on mechanical strength and healing of colonic anastomoses in
      rats.
AB  - OBJECTIVE: To find out what influence erythropoietin and granulocyte macrophage
      colony stimulating factor (GM-CSF) had on the healing of left colonic anastomoses
      in rats. DESIGN: Experimental study. SETTING: University hospital of Ioannina,
      Greece. ANIMALS: 40 rats. INTERVENTIONS: An end to end anastomosis was created in
      the left colon. The rats in the experimental groups were treated with
      erythropoietin, or GM-CSF, or the two in combination. MAIN OUTCOME MEASURES:
      Tensile breaking strength of the anastomosis, histological characteristics of the
      anastomosed segment, changes in body weight, and packed cell volume (PCV) during
      the experiment. RESULTS: The tensile breaking strength of the anastomosis on the
      seventh postoperative day was significantly greater in the erythropoietin group
      (mean 2.8N, 95% confidence interval (CI) 0.12N, p 0.0004) than in the control
      group (mean 1.60N, 95% CI 0.12N). It did not differ from the GM-CSF groups (mean
      1.67N, 95% CI 0.21N, p 0.68) or erythropoietin GM-CSF (mean 1.67N, 95% CI 0.11N,
      p 0.44). The PCV was significantly higher in the two groups given erythropoietin
      (p < 0.001) but not in the GM-CSF group (p 0.8) while that in the control group
      was significantly lower (p < 0.001). The body weight followed the same pattern,
      being significantly more in the two groups given erythropoietin (p = 0.03 and
      0.003) but not in controls (p = 0.09) or the GM-CSF group (p = 0.2). CONCLUSIONS:
      Erythropoietin enhances the healing of anastomosis in rat colon by increasing the
      number of fibroblasts and accelerating the maturation of new vessels.

PMID- 10574110
TI  - Invagination of the appendix with carcinoid tumour.

PMID- 10574111
TI  - Papillary thyroid carcinoma that metastasised to the choroid.

PMID- 10574112
TI  - Life-threatening liver failure after inguinal herniorrhaphy in patients with
      cirrhosis.

PMID- 10574113
TI  - Diagnostic work for research purpose should be acknowledged.

PMID- 10574114
TI  - Treatment of complicated pilonidal sinus.

PMID- 10574115
TI  - The surgeon and the Internet.

PMID- 10574116
TI  - Axons as computing devices: basic insights gained from models.
AB  - Detailed models of single neurons are typically focused on the dendritic tree and
      ignore the axonal tree, assuming that the axon is a simple transmission line. In
      the last 40 years, however, several theoretical and experimental studies have
      suggested that axons could implement information processing tasks by exploiting:
      1) the time delay in action potential (AP) propagation along the axon; 2) the
      differential filtering of APs into the axonal subtrees; and 3) their activity
      dependent excitability. Models for axonal trees have attempted to examine the
      feasibility of these ideas. However, because the physiological and anatomical
      data on axons are seriously limited, realistic models of axons have not been
      developed. The present paper summarizes the main insights that were gained from
      simplified models of axons; it also highlights the stochastic nature of axons, a
      topic that was largely neglected in classical models of axons. The advance of new
      experimental techniques makes it now possible to pay a very close experimental
      visit to axons. Theoretical tools and fast computers enable to go beyond the
      simplified models and to construct realistic models of axons. When tightly
      linked, experiments and theory will help to unravel how axons share the
      information processing tasks that single neurons implement.

PMID- 10574117
TI  - Visual inter-hemispheric processing: constraints and potentialities set by axonal
      morphology.
AB  - The largest bundle of axonal fibers in the entire mammalian brain, namely the
      corpus callosum, is the pathway through which almost half a billion neurons
      scattered over all neocortical areas can exert an influence on their
      contralateral targets. These fibers are thus crucial participants in the numerous
      cortical functions requiring collaborative processing of information across the
      hemispheres. One of such operations is to combine the two partial cortical maps
      of the visual field into a single, coherent representation. This paper reviews
      recent anatomical, computational and electrophysiological studies on callosal
      connectivity in the cat visual system. We analyzed the morphology of individual
      callosal axons linking primary visual cortices using three-dimensional light
      microscopic techniques. While only a minority of callosal axons seem to perform a
      strict 'point-to-point' mapping between retinotopically corresponding sites in
      both hemispheres, many others have widespread arbors and terminate into a handful
      of distant, radially oriented tufts. Therefore, the firing of a single callosal
      neuron might influence several cortical columns within the opposite hemisphere.
      Computer simulation was then applied to investigate how the intricate geometry of
      these axons might shape the spatio-temporal distribution of trans-callosal
      inputs. Based on the linear relation between diameter and conduction velocity of
      myelinated fibers, the theoretical delays required for a single action potential
      to reach all presynaptic boutons of a given arbor were derived from the caliber,
      g-ratio and length of successive axonal segments. This analysis suggests that the
      architecture of callosal axons is, in principle, suitable to promote the
      synchronous activation of multiple targets located across distant columns in the
      opposite hemisphere. Finally, electrophysiological recordings performed in
      several laboratories have shown the existence of stimulus-dependent
      synchronization of visual responses across the two hemispheres. Possible
      implications of these findings are discussed in the context of temporal tagging
      of neuronal assemblies.

PMID- 10574118
TI  - Gating of action potential propagation by an axonal A-like potassium conductance
      in the hippocampus: a new type of non-synaptic plasticity.
AB  - Synaptic plasticity is usually considered as the main form of activity-dependent
      functional plasticity in the mammalian brain. Short- and long-term regulation of
      synaptic transmission have been shown in various types of excitatory synapses
      including cortical and hippocampal synapses. In this review, we discuss a novel
      form of non-synaptic plasticity that involves voltage-gated K+ conductances in
      CA3 pyramidal cell axons. With experimental and theoretical arguments, we show
      that axons cannot only be considered as a simple structure that transmit reliably
      the action potential (AP) from the cell body to the nerve terminals. The axon is
      also able to express conduction failures in specific axonal pathways. We discuss
      possible physiological conditions in which these axonal plasticity may occur and
      its incidence on hippocampal network properties.

PMID- 10574119
TI  - Retrograde effects on synaptic transmission at the Ia/motoneuron connection.
AB  - The fidelity of impulse propagation through the complex axonal tree en route to
      the various target cells of that fiber is an important question in neurobiology.
      Anatomists can trace pathways, but if impulses fail to propagate down to the
      terminals to release transmitter onto the target cell, there is a significant
      'disconnect' between anatomy and physiology. These issues have been studied at
      length in the spinal cord of the cat where it has proven possible to examine the
      connections made by afferent fibers on motoneurons under different stimulus
      conditions. EPSP amplitude varies systematically during high frequency
      stimulation of the afferents according to the identity of the target motoneuron.
      This variation is a function of the state of the motoneuron's relation to its
      peripheral target. It changes after motoneuron axotomy and recovers with
      reinnervation of the periphery. Neurotrophins delivered to the axotomized motor
      axons fail to induce recovery. Chronic stimulation of the motor nerve alters
      muscle properties with coordinated changes in properties of the synapses on
      motoneurons innervating the stimulated muscle. We cannot yet definitively
      establish the mechanisms determining synaptic behavior during high frequency
      stimulation. However, the retrograde regulation of these properties suggests that
      it is an important variable and thus is worthy of intensive further study.

PMID- 10574120
TI  - Anatomical and functional differentiation of glutamatergic synaptic innervation
      in the neocortex.
AB  - Pyramidal neurons are the principal neurons of the neocortex and their excitatory
      impact on other pyramidal neurons and interneurons is central to neocortical
      dynamics. A fundamental principal that has emerged which governs pyramidal neuron
      excitation of other neurons in the local circuitry of neocortical columns is
      differential anatomical and physiological properties of the synaptic innervation
      via the same axon depending on the type of neuron targeted. In this study we
      derive anatomical principles for divergent innervation of pyramidal neurons of
      the same type within the local microcircuit. We also review data providing
      circumstantial and direct evidence for differential synaptic transmission via the
      same axon from neocortical pyramidal neurons and derive some principles for
      differential synaptic innervation of pyramidal neurons of the same type, of
      pyramidal neurons and interneurons and of different types of interneurons. We
      conclude that differential anatomical and physiological differentiation is a
      fundamental property of glutamatergic axons of pyramidal neurons in the
      neocortex.

PMID- 10574121
TI  - Functional multimodality of axonal tree in invertebrate neurons.
AB  - This review, based on invertebrate neuron examples, aims at highlighting the
      functional consequences of axonal tree organization. The axonal organization of
      invertebrate neurons is very complex both morphologically and physiologically.
      The first part shows how the transfer of information along sensory axons is
      modified by presynaptic inhibition mechanisms. In primary afferents, presynaptic
      inhibition is involved in: 1) increasing the dynamic range of the sensory
      response; 2) processing the sensory information such as increasing spatial and/or
      temporal selectivity; 3) discriminating environmental information from sensory
      activities generated by the animal's own movement; and 4) modulating the gain of
      negative feedback (resistance reflex) during active rhythmic movements such as
      locomotion. In a second part, the whole organization of other types of neurons is
      considered, and evidence is given that a neuron may not work as a unit, but
      rather as a mosaic of disconnected 'integrate-and-fire' units. Examples of
      invertebrate neurons are presented in which several spike initiating zones exist,
      such as in some stomatogastric neurons. The separation of a neuron into two
      functionally distinct entities may be almost total with distinct arborizations
      existing in different ganglia. However, this functional separation is not
      definitive and depends on the state of the neuron. In conclusion, the classical
      integrate-and-fire representation of the neuron, with its dendritic arborization,
      its spike initiating zone, its axon and axonal tree seems to be no more
      applicable to invertebrate neurons. A better knowledge of the function of
      vertebrate neurons would probably demonstrate that it is the case for a large
      number of them, as suggested by the complex architecture of some reticular
      interneurons in vertebrates.

PMID- 10574122
TI  - Presynaptic selection of afferent inflow in the spinal cord.
AB  - The synaptic effectiveness of sensory fibers ending in the spinal cord of
      vertebrates can be centrally controlled by means of specific sets of GABAergic
      interneurons that make axo-axonic synapses with the terminal arborizations of the
      afferent fibers. In the steady state, the intracellular concentration of chloride
      ions in these terminals is higher than that predicted from a passive
      distribution, because of an active transport mechanism. Following the release of
      GABA by spinal interneurons and activation of GABA(A) receptors in the afferent
      terminals, there is an outwardly directed efflux of chloride ions that produces
      primary afferent depolarization (PAD) and reduces transmitter release
      (presynaptic inhibition). Studies made by intrafiber recording of PAD, or by
      measuring changes in the intraspinal threshold of single afferent terminals
      (which is reduced during PAD), have further indicated that muscle and cutaneous
      afferents have distinctive, but modifiable PAD patterns in response to segmental
      and descending stimuli. This has suggested that PAD and presynaptic inhibition in
      the various types of afferents is mediated by separate sets of last-order
      GABAergic interneurons. Direct activation, by means of intraspinal
      microstimulation, of single or small groups of last-order PAD-mediating
      interneurons shows that the monosynaptic PAD elicited in Ia and Ib afferents can
      remain confined to some sets of the intraspinal collaterals and not spread to
      nearby collaterals. The local character of PAD allows cutaneous and descending
      inputs to selectively inhibit the PAD of segmental and ascending intraspinal
      collaterals of individual muscle spindle afferents. It thus seems that the
      intraspinal branches of the sensory fibers are not hard wired routes that diverge
      excitation to spinal neurons, but are instead dynamic pathways that can be
      centrally controlled to address information to selected neuronal targets. This
      feature appears to play an important role in the selection of information flow in
      muscle spindles that occurs at the onset of voluntary contractions in humans.

PMID- 10574123
TI  - Presynaptic inhibition and antidromic discharges in crayfish primary afferents.
AB  - The mechanisms of presynaptic inhibition have been studied in sensory afferents
      of a stretch receptor in an in vitro preparation of the crayfish. Axon terminals
      of these sensory afferents display primary afferent depolarisations (PADs)
      mediated by the activation of GABA receptors that open chloride channels.
      Intracellular labeling of sensory axons by Lucifer yellow combined with GABA
      immunohistochemistry revealed the presence of close appositions between GABA
      immunoreactive boutons and sensory axons close to their first branching point
      within the ganglion. Electrophysiological studies showed that GABA inputs
      mediating PADs appear to occur around the first axonal branching point, which
      corresponds to the area of transition between active and passive propagation of
      spikes. Moreover, this study demonstrated that whilst shunting appeared to be the
      sole mechanism involved during small amplitude PADs, sodium channel inactivation
      occurred with larger amplitude PADs. However, when the largest PADs (>25 mV) are
      produced, the threshold for spike generation is reached and antidromic action
      potentials are elicited. The mechanisms involved in the initiation of antidromic
      discharges were analyzed by combining electrophysiological and simulation
      studies. Three mechanisms act together to ensure that PAD-mediated spikes are not
      conveyed distally: 1) the lack of active propagation in distal regions of the
      sensory axons; 2) the inactivation of the sodium channels around the site where
      PADs are produced; and 3) a massive shunting through the opening of chloride
      channels associated with the activation of GABA receptors. The centrally
      generated spikes are, however, conveyed antidromically in the sensory nerve up to
      the proprioceptive organ, where they inhibit the activity of the sensory neurons
      for several hundreds of milliseconds.

PMID- 10574124
TI  - Antidromic discharges of dorsal root afferents in the neonatal rat.
AB  - Presynaptic inhibition of primary afferents can be evoked from at least three
      sources in the adult animal: 1) by stimulation of several supraspinal structures;
      2) by spinal reflex action from sensory inputs; or 3) by the activity of spinal
      locomotor networks. The depolarisation in the intraspinal afferent terminals
      which is due, at least partly, to the activation of GABA(A) receptors may be
      large enough to reach firing threshold and evoke action potentials that are
      antidromically conducted into peripheral nerves. Little is known about the
      development of presynaptic inhibition and its supraspinal control during
      ontogeny. This article, reviewing recent experiments performed on the in vitro
      brainstem/spinal cord preparation of the neonatal rat, demonstrates that a
      similar organisation is present, to some extent, in the new-born rat. A
      spontaneous activity consisting of antidromic discharges can be recorded from
      lumbar dorsal roots. The discharges are generated by the underlying afferent
      terminal depolarizations reaching firing threshold. The number of antidromic
      action potentials increases significantly in saline solution with chloride
      concentration reduced to 50% of control. Bath application of the GABA(A) receptor
      antagonist, bicuculline (5-10 microM) blocks the antidromic discharges almost
      completely. Dorsal root discharges are therefore triggered by chloride-dependent
      GABA(A) receptor-mediated mechanisms; 1) activation of descending pathways by
      stimulation delivered to the ventral funiculus (VF) of the spinal cord at the C1
      level; 2) activation of sensory inputs by stimulation of a neighbouring dorsal
      root; or 3) pharmacological activation of the central pattern generators for
      locomotion evokes antidromic discharges in dorsal roots. VF stimulation also
      inhibited the response to dorsal root stimulation. The time course of this
      inhibition overlapped with that of the dorsal root discharge suggesting that part
      of the inhibition of the monosynaptic reflex may be exerted at a presynaptic
      level. The existence of GABA(A) receptor-independent mechanisms and the roles of
      the antidromic discharges in the neonatal rat are discussed.

PMID- 10574125
TI  - Flexible processing of sensory information induced by axo-axonic synapses on
      afferent fibers.
AB  - Recent experiments indicate that afferent information is processed in the
      intraspinal arborisation of mammalian group I fibres. During muscle contraction,
      Ib inputs arising from tendon organs are filtered out by presynaptic inhibition
      after their entry in the spinal cord. This paper reviews the mechanisms by which
      GABAergic axo-axonic synapses, i.e., the morphological substrate of presynaptic
      inhibition, exert this filtering effect. Using confocal microscopy, axo-axonic
      synapses were demonstrated on segmental Ib collaterals. Most synapses were
      located on short preterminal and terminal branches. Using a simple compartmental
      model of myelinated axon, the primary afferent depolarisation (PAD), generated by
      such synapses, was predicted to reduce the amplitude of incoming action
      potentials by inactivating the sodium current, and this prediction was
      experimentally verified. A further theoretical work, relying on cable theory,
      suggests that the electrotonic structure of collaterals and the distribution of
      axo-axonic synapses allow large PADs (about 10 mV) to develop on some distal
      branches, which is likely to result in a substantial presynaptic inhibition. In
      addition, the electrotonic structure of group I collaterals is likely to prevent
      PAD from spreading to the whole arborisation. Such a non-uniform diffusion of the
      PAD accounts for differential presynaptic inhibition in intraspinal branches of
      the same fibre. Altogether, our experimental and theoretical works suggest that
      axo-axonic synapses can control the selective funnelling of sensory information
      toward relevant targets specified according to the motor task.

PMID- 10574126
TI  - Presynaptic inhibition in humans: a comparison between normal and spastic
      patients.
AB  - During the last 40 years, several studies in man have been devoted to the
      pathophysiological mechanisms underlying spasticity. Spasticity is characterised
      by a velocity dependent increase in muscle tone. Many spinal pathways control
      stretch reflex excitability and a malfunction in any one of them could
      theoretically produce the exaggeration of the stretch reflex. Delwaide showed
      that the vibration-induced inhibition of Ia fibres is reduced in spastic
      patients. However, the relation between a decrease in presynaptic Ia inhibition
      and the pathophysiology of spasticity has been recently questioned since it was
      argued that homosynaptic depression (or post-activation depression) also
      contributes to the vibratory-induced depression of monosynaptic reflexes. This
      paper is thus devoted to a review of the methods recently developed to study
      selectively presynaptic Ia inhibition in man and to a reevaluation of the
      relations between modifications in presynaptic Ia inhibition and spasticity in
      hemiplegic and spinal spastic patients.

PMID- 10574127
TI  - Modulation by corticospinal volleys of presynaptic inhibition to Ia afferents in
      man.
AB  - New methods have been recently developed to explore selectively presynaptic
      inhibition of Ia afferents in humans. They have allowed us to describe a highly
      specialized organisation in these pathways. A differential control has been
      disclosed during voluntary movements among various motoneuronal pools: at the
      onset of a selective voluntary contraction presynaptic inhibition of Ia afferents
      projecting to the 'contracting' motoneurons is strongly decreased whereas
      presynaptic inhibition of Ia afferents to antagonistic or synergistic
      motoneuronal pools, not involved in the contraction, is increased. Indirect
      arguments suggested that these modulations are centrally patterned. A
      differential control has been also disclosed between upper and lower limb
      pathways. Using transcranial magnetic stimulation to induce a descending
      corticospinal volley, we have shown that a corticospinal volley inhibits
      preferentially 'presynaptic interneurons'at the lumbar spinal level, an effect
      which is strengthened by a cutaneous input whereas it preferentially activates
      'presynaptic interneurons' at the cervical spinal level, an effect which is
      inverted by a cutaneous input.

PMID- 10574128
TI  - Ia presynaptic inhibition in human wrist extensor muscles: effects of motor task
      and cutaneous afferent activity.
AB  - The task-dependence of the presynaptic inhibition of the muscle spindle primary
      afferents in human forearm muscles was studied, focusing in particular on the
      modulation associated with the co-contraction of antagonist muscles and the
      activation of cutaneous afferents. The changes known to affect the motoneuron
      proprioceptive assistance during antagonist muscle co-activation in human leg and
      arm muscles were compared. The evidence available so far that these changes might
      reflect changes in the presynaptic inhibition of the muscle spindle afferent is
      briefly reviewed. The possible reasons for changes in presynaptic inhibition
      during the antagonist muscle co-contraction are discussed. Some new experiments
      on the wrist extensor muscles are briefly described. The results showed that the
      changes in the Ia presynaptic inhibition occurring during the co-contraction of
      the wrist flexor and extensor muscles while the hand cutaneous receptors were
      being activated (the subject's hand was clenched around a manipulandum) could be
      mimicked by contracting the wrist extensor muscles alone while applying
      extraneous stimulation to the hand cutaneous receptors. It is concluded that
      besides the possible contribution of inputs generated by the co-contraction of
      antagonist muscles and by supraspinal pathways, cutaneous inputs may play a major
      role in modulating the proprioceptive assistance during manipulatory movements.

PMID- 10574129
TI  - Portal vein thrombosis and prothrombotic disorders.

PMID- 10574130
TI  - Is Helicobacter pylori the primary cause of duodenal ulceration?
AB  - Helicobacter pylori infection may not be the primary cause of duodenal ulceration
      in cases not associated with non-steroidal anti-inflammatory drugs, but may be a
      secondary complication. In developing countries with a uniformly high prevalence
      of H. pylori infection there are marked regional differences in the prevalence of
      duodenal ulcer (DU). In some countries, especially those with a low prevalence of
      H. pylori, 30-40% or more patients with DU may be H. pylori negative. The absence
      of H. pylori infection in early cases of DU is also reported. In DU patients with
      antral H. pylori infection, duodenal colonization by H. pylori may often be
      absent. After complete H. pylori eradication, recurrence of DU within 6 months in
      some reports is as high as 20%. The evidence suggests that high acidity and
      reduced duodenal mucosal resistance remain the primary causes of DU and that H.
      pylori infection, when present, results in chronicity. Reduced mucosal resistance
      results in duodenal gastric metaplasia which permits colonization of the duodenum
      with H. pylori from the antrum. Therefore, whatever causes reduced mucosal
      resistance may be the primary factor and evidence suggests that this cause may be
      diet related. This would explain the enigma of regional variations in DU
      prevalence unrelated to H. pylori prevalence.

PMID- 10574131
TI  - Budd-Chiari syndrome: a short radiological review.
AB  - A short review of Budd-Chiari syndrome (BCS) is given with detailed radiological
      findings from ultrasound, computed tomography (CT) and angiography and
      illustrated with two case reports. The cases had different clinical
      presentations: one antedated by Behcet's syndrome and complicated with aortic
      aneurysm, the other with a provisional diagnosis of a tuberculous abdomen. The
      radiological features of BCS, especially the changing appearance under dual-phase
      CT, are discussed. The respective diagnostic sensitivity and efficacy of other
      imaging modalities are mentioned.

PMID- 10574132
TI  - Ethanol intake preceding Helicobacter pylori inoculation promotes gastric mucosal
      inflammation in Mongolian gerbils.
AB  - BACKGROUND: Mongolian gerbils have been reported to be a suitable model for
      Helicobacter pylori-associated gastric mucosal injury, including gastric cancer.
      Although ethanol is known to be one of the harmful substances in the gastric
      mucosa, the relationship between ethanol and H. pylori infection remains unknown.
      The aim of the present study is to investigate the effect of ethanol treatment
      prior to H. pylori inoculation on associated gastric mucosal injury. METHODS:
      Male Mongolian gerbils were used for the study. Helicobacter pylori was orally
      inoculated after 15 h fasting (Hp group). Thirty minutes prior to H. pylori
      inoculation, a group of gerbils was orally treated with 40% ethanol (20 mL/kg; E
      + Hp group). Another group of animals was treated either with H. pylori culture
      media alone (controls) or with 40% ethanol plus culture media (E group). Gerbils
      were killed 2, 4 or 12 weeks after H. pylori inoculation. Helicobacter pylori
      infection was confirmed by both histological examination and serological tests.
      Mucosal damage was evaluated histologically according to the modified Sydney
      system. RESULTS: Although in the controls and E group no significant change to
      the gastric mucose was observed, persistent H. pylori infection was seen in the
      mucosa and mucosal leucocyte infiltration and severe epithelial damage was
      observed in the Hp and E + Hp groups after 4 weeks. The histological scores for
      polymorphonuclear cell infiltration and myeloperoxidase activity were higher in
      the E + Hp group at 4 weeks than in the Hp group (P < 0.05). CONCLUSIONS: Ethanol
      intake preceding H. pylori inoculation could promote the progression of gastric
      mucosal inflammation in Mongolian gerbils.

PMID- 10574133
TI  - Gastric juice ascorbic acid is related to Helicobacter pylori infection but not
      ethnicity.
AB  - BACKGROUND: Maori and Pacific Island ethnic groups in New Zealand have a high
      risk for gastric cancer. Low levels of gastric juice ascorbic acid (vitamin C)
      have been suggested to be a risk factor for gastric cancer. Previous studies have
      shown that gastric juice ascorbic acid may be independently associated with both
      ethnicity and Helicobacter pylori infection. This study aimed to examine the
      interrelationship between H. pylori and ethnicity in New Zealand. METHODS:
      Gastric juice was collected into 70% perchloric acid preservative and stored at 
      80 degrees C. Ascorbic acid was analysed by high-performance liquid
      chromatography using ion-pair chromatography and electrochemical detection.
      Inflammation and atrophy was graded from biopsies from multiple sites in the
      antrum and body. Gastric juice was collected from 89 patients during routine
      endoscopy. RESULTS: There was a wide range of measured gastric juice ascorbic
      acid from 0.001 to 410 microg/mL. The median concentration of ascorbic acid for
      H. pylori-negative patients was 1.78 microg/mL (n = 57) and 0.12 microg/mL (n =
      32) for H. pylori-positive patients (P = 0.001). Gastric juice ascorbic acid
      concentration was not associated with age, endoscopic diagnosis or intestinal
      metaplasia, but was significantly associated with the degree of acute
      inflammation (P = 0.01) and the presence of atrophy (P = 0.04). The median
      ascorbic acid concentration for European patients was 0.92 microg/mL (n = 44) and
      0.09 microg/mL (n = 38) for Maori and Pacific Island ethnic groups combined (P =
      0.1). Multiple step-wise regression analysis showed that only H. pylori infection
      was a significant factor for predicting ascorbic acid concentrations (r2 = 0.12).
      CONCLUSIONS: This study has confirmed that gastric juice ascorbic acid
      concentration is lower in the presence of H. pylori infection.

PMID- 10574134
TI  - Long-term survival among patients operated upon for peptic ulcer disease.
AB  - BACKGROUND: Although surgery has been used widely for treating peptic ulcer
      disease, there is conflicting evidence with respect to subsequent life expectancy
      and the determinants of mortality. Our aim was to compare long-term survival in a
      large, population-based cohort of operated patients with that expected in the
      general population. METHODS: We followed 471 Rochester, Minnesota residents who
      had surgery for peptic ulcer at the Mayo Clinic during 1956-85 for a total of
      6174 person-years. Patients were followed through their complete (inpatient and
      outpatient) medical records in the community until death or last clinical contact
      and death certificates were obtained for all who succumbed. We compared observed
      survival and cause-specific death rates in this cohort with expected values and
      identified the determinants of short (30 day) and long-term mortality. RESULTS
      AND CONCLUSIONS: Survival was worse than expected, but excess deaths were
      confined to those with perforated ulcers (42 deaths observed; 18.8 expected).
      Independent predictors of death included age, male gender, emergency operation,
      gastric ulcer and cigarette smoking. Most deaths were due to heart disease and
      cancer, but only those due to digestive diseases (standardized mortality ratio
      (SMR) 3.8, 95% CI 2.4-5.7) and respiratory diseases (SMR 1.9, 95% CI 1.3-2.7)
      were increased compared to expected figures. Overall survival was reduced in this
      cohort but was normal among those whose ulcers were not perforated. However, the
      data suggest an adverse role for alcohol and smoking in these patients.

PMID- 10574135
TI  - Prevalence of non-ulcer dyspepsia in the Japanese population.
AB  - BACKGROUND: Non-ulcer dyspepsia (NUD) is one of the most frequently encountered
      disorders in general practice in Western countries. The prevalence of this
      disorder in the Japanese, however, has not been fully investigated. This study is
      designed to clarify the characteristics and prevalence of dyspepsia in the
      Japanese. METHODS: The subjects were 1139 people who visited our institutes for
      their annual medical check up for gastric cancers. After routine medical
      examination, all subjects were asked standardized questions in order to check for
      the presence of any symptoms suggesting dyspepsia. RESULTS: The results of the
      study showed that dysmotility-like dyspepsia, characterized by the presence of
      nausea, fullness and early satiety, is the most frequently observed dyspepsia in
      Japanese and that this type of dyspepsia decreases with age. Ulcer-like
      dyspepsia, which is the major type of dyspepsia in Western countries, is the
      least frequently experienced dyspepsia in the Japanese. CONCLUSIONS: This study
      clarified that NUD is also one of the most prevalent disorders in the Japanese,
      although its characteristics may be somewhat different from those in Western
      countries.

PMID- 10574136
TI  - Zinc sulphate solution enema decreases inflammation in experimental colitis in
      rats.
AB  - BACKGROUND: It has been reported that zinc sulphate contributes an anti
      inflammatory action in many animal models; however, the impact of zinc in colitis
      remains unclear. The aim of the present study was to examine the role of zinc
      sulphate in experimental colitis. METHODS: Colitis was induced by 2,4,6
      trinitrobenzenesulphonic acid (TNB) in rats. Beginning at the first day of TNB
      colitis, the rats were treated with a zinc sulphate enema once daily for 6 days.
      The rats were examined 8 days later. RESULTS: The TNB induced severe colitis as
      evidenced by increased mucosal lesion area, mucosal myeloperoxidase (MPO)
      activity and prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) levels. Six days
      after the application of the zinc sulphate enema, the mucosal lesion area, MPO
      activity, PGE2 and LTB4 levels all decreased significantly. Mucosal superoxide
      dismutase activity remained unchanged after zinc treatments. CONCLUSIONS: Our
      data suggest that zinc sulphate enemas have an anti-inflammatory action on
      experimental colitis.

PMID- 10574137
TI  - Intravenous glycyrrhizin for the treatment of chronic hepatitis C: a double
      blind, randomized, placebo-controlled phase I/II trial.
AB  - BACKGROUND: In Japan, glycyrrhizin therapy is widely used for chronic hepatitis C
      and reportedly reduces the progression of liver disease to hepatocellular
      carcinoma. The aims of this study were to evaluate the effect of glycyrrhizin on
      serum alanine aminotransferase (ALT), hepatitis C virus (HCV)-RNA and its safety
      in European patients. METHODS: Fifty-seven patients with chronic hepatitis C, non
      responders or unlikely to respond (genotype 1/cirrhosis) to interferon therapy,
      were randomized to one of the four dose groups: 240, 160 or 80 mg glycyrrhizin or
      placebo (0 mg glycyrrhizin). Medication was administered intravenously thrice
      weekly for 4 weeks; follow up also lasted for 4 weeks. RESULTS: Within 2 days of
      start of therapy, serum ALT had dropped 15% below baseline in the three dosage
      groups (P < 0.02). The mean ALT decrease at the end of active treatment was 26%,
      significantly higher than the placebo group (6%). A clear dose-response effect
      was not observed (29, 26, 23% ALT decrease for 240, 160 and 80 mg, respectively).
      Normalization of ALT at the end of treatment occurred in 10% (four of 41). The
      effect on ALT disappeared after cessation of therapy. During treatment, viral
      clearance was not observed: the mean decrease in plasma HCV-RNA after active
      treatment was 4.1 x 10(6) genome equivalents/mL (95% confidence interval, 0-8.2 x
      10(6); P > 0.1). No major side-effects were noted. None of the patients withdrew
      from the study because of intolerance. CONCLUSIONS: Glycyrrhizin up to 240 mg,
      thrice weekly, lowers serum ALT during treatment, but has no effect on HCV-RNA
      levels. The drug appears to be safe and is well tolerated. In view of the
      reported long-term effect of glycyrrhizin, further controlled investigation of
      the Japanese mode of administration (six times weekly) for induction appears of
      interest.

PMID- 10574138
TI  - Modelling the hepatitis C virus epidemic in Australia. Hepatitis C Virus
      Projections Working Group.
AB  - INTRODUCTION: In Australia, to the end of 1997, more than 110,000 people have
      been diagnosed with hepatitis C virus (HCV) antibodies and reported to
      State/Territory surveillance systems. The available data indicate that the
      overwhelming majority (around 80%) of people with HCV antibodies were infected
      through injecting drug use. METHODS: Models of the HCV epidemic in Australia were
      developed based on estimates of the pattern of injecting drug use in Australia.
      Estimates of HCV infections due to injecting drug use thus obtained were then
      adjusted to allow for HCV infections resulting from other transmission routes.
      Projections of cirrhosis and hepatocellular carcinoma (HCC) resulting from HCV
      were obtained by combining modelled HCV incidence with estimates of the
      progression rates to these outcomes. RESULTS: Based on the models, it was
      estimated that there were 196,000 (lower and upper limits of 149,000 and 234,000)
      people in Australia living with HCV antibodies at the end of 1997, with HCV
      incidence in 1997 estimated to be 11,000 (8500-13,500). It was estimated that
      8500 (4000-13,000) people were living with HCV-related cirrhosis in 1997 and that
      there were 80 (40-125) incident cases of HCV-related HCC. DISCUSSION: Model-based
      estimates were broadly consistent with other sources of information on the HCV
      epidemic in Australia. These models suggest that the prevalence of HCV-related
      cirrhosis and the incidence of HCV-related HCC will more than double in Australia
      by 2010.

PMID- 10574139
TI  - Mixed cryoglobulinaemia associated with hepatitis C virus infection: a predictor
      factor for treatment with interferon?
AB  - BACKGROUND AND AIMS: Mixed cryoglobulinaemia (MC) is a frequent finding among
      patients infected with hepatitis C virus (HCV). The response to treatment with
      alpha-interferon (alpha-IFN) in these patients is linked to predictive factors.
      The aim of this study was to ascertain whether the presence of MC was a
      predictive factor of response in patients treated with alpha-IFN for chronic
      hepatitis due to HCV. METHODS: Thirty-two patients with MC and HCV infection (24
      with chronic hepatitis and eight with cirrhosis) were compared with 30 patients
      with HCV infection without MC (23 chronic hepatitis, seven cirrhosis) of a
      similar mean age. All were treated with lymphoblastoid alpha-IFN, at 3 MU,
      t.i.w., for 6-12 months and then followed up. RESULTS: No statistical difference
      was observed between the two groups in terms of sustained response (P = 0.83),
      relapse (P = 0.88) and non-response (P = 0.92). The mean follow up was 24.3
      months (range 17-28) for patients with sustained response and for the patients
      with MC and 22.6 months (range 15-26) for patients without MC. CONCLUSIONS: The
      presence of cryoglobulinaemia does not influence the response to alpha-IFN in
      patients with chronic HCV infection.

PMID- 10574140
TI  - Effects of end-to-side portacaval shunt and distal splenorenal shunt on systemic
      and pulmonary haemodynamics in patients with cirrhosis.
AB  - BACKGROUND: Patients with cirrhosis exhibit splanchnic, peripheral and pulmonary
      vasodilation, which are thought to play a role in increasing portal pressure,
      promoting sodium retention and determining arterial hypoxaemia. The present study
      investigated whether these abnormalities are influenced by portal hypertension or
      by portal systemic shunting. METHODS: Sixty-one patients with cirrhosis who had
      haemodynamic measurements before and after end-to-side portacaval shunt (n = 30)
      or distal splenorenal shunt (n = 31) were evaluated. RESULTS: End-to-side
      portacaval shunts were more effective than distal splenorenal shunts in
      decompressing the portal system (portocaval pressure gradient 3.2 +/- 2.5 vs
      splenocaval gradient 6.5 +/- 3.2 mmHg, P < 0.0001), because of a greater shunt
      blood flow (33 +/- 12 vs 21 +/- 12 mL/min per kg, P < 0.005). Azygos blood flow
      and hepatic blood flow decreased significantly after both surgical shunts.
      However, end-to-side portacaval shunts caused a greater decrease in peripheral
      resistance than distal splenorenal shunts (-23 +/- 18 vs -11+/- 27%, P < 0.05).
      Mean arterial pressure and pulmonary vascular resistance were significantly
      reduced after an end-to-side portacaval shunt (-7 +/- 10%, P < 0.001 and -14 +/-
      33%, P < 0.004, respectively), but not after splenorenal shunt. CONCLUSIONS:
      These results show that end-to-side portacaval shunts, despite normalizing portal
      pressure, worsen the peripheral and pulmonary vasodilatation. The splenorenal
      shunt that maintained a higher portal pressure, caused less peripheral
      vasodilatation and did not enhance pulmonary vasodilatation. These findings
      suggest that portal systemic shunting is more important than increased portal
      pressure in determining peripheral vasodilatation in cirrhosis.

PMID- 10574141
TI  - Case report: portal vein thrombosis associated with hereditary protein C
      deficiency: a report of two cases.
AB  - Protein C deficiency is one of the causes of curable or preventable portal vein
      thrombosis. We report two patients of portal vein thrombosis associated with
      hereditary protein C deficiency. The first patient presented with continuous
      right upper quadrant pain and high fever. The abdominal sonography revealed
      normal liver parenchyma but portal vein and superior mesenteric vein thrombosis.
      Based on a 55% (normal 70-140%) plasma protein C level, he was diagnosed as
      having protein C deficiency. A trace of his family history showed that his elder
      brother also had protein C deficiency with a 50% plasma C level. Both patients
      received anticoagulant therapy. The younger brother showed good response.
      Unfortunately, the elder one suffered from recurrent episodes of variceal
      bleeding and received a life-saving splenectomy and devascularization. We herein
      remind clinicians that early screening and therapy are helpful in preventing late
      complications of protein C deficiency with portal vein thrombosis.

PMID- 10574142
TI  - Case report: Hepatic involvement in antiphospholipid syndrome.
AB  - Three cases of hepatic involvement in antiphospholipid syndrome are described.
      One patient had catastrophic antiphospholipid syndrome with haemorrhages and
      necrosis in the liver parenchyma. The second patient had blood clots in the small
      hepatic vessels. The third patient had autoimmune hepatitis type I associated
      with antiphospholipid syndrome. Other possible hepatic manifestations of
      antiphospholipid syndrome are also discussed.

PMID- 10574143
TI  - Case report: acute encephalitis immediately prior to acute onset of hepatitis C
      virus infection.
AB  - A 34-year-old male presented with acute viral encephalitis of unknown aetiology
      with subsequent acute onset of hepatitis C virus (HCV) infection. Although the
      neurological syndrome improved after administration of acyclovir, jaundice
      appeared. Neurological complications of HCV infections have rarely been
      described. In this case report, we discuss the close relationship between
      neurological syndromes and HCV infection. In the future, we hope that further
      discussion of clinical cases will determine whether or not the HCV produces
      neurological manifestations.

PMID- 10574144
TI  - Case report: adenocarcinoma arising in a Crohn's stricture of the jejunum.
AB  - Patients with Crohn's disease affecting the small intestine appear to have an
      increased risk of developing adenocarcinoma. However, it remains an uncommon
      complication of an uncommon disease. The diagnosis is difficult to make both pre-
      and intra-operatively, and is most commonly made postoperatively on
      histopathology. Hence, at laparotomy, consideration should be given to performing
      a frozen section on all small bowel strictures due to Crohn's disease to define
      the presence of dysplasia or cancer. This will assist the surgeon in deciding
      whether to perform a stricturoplasty or a resection.

PMID- 10574145
TI  - Hepatobiliary and pancreatic: a man with fever and hepatomegaly.

PMID- 10574146
TI  - Gastrointestinal: Brunner's gland hyperplasia.

PMID- 10574147
TI  - Laser surgery for allergic and hypertrophic rhinitis.
AB  - Laser surgery, which is one type of surgical treatment for allergic and
      hypertrophic rhinitis, was investigated basically and clinically. The basic
      investigation showed morphological changes in the nasal mucosa before and after
      laser surgery. Before laser surgery, hyperplasia of the mucous epithelium,
      thickening of the basement membrane, edema of the lamina propria mucosa,
      eosinophilic infiltration, and enlargement of the nasal glands were noted. After
      laser surgery, the nasal mucosa was covered with 1) epithelium that was
      squamatized or cuboidal and/or 2) columnar epithelium that was stratified.
      Granulation-like tissue or cicatricial tissue was found in the lamina propria
      mucosa. Clinically, we performed laser surgery in 204 cases. Regarding the short
      term results, laser surgery was effective in 87%. In the long term, the short
      term results persisted in 81% of cases treated for sneezing, 78% for nasal
      discharge, and 76% for nasal obstruction. From these results, we concluded that
      laser surgery was a useful surgical treatment for allergic and hypertrophic
      rhinitis.

PMID- 10574148
TI  - The thymus: at the interface between immunology and neuroendocrinology.

PMID- 10574149
TI  - Pathological aspects of malignant and benign thymic disorders.
AB  - A WHO committee recently defined criteria for distinguishing between thymic
      epithelial tumours (TET) and classified them as type A, AB, B1-3 and C thymomas.
      As the terminology for each WHO type is still controversial, it is recommended to
      use also other names in addition to the WHO classification to allow comparability
      of future clinicopathological studies. We consider type A and AB thymomas
      (medullary and mixed thymomas) clinically benign, whereas type B1-3 thymomas
      (predominantly cortical and cortical thymomas and well-differentiated thymic
      carcinomas) are of low-grade malignant potential and most type C thymomas
      (category II malignant thymomas) are highly malignant. Not yet approved by the
      WHO are the recently described 'thymoma with pseudosarcomatous stroma' and the
      'low-grade metaplastic carcinoma of the thymus', which are considered as benign
      or low-grade malignant tumours, respectively. Thymic pathology frequently occurs
      in myasthenia gravis (MG). Production of autoantibodies against the acetylcholine
      receptor results from an antigen-driven immune reaction that starts inside the
      thymus, is maintained there but spreads to extrathymic sites already during the
      early phase of MG. Paraneoplastic MG occurs only in type A, AB and B1-3 thymomas.
      Abnormal TET microenvironments trigger nontolerogenic T-cell selection by
      neoplastic epithelial cells. Only after export of substantial numbers of naive,
      potentially autoreactive T cells to extratumorous sites does T-cell activation
      outside the thymoma initiate the autoimmune process. Early surgery after onset of
      MG is essential in thymitis to prevent substantial export of autoreactive T cells
      from the inflamed thymus to extrathymic organs, and it usually alleviates MG
      symptoms. In thymoma, 'dissemination' of autoreactive T cells to extratumorous
      sites has already continued for many months or even years before emergence of
      symptoms of MG. Therefore, thymoma surgery is aimed against oncological and local
      cardiovascular complications and rarely succeeds in alleviating symptoms of MG.

PMID- 10574150
TI  - Neuropeptides and their receptors in the immune system.
AB  - Neuropeptides and their receptors are produced and expressed by neuroendocrine
      tissues and function as neurotransmitters and/or mediators of well-defined
      hormonal activities in specific tissues and cells. However, neuropeptides and
      their receptors are also found in the immune system, and various neuropeptides
      are involved in both systems. In this review we discuss the role of two of these
      neuropeptides, somatostatin and substance P, with regard to their receptor
      expression in the human immune system and their role in the diagnosis and
      treatment of immune-mediated diseases.

PMID- 10574151
TI  - Functional role of somatostatin receptors in neuroendocrine and immune cells.
AB  - During the last decade the concept of a narrow communication between the immune
      and classical neuroendocrine systems has been supported by cumulative evidence.
      One of the common links between the two systems is formed by the production of
      somatostatin (SS), the presence of SS receptors (SS-R) and the functional effects
      of SS on both endocrine and immune cells. While in the endocrine system SS-R
      activation is coupled to mainly inhibitory effects, both inhibitory and
      stimulatory effects of SS have been demonstrated on the function of immune cells
      (ie proliferation and secretion). Moreover, in contrast to endocrine cells (ie
      growth hormone (GH)-secreting pituitary cells) in which SS and its analogues
      inhibit GH secretion in the nanomolar range in a dose-dependent manner achieving
      maximal inhibitory effects at higher concentrations, biphasic effects of SS are
      generally found on the function of immune cells with inhibition at low
      (nanomolar) concentrations and absence of an effect at higher (micromolar)
      concentrations. Neuroendocrine cells often express multiple SS-R subtypes, which
      may be linked to specific functions. Scarce information is available so far on
      the SS-R subtype expression pattern as well as on the second messenger systems
      linked to SS-R activation in human lymphoid cells. The recent development of
      novel SS-R subtype-selective SS analogues will be helpful in unravelling the
      functional roles of the individual SS-R subtypes in SS-R-expressing human
      neuroendocrine and immune cells.

PMID- 10574152
TI  - Somatostatin receptors in the thymus.
AB  - The thymus is the primary lymphoid organ where different factors participate in
      regulating the proliferation and differentiation of T cells. The thymic
      epithelium is the main cellular component in driving the maturation of thymocytes
      through cell-to-cell and extracellular matrix-mediated interactions. Thymic
      hormones and cytokines play a critical role in the proliferation, differentiation
      and selection of precursor cells along the T-cell lineage. However, other locally
      produced hormones and neuropeptides participate in thymic functions in an
      autocrine and paracrine manner. Some of them have well-characterized actions,
      whereas somatostatin (SS), although it has been identified, has not been
      investigated in detail. SS inhibits hormone and exocrine secretion, modulates
      neurotransmission and inhibits cell proliferation. The biological effects of SS
      are mediated through five G protein-coupled membrane receptor subtypes (sst1-5).
      SS receptors (SS-R) have been demonstrated in normal tissues and tumours at the
      protein and mRNA levels. Sst2 mRNA has been detected in the murine thymus,
      whereas sst3 and sst4 mRNAs are expressed in the rat immune system. The
      significance of the presence of specific SS-R subtypes remains to be clarified.
      Moreover, the activation of lymphoid cells seems to modify their SS-R expression
      pattern. SS, sst1, sst2A and sst3 mRNAs have been found in normal human thymic
      tissue, whereas enriched cultured thymic epithelial cells (TEC) selectively
      express SS, sst1 and sst2A mRNAs. Furthermore, TEC respond in vitro to SS and
      octreotide by inhibiting cell proliferation. Immunoreactivity for sst2A has been
      detected primarily in the medulla, where TEC, dendritic cells and macrophages are
      the major components, in line with the predominant binding of the sst2 receptor
      preferring ligand [125I-Tyr3]-octreotide in this region. The heterogeneous
      distribution of SS-R subtypes on specific cell subsets indicates that SS may play
      a paracrine and/or autocrine role in regulating cell activities in the thymus.

PMID- 10574153
TI  - Role of thymic peptides as transmitters between the neuroendocrine and immune
      systems.
AB  - Thymic peptides, a heterogenous family of polypeptidic hormones synthesized
      within the thymus, not only exert important regulatory effects within both the
      immune and neuroendocrine systems but are also themselves subject to control by
      hormones derived from the hypothalamic-pituitary-adrenal axis (HPA) and other
      endocrine glands. Regarding thymic hormonal function, thymulin production is up
      regulated by several hormones, including prolactin, growth hormone and thyroid
      hormones. Other aspects of the physiology of thymic epithelial cells can also be
      modulated by hormones and neuropeptides, particularly cytokeratin expression,
      cell growth and production of extracellular matrix proteins, thus characterizing
      the pleiotrophic action of these molecules on the thymic epithelium. Conversely,
      thymic-derived peptides also regulate hormone release from the HPA axis and may
      act directly on target endocrine glands of this axis, modulating gonadal tissues.
      In addition, it has recently been shown that thymulin can modulate some
      peripheral nervous sensory functions, including those related to sensitivity to
      pain. According to the dose given, thymulin induces or reduces hyperalgesia
      related to both mechanical and thermal nociceptors and thus represents an
      important interface between the immune, endocrine and nervous systems.

PMID- 10574154
TI  - Thymic hormones, cancer and behavioural adaptive responses.
AB  - The effects of thymic hormones are not restricted within the immune system but
      are rather pleiotropic. Through neuropeptides the neuroendocrine system
      participates in the regulation of homeostasis as well as in the control of stress
      response and behavioural outputs. Thymic hormones increase spontaneous behaviour,
      inhibit anxiety-like responses and improve resistance to stress in tumour-bearing
      mice. In addition, thymic hormones modulate secretion of pituitary
      adrenocorticotrophin (ACTH) and beta-endorphin in both primates and rodents. In
      turn, both ACTH and beta-endorphin influence stress response and behaviour.
      Besides their neuroendocrine effects, thymic hormones have radioprotective
      effects either when administered alone or when associated with other
      radioprotective agents. Thymic hormones are possibly able to reduce
      postirradiation tissue damage in the bone marrow and in the central nervous
      system. Finally, evidence suggests a potentiating effect of thymic hormones when
      associated with current anticancer drugs. From the data reviewed it seems
      reasonable to conclude that the combination of thymic hormones with cancer
      therapy is associated with improvement of behaviour and well-being status,
      protection of tissues from detrimental effects of cancer treatment, and possibly
      also with potentiation of the antiproliferative effects of other drugs. Thus,
      thymic hormones could be envisioned as a valuable adjunct to actual cancer
      therapy.

PMID- 10574155
TI  - Thymic disorders and myasthenia gravis: genetic aspects.
AB  - Myasthenia gravis (MG) is an autoimmune disease characterized by production of
      antibodies to acetylcholine receptor at the motor end-plate responsible for
      impairment of neuromuscular transmission. There is general agreement about the
      involvement of the thymus in the pathogenesis of MG, and thymic pathological
      changes are commonly found in MG patients. Genetic factors seem to play an
      important role in susceptibility to MG. As with other autoimmune diseases,
      genetic predisposition to MG probably involves multiple genes. Ample evidence
      suggests that genes within the major histocompatibility complex (MHC) are
      involved in susceptibility to autoimmune diseases. Both data from the literature
      and our findings indicate that different genes within the MHC could predispose to
      various forms of MG, and that particularly the tumour necrosis factor genes may
      play a role in the association between the different thymic disorders and MG.

PMID- 10574156
TI  - The thymus and myasthenia gravis: immunological and neurophysiological aspects.
AB  - Myasthenia gravis (MG) is an autoimmune disorder, in which end-plate membrane
      damage is induced by antibodies directed toward various epitopes of the main
      immunogenic region of the nicotinic acetylcholine receptor (AChR). This article
      reviews the mechanisms responsible for the development of MG. Recent
      investigations into the roles of the thymus, antibodies against AChR, cytokines,
      and neuromuscular transmission have given new insight into the pathogenesis of
      MG. These new advances have led to a better understanding of the immune
      mechanisms in MG and have opened new therapeutic horizons.

PMID- 10574157
TI  - Morphological imaging of thymic disorders.
AB  - The thymus is a bilobed lymphoid organ the morphology of which varies
      considerably with age as a result of a process of fatty infiltration occurring
      after puberty. Although several diseases can arise in the thymic parenchyma,
      including germ cell and neuroendocrine tumours, primitive epithelial neoplasms
      (thymomas) are the most common neoplasms and account for almost 10% of
      mediastinal masses. Thymomas are usually benign but can be locally invasive. Up
      to 30% of patients with a thymoma have myasthenia gravis, which is more commonly
      associated with thymic hyperplasia. The latter results in a symmetric diffuse
      enlargement of the thymus. However, thymic hyperplasia can be histologically
      found in up to 50% of normal-sized thymuses on computed tomography (CT). CT is
      much more accurate in detecting thymomas than it is in detecting thymic
      hyperplasia, although CT findings may be unspecific. CT can be exhaustive in the
      case of an encapsulated thymoma (65% of all thymomas), which appear as a solid
      homogeneous mass with a slight contrast enhancement and a well-defined
      surrounding fat plane. These tumours rarely recur after surgery. CT can also
      accurately detect a spread through the capsule into the adjacent mediastinal fat,
      which characterizes invasive thymomas (35%). These, however, are best evaluated
      by magnetic resonance imaging (MRI). On T1-weighted MR scans the thymus is well
      delineated against the mediastinal fat, whereas marked inhomogeneity of the
      signal may appear on T2-weighted images as a result of areas of cystic
      degeneration in the tumour mass. The superior contrast resolution of MRI and the
      multiplanar images that can be produced with it are well suited for documenting
      the mediastinal spread of invasive thymomas. MRI depicts accurately pleural
      and/or pericardial implants as well as the involvement of great vessels, offering
      considerable aid in the planning of surgery.

PMID- 10574158
TI  - Functional imaging of thymic disorders.
AB  - Human thymomas are rare tumours which usually develop in the chest. The diagnosis
      via guided biopsy, the evaluation of the extent of the tumour and its boundaries
      with adjacent organs, the choice of the appropriate therapeutic option, and the
      assessment of response to treatment are usually made with computed tomography
      (CT) alone or in combination with magnetic resonance imaging (MRI). More
      recently, radiopharmaceuticals and nuclear medicine procedures have been used
      increasingly in the imaging and functional characterization of benign and
      malignant thymic disorders. Two groups of radiopharmaceuticals have been used.
      The first includes several oncotropic tracers, such as 201Tl-chloride, 99mTc
      sestamibi and 18F-fluorodeoxyglucose, which are significantly concentrated in
      thymic tumours. Their uptake correlates with tumour grades and cellularity. The
      second class includes two radioligands: [(111)In-DTPA-D-Phe1]-octreotide (DTPA,
      diethylenetriamine penta-acetic acid) and [(111)In-DTPA-Arg1]-substance P, which
      bind to specific receptors. [(111)In-DTPA-Arg1]-substance P binds to its
      receptors that are largely expressed in the thymus of patients with autoimmune
      diseases. [(111)In-DTPA-D-Phe1]-octreotide recognizes the somatostatin receptor
      subtype 2. In patients with active disease investigated in our institution
      [(111)In-DTPA-D-Phe1]-octreotide has been shown to concentrate in the majority of
      thymoma deposits. Conversely, it is not concentrated in adult patients with
      benign lymphofollicular thymic hyperplasia. This finding has had a significant
      impact on the management of patients with myasthenia gravis as it differentiates
      early-stage thymoma from benign hyperplasia, unlike CT and MRI, which often fail
      to distinguish between the two. In addition to its role in diagnostic imaging,
      somatostatin receptor scintigraphy also enables us to select patients with
      advanced or metastatic thymoma unresponsive to conventional therapies, who might
      benefit from a somatostatin analogue-based treatment, serving thus as a link
      between diagnosis and therapy. In this article, we discuss and analyse the
      results of functional imaging with different radiopharmaceuticals, primarily
      those that we have obtained with [(111)In-DTPA-D-Phe1]-octreotide.

PMID- 10574159
TI  - Role of surgery in thymic disorders.
AB  - Thymomas are relatively slow-growing neoplasms that should be considered
      malignant tumours. When treated in the early stages, however, they have an
      excellent prognosis for long-term survival. Surgery, radiation therapy and
      chemotherapy all play a role in the management of these neoplasms. Surgery is the
      treatment of choice in thymoma patients and has become an increasingly accepted
      procedure in the treatment of myasthenia gravis (MG) since 1936, when thymectomy
      was performed for this disease for the first time. Improvement in myasthenic
      symptoms is nearly always observed following thymectomy, but the rates of
      complete remission vary from 7% to 63%. We have studied the potential
      preoperative factors predicting the evolution of MG.

PMID- 10574160
TI  - Current approaches to the treatment of thymoma.
AB  - Thymoma is an unusual tumour, but it is the most common malignancy in the
      anterior mediastinum. This tumour is unique in its frequent association with
      paraneoplastic syndrome and its potential for indolent growth. The distinction
      between thymomas and other tumours which arise in the anterior or superior
      mediastinum is important, and the optimal therapy for these malignancies is quite
      different. Indeed, even in advanced disease, systemic therapy may not only
      prolong the disease-free survival, but may also be curative in various
      malignancies. The therapy for patients with thymoma has been evolving over the
      past few years.

PMID- 10574161
TI  - Role of somatostatin analogue-based therapy in unresponsive malignant thymomas.
AB  - Thymomas are rare neoplasms that are usually associated with parathymic
      syndromes, pure red cell aplasia, myasthenia gravis, hypogammaglobulinaemia and
      other mainly immunological disorders. Therefore, the management of thymoma
      patients is often complex and presents many diagnostic and therapeutic issues.
      Controversies concerning the definition of the histological subtypes and the role
      played by thymoma-associated syndromes are of primary importance in determining
      the oncological approach. Although low-stage thymomas have a high percentage of
      recovery, thymomas which are locally advanced, metastatic or previously treated
      with standard therapeutic options have no well-defined and effective treatment
      approaches. The data previously described by us on somatostatin receptor
      scintigraphy showing high uptake of indium-labelled octreotide by thymic masses
      and the successful treatment of a patient with thymoma and pure red cell aplasia
      with octreotide and prednisone has provided us the rationale for using such
      treatment in patients with advanced thymoma.

PMID- 10574162
TI  - Immunological findings in thymoma and thymoma-related syndromes.
AB  - Human thymoma is a neoplasm of thymic epithelial cells associated with several
      clinical syndromes ranging from autoimmune disease to immunodeficiency. The aim
      of our research was to investigate T cell-mediated immune response in patients
      with thymoma. Initially eight patients were enrolled in this study. Four patients
      underwent surgical removal of the thymus, while four were submitted to diagnostic
      procedures only. Inversion of the CD4:CD8 ratio was found in three patients. Only
      one subject displayed a normal CD19 count in peripheral blood. The mean value (+/
      SD) of the CD19 percentage in the patient group was 2 +/- 2.2. Notably, the
      patients with thymoma had fewer mature B lymphocytes than the thymectomized
      patients. The T-cell receptor (TCR) repertoire was investigated in three
      individuals affected by thymoma: one underwent thymectomy, while the two others,
      one of which presented with lymphocytosis, were submitted to diagnostic biopsies
      only. The preliminary results showed a marked alteration in the CD8 repertoire of
      the thymectomized patient but not in that of the lymphocytotic patient. However,
      alterations in the TCR repertoire were also found in one patient with thymoma.
      Altogether, these preliminary findings reveal that loss of CD19+ lymphocytes in
      peripheral blood is a frequent phenomena in thymoma patients. In this article we
      discuss this aspect in the context of alterations of the TCR repertoire.

PMID- 10574163
TI  - Clinical correlation is suggested.

PMID- 10574164
TI  - Subjective swelling: a new sign for carpal tunnel syndrome.
AB  - This single-blinded, randomized cohort study of 186 patients was conducted to
      determine whether the subjective complaint of swelling of the hand or wrist is
      associated with the diagnosis and/or prognosis of carpal tunnel syndrome. All
      patients were referred for splinting with a presenting clinical diagnosis of
      carpal tunnel syndrome from outpatient specialty clinics, including orthopedics,
      rheumatology, and neurology. Patients were assessed before splinting for the
      complaint of subjective swelling and underwent a clinical examination including
      Phalen testing and carpal compression testing. In addition, 211 of the 290 joints
      underwent electrodiagnostic testing by the end of this study. Among the 211
      joints for which electrodiagnosis was used, a chi2 analysis was performed to
      determine the correlation among subjective swelling, the Phalen and carpal
      compression tests, and the electrodiagnostically verified carpal tunnel syndrome.
      Two weeks after splinting, an assessment was made of the subjective response to
      splinting. Chi2 analysis was then performed to assess the correlation among the
      Phalen test, carpal compression test, and nerve conduction study results and the
      symptom of subjective swelling at presentation with that of response to
      splinting. Subjective swelling of the hand showed a trend toward association with
      electrodiagnostic results (although this finding was not statistically
      significant) and proved to be significantly correlated with a poor clinical
      response to splinting. Positive electrodiagnostic findings were significantly,
      though positively, correlated with pain relief from splinting. This study,
      therefore, introduces the complaint of subjective swelling of the affected hand
      as an important diagnostic and prognostic symptom for the assessment and
      treatment of carpal tunnel syndrome.

PMID- 10574165
TI  - Life Satisfaction Index: Italian version and validation of a short form.
AB  - The Life Satisfaction Index-version A (LSIA) is a 20-item questionnaire providing
      a cumulative score acknowledged as a valid index of quality of life. In the
      present study, an Italian version was produced through validated procedures of
      repeated back-translations. The final Italian version (LSIA.it) was administered
      to 90 healthy subjects (55 women; aged 40-65 yr, median 51). Cronbach alpha was
      0.74, in agreement with previous studies on English, Greek, and Spanish versions,
      suggesting satisfactory internal consistency of the scale. Also in agreement with
      previous studies, factor analysis identified three factors (mood tone, zest for
      life, and congruence between desired and achieved goals), with eigenvalues of
      2.80, 1.72, and 1.34, respectively. Nine of the original 20 items were dropped
      because of inconsistency with the overall scale and/or because of ambiguous
      loading onto the extracted factors. The resulting 11-item short form (LSI-11) had
      alpha = 0.69 and Kaiser-Meyer-Olkin measure of sample adequacy = 0.65. In our
      sample, the mean score of LSIA.it was almost the same as that previously reported
      in the literature for LSIA, and the correlation between LSIA and LSI-11 was very
      high (r = 0.91). In a test-retest trial, the cumulative score of LSI-11 showed a
      percentage of agreement ranging from 73.9 to 100 and Cohen's k statistic for
      reliability ranging from 0.51 to 1. The individual items of the LSI-11 presented
      substantial (k > 0.6) to excellent (k > 0.8) levels of agreement. The
      responsiveness of LSIA and LSI-11 during a hospital stay for 30 consecutive
      inpatients for medical rehabilitation programs, as measured by effect size, was
      0.57 and 0.63, respectively. The results suggest that (1) the LSIA it has
      cultural equivalence with the English LSIA and that (2) the 11-item short form of
      LSIA is not only simpler but also more valid from a psychometric standpoint.

PMID- 10574166
TI  - Effect of shoe modifications on center of pressure and in-shoe plantar pressures.
AB  - This study was conducted to determine the effect of footwear modification on
      patients with neuromusculoskeletal disorders. Two analyses, the center of
      pressure and the in-shoe plantar pressures, were studied with the help of healthy
      volunteers so that the effect of shoe modifications could be assessed. The ground
      force under the sole of the shoe was measured while the subjects were walking,
      and the plantar pressure at the foot-insole interface and its distribution were
      measured while the subjects were in both the standing and walking positions,
      wearing the trial shoes. The trial shoes had three different types of heels
      standard heel, Thomas heel, and reverse Thomas heel-and had three different
      locations for the rocker bar--just under the metatarsophalangeal joint, 1 cm
      behind the metatarsophalangeal joint, and 1 cm before the metatarsophalangeal
      joint. The shift change at the center of pressure showed that the Thomas heel
      generally pushed the center of pressure more laterally and the reverse Thomas
      heel shifted it medially more than the standard heel did. While the subjects were
      in a stable standing position wearing the Thomas heel shoes, the medial forefoot
      and the lateral heel region's pressure showed significant reduction in the
      plantar pressure and the lateral forefoot and the medial heel showed a tendency
      to rise, compared with the standard heel condition. When the trial shoes' heels
      were changed to the reverse Thomas heel, the above changes tended to reverse.
      Tests at the foot-insole interface showed that the different types of heels and
      the location of the bar could change not only the pressure distribution but also
      the duration of the plantar pressure under the lateral area that shifted to the
      medial area when the subjects walked. This pressure measurement method was very
      useful for the design and evaluation of such footwear.

PMID- 10574167
TI  - The role of spouse responses to disability and family environment in multiple
      sclerosis.
AB  - Research in the area of family issues and multiple sclerosis has mainly focused
      on the impact of multiple sclerosis on the spouse. The aim of the current study
      was to examine the relationship between patients' ratings of their spouses'
      responses to multiple sclerosis patient disability behaviors and the impact on
      patient psychological and physical functioning. Multiple sclerosis patients were
      interviewed over the telephone using standardized questionnaires to assess
      patient physical and psychological functioning, spouse responses to patient
      disability and well behaviors (i.e., how does the spouse respond when you're
      having difficulties related to multiple sclerosis?), and family environment
      factors. The study was set in a large university-based Multiple Sclerosis
      Clinical Center. Forty-four of 64 patients approached with definite multiple
      sclerosis participated in the study. Physical functioning was assessed by the
      Kurtzke-EDSS, SIP, SF-36, and psychological functioning was assessed by the CES-D
      and SF-36. Scores on the SF-36 were generally lower compared with a normative
      sample of individuals with major medical problems; however, mean Kurtzke scores
      of 5.60 reflected moderate to severe impairment. Exploring spouse responses to
      disability, correlation analyses revealed that solicitous spouse responses to
      patient disability behaviors were significantly associated with greater multiple
      sclerosis-related physical disability. This relationship was stronger for
      patients who were more depressed. Spouse negative responses to patient disability
      behaviors were associated with poorer mental health, whereas spouses'
      encouragement of patient well behaviors was associated with lower emotional
      distress. Poorer psychological functioning was found in patients with families
      who were reported to have higher conflict and/or who were more controlling.
      Higher levels of independence in families were associated with better
      psychological and physical functioning in the patients. These preliminary
      findings suggest that patients' perceptions of their families' responses to
      disability and family environment factors may be important areas for further
      research. The findings may also provide potential targets for clinical
      intervention in the future.

PMID- 10574168
TI  - Do physical therapy and occupational therapy reduce the impairment percentage in
      reflex sympathetic dystrophy?
AB  - Reflex sympathetic dystrophy (RSD) is a disorder that can potentially result in
      permanent impairment. Because there are no adequate comparative studies regarding
      the additional value of physical therapy (PT) or occupational therapy (OT) for
      reducing the severity of permanent impairment in RSD, we prospectively
      investigated their effectiveness. At two university hospitals, we randomly
      assigned 135 patients with RSD of one upper limb, existing for <1 yr, to PT, OT,
      or control therapy (CT). One year after inclusion, impairment percentages were
      calculated according to the general method of the American Medical Association's
      Guides to the Evaluation of Permanent Impairment. For statistical evaluation, the
      Wilcoxon's signed-rank test (two-sided; alpha = 0.05) was used. The mean whole
      body impairments were as follows: PT, 21.6% and 19.1%; OT, 22.8% and 22.1%; CT,
      22.0% and 22.1% (intention-to-treat and per protocol analysis, respectively).
      There were no significant differences between the groups. We conclude that
      impairment percentages in RSD patients treated with PT or OT did not differ
      significantly from those treated with CT at 12 months after inclusion.

PMID- 10574169
TI  - Influence of daily activity on changes in physical fitness for people with post
      stroke hemiplegia.
AB  - To investigate the influence of daily activity on changes in the physical fitness
      of people with post-stroke (cerebrovascular disorders) hemiplegia, we evaluated
      the follow-up exercise load test of 30 ambulatory male patients with post-stroke
      hemiplegia. Between the times of the two tests, patients had no special
      supervised training. They were advised by their physicians to exercise according
      to the result of an exercise-loading test. We determined peak oxygen uptake and
      O2 consumption at the ventilatory threshold point. After 9.4 months, the mean
      peak oxygen uptake improved significantly from 17.7 to 21.1 ml/min/kg, and
      ventilatory threshold point also improved significantly from 11.4 to 13.6
      ml/min/kg. Among the nine subjects who returned to their jobs, subjects who
      previously went to their offices by public transportation showed more improvement
      in ventilatory threshold point level than did subjects who previously walked to
      their offices. Among the 21 subjects who did not return to work, those who
      exercised regularly (primarily by walking) showed more improvement of peak oxygen
      uptake level than did subjects who did not exercise regularly. In conclusion,
      people with hemiplegia who are living in the community can improve their physical
      fitness without formal supervised training by simply increasing their daily
      activities.

PMID- 10574170
TI  - Neuromuscular and psychological characteristics in subjects with work-related
      forearm pain.
AB  - There are scant data available on the neuromuscular and psychological
      characteristics of patients with cumulative trauma disorders. We compared 16
      subjects with work-related forearm and hand pain in the dominant upper limb with
      9 age-matched control subjects. Pain subjects were divided into two groups based
      on nerve conduction studies: eight subjects were in the study group for median
      neuropathy at the wrist (MN, median transcarpal latency >2.3 ms), and eight were
      in the study group for electrodiagnostically negative pain (EN). Average pain,
      forearm muscle tenderness, grip strength, pinch strength, and wrist flexor and
      extensor strength were measured. The Health Status Questionnaire and the Beck
      Depression Inventory were used to measure health perception and depressive
      symptoms, respectively. Work satisfaction was determined by a newly devised
      scale. Statistical analysis was by analysis of variance and planned comparison
      analysis. The MN and EN groups did not significantly differ on any of the
      measures except median transcarpal latency. Both pain groups had significantly (P
      < 0.05) greater average pain, greater extensor muscle tenderness, higher Beck
      Depression Inventory scores, higher pain rating, and poorer physical functioning
      on the Health Status Questionnaire than did the normal control group. Grip
      strength and wrist extension force were diminished in both cumulative trauma
      groups compared with control subjects; however, only grip strength in the MN
      group and wrist extension force in the EN group differed significantly (P < 0.05)
      from control subjects. Only the EN group had significantly less work satisfaction
      than did the control group. Overall, both pain groups differed from control
      subjects and shared similar characteristics, with the exception of median
      neuropathy.

PMID- 10574171
TI  - Predictors of restful sleep in a rehabilitation hospital.
AB  - The effect of hypnotic use on self-rated quality of sleep and therapist-rated
      level of alertness was examined in an inpatient rehabilitation setting. We
      examined what other factors were predictive of a restful sleep in this
      population. Seventy-five inpatients at the Jewish Rehabilitation Hospital in
      Montreal were included. Patients were asked to rate the quality of their own
      sleep on a given night. Night nurses recorded whether sleeping pills had been
      used and rated patients' sleep and number of awakenings during the same night.
      Patients were evaluated by their physiotherapists and occupational therapists the
      next day regarding how well rested they seemed according to three parameters:
      alertness, fatigue, and level of participation in therapy. Thirty-three percent
      of the patients received sleeping pills on the study night. Sleeping pill use did
      not predict patient perception of getting a good night of sleep or the somewhat
      more objective sleep rating by the night nurse. Whether a sleeping pill was taken
      was also found not to be predictive of restful sleep as estimated by the physical
      and occupational therapists. Variables significantly associated with therapists'
      ratings of apparently restful sleep included number of comorbidities, the nurses'
      rating of how well the patient had slept, the patients' self-assessment of sleep,
      and whether the patient felt well rested the morning after sleep. However, the
      patients' own assessment of sleep quality was negatively related to their
      performance in rehabilitation therapy. This suggests that patient self-report of
      sleeping difficulty may not be the best or only guideline to follow when
      considering intervention such as prescribing sleeping pills, particularly because
      sleeping pill use seems not to influence either patient perception of sleep or
      how well rested they seem in therapy.

PMID- 10574172
TI  - Continuing medical education: interests of former and current residents of a
      physical medicine and rehabilitation residency program.
AB  - To plan targeted, relevant continuing medical educational activities, a study was
      undertaken to assess demographic data, practice patterns, and current continuing
      medical educational needs of former graduates of the physical medicine and
      rehabilitation program. A survey was sent to the 168 physicians who had completed
      a physical medicine and rehabilitation residency program from 1961 to 1995 and to
      the 34 then current residents in the program. Questions were asked regarding
      gender, year of completion of residency, certification, fellowships, current
      employment situation, size of practice community, work time distribution, and
      busiest areas of clinical practice. In addition, from a list of 47 topics plus
      "other," the respondents indicated in which topics they had a current strong
      interest in continuing their education. They also responded to questions about
      their most important considerations when deliberating about attending an
      educational activity, the amount of notice required regarding an upcoming course,
      and the preferred duration of educational activities. The response rate of former
      residents was 56% and of then current residents was 100%. Topics of interest to
      greater than half of the respondents, in descending order, were
      musculoskeletal/soft tissue disorders, therapeutic injections/nerve blocks,
      industrial medicine, back and neck pain rehabilitation, and sports-related
      disorders. There were significant differences on some topics based on gender,
      year of residency completion, academic affiliation, private practice, and ratings
      of residency training in that topic. The most important consideration when
      deciding whether to attend an educational activity was, by far, interest in
      topic, followed by provision of continuing medical educational credits. There are
      among physiatrists several differences in educational interests that challenge
      continuing medical education planners to determine efficient, effective ways to
      deliver continuing medical education to meet these needs within the financial and
      time constraints imposed by today's clinical practice.

PMID- 10574173
TI  - Greater trochanter enthesopathy: an example of "short course retinoid
      enthesopathy": a case report.
AB  - Irreversible skeletal changes have been described in patients with dermatologic
      disorders treated with isotretinoin (Accutane), a synthetic vitamin A derivative.
      Although retinoids were developed to avoid toxicity associated with vitamin A,
      skeletal lesions and rheumatologic consequences are possible hazards of
      isotretinoin treatment. Enthesopathy is one of the potential musculoskeletal
      sequelae and is characterized by pathologic, sometimes painful changes at the
      insertion sites (entheses) of tendons, ligaments, and articular capsules into
      bone. We report a patient who was referred secondary to an extended history of
      bilateral hip region pain. She was subsequently found to have a greater
      trochanteric enthesopathy. A detailed patient history revealed past use of
      Accutane for cystic acne. The subsequent treatment course, including medications,
      corticosteroid injections, physical therapy, and activity modifications, is
      described and the pertinent literature is reviewed. We believe that patients who
      are prescribed isotretinoin should be warned about this potential pathologic
      condition at the initiation of treatment and that physicians who are treating
      patients with a history of Accutane use should be suspicious of underlying
      enthesopathies as the etiology behind pain of musculoskeletal origin.

PMID- 10574174
TI  - Adhesive capsulitis of the glenohumeral joint with an unusual neuropathic
      presentation: a case report.
AB  - A 37-yr-old woman presented with a 7-mo history of unilateral shoulder girdle
      stiffness, pain, and weakness and had already been diagnosed with frozen
      shoulder. Physical examination revealed scapular winging and suspicious focal
      paralysis of shoulder girdle muscles. Subsequently, electrodiagnostic studies
      reported denervation of deltoid, infraspinatus, serratus anterior, and lower
      cervical paraspinal muscles, in addition to a prolonged long thoracic nerve
      latency. The history, physical examination, and cervical magnetic resonance
      imaging scan seemed most consistent with neuralgic amyotrophy, although the
      electrodiagnostic examination could be interpreted as cervical radiculopathy.
      Some of the difficulties in identifying neuralgic amyotrophy and distinguishing
      it from cervical radiculopathy are discussed herein. Historically, frozen
      shoulder has seemed to develop as a complication of the neuropathic process. Both
      neuralgic amyotrophy and frozen shoulder have a poorly understood pathogenesis,
      and their combined presence is presumed to be rare. Because of difficulties
      inherent in the physical examination of frozen shoulder, a coexistent neuropathic
      process may go undetected.

PMID- 10574175
TI  - Measuring the impairment consequences of spinal cord injury.
AB  - The objectives of this study were to develop and validate an equal-interval
      measure of neurologic impairment from the International Standards for
      Neurological and Functional Classification of Spinal Cord Injury Patients
      developed by the American Spinal Injury Association. These standards were used to
      rate impairment at admission and discharge to Model System facilities. The
      results demonstrate that the standards fulfill their purpose of characterizing
      sensory-motor impairment. Developed was a self-scoring key that rehabilitation
      clinicians can use to obtain a measure of severity that combines sensory and
      motor level ratings and completeness classifications to describe impairment more
      precisely and illustrate the magnitude of reductions in impairment. This measure
      can be used to monitor improvement over time and compare severity across
      individuals or groups.

PMID- 10574176
TI  - Near field and far field source characteristics with respect to bioelectric
      source generators in volume conductors.

PMID- 10574177
TI  - Human cytomegalovirus: challenges, opportunities and new drug development.
AB  - In the age of highly active antiretroviral therapy, the incidence of human
      cytomegalovirus (HCMV) retinitis in AIDS patients has decreased substantially.
      However, this change does not indicate that HCMV disease in AIDS patients and
      other immunocompromised patients has abated and is no longer a concern. On the
      contrary, HCMV disease in graft recipients, newborns, and even in AIDS patients
      still accounts for considerable morbidity, and drug resistance to the anti-HCMV
      compounds is a major problem. Furthermore, HCMV may have a role in metabolic
      diseases, such as atherosclerosis. Fortunately there are novel and potentially
      very effective new compounds undergoing pre-clinical and clinical evaluation.
      These developments point the way toward new therapies and also to a clearer
      understanding of the biology of HCMV replication, infection and disease.

PMID- 10574178
TI  - Structure-based design of non-nucleoside reverse transcriptase inhibitors of drug
      resistant human immunodeficiency virus.
AB  - A computer model of reverse transcriptase (RT) from human immunodeficiency virus
      type 1 (HIV-1) was used to design thiourea compounds that were predicted to
      inhibit RT. The RT model was used to approximate how changes in binding pocket
      shape, volume and chemical properties resulting from residue mutations would
      affect inhibitor binding. Our lead compound, N-[2-(2,5-dimethoxyphenylethyl)]-N'
      [2-(5-bromopyridyl)]-thi ourea (HI-236) was tested against clinically observed
      non-nucleoside inhibitor (NNI)-resistant mutated strains of HIV. HI-236 was more
      potent than trovirdine, MKC-442 and zidovudine against the drug-sensitive HIV-1
      strain IIIB, 50-100 times more effective than delavirdine or nevirapine and twice
      as effective as our recently reported lead compound N-[2-(2-fluorophenethyl)]-N'
      [2-(5-bromopyridyl)]-thiourea (HI-240) against the NNI-resistant Y181C mutant HIV
      1 strain A17. HI-236 was highly effective against the multidrug-resistant HIV-1
      strain RT-MDR containing multiple mutations involving the RT residues 74V, 41L,
      106A and 215Y. In general, thiourea compounds such as HI-236 and HI-240 showed
      better inhibition of drug-resistant strains of HIV-1 than thioalkylbenzyl
      pyrimidine compounds such as HI-280 and HI-281. The improved activity of
      thioureas against RT mutants is consistent with a structural analysis of the NNI
      binding pocket model of RT. The activity of HI-236 against RT-MDR was superior to
      that of other anti-HIV agents tested, in the following order, from high to low
      activity; HI-236 (IC50 5 nM), HI-240 (IC50 6 nM), trovirdine (IC50 20 nM),
      zidovudine (IC50 150 nM), MKC-442 (IC50 300 nM), delavirdine (IC50 400 nM) and
      nevirapine (IC50 5 microM).

PMID- 10574179
TI  - Novel 6-azapyrimidine-2'-deoxy-4'-thionucleosides: synthesis, biological
      evaluation and conformational analysis.
AB  - We report the synthesis of novel 1-(2'-deoxy-4'-thio-beta-D-erythro
      pentofuranosyl)-(6-azapyrimidine) nucleosides and the subsequent preparation of a
      series of N3-substituted analogues. All the novel compounds were evaluated
      against a range of viruses, however they lacked any measurable activity. The lack
      of anti-herpetic activity may be a result of the parent nucleoside having poor
      affinity for herpes simplex virus type 1 thymidine kinase. Conformational
      analysis of the parent nucleoside showed a twist (3T2) sugar conformation
      commonly displayed by 2'-deoxy-4'-thionucleosides and the anti-human
      immunodeficiency virus type 1 agents zidovudine and 3'-fluoro-ddT.

PMID- 10574180
TI  - Acyclovir treatment of skin lesions results in immune deviation in mice infected
      cutaneously with herpes simplex virus.
AB  - Clinical observations indicate that the antibody response to herpes simplex virus
      (HSV) in patients undergoing acyclovir treatment is reduced and, although the
      exact mechanism is not clear, some authors interpret it as immunosuppression. In
      order to clarify the mechanism, we cutaneously infected mice with HSV-1 and
      treated the resulting skin lesions with acyclovir. The immune response to
      infection and treatment in these mice was then analysed. Acyclovir treatment was
      given orally (20 mg/kg, three times daily), starting on day 0 (D0), 2 (D2) or 4
      (D4) after infection and continuing until day 10. The serum antibody titre and
      the severity of skin lesions were significantly higher in the shortest treatment
      group (D4) than in the longer treatment groups (D0 and D2). In contrast, a skin
      test analysing delayed-type hypersensitivity (DTH) to HSV antigen showed that the
      D0 and D2 groups exhibited stronger DTH than the D4 group. Acyclovir treatment
      failed to cause a dissociation between DTH and antibody production in mice
      immunized with inactivated HSV antigen. However, acyclovir treatment in infected
      mice suppressed the development of skin lesions and resulted in a dissociation
      between DTH response and antibody production, indicating a typical immune
      deviation. This was supported by a change in the ratio of the isotype antibody
      IgG2a to IgG1. The treatment of skin lesions with acyclovir reduced the level of
      antibody response, as observed clinically. This indicates that the reduced
      antibody response in patients treated with acyclovir may be, at least in part,
      due to immune deviation and not immunosuppression.

PMID- 10574181
TI  - The design and synthesis of potent inhibitors of hepatitis C virus NS3-4A
      proteinase.
AB  - Hepatitis C virus (HCV) is the cause of the majority of transfusion-associated
      hepatitis and a significant proportion of community-acquired hepatitis worldwide.
      Infection by HCV frequently leads to persistent infections that result in a range
      of clinical conditions including an asymptomatic carrier state, severe chronic
      active hepatitis, cirrhosis and, in some cases, hepatocellular carcinoma. The HCV
      genome consists of a single-stranded, positive sense RNA containing an open
      reading frame of approximately 9060 nucleotides. This is translated into a single
      polyprotein of approximately 3020 amino acids (C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A
      NS5B), which in turn is processed by a series of host and viral proteinases into
      at least 10 cleavage products. The N-terminal portion of the NS3 protein encodes
      a serine proteinase that is responsible for the cleavage at the NS3-4A, NS4A-4B,
      NS4B-5A and NS5A-5B junctions. The 54 amino acid NS4A protein is a cofactor that
      binds to the NS3 protein and enhances its proteolytic activity. This report
      describes the expression of a recombinant NS3-4A proteinase fusion protein in
      Escherichia coli and the in vitro characterization of the enzyme activity using
      synthetic peptide substrates. It then demonstrates how these results were
      employed to guide the design of potent inhibitors of this enzyme.

PMID- 10574182
TI  - Isoquinolinesulphonamide derivatives inhibit transcriptional elongation of human
      immunodeficiency virus type 1 RNA in a promyelocytic model of latency.
AB  - Using the OM-10.1 promyelocytic model of inducible human immunodeficiency virus
      type 1 (HIV-1) infection, we tested a panel of known protein kinase inhibitors
      for an ability to block tumour necrosis factor-alpha-induced HIV-1 expression.
      Among the compounds tested, the broad-spectrum protein kinase inhibitor H-7
      uniquely blocked HIV-1 expression at the level of viral transcription, but did
      not inhibit nuclear factor kappaB activation or function. In structure-activity
      analysis this inhibitory activity of H-7 on HIV-1 expression corresponded with
      the known structural requirements for the interaction of H-7 with the ATP-binding
      region of protein kinase C, suggesting that it was indeed related to the kinase
      inhibitory properties of H-7. The mechanism of H-7 transcriptional inhibition did
      not involve chromatin remodelling at the HIV-1 long terminal repeat promoter, as
      shown by nuc-1 disruption, and appeared to involve HIV-1 RNA elongation but not
      initiation. Therefore, H-7 and related isoquinolinesulphonamide analogues are
      most likely inhibiting a kinase target essential for HIV-1 transcriptional
      elongation whose identity may provide new therapeutic targets for intervention.

PMID- 10574183
TI  - On-line derivatization for continuous and automatic monitoring of brain
      extracellular glutamate levels in anesthetized rats: a microdialysis study.
AB  - Glutamate is an important excitatory amino acid in central nervous system. We
      developed a method for in vivo, continuous and automatic monitoring of brain
      extracellular glutamate, as well as other amino acids in anesthetized rat. This
      method involves the use of microdialysis perfusion technique and a high
      performance liquid chromatography system equipped with a fluorescence detector.
      The microdialysate (perfused at a flow-rate of 1 microl/min) was on-line
      derivatized with o-phthaldehyde (perfused at 2 microl/min) through a mixing tee
      prior to the injection onto the HPLC column. The efficiency of this on-line
      derivatization was equivalent to that performed with an off-line manner. The
      effect of cerebral ischemia (2 h) and reperfusion (2 h) in brain cortex of
      anesthetized rats was monitored using this method. In addition to glutamate,
      extracellular concentrations of other amino acids, such as aspartate, glutamine,
      glycine, taurine and gamma-aminobutyric acid, were also simultaneously monitored
      with this on-line method. Since monitoring of extracellular amino acids by
      microdialysis perfusion is intensively used in neuroscience investigations, this
      simple and convenient method would be useful in the future applications.

PMID- 10574184
TI  - Determination of flumequine and doxycycline in milk by a simple thin-layer
      chromatographic method.
AB  - Tetracycline and quinolone antibiotics have for many years served as important
      classes of veterinary drugs. Two representatives of both classes: doxycycline
      from tetracyclines and flumequine from quinolones are often administered
      together. When the withdrawal periods are not obeyed, the antibiotic residues may
      be present in edible products, e.g., in meat, eggs or milk. In the present paper
      a simple thin-layer chromatography (TLC) screening method is established for
      determining these drugs in milk. Only two developments of the plate with
      concentrating zone are needed: one as a clean-up procedure, the other as a proper
      analysis. The spots were detected both by UV lamp with dual wavelength (254 and
      366 nm) and by densitometry.

PMID- 10574185
TI  - Partial purification of penicillin acylase from Escherichia coli in poly(ethylene
      glycol)-sodium citrate aqueous two-phase systems.
AB  - Studies on the partition and purification of penicillin acylase from Escherichia
      coli osmotic shock extract were performed in poly(ethylene glycol)-sodium citrate
      systems. Partition coefficient behavior of the enzyme and total protein are
      similar to those described in other reports, increasing with pH and tie line
      length and decreasing with PEG molecular weight. However, some selectivity could
      be attained with PEG 1000 systems and long tie line at pH 6.9. Under these
      conditions 2.6-fold purification with 83% yield were achieved. Influence of pH on
      partition shows that is the composition of the system and not the net charge of
      the enzyme that determines the behaviour in these conditions. Addition of NaCl to
      PEG 3350 systems significantly increases the partition of the enzyme. Although
      protein partition also increased, purification conditions were possible with 1.5
      M NaCl where 5.7-fold purification and 85% yield was obtained. This was possible
      due to the higher hydrophobicity of the enzyme compared to that of most
      contaminants proteins.

PMID- 10574187
TI  - Capillary electrophoretic immunoassays for digoxin and gentamicin with laser
      induced fluorescence polarization detection.
AB  - New immunoassays for therapeutic drugs digoxin and gentamicin have been
      described, which involved the separation of free and antibody-bound drug by
      capillary electrophoresis (CE) and the detection by laser-induced fluorescence
      polarization (LIFP). While the fluorescein-labeled digoxin and gentamicin
      (tracers) displayed negligible fluorescence polarization in solution, the complex
      formation between these small molecules and their antibodies resulted in
      substantial increases in fluorescence polarization due to the increase in
      molecular size. The LIFP detection, capable of measuring vertically and
      horizontally polarized fluorescence components simultaneously, provides enhanced
      capability for the identification of complex in capillary electrophoretic
      immunoassays. Proper adjustments of the running buffer pH and the ratio of
      antibody to tracer are essential for optimization of the performance of these
      assays. The digoxin-antibody complex remained stable during CE separation with
      running buffer pH ranging from 9.3 to 12. Calibration curves covering a
      concentration range of 0.05 to 0.5 ng/ml were obtained with a running buffer of
      pH 12. The concentration and mass detection limits were 0.02 ng/ml and 26 zmol,
      respectively. For gentamicin assay, the running buffer pH 10 was used to reduce
      the adsorption of the tracer while minimizing the dissociation of the antibody
      tracer complex during the separation. The calibration curves covered a
      concentration range 0.05-1.0 microg/ml, with a concentration detection limit of
      25 ng/ml and a mass detection limit of 52 amol of gentamicin.

PMID- 10574186
TI  - Novel sensitive high-performance liquid chromatographic method for assay of
      coumarin 7-hydroxylation.
AB  - In this paper, a novel HPLC-based method with fluorometric detection of coumarin
      7-hydroxylase is presented. The described method provides a time-effective, more
      sensitive and specific alternative to the previously used spectrofluorometric
      assay. Using the developed method, metabolism of coumarin in 11 samples of human
      liver microsomes was evaluated and 1790+/-690 pmol/min/nmol cytochrome P450 (CYP)
      activity was found. Kinetic parameters and linearity of coumarin 7-hydroxylation
      were studied in a reconstituted system consisting of recombinant CYP2A6 expressed
      in Escherichia coli, rat NADPH-CYP reductase and usual components. It was found
      that a 3.5 to 30 min time of incubation is suitable for estimation of coumarin 7
      hydroxylase activity. Observed Km and Vmax values in the CYP2A6 reconstituted
      system were 1.48+/-0.37 microM and 3360+/-180 pmol product/min/nmol CYP,
      respectively.

PMID- 10574188
TI  - Determination of a novel calmodulin antagonist, 3-[2-[4-(3-chloro-2-methylphenyl)
      1-piperazinyl]ethyl]-5,6-dimethoxy-1- (4-imidazolylmethyl)-1H-indazole
      dihydrochloride 3.5 hydrate, DY-9760e, in human plasma using solid-phase
      extraction and high-performance liquid chromatography with fluorescence
      detection.
AB  - A high-performance liquid chromatographic method for the determination of a novel
      calmodulin antagonist, 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6
      dimethoxy-1-( 4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate, DY
      9760e and its major metabolite, 3-[2-[4-(3-chloro-2-methylphenyl)-1
      piperazinyl]ethyl]-5,6-dimethoxyi ndazole, DY-9836 in human plasma has been
      developed. DY-9760e, DY-9836 and the internal standard (I.S.) were extracted from
      plasma by means of an Isolute C18 (EC) column. The extracts were chromatographed
      on a reversed-phase TSK-gel ODS-80Ts column using 0.1 M acetate buffer (pH 5)
      CH3CN (65:35, v/v) as the mobile phase at a flow-rate of 1.0 ml/min. Fluorescence
      detection at an excitation wavelength of 303 nm and an emission wavelength of 347
      nm resulted in a limit of quantitation of 1.000 ng/ml for plasma. The method
      showed satisfactory sensitivity, precision, accuracy, recovery and selectivity.
      Stability studies showed that DY-9760 and DY-9836 were stable in plasma up to at
      least eight weeks at -80 degrees C.

PMID- 10574189
TI  - Rapid method for relative gene expression determination in human tissues using
      automated capillary gel electrophoresis and multicolor detection.
AB  - The aim of this study was to evaluate a direct and automated post-polymerase
      chain reaction (PCR) detection system to simultaneously determine the relative
      gene expression levels of nine cancer-related human genes. Total RNA was prepared
      from flash-frozen biopsies derived from human colorectal tumors or normal mucosa
      and reverse-transcribed to cDNA which was PCR-amplified using primer pairs
      corresponding to the studied genes. In each reaction, the forward primer was
      labeled with a fluorescent dye. The PCR products were pooled and an internal size
      standard with a uniquely colored fluorescent dye was added. The samples were then
      subjected to automated capillary gel electrophoresis. Fragment analysis software
      was used to calculate the relative gene expression using beta-actin as the
      reference gene. We found that automated capillary gel electrophoresis with
      multicolor detection is a rapid, accurate and highly reproducible method for
      separation and quantification of PCR-amplified cDNA.

PMID- 10574190
TI  - Quantitative determination of efavirenz (DMP 266), a novel non-nucleoside reverse
      transcriptase inhibitor, in human plasma using isocratic reversed-phase high
      performance liquid chromatography with ultraviolet detection.
AB  - Efavirenz is a novel non-nucleoside reverse transcriptase inhibitor for the
      treatment of HIV-1-infected individuals. A simple and rapid high-performance
      liquid chromatographic method for the quantification of efavirenz in human plasma
      suitable for therapeutic drug monitoring in plasma is described. Sample
      pretreatment consists of protein precipitation with acetonitrile and subsequent
      evaporation of the extract to concentrate the analyte. The drug is separated from
      endogenous compounds by isocratic reversed-phase high-performance liquid
      chromatography with ultraviolet detection at 246 nm. The method has been
      validated over the range of 10 to 10,000 ng/ml using a volume of 250 microl of
      plasma. The assay is linear over this concentration range as indicated by the F
      test for lack of fit. Within- and between-day precisions are less than 4.3% for
      all quality control samples. The lower limit of quantitation is 10 ng/ml and the
      recovery of efavirenz from human plasma is 106.4% (+/- 1.8%). Frequently co
      administered drugs did not interfere with the described methodology. Efavirenz is
      stable under various relevant storage conditions, for example when stored for 24
      h at room temperature. This validated assay is suited for use in pharmacokinetic
      studies with efavirenz and can readily be implemented in the setting of a
      hospital laboratory for the monitoring of efavirenz concentrations.

PMID- 10574191
TI  - Determination of indinavir in human cerebrospinal fluid and plasma by solid-phase
      extraction and high-performance liquid chromatography with column switching.
AB  - A rapid, sensitive and robust sample preparation procedure for the quantitative
      determination of indinavir in human cerebrospinal fluid (CSF) and plasma is
      described. Indinavir and the internal standard were isolated from CSF or plasma
      samples by cation-exchange solid-phase extraction with SCX cartridges, while the
      chromatographic separation was adopted from a previous method, using a cyano
      column connected by a switching valve to a C18 column. UV detection was set at
      210 nm. The standard curve was linear over the concentration range of 2 to 2000
      ng/ml in CSF and 5 to 2000 ng/ml in plasma. The intra-day coefficients of
      variation at all concentration levels were < or = 5.9%. The inter-day consistency
      was assessed by running QC samples during each daily run. The coefficients of
      variation for quality control samples in both matrixes were < or = 6.1%. The
      method has been utilized to support clinical pharmacokinetic studies.

PMID- 10574193
TI  - Analysis of isobutyl nitrite inhalant in rat and human blood: application for
      pharmacokinetic investigations.
AB  - Organic nitrites have been used therapeutically for the treatment of angina
      pectoris and as diagnostic agents for the evaluation of cardiac heart murmurs. In
      addition, these highly volatile vasodilators are being used as inhalant drugs of
      abuse. We developed a gas chromatographic assay using electron capture detection
      for the analysis of a representative nitrite inhalant, isobutyl nitrite (ISBN),
      in rat and human whole blood. Unconventional sampling and processing techniques
      were required because of the high volatility and chemical instability of nitrites
      in biological fluids. Our method produced a mean recovery of ISBN from rat blood
      of about 86% over a concentration range of 1.0 to 400 ng/ml. The inter-day
      coefficient of variation was below 15% at the lowest quantifiable concentration
      of 1 ng/ml ISBN in rat blood. In this report, we applied the analytical method to
      obtain new pharmacokinetic information about ISBN. Results show that rats
      inhaling 900 ppm ISBN for 45 min produced steady-state blood concentrations of
      about 290 ng/ml, and a rapid elimination half-life of 1.4 min.

PMID- 10574192
TI  - Determination of testosterone and 6beta-hydroxytestosterone by gas chromatography
      selected ion monitoring-mass spectrometry for the characterization of cytochrome
      p450 3A activity.
AB  - A method for the determination of testosterone and its metabolite, 6beta
      hydroxytestosterone, in liver microsomal incubates employing gas chromatography
      with selected ion monitoring mass spectrometric detection (GC-SIM-MS) has been
      developed. The method is more rapid than previously reported methods.
      Testosterone and its metabolites are extracted from the incubation mixture in a
      single step with methylene chloride. The method does not require derivatization
      and testosterone and its metabolites are separated on a HP-5MS fused-silica
      capillary column in less than 15 min. The retention times of testosterone (m/z
      288), methyltestosterone (m/z 302), and 6beta-hydroxytestosterone (m/z 304) are
      approximately 12.7, 12.8, and 13.4 min, respectively. There are no interferences
      from other known CYP450 metabolites of testosterone. In addition, the selectivity
      and specificity of the mass spectrometer helps eliminate possible interferences
      from drugs and new chemical entities evaluated using this methodology.
      Calibration curves for testosterone and 6beta-hydroxytestosterone are linear from
      0.25 to 100 microM. Extraction recoveries are better than 92% for both analytes
      and the internal standard, methyltestosterone. Over the course of five separate
      runs, within-day and inter-day precision (expressed as relative standard
      deviation) was less than 5% for all concentrations of testosterone and 6beta
      hydroxytestosterone. Accuracies ranged from 95.8 to 105.8% for testosterone and
      94.6 to 104.2% for 6beta-hydroxytestosterone. The assay has been used to
      characterize the CYP3A metabolic activity of multiple preparations of human, rat,
      and dog liver microsomes.

PMID- 10574194
TI  - Field- and flow-dependent trapping of red blood cells on polycarbonate
      accumulation wall in sedimentation field-flow fractionation.
AB  - Sedimentation field-flow fractionation (SdFFF) instrumentation is now mature.
      Methodological procedure and particle separation development rules are well
      established even in the case of biological species. However, in some biological
      applications, retention properties of samples not predicted by any field-flow
      fractionation (FFF) elution models are observed. It is demonstrated that the
      trapping of cellular material in the separation system is not related to
      geometrical instrumentation features but to channel wall characteristics. The
      physicochemical particle-wall attractive interactions are different depending on
      the flow-rate and field intensity applied. Separation power in SdFFF for
      biological species is therefore limited by the intensity of these interactions.
      In terms of separation, a balance is to be found between external field and flow
      intensity to limit particle-wall interactions.

PMID- 10574195
TI  - Application of liquid chromatography-turbo ion spray tandem mass spectrometry for
      quantitative analysis of a potent motilin receptor agonist, EM574, and its
      metabolites in human plasma.
AB  - A liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for the
      simultaneous determination of a new potent motilin receptor agonist as
      erythromycin derivative, EM574 (erythromycin derivative), and its three
      metabolites, M-IV, M-V and M-VI, in human plasma was developed. The internal
      standards (I.S.s) used were deuterated EM574, M-IV and M-V. For the quantitation
      of M-VI, deuterated M-V was used. The analytes and I.S. were extracted from
      plasma samples with diethyl ether at neutral pH. A turbo ion spray interface was
      used as the ion source of LC-MS-MS, and the analysis was performed in the
      selected reaction monitoring mode. The lower quantitation limits for all the
      analytes were 0.05 ng/ml when 0.2 ml of plasma was used, and the standard curves
      were linear in the range 0.05 to 20 ng/ml. The method was precise; the intra- and
      inter-day precisions of the method were not more than 19.8% for all the analytes.
      The accuracy of the method was good with the deviations between added and
      calculated concentrations of each analyte being typically within +/- 11.2%.

PMID- 10574196
TI  - Gas chromatographic-mass spectrometric analysis of veterinary tranquillizers in
      urine: evaluation of method performance.
AB  - A method for analysis of veterinary tranquillizers in urine using gas
      chromatography-mass spectrometry (GC-MS) is described. Detection limits are 5
      microg/l for ketamine, azaperone and the phenothiazines (chlor-, aceto- and
      propionylpromazine), 10 microg/l for haloperidol, 20 microg/l for xylazine and 50
      microg/l for azaperol, recoveries for all analytes were higher than 70%. Method
      performance in terms of within-batch, between-days and between-analysts
      reproducibility was studied and found to be acceptable. Compliance with European
      Union criteria for confirmation of GC-MS "positive" results is evaluated and
      discussed.

PMID- 10574197
TI  - Determination of cefepime and cefpirome in human serum by high-performance liquid
      chromatography using an ultrafiltration for antibiotics serum extraction.
AB  - The aim of this study was to describe a high-performance liquid chromatography
      (HPLC) assay for the determination of cefepime and cefpirome in human serum
      without changing chromatographic conditions. The assay consisted to measure
      cefepime and cefpirome which were unbound to proteins having a molecular mass of
      10,000 or more by ultrafiltration followed by HPLC with a Supelcosil ABZ+ column
      and UV detection at a wavelength of 263 nm. The assay was been found to be linear
      and has been validated over the concentration range 200 to 0.50 microg/ml for
      both cefepime and cefpirome, from 200 microl serum, extracted. In future, the
      assay will support therapeutic drug monitoring for cefepime and cefpirome in
      neutropenic patients in correlation with microbiological parameters such as MIC90
      (minimal inhibitory concentration of antibiotic which kills 90% of the initial
      bacterial inoculum) and clinical efficacy.

PMID- 10574198
TI  - Determinaton of two major metabolites of the novel anti-tumour agent 5,6
      dimethylxanthenone-4-acetic acid in hepatic microsomal incubations by high
      performance liquid chromatography with fluorescence detection.
AB  - High-performance liquid chromatographic methods have been developed and validated
      for the glucuronidated and oxidative metabolites of the novel anti-tumour agent
      5,6-dimethylxanthenone-4-acetic acid (DMXAA), produced in human liver microsomal
      incubations. Calibration curves for DMXAA acyl glucuronide (DMXAA-Glu) and 6
      hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA) were constructed over
      the concentration ranges of 0.25 to 20 and 0.5 to 40 microM, respectively. Assay
      performance was determined by intra- and inter-day accuracy and precision of
      quality control (QC) samples. The difference between the theoretical and measured
      concentration, and the coefficient of variation, were less than 15% at low QC
      concentrations, and less than 10% at medium and high QC concentrations for both
      analytes. The methods presented good accuracy, precision and sensitivity for use
      in kinetic studies of the glucuronidated and oxidative metabolites of DMXAA in
      human liver microsomes.

PMID- 10574199
TI  - Sensitive and specific determination of midazolam and 1-hydroxymidazolam in human
      serum by liquid chromatography-electrospray mass spectrometry.
AB  - A liquid chromatographic-mass spectrometric technique was designed for the
      determination of the anaesthetic benzodiazepine midazolam (MID) and its active
      metabolite 1-hydroxymidazolam (1-OHM), with the aim of conducting
      pharmacokinetic/pharmacodynamic studies. MID and 1-OHM were extracted from
      alkalinised (pH 9.5) spiked and clinical serum samples using a single step,
      liquid-liquid extraction procedure with diethyl ether-2-propanol (98:2, v/v). The
      chromatographic separation was performed on a Nucleosil C18, 5 microm (150x1 mm
      I.D.) column, using a gradient of acetonitrile in 5 mM ammonium formate, pH 3.0
      as the mobile phase, delivered at a flow-rate of 50 microl/min. The compounds
      were ionised in the ionspray source of an atmospheric pressure mass spectrometer,
      fragmented by in-source collisions and the pseudomolecular and fragment ions
      detected in the selected ion monitoring mode. The recovery was between 79 and 87%
      for MID, between 83 and 87% for 1-OHM and 81.5% for methylclonazepam. The limit
      of detection was 0.2 microg/l for MID and 0.5 microg/l for 1-OHM, the limit of
      quantitation (LOQ) was 0.5 microg/l for both. Linearity was verified from these
      LOQs up to 2000 microg/l and the method was found accurate and precise over this
      range. It was successfully applied to a preliminary study to establish the
      concentration versus time curve of MID and 1-OHM in a patient administered
      midazolam by continuous infusion.

PMID- 10574200
TI  - Determination of imidapril and imidaprilat in human plasma by high-performance
      liquid chromatography-electrospray ionization tandem mass spectrometry.
AB  - A sensitive and specific assay of imidapril and its active metabolite,
      imidaprilat, in human plasma has been developed. This method is based on rapid
      isolation and high-performance liquid chromatography (HPLC)-electrospray
      ionization (ESI)-tandem mass spectrometry (MS-MS). Imidapril and imidaprilat were
      isolated from human plasma using OASIS HLB (solid-phase extraction cartridge),
      after deproteinization. The eluent from the cartridge was evaporated to dryness,
      and the residue was reconstituted in mobile phase and injected into the HPLC-ESI
      MS-MS system. Each compound was separated on a semi-micro ODS column in
      acetonitrile-0.05% (v/v) formic acid (1:3, v/v). The selected ion monitoring
      using precursor-->product ion combinations of m/z 406-->234 and 378-->206, was
      used for determination of imidapril and imidaprilat, respectively. The linearity
      was confirmed in the concentration range of 0.2 to 50 ng/ml in human plasma, and
      the precision of this assay, expressed as a relative standard deviation, was less
      than 13.2% over the entire concentration range with adequate assay accuracy. The
      HPLC-ESI-MS-MS method correlates well with the radioimmunoassay method,
      therefore, it is useful for the determination of imidapril and imidaprilat with
      sufficient sensitivity and specificity in clinical studies.

PMID- 10574201
TI  - Analysis of methanol or formic acid in body fluids by headspace solid-phase
      microextraction and capillary gas chromatography.
AB  - Methanol and its metabolite formic acid have been found extractable from human
      whole blood and urine by headspace solid-phase microextraction (SPME) with a
      Carboxen/polydimethylsiloxane fiber. The headspace SPME for formic acid was
      carried out after derivatization to methyl formate under acidic conditions. The
      determinations of both compounds were made by using acetonitrile as internal
      standard (IS) and capillary gas chromatography (GC) with flame ionization
      detection. The headspace SPME-GC gave sharp peaks for methanol, methyl formate
      and I.S.; and low background noises for whole blood and urine samples. Extraction
      efficiencies were 0.25-1.05% of methanol and 0.38-0.84% formic acid for whole
      blood and urine. The calibration curves for methanol and formic acid showed
      excellent linearity in the range of 1.56 to 800 and 1.56 to 500 microg/0.5 ml of
      whole blood or urine, respectively. The detection limits were 0.1-0.5 microg/0.5
      ml for methanol and 0.6 microg/0.5 ml for formic acid for both body fluids. The
      within-day relative standard deviations in terms of extraction efficiency for
      both compounds in whole blood and urine samples were not greater than 9.8%. By
      using the established SPME method, methanol and formic acid were successfully
      separated and determined in rat blood after oral administration of methanol.

PMID- 10574202
TI  - Extraction and determination of oxybutynin in human bladder samples by reversed
      phase high-performance liquid chromatography.
AB  - A reversed-phase high-performance liquid chromatography method is described for
      the determination of oxybutynin (OXB) in human bladder samples. Following
      homogenization, tissue samples underwent double extraction with hexane and
      eventually were concentrated by freeze-drying before analysis. Chromatographic
      separation was performed with a mobile phase of acetonitrile-water-1 M ammonium
      acetate, pH 7.0 (85:13:2, v/v/v) at a flow-rate of 0.5 ml/min and double
      (electrochemical and UV) detection was applied. The retention time of oxybutynin
      eluting peak was around 18 min. Using a standard curve range of 10 to 500 ng/ml
      the quantification limit with electrochemical detection was 5 ng/ml with an
      injection volume of 100 microl. Within-day and day-to-day relative standard
      deviation values were 4.9 and 9.81%, respectively, while a 94% accuracy and a 72%
      recovery was attained. We applied this method to compare the OXB levels into
      bladder wall tissue samples after passive diffusion and after electromotive drug
      administration (EMDA), using a two-chambered poly(vinyl chloride) diffusion cell
      designed and developed in our laboratory. The results obtained show that EMDA
      enhanced OXB penetration into bladder wall and that this novel way of local drug
      administration can be potentially used in patients with neurogenic bladder
      dysfunction or urinary incontinence.

PMID- 10574204
TI  - Determination of urinary orotic acid and uracil by capillary zone
      electrophoresis.
AB  - We describe a simple method for measuring orotic acid and uracil concentration in
      urine by capillary zone electrophoresis in 20 mM Na-borate buffer, pH 9.2. The
      method was applied for studying a patient with HHH (hyperomithinemia,
      hyperammonemia and homocitrullinuria) syndrome. A high value of uracil excretion
      was found during periods of relatively low orotic acid excretion and normal
      ammonemia. The orotic acid level in urine was increased by increasing protein
      intake.

PMID- 10574203
TI  - Carbohydrate release from picomole quantities of glycoprotein and
      characterisation of glycans by high-performance liquid chromatography and mass
      spectrometry.
AB  - Samples of 5 to 20 microg of human IgG were subjected to dithiothreitol treatment
      to reduce disulphide bridges, followed by tryptic digestion. Glycans released
      from the tryptic peptide mixture by PNGase F digestion were then derivatised with
      2-aminoacridone. Labelled oligosaccharides were separated by normal-phase high
      performance liquid chromatography and individual components were collected for
      matrix-assisted laser desorption ionization time-of-flight and electrospray mass
      spectrometric analysis.

PMID- 10574205
TI  - Shape-selective separation of polycyclic aromatic hydrocarbons on protoporphyrin
      silica phases. Effect of surface porphyrin distribution on column efficiency.
AB  - The chromatographic performance of various metalloprotoporphyrin-silica (MProP
      silica) packing materials prepared using different porphyrin immobilization
      schemes is examined. Column efficiency and solute resolution for the shape
      selective separation of polycyclic aromatic hydrocarbons (PAHs) can be improved
      significantly by preparing phases with lower porphyrin coverages and with a more
      homogeneous distribution of the porphyrin species on the surface. The latter is
      accomplished by spreading/diluting the number of aminopropyl reactive sites on
      the silica surface via mixing an inert methyltrimethoxysilane with 3
      aminopropyltriethoxysilane during this preliminary reaction step. Subsequent
      covalent attachment of the ProP via amide bonds to the pendant amine sites
      results in a more even distribution of the porphyrins on the surface. Band shapes
      and retention times as a function of injected solute concentration as well as
      HPLC separation of various test mixtures of PAHs (including standard reference
      material SRM 869) are used to confirm the enhanced performance of these so-called
      "spread" phases. Changes in the nature of the immobilized porphyrin distribution
      on the silica surface are further probed by a coupled redox/UV-Vis absorbance
      method, and results suggest a decrease in the number of ProP species immobilized
      as aggregates on the surface.

PMID- 10574206
TI  - High-performance liquid chromatography study of the enantiomer separation of
      chrysanthemic acid and its analogous compounds on a terguride-based stationary
      phase.
AB  - The direct enantioseparation of chrysanthemic acid [2,2-dimethyl-3-(2
      methylpropenyl)-cyclopropanecarboxylic acid] and its halogen-substituted
      analogues was systematically studied by HPLC using a terguride-based chiral
      stationary phase in combination with a UV diode array and chiroptical detectors.
      Isomers with (1R) configuration always eluted before those with (IS)
      configuration. The elution sequence of cis- and trans-isomers was strongly
      affected by mobile phase pH, whereas the enantioselectivity remained the same.
      Conditions for the separation of all the enantiomers were also examined. This
      method was used for monitor the hydrolytic degradation products of Cyfluthrin
      (Baythroid) in soil under laboratory conditions.

PMID- 10574207
TI  - Convenient synthesis of pi-acceptor chiral stationary phases for high-performance
      liquid chromatography from halogen-substituted 3,5-dinitrobenzoylamides.
AB  - A convenient method for the "in column" synthesis of chiral stationary phases for
      high-performance liquid chromatography was elaborated. It involves preparation of
      chiral amides of 2-bromo- or 4-chloro-substituted 3,5-dinitrobenzoic acids
      followed by nucleophilic substitution of the halogen in the aromatic moiety with
      3-aminopropyl groups of silanized silica gel at ambient temperature. A series of
      pi-donor compounds, such as amides and alkyl aryl carbinols, were chromatographed
      on the prepared chiral stationary phases. The results were compared with data
      reported for chiral separations of the same substrates on similar (R)-N-(3,5
      dinitrobenzoyl)-alpha-phenylglycine-derived CSP. An example of indirect
      enantioseparation of racemic alpha-phenylethylamine was also described using (R)
      2-(2-bromo-3,5-dinitrobenzoylamino)-2-phenylethanol as a chiral derivatizing
      reagent.

PMID- 10574208
TI  - Statistics aided optimization for high-performance liquid chromatographic
      analysis of organic acids in tobacco.
AB  - HPLC analysis for organic acids in tobacco was optimized with the aid of
      statistical experimental design, a central composite face-centered design. In the
      design, only thirteen HPLC analyses were needed for identifying two optimal
      separation parameters. A Bio-Rad Aminex HPX-87H column was used for the analyses.
      An optimal separation for seven acids in tobacco was found at a temperature of 57
      degrees C and a mobile phase of 0.032 N sulfuric acid solution, or at a
      temperature of 70 degrees C and a mobile phase of 0.024 N sulfuric acid solution,
      with a flow rate of 0.6 ml min(-1).

PMID- 10574209
TI  - Solid-phase microextraction coupled with gas chromatography-ion trap mass
      spectrometry for the analysis of haloacetic acids in water.
AB  - Headspace solid-phase microextraction (SPME) was studied as a possible
      alternative to liquid-liquid extraction for the analysis of haloacetic acids
      (HAAs) in water. The method involves derivatization of the acids to their ethyl
      esters using sulphuric acid and ethanol after evaporation, followed by headspace
      SPME with a polydimethylsiloxane fibre and gas chromatography-ion trap mass
      spectrometry (GC-IT-MS). The derivatization procedure was optimized: maximum
      sensitivity was obtained with esterification for 10 min at 50 degrees C in 30
      microl of sulphuric acid and 40 microl of ethanol. The headspace SPME conditions
      were also optimized and good sensitivity was obtained at a sampling temperature
      of 25 degrees C, an absorption time of 10 min, the addition of 0.1 g of anhydrous
      sodium sulfate and a desorption time of 2 min. Good precision (RSD lower than
      10%) and detection limits in the ng l(-1) range (from 10 to 200 ng l(-1)) were
      obtained for all the compounds. The optimized procedure was applied to the
      analysis of HAAs in tap water and the results obtained by standard addition
      agreed with those of EPA method 552.2, whereas discrepancies due to matrix
      interferences were observed using external calibration. Consequently, headspace
      SPME-GC-IT-MS with standard addition is recommended for the analysis of these
      compounds in drinking water.

PMID- 10574210
TI  - Non-suppressed conductivity and indirect UV detection of carboxylic acids in
      environmental samples by ion-exclusion chromatography using 2,6
      pyridinedicarboxylic acidic eluent.
AB  - 2,6-Pyridinedicarboxylic acid (PDCA) was evaluated as an eluent for indirect UV
      and non-suppressed conductivity detection of carboxylic acids in ion-exclusion
      chromatography. The effect of PDCA concentration on the separation and detection
      sensitivity was investigated. The reasonable resolutions between carboxylic acids
      were achieved using 1 mM PDCA eluent. Detection limits were 1.0-7.0 microM for
      conductivity detection and 8-30 microM for UV detection. Compared to the eluent
      containing 1 mM sulfuric acid, the method offers a high resolution and high
      detection sensitivity for both detectors due to its high molar absorptivity and
      low background conductance. The proposed method was demonstrated to be useful for
      the determination of carboxylic acids in environmental samples with direct sample
      injection.

PMID- 10574212
TI  - Analysis of some pesticides in water samples using solid-phase microextraction
      gas chromatography with different mass spectrometric techniques.
AB  - A solid-phase microextraction (SPME)-GC procedure has been developed for the
      analysis of four selected pesticides (propanil, acetochlor, myclobutanil and
      fenoxycarb) in water samples. Mass spectrometry (MS) was used and two different
      instruments, a quadrupole MS system and an ion trap operating in the MS-MS mode,
      were compared. A Carbowax-divinylbenzene SPME fiber was used. The performances of
      the two GC-MS instruments were comparable in terms of linearity (in the range of
      0.1-10 microg/l in water samples) and sensitivity (limits of detection were in
      the low ng/l range); the quadrupole MS instrument gave better precision than the
      ion trap MS-MS system, but generally the relative standard deviations for
      replicates were acceptable for both instruments (<15%). Specificity with these
      two instruments was comparable in the analysis of ground water samples. Recovery
      tests were made to assess the applicability of the SPME procedure in the
      quantitative analysis of contaminated groundwaters.

PMID- 10574211
TI  - Pre-column derivatization and gas chromatographic determination of alkaloids in
      bulbs of Fritillaria.
AB  - A method of precolumn derivatization GC with FID detection was developed for a
      simultaneous analysis of five major steroidal alkaloids of Fritillaria species,
      namely ebeiedine, ebeiedinone, verticine, verticinone and imperialine.
      Derivatization was carried out by trimethylsilylation of the hydroxyl-containing
      Fritillaria alkaloids to the corresponding trimethylsilylates with
      trimethylsilylimidazole. Reaction conditions were optimised and the alkaloids
      derivatives were characterised by on-line GC-MS. The validated GC method
      demonstrated a good linearity at the sampling ranges used. This analytical method
      is simple, convenient and reproducible. The developed assay was successfully
      applied to the determination of the major pharmacologically active alkaloids in
      three commonly used antitussive Fritillaria species: F. cirrhosa, F. thunbergii
      and F. pallidiflora.

PMID- 10574213
TI  - Efficiency studies in nonaqueous capillary electrophoresis.
AB  - Nonaqueous capillary electrophoresis (NACE) is a relatively new area with several
      advantages that include enhanced efficiency and improved detection sensitivity.
      The goal of this study was to investigate the influence of NACE compared to
      aqueous CE on the separation efficiency of oligosaccharides. The applied voltage
      and buffer concentration were optimized for the aqueous and nonaqueous buffer
      media to minimize the band broadening effects of Joule heating and
      electrophoretic dispersion. At the optimized conditions a 1.5-fold enhancement in
      efficiency was obtained with the nonaqueous buffer medium.

PMID- 10574214
TI  - Differential signal detection system for improved analysis of overlapping signals
      in liquid chromatography.
AB  - We have developed a differential signal detection system for the analysis of
      liquid chromatographic signals using two or more detectors and a differential
      amplifier circuit. The proposed detection system is an improvement on
      conventional chromatography in which signals are detected by means of a single
      detector. The differential signal detection system eliminates difficulties of
      isolating minor components of the signal which are masked by the major component,
      as well as difficulties of separating two components of the signal having similar
      retention times.

PMID- 10574215
TI  - Liquid chromatographic determination of aniline in table-top sweeteners based on
      pre-column derivatization with 1,2-naphthoquinone-4-sulfonate.
AB  - A liquid chromatographic method for the determination of aniline in cyclamate
      sweeteners based on a pre-column derivatization with 1,2-naphthoquinone-4
      sulfonate (NQS) is proposed. Aniline traces were extracted from the cyclamate
      samples using dichloromethane. After solvent evaporation, the dry residue was
      derivatized with NQS at pH 9.5 and 85 degrees C for 1 min. The aniline
      derivative, which was extracted from the reacting mixture, was redissolved in the
      eluent solution and injected into the chromatographic system. The separation of
      aniline derivative from other amine impurities was carried out in a C18 column
      using a 2% acetic acid-methanol (40:60, v/v) mobile phase. Results from the
      analysis of aniline in the sweetener samples with the proposed method were
      compared with those from the standard method. A good concordance between the two
      methods was observed.

PMID- 10574216
TI  - Application of polydivinylbenzene liquid chromatography columns to remove lipid
      material from fish tissue extracts for the analysis of semivolatile organics.
AB  - Liquid chromatography columns of 100% polydivinylbenzene (DVB) (packing) were
      used to remove lipid material from fish extracts before analysis of several
      semivolatile organic pollutants by gas chromatography-mass spectrometry (GC-MS).
      This packing material was found to be durable as the columns could be operated to
      about 900 p.s.i. resulting in high efficiency separation. Recoveries and relative
      standard deviations for 18 polynuclear aromatic hydrocarbons fortified into a
      fish extract and cleaned up by multiple DVB columns in series were in the range
      of 86 to 123% and 4 to 11%, respectively.

PMID- 10574217
TI  - Distinct levels of regulation in organ-specific autoimmune diseases.
AB  - Immune regulatory interactions have been largely attributed to antagonistic T
      helper cell subsets whose cytokines are mutually inhibitory (Th1 vs. Th2). Here
      we emphasize two additional levels of regulation: the first involves the
      recognition of portions of antigen receptors of effector T cells, resulting in
      the induction of both CD4 and CD8 regulatory populations, capable of diminishing
      the responses by the pathogenic effector itself. The second includes a collection
      of cell populations found constitutively in all individuals whose specificity for
      antigen, if any, is being currently investigated. These two additional types of
      interaction involve cells belonging to a functional regulatory subset and include
      contributions from both innate and adaptive mechanisms of immune regulation. The
      answers to many quandaries in autoimmune disease may be sought by seeking to
      engage these lesser-understood regulatory populations.

PMID- 10574218
TI  - Hyperthermia-enhanced serotonin (5-HT) depletion resulting from d-fenfluramine
      exposure is preventable.
AB  - Recent findings indicate that elevations in body temperature during acute d
      fenfluramine (Fen) exposure enhance long-term 5-HT depletion. Therefore, we
      hypothesized that when repeated exposure to d-Fen produced repeated elevations in
      body temperature, 5-HT reductions would be greater in comparison to a single d
      Fen exposure. Groups of animals were exposed to d-Fen for 1 or 4 days in a 28
      degrees C environment. Exposure to d-Fen in the 28 degrees C environment induced
      an increase in body temperature and resulted in a long-term decrease in brain 5
      HT. However, brain 5-HT was not different between the two groups. An additional
      experiment revealed that if the initial exposure to d-Fen does not induce
      elevations in body temperature, then long-term 5-HT depletion can be prevented.
      We conclude that the central nervous system rapidly adapts to the 5-HT depleting
      action of d-Fen thereby preventing further decreases in 5-HT concentrations from
      d-Fen exposure. In addition, this rapid adaptation circumvented the hyperthermia
      enhanced 5-HT depletion that results from d-Fen exposure in a warm environment.

PMID- 10574219
TI  - Inhibition of endothelium-dependent relaxation by Candida albicans.
AB  - This study examines the effects of Candida albicans on acethylcholine-induced,
      endothelium-dependent relaxation of thoracic aorta of rabbits, precontracted by
      phenylephrine (10(-7) M). Isolated vessel rings were incubated with C. albicans,
      Saccharomyces cerevisiae, or their mannans, and endothelium-dependent relaxation
      was measured by the induction of acethylcholine. Endothelium-dependent relaxation
      remained unaffected after 3 hours by either C. albicans or S. cerevisiae, or
      their mannans. After 24 hours, however, incubation with C. albicans had
      completely abolished relaxation, whereas relaxation was decreased by mannan of C.
      albicans and continued unaffected by S. cerevisiae. In contrast, no change was
      registered with a 24 hours incubation of C. Albicans in a sodium nitroprusside
      induced, endothelium-independent, vascular smooth muscle relaxation.
      Microscopical investigation of the morphological structure of vessel walls
      revealed penetration of C. albicans on the intimal surface after 3 hours
      incubation and infiltration of the yeast through the vessel wall after 24 hours.
      No changes in vessel morphology occurred after 3 or 24 hours with S. cerevisiae
      or the mannan of C. albicans. These results show the ability of C. albicans to
      inhibit endothelium-dependent, but not endothelium-independent, relaxation of
      vascular smooth muscle and may have important implications for functional damage
      to endothelial cells and the regulation of vessel tone and blood flow.

PMID- 10574220
TI  - The role of beta 2-adrenergic vascular receptors in the peripheral vasodilation
      caused by 17 beta-estradiol in anesthetized pigs.
AB  - It has been previously shown in anesthetized pigs that intravenous infusion of 2
      microg/h of 17beta-estradiol primarily dilated renal, iliac and coronary
      circulations, while higher doses of the hormone were required to cause
      vasodilation also in the mesenteric vascular bed. In the same experimental model,
      a tonic beta2-adrenoceptor mediated vasodilation, which could be argued to
      attenuate the vasodilator effect of 17beta-estradiol, has been described. The
      present study was planned to investigate the role of beta2-adrenergic receptors
      in the hemodynamic responses of renal and mesenteric vascular beds to 17beta
      estradiol. Changes in flow caused by intravenous infusion of 2 microg/h of the
      hormone at constant heart rate and aortic blood pressure in the left renal and
      superior mesenteric arteries were assessed using electromagnetic flowmeters. In
      six pigs, infusion of 17beta-estradiol caused an increase in renal blood flow,
      which averaged 12.1% of the control values, without affecting mesenteric blood
      flow. In the same pigs, after hemodynamic variables had returned to the baseline
      values, blockade of beta2-adrenergic receptors with butoxamine caused an increase
      in aortic blood pressure and an increase in renal and mesenteric resistance. The
      subsequent infusion of 17beta-estradiol elicited increases in renal and
      mesenteric blood flow which respectively averaged 19.6% and 12.8%. Therefore, the
      present study in anesthetized pigs have shown that the vasodilator responses of
      the renal and mesenteric circulations to 17beta-estradiol were attenuated and
      even masked by a tonic beta2-adrenoceptor mediated vasodilation. This indicates
      that some vasodilator effects elicited by normally used replacement doses of the
      hormone may not be apparent.

PMID- 10574221
TI  - Erigeron breviscapus prevents defective endothelium-dependent relaxation in
      diabetic rat aorta.
AB  - We examined the endothelium-dependent relaxation response to acetylcholine (Ach)
      in streptozotocin-induced diabetic rat aorta at the stages of 2- and 6-wks'
      duration in vitro, and compared with another two groups which were treated with
      dietary supplement of 0.1% Aminoquanidine (AG) and 0.5% Erigeron breviscapus (EB)
      from 1-week of diabetes induction. At the stage of 2-wks' duration of diabetes,
      relaxation responses to lower concentrations of Ach in 0.3 uM phenylepherine
      precontracted aortas were diminished significantly (P<0.05) compared with age
      matched control, but the maximal relaxation of Ach remained unchanged. At the
      stage of 6-wks' duration, diabetes caused an approximately 60% (P<0.001) deficit
      in maximum relaxation, and this was significantly (P<0.001) prevented in AG and
      EB treated groups. There was an approximately 40% enhancement in the maximum
      contractile response to phenylepherine with diabetes (P<0.05), which was
      unaffected significantly by AG and EB treatments. The data suggest that the
      defective endothelium-dependent relaxation in diabetic rat aorta occurred as
      early as 2-wks' duration of diabetes, and the treatments of AG and EB could
      protect vascular endothelium although the deficits in vascular smooth muscle
      contractile responses were not protected.

PMID- 10574222
TI  - Involvement of peripheral type of benzodiazepine receptor in social isolation
      stress-induced decrease in pentobarbital sleep in mice.
AB  - Our previous studies have shown that central-type benzodiazepine (BZD) receptors
      (CBR) and neurosteroids capable of modulating GABA(A) receptor function are
      involved in the decrease of pentobarbital (PB)-induced sleep caused by social
      isolation stress in mice. In this study, to further clarify the mechanism
      underlying this decrease, we investigated the possible involvement of peripheral
      type BZD receptors (PBR) which play an important role in neurosteroidogenesis in
      PB sleep in socially isolated mice. Socially isolated mice showed significantly
      shorter duration of PB-induced sleep than group-housed animals. When injected
      intracerebroventricularly (i.c.v.), FGIN-1-27 (FGIN, 25-100 nmol), a selective
      PBR agonist, and PK11195 (PK, 14-28 nmol), a PBR antagonist, and pregnenolone
      (PREG, 15-30 nmol), a neurosteroid precursor, dose-dependently normalized the PB
      sleep in isolated mice without having an effect on the group-housed animals. In
      contrast, pregnenolone sulfate (PS, 24 nmol), an endogenous neurosteroidal
      negative allosteric modulator of the GABA(A) receptor, reduced PB sleep in group
      housed but not isolated mice. PS, at the same dose, significantly attenuated the
      effects of FGIN (100 nmol), PK (28 nmol) and PREG (30 nmol) in isolated mice,
      while FGIN (100 nmol), PK (28 nmol) and pregnenolone (30 nmol) significantly
      blocked the effect of PS (24 nmol) in group-housed mice. These results suggest
      that the PBR-mediated decrease in the genesis of neurosteroid(s) possessing a
      GABA(A) receptor agonistic profile is also partly involved in the down regulation
      of the GABA(A) receptor following long-term social isolation and contributes to
      the decrease of PB-induced sleep in isolation stressed mice.

PMID- 10574223
TI  - Ca2+ mobilization and activation of extracellular acidification by carbachol in
      acutely dispersed cells from guinea pig detrusor: Fura 2 fluorometry and
      microphysiometry using the cytosensor.
AB  - The study aim was to develop a simple in vitro model for pharmacophysiological
      investigation of urinary bladder smooth muscles. Smooth muscle cells from guinea
      pig detrusor were dissociated, and the suspended cells were stimulated with
      carbachol (CCh), an acetylcholine receptor agonist. Cytosolic Ca2+ levels were
      determined using Fura 2 fluorescence and extracellular acidification rates were
      monitored by the Cytosensor microphysiometer. CCh dose-dependently increased
      cytosolic Ca2+ levels and extracellular acidification rates, with EC50 values of
      approximately 1 microM. Both the acetylcholine muscarinic receptor antagonist
      atropine and the M3 muscarinic receptor-preferring antagonist 4-diphenylacetoxy-N
      methylpiperidine (4-DAMP) inhibited the effects of CCh, three orders of magnitude
      more potently than the selective M2 muscarinic receptor antagonist,
      methoctramine. These data indicate the dominant role of M3 receptors in guinea
      pig bladder but fail to show clear evidence of any functional role for M2
      receptors. Since this finding agrees with a number of other studies using in vivo
      and in vitro models (1), cell suspensions such as these may prove to be simple
      tools for the pharmacological study of urinary bladder smooth muscle tissue.

PMID- 10574224
TI  - 1-Naphthol beta-D-glucuronide formed intraluminally in rat small intestine mucosa
      and absorbed into the colon.
AB  - UDP-glucuronosyltransferase expressed in the rat intestinal epithelial cells is
      important as the first barrier against chemicals. The distribution of 1-naphthol
      and its glucuronide formed in rat intestine was estimated by using everted
      intestine. Roughly 60% of the 1-naphthol added to the mucosal fluid was absorbed
      into the mucosa of the small intestine and colon within 30 min. Approximately 66%
      of the 1-naphthol absorbed in the proximal intestine was secreted intraluminally
      as a glucuronide, and a minimal 9% was transported into the serosal fluid as a
      glucuronide. In the distal intestine, approximately 34% was secreted
      intraluminally and 30% was transported into the serosal fluid as a glucuronide.
      The greatest amount of the glucuronide (37% of the absorbed 1-naphthol) was
      transported into the serosal fluid, whereas a minimal 7% was secreted
      intraluminally in the colon. In marked contrast, the colon was found to transport
      1-naphthol-glucuronide from the mucosal fluid into the serosal fluid at an
      approximately 8-fold higher rate than that of the small intestine. These results
      suggest that, in the small intestine, phenolic xenobiotics are mostly
      glucuronidated and secreted intraluminally and that the resulting glucuronide is
      absorbed and transported into the serosal side of the colon.

PMID- 10574225
TI  - Analgesic activity and selectivity of isothiocyanate derivatives of fentanyl
      analogs for opioid receptors.
AB  - The analgesic activity and opioid receptor binding characteristics were studied
      for the isothiocyanate ohmefentanyl (OMFIT), and isothiocyanate carfentanil
      (CarFIT), isothiocyanate 4-methoxymethylfentanyl (MethoFIT), isothiocyanate 3
      methylfentanyl (superFIT) and their amide analogs. Antinociceptive activity was
      evaluated using the mouse hot plate test; selectivity for opioid receptor was
      determined in bioassay and binding assay. SuperFIT, CarFIT, OMFIT and MethoFIT
      exhibited an analgesic ED50 lower than those of their parent compounds without
      isothiocyanate (SCN) group. Furthermore these compounds exhibited potent
      inhibitory actions on the electrically evoked contractions of mouse vas deferens,
      which could be antagonized by naloxone, but their actions were weaker than those
      of their parent compounds without SC N-group. The inhibitory actions of these
      compounds on binding of [3H]OMF to mouse brain membrane was weaker than those of
      their parent compounds without SCN-group. CarFIT and MethoFIT showed weaker
      inhibitory actions on the binding of [3H] DADLE than their parent compounds
      without SCN-group, but SuperFIT and OMFIT stronger than their parent compounds, 3
      methylfentanyl and ohmefentanyl. The selectivity of these isothiocyanate
      derivatives for delta opioid receptors increased. In conclusion, introducing
      isothiocyanato-group into 1-position of phenyl ring of ohmefentanyl and other
      fentanyl analogs would enhance the selectivity of these compounds for delta
      opioid receptors, but decrease their analgesic activity.

PMID- 10574226
TI  - Calcium handling proteins in isolated spinal motoneurons.
AB  - Amyotrophic lateral sclerosis is characterized by motoneuron degeneration, in
      which glutamate-induced cell death is thought to play a pathogenic role. This
      excitotoxic process is mediated by cytosolic Ca2+ overload. The glutamatergic
      ionotropic channel molecules, which constitute a major route of Ca2+ entry, were
      present on cultured spinal motoneurons. Using ratio RT-PCR, the relative presence
      in isolated motoneurons of the GluR subunits of the alpha-amino-3-hydroxy-5
      methyl-4-isoxazole-propionic acid (AMPA) receptor was evaluated. GluR1 and GluR2
      mRNAs were present abundantly, while GluR3 and GluR4 mRNAs were much less
      abundant. The relative amount of mRNAs encoding the different protein isoforms
      responsible for Ca2+ uptake into the internal stores and for controlled release
      of Ca2+ from these stores was also determined. For the sarco/endoplasmic
      reticulum Ca2+ ATPases (SERCAs), only the SERCA2b class 4 splice variant was
      found. The inositol 1,4,5-trisphosphate receptor (IP3R) mRNAs were mainly
      transcribed from the IP3RI and IP3RII genes. Heterogeneity was also observed for
      the ryanodine receptors (RyR) as the RyR1, RyR2 and RyR3 mRNAs were present.

PMID- 10574227
TI  - Antiinflammatory activity of adrenomedullin in the acetic acid peritonitis in
      rats.
AB  - The antiinflammatory effect of ADM was studied in different models of
      inflammation and compared to the one of CGRP. Peptides were active against acetic
      acid-induced peritonitis in the rats. ADM and CGRP exerted the antiinflammatory
      effect at different doses, 400 and 20 ng/kg respectively, but with different
      efficacy (ADM >CGRP). This effect was blocked by pretreatment with CGRP (8-37)
      fragment or with L-NAME. No antiinflammatory activity was evidenced against
      serotonin- or carrageenin-induced rat paw edema. Our data suggest that ADM exerts
      antiinflammatory activity in the model characterized by a vascular component.
      This effect involves CGRP receptors and appears to be mediated by nitric oxide
      system.

PMID- 10574228
TI  - Effects of ginseng components on c-DNA-expressed cytochrome P450 enzyme catalytic
      activity.
AB  - Because little is known about the interactions between herbal products and
      standard medications, the effects of seven ginsenosides and two eleutherosides
      (active components of the ginseng root) on the catalytic activity of c-DNA
      expressed cytochrome P450 isoforms were studied in in vitro experiments.
      Increasing concentrations of ginsenosides Rb1, Rb2, Rc, Rd, Re, Rf, and Rg1 and
      eleutherosides B and E were incubated with a panel of recombinant human CYP
      isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) and their effects on the
      conversion of specific surrogate substrates measured fluorometrically in a 96
      well plate format. For each test substance, the IC50 (the concentration required
      to inhibit the metabolism of the surrogate substrates by 50%) was estimated and
      this value compared with that obtained for positive control inhibitory drugs
      furafylline, sulfaphenazole, tryanylcypromine, quinidine, and ketoconizole. Of
      the components tested, three ginsenosides (Rd, Rc, and Rf) modified the activity
      of the recombinant enzymes. Ginsenoside Rd produced weak inhibitory activity
      against the surrogate substrates for CYP3A4 and CYP2D6 and even weaker inhibitory
      activity against the surrogate substrates for CYP2C19 and CYP2C9. The IC50 values
      of 58 and 74 uM for the two substrates for CYP3A4 are orders of magnitude higher
      than that for the potent inhibitor ketoconazole used as a positive control.
      Ginsenoside Rc produced an increase in the activity of CYP2C9 (70% at 200 uM) and
      ginsenoside Rf produced an increase in the activity of CYP3A4 (54% at 200 uM).
      The biological significance of this is unclear at this time. Enzyme "activation",
      the process by which direct addition of one compound to an enzyme enhances the
      rate of reaction of the substrate, has been observed in a number of cases with
      P450 enzymes; however, a matrix effect caused by the test compound fluorescing at
      the same wavelength as the metabolite of the marker substrate cannot be ruled
      out. In summary, these studies suggest that the ginsenosides and eleutherosides
      tested are not likely to inhibit the metabolism of coadministered medications in
      which the primary route of elimination is via cytochrome P450; the potential of
      ginsenosides to enhance the catalysis of certain substrates requires further
      investigation.

PMID- 10574229
TI  - Inhibition of glucose uptake and suppression of glucose transporter 1 mRNA
      expression in L929 cells by tumour necrosis factor-alpha.
AB  - Recombinant human tumour necrosis factor-alpha (rhTNF-alpha) arrested the growth
      and suppressed glucose uptake of mouse fibrosarcoma L929 cells in vitro. When the
      cells were treated with rhTNF-alpha for 24 hours, the mRNA level of glucose
      transporter 1 (GLUT 1), which is the only GLUT found to be present in L929 cells
      in our study, was suppressed in a dose-dependent manner. Since the growth of
      tumour cells depends mainly on glucose catabolism, our findings may indicate that
      rhTNF-alpha inhibits L929 cells growth by lowering the glucose transport through
      suppression of GLUT 1 mRNA expression in the cells.

PMID- 10574230
TI  - Nimodipine inhibits calcium-independent nitric oxide synthase activity in
      transient focal cerebral ischemia rats and cultured mouse astroglial cells.
AB  - The effect of nimodipine on nitric oxide synthase (NOS) activities in brains in
      transient focal cerebral ischemia rats, in cultured mouse neurons and astroglial
      cells and bovine brain capillary endothelial cells (BCECs) was investigated. The
      administration of nimodipine (3 mg.kg(-1), p.o., twice a day, for 3 days) before
      middle cerebral artery (MCA) occlusion significantly reduced infarct size,
      decreased nitrite/nitrate (NOx) content and inhibited Ca2+-independent NOS
      activity in the infarct area. Nimodipine inhibited the Ca2+-independent NOS
      activity induced by lipopolysaccharide (LPS) + tumor necrosis factor alpha (TNF
      alpha) in mouse astroglial cells with an IC50 value of 0.036+/-0.003 mM and Ca2+
      dependent NOS activity in mouse neurons with an IC50 value of 0.047+/-0.003 mM,
      but did not affect Ca2+-dependent NOS activity in BCECs. The inhibition of Ca2+
      independent NOS activity by nimodipine in astroglial cells was competitive with
      respect to L-arginine. Nimodipine also inhibited the induction of Ca2+
      independent NOS activity in vitro. These results suggest that nimodipine in
      addition to its cerebral vasodilating effect may protect brain from ischemic
      neuronal damage through modifying NOS activity.

PMID- 10574231
TI  - Psychological impact of predicting individuals' risks of illness: a systematic
      review.
AB  - The aim of this review is to determine the frequency and circumstances under
      which predicting individuals' risk of illness has adverse psychological effects.
      Using systematic review methodology, the literature was searched for studies that
      had assessed the adverse psychological outcomes of risk assessment programmes.
      The outcomes investigated are emotional (anxiety, depression, distress) cognitive
      (intrusive thoughts, perceptions of health) and behaviour (work absenteeism). The
      impact of both positive and negative test results are summarised in terms of the
      number of studies showing significant effects between and within groups in the
      short (one month or less) and longer term (more than one month). Where sufficient
      data were available, a meta-analysis was conducted to assess effect size. Fifty
      four studies met the criteria for inclusion. The studies assessed the impact of
      informing individuals about cardiovascular risk (21), risk of AIDS (eight), risk
      of cancer (10), risk of Huntington's disease (10), risk of diabetes (two), risk
      of spinocerebellar ataxia (one) and risk of osteoporosis (two). Overall, the
      quality of studies assessed was limited, with only two using a randomised design
      to determine the psychological impact of risk assessment. Receiving a positive
      test result was associated in the short term in the great majority of studies
      with depression, anxiety, poorer perceptions of health and psychological
      distress. Data were available for a quantitative synthesis of results on three
      outcomes, anxiety, depression and distress. Anxiety and depression were
      significantly higher in those tested positive compared with those tested negative
      in the short term but not the longer term. Distress could only be assessed in the
      longer term: there was no evidence of an increase for those receiving positive
      test results. The five experimental studies that reported interventions aimed at
      preventing some of these adverse effects all reported favourable results. There
      was little evidence of any adverse psychological effects of receiving an
      unfavourable test result. Adverse psychological effects are a common immediate
      consequence of positive test results following risk assessment. Results from the
      few experimental studies reviewed suggest that these adverse outcomes should not
      be seen as inevitable.

PMID- 10574232
TI  - Social network influences on reproductive health behaviors in urban northern
      Thailand.
AB  - Prevention approaches for reproductive health have evolved from an emphasis on
      individually focused models of behavior change to a recognition that risk
      reduction occurs within a context of social norms. Prevention programs can be
      improved by understanding how social structure influences sexual behavior and
      using that understanding to develop strategies for positive change. In a dynamic,
      urban context, communities are better conceptualized as informal networks of
      ties. These network structures may help to protect, or conversely, expose members
      to reproductive risk behaviors. Using data from a study of social and sexual
      networks conducted in northern Thailand, this article describes partner relations
      and social structure in the modern, urban context, and illustrates the links
      between individual, relational and structural properties and reproductive risk
      behaviors. Triangulation of ethnographic, survey and social network data
      collection and analytic tools provide an opportunity to interpret individual
      behaviors, meanings of relationships and structural properties of networks.
      Intervention approaches should build on existing networks, and address the
      complex meanings of romantic and sexual partnerships.

PMID- 10574233
TI  - Family focus or career focus: controlling for infertility.
AB  - In order to shed light on the direction of causality between fertility timing and
      earnings, this paper uses medical diagnoses of infertility as instruments for age
      at first birth (for those women who did give birth) and childlessness among
      married women. Although multivariate ordinary least squares regression results
      find a positive correlation between childbirth at later ages and higher wages as
      well as between childlessness and increased wages, delays in childbearing due to
      infertility do not significantly increase a woman's wages. Thus, data from the
      1995 National Survey of Family Growth (NSFG) indicate that delaying childbirth
      does not, by itself, guarantee higher wages in the labor market. Therefore, this
      study does not support the conventional notion of the 'mommy track' in which
      career success and motherhood are incompatible.

PMID- 10574234
TI  - Health inequality and population variation in fertility-timing.
AB  - We estimate the impact of fertility-timing on the chances that children in poor
      urban African American communities will have surviving and able-bodied parents
      until maturity. To do so, we use census and vital statistics data to compute age-
      and sex-specific rates of mortality and functional limitation among prime-aged
      adult residents of impoverished African American areas in Harlem, Detroit,
      Chicago, and the Watts area of Los Angeles and for blacks and whites nationwide.
      Findings are consistent with the hypothesis that the early fertility-timing
      characteristic of poor urban African American populations mitigates some of the
      costs to families associated with excess mortality and early health deterioration
      in young through middle adulthood.

PMID- 10574235
TI  - Does financial hardship account for elevated psychological distress in lone
      mothers?
AB  - Lone mothers have been shown to have higher levels of psychological distress than
      married mothers, but it is not clear how this difference arises. Using data from
      the 1958 British birth cohort followed to age 33, we investigated alternative
      explanations for the excess distress of lone mothers. Logistic regression models
      were used to estimate odds ratios for distress (measured using the Malaise
      Inventory) in lone vs married mothers. Odds ratios were adjusted to assess the
      contribution of explanatory factors. At age 33, psychological distress was
      greater among lone than married mothers (OR 2.59, 95% CI 1.97, 3.41). The odds
      ratio decreased to 1.43 (95% CI 1.02, 2.01) after adjustment for all explanatory
      factors (prior psychological distress, age of youngest child and number of
      children in the household, and contemporary measures of financial hardship,
      employment, and social support). Attenuation of the odds ratio was most marked
      after taking account of financial hardship. Psychological distress was greater
      among divorced mothers than never married mothers, though not significantly (OR =
      1.70, 95% CI 0.88, 3.28). This difference was not explained by the factors
      examined, and was not due to the immediate distress associated with a recent
      divorce. Elevated psychological distress of lone mothers appears to be related to
      financial hardship, while other explanations, including social support and
      selection, have a more modest impact. Not all of the elevated psychological
      distress among lone mothers was accounted for, particularly among divorced lone
      mothers.

PMID- 10574236
TI  - What makes new mothers unhappy: psychological distress one year after birth in
      Italy and France.
AB  - The aim of this report is to present results on the factors associated with
      psychological distress in 724 Italian and 629 French women 12 months after birth.
      The prevalence of distress was ascertained by the 12-item Goldberg Health
      Questionnaire (GHQ), using a cut-off score of > 5. Results show that, in both
      countries, after controlling for previous psychological health, the variables
      significantly associated with mothers' distress were: an unsatisfactory couple
      relationship; lack of a confidante; a baby with serious health problems,
      financial worries. In Italy, also being an older mother and a discrepancy between
      actual and desired employment status were associated with a high GHQ score. These
      results point out to the high prevalence of mothers' psychological distress in
      Latin countries too, and stress the role played by family and social factors.

PMID- 10574237
TI  - Complaining about chronic pain.
AB  - This paper examines how a group of working class people describes and experiences
      chronic pain. This hermeneutical-phenomenological study concentrates on the lived
      body of pain from three perspectives, drawing on interviews with 14 people who
      were attending a pain management program. First I consider the terms in which
      pain is circumscribed in the narratives, stories told in the context of learning
      to manage pain. These terms are polarities, ways of specifying and legitimating
      pain in relation to "mind" and "body." Pain, in the discursive polarities that
      define it, is the private property of an individual, who must in some fashion
      prove that pain exists in an objective manner. The speaker, in this discourse,
      stands as the one responsible for the production of pain. In the second part, the
      analysis turns to what this discourse reveals about pain as a lived body
      phenomenon. Here the analysis centers upon the torment of having to inhabit the
      intolerable, upon how pain unmakes the lifeworld of the sufferer, and how,
      simultaneously, people make pain. The place of pain is the body, as body-in
      place. The place of pain is at the boundaries of human dwelling, a kind of non
      place, expressed metaphorically as "prison" or "homelessness." Finally, after
      these considerations of how pain is described, in part three, I turn to the act
      of "saying" pain, that is, to the narratives as addressed to someone else. The
      participants were not simply dispensing information; they were saying something
      to me. The narratives had the form of complaints. The form of the narratives, in
      the context of the pain program, was a quasi-legal call to rectify wrongs.

PMID- 10574238
TI  - Household nutrition and health in Poland.
AB  - Data from 600 households in the province of Lublin, Poland, are used to assess
      the relationships among self-rated household health, change in health status,
      sociodemographic characteristics, food purchasing behavior changes, and health
      care seeking behaviors. High ratings of health are enjoyed by rural families
      headed by comparatively young individuals with high education. Average household
      health is also a function of household changes in food purchasing behavior over
      the past 5 years and per capita consumption of starch-based foods. Families
      consuming greater proportions of bread and potatoes and purchasing foods of
      reduced quality, quantity, and price experience lower average levels of
      subjective physical health than other families. Reduction or postponement of
      medical or dental care over the past 5 years did not affect health status in this
      model.

PMID- 10574239
TI  - The emerging international policy agenda for reproductive health services in
      conflict settings.
AB  - Over the past 20 years, shifts in the nature of conflict and the sheer numbers of
      civilians affected have given rise to increasing concern about providing
      appropriate health services in unstable settings. Concurrently, international
      health policy attention has focused on sexual and reproductive health issues and
      finding effective methods of addressing them. This article reviews the background
      to the promotion and development of reproductive health services for conflict
      affected populations. It employs qualitative methods to analyse the development
      of policy at international level. First we examine the extent to which
      reproductive health is on the policy agendas of organisations active in
      humanitarian contexts. We then discuss why and how this has come about, and
      whether the issue has sufficient support to ensure effective implementation. Our
      findings demonstrate that reproductive health is clearly on the agenda for
      agencies working in these settings, as measured by a range of established
      criteria including the amount of new resources being attracted to this area and
      the number of meetings and publications devoted to this issue. There are,
      however, barriers to the full and effective implementation of reproductive health
      services. These barriers include the hesitation of some field-workers to
      prioritise reproductive health and the number and diversity of the organisations
      involved in implementation. The reasons for these barriers are discussed in order
      to highlight areas for action before effective reproductive health service
      provision to these populations can be ensured.

PMID- 10574240
TI  - Patterns of vaccination acceptance.
AB  - Immunization is one of the major public health interventions to prevent childhood
      morbidity and death. The Expanded Programme on Immunization has gathered momentum
      worldwide since 1974. The range of vaccines in the programme is being expanded in
      the years to come. All across the globe, a high level of vaccination coverage has
      been reached and now needs to be sustained. In part, the coverage has been made
      possible by the broad acceptance of vaccinations, although there are variations
      resulting in different configurations of fully, partially and non-immunized
      children. Using the results of studies carried out by the Social Science and
      Immunization Project in Bangladesh, Ethiopia, India, Malawi, the Netherlands and
      the Philippines, this article describes and discusses patterns of vaccination
      acceptance and non-acceptance. It shows how context affects acceptance of
      vaccinations, and analyses the underlying reasons behind refusal and resistance.
      The article also develops conceptual tools for the analysis of acceptance and non
      acceptance and discusses explanatory theoretical perspectives.

PMID- 10574241
TI  - Religious characteristics of US women physicians.
AB  - Physicians' religious attributes are unknown, and may affect patient care. The
      Women Physicians' Health Study (WPHS) is a random sample (n = 4501 respondents,
      59% response rate) of US women physicians aged 30-70; the first large, national
      study of US women physicians. In this study US women physicians were less likely
      to be Christian than were other Americans (61.2% of women physicians versus 85.1%
      of the general population), but were more likely to be Jewish (13.2% vs 2.0%),
      Buddhist (1.4% vs 0.3%), Hindu (3.9% vs 0.4%), or atheist/agnostic (5.9% vs
      0.6%). Protestantism (29.3% of the population) and Catholicism (24.9%) were the
      most commonly reported religious identities. The strongest religious identity was
      claimed by Mormons and Seventh Day Adventists. Thus, women physicians' religious
      beliefs differ from those of the general population in the US. This may be
      particularly important for physicians practicing with patient populations with
      different religious affiliations, and in addressing clinical questions with
      ethical or religious dimensions.

PMID- 10574242
TI  - Esthesioneuroblastoma is not a member of the primitive peripheral neuroectodermal
      tumour-Ewing's group.
AB  - Esthesioneuroblastoma (ENB) is a rare, site-specific, locally aggressive neuronal
      malignancy so far thought to belong to primitive peripheral neuroectodermal
      tumour-Ewing's tumour (pPNETs-ETs). Its anatomical location, in addition to
      morphologic, immunophenotypic and ultrastructural features, suggests its origin
      in the neuronal or neuroendocrine cells of the olfactory epithelium. However, the
      cytogenetic and molecular data currently available appear controversial on the
      presence of the typical translocation t(11;22)(q24;q12) and of trisomy 8,
      chromosomal changes that characterize the tumours belonging to the pPNETs-ETs.
      Herein we have analysed five ENB tumour specimens for trisomy 8 by fluorescence
      in situ hybridization (FISH), for the presence of EWS gene rearrangements by
      FISH, reverse transcription polymerase chain reaction and Southern blot analyses,
      as well as for the expression of the Ewing sarcoma-associated MIC2 antigen by
      immunohistochemistry. Neither EWS/FLI-I, EWS/ERG and EWS/FEV fusion genes nor
      MIC2 expression were found in any tumour, whereas trisomy 8 was found in one case
      only. Moreover, DNA from three cases analysed by Southern blot did not show EWS
      gene rearrangements. Our results support the evidence that ENB is not a member of
      the pPNETs-ETs.

PMID- 10574243
TI  - Expression of caspases 3, 6 and 8 is increased in parallel with apoptosis and
      histological aggressiveness of the breast lesion.
AB  - The aim of this investigation was to study the expression of caspases 3, 6 and 8
      and their association to apoptosis in preneoplastic and neoplastic lesions of the
      breast. The material consisted of nine benign breast epithelial hyperplasias, 15
      atypical hyperplasias, 74 in situ and 82 invasive carcinomas. The extent of
      apoptosis was assessed by the TUNEL method and caspase 3, 6 and 8 expression by
      immunohistochemistry with specific antibodies. Increased caspase 3
      immunopositivity, as compared to staining of normal breast ductal epithelium, was
      seen in 22% of benign epithelial hyperplasias, 25% of atypical hyperplasias, 58%
      of in situ carcinomas and 90% of invasive carcinomas. The corresponding
      percentages for caspase 6 and 8 were 11%, 25%, 60%, 87% and 22%, 57%, 84%, 83%
      respectively. In high-grade in situ lesions there were significantly more cases
      with strong caspase 3, 6 and 8 immunoreactivity than in low- and intermediate
      grade lesions (P = 0.0045, P = 0.049 and P = 0.0001 respectively). In invasive
      carcinomas, however, no association between a high tumour grade and caspase 3, 6
      or 8 expression was found (P = 0.27, P = 0.26 and P = 0.69 respectively). The
      mean apoptotic index was 0.14 +/- 0.14% in benign epithelial hyperplasias, 0.17
      +/- 0.12% in atypical hyperplasias, 0.61 +/- 0.88% in in situ carcinomas and 0.94
      +/- 1.21% in invasive carcinomas. In all cases strong caspase 3, 6 and 8
      positivity was significantly associated with the extent of apoptosis (P < 0.001,
      P = 0.015 and P = 0.050 respectively). The results show that synthesis of
      caspases 3, 6 and 8 is up-regulated in neoplastic breast epithelial cells in
      parallel to the increase in the apoptotic index and progression of the breast
      lesions.

PMID- 10574244
TI  - Effective treatment of liver metastases with photodynamic therapy, using the
      second-generation photosensitizer meta-tetra(hydroxyphenyl)chlorin (mTHPC), in a
      rat model.
AB  - The only curative treatment for patients with liver metastases to date is
      surgery, but few patients are suitable candidates for hepatic resection. The
      majority of patients will have to rely on other treatment modalities for
      palliation. Photodynamic therapy (PDT) could be a selective, minimally invasive
      treatment for patients with liver metastases. We studied PDT in an implanted
      colon carcinoma in the liver of Wag/Rij rats, using the photosensitizer meta
      tetra(hydroxyphenyl)chlorin (mTHPC). mTHPC tissue kinetics were studied using ex
      vivo extractions and in vivo fluorescence measurements. Both methods showed that
      mTHPC kinetics were different for liver and tumour tissue. After initial high
      levels at 4 h after administration (0.1 and 0.3 mg kg(-1)) mTHPC in liver tissue
      decreased rapidly in time. In tumour tissue no decrease in photosensitizer levels
      occurred, with mTHPC remaining high up to 48 h after administration. Both
      concentration data and fluorescence data showed an increase in tumour to liver
      ratios of up to 6.3 and 5.0 respectively. Illumination with 652 nm (15 J)
      resulted in extensive damage to tumour tissue, with necrosis of up to 13 mm in
      diameter. Damage to normal liver tissue was mild and transient as serum aspartate
      aminotransferase and alanine aminotransferase levels normalized within a week
      after PDT treatment. Long-term effects of mTHPC-PDT were studied on day 28 after
      treatment. Regardless of drug dose and drug-light interval, PDT with mTHPC
      resulted in complete tumour remission in 27 out of 31 treated animals (87%), with
      only four animals in which tumour regrowth was observed. Non-responding tumours
      proved to be significantly larger (P < 0.001) in size before PDT treatment. This
      study demonstrates that mTHPC is retained in an intrahepatic tumour and that
      mTHPC-PDT is capable of inducing complete tumour remission of liver tumours.

PMID- 10574245
TI  - Docetaxel and gemcitabine activity in NSCLC cell lines and in primary cultures
      from human lung cancer.
AB  - The activity of the following drugs was investigated in two established NSCLC
      cell lines: docetaxel, gemcitabine, vinorelbine, paclitaxel, doxorubicin (0.01,
      0.1, 1 microg ml(-1)), cisplatin, ifosfamide (1, 2, 3 microg ml(-1)) and
      carboplatin (2, 4, 6 microg ml(-1)). The cytotoxic activity was evaluated by the
      sulphorhodamine B assay. The two most active drugs, docetaxel and gemcitabine,
      used singly and in association, were investigated as a function of treatment
      schedule. The sequence docetaxel-->gemcitabine produced only a weak synergistic
      interaction in RAL but a strong synergism in CAEP cells. The synergistic
      interaction increased in both cell lines after a 48-h washout between the drug
      administrations. Flow cytometric analysis showed that in docetaxel-->gemcitabine
      sequence, docetaxel produced a block in G2/M phase and, after 48 h, provided
      gemcitabine with a large fraction of recovered synchronized cells in the G1/S
      boundary, which is the specific target phase for gemcitabine. Conversely,
      simultaneous treatment induced an antagonistic effect in both cell lines, and the
      sequential scheme gemcitabine-->docetaxel produced a weak synergistic effect only
      in RAL cells. Moreover, the synergistic interaction disappeared when washout
      periods of 24 or 48 h between two drug administrations were adopted. The
      synergistic activity of docetaxel-->48-h washout-->gemcitabine was confirmed in
      11 of 14 primary cultures, which represents an important means of validating
      experimental results before translating them into clinical practice.

PMID- 10574246
TI  - 31P magnetic resonance spectroscopy as a predictor of efficacy in photodynamic
      therapy using differently charged zinc phthalocyanines.
AB  - Photodynamic therapy (PDT) is a developing approach to the treatment of solid
      tumours which requires the combined action of light and a photosensitizing drug
      in the presence of adequate levels of molecular oxygen. We have developed a novel
      series of photosensitizers based on zinc phthalocyanine which are water-soluble
      and contain neutral (TDEPC), positive (PPC) and negative (TCPC) side-chains. The
      PDT effects of these sensitizers have been studied in a mouse model bearing the
      RIF-1 murine fibrosarcoma line studying tumour regrowth delay, phosphate
      metabolism by magnetic resonance spectroscopy (MRS) and blood flow, using D2O
      uptake and MRS. The two main aims of the study were to determine if MRS
      measurements made at the time of PDT treatment could potentially be predictive of
      ultimate PDT efficacy and to assess the effects of sensitizer charge on PDT in
      this model. It was clearly demonstrated that there is a relationship between MRS
      measurements during and immediately following PDT and the ultimate effect on the
      tumour. For all three drugs, tumour regrowth delay was greater with a 1-h time
      interval between drug and light administration than with a 24-h interval. In both
      cases, the order of tumour regrowth delay was PPC > TDEPC = TCPC (though the data
      at 24 h were not statistically significant). Correspondingly, there were greater
      effects on phosphate metabolism (measured at the time of PDT or soon after) for
      the 1-h than for the 24-h time interval. Again effects were greatest with the
      cationic PPC, with the sequence being PPC > TDEPC > TCPC. A parallel sequence was
      observed for the blood flow effects, demonstrating that reduction in blood flow
      is an important factor in PDT with these sensitizers.

PMID- 10574247
TI  - Effects of new 17alpha-hydroxylase/C(17,20)-lyase inhibitors on LNCaP prostate
      cancer cell growth in vitro and in vivo.
AB  - Our laboratory has been developing new inhibitors of a key regulatory enzyme of
      testicular and adrenal androgen synthesis 17alpha-hydroxylase/C(17,20)-lyase
      (P450c17), with the aim of improving prostate cancer treatment. We designed and
      evaluated two groups of azolyl steroids: delta5-non-competitive inhibitors
      (delta5NCIs), VN/63-1, VN/85-1, VN/87-1 and their corresponding delta4
      derivatives (delta4NCIs), VN/107-1, VN/108-1 and VN/109-1. The human P450c17 gene
      was transfected into LNCaP human prostate cancer cells, and the resultant LNCaP
      CYP17 cells were utilized to evaluate the inhibitory potency of the new azolyl
      steroids. VN/85-1 and VN/108-1 had the lowest IC50 values of 1.25 +/- 0.44 nM and
      2.96 +/- 0.78 nM respectively, which are much lower than that of the known P450
      inhibitor ketoconazole (80.7 +/- 1.8 nM). To determine whether the compounds had
      direct actions on proliferation of wild-type LNCaP cells, cell growth studies
      were performed. All of the delta5NCIs and VN/108-1 blocked the growth-stimulating
      effects of androgens. In steroid-free media, the delta5NCIs decreased the
      proliferation of LNCaP cells by 35-40%, while all of the delta4NCIs stimulated
      LNCaP cells growth 1.5- to 2-fold. In androgen receptor (AR) binding studies,
      carried out to determine the mechanism of this effect, all of the delta4NCIs (5
      microM) displaced 77-82% of synthetic androgen R1881 (5 nM) from the LNCaP AR.
      The anti-androgen flutamide and the delta5NCIs displaced 53% and 32-51% of R1881
      bound to AR respectively. These results suggested that the delta5NCIs may also be
      acting as anti-androgens. We further evaluated our inhibitors in male severe
      combined immunodeficient mice bearing LNCaP tumour xenografts. In this model
      VN/85-1 was as effective as finasteride at inhibiting tumor growth (26% and 28%
      inhibition, respectively) and the inhibitory effect of VN/87-1 was similar to
      that of castration (33% and 36% inhibition respectively). These results suggest
      that VN/85-1 and VN/87-1 may be potential candidates for treatment of prostate
      cancer.

PMID- 10574248
TI  - Minimally-invasive debulking of ovarian cancer in the rat pelvis by means of
      photodynamic therapy using the pegylated photosensitizer PEG-m-THPC.
AB  - Interstitial photodynamic therapy (PDT) using the pegylated photosensitizer PEG-m
      THPC was evaluated as a minimally-invasive procedure to selectively debulk
      unrespectable pelvic ovarian cancer (NuTu-19) in immunocompetent rats. To assess
      tumour selectivity, PEG-m-THPC at dosages of 0.3, 3.0 and 30 mg kg(-1) body
      weight was administered intravenously to 30 rats 4 weeks following tumour
      induction. Eight days later laser light at 652 nm and optical doses ranging from
      100 to 900 J cm(-1) diffuser-length was delivered by an interstitial cylindrical
      diffusing fibre inserted blindly into the pelvis. Three days following light
      application, the volume of necrosis was measured and the damage to pelvic organs
      was assessed histologically on cross sections. For analysis of survival, 20
      tumour-bearing rats received PDT using drug doses of 3 or 9 mg kg(-1) body weight
      and an optical dose of 900 J cm(-1) diffuser-length, whereas ten untreated tumour
      bearing rats served as controls. The histological assessment of PDT induced
      necrosis showed a non-linear dose-response for both the photosensitizer dose and
      the optical dose. The lowest drug dose activated with the highest optical dose
      did not induce more necrosis than seen in tumour-bearing control animals. The
      same optical dose induced necrosis of 17 mm in diameter using 30 mg kg(-1) and 11
      mm using 3 mg kg(-1) photosensitizer. The optical threshold for induction of
      significant necrosis was between 100 and 300 J cm(-1) diffuser-length for 30 mg
      kg(-1) and between 300 and 500 J cm(-1) for 3 mg kg(-1) PEG-m-THPC. Significant
      damage to normal pelvic organs was only seen if 30 mg kg(-1) photosensitizer was
      activated with optical doses of 700 J cm(-1) or more. In the survival study, all
      treated animals survived PDT for at least 2 weeks and the intestinal and urinary
      tract remained functional. No clinical signs of blood vessel or nerve injury were
      observed. Mean overall survival of untreated tumour-bearing rats was 25.0 +/- 4.5
      days compared to 38.4 +/- 3.8 days and 40.0 +/- 3.6 days for rats treated with 3
      mg kg(-1) or 9 mg kg(-1) PEG-m-THPC mediated PDT respectively (P < 0.05). We
      conclude that PEG-m-THPC mediated PDT has a favourable therapeutic window and
      that this minimally-invasive procedure can reduce pelvic cancer bulks effectively
      and selectively.

PMID- 10574249
TI  - Characterization of a novel transplantable orthotopic rat bladder transitional
      cell tumour model.
AB  - An animal tumour model that mimics the human counterpart is essential for
      preclinical evaluation of new treatment modalities. The objective of this study
      was to develop and characterize such a model. To accomplish this, the established
      AY-27 rat bladder transitional cell carcinoma (TCC) cell line was transplanted
      orthotopically into Fischer CDF344 female rats. AY-27 TCC cells were grown in
      monolayer cell culture and instilled intravesically as single cell suspensions
      into bladders that had been conditioned with mild acid washing. Tumour growth was
      assessed weekly by subjecting the rats to magnetic resonance imaging (MRI). At
      intervals following implantation and MRI tumour detection, the animals were
      sacrificed for necropsy, histological examination and immunocytochemical studies.
      Flow cytometry was also performed for detection of Fas or Fas-ligand expression
      on AY-27 cells. The overall tumour establishment was 95% (97/102 rats) at 12-50
      days, while in a subgroup of animals sacrificed at 16 days, 80 out of 82 animals
      (97%) developed TCC, the majority of which was superficial. Tumour stage was
      assessed by gross pathology and light microscopy. Histological examination of the
      tumour specimens confirmed the presence of grade II-III TCC. Immunocytochemistry
      confirmed that the tumour model maintained the features of TCC. The changes seen
      on MRI correlated well with the extent of tumour invasion identified
      histologically. Patchy carcinoma in situ could be detected histologically 12-13
      days post-inoculation, and progressed to papillary tumour or invasive disease
      thereafter. Neither Fas nor Fas-ligand was expressed on AY-27 cells. The
      orthotopic AY-27 TCC model is highly reproducible and is ideal for preclinical
      studies on experimental intravesical therapies.

PMID- 10574250
TI  - Transfection of interleukin-8 increases angiogenesis and tumorigenesis of human
      gastric carcinoma cells in nude mice.
AB  - The growth and spread of tumour cells depends on adequate vasculature. We have
      previously reported that the expression of interleukin-8 (IL-8) directly
      correlates with the vascularity of human gastric carcinomas. To provide evidence
      for a causal role of IL-8 in angiogenesis and tumorigenicity of human gastric
      cancer, we used the lipofectin method to stably transfect the human TMK-1 gastric
      carcinoma cells (low endogenous IL-8) with an IL-8 expression vector or control
      vector. Transfection with IL-8 did not affect the proliferation of cultured
      cells, yet the culture supernatants of the transfected (but not control) cells
      stimulated proliferation of human umbilical vein endothelial cells. The IL-8
      transfected and control cells were injected into the gastric wall of nude mice.
      IL-8-transfected cells produced rapidly growing, highly vascular neoplasms as
      compared to control cells. These results provide direct evidence for the role of
      IL-8 in the angiogenesis and tumorigenicity of human gastric carcinomas.

PMID- 10574251
TI  - Cross-linked telopeptides of type I and III collagens in malignant ovarian
      tumours in vivo.
AB  - Malignant tumours often induce a fibroproliferative response in the adjacent
      stroma, characterized by increased expression of type I and type III
      procollagens. In normal tissues, fibrillar collagens normally undergo extensive
      intermolecular cross-linking that provides tensile strength to the tissue. Here
      we set out to characterize collagen cross-linking in human ovarian carcinoma
      tissue in vivo. Biochemical and immunochemical methods were used for cross-linked
      telopeptides of type I and III collagens in samples of benign and malignant
      serous tumours. The locations and staining patterns of these proteins were
      visualized immunohistochemically. The contents of both total collagen and the
      cross-linked type I and type III collagens in the malignant samples were only
      about 20% of those in the benign tumours. The cross-linked telopeptide antigens
      derived from the collagens were smaller and more heterogeneous in size in the
      malignant than in the benign tumours, indicating a defective cross-linking
      process scarcely leading to the formation of mature cross-links in the collagen
      fibres in malignancy. Immunostaining revealed disorganized type I and type III
      collagen bundles in carcinomas. These findings suggest that the collagen cross
      linking process is aberrant in malignant tumours, possibly resulting in increased
      susceptibility of tumour collagens for the proteolysis often associated with
      tumour invasion.

PMID- 10574252
TI  - CA 125 regression after two completed cycles of chemotherapy: lack of prediction
      for long-term survival in patients with advanced ovarian cancer.
AB  - The prognostic influence of CA 125 regression between the time point before
      surgery and after two completed courses of chemotherapy was studied in 210
      patients with advanced ovarian cancer, and was compared to other well established
      prognostic factors. CA 125 blood samples were collected preoperatively (CA 125
      pre) and 3 months after surgery (CA 125 3 mo) (at the beginning of the 3rd cycle
      of chemotherapy). The parameter CA 125 regression defined as log10 (CA 125 3
      mo/CA 125 pre) was used for statistical analysis. In a survival analysis using a
      Cox proportional hazards model, CA 125 regression (P = 0.0001), residual tumour
      (P = 0.0001), age (P = 0.0095) and grading (P = 0.044) were independent
      variables, whereas stage of disease, histology, ascites and type of surgery
      failed to retain significance. Using log10 (CA 125 3 mo/CA 125 pre) as simple
      covariate in a Cox model showed a hazard ratio of 1.70 (95% confidence interval
      1.32-2.19, P = 0.0001). However, a detailed analysis of the interaction of time
      with the prognostic factor CA 125 regression on survival revealed a strong time
      dependent effect with a hazard ratio of more than 6 immediately after two courses
      of chemotherapy, whereas within approximately 1 year the hazard ratio for the
      surviving patients dropped quickly to the neutral level of 1. In summary, CA 125
      regression is an independent prognostic factor for survival of women with
      advanced ovarian cancer and allows an identification of a high-risk population
      among patients with advanced ovarian cancer. However, the discriminating power of
      serial CA 125 for long-term survival seems to be temporary and prediction of
      individual patients outcome is far less precise.

PMID- 10574253
TI  - Chromogranin A, a significant prognostic factor in small cell lung cancer.
AB  - Chromogranin A (CgA) is a protein present in neuroendocrine vesicles. Small cell
      lung cancer (SCLC) is considered a neuroendocrine tumour. It is possible to
      demonstrate CgA expression in SCLC by immunohistochemical methods. Since CgA is
      released to the circulation it might also work as a clinical tumour marker. We
      used a newly developed two-site enzyme-linked immunosorbent assay for CgA in
      plasma from 150 newly diagnosed patients with SCLC. Follow-up was for a minimum
      of 5 years. Thirty-seven per cent of the patients had elevated pretreatment
      values and the values were significantly related to stage of disease.
      Multivariable analysis by Cox's proportional hazard model including nine known
      prognostic factors disclosed performance status as the most influential
      prognostic factor followed by stage of disease, CgA and LDH. A simple prognostic
      index (PI) could be established based on these four pretreatment features. In
      this way the patients could be separated into three groups with significant
      different prognosis. The median survival and 95% confidence intervals for the
      three groups were as follows: 424 days (311-537), 360 days (261-459) and 174 days
      (105-243).

PMID- 10574254
TI  - CAG repeat length in the androgen receptor gene is related to age at diagnosis of
      prostate cancer and response to endocrine therapy, but not to prostate cancer
      risk.
AB  - The length of the polymorphic CAG repeat in the N-terminal of the androgen
      receptor (AR) gene is inversely correlated with the transactivation function of
      the AR. Some studies have indicated that short CAG repeats are related to higher
      risk of prostate cancer. We performed a case-control study to investigate
      relations between CAG repeat length and prostate cancer risk, tumour grade,
      tumour stage, age at diagnosis and response to endocrine therapy. The study
      included 190 AR alleles from prostate cancer patients and 186 AR alleles from
      female control subjects. All were whites from southern Sweden. The frequency
      distribution of CAG repeat length was strikingly similar for cases and controls,
      and no significant correlation between CAG repeat length and prostate cancer risk
      was detected. However, for men with non-hereditary prostate cancer (n = 160),
      shorter CAG repeats correlated with younger age at diagnosis (P = 0.03). There
      were also trends toward associations between short CAG repeats and high grade (P
      = 0.07) and high stage (P = 0.07) disease. Furthermore, we found that patients
      with long CAG repeats responded better to endocrine therapy, even after adjusting
      for pretreatment level of prostate-specific antigen and tumour grade and stage (P
      = 0.05). We conclude that short CAG repeats in the AR gene correlate with young
      age at diagnosis of prostate cancer, but not with higher risk of the disease.
      Selection of patients with early onset prostate cancer in case-control studies
      could therefore lead to an over-estimation of the risk of prostate cancer for men
      with short CAG repeats. An association between long CAG repeats and good response
      to endocrine therapy was also found, but the mechanism and clinical relevance are
      unclear.

PMID- 10574255
TI  - High prevalence of p16 genetic alterations in head and neck tumours.
AB  - Inactivation of the p16 gene is believed to contribute to the tumorigenic process
      of several neoplasms, including head and neck tumours. In the present study, DNA
      samples from paired tumour and adjacent normal tissue from 47 patients with
      squamous cell carcinoma of the head and neck were investigated for the occurrence
      of p16 genetic alterations. Single-strand conformation polymorphism and direct
      DNA sequence analysis led to the identification of p16 mutations in six cases
      (13%). Southern blot analysis showed that homozygous deletion is a rare event in
      the group of tumours analysed. Loss of heterozygosity (LOH) analysis was
      performed by polymerase chain reaction (PCR) using two microsatellite markers
      (IFNA and D9S171) from the 9p21 region. Taking into account only the informative
      cases, 17 of 32 tumours (53%) showed LOH for at least one of the markers
      analysed. The methylation status of the CpG sites in the exon 1 of the p16 gene
      was analysed using methylation-sensitive restriction enzymes and PCR
      amplification. Hypermethylation was observed in 22 (47%) of the head and neck
      tumours analysed. In our series of head and neck tumours, evidence for
      inactivation of both p16 alleles was observed in 13 cases with hypermethylation
      and LOH, two cases with hypermethylation and mutation, four cases with mutation
      and LOH and one case with homozygous deletion. These findings provide further
      evidence that genetic alterations, especially hypermethylation and LOH, leading
      to the inactivation of the p16 tumour suppressor gene are common in primary head
      and neck tumours.

PMID- 10574256
TI  - Increasing genome instability in adrenocortical carcinoma progression with
      involvement of chromosomes 3, 9 and X at the adenoma stage.
AB  - The investigation of chromosomal aberrations in adrenocortical tumours has been
      limited by the difficulties of applying classical cytogenetics to tumours with
      low levels of proliferation. We have therefore applied the technique of
      interphase cytogenetics to paraffin-embedded archival specimens of 14
      adrenocortical adenomas and 13 carcinomas. Hybridizations were performed using
      centromere-specific probes to chromosomes 3, 4, 9, 17, 18 and X, which have been
      shown to be altered in other types of tumours. Chromosomal imbalance was defined
      on the basis of changes in both chromosome index (CI) and signal distribution
      (SD). Where only one of these was altered, this was classified as a tendency to
      gain or loss. On the basis of the analysis of optimal hybridizations, carcinomas
      showed gains in all chromosomes studied, five of nine showing gains in multiple
      chromosomes. Gains were most common in chromosomes 3, 9 and, in particular X,
      eight of 11 showing gain, and one a tendency to gain. Chromosomal gain was seen
      less commonly in adenomas, but again chromosomes 3, 9 and X were involved. Losses
      were infrequent, only one carcinoma showing loss of chromosome 18, and adenomas
      showing a tendency to loss of chromosomes 4 (two cases), 17 (one case) and 18
      (two cases). Our data suggest that changes in chromosomes 3, 9 and X are early
      events in adrenocortical tumorigenesis, and that there is increasing chromosomal
      instability with tumour progression.

PMID- 10574258
TI  - Predictive value of expression of p16INK4A, retinoblastoma and p53 proteins for
      the prognosis of non-small-cell lung cancers.
AB  - The predictive value of expression of p16INK4A, retinoblastoma (Rb) and p53
      proteins for prognosis was evaluated in 76 patients with non-small-cell lung
      cancers (NSCLCs) that were potentially curatively resected between 1990 and 1995,
      using the results of immunostaining analyses of these proteins as reported in our
      previous study (Kinoshita et al, 1996). Of these NSCLCs, 22 (29%) lacked p16
      protein expression and eight (11%) Rb protein, while 30 (39%) showed positive
      (altered) p53 protein expression. Survival of patients with p16-negative tumours
      was not significantly different from that of patients with p16-positive tumours
      (5-year survival rates 67% and 72% respectively, P = 0.8), nor was survival of
      patients with Rb-negative tumours significantly different from that of patients
      with Rb-positive tumours (5-year survival rates 42% and 69% respectively, P =
      0.9). Moreover, survival of patients with p16/Rb-negative (either p16- or Rb
      negative) tumours was not significantly different from that of patients with
      p16/Rb-positive (both p16- and Rb-positive) tumours (5-year survival rates 67%
      and 68% respectively, P = 0.7). In contrast, survival of patients with p53
      positive (altered) tumours tended to be shorter than that of patients with p53
      negative (unaltered) tumours (5-year survival rates 56% and 78% respectively, P =
      0.06). In univariate analysis of potential prognostic factors, p16, Rb and p16/Rb
      proteins were not significant prognostic factors in the present cohort of
      potentially curatively resected NSCLCs. Altered p53 protein status tended to be a
      negative prognostic factor (P = 0.06 by the univariate analysis). These results
      indicate that loss of p16 protein alone, or in combination with loss of Rb
      protein, does not predict the clinical outcome of patients with resected NSCLCs.

PMID- 10574257
TI  - In vivo and in vitro expression of steroid-converting enzymes in human breast
      tumours: associations with interleukin-6.
AB  - Enzymes modulating local steroid availability play an important role in the
      progression of human breast cancer. These include isoforms of 17beta
      hydroxysteroid dehydrogenase (17-HSD), aromatase and steroid sulphatase (STS).
      The aim of this study was to investigate the expression, by reverse transcription
      polymerase chain reaction, of 17-HSD types I-IV, aromatase and steroid STS in a
      series of 51 human breast tumour biopsies and 22 primary cultures of epithelial
      and stromal cells derived from these tumours, giving a profile of the steroid
      regulating network for individual tumours. Correlations between enzyme expression
      profiles and expression of the interleukin (IL)-6 gene were also sought. All
      except one tumour expressed at least one isoform of 17-HSD, either alone or in
      combination with aromatase and STS. Expression of 17-HSD isoforms I-IV were
      observed in nine tumours. Of the 15 tumours which expressed three isoforms, a
      combination of 17-HSD II, III and IV was most common (6/15 samples). The majority
      of tumours (n = 17) expressed two isoforms of 17-HSD with combinations of 17-HSD
      II and IV predominant (7/17 samples). Eight tumours expressed a single isoform
      and of these, 17-HSD I was in the majority (5/8 samples). In primary epithelial
      cultures, enzyme expression was ranked: HSD I (86%) > STS (77%) > HSD II (59%) >
      HSD IV (50%) = aromatase (50%) > HSD III (32%). Incidence of enzyme expression
      was generally reduced in stromal cultures which were ranked: HSD I (68%) > STS
      (67%) > aromatase (48%) > HSD II (43%) > HSD IV (28%) > HSD III (19%). Expression
      of IL-6 was associated with tumours that expressed > or = 3 steroid-converting
      enzymes. These tumours were of higher grade and tended to come from patients with
      family history of breast cancer. In conclusion, we propose that these enzymes
      work in tandem with cytokines thereby providing sufficient quantities of
      bioactive oestrogen from less active precursors which stimulates tumour growth.

PMID- 10574259
TI  - Serum p53 autoantibodies in patients with minimal lesions of ductal carcinoma in
      situ of the breast.
AB  - Five of 43 patients (11.6%) with ductal carcinoma in situ of the breast presented
      with p53 autoantibodies at diagnosis. Three seropositive patients demonstrated
      tumour sizes of < or = 5 mm. There was no association of p53 autoantibody status
      with age, clinical presentation, histological subtype, tumour size, grading, p53
      immunohistochemistry or hormone receptor status.

PMID- 10574260
TI  - Activation of cyclin D1-related kinase in human lung adenocarcinoma.
AB  - Cyclin D1 gene amplification is an important event in many cancers, but it is
      rarely found in non-small-cell lung cancer (NSCLC). This study was conducted in
      an attempt to clarify any other mechanisms related to cyclin D1 involvement in
      the malignant transformation of NSCLC, and we clearly showed for the first time
      that cyclin D1-related kinases are activated in NSCLC, especially in
      adenocarcinoma but not in squamous cell carcinoma. The results of this study
      strongly suggest that enhanced cyclin D1-related kinase activity could contribute
      to a progression of adenocarcinoma in NSCLC.

PMID- 10574262
TI  - Hepatocyte growth factor and invasion-stimulatory activity are induced in pleural
      fluid by surgery in lung cancer patients.
AB  - Hepatocyte growth factor (HGF) is a stromal cell-derived cytokine that can
      stimulate matrix invasion by carcinoma cells. We analysed the concentrations of
      HGF and invasion-stimulatory activity in pleural fluid after lung surgery. The
      concentration of HGF in pleural fluids was measured by enzyme-linked
      immunosorbent assay in seven patients who underwent pulmonary resection for
      primary or metastatic lung cancer. The effect of the pleural fluid on cancer cell
      invasion across reconstituted basement membrane (Matrigel) was assessed with a
      Boyden chamber assay using a lung adenocarcinoma cell line, A549. HGF levels in
      the pleural fluid after lung surgery ranged from 6.0 to 23.0 ng ml(-1) (average:
      10.2 +/- 4.3 ng ml(-1)). The matrix invasion of lung carcinoma cells in the
      presence of the pleural fluid was significantly higher than that in the presence
      of culture medium alone or sera from normal subjects (P < 0.01). The invasion
      stimulatory activity of the pleural fluid was strongly inhibited by HGF
      neutralizing antibody. Positive correlation was found between the HGF level and
      invasion-stimulatory activity in the pleural fluids and normal sera (P = 0.0073).
      This is the first report demonstrating that the lung surgery induces a
      considerable amount of HGF, which is closely correlated with the invasion
      stimulatory activity of the pleural fluid.

PMID- 10574261
TI  - Metallothionein expression correlates with metastatic and proliferative potential
      in squamous cell carcinoma of the oesophagus.
AB  - The goal of this study is to clarify whether the expression of metallothionein
      (MT) could affect the prognosis and the metastatic potential of squamous cell
      carcinoma (SCC) of the oesophagus. In paraffin-embedded specimens resected from
      57 patients, MT mRNA and protein expressions were detected by in situ
      hybridization and immunohistochemistry respectively. The expression of MT was
      evaluated in respect of clinicopathologic variables and patients' survival. MT
      mRNA expression was significantly associated with the proportion of lymph node
      metastasis (71% in MT mRNA-positive tumours vs 42% in MT mRNA-negative tumours; P
      = 0.0343) and that of distant metastasis (29% in MT mRNA-positive tumours vs 5%
      in MT mRNA-negative tumours; P = 0.0452). In respect of MT protein expression,
      the frequency of distant metastasis was more common in MT-positive tumours than
      in MT-negative tumours (30% in MT-positive tumours vs 8% in MT-negative tumours;
      P = 0.0446). The survival rate of the patients with MT protein-negative tumours
      was significantly better than that of the patients with MT protein-positive
      tumours (P = 0.0340). There was a positive correlation between the expression of
      MT protein and that of proliferating cell nuclear antigen (P = 0.0018).
      Therefore, we conclude that MT expression, both at the mRNA and protein levels,
      may be a potential marker predicting metastatic and proliferative activities of
      oesophageal SCC.

PMID- 10574263
TI  - Does vascular endothelial growth factor (VEGF) predict local relapse and survival
      in radiotherapy-treated node-negative breast cancer?
AB  - The aim of this study was to determine the association of vascular endothelial
      growth factor (VEGF) content in 302 consecutive node-negative breast cancer
      (NNBC) patients treated with only locoregional radiotherapy to relapse free-
      (RFS) and overall survival (OS). VEGF content in tumour cytosols was measured by
      an enzymatic immunoassay for the major isoform VEGF165. The median age was 56
      years, the median follow-up time 56 months. A wide range (0.01-144.79 pg microg(
      1) DNA) of VEGF content was found (median 1.92). Significant associations were
      found between VEGF and oestrogen receptor (ER) content, progesterone receptor
      (PR) and tumour size (P = 0.005). Univariate analysis displayed significant
      reduced RFS and OS for patients with higher VEGF content (P = 0.0113 and P =
      0.0075 respectively). A total of 43 recurrences have been found (ten local
      relapses within the breast, five in the axillary or supraclavicular lymph nodes
      and 28 distant metastasis). There was no significant correlation between the
      localization of the relapse and the VEGF content. Multivariate analysis suggested
      VEGF as the only predictor of OS (relative risk (RR) = 3.6, 95% confidence
      interval (CI) = 0.97-13.37), and in patients with T1 tumours (n = 236) the
      multivariate analysis clearly displayed VEGF as the only independent predictor of
      both RFS and OS (RR = 5.1, CI = 1.07-24.59). In the subgroup with ER-positive
      tumours (n = 229), multivariate analysis showed VEGF as the only significant
      predictor of RFS and OS (RR = 10.44, CI = 1.26-86.38). The results suggest
      VEGF165 as a predictor of RFS and OS in NNBC patients treated with locoregional
      radiotherapy, comprising especially patients with favourable prognosis of T1
      tumours, or ER-positive tumours. The high VEGF expression might define a
      radioresistant phenotype, or indicate an early distant spread which might require
      adjuvant systemic treatment.

PMID- 10574264
TI  - p53 overexpression is associated with cytoreduction and response to chemotherapy
      in ovarian cancer.
AB  - The aim of this study was to assess the association of p53 status with primary
      cytoreduction, response to chemotherapy and outcome in stage III-IV primary
      ovarian cancer patients. Immunohistochemical analysis of p53 was performed on
      formalin-fixed, paraffin-embedded specimens from 168 primary ovarian carcinomas
      by using the DO-7 monoclonal antibody. p53 nuclear positivity was found in 84 out
      of 162 (52%) malignant tumours. A higher percentage of p53 nuclear positivity was
      observed in patients with advanced stage of disease than in stage I-II (57% vs
      23% respectively; P = 0.0022) and in poorly differentiated versus well/moderately
      differentiated tumours (59% vs 32% respectively; P = 0.0038). The multivariate
      analysis aimed to investigate the association of FIGO stage, grade and p53 status
      with primary cytoreduction in 136 stage III-IV patients showed that stage IV
      disease may influence the possibility to perform primary cytoreduction in ovarian
      cancer patients. p53-positivity also maintained a trend to be associated with
      poor chance of cytoreduction. In patients who underwent pathologic assessment of
      response, cases who did not respond to chemotherapy were much more frequently p53
      positive than p53-negative (86% vs 14% respectively; P = 0.012). Moreover,
      patients with stage III disease and < 2-cm residual tumour were more likely to
      respond to treatment. In multivariate analysis, FIGO stage and p53 expression
      were independently correlated with pathologic response to chemotherapy. Time to
      progression and survival rates were shown not to be different in p53-positive
      versus p53-negative patients.

PMID- 10574266
TI  - Both cell proliferation and apoptosis significantly predict shortened disease
      free survival in hepatocellular carcinoma.
AB  - In this study, we investigated the proliferating cell index by the percentage of
      Ki-67 expressing cells (Ki-67 LI) and the apoptotic index (AI) by the number of
      morphologically apoptotic cells per 1000 carcinoma cells in haematoxylin and
      eosin sections of 76 hepatocellular carcinomas (HCC). Both indices showed
      excellent correlation with each other (P < 0.0001) and were significantly higher
      in cases of poor differentiation, of advanced stages, with portal invasion and
      with intrahepatic metastasis. Furthermore, cases with higher Ki-67 LI or higher
      AI displayed poor outcomes for disease-free survival (P = 0.0001 and P = 0.0005)
      by univariate analysis. By multivariate analysis, both indices could be regarded
      as independent prognostic factors. These results strongly suggest that Ki-67 LI
      and AI have very similar clinical significance, reflecting the existence of
      biologically aggressive phenotypes and poor disease-free survival rate in HCC.

PMID- 10574265
TI  - MN/CA IX/G250 as a potential target for immunotherapy of renal cell carcinomas.
AB  - The monoclonal antibody G250 (mAbG250) raised against a human renal cell
      carcinoma (RCC) has been shown to react with a large number of RCCs. Recently,
      G250 antigen was isolated and found to be homologous to the MN/CA9 gene
      originally identified in HeLa cells. To determine whether G250 antigen (MN/CA
      IX/G250) could be a potential therapeutic target and a tumour marker, a total of
      147 cases of RCC were investigated immunohistochemically as well as by reverse
      transcriptase polymerase chain reaction (RT-PCR) analysis. In addition, total
      RNAs extracted from patients' peripheral blood samples were analysed for
      MN/CA9/G250 mRNA signals. Immunohistochemistry demonstrated strong expression in
      128/147 (87.1%) of RCCs, in contrast to the lack of expression observed in normal
      tissues. RT-PCR analyses of frozen specimens resulted in the clear detection of
      MN/CA9/G250 mRNA signals in 137/147 (93.2%), and despite subtle differences the
      results were almost identical to those for immunohistochemistry. Although high
      grade and -stage tumours exhibited significantly lower expression than low-grade
      and -stage tumours, a large proportion of tumours expressed MN/G250 protein as
      well as mRNA. RT-PCR analysis of patients' blood samples revealed the presence of
      circulating MN/CA9/G250 expressing cells. These findings suggest that this
      antigen may be a potential therapeutic target as well as diagnostic marker for
      RCCs.

PMID- 10574267
TI  - Veterinarian awarded World Food Prize.

PMID- 10574269
TI  - As minister sets out the government's strategy for change.

PMID- 10574268
TI  - Replacement of quarantine: BVA highlights concerns about enforcement...

PMID- 10574270
TI  - Depressed state of the livestock sector reflected in submissions to the VLA.

PMID- 10574271
TI  - Two-year study of bovine hepatic abscessation in 10 abattoirs in County Cork,
      Ireland.
AB  - The livers from 6337, 12- to 16-month-old heifers slaughtered in 10 domestic
      abattoirs over a period of two years were examined; 368 (5.8 per cent) had gross
      lesions, of which 120 (1.9 per cent) had abscesses, 74 (1.17 per cent) had only
      scarring, and 44 (0.7 per cent) had telangiectasis (so-called 'sawdust' liver).
      Of the 120 livers in which abscesses were detected, 53 (44 per cent) had a single
      large abscess (>4 cm diameter), 44 (36.6 per cent) had a single small abscess (<4
      cm), and 23 (19 per cent) had more than two abscesses; in 20 of them (16.6 per
      cent) the abscesses were resolving, and in 10 (8.3 per cent) the abscesses were
      ruptured. Forty-three (35.8 per cent) of the livers with abscesses had adhesions
      to the diaphragm and diaphragmatic lung lobes, three (2.5 per cent) had adhesions
      to other abdominal organs, 12 (10 per cent) also had scarring and two (1.7 per
      cent) also had lesions due to liver fluke. There was no significant association
      between the liver fluke lesions and the abscesses. In 46 (38.3 per cent) of the
      livers the abscesses were located in the mid-dorsal diaphragmatic or dorsocranial
      area of the liver; 28 (23.3 per cent) were adjacent to the posterior vena cava
      and could as a result have caused thromboembolic disease. Clinical signs
      attributable to the abscesses were observed in only one animal.

PMID- 10574272
TI  - Effect of very low pulsed direct currents at high frequency on the return of neck
      tension in broilers.
AB  - Broiler chickens were stunned electrically for one second or 10 seconds with a
      unipolar pulsed direct current (DC) at 550 Hz. The effectiveness of the stun was
      assessed from the birds' behaviour. All the birds were stunned effectively when
      more than 15 mA true root mean square DC was applied for either period. An
      increase in the duration of the applied current resulted in an increased duration
      of unconsciousness. However, the unipolar pulsed DC at 550 Hz did not induce
      cardiac arrest, and it must therefore be accompanied by a prompt and effective
      neck cut, severing both carotid arteries.

PMID- 10574273
TI  - Pharmacokinetics of florfenicol after treatment of pigs with single oral or
      intramuscular doses or with medicated feed for three days.
AB  - The pharmacokinetics of florfenicol, a structural analogue of thiamphenicol, were
      studied in six pigs after single oral and intramuscular doses of 15 mg/kg
      bodyweight, and after feeding them with medicated feed containing 250 mg/kg for
      three days, a concentration which provided approximately the same dose rate of
      the drug. The oral doses contained a specially prepared pelleted formulation of
      the drug. The bioavailability of the drug was similar for the oral and
      intramuscular doses. Florfenicol was absorbed rapidly from the feed and its
      concentration in plasma remained between 2 and 6 microg/ml - above the minimum
      inhibitory concentration values for common pig pathogens - during the three days.

PMID- 10574275
TI  - 38,XX/38,XY chromosome chimaerism in three feline siblings.

PMID- 10574274
TI  - Epidemic infection caused by Citrobacter rodentium in a gerbil colony.
AB  - Non-motile, Gram-negative rods, isolated from the intestinal tract and kidney of
      several dead animals in a gerbil colony, were identified as Citrobacter rodentium
      (formerly included in C. freundii species) on the basis of 31 biochemical tests.
      The isolates were tested against 40 antimicrobial agents and were all susceptible
      to ticarcillin plus clavulanate, ceftazidime and most of the quinolones studied,
      but were all resistant to most of the penicillins and aminoglycosides tested, and
      to fosfomycin, metronidazole and tiamulin. This bacterial species has been
      primarily associated with transmissible murine colonic hyperplasia, and this
      appears to be the first report of an epidemic infection in a gerbil colony with a
      fatal outcome in most of the animals affected.

PMID- 10574276
TI  - Scrapie occurrence in Great Britain.

PMID- 10574277
TI  - Pyrantel-resistant large strongyles in racehorses.

PMID- 10574278
TI  - Recall of '999' microchips.

PMID- 10574279
TI  - Veterinary medicines and the FSA.

PMID- 10574280
TI  - Sympathetic skin response following thermal, electrical, acoustic, and
      inspiratory gasp stimulation in familial dysautonomia patients and healthy
      persons.
AB  - To determine whether sympathetic skin response (SSR) testing evaluates afferent
      small or efferent sympathetic nerve fiber dysfunction, we studied SSR in patients
      with familial dysautonomia (FD) in whom both afferent small and efferent
      sympathetic fibers are largely reduced. We analyzed whether the response pattern
      to a combination of stimuli specific for large or small fiber activation allows
      differentiation between afferent and efferent small fiber dysfunction. In 52
      volunteers and 13 FD patients, SSR was studied at palms and soles after warm,
      cold and heat as well as electrical, acoustic, and inspiratory gasp stimulation.
      In addition, thermal thresholds were assessed at four body sites using a
      Thermotest device (Somedic; Stockholm, Sweden). In volunteers, any stimulus
      induced reproducible SSRs. Only cold failed to evoke SSR in two volunteers. In
      all FD patients, electrical SSR was present, but amplitudes were reduced. Five
      patients had no acoustic SSR, four had no inspiratory SSR. Thermal SSR was absent
      in 10 patients with abnormal thermal perception and present in one patient with
      preserved thermal sensation. In two patients, thermal SSR was present only when
      skin areas with preserved temperature perception were stimulated. In patients
      with FD, preserved electrical SSR demonstrated the overall integrity of the SSR
      reflex but amplitude reduction suggested impaired sudomotor activation. SSR
      responses were dependent on the perception of the stimulus. In the presence of
      preserved electrical SSR, absent thermal SSR reflects afferent small fiber
      dysfunction. A combination of SSR stimulus types allows differentiation between
      afferent small or efferent sympathetic nerve fiber dysfunction.

PMID- 10574281
TI  - Autonomic control of heart rate variability in vasovagal syncope: a study of the
      nighttime period in 24-hour recordings.
AB  - Patients experiencing vasovagal syncope have been claimed to show reduced vagal
      tone over 24-hour electrocardiography recordings. Assessment of sympathovagal
      balance in the absence of external stimuli, i.e., nighttime electrocardiography
      monitoring, might help to clarify if increased sympathetic activity is present in
      these patients. Heart rate variability was examined at nighttime in 40 patients
      with recurrent episodes of vasovagal syncope within the last 2 years (22 men;
      mean age, 37 years) and 20 comparable healthy volunteers. Time domain parameters
      (pNN50 [proportion of successive RR intervals difference >50 ms in %] and rMSSD
      [root-mean-square successive difference of RR intervals in ms]), indexes of vagal
      tone, and frequency domain parameters, expressing the overall heart rate
      variability, vagal (high frequency [HF]) and sympathetic (low frequency [LF])
      activity, and autonomic balance (LF/HF ratio) were compared between groups by
      Mann-Whitney test. Significant (p<0.05) reduction of heart rate variability and
      vagal tone (pNN50 and rMSSD) were found for patients with vasovagal syncope,
      together with increased sympathetic activity (increased LF/HF ratio). These
      findings could open new insights in the pathogenesis of vasovagal syncope because
      of the shift of the autonomic balance toward sympathetic activation near the
      syncopal episode.

PMID- 10574283
TI  - Modern electroencephalography: its role in epilepsy management.
AB  - Epilepsy is the area in which electroencephalography is probably of greatest
      potential clinical value, and yet is most abused. In general, the sensitivity of
      the waking interictal EEG for detecting epilepsy and its specificity for
      distinguishing epilepsy from other episodic disorders are both very limited, and
      routine examination for diagnostic screening or follow up is of little value.
      However, as this review attempts to demonstrate, EEG is of crucial importance for
      answering specific, clearly defined questions which commonly arise in the
      management of seizure disorders, especially so, when non-routine and if necessary
      complex investigations are undertaken, to address the problems of individual
      patients.

PMID- 10574282
TI  - Estimation of beat-to-beat changes in stroke volume from arterial pressure: a
      comparison of two pressure wave analysis techniques during head-up tilt testing
      in young, healthy men.
AB  - OBJECTIVE: The aim of this study was to compare beat-to-beat changes in stroke
      volume (SV) estimated by two different pressure wave analysis techniques during
      orthostatic stress testing: pulse contour analysis and Modelflow, i.e.,
      simulation of a three-element model of aortic input impedance. METHODS: A
      reduction in SV was introduced in eight healthy young men (mean age, 25; range,
      19-32 y) by a 30-minute head-up tilt maneuver. Intrabrachial and noninvasive
      finger pressure were monitored simultaneously. Beat-to-beat changes in SV were
      estimated from intrabrachial pressure by pulse contour analysis and Modelflow. In
      addition, the relative differences in Modelflow SV obtained from intrabrachial
      pressure and noninvasive finger pressure were assessed. RESULTS: Beat-to-beat
      changes in Modelflow SV from intrabrachial pressure were comparable with pulse
      contour measures. The relative difference between the two methods amounted to
      0.1+/-1% (mean +/- SEM) and was not dependent on the duration of tilt. The
      difference between Modelflow applied to intrabrachial pressure and finger
      pressure amounted to -2.7+/-1.3% (p = 0.04). This difference was not dependent on
      the duration of tilt or level of arterial pressure. CONCLUSIONS: Based on
      different mathematical models of the human arterial system, pulse contour and
      Modelflow compute similar changes in SV from intrabrachial pressure during
      orthostatic stress testing in young healthy men. The magnitude of the difference
      in SV derived from intrabrachial and finger pressure may vary among subjects;
      Modelflow SV from noninvasive finger pressure tracks fast and brisk changes in SV
      derived from intrabrachial pressure.

PMID- 10574284
TI  - Is the frontal N30 component of the somatosensory evoked potentials a reliable
      physiological index of the dopaminergic motor pathways?

PMID- 10574285
TI  - The effect of deep brain stimulation on the frontal N30 component of
      somatosensory evoked potentials in advanced Parkinson's disease patients.
AB  - OBJECTIVES: In the present study we investigated whether in advanced Parkinson's
      disease (PD) patients the frontal component of short somatosensory evoked
      potentials (SEPs) to median nerve stimulation may be modified by basal ganglia
      deep brain stimulation (DBS). METHODS: We recorded the SEPs in 6 PD patients
      undergoing bilateral functional neurosurgery in the internal globus pallidus
      (GPi) (4 patients) and in the nucleus subthalamicus (STN) (two patients) during
      ineffective and effective bilateral BDS. Pre-operatively, the SEPs were also
      recorded in off therapy and during apomorphine infusion. RESULTS: From the
      evaluation of the latency and the amplitude characteristics of the major parietal
      (N20 and P25) and frontal (N30) components, we observed that whereas the parietal
      waves did not vary in any condition, the N30 potential showed a remarkable
      amplitude increase during apomorphine as well as during effective bilateral GPi
      or STN DBS. Furthermore, after the stimulators were turned off we noticed that
      the N30 amplitude potential progressively faded almost in parallel with the
      attenuation of DBS clinical effects. CONCLUSIONS: Our results lead to the
      conclusion that the bilateral DBS of both GPi and STN is really effective in
      producing a selective increase of frontal N30 amplitude probably improving the
      supplementary motor area functional activity, but these results do not clarify
      whether this amelioration is due to a central or a 'long loop' mechanism.

PMID- 10574286
TI  - Long-term intra-individual variability of the background EEG in normals.
AB  - OBJECTIVES: Forty-five healthy adult volunteers underwent repeated qEEG
      examinations with retest intervals 25-62 months in order to investigate the long
      term intra-individual variability of several qEEG features such as, absolute and
      relative power, power asymmetry, coherence, mean and peak frequency and entropy.
      Prior to any computations all parameters were transformed to Z-scores on the
      basis of a normal database. METHODS: Correlation coefficients were used to test
      the effect of the time on the test-retest differences. Correlation coefficients
      were also computed between baseline and retest values, as a measure of intra
      individual stability, to make our results comparable to most literature data. By
      computing the standard deviations for test-retest differences, the intra
      individual variabilities of the examined parameters were obtained in the unit of
      inter-individual variability of normal population. The same calculations were
      carried out with values obtained from the odd and even numbered epochs of the
      same EEG sections. This way, that portion of the intra-individual variability was
      estimated that might be introduced even by chance only when the epochs were
      selected randomly from the same section of EEG conforming to selection criteria.
      RESULTS: As for our results, further increase of test-retest differences with
      time after 25 months might be so insignificant that it could not be demonstrated
      in our test material. The long-term intra-individual variability for most
      parameters, especially for total absolute power and alpha mean frequency, was
      less than the inter-individual variability in the normal population. The moment
      to-moment variability was least in the case of the absolute power. CONCLUSIONS:
      Estimates for intra-individual variability expressed this way in Z-scores might
      easily be used in the follow-up of patients even for a few years.

PMID- 10574287
TI  - Measuring the coherence of intracranial electroencephalograms.
AB  - OBJECTIVE: Previous coherence studies of human intracranial electroencephalograms
      (EEGs) can be faulted on two methodological issues: (1) coherence estimates in a
      majority were formed from a very small number of independent sample spectra, and
      (2) the statistical significance of coherence estimates was either not reported
      or was poorly evaluated. Coherence estimator performance may be poor when a small
      number of independent sample spectra are employed, and the coupling of poor
      estimation and statistical testing can result in inaccuracy in the measurement of
      coherence. The performance characteristics of the coherence estimator and
      statistical testing of coherence estimates are described in this manuscript.
      METHODS: The bias, variance, probability density functions, and confidence
      intervals of the estimate of magnitude squared coherence (MSC); and power
      analysis for the test of zero MSC were developed from the exact analytic form of
      the probability density function of the estimate of MSC for Gaussian random
      processes. The coherence of a single epoch of background EEG, recorded from a
      patient with intractable seizures, was evaluated with different parameter values
      to aid in the exposition of the concepts developed here. RESULTS: The statistical
      characteristics of WOSA coherence estimates are a function of a single estimator
      parameter, the number of independent sample spectra employed in the estimation.
      Bias and variance are high, confidence intervals may be large, and the
      probability of Type II errors is high if a small number of independent sample
      spectra are employed. A considerable improvement in measurement accuracy is
      possible with careful selection of estimator parameter values. CONCLUSIONS:
      Coherence measurement accuracy can be improved over previous applications by
      attention to estimator performance and accurate statistical testing of coherence
      estimates.

PMID- 10574288
TI  - Non-linear analysis of intracranial human EEG in temporal lobe epilepsy.
AB  - OBJECTIVE: Intracranial EEG recordings from patients suffering from medically
      intractable temporal lobe epilepsy were analyzed with the aim of characterizing
      the dynamics of EEG epochs recorded before and during a seizure and comparing the
      classification of the EEG epochs on the basis of visual inspection to the results
      of the numerical analysis. METHODS: The stationarity of the selected EEGs was
      assessed qualitatively. The coarse-grained correlation dimension and coarse
      grained correlation entropy were used for the non-linear characterization of the
      EEG epochs. RESULTS: High-pass filtering was necessary in order to make the
      majority of the epochs appear stationarity beyond a time scale of about 2 s. It
      was found that the dimension of the ictal EEGs decreased with respect to the
      epochs containing ongoing (interictal) activity. The entropy of the ictal
      recordings however increased. A scaling of the entropy was applied and it was
      found that the scaled entropy of the ictal EEG decreased, consistent with the
      increased regularity of the ictal EEG. The coarse-grained quantities
      discriminated well between EEG epochs recorded prior to and during seizures at
      locations displaying ictal activity and classification improved by including the
      linear autocorrelation time in the analysis. CONCLUSIONS: It is concluded that
      ictal and non-ictal EEG can be well distinguished on the basis of non-linear
      analysis. The results are in good agreement with the visual analysis.

PMID- 10574289
TI  - Seizures of temporal lobe epilepsy: identification of subtypes by coherence
      analysis using stereo-electro-encephalography.
AB  - OBJECTIVES: Two subtypes of temporal lobe epilepsy (TLE) according to the
      structures initially involved during seizures are currently recognized: medial
      TLE (MTLE) and lateral (or neocortical) TLE (LTLE). A few reports have suggested
      that the classification of TLE subtypes might be larger according to variations
      in the interactions between medial structures and the neocortex. In this study,
      we analyzed these interactions using coherence analysis of stereo
      encephalographic (SEEG) signals during spontaneous seizures. METHODS: Twenty
      seven patients with drug-resistant TLE, diagnosed from ictal SEEG recordings
      obtained during pre-surgical evaluation, were studied. Orthogonally implanted
      depth electrodes with multiple leads according to Talairach's method were used to
      sample medial and neocortical structures. Coherence analysis of ictal discharges
      was performed between two SEEG bipolar signals from adjacent leads located either
      in medial structures (amygdala and hippocampus) or in neocortical regions of the
      temporal lobe. A new algorithm, which was designed to reduce the bias inherent in
      coherence estimation, was used to compute the coherence. RESULTS: We were able to
      classify TLE seizures (TLES) into 4 distinct categories: (1) 'medial' TLES,
      characterized by medial onset with later involvement of the neocortex in the form
      of a 'phasic' discharge. High ictal coherence values were observed between medial
      structures; (2) 'medial-lateral' TLES which started in medial structures with a
      fast low-voltage discharge (FLVD) which rapidly affects the neocortex (< or = 3
      s). High coherence values were observed between medial and lateral structures;
      (3) 'lateral-medial' TLES, which are different from medial-lateral TLES in that
      the FLVD starts in the lateral neocortex and involves the amygdala and/or
      hippocampus almost immediately after; (4) 'lateral' TLES: characterized by a
      neocortical onset, a delayed involvement of medial structures (when present), and
      high coherence values between neocortical structures. CONCLUSIONS: These results
      demonstrate the existence of numerous interactions between medial limbic
      structures and the neocortex during TLE seizures. Such findings could have
      implications for surgical strategies and the prognosis of epilepsy surgery,
      particularly when limited resection is indicated.

PMID- 10574290
TI  - Isolation of epileptiform discharges from unaveraged EEG by independent component
      analysis.
AB  - OBJECTIVE: We propose a method that allows the separation of epileptiform
      discharges (EDs) from the EEG background, including the ED's waveform and spatial
      distribution. The method even allows to separate a spike in two components
      occurring at approximately the same time but having different waveforms and
      spatial distributions. METHODS: The separation employs independent component
      analysis (ICA) and is not based on any assumption regarding generator model. A
      simulation study was performed by generating ten EEG data matrices by computer:
      each matrix included real background activity from a normal subject to which was
      added an array of simulated unaveraged EDs. Each discharge was a summation of two
      transients having slightly different potential field distributions and small
      jitters in time and amplitude. Real EEG data were also obtained from three
      epileptic patients. RESULTS: Through ICA, we could isolate the two epileptiform
      transients in every simulation matrix, and the retrieved transients were almost
      identical as the originals, especially in their spatial distributions. Two
      epileptic components were isolated by ICA in all patients. Each estimated
      epileptic component had a consistent time course. CONCLUSION: ICA appears
      promising for the separation of unaveraged spikes from the EEG background and
      their decomposition in independent spatio-temporal components.

PMID- 10574291
TI  - EEG correlates of finger movements with different inertial load conditions as
      revealed by averaging techniques.
AB  - OBJECTIVE: The present study was aimed to further address the general empirical
      question regarding the sensitivity of EEG correlates toward specific kinematic
      and/or kinetic movement parameters. In particular, we examined whether adding
      different inertial loads to the index finger, while a subject produced various
      amplitudes of discrete finger movements, influenced the movement-related
      potentials (MRP). METHODS: Our experimental design systematically controlled the
      angular displacement, velocity and acceleration (kinematic) profiles of finger
      movement while torque (kinetics) was varied by adding different external loads
      opposing finger flexion movement. We applied time-domain averaging of EEG single
      trials in order to extract three movement-related potentials (BP-600 to -500 BP
      100 to 0 and N0 to 100) preceding and accompanying 25, 50 and 75 degrees
      unilateral finger movements with no inertial load, small (100 g) and large (200
      g) loading. RESULTS: It was shown that both inertial load and the degree of
      angular displacement of index finger flexion increased the amplitude of late
      components of MRP (BP-100 to 0 and N0 to 100) over frontal and precentral areas.
      In contrast, the external load and movement amplitude manipulations did not
      influence the earlier component of the MRP (BP- 600 to -500). CONCLUSIONS:
      Overall, the data demonstrate that adding inertial load to the finger with larger
      angular displacements involves systematic increase in activation across frontal
      and precentral areas that are related to movement initiation as reflected in BP
      100 to 0 and N0 to 100.

PMID- 10574292
TI  - Side-to-side correlation of muscle activity in physiological and pathological
      human tremors.
AB  - OBJECTIVE: Many tremors occur always or often bilaterally. The question arises
      whether this could be explained by a common source or commonly transmitting
      pathways or by bilaterally represented, independent structures with the same
      oscillatory properties. A similar tremor frequency does not provide sufficient
      information to clarify this question. METHODS: We analyze coherencies between
      surface electromyographies (EMG) to investigate if bilateral physiologic (PT),
      essential (ET), Parkinsonian (PD) and orthostatic (OT) tremors originate from a
      common source for both sides of the body. We show that commonly used techniques
      to test whether coherencies are significant could lead to false positive results
      for tremor EMGs. A new estimation procedure is proposed to test EMG tremor time
      series on their linear independence. We apply this test to bilateral tremors.
      RESULTS: All measured EMG-pairs in OT (n = 7) were highly coherent between both
      sides with reproducible coherency values of up to 0.99. All other investigated
      tremors, i.e. PT and enhanced physiological tremors (EPT, n = 117), ET (n = 76)
      and PD resting and postural tremors (n = 70) do not show a significant side-to
      side correlation. CONCLUSIONS: This finding shows that the pathophysiologies of
      OT and other pathological tremors are definitely different. Either they have
      different origins or different kinds of transmitting pathways. The proposed
      method might also be used to investigate other electrophysiological data and is a
      helpful, easy to use investigation for a daily clinical routine.

PMID- 10574293
TI  - Event-related alpha oscillations in task processing.
AB  - OBJECTIVES: Recent findings substantiate the view that electroencephalographic
      (EEG) alpha rhythm (7-13 Hz) is functionally involved in information processing.
      However, the association of alpha rhythms with cognitive brain processes is less
      well understood because both augmentation and suppression of alpha oscillations
      have been observed to accompany task performance. The present study evaluates the
      effect of task processing on event-related alpha oscillations at the level of
      single-sweep analysis. METHODS: EEG was recorded from Fz, Cz and Pz electrodes in
      10 subjects participating in two experimental sessions, in which auditory stimuli
      with equal physical parameters were presented under different instructions
      (passive and task). Separate measurements of single-sweep amplitude and phase
      locking were performed and statistically analyzed for consecutive time windows in
      the poststimulus epoch. RESULTS: Major results show that, during the cognitive
      task, the phase-locking of alpha oscillations at the frontal site is
      significantly increased for the time window of 500-1000 ms after stimulation.
      CONCLUSIONS: The involvement of enhanced and synchronized frontal alpha activity
      in higher brain processes is strongly emphasized.

PMID- 10574294
TI  - Using multi-stimulus VEP source localization to obtain a retinotopic map of human
      primary visual cortex.
AB  - OBJECTIVE: The goal of this study was to acquire a detailed spatial and temporal
      map of primary visual cortex using a novel VEP stimulus and analysis technique.
      METHODS: A multi-stimulus array spanning the central 18 degrees of the visual
      field was used where each of 60 checkerboard stimulus 'patches' was
      simultaneously modulated with an independent binary m-sequence (Sutter, 1992).
      VEPs corresponding to each patch were recorded from 3 subjects using a dense
      posterior electrode array. For each stimulus patch, single dipole source
      localization was conducted to determine the location, magnitude, and time
      function of the underlying neural activation. To reduce ambiguity in the
      solution, a common time-function was assumed for stimulus patches at the same
      visual eccentricity (defining an annulus). The analysis was conducted
      independently for each annulus composed of 4-12 patches. RESULTS: The loci of the
      dipole solutions followed a smooth retinotopic pattern across annuli consistent
      with the classical organization of primary visual cortex. Specifically, each
      dipole was found contralateral to the corresponding stimulus patch and field
      inversion was observed for all subjects. CONCLUSIONS: Using this technique, the
      most detailed spatial and temporal retinotopic map of primary visual cortex to
      date has been obtained.

PMID- 10574295
TI  - Dynamics of the human alpha rhythm: evidence for non-linearity?
AB  - OBJECT: For a better understanding of the physiological mechanisms responsible
      for alpha rhythms it is important to know whether non-linear processes play a
      role in their generation. We used non-linear forecasting in combination with
      surrogate data testing to investigate the prevalence and nature of alpha rhythm
      non-linearity, based on EEG recordings from humans. We interpreted these findings
      using computer simulations of the alpha rhythm model of Lopes da Silva et al.
      (1974). METHODS: EEGs were recorded at 02 and O1 in 60 healthy subjects (30
      males; 30 females; age: 49.28 years; range 11-84) during a resting eyes-closed
      state. Four artefact-free epochs (2.5 s; sample frequency 200 Hz) from each
      subject were tested for non-linearity using a non-linear prediction statistic and
      phase-randomized surrogate data. A similar type of analysis was done on the
      output of the alpha model for different values of input. RESULTS: In the 480 (60
      subjects, 2 derivations, 4 blocks) epochs studied, the null hypothesis that the
      alpha rhythms can result from linearly filtered noise, could be rejected in 6
      cases (1.25%). The alpha model showed a bifurcation from a point attractor to a
      limit cycle at an input pulse density of 615 pps. Non-linearity could only be
      detected in the model output close to and beyond this bifurcation point. The
      sources of the non-linearity are the sigmoidal relationships between average
      membrane potential and output pulse density of the various cells of the neuronal
      populations. CONCLUSION: The alpha rhythm is a heterogeneous entity dynamically:
      98.75% of the epochs (type I alpha) cannot be distinguished from filtered noise.
      Apparently, during these epochs the activity of the brain has such a high
      complexity that it cannot be distinguished from a random process. In 1.25% of the
      epochs (type II alpha) non-linearity was found which may be explained by dynamics
      in the vicinity of a bifurcation to a limit cycle. There is thus experimental
      evidence from the point of view of dynamics for the existence of the two types of
      alpha rhythm and the bifurcation predicted by the model.

PMID- 10574297
TI  - Autism in tuberous sclerosis: evoked potential evidence for a deficit in auditory
      sensory processing.
AB  - OBJECTIVE: Autism is a frequent manifestation of tuberous sclerosis complex (TSC)
      being reported in up to 60% of the patients. Its presence is in association with
      cortical and subcortical lesions involving the temporal lobes. This study was
      designed to shed light on the functional mechanisms linking anatomical lesions of
      TSC and behavioural phenotype by investigating scalp recorded event related
      potentials to auditory stimuli. METHODS: Fourteen children with TSC, seven of
      which fulfilled the DSM IV criteria for autistic disorder were selected for this
      study. All of the subjects underwent high resolution MRI, EEG, brainstem auditory
      evoked potentials, cognitive and behavioural evaluation. Electrical evoked
      responses to two different pitches, presented with different probability (80%
      1000 Hz, 20% 1500 Hz) were recorded from 21 scalp electrodes in the autistic and
      non-autistic subgroups, to assess central auditory processing and automatic
      memory. RESULTS: The first component of the long latency auditory response (N1)
      had a significantly prolonged latency with lower amplitude in all of the patients
      with autistic behaviour who, contrary to non-autistics had MRI lesions involving
      one or both temporal lobes. A mismatch negativity was detected in all subjects
      and had a longer latency in subjects with autistic behaviour. CONCLUSIONS: To our
      knowledge this is the first electrophysiological evidence of a deficit in
      auditory information processing and automatic memory in TSC patients with
      autistic behaviour.

PMID- 10574296
TI  - Variation in diagnostic strategy of the EMG examination--a multicentre study.
AB  - OBJECTIVES: In order to improve the universal quality of the EMG examination,
      knowledge about the variation among physicians is needed. METHODS: The variation
      among physicians in diagnostic strategy or criteria for diagnosing was analysed
      from a multicentre database with 940 EMG examinations sampled by seven physicians
      from six laboratories in Europe. RESULTS: For the whole group of patients as well
      as for the subgroup of patients with polyneuropathy, variation among physicians
      in examination techniques, number of examined structures per patient and number
      of abnormal structures per patient required for a diagnosis was found. Some of
      the variation may be explained by use of different techniques, which showed
      differences in sensitivity, while some of the variation may be due to differences
      in diagnostic strategy and criteria for diagnosing. CONCLUSIONS: The study
      indicates a need for development and revision of international guidelines for EMG
      practice although implementation of standards requires caution.

PMID- 10574298
TI  - EEG spectral profile to stage Alzheimer's disease.
AB  - OBJECTIVE: The present study was undertaken to investigate whether a synoptic
      parameter of quantitative EEG (qEEG), such as the power spectral profile, may be
      used as a simple marker to stage Alzheimer's disease (AD) in the clinical
      setting. METHODS: To this purpose, the qEEG spectral profile was examined in 48
      patients (mean age: 73 years) with probable (NINCDS-ADRDA criteria) AD, who were
      divided into 4 groups, according to the Global Deterioration Scale (GDS; score: 3
      6). The spectral profile of each patient was expressed by the relative power of
      seven frequency bands (2-3.5, 4-5.5, 6-7.5, 8-9.5, 10-11.5, 12-13.5, 14-22.5 Hz).
      Mean values in each of the four GDS groups as well as in a control group of 18
      healthy elderly subjects underwent multivariate analysis of variance. RESULTS: A
      normally shaped but shifted-to-the left spectral profile was found in GDS 3
      group, whereas a reduced background rhythm with various increase in slow activity
      power characterized both GDS 4 and 5 groups. Finally, an 'exponential asymptotic'
      profile with the highest power in the lowest frequencies was the hallmark of GDS
      6 group. Overall, the 4-5.5 Hz and the 10-11.5 Hz band powers showed the highest
      statistical significance in differentiating the patient groups between one
      another and from controls (P < 0.0001). CONCLUSIONS: These data show that
      spectral profile is a very simple parameter which can be used to stage the
      disease on a pathophysiological basis.

PMID- 10574300
TI  - Predictors of polydrug use among four ethnic groups: a 12-year longitudinal
      study.
AB  - We examined adolescent risk and protective constructs associated with adult
      polydrug use among four ethnic groups. Both mean and relational differences among
      the constructs were examined by ethnic group. Teenage polydrug use was a
      significant predictor of adult polydrug use for Caucasians, African-Americans,
      and Latinos. Although this relationship was not evident for Asians, teenage
      alcohol use increased adult cigarette use, and early religiosity increased adult
      alcohol use. Early parental support/bonding predicted less adult Polydrug Use for
      Caucasians. For Latinos, general social conformity and low liberalism decreased
      cigarette use as an adult. In general, the implications of the results are that
      prevention strategies should emphasize the reduction of teenage drug use to
      decrease adult polydrug use among Caucasians, Latinos, and African-Americans.
      Future research should examine other possible risk and protective conditions
      related to adult polydrug use among diverse populations.

PMID- 10574299
TI  - General and alcohol-specific social support following treatment.
AB  - Both general and alcohol-specific support have been shown, albeit inconsistently,
      to affect drinking behavior. The discrepant findings may be clarified by
      examining how they work together. In exploratory analysis of clients following
      private outpatient alcoholism treatment, we found that the two variables add
      uniquely to the explanation of the variance in proportion of days abstinent
      (PDA). Both contribute significantly in the short term (3 months posttreatment),
      but only alcohol-specific support helps to explain variance over the longer term
      (15 months posttreatment), and alcohol-specific support explains more of the
      variance in PDA than general support at both time periods. More complex
      relationships are operating when short-term treatment effects have diminished.
      Alcohol-specific support mediates the relationship between general support and
      PDA, and both general social support and alcohol-specific support are moderators
      of one another in their relationships to PDA. Knowing how different types of
      social support affect drinking behavior at different intervals following
      treatment may help treatment providers to better prepare their clients for the
      posttreatment social environment.

PMID- 10574301
TI  - The effects of alcohol and alcohol expectancies on subjective reports and
      physiological reactivity: a meta-analysis.
AB  - The balanced placebo design (BPD) has been used to understand the etiology and
      maintenance of alcohol consumption. The utility of this design lies in its
      ability to examine both actual alcohol consumption and the expectation of alcohol
      consumption. A meta-analysis of the BPD literature was conducted in the context
      of cue-reactivity, which may be characterized as an experimental phenomenon
      observed in studies utilizing alcohol. Sixty-four studies were obtained in
      literature searches and coded for type of experimental setting and cues present
      during the actual beverage consumption. Lab setting was a moderator for both
      pharmacological (alcohol) and expectancy effects with the largest effects (in the
      same direction) noted in natural environment labs (i.e., an easy chair and casual
      environment). Contrary to predictions, the bar lab produced the smallest effects.
      Cues present during alcohol consumption served as a moderator of pharmacological
      effect, with the largest effect observed when alcohol was placed on the rim of
      the glass. Implications of these findings for cue-reactivity studies and the
      treatment of alcohol abuse are discussed.

PMID- 10574302
TI  - Integrative modeling of client engagement and outcomes during the first 6 months
      of methadone treatment.
AB  - Integrative models containing client and treatment components were tested in a
      sample of 396 daily opioid users from three methadone maintenance treatment
      sites. Measures included client motivation at intake as well as repeated
      assessments of therapeutic engagement (relationships between clients and their
      counselors, session attendance, and results of urine testing) during the first 6
      months of treatment. There was a positive effect of pretreatment motivation on
      greater engagement and a reciprocal positive relationship between components of
      engagement and their effects on lowering drug use throughout treatment. Further
      analyses addressed differential effects of group versus individual counseling and
      showed that group session attendance was associated with higher rates of drug
      negative urines.

PMID- 10574303
TI  - Older and younger male alcoholics in outpatient treatment.
AB  - In the coming decades, the proportion of the older age groups in the total
      population, and, therefore, in the alcoholic population, will be increasing. The
      aim of the study is to assess to what extent older alcoholics form a distinct
      group within the problem-drinking population. Alcoholics in outpatient treatment
      of over 50 years of age (n = 52) are compared with those from the modal age group
      (ages 35-44, n = 55). Results indicate that problems with alcohol are less severe
      among older alcoholics. Contrary to expectation, older alcoholics did not report
      more health problems. No differences were observed in the duration of the
      treatment career. It is concluded that older alcoholics show the same types of
      problems, but less so than younger alcoholics. Further research is indicated
      regarding late onset, older alcoholics with multiple diagnosis, and drinking
      problems in the age group over 70.

PMID- 10574304
TI  - Age at smoking onset and its effect on smoking cessation.
AB  - The aim of this study was to examine the relationship between cessation and age
      at which person starts smoking. Data from a survey of nine neighborhoods in
      Philadelphia (1985-1987) were analyzed. Interviews were conducted in the home
      using a structured questionnaire. Participants were from a probability sample (n
      = 1,700) of males aged 35 years or older. Sixty-six percent of the smokers in
      this series started smoking before 18 years of age. Smoking cessation rate was
      58.1% in Whites and 38.8% in Blacks. Age, race, marital status, education, health
      condition, amount smoked, and duration of smoking were significant predictors of
      smoking cessation. Age at initiation of smoking was a significant factor for
      continuation of smoking. Men who started smoking before 16 years of age had an
      odds ratio of 2.1 (95% confidence interval: 1.4-3.0) for not quitting smoking
      compared to those who started at a later age. These findings emphasize the need
      for prevention program targeted to children below 16 years of age.

PMID- 10574305
TI  - Restraint, weight suppression, and self-report reliability: how much do you
      really weigh?
AB  - This study examined the effects of weight suppression on eating behaviors in a
      standard restraint ice cream taste-test paradigm. Participants were 58 female
      restrained eaters categorized by self-report as either high- or low-weight
      suppressors. Prior to the taste test, half of the participants received a
      milkshake preload. The amount of ice cream consumed during the taste test was the
      primary measure of interest. A 2 x 2 analysis of variance (ANOVA) indicated no
      significant differences between groups. This contradicts previously reported
      results in which restrained eaters consumed more following a preload than in the
      no-preload condition and provides further evidence that restraint is not a
      homogeneous construct. These results also question the use of self-report
      measures to determine an individual's level of weight suppression.

PMID- 10574306
TI  - Help-seeking by African American drug users: a prospective analysis.
AB  - In this study, help-seeking was significantly more likely for African American
      drug users with more formal education and those scoring higher on both drug
      related problem recognition and ethnic identity. This latter result suggests that
      ethnic identity, despite having no main effect on help-seeking in this sample,
      may nonetheless make an important contribution to help-seeking by "potentiating"
      the influence of drug problem recognition.

PMID- 10574307
TI  - Stress, cognitive factors, and coping resources as predictors of relapse in
      alcoholics.
AB  - One hundred alcohol-dependent individuals attending a detoxification unit were
      assessed on a variety of psychological, social and demographic variables. Sixty
      one participants were contacted at follow-up over 1 year later. Alcohol
      consumption was assessed through self-report and corroborative information. Self
      reported levels of stress and social support were also obtained. High self
      efficacy predicted low levels of self reported drinking at follow-up. Negative
      coping predicted higher levels of drinking as reported by the corroborator. High
      levels of stress in the month prior to follow-up were related to self-reported
      poor drinking outcomes, while ongoing social support since treatment was
      associated with favorable drinking outcomes. Overall, higher levels of self
      efficacy during detoxification and social support following treatment were the
      best predictors of a favourable drinking outcome.

PMID- 10574308
TI  - Topography of sham and real puffing examined using a paced smoking regimen.
AB  - Topographical patterns of normal puffing on a cigarette may be reflected in the
      topographical patterns of sham puffing (Morris & Gale, 1994). To test further the
      possibility of measuring behavior associated with cigarette smoke self
      administration without actual smoke intake, we compared sham and real puffing
      using a paced smoking regimen under different levels of smoke deprivation.
      Cigarette smokers were instructed to draw and inhale six times on their unlit and
      then subsequently on their lit cigarette. Intensity, maximum, area and duration
      of puffs were lower for sham as opposed to real puffing; however, sham and real
      puffing showed parallel changes in response to deprivation, and significant
      positive correlations were found between the two puffing conditions for puff
      intensity, maximum and area. Therefore, we confirmed a similarity of real puffing
      with puffing under placebo conditions. Discussed was smoking as an automatic
      motor behavior.

PMID- 10574309
TI  - Association of school dropout with recent and past injecting drug use among
      African American adults.
AB  - We hypothesized that, among African American adults, starting and maintaining
      injecting drug use (IDU) would be associated with dropping out of high school,
      and that starting and stopping IDU would be associated with earning the general
      equivalency diploma (GED) after school dropout. Drawn from the 1991-1993 National
      Household Surveys on Drug Abuse (NHSDA), the nationally representative sample of
      African Americans consisted of 117 recent and 109 past IDUs. Conditional multiple
      logistic regression was used to estimate the hypothesized associations. African
      American high school dropouts and GED holders were 2-3 times more likely to have
      started and maintained IDU, as compared to high school graduates. Earning the GED
      was associated with starting and then stopping IDU. These findings merit further
      investigation because they might have significant public health implications for
      the prevention of IDU among African Americans.

PMID- 10574310
TI  - Craving patterns in methadone maintenance treatment with dextromoramide as
      adjuvant.
AB  - A study was performed to establish the effect on opiate craving among six long
      term opiate-dependent subjects in methadone maintenance treatment. Subjects
      currently stabilised on methadone, received 5 or 10 mg dextromoramide besides
      methadone. During the study the usual methadone dose was diminished according to
      the individual subject's expectation of the effect of dextromoramide addition. A
      clear drug-effect relationship between the increment of dextromoramide plasma
      concentration and decrement of opiate craving could be seen. A craving increase
      before drug administration was seen in three cases. The results could imply
      beneficial effects of a short-acting opiate on diminishing craving in opiate
      addicts who are difficult to stabilise with methadone maintenance treatment.

PMID- 10574311
TI  - Self-control in relation to problem drinking and symptoms of disordered eating.
AB  - The present study investigated problem drinking and symptoms of disordered eating
      in relation to (a) restrained drinking and eating and (b) cognitive self-control.
      One hundred ninety-eight high school students (97 males and 101 females: mean age
      = 16.45 years) completed questionnaires which assessed problem drinking, symptoms
      of disordered eating, restrained eating and drinking, and cognitive self-control.
      Using principal components analysis, three factors with eigenvalues greater than
      one were found to summarise the interrelationships among the examined measures.
      For both sexes, the first two factors primarily reflected problem drinking and
      restrained drinking, and problem eating and restrained eating, respectively. The
      third factor reflected a more general problem with control underlying aspects of
      both problem drinking and problem eating.

PMID- 10574312
TI  - Validation of cocaine and marijuana effect expectancies in a treatment setting.
AB  - This study sought to establish the validity of the Cocaine Effect Expectancy
      Questionnaire (CEEQ), and the Marijuana Effect Expectancy Questionnaire (MEEQ) in
      discriminating between patterns of drug use in a clinical population. Prior
      research with these questionnaires has involved primarily nonclinical samples.
      Expectancy literature has yielded ambiguous results in demonstrating the role of
      both positive and negative expectancies in regards to drug use patterns. The
      sample consisted of 149 males on an inpatient V.A. substance abuse unit. On the
      CEEQ, cocaine users, particularly frequent users, endorsed fewer global positive
      cocaine expectancies than infrequent or nonusers. Present-infrequent users
      endorsed greater arousal effects than either present-frequent or nonusers.
      Nonusers of cocaine endorsed greater relaxation than present users. On the MEEQ,
      nonusers expected more negative effects from marijuana than users. Present users
      expected greater relaxation and craving effects than past users or nonusers.
      These results indicate different roles for positive and negative expectancies in
      cocaine and marijuana use.

PMID- 10574313
TI  - HIV risk behavior among alcoholic inpatients before and after treatment.
AB  - In order to evaluate the natural history of HIV risk behavior among alcoholics
      during pretreatment active alcoholism, posttreatment sobriety, and posttreatment
      postrelapse periods, self-report data were collected from alcoholic inpatients at
      two times. During treatment, patients reported pretreatment behaviors. At 90 day
      follow-up, patients reported behavior during posttreatment sobriety, and if
      appropriate, during posttreatment postrelapse periods. A total of 68 patients
      participated, with 28 (41.2%) completing follow-up questionnaires. There were no
      differences on pretreatment HIV risk behaviors between completers and those lost
      to follow-up, although there were several differences on age of onset of
      alcoholism. Among the 28 completers, 9 relapsed before follow-up. Data were
      analyzed comparing pretreatment and posttreatment sobriety behaviors on all 28
      patients, and pretreatment, posttreatment sobriety, and posttreatment postrelapse
      behaviors on the 9 relapsers. Findings indicated that survivors (those who had
      not relapsed) significantly decreased HIV risk behavior during posttreatment
      sobriety. There was a relapse by time interaction such that relapsers reported
      more sex partners per day during posttreatment sobriety than did survivors. There
      was no significant change upon relapse, although this may have reflected the low
      power of this pilot study. The author concludes that HIV risk behaviors among
      alcoholics are associated with the context of active alcoholism. Relapsers
      appeared to continue in that context, with its concomitant HIV risk behavior,
      even during posttreatment sobriety.

PMID- 10574314
TI  - Relationship between substance abuse and panic attacks.
AB  - This study was done to determine the strength of association between substance
      abuse and panic states, including subsyndromal panic, its temporal relationship,
      and self-medication for panic using abusable substances. A community-based sample
      was screened for panic using DSM-III-R criteria. Panic and matched control groups
      participated in a structured interview concerning the presence of substance
      abuse, use of substances to treat panic symptoms, and the age-of-onset of panic
      and substance abuse. Of 97 individuals with panic, 39% had abused at least one
      substance. None of the panic disorder-subsyndromal panic differences reached
      significance. Only 10% of subjects reported using alcohol and 6% reported ever
      using illicit drugs to treat their panic. The majority (63%) of those abusing
      alcohol reported that alcohol use began prior to onset of panic, and the majority
      (59%) of those abusing illicit drugs reported that drug use began first. This
      study documents the panic-substance abuse relationship even in those with
      subsyndromal panic. Substance abuse began prior to onset of panic and substances
      were used to self-medicate for panic attacks by only a few subjects.

PMID- 10574315
TI  - The vision: why a national call to action.

PMID- 10574316
TI  - National call to action: Working toward the elimination of child maltreatment.
      The message.

PMID- 10574317
TI  - National call to action: Working toward the elimination of child maltreatment.
      The politics.

PMID- 10574318
TI  - National call to action: Working toward the elimination of child maltreatment.
      The science.

PMID- 10574320
TI  - National call to action: Working toward the elimination of child maltreatment.
      The practice.

PMID- 10574319
TI  - National call to action: Working toward the elimination of child maltreatment.
      The economics.
AB  - No reliable estimates exist of the overall costs to society of child maltreatment
      that will withstand serious examination. Arguably some of the most important
      human costs of maltreatment are unquantifiable. Moreover, in many cases it is
      difficult if not impossible to separate the economics of child abuse and neglect
      from the economics of a host of other problems facing families. Still, even
      conservative estimates of government spending on behalf of abused and neglected
      children and their families illustrate that child maltreatment costs society a
      great deal, with much of that expense going for deep-end intervention rather than
      family support and prevention. Government expenditures directed at this social
      problem have grown rapidly since the rediscovery of child abuse in the 1960s and
      now exceed spending for a number of essential supports for children and families.
      Moreover, the new era of continuing commitment to child protection in the context
      of a revised social contract with the nation's poor raises serious questions
      about the economics of child maltreatment in the future.

PMID- 10574321
TI  - National call to action: Working toward the elimination of child maltreatment.
      The media.

PMID- 10574322
TI  - National call to action: Working toward the elimination of child maltreatment.
      The call to action.

PMID- 10574323
TI  - The summary chapter--the national call to action: moving ahead.

PMID- 10574324
TI  - Coupling the TCR to downstream signalling pathways: the role of cytoplasmic and
      transmembrane adaptor proteins.
AB  - Engagement of the T-cell receptor (TCR) complex initiates a cascade of
      intracellular events ultimately leading to T-cell proliferation and
      differentiation. One of the first detectable consequences of TCR triggering is
      the activation of cytoplasmic protein kinases which, through phosphorylation of
      specific substrates, couple the TCR to downstream signalling cascades. Although
      it is well established that activation of the Ras- and the calcium-dependent
      calcineurin pathway is required for the achievement of T-cell activation, the
      precise mechanism as to how the TCR is connected to these intracellular effector
      molecules is still unclear. Major progress has been made in this regard with the
      molecular characterization of novel cytoplasmic and transmembrane molecules
      called adaptor proteins which integrate TCR-mediated signals at the intracellular
      level thus allowing fine tuning of T-cell responses.

PMID- 10574326
TI  - Dissociation of PTPase levels from their modulation of insulin receptor signal
      transduction.
AB  - Protein tyrosine phosphatases have been implicated in the regulation of receptor
      tyrosine kinase signalling pathways, including that of the insulin receptor.
      Here, cell density-dependent changes in PTPase expression have been exploited to
      investigate the relationship between cellular PTPase levels and the insulin
      receptor signal transduction pathway. Increasing cell density (20%, 50%, and
      >90%) in the rat McA-RH7777 hepatoma cell line resulted in increased protein
      expression of the receptor-like PTPase LAR (14-fold), and the nonreceptor PTPases
      PTP1B (11-fold) and SHP2 (10-fold). Each of these PTPases has previously been
      implicated in regulating insulin receptor signal transduction. Despite these
      marked increases, maximum insulin receptor autophosphorylation as well as
      receptor expression actually increased 2-fold. MAP kinase also increased
      approximately 2-fold as a function of cell density and paralleled increases in
      expression levels. Neither sensitivity nor maximum responsiveness to insulin were
      decreased at increasing cell densities as assessed by activation of PI 3-kinase.
      Duration of response was also unimpaired. These results suggest that expression
      levels of relevant PTPases are not the primary determinant in their modulation of
      insulin receptor kinase activity. Restricted accessibility at the molecular level
      or involvement of accessory proteins may be more critical parameters.

PMID- 10574325
TI  - Involvement of PI 3-kinase and activated ERK in facilitating insulin-stimulated
      triacylglycerol synthesis in hepatocytes.
AB  - Triacylglycerol synthesis was studied in hepatocytes isolated from fasted/refed
      rats by EDTA perfusion. Insulin induced a 1.5-fold increase in glucose
      incorporation into triacylglycerol. Insulin-stimulated triacylglycerol synthesis
      and insulin-stimulated protein kinase B/Akt activity were inhibited by the
      phosphatidylinositol 3-kinase inhibitors wortmannin and LY 294002, and the
      mitogen-activated protein kinase kinase inhibitor PD 98059. Inhibition of p70
      ribosomal protein-S6 kinase with rapamycin was without effect. Insulin-stimulated
      pyruvate dehydrogenase activity was abolished by phosphatidylinositol 3-kinase
      inhibitors. No effect of insulin on acetyl CoA carboxylase activity was observed.

PMID- 10574327
TI  - Phenylarsine oxide evokes intracellular calcium increases and amylase secretion
      in isolated rat pancreatic acinar cells.
AB  - The effects of the thiol reagent, phenylarsine oxide (PAO, 10(-5)-10(-3) M ), a
      membrane-permeable trivalent arsenical compound that specifically complexes
      vicinal sulfhydryl groups of proteins to form stable ring structures, were
      studied by monitoring intracellular free calcium concentration ([Ca2+]i) and
      amylase secretion in collagenase dispersed rat pancreatic acinar cells. PAO
      increased [Ca2+]i by mobilizing calcium from intracellular stores, since this
      increase was observed in the absence of extracellular calcium. PAO also prevented
      the CCK-8-induced signal of [Ca2+]i and inhibited the oscillatory pattern
      initiated by aluminium fluoride (AlF-4). In addition to the effects of PAO on
      calcium mobilization, it caused a significant increase in amylase secretion and
      reduced the secretory response to either CCK-8 or AlF-4. The effects of PAO on
      both [Ca2+]i and amylase release were reversed by the sulfhydryl reducing agent,
      dithiothreitol (2 mM). Pretreatment of acinar cells with high concentration of
      ryanodine (50 microM) reduced the PAO-evoked calcium release. However, PAO was
      still able to release a small fraction of Ca2+ from acinar cells in which agonist
      releasable Ca2+ pools had been previously depleted by thapsigargin (0.5 microM)
      and ryanodine receptors were blocked by 50 microM ryanodine. We conclude that, in
      pancreatic acinar cells, PAO mainly releases Ca2+ from the ryanodine-sensitive
      calcium pool and consequently induces amylase secretion. These effects are likely
      to be due to the oxidizing effects of this compound.

PMID- 10574328
TI  - Genomic organisation of the human cyclic AMP-specific phosphodiesterase PDE4C
      gene and its chromosomal localisation to 19p13.1, between RAB3A and JUND.
AB  - PDE4C is one of four mammalian genes that encode multiple PDE4 cyclic AMP
      specific phosphodiesterase isoforms that are inhibited by rolipram. Fluorescent
      in situ hybridisation localised PDE4C to the p13.1 region of human chromosome 19.
      Overlapping cosmid clones spanning the human PDE4C gene were identified and
      characterised. Analysis of this locus indicated that the PDE4C gene spans at
      least 38 kb, consists of at least 18 exons, and contains the marker D19S212
      within an intron. Comparison of published human PDE4C cDNA sequences with those
      of the genomic DNA identified four alternatively spliced exons and the
      possibility that the PDE4C locus contains at least three alternative promoters.
      PDE4C-containing cosmids also contained the genes for the growth regulatory
      transcription factor, JUND, and the mini guanine nucleotide regulatory protein,
      RAB3A. The RAB3A gene was shown to consist of 5 exons spanning 7.9 kb, while the
      JUND gene was found to contain no introns. Analysis of cosmids containing PDE4C,
      JUND, and RAB3A showed that 27 kb separate JUND and PDE4C, while only 3.7 kb
      separate PDE4C and RAB3A. The three genes share the same orientation of
      transcription and are arranged in the order cen- 5'- JUND-PDE4C-RAB3A-3'-tel.

PMID- 10574329
TI  - Homologous and heterologous phosphorylation of the vasopressin V1a receptor.
AB  - The vasopressin V1a receptor undergoes homologous and heterologous
      desensitizations which can be mimicked by activation of protein kinase C. This
      suggests that phosphorylation of the V1a receptor may be involved in the
      desensitization mechanisms. Such a phosphorylation was presently investigated in
      HEK 293 cells stably transfected with rat vasopressin V1a receptor. Metabolic
      labelling and immunoprecipitation of epitope-tagged V1a receptor evidenced a 52
      kDa band and a 92-kDa band. Glycosidase treatments and immunoblotting experiments
      suggest that the 52-kDa band corresponds to an immature unprocessed receptor
      protein, whereas the 92-kDa band would correspond to a highly glycosylated form
      of the mature V1a receptor. Exposure of the cells to vasopressin induced a
      selective 32P phosphate incorporation in the 92-kDa form of the receptor. This
      homologous ligand-induced phosphorylation was dose dependent with maximal
      phosphate incorporation corresponding to four times the basal level. Stimulation
      of the endogenous phospholipase C-coupled m3 muscarinic receptor by carbachol
      induced heterologous phosphorylation of the V1a receptor whose amplitude was half
      that of the homologous phosphorylation. This heterologous phosphorylation was
      associated with a reduced vasopressin-dependent increase in intracellular
      calcium.

PMID- 10574330
TI  - Constitutive and regulated secretion of epidermal growth factor and transforming
      growth factor-beta1 in MDA-MB-231 breast cancer cell line in 11-day cultures.
AB  - Epidermal growth factor (EGF) and transforming growth factor type beta1 (TGF
      beta1) exert opposite effects in most cells. A potential regulation between the
      two factors has been studied at a transcriptional level, but never at a protein
      level. MDA-MB-231 is a breast carcinoma cell line which possesses large
      quantities of membrane receptors and expresses high activities for both factors.
      In this study, conditioned mediums (CM) of 11-day cultures of these cells were
      collected to measure EGF and TGF-beta1 by immunochemical assays. Four types of
      cultures were tested: (1) controls; (2) after treatment with 17-beta-estradiol;
      (3) treated with EGF; and (4) treated with TGF-beta1. These cells secreted
      constitutively quantifiable concentrations of both factors to the CM. EGF
      treatment inhibited TGF-beta1 levels in CM throughout the study period (P =
      0.002), while EGF levels diminished after TGF-beta1 treatment (P = 0.05). This
      finding suggests a dual regulation between EGF and TGF-beta1, at a protein level,
      in this cell line.

PMID- 10574331
TI  - Galpha(i2)-mRNA and -protein regulation as a mechanism for heterologous
      sensitization and desensitization of insulin secretion.
AB  - Prolonged exposure of cells to an agonist of a G-protein-coupled receptor usually
      results in an attenuation of the cellular response. To elucidate the cellular
      mechanisms of sensitization or desensitization in an insulin secretory cell
      system (INS-1 cells), we investigated a regulatory link between G-protein
      alpha(s)- and alpha(i2)-subunits mRNA, their protein levels and insulin secretion
      as the biological effect using various compounds. Incubation with epinephrine (50
      microM) for 8 h decreased alpha(s)- and alpha(i2)-mRNA levels to 58% and 72%,
      respectively, which is reversed after a longer incubation. From results using
      isoprenaline and the alpha2-agonist UK 14,304 epinephrine is shown to mediate its
      actions via alpha2- but not beta-adrenoceptors. The insulin inhibitory
      neuropeptide galanin (50 nM) caused a decrease of alpha(s)- and alpha(i2)-mRNA
      levels, whereas insulinotropic compounds (incretin hormones) such as GIP or GLP-1
      (both 10 nM) led to an increase of alpha(s)- and alpha(i2)-mRNA levels. By using
      the Ca2+ channel blocker verapamil (50 microM) alpha(i2)-mRNA changes clearly
      depend on Ca2+ influx. The effects on alpha(i2)-mRNA were accompanied by a
      parallel, albeit weaker effect on the protein level (only GIP and UK 14,304 were
      investigated). The changes in alpha(i2)-mRNA levels by either compound were
      paralleled by inverse changes in insulin secretion: preincubation with UK 14,304
      for 8 h led to an increased insulin secretion when challenged by either GLP-1,
      GIP or glucose (8.3 mM). This was similar for galanin, another potent inhibitor
      of insulin release. On the other hand, exposure to the incretins GIP or GLP-1 for
      8 h induced a smaller insulin release when challenged afterwards by either UK
      14,304, galanin, GIP, GLP-1, or glucose. Thus the influence on insulin secretion
      of various compounds is reciprocal to the regulation of alpha(i2)-mRNA levels but
      not alpha(s)-mRNA levels. There is, therefore, evidence from all the manoeuvres
      used that alpha(i2)-mRNA regulation may play a role in heterologous sensitization
      and desensitization of insulin secretion.

PMID- 10574333
TI  - Ultrasound during pregnancy and birthweight, childhood malignancies and
      neurological development.
AB  - The present paper summarizes some of the epidemiological studies of in utero
      ultrasound exposure and subsequent childhood development. Emphasis is placed on
      birthweight, childhood malignancies and neurological development. A meta
      analysis, including neurological outcomes such as handedness, speech development,
      motor development, hearing and vision, is presented. The epidemiological evidence
      does not indicate any association between diagnostic ultrasound exposure during
      pregnancy and reduced birthweight, childhood malignancies or neurological
      maldevelopment. The possible association between ultrasound and
      nonrighthandedness among boys needs further evaluation.

PMID- 10574332
TI  - Interferon-alpha inhibits proliferation of Ba/F3 cells by interfering with
      interleukin-3 action.
AB  - Interferons (IFNs) are potent inhibitors of cell proliferation that are used for
      the treatment of several haematological malignancies. The mechanisms through
      which IFNs exert their antiproliferative effects on target cells, however, are
      largely unknown. Here we show that IFN-alpha, in murine Ba/F3 cells, directly
      interferes with the action of the essential mitogen interleukin (IL)-3. In
      transiently transfected Ba/F3 cells, IFN-alpha efficiently inhibited the IL-3
      stimulated expression of a luciferase reporter construct, GAS-luc, that is
      activated through the JAK2/STAT5 pathway. Electrophoretic mobility shift assays
      and Northern blot experiments, however, revealed that neither the IL-3-induced
      DNA binding of STAT5 nor the transcription of the STAT5-dependent genes
      oncostatin-M, pim-1 and c-fos were suppressed by IFN-alpha, suggesting that the
      diminished expression of the luciferase protein was due to a direct inhibition of
      IL-3-stimulated protein synthesis. This hypothesis was supported by the
      observation that IFN-alpha, even though it had no effect on the transcription of
      the c-fos gene, efficiently suppressed the IL-3-dependent expression of the c-Fos
      protein. Furthermore, our results indicate that IFN-alpha induced an
      overexpression of the double-stranded RNA-activated protein kinase (PKR), an
      enzyme that inhibits protein synthesis through the phosphorylation and
      inactivation of the eukaryotic initiation factor-2. Therefore, we hypothesize
      that IFN-alpha, in Ba/F3 cells, interrupts IL-3-dependent mitogenic signals, at
      least in part, through the suppression of protein synthesis and that induction of
      PKR activity may play a pivotal role in this process.

PMID- 10574334
TI  - Early detection of renal cell carcinoma by ultrasonographic screening--based on
      the results of 13 years screening in Japan.
AB  - Abdominal ultrasonographic (US) screening of 219,640 persons has been performed
      in the past 13 y, and 723 (0.33%) cases of malignant neoplasm were detected.
      Renal cell carcinoma (RCC) was detected in 192 cases (0.09% of the examinees). In
      almost all cases of RCC, no symptoms were evident and no abnormalities were
      detected in the blood chemistry tests or urinalyses. A total of 189 cases (98%)
      were resected curatively, and 38% of the tumors were less than 25 mm in size
      (T1). With respect to pTNM classification, 35% were pT1 and 52% were pT2. No
      metastasis to the lymph nodes or other organs was found in any case. The
      cumulative survival rate for cases resected was 97% at 5 y, and 95% at 10 y.
      Regarding US features of RCC, the internal echo pattern of half of T1 tumors
      showed homogeneous and hyperechoic, and became heterogeneous as they grew. Other
      notable US findings in cases of RCC were marginal hypoechoic zone (29%), anechoic
      component in the tumor (23%), and protrusion from the kidney (85%, 71% of the T1
      tumors). US screening is useful for detection of RCC in the early stage. However,
      to detect small tumors, it is very important to know well the US features of RCC.
      For cost-effectiveness analysis, it is more effective to examine, not only the
      kidney, but other abdominal organs. It is expected that many other abdominal
      cancers, such as hepatocellular carcinoma, gallbladder cancer, pancreatic cancer,
      and so on, could be found in the early stage by broad implementation of US
      screening.

PMID- 10574335
TI  - Transvaginal color Doppler for predicting pathological response to preoperative
      chemoradiation in locally advanced cervical carcinoma: a preliminary study.
AB  - To evaluate the role of transvaginal color Doppler ultrasonography (TCD) in
      predicting pathological response to preoperative chemoradiation in patients with
      locally advanced cervical cancer, 10 patients (mean age: 45.2 y, range: 31 to 75
      y) with histologically proven locally advanced cervical cancer who were scheduled
      for preoperative chemoradiation were evaluated by TCD prior to beginning the
      treatment protocol. Tumor volume, number of vessels within the tumor, lowest
      resistance index (RI), maximum peak systolic velocity (PSV), and the ratio
      between the number of vessels and tumor volume (tumor vascular density, TVD) were
      calculated. All patients underwent preoperative chemoradiation and radical
      surgery. Complete pathological response (pathCR) was considered when no residual
      tumor was found on surgical specimens. Partial pathological response (pathPR) was
      considered when residual tumor was found. PathCR was achieved in three patients
      (30%), whereas 7 (70%) had pathPR. Mean tumoral volume was not statistically
      different between those with pathCR (33.2 cm3) and those with pathPR (20.3 cm3)
      (p = 0.305). Those tumors with pathCR had lower mean number of vessels (3.3 vs.
      5.3, p = 0.01), lower TVD (0.1 vs. 1.1, p = 0.05) and higher RI (0.41 vs. 0.29, p
      = 0.03). No differences were found in PSV. Although these data are preliminary,
      our results suggest that TCD may be used to predict pathological response to
      preoperative chemoradiation in patients with locally advanced cervical cancer.

PMID- 10574336
TI  - Ultrasound backscatter and attenuation in human liver with diffuse disease.
AB  - Ultrasound backscatter and attenuation in the liver were measured in patients
      with diffuse liver disease and in 35 volunteers who had no history of liver
      ailments. Measurements were done using radiofrequency (RF) echo signals derived
      from a clinical scanner; a reference phantom was scanned to account for effects
      of gain, transmit-receive frequency response and transducer beam patterns on echo
      data. The mean backscatter coefficient at 3 MHz in livers of 7 patients with
      fatty infiltration was 6.8 x 10(-3) cm(-1)sr(-1) compared to a mean of 0.5 x 10(
      3) cm(-1)sr(-1) in healthy patients. Mean attenuation at 3 MHz was 2.54 dB/cm in
      fatty livers compared to 1.66 dB/cm in healthy patients. A total of 7 patients
      with end-stage liver disease (cirrhosis) had attenuation values similar to those
      in the healthy group, and their mean liver backscatter was somewhat greater than
      the mean backscatter for healthy livers. Quantitating both backscatter and
      attenuation should be considered for detecting fatty infiltration; additional
      processing methods are needed to differentiate cirrhotic changes on the basis of
      acoustic signals.

PMID- 10574337
TI  - Signal from hepatic hemangiomas on power Doppler US: real or artefactual?
AB  - To describe imaging findings of hepatic hemangiomas on power Doppler (PD)
      ultrasound (US) with revised Doppler parameters for preventing PD artefacts from
      stationary hyperechoic tissue, we prospectively evaluated 48 hemangiomas by PD US
      with predetermined PD settings to prevent artefactual signals from stationary
      hyperechoic tissue (pulse repetition frequency of 1000 Hz, medium wall filter,
      and PD gain of 60-85%). Intratumoral PD signals were not seen in 32 lesions
      (67%). Minimal (n = 15) or moderate (n = 1) intratumoral PD signals were seen in
      16 lesions (33%) and were distributed in the peripheral portion only in 12
      lesions (75%) and in the peripheral and central portion in 4 lesions (25%). Due
      to the lack of sensitivity of PD to detect slow flow in hemangiomas, PD US should
      no longer be used for the evaluation of echogenic liver masses caused by
      hemangiomas from other hypovascular malignant lesions of the liver.

PMID- 10574338
TI  - Effect of echo contrast media on the visualization of transverse sinus thrombosis
      with transcranial 3-D duplex sonography.
AB  - Transcranial duplex sonography has the capacity of detecting venous flow as in
      the transverse sinus. During a 6-month period, 28 consecutive patients (mean age
      55 y) with a clinically suspected diagnosis of cerebral sinus thrombosis were
      included in the study. All patients were examined using 3-D ultrasound equipment
      within 24 h of having undergone either venous computerized tomography (CT),
      venous magnetic resonance imaging (MRI) or cerebral angiography. A total of 22
      healthy patients had a normal venous CT, venous MRI or cerebral angiography of
      both transverse sinuses. Before echo contrast enhancement, the transverse sinus
      could be visualized in only 2 of these 44 sinuses (22 patients). A total of 6
      patients with an unilaterally missed transverse sinus in 3-D ultrasound suffered
      from sinus thrombosis (n = 3), hypoplasia (n = 2) or aplasia (n = 1) of the
      unilateral transverse sinus in neuroradiological tests. In none of the patients
      with an thrombosis of the transverse sinus did ultrasound contrast media
      application improve the visualization of the affected sinus. Our study confirms
      that the normal transverse sinus, insonated through the contralateral temporal
      bone, often cannot be visualized without the use of contrast agents. With
      transcranial 3-D duplex sonography, a differentiation between thrombosis,
      hypoplasia and aplasia of the sinus was not possible.

PMID- 10574339
TI  - Artificial neural networks and spatial temporal contour linking for automated
      endocardial contour detection on echocardiograms: a novel approach to determine
      left ventricular contractile function.
AB  - This study investigated the use of artificial neural networks (ANN) for image
      segmentation and spatial temporal contour linking for the detection of
      endocardial contours on echocardiographic images. Using a backpropagation
      network, the system was trained with 279 sample regions obtained from eight
      training images to segment images into either tissue or blood pool region. The
      ANN system was then applied to parasternal short axis images of 38 patients.
      Spatial temporal contour linking was performed on the segmented images to extract
      endocardial boarders. Left ventricular areas (end-systolic and end-diastolic)
      determined with the automated system were calculated and compared to results
      obtained by manual contour tracing performed by two independent investigators. In
      addition, ejection fractions (EF) were derived using the area-length method and
      compared with radionuclide ventriculography. Image quality was classified as good
      in 12 (32%), moderate in 13 (34%) and poor in 13 (34%) patients. The ANN system
      provided estimates of end-diastolic and end-systolic areas in 36 (89%) of
      echocardiograms, which correlated well with those obtained by manual tracing (R =
      0.99, SEE = 1.44). A good agreement was also found for the comparison of EF
      between the ANN system and Tc-radionuclide ventriculography (RNV, R = 0.93, SEE =
      6.36). The ANN system also performed well in the subset of patients with poor
      image quality. Endocardial contour detection using artificial neural networks and
      spatial temporal contour linking allows accurate calculations of ventricular
      areas from transthoracic echocardiograms and performs well even in images with
      poor quality. This system could greatly enhance the feasibility, accuracy and
      reproducibility of calculating cardiac areas to derive left ventricular volumes
      and ejection fractions.

PMID- 10574340
TI  - Intracardiac echocardiography (9 MHz) in humans: methods, imaging views and
      clinical utility.
AB  - A new low-frequency (9 MHz, 9 Fr) catheter-based ultrasound (US) transducer has
      been designed that allows greater depth of cardiac imaging. To demonstrate the
      imaging capability and clinical utility, intracardiac echocardiography (ICE)
      using this lower frequency catheter was performed in 56 patients undergoing
      invasive electrophysiological procedures. Cardiac imaging and monitoring were
      performed with the catheter transducer placed in the superior vena cava (SVC),
      right atrium (RA) and/or right ventricle (RV). In all patients, ICE identified
      distinct endocardial structures with excellent resolution and detail, including
      the crista terminalis, RA appendage, caval and coronary sinus orifices, fossa
      ovalis, pulmonary vein orifices, ascending aorta and its root, pulmonary artery,
      RV and all cardiac valves. The left atrium and ventricle were imaged with the
      transducer at the limbus fossa ovalis of the interatrial septum and in the RV,
      respectively. ICE was important in identifying known or unanticipated aberrant
      anatomy in 11 patients (variant Eustachian valve, atrial septal aneurysm and
      defect, lipomatous hypertrophy, Ebstein's anomaly, ventricular septal defect,
      tetralogy of Fallot, transposition of the great arteries, disrupted chordae
      tendinae and pericardial effusion) or in detecting procedure-related
      abnormalities (narrowing of SVC-RA junction orifice or pulmonary venous lumen,
      atrial thrombus, interatrial communication). In patients with inappropriate sinus
      tachycardia, ICE was the primary ablation catheter-guidance technique for sinus
      node modification. With ICE monitoring, the evolution of lesion morphology with
      the three imaging features including swelling, dimpling and crater formation was
      observed. In all patients, ICE was contributory to the mapping and ablation
      process by guiding catheters to anatomically distinct sites and/or assessing
      stability of the electrode-endocardial contact. ICE was also used to successfully
      guide atrial septal puncture (n = 9) or RA basket catheter placement (n = 4).
      Thus, ICE with a new 9-MHz catheter-based transducer has better imaging
      capability with a greater depth. Normal and abnormal cardiac anatomy can be
      readily identified. ICE proved useful during electrophysiological mapping and
      ablation procedures for guiding interatrial septal puncture, assessing placement
      and contact of mapping and ablation catheters, monitoring ablation lesion
      morphological changes, and instantly diagnosing cardiac complications.

PMID- 10574341
TI  - In vivo demonstration of noninvasive thermal surgery of the liver and kidney
      using an ultrasonic phased array.
AB  - A 256-element, continuous-wave ultrasonic phased array has been used to thermally
      coagulate deep-seated liver and kidney tissue. The array elements were formed on
      a 1-3 piezocomposite bowl with a 10-cm radius of curvature and 12-cm diameter.
      The 0.65 x 0.65 cm2 projection elements were driven at 1.1 MHz by a custom-built
      amplifier system. A series of in vivo porcine experiments demonstrated the
      ability to coagulate liver and kidney tissue using the large-scale phased array.
      The temperature response of the treatment was guided and monitored using magnetic
      resonance (MR) images. Focal lesion volumes greater than 0.5 cm3 in kidney and 2
      cm3 in liver were formed from a single 20-s sonication.

PMID- 10574342
TI  - Elastographic characterization of HIFU-induced lesions in canine livers.
AB  - The elastographic visualization and evaluation of high-intensity focused
      ultrasound (HIFU)-induced lesions were investigated. The lesions were induced in
      vitro in freshly excised canine livers. The use of different treatment intensity
      levels and exposure times resulted in lesions of different sizes. Each lesion was
      clearly depicted by the corresponding elastogram as being an area harder than the
      background. The strain contrast of the lesion/background was found to be
      dependent on the level of energy deposition. A lesion/background strain contrast
      between -2.5 dB and -3.5 dB was found to completely define the entire zone of
      tissue damage. The area of tissue damage was automatically estimated from the
      elastograms by evaluating the number of pixels enclosed inside the isointensity
      contour lines corresponding to a strain contrast of -2.5, -3 and -3.5 dB. The
      area of the lesion was measured from a tissue photograph obtained at
      approximately the same plane where elastographic data were collected. The
      estimated lesion areas ranged between approximately 10 mm2 and 110 mm2. A high
      correlation between the damaged areas as depicted by the elastograms and the
      corresponding areas as measured from the gross pathology photographs was found
      (r2 = 0.93, p value < 0.0004, n = 16). This statistically significant high
      correlation demonstrates that elastography has the potential to become a reliable
      and accurate modality for HIFU therapy monitoring.

PMID- 10574343
TI  - Power spectral strain estimators in elastography.
AB  - Elastography can produce quality strain images in vitro and in vivo. Standard
      elastography uses a coherent cross-correlation technique to estimate tissue
      displacement and tissue strain using a subsequent gradient operator. Although
      coherent estimation methods generally have the advantage of being highly accurate
      and precise, even relatively small undesired motions are likely to cause enough
      signal decorrelation to produce significant degradation of the elastogram. For
      elastography to become more universally practical in such applications as hand
      held, intravascular and abdominal imaging, the limitations associated with
      coherent strain estimation methods that require tissue and system stability, must
      be overcome. In this paper, we propose the use of a spectral-shift method that
      uses a centroid shift estimate to measure local strain directly. Furthermore, we
      also show theoretically that a spectral bandwidth method can also provide a
      direct strain estimation. We demonstrate that strain estimation using the
      spectral-shift technique is moderately less precise, but far more robust than the
      cross-correlation method. A theoretical analysis, simulations and experimental
      results are used to illustrate the properties associated with this method.

PMID- 10574344
TI  - Voltage sensitivity response of ultrasonic hydrophones in the frequency range
      0.25-2.5 MHz.
AB  - Frequency responses of different PVDF polymer hydrophones, including membrane and
      needle designs, were measured and are presented in terms of end-of-cable voltage
      sensitivity vs. frequency over a wide, 4.5-octave bandwidth ranging from 0.25-2.5
      MHz. The experimental data indicate that the membrane PVDF hydrophones can
      exhibit uniform, to within +/- 0.75 dB, responses. However, a widely used
      bilaminar membrane hydrophone-preamplifier combination may display sensitivity
      variations of +/- 2 dB. Also, even well-designed needle-type hydrophones show a
      more distinct sensitivity variation below 1 MHz that is on the order of 3-4 dB.
      The overall uncertainty of the calibration technique was estimated to be better
      than +/- 2 dB in the frequency range considered. The technique, which uses a
      combination of swept frequency chirp and reciprocity so that both the relative
      and absolute plots of sensitivity vs. frequency can be obtained, is also briefly
      described. The results of this work are important to implement procedures for
      adequate determination of the mechanical index of ultrasound (US) imaging
      devices. Mechanical index is widely accepted as a predictor of potential
      bioeffects associated with cavitation phenomena. Also, absolute calibration data
      are essential in development of therapeutic procedures based on the use of high
      intensity focused ultrasound (HIFU), and in characterization of conventional
      therapeutic US applicators operating at frequencies below 1 MHz.

PMID- 10574345
TI  - Hemorrhage in murine fetuses exposed to pulsed ultrasound.
AB  - In the late-gestation fetal mouse, exposure to piezoelectric lithotripter fields
      at amplitudes < 1 MPa produced hemorrhages in tissues near developing bone, such
      as the head and limbs. This study was undertaken to determine if exposure to
      pulsed ultrasound at diagnostic frequencies produces similar hemorrhages in the
      late-gestation fetal mouse. On the 18th day of gestation, fetal mice were exposed
      in utero to pulsed ultrasound with a 10-micros pulse duration and 100-Hz pulse
      repetition frequency for a total exposure duration of 3 min. Hemorrhages occurred
      most often to the developing fetal head. At 1.2 MHz, a threshold for hemorrhage
      to the fetal head was determined at positive exposure pressures of approximately
      4 MPa and corresponding negative pressures of approximately 2.5 MPa. The
      threshold increased with at least the first power of frequency.

PMID- 10574346
TI  - Heating vs. cavitation in the induction of mouse hindlimb paralysis by
      ultrasound.
AB  - Grip strength tests were performed on hairless mice before and after various
      ultrasound exposures in a temperature-controlled water bath at 37 degrees C.
      Lithotripter exposure of 800 shock waves produced no effect on hindlimb function.
      In contrast, 1.09-MHz exposures at 1 MPa with 10:100 ms burst mode did produce a
      statistically significant reduction in grip strength of about 60%. The exposure
      duration was important for the 1.0-MPa burst mode exposure, with grip-strength
      reductions appearing after 150 s or longer exposures. Continuous exposure at 3.3
      W cm(-2) (0.32 MPa peak) for 200 s produced the same effect as burst mode
      exposure at 3.3 W cm(-2) (1 MPa peak) for 200 s, which implicates the temporal
      average intensity as an important factor. The temperature elevations for 1-MPa
      burst mode was estimated from thermocouple measurements in the spine to be 12
      degrees C after 200-s exposure. Although tests of exposures in cool (32 degrees
      C) and warm (42 degrees C) baths produced inconclusive results in regard to the
      thermal mechanism, the effects observed appear to result from ultrasonic heating
      (rather than from cavitation). Thus, any potentially harmful consequences
      associated with the effects examined might be related more, for example, to
      ultrasonic hyperthermia therapy than to shock-wave lithotripsy.

PMID- 10574347
TI  - Ultrasonic backscattering from porcine whole blood of varying hematocrit and
      shear rate under pulsatile flow.
AB  - It was shown previously that ultrasonic scattering from whole blood varies during
      a flow cycle under pulsatile flow both in vitro and in vivo. It has been
      postulated that this cyclic variation may be associated with the dynamics of red
      cell aggregation because the shearing force acting on the red cell aggregates
      across the lumen is a function of time during a flow cycle. In all studies, the
      local shear rate variation as a function of time is unknown. The effect of shear
      rate on the red cell aggregation and, thus, on ultrasonic scattering from blood
      can only be merely speculated. One solution to this problem is to estimate the
      shear rate in a flow conduit by finite element analysis (FEA). An FEA
      computational fluid dynamics (CFD) tool was used to calculate local shear rate in
      a series of experiments in which ultrasonic backscattering from porcine whole
      blood under pulsatile flow was measured as a function of hematocrit and shear
      rate intravascularly with a 10-MHz catheter-mounted transducer in a mock flow
      loop. The results show that, at 20 beats per min (BPM), the magnitudes of the
      cyclic variation for hematocrits at 30, 40, and 50% were approximately 4 dB.
      However, at 60 BPM, the magnitude of cyclic variation was found to be minimal.
      The results also confirm previous findings that the amplitude and the timing of
      the peak of ultrasonic backscattering from porcine whole blood under pulsatile
      flow during a flow cycle are dependent upon the shear rate and hematocrit in a
      complicated way.

PMID- 10574348
TI  - Caspase activation during apoptotic cell death induced by expanded polyglutamine
      in N2a cells.
AB  - Huntington disease (HD) is an autosomal dominant neurodegenerative disorder. To
      investigate the mechanism of neurodegeneration induced by mutant huntingtin, we
      developed a stable neuro2a cell line expressing truncated N-terminal huntingtin
      (tNhtt) with EGFP using the ecdysone-inducible system. The formation of
      aggregates and the cell death induced by expression of tNhtt with expanded
      polyglutamine was repeat length- and dose-dependent. Caspases were activated, and
      the death substrates of caspases, lamin B and ICAD (an inhibitor of caspase
      activated DNase), were cleaved in this cell death process. The cleavage of lamin
      B was inhibited by caspase inhibitors. These findings suggest that the cell death
      induced by tNhtt with expanded polyglutamine is mediated by caspases.

PMID- 10574349
TI  - Traumatic injury in vitro induces IEG mRNAs in cultured glial cells, suppressed
      by co-culture with neurons.
AB  - Glial changes following traumatic injury to glial monolayers as well as to
      neuronal-glial co-culture systems in vitro were examined with a focus on the
      expression of mRNAs coding for the immediate early genes (IEG) c-fos, c-jun and
      zif/268, demonstrated using in situ hybridization. Glial cells along scratch
      wound lines extended cytoplasmic processes as early as 10 min post-injury and the
      whole wound was covered with gliosis by 24 h. For complete restoration in the
      case of glial cells co-cultured with neurons, this required 48 h. Induction of
      the three IEG mRNAs was eminent along the edges of scratch wound, peaking at 30
      60 min post-injury and subsiding by 3 h. The peak expression of IEG mRNAs was
      delayed to 1-3 h post-injury and became undetectable at 6 h in neuronal-glial co
      cultures. The data suggest that mechanical injury to glial cells causes gliosis
      and the expression of IEG mRNAs, which are suppressed by co-culture with neurons,
      indicating some influence of neuronal-glial interactions.

PMID- 10574350
TI  - Left-hemisphere processing of emotional connotation during word generation.
AB  - Areas of the brain's left hemisphere involved in retrieving words with emotional
      connotations were studied with fMRI. Participants silently generated words from
      different semantic categories which evoked either words with emotional
      connotations or emotionally neutral words. Participants repeated emotionally
      neutral words as a control task. Compared with generation of emotionally neutral
      words, generation of words with emotional connotations engaged cortices near the
      left frontal and temporal poles which are connected to the limbic system. Thus,
      emotional connotations of words are processed in or near cortices with access to
      emotional experience.

PMID- 10574351
TI  - Pre-movement gating of short-latency somatosensory evoked potentials.
AB  - Somatosensory evoked potentials (SEPs) are reduced in amplitude during movement
      (gating). The mechanism involves central gating of afferent input and competition
      from other afferents activated by the movement. We distinguished these two by
      giving 11 normal subjects a warning sound followed 1 s later by an electric
      stimulus to the right median nerve at the wrist. The latter served both as a cue
      to start a finger movement and as stimulation to evoke SEPs. Gating effects were
      widespread in frontal (N30) and central (N60) areas, but were also seen, albeit
      to a lesser extent, in the recordings at P3 (P30). Since finger movement began
      after the stimulus, such gating must have been purely central in origin,
      presumably reflecting motor preparation.

PMID- 10574352
TI  - Pathological perceptual completion in hemianopia extends to the control of reach
      to-grasp movements.
AB  - The neuropsychological phenomenon of blindsight is observed when patients who are
      cortically blind exhibit residual visual processing capabilities for stimuli
      presented within their scotoma to which they are otherwise unaware. Cortically
      blind patients may also exhibit the phenomenon of pathological visual completion
      in which, paradoxically, they can become aware of a complete visual stimulus even
      when a significant portion of that stimulus falls within their blind hemifield.
      In this study, the ability of a blindsight patient (G.Y.) to use visual
      information to control reach-to-grasp movements to static objects presented
      within his blind hemifield was investigated. The results indicate that while G.Y.
      was insensitive to variations in object size when reaching for objects presented
      entirely within his blind hemifield, his ability to accurately grasp objects
      located within his blind field was vastly improved if part of the object to be
      grasped extended into his seeing hemifield. This finding demonstrates that visual
      awareness can facilitate the visuomotor processing of object form within G.Y.'s
      apparently blind field, and suggests that the primary deficit in blindsight may
      be an impairment of visual consciousness rather than an absolute loss of visual
      function.

PMID- 10574353
TI  - Global and local processing of musical sequences: an event-related brain
      potential study.
AB  - Musical processing can be decomposed into the appreciation of global/holistic and
      local elements. Here, we investigated the pattern of neural activity associated
      with the processing of contour-violated (CV) and contour-preserved (CP) melodies.
      The CV and CP musical sequences were obtained by altering the pitch value of one
      note within the musical phrase, while keeping both the scale and the key
      constant. In the unadulterated melody, there was a sustained negativity that was
      larger over the right than left fronto-central regions. Participants were equally
      accurate in detecting CV and CP trials, but were slower in detecting CP than CV
      trials. Globally altered melodies (i.e. CV) generated an early, negative waveform
      (N2) and a P3b deflection, whereas the CP target only generated a P3b wave. This
      suggests that global precedence may occur at an early perceptual stage and argues
      in favor of fractionating musical processing into global and local components.

PMID- 10574354
TI  - The head midline as a reliable reference frame for encoding head-on-body
      orientation.
AB  - Twelve right-handed male subjects were asked to use each hand to point accurately
      toward the center of their forehead, determining the correct position according
      to their mental representation, while the head was either aligned with the trunk
      or tilted 30 degrees to the right or left. Analysis of end-positions of pointing
      revealed that the right hand exhibited a slight leftward bias with respect to the
      putative head midline passing through the center of the glabella and the center
      of the fissure between the two upper central incisors, regardless of the head-on
      body orientation, whereas the left hand proved very accurate when the head was
      aligned with the trunk but, when the head was tilted either way, it deviated to
      the opposite side. These results lead to the conclusion that the head midline
      appears to act as a reliable reference frame for encoding head-on-body
      orientation when pointing is carried out by the dominant hand.

PMID- 10574355
TI  - Asymmetry in visual motion processing.
AB  - The smooth pursuit system is traditionally employed using a single small target
      moving on a homogeneous background. It still is not fully understood, however,
      how accurate tracking is sustained in the presence of a structured background,
      which will activate global motion processing in the opposite direction as a
      consequence of the ongoing eye movement. To further study this interaction, we
      used brief shifts of a textured background injected at various times during the
      initiation of smooth pursuit. While shifts opposite to the target direction did
      not alter smooth pursuit performance, those in the same direction resulted in a
      marked transient perturbation of the pursuit. These results suggest a simple yet
      limited mechanism that adjusts the sensitivity of global motion processing.

PMID- 10574356
TI  - A hemispherically asymmetrical MEG response to vowels.
AB  - Neuromagnetic fields elicited by vowels and tones were recorded and sources were
      modeled as single equivalent current dipoles (ECDs) in 1 ms steps 80-400 ms post
      stimulus. To vowels, the left hemisphere (LH) auditory cortex had nearly twice as
      many satisfactory ECD fits as the right hemisphere (RH). Tones did not evoke such
      asymmetry. In particular, in the late field (150-400 ms) the LH had more than
      twice as many ECDs as the RH, and the spatial distribution of LH sources was more
      clustered than in the RH. An asymmetrical, focal cortical mechanism for vowel
      processing was identified that intensified in later auditory processing stages.
      These data suggest that MEG might be used for non-invasive, language laterality
      determination with simple vowel-like stimuli.

PMID- 10574357
TI  - Sex differences in the vocal motor pathway of the zebra finch revealed by real
      time optical imaging technique.
AB  - Male zebra finches sing, whereas female zebra finches do not. To elucidate the
      neural mechanisms underlying sexual dimorphism in song behavior, the spatio
      temporal properties of neural activity in the vocal motor pathway of the zebra
      finch were examined in sliced brain preparations using a real-time optical
      recording technique. Electrical stimulation to higher vocal center (HVC) fibers
      induced within 20 ms neural activities in the robust nucleus of the archistriatum
      (RA) of both male and female finches, although the amplitude was smaller and the
      latency was greater in females than in males. Bicuculline, a GABA(A) receptor
      antagonist, induced a robust activity in female RA, but had little effect in
      males. This suggests that neural connections from HVC to RA in female zebra
      finches are inhibited by GABAergic inputs. The results provide first evidence
      that an inhibitory neurotransmitter is involved in the sex difference in the
      motor vocal pathway of song birds.

PMID- 10574358
TI  - Age-related changes in regional cerebral blood flow among young to mid-life
      adults.
AB  - Using PET with [(15)O]H2O, we examined age in relation to regional cerebral blood
      flow (rCBF) among young to mid-life adults. Previous work has largely contrasted
      rCBF between young and elderly age groups dichotomously. This study maps the
      continuum of normal age-related changes in rCBF from early to mid-adulthood. We
      obtained images from 37 healthy volunteers between 19 and 50 years of age during
      an eyes-closed resting baseline condition. There was a negative correlation
      between age and rCBF in mesial frontal cortex, involving the anterior cingulate
      region (r = 0.63, p<0.001). These findings reflect differences in the
      distribution of rCBF evident in early to mid-adulthood that may be associated
      with subsequent changes in memory and executive functioning in later life.

PMID- 10574359
TI  - Involvement of alpha6 nicotinic receptor subunit in nicotine-elicited locomotion,
      demonstrated by in vivo antisense oligonucleotide infusion.
AB  - Enhanced locomotion in a habituated environment is a well documented effect of
      nicotine mediated by the mesotelencephalic dopaminergic system. The nicotinic
      receptor subunit alpha6 is, among other subunits, strongly expressed in the
      dopaminergic neurons of the mesencephalon. To examine the functional role of this
      subunit, we inhibited its expression in vivo using antisense oligonucleotides. In
      vitro treatments of embryonic mesencephalic neuron cultures demonstrated that the
      alpha6 antisense oligonucleotides caused a marked decrease in the level of alpha6
      subunit protein. In vivo, 1 week infusion of alpha6 antisense oligonucleotides by
      osmotic mini-pump reduced the effect of nicotine on locomotor activity in
      habituated environment by 70%. These data support the notion that the effects of
      nicotine on the dopaminergic system involve alpha6 subunit containing nAChRs.

PMID- 10574360
TI  - Macrocurrents of voltage gated Na+ and K+ channels from the crayfish stretch
      receptor neuronal soma.
AB  - Currents from the slowly adapting stretch receptor neuron of the crayfish
      (Pacifastacus leniusculus) were studied in a cell attached configuration using
      patch pipettes with an opening diameter of 2-10 microm. The neuronal membrane was
      enzymatically freed from the glial layer. The voltage gated Na+ and K+ channels
      seemed to be more concentrated in the lower part of soma close to the axon
      hillock. The Na+ and K+ currents could be analysed by fitting the currents to a
      fourth-order exponential function for Na+ current and a second-order exponential
      function for the K+ current. The macropatch recordings of enzymatically treated
      neurons are superior to two electrode voltage clamp recordings when analyzing
      voltage gated Na+ and K+ currents.

PMID- 10574361
TI  - Occurrence of dentate granule cell LTP without proximal dendritic Ca2+ increase.
AB  - We investigated activity-dependent calcium increases in proximal dendrites of
      dentate granule cells in the rat hippocampus, and its relationship with induction
      of LTP at perforant path synapses (PP-synapses). LTP was induced at PP-synapses
      by high-frequency stimulation (HFS; 100 Hz for 0.4 s), and the same HFS evoked a
      dendritic calcium increase in the proximal dendrite. However, bath-application of
      the L-type voltage-dependent calcium channel (VDCC) blocker nimodipine noticeably
      reduced this calcium increase without abolishing induction of LTP. This calcium
      increase mediated by high-threshold VDCCs is likely to be evoked by action
      potentials. LTP induction at PP-synapses is hence suggested to be independent of
      action potential-induced calcium increases in the proximal dendrite.

PMID- 10574362
TI  - Geometrical and topological relationships between multiple functional maps in cat
      primary visual cortex.
AB  - The mammalian striate cortex is organized such that the receptive field
      properties of neighboring neurons change gradually across the cortical surface,
      forming so-called cortical maps. The presence of such maps has been demonstrated
      in different species of mammals for several parameters characterizing the visual
      space: retinotopy, ocular dominance, orientation, direction of motion and spatial
      frequency. In this study we used the optical imaging of intrinsic signals to
      simultaneously record the multiple functional maps in the same animal in order to
      obtain a comprehensive set of rules that govern mutual dependencies among the
      functional maps. Our results indicate that while orientation, direction and
      ocular dominance are represented on the cortex in a mutually dependent manner,
      the representation of spatial frequency is independent of the other types of
      cortical representations. The presence and/or absence of mutual dependence among
      the multiple functional maps are suggested to provide an important clue for the
      understanding of the development of visual cortical information representation in
      neonatal animals.

PMID- 10574363
TI  - Spatiotemporal modulation of attention during smooth pursuit eye movements.
AB  - The present investigation examined how attention is distributed across both space
      and time during smooth pursuit eye movements. This was accomplished by measuring
      manual button pressing latencies to the sudden appearance of a peripheral target
      during the onset, maintenance, or offset of the pursuit response to a step-ramp
      target motion. The results showed that manual response latencies were shorter for
      stimuli flashed ahead of the pursuit target than for those presented in its wake.
      In addition, the latencies to the peripheral target appearance were shorter
      overall during pursuit maintenance compared to pursuit onset or offset. Taken
      together, these results indicate that attention is significantly modulated both
      in space and time during smooth pursuit eye movements.

PMID- 10574364
TI  - The role of beta-catenin stability in mutant PS1-associated apoptosis.
AB  - Most early onset cases of familial Alzheimer's disease (FAD) are caused by
      mutations in presenilin-1 (PS1) and presenilin-2 (PS2). These mutations lead to
      increased beta-amyloid formation and induce apoptosis when expressed in vitro.
      Recently, PS1 has been reported to associate with beta-catenin, an armadillo
      repeat protein. PS1 may regulate the function of beta-catenin, and mutant PS1 may
      disrupt this regulation. In the present study, we confirm that PS1-WT, as well as
      mutant PS1, associates with beta-catenin, and that mutant PS1 expression
      decreases the stability and/or enhances the degradation of beta-catenin. Most
      importantly, we correlate beta-catenin's destabilization with mutant PS1
      associated apoptosis by administering drugs that alter the stability of beta
      catenin. The application of LiCl and a proteasome inhibitor, N-acetyl-leu-leu
      norleucinal (ALLN), increased the stability of cytosolic beta-catenin in mutant
      PS1-expressing cells leading to rescue of these cells from apoptosis. These
      studies suggest that beta-catenin is a key mediator of mutant PS1-associated
      apoptosis and FAD pathogenesis.

PMID- 10574365
TI  - Disruption of prepulse inhibition following N-methyl-D-aspartate infusion into
      the ventral hippocampus is antagonized by clozapine but not by haloperidol: a
      possible model for the screening of atypical antipsychotics.
AB  - The present study tested the effects of the typical neuroleptic haloperidol and
      an atypical neuroleptic clozapine on ventral hippocampus stimulation-induced
      disruption of prepulse inhibition (PPI). Bilateral infusions of 0.7 microg NMDA
      into the ventral hippocampus disrupted PPI. The impairment of PPI following the
      infusion was completely normalized 24 h after the infusion. This disruption of
      PPI was antagonized by clozapine (5.0 mg/kg), but not by haloperidol (0.2 mg/kg).
      Since disruption of PPI is considered to constitute an animal model of
      schizophrenia that is related to the deficit of sensorimotor gating observed in
      schizophrenic patients, these results suggest that PPI disruption induced by
      intra-ventral hippocampal infusions of NMDA may serve as an animal model for the
      selective detection of atypical antipsychotics.

PMID- 10574366
TI  - Calcium-containing endosomes at oculomotor terminals in animal models of ALS.
AB  - Altered calcium homeostasis has been demonstrated in human spinal cord motor axon
      terminals of ALS patients, in spinal motor neurons of mutant SOD transgenic mice
      and following injection of ALS immunoglobulins. In all three paradigms oculomotor
      neurons are relatively spared. To explore mechanisms of selective resistance, we
      applied similar calcium localization techniques to terminals of oculomotor
      neurons in the two animal models. In both cases large vacuoles, which connect
      with the extracellular space, accumulated the majority of intracellular calcium,
      while terminals of vulnerable neurons (e.g. innervating interosseus muscle),
      which possess no such vacuoles, displayed evenly distributed calcium. These
      relatively unique membrane enveloped structures may permit neurons to control
      their cytoplasmic Ca2+ concentration and contribute to selective resistance.

PMID- 10574367
TI  - Finger kinaesthesia: cognitive electrogeneses to attended joint input.
AB  - Study of brain mechanisms subserving perception of passive finger movements
      revealed an unexpected contrast between cutaneous and deep inputs from fingers.
      Selective attention to tactile inputs from finger tips did not change the first
      response of primary area 3b, but elicited a cognitive P40 in second order
      postcentral cortex. For finger joint inputs, attention enhanced the very first
      cortical response elicited by thalamo-cortical input in postcentral area 2
      whereby finger kinaesthesia information was integrated with the cutaneous
      features information received from primary somatic areas via corticocortical
      connections. Cognitive electrogeneses P40, P100, N140 and P300 manifested serial
      sensory features processing and prefrontal working memory matching whereby
      manipulated objects can be identified from their shape and texture in active
      touch.

PMID- 10574368
TI  - Neonatal footshock stress alters adult behavior and hippocampal corticosteroid
      receptors.
AB  - To determine the effects of stress early in life on adult behavior and
      hippocampal corticosteroid receptors, rats were exposed to footshocks (0.8 mA, 60
      times/day, randomly apart) on postnatal days 14, 17 and 20. When they reached 6
      months of age, neurobehavioral alterations were measured. The footshock
      experienced rats learned more rapidly in the autoshaped learning test than
      similarly handled controls. They also stabilized more quickly after exposure to a
      novel environment than the handled controls, but only at the same rate as animals
      which had not been handled except for weighing. The density of [3H]dexamethasone
      binding sites increased and that of [3H]corticosterone binding sites decreased in
      the hippocampi of these rats. These results indicate that early life stress
      results in altered behavior and hippocampal corticosteroid receptors at
      adulthood, and suggest that the mineralocorticoid and the glucocorticoid
      receptors are differentially regulated by early life stress.

PMID- 10574369
TI  - High titre anti-sulphatide antibodies in HIV-infected individuals.
AB  - Plasma samples from 35 individuals with human immunodeficiency virus (HIV)
      infection but without peripheral neuropathy were screened by enzyme linked
      immunosorbent assay (ELISA) for IgM and IgG antibodies against sulphatide (GalS).
      Five of these were shown to contain raised anti-GalS IgM antibody titres, while
      six had raised IgG titres. All plasma samples screened were compared to an
      internal neurological disease control which contained raised anti-GalS IgM
      antibody titres. Anti-GalS IgM antibody titres in the HIV cohort ranged between
      200 and 2000 arbitrary units/litre (AU/l), whereas, IgG titres were between 200
      and 10,000 AU/l. Two of four plasma samples from HIV-infected individuals with
      neuropathy (HIV+PN) also showed IgM reactivity with GalS; one also binding to the
      gangliosides GM1, GD1a, GD1b and GT1b. The other two samples showed IgG
      reactivity against GalS. These data indicate that antibodies against GalS occur
      more frequently in HIV infection than in HIV-seronegative individuals with and
      without neurological disease and may participate in the pathogenesis of
      neuropathies associated with HIV infection.

PMID- 10574370
TI  - Inhibition of DNA synthesis in human gliomas by roscovitine.
AB  - The early effect of 1-100 microM roscovitine, a purine analogue and cyclin
      dependent kinase inhibitor, was studied on tissue specimens from eight human
      malignant gliomas. The tissue was incubated immediately after resection with DMEM
      containing [3H]methylthymidine plus vehicle alone or the proper concentration of
      roscovitine for 30-90 min. The DNA synthesis rate was assessed by measurement of
      [3H]methylthymidine incorporation into trichloroacetic acid insoluble material/mg
      protein/min. In all gliomas, 100 microM roscovitine inhibited DNA synthesis by 71
      97% (average 89 +/- 8%, p<0.0001). This inhibitory effect of roscovitine appeared
      within 30 min of incubation and was concentration dependent.

PMID- 10574371
TI  - Additive effect of NOS inhibitor and neurotrophic factors on the survival of
      injured Clarke's neurons.
AB  - The present study examined the effect of treatment with the NOS inhibitor N(G)
      nitro-L-arginine methyl ester (L-NAME) together with peripheral nerve (PN) graft
      or brain-derived neurotrophic factor (BDNF) on the survival of CN neurons at the
      L1 level of the spinal cord following hemisection at T11. In control animals 41%
      of CN neurons survived 15 days after the hemisection, and 48% of these expressed
      NOS. Treatment with either PN graft implantation or continuous infusion of BDNF
      increased the survival rate of CN neurons to 70%; 70% of these expressed NOS.
      Combined L-NAME and PN graft or L-NAME and BDNF improved the rescue rate up to
      94%, but only approximately 33% expressed NOS. Our results suggest that the
      expression of NOS might adversely influence the neuroprotective function of
      neurotrophic factors on injured CN neurons in the spinal cord.

PMID- 10574372
TI  - Genomic organization of the human X11L2 gene (APBA3), a third member of the X11
      protein family interacting with Alzheimer's beta-amyloid precursor protein.
AB  - Recently we cloned a new member of the X11 protein family, X11L2 (gene symbol
      APBA3) which interacts with Alzheimer's beta-amyloid precursor protein (APP) and
      has three protein-protein interaction domains, a phosphotyrosine interacting
      domain (PID) and two PDZ. Here, we report the genomic structure and mapping of
      the APBA3. The gene spans about 11 kb and is composed of ten coding exons and one
      untranslated exon. The transcription start site of APBA3 was found in a CpG
      island. About 1.2 kb of the 5'-flanking region was also sequenced, and its
      functional promoter activity was confirmed by transient transfection experiments.
      The APBA3 was localized by the radiation hybrid mapping to chromosome 19.
      Determination of the APBA3 genome structure will facilitate the linkage analysis
      and search for mutations in the APBA3 in patients with Alzheimer's disease.

PMID- 10574373
TI  - ATP-gated ion channel expression in primary auditory neurones.
AB  - Extracellular ATP acts via ionotropic P2X receptors to mediate fast
      neurotransmission in the central and autonomic nervous systems. Recent data,
      including identification of P2X2 receptor mRNA expression by spiral ganglion
      neurones, suggests that purinergic signalling may influence auditory
      neurotransmission via ATP-gated ion channels assembled from these subunits.
      Expression of the P2X2 receptor was localized to the region of the spiral
      ganglion neurone synapses with the inner hair cells using a P2X2 receptor
      specific antiserum. Whole-cell patch clamping of neurones cultured from post
      natal day 3-5 spiral ganglia demonstrated a heterogeneity of ATP-activated
      conductances, consistent with the functional expression of P2X2 receptor subunit
      isoforms along with possible co-expression of additional P2X receptor subunits.
      These data provide substantive support for a purinergic transmission element at
      the peripheral auditory synapse.

PMID- 10574374
TI  - Hemispheric differences on auditory evoked response suppression in schizophrenia.
AB  - Using binaural stimuli, schizophrenia subjects have worse auditory evoked
      response (AER) suppression than normals in a paired-click paradigm. In this study
      we investigated hemispheric differences in AER suppression between groups using
      monaural and binaural stimulus presentation. Auditory evoked responses from 12
      schizophrenia and 12 normal subjects were recorded with a 148-channel whole-head
      biomagnetometer. One hundred and twenty pairs of clicks were presented in three
      counterbalanced blocks (left, right, binaural). With monaural stimuli, patients
      had worse M100 suppression than normals in ipsilateral (effect size -2.13) but
      not in contralateral hemisphere (effect size -0.43). The groups did not differ on
      gamma band response suppression. Overall, the best group separations were
      obtained with binaural stimulus presentation on M100 suppression (effect size 
      4.14).

PMID- 10574375
TI  - Zn2+ differentially modulates kinetics of GABA(C) vs GABA(A) receptors in carp
      retinal bipolar cells.
AB  - GABA(C) and GABA(A) receptors co-exist in retinal bipolar cells. In the present
      study the effects of zinc on the kinetics of currents mediated by GABA(C) and
      GABA(A) receptors were investigated in isolated carp bipolar cells, using whole
      cell patch-clamp technique. We observed for the first time that zinc exerted
      opposite effects on kinetics of the GABA(C) and GABA(A) responses: zinc
      significantly slowed down activation and desensitization of the GABA(C) response,
      but accelerated those of the GABA(A) response; zinc dramatically accelerated
      deactivation of the GABA(C) response, whereas it had no apparent effect on
      deactivation of the GABA(A) response. These results suggest that zinc may be
      functionally important in regulating retinal signal transmission.

PMID- 10574376
TI  - Temporal sorting of neural components underlying phonological processing.
AB  - Event-related haemodynamic responses (EHRs) were recorded in subjects performing
      phonological tasks to test whether distinguishable temporal involvement of
      corresponding neural components would show through. A sequence of activation
      leading from primary auditory cortices to premotor regions emerged in the fast
      repetition and the phoneme monitoring tasks used. EHRs peaked significantly
      earlier in Wernicke's area (phonological decoding) than in Broca's area, the left
      supramarginal gyrus and the precentral gyrus (phonological rehearsal). Moreover,
      the sensitivity of within cluster temporal gradients to the nature of the tasks
      indicated either sensory to association cortex synchronization for fast
      repetition or delayed analysis for phoneme monitoring. These results are
      consistent with previous findings on working memory and show that fMRI permits
      temporal tracking of cognitive activations.

PMID- 10574377
TI  - Caspase inhibition protects nigral neurons against 6-OHDA-induced retrograde
      degeneration.
AB  - 6-Hydroxydopamine (6-OHDA) administered intrastriatally to adult rats in a single
      injection causes neurodegeneration of the nigrostriatal pathway and loss of > 50%
      of dopamine neurons in substantia nigra pars compacta 30 days after
      administration. The death of nigral neurons occurs, at least partially, by a
      caspase-mediated mechanism. The nigral loss of dopaminergic neurons could be
      prevented by stereotaxical administration of zVAD.fmk, a caspase inhibitor, into
      the substantia nigra, indicating that 6-OHDA-induced nigrostriatal degeneration
      involves caspase activation. These results suggest that caspases are probably
      involved in neurodegenerative chronic processes such as Parkinson's disease and
      might be considered as possible targets in the treatment of such neurological
      disorders.

PMID- 10574378
TI  - Temporal patterns of trigeminal respiratory activity in rat brainstem-spinal cord
      in vitro.
AB  - Respiratory activity in trigeminal (V) motoneurons was studied in rhythmically
      active en bloc brainstem-spinal cord preparations isolated from neonatal rats (P0
      P3). In the majority of preparations (83%), the temporal pattern of V activity
      consisted of spontaneous inspiratory phasic discharge with onset delayed or
      coincident with onset of phrenic motoneuron discharge. Blockade of alpha-2
      noradrenergic receptor activation shifted onset of V respiratory discharges
      earlier than phrenic discharges, while elevation of extracellular potassium
      concentration or blockade of GABAergic and glycinergic inhibitory synaptic
      transmission had little effect on temporary pattern of V respiratory discharges.
      We conclude V motoneurons in the in vitro preparation generate respiratory
      activity during inspiratory phase, and their temporal patterns are modulated by
      inhibitory noradrenergic synaptic transmission.

PMID- 10574379
TI  - Rat sensory neurons contain cytochrome b558 large subunit immunoreactivity.
AB  - Cytochrome b558 is part of the NADPH oxidase complex of phagocytes, but it has
      also been proposed to function as a cellular oxygen sensor, e.g. in the carotid
      body. Thus, we investigated whether cytochrome b558 is present in rat primary
      afferent neurons. Immunohistochemistry and Western blotting using the monoclonal
      antibody 54.1 directed towards the large subunit of cytochrome b558, gp91phox,
      revealed a ubiquituous occurrence of cytochrome b558-immunoreactivity in neurons
      of the petrosal ganglion that innervates the carotid body, and also in dorsal
      root ganglia. This ubiquituous occurrence in sensory neurons of various locations
      and functional modalities points to a general role of cytochrome b558 in primary
      afferent neurons rather than involvement in a specialized function such as
      arterial chemoreception.

PMID- 10574380
TI  - Response amplification in sensory-specific cortices during crossmodal binding.
AB  - Integrating information across the senses can enhance our ability to detect and
      classify stimuli in the environment. For example, auditory speech perception is
      substantially improved when the speaker's face is visible. In an fMRI study
      designed to investigate the neural mechanisms underlying these crossmodal
      behavioural gains, bimodal (audio-visual) speech was contrasted against both
      unimodal (auditory and visual) components. Significant response enhancements in
      auditory (BA 41/42) and visual (V5) cortices were detected during bimodal
      stimulation. This effect was found to be specific to semantically congruent
      crossmodal inputs. These data suggest that the perceptual improvements effected
      by synthesizing matched multisensory inputs are realised by reciprocal
      amplification of the signal intensity in participating unimodal cortices.

PMID- 10574381
TI  - What does the P300 brain response measure in children? New insight from stimulus
      sequence studies.
AB  - The decrease in the P300 brain response latency with increasing age is often
      taken to reflect maturation of cognitive processes in children. We found that in
      abnormally distractible children the auditory P300 latency decreased
      significantly when the inter-target interval (ITI) increased in a stimulus
      discrimination task. We speculate that the sensory memory trace of the target
      stimulus may decay in distractible children during longer ITIs, and consequently
      the next target stimulus may activate the brain's orienting networks that are
      known to generate shorter latency brain responses. The relative strength by which
      the functionally different neural networks underlying the cognitive brain
      responses are activated may contribute significantly to the latency measures of
      these responses. The presumption that a short P300 latency equals to fast
      processing may thus be over-simplistic, especially in children.

PMID- 10574382
TI  - Timing of activity in early visual cortex as revealed by transcranial magnetic
      stimulation.
AB  - To determine the timing of visual processing in the early visual cortex, we
      applied single pulse transcranial magnetic stimulation to the occipital pole of
      healthy subjects while they were engaged in a forced-choice visual letter
      identification task. We found two separate periods of activity, the first ranging
      from 20 to 60 ms after the onset of the visual stimulus, and the second ranging
      from 100 to 140 ms after the onset of the visual stimulus. We suggest that these
      two periods reflect necessary activity in V1, before and after re-entry.

PMID- 10574383
TI  - Smooth pursuit latency in gap and non-gap conditions in schizophrenic subjects.
AB  - It has been demonstrated in normal subjects that smooth pursuit latency is
      reduced in gap pursuit tasks. We have now measured smooth pursuit latency in a
      group of schizophrenic subjects in both gap and non-gap conditions. In non-gap
      tasks pursuit latency was longer in the schizophrenic subjects than in controls.
      While the addition of gaps produced reductions in pursuit latency in the
      schizophrenic subjects, the effect was more variable than in controls, with a
      greater asymmetry between rightward and leftward pursuit latencies. Our results
      are consistent with the hypothesis that pursuit initiation is modified in
      schizophrenia and that as with the gap effect on saccades, the gap effect on
      pursuit is also modified.

PMID- 10574384
TI  - Nitric oxide synthase in trigeminal ganglion cells projecting to the cochlea of
      rat and guinea pig.
AB  - Nitric oxide (NO) influences electrophysiological and morphological parameters of
      the mammalian cochlea. Recently, the isoform of the NO-producing enzyme neuronal
      NO synthase (nNOS) has been demonstrated in spiral ganglion cells and
      olivocochlear neurons. The cochlea is also innervated by fibers stemming from the
      trigeminal ganglion (TG) and superior cervical ganglion (SCG). Whether these
      ganglion cells contain nNOS is not known yet. We therefore identified TG and SCG
      cells upon injection of Fluoro-Gold (FG) into the cochlea and retrograde neuronal
      transport of FG in rat and guinea pig. These ganglion cells were investigated for
      neuronal NOS immunohistochemically. Perikarya labeled by FG were found in the
      ipsilateral TG and SCG. In both species investigated, a considerable number of FG
      labeled TG cells were also nNOS-immunoreactive whereas SCG cells were not. These
      data, demonstrating the existence of nNOS-containing TG cells that project to the
      cochlea, provide evidence that these neurons are further sources of nitric oxide
      in the cochlea.

PMID- 10574385
TI  - Microinjection of catalase cDNA prevents hydrogen peroxide-induced motoneuron
      death.
AB  - Oxidative stress is believed to play a central role in the pathogenesis of
      amyotrophic lateral sclerosis (ALS). We investigated the protective effects of
      overexpression of catalase in primary cultures of rat spinal motoneurons against
      the oxidative stress of hydrogen peroxide. Using microinjection, catalase
      encoding cDNA was transferred into the motoneurons. In another approach,
      motoneurons were injected with a catalase solution. Both procedures elevated the
      intracellular antioxidant status of the cultured motoneurons as evidenced by a
      significant protection against H2O2 toxicity. We conclude that modulating the
      expression of enzymes involved in cellular defense against oxidative stress can
      render cells more resistant to oxidant toxicity.

PMID- 10574386
TI  - Effects of ionotropic glutamate receptor blockade and 5-HT1A receptor activation
      on spreading depression in rat neocortical slices.
AB  - The effect of the AMPA antagonist NBQX (10 microM), NMDA antagonist ketamine (100
      microM) and 5-HT1A agonist 8-OH-DPAT (1, 10 and 100 microM) on the properties of
      a KCl-induced spreading depression (SD) was studied in parietal cortical slices
      of adult rats. Whereas NBQX did not significantly affect the SD, ketamine
      significantly (p < 0.01) reduced the amplitude of the first SD peak (12.8 +/- 4.6
      mV) and blocked the second SD peak when compared with the controls (19.8 +/- 5.2
      mV and 25 +/- 5 mV, respectively). Ketamine also decreased the SD duration at
      half maximal amplitude from 34.9 +/- 12.4 s to 22.2 +/- 12 s (p < 0.05). 8-OH
      DPAT attenuated the duration of the SD from 42 +/- 15.6 s to 21.2 +/- 10.6 s (p <
      0.05, 100 microM). These data indicate that not only NMDA receptor blockade, but
      also activation of the 5-HT1A receptor attenuates the SD and may be beneficial in
      the reduction of ischemic injury following focal cerebral ischemia.

PMID- 10574387
TI  - Solitary tract nucleus sensitivity to moderate changes in glucose level.
AB  - Many neurons in the caudal nucleus tractus solitarii (NTS) recorded in vivo
      respond to moderate glycemic fluctuations through the local action of glucose
      molecules. To investigate this sensitivity in vitro, the extracellular activity
      of 112 neurons was recorded in hindbrain slices: 57 changed in firing rate when
      the glucose level in the bathing medium was increased by 2 mM. Since the glucose
      responding neurons were located in catecholaminergic regions and depressed by the
      alpha-2 adrenoceptor agonist clonidine, they were likely to be adrenergic or
      noradrenergic. A comparison of the responses to glucose and 2-deoxy-D-glucose
      suggested that the bioenergetic metabolism is involved in NTS sensitivity to
      glucose.

PMID- 10574388
TI  - Modality-specific effects of immediate word repetition: electrophysiological
      evidence.
AB  - Event-related potentials (ERPs) elicited by visually presented words were
      employed to investigate whether the neural correlates of repetition within- and
      across-modality differ when repetition is immediate, and the influence of
      explicit memory maximal. Relative to the ERPs elicited by first presentations,
      ERPs elicited by immediate, within-modality repetitions began to differ from
      approximately 200 ms post-stimulus onset. ERP repetition effects elicited by
      across-modality repetition did not onset until approximately 150 ms later. Within
      and across-modality repetition effects were also dissociable neuroanatomically,
      exhibiting different scalp distributions. The findings support the proposal that
      the modality-sensitive component of visual word repetition effects operates at an
      early, pre-semantic processing stage.

PMID- 10574389
TI  - Orbital position dependency is different for the gain of externally and
      internally triggered saccades.
AB  - The gain of visually triggered saccades depends on orbital position. Centrifugal
      saccades have smaller gains and are slower than centripetal saccades elicited by
      the same target amplitude. We determined whether internally triggered saccades,
      e.g. scanning or memory saccades, exhibit the orbital position dependency evident
      in visually guided saccades. The search coil technique was used to record eye
      movements of healthy subjects while they performed horizontal 12.5 degree
      saccades under three paradigms (gap, scanning and memory saccades). Orbital
      position influenced externally triggered gap saccades but not the gain or peak
      eye velocity of scanning or memory saccades. These findings do not support the
      idea that position dependency caused by orbital mechanics is compensated for at
      the level of the common brainstem burst generator. Instead our results are
      consistent with the view that cortical output reflects the differences evident in
      the gain of visually triggered centrifugal and centripetal saccades.

PMID- 10574390
TI  - BDNF, but not NT-3, promotes long-term survival of axotomized adult rat
      corticospinal neurons in vivo.
AB  - Axotomy-induced death of corticospinal neurons (CSN) is prevented by
      intracotrical infusions of BDNF or NT-3 within the first week after axotomy. The
      present study examined whether this represents merely a delay of CSN death or
      whether BDNF and NT-3 can promote long-term survival of these neurons in vivo.
      The neurotrophins were infused for an initial period of 14 days to lesioned CSN
      which was followed by 28 days without treatment. BDNF was able to promote CSN
      survival for at least 42 days while NT-3 had no significant effect. These results
      suggest that initial BDNF treatment induces an endogamous mechanism that promotes
      survival of axotomized CSN without further exogenous neurotrophic factor supply.
      These findings may be important for the design of therapeutic strategies for
      motoneuron disease.

PMID- 10574391
TI  - Segregated expression of neurestin in the developing olfactory bulb.
AB  - Neurestin is a putative transmembrane protein whose expression is developmentally
      regulated in neurons. Here we examined neurestin expression pattern in
      mitral/tufted cells in the developing rat olfactory bulb. In the main olfactory
      bulb, neurestin expression was segregated in the dorso-rostral area and in the
      ventro-caudal area, but not in between. In the accessory olfactory bulb,
      neurestin expression was found only in the far caudal area. This area did not
      completely correspond to a caudal half of the vomeronasal nerve and glomerular
      layers positive for a G-protein Go alpha. These spatio-temporal expression
      patterns suggest that neurestin functions as a target recognition molecule that
      specifies zonal projection patterns of olfactory and vomeronasal sensory neurons.

PMID- 10574392
TI  - A powerful GABA(B) receptor-mediated inhibition of GABAergic neurons in arcuate
      nucleus.
AB  - We combined histofluorescence with in situ hybridization to identify GABAergic
      neurons in the arcuate nucleus (ARC) following electrophysiological recording,
      using GAD65 as a marker. Intracellular recordings 91 were made in hypothalamic
      slices prepared from ovariectomized guinea pigs. Over 90% of ARC neurons tested
      with the GABA(B) receptor agonist baclofen responded with a membrane
      hyperpolarization or an outward current. The hyperpolarization was dose
      dependent, and the GABA(B) receptor antagonist CGP 35,348 produced a rightward
      shift in the agonist dose-response curve. Agonist potency was lower, and the
      efficacy greater, in GAD-positive neurons. The use of this novel technique for
      identifying GABAergic neurons thus reveals differences in the pharmacodynamics of
      GABA(B) receptor activation between GABAergic and non-GABAergic ARC neurons.

PMID- 10574393
TI  - Heart Failure 99 -- the MOXCON story.

PMID- 10574394
TI  - Cardiac cachexia is a world-wide problem.

PMID- 10574395
TI  - Pulmonary autograft replacement of the bicuspid aortic valve: a successful
      surgical option for young adults.
AB  - A severely dysfunctioning congenitally bicuspid aortic valve may require surgical
      treatment within the fourth decade of life. Among conventional options, the
      pulmonary autograft (PA) offers many theoretical advantages particularly for
      young patients, including potential for growth, hemodynamic performance, no need
      for anticoagulants and freedom from endocarditis. However the operation is more
      complex and longer, may interfere with coronary and right ventricular anatomy and
      function and may expose the patient to the downside of two valves at risk. Aim of
      this retrospective study was to evaluate the mid-term results achieved with the
      PA performed in adolescents and young adults with a bicuspid aortic valve.
      Between July 94 and June 98, 26 patients, 22 males and four females, with a mean
      age of 24+/-10 years (range, 11 to 38), underwent bicuspid aortic valve
      replacement with a pulmonary autograft (stenosis 2-8%; insufficiency 13-50%;
      combined 11-42%). Eight patients (31%) were in NYHA FC I, 17 (65%) in II, and 1
      (4%) in III. Mean preoperative ejection fraction was 67+/-7%. Three patients
      (11.5%) had a past medical history of endocarditis (healed in all) and in two the
      PA was a re-do procedure. The PA was inserted as a subcoronary implant in one
      case (4%) and utilized as a root in the remaining 25 (96%). The right ventricular
      outflow tract was reconstructed with a cryopreserved pulmonary homograft conduit
      in all cases. Mean cardiopulmonary bypass and aortic crossclamp times were 204+/
      50 min (range, 174 to 300) and 157+/-35 min (range, 133 to 193) respectively. No
      early or late deaths had occurred at a mean follow-up of 22.5 months (range, 5 to
      47.5). The first patient in the series (4%) was reexplored for bleeding and
      needed transfusions. The subsequent routine use medical and surgical strategies
      resulted in no further need for postoperative reexploration, and successful
      containment of total postoperative blood loss (<350 ml/m2BSA). 2-D Echo
      evaluation of neo-aortic valve competence at 6 months, revealed no evidence of
      aortic valve regurgitation in 17 (65%), trivial regurgitation in seven (27%),
      mild in one (4%) and mild-to-moderate in one (4%). The latter patient
      (subcoronary implant PA) required reoperation. At six months, the mean degree of
      regression of left ventricular mass compared to pre-operative data, was 36%
      (333+/-94 to 212+/-60 gr, p<0.05). All patients are asymptomatic, in NYHA FC I,
      and enjoy normal social interaction. In conclusion, PA root implantation can be
      offered as a low-risk alternative to conventional prosthetic aortic valve
      replacement to adolescents and young adults with a bicuspid aortic valve. The
      routine achievement of blood loss containment has minimized the risk of
      transfusion thus contributing to expand the indication in young patients.
      Continued patients evaluation particularly with regard to evidence of neo-aortic
      valve degeneration, root dilatation and homograft dysfunction in the long term is
      warranted.

PMID- 10574396
TI  - Non-elective intra-coronary stenting: are the clinical outcomes comparable to
      elective stenting at 6 months?
AB  - The aim of this study was to compare prospectively the clinical outcome of
      patients treated with intra-coronary stents as a non-elective/bailout procedure
      for acute or threatened vessel closure, with those undergoing elective stenting
      at 6 months. Sixty-four patients (60.2+/-11.7 y) who underwent non-elective
      stenting for abrupt or threatened vessel closure and/or sub-optimal results were
      prospectively compared with 68 patients (62+/-10.0 y) who were stented
      electively. All patients had broadly similar pre-procedural clinical profiles.
      However, patients in the elective group had a higher incidence of previous PTCA
      (10.2% vs. 0%, P = 0.01) and bypass surgery (30.9% vs. 6.3%, P = 0.0003) compared
      with the non-elective group. A total of 158 stents (1.19 per patient) were
      implanted in 132 patients with a procedural success rate of 99.3%. At 6 months
      follow-up there was no statistical difference in the primary composite end-point
      of death, myocardial infarction and the need of repeat revascularisation (10.9%
      vs. 5.8%, P = 0.35) between the two groups. However, patients in the non-elective
      group showed a higher incidence of unstable angina compared with the elective
      group (25% vs. 1.4%, P = 0.0004). The findings of this study suggest that stents
      (single or multiple) can be effectively implanted in non-elective situations with
      no increase in the incidence of death, non-fatal myocardial infarction, and the
      need of repeat revascularisation at 6 months compared with elective stenting.

PMID- 10574397
TI  - The prevalence of left ventricular hypertrophy in elite professional footballers.
AB  - BACKGROUND: We evaluated the prevalence of left ventricular hypertrophy in elite
      footballers compared with sedentary controls. A total of 141 elite male
      professional footballers and 32 healthy sedentary controls were studied.
      Echocardiographic and demographic variables were compared between groups by
      unpaired t-test. RESULTS: The prevalence of left ventricular hypertrophy with
      maximal wall thickness values out with the normal range (>12 mm) was noted.
      Footballers were significantly younger than controls (20.9 vs. 24.3 years,
      P<0.005: 95% CI (-5.2, -1.73)) but there were no significant differences in
      height, weight or body surface area between the groups. Each of inter-ventricular
      septum (10.4 vs. 9.1 mm, P<0.0001; 95% CI (0.88, 1.72)), posterior wall (9.2 vs.
      8.5 mm, P<0.01; 95% CI (0.22, 1.21)), left ventricular cavity (systolic and
      diastolic) (34.5 vs. 28.4 mm, P<0.0001; 95% CI (4.31, 7.76) in systole; 50.1 vs.
      48.2 mm, P<0.05; 95% CI (0.15, 3.74) in diastole), aortic root size (29.1 vs.
      27.8 mm, P<0.05; 95% CI (0.03,2.49)) and left ventricular mass index (112 vs. 89
      g/m2, P<0.0001; 95% CI (14.4, 32.1)) were significantly greater in footballers
      than in controls. Absolute left ventricular wall thickness >12 mm was present in
      17 footballers (12%) (range 13-15 mm) and in no controls. CONCLUSIONS: Elite
      professional footballers have increased cardiac dimensions compared with healthy
      controls. The prevalence of absolute wall thicknesses out with the normal range
      is relatively high.

PMID- 10574398
TI  - Intermittently audible the "third heart sound" as a sign of complete atrio
      ventricular block in patients with a VVI pacemaker.
AB  - BACKGROUND: It is not known that an S3 can be audible intermittently. We have
      recognized this in patients with VVI pacing in whom sinus rhythm has been
      preserved. SUBJECTS AND METHODS: Subjects consisted of consecutive 39 patients
      with VVI pacemaker implantation and preservation of sinus rhythm. We tried to
      find out what percentage of these patients have an intermittent S3 and also to
      elucidate the mechanism of this sound by Doppler echocardiography. The PP
      interval and RR intervals were measured and ?PP-RR?/RR was calculated. One doctor
      carried out auscultation from the left sternal border to the apex for 5-6
      consecutive beats while the patients held their breath. Transmitral flow velocity
      was measured by pulsed Doppler echocardiography with a paper speed of 100 cm/sec.
      A wave velocity was measured when a P wave coincided with late diastole. E wave
      velocity was measured when no A wave was present in early diastole. The maximal
      summation of E and A waves (E+A) velocity was measured. RESULT: An intermittent
      S3, being audible in 21 patients (group A) and not audible in 18 patients (group
      B), coincided with maximal E+A velocity. There was no statistical age difference
      between the two groups. Both maximal E+A velocity, and A velocity were higher in
      group A than group B (116.2 cm/sec Vs 90.8 cm/sec P<0.0001, 80.6 cm/sec Vs 56.4
      cm/sec P<0.0001 respectively), while E velocity was not statistically different
      (68.3 cm/sec Vs 60.3 cm/sec). In 5 of 9 cases in whom an intermittent S3 was not
      audible regardless of more than 100 cm/sec of E+A velocity, the calculated ?PP
      RR?/RR was less than 0.1. CONCLUSION: An intermittently audible S3 is one of the
      physical signs of complete atrio-ventricular block. It occurs when a strong
      atrial contraction develops exactly at the time of rapid left ventricular
      filling. However, when the PP and RR intervals are too close, the S3 may be
      difficult to discern.

PMID- 10574399
TI  - A critical appraisal of the rate pressure product as index of myocardial oxygen
      consumption for the study of metabolic coronary flow regulation.
AB  - For the assessment of metabolic coronary vasodilatation, changes in systolic rate
      pressure product (RPP) are frequently used to estimate the pacing- or exercise
      induced changes in myocardial oxygen consumption (MVO2). The present study was
      designed to test whether this is justified in patients with coronary artery
      disease. To study the relation between RPP and changes in MVO2 under different
      conditions, we used data from 21 patients who participated in two previous
      studies investigating the effect of nitroglycerin (NTG) and anaesthesia on
      metabolic coronary flow regulation. At control, during administration of NTG 1
      microg/kg/min (n=11), and during anaesthesia (n=10), coronary sinus blood flow,
      MVO2 and RPP were measured at sinus rhythm and during atrial pacing (30 bpm above
      sinus rate) and the relation between the percentage increase in RPP (delta%RPP)
      and MVO2 delta%MVO2) was analysed, using standard linear regression analysis.
      Although a significant relation between delta%MVO2 and delta%RPP was found at
      control and during anaesthesia, prediction intervals were very wide and only 40%
      and 60% of the variation in delta%MVO2, respectively, could be explained by the
      variation in delta%RPP. During administration of NTG 1 microg/kg/min no
      significant relation was found between delta%MVO2 and delta%RPP. Thus, for the
      study of metabolic coronary flow regulation, pacing induced changes in MVO2
      cannot be predicted accurately from changes in RPP.

PMID- 10574400
TI  - Inverse relation of haematocrit to cardiac index in mitral stenosis and atrial
      fibrillation.
AB  - We investigated the relationship between atrial fibrillation and the red cell
      parameters haematocrit, red cell concentration and mean corpuscular volume in 95
      female patients with mitral stenosis (mean age 51+/-11 years, 38 patients in
      atrial fibrillation, 57 patients in sinus rhythm) who had undergone full blood
      examination and right and left heart catheterisation. Haematocrit was a positive
      correlate of atrial fibrillation (r=0.29, p<0.009) and a negative correlate of
      cardiac index (r=-0.37, p<0.003), but cardiac index was the only independent
      correlate of haematocrit on multivariate analysis (r2=0.14). The mean corpuscular
      volume was a positive correlate of age (r=0.42, p<0.0001) and atrial fibrillation
      (r=0.29, p<0.005) and a negative correlate of cardiac index (r=-0.22, p<0.04) and
      red cell concentration (r=-0.56, p<0.0001). On multivariate analysis, however,
      only age and red cell concentration were independent correlates of mean
      corpuscular volume (r2=0.43). Cardiac index was inversely correlated with both
      haematocrit and red cell concentration in the subgroup of patients with atrial
      fibrillation but not those with sinus rhythm. This study demonstrates that the
      major determinant of the higher haematocrit in mitral stenosis patients with
      atrial fibrillation is an associated reduction in cardiac index.

PMID- 10574401
TI  - Wall motion of noninfarcted myocardium. Relationship to regional and global
      systolic function and to early and late left ventricular dilation.
AB  - We studied the wall motion of the noninfarcted area and its role in left
      ventricular remodeling. The study group consisted of 43 patients with a first Q
      wave acute myocardial infarction and single-vessel disease. Cardiac
      catheterization was performed at the first week, and was repeated six months
      later. Left ventricular volumes, wall motion at the infarcted and noninfarcted
      area, ejection fraction and infarction-related artery status were quantified.
      Hyperkinesia was only found at the first week in 22% of cases, and at the sixth
      month in 26% of cases. Wall motion at the noninfarcted area correlated with wall
      motion at the infarcted area (one week: r=0.53 p<0.0001; six months: r=0.52
      p=0.01), ejection fraction (one week: r=0.69 p<0.0001; six months: r=0.56
      p=0.006), end-diastolic volume (one week: r=-0.48 p=0.002; six months: r=-0.48
      p=0.02) and end-systolic volume (one week: r=-0.70 p<0.0001; six months: r=-0.64
      p=0.001). The improvement of the noninfarcted area (from the first week to the
      sixth month) was only related to basal (one week) wall motion in this area (r=
      0.58 p=0.003). We conclude that after an intermediate-large infarction, most
      patients exhibit a normal or hypokinetic noninfarcted area. Patients with a more
      depressed infarcted area show poorer contractility at the noninfarcted area. area
      exhibit greater progressive improvement.

PMID- 10574402
TI  - Three-year follow-up of patients with silent ischemia in the subacute phase of
      myocardial infarction after thrombolysis and early coronary intervention.
AB  - In order to assess the prognostic value of silent myocardial ischemia in acute
      myocardial infarction after thrombolysis and early coronary angiography (14-48 h
      after start of thrombolysis) including percutaneous transluminal coronary
      angioplasty, if indicated, 126 patients underwent 24 h-Holter-monitoring in the
      early postinfarction period. The 24 h-Holter-recording was initiated directly
      after early coronary intervention (40+/-11 h after onset of symptoms). Of the 126
      patients initially eligible for the study 29 had to be excluded from further
      analysis for clinical or methodical reasons. Of the remaining 97 patients, 10
      (10%) had silent ischemia (group A) and 87/97 (90%) patients showed no
      significant ST-segment alterations. Both groups did not significantly differ from
      each other with regard to baseline clinical characteristics, severity of coronary
      artery disease and frequency of successful percutaneous transluminal coronary
      angioplasty. The left ventricular ejection fraction showed a trend towards lower
      values in patients with than in those without silent ischemia (47+/-15% vs. 55+/
      13%, p=0.07). When both silent ischemia and left ventricular ejection fraction
      <40% were present, a subset of patients at high risk for cardiac death could be
      identified (specificity: 98%, positive predictive accuracy: 75%). By Kaplan-Meier
      analysis, significantly more cardiac deaths occurred in group A than in group B
      (30% vs. 6%, p<0.01) during the three-year follow-up (950+/-392 days) after acute
      myocardial infarction. Regarding the cardiac events during long-term follow-up
      (emergency percutaneous transluminal coronary angioplasty, coronary artery bypass
      grafting, non-fatal reinfarction, and cardiac death) there was no significant
      difference between both groups (30% vs. 18%, NS). In conclusion, Holter monitor
      detected silent ischemia in the subacute phase of myocardial infarction after
      thrombolysis followed by early delayed coronary intervention occurs in 10% of the
      patients indicating either a residual ischemia in the infarcted zone despite a
      combined reperfusion strategy or a remote ischemic potential in case of
      multivessel disease. In this small selected group of infarct patients too, silent
      ischemia is to be considered as an important non-invasive parameter to predict
      cardiac death during long-term follow-up and provides valuable complementary
      information to left ventricular dysfunction, a well established prognostic marker
      in the postinfarction period.

PMID- 10574403
TI  - The electrocardiogram in traumatic right atrial rupture.
AB  - We report the case of a previously healthy 20-year-old man who had a traumatic
      rupture of the right atrium. On admission an electrocardiogram (ECG) was recorded
      which is highly remarkable and, retrospectively, suggestive for the diagnosis.
      The patient died soon after the ECG, and the diagnosis was made at autopsy.

PMID- 10574404
TI  - Rheumatoid arthritis and simultaneous aortic, mitral, and tricuspid valve
      incompetence.
AB  - We describe a 72-year-old woman with aortic, mitral, and tricuspid valve
      incompetence secondary to a rheumatoid granulomata. The cardiac valvular lesions
      developed simultaneously and deteriorated rapidly. The patient died after a
      transient relief of symptoms by high dose steroid therapy.

PMID- 10574405
TI  - Pseudoaneurysm of the descending aorta caused by Candida albicans.

PMID- 10574406
TI  - Atrial fibrillation in the Mahaim syndrome: atrial pacing and adenosine-induced
      AV block to unmask a Mahaim physiology.

PMID- 10574407
TI  - Effect of increasing age on diastolic motion of the left ventricular
      atrioventricular plane in normal subjects.

PMID- 10574408
TI  - The relationship between diastolic function of the left ventricle and QT
      dispersion in patients with myocardial infarction.

PMID- 10574409
TI  - Femoral neuropathy following cardiac catheterization for balloon mitral
      valvotomy.
AB  - Femoral neuropathy is a very rare complication of cardiac catheterization. We
      report an adult female who developed femoral neuropathy after undergoing cardiac
      catheterization through femoral vein for balloon mitral valvotomy. Neuropathy was
      confirmed by electromyography and nerve conduction studies and the patient showed
      spontaneous recovery over a course of 6 months. Use of prolonged digital pressure
      for post-procedural hemostasis is implicated as possible etiology. Such
      complications can be prevented by minimising the procedural time, avoiding injury
      to the vessels and maintaining optimal posture of patient's thigh by limiting
      abduction and external rotation of hip.

PMID- 10574410
TI  - Effect of moderate exercise training in healthy volunteers.

PMID- 10574411
TI  - Glycemic modulation of insulin/IGF-1 mediated skeletal muscle blood following
      sympathetic denervation in normal rats.
AB  - Both insulin and IGF-1 decrease vascular resistance and increase blood flow in
      skeletal muscle, and it has been suggested that the mechanistic action for
      insulin may be by increasing autonomic vasodilatory activity. In this study we
      evaluated the effects of insulin and IGF-1 on blood flow to denervated and non
      denervated skeletal muscle as part of a continuing investigation into the
      mechanism of regulation of cardiovascular responses by these hormones. Normal
      rats were prepared for measurements of mean arterial pressure (MAP), heart rate
      (HR) and vascular flow in the left and right iliac artery. Resection of the left
      lumbar sympathetic chain increased flow (expressed as conductance, flow/MAP) in
      the denervated left iliac but not in the intact right artery. Subsequent insulin
      infusion where hypoglycemia was allowed to occur increased conductance in both
      arteries, but more so in the denervated artery. Similarly, IGF-1 infusion
      increased conductances in both intact and denervated iliac arteries, and the
      effect was slightly greater in the denervated artery. Insulin infusion when
      euglycemia was maintained increased conductance to a similar extent in denervated
      and intact iliac arteries. Contrastingly, IGF-1 infusion under euglycemic
      conditions resulted in a much greater increased conductance in the intact iliac.
      We conclude that both insulin and IGF-1 increase conductance directly and that
      glycemic status and sympathetic nerve activity modulate these responses. The
      insulin-induced increase in conductance in the denervated limb under hypoglycemic
      conditions suggest that hypoglycemic-stimulated epinephrine release may enhance
      the dilatory response. while the greater response to IGF-1 in the intact vessel
      under euglycemic conditions may be due to IGF-1 capacity to decrease sympathetic
      activity leading to an enhanced conductance.

PMID- 10574412
TI  - Losartan reduces the vasorelaxant effect of atrial natriuretic peptide on basal
      tone in aorta.
AB  - The Ca2+ -and receptor-dependencies of the basal tone seen in angiotensin II (Ang
      II)-conditioned rabbit thoracic aortic rings were investigated. Ca2+ -free Krebs
      significantly and partially reversibly reduced basal tone in aortic rings that
      had recovered from an earlier challenge with Ang II; rings not previously exposed
      to Ang II were unaffected. The effect of Ca2+ -free Krebs was similar to the
      reduction in basal tone evoked by atrial natriuretic peptide (ANP), but was
      smaller than that seen with exposure to Ca2+ -free Krebs+EGTA+sodium
      nitroprusside (SNP). Pretreating rings with Ca2+ free Krebs blocked the
      vasorelaxant effects of ANP and Ca2+ -free Krebs+EGTA+SNP. Losartan, an AT1
      receptor antagonist, significantly attenuated ANP-induced relaxation, but did not
      otherwise alter basal tension in either unstimulated or Ang II-conditioned rings.
      The AT2 receptor antagonist, PD 123319, had no effect. These data suggest that
      transient exposure to Ang II induces prolonged, AT1-dependent increases in
      intracellular free Ca2+ which are antagonized by ANP.

PMID- 10574413
TI  - Long-term safety and antihypertensive efficacy of irbesartan: pooled results of
      five open-label studies.
AB  - An analysis of 5 multicenter, open-label studies was conducted to evaluate the
      long-term safety and efficacy of irbesartan in 1,006 patients with seated
      diastolic blood pressure (SeDBP) 95-110 mm Hg. Irbesartan monotherapy was started
      at 75 mg and titrated to 300 mg at 2- to 4-week intervals to achieve normalized
      blood pressure (SeDBP <90 mm Hg). If normalized BP was not attained with
      irbesartan 300 mg alone, adjunctive medications could be added. At 12 months of
      therapy, the mean reduction in seated systolic blood pressure/SeDBP was 21.0/15.8
      mm Hg, and 83% (684/821) of patients were normalized. Of those normalized, 64%
      were receiving irbesartan monotherapy and 86% were receiving irbesartan or
      irbesartan/hydrochlorothiazide only. No evidence of tachyphylaxis to the
      antihypertensive effect of irbesartan was noted. Thus, long-term irbesartan
      therapy, with or without other antihypertensives, achieved and maintained
      normalized BP in the majority of patients and was well tolerated.

PMID- 10574414
TI  - Effect of gamma-tocotrienol on blood pressure, lipid peroxidation and total
      antioxidant status in spontaneously hypertensive rats (SHR).
AB  - The aim of this study was to determine the effects of gamma tocotrienol on lipid
      peroxidation and total antioxidant status of spontaneously hypertensive rats
      (SHR), comparing them with normal Wistar Kyoto (WKY) rats. SHR were divided into
      three groups and treated with different doses of gamma tocotrienol (gamma1, 15
      mg/kg diet; gamma2, 30 mg/kg diet and gamma3, 150 mg/kg diet). Normal WKY and
      untreated SHR were used as normal (N) and hypertensive control (HC). Blood
      pressure were recorded every fortnightly for three months. At the end of the
      trial, animals were killed and measurement of plasma total antioxidant status,
      plasma superoxide dismutase (SOD) activity and lipid peroxide levels in plasma
      and blood vessels were carried out following well established methods. Study
      shows that lipid peroxides were significantly higher in hypertensive plasma and
      blood vessels compared to that of normal rats (Plasma- N: 0.06+/-0.01, HC: 0.13+/
      0.008; p<0.001, B1. Vessels - N: 0.47+/-0.17, HC: 0.96+/-0.37; p<0.001). SOD
      activity was significantly lower in hypertensive than normal rats (N = 148.58+/
      29.56 U/ml, HC = 110.08+/-14.36 U/ml; p = 0.014). After three months of
      antioxidant trial with gamma-tocotrienol, it was found that all the treated
      groups have reduced plasma lipid peroxides concentration but was only significant
      for group gamma1 (gamma1: 0.109+/-0.026, HC: 0.132+/-0.008; p = 0.034). On the
      other hand, lipid peroxides in blood vessels reduced significantly in all treated
      groups (gamma1; p<0.05, gamma2; p<0.001, gamma3; p<0.005). All the three treated
      groups showed improve total antioxidant status (p<0.001) significantly. SOD
      activity also showed significant improvement in all groups (gamma1: p<0.001,
      gamma2: p<0.05, gamma3: p<0.001). Correlation studies showed that, total
      antioxidant status (TAS) and SOD were significantly negatively correlated with
      blood pressure in normal rats (p = 0.007; p = 0.008) but not in SHR control. This
      correlation regained in all three groups SHR's after treatment with tocotrienol.
      Lipid peroxides in blood vessel and plasma showed a positive correlation with
      blood pressure in normal and SHR control. This correlation also remains in
      treated groups significantly except that in gamma3 where positive correlation
      with plasma lipid peroxide was not significant. In conclusion it was found that
      antioxidant supplement of gamma-tocotrienol may prevent development of increased
      blood pressure, reduce lipid peroxides in plasma and blood vessels and enhanced
      total antioxidant status including SOD activity.

PMID- 10574415
TI  - Lifetime treatment with captopril improves renal function in spontaneously
      hypertensive rats.
AB  - Lifetime treatment with captopril prevents the development of hypertension in
      spontaneously hypertensive rats (SHR). This study tests the hypothesis that
      compared to untreated hypertensive SHR, captopril-treated SHR display similar
      diuretic and natriuretic responses to an isotonic saline infusion despite
      significantly lower arterial pressure. Eight-week-old, male SHR were instrumented
      with femoral arterial, venous, and bladder catheters. Forty-eight hours later,
      each rat was infused intravenously with an isotonic saline load (5% of body
      weight; 0.5 ml/min). Lifetime captopril-treated SHR and untreated control SHR
      displayed nearly identical natriuretic and diuretic responses to the saline
      infusion. Thus, although lifetime captopril treatment significantly reduces mean
      arterial pressure in SHR, renal excretory responses appear to be unaltered.
      Moreover, histological examination of the kidneys of the lifetime captopril
      treated SHR did not reveal significant structural damage in the kidneys at either
      8 weeks of age or at 12 months of age. Together, the data suggest that lifetime
      captopril treatment does not adversely affect renal function and structure in
      SHR.

PMID- 10574416
TI  - Improvement of insulin resistance in essential hypertension by long-acting Ca
      antagonist benidipine.
AB  - To investigate whether the long-acting Ca channel blocker, benidipine improves
      insulin resistance in patients with essential hypertension, insulin sensitivity
      was measured using the steady state plasma glucose (SSPG) method in 11 or 14
      nonobese and nondiabetic hypertensive subjects before and after treatment with
      benidipine or placebo, respectively, and 11 healthy control subjects. SSPG level
      was significantly higher in two hypertensive groups, indicating reduced insulin
      sensitivity than in controls. SSPG level significantly decreased after benidipine
      treatment, with a decrease of blood pressure. SSPG level and blood pressure did
      not change in the placebo group. As for oral glucose tolerance test, the area
      under the curve of insulin diminished significantly after benidipine treatment.
      SSPG level significantly correlated with intra-platelet Ca2+ concentrations in 9
      hypertensive subjects. The long-acting Ca channel blocker benidipine has
      partially improved insulin resistance in essential hypertension, contributing to
      the prevention of atherosclerosis associated with insulin resistance.

PMID- 10574417
TI  - The effect of pravastatin on renal function and lipid metabolism in patients with
      renal dysfunction with hypertension and hyperlipidemia. Pravastatin and Renal
      Function Research Group.
AB  - The effect of pravastatin on renal function in hypertensive patients with mild
      renal dysfunction and hyperlipidemia was examined. A total of 57 subjects given
      dihydropyridine calcium blockers were randomly assigned to placebo (n = 25) and
      pravastatin groups (n = 32). The period of study was 6 months. In the placebo
      group, lipid metabolism did not change throughout the study period, but the serum
      creatinine concentration (Scr) increased from a baseline of 1.6+/-0.07 mg/dl to
      2.1+/-0.2 mg/dl in the 6th month of study and blood urea nitrogen (BUN) increased
      from 26.2+/-1.1 mg/dl to 32.4+/-30.1 mg/dl. In the pravastatin group, the serum
      total cholesterol decreased from a baseline of 251.4+/-7.3 mg/dl to 218.2+/-6.5
      mg/dl in the 6th month of study, while Scr (1.3+/-0.07 mg/dl vs. 1.3 +/-0.09
      mg/dl) and BNU (20.5+/-1.2 mg/dl vs. 21.0+/-1.4 mg/dl) did not change. The change
      in Scr in the placebo group was significantly different from that in the
      pravastatin group (F = 3.75, p = 0.05). The slope of the change in 1/Scr was
      0.02+/-0.07 dl x mg(-1) x month(-1) in placebo group and -0.01+/-0.03 dl x mg(-1)
      month(-1) in pravastatin group (P<0.05). The results indicate that pravastatin
      attenuates the deterioration of renal function in patients with mild renal
      dysfunction, together with an improvement of lipid metabolism.

PMID- 10574418
TI  - Abnormal cardiac autonomic activity and complexity in newly diagnosed and
      untreated hypertensive patients after general anesthesia.
AB  - To investigate change of cardiac autonomic activity and cardiac complexity during
      general anesthesia in hypertensive patients, we analyzed electrocardiographic
      (ECG) data using power spectral analysis and approximate entropy (ApEn).
      Anesthesia was performed by a mixture of enflurane and nitrous oxide. From 10
      minutes before induction of anesthesia(resting state) until 20 minutes after
      induction, ECG data were obtained from newly diagnosed and untreated hypertensive
      (n = 18) and normotensive patients (n = 18). Period 1 was defined as the initial
      10 minutes after induction and period 2 as the following 10 minutes. The low-,
      mid-, and high-frequency power and the values of ApEn of the two groups were
      calculated from ECG recording. At resting state, the powers in all frequency
      bands and the values of ApEn in hypertensive patients did not differ from those
      of normotensive patients. During periods 1 and 2, the powers of all frequency
      range significantly decreased in normotensive group (p<0.05), while they did not
      change in hypertensive group. The values of ApEn in normotensive patients
      decreased significantly only during period 2, while those in hypertensive
      patients decreased during periods 1 and 2 (p<0.05 and p<0.05, respectively).
      These results suggest that, in the hypertensive patients, persistent autonomic
      activity under the condition of suppressed cardiac complexity may contribute to
      the unstable hemodynamic insults from the outset of general anesthesia.

PMID- 10574419
TI  - The antihypertensive efficacy of the combination of irbesartan and
      hydrochlorothiazide assessed by 24-hour ambulatory blood pressure monitoring.
      Irbesartan Multicenter Study Group.
AB  - In a multicenter, double-blind, randomized trial, 178 patients with ambulatory
      diastolic blood pressure (BP) > or =85 mm Hg and seated diastolic BP (SeDBP) 95
      110 mm Hg received either once-daily irbesartan 75 mg/hydrochlorothiazide (HCTZ)
      12.5 mg, irbesartan 150 mg/HCTZ 12.5 mg, or placebo for 8 weeks to assess
      reductions in 24-hour ambulatory BP and office BP. Safety and tolerability of all
      treatment regimens were also evaluated. BP results and therapeutic response
      (trough SeDBP normalized to <90 mm Hg) were expressed as change from baseline to
      Week 8. Mean reductions in 24-hour ambulatory BP and office seated BP for
      irbesartan/HCTZ combinations were significantly greater compared with placebo
      (all, p<0.01). More patients were normalized with irbesartan/HCTZ (65%-69%) than
      placebo (24%, p<0.01). The frequency of adverse events was similar in all groups.
      Irbesartan/HCTZ given once-daily appears to be a well-tolerated, safe, and
      effective antihypertensive treatment.

PMID- 10574420
TI  - Potassium supplementation increases sodium excretion and nitric oxide production
      in hypertensive Dahl rats.
AB  - The present study was designed to investigate whether antihypertensive and
      natriuretic effects of K were achieved by elevation of nitric oxide (NO)
      production in Dahl salt-sensitive (DS) rats. The rats were placed in individual
      metabolic cage and fed a high sodium diet with or without K supplementation for 4
      weeks. K supplementation counteracted the blood-pressure raising effect of NaCl.
      K supplementation significantly enhanced sodium excretion and reduced sodium
      retention, increased the urinary nitrite plus nitrate excretion and kidney
      constitutive NO synthase activity in salt-loaded DS rats. These effect did not
      occur in the rats fed a low sodium diet with K supplementation. These results
      suggest that K supplementation attenuates development of hypertension with
      reduction of sodium retention in salt-loaded DS rats, which is mediated by the
      recovery of salt-induced NO production mechanism.

PMID- 10574421
TI  - Acute and chronic effects of a hypocaloric diet on 24-hour blood pressure, heart
      rate and heart-rate variability in mildly-to-moderately obese patients with
      essential hypertension.
AB  - We examined the acute and chronic effects of a nutritionally balanced, moderately
      hypocaloric diet on 24-hour ambulatory blood pressure, heart rate and heart-rate
      variability in mildly-to-moderately obese patients with essential hypertension.
      We enrolled 16 obese patients with essential hypertension [age: 51-76 years, body
      mass index (BMI): 26-32 kg/m2]. For the initial week, a standard diet of 2,000
      kcal/day was given, followed by a 3-week of a hypocaloric diet of 850 kcal/day.
      In the last period of the standard diet and in the first and the last periods of
      the hypocaloric diet, each subject's 24-hour ambulatory blood pressure, heart
      rate and R-R intervals of the electrocardiogram were recorded, and electrolytes
      and catecholamines in 24-hour urine samples were also measured. A power spectral
      analysis of the heart-rate variability was performed over a 24-hour period based
      on the autoregressive method. The subjects lost 3.7+/-0.3 kg (mean +/- s.e.m.) of
      body weight during the 3-week hypocaloric diet period. The 24-hour blood pressure
      did not differ between the last period of the standard diet and the first period
      of the hypocaloric diet; however, it showed a significant reduction after 3 weeks
      of the hypocaloric diet. The decrease in the 24-hour blood pressure during the
      study period was 10.5+/-1.5 mm Hg systole and 4.3+/-1.8 mm Hg diastole. In
      contrast, the 24-hour heart rate was significantly reduced in the first period of
      the hypocaloric diet, although the body weight and blood pressure did not change,
      and the rate was maintained even in the last period of the hypocaloric diet. The
      decrease in the 24-hour heart rate during the study period was 2.8+/-0.9 beats
      per minute. The hypocaloric diet did not change any autonomic indices obtained
      from a power spectral analysis of the heart-rate variability. In conclusion,
      different responses to a hypocaloric diet were observed between the blood
      pressure and the heart rate in obese hypertensive patients. The changes in power
      spectral parameters of the heart-rate variability were less apparent than those
      found with the blood pressure or the heart rate.

PMID- 10574422
TI  - Sexually dimorphic hemodynamic effects of intragastric ethanol in conscious rats.
AB  - This study investigated the gender-related differences in hemodynamic effects of
      small to moderate doses of intragastrically (i.g.) administered ethanol in
      conscious rats. Changes evoked by ethanol (0.25, 0.5 or 1 g/kg) in mean arterial
      pressure (MAP), heart rate, cardiac index (CI), stroke volume (SV), and total
      peripheral resistance (TPR) were followed for 90 min in age-matched male and
      female Sprague-Dawley rats. Baseline values of MAP (121+/-2 vs. 124+/-2 mm Hg)
      were similar whereas CI (55+/-2 vs. 43+/-2 ml/min/100 g) and TPR (2.2+/-0.1 vs.
      3.0+/-0.1 mm Hg/ml/min/100 g) were significantly (P<0.05) higher and lower,
      respectively, in female compared with male rats. In male rats, the middle dose
      (0.5 g/kg) of ethanol caused a slight increase in MAP due to significant (P<0.05)
      increases in CO whereas the other two doses (0.25 and 1 g/kg) had no effect on
      MAP. In female rats, MAP was not affected by ethanol (0.25 and 0.5 g/kg) and
      showed a significant reduction by the higher dose (1 g/kg) that was associated
      with decreases in CO and SV while TPR did not change. The hypotensive effect of
      ethanol (1 g/kg) in female rats started after 50 min, was maximal (13+/-1.7 mm
      Hg) at 70 min and remained so for the remaining 20 min of the study. Blood
      ethanol concentrations were similar in male and female rats. These findings
      suggest that the hemodynamic responses to i.g. ethanol are gender-related and
      that ethanol-evoked hypotension in female rats appears to involve a reduction in
      cardiac output.

PMID- 10574423
TI  - Antihypertensive profiles with ascending dose combinations of ramipril and
      felodipine ER.
AB  - The aim of the study was to identify the most appropriate dosage combination of
      ramipril and felodipine ER (an extended release tablet) for mild-to-moderate
      hypertension. Hypertensive patients (N = 507) with supinediastolic blood pressure
      (DBP) values between 100-115 mm Hg were included in a randomized, multicenter,
      double-blind study of 3x4 factorial design with a 2-4 week single-blind, placebo
      run-in and 6 week active treatment phase. The patients were randomized to 12
      groups: placebo, ramipril (2.5, 5, 10 mg), felodipine ER (5, 10 mg), or ramipril
      felodipine ER combinations (2.5/5 mg, 2.5/10 mg, 5/5 mg, 5/10 mg, 10/5 mg, 10/10
      mg). Although the greatest reductions in blood pressure were observed with
      ramipril-felodipine ER (10/10 mg), consideration of the antihypertensive efficacy
      and safety factors suggest that the ramipril-felodipine ER (5/5 mg) combination
      has the best efficacy/tolerability ratio of the combinations tested. The
      incidence of adverse events with ramipril-felodipine ER combination therapy was
      similar to that with felodipine ER monotherapy, but peripheral edema, tachycardia
      and vasodilatation occurred less frequently with ramipril-felodipine ER (5/5 mg)
      combination than with felodipine ER monotherapy. The combination of ramipril
      felodipine ER (5/5 mg) can be considered to be the most suitable option for
      hypertensive patients with an inadequate response to either of the
      monocomponents.

PMID- 10574424
TI  - My way in science.

PMID- 10574425
TI  - An attempt for the application of the basic Law of Psychophysics (Fechner-Stevens
      Law) in the domain of visceral stimuli in humans.
AB  - The validity of the basic Law of Psychophysics proposed originally by Fechner and
      revised by Stevens had been tested in the domain of visceral perception. The
      experiments were carried out on six adult colonostomy patients. The distension of
      the sigmoid colon (the phi-value of the Fechner-Stevens equation) had been
      undertaken by the aid of a rubber balloon inserted into the intestinal stoma
      orifice and controlled by a computerized pneumatic system. The tracking of
      sensations of "gut-feelings" by the subjects (the psi-value of the Fechner
      Stevens equation) had been made possible by applying the subjects' manipulation
      of a sliding potentiometer of a Visual Analogue Scale (VAS-device). The results
      seem to prove the extension of the validity of the Fechner-Stevens power equation
      to the field of visceral perception.

PMID- 10574426
TI  - The electrogenic sodium pump activity in Aplysia neurons is not potential
      dependent.
AB  - We have investigated the potential dependence of the electrogenic sodium pump in
      Aplysia neurons by recording the potential and current induced by sudden change
      of the artificial sea water from one containing K+ at various concentrations to
      K+ -free sea water in the presence or absence of ouabain. Both K+ free sea water
      and ouabain block sodium transport and result in a significant depolarization due
      to removal of a maintained outward current that is a result of transport of more
      Na+ out of the cell than K+ into the cell during pump operation. In the presence
      of ouabain there is, however, an inward current induced by changing external K+
      concentration from zero to some value between 1 and 20 mM, and this current is
      greater with a greater K+ concentration gradient. The current induced by change
      from zero to 1 mM K+ does not show any potential dependence, although those
      currents induced by higher K+ concentrations are potential dependent. We conclude
      that the activity of the electrogenic sodium pump is not potential dependent, but
      that the potential independence is obscured if higher concentrations of K+ are
      used to activate the electrogenic sodium pump.

PMID- 10574427
TI  - Aluminum enhances the voltage activated sodium currents in the neurons of the
      pond snail Lymnaea stagnalis L.
AB  - 1. The effects of aluminum on voltage activated sodium currents (VASCs) were
      investigated by using the conventional two-electrode voltage clamp technique in
      Lymnaea stagnalis L. neurons. The peak amplitude, kinetics, and voltage
      dependence of activation and inactivation of the sodium currents were studied in
      the presence of 5-500 microM AlCl3, at pH = 7.7. 2. There was a significant
      concentration-dependent increase in the peak amplitude of sodium currents after
      Al treatment, ED50 = 67 microM. The threshold concentration of the enhancement
      was 50 microM. The maximal peak increase of 143% was caused by a 500 microM
      aluminum. The action of aluminum on VASCs developed slowly, and it is not
      recovered by washing within 20 min. 3. There was little alteration of the voltage
      dependence of the current. It was not a significant effect on the activation- and
      inactivation time constants of INa, but the steady-state inactivation curve
      shifted to negative direction on the voltage axis in the presence of Al. 4. The
      leak currents were not influenced by aluminum up to the highest concentration
      applied.

PMID- 10574428
TI  - Effects of naloxone on c-jun/AP-1 in met-enkephalin-and FMRFamide-immunreactive
      neurons of a gastropod snail.
AB  - 1. Opioid- and FMRFamide (FMRFa)-ergic systems are believed to play antagonistic
      behavioral roles in both higher and lower animals. In our previous experiments on
      a snail, behavioral choice has been demonstrated to be dependent on a balance
      between FMRFa and enkephalins [7]. Here, we examined if the disturbance of the
      balance causes changes in the activity of both systems. Opiate receptor blocker
      naloxone was applied and its effect on c-jun expression of met-enkephalin (MEnk)-
      and FMRFa-ergic neurons was examined immunocytochemically in terrestrial
      gastropod snail Cepaea nemoralis. 2. In control, untreated snails, central
      neurons with c-jun/AP-1-like-immunoreactivity were found to occur. These included
      MEnk-, FMRFa- and 5HT-immunoreactive (-ir) neurons, as was revealed by double
      labelling. 3. After treatment with naloxone for 4 h, the following changes were
      observed: (i) increase in the number of MEnk-ir neurons; increase in the number
      of neurons showing c-jun/AP-1 and MEnk double-labeling; (ii) disappearance of c
      jun/AP-1-immunoreactivity from some FMRFa-ir neurons. 4. It is suggested that
      immediate early genes are involved in the mechanisms responsible for the
      reciprocal regulation of the opioid and antiopioid neuropeptide systems.

PMID- 10574429
TI  - MIP-immunoreactive innervation of the snail, Helix pomatia, heart. An
      ultrastructural study.
AB  - The ultrastructural characteristics of the innervation established by MIP
      (Mytilus inhibitory peptide) immunoreactive neurons was investigated in the heart
      of the snail, Helix pomatia, applying correlative light- and electron microscopic
      pre-embedding immunocytochemistry on Vibratome-slices. In both the auricle and
      ventricle, the muscle fibers receive a rich innervation by MIP-immunoreactive
      (IR) varicose fibers. However, the innervation is seasonally changing in the two
      parts of the heart. The varicosities, containing a morphologically uniform
      population of large (120-150 nm) electron-dense granules, can be found in three
      different positions in relation to the muscle fibers: (i) close (15-20 nm) but
      unspecialized membrane connections between MIP-(IR) varicosities and muscle
      fibers; (ii) MIP-IR varicosities located relatively far (0.5-several microm) from
      the muscles fibers; (iii) MIP-IR profiles localized freely in the extracellular
      space among the loosely arranged muscle fibers. A general modulatory role of MIP
      in regulating the heart activity of Helix is suggested.

PMID- 10574430
TI  - Guaiacol and vanilloid compounds modulate the A-type potassium currents in
      molluscan neurons.
AB  - The actions of guaiacol (2-methoxy-phenol), vanillin (4-hydroxy-3-methoxy
      benzaldehyd) and other vanilloid compounds such as zingerone (4-/4-hydroxy-3
      methoxyphenyl/-2-butanon) and eugenol(2-methoxy4-/2-propenyl/phenol) were
      investigated on the fast outward potassium currents (A-type currents) in
      molluscan neurons. Guaiacol (0.01-0.1%, w/v) moderately decreased the peak
      amplitude but increased the rate of inactivation of the A-currents in dose
      dependent way (Kd = 0.06% 4 mM, nH = 0.8). Vanillin (5 mM) slightly decreased the
      peak amplitude of the A-currents in Helix neurons but its action was more
      pronounced in dialysed Lymnaea nerve cells. However, vanillin similarly decreased
      the time-to-peak and the time constant of decay of the A-currents both in the
      faster and the slower inactivating Lymnaea and Helix neurons (Kd = 5 mM, nH =
      0.6). The voltage-dependence of activation and inactivation of the A-currents
      were not significantly influenced by guaiacol and vanillin in Helix or Lymnaea
      neurons. Vanillin hardly influenced the delayed outward currents, but decreased
      the leak currents in the identified LPa and RPa 2,3 neurons. A structure-activity
      analysis clearly showed that increasing alkyl tail length from the aldehyde side
      of the vanillin molecule increased the efficacy of the various compounds on the
      amplitude of the A-currents and modified the kinetical influence on the A-current
      channel. Furthermore, an attenuation of the late outward currents and an increase
      of the leak conductance also developed in the presence of zingerone or eugenol.
      Excitatory actions of the studied vanilloids predominated on the various
      molluscan neurons.

PMID- 10574431
TI  - In vitro and in vivo effects of formamidines in locust (Locusta migratoria
      migratorioides).
AB  - In vivo and in vitro experiments were used to study the effects of formamidines
      in the locust, Locusta migratoria migratorioides. In vivo the lethal and the
      antifeeding effects, in vitro the inhibition of the binding of a selective 3H
      ligand to the receptors of octopamine, tyramine, dopamine, serotonin and gamma
      amino butiric acid were studied. We have demonstrated that demethylchlordimeform
      is specific agonist to octopamine receptor, having high affinity to octopamine
      receptor, a moderate affinitiy to tyramine receptor and a low affinity to
      dopamine, serotonin and to gamma-amino butiric acid receptors. The demethylated
      chlordimeform analogoues, demethylchlordimeform and didemethylchlordimeform have
      higher affinity to the octopamine receptor than the parent compound. The
      formamidines had a toxic and an antifeeding effects when injected into the
      locust. The half lethal doses (LD50) and the feeding inhibition were correlated
      with the affinity of the compounds (Ki). The ring substitutions of the mulecule
      have alterated the both affinity and in vivo effect of the compounds. The most
      effective ring substitution pattern is 2,4-disubstitution with a combination of
      methyl groups or halogens. Our results suggest that the lethal effect of
      formamidines is mediated through the octopamine receptor.

PMID- 10574432
TI  - Development of a monitoring network for the analysis of elements in aerosol
      samples collected at Lake Balaton.
AB  - Determination of different toxic elements in aerosol and precipitation samples
      collected at Lake Balaton were carried out. A simple sequential leaching
      procedure was applied for the determination of the distribution of elements. The
      distribution of elements was determined among environmentally mobile, bound to
      carbonates and oxides, and bound to silicates and organic matters
      (environmentally immobile) fractions. Particular attention was paid to
      distinguish between environmentally mobile and environmentally immobile fractions
      because these represent the two extreme modes by which the metals are bound to
      the solid matrices. Aerosol samples were weekly collected in Tihany, Siofok and
      Keszthely on 5 cm diameter Teflon filters with a membrane pump. While Cd
      compounds have been found enormously in the environmentally mobile fractions, As
      compounds accumulated almost evenly among portions. The results of sequential
      leaching give an indication of the mobility of the elements once the aerosol is
      mixed directly into natural waters on during scavenging of the aerosol by wet
      deposition. Based upon the data it can be concluded that the effect of
      anthropogenic sources is minor in this area.

PMID- 10574433
TI  - Influence of HgCl2 on the osphradial multisensory system of Lymnaea stagnalis L.
AB  - The osphradial multisensory system of Lymnaea stagnalis L. (Pulmonata,
      Basommatophora) was used to demonstrate the modulation of chemosensory
      information both at periphery and central nervous system (CNS) following heavy
      metal treatments. A semi-intact preparation including osphradium, CNS and the
      right inner parietal nerve (r.i.p.n.) connecting them was used to record both
      extracellular activity of nerve and intracellular activity of central neurons
      receiving information from osphradium. The ion currents of osphradium were
      recorded using patch-clamp method. The changes in nerve and neuronal activity
      were expressed by averaging of firing frequency and interspike intervals. The
      chemosensory function of osphradium was shown by application of L-aspartate,
      urea, saccharose and stagnant water to its surface. The central neurons reacting
      to the stimulation ofosphradium were located to visceral, right parietal, pedal
      and cerebral ganglia of Lymnaea. Both the acute and chronic treatments with HgCl2
      damaged the sensory function of osphradium traced on the flow of information from
      periphery to central neurons. At the same time, mercury chloride modified the
      synaptic connections of respiratory pattern generators as well as the Ca- and K
      dependent ion currents of osphradial neurons. The results proved the multisensory
      role of osphradium sensing the alterations in the environment and its usefulness
      in monitoring the effects of pollutants at various level of regulation from
      chemosensory epithelium to CNS.

PMID- 10574434
TI  - Cellular analysis of appetitive learning in invertebrates.
AB  - In recent years significant progress has been made in the analysis of the
      cellular mechanisms underlying appetitive learning in two invertebrate species,
      the pond snail Lymnaea stagnalis and the honeybee Apis mellifera. In Lymnaea,
      both chemical (taste) and tactile appetitive conditioning paradigms were used and
      cellular traces of behavioural classical conditioning were recorded at several
      specific sites in the nervous system. These sites included sensory pathways,
      central pattern generator and modulatory interneurones as well as motoneurones of
      the feeding network. In the honeybee, a chemical (odour) appetitive conditioning
      paradigm resulted in cellular changes at different sites in the nervous system.
      In both the pond snail and the honeybee the activation of identified modulatory
      interneurones could substitute for the use of the chemical unconditioned
      stimulus, making these paradigms even more amenable to more detailed cellular and
      molecular analysis.

PMID- 10574435
TI  - Effects of veratridine and its derivatives on the Na-conducting channels in Helix
      neurons.
AB  - Effects of veratrum alkaloids were studied on the Na-channels of the land snail
      Helix pomatia. It was found that veratridine and its analogues depolarize the
      membrane due to the increased Na-permeability. The inactivation was shifted right
      along the voltage axis and the recovery from the inactivation was faster after
      veratridine treatment. After alkaloid treatment the selectivity of the Na-channel
      decreased, however, the selectivity sequence was not altered. The activation
      curve was not shifted. Veratridine derivatives, which appeared to be more
      effective on insects, had almost no effect on the Na-current.

PMID- 10574436
TI  - Birds as objects in bioindication of radioactive pollution.
AB  - This article is a review the recent results of research in the accumulation of
      natural and artificial radionuclides in birds from Russia (Adigea, Krasnodar,
      Rostov, Astrahan and Moscow regions, Novaya Zemlya isles), Ukraine, Vietnam,
      Poland, Ethiophia and Mongolia after global precipitation and local pollution,
      such as in the East-Urals radioactive region and radioactive zones after the
      Chernobyl accident. Resident birds reflect local level of radionuclide
      contamination. The 90Sr concentration in the food of the Pied Flycatcher had a
      tendency to increase in dependent of age. The Common Jay and the Mallard were the
      most contaminated with 137Cs in the Bryansk region. The total content of various
      radio-isotopes of plutonium in bird bones from Southwest Russia were hundred and
      thousand times more, than in Mongolia. Activity levels in specimens from Ethiopia
      bear record to Ethiopia can notbe a "pure" control site in radioecological
      research and radioactive background since it does not significantly differ from
      Turkmenia and Mongolia.

PMID- 10574437
TI  - The contribution of a pyrethroid insecticide to the massive eel (Anguilla
      anguilla) devastation, in Lake Balaton, in 1995.
AB  - In the summer of 1995, 30 tonnes of eel (Anguilla anguilla) died in Lake Balaton,
      Hungary. An investigation was carried out to find the causes of this
      ecocatastrophe. During this investigation, certain biochemical parameters, i.e.
      the blood sugar level, the acetylcholinesterase (AChE, EC 3.1.1.7), lactate
      dehydrogenase (LDH, EC 1.1.2.3), glutamic-oxaloacetic transaminase (GOT, EC
      2.6.1.1), and glutamic-pyruvic transaminase (GPT, EC 2.6.1.2) activities in the
      blood serum of the collected surviving and dying eels were examined.
      Deltamethrin, the active ingredient of the insecticide K-OTHRIN 1 ULV, used
      against mosquitoes was detected in different animal species, i.e. eel, bream
      (Abramis brama), pike perch (Stizostedion lucioperca), and the common gull (Larus
      canus) and in sediment samples from the lake. Additionally, laboratory
      experiments were carried out to study the effects of deltamethrin on eels. During
      the investigation in the field it appeared that the AChE activity was
      significantly lower in the blood serum of the dying eels as compared to that in
      living animals (P<0.05, Student's t-test). The blood glucose content exhibited a
      difference, too: it was 2.5 times higher in the dying eels than in the surviving
      ones. A huge increase in the LDH level was measured in the dying eels. The GOT
      activities of the serum were twice as high in the dying eels as in the living
      fish, while the GPT was not significantly changed. Deltamethrin was detected in
      different tissue samples of the dying eels: 2.70-18.1 microg/kg in the liver, 9.0
      31.1 microg/kg in the gill and 3.0 microg/kg wet tissue in the muscle.
      Deltamethrin residues were found in tissue samples from other animals, in the
      following concentrations: 0.44 microg/kg in bream, 2.14 microg/kg in pike perch
      and 1.06 microg/kg wet tissue in dead gulls. The sediment samples collected from
      the sites of the devastation contained deltamethrin in a concentration of 5.50
      30.00 microg/kg wet sediment at the time of the eel deaths, and in a
      concentration 7.00-8.75 microg/kg wet sediment a month later. Laboratory
      experiments with the insecticide K-OTHRIN 1 ULV revealed that 1.00 microg/l of
      its active ingredient, deltamethrin, caused the death of 50% of the eels after an
      exposure time of 96 h. During this experiments similar trends could be observed
      in changes of enzyme activities of the treated eels to those that were detected
      in filed study during the eel devastation in Lake Balaton. At the end of a one
      week treatment with the insecticide at the concentration of 0.5 microg/l of its
      active ingredient the gills of the treated eels contained deltamethrin at 12.6
      44.8 microg/kg wet tissue concentration, while at the 24th hour after the
      treatment (11.2-42.7 microg/kg wet tissue) deltamethrin concentration in the
      liver of treated eels could be detected. All the above-mentioned changes and the
      detected deltamethrin residue in the eels appear to demonstrate the contribution
      of deltamethrin to the severe eel devastation. This information on the ecological
      risk of pyrethroid insecticides might be useful in their further application.

PMID- 10574438
TI  - Serotonin inhibits ciliary transport in esophagus of the nudibranch mollusk
      Tritonia diomedea.
AB  - Both serotonin and the molluskan pedal neuropeptides (TPEPs) cause increased
      ciliary beating rate of cells of the foot epithelium of the nudibranch mollusk,
      Tritonia diomedea. Here we compared responses of the ciliated epithelium of the
      esophagus with that of the foot, and report fundamental differences. Serotonin
      reduces the ciliary transport rate of the esophagus. We find also that the
      serotonin driven inhibition of esophagus is blocked and the excitation of foot
      epithelium is reduced by the serotonin receptor blocker ketanserin. On the
      contrary, ergometrine completely blocked the serotonin effect in the esophagus,
      and does not block the serotonin effect in the foot. Neither the TPEP driven
      excitation of ciliated cells of the foot nor that of the esophagus is blocked by
      ketanserin and ergometrine. Clearly, serotonin and TPEP regulation of different
      ciliated epithelia involve different receptors. Thus, mechanisms of serotonin
      control of different ciliated epithelia in the same animal are apparently
      fundamentally different, and unlike responses in all previous reports, 5HT here
      inhibits a ciliated epihelium.

PMID- 10574439
TI  - The actions of FxRFamide related neuropeptides on identified neurones from the
      snail, Helix aspersa.
AB  - Intracellular recordings were made from identified neurones in the suboesophageal
      ganglia of the snail, Helix aspersa. The actions of the eight FxRFamide analogues
      were investigated on these neurones. These peptides included ones isolated from
      arthropods and nematodes. All the peptides excited certain neurones while
      inhibiting others, though their relative potencies varied. Overall on neurones
      inhibited by these peptides the potency order was: DNFLRFamide > FMRFamide >
      PDVDHVFLRFamide = KNEFIRFamide > FLRFamide >> SDRNFLRFamide = SDPNFLRFamide >
      KHEYLRFamide. However, if the responses are compared on individual cell types,
      then the picture becomes more complex. For example, on cell F-2, KNEFIRFamide
      proved to be potent with an EC-50 value of 0.54 microM. On neurones F-13/16 and E
      16, PDVDHVFLRFamide was inhibitory while FMRFamide, FLRFamide, SDRNFLRFamide and
      SDPNFLRFamide were excitatory. In terms of overall excitatory actions, the data
      are less complete but an approximate order of potency is: FMRFamide > DNFLRFamide
      >> SDPNFLRFamide > PDVDHVFLRFamide >> KNEFIRFamide = KHEYLRFamide =
      SDRNFLRFamide. However this again varies between specific neurones. These results
      demonstrate that peptides from insects, crustacea and nematodes are active on
      Helix neurones and may activate specific receptor subtypes, indicating the
      possible presence of endogenous analogues of these non-molluscan peptides in the
      Helix nervous system.

PMID- 10574440
TI  - Effect of volatile anaesthetics on the electrical activity and the coupling
      coefficient of weakly electrically coupled neurones.
AB  - 1. The application of the volatile anaesthetics, halothane and isoflurane (1% v/v
      and 2% v/v), to the CNS of Lymnaea reduced the firing frequency of the small
      weakly coupled pedal A cluster (PeA) neurones, which eventually become quiescent.
      There was no change in their resting membrane potential. 2. Met-enkephalin
      significantly increased the coupling coefficient between PeA neurones. 3. The
      volatile anaesthetics decreased the coupling coefficient even in the presence of
      met-enkephalin. 4. These effects were dose dependent and the effects of halothane
      were more rapid than those of isoflurane, reflecting their different anaesthetic
      potencies.

PMID- 10574441
TI  - Rainbow trout (Oncorhynchus mykiss) exposed to oxygen supersaturation and
      handling stress: plasma cortisol and hepatic glutathione status.
AB  - Three groups of one summer old rainbow trout were exposed for 22 days either to
      normoxia (100%) or moderate oxygen supersaturation; 120% and 140%. After the
      exposure, all groups were transported for three hours in hyperoxic conditions
      (123% O2) thus simultaneously experiencing density and handling stress. The
      recovery of rainbow trout to multiple stressors was measured in normoxic
      conditions. Moderate oxygen supersaturation did not have any negative effects on
      growth, feed conversion and blood hematology measured over 22 days. On the other
      hand, the combined effects of the stressful environment in the fish farm and
      oxygen supersaturation resulted in a 3-fold increase in plasma cortisol levels in
      those with 100% and 120% O2 supersaturation and a 2-fold increase in the 140%
      supersaturation group. Furthermore, the stress response after transportation was
      lowest in the 140% group 24 hours after recovery but highest after 70 hours.
      Moderate hyperoxia or transportation stress did not change glutathione
      concentrations in liver indicating that routine sampling does not affect hepatic
      glutathione status. Our results indicate that moderate O2 supersaturation (<140%)
      could be considered as feasible in cultivation of rainbow trout since no harmful
      effects were found.

PMID- 10574442
TI  - Nitric oxide selectively enhances cAMP levels and electrical coupling between
      identified RPaD2/VD1 neurons in the CNS of Lymnaea stagnalis (L.).
AB  - The isolated CNS of the freshwater mollusc Lymnaea stagnalis was used as a model
      to study the role of cAMP in NO-mediated mechanisms. The NO donor, DEA/NO (10(-5)
      10(-3) M) increased cAMP concentrations in the cerebral, pedal, pleural, parietal
      and visceral ganglia. In contrast, in the buccal ganglia the same doses of DEA/NO
      decreased the level of cAMP production. The NOS inhibitor, L-NNA (10(-4) M)
      increased cAMP concentrations in all areas of the CNS. L-arginine (1 mM), a
      metabolic precursor of NO, mimicked the action of the NO-donor. The coefficient
      of electrical coupling between two viscero-parietal peptidergic neurons
      (VD1/RPaD2) was enhanced by both DEA/NO (10(-4) M) and 8-Br-cAMP (10(-4) M)
      whereas 8-Br-cGMP (2x10(-4) M) reduced the coupling. We suggest that cAMP
      dependent mechanisms are involved in neuronal NO signaling in this simpler
      nervous system.

PMID- 10574443
TI  - Elementary and compound postsynaptic potentials in the defensive command neurons
      of Helix lucorum.
AB  - The present communication concerns with the analysis of elementary and the
      compound excitatory postsynaptic potentials (eEPSPs and cEPSPs) recorded by
      intracellular microelectrode from an identified defensive command neuron of the
      snail Helix lucorum. The eEPSPs were evoked by single presynaptic action
      potentials (APs) elicited by cationic current injection into one of the
      identified sensory neurons synapsing on the respective command neuron. The cEPSPs
      were elicited by local brief tactile stimuli on the skin or internal organs. It
      was shown that the cEPSPs amplitudes depend mainly on the number of activated
      sensory neurons. Compound EPSPs depend also on frequency and the number of APs in
      the bursts occurring in a single neuron. Presynaptic APs having frequency 2-10 Hz
      evoke high frequency depression of that eEPSPs after an interval is followed by
      post-tetanic potentiation of single eEPSPs. Preceding stimulation of a pneumostom
      area facilitates the cEPSPs elicited by repeated stimulation of viscera. The
      eEPSPs from the same visceral area demonstrate no heterosynaptic facilitation in
      experiments with double parallel intracellular recording from responsive sensory
      and command neurons. The different types of the eEPSPs plasticity are discussed
      according to their contribution cEPSPs plastic changes.

PMID- 10574444
TI  - Inhibition of microglial egress in excised ganglia by human interleukin 10:
      implications for its activity in invertebrates.
AB  - We studied the effects of recombinant human interleukin-10 (IL-10) on
      invertebrate immunocytes and microglia. The present report demonstrates that the
      spontaneous activation of invertebrate immunocytes can be specifically inhibited
      by recombinant human IL-10. Induced immunocyte activation by fMLP can also be
      significantly diminished by IL-10. This inhibition becomes apparent over hours
      and causes ameboid cells to become round and nonmobile. Furthermore, Mytilus
      edulis pedal ganglia maintained in culture, over the course of 24 hours, emit
      microglia. IL-10 significantly reduces this microglial egress, an action that can
      be diminished by concomitant exposure of the excised ganglia to an antibody
      specific to IL-10 as well as IL-10. The anti-IL-10 alone is without effect.
      Active-ameboid microglia that egress become round and inactive following IL-10
      exposure, an action prevented by anti-IL-10. Lastly, a substance immunoreactively
      similar to human IL-10 can be detected in pedal ganglia homogenates. Taken
      together, and since the immunocytes and microglia are responding to IL-10, it
      implies that an IL-10-like substance could be present in invertebrates. In
      conclusion, the study demonstrates that both invertebrate immunocytes and
      microglia respond to IL-10, suggesting an early evolution of this generally
      inhibitory cytokine.

PMID- 10574445
TI  - The anticonvulsive effect of non-NMDA antagonist GYKI 52466 on 3-aminopyridine
      induced primary and secondary cortical ictal activity in rat.
AB  - The effect of GYKI 52466, a selective, non-competitive antagonist of the AMPA
      glutamate receptor subtype was investigated on the development, expression and
      propagation of 3-aminopyridine-induced cortical ictal activity, both in the
      primary and secondary focus. In one group of animals GYKI 52466 was administered
      intraperitoneally, 20 minutes prior to the local application of the convulsant
      the surface of the cortex of anaesthetized rats. Control animals were injected by
      physiological solution. Different parameters of electrographic ictal discharges
      were measured under the influence of the antagonist and compared to control
      values. The results demonstrate that GYKI 52466 exerts anticonvulsive effects on
      both the induction and the expression of primary and secondary electrical ictal
      activity, by delaying the onset of the first ictal period, shortening the
      duration of ictal activity and decreasing the amplitudes of epileptiform
      discharges. However, the seizure propagation was not influenced significantly. It
      is suggested that the initiation, maintenance and the propagation of spontaneous
      seizures may be controlled by separate mechanisms and that changes can occur in
      one of the procedures without parallel changes in others. The observations of the
      present study extend those reported previously by others, namely that activation
      of non-NMDA receptors is significantly involved in the initiation and maintenance
      of cortical epileptiform activity.

PMID- 10574446
TI  - Periodic and oscillatory firing patterns in identified nerve cells of Lymnaea
      stagnalis L.
AB  - Firing patterns in identified neurons of Lymnaea stagnalis L. were analyzed by
      various mathematical methods including spike density function (SDF), interspike
      interval histograms (ISI), Fourier transform and correlation analysis. Input-3
      (IP3) events observed in most of the neurons of the respiratory regulatory system
      caused prominent changes in the firing frequency of the cells. Similarly,
      quasiperiodic firing patterns were observed in the neurons of buccal ganglia
      controlling feeding behavior. Apart from the known periodic patterns a fine
      oscillation of firing rate was observed in a large number of neurons in the
      visceral and parietal ganglia. The frequency of this oscillation varied between
      0.2 and 0.4 Hz. The most obvious oscillatory patterns were found in the A-cells
      presumably resulted by periodically appearing synaptic excitation. Moderate
      intracellular hyperpolarizing current injection, low-Ca/high-Mg saline and
      application of d-tubocurarine failed to abolish the slow oscillations.
      Application of Ca-channel blocker cadmium, however, completely eliminated the
      oscillation in a reversible manner.

PMID- 10574447
TI  - Channel properties of the purified glutamate receptor from rat brain
      reconstituted in planar lipid bilayer membrane.
AB  - The properties of the purified rat brain glutamate receptor (GluR), reconstituted
      in planar lipid bilayer (BLM) were characterised. The single channel currents
      activated by glutamate and aspartate were similar. The different kinetics of
      current fluctuation were observed. Paroxysms of channel activity seems to be
      resulted from the transit of GluR through its active conformation from which it
      can open several times before desensitising. The effect of concanovaline A (Con
      A) as an agent blocking desensitisation of glutamatergic synapses was
      investigated. It was shown that Con A evokes high levels of conductivity and
      prolonged opening events of channels. Another agent, which stabilises glutamate
      activated conductivity, dithiothreitol (DTT), evokes "chronic" channel activity.
      This study demonstrates that purified GluR reconstituted in planar lipid bilayers
      exhibits the ion-conductivity properties that are associated with the
      postsynaptic membrane.

PMID- 10574448
TI  - Presynaptic modulation of transmitter release via alpha2-adrenoceptors:
      nonsynaptic interactions.
AB  - It is generally accepted that neurochemical transmission occurring at the synapse
      is the primary way of sending messages from one neuron to another.
      Neurotransmitters released from axon terminal in a [Ca2+]0-dependent manner act
      transsynaptically on the postsynaptic site. The past 30 years have witnessed
      something of a revolution in the understanding of how neurons communicate with
      each other. It has been shown that the exocytotic release of transmitters from
      axon terminals is subject to presynaptic modulation via presynatic hetero- and
      auto-receptors. For example via stimulation of alpha2-adrenoceptors expressed on
      varicosities and coupled to G-protein the stimulation-evoked release of different
      transmitters can be inhibited. This review will focus on nonsynaptic interactions
      between axon terminals. The present data clearly show that transmitters released
      from axon terminals without synaptic contact play an important role in the fine
      tuning of communication between neurons within a neuronal circuit.

PMID- 10574449
TI  - Comparison of the endogenous heptapeptide Met-enkephalin-Arg6-Phe7 binding in
      amphibian and mammalian brain.
AB  - In previous communications [4, 38] we published that [3H]Met-enkephalin-Arg6-Phe7
      (MERF) binds to opioid (kappa2 and delta) and sigma2 sites in frog and rat brain
      membrane preparations, however no binding to kappa1 sites could be established.
      In the present paper we compare the frog, rat and guinea pig brain membrane
      fractions with respect to their MERF binding data. No qualitative differences
      were found between the three species but specific binding of labelled MERF was
      maximal in frog brain and lowest in guinea pig brain, which corresponds to their
      kappa2 opioid receptor distribution. The naloxone resistant binding was also
      present in all investigated species and varied from 25% in frog and guinea pig
      cerebrum, to 50% in rat cerebrum and cerebellum, but no naloxone inhibition was
      found in guinea pig cerebellum where no kappa2 opioid receptors have been found.
      The presence of sigma2-like receptor was demonstrated in each investigated
      membrane fraction with displacement experiments using (-)N-allyl-normetazocine as
      competitor of tritiated MERF. It was shown that this site was responsible for 60
      80% of [3H]MERF binding. The remaining part of the naloxone resistant labelled
      MERF binding could be displaced only with endogenous opioid peptides as met
      enkephalin, dynorphin and beta-endorphin. The eventual physiological role of
      multiple MERF receptors is discussed.

PMID- 10574450
TI  - The chronoinotropic effects of new regulatory input to the heart of land
      pulmonates.
AB  - The postjunctional potentials and chronoinotropic reactions of the heart evoked
      by activation of multimodal neurons and/or left pallial nerve were investigated
      in three species of land pulmonates: Achatina fulica Ferrussac, Helix lucorum L.,
      Arianta arbustorum L. Both spikes of giant homologous neurons (d-VLN, d-RPLN by
      A. fulica, command neurons of pneumostoma LPa3, RPa3 by H. lucorum) and
      stimulation of the peripheral end of the left pallial nerve evoked the similar
      biphasic inhibitory-excitatory junction potentials in the heart, in mantle
      muscles and in different parts of visceral complex. The positive chronoinotropic
      effects of this input in the hearts of whole-mount preparations were modified due
      to interaction with well-known neural cardioregulating network of the system of
      intestinal nerve.

PMID- 10574452
TI  - Experimental analysis of recently transposed insertion sequences in the
      cyanobacterium Synechocystis sp. PCC 6803.
AB  - The genome DNA of the cyanobacterium Synechocystis sp. PCC 6803 carries a number
      of insertion sequences (Kaneko, T. et al. 1996, DNA Res., 3, 109-136). We
      analyzed one of the abundant ISs (ISY203 group of IS4 family) in the common three
      substrains of Synechocystis and found that the four ISs with identical nucleotide
      sequences were present only in the "Kazusa" strain, whose complete genome
      sequence had been determined, while absent in ancestral strains (the original
      strain from Pasteur Culture Collection and its glucose-tolerant derivative).
      Three of these ISs were found in the genomic sequence as transposase genes of
      sll1474, sll1780 and slr1635. The fourth was on the plasmid, pSYSM. On the other
      hand, all three strains had a novel IS (denoted ISY203x), of which the nucleotide
      sequence was totally identical to the four ISs found only in the Kazusa strain.
      Since the flanking regions of ISY203x did not match any part of the genome or of
      the known plasmids of Synechocystis, it is presumably located on a yet
      uncharacterized plasmid. These suggest that the four ISs in Kazusa strain were
      recently transposed from ISY203x. Apparently, the transposition inactivated four
      preexisting genes, of which modified forms are presented as putative genes
      (sll1473, sll1475, slr1862, slr1863, slr1635 and ssl2982) in the list of the
      complete genome (CyanoBase: http://www.kazusa.or.jp/cyano/cyano.html). The
      possible effects of transposition of ISs in Synechocystis are discussed in
      relation to phenotypic mutations and microevolution.

PMID- 10574451
TI  - Identification of yrrU as the methylthioadenosine nucleosidase gene in Bacillus
      subtilis.
AB  - Taking trimethoprim as the selective agent in the presence of thymine, we adapted
      to Bacillus subtilis a selection procedure depending on the peculiar organisation
      of the one-carbon metabolism. The corresponding pathways couple synthesis of
      thymine to tetrahydrofolate consumption as a substrate of the reaction mediated
      by thymidylate synthase, instead of being a co-enzyme as in the other reactions
      transferring one-carbon groups. Mutants obtained are thymidylate synthase
      deficient, and therefore auxotrophic for thymine. This provides positive
      selection in a first step for gene replacement by a thymidylate synthase
      cassette, and subsequently against its presence. For systematic recombination of
      mutations constructed in vitro, we used the property of B. subtilis to grow at
      high temperature, noting that the thyB gene product is inactive at 46 degrees C,
      while the product of thyA remains active at this temperature. As the first step,
      we built up a recipient thyA- background, deleting the gene by in situ
      recombination. This method was used to investigate the function of the yrrU gene,
      which is presumably involved in a sulfur recycling pathway associated with
      polyamine biosynthesis. We showed that yrrU codes for a protein recycling
      methylthioadenosine, probably a nucleosidase. In addition we observed that B.
      subtilis can use methylthioribose as a sulfur source, and that it is an efficient
      sulfur scavenger.

PMID- 10574453
TI  - Systematic isolation of genes expressed at low levels in inflorescence apices of
      Arabidopsis thaliana.
AB  - We constructed an equalized cDNA library from Arabidopsis inflorescence shoot
      apices including inflorescence meristem, floral meristem and flower tissue
      collected before stage 5 of flower development. The cDNA clones were arrayed on
      membranes and were differentially screened using cDNA pools from vegetative and
      inflorescence tissues as probes. Each clone was classified by expression
      specificity and expression level. By removing the clones that displayed
      hybridization signals, 384 out of 3264 clones in this library remained as
      candidates for inflorescence-specific mRNAs expressed at low levels. Sequence
      analysis of all selected clones indicated that 53 were identical and 120 were
      homologous to genes in public protein databases. The remaining 211 selected
      clones had no significant amino acid sequence similarities with those deduced
      from any reported genes, though 62 of them appeared in Arabidopsis expressed
      sequenced tags (ESTs). About 40% of the selected clones were novel, validating
      the present approach for gene discovery. Northern blot analysis of 22 randomly
      selected clones confirmed that most were expressed preferentially in
      inflorescence tissues. In addition, many clones were transcribed at relatively
      low levels. We demonstrate that the screening method of the present study is
      useful for systematic classification of cDNA species based on expression
      specificity.

PMID- 10574454
TI  - Complete structure of the chloroplast genome of Arabidopsis thaliana.
AB  - The complete nucleotide sequence of the chloroplast genome of Arabidopsis
      thaliana has been determined. The genome as a circular DNA composed of 154,478 bp
      containing a pair of inverted repeats of 26,264 bp, which are separated by small
      and large single copy regions of 17,780 bp and 84,170 bp, respectively. A total
      of 87 potential protein-coding genes including 8 genes duplicated in the inverted
      repeat regions, 4 ribosomal RNA genes and 37 tRNA genes (30 gene species)
      representing 20 amino acid species were assigned to the genome on the basis of
      similarity to the chloroplast genes previously reported for other species. The
      translated amino acid sequences from respective potential protein-coding genes
      showed 63.9% to 100% sequence similarity to those of the corresponding genes in
      the chloroplast genome of Nicotiana tabacum, indicating the occurrence of
      significant diversity in the chloroplast genes between two dicot plants. The
      sequence data and gene information are available on the World Wide Web database
      KAOS (Kazusa Arabidopsis data Opening Site) at http://www.kazusa.or.jp/arabi/.

PMID- 10574456
TI  - Phylogenetic analysis of the third hsp70 homolog in Escherichia coli; a novel
      member of the Hsc66 subfamily and its possible co-chaperone.
AB  - Novel members of the highly conserved protein family, Hsp70, have been found in
      the complete sequences of several genomes. To elucidate a phylogenetic
      relationship among Hsp70 proteins of Escherichia coli, we searched all open
      reading frames derived from 13 complete genomes for Hsp70/actin-related proteins
      by the single-linkage clustering method. Phylogenetic analysis of this
      superfamily revealed that E. coli possesses at least three Hsp70 homologs (DnaK,
      Hsc66 and Hsc62). We found that Hsc62, which is the product of hscC, is a new
      member of the Hsc66 subfamily, and is specific to E. coli. The analysis also
      suggested that YegD of E. coli is closely related to the actin family, which
      consists of the actin, FtsA and MreB subfamilies. A further database search
      revealed that two dnaJ homologs, ybeS and ybeV, were located on the opposite
      strand near hscC. Consequently, E. coli seems to have three gene clusters
      composed of DnaK and DnaJ homologs.

PMID- 10574457
TI  - Structural features of a gene encoding the vacuolar H+-ATPase c subunit from a
      marine red alga, Porphyra yezoensis.
AB  - We report the nucleotide sequence of a gene encoding the c ('16 kDa') subunit of
      the vacuolar-type H+-ATPase (V-ATPase) from a marine red alga, Porphyra
      yezoensis. A cDNA clone was isolated from a leafy gametophyte cDNA library and
      analyzed for the sequence. The genomic DNA sequence was directly determined by
      nested PCR. The structural gene contained four introns within a coding sequence
      of 483 base pairs which encodes a polypeptide of 161-amino acids with four
      hydrophobic transmembrane-spanning regions. Comparison of the deduced amino acid
      sequences showed higher similarity to the land plant Oryza sativa (69.1%) than to
      the Ulvophyceae Acetabularia acetabulum (64.1%). The mRNA was detected both in
      the leafy gametophytes and filamentous sporophytes.

PMID- 10574455
TI  - Characterization of the human dihydropyrimidinase-related protein 2 (DRP-2) gene.
AB  - The genes within the dihydropyrimidinase-related protein (DRP) family, were
      originally identified in humans by their homology to dihydropyrimidinase (DHP).
      Four members of this gene family, DRP-1, -2, -3 and -4, are expressed mainly in
      the fetal and neonatal brains of mammals and chickens, and have been implicated
      as intracellular signal transducers in the development of the nervous system. We
      isolated the human DRP-2 gene, and determined its transcriptional start site and
      exon/intron organization. The gene spanned more than 62 kb, and contained 14
      exons with lengths ranging from 62 bp to 2606 bp. The transcriptional start site
      was determined by an RNase protection assay and 5' rapid amplification of cDNA
      ends (RACE), and a highly GC-rich promoter was identified that contained possible
      regulatory elements such as a TATA box, CAAT box and three GC boxes. Comparison
      of the phase and position of intron insertions within the human DRP-2 gene with
      those within DRP-1, DHP and two Caenorhabditis elegans DRP/DHP homologs,
      indicated that DRPs are more conserved in their exon/intron organization than
      DHP.

PMID- 10574458
TI  - Structural analysis of the TNIT4 genes encoding nitrilase-like protein from
      tobacco.
AB  - Nitrilase (nitrile aminohydrolase, EC 3.5.5.1) catalyzes the hydrolysis of indole
      3-acetonitrile (IAN) to indole-3-acetic acid (IAA). The Arabidopsis thaliana
      genome has four nitrilase genes (NIT1 to NIT4), while tobacco (Nicotiana tabacum)
      has only NIT4 homologs (TNIT4A and TNIT4B) and no NIT1 to NIT3 homologs. We have
      cloned the promoter region of TNIT4B and determined the transcriptional start
      sites which are the same sites in both TNIT4A and TNIT4B. The TNIT4 genes are
      expressed in various organs at low levels. The positions of the exon-intron
      splicing junctions in Arabidopsis NIT1 to NIT3 are completely conserved in
      TNIT4A.

PMID- 10574459
TI  - cDNA cloning, tissue expression, and chromosomal assignment of a mouse gene,
      encoding a 127 kDa UV-damaged DNA binding protein which is defective in XPE
      cells.
AB  - A subset of xeroderma pigmentosum (XP) group E cells lack a factor of the UV
      damaged DNA binding activity. Both 127 kDa and 48 kDa proteins have been reported
      to be responsible for the binding activity. A cDNA for the 127 kDa UV-damaged DNA
      binding protein (p127-Ddb1) was isolated from a mouse fetal brain full length
      enriched cDNA library, and an open reading frame of 1140 amino acids was
      identified. Reverse transcription-coupled polymerase chain reaction (RT-PCR)
      showed that mouse Ddb1 messenger is ubiquitously expressed in adult tissues as
      well as in embryo's. The gene was mapped to near the public locus D19Mit22 region
      of mouse chromosome 19.

PMID- 10574460
TI  - Genomic structure and localization of the human protein phosphatase 2A BRgamma
      regulatory subunit.
AB  - In the course of our analysis of genomic sequence from the human chromosome
      4p16.1 region harboring both the Wolfram and Ellis van Creveld syndrome genes we
      have identified a sequence with high homology (98% at the amino acid level) to
      the rat cDNA coding for the protein phosphatase 2A BRgamma (PP2ABRgamma)
      regulatory subunit. Although the human cDNAs for both the BRalpha and BRbeta
      isoforms have been described previously, the BRgamma subunit has not yet been
      identified in humans. Here we describe the precise genomic organization and
      genetic localization of the human PP2ABRgamma gene.

PMID- 10574461
TI  - Characterization of cDNA clones selected by the GeneMark analysis from size
      fractionated cDNA libraries from human brain.
AB  - We have conducted a sequencing project of human cDNAs which encode large proteins
      in brain. For selection of cDNA clones to be sequenced in this project, cDNA
      clones have been experimentally examined by in vitro transcription/translation
      prior to sequencing. In this study, we tested an alternative approach for picking
      up cDNA clones having a high probability of carrying protein coding region. This
      approach exploited 5'-end single-pass sequence data and the GeneMark program for
      assessing protein-coding potential, and allowed us to select 74 clones out of
      14,804 redundant cDNA clones. The complete sequence data of these 74 clones
      revealed that 45% of them encoded proteins consisting of more than 500 amino acid
      residues while all the clones thus selected carried possible protein coding
      sequences as expected. The results indicated that the GeneMark analysis of 5'-end
      sequences of cDNAs offered us a simple and effective means to select cDNA clones
      with protein-coding potential although the sizes of the encoded proteins could
      not be predicted.

PMID- 10574463
TI  - Molecular cloning and functional characterization of the upstream promoter region
      of the human p73 gene.
AB  - The p73 gene encodes a protein that shares structural and functional homologies
      with the p53 tumor suppressor protein. To investigate the mechanism of
      transcriptional regulation of the p73 gene, we isolated a genomic DNA fragment
      spanning the 5' upstream region of the human p73 gene and characterized the
      promoter region. Unlike the p53 gene promoter, the human p73 gene promoter
      contained a putative TATA-box, and did not exhibit any extended homology to the
      p53 gene. Two CpG islands were located in the 5' upstream region. Transient
      transfection assays using progressive truncations of the p73 promoter showed that
      deletion from -119 to +19 relative to exon 1 resulted in a 13- to 20-fold
      reduction in the p73 promoter activity, suggesting that the elements for basal
      promoter activity exist in this region, where putative Sp1, AP-2 and Egr-1, 2, 3
      sites are located and CpG dinucleotides are especially concentrated.

PMID- 10574462
TI  - Prediction of the coding sequences of unidentified human genes. XV. The complete
      sequences of 100 new cDNA clones from brain which code for large proteins in
      vitro.
AB  - In order to obtain information on the coding sequences of unidentified human
      genes, we newly determined the sequences of 100 cDNA clones of unknown human
      genes, which we named KIAA1193 to KIAA1292, from two sets of size-fractionated
      human adult and fetal brain cDNA libraries. The results of our particular
      strategy to select cDNA clones which have the potentiality of coding for large
      proteins in vitro revealed that the average sizes of the inserts and the
      corresponding open reading frames reached 5.2 kb and 2.8 kb (933 amino acid
      residues), respectively. By the computational analysis of the predicted amino
      acid sequences against the OWL and Pfam databases, 58 predicted gene products
      were classified into the following five functional categories: cell
      signaling/communication, cell structure/motility, nucleic acid management,
      protein management and metabolism. It was also found that 30 gene products had
      homologues in the public databases which were similar in sequence throughout
      almost their entire regions to the newly identified genes. The chromosomal loci
      of the genes were assigned by using human-rodent hybrid panels unless their
      mapping data were already available in the public databases. The expression
      profiles of the genes were studied in 10 human tissues, 8 brain regions, spinal
      cord, fetal brain and fetal liver by reverse transcription-coupled polymerase
      chain reaction, products of which were quantified by enzyme-linked immunosorbent
      assay.

PMID- 10574464
TI  - cDNA cloning of a human brain finger protein, BFP/ZNF179, a member of the RING
      finger protein family.
AB  - The rat bfp/znf179 transcript for a member of the RING finger protein family, is
      expressed in brain and up-regulated in neural differentiation of P19 embryonic
      carcinoma cells. Here we report the full-length cDNA structure of human
      BFP/ZNF179 and its expression profile. The cDNA clone consists of 3082
      nucleotides and encodes an open reading frame of a 632-amino acid protein that
      contains a RING finger domain at its N-terminus, and alanine-rich and glycine
      rich domains at its C-terminus. Reverse transcriptase polymerase chain reaction
      analysis of various human tissues indicated that BFP/ZNF179 is predominantly
      expressed in brain.

PMID- 10574465
TI  - Human SOX11, an upregulated gene during the neural differentiation, has a long 3'
      untranslated region.
AB  - To obtain essential genes for neuronal development, we have performed a molecular
      indexing method using a human teratocarcinoma cell line, NTera-2. We isolated a
      cDNA fragment, designated B18, as an upregulated gene during the neural
      differentiation. From the complete cDNA sequence of B18 it was revealed that this
      cDNA was the human SOX11 gene. While a previous report has determined only a
      approximately 2 kb of the SOX11 cDNA including the entire open reading frame, our
      full length cDNA was 8743 bp possessing a long 3' untranslated region. Human
      SOX11 cDNA was mapped to chromosome region 2p25.3 between markers AFMA070WC9 and
      WI-1412 by radiation hybrid mapping.

PMID- 10574466
TI  - Actions of sodium valproate on the central nervous system.
AB  - The branched chain fatty acid, valproate, has a number of distinct
      pharmacological effects on the central nervous system. In experimental animals it
      showed clear anticonvulsant activity, an observation which led to its major
      clinical use as an antiepileptic agent, especially in petit mal seizures. More
      recently, valproate has shown its usefulness in treating mood disorders and
      migraine headaches. The basis for its clinical efficacy might be related to its
      ability to enhance central GABAergic neurotransmission or perhaps to its
      inhibition of Na+ channels. Whether each of the distinct therapeutic effects of
      valproate has the same molecular basis is not known.

PMID- 10574467
TI  - Social stress adapts signaling pathways involved in stimulation of the
      hypothalamic-pituitary-adrenal axis.
AB  - In socially organized mammals the predominating stressors are not physical events
      but arise from the immediate social environment of the animal. Crowding typically
      evokes social stress reactions with prominent psychosocial components mimicking
      emotional state alterations. Depending on the nature, intensity and duration of
      the initial stimuli, they can either reduce or increase the response of the
      hypothalamic-pituitary adrenal (HPA) axis. In homologous desensitization only
      stimulation by desensitizing hormone is attenuated, in heterologous
      desensitization diminished responsiveness to additional activators occurs. Social
      stress of crowding (21 rats in a cage for 7) for 3, 7, 14 and 21 days
      considerably reduced the corticosterone response to intracerebroventricular (icv)
      administration of carbachol, a cholinergic muscarinic receptor agonist due to a
      homologous desensitization and down-regulation of central muscarinic receptors by
      an increased secretion of acetylcholine. Crowding stress significantly reduced
      the HPA response to icv isoprenaline, a beta-adrenergic agonist and clonidine, an
      alpha2-adrenergic agonist and only moderately diminished the response to
      phenylephrine -- an alpha1-adrenergic agonist. The stimulatory effect of
      dimaprit, a nonselective histamine H2-receptor agonist on HPA axis was
      considerably impaired in crowded rats while the response to 2-pyridylethylamine,
      a H1-receptor agonist was moderately affected. Social crowding stress did not
      substantially alter the CRH-induced ACTH and corticosterone response while it
      suppressed the vasopressin-induced responses. Indomethacin did not change basal
      plasma ACTH and corticosterone levels, indicating that prostaglandins are not
      involved in basal regulation of the HPA activity. Inhibition of prostaglandins
      synthesis by indomethacin significantly diminished the vasopressin-induced HPA
      response under both basal and social stress conditions, whereas it did affect the
      CRH-elicited HPA stimulation under both these circumstances. Social stress
      inhibits the nitric oxide effect on the CRH-induced ACTH response but it does not
      alter the AVP-induced responses. These results indicate a specific and distinct
      influences of social crowding stress on the neurotransmitters- neurohormones-
      prostaglandins- and nitric oxide-induced HPA responses.

PMID- 10574468
TI  - 4-Aminopyridine induces positive lusitropic effects and prevents the negative
      inotropic action of phenylephrine in the rat cardiac tissue subjected to
      ischaemia.
AB  - The effects of 4-aminopyridine (4-AP) at concentration of 1 mM on the
      contractility of rat isolated papillary muscle subjected to simulated ischaemia
      has been evaluated. Additionally, the effects of 4-AP on the phenylephrine
      inotropic action (a selective agonist of alpha1-adrenergic receptor) on rat
      isolated cardiac tissue underwent simulated ischaemia and reperfusion was
      studied. Experiments were performed on rat isolated papillary muscles obtained
      from left ventricle. The following parameters have been measured: force of
      contraction (Fc), velocity of contraction (+dF/dt), velocity of relaxation (
      dF/dt) and the ratio between time to peak contraction (ttp) and relaxation time
      at the level of 10% of total contraction amplitude (tt10) as an index of
      lusitropic effects. Simulated ischaemia lasting 45 min was induced by replacement
      of standard normoxic solution by no-substrat one gassing with 95% N2/5%CO2.
      Although 4-AP exerted a slight, but significant positive inotropic action itself,
      pretreatment with 1 mM of this compound significantly depressed a recovery of Fc
      and +dF/dt, but improves recovery of -dF/dt in the rat papillary muscle during
      reperfusion as compared with control group of preparations. Moreover, the
      paradoxical negative inotropic action of phenylephrine observed in rat stunned
      papillary muscle was prevented in preparations previously treated by 4-AP. These
      findings suggest that an inhibition of outward K+ current (probably transient
      outward and rapid component of delayed rectifying currents at 1 mM of 4-AP)
      aggravates ischaemia-induced failure in contractility but prevents changes in
      alpha1-adrenergic receptor signaling pathway occuring during ischaemia.

PMID- 10574469
TI  - Effect of ebrotidine on gastric mucosal inflammatory responses to Helicobacter
      pylori lipopolysaccharide.
AB  - Helicobacter pylori lipopolysaccharide is a primary virulence factor responsible
      for eliciting acute mucosal inflammatory responses associated with H. pylori
      infection. In this study, we applied the animal model of H. pylori
      lipopolysaccharide-induced acute gastritis to assess the effect of antiulcer
      agent, ebrotidine, on the gastric mucosal inflammatory responses by analyzing the
      interplay between the activity of a key apoptotic caspase, caspase-3, epithelial
      cell apoptosis, and the expression of inducible nitric oxide synthase (NOS-2).
      METHODS: Rats, pretreated twice daily with ebrotidine at 100 mg/kg, or the
      vehicle, were subjected to intragastric application of H. pylori
      lipopolysaccharide at 50 microg/animal, and after 4 additional days on the
      antiulcer drug or vehicle regimen their mucosal tissue used for histologic
      assessment, assays of epithelial cells apoptosis, and the measurements of caspase
      3 and NOS-2 activities. RESULTS: In the absence of antiulcer agent, H. pylori
      lipopolysaccharide induced acute reaction characterized by the inflammatory
      infiltration of the lamina propria, hyperemia, and epithelial hemorrhage. This
      was accompanied by an 11.2-fold increase in epithelial cell apoptosis, a 6.5-fold
      induction in mucosal expression of NOS-2, and a 5.4-fold increase in caspase-3
      activity. Treatment with H2-receptor antagonist ebrotidine, also known for its
      gastroprotective effects, produced a 50.9% reduction in the extent of mucosal
      inflammatory changes elicited by H. pylori lipopolysaccharide and an 82.5%
      decrease in the epithelial cells apoptosis, while the activity of caspase-3
      decreased by 33.7% and that of NOS-2 showed a 72.8% decline. CONCLUSIONS: The
      findings implicate caspase-3 involvement in gastric mucosal inflammatory
      responses to H. pylori lipopolysaccharide, and point towards participation of NOS
      2 in the amplification of the cell death-signaling cascade. Our study also
      demonstrate that ebrotidine exerts modulatory effect on the H. pylori-induced
      mucosal inflammatory responses by interfering with the events propagated by NOS-2
      and caspase-3.

PMID- 10574470
TI  - Dual action of nitric oxide in pathogenesis of indomethacin-induced small
      intestinal ulceration in rats.
AB  - We investigated the pathogenic role of nitric oxide (NO) in indomethacin-induced
      intestinal ulceration in rats. Nonfasting animals responded to a single
      administration of indomethacin (10 mg/kg, s.c.), resulting in multiple
      hemorrhagic lesions in the small intestine, mostly the jejunum and ileum. The
      damage was first observed 6 hr after indomethacin, the severity increasing
      progressively with time up to 24 hr later, accompanied with the gene expression
      of inducible NO synthase (iNOS) and the increase of nitrite and nitrate (NOx)
      contents in the mucosa. The ocurrence of damage was significantly prevented when
      iNOS induction was inhibited by dexamethasone given either once 0.5 hr before or
      twice 0.5 hr before and 6 hr after indomethacin. Likewise, aminoguanidine (a
      relatively selective iNOS inhibitor) reduced the severity of damage, irrespective
      whether given twice or as a single injection 6 hr after indomethacin. By
      contrast, the non-selective NOS inhibitor N(G)-nitro-L-arginine methyl ester (L
      NAME) exhibited a biphasic effect, depending on the time of administration; the
      pre-administration worsened the damage, while the later administration reduced
      the severity of these lesions, yet both responses occureed in a L-arginine
      sensitive manner. Pre-administration of L-NAME, but not aminoguanidine,
      significantly decreased NOx production in the intestinal mucosa of normal rats,
      while the increase of NOx production following indomethacin was significantly
      suppressed by the later administration of aminoguanidine as well as L-NAME. These
      results suggest that NO exerts a dual action in the pathogenesis of indomethacin
      induced intestinal ulceration; NO generated by cNOS is protective against
      indomethacin, by maintaining the integrity of intestinal mucosa, while NO derived
      by iNOS plays a key pathogenic role in the ulcerogenic process.

PMID- 10574471
TI  - Corticotropin releasing hormone (CRH) increases beta-endorphin (beta-end like)
      concentration in cerebrospinal fluid of rats with vasospasm following
      subarachnoid hemorrhage.
AB  - The chronic stage of vasospasm occurring several days after subarachnoid
      hemorrhage (SAH) is characterized by the development of histopathologic changes
      in cerebral arteries causing cerebral ischemia. Numerous experimental data
      indicate the involvement of immune mechanisms in the angiopathy caused by SAH.
      Endogenous opioids play also an important role in the ischemic lesions of the
      brain. Corticotropin releasing hormone (CRH) induces the release of beta
      endorphin (beta-END) from hypothalamic neurons and also from mononuclear white
      blood cells. The function of CRH and beta-END in vasospasm following SAH and the
      interrelationship between neuroendocrine and immune changes requires further
      elucidation. In the present study we investigated the influence of CRH injected
      into cerebral cisterna magna (CM) of rats on beta-END-like level in cerebrospinal
      fluid (CSF) in acute and chronic phase of cerebral vasospasm following artificial
      SAH. Acutely CRH induced a significant rise of beta-END-like in CSF both in SAH
      and sham SAH rats. However, in rats subjected to SAH, a single injection of CRH
      caused a prolonged rise of 5-END in CSF, which was also seen 2 days after SAH,
      during the chronic phase of vasospasm. The obtained results indicate that CRH
      increases neuroendocrine changes induced by SAH, probably by an activation of
      immune cells involved in the patomechanism of chronic vasospasm.

PMID- 10574472
TI  - Oxidized low density lipoprotein inhibits inducible nitric oxide synthase, GTP
      cyclohydrolase I and transforming growth factor beta gene expression in rat
      macrophages.
AB  - Several studies have already demonstrated that oxidized- LDL decreases nitric
      oxide (NO) generation by cytokine-stimulated macrophages. However, the mechanisms
      of such an inhibition have not been yet elucidated. NO generation by inducible
      nitric oxide synthase (iNOS) is dependent on the presence of cofactors for NO
      generation, tetrathydrobiopterin (BH4) among them. The NO generation by these
      cells is also regulated by some endogenous inhibitors, like TGF-beta. Therefore,
      the aim of our recent study was to investigate the influence of ox-LDL on the
      expression of iNOS and GTP cyclohydrolase I (GTP-CH I), the key enzyme involved
      in the BH4 synthesis as well as the ox-LDL effect on TGF-beta expression in rat
      macrophages stimulated with IFNgamma (250 U/ml) and LPS (500 ng/ml). Macrophages,
      activated in this way, express iNOS, GTP-CH I, and TGF-beta mRNA. This expression
      was inhibited when the macrophages were preincubated for 24 hours with ox-LDL
      (100 microg/ml). Quantitative PCR revealed about 10-fold inhibition of iNOS gene
      expression by ox-LDL. As a consequence of down-regulation of iNOS and GTP-CH I
      genes, almost 3-fold diminished generation of NO2- by rat macrophages was
      observed. An inhibition of the TGFbeta mRNA expression was also found. Our
      studies indicate that decreased NO generation by ox-LDL treated macrophages may
      be the result of the diminished expression of both iNOS and GTP-CH I genes. This
      effect may be mediated by the activity of certain endogenous inhibitors of gene
      expression, however, our studies exclude the TGF-beta as a candidate for this
      activity.

PMID- 10574473
TI  - Endotoxaemia in rats: role of NO, PAF and TXA2 in pulmonary neutrophil
      sequestration and hyperlactataemia.
AB  - OBJECTIVE AND DESIGN: The involvement of PAF, TXA2 and NO in LPS-induced
      pulmonary neutrophil sequestration an hyperlactataemia was studied in conscious
      rats. As pharmacological tools WEB 2170 (PAF receptor antagonist, 20 mg/kg),
      camongarel (inhibitor of TXA2 synthase, 30 mg/kg), N(G)-nitro L-arginine methyl
      ester (L-NAME -- non-selective nitric oxide synthase inhibitor, 30 mg/kg) were
      used. METHODS: Plasma lactate and NO2-/NO3- levels as well as myeloperoxidase
      (MPO) activity in lung tissue were measured one and five hours after
      administration of LPS (4 mg/kg(-1)). RESULTS: LPS induced a twofold increase in
      plasma lactate levels and nearly 10-fold increase in plasma NO2-/NO3- levels five
      but not one hour after LPS administration. However, LPS-induced increase in
      pulmonary MPO activity was seen at both time intervals. Neither WEB 2170 nor
      camonagrel changed one or five hours responses to LPS (lactate, NO2-/NO3-, MPO).
      L-NAME potentiated LPS-induced rise in MPO activity in the lung and this
      potentiation was not affected by WEB 2170 or camonagrel. L-NAME supressed plasma
      NO2-/NO3- response and substantially potentiated plasma lactate response to LPS
      and both effects were partially reversed by WEB 2170 or camonagrel. CONCLUSIONS:
      In summary, we demonstrated that PAF and TXA 2 play a role in overproduction of
      lactate during endotoxaemia in NO-deficient rats. However, these lipids do not
      mediate endotoxin-induced sequestration of neutrophils in the lung.

PMID- 10574474
TI  - Response of human blood platelet membrane to sodium selenite.
AB  - It was demonstrated that incubation of blood platelets with sodium selenite (1
      100 microM) resulted in a dose- and time-dependent loss of platelet thiols (both
      glutathione and protein -SH groups). The effects of sodium selenite on platelet
      membrane lipid fluidity by the EPR spin-labelling method was also investigated.
      We showed there were no alterations in membrane fluidity at the deeper regions
      (12-DOXYL-Ste) in lipid bilayer, a slight increase (approx. 7%, p < 0.03) of h
      +1/h0 for spin probe 5-DOXYL-Ste was monitored. The amount of Triton-insoluble
      protein fraction isolated from platelets after incubation (60 min) with selenite
      was significantly elevated (p < 0.006). It has been suggested that limited
      increase in lipid fluidity at the surface regions in the lipid bilayer of the
      platelet membrane in selenite-treated platelets may be the result of alteration
      in lipid-protein interactions caused by protein conformational changes.

PMID- 10574475
TI  - In vitro effect of glutathione precursors on cytotoxicity of amino acids to human
      mesothelial cells.
AB  - Amino acids (AA) which were proposed as an alternative osmotically active agents
      in dialysates are toxic to human peritoneal mesothelial cells (HPMC) due to
      disturbance of the antioxidant-oxidant balance in cells by reducing level of
      glutathione. We assessed if the addition intracellular glutathione precursors: N
      acetyl-cysteine (NAC), tioproline (TP), L--2-oxo--4-thiazolidine acid (PC), and
      glutathione (GSH) could reduce the cytotoxicity of AA, as measured by inhibition
      of cells proliferation and disorders of intracellular 86Rb transport. HPMC were
      obtained from omentum from nonuremic donors and cultured in in vitro conditions.
      The HPMC proliferation capacity was assessed indirectly by the 3H-methyl
      thymidine incorporation assay. The injury to HPMC membrane integrity was assessed
      by the release of radioisotope molecules of 86Rb from the prelabelled cells. We
      have found that AA diminished the intracellular potassium (86Rb) influx.
      Supplementation of AA mixture with NAC enhanced the total 86Rb influx into HMC.
      Other precursors of intracellular glutathione (TP,PC,GSH) tested in the presence
      of AA significantly stimulated intracellular transport of 86Rb via Na,K-ATPase
      dependent channel, but the total intracellular transport of 86Rb was still lower
      than in control. HMC proliferation was significantly inhibited by AA what was
      measured by incorporation of H-metyl-tymidine. In the presence of NAC inhibition
      of HMC proliferation caused by AA was weaker. Our results suggest that some of
      intracellular glutathione precursors may reduce the disturbances of the HMC
      function caused by AA.

PMID- 10574476
TI  - Effect of genistein, tyrphostin and herbimycin on prolactin-stimulated
      progesterone production by porcine theca and luteal cells.
AB  - The potential involvement of protein tyrosine kinases (PTK) in the mechanism of
      prolactin (Prl) action on ovarian cell steroidogenesis has not been elucidated
      and information about research on this subject is scarce. In this preliminary
      study pharmacological intervention was used to provide support for a possible
      involvement of tyrosine kinases in prolactin induction of progesterone secretion
      by porcine thecal and luteal cells. Material used in this experiment were
      cultures of porcine follicular theca interna and early corpus luteum cells. The
      former were isolated from, proestrous preovulatory follicles and the latter were
      obtained by enzymatic dispersion of luteal tissue. Three of tyrosine kinase
      inhibitors, genistein, herbimycin and tyrphostin, were applied. They act through
      different mechanisms, partially blocking Prl-stimulated progesterone secretion.
      Herbimycin at a dose of 3 microM inhibited Prl-stimulated progesterone secretion
      beneath the control level in theca and by 70% in luteal cells. Genistein at a
      dose of 45 microM inhibited Prl-stimulated progesterone secretion beneath the
      control level in theca and down to the control in luteal cells. On the other
      hand, tyrphostin at a dose of 100 microM only slightly suppressed Prl-stimulated
      progesterone secretion by thecal and luteal cells (33% and 40% respectively).
      This investigation is the first search for evidence of involvement of tyrosine
      kinases in Prl-stimulated progesterone production by ovarian cells in the pig.

PMID- 10574477
TI  - Effect of growth hormone, glutamine, and diet on body composition in short bowel
      syndrome: a randomized, controlled study.
AB  - BACKGROUND: A previous controlled study of ten patients with short bowel syndrome
      (SBS) reported human recombinant growth hormone resulted in a significant
      increase in body weight and lean body mass (LBM) without clinical edema. The aim
      of this study was to assess the effect of growth hormone, glutamine, and diet on
      body composition. METHODS: A randomized, 6-week, double-blind, placebo
      controlled, crossover study was performed in eight patients. Active treatment was
      21 days of growth hormone, oral glutamine, and a high-carbohydrate-low-fat (HCLF)
      diet. Body composition was determined by dual-energy x-ray absorptiometry (DEXA)
      scan. Treatments were compared by paired t test. RESULTS: Active treatment
      resulted in significant increases in body weight (mean 3.02 +/- 0.7 kg, p < .05)
      and lean body mass, (mean 3.96 +/- 0.5 kg, p < .001). Percent body fat was
      significantly reduced in the actively treated group (mean -2.51% +/- 0.4, p <
      .001). Body weight returned to base-line within 2 weeks of discontinuing active
      treatment. Macronutrient and fluid absorption did not increase with active
      treatment. CONCLUSIONS: Treatment with growth hormone, glutamine, and HCLF diet
      resulted in decreased percent body fat and increased body weight and LBM in
      patients with SBS, without an increase in macronutrient or fluid absorption. The
      positive findings are most likely a reflection of increased extracellular fluid
      because all eight patients developed peripheral edema on active treatment.
      Furthermore, the positive effect of active treatment does not appear to be
      sustained once discontinued.

PMID- 10574478
TI  - A prospective, randomized clinical trial on perioperative feeding with an
      arginine-, omega-3 fatty acid-, and RNA-enriched enteral diet: effect on host
      response and nutritional status.
AB  - BACKGROUND: The use of immune-enhancing enteral diets in the postoperative period
      has given contrasting results. The purpose of this prospective, randomized,
      double-blinded clinical study was to evaluate the effect of immunonutrition given
      perioperatively on cytokine release and nutritional parameters. METHODS: Patients
      with cancer of the stomach or colo-rectum were eligible. Subjects consumed 1 L/d
      of either a control enteral formula (n = 25; control group) or a formula
      supplemented with arginine, omega-3 fatty acids, and RNA (n = 25; verum group)
      for 1 week before surgery. Both formulas were given by mouth. Six hours after the
      operation, jejunal infusion with the same diets was started and maintained for 7
      days. Blood was drawn at different time points to assess albumin, prealbumin
      (PA), transferrin, cholinesterase activity, retinol binding protein (RBP),
      interleukin-2 receptors alpha (IL-2Ralpha), IL-6, and IL-1 soluble receptors (IL
      1RII). The composite score of delayed hypersensitivity response (DHR) to skin
      test also was determined (the higher the score, the lower the immune response).
      RESULTS: During the 7 days of presurgical feeding, none of the above parameters
      changed in either group. Eight days after operation, in the control group, the
      concentration of PA and RBP was lower than in the verum group (0.18 vs 0.26 g/L
      for PA and 30.5 vs 38.7 mg/L for RBP; p < .05). IL-2Ralpha concentration was 507
      pg/mL in the verum group vs 238 pg/mL in the control group (p < .001), whereas IL
      6 and IL-1RII were higher in the control group than in the verum group (104 vs 49
      and 328 vs 183 pg/mL, respectively; p < .01). The DHR score was 0.68 in the
      control group vs 0.42 in the verum group (p < .05). CONCLUSIONS: Perioperative
      feeding with a supplemented enteral diet modulates cytokine production and
      enhances cell-mediated immunity and the synthesis of short half-life proteins.

PMID- 10574479
TI  - The dimer and trimer of 3-hydroxybutyrate oligomer as a precursor of ketone
      bodies for nutritional care.
AB  - BACKGROUND: Ketone bodies have been considered as a means of providing energy
      because of their good penetration and rapid diffusion in peripheral tissues.
      However, because the currently available form of 3-hydroxybu-tyrate is the sodium
      salt, the sodium load is problematic. To avoid it, a mixture of dimer and trimer
      has been prepared as a precursor of D-3-hydroxybutyrate. The purpose of this
      study was to investigate whether and how the solution would be converted to
      monomers. METHODS: The plasma concentration of 3-hydroxybutyrate monomer was
      measured in 10 rats during infusion of dimer and trimer. Stepwise dilutions of
      the solution were incubated with serum and liver homogenates from five rats,
      serum samples from five volunteers, and a liver sample from one patient with
      liver injury. The solution also was incubated with carboxylesterase and
      triacylglycerol lipase. The concentration of monomer in the medium was measured
      after incubation. RESULTS: The plasma concentration of 3-hydroxybutyrate monomer
      reached 572 +/- 11 micromol/L 15 minutes after beginning infusion of the mixture
      at a rate of 25 micromol x kg(-1) x min(-1) and 270 +/- 40 micromol/L at a rate
      of 12.5 micromol x kg(-1) min(-1). The solution was converted completely to
      monomers when incubated with rat serum or liver homogenate for 10 minutes. The
      mixture also was hydrolyzed by human liver homogenate but not by serum.
      CONCLUSIONS: The dimer and trimer of 3-hydroxybutyrate can be converted rapidly
      to monomer in rat and human tissues. 3-Hydroxybutyrate oligomers could be an
      energy substrate for injured patients.

PMID- 10574480
TI  - Sodium d-fructose-1,6-diphosphate vs. sodium monohydrogen phosphate in total
      parenteral nutrition: a comparative in vitro assessment of calcium phosphate
      compatibility.
AB  - BACKGROUND: The supply of high amounts of calcium (Ca) and phosphorus (P) during
      total parenteral nutrition (TPN) is matter of concern because of the risk
      associated with calcium phosphate precipitation. The in vitro Ca-P compatibility
      in ready-for-use TPN solutions after the addition of different concentrations of
      inorganic phosphate or d-fructose-1,6-diphosphate (FDP) and calcium chloride was
      evaluated. METHODS: Four series of experiments for each Ca + P couple were
      carried out by varying amino acid concentrations (2% or 4%), temperature (25
      degrees C or 37 degrees C), and pH. The extent of precipitation was estimated by
      visual inspection and particle count. The areas of maximal compatibility (ie,
      areas showing the complete absence of precipitates) were drawn from the
      precipitation curves. RESULTS: The precipitation extent was considerably higher
      in conditions mimicking body environment for both Ca + P couples. The
      compatibility area at 37 degrees C and 2% amino acid for CaCl2 + Na2HPO4
      admixtures was included within 2.50 mmol/L CaCl2 and 2.22 mmol/L Na2HPO4, whereas
      that for CaCl2 + FDP was within 33.3 mmol/L CaCl2 and 10.0 mmol/L FDP (20 mEq/L
      of P). Unlike inorganic calcium phosphate, FDP dicalcium salt precipitation was
      kinetically delayed and was only minimally enhanced by decreasing amino acid
      concentration. CONCLUSIONS: Our data indicated that the use of FDP as the P
      source in parenteral nutrition solutions was effective in avoiding the life
      threatening calcium phosphate precipitation. Thus, the addition of FDP to TPN
      admixtures represents a safe choice, allowing the simultaneous administration of
      high amounts of Ca and P in restricted fluid volumes, even at low amino acid
      concentrations.

PMID- 10574482
TI  - Total parenteral nutrition alters molecular and cellular indices of intestinal
      inflammation in neonatal piglets.
AB  - BACKGROUND: The adverse effects of TPN on systemic immunity are well-documented;
      however, the impact of IV feeding on neonatal intestinal immunity is unknown.
      METHODS: A piglet TPN model was used to compare immune cell composition within
      the intestinal epithelium and lamina propria of parenterally and orally fed
      piglets. RESULTS: Small intestinal weight of piglets maintained intravenously was
      reduced 50% after 7 days. Intestinal atrophy in piglets fed parenterally was
      evidenced by decreased width of intestinal villi and colon cuffs and reduced
      intestinal crypt depth. The numbers of CD4+ and CD8+ T lymphocytes were threefold
      greater within the lamina propria of jejunal and ileal villi of piglets supported
      intravenously. Inverse correlations were observed between villus height or width
      and T-lymphocyte numbers (r = -.80; p < .05). Major histocompatibility complex
      class II mRNA expression, an indicator of localized inflammation, was increased
      in the ileum and colon of piglets receiving parenteral nutrition. Goblet cell
      numbers were two-fold greater in jejunal and ileal villi, and mast cells were
      more abundant in the colon of piglets fed parenterally. Furthermore, jejunal T
      lymphocyte numbers were correlated with goblet cell numbers (r = .80; p = .01).
      CONCLUSIONS: These data identify molecular and cellular indices of intestinal
      inflammation that are responsive to IV feeding in neonates and provide a novel
      framework to investigate mechanisms underlying gut atrophy during TPN.

PMID- 10574481
TI  - Hypermanganesemia in patients receiving total parenteral nutrition.
AB  - BACKGROUND: Manganese is one of the trace elements that is routinely administered
      to total parenteral nutrition (TPN) patients. The recommended daily IV dosage
      ranges from 100 to 800 MICROg. We have used 500 microg daily. Recent reports have
      suggested neurologic symptoms seen in some patients receiving home parenteral
      nutrition (HPN) may be due to hypermanganesemia. Therefore, HPN patients and some
      short-term inpatients receiving TPN were studied to ascertain the relationship
      between dose and blood levels. METHODS: Red blood cell manganese levels were
      obtained by atomic absorptiometry. RESULTS: The levels in 36 hospitalized, short
      term patients obtained within 48 hours of initiating TPN were all normal. The 30
      patients receiving TPN from 3 to 30 days had levels that ranged from 4.8 to 28
      microg/L (normal, 11 to 23 microg/L). Two patients had abnormal levels, at days
      14 and 18. Fifteen of the 21 patients receiving inpatient TPN or HPN for 36 to
      5075 days had elevated Mn levels. Only one patient with hypermanganesemia, an
      inpatient, had abnormal biochemical liver tests (bilirubin and alkaline
      phosphatase). One of the patients with a high level had some vestibular symptoms
      attributed to aminoglycoside use and had increased signal density in the globus
      pallidus on T1-weighted images on magnetic resonance imaging (MRI). A second
      patient with Mn levels twice normal had no neurologic symptoms, but had similar
      MRI findings. A third had some basal ganglia symptoms, confirmed by a neurologic
      evaluation, seizures, and very high Mn levels. The MRI showed no signal
      enhancement, but motion artifacts limited the study technically. CONCLUSIONS:
      Hypermanganesemia is seen in HPN patients receiving 500 microg manganese daily
      and may have resulted in some neurologic damage in three patients.
      Hypermanganesemia is sometimes seen after a short course of TPN in inpatients, as
      early as 14 days. Patients should be monitored for hypermanganesemia if they
      receive Mn in their TPN for >30 days. A 500 microg/d dose of Mn is probably
      excessive, and 100 microg/d should probably never be exceeded. Mn should be
      eliminated from the solution if the Mn level is elevated and should not be
      readministered unless the level returns to normal or subnormal. Mn should not be
      supplemented if the patient has liver disease with an elevated bilirubin.

PMID- 10574483
TI  - Validation of bioimpedance analysis as a measure of change in body cell mass as
      estimated by whole-body counting of potassium in adults.
AB  - BACKGROUND: The body cell mass (BCM) is an important measure of macronutrient
      status, but measurements are difficult to obtain outside of sophisticated
      research laboratories. Bioimpedance analysis (BIA) is a simple technique that
      holds promise as a means of estimating body composition. The purpose of this
      study was to evaluate the ability of BIA to estimate changes in BCM as measured
      by whole body counting of 40K (TBK). METHODS: Paired studies of BCM, including
      both TBK and BIA, were compared in 87 human immunodeficiency virus-positive
      subjects and in 62 healthy, weight-stable control adults. Potential errors in the
      predictions were examined. RESULTS: BCM change by TBK and BIA correlated closely
      (r = .755). After accounting for errors related to repeat measures of TBK, the
      correlation coefficient was .784, with a standard error of the estimate of 1.24
      kg. The differences between predicted and measured BCM change were consistent
      with a normal distribution. However, there was a systematic error in prediction,
      with BIA underpredicting the magnitudes of both gains and losses in BCM by TBK.
      CONCLUSIONS: BIA is a useful surrogate for measuring changes in BCM in clinical
      circumstances. Because TBK assesses only intracellular potassium, whereas BIA
      reflects all intracellular cations, the underprediction of BCM change by BIA
      compared with TBK could be related to changes in intracellular potassium
      concentration as a result of malnutrition or its treatment.

PMID- 10574484
TI  - Hypermanganesemia in long-term intravenous nutrition and chronic liver disease.
AB  - BACKGROUND: Hypermanganesemia and cholestatic liver disease are both recognized
      complications of long-term IV nutrition. Manganese is primarily excreted in bile,
      and recent studies have indicated that manganese toxicity may play a role in the
      pathogenesis of IV nutrition-associated cholestasis. METHODS: Whole blood and
      plasma manganese concentrations were measured in patients receiving long-term
      home IV nutrition (HIN, n = 30). Whole blood manganese concentrations also were
      measured in patients with chronic liver disease (CLD, n = 10) and control
      subjects (n = 10). RESULTS: Whole blood manganese concentrations of all CLD
      patients were within the reference interval (73 to 210 nmol/L) and were not
      different from those of the control group (151 +/- 44 nmol/L, CLD vs 155 +/- 35
      nmol/L, control; not significant), despite the presence of cholestasis. In
      contrast, whole blood manganese concentration was increased (>210 nmol/L) in 26
      patients, and plasma manganese concentration increased (>23 nmol/L) in 23 of the
      patients receiving HIN. None of the patients exhibited neurologic signs of
      manganese toxicity. There was no correlation between whole blood manganese
      concentrations and markers of cholestasis, IV manganese intake, or duration of
      HIN. However, plasma manganese concentration correlated both with average weekly
      IV manganese intake (r = .44, p = .02) and with gamma-glutamyl transferase (r =
      .43, p = .02) and alkaline phosphatase activities (r = .55, p = .003).
      CONCLUSIONS: Cholestatic liver disease does not appear to contribute to increased
      whole blood manganese concentrations in patients not receiving HIN. Plasma
      manganese concentrations in patients receiving HIN reflect recent manganese
      exposure and impaired excretion where cholestasis is present. The lack of
      relationship between plasma and whole blood manganese concentrations suggests
      that factors other than manganese intake and excretion affect intracellular
      concentrations.

PMID- 10574485
TI  - Jejunostomy tube feedings should not be stopped in the perioperative patient.
AB  - BACKGROUND: Anesthetic standard of care is to restrict oral intake for 8 hours
      before elective surgery. There is no research addressing appropriate preoperative
      discontinuation of jejunostomy tube (J-tube) feedings. We hypothesized that
      patients could be fed safely, via a J-tube, until the time of surgery. METHODS:
      Patients admitted to a Level I Trauma Center, having J-tubes and undergoing a
      nonabdominal operation, were prospectively evaluated. Group I patients received J
      tube feedings until transport to the operating room. Group II patients had tube
      feedings discontinued for at least 8 hours before surgery. Data were compared
      using the Student's t test and contingency table analysis. RESULTS: There were 46
      patients in group I and 36 in group II. There was no incidence of aspiration.
      Patient groups did not differ in age, mortality, length of stay, injury severity
      score, or ventilator days. Group I patients had tube feedings discontinued for
      fewer hours before and after surgery than group II patients (before surgery: 1.40
      +/- 1.20 vs 11.61 +/- 5.01, respectively; p < .001; after surgery: 2.99 +/- 7.49
      vs 7.11 +/- 9.03, respectively; p = .043); received more kilocalories/ grams of
      protein on the day of surgery (group I vs group II, 1676.15/89.57 +/-
      1133.21/38.04 vs 791.14/57.58 +/-498.66/79.87, respectively; p = .001/p = .032)
      and more kilocalories/grams of protein on the first postoperative day (group I vs
      group II, 1580.74/92.57 +/- 600.53/37.96 vs 1152.47/63.53 +/- 733.96/39.40,
      respectively; p = .006/p = .001). CONCLUSIONS: Patients receiving J-tubes who are
      undergoing nonabdominal operations may safely continue enteral nutrition at
      maximum protein and caloric intake until surgery.

PMID- 10574486
TI  - Ultrasonic investigation of the effect of topical glyceryl trinitrate on
      peripheral arm vein diameter: implications for intravenous nutrition.
AB  - BACKGROUND: It has been suggested that topical glyceryl trinitrate (GTN) ointment
      may cause venodilatation and hence deter thrombophlebitis. However, objective
      evidence of an increase in vein diameter has not been demonstrated. METHODS: B
      mode ultrasonography was used to measure arm vein diameter. In a prospective
      study, measurements were taken before and after 24 hours of exposure to topical
      GTN. RESULTS: Reproducibility of vein diameter measurement was demonstrated.
      Basilic veins were larger than cephalic veins, but exposure to GTN ointment for
      24 hours was not associated with measurable venodilatation. CONCLUSIONS:
      Ultrasonography enabled noninvasive measurement of intraluminal vein diameter. It
      is unlikely that GTN prevents thrombophlebitis in superficial arm veins by
      causing venodilatation.

PMID- 10574487
TI  - Tunneled right atrial catheter infection presenting as renal failure.
AB  - We report two cases of progressive renal failure secondary to
      membranoproliferative glomerulonephritis associated with subclinical septicemia
      from a tunneled right atrial catheter used for home parenteral nutrition
      administration. Although the occurrence of line infection and septicemia is a
      common complication of central venous catheters, a review of the literature
      reveals only one case report of renal failure secondary to an infected implanted
      central venous device. Both patients presented with azotemia and had biopsy
      proven membranoproliferative glomerulonephritis, accompanied by leukocytoclastic
      vasculitis. In both cases, removal of the right atrial catheter and prolonged
      antibiotic therapy was effective in resolving the ongoing infection and resulted
      in marked improvement in renal function. A high index of suspicion for catheter
      sepsis should be maintained in patients with tunneled right atrial catheters
      presenting with subacute renal failure.

PMID- 10574488
TI  - Prevention of liver injury by cytokines.

PMID- 10574489
TI  - PEG and PEG-J for nutrition support in pregnancy.

PMID- 10574490
TI  - Subthreshold (invisible) modified grid diode laser photocoagulation and diffuse
      diabetic macular edema (DDME)

PMID- 10574491
TI  - Subthreshold (invisible) modified grid diode laser photocoagulation in diffuse
      diabetic macular edema (DDME)
AB  - BACKGROUND AND OBJECTIVE: To determine the effectiveness of subthreshold
      (invisible) diode laser (810 nm) modified grid photocoagulation for the treatment
      of diffuse diabetic macular edema (DDME). METHODS: Fifty eyes of 29 patients were
      treated with subthreshold (invisible) diode laser modified grid photocoagulation
      for DDME in a prospective pilot clinical trial. Follow-up was conducted for a
      minimum of 6 months (average: 14.11 +/- 6.15 months). Re-treatment was performed
      for residual edema involving the foveal avascular zone. Ten patients were tested
      with Goldman visual field pre- and post-treatment. Visual improvement, visual
      loss, visual field, reduction/elimination of macular edema, and the number of
      treatments per eye were studied. RESULTS: Reduction/elimination of DDME was
      observed in 39% of the eyes after 1 to 3 treatments (2.22 +/- 0.84 treatments) in
      6 to 12 months; and in 74% of eyes after 1 to 5 treatments (2.90 +/- 1.02
      treatments) 15-24 months follow-up. The presence of cystoid macular edema,
      initial poor visual acuity, or a history of systemic hypertension did not affect
      the outcome. Patients without a history of systemic vascular diseases had a
      better chance of visual stabilization or improvement. Eighty-eight percent of the
      patients had at least stable vision at the last follow-up. Two out of 10 visual
      field tests showed a decrease in paracentral scotomas; no post-treatment
      subjective complaints of increased paracentral scotomas were encountered.
      CONCLUSION: Subthreshold (invisible) diode laser modified grid photocoagulation
      is effective in reducing/eliminating DDME, although resolution of edema may be
      slightly prolonged. However, this method may be advantageous in that it appears
      to reduce the objective and subjective effect on the paracentral visual field.
      Subthreshold (invisible) diode laser modified grid photocoagulation substantially
      reduces the post-treatment atrophic scarring.

PMID- 10574492
TI  - Perfluoro-N-octane (PFO) in the repair of complicated retinal detachments due to
      severe proliferative diabetic retinopathy.
AB  - PURPOSE: To report our experience with perfluoro-N-octane (PFO) in the surgical
      management of complicated retinal detachments due to proliferative diabetic
      retinopathy. METHODS: Retrospective review of 18 consecutive eyes of 18 patients
      with tractional or combined tractional and rhegmatogenous retinal detachments due
      to severe proliferative diabetic retinopathy managed by pars plana vitrectomy and
      the intraoperative use of PFO. Preoperative characteristics, intraoperative
      findings and procedures and postoperative results were recorded. RESULTS: The
      mean preoperative acuity was 2/200 (range, 20/25 to light perception). The mean
      final visual acuity was 4/200 (range, 20/20 to no light perception). With a mean
      follow-up of 6 months, there was an 89% anatomic reattachment rate at the last
      visit and visual acuity was stable or improved in 72% of eyes. CONCLUSIONS: In
      our experience, PFO is a helpful surgical adjunct in the anatomic reattachment of
      tractional or combined tractional and rhegmatogenous diabetic retinal
      detachments. Visual acuity was stabilized or improved in the majority of eyes.

PMID- 10574493
TI  - Intraocular pressure changes in the vitreon study.
AB  - BACKGROUND AND OBJECTIVE: To detect the effect of Perfluoroperhydrophenanthrene
      (vitreon) on intraocular pressure (IOP) changes. PATIENTS AND METHODS: One
      hundred-five eyes with proliferative vitreoretinopathy undergoing vitrectomy
      using vitreon as an intraoperative surgical adjunct were randomized to 2 groups.
      Vitreon was completely removed in 43 eyes (Group A) at the end of operation while
      it was left intravitreally in 62 eyes (Group B) for 4 weeks. Patients were
      followed for at least 18 months. RESULTS: During the first postoperative week, 6
      eyes (14%) in Group A and 14 eyes (22%) in Group B had IOP of 23 mm Hg or more (P
      = .393) while no eyes in either group had hypotony. At the last follow-up 2 eyes
      (5%) in Group A and 6 eyes (10%) in Group B showed chronic hypotony (P = .561).
      CONCLUSION: Although postoperative chronic hypotony risk increased twofold by
      vitreon when it was left intravitreally for 4 weeks, this difference was
      statistically insignificant. Vitreon can be used as a vitreous substitute for 4
      weeks in this regard.

PMID- 10574494
TI  - Surgical outcome after early intraocular pressure elevation following combined
      cataract extraction and trabeculectomy.
AB  - BACKGROUND AND OBJECTIVES: We report on the incidence and course of early
      postoperative intraocular pressure (IOP) elevation and related surgical outcome
      following combined manual extracapsular cataract extraction (ECCE), using a
      sclerocorneal tunnel incision and trabeculectomy. PATIENTS AND METHODS: The
      combined procedure was the initial surgery in each eye. Intraocular pressure was
      measured during the first 4 days, at 1 week, and thereafter following surgery.
      RESULTS: Of 38 eyes (38 consecutive adults), postoperative IOP elevation to > 25
      mm Hg was found in 7 eyes (18.4%) during the first 3 postoperative days. The IOP
      was reduced to < or = 20 mm Hg without hypotensive medication in 3 of them within
      the first 3-7 postoperative days, and remained so after 7-16 months (mean, 10.3
      +/- 4.9 months). Each of the other 4 eyes underwent argon-laser suture lysis 8-10
      days after surgery due to unstable IOP which rose to > 30 mm Hg. Two weeks after
      the operation and thereafter, ie, after 8-22 months (mean, 12.8 +/- 6.4 months),
      each of these 4 eyes necessitated 1-4 (mean, 2.5 +/- 1.3) hypotensive
      medications. CONCLUSION: This study raises the possibility that in eyes with
      early IOP elevation, a delay in promoting aqueous outflow beyond a critical
      period during the first postoperative week might become a risk factor for full
      surgical success.

PMID- 10574495
TI  - Penetrating keratoplasty in patients with corneal scarring due to trachoma.
AB  - BACKGROUND AND OBJECTIVE: Trachoma remains the leading cause of preventable
      corneal blindness. The outcome of penetrating keratoplasty (PK) in these patients
      is usually poor because of the extensive corneal vascularization, adnexal and
      ocular surface problems. We evaluated the long-term results of PK in patients
      with corneal scarring due to trachoma. PATIENTS AND METHODS: The fiels of 16 eyes
      of 13 patients who underwent PK due to late sequel of trachoma were reviewed.
      RESULTS: Preoperative visual acuity ranged from light perception to finger
      counting levels. Preoperatively, dry-eyes, meibomian gland dysfunction,
      trichiasis and cicatricial entropion were treated. Over a mean postoperative
      follow-up of 26.1 +/- 15.6 months (range of 14-61 months), eyes required
      redrafting due to graft rejection and failure, and corneal ulceration (12.5%).
      Fourteen eyes remained clear grafts (87.5%), and 13 eyes (81.3%) achieved 0.1 or
      better visual acuity. CONCLUSIONS: These results suggest that although patients
      with corneal scarring due to trachoma are at high risk, PK may be helpful for
      visual rehabilitation.

PMID- 10574496
TI  - An in vivo model of femtosecond laser intrastromal refractive surgery.
AB  - BACKGROUND AND OBJECTIVE: To develop an animal model for evaluation of
      femtosecond laser intrastromal refractive surgery. METHODS: Intrastromal
      photodisruption was performed in New Zealand Albino rabbits using a femtosecond
      laser system. This surgical pattern consisted of a 100 microm-tick pyramid of
      laser pulses starting 180 microm below the corneal surface. Animals underwent
      serial slit lamp examinations and corneal thickness measurements at 1,3,7,14, and
      28 days, then monthly up to 1 year. RESULTS: Approximately 70 microm of central
      corneal thinning were seen at 1 week, remaining stable up to 7 months.
      CONCLUSIONS: Intrastromal photodisruption with femtosecond lasers produced
      consistent changes in corneal thickness without loss of corneal transparency.
      These changes were more stable than those produced with excimer laser procedures
      in a similar animal model.

PMID- 10574497
TI  - Fluorescence properties of a hydrophilic sensitizer in pigmented rats, rabbits,
      and monkeys.
AB  - BACKGROUND AND OBJECTIVE: To evaluate fluorescence properties of mono-L-aspartyl
      chlorin e6 (NPe6; Meija Seika Kaisha, Ltd., Tokyo, Japan) photodynamic therapy,
      which allows real-time simultaneous imaging of choroidal and retinal vasculature
      during treatment without the addition of another dye. MATERIALS AND METHODS: Four
      pigmented rabbits, 4 pigmented rats, and 2 African green monkeys were
      administered intravenous injections of the NPe6 dye. The animals were immediately
      placed in front of the scanning laser ophthalmoscope and the fundus was viewed
      with the helium-neon laser. The resulting fluorescence was viewed and recorded on
      super-VHS videotape. RESULTS: Fluorescence demonstrated clearly that NPe6 entered
      the retinal and choroidal circulation within seconds of intravenous injection.
      The concentration of NPe6 was diminished over a period of 1.5 hours in the monkey
      and 5 hours in the rat, as evidenced by considerable diminution of the intensity
      of fluorescence. CONCLUSION: NPe6 fluorescence allows evaluation of drug
      availability within the retinal and choroidal circulation and visualization of
      pathological lesions before commencement of photodynamic therapy.

PMID- 10574498
TI  - Surgical excision of selected amblyogenic periorbital capillary hemangiomas.
AB  - To report the successful surgical excision of well-circumscribed capillary
      hemangiomas of the eyelid and orbit inducing occlusion amblyopia in 2 cases with
      immediate improvement of the patient's symptoms. A 2-month-old girl was diagnosed
      with a massive, amblyogenic orbital tumor which was removed intact via an
      inferior transconjunctival orbitotomy after magnetic resonance imaging (MRI)
      revealed a well-defined mass filling the entire inferior orbit. Histopathologic
      examination confirmed the diagnosis of orbital capillary hemangioma. A 1-month
      old girl developed occlusion amblyopia due to an enlarging subcutaneous tumor of
      the left upper eyelid. The discrete mass was excised via an eyelid crease
      approach and confirmed to be an eyelid capillary hemangioma. There were no short
      term or long-term complications in either case. In both cases, immediate
      resolution of occlusion amblyopia and cosmetic disfiguration was achieved. The
      final visual acuities were 20/20 at 5 years in the first patient and 20/30 at 4
      years follow-up in the second patient. Orbital and eyelid capillary hemangiomas
      can induce profound permanent amblyopia. If the tumor is well-circumscribed,
      confirmed with orbital imaging, then surgical excision, with immediate resolution
      of amblyogenic factors, can be considered as a treatment option.

PMID- 10574499
TI  - Incising the thick retrolental fibrovascular tissue with a hooked sclerotome in
      persistent hyperplastic primary vitreous.
AB  - A technique for incising thick retrolental fibrovascular tissue and extensive
      cyclitic membrane is reported in a case of anterior persistent hyperplastic
      primary vitreous. A membranectomy was performed in a 1-month-old post-lensectomy
      baby via a limbal approach. A sclerotome tip was hooked to cut through an
      extremely thick fibrovascular tissue by rotating the sclerotome by its grip.
      Sutherland microscissors (Grieshaber, Switzerland) and a vitrectomy cutter were
      used for further membranectomy. The baby was followed-up until age 18 months. A
      total of 3 membranectomy sessions were required because of rapid cyclitic
      membrane formation, severe centripetal retraction of the membrane on the ciliary
      processes, and posterior synechia. Thorough membranectomy and cutting the iris
      edge maintained a clear pupillary area during the 13-month postoperative period.
      Extremely thick retrolental fibrovascular tissue is a challenging condition that
      can be dealt with by delicate instrumentation.

PMID- 10574500
TI  - Retinal tears associated with panuveitis and Behcet's disease.
AB  - To report retinal tears formation in 3 eyes of 2 patients with active panuveitis
      and Behcet's disease. We describe 2 patients that were diagnosed and treated for
      Behcet's disease with active panuveitis. Retinal tears developed while the
      inflammation was active. The patients were treated with topical, oral steroids,
      and cyclosporine therapy for bilateral panuveitis. One patient presented with a
      retinal tear located at the periphery of the active retinal lesion. The other had
      multiple tears associated with active retinal lesions in both eyes. Argon laser
      photocoagulation was performed in both patients as soon as the tears were
      detected. Ocular inflammation was controlled with this therapy, and only a few
      mild flare-ups occurred. The patients have been followed up for 8 and 16 months,
      respectively. During this period no new retinal tears have developed. Although
      retinal tear formation is rarely associated with Behcet's panuveitis, the
      clinician should be aware of this as a possible complication. When structural
      changes are present in the vitreous, detailed ophthalmoscopy is indicated to
      assess for retinal tears. If a tear is detected in a patient with panuveitis and
      Behcet's disease, laser photocoagulation therapy should be performed immediately
      to prevent retinal detachment.

PMID- 10574501
TI  - Why do we fail with penicillin in the treatment of group A streptococcus
      infections?
AB  - Acute pharyngotonsillitis caused by beta-haemolytic group A streptococcus (GAS)
      is a common childhood disease. Phenoxymethyl penicillin remains the drug of
      choice, as no resistance has been reported so far. Nevertheless, the failure of
      penicillin to eradicate streptococci from the throat occurs in up to 35% of
      patients with pharyngotonsillitis, and might present clinical concern. Various
      explanations have been proposed over the years to account for this perplexing
      phenomenon. Among these are coexistence of oropharyngeal beta-lactamase-producing
      bacteria that degrade penicillin, growth interference by aerobic and anaerobic
      commensals, penicillin tolerance, reinfection, and poor antibiotic compliance.
      Although GAS has been considered an extracellular pathogen, recent studies have
      demonstrated that strains of this bacterium can internalize epithelial cells both
      in vitro and in vivo. The intracellular niche may protect the bacterium from
      penicillin that does not gain high intracellular concentration. In support of
      this hypothesis, GAS strains were shown to survive 4-7 days inside cultured
      epithelial cells. In addition, it was found that GAS strains isolated from
      patients with eradication failure harbour the internalization-associated gene,
      prtF1/sfbI, in higher prevalence than do strains recovered from patients with
      successful eradication. Thus, internalization and intracellular survival
      represent a novel explanation for penicillin eradication failure.

PMID- 10574502
TI  - Fetal RhD genotyping from maternal plasma.
AB  - The prenatal diagnosis of fetal rhesus D (RhD) status is useful for the
      management of RhD-negative women with partners heterozygous for the RHD gene.
      Conventional methods for prenatal fetal RhD status determination involve invasive
      procedures such as fetal blood sampling and amniocentesis. The recent
      demonstration of the existence of cell-free fetal DNA in maternal plasma and
      serum opens up the possibility of determining fetal RhD status by analysis of
      maternal plasma or serum DNA. This possibility has recently been realized by
      three independent groups of investigators. This development represents an
      important step towards the routine application of noninvasive fetal blood group
      diagnosis in sensitized pregnancies and may become a model for developing safer
      noninvasive prenatal tests for other single-gene disorders.

PMID- 10574503
TI  - Effectiveness and role of zanamivir in the treatment of influenza infection.
AB  - Influenza is a worldwide public health issue. The virus circulates annually in
      winter and can cause significant morbidity in the general population and
      increased mortality rates in those who are more susceptible to complications if
      infected by the virus, especially the elderly. Although antivirals to treat and
      prevent influenza have been available in several countries for up to 30 years,
      annual influenza vaccination strategies remain the primary focus in reducing the
      burden of illness caused by this viral infection. Zanamivir is the first of a new
      class of compounds to offer significant advantages over existing influenza
      treatments. It is a potent and specific competitive inhibitor of both influenza A
      and B virus neuraminidase. The drug is administered topically by inhalation
      directly to the site of virus replication in a dose of 10 mg twice daily for 5
      days. In both experimental and naturally acquired treatment studies, zanamivir
      has been shown to have efficacy against both influenza A and B virus and to be
      well tolerated. Significant treatment benefits resulting in reductions in illness
      of up to 2.5 days have been demonstrated in both the general population and in
      patients considered at high risk. In addition, patients receiving zanamivir have
      been able to return to normal activities significantly faster.

PMID- 10574504
TI  - Role of arginine, taurine and homocysteine in cardiovascular diseases.
AB  - Arginine, taurine and homocysteine are amino acids which have been shown to
      affect the risk factors of cardiovascular diseases in humans. Arginine and
      taurine may protect against cardiovascular diseases while homocysteine may be a
      risk factor for them. Both arginine and taurine seem to lower blood pressure,
      arginine may also inhibit atherogenesis, and taurine may have antioxidant
      properties. However, the evidence of the beneficial effects of arginine and
      taurine supplementation from human studies is insufficient. Elevated levels of
      plasma homocysteine may be associated with atherosclerotic and thromboembolic
      cardiovascular diseases. Supplementation with folic acid seems to be effective in
      reducing hyperhomocysteinaemia, but there is an insufficient number of studies
      showing that lowering of homocysteine levels with vitamin supplementation will
      reduce the risk of cardiovascular diseases. In conclusion, further research is
      needed to determine the optimal levels for taurine and arginine in the human diet
      in order to decrease the risk factors for cardiovascular diseases, and to whom
      supplementation with folic acid should possibly be recommended to reduce
      hyperhomocysteinaemia. Even though the use of arginine and taurine supplements to
      reduce cardiovascular risk factors is an interesting possibility, the reported
      health-promoting effects and the safety of such a supplementation should first be
      confirmed.

PMID- 10574505
TI  - New perspectives in the diagnosis of systemic fungal infections.
AB  - Profound and prolonged neutropenia following chemotherapy is a major risk factor
      for systemic fungal infections. Mortality associated with disseminated fungal
      infection is high, and treatment with conventional amphotericin B is complicated
      by renal toxicity. Candida and Aspergillus are among the major pathogens in these
      patients. Many patients remaining neutropenic over a prolonged period of time
      will receive empirical antifungal therapy. The clinical and laboratory diagnoses
      of these infections are neither sensitive nor specific and are generally limited
      in the early detection of invasive fungal infection. However, several new
      approaches to diagnosis are being developed, which should be translated into
      routine practice, based on a greater understanding of the pathogenesis of
      systemic fungal infection and virulence determinants of fungal pathogens. These
      include antigen detection and polymerase chain reaction. Patients with presumed
      fungal infection require more intense and accurate monitoring for signs of
      disseminated infection. Early diagnosis may guide appropriate treatment and
      prevent mortality. Continued development of commercial tests should help achieve
      the objective of definitive diagnostic tests for systemic fungal infections.

PMID- 10574506
TI  - How should doctors communicate the diagnosis of cancer to patients?
AB  - The majority of doctors in North America, Australia and much of Europe now inform
      patients about a cancer diagnosis. However, many doctors report that they have
      difficulty disclosing a cancer diagnosis. Poor doctor-patient communication
      skills may lead to psychological distress including increased anxiety and
      depression and poorer psychological adjustment to cancer. Presenting 'bad' news
      in an unhurried, honest, balanced and empathic fashion has been shown to produce
      greater satisfaction with communication of the news. Consensus guidelines have
      been developed to assist doctors to disclose a cancer diagnosis. Important
      aspects include exploring the patient's expectations, warning him/her that the
      news is bad, giving the news at the patient's own pace, allowing time for the
      patient to react and eliciting the patient's concerns. Doctor-patient
      communication can be improved by including training courses in communication
      skills for medical students and clinicians and providing audiotapes of bad news
      consultations to enhance patient recall of information and increase patient
      satisfaction with communication. Additional research is needed to investigate
      effects of strategies to implement guidelines for delivering a cancer diagnosis.

PMID- 10574507
TI  - Peroxisome proliferator-activated receptor-gamma: a versatile metabolic
      regulator.
AB  - The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear
      receptor that controls the expression of a large array of genes involved in
      adipocyte differentiation, lipid storage and insulin sensitization. PPARgamma is
      bound and activated by prostaglandin J2 and fatty acid derivatives, which are its
      natural ligands. In addition, thiazolidinediones and nonsteroidal anti
      inflammatory drugs are synthetic ligands and agonists of this receptor. Several
      studies have recently shown that this nuclear receptor has a role expanding
      beyond metabolism (diabetes and obesity) with functions in cell cycle control,
      carcinogenesis, inflammation and atherosclerosis. This review addresses the role
      of PPARgamma in these processes.

PMID- 10574508
TI  - Mixed cryoglobulinaemia in patients with chronic hepatitis C infection:
      prevalence, significance and relationship with different viral genotypes.
AB  - In order to analyse the prevalence and significance of cryoglobulinaemia in
      patients with chronic hepatitis C virus (HCV) infection and the possible
      relationship of cryoglobulinaemia with the genotypes of HCV, we studied 89
      patients with chronic HCV infection, 42 healthy controls and 22 patients with
      alcoholic cirrhosis. The patients with HCV were divided into three different
      groups according to the presence of cirrhosis and alanine aminotransferase
      levels. Moreover, in 20 patients with HCV and cryoglobulinaemia, HCV RNA
      sequences were quantified in serum and in cryoprecipitate. Cryoglobulins were
      detected more frequently in patients with chronic HCV infection than in healthy
      controls (42.6% vs. 4.7%; P<0.0001). Cryoglobulins were present in 68.4% of
      patients with HCV-related cirrhosis, which was nearly twice the figure in
      noncirrhotic HCV-infected patients and alcoholic cirrhotic patients. There were
      no differences in age, sex, aminotransferase levels or HCV genotype distribution
      in HCV-infected patients with or without cryoglobulinaemia. Only 13% of patients
      with chronic HCV infection and cryoglobulins showed symptoms of
      cryoglobulinaemia. There was a linear association between HCV RNA concentration
      in sera and in cryoprecipitates (P<0.0005). Patients with chronic HCV infection
      had a high prevalence of cryoglobulinaemia, especially in advanced forms of the
      disease, but clinical findings are few. There was no relationship with the
      genotype of HCV. The presence of HCV RNA in cryoprecipitates supported the
      hypothesis on the aetiological role of HCV in mixed cryoglobulinaemia.

PMID- 10574509
TI  - Pharmaceutical cost savings of treating obesity with weight loss medications.
AB  - OBJECTIVE: To evaluate, in compliant patients, the pharmaceutical costs of
      treating obesity with fenfluramine/mazindol, fenfluramine/phentermine,
      caffeine/ephedrine, or mazindol relative to the pharmaceutical costs of treating
      obesity-related comorbid conditions and reducing cardiovascular risk. METHODS AND
      PROCEDURES: Subjects were between 18 and 60 years of age with a BMI of >30 kg/m2.
      Pharmaceutical costs were evaluated in 73 of 220 subjects taking medications for
      diabetes, hyperlipidemia, or hypertension before and after treatment using
      fenfluramine with mazindol or phentermine. The pharmaceutical cost of weight
      loss, cardiac risk reduction, and low-density lipoprotein (LDL) cholesterol
      reduction was calculated for fenfluramine with mazindol or phentermine, caffeine
      with ephedrine, or mazindol alone, and compared to approved lipid-lowering
      medications. RESULTS: Losses of 6% to 10% of initial body weight reduced pharmacy
      costs $122.64/month for insulin treated diabetes, $42.92/month for sulfonylurea
      treated diabetes, $61.07/month for hyperlipidemia treated with medication, and
      $0.20/month for hypertension treated with medication. Blood pressure and
      laboratory evidence of insulin resistance improved in all medication groups.
      Caffeine/ephedrine was most cost-effective of the three treatments in reducing
      weight, cardiac risk, and LDL cholesterol. DISCUSSION: Obesity medications
      produced a substantial weight loss in compliant patients and resulted in a net
      pharmaceutical cost savings compared to treating obesity related comorbid
      conditions.

PMID- 10574510
TI  - Sequence variants in the human cocaine and amphetamine-regulated transcript
      (CART) gene in subjects with early onset obesity.
AB  - OBJECTIVE: The cocaine and amphetamine-regulated transcript (CART) is expressed
      in the brain of rodents and humans, and intracerebroventricular injection of the
      peptide in rats reduces food intake. The objective of the present study was to
      chromosomally map the CART gene and to examine the coding region of the gene for
      variability in obese subjects. METHODS: The coding region of the CART gene was
      analyzed by single-strand conformation polymorphism analysis in 84 subjects with
      early onset obesity. The prevalence of identified mutations was estimated in a
      cohort of 757 subjects with juvenile onset obesity [body mass index (BMI) =
      35.7+/-5.7 kg/m2+/-standard deviation (S)] and in 890 random control subjects
      (BMI = 26.1+/-3.6 kg/m2+/-S). Furthermore, using radiation hybrid mapping we
      mapped the chromosomal localization of the human CART gene. RESULTS: Radiation
      hybrid mapping co-localized the CART gene with a recently published human obesity
      locus at chromosome 5q13-14 corresponding also to an obesity locus at the similar
      syntenic region in mice. We identified two silent polymorphisms in the 3'UTR
      region of the gene (position 1457 deletion of A and position 1475 A-->G
      substitution) and the prevalence of these was determined among obese and control
      subjects. However, none of the variants were associated with either obesity or
      weight gain during an average follow-up period of 27.4+/-8.4 years (S).
      CONCLUSION: Mutations in the coding region of the CART gene are unlikely to be
      involved in body weight control in Danish Caucasians with early onset obesity.

PMID- 10574511
TI  - Basal and stimulated plasma leptin in diabetic subjects.
AB  - OBJECTIVE: To determine whether leptin secretion is impaired in diabetes, we
      compared basal and stimulated plasma leptin levels in diabetic subjects and
      healthy controls. RESEARCH METHODS AND PROCEDURES: Blood samples for assay of
      leptin and other hormones were obtained at baseline in 54 diabetic patients and
      65 controls, and 8 hours, 16 hours, and 40 hours following ingestion of
      dexamethasone (4 mg) in 6 healthy and 12 controls. C-peptide status was defined
      as "negative" if < or =0.1 ng/mL or "positive" if > or =0.3 ng/mL, in fasting
      plasma. RESULTS: Basal plasma leptin levels were 19.7+/-2.2 ng/mL in nondiabetic
      subjects, 13.4+/-1.5 ng/ml in C-peptide negative (n = 28) and 26.1+/-3.7 ng/mL in
      C-peptide positive (n = 26, p = 0.001) diabetic patients. Dexamethasone increased
      leptin levels of controls (n = 6) to 145+/-17% of baseline values at 8 hours (p =
      0.03), 224+/-18% at 16 hours (p = 0.01), and 134+/-18% at 40 hours (p=0.05). The
      corresponding changes were 108+/-13%, 126+/-23%, and 98+/-16% in C-peptide
      negative (n=6), and 121+/-10%, 144+/-16% (p=0.03), and 147+/-23% (p=0.11) in C
      peptide positive (n = 6) diabetic patients, respectively. The peak stimulated
      leptin levels were lower in the diabetic patients, compared with controls. Plasma
      insulin increased (p = 0.02) in controls, but not in the diabetic patients,
      following dexamethasone. DISCUSSION: Although diabetic patients have normal
      plasma leptin levels under basal conditions, their leptin responses to
      glucocorticoid are impaired, probably because of the concomitant insulin
      secretory defect. A subnormal leptin secretory response could worsen obesity and
      insulin resistance in diabetes.

PMID- 10574512
TI  - Spousal resemblance and risk of 7-year increases in obesity and central adiposity
      in the Canadian population.
AB  - OBJECTIVE: Spousal similarities in 7-year changes in obesity and obesity-related
      phenotypes were examined in a subsample of 376 pairs of spouses from a sample of
      1487 participants in the 1988 Campbell's Survey follow-up of the 1981 Canada
      Fitness Survey. MEASURES: Indicators of body fatness included the body mass index
      (BMI), the sum of five skinfolds (SF5), and waist circumference (WAIST), whereas
      those for relative adipose tissue (AT) distribution included the ratio of two
      trunk to three extremity skinfolds, adjusted for SF5 (TERadj), and WAIST adjusted
      for BMI (WAISTadj). RESULTS: Spouse correlations were 0.17, 0.17, and 0.17 for
      the BMI (p<0.05) and 0.20, 0.20, and 0.21 for SF5 (p<0.05) for the initial
      measurement, follow-up, and 7-year change, respectively. Spouse correlations for
      WAIST were somewhat lower: 0.16 (p<0.05), 0.11 (p<0.05), and 0.11 (p<0.05) for
      the initial measurement, follow-up, and 7-year change, respectively, whereas
      those for TERadj and WAISTadj were low and not significant. Spouses of probands
      who had increases in adiposity and central AT distribution had elevated risks of
      also increasing in these parameters. Spousal risks (risk ratios) were 1.48 (95%
      CI = 1.08-2.03), 1.49 (95% CI = 1.10-2.02), and 1.68 (95% CI = 1.28-2.21) for
      increases in BMI, SF5, and WAIST, respectively, whereas the risks for increases
      in central adiposity were 1.22 (95% CI = 0.86-1-73), and 1.05 (95% CI = 0.72
      1.53) for TERadj, and WAISTadj, respectively. DISCUSSION: The results indicate
      significant spousal resemblance and risk for increases in fatness in the general
      Canadian population, whereas both the spousal resemblance and risks for increases
      in AT distribution, adjusted for level of fatness, are non-significant. The
      results suggest that shared environmental factors may be important determinants
      of spousal similarities in changes in total body fatness over time; however,
      cohabitation in the short term may not lead to increases in spousal resemblance.

PMID- 10574513
TI  - Self-efficacy in overweight individuals with binge eating disorder.
AB  - OBJECTIVE: To evaluate the relationship between self-efficacy judgments in obese
      individuals with binge eating disorder, "borderline" binge eating disorder, and
      no binge eating problems. RESEARCH METHODS AND PROCEDURES: Before participation
      in a residential weight management program, 79 male and female subjects were
      administered the Weight Efficacy Lifestyle Questionnaire (WEL) and the Binge
      Eating Scale (BES). Based on DSM-IV diagnostic questions, subjects were
      categorized as BED, Borderline BED, or non-BED. RESULTS: Krusal-Wallace Rank
      Order analysis of variance revealed significant negative associations between
      binge eating and total WEL scores as well as the subscales of Negative Emotions,
      Social Pressure, Physical Discomfort, and Positive Activities. Differences were
      significant between the BED and the Borderline BED groups with the exception of
      the Social Pressure scale and the Total WEL scores. BED diagnosis as well as
      severity of binge eating were strongly associated with low self-efficacy ratings.
      DISCUSSION: These results indicate that obese individuals with binge eating
      disorder demonstrate lower self-efficacy than those without this condition and
      that self-efficacy is related to the severity of binge eating.

PMID- 10574514
TI  - Metabolic fitness in active reduced-obese individuals.
AB  - OBJECTIVE: To verify whether a physical activity-low-fat diet follow-up could
      normalize the metabolic risk profile of reduced-obese men and women having
      undergone considerable weight loss through energy restriction and drug therapy.
      RESEARCH METHODS AND PROCEDURES: Twenty obese individuals (12 men, 8 women)
      participated in a weight-reducing program that included two phases. In the first
      phase, a non-macronutrient-specific dietary restriction of about 700 kcal/day was
      prescribed to induce weight loss over 15 weeks, with either fenfluramine or
      placebo. The second phase consisted of a physical activity-low-fat diet follow-up
      that was maintained as long as subjects did not experience resistance to further
      body weight and fat loss. Resistance to lose fat occurred after a mean cumulative
      fat loss of 14 and 8 kg in men and women, respectively. RESULTS: Despite this
      substantial decrease in body fat, subjects' adiposity remained much higher at the
      end of this protocol than values observed in lean control subjects. However,
      fasting plasma levels of insulin, cholesterol, high-density lipoprotein
      cholesterol, low-density lipoprotein-cholesterol, and triglyceride as well as the
      response of insulin and glucose to oral glucose were normalized at the end of the
      physical activity-low-fat diet follow-up. DISCUSSION: These results indicate that
      further weight and fat losses may not be justified when a moderate body weight
      loss resulting in a highly favorable improvement of metabolic risk profile is
      achieved in patients who would have still been diagnosed as overweight or obese
      on the basis of criteria currently promoted by public health agencies.

PMID- 10574515
TI  - Overeating in America: association between restaurant food consumption and body
      fatness in healthy adult men and women ages 19 to 80.
AB  - PURPOSE: To examine the association between the frequency of consuming restaurant
      food and body fatness in adults. RESEARCH METHODS AND PROCEDURES: Usual free
      living dietary intake and the frequency of consuming food from seven different
      restaurant types (fried chicken, burger, pizza, Chinese, Mexican, fried fish, and
      "other") were assessed by food frequency questionnaire in 73 healthy men and
      women [ages 19 to 80, body mass index (BMI) 18 to 33]. In addition, body fatness
      (percent weight) was determined by hydrostatic weighing, and physical activity
      and other lifestyle parameters were assessed by questionnaire. The relationship
      between the frequency of consuming restaurant food and body fatness was
      determined after controlling for age, sex, and other confounders by using
      multiple regression techniques. RESULTS: Restaurant food consumption averaged
      7.5+/-8.5 (Standard Deviation) times/month. After controlling for age and sex,
      the frequency of consuming restaurant food was positively associated with body
      fatness (partial r = 0.36, p = 0.003). The strength of this association did not
      change after controlling for education level, smoking status, and alcohol intake,
      but after additionally controlling for physical activity, the partial r increased
      to 0.42 (p = 0.004). Total daily intakes of energy, fat, and fiber were
      significantly associated with restaurant food consumption frequency (r = 0.59,
      0.28, and -0.45, respectively, p = 0.02 to 0.0001). DISCUSSION: The frequency of
      consuming restaurant food was positively associated with increased body fatness
      in adults. The increasing proportion of household food income spent on food
      prepared away from home in the United States may therefore help explain the
      rising national prevalence of obesity.

PMID- 10574516
TI  - Mistreatment due to weight: prevalence and sources of perceived mistreatment in
      women and men.
AB  - OBJECTIVE: Previous research has documented prejudicial attitudes and
      discrimination against overweight people. Yet the extent to which overweight
      people themselves perceive that they have been mistreated because of their weight
      has not been carefully studied. The purpose of this study was to examine the
      prevalence of perceived mistreatment due to weight and sources of perceived
      mistreatment. METHODS AND PROCEDURES: A non-clinical sample of healthy adults
      (187 men and 800 women) enrolled in a weight gain prevention program comprised
      the study population. A self-administered questionnaire was used to measure
      perceived mistreatment due to weight. RESULTS: Overall, 22% of women and 17% of
      men reported weight-related mistreatment. The most commonly reported sources of
      mistreatment among women were strangers (12.5%) and a spouse or loved one
      (11.9%). Men were most likely to report mistreatment by a spouse or loved one
      (10.2%) and friends (7.5%). Somewhat surprisingly, sex differences in perceived
      weight-related mistreatment were significant only for stranger as the source.
      Perceived weight-related mistreatment was positively associated with body mass
      index (BMI) (r = 0.39, p<0.0001). Reported mistreatment was nearly ten times as
      pervalent among individuals in the highest quartile of the BMI distribution
      (42.5%) than among those in the lowest BMI quartile (5.7%), but was significantly
      greater than zero in all but the very lean. DISCUSSION: Perceived mistreatment
      due to weight is a common experience and is not restricted to the morbidly obese.
      Results are discussed in light of the sociocultural value for thinness.

PMID- 10574517
TI  - Biologic response to peripheral and central administration of recombinant human
      leptin in dogs.
AB  - OBJECTIVE: Because leptin is believed to act within the central nervous system,
      the objective of this study was to test that presumption by comparing the
      biologic responses to recombinant human leptin (rHuLeptin) when delivered either
      subcutaneously or intrathecally in a large animal species, the beagle dog.
      METHODS AND PROCEDURES: Adult beagle dogs were used for all studies (n=3 to 14).
      Treatment with rHuLeptin was either as daily subcutaneous or intermittent
      intrathecal injections. RESULTS: Subcutaneously administered rHuLeptin was
      absorbed with peak concentrations appearing at 2 to 4 hours. After intrathecal
      administration, cerebral spinal fluid concentrations declined in a bi-phasic
      manner with a terminal half-life of -6 to 8 hours. When lean beagles were given
      leptin subcutaneously, at 0.05 to 5 g/kg/day for up to 6 months, reductions in
      body weight (up to 30%) and food intake (up to 75%) were observed. Body fat loss
      was observed in both lean and obese dogs, and confirmed by dual energy X-ray
      absorptiometry and histology of adipose tissue. When rHuleptin was delivered
      intrathecally at 4 to 1000 microg/dose for up to 3 months, the primary effects
      observed were reductions in body weight and food intake. In general all findings
      reported in the intrathecal studies were consistent with those noted in the
      subcutaneous studies; however, the required intrathecal dose was substantially
      lower than that for subcutaneous delivery. DISCUSSION: These studies demonstrate
      that both subcutaneous and intrathecal treatment of rHuLeptin was associated with
      effects on body weight, food intake, and body fat in dogs. These results support
      the concept that the central nervous system is the probable primary site of
      action for leptin and suggest that rHuLeptin has similar physiologic activities
      that influence body weight, body fat, and metabolism in large animals to those
      reported previously in rodents.

PMID- 10574518
TI  - Effects of exogenous gonadal steroids on leptin homeostasis in rats.
AB  - BACKGROUND: In humans, circulating concentrations of the hormone leptin,
      normalized to body fat mass, are significantly higher in females compared to
      males. This experiment was designed to determine whether the administration of
      exogenous androgen or estrogen would significantly alter the relationship between
      plasma leptin and fat mass in rats. METHODS: In the first experiment, plasma
      leptin and retroperitoneal and parametrial (female)/epididymal (male) adipose
      tissue expression of leptin mRNA were measured in five male and five female 9.5
      week-old Sprague-Dawley rats. In a second experiment, gonadectomized 10.5-week
      old female Sprague-Dawley rats received 1 or 2 weeks of daily intraperitoneal
      injections (in oil) of 750 mg testosterone propionate, 2.5 microg of estradiol
      benzoate or vehicle. At 0, 1, and 2 weeks, plasma concentrations of leptin, fat
      pad weight of parametrial and retroperitoneal fat pads, and leptin mRNA
      expression by Northern blot in retroperitoneal fat pads were determined. Daily
      weight and food intake of animals were monitored throughout the study. RESULTS:
      Circulating leptin concentrations per unit of fat pad mass and leptin mRNA
      expression normalized to actin mRNA were higher in gonadally intact female
      compared to male rats. Compared to placebo, estrogen administration decreased
      food intake and body weight, but had no significant effect on leptin mRNA
      expression or on circulating leptin concentration. Testosterone administration
      increased body weight and decreased expression of leptin mRNA (only after 2
      weeks), but did not change food intake or circulating leptin concentration.
      CONCLUSIONS: Administration of estrogen did not affect either leptin expression
      or the circulating concentration of leptin. Administration of androgen decreased
      expression of leptin mRNA. However, even after 2 weeks of testosterone
      administration to gonadectomized females, plasma leptin concentration, corrected
      for fat pad weight, was higher in gonadectomized females than in intact males.
      Thus, sex steroid-associated changes in plasma leptin concentration and leptin
      mRNA expression are not sufficient to explain the observed sexual dimorphism in
      plasma leptin concentrations in rats.

PMID- 10574519
TI  - Methods to maximize retention in weight loss studies.
AB  - OBJECTIVE: Dropouts from clinical trials decrease quality and increase costs.
      Free participation, paid participation, and contingency contracting are three
      study retention methods. Contingency contracting, or depositing a fee to be
      refunded contingent upon attendance in a clinical trial, has been reported to
      decrease dropouts without affecting weight loss. These three methods of retention
      were compared with a commercial weight loss clinic's practice of charging
      nonrefundable fees. METHODS AND PROCEDURES: Dropouts were compared in two studies
      testing mazindol, with one study using free care and the other using contingency
      contracting; two studies testing phenylpropanolamine, one using free care and the
      other using contingency contracting; and in studies with phenylpropanolamine on
      file with Thompson Medical Company using free care, paid participation, and
      contingency contracting. RESULTS: The dropout rate was 50% at 8 weeks in a trial
      of mazindol with free care vs. 7% for contingency contracting (p<0.001). The two
      phenylpropanolamine studies gave the same weight losses, but the dropouts were
      37% at 8 weeks for free care vs. 11% for contingency contracting (p<0.001). The
      studies of phenylpropanolamine on file at the Thompson Medical Company had 28%
      dropouts at 8 weeks using free care vs. 19% for paid participation (p<0.001), and
      11% for contingency contracting (p<0.005). Dropouts with contingency contracting
      (11%) were not different from the commercial weight loss program (13%).
      DISCUSSION: Contingency contracting can decrease dropouts, improve quality, and
      decrease costs without affecting weight loss in clinical trials for obesity.

PMID- 10574520
TI  - Differences in fat, carbohydrate, and protein metabolism between lean and obese
      subjects undergoing total starvation.
AB  - Despite extensive experimental studies on total starvation, many of the findings
      relating to protein, fat (plus ketone body), and carbohydrate metabolism remain
      confusing, although they become more consistent when considered in relation to
      the degree of initial obesity. During prolonged starvation, protein loss and
      percent energy derived from protein oxidation are 2- to 3-fold less in the obese
      than in the lean; percent urine N excreted as urea is 2-fold less in the obese;
      and the contribution of protein to net glucose production is only about half in
      the obese compared to lean subjects. During short-term starvation (first few
      days) the following differences are reported: hyperketonaemia is typically 2-fold
      greater in lean subjects, but associated with a 2-fold lower uptake of ketone
      bodies by forearm muscle; glucose tolerance becomes impaired more in lean
      subjects; and both protein turnover and leucine oxidation increase in the lean,
      but may show no significant change in the obese. It is no longer acceptable to
      describe the metabolic response to starvation as a single typical response. The
      differences between lean and obese subjects have important physiological
      implications, some of which are of obvious relevance to survival.

PMID- 10574521
TI  - Treatment of obesity: can it become a science?

PMID- 10574522
TI  - Distribution of life cycle stages of Sarcoptes scabiei var wombati and effects of
      severe mange on common wombats in Victoria.
AB  - Seven female and three male common wombats (Vombatus ursinus) collected from
      forested areas of Victoria (Australia) over a 10 mo period, 10 April 1997 to 22
      February 1998 had at least 30% of their skin affected by severe hyperkeratotic
      sarcoptic mange. Mangy wombats were grazing during the day, could be readily
      approached, were in poor body condition, and lacked subcutaneous fat. The
      anterolateral surface of the body was most heavily parasitised with Sarcoptes
      scabiei var wombati followed by the posterolateral surface, the dorsal region
      between the ears, the ears, ventral abdomen, medial aspect of the legs, axillary
      and inguinal areas, and the dorsal midline. Larvae were the most prevalent life
      cycle stage followed by eggs, nymphs, females, and males. Mite numbers and the
      severity of clinical signs, namely thickness of scale crust and the degree of
      alopecia, were correlated and were symmetrical on each side of the body.
      Fissuring of crust and skin only occurred when scale crust was present. Bacterial
      infections occurred in three of 10 wombats within lymph nodes or the pleural
      cavity. Lymphoid depletion did not occur in lymph nodes or spleens and
      prescapular lymph nodes contained a greater amount of nuclear debris in germinal
      centres than non-mangy wombats. Seven wombats had fatty change in their livers.
      Gonads of mature wombats were not active or had minimal activity. Significant
      histopathological changes were not seen in the gastrointestinal tract, kidney,
      brain, myocardium, spleen, thyroid, reproductive tract, and gonads. Hematocrit,
      mean corpuscular volume, mean corpuscular hemoglobin, and concentrations of
      hemoglobin, lymphocytes, calcium, glucose, creatinine, total solids, total
      protein, albumin determined both colormetrically and electrophoretically, and
      globulins were significantly lower and concentrations of neutrophils, monocytes,
      phosphorus, urea, glutamate dehydrogenase, aspartate aminotransferase and
      creatine kinase were significantly higher in mangy versus captive wombats.
      Concentrations of erythrocytes, mean corpuscular hemoglobin, leucocytes, band
      neutrophils, eosinophils, nucleated erythrocytes, sodium, potassium, chloride,
      total bilirubin, alkaline phosphatase, and gamma glutamyltransferase for mangy
      wombats were not significantly different from that reported for captive wombats.
      Hematological and pathological changes in mangy wombats were consistent with
      anemia, inflammation, and changes seen with starvation.

PMID- 10574523
TI  - Sarcoptic mange in Spanish ibex from Spain.
AB  - The Spanish ibex (Capra pyrenaica hispanica) population of the "Sierras de
      Cazorla, Segura y Las Villas" Nature Park (Spain) was isolated as the result of a
      severe epidemic of sarcoptic mange. In this context, the dynamic characteristics
      of the disease were analyzed in a wild group consisting of 35 animals from the
      beginning of the epizootic (when the mating period started) to the extinction of
      the population due to mange. Monthly tracking permitted the sequential
      characterization of the pathology in each animal. The duration of the disease was
      2 to 3 mo, evolving to severe disease and terminating in death. Incidence and
      prevalence rates in terms of morbidity and severity, and mortality and lethality
      were calculated. At the end of the mating season, 81% of the population were
      affected. There were no statistically significant differences in severity of the
      disease across sex or age categories of the animals. Most of the carcasses were
      found in caves used as refuge and/or near rivers or streams. Additionally, 46 of
      the 63 (73%) ibex captured in different areas of the nature park were naturally
      infected with the Sarcoptes scabiei. Infected ibex were examined for number of
      mites during the initial stage of the disease (n = 3), in the development stage
      (n = 12), in the consolidation stage (n = 17), and in the chronic stage (n = 14).
      The prevalence of mites in different anatomical regions was determined in each of
      these phases of the infection. A histological study of the skin lesions was
      conducted in 22 animals. Both the clinical and the pathological (macroscopic and
      microscopic) aspects of the sarcoptic mange in Spanish ibex corresponded to the
      classic description of sarcoptic mange in other wild and domestic small
      ruminants.

PMID- 10574524
TI  - The Norway rat as a reservoir host of Cryptosporidium parvum.
AB  - The potential of Norway rats (Rattus norvegicus) to spread the parasite
      Cryptosporidium parvum was investigated by examining parasite prevalence in
      relation to the structure and movements of three permanent rat populations living
      on farmland in Warwickshire (UK) from October 1994 to March 1997. One population
      lived among a group of farm buildings housing cattle, while the other two had no
      contact with livestock, one living around a pond and its outflowing stream and
      the other on a rubbish tip. Overall, parasite occurrence was 24% (n = 438), but
      it varied according to body weight (age) with 40% of juveniles (< or =100 g)
      infected decreasing to 12% for adults >400 g, suggesting that actively breeding
      populations are potentially more likely to spread the parasite than non-breeding
      populations. There was no difference in prevalence between the three populations.
      The parasite was detected in more males (29%) than females (19%). Seasonally, on
      the livestock farm, prevalence was significantly lower in autumn (10%), but
      varied little (31-36%) from winter to summer. In contrast, on the arable farm,
      prevalence peaked in summer (50%) with a trough in winter (6%). Infection in rats
      appeared to last <67 days. Rats living on the livestock farm had home ranges
      largely confined to the cattle sheds, thereby maintaining a potential source of
      infection for livestock if rodent control was not part of a decontamination
      program. Equally, rats living around the pond on the arable farm provided a
      source of oocysts to contaminate the pond water, as well as being able to carry
      the parasite to nearby farm buildings or even to neighboring farms.

PMID- 10574525
TI  - Viremia and virus shedding in elk infected with type 1 and virulent type 2 bovine
      viral diarrhea virus.
AB  - In order to determine whether elk (Cervus elaphus) could be infected with and
      shed bovine viral diarrhea virus (BVDV) and to determine whether BVDV could cause
      disease in elk, two groups of five yearling elk each and two control cattle were
      experimentally inoculated intranasally with type 1 Singer strain or a virulent
      type 2 isolate of BVDV, strain 24515. Virulence of the type 2 isolate was
      confirmed by inoculation of a control bovine cow which developed diarrhea,
      dehydration, severe thrombocytopenia, hemorrhages, and enteritis with intestinal
      necrosis. None of the elk inoculated with type 1 or type 2 BVDV developed
      clinical signs of illness. However, all elk became infected as demonstrated by
      viremia, nasal shedding, and/or seroconversion. One uninoculated, in-contact elk
      contracted type 1 BVDV and seroconverted. Thus, although BVDV does not appear
      capable of producing disease in nonpregnant elk, the species is susceptible to
      infection and can shed and transmit BVDV.

PMID- 10574526
TI  - Viral infections in free-living populations of the European wildcat.
AB  - While the importance of viral infections is well studied in domestic cats, only
      limited information is available on their occurence and prevalence in the
      European wildcat (Felis silvestris silvestris). The aim of this study was to
      determine the prevalence of antibodies to feline coronavirus (FCoV), calicivirus
      (FCV), herpesvirus (FHV), parvovirus (FPV), immunodeficiency virus (FIV),
      leukemia virus (FeLV), and FeLV antigenemia in 51 European wildcat sera. Samples
      were collected between 1996 and 1997 from wildcat populations in France,
      Switzerland, and Germany. Antibodies to FCoV were detected in two cats (4%) and
      FCoV RNA was detected in feces of one of these two cats. Antibodies to FCV, FHV
      and FPV were found at relatively low frequencies of 16%, 4%, and 2%,
      respectively. Antibodies to FIV were not detected. Although antigen and
      antibodies to FeLV were detected in 49%, and 75%, respectively, no evidence of
      FeLV-associated pathology was found. From the low prevalence of FCoV, FCV, FHV
      and FPV infections and from the fact that the European wildcats live solitarily,
      it was concluded that these viral infections do not spread readily within a
      population. Therefore, it may be assumed that release into the wild of European
      wildcats bred in captivity would not bring about a high risk of introducing of
      these viral infections to the free-ranging wildcats. As an exception, wildcats
      should be tested for absence of FIV infection before release if they were at risk
      to acquire this infection from domestic cats.

PMID- 10574527
TI  - Oral rabies vaccine contact by raccoons and nontarget species in a field trial in
      Florida.
AB  - Rabies is enzootic in raccoons (Procyon lotor) in the eastern United States. Oral
      vaccination of free-ranging raccoons against rabies has the potential to control
      the disease in a principal reservoir and reduce the risk of rabies exposure among
      domestic animals and humans. Free-ranging animal contact with baits containing a
      vaccinia virus recombinant vaccine expressing the rabies glycoprotein gene (V-RG)
      was monitored in Pinellas County (Florida, USA) from February through May 1997.
      Bait contact was assessed with 423 tracking plate nights; conducted in four land
      use zones: single residential, multiple residential, industrial-commercial, and
      undeveloped. The undeveloped land use zone was further described by six
      vegetation communities: mangrove swamp, red maple swamp, beach dune, pine forest,
      mixed oak hammock, and cabbage palm hammock. Seven animal taxa contacted the
      baited tracking plates across the four land use zones: raccoons, opossums
      (Didelphis virginiana), cats (Felis catus), dogs (Canis familiaris), rabbits
      (Sylvilagus sp.), unidentified rodents, and birds. A total of 252/413 (61%) of
      the baits was contacted by animals; 95 (38%) of these were specifically by the
      raccoon, the target species. Overall bait contact by all animals was
      significantly different among the four land use zones, being highest in the
      undeveloped zone (82%) and lowest in the industrial-commercial zone (34%). Bait
      contact by raccoons also was significantly different among the undeveloped and
      pooled urban zones. Among the six vegetation communities, bait contact by all
      animals was significantly different ranging from 95% in the mangrove to 50% in
      the cabbage palm hammock. Among the four vegetation communities tested, bait
      contact by raccoons also was significantly different.

PMID- 10574528
TI  - Susceptibility of red and gray foxes to infection by Ehrlichia chaffeensis.
AB  - Red foxes (Vulpes vulpes) and gray foxes (Urocyon cinereoargenteus) were
      evaluated for their susceptibility to experimental infection with Ehrlichia
      chaffeensis, the causative agent of human monocytotropic ehrlichiosis. Two red
      foxes and three gray foxes were inoculated intravenously with E. chaffeensis (15B
      WTD-GA strain) and were monitored at 7, 14, 21, and 28 days post inoculation
      (DPI) for evidence of infection using an indirect fluorescent antibody (IFA)
      assay, light microscopy, polymerase chain reaction (PCR), and cell culture
      methods. One red fox and one gray fox served as negative controls. Red foxes were
      susceptible to infection based on reisolation of E. chaffeensis from blood at 7
      and 14 DPI, seroconversion by 7 DPI, and positive PCR assays on spleen and lymph
      nodes at 28 DPI. Morulae were not found in circulating leukocytes and clinical
      signs or lesions of ehrlichiosis were not observed. In contrast, gray foxes were
      refractory to infection based on negative results on all culture, PCR, serologic,
      and microscopic examinations. These findings imply that red foxes, but not gray
      foxes, are potential vertebrate reservoirs for E. chaffeensis. These findings
      also illustrate the need to verify serologic evidence of E. chaffeensis infection
      among wild animals.

PMID- 10574529
TI  - Granulocytic ehrlichiosis and tick infestation in mountain lions in California.
AB  - Forty-seven mountain lions (Puma concolor) collected year-round in 1996 to 1998
      from the Sierra Nevada foothills, the northern coast ranges, and in Monterey
      County (California, USA) were examined for infestation with Ixodes pacificus and
      Dermacentor variabilis ticks. Ticks were found predominantly in winter and
      spring. The seroprevalence of granulocytic ehrlichiae (GE) antibodies (Ehrlichia
      equi or the agent of human granulocytic ehrlichiosis) was 17% and the PCR
      prevalence of DNA characteristic of GE in blood was 16%. There were eight
      polymerase chain reaction (PCR)-positive but seronegative mountain lions, one
      that was PCR-positive and seropositive, and eight that were PCR-negative and
      seropositive. Nineteen percent of engorged tick pools from mountain lions were
      PCR-positive. Because mountain lions inhabit tick-infested habitat and are
      frequently bitten by I. pacificus, surveillance for GE antibodies and DNA in
      mountain lions and other vertebrate hosts may be useful as indicators for
      geographical regions in which humans are at risk of GE infection.

PMID- 10574530
TI  - Immunization of ducks for type C botulism.
AB  - A single subcutaneous immunization with a vaccine used for protecting ranch mink
      (Mustela vison) against type C botulism reduced morbidity and mortality in
      mallard (Anas platyrhynchos) and northern pintail (Anas acuta) ducks challenged
      with approximately 4.5 x 10(4) and 2.25 x 10(4) mouse lethal doses (MLD50),
      respectively, of botulinum toxin at 10 and 15 days post-immunization (pi). There
      was no significant protection at 5 days pi. Protection persisted in mallards for
      90 days pi. To simulate use of vaccine as a part of treatment of sick birds in
      the field, mallards were exposed to toxin and, when clinical signs were evident,
      each bird was treated by intraperitoneal injection of type C botulinum antitoxin
      and one-half of the birds were immunized. Immunization had no significant effect
      on recovery from intoxication. At 10 days posttreatment, all birds were
      challenged with toxin. Clinical signs and mortality were significantly less
      frequent among immunized birds than among non-immunized birds after the second
      exposure. Immunization might be useful as part of the treatment regimen in
      botulism outbreaks.

PMID- 10574531
TI  - Seroepidemiology of upper respiratory tract disease in the desert tortoise in the
      western Mojave Desert of California.
AB  - Several factors have combined with an upper respiratory tract disease (URTD) to
      produce declines on some population numbers of desert tortoises (Gopherus
      agassizii) in the western USA. This study was designed to determine the
      seroepidemiology of URTD in a population of wild adult tortoises at the Desert
      Tortoise Research Natural Area (DTNA) study site in Kern County (California,
      USA). Prior to initiation of the study, there was a dramatic decline in the
      number of individuals in this population. At each individual time point, samples
      were obtained from 12 to 20 tortoises with radiotransmitters during winter,
      spring, summer, and fall from 1992 through 1995. During the course of the study,
      35 animals were sampled at one or more times. Only 10 animals were available for
      consistent monitoring throughout the 4 yr period. Specific antibody (Ab) levels
      to Mycoplasma agassizii were determined for individual tortoises by an enzyme
      linked immunosorbent assay (ELISA) test. Specific Ab levels were not influenced
      by the gender of the tortoise. Levels of Ab and distribution of ELISA+, ELISA-
      and suspect animals were not consistently affected by season within a single year
      or for a season among the study years. Significantly more tortoises presented
      with clinical signs in 1992 and 1995. The profile of ELISA+ animals with clinical
      signs shifted from 5% (1992) to 42% (1995). In 1992, 52% of tortoises lacked
      clinical signs and were ELISA-. In 1995, this category accounted for only 19% of
      tortoises. Based on the results of this study, we conclude that URTD was present
      in this population as evidenced by the presence of ELISA+ individual animals, and
      that the infectious agent is still present as evidenced by seroconversion of
      previously ELISA- animals during the course of the study. There is evidence to
      suggest that animals may remain ELISA+ without showing overt disease, a clinical
      pattern consistent with the chronic nature of most mycoplasmal infections.
      Further, there are trends suggesting that the clinical expression of disease may
      be cyclical. Continued monitoring of this population could provide valuable
      information concerning the spread of URTD in wild tortoise populations.

PMID- 10574532
TI  - Periodontal and dental lesions in raccoons from a farming and a recreational area
      in Illinois.
AB  - Dental health was evaluated in two populations of raccoons (Procyon lotor) in
      western Illinois (USA); one was from a rural agricultural area with low human
      density and the other from a nearby state park heavily used by humans and
      raccoons. From 1989 through 1993, 300 raccoons were live-trapped in the
      agricultural area and 246 raccoons were live-trapped in the park. Oral health was
      assessed using gingival and calculi indices and by measuring loss of attachment
      and tooth wear. Raccoons from the park were significantly older and smaller, but
      not thinner, than raccoons from the farmed area. Gingival and periodontal
      indices, tooth wear, tooth loss, and caries increased significantly from
      juveniles to yearlings to adults, at both sites. Males had higher levels of
      gingivitis and loss of periodontal attachment than females, but were similar on
      other dental measures. There were no seasonal differences between raccoons in
      dental indices. Animals with high scores for one oral measure tended to have high
      values for all indices. Dental health was generally good for juveniles and
      yearlings from both sites. Among adults, periodontal indices and the prevalence
      of caries were significantly higher in the park, but prevalence of broken or
      missing teeth was similar for both populations. There was no association between
      body condition, and a higher dental score or more missing or broken teeth.

PMID- 10574534
TI  - Organochlorine contaminant levels in Eskimo harvested bowhead whales of arctic
      Alaska.
AB  - Organochlorine (OC) levels in liver and blubber of 20 bowhead whales (Balaena
      mysticetus) collected during the Eskimo subsistence harvest at Barrow (Alaska,
      USA) in 1992 and 1993 are presented. Liver sum DDT (lipid weight) was
      significantly greater in male whales than in females. Most of the organochlorines
      measured were at higher levels in longer (older) than in shorter (younger) males.
      For female bowhead whales, hexachlorobenzene and lipid levels decreased and other
      OC levels did not change significantly with increasing length. Most
      organochlorine contaminants have low concentrations in tissues of the bowhead
      whale compared to concentrations in tissues of other cetaceans, especially
      Odontocetes. Based on allowable daily intakes (ADI) levels established by the
      Canadian Northern Contaminants Program (Ottawa, Ontario, Canada) "safe" levels of
      blubber to consume were calculated. Chlordane levels in bowhead whale blubber
      results in the most restrictive consumption amount (50 g blubber/day). We expect
      no adverse effects related to these organochlorine contaminants to occur in
      bowhead whales or in consumers of their tissues. However, investigation of low
      level chronic exposure effects and a more rigorous assessment of histopathology,
      biomarkers, and immune status in the bowhead whale would be required to conclude
      "no effect" with more certainty.

PMID- 10574533
TI  - Antibiotic treatment and post-handling survival of reindeer calves in Alaska.
AB  - Free ranging reindeer (Rangifer tarandus tarandus) are driven into corral systems
      and handled each summer on the Seward Peninsula (Alaska, USA). During June and
      July of 1995-96 reindeer calves were inspected for injury, handled, weighed, and
      randomly treated with long-acting oxytetracycline. Calves that returned to
      subsequent handlings within the same year, received treatment only if they had
      been treated during their first handling. The effects of prophylactic antibiotic
      treatment and other factors, including weight, handling related injury, and sex
      on post-handling survival in reindeer calves were evaluated. Return rates of
      yearlings in 1996 and 1997 were analyzed using logistic regression. Weight change
      of calves between handlings was examined using a general linear model. Calf
      weight and handling injury were the only factors that significantly affected calf
      survival. No factor had a significant effect on calf weight change between
      handlings. Apparently, long-acting oxytetracycline was not an effective
      prophylactic treatment for this capture operation. The benefits of prophylactic
      antibiotic treatment have not been quantified and further studies of the effects
      and efficacy of prophylactic treatments are recommended. Ineffective treatments
      should be avoided because they may add additional stress to the captured animal.
      Managers should evaluate the potential effectiveness of a prophylactic treatment
      before indiscriminately applying one. Preventing calf injuries was the most
      effective method of reducing post-handling mortality in this study and should be
      given a high priority in the design of capture operations.

PMID- 10574535
TI  - Descriptive epidemiology of roe deer mortality in Sweden.
AB  - A retrospective epidemiologic study was conducted to examine causes of mortality
      of 985 wild roe deer (Capreolus capreolus) submitted to the National Veterinary
      Institute (SVA; Uppsala, Sweden) from January 1986 to December 1995. Age, sex,
      body condition, and geographic distribution as related to disease conditions are
      reported herein. The most common causes of mortality in roe deer were trauma
      (19%), winter starvation (18%), gastritis/enteritis (15%), bacterial infections
      (11%), parasitic infection (11%), systemic diseases (11%), neoplasia (2%),
      congenital disorders (1%), and miscellaneous causes (6%). Cause of death was not
      determined in 6% of the cases. The distribution of causes of death reported in
      this study differ from previous works in Sweden in that infectious and parasitic
      diseases were more common than winter starvation. The pathologic findings in
      studies like this do not necessarily represent what is occurring in the natural
      environment, but they do provide a good indication of distribution of diseases
      over time as well as age and sex structure in relation to disease conditions.
      Further research and more detailed studies are in progress to better understand
      specific mortality factors as well as etiologies of certain described diseases in
      roe deer in Sweden.

PMID- 10574536
TI  - Lead poisoning in woodpeckers in Sweden.
AB  - Lead poisoning was demonstrated in two gray-headed woodpeckers (Picus canus) and
      one white-backed woodpecker (Dendrocopus leucotos) in Sweden; they had liver lead
      levels between 9.4 and 26.2 mg(-1) wet weight. At necropsy one gray-headed
      woodpecker showed signs of emaciation and the other one had severe traumatic
      injuries, caused by a cat. The white-backed woodpecker died in the transportation
      box during a translocation program. The source of the lead could not be
      determined, but it was suspected that it may have originated from lead pellets
      shot into trees and picked out by the woodpeckers during food search.

PMID- 10574537
TI  - Lead poisoning in wild waterfowl in Japan.
AB  - We collected 430 harvested ducks (Anas sp. and Aythya sp.) from nine prefectures
      in Japan between 1994 and 1997. Fifteen (4%) of 363 birds harvested during and
      after hunting seasons had one lead pellet each in the proventriculus and gizzard.
      In addition, 32 (34%) of 93 swans (Cygnus sp.) and two of 14 geese (Anser sp.)
      found dead from various wetlands had lesions consistent with lead poisoning. One
      to nine swans suspected of having toxicosis from ingestion of lead shot were
      found dead each year. Twenty-seven (84%) of the 32 lead-exposured swans were
      found in Hokkaido Prefecture. We concluded that lead poisoning is still a serious
      threat to waterfowl in Japan and that there is considerable need for
      environmental improvement concerning this problem.

PMID- 10574538
TI  - Effect of emanciation on liver histology of alpine chamois during winter.
AB  - With the aim of describing the effect of severe feed restriction on the liver
      histology, morphometrical analysis of liver sections of 10 alpine chamois
      (Rupicapra rupicapra) was performed. Five animals were found dead during the
      winter season 1995-96 and five were collected during the hunting season 1996.
      Hepatocyte nuclear size was measured in squared micrometers using Image-Pro Plus
      software. A significant decrease in the mean size of the nuclei of hepatocytes in
      emaciated chamois, as compared to harvested animals was observed. The reduction
      in cell nuclear size may be linked to the mobilization of body protein to prevent
      ketosis during severe food restriction, as hypothesized for other wild ungulates.
      The change in hepatocyte size may be the consequence of a strategy to minimize
      energy expenditure and may be proposed as an index of metabolic stress during
      winter undernutrition.

PMID- 10574539
TI  - Immobilization of sika deer with medetomidine and ketamine, and antagonism by
      atipamezole.
AB  - Forty wild sika deer (Cervus nippon) were immobilized with medetomidine and
      ketamine and reversed by atipamezole in summer and fall captures from September
      1994 to October 1995. For large yearling and older deer, mean +/- SD doses of
      57.0+/-15.6 microg/kg medetomidine and 1.64+/-0.49 mg/kg (male) or 4.02+/-1.16
      mg/kg (female) of ketamine were administered by intramuscular injection. For
      calves and small yearlings, 69.3+/-7.0 microg/kg medetomidine and 2.69+/-0.44
      mg/kg ketamine were administered. While immobilized, deer were easy to handle,
      and muscles were well relaxed. After intramuscular administration of atipamezole
      (about 5 times the dose of medetomidine), deer recovered rapidly and smoothly.

PMID- 10574540
TI  - Giardiasis in pinnipeds from eastern Canada.
AB  - Cysts of Giardia sp. were detected in feces from the rectum of 20 of 74 pinnipeds
      examined from the eastern coast of Canada in 1997 and 1998 using a monoclonal
      antibody technique. Infected pinnipeds included 15 adult harp seals (Phoca
      groenlandica), four adult grey seals (Halichoerus grypus), and one juvenile
      harbor seal (Phoca vitulina). Cysts were not detected in 15 seal pups <1-yr-old.
      The highest prevalence (50%) occurred in adult harp seals collected near the
      Magdalen Islands in the Gulf of St. Lawrence. The overall prevalence of Giardia
      sp. in grey and harbor seals, excluding pups, from the Gulf and St. Lawrence
      estuary was 23%. Feces from 11 beluga (Delphinapterus leucas) and one northern
      bottle-nosed whale (Hyperoodon ampullatus) stranded in the St. Lawrence estuary
      were negative for Giardia sp. cysts. The significance of Giardia sp. in marine
      mammals, shown here for the first time in eastern coastal Canada, is unknown.

PMID- 10574541
TI  - The potential for false-positive diagnosis of protostrongyliasis by extraction of
      larvae from feces.
AB  - The potential of protostrongylid first-stage larvae (L1) to survive passage
      through the alimentary canal of non-infected mammals was investigated.
      Parelaphostrongylus tenuis L1 were collected from feces of an experimentally
      infected white-tailed deer (Odocoileus virginianus). We utilized two red deer
      (Cervus elaphus) and four laboratory rats (Rattus norvegicus) which were each fed
      the L1 of P. tenuis. Larvae were recovered, intact and alive, from the fecal
      samples of all six animals. Larvae of P. tenuis, and probably of other related
      species, can survive passage through the alimentary canal of uninfected mammals
      and they can be collected from feces using the Baermann technique and other
      related larval extraction methods. Rain water was found to be successful in the
      dispersal of P. tenuis L1 from the feces of infected animals. These findings
      raise the possibility of ingestion of L1 and their subsequent passage, by
      uninfected animals. This potential for false-positive diagnosis of infection in
      live animals necessitates accurate interpretation of a host's infection-status.
      Such findings reinforce the need for a reliable method of diagnosing infections
      in live animals.

PMID- 10574542
TI  - Elaeophorosis in bighorn sheep in New Mexico.
AB  - Two bighorn sheep (Ovis canadensis) in New Mexico (USA) were found to be
      naturally infected with Elaeophora schneideri. An adult ram examined in 1997 in
      the Fra Cristobal Mountains had 26 nematodes in the carotid and iliac arteries,
      and microfilariae were present in the skin, nasal mucosa, brain, and lungs. This
      ram was markedly debilitated prior to euthanasia and extensive crusty, scabby
      lesions were observed on its head. In 1998, a yearling ewe found dead adjacent to
      Watson Mountain near the Gila Wilderness area was found to have 13 nematodes
      present in its heart. This is the first report of E. schneideri in bighorn sheep,
      and we suggest that bighorn sheep are susceptible to E. schneideri infection
      wherever they coexist with mule deer (Odocoileus hemionus hemionus) and
      appropriate tabanid vectors.

PMID- 10574543
TI  - Nasal zygomycosis and pulmonary aspergillosis in an American bison.
AB  - Concomitant nasal zygomycosis and pulmonary aspergillosis was diagnosed in a 3-mo
      old female American bison calf (Bison bison) in Pennsylvania (USA). Etiologic
      diagnosis was made by immunohistochemistry using a panel of monoclonal antibodies
      and heterologously absorbed polyclonal antibodies. In the lungs fungal infection
      was accompanied by hemorrhage, fibrin exudation, and infiltration with
      neutrophils. Fungi were observed to penetrate apparently normal epithelial lining
      of the nasal turbinates, and there was hemorrhage, edema, and invasion of blood
      vessels in the submucosa. In vessels fungi were typically associated with
      thrombosis. The calf may have been infected due to a high level of exposure to
      mouldy feed and litter in the environment in combination with a collapse of it's
      natural defence mechanisms.

PMID- 10574544
TI  - Tuberculosis in a wild subantarctic fur seal from Argentina.
AB  - The first case of tuberculosis is described in a wild subantarctic fur seal
      (Arctocephalus tropicalis) found on the Argentine coast. There was hydrothorax
      and white firm granulomatous lesions of 40-50 mm in diameter in the lungs.
      Lesions consisted of a central area of caseous necrosis, an intermediate zone of
      epithelioid and lymphocytic mononuclear cells, and a peripheral zone of
      connective tissue. Biochemical and drug sensitivity tests and inoculation of
      Guinea pigs confirmed the identification as Mycobacterium tuberculosis complex.
      Arctocephalus tropicalis is the fifth pinniped species in which the M.
      tuberculosis complex has been detected. Since subantarctic fur seals are widely
      distributed in the Southern Hemisphere, it is possible that the tuberculosis
      cases may have a common origin and could spread to other austral regions and
      species.

PMID- 10574545
TI  - Serosurvey for selected disease agents in white-tailed deer from Mexico.
AB  - Serum samples from 350 white-tailed deer (Odocoileus virginianus texanus)
      collected in March 1994 from northeastern Mexico were tested for the prevalence
      of antibody activity against five infectious diseases of ruminants. The
      prevalence rate was 81% for bluetongue virus (BTV) of all serotypes, 72% for
      epizootic hemorrhagic disease virus (EHDV), 3% for Borrelia burgdorferi, 69% for
      Anaplasma marginale, and 0% for Brucella abortus, B. melitensis, and B. ovis.
      These are diseases that affect domestic ruminants, and deer may act as a
      reservoir of infection. In addition, if deer are translocated, they may introduce
      pathogens to formerly disease-free areas. The high seroprevalence of BTV and EHDV
      cannot be related to the presence of hemorrhagic disease in the deer in this
      region. This is the first report to indicate the presence of B. burgdorferi
      infection of deer in Mexico. Despite the high prevalence of A. marginale titers,
      it is uncertain that deer play a role in the epizootiology of cattle anaplasmosis
      in the region. Apparently, white-tailed deer are unimportant in the epizootiology
      of brucellosis of both cattle and goats in northeastern Mexico.

PMID- 10574546
TI  - Relating tumor score to hematology in green turtles with fibropapillomatosis in
      Hawaii.
AB  - The relationship between hematologic status and severity of tumor affliction in
      green turtles (Chelonia mydas) with fibropapillomatosis (FP) was examined. During
      1 wk periods in July 1997 and July 1998, we bled 108 free-ranging green turtles
      from Pala'au (Molokai, Hawaii, USA) where FP is endemic. Blood was analyzed for
      hematocrit, estimated total solids, total white blood cell (WBC) count and
      differential WBC count. Each turtle was assigned a subjective tumor score ranging
      from 0 (no visible external tumors) to 3 (heavily tumored) that indicated the
      severity of FP. There was a progressive increase in monocytes and a decrease in
      all other hematologic parameters except heterophils and total numbers of white
      blood cells as tumor score increased. These data indicate that tumor score can
      relate to physiologic status of green turtles afflicted with FP, and that tumor
      score is a useful field monitor of severity of FP in this species.

PMID- 10574548
TI  - D3 receptor knockdown through antisense oligonucleotide administration supports
      its inhibitory role in locomotion.
AB  - To study the specific contribution of the D3 dopamine receptor in the generation
      of locomotor activity, total or partially dopamine-depleted rats were pretreated
      with an antisense oligodeoxynucleotide for the D3 receptor (D3R-as) and locomotor
      activity induced by apomorphine was measured. A 35.7% increase in locomotor
      activity was seen in the totally dopamine-depleted rats pretreated with the D3R
      as, whereas the same antisense, caused a significantly greater increase in the
      locomotor response (95%) in the partially dopamine-depleted rats compared with
      control groups (pretreated with a control oligodeoxynucleotide or vehicle). In
      situ autoradiography for D3 receptors showed a 27% fall in the density of D3
      receptors in the islands of Calleja compared with control animals. Our results
      seem to confirm that D3 receptors exert an inhibitory effect on locomotor
      activity, through the stimulation of both pre- and postsynaptic components.

PMID- 10574547
TI  - Highly delta selective antagonists in the RVM attenuate the antinociceptive
      effect of PAG DAMGO.
AB  - The present study tested the hypothesis that endogenous opioid peptides acting at
      the delta-opioid receptor (DOR) in the rostral ventromedial medulla (RVM)
      contribute to the antinociception elicited by the mu-opioid receptor (MOR)
      agonist DAMGO in the midbrain periaqueductal gray (PAG). Following microinjection
      of DAMGO into the PAG, either the highly selective DOR antagonist TIPP[psi] or
      the DOR2 antagonist naltriben (NTB) was microinjected into the RVM. Both
      TIPP[psi] (1.0 microg) and NTB (5.0 ng) significantly attenuated the analgesic
      effect of PAG DAMGO but had no effect when given before PAG saline. These results
      confirm and extend previous studies suggesting that PAG mu-opioids activate a
      descending system with a DOR mediated endogenous opioid link in the RVM.

PMID- 10574549
TI  - Spatial attention modulates the cortical somatosensory representation of the
      digits in humans.
AB  - The topographic organization of the primary somatosensory cortex adapts to
      alterations of afferent input. Here, electric source imaging was used to show
      that spatial attention modifies cortical somatosensory representations in humans.
      The cortical representation of the electrically stimulated digit 2 (resp. digits
      2 and 3) of the right hand was more medial along the somatosensory area 3b in
      subjects who focused attention on digit 4 of the right hand, while it was more
      lateral when subjects attended digit 4 of the contralateral hand. This effect was
      very fast since the direction of attention was changed every 6 min. The results
      indicate that cortical somatosensory representations not only depend on afferent
      input but vary when spatial attention is directed towards different parts of the
      body.

PMID- 10574550
TI  - Ipsilesional line bisection bias in patients with chronic parietal lesions.
AB  - The current study investigated whether an ipsilesional bias in line bisection, a
      conventional measure for diagnosing hemispatial neglect, persists even in the
      absence of this syndrome in patients with chronic lesions restricted to posterior
      association cortex or dorsolateral prefrontal cortex. Both left and right
      hemisphere parietal lesions produced ipsilesional bisection errors, and to a
      comparable degree. Patients with lesions in frontal cortex, on the other hand,
      did not show a consistent bias. We conclude that chronic parietal lesions produce
      an ipsilesional bias in line bisection, even in the absence of other clinical
      signs of neglect, and that left hemisphere lesions can affect line bisection to
      the same degree as right hemisphere lesions.

PMID- 10574551
TI  - Experimental schizencephaly induced by Kilham strain of mumps virus: pathogenesis
      of cleft formation.
AB  - The pathogenesis of cleft formation in schizencephaly was analyzed by examining
      the brain lesions produced by the infection of the Kilham strain of mumps virus
      during the period of neuronal migration in hamsters. Mumps virus antigen was
      detected in the neuroepithelial cells within the ventricular zone, the choroid
      plexus in the lateral ventricles, and vimentin-immunoreactive radial glial
      fibers. The main pathological findings were cerebral hemorrhage, neuronal
      necrosis, microsulci on the cerebral cortex and cleft formation through the
      entire thickness of the cerebral mantle. The clefts seen in these experiments
      were lined by embryonal elements such as neuroepithelial cells and germinal
      cells. Based on these results and the original definition by Yakovlev and
      Wadsworth, the following two conclusions were suggested. First, the mumps virus
      localized to the neuroepithelial cells within the ventricular zone and the radial
      glial fibers may induce a destructive process and subsequent anomalous neuronal
      migration, resulting in cleft formation. Second, the formation of the ventricular
      cleft extending to the pial surface, which should be complete before the cortical
      infolding appears, is necessary in order to produce the characteristic cleft in
      schizencephaly which is associated with the pial-ependymal seam.

PMID- 10574552
TI  - Influence of NOS inhibitors on changes in ACH release and NO level in the brain
      elicited by amphetamine neurotoxicity.
AB  - We studied the possible role of neurotoxicity in the d,l-amphetamine (AMPH)
      induced release of acetylcholine (ACH) in the nucleus accumbens (Nac) and the
      involvement of endogenous NO in this process. For determination of ACH release
      the Nac was superfused using the push-pull-technique. NO was directly measured
      using the electron paramagnetic resonance technique. Repeated administration of
      AMPH increased ACH release by about 400%. N-nitro-L-arginine (L-NNA) and 7
      nitroindazole (7-NI) nearly abolished the AMPH-induced increase in ACH release.
      AMPH increased NO as well as lipid peroxidation (LPO) products in the cortex. L
      NNA and 7-NI substantially diminished NO increase. AMPH-evoked LPO was only
      slightly reduced by these compounds. It is concluded that AMPH enhances ACH
      release through increased NO synthesis and induces neurotoxicity via NO and by
      LPO independent NO generation.

PMID- 10574553
TI  - Calbindin expression in the hamster SCN is influenced by circadian genotype and
      by photic conditions.
AB  - Circadian rhythmicity in mammals, is controlled by the suprachiasmatic nuclei
      (SCN) of the hypothalamus. We previously described a discrete subnucleus in the
      core of the hamster SCN containing calbindin-D28k-positive cells which are fos
      positive in response to a light pulse. Ablation of this subnucleus results in
      loss of circadian locomotor rhythmicity even when other parts of the SCN are
      spared. Here we show that Tau mutant hamsters have significantly more calbindin
      D28k in the SCN than do wild type hamsters, and that SCN calbindin
      immunoreactivity in the SCN increases in the dark. This is correlated with
      changes in magnitude of light mediated phase shifts in locomotion. The data are
      consistent with a role for calbindin cells in light mediated entrainment and
      phase shifting.

PMID- 10574555
TI  - Brain responses during sentence reading: visual input affects central processes.
AB  - The effect of visual contrast on sentence reading was investigated using event
      related brain potentials (ERPs). Under the low contrast condition semantic
      integration as reflected in the N400 ERP component was delayed to some degree.
      The left anterior negativity (LAN) reflecting initial syntactic processes, in
      contrast, seemed to change its characteristics as a function of visual input. In
      the high contrast condition the LAN preceded the P200 component whereas in the
      low contrast condition it was present after this component. These ERP-data from
      word-by-word sentence reading together with prior results from sentence listening
      suggest that the physical characteristics of the input must fall within a certain
      optimal range to guarantee ERP-effects of fast initial syntactic processes.

PMID- 10574554
TI  - Multiple regulatory elements result in regional specificity in circadian rhythms
      of neuropeptide expression in mouse SCN.
AB  - It is well established that the mammalian circadian system consists of pacemaker
      cells in the suprachiasmatic nuclei (SCN). The mouse has become increasingly
      important in understanding the circadian timing system, due to the availability
      of mutant animals with abnormal circadian rhythms. In the present paper, we
      describe the organization of the mouse SCN, comparing the wild type and Clock
      mutant animal, with a special focus on those peptides bearing an upstream E-box
      element (vasopressin, vasoactive intestinal peptide, cholecystokinin and
      substance P). To this end, we describe the distribution of the foregoing SCN
      peptidergic cell types as well as gastrin-related peptide, calretinin, calbindin,
      somatostatin, neurotensin and retinal input to the SCN (determined by both tract
      tracing and fos-immunoreactivity in response to a light pulse). The Clock mutant
      mouse has decreased expression of vasopressin mRNA and protein in the SCN, with
      normal patterns of expression elsewhere in the brain. No other differences were
      detected between the Clock mutant and the wild type mouse. The results are
      consistent with the hypothesis that there are multiple regulatory elements of
      clock-controlled genes in the SCN.

PMID- 10574556
TI  - Inhibition of N- and L-type Ca2+ currents by dopamine in lamprey spinal
      motoneurons.
AB  - Dopamine is co-localized with 5-hydroxytryptamine in a ventromedially located
      plexus in the lamprey spinal cord and reduces Ca2+ currents in motoneurons that
      express high-voltage activated Ca2+ currents of the N-, L- and P/Q-types.
      Blockade of L- and P/Q- type channels leaving N-type channels intact reduced but
      did not prevent the inhibition of the Ca2+ current by dopamine. Dopamine also
      reduced the L-type current potentiated by BAY K 8644. During simultaneous
      blockade of N-type and L-type currents, dopamine was unable to affect the
      remaining Ca2+ current. In addition, blockade of G-proteins abolished the
      dopaminergic modulation. The inhibition was unaffected by depolarizing prepulses.
      Thus, dopamine mediates inhibition of N- and L-type currents through a G-protein
      dependent, voltage-independent pathway in lamprey spinal motoneurons.

PMID- 10574557
TI  - Between-task habituation in functional transcranial Doppler ultrasonography.
AB  - We investigated the variability of absolute blood flow velocity (BFV) and task
      induced BFV change over consecutive cognitive tasks and compared two methods of
      baseline determination that are used to calculate relative BFV changes. Bilateral
      transcranial Doppler ultrasonography recordings of BFV in the middle cerebral
      arteries was performed in 90 right-handed volunteers during 13 cognitive tasks
      and their preceding rest periods. Both absolute BFV and elicited BFV changes
      between rest and activation significantly decreased over successive tasks.
      Instead of calculating an averaged baseline value, our results suggest that the
      rest phase immediately preceding the activation phase should be selected for
      baseline measurement. The between-task habituation effect could be due to a
      fading of attentional resources during the sustained and demanding performance.

PMID- 10574559
TI  - Localization of the 5-HT1A receptors in the brain of opossum Monodelphis
      domestica.
AB  - This paper describes the distribution of 5-HT1A receptors in the brain of opossum
      Monodelphis domestica. They were visualized by immunohistological staining with
      an antibody against the amino acid sequence (170-186) of this receptor that was
      previously successfully used in the rat and monkey. As in Eutherians, high levels
      of immunostaining were present in the septum, hippocampus, raphe nuclei and some
      other brain stem nuclei. Neocortex, several thalamic nuclei and hypothalamus
      showed moderate density of the labeled structures. Moderate levels of 5-HT1A
      receptors were also observed in the caudate nucleus and putamen, unlike in the
      rat, in which labeling in these nuclei was almost absent. Another difference with
      the rat was observed in the neocortex: in the opossum immunostaining was absent
      in the layer 4 of many cortical areas. In general, distribution and density of
      this important receptor in the opossum is very similar to that described in the
      rat and monkey and therefore it follows a general mammalian pattern.

PMID- 10574558
TI  - Subjective straight-ahead during neck muscle vibration: effects of ageing.
AB  - The subjective visual straight-ahead (SVA) was measured psychophysically before
      and during unilateral vibration of the posterior neck muscles in order to
      determine the particular contribution of neck muscle spindles to the perception
      of body orientation during ageing. We found a symmetrical increase of the
      vibration-induced displacement of the SVA with advancing age (R = +0.73, p <
      0.01, n = 60) in 30 healthy subjects of different ages (range 20-81 years). These
      data indicate the cervical proprioceptive contribution to multisensory body
      orientation increases with ageing. One possible interpretation is that the
      sensorial weight of proprioception increases as the peripheral vestibular input
      decreases with advancing age, thereby substituting for the lack of vestibular
      function.

PMID- 10574560
TI  - Sensory funneling of liminal multiple- point air-puff stimulation produces
      dramatic reduction in reaction time but relatively invariant P300 somatosensory
      evoked potential.
AB  - Sensory funneling of liminal multiple-point air-puff stimulation on the skin was
      evaluated by measuring somatosensory evoked potentials (SEPs), reaction time (RT)
      and subjective detection threshold. Single-point air-puffs at the threshold
      intensity, and 2-point and 3-point air-puffs (10 mm apart) of the same intensity
      were delivered to the volar hand for recording SEPs, RT and detection threshold.
      Two- and 3-point stimulation produced a funneled sensation which feels stronger
      than the sensation produced by the single-point stimulation. Thus, the detection
      threshold was lower and the detection probability high with multiple-point
      stimulation. The latency of P300 SEP component showed a trend for shortening,
      while the P300 amplitude was reduced with multiple-point stimulation. However,
      these differences did not reach statistical significance. In sharp contrast with
      the relatively invariant SEP measures, the RT showed a dramatic reduction with
      multiple-point stimulation. The results suggest that P300 SEP component is less
      affected by the funneling of sensory input but is related to the detection of the
      threshold stimulus in an all-or-none fashion. In contrast, the RT is linearly
      related to the funneling of input and the resultant higher detection probability.
      We speculate that an intermediate neural process between the P300 elicitation and
      the motor command was facilitated by the funneling of multiple air-puffs.

PMID- 10574561
TI  - Interactions of etifoxine with the chloride channel coupled to the GABA(A)
      receptor complex.
AB  - This study examined the nature of the interactions of etifoxine, an anxiolytic
      and anticonvulsant compound, with the GABA(A) receptor/chloride channel complex.
      In membrane preparations of Sprague-Dawley rat cerebral cortex, etifoxine
      competitively inhibited the binding of [35S]t-butylbicyclophosphoro-thionate
      (TBPS), a specific ligand of the GABA(A) receptor chloride channel site. In vivo
      studies demonstrated an anticonvulsant effect of etifoxine (50 and 75 mg/kg,
      i.p.) against the clonic convulsions induced by TBPS in CD1 mice. Flumazenil (10
      and 40 mg/kg, i.p.), an antagonist of benzodiazepine sites at GABA(A) receptors,
      had no effect on the action of etifoxine. These findings suggest that etifoxine
      exerts its effect by interacting with the Cl- channel of GABA(A) receptors and
      probably by facilitating GABAergic inhibition.

PMID- 10574562
TI  - Elevation of hypothalamic neuropeptide Y-neurons in adult offspring of diabetic
      mother rats.
AB  - We recently reported on an elevation of neurons expressing the main orexigenic
      peptide neuropeptide Y (NPY) in the arcuate hypothalamic nucleus (ARC) of
      neonatally hyperinsulinaemic offspring of gestational diabetic mother rats (GD)
      at weaning. To investigate possible consequences, the long-term outcome of those
      animals was examined. At adult age, GD offspring showed hyperphagia (p < 0.001),
      basal hyperinsulinaemia (p < 0.05) and impaired glucose tolerance (p < 0.05), and
      were overweight (p < 0.01). This was accompanied by an elevated number of NPY
      neurons (p < 0.001) and galanin neurons (p < 0.001) in the ARC in adult GD
      offspring under basal conditions. These findings support our hypothesis on
      perinatally acquired, persisting malformation and/or malprogramming of
      peptidergic hypothalamic neurons in the offspring of GD mothers, possibly
      promoting the development of overweight and diabetogenic disturbances during
      life.

PMID- 10574563
TI  - Intracerebroventricular leptin inhibits gastric emptying of a solid nutrient meal
      in rats.
AB  - The effects of leptin injected intracerebroventricularly (i.c.v.) or i.p. on food
      intake and gastric emptying of a solid nutrient meal were studied in fasted Long
      Evan rats. Leptin (3 microg, i.c.v.) reduced the 5 h cumulative food intake by
      39% and gastric transit by 50% while i.p. leptin (300 microg) resulted in a 35%
      decrease in food intake and no change in gastric transit after 5 h. Lower i.p.
      doses of leptin (30 or 3 microg) did not alter food intake. These results show
      that central, unlike peripheral, injection of leptin inhibits gastric transit of
      an ingested meal; such a central action of leptin may contribute to the greater
      potency of i.c.v. than i.p. leptin to suppress food intake.

PMID- 10574564
TI  - 'Natural' and artificial monocular deprivation effects on thalamic soma sizes in
      pigeons.
AB  - The dominance for visual pattern analysis of the left hemisphere in normal
      pigeons and the concomitant morphological asymmetries in the optic tectum can be
      attributed to a 'natural' prehatch monocular deprivation of the left eye
      resulting from an asymmetrical embryonic position within the egg. Using control
      animals and pigeons which were monocularly deprived for 10 days after hatching,
      the present study could show that the cellular soma sizes of the nucleus rotundus
      within the tectofugal visual pathway are modified by light experience depending
      on the timepoint and direction of lateralized stimulation. Although rotundal cell
      size is thus ontogenetically modified in an activity-dependent manner, a detailed
      comparison makes it likely that the mechanisms which govern developmental
      plasticity of visual pathways differ between birds and mammals.

PMID- 10574565
TI  - Serum amyloid P is not present in amyloid beta deposits of a transgenic animal
      model.
AB  - Serum amyloid P component (SAP) is associated with amyloid beta (A beta)
      deposition in Alzheimer disease (AD). Since SAP is exclusively synthesized by
      peripheral organs, its presence in the brain of AD suggests impairment of the
      blood-brain barrier (BBB). We studied the association of SAP with A beta deposits
      in a transgenic mouse model overexpressing beta-protein precursor (betaPP). Both
      SAP and another extracellular matrix binding protein, basic fibroblastic growth
      factor bind to the heparinase sensitive sites of A beta deposits in this model.
      However, no endogenous SAP immunoreactivity was found in the transgenic mouse
      brain. These results suggest that SAP is not required for A beta deposition, and
      that this mouse model does not develop the same BBB abnormalities as those seen
      in AD.

PMID- 10574566
TI  - Centrally nucleated fibers (CNFs) compensate the fragility of myofibers in mdx
      mouse.
AB  - Centrally nucleated fibers (CNFs) are the myofibers which have nuclei in the
      center of cytoplasm, and are generally recognized as regenerated myofibers. They
      are commonly observed in the histopathology of the patients with several types of
      muscular dystrophies and their animal models. In the mdx mouse, an animal model
      of Duchenne muscular dystrophy, CNFs are more resistant than non-CNFs to
      mechanical stresses, as evidenced by the Evans blue infiltration. In relation to
      the population among muscles, CNFs are supposed to compensate the fragility of
      muscular tissue in muscular dystrophies and their animal models.

PMID- 10574567
TI  - The hypnotic actions of oleamide are blocked by a cannabinoid receptor
      antagonist.
AB  - The unsaturated fatty acid amide oleamide (OA), which accumulates in the CSF of
      rats during sleep deprivation, induces electroencephalographically measured sleep
      when administered intracerebroventricularly. The mechanism of sleep induction by
      OA is unclear but may derive from enhancements of GABA or 5-HT receptor function,
      or alternatively from changes in the catabolism or uptake of the related fatty
      acid amide anandamide, an endogenous cannabinoid-1 (CB1) receptor ligand. The
      present study tests the latter hypothesis by administering OA alone and in
      combination with the CB1 receptor antagonist SR141716. As previously reported,
      2.8 microg OA administered intracerebroventricularly significantly shortened
      electroencephalographic sleep latency. SR141716 in a dose of 3 microg had no
      effects on sleep by itself, but when co-administered with OA prevented its sleep
      inducing effects. These data suggest that at least one aspect of the hypnotic
      action of OA involves interactions with the CB1 receptor system, possibly by
      blocking the metabolism of the endogenous CB1 receptor agonist anandamide.

PMID- 10574568
TI  - Local effects of the serotonin agonist quipazine on the suprachiasmatic nucleus
      of rats.
AB  - In mammals, circadian rhythms of locomotor activity and many other behavioral and
      physiological functions are controlled by an endogenous pacemaker located in the
      hypothalamic suprachiasmatic nucleus (SCN). One of the SCN's afferents is a dense
      serotonergic input from the mesencephalic raphe complex. Previous work from this
      laboratory demonstrated that systemic administrations of the serotonin agonist
      quipazine mimic the effects of light on the circadian system of rats, i.e. they
      induce photic-like phase shifts of the circadian activity rhythm as well as c-Fos
      expression in the SCN. In contrast, no such effect has been demonstrated so far
      in the isolated rat SCN slice preparation. In this study we demonstrate that
      local injections of quipazine (0.5 microg/kg) into the region of the SCN induce
      photic-like effects similar to those induced by systemic injections. These
      findings suggest a role for 5-HT in the transmission of photic information to the
      rat circadian system through a direct action at the level of the SCN.

PMID- 10574569
TI  - Intrathecal adenosine does not relieve allodynia-like behavior in spinally
      injured rats.
AB  - The intrathecal (i.t.) administration of the adenosine A1-receptor agonist R
      phenylisopropyl-adenosine (R-PIA) reduced pain-related behaviors after peripheral
      nerve or spinal cord injury in rats. The endogenous ligand adenosine is
      clinically available and has been tested i.t. as an analgesic. Thus, we set out
      to investigate whether i.t. adenosine could reduce allodynia in a model of
      central pain in spinally injured rats. I.t. adenosine did not reduce mechanical
      and cold allodynia-like behaviors at doses of 10, 100 and 187 nmol, whereas i.t.
      R-PIA at 10 nmol markedly alleviated allodynia in the same animals. The lack of
      effect by exogenous adenosine may be due to pharmacokinetic or pharmacodynamic
      reasons. Alternatively, adenosine may have reduced affinity and selectivity
      towards the A1-receptors which may be important for the antiallodynic effect.

PMID- 10574570
TI  - Effects of calcitonin on animal and in vitro models of skeletal metabolism.
AB  - During the 40 years since its discovery, calcitonin (CT) has been regarded
      primarily as an inhibitor of bone resorption and its therapeutic applications
      have been based on this property. A significant body of literature also indicates
      additional anabolic effects in animal and in vitro models. In a variety of bone
      loss histomorphometric models in the rat, CT, especially the salmon species,
      prevents or retards bone loss. In other species, similar results have been
      obtained, except in the beagle given human CT, in which a recent study reported
      increased bone resorption and bone loss. Consonant with the histomorphometric
      effects in several different species, bone mass (density) measured by a variety
      of methods increases, reversing the bone loss induced by the model. In related
      studies of mechanical properties, bone strength is increased by CT except in the
      beagle study which utilized human CT. In other species, experimentally induced
      fractures show either accelerated healing or heal normally, and there is no
      effect of CT to impair healing. Finally, studies of bone formation/mineralization
      strongly suggest an anabolic effect on cartilage formation, bone matrix synthetic
      activity, and bone growth. These animal effects are reflected by recent fracture
      prevention studies in humans. If its anabolic effects are ultimately found to be
      separable and additive to CT's basic action to inhibit bone resorption, new
      approaches to osteoporosis prevention, and possibly other treatment situations
      such as cartilage regeneration, may evolve using novel CT-like molecules.

PMID- 10574571
TI  - Osteoblasts/stromal cells stimulate osteoclast activation through expression of
      osteoclast differentiation factor/RANKL but not macrophage colony-stimulating
      factor: receptor activator of NF-kappa B ligand.
AB  - We previously reported that osteoblasts/stromal cells are essentially involved in
      the activation as well as differentiation of osteoclasts through a mechanism
      involving cell-to-cell contact between osteoblasts/stromal cells and osteoclast
      precursors/osteoclasts. Osteoclast differentiation factor (ODF, also called
      RANKL/OPGL/TRANCE) and macrophage colony-stimulating factor (M-CSF, also called
      CSF-1) are two essential factors produced by osteoblasts/stromal cells for
      osteoclastogenesis. In other words, osteoblasts/stromal cells were not necessary
      to generate osteoclasts from spleen cells in the presence of both ODF/RANKL and M
      CSF. In the present study, we examined the precise roles of ODF/RANKL and M-CSF
      in the activation of osteoclasts induced by calvarial osteoblasts. Osteoclasts
      were formed in mouse bone marrow cultures on collagen gel-coated dishes in
      response to a soluble form of ODF/RANKL (sODF/sRANKL) and M-CSF, and recovered by
      collagenase digestion. When recovered osteoclasts were further cultured on
      plastic dishes, most of the osteoclasts spontaneously died within 24 h.
      Osteoclasts cultured for 24 h on dentine slices could not form resorption pits.
      Addition of sODF/sRANKL to the recovered osteoclasts markedly enhanced their
      survival and pit-forming activity. M-CSF similarly stimulated the survival of
      osteoclasts, but did not induce their pit-forming activity. When primary mouse
      osteoblasts were added to the recovered osteoclasts, resorption pits were formed
      on dentine slices. Bone-resorbing factors such as 1alpha,25-dihydroxyvitamin D3,
      parathyroid hormone, or prostaglandin E2 enhanced pit-forming activity of
      osteoclasts only in the presence of osteoblasts. M-CSF-deficient osteoblasts
      prepared from op/op mice similarly enhanced pit-forming activity of osteoclasts.
      The pit-forming activity of osteoclasts induced by sODF/sRANKL or osteoblasts was
      completely inhibited by simultaneous addition of
      osteoprotegerin/osteoclastogenesis inhibitory factor, a decoy receptor of
      ODF/RANKL. Primary osteoblasts constitutively expressed ODF/RANKL mRNA, and its
      level was upregulated by treatment with 1alpha,25-dihydroxyvitamin D3,
      parathyroid hormone, and prostaglandin E2. These results, obtained by using an
      assay system that unequivocally assesses osteoclast activation, suggest that
      ODF/RANKL but not M-CSF mediates osteoblast-induced pit-forming activity of
      osteoclasts, and that bone-resorbing factors stimulate osteoclast activation
      through upregulation of ODF/RANKL by osteoblasts/stromal cells.

PMID- 10574572
TI  - Localization of RANKL (receptor activator of NF kappa B ligand) mRNA and protein
      in skeletal and extraskeletal tissues.
AB  - RANKL (receptor activator of NFkappaB ligand) is a membrane-associated
      osteoblastic molecule, and along with macrophage-colony-stimulating factor, is
      crucial for osteoclast formation. RANKL is known to be strongly expressed in
      osteoblasts and lymphoid tissues. We have sought to determine the skeletal and
      extraskeletal sites of production of RANKL mRNA and protein using the techniques
      of in situ hybridization and immunohistochemistry. Expression of RANKL mRNA and
      protein were determined in the developmental progression of endochondral bone
      formation in mouse, intramembranous bone formation in a rabbit model (mRNA only),
      in human giant cell tumors of bone, and at extraskeletal sites in the mouse.
      RANKL mRNA was expressed in prehypertrophic and hypertrophic chondrocytes at day
      E15 embryonic mouse long bone, and its expression was maintained at these sites
      throughout development. In newborn and adult mice, high levels of RANKL mRNA were
      expressed in mesenchymal cells of the periosteum and in mature osteoblasts, while
      megakaryocytes within the marrow microenvironment expressed RANKL mRNA from 1
      week of age. Immunohistochemical analysis revealed a similar localization pattern
      of RANKL protein at the sites described. In the intramembranous bone formation
      model, RANKL mRNA was expressed in mesenchymal cells and in actively synthesizing
      osteoblasts, but not in flattened lining osteoblasts or late osteocytes.
      Expression of RANKL mRNA and protein in osteoclasts was variable with those
      within resorption lacunae showing the strongest signal/staining. Likewise,
      expression varied in osteoclasts from giant cell tumor of bone with a minority of
      tartrate-resistant acid phosphatase-positive multinucleated cells having no
      detectable RANKL mRNA or protein. In extraskeletal tissues, RANKL mRNA and
      protein were detected in the brain, heart, kidney, skeletal muscle, and skin
      throughout mouse development, suggesting the possibility of several other
      functions of the molecule. RANKL was also developmentally regulated, as evidenced
      by its expression in the intestine, liver, and lung at E15 and newborn mouse but
      not in the adult.

PMID- 10574573
TI  - Evidence that conditionally immortalized human osteoblasts express an osteocalcin
      receptor.
AB  - Osteocalcin (OC) is an abundant noncollagenous bone matrix protein, yet its
      function is largely unknown. However, targeted ablation of two OC genes in mice
      lead to increased bone formation (Ducy et al. Nature 382:448-452; 1996). This
      implied that OC inhibits osteoblast activity, and that these cells express an OC
      receptor. In order to characterize the putative OC receptor, we used the
      Cytosensor microphysiometer to measure responses of a proliferative-stage,
      conditionally immortalized human osteoblast cell line (HOB-03-C5) to purified
      bovine OC (bOC). The Cytosensor measures a change in the extracellular
      acidification rate, which is primarily a measurement of metabolic activity.
      Treatment of the HOB cells for 5-60 sec with 0.17 micromol/L bOC generated a time
      dependent, transient increase in the acidification rate that became optimal after
      25 sec. Likewise, treatment of the cells for 25 sec with 0.021 to 1.9 micromol/L
      bOC caused a dose-dependent 70% increase in the acidification rate. Pre-treatment
      of the cells for 2 h with inhibitors of adenylyl cyclase, phospholipase C, and
      intracellular calcium release inhibited the response of the cells to bOC by 50%
      100%, which suggested that the putative OC receptor was coupled to a G-protein.
      These observations from the Cytosensor were confirmed by measuring intracellular
      cyclic-adenosine monophosphate (cAMP) concentrations in response to bOC.
      Treatment of the cells for 10 min with bOC decreased basal cAMP levels by 65% in
      a dose-dependent manner with an IC50 of 0.22 microM. However, cotreatment of the
      cells with forskolin, which activates adenylyl cyclase, blunted this suppression.
      Moreover, pretreatment of the cells with pertussis toxin for 48 h, which inhibits
      G(alpha)i proteins, reversed the suppressive effects of bOC on cAMP production.
      Treatment of the HOB cells for 48 h with 0.19 to 1.5 micromol/L bOC caused a dose
      dependent 40% decrease in alkaline phosphatase activity with an IC50 of 0.21
      micromol/L, which suggested that OC may inhibit HOB activity. Finally, although
      the maturation stage, conditionally immortalized HOB-02-C1 cells also responded
      to bOC as measured by the Cytosensor, two osteosarcoma cell lines, SaOS-2 and ROS
      17/2.8, exhibited a 5- to 10-fold lower response to the bone matrix protein,
      suggesting that the putative OC receptor was downregulated in these cells.
      However, all of these bone cell lines responded to parathyroid hormone treatment.
      In conclusion, these results provide evidence that the HOB cells express an OC
      receptor, and that this receptor appears to be coupled to a G(alpha)-protein.

PMID- 10574574
TI  - Chemical sympathectomy impairs bone resorption in rats: a role for the
      sympathetic system on bone metabolism.
AB  - The possibility that the nervous system may control bone metabolism has been
      raised, as neuromediators physiologically conveyed by sympathetic fibers (eg,
      vasoactive intestinal peptide) influence bone resorption in vitro. In this study,
      the sympathetic system was inactivated by treating rats with guanethidine (40
      mg/kg/day), a sympathetic neurotoxic, for 21 days, after which a wave of
      osteoclastic resorption was induced along the mandibular buccal cortex. The
      effects of denervation were assessed 4 days later (corresponding to the peak of
      resorption in this model). The rats exhibited ptosis soon after starting
      guanethidine, proving the success of the sympathectomy. This was associated with
      a significant increase in calcitonin gene-related peptide- (+54%, p < 0.02) and
      substance P-immunoreactive sensory fibers (+29%,p < 0.02), a known effect of
      sympathectomy. For the quantitation of the bone parameters, the study zone was
      divided into a juxta-osseous alkaline phosphatase-positive osteogenic compartment
      and a nonosteogenic compartment. In the osteogenic compartment, the resorption
      surface was reduced by 56% (p < 0.001) in the treated animals, together with a
      fall in the number of osteoclasts (-25%,p < 0.05) and impaired osteoclast access
      to the bone surface. Tartrate-resistant acid phosphatase-positive (TRAP+)
      mononuclear preosteoclasts were found only in this compartment; they were reduced
      by 43% (p < 0.05) by the sympathectomy. No change in non-specific esterase (NSE)+
      osteoclast precursors was found. In the nonosteogenic compartment, vasodilation
      was the only effect of sympathectomy (+80%,p < 0.05); in particular, the number
      of NSE+ cells was not modified. Our results indicate that: (1) interactions of
      NSE+ precursors with osteogenic cells are required for their differentiation into
      TRAP+ preosteoclasts; (2) the sympathetic nervous system is not involved in
      osteoclast precursor recruitment; but (3) has a significant effect on resorption
      by inhibiting preosteoclast differentiation and disturbing osteoclast activation.
      These data suggest that depletion of sympathetic mediators may disturb osteogenic
      cell-mediated osteoclast differentiation.

PMID- 10574575
TI  - Skeletal mass, chemistry, and growth during and after multiple reproductive
      cycles in the rat.
AB  - There are dramatic changes in skeletal physiology and metabolism to accommodate
      the mineral requirements of the developing fetus during pregnancy and milk
      production during lactation. The purpose of this study was to document changes in
      skeletal growth, chemistry, and mass during and after multiple reproductive
      cycles in the rat, with emphasis on the putative reconstitution of the skeleton
      after lactation. To determine skeletal changes, experimental groups included rats
      at the end of the first and second lactation, at the end of the second pregnancy,
      and at various times after the first and second lactation. These groups were also
      compared with aged-matched, nulliparous animals. There were decreases in femoral
      ash weights and bone mineral densities (BMDs) during the first and second
      lactations, but accelerated rates of gain after lactation, compared with the
      nulliparous controls. The changes in bone ash were even more pronounced when
      normalized to the maternal body weight changes during and after the reproductive
      cycles. The rates and amount of bone mineral (ash) gain after the first and
      second reproductive cycles were similar; however, neither bone mineral nor BMD
      returned to levels found in nulliparous animals after the first and subsequent
      reproductive cycle. There was also a decrease in ash/dry weight ratio of the
      femur during the second lactation, suggesting a preferential loss of more
      mineralized bone. This decrease in ash/dry weight ratio reversed after lactation,
      indicating a relative accumulation of bone mineral during the postlactational
      period. As expected, endochondral growth was substantially suppressed during
      lactation, but rebounded during the postlactational period. These data
      collectively support the notion that the female rat has excess skeletal mass to
      accommodate losses associated with the first reproductive cycle. After the first
      reproductive cycle, a new optimal skeletal mass is achieved. These data also
      demonstrate that the postlactational period is "anabolic" with accelerated rates
      of bone growth and accumulation of bone mineral and bone mineral density with
      increases in the ratios of the inorganic to organic composition of the bone. This
      postlactational recovery phase may serve to at least partially reconstitute
      skeletal mineral depleted during lactation and perhaps to prepare the skeleton
      for the next reproductive cycle.

PMID- 10574576
TI  - Long-term therapy of ovariectomy-induced osteopenia with parathyroid hormone
      analog SDZ PTS 893 and bone maintenance in retired breeder rats.
AB  - The aim of the study was to assess the long-term anabolic effect of the
      parathyroid hormone (PTH) analog SDZ PTS 893 in a dose-response manner, and to
      determine the ability of the antiresorptive agents estradiol and alendronate to
      maintain bone mass after withdrawal of SDZ PTS 893. One hundred thirty retired
      breeder Wistar rats were distributed into 13 groups with 10 rats in each group: 1
      baseline group, 2 sham groups, and 10 ovariectomized groups. Treatment was
      initiated 12 weeks after ovariectomy. SDZ PTS 893 treatment was administered
      daily subcutaneously (Monday to Friday) for 36 weeks. Treatment regimens were as
      follows: (1) baseline (-12 weeks); (2) ovariectomy (ovx) (0 weeks); (3) sham (36
      weeks); (4) ovx (36 weeks); (5) SDZ PTS 893 12.5 microg/kg/day (36 weeks); (6)
      SDZ PTS 893 25 microg/kg/day (36 weeks); (7) SDZ PTS 893 50 microg/kg/day (36
      weeks); (8) SDZ PTS 893 100 microg/kg/day (36 weeks); for the maintenance part of
      the study: (9) sham (48 weeks); ovx animals treated with SDZ PTS 893, 50
      microg/kg/day for 36 weeks followed by 12 weeks of treatment regimens: (10)
      placebo; (11) SDZ PTS 893 50 microg/kg/day; (12) estradiol 10 microg/kg/day; or
      (13) alendronate 28 microg/kg (2 injections/week). The effects of ovx, SDZ PTS
      893 treatment, and maintenance regimens were measured at four skeletal sites:
      lumbar vertebra; femoral diaphysis; distal femoral metaphysis; and proximal
      femoral metaphysis (femoral neck). At these sites, bone density and bone strength
      were measured as treatment endpoints. Furthermore, bone dimensions were measured
      at the midpoint of the femur. The results showed that SDZ PTS 893 increased bone
      strength in a dose-dependent manner at all skeletal sites tested. At the
      vertebral body and distal femoral metaphysis, apparent ash density increased in a
      similar way. There was a slight decrease in cortical density at the mid
      diaphyseal site. Static histomorphometry showed increased bone area due to a
      decreased marrow area (endosteal net bone gain) but also due to increased tissue
      area (periosteal net bone gain). For maintenance, continuous SDZ PTS 893 therapy
      was most efficient, followed by alendronate and estradiol treatment with regard
      to preservation of bone mass and strength. It is concluded that the new PTH
      analog SDZ PTS 893 has a highly anabolic, dose- and time-dependent effect on all
      skeletal sites tested. Bone formation is induced at both endosteal and periosteal
      surfaces.

PMID- 10574577
TI  - In vivo matrix microdamage in a naturally occurring canine fatigue fracture.
AB  - Greyhound central tarsal bone (CTB) from animals with (n = 11) and without CTB
      fatigue fracture (n = 15) was examined histologically for the presence, numerical
      density, and morphology of in vivo microdamage. Complete fracture of the right
      CTB is a common occurrence during dog racing, because this is the outside limb
      when running counterclockwise on a circular or oval track. The CTB consisted of
      both remodeled cortical bone and inner trabecular bone. Thickening and
      coalescence of trabeculae were observed, particularly dorsally and medially,
      causing reduction or elimination of the marrow void spaces. A band of tightly
      packed transverse osteons was also observed adjacent to the concave proximal
      joint surface. Typical linear microcracks were most often seen in remodeled
      cortical and trabecular bone and were often observed adjacent to vascular
      channels. In contrast, ultra-microcracking, represented by diffuse staining with
      basic fuchsin, was consistently observed in the plantar process around the
      attachment site for the plantar ligament complex. Dog status (fractured or
      intact) and side (left or right) both had a significant effect on microcrack
      density and microcrack surface density (p < 0.05). Microcrack density and
      microcrack surface density were increased in the right (fractured) CTB from
      greyhounds with CTB fracture. There was also a trend for side to have a
      significant effect on microcrack length, with microcrack lengths being higher in
      the right CTB of both intact and fractured dogs. These data support the general
      hypothesis that fatigue fracture occurs because of ongoing cyclic stresses after
      induction of reparative remodeling. Development of methods for biomechanical
      testing of small cuboidal bones should allow investigation of relationships
      between accumulation of loading cycles and bone weakening because of microdamage.

PMID- 10574578
TI  - Differences in static cortical bone remodeling parameters in human mandible and
      iliac crest.
AB  - Knowledge of the baseline turnover characteristics, and of possible general and
      local factors influencing alveolar bone responses, is particularly important in
      the planning of oral rehabilitation. The conventional tool used to obtain
      information on bone turnover is the iliac crest biopsy, but it is not clear
      whether it mirrors the situation involving the jaws. The aim of this study was to
      compare static bone remodeling parameters in the mandible and in the iliac crest
      to obtain baseline values for the mandible and to test the hypothesis of site
      specificity of bone remodeling. Bone specimens were obtained from 50 subjects
      (mean age 64 +/- 17) at autopsy. Three sites were sampled: iliac crest; jaw
      angle; and foramen mentalis area. In addition, occlusal status was recorded. On
      undecalcified thin sections, cortical porosity (Ct.Po), eroded sites (ESi),
      formative sites (FSi), osteonal diameter (On.Dm), Haversian canal diameter
      (H.Ca.Dm), and wall width (W.Wi) were measured. Ct.Po in the jaw angle and in the
      foramen mentalis area was lower (48% and 50%, respectively) than in the iliac
      crest, as was ESi and FSi (80% in the jaw angle and 74% in the foramen mentalis
      area). In the foramen mentalis area, Ct.Po was greater in subjects with
      occlusion. On.Dm, H.Ca.Dm, and W.Wi were significantly larger and mutually
      correlated within the mandible, whereas no correlation was found between
      mandibular sites and iliac crest. Static cortical bone remodeling parameters are
      different in the mandible and the iliac crest, thus confirming the hypothesis of
      site specificity of bone remodeling. Within the mandible, the parameters were
      correlated, whereas there was no correlation between the mandible and the iliac
      crest. This could be ascribed to the different functional demands to the mandible
      and the iliac crest, which was also reflected in the observed influence of
      functional occlusion on bone remodeling in the mandible. It can thus be concluded
      that bone reaction to dental intervention is more dependent on the local
      environment than on general bone turnover as reflected by the iliac crest.

PMID- 10574579
TI  - The relationship between basic multicellular unit activation and origination in
      cancellous bone.
AB  - Activation frequency is often used as a measure of basic multicellular unit (BMU)
      activity in cancellous bone. However, activation frequency expresses the rate of
      BMU appearance in a histologic slide and not the rate of origination, which is a
      more physiologic indicator of remodeling activity and is necessary for the
      development of BMU-level bone remodeling simulations. Using identical assumptions
      to those for calculating the activation frequency, it is shown that the
      origination frequency in cancellous bone is equal to the activation frequency
      divided by the total distance traveled by the BMU and its width.

PMID- 10574580
TI  - Primary hyperparathyroidism: effect of parathyroidectomy on regional bone mineral
      density in Danish patients: a three-year follow-up study.
AB  - Changes in skeletal remodeling (biochemical bone markers) and regional bone
      mineral density (spine, hip, and forearm bone mineral density [BMD]) were
      observed for 3 years in 20 patients (15 women and 5 men; age 54 +/- 11 years,
      range 29-69 years) after successful surgery for primary hyperparathyroidism
      (PHPT). Fifteen PHPT patients were compared with 15 normal controls who were
      exactly matched with respect to age, gender, and menopausal status (10 women and
      5 men; age 53 +/- 12 years, range 29-65 years [PHPT] and 29-66 years [controls]).
      All bone markers (serum osteocalcin, bone alkaline phosphatase, and type I
      collagen telopeptide [ICTP], and urinary hydroxyproline and NTx/creatinine ratio)
      declined significantly and reached normal levels within 6 months. No major
      changes took place during the remaining 2.5 years, apart from urine
      hydroxyproline, which disclosed a small peak around 12 months with a further
      decline towards study end (p < 0.05). Bone mineral density increased
      significantly in all regions (p < 0.001). At all locations, except the
      intertrochanteric region of the hip, the increase continued from 6 months until
      study end (p < 0.05). The increase in BMD was unequally distributed among regions
      (p < 0.001). The increase at the proximal forearm was less than in the spine (p <
      0.05), the trochanteric region of the hip (p < 0.05), and the distal forearm (p <
      0.05). No difference in BMD increase was observed between men, and pre- and
      postmenopausal women. Compared with the matched control group, PHPT patients had
      significantly lower BMD at baseline in the proximal (p < 0.02) and distal (p <
      0.05) forearm. Furthermore, during the 3-year follow-up period, the PHPT patients
      showed a significant increase in BMD compared with controls in the spine (p <
      0.005), the trochanteric and intertrochanteric regions of the hip (p < 0.005 and
      p < 0.05, respectively), and the distal forearm (p < 0.005). In conclusion, bone
      remodeling is normalized within the first 6 months after successful parathyroid
      surgery, with no major changes during the following 2.5 years. Bone mineral
      density increases at both cancellous and cortical sites, but in predominantly
      cortical bone, the recovery in BMD is less than in cancellous bone-rich areas.

PMID- 10574581
TI  - Primary hyperparathyroidism: whole-body bone mineral density in surgically
      treated Danish patients: a three-year follow-up study.
AB  - Whole-body bone mineral density (BMD) and body composition were measured before
      surgery in 25 patients (20 women and 5 men, aged 53 +/- 13 years, range 26-73
      years) with mild to moderate primary hyperparathyroidism (PHPT) and compared with
      25 controls exactly matched with respect to age, gender, and menopausal status.
      Fifteen pairs of matched patients and controls were reexamined 3 years later (5
      men and 10 women, aged 53 +/- 12 years in both groups). In the untreated PHPT
      patients, whole-body BMD was 95.4% +/- 10.5% (SD) of control BMD (p < 0.05). Body
      weight and height, body mass index, whole-body fat mass, and lean body mass did
      not differ significantly between the groups. Relative to values in matched
      controls, whole-body bone mineral content (BMC) and BMD increased by 4.4% and
      3.0%, respectively, in PHPT patients (p < 0.005) during the 3-year follow-up.
      Neither whole-body BMC nor BMD differed between patients and controls after the 3
      year follow-up. A positive correlation was observed between initial serum calcium
      levels and the 3-year increase in whole-body BMD (r(s) = 0.645, p < 0.01).
      Baseline serum osteocalcin, serum pyridinoline crosslinked telopeptide of Type I
      collagen and several histomorphometric indices of trabecular bone turnover
      (eroded and labeled surfaces, bone formation rate, and activation frequency) also
      correlated positively with the subsequent increase in whole-body BMD. Six
      patients disclosed transient postoperative secondary hyperparathyroidism,
      probably due to hungry bones. Four of these patients completed 3 years of follow
      up and had higher increases in whole-body BMD than the remaining normo
      parathyroid patients (7.9% +/- 4.5%, range 4.3-14.3% versus 1.9% +/- 2.1%, p <
      0.01). It is concluded that Danish patients with mild to moderate PHPT only
      reveal small reductions in whole-body mineral density. Furthermore, within 3
      years after parathyroid surgery, most of the lost bone mineral is regained even
      in patients with initial high bone turnover. Finally, PHPT in these patients is
      not associated with substantial changes in body compositions.

PMID- 10574582
TI  - Treatment of childhood hypophosphatasia with nonsteroidal antiinflammatory drugs.
AB  - Hypophosphatasia (HP) is an inborn error of metabolism that is characterized by
      reduced bone mineralization. The aim of this investigation was to evaluate
      treatment of incapacitating lower limb pain in patients with childhood HP using
      nonsteroidal antiinflammatory drugs (NSAID). All patients (seven boys; age 32
      months to 16 years) presented with delayed walking, the typical waddling gait,
      muscular weakness of the lower limbs, and a limited walking distance. Six
      patients had severe diffuse lower limb pain following physical activity and were
      therefore treated with NSAID. The benefit of this treatment was evaluated
      clinically and by measurement of renally (PGE2) and systemically (PGE-M) derived
      prostaglandins (PG) in urine before and during therapy. After treatment with
      NSAID all six patients showed marked clinical improvement with reduced pain,
      increased muscle strength, and a normalized walking distance. Levels of PGE-M,
      which had been elevated in four patients prior to therapy, returned to normal.
      The use of NSAID in childhood HP should be considered as a possible therapeutic
      approach because the quality of life in these patients is markedly impaired by
      pain of the limbs. Elevated PG might play a role in the bone metabolism of HP
      patients.

PMID- 10574583
TI  - Prevalence of hypovitaminosis D in Indo-Asian patients attending a rheumatology
      clinic.
AB  - This study was performed to determine the prevalence of hypovitaminosis D (HD)
      and hypovitaminosis D associated with secondary hyperparathyroidism (HD-SHPT)
      among Indo-Asians attending rheumatology clinics in Wolverhampton. A cross
      sectional survey of 98 clinic attenders and 36 normal controls subjects was
      undertaken. The groups were matched for age, gender, and body mass index. There
      was a high prevalence of vegetarianism, and milk consumption was low in both
      groups. Clinical scores for musculoskeletal pain, gait, and muscle strength were
      all significantly worse in clinic attenders (p < 0.001). Comparing clinic
      attenders with controls, 25-OH-vitamin D levels were 6.6 +/- 3.9 vs. 8.2 +/- 4.8
      microg/L (p < 0.01) and the prevalence of HD (<8 microg/L) was 78% vs. 58% (p <
      0.05), but neither parathyroid hormone levels (53 +/- 60 vs. 50 +/- 18 ng/L,
      n.s.) nor HD-SHPT prevalence (22% vs. 33%, n.s.) were significantly different.
      Routine biochemical tests were not discriminant, but none of the controls and 10
      of 98 (10%) clinic attenders had elevated alkaline phosphatase levels: 6 with HD
      and 3 with HD-SHPT. Vitamin D deficiency has an extremely high prevalence among
      Indo-Asians in the U.K., particularly in those attending rheumatology clinics.
      Detection of HD and HD-SHPT is only possible using measurements of 25-OH-vitamin
      D and PTH.

PMID- 10574584
TI  - Association of prevalent vertebral fractures, bone density, and alendronate
      treatment with incident vertebral fractures: effect of number and spinal location
      of fractures. The Fracture Intervention Trial Research Group.
AB  - Vertebral fractures are the most common osteoporotic fracture and are associated
      with significant pain and disability. Prior vertebral fracture and low bone
      mineral density (BMD) are strong predictors of new vertebral fracture. Using data
      from 6082 women, ages 55-80 years, in the Fracture Intervention Trial (a
      randomized, placebo-controlled trial of the antiresorptive agent, alendronate),
      we explored the association of the number of prior vertebral fractures with the
      risk of new fractures and whether this association is influenced by the spinal
      location of fractures. The risk of future vertebral fractures increased with the
      number of prevalent fractures, independently of age and BMD; in the placebo
      group, more than half of the women with five or more fractures at baseline
      developed new vertebral fractures, compared to only 3.8% of women without prior
      vertebral fractures. The magnitude of association with an increased risk of
      future vertebral fractures was equal for prevalent fractures located in either
      the "lower" (T12-L4) (relative risk [RR] = 2.9; 95% CI = 1.9, 3.6) or "upper" (T4
      10) spine (RR = 2.6; 95% CI = 1.9, 3.6). We found no evidence that the
      effectiveness of alendronate in reducing the risk of future vertebral fracture
      was attenuated in women with up to five or more prevalent fractures, or that it
      varied by the location of prevalent fractures. However, prevalent vertebral
      fractures in any location were more strongly associated with risk of new
      fractures in the upper (RR = 5.2; 95% CI = 3.2, 8.3) than in the lower spine
      (2.3; 1.6, 3.3). In addition, each 1 SD decrease in spinal BMD was associated
      with a 2.1 (1.7, 2.6) times greater odds of new fracture in the upper spine,
      compared with 1.5 (1.3, 1.8) for the lower spine. These findings suggest that, in
      older women, osteoporosis may be a stronger risk factor for new fractures in the
      upper (vs. lower) thoracolumbar spine, although we found no evidence that the
      location of prior fractures should influence treatment decisions. Physicians
      should recognize that prior vertebral fractures are a strong risk factor for
      future fractures, and consider treating such patients to reduce their risk of
      subsequent fractures.

PMID- 10574585
TI  - Oxidized low-density lipoprotein inhibits the binding of monoclonal antibody to
      platelet glycoprotein IIB-IIIA.
AB  - Previous studies have shown that oxidized low-density lipoprotein (LDL) induces
      platelet activation more effectively than native LDL. To achieve a better
      understanding of the mechanism underlying the activation of human platelets by
      oxidized LDL, the present study relates the effect of oxidized LDL to changes of
      binding characteristics for glycoprotein (GP) IIb-IIIa. Washed human platelets
      were treated by monoclonal antibody against GP IIb-IIIa, and the ligand-receptor
      complexes were revealed by immunocytochemical techniques on the ultrastructural
      level. The localization of the antiglycoprotein IIb-IIIa was time-dependent.
      After binding to the platelet surface membrane and open canalicular system, the
      surface-membrane labeling decreased during longer incubation periods.
      Preincubation with oxidized LDL inhibited the binding of antiglycoprotein IIb
      IIIa. Our findings suggest that GP IIb-IIIa acts as a receptor for oxidized LDL.
      The binding of oxidized LDL to the GP IIb-IIIa might be the first step in
      platelet activation by plasma lipoproteins.

PMID- 10574586
TI  - N-glycosylation contributes to the intracellular stability of prothrombin
      precursors in the endoplasmic reticulum.
AB  - Rat prothrombin (rFII) and human prothrombin (hFII) are processed differently
      during their biosynthesis in a manner dependent upon gamma-glutamyl
      carboxylation, a vitamin K-dependent posttranslational modification of
      prothrombin precursors. The role of N-glycosylation in the cellular processing of
      prothrombin was examined in hepatoma (H-35 and HepG2) and transformed kidney
      (HEK293) cell lines. Aglyco-rFII obtained by tunicamycin treatment was degraded
      in warfarin-treated H-35 cells, but not in vitamin K-treated cells. Fully
      glycosylated rFII is also selectively retained and degraded in warfarin-treated H
      35 cells. When rFII and hFII were transiently expressed in tunicamycin-treated
      HEK293 cells, rFII but not hFII was degraded to generate a 48-KD species. This
      degradation was independent of gamma-carboxylation, indicating that the
      sensitivity of aglyco-rFII and aglyco-hFII toward this specific proteolysis
      differs in HEK293 cells. By expressing chimeric rFII/hFII constructs in
      tunicamycin-treated HEK293 cells, it was shown that the kringle 2 structure of
      prothrombin was responsible for this difference. The 48-KD species was not
      observed in tunicamycin-treated H-35 cells, suggesting that this specific
      proteolytic processing of aglyco-rFII is also cell-type specific. Expression of
      rFII in other tunicamycin-treated nonhepatic cells suggests that this cell
      specific difference in processing might be determined by a difference between
      hepatic and nonhepatic cells. The site-directed mutagenesis utilized in these
      studies also establishes that the N-glycosylation sites of rFII are at residues
      Asn77, 101, 378, and 518.

PMID- 10574587
TI  - Coagulation and fibrinolysis after open infrarenal abdominal aortic aneurysm
      repair in a long-term perspective.
AB  - In patients with abdominal aortic aneurysms (AAA) the coagulation and
      fibrinolytic systems have been found to be activated preoperatively. Does the
      increased activity of the coagulation and fibrinolytic systems persist after AAA
      surgery in a long-term perspective? Prothrombin fragment 1+2 (F1+2), thrombin
      antithrombin complex (TAT), tissue plasminogen activator (tPA), human plasminogen
      activator inhibitor type 1, and human cross-linked fibrin degradation product (D
      dimer) were analysed in 18 patients after open AAA surgery (postop-AAA). The
      median time between surgery and blood sampling was 19 months (range, 5-37
      months). Comparisons were made with both preoperative values of 23 patients with
      AAA (preop-AAA) as well as 20 age-matched healthy controls (AMC). F1+2, TAT, and
      D-dimer in preop-AAA were significantly higher compared to AMC (p<0.001). In post
      op AAA patients these parameters were significantly lower compared to preop-AAA
      (p<0.05 for F1+2 and TAT, p<0.001 for D-dimer). However, TAT and D-dimer levels
      were still higher in postop-AAA than in AMC (p<0.01 for both). The activity of
      the coagulation and fibrinolytic systems seems to decrease after AAA surgery.
      However, the activity is still higher than in healthy AMC. A possible explanation
      may be that the thrombogenicity is lower in a vascular graft than in an
      aneurysmal sac but still higher than in a nonaneurysmal aorta.

PMID- 10574588
TI  - Tissue factor and tissue factor pathway inhibitor levels during and after
      cardiopulmonary resuscitation.
AB  - Disseminated intravascular coagulation frequently occurs after global ischemia
      and reperfusion due to cardiac arrest. The present study was performed to
      demonstrate the role of tissue factor for coagulation pathway activation, as well
      as to investigate the precise time course of tissue factor pathway inhibitor
      (TFPI) during and after cardiopulmonary resuscitation (CPR). Thirty-two of out-of
      hospital cardiac arrest patients were classified into two groups, those who
      achieved return of spontaneous circulation (ROSC) (n=13) and those without ROSC
      (n=19). Ten normal healthy volunteers served as control subjects. Serial levels
      of tissue factor and TFPI were measured during and after cardiac arrest and CPR.
      In patients with ROSC, cardiac arrest and CPR led to persistent increases in the
      levels of tissue factor that peaked 6 hours after arrival at the Emergency
      Department. Tissue factor levels in patients without ROSC also showed marked
      elevations compared to those of the control subjects. In both groups, the levels
      of TFPI were significantly lower than those in the control subjects. However, we
      could not find differences in the levels of the two markers between the patients
      with ROSC and those without ROSC. In conclusion, we demonstrated persistent
      elevation of the tissue factor levels associated with low TFPI during and after
      CPR in patients with out-of-hospital cardiac arrest. These results indicate the
      activation of the extrinsic coagulation pathway without adequate TFPI generation,
      which may contribute to thrombin activation and fibrin formation after whole-body
      ischemia and reperfusion.

PMID- 10574590
TI  - The Factor V (Leiden) test: evaluation of an assay based on dilute Russell Viper
      Venom Time for the detection of the Factor V Leiden mutation.
AB  - In the present study a new clotting assay for the detection of an increased
      resistance of coagulation factor V against degradation by activated protein C
      (Factor V Leiden mutation, FVLM) was evaluated. The Factor V (Leiden) Test
      (Gradipore, North Ryde NSW, Australia) is based on the dilute Russell Viper Venom
      Time (DRVVT), which is prolonged when the plasma sample is preincubated with
      dilute whole Agkistrodon contortrix contortrix venom for activation of protein C
      (PC). In contrast to the DRVVT based global assay, Protein C Pathway Test
      (Gradipore, North Ryde NSW, Australia) this new assay is expected to be more
      specific for FVLM because of optimized amounts of the venom. The test result is
      expressed as the ratio between the DRVVT with and without addition of the venom.
      The following precision values were found: intraassay coefficient of variation
      (CV): 5.53% (n=20) in the normal range, 4.30% (n=20) in the pathological range;
      interassay CV: 6.90% (n=10) and 7.64% (n=10), respectively. A normal range (5th
      to 95th percentile) of 2.12 to 3.08 was calculated from 50 healthy controls. A
      ratio below 2.12 was found in all samples from patients with FVLM (n=21), in 9 of
      12 patients with PC, in 0 of 6 with protein S (PS), and in 0 of 4 with
      antithrombin (AT) deficiency. There was, however, a good discrimination between
      carriers of the FVLM (highest ratio 1.44) and patients deficient in PC (lowest
      ratio 1.59), in particular when samples were prediluted with factor V deficient
      plasma FVDP (1.16 vs. 1.96, respectively). Predilution of samples with FVDP
      caused a clear discrimination between controls and patients deficient in PC, PS,
      AT, and FVLM-positive individuals and also in patients on oral anticoagulant
      treatment. Our data show that the Factor V (Leiden) Test discriminates well
      between carriers of the FVLM and healthy controls or patients deficient in PC,
      PS, and AT. Individuals presenting values between the lower cutoff of controls
      and the range in which FVLM-positive individuals are found are highly suspicious
      for protein C deficiency.

PMID- 10574589
TI  - Laboratory monitoring of pentasaccharide in a dog model of hemodialysis.
AB  - Varying dosages of pentasaccharide (400-800 nmol/kg) were compared to a 250-U/kg
      single bolus dosage of unfractionated heparin (UFH) in a dog model of
      hemodialysis. Several laboratory assays were used to monitor the effects of
      pentasaccharide and UFH. The pentasaccharide did not produce any anticoagulant
      effects as measured by the activated partial thromboplastin time. However, in the
      anti-Xa chromogenic assay and the Heptest assays, there was a dose-dependent
      prolongation after pentasaccharide administration. In the group of dogs
      administered 800 nmol/kg of pentasaccharide, there was a 50% decrease in the
      thrombin antithrombin (TAT) complex level after 60 minutes on dialysis. In the
      UFH-treated dogs, wide variations in assays were observed. There was a marked
      elevation in the activated partial thromboplastin time and Heptest assays up to 6
      hours after UFH administration. Both anti-Xa and anti-IIa activity was measured
      up to 4 hours. In the TAT assay, UFH was found to have a stronger effect in
      suppressing the formation of TAT in comparison to the pentasaccharide. These
      results suggest that pentasaccharide can be used as a replacement for UFH in a
      dog model of hemodialysis to keep the dialysis circuit patent. In addition, the
      anti-Xa-based assays such as the Heptest and the chromogenic anti-Xa assays can
      be used to monitor the effects of pentasaccharide in this model.

PMID- 10574591
TI  - A specific inhibitor of factor Xa, DX-9065a, exerts effective protection against
      experimental tumor induced disseminated intravascular coagulation in rats.
AB  - (+)-2S-2-[4-[[(35S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-[7- amidino-2
      napthyl]propanoic acid hydrochloride pentahydrate (DX-9065a) is an antithrombin
      III-independent, selective inhibitor of activated blood coagulation factor X
      (FXa). We investigated the protective effects of DX-9065a against tumor-bearing
      experimental disseminated intravascular coagulation (DIC) induced by the
      inoculation of AH-109A cells into rats. DX-9065a was subcutaneously administered
      at doses of 0.03 and 0.1 mg/kg/hour through an osmotic pump transplanted
      immediately after the inoculation of the tumor cells during the observation
      period. Platelet count decreased 12 days after the inoculation, concomitant with
      an increase in the thrombin-antithrombin III complex and fibrin and fibrinogen
      degradation products. Doses of 0.03 and 0.1 mg/kg/hour of DX-9065a significantly
      inhibited the decrease in plasma fibrinogen concentration and platelet count 13
      days after the inoculation, respectively. These findings suggest that direct,
      selective inhibition of FXa by DX-9065a improves the hypercoagulable state
      induced by the progress of solid tumor.

PMID- 10574593
TI  - Murine microvascular anastomosis model of thrombosis.

PMID- 10574592
TI  - A laboratory method for determination of overall haemostatic potential in plasma.
      I. Method design and preliminary results.
AB  - The aim of this study was to design a simple laboratory method that can screen
      the overall haemostatic potential in plasma (OHPP) when a hyper- or
      hypocoagulable state is present. A fibrin time curve was made via
      spectrophotometric registration of fibrin generation and lysis in plasma, to
      which exogenous thrombin and tissue type plasminogen activator was added. The
      area under the curve, calculated by the sum of absorbance (ABS-sum), varied in
      correlation to the concentrations of platelets or purified pro-/anticoagulants:
      tissue factor, von Willebrand factor, fibrinogen, antithrombin, plasminogen, or
      plasminogen activator inhibitor type 1. The ABS-sums also changed in positive
      relation to the haemostatic function investigated in 16 menopausal women and 14
      young healthy nonpregnant women (controls). The findings imply that the ABS-sums
      not only offer a general information about fibrin generation and lysis in vitro,
      but also reflect the OHPP (i.e., final combined effects of platelet activity,
      coagulation, and fibrinolysis in vivo). Preliminary results were satisfactory;
      the levels of OHPP, expressed as the ABS-sums, were higher in normal pregnant
      women than in the controls, and even higher in preeclamptic patients than in
      pregnant women with no complications, which corresponds to the different grades
      of hypercoagulability in the three groups. Moreover, the level of OHPP was
      considerably lower in an untreated infant with von Willebrand's disease type 3
      and in factor VIII- or factor IX-deficient plasma samples.

PMID- 10574594
TI  - The effect of polyclonal antibody against fibronectin on von Willebrand Factor
      multimeric size.

PMID- 10574595
TI  - The diagnostic value of computer-assisted primary cervical smear screening: a
      longitudinal cohort study.
AB  - OBJECTIVES: To assess computer-assisted (neural network based) cervical smear
      screening as a primary tool for the early detection of cervical dysplasia.
      DESIGN: Longitudinal cohort study. SETTING: Cytology laboratory reviewing
      cervical smears taken by general practitioners in a mass screening program in the
      Netherlands. SUBJECTS: 846 women who developed (pre-)neoplasia of the cervix in
      the seven years after the baseline smear, and 5217 controls. INTERVENTIONS:
      Cervical smears were evaluated both by conventional light microscopy and with use
      of the PAPNET Testing System by the same cytotechnologists. MAIN OUTCOME
      MEASURES: Seven year histological and cytological follow-up results were obtained
      for all women from a nation-wide pathology database. RESULTS: Conventional
      screening diagnosed dysplasia or carcinoma in the baseline smears of 458 (54.1%)
      of the 846 women who were diagnosed with (pre-)neoplasia during follow-up,
      whereas computer-assisted PAPNET analysis detected such lesions in 462 (54.6%) of
      these women. In the control population of 5217 (86.0%) women, in whom follow-up
      revealed no cervical dysplasia, conventional screening gave false positive
      results in 210 (4.0%) and computer-assisted PAPNET analysis gave false positive
      results in 207 (4.0%) smears. The areas under the receiver operation curves (AUC)
      were 80% (95% confidence interval, 78 to 82%) and 79% (95% confidence interval,
      77 to 81%) for conventional and PAPNET-assisted screening, respectively.
      CONCLUSIONS: The PAPNET Testing System has similar diagnostic value as the
      conventional screening of Pap smears when used for primary screening.

PMID- 10574596
TI  - Comparative immunohistochemical and molecular analysis of uterine and
      extrauterine leiomyosarcomas.
AB  - Histologic criteria defining malignancy in smooth muscle tumors are currently
      site specific. This study was undertaken to determine whether, in leiomyosarcomas
      (LMS) occurring in different anatomic locations, there were differences in
      patterns of expression of molecules that have been demonstrated to be associated
      with biologically aggressive behavior in malignant neoplasms, and also to
      determine their diagnostic utility. Formalin-fixed paraffin-embedded tissue
      blocks were selected from 16 extrauterine leiomyosarcomas (EULMS), 14 cases of
      uterine leiomyosarcomas (ULMS) and from five cases each of uterine and
      extrauterine leiomyomas (LM). Utilizing immunohistochemical (ABC) techniques with
      antigen retrieval, we assessed serial sections of each tumor for immunoreactivity
      with Glut1, CD44s, bcl2, cyclin D1, and estrogen receptor. Molecular genotyping
      for detecting k-ras-2 point mutation, p53 gene loss, and mdm2 gene amplification
      was performed on microdissected tumor samples from the same histologic sections.
      All of the uterine and extrauterine LM were diffusely positive for CD44s, bcl2,
      and cyclin D1, and uniformly negative for Glut1. In contrast, 50% of the ULMS and
      25% of EULMS were Glutl positive. Moreover, Glut1 positivity closely correlated
      with aggressive biologic behavior reflected by distant metastatic spread. Eighty
      percent of LM and 70% of the ULMS were estrogen receptor positive, whereas only
      one retroperitoneal tumor had focal weak positivity. Over 80% of the extrauterine
      and 50% of the uterine sarcomas showed absence of CD44s immunoreactivity.
      Percentage of cyclin D1 immunoreactivity was independent of tumor grade and
      inversely proportional to the percent of bcl2 positivity. An LMS of the male
      breast contained k-ras-2 exon 1 point mutation (codon 12 aspartate substitution
      of glycine). P53 allelic imbalance was present in 29% of ULMS and 57% EULMS. Mdm2
      amplification was present in three of six EULMS but not in ULMS. In addition to
      clinical staging, Glut1 positivity together with patterns of immunoreactivity of
      CD44 and bcl2 may be helpful in identifying aggressive smooth muscle tumors of
      the uterus and some EULMS. The presence of estrogen receptor staining may be
      helpful in identifying uterine versus nonuterine LMS. Although sample numbers are
      too small for definite conclusions, this study suggests that there are
      differences in glucose transport, expression of adhesion molecules, and estrogen
      receptors in ULMS and EULMS, which in part may be due to the estrogen dependency
      of the ULMS. P53 mutations and mdm2 amplifications appear to be more frequent in
      EULMS.

PMID- 10574597
TI  - Oncoprotein MDM2 overexpression is associated with poor prognosis in distinct non
      Hodgkin's lymphoma entities.
AB  - MDM2 is an oncoprotein involved in the regulation of p53. MDM2 exerts its
      tumorigenic potential through p53-dependent and -independent mechanisms. It is
      frequently overexpressed in various malignancies. Little is known about the
      prognostic value of MDM2 expression in non-Hodgkin's lymphomas (NHL). We analyzed
      MDM2 expression immunohistochemically in 188 NHL cases from a prospective
      population-based NHL registry. The aim was to identify MDM2 expression profiles
      in various histological NHL subtypes and analyze whether MDM2 expression
      correlated with clinical variables and p53 status. MDM2 overexpression was
      present in 42 (22%) of 188 cases. The frequency was highest in aggressive/very
      aggressive NHL (P < .0001). Furthermore, within follicle center lymphomas, MDM2
      overexpression was associated with higher-grade disease (P = .008). MDM2
      overexpression was not related to a phenotype indicating altered p53. In
      univariate analysis MDM2 overexpression associated with short survival in
      follicle center lymphomas (P = .0256), extranodal marginal zone lymphomas (P <
      .0001), and mantle cell lymphomas (P = .0047). The relation to poor prognosis was
      maintained in a Cox regression analysis including known prognostic factors
      (relative risk 5.5, P = .0022). The results of the present study suggest that
      MDM2 may play a role in lymphomagenesis and lymphoma progression through p53
      independent mechanisms, and that MDM2 overexpression identifies a small fraction
      of follicle center lymphomas, extranodal marginal zone lymphomas, and mantle cell
      lymphomas with poor prognosis.

PMID- 10574598
TI  - Gastric cardia inflammation and intestinal metaplasia: associations with reflux
      esophagitis and Helicobacter pylori.
AB  - Gastric cardia inflammation and intestinal metaplasia are the subjects of recent
      investigation. Some authors have found associations with gastroesophageal reflux
      disease, whereas others have identified relationships with Helicobacter pylori
      (HP). We studied 150 consecutive patients who underwent upper endoscopy, had
      normal gastroesophageal anatomy, and had biopsies of the antrum, cardia, and
      lower esophagus, to evaluate relationships between reflux esophagitis, cardia
      inflammation, intestinal metaplasia, and HP gastritis. Forty-two patients had HP
      infection. Cardia inflammation was significantly related to esophageal squamous
      inflammation in the non-HP-infected patient group and to antral inflammation and
      cardia HP infection in the HP-infected patient group. The differences between the
      patient groups was most apparent in the patients with moderate or marked
      inflammation. Twenty-seven percent of patients had cardia intestinal metaplasia
      that was related to cardia inflammation. Cardia inflammation and intestinal
      metaplasia probably have multiple causes. Pathologists should refrain from
      applying the term Barrett's esophagus for biopsies procured from the cardia that
      show intestinal metaplasia in patients with a normal squamocolumnar junction.

PMID- 10574600
TI  - Extrapleural solitary fibrous tumor: a clinicopathologic study of 24 cases.
AB  - Solitary fibrous tumors (SFTs), rare in extrapleural sites, can present
      difficulties in diagnosis at these locations. From the files of the M. D.
      Anderson Cancer Center, we accessed 24 cases of extrapleural SFT (14 females, 10
      males, ages 19 to 85 yr) obtained for clinical, histologic, immunohistochemical,
      and follow-up findings. Tumor locations included the head and neck (n = 12), the
      abdomen (n = 10), and the extremities (n = 2). Tumors were 2 to 25 cm in greatest
      dimension (mean, 8.2 cm) and were well circumscribed or encapsulated. Histologic
      features were typical of their pleural counterparts, e.g., bland spindle cells
      with some hypercellular areas and myxoid to hyalinized backgrounds. A
      hemangiopericytic vascular pattern was present in 19 cases and prominent in 11.
      Mitotic activity ranged from 0 to 4 counts per 10 high-power fields. Necrosis was
      seen in two cases. Focally increased cellularity was seen in seven cases and
      margins were positive in another seven cases. Spindle cells were positive for
      vimentin (19 of 19) and CD34 (18 of 20), and negative for cytokeratin (0 of 19).
      Fibroblastic differentiation was present in the three cases studied by electron
      microscopy. Flow cytometry in three cases revealed diploid cell populations.
      Follow-up for 19 cases (9 to 99 mo) revealed no evidence of metastasis, although
      one patient had residual tumor after an incomplete excision, and one patient died
      of unrelated causes. Histologic findings such as mitotic counts, necrosis,
      cellularity, and marginal status were not associated with outcome. We conclude
      that extrapleural SFTs are clinically and histologically similar to their pleural
      counterparts. Although the length of clinical follow-up was short (mean follow
      up, 41.4 mo), recognizing these lesions is important because they typically
      follow an indolent clinical course if completely excised. Although CD34 is
      nonspecific, it is usually positive in SFTs and may aid in their diagnosis.

PMID- 10574599
TI  - Apoptosis in gestational trophoblastic disease is correlated with clinical
      outcome and Bcl-2 expression but not Bax expression.
AB  - Apoptosis has been found to play a crucial role in the pathogenesis and prognosis
      of many human diseases. The pathogenesis of gestational trophoblastic disease
      (GTD), which encompasses hydatidiform moles (HMs) and choriocarcinomas (CCAs), is
      not fully understood. Prognostic indicators of HM have also been scanty. In this
      study, we investigated apoptotic activity and the expression of two apoptosis
      regulatory genes, Bcl-2 and Bax, in an attempt to determine the role of apoptosis
      in GTD. Formalin-fixed paraffin-embedded tissue of 33 normal placentas, 14
      spontaneous abortions, 14 partial moles, 34 complete moles, and eight CCAs were
      examined. Apoptotic activity was assessed by the terminal deoxynucleotidyl
      transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) method.
      Quantitative assessment of apoptotic index (AI) was calculated as a percentage of
      TUNEL-positive nuclei. Expression of Bcl-2 and Bax were assessed
      immunohistochemically. Extensive apoptosis was located in syncytiotrophoblasts,
      cytotrophoblasts, and villous stromal cells in all HM cases. Apoptosis was
      detected at a much lower level in spontaneous abortions and normal placentas.
      Moreover, in normal placentas, TUNEL positive nuclei were exclusively found in
      syncytiotrophoblasts. AIs were significantly different among various categories
      of trophoblastic lesions (P < .001) in an ascending order: normal placentas less
      than spontaneous abortions less than CCAs less than HMs. Furthermore, AIs of
      those cases that spontaneously regressed was statistically higher than those that
      developed persistent trophoblastic disease requiring chemotherapy. AIs of
      trophoblastic lesions in general inversely correlated with Bcl-2 expression (P <
      .001), but no significant correlation was found between AI and Bax expression (P
      > .5). We conclude that AI may be a useful prognostic marker for clinical
      progress of HMs. Bcl-2 expression is probably regulating apoptosis in normal
      placentas and GTD, whereas Bax expression is not. The difference in AI and Bcl-2
      expression between non-molar placentas and HMs offers a potential adjunctive
      diagnostic tool to distinguish the two entities.

PMID- 10574601
TI  - Tissue quantification of hepatitis C virus RNA with morphologic correlation in
      the diagnosis of recurrent hepatitis C virus in human liver transplants.
AB  - BACKGROUND: Histologic findings and liver enzymes in liver transplants are often
      non-diagnostic of recurrent hepatitis C virus (HCV) disease. In addition, the
      relationship between HCV replication and the presence of recurrent HCV hepatitis
      after liver transplantation remains unclear. We studied liver transplant
      recipients to determine if quantitation of HCV RNA in liver tissue by reverse
      transcriptase-polymerase chain reaction (RT-PCR) correlates with histopathologic
      disease and/or liver enzymes. METHODS: Twenty-six patients who received liver
      transplants for HCV infection were evaluated. Four sequential biopsies were
      analyzed for each patient. HCV RNA was extracted and quantified using the
      Amplicor HCV Monitor Test. Histologic examination and RNA quantitation were
      blinded. All available liver enzymes on the day of liver biopsy were analyzed.
      RESULTS: HCV RNA quantity in liver tissue was significantly increased at the time
      of clinically-suspected recurrence (P < .0001). HCV RNA levels were highest in
      biopsies with lobular hepatitis and nonspecific inflammation, followed by
      biopsies with cytomegalovirus infection, chronic hepatitis, and acute cellular
      rejection. HCV RNA quantity had a significant correlation with increasing portal
      inflammation (P = .0002), decreasing amount of interface hepatitis (P = .0333),
      and presence of acidophilic bodies (P = .0316). Increasing HCV RNA levels
      significantly correlated with decreasing number of episodes of treated rejection.
      HCV RNA quantity did not correlate with other histologic features or liver
      enzymes. CONCLUSIONS: HCV RNA levels are highest at the time of active
      hepatocellular destruction. Elevated HCV RNA indicates recurrence. HCV RNA
      quantitation may be a useful diagnostic test for determining recurrent disease
      and distinguishing it from other causes of inflammation, such as rejection.

PMID- 10574602
TI  - Cytotoxic phenotype of tumor infiltrating lymphocytes in medullary carcinoma of
      the breast.
AB  - Medullary carcinoma (MC) of the breast is considered to carry a more favorable
      prognosis than other subtypes of infiltrating ductal carcinoma This is a
      biological paradox because its clinical behavior contrasts with its anaplastic
      morphology. MC is characterized by a dense lymphocytic infiltrate. In this study,
      we determined the cytotoxic potential and activity of tumor infiltrating
      lymphocytes (TILs) in MC by CD3, CD8, TIA-1, and granzyme B immunostaining on
      paraffin-embedded sections. Fourteen cases of typical MC (TMC) and 15 cases of
      atypical MC (AMC) classified according to Ridolfi criteria, and 19 cases of
      poorly differentiated infiltrating ductal carcinoma (PDC) were studied. TILs were
      quantified separately into two groups: cells infiltrating tumor nests and cells
      within stroma The number of CD8+ and TIA-1+ cells infiltrating tumor cell nests
      were markedly increased in TMC and AMC, as opposed to the PDC subgroup (159.6+/
      132.8; 77.4+/-59.3; 9.4+/-10.5 and 171.2+/-152.4; 72.3+/-55.0; 10.8+/-12.7 per
      high power field, respectively). The number of tumor infiltrating granzyme B+
      cells was significantly greater in TMC and AMC, as compared with the PDC subgroup
      (82.1+/-64.9, 33.9+/-19.7, and 3.1+/-5.1, respectively). Although no significant
      difference was found between the number of stromal CD3+ and CD8+ lymphocytes
      among the three subgroups, stromal granzyme B+ cells were significantly elevated
      in TMC and AMC as compared with the PDC subgroup. Finally, the relative
      proportion of granzyme B+ as opposed to CD3+ intraepithelial and stromal
      lymphocytes was greater in TMC and AMC as compared with the PDC subgroup (0.52+/
      0.29; 0.47+/-0.31; 0.19+/-0.18 and 0.18+/-0.11; 0.13+/-0.11; 0.06+/-0.05,
      respectively). The presence of increased numbers of activated cytotoxic
      lymphocytes in MC of the breast may be a key mechanism active in the host versus
      tumor response leading to improved prognosis.

PMID- 10574603
TI  - Accumulated basement membrane material in hyalinizing trabecular tumors of the
      thyroid.
AB  - We report here four additional cases of hyalinizing trabecular adenoma of the
      thyroid and describe the findings of the accumulated basement membrane (BM)
      material. Focal lumpy depositions of BM material were noted in the stroma of all
      four tumors and were particularly prominent in two. Antibodies against type IV
      collagen and laminin strongly immunoreacted with this material, which also showed
      diastase-resistant periodic acid-Schiff positivity. The ultrastructural findings
      of accumulated basement membrane was examined in detail. The most striking
      ultrastructural findings were seen at the periphery of the cell clusters, where
      the basal aspect of the tumor cells rested on a highly accumulated BM materials
      displaying mesh-like, fir-branching, or frame-like appearances. Intracytoplasmic
      BM islands were frequently observed in neoplastic cells. These BM islands were
      membrane-bounded and focally continuous with the cell surface membrane,
      suggesting pseudointracytoplasmic depositions of BM material due to marked
      cytoplasmic infoldings. From the findings, electron microscopic features of
      accumulated BM material are very characteristic in hyalinizing trabecular
      adenomas and can be discernible from other histologic types of BM-producing
      tumors.

PMID- 10574605
TI  - "Histiocytic markers" in melanoma.
AB  - BACKGROUND: Tumor cells of malignant melanoma, the "great imitator," may
      morphologically mimic almost any cell, including histiocytes. Immunohistochemical
      stains for histiocytes are often used to distinguish histiocytic lesions that
      resemble melanomas, but we have noted and others have reported that these markers
      may be immunoreactive in melanomas. METHODS: We evaluated 43 primary and
      metastatic melanomas with traditional markers for melanomas (S100, HMB45, and NKI
      C3) and common markers used for histiocytes (alpha-1-antitrypsin or AAT,
      CD68/KP1, HAM56, Mac387, and Muramidase). The extent (<5%, 5 to 30%, 30 to 60%,
      60 to 90%, >90%) and intensity (1+ to 4+) of staining were recorded semi
      quantitatively. RESULTS: Melanoma immunoreactivity (>5% of tumor cells) was as
      follows: S100, 100%; HMB45, 91%; NKI, 91%; AAT, 95%; CD68, 86%; HAM56, 26%;
      Mac387, 7%; and Muramidase, 30%. Among the histiocytic markers, staining by AAT
      and CD68 was typically diffuse but weak. Staining by HAM56, Mac387, and
      Muramidase was usually focal. In contrast, the traditional melanoma markers
      showed diffuse and strong staining. Interpretation of the histiocytic markers was
      complicated by scattered atypical histiocytes and pigmented tumor cells.
      CONCLUSION: Melanomas are commonly immunoreactive for histiocytic markers. AAT
      and CD68 immunostains are diffusely positive almost as frequently as traditional
      melanoma markers, although with weaker intensity. HAM56, Mac387, and Muramidase
      are less commonly positive and exhibit focal staining. Therefore, depending on
      the context, histiocytic markers may not be helpful in differentiating
      histiocytes and histiocytic tumors from melanomas.

PMID- 10574604
TI  - p16INK4A is regularly expressed in Hodgkin's disease: comparison with
      retinoblastoma, p53 and MDM2 protein status, and the presence of Epstein-Barr
      virus.
AB  - In order to understand better the possible role of cell-cycle regulating
      molecules in the pathogenesis of Hodgkin's disease (HD), the immunohistochemical
      distribution pattern of p16INK4A was investigated and compared with pRb, p53, and
      MDM2 protein status in 44 HD cases. Our findings were correlated to the presence
      of Epstein-Barr virus as detected by RNA in situ hybridization and
      clinicopathological parameters. p16INK4A protein immunoreactivity was found in
      all 44 cases with a proportion of Hodgkin-Reed-Sternberg (HRS) cells ranging from
      30 to 90%. In 93% of the cases studied, pRb was detected in HRS, whereas all
      cases showed overexpression of p53. Almost all specimens (98%) were MDM2-positive
      as evaluated by 1B10 and/or IF2 monoclonal antibodies. EBER 1/2-transcripts were
      detected in 31.8% (14 of 44) of the examined samples. A significant correlation
      was observed between immunoreactivity of p16INK4A and MDM2 and the number of HRS
      cells (P = .0012 and P = .018, respectively). In a subgroup of cases, with
      p16INK4A expression in more than 50% of HRS cells, the percentage of pRb-positive
      neoplastic cells was inversely related to that of p16-positive ones (P = .007).
      No clinicopathological parameters or clinical prognostic indicators, including
      duration of response to therapy, were statistically related to the expression
      levels of any of the four proteins investigated or the presence of Epstein-Barr
      virus. Our findings suggest that p16 and pRb are regularly expressed and that
      their pathway in cell-cycle machinery seems to be intact in HD. However, further
      investigation is needed to shed light on the involvement of cell-cycle molecules
      in Hodgkin's lymphomagenesis and longer patient follow-up is required for
      conclusive prognostic correlation.

PMID- 10574606
TI  - Influence of polyethylene terephthalate on the release of growth factors by human
      endothelial cells.
AB  - The influence of polyethylene terephthalate (PET) on the release of platelet
      derived growth factor AB (PDGF-AB) and basic fibroblast growth factor (bFGF) by
      in vitro cultured human endothelial cells was assessed by enzyme immunoassay. No
      significant differences were observed in the production of PDGF-AB with respect
      to the negative control cultures. A significant increase was observed in the
      production of bFGF after 48 and 72 h with respect to the negative control
      cultures. It can be concluded that PET may induce an increase in the production
      of basic FGF in endothelial cells.

PMID- 10574607
TI  - Preparations and properties of a novel grafted segmented polyurethane-bearing
      glucose groups.
AB  - Novel grafted polyurethane-bearing glucose groups were synthesized through a
      graft copolymerization of a prefabricated polyurethane containing poly(butadiene)
      glycol (PBD) and hydrogenated poly(butadiene) glycol (HPBD) soft segments, and
      4,4'-methylenediphenyl diisocyanate (MDI) hard segment with a hydrophilic monomer
      glycosylethyl methacrylate (GEMA) in solution in the presence of 2,2'
      azobis(isobutyronitrile) (AIBN) as an initiator. The bulk characteristics of the
      grafted polyurethanes were investigated by infra-red (IR) spectroscopy and gel
      permeation chromatography (GPC) measurements. The glucose groups were oriented on
      the surface of the cast film of grafted polyurethane with different graft-on
      percentages as revealed by electron spectroscopy for chemical analysis (ESCA),
      attenuated total reflectance infra-red spectroscopy (ATR-FTIR), and water contact
      angle. The grafted polyurethane surfaces which showed decreased water contact
      angles also indicate that hydrophilic glucose groups are present at the surface.
      The hemocompatibilities of these polymer surfaces were evaluated by platelet-rich
      plasma (PRP) contacting tests. It was found that the surface of grafted
      polyurethane with a graft-on percentage of 23.4% showed a good hemocompatibility
      in terms of platelet adhesion and shape variation. It indicates that glucose
      groups on the surface are effective for the improvement of hydrophilicity as well
      as hemocompatibility.

PMID- 10574608
TI  - Mn-porphyrin derivatives as an antioxidant for medical devices.
AB  - It is well known that reactive oxygen species such as O*2- and H2O2 induce the
      biodegradation or cracking of medical devices in vivo or that they are released
      from inflammatory cells activated by devices to oxidize low-density lipoprotein.
      Therefore, the development of a novel antioxidant is required to eliminate the
      reactive oxygen species. In this paper, we report that Mn-porphyrin derivatives
      containing a macromolecular Mn-porphyrin are relatively stable compounds that can
      eliminate O*2- and/or H2O2. The dismutation of O*2- in the porphyrins was
      determined using a cytochrome c-assay by the xanthine/xanthine oxidase system and
      using the stopped-flow kinetic analysis technique. The possibility of porphyrins
      as scavengers of H2O2 was evaluated by in situ measurement with a Clark
      electrode. As a result, it has been found that Mn-porphyrin derivatives may be a
      vastly better scavenger of reactive oxygen species in vivo.

PMID- 10574609
TI  - Phosphorylcholine-containing polyurethanes for the control of protein adsorption
      and cell attachment via photoimmobilized laminin oligopeptides.
AB  - In this study, we synthesized a biomaterial whose surface inhibits non-specific
      protein and cell attachment. The polymer was designed to mimic the external cell
      plasma membrane properties through the introduction of particular chemical
      constituents of the cell membrane: phospholipid polar headgroups. This was done
      by copolymerizing phosphorylcholine (PC) groups into a polyurethane polymer
      backbone (PCPUR). Peptides known to induce specific cell attachment were
      subsequently bound to the surface of this copolymer in a photoadressible manner
      to obtain surfaces that allowed the attachment of cells in a specific pattern.
      Two polymers with different phosphorylcholine concentrations were synthesized and
      their bulk and surface properties were characterized through differential
      scanning calorimetry, wettability measurements, angle-resolved X-ray
      photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry.
      Protein and lipid adsorption investigation using optical waveguide light mode
      spectroscopy showed that the irreversible adsorption of both proteins and lipids
      is drastically reduced as a result of simultaneous contributions of the PC
      groups, molecular mobility and strong hydrophilicity of the polymers.
      Consequently, this leads to a marked reduction in the cellular attachment
      response, which further decreases with increasing PC concentration. Finally, when
      the polymer surface was photo-derivatized, attachment of the neural NG108-15 cell
      line occurred only on the areas of the PCPUR where the laminin CDPGYIGSR peptide
      sequence was photoimmobilized. Cell attachment was nevertheless found to be non
      specific with respect to the peptide sequence used and reasons for such results
      are therefore discussed.

PMID- 10574610
TI  - Vascularization into a porous sponge by sustained release of basic fibroblast
      growth factor.
AB  - Vascularization into a poly(vinyl alcohol) (PVA) sponge was investigated using
      basic fibroblast growth factor (bFGF). This growth factor was impregnated into
      biodegradable gelatin microspheres for its sustained release and then the bFGF
      containing microspheres or free bFGF were incorporated into PVA sponges.
      Following subcutaneous implantation into the back of mice, the bFGF-containing
      gelatin microspheres induced vascularization in and around the sponge to a
      significantly greater extent than that of free bFGF from 3 days after
      implantation. Significant ingrowth of fibrous tissue into the sponge was also
      observed when bFGF-containing microspheres were added to the sponge in contrast
      to free bFGF. Tissue ingrowth occurred into the deeper portion of the sponge over
      time while it accompanied formation of new capillaries. Empty gelatin
      microspheres had no effect on vascularization and the level of fibrous tissue
      ingrowth into the sponge was similar to that of the control group. It was
      concluded that incorporation of gelatin microspheres containing bFGF into the PVA
      sponge was effective in prevascularization of the sponge pores.

PMID- 10574611
TI  - New biodegradable hydrogels based on an acryloylated polyaspartamide cross-linked
      by gamma irradiation.
AB  - Alpha, beta-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA), a synthetic
      biocompatible macromolecule, was functionalized with glycidyl methacrylate (GMA)
      in order to introduce in its side chains residues having double bonds and ester
      groups. The copolymer (PHG), obtained from PHEA and GMA, had a degree of
      derivatization of 29 mol%. PHG aqueous solutions are cross-linked by gamma
      radiation at 0 degrees C either in the presence or absence of N,N'
      methylenebisacrylamide (BIS) giving rise to new hydrogel systems. In both cases
      gelation occurs at quite low doses (0.26 and 0.4 kGy, respectively). The obtained
      networks were characterized by FT-IR spectrophotometry which confirmed that the
      cross-linking process involves the vinyl groups of the polymer chains. Swelling
      measurements evidenced the high affinity of aqueous media at different pH-values
      towards PHG hydrogels. The sol fractions of the irradiated samples, properly
      purified, were characterized by FT-IR and 1H-NMR analyses and reduced viscosity
      measurements. Finally, in vitro chemical or enzymatic hydrolysis studies
      suggested that the prepared samples undergo a partial degradation at pH 1 and 10
      or after incubation with enzymes such as esterase, pepsin, and alpha
      chymotrypsin.

PMID- 10574612
TI  - Production of growth factors by in vitro cultured human endothelial cells after
      contact with carbon coated polyethylene terephthalate.
AB  - The release of basic fibroblast growth factor (bFGF) and platelet derived growth
      factor AB (PDGF-AB) by in vitro cultured human umbilical endothelial cells in
      contact with carbon and collagen coated polyethylene terephthalate (PET + PC) was
      assessed by enzyme immunoassay. The same cells cultured on polystyrene without
      biomaterials were tested as negative control. PET + PC induced a significant
      increase in the release of bFGF after 72 h and a significative reduction in the
      release of PDGF-AB after 48 and 72 h, compared to the negative control.

PMID- 10574613
TI  - Solute transport analysis in pH-responsive, complexing hydrogels of
      poly(methacrylic acid-g-ethylene glycol).
AB  - We report on the preparation and properties of hydrogels of poly(methacrylic acid
      g-ethylene glycol) that exhibit pH-responsive swelling behavior due to the
      reversible formation/dissociation of interpolymer complexes. Because of their
      nature, these materials may be useful in drug delivery applications. In this
      work, we studied the diffusional behavior of three solutes of varying molecular
      size in the complexing hydrogels as a function of solution pH. The ability of
      these gels to control the solute diffusion rates was strongly dependent on the
      molecular size of the solute and the environmental pH. The diffusion coefficients
      for solutes were calculated as a function of pH and were lower in acidic than
      neutral or basic media due to the formation of interpolymer complexes in the
      gels. However, the ratio of the solute radius to the network mesh size also was a
      significant factor in the overall behavior of these gels. The diffusion
      coefficient of the smallest solute, proxyphylline, studied only changed by a
      factor of five between the complexed and uncomplexed state. However, for the
      largest solute, FITC-dextran, which has a molecular radius ten times greater than
      proxyphylline, the diffusion coefficients of the drugs in complexed and
      uncomplexed gels varied by almost two orders of magnitude. These results are
      explained in terms of mesh size characteristics of the gels.

PMID- 10574614
TI  - Identification of functional domains of the interferon-induced enzyme PKR in
      cells lacking endogenous PKR.
AB  - The interferon (IFN)-induced, double-stranded RNA (dsRNA)-activated human protein
      kinase (PKR) has been shown to exert antiviral and antiproliferative effects.
      Activation of the enzyme in mammalian cells results in protein synthesis
      inhibition and cell death by apoptosis. Previous studies on the structure
      function relationship of PKR have been based on vectors expressing the enzyme in
      mammalian cells containing endogenous PKR. As exogenously expressed PKR can form
      heterodimers with endogenous PKR, the results obtained on the functional
      characterization of mutant forms of PKR have been taken with caution. To address
      the natural consequences of heterodimer formation between endogenous and
      exogenous PKR, we have analyzed the structure-function relationship of PKR
      ectopically expressed from vaccinia virus (VV) recombinants in cells lacking the
      endogenous enzyme. We demonstrate that PKR-mediated inhibition of protein
      synthesis and induction of apoptosis is not dependent on the presence of
      endogenous PKR. Further, PKR activity is independent of the presence of dsRNA
      binding motifs (dsRBM). Moreover, single-point mutations of the third basic
      domain decreased PKR activation. Our findings demonstrate that PKR can be
      activated in the absence of its N-terminal domain (amino acids 1-232) and that
      the third basic domain is important for its biologic function.

PMID- 10574615
TI  - Addiction of anti-CD28 antibodies restores PBMC proliferation and IFN-gamma
      production in lepromatous leprosy patients.
AB  - During antigen recognition, T lymphocytes are primed by a physical interaction
      with antigen-presenting cells (APC). At least two signals are needed to activate
      T cells. One is provided by T cell receptor (TCR)/CD3 in the context of the mayor
      histocompatibility complex (MHC), and another signal is mediated by antigen
      independent molecules, that is T cell membrane-bound CD28 and its specific ligand
      B7-1 (CD80) present in APC. Both signals trigger a series of metabolic events
      initiating right at the cell membrane and ending with activation and
      proliferation of T cells as well as specific cytokines synthesis. Our main goal
      was to determine whether deficiency in interferon-gamma (IFN-gamma) production
      shown by peripheral blood mononuclear cells (PBMC) from lepromatous leprosy (LL)
      patients, could be overcome by reconstituting in vitro the appropriate signals
      (by means of addition of anti-CD28 and anti-CD80 monoclonal antibodies). We also
      determined the stimulation index (SI) in the same PBMC. Our results demonstrated
      no significant differences in CD80 expression monocytes and B lymphocytes from LL
      patients when compared with healthy subjects. Nonetheless, CD28 expression
      significantly decreased in lymphocytes from LL patients (p < 0.01). Regarding IFN
      gamma levels and SI, LL-PBMC failure before mitogenic stimuli could be reversed
      by further incubation with anti-CD28 antibody, but stimulation by specific
      antigen of Mycobacterium leprae was not changed. Addition of anti-CD80 antibody
      significantly increased IFN-gamma levels in phytohemagglutinin (PHA)-stimulated
      PBMC, although proliferation deficiency persisted. Cells stimulated with specific
      antigen did not modify either their proliferation or IFN-gamma levels.

PMID- 10574616
TI  - Subcellular localization of interferon-inducible Myc/stat-interacting protein Nmi
      is regulated by a novel IFP 35 homologous domain.
AB  - Nmi was initially identified through a yeast two-hybrid interaction with N-Myc
      but it also interacts with c-Myc, Max, Fos, and several other transcription
      factors, including signal transducer and activator of transcription (Stat)
      proteins. Nmi is an interferon (IFN)-inducible protein with 25% amino acid
      identity to the IFN-inducible protein IFP 35. We have found that this homology
      consists of a novel domain of approximately 90-92 amino acids (aa) that is
      repeated in tandem in each protein. This region, termed Nmi/IFP 35 domain (NID),
      is important for subcellular localization of Nmi. Full-length Nmi protein or
      deletion constructs containing a single NID are localized to the cytoplasm, but
      amino-terminal Nmi fragments of up to 92 aa containing neither NID are nuclear.
      Fusion of the amino-terminal end of Nmi to pyruvate kinase, an exclusively
      cytoplasmic protein, results in a cytoplasmic fusion protein, suggesting that the
      amino-terminal end of Nmi does not contain a classic nuclear localization signal
      (NLS). Fusion of the amino-terminal end of Nmi to green fluorescent protein
      (GFP), which is normally found in both nuclear and cytoplasmic compartments, does
      not alter GFP distribution, whereas fusion of a single NID to GFP targets the
      fusion to the cytoplasm. Fusion of a nuclear localization signal (NLS) to full
      length Nmi or NID repeats targets the hybrid to the nucleus, suggesting that a
      strong NLS is dominant to the cytoplasmic localization function of NID. NID may
      mediate cytoplasmic localization of the full-length Nmi protein through NID-NID
      protein interactions as demonstrated by yeast two-hybrid assay,
      immunoprecipitation, and the presence of Nmi in a high molecular weight protein
      complex. These results suggest that Nmi is composed of a modular structure with
      an amino-terminal domain that when separated from the rest of the protein is
      nuclear. The carboxy-terminal two thirds of the protein is composed of two NID
      that mediate cytoplasmic localization of the full-length protein.

PMID- 10574617
TI  - A pilot study of recombinant human interleukin-4 therapy of myelofibrosis.
AB  - Twelve patients with myelofibrosis were treated with recombinant human
      interleukin-4 (IL-4) administered subcutaneously thrice weekly. Dosage ranged
      from 1 microg/kg to 4 microg/kg. Median patient age was 65 years (range 36-74).
      Five patients had transient minor responses, and 5 patients had progressive
      disease. One patient had a transient minor response, rapidly followed by
      progressive disease. One patient suffered angioneurotic edema with first
      injection. Other significant toxicities included fever, flu-like symptoms,
      peripheral edema, and ascites. IL-4 at this schedule was toxic and had no
      significant activity in myelofibrosis.

PMID- 10574618
TI  - Pharmacodynamic comparison of single doses of IFN-beta1a and IFN-beta1b in
      healthy volunteers.
AB  - In a study in 75 volunteers, preparations of interferon-beta1b (IFN-beta1b) and
      IFN-beta1a were compared in terms of the resulting serum concentrations of three
      biologic markers, neopterin, human Mx protein, and 2',5' oligoadenylate
      synthetase. Each preparation was tested at five dose levels, the middle dose
      being that recommended for use in patients with multiple sclerosis on the basis
      of large clinical trials. Five randomly chosen volunteers each received a single
      subcutaneous dose of one of the IFN or of IFN-beta1a given intramuscularly. The
      amounts of each marker induced were dose related. There were no major differences
      between the results with the two IFN or in the duration of the changes in the
      markers after the two routes of injection. The data indicated that 8 million
      international units (MIU) of IFN-beta1b and 6 MIU of IFN-beta1a had very similar
      effects. Even after the highest single dose tested, the increase in the biologic
      markers were not sustained for a full week.

PMID- 10574619
TI  - A pilot study of daily subcutaneous interleukin-10 in patients with chronic
      hepatitis C infection.
AB  - The Th1/Th2 cytokine balance is important in persistence of infection and liver
      injury in chronic hepatitis C. The aim of this study was to administer the anti
      inflammatory cytokine, recombinant human interleukin-10 (rHuIL-10), for 28 days
      in patients with chronic hepatitis C and to assess the safety and measure the
      effect on alanine aminotransferase (ALT, a marker of hepatic inflammation) levels
      and serum hepatitis C virus (HCV) RNA values. Three treatment-naive and 13
      interferon (IFN) nonresponder patients (total 16 patients) with compensated
      chronic HCV infection were enrolled in this study. Patients were randomized to
      receive rHuIL-10 at a dose of 4 or 8 microg/kg/day as a single daily subcutaneous
      injection for 28 days. ALT values and serum HCV RNA were measured at days 0, 1,
      3, 8, 15, 22, and 28 during therapy and at follow-up 2 and 4 weeks after
      cessation of the 4-week treatment period. ALT values normalized in 9 of 16
      patients during therapy and remained normal until the end of treatment in 8
      patients. The decreases in ALT values occurred in both the 4 microg and 8 microg
      dosage groups and were seen in both IFN naive and nonresponder patients. Mean ALT
      values fell significantly during the study period but usually returned to
      pretreatment levels by the end of the 4-week follow-up period (p < 0.05). HCV RNA
      concentrations did not vary significantly during or after therapy. (No patient
      had either an increase or a decrease in HCV RNA levels of > or =1.5 log during
      the study.) The drug was well tolerated, with no adverse symptoms noted. Platelet
      counts fell transiently to 73,000 and 63,000 in 2 patients. No other toxicity was
      observed, and no patients discontinued therapy. In chronic hepatitis C, short
      term therapy with IL-10 was well tolerated and caused transient normalization of
      ALT values in 50% of patients, which returned to pretreatment levels on cessation
      of treatment. There were no significant changes observed in serum HCV RNA
      concentrations during the study. These immunomodulatory effects are similar to
      those observed with ribavirin monotherapy in chronic hepatitis C. Further study
      of rHuIL-10 alone or in combination with antiviral agents in chronic hepatitis C
      is warranted.

PMID- 10574620
TI  - Dose-dependent effects of recombinant human interleukin-6 on the pituitary
      testicular axis.
AB  - Inflammatory cytokines are soluble mediators of immune function that also
      regulate intermediate metabolism and several endocrine axes. To examine the
      effects of interleukin-6 (IL-6), the main circulating cytokine, on the
      hypothalamic-pituitary-testicular axis in men, we performed dose-response studies
      of recombinant human IL-6 (rHuIL-6) in normal volunteers. Increasing single doses
      of IL-6 (0.1, 0.3, 1.0, 3.0, and 10.0 microg/kg body weight) were injected
      subcutaneously into 15 healthy male volunteers (3 at each dose) in the morning.
      We measured the circulating levels of testosterone, luteinizing hormone (LH),
      follicle-stimulating hormone (FSH), and sex hormone binding globulin (SHBG) at
      baseline and then at 24 h, 48 h, and 7 days after the IL-6 injection. LH and FSH
      levels were also measured half-hourly for the first 4 h after the IL-6 injection.
      All IL-6 doses were tolerated well and produced no significant adverse effects.
      Mean peak plasma IL-6 levels achieved after IL-6 administration were 8 +/- 1, 22
      +/- 5, 65 +/- 22, 290 +/- 38, and 4050 +/- 149 pg/ml, respectively for the five
      doses. We observed no significant changes in plasma testosterone levels after the
      two smaller IL-6 doses. The three higher IL-6 doses, however, caused significant
      decreases in testosterone levels by 24 h, which persisted at 48 h and returned to
      baseline by 7 days. The higher testosterone suppression was after the 3.0
      microg/kg dose, making the dose-response curve bell-shaped. There also appeared
      to be small but not significant increases in LH levels after the three higher IL
      6 doses, which were not acute and seemed to follow temporally the testosterone
      decreases. The concurrent plasma levels of FSH and SHBG were not appreciably
      affected by any IL-6 dose. In conclusion, subcutaneous IL-6 administration, which
      caused acute elevations in circulating IL-6 levels of a similar magnitude to
      those observed in severe inflammatory and noninflammatory stress, induced
      prolonged suppression in testosterone levels in healthy men without apparent
      changes in gonadotropin levels. This suggests that IL-6 might induce persistent
      testicular resistance to LH action or suppression of Leydig cell steroidogenesis
      or both, with potential adverse effects on male reproductive function.

PMID- 10574621
TI  - Selective proteolytic cleavage of IL-2 receptor and IL-6 receptor ligand binding
      chains by neutrophil-derived serine proteases at foci of inflammation.
AB  - Traumatic brain injuries induce a strong, locally restricted inflammatory
      response. Here we demonstrate that activated neutrophils infiltrate the site of
      tissue destruction and release large amounts of enzymatically active elastase,
      cathepsin G, and proteinase 3. High intracerebral protease concentrations were
      found to be accompanied by a reduced inhibitory potential at foci of
      inflammation. In 39 neurotrauma patients, a temporal correlation between the
      protease release from neutrophils and the solubilization of interleukin-2 (IL-2)
      receptor and IL-6 receptor ectodomains at sites of tissue destruction was
      observed, suggesting that neutrophil-derived proteases may play a crucial role in
      the cytokine receptor shedding at foci of inflammation. Under in vitro
      conditions, the cleavage of membrane-bound IL-2Ralpha was found to be
      predominantly catalyzed by elastase and, to a lesser extent, by proteinase 3.
      Cathepsin G was found to be incapable of solubilizing this receptor. In contrast,
      the cleavage of the IL-6R 80 kDa chain was catalyzed by cathepsin G but not by
      elastase or proteinase 3. The receptor fragments released by the action of these
      enzymes were found to retain their ligand-binding capacity. These results
      strongly suggest a pathophysiologic role of neutrophil-derived serine proteases,
      particularly in regulation of the expression of functional IL-2 and IL-6
      receptors at foci of inflammation.

PMID- 10574622
TI  - Molecular cloning of porcine interleukin-1beta converting enzyme and differential
      gene expression of IL-1beta converting enzyme, IL-1beta, and IL-18 in porcine
      alveolar macrophages.
AB  - We have cloned and sequenced a cDNA that contains the coding sequence of porcine
      interleukin-1beta (IL-1beta) converting enzyme (ICE). Using degenerate
      oligonucleotide primers based on the amino acid sequences of the human, murine,
      and rat ICE, we performed the reverse transcription polymerase chain reaction (RT
      PCR) with total RNA prepared from porcine alveolar macrophages stimulated with
      lipopolysaccharide (LPS) to clone the cDNA of porcine ICE. The open reading frame
      (ORF) of the porcine ICE cDNA is 1215 base pairs (bp) in length and encodes 404
      amino acids. The predicted amino acid sequence is 72.5%, 62.6%, and 64.1%
      homologous to the human, murine, and rat amino acid sequences, respectively. The
      kinetics of mRNA expression of ICE, IL-1beta, and IL-18 in porcine alveolar
      macrophages after LPS stimulation revealed that ICE transcripts were weakly
      expressed in nonstimulated condition and upregulated after LPS stimulation.
      Moreover, IL-1beta and IL-18 transcripts were differently expressed after LPS
      stimulation.

PMID- 10574623
TI  - Role of vacuolar H(+)-ATPase in interferon-induced inhibition of viral
      glycoprotein transport.
AB  - We have shown previously that interferon-beta (IFN-beta) induces the
      alkalinization of trans-Golgi network (TGN) and inhibits the transport of G
      protein of vesicular stomatitis virus (VSV) in L(B) cells and gD protein of
      herpes simplex virus (HSV-1) in LMtk- cells transfected with gD cDNA. The
      vacuolar H(+)-ATPase (V-ATPase) is responsible for maintaining pH in TGN, and V
      ATPase-mediated acidification is required for normal transport of proteins. To
      examine whether alkalinization caused by IFN is mediated through V-ATPase, the
      activity of V-ATPase was determined in IFN-treated cells by coupling ATP
      hydrolysis to NADH oxidation. Bafilomycin (Baf) was used as positive control, as
      it specifically inhibits V-ATPase. The activity of V-ATPase was reduced in IFN
      treated or Baf-treated cells compared with untreated cells. Doses of IFN-beta or
      Baf that neither alter pHi nor inhibit the transport of viral glycoproteins
      concomitantly inhibited the transport of G and gD proteins in TGN, as
      demonstrated by indirect immunofluorescence studies, and raised the pH of TGN as
      demonstrated by a decrease in the uptake of DAMP. Further, the effect of Baf on
      IFN-induced antiviral activity against VSV was examined to correlate the biologic
      significance of these findings. Data showed that Baf significantly enhances (5-50
      fold) the IFN-induced antiviral activity as demonstrated by viral titers from
      supernatants. These findings suggest that the inhibition of transport of G and gD
      proteins by IFN-beta, may be related to the inhibition of V-ATPase-mediated
      acidification of TGN.

PMID- 10574624
TI  - Type I consensus IFN (IFN-con1) gene transfer into KSHV/HHV-8-infected BCBL-1
      cells causes inhibition of viral lytic cycle activation via induction of
      apoptosis and abrogates tumorigenicity in sCID mice.
AB  - In this study, we investigated the effects of human type I consensus interferon
      (IFN-con1) (Amgen) gene transfer into body cavity-based lymphomas (BCBL)-1 cells,
      which are latently infected with Kaposi's sarcoma-associated herpesvirus (KSHV)
      human herpesvirus-8 (HHV-8). Both the basal and 12-O-tetradecanoyl phorbol-13
      acetate (TPA)-stimulated production of KSHV/HHV-8 mature virions was strongly
      inhibited in genetically modified IFN-producing BCBL-1 cells as compared with
      parental or control transduced counterparts. A similar inhibition was obtained on
      treatment of parental BCBL-1 cells with exogenous IFN-con1. The reduction in
      KSHV/HHV-8 production was associated with a decrease in the basal and TPA
      stimulated intracellular amount of the linear form of the viral genome.
      Interestingly, 25%40% of the IFN-producing BCBL-1 cell population underwent
      spontaneous apoptosis in vitro. TPA treatment, which did not significantly affect
      the viability of the parental and control BCBL-1 cells, resulted in the apoptotic
      death of up to 70% of the IFN-producing cell population. Addition of exogenous
      IFN-con1 to parental BCBL-1 cells produced similar effects, although less
      intense. Injection of either parental or control-transduced BCBL-1 cells into
      SCID mice resulted in progressively growing tumors characterized by an unusually
      high level of tumor angiogenesis. In contrast, complete tumor regression was
      observed in all the mice injected either subcutaneously (s.c.) or
      intraperitoneally (i.p.) with the IFN-producing BCBL-1 cells. These results
      represent the first evidence that type I IFN can counteract the activation of a
      productive herpesvirus infection in latently infected tumor cells by the
      induction of apoptosis, providing an interesting link between the antiviral and
      antitumor activities of this cytokine. These data suggest the possible advantages
      of strategies of type I IFN gene transfer (with respect to the use of the
      exogenous cytokine) for the treatment of patients with some HHV-8-induced
      malignancies.

PMID- 10574625
TI  - Immunoregulatory roles of interleukin-13 in cattle.
AB  - Interleukin-13 (IL-13) is produced predominantly by helper T lymphocytes of the
      Th2 phenotype and mediates its effects on several immune cells, including B
      lymphocytes and macrophages, stimulating their proliferation, differentiation,
      and effector functions. IL-13 activates human B cells but has no detectable
      activity on murine B lymphocytes, suggesting that the activity of IL-13 varies
      among species. Our studies show that IL-13 enhances proliferation and
      differentiation of bovine B cells and upregulates cell surface major
      histocompatibility complex (MHC) class II expression. We examined mRNA expression
      of the putative signaling component of the bovine IL-13Ralpha1 homolog in several
      peripheral blood populations. After stimulation with calcium ionophore and
      phorbol ester, IL-13Ralpha1 mRNA levels appeared to be downmodulated in T cells,
      upregulated in macrophages and B cells, and unchanged in neutrophils. Together,
      these studies begin to provide insight into the relative importance of IL-13 in
      immunoregulation in cattle.

PMID- 10574626
TI  - Human interleukin-1 receptor antagonist: large-scale expression in Bacillus
      brevis 47-5Q.
AB  - Interleukin-1 receptor antagonist (IL-1RA) has been used as a tool to study the
      biologic activity of IL-1 and as a possible therapeutic substance for
      inflammatory disease. To perform in vivo study, however, large quantities of IL
      1RA are required. Bacillus brevis strains secrete large amounts of protein but
      little protease into the medium. Using B. brevis 47-5Q, we developed a large
      scale expression system of human IL-1RA (HuIL-1RA). The bacteria secreted HuIL
      1RA into the culture medium at very high levels, approximately 200 mg/L. The
      protein was isolated in one-step purification with monoclonal antibody (mAb)
      against HuIL-1RA. The IL-1RA molecule was determined to be functionally active by
      the inhibiting assay of HuIL-1-induced cell proliferation in a mouse T cell line,
      D10N4M.

PMID- 10574627
TI  - Immunomodulatory activity of curcumin.
AB  - Curcumin, an active ingredient present in Curcuma longa, was analysed for the
      immunomodulatory activity in Balb/c mice. Curcumin administration was found to
      increase the total WRC count (15,290) significantly on the 12th day Group of
      animals treated with vehicle alone showed results similar to that of normal
      animal (10,130 on 12th day). Curcumin increased the circulating antibody titre
      (512) against SRBC. Curcumin administration increased the plaque forming cells
      (PFC) in the spleen and the maximum number of PFC was observed on the 6th day
      (1,130 PFC/10(6) spleen cells) after immunization with SRBC. Rone marrow
      cellularity (16.9x10(6) cells/femur) and alpha-esterase positive cells
      (1,622/4000 cells) were also enhanced by Curcumin administration. A significant
      increase in macrophage phagocytic activity was also observed in Curcumin treated
      animals (P<0.001). These results indicate the immunostimulatory activity of
      Curcumin.

PMID- 10574628
TI  - Ascites produced in rats without tubercle bacilli or tumor cells.
AB  - Intraperitoneal injection of rats with two doses of pertussis vaccine produces a
      small amount of ascitic fluid. Much larger amounts of fluid are produced when two
      spaced injections of the vaccine are preceded by a small amount of liquid
      petrolatum. A similar result is obtained by a single injection of pertussis
      vaccine emulsified in liquid petrolatum and Arlacel A. Ascites produced without
      tubercle bacilli or tumor cells may increase the use of rats for antibody
      production.

PMID- 10574629
TI  - Correlation of alternative pathway (AP) lytic activity and AP-dependent
      neutrophil phagocytosis with factor B levels and consumption in serum.
AB  - This work investigated the correlation between serum levels of factor B, AP-lytic
      activity, ratio of factor B activation by zymosan, and AP-dependent neutrophil
      phagocytosis in samples of normal human serum (NHS). In addition, since the
      antithyroid drug propylthiouracil (PTU) induces increased levels of AP lytic
      activity in rats, groups of these animals were treated with this drug in order to
      increase AP titers and to evaluate those parameters also in this condition. The
      results showed no correlation between factor B concentration and AP lytic
      activity in 18 samples of NHS or between factor B concentration and proportion of
      consumption by zymosan. Interestingly, this consumption was also not correlated
      with phagocytosis as measured by the chemiluminescence (CL) response of
      neutrophils to the opsonized particles. The two biological properties of
      phagocytosis and lytic activity, dependent of AP, were not correlated to each
      other in the NHS samples. In the samples of rat serum with increased AP lytic
      levels a different result was observed. A positive correlation between CL
      response and lytic activity occurred in serum of animals receiving a low PTU
      dose, but not in serum of animals receiving a high dose, where CL responses were
      lower than those of controls. The results are compared to literature data and
      discussed in terms of individual differences in resistance or susceptibility to
      infections and or diseases involving the complement system.

PMID- 10574630
TI  - Mapping of IgE binding regions in the major rat urinary protein, alpha 2u
      globulin, using overlapping peptides.
AB  - Exposure to laboratory animals poses a hazard for development of occupational
      allergy. Identification of antigenic determinants of allergenic proteins may be
      valuable for immunotherapeutic purposes. Overlapping peptides of the major
      allergen in rat urine, Rat n 1.02, corresponding to the protein alpha2u-globulin
      were synthesised on solid support and screened simultaneously to locate IgE
      binding linear epitopes using a simple modified ELISA procedure. Thirty-nine
      peptides were synthesised, each 8 amino acids long with 4 amino acids overlaps.
      Sera from fifteen rat-sensitized subjects were analyzed and as controls sera from
      7 non-rat-sensitized individuals were used. In general low binding and a great
      individual variation between sera from rat allergic individuals were seen. Some
      peptides were more frequently recognized by IgE antibodies in sera from rat
      allergics. These peptides were mainly clustered towards the N-terminal and C
      terminal parts of the protein. Taken together our data suggest the existence of
      linear IgE binding epitopes in the rat urine allergen, Rat n 1.02. However, the
      role of these sequences in the allergic reaction needs further investigation.

PMID- 10574631
TI  - Efficacy of intraduodenal, oral and parenteral boosting in inducing intestinal
      mucosal immunity to cholera toxin in rats.
AB  - Considerable effort has been directed toward developing effective mucosal
      vaccines, especially those targeted to the intestine, and appropriate delivery
      systems. Numerous studies have demonstrated that direct immunization of the
      intestinal mucosa is the most efficient route for generating an intestinal IgA
      response. The present study examined the effect of three different routes of
      secondary immunization (boosting), i.e. intraduodenal, oral and parenteral
      (subcutaneous) on the intensity of the intestinal mucosal immune response in rats
      subjected to primary intraduodenal immunization with cholera holotoxin. Specific
      antibody titers and the relative numbers of antibody-secreting cells in the
      peripheral blood and antibody-containing cells in the intestinal lamina propria
      concur that vaccination of the intestinal mucosa directly or in combination with
      an oral boost yields a more vigorous mucosal immune response in comparison to a
      parenteral boost.

PMID- 10574632
TI  - Enhanced IL-10 production in vitro by monocytes in autoimmune haemolytic anaemia.
AB  - Our previous studies on autoimmune haemolytic anaemia (AIHA) have shown a
      hyperactivation concerning cytokine production in T and B lymphocytes obtained
      from AIHA patients. In this study the production of interleukin (IL)-10, basal
      and stimulated by lipopolysaccharide (LPS), was determined in cultured monocytes
      obtained from patients affected by AIHA, either idiopathic or associated with
      other autoimmune diseases, e.g. idiopathic thrombocytopenic purpura (ITP),
      systemic lupus erythematosus (SLE), myastenia gravis (MG). In cultured AIHA
      monocytes the IL-10 basal production (mean+/-SD) was increased in all but one
      patient, compared to the controls, 125.96+/-76.10 pg/mL and 19.18+/-15.80 pg/mL
      respectively. Specifically, LPS stimulation was able to induce a higher IL-10
      production by monocytes in two AIHA cases, whereas in five patients there was no
      difference and in two cases the LPS stimulated IL-10 production was even
      decreased compared to the levels observed in the controls. Interestingly in the
      latter two cases AIHA was associated with other autoimmune diseases (ITP, SLE).
      These results indicate a constitutively higher basal IL-10 production in
      monocytes from AIHA patients. The increased level of IL-10 could play an
      important role in the modified pathways of the immune response in AIHA.

PMID- 10574633
TI  - Modulation of leukocyte phagocytic and oxidative burst responses by human seminal
      plasma.
AB  - The typical absence of immune responses to spermatozoa in the female reproductive
      tract at the time of insemination, despite the presence of a marked leukocytic
      infiltrate into the cervical mucus is intriguing. It may be that localised
      immunoregulatory mechanisms exist and this study used whole blood flow cytometry
      to determine the effects of human seminal plasma on neutrophil and monocyte
      function. Seminal plasma inhibited the proportion of neutrophils and monocytes
      phagocytosing E. coli, and the intensity of neutrophil phagocytosis, but enhanced
      the magnitude of the phagocytic response of those monocytes that escaped
      inhibition relative to PBS treated controls. Oxidative burst responses to E. coli
      were also inhibited and this effect was mediated by low molecular weight species,
      as dialysis totally abrogated the inhibitory activity. Seminal plasma had no
      effect on the neutrophil burst response to fMLP when compared to the controls,
      however there was a significant difference between the responses of undialysed
      and dialysed seminal plasma treated samples. Undialysed seminal plasma
      significantly inhibited the proportion of monocytes undergoing the burst response
      to fMLP and there were significant differences between the proportion of cells
      responding and their intensity in undialysed and dialysed seminal plasma treated
      samples. In summary, this study reports differential modification of neutrophil
      and monocyte function by human seminal plasma. The residual capacity of these
      cells to undergo phagocytosis and generate oxidative burst responses suggests
      that localised innate immune function remains intact and is possibly enhanced in
      the female reproductive tract at the time of insemination. Other mechanisms must
      protect inseminated sperm at this time.

PMID- 10574634
TI  - Opposing effects of sodium salicylate and haematopoietic cytokines IL-3, IL-5 and
      GM-CSF on mitogen-activated protein kinases and apoptosis of EoL-1 cells.
AB  - Haematopoietic cytokines such as IL-3, IL-5 and GM-CSF not only activate
      eosinophils but also prolong their life span by inhibiting their apoptotic cell
      death. We have studied the effects of IL-3, IL-5 and GM-CSF on apoptosis and
      mitogen-activated protein kinases (MAPKs) in a human eosinophilic leukaemic cell
      line (EoL-1). Results demonstrated that all three cytokines could trigger the
      receptor-mediated activation of extracellular signal-regulated kinase (ERK)
      within one hour but not p38 MAPK activity in EoL-1 cells. In contrast, sodium
      salicylate (NaSal), a nonsteroidal anti-inflammatory drug (NSAID), could activate
      p38 MAPK but not ERK within one hour. Both cytokines and specific p38 MAPK
      inhibitor SB 203580 could partly block the NaSal-induced apoptosis in EoL-1
      cells. A specific MAPK/ERK kinase (MEK) inhibitor, PD 098059, could induce
      apoptosis and eliminate the protective effect of IL-3, IL-5 and GM-CSF against
      NaSal-induced apoptosis in EoL-1 cells. Taken together, cytokines IL-3, IL-5 and
      GM-CSF could prolong EoL-1 cells survival through the transient activation of
      ERK. On the other hand, activation of p38 MAPK in EoL-1 cells by NaSal could lead
      to apoptosis. Activation of p38 MAPK and the resulting induction of apoptosis in
      EoL-1 cells may be important to explain the anti-inflammatory action of NSAID in
      allergic inflammation.

PMID- 10574635
TI  - Enhanced expression of constitutive endothelial nitric oxide synthase by
      astrocytes in the spinal cords of rats with experimental autoimmune
      encephalomyelitis.
AB  - To investigate the expression of eNOS in a disease affecting the CNS, we induced
      EAE and analyzed the expression of eNOS by Western blot analysis and
      immunohistochemistry. Western blot analysis indicated that eNOS increased
      substantially in the spinal cords of rats with EAE compared with the spinal cords
      of normal and adjuvant sensitized rats. Immunohistochemistry revealed that eNOS
      was positive for some macrophages and astrocytes in EAE lesions. The vascular
      endothelial cells in EAE lesions also showed a light increase of eNOS
      immunoreactivity. This trial demonstrated that eNOS is increased in the diseased
      EAE spinal cord and that the source of eNOS is from the exogenous inflammatory
      cells and from the endogenous spinal cord cells including astrocytes.

PMID- 10574636
TI  - Activation of coagulation in smoking and non-smoking women using a third
      generation oral contraceptive containing desogestrel.
AB  - The concurret use of smoking and oral contraceptives affects the hemostatic
      balance, thereby inducing a thrombophilic state. In order to clarify the effects
      of this association on the hemostatic system, the possible changes in the markers
      of activation of coagulation (thrombin-antithrombin III complexes and prothrombin
      fragment F1+2) were evaluated in 35 women given a third-generation oral
      contraceptive for 6 months; 13 of these women (37.1%) were mild or moderate
      smokers. No differences were found in basal levels of the coagulation and
      fibrinolytic parameters between smokers and non-smokers. During oral
      contraceptive administration, both F1+2 fragment and thrombin-antithrombin III
      complex concentrations significantly increased both in smokers and in non-smokers
      (p < 0.01). Fibrinogen plasma levels increased in both groups (p < 0.01).
      Antithrombin III activity was reduced in both groups during treatment, but the
      difference was significant only in smokers (p < 0.05). Although the sample size
      of smokers was too small to draw definitive conclusions, present results appeared
      to confirm previous data about the effect of the concurrent use of smoking and
      oral contraceptives on antithrombin III levels, but did not demonstrate any
      additional effect of moderate smoking on the activation of the clotting system
      induced by this oral contraceptive preparation.

PMID- 10574637
TI  - Analysis of pill knowledge amongst oral contraceptive users in Scotland according
      to client characteristics.
AB  - OBJECTIVES: The primary objective of this study was to investigate the
      relationship between various client characteristics and knowledge of oral
      contraceptives amongst pill users. METHOD: This was a subanalysis of the data
      from the national audit of Scottish family planning clinics. RESULTS: There were
      significant differences in knowledge about many different criteria according to
      the characteristics of the client group. Low educational attainment, unemployment
      and more rural residence produced greater significant differences in
      contraception knowledge than social deprivation according to postcode (zipcode).
      Age and duration of use affected different criteria to varying degrees, but
      teenagers scored relatively poorly compared to the general population and
      knowledge did not significantly improve overall with duration of use. CONCLUSION:
      Client characteristics do affect levels of pill knowledge. Clinicians must
      reflect on how to communicate more effectively with all types of pill users. They
      should take the opportunity of clinic visits for repeat pill prescriptions to
      improve knowledge levels.

PMID- 10574638
TI  - The patient's perspective of commercial clinical trials.
AB  - All drugs are tested on a large number of volunteers and patients prior to
      licensing by the Medical Controls Agency. Patients are often recruited while
      attending National Health Service (NHS) clinics. This paper reports a survey
      designed to ascertain patients' views of the desirability of such trials being
      undertaken in the NHS. Patients have a sophisticated understanding of who
      benefits from commercial clinical trials. Nonetheless, those taking part in
      trials did feel the process had some personal benefit. The patients
      overwhelmingly supported such clinical trials being undertaken in the NHS and
      felt that they were likely to raise the overall quality of care. The results can
      be used to influence the design of future patient information leaflets and the
      trial process.

PMID- 10574639
TI  - Increased resistance to activated protein C and factor V Leiden in recurrent
      abortions. Review of other hypercoagulability factors.
AB  - OBJECTIVE: To evaluate hereditary and acquired hemostatic abnormalities
      associated with recurrent spontaneous early (first-trimester) abortions. METHOD:
      A group of 56 Greek women with two or more unexplained primary spontaneous
      abortions, and a reference group of 148 women without a history of recurrent
      abortions, were screened for hypercoagulability. A randomly selected population
      of first-trimester pregnant women was also chosen for factor V Leiden genetic
      screening. RESULTS: A total of 21% of the women with recurrent abortions,
      compared with 12% of the reference group, showed increased activated protein C
      resistance. Fourteen per cent had positive lupus anticoagulant, compared with
      11.5% of the reference group. For the rest of the parameters, there was no
      difference between the two groups. Of 22 women studied for factor V Leiden, one
      was homozygous and one was heterozygous. Results were compared using Fisher's
      exact test and two-tailed Student's t tests. CONCLUSIONS: Increased activated
      protein C resistance appears to be an important factor in women with recurrent
      abortions. These data indicate the need for routine investigation of activated
      protein C resistance in women with recurrent abortions.

PMID- 10574640
TI  - A comparative study of the hemostatic effects of two monophasic oral
      contraceptives containing 30 mu(g) ethinylestradiol and either 2 mg chlormadinone
      acetate or 150 mu(g) desogestrel.
AB  - OBJECTIVES: To determine the effect of two low-dose monophasic oral
      contraceptives containing either 2 mg chlormadinone acetate or 150 microg
      desogestrel on blood clotting and fibrinolysis. METHODS: In vivo markers of
      intravascular coagulatory and fibrinolytic activity were measured in 45
      volunteers randomly assigned to a 6-month treatment with one of the two study
      preparations. RESULTS: During oral contraceptive use, the procoagulatory activity
      increased (increased prothrombin fragment 1+2), the anticoagulatory capacity
      changed (increased protein C activity, decreased activated protein C sensitivity,
      decreased protein S activity and decreased antithrombin III activity) and the
      fibrinolytic system was activated (increased concentrations of plasmin
      antiplasmin complexes and D-dimer as well as total fibrin degradation products).
      There were no relevant differences between the two medication groups. CONCLUSION:
      Our results demonstrate that both oral contraceptive preparations have comparable
      effects on the hemostatic system. There was a shift towards a new equilibrium of
      hemostatic activities, both coagulatory and fibrinolytic, at a higher turnover
      rate. Changes did not exceed the range of normal variation and were comparable to
      the published effects of other low-dose oral contraceptives. There was no
      evidence ofa differential risk of deep vein thrombosis between the two
      preparations.

PMID- 10574641
TI  - The efficacy and tolerability of Valette: a postmarketing surveillance study.
AB  - OBJECTIVES AND METHODS: A postmarketing survey was carried out to determine the
      efficacy and tolerability of Valette (dienogest 2.0 mg and ethinylestradiol 0.03
      mg) in routine gynecological practice. RESULTS: Valette had excellent
      contraceptive efficacy (unadjusted Pearl index 0.14), with 11 unplanned
      pregnancies from a total of 92 146 cycles of exposure, of which at least four
      were attributable to user failure. Cycle control was good, with spotting and
      breakthrough bleeding, which affected 5.0% and 3.4% of women, respectively,
      during the first cycle, becoming less frequent thereafter. Silent menstruation,
      i.e. the absence of withdrawal bleeding, affected on average 2.0% of women per
      cycle and 5.9% within the observation period. Valette was well tolerated. The
      most common adverse drug reactions were mastalgia (1.46% of all users), weight
      gain (1.11%), headache (0.98%), nausea/vomiting (0.96%), dysmenorrhea (0.35%),
      decreased libido (0.31%) and depressive moods (0.28%). The dropout rate due to
      adverse drug reactions was only 3.2%. Only six of the 16 267 women reported
      events which were considered to be serious adverse drug reactions; all recovered
      with appropriate treatment. CONCLUSIONS: These results confirm those from
      previous clinical trials, and demonstrate that Valette is highly effective, very
      well tolerated and produces excellent cycle control in routine practice.

PMID- 10574642
TI  - Health care of female commercial sex workers.
AB  - This article highlights health issues related to prostitution, with special
      reference to the situation in Europe. Strategies aimed at improving the health
      care of commercial sex workers, including programs for screening for sexually
      transmitted infections, are discussed. Problems related to failure to follow-up,
      particularly of mobile (migratory, international) commercial sex workers, are
      considered. Other topics covered include counselling on sexual risk reduction,
      including medical hotline telephone services and clinical outreach work.
      Counselling commercial sex workers on contraception, desired termination of
      pregnancy and hazards of illicit drug use are also highlighted. The public-health
      consequences of delivering poor health care to commercial sex workers are
      generally severely underestimated, particularly in societies where prostitution
      is illegal.

PMID- 10574643
TI  - FemCap studies.

PMID- 10574644
TI  - Temperature and hemodynamic changes associated with increased neural damage to
      global hemispheric hypoxic ischemia by prior prostaglandin E2, D2 and F2alpha
      administration.
AB  - Experiments compared the hemispheric neural damage resulting from global
      hemispheric hypoxic ischemia (GHHI, ligation of right common carotid artery plus
      35 min of 12% O2) in groups of anesthetized, male Long Evans rats, 9-10 weeks of
      age, kept at 37 degrees C, and previously given an intracerebroventricular
      (i.c.v., 2.5 microl) injection of 28 or 70 pmoles of PGE2, PGF2alpha or PGD2 or
      sterile saline (SS) 30 min beforehand. Mean arterial pressure (MAP), ipsilateral
      cortical capillary blood flow (CBF), colonic (Tc), ipsilateral (Tipsi) and
      contralateral (Tcontra), temporalis muscle temperatures were measured before,
      during and for 15 min after GHHI. Necrotic neural damage was assessed 7 days post
      GHHI. All groups given GHHI + PGs showed increased ipsilateral hemispheric damage
      to GHHI especially due to enhanced neocortical damage, compared to the saline
      control group given the same insult. PGD2 was the most potent PG to cause further
      damage to the global insult. Tc, Tipsi, Tcontra and MAP increased following the
      i.c.v. injection of PGE2. I.c.v. PGF2alpha transiently decreased MAP, PGD2 tended
      to decrease cerebral blood flow and neither evoked changes in temperature
      compared to respective pre-injection control values. Results demonstrate
      increased neural damage to GHHI with prior i.c.v. PGE2, PGF2alpha or PGD2
      administration.

PMID- 10574645
TI  - Selective retention of n-3 and n-6 fatty acids in human milk lipids in the face
      of increasing proportions of medium chain-length (C10-14) fatty acids.
AB  - This paper reports the results of our analysis of the impact high levels of de
      novo fatty acids have on the proportions of essential and non-essential fatty
      acids in human milk lipids. The data for seven fatty acids (linoleic, alpha
      linolenic, arachidonic (AA), docosahexaenoic (DHA), palmitic, stearic and oleic)
      were derived from several studies conducted in Nigeria. The proportion by weight
      of each of these fatty acids was plotted versus the proportion of C10-14 fatty
      acids. As the proportion of C10-14 fatty acids increased from 15 to 65%, there
      was not a proportional decrease in the percentages of all seven fatty acids, but,
      instead, preferential incorporation of the essential fatty acids, AA and DHA into
      the triacylglycerol component of the milk. At the same time, the proportions of
      stearic and oleic acid declined by 69% and 86%, respectively. However, the
      proportions of linoleic acid, palmitic acid, DHA, AA and alpha-linolenic acid, in
      milk lipids decreased by only 44%, 40%, 39%, 28% and 2.3%, respectively. These
      observations indicate that as the contribution of C10-14 fatty acids increases,
      essential fatty acids are preferentially incorporated into milk triacylglycerols
      at the expense of oleic acid and stearic acid.

PMID- 10574646
TI  - Regulation of fatty acid biosynthesis as a possible mechanism for the
      mitoinhibitory effect of fumonisin B1 in primary rat hepatocytes.
AB  - The mitoinhibitory effect of fumonisin B1 (FB1) on the mitogenic response of
      epidermal growth factor (EGF) was investigated in primary hepatocyte cultures
      with respect to the alterations in the omega6 fatty acid metabolic pathway. Fatty
      acid analyses of hepatocytes showed that EGF treatment resulted in a significant
      decrease in the relative levels of 20:4omega6 (arachidonic acid) and an increase
      in 18:2omega6 (linoleic acid). Supplementation of the hepatocyte cultures with
      20:4omega6 in the absence of EGF resulted in an increase in the total omega6 and
      omega6/omega3 fatty acid ratio. Addition of 20:5omega3 (eicosapentaenoic acid)
      resulted in an increase of the relative levels of the long chain omega3 fatty
      acids at the expense of the omega6 fatty acids. When 20:4omega6 and 20:5omega3
      was added in the presence of EGF, the mitogenic response of EGF was increased and
      decreased respectively. When compared to the fatty acid profiles in the absence
      of EGF, the decreased mitogenic response coincided with a decrease of total
      omega6 fatty acids and total polyunsaturated fatty acids (PUFA). In addition, the
      saturated and mono-unsaturated fatty acids increased and the
      polyunsaturated/saturated (P/S) fatty acid ratio decreased which implied a more
      rigid membrane structure. Addition of prostaglandin E2 (PGE2) and prostaglandin
      E1 (PGE1) stimulated and inhibited the mitogenic response respectively.
      Ibuprofen, a known cyclooxygenase inhibitor, and FB1 inhibited the EGF-induced
      mitogenic response in a dose-dependent manner. The mitoinhibitory effect of FB1
      on the EGF response was counteracted by the addition of PGE2. FB1 also disrupts
      the omega6 fatty acid metabolic pathway in primary hepatocytes, resulting in the
      accumulation of C18:2omega6 in phospatidylcholine and triacylglicerol. The
      disruption of the omega6 fatty acid metabolic pathway and/or prostaglandin
      synthesis is likely to be an important event in the mitoinhibitory effect of FB1
      on growth factor responses.

PMID- 10574647
TI  - Development of low-birthweight infants at 19 months of age correlates with early
      intake and status of long-chain polyunsaturated fatty acids.
AB  - We investigated the influence of early nutrition with and without long-chain
      polyunsaturated fatty acids (LCP) on later development of < or = 2500 g newborns
      receiving preterm formula without LCP (n=75), preterm formula with 18:3omega6 and
      LCPomega3 (at two doses; n=26) or their mother's own milk (n=27). All diets were
      given from birth to day 42. Erythrocytes (RBC) fatty-acid compositions were
      determined on day 42. Bayley's mental development (MDI) and psychomotor
      development (PDI) indices were assessed at 19 months. Multivariate regression
      analysis revealed that PDI was most strongly related to RBC 22:6omega3 in the
      cohort of 101 infants who received formula. The most consistent correlations were
      between development and early LCPomega3 intake, and between development and
      parameters of RBC LCPomega3 status day 42, in infants who received formula with
      18:3omega6 and LCPomega3. Development of formula-fed low-birthweight infants
      seems positively influenced by early dietary LCPomega3.

PMID- 10574648
TI  - Omega-3 polyunsaturated fatty acids and ventricular fibrillation: the possible
      involvement of eicosanoids.
AB  - Increased dietary omega-3 polyunsaturated fatty acids (PUFAs) reduce the
      incidence and severity of ventricular fibrillation (VF) in laboratory animals
      subjected to partial ischaemia and reduce the risk of cardiac arrest in humans
      after myocardial infarction. In whole animals there is considerable evidence
      which suggests that incorporation of these fatty acids into cardiac membrane
      phospholipids influences the production of a variety of eicosanoids having
      opposing arrhythmogenic or anti-arrhythmogenic properties, and that the balance
      of these actions is shifted in favour of an anti-arrhythmogenic state by feeding
      fish oil dietary supplements rich in omega-3 PUFA. However, differences in
      eicosanoid biosynthesis between species, between tissues of the same species and
      even between different intracellular sites within cells of the same tissue could
      influence experimental outcomes. The importance of further studies with the most
      appropriate whole animal models or tissues is emphasized, as is the difference
      between the structural integrity of cardiac muscle and cardiomyocytes in vitro.

PMID- 10574649
TI  - The anhydrous milk fat, ghee, lowers serum prostaglandins and secretion of
      leukotrienes by rat peritoneal macrophages.
AB  - Ghee, the anhydrous milk fat, is one of the most important sources of dietary fat
      in India. Male Wistar rats were fed diets containing 2.5, 5.0 and 10 wt% ghee for
      a period of 8 weeks. The diets were made isocaloric with groundnut oil. The
      results showed that serum thromboxane levels decreased by 27-35%, and 6-keto
      prostaglandin F1alpha by 23-37% when ghee was incorporated at level of 10% in the
      diet. Prostaglandin E2 levels in serum and secretion of leukotrienes B4, C4 and
      D4 by peritoneal macrophages activated with calcium ionophore decreased when
      increased amounts of ghee from 2.5 to 10% were included in the diet. Arachidonic
      acid levels in macrophage phospholipids decreased when incremental amounts of
      ghee were fed to rats. These studies indicate that ghee in the diet not only
      lowers the prostaglandin levels in serum but also decreases the secretion of
      leukotrienes by macrophages.

PMID- 10574650
TI  - Lipid peroxides, nitric oxide and essential fatty acids in patients with
      Plasmodium falciparum malaria.
AB  - Long chain polyunsaturated fatty acids derived from essential fatty acids have
      been shown to be toxic to Plasmodium falciparum both in vitro and in vivo. Here,
      we present evidence to suggest that in patients with Plasmodium falciparum
      malaria the levels of lipid peroxides (a marker of free radical generation)
      nitric oxide (a potent free radical with immunomodulatory actions), and
      concentrations of linoleic acid (LA) and alpha-linolenic acid (ALA) are low,
      whereas those of eicosapentaenoic acid (EPA) are high. The ability of the fatty
      acids to kill P. falciparum is dependent on their capacity to stimulate free
      radical generation in neutrophils and macrophages. EPA is more potent than LA in
      killing the parasite. In view of this, the results of the present study suggest
      that in patients with P. falciparum malaria the decreased levels of lipid
      peroxides and nitric oxide may contribute to the persistence of the infection,
      whereas elevated levels of EPA may be a feeble attempt to overcome this defect.

PMID- 10574651
TI  - N-3, n-6 and n-9 dietary fatty acids modulate the growth parameters of murine
      salivary gland tumors induced by dimethylbenzanthracene.
AB  - Variations in dietary fatty acid composition influence the biological behaviour
      of certain tumours. Diets enriched with oleic acid (18:1 n-9) seem to promote
      tumour progression on several lines due perhaps to the development of essential
      fatty acid deficiency (EFAD), whereas n-3 fatty acids have a protective effect.
      Since the role played by lipids on salivary gland tumorigenesis has not yet been
      studied, an experimental model is presented. BALB/c mice were fed on four
      different diets: control, corn oil, fish oil and olein groups. Salivary gland
      adenocarcinomas were chemically induced by using 9,10-dimethyl-1,2
      benzanthracene. Animals were sacrificed at the 20th post-injection week and
      several tumour parameters were analysed. Linoleic acid showed no promoting
      activity. Tumour size was larger in the olein group than in fish oil fed mice,
      indicating that the oleic acid, linked to the induced EFAD condition, has a
      protumorigenic activity whereas n-3 polyunsaturated fatty acids appear to exert a
      protective effect.

PMID- 10574652
TI  - Lipidemic effects of an interesterified mixture of butter, medium-chain
      triacylglycerol and safflower oils.
AB  - The objective of this study was to determine if the positional structure of
      dietary triacylglycerol affected lipidemic responses. Thirty healthy adults (16
      men and 14 postmenopausal women) with low-density lipoprotein cholesterol (LDL-C)
      concentrations >3.37 mM (130 mg/dL) enrolled in a prospective, single-blind,
      cross-over outpatient clinical trial that consisted of two 5-wk dietary phases.
      After baseline screening, subjects were instructed to follow individualized meal
      plans (weight maintenance diets with 36% of total energy from fat, half of which
      was from a test oil) and randomized to receive either butter (B) or an
      interesterified mixture (IM) of butter, medium-chain triacylglycerol (MCT), and
      safflower oils. Blood drawn during weeks 5 and 10 of feeding was analyzed for
      total cholesterol (TC), high density lipoprotein cholesterol (HDL-C),LDL-C, and
      triacylglycerols (TAG). Mean plasma levels of TC (B, 6.98+/-1.06 mM; IM, 7.09+/
      1.20 mM), HDL-C (B,1.30+/-0.35 mM; IM, 1.29+/-0.34 mM), and LDL-C (B, 4.91+/-0.95
      mM; IM, 4.92+/-1.10 mM) were not significantly different between the two dietary
      treatments. Mean TAG levels were higher for the interesterified B-MCT mixture (B,
      1.75+/-0.72 mM; IM, 1.96+/-0.86 mM, P < 0.05). We conclude that an IM of B, MCT,
      and safflower oils as compared to native B has no appreciable effect on plasma
      cholesterol concentrations but is associated with a modest rise in plasma TAG.

PMID- 10574653
TI  - Mechanisms mediating lipoprotein responses to diets with medium-chain
      triglyceride and lauric acid.
AB  - Medium-chain triglycerides (MCT) are often used in specialized formula diets or
      designer fats because of their special properties. Yet their influence on lipid
      metabolism is not completely understood. In this two-period cross-over study, the
      effects of MCT (8:0 + 10:0) in contrast to a similar saturated fatty acid (12:0)
      were compared. Eighteen healthy women ate a baseline diet [polyunsaturated
      (PUFA)/saturated fat = 0.9] for 1 wk. Then, they consumed test diets
      (PUFA/saturated fat = 0.2) for 4 wk. Monounsaturated fat and cholesterol were
      constant in baseline and treatment diets. MCT and 12:0, substituted for part of
      the PUFA, provided 14 energy (en)% of the test diets. In comparison to the PUFA
      baseline diet, a 16% increase in mean serum low density lipoprotein (LDL)
      cholesterol (C) on the 12:0 diet was accompanied by a 21% decrease in mean
      receptor-mediated degradation of LDL by freshly isolated mononuclear cells (MNC)
      in vitro. The MNC assay theoretically gives an indication of receptor-mediated
      degradation of LDL. In contrast, the MCT diet raised mean receptor-mediated
      degradation of LDL by 42%, a finding out of line with the mean 11% increase in
      serum LDL-C. Perhaps MCT, by increasing the rate of LDL-C production, overcame
      the rate of LDL-C clearance. The 12:0 diet enhanced some factors involved in
      reverse cholesterol transport (e.g., high density lipoprotein fractions) while
      MCT had a different or less pronounced effect. The overall effects of MCT on
      cholesterol metabolism may or may not be desirable, whereas those of 12:0 appear
      largely undesirable as previously reported.

PMID- 10574654
TI  - Hepatic zonation of the formation and hydrolysis of cholesteryl esters in
      periportal and perivenous parenchymal cells.
AB  - The periportal (PP) and perivenous (PV) zones of the liver acinus differ in
      enzyme complements and capacities for cholesterol and bile acid synthesis and
      other metabolic processes. The aim of this investigation was to determine the
      acinar distribution of the catalytic activity of the enzymes governing the
      formation and hydrolysis of cholesteryl esters using PP and PV hepatocytes from
      normal or cholestyramine-fed rats. The hepatocyte subpopulations were isolated by
      centrifugal elutriation, characterized according to the distribution pattern of a
      number of cell parameters and marker enzymes, and assayed for acyl
      CoA:cholesterol acyltransferase (ACAT) and lysosomal, cytosolic and microsomal
      cholesteryl ester hydrolase (CEH). In normally fed rats, no zonation was found in
      the activity of lysosomal CEH and ACAT, and the activity of both cytosolic and
      microsomal CEH zonated toward the PV zone of the acinus. Concentrations of free
      and esterified cholesterol in homogenates, cytosol, and microsomes of PP and PV
      cells were, however, similar. Cholestyramine raised significantly the PV/PP ratio
      of ACAT because of an exclusive PP reduction of activity and abolished the
      heterogeneity in microsomal CEH because of a greater inhibitory PV response,
      whereas the PV dominance of cytosolic CEH and the homogeneous distribution of
      lysosomal CEH were unaffected. These results demonstrated homogeneity within the
      liver acinus for the enzymatic degradation of endocyted lipoprotein-derived
      cholesteryl esters, a structural zonation of the cytosolic CEH and a dynamic
      zonation of ACAT and the microsomal CEH, with a PV dominance of the enzymatic
      capacity for the degradation of stored cholesteryl esters in normal livers.

PMID- 10574655
TI  - Eicosapentaenoic acid and docosahexaenoic acid selectively attenuate U46619
      induced smooth muscle cell proliferation.
AB  - It is well known that vascular smooth muscle cell (SMC) proliferation is a key
      step in atheromatous plaque formation. Thromboxane A2 (TxA2), released from
      aggregating platelets and an injured vessel wall, may play an important role in
      the development of atheromatous plaque. Many animal studies have suggested that n
      3 polyunsaturated fatty acids eicosapentaenoic acid (EPA, 20:5n-3) and
      docosahexaenoic acid (DHA, 22:6n-3) present in the fish oils have
      antiatherosclerotic effects. In the present study, we investigated the effect of
      EPA and DHA on TxA2-induced SMC proliferation. To determine the functional
      selectivity of n-3 fatty acids, we also tested the effect of arachidonic acid
      (AA, 20:4n-6), gamma-linolenic acid) (LNA, 18:3n-6), and oleic acid (OA, 18:1n-9)
      on TxA2-induced SMC proliferation. Only EPA and DHA prevented the SMC
      proliferation induced by the TxA2 mimetic U46619. When EPA and DHA were added
      together in the ratio in which they are present in menhaden oil, EPA and DHA
      acted synergistically to block the SMC proliferation induced by the TXA2-mimetic.
      These findings suggest that the n-3 polyunsaturated fatty acids in fish oils may
      exert antiatherosclerotic effects by blocking the mitogen-stimulated
      proliferation of SMC.

PMID- 10574657
TI  - Acyltransferase activities in the yolk sac membrane of the chick embryo.
AB  - The activities of some enzymes of glycerolipid synthesis and fatty acid oxidation
      were measured in subcellular fractions of the yolk sac membrane (YSM), an extra
      embryonic tissue that mediates the transfer of lipid from the yolk to the
      circulation of the chick embryo. The activities of monoacylglycerol
      acyltransferase and carnitine palmitoyl transferase-1 in the YSM (respectively,
      284.8+/-13.2 nmol/min/mg microsomal protein and 145.6+/-9.1 nmol/min/mg
      mitochondrial protein; mean +/- SE; n = 4) at day 12 of development appear to be
      the highest yet reported for any animal tissue. Also, the carnitine palmitoyl
      transferase-1 of the YSM was very insensitive to inhibition by malonyl CoA. The
      maximal activities of glycerol-3-phosphate acyltransferase and diacylglycerol
      acyltransferase in the YSM (respectively, 26.7+/-2.2 and 36.1+/-2.1 nmol/min/mg
      microsomal protein) were also high compared with the reported values for various
      animal tissues. The very high enzymic capacity for glycerolipid synthesis
      supports the hypothesis that the yolk-derived lipids are subjected to hydrolysis
      followed by reesterification during transit across the YSM. The monoacylglycerol
      pathway appears to be the main route for glycerolipid resynthesis in the YSM. The
      results also suggest that the YSM has the capacity to perform simultaneously beta
      oxidation at a high rate in order to provide energy for the lipid transfer
      process.

PMID- 10574656
TI  - Induction of apoptosis and apoptotic mediators in Balb/C splenic lymphocytes by
      dietary n-3 and n-6 fatty acids.
AB  - The present study was designed to investigate the effect of dietary n-6 and n-3
      polyunsaturated fatty acids (PUFA) on anti-CD3 and anti-Fas antibody-induced
      apoptosis and its mediators in mouse spleen cells. Nutritionally adequate
      semipurified diets containing either 5% w/w corn oil (n-6 PUFA) or fish oil (n-3
      PUFA) were fed to weanling female Balb/C mice, and 24 wk later mice were
      sacrificed. In n-3 PUFA-fed mice, serum and splenocyte lipid peroxides were
      increased by 20 and 28.3% respectively, compared to n-6 PUFA-fed mice. Further,
      serum vitamin E levels were decreased by 50% in the n-3 PUFA-fed group, whereas
      higher anti-Fas- and anti-CD3-induced apoptosis (65 and 66%) and necrosis (17 and
      25%), compared to the n-6 PUFA-fed group, were found when measured with Annexin V
      and propidium iodide staining, respectively. In addition, decreased Bcl-2 and
      increased Fas-ligand (Fas-L) also were observed in the n-3 PUFA-fed group
      compared to the n-6 PUFA-fed group. No difference in the ratio of splenocyte
      subsets nor their Fas expression was observed between the n-3 PUFA-fed and n-6
      PUFA-fed groups, whereas decreased proliferation of splenocytes was found in n-3
      PUFA-fed mice compared to n-6 PUFA-fed mice. In conclusion, our results indicate
      that dietary n-3 PUFA induces higher apoptosis by increasing the generation of
      lipid peroxides and elevating Fas-L expression along with decreasing Bcl-2
      expression. A reduced proliferative response of immune cells also was observed in
      n-3 PUFA-fed mice.

PMID- 10574658
TI  - Lipid composition of hepatocyte plasma membranes from geese overfed with corn.
AB  - Twelve-week-old Landes male geese were overfed with corn for 21 d in order to
      induce liver steatosis (fatty liver). Lipid composition of hepatocyte plasma
      membranes from fatty livers was compared to that of lean livers obtained from
      geese fed a normal diet. The ratio cholesterol/phospholipids was higher in fatty
      hepatocyte plasma membranes (0.63 vs. 0.47), whereas the phospholipid/protein
      ratio was less than half. Overfeeding induced changes in fatty acid composition
      of hepatocyte plasma membranes, including a greater than twofold increase in the
      percentage of oleic acid (29.7 vs. 13.8%) and a somewhat lesser increase in
      lauric, palmitic, and palmitoleic acid contents of plasma membrane lipids of
      fatty livers. A concomitant reduction in the proportion of stearic acid (18.4 vs.
      25.1%) was also observed. In fatty livers, the increased ratio of saturated to
      polyunsaturated fatty acids (PUFA) (1.5 vs. 1.0) was related to a significant
      decrease in PUFA content. Among all the PUFA, only the eicosatrienoic acid (20:3n
      9) percentage was increased by liver steatosis. Overfeeding with corn appeared to
      induce competition between de novo synthesized and dietary fatty acids
      incorporated in hepatocyte plasma membranes. This resulted in an accumulation of
      de novo synthesized monounsaturated and derived fatty acids in plasma membranes
      from overfed birds. A defect in the incorporation of linoleic acid and linoleic-
      and linolenic-derived PUFA was observed despite the high proportion of these
      essential fatty acids in the diet. It was concluded that in overfed palmipeds, de
      novo hepatic lipogenesis prevails over dietary lipid intake to modulate lipid
      composition of the fatty liver plasma membrane.

PMID- 10574659
TI  - Metabolism of trideuterated iso-lignoceric acid in rats in vivo and in human
      fibroblasts in culture.
AB  - Saturated very long chain fatty acids (fatty acids with greater than 22 carbon
      atoms; VLCFA) accumulate in peroxisomal disorders, but there is little
      information on their turnover in patients. To determine the suitability of using
      stable isotope-labeled VLCFA in patients with these disorders, the metabolism of
      22-methyl[23,23,23-2H3]tricosanoic (iso-lignoceric) acid was studied in rats in
      vivo and in human skin fibroblasts in culture. The deuterated iso-VLCFA was
      degraded to the corresponding 16- and 18-carbon iso-fatty acids by rats in vivo
      and by normal human skin fibroblasts in culture, but there was little or no
      degradation in peroxisome-deficient (Zellweger's syndrome) fibroblasts,
      indicating that its oxidation was peroxisomal. Neither the 14-, 20-, and 22
      carbon iso-fatty acids nor the corresponding odd-chain metabolites could be
      detected. In the rat, the organ containing most of the iso-lignoceric acid, and
      its breakdown products, was the liver, whereas negligible amounts were detected
      in the brain, suggesting that little of the fatty acid crossed the blood-brain
      barrier. Our data indicate that VLCFA labeled with deuterium at the omega
      position of the carbon chain are suitable derivatives for the in vivo
      investigation of patients with defects in peroxisomal beta-oxidation because they
      are metabolized by the same pathways as the corresponding n-VLCFA. Moreover, as
      iso-VLCFA and their beta-oxidation products are readily separated from the
      corresponding n-fatty acids by normal chromatographic procedures, the turnover of
      VLCFA can be more precisely measured.

PMID- 10574661
TI  - Effects of conjugated linoleic acid isomers on the hepatic microsomal
      desaturation activities in vitro.
AB  - The influence of individual conjugated linoleic acid (CLA) isomers on the delta6
      desaturation of linoleic and alpha-linolenic acids and on the delta9 desaturation
      of stearic acid was investigated in vitro, using rat liver microsomes. The delta6
      desaturation of 18:2n-6 was decreased from 23 to 38% when the ratio of
      9cis,11trans-18:2 to 18:2n-6 increased from 0.5 to 2. The compound 10trans,12cis
      18:2 exhibited a similar effect only at the highest concentration. The delta6
      desaturation of alpha-linolenic acid was slightly affected by the presence of CLA
      isomers. The sole isomer to induce an inhibitory effect on the delta9
      desaturation of stearic acid was 10trans,12cis-18:2.

PMID- 10574662
TI  - Delta9 desaturase activity in bovine subcutaneous adipose tissue of different
      fatty acid composition.
AB  - Two experiments were conducted to investigate the relationship between delta9
      desaturase (stearoyl-coenzyme A desaturase) activity and fatty acid composition
      in subcutaneous adipose tissue from cattle of different backgrounds. In
      Experiment 1, subcutaneous adipose tissue samples were taken from carcasses of
      pasture-fed cattle and feedlot cattle fed for 100, 200, or 300 d. Adipose tissue
      from pasture-fed cattle had significantly lower total saturated fatty acids and
      higher total unsaturated fatty acids than feedlot cattle. Desaturase activity
      correspondingly was 60-85% higher in pasture-fed cattle than in feedlot cattle.
      There was no difference in the fatty acid composition or desaturase activity
      among samples from the 100-, 200-, and 300-d feedlot cattle. In Experiment 2,
      adipose tissue samples were collected from carcasses of feedlot cattle fed for
      180 d with either a standard feedlot ration (control group), or a ration
      containing rumen-protected cottonseed oil (CSO) for the last 70-80 d. Adipose
      tissue from the CSO-fed cattle was more saturated than that from the control
      group, having significantly more 18:0 and less 16:1 and 18:1. Correspondingly,
      adipose tissue from the CSO group had significantly lower desaturase activity.
      The elevated 18:2 in adipose tissue from the CSO group confirmed that unsaturated
      fatty acids (including cyclopropenoid fatty acids) were protected from
      biohydrogenation. Further studies are needed to determine whether the repression
      of desaturase activity results from direct inhibition by cyclopropenoic acids or
      by higher dietary contents of 18:2.

PMID- 10574663
TI  - Lipase-catalyzed fractionation of conjugated linoleic acid isomers.
AB  - The abilities of lipases produced by the fungus Geotrichum candidum to
      selectively fractionate mixtures of conjugated linoleic acid (CLA) isomers during
      esterification of mixed CLA free fatty acids and during hydrolysis of mixed CLA
      methyl esters were examined. The enzymes were highly selective for cis-9,trans-11
      18:2. A commercial CLA methyl ester preparation, containing at least 12 species
      representing four positional CLA isomers, was incubated in aqueous solution with
      either a commercial G. candidum lipase preparation (Amano GC-4) or lipase
      produced from a cloned high-selectivity G. candidum lipase B gene. In both
      instances selective hydrolysis of the cis-9,trans-11-18:2 methyl ester occurred,
      with negligible hydrolysis of other CLA isomers. The content of cis-9, trans-11
      18:2 in the resulting free fatty acid fraction was between 94 (lipase B reaction)
      and 77% (GC-4 reaction). The commercial CLA mixture contained only trace amounts
      of trans-9,cis-11-18:2, and there was no evidence that this isomer was hydrolyzed
      by the enzyme. Analogous results were obtained with these enzymes in the
      esterification in organic solvent of a commercial preparation of CLA free fatty
      acids containing at least 12 CLA isomers. In this case, G. candidum lipase B
      generated a methyl ester fraction that contained >98% cis-9,trans-11-18:2.
      Geotrichum candidum lipases B and GC-4 also demonstrated high selectivity in the
      esterification of CLA with ethanol, generating ethyl ester fractions containing
      96 and 80%, respectively, of the cis-9,trans-11 isomer. In a second set of
      experiments, CLA synthesized from pure linoleic acid, composed essentially of two
      isomers, cis-9,trans-11 and trans-10,cis-12, was utilized. This was subjected to
      esterification with octanol in an aqueous reaction system using Amano GC-4 lipase
      as catalyst. The resulting ester fraction contained up to 97% of the cis-9,trans
      11 isomer. After adjustment of the reaction conditions, a concentration of 85%
      trans-10,cis-12-18:2 could be obtained in the unreacted free fatty acid fraction.
      These lipase-catalyzed reactions provide a means for the preparative-scale
      production of high-purity cis-9,trans-11-18:2, and a corresponding CLA fraction
      depleted of this isomer.

PMID- 10574660
TI  - Eicosapentaenoic and docosahexaenoic acid affect mitochondrial and peroxisomal
      fatty acid oxidation in relation to substrate preference.
AB  - Decreased triacylglycerol synthesis within hepatocytes due to decreased
      diacylglycerol acyltransferase (DGAT) activity has been suggested to be an
      important mechanism by which diets rich in fish oil lower plasma triacylglycerol
      levels. New findings suggest that eicosapentaenoic acid (EPA), and not
      docosahexaenoic acid (DHA), lowers plasma triacylglycerol by increased
      mitochondrial fatty acid oxidation and decreased availability of fatty acids for
      triacylglycerol synthesis. To contribute to the understanding of the
      triacylglycerol-lowering mechanism of fish oil, the different metabolic
      properties of EPA and DHA were studied in rat liver parenchymal cells and
      isolated rat liver organelles. EPA-CoA was a poorer substrate than DHA-CoA for
      DGAT in isolated rat liver microsomes, and in the presence of EPA, a markedly
      lower value for the triacyl[3H]glycerol/diacyl[3H]glycerol ratio was observed.
      The distribution of [1-14C]palmitic acid was shifted from incorporation into
      secreted glycerolipids toward oxidation in the presence of EPA (but not DHA) in
      rat liver parenchymal cells. [1-14C]EPA was oxidized to a much greater extent
      than [1-14C]DHA in rat liver parenchymal cells, isolated peroxisomes, and
      especially in purified mitochondria. As the oxidation of EPA was more effective
      and sensitive to the CPT-I inhibitor, etomoxir, when measured in a combination of
      both mitochondria and peroxisomes, we hypothesized that both are involved in EPA
      oxidation, whereas DHA mainly is oxidized in peroxisomes. In rats, EPA treatment
      lowered plasma triacylglycerol and increased hepatic mitochondrial fatty acid
      oxidation and carnitine palmitoyltransferase (CPT)-I activity in both the
      presence and absence of malonyl-CoA. Whereas only EPA treatment increased the
      mRNA levels of CPT-I, DHA treatment increased the mRNA levels of peroxisomal
      fatty acyl-CoA oxidase and fatty acid binding protein more effectively than EPA
      treatment. In conclusion, EPA and DHA affect cellular organelles in relation to
      their substrate preference. The present study strongly supports the hypothesis
      that EPA, and not DHA, lowers plasma triacylglycerol by increased mitochondrial
      fatty acid oxidation.

PMID- 10574664
TI  - Enhancement of both reaction yield and rate of synthesis of structured
      triacylglycerol containing eicosapentaenoic acid under vacuum with water activity
      control.
AB  - Production of structured triacylglycerols (sTAG) containing eicosapentaenoic acid
      (EPA) at the sn-1 (or 3) position using Lipozyme in a solvent-free system was
      studied. Optimal water activity (a(w)) for the synthesis of the sTAG was
      investigated. Vacuum was applied to shift reaction equilibrium toward the
      synthesis reaction by removing by-products. During vacuum application, the water
      level of the reaction system was controlled at the optimal level by addition of a
      suitable amount of water at a predetermined interval. Intermittent periodic
      addition of a suitable amount of water into the reaction mixture made the
      reaction rate faster than that without adding water. A molar yield of 89.7% of
      the targeted sTAG was obtained after 16 h reaction with a(w) control during the
      vacuum application as compared with the yield of 87.0% after 24 h of reaction
      without a(w) control during the vacuum application.

PMID- 10574665
TI  - Dietary conjugated linoleic acid reciprocally modifies ketogenesis and lipid
      secretion by the rat liver.
AB  - The effects of dietary conjugated linoleic acid (CLA) and linoleic acid (LA) on
      ketone body production and lipid secretion were compared in isolated perfused rat
      liver. After feeding the 1% CLA diet for 2 wk, the concentration of post-perfused
      liver cholesterol was significantly reduced by CLA feeding, whereas that of
      triacylglycerol remained unchanged. Livers from CLA-fed rats produced
      significantly more ketone bodies; and the ratio of beta-hydroxybutyrate to
      acetoacetate, an index of mitochondrial redox potential, tended to be
      consistently higher in the liver perfusate. Conversely, cumulative secretions of
      triacylglycerol and cholesterol were consistently lower in the livers of rats fed
      CLA, and the reduction in the latter was statistically significant. Thus dietary
      CLA appeared to exert its hypolipidemic effect at least in part through an
      enhanced beta-oxidation of fatty acids at the expense of esterification of fatty
      acid in the liver.

PMID- 10574667
TI  - Presurgical nasoalveolar molding in infants with cleft lip and palate.
AB  - Presurgical infant orthopedics has been employed since the 1950s as an adjunctive
      neonatal therapy for the correction of cleft lip and palate. In this paper, we
      present a paradigm shift from the traditional methods of presurgical infant
      orthopedics. Some of the problems that the traditional approach failed to address
      include the deformity of the nasal cartilages in unilateral as well as bilateral
      clefts of the lip and palate and the deficiency of columella tissue in infants
      with bilateral clefts. The nasoalveolar molding (NAM) technique we describe uses
      acrylic nasal stents attached to the vestibular shield of an oral molding plate
      to mold the nasal alar cartilages into normal form and position during the
      neonatal period. This technique takes advantage of the malleability of immature
      cartilage and its ability to maintain a permanent correction of its form. In
      addition, we demonstrate the ability to nonsurgically construct the columella
      through the application of tissue expansion principles. This construction is
      performed by gradual elongation of the nasal stents and the application of tissue
      expanding elastic forces that are applied to the prolabium. Use of the NAM
      technique has eliminated surgical columella reconstruction and the resultant scar
      tissue from the standard of care in this cleft palate center.

PMID- 10574666
TI  - State of the art in craniofacial surgery: nonsyndromic craniosynostosis.
AB  - Craniosynostosis refers to the premature fusion of one of the six major sutures
      of the cranial vault. Functionally, craniosynostosis may be defined as the
      premature conversion of the dynamic region of growth and resorption between two
      adjacent bones of the cranium into a static region of bony union. Molecular
      analysis has blurred the traditional categories of nonsyndromic and syndromic
      synostosis to some extent, but, in general, the distinctions between the two
      groups still hold true. The complexity of the congenital anomalies may be limited
      with the former, whereas the latter usually requires reoperations and correction
      of the facial skeleton. This article briefly outlines the characteristic
      deformities produced from nonsyndromic craniosynostosis. Various approaches to
      surgical correction of the deformities are described. Finally, new biomaterials
      that are used in the correction of nonsyndromic craniosynostosis are reviewed.

PMID- 10574668
TI  - A study of the measurement errors associated with the analysis of velar movements
      assessed from lateral videofluoroscopic investigations.
AB  - OBJECTIVE: The analysis of lateral videofluoroscopic images of velar movements
      during speech is a commonly used tool in the management of the cleft palate
      patient. This study tests the general hypothesis that measurements of velar
      movements taken from lateral videofluoroscopic images are accurate and reliable.
      METHOD: A measurement system was used that allowed for the rapid assessment of
      velopharyngeal distance, soft palate velocity during the closure cycle, extension
      of the soft palate at maximum closure, and the angular lift of the soft palate
      above the plane of the hard palate. Ten recordings of soft palate movement during
      speech were randomly chosen from lateral X-rays of 27 normal adults. The video
      recordings were captured by digital frame grabber for subsequent analysis by
      three operators using a standard PC that was running image-analysis software. The
      uncertainties associated with the above measurements were analyzed in terms of
      the errors introduced by the inherent calibration and nonlinearity of the imaging
      system, the inaccuracy of the patient setup, and the operator-dependent
      measurement error. RESULTS: For both absolute dimensions and ratiometric
      measurements, the measurement uncertainties related to the inherent nonlinearity
      in the imaging system were shown to be less than 2%. Typical patient
      misalignments as a result of a 10 degree head rotation and a 10-mm translation
      out of the measurement plane introduced errors of between 2% and 3%. Results
      showed that the average standard deviation for measurement of gap size was 1.2
      mm, extension ratio was 0.11, angular lift was 3.1 degrees, and soft palate
      velocity was 15.5 mm/second. The intra-class correlation coefficient generally
      showed a good agreement between operators, typically in the range 0.8 to 0.9.
      CONCLUSION: Measurements of velopharyngeal distance, extension of the soft palate
      at maximum closure, and the angular lift of the soft palate above the plane of
      the hard palate assessed from lateral videofluoroscopic images are reliable and
      accurate. The soft palate velocity during the closure cycle can also be
      determined, but clinical interpretations based on this parameter should be
      constrained by the measurement uncertainties.

PMID- 10574669
TI  - Speech sample effects on pressure and flow measures in children with normal or
      abnormal velopharyngeal function.
AB  - OBJECTIVE: This study examined the effect of certain test phoneme contexts on
      oral pressure and nasal flow values in young children with normal velopharyngeal
      (VP) function. Comparison was made with responses from children with abnormal
      function. SPEAKERS: Ten children judged to have normal VP function (mean age =
      5.2 years) and five children with VP incompetence (mean age = 7.8 years) were
      evaluated. Both groups were able to produce the speech sample with standard
      articulatory postures. Subjects were from the local community and a university
      cleft palate clinic. DESIGN: Simultaneous oral pressure and nasal flow recordings
      were obtained from the speakers as they produced /p/ in speech stimuli that
      varied in terms of test phoneme position in the syllable (releasing and
      arresting), adjacent vowel height (high, middle, and low), or adjacent consonant
      characteristics (voicing, placement, and manner). Within-subject differences in
      pressure and flow were examined to evaluate specific stimulus contrasts in each
      speaker group. SETTING: Data were collected in the Speech Physiology Laboratory
      in the Hearing and Speech Department at the University of Kansas Medical Center.
      RESULTS: There were few speech sample effects on oral pressure for children with
      VP competence. Nasal flow for this group occurred infrequently but was present at
      least once in 80% of the subjects. The speakers with VP incompetence demonstrated
      predictable phoneme context effects (higher flow and lower pressure for a nasal
      context; higher flow for a high vowel context). CONCLUSION: The finding of no
      significant stimulus effects for the normal speakers suggests the need for little
      concern when choosing stimuli for normative study of oral pressure. However,
      certain stimulus contexts should be considered for data collection if results are
      to be applied to children with abnormal velopharyngeal function.

PMID- 10574670
TI  - Changes produced by presurgical orthopedic treatment before cheiloplasty in cleft
      lip and palate patients.
AB  - OBJECTIVE: The purpose of this study was to test the hypothesis that, with the
      use of preoperative treatment, the dimensions of the upper part of the oral
      cavity of an infant with unilateral cleft lip and palate (UCLP) become more
      similar to those of a noncleft infant. DESIGN: This was a retrospective study of
      upper dental casts taken at birth and prior to lip repair at 6 months of age. A
      treated group, an untreated group, and a group of noncleft contemporaries were
      compared cross-sectionally and longitudinally. Models were analyzed by the
      trigonometric method. SETTING: The study was performed at a maxillofacial center
      servicing a population of two million. PARTICIPANTS: The treated group consisted
      of 24 babies born after 1990 with UCLP that started presurgical treatment within
      20 days of life. The untreated group consisted of 25 randomly selected UCLP casts
      taken at birth and 25 casts taken just before lip surgery. The noncleft group
      consisted of 25 full-term infants whose mothers participated in the longitudinal
      growth study. All participants belonged to the same ethnic group. INTERVENTIONS:
      Presurgical treatment consisted of the babies constantly wearing a thin, passive
      acrylic plate mimicking the normal palate and a slim adhesive tape fixed to the
      lip segments to bring them slightly together. RESULTS: The upper oral cavity in a
      newborn with UCLP was significantly larger than in a noncleft infant, the only
      exception being in the sagittal dimension. After presurgical treatment, the upper
      oral cavity was remodeled and slightly enlarged; there was a lesser difference
      from the noncleft at 6 months than at birth. The cleft in the alveolus reduced
      significantly, and the position of the incisive point improved. The group without
      presurgical treatment had no remodeling, and the growth dynamics were similar to
      the noncleft so that the dimensional differences from the normal remained the
      same as at birth. CONCLUSION: The morphological characteristics of the upper part
      of the mouth change if the functional conditions in the oral cavity are changed.
      Infants with presurgical orthopedics become more similar to noncleft
      contemporaries than those without presurgical orthopedics.

PMID- 10574671
TI  - Caries prevalence and bottle-feeding practices in 2-year-old children with cleft
      lip, cleft palate, or both in Taiwan.
AB  - OBJECTIVE: The purposes of this study were to investigate the caries prevalence
      in cleft lip, cleft palate, or both in children under the age of 2 years and to
      evaluate parental attitudes toward bottle-feeding, dental care, and their
      relationship to baby bottle tooth decay (BBTD) in Taiwan. DESIGN: Randomized and
      prospective study. SETTING: Institutional setting. PATIENTS AND METHODS: One
      hundred twenty-three 2-year-old children (68 boys and 55 girls) with cleft lip,
      cleft palate, or both were selected for this study. A questionnaire that asked
      questions about knowledge of oral health, knowledge and beliefs about BBTD,
      children's feeding habits, children's dental care, and parenting attitudes toward
      children with clefts was completed by the parents or caretakers. Children were
      divided into bottle-feeding and non-bottle-feeding groups according to the
      questionnaire responses of parents or caretakers. Each child was examined with a
      dental mirror and explorer under focused flashlight using defs index to determine
      the presence of BBTD. RESULTS: Thirty-nine percent (48) subjects reported a
      bottle-feeding habit; the overall prevalence of BBTD was 15.4%. The habit of
      bottle-feeding was significantly related to BBTD (p = .019). The defs score for
      children who were bottle-fed was significantly higher than children who were not
      bottle-fed (p = .045). Parents or caretakers of both bottle-feeding and non
      bottle-feeding children showed no significant differences in their attitudes
      toward bottle-feeding and feeding habits (p > .05). However, parents of non
      bottle-fed children had significantly better dental care than parents of bottle
      fed children in brushing frequency (p < .001) and brushing before bed (p < .001).
      CONCLUSIONS: Children with clefts who took a bottle to bed showed an increased
      risk of developing BBTD. The parents or caretakers of bottle-fed children also
      showed a lack of motivation to perform regular preventive dental home care for
      their children. This suggests that oral health promotion programs should begin in
      infancy for children with clefts and their parents.

PMID- 10574672
TI  - Asymmetry of left versus right unilateral cleft impairments: an experimental
      study of face perception.
AB  - OBJECTIVE: Previous psychosocial studies of adults born with cleft lip and palate
      have provided circumstantial evidence that surgically repaired right-sided
      unilateral clefts may be more disfiguring than left-sided clefts. The present
      study asked if such asymmetries are physiognomic asymmetries or arise "in the eye
      of the beholder," representing perceptual processes in face recognition. DESIGN:
      Color slides of 160 children (6 years of age) and young teenagers (16 years of
      age) were rated by subjects for perceived disfigurement. Sixty of the subjects
      had unilateral complete cleft lip and palate (30 had a right-sided cleft and 30
      had a left-sided cleft), 60 had unilateral cleft lip/alveolus (30 right-sided and
      30 left-sided clefts), 32 children had bilateral cleft lip and palate, and 8
      children had cleft palate only. Faces were shown in normal and in mirror-reversed
      versions; the order in which faces were shown was randomized, as were other
      stimulus factors such as cleft type, age, and gender. SETTING: The study was
      conducted as a classroom-type experiment at the Vision Laboratory, Department of
      Psychology, Oslo, Norway. PARTICIPANTS: Thirty-seven students of psychology at
      the University of Oslo, who were ignorant of the purpose of the study, acted as
      subjects. MAIN OUTCOME MEASURE: Subjects rated perceived disfigurement using a
      visual analog scale. RESULTS: Modest but highly consistent hemifacial asymmetries
      in judged disfigurement were found, with left-sided unilateral clefts rated as
      less disfiguring than right-sided unilateral clefts. Unilateral clefts were
      judged as being less disfiguring than the bilateral clefts, and cleft
      lip/alveolus was judged as being less disfiguring than cleft lip and palate. The
      patterns of facial judgments were almost identical in the normal and reversed
      slides conditions. CONCLUSIONS: Asymmetries between left- and right-sided clefts
      reside in physiognomic factors rather than in hemispheric asymmetries controlling
      the perceptual process of face judgment.

PMID- 10574673
TI  - A novel FGFR2 gene mutation in Crouzon syndrome associated with apparent
      nonpenetrance.
AB  - OBJECTIVE: To determine whether specific mutations within the fibroblast growth
      factor receptor 2 (FGFR2) gene that are associated with Crouzon syndrome can be
      present in an individual who had been assumed to be "clinically normal." METHODS:
      Most mutations responsible for Crouzon syndrome occur in exons IIIa (U) or IIIc
      (B) of the FGFR2 gene, which facilitates allelotyping using polymerase chain
      reaction (PCR)-mediated mutation analysis. Once a specific mutation was
      identified in the index case, remaining affected family members and "clinically
      normal" first-degree relatives were analyzed in order to correlate genotype with
      phenotype. RESULTS: A novel missense mutation--a G to T transversion--involving
      the first base of codon 362 was identified in all Crouzon syndrome-affected
      family members and in one "clinically normal"-appearing parent following DNA
      sequencing of exon B of the FGFR2 gene and specific BstNI restriction fragment
      length polymorphism. Pattern profile analysis demonstrated a consistent
      collection of abnormal cephalometric measurements in the Crouzon-affected family
      members and, to a lesser degree, in the "clinically normal" parent. CONCLUSION:
      We have identified a novel missense mutation in the FGFR2 gene that predicts an
      Ala362Ser substitution shared by all family members affected by Crouzon syndrome
      and by a "clinically normal"-appearing father. These data support nonpenetrance
      of Crouzon syndrome when the diagnosis is based on clear clinical findings. Only
      through cephalometry was there an indication of minimal expression of Crouzon
      syndrome in the "clinically normal"-appearing father.

PMID- 10574674
TI  - The early prenatal diagnosis of cleft lip and the decision-making process.

PMID- 10574675
TI  - Preoperative chemotherapy in stage III non-small cell lung cancer: long-term
      outcome.

PMID- 10574676
TI  - Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year
      assessment of a randomized controlled trial.
AB  - In 1989, we began a multicenter study to evaluate the potential benefit of
      preoperative chemotherapy with cisplatin, ifosfamide and mitomycin over surgery
      alone in CT-visible N2 non-small-cell lung cancer. We present here a 7-year
      assessment of this randomized trial. Sixty patients were randomized to receive
      either surgery alone or three cycles of mitomycin 6 mg/m2, ifosfamide 3 g/m2 and
      cisplatin 50 mg/m2, given intravenously on day 1 of each cycle at 3-week
      intervals and followed by surgery. All patients received thoracic irradiation
      after surgery. The resected tumors were evaluated for the presence of K-ras gene
      point mutations. Treatment arms were well-balanced in characteristics such as
      gender, age, histology, and tumor size. Mediastinoscopy and/or mediastinotomy
      (Chamberlain procedure) with a biopsy was performed in all patients with N2 stage
      detected by CT scan of the chest (83% of the patients in the preresectional
      chemotherapy arm and 63% of those in the surgery arm). In eight of the 25
      patients (32%) who had mediastinoscopy in the preresectional chemotherapy arm,
      the initially positive mediastinal lymph nodes were downstaged. For the 30
      patients who received preresectional chemotherapy, overall median survival was 22
      months (95% CI, 13.4 30.6). Of the 30 patients who received surgery alone,
      overall median survival was 10 months (95% CI, 7.4-12.6; P = 0.005 by the log
      rank test). Updated survival data reveals a plateau in the preresectional
      chemotherapy group, and this still significant long-term survival benefit prompts
      us to hypothesize that even with short-term preresectional chemotherapy, the
      natural history of still resectable CT-visible N2 non-small cell lung cancer is
      favorably altered. The results of our study mirror the long-term survival
      recently reported in the MD Anderson randomized study.

PMID- 10574677
TI  - DNA mismatch binding in human lung tumor cell lines.
AB  - Defects in mismatch repair (MMR) genes have been involved in several types of
      sporadic and hereditary cancers. In order to elucidate the role of MMR in human
      lung carcinogenesis we examined DNA mismatch binding in cell-free extracts of
      seven lung tumor cell lines and five corresponding lymphoblastoid cell lines from
      lung cancer patients. Using the technique of bandshift assay we have demonstrated
      that 2/7 of the tumor cell lines are aberrant in binding to specific DNA
      mismatches while all lymphoblastoid cell lines were proficient in binding to all
      tested mismatches. Both extracts were aberrant in binding to G/T mismatch whereas
      one of the cell lines showed deficiency in binding to the C:A mismatches as well.
      Immunoblotting analysis showed that all known DNA mismatch repair (MMR) proteins
      were present in these extracts. The cell line deficient in binding to both G:T
      and C:A mismatches showed microsatellite instability (MSI) in tumor DNA and
      higher resistance to the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine
      (MNNG). This report indicates that DNA mismatch binding deficiencies may be
      implicated in at least a subgroup of human lung cancer.

PMID- 10574678
TI  - Cytochrome P4502E1 genetic polymorphisms and lung cancer in a Taiwanese
      population.
AB  - Cytochrome P4502E1 (CYP2E1) is involved in metabolic activation of carcinogenic
      nitrosamines, benzene and low molecular weight halogenated hydrocarbons. In this
      study, we assessed the association between CYP2E1 RsaI and DraI genetic
      polymorphisms and lung cancer in a Taiwanese population. The RsaI genotype
      distribution was significantly different between 119 lung cancer patients and 231
      non-cancer controls. The homozygote variants of RsaI genotypes were more common
      in controls (6.9%) than in lung cancer patients (0.8%). The estimated odds ratio
      (OR) was 0.11 (95% confidence interval (CI), 0.01-0.87). After adjusting for age,
      sex, and smoking status, the OR was 0.12 (95%, CI, 0.02-0.95). This is the first
      observation of a positive association between this locus and lung cancer in an
      Asian population. No significant differences in CYP2E1 DraI genotype
      distributions were found between cases and controls. The results of this study
      indicate that CYP2E1 RsaI polymorphism, but not DraI polymorphism, may contribute
      to the development of lung cancer in Taiwan.

PMID- 10574679
TI  - Concomitant brain radiotherapy and vinorelbine-ifosfamide-cisplatin chemotherapy
      in brain metastases of non-small cell lung cancer.
AB  - AIM: To determine whether or not brain radiotherapy and concomitant three-drug
      chemotherapy is feasible and yields anti-tumour activity in patients with non
      small cell lung cancer and brain metastases at time of presentation. PATIENTS AND
      METHODS: Twenty-three previously untreated patients suffering from non-small cell
      lung cancer and brain metastasis were prospectively included in this feasibility
      study. Most of the patients had neurological symptoms and an Eastern
      Collaborative Oncology Group (ECOG) performance index over 2. Treatment consisted
      of three courses of whole brain radiotherapy (18 Gy in 10 fractions) and
      vinorelbine, 30 mg/m2 on days 1 and 8, ifosfamide, 1.5 g/m2 daily from day 1
      through day 3 with uromitexan uroprotection, and cisplatin, 100 mg/m2 on day 2. A
      cycle restarted every 28 days. RESULTS: Eighteen patients completed the three
      cycle programme. All patients were affected by a grade 4 neutropenia and 14 of
      them experienced a febrile episode. Other toxicities were mild to moderate and
      manageable. Received-dose intensities of vinorelbine, ifosfamide and cisplatin
      were 80, 90 and 90%, respectively. Overall response rate was 30%. Specific
      evaluation of brain response demonstrated complete response for seven patients,
      and partial response in six (objective brain response rate, 56%). All responders
      benefited by a remission of symptoms and improvement of performance index. Median
      survival from start of protocol was 7.6 months. CONCLUSION: Although the high
      rate of toxicity requiring re-admission, concomitant brain radiotherapy plus
      vinorelbine, ifosfamide and cisplatin chemotherapy is feasible in patients
      suffering from brain metastasis, and demonstrates an anti-tumour activity for
      this particular subset of stage IV non-small cell lung cancer. The development of
      such an aggressive approach needs further comparative evaluation.

PMID- 10574680
TI  - Flunitrazepam oxidative metabolism in human liver microsomes: involvement of
      CYP2C19 and CYP3A4.
AB  - The aims were to examine the kinetics of the oxidative metabolism of
      flunitrazepam in vitro when flunitrazepam was dissolved in dimethylformamide and
      acetonitrile, and to determine which cytochrome P450 isoform(s) are involved. The
      kinetics of the formations of 3'-hydroxyflunitrazepam and desmethyl-flunitrazepam
      were non-linear and best estimated using the Hill equation. Inhibition of their
      formation was studied using specific chemical inhibitors, expressed enzyme
      systems and specific antibodies. Ks, Vmax, Clmax and n (slope factor) for the
      formation of 3'-hydroxyflunitrazepam and desmethylflunitrazepam had ranges of 165
      338 and 179 391 microM, 22-81 and 3-10 nmol x mg protein(-1) x h(-1), 6-17 and
      0.9-1.9 microl x mg protein(-1) x h(-1), and 2.3-3.6 and 1.6-2.6 respectively
      when dimethylformamide was the organic solvent. When acetonitrile was the
      solvent, Ks, Vmax, Clmax and n (slope factor) for the formation of 3'
      hydroxyflunitrazepam and desmethylflunitrazepam had ranges of 173-231 and 74-597
      microM, 35-198 and 2.7-48 nmol.mg protein(-1) x h(-1), 1347 and 0.7-6.3 microl.mg
      protein(-1) x h(-1), and 1.5-3.6 and 1.1-2.7 respectively. CYP2C19, CYP3A4 and
      CYP1A2 mediated the formation of both 3'-hydroxyflunitrazepam and
      desmethylflunitrazepam. Investigators need carefully to consider the choice of
      organic solvent to avoid false CYP identification.

PMID- 10574681
TI  - Metabolic inactivation of 2-oxiranylmethyl 2-ethyl-2,5-dimethylhexanoate (C10GE)
      in skin, lung and liver of human, rat and mouse.
AB  - The inactivation of 2-oxiranylmethyl 2-ethyl-2,5-dimethylhexanoate (C10GE), one
      of the most abundant isomers of the epoxy-resin Carduras E-10 glycidyl ester, was
      studied in subcellular fractions of human, C3H mouse and F344 rat liver, lung and
      skin. C10GE is chemically very stable and resistant to aqueous hydrolysis, but it
      was rapidly metabolized in both cytosolic and microsomal fractions of all organs
      by epoxide hydrolase (EH)-catalysed hydrolysis of the epoxide moiety as well as
      carboxylesterase (CE)-catalysed hydrolysis of the ester bond. In cytosol the
      epoxide group was also efficiently conjugated with glutathione, catalysed by
      glutathione S-transferase (GST), but this conjugation was much less important
      than hydrolysis in human as well as rodent samples. Although CE-catalysed
      hydrolysis of C10GE would theoretically give rise to the formation of glycidol, a
      directly acting mutagen, it is highly unlikely that any significant level of
      glycidol would occur in vivo since reported rates of inactivation of glycidol
      exceed the total rate of hydrolysis of C10GE. The overall rates of inactivation
      in vitro decreased in the following order: mouse > rat > human. Scaling of the
      data in vitro to clearances in vivo suggests that the detoxifying capacity in the
      rodents is similar and about an order of magnitude greater than in human.
      Nevertheless, the rate of inactivation is 2-3 orders of magnitude greater than
      for simple epoxides such as butadiene monoxide and about one order of magnitude
      higher than for the diglycidyl ether of bisphenol A (BADGE). The transdermal
      penetration and metabolism of [14C]-C10GE was studied in fresh full-thickness
      mouse, and dermatomized human and rat skin. Of the total radioactivity applied on
      the skin, only 0.24+/-0.06 (SD), 1.8+/-0.2 and 6.8+/-0.6% penetrated through
      human, mouse and rat skin respectively. The corresponding apparent skin
      permeability constants were 0.81, 6.42 and 26.4 x 10(-6) cm/h. During transdermal
      penetration, [14C]-C10GE was extensively hydrolysed to the corresponding diol and
      the free acid. Only 0.01, 0.11 and 0.21]% of the applied dose was absorbed
      unchanged through the human, mouse and rat skin respectively.

PMID- 10574682
TI  - In vitro study of fenoprofen chiral inversion in rat: comparison of brain versus
      liver.
AB  - The extent and the overall stereoselectivity of the combined steps involved in
      the chiral inversion of fenoprofen, a non-steroidal anti-inflammatory drug, was
      investigated in rat brain microsomes and cytosol. Results were compared with
      those obtained with the same liver subcellular compartments. Brain microsomes
      catalysed the stereoselective activation of the R(-)-enantiomer to its coenzyme A
      thioester with a specific activity approximately 10-fold less than that obtained
      with liver microsomes. Rat brain microsomes and cytosol mediated the racemization
      and hydrolysis of both R(-)- and S( + )-fenoprofenoyl-CoA. In brain fractions the
      epimerase activity was lower than in liver, whereas the hydrolysis process
      appeared more efficient. Thus, the data indicated that the three-step mechanism
      occurred in brain subcellular compartments leading to a minor chiral inversion of
      fenoprofen compared with that in liver.

PMID- 10574683
TI  - Disposition of tiludronate (Skelid) in animals.
AB  - The disposition of tiludronate in mouse, rat, rabbit, dog and monkey has been
      studied after oral and intravenous doses. Like other bisphosphonates, tiludronate
      was characterized by poor absorption from the gastrointestinal tract. Peak plasma
      concentrations appeared shortly (0.5-1 h) after dosing, except for the baboon
      (4.5 h). Food intake highly impaired intestinal absorption The affinity of
      tiludronate for bone and the slow release from this deep compartment could
      account for the large volume of distribution and the low plasma clearance found
      in all species. Tiludronate has low affinity for red blood cells and binds
      moderately to serum proteins, mainly to serum albumin. Calcified tissues appeared
      to be the main target for deposition. Distribution into bone was not homogenous,
      with higher levels in the trabecular bone than in the corticol part of the long
      bones. The uptake of tiludronate into bone was unequivocally less in the older
      animal. No metabolism occurred in the tested animal species. The major route of
      elimination of the absorbed drug is urine. Preclinical observations made with
      tiludronate, like with other bisphosphonates, were predictive of results obtained
      in clinical investigation.

PMID- 10574684
TI  - Metabolism and excretion of citalopram in man: identification of O-acyl- and N
      glucuronides.
AB  - The antidepressant citalopram (CT), a selective serotonin uptake inhibitor, was
      given in its labelled form, [14C]-CT, as a single oral dose in 50 ml aqueous
      solution (0.1 mmol/30 microCi/1.1 MBq) to four healthy male volunteers.
      Concentrations of radioactivity in whole blood and plasma were similar. The
      respective pharmacokinetic parameters were: Cmax = 214+/-41 and 246+/-69 nmol
      eq./litre, Tmax = 3 and 2 h, AUC = 18289+/-2959 and 14537+/-2883 nmol eq.
      h/litre, and t1/2 = 90.2+/-22.5 and 79.5 +/- 14.9 h respectively. A mean of 85.2
      +/- 10.4% of the radioactive dose was recovered after 17 days of collection of
      excreta. The majority of radioactivity was excreted in urine (74.7+/-8.9%) and
      the remaining part in faeces (10.5+/-2.3%). The HPLC profile of urinary
      components showed that besides the known metabolites of citalopram, three
      glucuronides were present. The relative amounts of CT and its metabolites in
      urine collected for 7 days were: CT (26 %), N-demethyl-CT (DCT, 19%), N,N
      didemethyl-CT (DDCT,9%), the N-oxide (7%), the quaternary ammonium glucuronide of
      CT (CT-GLN, 14%), the N-glucuronide of DDCT (DDCT-GLN, 6%), and the glucuronide
      of the acid metabolite (CT-acid-GLN, 12%) formed by N,N-dimethyl deamination of
      CT. CT-GLN was isolated using preparative chromatography and identified by LC-MS
      MS and NMR. DDCT-GLN and CT-acid-GLN were identified by LC-MS. This study shows
      that protracted renal excretion represents the major route of elimination, with a
      small fraction voided with faeces. A considerable portion of the urinary excreted
      dose consists of N-glucuronides of CT and DDCT together with the O-acyl
      glucuronide of CT-acid.

PMID- 10574685
TI  - Metabolism of pamaqueside, a cholesterol absorption inhibitor, in Long-Evans rat:
      effect of bile duct cannulation on absorption.
AB  - The metabolism of pamaqueside, a cholesterol absorption inhibitor, was studied in
      the bile duct cannulated and non-cannulated rat after an oral dose (100 mg/kg)
      and an i.v. dose (6 mg/kg) of [14C]pamaqueside. Faeces was the major route of
      excretion in all rat. Only 0.1% of the radioactivity was recovered in the urine
      of the non-cannulated rat. In contrast, approximately 17% of the total dose was
      recovered in the bile and urine in the bile duct cannulated rat. Following an
      i.v. dose, an almost equal percentage of radioactivity was excreted in the bile
      and urine of the bile duct cannulated rat. 3. The aglycone (M1) was the major
      metabolite in rat and was present in greater amounts in the faeces of the bile
      duct cannulated rat. The structural elucidation of metabolites in the bile and
      urine indicated that M1 was metabolized oxidatively via a novel ring opening, and
      the oxidative metabolites further underwent sulphate conjugation. The oxidative
      ring opening of pamaqueside (the cellobioside ring intact) was also observed
      following an i.v. dose to rat suggesting that oxidative ring opening was the
      major route of metabolism of saponins, at least in rat. The study demonstrated
      that the absorption and metabolism of pamaqueside was altered by surgical
      cannulation of rat.

PMID- 10574686
TI  - Glycosylation in Pichia pastoris.

PMID- 10574687
TI  - Glycosylation of Pichia pastoris-derived proteins.
AB  - The Pichia pastoris system for expression of heterologous recombinant proteins is
      being used increasingly because of the large yields of properly folded proteins
      that result and the ease of scaling preparations into large-biomass fermentors.
      Another advantage of this system centres on the type of glycosylation that
      results, generally yielding protein-bound oligosaccharides that are of much
      shorter chain length than found in Saccharomyces cerevisiae. This review is a
      summary of the current state of knowledge of glycosylation of proteins in this
      methylotrophic yeast.

PMID- 10574689
TI  - Photoproduction of L-tryptophan from indole and glycine by Rhodobacter
      sphaeroides OU5.
AB  - A purple non-sulphur anoxygenic phototrophic bacterium Rhodobacter sphaeroides
      could synthesize L-tryptophan from indole and glycine with intermediate formation
      of D,L-alanine and L-serine. Presence of externally supplied keto acids has
      enhanced the rate and yields of L-tryptophan photoproduction.

PMID- 10574688
TI  - Solvent effect on kinetics of appearance of neokyotorphin, VV-haemorphin-4 and a
      bradykinin-potentiating peptide in the course of peptic hydrolysis of bovine
      haemoglobin.
AB  - The kinetics of appearance of bioactive peptides (neokyotorphin, VV-haemorphin-4
      and a bradykinin-potentiating peptide) were investigated in the course of the
      hydrolysis of haemoglobin by pepsin at 23 degrees C in 0.1 M sodium acetate
      buffer at pH 4.5. Isolation of these peptides was performed in one step by C(4)
      reversed-phase HPLC. We have shown that neokyotorphin, and VV-haemorphin-4 are
      two final peptides and that the bradykinin-potentiating peptide is an
      intermediate peptide. At pH 4. 5, LVV-haemorphin-7, VV-haemorphin-7 and VV
      haemorphin-4 appeared successively in the course of the peptic hydrolysis. At pH
      2, the optimum pH of the pepsin hydrolysis, VV-haemorphin-4 was not detected. The
      effect of the composition of the solvent on the peptic hydrolysis was studied to
      improve the preparation of these active peptides. The kinetics of appearance of
      these peptides were compared in the presence of 20% (v/v) ethanol, a stabilizing
      solvent of haemoglobin and in the presence of urea, a denaturant agent. The best
      conditions for preparing neokyotorphin and VV-haemorphin-4 were to achieve the
      peptic reaction in the buffer alone or in the presence of urea at a high degree
      of hydrolysis. For the preparation of the bradykinin-potentiating peptide, the
      hydrolysis of haemoglobin in the urea-containing buffer at a moderate degree of
      hydrolysis of 10% was suitable.

PMID- 10574690
TI  - Physical and biochemical stability of Optison, an injectable ultrasound contrast
      agent.
AB  - Optison(R) is an ultrasound contrast agent, consisting of gas-filled microspheres
      surrounded by a solid shell of heat-denatured human albumin. Size-distribution
      measurements of these microspheres are a critical stability indicating factor,
      because loss of encapsulated gas eliminates ultrasound contrast activity.
      Composition of the encapsulated gas is also critical, because air-filled
      microspheres do not persist nearly as long in vivo as microspheres filled with
      less soluble gases. Optison(R) stability has been tested during exposure to
      chemical substances expected to dissolve microsphere shells. In addition, size
      distribution and gas-composition measurements were used to evaluate the effects
      of external gas composition, elevated temperature, mixing, needle shear and
      pressure on product stability. Optison(R) microsphere shells dissolve only when
      exposed to relatively extreme chemical conditions, such as low pH (<4.0),
      detergents or chaotropic salts. The shells are highly gas-permeable, and
      microspheres lose encapsulated gas rapidly and irreversibly when exposed to gas
      deficient liquids. Pressure, impact stress, and the application of ultrasound
      energy all cause liquids to become gas-deficient, and also cause irreversible gas
      loss. Pressure sensitivity differs dramatically between mixed and unmixed
      microspheres, further supporting the conclusion that gas diffusion is the major
      cause of Optison(R) instability. To preserve the efficacy of Optison(R) as an
      ultrasound contrast agent, it is necessary to devote special attention to
      minimizing opportunities for gas exchange, mixing and exposure to gas-deficient
      liquids, so that the size distribution and gas composition of the original
      product are maintained during handling.

PMID- 10574691
TI  - Butyrylcholinesterase formulated in liposomes.
AB  - Exogenous cholinesterases have the potential to take part in defence against
      organophosphate toxins, by acting as scavenger systems. Postulating that
      formulation in liposomes could enhance the toxin-scavenging potential of these
      enzymes, we have initiated studies of such formulations and are reporting here
      our first steps, exploring butyrylcholinesterase (BChE) in multilamellar
      liposomes composed of phosphatidylcholine. We started by developing an essential
      research tool: a multisample, sensitive and rapid enzyme-activity assay, based on
      the Ellman reaction, that could be performed directly on liposome-containing
      samples. Using an ELISA reader equipped to follow time-dependant absorbency
      changes, 10 min sufficed to assay 96 samples simultaneously. Next, several key
      properties of liposome-formulated BChE were explored and the major findings were:
      (i) the encapsulated enzyme was found to retain its activity. (ii) Enzyme
      activity was found to increase (at constant enzyme concentration) in the presence
      of the lipid, in a lipid-concentration-dependant manner. Through data analysis it
      was possible to attribute this effect to changes in k(cat). (iii) Good,
      reproducible, encapsulation efficiencies (for macromolecules) in the range of 30%
      were obtained at liposome concentrations of 100 mM lipid. (iv) Free BChE was
      completely susceptible to proteolysis under conditions mimicking enzymically
      hostile biological environments, whereas > or = 60% of the liposome-formulated
      BChE was protected, found to be inaccessible to the proteolytic enzymes. (v)
      Short-term exposures of free and liposome-encapsulated BChE to the inhibitor
      paraoxon, generated significant losses in enzyme activity. Residual activities of
      both BChE formulations dropped considerably over the paraoxon concentration range
      of 0.02-0.11 microM, down to 3 and 11% for free and liposome-encapsulated enzyme
      respectively. These data are a clear indication that the encapsulated BChE was
      accessible to the inhibitor, indicating that such liposomal formulations have the
      potential to perform as the desired scavenger systems.

PMID- 10574692
TI  - Immobilization of cholesterol oxidase on Formvar using organic solvents.
AB  - The present study describes a new immobilization support for the preparation of
      enzyme membrane in the presence of organic solvents. The support was composed of
      Formvar solubilization in organic solvents with enzyme. More than 90% of the
      enzyme was immobilized on the membrane. The membrane was prepared by mixing 4%
      Formvar in organic solvents and 1% cholesterol oxidase was immobilized by
      entrapment technique. Practically no leaching of the entrapped enzyme was
      observed. The resultant immobilized enzyme membrane was stored at 4 degrees C for
      10 days without losing its activity. The pH and temperature stabilities were
      greater than those of the native enzyme. The immobilized enzyme membrane has a
      long life due to its hydrophobic nature, as compared with other membranes.

PMID- 10574693
TI  - Expression system for foreign genes using the fission yeast Schizosaccharomyces
      pombe.
AB  - Foreign-gene expression systems using mammalian cells, Escherichia coli, insect
      cells, yeast and other organisms as hosts have been developed. The demand for
      protein-production systems will be further increased in basic research, medical
      science and the biotechnological industry. Systems using the fission yeast
      Schizosaccharomyces pombe as a host have only recently received attention. The
      advantages of this yeast, which is more advanced evolutionarily than other types
      of yeast, the expression vectors available and examples of heterologous protein
      produced with this system, are reviewed here.

PMID- 10574694
TI  - Immobilized lipoxygenase in a packed-bed column bioreactor: continuous
      oxygenation of linoleic acid.
AB  - The continuous oxygenation of linoleic acid (LA) by immobilized lipoxygenase
      (LOX) was studied. Enzymatic oxidation was carried out in a recirculating packed
      column reactor using immobilized LOX as the stationary phase and LA as the
      substrate. The column, when packed with LOX immobilized in either a calcium
      alginate sol-gel matrix or a phyllosilicate sol-gel matrix, is equivalent to five
      continuous stirred tank reactors (CSTRs). The reactor cascade was calculated from
      the residence-time distribution for the reactor. Based on mass-balance
      calculations, a set of mathematical equations for predicting the concentration of
      oxygenated product generated in each CSTR was calculated. Product formation in
      the packed column reactor was simulated and results calculated with the model
      were compared with the experimental results. The data indicated that product
      yield (hydroperoxyoctadecadienoic acid, HPOD) increased asymptotically with
      reaction time. Experimentally, when the bioreactor was packed with calcium
      alginate sol-gel-immobilized LOX, an initial linear increase in HPOD production
      with time was observed, but reached a steady state. For the bioreactor packed
      with phyllosilicate sol-gel-immobilized LOX, initial HPOD production increased
      more rapidly but reached a lower steady-state concentration. From these data, a
      simple computer simulation model was developed to determine the process kinetics
      of this reactor design.

PMID- 10574695
TI  - Purification and characterization of a Pseudomonas sp. lipase and its properties
      in non-aqueous media.
AB  - An extracellular lipase from Pseudomonas sp. was purified to homogeneity by
      extraction, Bio-gel P-10 chromatography and Superose 12B chromatography, and a 37
      fold purification was attained. The purified enzyme showed a single band when it
      was subjected to SDS/PAGE and isoelectric focusing. The SDS/PAGE electrophoresis
      indicated a molecular mass of 30 kDa for this lipase. Its isoelectric point was
      4.5. The optimum pH and temperature for hydrolysis were 7.0-9.0 and 45-60 degrees
      C, respectively. The enzyme was stable between pHs 6 and 12 and below 60 degrees
      C. In the presence of Ca(2+) and Bi(3+), the lipase activity was dramatically
      enhanced by 250% and 154%, respectively. Fe(3+), Fe(2+), Al(3+), Zn(2+) and
      Mn(2+) could inhibit this lipase, but Ag(+) and Pb(2+) showed no influence on
      hydrolysis activity. Properties of purified lipase for lactonization in organic
      solvent were also determined. The purified lipase displayed the characteristic of
      'pH memory' in organic media. This lipase was also thermostable in organic
      solvent with an optimum temperature range from 45 to 60 degrees C. Salt
      dramatically affected the lactonization activity of this lipase.

PMID- 10574696
TI  - Good manufacturing practice (GMP) compliance in the biologics sector: plasma
      fractionation.
AB  - The U.S. blood supply is the safest it has ever been. Due to blood safety and the
      introduction of viral inactivation/clearance technologies, protein therapies
      derived from human blood have also in recent years had a history of product
      safety. Nevertheless, since 1995, the plasma-fractionation industry has
      experienced increased compliance-related actions by the Food and Drug
      Administration (FDA), as shown by a substantive increase in the number of FDA 483
      inspectional observations, FDA warning letters and other FDA regulatory action.
      An evaluation of these trends shows that they reflect the implementation by the
      FDA of increased inspectional interest in the plasma-fractionation industry and
      an evolution of inspectional practices and standards of current good
      manufacturing practice (cGMP). Plasma fractionators have responded to FDA actions
      by carefully evaluating and addressing each inspectional observation, assessing
      impact to product and taking appropriate actions, including corrective actions to
      prevent future occurrence. They have made major investments in facilities,
      quality systems, personnel and training to meet the evolving standards of cGMP
      and in an effort to implement these standards systemically. Through industry
      associations, manufacturers have further enhanced product safety by adopting
      additional voluntary standards for plasma to prevent the entry of potentially
      unsuitable plasma into the production process. The industry remains committed to
      application of cGMP and to working with the FDA in further evolution of these
      standards while striving to assure a continued supply of safe, pure and effective
      plasma-derived therapies.

PMID- 10574697
TI  - Production of carcinoembryonic antigen (CEA) N-A3 domain in Pichia pastoris by
      fermentation.
AB  - Carcinoembryonic antigen (CEA) is a 180-kDa glycoprotein found on the surface of
      normal colon and malignant human adenocarcinomas. Recently, a fusion protein
      containing two of the seven Ig-like domains present in CEA (N and A3) has been
      constructed and expressed in Pichia pastoris [You, Hefta, Yazaki, Wu and Shively
      (1998) Anticancer Res. 18, 3193-3201]. Here, we report the generation and
      selection of a multi-copy clone expressing this fusion protein, the optimization
      of the shake-flask expression protocol and the upscaled production of CEA N-A3
      using fermentation technology. P. pastoris transformants secreting the CEA N-A3
      domain were generated by electrotransformation of the GS115 host strain with the
      pPIC9K vector containing the CEA N-A3 cDNA [You, Hefta, Yazaki, Wu and Shively
      (1998) Anticancer Res. 18, 3193-3201] then screened for CEA N-A3 expression and
      G418 resistance. The recombinant CEA N-A3 domain was detected in the culture
      supernatant using the monoclonal anti-CEA antibody T84.66. Optimization of
      methanol-induction conditions resulted in a high-methanol shake-flask expression
      protocol yielding significantly increased CEA N-A3 levels. Fermentation and
      culture conditions were optimized for 5-l working-volume fermentations and CEA N
      A3 was affinity purified using Ni-IDA (imino di-acetic acid) affinity
      chromatography from the clarified fermentation supernatant. Peptide N-glycosidase
      F treatment revealed that the recombinant protein was heavily glycosylated but
      expressed as a single polypeptide of 28 kDa with no evidence of proteolytic
      degradation. Our results demonstrate that functional CEA N-A3 domain can be
      produced in sufficient quantities in P. pastoris for structural analysis or
      diagnostic applications. To our knowledge, this article represents the first
      report on the production of a human tumour antigen through fermentation.

PMID- 10574698
TI  - Integrin-linked kinase and PINCH: partners in regulation of cell-extracellular
      matrix interaction and signal transduction.
AB  - Integrin-linked kinase (ILK) is a focal adhesion serine/threonine protein kinase
      that is emerging as a key signaling protein functioning at one of the early
      convergence points of integrin- and growth factor-signaling pathways. ILK binds
      to PINCH through the N-terminal ankyrin (ANK) repeat domain and the PINCH binding
      is crucial for focal adhesion localization of ILK. The ILK-PINCH interaction also
      connects ILK to Nck-2, an SH2-SH3-containing adaptor protein that interacts with
      components of growth factor and small GTPase signaling pathways. The kinase
      activity of ILK is regulated by both cell adhesion and growth factors in a
      phosphoinositide 3-kinase (PI3K)-dependent manner. ILK phosphorylates downstream
      targets such as protein kinase B (PKB, also known as Akt) and glycogen synthase
      kinase 3 (GSK-3) and regulates their activities. Overexpression of ILK in
      epithelial cells leads to striking morphological changes mimicking epithelial
      mesenchymal transition, including upregulation of integrin-mediated fibronectin
      matrix assembly and downregulation of cell-cell adhesions. Furthermore, ILK
      regulates nuclear translocation of (beta)-catenin and gene expression, and
      promotes cell cycle progression and tumor formation. Recent genetic studies in
      Drosophila melanogaster and Caenorhabditis elegans have shown that lack of
      expression of ILK or PINCH results in phenotypes resembling those of integrin
      null mutants, which demonstrates that ILK and PINCH are indispensable for
      integrin function during embryonic development.

PMID- 10574699
TI  - Cell adhesion and Rho small GTPases.
AB  - The Rho small GTPases, Cdc42, Rac1 and Rho, are implicated in regulation of
      integrin-mediated cell-substratum adhesion and cadherin-mediated cell-cell
      adhesion. Identification and characterization of effectors of these GTPases have
      provided insights into their modes of action. Rho-kinase, an effector of Rho,
      regulates integrin-mediated cell-substratum adhesion (focal adhesion) by
      regulating the phosphorylation state of myosin light chain (MLC): it directly
      phosphorylates MLC and also inactivates myosin phosphatase. IQGAP1, an effector
      of Cdc42 and Rac1, regulates cadherin-mediated cell-cell adhesion by interacting
      with (beta)-catenin and dissociating (alpha)-catenin from the cadherin-catenins
      complex. Activated Cdc42 and Rac1 inhibit IQGAP1, thereby stabilizing the
      cadherin-catenins complex. Cdc42/Rac1 and IQGAP1 thus appear to constitute a
      switch that regulates cadherin-mediated cell-cell adhesion.

PMID- 10574700
TI  - Domain necessary for Drosophila ELAV nuclear localization: function requires
      nuclear ELAV.
AB  - The neuron specific Drosophila ELAV protein belongs to the ELAV family of RNA
      binding proteins which are characterized by three highly conserved RNA
      recognition motifs, an N-terminal domain, and a hinge region between the second
      and third RNA recognition motifs. Despite their highly conserved RNA recognition
      motifs the ELAV family members are a group of proteins with diverse
      posttranscriptional functions including splicing regulation, mRNA stability and
      translatability and have a variety of subcellular localizations. The role of the
      ELAV hinge in localization and function was examined using transgenes encoding
      ELAV hinge deletions, in vivo. Subcellular localization of the hinge mutant
      proteins revealed that residues between amino acids 333-374 are necessary for
      nuclear localization. This delineated sequence has no significant homology to
      classical nuclear localization sequences, but it is similar to the recently
      characterized nucleocytoplasmic shuttling sequence, the HNS, from a human ELAV
      family member, HuR. This defined sequence, however, was insufficient for nuclear
      localization as tested using hinge-GFP fusion proteins. Functional assays
      revealed that mutant proteins that fail to localize to the nucleus are unable to
      provide ELAV vital function, but their function is significantly restored when
      translocated into the nucleus by a heterologous nuclear localization sequence
      tag.

PMID- 10574701
TI  - CpG methylation reduces genomic instability.
AB  - Hypomethylation of DNA in tumor cells is associated with genomic instability and
      has been suggested to be due to activation of mitotic recombination. We have
      studied the methylation patterns in two 650 kb double minute chromosomes present
      in two mouse tumor cell lines, resistant to methotrexate. Multiple copies of the
      double minute chromosomes amplifying the dihydrofolate reductase gene are present
      in both the cell lines. In one of the cell lines (Mut F), two unmethylated CpG
      islands in the double minute chromosomes are readily cleaved by methylation
      sensitive rare-cutting restriction endonucleases. In the other cell line (Mut C),
      the cleavage sites in the double minute chromosomes are partially methylated and
      resistant to cleavage. The double minute chromosomes with the two unmethylated
      CpG islands undergo rapid dimerization, whereas the double minute chromosomes
      with the partially methylated CpG islands are unchanged in size for over a year
      in continuous culture. The partially methylated CpG islands can be demethylated
      by azacytidine treatment or naturally by extended time in culture, and become
      sensitive to cleavage with the rare-cutting restriction endonucleases. The Mut C
      double minute chromosomes, with the newly demethylated CpG islands, but not the
      double minute chromosomes with the partially methylated CpG islands, undergo
      deletions and dimerizations. These results suggest a role for CpG island
      methylation controlling mitotic recombination between and within large DNA
      molecules.

PMID- 10574702
TI  - Detection of cytokeratin dynamics by time-lapse fluorescence microscopy in living
      cells.
AB  - To monitor the desmosome-anchored cytokeratin network in living cells fusion
      protein HK13-EGFP consisting of human cytokeratin 13 and the enhanced green
      fluorescent protein was stably expressed in vulvar carcinoma-derived A-431 cells.
      It is shown for A-431 subclone AK13-1 that HK13-EGFP emits strong fluorescence in
      fixed and living cells, being part of an extended cytoplasmic intermediate
      filament network that is indistinguishable from that of parent A-431 cells.
      Biochemical, immunological and ultrastructural analyses demonstrate that HK13
      EGFP behaves identically to the endogenous cytokeratin 13 and is therefore a
      reliable in vivo tag for this polypeptide and the structures formed by it. Time
      lapse fluorescence microscopy reveals that the cytokeratin 13-containing network
      is in constant motion, resulting in continuous restructuring occurring in single
      and migratory cells, as well as in desmosome-anchored cells. Two major types of
      movement are distinguished: (i) oscillations of mostly long filaments, and (ii)
      an inward-directed flow of fluorescence originating as diffuse material at the
      cell periphery and moving in the form of dots and thin filaments toward the
      deeper cytoplasm where it coalesces with other filaments and filament bundles.
      Both movements are energy dependent and can be inhibited by nocodazole, but not
      by cytochalasin D. Finally, disassembly and reformation of cytokeratin filament
      networks are documented in dividing cells revealing distinct and rapidly
      occurring stages of cytokeratin organisation and distribution.

PMID- 10574703
TI  - Bile acid secretion and direct targeting of mdr1-green fluorescent protein from
      Golgi to the canalicular membrane in polarized WIF-B cells.
AB  - The bile canalicular membrane contains several ATP-dependent transporters that
      are involved in biliary secretion. Canalicular transporters are synthesized in
      ER, modified in Golgi and transported to the apical plasma membrane. However, the
      route and regulation of intracellular trafficking of ATP-dependent transporters
      have not been elucidated. In the present study, we generated a translational
      fusion of mdr1 and green fluorescent protein and investigated bile acid secretion
      and intracellular trafficking of mdr1 in WIF-B cells, a polarized liver derived
      cell line. Similar to hepatocytes, WIF-B cells secrete bile acids and organic
      cations (i.e. rhodamine-123) into the bile canaliculi. Canalicular secretion of
      fluorescein isothiocyanate-glycocholate was stimulated by taurocholate and a
      decapeptide activator of phosphoinositide 3-kinase and was decreased by
      wortmannin. WIF-B9 cells were transiently and stably transfected with a mdr1-GFP
      construct. Fluorescence was observed in the canalicular membrane, pericanalicular
      punctate structures and Golgi region. Time lapse microscopy revealed that mdr1
      GFP is transferred from Golgi as tubular vesicular structures the majority of
      which traveled directly to the canalicular membrane. Recycling between the
      canalicular membrane and subapical region was also observed. At no time was mdr1
      GFP detected in the basolateral plasma membrane. At 15 degrees C, mdr1-GFP
      accumulated in Golgi; after a shift to 37 degrees C, fluorescence moved directly
      to the canalicular membrane. This process was enhanced by taurocholate and
      blocked by wortmannin. In these studies as well, no mdr1-GFP fluorescence was
      observed at any time in basolateral membranes or other intracellular organelles.
      In conclusion, in WIF-B cells, there is a direct route from Golgi to the
      canalicular membrane for trafficking of mdr1, a bile canalicular ATP-dependent
      transporter of organic cations. As in normal hepatocytes, phosphoinositide 3
      kinase regulates bile acid secretion and intracellular trafficking of mdr1 in WIF
      B cells. WIF-B cells stably transfected with mdr1-GFP provide an important model
      in which to study trafficking and regulation of canalicular transporters. Movies
      available on-line: http://www.healthsci.tufts.edu/LABS/IMArias++ + /Sai_F9.html

PMID- 10574704
TI  - Identification of the putative mammalian orthologue of Sec31P, a component of the
      COPII coat.
AB  - The regulation of intracellular vesicular trafficking is mediated by specific
      families of proteins that are involved in vesicular budding, translocation, and
      fusion with target membranes. We purified a vesicle-associated protein from
      hepatic microsomes using sequential column chromatography and partially sequenced
      it. Oliogonucleotides based on these sequences were used to clone the protein
      from a rat liver cDNA library. The clone encoded a novel protein with a predicted
      mass of 137 kDa (p137). The protein had an N terminus WD repeat motif with
      significant homology to Sec31p, a member of the yeast COPII coat that complexes
      with Sec13p. We found that p137 interacted with mammalian Sec13p using several
      approaches: co-elution through sequential column chromatography, co
      immunoprecipitation from intact cells, and yeast two-hybrid analysis.
      Morphologically, the p137 protein was localized to small punctate structures in
      the cytoplasm of multiple cultured cell lines. When Sec13p was transfected into
      these cells, it demonstrated considerable overlap with p137. This overlap was
      maintained through several pharmacological manipulations. The p137 compartment
      also demonstrated partial overlap with ts045-VSVG protein when infected cells
      were incubated at 15 degrees C. These findings suggest that p137 is the mammalian
      orthologue of Sec31p.

PMID- 10574705
TI  - TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to
      mesenchymal transdifferentiation in NMuMG breast epithelial cells.
AB  - The capacities of different transforming growth factor-(beta) (TGF-(beta))
      superfamily members to drive epithelial to mesenchymal transdifferentiation of
      the murine mammary epithelial cell line NMuMG were investigated. TGF-(beta)1, but
      not activin A or osteogenic protein-1 (OP-1)/bone morphogenetic protein-7 (BMP
      7), was able to induce morphological transformation of NMuMG cells as shown by
      reorganisation of the actin cytoskeleton and relocalisation/downregulation of E
      cadherin and (beta)-catenin, an effect that was abrogated by the more general
      serine/threonine kinase and protein kinase C inhibitor, staurosporine. TGF
      (beta)1 bound to TGF-(beta) type I receptor (T(beta)R-I)/ALK-5 and T(beta)R-II,
      but not to activin type I receptor (ActR-I)/ALK-2. Activin A bound to ActR-IB/ALK
      4 and ActR-II, and BMP-7 bound to ActR-I/ALK-2, BMP type I receptor (BMPR-I)/ALK
      3, ActR-II and BMPR-II. TGF-(beta)1 and BMP-7 activated the Smad-binding element
      (SBE)(4) promoter with equal potency, whereas activin A had no effect.
      Transfection of constitutively active (CA)-ALK-4 activated the 3TP promoter to
      the same extent as TGF-(beta)1 and CA-ALK-5 indicating that activin signalling
      downstream of type I receptors was functional in NMuMG cells. In agreement with
      this, activin A induced low levels of plasminogen activator inhibitor I
      expression compared to the high induction by TGF-(beta)1. In contrast to activin
      A and BMP-7, TGF-(beta)1 strongly induced Smad2 phosphorylation. Consistent with
      these findings, TGF-(beta)1 induced the nuclear accumulation of Smad2 and/or
      Smad3. In addition, NMuMG cells transiently infected with adenoviral vectors
      expressing high level CA-ALK-5 exhibited full transdifferentiation. On the other
      hand, infections with low level CA-ALK-5, which alone did not result in
      transdifferentiation, together with Smad2 and Smad4, or with Smad3 and Smad4 led
      to transdifferentiation. In conclusion, TGF-(beta)1 signals potently and passes
      the activation threshold to evoke NMuMG cell transdifferentiation. The TGF-(beta)
      type I receptor (ALK-5) and its effector Smad proteins mediate the epithelial to
      mesenchymal transition. Activin A does not induce mesenchymal transformation,
      presumably because the number of activin receptors is limited, while BMP-7
      initiated signalling cannot mediate transdifferentiation.

PMID- 10574706
TI  - Inhibition of cadherin function differentially affects markers of terminal
      differentiation in cultured human keratinocytes.
AB  - Cadherin function is required for normal keratinocyte intercellular adhesion and
      stratification. In the present study, we have investigated whether cadherin
      cadherin interactions may also modulate keratinocyte differentiation, as
      evidenced by alterations in the levels of several differentiation markers.
      Confluent keratinocyte cultures, propagated in low Ca(2+) medium in which
      cadherins are not active, were pre-incubated with antibodies that block the
      function of E-cadherin and/or P-cadherin; Ca(2+ )was then elevated to 1 mM to
      activate the cadherins and induce differentiation. In control cultures (incubated
      with no antibody or with antibodies to other cell surface molecules), Ca(2+)
      elevation induced an increase in type 1 transglutaminase, profilaggrin, and
      loricrin, as measured by western blotting and in agreement with previous results.
      However, the concurrent addition of antibodies against both E- and P-cadherin
      prevented this increase in transglutaminase 1 protein. Incubation with either
      antibody alone had no consistent effect. Profilaggrin and loricrin, which are
      later markers of keratinocyte differentiation, responded differently from
      transglutaminase 1 to addition of antibodies. In the presence of anti-E-cadherin
      antibody, both loricrin and profilaggrin levels were dramatically enhanced
      compared to the high Ca(2+) control cells, while addition of antibody to P
      cadherin slightly attenuated the Ca(2+)-induced increase. In the presence of both
      antibodies, loricrin and profilaggrin protein levels were intermediate between
      those observed in the presence of either antibody alone. The expression of
      involucrin, however, was unaffected by addition of antibodies. In addition,
      effects of the anti-cadherin antibodies were not secondary to alterations in
      proliferation or programmed cell death, as determined by several independent
      assays of these processes. Thus, the consequences of cadherin inhibition depend
      upon both the particular cadherin and the differentiation marker under study.
      Taken together, these data suggest that E-cadherin and P-cadherin contribute to
      the orderly progression of terminal differentiation in the epidermis in multiple
      ways.

PMID- 10574707
TI  - Cell cycle regulation of PML modification and ND10 composition.
AB  - The nuclear sub-structures known as ND10, PODs or PML nuclear bodies can be
      rapidly modified by diverse stimuli, and the resultant structural changes
      correlate with events such as cellular transformation and successful virus
      infection. We show that the ND10 components PML and Sp100 undergo profound
      biochemical changes during the cell cycle. Both proteins are conjugated to the
      ubiquitin-like protein SUMO-1 during interphase, but they become de-conjugated
      during mitosis and an isoform of PML of distinct electrophoretic mobility
      appears. This mitosis-specific form of PML is highly labile in vitro, but is
      partially stabilised by phosphatase inhibitors. Treatment of interphase cells
      with phosphatase inhibitors induces the production of a PML isoform of similar
      gel mobility to the mitosis-specific species, and taken together these results
      suggest that phosphorylation is an important factor in the differential
      modification of PML during the cell cycle. PML and Sp100 normally tightly co
      localise in ND10 in interphase cells, but they become separated during mitosis.
      Interphase cells treated with phosphatase inhibitors or subjected to heat shock
      also show structural changes in ND10, accompanied by alterations to the normal
      pattern of PML modification. Taken with previous findings on the effects of
      infection by herpes simplex virus and adenovirus on ND10 structure and PML
      modification, these results suggest that the many factors which have been shown
      to modify ND10 structure may do so by interaction with the biochemical mechanisms
      that act on ND10 components during the cell cycle.

PMID- 10574708
TI  - Integrin-linked kinase is localized to cell-matrix focal adhesions but not cell
      cell adhesion sites and the focal adhesion localization of integrin-linked kinase
      is regulated by the PINCH-binding ANK repeats.
AB  - Integrin-linked kinase (ILK) is a ubiquitously expressed protein serine/threonine
      kinase that has been implicated in integrin-, growth factor- and Wnt-signaling
      pathways. In this study, we show that ILK is a constituent of cell-matrix focal
      adhesions. ILK was recruited to focal adhesions in all types of cells examined
      upon adhesion to a variety of extracellular matrix proteins. By contrast, ILK was
      absent in E-cadherin-mediated cell-cell adherens junctions. In previous studies,
      we have identified PINCH, a protein consisting of five LIM domains, as an ILK
      binding protein. We demonstrate in this study that the ILK-PINCH interaction
      requires the N-terminal-most ANK repeat (ANK1) of ILK and one (the C-terminal) of
      the two zinc-binding modules within the LIM1 domain of PINCH. The ILK ANK repeats
      domain, which is capable of interacting with PINCH in vitro, could also form a
      complex with PINCH in vivo. However, the efficiency of the complex formation or
      the stability of the complex was markedly reduced in the absence of the C
      terminal domain of ILK. The PINCH binding defective ANK1 deletion ILK mutant,
      unlike the wild-type ILK, was unable to localize and cluster in focal adhesions,
      suggesting that the interaction with PINCH is necessary for focal adhesion
      localization and clustering of ILK. The N-terminal ANK repeats domain, however,
      is not sufficient for mediating focal adhesion localization of ILK, as an ILK
      mutant containing the ANK repeats domain but lacking the C-terminal integrin
      binding site failed to localize in focal adhesions. These results suggest that
      focal adhesions are a major subcellular compartment where ILK functions in
      intracellular signal transduction, and provide important evidence for a critical
      role of PINCH and integrins in regulating ILK cellular function.

PMID- 10574710
TI  - Vimentin contributes to human mammary epithelial cell migration.
AB  - Vimentin expression in human mammary epithelial MCF10A cells was examined as a
      function of their migratory status using an in vitro wound-healing model.
      Analysis of the trajectories of the cells and their migratory speeds by time
      lapse-video microscopy revealed that vimentin mRNA and protein expression were
      exclusively induced in cells at the wound's edge which were actively migrating
      towards the center of the lesion. Actin labeling showed the reorganization of
      actin filaments in cells at the wound's edge which confirmed the migratory
      phenotype of this cell subpopulation. Moreover, the vimentin protein disappeared
      when the cells became stationary after wound closure. Using cells transfected
      with the vimentin promoter controlling the green fluorescent protein gene, we
      also demonstrated the specific activation of the vimentin promoter in the
      migratory cells at the wound's edge. Transfection of the antisense vimentin cDNA
      into MCF10A cells clearly reduced both their ability to express vimentin and
      their migratory speed. Taken together, these observations demonstrate that
      vimentin is transiently associated with, and could be functionally involved in,
      the migratory status of human epithelial cells.

PMID- 10574709
TI  - Identification of PA2.26 antigen as a novel cell-surface mucin-type glycoprotein
      that induces plasma membrane extensions and increased motility in keratinocytes.
AB  - PA2.26 antigen was identified as a cell-surface protein induced in epidermal
      carcinogenesis and skin remodeling processes. PA2.26 is expressed in carcinoma
      cell lines and cultured fibroblasts but absent in nontumorigenic keratinocytes.
      In tissues, PA2.26 is present in epithelial cells of the choroid plexus,
      ependyma, glomerulus and alveolus, in mesothelial cells, and in endothelia of
      lymphatic vessels. Biochemical characterization of PA2.26 protein and sequence
      analysis of the isolated cDNA demonstrate that PA2.26 antigen is a mucin-like
      transmembrane glycoprotein. Confocal and immunoelectron microscopy analysis in
      cultured cells reveal that PA2. 26 is concentrated in actin-rich microvilli and
      plasma membrane projections, such as filopodia, lamellipodia and ruffles, where
      it colocalizes with members of the ERM (ezrin, radixin, moesin) family protein.
      Ezrin and moesin, but not radixin, can be coimmunoprecipitated together with
      PA2.26 from cell lysates. Ectopic expression of PA2.26 in immortalized,
      nontumorigenic, keratinocytes induces an epithelial-fibroblastoid morphological
      conversion with increased plasma membrane extensions, concomitantly to a major
      reorganization of the actin cytoskeleton, redistribution of ezrin to cell-surface
      projections, and enhanced motility. These findings suggest an involvement of
      PA2.26 in cell migration.

PMID- 10574712
TI  - Evidence for novel cell cycle checkpoints in trypanosomes: kinetoplast
      segregation and cytokinesis in the absence of mitosis.
AB  - Trypanosoma brucei has a single nucleus and a single kinetoplast (the
      mitochondrial genome). Each of these organelles has a distinct S phase, which is
      followed by a segregation period, prior to cell division. The segregation of the
      two genomes takes place in a specific temporal order by interaction with
      microtubule-based structures, the spindle for nuclear DNA and the flagellum basal
      bodies for the kinetoplast DNA. We used rhizoxin, the anti-microtubule agent and
      polymerisation inhibitor, or the nuclear DNA synthesis inhibitor aphidicolin, to
      interfere with cell cycle events in order to study how such events are co
      ordinated. We show that T. brucei cytokinesis is not dependent upon either
      mitosis or nuclear DNA synthesis, suggesting that there are novel cell cycle
      checkpoints in this organism. Moreover, use of monoclonal antibodies to reveal
      cytoplasmic events such as basal body duplication shows that some aphidicolin
      treated cells appear to be in G(1) phase (1K1N) but have activated some
      cytoplasmic events characteristic of G(2) phase (basal body segregation). We
      discuss a possible dominant role in trypanosomes for kinetoplast/basal body
      segregation in control of later cell cycle events such as cytokinesis

PMID- 10574711
TI  - Chromatin-association of the Polycomb group protein BMI1 is cell cycle-regulated
      and correlates with its phosphorylation status.
AB  - The human proto-oncogene Bmi1 is a member of the mammalian Polycomb Group (Pc-G)
      genes. The subnuclear distribution of the BMI1 protein was studied in several
      primary human and tumor-derived cell lines using immunohistochemical and
      biochemical methods. In primary and tumor cells, nuclear BMI1 shows a fine-grain
      distribution over chromatin, usually dense in interphase nuclei and significantly
      weaker along mitotic chromosomes. In addition, BMI1 preferentially associates
      with several distinct heterochromatic domains in tumor cell lines. In both
      primary and tumor cell lines a marked cell cycle-regulation of Pc-G-chromatin
      interaction is observed: nuclear BMI1-staining dissipates in late S phase and is
      re-established early in G(1)-phase. Chromatin-association of BMI1 inversely
      correlates with its phosphorylation status in a cell cycle-dependent fashion: at
      G(1)/S, hypophosphorylated BMI1 is specifically retained in the chromatin
      associated nuclear protein fraction, whereas during G(2)/M, phosphorylated BMI1
      is not chromatin-bound. Our findings indicate a strict cell cycle-controlled
      regulation of Pc-G complex-chromatin association and provide molecular tools for
      improving our understanding of Pc-G complex regulation and function in mammalian
      cells.

PMID- 10574713
TI  - Colocalization of intranuclear lamin foci with RNA splicing factors.
AB  - The lamins form a fibrous network underlying the inner nuclear membrane termed
      the nuclear lamina. In order to gain insights into the role of lamins in nuclear
      organization, we have characterized a monoclonal antibody (LA-2H10) raised
      against recombinant rat lamin A that labels nuclei in a speckled pattern in all
      cells of unsynchronized populations of HeLa and rat F-111 fibroblast cells,
      unlike the typical nuclear periphery staining by another monoclonal antibody to
      lamin A, LA-2B3. In immunolocalization studies the lamin A speckles or foci were
      found to colocalize with the RNA splicing factors SC-35 and U5-116 kD, but not
      with p80 coilin found in coiled bodies. Lamin B1 was also associated with these
      foci. These foci dispersed when cells entered mitosis and reformed during
      anaphase. The differential reactivity of LA-2H10 and LA-2B3 was retained after
      nuclei were extracted with detergents, nucleases and salt to disrupt interactions
      of lamins with chromatin and other nuclear proteins. Using deletion fragments of
      recombinant lamin A, the epitope recognized by LA-2H10 was located between amino
      acids 171 and 246. Our findings are consistent with a structural role for lamins
      in supporting nuclear compartments containing proteins involved in RNA splicing.

PMID- 10574714
TI  - Reduced expression of (alpha)5(beta)1 integrin prevents spreading-dependent cell
      proliferation.
AB  - Cell adhesion to substratum results in the initiation of integrin signaling and
      an integrin-dependent organization of the cytoskeleton (cell spreading). To
      address the potential relationships between these events and cell proliferation,
      we transfected NRK fibroblasts with an antisense cDNA encoding a 1.3 kb ATG
      spanning portion of (alpha)5 integrin subunit and obtained stable clones in which
      the surface expression of (alpha)5(beta)1 integrin was selectively reduced.
      (alpha)5-antisense NRK cells are less spread than the control transfectants, have
      poorly defined stress fibers, and an increased amount of cortical actin. The
      antisense clones remained anchorage-dependent, but they proliferated very slowly.
      Serum dose-response curves showed that they have an impaired response to
      mitogens. Importantly, cell spreading and stress fiber formation could be
      completely restored by plating the antisense cells on collagen, but cell
      spreading failed to rescue proliferation. These data indicate that cell spreading
      can be uncoupled from cell proliferation and that cytoskeletal organization is
      important for NRK cell proliferation because it enforces the proliferative effect
      of (alpha)5(beta)1 integrin. Our results also indicate that reduced surface
      expression of (alpha)5(beta)1 integrin is not sufficient to confer the anchorage
      independent phenotype to nontransformed cells.

PMID- 10574715
TI  - Dynamic association of cytoplasmic dynein heavy chain 1a with the Golgi apparatus
      and intermediate compartment.
AB  - Microtubule motors, such as the minus end-directed motor, cytoplasmic dynein,
      play an important role in maintaining the integrity, intracellular location, and
      function of the Golgi apparatus, as well as in the translocation of membrane
      between the endoplasmic reticulum and Golgi apparatus. We have immunolocalised
      conventional cytoplasmic dynein heavy chain to the Golgi apparatus in cultured
      vertebrate cells. In addition, we present evidence that cytoplasmic dynein heavy
      chain cycles constitutively between the endoplasmic reticulum and Golgi
      apparatus: it colocalises partially with the intermediate compartment, it is
      found on nocodazole-induced peripheral Golgi elements and, most strikingly, on
      Brefeldin A-induced tubules that are moving towards microtubule plus ends. The
      direction of movement of membrane between the endoplasmic reticulum and Golgi
      apparatus is therefore unlikely to be regulated by controlling motor-membrane
      interactions: rather, the motors probably remain bound throughout the whole
      cycle, with their activity being modulated instead. We also report that the
      overexpression of p50/dynamitin results in the loss of cytoplasmic dynein heavy
      chain from the membrane of peripheral Golgi elements. These results explain how
      dynamitin overexpression causes the inhibition of endoplasmic reticulum-to-Golgi
      transport complex movement towards the centrosomal region, and support the
      general model that an intact dynactin complex is required for cytoplasmic dynein
      binding to all cargoes.

PMID- 10574716
TI  - Characterization of a coiled coil protein present in the basal body of
      Trypanosoma brucei.
AB  - TBBC (for Trypanosoma brucei basal body component) is a unique gene transcribed
      in a 4.8 kb mRNA encoding a 1,410 amino acid protein that consists almost
      entirely of a coiled coil structure. This protein appeared to localize in the
      basal body, with an accessory presence at the posterior end of the cell, the
      nucleus and over the flagellum. Since the two other known components of the
      trypanosome basal body are (gamma)-tubulin and an uncharacterized component
      termed BBA4 we performed double immunofluorescence experiments with anti-TBBC and
      either anti-BBA4 or anti-(gamma)-tubulin antibodies. These three components did
      not colocalize but were very closely associated, BBA4 being the most proximal to
      the kinetoplast DNA. Anti-TBBC antibodies detected a 170 kDa protein in western
      blots of total HeLa cell extracts. Moreover, these antibodies stained the
      centriole of HeLa and COS cells as well as the centriole of mouse spermatozoa,
      indicating that a TBBC-like centriolar component has been conserved during the
      evolution of eukaryotes.

PMID- 10574717
TI  - Characterisation of the tumour necrosis factor (TNF)-(alpha) response elements in
      the human ICAM-2 promoter.
AB  - ICAM-2 is a cell surface adhesion molecule constitutively expressed on the
      endothelium, involved in leukocyte recruitment into tissues. We recently showed
      that pro-inflammatory cytokines tumour necrosis factor (TNF)-(alpha) and
      interleukin (IL)-1(beta) down-regulate ICAM-2 expression at the transcriptional
      level. Here we investigate the elements in the ICAM-2 promoter required for the
      TNF-(alpha)-mediated down-regulation. Site directed mutagenesis of the ICAM-2
      promoter implicated three consensus sites for Ets transcription factors in basal
      activity; two of these sites were also involved in the TNF-(alpha)-induced down
      regulation. Electrophoretic mobility shift assays (EMSA) performed in human
      umbilical vein endothelial cells (HUVEC) showed that all three Ets binding sites
      (EBS) bind nuclear proteins. TNF-(alpha) treatment (10 ng/ml for 24 hours)
      decreased binding to the double -135/-127EBS, but not to the -44EBS. The Ets
      family member Erg was found to be constitutively expressed in HUVEC, and TNF
      (alpha) down-regulated Erg protein levels. Furthermore, an Erg cDNA
      transactivated the ICAM-2 promoter when transiently transfected into both HeLa
      cells and HUVEC. Protein expression of ICAM-2 and Erg was found to be similarly
      regulated by TNF-(alpha) in an ex vivo artery model. These data suggest that
      constitutive endothelial genes ICAM-2 and Erg are on the same pathway of cytokine
      dependent regulation of gene expression.

PMID- 10574718
TI  - Isolation and characterization of monoclonal antibodies directed against novel
      components of macrophage phagosomes.
AB  - In order to identify novel proteins associated with various stages of macrophage
      phagocytosis, we have generated monoclonal antibodies that recognize phagosomes.
      Purified Fc receptor-mediated phagosomes, isolated by feeding IgG-conjugated
      magnetic beads to LPS-primed murine peritoneal macrophages, were used as the
      immunogen. An immunofluorescence screen was used to isolate and single-cell clone
      approximately 150 monoclonal antibodies that recognize mouse macrophage
      phagosomes as well as labeling other cellular components in patterns which are
      frequently distinct from those observed with previously characterized phagosome
      associated proteins. Predominant morphological categories (in addition to
      phagosome labeling) include staining of one or more of the following:
      cytoskeletal patterns, vesicular patterns and plasma membrane localization. In
      this paper, we describe the antibody screen, preliminary characterization of the
      antibodies and our identification of the antigens for three representative
      monoclonal antibodies. These antibodies identify a plasma membrane associated
      receptor (Mac-1, a subunit of the complement receptor), an actin binding protein
      (coronin-2) and a vesicular protein (amphiphysin II). Some of the antibodies
      recognize many cell types, whereas other antibodies are apparently macrophage
      specific as assessed by flow cytometry and histology. Remarkably, several of the
      antibodies cross-react with the phagocytic slime mold, Dictyostelium discoideum,
      recognizing phagosomes and other cellular elements as assessed by
      immunofluorescence and immunoblots. These results indicate that macrophage
      phagocytosis has both conserved ancestral features and unique specialized aspects
      associated with the role of these phagocytes in immunity.

PMID- 10574719
TI  - Adhesion and migration of avian neural crest cells on fibronectin require the
      cooperating activities of multiple integrins of the (beta)1 and (beta)3 families.
AB  - Based on genetic, functional and histological studies, the extracellular matrix
      molecule fibronectin has been proposed to play a key role in the migration of
      neural crest cells in the vertebrate embryo. In the present study, we have
      analyzed in vitro the repertoire and function of integrin receptors involved in
      the adhesive and locomotory responses of avian truncal neural crest cells to
      fibronectin. Immunoprecipitation experiments showed that neural crest cells
      express multiple integrins, namely (alpha)3(beta)1, (alpha)4(beta)1,
      (alpha)5(beta)1, (alpha)8(beta)1, (alpha)v(beta)1, (alpha)v(beta)3 and a (beta)8
      integrin, as potential fibronectin receptors, and flow cytometry analyses
      revealed no major heterogeneity among the cell population for expression of
      integrin subunits. In addition, the integrin repertoire expressed by neural crest
      cells was found not to change dramatically during migration. At the cellular
      level, only (alpha)v(beta)1 and (alpha)v(beta)3 were concentrated in focal
      adhesion sites in connection with the actin microfilaments, whereas the other
      integrins were predominantly diffuse over the cell surface. In inhibition assays
      with function-perturbing antibodies, it appeared that complete abolition of cell
      spreading and migration could be achieved only by blocking multiple integrins of
      the (beta)1 and (beta)3 families, suggesting possible functional compensations
      between different integrins. In addition, these studies provided evidence for
      functional partitioning of integrins in cell adhesion and migration. While
      spreading was essentially mediated by (alpha)v(beta)1 and (alpha)8(beta)1,
      migration involved primarily (alpha)4(beta)1, (alpha)v(beta)3 and (alpha)8(beta)1
      and, more indirectly, (alpha)3(beta)1. (alpha)5(beta)1 and the (beta)8 integrin
      were not found to play any major role in either adhesion or migration. Finally,
      consistent with the results of inhibition experiments, recruitment of
      (alpha)4(beta)1 and (alpha)v(beta)3, individually or in combination using
      antibodies or recombinant VCAM-1 and PECAM-1 molecules as a substratum, was
      required for migration but was not sufficient to produce migration of the cell
      population as efficiently as with fibronectin. In conclusion, our study indicates
      that neural crest cells express a multiplicity of fibronectin-binding integrins
      and suggests that dispersion of the cell population requires cooperation between
      distinct integrins regulating different events of cell adhesion, locomotion and,
      possibly, proliferation and survival.

PMID- 10574720
TI  - Abnormal synapse formation in agrin-depleted hippocampal neurons.
AB  - Agrin, a 200 kDa extracellular matrix protein, participates in the maturation of
      the postsynaptic target at the neuromuscular junction. Although agrin has also
      been detected in central neurons, little is known about its role in the formation
      of their synapses. In the present study, the pattern of expression, localization
      and function of agrin in developing hippocampal neurons were analyzed. The
      results indicate that an increase in agrin protein levels precedes synaptogenesis
      in cultured hippocampal neurons. This increase in agrin expression is accompanied
      by its extracellular deposition along the distal third of the axon. To
      investigate whether agrin plays a role during synapse formation, its expression
      in cultured hippocampal neurons was suppressed by means of antisense
      oligonucleotide treatment. The suppression of agrin expression results in the
      impairment of dendritic development and the formation of fewer synapses than in
      non-treated or sense-treated neurons. Moreover, this decreased synaptic density
      is accompanied by a selective inhibition of the clustering of GABA receptors.
      These results lead to the conclusion that agrin may be an important regulator of
      the maturation of dendrites and synaptogenesis in central neurons.

PMID- 10574721
TI  - A potential role for the plasmin(ogen) system in the posttranslational cleavage
      of the neural cell adhesion molecule L1.
AB  - L1 is a neural recognition molecule that promotes neural developmental and
      regenerative processes. Posttranslational cleavage of L1 is believed to be
      important for regulating its function in vivo, but little is known of the
      proteolytic systems responsible. In this study we present evidence that plasmin
      can regulate both L1 expression and function. The addition of plasmin to cell
      lines results in a dose-dependent loss of surface L1 expression, with the
      simultaneous appearance of soluble L1 species. The addition of plasminogen to
      primary neurons and melanoma cells also resulted in the generation of plasmin and
      the concomitant release of L1. One product of plasmin-mediated cleavage is an
      amino-terminal fragment of approximately 140 kDa that has been previously
      described as a natural posttranslational cleavage product in vivo. This fragment
      was confirmed to result from cleavage at two sites in the middle of the third
      fibronectin-like domain of L1. Cleavage at a further site, proximal to the
      transmembrane domain of L1, was also observed at higher plasmin concentrations.
      Plasmin was further confirmed to abrogate homophilic L1 interactions required for
      cellular aggregation. Based on these findings we propose that plasmin is likely
      to be an important regulator of L1-mediated processes including those documented
      in the nervous system.

PMID- 10574722
TI  - Integrin subunits (beta)1C-1 and (beta)1C-2 expressed in GD25T cells are retained
      and degraded intracellularly rather than localised to the cell surface.
AB  - We have previously identified the integrin (beta)1C-2 and characterised the
      distribution of (beta)1C-1 and (beta)1C-2 transcripts in various cell lines and
      normal cells. In this study we have investigated the expression of the two
      (beta)1C-variants in integrin (beta)1 deficient mouse GD25T cells. After stable
      transfection of the GD25T cells with cDNAs coding for (beta)1A, (beta)1C-1 and
      (beta)1C-2, the cell surface expression of the (beta)1C-1 and (beta)1C-2 variants
      was found to be very low while the (beta)1A variant was expressed at high levels.
      Northern blot analysis showed that the level of (beta)1-transcript in the
      (beta)1C-1 and (beta)1C-2 clones was equal or higher than in the (beta)1A clones.
      Metabolic labelling and deglycosylation by endoglycosidase H treatment clearly
      demonstrated that the majority of the (beta)1C-1 and (beta)1C-2 chains did not
      become maturely glycosylated, nor did they dimerize with (alpha) subunits. After
      20 hours of chase, the labelled (beta)1C-1 and (beta)1C-2 chains had been
      gradually degraded, whereas immature (beta)1A was converted into the maturely
      glycosylated form during the same period of time. Immunostaining showed
      intracellular (beta)1 localisation in the (beta)1C-1 and (beta)1C-2 expressing
      clones, while in the (beta)1A expressing clones the (beta)1 chains were mainly
      localised to focal adhesion sites and along fibronectin fibres. Taken together,
      we have shown that expression of both integrin (beta)1C-1 and (beta)1C-2 in GD25T
      cells result in very low cell surface expression compared with the normal
      (beta)1A isoform. Instead, both (beta)1C-1 and (beta)1C-2 chains remain in the
      endoplasmic reticulum until they are intracellularly degraded.

PMID- 10574723
TI  - Involvement of Rho GTPases in calcium-regulated exocytosis from adrenal
      chromaffin cells.
AB  - The Rho GTPase family, including Rho, Rac and Cdc42 proteins, is implicated in
      various cell functions requiring the reorganization of actin-based structures. In
      secretory cells, cytoskeletal rearrangements are a prerequisite for exocytosis.
      We previously described that, in chromaffin cells, the trimeric granule-bound Go
      protein controls peripheral actin and prevents exocytosis in resting cells
      through the regulation of RhoA. To provide further insight into the function of
      Rho proteins in exocytosis, we focus here on their intracellular distribution in
      chromaffin cells. By confocal immunofluorescence analysis, we found that Rac1 and
      Cdc42 are exclusively localized in the subplasmalemmal region in both resting and
      nicotine-stimulated cells. In contrast, RhoA is associated with the membrane of
      secretory granules. We then investigated the effects of clostridial toxins, which
      differentially impair the function of Rho GTPases, on the subplasmalemmal actin
      network and catecholamine secretion. Clostridium difficile toxin B, which
      inactivates Rho, Rac and Cdc42, markedly altered the distribution of peripheral
      actin filaments. Neither Clostridium botulinum C3 toxin, which selectively ADP
      ribosylates Rho, nor Clostridium sordellii lethal toxin, which inactivates Rac,
      affected cortical actin, suggesting that Cdc42 plays a specific role in the
      organization of subplasmalemmal actin. Indeed, toxin B strongly reduced
      secretagogue-evoked catecholamine release. This effect on secretion was not
      observed in cells having their actin cytoskeleton depolymerized by cytochalasin E
      or Clostridium botulinum C2 toxin, suggesting that the inhibition of secretion by
      toxin B is entirely linked to the disorganization of actin. C. sordellii lethal
      toxin also inhibited catecholamine secretion, but this effect was not related to
      the actin cytoskeleton as seen in cells pretreated with cytochalasin E or C2
      toxin. In contrast, C3 exoenzyme did not affect secretion. We propose that Cdc42
      plays an active role in exocytosis by coupling the actin cytoskeleton to the
      sequential steps underlying membrane trafficking at the site of exocytosis.

PMID- 10574724
TI  - Biochemical analysis of distinct Rab5- and Rab11-positive endosomes along the
      transferrin pathway.
AB  - Rab GTPases are associated with distinct cellular compartments and function as
      specific regulators of intracellular transport. In the endocytic pathway, it is
      well documented that Rab5 regulates transport from plasma membrane to early
      (sorting) endosomes. In contrast, little is known about the precise localization
      and function of Rab4 and Rab11, which are believed to control endocytic
      recycling. In the present study we have analysed the protein composition of Rab5-
      and Rab11-carrying endosomes to gain further insight into the compartmental
      organization of the endocytic and recycling pathway. Endosome populations of this
      transport route were purified by immunoadsorption from endosome-enriched
      subcellular fractions using antibodies directed against the cytoplasmic tail of
      the transferrin receptor, Rab5 or Rab11. Endocytosed transferrin moved
      sequentially through compartments that could be immunoadsorbed with anti-Rab5 and
      anti-Rab11, consistent with the theory that Rab5 and Rab11 localise to sorting
      and recycling endosomes, respectively. These compartments exhibited morphological
      differences, as determined by electron microscopy. Although their overall protein
      compositions were very similar, some proteins were found to be selectively
      enriched. While Rab4 was present on all endosome populations, Rab5 and Rab11 were
      strikingly segregated. Furthermore, the Rab11-positive endosomes were rich in
      annexin II, actin and the t-SNARE syntaxin 13, compared to Rab5-containing
      endosomes. In an in vitro assay, the Rab5 effector protein EEA1 was
      preferentially recruited by Rab5-positive endosomes. Taken together, our data
      suggest an organization of the transferrin pathway into distinct Rab5- and Rab11
      positive compartments.

PMID- 10574725
TI  - Induction of DNA replication by peroxisome proliferators is independent of both
      tumour necrosis factor (alpha) priming and EGF-receptor tyrosine kinase activity.
AB  - Peroxisome proliferators (PPs) cause hepatocyte proliferation and tumorigenesis
      in rodent liver. PPs induce hepatocyte DNA synthesis although the mechanism is
      unclear. Tumour necrosis factor (alpha) (TNF(alpha)) and epidermal growth factor
      (EGF) have been implicated in mediating this growth response since these factors
      induce a threefold and 17.2-fold increase, respectively, in DNA synthesis in rat
      primary hepatocyte cultures. Previously, others have suggested that TNF(alpha)
      acts as a primer to sensitise hepatocytes to the proliferative effects of growth
      factors. Indeed, here we show that costimulation with TNF(alpha) and a suboptimal
      (4-20% of optimal) concentration of EGF permits an 11.7-fold increase in DNA
      synthesis in rat primary hepatocyte cultures. The PP nafenopin induced a 2. 3
      fold increase in DNA synthesis but there was no further increase upon co
      administration of either TNF(alpha) or a suboptimal concentration of EGF.
      Furthermore, there was no gross dysregulation of the CDK and cyclin protein
      expression profile upon stimulation with nafenopin. Using a specific epidermal
      growth factor receptor tyrosine kinase inhibitor (4-(3-chloro-4
      fluorophenylamino)-7-methoxy-6- (3-?1-pyrolidino)-propoxyquinazoline, EGFR-TKI),
      we show that signalling through EGF-R is not required for nafenopin-induced DNA
      synthesis. The EGFR-TKI also prevented progression into S phase upon stimulation
      with TNF(alpha), but DNA synthesis was not reduced to control levels, indicating
      that TNF(alpha) has a mitogenic activity in the absence of EGF signalling.
      Therefore, although TNF(alpha) can act as a priming factor for growth factors
      such as EGF, nafenopin does not appear to act via this mechanism.

PMID- 10574726
TI  - Association of AP1 adaptor complexes with GLUT4 vesicles.
AB  - Nycodenz gradients have been used to examine the in vitro effects of GTP-(gamma)
      S on adaptor complex association with GLUT4 vesicles. On addition of GTP-(gamma)
      S, GLUT4 fractionates as a heavier population of vesicles, which we suggest is
      due to a budding or coating reaction. Under these conditions there is an increase
      in co-sedimentation of GLUT4 with AP1, but not with AP3. Western blotting of
      proteins associated with isolated GLUT4 vesicles shows the presence of high
      levels of AP1 and some AP3 but very little AP2 adaptor complexes. Cell free, in
      vitro association of the AP1 complex with GLUT4 vesicles is increased
      approximately 4-fold by the addition of GTP-(gamma)-S and an ATP regenerating
      system. Following GTP-(gamma)-S treatment in vitro, ARF is also recruited to
      GLUT4 vesicles, and the temperature dependence of ARF recruitment closely
      parallels that of AP1. The recruitment of both AP1 and ARF are partially blocked
      by brefeldin A. These data demonstrate that the coating of GLUT4 vesicles can be
      studied in isolated cell-free fractions. Furthermore, at least two distinct
      adaptor complexes can associate with the GLUT4 vesicles and it is likely that
      these adaptors are involved in mediating distinct intracellular sorting events at
      the level of TGN and endosomes.

PMID- 10574727
TI  - In vivo sequential changes in chloride cell morphology in the yolk-sac membrane
      of mozambique tilapia (Oreochromis mossambicus) embryos and larvae during
      seawater adaptation
AB  - Changes in chloride cell morphology were examined in the yolk-sac membrane of
      Mozambique tilapia (Oreochromis mossambicus) embryos and larvae transferred from
      fresh water to sea water. By labelling chloride cells with DASPEI, a fluorescent
      probe specific for mitochondria, we observed in vivo sequential changes in
      individual chloride cells by confocal laser scanning microscopy. In embryos
      transferred from fresh water to sea water 3 days after fertilization, 75 % of
      chloride cells survived for 96 h, and cells showed a remarkable increase in size.
      In contrast, the cell size did not change in embryos and larvae kept in fresh
      water. The same rate of chloride cell turnover was observed in both fresh water
      and sea water. Using differential interference contrast (DIC) optics and whole
      mount immunocytochemistry with anti-Na(+)/K(+)-ATPase, we classified chloride
      cells into three developmental stages: a single chloride cell without an apical
      pit, a single chloride cell with an apical pit, and a multicellular complex of
      chloride and accessory cells with an apical pit. DIC and immunofluorescence
      microscopy revealed that single chloride cells enlarged and were frequently
      indented by newly differentiated accessory cells to form multicellular complexes
      during seawater adaptation. These results indicate that freshwater-type single
      chloride cells are transformed into seawater-type multicellular complexes during
      seawater adaptation, suggesting plasticity in the ion-transporting functions of
      chloride cells in the yolk-sac membrane of tilapia embryos and larvae.

PMID- 10574728
TI  - Dominance hierarchy formation in juvenile crayfish procambarus clarkii
AB  - The formation of social dominance hierarchies was studied in groups of five
      juvenile crayfish, 1.3-1.8 cm in length. Animals were grouped together in a
      small, featureless aquarium after having lived in isolation for more than a
      month. The occurrence of each of four behavior patterns ('attack', 'approach',
      'retreat' and 'escape') was recorded for each animal, together with the frequency
      of encounters and the frequency of wins and losses. The frequencies of wins and
      losses were used to calculate the relative dominance value of each animal in the
      group. High levels of fighting developed immediately upon grouping the animals,
      and a positive feedback relationship between attacking and winning enabled one
      animal in each group to emerge quickly as the superdominant. If that animal was
      the largest, it remained as the superdominant; otherwise, it was replaced as
      superdominant within the first few days by the largest animal. This form of
      dominance hierarchy, with one superdominant and four subordinates, persisted
      throughout the duration of the grouping. Fighting declined over the first hour
      and by 24 h had dropped to low levels. After the first day, approaches were used
      together with attacks, and retreats replaced escapes. Attack and approach were
      the behavior patterns displayed most frequently by animals with high dominance
      values, whereas retreat and escape were performed by animals of low dominance.
      All these trends continued to develop over the next 2 weeks as the number of
      agonistic encounters declined to a low level.

PMID- 10574729
TI  - Coherent light scattering by nanostructured collagen arrays in the caruncles of
      the malagasy asities (Eurylaimidae: aves)
AB  - We investigated the anatomy, nanostructure and biophysics of the structurally
      coloured facial caruncles of three species in a clade of birds endemic to
      Madagascar (Philepittinae, Eurylaimidae: Aves). Caruncle tissues of all species
      had reflectance spectra with prominent, peak hues between 403 and 528 nm. Dark
      blue Neodrepanis tissues had substantial reflectance in the near ultraviolet (320
      400 nm), which is visible to birds but not to humans, providing the first
      evidence of ultraviolet skin colours in birds and the first indications of the
      possible function of ultraviolet skin colours in avian communication. These
      structural colours are produced by coherent scattering from arrays of parallel
      collagen fibres in the dermis. Tissues of Philepitta castanea were organized into
      hexagonal, crystal-like arrays, whereas Neodrepanis tissues were quasiordered.
      Predictions of the peak hues of reflectance ( &lgr; (max)) using Bragg's law were
      relatively accurate, but Bragg's law requires physical assumptions that are
      obviously violated by these structures. A two-dimensional discrete Fourier
      analysis of the spatial variation in refractive index within the tissues
      documented that all the tissues are substantially nanostructured at the
      appropriate spatial scale to scatter visible light coherently. Predicted
      reflectance spectra based on the two-dimensional Fourier power spectra are
      relatively accurate at predicting the hue and shape of the reflectance spectra of
      the tissues. These results confirm that the nanostructure of the collagen arrays
      determines the colours that are coherently scattered by these tissues. The
      evolution of the anatomy and nanostructure of asity caruncles is discussed.

PMID- 10574730
TI  - Functional morphology of undulatory pectoral fin locomotion in the stingray
      taeniura lymma (Chondrichthyes: dasyatidae)
AB  - Rajiform locomotion is a unique swimming style found in the batoid fishes (skates
      and rays) in which thrust is generated by undulatory waves passing down the
      enlarged pectoral fins. We examined the kinematic patterns of fin motion and the
      motor patterns of pectoral fin muscles driving the locomotor system in the blue
      spot stingray Taeniura lymma. Our goals in this study were to determine overall
      patterns of fin motion and motor control during undulatory locomotion, to
      discover how these patterns change with swimming velocity and to correlate muscle
      function with kinematics and pectoral morphology. Kinematic data were recorded
      from five individuals over a range of swimming speeds from 22 to 55 cm s(-)(1)
      (0.9-3.0 DL s(-)(1), where DL is body disc length). Electromyographic (EMG) data
      were recorded from three individuals over a range of velocities (1.2-3.0 DL s(
      )(1)) at seven locations (four dorsal, three ventral) along the pectoral fin. As
      swimming velocity increases, fin-beat frequency, wavespeed and stride length
      increase, number of waves and reduced frequency decrease and fin amplitude
      remains constant. There is variability among individuals in frequency and
      amplitude at a given speed. An inverse relationship was found in which a high fin
      beat frequency is associated with a low fin amplitude and a low fin-beat
      frequency is associated with a high fin amplitude. The motor pattern of
      undulatory locomotion is alternate firing activity in the dorsal and ventral
      muscles as the wave moves along the fin from anterior to posterior. Fin muscles
      are active along the entire length of the fin except at the lowest speeds. As
      swimming velocity and fin-beat frequency increase, the time of activation of
      posterior muscles becomes earlier relative to the onset of activity in the
      anterior dorsal muscles. The duration of muscle activity is longer in the ventral
      muscles than in the dorsal muscles, indicating that they play a central role in
      the power stroke of the fin-beat cycle. The anterior muscles (dorsal and ventral)
      are active for a relatively longer part of the stride cycle than the posterior
      muscles. Both the anterior position and the large duty factor of the anterior
      muscles reflect the role of these muscles in initial wave generation. Synchronous
      recordings of kinematic data with EMG data reveal that the anterior dorsal and
      middle ventral muscles do mostly positive work, whereas the dorsal and ventral
      posterior muscles do negative work at most swimming speeds.

PMID- 10574731
TI  - Redox control in development and evolution: evidence from colonial hydroids
AB  - Redox chemistry, involving the transfer of electrons and hydrogen atoms, is
      central to energy conversion in respiration, and the control of gene expression
      by redox state commonly occurs in bacteria, allowing rapid responses to
      environmental changes, for instance, in the food supply. Colonial metazoans often
      encrust surfaces over which the food supply varies in time or space; hence, in
      these organisms, redox control of the development of feeding structures and
      gastrovascular connections could be similarly adaptive, allowing colonies to
      adjust the timing and spacing of structures in response to a variable food
      supply. To investigate the possibility of redox control of colony development,
      the redox states of hydractiniid hydroid colonies were manipulated
      experimentally. As in many colonial animals, hydractiniid hydroids display a
      range of morphological variation from sheet-like forms (i.e. closely spaced
      polyps with high rates of stolon branching) to runner-like forms (i. e. widely
      spaced polyps with low rates of stolon branching). In the runner-like Podocoryna
      carnea, azide, a blocker of the electron transport chain, and dinitrophenol, an
      uncoupler of oxidative phosphorylation, diminished the largely polyp-driven
      gastrovascular flow to a similar extent. Measures of the redox state of the polyp
      epitheliomuscular cells using the fluorescence of NAD(P)H suggest that azide
      shifts the redox state in the direction of reduction, while dinitrophenol shifts
      the redox state in the direction of oxidation. Colony development corresponds to
      redox state in that azide-treated colonies were more runner-like, while
      dinitrophenol-treated colonies were more sheet-like. Nevertheless, the functional
      role of polyps in feeding and generating gastrovascular flow probably contributed
      to a trade-off between polyp number and size such that azide-treated colonies had
      few large polyps, while dinitrophenol-treated colonies had many small polyps.
      Regardless of the treatment, P. carnea colonies developed to maturity and
      produced swimming medusae in the normal fashion. In the sheet-like Hydractinia
      symbiolongicarpus, treatment with azide resulted in complete suppression of the
      development of both the stolonal mat and the blastostyles, the reproductive
      polyps. Azide-treated H. symbiolongicarpus colonies therefore developed in a
      juvenilized, runner-like manner and much resembled colonies of P. carnea.
      Following cessation of azide treatment in H. symbiolongicarpus, normal colony
      development ensued, and both a stolonal mat and blastostyles formed. In both
      hydroid species, relative oxidization favors sheet-like growth, while relative
      reduction favors runner-like growth. Since feeding triggers strong contractions
      of polyp epitheliomuscular cells and results in relative oxidation, this
      experimental evidence supports the hypothesis of adaptive redox control of colony
      development and evolution.

PMID- 10574732
TI  - Differential activation of octopaminergic (DUM) neurones via proprioceptors
      responding to flight muscle contractions in the locust
AB  - The synaptic potentials generated in neuromodulatory octopaminergic dorsal
      unpaired median (DUM) neurones by afferents excited by twitch contractions of a
      dorso-ventral flight muscle were investigated in the locust. Responses to
      stimulation of the metathoracic wing elevator muscle 113 were obtained in locusts
      in which all sensory feedback from the thorax had been removed, except for
      feedback from the thoracic chordotonal organs, the axons of which enter via the
      purely sensory nerve 2. Afferents in nerve 2C, which originates from two
      chordotonal organs, responded reliably to twitch contractions of this flight
      muscle. Octopaminergic neurones innervating leg muscles (DUM5 neurones) received
      depolarising inputs and often spiked following stimulation of the muscle. In
      contrast, those innervating the wing muscles themselves (DUM3 and DUM3,4
      neurones) received inhibitory inputs. The responses of DUM3,4,5 neurones, which
      project mainly to leg muscles, were more complex: most were excited by twitch
      contractions of M113 but some were inhibited. DUMDL, which innervates the dorsal
      longitudinal indirect flight muscles, showed no clear response. Direct
      stimulation of nerve 2C evoked depolarising inputs and spikes in DUM5 neurones
      and hyperpolarising inputs in DUM3 and DUM3,4 neurones. Our data suggest that
      sensory feedback from thoracic chordotonal organs, which are known to be
      activated rhythmically during flight, contributes to the differential activation
      of efferent DUM neurones observed during flight.

PMID- 10574734
TI  - Timing of elevator muscle activity during climbing in free locust flight
AB  - Despite detailed knowledge of the sensory-motor interactions during elevator
      muscle timing for the generation of a 'functional' flight motor pattern in flying
      locusts, there is little information about how a possible shift in the onset of
      elevator activity is correlated with changes in flight variables under closed
      loop conditions (i.e. during free flight). Free-flight variables were
      investigated with respect to ascent angle during climbing flight in locusts
      Schistocerca gregaria. The motor pattern during free flight was examined by
      telemetric electromyography of particular antagonistic flight muscles in both
      ipsilateral hemisegments of the pterothorax while flight variables were recorded
      simultaneously on video. In the majority of the animals tested, the onset of
      elevator muscle activity within the wingbeat cycle is delayed when animals
      increase their ascent angle during climbing flight. In accordance with the motor
      pattern, the downstroke phase and the stroke amplitude of the wings increased
      with increasing the ascent angle. This suggests that the relative elevator timing
      during the wingbeat cycle may be related to the generation of the additional
      aerodynamic lift required for ascending flight and may, therefore, play a role in
      the regulation of ascent angle during free flight in the locust.

PMID- 10574733
TI  - Acceleration and balance in trotting dogs.
AB  - During quadrupedal trotting, diagonal pairs of limbs are set down in unison and
      exert forces on the ground simultaneously. Ground-reaction forces on individual
      limbs of trotting dogs were measured separately using a series of four force
      platforms. Vertical and fore-aft impulses were determined for each limb from the
      force/time recordings. When mean fore-aft acceleration of the body was zero in a
      given trotting step (steady state), the fraction of vertical impulse on the
      forelimb was equal to the fraction of body weight supported by the forelimbs
      during standing (approximately 60 %). When dogs accelerated or decelerated during
      a trotting step, the vertical impulse was redistributed to the hindlimb or
      forelimb, respectively. This redistribution of the vertical impulse is due to a
      moment exerted about the pitch axis of the body by fore-aft accelerating and
      decelerating forces. Vertical forces exerted by the forelimb and hindlimb resist
      this pitching moment, providing stability during fore-aft acceleration and
      deceleration.

PMID- 10574735
TI  - Comparative study on the metabolic responses of subterranean and surface-dwelling
      amphipods to long-term starvation and subsequent refeeding
AB  - The effects of long-term starvation and subsequent refeeding on intermediary and
      energy metabolism were investigated in two subterranean aquatic crustaceans,
      Niphargus rhenorhodanensis and Niphargus virei, and in a morphologically similar
      surface-dwelling species, Gammarus fossarum. The metabolic response to prolonged
      food deprivation was monophasic in G. fossarum, showing an immediate, linear and
      large decline in all of the energy reserves. In contrast, both subterranean
      organisms displayed successive periods of glucidic, proteo-glucidic then lipidic
      dominant catabolism during food deprivation. In both subterranean species, lipids
      (51 % of the energy consumed during a 180-day starvation period) and proteins (44
      %) were the most metabolized substrates in terms of total energy, whereas
      glycogen (5 %) contributed little energy. G. fossarum displayed a different
      energetic strategy: proteins comprised 56 % of the energy losses during a 28-day
      starvation period, total lipids some 39 % and glycogen reserves only 5 %. We
      propose an energy strategy for food-limited subterranean crustaceans involving
      the possession of (1) higher amounts of stored arginine phosphate, triglycerides
      and glycogen and (2) lower utilization rates of stored metabolites than G.
      fossarum and numerous other surface-dwelling crustaceans, making the fueling of
      food deprivation possible for a longer time. In addition, these species had a
      faster and more efficient assimilation of available nutrients during recovery
      from food deprivation, enabling preparation for a new nutritional stress. These
      specific adaptive responses might be considered, for N. virei and N.
      rhenorhodanensis, as an efficient energy-saving strategy for an environment where
      extended starvation periods alternate with sporadic feeding events, therefore
      improving their competitive advantages.

PMID- 10574736
TI  - Trimethylamine oxide stabilizes teleost and mammalian lactate dehydrogenases
      against inactivation by hydrostatic pressure and trypsinolysis.
AB  - Trimethylamine N-oxide (TMAO) is an organic osmolyte present at high levels in
      elasmobranchs, in which it counteracts the deleterious effects of urea on
      proteins, and is also accumulated by deep-living invertebrates and teleost
      fishes. To test the hypothesis that TMAO may compensate for the adverse effects
      of elevated pressure on protein structure in deep-sea species, we studied the
      efficacy of TMAO in preventing denaturation and enhanced proteolysis by
      hydrostatic pressure. TMAO was compared to a common 'compatible' osmolyte,
      glycine, using muscle-type lactate dehydrogenase (A(4)-LDH) homologs from three
      scorpaenid teleost fish species and from a mammal, the cow. Test conditions
      lasted 1 h and were: (1) no addition, (2) 250 mmol l(-)(1) TMAO and (3) 250 mmol
      l(-)(1) glycine, in the absence and presence of trypsin. Comparisons were made at
      0. 1 and 101.3 MPa for the deeper occurring Sebastolobus altivelis, 0.1, 50.7 and
      101.3 MPa for the moderate-depth congener S. alascanus, 0. 1 and 25.3 MPa for
      shallow-living Sebastes melanops and 0.1 and 50.7 MPa for Bos taurus.
      Susceptibility to denaturation was determined by the residual LDH activity. For
      all the species and pressures tested, 250 mmol l(-)(1) TMAO reduced trypsinolysis
      significantly. For all except S. altivelis, which was minimally affected by 101.3
      MPa pressure, TMAO stabilized the LDH homologs and reduced pressure denaturation
      significantly. Glycine, in contrast, showed no ability to reduce pressure
      denaturation alone, and little or no ability to reduce the rate of proteolysis.

PMID- 10574738
TI  - Physiological disturbances at critically high temperatures: a comparison between
      stenothermal antarctic and eurythermal temperate eelpouts (Zoarcidae)
AB  - The effect of gradually increased water temperature on the metabolism of
      temperate eelpout from the North Sea (Zoarces viviparus) and Antarctic eelpout
      (Pachycara brachycephalum) was investigated. Standard metabolic rate (SMR) was
      similar in cold-adapted P. brachycephalum and cold-acclimated Z. viviparus in the
      low temperature range. This indicates that Antarctic eelpout show no metabolic
      cold adaptation (as originally defined by Wohlschlag); however, they do show a
      compensatory increase of oxygen consumption compared to warm-acclimated eelpout.
      SMR increased more strongly with rising temperature in P. brachycephalum than in
      Z. viviparus, which is reflected in a higher Arrhenius activation energy for
      oxygen consumption (99+/-5 kJ mol(-)(1), versus 55+/-3 kJ mol(-)(1) for cold
      acclimated Z. viviparus; means +/- s.d.). The intracellular pH in the white
      musculature of Z. viviparus follows alphastat regulation over the whole
      investigated temperature range and dropped at a rate of -0.016 pH units per
      degrees C between 3 degrees C and 24 degrees C. In Antarctic eelpout white muscle
      pH declined at a rate of -0.015 pH units per degrees C between 0 degrees C and 3
      degrees C, but deviated from alphastat at higher temperatures, indicating that
      thermal stress leads to acid-base disturbances in this species. The upper
      critical temperature limit (Tc(II); characterised by a transition to anaerobic
      metabolism) was found to be between 21 degrees C and 24 degrees C for Z.
      viviparus and around 9 degrees C for P. brachycephalum. In both species a rise of
      succinate concentration in the liver tissue turned out to be the most useful
      indicator of Tc(II). Obviously, liver is more sensitive to heat stress than is
      white muscle. Accordingly, the energy status of white muscle is not diminished at
      Tc(II). Heat-induced hyperglycaemia was observed in Antarctic eelpout (at 9
      degrees C and 10 degrees C), but not in common eelpout. Based on our results and
      on literature data, impaired respiration in combination with circulatory failure
      is suggested as the final cause of heat death. Our data suggest that the southern
      distribution limit of Zoarces viviparus is correlated with the limit of thermal
      tolerance. Therefore, it can be anticipated that global warming would cause a
      shift in the distribution of this species.

PMID- 10574737
TI  - Characterization of an endothelin ET(B) receptor in the gill of the dogfish shark
      Squalus acanthias.
AB  - Endothelins (ETs) are potent vasoconstrictive peptides that are secreted by the
      vascular endothelium and other tissues in vertebrates. Previous studies have
      demonstrated that ETs are expressed in a variety of fish tissues and contract
      various blood vessels. In order to determine if receptors for ET are expressed in
      fish gill tissue, we examined the binding kinetics of (125)I-labeled, human ET-1
      to membrane fragments isolated from the gill of the dogfish shark, Squalus
      acanthias. (125)I-ET-1 bound at a single site, with a dissociation constant
      (K(d)) and binding site number (B(max)) very similar to those described in a
      variety of mammalian blood vessels. ET-1 and ET-3 competed equally with (125)I-ET
      1, suggesting that the receptor was ET(B), which has been shown in mammalian
      systems to bind to both ligands equally. The ET(B)-specific agonists sarafotoxin
      S6c, IRL-1620, and BQ-3020 also competed against (125)I-ET-1 at a single site,
      supporting this hypothesis. We conclude that the shark gill expresses an ET(B)
      receptor with substantial homology to the mammalian receptor and that ET may play
      an important role in modulating such vital gill functions as gas exchange, ion
      regulation, acid-base balance, and excretion of nitrogen.

PMID- 10574740
TI  - Daphnia pulex swims towards the most strongly polarized light - a response that
      leads to 'shore flight'
AB  - When Daphnia pulex are presented on one side of their visual field with diffuse,
      large-area linearly polarized light with a horizontal e-vector and on the other
      side of their visual field with large-area polarized light with a lower degree of
      polarization, they swim towards the place with the higher degree of polarization.
      The response is intensity-invariant: Daphnia pulex swim towards the place of
      maximal polarization regardless of which side of their visual field has the
      higher intensity of light. As a result of Rayleigh scattering in a pond, the
      light surrounding the Daphnia is polarized and has a horizontal e-vector. Near
      the shore, polarization is not homogeneous. The light seen in the direction of
      the open water has a higher degree of polarization than that seen in the
      direction towards the shore. Therefore, in a pond, swimming towards the place
      with the highest degree of polarization leads the Daphnia away from the shore.
      For Daphnia, this response explains a mechanism that underlies the well-known
      phenomenon of 'shore flight', the active departure of small pelagic crustaceans
      from shore zones.

PMID- 10574739
TI  - Antarctic fishes have a limited capacity for catecholamine synthesis.
AB  - To determine whether an attenuated stress response is a general feature of
      Antarctic fish or is dependent on ecotype, the capacity for catecholamine
      synthesis within the head kidney and plasma levels of the primary stress hormones
      (catecholamines and cortisol) were determined in species with a range of activity
      patterns. Tyrosine hydroxylase (TH) activities were similar in both sluggish
      (Gobionotothen gibberifons, 153+/-22 nmol g(-)(1 )h(-)(1), mean +/- s.e.m.) and
      active (Notothenia rossii, 185+/-39 nmol g(-)(1 )h(-)(1), Dissostichus mawsoni,
      128+/-31 nmol g(-)(1 )h(-)(1)) pelagic nototheniids, but only 30 % of those in
      Atlantic cod (Gadus morhua, 393+/-88 nmol g(-)(1 )h(-)(1)) at the same
      temperature. TH activities were even lower in white-blooded channichthyids
      (Chaenocephalus aceratus, 74+/-16 nmol g(-)(1 )h(-)(1) and Champsocephalus
      gunnari, 53+/-17 nmol g(-)(1 )h(-)(1)), although values in Chionodraco
      rastrospinosus were similar to red-blooded species (178+/-45 nmol g(-)(1 )h(
      )(1)). Circulating catecholamine levels were extremely high in all species after
      fishing stress, with adrenaline levels 3-4 times higher than noradrenaline
      levels. Cortisol levels remained low, ranging from 1.33+/-0.58 ng ml(-)(1) in
      Champsocephalus gunnari to 44.9+/-25.0 ng ml(-)(1 )in Dissostichus mawsoni. These
      data suggest that depressed catecholamine synthesis is typical of Antarctic fish
      regardless of life style, although they are able to release extensive stores from
      the chromaffin tissue under conditions of extreme trauma. Cortisol does not
      appear to be an important primary stress hormone in these species.

PMID- 10574741
TI  - Hypoxia accelerates the development of respiratory regulation in brine shrimp -
      but at a cost
AB  - The ability to regulate O(2) uptake during exposure to acutely declining O(2)
      tensions developed early (stage 6) in the brine shrimp Artemia franciscana and co
      occurred with the appearance of a functional heart and gills. Culture under
      chronic hypoxia (P(O2)=10 kPa) resulted in this regulation being brought forward
      both in development (to stage 3) and in time (hypoxia stimulated early growth),
      but still before heart and gill formation took place. Consequently, it was
      suggested that the hypoxia-related early appearance of respiratory regulation is
      most probably linked to an increase in haemoglobin concentration that occurred at
      this time. Brine shrimp cultured under conditions of intermittent hypoxia
      exposure (16 h of normoxia, 8 h of hypoxia) showed a pattern of regulation
      development intermediate between that of individuals reared in normoxic and
      chronically hypoxic culture. This occurrence of hypoxia-related, physiological
      'heterochrony' in brine shrimp resulted in a decrease in Darwinian fitness (as
      indicated by a decrease in individual lifetime reproductive output), indicating
      that, in some cases at least, relatively small alterations in the expression of
      physiological traits may well have major ecological, and ultimately evolutionary,
      consequences.

PMID- 10574742
TI  - Cardiorespiratory responses of the toad (Bufo marinus) to hypoxia at two
      different temperatures.
AB  - Central vascular blood flows and ventilation were measured in conscious toads
      (Bufo marinus) at 15 and 25 degrees C. The animals were exposed to hypoxia
      (Fi(O)(sum)=0.10 and 0.05, where Fi(O)(sum) is the fractional oxygen
      concentration of inspired air) at both temperatures. In addition, the
      cardiorespiratory responses to hypercapnia (Fi(CO)(sum)=0.05) and atropine
      injection (5 mg kg(-)(1); 7.4 micromol kg(-)(1)) were studied at 25 degrees C. At
      25 degrees C, systemic blood flow ( q_dot (sys)) exceeded pulmocutaneous blood
      flow ( q_dot (pc)), indicating a large net right-to-left shunt ( q_dot (pc)/
      q_dot (sys) was 0.39). q_dot (pc)/ q_dot (sys) was reduced significantly to 0.22
      at 15 degrees C. At both temperatures, q_dot (pc) increased significantly during
      hypoxia (from 26.2 to 50.8 ml min(-)(1 )kg(-)(1) at 25 degrees C and from 11. 2
      to 18.9 ml min(-)(1 )kg(-)(1) at 15 degrees C), whereas q_dot (sys) changed
      little (from 77.2 to 66.2 ml min(-)(1 )kg(-)(1) at 25 degrees C and from 54.3 to
      50.1 ml min(-)(1 )kg(-)(1) at 15 degrees C). As a result, the net right-to-left
      shunt was greatly reduced, while total cardiac output remained almost unaffected.
      The ventilatory response was more pronounced during hypercapnia but, since q_dot
      (pc) and q_dot (sys) were affected similarly, there was no change in the shunt
      pattern. In undisturbed toads at 25 degrees C, atropine injection increased q_dot
      (pc) and eliminated the net right-to-left shunt. This is consistent with the
      known vagal innervation of the pulmonary artery. The present study shows that the
      cardiac right-to-left shunt that prevails in undisturbed and resting toads is
      reduced with increased temperature and during hypoxia. These findings are
      consistent with the general view that the cardiac right-to-left shunt is
      regulated and reduced whenever oxygen delivery is compromised or metabolic rate
      is increased.

PMID- 10574743
TI  - In vivo bafilomycin-sensitive Na(+) uptake in young freshwater fish
AB  - In vivo treatment with external bafilomycin A(1), a selective inhibitor of V
      ATPase H(+) pumps, reduced whole-body Na(+) influx by up to 90 % in young tilapia
      and 70 % in young carp. The inhibition was rapidly reversible, with whole-body
      Na(+) influx rebounding to 280 % of pre-treatment values within 20 min of removal
      from the bafilomycin. This rebound effect is consistent with the prior
      accumulation of protons during the period when the cells were exposed to
      bafilomycin. Bafilomycin also inhibited Cl(-) uptake, an effect that was still
      apparent 30 min after the removal of bafilomycin. These data provide
      circumstantial evidence for previous suggestions that Na(+) uptake in freshwater
      fish is associated with a proton-motive force created by a proton pump and
      indirect evidence for the major significance of this mechanism in the branchial
      uptake of Na(+) by freshwater fish.

PMID- 10574745
TI  - Gas exchange and ventilation during dormancy in the tegu lizard tupinambis
      merianae
AB  - The tegu lizard Tupinambis merianae exhibits an episodic ventilatory pattern when
      dormant at 17 degrees C but a uniform ventilatory pattern when dormant at 25
      degrees C. At 17 degrees C, ventilatory episodes were composed of 1-22 breaths
      interspaced by non-ventilatory periods lasting 1.8-26 min. Dormancy at the higher
      body temperature was accompanied by higher rates of O(2) consumption and
      ventilation. The increase in ventilation was due only to increases in breathing
      frequency with no change observed in tidal volume. The air convection requirement
      for O(2) did not differ at the two body temperatures. The respiratory quotient
      was 0.8 at 17 degrees C and 1.0 at 25 degrees C. We found no consistent
      relationship between expired gas composition and the start/end of the ventilatory
      period during episodic breathing at 17 degrees C. However, following non
      ventilatory periods of increasing duration, there was an increase in the
      pulmonary O(2) extraction that was not coupled to an equivalent increase in
      elimination of CO(2) from the lungs. None of the changes in the variables studied
      could alone explain the initiation/termination of episodic ventilation in the
      tegus, suggesting that breathing episodes are shaped by a complex interaction
      between many variables. The estimated oxidative cost of breathing in dormant
      tegus at 17 degrees C was equivalent to 52.3 % of the total metabolic rate,
      indicating that breathing is the most costly activity during dormancy.

PMID- 10574744
TI  - Isolation and characterization of a leucokinin-like peptide of Drosophila
      melanogaster.
AB  - The leucokinin (LK) family of neuropeptides has been found widely amongst
      invertebrates. A member of this family was purified from adults of the fruit fly
      Drosophila melanogaster. The peptide sequence for Drosophila leucokinin (DLK) was
      determined as Asn-Ser-Val-Val-Leu-Gly-Lys-Lys-Gln-Arg-Phe-His-Ser-Trp-Gly-amide,
      making it the longest member of the family characterized to date. Synthetic DLK
      peptide was shown to act to stimulate fluid secretion in D. melanogaster
      Malpighian (renal) tubules by approximately threefold, with an EC(50) of
      approximately 10(-)(10 )mol l(-)(1), and a secondary effect at approximately 10(
      )(7 )mol l(-)(1). DLK also acted to elevate intracellular [Ca(2+)] in the
      Malpighian tubules by approximately threefold, with an EC(50) of 10(-)(10) to 10(
      )(9 )mol l(-)(1). Responses were detected in stellate cells and occasionally in
      principal cells, although at no concentration tested did [Ca(2+)] in the
      principal cell increase significantly above background. In stellate cells, DLK
      produced a biphasic rise in intracellular [Ca(2+)] from resting levels of 80-100
      nmol l(-)(1), with a transient peak being followed by a slower rise that peaked
      at 200-300 nmol l(-)(1) after 3 s, then decayed over approximately 10 s. The wide
      range of concentrations over which DLK acts suggests the involvement of more than
      one receptor. The genomic sequence encoding the DLK peptide has been identified,
      and the gene has been named pp. The gene resides at cytological location 70E3
      70F4 of chromosome 3L. The localisation of this first Drosophila LK gene in a
      genetic model permits a genetic analysis of the locus.

PMID- 10574746
TI  - Cranial kinesis in gekkonid lizards
AB  - Cranial kinesis was studied in two species of gekkonid lizard, Gekko gecko and
      Phelsuma madagascariensis, using cineradiography and electromyography. The skull
      of these geckoes showed the three types of kinesis described by Versluys at the
      beginning of this century: streptostyly, mesokinesis and metakinesis. In
      accordance with the later model of Frazzetta, the skull of these animals can be
      modelled by a quadratic crank system: when the mouth opens during feeding, the
      quadrate rotates forward, the palato-maxillary unit is lifted and the occipital
      unit swings forward. During jaw closing, the inverse movements are observed;
      during crushing, the system is retracted beyond its resting position. The data
      gathered here indicate that the coupled kinesis (streptostyly + mesokinesis) is
      most prominently present during the capture and crushing cycles of feeding and is
      largely absent during late intraoral transport, swallowing, drinking and
      breathing. The electromyographic data indicate a consistent pattern of muscular
      activation, with the jaw opener and pterygoid protractor always active during the
      fast opening phase, and the jaw closers active during closing and crushing. Our
      data generally support the model of Frazzetta. Although the data gathered here do
      not allow speculation on the functional significance of the kinesis, they clearly
      provide some key elements required for a further investigation of the functional
      and adaptive basis of the system.

PMID- 10574747
TI  - Motor control of tongue movement during prey capture in plethodontid salamanders
AB  - Four species of salamander of the family Plethodontidae were examined using
      electromyographic (EMG) recording during prey-capture behavior to test the
      hypotheses that the tongue retractor, tongue protractor and jaw depressor muscles
      are activated simultaneously and in a stereotyped pattern, as was found in other
      salamanders, and to determine whether species with different tongue morphologies
      and tongue protraction abilities exhibit different motor control strategies. The
      results show that sequential activation was observed far more frequently than
      simultaneous activation; the jaw depressor muscle was activated first, followed
      by the tongue protractor and then the tongue retractor. Species with short,
      attached tongues (Desmognathus quadramaculatus and Plethodon jordani) showed
      simultaneous activation more often than species with long, free tongues
      (Pseudotriton ruber and Hydromantes supramontis), which showed strongly non
      simultaneous activation. Most EMG variables showed no effect of prey-capture
      success, suggesting that sensory feedback is not involved in modulating the motor
      pattern during the prey-capture strike. Hydromantes supramontis was examined for
      modulation of its motor pattern in response to prey distance, and several EMG
      variables were found to be positively correlated with tongue protraction
      distance. The motor pattern of strongly non-simultaneous activation of
      antagonistic tongue muscles has evolved along with the evolution of long, free
      tongues in plethodontids. The variable motor patterns observed provide further
      evidence that amphibian feeding in general is not as highly stereotyped as has
      been previously thought.

PMID- 10574748
TI  - Feeding kinematics of phelsuma madagascariensis (Reptilia: gekkonidae): testing
      differences between iguania and scleroglossa
AB  - The kinematics of feeding in the gekkotan lizard Phelsuma madagascariensis
      (Scleroglossa) was investigated using high-speed cinematography (200-300 frames
      s(-)(1)) and X-ray films (64 frames s(-)(1)). Qualitative kinematic analysis of
      the head and jaw displacement of the prey to (capture) and within (reduction,
      transport, swallowing, licking) the buccal cavity are compared for two types of
      prey (crickets and mealworms) in 30 feeding sequences from four individuals.
      Maximal displacement of structures and timing of events are compared
      statistically to assess the differences among the phases and the prey using
      analysis of variance. P. madagascariensis uses its jaws only to capture the two
      types of prey item, and the capture jaw cycle is divided into fast-opening (FO),
      fast-closing (FC) and slow-closing (SC) stages only. As in iguanians and other
      scleroglossans, the reduction and transport cycles always involve a slow opening
      (SOI and SOII) stage before the FO stage, followed by FC and SC stages: this last
      stage was not easily identified in all feeding phase. Transport of the prey was
      followed by a large number of licking cycles. Our data show (i) that the capture
      profile in gekkotans is similar to that observed for other scleroglossans and
      different from that described for iguanians (e.g. the absence of an SO stage);
      (ii) that the kinematics of jaw and related hyo-lingual cycles of intraoral
      manipulation (reduction and transport) are similar in lizards with a very
      different hyo-lingual system (Iguania, Gekkota and Scincomorpha), suggesting a
      basic mechanism of feeding cycles in squamates, transformed in varanids and
      snakes; and (iii) that prey type affects the kinematics of capture and
      manipulation, although the high level of variation among lizards suggests a
      possible individual modulation of feeding mechanism. A principal components
      analysis was performed to compare capture and transport cycles in this study of
      P. madagascariensis (Gekkota) and a previous study of Oplurus cuvieri (Iguania).
      This analysis separated the capture cycle of each species, but the transport
      cycles were not completely separated. These results demonstrate the complexity of
      the modulation and evolution of feeding process in squamates.

PMID- 10574749
TI  - Natural killer cells: stress out, turn on, tune in.
AB  - Natural killer cells attack tumor cells, infected cells and some normal cells,
      but the basis of their specificity is not completely understood. Recent studies
      indicate that epithelial tumor cells upregulate a stress-induced MHC class-I-like
      protein termed MICA, triggering NK cells via a recently described receptor called
      NKG2D.

PMID- 10574750
TI  - Synapse structure: glutamate receptors connected by the shanks.
AB  - A family of proteins has been identified whose members, the Shanks, physically
      link two major receptor complexes at excitatory synapses - NMDA receptors and
      metabotropic glutamate receptors.

PMID- 10574751
TI  - Cytoskeletal linkers: new MAPs for old destinations.
AB  - A new isoform of the actin-neurofilament linker protein BPAG has been found that
      binds to and stabilizes axonal microtubules. This and other newly identified
      microtubule-associated proteins are likely to be just the tip of an iceberg of
      multifunctional proteins that stabilize and crosslink cytoskeletal filament
      networks.

PMID- 10574752
TI  - Plant development: YABBYs claw to the fore.
AB  - The YABBY gene family was identified recently by homology to CRABS CLAW, a gene
      involved in carpel and nectary development in Arabidopsis. Several of the
      transcription factors encoded by the YABBY genes appear to have conserved roles
      in specifying abaxial cell fate in leaves, floral organs and ovules.

PMID- 10574753
TI  - Molecular evolution: aminoacyl-tRNA synthetases on the loose.
AB  - Modified versions - paralogs - of the catalytic domain of at least three
      different aminoacyl-tRNA synthetases have been found to serve catalytic or
      regulatory roles in other reactions. These findings suggest that the first modern
      tRNA-synthetases could have been derived from amino-acid biosynthetic enzymes.

PMID- 10574754
TI  - Molecular motors: Walking talking heads.
AB  - Small tension signals that pass between the two linked heads of kinesin allow the
      motor protein to coordinate its walking action. Two new studies suggest that
      certain members of the two other major families of motor proteins, the myosins
      and dyneins, can do the same thing.

PMID- 10574755
TI  - Yeast prions: bungee cord domains' balancing act.
AB  - The yeast prion-like protein Sup35 has repeats responsible for the reversible
      induction of an altered, but advantageous phenotype. The expansion of similar
      repeat domains in several mammalian proteins is associated with neurodegenerative
      disease - so why are these 'bungee cord' domains conserved?

PMID- 10574756
TI  - Peripheral membrane proteins: FYVE sticky fingers.
AB  - The recently determined structure of the lipid-binding 'FYVE' domain provides
      several clues to the mode of interaction for this class of peripheral membrane
      proteins. However, the application of traditional modes of structural analysis to
      diffusible membrane-binding proteins exposes some limitations of these
      techniques.

PMID- 10574757
TI  - Molecular motors: sensing a function for myosin-VIIa.
AB  - Mutations affecting myosin-VIIa are known to cause deafness and blindness in
      human Usher syndrome. Mutation of the Dictyostelium myosin-VII gene has now
      revealed a role for this unconventional myosin in phagocytic events, providing a
      possible clue to the role of mammalian myosin-VIIa in the inner ear and retina.

PMID- 10574758
TI  - Functional conservation of the wingless-engrailed interaction as shown by a
      widely applicable baculovirus misexpression system.
AB  - BACKGROUND: The expression patterns of the segment polarity genes wingless and
      engrailed are conserved during segmentation in a variety of arthropods,
      suggesting that the regulatory interactions between these two genes are also
      evolutionarily conserved. Hypotheses derived from such comparisons of gene
      expression patterns are difficult to test experimentally as genetic manipulation
      is currently possible for only a few model organisms. RESULTS: We have developed
      a system, using recombinant baculoviruses, that can be applied to a wide variety
      of organisms to study the effects of ectopic expression of genes. As a first
      step, we studied the range and type of infection of several reporter viruses in
      the embryos of two arthropod and one vertebrate species. Using this system to
      express wingless, we were able to induce expression of engrailed in the anterior
      half of each parasegment in embryos of the fruit fly Drosophila melanogaster.
      Virus-mediated wingless expression also caused ectopic naked ventral cuticle
      formation in wild-type Drosophila larvae. In the flour beetle, Tribolium
      castaneum, ectopic wingless also induced engrailed expression. As in Drosophila,
      this expression was only detectable in the anterior half of the parasegment.
      CONCLUSIONS: The functional interaction between wingless and engrailed, and the
      establishment of cells competent to express engrailed, appears to be conserved
      between Drosophila and Tribolium. The data on the establishment of an engrailed
      competent domain also support the idea that prepatterning by pair-rule genes is
      conserved between these two insects. The recombinant baculovirus technology
      reported here may help answer other long-standing comparative evolutionary
      questions.

PMID- 10574759
TI  - Ectopic gene expression and homeotic transformations in arthropods using
      recombinant Sindbis viruses.
AB  - BACKGROUND: The morphological diversity of arthropods makes them attractive
      subjects for studying the evolution of developmental mechanisms. Comparative
      analyses suggest that arthropod diversity has arisen largely as a result of
      changes in expression patterns of genes that control development. Direct analysis
      of how a particular gene functions in a given species during development is
      hindered by the lack of broadly applicable techniques for manipulating gene
      expression. RESULTS: We report that the Arbovirus Sindbis can be used to deliver
      high levels of gene expression in vivo in a number of non-host arthropod species
      without causing cytopathic effects in infected cells or impairing development.
      Using recombinant Sindbis virus, we investigated the function of the homeotic
      gene Ultrabithorax in the development of butterfly wings and beetle embryos.
      Ectopic Ultrabithorax expression in butterfly forewing imaginal discs was
      sufficient to cause the transformation of characteristic forewing properties in
      the adult, including scale morphology and pigmentation, to those of the hindwing.
      Expression of Ultrabithorax in beetle embryos outside of its endogenous
      expression domain affected normal development of the body wall cuticle and
      appendages. CONCLUSIONS: The homeotic genes have long been thought to play an
      important role in the diversification of arthropod appendages. Using recombinant
      Sindbis virus, we were able to investigate homeotic gene function in non-model
      arthropod species. We found that Ultrabithorax is sufficient to confer hindwing
      identity in butterflies and alter normal development of anterior structures in
      beetles. Recombinant Sindbis virus has broad potential as a tool for analyzing
      how the function of developmental genes has changed during the diversification of
      arthropods.

PMID- 10574760
TI  - Inhibition of sonic hedgehog signaling in vivo results in craniofacial neural
      crest cell death.
AB  - BACKGROUND: Sonic hedgehog (Shh) is well known for its role in patterning
      tissues, including structures of the head. Haploinsufficiency for SHH in humans
      results in holoprosencephaly, a syndrome characterized by facial and forebrain
      abnormalities. Shh null mice have cyclopia and loss of branchial arch structures.
      It is unclear, however, whether these phenotypes arise solely from the early
      function of Shh in patterning midline structures, or whether Shh plays other
      roles in head development. RESULTS: To address the role of Shh after floorplate
      induction, we inhibited Shh signaling by injecting hybridoma cells that secrete a
      function-blocking anti-Shh antibody into the chick cranial mesenchyme. The
      antibody subsequently bound to Shh in the floorplate, notochord, and the
      pharyngeal endoderm. Perturbation of Shh signaling at this stage resulted in a
      significant reduction in head size after 1 day, loss of branchial arch structures
      after 2 days, and embryos with smaller heads after 7 days. Cell death was
      significantly increased in the neural tube and neural crest after 1 day, and
      neural crest cell death was not secondary to the loss of neural tube cells.
      CONCLUSIONS: Reduction of Shh signaling after neural tube closure resulted in a
      transient decrease in neural tube cell proliferation and an extensive increase in
      cell death in the neural tube and neural crest, which in turn resulted in
      decreased head size. The phenotypes observed after reduction of Shh are similar
      to those observed after cranial neural crest ablation. Thus, our results
      demonstrate a role for Shh in coordinating the proliferation and survival of
      cells of the neural tube and cranial neural crest.

PMID- 10574761
TI  - A class VII unconventional myosin is required for phagocytosis.
AB  - BACKGROUND: Phagocytosis, the process by which cells internalize particles, is
      essential for the defense of multicellular organisms against invading pathogens
      and is the major means by which many unicellular organisms obtain nutrients. The
      actin cytoskeleton plays a critical role in phagocytosis and the observation that
      a significant amount of force (10-20 nN) is generated during internalization,
      suggests that a myosin participates in the process. Although more than 15
      distinct classes of myosin have been identified, their roles in phagocytosis are
      unknown. RESULTS: The identification of a class VII unconventional myosin
      (DdMVII) in the Dictyostelium discoideum amoeba, which is a model for
      phagocytosis, is reported here. Mutant cells lacking DdMVII exhibited an 80%
      decrease in the uptake of particles whereas all other actin-based behaviors that
      were tested, including pinocytosis, exocytosis, cytokinesis and morphogenesis,
      proceeded normally. The defect in phagocytosis was neither because of altered
      particle binding nor inability to form actin-filled phagocytic cups. CONCLUSIONS:
      Molecular genetic analysis of Dictyostelium myosin VII reveals that this motor
      protein plays a specific and significant role in phagocytosis.

PMID- 10574762
TI  - Deep common ancestry of indian and western-Eurasian mitochondrial DNA lineages.
AB  - About a fifth of the human gene pool belongs largely either to Indo-European or
      Dravidic speaking people inhabiting the Indian peninsula. The 'Caucasoid share'
      in their gene pool is thought to be related predominantly to the Indo-European
      speakers. A commonly held hypothesis, albeit not the only one, suggests a massive
      Indo-Aryan invasion to India some 4,000 years ago [1]. Recent limited analysis of
      maternally inherited mitochondrial DNA (mtDNA) of Indian populations has been
      interpreted as supporting this concept [2] [3]. Here, this interpretation is
      questioned. We found an extensive deep late Pleistocene genetic link between
      contemporary Europeans and Indians, provided by the mtDNA haplogroup U, which
      encompasses roughly a fifth of mtDNA lineages of both populations. Our estimate
      for this split is close to the suggested time for the peopling of Asia and the
      first expansion of anatomically modern humans in Eurasia [4] [5] [6] [7] [8] and
      likely pre-dates their spread to Europe. Only a small fraction of the 'Caucasoid
      specific' mtDNA lineages found in Indian populations can be ascribed to a
      relatively recent admixture.

PMID- 10574763
TI  - The human homologue of Caenorhabditis elegans CED-6 specifically promotes
      phagocytosis of apoptotic cells.
AB  - A key feature of the process of programmed cell death (apoptosis) is the
      efficiency with which the dying cells are recognized and engulfed by phagocytes
      [1]. Apoptotic cells are rapidly cleared either by neighbouring cells acting as
      semi-professional phagocytes or by experts of the macrophage line, so that an
      inflammatory response is avoided [2]. The Caenorhabditis elegans gene ced-6 is
      required for efficient engulfment of apoptotic cells [3] and is one of a group of
      genes that define two partially redundant parallel pathways for the engulfment
      process [4] [5]. These pathways may be conserved across evolution, as two other
      engulfment genes have human homologues. A CED-5 homologue is part of a human
      CrkII-DOCK180-Rac signaling pathway proposed to mediate cytoskeletal
      reorganization [6] [7] [8] and a CED-7 homologue is similar to the ABC
      transporters [9] [10]. Here, we report the cloning and characterization of human
      CED-6, a human homologue of C. elegans CED-6. The 34 kDa hCED-6 protein is
      expressed in most tissues, some human cancer cells, and in primary human
      macrophages. We developed an assay that quantitates the phagocytic activity of
      mammalian macrophages: the number of apoptotic cells that have been internalized
      is measured by the uptake of lacZ-positive apoptotic cells by adherent transgenic
      macrophages. The results of this assay demonstrate that overexpression of hCED-6
      promotes phagocytosis only of apoptotic cells and suggest that hCED-6 is the
      mammalian orthologue of C. elegans CED-6 and is a part of a highly conserved
      pathway that specifically mediates the phagocytosis of apoptotic cells.

PMID- 10574764
TI  - Active manual control of object views facilitates visual recognition.
AB  - Active exploration of large-scale environments leads to better learning of
      spatial layout than does passive observation [1] [2] [3]. But active exploration
      might also help us to remember the appearance of individual objects in a scene.
      In fact, when we encounter new objects, we often manipulate them so that they can
      be seen from a variety of perspectives. We present here the first evidence that
      active control of the visual input in this way facilitates later recognition of
      objects. Observers who actively rotated novel, three-dimensional objects on a
      computer screen later showed more efficient visual recognition than observers who
      passively viewed the exact same sequence of images of these virtual objects.
      During active exploration, the observers focused mainly on the 'side' or 'front'
      views of the objects (see also [4] [5] [6]). The results demonstrate that how an
      object is represented for later recognition is influenced by whether or not one
      controls the presentation of visual input during learning.

PMID- 10574765
TI  - Mis-specification of cortical identity in a fission yeast PAK mutant.
AB  - The regulation of cell polarity in the fission yeast Schizosaccharomyces pombe is
      apparent in the restriction of extensile growth to the two ends of a
      cylindrically shaped cell, and in a specific transition - termed 'new-end take
      off' (NETO) - between monopolar and bipolar growth mid-way through the cell cycle
      [1]. Several genes have been identified that affect one or more aspects of cell
      polarity (reviewed in [2] [3]), and the molecular pathways regulating cell
      polarity in fission yeast appear to be conserved among eukaryotes [3] [4] [5] [6]
      [7] [8] [9], but it is less clear how the proteins involved organize polarity at
      the level of the entire cell. Here, we describe novel cytological markers of cell
      polarity in fission yeast and their unusual localization in the monopolar growth
      mutant orb2-34, which carries a non-lethal mutation in the essential gene
      shk1(+)/pak1(+)/orb2(+), which encodes a p21-activated kinase (PAK) family member
      [8] [9] [10] [11] [12]. Our results suggest that, in contrast to other monopolar
      growing mutants, the monopolar phenotype of the orb2-34 mutant might not be due
      to a defect in activating end growth per se, but rather reflects a failure of one
      of the cell ends to maintain the molecular properties that identify an end. Thus,
      one role of the Shk1/Pak1 kinase in vivo might be to contribute to how a cell
      recognizes its ends as sites for growth.

PMID- 10574766
TI  - Fibroblast growth factor receptor signalling is dictated by specific heparan
      sulphate saccharides.
AB  - Signalling by fibroblast growth factors (FGFs) through FGF receptors (FGFRs)
      depends on the cell-surface polysaccharide heparan sulphate (HS) [1] [2]. HS has
      an ordered domain structure of highly diverse saccharide motifs that present
      unique displays of sulphate, carboxyl and hydroxyl groups [3]. These motifs
      interact with many proteins, particularly growth factors. HS binds both to FGFs
      [4] [5] [6] and FGFRs [7], and probably activates signalling by facilitating
      ligand-induced receptor dimerisation [8] [9]. Nevertheless, the extent to which
      specific HS saccharide sequences play a regulatory role has not been established.
      By screening a library of structurally diverse HS decasaccharides in bioassays of
      FGF signalling mediated by three different FGFR isoforms, we found that
      saccharides showed specificity for both ligands and receptors; some saccharides
      selectively activated FGF signalling through different FGFR isoforms, others
      acted as negative regulators. We conclude that HS saccharides play critical roles
      in dictating the specificity of ligand-receptor interactions in FGFR signalling.
      Controlled alterations in HS structures [10] would provide a mechanism for
      regulation of cellular responsiveness to growth factors that bind HS.

PMID- 10574767
TI  - Distinct and regulated activities of human Gli proteins in Drosophila.
AB  - In both vertebrates and Drosophila, limb development is organized by a
      posteriorly located source of the signalling protein Hedgehog (Hh) [1] [2] [3]
      [4]. In Drosophila, the expression of Hh target genes is controlled by two
      opposing activities of the transcriptional regulator Cubitus interruptus (Ci),
      which activates target genes in response to Hh signalling but is converted into a
      repressor form in the absence of Hh [5] [6] [7] [8] [9] [10]. Three homologs of
      Ci (Gli1, Gli2, and Gli3) have been implicated in mediating responses to Sonic
      hedgehog (Shh) in vertebrates [11] [12]. Much attention has been devoted to the
      expression pattern of GLI genes; GLI1 is induced by Shh, whereas GLI3
      transcription appears to be repressed by Shh signalling [13] [14] [15]. The
      regulation of GLI gene expression is therefore one important mechanism by which
      GLI genes organize pattern. It is not well understood, however, whether Shh
      signalling also controls the activities of Gli proteins post-translationally and
      whether these activities have activating or repressing effects on target genes in
      vivo. Here, we have subjected the human proteins Gli1 and Gli3 to the precise and
      well-defined Hh signalling assay of Drosophila wing development and established
      that Gli1 functions as an activator and Gli3 as a repressor of Hh target genes;
      that the activating transcriptional activity of Gli1 and the repressing activity
      of Gli3 are both subject to Hh regulation in vivo; and that the combined
      activities of Gli1 and Gli3 can substitute for Ci in controlling Hh target gene
      expression during embryonic and larval development.

PMID- 10574769
TI  - The laminin alpha2 expressed by dystrophic dy(2J) mice is defective in its
      ability to form polymers.
AB  - Mutations in LAMA2 cause severe congenital muscular dystrophy accompanied by
      nervous system defects [1]. Mice homozygous for the dy(2J) allele of LAMA2
      express a laminin alpha2 subunit that has a deletion in the amino-terminal domain
      VI, providing an animal model for study of the molecular basis of congenital
      muscular dystrophy [2] [3]. Domain VI is predicted to be involved in laminin
      polymerization, along with amino-terminal domains from laminin beta and gamma
      chains [4]. In a solution-polymerization assay, we found that purified dy(2J)
      laminin assembled poorly and formed little polymer, in contrast to wild-type
      muscle laminin. Furthermore, dissolution of the collagen IV network caused dy(2J)
      laminin to be released into solution, indicating that laminin polymers within the
      skeletal muscle basement membrane were defective. In addition to loss of
      polymerization, dy(2J) laminin had a reduced affinity for heparin. Finally,
      recombinant laminin engineered with the dy(2J) deletion was more sensitive to
      proteolysis and was readily cleaved near the junction of domains V and VI. Thus,
      the dy(2J) deletion selectively disrupts polymer formation, reduces affinity for
      heparin, and destabilizes domain VI. These are the first specific functional
      defects to be identified in a muscular dystrophy laminin, and it is likely that
      these defects contribute to the abnormalities seen in dy(2J)/dy(2J) muscle and
      nerve.

PMID- 10574768
TI  - Synthesis of diphosphoinositol pentakisphosphate by a newly identified family of
      higher inositol polyphosphate kinases.
AB  - Inositol (1,4,5) trisphosphate (Ins(1,4,5)P(3)) is a well-known messenger
      molecule that releases calcium from intracellular stores. Homologues with up to
      six phosphates have been characterized and recently, homologues with seven or
      eight phosphate groups, including pyrophosphates, have been identified. These
      homologues are diphosphoinositol pentakisphosphate (PP-InsP(5)/InsP(7)) and
      bis(diphospho)inositol tetrakisphosphate (bis-PP-InsP(4)/InsP(8)) [1], the rapid
      turnover of which [2] is regulated by calcium [2] and adrenergic receptor
      activity [3]. It has been proposed that the high-energy pyrophosphates might
      participate in protein phosphorylation [4]. We have purified InsP(6) kinase [5]
      and PP-InsP(5) kinase [6], both of which display ATP synthase activity,
      transferring phosphate to ADP. Here, we report the cloning of two mammalian
      InsP(6) kinases and a yeast InsP(6) kinase. Furthermore, we show that the yeast
      protein, ArgRIII, is an inositol-polyphosphate kinase that can convert InsP(3) to
      InsP(4), InsP(5) and InsP(6). We have identified a new family of highly conserved
      inositol-polyphosphate kinases that contain a newly identified, unique consensus
      sequence.

PMID- 10574773
TI  - Remembrance of things past...rumination.

PMID- 10574771
TI  - Human CED-6 encodes a functional homologue of the Caenorhabditis elegans
      engulfment protein CED-6.
AB  - The rapid engulfment of apoptotic cells is a specialized innate immune response
      used by organisms to remove apoptotic cells. In mammals, several receptors that
      recognize apoptotic cells have been identified; molecules that transduce signals
      from these receptors to downstream cytoskeleton molecules have not been found,
      however [1] [2] [3]. Our previous analysis of the engulfment gene ced-6 in
      Caenorhabditis elegans has suggested that CED-6 is an adaptor protein that
      participates in a signal transduction pathway that mediates the specific
      recognition and engulfment of apoptotic cells [1]. Here, we describe our
      isolation and characterization of a human cDNA encoding a protein, hCED-6, with
      strong sequence similarity to C. elegans CED-6. As is the case with the worm
      protein, hCED-6 contains a phosphotyrosine-binding (PTB) domain and potential Src
      homology domain 3 (SH3) binding sites. Both CED-6 and hCED-6 contain a predicted
      coiled-coil domain in the middle region. The hCED-6 protein lacks the extended
      carboxyl terminus found in worm CED-6; this carboxy-terminal extension appears
      not to be essential for CED-6 function in C. elegans, however. Overexpression of
      hCED-6 rescues the engulfment defect of ced-6 mutants in C. elegans
      significantly, suggesting that hCED-6 is a functional homologue of C. elegans CED
      6. Human ced-6 is expressed widely in most human tissues. Thus, CED-6, and the
      CED-6 signal transduction pathway, might be conserved from C. elegans to humans
      and are present in most, if not all, human tissues.

PMID- 10574770
TI  - A role of the cryptic gene in the correct establishment of the left-right axis.
AB  - During vertebrate embryogenesis, a left-right axis is established. The heart,
      associated vessels and inner organs adopt asymmetric spatial arrangements and
      morphologies. Secreted growth factors of the TGF-beta family, including nodal,
      lefty-1 and lefty-2, play crucial roles in establishing left-right asymmetries
      [1] [2] [3]. In zebrafish, nodal signalling requires the presence of one-eyed
      pinhead (oep), a member of the EGF-CFC family of membrane-associated proteins
      [4]. We have generated a mutant allele of cryptic, a mouse EGF-CFC gene [5].
      Homozygous cryptic mutants developed to birth, but the majority died during the
      first week of life because of complex cardiac malformations such as
      malpositioning of the great arteries, and atrial-ventricular septal defects.
      Moreover, laterality defects, including right isomerism of the lungs, right or
      left positioning of the stomach and splenic hypoplasia were observed. Nodal gene
      expression in the node was initiated in cryptic mutant mice, but neither nodal,
      lefty-2 nor Pitx2 were expressed in the left lateral plate mesoderm. The
      laterality defects observed in cryptic(-/-) mice resemble those of mice lacking
      the type IIB activin receptor or the homeobox-containing factor Pitx2 [6] [7] [8]
      [9], and are reminiscent of the human asplenic syndrome [10]. Our results provide
      genetic evidence for a role of cryptic in the signalling cascade that determines
      left-right asymmetry.

PMID- 10574772
TI  - The fukutin protein family--predicted enzymes modifying cell-surface molecules.

PMID- 10574774
TI  - John Sulston: a life in sequence.

PMID- 10574775
TI  - XML - extremely muddled language, or the future of the internet?

PMID- 10574777
TI  - Introns

PMID- 10574776
TI  - V(D)J recombination.

PMID- 10574778
TI  - Design of a triple-helix-specific cleaving reagent.
AB  - BACKGROUND: Double-helical DNA can be recognized sequence specifically by
      oligonucleotides that bind in the major groove, forming a local triple helix.
      Triplex-forming oligonucleotides are new tools in molecular and cellular biology
      and their development as gene-targeting drugs is under intensive study.
      Intramolecular triple-helical structures (H-DNA) are expected to play an
      important role in the control of gene expression. There are currently no good
      probes available for investigating triple-helical structures. We previously
      reported that a pentacyclic benzoquinoquinoxaline derivative (BQQ) can strongly
      stabilize triple helices. RESULTS: We have designed and synthesized the first
      triple-helix-specific DNA cleaving reagent by covalently attaching BQQ to
      ethylenediaminetetraacetic acid (EDTA). The intercalative binding of BQQ should
      position EDTA in the minor groove of the triple helix. In the presence of Fe(2+)
      and a reducing agent, the BQQ-EDTA conjugate can selectively cleave an 80 base
      pair (bp) DNA fragment at the site where an oligonucleotide binds to form a local
      triple helix. The selectivity of the BQQ-EDTA conjugate for a triplex structure
      was sufficiently high to induce oligonucleotide-directed DNA cleavage at a single
      site on a 2718 bp plasmid DNA. CONCLUSIONS: This new class of structure-directed
      DNA cleaving reagents could be useful for cleaving DNA at specific sequences in
      the presence of a site-specific, triple-helix-forming oligonucleotide and also
      for investigating triple-helical structures, such as H-DNA, which could play an
      important role in the control of gene expression in vivo.

PMID- 10574779
TI  - Expressed protein ligation to probe regiospecificity of heterocyclization in the
      peptide antibiotic microcin B17.
AB  - BACKGROUND: The Escherichia coli peptide antibiotic microcin B17 (MccB17)
      contains thiazole and oxazole heterocycles derived from a distributive yet
      directional cyclization of cysteines and serines in the McbA precursor catalyzed
      by MccB17 synthetase. Whether the formation of upstream rings potentiates
      downstream heterocyclization has not been previously determined. RESULTS: McbA
      fragments (46-61 residues) containing glycine substitutions or homocysteine at
      select upstream cysteine or serine sites were assembled using expressed protein
      ligation (EPL). Most of these substrates were only partially cyclized by MccB17
      synthetase, in contrast to the efficient processing of wild-type McbA(1-61).
      Homocysteine was not processed to the six-membered heterocycle. CONCLUSIONS: The
      formation of upstream rings in McbA potentiates the cyclization of carboxy
      terminal cysteines and serines, probably by selecting against unfavorable
      substrate conformations. EPL allows structure-function analysis including
      unnatural amino acid placements to probe the regiospecificity and
      chemoselectivity of post-translational heterocyclization during antibiotic
      maturation.

PMID- 10574780
TI  - A ribozyme and a catalytic DNA with peroxidase activity: active sites versus
      cofactor-binding sites.
AB  - BACKGROUND: An 18-nucleotide DNA oligomer, PS2.M, derived using an in vitro
      selection method was previously reported to bind hemin (Fe(III)-protoporphyrinIX)
      with submicromolar affinity. The DNA-hemin complex exhibited DNA-enhanced
      peroxidative activity. PS2. M is guanine-rich and requires potassium ions to fold
      to its active conformation, consistent with its forming a guanine-quaduplex. In
      investigating the specific catalytic features of PS2.M we tested the peroxidative
      properties of its RNA version (rPS2.M) as well as that of an unrelated DNA
      guanine-quadruplex, OXY4. RESULTS: The hemin-binding affinity of rPS2.M was found
      to be 30-fold weaker than that of PS2.M. The UV-visible spectra and kinetics of
      enzymatic peroxidation of the RNA-hemin complex, however, were nearly identical
      to those of its DNA counterpart. Both displayed peroxidase activity substantially
      greater than those of heme proteins such as catalase and Fe(III)-myoglobin.
      Kinetic analysis suggested that PS2. M and rPS2.M catalyzed the breakdown of the
      hemin-hydrogen peroxide covalent complex to products. The hemin complex of folded
      OXY4 (which bound hemin as strongly as did rPS2.M) had a distinct absorption
      spectrum and only a minor peroxidase activity above the background level.
      CONCLUSIONS: The results indicated that it is possible for RNA and DNA of the
      same sequence to fold to form comparable cofactor-binding sites, and to show
      comparable catalytic behavior. The results further suggest that only a subset of
      cofactor-binding sites formed within folded nucleic acids might be able to
      function as active sites, by providing the appropriate chemical environments for
      catalysis.

PMID- 10574781
TI  - Probing the binding of Tb(III) and Eu(III) to the hammerhead ribozyme using
      luminescence spectroscopy.
AB  - BACKGROUND: Divalent metal ions serve as structural as well as catalytic
      cofactors in the hammerhead ribozyme reaction. The natural cofactor in these
      reactions is Mg(II), but its spectroscopic silence makes it difficult to study.
      We previously showed that a single Tb(III) ion inhibits the hammerhead ribozyme
      by site-specific competition for a Mg(II) ion and therefore can be used as a
      spectroscopic probe for the Mg(II) it replaces. RESULTS: Lanthanide luminescence
      spectroscopy was used to study the coordination environment around Tb(III) and
      Eu(III) ions bound to the structurally well-characterized site on the hammerhead
      ribozyme. Sensitized emission and direct excitation experiments show that a
      single lanthanide ion binds to the ribozyme under these conditions and that three
      waters of hydration are displaced from the Tb(III) upon binding the RNA.
      Furthermore, we show that these techniques allow the comparison of binding
      affinities for a series of ions to this site. The binding affinities for ions at
      the G5 site correlates linearly with the function Z(2)/r of the aqua ion (where Z
      is the charge and r is the radius of the ion). CONCLUSIONS: This study compares
      the crystallographic nature of the G5 metal-binding site with solution
      measurements and gives a clearer picture of the coordination environment of this
      ion. These results provide one of the best characterized metal-binding sites from
      a ribozyme, so we use this information to compare the RNA site with that of
      typical metalloproteins.

PMID- 10574782
TI  - Towards subunit-specific proteasome inhibitors: synthesis and evaluation of
      peptide alpha',beta'-epoxyketones.
AB  - BACKGROUND: The proteasome is a large multicatalytic protease complex (700 kDa)
      involved in a number of highly regulated processes. It has three major catalytic
      activities: a chymotrypsin-like activity, a trypsin-like activity and a post
      glutamyl peptide hydrolyzing (PGPH) activity. To be useful as molecular probes,
      which could help dissect the cellular functions of the proteasome, inhibitors
      should be specific for the proteasome, active in vivo and selectively block only
      one of the three catalytic activities. To date, few inhibitors fulfill these
      requirements so we set out to make novel proteasome inhibitors that incorporate
      these characteristics. RESULTS: A panel of amino-terminally acetylated peptide
      alpha',beta'-epoxyketones with leucine in P1 and various aliphatic or aromatic
      amino acids in P2-P4 were prepared and evaluated. Most compounds selectively
      inhibited the chymotrypsin-like activity, while only weakly inhibiting the
      trypsin-like and PGPH activities. After optimization, one inhibitor, Ac-hFLFL
      epoxide, was found to be more potent and selective for the inhibition of the
      chymotrypsin-like activity than several previously described inhibitors. This
      inhibitor also exhibited strong in vivo anti-inflammatory activity. CONCLUSIONS:
      Optimization of amino-terminally acetylated peptide alpha',beta'-epoxyketones
      furnished a potent proteasome inhibitor, Ac-hFLFL-epoxide, that has an excellent
      selectivity for the chymotrypsin-like activity. The inhibitor also proved to be a
      potent antiproliferative and anti-inflammatory agent. The strong in vivo and in
      vitro activities suggest that this class of proteasome inhibitors could be both
      molecular probes and therapeutic agents.

PMID- 10574783
TI  - Expression of cre recombinase as a reporter of signal transduction in mammalian
      cells.
AB  - BACKGROUND: Cell-based reporter assays, which rely on a reporter gene under the
      control of a regulated promoter, are widely used to screen chemical libraries for
      novel receptor ligands. Here, we describe a reporter system that is based on
      ligand-induced DNA recombination to express the reporter gene. This system
      converts a transient activation of a signal transduction pathway into an
      amplified, constitutive and heritable expression of the reporter gene. RESULTS:
      We constructed gene fusions of Cre recombinase and mammalian promoters regulated
      by calcium, nuclear receptors or cyclic AMP. Reporter systems, comprising a Cre
      gene fusion and a loxP/reporter gene, were used to study the kinetics and dose
      responses to compounds that activate or inhibit the corresponding signal
      transduction pathway. We compared these reporters with conventional reporter
      systems in which the reporter gene is under the direct control of the responsive
      promoter. Reporter gene expression of the Cre reporters was greater than that of
      conventional reporters and could be measured more than a week after adding the
      stimulus. For all pathways studied here, the dose responses of the Cre reporters
      are nearly identical to those of conventional reporter systems. CONCLUSIONS: We
      have shown that Cre recombinase can be regulated by a variety of signal
      transduction pathways. It should therefore be possible to use receptor ligands to
      induce phenotypic conversion of mammalian cells for use in a variety of
      applications. One such application is high-throughput screening, and we developed
      loxP/luciferase reporter genes that provide an amplified and sustained
      luminescent response.

PMID- 10574784
TI  - Selective inhibition of amino-terminal methionine processing by TNP-470 and
      ovalicin in endothelial cells.
AB  - BACKGROUND: The angiogenesis inhibitors TNP-470 and ovalicin potently suppress
      endothelial cell growth. Both drugs also specifically inhibit methionine
      aminopeptidase 2 (MetAP2) in vitro. Inhibition of MetAP2 and changes in initiator
      methionine removal in drug-treated endothelial cells have not been demonstrated,
      however. RESULTS: Concentrations of TNP-470 sufficient to inactivate MetAP2 in
      intact endothelial cells were comparable to those that inhibited cell
      proliferation, suggesting that MetAP2 inhibition by TNP-470 underlies the ability
      of the drug to inhibit cell growth. Both drug-sensitive and drug-insensitive cell
      lines express MetAP1 and MetAP2, indicating that drug sensitivity in mammalian
      cells is not simply due to the absence of compensating MetAP activity. With a
      single exception, detectable protein N-myristoylation is unaffected in sensitive
      endothelial cells treated with TNP-470, so MetAP1 activity can generally
      compensate when MetAP2 is inactive. Analysis of total protein extracts from cells
      pulse-labeled with [(35)S]-methionine following TNP-470 treatment revealed
      changes in the migration of several newly synthesized proteins. Two of these
      proteins were identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and
      cyclophilin A. Purification and amino-terminal sequencing of GAPDH from TNP-470
      treated cells revealed partial retention of its initiator methionine, indicating
      that methionine removal from some, but not all, proteins is affected by MetAP2
      inactivation. CONCLUSIONS: Amino-terminal processing defects occur in cells
      treated with TNP-470, indicating that inhibition of MetAP2 by the drug occurs in
      intact cells. This work renders plausible a mechanism for growth inhibition by
      TNP-470 as a consequence of initiator methionine retention, leading to the
      inactivation of as yet unidentified proteins essential for endothelial cell
      growth.

PMID- 10574785
TI  - Combinatorial catalysis: identification of potent chiral catalysts through
      fluorescent bead signaling.
AB  - Simultaneous labeling of beads with a fluorescent sensor and a unique catalyst
      allows chemists to identify the most active catalyst within a mixture. This
      approach is a valuable addition to the protocols available in the growing field
      of combinatorial catalysis.

PMID- 10574786
TI  - Fix L, a haemoglobin that acts as an oxygen sensor: signalling mechanism and
      structural basis of its homology with PAS domains.
AB  - Fix L, which contains a haemoglobin domain homologous to the PAS family and a
      histidine kinase domain, forms, with Fix J, a two-component signalling complex
      that regulates expression of nitrogenase genes in Rhizobium. Spin transitions of
      its haem iron trigger stereochemical changes in and around the haem that,
      together with steric effects, control the activity of the kinase. Homology with
      the PAS family is based on a common core of about 20 structurally equivalent
      sites from which polar residues are excluded.

PMID- 10574787
TI  - Telomerase as a possible target for anticancer therapy.
AB  - Telomeres, the termini of chromosomes, provide essential stability to linear
      eukaryotic chromosomes. The enzyme telomerase is one mechanism that maintains
      telomeres, and is activated in 85% of human cancer cells. New studies on peptide
      nucleic acids (PNAs) that inhibit telomerase have demonstrated that unexpected
      regions of the enzyme can serve as targets for inhibitors. The novel delivery
      method used expands the utility of PNAs.

PMID- 10574788
TI  - The pre-hydrolysis state of p21(ras) in complex with GTP: new insights into the
      role of water molecules in the GTP hydrolysis reaction of ras-like proteins.
AB  - BACKGROUND: In numerous biological events the hydrolysis of guanine triphosphate
      (GTP) is a trigger to switch from the active to the inactive protein form. In
      spite of the availability of several high-resolution crystal structures, the
      details of the mechanism of nucleotide hydrolysis by GTPases are still unclear.
      This is partly because the structures of the proteins in their active states had
      to be determined in the presence of non-hydrolyzable GTP analogues (e.g. GppNHp).
      Knowledge of the structure of the true Michaelis complex might provide additional
      insights into the intrinsic protein hydrolysis mechanism of GTP and related
      nucleotides. RESULTS: The structure of the complex formed between p21(ras) and
      GTP has been determined by X-ray diffraction at 1.6 A using a combination of
      photolysis of an inactive GTP precursor (caged GTP) and rapid freezing (100K).
      The structure of this complex differs from that of p21(ras)-GppNHp (determined at
      277K) with respect to the degree of order and conformation of the catalytic loop
      (loop 4 of the switch II region) and the positioning of water molecules around
      the gamma-phosphate group. The changes in the arrangement of water molecules were
      induced by the cryo-temperature technique. CONCLUSIONS: The results shed light on
      the function of Gln61 in the intrinsic GTP hydrolysis reaction. Furthermore, the
      possibility of a proton shuffling mechanism between two attacking water molecules
      and an oxygen of the gamma-phosphate group can be proposed for the basal GTPase
      mechanism, but arguments are presented that render this protonation mechanism
      unlikely for the GTPase activating protein (GAP)-activated GTPase.

PMID- 10574789
TI  - The structure of Escherichia coli DNA topoisomerase III.
AB  - BACKGROUND: DNA topoisomerases are enzymes that change the topology of DNA. Type
      IA topoisomerases transiently cleave one DNA strand in order to pass another
      strand or strands through the break. In this manner, they can relax negatively
      supercoiled DNA and catenate and decatenate DNA molecules. Structural information
      on Escherichia coli DNA topoisomerase III is important for understanding the
      mechanism of this type of enzyme and for studying the mechanistic differences
      among different members of the same subfamily. RESULTS: The structure of the
      intact and fully active E. coli DNA topoisomerase III has been solved to 3.0 A
      resolution. The structure shows the characteristic fold of the type IA
      topoisomerases that is formed by four domains, creating a toroidal protein. There
      is remarkable structural similarity to the 67 kDa N-terminal fragment of E. coli
      DNA topoisomerase I, although the relative arrangement of the four domains is
      significantly different. A major difference is the presence of a 17 amino acid
      insertion in topoisomerase III that protrudes from the side of the central hole
      and could be involved in the catenation and decatenation reactions. The active
      site is formed by highly conserved amino acids, but the structural information
      and existing biochemical and mutagenesis data are still insufficient to assign
      specific roles to most of them. The presence of a groove in one side of the
      protein is suggestive of a single-stranded DNA (ssDNA)-binding region.
      CONCLUSIONS: The structure of E. coli DNA topoisomerase III resembles the
      structure of E. coli DNA topoisomerase I except for the presence of a positively
      charged loop that may be involved in catenation and decatenation. A groove on the
      side of the protein leads to the active site and is likely to be involved in DNA
      binding. The structure helps to establish the overall mechanism for the type IA
      subfamily of topoisomerases with greater confidence and expands the structural
      basis for understanding these proteins.

PMID- 10574790
TI  - Crystal structure of colicin E3 immunity protein: an inhibitor of a ribosome
      inactivating RNase.
AB  - BACKGROUND: Colicins are antibiotic-like proteins of Escherichia coli that kill
      related strains. Colicin E3 acts as an RNase that specifically cleaves 16S rRNA,
      thereby inactivating the ribosomes in the infected cell. The producing organism
      is protected against colicin E3 by a specific inhibitor, the immunity protein
      Im3, which forms a tight 1:1 complex with colicin E3 and renders it inactive.
      Crystallographic studies on colicin E3 and Im3 have been undertaken to unravel
      the structural basis for the ribonucleolytic activity and its inhibition.
      RESULTS: The crystal structure of Im3 has been determined to a resolution of 1.8
      A. The structure consists of a four-standard antiparallel beta sheet flanked by
      three alpha helices on one side of the sheet. Thr7, Phe9, Phe16 and Phe74 form a
      hydrophobic cluster on the surface of the protein in the vicinity of Cys47. This
      cluster is part of a putative binding pocket which also includes nine polar
      residues. CONCLUSIONS: The putative binding pocket of Im3 is the probable site of
      interaction with colicin E3. The six acidic residues in the pocket may interact
      with some of the numerous basic residues of colicin E3. The involvement of
      hydrophobic moieties in the binding is consistent with the observation that the
      tight complex can only be dissociated by denaturation. The structure of Im3
      resembles those of certain nucleic acid binding proteins, in particular domain II
      of topoisomerase I and RNA-binding proteins that contain the ribonucleoprotein
      (RNP) sequence motif. This observation suggests that Im3 has a nucleic acid
      binding function in addition to binding colicin E3.

PMID- 10574791
TI  - Crystal structure of Escherichia coli PurE, an unusual mutase in the purine
      biosynthetic pathway.
AB  - BACKGROUND: Conversion of 5-aminoimidazole ribonucleotide (AIR) to 4
      carboxyaminoimidazole ribonucleotide (CAIR) in Escherichia coli requires two
      proteins - PurK and PurE. PurE has recently been shown to be a mutase that
      catalyzes the unusual rearrangement of N(5)-carboxyaminoimidazole ribonucleotide
      (N(5)-CAIR), the PurK reaction product, to CAIR. PurEs from higher eukaryotes are
      homologous to E. coli PurE, but use AIR and CO(2) as substrates to produce CAIR
      directly. RESULTS: The 1.50 A crystal structure of PurE reveals an octameric
      structure with 422 symmetry. A central three-layer (alphabetaalpha) sandwich
      domain and a kinked C-terminal helix form the folded structure of the monomeric
      unit. The structure reveals a cleft at the interface of two subunits and near the
      C-terminal helix of a third subunit. Co-crystallization experiments with CAIR
      confirm this to be the mononucleotide-binding site. The nucleotide is bound
      predominantly to one subunit, with conserved residues from a second subunit
      making up one wall of the cleft. CONCLUSIONS: The crystal structure of PurE
      reveals a unique quaternary structure that confirms the octameric nature of the
      enzyme. An analysis of the native crystal structure, in conjunction with sequence
      alignments and studies of co-crystals of PurE with CAIR, reveals the location of
      the active site. The environment of the active site and the analysis of conserved
      residues between the two classes of PurEs suggests a model for the differences in
      their substrate specificities and the relationship between their mechanisms.

PMID- 10574792
TI  - The crystal structure of the dimerization initiation site of genomic HIV-1 RNA
      reveals an extended duplex with two adenine bulges.
AB  - BACKGROUND: An important step in retroviral replication is dimerization of the
      genomic RNA prior to encapsidation. Dimerization is initiated by the formation of
      a transient 'kissing-loop complex' that is thought to be subsequently matured
      into an extended duplex by the nucleocapsid protein (NCp). Although chemical
      probing and nuclear magnetic resonance spectroscopy have provided insight into
      the structure of the kissing-loop structure, no structural information concerning
      the extended-duplex state is available so far. RESULTS: The structure of a
      minimal HIV-1 RNA dimerization initiation site has been solved at 2.3 A
      resolution in two different space groups. It reveals a 22 base pair extended
      duplex with two noncanonical Watson-Crick-like G-A mismatches, each adjacent to a
      bulged-out adenine. The structure shows significant asymmetry in deep groove
      width and G-A base-pair conformations. A network of eight magnesium cations was
      clearly identified, one being unusually chelated by the 3' phosphate of each
      bulge across an extremely narrowed deep major groove. CONCLUSIONS: These crystal
      structures represent the putative matured form of the initial kissing-loop
      complex. They show the ability of this self-complementary RNA hairpin loop to
      acquire a more stable extended duplex structure. Both bulged adenines form a
      striking 'base grip' that could be a recognition signal, either in cis for
      another viral RNA sequence, or in trans for a protein, possibly the NCp.
      Magnesium binding might be important to promote and stabilize the observed
      extrahelical conformation of these bulges.

PMID- 10574794
TI  - A new class of hexahelical insect proteins revealed as putative carriers of small
      hydrophobic ligands.
AB  - BACKGROUND: THP12 is an abundant and extraordinarily hydrophilic hemolymph
      protein from the mealworm Tenebrio molitor and belongs to a group of small insect
      proteins with four highly conserved cysteine residues. Despite their sequence
      homology to odorant-binding proteins and pheromone-binding proteins, the function
      of these proteins is unclear. RESULTS: The first three-dimensional structure of
      THP12 has been determined by multidimensional NMR spectroscopy. The protein has a
      nonbundle helical structure consisting of six alpha helices. The arrangement of
      the alpha helices has a 'baseball glove' shape. In addition to the hydrophobic
      core, electrostatic interactions make contributions to the overall stability of
      the protein. NMR binding studies demonstrated the binding of small hydrophobic
      ligands to the single hydrophobic groove in THP12. Comparing the structure of
      THP12 with the predicted secondary structure of homologs reveals a common fold
      for this new class of insect proteins. A search with the program DALI revealed
      extensive similarity between the three-dimensional structure of THP12 and the N
      terminal domain (residues 1-95) of recoverin, a member of the family of calcium
      binding EF-hand proteins. CONCLUSIONS: Although the biological function of this
      new class of proteins is as yet undetermined, a general role as alpha-helical
      carrier proteins for small hydrophobic ligands, such as fatty acids or
      pheromones, is proposed on the basis of NMR-shift perturbation spectroscopy.

PMID- 10574793
TI  - Sidechain interactions in parallel beta sheets: the energetics of cross-strand
      pairings.
AB  - BACKGROUND: Both backbone hydrogen bonding and interactions between sidechains
      stabilize beta sheets. Cross-strand interactions are the closest contacts between
      the sidechains of a beta sheet. Here we investigate the energetics of cross
      strand interactions using a variant of the B1 domain of immunoglobulin G (IgG)
      binding protein G (beta1) as our model system. RESULTS: Pairwise mutations of
      polar and nonpolar residues were made at a solvent-exposed site between the two
      central parallel beta strands of beta1. Both stabilizing and destabilizing
      interactions were measured. The greatest stabilizations were observed for charge
      charge interactions. Our experimental study of sidechain interactions correlates
      with statistical preferences: residue pairs for which we measure stabilizing
      interaction energies occur together frequently, whereas destabilizing pairs are
      rarely observed together. CONCLUSIONS: Sidechain interactions modulate the
      stability of beta sheets. We propose that cross-strand sidechain interactions
      specify correct strand register and ordering through the energetic benefit of
      optimally arranged pairings.

PMID- 10574795
TI  - Binding of non-catalytic ATP to human hexokinase I highlights the structural
      components for enzyme-membrane association control.
AB  - BACKGROUND: Hexokinase I sets the pace of glycolysis in the brain, catalyzing the
      ATP-dependent phosphorylation of glucose. The catalytic properties of hexokinase
      I are dependent on product inhibition as well as on the action of phosphate. In
      vivo, a large fraction of hexokinase I is bound to the mitochondrial outer
      membrane, where the enzyme adopts a tetrameric assembly. The mitochondrion-bound
      hexokinase I is believed to optimize the ATP/ADP exchange between glucose
      phosphorylation and the mitochondrial oxidative phosphorylation reactions.
      RESULTS: The crystal structure of human hexokinase I has been determined at 2.25
      A resolution. The overall structure of the enzyme is in keeping with the closed
      conformation previously observed in yeast hexokinase. One molecule of the ATP
      analogue AMP-PNP is bound to each N-terminal domain of the dimeric enzyme in a
      surface cleft, showing specific interactions with the nucleotide, and localized
      positive electrostatic potential. The molecular symmetry brings the two bound AMP
      PNP molecules, at the centre of two extended surface regions, to a common side of
      the dimeric hexokinase I molecule. CONCLUSIONS: The binding of AMP-PNP to a
      protein site separated from the catalytic centre of human hexokinase I can be
      related to the role played by some nucleotides in dissociating the enzyme from
      the mitochondrial membrane, and helps in defining the molecular regions of
      hexokinase I that are expected to be in contact with the mitochondrion. The
      structural information presented here is in keeping with monoclonal antibody
      mapping of the free and mitochondrion-bound forms of the enzyme, and with
      sequence analysis of hexokinases that differ in their mitochondria binding
      properties.

PMID- 10574796
TI  - Diverse structural solutions to catalysis in a family of antibodies.
AB  - BACKGROUND: Small organic molecules coupled to a carrier protein elicit an
      antibody response on immunisation. The diversity of this response has been found
      to be very narrow in several cases. Some antibodies also catalyse chemical
      reactions. Such catalytic antibodies are usually identified among those that bind
      tightly to an analogue of the transition state (TSA) of the relevant reaction;
      therefore, catalytic antibodies are also thought to have restricted diversity. To
      further characterise this diversity, we investigated the structure and
      biochemistry of the catalytic antibody 7C8, one of the most efficient of those
      which enhance the hydrolysis of chloramphenicol esters, and compared it to the
      other catalytic antibodies elicited in the same immunisation. RESULTS: The
      structure of a complex of the 7C8 antibody Fab fragment with the hapten TSA used
      to elicit it was determined at 2.2 A resolution. Structural comparison with
      another catalytic antibody (6D9) raised against the same hapten revealed that the
      two antibodies use different binding modes. Furthermore, whereas 6D9 catalyses
      hydrolysis solely by transition-state stabilisation, data on 7C8 show that the
      two antibodies use mechanisms where the catalytic residue, substrate specificity
      and rate-limiting step differ. CONCLUSIONS: Our results demonstrate that
      substantial diversity may be present among antibodies catalysing the same
      reaction. Therefore, some of these antibodies represent different starting points
      for mutagenesis aimed at boosting their activity. This increases the chance of
      obtaining more proficient catalysts and provides opportunities for tailoring
      catalysts with different specificities.

PMID- 10574797
TI  - Molecular views of viral polyprotein processing revealed by the crystal structure
      of the hepatitis C virus bifunctional protease-helicase.
AB  - BACKGROUND: Hepatitis C virus (HCV) currently infects approximately 3% of the
      world's population. HCV RNA is translated into a polyprotein that during
      maturation is cleaved into functional components. One component, nonstructural
      protein 3 (NS3), is a 631-residue bifunctional enzyme with protease and helicase
      activities. The NS3 serine protease processes the HCV polyprotein by both cis and
      trans mechanisms. The structural aspects of cis processing, the autoproteolysis
      step whereby the protease releases itself from the polyprotein, have not been
      characterized. The structural basis for inclusion of protease and helicase
      activities in a single polypeptide is also unknown. RESULTS: We report here the
      2.5 A resolution structure of an engineered molecule containing the complete NS3
      sequence and the protease activation domain of nonstructural protein 4A (NS4A) in
      a single polypeptide chain (single chain or scNS3-NS4A). In the molecule, the
      helicase and protease domains are segregated and connected by a single strand.
      The helicase necleoside triphosphate and RNA interaction sites are exposed to
      solvent. The protease active site of scNS3-NS4A is occupied by the NS3 C
      terminus, which is part of the helicase domain. Thus, the intramolecular complex
      shows one product of NS3-mediated cleavage at the NS3-NS4A junction of the HCV
      polyprotein bound at the protease active site. CONCLUSIONS: The scNS3-NS4A
      structure provides the first atomic view of polyprotein cis processing. Both
      local and global structural rearrangements follow the cis cleavage reaction, and
      large segments of the polyprotein can be folded prior to proteolytic processing.
      That the product complex of the cis cleavage reaction exists in a stable
      molecular conformation suggests autoinhibition and substrate-induced activation
      mechanisms for regulation of NS3 protease activity.

PMID- 10574798
TI  - The 2 A structure of helix 6 of the human signal recognition particle RNA.
AB  - BACKGROUND: The mammalian signal recognition particle (SRP) is an essential
      cytoplasmic ribonucleoprotein complex involved in targeting signal-peptide
      containing proteins to the endoplasmic reticulum. Assembly of the SRP requires
      protein SRP19 to bind first to helix 6 of the SRP RNA before the signal-peptide
      recognizing protein, SRP54, can bind to helix 8 of the RNA. Helix 6 is closed by
      a GGAG tetraloop, which has been shown to form part of the SRP19-binding site.
      RESULTS: The high-resolution (2.0 A) structure of a fragment of human SRP RNA
      comprising 29 nucleotides of helix 6 has been determined using the multiple
      anomalous dispersion (MAD) method and bromine-labelled RNA. In the crystal the
      molecule forms 28-mer duplexes rather than the native monomeric hairpin
      structure, although two chemically equivalent 11 base pair stretches of the
      duplex represent the presumed native structure. The duplex has highly distorted A
      RNA geometry caused by the occurrence of several non-Watson-Crick base pairs.
      These include a 5'-GGAG-3'/3'-GAGG-5' purine bulge (which replaces the tetraloop)
      and a 5'-AC-3'/3'-CA-5' tandem mismatch that, depending on the protonation state
      of the adenine bases, adopts a different conformation in the two native-like
      parts of the structure. The structure also shows the 2'3'-cyclic phosphate
      reaction product of the hammerhead ribozyme cleavage reaction. CONCLUSIONS: The
      29-mer RNA is the first RNA structure of the human SRP and provides some insight
      into the binding mode of SRP19. The observed strong irregularities of the RNA
      helix make the major groove wide enough and flat enough to possibly accommodate
      an alpha helix of SRP19. The variety of non-canonical base pairs observed
      enlarges the limited repertoire of irregular RNA folds known to date and the
      observed conformation of the 2'3'-cyclic phosphate containing Ade29 is consistent
      with the current understanding of the hammerhead ribozyme reaction mechanism.

PMID- 10574800
TI  - Glycyl radical enzymes: a conservative structural basis for radicals.
AB  - The first structures of glycyl radical enzymes, the anaerobic ribonucleotide
      reductase from bacteriophage T4 and pyruvate formate lyase from Escherichia coli,
      have been recently determined. This work provides new insights into the structure
      and chemistry of glycyl radical sites.

PMID- 10574799
TI  - The crystal structure of the minus-end-directed microtubule motor protein ncd
      reveals variable dimer conformations.
AB  - BACKGROUND: The kinesin superfamily of microtubule-associated motor proteins are
      important for intracellular transport and for cell division in eukaryotes.
      Conventional kinesins have the motor domain at the N terminus of the heavy chain
      and move towards the plus end of microtubules. The ncd protein is necessary for
      chromosome segregation in meiosis. It belongs to a subfamily of kinesins that
      have the motor domain at the C terminus and move towards the minus end of
      microtubules. RESULTS: The crystal structure of dimeric ncd has been obtained at
      2.9 A resolution from crystals with the C222(1) space group, with two independent
      dimers per asymmetric unit. The motor domains in these dimers are not related by
      crystallographic symmetry and the two ncd dimers have significantly different
      conformations. An alpha-helical coiled coil connects, and interacts with, the
      motor domains. CONCLUSIONS: The ncd protein has a very compact structure, largely
      due to extended interactions of the coiled coil with the head domains. Despite
      this, we find that the overall conformation of the ncd dimer can be rotated by as
      much as 10 degrees away from that of the twofold-symmetric archetypal ncd. The
      crystal structures of conventional kinesin and of ncd suggest a structural
      rationale for the reversal of the direction of movement in chimeric kinesins.

PMID- 10574801
TI  - Producing selenomethionine-labeled proteins with a baculovirus expression vector
      system.

PMID- 10574802
TI  - Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus.
AB  - BACKGROUND: Hepatitis C virus (HCV) is the major etiological agent of
      hepatocellular carcinoma, and HCV RNA-dependent RNA polymerase (RdRp) is one of
      the main potential targets for anti-HCV agents. HCV RdRp performs run-off copying
      replication in an RNA-selective manner for the template-primer duplex and the
      substrate, but the structural basis of this reaction mechanism has still to be
      elucidated. RESULTS: The three-dimensional structure of HCV RdRp was determined
      by X-ray crystallography at 2.5 A resolution. The compact HCV RdRp structure
      resembles a right hand, but has more complicated fingers and thumb domains than
      those of the other known polymerases, with a novel alpha-helix-rich subdomain
      (alpha fingers) as an addition to the fingers domain. The other fingers subdomain
      (beta fingers) is folded in the same manner as the fingers domain of human
      immunodeficiency virus (HIV) reverse transcriptase (RT), another RNA-dependent
      polymerase. The ribose-recognition site of HCV RdRp is constructed of hydrophilic
      residues, unlike those of DNA polymerases. The C-terminal region of HCV RdRp
      occupies the putative RNA-duplex-binding cleft. CONCLUSIONS: The structural basis
      of the RNA selectivity of HCV RdRp was elucidated from its crystal structure. The
      putative substrate-binding site with a shallow hydrophilic cavity should have
      ribonucleoside triphosphate (rNTP) as the preferred substrate. We propose that
      the unique alpha fingers might represent a common structural discriminator of the
      template-primer duplex that distinguishes between RNA and DNA during the
      replication of positive single-stranded RNA by viral RdRps. The C-terminal region
      might exert a regulatory function on the initiation and activity of HCV RdRp.

PMID- 10574803
TI  - Putting two and two together: crystal structure of the FGF-receptor complex.
AB  - The recently determined crystal structure of an FGF-receptor complex reveals a
      surprising architecture and a novel mode of receptor dimerization. The structure
      also elucidates the role of heparan sulfate proteoglycans in receptor activation,
      showing significant differences from previously proposed models.

PMID- 10574804
TI  - Importance of early diagnosis of retinoblastoma.

PMID- 10574805
TI  - Advancing microsurgical instrumentation into the 21st century.

PMID- 10574806
TI  - Delay in diagnosis of retinoblastoma: risk factors and treatment outcome.
AB  - BACKGROUND: Delay in diagnosis of retinoblastoma causes considerable parental
      distress; however, the primary healthcare professional (PHP) may have difficulty
      detecting the most common presenting symptom-leucocoria. Alternatively, the PHP
      may not appreciate that retinoblastoma is the pathology underlying more common
      ocular symptoms in infants and young children. METHOD: The parents of 100
      recently diagnosed patients with retinoblastoma were interviewed to establish the
      extent of diagnostic delay, ascertain any associated risk factors, and to
      determine whether or not delay influenced treatment outcome. RESULTS: Although
      nearly 50% of patients were referred to an ophthalmologist within 1 week of first
      consulting a PHP, one quarter waited more than 8 weeks. There was a significantly
      increased risk of diagnostic delay in younger patients, those presenting with
      squint rather than leucocoria, and those first presenting to a health visitor
      rather than to a general practitioner. The risk of local tumour invasion was
      significantly increased by diagnostic delay. Treatment with primary enucleation
      was not increased by diagnostic delay. There were no deaths during the study
      period. CONCLUSION: Primary healthcare professionals require education about the
      importance of ocular symptoms, especially squint, in paediatric patients.

PMID- 10574807
TI  - Ocular arterial blood flow of choroidal melanoma eyes before and after
      stereotactic radiotherapy using Leksell gamma knife: 2 year follow up.
AB  - AIMS: To evaluate the effect of high dose stereotactic radiotherapy on the ocular
      blood flow of patients with uveal melanoma. METHODS: Colour Doppler imaging (CDI)
      was used to measure blood flow velocity and vascular resistance in the
      ophthalmic, short posterior, and central retinal arteries of nine patients
      suffering from uveal melanoma. The measurements were taken before, 6 months, 1
      year, and 2 years after stereotactic radiotherapy. Irradiation was performed with
      the Leksell gamma knife with the 59 (41-66.5) Gy total marginal dose divided in
      two equal fractions. CDI results were compared with age and sex matched healthy
      control eyes. RESULTS: At each time of measurement, blood flow velocity in the
      central retinal artery of the affected eyes was significantly reduced whereas
      vascular resistance was only increased at the 2 year follow up. Blood flow
      velocity and vascular resistance in the short posterior arteries of melanoma eyes
      were also only significantly altered at the 2 year follow up. Blood flow velocity
      and vascular resistance in the ophthalmic artery of melanoma eyes were not
      changed at all follow ups. CONCLUSIONS: In the melanoma eyes, blood flow velocity
      in the central retinal artery is reduced. High dose stereotactic radiotherapy
      with the Leksell gamma knife and a 59 (41-66.5) Gy total marginal dose in two
      fractions leads to a significant reduction of blood flow and a significant
      increase in resistance variables in the small ocular arteries within 2 years.

PMID- 10574808
TI  - Perifoveal microcirculation in eyes with epiretinal membranes.
AB  - BACKGROUND/AIMS: Eyes with epiretinal membranes (ERMs) often have alterations of
      retinal vessels. The authors studied perifoveal microcirculation in eyes with
      epiretinal membranes (ERMs) using scanning laser ophthalmoscope (SLO) fluorescein
      angiography. METHODS: Mean capillary blood flow velocity (CFV) was measured as an
      index of perifoveal microcirculation by SLO fluorescein angiography in 26 eyes
      with ERMs (19 eyes with idiopathic epiretinal membranes, seven eyes with
      epiretinal membranes after retinal detachment surgery) before and 6 months after
      vitreous surgery, and in 23 healthy control subjects. RESULTS: The mean CFV was
      significantly reduced in eyes with ERMs compared with healthy controls (p=0.012),
      and the postoperative mean CFV was significantly increased compared with the
      preoperative mean CFV (p=0.041). CONCLUSION: Significant changes of capillary
      blood flow velocity in the perifoveal areas were observed between normal subjects
      and eyes with epiretinal membranes. This indicates that eyes with ERMs show
      abnormal haemodynamics in the perifoveal capillaries.

PMID- 10574809
TI  - Alterations in the conjunctival bacterial flora following a single dose of
      azithromycin in a trachoma endemic area.
AB  - BACKGROUND/AIMS: The World Health Organisation has recommended repeated mass
      treatment of children in trachoma endemic areas with oral azithromycin. While
      chlamydia, the causative agent of trachoma, remains universally sensitive to
      azithromycin, there is concern that large scale programmes may alter the
      bacterial flora and induce resistance in streptococcal species. In this study the
      effect of a single dose of azithromcyin on the prevalence, species distribution,
      and resistance of conjunctival bacterial flora was determined. METHODS: Baseline
      and 14 day follow up bacterial cultures were taken from the conjunctivae of 121
      children who reside in a trachoma endemic area of Nepal. 91 children were treated
      with azithromycin at baseline and 31 children received deferred treatment at the
      14 day follow up. RESULTS: Although the prevalence of bacterial pathogens
      decreased significantly with azithromycin treatment, a significant change in the
      distribution of specific bacterial pathogens could not be demonstrated.
      Streptococcal resistance to azithromycin was found significantly more frequently
      after treatment. No change in the prevalence, distribution, or resistance pattern
      was found in the untreated control group. CONCLUSION: Repeated mass treatment of
      trachoma endemic areas with oral azithromycin will have an effect on bacterial
      flora. However, further work needs to be done to determine if this will have any
      clinical relevance.

PMID- 10574810
TI  - National cataract surgery survey 1997-8: a report of the results of the clinical
      outcomes.
AB  - AIMS: A national survey of over 100 hospitals in the UK was carried out to
      collect routine clinical information on the outcomes of cataract surgery. The
      clinical outcomes of interest were: visual acuity at time of discharge from
      postoperative hospital follow up, visual acuity at time of final refraction;
      complications related to surgery occurring during the operation, within 48 hours
      of surgery, and within 3 months of surgery. In addition, information on age and
      comorbidity was obtained. This article reports on the findings of the experience
      of approximately 18 000 patients who had cataract surgery in the hospital eye
      service of the NHS. RESULTS: Of those with no ocular comorbidity, 85% achieved a
      visual acuity of 6/12 or better on discharge from postoperative hospital follow
      up, while 65% of patients with a serious co-existing eye disease achieved this
      level of acuity at this time. At final refraction, 92% of patients without ocular
      comorbidity and 77% of patients with ocular comorbidity achieved 6/12 or better
      visual acuity. The following main risk indicators were associated with visual
      outcomes and complications related to surgery: age, other eye diseases, diabetes
      and stroke, type of surgical procedure, and grade of surgeon. CONCLUSIONS: The
      acceptability of these findings could fruitfully be the subject of discussion
      within the ophthalmic community and hopefully issues arising out of the study can
      lead to research, especially in-depth studies of the outcomes of cataract surgery
      in those patients with co-existing serious eye conditions.

PMID- 10574811
TI  - Full text reading with a central scotoma: pseudo regressions and pseudo line
      losses.
AB  - AIMS: To investigate the reading strategy of a patient with central scotoma,
      using several preferred retinal loci (PRL). METHODS: A 47 year old man with
      Stargardt's disease was asked to decipher texts projected onto his retina using a
      scanning laser ophthalmoscope. A recording of the fundus image, on which the
      projected texts were superimposed, was analysed frame by frame. RESULTS: The
      subject used a combination of three PRL, located above the scotoma and laterally
      to the left and right of it. He first used his left PRL to search for the
      beginning of a line, then switched to his right PRL, thus performing an apparent
      regression which was called "pseudo regression", to read the line with successive
      rightward saccades. To decipher a particularly difficult word, he switched to his
      upper PRL, showing an apparent line loss which was called ("pseudo line loss"),
      and then used his three PRL in combination. CONCLUSION: The patient used a
      complex, well structured reading strategy. These data showed that backward
      saccades and unexpected line losses, hitherto thought to be inappropriate and
      uneconomical, may in fact represent purposeful changes of PRL. It is thought that
      this is the first structured reading behaviour ever identified in such a
      condition. Such adaptive oculomotor behaviour should be taken into account when
      considering rehabilitation procedures.

PMID- 10574812
TI  - Randomised controlled trial of corticosteroid regimens in endothelial corneal
      allograft rejection.
AB  - AIM: To determine whether the addition of systemic corticosteroid to local
      intensive corticosteroid therapy of endothelial corneal allograft rejection
      improves outcome. METHODS: A prospective randomised treatment trial was carried
      out at a tertiary referral centre. 36 consecutive corneal graft recipients,
      presenting with a first episode of endothelial graft rejection, received either
      (i) one intravenous pulse of methylprednisolone 500 mg in addition to local
      corticosteroid treatment, or (ii) local treatment only. The regimen of local
      treatment standardised in all cases for the first 24 hours consisted of one
      subconjunctival betamethasone 2 mg injection and dexamethasone 0.1% drops in the
      affected eye every hour for 24 hours. RESULTS: Failure to reverse the graft
      rejection episode was found in 3/36 (8%) patients. Each of these had been treated
      with local steroid only. Graft failure from any cause occurred in 9/36 (25%)
      within 2 years of follow up. No statistically significant difference was found
      between the two groups with regard to reversal of the graft rejection episode,
      later recurrence of graft rejection, or graft failure. CONCLUSIONS: In treatment
      of graft rejection, additional systemic treatment with 500 mg methylprednisolone
      yields no significant benefit over intensive local corticosteroid alone. Graft
      survival following treatment of a rejection episode with local corticosteroid
      treatment alone is good in those patients without other risk factors for graft
      failure and much higher than reported previously.

PMID- 10574813
TI  - Cellular photoablation to control postoperative fibrosis in a rabbit model of
      filtration surgery.
AB  - AIM: To evaluate the feasibility of cellular photoablation using fluorescence
      generated photoreaction products as a method to control postoperative fibrosis.
      METHODS: The fluorescent probe, 2',7'-bis-(2-carboxyethyl)-5-(and-6)
      carboxyfluorescein, acetoxymethyl ester (BCECF-AM) is a cell membrane permeable
      compound rendered membrane impermeable and fluorescent upon cleavage by
      intracellular esterases. Rabbits (ChBB:CH; n=20) received a unilateral
      subconjunctival injection of BCECF-AM (40, 70, 80, or 100 microg) 30 minutes
      before surgery followed by intraoperative illumination with diffuse blue light
      (450-490 nm; 51.9 x 10(3) cd/m(2)) for 10 minutes. Controls received either the
      probe or illumination. Antifibrotic efficacy was established by clinical response
      and histological examination. Clinical response was assessed by comparing
      intraocular pressure (IOP) between the treated experimental eye and the fellow
      eye, which served as control. Success was defined by >20% difference in IOP.
      RESULTS: IOP was significantly decreased in all groups within 4 days
      postoperatively. In control groups IOP rose within 10 days to normal levels. This
      was similar in the group receiving 40 microg of BCECF-AM. In the other groups
      (subconjunctival injection of 70-100 microg BCECF-AM) IOP was significantly (p <
      0.02) decreased for 2-3 weeks. Clinical and histological examination revealed no
      toxic damage to adjacent tissues. CONCLUSIONS: Cellular photoablation in contrast
      with chemotherapeutic agents acts on cells that have incorporated BCECF-AM and
      have been exposed to light at the appropriate wavelength. Though safety and
      reliability demand further studies this method might be an useful therapeutic
      approach to control postoperative fibrosis in humans undergoing filtration
      surgery.

PMID- 10574814
TI  - Soluble Fas and Fas ligand in human tear fluid after photorefractive keratectomy.
AB  - BACKGROUND/AIMS: The Fas-Fas ligand system is thought to be involved in stromal
      cell apoptosis after corneal wounding. The aim was to measure changes in human
      tear fluid levels of soluble Fas (sFas) and Fas ligand (sFasL) following myopic
      photorefractive keratectomy (PRK). METHODS: Tear samples of 59 patients were
      collected preoperatively, and 1 or 2 days after PRK. Tear fluid sFas or sFasL
      concentrations were determined using sandwich ELISAs. Subsequently, tear flow
      corrected concentrations (releases) were calculated to compensate for the
      postoperative tear hypersecretion. RESULTS: The preoperative tear fluid flows
      (TFF) were 6.4 (1.7) microl/min (mean (SEM)) in sFas group (n = 18), and 7.5
      (1.5) microl/min in sFasL group (n = 39). Postoperatively TFFs increased to 37.9
      (10.9) microl/min (p = 0.003) and 58.3 (7.0) microl/min (p = 0.000),
      respectively. The mean preoperative sFas concentration (24.4 (11.6) U/ml)
      decreased to 9.7 (4.1) U/ml (p = 0.001) postoperatively, and the mean sFasL
      concentration (299.1 (28.8) ng/l) to 118.7 (15.9) ng/l (p = 0.000). However, the
      release of both substances increased significantly: sFas from 87.3 (29.4) mU/min
      to 229.4 (82.9) mU/min (p = 0.002) and sFasL from 1620.6 (226.4) fg/min to 4777.1
      (596.1) fg/min (p = 0.000). CONCLUSIONS: Both sFas and sFasL are normal
      constituents of human tears. Despite a decrease in concentrations related to
      reflex tears, the release of sFas and sFasL increases significantly after excimer
      laser photorefractive keratectomy, which suggests that they are involved in
      corneal healing after PRK in humans.

PMID- 10574815
TI  - Cell subpopulations in failed human corneal grafts.
AB  - BACKGROUND/AIMS: Inflammatory cells and antigen presenting cells (APC) are not
      present under normal circumstances in the centre of the healthy cornea. The
      purpose of this study was to investigate and phenotype the inflammatory cell
      populations, particularly with reference to T cell subpopulations and
      macrophages, and to localise dendritic cells (DC) and other MHC class II positive
      cells in three groups of grafted corneas: rejected non-inflamed, rejected
      inflamed grafts, and control dystrophic explants. METHODS: 15 corneal buttons
      removed during keratoplasty from non-inflamed "quiet" previously grafted corneas,
      five inflamed corneas requiring urgent regrafting for "graft melting" (in "high
      risk" corneas), and 10 control dystrophic opaque corneas explanted during their
      first graft procedure were examined. Cryosections of corneas were immunostained
      with a panel of monoclonal antibodies (mAb) against CD3, CD4, CD8, CD14, CD25,
      CD68, HLA-DP, and HLA-DR molecules using the StreptABC method. DC were detected
      by dual immunostaining as CD1a+ and MHC class II+ and CD19-. Cell densities in
      immunostained tissue sections were evaluated using a scale from 0 to +4. RESULTS:
      Immunostaining in control dystrophic corneas was negative for all antibodies. A
      moderate to high density of CD8+, CD14+, and CD68+ cells was observed in the
      majority of rejected non-inflamed as well as in rejected inflamed corneal
      buttons. Strong positivity for HLA-DP and HLA-DR molecules in the epithelium,
      stroma, and endothelium was also demonstrated. Weak positivity for CD4 and CD25
      was observed in six of 15 and 11 of 15 rejected corneas, respectively. The
      presence of dendritic cells in the basal layer of the epithelium and in the
      stroma was observed in 50% of the grafts. CONCLUSIONS: A high frequency of
      macrophages, the presence of DC in the explants, and strong expression of HLA-DP
      and HLA-DR molecules on resident cells are characteristics of rejected corneal
      allografts, whether actively inflamed or not. The presence of DC in the stroma of
      the grafted cornea suggests that they may be mainly responsible for T cell
      activation and graft rejection since DC are known to be a 100-fold more potent
      than macrophages as APC.

PMID- 10574818
TI  - Environmental scanning electron microscopic study of macrophages associated with
      the tunica vasculosa lentis in the developing rat eye.
AB  - AIMS: To demonstrate the value of environmental scanning electron microscopy
      (ESEM) when used in combination with immunogold/silver enhancement methods as a
      valuable tool in ocular research, and to determine the phenotype of macrophages
      associated with the tunica vasculosa lentis while maintaining a topographical
      view of the lens surface. METHODS: Prenatal and postnatal rat eyes were
      investigated by conventional scanning electron microscopy and ESEM. In the latter
      case tissues were prestained with a panel of antileucocyte monoclonal antibodies
      and visualised with colloidal gold conjugated secondary antibody followed by
      silver enhancement. RESULTS: The preliminary data demonstrate that ED1(+) ED2(+)
      macrophages occur in large numbers around the lens and are associated with
      sectors of both normal vessels and those undergoing regression. CONCLUSION: The
      present study demonstrates that ESEM is an ideal way to combine scanning electron
      microscopy with immunohistochemistry and is therefore likely to have multiple
      other applications in ocular research.

PMID- 10574816
TI  - Biochemical and ultrastructural changes in rabbit sclera after treatment with 7
      methylxanthine, theobromine, acetazolamide, or L-ornithine.
AB  - AIMS: To examine a possible effect of 7-methylxanthine, theobromine,
      acetazolamide, or L-ornithine on the ultrastructure and biochemical composition
      of rabbit sclera. METHODS: Groups of pigmented rabbits, six in each group, were
      dosed during 10 weeks with one of the substances under investigation, and one
      untreated group was the control. Samples of anterior and posterior sclera were
      taken for determination of hydroxyproline, hydroxylysine, proline, proteoglycans,
      uronic acids and dermatan sulphate, chondroitin sulphate, and hyaluronic acid.
      Sections were examined with electron microscopy, and the diameter of the
      individual collagen fibrils was measured. RESULTS: Treatment with theobromine
      produced a significant increase in the contents of hydroxylysine, hydroxyproline,
      and proline in both anterior and posterior sclera, while 7-methylxanthine
      increased the contents of hydroxyproline and proline selectively in posterior
      sclera. Acetazolamide, on the other hand, significantly decreased the contents of
      hydroxyproline and proline in samples from anterior sclera. Uronic acids in both
      anterior and posterior sclera were significantly reduced by treatment with 7
      methylxanthine, and L-ornithine significantly reduced uronic acids in posterior
      sclera. An inverse correlation between contents of hydroxyproline and uronic
      acids was found. The mean diameter of collagen fibrils was significantly higher
      in the posterior sclera from rabbits treated with 7-methylxanthine or
      theobromine, and significantly lower in rabbits treated with acetazolamide or L
      ornithine compared with controls. In the anterior sclera, fibril diameter was
      significantly reduced in all treatment groups compared with controls. A positive,
      significant correlation between fibril diameter and content of hydroxyproline and
      proline was found in posterior sclera. CONCLUSION: 7-Methylxanthine, a metabolite
      of caffeine, increases collagen concentration and the diameter of collagen
      fibrils in the posterior sclera, and may be useful for treatment or prevention of
      conditions associated with low level and/or inferior quality of scleral collagen,
      such as axial myopia, chronic open angle glaucoma, and possibly neovascular age
      related macular degeneration. The apparent loss of collagen induced by chronic
      treatment with acetazolamide should be taken into consideration as a potentially
      harmful side effect. These results may indicate that scleral biochemistry and
      ultrastructure are influenced by the retinal pigment epithelium. One possible
      explanation is that the scleral fibroblasts which produce the collagen are
      sensitive to changes in the physiological electric field created by the retinal
      pigment epithelium.

PMID- 10574817
TI  - Role of ocular matrix metalloproteinases in peripheral ulcerative keratitis.
AB  - AIM: Peripheral ulcerative keratitis (PUK) is an ocular manifestation of
      rheumatoid arthritis and other similar systemic diseases. The purpose of this
      inquiry was to investigate the involvement of matrix metalloproteinases (MMPs) in
      the induction and/or maintenance of PUK. METHODS: Substrate gel electrophoresis
      was used to characterise the MMP activities secreted by primary cultures of
      keratocytes derived from normal and perforated pathological corneal specimens,
      and those present in tears of normal subjects and patients with PUK. Substrate
      specificity and the in vivo activity status of the secreted MMPs was assessed by
      SDS-polyacrylamide gel electrophoresis of standard collagens incubated in the
      presence or absence of the various enzyme preparations. RESULTS: In addition to
      MMP-2 of M(r) 66,000, cultured keratocytes derived from perforated corneas of
      patients with PUK abnormally produce the MMP-2 of apparent M(r) 62,000. Other
      MMPs and in particular MMP-9 of M(r) 92,000, also occur in the tears of these
      patients. Their visualisation on substrate polyacrylamide gels correlated with
      clinical manifestations of disease activity; during periods of disease quiescence
      they were barely detectable. The steroid prednisolone, frequently used in
      systemic therapy, had no effect on the in vitro activity of MMP-2, or on its
      production by cultured corneal keratocytes. Although the in vitro activity of MMP
      2 was inhibited by both Cu(2+) and Zn(2+), Cu(2+) apparently induced the
      keratocytes to produce activated enzyme and Zn(2+) irreversibly inhibited their
      production of MMP-2. CONCLUSION: Overexpression of corneal MMP-2 and tear film
      MMP-9 are characteristic features of patients with PUK and their activation may
      be a crucial facet of disease initiation or progression. Although effective in
      systemic therapy for PUK, prednisolone had no direct control over corneal MMP-2
      production or activity. Zn(2+) on the other hand inhibited both MMP-2 production
      and MMP-2 activity and may, therefore, be of therapeutic value if suitably
      formulated and used in conjunction with systemic steroid treatment.

PMID- 10574819
TI  - CD56+ T cells in the peripheral blood of uveitis patients.
AB  - AIMS: Natural killer T (NKT) cells, T lymphocytes expressing both T cell and NK
      cell markers, are suggested to be involved in autoimmune diseases. To examine the
      relation between the pathogenesis of uveitis and CD56+ T cells, which are thought
      to be a type of human NKT cells, we investigated peripheral CD56+ T cells in
      uveitis patients. METHODS: 41 uveitis patients (Behcet's disease (BD), 14;
      sarcoidosis (SAR), eight; Vogt-Koyanagi-Harada disease (VKH), five; idiopathic
      uveitis (IU), nine; and others, five) and 19 healthy controls participated in
      this study. Cell surface antigens of lymphocytes were analysed by use of
      monoclonal antibodies and flow cytometry. RESULTS: The proportion of CD56+ T
      cells in patients with BD was higher than in controls and in patients with SAR,
      VKH, IU, and others. CONCLUSION: Increased peripheral CD56+ T cells might be
      relevant to the pathogenesis of uveitis in BD, and increase of peripheral CD56+ T
      cells may be one of the laboratory findings to suggest that uveitis originates
      from BD.

PMID- 10574820
TI  - Ocular complications of acoustic neuroma surgery.
AB  - AIM: To analyse the risk factors involved in the development of ocular
      complications after acoustic neuroma resection, in particular corneal
      complications and visual loss, and to identify measures that may reduce these.
      METHODS: 62 patients who underwent surgery for acoustic neuroma had a
      standardised ophthalmic examination and retrospective case note review. RESULTS:
      At final review (mean 37.6 months), although 38 patients reported ocular
      symptoms, only 22% saw 6/12 or worse. Patients with hypoaesthetic corneas had a
      higher incidence of corneal pathology (79%) than those with normal sensation
      (39%). Lagophthalmos increased the incidence of corneal pathology (to 80%); in
      those with normal closure, the incidence was only 46%. 20 patients required at
      least one ophthalmic surgical procedure. CONCLUSIONS: After acoustic neuroma
      resection patients place a considerable burden on the ophthalmologist. Immediate
      referral postoperatively, and frequent review of those with abnormal sensation
      may reduce the severity of long term ocular complications.

PMID- 10574821
TI  - The pituitary-adrenal axis in idiopathic retinal vasculitis.
AB  - AIMS: To determine whether patients with idiopathic retinal vasculitis have
      altered production of cortisol and dehydroepiandrosterone sulphate (DHEA-S), and
      whether differences in these variables occur between those who are sensitive (SS)
      and resistant (SR) to steroids. METHODS: 20 patients with retinal vasculitis (off
      treatment) and 10 control subjects were prospectively recruited. Morning cortisol
      and DHEA-S levels were measured, and cortisol secretion rates and short synacthen
      tests (SST) carried out in patients before treatment, when on prednisolone 20
      mg/day, and in controls. RESULTS: There were no differences in any variables
      between patients and controls. For retinal vasculitis patients pretreatment, the
      SST was lower in SR patients (p=0.02). More of the SR patients had ischaemic
      retinal vasculitis ( p<0.001). CONCLUSIONS: Cortisol and DHEA-S are not involved
      in the pathogenesis of retinal vasculitis. SR in retinal vasculitis may be
      associated with a defective hypothalamic-pituitary-adrenal axis.

PMID- 10574823
TI  - Allo-limbal transplantation in patients with limbal stem cell deficiency.

PMID- 10574822
TI  - Acquired colour vision defects in glaucoma-their detection and clinical
      significance.

PMID- 10574824
TI  - Limbal allografting using FK-506.

PMID- 10574825
TI  - Amniotic membrane transplantation in ophthalmology (fresh v preserved tissue)

PMID- 10574826
TI  - Ocular abnormalities in a cohort of children born prematurely: effects of
      selection bias and possible confounding.

PMID- 10574828
TI  - Atlas of eyelid and conjunctival tumors

PMID- 10574827
TI  - Retinal nerve fibre layer thickness.

PMID- 10574829
TI  - Corneal topography, principles and applications

PMID- 10574830
TI  - The eye in contact lens wear

PMID- 10574831
TI  - The hong kong ophthalmological symposium 99

PMID- 10574832
TI  - Why do babies cry? We still know too little about what will ease babies' pain.

PMID- 10574833
TI  - Meeting the demand for donor organs in the US. It's time for bold public policy,
      such as mandated choice or presumed consent.

PMID- 10574834
TI  - Markets, politicians, and the NHS. Enthoven's analysis still illuminates the NHS.

PMID- 10574835
TI  - Healthy living centres deserve evaluation, even though evaluation is complex.

PMID- 10574837
TI  - UN warns that AIDS deaths are set to reach record level.

PMID- 10574836
TI  - Postnatal dexamethasone in preterm infants is potentially lifesaving, but follow
      up studies are urgently needed.

PMID- 10574839
TI  - Oocytes matured in vitro achieve high pregnancy rates.

PMID- 10574838
TI  - Whistleblower in Bristol case says funding was put before patients.

PMID- 10574840
TI  - Drug company threatens legal action over Canadian guidelines.

PMID- 10574842
TI  - UK community groups reject mental health reforms.

PMID- 10574843
TI  - Publishers to link science journals on line.

PMID- 10574844
TI  - EU makes mental illness top priority.

PMID- 10574845
TI  - UK review finds statins are cost effective in secondary prevention.

PMID- 10574846
TI  - Japan moves towards legal ban on human cloning.

PMID- 10574847
TI  - BMA welcomes plans to regulate private care.

PMID- 10574848
TI  - Health authority loses cervical smear appeal.

PMID- 10574849
TI  - Studies reveal increased smoking among students in Canada.

PMID- 10574850
TI  - EU plans tighter controls on tobacco.

PMID- 10574851
TI  - England sets standards to reduce hospital acquired infection.

PMID- 10574853
TI  - European parliament supports juniors on working hours.

PMID- 10574852
TI  - MPs call for database of adverse incidents.

PMID- 10574854
TI  - Randomised trial of analgesic effects of sucrose, glucose, and pacifiers in term
      neonates.
AB  - OBJECTIVES: To assess and compare the analgesic effects of orally administered
      glucose and sucrose and pacifiers. To determine the synergistic analgesic effect
      of sucrose and pacifiers. DESIGN: Randomised prospective study with validated
      behavioural acute pain rating scale. SETTING: Maternity ward. PARTICIPANTS: 150
      term newborns undergoing venepuncture randomly assigned to one of six treatment
      groups: no treatment; placebo (2 ml sterile water); 2 ml 30% glucose; 2 ml 30%
      sucrose; a pacifier; and 2 ml 30% sucrose followed by a pacifier. RESULTS: Median
      (interquartile) pain scores during venepuncture were 7 (5-10) for no treatment; 7
      (6-10) for placebo (sterile water); 5 (3-7) for 30% glucose; 5 (2-8) for 30%
      sucrose; 2 (1-4) for pacifier; and 1 (1-2) for 30% sucrose plus pacifier. Mann
      Whitney U test P values for comparisons of 30% glucose, 30% sucrose, pacifier,
      and 30% sucrose plus pacifier versus placebo (sterile water) were 0.005, 0.01,
      <0.0001, and <0.0001, respectively. Differences between group median pain scores
      for these comparisons were 2 (95% confidence interval 1 to 4), 2 (0 to 4), 5 (4
      to 7), and 6 (5 to 8), respectively. P values for comparisons of 30% glucose, 30%
      sucrose, and 30% sucrose plus pacifier versus pacifier were 0.0001, 0.001, and
      0.06, respectively. Differences between group medians for these comparisons were
      3 (2 to 5), 3 (1 to 5), and 1 (0 to 2), respectively. CONCLUSION: The analgesic
      effects of concentrated sucrose and glucose and pacifiers are clinically apparent
      in newborns, pacifiers being more effective than sweet solutions. The association
      of sucrose and pacifier showed a trend towards lower scores compared with
      pacifiers alone. These simple and safe interventions should be widely used for
      minor procedures in neonates.

PMID- 10574855
TI  - Rates and implications of caesarean sections in Latin America: ecological study.
AB  - OBJECTIVES: To estimate the incidences of caesarean sections in Latin American
      countries and correlate these with socioeconomic, demographic, and healthcare
      variables. DESIGN: Descriptive and ecological study. SETTING: 19 Latin American
      countries. MAIN OUTCOME MEASURES: National estimates of caesarean section rates
      in each country. RESULTS: Seven countries had caesarean section rates below 15%.
      The remaining 12 countries had rates above 15% (range 16.8% to 40.0%). These 12
      countries account for 81% of the deliveries in the region. A positive and
      significant correlation was observed between the gross national product per
      capita and rate of caesarean section (r(s)=0.746), and higher rates were observed
      in private hospitals than in public ones. Taking 15% as a medically justified
      accepted rate, over 850 000 unnecessary caesarean sections are performed each
      year in the region. CONCLUSIONS: The reported figures represent an unnecessary
      increased risk for young women and their babies. From the economic perspective,
      this is a burden to health systems that work with limited budgets.

PMID- 10574856
TI  - Growth in utero and during childhood among women who develop coronary heart
      disease: longitudinal study.
AB  - OBJECTIVE: To examine whether women who develop coronary heart disease have
      different patterns of fetal and childhood growth from men in the same cohort who
      develop the disease. DESIGN: Follow up study of women whose body size at birth
      was recorded and who had an average of 10 measurements of height and weight
      during childhood. SETTING: Helsinki, Finland. SUBJECTS: 3447 women who were born
      in Helsinki University Central Hospital during 1924-33 and who went to school in
      Helsinki. MAIN OUTCOME MEASURES: Hazard ratios for hospital admission for or
      death from coronary heart disease. Results Coronary heart disease among women was
      associated with low birth weight (P=0.08 after adjustment for gestation, P=0.007
      after adjustment for placental weight) and was more strongly associated with
      short body length at birth (P=0.001 and P<0.0001, respectively). The hazard ratio
      for women developing coronary heart disease increased by 10.2% (95% confidence
      interval 4.3 to 15.7) for each cm decrease in length at birth. The effect of
      short length at birth was greatest in women whose height "caught up" after birth
      so that as girls they were tall. Such girls tended to have tall mothers. In
      contrast, men in the same cohort who developed the disease were thin at birth
      rather than short, showed "catch up" growth in weight rather than height, and
      their mothers tended to be overweight rather than tall. CONCLUSION: Coronary
      heart disease among both women and men reflects poor prenatal nutrition and
      consequent small body size at birth combined with improved postnatal nutrition
      and "catch up" growth in childhood. The disease is associated with reductions in
      those aspects of body proportions at birth that distinguish the two sexes-short
      body length in women and thinness in men.

PMID- 10574857
TI  - Overnight calls in primary care: randomised controlled trial of management using
      nurse telephone consultation.

PMID- 10574858
TI  - Comparison of stool immunoassay with standard methods for detecting Helicobacter
      pylori infection.

PMID- 10574859
TI  - Alternative therapies.

PMID- 10574860
TI  - On ageing: oh dear!

PMID- 10574861
TI  - Tensions between policy makers and general practitioners in implementing new
      genetics: grounded theory interview study.
AB  - OBJECTIVE: To explore general practitioners' perceptions of their role in
      implementing genetic technology. DESIGN: Grounded theory interview study.
      SETTING: Primary care. SUBJECTS: Purposive sample of 30 general practitioners
      with a further theoretical sample of 14. RESULTS: Inconsistencies were identified
      between policy makers' and general practitioners' definitions of general
      practitioners' role in implementing the new genetics. General practitioners
      emphasised the need to build on current practice, whereas policy makers focused
      on transforming practice to include the new specialised roles and skills. Two
      core themes were identified: genetics in a generalist context, which included
      appropriate generalist intervention, the ethical dilemmas implicit in the
      "therapeutic gap," the familial-hereditary distinction in primary care, and the
      implications for generalist identity, including the potential marginalisation of
      generalism. CONCLUSION: New technologies such as genetics that require
      implementation in general practice should be integrated within existing
      generalist frameworks.

PMID- 10574862
TI  - Of parents and children.

PMID- 10574863
TI  - Management of self poisoning.

PMID- 10574864
TI  - Insulin as a substance of misuse in a patient with insulin dependent diabetes
      mellitus.

PMID- 10574866
TI  - Honey poisoning.

PMID- 10574865
TI  - ABC of complementary medicine. Unconventional approaches to nutritional medicine.

PMID- 10574868
TI  - Parental review.

PMID- 10574867
TI  - The value of DALY life: problems with ethics and validity of disability adjusted
      life years.

PMID- 10574869
TI  - Healthcare rationing-are additional criteria needed for assessing evidence based
      clinical practice guidelines?

PMID- 10574870
TI  - Public sponsors must follow ethical rules too.

PMID- 10574871
TI  - Guidelines on HIV prophylaxis must be implemented.

PMID- 10574872
TI  - Prevention of vertical transmission of HIV in South Africa. Findings probably do
      not apply to rest of sub-saharan Africa.

PMID- 10574873
TI  - Children were guaranteed regular check ups in dental study.

PMID- 10574874
TI  - Use of iron pots in South Africa led to haemosiderosis.

PMID- 10574875
TI  - Better evidence must be collected on childhood injuries.

PMID- 10574876
TI  - Japanese government should also ban tobacco advertising.

PMID- 10574877
TI  - Automatic replies can be sent to unsolicited email from general public.

PMID- 10574878
TI  - Suicide within 12 months of contact with mental health services. Local data vary
      from national data.

PMID- 10574879
TI  - Cochrane reviews will be in Medline.

PMID- 10574880
TI  - Searching for reliable research evidence need not be difficult.

PMID- 10574881
TI  - Screening of newborn infants for cholestatic hepatobiliary disease. Does test
      fulfil screening criteria?

PMID- 10574882
TI  - Earlier discharge for newborns may increase health risks.

PMID- 10574883
TI  - Do we need a new word for patients?. "Users" isn't an appropriate alternative.

PMID- 10574884
TI  - GMC should just continue its role as policeman and not try to improve clinical
      standards.

PMID- 10574885
TI  - John ("Jack") Parsons Shillingford.

PMID- 10574886
TI  - Guidance needed on the use of the internet.

PMID- 10574888
TI  - The Virtual Surgeon: ACL Reconstruction.

PMID- 10574887
TI  - The Government's Annual Report 98/99.

PMID- 10574889
TI  - Only Human.

PMID- 10574890
TI  - Dogma in retreat.

PMID- 10574891
TI  - Babies in pain.

PMID- 10574892
TI  - Organ donation: Can the US do better?

PMID- 10574893
TI  - BIBA but LGFTD.

PMID- 10574894
TI  - Politically incorrect surgery.

PMID- 10574895
TI  - Sweetness and sucking have analgesic effect in babies.

PMID- 10574896
TI  - Caesarean section rates are too high in Latin America.

PMID- 10574897
TI  - Slower fetal development may protect women from heart disease.

PMID- 10574898
TI  - Night time nurse telephone consultations reduce general practitioners' workload.

PMID- 10574899
TI  - New stool immunoassay offers routine diagnostic tool for H pylori infection.

PMID- 10574900
TI  - GPs want to keep generalist role in genetic testing.

PMID- 10574901
TI  - Future management of heart failure.

PMID- 10574902
TI  - Recent clinical data regarding the use of beta blockers in heart failure: focus
      on CIBIS II.

PMID- 10574903
TI  - Possible mechanisms of action in the positive effect of beta blockers in heart
      failure.

PMID- 10574904
TI  - The scale of heart failure: diagnosis and management issues for primary care.

PMID- 10574905
TI  - Health economics of heart failure.

PMID- 10574906
TI  - Major beta blocker mortality trials in chronic heart failure: a critical review.

PMID- 10574907
TI  - Cortical actin organization: lessons from ERM (ezrin/radixin/moesin) proteins.

PMID- 10574908
TI  - Inhibition of hepatitis C virus NS2/3 processing by NS4A peptides. Implications
      for control of viral processing.
AB  - The NS2/3 protease of hepatitis C virus is responsible for a single cleavage in
      the viral polyprotein between the nonstructural proteins NS2 and NS3. The minimal
      protein region necessary to catalyze this cleavage includes most of NS2 and the N
      terminal one-third of NS3. Autocleavage reactions using NS2/3 protein translated
      in vitro are used here to investigate the inhibitory potential of peptides likely
      to affect the reaction. Peptides representing the cleaved sequence have no effect
      upon reaction rates, and the reaction rate is insensitive to dilution. Both
      results are consistent with prior suggestions that the NS2/3 cleavage is an
      intramolecular reaction. Surprisingly, peptides containing the 12-amino acid
      region of NS4A responsible for binding to NS3 inhibit the NS2/3 reaction with
      K(i) values as low as 3 microM. Unrelated peptide sequences of similar
      composition are not inhibitory, and neither are peptides containing incomplete
      segments of the NS4A region that binds to NS3. Inhibition of NS2/3 by NS4A
      peptides can be rationalized from the organizing effect of NS4A on the N terminus
      of NS3 (the NS2/3 cleavage point) as suggested by the known three-dimensional
      structure of the NS3 protease domain (Yan, Y., Li, Y., Munshi, S., Sardana, V.,
      Cole, J. L., Sardana, M., Steinkuhler, C., Tomei, L., De Francesco, R., Kuo, L.
      C., and Chen, Z. (1998) Protein Sci. 7, 837-847). These findings may imply a
      sequential order to proteolytic maturation events in hepatitis C virus.

PMID- 10574909
TI  - Temperature-sensitive ZAP70 mutants degrading through a proteasome-independent
      pathway. Restoration of a kinase domain mutant by Cdc37.
AB  - CD8 deficiency is an autosomal recessive form of severe combined immunodeficiency
      diseases characterized by the absence of CD8(+) T lymphocytes and impaired T cell
      functions. We identified two novel mis-sense mutations in the zap70 genes of a
      CD8-deficiency patient. One mutation (P80Q) affects a residue in an SH2 domain
      and another (M572L) in the kinase subdomain XI. Both mutations cause a
      degradation of ZAP70 protein in a temperature-sensitive manner through an ATP
      dependent and proteasome-independent pathway. We further demonstrated that Cdc37,
      a protein kinase-specific chaperone, bound to M572L but not P80Q mutant and
      restored the expression of the M572L mutant when overexpressed. The restoration
      of M572L mutant by Cdc37 required the function of HSP90. These results indicate
      that Cdc37 in conjunction with HSP90 functions as a molecular chaperone for a
      temperature-sensitive kinase domain mutant of ZAP70.

PMID- 10574910
TI  - Novel human N-acetyltransferase 2 alleles that differ in mechanism for slow
      acetylator phenotype.
AB  - Three novel human NAT2 alleles (NAT2*5D, NAT2*6D, and NAT2*14G) were identified
      and characterized in a yeast expression system. The common rapid (NAT2*4) and
      slow (NAT2*5B) acetylator human NAT2 alleles were also characterized for
      comparison. The novel recombinant NAT2 allozymes catalyzed both N- and O
      acetyltransferase activities at levels comparable with NAT2 5B and significantly
      below NAT2 4, suggesting that they confer slow acetylation phenotype. In order to
      investigate the molecular mechanism of slow acetylation in the novel NAT2
      alleles, we assessed mRNA and protein expression levels and protein stability. No
      differences were observed in NAT2 mRNA expression among the novel alleles, NAT2*4
      and NAT2*5B. However NAT2 5B and NAT2 5D, but not NAT2 6D and NAT2 14G protein
      expression were significantly lower than NAT2 4. In contrast, NAT2 6D was
      slightly (3.4-fold) and NAT2 14G was substantially (29-fold) less stable than
      NAT2 4. These results suggest that the 341T --> C (Ile(114) --> Thr) common to
      the NAT2*5 cluster is sufficient for reduction in NAT2 protein expression, but
      that mechanisms for slow acetylator phenotype differ for NAT2 alleles that do not
      contain 341T --> C, such as the NAT2*6 and NAT2*14 clusters. Different mechanisms
      for slow acetylator phenotype in humans are consistent with multiple slow
      acetylator phenotypes.

PMID- 10574911
TI  - Substrate recognition of collagen-specific molecular chaperone HSP47. Structural
      requirements and binding regulation.
AB  - Prior to secretion, procollagen molecules are correctly folded to triple helices
      in the endoplasmic reticulum (ER). HSP47 specifically associates with procollagen
      in the ER during its folding and/or modification processes and is thought to
      function as a collagen-specific molecular chaperone (Nagata, K. (1996) Trends
      Biochem. Sci. 21, 23-26). However, structural requirements for substrate
      recognition and regulation of the binding have not yet been elucidated. Here, we
      show that a typical collagen model sequence, (Pro-Pro-Gly)(n), possesses
      sufficient structural information required for recognition by HSP47. A structure
      activity relationship study using synthetic analogs of (Pro-Pro-Gly)(n) has
      revealed the requirements in both chain length and primary structure for the
      interaction. The substrate recognition of HSP47 has also been shown to be similar
      but distinct from that of prolyl 4-hydroxylase, an ER resident enzyme. Further,
      it has shown that the interaction of HSP47 with the substrate peptides is
      abolished by prolyl 4-hydroxylation of the second Pro residues in Pro-Pro-Gly
      triplets and that the fully prolyl 4-hydroxylated peptide, (Pro-Hyp-Gly)(n), does
      not interact with HSP47. We thus have proposed a model in which HSP47 dissociates
      from procollagen during the process of prolyl 4-hydroxylation in the ER.

PMID- 10574912
TI  - Cyclin K functions as a CDK9 regulatory subunit and participates in RNA
      polymerase II transcription.
AB  - Important progress in the understanding of elongation control by RNA polymerase
      II (RNAPII) has come from the recent identification of the positive transcription
      elongation factor b (P-TEFb) and the demonstration that this factor is a protein
      kinase that phosphorylates the carboxyl-terminal domain (CTD) of the RNAPII
      largest subunit. The P-TEFb complex isolated from mammalian cells contains a
      catalytic subunit (CDK9), a cyclin subunit (cyclin T1 or cyclin T2), and
      additional, yet unidentified, polypeptides of unknown function. To identify
      additional factors involved in P-TEFb function we performed a yeast two-hybrid
      screen using CDK9 as bait and found that cyclin K interacts with CDK9 in vivo.
      Biochemical analyses indicate that cyclin K functions as a regulatory subunit of
      CDK9. The CDK9-cyclin K complex phosphorylated the CTD of RNAPII and functionally
      substituted for P-TEFb comprised of CDK9 and cyclin T in in vitro transcription
      reactions.

PMID- 10574913
TI  - Feedback inhibition of G protein-coupled receptor kinase 2 (GRK2) activity by
      extracellular signal-regulated kinases.
AB  - G protein-coupled receptor kinase (GRK)-mediated receptor phosphorylation and
      beta-arrestin binding uncouple G protein-coupled receptors (GPCRs) from their
      respective G proteins and initiates the process of receptor internalization. In
      the case of the beta(2)-adrenergic receptor and lysophosphatidic acid receptor,
      these processes can lead to ERK activation. Here we identify a novel mechanism
      whereby the activity of GRK2 is regulated by feedback inhibition. GRK2 is
      demonstrated to be a phosphoprotein in cells. Mass spectrometry and mutational
      analysis localize the site of phosphorylation on GRK2 to a carboxyl-terminal
      serine residue (Ser(670)). Phosphorylation at Ser(670) impairs the ability of
      GRK2 to phosphorylate both soluble and membrane-incorporated receptor substrates
      and dramatically attenuates Gbetagamma-mediated activation of this enzyme.
      Ser(670) is located in a peptide sequence that conforms to an ERK consensus
      phosphorylation sequence, and in vitro, in the presence of heparin, ERK1
      phosphorylates GRK2. Inhibition of ERK activity in HEK293 cells potentiates GRK2
      activity, whereas, conversely, ERK activation inhibits GRK2 activity. The
      discovery that ERK phosphorylates and inactivates GRK2 suggests that ERK
      participates in a feedback regulatory loop. By negatively regulating GRK-mediated
      receptor phosphorylation, beta-arrestin-mediated processes such as Src
      recruitment and clathrin-mediated internalization, which are required for GPCR
      mediated ERK activation, are inhibited, thus dampening further ERK activation.

PMID- 10574914
TI  - Characteristics for a salt-bridge switch mutation of the alpha(1b) adrenergic
      receptor. Altered pharmacology and rescue of constitutive activity.
AB  - Agonist-dependent activation of the alpha(1)-adrenergic receptor is postulated to
      be initiated by disruption of an interhelical salt-bridge constraint between an
      aspartic acid (Asp-125) and a lysine residue (Lys-331) in transmembrane domains
      three and seven, respectively. Single point mutations that disrupt the charges of
      either of these residues results in constitutive activity. To validate this
      hypothesis, we used site-directed mutagenesis to switch the position of these
      amino acids to observe, if possible, regeneration of the salt-bridge reverses
      that the constitutive activity of the single point mutations. The transiently
      expressed switch mutant receptor displayed an altered pharmacological profile.
      The affinity of selective alpha(1b)-adrenergic receptor antagonists for the
      switch mutant (D125K/K331D) was no different from the wild-type alpha(1b)
      adrenergic receptor, suggesting that both receptors are maintaining similar
      tertiary structures in the cell membrane. However, there was a significant 4-6
      fold decrease in the affinity of protonated amine receptor agonists and a 3-6
      fold increase in the affinity of carboxylated catechol derivatives for the switch
      mutant compared with the wild-type alpha(1b)-adrenergic receptor. This
      pharmacology is consistent with a reversed charge at position 125 in
      transmembrane domain three. Interestingly, the ability of either a negatively or
      positively charged agonist to generate soluble inositol phosphates was similar
      for both types of receptors. Finally, the switch mutant (D125K/K331D) displayed
      similar basal signaling activity as the wild-type receptor, reversing the
      constitutive activity of the single point mutations (D125K and K331D). This
      suggests an ionic constraint has been reformed in the switch mutant analogous to
      the restraint previously described for the wild-type alpha(1b)-adrenergic
      receptor. These results strongly establish the disruption of an electrostatic
      interaction as an initial step in the agonist-dependent activation of alpha(1)
      adrenergic receptors.

PMID- 10574915
TI  - Direct NMR observation of the thioredoxin-mediated reduction of the chloroplast
      NADP-malate dehydrogenase provides a structural basis for the relief of
      autoinhibition.
AB  - The chloroplastic NADP-dependent malate dehydrogenase (NADP-MDH) catalyzing the
      reduction of oxaloacetate into L-malate is regulated by light. Its activation
      results from the thioredoxin-mediated reduction of two disulfides, located,
      respectively, in N- and C-terminal sequence extensions typical of all NADP
      dependent light-regulated forms. Site-directed mutagenesis studies and the
      resolution of the three-dimensional structure of the oxidized (inactive) Sorghum
      vulgare enzyme showed that the C-terminal Cys(365)-Cys(377) disulfide constrains
      the C-terminal extension to fold into the active site where it acts as an
      internal inhibitor. In the present study, two-dimensional proton NMR spectra of
      an engineered NADP-MDH rendered monomeric by a 33-amino acid deletion at the N
      terminus (38 kDa) revealed that a 15-amino acid-long C-terminal peptide (Ala(375)
      to C-terminal Val(389)) acquired an increased mobility upon reduction, allowing
      its direct sequence-specific NMR assignment. The location of the flexible peptide
      in the sequence suggests that the first part of the C-terminal peptide is still
      folded near the core of the enzyme, so that cysteines 365 and 377 remain in
      proximity to allow for an efficient reoxidation/inactivation of the enzyme.

PMID- 10574916
TI  - Roles of superoxide radical anion in signal transduction mediated by reversible
      regulation of protein-tyrosine phosphatase 1B.
AB  - Growth factors induce intracellular production of reactive oxygen species in non
      phagocytic cells and elevation of their phosphorylated protein tyrosine level.
      The latter can be achieved by activating protein-tyrosine kinases and/or
      inactivating protein-tyrosine phosphatases (PTPs). A highly abundant PTP, PTP-1B,
      is known to be inactivated by oxidation of its catalytic site Cys-215. We show
      that O-(2) is kinetically more efficient and chemically more specific oxidant
      than H(2)O(2) for inactivating PTP-1B. The second-order rate constant for the O
      (2)- and H(2)O(2)-mediated inactivation is 334 +/- 45 M(-1) s(-1) and 42.8 +/-
      3.8 M(-1) s(-1), respectively. PTP-1B oxidized by H(2)O(2) exhibits significantly
      more oxidized methionine residues and shows a lower degree of reversibility. The
      initial oxidative product, the Cys-215 sulfenic derivative, can easily be
      oxidized further to its irreversible sulfinic and sulfonic derivatives. This step
      is prevented by glutathionylation of the sulfenic derivative to form a S
      glutathionylated PTP-1B, which can be reactivated by dithiothreitol or
      thioltransferase. Thus, a signal transduction mechanism mediated by the O-(2) and
      the participation of glutathione is proposed for the regulation of PTP-1B. This
      mechanism is supported by the in vivo demonstration that glutathionylated PTP-1B
      at Cys-215 is formed in A431 cells when they were treated with epidermal growth
      factor.

PMID- 10574917
TI  - Polypurine tract primer generation and utilization by Moloney murine leukemia
      virus reverse transcriptase.
AB  - During reverse transcription, the RNase H activity of reverse transcriptase
      specifically cleaves the viral genome within the polypurine tract (PPT) to create
      the primer used for the initiation of plus-strand DNA synthesis and
      nonspecifically cleaves the viral genome to facilitate synthesis of plus-strand
      DNA. To understand how primer length and sequence affect generation and
      utilization of the PPT, we employed short hybrid substrates containing or lacking
      the PPT to evaluate cleavage, extension, and binding by reverse transcriptase.
      Substrates containing RNAs with the correct 3' end for initiation of plus-strand
      synthesis were extended equally well by reverse transcriptase, but primer length
      affected susceptibility to RNase H cleavage. RNA substrates with 3' ends
      extending beyond the plus-strand initiation site were extended poorly but were
      specifically cleaved to generate the correct 3' end for initiation of plus-strand
      synthesis. Substrates containing RNAs lacking the PPT were cleaved
      nonspecifically and extended inefficiently. Specific cleavages to generate the
      plus-strand primer and 5'-end-directed cleavages were kinetically favored over
      cleavages that destroyed the PPT primer or degraded other short RNA fragments.
      The PPT was not intrinsically resistant to cleavage by the isolated RNase H
      domain, and the isolated polymerase domain extended RNA primers containing the
      PPT sequence irrespective of the primer 3' end. These results provide insights
      into how reverse transcriptase generates and selectively utilizes the PPT primer
      for initiation of plus-strand DNA synthesis.

PMID- 10574918
TI  - Enhancement of heparin cofactor II anticoagulant activity.
AB  - Heparin cofactor II (HCII) is a serpin whose thrombin inhibition activity is
      accelerated by glycosaminoglycans. We describe the novel properties of a carboxyl
      terminal histidine-tagged recombinant HCII (rHCII-CHis(6)). Thrombin inhibition
      by rHCII-CHis(6) was increased >2-fold at approximately 5 microgram/ml heparin
      compared with wild-type recombinant HCII (wt-rHCII) at 50-100 microgram/ml
      heparin. Enhanced activity of rHCII-CHis(6) was reversed by treatment with
      carboxypeptidase A. We assessed the role of the HCII acidic domain by
      constructing amino-terminal deletion mutants (Delta1-52, Delta1-68, and Delta1
      75) in wt-rHCII and rHCII-CHis(6). Without glycosaminoglycan, unlike wt-rHCII
      deletion mutants, the rHCII-CHis(6) deletion mutants were less active compared
      with full-length rHCII-CHis(6). With glycosaminoglycans, Delta1-68 and Delta1-75
      rHCIIs were all less active. We assessed the character of the tag by comparing
      rHCII-CHis(6), rHCII-CAla(6), and rHCII-CLys(6) to wt-rHCII. Only rHCII-CHis(6)
      had increased activity with heparin, whereas all three mutants have increased
      heparin binding. We generated a carboxyl-terminal histidine-tagged recombinant
      antithrombin III to study the tag on another serpin. Interestingly, this mutant
      antithrombin III had reduced heparin cofactor activity compared with wild-type
      protein. In a plasma-based assay, the glycosaminoglycan-dependent inhibition of
      thrombin by rHCII-CHis(6) was significantly greater compared with wt-rHCII. Thus,
      HCII variants with increased function, such as rHCII-CHis(6), may offer novel
      reagents for clinical application.

PMID- 10574919
TI  - Cloning and functional expression of novel N-type Ca(2+) channel variants.
AB  - Voltage-dependent Ca(2+) channels are structurally and functionally diverse. As
      Ca(2+) currents recorded from embryonic chick dorsal root ganglion (DRG) neurons
      differ significantly from their mammalian counterparts, information on the
      primary sequence of the chick channels will help define the structural
      underpinnings of Ca(2+) channel function. Here, we report the cloning and
      functional expression of full-length Ca(2+) channel alpha(1B) subunit cDNAs
      derived from chick DRGs. Two variable regions (A and B) have been identified in
      the cytoplasmic linker between repeats I and II; a third (C) in the carboxyl
      terminus extends the open reading frame by 525 nucleotides. The A and C inserts
      are absent, and the B insert is present in all other class B clones reported to
      date. The unique shorter channels appear to predominate in DRG neurons. Results
      represent a requisite first step in defining the structural elements that
      underlie variations in function and modulation of Ca(2+) channels.

PMID- 10574920
TI  - Evidence against the generation of free hydroxyl radicals from the interaction of
      copper,zinc-superoxide dismutase and hydrogen peroxide.
AB  - Prior spin trapping studies reported that H(2)O(2) is metabolized by copper,zinc
      superoxide dismutase (SOD) to form (.)OH that is released from the enzyme,
      serving as a source of oxidative injury. Although this mechanism has been invoked
      in a number of diseases, controversy remains regarding whether the hydroxylation
      of spin traps by SOD is truly derived from free (.)OH or (.)OH scavenged off the
      Cu(2+) catalytic site. To distinguish whether (.)OH is released from the enzyme,
      a comprehensive EPR investigation of radical production and the kinetics of spin
      trapping was performed in the presence of a series of structurally different
      (.)OH scavengers including ethanol, formate, and azide. Although each of these
      have similar potency in scavenging (.)OH as the spin trap 5, 5-dimethyl-1
      pyrroline-N-oxide and form secondary radical adducts, each exhibited very
      different potency in scavenging (.)OH from SOD. Ethanol was 1400-fold less potent
      than would be expected for reaction with free (.)OH. The anionic scavenger
      formate, which readily accesses the active site, was still 10-fold less effective
      than would be predicted for free (.)OH, whereas azide was almost 2-fold more
      potent than would be predicted. Analysis of initial rates of adduct formation
      indicated that these reactions did not involve free (.)OH. EPR studies of the
      copper center demonstrated that while high H(2)O(2) concentrations induce release
      of Cu(2+), the magnitude of spin adducts produced by free Cu(2+) was negligible
      compared with that from intact SOD. Further studies with a series of peroxidase
      substrates demonstrated that characteristic radicals formed by peroxidases were
      also efficiently generated by H(2)O(2) and SOD. Thus, SOD and H(2)O(2) oxidize
      and hydroxylate substrates and spin traps through a peroxidase reaction with
      bound (.)OH not release of (.)OH from the enzyme.

PMID- 10574922
TI  - Phylogenetic analysis of the apolipoprotein B mRNA-editing region. Evidence for a
      secondary structure between the mooring sequence and the 3' efficiency element.
AB  - Apolipoprotein (apo) B mRNA editing is the deamination of C(6666) to uridine,
      which changes the codon at position 2153 from a genomically encoded glutamine
      (CAA) to an in-frame stop codon (UAA). The apoB mRNA-editing enzyme complex
      recognizes the editing region of the apoB pre-mRNA with exquisite precision. Four
      sequence elements spanning 139 nucleotides (nt) on the apoB mRNA have been
      identified that specify this precision. In cooperation with the indispensable
      mooring sequence and spacer element, a 5' efficiency element and a 3' efficiency
      element enhance editing in vitro. A phylogenetic comparison of 32 species showed
      minor differences in the apoB mRNA sequence, and the apoB mRNA from 31 species
      was robustly edited in vitro. However, guinea pig mRNA was poorly edited.
      Compared with the consensus sequences of these 31 species, guinea pig apoB mRNA
      has three variations in the 3' efficiency element, and the conversion of these to
      the consensus sequence increased editing to the levels in the other species. From
      this information, a model for the secondary structure was formulated in which the
      mooring sequence and the 3' efficiency element form a double-stranded stem.
      Thirty-one mammalian apoB mRNA sequences are predicted to form this stem
      positioning C(6666) two nucleotides upstream of the stem. However, the guinea pig
      apoB mRNA has a mutation in the 3' efficiency element (C(6743) to U) that
      predicts an extension of the stem and hence the lower editing efficiency. A test
      of this model demonstrated that a single substitution at 6743 (U to C) in the
      guinea pig apoB mRNA, that should reduce the stem, enhanced editing, and
      mutations in the 3' efficiency element that extended the stem for three base
      pairs dramatically reduced editing. Furthermore, the addition of a 20-nucleotide
      3' efficiency element RNA, to a 58-nucleotide guinea pig apoB mRNA lacking the 3'
      efficiency element more than doubled the in vitro editing activity. Based on
      these results, a model is proposed in which the mooring sequence and the 3'
      efficiency element form a double-stranded stem, thus suggesting a mechanism of
      how the 3' efficiency element enhances editing.

PMID- 10574921
TI  - Gangliosides activate cultured rat brain microglia.
AB  - Microglia, brain resident macrophages, are activated in brain injuries and
      several neurodegenerative diseases. However, microglial activators that are
      produced in the brain are not yet defined. In this study, we showed that
      gangliosides, sialic acid-containing glycosphingolipids, could be a microglial
      activator. Gangliosides induced production of nitric oxide (NO) and tumor
      necrosis factor-alpha (TNF-alpha) and expression of cyclooxygenase-2 (COX-2). The
      effect of gangliosides on NO release increased dose-dependently in the range of
      10-100 microgram/ml; however, the effect decreased at concentrations higher than
      200 microgram/ml. Specific types of gangliosides showed differential effects on
      microglial activation. Similar to gangliosides, GT1b induced production of NO and
      TNF-alpha and expression of COX-2. However, GM1 and GD1a induced expression of
      COX-2 but had little effect on NO and TNF-alpha release. The effect of
      gangliosides and GT1b on NO release was reduced in the presence of neuraminidase,
      which removes sialic acid residues from gangliosides and GT1b. Gangliosides
      activated extracellular signal-regulated kinase significantly but activated c-jun
      N-terminal kinase/stress-activated protein kinase and p38 relatively weakly. The
      inhibition of extracellular signal-regulated kinase by PD98059 reduced NO release
      from both gangliosides- and GT1b-treated microglia whereas inhibition of p38 by
      SB203580 increased it rather slightly. Gangliosides activated NF-kappaB, and N
      acetyl cystein, an inhibitor of NF-kappaB, reduced NO release. These results
      suggest that gangliosides could be a microglial activator that functions via
      activation of mitogen-activated protein kinase and NF-kappaB.

PMID- 10574923
TI  - Autoantibodies define a family of proteins with conserved double-stranded RNA
      binding domains as well as DNA binding activity.
AB  - Cellular responses to viral infection are signaled by double-stranded (ds) RNA,
      which is not found in substantial amounts in uninfected cells. Although cellular
      dsRNA-binding proteins have been described, their characterization is incomplete.
      We show that dsRNA-binding proteins are prominent autoantigens. Sera from B6 and
      B10.S mice with pristane-induced lupus and human autoimmune sera
      immunoprecipitated a novel set of 130-, 110-, 90-, 80-, and 45-kDa proteins. The
      proteins were all major cellular poly(IC)-binding factors. N-terminal amino acid
      sequences of p110 and p90 were identical and matched nuclear factor (NF) 90 and M
      phase phosphoprotein 4. p45 and p90 were identified as the NF45.NF90 complex,
      which binds the interleukin-2 promoter as well as certain highly structured viral
      RNAs. NF90.NF45 and M phase phosphoprotein 4 belong to a large group of proteins
      with conserved dsRNA-binding motifs. Besides binding dsRNA, NF90.NF45, p110, and
      p130 had single-stranded and dsDNA binding activity. Some sera contained
      autoantibodies whose binding was inhibited by poly(IC) but not single-stranded
      DNA or vice versa, suggesting that the DNA- and RNA-binding sites are different.
      These autoantibodies will be useful probes of the function of dsRNA-binding
      proteins. Their interaction with dsRNA, an immunological adjuvant, also could
      promote autoimmunity.

PMID- 10574924
TI  - Regulated expression of human angiotensinogen gene by hepatocyte nuclear factor 4
      and chicken ovalbumin upstream promoter-transcription factor.
AB  - We previously identified various upstream and downstream regulatory elements and
      factors important for hepatic expression of the human angiotensinogen (ANG) gene,
      the precursor of vasoactive octapeptide angiotensin II. In the present study, to
      further investigate the molecular mechanism of human ANG transcriptional
      regulation, we generated transgenic mice carrying the fusion gene composed of the
      1. 3-kilobase promoter of the human ANG gene, its downstream enhancer, and the
      chloramphenicol acetyltransferase reporter gene. Because expression of the
      chloramphenicol acetyltransferase gene was observed strongly in the liver and
      weakly in the kidney, we suspected that hepatocyte nuclear factor (HNF) 4 with a
      tissue expression pattern similar to that of the reporter gene would regulate ANG
      transcription. In vitro assays indicated that HNF4 bound to the promoter elements
      and strongly activated the ANG transcription, but that chicken ovalbumin upstream
      promoter transcription factor (COUP-TF), a transcriptional repressor,
      dramatically repressed human ANG transcription through the promoter elements and
      the downstream enhancer core elements. Furthermore, COUP-TF dramatically
      decreased the human ANG transcription in the mouse liver by the Helios Gene Gun
      system in vivo. These results suggest that an interplay between HNF4 and COUP-TF
      could be important in hepatic human ANG transcription.

PMID- 10574925
TI  - Expression of an active, monomeric catalytic domain of the cGMP-binding cGMP
      specific phosphodiesterase (PDE5).
AB  - Phosphodiesterases (PDEs) comprise a superfamily of phosphohydrolases that
      degrade 3',5'-cyclic nucleotides. All known mammalian PDEs are dimeric, but the
      functional significance of dimerization is unknown. A deletion mutant of cGMP
      binding cGMP-specific PDE (PDE5), encoding the 357 carboxyl-terminal amino acids
      including the catalytic domain, has been generated, expressed, and purified. The
      K(m) of the catalytic fragment for cGMP (5.5 +/- 0. 51 microM) compares well with
      those of the native bovine lung PDE5 (5.6 microM) and full-length wild type
      recombinant PDE5 (2 +/- 0.4 microM). The catalytic fragment and full-length PDE5
      have similar IC(50) values for the inhibitors 3-isobutyl-1-methylxanthine (20
      microM) and sildenafil (Viagra(TM))(4 nM). Based on measured values for Stokes
      radius (29 A) and sedimentation coefficient (2.9 S), the PDE5 catalytic fragment
      has a calculated molecular mass of 35 kDa, which agrees well with that predicted
      by amino acid content (43.3 kDa) and with that estimated using SDS-polyacrylamide
      gel electrophoresis (39 kDa). The combined data indicate that the recombinant
      PDE5 catalytic fragment is monomeric, and retains the essential catalytic
      features of the dimeric, full-length enzyme. Therefore, the catalytic activity of
      PDE5 holoenzyme requires neither interaction between the catalytic and regulatory
      domains nor interactions between subunits of the dimer.

PMID- 10574926
TI  - Mass spectrometric quantification of 3-nitrotyrosine, ortho-tyrosine, and o,o'
      dityrosine in brain tissue of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine
      treated mice, a model of oxidative stress in Parkinson's disease.
AB  - Oxidative stress is implicated in the death of dopaminergic neurons in
      Parkinson's disease and in the 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine
      (MPTP) model of Parkinson's disease. Oxidative species that might mediate this
      damage include hydroxyl radical, tyrosyl radical, or reactive nitrogen species
      such as peroxynitrite. In mice, we showed that MPTP markedly increased levels of
      o, o'-dityrosine and 3-nitrotyrosine in the striatum and midbrain but not in
      brain regions resistant to MPTP. These two stable compounds indicate that tyrosyl
      radical and reactive nitrogen species have attacked tyrosine residues. In
      contrast, MPTP failed to alter levels of ortho-tyrosine in any brain region we
      studied. This marker accumulates when hydroxyl radical oxidizes protein-bound
      phenylalanine residues. We also showed that treating whole-brain proteins with
      hydroxyl radical markedly increased levels of ortho-tyrosine in vitro. Under
      identical conditions, tyrosyl radical, produced by the heme protein
      myeloperoxidase, selectively increased levels of o,o'-dityrosine, whereas
      peroxynitrite increased levels of 3-nitrotyrosine and, to a lesser extent, of
      ortho-tyrosine. These in vivo and in vitro findings implicate reactive nitrogen
      species and tyrosyl radical in MPTP neurotoxicity but argue against a deleterious
      role for hydroxyl radical in this model. They also show that reactive nitrogen
      species and tyrosyl radical (and consequently protein oxidation) represent an
      early and previously unidentified biochemical event in MPTP-induced brain injury.
      This finding may be significant for understanding the pathogenesis of Parkinson's
      disease and developing neuroprotective therapies.

PMID- 10574927
TI  - Lipoprotein lipase enhances the binding of native and oxidized low density
      lipoproteins to versican and biglycan synthesized by cultured arterial smooth
      muscle cells.
AB  - Retention of low density lipoproteins (LDL) by vascular proteoglycans and their
      subsequent oxidation are important in atherogenesis. Lipoprotein lipase (LPL) can
      bind LDL and proteoglycans, although the effect of different proteoglycans to
      influence the ability of LPL to act as a bridge in the formation of LDL
      proteoglycan complexes is unknown. Using an electrophoretic gel mobility shift
      assay, [(35)S]SO(4)-labeled versican and biglycan, two extracellular
      proteoglycans secreted by vascular cells, bound native LDL in a saturable
      fashion. The addition of bovine milk LPL dose-dependently increased the binding
      of native LDL to both versican and biglycan, approaching saturation at 30-40
      microgram/ml LPL for versican and 20 microgram/ml LPL for biglycan. LDL was
      oxidized by several methods, including copper, 2, 2-azo-bis(2-amidinopropane)
      2HCl and hypochlorite. Extensively copper- and hypochlorite-oxidized LDL bound
      poorly to versican and biglycan. Proteoglycan binding to LDL was correlated
      inversely with the extent of LDL; however, the addition of LPL to oxidized LDL
      together with biglycan or versican allowed the oxidized LDL to bind the
      proteoglycans in an LPL dose-dependent manner. Addition of LPL had a greater
      relative effect on the binding of extensively oxidized LDL to proteoglycans
      compared with native LDL. LPL had a slightly greater effect on increasing the
      binding of native and oxidized LDL to biglycan than versican. Thus, LPL in the
      artery wall might increase the atherogenicity of oxidized LDL, since it enables
      its binding to vascular biglycan and versican.

PMID- 10574928
TI  - Tropomodulin increases the critical concentration of barbed end-capped actin
      filaments by converting ADP.P(i)-actin to ADP-actin at all pointed filament ends.
AB  - The pointed end capping protein, tropomodulin, increases the critical
      concentration of barbed end capped actin, i.e. it lowers the apparent affinity of
      pointed ends for actin monomers. We show here that this is due to the conversion
      of pointed end ADP. P(i)-actin (low critical concentration) to ADP-actin (high
      critical concentration) when 70-98% of the ends are capped by tropomodulin. We
      propose that this is due to the low affinity of tropomodulin for pointed ends
      (K(d) approximately 0.3 microM), which allows tropomodulin to rapidly exchange
      binding sites and transiently block access of actin monomers to all pointed ends.
      This leaves time for ATP hydrolysis and phosphate release to go to completion
      between successive monomer additions to the pointed end. When the affinity of
      tropomodulin for pointed ends was increased about 1000-fold by the presence of
      tropomyosin (K(d) < 0.05 nM), capping of 95% of the ends by tropomodulin did not
      alter the critical concentration. However, the critical concentration did
      increase when the tropomodulin concentration was raised to the high values
      effective in the absence of tropomyosin. This may reflect transient tropomodulin
      binding to tropomyosin-free actin molecules at the pointed ends of the
      tropomyosin-actin filaments without a high affinity tropomodulin cap, i.e. the
      ends that determine the value of the actin critical concentration.

PMID- 10574929
TI  - The novel kinase peptidylglycine alpha-amidating monooxygenase cytosolic
      interactor protein 2 interacts with the cytosolic routing determinants of the
      peptide processing enzyme peptidylglycine alpha-amidating monooxygenase.
AB  - The cytosolic domain of the peptide-processing integral membrane protein
      peptidylglycine alpha-amidating monooxygenase (PAM; EC 1.14. 17.3) contains
      multiple signals determining its subcellular localization. Three PAM cytosolic
      interactor proteins (P-CIPs) were identified using the yeast two hybrid system
      (Alam, M. R., Caldwel, B. D., Johnson, R. C., Darlington, D. N., Mains, R. E.,
      and Eipper, B. A. (1996) J. Biol. Chem. 271, 28636-28640); the partial amino acid
      sequence of P-CIP2 suggested that it was a protein kinase. In situ hybridization
      and immunocytochemistry show that P-CIP2 is expressed widely throughout the
      brain; PAM and P-CIP2 are expressed in the same neurons. Based on subcellular
      fractionation, the 47-kDa P-CIP2 protein is mostly cytosolic. P-CIP2 is a highly
      selective kinase, phosphorylating the cytosolic domain of PAM, but not the
      corresponding region of furin or carboxypeptidase D. Although P-CIP2 interacts
      with stathmin, it does not phosphorylate stathmin. Site-directed mutagenesis,
      phosphoamino acid analysis, and use of synthetic peptides demonstrate that PAM
      Ser(949) is the major site phosphorylated by P-CIP2. Based on both in vitro
      binding experiments and co-immunoprecipitation from cell extracts, P-CIP2
      interacts with PAM proteins containing the wild type cytosolic domain, but not
      with mutant forms of PAM whose trafficking is disrupted. P-CIP2, through its
      highly selective phosphorylation of a key site in the cytosolic domain of PAM,
      appears to play a critical role in the trafficking of this protein.

PMID- 10574931
TI  - Functional interaction between SHPTP1 and the Lyn tyrosine kinase in the
      apoptotic response to DNA damage.
AB  - The Lyn protein-tyrosine kinase is activated in the cellular response to DNA
      damaging agents. Here we demonstrate that Lyn associates constitutively with the
      SHPTP1 protein-tyrosine phosphatase. The SH3 domain of Lyn interacts directly
      with SHPTP1. The results show that Lyn phosphorylates SHPTP1 at the C-terminal
      Tyr-564 site. Lyn-mediated phosphorylation of SHPTP1 stimulates SHPTP1 tyrosine
      phosphatase activity. We also demonstrate that treatment of cells with 1-beta-D
      arabinofuranosylcytosine and other genotoxic agents induces Lyn-dependent
      phosphorylation and activation of SHPTP1. The significance of the Lyn-SHPTP1
      interaction is supported by the demonstration that activation of Lyn contributes
      in part to the apoptotic response to ara-C treatment and that SHPTP1 attenuates
      this response. These findings support a functional interaction between Lyn and
      SHPTP1 in the response to DNA damage.

PMID- 10574930
TI  - Immunosuppressant FK506 activates NF-kappaB through the proteasome-mediated
      degradation of IkappaBalpha. Requirement for Ikappabalpha n-terminal
      phosphorylation but not ubiquitination sites.
AB  - The immunosuppressant FK506 activates NF-kappaB through IkappaBalpha degradation
      in nonlymphoid cells. In the present study, we analyzed mechanisms by which FK506
      induces IkappaBalpha degradation. We found that FK506 induces the degradation of
      both IkappaBalpha and IkappaBbeta and that the time courses of the FK506-induced
      degradation are quite different from degradation induced by interleukin 1 (IL-1).
      Despite this difference, FK506-induced IkappaBalpha degradation was dependent on
      the N-terminal Ser-32 and Ser-36 phosphorylation sites and was mediated by
      proteasomes, as is the case for IL-1-induced IkappaBalpha degradation. We further
      showed that FK506 induces weak and slow phosphorylation of IkappaBalpha at Ser
      32. However, unlike IL-1-induced degradation, IKK-1 and IKK-2 were not activated
      significantly nor was FK506-induced IkappaBalpha degradation dependent on the N
      terminal ubiquitination sites (Lys-21 and Lys-22). These results therefore
      indicate that FK506 and IL-1 utilize similar but distinct mechanisms to induce
      the phosphorylation and degradation of IkappaBalpha.

PMID- 10574932
TI  - Transcriptional regulation of endothelial nitric-oxide synthase by an interaction
      between casein kinase 2 and protein phosphatase 2A.
AB  - We previously demonstrated that lysophosphatidylcholine up-regulated endothelial
      nitric-oxide synthase promoter activity by increasing Sp1 binding via the action
      of protein serine/threonine phosphatase 2A (Cieslik, K., Zembowicz, A., Tang, J.
      L., and Wu, K.K. (1998) J. Biol. Chem. 273, 14885-14890). To characterize the
      regulation of basal endothelial nitric-oxide synthase promoter activity and the
      signaling pathway through which lysophosphatidylcholine augments endothelial
      nitric-oxide synthase transcription, we used a casein kinase 2 inhibitor coupled
      with immunoprecipitation to demonstrate that basal Sp1 binding and endothelial
      nitric-oxide synthase promoter activity were controlled by casein kinase 2
      complexed with protein serine/threonine phosphatase 2A. Casein kinase 2 catalyzed
      protein serine/threonine phosphatase 2A phosphorylation thereby inhibiting its
      activity. Lysophosphatidylcholine selectively activated p42/p44 mitogen-activated
      protein kinase. Purified extracellular regulated kinase 2 blocked casein kinase 2
      activity and increased protein serine/threonine phosphatase 2A activity,
      resulting in an increased Sp1 binding and endothelial nitric-oxide synthase
      promoter activity. These results indicate that Sp1 binding to its cognate site on
      the endothelial nitric-oxide synthase promoter and its transactivation of
      endothelial nitric-oxide synthase is regulated by post-translational Sp1
      phosphorylation and dephosphorylation through a dynamic interaction between
      casein kinase 2 and protein serine/threonine phosphatase 2A.

PMID- 10574933
TI  - Cyclin D3 regulates proliferation and apoptosis of leukemic T cell lines.
AB  - Activation of the T cell receptor in leukemic T cell lines or T cell hybridomas
      causes growth inhibition. A similar growth inhibition is seen when protein kinase
      C is activated through addition of phorbol myristate acetate. This inhibition is
      due to an arrest of cell cycle progression in G(1) combined with an induction of
      apoptosis. Here we have investigated the mechanism by which these stimuli induce
      inhibition of proliferation in Jurkat and H9 leukemic T cell lines. We show that
      expression of cyclin D3 is reduced by each of these stimuli, resulting in a
      concomitant reduction in cyclin D-associated kinase activity. This reduction in
      cyclin D3-expression is crucial to the observed G(1) arrest, since ectopic
      expression of cyclin D3 can abrogate the G(1) arrest seen with each of these
      stimuli. Moreover, ectopic expression of cyclin D3 also prevents the induction of
      programmed cell death by phorbol myristate acetate and T-cell receptor
      activation, leading us to conclude that cyclin D3 not only plays a crucial role
      in progression through the G(1) phase, but is also involved in regulating
      apoptosis of T cells.

PMID- 10574934
TI  - Cloning and characterization of a bifunctional leukotriene A(4) hydrolase from
      Saccharomyces cerevisiae.
AB  - In mammals, leukotriene A(4) hydrolase is a bifunctional zinc metalloenzyme that
      catalyzes hydrolysis of leukotriene A(4) into the proinflammatory leukotriene
      B(4) and also possesses an arginyl aminopeptidase activity. We have cloned,
      expressed, and characterized a protein from Saccharomyces cerevisiae that is 42%
      identical to human leukotriene A(4) hydrolase. The purified protein is an anion
      activated leucyl aminopeptidase, as assessed by p-nitroanilide substrates, and
      does not hydrolyze leukotriene A(4) into detectable amounts of leukotriene B(4).
      However, the S. cerevisiae enzyme can utilize leukotriene A(4) as substrate to
      produce a compound identified as 5S,6S-dihydroxy-7,9-trans-11, 14-cis
      eicosatetraenoic acid. Both catalytic activities are inhibited by 3-(4
      benzyloxyphenyl)-2-(R)-amino-1-propanethiol (thioamine), a competitive inhibitor
      of human leukotriene A(4) hydrolase. Furthermore, the peptide cleaving activity
      of the S. cerevisiae enzyme was stimulated approximately 10-fold by leukotriene
      A(4) with kinetics indicating the presence of a lipid binding site. Nonenzymatic
      hydrolysis products of leukotriene A(4), leukotriene B(4), arachidonic acid, or
      phosphatidylcholine were without effect. Moreover, leukotriene A(4) could
      displace the inhibitor thioamine and restore maximal aminopeptidase activity,
      indicating that the leukotriene A(4) binding site is located at the active center
      of the enzyme. Hence, the S. cerevisiae leukotriene A(4) hydrolase is a
      bifunctional enzyme and appears to be an early ancestor to mammalian leukotriene
      A(4) hydrolases.

PMID- 10574936
TI  - Characterization of the cryptogein binding sites on plant plasma membranes.
AB  - Cryptogein is a 98-amino acid proteinaceous elicitor of tobacco defense
      reactions. Specific binding of cryptogein to high affinity binding sites on
      tobacco plasma membranes has been previously reported (K(d) = 2 nM; number of
      binding sites: 220 fmol/mg of protein). In this study, biochemical
      characterization of cryptogein binding sites reveals that they correspond to a
      plasma membrane glycoprotein(s) with an N-linked carbohydrate moiety, which is
      involved in cryptogein binding. Radiation inactivation experiments performed on
      tobacco plasma membrane preparations indicated that cryptogein bound specifically
      to a plasma membrane component with an apparent functional molecular mass of 193
      kDa. Moreover, using the homobifunctional cross-linking reagent disuccinimidyl
      suberate and tobacco plasma membranes incubated with (125)I-cryptogein, we
      identified, after SDS-polyacrylamide gel electrophoresis and autoradiography, two
      (125)I-cryptogein linked N-glycoproteins of about 162 and 50 kDa. Similar results
      were obtained using Arabidopsis thaliana and Acer pseudoplatanus plasma membrane
      preparations, whereas cryptogein did not induce any effects on the corresponding
      cell suspensions. These results suggest that either cryptogein binds to
      nonfunctional binding sites, homologues to those present in tobacco plasma
      membranes, or that a protein involved in signal transduction after cryptogein
      recognition is absent or inactive in both A. pseudoplatanus and A. thaliana.

PMID- 10574935
TI  - Phospholipase D stimulation by receptor tyrosine kinases mediated by protein
      kinase C and a Ras/Ral signaling cascade.
AB  - Stimulation of phospholipase D (PLD) in HEK-293 cells expressing the M(3)
      muscarinic receptor by phorbol ester-activated protein kinase C (PKC) apparently
      involves Ral GTPases. We report here that PKC, but not muscarinic receptor
      induced PLD stimulation in these cells, is strongly and specifically reduced by
      expression of dominant-negative RalA, G26A RalA, as well as dominant-negative
      Ras, S17N Ras. In contrast, overexpression of the Ras-activated Ral-specific
      guanine nucleotide exchange factor, Ral-GDS, specifically enhanced PKC-induced
      PLD stimulation. Moreover, recombinant Ral-GDS potentiated Ral-dependent PKC
      induced PLD stimulation in membranes. Epidermal growth factor, platelet-derived
      growth factor, and insulin, ligands for receptor tyrosine kinases (RTKs)
      endogenously expressed in HEK-293 cells, apparently use the PKC- and Ras/Ral
      dependent pathway for PLD stimulation. First, PLD stimulation by the RTK agonists
      was prevented by PKC inhibition and PKC down-regulation. Second, expression of
      dominant-negative RalA and Ras mutants strongly reduced RTK-induced PLD
      stimulation. Third, overexpression of Ral-GDS largely potentiated PLD stimulation
      by the RTK agonists. Finally, using the Ral binding domain of the Ral effector
      RLIP as an activation-specific probe for Ral proteins, it is demonstrated that
      endogenous RalA is activated by phorbol ester and RTK agonists. Taken together,
      strong evidence is provided that RTK-induced PLD stimulation in HEK-293 cells is
      mediated by PKC and a Ras/Ral signaling cascade.

PMID- 10574937
TI  - Matrix metalloproteinase homologues from Arabidopsis thaliana. Expression and
      activity.
AB  - Five genes potentially encoding novel matrix metalloproteinases (MMPs) have been
      identified on the Arabidopsis thaliana data base. The predicted proteins have a
      similar domain structure to mammalian MMP-7, with a propeptide and catalytic
      domain but no C-terminal hemopexin-like domain. Four of the A. thaliana MMPs (At
      MMPs) have a predicted C-terminal transmembrane domain. The At-MMPs are
      differentially expressed in flower, leaf, root, and stem tissues from 14-day-old
      plants. The cDNA for one of the At-MMPs (At1-MMP) was cloned and expressed in
      Escherichia coli. Following refolding and purification, the proenzyme At1-MMP was
      shown to undergo autolytic activation in the presence of an organomercurial with
      a concomitant decrease in M(r). In contrast to this, trypsin-treatment led to the
      formation of an inactive product. The activated At1-MMP digested myelin basic
      protein, but was unable to digest gelatin or casein. Three peptide substrates for
      MMPs were also cleaved by At1-MMP. The enzyme activity of At1-MMP was inhibited
      by human tissue inhibitors of metalloproteinases 1 and 2 and the hydroxamate
      inhibitor BB-94.

PMID- 10574939
TI  - Multiple charged and aromatic residues in CCR5 amino-terminal domain are involved
      in high affinity binding of both chemokines and HIV-1 Env protein.
AB  - CCR5 is a functional receptor for MIP-1alpha, MIP-1beta, RANTES (regulated on
      activation normal T cell expressed), MCP-2, and MCP-4 and constitutes the main
      coreceptor for macrophage tropic human and simian immunodeficiency viruses. By
      using CCR5-CCR2b chimeras, we have shown previously that the second extracellular
      loop of CCR5 is the major determinant for chemokine binding specificity, whereas
      the amino-terminal domain plays a major role for human immunodeficiency virus
      type 1 (HIV-1) and simian immunodeficiency virus coreceptor function. In the
      present work, by using a panel of truncation and alanine-scanning mutants, we
      investigated the role of specific residues in the CCR5 amino-terminal domain for
      chemokine binding, functional response to chemokines, HIV-1 gp120 binding, and
      coreceptor function. Truncation of the amino-terminal domain resulted in a
      progressive decrease of the binding affinity for chemokines, which correlated
      with a similar drop in functional responsiveness. Mutants lacking residues 2-13
      exhibited fairly weak responses to high concentrations (500 nM) of RANTES or MIP
      1beta. Truncated mutants also exhibited a reduction in the binding affinity for
      R5 Env proteins and coreceptor activity. Deletion of 4 or 12 residues resulted in
      a 50 or 80% decrease in coreceptor function, respectively. Alanine-scanning
      mutagenesis identified several charged and aromatic residues (Asp-2, Tyr-3, Tyr
      10, Asp-11, and Glu-18) that played an important role in both chemokine and Env
      high affinity binding. The overlapping binding site of chemokines and gp120 on
      the CCR5 amino terminus, as well as the involvement of these residues in the
      epitopes of monoclonal antibodies, suggests that these regions are particularly
      exposed at the receptor surface.

PMID- 10574938
TI  - Large scale purification of detergent-soluble P-glycoprotein from Pichia pastoris
      cells and characterization of nucleotide binding properties of wild-type, Walker
      A, and Walker B mutant proteins.
AB  - P-glycoprotein (Pgp; mouse MDR3) was expressed in Pichia pastoris, grown in
      fermentor culture, and purified. The final pure product is of high specific
      ATPase activity and is soluble at low detergent concentration. 120 g of cells
      yielded 6 mg of pure Pgp; >4 kg of cells were obtained from a single fermentor
      run. Properties of the pure protein were similar to those of previous
      preparations, except there was significant ATPase activity in absence of added
      lipid. Mutant mouse MDR3 P-glycoproteins were purified by the same procedure
      after growth of cells in flask culture, with similar yields and purity. This
      procedure should open up new avenues of structural, biophysical, and biochemical
      studies of Pgp. Equilibrium nucleotide-binding parameters of wild-type mouse MDR3
      Pgp were studied using 2'-(3')-O-(2,4,6-trinitrophenyl)adenosine tri- and
      diphosphate. Both analogs were found to bind with K(d) in the low micromolar
      range, to a single class of site, with no evidence of cooperativity. ATP
      displacement of the analogs was seen. Similar binding was seen with K429R/K1072R
      and D551N/D1196N mutant mouse MDR3 Pgp, showing that these Walker A and B
      mutations had no significant effect on affinity or stoichiometry of nucleotide
      binding. These residues, known to be critical for catalysis, are concluded to be
      involved primarily in stabilization of the catalytic transition state in Pgp.

PMID- 10574940
TI  - A conserved seven amino acid stretch important for murine mitochondrial glycerol
      3-phosphate acyltransferase activity. Significance of arginine 318 in catalysis.
AB  - Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the initial and committed
      step in glycerolipid biosynthesis. We previously cloned the cDNA sequence to
      murine mitochondrial GPAT (Yet, S-F., Lee, S., Hahm, Y. T., and Sul, H.S. (1993)
      Biochemistry 32, 9486-9491). We expressed the protein in insect cells which was
      targeted to mitochondria, purified, and reconstituted mitochondrial GPAT activity
      using phospholipids (Yet, S.-F., Moon, Y., and Sul, H. S. (1995) Biochemistry 34,
      7303-7310). Deletion of the seven amino acids from mitochondrial GPAT,
      (312)IFLEGTR(318), which is highly conserved among acyltransferases in
      glycerolipid biosynthesis, drastically reduced mitochondrial GPAT activity.
      Treatment of mitochondrial GPAT with arginine-modifying agents, phenylglyoxal and
      cyclohexanedione, inactivated the enzyme. Two highly conserved arginine residues,
      Arg-318, in the seven amino stretch, and Arg-278, were identified. Substitution
      of Arg-318 with either alanine, histidine, or lysine reduced the mitochondrial
      GPAT activity by over 90%. On the other hand, although substitution of Arg-278
      with alanine and histidine decreased mitochondrial GPAT activity by 90%,
      replacement with lysine reduced activity by only 25%. A substitution of the
      nonconserved Arg-279 with either alanine, histidine, or lysine did not alter
      mitochondrial GPAT activity. Moreover, R278K mitochondrial GPAT still showed
      sensitivity to arginine-modifying agents, as in the case of wild-type
      mitochondrial GPAT. These results suggest that Arg-318 may be critical for
      mitochondrial GPAT activity, whereas Arg-278 can be replaced by a basic amino
      acid. Examination of the other conserved residues in the seven amino acid stretch
      revealed that Phe-313 and Glu-315 are also important, but conservative
      substitutions can partially maintain activity; substitution with alanine reduced
      activity by 83 and 72%, respectively, whereas substituting Phe-313 with tyrosine
      and Glu-315 with glutamine had even lesser effect. In addition, there was no
      change in fatty acyl-CoA selectivity. Kinetic analysis of the R318K and R318A
      mitochondrial GPAT showed an 89 and 95%, respectively, decrease in catalytic
      efficiency but no major change in substrate binding as indicated by the K(m)
      values for palmitoyl-CoA and glycerol 3-phosphate. These studies indicate
      importance of the conserved seven amino acid stretch for mitochondrial GPAT
      activity and the significance of Arg-318 for catalysis.

PMID- 10574941
TI  - Enzymatic synthesis of unlabeled and beta-(32)P-labeled beta-L-2', 3'
      dideoxyadenosine-5'-triphosphate as a potent inhibitor of adenylyl cyclases and
      its use as reversible binding ligand.
AB  - beta-L-2',3'-Dideoxyadenosine-5'-triphosphate (beta-L-2', 3'-dd-5'-ATP) was
      prepared enzymatically from the corresponding monophosphate by the use of
      adenylate kinase, creatine phosphate, and creatine kinase in a single step. The
      beta-(32)P-labeled analog was prepared similarly, but in a two step reaction.
      beta-L-2', 3'-dd-5'-ATP inhibited adenylyl cyclase from rat brain competitively
      with respect to substrate (5'-ATP.Mn(2+)) and exhibited an IC(50) approximately
      24 nM. The labeled ligand was used in the development of a reversible binding
      assay for adenylyl cyclases. Binding of beta-L-2',3'-dd-[beta-(32)P]5'-ATP was
      saturable with increasing concentrations of ligand and increased in proportion to
      membrane protein, and was enhanced by Mn(2+) to a greater extent than by Mg(2+).
      Binding was displaced with adenine nucleotides known to be either competitive or
      noncompetitive inhibitors but not by agents known not to act on the cyclase, or
      by 3-isobutyl-1-methylxanthine, creatine phosphate, or creatine kinase. Binding
      was rapid, with a half-time for the on-rate <1.8 min and for the off-rate <0.8
      min. The potency and mechanism of the inhibition of this ligand and the pattern
      of agents that displace binding suggest an interaction with adenylyl cyclase per
      se and to a configuration of the enzyme consistent with an interaction at the
      catalytic active site. The data suggest that this is a pretransition state
      inhibitor and contrasts with the equipotent 2',5'-dd-3'ATP, a post-transition
      state noncompetitive inhibitor.

PMID- 10574942
TI  - Inhibition of adenylyl cyclase by acyclic nucleoside phosphonate antiviral
      agents.
AB  - Acyclic derivatives of adenine, known as highly effective nucleotide analogs with
      broad spectrum antiviral activity, were evaluated for potential cross-reactivity
      with adenylyl cyclases, a family of membrane-bound enzymes that share putative
      topologies at their catalytic sites with oligonucleotide polymerases and reverse
      transcriptases. A series of derivatives of 9-(2-phosphonylmethoxyethyl)adenine
      (PMEA) inhibited a preparation of adenylyl cyclase derived from rat brain with
      IC(50) values that ranged from 66 microM (PMEA) to 175 nM for its diphosphate
      derivative (PMEApp) and mimics of it. PMEApp mimics included PMEAp(NH)p,
      PMEAp(CH(2))p, PMEAp(CX(2))p (X = fluorine, chlorine, or bromine), PMEAp(CHX)pp,
      and PMEAp(C(OH)CH(3)pp. The data suggest that inhibition of adenylyl cyclases may
      contribute to the therapeutic action of some of these or similar compounds or
      constitute part of their side effects in therapeutic settings.

PMID- 10574943
TI  - Covalent labeling of adenylyl cyclase cytosolic domains with gamma
      methylimidazole-2',5'-dideoxy-[gamma-(32)P]3'-ATP and the mechanism for P-site
      mediated inhibition.
AB  - A truncated first cytosolic domain of type V adenylyl cyclase (VC(1)) and a
      truncated second cytosolic domain of type II adenylyl cyclase (IIC(2)) were used
      alone and in the readily reversible complex (VC(1).IIC(2)) to evaluate
      interactions with each other and with reversible and irreversible P-site ligands.
      Enzyme activity was used to assess formation and dissolution of VC(1).IIC(2). The
      data suggest that binding of 2',5'-dideoxy-3'-ATP to VC(1) and IIC(2) prevented
      formation of VC(1).IIC(2) and that 2',5'-dideoxy-3'-ATP dissociation occurred
      slowly. To enable configuration specific cross-linking to the catalytic site,
      2',5'-dideoxyadenosine 3'-[gamma-(1-methylimidazole)-triphosphate] (gamma-MetIm
      2', 5'-dd-3'-ATP) and 2',5'-dd-adenosine 3'-(gamma-azidoanilido)-triphosphate
      (gamma-azidoanilido-2', 5'-dd-3'-ATP) were synthesized, the former also as its
      gamma-(32)P-labeled analog. gamma-Azidoanilido-2',5'-dd-3'-ATP exhibited an
      inhibitory potency comparable with that of 2', 5'-dd-3'-ATP. gamma-MetIm-2',5'-dd
      [gamma-(32)P]3'-ATP labeled the individual VC(1) and IIC(2) domains comparably
      and covalently to approximately 20% within 1 h. Formation of VC(1).IIC(2)
      resulted in reduced labeling of VC(1) but enhanced labeling of IIC(2). The data
      imply that formation of the catalytically active VC(1).IIC(2) complex affects the
      interaction of each domain with the 2', 5'-dd-3'-ATP, the binding of which also
      affects the interaction between the two cytosolic domains, leading to a pseudo
      irreversible inhibition.

PMID- 10574944
TI  - Thermally triggered metal binding by recombinant Thermus thermophilus manganese
      superoxide dismutase, expressed as the apo-enzyme.
AB  - Manganese superoxide dismutase from the extremely thermophilic eubacterium
      Thermus thermophilus has been cloned and expressed at high levels in a mesophilic
      host (Escherichia coli) as a soluble tetrameric protein mainly present as the
      metal-free apo-enzyme. Incubation of the purified apo-enzyme with manganese salts
      at ambient temperature did not restore superoxide dismutase activity, but
      reactivation could be achieved by heating the protein with Mn(II) at higher
      temperatures, approaching the physiological growth temperature for T.
      thermophilus. Heat annealing followed by incubation with manganese at lower
      temperature fails to reactivate the enzyme, demonstrating that a simple
      misfolding of the protein is not responsible for the observed behavior. The in
      vitro metal uptake is nonspecific, and manganese, iron, and vanadium all bind,
      but only manganese restores catalytic activity. Bound metal ions do not exchange
      during heat treatment, indicating that the formation of the metal complex is
      effectively irreversible under these conditions. The metallation process is
      strongly temperature-dependent, suggesting that substantial activation barriers
      to metal uptake at ambient temperature are overcome by a thermal transition in
      the apo-protein structure. A mechanism for SOD metallation is proposed, focusing
      on interactions at the domain interface.

PMID- 10574945
TI  - Mammalian TOR controls one of two kinase pathways acting upon nPKCdelta and
      nPKCepsilon.
AB  - There are three conserved phosphorylation sites in protein kinase C (PKC)
      isotypes that have been termed priming sites and play an important role in PKC
      function. The requirements and pathways involved in novel (nPKC) phosphorylation
      have been investigated here. The evidence presented for nPKCdelta shows that
      there are two independent kinase pathways that act upon the activation loop (Thr
      505) and a C-terminal hydrophobic site (Ser-662) and that the phosphorylation of
      the Ser-662 site is protected from dephosphorylation by the Thr-505
      phosphorylation. Both phosphorylations require C1 domain-dependent allosteric
      activation of PKC. The third site (Ser-643) appears to be an autophosphorylation
      site. The serum-dependent phosphorylation of the Thr-505 and Ser-662 sites
      increases nPKCdelta activity up to 80-fold. Phosphorylation at the Ser-662 site
      is independently controlled by a pathway involving mammalian TOR (mTOR) because
      the rapamycin-induced block of its phosphorylation is overcome by co-expression
      of a rapamycin-resistant mutant of mTOR. Consistent with this role of mTOR, amino
      acid deprivation selectively inhibits the serum-induced phosphorylation of the
      Ser-662 site in nPKCdelta. It is established that nPKCepsilon behaves in a manner
      similar to nPKCdelta with respect to phosphorylation at its C-terminal
      hydrophobic site, Ser-729. The results define the regulatory inputs to nPKCdelta
      and nPKCepsilon and establish these PKC isotypes downstream of mTOR and on an
      amino acid sensing pathway. The multiple signals integrated in PKC are discussed.

PMID- 10574946
TI  - The HIV Nef protein alters Ca(2+) signaling in myelomonocytic cells through SH3
      mediated protein-protein interactions.
AB  - Human immunodeficiency virus Nef plays an important role in AIDS pathogenesis. In
      addition to the well known down-regulation of cell surface receptors (CD4, MHCI),
      Nef is able to alter cellular signaling. Of particular interest for this study is
      the ability of Nef to bind with a very high affinity to SH3 domains of
      myelomonocyte-specific protein-tyrosine kinases of the Src family (Src-like PTK).
      We have therefore investigated Ca(2+) signaling in HL60 cells retrovirally
      transduced with wild type Nef or with a Nef mutant deficient in the SH3
      interacting proline-rich motif (Nef((PXXP)4(-))). In differentiated HL60 cells,
      Nef markedly altered cellular Ca(2+) signaling; the amount of intracellularly
      stored Ca(2+) was increased, and as a consequence, store-operated Ca(2+)-influx
      was decreased. This effect was not observed in undifferentiated HL60 cells or in
      CEM T-lymphocytes and correlated with the differentiation-induced up-regulation
      of Src-like PTK. The Nef effect on Ca(2+) signaling depended entirely on the
      integrity of its PXXP motif. The Src-like PTK p56/59(hck) co-immunoprecipitated
      with both Nef and with the inositol 1,4,5-trisphosphate receptor, providing a
      possible mechanistic link between the viral protein and intracellular Ca(2+)
      stores of the host cell. Collectively, our results demonstrate that the human
      immunodeficiency virus 1 Nef protein manipulates intracellular Ca(2+) stores
      through SH3-mediated interactions in myelomonocytic cells.

PMID- 10574947
TI  - Differential temperature-dependent chaperone-like activity of alphaA- and alphaB
      crystallin homoaggregates.
AB  - alpha-Crystallin, a heteromultimeric protein made up of alphaA- and alphaB
      crystallins, functions as a molecular chaperone in preventing the aggregation of
      proteins. We have shown earlier that structural perturbation of alpha-crystallin
      can enhance its chaperone-like activity severalfold. The two subunits of alpha
      crystallin have extensive sequence homology and individually display chaperone
      like activity. We have investigated the chaperone-like activity of alphaA- and
      alphaB-crystallin homoaggregates against thermal and nonthermal modes of
      aggregation. We find that, against a nonthermal mode of aggregation, alphaB
      crystallin shows significant protective ability even at subphysiological
      temperatures, at which alphaA-crystallin or heteromultimeric alpha-crystallin
      exhibit very little chaperone-like activity. Interestingly, differences in the
      protective ability of these homoaggregates against the thermal aggregation of
      beta(L)-crystallin is negligible. To investigate this differential behavior, we
      have monitored the temperature-dependent structural changes in both the proteins
      using fluorescence and circular dichroism spectroscopy. Intrinsic tryptophan
      fluorescence quench-ing by acrylamide shows that the tryptophans in alphaB
      crystallin are more accessible than the lone tryptophan in alphaA-crystallin even
      at 25 degrees C. Protein-bound 8-anilinonaphthalene-1-sulfonate fluorescence
      demonstrates the higher solvent accessibility of hydrophobic surfaces on alphaB
      crystallin. Circular dichroism studies show some tertiary structural changes in
      alphaA-crystallin above 50 degrees C. alphaB-crystallin, on the other hand, shows
      significant alteration of tertiary structure by 45 degrees C. Our study
      demonstrates that despite a high degree of sequence homology and their generally
      accepted structural similarity, alphaB-crystallin is much more sensitive to
      temperature-dependent structural perturbation than alphaA- or alpha-crystallin
      and shows differences in its chaperone-like properties. These differences appear
      to be relevant to temperature-dependent enhancement of chaperone-like activity of
      alpha-crystallin and indicate different roles for the two proteins both in alpha
      crystallin heteroaggregate and as separate proteins under stress conditions.

PMID- 10574948
TI  - p34(Cdc2) kinase activity is excluded from the nucleus during the radiation
      induced G(2) arrest in HeLa cells.
AB  - The progression of cells from G(2) into mitosis is blocked by exposure to DNA
      damaging agents such as ionizing radiation. This G(2) delay is associated with
      reduced cyclin B1-specific associated histone H1 kinase activity, increased
      inhibitory phosphorylation of p34(Cdc2), and depressed cyclin B1 levels in HeLa
      cells. Induction of cyclin B1 or expression of Cdc2AF, a mutant p34(Cdc2) that
      lacks the sites of inhibitory phosphorylation, only partially reverses the
      radiation-associated G(2) delay, although both maneuvers rapidly result in
      increased histone H1 kinase activity. To account for the persistent G(2) delay in
      the face of active p34(Cdc2) kinase, we determined the location of the kinase
      activity. Although p34(Cdc2) was active in the cytoplasm, the nuclear p34(Cdc2)
      was inactive. Irradiation led to nuclear accumulation of the inactive tyrosine
      phosphorylated form of p34(Cdc2), whereas the active form was seen in the
      cytoplasm. At later times when cells had resumed cell cycle progression, nuclear
      kinase activity was detectable. These results give evidence of segregation of
      cytoplasmic and nuclear kinase activity after DNA damage that has the effect of
      enhancing checkpoint control. Shielding the nucleus from the potentially
      deleterious effects of kinase activity after DNA damage may help irradiated human
      cancer cells respond to irradiation.

PMID- 10574949
TI  - Mapping ligand binding domains in chimeric fibroblast growth factor receptor
      molecules. Multiple regions determine ligand binding specificity.
AB  - Fibroblast growth factors (FGFs) mediate essential cellular functions by
      activating one of four alternatively spliced FGF receptors (FGFRs). To determine
      the mechanism regulating ligand binding affinity and specificity, soluble FGFR1
      and FGFR3 binding domains were compared for activity. FGFR1 bound well to FGF2
      but poorly to FGF8 and FGF9. In contrast, FGFR3 bound well to FGF8 and FGF9 but
      poorly to FGF2. The differential ligand binding specificity of these two
      receptors was exploited to map specific ligand binding regions in mutant and
      chimeric receptor molecules. Deletion of immunoglobulin-like (Ig) domain I did
      not effect ligand binding, thus localizing the binding region(s) to the distal
      two Ig domains. Mapping studies identified two regions that contribute to FGF
      binding. Additionally, FGF2 binding showed positive cooperativity, suggesting the
      presence of two binding sites on a single FGFR or two interacting sites on an
      FGFR dimer. Analysis of FGF8 and FGF9 binding to chimeric receptors showed that a
      broad region spanning Ig domain II and sequences further N-terminal determines
      binding specificity for these ligands. These data demonstrate that multiple
      regions of the FGFR regulate ligand binding specificity and that these regions
      are distinct with respect to different members of the FGF family.

PMID- 10574950
TI  - beta(3)-adrenergic stimulation differentially inhibits insulin signaling and
      decreases insulin-induced glucose uptake in brown adipocytes.
AB  - Activity of the sympathetic nervous system is an important factor involved in the
      pathogenesis of insulin resistance and associated metabolic and vascular
      abnormalities. In this study, we investigate the molecular basis of cross-talk
      between beta(3)-adrenergic and insulin signaling systems in mouse brown
      adipocytes immortalized by SV40 T infection. Insulin-induced tyrosine
      phosphorylation of the insulin receptor, insulin receptor substrate 1 (IRS-1),
      and IRS-2 was reduced by prestimulation of beta(3)-adrenergic receptors
      (CL316243). Similarly, insulin-induced IRS-1-associated and phosphotyrosine
      associated phosphatidylinositol 3-kinase (PI 3-kinase) activity, but not IRS-2
      associated PI 3-kinase activity, was reduced by beta(3)-adrenergic
      prestimulation. Furthermore, insulin-stimulated activation of Akt, but not
      mitogen-activated protein kinase, was diminished. Insulin-induced glucose uptake
      was completely inhibited by beta(3)-adrenergic prestimulation. These effects
      appear to be protein kinase A-dependent. Furthermore inhibition of protein kinase
      C restored the beta(3)-receptor-mediated reductions in insulin-induced IRS-1
      tyrosine phosphorylation and IRS-1-associated PI 3-kinase activity. Together,
      these findings indicate cross-talk between adrenergic and insulin signaling
      pathways. This interaction is protein kinase A-dependent and, at least in part,
      protein kinase C-dependent, and could play an important role in the pathogenesis
      of insulin resistance associated with sympathetic overactivity and regulation of
      brown fat metabolism.

PMID- 10574951
TI  - Inhibition of hepatoma cell growth in vitro by arylating and non-arylating K
      vitamin analogs. Significance of protein tyrosine phosphatase inhibition.
AB  - We recently found that a thioether analog of K vitamin (Cpd 5) inhibited the
      activity of protein-tyrosine phosphatases (PTPases) and induced protein-tyrosine
      phosphorylation in a human hepatoma cell line (Hep3B). We have now examined the
      structural requirements for induction of protein-tyrosine phosphorylation and
      PTPase inhibition by several K vitamin analogs. Thioether analogs with sulfhydryl
      arylation capacity, especially those with a hydroxy (Cpd 5) or a methoxy group at
      the end of the side chain, induced protein-tyrosine phosphorylation, but non
      arylating analogs, such as those with an all-carbon or O-ether side chain, did
      not. Among the receptor-tyrosine kinases, epidermal growth factor receptors were
      tyrosine-phosphorylated by treatment with thioether analogs, whereas insulin and
      hepatocyte growth factor receptors were not. An increase in tyrosine
      phosphorylated ERK2 mitogen-activated protein kinase was also observed. The
      activity of purified T cell PTPase was inhibited only by the thioether analogs,
      but not by non-arylating analogs. Furthermore, the epidermal growth factor
      receptor dephosphorylation activity of Hep3B cell lysates was inhibited by Cpd 5
      treatment. A similar induction of protein-tyrosine phosphorylation by Cpd 5 was
      seen in other human hepatoma cell lines together with growth inhibition. However,
      one cell line (HepG2), which was relatively resistant to growth inhibition by Cpd
      5, did not increase its phosphorylation levels upon Cpd 5 treatment. These
      results suggest that cell growth inhibition by thioether analogs is closely
      associated with inhibition of PTPases by sulfhydryl arylation and with tyrosine
      phosphorylation of selected proteins.

PMID- 10574952
TI  - Tumor cell viability in clear cell sarcoma requires DNA binding activity of the
      EWS/ATF1 fusion protein.
AB  - Chimeric proteins resulting from characteristic chromosomal translocations are
      believed to play a key role in the development of neoplasia. The consistent
      chromosomal translocation t(12;22) found in Clear Cell sarcoma (CCS) fuses the
      genes for Ewing's sarcoma protein (EWS) and activating transcription factor 1
      (ATF1). Contribution of the chimeric EWS/ATF1 protein to maintenance of the tumor
      phenotype was investigated using intracellular expression of an inhibitory anti
      ATF1 single chain antibody fragment (scFv4). Transfection of scFv4 into a cell
      line (SU-CCS-1) derived from CCS resulted in a 90% reduction in cyclic AMP
      response element-driven reporter activity. The delivery of scFv4 into SU-CCS-1
      cells by a Moloney sarcoma retroviral vector (SRalpha-Fv4) significantly reduced
      viability and induced apoptosis as measured by terminal
      deoxynucleotidetransferase-mediated dUTP-biotin nick end labeling and flow
      cytometry. Conversely, scFv4 had no effect on viability of HeLa cells. The level
      of EWS/ATF1 expression was found to be significantly higher in primary tumor
      tissue than in SU-CCS-1 cells or in 293T cells following introduction of an
      EWS/ATF1 expression vector. These studies demonstrate a direct role for the
      EWS/ATF1 fusion protein in maintaining tumor cell viability of Clear Cell sarcoma
      and indicate that intracellular antibodies may be used to achieve a phenotypic
      knockout of tumor-related proteins as a method to explore their function.

PMID- 10574953
TI  - The use of ATP and initiating nucleotides during postrecruitment steps at the
      activated adenovirus E4 promoter.
AB  - Permanganate probing has been used to follow the progress and ATP dependence of
      promoter opening during activated adenovirus E4 initiation and clearance. Using
      templates designed to restrict synthesis to defined positions, formation of a 3
      nucleotide-long RNA was found to be sufficient to trigger expansion of the
      initial transcription bubble. This occurred by a discrete transition that
      expanded the downstream limit of melting from position 1 to 15. Subsequent
      clearance of the bubble from the promoter region also occurred without detectable
      intermediates. Thus, initial opening, extension, and the clearance of the
      promoter bubble appear to occur as discrete, unique transitions. The apparent
      K(m) values for these three steps were determined to be near 5, 9, and 50 microM,
      respectively. Comparison of these values with ATPase activities within known
      transcription factors raises the possibility that different activities could be
      responsible for each step.

PMID- 10574954
TI  - Misfolding of mutant aquaporin-2 water channels in nephrogenic diabetes
      insipidus.
AB  - We reported that several aquaporin-2 (AQP2) point mutants that cause nephrogenic
      diabetes insipidus (NDI) are retained in the endoplasmic reticulum (ER) of
      transfected mammalian cells and degraded but can be rescued by chemical
      chaperones to function as plasma membrane water channels (Tamarappoo, B. K., and
      Verkman, A. S. (1998) J. Clin. Invest. 101, 2257-2267). To test whether mutant
      AQP2 proteins are misfolded, AQP2 folding was assessed by comparative detergent
      extractability and limited proteolysis, and AQP2 degradation kinetics was
      measured by label-pulse-chase and immunoprecipitation. In ER membranes from
      transfected CHO cells containing [(35)S]methionine-labeled AQP2, mutants T126M
      and A147T were remarkably detergent-resistant; for example wild-type AQP2 was
      >95% solubilized by 0.5% CHAPS whereas T126M was <10% solubilized. E258K, an NDI
      causing AQP2 mutant which is retained in the Golgi, is highly detergent soluble
      like wild-type AQP2. The mutants and wild-type AQP2 were equally susceptible to
      digestion by trypsin, thermolysin, and proteinase K. Stopped-flow light
      scattering measurements indicated that T126M AQP2 at the ER was fully functional
      as a water channel. Pulse-chase studies indicated that the increased degradation
      rates for T126M (t((1)/(2)) 2.5 h) and A147T (2 h) compared with wild-type AQP2
      (4 h) involve a brefeldin A-resistant, ER-dependent degradation mechanism. After
      growth of cells for 48 h in the chemical chaperone glycerol, AQP2 mutants T126M
      and A147T became properly targeted and relatively detergent-soluble. These
      results provide evidence that NDI-causing mutant AQP2 proteins are misfolded, but
      functional, and that chemical chaperones both correct the trafficking and folding
      defects. Strategies to facilitate protein folding might thus have therapeutic
      efficacy in NDI.

PMID- 10574955
TI  - Role of iron and superoxide for generation of hydroxyl radical, oxidative DNA
      lesions, and mutagenesis in Escherichia coli.
AB  - We measured the generation of hydroxyl radical (OH(.)) and oxidative DNA lesions
      in aerobically grown Escherichia coli cells lacking in both superoxide dismutases
      (SodA SodB) and repressor of iron uptake (Fur) using electroparamagnetic
      resonance and gas chromatography-mass spectrometry with a selected-ion monitoring
      method. A specific signal corresponding to OH(.) generation and an increase in
      oxidative DNA lesions such as 7,8-dihydro-8-oxoguanine and 1,2-dihydro-2
      oxoadenine were detected in the strain deficient in sodA sodB fur. We showed that
      iron metabolism deregulation in fur mutant produced a 2.5-fold iron overload. The
      sodA sodB fur strain was about 100-fold higher mutability than the wild-type
      strain. The mutation spectrum in the strain was found to induce GC --> TA and AT 
      -> CG transversions predominantly. The hypermutability of the strain was
      suppressed by the tonB mutation which reduces iron transport. Thus, excess iron
      and excess superoxide were responsible for OH(.) generation, oxidative DNA lesion
      formation, and hypermutability in E. coli.

PMID- 10574956
TI  - Dimerization of the interferon type I receptor IFNaR2-2 is sufficient for
      induction of interferon effector genes but not for full antiviral activity.
AB  - We constructed chimeric receptors wherein the extracellular domain of the
      erythropoietin receptor (EpoR) was fused to the transmembrane and intracellular
      domains of the interferon (IFN) type I receptor subunits, IFNaR1 or IFNaR2-2.
      Transfection into 2fTGH and Tyk2-deficient 11,1 cells showed that EpoR/IFNaR2-2
      alone was able to transduce a signal upon stimulation with erythropoietin (Epo),
      as judged by induction of the interferon type I-inducible 6-16 promoter. In
      contrast, protection against infection with encephalomyocarditis virus or
      vesicular stomatitis virus was reduced or absent, respectively. To further
      investigate the role of IFNaR1 in the induction of an antiviral state, we
      analyzed the Epo- versus IFNalpha-induced transcription of a set of genes,
      involved in antiviral protection. Up to 24 h after stimulation with Epo or
      IFNalpha, comparable transcription of the p56, dsRNA-dependent protein kinase, 2'
      5'A synthetase, and MxA genes was seen. However, at later time points, only in
      the case of Epo induction, a sharp decrease of mRNA levels was observed. Western
      blotting analysis of dsRNA-dependent protein kinase showed a similar pattern at
      the protein level. Taken together, our results imply a role for IFNaR1 in the
      induction of sustained mRNA and protein levels that are likely required for
      optimal antiviral activity.

PMID- 10574957
TI  - Prion protein glycosylation is sensitive to redox change.
AB  - The conversion of soluble prion protein into an insoluble, pathogenic, protease
      resistant isoform is a key event in the development of prion diseases. Although
      the mechanism by which the conversion engenders a pathogenic event is unclear,
      there is increasing evidence to suggest that this may depend on the function of
      the prion protein in preventing oxidative damage. Therefore, in this study, we
      assessed the interrelationship between redox-sensitive cysteine, glycosylation,
      and prion metabolism. Cells were treated with a thioreductant, dithiothreitol, to
      assess the effect of the cellular oxidation state on the synthesis of the prion
      protein. This change in redox balance affected the glycosylation of the prion
      protein, resulting in the sole production of glycosylated forms. The role of the
      single disulfide bridge in mediating this effect within the prion protein was
      confirmed by mutating the cysteine residues involved in its formation. These data
      suggest that conditions that increase the rate of formation of the disulfide
      bridge favor formation of the unglycosylated prion protein. Thus, since the
      presence of glycans on the prion protein is protective against its pathogenic
      conversion, a change in the redox status of the cell would increase the risk of
      developing a prion disease by favoring the production of the unglycosylated form.

PMID- 10574958
TI  - Variability among the sites by which curaremimetic toxins bind to torpedo
      acetylcholine receptor, as revealed by identification of the functional residues
      of alpha-cobratoxin.
AB  - alpha-Cobratoxin, a long chain curaremimetic toxin from Naja kaouthia venom, was
      produced recombinantly (ralpha-Cbtx) from Escherichia coli. It was
      indistinguishable from the snake toxin. Mutations at 8 of the 29 explored toxin
      positions resulted in affinity decreases for Torpedo receptor with DeltaDeltaG
      higher than 1.1 kcal/mol. These are R33E > K49E > D27R > K23E > F29A >/= W25A >
      R36A >/= F65A. These positions cover a homogeneous surface of approximately 880
      A(2) and mostly belong to the second toxin loop, except Lys-49 and Phe-65 which
      are, respectively, on the third loop and C-terminal tail. The mutations K23E and
      K49E, and perhaps R33E, induced discriminative interactions at the two toxin
      binding sites. When compared with the short toxin erabutoxin a (Ea), a number of
      structurally equivalent residues are commonly implicated in binding to muscular
      type nicotinic acetylcholine receptor. These are Lys-23/Lys-27, Asp-27/Asp-31,
      Arg-33/Arg-33, Lys-49/Lys-47, and to a lesser and variable extent Trp-25/Trp-29
      and Phe-29/Phe-32. In addition, however, the short and long toxins display three
      major differences. First, Asp-38 is important in Ea in contrast to the homologous
      Glu-38 in alpha-Cbtx. Second, all of the first loop is insensitive to mutation in
      alpha-Cbtx, whereas its tip is functionally critical in Ea. Third, the C-terminal
      tail may be specifically critical in alpha-Cbtx. Therefore, the functional sites
      of long and short curaremimetic toxins are not identical, but they share common
      features and marked differences that might reflect an evolutionary pressure
      associated with a great diversity of prey receptors.

PMID- 10574959
TI  - p90(RSK) blocks bad-mediated cell death via a protein kinase C-dependent pathway.
AB  - Although activation of protein kinase C (PKC) is known to promote cell survival
      and protect against cell death, the PKC targets and pathways that serve this
      function have remained elusive. Here we demonstrate that two potent activators of
      PKC, 12-O-tetradecanoylphorbol-13-acetate and bryostatin, both stimulate
      phosphorylation of Bad at Ser(112), a site known to regulate apoptotic cell death
      by interleukin-3. PKC inhibitors but not PI 3-kinase/Akt inhibitors block 12-O
      tetradecanoylphorbol-13-acetate-stimulated Bad phosphorylation. PKC isoforms
      tested in vitro were unable to phosphorylate Bad at Ser(112), suggesting that PKC
      acts indirectly to activate a downstream Bad kinase. p90(RSK) and family members
      RSK-2 and RSK-3 are activated by phorbol ester and phosphorylate Bad at Ser(112)
      both in vitro and in vivo. p90(RSK) stimulates binding of Bad to 14-3-3 and
      blocks Bad-mediated cell death in a Ser(112)-dependent manner. These findings
      suggest that p90(RSK) can function in a PKC-dependent pathway to promote cell
      survival via phosphorylation and inactivation of Bad-mediated cell death.

PMID- 10574960
TI  - The cyclization mechanism of cyclodextrin glycosyltransferase (CGTase) as
      revealed by a gamma-cyclodextrin-CGTase complex at 1.8-A resolution.
AB  - The enzyme cyclodextrin glycosyltransferase is closely related to alpha-amylases
      but has the unique ability to produce cyclodextrins (circular alpha(1-->4)-linked
      glucoses) from starch. To characterize this specificity we determined a 1.8-A
      structure of an E257Q/D229N mutant cyclodextrin glycosyltransferase in complex
      with its product gamma-cyclodextrin, which reveals for the first time how
      cyclodextrin is competently bound. Across subsites -2, -1, and +1, the
      cyclodextrin ring binds in a twisted mode similar to linear sugars, giving rise
      to deformation of its circular symmetry. At subsites -3 and +2, the cyclodextrin
      binds in a manner different from linear sugars. Sequence comparisons and site
      directed mutagenesis experiments support the conclusion that subsites -3 and +2
      confer the cyclization activity in addition to subsite -6 and Tyr-195. On this
      basis, a role of the individual residues during the cyclization reaction cycle is
      proposed.

PMID- 10574961
TI  - Biochemical and structural characterization of a divergent loop cyclophilin from
      Caenorhabditis elegans.
AB  - Cyclophilin 3 (CYP-3) is one of the most abundantly expressed cyclophilin
      isoforms in the free living nematode Caenorhabditis elegans. The detailed post
      embryonic expression pattern of the cyp-3 transcript is unusual, peaking during
      early larval development. The spatial expression pattern was examined via
      reporter gene analysis demonstrating that the cyp-3 transcript is exclusively
      expressed in the single anterior excretory cell. Recombinant cyclophilin 3 has
      been purified, crystallized and solved to a resolution of 1.8 A. The peptidyl
      prolyl isomerase activity of CYP-3 has been characterized against the substrate N
      succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, and gives a k(cat)/K(m) value of 2.4 x
      10(6) M(-1) s(-1). The immunosuppressive drug cyclosporin A binds and inhibits
      CYP-3 with an IC(50) value of 16 nM, comparable with the range of values found
      for human cyclophilin A. The x-ray structure shows that the overall fold and
      active site geometry is similar to other cyclophilin structures. There are
      however a number of distinctive features, and we use this structure and amino
      acid sequence alignment analysis to identify a subgroup of "divergent-loop
      cyclophilins". This subgroup has a number of uniquely conserved features: an
      additional loop between residues 48 and 54 (KSGKPLH); two cysteine residues
      (Cys(40) and Cys(168)) that are in close proximity but remain in the unoxidized
      form, and two other conserved residues, His(54) and Glu(83). We suggest that
      these features are functionally important for the role played by this class of
      cyclophilins during cellular responses to stress caused by changes in the redox
      environment or by up-regulation of cellular activity. This study represents a
      detailed biological, biochemical, and structural characterization of a single
      cyclophilin isoform in the model organism Caenorhabditis elegans.

PMID- 10574962
TI  - A mutant form of vascular endothelial growth factor (VEGF) that lacks VEGF
      receptor-2 activation retains the ability to induce vascular permeability.
AB  - Vascular endothelial growth factor (VEGF) is a major mediator of vasculogenesis
      and angiogenesis both during development and in pathological conditions. VEGF has
      a variety of effects on vascular endothelium, including the ability to stimulate
      endothelial cell mitogenesis, and the potent induction of vascular permeability.
      These activities are at least in part mediated by binding to two high affinity
      receptors, VEGFR-1 and VEGFR-2. In this study we have made mutations of mouse
      VEGF in order to define the regions that are required for VEGFR-2-mediated
      functions. Development of a bioassay, which responds only to signals generated by
      cross-linking of VEGFR-2, has allowed evaluation of these mutants for their
      ability to activate VEGFR-2. One mutant (VEGF0), which had amino acids 83-89 of
      VEGF substituted with the analogous region of the related placenta growth factor,
      demonstrated significantly reduced VEGFR-2 binding compared with wild type VEGF,
      indicating that this region was required for VEGF-VEGFR-2 interaction.
      Intriguingly, when this mutant was evaluated in a Miles assay for its ability to
      induce vascular permeability, no difference was found when compared with wild
      type VEGF. In addition we have shown that the VEGF homology domain of the
      structurally related growth factor VEGF-D is capable of binding to and activating
      VEGFR-2 but has no vascular permeability activity, indicating that VEGFR-2
      binding does not correlate with permeability activity for all VEGF family
      members. These data suggest different mechanisms for VEGF-mediated mitogenesis
      and vascular permeability and raise the possibility of an alternative receptor
      mediating vascular permeability.

PMID- 10574963
TI  - Brain insulin receptors and spatial memory. Correlated changes in gene
      expression, tyrosine phosphorylation, and signaling molecules in the hippocampus
      of water maze trained rats.
AB  - Evidence accumulated from clinical and basic research has indirectly implicated
      the insulin receptor (IR) in brain cognitive functions, including learning and
      memory (Wickelgren, I. (1998) Science 280, 517-519). The present study
      investigates correlative changes in IR expression, phosphorylation, and
      associated signaling molecules in the rat hippocampus following water maze
      training. Although the distribution of IR protein matched that of IR mRNA in most
      forebrain regions, a dissociation of the IR mRNA and protein expression patterns
      was found in the cerebellar cortex. After training, IR mRNA in the CA1 and
      dentate gyrus of the hippocampus was up-regulated, and there was increased
      accumulation of IR protein in the hippocampal crude synaptic membrane fraction.
      In the CA1 pyramidal neurons, changes in the distribution pattern of IR in
      particular cellular compartments, such as the nucleus and dendritic regions, was
      observed only in trained animals. Although IR showed a low level of in vivo
      tyrosine phosphorylation, an insulin-stimulated increase of in vitro Tyr
      phosphorylation of IR was detected in trained animals, suggesting that learning
      may induce IR functional changes, such as enhanced receptor sensitivity.
      Furthermore, a training-induced co-immunoprecipitation of IR with Shc-66 was
      detected, along with changes in in vivo Tyr phosphorylation of Shc and mitogen
      activated protein kinase, as well as accumulation of Shc-66, Shc-52, and Grb-2 in
      hippocampal synaptic membrane fractions following training. These findings
      suggest that IR may participate in memory processing through activation of its
      receptor Tyr kinase activity, and they suggest possible engagement of Shc/Grb
      2/Ras/mitogen-activated protein kinase cascades.

PMID- 10574964
TI  - Patch clamp studies on V-type ATPase of vacuolar membrane of haploid
      Saccharomyces cerevisiae. Preparation and utilization of a giant cell containing
      a giant vacuole.
AB  - A method for obtaining giant protoplasts of Escherichia coli (the spheroplast
      incubation (SI) method: Kuroda et al. (Kuroda, T., Okuda, N., Saitoh, N., Hiyama,
      T., Terasaki, Y., Anazawa, H., Hirata, A., Mogi, T., Kusaka, I., Tsuchiya, T.,
      and Yabe, I. (1998) J. Biol. Chem. 273, 16897-16904) was adapted to haploid cells
      of Saccharomyces cerevisiae. The yeast cell grew to become as large as 20
      micrometer in diameter and to contain an oversized vacuole inside. A patch clamp
      technique in the whole cell/vacuole recording mode was applied for the vacuole
      isolated by osmotic shock. At zero membrane potential, ATP induced a strong
      current (as high as 100 pA; specific activity, 0.1 pA/micrometer(2)) toward the
      inside of the vacuole. Bafilomycin A(1,) a specific inhibitor of the V-type
      ATPase, strongly inhibited the activity (K(i) = 10 nM). Complete inhibition at
      higher concentrations indicated that any other ATP-driven transport systems were
      not expressed under the present incubation conditions. This current was not
      observed in the vacuoles prepared from a mutant that disrupted a catalytic
      subunit of the V-type ATPase (RH105(Deltavma1::TRP)). The K(m) value for the ATP
      dose response of the current was 159 microM and the H(+)/ATP ratio estimated from
      the reversible potential of the V-I curve was 3.5 +/- 0.3. These values agreed
      well with those previously estimated by measuring the V-type ATPase activity
      biochemically. This method can potentially be applied to any type of ion channel,
      ion pump, and ion transporter in S. cerevisiae, and can also be used to
      investigate gene functions in various organisms by using yeast cells as hosts for
      homologous and heterogeneous expression systems.

PMID- 10574965
TI  - Inhibition of G-protein-coupled receptor function by disruption of transmembrane
      domain interactions.
AB  - G-protein-coupled receptors (GPCR) represent a superfamily of proteins that
      mediate the function of neurotransmitters and peptide hormones and are involved
      in viral entry and perception of light, smell, and taste. GPCRs are characterized
      by the presence of seven transmembrane domains (TMs). We demonstrate here that
      structural analogs of individual TMs of GPCRs can serve as potent and specific
      receptor antagonists. Peptides derived from the transmembrane regions of CXCR4
      and CCR5 chemokine receptors specifically inhibited receptor signaling and the in
      vitro replication of human immunodeficiency virus-1 (HIV-1) at concentrations as
      low as 0.2 microM. Similarly, peptides mimicking the TMs of cholecystokinin
      receptor A, were found to abolish ligand binding and signaling through the
      receptor. Negative charges positioned at the extracellular termini of peptide
      antagonists appeared to be important for correct spontaneous insertion of the
      compounds into the cell membrane and for their activity. Targeting of the
      specific interactions between transmembrane domains of GPCRs is suggested as a
      general sequence-based method to disrupt receptor function for application in
      drug design and for structure-function studies of the receptors.

PMID- 10574966
TI  - Territrem B, a tremorgenic mycotoxin that inhibits acetylcholinesterase with a
      noncovalent yet irreversible binding mechanism.
AB  - Territrem B (TRB) is a fungal metabolite isolated from Aspergillus terreus shown
      previously to be a potent and irreversible inhibitor of acetylcholinesterase
      (AChE). In the present study, a number of binding and inhibition assays were
      carried out to further characterize the inhibitory effect of TRB. The results
      indicate that the binding of TRB (a) is much more selective than a well
      characterized selective inhibitor of AChE, BW284C51, (b) adopts a one-to-one
      stoichiometry with the enzyme, (c) cannot be undone by an AChE-regenerating oxime
      agent, which contrasts the ability of 8 M urea to release AChE-bound TRB, (d) is
      enhanced by high concentration NaCl but prevented, unless preincubated, by Triton
      X-100, and (e) exhibits quasi-first order kinetics with an overall inhibition
      constant of 0.01 nM(-1) min(-1). Together these results suggest a very different
      irreversible binding (a noncovalent type) from that of the covalent type, which
      involves typical irreversible AChE inhibitors such as diisopropylfluorophosphate
      and neostigmine. According to the prediction of a molecular modeling study, the
      distinct AChE inhibitory characteristics of TRB may arise from the inhibitor
      being noncovalently trapped within a unique active-site gorge structure of the
      enzyme. It was predicted that an optimal TRB. AChE binding would position a
      narrowing connection of the TRB structure at a constricted area near the entrance
      of the gorge, thereby providing a structural basis for the observed irreversible
      binding.

PMID- 10574967
TI  - Conformational and molecular basis for induction of apoptosis by a p53 C-terminal
      peptide in human cancer cells.
AB  - A p53-derived C-terminal peptide induced rapid apoptosis in breast cancer cell
      lines carrying endogenous p53 mutations or overexpressed wild-type (wt) p53 but
      was not toxic to nonmalignant human cell lines containing wt p53. Apoptosis
      occurred through a Fas/APO-1 signaling pathway involving increased extracellular
      levels of Fas/FasL in the absence of protein synthesis, as well as activation of
      a Fas/APO-1-specific protease, FLICE. The peptide activity was p53-dependent, and
      it had no effect in three tumor cell lines with null p53. Furthermore, the C
      terminal peptide bound to p53 protein in cell extracts. Thus, p53-dependent,
      Fas/APO-1 mediated apoptosis can be induced in breast cancer cells with mutant
      p53 similar to the recently described Fas/APO-1 induced apoptosis by wt p53.
      However, mutant p53 without p53 peptide does not induce a Fas/APO-1 activation or
      apoptosis. Docking of the computed low energy conformations for the C-terminal
      peptide with those for a recently defined proline-rich regulatory region from the
      N-terminal domain of p53 suggests a unique low energy complex between the two
      peptide domains. The selective and rapid induction of apoptosis in cancer cells
      carrying p53 abnormalities may lead to a novel therapeutic modality.

PMID- 10574968
TI  - Balance between activities of Rho kinase and type 1 protein phosphatase modulates
      turnover of phosphorylation and dynamics of desmin/vimentin filaments.
AB  - To analyze the cell cycle-dependent desmin phosphorylation by Rho kinase, we
      developed antibodies specifically recognizing the kinase-dependent
      phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies,
      phosphorylation of desmin was observed specifically at the cleavage furrow in
      late mitotic Saos-2 cells. We then found that treatment of the interphase cells
      with calyculin A revealed phosphorylation at all the three sites of desmin. We
      also found that an antibody, which specifically recognizes vimentin
      phosphorylated at Ser-71 by Rho kinase, became immunoreactive after calyculin A
      treatment. This calyculin A-induced interphase phosphorylation of vimentin at Ser
      71 was blocked by Rho kinase inhibitor or by expression of the dominant-negative
      Rho kinase. Taken together, our results indicate that Rho kinase is activated not
      only in mitotic cells but also interphase ones, and phosphorylates intermediate
      filament proteins, although the apparent phosphorylation level is diminished to
      an undetectable level due to the constitutive action of type 1 protein
      phosphatase. The balance between intermediate filament protein phosphorylation by
      Rho kinase and dephosphorylation by type 1 protein phosphatase may affect the
      continuous exchange of intermediate filament subunits between a soluble pool and
      polymerized intermediate filaments.

PMID- 10574969
TI  - Histone deacetylase inhibition selectively alters the activity and expression of
      cell cycle proteins leading to specific chromatin acetylation and
      antiproliferative effects.
AB  - Histone acetylation is emerging as a major regulatory mechanism thought to
      modulate gene expression by altering the accessibility of transcription factors
      to DNA. In this study, treatment of human tumor cells with the histone
      deacetylase inhibitor, trapoxin (TPX), resulted in selective changes in genes
      that control the cell cycle. TPX activated p21(waf1) transcription that led to
      elevated p21(waf1) protein levels in three human tumor cell lines without
      altering the protein levels of cdk2, cdk4, or cyclin B. In addition, TPX
      increased cyclin E transcription without increasing the levels of Rb, E2F,
      dihydrofolate reductase, or glyceraldehyde-3-phosphate dehydrogenase. The
      elevated levels of p21(waf1) protein led to decreased Rb phosphorylation and cdk2
      activity. These effects resulted in G(1) and G(2) cell cycle arrest in H1299
      human lung and MDA-MB-435 breast carcinoma cells and apoptosis in A549 lung
      carcinoma cells. Chromatin immunoprecipitation assays revealed that TPX increased
      the level of chromatin acetylation associated with histone H3 in the trapoxin
      responsive region of the p21(waf1) promoter. This study demonstrates that
      inhibition of HDAC by TPX increases acetylation of H3-associated chromatin and
      alters gene expression with marked selectivity.

PMID- 10574970
TI  - LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney
      and intestine.
AB  - Glycoprotein-associated amino acid transporters (gpaAT) are permease-related
      proteins that require heterodimerization to express their function. So far, four
      vertebrate gpaATs have been shown to associate with 4F2hc/CD98 for functional
      expression, whereas one gpaAT specifically associates with rBAT. In this study,
      we characterized a novel gpaAT, LAT2, for which mouse and human cDNAs were
      identified by expressed sequence tag data base searches. The encoded ortholog
      proteins are 531 and 535 amino acids long and 92% identical. They share 52 and
      48% residues with the gpaATs LAT1 and y(+)LAT1, respectively. When mouse LAT2 and
      human 4F2hc cRNAs were co-injected into Xenopus oocytes, disulfide-linked
      heterodimers were formed, and an L-type amino acid uptake was induced, which
      differed slightly from that produced by LAT1-4F2hc: the apparent affinity for L
      phenylalanine was higher, and L-alanine was transported at physiological
      concentrations. In the presence of an external amino acid substrate, LAT2-4F2hc
      also mediated amino acid efflux. LAT2 mRNA is expressed mainly in kidney and
      intestine, whereas LAT1 mRNA is expressed widely. Immunofluorescence experiments
      showed colocalization of 4F2hc and LAT2 at the basolateral membrane of kidney
      proximal tubules and small intestine epithelia. In conclusion, LAT2 forms with
      LAT1 a subfamily of L-type gpaATs. We propose that LAT1 is involved in cellular
      amino acid uptake, whereas LAT2 plays a role in epithelial amino acid
      (re)absorption.

PMID- 10574971
TI  - Characterization of the adenylation site in the RNA 3'-terminal phosphate cyclase
      from Escherichia coli.
AB  - RNA 3'-terminal phosphate cyclases are a family of evolutionarily conserved
      enzymes that catalyze ATP-dependent conversion of the 3'-phosphate to the 2',3'
      cyclic phosphodiester at the end of RNA. The precise function of cyclases is not
      known, but they may be responsible for generating or regenerating cyclic
      phosphate RNA ends required by eukaryotic and prokaryotic RNA ligases. Previous
      work carried out with human and Escherichia coli enzymes demonstrated that the
      initial step of the cyclization reaction involves adenylation of the protein. The
      AMP group is then transferred to the 3'-phosphate in RNA, yielding an RNA
      N(3')pp(5')A (N is any nucleoside) intermediate, which finally undergoes
      cyclization. In this work, by using different protease digestions and mass
      spectrometry, we assign the site of adenylation in the E. coli cyclase to His
      309. This histidine is conserved in all members of the class I subfamily of
      cyclases identified by phylogenetic analysis. Replacement of His-309 with
      asparagine or alanine abrogates both enzyme-adenylate formation and cyclization
      of the 3'-terminal phosphate in a model RNA substrate. The cyclase is the only
      known protein undergoing adenylation on a histidine residue. Sequences flanking
      the adenylated histidine in cyclases do not resemble those found in other
      proteins modified by nucleotidylation.

PMID- 10574972
TI  - Nuclear import of metallothionein requires its mRNA to be associated with the
      perinuclear cytoskeleton.
AB  - The influence of mRNA localization on metallothionein-1 protein distribution was
      studied by immunocytochemistry. We used Chinese hamster ovary cells that had been
      transfected with either a native metallothionein-1 gene construct or
      metallothionein-1 5'-untranslated region and coding sequences linked to the 3'
      untranslated region from glutathione peroxidase. The change in the 3'
      untranslated region caused the delocalization of the mRNA with a loss of the
      perinuclear localization and association with the cytoskeleton. Clones were
      selected which expressed similar levels of metallothionein-1 protein, as assessed
      by radioimmunoassay. The results showed that loss of metallothionein-1 mRNA
      localization was associated with a loss of metallothionein-1 protein
      localization, most notably with a lack of metallothionein-1 protein in the
      nucleus of synchronized cells which were beginning to synthesize DNA. This
      indicates that the association of metallothionein-1 mRNA with the cytoskeleton
      around the nucleus is essential for efficient shuttling of the protein into the
      nucleus during the G(1) to S phase transition. This is the first demonstration of
      a physiological role for perinuclear mRNA localization and we propose that such
      localization may be important for a wide range of nuclear proteins, including
      those that shuttle between nucleus and cytoplasm in a cell cycle dependent
      manner.

PMID- 10574973
TI  - Bisphosphonates act directly on the osteoclast to induce caspase cleavage of mst1
      kinase during apoptosis. A link between inhibition of the mevalonate pathway and
      regulation of an apoptosis-promoting kinase.
AB  - Bisphosphonates (BPs) include potent inhibitors of bone resorption used to treat
      osteoporosis and other bone diseases. BPs directly or indirectly induce apoptosis
      in osteoclasts, the bone resorbing cells, and this may play a role in inhibition
      of bone resorption. Little is known about downstream mediators of apoptosis in
      osteoclasts, which are difficult to culture. Using purified osteoclasts, we
      examined the effects of alendronate, risedronate, pamidronate, etidronate, and
      clodronate on apoptosis and signaling kinases. All BPs induce caspase-dependent
      formation of pyknotic nuclei and cleavage of Mammalian Sterile 20-like (Mst)
      kinase 1 to form the active 34-kDa species associated with apoptosis. Withdrawal
      of serum and of macrophage colony stimulating factor, necessary for survival of
      purified osteoclasts, or treatment with staurosporine also induce apoptosis and
      caspase cleavage of Mst1. Consistent with their inhibition of the mevalonate
      pathway, apoptosis and cleavage of Mst1 kinase induced by alendronate,
      risedronate, and lovastatin, but not clodronate, are blocked by geranylgeraniol,
      a precursor of geranylgeranyl diphosphate. Together these findings suggest that
      BPs act directly on the osteoclast to induce apoptosis and that caspase cleavage
      of Mst1 kinase is part of the apoptotic pathway. For alendronate and risedronate,
      these events seem to be downstream of inhibition of geranylgeranylation.

PMID- 10574974
TI  - Role of reactive oxygen species and p53 in chromium(VI)-induced apoptosis.
AB  - Apoptosis is a programmed cell death mechanism to control cell number in tissues
      and to eliminate individual cells that may lead to disease states. The present
      study investigates chromium(VI) (Cr(VI))-induced apoptosis and the role of
      reactive oxygen species (ROS) and p53 in this response. Treatment of human lung
      epithelial cells (A549) with Cr(VI) caused apoptosis as measured by DNA
      fragmentation, mitochondria damage, and cell morphology. Cr(VI)-induced apoptosis
      is contributed to ROS generation, resulting from cellular reduction of Cr(VI) as
      measured by flow cytometric analysis of the stained cells, oxygen consumption,
      and electron spin resonance spin trapping. Scavengers of ROS, such as catalase,
      aspirin, and N-acetyl-L-cysteine, decreased Cr(VI)-induced apoptosis, whereas
      NADPH and glutathione reductase, enhancers of Cr(VI)-induced ROS generation,
      increased it. p53 is activated by Cr(VI), mostly by ROS-mediated free radical
      reactions. Cr(VI)-induced ROS generation occurred within a few minutes after
      Cr(VI) treatment of the cells, whereas p53 induction took at least 5 h. The level
      of Cr(VI)-induced apoptosis was similar in both p53-positive cells and p53
      negative cells independent of p53 status in the early stage (0-3 h) of Cr(VI)
      treatment. However, at the later stage (3-24 h), the level of the apoptosis is
      higher in p53-positive cells than in p53-negative cells. These results suggest
      that ROS generated through Cr(VI) reduction is responsible to the early stage of
      apoptosis, whereas p53 contributes to the late stage of apoptosis and is
      responsible for the enhancement of Cr(VI)-induced apoptosis at this stage.

PMID- 10574975
TI  - Structural studies of the detergent-solubilized and vesicle-reconstituted insulin
      receptor.
AB  - Insulin binding to the insulin receptor initiates a cascade of cellular events
      that are responsible for regulating cell metabolism, proliferation, and growth.
      We have investigated the structure of the purified, functionally active, human
      insulin receptor using negative stain and cryo-electron microscopy. Visualization
      of the detergent-solubilized and vesicle-reconstituted receptor shows the
      alpha(2)beta(2) heterotetrameric insulin receptor to be a three-armed pinwheel
      like complex that exhibits considerable variability among individual receptors.
      The alpha-subunit of the receptor was labeled with an insulin
      analogue.streptavidin gold conjugate, which facilitated the identification of the
      receptor arm responsible for insulin binding. The gold label was localized to the
      tip of a single receptor arm of the three-armed complex. The beta-subunit of the
      insulin receptor was labeled with a maleimide-gold conjugate, which allowed
      orientation of the receptor complex in the membrane bilayer. The model derived
      from electron microscopic studies displays a "Y"-like morphology representing the
      predominant species identified in the reconstituted receptor images. The insulin
      receptor dimensions are approximately 12.2 nm by 20.0 nm, extending 9.7 nm above
      the membrane surface. The beta-subunit-containing arm is approximately 13.9 nm,
      and each alpha-subunit-containing arm is 8.6 nm in length. The model presented is
      the first description of the insulin receptor visualized in a fully hydrated
      state using cryo-electron microscopy.

PMID- 10574976
TI  - Topology, subcellular localization, and sequence diversity of the Mlo family in
      plants.
AB  - Barley Mlo defines the founder of a novel class of plant integral membrane
      proteins. Lack of the wild type protein leads to broad spectrum disease
      resistance against the pathogenic powdery mildew fungus and deregulated leaf cell
      death. Scanning N-glycosylation mutagenesis and Mlo-Lep fusion proteins
      demonstrated that Mlo is membrane-anchored by 7 transmembrane (TM) helices such
      that the N terminus is located extracellularly and the C terminus
      intracellularly. Fractionation of leaf cells and immunoblotting localized the
      protein to the plant plasma membrane. A genome-wide search for Mlo sequence
      related genes in Arabidopsis thaliana revealed approximately 35 family members,
      the only abundant gene family encoding 7 TM proteins in higher plants. The
      sequence variability of Mlo family members within a single species, their
      topology and subcellular localization are reminiscent of the most abundant class
      of metazoan 7 TM receptors, the G-protein-coupled receptors.

PMID- 10574977
TI  - The structures of the horseradish peroxidase C-ferulic acid complex and the
      ternary complex with cyanide suggest how peroxidases oxidize small phenolic
      substrates.
AB  - We have solved the x-ray structures of the binary horseradish peroxidase C
      ferulic acid complex and the ternary horseradish peroxidase C-cyanide-ferulic
      acid complex to 2.0 and 1.45 A, respectively. Ferulic acid is a naturally
      occurring phenolic compound found in the plant cell wall and is an in vivo
      substrate for plant peroxidases. The x-ray structures demonstrate the flexibility
      and dynamic character of the aromatic donor binding site in horseradish
      peroxidase and emphasize the role of the distal arginine (Arg(38)) in both
      substrate oxidation and ligand binding. Arg(38) hydrogen bonds to bound cyanide,
      thereby contributing to the stabilization of the horseradish peroxidase-cyanide
      complex and suggesting that the distal arginine will be able to contribute with a
      similar interaction during stabilization of a bound peroxy transition state and
      subsequent O-O bond cleavage. The catalytic arginine is additionally engaged in
      an extensive hydrogen bonding network, which also includes the catalytic distal
      histidine, a water molecule and Pro(139), a proline residue conserved within the
      plant peroxidase superfamily. Based on the observed hydrogen bonding network and
      previous spectroscopic and kinetic work, a general mechanism of peroxidase
      substrate oxidation is proposed.

PMID- 10574979
TI  - Mutations uncouple human fibroblast growth factor (FGF)-7 biological activity and
      receptor binding and support broad specificity in the secondary receptor binding
      site of FGFs.
AB  - The fibroblast growth factor (FGF) family plays a key role in a multitude of
      physiological and pathological processes. The activities of FGFs are mediated by
      a family of tyrosine kinase receptors, designated FGFRs. The mechanism by which
      FGFs induce receptor activation is controversial. Despite their structural
      similarity, FGFs display distinct receptor binding characteristics and cell type
      specificity. Previous studies with FGF-2 identified a low affinity receptor
      binding site that is located within a loop connecting its 9th and 10th beta
      strands. The corresponding residues in the other family members are highly
      variable, and it was proposed that the variability might confer on FGFs unique
      receptor binding characteristics. We studied the role of this loop in FGF-7 by
      both site-directed mutagenesis and loop replacement. Unlike the other members of
      the FGF family, FGF-7 recognizes only one FGFR isoform and is, therefore, ideal
      for studies of how the specificity in the FGF-FGFR interaction is conferred at
      the structural level. Point mutations in the loop of FGF-7 did not change
      receptor binding affinity but resulted in reduced mitogenic potency and reduced
      ability to induce receptor-mediated phosphorylation events. These results suggest
      that the loop of FGF-7 fulfills the role of low affinity binding site required
      for receptor activation. The observation that it is possible to uncouple FGF-7
      receptor binding and biological activity favors a bivalent model for FGFR
      dimerization, and it may be clinically relevant to the design of FGF-7
      antagonists. Reciprocal loop replacement between FGF-7 and FGF-2 had no effect on
      their known receptor binding affinities nor did it alter their known specificity
      in eliciting a mitogenic response. In conclusion, these results suggest that,
      despite the diversity in the loop structure of FGF-2 and FGF-7, the loop has a
      similar function in both growth factors.

PMID- 10574978
TI  - Circadian rhythm of patched1 transcription in the pineal regulated by adrenergic
      stimulation and cAMP.
AB  - The tumor suppressor patched1 (PTC1), a product of the mammalian homologue of the
      Drosophila segment polarity gene patched, is a receptor for hedgehog (HH) and is
      crucial for embryonic development. Although little is known about the signal
      transduction pathways leading to the activation of ptc1, increased ptc1
      transcription has always been associated with elevated HH activity and decreased
      activity of cAMP-dependent protein kinase A. Here, we demonstrate that in the
      mammalian pineal gland, ptc1 expression exhibits a dramatic diurnal rhythm with
      peak expression at midnight. ptc1 mRNA expression in the pineal is regulated by a
      clock mechanism mediated by the superior cervical ganglion. Most importantly,
      ptc1 transcription can be induced by agents activating the cAMP signal
      transduction pathway both in vivo and in vitro and appears to be independent of
      HH signaling.

PMID- 10574980
TI  - Response to the sexual pheromone and wounding in the green alga volvox: induction
      of an extracellular glycoprotein consisting almost exclusively of hydroxyproline.
AB  - The extracellular matrix (ECM) of Volvox is modified during development or in
      response to external stimuli, like the sex-inducing pheromone. It has recently
      been demonstrated that a number of genes triggered by the sex-inducing pheromone
      are also inducible by wounding. By differential screening of a cDNA library, a
      novel gene was identified that is transcribed in response to the pheromone. Its
      gene product was characterized as an ECM glycoprotein with a striking feature: it
      exhibits a hydroxyproline content of 68% and therefore is an extreme member of
      the family of hydroxyproline-rich glycoproteins (HRGPs). HRGPs are known as
      constituents of higher plant ECMs and seem to function as structural barriers in
      defense responses. The Volvox HRGP is also found to be inducible by wounding.
      This indicates that the wound response scenarios of higher plants and
      multicellular green algae may be evolutionary related.

PMID- 10574981
TI  - p56(lck), ZAP-70, SLP-76, and calcium-regulated effectors are involved in NF
      kappaB activation by bisperoxovanadium phosphotyrosyl phosphatase inhibitors in
      human T cells.
AB  - This study investigates the second messengers involved in NF-kappaB activation by
      the bisperoxovanadium (bpV) phosphotyrosyl phosphatase inhibitors. We first
      initiated a time course analysis of bpV-mediated activation of the human
      immunodeficiency virus type-1 long terminal repeat- and NF-kappaB-driven reporter
      gene. Our results showed a slower and more transient activation of both kappaB
      regulated luciferase-encoding vectors by bpV compounds when compared with the
      action of tumor necrosis factor-alpha (TNF). Time course analyses of NF-kappaB
      translocation by shift assay experiments further confirmed these results, hence
      implying distinct pathways of NF-kappaB activation for bpV compounds and TNF.
      Attempts to characterize the bpV-dependent signaling cascade revealed that the
      src family protein tyrosine kinase p56(lck) was critical for NF-kappaB induction
      by bpV. Furthermore, p56(lck) interaction with the intracytoplasmic tail of CD4
      markedly enhanced such induction. Optimal activation of NF-kappaB following bpV
      treatment necessitated downstream effectors of p56(lck) such as the syk family
      protein tyrosine kinase ZAP-70 and the molecular adaptor SLP-76. Importantly,
      reduced NF-kappaB activation was observed when capacitative calcium entry was
      deficient but also upon pharmacological inhibition of calmodulin and calcineurin.
      Altogether, these results suggest that induction of NF-kappaB by phosphotyrosyl
      phosphatase bpV inhibitors necessitates both proximal and distal effectors of T
      cell activation.

PMID- 10574982
TI  - The delayed activation of the prostaglandin G/H synthase-2 promoter in bovine
      granulosa cells is associated with down-regulation of truncated upstream
      stimulatory factor-2.
AB  - To elucidate the molecular mechanisms involved in the delayed induction of PGHS-2
      in species with a long ovulatory process, a 1. 6-kilobase fragment of the bovine
      PGHS-2 promoter was isolated, and its activity was characterized in primary
      cultures of bovine granulosa cells. Promoter activity assays performed with a
      series of deletion mutants revealed that the promoter region from -149 to -2 (+1
      = transcription start site) confers full-length promoter activity in response to
      forskolin (10 microM). Four consensus cis-elements were identified within this
      region, including an E-box, ATF/CRE, C/EBP, and AP2 site. Site-directed
      mutagenesis showed that the E-box was required for PGHS-2 promoter activity, that
      disruption of the C/EBP element decreased forskolin inducible activity by 29%,
      whereas point mutation within the ATF/CRE and AP2 element had no inhibitory
      effect. Electrophoretic mobility shift assays (EMSAs) performed with the -149/-2
      fragment and granulosa cell nuclear extracts obtained before (0 h) and after (18
      and 20 h) human chorionic gonadotropin (hCG) revealed the regulation of multiple
      DNA-protein complexes. The 0-h extract generated four complexes at the E-box,
      whereas only one complex was produced at this site with the 18-h extract.
      Supershift EMSAs identified that upstream stimulatory factor-1 and -2 (USF-1 and 
      2) were part of these complexes. Interestingly, the presence of the amino
      terminal truncated USF-2, which lacks the transcription activation domain, was
      detected in the 0-h extract, but not in extracts prepared post-hCG. Supershift
      EMSAs also indicated high levels of C/EBPbeta binding to its cis-element in the 0
      h extract, which contrasts with results previously reported in rats. Thus, high
      levels of amino-terminal truncated USF-2 and C/EBPbeta in bovine granulosa cells
      prior to hCG treatment could repress gene expression, and be involved in the
      delayed induction of PGHS-2 in species with a long ovulatory process.

PMID- 10574983
TI  - Characterization of plasmin-mediated activation of plasma procarboxypeptidase B.
      Modulation by glycosaminoglycans.
AB  - Plasma carboxypeptidase B (PCB) is an exopeptidase that exerts an
      antifibrinolytic effect by releasing C-terminal Lys and Arg residues from
      partially degraded fibrin. PCB is produced in plasma via limited proteolysis of
      the zymogen, pro-PCB. In this report, we show that the K(m) (55 nM) for plasmin
      catalyzed activation of pro-PCB is similar to the plasma concentration of pro-PCB
      (50-70 nM), whereas the K(m) for the thrombin- or thrombin:thrombomodulin
      catalyzed reaction is 10-40-fold higher than the pro-PCB level in plasma.
      Additionally, tissue-type plasminogen activator triggers activation of pro-PCB in
      blood plasma in a reaction that is stimulated by a neutralizing antibody versus
      alpha(2)-antiplasmin. Together, these results show that plasmin-mediated
      activation of pro-PCB can occur in blood plasma. Heparin (UH) and other anionic
      glycosaminoglycans stimulate pro-PCB activation by plasmin but not by thrombin or
      thrombin:thrombomodulin. Pro-PCB is a more favorable substrate for plasmin in the
      presence of UH (16-fold increase in k(cat)/K(m)). UH also stabilizes PCB against
      spontaneous inactivation. The presence of UH in clots prepared with prothrombin
      deficient plasma delays tissue-type plasminogen activator-triggered lysis; this
      effect of UH on clot lysis is blocked by a PCB inhibitor from potato tubers.
      These results show that UH accelerates plasmin-catalyzed activation of pro-PCB in
      plasma and PCB, in turn, stabilizes fibrin against fibrinolysis. We propose that
      glycosaminoglycans in the subendothelial extracellular matrix serve to augment
      the levels of PCB activity thereby stabilizing blood clots at sites where there
      is a breach in the integrity of the vasculature.

PMID- 10574984
TI  - Transforming growth factor-beta-mediated p15(INK4B) induction and growth
      inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in
      human glioma cell lines.
AB  - We sought to characterize the pathway by which the multifunctional cytokine
      transforming growth factor-beta (TGF-beta) inhibits the proliferation of normal
      astrocytes, and we analyzed the alterations in the TGF-beta pathway in human
      glioma cell lines. Upon TGF-beta treatment, primary rat astrocytes showed a
      significant decrease in DNA synthesis upon thymidine incorporation with a cell
      cycle arrest in the G(1) phase. Western analysis of the astrocytes revealed that
      the expression of the cyclin-dependent kinase inhibitor (CdkI) p15(INK4B) was
      significantly up-regulated upon TGF-beta treatment without a change in other CdkI
      levels. The retinoblastoma protein (Rb) became hypophosphorylated, and Cdk2
      activity decreased. Analysis of Smad3 null mouse astrocytes showed a significant
      loss of both TGF-beta-mediated growth inhibition and p15(INK4B) induction
      compared with wild-type mouse astrocytes. Infection of rat astrocytes by SMAD3
      and SMAD4 adenoviruses failed to induce increased expression of p15(INK4B),
      implying indirect transcriptional regulation of p15(INK4B) by SMAD3. High-grade
      human gliomas secrete TGF-beta, yet are resistant to its growth inhibitory
      effects. Analysis of the effects of TGF-beta on 12 human glioma cell lines showed
      that TGF-beta mildly inhibited the growth of six lines, had no effect on four
      lines, and stimulated the growth of two lines. The majority of glioma lines had
      homozygous deletions of the p15(INK4B) gene, except for two lines that expressed
      p15(INK4B) protein, which was induced further upon TGF-beta treatment. Three
      lines mildly induced CdkI p21(WAF1) expression in response to TGF-beta. Most
      tumor lines retained other TGF-beta-mediated responses, including extracellular
      matrix protein and angiogenic factor secretion, which may contribute to increased
      malignant behavior. This suggests that the loss of p15(INK4B) may explain, in
      part, the selective loss of growth inhibition by TGF-beta in gliomas to form a
      more aggressive tumor phenotype.

PMID- 10574985
TI  - Mechanistic studies of the processing of human S-adenosylmethionine decarboxylase
      proenzyme. Isolation of an ester intermediate.
AB  - Human S-adenosylmethionine decarboxylase is synthesized as a proenzyme that
      undergoes an autocatalytic cleavage reaction generating the alpha and beta
      subunits and forming the pyruvate prosthetic group, which is derived from an
      internal Ser residue (Ser-68). The mechanism of this processing reaction was
      studied using site-directed mutagenesis of conserved residues (His-243 and Ser
      229) located close to the cleavage site. Mutant S229A failed to process, and
      mutant S229C cleaved very slowly, whereas mutant S229T processed normally,
      suggesting that the hydroxyl group of residue 229 is required for the processing
      reaction where Ser-229 may act as a proton acceptor. Mutant His-243A cleaved very
      slowly, forming a small amount of the correctly processed pyruvoyl enzyme but a
      much larger proportion of the alpha subunit with an amino-terminal Ser. The
      cleavage to form the latter was greatly enhanced by hydroxylamine. This result
      suggests that the N-O acyl shift needed for ester formation occurs normally in
      this mutant but that the next step, which is a beta-elimination reaction leading
      to the two subunits, does not occur. His-243 may therefore act as the basic
      residue that extracts the hydrogen of the alpha-carbon of Ser-68 in the ester in
      order to facilitate this reaction. The availability of the recombinant H243A S
      adenosylmethionine decarboxylase proenzyme provides a useful model system to
      examine the processing reaction in vitro and test the design of specific
      inactivators aimed at blocking the production of the pyruvoyl prosthetic group.

PMID- 10574986
TI  - A homolog of old yellow enzyme in tomato. Spectral properties and substrate
      specificity of the recombinant protein.
AB  - A cDNA was isolated and characterized from a tomato shoot cDNA library, the
      deduced amino acid sequence of which exhibited similarity with yeast Old Yellow
      Enzymes (OYEs) and related enzymes of bacterial and plant origin. Sequence
      identity was particularly high with 12-oxophytodienoate 10,11-reductase (OPR)
      from Arabidopsis thaliana. The cDNA-encoded protein was expressed as a
      glutathione S-transferase fusion protein in Escherichia coli and was purified
      from bacterial extracts. The protein was found to be a flavoprotein catalyzing
      the NADPH-dependent reduction of the olefinic bond of alpha,beta-unsaturated
      carbonyl compounds, including 12-oxophytodienoic acid. Thus, the tomato enzyme
      was termed LeOPR. The catalytic efficiency of LeOPR was highest with N
      ethylmaleimide followed by 12-oxophytodienoic acid and maleic acid as substrates.
      Photoreduction of the LeOPR-bound FMN resulted in the formation of a red, anionic
      semiquinone prior to the formation of the fully reduced flavin dihydroquinone.
      Spectroscopic characterization of LeOPR revealed the formation of charge transfer
      complexes upon titration with para-substituted phenolic compounds, a distinctive
      feature of the enzymes of the OYE family. The ligand binding properties were
      compared between LeOPR and OYE, and the findings are discussed with respect to
      structural differences between the active sites of OYE and LeOPR.

PMID- 10574987
TI  - Distinct factor requirements for exonic splicing enhancer function and binding of
      U2AF to the polypyrimidine tract.
AB  - Exonic splicing enhancer (ESE) sequences are important for the recognition of
      adjacent splice sites in pre-mRNA and for the regulation of splice site
      selection. It has been proposed that ESEs function by associating with one or
      more serine/arginine-repeat (SR) proteins which stabilize the binding of the U2
      small nuclear ribonucleoprotein particle (snRNP) auxiliary factor (U2AF) to the
      polypyrimidine tract upstream of the 3' splice site. We have tested this model by
      analyzing the composition of splicing complexes assembled on an ESE-dependent pre
      mRNA derived from the doublesex gene of Drosophila. Several SR proteins and
      hTra2beta, a human homolog of the Drosophila alternative splicing regulator
      Transformer-2, associate with this pre-mRNA in the presence, but not in the
      absence, of a purine-rich ESE. By contrast, the 65-kDa subunit of U2AF (U2AF-65
      kDa) bound equally to the pre-mRNA in the presence and absence of the ESE. Time
      course experiments revealed differences in the levels and kinetics of association
      of individual SR proteins with the ESE-containing pre-mRNA, whereas U2AF-65 kDa
      bound prior to most SR proteins and hTra2beta and its level of binding did not
      change significantly during the course of the splicing reaction. Binding of U2AF
      65 kDa to the ESE-dependent pre-mRNA was, however, dependent on U1 snRNP. The
      results indicate that an ESE promotes spliceosome formation through interactions
      that are distinct from those required for the binding of U2AF-65 kDa to the
      polypyrimidine tract.

PMID- 10574988
TI  - A binding site for the transcription factor Grainyhead/Nuclear transcription
      factor-1 contributes to regulation of the Drosophila proliferating cell nuclear
      antigen gene promoter.
AB  - The Drosophila proliferating cell nuclear antigen promoter contains multiple
      transcriptional regulatory elements, including upstream regulatory element (URE),
      DNA replication-related element, E2F recognition sites, and three common
      regulatory factor for DNA replication and DNA replication-related element-binding
      factor genes recognition sites. In nuclear extracts of Drosophila embryos, we
      detected a protein factor, the URE-binding factor (UREF), that recognizes the
      nucleotide sequence 5'-AAACCAGTTGGCA located within URE. Analyses in Drosophila
      Kc cells and transgenic flies revealed that the UREF-binding site plays an
      important role in promoter activity both in cultured cells and in living flies. A
      yeast one-hybrid screen using URE as a bait allowed isolation of a cDNA encoding
      a transcription factor, Grainyhead/nuclear transcription factor-1 (GRH/NTF-1).
      The nucleotide sequence required for binding to GRH was indistinguishable from
      that for UREF detected in embryo nuclear extracts. Furthermore, a specific
      antibody to GRH reacted with UREF in embryo nuclear extracts. From these results
      we conclude that GRH is identical to UREF. Although GRH has been thought to be
      involved in regulation of differentiation-related genes, this study demonstrates,
      for the first time, involvement of a GRH-binding site in regulation of the DNA
      replication-related proliferating cell nuclear antigen gene.

PMID- 10574989
TI  - Yeast SMF1 mediates H(+)-coupled iron uptake with concomitant uncoupled cation
      currents.
AB  - Yeast membrane proteins SMF1, SMF2, and SMF3 are homologues of the DCT1 metal ion
      transporter family. Their functional characteristics and the implications of
      these characteristics in vivo have not yet been reported. Here we show that SMF1
      expressed in Xenopus oocytes mediates H(+)-dependent Fe(2+) transport and
      uncoupled Na(+) flux. SMF1-mediated Fe(2+) transport exhibited saturation
      kinetics (K(m) = 2.2 microM), whereas the Na(+) flux did not, although both
      processes were electrogenic. SMF1 is also permeable to Li(+), Rb(+), K(+), and
      Ca(2+), which likely share the same uncoupled pathway. SMF2 (but not SMF3)
      mediated significant increases in both Fe(2+) and Na(+) transport compared with
      control oocytes. These data are consistent with the concept that uptake of
      divalent metal ions by SMF1 and SMF2 is essential to yeast cell growth. Na(+)
      inhibited metal ion uptake mediated by SMF1 and SMF2 expressed in oocytes.
      Consistent with this, we found that increased sensitivity of yeast to EGTA in the
      high Na(+) medium is due to inhibition of SMF1- and SMF2-mediated metal ion
      transport by uncoupled Na(+) pathway. Interestingly, DCT1 also mediates Fe(2+)
      activated uncoupled currents. We propose that uncoupled ion permeabilities in
      metal ion transporters protect cells from metal ion overload.

PMID- 10574990
TI  - Forced expression of essential myosin light chain isoforms demonstrates their
      role in smooth muscle force production.
AB  - The molecular determinants of the contractile properties of smooth muscle are
      poorly understood, and have been suggested to be controlled by splice variant
      expression of the myosin heavy chain near the 25/50-kDa junction (Kelley, C. A.,
      Takahashi, M., Yu, J. H., and Adelstein, R. S. (1993) J. Biol. Chem. 268, 12848
      12854) as well as by differences in the expression of an acidic (MLC(17a)) and a
      basic (MLC(17b)) isoform of the 17-kDa essential myosin light chain (Nabeshima,
      Y., Nonomura, Y., and Fujii-Kuriyama, Y. (1987) J. Biol. Chem. 262, 106508
      10612). To investigate the molecular mechanism that regulates the mechanical
      properties of smooth muscle, we determined the effect of forced expression of
      MLC(17a) and MLC(17b) on the rate of force activation during agonist-stimulated
      contractions of single cultured chicken embryonic aortic and gizzard smooth
      muscle cells. Forced expression of MLC(17a) in aortic smooth muscle cells
      increased (p < 0.05) the rate of force activation, forced expression of MLC(17b)
      in gizzard smooth muscle cells decreased (p < 0.05) the rate of force activation,
      while forced expression of the endogenous MLC(17) isoform had no effect on the
      rate of force activation. These results demonstrate that MLC(17) is a molecular
      determinant of the contractile properties of smooth muscle. MLC(17) could affect
      the contractile properties of smooth muscle by either changing the stiffness of
      the myosin lever arm or modulating the rate of a load-dependent step and/or
      transition in the actomyosin ATPase cycle.

PMID- 10574991
TI  - Pig-n, a mammalian homologue of yeast Mcd4p, is involved in transferring
      phosphoethanolamine to the first mannose of the glycosylphosphatidylinositol.
AB  - Many cell surface proteins are anchored to the membrane via a
      glycosylphosphatidylinositol (GPI) moiety, which is attached to the C terminus of
      the proteins. The core of the GPI anchor is conserved in all eukaryotes but is
      modified by various side chains. We cloned a mouse phosphatidylinositol glycan
      class N (Pig-n) gene that encodes a 931amino acid protein expressed in the
      endoplasmic reticulum, which is homologous to yeast Mcd4p. We disrupted the gene
      in F9 embryonal carcinoma cells. In the Pig-n knockout cells, the first mannose
      in the GPI precursors was not modified by phosphoethanolamine. Nevertheless,
      further biosynthetic steps continued with the addition of the third mannose and
      the terminal phosphoethanolamine. The surface expression of Thy-1 was only
      partially affected, indicating that modification of the first mannose by
      phosphoethanolamine is not essential for attachment of GPI anchors in mammalian
      cells. An inhibitor of GPI biosynthesis, YW3548/BE49385A, inhibited transfer of
      phosphoethanolamine to the first mannose in mammalian cells but only slightly
      affected the surface expression of GPI-anchored proteins. Biosynthesis of GPI in
      the Pig-n knockout cells was not affected by YW3548/BE49385A, and yeast
      overexpressing MCD4 was highly resistant to YW3548/BE49385A, suggesting that Pig
      n and Mcd4p are targets of this drug.

PMID- 10574992
TI  - Transcriptional down-regulation of poly(ADP-ribose) polymerase gene expression by
      E1A binding to pRb proteins protects murine keratinocytes from radiation-induced
      apoptosis.
AB  - Adenovirus E1A confers enhanced cell sensitivity to radiation and drug-induced
      DNA damage by a mechanism involving the binding to cellular proteins. Mutant
      analysis in E1A-transfected murine keratinocytes demonstrates that increased
      sensitivity to DNA damage requires at least E1A binding to the p300/CREB-binding
      protein (CBP) transcriptional coactivators and to pRb family members, indicating
      that this biological activity of E1A is the result of the concomitant
      perturbation of different cell pathways. Here we show that in the same cells E1A
      binding to members of the retinoblastoma protein family induces transcriptional
      down-regulation of the poly(ADP-ribose) polymerase (PARP) gene, coding for a NAD
      dependent enzyme stimulated by DNA breaks. Inhibition of PARP expression is
      accompanied by a decrement of gamma-irradiation-induced apoptosis, which is
      overridden by reconstitution of wild type levels of PARP. Hence, E1A effects on
      PARP transcription are central determinant of the apoptotic sensitivity of E1A
      expressing keratinocytes. Conversely, E1A binding to only p300/CBP results in an
      increase in PARP enzyme activity and consequently in cell death susceptibility to
      irradiation, which is effectively counteracted by the PARP chemical inhibitor 3
      aminobenzamide. Therefore, our results identify in the E1A-mediated effects on
      PARP expression and activity a key molecular event involved in E1A-induced cell
      sensitization to genotoxic stress.

PMID- 10574993
TI  - Interaction of c-Jun amino-terminal kinase interacting protein-1 with p190 rhoGEF
      and its localization in differentiated neurons.
AB  - c-Jun amino-terminal kinase (JNK) interacting protein-1 (JIP-1) was originally
      identified as a cytoplasmic inhibitor of JNK. More recently, JIP-1 was proposed
      to function as a scaffold protein by complexing specific components of the JNK
      signaling pathway, namely JNK, mitogen-activated protein kinase kinase 7, and
      mixed lineage kinase 3. We have identified the human homologue of JIP-1 that
      contains a phosphotyrosine binding (PTB) domain in addition to a JNK binding
      domain and an Src homology 3 domain. To identify binding targets for the hJIP-1
      PTB domain, a mouse embryo cDNA library was screened using the yeast two-hybrid
      system. One clone encoded a 191-amino acid region of the neuronal protein rhoGEF,
      an exchange factor for rhoA. Overexpression of rhoGEF promotes cytoskeletal
      rearrangement and cell rounding in NIE-115 neuronal cells. The interaction of JIP
      1 with rhoGEF was confirmed by coimmunoprecipitation of these proteins from
      lysates of transiently transfected HEK 293 cells. Using glutathione S-transferase
      rhoGEF fusion proteins containing deletion or point mutations, we identified a
      putative PTB binding site within rhoGEF. This binding site does not contain
      tyrosine, indicating that the JIP PTB domain, like that of Xll alpha and Numb,
      binds independently of phosphotyrosine. Several forms of endogenous JIP-1 protein
      can be detected in neuronal cell lines. Indirect immunofluorescence analysis
      localized endogenous JIP-1 to the tip of the neurites in differentiated NIE-115
      and PC12 cells. The interaction of JIP-1 with rhoGEF and its subcellular
      localization suggests that JIP-1 may function to specifically localize a
      signaling complex in neuronal cells.

PMID- 10574994
TI  - Conformational and biochemical differences in the TCR.CD3 complex of CD8(+)
      versus CD4(+) mature lymphocytes revealed in the absence of CD3gamma.
AB  - Mature CD4(+) and CD8(+) T lymphocytes are believed to build and express
      essentially identical surface alphabeta T-cell receptor-CD3 (TCR.CD3) complexes.
      However, TCR.CD3 expression has been shown to be more impaired in CD8(+) cells
      than in CD4(+) cells when CD3gamma is absent in humans or mice. We have addressed
      this paradox by performing a detailed phenotypical and biochemical analysis of
      the TCR.CD3 complex in human CD3gamma-deficient CD8(+) and CD4(+) T cells. The
      results indicated that the membrane TCR.CD3 complex of CD8(+) T lymphocytes was
      conformationally different from that of CD4(+) lymphocytes in the absence of
      CD3gamma. In addition, CD8(+), but not CD4(+), CD3gamma-deficient T lymphocytes
      were shown to contain abnormally glycosylated TCRbeta proteins, together with a
      smaller, abnormal TCR chain (probably incompletely processed TCRalpha). These
      results suggest the existence of hitherto unrecognized biochemical differences
      between mature CD4(+) and CD8(+) T lymphocytes in the intracellular control of
      alphabetaTCR. CD3 assembly, maturation, or transport that are revealed when
      CD3gamma is absent. Such lineage-specific differences may be important in
      receptor-coreceptor interactions during antigen recognition.

PMID- 10574995
TI  - The activity of a putative polyisoprenol-linked sugar translocase (Wzx) involved
      in Escherichia coli O antigen assembly is independent of the chemical structure
      of the O repeat.
AB  - During O antigen lipopolysaccharide (LPS) synthesis in bacteria, transmembrane
      migration of undecaprenylpyrophosphate (Und-P-P)-bound O antigen subunits occurs
      before their polymerization and ligation to the rest of the LPS molecule. Despite
      the general nature of the translocation process, putative O-antigen translocases
      display a low level of amino acid sequence similarity. In this work, we
      investigated whether complete O antigen subunits are required for translocation.
      We demonstrate that a single sugar, GlcNAc, can be incorporated to LPS of
      Escherichia coli K-12. This incorporation required the functions of two O antigen
      synthesis genes, wecA (UDP-GlcNAc:Und-P GlcNAc-1-P transferase) and wzx (O
      antigen translocase). Complementation experiments with putative O-antigen
      translocases from E. coli O7 and Salmonella enterica indicated that translocation
      of O antigen subunits is independent of the chemical structure of the saccharide
      moiety. Furthermore, complementation with putative translocases involved in
      synthesis of exopolysaccharides demonstrated that these proteins could not
      participate in O antigen assembly. Our data indicate that recognition of a
      complete Und-P-P-bound O antigen subunit is not required for translocation and
      suggest a model for O antigen synthesis involving recognition of Und-P-P-linked
      sugars by a putative complex made of Wzx translocase and other proteins involved
      in the processing of O antigen.

PMID- 10574996
TI  - Expression of alpha2,8/2,9-polysialyltransferase from Escherichia coli K92.
      Characterization of the enzyme and its reaction products.
AB  - The capsular polysaccharide of Escherichia coli K92 contains alternating -8
      NeuAcalpha2- and -9-NeuAcalpha2- linkages. The enzyme catalyzing this
      polymerizing reaction has been cloned from the genomic DNA of E. coli K92. The
      1.2-kilobase polymerase chain reaction fragment was subcloned in pRSET vector and
      the protein was expressed in the BL21(DE3) strain of E. coli with a hexameric
      histidine at its N-terminal end. The enzyme was isolated in the supernatant after
      lysis of the cells and fractionated by ultracentrifugation. Western blotting
      using anti-histidine antibody showed the presence of a band that migrated at
      about 47.5 kDa on both reducing and nonreducing SDS-polyacrylamide gel
      electrophoresis, indicating a monomeric enzyme. Among the carbohydrate acceptors
      tested, N-acetylneuraminic acid and the gangliosides G(D3) and G(Q1b) were
      preferred substrates. The cell-free enzyme reaction products obtained were
      characterized by NMR and mass spectrometry, which indicated the presence of both
      alpha2,9- and alpha2,8-linked polysialyl structure. The K92 neuS gene was used to
      transform the K1 strain of E. coli, the capsule of which contains only -8
      NeuAcalpha2- linkages. Analysis of the polysaccharides isolated from these
      transformed cells is consistent with the presence of both -8-NeuAcalpha2- and -9
      NeuAcalpha2- linkages. Our results suggest that the neuS gene product of E. coli
      K92 catalyzes the synthesis of polysialic acid with alpha2,9- and alpha2,8
      linkages in vitro and in vivo.

PMID- 10574997
TI  - Mammalian HSP60 is a major target for an immunosuppressant mizoribine.
AB  - It has been reported that immunosuppressant cyclosporin A or FK506 binds to
      immunophilins in the cell and that these immunophilins make a complex with
      molecular chaperones HSP70 or HSP90. Although mizoribine has been used clinically
      as an immunosuppressant, immunophilins of the agent have not yet been fully
      understood. We investigated their specific binding proteins using mizoribine
      affinity column chromatography and porcine kidney cytosols. By increasing
      mizoribine in the eluant from the column, two major proteins (with molecular
      masses of 60 and 43 kDa) were detected by SDS-polyacrylamide gel electrophoresis.
      Based on the amino acid sequence analysis of these proteins, 60- and 43-kDa
      mizoribine-binding proteins were identified with HSP60 and cytosolic actin,
      respectively. A considerable amount of actin was also eluted from the affinity
      column by nucleotides, but a very low quantity of HSP60 was eluted under the same
      conditions. On the other hand, HSP60 was eluted as a major protein in the eluant
      that was eluted preferentially, with nucleotide followed by mizoribine. Actin was
      also detected in the eluant, but the quantity of the protein was very low. These
      results indicated that HSP60 has high affinity to mizoribine, and the interaction
      was also observed on surface plasmon resonance analysis. Although HSP60 or GroE
      facilitated refolding of citrate synthase in vitro, mizoribine interfered with
      the chaperone activity of HSP60. On different types of mizoribine affinity
      columns, HSP60 or actin recognized the NH(2) group of mizoribine, and this group
      may be a functional group of the agent.

PMID- 10574998
TI  - Characterization of the amino-terminal activation domain of peroxisome
      proliferator-activated receptor alpha. Importance of alpha-helical structure in
      the transactivating function.
AB  - The transactivating function of the A/B region of mouse peroxisome proliferator
      activated receptor alpha (PPARalpha; NR1C1) was characterized. The truncated
      version of PPARalpha lacking the A/B region had 60-70% lower transactivating
      function than full-length PPARalpha in both the presence and absence of the
      peroxisome proliferator ciprofibrate. When tethered to the yeast Gal4 DNA-binding
      domain, the A/B region exhibited the significant ligand-independent
      transactivating function, AF-1 activity. The first 44 amino acid residues were
      necessary for maximal transactivation, and the minimally essential region was
      further delimited to amino acids 15-44. This region is highly enriched with
      acidic residues, but mutational analyses showed that the protein structure,
      rather than the negative charge itself, was important for the AF-1 activity. An
      alpha-helical configuration was predicted for this region, and a CD spectrum
      analysis of the synthetic peptides showed that mutant sequences with higher AF-1
      activity have higher helical contents and vice versa. The most active mutant, in
      which Met(31) was replaced with Leu, was approximately 5-fold more potent than
      the wild-type A/B region. These findings indicate that the AF-1 region of
      PPARalpha is an acidic activation domain and that the helix-forming property is
      implicated in the transactivating function.

PMID- 10574999
TI  - Organization and ligand binding properties of the tail of Acanthamoeba myosin-IA.
      Identification of an actin-binding site in the basic (tail homology-1) domain.
AB  - The Acanthamoeba myosin-IA heavy chain gene encodes a 134-kDa protein with a
      catalytic domain, three potential light chain binding sites, and a tail with
      separately folded tail homology (TH) -1, -2, and -3 domains. TH-1 is highly
      resistant to trypsin digestion despite consisting of 15% lysine and arginine. TH
      2/3 is resistant to alpha-chymotrypsin digestion. The peptide link between TH-1
      and TH-2/3 is cleaved by trypsin, alpha-chymotrypsin, and endo-AspN but not V8
      protease. The CD spectra of TH-2/3 indicate predominantly random structure,
      turns, and beta-strands but no alpha-helix. The hydrodynamic properties of TH-2/3
      (Stokes' radius of 3.0 nm, sedimentation coefficient of 1.8 S, and molecular mass
      of 21.6 kDa) indicate that these domains are as long as the whole myosin-I tail
      in reconstructions of electron micrographs. Furthermore, separately expressed and
      purified TH-1 binds with high affinity to TH-2/3. Thus we propose that TH-1 and
      TH-2/3 are arranged side by side in the myosin-IA tail. Separate TH-1, TH-2, and
      TH-2/3 each binds muscle actin filaments with high affinity. Salt inhibits TH-2/3
      binding to muscle actin but not amoeba actin filaments. TH-1 enhances binding of
      TH-2/3 to muscle actin filaments at physiological salt concentration, indicating
      that TH-1 and TH-2/3 cooperate in actin binding. An intrinsic fluorescence assay
      shows that TH-2/3 also binds with high affinity to the protein Acan125 similar to
      the SH3 domain of myosin-IC. Phylogenetic analysis of SH3 sequences suggests that
      myosin-I acquired SH3 domain after the divergence of the genes for myosin-I
      isoforms.

PMID- 10575000
TI  - Placenta growth factor and vascular endothelial growth factor B and C expression
      in microvascular endothelial cells and pericytes. Implication in autocrine and
      paracrine regulation of angiogenesis.
AB  - We have shown previously that vascular endothelial growth factor (VEGF)
      synthesized by the cellular constituents of small vessels per se, viz.
      endothelial cells and pericytes, participates in the hypoxia-driven proliferation
      of both cell types (Nomura, M., Yamagishi, S., Harada, S., Hayashi, Y.,
      Yamashima, T., Yamashita, J., Yamamoto, H. (1995) J. Biol. Chem. 270, 28316
      28324; Yamagishi, S., Yonekura, H., Yamamoto, Y., Fujimori, H., Sakurai, S.,
      Tanaka, N., and Yamamoto, H. (1999) Lab. Invest. 79, 501-509). In this study, we
      examined the expression of the recently isolated VEGF gene family members
      (placenta growth factor (PlGF), VEGF-B, and VEGF-C) in human dermal microvascular
      endothelial cells and bovine retinal pericytes cultured under various oxygen
      tensions. Quantitative reverse transcription-polymerase chain reaction analyses
      demonstrated that the two cell types possess not only VEGF (VEGF-A) mRNA, but
      also VEGF-B, VEGF-C, and PlGF mRNAs. Among them, only VEGF-A mRNA was induced
      under hypoxia. Competitive reverse transcription-polymerase chain reaction showed
      that, under normoxic conditions, the rank order of mRNA content in endothelial
      cells was PlGF > VEGF-B > VEGF-C > VEGF-A and that mRNA coding for PlGF was
      expressed at >100-fold higher levels than VEGF-A mRNA. In pericytes, the rank
      order was VEGF-C > VEGF-A > VEGF-B > PlGF, and approximately 7-fold higher levels
      of VEGF-C mRNA compared with VEGF-A mRNA were noted in this cell type.
      Furthermore, antisense inhibition of PlGF protein production lowered the
      endothelial cell synthesis of DNA under hypoxic conditions. The results suggest
      that these VEGF family members may also take active parts in angiogenesis.

PMID- 10575001
TI  - Protein interactions at the tight junction. Actin has multiple binding partners,
      and ZO-1 forms independent complexes with ZO-2 and ZO-3.
AB  - Defining how the molecular constituents of the tight junction interact is a
      prerequisite to understanding tight junction physiology. We utilized in vitro
      binding assays with purified recombinant proteins and immunoprecipitation
      analyses to define interactions between ZO-1, ZO-2, ZO-3, occludin, and the actin
      cytoskeleton. Actin cosedimentation studies showed that ZO-2, ZO-3, and occludin
      all interact directly with F-actin in vitro, indicating that actin is engaged in
      multiple interactions at the tight junction. Low speed sedimentation analyses
      demonstrated that neither ZO-2, ZO-3, nor occludin act as F-actin cross-linking
      proteins, and further evidence indicates that these proteins do not bind to actin
      filament ends. The binding interactions of ZO-2, ZO-3, and occludin were
      corroborated in vivo by immunofluorescence colocalization experiments which
      showed that all three proteins colocalized with actin aggregates at cell borders
      in cytochalasin D-treated Madin-Darby canine kidney cells. Exploration of other
      tight junction protein interactions demonstrated that ZO-2 binds directly to both
      ZO-1 and occludin. Contrary to previous beliefs, our immunoprecipitation results
      indicate that ZO-1, ZO-2, and ZO-3 exist in situ primarily as independent ZO-1.ZO
      2 and ZO-1.ZO-3 complexes rather than a trimeric ZO-1.ZO-2.ZO-3 grouping. These
      studies elucidate direct binding interactions among tight junction-associated
      proteins, giving insight into their organization as a multimolecular structure.

PMID- 10575002
TI  - The steroid hormone dehydroepiandrosterone inhibits CYP1A1 expression in vitro by
      a post-transcriptional mechanism.
AB  - The adrenal steroid hormone dehydroepiandrosterone (DHEA) is a potent inhibitor
      of mammary carcinogenesis induced by polycyclic aromatic hydrocarbons (PAH),
      though its mechanism is unclear. We examined the effect of DHEA on the expression
      of the carcinogen-activating enzyme cytochrome P450 1A1 (CYP1A1) in MCF-7 human
      breast epithelial carcinoma cells. DHEA inhibited the increase in CYP1A1 enzyme
      activity that occurs when MCF-7 cells are exposed to the PAH
      dimethylbenzanthracene (DMBA) or 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD).
      However, DHEA did not directly inhibit enzyme activity as it had no effect when
      added to the cells after induction by DMBA or TCDD. We observed that the increase
      of CYP1A1 mRNA in MCF-7 cells caused by DMBA or TCDD was inhibited by DHEA in a
      concentration-dependent manner. However, DHEA did not inhibit CYP1A1 promoter
      driven transcription, indicating that it did not affect the aryl hydrocarbon
      receptor, which regulates transcription of the CYP1A1 gene. Actinomycin D chase
      experiments showed that DHEA caused a time- and concentration-dependent decrease
      in CYP1A1 mRNA levels, indicating that DHEA inhibits CYP1A1 expression by
      decreasing CYP1A1 mRNA stability. These data demonstrate that DHEA inhibits PAH
      induced CYP1A1 mRNA expression and enzyme activity in vitro by a post
      transcriptional mechanism. This regulation of the expression of carcinogen
      activating enzymes may be responsible for the chemopreventive activity of DHEA
      and may be one of its physiologic functions in vivo.

PMID- 10575003
TI  - Annexin VI participates in the formation of a reversible, membrane-cytoskeleton
      complex in smooth muscle cells.
AB  - The plasmalemma of smooth muscle cells is periodically banded. This arrangement
      ensures efficient transmission of contractile activity, via the firm, actin
      anchoring regions, while the more elastic caveolae-containing "hinge" regions
      facilitate rapid cellular adaptation to changes in cell length. Since cellular
      mechanics are undoubtedly regulated by components of the membrane and
      cytoskeleton, we have investigated the potential role played by annexins (a
      family of phospholipid- and actin-binding, Ca(2+)-regulated proteins) in
      regulating sarcolemmal organization. Stimulation of smooth muscle cells elicited
      a relocation of annexin VI from the cytoplasm to the plasmalemma. In smooth, but
      not in striated muscle extracts, annexins II and VI coprecipitated with
      actomyosin and the caveolar fraction of the sarcolemma at elevated Ca(2+)
      concentrations. Recombination of actomyosin, annexins, and caveolar lipids in the
      presence of Ca(2+) led to formation of a structured precipitate. Participation of
      all 3 components was required, indicating that a Ca(2+)-dependent, cytoskeleton
      membrane complex had been generated. This association, which occurred at
      physiological Ca(2+) concentrations, corroborates our biochemical fractionation
      and immunohistochemical findings and suggests that annexins play a role in
      regulating sarcolemmal organization during smooth muscle contraction.

PMID- 10575004
TI  - Interferon regulatory factor 1 mediates the interferon-gamma induction of the
      human immunoproteasome subunit multicatalytic endopeptidase complex-like 1.
AB  - Proteasomes generate antigenic peptides from intracellular proteins for
      presentation to the immune system by the major histocompatibility complex class I
      molecules. The antiviral cytokine IFN-gamma alters the catalytic specificity of
      proteasomes by inducing the synthesis of an alternative set of three
      proteolytically active proteasome subunits. We have analyzed the mechanism of IFN
      gamma induction for the IFN-gamma-induced subunit multicatalytic endopeptidase
      complex-like 1 (MECL1). The human MECL1 promoter contains two interferon
      stimulated response elements (ISREs), generally known to bind members of the
      interferon regulatory factor (IRF) family. The importance of these elements for
      IFN-gamma induction of MECL1 was addressed by transfecting an endothelial cell
      line with MECL1 promoter constructs. By deletions and mutations of the ISRE
      sequences, we demonstrated that both ISREs were needed for full IFN-gamma
      induction of the reporter gene. The second (downstream) ISRE was essential for
      both IFN-gamma-induced and basal transcriptional activity of the promoter. In
      electrophoretic mobility shift assays, anti-IRF-1 antibodies supershifted an IFN
      gamma-induced protein binding specifically to both ISRE sequences, whereas IRF-2
      bound the second ISRE before induction. Co-transfection of IRF-1 resulted in
      induced MECL1 promoter activity in the absence of IFN-gamma. These data indicate
      that the IFN-gamma induction of human MECL1 is mediated by IFN-gamma-induced IRF
      1.

PMID- 10575005
TI  - Transcriptional regulation of Fas gene expression by GA-binding protein and AP-1
      in T cell antigen receptor.CD3 complex-stimulated T cells.
AB  - Fas (CD95 or APO-1), a transmembrane cell surface receptor of the tumor necrosis
      factor receptor family, is up-regulated in activated T lymphocytes. Our present
      study identified an upstream enhancer element (between nucleotide positions -862
      and -682) containing a GA-binding protein (GABP) site and a low affinity
      activating protein-1 (AP-1)-binding site. T cell activation increased the DNA
      binding of GABP and AP-1 to this enhancer site. The specificity of GABP and AP-1
      binding was demonstrated by competition electrophoretic mobility shift assay and
      supershift electrophoretic mobility shift assay with antibodies against GABP and
      AP-1, respectively. Mutational analysis of Fas promoter revealed that both GABP-
      and AP-1-binding sites were required for initiating Fas gene transcription. We
      further show that anti-CD3 mAb, phorbol 12-myristate 13-acetate, and phorbol 12
      myristate 13-acetate/ionomycin strongly activated promoters carrying multiple
      copies of the Fas enhancer, and mutation of either the GABP or AP-1 binding site
      severely reduced transcriptional activity. Taken together, these results suggest
      that the transcription factors GABP and AP-1 play a critical role in the
      induction of Fas gene expression in T cell antigen receptor.CD3-stimulated Jurkat
      cells.

PMID- 10575006
TI  - Cell-specific glycoforms of sialoadhesin and CD45 are counter-receptors for the
      cysteine-rich domain of the mannose receptor.
AB  - We previously reported that CR-Fc, an Fc chimeric protein containing the cysteine
      rich (CR) domain of the mannose receptor, binds to marginal zone metallophilic
      macrophages (Mo) and B cell areas in the spleen and to subcapsular sinus Mo in
      lymph nodes of naive mice (CR-Fc(+) cells). Several CR-Fc ligands were found in
      spleen and lymph node tissue lysates using ligand blots. In this paper we report
      the identification of two of these ligands as sialoadhesin (Sn), an Mo-specific
      membrane molecule, and the leukocyte common antigen, CD45. CR-Fc bound
      selectively to Sn purified from spleen and lymph nodes and to two low molecular
      weight isoforms of CD45 in a sugar-dependent manner. CR-Fc binding and non
      binding forms of Sn, probably derived from CR-Fc(+) and CR-Fc(-) cells
      respectively, were selected from spleen lysates. Analysis of the glycan pool
      associated with the CR-Fc-binding form revealed the presence of charged
      structures resistant to sialidase, absent in the non-binding form, that could
      correspond to sulfated structures. These results confirm the identification of
      the CR region of the mannose receptor as a lectin. We also demonstrate that the
      same glycoprotein expressed in different cells of the same organ can display
      distinct sugar epitopes that determine its binding properties.

PMID- 10575007
TI  - An extrahepatic receptor-associated protein-sensitive mechanism is involved in
      the metabolism of triglyceride-rich lipoproteins.
AB  - We have used adenovirus-mediated gene transfer in mice to investigate low density
      lipoprotein receptor (LDLR) and LDLR-related protein (LRP)-independent mechanisms
      that control the metabolism of chylomicron and very low density lipoprotein
      (VLDL) remnants in vivo. Overexpression of receptor-associated protein (RAP) in
      mice that lack both LRP and LDLR (MX1cre(+)LRP(flox/flox)LDLR(-/-)) in their
      livers elicited a marked hypertriglyceridemia in addition to the pre-existing
      hypercholesterolemia in these animals, resulting in a shift in the distribution
      of plasma lipids from LDL-sized lipoproteins to large VLDL-sized particles. This
      dramatic increase in plasma lipids was not due to a RAP-mediated inhibition of a
      unknown hepatic high affinity binding site involved in lipoprotein metabolism,
      because no RAP binding could be detected in livers of
      MX1cre(+)LRP(flox/flox)LDLR(-/-) mice using both membrane binding studies and
      ligand blotting experiments. Remarkably, RAP overexpression also resulted in a 7
      fold increase (from 13.6 to 95.6 ng/ml) of circulating, but largely inactive,
      lipoprotein lipase (LPL). In contrast, plasma hepatic lipase levels and activity
      were unaffected. In vitro studies showed that RAP binds to LPL with high affinity
      (K(d) = 5 nM) but does not affect its catalytic activity, in vitro or in vivo.
      Our findings suggest that an extrahepatic RAP-sensitive process that is
      independent of the LDLR or LRP is involved in metabolism of triglyceride-rich
      lipoproteins. There, RAP may affect the functional maturation of LPL, thus
      causing the accumulation of triglyceride-rich lipoproteins in the circulation.

PMID- 10575008
TI  - The rate of activation by calmodulin of isoform 4 of the plasma membrane Ca(2+)
      pump is slow and is changed by alternative splicing.
AB  - A reconstitution system allowed us to measure the ATPase activity of specific
      isoforms of the plasma membrane Ca(2+) pump continuously, and to measure the
      effects of adding or removing calmodulin. The rate of activation by calmodulin of
      isoform 4b was found to be very slow, with a half-time (at 235 nM calmodulin and
      0.5 microM free Ca(2+)) of about 1 min. The rate of inactivation of isoform 4b
      when calmodulin was removed was even slower, with a half-time of about 20 min.
      Isoform 4a has a lower apparent affinity for calmodulin than 4b, but its
      activation rate was surprisingly faster (half time about 20 s). This was coupled
      with a much faster inactivation rate, consistent with its low affinity. A
      truncated mutant of isoform 4b also had a more rapid activation rate, indicating
      that the downstream inhibitory region of full-length 4b contributed to its slow
      activation. The results indicate that the slow activation is due to occlusion of
      the calmodulin-binding domain of 4b, caused by its strong interaction with the
      catalytic core. Since the activation of 4b occurs on a time scale comparable to
      that of many Ca(2+) spikes, this phenomenon is important to the function of the
      pump in living cells. The slow response of 4b indicates that this isoform may be
      the appropriate one for cells which respond slowly to Ca(2+) signals.

PMID- 10575009
TI  - The influence of endoproteolytic processing of familial Alzheimer's disease
      presenilin 2 on abeta42 amyloid peptide formation.
AB  - Mutant presenilins (PS) contribute to the pathogenesis of familial Alzheimer's
      disease (FAD) by enhancing the production of Abeta42 from beta-amyloid precursor
      protein. Presenilins are endoproteolytically processed to N-terminal and C
      terminal fragments, which together form a stable 1:1 complex. We have mapped the
      cleavage site in the PS2 protein by direct sequencing of its C-terminal fragment
      isolated from mouse liver. Three different N-terminal residues were identified
      starting at Val-299, Thr-301, and Leu-307 that correspond closely to the
      previously described N termini of the C-terminal fragment of human PS1.
      Mutational analysis of the PS2 cleavage site indicates that the principal
      endoproteolytic cleavage occurs at residues Met-298/Val-299 and that the N
      terminus is subsequently modified by secondary proteolytic cleavages. We have
      generated cleavage defective PS2 constructs, which accumulate exclusively as full
      length polypeptides in transfected Neuro2a cells. Functional analysis of such
      cleavage defective PS2 carrying the FAD mutation Asn-141 --> Ile showed that its
      Abeta42 producing activity was strongly reduced compared with cleavage-competent
      FAD PS2. In contrast, cleavage defective PS2 was active in rescuing the egg
      laying defect of a sel-12 mutant in Caenorhabditis elegans. We conclude that PS2
      endoproteolytic cleavage is not an absolute requirement for its activities but
      may rather selectively enhance or stabilize its functions.

PMID- 10575010
TI  - Benzo[a]pyrene activates the human p53 gene through induction of nuclear factor
      kappaB activity.
AB  - p53 is known to be recruited in response to DNA-damaging genotoxic stress and
      plays an important role in maintaining the integrity of the genome. In the
      present study, the effect of a potent lung cancer carcinogen, benzo[a]pyrene
      (B[a]P) on p53 expression was investigated. We showed that exposure of A549 and
      NIH 3T3 cells to B[a]P resulted in an increase in p53 mRNA levels and in p53
      promoter activation, indicating that B[a]P-induced p53 expression is partly
      regulated at the transcriptional level. The p53 promoter region which extends
      from -58 to -43, overlapping the kappaB motif, is essential for both the p53
      basal promoter activity and p53 promoter activation induced by B[a]P. Nuclear
      factor kappaB (NF-kappaB) proteins have been revealed to be activated in B[a]P
      induced p53 expression. Activated NF-kappaB complexes were shown to contain
      predominantly p50 and p65 subunit components in A549 cells and p65 subunit in NIH
      3T3 cells. In addition, the overexpression of IkappaBalpha completely inhibited
      NF-kappaB activation, p53 promoter transactivation and the stimulatory effect on
      p53 transcription induced by B[a]P. We therefore conclude that B[a]P
      transcriptionally activates the human p53 gene through the induction of NF-kappaB
      activity.

PMID- 10575011
TI  - Axin forms a complex with MEKK1 and activates c-Jun NH(2)-terminal kinase/stress
      activated protein kinase through domains distinct from Wnt signaling.
AB  - Axin negatively regulates the Wnt pathway during axis formation and plays a
      central role in cell growth control and tumorigenesis. We found that Axin also
      serves as a scaffold protein for mitogen-activated protein kinase activation and
      further determined the structural requirement for this activation. Overexpression
      of Axin in 293T cells leads to differential activation of mitogen-activated
      protein kinases, with robust induction for c-Jun NH(2)-terminal kinase
      (JNK)/stress-activated protein kinase, moderate induction for p38, and negligible
      induction for extracellular signal-regulated kinase. Axin forms a complex with
      MEKK1 through a novel domain that we term MEKK1-interacting domain. MKK4 and
      MKK7, which act downstream of MEKK1, are also involved in Axin-mediated JNK
      activation. Domains essential in Wnt signaling, i. e. binding sites for
      adenomatous polyposis coli, glycogen synthase kinase-3beta, and beta-catenin, are
      not required for JNK activation, suggesting distinct domain utilization between
      the Wnt pathway and JNK signal transduction. Dimerization/oligomerization of Axin
      through its C terminus is required for JNK activation, although MEKK1 is capable
      of binding C terminus-deleted monomeric Axin. Furthermore, Axin without the MEKK1
      interacting domain has a dominant-negative effect on JNK activation by wild-type
      Axin. Our results suggest that Axin, in addition to its function in the Wnt
      pathway, may play a dual role in cells through its activation of JNK/stress
      activated protein kinase signaling cascade.

PMID- 10575012
TI  - The adenosine transporter of Toxoplasma gondii. Identification by insertional
      mutagenesis, cloning, and recombinant expression.
AB  - Purine transport into the protozoan parasite Toxoplasma gondii plays an
      indispensable nutritional function for this pathogen. To facilitate genetic and
      biochemical characterization of the adenosine transporter of the parasite, T.
      gondii tachyzoites were transfected with an insertional mutagenesis vector, and
      clonal mutants were selected for resistance to the cytotoxic adenosine analog
      adenine arabinoside (Ara-A). Whereas some Ara-A-resistant clones exhibited
      disruption of the adenosine kinase (AK) locus, others displayed normal AK
      activity, suggesting that a second locus had been tagged by the insertional
      mutagenesis plasmid. These Ara-A(r) AK+ mutants displayed reduced adenosine
      uptake capability, implying a defect in adenosine transport. Sequences flanking
      the transgene integration point in one mutant were rescued from a genomic library
      of Ara-A(r) AK+ DNA, and Southern blot analysis revealed that all Ara-A(r) AK+
      mutants were disrupted at the same locus. Probes derived from this locus,
      designated TgAT, were employed to isolate genomic and cDNA clones from wild-type
      libraries. Conceptual translation of the TgAT cDNA open reading frame predicts a
      462 amino acid protein containing 11 transmembrane domains, a primary structure
      and membrane topology similar to members of the mammalian equilibrative
      nucleoside transporter family. Expression of TgAT cRNA in Xenopus laevis oocytes
      increased adenosine uptake capacity in a saturable manner, with an apparent K(m)
      value of 114 microM. Uptake was inhibited by various nucleosides, nucleoside
      analogs, hypoxanthine, guanine, and dipyridamole. The combination of genetic and
      biochemical studies demonstrates that TgAT is the sole functional adenosine
      transporter in T. gondii and a rational target for therapeutic intervention.

PMID- 10575013
TI  - Fetal Alz-50 clone 1, a novel zinc finger protein, binds a specific DNA sequence
      and acts as a transcriptional regulator.
AB  - Fetal Alz-50 clone 1 (FAC1) is a novel, developmentally regulated gene that
      exhibits changes in protein expression and subcellular localization during
      neuronal development and neurodegeneration. To understand the functional
      implications of altered subcellular localization, we have established a normal
      cellular function of FAC1. The FAC1 amino acid sequence contains regional
      homology to transcriptional regulators. Using the polymerase chain reaction
      assisted binding site selection assay, we have identified a DNA sequence
      recognized by recombinant FAC1. Mutation of any 2 adjacent base pairs in the
      identified binding site dramatically reduced the binding preference of FAC1,
      demonstrating that the binding is specific for the identified site. Nuclear
      extracts from neural and non-neural cell lines contained a DNA-binding activity
      with similar specificity and nucleotide requirements as the recombinant FAC1
      protein. This DNA-binding activity can be attributed to FAC1 since it is
      dependent upon the presence of FAC1 and behaves identically on a nondenaturing
      polyacrylamide gel as transiently transfected FAC1. In NIH3T3 cells, luciferase
      reporter plasmids containing the identified binding site (CACAACAC) were
      repressed by cotransfected FAC1 whether the binding site was proximal or distal
      to the transcription initiation site. This study indicates that FAC1 is a DNA
      binding protein that functions as a transcription factor when localized to the
      nucleus.

PMID- 10575014
TI  - c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta
      signaling through interaction with smads.
AB  - Smads are intracellular signaling mediators of the transforming growth factor
      beta (TGF-beta) superfamily that regulates a wide variety of biological
      processes. Among them, Smads 2 and 3 are activated specifically by TGF-beta. We
      identified c-Ski as a Smad2 interacting protein. c-Ski is the cellular homologue
      of the v-ski oncogene product and has been shown to repress transcription by
      recruiting histone deacetylase (HDAC). Smad2/3 interacts with c-Ski through its C
      terminal MH2 domain in a TGF-beta-dependent manner. c-Ski contains two distinct
      Smad-binding sites with different binding properties. c-Ski strongly inhibits
      transactivation of various reporter genes by TGF-beta. c-Ski is incorporated in
      the Smad DNA binding complex, interferes with the interaction of Smad3 with a
      transcriptional co-activator, p300, and in turn recruits HDAC. c-Ski is thus a
      transcriptional co-repressor that links Smads to HDAC in TGF-beta signaling.

PMID- 10575015
TI  - Activation of Src family kinase yes induced by Shiga toxin binding to
      globotriaosyl ceramide (Gb3/CD77) in low density, detergent-insoluble
      microdomains.
AB  - Shiga toxin (Stx) is an enterotoxin produced by Shigella dysenteriae serotype 1
      and enterohemorrhagic Escherichia coli, which binds specifically to
      globotriaosylceramide, Gb3, on the cell surface and causes cell death. We
      previously demonstrated that Stx induced apoptosis in human renal tubular cell
      line ACHN cells (Taguchi, T., Uchida, H., Kiyokawa, N., Mori, T., Sato, N.,
      Horie, H., Takeda, T and Fujimoto, J. (1998) Kidney Int. 53, 1681-1688). To study
      the early signal transduction after Stx addition, Gb3-enriched microdomains were
      prepared from ACHN cells by sucrose density gradient centrifugation of Triton X
      100 lysate as buoyant, detergent-insoluble microdomains (DIM). Gb3 was only
      recovered in DIM and was associated with Src family kinase Yes. Phosphorylation
      of tyrosine residues of proteins in the DIM fraction increased by 10 min and
      returned to the resting level by 30 min after the addition of Stx. Since the
      kinase activity of Yes changed with the same kinetics, Yes was thought to be
      responsible for the hyperphosphorylation observed in DIM proteins. Unexpectedly,
      however, all of the Yes kinase activity was obtained in the high density,
      detergent-soluble fraction. Yes was assumed to be activated and show increased
      Triton X-100 solubility in the early phase of retrograde endocytosis of Stx-Gb3
      complex. Since Yes activation by the Stx addition was suppressed by filipin
      pretreatment, Gb3-enriched microdomains containing cholesterol were deeply
      involved in Stx signal transduction.

PMID- 10575016
TI  - Glutamate induces rapid upregulation of astrocyte glutamate transport and cell
      surface expression of GLAST.
AB  - Glutamate transporters clear glutamate from the extracellular space by high
      affinity binding and uptake. Factors that regulate glutamate transporter
      expression and activity can thereby influence excitatory neurotransmission.
      Transporter function in GABAergic and other systems has been shown to be
      regulated by transporter substrates. Here, glutamate regulation of glutamate
      transport was studied using primary murine astrocyte cultures that express the
      GLAST (EAAT1) and GLT-1 (EAAT2) transporter subtypes. Glutamate was found to
      stimulate glutamate transport capacity (V(max)) in a dose- and time-dependent
      manner. The maximal increase was 100%, with an ED(50) of 40 microM glutamate and
      with onset beginning approximately 15 min after onset of glutamate exposure. The
      uptake stimulation was reproduced by D-aspartate, which is also a transporter
      substrate, but not by nontransported glutamate receptor agonists. Moreover,
      glutamate incubation did not stimulate transport when performed in a sodium-free
      medium, suggesting that the stimulatory effect of glutamate is triggered by
      increased transporter activity rather than receptor activation. Treatment with
      the actin-disrupting agents cytochalasin B or cytochalasin D prevented the
      glutamate-induced increase in glutamate uptake. Biotinylation labeling of
      membrane surface proteins showed that glutamate incubation produced an increase
      in GLAST expression at the astrocyte cell surface. These results suggest that
      cell-surface expression of GLAST can be rapidly regulated by glutamate through a
      process triggered by GLAST activity and involving the actin cytoskeleton. This
      feedback loop provides a mechanism by which changes in extracellular glutamate
      concentrations could rapidly modulate astrocyte glutamate transport capacity.

PMID- 10575017
TI  - A role for the clathrin assembly domain of AP180 in synaptic vesicle endocytosis.
AB  - We have used the squid giant synapse to determine whether clathrin assembly by
      AP180 is important for synaptic vesicle endocytosis. The squid homolog of AP180
      encodes a 751 amino acid protein with 40% sequence identity to mouse AP180.
      Alignment of squid AP180 with other AP180 homologs shows that amino acid identity
      was highest in the N-terminal inositide-binding domain of the protein and weakest
      in the C-terminal clathrin assembly domain. Recombinant squid AP180 was able to
      assemble clathrin in vitro, suggesting a conserved three-dimensional structure
      that mediates clathrin assembly despite the divergent primary sequence of the C
      terminal domain. Microinjection of the C-terminal domains of either mouse or
      squid AP180 into the giant presynaptic terminal of squid enhanced synaptic
      transmission. Conversely, a peptide from the C-terminal domain of squid AP180
      that inhibited clathrin assembly in vitro completely blocked synaptic
      transmission when it was injected into the giant presynaptic terminal. This
      inhibitory effect occurred over a time scale of minutes when the synapse was
      stimulated at low (0.03 Hz), physiological rates. Electron microscopic analysis
      revealed several structural changes consistent with the inhibition of synaptic
      vesicle endocytosis; peptide-injected terminals had far fewer synaptic vesicles,
      were depleted of coated vesicles, and had a larger plasma membrane perimeter than
      terminals injected with control solutions. In addition, the remaining synaptic
      vesicles were significantly larger in diameter. We conclude that the clathrin
      assembly domain of AP180 is important for synaptic vesicle recycling at
      physiological rates of activity and that assembly of clathrin by AP180 is
      necessary for maintaining a pool of releasable synaptic vesicles.

PMID- 10575018
TI  - Identification of transduction elements for benzodiazepine modulation of the
      GABA(A) receptor: three residues are required for allosteric coupling.
AB  - Modulation of GABA(A) receptors by benzodiazepines (BZDs) is believed to involve
      two distinct steps: a recognition step in which BZDs bind and a conformational
      transition step in which the affinity of the receptor for GABA changes.
      Previously, using gamma(2)/alpha(1) chimeric subunits (chi), we demonstrated that
      although the N-terminal 167 gamma(2) amino acid residues confer high-affinity BZD
      binding, other gamma(2) domains couple BZD binding to potentiation of the GABA
      mediated Cl(-) current (I(GABA)). To determine which gamma(2) regions couple
      binding to potentiation, we generated chis with longer N-terminal gamma(2)
      segments for voltage-clamp experiments in Xenopus oocytes. Chimeras containing
      greater than the N-terminal 167 gamma(2) residues showed incremental gains in
      maximal potentiation for diazepam enhancement of I(GABA). Residues in gamma(2)199
      236, gamma(2)224-236 (pre-M1), and particularly gamma(2)257-297 (M2 and
      surrounding loops) are important for BZD potentiation. For several positive BZD
      modulators tested, the same regions restored potentiation of I(GABA). In
      contrast, beta-carboline inverse-agonism was unaltered in chimeric receptors,
      suggesting that structural determinants for positive and negative BZD allosteric
      modulation are different. Dissection of the gamma(2)257-297 domain revealed that
      three residues in concert, gamma(2)T281, gamma(2)I282 (M2 channel vestibule), and
      gamma(2)S291 (M2-M3 loop) are necessary to impart full BZD potentiation to
      chimeric receptors. Thus, these residues participate in coupling distant BZD
      binding events to conformational changes in the GABA(A) receptor. The location of
      these novel residues provides insight into the mechanisms underlying allosteric
      coupling for other members of the ligand-gated ion channel superfamily.

PMID- 10575019
TI  - Activation of presynaptic cAMP-dependent protein kinase is required for induction
      of cerebellar long-term potentiation.
AB  - Cerebellar long-term potentiation (LTP) is a persistent increase in the strength
      of the granule cell-Purkinje neuron synapse that occurs after brief stimulation
      of granule cell axons at 2-8 Hz. Previous work has indicated that cerebellar LTP
      induction requires presynaptic Ca influx, stimulation of Ca-sensitive adenylyl
      cyclase, and activation of PKA. The evidence implicating PKA has come from bath
      application of drugs during LTP induction, an approach that does not distinguish
      between PKA activation in the presynaptic or postsynaptic cell. Although bath
      application of PKA inhibitor drugs (KT5720, Rp-8CPT-cAMP-S) blocked LTP induction
      in granule cell-Purkinje neuron pairs in culture, selective application to
      granule cell or Purkinje neuron somata via patch pipettes did not. We
      hypothesized that presynaptic PKA activation is required for LTP induction but
      that drugs applied to the granule cell soma cannot diffuse to the terminal within
      this timescale. To test this hypothesis, we transfected cerebellar cultures with
      an expression vector encoding a peptide inhibitor of PKA [Rous sarcoma virus
      (RSV)-protein kinase A inhibitor (PKI)]. Transfection of RSV-PKI into presynaptic
      granule cells, but not postsynaptic Purkinje neurons or glial cells, blocked LTP
      induction produced by either synaptic stimulation or an exogenous cAMP analog. An
      expression vector encoding a control peptide with no PKA inhibitory activity was
      ineffective. These results show that induction of cerebellar LTP requires a
      presynaptic signaling cascade, including Ca influx, stimulation of Ca-sensitive
      adenylyl cyclase, and activation of PKA, and argue against a requirement for
      postsynaptic Ca signals or their sequelae.

PMID- 10575020
TI  - Cell surface expression of polysialic acid on NCAM is a prerequisite for activity
      dependent morphological neuronal and glial plasticity.
AB  - Polysialic acid (PSA) on the extracellular domain of the neural cell adhesion
      molecule (NCAM) reduces cell adhesion and is considered an important regulator of
      cell surface interactions. The hypothalamo-neurohypophysial system (HNS), whose
      glia, neurons, and synapses undergo striking, reversible morphological changes in
      response to physiological stimulation, expresses high levels of PSA-NCAM
      throughout life. Light and electron microscopic immunocytochemistry in normal
      rats and rats in which cell transport was blocked with colchicine showed that PSA
      NCAM is expressed in both HNS neurons and glia, particularly at the level of
      astrocytic processes that envelop neuronal profiles and can undergo remodeling.
      Moreover, we confirmed that the overall levels of PSA-NCAM were not greatly
      altered by stimulation (lactation and chronic salt ingestion). Nevertheless, PSA
      is essential to morphological plasticity. Using comparative ultrastructural
      analysis, we found that, after specific enzymatic removal of PSA from NCAM by
      microinjection of endoneuraminidase close to the hypothalamic magnocellular
      nuclei in vivo, there was no apparent withdrawal of astrocytic processes nor any
      increase in synaptic contacts normally induced by lactation and dehydration. Our
      observations demonstrate, therefore, that expression of PSA on cell surfaces in
      the adult HNS is indispensable to its capacity for activity-dependent
      morphological neuronal-glial and synaptic plasticity. The carbohydrate PSA on
      NCAM can thus be considered a necessary permissive factor to allow neuronal and
      glial remodeling to occur whenever the proper inductive stimulus intervenes.

PMID- 10575021
TI  - Regulation of the subcellular distribution of m4 muscarinic acetylcholine
      receptors in striatal neurons in vivo by the cholinergic environment: evidence
      for regulation of cell surface receptors by endogenous and exogenous stimulation.
AB  - Our aim was to determine how the cholinergic environment influences, in vivo, the
      membrane abundance and the intracellular trafficking of the muscarinic receptor
      m4 (m4R). Immunohistochemistry at light and electron microscopic level was used
      to detect the subcellular localization of m4R in several populations of striatal
      cholinoceptive neurons, including cholinergic neurons and medium spiny neurons.
      (1) In control rats, in cholinergic neurons, m4R is mostly restricted to
      intracytoplasmic sites involved in its synthesis, especially endoplasmic
      reticulum. In contrast, m4R is preferentially located at the plasma membrane in
      cell bodies and dendritic shafts and spines of medium spiny neurons. The density
      of m4R was greater at the membrane of perikarya in patches (striatal areas with
      low acetylcholine activity) than in matrix (striatal areas with high
      acetylcholine activity). (2) Stimulation of muscarinic receptor with oxotremorine
      provokes translocation of m4R from the membrane to endosomes in perikarya and
      dendrites of medium spiny neurons but has no influence on the localization of m4R
      in the cytoplasm of cholinergic cell bodies. Our results suggest that the
      intraneuronal trafficking and the abundance of membrane-bound m4R in vivo is
      under regulation of the cholinergic environment. The m4R subcellular
      compartmentalization depends on the phenotype of the cholinoceptive neuron and on
      its neurochemical environment. Such regulation, by modulating availability of
      receptor for endogenous and exogenous ligands, may play key roles in the response
      of target neurons.

PMID- 10575022
TI  - Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in
      the hippocampus.
AB  - Long-term potentiation (LTP) in the hippocampus has an early phase (E-LTP) that
      can be induced by one- or two-train tetanization, lasts approximately 1 hr, and
      is cAMP-dependent protein kinase (PKA) and protein synthesis independent and a
      late phase (L-LTP) that can be induced by three- or four-train tetanization,
      lasts >3 hr, and is reduced by inhibitors of PKA and of protein or RNA synthesis.
      Nitric oxide (NO) is thought to be involved in E-LTP, but until now there has
      been no information about the role of the NO-signaling pathway in L-LTP. We
      examined this question at the Schaffer collateral-CA1 synapses in slices of mouse
      hippocampus. An inhibitor of NO synthase blocked L-LTP induced by three-train
      tetanization and reduced L-LTP induced by four-train tetanization, whereas an
      inhibitor of PKA was more effective in blocking four-train L-LTP than three-train
      L-LTP. Three-train L-LTP was also blocked by inhibitors of guanylyl cyclase or
      cGMP-dependent protein kinase (PKG). Conversely, either NO or cGMP analogs paired
      with one-train tetanization produced late-phase potentiation, and the cGMP
      induced potentiation was blocked by inhibitors of protein or RNA synthesis and an
      inhibitor of PKG, but not by an inhibitor of PKA. To test a possible downstream
      target of PKG, we examined changes in phospho-CRE-binding protein (phospho-CREB)
      immunofluorescence in the CA1 cell body area and obtained results similar to
      those of the electrophysiology experiments. These results suggest that NO
      contributes to L-LTP by stimulating guanylyl cyclase and cGMP-dependent protein
      kinase, which acts in parallel with PKA to increase phosphorylation of the
      transcription factor CREB.

PMID- 10575023
TI  - Protein kinase C activators inhibit the visual cascade in Limulus ventral
      photoreceptors at an early stage.
AB  - The phosphoinositide cascade mediates visual transduction in invertebrate
      photoreceptors. Phospholipase C (PLC) catalyzes the hydrolysis of
      phosphatidylinositol bisphosphate, producing inositol trisphosphate (InsP(3)) and
      diacylglycerol (DAG). Protein kinase C (PKC) is a major target of DAG in many
      cell types. We have used PKC activators to investigate the function of the kinase
      in the phototransduction cascade in Limulus polyphemus ventral photoreceptors.
      Extracellular application of (-)-indolactam V (0. 03-30 microM) or phorbol-12,13
      dibutyrate (10 microM) reversibly reduced the sensitivity of the electrical
      response of the photoreceptors to light by up to 1000-fold. The inert
      stereoisomer (+)-indolactam V and 4alpha-phorbol had no effect. The effect of (-)
      indolactam V was antagonized by the PKC inhibitors bisindolylmaleimide I and Go
      6976. Coapplication of bisindolylmaleimide V, used as a negative control compound
      for PKC inhibition, did not reduce the effectiveness of (-)-indolactam V. These
      findings are consistent with (-)-indolactam V activating PKC and desensitizing
      the light response. Furthermore, our pharmacological results indicate that PKC
      activation does not appear to play a role in light adaptation. We localized the
      position of the target of PKC in the visual cascade. We chemically excited the
      cascade at various stages to determine the kinase's target. PKC activation by (-)
      indolactam V decreased the light-induced elevation of intracellular calcium but
      had no effect on the photoreceptor's excitatory response to intracellular
      injection of InsP(3). However, the PKC activator greatly reduced the excitation
      caused by GTP-gamma-S injection. We propose that PKC inhibits the visual
      transduction cascade at the G-protein and/or PLC stage.

PMID- 10575024
TI  - Overexpression of cysteine-string proteins in Drosophila reveals interactions
      with syntaxin.
AB  - Cysteine-string proteins (CSPs) are associated with secretory vesicles and
      critical for regulated neurotransmitter release and peptide exocytosis. At nerve
      terminals, CSPs have been implicated in the mediation of neurotransmitter
      exocytosis by modulating presynaptic calcium channels; however, studies of CSPs
      in peptidergic secretion suggest a direct role in exocytosis independent of
      calcium transmembrane fluxes. Here we show that the individual expression of
      various CSP isoforms in Drosophila similarly rescues the loss of evoked
      neurotransmitter release at csp null mutant motor nerve terminals, suggesting
      widely overlapping functions for each isoform. Thus, the structural difference of
      CSP variants may not explain the opposing putative functions of CSP in
      neurotransmitter and peptide exocytosis. Consistently, the individual
      overexpression of each CSP isoform in wild-type Drosophila shows similar effects
      such as impaired viability and interference with wing and eye development. The
      dominant effects caused by the overexpression of CSP are suppressed by the
      simultaneous overexpression of syntaxin-1A but not by the coexpression of SNAP
      25. Although overexpression of CSP itself has no apparent effect on the synaptic
      physiology of larval motor nerve terminals, it fully suppresses the decrease of
      evoked release induced by the overexpression of syntaxin-1A. A direct protein
      protein interaction of CSP with syntaxin is further supported by
      coimmunoprecipitations of syntaxin with CSP and by protein binding assays using
      recombinant fusion proteins. Together, the genetic and biochemical interactions
      of CSP and syntaxin-1A suggest that CSP may chaperone or modulate protein-protein
      interactions of syntaxin-1A with either calcium channels or other components of
      the regulatory machinery mediating depolarization-dependent neurotransmitter
      exocytosis.

PMID- 10575025
TI  - Actin filaments and the opposing actions of CaM kinase II and calcineurin in
      regulating alpha7-containing nicotinic receptors on chick ciliary ganglion
      neurons.
AB  - Nicotinic acetylcholine receptors containing alpha7 subunits have a high relative
      permeability to calcium and influence numerous calcium-dependent cellular events.
      On chick ciliary ganglion neurons the receptors are concentrated on somatic
      spines containing actin filaments. Using conventional whole-cell patch-clamp
      recording from dissociated ciliary ganglion neurons, we show that responses from
      alpha7-containing receptors undergo substantial rundown when the receptors are
      repeatedly challenged with nicotine. Stabilization of actin filaments with
      phalloidin partially prevents the rundown, whereas collapse of actin filaments
      with latrunculin A exacerbates it. The rundown depends on calcium influx through
      the receptors because it requires receptor activation and can be prevented by
      replacing extracellular calcium with barium or by intracellular dialysis with
      BAPTA. Thapsigargin and ryanodine each inhibit the rundown, demonstrating further
      a requirement for calcium release from internal stores. Blockade of calmodulin by
      calmidazolium or blockade of CaM kinase II with either KN93 or autocamtide-2
      related inhibitory peptide each prevents the rundown; blockade of the phosphatase
      calcineurin with either cyclosporin A or deltamethrin increases the rundown. The
      results indicate a balance of calcium-dependent kinase and phosphatase activities
      in regulating the function of alpha7-containing receptors. Manifestation of the
      rundown depends in part on the loss of intracellular components via dialysis
      because little rundown is seen if perforated patch-clamp recording is used to
      monitor receptor responses even in latrunculin A-treated cells. A membrane
      permeable calcineurin inhibitor, however, still decreases the nicotinic response
      in a calcium-dependent manner, confirming that calcium-dependent
      phosphoregulation of alpha7-containing receptors occurs in the intact cell.

PMID- 10575026
TI  - Peroxynitrite inactivation of tyrosine hydroxylase: mediation by sulfhydryl
      oxidation, not tyrosine nitration.
AB  - Tyrosine hydroxylase (TH) is the initial and rate-limiting enzyme in the
      biosynthesis of dopamine (DA). TH activity is significantly diminished in
      Parkinson's disease (PD) and by the neurotoxic amphetamines, thereby accentuating
      the reductions in DA associated with these conditions. Reactive oxygen and
      nitrogen species have been implicated in the damage to DA neurons seen in PD and
      in reaction to amphetamine drugs of abuse, so we investigated the hypothesis that
      peroxynitrite (ONOO(-)) could interfere with TH catalytic function. ONOO(-)
      caused a concentration-dependent inactivation of TH. The inactivation was
      associated with tyrosine nitration (maximum of four tyrosine residues nitrated
      per TH monomer) and extensive sulfhydryl oxidation. Tetranitromethane, which
      causes sulfhydryl oxidation at pH 6 and 8 but which nitrates tyrosines only at pH
      8, inactivated TH equally at either pH. Bicarbonate protected TH from ONOO(-)
      induced inactivation and sulfhydryl oxidation but increased significantly
      tyrosine nitration. PNU-101033 blocked ONOO(-)-induced tyrosine nitration in TH
      but could not prevent enzyme inactivation or sulfhydryl oxidation. Together,
      these results indicate that the inactivation of TH by ONOO(-) is mediated by
      sulfhydryl oxidation. The coincident nitration of tyrosine residues appears to
      exert little influence over TH catalytic function.

PMID- 10575027
TI  - Conservation of expression of neuropeptide Y5 receptor between human and rat
      hypothalamus and limbic regions suggests an integral role in central
      neuroendocrine control.
AB  - Neuropeptide Y receptors belong to the G-protein-coupled receptor superfamily and
      mediate a wide variety of physiological functions, including blood pressure
      regulation, hormone release, appetite control, seizure propensity, cognition, and
      emotion. The recent description of a new neuropeptide Y receptor, Y5, expressed
      in hypothalamic nuclei in rat brain, raised the possibility that Y5 was the
      receptor mediating the feeding and appetite-related functions of neuropeptide Y.
      This was supported by subsequent data showing a downregulation of this "feeding"
      receptor in the brain of the obese Zucker rat (Widdowson, 1997). We have
      performed a detailed analysis of Y5 expression in rat brain using in situ
      hybridization histochemistry with digoxygenin-labeled riboprobes and compared
      this to expression of Y5 in human brain regions. mRNA for the human Y5 receptor
      was highly expressed in human hypothalamic and thalamic nuclei. In particular,
      the arcuate and paraventricular nuclei of the hypothalamus, midline thalamic
      nuclei, and amygdala showed very high levels of expression with high levels in
      hippocampus. The striking conservation of expression of the rat and human Y5
      receptors in relevant hypothalamic and other nuclei implies sharing of a major
      neuroendocrine functional role by this receptor.

PMID- 10575028
TI  - Identification and characterization of glucoresponsive neurons in the enteric
      nervous system.
AB  - We tested the hypothesis that a subset of enteric neurons is glucoresponsive and
      expresses ATP-sensitive K(+) (K(ATP)) channels. The immunoreactivities of the
      inwardly rectifying K(+) channel 6.2 (Kir6.2) and the sulfonylurea receptor
      (SUR), now renamed SUR1, subunits of pancreatic beta-cell K(ATP) channels, were
      detected on cholinergic neurons in the guinea pig ileum, many of which were
      identified as sensory by their costorage of substance P and/or calbindin.
      Glucoresponsive neurons were distinguished in the myenteric plexus because of the
      hyperpolarization and decrease in membrane input resistance that were observed in
      response to removal of extracellular glucose. The effects of no-glucose were
      reversed on the reintroduction of glucose or by the K(ATP) channel inhibitor
      tolbutamide. No reversal of the hyperpolarization was observed when D-
      mannoheptulose, a hexokinase inhibitor, was present on the reintroduction of
      glucose. Application of the K(ATP) channel opener diazoxide or the ob gene
      product leptin mimicked the effect of glucose removal in a reversible manner;
      moreover, hyperpolarizations evoked by either agent were inhibited by
      tolbutamide. Glucoresponsive neurons displayed leptin receptor immunoreactivity,
      which was widespread in both enteric plexuses. Superfusion of diazoxide inhibited
      fast synaptic activity in myenteric neurons, via activation of presynaptic K(ATP)
      channels. Diazoxide also produced a decrease in colonic motility. These
      experiments demonstrate for the first time the presence of glucoresponsive
      neurons in the gut. We propose that the glucose-induced excitation of these
      neurons be mediated by inhibition of K(ATP) channels. The results support the
      idea that enteric K(ATP) channels play a role in glucose-evoked reflexes.

PMID- 10575029
TI  - Cerebellar granule cell-specific and inducible expression of Cre recombinase in
      the mouse.
AB  - To develop a cell type-specific and temporal regulation system of gene targeting
      in the cerebellum, we used the NMDA-type glutamate receptor GluRepsilon3 subunit
      gene and Cre recombinase-progesterone receptor fusion (CrePR) gene in
      combination. Injection of the CrePR gene placed under the control of the 10 kb 5'
      region of the GluRepsilon3 gene into C57BL/6 eggs yielded the ECP25 line that
      strongly expressed the CrePR mRNA selectively in the granule cells of the
      cerebellum. Using a transgenic mouse carrying a reporter gene for Cre-mediated
      recombination, we showed that antiprogestins could induce the recombinase
      activity of CrePR protein in the cerebellar granule cells of the ECP25 line.
      Thus, the established mouse line will provide a valuable tool to investigate the
      mechanism of cerebellar function by manipulating molecules in the temporally
      regulated and granule cell-specific manner.

PMID- 10575030
TI  - Dynamics of tubulovesicular recycling endosomes in hippocampal neurons.
AB  - Neurons are polarized cells, the activity of which relies on the morphological
      and functional differences between their axonal and somatodendritic domains. One
      mechanism for establishing and maintaining neuronal polarity is via the selective
      targeting of proteins to these domains. The endocytic pathway plays a major role
      in the generation and maintenance of cellular polarity by selectively sorting and
      recycling endocytosed plasma membrane proteins. In this study we first show that
      endogenous syntaxin 13 localizes to tubulovesicular organelles that are present
      in the somatodendritic and axonal domains of neurons. These organelles contain
      and actively recycle transferrin receptor and are sensitive to brefeldin A,
      suggesting that they are analogous to the tubulovesicular recycling endosomes in
      non-neuronal cells. We next use a syntaxin 13-GFP fusion protein transiently
      expressed in hippocampal neurons, together with time-lapse microscopy, to study
      the dynamics of the endosomal system in neurons. The analysis revealed the
      presence of two distinct classes of syntaxin 13-labeled endosomes: round-oval
      stationary organelles and highly mobile tubulovesicular structures. The dynamic
      population of tubulovesicular endosomes travels in both directions along
      microtubules in dendrites and axons. The mobile organelles appear to fuse with
      and bud from the stationary endosomes, possibly as a means of delivering and
      picking up their cargo.

PMID- 10575031
TI  - Analysis of the role of heat shock protein (Hsp) molecular chaperones in
      polyglutamine disease.
AB  - Polyglutamine (polygln) diseases are a group of inherited neurodegenerative
      disorders characterized by protein misfolding and aggregation. Here, we
      investigate the role in polygln disease of heat shock proteins (Hsps), the major
      class of molecular chaperones responsible for modulating protein folding in the
      cell. In transfected COS7 and PC12 neural cells, we show that Hsp40 and Hsp70
      chaperones localize to intranuclear aggregates formed by either mutant ataxin-3,
      the disease protein in spinocerebellar ataxia type 3/Machado-Joseph disease
      (SCA3/MJD), or an unrelated green fluorescent protein fusion protein containing
      expanded polygln. We further demonstrate that expression of expanded polygln
      protein elicits a stress response in cells as manifested by marked induction of
      Hsp70. Studies of SCA3/MJD disease brain confirm these findings, showing
      localization of Hsp40 and, less commonly, Hsp70 chaperones to intranuclear ataxin
      3 aggregates. In transfected cells, overexpression of either of two Hsp40
      chaperones, the DNAJ protein homologs HDJ-1 and HDJ-2, suppresses aggregation of
      truncated or full-length mutant ataxin-3. Finally, we extend these studies to a
      PC12 neural model of polygln toxicity in which we demonstrate that overexpression
      of HDJ-1 suppresses polygln aggregation with a parallel decrease in toxicity.
      These results suggest that expanded polygln protein induces a stress response and
      that specific molecular chaperones may aid the handling of misfolded or
      aggregated polygln protein in neurons. This study has therapeutic implications
      because it suggests that efforts to increase chaperone activity may prove
      beneficial in this class of diseases.

PMID- 10575032
TI  - The ETS domain factor Pet-1 is an early and precise marker of central serotonin
      neurons and interacts with a conserved element in serotonergic genes.
AB  - Serotonin (5-HT) plays a crucial neuromodulatory role in numerous physiological
      and behavioral functions, and dysfunction of the serotonergic system has been
      implicated in several psychiatric disorders. Despite the widespread importance of
      the central serotonergic neurotransmitter system, little is known about the
      molecular mechanisms controlling the development of 5-HT neurons. We previously
      identified an ETS domain transcription factor, Pet-1, that is expressed in a
      small number of tissues, including the brain. Here, we show that expression of
      Pet-1 RNA in the brain is restricted to, and marks, the entire rostrocaudal
      extent of rat serotonergic hindbrain raphe nuclei. Remarkably, Pet-1 RNA
      colocalizes with tryptophan hydroxylase-positive neurons in raphe nuclei but not
      with their nonserotonergic neuron or non-neuronal neighbors. Pet-1 RNA is limited
      to two domains in the developing hindbrain, which precedes the appearance of 5-HT
      in each domain by approximately a half day. Conserved Pet-1 binding sites are
      present in or near the promoter regions of the human and mouse 5-HT1a receptor,
      serotonin transporter, tryptophan hydroxylase, and aromatic L-amino acid
      decarboxylase genes whose expression is characteristic of the serotonergic neuron
      phenotype. These sites are capable of supporting transcriptional activation
      through interactions with the Pet-1 ETS domain and can function as enhancers.
      Together, our findings establish Pet-1 as an early and precise marker of 5-HT
      neurons and suggest that it functions specifically in the differentiation and
      maintenance of these neurons.

PMID- 10575033
TI  - Sequence of neuron origin and neocortical laminar fate: relation to cell cycle of
      origin in the developing murine cerebral wall.
AB  - Neurons destined for each region of the neocortex are known to arise
      approximately in an "inside-to-outside" sequence from a pseudostratified
      ventricular epithelium (PVE). This sequence is initiated rostrolaterally and
      propagates caudomedially. Moreover, independently of location in the PVE, the
      neuronogenetic sequence in mouse is divisible into 11 cell cycles that occur over
      a 6 d period. Here we use a novel "birth hour" method that identifies small
      cohorts of neurons born during a single 2 hr period, i.e., 10-20% of a single
      cell cycle, which corresponds to approximately 1.5% of the 6 d neuronogenetic
      period. This method shows that neurons arising with the same cycle of the 11
      cycle sequence in mouse have common laminar fates even if they arise from widely
      separated positions on the PVE (neurons of fields 1 and 40) and therefore arise
      at different embryonic times. Even at this high level of temporal resolution,
      simultaneously arising cells occupy more than one cortical layer, and there is
      substantial overlap in the distributions of cells arising with successive cycles.
      We demonstrate additionally that the laminar representation of cells arising with
      a given cycle is little if at all modified over the early postnatal interval of
      histogenetic cell death. We infer from these findings that cell cycle is a
      neuronogenetic counting mechanism and that this counting mechanism is integral to
      subsequent processes that determine cortical laminar fate.

PMID- 10575034
TI  - The establishment of GABAergic and glutamatergic synapses on CA1 pyramidal
      neurons is sequential and correlates with the development of the apical dendrite.
AB  - We have performed a morphofunctional analysis of CA1 pyramidal neurons at birth
      to examine the sequence of formation of GABAergic and glutamatergic postsynaptic
      currents (PSCs) and to determine their relation to the dendritic arborization of
      pyramidal neurons. We report that at birth pyramidal neurons are heterogeneous.
      Three stages of development can be identified: (1) the majority of the neurons
      (80%) have small somata, an anlage of apical dendrite, and neither spontaneous
      nor evoked PSCs; (2) 10% of the neurons have a small apical dendrite restricted
      to the stratum radiatum and PSCs mediated only by GABA(A) receptors; and (3) 10%
      of the neurons have an apical dendrite that reaches the stratum lacunosum
      moleculare and PSCs mediated both by GABA(A) and glutamate receptors. These three
      groups of pyramidal neurons can be differentiated by their capacitance (C(m) =
      17.9 +/- 0.8; 30.2 +/- 1.6; 43.2 +/- 3.0 pF, respectively). At birth, the
      synaptic markers synapsin-1 and synaptophysin labeling are present in dendritic
      layers but not in the stratum pyramidale, suggesting that GABAergic peridendritic
      synapses are established before perisomatic ones. The present observations
      demonstrate that GABAergic and glutamatergic synapses are established
      sequentially with GABAergic synapses being established first most likely on the
      apical dendrites of the principal neurons. We propose that different sets of
      conditions are required for the establishment of functional GABA and glutamate
      synapses, the latter necessitating more developed neurons that have apical
      dendrites that reach the lacunosum moleculare region.

PMID- 10575035
TI  - Bipotent cortical progenitor cells process conflicting cues for neurons and glia
      in a hierarchical manner.
AB  - Neurons and glia of the cerebral cortex are thought to arise from a common,
      multipotent progenitor cell that is instructed toward alternate fates by
      extracellular cues. How do these cells behave when confronted with conflicting
      cues? We show here that nestin-positive neuroepithelial (NE) cells from embryonic
      day 14 rat cortex coexpress surface receptor proteins for ciliary neurotrophic
      factor (CNTF) and platelet-derived growth factor (PDGF). Both sets of these
      receptor proteins are functional in NE cells, as shown by ligand-dependent
      activation of downstream signal-generating proteins. Transient (30') exposure to
      CNTF instructs NE cells toward an astrocyte fate. Brief exposure to PDGF
      initiates neuronal differentiation. However, when challenged with conflicting
      cues, PDGF is dominant to CNTF. Moreover, CNTF-treated NE cells can be
      "redirected" by a subsequent exposure to PDGF to form neurons instead of
      astrocytes, whereas the converse is not true. The asymmetric relationship between
      CNTF and PDGF indicates that these two growth factors act on a common progenitor
      cell that has, at a minimum, two fates available to it rather than separate
      populations of precommitted neuroblasts and astroblasts. This bipotent progenitor
      cell processes conflicting cues for neurons and glia in a hierarchical manner.

PMID- 10575036
TI  - Glial cells promote muscle reinnervation by responding to activity-dependent
      postsynaptic signals.
AB  - After nerve injury, denervated synaptic sites in skeletal muscle commonly become
      reinnervated by sprouts that grow from nerve terminals on nearby muscle fibers.
      These terminal sprouts grow along a glial cell guide or "bridge" formed by
      Schwann cell (SC) processes that extend from denervated synaptic sites. Data
      presented here show that most bridges connect innervated and denervated synaptic
      sites rather than pairs of denervated sites even when most sites in the muscle
      are denervated. Furthermore, bridges are inhibited by presynaptic or postsynaptic
      blockade of synaptic transmission, manipulations that do not alter the extent of
      SC growth. These results show that an activity-dependent postsynaptic signal
      promotes the formation and/or maintenance of glial bridges and thus muscle
      reinnervation.

PMID- 10575037
TI  - Developmental tuning in a spinal nociceptive system: effects of neonatal
      spinalization.
AB  - Recent studies indicate a modular organization of the nociceptive withdrawal
      reflex system. Each module has a characteristic receptive field, closely matching
      the withdrawal movement caused by its effector muscle. In the rat, the strength
      of the sensory input to each module is tuned during the first postnatal weeks,
      i.e., erroneous spinal connections are depressed, and adequate connections are
      strengthened. To clarify if this tuning is dependent on supraspinal structures,
      the effect of a complete neonatal spinal cord transection on the postnatal tuning
      of withdrawal reflexes was studied. The nociceptive receptive fields of single
      hindlimb muscles and compound withdrawal reflexes were examined in decerebrate
      unanesthetized and awake rats, respectively. Noxious thermal CO(2) laser
      stimulation was used to evoke reflex responses. Neonatal spinal cord transection
      resulted in a disrupted reflex organization in the adult rat, resembling that
      previously found in neonatal rats. The receptive fields of single hindlimb
      muscles exhibited abnormal distribution of sensitivity not matching the
      withdrawal action of the effector muscles. Likewise, the composite nocifensive
      movements, as documented in the awake rat, often resulted in erroneous movements
      toward the stimulus. It is concluded that withdrawal reflexes do not become
      functionally adapted in rats spinalized at birth. These findings suggest a
      critical role for supraspinal systems in the postnatal tuning of spinal
      nociceptive systems.

PMID- 10575038
TI  - Responses of macaque perirhinal neurons during and after visual stimulus
      association learning.
AB  - Recent lesion studies have implicated the perirhinal cortex in learning that two
      objects are associated, i.e., visual association learning. In this experiment we
      tested whether neuronal responses to associated stimuli in perirhinal cortex are
      altered over the course of learning. Neurons were recorded from monkeys during
      performance of a visual discrimination task in which a predictor stimulus was
      followed, after a delay, by a GO or NO-GO choice stimulus. Association learning
      had two major influences on neuronal responses. First, responses to frequently
      paired predictor-choice stimuli were more similar to one another than was the
      case with infrequently paired stimuli. Second, the magnitude of activity during
      the delay was correlated with the magnitude of responses to both the predictor
      and choice stimuli. Both of these learning effects were found only for stimulus
      pairs that had been associated on at least 2 d of training. Early in training,
      the delay activity was correlated only with the response to the predictor
      stimuli. Thus, with long-term training, perirhinal neurons tend to link the
      representations of temporally associated stimuli.

PMID- 10575039
TI  - Brain uncoupling protein 2: uncoupled neuronal mitochondria predict thermal
      synapses in homeostatic centers.
AB  - Distinct brain peptidergic circuits govern peripheral energy homeostasis and
      related behavior. Here we report that mitochondrial uncoupling protein 2 (UCP2)
      is expressed discretely in neurons involved in homeostatic regulation. UCP2
      protein was associated with the mitochondria of neurons, predominantly in axons
      and axon terminals. UCP2-producing neurons were found to be the targets of
      peripheral hormones, including leptin and gonadal steroids, and the presence of
      UCP2 protein in axonal processes predicted increased local brain mitochondrial
      uncoupling activity and heat production. In the hypothalamus, perikarya producing
      corticotropin-releasing factor, vasopressin, oxytocin, and neuropeptide Y also
      expressed UCP2. Furthermore, axon terminals containing UCP2 innervated diverse
      hypothalamic neuronal populations. These cells included those producing orexin,
      melanin-concentrating hormone, and luteinizing hormone-releasing hormone. When c
      fos-expressing cells were analyzed in the basal brain after either fasting or
      cold exposure, it was found that all activated neurons received a robust UCP2
      input on their perikarya and proximal dendrites. Thus, our data suggest the novel
      concept that heat produced by axonal UCP2 modulates neurotransmission in
      homeostatic centers, thereby coordinating the activity of those brain circuits
      that regulate daily energy balance and related autonomic and endocrine processes.

PMID- 10575040
TI  - Selective discrimination learning impairments in mice expressing the human
      Huntington's disease mutation.
AB  - Cognitive decline is apparent in the early stages of Huntington's disease and
      progressively worsens throughout the course of the disease. Expression of the
      human Huntington's disease mutation in mice (R6/2 line) causes a progressive
      neurological phenotype with motor symptoms resembling those seen in Huntington's
      disease. Here we describe the cognitive performance of R6/2 mice using four
      different tests (Morris water maze, visual cliff avoidance, two-choice swim tank,
      and T-maze). Behavioral testing was performed on R6/2 transgenic mice and their
      wild-type littermates between 3 and 14.5 weeks of age, using separate groups of
      mice for each test. R6/2 mice did not show an overt motor phenotype until
      approximately 8 weeks of age. However, between 3.5 and 8 weeks of age, R6/2 mice
      displayed progressive deterioration in specific aspects of learning in the Morris
      water maze, visual cliff, two-choice swim tank, and T-maze tasks. The age of
      onset and progression of the deficits in the individual tasks differed depending
      on the particular task demands. Thus, as seen in humans with Huntington's
      disease, R6/2 mice develop progressive learning impairments on cognitive tasks
      sensitive to frontostriatal and hippocampal function. We suggest that R6/2 mice
      provide not only a model for studying cognitive and motor changes in
      trinucleotide repeat disorders, but also a framework within which the functional
      efficacy of therapeutic strategies aimed at treating such diseases can be tested.

PMID- 10575041
TI  - The contribution of facilitation of monosynaptic PSPs to dishabituation and
      sensitization of the Aplysia siphon withdrawal reflex.
AB  - To examine the relationship between synaptic plasticity and learning and memory
      as directly as possible, we have developed a new simplified preparation for
      studying the siphon-withdrawal reflex of Aplysia in which it is relatively easy
      to record synaptic connections between individual identified neurons during
      simple forms of learning. We estimated that monosynaptic EPSPs from LE siphon
      sensory neurons to LFS siphon motor neurons mediate approximately one-third of
      the reflex response measured in this preparation, which corresponds to siphon
      flaring in the intact animal. To investigate cellular mechanisms contributing to
      dishabituation and sensitization, we recorded evoked firing of LFS neurons, the
      siphon withdrawal produced by stimulation of an LFS neuron, the complex PSP in an
      LFS neuron, and the monosynaptic PSP from an "on-field" or "off-field" LE neuron
      to an LFS neuron during behavioral training. Unlike the simplified gill
      withdrawal preparation (Cohen et al., 1997; Frost et al., 1997), in the siphon
      withdrawal preparation we found no qualitative differences between the major
      cellular mechanisms contributing to dishabituation and sensitization, suggesting
      that dissociations that have been observed previously may be attributable to
      transient inhibition that does not occur for this component of the reflex.
      Furthermore, in the siphon-withdrawal preparation, all of the various cellular
      measures, including monosynaptic PSPs from either on-field or off-field LE
      neurons, changed approximately in parallel with changes in the behavior. These
      results provide the most direct evidence so far available that both
      dishabituation and sensitization involve multiple mechanisms, including
      heterosynaptic facilitation of sensory neuron-motor neuron PSPs.

PMID- 10575042
TI  - Trial-to-trial variability and state-dependent modulation of auditory-evoked
      responses in cortex.
AB  - Recent experimental work has provided evidence that trial-to-trial variability of
      sensory-evoked responses in cortex can be explained as a linear superposition of
      random ongoing background activity and a stationary response. While studying
      single trial variability and state-dependent modulation of evoked responses in
      auditory cortex of ketamine/xylazine-anesthetized rats, we have observed an
      apparent violation of this model. Local field potential and unit spike trains
      were recorded and analyzed during different anesthesia depths-deep, medium, and
      light-which were defined by the pattern of ongoing cortical activity. Estimation
      of single trial evoked response was achieved by considering whole waveforms,
      rather than just one or two peak values from each wave. Principal components
      analysis was used to quantitatively classify waveforms on the basis of their time
      courses (i.e., shapes). We found that not only average response but also response
      variability is modulated by depth of anesthesia. Trial-to-trial variability is
      highest under medium levels of anesthesia, during which ongoing cortical activity
      exhibits rhythmic population bursting activity. By triggering the occurrence of
      stimuli from the spontaneously occurring burst events, we show that the observed
      variability can be accounted for by the background activity. In particular, the
      ongoing activity was found to modulate both amplitude and shape (including
      latency) of evoked local field potentials and evoked unit activity in a manner
      not predicted by linear superposition of background activity and a stereotyped
      evoked response. This breakdown of the linear model is likely attributable to
      rapid transitions between different levels of thalamocortical excitability (e.g.,
      spike-wave discharges), although brain "state" is relatively fixed.

PMID- 10575043
TI  - Singing-related neural activity in a dorsal forebrain-basal ganglia circuit of
      adult zebra finches.
AB  - The anterior forebrain pathway (AFP) of songbirds, a specialized dorsal forebrain
      basal ganglia circuit, is crucial for song learning but has a less clear function
      in adults. We report here that neurons in two nuclei of the AFP, the lateral
      magnocellular nucleus of the anterior neostriatum (LMAN) and Area X, show marked
      changes in neurophysiological activity before and during singing in adult zebra
      finches. The presence of modulation before song output suggests that singing
      related AFP activity originates, at least in part, in motor control nuclei. Some
      neurons in LMAN of awake birds also responded selectively to playback of the
      bird's own song, but neural activity during singing did not completely depend on
      auditory feedback in the short term, because neither the level nor the pattern of
      this activity was strongly affected by deafening. The singing-related activity of
      neurons in AFP nuclei of songbirds is consistent with a role of the AFP in adult
      singing or song maintenance, possibly related to the function of this circuit
      during initial song learning.

PMID- 10575044
TI  - The hamster circadian rhythm system includes nuclei of the subcortical visual
      shell.
AB  - The clock regulating mammalian circadian rhythmicity resides in the
      suprachiasmatic nucleus. The intergeniculate leaflet, a major component of the
      subcortical visual system, has been shown to be essential for certain aspects of
      circadian rhythm regulation. We now report that midbrain visual nuclei afferent
      to the intergeniculate leaflet are also components of the hamster circadian
      rhythm system. Loss of connections between the intergeniculate leaflet and visual
      midbrain or neurotoxic lesions of pretectum or deep superior colliculus (but not
      of the superficial superior colliculus) blocked phase shifts of the circadian
      activity rhythm in response to a benzodiazepine injection during the subjective
      day. Such damage did not disturb phase response to a novel wheel stimulus. The
      amount of wheel running or open field locomotion were equivalent in lesioned and
      control groups after benzodiazepine treatment. Electrical stimulation of the deep
      superior colliculus, without its own effect on circadian rhythm phase, greatly
      attenuated light-induced phase shifts. Such stimulation was associated with
      increased FOS protein immunoreactivity in the suprachiasmatic nucleus. The
      results show that the circadian rhythm system includes the visual midbrain and
      distinguishes between mechanisms necessary for phase response to benzodiazepine
      and those for phase response to locomotion in a novel wheel. The results also
      refute the idea that benzodiazepine-induced phase shifts are the consequence of
      induced locomotion. Finally, the data provide the first indication that the
      visual midbrain can modulate circadian rhythm response to light. A variety of
      environmental stimuli may gain access to the circadian clock mechanism through
      subcortical nuclei projecting to the intergeniculate leaflet and, via the final
      common path of the geniculohypothalamic tract, from the leaflet to the
      suprachiasmatic nucleus.

PMID- 10575045
TI  - Effects of chronic antidepressant treatments on serotonin transporter function,
      density, and mRNA level.
AB  - To investigate functional changes in the brain serotonin transporter (SERT) after
      chronic antidepressant treatment, several techniques were used to assess SERT
      activity, density, or its mRNA content. Rats were treated by osmotic minipump for
      21 d with the selective serotonin reuptake inhibitors (SSRIs) paroxetine or
      sertraline, the selective norepinephrine reuptake inhibitor desipramine (DMI), or
      the monoamine oxidase inhibitor phenelzine. High-speed in vivo electrochemical
      recordings were used to assess the ability of the SSRI fluvoxamine to modulate
      the clearance of locally applied serotonin in the CA3 region of hippocampus in
      drug- or vehicle-treated rats. Fluvoxamine decreased the clearance of serotonin
      in rats treated with vehicle, DMI, or phenelzine but had no effect on the
      clearance of serotonin in SSRI-treated rats. SERT density in the CA3 region of
      the hippocampus of the same rats, assessed by quantitative autoradiography with
      tritiated cyanoimipramine ([(3)H]CN-IMI), was decreased by 80-90% in SSRI-treated
      rats but not in those treated with phenelzine or DMI. The serotonin content of
      the hippocampus was unaffected by paroxetine or sertraline treatment, ruling out
      neurotoxicity as a possible explanation for the SSRI-induced decrease in SERT
      binding and alteration in 5-HT clearance. Levels of mRNA for the SERT in the
      raphe nucleus were also unaltered by chronic paroxetine treatment. Based on these
      results, it appears that the SERT is downregulated by chronic administration of
      SSRIs but not other types of antidepressants; furthermore, the downregulation is
      not caused by decreases in SERT gene expression.

PMID- 10575046
TI  - How the basal ganglia use parallel excitatory and inhibitory learning pathways to
      selectively respond to unexpected rewarding cues.
AB  - After classically conditioned learning, dopaminergic cells in the substantia
      nigra pars compacta (SNc) respond immediately to unexpected conditioned stimuli
      (CS) but omit formerly seen responses to expected unconditioned stimuli, notably
      rewards. These cells play an important role in reinforcement learning. A neural
      model explains the key neurophysiological properties of these cells before,
      during, and after conditioning, as well as related anatomical and
      neurophysiological data about the pedunculopontine tegmental nucleus (PPTN),
      lateral hypothalamus, ventral striatum, and striosomes. The model proposes how
      two parallel learning pathways from limbic cortex to the SNc, one devoted to
      excitatory conditioning (through the ventral striatum, ventral pallidum, and
      PPTN) and the other to adaptively timed inhibitory conditioning (through the
      striosomes), control SNc responses. The excitatory pathway generates CS-induced
      excitatory SNc dopamine bursts. The inhibitory pathway prevents dopamine bursts
      in response to predictable reward-related signals. When expected rewards are not
      received, striosomal inhibition of SNc that is unopposed by excitation results in
      a phasic drop in dopamine cell activity. The adaptively timed inhibitory learning
      uses an intracellular spectrum of timed responses that is proposed to be similar
      to adaptively timed cellular mechanisms in the hippocampus and cerebellum. These
      mechanisms are proposed to include metabotropic glutamate receptor-mediated
      Ca(2+) spikes that occur with different delays in striosomal cells. A
      dopaminergic burst in concert with a Ca(2+) spike is proposed to potentiate
      inhibitory learning. The model provides a biologically predictive alternative to
      temporal difference conditioning models and explains substantially more data than
      alternative models.

PMID- 10575047
TI  - L-type voltage-gated calcium channels mediate NMDA-independent associative long
      term potentiation at thalamic input synapses to the amygdala.
AB  - Long-term potentiation (LTP) in the amygdala is a leading candidate mechanism to
      explain fear conditioning, a prominent model of emotional memory. LTP occurs in
      the pathway from the auditory thalamus to the lateral amygdala, and during fear
      conditioning LTP-like changes occur in the synapses of this pathway.
      Nevertheless, LTP has not been investigated in the thalamoamygdala pathway using
      in vitro recordings; hence little is known about the underlying mechanisms. We
      therefore examined thalamoamygdala LTP in vitro using visualized whole-cell patch
      recording. LTP at these synapses was dependent on postsynaptic calcium entry,
      similar to synaptic plasticity in other regions of the brain. However, unlike
      many forms of synaptic plasticity, thalamoamygdala LTP was independent of NMDA
      receptors, despite their presence at these synapses, and instead was dependent on
      L-type voltage-gated calcium channels. This was true when LTP was induced by
      pairing presynaptic activity with either action potentials or constant
      depolarization in the postsynaptic cell. In addition, the LTP was associative, in
      that it required concurrent pre- and postsynaptic activity, and it was synapse
      specific. Thus, although this LTP is different from that described at other
      synapses in the brain, it is nonetheless well suited to mediate classical fear
      conditioning.

PMID- 10575048
TI  - Opiate states of memory: receptor mechanisms.
AB  - The present studies characterized the receptor mechanisms of morphine-induced
      states of memory. Morphine (5 mg/kg) produced a state in which rats could learn
      and retrieve an operant response; retrieval was impaired, however, when the rats
      were tested in the normal state. Conversely, rats that were trained in the normal
      state failed to retrieve the response in the morphine state. In either case the
      mnesic state was dose dependent, commencing at morphine doses as low as 0.8
      mg/kg. In rats trained with 5 mg/kg of morphine, retrieval was fully adequate
      when tested with this same dose but not when tested with either lower or higher
      doses. Naloxone, but not naltrindole, antagonized the morphine-induced state;
      heroin and (-)-cyclazocine, but not U50,488H, (+)-cyclazocine and SNC80, produced
      a state in which retrieval occurred at least partially. Time-effect studies in
      which injections were made from 0 to 240 min before the sessions indicated that
      the retrieval in saline-to-morphine and morphine-to-saline conditions occurred
      along different time courses; a theory of opiate signal transduction suggests
      that these temporal profiles result from morphine producing two bi-directional
      mnesic states that may differ as much as the analgesia and hyperalgesia that
      morphine also induces. It appears that a particular magnitude of mu opiate
      receptor activation produces a state to which a memory trace can be confined in a
      highly selective manner. The normal and this particular morphine state are only
      some of the many mutually inaccessible and molecularly definable states of memory
      that are likely to exist, thus challenging the unitary concept of an individual
      organism's memory.

PMID- 10575049
TI  - Biphasic modulation of hippocampal plasticity by behavioral stress and
      basolateral amygdala stimulation in the rat.
AB  - Explicit memory may depend on the hippocampus, whereas the amygdala may be part
      of an emotional memory system. Priming stimulation of the basolateral group of
      the amygdala (BLA) resulted in an enhanced long-term potentiation (LTP) in the
      dentate gyrus (DG) to perforant path (PP) stimulation 30, 90, 150, and 180 min
      after high-frequency stimulation (HFS). Exposure of rats to a behavioral stress
      is reported to inhibit DG LTP. Because the amygdala is thought to mediate
      emotional responses, we examined the apparent discrepancy between the effects of
      behavioral stress induced 1 hr before HFS to the PP and of amygdala priming on
      hippocampal plasticity by stimulating the BLA 1 hr before HFS to the PP. The two
      delayed protocols inhibited the expression of LTP to PP stimulation, whereas
      priming the BLA immediately before HFS to the PP enhanced DG LTP. Moreover,
      exposure to the behavioral stress blocked the enhancing effects of BLA priming on
      LTP. We propose that the activation of the BLA (either by behavioral stress or by
      direct electrical stimulation) has a biphasic effect on hippocampal plasticity:
      an immediate excitatory effect and a longer-lasting inhibitory effect.

PMID- 10575050
TI  - Asymmetric suppression outside the classical receptive field of the visual
      cortex.
AB  - Areas beyond the classical receptive field (CRF) can modulate responses of the
      majority of cells in the primary visual cortex of the cat (). Although general
      characteristics of this phenomenon have been reported previously, little is known
      about the detailed spatial organization of the surrounds. Previous work suggests
      that the surrounds may be uniform regions that encircle the CRF or may be limited
      to the "ends" of the CRF. We have examined the spatial organization of surrounds
      of single-cell receptive fields in the primary visual cortex of anesthetized,
      paralyzed cats. The CRF was stimulated with an optimal drifting grating, whereas
      the surround was probed with a second small grating patch placed at discrete
      locations around the CRF. For most cells that exhibit suppression, the surrounds
      are spatially asymmetric, such that the suppression originates from a localized
      region. We find a variety of suppressive zone locations, but there is a slight
      bias for suppression to occur at the end zones of the CRF. The spatial pattern of
      suppression is independent of the parameters of the suppressive stimulus used,
      although the effect is clearest with iso-oriented surround stimuli. A subset of
      cells exhibit axially symmetric or uniform surround fields. These results
      demonstrate that the surrounds are more specific than previously realized, and
      this specialization has implications for the processing of visual information in
      the primary visual cortex. One possibility is that these localized surrounds may
      provide a substrate for figure-ground segmentation of visual scenes.

PMID- 10575051
TI  - Deafening alters neuron turnover within the telencephalic motor pathway for song
      control in adult zebra finches.
AB  - In the telencephalon of adult songbirds, projection neurons are lost and replaced
      within the efferent pathway controlling learned vocal behavior. We examined the
      potential role of auditory experience in regulating the addition and long-term
      survival of vocal control neurons in adult male zebra finches. Deafened and
      control birds were injected with the cell birth marker [(3)H]thymidine and then
      killed 1 or 4 months later. At the 1 month survival time, the number of [(3)H]
      labeled neurons present in the high vocal center (HVC) was 70% lower in deafened
      birds compared with controls. This was true for all [(3)H]-labeled HVC neurons,
      as well as the subset that projected to the robust nucleus of the archistriatum.
      Over the next 3 months, two-thirds of the [(3)H]-labeled HVC neurons in control
      birds were lost, presumably through cell death. Surprisingly, deafened birds
      showed no loss over this interval. The total number of HVC neurons did not differ
      between control and deafened birds at either survival time. Nuclear diameters of
      [(3)H]-labeled HVC neurons decreased with cell age in both control and deafened
      birds, a process that may relate to the eventual death and replacement of these
      cells. These results suggest that experience influences the addition and also the
      longer-term fate of neurons formed in adulthood. We propose that auditory
      deprivation decreases the incorporation of new neurons and prolongs their life
      span. Alterations in the neuronal replacement cycle may relate to the gradual
      deterioration in song that occurs after deafening in adult zebra finches.

PMID- 10575052
TI  - Dynamic filtering of recognition memory codes in the hippocampus.
AB  - Principal cells of the dentate gyrus (DG), CA3, and CA1 subfields of the
      hippocampus were recorded in rat during performance of an odor-guided delayed
      nonmatch-to-sample task with distinct sample and test phases. The hippocampus was
      found to possess multiple encoding modes. In the sample phase, odor-selective
      activity was restricted primarily to CA1 and, to a lesser extent, CA3. Odor
      representations in half of these cells were predictive of subsequent performance
      (i. e., correct vs error) in the test phase. Cells in each hippocampal subfield
      maintained elevated or suppressed activity in the delay interval relative to pre
      odor baseline, but were indiscriminate with regard to sample odor identity. In
      the test phase, the regional distribution of odor-selective activity was inverse
      to that for the sample: maximal in DG and minimal in CA1. The inverted
      distribution of odor selectivity was also observed for cells that discriminated
      match/nonmatch trial types. Most match/nonmatch cells exhibited greater activity
      on correct nonmatch than error match trials, indicating the presence of a
      hippocampal recognition memory signal on trials where recognition occurred and
      its absence on trials where recognition failed. These findings reveal the
      hippocampus as a highly dynamic encoding device, restricting perceptual stimulus
      information to different subfields (or none, in the delay phase) depending on
      memory task contingencies. Moreover, the reduction in cue-specificity of
      match/nonmatch comparison signals as they pass through the hippocampal
      trisynaptic circuit may contribute to a generalized recognition signal for use in
      guiding behavior.

PMID- 10575053
TI  - An inhibitory interface gates impulse traffic between the input and output
      stations of the amygdala.
AB  - The central amygdaloid nucleus projects to brainstem and hypothalamic nuclei
      mediating fear responses and receives convergent sensory inputs from the
      basolateral amygdaloid complex. However, interposed between the basolateral
      complex and central nucleus is a string of interconnected GABAergic cell
      clusters, the intercalated cell masses. Here, we analyzed how intercalated
      neurons influence impulse traffic between the basolateral complex and central
      nucleus using whole-cell recordings, microstimulation, and local application of
      glutamate receptor antagonists in brain slices. Our results suggest that
      intercalated neurons receive glutamatergic inputs from the basolateral complex
      and generate feedforward inhibition in neurons of the central nucleus. As the
      position of the recording site was shifted medially, intercalated cells projected
      to gradually more medial sectors of the central nucleus and were maximally
      responsive to progressively more medial stimulation sites in the basolateral
      complex. Thus, there is a lateromedial correspondence between the position of
      intercalated cells, their projection site in the central nucleus, and the source
      of their excitatory afferents in the basolateral complex. In addition,
      basolateral stimulation sites eliciting maximal excitatory responses in
      intercalated neurons were flanked laterally by sites eliciting prevalently
      inhibitory responses via the activation of intercalated cells located more
      laterally. As a result, the feedforward inhibition generated by intercalated
      neurons and, indirectly, the amplitude of the responses of central neurons could
      be increased or decreased depending on which combination of amygdala nuclei are
      activated and in what sequence. Thus, the output of the central nucleus depends
      not only on the nature and intensity of sensory inputs but also on their timing
      and origin.

PMID- 10575054
TI  - The performance of synapses that convey discrete graded potentials in an insect
      visual pathway.
AB  - Synapses from nonspiking neurons transmit small graded changes in potential, but
      variability in their postsynaptic potential amplitudes has not been extensively
      studied. At synapses where the presynaptic signal is an all-or-none spike, the
      probabilistic manner of neurotransmitter release causes variation in the
      amplitudes of postsynaptic potentials. I have measured the reliability of the
      operation of synapses that convey small graded potentials between pairs of
      identified large, second-order neurons in the locust ocellar system. IPSPs are
      mediated by small rebound spikes, which are graded in amplitude, in the
      presynaptic neuron. A transfer curve plotting amplitudes of spikes against
      amplitudes of IPSPs has a characteristic S shape with a linear central portion
      where IPSP amplitude is between -0.2 and -0.6 as large as spike amplitude but
      shows appreciable scatter. Approximately half of the scatter is attributable to
      background noise, most of which originates in photoreceptors and persists in
      darkness. The remaining noise is intrinsic to the synapse itself and is usually
      0.3-0.7 mV in amplitude. It limits the resolution with which two spike amplitudes
      can be distinguished from one another to approximately 2 mV and, because the
      linear part of the transfer curve occupies approximately 10 mV in spike
      amplitudes, limits the number of discrete signal levels that can be conveyed
      across the synapse to approximately five. The amplitude of the noise is constant
      throughout the synaptic operating range, which means it is unlikely that
      presynaptic membrane potential controls transmitter release by setting a single
      probability level for quantal release.

PMID- 10575055
TI  - Cellular analog of differential classical conditioning in Aplysia: disruption by
      the NMDA receptor antagonist DL-2-amino-5-phosphonovalerate.
AB  - We previously showed that the associative enhancement of Aplysia siphon
      sensorimotor synapses in a cellular analog of classical conditioning is disrupted
      by infusing the Ca(2+) chelator 1, 2-bis(2-aminophenoxy)ethane-N,N-N',N'
      tetraacetic acid into the postsynaptic motor neuron before training or by
      training in the presence of the NMDA receptor antagonist DL-2-amino-5
      phosphonovalerate (APV). Our earlier experiments with APV used a nondifferential
      training protocol, in which different preparations were used for associative and
      nonassociative training. In the present experiments we extended our investigation
      of the role of NMDA receptor type potentiation in learning in Aplysia to
      differential conditioning. A cellular analog of differential conditioning was
      performed with a reduced preparation that consisted of the CNS plus two pedal
      nerves. A siphon motor neuron and two siphon sensory neurons, both of which were
      presynaptically connected to the motor neuron, were impaled with sharp
      microelectrodes. One sensorimotor synapse received paired stimulation with a
      conditioned stimulus (brief activation of a single sensory neuron) and an
      unconditioned stimulus (pedal nerve shock), whereas the other sensorimotor
      synapse received unpaired stimulation. Training in normal artificial seawater
      (ASW) resulted in significant differential enhancement of synapses that received
      the paired stimulation. Training in APV blocked this differential synaptic
      enhancement. A comparison of the present data with the data from earlier
      experiments that used nondifferential training is consistent with the possibility
      that differential training comprises competition between the presynaptic sensory
      neurons. Synaptic competition may contribute significantly to the associative
      effect of paired stimulation in the differential training paradigm.

PMID- 10575056
TI  - Mechanisms modifying atherosclerotic disease - from lipids to vascular biology.
AB  - Recent clinical trials of three statins, pravastain, simvastatin and lovastatin,
      have demonstrated a major reduction in acute coronary events typically
      precipitated by plaque rupture. However, angiographic studies with several
      statins have shown that they do not appear to greatly affect the size of pre
      existing plaques. These findings strongly suggest that the demonstrated
      protective effect of these statins is mediated through changes in plaque
      composition rather than size, highlighting the greater importance of composition
      than size in determining clinical outcome. Atherosclerotic plaques are composed
      of a thrombogenic lipid-rich core protected by a fibrous cap comprising smooth
      muscle cells (SMCs) and inflammatory cells, predominantly macrophages. SMCs are
      the only cell type in the atherosclerotic plaque capable of synthesizing a strong
      fibrous cap. Their survival is therefore crucial to plaque stability. In
      contrast, inflammatory cells such as macrophages increase the risk of plaque
      rupture by a number of mechanisms. Thus, in atherosclerosis, there is a balance
      between the influence of inflammatory cells tending towards plaque instability
      and the reparative influence of SMCs tending to plaque stability. The implication
      of the successful outcome studies is that the statins tested may beneficially
      influence this balance either by decreasing inflammation or promoting repair or
      both. However, because statins do not have a uniform effect on all the biological
      processes contributing to plaque rupture and subsequent thrombosis, the potential
      benefit from treating with a statin cannot necessarily be presumed or predicted
      from its lipid lowering potency alone. Therefore prescription of statins to
      prevent cardiovascular events should be based on the evidence of outcome trials.

PMID- 10575057
TI  - Beyond lipids - the role of the endothelium in coronary artery disease.
AB  - The beneficial effects of statin therapy in patients with coronary heart disease
      (CHD) outweigh those expected from simply lowering low-density lipoprotein (LDL)
      cholesterol, and occur too early in treatment to be due to this mechanism alone.
      Endothelial dysfunction is present in patients with atherosclerosis, even in the
      early stages before plaque formation, making it a useful marker for early
      cardiovascular disease. Statins reduce endothelial dysfunction, which improves
      myocardial perfusion and angina pectoris. In recent studies with statin therapy,
      the improvement in endothelial function has been attributed, in part, to an
      increased production of nitric oxide (NO), a key vasodilator, from the
      endothelium. These studies have shown that pravastatin and simvastatin improve
      endothelial function in the short term, with variable effects on vasodilation,
      which may be due to differences in their effects on NO production. Whether these
      differences between the statins may result in long-term differences in net
      clinical benefit has to be awaited.

PMID- 10575058
TI  - Evidence for the benefit of early intervention with pravastatin for secondary
      prevention of cardiovascular events.
AB  - Treatment with HMG-CoA reductase inhibitors (or statins) lowers total and LDL
      cholesterol and decreases the risk of cardiovascular events. The absolute
      benefits are greater in patients with a higher baseline cardiovascular risk, so
      statins are particularly suited to secondary prevention. Although three large
      studies have shown convincingly that, in patients with a history of
      cardiovascular disease, simvastatin or pravastatin treatment reduces the risk of
      further events and lowers overall mortality, those studies have not included
      patients in the period immediately after an acute coronary event. They are,
      therefore, of limited value in answering the question of when to start statin
      treatment. However, there are practical reasons for starting statin treatment as
      early as possible, and results of clinical studies have now shown this to be a
      safe option for pravastatin. Early treatment with pravastatin can stabilize
      coronary atherosclerosis and improve endothelial function. More importantly,
      there is also evidence that early treatment with pravastatin can produce a
      clinical benefit a few months after the initial coronary event.

PMID- 10575059
TI  - 'Fire and forget?' - pharmacological considerations in coronary care.
AB  - The potential risk of drug-drug interactions is often overlooked during drug
      therapy selection. Multiple risk factors for drug-drug interactions exist in both
      the acute and chronic phases of acute coronary syndrome (ACS), including
      concomitant medications and underlying diseases. Some statins have been used for
      secondary prevention of coronary heart disease (CHD) in these patients and are
      not all equivalent in their susceptibility to drug-drug interactions. The
      lipophilic drugs lovastatin, simvastatin, atorvastatin, cerivastatin and
      fluvastatin are metabolized via the cytochrome P450 (CYP450) system in the liver
      and the gut, making them subject to potential interactions with concomitantly
      administered drugs that are competing for metabolism via this system. Clinically
      important interactions with simvastatin or lovastatin and drugs that inhibit the
      3A4 isoenzyme (part of the CYP450 system) may result in myopathy and
      rhabdomyolysis, which can be fatal. However, pravastatin is water-soluble, it
      does not undergo metabolism via CYP450 to any significant extent (<1%), is
      excreted essentially unchanged and has not been shown to participate in any
      clinically relevant drug-drug interactions with CYP450 agents. When selecting
      drug therapy, knowledge of a drug's route of metabolism is important to predict
      and prevent life-threatening drug-drug interactions.

PMID- 10575060
TI  - The therapeutic gap--compliance with medication and guidelines.
AB  - Hospitals, clinics and cardiologists have a significant impact on prescribing in
      general practice. Physicians in primary care rank hospital recommendations as one
      of the most important sources of information on new drugs. However, recent
      surveys of coronary heart disease (CHD) prevention paint a depressing picture
      about the current evidence-based management of risk factors, such as
      hypercholesterolaemia and hypertension, in both secondary- and primary-care
      settings. European guidelines have identified secondary prevention as the top
      priority in patients with established CHD and lowered cholesterol thresholds in
      light of evidence, not only from the 4S study, but also from the CARE and LIPID
      studies, which highlighted the risks posed by even normal or moderately elevated
      cholesterol levels. There is a clear need for those involved in quality assurance
      in hospital care to take ownership of such guidelines. Cardiologists can play a
      key role - they do not face the problem alone, but evidence suggests that they
      can have a significant positive impact on the management of CHD risk factors in
      primary care.

PMID- 10575061
TI  - After 4S, CARE and LIPID--is evidence-based medicine being practised?
AB  - Between 1994 and 1997, three major trials - 4S, CARE and LIPID - showed that
      simvastatin and pravastatin reduced the risk of a recurrent coronary event in
      patients with established coronary heart disease (CHD) [Scandinavian Simvastatin
      Survival Study (4S) Group. Lancet 1994;344:1383-89; Sacks FM et al. New Engl. J.
      Med. 1996;335: 1001-9; Long-term Intervention with Pravastatin in Ischaemic
      Disease (LIPID) Study Group. New Engl. J. Med. 1998;339:1349-57]. The results of
      CARE and LIPID, with pravastatin, also showed that the benefits of improved
      survival extended to the majority of patients with CHD whose cholesterol levels
      were in the 'normal' range. Despite this compelling evidence, recent CHD
      prevention surveys between 1994 and 1998 have unveiled a wide therapeutic gap
      between scientific evidence and practice in the secondary prevention of CHD.
      These recent surveys revealed a high prevalence of hypercholesterolaemia in
      patients discharged from hospital and after 6 months following a coronary event,
      but low levels of statin prescribing in these patients. Of the minority of
      patients prescribed a statin by a consultant on discharge from hospital, nearly
      all were still receiving this treatment in primary care 6 months later. These
      findings therefore clearly highlight the need for an integrated approach
      involving hospital specialists, primary-care physicians and the patient, to
      overcome the wide treatment gap in lowering even 'normal' cholesterol levels in
      high-risk patients in line with evidence-based medicine.

PMID- 10575062
TI  - From best evidence to best practice - what are the obstacles?
AB  - There are numerous obstacles to overcome when implementing measures resulting
      from new evidence in clinical practice - some relate to practitioners in
      hospitals and primary care, others to patients, their relatives and public
      opinion. Many post-myocardial infarction (MI) patients are still discharged from
      hospital without any specific recommendations for risk-factor management, despite
      the fact that the hospital stay provides an excellent window of opportunity for
      treatment. Conversely, the primary-care physician may assume that as these
      measures were not implemented in hospital, they are unimportant. Even if
      recommendations for risk modification are made, the patient's attitude towards
      risk reduction can reduce its effectiveness. The HELP study found that the public
      had a reasonable knowledge of coronary heart disease (CHD) and the risks
      involved. However, their attitude was remarkably indifferent; even in post-MI
      patients, 24% were aware of lipid-lowering treatments, but did not take them,
      while 38% were not even aware of this form of therapy. Despite this, the medical
      profession was found to be the most credible source of information about CHD.
      Healthcare professionals, therefore, have an obligation to ensure patients
      receive the maximum benefit from medical advances by working together to overcome
      the barriers.

PMID- 10575063
TI  - Overcoming the obstacles--the outsider's view.
AB  - The cost to patients, their relatives, the medical establishment and the
      economies of individual countries is such that compliance with, or adherence to,
      prescribed therapy is a major issue. There are relatively simple and systematic
      measures by which medical specialists can increase patient compliance and so save
      costs, time and lives. From a psychological perspective, the earlier these
      measures are instigated, for example before patients are discharged from hospital
      after an acute coronary syndrome, the greater is the likelihood of patient
      adherence to treatment.

PMID- 10575064
TI  - Assessment of rectus femoris function during initial swing phase.
AB  - The normal human gait cycle is divided into two phases, namely, stance and swing.
      The objective of stance is to provide support, stability and propulsion and that
      of swing is to provide ground clearance and limb advancement. Knee flexion is
      essential during swing to lift the foot off the ground for limb advancement. The
      complex mechanisms involved in producing limb advancement can produce excessive
      knee flexion at faster walking speeds. Under these circumstances the shank needs
      to be decelerated to reduce the amount of knee flexion. It is assumed that rectus
      femoris (RF) is active for a very short period at the beginning of the swing
      phase (Perry J. Gait Analysis-Normal and Pathological Gait. Slack Incorporated,
      USA, 1992; Scott L, Ringwelsky D, Carroll N. Transfer of rectus femoris: effects
      of transfer site on moment arms about the knee and hip. J Biomech 27;1994:1201
      1211) and the amount of this activation is proportional to the walking speed and
      thus to the generated knee moment and the angular acceleration of the lower limb
      segments. However, there is very little evidence to support these assumptions.
      The objective of this study was to study this relationship. Quantified
      electromyogram of RF and vastus lateralis (VL), using surface electrodes, were
      examined, body mounted kinematic sensors such as seismic accelerometers and
      gyroscopes were used to measure segments' angular accelerations and the net
      muscular knee torque calculated from the kinematics of the segments at various
      speeds. The results showed that RF and VL work independent of each other during
      the initial swing phase. The amount of RF activity is clearly related to walking
      speed. The muscle activity increases with increasing walking speed. The
      relationship between the angular acceleration of the shank and the amount of RF
      activity is linear. The active knee moment, as a function of the shank's angular
      acceleration, shows the same high correlation to the EMG signal of RF.

PMID- 10575065
TI  - Bootstrap prediction and confidence bands: a superior statistical method for
      analysis of gait data.
AB  - Gait analysis studies typically utilize continuous curves of data measured over
      the gait cycle, or a portion of the gait cycle. Statistical methods which are
      appropriate for use in studies involving a single point of data are not adequate
      for analysis of continuous curves of data. This paper determines the operating
      characteristics for two methods of constructing statistical prediction and
      confidence bands. The methods are compared, and their performance is evaluated
      using cross-validation methodology with a data set of the sort commonly evaluated
      in gait analysis. The methods evaluated are the often-used point-by-point
      Gaussian theory intervals, and the simultaneous bootstrap intervals of Sutherland
      et al. The Development of Mature Walking, MacKeith Press, London, 1988 and Olshen
      et al. Ann. Statist. 17 (1989) 1419-40. The bootstrap bands are shown to provide
      appropriate coverage for continuous curve gait data (86% coverage for a targeted
      coverage of 90%). The Gaussian bands are shown to provide inadequate coverage
      (54% for a targeted coverage of 90%). The deficiency in the Gaussian method can
      lead to inaccurate conclusions in gait studies. Bootstrap prediction and
      confidence bands are advocated for use as a standard method for evaluating gait
      data curves because the method is non-parametric and maintains nominal coverage
      levels for entire curves of gait data.

PMID- 10575066
TI  - Measurement of lumbar spine kinematics in incline treadmill walking.
AB  - A study was undertaken to analyse and compare the pelvic (S1) and the trunk (T12)
      oscillations during level and uphill walking and to provide kinematic baseline
      data of the lumbar region in incline walking for future comparisons with
      pathological gait patterns. An ultrasonic movement analysis device (Zebris(R) CMS
      50) was used to obtain three-dimensional kinematic data for the pelvis and
      thorax. Data from treadmill walking at 0 and 10% incline of 22 adults were used
      for within subject analysis. Crosscorrelation values ranged from r=0.76 to 0.98
      (P<0.001) demonstrating a strong degree of agreement between the temporal
      patterns of angular displacement of the trunk and pelvis in the sagittal,
      transverse and frontal plane in incline compared to level ambulation. However,
      Student's t-tests revealed significantly (P<0.01) higher amplitudes for thorax
      displacements in the frontal and transverse plane in uphill walking. No
      significant differences were detected for amplitude parameters of the pelvis. It
      could be stated that the phasic patterns in level walking are not different from
      that obtained for incline walking. It is concluded that incline ambulation exerts
      the major influences in the thoracic region by increasing amplitudes of axial
      rotations.

PMID- 10575067
TI  - A biomechanical evaluation of one-stage vs two-stage bilateral knee arthroplasty
      patients.
AB  - In this study the functional abilities of eight one-stage bilateral total knee
      replacement (TKR) patients were compared to five two-stage bilateral TKR and nine
      control subjects. The TKR individuals were an average of 62 months post
      operative. Based on gait analysis, ground reaction force profiles during walking
      and isometric knee strength assessment, the one-stage individuals did not differ
      significantly from the control subjects. The two-stage individuals had
      significantly less knee range of motion during gait and smaller vertical ground
      reaction forces during the braking phase than the control and one-stage
      individuals. To compare left and right sides, a symmetry index was computed and
      there were no significant differences among the three groups. Based on the
      variables tested in this biomechanical evaluation it can be concluded that for
      individuals facing bilateral knee replacement a one-stage procedure can result in
      functional capabilities at least comparable to a two-stage procedure.

PMID- 10575068
TI  - The shock attenuation characteristics of four different insoles when worn in a
      military boot during running and marching.
AB  - A study was undertaken to determine if placing shock absorbing insoles in the
      boots of Royal Marine recruits would attenuate the peak pressure at the foot-boot
      interface, when marching at 4.8 kph carrying a 32 kg (70 lb) Bergen and running
      at 12.8 kph in loose order plus webbing weighing 10 kg (22 lb). Four types of
      insoles were assessed: viscoelastic polymetric insole (Cambion(R)) polymetric
      foam insole (PPT(R)) Saran insole (military issue) and Sorbothane(R). There was a
      fifth control condition in which no insoles were used. Pressure measurements
      during heel strike and forefoot loading were taken using Paratec equipment with
      pressure measuring insoles placed in the boots. Data were obtained from eleven
      subjects and indicated that all the insoles significantly (P<0.05) attenuated the
      peak pressures generated during heel strike and forefoot loading. The performance
      of the four insoles in terms of peak pressure attenuation ranked in order with
      the best first were: Sorbothane Cambion PPT Saran. The Sorbothane insole was
      substantially and significantly (P<0.05) better than the other insoles in terms
      of attenuating peak pressures during heel strike. During running, mean peak
      pressure at heel strike was 494 kPa in the control condition, this was reduced to
      377 kPa when wearing Sorbothane insoles (a reduction of 27%). When marching the
      Sorbothane insoles reduced the mean peak pressure at heel strike from 395 kPa
      (control) to 303 kPa (23% reduction). During forefoot loading the peak pressure
      attenuation of all four insoles was similar, although on average the Sorbothane
      insole performed slightly better than the others and was significantly different
      (P<0. 05) to the Cambion insole. Mean peak forefoot loading pressure in the
      control condition when running was 413 kPa, with the Sorbothane insole it was 367
      kPa, during marching the respective mean peak pressures were 397 and 323 kPa. It
      is concluded that of the four types of insoles assessed the Sorbothane insoles
      attenuated the greatest amounts of the peak pressure generated at heel strike and
      during forefoot loading when running and marching wearing military boots.

PMID- 10575069
TI  - Evaluation of a model that determines the stability limits of dynamic balance.
AB  - A recent model of balance control has revealed two types of boundaries describing
      stability limits for center of mass (CM) dynamics: torque boundaries and state
      boundaries. The purpose of this study was to determine if these boundaries
      correctly characterize empirical data. We analyzed 2367 trials from 10 subjects
      who recovered their balance after they voluntarily pulled on a handle. We
      hypothesized that if model predictions were valid, both types of boundaries
      should encompass the empirical trajectories. We also hypothesized that each
      trajectory's nearest distance to the torque boundaries (the torque safety margin)
      would be correlated with the center of pressure (COP) safety margin, defined as
      the COP's nearest distance to the edge of the feet. The results supported the
      accuracy of the model-derived boundaries, with torque boundaries encompassing
      100% and state boundaries encompassing 99.8% of the trials. Moreover, torque
      safety margins were highly correlated with COP safety margins, supporting the use
      of COP safety margins for estimating relative stability in dynamic tasks where
      balance is maintained. The distributions of the trajectories also suggested that
      a safety margin-oriented control strategy might be a robust alternative to the
      hypothesis that the central nervous system strives to optimize motion. The
      distinctions among different safety margins are discussed.

PMID- 10575070
TI  - The second order autoregressive model in the evaluation of postural stability.
AB  - The properties of a new postural stability criterion based on the analysis of the
      difference between centre of pressure and centre of gravity are discussed. This
      difference may be regarded as the control variable representing active work of
      ankle muscles allowing to maintain equilibrium and can be effectively modelled as
      the second order autoregressive process. The model includes two parameters, which
      allow us to compute stability margin and respective peak frequency considered
      here as stability biomarkers characterising the human posture control system. The
      approach, originally designed for quiet stance, lets us effectively assess the
      stability changes during performance of postural tasks at different levels of
      difficulty. The latter feature may indicate that the method can find clinical
      application in the assessment of postural disorders as a supplementary tool
      reinforcing traditional measures of postural sway. This is particularly
      convincing in view of the fact that the correlations between old and new measures
      are low, what implies that the stability biomarkers contain different information
      concerning the stability of posture as compared with other indices.

PMID- 10575071
TI  - Effects of the type of holds and movement amplitude on postural control
      associated with a climbing task.
AB  - The aim of the present work was to characterize the modifications of the postural
      adjustments during a climbing task as a function of postural and/or movement
      constraints. The variations of the horizontal and vertical forces and momentum
      were analyzed for different movement amplitudes and types of holds. The results
      show that the horizontal momentum is influenced by all experimental conditions
      before the onset of movement. By contrast, the vertical momentum is only
      influenced by the amplitude of the movement, after its onset. These results
      confirm the hypothesis of a dual function of the anticipatory postural
      adjustments. The horizontal momentum is mainly involved in the control of
      equilibrium. The vertical momentum contributes to the movement initiation.

PMID- 10575072
TI  - Recurrence quantification analysis of postural fluctuations.
AB  - A technique (recurrence quantification analysis; RQA) for analyzing center of
      pressure (COP) signals is presented and applied to data obtained by having
      participants stand with the head forward or sideways and with eyes open or
      closed. RQA is suitable for short, nonstationary signals and quantifies dynamical
      (deterministic) structure and nonstationarity. Results indicated that vision
      affects the deterministic structure (in degree and complexity) of COP motions and
      that differential optical flow structure (radial versus lamellar flow) induced by
      spontaneous sway under different head orientations affects COP nonstationarity.
      Implications of these findings and the sensitivity of RQA to subtle time
      evolutionary properties of the COP are discussed.

PMID- 10575073
TI  - Angular movements of the pelvis and lumbar spine during self-selected and slow
      walking speeds.
AB  - We studied the effect of walking at a self-selected and at a slower speed on the
      angular movements of the pelvis and lumbar spine. We also studied how
      interpretation of speed effects on lumbar spine movements was influenced by frame
      of reference, either relative to the pelvis or relative to a global reference
      frame. Twenty-seven subjects without pathology walked on a treadmill at either
      self-selected or 60% of self-selected speed. The movements of the pelvis and
      lumbar spine, as represented by surface markers, were recorded by videocameras
      and the three-dimensional angles computed by the PEAK motion measurement system.
      Results indicated that the amplitudes of pelvic list (P<0.05) and pelvic axial
      rotation (P<0. 05) were decreased at slow walking speed. Relative to the pelvis,
      the amplitude of lumbar lateral flexion was decreased with slower walking
      (P<0.01). In contrast, when lumbar spine movements were measured relative to a
      global reference frame, no differences were detected due to decreased walking
      speed. This suggests, firstly, that the effect of walking speed when evaluating
      the significance of decreased movements of the pelvis and of the lumbar spine
      (relative to the pelvis) of subjects walking at slower than self-selected speeds
      should be considered and secondly, that movement of the lumbar spine should be
      interpreted with respect to a frame of reference.

PMID- 10575074
TI  - Comparison of gait with and without shoes in children.
AB  - Full body gait analysis was used to determine if differences exist in kinematic,
      kinetic, and temporal-spatial data with and without shoes in able-bodied
      children. The greatest difference noted between conditions was an increase in
      stride length with shoes. Minimal changes were seen in kinematics and kinetics
      with the addition of shoes. Due to the very tight standard deviations of the
      data, these minimal changes in the magnitude of the curves resulted in
      statistically significant differences, yet these changes do not appear to be
      clinically significant. It is believed that this study establishes that barefoot
      gait analysis is sufficient for most clinical studies, and an additional
      assessment undertaken while wearing shoes is not necessary.

PMID- 10575075
TI  - The 'Entlastungsgang'. A hip unloading gait as a new conservative therapy for hip
      pain in the adult.
AB  - 'Entlastungsgang' is a gait modification aiming to unload the hip joint by
      producing a modified Duchenne-limp (straight spinal column, additional lifting of
      the pelvis on the side of the swinging leg and a consecutive side shift of the
      pelvis) and a wide stance gait. Sixteen patients suffering from hip pain caused
      mainly by hip dysplasia were investigated. They received daily gait training for
      12 h combined with intensive physical therapy as in-patients for 3-4 weeks. The
      external muscle torque acting on the hip joint was determined by 3D-gait analysis
      before, during and after the gait training. We found a reduction of the muscle
      torque after gait training to 77.2% of the initial value. At an average follow up
      of 12 months we found a persisting reduction of the muscle torque to 87. 0% at
      spontaneous gait that was further reduced to 81.3% of the initial value. The hip
      score for two components of the Merle d'Aubigne and Postel score for pain and
      walking was significantly improved from 7.4 to 10.8 points.

PMID- 10575076
TI  - A mechanical energy analysis of gait initiation.
AB  - The analysis of gait initiation (the transient state between standing and
      walking) is an important diagnostic tool to study pathologic gait and to evaluate
      prosthetic devices. While past studies have quantified mechanical energy of the
      body during steady-state gait, to date no one has computed the mechanical energy
      of the body during gait initiation. In this study, gait initiation in seven
      normal male subjects was studied using a mechanical energy analysis to compute
      total body energy. The data showed three separate states: quiet standing, gait
      initiation, and steady-state gait. During gait initiation, the trends in the
      energy data for the individual segments were similar to those seen during steady
      state gait (and in Winter DA, Quanbury AO, Reimer GD. Analysis of instantaneous
      energy of normal gait. J Biochem 1976;9:253-257), but diminished in amplitude.
      However, these amplitudes increased to those seen in steady-state during the gait
      initiation event (GIE), with the greatest increase occurring in the second step
      due to the push-off of the foundation leg. The baseline level of mechanical
      energy was due to the potential energy of the individual segments, while the
      cyclic nature of the data was indicative of the kinetic energy of the particular
      leg in swing phase during that step. The data presented showed differences in
      energy trends during gait initiation from those of steady state, thereby
      demonstrating the importance of this event in the study of locomotion.

PMID- 10575077
TI  - Effects of reduced ankle dorsiflexion following lateral ligament sprain on
      temporal and spatial gait parameters.
AB  - Partial rupture of the lateral ligament complex of the ankle is the commonest
      soft tissue injury affecting the lower limb. The effect of the limitation of
      motion at the ankle, particularly of dorsiflexion, on gait is unclear. In this
      study, 34 subjects were measured during their recovery from a partial rupture of
      the lateral ligament for both range of dorsiflexion and the temporal and spatial
      parameters of walking. Consistent relationships were identified between the range
      and the gait variables which were in concordance with the characteristics
      expected from an antalgic gait pattern.

PMID- 10575078
TI  - The effect of segment parameter error on gait analysis results.
AB  - The extent to which errors in predicting body segment parameters (SP) influence
      biomechanical analysis of human motion is unclear. Therefore, the current study
      quantitatively evaluated the differences in SP estimates using literature
      predictive functions and computed the effect of SP variation on the kinetic
      output of walking. For a group of 15 young males, significant differences (P<0.
      05) were observed between SP estimates for the leg and thigh using the literature
      predictive functions, with mass and moment of inertial values differing by more
      than 40%. Using kinematic and ground reaction force data collected for each
      subject while walking, inverse dynamic analysis was performed iteratively to
      compute hip forces and moments while simultaneously varying SP values over nine
      intervals within +/-40% of a baseline value. SP variations were found to
      significantly affect (P<0.05) most of the kinetic estimates produced,
      particularly those taken during the swing phase. However, the magnitude of these
      effects was generally less than 1% of body weight. The data from the current
      study allows researchers to estimate the errors in kinetic measures due to SP
      variation. The results also indicate that the accuracy of SP prediction should be
      of concern in biomechanical research particularly for open chain and high
      acceleration activities. Further study is necessary to identify the importance of
      SP variation on other motion skills.

PMID- 10575079
TI  - Analysis of gait in cervical myelopathy.
AB  - Gait disorders are a frequent symptom of cervical spondylotic myelopathy (CSM).
      Twelve patients with CSM underwent gait analysis before and after decompressive
      surgery. They were assessed on a walkway and a treadmill and compared with a
      healthy matched control group. The following features were observed in the CSM
      group before surgery: significantly reduced gait velocity and step length (P<0.
      05), prolonged double support, increased step width, and reduced ankle joint
      extension during treadmill walking. Knee and hip kinematics did not differ from
      controls. Two months after surgery, spatio-temporal parameters had moved towards
      normal values, velocity, step length and cadence had increased significantly, and
      there was reduction of step width during treadmill walking, indicating improved
      equilibrium. Gait analysis is an objective tool to document functional recovery
      after decompressive surgery in CSM.

PMID- 10575080
TI  - The control of lateral stability during rapid stepping reactions evoked by antero
      posterior perturbation: does anticipatory control play a role?
AB  - Volitional step initiation invariably includes a medio-lateral anticipatory
      postural adjustment (ML APA), which causes the center of mass (COM) to be
      propelled toward the stance-limb side prior to the lifting of the swing foot. The
      present study examined whether this type of anticipatory control plays a
      functional role in maintaining lateral stability during the rapid compensatory
      stepping reactions that are evoked when whole-body stability is challenged by
      unpredictable perturbation. Forward and backward stepping reactions were
      evaluated in five healthy young adults (ages 22-28) under three task conditions:
      (1) unconstrained compensatory stepping evoked by platform translation (no
      specific instructions), (2) constrained compensatory stepping cued by platform
      translation (prior instruction to step rapidly), and (3) rapid voluntary stepping
      to a light cue. ML APAs occurred during 70% of perturbation reactions but were
      too small and brief to have a substantive influence on the lateral movement of
      the COM occurring during leg lift or swing phase. In contrast, during the light
      cued stepping, the ML APA propelled the COM toward the stance-limb side prior to
      the lifting of the swing limb, and effectively reduced the tendency of the COM to
      fall toward the swing-limb side during the execution of the step. It is proposed
      that the presence of an ML APA during compensatory stepping may represent an
      attempt to preplan a stereotypical stepping response, but that the ability to
      fully express the anticipatory phase is disrupted by the need to react rapidly to
      the unpredictable antero-posterior instability imposed by the perturbation. The
      results suggest that anticipatory control is not the primary mechanism by which
      the central nervous system deals with the lateral instability arising during
      rapid compensatory stepping reactions evoked by large, unpredictable antero
      posterior perturbation.

PMID- 10575081
TI  - Kinematic compensations as children reciprocally ascend and descend stairs with
      unilateral and bilateral solid AFOs.
AB  - The aim of this study was to identify the compensations made when a child with
      normal motor control ascends and descends stairs while wearing a solid AFO. Ten
      healthy children were asked to ascend and descend stairs with shoes, right and
      bilateral AFOs. Repeated measures ANOVA identified differences in selected
      kinematic parameters. Peak-to-peak excursion of pelvic rotation, pelvic
      obliquity, and hip ab/adduction increased with AFO use (P<0.05). Mean anterior
      pelvic tilt increased with AFO use (P<0.05). Compensations at the trunk and the
      pelvis facilitated limb advancement and clearance. This information may be
      helpful in developing strategies for training patients with motor planning
      difficulties.

PMID- 10575082
TI  - The energy expenditure of normal and pathologic gait.
AB  - Physiological energy expenditure measurement has proven to be a reliable method
      of quantitatively assessing the penalties imposed by gait disability. The purpose
      of this review is to outline the basic principles of exercise physiology relevant
      to human locomotion; detail the energy expenditure of normal walking; and
      summarize the results of energy expenditure studies performed in patients with
      specific neurologic and orthopedic disabilities. The magnitude of the
      disabilities and the patients' capacity to tolerate the increased energy
      requirements are compared. This paper also will examine the effectiveness of
      rehabilitation interventions at mitigating the energetic penalties of disability
      during ambulation.

PMID- 10575083
TI  - Adenosine-amino acid interactions in the chick brain: a role in passive avoidance
      learning.
AB  - The present work describes interactions between adenosine and the amino acids
      glutamate and GABA in slices of intermediate medial hyperstriatum ventrale
      (IMHV), an area of the chick brain known to be involved in learning and memory
      events associated with a one-trial passive avoidance task. In slices derived from
      the IMHV of untrained chicks, the A(1) receptor agonist N(6)-cyclohexyladenosine
      (CHA; 10 microM) specifically inhibited glutamate release. Conversely,
      cyclopentyltheophylline (CPT; 100 microM an A(1) antagonist) increased glutamate
      release from the slices and blocked the CHA-induced inhibition of glutamate. The
      A(2) receptor agonist 2-p-(2-carboxylethyl)-phenylamino-5'-N-ethylcarboxamido
      adenosine hydrochloride (CGS 21680) selectively increased glutamate release when
      applied at 5 microM while it selectively inhibited GABA release at a lower
      concentration (10 nM). The addition of NMDA to the medium, resulted in increased
      adenosine release equivalent to that found following stimulation with 50 mM KCl.
      Both the NMDA and the KCl-induced increases were eliminated by addition of D-2
      amino-5 phosphopentanoic acid (D-AP5), an NMDA-receptor antagonist. Slices
      prepared from the IMHV of chicks following successful training on the task showed
      enhanced adenosine release 30 min, 1, 3 and 6.5 h after training compared to
      chicks trained to peck a water-coated bead. The results show that changes in
      adenosine release from the IMHV accompany memory formation in the chick. We
      suggest that adenosine-amino acid transmitter interactions potentially via the
      activation of NMDA receptors, a necessary step in long-term memory formation for
      the task, may modulate the formation of memory for the one-trial passive
      avoidance task.

PMID- 10575084
TI  - Alcohol drinking produces brain region-selective changes in expression of
      inducible transcription factors.
AB  - Mapping the effects of alcohol consumption on neural activity could provide
      valuable information on mechanisms of alcohol's effects on behavior. The present
      study sought to identify effects of alcohol consumption on expression of
      inducible transcription factors (ITFs) in mouse brain. C57BL/6J mice were trained
      to consume 10% ethanol/10% sucrose solution during a 30-min limited access
      period. Control animals were given access to 10% sucrose solution or water.
      Following the final day of the procedure, animals were sacrificed and
      immunohistochemical analyses were performed for three ITFs (c-Fos, FosB, and
      Zif268). Alcohol-consuming animals had increased ITF expression in several brain
      areas. Specifically, c-Fos was significantly induced in the nucleus accumbens
      core (AcbC), the medial posteroventral portion of the central nucleus of the
      amygdala (CeMPV), and the Edinger-Westphal nucleus (EW). Expression of c-Fos was
      significantly lower in the dentate gyrus of alcohol-consuming animals vs. sucrose
      consuming animals. However, it was not significantly different from the water
      controls. Induction of c-Fos in AcbC, CeMPV and EW was significantly related to
      blood alcohol concentrations (BAC). Furthermore, FosB expression in the CeMPV and
      the EW was also significantly higher in the alcohol-consuming animals vs. water
      controls. FosB expression in the EW was significantly related to BAC. The
      significance of these results is two-fold. First, our experiments demonstrate
      that ITF mapping is an effective strategy in identifying alcohol-induced changes
      following voluntary consumption. Second, they suggest a relationship between ITF
      expression in AcbC, CeMPV and EW and the level of alcohol intoxication.

PMID- 10575085
TI  - Deficiency of intercellular adhesion molecule 1 fails to mitigate selective
      neuronal death after transient global ischemia.
AB  - Recent studies have shown a crucial role of intercellular adhesion molecule 1
      (ICAM-1) in expansion of infarction after focal cerebral ischemia. The purpose of
      the present study was to assess whether ICAM-1 is involved in selective neuronal
      vulnerability and reactive gliosis after transient forebrain ischemia. ICAM-1
      knockout mice and wild-type mice were subjected to transient forebrain ischemia
      for 5, 10 or 15 min, and the hippocampus and caudoputamen were examined 7 days
      later with conventional histological and immunohistochemical methods. Bilateral
      common carotid artery occlusion with less than 10% of baseline cortical
      microperfusion for 10 or 15 min resulted in ischemic neuronal damage in the
      hippocampus and caudoputamen. The frequency and the severity of neuronal damage
      were similar in wild-type and knockout mice. Proliferation of reactive astrocytes
      in the hippocampus was also similar in both types of mice. Therefore, it is
      highly unlikely that ICAM-1 plays a key role in delayed neuronal death after
      transient global ischemia or in astroglial responses after ischemic neuronal
      injury.

PMID- 10575086
TI  - GABA(B) receptor activation inhibits N- and P/Q-type calcium channels in cultured
      lamprey sensory neurons.
AB  - In lamprey, sensory transmission from mechanosensory receptors (dorsal cells) to
      central neurons is presynaptically inhibited by GABA(B) receptor activation. The
      mechanisms underlying this effect were investigated using isolated dorsal cells,
      where voltage-dependent calcium currents were recorded in the whole-cell
      configuration. Activation of GABA(B) receptors by baclofen decreased the peak
      amplitude of high voltage-activated (HVA) calcium currents and slowed the
      activation phase. The role of G-proteins in mediating the effects of baclofen was
      examined. Intracellular dialysis of GTPgammaS occluded the effects of baclofen.
      Intracellular dialysis of GDPbetaS and preincubation in pertussis toxin both
      attenuated the effect of baclofen. Specific calcium channel blockers were used to
      study the types of HVA calcium channels involved in the GABA(B)-mediated
      modulation. The baclofen-induced inhibition was not affected by the L-type
      calcium channel antagonist nimodipine, but was partially blocked by the N-type
      blocker omega-conotoxin GVIA, and completely occluded by omega-conotoxin MVIIC, a
      blocker of both N- and P/Q-type channels. The pharmacology of dorsal cell GABA(B)
      receptors was studied using two agonists, baclofen and CGP 27492, and four
      antagonists, CGP 35348, CGP 55845, phaclofen and saclofen. The inhibition induced
      by either of the two agonists was blocked by CGP 55845, phaclofen and saclofen.
      The antagonist CGP 35348 completely blocked the inhibition of HVA calcium current
      induced by the agonist CGP 27492, but had no effect on baclofen-induced GABA(B)
      receptor activation. This study thus demonstrates that GABA(B) receptor
      activation in lamprey mechanosensory neurons inhibits N- and P/Q-type calcium
      channels in a voltage- and G-protein-dependent manner.

PMID- 10575087
TI  - Transgenic rescue of SNAP-25 restores dopamine-modulated synaptic transmission in
      the coloboma mutant.
AB  - Many of the molecular components constituting the exocytotic machinery
      responsible for neurotransmitter release have been identified, yet the precise
      role played by these proteins in synaptic transmission, and their impact on
      neural function, has not been resolved. The mouse mutation coloboma is a
      contiguous gene defect that leads to electrophysiological and behavioral deficits
      and includes the gene-encoding SNAP-25, an integral component of the synaptic
      vesicle-docking/fusion core complex. The involvement of SNAP-25 in the
      hyperactive behavior of coloboma mice, which can be ameliorated by the indirect
      dopaminergic agonist, amphetamine, has been demonstrated by genetic rescue using
      a SNAP-25 transgene. Coloboma mice also exhibit increased recurrent inhibition,
      reduced theta rhythm by tail-pinch and reduced long-term potentiation in the
      hippocampal dentate gyrus that, as the hyperkinesis seen in these mutants
      suggests, may reflect impaired monoaminergic modulation. We sought to identify
      neurophysiological correlates of the rescued hyperactivity within hippocampal
      synaptic circuitry of SNAP-25 transgenic coloboma mutant mice. In contrast to the
      differences between coloboma and wild-type mice, there was no significant
      difference in the duration or amplitude of theta rhythmic activity (4-6 Hz)
      induced by tail-pinch (10 s), afferent-evoked field potentials, or paired-pulse
      responses recorded in the dentate gyrus of SNAP-25 transgenic coloboma and wild
      type mice. Amphetamine (3.0 mg/kg, i.p.) produced disinhibition of dentate paired
      pulse responses in both SNAP-25 transgenic and wild-type mice but increased
      inhibition in non-transgenic coloboma mice. These findings support the hypothesis
      that alteration of monoaminergic neurotransmission, which can be reversed by the
      indirect agonist, amphetamine, is particularly sensitive to alterations in the
      expression of SNAP-25.

PMID- 10575088
TI  - Glial cell line-derived neurotrophic factor-like immunoreactivity in human
      trigeminal ganglion and nucleus.
AB  - Glial cell line-derived neurotrophic factor (GDNF) is shown by
      immunohistochemistry in human trigeminal sensory system from 22 weeks of
      gestation to adulthood. In the trigeminal ganglion, a distinct subpopulation of
      GDNF-positive neurones is observed, which amounts to about 15% at early pre-term
      and adult ages and peaks to around 30% at perinatal ages. Labelled neurones are
      mostly small- and medium-sized. Occasionally, Schwann and satellite cells are
      stained. GDNF/substance P (SP) and GDNF/calcitonin gene-related peptide (CGRP)
      double stained neurones occur at all ages examined, whereas GDNF/trkA coexistence
      can be observed in pre- and full-term newborns only. Centrally, GDNF
      immunostained fibers and terminal-like structures are mainly restricted to the
      spinal trigeminal nucleus, where they are codistributed with SP and CGRP. In the
      subnucleus caudalis, positive neurones can also be observed both in the
      superficial laminae and in the magnocellular part, with higher frequency in
      adults. These results suggest that GDNF may play a functional role in human
      trigeminal primary sensory neurones throughout life and provide indication for
      its possible involvement in the regulation of pain-related neuronal circuits in
      human trigeminal sensory system.

PMID- 10575090
TI  - Long-term changes in mineralocorticoid and glucocorticoid receptor occupancy
      following exposure to an acute stressor.
AB  - Stressors produce rapid activation of the hypothalamic-pituitary-adrenal axis,
      which typically resolves within 60-90 min following termination of the stressor.
      In addition, some stressors such as inescapable tailshock (IS) also produce
      elevated basal levels of corticosterone (CORT), and reduced serum levels of
      corticosteroid binding globulin (CBG). The elevated basal levels of CORT produced
      by IS are only observed at the trough of the circadian rhythm of CORT secretion,
      and are sustained for 2-3 days following stressor termination. The goal of the
      following experiments was to determine the extent to which the elevated basal
      levels of CORT observed following IS exposure produced greater corticosteroid
      receptor occupancy in the brain and pituitary. To do so, rats (n=8-10 per group)
      received either sham or bilateral adrenalectomy (with CORT replacement in their
      drinking water; 25 microg/ml) and were given 3 days to recover. Rats were then
      exposed to 100 ISs (1.6 mA, 5 s each) administered on a 60 s variable intertrial
      interval, or remained in their home cages. As seen previously, IS produced an
      increase in basal CORT (5 microg/dl) and a decrease in CBG (30% decrease). Rats
      were sacrificed 24 h following IS for trunk blood samples and brain dissections.
      IS exposure had very little effect on corticosteroid receptor protein expression
      as determined by mineralocorticoid receptor (MR) and glucocorticoid receptor (GR)
      binding levels in ADX rats. In addition, no changes in whole cell GR levels (as
      detected by Western blot) were observed in sham rats exposed to IS. On the other
      hand, IS exposure led to greater occupancy of MR (ranging from 25%-50%) in
      hippocampus, hypothalamus, pituitary, and posterior cortex. IS also produced
      greater occupancy of GR (approximately 20%) in hypothalamus and posterior cortex.
      These long-term changes in corticosteroid receptor activation, evident 24 h after
      IS exposure, may be responsible for some of the long-term neural, behavioral and
      immune changes observed following this acute stress procedure.

PMID- 10575089
TI  - Free radicals and lipid peroxidation do not mediate beta-amyloid-induced neuronal
      cell death.
AB  - "beta Amyloid (Abeta)-induced free radical-mediated neurotoxicity" is a leading
      hypothesis as a cause of Alzheimer's disease (AD). Abeta increased free radical
      production and lipid peroxidation in PC12 nerve cells, leading to increased 4
      hydroxy-2-nonenal (HNE) production and modification of specific mitochondrial
      target proteins, apoptosis and cell death. Pretreatment of the cells with
      isolated ginkgolides, the anti-oxidant component of Ginkgo biloba leaves, or
      vitamin E, prevented the Abeta-induced increase of reactive oxygen species (ROS).
      Ginkgolides, but not vitamin E, inhibited the Abeta-induced HNE modification of
      mitochondrial proteins. However, treatment with these anti-oxidants did not
      rescue the cells from Abeta-induced apoptosis and cell death. These results
      indicate that free radicals and lipid peroxidation may not mediate Abeta-induced
      neurotoxicity.

PMID- 10575091
TI  - Septo-hippocampal drug interactions in post-trial memory processing.
AB  - To determine if serotonin and GABA regulate post-trial memory processing of the
      cholinergic projection from the septum to the hippocampus, mice were trained on
      footshock avoidance in a T-maze. Immediately after training, drugs were injected
      into the septum, hippocampus or both. Retention was tested 1 week after training
      and drug administration. Ketanserin, a serotonin type 2 receptor antagonist at a
      dose of 0.5 ng, had no measurable effect on retention, but it reduced the dose of
      bicuculline, in the septum, or arecoline in the hippocampus that was needed to
      improve retention. DOI, a serotonin type 2 receptor agonist at a dose of 2.5 ng,
      had the opposite effect of increasing the doses of bicuculline and arecoline
      needed to improve retention. Bicuculline, a GABA(A) receptor antagonist at a dose
      of 0.1 pg, did not affect retention when injected alone into the septum, but it
      reduced the dose of arecoline needed to improve retention in the hippocampus.
      Muscimol, a GABA(A) receptor agonist at a dose of 5 ng, injected into the septum,
      increased the dose of arecoline needed to improve retention. The results of this
      study are compatible with models that propose that serotonin innervation from the
      median raphe drives GABA interneurons in the medial septum that synapse on
      cholinergic neurons projecting to the hippocampus.

PMID- 10575092
TI  - Congenital hypothyroidism impairs response alternation discrimination behavior.
AB  - The behavior of six congenitally hypothyroid and six normal control rats was
      assessed under forced alternation fixed-ratio, alternating lever cyclic-ratio
      (ALCR) and progressive-ratio schedules of reinforcement. Hypothyroidism was
      produced by adding methimazole (MMI) to the drinking water of pregnant dams from
      embryonic day 16 to postnatal day 25. There were no differences in behavioral
      performance between MMI-treated and control animals under the fixed-ratio and
      progressive ratio schedules. There were also no differences in circulating
      triiodothyronine levels between groups at the end of the study. Under the ALCR
      schedule, when alternation of responding was forced during the first three cycles
      but both levers (choice) were presented during the last three cycles (correct
      lever active), the entire control group reached a competency criteria in nine
      sessions. In contrast, only two MMI-treated animals reached criteria after 17
      sessions, and the remaining four MMI-treated animals did not reach criteria by 30
      sessions of training. These results suggest that congenital hypothyroidism
      impairs learning when a discrimination between correct and incorrect operanda is
      made available.

PMID- 10575093
TI  - Chronic dexamethasone treatment potentiates insult to olfactory receptor cells
      produced by 3-methylindole.
AB  - The effect of chronic dexamethasone treatment on damage to olfactory receptor
      cells produced by 3-methylindole (3-MI) was examined. Twelve rats were injected,
      every other day, with dexamethasone (1.5 mg/kg, i.p.), and 12 rats with saline
      alone. Injections began 1 week before and continued, in different rats, from 1 to
      4 weeks after a single intraperitoneal administration of 150 mg/kg 3-MI. One,
      two, three, and four weeks after exposure to 3-MI, different groups of rats,
      three specimens per each treatment condition, received bilateral application of
      horseradish peroxidase to the olfactory mucosa and were subsequently sacrificed.
      Anterograde labeling of primary afferents, i.e., an inverse correlate of the
      degree of cellular damage, was quantitatively determined by measuring the mean
      optical density (MOD) of staining in sections of the olfactory bulb. In saline
      injected rats, the MOD values were 27.0, 46.6, 87.1, and 104.7 for one, two,
      three, and four post-3-MI weeks, respectively. The corresponding values in the
      dexamethasone-treated rats were 15.7, 29.7, 87.5, and 110.5. The MOD values of
      the dexamethasone-injected rats were significantly lower than those of the saline
      injected rats for post-3-MI weeks 1 and 2, indicative of stronger damage to
      olfactory receptor cells in the rats treated with the glucocorticoid. The data
      suggest that dexamethasone potentiates the 3-MI olfactotoxicity during the first
      2 weeks after insult. This effect, at least partly, may be due to the inducing
      action of dexamethasone on the cytochrome P450 responsible for metabolic
      bioactivation of 3-MI.

PMID- 10575095
TI  - Bombesin microinjection into the basolateral amygdala influences feeding behavior
      in the rat.
AB  - It has been demonstrated that the basolateral amygdala (ABL) represents a satiety
      mechanism. Experimental data indicate that peripheral or central applications of
      neuropeptide bombesin (BN) and BN-like peptides inhibit feeding. Since the
      amygdala (AMY) is rich in BN-like immunoreactive elements, the present study was
      performed to determine whether 10 or 40 ng doses of BN microinjected bilaterally
      into the ABL could modify solid food intake. Twenty nanograms of BN (10 ng per
      injection site) in 24-h deprived rats caused transient inhibition of food intake
      and 80 ng resulted in a significant reduction of food consumption for 1 h. This
      inhibitory effect of BN on feeding was eliminated by prior BN antagonist
      treatment. Results of behavioral tests showed that BN microinjections into the
      ABL specifically reduced food intake without altering behavioral patterns or
      influencing the body temperature. Present results suggest that BN-like peptides
      may act as a complex satiety signal in the ABL.

PMID- 10575094
TI  - Role of insulin-like growth factor binding proteins in limitation of IGF-I
      degradation into the N-methyl-D-aspartate receptor antagonist GPE: evidence from
      gonadotrophin-releasing hormone secretion in vitro at two developmental stages.
AB  - We showed previously that insulin-like growth factor-I (IGF-I) could inhibit the
      secretion of gonadotrophin-releasing hormone (GnRH) evoked in vitro by N-methyl-D
      aspartate (NMDA) or veratridine depolarization. Such an IGF-I effect appeared to
      be mediated by its physiological breakdown product, the N-terminal tripeptide
      GPE. That effect was developmentally regulated since IGF-I could inhibit GnRH
      secretion from hypothalamic explants of 50-day-old adult rats but not from
      immature 15-day-old explants. We hypothesized that the IGF-binding proteins (BPs)
      could limit the peptide availability to endopeptidases and account for the absent
      IGF-I effects at 15 days. In this paper, we show that the inhibition of GnRH
      secretion by 10(-10) M of IGF-I at 50 days is prevented in a dose-dependent
      manner by 0.3 to 3 nM of IGF-BP2 as well as IGF-BP3. The inhibition caused by 10(
      10) M of GPE is not affected under similar conditions. Using explants obtained at
      15 days, a significant inhibition of GnRH secretion can be obtained by 10(-10) M
      of IGF-I in the presence of an anti IGF-BP2 antiserum used at 1:3000 and 1:1000
      concentrations. These data indicate that in the immature rat brain, the IGF-BPs
      could act as modulators of IGF-I degradation into its subproduct GPE, a possible
      endogenous antagonist at NMDA receptors.

PMID- 10575096
TI  - Effect of intracerebral norepinephrine depletion on outcome from severe forebrain
      ischemia in the rat.
AB  - Manipulations of plasma catecholamine concentrations influence outcome from
      ischemic brain insults. It has been suggested that these effects are mediated by
      influences on brain catecholamine concentrations. This study examined whether
      major changes in brain norepinephrine concentrations can alter outcome from
      severe forebrain ischemia. Sprague-Dawley rats were administered 50 mg/kg i. p. N
      (chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) or were left untreated
      (control). One week later, these rats were subjected to either 7 or 8 min of
      normothermic forebrain ischemia (bilateral carotid occlusion and MABP=30 mmHg)
      and allowed to recover for 4 days. Histologic damage was then evaluated. In other
      control and DSP-4-treated animals, hippocampal microdialysate norepinephrine
      concentrations were measured before, during and after 8 min of forebrain
      ischemia. Norepinephrine concentrations were also determined in brain homogenates
      from non-ischemic DSP-treated and control rats. A 95% depletion of norepinephrine
      was observed in brain homogenates from non-ischemic DSP-4-treated rats compared
      with control. During ischemia, microdialysate norepinephrine concentrations
      increased in control but not in DSP-4-treated rats (P=0.002). For plasma, intra
      ischemic epinephrine concentrations increased 8-10-fold and returned to baseline
      values post-ischemia with no differences between groups. Plasma norepinephrine
      values remained unchanged in both groups. Histologic damage resulting from either
      7 or 8 min of ischemia in hippocampal structures, caudoputamen, and neocortex was
      similar between DSP-4-treated and control groups. This study could not identify
      any effect of major changes in brain norepinephrine concentrations on ischemic
      brain damage. These data indicate that peripheral catecholamine effects on near
      complete forebrain ischemic outcome are unlikely to be mediated by effects on
      central catecholamine concentrations.

PMID- 10575097
TI  - Melittin enhances amino acid and free fatty acid release from the in vivo
      cerebral cortex.
AB  - The effects of the phospholipase activator melittin on amino acid and free fatty
      acid release from the rat cerebral cortex were monitored and compared with those
      of a secretory PLA(2), using a cortical cup technique with topical application of
      these agents in artificial cerebrospinal fluid. Melittin (10 microg/ml; 3.5
      microM) elicited a rapid increase in the levels of superfusate amino acids;
      aspartate, glutamate, GABA, glycine, taurine, glutamine, phosphoethanolamine,
      alanine, serine and the free fatty acids arachidonic, linoleic, palmitic and
      oleic acid. PLA(2) (25 microg/ml) also enhanced amino acid efflux but its effects
      were significantly slower to develop than those of melittin. The results confirm
      previous indications of an ability of phospholipases to augment extracellular
      levels of several amino acids, including the excitotoxins glutamate and
      aspartate, and further implicate phospholipase activation as a significant
      contributor to cerebral ischemic injury. Melittin has the potential to be a
      useful tool with which to evaluate the role of phospholipases in ischemia injury.

PMID- 10575098
TI  - Interleukin-6 increases sensitivity to the locomotor-stimulating effects of
      amphetamine in rats.
AB  - Interleukin (IL)-6 mediates brain-immune interactions, influences the survival of
      postnatal mesencephalic and basal forebrain cells, influences mesocorticolimbic
      dopamine and serotonin neurotransmission, and is linked with various central
      nervous system disorders. In the present study, single injections of IL-6 (1 or 2
      microg/Long-Evans rat, i.p.) induced modest elevations of locomotor activity. The
      locomotor increases were not augmented by repeated intermittent injections of IL
      6 (five daily injections; 1 microg/rat), however. Nonetheless, repeated IL-6
      treatment increased sensitivity to the locomotor-stimulating effects of 1.0 and
      0.5 mg/kg amphetamine, when tested 5, 7, or 14 days following interruption of the
      cytokine treatment. The ability of acute IL-6 injections to alter locomotor
      activity and the ability of repeated IL-6 injections to produce long-lasting
      sensitization to the locomotor-stimulating effects of amphetamine suggest an
      interaction of this cytokine with the mesolimbic dopamine system, a system
      implicated in aspects of schizophrenia, addiction, and movement disorders. The
      fact that IL-6 caused a lasting change in responsiveness to amphetamine implies a
      mechanism by which immunogenic stimuli can alter brain circuitry, changing its
      sensitivity to seemingly unrelated subsequent stimuli or events.

PMID- 10575099
TI  - Threshold relationship between lesion extent of the cholinergic basal forebrain
      in the rat and working memory impairment in the radial maze.
AB  - The cholinergic basal forebrain (CBF) degenerates in Alzheimer's Disease (AD),
      and the degree of this degeneration correlates with the degree of dementia. In
      the present study we have modeled this degeneration in the rat by injecting
      various doses of the highly selective immunotoxin 192 IgG-saporin (192-sap) into
      the ventricular system. The ability of 192-sap-treated rats to perform in a
      previously learned radial maze working memory task was then tested. We report
      here that 192-sap created lesions of the CBF and, to a lesser extent, cerebellar
      Purkinje cells in a dose-dependent fashion. Furthermore, we found that rats
      harboring lesions of the entire CBF greater than 75% had impaired spatial working
      memory in the radial maze. Correlational analysis of working memory impairment
      and lesion extent of the component parts of the CBF revealed that high-grade
      lesions of the hippocampal-projecting neurons of the CBF were not sufficient to
      impair working memory. Only rats with high-grade lesions of the hippocampal and
      cortical projecting neurons of the CBF had impaired working memory. These data
      are consistent with other 192-sap reports that found behavioral deficits only
      with high-grade CBF lesions and indicate that the relationship between CBF lesion
      extent and working memory impairment is a threshold relationship in which a high
      degree of neuronal loss can be tolerated without detectable consequences.
      Additionally, the data suggest that the CBF modulates spatial working memory via
      its connections to both the hippocampus and cortex.

PMID- 10575100
TI  - Ischemic "cross" tolerance in hypoxic ischemia of immature rat brain.
AB  - The phenomenon of ischemic tolerance has been closely associated with the
      expression of heat shock proteins but recently, stress tolerance not related to
      hsp72 has been reported. In the present study, we focused on ischemic tolerance
      induced by hypoxia and hyperthermia in neonatal rat brain and analyzed the
      expression of hsp72. In a neonatal rat model of hypoxic ischemia (H-I),
      preconditioning by whole-body hyperthermia or hypoxia was induced 24 h prior to
      the ischemia. Brain damage was histologically evaluated and the expressions of
      hsp72 were analyzed. Hyperthermic preconditioning at 41 degrees C for 15 min, as
      well as hypoxic preconditioning with 8% hypoxia for 3 h, had almost complete
      neuroprotective effects. However, we failed to detect the expression of hsp72 in
      any of preconditioning. Only the H-I insult itself induced hsp72 in the dorsal
      striatum and slightly in the thalamus and the hippocampus. Hyperthermic
      preconditioning has neuroprotective effects which are comparable to hypoxic
      preconditioning in immature brain. The expression of hsp72 is not likely
      necessary for the ischemic tolerance in immature brain.

PMID- 10575101
TI  - N-ethylmaleimide selectively blocks presynaptic GABA-B autoreceptor but not
      heteroreceptor-mediated inhibition in adult rat striatal slices.
AB  - Intracellular recording techniques were used in slices of adult rat striatum to
      compare the sensitivity of presynaptic gamma-aminobutyric acid type B (GABA-B)
      autoreceptor and heteroreceptor-mediated inhibition to the sulfhydryl alkylating
      agent, N-ethylmaleimide (NEM). NEM (100 microM) alone had no significant effect
      on resting potential or input resistance and did not consistently effect stimulus
      evoked responses. Treatment of slices with NEM for up to 1 h, either in the
      presence or the absence of the GABA-B receptor-specific agonist, baclofen (BAC;
      100 microM), completely blocked the BAC-induced depression of inhibitory, but not
      excitatory, postsynaptic potentials. This differential sensitivity to NEM
      alkylation suggests that in the adult rat striatum, the presynaptic GABA-B
      autoreceptors and heteroreceptors may exhibit distinct receptor-effector coupling
      mechanisms.

PMID- 10575102
TI  - Prevention of 6-hydroxydopamine-induced rotational behavior by BDNF somatic gene
      transfer.
AB  - Brain-derived neurotrophic factor (BDNF) was expressed via injection of viral
      vector into the substantia nigra pars compacta (SNc) to investigate its influence
      on nigrostriatal dopaminergic activity and locomotor behavior. The recombinant
      adeno-associated virus (rAAV) vector, pTR-BDNFmyc, incorporated the neuron
      specific enolase (NSE) promoter and the internal ribosome entry site (IRES)
      element driving expression of both epitope-tagged BDNF and green fluorescent
      protein (GFP) bicistronically. The control vector, pTR-UF4, incorporated NSE
      promoter-driven GFP expression only. Transgene expression persisted in both
      vector groups throughout the 9 month course of the study. Partial 6
      hydroxydopamine (6-OHDA) lesions were conducted in the SNc ipsilateral to, and 6
      months after, transduction with either the pTR-BDNFmyc or the pTR-UF4. Transgenic
      BDNFmyc had no effect on the number of tyrosine hydroxylase (TH)-labeled neurons
      in the SNc after 6-OHDA-lesions, but did block the amphetamine-induced,
      ipsiversive, turning-behavior caused by the lesion in the pTR-UF4 group. The
      BDNFmyc-transduced group also demonstrated more locomotor activity and rotational
      activity contralateral to the lesioned side than did the pTR-UF4-transduced
      group. Long-term, stable expression of BDNF can therefore modulate locomotor
      activity without significantly affecting nigrostriatal dopaminergic survival.

PMID- 10575103
TI  - Excitability of spinal cord and gracile nucleus neurons in rats with chronically
      injured sciatic nerve examined by c-fos expression.
AB  - Low-threshold sensory pathways have been suggested to have an important role in
      the formation and maintenance of sensory abnormalities which are observed after
      peripheral nerve injury. Fos-like immunoreactive (Fos-LI) neurons are expressed
      in spinal cord laminae III-IV and the gracile nucleus by electrically stimulating
      the injured nerves at Abeta strength after sciatic nerve transection in rats.
      This suggests that the excitability of these neurons is increased by nerve
      injury. In this study, we investigated which receptors are involved in the
      regulation of the increased excitability in spinal and gracile nucleus neurons.
      The sciatic nerve of Sprague-Dawley rats (150 g) was transected 7 days before the
      experiment day. The rats were administered morphine, muscimol, baclofen, MK-801,
      CNQX, N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) or clonidine
      i.p., and then electrically stimulated at 0.1 mA to the proximal region to the
      nerve injury site under urethane anesthesia. Two hours after the stimulation, Fos
      LI expression was increased in the spinal cord dorsal horn and the gracile
      nucleus in control rats. Baclofen inhibited the Fos-LI expression both in the
      spinal cord and the gracile nucleus. Morphine inhibited only the Fos-LI
      expression in the posterior cutaneous (PC) nerve territory of laminae I-II, but
      not in the sciatic nerve (SC) territory, laminae III-IV nor the gracile nucleus.
      MK-801 had an inhibitory but complicated effect in laminae I-II and the gracile
      nucleus. The other drugs were not effective on Fos-LI expression. It is suggested
      that the GABA(B) receptor has a pivotal role in the regulation of Fos-LI
      expression after electrical stimulation to the injured low-threshold sensory
      fibers, and other receptors have little effect on the Fos-LI expression.

PMID- 10575104
TI  - Abnormal Ca(2+) regulation in oligodendrocytes from the dysmyelinating jimpy
      mouse.
AB  - Jimpy (jp) is a point mutation in the gene on the X chromosome which codes for
      the major myelin proteolipid protein. Most oligodendrocytes (OLs) in the jp mouse
      undergo cell death at the time when they should be actively myelinating. Loss of
      mature OLs results in severe CNS dysmyelination. Dying jp OLs have the morphology
      of apoptotic cells but it is not clear how the mutation activates biochemical
      pathways which lead to programmed death of OLs in jp CNS. There is compelling
      evidence from a number of systems that high levels of intracellular Ca(2+)
      ([Ca2+]i) can activate downstream processes which result in both apoptotic and
      necrotic cell death. To determine whether [Ca2+](i) dysregulation might be
      involved in the death of jp OLs, we used ratiometric imaging to determine levels
      of [Ca2+](i) in OLs cultured from jp and normal CNS and in immortalized cell
      lines derived from jp and normal OLs. Immortalized jp OLs and OLs isolated
      directly from jp brain both showed a similar elevation in [Ca2+](i) ranging from
      60% to 150% over control values. A higher baseline [Ca2+](i) in jp OLs might
      increase their vulnerability to other insults due to abnormal protein processing
      or changes in signaling pathways which act as a final trigger for cell death.

PMID- 10575105
TI  - Receptor tyrosine kinase tie 1 mRNA is upregulated on cerebral microvessels after
      embolic middle cerebral artery occlusion in rat.
AB  - Tie 1 is an endothelial specific transmembrane receptor tyrosine kinase and may
      be required during angiogenesis. Using in situ hybridization, we measured tie 1
      mRNA in ischemic brain (n=15). Rats were subjected to middle cerebral artery
      (MCA) occlusion by a single fibrin rich clot. Expression of tie 1 was not
      detected in non ischemic brain. Cerebral microvessels expressed tie 1 in the
      ischemic lesion as early as 2 h after MCA occlusion. The number of microvessels
      containing tie 1 mRNA decreased in the ischemic lesion at 8 h after MCA
      occlusion. However, expression of tie 1 increased on microvessels at 24 h and 14
      days after ischemia and tie 1 was primarily localized to the microvessels
      bordering pan necrotic tissue. Ninety-seven percent of cerebral vessels which
      expressed tie 1 mRNA had diameters of 3.7+/-0.17 microm. Our findings suggest a
      role for tie 1 in cerebral microvascular remodeling after embolic stroke.

PMID- 10575106
TI  - Synchronous changes in ear and tail blood flow following salient and noxious
      stimuli in rabbits.
AB  - Simultaneous recordings were made of ear and tail blood flow during alerting
      responses to salient environmental stimuli in conscious rabbits, and during
      electrical stimulation of the spinal trigeminal tract and raphe pallidus in
      anesthetized rabbits. Blood flow fell in a highly correlated manner (Pearson
      coefficient ranging from 0.52 to 0.95) in these experimental situations. Salient
      stimuli in conscious rabbits, and noxious stimuli in anesthetized rabbits appear
      to cause a generalized vasoconstriction in cutaneous beds.

PMID- 10575107
TI  - Formation of free hydroxyl radicals after pentylenetetrazol-induced seizure and
      kindling.
AB  - The present study indicates that free radicals have been implicated in
      pentylenetetrazol (PTZ)-induced seizure and kindling. In our experiments we used
      a method in which free hydroxyl radicals (* OH) are trapped by systemically
      applied salicylate in vivo, resulting in the stable and quantifiable products, 2,
      3-dihydroxybenzoic acid (DHBA) and 2,5-DHBA. We investigated the formation of
      both 2,3- and 2,5-DHBA in the whole brain (without cerebellum) of rats treated
      with an acute seizure-inducing dose of 48 mg/kg PTZ and in PTZ-kindled animals
      which were injected with the kindling dose of 37.5 mg/kg PTZ at different times
      after the last PTZ injection. An increase of * OH was observed in kindled rats
      compared with acutely convulsing animals when the PTZ application was performed 1
      min after the salicylate treatment. The amount of DHBAs increased significantly
      in both convulsed groups 30 min after the application of PTZ compared with
      animals treated with NaCl instead of PTZ. Sixty minutes after PTZ the DHBA levels
      normalized to NaCl control values.

PMID- 10575108
TI  - Decline in brainstem auditory-evoked potentials coincides with loss of spiral
      ganglion cells in arylsulfatase A-deficient mice.
AB  - Arylsulfatase A (ASA)-deficient mice constitute an animal model for the inherited
      lysosomal storage disease, metachromatic leukodystrophy (MLD). Brainstem auditory
      evoked potentials (BAEPs) were recorded in control and ASA-deficient mice of 3,
      6, 9 and 12 months. BAEPs were evoked in control mice of all ages studied, but
      were completely absent in ASA (-/-) mice of 9 and 12 months. A significant delay
      in the wave pattern was noted in 6-month-old ASA (-/-) mice. Histological
      examination and morphometric analysis showed that the decline of BAEPs in ASA (-/
      ) mice was paralleled by a decrease in spiral ganglion cell numbers.

PMID- 10575109
TI  - Cytochrome c redistribution in apoptosis of guinea pig vestibular hair cells.
AB  - We examined the cellular location of cytochrome c in healthy and in streptomycin
      damaged vestibular hair cells by immunohistochemistry. Staining for cytochrome c
      revealed an immunostain pattern that was consistent with a mitochondrial
      distribution of this enzyme in healthy hair cells, while in hair cells affected
      by aminoglycosides, a diffuse distribution in the cytoplasm was found together
      with apoptotic nuclear morphology. These findings suggest that redistribution of
      cytochrome c is involved in the pathway of apoptosis in vestibular hair cells
      induced by aminoglycosides.

PMID- 10575110
TI  - Influence of contralateral acoustic stimulation on distortion-product and
      spontaneous otoacoustic emissions in the barn owl.
AB  - The avian auditory papilla provides an interesting object on which to study
      efferent influences, because whereas a significant population of hair cells in
      birds is not afferently innervated, all hair cells are efferently innervated
      (Fischer, 1992, 1994a, b). Previous studies in mammals using contralateral sound
      to stimulate the efferent system demonstrated a general suppressive effect on
      spontaneous and click-evoked, as well as on distortion-product otoacoustic
      emissions (DPOAE). As little is known about the effects of contralateral
      stimulation on hearing in birds, we studied the effect of such stimuli (broadband
      noise, pure tones) on the amplitude of the DPOAE 2f(1)-f(2) and on spontaneous
      otoacoustic emissions (SOAE) in the barn owl, Tyto alba. For the DPOAE
      measurements, fixed primary-tone pairs [f(1)=8.875 kHz (ratio=1.2), f(1)=8.353
      kHz (ratio=1.15) and f(1)=7.889 kHz (ratio=1.1)] were presented and the DPOAE
      measured in the presence and absence of continuous contralateral stimulation. The
      DPOAE often declined in amplitude but in some cases we observed DPOAE
      enhancement. The changes in amplitude were as large as 9 dB. The influence of the
      contralateral noise changed over time, however, and the effects of contralateral
      tones were frequency-dependent. SOAE were suppressed in amplitude and shifted in
      frequency by contralateral broadband noise. Control measurements in animals after
      middle-ear muscle resection showed that these phenomena were not attributable to
      the acoustic middle-ear reflex. The finding of DPOAE enhancement is interesting,
      because a type of efferent fiber that suppressed its discharge rate during
      stimulation has been described in birds (Kaiser and Manley, 1994).

PMID- 10575111
TI  - D-Methionine protects against cisplatin damage to the stria vascularis.
AB  - D-Methionine (D-met) protects against cisplatin (CDDP)-induced hearing loss and
      outer hair cell loss (Campbell et al., 1996). However, D-met's protective effects
      on the stria vascularis has not been previously investigated. The purpose of this
      study was to examine, using semi-quantitative analysis, whether D-met also
      protects the stria vascularis. We removed a basal turn section of the stria
      vascularis from five groups of five male Wistar rats each: (1) a CDDP-treated
      control group receiving a 30 min i.p. infusion of 16 mg/kg CDDP, (2) a saline
      injected control group receiving an equivalent volume of saline, and (3) three
      groups injected with either 75, 150, or 300 mg/kg D-methionine (D-met) i.p. 30
      min prior to receiving the 16 mg/kg CDDP dosing. Using transmission electron
      microscopy and light microscopy, we analyzed strial volume (i.e. edema), marginal
      cell damage classification (bulging and/or compression), and relative optical
      density (ROD) ratios (i.e. depletion of marginal cell cytoplasmic organelles).
      All three levels of D-met provided complete protection against marginal cell
      bulging and/or compression but only partial protection against strial edema. At
      300 mg/kg, D-met significantly reduced ROD ratio degradation in the spiral
      prominence and middle stria vascularis regions. In Reissner's membrane region,
      values from the D-met pretreated group were not significantly different from
      either the treated or untreated control groups suggesting only partial protection
      for that area. Protection of marginal cell cytoplasmic organelles was also noted.
      In summary, D-met partially or fully protects the stria vascularis from several
      types of CDDP-induced damage.

PMID- 10575112
TI  - Effects of interaural time differences on the responses of chinchilla inferior
      colliculus neurons to consonant-vowel syllables.
AB  - The responses of 100 inferior colliculus neurons to syllables differing in voice
      onset time (VOT) presented binaurally were studied. As in a previous study of
      monaural responses (Chen et al., 1996), the responses consisted of 1-3 response
      'components', referred to as release responses, VOT responses or vowel responses.
      The discharge rate of all response components could vary cyclically with the
      interaural time difference (ITD). The maximal rate often occurred at an ITD
      around +0.2 ms (contralateral ear leading). Response frequencies (RF) based on
      the periodicity of the delay curves varied with the characteristic frequency (CF)
      and VOT. RF also varied across response components. Overall, RF was correlated
      with the 'most effective frequency', the spectral component with the highest
      amplitude, relative to the tuning curve. VOT response latency for a given
      syllable could change by a few ms with ITD, but those changes were small,
      relative to the range of latencies observed over the entire range of VOTs.
      Changes in ITD produced large changes in the overall shape of the peristimulus
      time histogram. There was no relation between the histogram shape and perceptual
      consonant categories.

PMID- 10575113
TI  - Tonotopic changes in 2-deoxyglucose activity in chick cochlear nucleus during
      hair cell loss and regeneration.
AB  - Following cochlear ablation, auditory neurons in the central nervous system (CNS)
      undergo alterations in morphology and function, including neuronal cell death.
      The trigger for these CNS changes is the abrupt cessation of eighth nerve fiber
      activity. Gentamicin can cause ototoxic damage to cochlear hair cells responsible
      for high frequency hearing. In birds, these hair cells can regenerate. Therefore,
      gentamicin causes a partial, yet reversible insult to the ear. It is not known
      how this partial hair cell damage affects excitatory input to the cochlear
      nucleus. We examined chick cochlear nucleus activity during hair cell loss and
      regeneration by measuring 2-deoxyglucose (2DG) uptake. Normal animals showed a
      rostral to caudal gradient of 2DG activity, with higher activity in caudal
      regions. When hair cells are damaged (2, 5 days), 2DG uptake is decreased in
      cochlear nucleus. When hair cells regenerate (9, 16, 28 days), 2DG uptake returns
      to control levels. This decrease and subsequent return of activity only occurs in
      the rostral, high frequency region of the cochlear nucleus. No changes are seen
      in the caudal, low frequency region. These results suggest that changes in
      activity of cochlear nucleus occur at a similar time course to anatomical changes
      in the cochlea.

PMID- 10575114
TI  - P2X receptor-mediated changes in cochlear potentials arising from exogenous
      adenosine 5'-triphosphate in endolymph.
AB  - Our previous studies have determined the presence of adenosine 5'-triphosphate
      (ATP) in the cochlear fluids and shown that extracellular ATP introduced into the
      endolymphatic compartment of the guinea pig cochlea has a significant dose
      dependent suppressive effect on both endocochlear potential (EP) and cochlear
      microphonic (CM), which is mediated via P2 receptors. In the present study, the
      influence of P2 receptor agonists and antagonists on this suppressive effect was
      investigated to characterise the subtypes of P2 receptor mediating the ATP
      induced effect on cochlear function. Using a double-barreled pipette attached to
      a pressure injector, small volumes (2-10 nl) of ATP (0.01-1 mM) and P2 receptor
      agonists or P2 receptor antagonists in artificial endolymph were introduced into
      the scala media of the first (basal) and third turns of the guinea pig cochlea,
      while the EP and CM were monitored. ATP and P2 receptor agonists (5x10(-14)-1x10(
      11)cibacron blue. Neither adenosine nor uridine 5'-triphosphate (2x10(-13)-2x10(
      11) moles) nor the P2 receptor antagonists on their own had any effect on EP and
      CM. The ATP effect on the potentials was greater at the third cochlear turn when
      compared to the first turn. These results provide evidence that in the
      endolymphatic compartment of the guinea pig, the extracellular ATP effect on
      cochlear function is likely mediated through an interaction with P2 receptors
      which assemble as ATP-gated ion channels.

PMID- 10575115
TI  - Distortion product otoacoustic emissions and outer hair cell defects in the
      hyt/hyt mutant mouse.
AB  - Thyroid hormone plays an important role in hearing development. Hereditary
      hypothyroidism is frequently associated with sensorineural hearing loss as
      identified in both animal models and human patients. Building upon our original
      demonstration of congenital deafness and hair cell abnormality in a hyt/hyt mouse
      model which carries an autosomal recessive mutation causing hereditary
      hypothyroidism, we investigated the functional capacity of the outer hair cell
      (OHC) system in these animals using distortion product otoacoustic emissions
      (DPOAEs). In particular, the amplitude and detection features of DPOAEs were
      correlated with measures of the auditory brainstem response (ABR) as well as the
      cellular structure and ultrastructure of the organ of Corti. Input-output (I/O)
      functions for the 2f(2)-f(1) DPOAEs were obtained for frequencies from 2 to 18
      kHz. The thresholds were significantly higher and amplitudes were significantly
      lower in the homozygous mice (hyt/hyt) than in both heterozygous mice (hyt/+) and
      wild-type controls at DPOAE frequencies recorded above 6 kHz. Hearing thresholds
      were significantly elevated in the mutant compared to control mice. In addition,
      morphological studies revealed consistent inner ear defects in hyt/hyt animals
      including distortion of the tectorial membrane, dysplasia of the tunnel of Corti
      and distinct OHC abnormalities. The most striking histopathological finding was a
      contiguous membrane along the apices of all of the OHC stereocilia. Such
      ultrastructural changes in the stereocilia of the OHC may limit the deflection of
      the stereocilia and therefore affect an active cochlear function that produces
      otoacoustic emissions as well as cause a failure to evoke the normal action
      potentials in the auditory nerve. From both functional and morphologic
      evaluations, it was concluded that the OHC system is the most susceptible to the
      developmental effects of congenital hypothyroidism in the hyt/hyt mouse. The
      normal OHCs with well-developed ciliary bundles are crucial to maintain the
      activity of biological mechanisms within the cochlea.

PMID- 10575116
TI  - The neurotrophins act synergistically with LIF and members of the TGF-beta
      superfamily to promote the survival of spiral ganglia neurons in vitro.
AB  - A number of growth factor families have been implicated in normal inner ear
      development, auditory neuron survival and protection. Several growth factors,
      including transforming growth factor-beta5 (TGF-beta5) and TGF-beta3,
      neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF) and leukemia
      inhibitory factor (LIF) were tested for their ability, individually or in
      combination, to promote auditory neuron survival in dissociated cell cultures of
      early rat post-natal spiral ganglion cells (SGCs). The results indicate that at
      discrete concentrations all growth factors act in an additive fashion and some in
      synergy when promoting neuronal survival. These findings support the hypothesis
      that growth factors from different families may be interdependent when sustaining
      neuronal integrity.

PMID- 10575117
TI  - Morphological changes of the endolymphatic sac induced by microinjection of
      artificial endolymph into the cochlea.
AB  - Morphological changes of the endolymphatic sac were analyzed in guinea pigs
      following microinjection of artificial endolymph into the cochlea or withdrawal
      of a quantity of native endolymph. Injections were performed into the second turn
      of scala media with a micro-pump at a rate of 60-100 nl/min, lasting for a period
      of 4, 7. 5, 15 or 18 min. In withdrawal experiments, endolymph was aspirated from
      the second cochlear turn over a period of 8 min. For each procedure the
      contralateral (non-treated) ear served as a histological control. Following
      artificial endolymph injections of 7. 5 min or more there was an almost total
      absence of the normal intraluminal homogeneous substance (HS) on the injected
      side. Our observations suggest that the disappearance of the HS occurs by both
      enzymatic and macrophagic activity. After endolymphatic withdrawals the ES was
      found to contain increased amounts of HS. The results could suggest that the
      volume of fluid in the ES, and hence the volume of the entire membranous
      labyrinth, may be regulated by a dynamic relationship between active secretion
      and enzymatic degradation of a lumen-expanding substance that is intimately
      related to the intraluminal macrophages. The exact mechanism governing these
      regulatory systems, and their relationship to ion and water movements across the
      epithelium of the sac, remain to be elucidated.

PMID- 10575118
TI  - Age-related loss of distortion product otoacoustic emissions in four mouse
      strains.
AB  - Changes in cochlear function in four inbred strains of mice, CBA/CaJ (CBA),
      C57BL/6J (C57), BALB/cByJ (BALB), and WB/ReJ (WB), previously used to study age
      related hearing loss, were evaluated serially as a function of age with 2f(1)
      f(2) distortion-product otoacoustic emissions (DPOAEs). DPOAE levels in response
      to equilevel primary tones for geometric-mean (GM) frequencies from 5.6 to 48.5
      kHz were recorded systematically as DP-grams and response/growth or input/output
      (I/O) functions at monthly intervals from about 2 to 15 months of age. Over the
      approximate 13-month measurement period, CBAs showed robust and unchanged DPOAEs
      for all tested frequencies, while BALBs, C57s, and WBs showed strain-specific,
      age-related decreases in DPOAEs that progressed systematically from the high to
      low frequencies. Specifically, for the youngest WBs at 2 months of age, no DPOAEs
      were recordable for GM frequencies > or = 32 kHz, while C57s and BALBs reached
      the identical stage of cochlear dysfunction by 5 and 8 months, respectively. The
      differential decline in DPOAE activity shown for WB, C57, and BALB mice supports
      the notion that they represent unique animal models of age-related changes in
      cochlear function. In contrast, the unchanging DPOAEs for CBAs over the same time
      period indicate that this strain makes an effective control for normal cochlear
      function in the mouse, at least, up to 15 months of age.

PMID- 10575120
TI  - Basic properties of the sound-evoked post-auricular muscle response (PAMR).
AB  - One objective electrophysiological test for deafness involves presenting a brief
      acoustic stimulus to a subject and measuring the electrical activity evoked in
      the muscle located just behind the ear (the post-auricular muscle or PAM).
      Although this electrical response has been known for many years, it has been
      ignored by most clinicians and frequently misreported in the literature. This
      paper presents the fundamental properties of the PAM electrical response (the
      PAMR) and examines ways in which its measurement can be improved by altering the
      standard electrode position and filtering. The response consists of a simple
      bipolar compound action potential with a first peak latency of between 12.5 and
      15 ms, depending on the stimulus intensity and PAM muscle tone. The largest
      recordings can be made with an active electrode over the PAM and with the
      reference electrode on the dorsal surface of the pinna. It can be obtained with
      click and tone-burst stimuli within 20 dB of the subjective detection threshold,
      can be evoked with tone-bursts between 500 Hz and 16 kHz and grows either
      linearly with the click level or approximately exponentially with the tone-burst
      level, reaching a maximum of as large as 250 microV pp in some subjects. It has a
      frequency spectrum mostly between 25 and 200 Hz. The response is often visible in
      raw recordings, with as few as 20 averages required for obtaining a stable
      waveform. There is very little amplitude and latency difference in stimulating
      the ear on the same side or opposite side to the recording electrodes and the
      binaurally evoked response is similar to the simple arithmetic sum of the
      waveforms obtained with monaural stimulation. The response latency and duration
      are longer in very young infants, but reach adult values by 12 months of age. In
      a companion paper, we describe a method of enhancing the PAMR using lateral eye
      movement (Patuzzi and O'Beirne, 1999a).

PMID- 10575119
TI  - The commissure of probst as a source of GABAergic inhibition.
AB  - Whole-cell patch-clamp recordings were made from neurons in the rat's dorsal
      nucleus of the lateral lemniscus (DNLL) in a brain slice preparation. Planes of
      section were chosen to preserve the integrity of fibers in the commissure of
      Probst (CP) and postsynaptic responses were evoked by electrical stimulation
      along its length. Results showed that the crossed projection to the DNLL through
      the CP is mainly, if not exclusively, inhibitory in the rat. Inhibitory
      postsynaptic responses (IPSPs) evoked by stimulation of the CP were blocked by
      the gamma-aminobutyric acid (GABA)(A) receptor antagonist bicuculline, but were
      unaffected by the glycine receptor antagonist strychnine, supporting the
      conclusion that the crossed inhibitory projection to DNLL from the contralateral
      DNLL is GABAergic. Stimulation of the CP close to the DNLL frequently evoked
      excitatory postsynaptic responses as well as IPSPs, but stimulation near the
      midline evoked IPSPs only. Thus, the excitatory responses probably originated
      from a pathway other than the projection to the DNLL from the contralateral DNLL
      through the CP.

PMID- 10575121
TI  - Effects of eye rotation on the sound-evoked post-auricular muscle response
      (PAMR).
AB  - One objective electrophysiological test for deafness involves presenting a brief
      acoustic stimulus to a subject and measuring the electrical activity evoked in
      the muscle located just behind the ear (the post-auricular muscle or PAM). We
      describe a method for enhancing this post-auricular muscle response (PAMR) using
      lateral eye movement, which increases both the tonic EMG activity in the PAM and
      the magnitude of the PAMR, and decreases response latency. EMG activity in most
      subjects tested (more than 30) increased almost instantly on rotation of the
      eyes, and thereafter grew more slowly with maintained lateral gaze, with the
      largest increase occurring with eye rotation towards rather than away from the
      measurement electrodes over the PAM. The EMG activity returned rapidly to near
      pre-rotation levels when the eyes were returned to the forwards position, with
      full recovery taking some minutes. While there was a similar increase and return
      of the PAMR amplitude with eye rotation, the time-course of these changes was
      somewhat different, largely because the EMG activity and the PAMR amplitude were
      not proportional. Rather the PAMR amplitude was a saturating function of EMG
      level, so that the PAMR response did not fall as markedly as the EMG when the
      eyes were returned to a forwards gaze, and the recovery of the PAMR amplitude to
      pre-rotation levels appeared to take longer. We discuss the neural mechanisms
      that may be responsible for this PAMR potentiation with eye movement and discuss
      its probable role in increasing variability in early studies which did not
      control for eye movement. We also discuss the utility of eye rotation in
      potentiating and stabilising the PAMR to allow its use in screening for deafness.

PMID- 10575122
TI  - A correlation method for detecting the sound-evoked post-auricular muscle
      response (PAMR).
AB  - We have made detailed measurements of the sound-evoked post-auricular muscle
      response (PAMR) in four adults and two infants, in an attempt to understand the
      inter-relationships between sound level, potentiation of the PAMR with voluntary
      PAM contraction or eye rotation, electromyographic (EMG) noise, amplitude of the
      PAMR, and a correlation measure of the presence of the PAMR. We have found that
      the amplitude of the PAMR is a simple linear function of the decibel level of a
      monophasic click (0.1 ms duration), and that the PAMR amplitude is also a
      saturating power function of the level of tonic EMG. As a result, PAMR=PAM(o).SL.
      (EMG-EMG(noise))(2)/[(EMG-EMG(noise))(2)+beta(2)], where SL is the decibel level
      of a click above subjective threshold, PAM(o) is a parameter accounting for the
      differing PAMR amplitude across individuals or with altered electrode placement,
      EMG(noise) is the component of EMG not associated with PAMR potentiation, and
      beta determines the initial rate of growth of PAMR at low levels of PAM
      activation. We have also found that the correlation measure (C) of the PAMR
      follows a saturating power function of the signal-to-noise ratio (SNR=PAMR/EMG),
      with C=SNR(2)/(SNR(2)+delta(2)), where delta determines the onset of saturation
      in the correlation as a function of SNR. The combination of these two
      relationships means that correlation is a non-monotonic function of the EMG (PAM
      activation): it can be large for moderate levels of EMG, but small for high
      levels of EMG, because the PAMR amplitude saturates but the EMG does not. The
      correlation is a fast, convenient means of detecting the PAMR, whether using
      clicks or tone-bursts, and can be used effectively in adults or infants, as long
      as the reflex is moderately activated. This moderate activation is most
      effectively produced by eye rotation towards the recording electrodes.

PMID- 10575123
TI  - The influence of karyotype on the auricle, otitis media and hearing in Turner
      syndrome.
AB  - The study has investigated the relationship between the chromosomal aberration
      and ear and/or hearing disorders in 115 girls/women with Turner syndrome (TS). A
      dose-response relationship was found between the karyotype and hearing function.
      Hearing deteriorated more rapidly with increasing age in TS women lacking the
      whole p-arm of chromosome X (i.e. monosomy 45,X, or isochromosome cases
      46,X,i(Xq)) as compared to women having a partial deletion of the p-arm
      (structural deletions or mosaicism cases), who, in turn, had poorer hearing than
      a female random population sample (46,XX) (P<0.001). Moreover, TS subjects having
      total deletion of the p-arm were three times more likely to have auricular
      anomalies or conductive hearing loss due to otitis media than subjects with
      partial deletion (P<0. 05). The results support the hypothesis that lack of
      growth-regulating genes such as the short stature homeobox-containing gene
      (SHOX), which is located within the pseudo-autosomal region on the p-arm of the X
      chromosome, may increase the occurrence of auricular malformations and otitis
      media and also induce an earlier loss of hearing function. Accordingly, the ear
      and hearing disorders in TS may be a result of growth disturbances of the
      auricle, the mastoid, the Eustachian tube and the organ of Corti during
      development. It is suggested that karyotype may be used as a predictor for future
      ear and hearing problems in TS.

PMID- 10575125
TI  - Intermittent noise-induced hearing loss and the influence of carbon monoxide.
AB  - Intermittent noise causes less hearing loss than continuous noise of equal
      intensity. The reduction in damage observed with intermittent noise may be
      explained by the fact that the auditory system has time to recover between the
      noise phases. Simultaneous carbon monoxide (CO) exposure produces greater noise
      induced hearing loss than does noise alone (Chen and Fechter, 1999). In the
      present study, intermittent noise (octave-band with a center frequency of 13.6
      kHz, 100 dB) of a 2 h total duration but with a different duty cycle (% of noise
      during exposure) was used. The intermittent exposure that had a shorter noise
      duty cycle induced a less permanent threshold shift (PTS) than those that had a
      longer noise duty cycle (or less rest periods). This relation between the loss in
      compound action potential (CAP) sensitivity and the noise duty cycle (or rest
      period) was abolished by the presence of CO. The cochlear microphonic (CM)
      amplitude revealed similar results to those seen using the CAP. While
      intermittent noise that had a short noise duty cycle did not cause hair cell loss
      by itself, the combined exposure to noise and CO (1200 ppm) caused remarkable OHC
      loss in the basal turn.

PMID- 10575124
TI  - Membrane properties and the excitatory junction potentials in smooth muscle cells
      of cochlear spiral modiolar artery in guinea pigs.
AB  - Blood circulation changes in the inner ear play an important role in many
      physiological and pathological conditions of hearing function. The spiral
      modiolar artery (SMA) is the terminal artery to the cochlea. It was surrounded
      with nerve fibers immunostained by an antibody for tyrosine hydroxylase. By using
      intracellular recording techniques on the acutely isolated SMA, membrane
      properties of the smooth muscle cells and the neuromuscular transmission in this
      preparation were investigated. With minimum tension and normal extracellular K(+)
      concentration (5 mM), the majority of muscle cells showed a resting potential
      near -80 mV and an input resistance of about 8 MOmega. V/I plot showed an inward
      rectification in these cells. Barium (50-500 microM) caused strong depolarization
      and an increase in input resistance. Transmural electrical stimulation evoked
      stimulation intensity-dependent depolarizations (2-31 mV) following a short
      latency ( approximately 20 ms). The evoked potential by a low intensity stimulus
      was completely blocked by 1 microM tetrodotoxin. The potential and a
      depolarization induced by norepinephrine (10 microM) was usually partially (40
      90%) blocked by alpha-receptor antagonists prazosin and/or idazoxan with
      concentrations up to 1 microM. Action potentials were observed when the
      depolarization was more than -40 mV. It is concluded that SMA smooth muscle
      cells, similar to those in other brain small arteries, highly express inward
      rectifying potassium channels; the cells receive catecholaminergic innervation,
      and stimulation of the nerves elicited an excitatory junction potential that is
      partially mediated by adrenergic receptors.

PMID- 10575128
TI  - Special issue. Eijkman Centennial on Infections in the 21st Century: Successes
      from the past, challenges for the future.

PMID- 10575126
TI  - An interaction between PPADS, an ATP antagonist, and a moderately intense sound
      in the cochlea.
AB  - In the organ of Corti ionotropic receptors for ATP (ATPRs) on cells that are
      bathed by perilymph have been suggested to modulate cochlear mechanics. The
      purpose of the present study was to test the hypothesis that endogenous
      extracellular ATP acting through ATPRs is involved in modulating cochlear
      mechanics during moderately intense sound exposure. Guinea pigs were exposed to
      either: (1) a perilymphatic administration of pyridoxal-phosphate-6-azophenyl-2',
      4'-disulfonic acid (PPADS, 1 mM), an ATP antagonist; (2) a moderately intense
      sound (6.7 kHz tone, 95 dB SPL, 15 min); or (3) a combination of both the PPADS
      and the sound. The effects on cochlear potentials (cochlear microphonic, CM;
      negative summating potential, SP; compound action potential of the auditory
      nerve, CAP; and N(1) latency) evoked by a 10 kHz tone pip were monitored. PPADS
      alone reduced the CAP and the SP and increased N(1) latency. The intense sound
      alone reduced the CAP and SP. The combination of PPADS with the intense tone
      induced reversible effects on cochlear potentials that were greater than induced
      by either treatment alone. The effect on N(1) latency and low intensity CM was a
      potentiation since the effect was greater than a simple addition of the effect of
      either treatment alone. The effects of the combination treatment on CAP, SP and
      high intensity CM were not different from additive. Results are consistent with
      the hypothesis that ATPRs in the organ of Corti are involved in modulating
      cochlear mechanics during moderately intense sound exposure.

PMID- 10575129
TI  - Respiratory viral infection predisposing for bacterial disease: a concise review.
AB  - Although bacterial superinfection in viral respiratory disease is a clinically
      well documented phenomenon, the pathogenic mechanisms are still poorly
      understood. Recent studies have revealed some of the mechanisms involved.
      Physical damage to respiratory cells as a result of viral infection may lead to
      opportunistic adherence of bacteria. Enhanced bacterial adherence by specific
      mechanisms has been documented for respiratory cells infected with influenza A
      virus, respiratory syncytial virus and adenovirus in both in vitro and in vivo
      models. To date, results of various experimental studies indicate that different
      mechanisms for increased bacterial adherence induced by viruses are operating for
      specific viral-bacterial combinations. In the present review, a number of key
      findings obtained during the past two decades is presented and discussed.

PMID- 10575130
TI  - New insights into the role of serum amyloid P component, a novel
      lipopolysaccharide-binding protein.
AB  - Serum amyloid P component (SAP) is a highly preserved plasma protein named for
      its ubiquitous presence in amyloid deposits. Although SAP is described to bind
      many ligands, no clear biological function has been ascribed to it as yet. This
      review summarizes the current knowledge about the protein SAP, its ligands and
      functional properties. Finally, the author focuses on the recent finding of the
      binding of SAP to lipopolysaccharide (LPS) and Gram-negative bacteria and the
      possible functional consequences of these interactions.

PMID- 10575132
TI  - Molecular mimetics of polysaccharide epitopes as vaccine candidates for
      prevention of Neisseria meningitidis serogroup B disease.
AB  - Neisseria meningitidis is a major cause of meningitis and sepsis. Despite nearly
      25 years of work, there is no promising vaccine candidate for prevention of
      disease caused by meningococcal B strains. This review summarizes newer
      approaches for eliciting protective meningococcal B immune responses, including
      the use of molecular mimetics of group B polysaccharide and conserved membrane
      proteins as immunogens. The capsular polysaccharide of this organism is conserved
      and serum antibody to this capsule confers protection against disease. However,
      the immunogenicity of meningococcal B polysaccharide-based vaccines is poor.
      Further, a portion of the antibody elicited has autoantibody activity. Recently,
      our laboratory produced a panel of murine monoclonal antibodies (Mabs) that react
      specifically with capsular polysaccharide epitopes on meningococcal B that are
      distinct from host polysialic acid. These Mabs elicit complement-mediated
      bactericidal activity and confer passive protection in animal models. The anti
      capsular Mabs were used to identify molecular mimetics from phage display peptide
      libraries. The resulting peptides were antigenic mimetics as defined by binding
      to the Mabs used to select them but, to date, are poor immunogenic mimetics in
      failing to elicit anti-capsular antibodies.

PMID- 10575131
TI  - Evidence for an intracellular niche for Bordetella pertussis in broncho-alveolar
      lavage cells of mice.
AB  - Bordetella pertussis can attach, invade and survive intracellularly in human
      macrophages in vitro. To study the significance of this bacterial feature in
      vivo, we analyzed the presence of viable bacteria in broncho-alveolar lavage
      (BAL) cells of mice infected with B. pertussis. We found B. pertussis to be
      present in a viable state in BAL fluid cells until at least 19 days after
      infection, suggesting B. pertussis to be able to survive in those cells. This
      intracellular niche may play an important role in the pathogenesis of pertussis.
      Pertussis toxin and the RGD sequence of the virulence factor filamentous
      hemagglutinin (FHA) both play a role in the attachment of B. pertussis to human
      and mouse macrophages in vitro and we hypothesized these virulence factors to be
      required for invasion and subsequent intracellular survival of B. pertussis in
      macrophages in vivo. A B. pertussis double mutant, in which the FHA RGD motif was
      changed to RAD and the ptx genes were deleted, was also found in a viable state
      in BAL fluid cells, albeit at lower levels than the wild-type strain. In our
      model, uptake of B. pertussis by alveolar phagocytes in vivo is thus, at least in
      part, determined by the bacterial virulence factors FHA and pertussis toxin.

PMID- 10575133
TI  - Viruses, cancer and AIDS.
AB  - Patients with AIDS are at risk of lymphoma and Kaposi's sarcoma. These tumours
      are associated with the gamma herpesviruses, Epstein-Barr virus (EBV) and human
      herpesvirus 8 (HHV-8), although a proportion of AIDS lymphomas lacks both
      viruses. EBV and HHV-8 are latent in the tumour cells, with genes that play a
      direct role in driving cell proliferation. Human immunodeficiency virus, in
      contrast, while being the greatest risk factor for lymphoma and Kaposi's sarcoma,
      acts indirectly, mainly by causing immune suppression, as immunosuppressed
      transplant patients are at risk for the same types of tumour.

PMID- 10575134
TI  - The neuropathogenesis of HIV-1 infection.
AB  - HIV encephalitis is the common pathologic correlate of HIV-dementia (HAD). HIV
      infected brain mononuclear phagocytes (MP) (macrophages and microglia) are
      reservoirs for persistent viral infection. When activated, MP contribute to
      neuronal damage. Such activated and virus-infected macrophages secrete cellular
      and viral factors, triggering neural destructive immune responses. Our Center's
      laboratories have begun to decipher the molecular and biochemical pathways for MP
      mediated neuronal damage in HAD. This review will discuss the salient clinical
      and pathological features of HAD and highlight the recent advances made, by our
      scientists and elsewhere, in unraveling disease mechanisms, including the role of
      chemokines and their receptors in the neuropathogenesis of HIV-1 encephalitis.

PMID- 10575135
TI  - Potential role of CCR5 polymorphism in the development of AIDS dementia complex.
AB  - The chemokine receptor CCR5 and to a lesser extent CCR2b and CCR3 have been shown
      to serve as coreceptors for HIV-1 entry into macrophages. Individuals that are
      homozygous for a defective CCR5 allele (DeltaCCR5) are highly, but not fully,
      resistant to infection with HIV-1. Here, we want to emphasize the importance of
      DeltaCCR5 in in vitro as well as in vivo studies. We provide data that suggest
      that CCR5 polymorphism may affect the onset of AIDS dementia complex in vivo and
      data that show that HIV-1 replication is influenced by the DeltaCCR5 allele in
      vitro. Knowing the CCR5 genotype of an individual will help to better interpret
      research results and may even provide new information about mechanisms of
      disease.

PMID- 10575136
TI  - Expression of zeta molecules is decreased in NK cells from HIV-infected patients.
AB  - Cytolysis by natural killer (NK) cells is impaired in HIV infection. We
      investigated whether the expression of zeta (zeta) molecules, essential elements
      of signalling initiated upon ligation of, e.g., CD16, is reduced and if so,
      whether this reduction could be involved in defective cytolysis. FACS analysis
      revealed significantly lower levels of zeta in NK cells from AIDS patients
      compared to cells from patients without AIDS and healthy controls. CD16-dependent
      cytolysis by NK cells correlated with expression of zeta molecules and CD16, the
      latter possibly related to zeta expression. No correlation was observed between
      CD16-independent cytolysis and zeta expression. Reduced expression of zeta
      molecules by NK cells from HIV-infected patients thus correlates with disease
      progression and may, in part, explain the defective cytolysis by these cells.

PMID- 10575137
TI  - Immune dysfunction in patients with diabetes mellitus (DM).
AB  - Patients with diabetes mellitus (DM) have infections more often than those
      without DM. The course of the infections is also more complicated in this patient
      group. One of the possible causes of this increased prevalence of infections is
      defects in immunity. Besides some decreased cellular responses in vitro, no
      disturbances in adaptive immunity in diabetic patients have been described.
      Different disturbances (low complement factor 4, decreased cytokine response
      after stimulation) in humoral innate immunity have been described in diabetic
      patients. However, the clinical relevance of these findings is not clear.
      Concerning cellular innate immunity most studies show decreased functions
      (chemotaxis, phagocytosis, killing) of diabetic polymorphonuclear cells and
      diabetic monocytes/macrophages compared to cells of controls. In general, a
      better regulation of the DM leads to an improvement of these cellular functions.
      Furthermore, some microorganisms become more virulent in a high glucose
      environment. Another mechanism which can lead to the increased prevalence of
      infections in diabetic patients is an increased adherence of microorganisms to
      diabetic compared to nondiabetic cells. This has been described for Candida
      albicans. Possibly the carbohydrate composition of the receptor plays a role in
      this phenomenon.

PMID- 10575138
TI  - Evidence-based antibiotic therapy of diabetic foot infections.
AB  - In addition to proper cleansing, debridement and local wound care, foot
      infections in diabetic patients require carefully selected antibiotic therapy.
      Serious infections necessitate hospitalization for initial parenteral broad
      spectrum antibiotic therapy. Appropriately selected patients with mild infections
      can be treated as outpatients with oral (or even topical) therapy. Initial
      antibiotic selection is usually empirical, but definitive therapy may be modified
      based on culture results and the clinical response. Therapy should nearly always
      be active against staphylococci and streptococci, with broader-spectrum agents
      indicated if Gram-negative or anaerobic organisms are likely. In infected foot
      tissues levels of most antibiotics, except fluoroquinolones, are often
      subtherapeutic. The duration of therapy ranges from a week (for mild soft tissue
      infections) to over 6 weeks (for osteomyelitis). Recent antibiotic trials have
      shown that several intravenously or orally administered agents are effective in
      treating these infections, with no one agent or combination emerging as optimal.
      Suggested regimens based on the severity of infection are provided.

PMID- 10575139
TI  - The Dutch consensus on the diabetic foot.
AB  - In 1996 the Dutch Diabetes Federation installed a consensus committee to
      formulate practical guidelines for daily practice to prevent, diagnose and treat
      foot-related complications in patients with diabetes mellitus. A list of
      definitions was formulated. A new ulcer classification was introduced.
      Pathophysiology, diagnostic and therapeutic strategies were discussed with
      special attention for patients with a high risk foot and for prevention
      instruction. After several rounds of implementation the definite document was
      unanimously accepted in the fall of 1998.

PMID- 10575140
TI  - Molecular epidemiology of quinolone resistance and comparative in vitro
      activities of new quinolones against European Staphylococcus aureus isolates.
AB  - New fluoroquinolones (FQ) may possibly be used as alternative therapeutic options
      for Staphylococcus aureus infections. Our objectives were: (1) to define the in
      vitro activities of seven FQs in a collection of 434 methicillin-susceptible and
      457 methicillin-resistant S. aureus from 23 European university hospitals; (2) to
      characterise the prevalence of mutations in the grlA and gyrA genes in all
      ciprofloxacin-resistant (n=433) isolates of S. aureus; (3) to determine the
      percentage of ciprofloxacin-resistant S. aureus strains with measurable quinolone
      efflux. METHODS: (1) The in vitro activities of different FQs were determined by
      microdilution tests. (2) PCR-amplified DNA was sequenced. (3) Ciprofloxacin
      minimum inhibitory concentrations (MIC) were determined in the presence and
      absence of reserpine, which inhibits efflux pumps. RESULTS: (1) Irrespective of
      the methicillin resistance of the isolates, sitafloxacin and clinafloxacin showed
      the best in vitro activities. (2) All ciprofloxacin-resistant isolates exhibited
      GrlA alterations, namely Ser-80-->Phe or Tyr or Glu-84-->Lys or Ala-116-->Glu or
      Pro or a combination of Ser-80-->Phe and Glu-84-->Val. These alterations in GrlA
      were combined with alterations in GyrA, namely Ser-84-->Leu or Lys or Glu-88-
      >Lys or Val. (3) Reserpine reduced ciprofloxacin MIC values in ca. 30% of the
      clinical isolates tested. CONCLUSIONS: (1) This current European overview of
      mutations involved in FQ resistance demonstrates that only a limited number of
      classical mutations in grlA and gyrA contributed to resistance in clinical
      isolates. (2) An efflux pump is involved in ca. 30% of ciprofloxacin-resistant S.
      aureus isolates. (3) Sitafloxacin and clinafloxacin are two very promising new
      FQs with good anti-staphylococcal activity. New FQs, perhaps in combination with
      efflux pump inhibitors, might play a role in the treatment of S. aureus
      infections.

PMID- 10575141
TI  - Iron chelators as anti-infectives; malaria as a paradigm.
AB  - Malaria is the major life threatening parasitic disease and the cause of a global
      public health problem. The failure of vector eradication programs and the
      appearance and spread of drug resistant parasites have posed the urgent challenge
      of developing effective, safe and affordable anti-malarial drugs. The design of
      such drugs is largely based on the targeting of agents to the parasite-based
      machinery for host digestion and to the products of hemoglobin catabolism. Iron
      chelators, by depriving intracellular parasites from essential iron, lead to
      selective suppression of parasite growth. However, by acting on parasite-impaired
      macrophages, chelators can also expedite resumption of phagocytosis and
      elimination of parasites. In order to be clinically effective, chelators need to
      be maintained in the blood for extensive time periods. Therapeutic doses can be
      attained with appropriate drug combinations and formulations or delivery devices
      and these must be presented in a form well tolerated by the host. The early
      documentation that chelation therapy has activity against human malaria has paved
      the road for the design of novel and more efficient remedies based on short-term
      iron deprivation.

PMID- 10575142
TI  - Modulation of neutrophil function in host defense against disseminated Candida
      albicans infection in mice.
AB  - Neutrophils (PMNs) constitute the main mechanism of host defense against acute
      invasive and disseminated candidiasis. Recent studies have demonstrated that
      tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6) and granulocyte
      colony-stimulating factor (G-CSF) play an important role in the recruitment of
      PMNs at the site of invasive Candida infection. In the absence of either TNFalpha
      or IL-6, the course of experimental disseminated candidiasis is more severe, due
      to defective PMN recruitment. Treatment of mice with recombinant G-CSF (rG-CSF)
      leads to a significantly reduced mortality during disseminated candidiasis. The
      outgrowth of Candida albicans from the organs of rG-CSF-treated mice is
      significantly decreased. Treatment with the combination of rG-CSF and fluconazole
      has an additive effect on the reduction of fungal load in the organs. In subacute
      or chronic disseminated Candida infection, rG-CSF is less effective, indicating
      that neutrophil recruitment and activation are crucial in acute, life-threatening
      candidiasis, whereas other host defense mechanisms control the outcome of less
      overwhelming invasive Candida infection.

PMID- 10575143
TI  - Cryptococcus neoformans and its cell wall components induce similar cytokine
      profiles in human peripheral blood mononuclear cells despite differences in
      structure.
AB  - We studied the cytokine profile of peripheral blood mononuclear cells after
      stimulation with various cryptococcal strains or its purified cell wall
      components. After 3 h of stimulation, tumor necrosis factor (TNF) alpha levels
      were strongly increased, whereas interferon (IFN) gamma and interleukin (IL) 10
      levels were increased only slightly, or not at all (respectively). In contrast,
      after 18 h, TNF-alpha and IFN-gamma levels were (strongly) decreased, whereas the
      IL-10 levels were increased. The IL-1beta, IL-6 and IL-8 levels were equally high
      throughout the experiment. In order to establish which of the cryptococcal
      envelope components contributed most to the observed cytokine profile induced by
      whole cryptococci, glucuronoxylomannan, galactoxylomannan and mannoproteins were
      purified and partially characterized biochemically. All cryptococcal components
      elicited a similar cytokine pattern despite the differences in structure.

PMID- 10575144
TI  - Controlling the spread of vancomycin-resistant enterococci with contact
      precautions: time for a randomized trial.

PMID- 10575146
TI  - Genotype and allele frequency of a 32-base pair deletion mutation in the CCR5
      gene in various ethnic groups: absence of mutation among Asians and Pacific
      Islanders.
AB  - BACKGROUND: A 32-base pair (bp) deletion mutation in the beta-chemokine receptor
      CCR5 gene has been associated with resistance against human immunodeficiency
      virus type 1 (HIV-1) infection and disease. Large-scale studies conducted among
      Caucasians indicate that individuals who are homozygous for this deletion
      mutation (D32/D32) are protected against HIV-1 infection despite multiple high
      risk exposures, whereas CCR5/ D32 heterozygotes have a slower progression to
      acquired immunodeficiency syndrome (AIDS). OBJECTIVE: To determine the genotype
      and allele frequencies of the CCR5 gene 32-bp deletion mutation among ethnically
      diverse non-Caucasian populations. METHODS: DNA, extracted from blood collected
      between 1980 and 1997 from 1912 individuals belonging to various ethnic groups,
      including 363 Caucasians, 303 Puerto Rican Hispanics, 150 Africans, 606 Asians,
      and 490 Pacific Islanders, were analyzed for the CCR5 gene 32-bp deletion
      mutation by a polymerase chain reaction (PCR)-based assay, using an
      oligonucleotide primer pair designed to discriminate CCR5 alleles without
      restriction endonuclease analysis. RESULTS: The comparative frequency of CCR5/D32
      heterozygosity was 61 of 363 (16. 8%) in Caucasians, 17 of 303 (5.6%) in Puerto
      Rican Hispanics, 9 of 490 (1.8%) in Pacific Islanders, 0 of 606 (0%) in Asians,
      and 0 of 150 (0%) in Africans. CONCLUSIONS: The data confirm the high frequency
      of CCR5/D32 heterozygosity among Caucasians. Intermediate and low-level D32
      allele frequencies among Puerto Rican Hispanics and Hawaiians could be attributed
      to recent European Caucasian gene flow. By contrast, the inability to detect the
      D32 allele among Asians and other Pacific Islander groups suggests that other
      mechanisms are responsible for resistance to HIV-1 infection in these
      populations.

PMID- 10575145
TI  - Lack of association between acquisition of TT virus and risk behavior for HIV and
      HCV infection in Vietnam.
AB  - BACKGROUND: The search for the cause of chronic hepatitis among individuals with
      non-A to G hepatitis has led to the discovery of a post-transfusion hepatitis
      related DNA virus, designated TT virus (TTV), which, based on viral sequences,
      belongs to a new virus family. The principal modes of infection with TTV are
      poorly understood, and its role in human immunodeficiency virus type 1 (HIV-1)
      infection is unclear. OBJECTIVE: To determine if injection drug use (IDU) and
      high-risk heterosexual activity (HRHA), principal modes of acquiring HIV-1
      infection, place individuals at greater risk of acquiring TTV. METHODS: The
      authors analyzed DNA, extracted from sera or filter paper-blotted whole blood,
      obtained during August 1997 and June 1998 from 324 Vietnamese (148 male; 176
      female), for TTV sequences by hot-start, heminested polymerase chain reaction.
      RESULTS: Prevalence of TTV viremia was similar among individuals engaging in IDU
      or HRHA (23.4% vs. 20.2%; P > 0.5), with no age- or gender-specific differences.
      No association was found between TTV viremia and co-infection with HIV-1 or
      hepatitis C virus (HCV). Phylogenetic analysis of 30 TTV sequences revealed two
      distinct genotypes and four subtypes that did not segregate according to gender,
      HIV-1 and HCV risk behaviors, or geographic residence. CONCLUSIONS: Among HIV-1-
      or HCV-infected Vietnamese, who presumably acquired their infection by either the
      parenteral or nonparenteral route, the data indicate no clear association between
      acquisition of TTV infection and risk behavior for HIV-1 or HCV infection,
      suggesting that the usual route of TTV transmission in Vietnam is other than
      parenteral or sexual.

PMID- 10575147
TI  - IS1245 genotypic analysis of Mycobacterium avium isolates from patients in
      Brazil.
AB  - OBJECTIVE: Disseminated Mycobacterium avium infection is an emerging
      opportunistic disease among patients with acquired immunodeficiency syndrome
      (AIDS) in Brazil. The mode of transmission of M. avium in a developing country
      setting needs to be better characterized. METHODS: Mycobacterium avium strain
      collections in Sao Paulo and Rio de Janeiro were analyzed according to the
      strains' IS1245 DNA gel electrophoretic migration patterns. Medical records of
      the patients from whom M. avium isolates were available were reviewed, and their
      demographic characteristics were stratified according to the isolates' IS1245 DNA
      fingerprint patterns. RESULTS: Of 105 patients, 33 (31%) with M. avium isolated
      between 1990 and 1994 had strains having IS1245 patterns identical in patterns
      seen in isolates from two or more patients (designated as cluster pattern
      strains). Cluster pattern strains were isolated from 21 (39%) of 54 patients with
      disseminated infection (defined as infection due to M. avium isolated from a
      sterile site in an adult patient). Six of the cluster pattern strains were
      isolated only from sterile sites. In Sao Paulo, cluster pattern strains were
      significantly more likely to be isolated from patients with disseminated disease.
      CONCLUSIONS: These preliminary observations suggest that in large cities of
      Brazil, a high proportion (at least 39%) of disseminated M. avium infections in
      patients with AIDS results from a recent transmission. Some strains of M. avium
      may be more likely to cause disseminated disease than others after an infection.

PMID- 10575148
TI  - Reduced incidence of necrotizing enterocolitis associated with enteral
      administration of Lactobacillus acidophilus and Bifidobacterium infantis to
      neonates in an intensive care unit.
AB  - OBJECTIVES: Necrotizing enterocolitis (NEC) has been associated with a wide
      variety of bacteria and their cytotoxins. The content and the nature of gut
      bacterial colonization in newborns that require intensive care hospitalization
      has been demonstrated to be abnormal. In the 25-bed neonatal intensive care unit
      in Hospital Simon Bolivar, in Bogota, Colombia, cases of NEC are common causes of
      morbidity and mortality. This article examines the hypothesis that oral
      administration of prophylactic Lactobacillus acidophilus and Bifidobacterium
      infantis to all neonates in an intensive care unit, would decrease the incidence
      of NEC. METHODS: Daily doses of 250 million live L. acidophilus and 250 million
      B. infantis were given to all 1237 newborns (both inpatients and transfer
      patients) admitted to the unit during 1 year, until they were discharged from the
      hospital. In this study, 1282 patients hospitalized during the previous year were
      used as controls. RESULTS: There were no complications attributed to the daily
      administration of L. acidophilus and B. infantis. The study groups were compared
      for place of origin, clinical, and demographic variables, and there was no
      statistically significant difference in those variables. In the historic control
      group, there were 85 NEC cases compared to 34 cases in the group that received
      probiotic prophylaxis (P < 0.0002). In the historic control group, there were 35
      NEC-associated fatalities compared to 14 fatalities in the group that received
      probiotic prophylaxis (P < 0.005). CONCLUSIONS: The positive results in this
      study support the need for further investigation of bacterial colonization and
      its role in NEC.

PMID- 10575149
TI  - Prevalence of intestinal parasitic infections in patients with acquired
      immunodeficiency syndrome in Brazil.
AB  - OBJECTIVES: To evaluate the prevalence of intestinal parasitic infections and to
      investigate the possible associations of clinical status and laboratory findings
      with the different parasites found in stool samples. METHODS: Each patient was
      provided with one standard fecal collection vial containing 10% formalin for
      detecting ova, larvae, and cysts. To detect Cryptosporidium parvum and Isospora
      belli, the acid-fast Kinyoun stain and fluorescent auramine-rhodamine stain were
      used. RESULTS: A total of 200 patients with acquired immunodeficiency syndrome
      participated in this study; 40% were infected with at least one pathogenic
      species. The total prevalence of parasites was 16% for Giardia lamblia, 13% for
      Entamoeba coli, 7% for Cryptosporidium parvum, 3.5% for Endolimax nana, 2.5% for
      Ascaris lumbricoides, 2.5% for Strongyloides stercoralis, 2% for Isospora belli,
      and 0.5% for Blastocystis hominis. Results showed that diarrhea was significantly
      associated with cryptosporidiosis, giardiasis, and isosporiasis. However, no
      association was observed between the CD4+ cell counts and the manifestation of
      any particular parasite. CONCLUSIONS: The data support the value of standard
      fecal examinations in human immunodeficiency virus-infected patients, even in the
      absence of diarrhea, since these examinations easily can be performed, with low
      costs, and frequently disclose treatable conditions.

PMID- 10575150
TI  - Surgical procedures as a major risk factor for chronic hepatitis C virus
      infection in Italy: evidence from a case-control study.
AB  - OBJECTIVES: The study was carried out to evaluate the risk factors associated
      with chronic hepatitis C virus (HCV) infection. METHODS: This case-control study
      used multiple logistic regression analysis to determine risk factors associated
      with HCV infection. Study participants were followed at 10 liver or
      gastroenterologic units and included 294 subjects with chronic HCV infection and
      295 age and sex matched anti-HCV-negative controls. RESULTS: The use of glass
      syringes and surgical procedures was reported by as many as 77.6% and 73.8% of
      cases, respectively; blood transfusion was recorded in nearly a quarter of cases;
      10.2% of cases, but none of the controls, reported past or current intravenous
      drug use. Multiple logistic regression analysis showed that blood transfusion,
      being the sexual partner of an intravenous drug user, and surgery all were
      independent predictors of the likelihood of HCV infection. CONCLUSIONS: These
      findings indicate that, besides the well-known sources of infection, such as
      blood transfusion and intravenous drug use, surgical procedures may play an
      important role in the spread of HCV infection in Italy. Given that a large
      proportion of the general population undergoes surgery, a rational and relatively
      inexpensive policy for the prevention of HCV infection must focus on implementing
      efficient procedures for the sterilization of instruments and the use of
      disposable materials in surgical units.

PMID- 10575151
TI  - Nasopharyngeal carriage of multidrug-resistant Streptococcus pneumoniae in
      institutionalized HIV-infected and HIV-negative children in northeastern Romania.
AB  - OBJECTIVES: The study compared nasopharyngeal carriage of resistant pneumoniae in
      human immunodeficiency virus (HIV)-seropositive and -seronegative children.
      METHODS: Nasopharyngeal colonization with Streptococcus pneumoniae was
      investigated during May 1996 in 162 HIV-negative infants and children (age range,
      1-38 mo) and 40 HIV-infected children (age range, 39-106 mo) living in an
      orphanage in Iasi, northeastern Romania. The HIV-infected children lived
      separated from the other children and were cared for by a different staff.
      Streptococcus pneumoniae was isolated from 12 of 40 (30%) HIV-infected and from
      81 of 160 (50%) HIV-negative children. Antimicrobial susceptibility to penicillin
      and ceftriaxone was determined by E-test, and to another five antibiotics by disk
      diffusion. Serotyping was performed by the Quellung method on 81 of 93 (87%)
      isolates. RESULTS: Serotypes 6A, 6B, 19A, and 23F together represented 98% of all
      isolates. Ninety-nine percent of S. pneumoniae isolates were resistant to
      penicillin, and 74% were highly resistant to penicillin (minimum inhibitory
      concentration [MIC] > 1 mg/mL); MIC50 and MIC90 to penicillin of the isolates
      were 2 mg/mL and 8 mg/mL, respectively. Eighty-nine of ninety-one isolates were
      susceptible to ceftriaxone; 99%, 87%, 87%, 48%, and 21% of the isolates were
      resistant to trimethoprim-sulphamethoxazole, erythromycin, clindamycin,
      tetracycline, and chloramphenicol, respectively. Eighty-two (89%) isolates were
      multidrug resistant (resistant to =/>3 antibiotic classes); 37 of 92 (40%)
      isolates were resistant to 5 or more antibiotic classes, and 16 of these 37 (43%)
      belonged to serotype 19A. All serotype 19 isolates were highly resistant to
      penicillin. CONCLUSIONS: No significant differences were observed in the
      resistance rates of S. pneumoniae in HIV-infected children compared to HIV
      negative children. Multidrug-resistant pneumococci were highly prevalent in this
      Romanian orphanage in both HIV-negative and older HIV-infected children. The
      observed high prevalence of multidrug-resistant pneumococci (coupled with high
      penicillin resistance) with a limited number of circulating serotypes emphasizes
      the need to further evaluate the conjugate vaccines in children at risk for
      invasive pneumococcal infection.

PMID- 10575152
TI  - Trichinosis outbreak after ingestion of barbecued badger.

PMID- 10575153
TI  - Pulmonary edema in malaria.

PMID- 10575155
TI  - The etiology of malignant melanoma.
AB  - The etiology of malignant melanoma has been intensely studied over the last
      decade. Much of the recent work focuses on oncongenes and tumour suppressor genes
      and the role of apoptosis in melanoma. Loss of tumour suppressor proteins such as
      p16 has been documented in melanoma and correlates with tumour progression.
      Mutations in the tumour suppressor p53 have also been documented in melanoma. The
      proto-oncongene Bcl-2 encodes a protein that inhibits apoptosis. Bcl-2 is found
      in normal melanocytes and benign nevi. However, lower levels are seen in
      melanoma. To investigate the relationship between melanoma and nevi, in our Basic
      and Clinical Science section, Dr. Radhi examines the expression of p53, p16, and
      Bcl in malignant melanoma arriving in benign nevi. P53 immunoreactivity was found
      only in the malignant component, with no expression being seen in the benign
      components of the lesion. This suggests that this tumour suppressor gene is
      involved in the pathogenesis of melanoma.

PMID- 10575154
TI  - Hepatitis G virus: molecular organization, methods of detection, prevalence, and
      disease association.
AB  - This article reviews data on hepatitis G virus (HGV) prevalence and possible
      disease associations in various groups of patients. An important fraction of
      acute or chronic hepatitis cases probably have a viral etiology and are not
      attributable to known hepatitis viruses. Therefore, researchers continually are
      looking for new hepatitis viruses. Among the agents found are members of GB
      hepatitis viruses, including GB-C virus, or HGV. This review presents the history
      of the discovery of HGV, its molecular biology and some methods of detection;
      results of clinical and molecular studies of HGV infection also are discussed.

PMID- 10575156
TI  - Three point-advancement closure for skin defects.
AB  - BACKGROUND: Circular skin defects are common following Mohs' surgery. Traditional
      closure (primary, flap, or graft) may involve extensive surgery. Multidirectional
      advancement closures such as the purse-string closure have been advocated as
      another useful tool in such cases. OBJECTIVE: To describe a variation on purse
      string closure that, in certain cases, is an excellent alternative to other
      reconstructions, and will provide good cosmetic and functional outcome. METHOD: A
      three-point anchoring suture is placed after undermining to advance the
      surrounding tissue toward the centre, creating a "Mercedes Benz" or tripod
      closure following removal of "dog-ears." RESULTS: Circular wounds in designated
      areas can be more easily closed, creating well-tolerated, favourable scars.
      CONCLUSION: Large wounds may be closed with the advantage of avoidance of larger
      flaps, of decreased wound healing compared to second intention, and of minimizing
      removal of healthy tissue. An initial trial of closure with this method does not
      limit subsequent use of other repairs should it be less than satisfactory.

PMID- 10575157
TI  - Malignant melanoma arising from nevi, p53, p16, and Bcl-2: expression in benign
      versus malignant components.
AB  - BACKGROUND: The etiology of malignant melanoma has been the subject of much
      study. Tumour suppressor genes p53 and p16 and the antiapoptotic, Bcl-2, are
      implicated in the development and progression of malignant melanoma. OBJECTIVE:
      To compare the expression of p53, p16, and the Bcl-2 genes in both benign and
      malignant components of malignant melanoma arising from pre-existing nevocellular
      nevi. METHODS: Twenty cases of malignant melanoma arising from pre-existing nevi
      were selected and studied by immunohistochemistry for the expression of p53 (D07)
      CDK4I/MTS-1/INK <4, which detects both wild and mutant type, p16 CDK4I/MTS-1/INK
      <4, and Bcl-2 using an avidin-biotin technique on formalin-fixed, paraffin
      embedded sections. RESULTS: Fifteen cases demonstrated p53 immunoreactivity in
      the malignant components ranging from 5 to 20% with no expression being seen in
      the benign components. The p16 gene showed strong nuclear reactivity in the
      benign components of 14 cases and weak reaction in 6 cases; the malignant
      components expressed weak nuclear staining in 18 cases and cytoplasmic staining
      in all cases. The Bcl-2 gene was expressed strongly to moderately in benign
      components and weakly in malignant components of nine cases, and was negative in
      11 cases. CONCLUSION: Immunostaining for p53 is expressed only in the malignant
      component, whereas p16 and Bcl-2 showed decreased staining and a different
      pattern in malignant compared with benign components. These findings suggest that
      expression and alterations in the subcellular localization of the cell cycle
      regulators may contribute to the mechanism of tumourigenesis.

PMID- 10575159
TI  - Sarcoidosis presenting as nail dystrophy.
AB  - A 45-year-old woman was referred to the dermatology clinic for assessment of
      "refractory onychogryphosis." She had a 3-year history of lesions involving
      distal phalanges of the first and third of her left foot. Initially she described
      periungual erythema and swelling. Three weeks later she noted a whitish growth
      and thickening of her third toenail. X-ray films of the digit were reported as
      normal. Several months later the same changes occurred in her great toe. These
      lesions were asymptomatic. There was no history of trauma. Numerous fungal
      cultures were negative. No light microscopic examinations were undertaken. She
      had a trial of both topical and systemic terbinafine of 3-months duration with no
      clinical improvement. Several clinical opinions were obtained from two
      dermatologists, a surgeon, and a chiropodist. Past medical history of note was
      significant for tubal ligation, cervical cancer, and chronic sinusitis. The
      latter condition in retrospect was thought to be secondary to sarcoidosis.
      Physical examination revealed periungual violaceous discolouration of the first
      and third toes of the left foot. There was evidence of significant nail changes
      including dystrophy, onycholysis, and hyperkeratosis (Fig. 1). The fingernails
      were normal. There were no other skin abnormalities. A punch biopsy of the tip of
      the third toe showed granulomatous inflammation. There was evidence of
      hyperkeratosis, exocytosis, and a dense infiltrate composed of collections of
      histiocytes and a few giant cells forming granulomas (Fig. 2). Repeat x-ray films
      of the foot showed soft tissue swelling of the first and third digits. There was
      bony resorption in the distal phalanges with a lacey trabecular pattern
      compatible with sarcoidosis (Fig. 3). Chest x-ray films revealed marked hilar
      adenopathy. The patient was sent to a respirologist who concurred with the
      diagnosis of sarcoidosis. Further investigations included a low serum calcium of
      2.07 mmol/L, serum ACE of 70 U/L (upper limit of normal is 75), Wintrobe
      erythrocyte sedimentation rate (ESR) of 10 mm per hour, thyroid stimulating
      hormone concentration of 0.65 mU/L, and a urinary calcium excretion rate that was
      elevated at 7.3 mmol/day. Pulmonary function tests were unremarkable. The patient
      was initially treated with clobetasol under occlusion and intralesional
      triamcinolone with minimal improvement. She was subsequently started on
      prednisone, 15 mg per os daily because of the lung and bone involvement with
      significant improvement noted in the toe lesions with diminution of both the
      swelling and violaceous discolouration.

PMID- 10575158
TI  - Comparative irritancy study among retinoid creams and gels.
AB  - BACKGROUND: Topical retinoids, although very useful in dermatology, may be
      irritating to some patients. OBJECTIVE: There are a number of topical retinoids
      available in Canada, and the objective of the present study was to evaluate the
      irritancy potential in humans of retinoid gels and creams presently available in
      Canada. METHODS: Thirty healthy adults were administered 10 products (five
      creams, three gels, petrolatum, and sodium lauryl sulfate (SLS) 0.1% w/v) for up
      to 21 consecutive days. RESULTS: Early termination of patching due to irritation
      was required for the tretinoin creams and gels and SLS more frequently and
      earlier in the study than for adapalene and petrolatum (p =.001). Statistically
      significant, among-group differences were noted in the severity of irritation at
      each day and for the cumulative score for both the creams and the gels (p
      =.0001), in favour of adapalene over the tretinoin products. CONCLUSION: By
      several measures, adapalene cream and gel were less irritating upon multiple
      dosing than various tretinoin creams and gels.

PMID- 10575160
TI  - Lyme disease: summary notes.
AB  - The intention of the Summary Notes section is to provide the practitioner and
      trainee with a current, concise reference source to dermatologic diseases and to
      serve as a form of Continuing Medical Education. Each installment will deal with
      a specific disease. When included, the pretest questions indicate some of the
      areas to be covered and will challenge your present knowledge of the material
      before reading further. The self-assessment post-test questions appear on page
      308; the answers are on page 316.

PMID- 10575161
TI  - Of hairless mice and men: the genetic basis of congenital alopecia
      universalis/congenital atrichia.
AB  - BACKGROUND: Mouse models of human diseases help identify gene defects. OBJECTIVE:
      The methods of homozygosity mapping and mouse/human homology to identify genes
      are reviewed. The genotype/phenotype correlation in two clinical entities with
      mutations in the human hairless gene are discussed. METHODS: The example of the
      hairless mouse's contribution to our knowledge of hereditary alopecia is used,
      and the utility of consanguineous families for genetic studies is highlighted.
      RESULTS: Mutations in the human homolog of the mouse hairless gene lead to
      congenital alopecia universalis and atrichia with papules. CONCLUSION: A mouse
      model of congenital alopecia has led to understanding the molecular basis of at
      least one type of severe human alopecia.

PMID- 10575162
TI  - Understanding research about quality of life and other health outcomes.
AB  - BACKGROUND: Papers reporting studies of health outcomes, particularly patients'
      perceptions, are becoming more common. Understanding the characteristics of tools
      used to measure these health outcomes is important for interpreting these studies
      accurately and applying them to clinical care. OBJECTIVE: The purpose of this
      article is to describe important features of the measurement of patient-perceived
      health outcomes, and to illustrate how a consideration of these features can help
      in applying study results to individual patients. CONCLUSION: Understanding the
      principles of measurement is particularly important for interpreting studies of
      dermatological care, in which patients' perceptions are a crucial outcome.

PMID- 10575163
TI  - Trichoepithelioma associated with cellular blue nevus.
AB  - BACKGROUND: Epithelial elements, such as trichoepithelioma, are occasionally
      associated with melanocytic nevi. OBJECTIVE: A case of trichoepithelioma in
      association with cellular blue nevus is reported. METHODS AND RESULTS: A
      solitary, pigmented nodule was removed from the scalp of a middle-aged woman.
      Histopathologic examination demonstrated a circumscribed cellular blue nevus
      within which were embedded epithelial strands and cystic structures consistent
      with trichoepithelioma. CONCLUSION: Trichoepitheliomas have been described in
      relation to common acquired nevi, but an association with a blue nevus is rare.
      The intimate admixture of trichoepithelioma within the nodule of a nevus supports
      the concept of epithelial induction by melanocytic nevi.

PMID- 10575164
TI  - Interferon-induced cutaneous necrosis.
AB  - BACKGROUND: Due to advances in recombinant DNA technology, interferons are now
      readily available and are frequently used in all branches of medicine. These
      potent biologic response modifiers carry a number of systemic and local side
      effects. These cytokines are usually administered subcutaneously, and recent
      studies have described the occurrence of inflammation or necrosis at the site of
      injection. OBJECTIVE: We report a case of cutaneous necrosis at the sites of
      interferon injections in a 35-year-old man treated for chronic myeloid leukemia
      with high, daily doses of interferon alfa. In addition, we review the existing
      literature on interferon-induced cutaneous necrosis and discuss preventive
      strategies. CONCLUSION: Cutaneous inflammation or necrosis at interferon
      injection sites is not uncommon. Although interferon beta-1b is most commonly
      responsible for this complication, it is now increasingly reported with
      interferon alfa. It appears to be secondary to the proinflammatory effects of
      these cytokines or to their unmasking of a subtle hypercoagulable state.

PMID- 10575165
TI  - Current topics in nail surgery
AB  - BACKGROUND: Nail surgery can be performed in an office-based dermatology practice
      with a limited amount of specialized equipment and training. Several excellent
      reviews have been published in recent years that detail the techniques of nail
      surgery for both the novice and the experienced practitioner. OBJECTIVE: In this
      article recent developments in nail surgery are discussed. Topics that are
      treated include the general principles of nail surgery, including epidemiologic
      issues, studies of nail anatomy, instrumentation, and anesthesia. The
      reconstruction of injuries and congenital defects involving the nail is
      explained, and the role of the hand surgeon clarified. Appropriate removal of
      tumours and cysts is considered, with special attention to the management of
      malignant lesions. The controversy regarding more or less conservative management
      of melanonychia striata is addressed, and the need for early diagnosis of
      subungual melanoma is emphasized. Other topics are surgical management of ingrown
      nails and onychomycosis. Newer areas of nail surgery, such as laser surgery of
      the nail, psychodermatology of the nail, and the role of primary care physicians
      in simple nail surgery are also examined.

PMID- 10575166
TI  - Duhring on dermatitis herpetiformis.
AB  - BACKGROUND: In the late 1800s there was much confusion over the nomenclature and
      classification of persistent, very itchy vesiculo-bullous eruptions. OBJECTIVE:
      To review Duhring's contribution to clarifying this confusion. CONCLUSION: By his
      detailed, perceptive, clinical, and histologic reports over many years, Duhring
      contributed greatly to organizing our clinical concepts of bullous disorders.

PMID- 10575167
TI  - Reflections on becoming a dermatologist.

PMID- 10575168
TI  - Trends in the workload of the two high altitude aid posts in the Nepal Himalayas.
AB  - BACKGROUND: Acute mountain sickness (AMS), High altitude pulmonary edema (HAPE)
      and High Altitude Cerebral Edema (HACE) are well known problems in the high
      altitude region of the Nepal Himalayas. To assess the proportion of AMS, HAPE,
      and HACE from 1983 to 1995 in the Himalaya Rescue Association (HRA) aid posts'
      patients at the Everest (Pheriche 4,243 m) and Annapurna (Manang 3,499 m)
      regions, the two most popular trekking areas in the Himalayas. A retrospective
      study was conducted at the HRA medical aid posts in Manang (3,499 m) and Pheriche
      (4,243 m) in the Himalayas, where 4,655 trekkers (tourists, mostly Caucasians)
      and 4,792 Nepalis (mostly porters and villagers) were seen at the two high
      altitude clinics from 1983 to 1995, for a variety of medical problems, including
      AMS. METHODS: The number of trekking permits issued for entering the two most
      popular regions in the Himalayas was calculated and referenced to the proportion
      of trekkers with medical conditions. Well established guidelines like the Lake
      Louise Diagnostic Criteria were used in the assessment of AMS, HAPE and HACE.
      Linear regression analyses were performed on data collected from the two aid
      posts to determine the effect of time on each variable. For comparison between
      the aid posts, angular transformation (arcsine) and analysis of variance (ANOVA)
      were performed on all proportional (incidence) data. RESULTS: Approximately 20%
      of all visitors (Nepali plus trekkers) who visited the higher Pheriche aid post
      were diagnosed with AMS compared to around 6% at the lower Manang aid post. There
      was a linear increase over time in the number of trekkers entering the Everest
      (r=0.904, p<.001) and the Annapurna (r=0.887, p<.001) regions. The proportion of
      trekker patients with any medical condition visiting the two HRA aid posts at
      Manang and Pheriche, expressed as a function of the total number of trekkers
      entering the Everest and Annapurna regions, was not significantly different
      between Pheriche (average 4%) and Manang (average 1%). However, the proportion of
      AMS, HAPE and HACE in patients (Nepali plus trekkers) to the aid posts was
      greater in those visiting the higher Pheriche aid post compared to the lower
      Manang aid post (f=56.74, n=13; p<. 001). Importantly, only the proportion of AMS
      (r=0.568; p<.05) and not HAPE or HACE increased over time in Pheriche, alongside
      an unchanged proportion of trekker patients, amongst all Pheriche aid post
      patients. There was no increase of AMS, HAPE or HACE in Manang. CONCLUSIONS: HAPE
      and HACE are the life-threatening forms of AMS and although there is a linear
      increase of trekkers entering the Himalayas in Nepal, the findings revealed that
      HAPE and HACE have not increased over time. One possible explanation may be that
      awareness drives by organizations like the Himalayan Rescue Association may be
      effective in preventing the severe forms of AMS.

PMID- 10575169
TI  - Microsporidiosis in travelers with diarrhea from the tropics.
AB  - BACKGROUND: Microsporidia are protozoa which mainly affect severely
      immunodepressed AIDS patients in developed countries as well as those in
      developing ones. Traveler's diarrhea affects approximately 40% of people
      traveling from industrialized countries to developing ones, and no pathogens are
      identified in many of those patients on their returning, suggesting that known
      enteropathogens escape detection or entirely new ones could be responsible. Very
      few reports of travel-related microsporidiosis have been described. METHODS:
      Between January, 1996 and January, 1998, a total of 40 European travelers from
      the tropics with a clinical picture of protected diarrhea (three or more loose
      stools per day lasting for more than 3 weeks) were evaluated. Weber's trichrome
      modified by Kokoskin stain for microsporidial spores were performed in stool
      samples of every patient. Microsporidial DNA extraction and PCR amplification
      were attempted in every stool sample where microsporidial spores were observed.
      RESULTS: Four cases of imported Enterocytozoon bieneusi were detected: one HIV
      infected short term traveler, a pregnant long term traveler, and two
      immunocompetent short term travelers. Diarrhea was self-limited, and the spores
      cleared from the stools in all HIV-non infected travelers, but showed a chronic
      course in the HIV-infected one. CONCLUSIONS: Available data is too limited to
      affirm that residence or travel in tropical countries increases the risk for
      microsporidial infection, but the cases presented here suggest that E. bieneusi
      could be a cause of self-limited diarrhea in immunocompetent travelers returning
      from the tropics or could chronically affect immunocompromised HIV-infected
      travelers.

PMID- 10575170
TI  - Tolerance and immunogenicity of the simultaneous administration of virosome
      hepatitis A and yellow fever vaccines.
AB  - BACKGROUND: The purpose of this study was to evaluate the tolerance and
      immunogenicity of a hepatitis A vaccine using immunopotentiating reconstituted
      influenza virosomes (IRIV) as adjuvant when administered simultaneously with a
      yellow fever vaccine (YFV). METHOD: An open prospective trial with two parallel
      groups was conducted with 105 volunteers to study the effect of these
      vaccinations on the anti-hepatitis A virus (HAV) antibody response. Half of the
      volunteers (53) received one dose of IRIV-HAV vaccine (Epaxal) and one dose of
      live attenuated YFV (Stamaril) on the same day at two different sites. Fifty-six
      volunteers were given a single injection of IRIV-HAV as a control group. Anti-HAV
      titers were measured at days 14, 28, months 3, 12, 13, and 24 using a
      standardized test (Enzymun test Anti-HAV). Neutralizing yellow fever antibodies
      were measured at days 14 and 28 for the YFV recipients. Regarding vaccine
      tolerance, the volunteers were asked to record all their adverse reactions on a
      standard report sheet for the 6 days following the immunization. RESULTS:
      Seroconversion rates for HAV were 88% after 14 days and 100% after 4 weeks. There
      was no statistically significant difference between the two groups every time the
      titers were checked (IRIV-HAV vs HAV only: D14: 81 vs 101; D28: 275 vs 368; M3:
      153 vs 169; M12: 117 vs 226; geometrical mean titers (GMT) in mIU/mL). However,
      lower titers were found among male volunteers, and were not attributable to YFV
      administration. The seroconversion rates for YFV were 90% after 14 days and 96%
      after 4 weeks. No serious general side-effects and only mild local reactions were
      reported. The administration of a booster of IRIV-HAV at 12 months resulted in a
      24-fold increase in GMT. CONCLUSION: When needed, the simultaneous administration
      of the IRIV-HAV and YFV is immunogenic, safe and well-tolerated, as volunteers
      seroconverted to both antigens, with no cross-interference.

PMID- 10575171
TI  - Immunogenicity of rabies postexposure booster injections in subjects who had
      previously received intradermal preexposure vaccination.
AB  - BACKGROUND: Preexposure rabies vaccination is recommended using the full dose
      intramuscular or less expensive reduced dose intradermal method. The reliability
      of the reduced dose intradermal preexposure regimen is still controversial. The
      objective of this study was to determine whether it will mount a predictable
      accelerated immune response after a simulated rabies exposure. METHOD: One
      hundred and thirty-eight veterinary students received intradermal or
      intramuscular preexposure vaccination using a potent batch of purified chick
      embryo rabies vaccine. They then received booster injections one year later.
      RESULTS: Subjects who received intradermal rabies preexposure vaccination, using
      0.1 mL of a potent tissue culture vaccine on days 0, 7, and 28, had a lower
      postexposure booster antibody response 1 year later than subjects given the
      preexposure series intramuscularly. A significant number showed an unsatisfactory
      early anamnestic response. Residual neutralizing antibodies, 1 year after the
      intramuscular preexposure series, were also significantly higher in the
      intramuscular than in the 0.1 mL dose intradermal group. However, all study
      subjects had antibody titers above the minimum recommended level of 0.5 IU/mL by
      day 14. CONCLUSIONS: We conclude that not all subjects who received an
      intradermal preexposure vaccine series may be fully protected during the first 5
      days after an exposure. Rabies immune globulin, injected into bite wounds and
      followed by a complete postexposure vaccine series, may be indicated if such a
      patient experiences a severe rabies exposure.

PMID- 10575172
TI  - Economic issues in postexposure rabies treatment.
AB  - Rabies remains a worldwide public health problem even though means to control
      this disease are known. Logistic problems and cultural barriers for effective dog
      control in many countries and the high cost of human postexposure treatment,
      account for much of the remaining worldwide human toll. Efforts to make vaccines,
      with effective and safe tissue or avian culture products and immune globulin,
      more affordable have been only marginally successful. Second generation rabies
      vaccines (purified Vero-, chick and duck embryo cell products) are effective,
      safe and less expensive than human diploid cell rabies vaccine. Reduced dose
      intradermal postexposure vaccination works, is affordable, and has helped abolish
      the use of dangerous and poorly immunogenic brain tissue-derived vaccines in
      Thailand, the Philippines, and Sri Lanka. The use of purified equine rabies
      immune globulin has been found to be safe and cost-effective. It is,
      unfortunately, in short supply worldwide. Preexposure rabies vaccination for
      travelers to endemic regions is recommended and should be administered by the
      intramuscular route whenever possible.

PMID- 10575173
TI  - Travel insurance and health.
AB  - Travel insurance normally underwrites travel, medical, and dental expenses
      incurred by travelers abroad and arranges aeromedical evacuation of travelers
      under conditions specified by the travel insurance policy. Because of the costs
      of medical and dental treatment abroad and the high cost associated with
      aeromedical evacuation, all travelers should be advised of the need for
      comprehensive travel insurance and be advised to read their policies carefully to
      see what is covered and to check for any exclusions. In particular, those
      travelers who have known preexisting conditions, who are working overseas, or who
      are going to undertake any form of hazardous recreational pursuit may need to
      obtain a special travel insurance policy, which may attract a higher premium.
      Conservatively, it is estimated that between 30-50% of travelers become ill or
      injured whilst traveling. Relative estimated monthly incidence rates of various
      health problems have been compiled elsewhere. The risk of severe injury is
      thought to be greater for people when traveling abroad. These risks should be
      covered by travel insurance to protect the traveler, however it is not known what
      proportion of travel agents or airlines give advice routinely on travel
      insurance. Travel insurance is the most important safety net for travelers in the
      event of misadventure, and should be reinforced by travel health advisers.
      Although only 4% of general practitioners (GPs) in a late 1980's study in the
      United Kingdom would advise a traveler going to Turkey about travel insurance,4
      more recent studies have shown about 60% of GPs in New Zealand and 39% of travel
      clinics worldwide usually advised travelers concerning travel insurance. In
      addition, 54% of GPs in New Zealand usually also advised travelers about finding
      medical assistance abroad, but only 19% of GPs recommended travel insurance
      companies as a source of medical assistance while traveling.

PMID- 10575174
TI  - Cystic echinococcosis in a Jordanian patient: albendazole in a short-term
      immigrant.
AB  - With an ever increasing number of international travelers, physicians should be
      aware of the diseases that have rarely been encountered in their home countries.
      Cystic echinococcosis (CE) caused by Echinococcus granulosus is seldom seen in
      Japan despite frequent occurrence of the other type of echinococcosis, alveolar
      echinococcosis (AE) caused by E. multilocularis, in its northern parts. However,
      CE is prevalent in many parts of the world including the United Kingdom,
      Mediterranean basin, Middle East, South America, and Australia, and is supposed
      to be resurgent in several parts of the world. The disease is acquired by the
      oral ingestion of the eggs of E. granulosus passed into the feces of several
      definitive host animals carrying tapeworms, mostly dogs. These definitive hosts
      are infected by cannibalizing intermediate host animals including sheep and
      cattle whose livers and/or lungs are affected by cystic lesions that contain
      protoscoleces. In endemic areas the diagnosis of CE is not considered to be
      complicated; typical morphological features composed of cysts as revealed by
      ultrasonography and/or computerized tomography (CT) scan. The diagnosis is also
      aided by serological methods detecting serum antibodies. However, imaging
      procedures show a variety of features that could often lead to misdiagnosis as
      other diseases. Moreover, serological assays are sometimes difficult to interpret
      because of their incomplete sensitivities and specificities. Hence, a
      comprehensive understanding of a spectrum of imaging features and the application
      of serological methods with better sensitivities and specificities are
      indispensable. The mainstay of treatment of the disease is still surgical removal
      of cysts that has the potential to lead to a complete cure. Recently, the less
      invasive method PAIR (Puncture of cysts percutaneously, Aspiration of fluid,
      Introduction of protoscolicidal agent, and Reaspiration) was introduced with
      considerable success, and could be a promising alternative to surgery. Lastly,
      medical treatment with oral mebendazole or albendazole, especially the latter,
      can be beneficial not only as a adjunctive to surgery or PAIR, but as a sole
      treatment in cases in which invasive methods are not indicated. Here we report a
      Jordanian patient with CE whose diagnosis was substantiated by a novel immunoblot
      assay and who showed a rapid improvement during albendazole therapy.

PMID- 10575175
TI  - Malaria protection measures used by in-flight travelers to South African game
      parks.
AB  - Malaria prevention in travelers depends upon dissemination of accurate
      information about malaria risk, prevention of mosquito bites, appropriate
      chemoprophylaxis use and knowledge of the symptoms of malaria. A study was
      undertaken of travelers to the Kruger National Park and private game parks in
      Mpumalanga Province, South Africa to investigate travelers knowledge, of malaria,
      chemoprophylaxis use, and experience of adverse events. In-flight self
      administered questionnaires were distributed and completed by travelers on
      flights returning to Johannesburg International Airport, from the malaria areas.
      The study was conducted during the highest malaria risk period during 1996. The
      Mpumalanga game parks are those most visited in South Africa and are found in the
      extreme northeast of the country, which adjoins Mozambique in the east and
      Zimbabwe in the north. This area is classified by the South African health
      authorities as being a high risk Malaria area.10 Chloroquine-resistant Plasmodium
      falciparum malaria has been described in this area.2,3 The Department of Health
      in South Africa recommends the use of mefloquine alone or the combination of
      chloroquine and proguanil, (doxycycline is prescribed for travelers in which the
      former antimalarials cannot be utilized), for visitors to this area during the
      high risk period for malaria, which extends from October to May.4 For the
      remainder of the year mosquito avoidance measures are recommended. Little is
      known about travelers' compliance with these recommendations and their knowledge
      of malaria. A study to explore these factors was undertaken as a joint initiative
      between the SAIMR travel clinic, Mpumalanga Department of Health, and the South
      African National Parks.

PMID- 10575176
TI  - Bat-associated histoplasmosis in returning travelers: case presentation and
      description of a cluster.
AB  - Histoplasma capsulatum is a dimorphic fungus with the mycelial form producing
      spores that are readily airborne and able to reach small bronchi and alveoli.
      Isolation of the mycelial form of H. capsulatum in nature shows a striking
      correlation with moist, acidic soils, frequently contaminated with bird or bat
      excreta. Bats, but not birds, may be infected by H. capsulatum and may excrete
      the fungus in their feces. Skin test surveys show that the infectious agent is
      present worldwide in the areas between 45 degrees north and 30 degrees south of
      the equator. Clusters of cases may occur because of the disturbance of soil
      contaminated with H. capsulatum, or by visiting bat caves. Cave-associated
      histoplasmosis has been reported from the Americas, Africa, Oceania, and Africa.
      Recently, cave-associated histoplasmosis has been reported in travelers returning
      from Costa Rica and Peru. We report a cluster of cave-associated acute
      histoplasmosis that occurred in college students returning from Ecuador. Advice
      regarding histoplasmosis prevention should be given to travelers planning to
      visit bat-infested caves, and histoplasmosis should be considered in the
      differential diagnosis of febrile illness in returning travelers with a history
      of epidemiologic or geographic exposure.

PMID- 10575177
TI  - Honeymoon malaria and "herbal" therapy: A case report.
AB  - A marked rise in the number of cases of malaria in the UK contracted in east
      Africa has been reported in 1998. This may be explained by the "Lariam"-media
      hype, poor understanding, poverty of health education, or increase in travel to
      more exotic destinations. European centers have experienced changes in the
      pattern of imported malaria and constant up-dates are essential. However even the
      best informed may still acquire malaria.

PMID- 10575178
TI  - Suboptimal prophylaxis for P. falciparum.

PMID- 10575179
TI  - Epidemiology and natural history of hepatitis G virus infection in chronic
      hemodialysis patients.
AB  - Patients on chronic hemodialysis (HD) have recently been identified as having a
      high prevalence of hepatitis G virus (HGV) infection. The clinical significance
      of HGV in this population remains unclear, with no data available as to the
      acquisition and natural history of HGV infection in this group. AIMS: To assess
      the prevalence and risk factors of HGV in a large cohort of chronic HD patients,
      and to evaluate the incidence and clinical consequences of HGV over time in this
      population. METHODS: Paired sera from 292 patients undergoing chronic HD
      treatment in four units in the Los Angeles area were tested for HGV RNA before
      and after they had been on HD for a mean period of 9.7 +/- 1.9 months. HGV was
      tested by a single-step RT-PCR using two couples of primers located in two
      different portions (5'UTR, NS5a) of the genome. The amplified products were
      detected by hybridization with 5' biotin-labeled probes specific for each region.
      RESULTS: At study entry there were 50 HGV RNA-positive patients, thus the HGV
      prevalence was 17% (50/292). The multivariate analysis by ordinal logistic
      regression model showed association (p = 0.0013) between HGV RNA and the location
      of patients among the HD units. No other significant associations were observed.
      Three (3/50 = 6%) HGV RNA-positive patients at study entry and 3 (3/41 = 7%) at
      the end of the follow-up showed a mild increase of alanine aminotransferase (ALT)
      activity in absence of other apparent causes of liver damage. 35 (70%) out of 50
      HGV viremic patients had persistently detectable viremia during the study period;
      15 (30%) had non-persistently detectable HGV RNA in the second serum specimen.
      There was no significant difference between the patients with persistently
      detectable HGV RNA and those who showed non-persistently detectable HGV viremia
      with regard to demographic, clinical or virological features. Six patients
      without detectable HGV viremia at the start of the study showed de novo HGV
      infection during the follow-up, thus the HGV incidence was 3.07% per year. These
      individuals did not simultaneously acquire HBV or HCV markers; de novo HGV
      infection was not associated with other demographic, clinical or virological
      features. One (16.7%) out of 6 individuals with HGV acquisition had persistently
      raised ALT levels and chronic HBsAg positivity. The prevalence of HGV was 14%
      (41/292) at the end of the observation period. CONCLUSIONS: The prevalence of HGV
      in our HD population was high; HGV positivity was strongly associated with the
      location of HD patients among the units; some HD individuals with current HGV
      infection showed biochemical signs of liver disease without other apparent
      causes. De novo acquisition of HGV occurred within HD units in the absence of
      evident parenteral risk factors for HGV other than their presence in the HD
      environment. A large portion of HGV viremic patients showed non-persistently
      detectable HGV viremia during the study. Acquisition of HGV was not associated
      with a rise in ALT activity unlike prior experience with de novo HCV in HD
      patients. Further investigations are warranted to explain the modes of HGV
      acquisition and the clinical significance of HGV in th HD population.

PMID- 10575180
TI  - Magnetic resonance imaging of pseudotumors of the craniovertebral junction in
      long-term hemodialysis patients.
AB  - BACKGROUND/AIMS: Pseudotumors of the craniovertebral junction (PTCVJ) are
      observed in long-term hemodialysis (HD) patients. There are neither criteria for
      diagnosis nor guidelines for screening. We attempted to determine magnetic
      resonance imaging (MRI) findings that could be used to detect PTCVJ, to determine
      the prevalence of PTCVJ, and to evaluate whether destructive spondyloarthropathy
      (DSA) might be a yardstick for selection of patients for MRI examination for
      PTCVJ. METHODS: MRI were examined in 19 DSA patients (8 males, 11 females, age
      61.4 +/- 7.3 years, HD duration 17.0 +/- 4.4 years) and in 20 sex-, age-, and HD
      duration-matched non-DSA patients (9 males, 11 females, age 57.5 +/- 6.6 years,
      HD duration 17.7 +/- 4.9 years). We evaluated MRI characteristics of PTCVJ
      according those which occur due to rheumatoid arthritis. RESULTS: PTCVJ were
      characterized as follows: disappearance of fat pads in the upper region
      (supradental PTCVJ), intensity change of the 'predental triangle' in the anterior
      region (predental PTCVJ), and thickening of cruciform ligaments (retrodental
      PTCVJ). The prevalence of PTCVJ among patients undergoing HD more than 10 years
      was high (26 out of 39; 66.7%). The prevalence of PTCVJ was not different between
      DSA and non-DSA groups. CONCLUSION: We verified that the above MRI findings might
      be helpful in the detection of PTCVJ. These findings were observed frequently and
      independently also in patients with DSA.

PMID- 10575181
TI  - Circadian blood pressure changes and cardiac abnormalities in IgA nephropathy.
AB  - The absence of diurnal blood pressure rhythm is characteristic of patients with
      chronic glomerulonephritis already before they develop hypertension. The
      prognostic importance and possible target organ-damaging effect of the absence
      are unknown. Simultaneously, 24-hour ambulatory blood pressure monitoring and
      echocardiographic investigations were done in 12 normotensive and 38 hypertensive
      IgA nephropathy patients. The hypertensive patients were treated with either
      angiotensin-converting enzyme inhibitor (ACEI) alone or in combination with a non
      dihydropyridine calcium channel blocker. The absence of a night-time blood
      pressure reduction was frequent in both groups (5/12 vs. 20/38). In the
      hypertensive patients, blood pressure and left ventricular mass index were higher
      (124.6 +/- 23. 3/81.2 +/- 15.3 vs. 106.6 +/- 33.4/67.4 +/- 21.8 mm Hg, p < 0.001,
      and 124.1 +/- 46.2 vs. 89.2 +/- 45.6 g/m(2), p < 0.01). Diastolic left
      ventricular function was better in normotensive patients, in whom E wave/A wave
      ratio (E/A) and decelaration time values correlated closely with the diastolic
      diurnal index (E/A, r = 0.86, p < 0.01; DT, r = -0.70, p < 0.01). In the
      hypertensive patients, both the left ventricular wall thickness and diastolic
      function were significantly related to nighttime blood pressure and diurnal index
      values, but there was no relationship with daytime blood pressure. In conclusion,
      in IgA nephropathy patients there are mild cardiac abnormalities before they
      develop hypertension, the abnormalities bearing the closest correlation with the
      decrease in diurnal blood pressure rhythm. These data suggest the inefficacy of
      ACEI and calcium channel blockers in treating nighttime hypertension and in
      reestablishing diurnal rhythm. These phenomena are of great importance in the
      development of left ventricular hypertrophy and diastolic malfunction.

PMID- 10575182
TI  - Renal reabsorption of phosphate in children with sickle cell anemia.
AB  - It has previously been reported that in adult patients with sickle-cell anemia
      the serum phosphate value and the maximum tubular reabsorption of phosphate per
      liter of glomerular filtrate (TmP/GFR) were significantly higher than in normal
      controls. This does not appear to have been studied in children with sickle cell
      anemia (young sicklers) and this prompted us to assess renal phosphate
      reabsorption in this group of patients. We looked at serum phosphate level and
      calculated renal phosphate reabsorption (TP/GFR) in children taking random urine
      and blood samples at the same time and using the formula TP/GFR = Sp - Up x SCr:
      UCr, in 30 young sicklers all of whom had normal renal function (mean age 7.3
      years) and 40 normal matching controls (mean age 6.5 years). The mean serum
      phosphate value in young sicklers was significantly lower than in controls (4.3
      against 5.3 mg/dl) while the mean value of TP/GFR was 4.09 +/- 0.74 mg/dl in
      young sicklers compared to 4.65 +/- 0.75 mg/dl in the control group (p = 0.0026).
      Therefore, the TP/GFR in young sicklers was also significantly lower (p = 0.0026)
      than in the control group. This may be explained by the high serum level of
      parathyroid hormone reported previously in patients with sickle cell anemia which
      is expected to lower phosphate reabsorption (TmP/GFR and TP/GFR are identical in
      children). The lower serum phosphate value and TP/GFR in younger sicklers seems
      to be in contrast with the relatively high serum phosphate value and TP/GFR
      previously reported in adults with sickle cell anemia.

PMID- 10575183
TI  - Use of cefazolin for peritonitis treatment in peritoneal dialysis patients.
AB  - For over two decades, intraperitoneal administration of vancomycin and an
      aminoglycoside has been an accepted regimen for the empiric treatment of
      peritonitis in the peritoneal dialysis patient, until definite identification of
      the organism has been made. The recent emergence of vancomycin-resistant
      organisms has been of great concern in many centers. The current treatment
      recommendation therefore is to use cefazolin in place of vancomycin. We analyzed
      peritonitis data from January 1, 1996 to June 30, 1997, prior to switching over
      to cefazolin. Seventy-five percent (27 episodes) in 1997 as compared to 78% in
      1996 were due to gram-positive organisms. Twenty-two percent (8 episodes) were
      due to gram- negative organisms in 1997, 21% in 1996, and 3% (1 episode) due to
      yeast in 1997, 3% in 1996. Staphylococcus epidermidis (SE) caused 33% of the gram
      positive peritonitis episodes in 1997 as compared to 37% in 1996. Twenty-two
      percent of the gram-positive episodes were due to Staphylococcus aureus (SA) in
      1997 and 46% in 1996. Enterococcal infections were 26% in 1997 and 1% in 1996.
      All of these were confined to only 1 patient. The antibiogram revealed 100%
      sensitivity of both SA and SE to vancomycin and 100% sensitivity of SA to
      cefazolin, but only 11% sensitivity of SE to cefazolin. The same patient
      population had a 48% sensitivity of SE to cefazolin in 1996, showing a sudden and
      substantial increase in resistance to SE. Even though SE is thought to be a less
      virulent organism, treating patients with a high probability of being infected by
      SE with an antibiotic showing 89% resistance is not warranted.

PMID- 10575184
TI  - Short- and long-term outcome of total parathyroidectomy with immediate
      autografting versus subtotal parathyroidectomy in patients with end-stage renal
      disease.
AB  - A retrospective study was performed in 36 patients with end-stage renal disease
      (ESRD) comparing total parathyroidectomy followed by immediate autografting into
      the forearm (total PTX + IA) with parathyroidectomy (subtotal PTX) over a five
      year period. Twenty-eight patients underwent subtotal PTX and 8 had total PTX +
      IA. The two surgical methods were evaluated with respect to preoperative severity
      of hyperparathyroidism, perioperative morbidity, and the incidence of recurrent
      hyperparathyroidism. Eleven patients in total (30.6%) developed recurrent
      hyperparathyroidism; 2/8 (25%) in the total PTX + IA group compared to 9/28
      (32.1%) in the subtotal PTX group (p = 0.699). The median time to recurrence was
      longer in the total PTX + IA group (39 vs. 16 months), and the median long-term
      postoperative PTH value was lower (81 vs. 199 ng/l), but these differences did
      not reach statistical significance. In conclusion, the incidence of recurrent
      hyperparathyroidism is high regardless of surgical modality. However, total PTX +
      IA may produce more favorable results with respect to median postoperative PTH
      level and time to recurrence.

PMID- 10575185
TI  - Risk factors for hospitalization in well-dialyzed chronic hemodialysis patients.
AB  - BACKGROUND/AIMS: Hemodialysis (HD) patients are hospitalized more frequently than
      patients with other chronic diseases, averaging 11.5 hospital days/patient/year.
      Hospital costs attributable to renal failure in the US exceed $2 billion per
      year. The present healthcare climate continues to force dialysis providers to
      focus on these issues in order to optimize patient care while limiting cost.
      METHODS: We used a novel method for analyzing hospitalization risk, a multiple
      event Cox proportional hazards model, to identify factors that influenced
      hospitalization in a HD unit population over a two-year period. This model allows
      individual patients to contribute multiple failure events to the model while
      controlling for the serial dependency of events. RESULTS: 178 HD patients were
      retrospectively examined. There were 381 hospitalizations during the study
      period, averaging out to 1.9 hospitalizations and 10.5 hospital days/patient
      year. Substance abuse and diabetes conveyed the largest risks for hospitalization
      (diabetes RR: 2.09; substance abuse RR: 2.24) in the study cohort, exposing the
      necessity for examining practice patterns and behavioral interventions as means
      for improving HD patient care. CONCLUSION: Despite the small numbers of patients
      in this single-center HD population, the model achieved adequate statistical
      power. Therefore, it has the potential to serve as a continuous quality
      improvement (CQI) tool in particular HD patient sub-groups, or in individual HD
      units.

PMID- 10575186
TI  - Circulating concentrations of soluble interleukin 6 receptors gp80 and gp130 in
      chronic renal failure and effects of renal replacement therapy.
AB  - BACKGROUND: Circulating receptors modulate the biological effects of cytokines.
      Renal insufficiency is known to influence the concentrations of the soluble tumor
      necrosis factor (TNF) receptors p55 and p75. No data are available on the
      concentrations of the circulating interleukin 6 (IL-6) receptors gp80 and gp130
      during chronic renal insufficiency. METHODS: We compared the serum concentrations
      of the IL-6 receptors gp80 and gp130 to those of the TNF receptors p55 and p75 in
      end-stage chronic renal failure, continuous ambulatory peritoneal dialysis, and
      hemodialysis (HD). RESULTS: In healthy controls the concentrations of gp80,
      gp130, p55, and p75 in serum were 82.1 +/- 24.3, 87.9 +/- 20.2, 1.1 +/- 0.2, and
      1.7 +/- 0.3 ng/ml, respectively. These concentrations were increased to,
      respectively, 112.2 +/- 18.0, 186.0 +/- 37.7, 10.5 +/- 4.3, and 15.0 +/- 7.5
      ng/ml in chronic renal failure, to 138.8 +/- 18.0, 181. 3 +/- 46.1, 25.5 +/- 5.2,
      and 19.1 +/- 3.4 ng/ml in continuous ambulatory peritoneal dialysis, and to 107.9
      +/- 29.4, 146.6 +/- 30. 5, 22.9 +/- 6.3, and 16.8 +/- 6.0 ng/ ml in HD (before
      dialysis session). The concentrations after HD were higher for p75 only.
      CONCLUSIONS: The data show that the concentrations of the IL-6 receptors (gp80
      and gp130) are elevated in chronic renal insufficiency. The increase is
      relatively low as compared with the elevation of the TNF receptors in this
      situation. HD does not result in a consistent change in serum concentrations of
      the various receptors.

PMID- 10575187
TI  - A prospective study of hepatitis C viremia in renal allograft recipients.
AB  - In an attempt to study the impact of HCV viremia on renal transplant clinical
      course and outcome, we prospectively followed 133 HBsAg-negative end stage renal
      disease (ESRD) patients, in whom HCV-RNA-PCR results were available, from the pre
      to post-transplant period. Eighty (60%) ESRD patients tested PCR-positive, of
      these, 12 (15%) were anti-HCV negative by second generation ELISA. The viremic
      patients had a longer time on dialysis (p < 0.001), received more blood units (p
      < 0.001) and had a higher frequency of pre-transplantation liver disease (p <
      0.001). Further, 41% of PCR-positive patients gave a history of antischistosomal
      treatment compared with 23% of PCR-negative ones (p = 0.048). Recipients with and
      without HCV viremia were followed for a mean of 31.8 +/- 5.8 (range 6-42) months
      and 29.8 +/- 9 (range 6-41) months respectively, p = 0.14. While the prevalence
      of HCV viremia increased from 60 to 64% at the last follow-up, the anti-HCV
      seroprevalence decreased from 63 to 61%. PCR-positive patients had higher rates
      of both acute (p = 0.005) and chronic (p < 0.001) liver disease after
      transplantation compared with PCR-negative patients. However, none of our HCV RNA
      positive recipients developed a fulminant liver disease or hepatic failure until
      the last follow-up. Stepwise logistic regression analysis identified pre
      transplant liver disease (Odds ratio = 2.4; p = 0.07) and a cumulative
      corticosteroid dose in excess of 15 g at the last follow-up (Odds ratio = 3; p =
      0.03) as independent predictors of post-transplant hepatic dysfunction in PCR
      positive patients. Azathioprine was discontinued due to hepatic dysfunction in a
      significantly (p = 0.005) higher proportion of viremic patients compared with the
      non-viremic ones. There were no significant differences between PCR-positive and 
      negative patients in terms of frequencies and individual causes of graft and
      patient losses. Our results demonstrate that HCV infection is extremely prevalent
      in Egyptian hemodialysis patients and is responsible for most hepatic
      dysfunctions after transplantation. Although HCV viremia did not negatively
      affect graft or patient outcome until 31 months post-transplantation, the authors
      would recommend that a viremic patient should have a liver biopsy before
      transplantation and be immunosuppressed with caution post-transplantation. A
      longer follow-up may be required to exclude increased rates of HCV-induced
      hepatic mortalities.

PMID- 10575188
TI  - Mycobacterium fortuitum peritonitis in two patients receiving continuous
      ambulatory peritoneal dialysis.
AB  - We present two cases of non-resolving peritonitis treated with a standard
      peritonitis protocol. The organism identified from the peritoneal effluent was
      Mycobacterium fortuitum, a group IV (Runyon's classification) rapidly growing,
      nontuberculous mycobacterium. M. fortuitum is ubiquitous and can be isolated from
      a number of natural sources. Risk factors these two patients had for developing
      M. fortuitum peritonitis included underdialysis, the immunocompromised state
      associated with end stage renal disease, prior or prolonged broad spectrum
      antibiotic treatment, and possible exposure to environmental factors, since both
      were hospitalized at about the same time. The isolates were resistant to the
      conventional antibiotics recommended for the treatment of this mycobacterium.
      Both patients, however, responded to catheter removal and antibiotics
      administered according to the sensitivities of the mycobacterium isolated.

PMID- 10575189
TI  - Thrombotic microangiopathy with renal failure in two patients undergoing
      gemcitabine chemotherapy.
AB  - Described here are 2 patients who developed thrombotic microangiopathy of the
      kidneys after receiving high cumulative doses of the new anticancer drug
      gemcitabine. The first patient, who received gemcitabine for treatment of a
      carcinoma of the pancreas, required hemodialysis for 6 months. In the second
      case, a woman suffering from a cholangiocellular carcinoma, end-stage renal
      disease was irreversible. Clinical awareness, timely detection and
      discontinuation of gemcitabine are mandatory to prevent this rare but disastrous
      complication of gemcitabine therapy.

PMID- 10575190
TI  - A case of primary antiphospholipid antibody syndrome with acute renal failure
      showing thrombotic microangiopathy.
AB  - An 18-year-old woman complained of fever and edema and was admitted to Showa
      University Hospital for treatment of thrombocytopenia and deteriorating renal
      function. Laboratory studies demonstrated the presence of lupus anticoagulant
      (LA), prolongation of prothrombin time, hemolytic anemia, a negative Coombs'
      test, the absence of antinuclear antibodies, and a normal fibrinogen level. Renal
      biopsy revealed mesangial hypercellularity, severe endocapillary cell damage, and
      double contour of the basement membrane walls. Immunofluorescence studies
      demonstrated focal, peripheral, and finely granular deposits for IgG, IgM, and
      IgA but were negative for fibrinogen. Electron microscopy showed glomerular
      capillary loops with subendothelial widening and subendothelial deposits,
      mesangiolysis, mesangial interposition, and marked luminal narrowing. Biopsy
      findings were consistent with thrombotic microangiopathy. The patient was treated
      with hemodialysis, methylprednisolone pulse therapy, and dipyridamole. After
      treatment, LA disappeared, the prothrombin time became normal, and renal function
      improved. The renal lesions in this patient were caused by primary
      antiphospholipid antibody syndrome. This case strongly suggests an important
      causal relationship between LA and renal lesions in thrombotic microangiopathy.
      We present this case to promote understanding of the pathogenesis of primary
      antiphospholipid antibody syndrome.

PMID- 10575191
TI  - Membranoproliferative glomerulonephritis type I, mixed cryoglobulinemia and
      lymphoma in the absence of hepatitis C infection.
AB  - Chronic hepatitis C virus infection has been linked to cryoglobulinemia,
      membranoproliferative glomerulonephritis, and malignant B-cell
      lymphoproliferation, suggesting a possible pathogenetic link between these
      disorders. We report a patient with the latter clinical triad in the absence of
      hepatitis C infection. We postulate that the persistent and dysregulated
      immunologic activity associated with chronic antigen stimulation, inflammation
      and/or B-cell malignancy induces nephritogenic autoantibodies, including
      cryoglobulins, that produce a similar clinical syndrome in genetically
      susceptible individuals.

PMID- 10575192
TI  - Staphylococcus lugdunensis pulmonary valve endocarditis in a patient on chronic
      hemodialysis.
AB  - We describe a case of Staphylococcus lugdunensis pulmonary valve endocarditis in
      a 65-year-old woman on chronic hemodialysis and provide a review of previously
      reported cases. The patient presented with fever and altered mental status, but
      had no other localizing symptoms or signs; coagulase-negative staphylococcus
      (subsequently identified as S. lugdunensis) was isolated from two sets of blood
      cultures. Transthoracic and transesophageal echocardiograms showed a large (2.3 x
      3.1 cm) vegetation on the pulmonary valve with moderate valvular insufficiency.
      The patient was treated with 6 weeks of antibiotic therapy and is stable 4 months
      following the completion of therapy; no surgical intervention was performed. Of
      the 28 previously reported cases of S. lugdunensis endocarditis, only 1 had
      previously survived with medical therapy alone. This is the 3rd case report of S.
      lugdunensis endocarditis in a patient on hemodialysis; the presumed portal of
      entry in this and previously reported cases was the vascular access device.
      Endocarditis due to this organism is characterized by a high mortality, rapid
      tissue destruction, and a predilection for native valves. Because the clinical
      outcome is much more favorable with valvular replacement, speciation of the
      organism assumes great importance in defining the therapeutic approach.

PMID- 10575193
TI  - Antioxidant effect of zinc on acute renal failure induced by ischemia-reperfusion
      injury in rats.
AB  - Zinc may have an antioxidant effect mediated by induction of metallothionein.
      Based on the assumption that metallothionein can scavenge oxygen free radicals,
      we examined whether zinc administration prior to renal ischemia would improve
      renal dysfunction caused by ischemia-reperfusion injury in rats. Wistar rats
      weighing 265 g were treated with an intraperitoneal injection of 20 mg/kg zinc 24
      h prior to the renal ischemia-reperfusion procedure, which was achieved by a 30
      min clamping of the bilateral renal vessels and subsequent 90-min reperfusion.
      Thirty-minute renal clearance tests were performed before and after renal
      ischemia in zinc- (n = 11) and saline-treated (n = 8) rats. Thiobarbituric acid
      reactive substance, conjugated diene, and metallothionein levels in the renal
      tissues were also determined. Sham-operated rats (n = 5 in each treatment) served
      as control for the ischemia-reperfusion rats. Ischemia-reperfusion resulted in
      significantly lower glomerular filtration rate values and marked increases in
      tissue concentrations of thiobarbituric acid reactive substance and conjugated
      diene compared with sham-operation. Zinc administration improved the reduced
      glomerular filtration rate values seen after the ischemia-reperfusion procedure,
      but not to the extent of pre-ischemic levels. Zinc pretreatment significantly
      reduced the increased levels of thiobarbituric acid reactive substance and
      conjugated diene during ischemia-reperfusion and increased metallothionein levels
      compared with saline injection. These findings suggest that zinc has an
      antioxidant effect mediated through the induction of metallothionein, but appears
      only to have a minor protective effect on renal function induced by renal
      ischemia-reperfusion injury.

PMID- 10575195
TI  - Nephrotic syndrome with acute renal failure and cerebral infarction in a patient
      with myasthenia gravis.

PMID- 10575194
TI  - Treatment with a Ca(2+) channel blocker, barnidipine, reduces platelet-derived
      growth factor B-chain mRNA in glomeruli of spontaneously hypertensive rats.
AB  - We investigated the effect of barnidipine hydrochloride, a Ca(2+) channel
      blocker, on the glomerular level of mRNA expression of platelet-derived growth
      factor (PDGF) B-chain and transforming growth factor (TGF)-beta(1) in
      spontaneously hypertensive rats (SHR) with reverse transcription and polymerase
      chain reaction. Thirteen-week-old SHR were provided with food containing
      barnidipine (0.6 mg/g of food, average dose during treatment: 53 mg/kg of body
      mass/day) for 3 weeks. A stable reduction in systolic blood pressure relative to
      that of age-matched control SHR was recorded after week 1 of therapy. Although no
      renal histological changes were observed after 3 weeks of treatment with
      barnidipine, the level of expression of PDGF B-chain mRNA in glomeruli was
      significantly reduced relative to that in control SHR. The glomerular level of
      TGF-beta(1) mRNA expression was not affected by the treatment. Treatment with
      barnidipine significantly reduced the excretion of urinary protein. Thus, the
      stable reduction in systemic blood pressure by barnidipine is associated with a
      reduction in PDGF B-chain mRNA expression in the glomerulus and reduction in
      urinary protein excretion in SHR.

PMID- 10575196
TI  - Structure and function of cardiac pacemaker channels.
AB  - Cardiac pacemaking is controlled by a mixed Na(+)/K(+) current named I(f), which
      is activated by hyperpolarized membrane potentials. Recently, a family of
      hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels has
      been cloned. The members of this family exhibit the general features of I(f)
      channels. This review describes the molecular diversity of the HCN channel family
      and the structural determinants of channel function including activation by
      voltage, modulation by cyclic nucleotides and ion permeation. The relationships
      between cloned HCN channel types and native cardiac I(f) currents are explored.

PMID- 10575197
TI  - Isoform diversity and modulation of sodium channels by protein kinases.
AB  - Although voltage-dependent sodium channels from the brain have been realized as
      targets for regulatory protein phosphorylation since the first isolation of
      sodium channels as proteins, the functional role of phosphoprotein formation has
      been obscured until recently. The review summarizes progress on the modulation of
      voltage-dependent sodium channels by serine/threonine protein kinases, i.e. PKA
      and PKC. Divergent modulation is discussed in context with divergent primary
      structure of the alpha-subunit.

PMID- 10575198
TI  - Biophysical properties and molecular basis of cardiac rapid and slow delayed
      rectifier potassium channels.
AB  - Normal cardiac action potential repolarization is dependent on activation of
      several K(+) currents, including I(Kr) and I(Ks). I(Kr) activates rapidly at
      positive potentials, exhibits inward rectification caused by C-type inactivation,
      and is potently blocked by methanesulfon-anilide antiarrhythmic drugs and several
      other common medications. I(Ks) activates very slowly, does not inactivate and is
      blocked by some benzodiazepines and a chromanol. HERG encodes subunits that form
      channels that mediate I(Kr). KVLQT1 and minK encode subunits that coassemble to
      form channels that mediate I(Ks). Mutations in any of these genes cause long QT
      syndrome, a disorder of cardiac repolarization that predisposes individuals to
      lethal arrhythmias. In this review, we summarize recent studies of the
      biophysical and pharmacological properties of HERG and KvLQT1/minK K(+) channels.

PMID- 10575199
TI  - Cardiac ultrarapid delayed rectifiers: a novel potassium current family o f
      functional similarity and molecular diversity.
AB  - Classical cardiac delayed rectifier currents activate at least two orders of
      magnitude slower than delayed rectifier currents in nerve and skeletal muscle
      tissue. It has recently become evident that many cardiac tissues express delayed
      rectifier currents with kinetics similar to those of nerve and muscle. These
      currents have been designated I(Kur) (for 'ultrarapid' delayed rectifier), in
      contrast to the classical cardiac rapid (I(Kr)) and slow (I(Ks)) delayed
      rectifier components. Although the kinetics of I(Kur) in different species and
      tissues are similar, their pharmacological properties vary greatly. It now
      appears that the differences among various I(Kur)s are due to differences in the
      molecular basis. A variety of Shaker-related clones (Kv1.2, 1.5, 2.1 and 3.1)
      that form I(Kur) channels upon heterologous expression have been identified with
      specific I(Kur)s (e.g. Kv1.2, rat atrium; Kv1.5, mouse ventricle and human
      atrium; Kv3.1, dog atrium). The present article reviews the distribution,
      biophysical and pharmacological properties, molecular basis and functional role
      of I(Kur), as well as the potential value of I(Kur) as a target for new
      antiarrhythmic drug development.

PMID- 10575200
TI  - Molecular basis, pharmacology and physiological role of cardiac K(ATP) channels.
AB  - ATP-dependent potassium (K(ATP)) channels exist in high density in the
      sarcolemmal membrane of heart muscle cells. Under normoxic conditions these
      channels are closed, but they become active when the intracellular ATP level
      falls. This leads to a shortening of the action potential duration, rendering the
      heart susceptible for life-threatening arrhythmias. Molecular biology has
      revealed that K(ATP) channels consist of heteromultimers of the inwardly
      rectifying channel Kir6.2 and the sulfonylurea receptor SUR. To date, three types
      of SURs were identified, representing the pancreatic (SUR1), the cardiac (SUR2A)
      and the smooth muscle (SUR2B) K(ATP) channel. In order to develop a novel
      therapeutic principle against ischemia-induced life-threatening arrhythmias
      leading to sudden cardiac death, the cardioselective K(ATP) channel blocker HMR
      1883 was developed. This substance inhibits the sarcolemmal cardiac K(ATP)
      channel activated by the channel opener rilmakalim half-maximally at
      concentrations of 0.6-2.2 micromol/l, and substantially affects pancreatic K(ATP)
      channels at 9-50 times higher concentrations. K(ATP) channels of the coronary
      vascular system are only slightly blocked by HMR 1883 when activated by hypoxia.
      The substance was potently effective in preventing ventricular fibrillation in a
      conscious dog model, and thus can be considered to be a potential novel drug
      candidate against sudden cardiac death.

PMID- 10575201
TI  - Pharmacology, structure and function of cardiac L-type Ca(2+) channels.
AB  - Voltage-gated L-type Ca(2+) channels control depolarization-induced Ca(2+) entry
      in different electrically excitable cells, including mammalian heart. Important
      molecular and functional details providing new insight into L-type channel
      structure and modulation are reviewed in this article. This includes the
      identification of amino acid residues responsible for drug binding, the role of
      accessory subunits and alternative splicing for fine-tuning channel activity and
      modulation by protein kinases (A, C, tyrosine kinases), cGMP-dependent pathways,
      calmodulin and Ca(2+). Alterations in Ca(2+) channel activity under pathological
      conditions such as in heart failure or during ischemia could provide new clues
      for the development of drugs to treat cardiovascular diseases.

PMID- 10575202
TI  - Store-operated cation channels in the heart and cells of the cardiovascular
      system.
AB  - In many nonexcitable cells, activation of phospholipase C (PLC)-linked receptors
      results in a release of Ca(2+) from intracellular stores followed by a
      transmembrane Ca(2+) entry. This Ca(2+) entry underlies the sustained phase of
      [Ca(2+)](i) increase, is important for various cellular functions including gene
      expression, secretion and cell proliferation, and is supported by agonist
      activated Ca(2+)-permeable ion channels. Ca(2+)-permeable channels which are
      activated by store depletion and which are therefore referred to as store-
      operated channels or SOCs form a major pathway for agonist-induced Ca(2+) influx.
      So far, the molecular structures of these channels have not been identified.
      Potential candidates are encoded by members of the TRP family, a class of ion
      channels initially discovered in Drosophila and involved in the PLC-dependent
      transduction of visual stimuli. Here, we review recent evidence that agonist
      induced Ca(2+) influx and especially SOCs are present in different cell types of
      the heart and of the cardiovascular system and compare these findings with the
      possible functions and tissue-specific expression of mammalian TRP proteins.

PMID- 10575203
TI  - Report of the Sixth International Workshop on Human Chromosome 11 Mapping 1998.
      Nice, France, May 2-5, 1998.

PMID- 10575204
TI  - Towards identification of individual homologous chromosomes: comparative genomic
      hybridization and spectral karyotyping discriminate between paternal and maternal
      euchromatin in Mus musculus x M. spretus interspecific hybrids.
AB  - We have developed an in situ technique to label individual euchromatic chromosome
      arms in interspecific crosses between Mus musculus (MMU) and M. spretus (MSP).
      The MMU and MSP genomes diverged 2-3 million years ago and show an overall
      sequence divergence of approximately 1%. Comparative hybridization of MMU versus
      MSP DNA and subsequent spectral analysis of the euchromatic hybridization
      profiles discriminated between maternal (MMU) and paternal (MSP) chromosomes in
      F(1) hybrids. Dispersed repetitive DNA elements were the preferred hybridization
      target of MMU DNA on maternal chromosomes and of MSP DNA on paternal chromosomes.
      Differences in centromeric satellite DNAs were detected by conventional
      fluorescence in situ hybridization and served as internal controls. Our
      experiments suggest that it is possible, in principle, to discriminate between
      paternal and maternal chromosomes on the basis of sequence differences.

PMID- 10575206
TI  - Telomeric repeat organization--a comparative in situ study between man and
      rodent.
AB  - Human, hamster, and mouse chromosomes show both similarities and differences in
      telomeric organization, detectable with a novel version of the PRINS technique.
      The differences allowed us to investigate the fate of the telomeres on a
      chromosome from one species when this chromosome was introduced into the cells of
      another species. For this purpose, we tested telomeres in cell lines of somatic
      cell hybrids containing human chromosomes on a rodent background, finding that
      the telomeres on human chromosomes could not be discriminated from the telomeres
      on rodent chromosomes. All telomeres in the cell lines were much shorter than the
      telomeres in normal cells. In the mouse-derived cell lines, half of the mouse
      chromosomes were fused to other mouse chromosomes at the ends of their short
      arms. At the points of fusion we were generally unable to detect telomeric
      signals. In these cell lines, we also found a fraction of chromosomes ends with
      only one telomeric signal. In chromosomes where both ends showed only one signal,
      the relative orientation of the signals appeared to be nonrandom with respect to
      sister chromatids.

PMID- 10575205
TI  - Targeted integration of a dominant neo(R) marker into a 2- to 3-Mb human
      minichromosome and transfer between cells.
AB  - The physical and genetic characterization of a stable human minichromosome in a
      Chinese hamster hybrid cell is described. The minichromosome is 2-3 Mb in size,
      is linear, and contains a complementing SDHC gene. It is derived from a human
      chromosome 1, including the centromere, some pericentric heterochromatin from
      1q12, and 1-2 Mb of 1q21. Genomic DNA surrounding the SDHC gene was used to
      construct a targeting vector with a selectable drug resistance marker (neo(R));
      the marker was then successfully integrated into the minichromosome. With the new
      selectable marker, the 8.2.3 minichromosome could be transferred into mouse LMTK(
      ) and 3T3 TK(-) cells.

PMID- 10575207
TI  - Assignment of serine protease 17 (PRSS17) to human chromosome bands 19q13.3-
      >q13.4 by in situ hybridization.

PMID- 10575208
TI  - Exon structure and promoter identification of STIM1 (alias GOK), a human gene
      causing growth arrest of the human tumor cell lines G401 and RD.
AB  - The stromal interaction molecular 1 gene (STIM1) encodes a type I trans-membrane
      protein of unknown function, which induces growth arrest and degeneration of the
      human tumor cell lines G401 and RD but not HBL100 and CaLu-6, suggesting a role
      in the pathogenesis of rhabdomyosarcomas and rhabdoid tumors. Here, we describe
      the STIM1 genomic organization including the identification of the promoter
      region. The gene consists of 12 exons that span a region larger than 250 kb
      between the genes RRM1 and NUP98. Nucleotide sequences of all exon-intron
      boundaries were determined and oligonucleotide primers for the amplification of
      individual exons were designed. The promoter region was identified within a 1.8
      kb SacI fragment at the 5' end of the gene. In vitro CpG methylation of the
      promoter region indicated that transcription can be downregulated by this
      mechanism. The genetic tools developed in the present work will help to determine
      whether pathogenetic mechanisms that associate STIM1 with tumorigenesis involve
      mutations in coding sequences and/or promoter, and whether methylation could
      determine STIM1 transcriptional down-regulation in tumor samples.

PMID- 10575209
TI  - Cloning of the murine Mist1 gene and assignment to mouse chromosome band 5G2-5G3.
AB  - Mist1 is a basic helix-loop-helix (bHLH) transcription factor that is highly
      expressed in the adult pancreas. In this study, we isolated the mouse Mist1 gene
      and established its primary DNA sequence and complete genomic structure.
      Fluorescence in situ hybridization mapping located the Mist1 gene to the telomere
      of mouse chromosome 5 at position 5G2-5G3, an area which is syntenic to human
      chromosome 13q and which contains several additional pancreatic regulatory genes
      including IPF1 and CDX2.

PMID- 10575210
TI  - Assignment of the Madcam1 gene to rat chromosome 7q11.2-->q12 by fluorescence in
      situ hybridization, somatic cell hybrids and linkage analysis.

PMID- 10575212
TI  - Assignment of estrogen receptor beta (Esr2) to rat chromosome band 6q24 and
      (Estrb) to mouse chromosome band 12D1-D3 by in situ hybridization.

PMID- 10575211
TI  - Identification of two paralogous regions mapping to the short and long arms of
      human chromosome 2 comprising LIS1 pseudogenes.
AB  - Reiner et al. (1995b) reported on the existence of a gene with a coding region
      virtually identical to LIS1, the gene responsible for Miller-Dieker
      lissencephaly. This gene, LIS2, was mapped to chromosome 2p11.2, and a related
      pseudogene, LIS2P, was mapped to 2q13-->q14. By sequencing genomic clones that
      were mapped by means of 2p and 2q-only hybrids, we now demonstrate the existence
      of two LIS1 processed pseudogenes mapping to 2p11.2 and 2q13 (PAFAH1P1 and
      PAFAH1P2, respectively). The two sequences appear to lie within larger paralogous
      regions and share a 98.6% degree of identity. Comparative mapping data by
      cytogenetic analysis on great apes indicate that the duplication of the genomic
      region comprising the LIS1 pseudogenes occurred in humans. We also demonstrate
      that the cDNA sequence shown as part of the LIS2 gene and marking its chromosome
      2 specificity belongs to the 3' untranslated region of a different gene (C1orf6)
      that we mapped to 1q21 by FISH analysis.

PMID- 10575213
TI  - Assignment of the Zona pellucida 3 receptor (Zp3r) gene to mouse chromosome 1E-F
      by fluorescence in situ hybridization and confirmation by genetic mapping.

PMID- 10575214
TI  - High resolution physical mapping of human HDAC3, a potential tumor suppressor
      gene in the 5q31 region.
AB  - Histone deacetylases have been described as crucial cofactors of mammalian
      transcriptional complexes. We have recently identified human histone deacetylase
      HDAC3 on chromosome 5q31 by fluorescence in situ hybridization (FISH) in a region
      commonly deleted in malignant myeloid disease. Since HDAC3 carries strong
      potential to be a tumor suppressor gene, we report herein its exact position
      between the CD14 and GRIA1 genes within the 5q31.1 subband.

PMID- 10575215
TI  - Assignment of mitochondrial NAD(+)-specific isocitrate dehydrogenase beta subunit
      gene (IDH3B) to human chromosome band 20p13 by in situ hybridization and
      radiation hybrid mapping.

PMID- 10575216
TI  - Assignment of the 2P domain, acid-sensitive potassium channel OAT1 gene KCNK3 to
      human chromosome bands 2p24.1-->p23.3 and murine 5B by in situ hybridization.

PMID- 10575217
TI  - Assignment of the UGDH locus encoding UDP-glucose dehydrogenase to human
      chromosome band 4p15.1 by radiation hybrid mapping.

PMID- 10575218
TI  - Assignment of the human slit homologue SLIT2 to human chromosome band 4p15.2.

PMID- 10575219
TI  - Assignment of the serologically defined colon cancer antigen 1 gene (SDCCAG1) to
      human chromosome band 14q22 by in situ hybridization.

PMID- 10575220
TI  - Assignment of the human peptide chain release factor 3 (GSPT2) to Xp11.23-
      >p11.21 and of the distal marker DXS1039 by radiation hybrid mapping.

PMID- 10575221
TI  - Rabbit calcium-sensing receptor (CASR) gene: chromosome location and evidence for
      related genes.
AB  - Diverse cellular functions are regulated by the calcium-sensing receptor, encoded
      by the CASR gene, which plays an important role in calcium homeostasis. Here we
      provide the sequence for exon VII of the rabbit CASR gene and show that it is 91%
      identical to the human gene at the nucleotide level, and 95% identical at the
      amino acid level. The gene was mapped by fluorescence in situ hybridization,
      using a cosmid isolated from a genomic library, to chromosome 14q11 and this was
      confirmed independently by PCR amplification of flow sorted chromosomes. In
      addition, the cosmid detected sites with lower frequencies on four other
      chromosomes: 3q, 5p, 8p, and 13p. Two of these sites (5p and 13p) were also
      detected by a related but unidentical cosmid, and map to regions that are
      homologous to the mouse calcium-sensing receptor related sequences (Casr-rs);
      suggesting that they may represent CASR-related sequences in the rabbit. The data
      support the presence of a family of genes related to the calcium-sensing receptor
      in the G-protein coupled receptor (GPCR) superfamily, as well as extend the
      existing knowledge of homology for several human and rabbit chromosomes.

PMID- 10575223
TI  - Transcriptional map of chromosome region 6q16-->q21.
AB  - We present the transcription map of chromosome region 6q16-->q21 by mapping
      fifteen known genes within this region. Five genes lay in the subregion
      containing a tumor suppressor gene, eight genes are located in the subregion
      harboring a senescence gene, and two genes are distal to the latter region. The
      precise location of the genes was obtained using a previously described
      translocation and deletion mouse/human hybrid panel. An even more accurate
      definition was possible for the genes spanning the senescence gene region, since
      a previously described YAC contig with its restriction map was available. From
      this transcription map it is possible to derive a large region of synteny with
      mouse chromosome 10.

PMID- 10575222
TI  - Structural organization and chromosome location of the mouse elongin A gene
      (Tceb3).
AB  - Elongin A is the transcriptionally active subunit of the Elongin complex, which
      strongly increases the rate of elongation by RNA polymerase II by suppressing the
      transient pausing of the polymerase at many sites within transcription units. In
      the present study, we obtained the cDNA sequence of the mouse Elongin A gene
      (Tceb3) and characterized its genomic structure. The deduced 773-amino acid
      sequence of mouse Elongin A shows 91% and 81% identity with rat and human Elongin
      A, respectively. The Elongin A gene was mapped to mouse chromosome 4D3 by
      fluorescence in situ hybridization.

PMID- 10575224
TI  - Refined physical mapping and genomic structure of the EXTL1 gene.
AB  - Recently, the EXTL1 gene, a member of the EXT tumor suppressor gene family, has
      been mapped to 1p36, a chromosome region which is frequently implicated in a wide
      variety of malignancies, including breast carcinoma, colorectal cancer and
      neuroblastoma. In this study, we show that the EXTL1 gene is located between the
      genetic markers D1S511 and D1S234 within 200 kb of the LAP18 gene on chromosome
      1p36. 1, a region which has been proposed to harbor a tumor suppressor gene
      implicated in MYCN-amplified neuroblastomas. In addition, we determined the
      genomic structure of the EXTL1 gene, revealing that the EXTL1 coding sequence
      spans 11 exons within a 50-kb region.

PMID- 10575225
TI  - International system for standardized avian karyotypes (ISSAK): standardized
      banded karyotypes of the domestic fowl (Gallus domesticus).
AB  - The chicken genetic map is becoming very detailed. The genetic and physical maps
      need to be integrated in more detail. It is important to have a consensus banded
      karotype to permit this integration. An international committee met to develop a
      karyotype for the eight largest chromosomes and the Z and W chromosomes of the
      domestic fowl (Gallus domesticus). This map is presented in this report.

PMID- 10575226
TI  - TBL2, a novel transducin family member in the WBS deletion: characterization of
      the complete sequence, genomic structure, transcriptional variants and the mouse
      ortholog.
AB  - Williams-Beuren syndrome (WBS) is a developmental disorder with multi-system
      manifestations caused by haploinsufficiency for contiguous genes deleted in
      chromosome region 7q11.23. The size of the deletion is similar in most patients
      due to a genomic duplication that predisposes to unequal meiotic crossover
      events. While hemizygosity at the elastin locus is responsible for the
      cardiovascular features, the contribution of other genes to the WBS phenotype
      remains to be demonstrated. We have identified a novel gene, TBL2, in the common
      WBS deletion. TBL2 is expressed as a 2. 4-kb transcript predominantly in testis,
      skeletal muscle, heart and some endocrine tissues, with a larger approximately 5
      kb transcript detected ubiquitously at lower levels. TBL2 encodes a protein with
      four putative WD40-repeats. An alternatively spliced transcript in TBL2
      introduces a novel second exon with an in frame stop codon. This mRNA encodes a
      75 amino acid protein with 43 amino acids identical to TBL2 at the N-terminus and
      no known functional domain. The mouse homolog, Tbl2, shows 84% sequence identity
      at the nucleotide level and 92% similarity at the amino acid level. Comparison of
      the mouse and human sequences identifies a conserved region that extends upstream
      of the previously published sequence with an initiation codon common to both
      species that adds 21 amino acids at the N-terminus. The Tbl2 gene has been mapped
      to mouse chromosome 5 in a region of conserved synteny with human 7q11.23. Since
      haploinsufficiency has been shown for other WD-repeat containing proteins,
      hemizygosity of TBL2 may contribute to some of the aspects of the complex WBS
      phenotype.

PMID- 10575227
TI  - Interphase FISH for rapid identification of a down syndrome animal model.
AB  - Mouse models of Down syndrome (trisomy 21, DS) have been developed to study the
      consequences of triplication of regions syntenic to distal human chromosome 21.
      We report a technique for the identification of segmental trisomy 16 (Ts65Dn) and
      diploid progeny at any age using interphase fluorescence in situ hybridization
      (FISH) of uncultured tail fibroblasts. Our technique is faster and less expensive
      than blood karyotyping.

PMID- 10575228
TI  - The influence of interstitial telomeric sequences on chromosome instability in
      human cells.
AB  - Although most telomere repeat sequences are found at the ends of chromosomes,
      some telomeric repeat sequences are also found at intrachromosomal locations in
      mammalian cells. Several studies have found that these interstitial telomeric
      repeat sequences can promote chromosome instability in rodent cells, either
      spontaneously or following ionizing radiation. In the present study we describe
      the extensive cytogenetic analysis of three different human cell lines with
      plasmids containing telomeric repeat sequences integrated at interstitial sites.
      In two of these cell lines, Q18 and P8SX, instability has been detected in the
      chromosome containing the integrated plasmid, involving breakage/fusion/bridge
      cycles or amplification of the plasmid DNA, respectively. However, the data
      suggest that the instability observed is characteristic of the general
      instability in these cell lines and that the telomeric repeat sequences
      themselves are not responsible. Consistent with this interpretation, the
      chromosome containing an integrated plasmid with 500 bp of telomeric repeat
      sequences is highly stable in the third cell line, SNG28, which has a relatively
      stable genome. The stability of the chromosome containing the integrated plasmid
      sequences in SNG28 makes this an excellent cell line to study the effect of
      ionizing radiation on the stability of interstitial telomeric sequences in human
      cells.

PMID- 10575229
TI  - Identification of GTF2IRD1, a putative transcription factor within the Williams
      Beuren syndrome deletion at 7q11.23.
AB  - Williams-Beuren syndrome (WBS) is a microdeletion syndrome caused by
      haploinsufficiency of genes at 7q11.23. Here we describe the identification and
      characterization of a novel gene named GTF2IRD1, for GTF2I-repeat domain 1,
      within the WBS deletion region. Northern blot analysis revealed ubiquitous
      expression during development with two transcripts of 3.6 kb and 5.0 kb generated
      by alternative splicing. GTF2IRD1 encodes a protein of 944 amino acids that
      contains a region of high similarity to a unique motif with helix-loop-helix
      forming potential occurring within the transcription factor GTF2I. Analogous to
      TFII-I, the product of GTF2IRD1 may have the ability to interact with other HLH
      proteins and function as a transcription factor or as a negative transcriptional
      regulator. A recent report of the identification of a muscle-specific
      transcription factor, MusTRD1, supports this hypothesis (O'Mahoney et al., 1998).
      The open reading frame described for MusTRD1 is identical to that of GTF2IRD1;
      however, the putative MusTRD1-protein is 486 amino acids shorter than the
      predicted protein encoded by GTF2IRD1. A heterozygous deletion of GTF2IRD1 may
      contribute to the complex WBS phenotype.

PMID- 10575230
TI  - The human KRAB/FPB containing zinc finger gene ZNF2 maps to chromosome 2q11.2.

PMID- 10575231
TI  - Identification and characterization of a mouse homolog to yeast Cdc6p.
AB  - Periodic expression of the Cdc6 protein is essential for the entry of budding
      yeast cells into S phase, and also for participating in checkpoint controls that
      ensure that DNA replication is completed before mitosis is initiated. We have
      identified a mouse protein closely related to Cdc6p (MmCdc6p) as well as to its
      human and Xenopus homologs. The gene coding for MmCdc6p (Cdc6) is located at band
      D on murine chromosome 11. Analysis of its genomic region revealed that the 13-kb
      Cdc6 gene is divided into 12 exons by 11 introns. MmCdc6p has putative cyclin
      dependent phosphorylation sites, a destruction box, nuclear localization signals,
      a nucleotide triphosphate-binding motif, and a potential leucine zipper. None of
      these consensus motifs except the leucine-zipper and the destruction box overlaps
      an intron. Expression of MmCdc6 mRNA and protein is suppressed in mouse NIH3T3
      fibroblasts made quiescent by serum starvation. Upon replenishment of the medium,
      transcript and protein levels increase during progression through G(1), peaking
      as cells enter S phase. MmCdc6p is phosphorylated in vitro by cdk1/cyclin B,
      cdk4/cyclin D, cdk2/cyclin E, and cdk2/cyclin A, respectively at serine-residues.
      In vivo however, phosphorylation of MmCdc6p is carried out by cdk2/cyclin A at
      serine-residues exclusively. Conservation of structures among members of the Cdc6
      related proteins suggests that these proteins play a key role in the regulation
      of DNA replication during the cell cycle in all eukaryotes. These results
      strongly suggest, that Cdc6p plays an important role in cell cycle regulation and
      replication licensing.

PMID- 10575232
TI  - Complete homology maps of the rabbit (Oryctolagus cuniculus) and human by
      reciprocal chromosome painting.
AB  - Fluorescence in situ hybridization (FISH) was used to construct a homology map to
      analyse the extent of evolutionary conservation of chromosome segments between
      human and rabbit (Oryctolagus cuniculus, 2n = 44). Chromosome-specific probes
      were established by bivariate fluorescence activated flow sorting followed by
      degenerate oligonucleotide-primed PCR (DOP-PCR). Painting of rabbit probes to
      human chromosomes and vice versa allowed a detailed analysis of the homology
      between these species. All rabbit chromosome paints, except for the Y paint,
      hybridized to human chromosomes. All human chromosome paints, except for the Y
      paint, hybridized to rabbit chromosomes. The results obtained revealed extensive
      genome conservation between the two species. Rabbit chromosomes 12, 19 and X were
      found to be completely homologous to human chromosomes 6, 17 and X, respectively.
      All other human chromosomes were homologous to two or sometimes three rabbit
      chromosomes. Many conserved chromosome segments found previously in other mammals
      (e.g. cat, pig, cattle, Indian muntjac) were also found to be conserved in rabbit
      chromosomes.

PMID- 10575233
TI  - Correction and confirmation of the assignment of Cd1d the evolutionarily
      conserved CD1D class gene to rat chromosome 2q34 and its relationship to human
      and mouse loci.

PMID- 10575235
TI  - Assignment of pancreatic eIF-2alpha kinase (EIF2AK3) to human chromosome band
      2p12 by radiation hybrid mapping and in situ hybridization.

PMID- 10575234
TI  - Assignment of Neurod1 to rat chromosome 3 band 3q24-->q32 and mouse chromosome 2
      band 2E2-E3 by in situ hybridization.

PMID- 10575236
TI  - Assignment of the human alpha 1,3-fucosyltransferase IX gene (FUT9) to chromosome
      band 6q16 by in situ hybridization.

PMID- 10575237
TI  - Partial cloning and assignment of the canine bassoon gene (BSN) to chromosome
      20q15.1-->q15.2.

PMID- 10575238
TI  - Assignment of cytosine-5 DNA methyltransferases Dnmt3a and Dnmt3b to mouse
      chromosome bands 12A2-A3 and 2H1 by in situ hybridization.

PMID- 10575239
TI  - Infantile spasms: the development of nonverbal communication after epilepsy
      surgery.
AB  - The postoperative development of nonverbal communication was studied in 29
      children, aged 18.2 (SD = 11.54) months, who underwent multilobar resection or
      hemispherectomy for intractable symptomatic infantile spasms (IS). Using the
      Early Social Communication Scale, the IS subjects had little, if any, social
      interaction, joint attention or behavior regulation before surgery. After a mean
      follow-up of 24 months, most of the children continued to have delayed nonverbal
      communication skills compared to normal children. Seizure-related, surgical and
      cognitive factors were unrelated to the postsurgical development of nonverbal
      communication. The children with right-sided surgery had a statistically
      significant increase in the use of social interaction but not in other gestural
      behaviors. Removal of the frontal lobe was not related to the nonverbal
      communication outcome. The study's findings suggest that impaired use of
      nonverbal communication might be a feature of surgically treated children with
      medically intractable IS.

PMID- 10575240
TI  - Age and etiology as predictors of language outcome following hemispherectomy.
AB  - We report on the effects of etiology and age on the linguistic outcomes in a
      large pediatric hemispherectomy population. Four populations were considered
      separately: cortical dysplasia (multilobar involvement), Rasmussen's
      encephalitis, infarction as a primary etiology and, fourth, children who failed
      to develop language, regardless of etiology. We argue against the 'the-earlier
      the-better' hypothesis and propose our own hypothesis that weds maturational
      factors to etiological factors to predict language outcomes following pervasive
      brain insult. The implications of our 'critical impact point' hypothesis are
      discussed.

PMID- 10575241
TI  - Cognitive development in benign focal epilepsies of childhood.
AB  - Benign focal epilepsy of childhood (BFEC) is the most common form of epilepsy, in
      children from 3 to 12 years. Its prognosis is always favourable as far as the
      epilepsy is concerned. Nevertheless, recent clinical data suggest that children
      affected by BFEC are more likely to show learning difficulties and behavioural
      disturbances than their peers. We report here the preliminary findings of a
      prospective study of 22 children affected with BFEC. Electroclinical and
      neuropsychological changes observed during the first 18 months of the follow-up
      strengthen the conclusion of recent neuropsychological studies stressing the
      correlation between epilepsy and cognitive performances. The cognitive deficits
      affecting mainly non-verbal functions were significantly correlated with the
      frequency of seizures and spike-wave discharges and to the lateralization of the
      epileptic focus in the right hemisphere, whereas frontal functions like attention
      control, response organization and fine motor speed, were impaired in the
      presence of active BFEC independently of the lateralization of the epileptic
      focus. Our results indicate that maturing cognitive functions subserved by a
      cortical area distant from the epileptic focus are susceptible to interference
      with epilepsy.

PMID- 10575242
TI  - Functional MRI in children with epilepsy.
AB  - Advances in brain mapping with functional magnetic resonance imaging (fMRI) have
      opened an important window into understanding how language is organized in the
      developing brain. Children with epilepsy, particularly those anticipating
      surgical intervention, may benefit from preoperative language localization with
      fMRI, thus minimizing the risk of incurring new deficits. Clinical applications
      of fMRI, however, await more information on how different linguistic skills are
      represented in the developing brain and how epileptic lesions impact on this
      organization at different stages of cognitive development. This article presents
      some of the current methods for brain mapping in children as well as early
      results using fMRI for language mapping in pediatric epilepsy.

PMID- 10575243
TI  - Hippocampal T(2) abnormalities correlate with antecedent events and help predict
      seizure intractability.
AB  - INTRODUCTION: We performed hippocampal T(2) relaxometry as part of a routine
      magnetic resonance imaging (MRI) examination in 50 normal controls and 127
      consecutive patients referred because of suspected seizures. METHODS: On the
      basis of T(2) values in controls (100.2 +/- 4.2 ms) we defined normal as <110 ms
      (<mean + 2 SD), borderline as 110-113 ms (mean + 2 SD to mean + 3 SD) and
      abnormal as >113 ms (>mean + 3 SD). RESULTS: After detailed investigation, 103 of
      these 127 patients had epilepsy and 24 did not. In the nonepilepsy group, none
      had abnormal hippocampal T(2) values. Twenty-seven of the 103 patients in the
      epilepsy group had abnormal values, 7 were borderline and 69 were normal. Only 5
      patients with abnormal T(2) values did not have temporal lobe epilepsy: 1 had
      extratemporal lobe epilepsy, 1 had generalized epilepsy and 3 had unclassified
      epilepsy. Twenty-two of 27 (81%) patients with abnormal hippocampal T(2) values
      had intractable epilepsy [compared with 32 of 69 (46%) patients with normal
      values; p < 0.05, chi(2) test]. Two thirds of patients with abnormal values had a
      history of a major antecedent event (compared to only 7% of those with normal
      values, p < 0.05, chi(2) test). CONCLUSION: Abnormal T(2) relaxometry is
      significantly associated with intractable epilepsy as well as with major
      antecedent events.

PMID- 10575244
TI  - Hippocampal sclerosis: development in adult life.
AB  - Hippocampal sclerosis (HS) is the most common pathological lesion underlying
      intractable temporal lobe epilepsy. It is not known whether HS exists before the
      onset of epilepsy or whether it is caused by seizures. Its has been proposed that
      childhood seizures cause HS. Optimized magnetic resonance imaging (MRI),
      hippocampal volumes and T(2) signal quantitation were performed 2 weeks and 8
      months following at tonic-clonic seizure in a 23-year-old man. MRI 14 days after
      the seizure showed symmetrical hippocampal volumes (ratio R/L = 1.03) with intact
      internal architecture bilaterally but marked signal change in the right
      hippocampus (T(2) right = 121, T(2) left = 103, normal < or = 108 ms). Eight
      months later this hippocampus showed severe atrophy with a volume ratio of 0.65
      and T(2) values of 117 (right) and 109 ms (left). High-resolution imaging showed
      that volume loss occurred mainly in the CA1 region which showed high signal in
      the initial study. Characteristic MRI features of HS can develop in adults and HS
      cannot always be assumed to have its origins in childhood. Hypoxia in the context
      of seizures may be an important component in hippocampal damage. HS may be a
      preventable lesion and MRI signal change seen in the neuronal layers of the
      hippocampus may be an indication for neuroprotection.

PMID- 10575245
TI  - Developmental changes in NMDA-induced intrinsic optical signals in the
      hippocampal dentate gyrus of children with medically intractable seizures.
AB  - The N-methyl-D-aspartate (NMDA) receptor is one of the ionotropic glutamate
      receptor subtypes and exhibits a voltage-dependent blockade of its channel
      function by extracellular magnesium. This magnesium block is known to be absent
      or weak early in development and is gradually acquired while the brain matures.
      Interestingly, in adult patients with temporal lobe epilepsy, the magnesium block
      appears to be altered allowing more current to flow at a negative membrane
      potential. We are interested whether a similar change might be observed in
      children's hippocampi that have frequently been involved in medically intractable
      seizures. In the present study, we grouped the patients into 2 categories based
      on the degree of brain maturity: (I) children under the age of 2 (immature, n =
      2) and (II) children over the age of 2 (mature, n = 6). Dentate gyri were imaged
      in real time for intrinsic optical signals with the use of a transmitted light in
      hippocampal slice preparations. Light transmittance (LT), which reflects a
      neuronal synaptic depolarization and a concomitant change in cell volume, was
      calculated. In the immature hippocampus, LT increased significantly in response
      to NMDA in the presence of extracellular magnesium. However, the mature
      hippocampi showed little response to NMDA unless magnesium ions were removed from
      the extracellular artificial cerebrospinal fluid. LT increase was also induced in
      response to alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA);
      however, there were no age-dependent differences in the AMPA induced LT increase.
      Differential sensitivity of the NMDA receptor to extracellular magnesium between
      immature and mature hippocampi suggests the probable presence of developmental
      regulation of magnesium block for the NMDA receptor in the human hippocampus of
      children with medically intractable seizures.

PMID- 10575247
TI  - Hippocampal chemical anatomy in pediatric and adolescent patients with
      hippocampal or extrahippocampal epilepsy.
AB  - We determined whether age or seizure types were associated with hippocampal
      neuron loss, mossy fiber (MF) and GABAergic synaptic reorganizations or
      postsynaptic receptor densities. Children and adolescents were grouped into: (1)
      nonhippocampal sclerosis (non-HS; n = 11) and (2) hippocampal sclerosis (HS; n =
      11). The most important results showed that: (1) regardless of the etiology of
      the seizures, there were greater cell losses in Ammon's horn with older ages in
      years; in the non-HS group, cell losses were greater with the older ages or with
      longer epilepsy durations; however, in the HS patients, the cell losses were not
      related to the patients' ages or epilepsy durations; (2) in both HS and non-HS,
      CA1 had greater cell losses than CA4; (3) in HS, CA1 and CA4 had greater cell
      losses than those in non-HS; (4) in non-HS, MF sprouting was greater with ages or
      with longer epilepsy durations; by contrast, in HS, MF sprouting was not related
      to the patients' age or epilepsy duration; (5) densities for AMPA GluR1, GABA
      Abeta and for GABA axonal terminals were positively increased with age. These
      findings support the hypothesis that hippocampal cell losses and aberrant
      synaptic reorganizations are greater in the hippocampi of adolescents than in
      children, even for non-HS pathologies.

PMID- 10575246
TI  - Electrophysiological and morphological analyses of cortical neurons obtained from
      children with catastrophic epilepsy: dopamine receptor modulation of
      glutamatergic responses.
AB  - The present study examined the electrophysiological effects produced by
      activation of specific dopamine (DA) receptors and the distribution of DA
      receptor subtypes and glutamate receptor subunits [N-methyl-D-aspartate (NMDAR1)
      and GluR1] in cortical tissue samples obtained from children (ages 3 months to 16
      years) undergoing epilepsy surgery. DA receptor activation produced differential
      effects depending on the receptor subtype that was activated. D1 receptor family
      agonists generally enhanced cortical excitability and favored the emergence of
      epileptogenic activity. In contrast, D2 receptor family agonists had more
      variable effects on cortical excitability and the expression of epileptiform
      discharges. Activation of D1 or D2 receptors decreased the amplitude of non-NMDA
      mediated excitatory postsynaptic potentials. In contrast, DA and D1 agonists
      increased the amplitude of NMDA-mediated potentials. Immunohistochemical analysis
      showed that the DA receptor subtypes and glutamate receptor subunits examined
      were present in all cortical layers and areas throughout development. Whole-cell
      voltage clamp recordings of pyramidal neurons visualized with differential
      interference contrast optics and infrared videomicroscopy indicated that these
      neurons displayed a persistent Na(+) current, followed by an outward current. DA
      reduced the outward current but had little effect on the persistent Na(+)
      current. These results suggest a dual role for DA's actions in the human cerebral
      cortex. Activation of D2 receptors or antagonism of D1 receptors may help control
      seizures in children.

PMID- 10575248
TI  - Cortical dysplasia, genetic abnormalities and neurocutaneous syndromes.
AB  - Cortical dysplasia (CD) represents a common neuropathologic substrate of
      pediatric epilepsy, one frequently encountered in surgical resection specimens
      from infants and children with intractable seizure disorders, including infantile
      spasms. Severe CD shows similarities to structural features noted in tubers from
      individuals with tuberous sclerosis (TSC). The latter disorder, one with
      neurocutaneous and visceral manifestations, results from mutations in one of two
      recently cloned genes, TSC1 or TSC2, which encode (respectively) the proteins
      hamartin and tuberin. There is circumstantial evidence that both proteins may
      influence cell growth and differentiation, specifically that they may represent
      growth suppressors. Neither protein has a defined role in brain development. We
      discuss and illustrate neuropathologic features of both CD and TSC, and discuss
      the patterns and time course of hamartin/tuberin expression in normal brain, CD
      and TSC. Other recently cloned genes associated with cortical malformations
      encompassed by the term CD are briefly described.

PMID- 10575249
TI  - Cerebral cortical dysplasia: giant neurons show potential for increased
      excitation and axonal plasticity.
AB  - Cerebral cortical dysplasia (CD) is a common cause of intractable childhood
      epilepsy. Five cases of CD were analyzed for GABA(A) receptor subunit beta
      (GABA(Abeta)), glutamate decarboxylase, AMPA receptor subunit 1 (GluR1) and
      subunit 2/3 (GluR2/3), and NMDA receptor 2 (NMDAR2) immunoreactivity. Antisera to
      the highly polysialylated neural cell adhesion molecule (PSA-NCAM) and human unc
      33-like phosphoprotein 1 (hUlip 1) were used to identify neurons with
      'developmentally immature' characteristics. Differences between CD and comparison
      tissue (n = 3) included: (1) prominent GABA(Abeta) immunoreactivity of the
      cytoplasm of dysmorphic neurons in the subcortical white matter and cortex in 1
      CD case; (2) increased immunolabeling with anti-GluR1 and GluR2/3 antisera in
      dysmorphic neurons compared with more normal-appearing adjacent neurons and
      neurons from nondysplastic cortex; (3) varying numbers of cortical dysmorphic
      neurons stained for NMDAR2 in all 5 CD cases, in contrast to a complete lack of
      cellular immunoreactivity in 2/3 of the cases of nondysplastic cortex; (4) PSA
      NCAM and hUlip 1 expression (usually observed only in populations of neurons that
      undergo axonal growth) was observed in CD tissue, but not in normal brain tissue.
      In summary, dysmorphic neurons in cases of CD have increased immunoreactivity for
      several excitatory neurotransmitter receptor subunits, show variable
      immunoreactivity for GABA(Abeta) and show expression of several proteins that are
      normally expressed only in immature neurons or those with the potential for
      synaptic plasticity.

PMID- 10575250
TI  - Focal cortical dysplasia in children.
AB  - Cortical dysplasia (CD) is now recognized as one of the major causes of pediatric
      focal neocortical epilepsy, and surgical procedures have been considered early in
      life. However, the mechanisms involved in seizure generation and intractability
      in these patients are still unknown. We analyzed with immunocytochemistry for
      various antibodies the brain tissue from 4 children (10 months to 6 years old)
      with focal epilepsy due to focal CD in order to study the inhibitory and
      excitatory circuits in dysplastic areas. Our group had similar histopathological
      and clinical characteristics. In all patients we found areas of cortical
      disorganization with dysplastic neurons and balloon cells. We studied
      distributions of glial cells with glial fibrillary acidic protein (GFAP) and
      neurons with microtubule-associated protein 2 (MAP-2). Gliosis was present in all
      cases, and GFAP stained also some balloon cells. Dysplastic neurons were darkly
      stained by MAP-2, and we also found balloon cells weakly stained with MAP-2 in
      the same areas where GFAP was positive, suggesting coexpression of neuronal and
      glial markers in some of these cells. There was an increased expression of
      glutamate receptors, especially GluR2/3, but also N-methyl-D-aspartate receptors
      in dysplastic cortex. The inhibitory circuit does not seem to be decreased,
      rather we notice an increased amount of glutamate-decarboxylase-positive
      terminals around some of the big neurons. We discuss the possible role of these
      findings as mechanisms of epilepsy.

PMID- 10575252
TI  - Regional age-dependent effects of hemineodecortication upon contralateral
      neocortical thickness: comparison with other measures of cortical size.
AB  - This study investigated age-dependent changes in regional neocortical thickness
      after hemineodecortication in cats and compared the results to previously
      reported volumetric and cross-sectional data. Subjects sustained
      hemineodecortication on postnatal days (P) P10, P30, P60 or in adulthood.
      Neocortical thickness was quantified at 115 sites along 20 stereotaxic coronal
      anterior-posterior (AP) planes using defined sites of the main cerebral sulci for
      the measurements. The analysis established significantly lower thickness values
      for adult-lesioned as compared to (a) P30, P60 and control groups at AP +14, (b)
      P30 group at 7 planes along a range of AP +9 to AP +3, and (c) P10 and P60 groups
      at AP +6. Both the P10 and the P30 groups presented a significantly thicker
      neocortex than controls at select coronal planes clustering behind AP +10
      (parietal and temporal cortices). When analyzed by sulcus, results once again
      reflected significant advantages for the early-lesioned cats with a significantly
      thicker cortex found at 4 of the 8 sulci examined. Again, significant advantages
      were also discovered for early-lesion subjects compared with control cats
      (splenial, cruciate sulci). Overall, the range of significant effects (from AP
      +14 to AP 0) and the direction of the means suggested that there was a
      significant, age-dependent (P10-P60), regional sparing of neocortical thickness
      with a peak effect occurring at P30. We concluded that: (a) there was a regional
      sparing/increase of neocortical thickness suggesting that discrete cortical areas
      are selectively involved in the resistance to structural atrophy following
      hemineodecortication in young cats (P10-P60) and (b) the global loss of neocortex
      volume found in our previous study was not apparent using the present thickness
      measurement. It is suggested that both of these measurements must be taken into
      account when assessing morphological effects upon the neocortex either in human
      pathology (i.e. hemispherectomy, intractable epilepsy) or in animal models.

PMID- 10575251
TI  - Infantile spasms: hypothesis-driven therapy and pilot human infant experiments
      using corticotropin-releasing hormone receptor antagonists.
AB  - BACKGROUND AND RATIONALE: Infantile spasms (IS) are an age-specific seizure
      disorder occurring in 1:2,000 infants and associated with mental retardation in
      approximately 90% of affected individuals. The costs of IS in terms of loss of
      lifetime productivity and emotional and financial burdens on families are
      enormous. It is generally agreed that the seizures associated with IS respond
      poorly to most conventional anticonvulsants. In addition, in the majority of
      patients, a treatment course with high-dose corticotropin (ACTH) arrests the
      seizures completely within days, often without recurrence on discontinuation of
      the hormone. However, the severe side effects of ACTH require development of
      better treatments for IS. Based on the rapid, all-or-none and irreversible
      effects of ACTH and on the established physiological actions of this hormone, it
      was hypothesized that ACTH eliminated IS via an established neuroendocrine
      feedback mechanism involving suppression of the age-specific endogenous
      convulsant neuropeptide corticotropin-releasing hormone (CRH). Indeed, IS
      typically occur in the setting of injury or insult that activate the CNS stress
      system, of which CRH is a major component. CRH levels may be elevated in the IS
      brain, and the neuropeptide is known to cause seizures in infant rats, as well as
      neuronal death in brain regions involved in learning and memory. If 'excess' CRH
      is involved in the pathogenesis of IS, then blocking CRH receptors should
      eliminate both seizures and the excitotoxicity of CRH-receptor-rich neurons
      subserving learning and memory. PATIENTS AND METHODS: With FDA approval, alpha
      helical CRH, a competitive antagonist of the peptide, was given as a phase I
      trial to 6 infants with IS who have either failed conventional treatment or who
      have suffered a recurrence. The study was performed at the Clinical Research
      Center of the Childrens Hospital, Los Angeles. The effects of alpha-helical CRH
      on autonomic parameters (blood pressure, pulse, temperature, respiration) were
      determined. In addition, immediate and short-term effects on ACTH and cortisol
      and on electrolytes and glucose were examined. The potential efficacy of alpha
      helical CRH for IS was studied, using clinical diaries and video EEG. RESULTS:
      alpha-Helical CRH, a peptide, did not alter autonomic or biochemical parameters.
      Blocking peripheral CRH receptors was evident from a transient reduction in
      plasma ACTH and cortisol. No evidence for the compound's penetration of the blood
      brain barrier was found, since no central effects on arousal, activity or
      seizures and EEG patterns were observed. In addition, a striking resistance of
      the patients' plasma ACTH to the second infusion of alpha-helical CRH was noted.
      CONCLUSIONS: Peptide analogs of CRH do not cross the blood-brain barrier, and
      their effects on peripheral stress hormones are transient and benign. Nonpeptide
      compouds that reach CNS receptors are required to test the hypothesis that
      blocking CRH receptors may ameliorate IS and its cognitive consequences.

PMID- 10575253
TI  - Cellular morphology and physiology of the perinatal rat cerebral cortex.
AB  - The cellular morphology and electrophysiology of the rat neocortex between
      embryonic day (E) 18 and postnatal day (P) 3 was studied in vitro by
      extracellular biocytin injections and whole-cell recordings, respectively. Most
      neurons were characterized by a small number of short-range dendrites and a main
      axon that was directed towards the white matter. Biocytin injections into the
      marginal zone and the cortical plate labeled far-reaching connections extending
      up to 2 mm in horizontal direction, indicating the existence of a dense network
      of long-range intrinsic projections in the neonatal cortex. Action potentials
      could be elicited as early as E18 and repetitive firing could first be observed
      at P0. Electrical stimulation of the immature cortex at various positions
      elicited polyphasic and long-lasting (up to 1 s) excitatory postsynaptic
      potentials and currents, which were significantly reduced in amplitude by a
      selective N-methyl-D-aspartate receptor antagonist. Our data indicate that the
      perinatal cortex manifests the structural and functional conditions for powerful
      excitatory interactions, which increase the likelihood for the generation of
      epileptiform activity during this developmental period.

PMID- 10575254
TI  - Dual role of GABA in the neonatal rat hippocampus.
AB  - The effects of modulators of GABA-A receptors on neuronal network activity were
      studied in the neonatal (postnatal days 0-5) rat hippocampus in vitro. Under
      control conditions, the physiological pattern of activity of the neonatal
      hippocampal network was characterized by spontaneous network-driven giant
      depolarizing potentials (GDPs). The GABA-A receptor agonist isoguvacine (1-2
      microM) and the allosteric modulator diazepam (2 microM) induced biphasic
      responses: initially the frequency of GDPs increased 3 to 4 fold followed by
      blockade of GDPs and desynchronization of the network activity. The GABA-A
      receptor antagonists bicuculline (10 microM) and picrotoxin (100 microM) blocked
      GDPs and induced glutamate (AMPA and NMDA)-receptor-mediated interictal- and
      ictal-like activities in the hippocampal slices and the intact hippocampus. These
      data suggest that at early postnatal ages GABA can exert a dual - both excitatory
      and inhibitory - action on the network activity.

PMID- 10575255
TI  - Developmental seizure susceptibility of kv1.1 potassium channel knockout mice.
AB  - Potassium channels play a critical role in limiting neuronal excitability.
      Mutations in certain voltage-gated potassium channels have been associated with
      hyperexcitable phenotypes in both humans and animals. However, only recently have
      mutations in potassium channel genes (i.e. KCNQ2 and KCNQ3) been discovered in a
      human epilepsy, benign familial neonatal convulsions. Recently, it has been
      reported that mice lacking the voltage-gated Shaker-like potassium channel Kv1.1
      alpha-subunit develop recurrent spontaneous seizures early in postnatal
      development. The clinical relevance of the Kv1.1 knockout mouse has been
      underscored by a recent report of epilepsy occurring in a family affected by
      mutations in the KCNA1 locus (the human homologue of Kv1.1) which typically cause
      episodic ataxia and myokymia. Here we summarize preliminary studies
      characterizing the developmental changes in seizure susceptibility and neuronal
      activation in the three genotypes of Kv1.1 mice (-/-, +/-, +/+). Using behavioral
      and immediate-early gene indicators of regional brain excitability, we have found
      that a seizure-sensitive predisposition exists in Kv1.1 -/- animals at a very
      young age (P10), before either spontaneous seizure activity or changes in c-fos
      mRNA expression can be demonstrated. Kv1.1 +/- mice, although behaviorally
      indistinguishable from wild types, also have an increased susceptibility to
      seizures at a similar early age. The Kv1. 1 knockout mouse possesses many
      features desirable in a developmental animal epilepsy model and represents a
      clinically relevant model of early-onset epilepsies.

PMID- 10575256
TI  - Chronic epilepsy in developing hippocampal neurons: electrophysiologic and
      morphologic features.
AB  - Despite the susceptibility of immature neurons to seizures, there are few models
      of epilepsy in the developing brain. By taking advantage of activity-dependent
      developmental changes in young neurons, we have developed a novel model of
      chronic epilepsy in cultured hippocampal slices. Incubating slices in
      tetrodotoxin (TTX) for at least 1 week produced significant changes in the
      electrical activity and appearance of CA1 pyramidal neurons. Extracellular
      recordings revealed multiple population spikes, and, in whole-cell recordings,
      evoked synaptic potentials lasting hundreds of milliseconds with many
      superimposed action potentials were present. Spontaneous firing with burst-like
      discharges was also evident. These changes were secondary to increased AMPA
      receptor-mediated responses and decreased GABA(A) receptor events. Altered
      membrane properties involved increased expression of T-type Ca(2+) channels which
      are normally down-regulated in these neurons. TTX-treated neurons also showed
      abnormal dendritic branching. This model of chronic epilepsy in developing
      hippocampal neurons demonstrated many changes at the membrane, cellular and
      synaptic level that may provide new insights into the nature of epileptogenesis
      in the young brain.

PMID- 10575257
TI  - Prevalence of epileptic seizures along the wakefulness-sleep cycle in adult rats
      submitted to status epilepticus in early life.
AB  - In 70 adult Wistar rats submitted to pilocarpine-induced status epilepticus in
      early life the electro-oscillograms were recorded from neocortical areas 10, 3
      and 17, from CA1 and CA3 hippocampal fields and, in 10 rats, also from the
      ventrolateral nuclei and amygdala. Head, eye, rostrum + vibrissae, ear and
      forelimb movements were recorded as well. Fifty rats were subjected to 4-hour
      daily recording sessions and 20 to continuous 24-hour recordings. In all the rats
      spike-wave discharges (SWD) were found in every site from which the electro
      oscillograms were recorded, and clonic seizures were also displayed by all the
      animals. Most seizures (83.75%, mean = 6.59 fits/h) were concentrated in nearly 9
      h and 16.25% (mean = 0. 77 fits/h) in the remaining 15 h. Eye movements occurred
      during 49. 2% of the total duration of motor events, the head moved in 42.8% and
      the rostrum + vibrissae in 8.1% of the time, departing from normal rats.
      Therefore, pilocarpine-induced status epilepticus produces striking changes in
      the wakefulness-sleep cycle characteristics.

PMID- 10575258
TI  - Ontogeny of self-sustaining status epilepticus.
AB  - Rat pups of ages of 20, 25, 30 and 35 postnatal days were subjected to the
      perforant-path stimulation model of status epilepticus (SE). This treatment
      resulted in age- and stimulus-frequency-dependent loss of inhibition in the
      dentate granule cell layer. Only 35% of the 20-day-old animals, but 88% of the 35
      day-olds, progressed to self-sustaining status epilepticus (SSSE). Loss of
      inhibition as measured by 0.1-Hz paired-pulse testing and histologic damage that
      extended to the contralateral side, including both the hilus and some
      extrahippocampal limbic structures, were associated with SSSE. This model of SE
      differs from in vitro models of SE, in which immature animals show an increased
      susceptibility to epileptogenic stimuli, and provides us with a novel method to
      study epileptogenicity in the developing brain.

PMID- 10575260
TI  - Synaptic responses of neurons in heterotopic gray matter in an animal model of
      cortical dysgenesis.
AB  - Neuronal heterotopia is a malformation of cortical development that is closely
      associated with epilepsy in humans. Despite emerging interest in the structure
      and function of the heterotopic cortex, little is known about the membrane
      properties and synaptic connections of these displaced neurons. We used whole
      cell patch-clamp and extracellular field potential recordings from heterotopic
      neurons in slices from young adult rats with experimentally induced cortical
      dysgenesis to determine if local synaptic connections were present in nodular
      heterotopia. Complex synaptic responses were observed after electrical
      stimulation of adjacent white matter. The results suggest that neurons in nodular
      heterotopic gray matter can form local excitatory and inhibitory synaptic
      connections and may participate in epileptiform events.

PMID- 10575259
TI  - Development of a model of status epilepticus in pigtailed macaque infant monkeys.
AB  - Seizures, particularly multiple episodes and/or status epilepticus (SE) are
      prevalent in pediatric patients. Pediatric SE is associated with brain changes
      that have been hypothesized to contribute to the onset of temporal lobe epilepsy
      (TLE). In order to gain insight into the effects of seizures on the immature
      brain and the risk for later TLE, we have developed a model of limbic SE in the
      pigtailed macaque monkey. In separate studies, bicuculline methiodide or a
      bicuculline 'cocktail' was infused into three regions of the brain (area
      tempestas, hippocampus, entorhinal cortex) to induce seizures. Measures included
      MRI, electrophysiology, behavior and morphology. Our results suggest that monkey
      models of SE may provide useful tools for understanding the effects of prolonged
      seizures during infancy and the origins of TLE in humans.

PMID- 10575261
TI  - Electrophysiological responses in vivo of hippocampal CA1 pyramidal neurons in an
      animal model of neuronal migration disorders.
AB  - Cortical dysgenesis arising from neuronal migration disorders is closely
      associated with intractable epilepsy in humans. We used extracellular field
      potential and conventional intracellular recordings from the dorsal hippocampus
      of intact adult rats to determine if the excitability of CA1 pyramidal cells was
      enhanced in rats with experimentally induced hippocampal dysplasia. Electrical
      stimulation of afferent fibers resulted in more robust population responses in
      the CA1 region of irradiated rats versus controls. Synaptic inhibition of
      pyramidal cells was also reduced in these animals. These results suggest that the
      excitability of the CA1 region in rats with hippocampal dysplasia is greater than
      in control animals.

PMID- 10575262
TI  - Abnormal connections in the malformed cortex of rats with prenatal treatment with
      methylazoxymethanol may support hyperexcitability.
AB  - Prenatal treatment with methylazoxymethanol (MAM) in rats generates animals with
      a diffuse cortical malformation associated with hyperexcitability. These
      alterations are reminiscent of the cortical malformations associated with
      epilepsy in children. We hypothesised that one of the mechanisms supporting
      hyperexcitability in MAM rats could be the presence of abnormal cortical
      connections in the malformed cortex. Using a variety of anatomical techniques, we
      provide evidences for three types of such abnormal connections: (i) tangential
      bundles of corticocortical fibres in and below the neocortical molecular layer;
      (ii) partial deafferentation of neocortical heterotopias by afferent cortical
      fibres whatever their location; (iii) exuberant innervation of hippocampal CA3
      pyramidal cells by mossy fibres that form ectopic mossy boutons on their basal
      dendrites. We conclude that these abnormal intrinsic cortical connections may
      support the propagation of paroxymal activity in the neocortex of MAM-treated
      rats.

PMID- 10575263
TI  - Electrophysiological observations in hippocampal slices from rats treated with
      the ketogenic diet.
AB  - The electrophysiological effects of the high-fat, low-carbohydrate ketogenic diet
      (KD) were assessed in normal and epileptic [kainic-acid(KA)-treated] adult rats
      using hippocampal slices. In the first set of experiments, normal rats were fed
      the KD or a standard control diet for 6-8 weeks (beginning on postnatal day 56,
      P56), after which they were sacrificed for hippocampal slices. All rats on the KD
      became ketotic. The baseline effects of the KD were determined by comparing
      extracellular measures of synaptic transmission and responses to evoked
      stimulation, and hippocampal excitability was tested in Mg(2+)-free medium. There
      were no differences in EPSP slope, input/output relationship, responses to evoked
      stimulation or Mg(2+)-free burst frequency between slices from control and KD-fed
      rats. In another set of experiments, rats were made epileptic by intraperitoneal
      injection of kainic acid (KA) on P54, which caused status epilepticus followed by
      the development of spontaneous recurrent seizures (SRS) over the next few weeks.
      Two days after KA-induced status, rats were divided into a control-fed group and
      a KD-fed group. Animals on the KD had significantly fewer SRS over the ensuing 8
      weeks. In hippocampal slices from KA-treated, KD-fed rats, there were fewer
      evoked CA1 population spikes than from slices of control-fed rats. These results
      suggest that the KD does not alter baseline electrophysiological parameters in
      normal rats. In rats made chronically epileptic by administration of KA, KD
      treatment was associated with fewer spontaneous seizures and reduced CA1
      excitability in vitro. Therefore, at least part of the KD mechanism of action may
      involve long-term changes in network excitability.

PMID- 10575264
TI  - Path analysis shows that increasing ketogenic ratio, but not beta
      hydroxybutyrate, elevates seizure threshold in the Rat.
AB  - Previous work has identified several criteria that may be important in
      determining the efficacy of the ketogenic diet as a treatment for intractable
      epilepsy in children. The present study was designed to investigate the influence
      of four major variables on seizure threshold, i.e. ketogenic ratio, body weight,
      age at diet onset and beta-hydroxybutyrate in rats. Path analysis was used to
      statistically model and quantify the causal relationships among variables.
      Results indicate that seizure threshold was significantly elevated with
      increasing ketogenic ratios (i.e. more fats vs. carbohydrates and proteins) and
      decreasing weight. Conversely, age at diet onset and plasma levels of beta-OHB
      showed no causal relation to seizure resistance. These results suggest that the
      efficacy of the ketogenic diet is independent of the level of ketonemia but is
      markedly influenced by diet and growth.

PMID- 10575265
TI  - BCG's mechanism of action - increasing our understanding. For the EBIN Group.
AB  - BCG immunotherapy against superficial bladder carcinoma recurrences is regarded
      as the most successful to date. However, the mode of action has not yet been
      fully explained. In this field, several European groups have recently
      significantly contributed by adding more details to the complex picture of the
      immunological processes of BCG effector mechanisms. BCG inflammation obviously
      differs from non-specific inflammation by its quality and subclinical duration.
      Infiltration of immunocompetent cells into the bladder wall with secretion of
      cytokines into the urine has been characterized. Specific humoral responses of
      patients towards mycobacterial antigens have been determined. These data clearly
      present a large body of evidence that the inflammatory reaction induced by BCG
      correlates with the anti-tumour response. In vitro models of cytotoxic effector
      cells have shown interesting and selective effector mechanisms induced by BCG.
      Animal models have proven valuable in supporting ex vivo and in vitro data and in
      clarifying new aspects of the application of BCG in vivo. Future research efforts
      will certainly add understanding to the immediate and long-term humoral and
      cellular responses. All our investigations intend to define clearly surrogate
      parameters for efficacy and side-effects, to increase therapeutic efficacy
      further and to decrease side-effects associated with this therapy. Only the
      collaborative efforts of several groups will be able to achieve a highly
      effective immunotherapeutic regimen against bladder carcinoma.

PMID- 10575266
TI  - Preventing progression and improving survival with BCG maintenance.
AB  - BCG immunotherapy provides a superior reduction in tumour recurrence compared
      with chemotherapy. Unlike chemotherapy, however, it also appears to reduce
      disease progression. The benefit of BCG is long-term, but protection from disease
      progression without maintenance therapy is lost when comparisons are made after
      15 years. Data suggest that optimal maintenance therapy with BCG provides even
      better protection from tumour recurrence, reduces disease progression and
      improves survival. Maintenance BCG schedules using single instillations at 1-3
      month intervals have not been proved to be better than induction alone. However,
      a Southwest Oncology Group (SWOG) study using three, weekly instillations of
      Connaught BCG, found this regimen to be markedly superior. Before the
      introduction of BCG, carcinoma in situ (CIS) would progress to muscle invasion in
      52% of patients. In the SWOG study, the additional instillations increased the
      complete response rate in CIS from the expected 68% to 84%. With maintenance BCG,
      long-term (7 years) tumour recurrence in high-risk patients reduced from the
      expected 52% with a single 6-week course to only 25% (p < 0.000001). Worsening
      free survival, defined as the absence of evidence of disease progression,
      including pathologic stage T2 or greater disease, or the need for systemic
      chemotherapy, radiation therapy or cystectomy, significantly increased (p <
      0.049, log rank test). In 391 randomized patients, the already excellent 86%
      survival at 4 years observed with induction therapy improved to 92% in patients
      receiving maintenance BCG (p < 0.04). There is thus increasingly good evidence
      that BCG maintenance therapy, at the optimal treatment schedule, provides
      superior protection from tumour progression and recurrence, and improves long
      term survival.

PMID- 10575267
TI  - Improved patient outcomes with BCG immunotherapy vs. chemotherapy - Swedish and
      worldwide experience.
AB  - Intravesical therapy of superficial bladder cancer has been in routine use since
      the introduction of thiotepa in 1961. An empirical approach has been used to
      optimize this kind of treatment - clinical data are, unfortunately, often
      lacking. Marker lesion studies indicate that BCG is more effective than
      cytostatic drugs. For the prophylaxis of recurring disease, the recurrence rate
      is lower with chemotherapy than in controls, but no effect on the risk of
      progression has been verified. None of the chemotherapy drugs used has proved
      superior to the others. Randomized trials have recently been performed with
      mitomycin C vs. BCG. Comparison of the different trials is difficult due to the
      use of different methodologies. The majority of the studies found BCG to be more
      effective in lowering the number of recurrences, but progression rates were not
      significantly different. Trials with combinations of BCG-mitomycin C or
      epirubicin-interferon have yielded promising results.

PMID- 10575268
TI  - Sensitivity of BCG to modern antibiotics.
AB  - The viability of bacillus Calmette-Guerin (BCG) in intravesical instillation
      therapy has been demonstrated to be crucial for the prevention of bladder tumour
      recurrence. The aim of the present study was to determine the effects of modern
      antibacterial chemotherapeutics on BCG viability, particularly cycloserine, which
      has been recommended in the treatment of BCG-induced sepsis. The minimal
      inhibitory concentrations (MICs) of 32 antibacterial drugs potentially effective
      against the Connaught BCG strain were measured in vitro by the radiometric BACTEC
      460TB method. The MICs were compared with the drug concentrations achievable in
      blood and urine. Susceptibility testing of cycloserine was performed with three
      different strains (Connaught, Tice and RIVM), using the modified proportion
      method, as defined in the German guidelines for anti-tuberculosis drug testing.
      The Connaught BCG strain was highly susceptible to fluoroquinolones, but was
      resistant to beta-lactams, macrolides (except clarithromycin), and some
      aminoglycosides. It was also sensitive to doxycycline and gentamicin at dosages
      that typically occur in the urine of patients after a normal dose. Connaught BCG
      was susceptible to all the tuberculostatic drugs tested, except for pyrazinamide.
      All the BCG strains analysed were resistant to cycloserine. During intravesical
      BCG instillation therapy, simultaneous administration of fluoroquinolones,
      doxycycline or gentamicin should be avoided. In cases of severe systemic
      complications, or if one of the antituberculosis drugs is not tolerated,
      fluoroquinolones may be used. Cycloserine is no longer recommended for the early
      treatment of BCG sepsis.

PMID- 10575269
TI  - The effect of isoniazid on BCG-induced toxicity in patients with superficial
      bladder cancer.
AB  - The use of bacillus Calmette-Guerin in the treatment of transitional cell cancer
      of the bladder has caused concern because of its associated adverse effects. We
      conducted a randomized prospective, double-blind, multicentre study to determine
      whether isoniazid prophylaxis could reduce BCG-induced toxicity without
      compromising its immunotherapeutic effects. Patients (n = 160) with
      histologically documented urothelial cancer (pTa-T1, pTis, G1-3) were treated
      with 6 weekly instillations of BCG Connaught strain, 81 mg, administered
      concomitantly with a 3-day course of isoniazid (300 mg o.d.) or placebo. Side
      effects were recorded with each treatment and at follow-up. Of the patients
      treated with isoniazid, 19% remained free from side-effects, compared with 16% of
      the placebo group. Local side-effects confined to the bladder were significantly
      lower among those receiving isoniazid (35% vs. 48%, p < 0.01). Local side-effects
      together with systemic adverse effects such as fever, nausea or skin rash were
      experienced by 30% of patients in each arm. There were no differences in tumour
      recurrence between the two patient groups. Concomitant isoniazid reduces the
      local, but not the systemic side-effects of topically applied BCG without
      compromising the antitumour effect on superficial, transitional cell cancer of
      the bladder during a follow-up period that now exceeds 2 years.

PMID- 10575270
TI  - Modified induction course: a solution to side-effects?
AB  - Side-effects are commonly manifested during intravesical Bacillus Calmette-Guerin
      (BCG) immunotherapy of superficial bladder cancer. This often causes delays or
      interruptions of the instillations and consequently reduces the efficacy of
      treatment. Treatment strategies aimed at reducing the side-effects of BCG
      immunotherapy while maintaining efficacy are currently being considered in the
      search for an optimal treatment regimen. The following two approaches to BCG
      immunotherapy were investigated at the Department of Urology of Padova University
      by specific Phase II and III trials designed to evaluate the possibility of
      reducing BCG-related side-effects without compromising therapeutic efficacy: (1)
      by reducing the dose of BCG per instillation 'low-dose' regimen, (2) by delaying
      the interval of the instillations 'slow-rate' regimen.

PMID- 10575271
TI  - BCG intravesical instillations: recommendations for side-effects management.
AB  - Adverse events following intravesical BCG therapy are related to strain
      virulence, allergic reactions or to nosocomial urinary tract infections. Low
      grade fever and irritative symptoms are common side-effects of BCG. They subside
      within 48 hours and do not require any specific treatment, apart from standard
      painkillers and antispasmodics. Further instillations should be postponed until
      symptoms have resolved completely. If symptoms do not resolve, complementary
      investigations are recommended including urine culture, and isoniazid may be
      prescribed for 15 days. The BCG dose should be reduced if symptoms increase after
      subsequent instillations. Complications of BCG infection - either local or
      systemic - have been reported with an incidence of 10-15%. These complications
      include: granulomatous prostatitis or epididymitis (treated with isoniazid and
      rifampicin for 3 months), contracted bladder may occur, mainly during maintenance
      courses, systemic infection such as granulomatous nephritis and abscesses,
      pneumonitis, hepatitis, osteomyelitis (treated with isoniazid, rifampicin and
      ethambutol for 6 months), and life-threatening adverse events may be related to
      septicaemia or to immunoallergic reactions, the onset of which may be delayed
      several months after the end of BCG therapy. Such conditions require urgent
      treatment with standard antituberculous antibiotics and prednisolone. These
      complications are an absolute contraindication for further BCG instillations.
      Despite its toxicity, the risk-benefit ratio favours the use of BCG in patients
      who have moderate- and high-risk tumours.

PMID- 10575272
TI  - Analysis of immunoglobulin VH and TCR cbeta polymorphisms in a large family with
      thyroid autoimmune disorder.
AB  - In order to investigate the association of TCR Cbeta and immunoglobulin (Ig) VH
      polymorphisms with thyroid autoimmune diseases (TAD), we analyzed restriction
      endonuclease-generated polymorphisms using T-cell receptor (TCR) Cbeta and VH
      gene-family-specific probes. We tested genomic DNAs of patients isolated from a
      large family affected with Graves' disease and Hashimoto's thyroiditis as well as
      the genomic DNA of unrelated Tunisian controls. Hybridization of BglII-digested
      DNA with a TCR Cbeta probe revealed two alleles of 9.2 and 10 kb. These Cbeta
      polymorphisms have already been found in the Caucasian population. However, there
      was no abnormal distribution of this polymorphism in patients with TAD, compared
      to related healthy individuals and to unrelated Tunisian controls. Besides, there
      was a low VH polymorphism in members of the family affected with TAD. Analysis of
      the Ig gene families revealed no restriction site polymorphism pattern specific
      for TAD.

PMID- 10575273
TI  - HLA-DMA alleles are possible new markers of rheumatoid arthritis: study of a
      Corsican group.
AB  - The HLA-DMA gene, along with the HLA-DMB gene, encodes the not classical class II
      molecule. This molecule catalyzes the class-II-associated invariant-chain peptide
      (CLIP)-antigen peptide exchange in classical class II molecule peptide-binding
      groove. As such, the DM heterodimer is an antigen presentation regulator and may
      be linked to immune system deficiencies such as those observed in autoimmune
      diseases. The study of DMA gene polymorphism seems be a reasonable approach to
      provide an answer to this question. Thanks to PCR-derived methods, the
      relationship between DMA gene polymorphism and rheumatoid arthritis (RA) was
      demonstrated in the present study. The DMA*0101 allele was observed to confer a
      significant predisposition to RA while the DMA*0102 allele significantly
      protected from this disease. Polymorphism experiments with the HLA-DRB1 gene
      revealed that this relationship between DMA polymorphism and RA is not a
      consequence of a linkage disequilibrium with the HLA-DRB1 alleles implicated in
      this pathology. The study of the DMA gene could therefore prove to be very useful
      in the early diagnosis of RA.

PMID- 10575274
TI  - MHC class I cross-talk with CD2 and CD28 induces specific intracellular
      signalling and leads to growth retardation and apoptosis via a p56(lck)-dependent
      mechanism.
AB  - Ligation of the major histocompatibility complex class I molecules (MHC-I) on
      human T lymphoma cells (Jurkat) initiates p56(lck)-dependent intracellular
      signalling events (phosphotyrosine kinase activity; [Ca(2+)](i)) and leads to
      augmented growth inhibition and apoptosis. MHC-I ligation in concert with
      ligation of CD2 or CD28 augments, changes or modifies the pattern of activation.
      Ligation of MHC-I and CD2 alone resulted in growth inhibition, whereas CD28
      ligation alone had no effect on cell proliferation. Ligation of MHC-I together
      with CD2 augmented growth inhibition and enhanced the level of apoptosis. In
      parallel experiments with the p56(lck)-negative Jurkat mutant cell, JCaM1.6,
      cross-linking neither influenced cell signalling nor cellular growth functions,
      indicating a cardinal role of the src kinases in signal transduction via MHC-I,
      CD2 and CD28 molecules. The results presented here provide evidence for the
      involvement of MHC-I molecules in the modulation of signal transduction via the
      CD2 and CD28 costimulatory molecules.

PMID- 10575275
TI  - Modulation of C5a-mediated effector functions of human polymorphonuclear
      leukocytes by tumor necrosis factor alpha and granulocyte macrophage colony
      stimulating factor.
AB  - At the site of acute inflammation, leukocytes are confronted with multiple
      mediators which are expected to modulate each other with respect to cell
      responses to the individual ligand. In the present study, we compared the effects
      of the classical chemoattractants FMLP, PAF and LTB4, of the chemokine IL-8 and
      of TNFalpha, GM-CSF, IFN-gamma and IL-1beta on C5a-induced chemotaxis,
      degranulation, oxidative burst and expression of adhesion molecules of human
      neutrophils in vitro. Upon preincubation, TNFalpha as well as GM-CSF dose
      dependently inhibited C5a-mediated chemotaxis, but augmented the release of
      elastase as well as respiratory burst activity. The effects of the two cytokines
      were accompanied by a downregulation of C5a receptors as determined by Scatchard
      analysis using (125)I-labeled C5a. Compared on a molar basis, TNFalpha was more
      effective than GM-CSF. C5a-induced expression of beta(2)-integrins was only
      moderately influenced by TNFalpha and GM-CSF. C5a itself diminished chemotaxis as
      well as degranulation and oxidative burst in response to a second dose of the
      same ligand (homologous desensitization), whereas heterologous desensitization by
      FMLP and IL-8 was restricted to C5a-induced degranulation or not observed (PAF,
      LTB4]. The cytokine effects are likely to be a consequence of altered C5a
      receptor expression as well as of postreceptor events. In concert with C5a,
      certain cytokines may shift neutrophil effector functions from migration to
      exocytosis, an essential step within the sequence of events in a coordinated
      inflammatory response.

PMID- 10575277
TI  - Protein displays of the human immunoglobulin heavy, kappa and lambda variable and
      joining regions.
AB  - 'Protein displays of the Human Immunoglobulin Heavy, Kappa and Lambda Variable
      and Joining Regions', the 6th report of the 'IMGT Locus on Focus' section,
      comprises 4 figures: (1) 'Protein display of human IGH V-REGIONs'; (2) 'Protein
      display of human IGK V-REGIONs'; (3) 'Protein display of human IGL V-REGIONs and
      V-PREB REGION'; (4) 'Protein display of human IGH, IGK and IGL J-REGIONs', and 1
      table entitled: 'FR-IMGT and CDR-IMGT length of the human IGHV, IGKV, IGLV and V
      PREB genes'. These figures and table are available at the IMGT Marie-Paule page
      from IMGT, the international ImMunoGeneTics database (http://imgt.cnusc.fr: 8104)
      created by Marie-Paule Lefranc, Universite Montpellier II, CNRS, France.

PMID- 10575276
TI  - Superantigens are presented by and activate thymocytes from infants.
AB  - A high percentage of human fetal and postnatal thymocytes express MHC class II
      molecules. This raises the possibility that human thymocytes in early life are
      able to present peptides to other immature T cells and thereby initiate thymic
      selection of these cells. Here we address this question by exposing newly
      harvested infant thymocytes to superantigen (Sag) which binds to the T-cell
      receptor and to MHC class II chains outside the peptide binding groove. The
      results show that the thymocytes are able to present Sag and to be activated to
      proliferation as well as apoptosis by Sag presented by other thymocytes. The
      absence of responses to Sag with mutations in class II binding sites showed that
      class II molecules were necessary for the responses, and very low expression of
      class II molecules on CD4-8- cells indicates that the demonstrated T-cell/T-cell
      interactions are confined to T-cell receptor-positive CD4+8+, CD4+8-, and CD4-8+
      cells. These latter subsets were shown to be able to present Sag to each other.
      These findings suggest that class II+ thymocytes may participate in the selection
      of self-restricted T cells during a critical period in the shaping of the human
      immune system.

PMID- 10575278
TI  - [Micronutrients in cancer prevention].
AB  - Micronutrients are able to influence the process of carcinogenesis by
      chemoprotection. With regard to preventive medicine, the possible
      anticarcinogenic effects in the early stages of tumor development, the initiation
      and promotion stages, require the greatest interest. It is, however, an essential
      fact that the possible interactions between micronutrients and carcinogenesis are
      a complex problem that cannot be considered by a simple cause-effect
      relationship. The basis of our knowledge on a possible protective effect of
      micronutrients in carcinogenesis are results of in vitro studies and of animal
      experiments with doses of micronutrients never appearing in the normal nutrition
      of men. It therefore seems somewhat difficult to transfer the results of those
      studies to the real-life situation of men. Investigations in humans, mainly
      epidemiological studies, show controversial results. There has also to be
      considered that the chemopreventive effect may be different with regard to the
      single micronutrient. More extensive studies have been performed for beta-carotin
      or the vitamins A, C, and E as well as for the trace elements selenium and zinc
      and for calcium. Possible influences of these micronutrients seem to exist mainly
      in cancers of the breast, lung, gastro-intestinal tract, and prostate. However,
      chemoprevention may also be produced by various non-nutritive substances, present
      mainly in food of vegetable origin. Finally it has to be considered that a
      carcinoprotective effect may not only be induced by enhancing the amount of
      special micronutrients in the nutrition, but also by avoiding of possible
      carcinogenic nutrients. The difference between carcinoprotective and carcinogenic
      is, however, not only a question of quality but not seldom dependent on quantity.

PMID- 10575280
TI  - [Does the study "Complementary medicine in health insurance" provide a basis for
      scientifically valid conclusions?].
AB  - In Switzerland public attention was caught by a health economic analysis of
      health insurance's reimbursement of complementary medical procedures. Objectives
      of the study were 1) cost development, 2) health status development of insured
      citizens, 3) substitutional/additional use of complementary medical procedures.
      However, several conceptual, methodical and statistical flaws limit the
      conclusions that can be drawn from this study: The analysis claimed to be based
      on a large randomized trial. However, the attempt to achieve an unbiased equality
      in experimental and control group through stratified sampling grossly failed.
      Effects of complementary medical procedures on health status were inappropriately
      assessed and only based on 10 patients. The question whether complementary
      medicine is being used as a substitution or addition to conventional medicine was
      not even explored (the published result is based on a misleading interpretation
      of the health insurance's database). Finally, statements on cost developments
      were not based on estimations, but resulted from methodical and statistical
      artifacts. Furthermore, the study suffered from several other weaknesses, like a
      50% dropout rate, an inadequate description of statistical procedures, an
      extremely reduced statistical power, and a lack of clear distinction between
      experimental and retrospective analyses. Therefore, no valid conclusions can be
      drawn from this study.

PMID- 10575279
TI  - [Prophylactic effectiveness of propolis for immunostimulation: a clinical pilot
      study].
AB  - OBJECTIVE: The aim of this pilot investigation was to show the evidence of the
      prophylactic immunostimulating effectiveness caused by propolis. The immune
      response was determined by the measurement of the cytokine level in vivo and ex
      vivo (TNF-alpha, IL-6, IL-8). STUDY DESIGN: In an open prospective monocentric
      study, test persons received Propolis XNP. PATIENTS: 10 healthy test persons aged
      between 18 and 45 years, with normal weight and of either sex. INTERVENTIONS:
      Probands received over 13 days 500 mg Propolis XNP (2 capsules) for peroral
      application in the morning. MAIN OUTCOME MEASURES: Significant changes of the
      investigated cytokine secretion capacity during and after the treatment of
      propolis compared to the situation without medication. RESULTS: Although the
      cytokine plasma levels did not significantly change during the study, propolis
      led to a significant increase of both the spontaneous (TNF-alpha, p < 0. 05; IL
      6, p < 0.01; IL-8, p < 0.02; IL-1beta, not detectable) and LPS(lipopolysaccaride)
      induced (TNF-alpha, p < 0.001; IL-6, p < 0. 02; IL-8, p < 0.0005; IL-1beta, p <
      0.05) cytokine secretion capacity following short-term ex vivo culture of
      peripheral blood leukocytes. Whereas the IL-6 secretion capacity further
      increased during the 13-day application, the IL-8 and TNF-alpha secretion reached
      a plateau after day 4 and the TNF-alpha secretion even decreased, but the level
      at day 13 was still significantly higher than at day 0. CONCLUSION: As the
      cytokine secretion capacity but not the cytokine plasma levels increased
      significantly during therapy, the prophylactic application of propolis led to a
      time dependent enhanced immune reactivity without undesired side effects.

PMID- 10575281
TI  - [Cannabis and marijuana as multidrug mixture in phytotherapy].
AB  - Without doubt, Cannabis sativa L. is one of the oldest and best-known medical
      plants. Many traditional and modern ways of use potentially give hints for
      advantages and risks of different preparations. Several individual experiences of
      patients and physicians as well as some studies suggest that single substances
      extracted of or derived from cannabis are not the only useful way for the
      development of drugs. In comparison to single substances, multidrug mixtures
      prepared from Cannabis sativa, i. e. classical phytotherapeutics, can show a
      satisfying and possibly advantageous spectrum of desired but also of unwanted
      effects.

PMID- 10575282
TI  - [The effects of cannabis and THC].
AB  - Cannabis and THC exert manifold actions on a number of organ systems. A lethal
      dose of THC in humans is unknown. Above the psychotropic threshold, ingestion of
      cannabis causes an enhanced well-being and relaxation with an intensification of
      ordinary sensory experiences. The most important unwanted acute psychical effects
      are anxiety and panic attacks. Acute somatic effects are increased heart rate,
      changes of blood pressure, conjunctival injection and dry mouth. Properties that
      might be used therapeutically comprise analgesia, muscle relaxation, sedation,
      increase of mood, stimulation of appetite, antiemesis, lowering of intraoccular
      pressure and bronchodilation. Chronic use may lead to dependency and to a mild
      withdrawal syndrome. The extent of possible long-term damage on psyche and
      cognition, immune system, fertility and pregnancy remains controversial.
      Marijuana can induce a schizophrenic psychosis in vulnerable persons presumably
      without increasing the incidence of the disease. Disturbance of immunological and
      hormonal functions and long-term impairment of memory, attention, and complex
      cognitive processes are low and do not preclude a legitimate therapeutic use.

PMID- 10575283
TI  - Cannabis and cannabinoids: pharmacology and rationale for clinical use.
AB  - It is now known that there are at least two types of cannabinoid receptors. These
      are CB1 receptors, present mainly on central and peripheral neurones, and CB2
      receptors, present mainly on immune cells. Endogenous cannabinoid receptor
      agonists ('endocannabinoids') have also been identified. The discovery of this
      'endogenous cannabinoid system' has led to the development of selective CB1 and
      CB2 receptor ligands and fueled renewed interest in the clinical potential of
      cannabinoids. Two cannabinoid CB1 receptor agonists are already used clinically,
      as antiemetics or as appetite stimulants. These are D 9 - tetrahydrocannabinol
      (THC) and nabilone. Other possible uses for CB1 receptor agonists include the
      suppression of muscle spasm/spasticity associated with multiple sclerosis or
      spinal cord injury, the relief of chronic pain and the management of glaucoma and
      bronchial asthma. CB1 receptor antagonists may also have clinical applications,
      e. g. as appetite suppressants and in the management of schizophrenia or
      disorders of cognition and memory. So too may CB2 receptor ligands and drugs that
      activate cannabinoid receptors indirectly by augmenting endocannabinoid levels at
      cannabinoid receptors. When taken orally, THC seems to undergo variable
      absorption and to have a narrow 'therapeutic window' (dose range in which it is
      effective without producing significant unwanted effects). This makes it
      difficult to predict an oral dose that will be both effective and tolerable to a
      patient and indicates a need for better cannabinoid formulations and modes of
      administration. For the therapeutic potential of cannabis or CB1 receptor
      agonists to be fully exploited, it will be important to establish objectively and
      conclusively (a) whether these agents have efficacy against selected symptoms
      that is of clinical significance and, if so, whether the benefits outweigh the
      risks, (b) whether cannabis has therapeutic advantages over individual
      cannabinoids, (c) whether there is a need for additional drug treatments to
      manage any of the disorders against which cannabinoids are effective, and (d)
      whether it will be possible to develop drugs that have reduced psychotropic
      activity and yet retain the ability to act through CB1 receptors to produce their
      sought-after effects.

PMID- 10575284
TI  - Recent advantages in cannabinoid research.
AB  - Although the active component of cannabis Delta9-THC was isolated by our group 35
      years ago, until recently its mode of action remained obscure. In the last decade
      it was established that Delta9-THC acts through specific receptors - CB1 and CB2 
      and mimics the physiological activity of endogenous cannabinoids of two types,
      the best known representatives being arachidonoylethanolamide (anandamide) and 2
      arachidonoylglycerol (2-AG). THC is officially used against vomiting caused by
      cancer chemotherapy and for enhancing appetite, particularly in AIDS patients.
      Illegally, usually by smoking marijuana, it is used for ameliorating the symptoms
      of multiple sclerosis, against pain, and in a variety of other diseases. A
      synthetic cannabinoid, HU-211, is in advanced clinical tests against brain damage
      caused by closed head injury. It may prove to be valuable against stroke and
      other neurological diseases.

PMID- 10575285
TI  - Cancer cachexia and cannabinoids.
AB  - Anorexia and cachexia are diagnosed in more than two-thirds of all cancer
      patients with advanced disease, and are independent risk factors for morbidity
      and mortality. Anorexia, nausea and vomiting often are described as more
      significant inhibiting factors for quality of life of cancer patients than even
      intense pain. In 1986, delta-9-tetrahydrocannabinol (THC), the main effective
      constituent of cannabis, was licensed as an anti-emetic drug in cancer patients
      receiving chemotherapy. In addition, in clinical studies THC has shown
      significant stimulation of appetite and increase of body weight in HIV-positive
      and cancer patients. The appetite-stimulating effect of cannabis itself has also
      been well documented in many anecdotal cases. There are strong indications that
      cannabis is better tolerated than THC alone, because cannabis contains several
      additional cannabinoids, like cannabidiol (CBD), which antagonize the
      psychotropic actions of THC, but do not inhibit the appetite-stimulating effect.
      Therefore, we intend to compare the therapeutic effects of whole-plant extracts
      of cannabis to those of THC (dronabinol) alone in controlled studies.

PMID- 10575286
TI  - [Results of a standardized survey on the medical use of cannabis products in the
      German-speaking area].
AB  - The plant Cannabis sativa has a long history of medical use in the treatment of
      pain and spasms, the promotion of sleep, and the suppression of nausea and
      vomiting. However, in the early 70s cannabis was classified in the Narcotic Acts
      in countries all over the world as having no therapeutic benefit; therefore, it
      cannot be prescribed by physicians or dispensed by pharmacists. In the light of
      this contradictory situation an increasing number of patients practices a self
      prescription with cannabis products for relieving a variety of symptoms. An
      anonymous standardized survey of the medical use of cannabis and cannabis
      products of patients in Germany, Austria and Switzerland was conducted by the
      Association for Cannabis as Medicine (Cologne, Germany). During about one year
      170 subjects participated in this survey; questionnaires of 128 patients could be
      included into the evaluation. 68% of these participants were males, 32% females,
      with a total mean age of 37.5 (+/- 9.6) years. The most frequently mentioned
      indications for medicinal cannabis use were depression (12.0%), multiple
      sclerosis (10.8%), HIV-infection (9.0%), migraine (6.6%), asthma (6.0%), back
      pain (5.4%), hepatitis C (4. 8%), sleeping disorders (4.8%), epilepsy (3.6%),
      spasticity (3.6%), headache (3.6%), alcoholism (3.0%), glaucoma (3.0%), nausea
      (3.0%), disk prolapse (2.4%), and spinal cord injury (2.4%). The majority of
      patients used natural cannabis products such as marihuana, hashish and an
      alcoholic tincture; in just 5 cases dronabinol (Marinol) was taken by
      prescription. About half of the 128 participants of the survey (52.4%) had used
      cannabis as a recreational drug before the onset of their illness. To date 14.3%
      took cannabis orally, 49.2% by inhalation and in 36.5% of cases both application
      modes were used. 72.2% of the patients stated the symptoms of their illness to
      have 'much improved' after cannabis ingestion, 23.4% stated to have 'slightly
      improved', 4.8% experienced 'no change' and 1.6% described that their symptoms
      got 'worse'. Being asked for the satisfaction with their therapeutic use of
      cannabis 60.8% stated to be 'very satisfied', 24.0% 'satisfied', 11.2% 'partly
      satisfied' and 4.0% were 'not satisfied'. 70.8% experienced no side effects,
      26.4% described 'moderate' and 3.3% 'strong' side effects. 84.1% of patients have
      not felt any need for dose escalation during the last 3 months, 11.0% had to
      increase their cannabis dose 'moderately' and 4.8% 'strongly' in order to
      maintain the therapeutic effects. Thus, this survey demonstrates a successful use
      of cannabis products for the treatment of a multitude of various illnesses and
      symptoms. This use was usually accompanied only by slight and in general
      acceptable side effects. Because the patient group responding to this survey is
      presumably highly selected, no conclusions can be drawn about the quantity of
      wanted and unwanted effects of the medicinal use of the hemp plant for particular
      indications.

PMID- 10575287
TI  - [Some practice-relevant aspects of the pharmacokinetics of THC].
AB  - The pharmacokinetics of THC varies in dependence of its route of administration.
      Pulmonary assimilation of Cannabis (smoking, inhalation) leads to a maximum THC
      concentration within minutes, psychotropic effects start within seconds to a few
      minutes, reach a maximum after 15-30 min, and slope down within 1-2 h. In case of
      oral ingestion the effect sets in delayed after 30-90 min, reaches its maximum
      after 2-3 h and lasts about 4-8 h. Duration of action depends on measured
      parameters. Intestinal absorption of THC is increased by application in a
      lipophilic base. Cannabinoids are present in the plant mainly as
      pharmacologically inactive carboxylic acids (more than 95%), that are transformed
      into the active phenols by heating (smoking, baking). Heating of 5 min to 200
      degrees C seems to be optimal.

PMID- 10575288
TI  - The future of medical marijuana.
AB  - The medical value of marijuana is becoming increasingly clear, as it proves to be
      a remarkably versatile, safe, and inexpensive drug. Arrangements now being
      proposed for making cannabis constituents medically available include quasi-legal
      buyers clubs, restrictive classification as a prescription drug, the isolation of
      individual cannabinoids, and the manufacture of synthetic analogs. Careful
      analysis potentially of this inexpensive drug shows that all these proposals are
      unworkable. Furthermore, cannabis has so many beneficial uses that the strictly
      medical ones should not be singled out for approval, and its medical potential
      cannot be fully realized as long as its use for any other purpose is prohibited.
      Therefore cannabis should be made available under laws similar to those now
      applied to alcohol.

PMID- 10575290
TI  - New paradigm of gene therapy: skeletal-muscle-targeting gene therapy for kidney
      disease.

PMID- 10575289
TI  - Tubulointerstitium as predictor of progression of glomerular diseases.

PMID- 10575291
TI  - Size and charge selectivity of the glomerular filter in patients with insulin
      dependent diabetes mellitus: urinary immunoglobulins and glycosaminoglycans.
AB  - BACKGROUND: In diabetic nephropathy, a reduction in negative membrane charge in
      the glomerular filter, i.e., the number of sulphated groups of
      glycosaminoglycans, has been argued to lead to increases in excretion of
      negatively charged molecules, such as albumin and IgG4. However, albuminuria and
      an increased excretion rate of IgG may also be caused by an increase in radius or
      number of glomerular large pores. METHODS: Timed urinary excretion rates of
      sulphated glycosaminoglycans, albumin, and IgG2, IgG4, and IgM were analyzed in
      94 patients with insulin-dependent diabetes mellitus with different degrees of
      nephropathy and compared with the excretion rates in 26 control subjects.
      Sulphated glycosaminoglycans were measured spectrophotometrically after addition
      of 1, 9-dimethylmethylene blue. Albumin and immunoglobulins were measured by
      immunoassays. RESULTS: With increases in the albumin excretion rate the excretion
      of IgG2, IgG4, and IgM also increased, in contrast to a decrease in
      glycosaminoglycans and the ratio between IgG2 and IgG4 (selectivity index). This
      index decreased from 6.2 to 0.7 (median; p < 0.01). However, with linear
      regression analysis the excretion rates of albumin and immunoglobulins were not
      associated with those of glycosaminoglycans. CONCLUSION: In diabetic nephropathy
      changes in both large-pore number and in charge selectivity may be pathogenic
      mechanisms for albuminuria.

PMID- 10575292
TI  - A definite role for the kallikrein-kinin system in the renal hemodynamic response
      to an oral protein load during the aging process.
AB  - The effect of aging on the physiologic responses of renal plasma flow (RPF) and
      glomerular filtration rate to an acute oral protein load (renal reserve) is a
      poorly understood process. In this study of 37 healthy human volunteers,
      distributed among three groups (group 1: n = 13, age range 20-39 years; group 2:
      n = 13, age range 40-59 years; group 3: n = 11, age range 60-68 years), we
      evaluated the influence of age on some of the vasoactive systems such as plasma
      renin activity, urinary kallikrein, plasmatic prokallikrein, plasmatic
      kallikrein, and plasmatic kininogen on RPF and creatinine clearance (Ccr) in
      response to an acute oral protein load (1 g/kg body weight). The aging process
      diminished but did not cease the increments in RPF (group 1: 539.6 vs. 658.9
      ml/min/1.73 m(2), p < 0. 001; group 2: 509.0 vs. 570.7 ml/min/ 1.73 m(2), p <
      0.001; group 3: 453.9 vs. 506.0 ml/min/ 1.73 m(2), p < 0.001) and Ccr (group 1:
      139. 7 vs. 166.5 ml/ min/1.73 m(2), p < 0.001; group 2: 126.6 vs. 142.2
      ml/min/1.73 m(2), p < 0.001; group 3: 112.6 vs. 121.4 ml/min/ 1.73 m(2), p <
      0.01) after a protein overload. The plasma renin activity did not change after a
      meat meal. On the other hand, all parameters regarding the kinin system changed
      significantly in the direction of increased bradykinin formation, despite aging
      (urinary kallikrein - group 1: 0.25 vs. 0.44 mU/ml, p < 0.005; group 2: 0.25 vs.
      0.41 mU/ml, p < 0.005; group 3: 0.33 vs. 0.47 mU/ml, p < 0.005/plasmatic
      kininogen - group 1: 1.3 vs. 0.9 microg LBK/ml, p < 0.005; group 2: 1.1 vs. 0.7
      microg LBK/ml, p < 0.005; group 3: 0.8 vs. 0.7 microg LBK/ml, p < 0.005). These
      findings indicate that: (1) the aging process narrows but does not cease the
      increment range in Ccr and RPF after acute oral protein ingestion; (2) increased
      bradykinin formation plays a definite role in the acute renal vasodilatory
      response, and (3) contrary to previous clinical studies, our results suggest that
      the renal reserve is progressively and significantly reduced during the aging
      process.

PMID- 10575293
TI  - Evidence of altered homocysteine metabolism in chronic renal failure.
AB  - The fasting serum concentrations of total homocysteine and metabolites of
      transsulfuration (cystathionine, cysteine, methylmalonic acid, 2-methylcitric
      acid) and remethylation (methionine) were determined by gas chromatography-mass
      spectrometry in 40 nondialyzed patients with chronic renal disease and in 50
      patients with end-stage renal disease requiring chronic maintenance hemodialysis.
      The nondialyzed patients and 28 of the dialysis patients did not receive
      additional vitamin supplementations. Twenty-two of the dialysis patients received
      daily oral vitamin preparations containing 10 mg pyridoxine (vitamin B(6)), 6
      microg cyanocobalamin (vitamin B(12)), and 1 mg folic acid. In the nondialyzed
      patients, linear regression analysis showed positive correlations between serum
      concentrations of creatinine and total homocysteine (r = 0.68, p < 0.0001),
      cystathionine (r = 0.73, p < 0. 0001), methylmalonic acid (r = 0.77, p < 0.0001),
      and 2-methylcitric acid (r = 0.81, p < 0.0001). Serum homocysteine was positively
      correlated with serum concentrations of cystathionine (r = 0.59, p < 0.0001),
      cysteine (r = 0.69, p = 0.004), methylmalonic acid (r = 0. 64, p = 0.0001), and 2
      methylcitric acid (r = 0.64, p < 0.0001). There was no significant correlation
      between serum concentrations of homocysteine and methionine (r = -0.14, p =
      0.63). In the hemodialysis patients receiving oral vitamin supplementation, serum
      homocysteine and cystathionine concentrations were significantly lower than in
      hemodialysis patients not receiving vitamins (homocysteine 21.8 +/- 1.1 vs. 33.2
      +/- 3.7 micromol/l, p = 0.0004; cystathionine 2,075.9 +/- 387.1 vs. 3,171.3 +/-
      680.2 nmol/l, p = 0. 02; mean +/- SEM). In summary, our results show increased
      intermediate products of the transsulfuration pathway, but no increase in
      remethylation of homocysteine in chronic renal disease, including end-stage renal
      disease requiring chronic maintenance dialysis.

PMID- 10575294
TI  - Clinicopathologic correlations in lupus nephritis in Lima, Peru.
AB  - BACKGROUND: We assessed whether immunohistologic markers for glomerular or
      tubulointerstitial injury might provide better correlations with ongoing renal
      function and disease activity as compared with the WHO classification or the NIH
      activity and chronicity indices in lupus nephritis. METHODS: Thirty-three
      patients with clinically defined systemic lupus underwent renal biopsy over a 1
      year period at Hospital Loayza in Lima, Peru. Biopsy specimens were evaluated for
      macrophages, proliferating cells, alpha-actin expression, and type IV collagen
      deposition in both glomeruli and the tubulointerstitium and the results compared
      with the current WHO and NIH classifications in relation to the clinical
      presentation. RESULTS: Patients with WHO class IV lupus nephritis were more
      likely to have lower serum complements, greater proteinuria and hematuria, and
      worse renal function. An elevated NIH activity index correlated with
      microhematuria, proteinuria, and impaired renal function, whereas an elevated
      chronicity index correlated with renal function, hypertension, and
      microhematuria, but not with proteinuria. The presence of glomerular macrophages
      correlated with both glomerular alpha-actin expression and type IV collagen
      deposition, but did not correlate with renal function or proteinuria. In
      contrast, interstitial macrophages correlated not only with interstitial collagen
      deposition and myofibroblast accumulation, but also correlated with both renal
      function and the presence of nephrotic syndrome. CONCLUSIONS: Both the WHO
      classification and the NIH activity/chronicity indices correlate with clinical
      manifestations of lupus nephritis. While glomerular macrophage accumulation
      correlates with mesangial cell activation (alpha-actin expression) and collagen
      deposition, and interstitial macrophage accumulation correlates with interstitial
      fibroblast activation and collagen deposition, only interstitial macrophages
      correlate with renal function. Of particular interest will be future studies to
      determine whether these markers correlate with the prognosis.

PMID- 10575295
TI  - Metallothioneins in human kidneys and associated tumors.
AB  - Human kidneys and their associated tumors (nonneoplastic kidney tissues from
      patients with a transitional cell carcinoma or an adenocarcinoma and the
      adenocarcinomas themselves) were evaluated for their Zn, Cd, and Cu contents as
      well as for their metallothionein (MT) level. The total Cd content was correlated
      with the MT content, and both values were significantly decreased in the
      adenocarcinomas in comparison with the other tissues. After extraction and
      separation by anion-exchange chromatography, MT-0 was identified in the
      nonneoplastic tissues from both the adenocarcinomas as well as the transitional
      cell carcinomas. Since until now MT-0 protein was only found in human fetal liver
      and in Zn-stimulated human monocytes, a possible role for this isoform as an
      oncofetal marker is hypothesized. Separation of the isoforms of MT by reversed
      phase high-performance liquid chromatography and sequence analysis showed besides
      MT-1e and MT-1l the isoform-MT-1g, which is not expressed in the healthy kidney,
      and MT-1k, an isoform which is not yet demonstrated in renal tissues. We conclude
      that the expression profile of the MT isoforms in the kidney changes due to the
      presence of a tumor.

PMID- 10575296
TI  - Apoptosis induced by inhibition of contact with extracellular matrix in mouse
      collecting duct cells.
AB  - Cell-matrix interactions have major effects upon phenotypic features such as gene
      regulation, cytoskeletal structure, differentiation and aspects of cell growth
      control. Detachment from the matrix epithelial cells induces programmed cell
      death, and this cell detachment induced apoptosis has been referred to as
      'anoikis'. This study was undertaken to determine whether apoptosis is induced by
      inhibition of contact with extracellular matrix (ECM) in collecting duct cells
      and to investigate the signaling mechanisms of the process. Upon detachment from
      ECM, mouse inner medullary collecting duct cells (mIMCD-3) and mouse outer
      cortical collecting duct cells (M-1), which were derived from an SV40 transgenic
      mouse, entered into programmed cell death. Forced suspension of mIMCD-3 or M-1
      cells did not affect the expression of Bcl-2-related proteins and did not
      activate c-Jun NH(2)-terminal kinase. Detachment of cells from ECM activated p38
      mitogen-activated protein kinase (p38), but its inhibition with SB203580 did not
      protect cells from anoikis. Detachment of cells from matrix inhibited NF-kappaB
      activity, and the inhibition of NF-kappaB activity by overexpression of
      nonphosphorylatable I-kappaB increased detachment-induced apoptotic cell death in
      M-1 cells. Forced suspension of M-1 cells still activated p53 activity. Caspase-8
      was activated during anoikis, but the time course of its activation was in
      accordance with DNA fragmentation. These results indicate that detachment from
      ECM induces apoptosis in the kidney collecting duct cells. Changes in expression
      levels of Bcl-2-related proteins or activation of JNK/p38 kinase are not critical
      for anoikis. Decrease in NF-kappaB activity and activation of p53 induced by
      inhibition of interaction with ECM play roles in anoikis in SV-40-transformed
      collecting duct cells. Caspase-8 is activated during detachment-induced
      apoptosis, the mechanisms of which are independent of activation of cell death
      receptors.

PMID- 10575297
TI  - Adrenomedullin inhibits transmural pressure induced mesangial cell proliferation
      through activation of protein kinase A.
AB  - Adrenomedullin (AM), a hypotensive peptide isolated from human pheochromocytoma,
      inhibits the proliferation of mesangial cells (MC) induced by mitogens such as
      platelet-derived growth factor. Quite recently, we have demonstrated that
      transmural pressure applied to cultured MC increased DNA synthesis and cell
      proliferation through protein kinase C and tyrosine kinase pathways. However, the
      modulatory effect of AM on pressure-induced cell proliferation is as yet unknown.
      In the present study, we examined the effect of AM on transmural pressure-induced
      DNA synthesis in cultured rat MC. Pressure was applied to cells placed in a
      sealed chamber using compressed helium. Application of pressure resulted in an
      increase in [(3)H]thymidine incorporation (approximately 2.0-fold). AM clearly
      inhibited pressure-induced DNA synthesis in a concentration-dependent manner.
      This inhibition was paralleled by an increase in cellular cAMP levels evoked by
      AM. Forskolin and dibutyryl cAMP mimicked the inhibitory effect of AM. The
      protein kinase A inhibitor H-89 significantly attenuated the effect of AM. Human
      AM(22-52)-NH(2), a putative AM receptor antagonist, reversed the inhibitory
      effects of AM more potently than did human CGRP(8-37), a calcitonin gene related
      peptide receptor antagonist. Our results suggest that AM, by acting mainly on AM
      sensitive receptors, inhibits pressure-induced DNA synthesis in cultured rat MC
      through activation of protein kinase A. AM may play a protective role against MC
      proliferation in certain pathological conditions.

PMID- 10575298
TI  - Chronic idiopathic thrombocytopenic purpura in a patient with membranous
      glomerulonephritis.

PMID- 10575299
TI  - Intravascular haemolysis and interstitial nephritis in association with
      ciprofloxacin.

PMID- 10575300
TI  - Effects of taurine and vitamin E on microalbuminuria, plasma metalloproteinase-9,
      and serum type IV collagen concentrations in patients with diabetic nephropathy.

PMID- 10575301
TI  - Mesangial proliferative nephrosis with superimposed focal segmental
      glomerulosclerosis versus idiopathic nephrosis with focal segmental
      glomerulosclerosis.

PMID- 10575303
TI  - Routine upper gastrointestinal tract evaluation before renal transplantation - is
      it a must in all patients?

PMID- 10575302
TI  - Systemic vasculitis and p-ANCA positivity developing in a patient with ulcerative
      colitis and the antiphospholipid syndrome.

PMID- 10575304
TI  - Laparoscopic manipulation for outflow failure of peritoneal dialysis catheter.

PMID- 10575305
TI  - L-Carnitine effects on anemia in uremic rats treated with erythropoietin.

PMID- 10575306
TI  - Association of Bartter's syndrome and periodic paralysis.

PMID- 10575307
TI  - Correction of epoetin-resistant megaloblastic anaemia following vitamin B(12) and
      folate administration.

PMID- 10575308
TI  - Mizoribine for childhood IgA nephropathy.

PMID- 10575309
TI  - Combined treatment of metastatic osteosarcoma of the spine.
AB  - We report on a 28-year-old male with a single metastasis of an osteosarcoma in
      the twelfth thoracic vertebra occurring 9 years after initial diagnosis of the
      primary tumour in the left distal femur and neoadjuvant treatment according to a
      modified T-10 protocol. After pre-operative second-line combination chemotherapy
      with doxorubicin, carboplatin and etoposide leading to regression of the
      primarily inoperable metastasis wide resection of the tumour employing total
      spondylectomy was done. The duration of response had been 65 months since the end
      of subsequent postoperative chemotherapy with the same regimen.

PMID- 10575310
TI  - Initial experience with Healthport miniMax and other peripheral arm ports in
      patients with advanced gastrointestinal malignancy.
AB  - While central ports are located at the chest, peripheral ports (PP) are inserted
      at the patients' forearms. Two new PPs (Healthport miniMax((R)) and Bard Titan
      Low Profile Port) and two well-established types (Port-A-Cath((R)) P.A.S. Port
      and PeriPort(TM) peripheral access system) were tested. 125 patients were given
      the choice between PP and chest ports, and 100 of them chose PP. PP were inserted
      in patients suffering from gastrointestinal malignancies (n = 95), AIDS (n = 3)
      or Crohn's disease (n = 2). The first 30 patients were prospectively monitored by
      repeated color-coded duplex sonography examinations in order to evaluate
      clinically inapparent thromboses. Easy percutaneous needle puncture as early as 1
      day after surgery was possible using innovative ports with large septa. The
      following complications arose during 12,688 catheter placement days: difficult
      implantation (n = 5), intolerable pain at the insertion site (n = 1), port
      erosion of the skin (n = 1), catheter leaks (n = 4), disconnection of the
      catheter from the port (n = 1), systemic infections (n = 4), local infections (n
      = 6) and symptomatic deep vein thrombosis (n = 8) despite anticoagulation in 1 of
      these. Only systemic infections and intolerable pain resulted in PP explantation
      (n = 5); other complications were easily dealt with. No serious or life
      threatening complications occurred.

PMID- 10575311
TI  - Clinical implications of lymph node micrometastases in patients with colorectal
      cancers. A case control study.
AB  - There is no unanimity about the prognostic significance of lymph node
      micrometastases from colorectal cancer. A case-control study of patients with
      recurrent and nonrecurrent colorectal cancer who were closely matched for the
      Dukes stage, extent of lymph node dissection, tumor size, tumor location, number
      of resected lymph nodes, age and gender was performed. The presence of
      micrometastases in a total of 1,633 lymph nodes from 44 patients (22 with and 22
      without recurrence) were examined by immunohistochemistry using antibodies for
      cytokeratin (KL-1) and p53 (RSP53). Immunostaining with KL-1 revealed
      micrometastases in 15/22 patients [68%; 82/820 lymph nodes (10%)] and 15/22
      patients [68%; 45/813 lymph nodes (6%)] in the recurrent and nonrecurrent groups,
      respectively. Immunohistochemical analysis, using RSP53, of 18 paired patients
      with p53-positive primary tumor revealed micrometastases in 4/9 patients [44%;
      (7/265 lymph nodes (2.6%)] and 4/9 patients [44%; 6/257 lymph nodes (2.3%)] with
      and without recurrence, respectively. Neither the micrometastatic frequencies of
      the patients nor the resected lymph nodes of the recurrent and nonrecurrent
      groups differed significantly. Micrometastases in regional lymph nodes are an
      interesting phenomenon, but do not influence patients' prognoses if the involved
      lymph nodes are removed.

PMID- 10575312
TI  - Artificial neural networks applied to survival prediction in breast cancer.
AB  - In this study, we evaluated the accuracy of a neural network in predicting 5-, 10
      and 15-year breast-cancer-specific survival. A series of 951 breast cancer
      patients was divided into a training set of 651 and a validation set of 300
      patients. Eight variables were entered as input to the network: tumor size,
      axillary nodal status, histological type, mitotic count, nuclear pleomorphism,
      tubule formation, tumor necrosis and age. The area under the ROC curve (AUC) was
      used as a measure of accuracy of the prediction models in generating survival
      estimates for the patients in the independent validation set. The AUC values of
      the neural network models for 5-, 10- and 15-year breast-cancer-specific survival
      were 0.909, 0.886 and 0.883, respectively. The corresponding AUC values for
      logistic regression were 0.897, 0.862 and 0.858. Axillary lymph node status (N0
      vs. N+) predicted 5-year survival with a specificity of 71% and a sensitivity of
      77%. The sensitivity of the neural network model was 91% at this specificity
      level. The rate of false predictions at 5 years was 82/300 for nodal status and
      40/300 for the neural network. When nodal status was excluded from the neural
      network model, the rate of false predictions increased only to 49/300 (AUC 0.
      877). An artificial neural network is very accurate in the 5-, 10- and 15-year
      breast-cancer-specific survival prediction. The consistently high accuracy over
      time and the good predictive performance of a network trained without information
      on nodal status demonstrate that neural networks can be important tools for
      cancer survival prediction.

PMID- 10575313
TI  - Safety and cost of hyperhydration for the prevention of hemorrhagic cystitis in
      bone marrow transplant recipients.
AB  - Hemorrhagic cystitis is a major cause of morbidity after bone marrow
      transplantation. Traditional methods of prevention have included mesna (2
      mercaptoethane sodium sulfonate) and bladder irrigation. We report the use of
      hyperhydration as an alternative to these prophylactic measures. One hundred
      consecutive patients who underwent autologous or allogeneic bone marrow
      transplantation received high dose cyclophosphamide with hyperhydration using 5%
      dextrose normal saline at the rate of 250 ml/h and furosemide to maintain a urine
      output of >150 ml/h. Seventy-one of these patients also received high dose
      cyclophosphamide as mobilization chemotherapy. There were no episodes of
      hemorrhagic cystitis following mobilization chemotherapy. The incidence of
      hemorrhagic cystitis after transplant conditioning was 7% with 2 patients
      developing clinically significant hemorrhagic cystitis; one was a severe episode.
      The cost of hyperhydration was US$ 20 per course as opposed to US$ 1,500 per
      course for mesna, based on acquisition costs at our institution. We conclude that
      hyperhydration is a safe, inexpensive means of preventing hemorrhagic cystitis
      associated with high dose cyclophosphamide in bone marrow transplant recipients.

PMID- 10575314
TI  - Treatment resistant small cell carcinoma of the cervix.
AB  - BACKGROUND: Small cell undifferentiated carcinoma of the cervix is an uncommon
      malignancy with a poor prognosis. Treatment of localized disease has an
      approximate 40% 5-year survival with multimodality therapies. CASE REPORT: We
      describe the case of a 24-year-old woman with small cell carcinoma of the cervix
      that recurred locally despite intensive chemotherapy and radiotherapy.
      Hysterectomy was performed and the patient is now 18 months disease free.
      Following treatment, the pathological appearance of the tumor had changed from a
      typical small cell neuroendocrine malignancy to a more intermediate
      neuroendocrine cell type. CONCLUSION: Small cell carcinoma of the cervix is a
      rare aggressive malignancy that may require cytostatic multimodality therapy
      including chemotherapy, radiotherapy and surgery, even in early stage disease.

PMID- 10575315
TI  - Psychological distress in cancer patients attending the European Institute of
      Oncology in Milan.
AB  - BACKGROUND: The determination of the extent and specific features of the
      psychological distress to be expected in a cancer centre may influence the choice
      of interventions to be implemented for addressing these problems. This study was
      aimed at estimating the prevalence of psychological distress in patients
      attending a second reference cancer centre in Milan (Italy), and at identifying
      associated factors. PATIENTS AND METHODS: 190 consecutive patients were assessed
      within 3 days of hospital discharge using the Hospital Anxiety and Depression
      Scale. RESULTS: Major depressive disorders or generalised anxiety disorders were
      estimated in 16% of the patients. Only 2 of these patients were referred to the
      psycho-oncology unit, hence the psychological distress of many patients was not
      considered during their hospital stay. In the multiple regression analysis,
      independent predictors of psychological distress were female gender, experience
      of disturbance in family and social life due to illness, nausea and vomiting, and
      perception of being in a poor state of health (R(2) = 0.31, p value < 0.001),
      while physical functioning, fatigue and pain, significant factors in univariate
      analysis (p < 0. 05), sociodemographic and clinical factors were not predictors.
      CONCLUSIONS The psycho-oncology team should focus on helping doctors and nurses
      identify the patients' psychological problems, dealing with them or making a
      referral.

PMID- 10575316
TI  - Effect of granisetron on performance status during high-dose interferon therapy.
AB  - Two case reports demonstrating the new complete amelioration of the toxicity of
      alpha-2b recombinant interferon using granisetron i.v. or p.o.

PMID- 10575317
TI  - CDKN2 mutation is infrequent in german hepatocellular carcinoma.
AB  - For hepatocellular carcinoma, only scarce and controversial data on CDKN2
      alterations are available. A high rate of mutations in a Chinese study contrasts
      with a low rate found in Japanese tumors and a CDKN2 germline mutation in 4/26
      Swiss tumors examined. We analyzed 23 hepatocellular carcinomas from German
      patients for homozygous deletions of CDKN2 by coamplification with the human
      tyrosine hydroxylase (TH) gene and for CDKN2 mutations by PCR-single strand
      conformation polymorphism analysis and direct DNA sequencing. Our results
      indicate the lack of homozygous deletions. In one tumor, DNA sequencing showed a
      GCG-ACG (alanine-threonine) substitution at codon 148, a polymorphism in exon 2
      of CDKN2. We conclude that the alteration of CDKN2 by deletion or mutation
      appears not to be a frequent event in hepatocarcinogenesis in German patients.

PMID- 10575318
TI  - Prognostic value of p27(Kip1) and CyclinD1 expression in esophageal cancer.
AB  - It has recently been reported that the reduced expression of p27(Kip1) is a
      negative prognostic marker in several carcinomas. In this study, we examined the
      expression of p27(Kip1) in esophageal squamous cell carcinomas in order to
      understand its prognostic role. We also examined the expression of cyclinD1,
      which is believed to be correlated with the prognosis. Of the 128 cases, 64 cases
      (50.0%) showed low grade p27(Kip1) immunostaining and 64 cases (50.0%) high grade
      immunostaining; there was no significant difference in survival (p = 0.0915)
      between the two groups. On the other hand, 51 of the 156 cases (32.7%) were
      classified as the high cyclinD1 group, and 105 of the 156 cases (67.3%) as the
      low group, thus representing prognostic significance with regard to survival (p =
      0.0161). Multivariate analysis indicated that gender, lymph node metastasis and
      positive cyclinD1 were independent prognostic factors. Our results revealed that
      cyclinD1 was a significant prognostic predictor of esophageal squamous cell
      carcinomas, whereas p27(Kip1) was not a significant prognostic factor.

PMID- 10575319
TI  - Expression of p53 and glutathione S-transferase-pi relates to clinical drug
      resistance in non-small cell lung cancer.
AB  - To determine the predictive value of the expression of p53 and glutathione S
      transferase-pi (GST-pi) with respect to chemotherapy response, immunostaining was
      performed on transbronchial biopsy specimens from previously untreated patients
      with non-small cell lung cancer. Of the 54 patients, 34 patients (63%) and 37
      patients (69%) were positive for p53 and GST-pi, respectively. The response rates
      in the p53-positive and p53-negative group were 15 and 45%, and those in GST-pi
      positive and GST-pi-negative groups were 16 and 47%, respectively. A multiple
      logistic regression analysis revealed that positive immunostaining for GST-pi was
      a significant risk factor for clinical chemotherapy resistance. The combination
      of these two markers was the most important independent factor in predicting a
      response to chemotherapy in multiple logistic regression analysis.
      Immunohistochemical expression of p53 and GST-pi was independently related to
      clinical chemoresistance in patients with non-small cell lung cancer. Combined
      use of these two biomarkers may be a useful predictor of clinical
      chemoresistance.

PMID- 10575321
TI  - Plasma insulin-like growth factor-I and serum IGF-binding protein 3 can be
      associated with the progression of breast cancer, and predict the risk of
      recurrence and the probability of survival in African-American and Hispanic
      women.
AB  - In vitro studies have shown that insulin-like growth factor (IGF) is a mitogen
      for breast cancer cells. However, the associations of plasma IGF-I with tumor
      histopathology in high-risk groups need further investigation. We hypothesize
      that plasma IGF-I and serum IGFBP3 concentrations in breast cancer patients may
      provide useful information on the progression of their disease, and determine the
      probability of recurrence and survival. We have carried out a retrospective study
      on 130 minority breast cancer patients. Plasma IGF-I and serum IGFBP3 were
      correlated with tumor histopathology, menopausal status, treatment modality,
      recurrence rates, and probability of survival. Plasma IGF-I and serum IGFBP3 were
      measured by radioimmunoassay. Our studies show that breast cancer patients have
      elevated plasma IGF-I and serum IGFBP3 levels. In addition we observed the
      following: IGF-I did not correlate with age and nodal stage. IGF-I and IGFBP3
      increased with tumor size (T4). IGF-I did not correlate with estrogen receptor
      status, but did increase in progesterone-receptor-positive patients. IGF-I levels
      were higher in premenopausal patients and in women with cancer recurrence.
      Tamoxifen reduced IGF-I levels significantly and reduced the risk of recurrence.
      The survival probability was greater in patients with plasma IGF-I levels <120
      ng/ml. In conclusion, lowering of plasma IGF-I may offer the following benefits:
      (a) reduce the risk of developing breast cancer in high-risk groups; (b) slow the
      progression of breast cancer in patients at early stages of cancer; (c) lower the
      risk of recurrence, and (d) increase the probability of survival.

PMID- 10575320
TI  - p53 autoantibodies in patients with primary ovarian cancer are associated with
      higher age, advanced stage and a higher proportion of p53-positive tumor cells.
AB  - Autoantibodies (AAb) directed against the nuclear phosphoprotein p53 can be
      detected in patients with various forms of cancer. The objective was to determine
      the prevalence of p53 AAb at the time of diagnosis in ovarian cancer patients and
      to correlate the presence of p53 AAb with clinicopathological parameters. Sera of
      83 patients were analyzed by an ELISA using p53 expressed from a human wild-type
      cDNA. p53 AAb were detectable at all stages. The overall prevalence was 46%. p53
      AAb were more frequent in patients with higher age (p = 0.014), postmenopausal
      status (p = 0.050), or advanced tumor stage (p = 0.046). p53 AAb positivity was
      related to the proportion of cells positive in immunohistochemistry but not with
      the staining intensity. In bivariate analysis, patients with p53 AAb had a 1.96
      fold risk for relapse (95% confidence interval 1.02-3.78).

PMID- 10575322
TI  - The antihypertensive effect of the berberine derivative 6-protoberberine in
      spontaneously hypertensive rats.
AB  - Berberine is a natural isoquinoline alkaloid found in plants of the Ranunculaceae
      and Berberidaceae families. Extracts from berberine-containing plants have been
      used as traditional Chinese folk remedies for centuries. The antihypertensive
      effects of the berberine derivative 6-protoberberine (PTB-6) were studied in
      spontaneously hypertensive rats (SHRs). In conscious SHRs, PTB-6 lowered the
      systolic blood pressure in a dose-dependent manner (6-PTB: 5 mg/kg, -31.1 +/- 1.6
      mm Hg; 10 mg/kg, -42.4 +/- 3.1 mm Hg). Cardiac output using the thermodilution
      method was reduced in PTB-6-treated anesthetized SHRs with a tendency to decrease
      in heart rate. Injection of PTB-6 into the intracerebral ventricles of SHRs
      lowered the systolic arterial blood pressure and heart rate. The berberine
      derivative PTB-6 is an effective antihypertensive agent. The mechanism of the
      antihypertensive effect of PTB-6 is probably through a central sympatholytic
      effect.

PMID- 10575323
TI  - Pharmacological analysis of atypical beta-adrenoceptors in the guinea pig gastric
      fundus using the beta(3)-adrenoceptor antagonist bupranolol.
AB  - Atypical beta-adrenoceptor-mediated relaxations to catecholamines (isoprenaline,
      noradrenaline and adrenaline) and beta(3)-adrenoceptor agonists, BRL37344 [(R*,
      R*)-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]-propyl]phen oxyacetic
      acid sodium salt] and CGP12177A [(-)-4-(3-t-butylamino-2-hydroxy-
      propoxy)benzimidazol-2-one] in guinea pig gastric fundus were investigated. The
      five agonists induced concentration-dependent relaxation of the gastric fundus.
      In the presence of both atenolol and butoxamine only small rightward shifts of
      the concentration-response curves to these agonists were observed. Under this
      condition, however, bupranolol caused a concentration-dependent rightward shift
      of the concentration-response curve to catecholamines and beta(3)-adrenoceptor
      agonists. Schild plot analyses of bupranolol against these agonists gave pA(2)
      values of 6.08 (isoprenaline), 6. 04 (noradrenaline), 5.90 (adrenaline), 6.50
      (BRL37344) and 5.80 (CGP12177A), respectively. These results clearly suggest that
      the existence of functional atypical beta-adrenoceptors in the guinea pig gastric
      fundus and the relaxation of these agonists in this tissue are mediated via
      atypical beta-adrenoceptors.

PMID- 10575324
TI  - Studies on the stereoselective metabolism of citalopram by human liver microsomes
      and cDNA-expressed cytochrome P450 enzymes.
AB  - The involvement of CYP enzymes in the metabolism of citalopram was studied,
      inclusive the conversion of demethylcitalopram to didemethylcitalopram and the
      formation of citalopram N-oxide, which both have not been considered previously.
      Using human mixed liver microsomes and cDNA-expressed CYP enzymes, we confirmed
      that CYP3A4, 2C19 and 2D6 are involved in the first demethylation step of
      citalopram, all favouring conversion of the biologically active S-enantiomer.
      Inhibitor studies indicated that at therapeutic citalopram concentrations CYP3A4
      was responsible for 40-50% of demethylcitalopram formation, while the
      contribution of CYP2C19 increased and that of CYP2D6 tended to decrease with
      increasing drug concentration. CYP2D6 exclusively mediated the second
      demethylation step, and citalopram N-oxide was also exclusively formed by CYP2D6.
      None of the studied CYP enzymes mediated deamination to the propionic acid
      derivative.

PMID- 10575325
TI  - Intestinal motor depression by 7-nitroindazole through an action unrelated to
      nitric oxide synthase inhibition.
AB  - Nitric oxide (NO) is a cotransmitter of inhibitory motor neurons of the enteric
      nervous system. This study examined the effect of 7-nitroindazole (7-NI), an
      inhibitor of neuronal NO synthase (NOS), on intestinal peristalsis and muscle
      activity and compared 7-NI with N(G)-nitro-L-arginine methyl ester (L-NAME), a
      nonselective inhibitor of NOS isoforms. Peristalsis in isolated segments of the
      guinea pig small intestine was triggered by a perfusion-induced rise of the
      intraluminal pressure. While L-NAME (10-300 micromol/l) lowered the peristaltic
      pressure threshold (PPT) at which propulsive muscle contractions were elicited, 7
      NI (10-300 micromol/l) caused a concentration-related increase in PPT. L-Arginine
      (1-3 mmol/l) failed to reverse peristaltic motor depression evoked by 7-NI but
      annulled the L-NAME-evoked stimulation of peristalsis. Drugs which stimulated
      peristalsis, such as L-NAME, naloxone, apamin and suramin plus pyridoxal
      phosphate-6-azophenyl-2'-4'-disulphonic acid counteracted the inhibitory effect
      of submaximally effective concentrations of 7-NI on peristalsis. 7-NI (100-300
      micromol/l) inhibited circular muscle contractions evoked by cholecystokinin
      octapeptide, the NK(1) receptor agonist GR-73,632 and indomethacin whereas L-NAME
      (100-300 micromol/l) failed to inhibit any drug-evoked contraction. These data
      show that 7-NI, unlike L-NAME, inhibits circular muscle contractions of the gut
      and depresses intestinal peristalsis. It is concluded that the inhibitory motor
      action of 7-NI is unrelated to inhibition of neuronal NOS and arises from
      depression of smooth muscle activity.

PMID- 10575326
TI  - Sibling orders of schizophrenic patients in Austria and Pakistan.
AB  - The influence of siblings on the socialization of the individual has been
      recognized as a fact by both psychology and sociology. The significance of
      sibling order for the outbreak of psychiatric diseases on the other hand is still
      discussed controversially. In our study, we compared the expected values and the
      positions actually found in the sibling order of 379 (233 males, 146 females)
      Austrian and 144 (101 males, 43 females) Pakistani patients diagnosed with
      schizophrenia according to DSM-IV (295). The position in the sibling order had no
      influence on the outbreak of schizophrenia in Austria; with Austrian
      schizophrenics, the results found were very near to the expected values. In
      Pakistan on the other hand, the eldest brothers from families with 2-4 siblings
      had a significantly higher risk of falling ill. The investigation of the
      composition of the sibships of schizophrenic patients also showed a high
      overrepresentation of men in the firstborn position in Pakistan. These facts seem
      to exercise influences that may either protect against the outbreak or encourage
      it. The differences found agree well with the fact that in Pakistan, both the
      gender of a child and the position in the sibling order entail different ways of
      treatment and different scopes of responsibility. Socialization in Austria on the
      other hand, at least in the recent decades, has become very uniform for both
      sexes, regardless of the sibling position.

PMID- 10575327
TI  - Study of the onset of autism through home movies.
AB  - The authors describe the natural history and the beginning of pervasive
      developmental disorders (PDD) by the observation of home movies. The sample is
      composed of 26 children aged 18 months to 5 or 6 years at the first consultation.
      The methodology used in the observation of home movies includes: (1) application
      of the ERC-A-III scale for recognizing the precocious symptoms of autism; (2)
      analysis of the coming out and coming off of social, emotional and cognitive
      competences. The authors, starting from the analysis of these data, describe
      three kinds of onset and courses of PDD: progressive, regressive and fluctuating.
      The authors present some conclusive considerations on the different age of PDD
      onset in home movies, in anamnestic reconstruction and in recall for diagnosis.

PMID- 10575328
TI  - Winter depression with spring exacerbation: A frequent occurrence in women with
      seasonal affective disorder.
AB  - Winter depression (WD) usually starts in October/November and remits in
      February/March, but some experience a relatively short depressive exacerbation in
      spring. To further characterize this spring exacerbation (SE), 84 previously
      diagnosed WD patients rated in retrospect whether they had experienced SE after
      their otherwise typical WD in the years before receiving active treatment. Thirty
      nine percent of the women and 12% of the men reported to have experienced SE many
      times or practically every year; another 28 and 29%, respectively, had
      experienced SE a few times. In general, the symptomatology during SE was about
      the same as during WD. Female patients who had experienced SE many times or
      practically every year were marginally older (p = 0.05) and had suffered many
      more previous WD episodes (p = 0.0005) than female patients having experienced SE
      only a few times or never.

PMID- 10575329
TI  - Psychiatric comorbidity in Greek patients with generalized anxiety disorder.
AB  - From a total sample of 1,448 psychiatric outpatients, 81 (5.6%) received a
      diagnosis of generalized anxiety disorder (GAD) according to DSM-III-R criteria.
      Fifty-three (65%) of them had another Axis I diagnosis, while this percentage
      increased to 78% (63/81) when lifetime psychiatric diagnoses were recorded. The
      most frequent comorbid diagnoses were panic disorder, dysthymia, major depression
      and social phobia. Forty-three (53%) of the GAD patients met the criteria for
      personality disorder. They manifested obsessive-compulsive, avoidant personality
      and personalities of cluster C in general significantly more frequently than the
      rest of the total sample. The presence of a personality disorder was related to a
      significantly higher score on almost all the Minnesota Multiphasic Personality
      Inventory clinical and research scales, to a worse level of functioning and to an
      earlier age of onset of GAD. The results of the present study (1) support
      previous findings of high rates of comorbidity of clinical syndromes in GAD, (2)
      indicate that GAD co-occurs frequently with cluster C personality disorders,
      mainly avoidant and obsessive-compulsive, and (3) that the presence of a
      concomitant personality disorder is related to severer psychopathology and to a
      worse level of functioning.

PMID- 10575330
TI  - Dissociative symptoms in obsessive-compulsive dimensions.
AB  - Previous studies have described co-occurrence between obsessive-compulsive
      disorder (OCD) and dissociation. We intended to evaluate the phenomenological
      association between different obsessive-compulsive and dissociative symptoms more
      precisely. Seventy patients with OCD (DSM-IV) were evaluated with the Hamburg
      Obsessive-Compulsive Inventory (HZI) and the Dissociation Experience Scale.
      Correlation and discriminant analysis were performed. The dimensions 'Checking'
      and 'Symmetry and Ordering' were significantly related to dissociative
      symptomatology. A clear-cut lack of association was found in 'Washing and
      Cleaning', 'Counting and Touching' and 'Aggressive Impulses and Fantasies'. HZI
      dimensions significantly discriminated patients with high from patients with low
      dissociative symptomatology. Psychodynamic and therapeutical aspects of these
      findings are discussed.

PMID- 10575331
TI  - Recurring short delirium with postpartum onset in two sisters.
AB  - We report on a 30-year-old woman who twice developed a short postpartum psychosis
      with organic signs, but without obvious organic cause. Extensive investigations
      only yielded a state of moderate hypercoagulability. Her sister had developed
      similar signs and symptoms during her second puerperium and died 5 days after her
      delivery. We discuss the combination of various precipitating factors for
      postpartum psychosis, the possible impact of the findings on its cause and its
      classification.

PMID- 10575332
TI  - The lung in the immunocompromised host: diagnostic methods.

PMID- 10575333
TI  - N-acetylcysteine reduces the exacerbation rate in patients with moderate to
      severe COPD.
AB  - OBJECTIVE: This study was performed to confirm the efficacy of a 6-month therapy
      with a formulation of N-acetylcysteine (NAC; 600 mg/day p.o.) on frequency and
      severity of exacerbations in patients suffering from chronic obstructive
      pulmonary disease (COPD). METHODS: One hundred sixty-nine patients attending five
      Italian centres were recruited in an open, randomized, controlled study. The
      patients were randomly allocated to standard therapy plus NAC 600 mg once a day
      or standard therapy alone over a 6-month period. At baseline, medical history was
      evaluated, and physical examination was performed; occurrence and severity of
      exacerbations and side effects of NAC were analyzed after 3 and 6 months.
      RESULTS: The results showed a decreased number of exacerbations (by 41%) in the
      group of patients treated with NAC and standard treatment: 46 patients had at
      least one exacerbation as compared with 63 patients of the group treated with
      standard therapy alone. Also the number of the patients with two or more
      exacerbations was lower in the NAC group (26%) than in the standard-therapy group
      (49%). The number of sick days was less (82) in the NAC group as compared with
      the standard-therapy group (155). There was a small but significant improvement
      in FEV(1) and MEF(50) in the NAC group. NAC once a day was well tolerated. There
      were no differences in the number of side effects reported in both groups.
      CONCLUSIONS: These data confirm results of previous studies which reported a
      reduction in the number of exacerbations in patients having moderate to severe
      COPD treated with the antioxidant NAC. Further, the once-daily formulation is
      well tolerated and is likely to improve patient compliance with the prescribed
      regimen.

PMID- 10575334
TI  - In long-term smokers and former smokers the bronchodilator response is not
      related to the fall in FEV.
AB  - BACKGROUND: Cigarette smoking is the cardinal cause of chronic obstructive
      pulmonary disease (COPD), but only a relatively small percentage of smokers are
      developing clinically overt disease, suggesting, therefore, that other risk
      factors than smoking are involved. Several studies have shown that the
      bronchodilator response (BR) is related to the progress of COPD, as assessed by
      the fall in forced expiratory volume in 1 s (FEV(1)). However, the relationship
      between BR and fall in FEV(1), is a disputed one. OBJECTIVE: To assess the
      relationship between BR and fall in FEV(1) in a group of long-term smokers and ex
      smokers who were 60 years old on the average. METHODS: Questionnaire,
      spirographic tests and BR were assessed in 56 smokers and ex-smokers of mean age
      62.5 +/- (SD) 2.7 years at the end of a 13-year follow-up period. BR was
      expressed as a percentage change of the prebronchodilator value ('% initial') and
      as a percentage change of predicted value ('% predicted'). RESULTS: The FEV(1)/VC
      vital capacity was 68.9 +/- 7.6% at the start and 64.5 +/- 11.3% at the end of
      the study. The average fall in FEV(1) over 13 years was 26 +/- 25 ml/year. The
      FEV(1) increased after albuterol on the average with 5.9 +/- 6.6%, 4.5 +/- 3.9%
      of predicted, and the vital capacity with 2.5 +/- 6.5%, 2.3 +/- 6.4% of
      predicted. BR and fall in FEV(1) were correlated: the greater the BR, the more
      rapid the fall in FEV(1) (r = 0.4 and p < 0.01 for FEV(1)% and r = 0.3 and p <
      0.05 for FEV(1) predicted). However, when adjusting for prebronchodilator FEV(1),
      the BR was no more related to the fall in FEV(1) (r = 0.15, p > 0.05).
      CONCLUSIONS: In long-term smokers and ex-smokers, the BR measured at the end of
      the follow-up period was correlated with the fall in FEV(1). However, after
      adjusting for prebronchodilator FEV(1) values, BR was no more related to the
      decline in FEV(1). The BR appears not to be associated with the development of
      COPD.

PMID- 10575336
TI  - Length and lead time biases in radiologic screening for lung cancer.
AB  - OBJECTIVE: Our goal was to investigate whether the length and lead-time biases of
      radiologic screening for lung cancers vary according to the histologic type of
      the tumor. METHODS: We analyzed the survival rates and radiographs of 119 cases
      of adenocarcinomas-large-cell carcinomas (ALC) and 50 peripheral squamous cell
      carcinomas (PSQ) detected in 205,401 screened individuals. RESULTS: The
      sensitivity of screening and 5-year survival rates were 84.0% and 48.2% for ALC,
      and 52.0% and 18.5% for PSQ, respectively. The corrected length bias was 4.3% for
      ALC and 4. 6% for PSQ. Stage III-IV ALC was often identified on 1-year-old films,
      but stage III-IV PSQ was not. Half of stage I ALC presented 2 or more years
      before detection, while half of stage I PSQ appeared within 1 year before
      detection. The survival rate of nonresected cases with stage I ALC was decreased
      4 years after detection, while that of nonresected cases with stage I PSQ was
      decreased just after detection. The period of stage I ALC and PSQ was at least 6
      years and 1 year, respectively. CONCLUSIONS: Slowly growing ALC had high
      sensitivity in radiologic screening and a high rate in 5-year survival, but had
      long lead time and delay in detection. PSQ grew rapidly resulting in low
      sensitivity in radiologic screening, and short lead time and survival. In both
      types, the magnitude of corrected length bias was not remarkable. The survival of
      ALC should be carefully evaluated because of the long lead time.

PMID- 10575335
TI  - Detecting alveolar epithelial injury following volatile anesthetics by (99m)Tc
      DTPA radioaerosol inhalation lung scan.
AB  - BACKGROUND: Many volatile anesthetics have long been thought to affect alveolar
      epithelial permeability. OBJECTIVE: The purpose of this study was to examine the
      acute effects of volatile anesthetics on the permeability of the alveolocapillary
      barrier to (99m)Tc DTPA. METHODS: Twenty-seven patients (24 females, 3 males, age
      29-73 years) undergoing operation were enrolled in this study and grouped
      according to the type of anesthesia received. Group 1 patients were administered
      1% halothane. Group 2 patients were given 1.5% isoflurane. Intravenous anesthesia
      without volatile anesthetics were used for group 3 patients. Before and after
      anesthesia, (99m)Tc DTPA radioaerosol inhalation lung scans were performed to
      detect alveolar epithelial injury due to volatile anesthetics. The negative slope
      of the regression line was designated as the (99m)Tc DTPA pulmonary clearance
      rate and was expressed in terms of percentage decrease in radioactivity per
      minute. RESULTS: In group 1, the (99m)Tc DTPA clearance rates were 1.26 +/- 0.34
      and 1.29 +/- 0.38 before and after anesthesia, respectively. The difference was
      not significant (p > 0.05). In group 2, the rates were 0.76 +/- 0.20 and 1.10 +/-
      0. 37, before and after anesthesia, respectively. The difference was significant
      (p < 0.05). In group 3, the clearance rates were 1.07 +/- 0.38 and 1.21 +/- 0.48,
      before and after anesthesia, respectively. The difference was not significant.
      CONCLUSIONS: Following isoflurane administration, the more rapid pulmonary
      clearance of (99m)Tc DTPA indicates that isoflurane increases the permeability of
      the alveolo-capillary barrier.

PMID- 10575337
TI  - Effect of inhaled glutathione on airway response to 'Fog' challenge in asthmatic
      patients.
AB  - OBJECTIVE: We report on the effect of glutathione, an antioxidant compound on the
      airway response to the ultrasonically nebulised distilled water (UNDW, 'fog')
      challenge. METHODS: 12 subjects with mild-to-moderate bronchial asthma underwent
      double-blind, cross-over pretreatment, administered 30 min earlier, in a
      randomised order with inhaled glutathione (G) (600 mg), sodium cromoglycate (SCG)
      (20 mg) and placebo (P), followed by the challenge. RESULTS: After P pretreatment
      UNDW challenge caused a mean 20.41% decrease in FEV-1 (p < 0.05), after G, a mean
      6.04% fall in FEV-1 (p = n.s.), and after SCG a mean 5.99% fall in FEV-1 (p =
      n.s.). CONCLUSIONS: G significantly attenuated 'fog'-induced falls in FEV-1 (p <
      0.001 compared with P) and showed a protective effect on UNDW-induced
      bronchoconstriction.

PMID- 10575338
TI  - Effect of pulmonary edema on tracheal diameter.
AB  - BACKGROUND: Though it is well known that cardiogenic and noncardiogenic pulmonary
      edema can cause changes in lung mechanics, actual alterations in tracheal
      diameter have not been described. OBJECTIVE: To evaluate the effects of pulmonary
      edema induced by increased left atrial pressure (cardiogenic) and Perilla ketone
      (PK; noncardiogenic) on tracheal diameter in chronically instrumented awake
      sheep. METHODS: We investigated the effects of two mechanistically distinct types
      of pulmonary edema on tracheal diameter in chronically instrumented awake sheep.
      Cardiogenic pulmonary edema (analogous to congestive heart failure in humans) was
      induced by increasing left atrial pressure ( upward arrowP(LA)) by inflating the
      balloon on a Foley catheter positioned in the mitral valve annulus to cause
      partial obstruction to flow across the valve (n = 18). Noncardiogenic pulmonary
      edema (increased pulmonary microvascular permeability pulmonary edema analogous
      to the acute respiratory distress syndrome in humans) was produced by the
      intravenous administration of PK (n = 11). Lateral chest radiographs (CXRs) were
      scored by a standardized 5-point scoring system for the severity of pulmonary
      edema, and tracheal diameter was measured at a fixed location in the carina.
      Three radiologists, blinded to sheep identification number and experimental
      protocol, evaluated the radiographs independently at different points in time for
      edema severity and tracheal diameter. The sheep were sacrificed immediately after
      the final CXR, and wet/dry lung weight ratio (W/D ratio) was determined. RESULTS:
      Both upward arrowP(LA) and PK were associated with statistically significant
      tracheal narrowing ( upward arrowP(LA): 20.3 +/- 0.6 to 15.1 +/- 0.9 mm; PK: 20.2
      +/- 0.6 to 14.1 +/- 1.4 mm). Tracheal narrowing correlated with the severity of
      the pulmonary edema determined radiographically ( upward arrowP(LA): r = -0.69, p
      < 0.01; PK: r = -0.62, p < 0.01) and by W/D ratio ( upward arrowP(LA): r = -0.64,
      p < 0.05; PK: r = -0.54, p < 0. 05). CONCLUSIONS: We conclude that tracheal
      narrowing occurs in sheep models of both cardiogenic and noncardiogenic pulmonary
      edema and that the degree of narrowing correlates with the severity of the edema.

PMID- 10575339
TI  - Modulation of adhesion molecule profiles on alveolar macrophages and blood
      leukocytes.
AB  - BACKGROUND: Cell adhesion molecules are believed to be essential for blood cell
      recruitment to the lung and for the movement of alveolar macrophages (AM) within
      the lung. OBJECTIVE: To investigate the expression pattern of L-selectin and
      beta(2) integrins on blood leukocytes and AM, including AM of various maturity.
      METHODS: Flow cytometry was used to study the expression of L-selectin (CD62L)
      and of the beta(2) integrins CD11a, CD11b, and CD11c on AM (including density
      defined subpopulations), monocytes (Mo), polymorphonuclear neutrophils (PMN) and
      lymphocytes (Ly) sampled from healthy individuals, during incubation with and
      without lipopolysaccharide (LPS). RESULTS: A significantly different modulation
      pattern of beta(2) integrins and L-selectin was demonstrated on Mo and AM, cells
      of the same differentiation lineage. In contrast to AM, Mo had a marked ability
      to respond to LPS stimulation by increased expression of CD11a, CD11b and CD11c
      and decreased expression of L- selectin. These molecules were expressed to a
      similar degree on AM, whereas the basal levels of CD11b and L-selectin were
      considerably higher on Mo than on AM. A significantly different expression of
      CD11a as well as differences in the regulation of L-selectin during incubation
      were also demonstrated between density-defined subpopulations of AM. CD11a could
      not be upregulated on PMN, otherwise the modulation patterns of CD11b, CD11c and
      L-selectin were similar to that on Mo. The expression of CD11a on Ly was 3- to 6
      fold higher than on Mo, PMN and AM. The level of CD11b decreased significantly
      upon incubation (uninfluenced by LPS stimulation), and CD11c was hardly expressed
      on Ly. The level of L-selectin on Ly was higher than on Mo, AM and PMN and was
      not decreased during incubation. CONCLUSION: Developmental origin, degree of cell
      differentiation (maturity) as well as different environmental conditions all
      heavily influence the expression and modulation pattern of beta(2) integrins and
      L-selectin on leukocytes and Mo-derived AM.

PMID- 10575340
TI  - PACAP reverses airway hyperresponsiveness induced by ozone exposure in guinea
      pigs.
AB  - BACKGROUND: We previously demonstrated that pituitary adenylate cyclase
      activating peptide (PACAP) inhibits airway smooth muscle contraction and plasma
      extravasation. OBJECTIVE: We thus hypothesized that PACAP may regulate airway
      responsiveness through these effects and examined the effects of exogenously
      applied PACAP on the airway hyperresponsiveness induced by ozone exposure.
      METHODS: Ozone exposure was carried out in awake, spontaneously breathing guinea
      pigs using 3 ppm for 2 h. Airway responsiveness to histamine was determined
      before and 30 and 90 min after the termination of ozone exposure for 2 h in
      anesthetized animals. Extravasation of Evans blue was measured before and 90 min
      after the termination of ozone exposure. Either PACAP (10(-6) mol/kg) or vehicle
      was administered intravenously 60 min after exposure. The airway responsiveness
      was expressed as the concentration of histamine required to produce a 200%
      increase in total pulmonary resistance (PC(200)). RESULTS: Ozone exposure caused
      a significant decrease in PC(200) (n = 5, p < 0.05) 30 min after ozone exposure
      which persisted 90 min thereafter, thus suggesting that ozone caused airway
      hyperresponsiveness. PACAP significantly suppressed the increase in airway
      hyperresponsiveness induced by ozone 90 min after exposure (n = 5, p < 0.05). In
      contrast, this peptide did not have any effect on plasma extravasation.
      CONCLUSION: We thus conclude that PACAP decreases ozone-induced airway
      responsiveness, and, therefore, intravenously administered PACAP may be useful in
      reversing airway hyperresponsiveness.

PMID- 10575341
TI  - Ten years of second wind.

PMID- 10575342
TI  - Successful use of gonadotropin-releasing hormone agonist in a patient with
      pulmonary endometriosis.
AB  - A 26-year-old single female was admitted to hospital with recurrent chest pain,
      cough and hemoptysis. The symptoms developed 5 months before admission coinciding
      with menstruation. The disease was diagnosed as pulmonary endometriosis. She was
      treated with a long-acting gonadotropin-releasing hormone analogue (GnRH agonist;
      sustained-release leuprolide acetate, 3.75 mg/month, i.m.) for 6 months. She
      remained asymptomatic for 16 months with regular menstruation even after
      discontinuing the treatment. This indicates that the initial treatment of
      pulmonary endometriosis with a GnRH agonist is an acceptable medical alternative,
      especially in patients with a short duration of the disease from the onset of the
      chest symptoms.

PMID- 10575343
TI  - Bronchocentric granulomatosis as a first clinical manifestation in an adult
      patient with p67phox deficiency.
AB  - We report on a case of adult chronic granulomatous disease which first manifested
      as a pulmonary mass, and was histologically diagnosed as bronchocentric
      granulomatosis associated with aspergillosis in a patient with a deficiency of
      p67phox and a low oxidative response. Antifungal treatment was required for
      clinical resolution.

PMID- 10575344
TI  - Successful treatment with methylprednisolone pulse therapy for a life-threatening
      pulmonary insufficiency in a patient with chronic granulomatous disease following
      pulmonary invasive aspergillosis and Burkholderia cepacia infection.
AB  - A 14-year-old boy with X-linked chronic granulomatous disease developed severe
      invasive pulmonary aspergillosis. He was treated with itraconazole and
      amphotericin B. However, he deteriorated with progressive pulmonary lesions.
      Burkholderia cepacia was isolated from his bronchoalveolar lavage. Finally, he
      was given granulocyte transfusions. Following this procedure, his condition
      rapidly worsened leading to respiratory failure. His lung biopsy demonstrated
      organizing pneumonia at his right middle lobe. Then, a methylprednisolone pulse
      therapy was initiated together with the administration of appropriate antibiotics
      and adequate amounts of amphotericin B. Dramatically, his condition improved.
      Therefore, a methylprednisolone pulse therapy with appropriate antimicrobial
      drugs seems to be beneficial for severe pulmonary insufficiency in this type of
      patients.

PMID- 10575345
TI  - Lung cancer associated with pulmonary bulla. case report and review of
      literature.
AB  - A few reports have suggested the possible association between lung cancer and
      bullous disease. We report a surgical case of lung adenocarcinoma located in
      close proximity to pulmonary bullae. A 48-year-old nonsmoker, asymptomatic male
      was found to have a pulmonary tumor mass and giant bulla in the right lung.
      Thoracotomy identified a tumor arising from a firm, scarred and contracted area
      close to the bulla wall. Based on this report and review of other cases in the
      literature, we emphasize the need for physicians to be aware of the potential
      development of lung cancer in patients with pulmonary bulla.

PMID- 10575347
TI  - A 53-year-old patient with unilateral pulmonary infiltrates following a single
      dose of mitomycin, vindesine and cisplatin chemotherapy for non-small-cell lung
      cancer. Case discussed at the Zurich University Hospital, October 15, 1997.

PMID- 10575346
TI  - Fever, weight loss and night sweat on corticosteroid therapy for COPD.

PMID- 10575348
TI  - The multigene immunophilin family of Dictyostelium discoideum. Characterization
      of microsomal and mitochondrial cyclophilin isoforms.
AB  - The sequences of two cyclophilin (Cyp) isoforms from Dictyostelium discoideum
      have been determined. cyp2 is expressed as a 197 amino acid protein, which
      contains a 22 amino acid-long signal sequence, characteristic of endoplasmic
      reticulum localization signals, and that is cleaved in the mature protein. Mature
      Cyp2 has a molecular mass of 18 986 Da. The cyp3 gene encodes a 174 amino acid
      protein with a predicted molecular mass of 19 016 Da. Its sequence reveals no
      targeting sequence. From the MS analysis of affinity-purified cyclophilins from
      different subcellular compartments, we localized the previously described Cyp1
      (Barisic K. et al., Dev. Genet. 12 (1991) 50-53) in cytosol, Cyp2 in microsomes
      and Cyp3 in mitochondria, respectively. The expression of cyp1 mRNA is constant
      during differentiation, whereas the mRNA level of both cyp2 and cyp3 is regulated
      and decreases steadily during development.

PMID- 10575349
TI  - The protective effect on Cu2+- and AAPH-mediated oxidation of human low-density
      lipoproteins depends on glycosaminoglycan structure.
AB  - The effect of various glycosaminoglycans on Cu(2+)- and AAPH-induced oxidation of
      human low-density lipoprotein (LDL) was studied by monitoring conjugated diene
      formation. Heparin (Hep) increased the lag phase (t(lag)) of LDL oxidation, and
      fast moving and slow moving Hep species modified the kinetics of LDL oxidation to
      the same extent. Beef spleen heparan sulfate (HS) sample produced a significant
      increase of the t(lag) and a decrease of the conjugated diene formation of LDL
      whilst beef kidney HS species modified LDL oxidation kinetics to a lower extent.
      Dermatan sulfate (DS) from different sources caused a significant increase of the
      t(lag) and a decrease of the conjugated diene formation of LDL. Hyaluronic acid
      had no effect. Chondroitin sulfate (CS) from beef trachea produced a very strong
      protective antioxidant effect evaluated by increasing of the t(lag) and
      decreasing of the conjugated diene formation. Hep was completely ineffective in
      protecting LDL from 2, 2'-azobis(2-amidinopropane) hydrochloride (AAPH)-mediated
      oxidation, whilst DS was moderately effective. Beef trachea CS showed a very
      strong ability to protect LDL oxidation induced by 1 mM AAPH. The different
      protective effect on Cu(2+)- and AAPH-induced LDL oxidation by glycosaminoglycans
      is discussed considering their various structures and properties, and their
      capacity to interact to different extents with hydrophobic regions of LDL protein
      is confirmed by measuring the LDL-tryptophan fluorescence kinetics.

PMID- 10575351
TI  - Isoleucine 10 is essential for DNA gyrase B function in Escherichia coli.
AB  - DNA gyrase is an essential enzyme that regulates the DNA topology in bacteria. It
      belongs to the type II DNA topoisomerase family and is responsible for the
      introduction of negative supercoils into DNA at the expense of hydrolysis of ATP
      molecules. The aim of the present work was to study the contribution of I10, one
      of the most important residues responsible for the stabilization of GyrB dimer
      and involved in the ATP-binding step, in the ATP-hydrolysis reaction and in the
      DNA supercoiling mechanism. We constructed MBP-tagged GyrB mutants I10G and
      Delta4-14. Our results demonstrate that both mutations severely affect the DNA
      dependent ATPase activity and DNA supercoiling. Mutation of Y5 residue involved
      in the formation of ATPase catalytic site (Y5G mutant) had only little effect on
      the DNA-dependent ATPase activity and DNA supercoiling. Interestingly, the DNA
      relaxation activity of MBP-GyrB mutants and wild type was completely inhibited by
      ATP. Binding of ADPNP to MBP-tagged mutants was significantly decreased. ADPNP
      had no effect on DNA-relaxation activity of MBP-tagged mutants but was able to
      inhibit MBP-tagged wild type enzyme. Our results demonstrate that GyrB N-terminal
      arm, and specially I10 residue is essential for ATP binding/hydrolysis efficiency
      and DNA transfer through DNA gyrase.

PMID- 10575350
TI  - Expression of mitochondrial genes and of the transcription factors involved in
      the biogenesis of mitochondria Tfam, NRF-1 and NRF-2, in rat liver, testis and
      brain.
AB  - Mitochondrial function requires genes encoded in both mitochondrial and nuclear
      genomes. Tfam, the activator of mammalian mitochondrial transcription, is encoded
      in the nucleus and its expression has been shown in in vitro studies to be
      controlled by nuclear respiratory factors NRF-1 and NRF-2. In order to understand
      the physiological dependence of mitochondrial gene expression, we have analyzed
      in rat liver, testis and brain the expression level of mitochondrial genes in
      parallel with those of the three transcription factors. We found that: a) Tfam
      expression is down-regulated in rat testis, both at the protein and transcript
      level. The three-fold reduction in the abundance of Tfam protein in rat testis
      does not result in low steady-state levels of mitochondrial gene transcripts,
      suggesting that Tfam is in excess and does not limit transcription in vivo; and
      b) NRF-1 and NRF-2 (alpha, beta and gamma subunits) mRNAs were analyzed by
      Northern blotting; for each mRNA, several transcripts were observed as well as
      tissue-specific patterns of expression. The mRNA steady-state levels of NRF-1 and
      NRF-2 were higher in testis than in liver or brain. These data suggest that the
      low expression level of Tfam found in testis is not due to decreased NRF-1 and/or
      NRF-2 expression and further suggest the existence of tissue-specific post
      transcriptional regulatory mechanisms for the expression of NRF-1/NRF-2 genes.

PMID- 10575352
TI  - The structures of elastins and their function.
AB  - Elastin structures and their significance towards elastic recoil properties have
      been reviewed. Starting from the initial hypothesis that elastin conformation is
      conditioned by that of its monomer, the structure of tropoelastin was first
      described using theoretical and experimental methods and a beta class folding
      type was evidenced for the isolated unbound tropoelastin molecules. The structure
      of elastin in the solid state was consistent with that of its monomer and
      consequently, fibrous elastin appeared constituted of globular tropoelastin
      molecules. Finally, theoretical and experimental considerations have led us to
      the conclusion that the functional form of the elastomer, water swollen elastin,
      could be a triphasic system comprising the protein chains, hydration water and
      solvent water. Following this description, the dynamic structural equilibria
      occurring within elastin hydrophobic domains and the plasticizing effect of water
      could explain elastin elasticity, in keeping with a classical entropic mechanism.

PMID- 10575353
TI  - Initiation of Escherichia coli ribosomes on matrix coupled mRNAs studied by
      optical biosensor technique.
AB  - The optical biosensor technique, based on the surface plasmon resonance (SPR)
      phenomenon, has been used to study the initiation of protein synthesis by E. coli
      ribosomes on surface coupled mRNA. mRNA was first periodate oxidized and then
      hydrazide coupled to the surface of a CM5 sensor chip. The formation of
      initiation complexes on the surface coupled mRNA was monitored in real-time with
      a BIACORE 2000 instrument. Mature 70S*mRNA*fMet-tRNA(Met) initiation complexes
      were assembled on mRNA by sequential introduction of the 30S and 50S subunits
      supplemented with appropriate initiation factors and fMet-tRNA(Met). We show that
      the formation of 70S*mRNA complexes on the surface coupled mRNA proceeds
      efficiently only in the presence of tRNA. Moreover, 70S*mRNA*fMet-tRNA(Met)
      complexes formed with fMet-tRNA(Met) are more stable than similar complexes
      formed with deacylated tRNAs. The efficient formation and slow dissociation of
      mature 70S*mRNA*fMet-tRNA(Met) initiation complexes are most easily explained by
      the stabilization of the interaction of the ribosomal subunits by fMet-tRNA(Met).
      This work demonstrates the feasibility of the BIACORE technique for studying the
      initiation of protein synthesis.

PMID- 10575354
TI  - The mycotoxin fumonisin B1 inhibits integrin-mediated cell-matrix adhesion.
AB  - Fumonisin B1 (FB1), a mycotoxin produced by the corn fungus Fusarium moniliforme,
      causes a variety of animal diseases and is a suspected human carcinogen. The FB1
      molecule bears remarkable structural resemblance to the long-chain sphingoid base
      backbones of sphingolipids. The toxicity and carcinogenicity of FB1 has been
      ascribed to its ability to inhibit ceramide synthase, a key enzyme in the
      metabolism of complex sphingolipids. In this study we have investigated whether
      the exposure of B16-BL6 mouse melanoma cells to FB1 affects cell growth and
      integrin-mediated cell matrix adhesion. Cell treatment with the highest tested
      dose (75 microM) of FB1 for 72 h induced an about 20% inhibition of cell growth.
      FB1 strongly affected B16-BL6 cell adhesion to immobilized fibronectin, by
      causing a dose-dependent inhibition of cell attachment to this substrate. FB1
      also inhibited in a dose-dependent manner the adhesion of B16-BL6 cells to the
      immobilized anti-fibronectin receptor antibody, whereas it affected only to a low
      extent cell attachment to concanavalin A. Our results demonstrate that FB1
      treatment alters integrin adhesive activity, thus affecting all cellular integrin
      dependent functions.

PMID- 10575355
TI  - myo-[3H]-inositol loaded erythrocytes and white ghosts: two models to investigate
      the phosphatidylinositol synthesis in human red cells.
AB  - Human erythrocytes were loaded with myo-[(3)H]-inositol in the presence or
      absence of cytidine trisphosphate to investigate the synthesis of membrane
      phosphoinositides in the intact red cell. The addition of cytidylic nucleotides
      to the loading mixture yielded a four-fold increase in the [(3)H]-labeling of the
      membranes. The [(3)H]-labeling of phosphatidylinositol, phosphatidylinositol 4
      phosphate and phosphatidylinositol 4,5-bisphosphate was distinguished by two
      chromatographic techniques. Experiments performed on white ghosts demonstrated
      the presence of CDP-diacylglycerol synthase and phosphatidylinositol synthase.
      These results and those already reported allow to discuss a possible turnover of
      the inositol polar head.

PMID- 10575356
TI  - In vitro assembly of yeast 5S rRNA and a fusion protein containing ribosomal
      protein L5 and maltose binding protein.
AB  - Binding of yeast ribosomal protein L5 with 5S rRNA has long been considered a
      promising model for studying molecular mechanisms of protein-RNA interactions.
      However, in vitro assembly of a ribonucleoprotein (RNP) complex from purified
      yeast ribosomal protein L5 (also known as L1, L1a, or YL3) and 5S rRNA proved to
      be difficult, thus limiting the utility of this model. In the present report, we
      present data on the successful in vitro assembly of a RNP complex using a fusion
      (MBP-L5) protein consisting of the yeast ribosomal protein L5 fused to the
      carboxyl terminus of the E. coli maltose-binding protein (MBP). We demonstrated
      that: 1) the MBP-L5 protein binds yeast 5S rRNA but not 5.8S rRNA in vitro; 2)
      the MBP protein itself does not bind yeast 5S rRNA; 3) formation of the RNP
      complex is proportional to the concentration of MBP-L5 protein and 5S rRNA; and
      4) the MBP moiety of the fusion protein in the RNP complex can be removed with
      factor Xa. The electrophoretic mobility of the resultant RNP complex is
      indistinguishable from that of L5-5S rRNA complex isolated from the ribosome.
      Using this new experimental approach, we further showed that the RNA binding
      capability of a mutant L5 protein is decreased by 60% compared to the wild-type
      protein. Additionally, the mutant RNP complex migrates slower than the wild-type
      RNP complex suggesting that the mutant RNP complex has a less compact
      conformation. The finding provides a probable explanation for an earlier
      observation that the 60S ribosomal subunit containing the mutant protein is
      unstable.

PMID- 10575357
TI  - GSH system in relation to redox state in dystrophic skin fibroblasts.
AB  - Glutathione and GSH-related enzymes were determined in human Duchenne muscular
      dystrophy (DMD) and Becker muscular dystrophy (BMD) skin fibroblasts in order to
      relate muscular dystrophy to the redox state of the cell. The analysis of GSH,
      GSSG and total GSH levels in normal and dystrophic-cultured fibroblasts shows no
      differences in normal growth condition. However, the specific activity of two GSH
      related enzymes, glutathione S-transferases (GST) and gamma-glutamylcysteine
      synthetase (gamma-GCS), shows significant variations between normal and both
      types of dystrophic skin fibroblasts. These results suggest that even in normal
      growth condition some components of GSH metabolism may be altered. A condition of
      sublethal oxidation obtained by H(2)O(2) treatment was able to show a difference
      in the cellular response of GSH system components between normal and dystrophic
      cells. While in DMD cells there is a decrease of roughly 55% in GSH and of 30% in
      total GSH concentration, no changes are measured in normal and BMD cells. The
      remarkable increase in glutathione peroxidase (GPx) activity and decrease in GSH
      reductase (GR) activity measured in DMD cells can in part explain these changes.
      These results indicate a different capacity of DMD cells to support oxidative
      stress with respect to BMD and normal cells, and suggest a possible role of the
      GSH-antioxidant system in dystrophic pathology.

PMID- 10575359
TI  - Phenylalanyl-tRNA synthetase from the archaeon Methanobacterium
      thermoautotrophicum is an (alphabeta)2 heterotetrameric protein.
AB  - Phenylalanyl-tRNA synthetase from the methanogenic archaeon Methanobacterium
      thermoautotrophicum was purified to apparent homogeneity. The catalytically
      active enzyme is a heterotetramer composed of two subunits, alpha and beta. N
      terminal sequence data were obtained for both subunits and the open reading
      frames MT770 and MT742 of the genome sequence of M. thermoautotrophicum were
      identified as coding for these proteins. Two ORFs with similarity to non-archaeal
      PheRSs alpha-subunits had previously been found in the genome sequence, but these
      results show that only one of them, MT742, is part of the active PheRS.

PMID- 10575358
TI  - Acylphosphatase expression during macrophage differentiation and activation of U
      937 cell line.
AB  - The two acylphosphatase isoenzymes (muscle type and common type) are differently
      involved in cell differentiation processes. In this paper we investigate the
      expression of the two isoenzymes during macrophage differentiation and
      activation. The U-937 human promonocytic cell line is a model for cell
      differentiation induced by the tumor promoter phorbol myristic acetate (PMA).
      Here we show that only the expression of the muscle type acylphosphatase
      increases during U-937 differentiation and macrophage activation, confirming that
      the two isoenzymes are differently regulated. Moreover, we determined, in the
      same conditions, the level of specific mRNA. Results show that after an initial
      two-fold decrease during PMA stimulation, the muscle type acylphosphatase mRNA
      levels remain constant also after the treatment with lipopolysaccharide and gamma
      interferon, treatments that lead to macrophage activation. It is possible that
      post-transcription regulation is responsible for the regulation of muscle type
      acylphosphatase in the cell during differentiation and macrophage activation.

PMID- 10575360
TI  - Low enantioselectivities of human deoxycytidine kinase and human deoxyguanosine
      kinase with respect to 2'-deoxyadenosine, 2'-deoxyguanosine and their analogs.
AB  - The antiviral activity of L-nucleoside analogs depends in part on the
      enantioselectivity of nucleoside kinases which catalyse their
      monophosphorylation. The substrate properties of human recombinant deoxycytidine
      kinase (dCK) and human recombinant deoxyguanosine kinase (dGK) with respect to L
      adenosine and L-guanosine analogs, in the presence of saturating amounts of ATP
      and relatively high concentrations of substrates, demonstrated a marked lack of
      enantioselectivity of both these enzymes. Human dCK catalysed the phosphorylation
      of D- and L-enantiomers of beta-dA, beta-araA, and beta-dG with
      enantioselectivities favoring the unnatural enantiomer for the adenosine
      derivatives and the natural enantiomer for 2'-deoxyguanosine. No other tested L
      adenosine or L-guanosine analog was a substrate of dCK. Similarly, D- and L
      enantiomers of beta-dA, beta-araA, and beta-dG were substrates of human dGK but
      with different enantioselectivities compared to dCK, especially concerning beta
      dA. The present results indicate that human dCK and dGK have similar properties
      including substrate properties, relaxed enantioselectivities, and possibly
      catalytic cycles.

PMID- 10575361
TI  - Distribution and subcellular localization of acylpeptide hydrolase and acylase I
      along the hog gastro-intestinal tract.
AB  - The distribution of acylase I and acylpeptide hydrolase along the hog small
      intestine was investigated. No significant changes in their respective specific
      activity was found when the intestine was cut off and divided into eight segments
      (taken every 200 cm) so as to specifically study the duodenum, jejunum and ileum.
      Upon performing subcellular fractionation of hog enterocytes, it was observed
      that acylpeptide hydrolase is a soluble enzyme, while acylase I is essentially a
      soluble protein accounting for only 5% of the activity associated with the whole
      membrane fraction. The membrane-bound acylase I was neither solubilized by
      phosphatidylinositol-specific phospholipase C from Bacillus cereus nor by
      detergents which are commonly used to solubilize alkaline phosphatase, a
      glycosylphosphatidylinositol-anchored protein. When a phase separation was
      carried out in Triton X-114, all the anchored-membrane proteins of the intestinal
      membranes were located in the detergent-rich phase, while acylase I was present
      in the detergent-poor phase. Finally, the immunolabeling of intestinal cells with
      specific antibodies definitively established the cytoplasmic localization of
      acylase I. Acylpeptide hydrolase and acylase I therefore both are located in the
      enterocyte cytoplasm.

PMID- 10575362
TI  - Refolding of pyridoxine-5'-P oxidase assisted by GroEL.
AB  - The unfolding of brain pyridoxine-5'-P oxidase by guanidinium chloride has been
      investigated at equilibrium. Circular dichroism, fluorescence spectroscopy and
      gel exclusion chromatography were used to monitor the unfolding process. The
      enzyme dissociates reversibly into monomers, but the fluorescence properties of
      the cofactor FMN are not restored upon dilution with potassium phosphate buffer
      (pH 7.4). Spontaneous refolding leads to 20% recovery of the catalytic activity.
      Addition of GroEL to the renaturing buffer accelerates the recovery of catalytic
      activity that approaches a level of 80% with respect to the native enzyme. The
      rate of recovery of catalytic activity assisted by GroEL parallels the rate of
      FMN fluorescence quenching, suggesting that structural rearrangements of the
      catalytic domain is the last step to take place in the refolding process.

PMID- 10575363
TI  - A symbolic-numeric approach to find patterns in genomes. Application to the
      translation initiation sites of E. coli.
AB  - DNA sequence data provided by genome sequencing programs open new research
      prospects. In this respect, computational investigations are of major importance
      to discover new 'functional/structural patterns' and to improve biological
      process knowledge. For example, even though the principal steps of translation
      initiation in prokaryotes are known, it is difficult to point out the exact
      pattern of the mRNA that is recognized by the ribosome. In this study, we have
      carried out a systematic context analysis of the complete genome of E. coli,
      around codons in competition for translation initiation. Using a combinatorial
      approach, we first show that it is possible to accurately define the initiation
      site by looking for the localization of patterns representing various
      combinations of trinucleotides. We have combined this approach with a statistical
      analysis based on the frequencies of these patterns. This leads to a decision
      tree, able to discriminate true and false starts with a recognition level near
      90%. Our method may help to precisely localize the beginning of open reading
      frames, and point to likely mistakes for some genes in the database. The method
      may be included as a component of a gene recognition system, is not restricted to
      a particular genome or a two-classes discrimination, and may be applied to a
      broader class of biological patterns.

PMID- 10575364
TI  - Synthesis and antifungal activities of N-aryl-4-phenyl-3-(4
      phenoxyphenyl)butanamides.
AB  - Various N-aryl-4-phenyl-3-(4-phenoxyphenyl)butanamides (2 and 3) were tested for
      fungicidal activities against Pyricularia oryzae, Rhizoctonia solani, Botrytis
      cinerea, Phytophthora infestans, Puccinia recondita, and Erysiphe graminis in
      vivo. Butanamides (2 and 3a) that have an electron withdrawing group (Cl, F)
      attached to the meta position of the phenyl ring showed good to excellent
      activities against Pyricularia oryzae, Puccinia recondita, and Erysiphe graminis
      in high concentration while those that have a strong electron withdrawing group
      (CN, NO2) or electron donating group (OCH3, CH3) attached to the meta position
      did not show good activities against all test fungi at 250 mg L-1. The antifungal
      activities of the compounds synthesized were compared with reference compounds
      such as Tricyclazole, Moncozeb, and Benomyl.

PMID- 10575365
TI  - Synthesis of a novel series of imidazo[4,5-c]pyrazole derivatives and their
      evaluation as herbicidal agents.
AB  - Ever changing problems in agricultural weed control require periodic introduction
      of new herbicides. Imidazo[4,5-c]pyrazoles, which were considered of interest as
      potential herbicides, were synthesized and examined for the pre-emergence, post
      emergence, and post-transplant control of weeds in rice against broadleaf and
      grass weed species. The data obtained suggest that some imidazo[4,5-c]pyrazoles
      have potential herbicidal activity against a wide range of weeds, with 5-methyl,
      5-thiomethyl, and 5-unsubstituted derivatives being the most effective. No
      herbicidal activity was observed in the 5-methylsulfonylimidazo[4,5-c]pyrazole
      and imidazo[4,5-c]pyrazolone series.

PMID- 10575366
TI  - Synthesis and hypnotic activity of new 4-thiazolidinone and 2-thioxo-4,5
      imidazolidinedione derivatives.
AB  - Conveniently accessible 4-[(2-(3,4-dimethoxyphenyl)ethyl]-3-thiosemicarbazide (2)
      was converted to new 1-substituted benzylidene/furfurylidene-4- [2-(3,4
      dimethoxyphenyl)ethyl]-3-thiosemicarbazides (3) which furnished 2-(substituted
      benzylidene/furfurylidene) hydrazono-3-[2-(3,4-dimethoxyphenyl)ethyl]thiazolidin
      4-ones (4) and 1-(substituted benzylidene/furfurylidene)-amino -3-[2-(3,4
      dimethoxyphenyl)ethyl]-2-thioxo-4,5-imidazolidinedio nes (5) on reaction with
      chloroacetic acid and oxalyl chloride, respectively. The structure of 5 was
      confirmed by X-ray diffraction studies performed on 5a. 4 and 5 were evaluated
      for their potentiating effects on pentobarbital induced hypnosis. Most of the
      compounds caused remarkable increases in pentobarbital sleeping time.

PMID- 10575367
TI  - Synthesis and antiviral and cytostatic activities of carbocyclic nucleosides
      incorporating a modified cyclobutane ring. Part 1: Guanosine analogues.
AB  - Five new carbocyclic nucleosides were prepared by constructing a guanine
      (compounds 3, 5) or 8-azaguanine (compounds 4, 6, and 7) base on the amino group
      of (1'S,3'R)-3-(3'-amino-2',2'-dimethylcyclobutyl)propan-1-ol (8), and their
      activities against a variety of viruses and tumor cell lines were determined.
      Only compounds 3 and 7 showed a detectable activity at subtoxic concentrations
      against some viruses tested.

PMID- 10575368
TI  - Inhibitors of histone deacetylase suppress the growth of MCF-7 breast cancer
      cells.
AB  - Inhibitors of histone deacetylase are attracting increasing interest due to their
      influence on transcription, differentiation, and apoptosis. We have investigated
      two synthetic inhibitors 3 and 4 of histone deacetylase and the natural product
      inhibitor trichostatin A for their ability to suppress the growth of MCF-7 breast
      cancer cells and here present complete and improved synthetic procedures. The
      compounds show a dose dependent inhibition of growth with activities in the low
      micromolar and nanomolar range. Trichostatin shows cytocidal effects at 100 nM
      and still has activity comparable to cisplatin (0.5 microM) at 10 nM. Whereas the
      synthetic inhibitor 3 has cytocidal activity at 10 microM compound 4 shows a
      maximum of 40% growth suppression at that concentration.

PMID- 10575369
TI  - 1-Imidazolylcarbonyloxy-substituted tetrahydroquinolines and pyridines: synthesis
      and evaluation of P450 TxA2 inhibition.
AB  - The title compounds are derived from our model describing structural requirements
      for strong P450 TxA2 inhibition. In the present paper the syntheses of the 1
      imidazolylcarbonyloxy-substituted tetrahydroquinolines 1, 3, and 4, tetrahydro
      naphthalene 2 and 3-ethylpyridines 5 and 6 are described. Using our P450 TxA2
      inhibition assay, 1-6 were tested for enzyme inhibitory activity. Compound 1 (5
      (1-imidazolylcarbonyloxy)-5,6,7,8-tetrahydroquinoline) turned out to be the most
      active derivative showing a potency similar to the reference compound dazoxiben
      (IC50 values 1.6 and 1.1 microM).

PMID- 10575370
TI  - Synthesis, calcium channel antagonist activity, and anticonvulsant activity of 3
      ethyl 5-methyl 1,4-dihydro-2-[(2-hydroxyethoxy) methyl]-6-methyl-4-(2,3
      dichlorophenyl)-3,5-pyridinedicarboxylate coupled to a 1-methyl-1,4
      dihydropyridyl-3-carbonyl chemical delivery system.
AB  - 3-Ethyl 5-methyl 1,4-dihydro-2-[(2-hydroxyethoxy) methyl]-6-methyl-4-(2,3
      dichlorophenyl)-3,5-pyridinedicarboxylate (13), a bioisostere of amlodipine, was
      prepared by the reaction of ethyl 4-(2-hydroxyethoxy)acetoacetate (11) with
      methyl 2-(2,3-dichlorobenzylidene)acetoacetate (12) and NH4OAc. Compound 13 was
      elaborated to the target product 3-ethyl 5-methyl 1,4-dihydro-2-[2- [(1-methyl
      1,4-dihydropyridyl-3-carbonyloxy)ethoxy]methyl]- 6-methyl-4-(2,3-dichlorophenyl)
      3,5-pyridinedicarboxylate (16). The C-2 CH2OCH2CH2OH compound (13, IC50 = 6.56 x
      10(-9) M) was about 44-fold more active as a calcium channel antagonist than the
      reference drug nimodipine (IC50 = 1.49 x 10(-8) M), but 4-fold less potent than
      felodipine (IC50 = 1.45 x 10(-9) M). Compound 16, possessing the 1-methyl-3
      pyridylcarbonyloxy chemical delivery system moiety is a slightly less potent
      calcium channel antagonist (IC50 = 2.99 x 10(-8) M) than the parent compound 13.
      Compounds 13, 16, felodipine and nimodipine are highly lipophilic (Kp = 227, 344,
      442 and 187, respectively). The C-2 CH2OCH2CH2OH compound (13) exhibited
      equipotent anticonvulsant activity to nimodipine in the maximal electroshock
      (MES) anticonvulsant screen. Unlike nimodipine, 13 provided modest protection in
      the subcutaneous metrazol (scMet) anticonvulsant screen. In contrast, compound 16
      was inactive in both the MES and scMet screens.

PMID- 10575371
TI  - Plant-derived acetophenones with antiasthmatic and anti-inflammatory properties:
      inhibitory effects on chemotaxis, right angle light scatter and actin
      polymerization of polymorphonuclear granulocytes.
AB  - 3-Methoxy- and 2-hydroxy-3-methyl substituted 4-hydroxyacetophenones and some of
      the corresponding 4-O-glucosides revealed inhibitory activity on LTB4-, fMLP- and
      PAF-induced chemotaxis of polymorphonuclear granulocytes (PMN). Blocking of PMN
      myeloperoxidase (MPO), which is required for the intracellular activation of
      acetophenones, caused a loss of activity. By in vitro activation of apocynin (1)
      with human MPO and H2O2 and subsequent chromatographic purification an apocynin
      free fraction was obtained, which contained the major metabolite. The fraction
      showed strong anti-chemotactic activity, which was largely preserved despite of
      MPO-blockade. The influences on right angle light scatter and actin
      polymerization in PMN demonstrate the inhibitory effects of acetophenones on the
      cytoskeletal rearrangement after stimulation with fMLP. Acetosyringenin (2) was
      shown to reduce mastoparan-induced PMN migration. The inhibition of receptor
      independent motility of PMN suggests that the active metabolites of acetophenones
      may interfere with the post receptor signalling.

PMID- 10575372
TI  - Aggregation inhibitory activity of minor acetophenones from Paeonia species.
AB  - Two minor acetophenones, 2,5-dihydroxy-4-methoxy-acetophenone (2) and 2,5
      dihydroxy-4-methylacetophenone (7) from Paeonia species were found to selectively
      inhibit the aggregation of rabbit platelets induced by arachidonic acid. They
      were more potent than the major compound, paeonol (1), and 7 also inhibited the
      formation of TXA2 and PGD2 from arachidonic acid.

PMID- 10575373
TI  - Stimulation of mouse melanocyte proliferation by Piper nigrum fruit extract and
      its main alkaloid, piperine.
AB  - During a herbal screening programme to find potential repigmenting agents for the
      treatment of vitiligo, Piper nigrum L. fruit (black pepper) extract was found to
      possess growth-stimulatory activity towards cultured melanocytes. Its aqueous
      extract at 0.1 mg/ml was observed to cause nearly 300% stimulation of the growth
      of a cultured mouse melanocyte line, melan-a, in 8 days (p < 0.01). Piperine (1
      piperoylpiperidine), the main alkaloid from Piper nigrum fruit, also
      significantly stimulated melan-a cell growth. Both Piper nigrum extract and
      piperine induced morphological alterations in melan-a cells, with more and longer
      dendrites observed. The augmentation of growth by piperine was effectively
      inhibited by RO-31-8220, a selective protein kinase C (PKC) inhibitor, suggesting
      that PKC signalling is involved in its activity. This is the first full report on
      such an activity of black pepper and piperine.

PMID- 10575374
TI  - Antiviral and anticoagulant activities of a water-soluble fraction of the marine
      diatom Haslea ostrearia.
AB  - A water-soluble fraction from the marine diatom Haslea ostrearia was capable to
      inhibit the in vitro replication of HSV-1 in Vero cells with 50% inhibitory
      concentration (EC50) of 14 micrograms/ml at a multiplicity of infection of 0.01
      ID50/cells. In addition, this fraction delayed the HIV-1-induced syncitia
      formation on MT4 cells. At concentrations up to 200 micrograms/ml, no
      cytotoxicity was observed for both the Vero and MT4 cells. The fraction only
      inhibited the blood coagulation process at concentrations considerably exceeding
      the EC50.

PMID- 10575375
TI  - Choleretic effects of curcuminoids on an acute cyclosporin-induced cholestasis in
      the rat.
AB  - Former studies have shown that curcumin, which can be extracted from different
      Curcuma species, is able to stimulate bile flow in rats, whereas
      bisdemethoxycurcumin, which is mainly found in rhizomes of Curcuma longa, is
      believed to inhibit bile flow. To reevaluate this observation we investigated the
      influence of both curcuminoids on bile flow, bile acid concentration and
      excretion over a time period of 180 min in the bile fistula model in rats.
      Furthermore, we tested the ability of both curcuminoids to reduce cyclosporin
      induced cholestasis. 30 min after intravenous injection of 25 mg/kg of curcumin
      and bisdemethoxycurcumin bile flow was enhanced from 500 microliters/kg/15 min
      (100%) to 180% and to 220%, respectively. The choleretic effect of
      bisdemethoxycurcumin lasted longer than that of curcumin. Following intravenous
      injection of 30 mg/kg of cyclosporin, which reduced bile flow, bile acid
      concentration (15 mmol/l) and excretion (12.5 mumol/kg/15 min) to 40% of the
      initial value, administration of curcumin and bisdemethoxycurcumin transiently
      increased bile flow to 100% and to 125% of the starting value, respectively.
      However, only bisdemethoxycurcumin statistically significantly attenuated
      cyclosporin-induced reduction of bile acid excretion. We conclude that the
      beneficial properties of curcuminoids for the therapy of cyclosporin-induced
      cholestasis still remain to be proven.

PMID- 10575376
TI  - Panax ginseng administration in the rat prevents myocardial ischemia-reperfusion
      damage induced by hyperbaric oxygen: evidence for an antioxidant intervention.
AB  - The aim of this work was to investigate in the rat the protective effect of an
      oral administration (one week) of Panax ginseng (PG) extract (10 mg/ml in
      drinking water; 1.6 g/kg/day) on myocardial post-ischemic damage induced by
      hyperbaric oxygen (HBO) and on the loss in functionality of the endothelium in
      aorta ring preparations. The hearts from control rats (no-HBO and no-HBO-PG), and
      from rats exposed to HBO and to HBO after PG treatment were isolated and
      subjected to mild ischemia and then reperfused. HBO greatly worsens the post
      ischemic damage in controls, as demonstrated by the rise of left ventricular end
      diastolic pressure (LVEDP) and coronary perfusion pressure (CPP). PG
      significantly restrained the increase of LVEDP and CPP in respect to HBO
      untreated rats, as well as that of CPP induced by injection of angiotensin II
      during pre-ischemia. In HBO control rats the reduction of the vasorelaxant effect
      of acetylcholine on norepinephrine precontracted aortic rings, was markedly
      recovered by PG; a similar trend was observed in aortic rings challenged with the
      nitric oxide synthase inhibitor NG-monomethyl-L-arginine (56% recovery). These
      results strongly indicate that PG prevents the myocardial ischemia/reperfusion
      damage and the impairment of endothelial functionality induced by reactive oxygen
      species arising from HBO exposure, through an antioxidant intervention. The in
      vitro radical scavenging activity of PG seems to be too weak (0.05-0.5 mg/ml) to
      explain by itself the cardiac and extra-cardiac protective effects, and this
      suggests a role also for an indirect antioxidant action of the drug (endothelial
      nitric oxide synthase stimulation).

PMID- 10575377
TI  - Production of ginkgolides and bilobalide by Ginkgo biloba plants and tissue
      cultures.
AB  - The accumulation of the terpenes ginkgolides and bilobalide in Ginkgo biloba was
      reported in plants as well as in plant cell cultures. Several hundred plants
      cultivated under controlled conditions in the field have been analyzed for their
      terpene production over many years. Cross-pollination experiments were performed
      with mature trees and the terpene content of the progeny was analyzed. The age of
      the tree is the main factor influencing the terpene content of the leaves as the
      level always decreases dramatically between young and old trees. 80 cell culture
      strains have been established and ginkgolides analyzed by GC/MS. These cell
      cultures reveal very low amounts of terpenes (1 microgram g-1 D.W. or less). On
      the contrary, isolated in vitro root cultures accumulate terpenes at the same
      concentration as the young plant leaves (4 mg g-1 D.W.). Attempts to obtain rapid
      growing roots or even hairy-roots did not succeed but the possibility to
      transform Ginkgo cell strains has been demonstrated.

PMID- 10575378
TI  - Differentiation of medicinal Codonopsis species from adulterants by polymerase
      chain reaction-restriction fragment length polymorphism.
AB  - DNA sequence analysis of rDNA internal transcribed spacer (ITS) and polymerase
      chain reaction-restriction fragment length polymorphism (PCR-RFLP) were exploited
      for their applications in differentiating medicinal species Codonopsis pilosula,
      C. tangshen, C. modesta, and C. nervosa var. macrantha, from two related
      adulterants Campanumoea javania and Platycodon grandiflorus. The data
      demonstrated that the rDNA ITSI and ITSII sequences of the four Codonopsis are
      highly homologous but not identical, and are significantly different from those
      of the two adulterants. The sequence difference allows effective and reliable
      differentiation of Codonopsis from the adulterants by PCR-RFLP.

PMID- 10575379
TI  - Anti-inflammatory activity of diosmin and hesperidin in rat colitis induced by
      TNBS.
AB  - The intestinal anti-inflammatory activity of two flavonoids, hesperidin and
      diosmin, was evaluated in the acute stage of the trinitrobenzenesulfonic acid
      (TNBS) model of rat colitis. The results obtained showed that pretreatment with
      diosmin (10 mg/kg) or hesperidin (10 and 25 mg/kg) reduced colonic damage
      compared to TNBS control rats. This effect was confirmed biochemically by a
      reduction in colonic myeloperoxidase activity compared to non-treated colitic
      animals. Colonic glutathione levels in colitic animals were significantly
      increased after hesperidin or diosmin treatment. Diosmin decreased colonic MDA
      production and inhibited LTB4 synthesis, whereas hesperidin failed to do so.
      Conversely, only hesperidin improved colonic fluid absorption, which was impaired
      in colitic animals. In conclusion, both diosmin and hesperidin were able to
      prevent colonic inflammation, acting via a mechanism in which protection against
      oxidative insult may play a role.

PMID- 10575380
TI  - Inhibition of mast cell degranulation by tanshinones from the roots of Salvia
      miltiorrhiza.
AB  - The activity-guided fractionation of the extract of the root of Salvia
      miltiorrhiza B. (Labiatae, Tanshen), led to the isolation of four active
      components responsible for the anti-allergic activity in vitro. Among them, 15,16
      dihydrotanshinone-I and cryptotanshinone demonstrated significant inhibition of
      the release of beta-hexosaminidase from cultured RBL-2H3 cells in a dose
      dependent manner; the IC50 values were calculated as 16 and 36 microM,
      respectively.

PMID- 10575381
TI  - In vitro inducible nitric oxide synthesis inhibitory active constituents from
      Fraxinus rhynchophylla.
AB  - Bioassay-guided fractionation of an H2O extract of the barks of Fraxinus
      rhynchophylla has furnished two inducible nitric oxide synthase (iNOS) inhibitory
      compounds, ferulaldehyde (1) and scopoletin (3) together with a coumarin,
      fraxidin (2). Compounds 1 and 3 showed inhibition of nitric oxide (NO) synthesis
      in a dose-dependent manner by murine macrophage-like RAW 264.7 cells stimulated
      with interferon-gamma (IFN-gamma) plus lipopolysaccharide (LPS). The inhibition
      of NO synthesis of 1 was reflected in the decreased amount of iNOS protein, as
      determined by Western blotting.

PMID- 10575382
TI  - Anti-tumor-promoting rearranged abietane diterpenes from the leaves of Larix
      kaempferi.
AB  - Two novel rearranged abietane-type diterpene acids, karamatsuic acid (1) and
      larikaempferic acid (2) were isolated as their corresponding methyl esters, 1a
      and 2a, from the leaves of Larix kaempferi (Lamb.) Carr. Their structures were
      established as 9,10 alpha-epoxy-9,10-seco-abieta-8,11,13-trien-18-oic acid and 9
      alpha,13 alpha-epoxy-8-oxo-9(8-->7)abeo-7 beta H-abietan-18-oic acid,
      respectively, by spectral evidence. Compounds 1a, 2a and 12,15
      dihydroxydehydroabietic acid (3) exhibited potent inhibitory effects against 12-O
      tetradecanoylphorbol 13-acetate (TPA)-induced Epstein-Barr virus early antigen
      (EBV-EA) activation in Raji cells.

PMID- 10575384
TI  - Religious commitment and health status.

PMID- 10575383
TI  - The inhibiting effects of components of stinging nettle roots on experimentally
      induced prostatic hyperplasia in mice.
AB  - Direct implanting of fetal urogenital sinus (UGS) tissue into the ventral
      prostate gland of adult mice led to a 4-fold weight increase of the manipulated
      prostatic lobe. The induced growth could be reduced by the polysaccharide
      fraction (POLY-M) of the 20% methanolic extract of stinging nettle roots by
      33.8%.

PMID- 10575385
TI  - An overview of osteopathic medicine.
AB  - Despite an initial lack of acceptance by mainstream medicine, and amidst
      projections of a serious oversupply of physicians, the osteopathic profession
      continues to grow, successfully competing for shrinking health care resources and
      attracting the attention of insurers and those in managed care. However, a recent
      telephone survey of 800 health maintenance organization beneficiaries suggested
      that the public is not yet familiar with osteopathic medicine. The history,
      philosophy, and current status of the osteopathic profession are presented, along
      with theories of the physiologic basis of and supporting evidence for palpatory
      diagnosis and manipulative therapy.

PMID- 10575386
TI  - Preventable hospitalizations in primary care shortage areas. An analysis of
      vulnerable Medicare beneficiaries.
AB  - BACKGROUND: Health care outcomes among vulnerable elderly populations (defined in
      this study as Medicare beneficiaries who rated their overall general health as
      "fair" or "poor") are a growing concern. Recent studies suggest that potentially
      preventable hospitalizations may be useful for identifying poor ambulatory health
      care outcomes among vulnerable populations. OBJECTIVES: To determine if Medicare
      beneficiaries in fair or poor health are at increased risk of experiencing a
      preventable hospitalization if they reside in primary care health professional
      shortage areas. DESIGN: A survey of Medicare beneficiaries from the 1991 Medicare
      Current Beneficiary Survey. PATIENTS: Medicare beneficiaries living in the
      community. RESULTS: Medicare beneficiaries in fair or poor health were 1.82 times
      more likely to experience a preventable hospitalization if they resided in a
      primary care shortage area (95% confidence interval, 1.18-2.81). After
      controlling for educational level, income, and supplemental insurance, Medicare
      beneficiaries in fair or poor health were 1.70 times more likely to experience a
      preventable hospitalization if they resided in a primary care shortage area (95%
      confidence interval, 1.09-2.65). CONCLUSIONS: Medicare beneficiaries in fair or
      poor health are more likely to experience a potentially preventable
      hospitalization if they live in a county designated as a primary care shortage
      area. Provision of Medicare coverage alone may not be enough to prevent poor
      ambulatory health care outcomes such as preventable hospitalizations. Improving
      health care outcomes for vulnerable elderly patients may require structural
      changes to the primary care ambulatory delivery system in the United States,
      especially in designated shortage areas.

PMID- 10575387
TI  - When access-to-care indicators meet. Designated shortage areas and avoidable
      hospitalizations.

PMID- 10575388
TI  - Prognostic factors for persons with idiopathic chronic fatigue.
AB  - BACKGROUND: The simultaneous examination of a large number of patient
      characteristics in a prospective study of patients with chronic fatigue.
      OBJECTIVE: To compare the relative importance of these characteristics as
      prognostic factors. METHODS: The data analyzed were from 199 subjects in a
      registry of persons who were aged 18 years or older and had idiopathic fatigue
      for at least 6 months. All subjects completed an extensive baseline questionnaire
      that provided information about fatigue, demographic characteristics, medical
      conditions, lifestyle, sleeping habits, psychological characteristics, and the
      presence of criteria for chronic fatigue syndrome. Changes in fatigue severity
      from baseline to 2-year follow-up were tested for an association with risk
      factors at baseline and with changes in symptoms other than fatigue during the
      follow-up period. RESULTS: The following characteristics at baseline
      significantly and independently predicted greater fatigue improvement: less
      unclear thinking, fewer somatoform symptoms not used to define chronic fatigue
      syndrome, infrequent awakening, fewer hours sleeping, and being married. Of 29
      subjects who at baseline reported no somatoform symptoms unrelated to chronic
      fatigue syndrome and who thought clearly most of the time, 8 substantially
      improved, compared with 1 of 29 subjects who had more than 2 somatoform symptoms
      and never thought clearly (P = .01). Improvements in the following symptoms were
      significantly and independently associated with improvements in fatigue: unclear
      thinking, depression, muscle aches, and trouble falling asleep. CONCLUSIONS: This
      study identified characteristics of subjects that seem to be of prognostic
      importance for idiopathic chronic fatigue. Symptoms that change concomitantly
      with changes in fatigue may be intrinsically linked to fatigue.

PMID- 10575390
TI  - Do follow-up recommendations for abnormal Papanicolaou smears influence patient
      adherence?
AB  - OBJECTIVE: To compare adherence to follow-up recommendations for colposcopy or
      repeated Papanicolaou (Pap) smears for women with previously abnormal Pap smear
      results. DESIGN: Retrospective cohort study. SETTING: Three northern California
      family planning clinics. PATIENTS: All women with abnormal Pap smear results
      referred for initial colposcopy and a random sample of those referred for
      repeated Pap smear. Medical records were located and reviewed for 90 of 107 women
      referred for colposcopy and 153 of 225 women referred for repeated Pap smears.
      INTERVENTION: Routine clinic protocols for follow-up--telephone call, letter, or
      certified letter--were applied without regard to the type of abnormality seen on
      a Pap smear or recommended examination. MAIN OUTCOME MEASURES: Documented
      adherence to follow-up within 8 months of an abnormal result. Attempts to contact
      the patients for follow-up, adherence to follow-up recommendations, and patient
      characteristics were abstracted from medical records. The probability of
      adherence to follow-up vs the number of follow-up attempts was modeled with
      survival analysis. Cox proportional hazards models were used to examine
      multivariate relationships related to adherence. RESULTS: The rate of overall
      adherence to follow-up recommendations was 56.0% (136/243). Adherence to a second
      colposcopy was not significantly different from that to a repeated Pap smear
      (odds ratio, 1.40; 95% confidence interval, 0.80-2.46). The use of as many as 3
      patient reminders substantially improved adherence to follow-up. Women without
      insurance and women attending 1 of the 3 clinics were less likely to adhere to
      any follow-up recommendation (hazard ratio for no insurance, 0.43 [95% confidence
      interval, 0.20-0.93], and for clinic, 0.35 [95% confidence interval, 0.15-0.73]).
      CONCLUSIONS: Adherence to follow-up was low in this family planning clinic
      population, no matter what type of follow-up was advised. Adherence was improved
      by the use of up to 3 reminders. Allocating resources to effective methods for
      improving adherence to follow-up of abnormal results may be more important than
      which follow-up procedure is recommended.

PMID- 10575389
TI  - Is experience with human immunodeficiency virus disease related to clinical
      practice? A survey of rural primary care physicians.
AB  - BACKGROUND: Human immunodeficiency virus (HIV) disease is spreading to the rural
      United States, and medical care is increasingly provided by local primary care
      physicians. A volume-outcome relationship might exist in HIV care. However,
      little is known about the HIV experience and practices of rural primary care
      physicians. OBJECTIVES: To estimate the HIV experience of rural primary care
      physicians, and to determine whether experience is associated with use of newer
      management strategies, confidence in care, and consultation needs. DESIGN:
      Telephone survey of a random sample of primary care physicians. SETTING: Primary
      care sites in nonmetropolitan California. PARTICIPANTS: One hundred twenty
      eligible primary care physicians in nonmetropolitan California, with 102
      respondents (85.0%). MAIN OUTCOME MEASURES: Physicians' HIV experience, use of
      protease inhibitors and viral load tests, familiarity with vertical HIV
      transmission prophylaxis, confidence in HIV care, and consultation needs.
      RESULTS: Most physicians were low-volume providers of HIV care and had limited
      knowledge of newer management strategies. Experience with protease inhibitors and
      viral load tests was significantly related to number of recent patients with HIV;
      25.0% of those with 1 to 3 patients but 75.0% of those with 4 or more patients
      had prescribed protease inhibitors (P = .01), whereas 20.8% of those with 1 to 3
      patients but 83.3% of those with 4 or more patients had used a viral load test (P
      = .001). Only 59.8% of all respondents, but 100.0% of those with 4 or more
      patients, were familiar with vertical HIV transmission prophylaxis (P = .001).
      After adjustment for other characteristics, HIV experience remained significantly
      associated with use of newer management strategies (P = .01) and familiarity with
      vertical HIV transmission prophylaxis (P = .007). Physicians' confidence in HIV
      care increased with experience (P = .006), and consultation needs decreased (P =
      .006). CONCLUSIONS: Primary care physicians in rural California lacked in-depth
      experience with HIV disease. Experience was significantly associated with use of
      newer HIV management strategies, confidence, and consultation needs. Treating 4
      or more patients with HIV or acquired immunodeficiency syndrome may be the
      threshold above which primary care physicians rapidly adopt new strategies and
      have confidence in their care.

PMID- 10575391
TI  - Prevalence of gambling disorders in a primary care setting.
AB  - BACKGROUND: Pathologic gambling prevalence seems to be increasing as
      opportunities for gambling increase. Prevalence may be different in a primary
      care setting compared with population-based studies. OBJECTIVES: To determine the
      gambling disorder prevalence in a primary care setting and to investigate
      associations between gambling disorders and proximity to a casino, substance
      abuse, health ratings, age, sex, and socioeconomic status. DESIGN: Cross
      sectional survey of 1394 patients presenting to their primary care physicians
      between November 1, 1997, and April 1, 1998. SETTING: Three primary care clinics
      in Wisconsin. PATIENTS: Adults aged 18 years and older. MAIN OUTCOME MEASURES:
      Gambling disorders, defined by scores of 3 or greater on the South Oaks Gambling
      Screen (SOGS), and information about drug use (alcohol, tobacco, and marijuana),
      overall health, specific health symptoms, age, sex, race, and socioeconomic
      status. RESULTS: A total of 1051 patients completed the survey. More than 80.0%
      of the patients had gambled, and 6.2% met the criteria for gambling disorders.
      Gambling disorders were more prevalent in men, nonwhites, and patients from lower
      socioeconomic groups. Patients with gambling disorders were more likely to use
      tobacco and abuse alcohol compared with nonproblem gamblers. No relation was seen
      between marijuana use and gambling disorders. Patients with gambling disorders
      rated their health more poorly and reported more severe symptoms of heartburn and
      backache. CONCLUSIONS: A considerable percentage of patients presenting to
      primary care clinics are affected by their need to gamble. There is significant
      comorbidity with tobacco use and alcohol abuse. Primary care physicians should
      consider asking about gambling habits in high-risk patients.

PMID- 10575393
TI  - Quality of care for primary care patients with depression in managed care.
AB  - OBJECTIVE: To evaluate the process and quality of care for primary care patients
      with depression under managed care organizations. METHOD: Surveys of 1204
      outpatients with depression at the time of and after a visit to 1 of 181 primary
      care clinicians from 46 primary care clinics in 7 managed care organizations.
      Patients had depressive symptoms in the previous 30 days, with or without a 12
      month depressive disorder by diagnostic interview. Process indicators were
      depression counseling, mental health referral, or psychotropic medication
      management at index visit and the use of appropriate antidepressant medication
      during the last 6 months. RESULTS: Of patients with depressive disorder and
      recent symptoms, 29% to 43% reported a depression-specific process of care in the
      index visit, and 35% to 42% used antidepressant medication in appropriate dosages
      in the prior 6 months. Patients with depressive disorders rather than symptoms
      only and those with comorbid anxiety had higher rates of depression-specific
      processes and quality of care (P < .005). Recurrent depression, suicidal
      ideation, and alcohol abuse were not uniquely associated with such rates.
      Patients visiting for old problems or checkups received more depression-specific
      care than those with new problems or unscheduled visits. The 7 managed care
      organizations varied by a factor of 2-fold in rates of depression counseling and
      appropriate anti-depressant use. CONCLUSIONS: Rates of process and quality of
      care for depression as reported by patients are moderate to low in managed
      primary care practices. Such rates are higher for patients with more severe forms
      of depression or with comorbid anxiety, but not for those with severe but
      "silent" symptoms like suicide ideation. Visit context factors, such as whether
      the visit is scheduled, affect rates of depression-specific care. Rates of care
      for depression are highly variable among managed care organizations, emphasizing
      the need for process monitoring and quality improvement for depression at the
      organizational level.

PMID- 10575394
TI  - The role of vitamin E in the prevention of heart disease.
AB  - Data from the 1970s first suggested that vitamin E may be effective in decreasing
      mortality from cardiovascular disease. As the understanding of the antioxidant
      effect of this vitamin evolved, researchers began to further study the biologic
      effects of vitamin E. In vitro studies have shown vitamin E to have several
      potentially cardioprotective effects, including antagonizing the oxidation of low
      density lipoproteins, inhibiting platelet aggregation and adhesion, preventing
      smooth muscle proliferation, and preserving normal coronary dilation. Several
      prospective studies, including the US Nurses' Health Study and the US Health
      Professionals' Follow-up Study, found a 34% and 39% reduction, respectively, in
      the risk of having a cardiac event for those taking vitamin E supplements. The
      Iowa Women's Health Study found a 47% reduction in cardiac mortality. Results of
      randomized, controlled clinical trials have not found consistent benefit,
      however. The best known of these trials, the Cambridge Heart Antioxidant Study,
      found a 47% reduction in fatal and nonfatal myocardial infarction in patients
      with proven coronary atherosclerosis who were given 400 or 800 IU of vitamin E
      daily. There was, however, no effect on mortality. While emerging and promising
      data suggest the potential benefit of vitamin E for high-risk cardiac patients,
      physicians should be alert to the results of randomized, controlled clinical
      trials already in progress.

PMID- 10575392
TI  - Breast cancer trends of black women compared with white women.
AB  - OBJECTIVE: To investigate why breast cancer mortality rates have decreased in the
      1990's for white women but not for black women. DESIGN: Racial differences in
      breast cancer incidence, survival, and mortality rates were examined using
      regression methods and age-period-cohort models. SETTING: United States breast
      cancer mortality rates from 1970 through 1995, breast cancer incidence rates from
      1980 through 1995, and 3-year survival rates from 1980 through 1993. The
      incidence and survival data are from the Surveillance, Epidemiology, and End
      Results Program, representing 11% of the US population, of the National Cancer
      Institute, Bethesda, Md. RESULTS: For both white and black women aged 30 to 39
      years, breast cancer mortality rates began decreasing in 1987. For white women
      aged 40 to 79 years, breast cancer mortality rates declined after 1989, and for
      black women aged 40 to 69 years, mortality rates ceased increasing in the middle
      to late 1980s. Birth cohort trends were similar by race, but calendar period
      trends and survival rates differed. CONCLUSIONS: Declines in mortality rates in
      women younger than 40 years reflect a favorable birth cohort trend for women born
      after 1948 and likely reflect changes in risk factors. The increased early
      detection of breast cancer by mammography and improvements in breast cancer
      treatment appear to be contributing to the improving mortality trends in older
      women, although black women appear to have benefited less than white women from
      early detection and treatment advances. In addition, substantial increases in
      survival rates for white women with regional disease have contributed to their
      declining mortality rates and likely reflect an increasing use of beneficial
      adjuvant therapy.

PMID- 10575395
TI  - The Archives of Family Medicine continuing medical education program

PMID- 10575396
TI  - Patients and community together. A family medicine community-oriented primary
      care project in an urban private practice.
AB  - BACKGROUND: There has been considerable discussion in the literature regarding
      the value and feasibility of community-oriented primary care (COPC), but
      relatively few published real-world examples. OBJECTIVE: To examine the effect of
      a practice-based COPC project on rates of preventive health interventions within
      an inner-city family medicine practice. METHODS: A newly created community
      advisory board called Patients and Community Together (PACT) and the medical
      director of the practice in Rochester, NY, collaborated on all phases of the COPC
      project. Papanicolaou smear and mammography screening, childhood immunizations,
      diabetes control, and smoking cessation were targeted for intervention. A
      practice/community awareness campaign was instituted and individual and group
      incentives were developed. Progress was monitored through a computerized medical
      record that included all active patients in the practice. RESULTS: Rates of
      annual Papanicolaou smears increased from 46% to 71%; annual mammography for
      women older than age 50 years, from 56% to 86%; completed childhood immunizations
      when younger than 6 years, from 78% to 97%; and performance of semiannual
      glycosylated hemoglobin, from 85% to 92%. Rates of patients with glycosylated
      hemoglobin values under 10% improved from 56% to 77%. There were 5 smokers who
      successfully quit. CONCLUSION: This project illustrates how practice-based COPC
      can be successfully implemented within a private practice setting. It also shows
      how COPC principles can be used to achieve the goals for Healthy People 2000
      within inner-city practices.

PMID- 10575397
TI  - Community-oriented primary care. The state of an art.

PMID- 10575398
TI  - Traumatic complications of acupuncture. Therapists need to know human anatomy.
AB  - OBJECTIVES: To review the traumatic injuries that have been associated with
      acupuncture and to discuss how these adverse effects may be reduced by increased
      awareness of normal anatomy and anatomical variations. METHODS: Literature search
      accompanied by postmortem anatomical studies. RESULTS: Traumatic lesions after
      acupuncture have been described in thoracic and abdominal viscera, in the
      peripheral and central nervous systems, and in blood vessels. Deaths have been
      recorded from pneumothorax and cardiac tamponade. The anatomical structure of the
      body at several acupuncture points is such that needles can reach vulnerable
      structures. CONCLUSION: While the frequency of adverse effects of acupuncture is
      unknown and they may be rare, knowledge of normal anatomy and anatomical
      variations is essential for safe practice and should be reviewed by regulatory
      bodies and those responsible for training courses.

PMID- 10575399
TI  - Dear Sheena.

PMID- 10575400
TI  - International Conference on Diabetes and Cardiovascular Disease. Winnipeg,
      Manitoba, Canada. June 3-6, 1999. Abstracts.

PMID- 10575401
TI  - SIMLEP: a simulation model for leprosy transmission and control.
AB  - SIMLEP is a computer program for modeling the transmission and control of leprosy
      which can be used to project epidemiologic trends over time, producing output on
      indicators such as prevalence, incidence and case-detection rates of leprosy. In
      SIMLEP, health states have been defined that represent immunologic conditions and
      stages of leprosy infection and disease. Three types of interventions are
      incorporated: vaccination, case detection and chemotherapy treatment.
      Uncertainties about leprosy have led to a flexible design in which the user
      chooses which of many aspects should be included in the model. These aspects
      include natural immunity, asymptomatic infection, type distribution of new cases,
      delay between onset of disease and start of chemotherapy, and mechanisms for
      leprosy transmission. An example run illustrates input and output of the program.
      The output produced by SIMLEP can be readily compared with observed data, which
      allows for validation studies. The support that SIMLEP can give to health policy
      research and actual decision making will depend upon the extent of validation
      that has been achieved. SIMLEP can be used to improve the understanding of
      observed leprosy trends, for example, in relation to early detection campaigns
      and the use of multidrug therapy, by exploring which combinations of assumptions
      can explain these trends. In addition, SIMLEP allows for scenario analysis in
      which the effects of control strategies combining different interventions can be
      simulated and evaluated.

PMID- 10575402
TI  - Comparison of two methods of leprosy case finding in the circle of Kita in Mali.
AB  - Kita is a health district of Mali, a leprosy-endemic country in West Africa. We
      conducted a comparative study of passive and active case finding of leprosy in
      this district in 1997. In May and June, a mobile team realized active case
      finding by visiting 32 villages of more than 1000 inhabitants. For 12 months,
      peripheral health center nurses did passive detection after information and
      education sessions about the signs of leprosy in the other 37 main villages of
      Kita. The active detection rate (4.31 per 10,000) was threefold higher than the
      passive rate (1.5 per 10,000) and allowed us to find earlier cases of leprosy.
      Active case finding identified children and single-lesion disease; the passive
      method did not. Cost for finding a new case was estimated at 72 US$ by mobile
      team detection and 36 US$ by passive case finding. Although the active method
      looked more expensive than the passive one, it was the only effective strategy to
      detect leprosy patients in remote and difficult-to-access areas. Based upon the
      results of the study, a flow chart is proposed for the choice of case-finding
      method when designing a leprosy elimination program.

PMID- 10575403
TI  - Seroprevalence rates of antibodies to phenolic glycolipid-I among school children
      as an indicator of leprosy endemicity.
AB  - In order to study whether the seroprevalence of antibodies to phenolic glycolipid
      I (PGL-I) among school children is a useful indicator of the leprosy problem in
      certain areas, school surveys were carried out. These surveys have the advantage
      of targeting an easily accessible, stable and standardized population. Antibodies
      to the species-specific PGL-I of Mycobacterium leprae were detected in a simple
      gelatin particle agglutination test. We have determined the seroprevalence rates
      in 2835 school children from five different areas in three provinces of Sulawesi,
      Indonesia. Three areas with a case-detection rate of over 3.4/10,000 were
      designated as high-endemic areas. The other two were designated as low-endemic
      areas, having a case-detection rate of less than 1/10,000. The seroprevalence
      rates in the three high-endemic areas ranged from 26% to 28% (95% CI 21%-31%). In
      both low-endemic areas the seroprevalence rate was 7% (95% CI 5%-10%). In a
      second survey conducted in one high-endemic area 3 years after the first survey,
      the seroprevalence rate was the same as in the first survey. These results
      indicate that seropositivity rates among school children may reflect the leprosy
      incidence. They illustrate the potential applicability of seroprevalence as an
      indicator of the magnitude of the leprosy problem in a selected area.

PMID- 10575404
TI  - Disabilities in multibacillary leprosy following multidrug therapy with and
      without immunotherapy with Mycobacterium w antileprosy vaccine.
AB  - A vaccine based on autoclaved Mycobacterium w was administered, in addition to
      standard multidrug therapy (MDT), to 157 bacteriologically positive, lepromin
      negative, multibacillary leprosy patients supported by a well-matched control
      group of 147 patients with similar type of disease who received a placebo
      injection in addition to MDT. The MDT was given for a minimum period of 2 years
      and continued until skin-smear negativity, while the vaccine/placebo was given at
      3-month intervals up to a maximum of 8 doses in the initial 2 years. The overall
      incidence of type 1 and type 2 reactions and neuritis during treatment and follow
      up was nearly equal in the patients in the vaccine and placebo groups; the
      differences were not statistically significant. The occurrence of disabilities,
      such as anesthesia, trophic ulcers, claw hand and grade 3 deformities, were not
      different statistically in the vaccine and placebo groups, an observation valid
      both for deformities present at induction and for those which developed during
      the course of therapy and surveillance. A statistically significant difference
      was observed in the recovery of newly developed trophic ulcers; recovery was
      quicker in the vaccine group. The recovery rate for motor deformities was
      marginally higher in the vaccine group, although not significant (p = 0.068)
      statistically. There was a statistically significant reduction in the incidence
      of grade 3 deformities following MDT with and without immunotherapy. To conclude,
      the addition of vaccine to MDT did not precipitate neuritis or deformities over
      and above that encountered with MDT alone, although it did accelerate
      bacteriological clearance, histopathological upgrading, conversion to lepromin
      positivity, and clinical improvement.

PMID- 10575405
TI  - Induction of lepromin positivity following immuno-chemotherapy with Mycobacterium
      w vaccine and multidrug therapy and its impact on bacteriological clearance in
      multibacillary leprosy: report on a hospital-based clinical trial with the
      candidate antileprosy vaccine.
AB  - A vaccine based on autoclaved Mycobacterium w was administered, in addition to
      standard multidrug therapy (MDT), to 157 bacteriologically positive, lepromin
      negative, multibacillary (LL, BL and BB) leprosy patients. The vaccinees were
      supported by a well-matched control group of 147 patients with similar type of
      disease who received a placebo injection in addition to MDT. The MDT was given
      for a minimum period of 2 years and continued until skin-smear negativity, while
      the vaccine was given at 3-month intervals up to a maximum of 8 doses. The
      lepromin response evaluated in terms of percentage of subjects converting to
      positivity status, measurement in millimeters, and duration of lepromin
      positivity sustained, reflected a statistically significant better outcome in the
      vaccine group patients (especially LL and BL leprosy) in comparison to those in
      the placebo group. The data indicate that lepromin-positivity status seems to
      have an impact on accelerating the bacteriological clearance, as is evident by
      the statistically significant accelerated decline in the BI of those patients who
      converted to lepromin positivity as compared to those remaining lepromin negative
      throughout therapy and post-therapy follow up. To conclude, the addition of the
      Mycobacterium w vaccine to standard MDT induces a lepromin response of a
      statistically significant higher magnitude than that observed with MDT alone.

PMID- 10575406
TI  - Risk factors for erythema nodosum leprosum.
AB  - A retrospective study of new borderline lepromatous and lepromatous patients
      reporting for multidrug therapy (MDT) for leprosy at the Anandaban Leprosy
      Hospital, Kathmandu, Nepal, over an 8-year period was conducted to determine the
      prevalence of erythema nodosum leprosum (ENL), the time and frequency of
      reactions, and clinical and laboratory parameters associated with ENL. An overall
      prevalence of ENL in this cohort of 19% was found. One third of these reactions
      occurred in patients before MDT was given, one third in the first 6 months and
      one third after 6 months of treatment. Nearly 1 in 10 of the ENL reactions
      occurred in patients who had completed 2 years of MDT; 45% of patients with ENL
      had more than one episode. Data collected at the patients' first presentation was
      used to identify four major risk factors. Patients with lepromatous disease, skin
      infiltration or a bacterial index (BI) of > 4+ were at significantly increased
      risk. Patients older than 40 were at significantly decreased risk of ENL. There
      was a linear relationship in the risk of ENL with an increasing BI and an inverse
      relationship to increasing age. These observations should enable clinicians to
      recognize patients at first presentation who will be likely to develop ENL.

PMID- 10575407
TI  - Rapid method for diagnosis of leprosy by measurements of antibodies to the M.
      leprae 35-kDa protein: comparison with PGL-I antibodies detected by ELISA and
      "dipstick" methods.
AB  - A new rapid immuno-chromatographic test card for the detection of antibodies to
      the Mycobacterium leprae 35-kD protein is described. The new assay is compared in
      the same group of subjects with a direct enzyme ELISA method for 35-kD antibodies
      and with assays for anti-phenolic glycolipid-I (PGL-I) antibodies using a
      standard ELISA as well as the recently described "dipstick" method. Good
      concordance was found between the rapid methods and the corresponding ELISA
      methods. The detection of untreated paucibacillary leprosy by the 35-kD test card
      was 59% compared with 27% for the PGL-I dipstick; however, the specificity for
      the 35-kD test card was 90% compared with 100% for the PGL-I dipstick in an
      endemic population. The potential application of these new, rapid serologic
      methods for the diagnosis of leprosy under field conditions is discussed.

PMID- 10575408
TI  - Serum IL-1ra is elevated in lepromatous leprosy patients.
AB  - Patterns of production of specific cytokines are accepted as standards for T
      lymphocyte subsets in diseases caused by intracellular parasites. These
      lymphocyte subsets (Th1 and Th2) have been associated with the different poles of
      the leprosy spectrum. Lepromatous leprosy (LL) onset correlates with cytokines
      produced by Th2 cells on the grounds of the patient's poor cellular immune
      response, i.e., interleukin 2 (IL-2) and gamma interferon (IFN-gamma) deficiency.
      On the other hand, tuberculoid leprosy (TL) has been associated with a Th1
      response. Moreover, pro-inflammatory cytokines like IL-1 beta and tumor necrosis
      factor-alpha (TNF-alpha) play a major role in chronic inflammatory pathologies
      being IL-1ra and TNF-alpha soluble receptors, natural counterbalancing
      inhibitors. In light of this background, we decided to measure serum levels of IL
      1 beta, IL-1ra, TNF-alpha and IL-6 in LL and TL patients, and we also studied the
      production in vitro of Th1 (IFN-gamma, IL-2), Th2 (IL-4, IL-10) and TNF-alpha
      cytokines. Our data showed that IL-1ra is highly elevated in sera from LL
      patients; there were no differences in Th2 cytokine levels and there were
      diminished levels in Th1 cytokines.

PMID- 10575409
TI  - Nasal mucosa and skin of smear-positive leprosy patients after 24 months of fixed
      duration MDT: histopathological and microbiological study.
AB  - The skin and nasal mucosa of 10 lepromatous leprosy patients who had completed 24
      doses of fixed duration multidrug therapy (MDT) but who continued to be skin
      smear positive for acid-fast bacilli (AFB) were examined histopathologically. The
      nasal mucosa showed granuloma fractions that exceeded those seen in the skin
      specimens, signifying that activity in this region subsides much more gradually
      than the activity in the skin. Mouse foot pad studies done using T900r mice with
      an inoculum from the nasal mucosa biopsy specimens of these patients did not
      demonstrate any growth of Mycobacterium leprae, indicating that these bacilli
      were not viable. A skin specimen from one patient grew significant amounts of
      bacteria in the T900r mouse foot pad. These results show that 2 years of
      treatment with MDT would prevent dissemination of M. leprae from the nasal mucosa
      and, therefore, should preclude further transmission of the disease. It also
      indicates that viable bacteria might persist in the skin of patients, especially
      those with an initial bacterial index of > or = 4+ who have completed 24 doses of
      regular MDT. Therefore, a more cautious approach to administering only 12 doses
      of MDT to highly positive multibacillary patients is suggested.

PMID- 10575410
TI  - Corneal sensation in leprosy.

PMID- 10575411
TI  - A study on the methods for early serological diagnosis of leprosy and their
      potential use.
AB  - This is a serial study. In this series we have established 12 methods for the
      early serological diagnosis of leprosy, including the FLA-ABS test, ELISAs with
      artificial products (ND-O-, ND-P-, NT-O-, NT-P-BSA; PGL-I, whole M. leprae and M.
      smegmatis), monoclonal antibody specific binding assay (McAb/SBA), latex
      agglutination test (LAT), and MLPA. These methods were compared with each other
      on a large scale in leprosy patients and in the field. The results indicate that
      1) Excellent results were obtained when ELISAs were conducted with skim milk or
      egg albumin as the blocking agent and by using blood from earlobes instead of
      from venipuncture. 2) According to the four "S" standard (sensitivity,
      specificity, simplicity and speed), among the 12 methods the ND-O-BSA-ELISA (ND
      ELISA) is the best and the MLPA is more suitable for use in the field because it
      is simple and rapid. 3) In the ND-ELISA, the increase or decrease of the OD value
      has a positive correlation with the BI, and the order of positive rates was a) in
      various types of leprosy: LL > BL > BB > BT > TT; b) in household contacts (HC),
      random population (RP), normal controls in endemic areas (ENC) and normal
      controls in nonendemic areas (NNC): HC > RP > ENC > NNC. 4) In a population with
      subclinical M. leprae infection, the highest risk group was between the ages of
      15 and 25 and had an increase or a persistence of high OD values prior to onset
      of disease. 5) OD values gradually decreased over time following treatment and
      these declines paralleled declines in the BI. 6) In cases cured with dapsone
      therapy, there was an increase or a persistence of high OD values in ND-ELISA
      prior to the onset of a leprosy relapse. In conclusion, we have compared and
      evaluated 12 immuno-assays and have shown that the ND-ELISA is the most practical
      one for use in investigating sero-immunological epidemiology, subclinical
      infection with M. leprae, early detection of disease, monitoring of antimicrobial
      therapy, and even for the prediction of leprosy relapse.

PMID- 10575412
TI  - Vaccination of mice against the leprosy bacillus with skin-test antigens.

PMID- 10575413
TI  - Single-dose treatment for paucibacillary leprosy; feasibility of long-term follow
      up.

PMID- 10575414
TI  - Single-dose treatment for paucibacillary leprosy; clinical problems and
      management.

PMID- 10575415
TI  - Single-dose treatment for paucibacillary leprosy; field implications.

PMID- 10575416
TI  - A new ACE inhibitor and two new angiotensin receptor blockers for hypertension.

PMID- 10575417
TI  - SAMe for depression.

PMID- 10575418
TI  - Hypersensitivity reactions to rifampin. Pathogenetic mechanisms, clinical
      manifestations, management strategies, and review of the anaphylactic-like
      reactions.
AB  - Many of the adverse events induced by rifampin have been considered allergic in
      origin. The flu-like syndrome and other hypersensitivity reactions seem to be
      caused by immune complexes, although their pathogenetic mechanisms are not fully
      elucidated. Many cases have been reported of the flu-like syndrome,
      thrombocytopenia, hemolytic anemia, and renal failure caused by rifampin. In
      almost all of the patients in whom they were sought, nonreaginic antirifampin
      antibodies were detected. On the other hand, anaphylactic reactions seem to be
      IgE-mediated. We have analyzed the 18 reported cases of anaphylactic reactions
      severe enough to cause marked hypotension. The interval between the onset of
      treatment and the anaphylactic reaction was highly variable. Most patients
      presented with prodromes, mainly rash, before the development of anaphylactic
      symptoms, and, in most cases, the reaction occurred after reexposure to rifampin.
      Clinical findings include a variety of symptoms, such as fever, exanthem,
      dyspnea, abdominal pain, and vomiting. Seven of the 9 patients in whom HIV status
      was known were seropositive, including the only 2 patients who died. We believe
      that, in case of a non-life-threatening adverse reaction caused by immune
      complexes, rifampin could be readministered, if necessary, at a more frequent and
      reduced dose, perhaps with the addition of corticosteroids. In case of
      anaphylactic reactions the drug should be avoided, although desensitization
      procedures may be useful. Certain laboratory findings may serve as a clue to
      predict anaphylactic reactions in patients who have experienced minor adverse
      events to rifampin. However, the diagnostic value of such findings is not well
      established and, therefore, patients with previous adverse reactions should be
      carefully monitored if reexposure to rifampin is essential.

PMID- 10575419
TI  - Oligo-/monoclonal gammopathy and hypergammaglobulinemia in ataxia-telangiectasia.
      A study of 90 patients.
AB  - We investigated the presence of hypergammaglobulinemia and oligo-/monoclonal
      gammopathy in 90 patients (from 80 families) with ataxia-telangiectasia ranging
      in age from 2 to 29 years. Of the 90 patients, 38.8% displayed
      hypergammaglobulinemia. An isolated increase in IgM was the most common finding
      (23.3%) followed by a simultaneous increase in IgM and IgG (8.8%), an isolated
      increase in IgA (3.3%), an elevated level of IgG (2.2%) and a concomitant
      increase in IgM and IgA (1.1%), respectively. Seven of the patients (8.1%) had
      oligo-/monoclonal gammopathy. The gammopathies included all major immunoglobulin
      isotypes. Chemotherapeutic intervention in 2 cases precipitated the emergence of
      new clones within a matter of weeks. Further investigation of oligo-/monoclonal
      gammopathies in these patients may lead to a clearer understanding of the
      clinical course and provide further insight into the underlying mechanisms of B
      cell abnormalities in ataxia-telangiectasia.

PMID- 10575420
TI  - Renal transplantation in scleroderma.
AB  - Although the outcome of renal transplantation in patients with systemic lupus
      erythematosus (SLE) has been studied, there are few reports about the outcome of
      patients with systemic sclerosis who have undergone renal transplantation. We
      retrospectively collected data from the United Network for Organ Sharing (UNOS)
      Scientific Renal Transplant Registry from a 10-year period. From 1987 to 1997, 86
      patients with systemic sclerosis who had renal transplantation were identified.
      Of these 86 patients, 70% were women, 86% were Caucasian, and the mean age at
      transplantation was 50.4 years. The overall mortality was 24% of the patient
      group; 44% (38/86) of renal grafts failed. First- through fifth-year graft
      survival rates were 62%, 60%, 57%, 50%, and 47%, respectively. The causes of
      graft failure could not be ascertained in 24 of 38 patients (63%). Among the
      known causes, 5 had acute rejection, 4 had chronic rejection, 3 had recurrence of
      scleroderma, and 1 each had infection and graft thrombosis. Immunosuppressive
      regimens used in the patients with systemic sclerosis consisted of antilymphocyte
      globulin in at least 25%. Sixty percent received a combination of steroids,
      azathioprine, and cyclosporine. The use of cyclosporine was not associated with
      either improvement of graft survival or an increased rate of graft failure. Graft
      survival at 5 years in patients with systemic sclerosis was comparable to that of
      patients with SLE who received renal transplantation, according to existent
      medical literature. Based upon these data, renal transplantation is as effective
      a treatment for restoring renal function in patients with systemic sclerosis as
      it is in patients with SLE. Those patients with systemic sclerosis whose renal
      function did not improve with angiotensin-converting enzyme (ACE)-inhibitor
      treatments after scleroderma renal crisis should be considered as transplant
      candidates. Although the data are incomplete, the use of cyclosporine may not
      confer the advantage of improving graft survival in patients with systemic
      sclerosis as compared with SLE patients.

PMID- 10575421
TI  - Acute renal infarction. Clinical characteristics of 17 patients.
AB  - We analyzed the medical records of patients with an established diagnosis of
      acute renal infarction to identify predictive parameters of this rare disease.
      Seventeen patients (8 male) who were admitted to our emergency department between
      May 1994 and January 1998 were diagnosed by contrast-enhanced computed tomography
      (CT) as having acute renal infarction (0.007% of all patients). We screened the
      records of the 17 patients for a history with increased risk for thromboembolism,
      clinical symptoms, and urine and blood laboratory results known to be associated
      with acute renal infarction. A history with increased risk for thromboembolism
      with 1 or more risk factors was found in 14 of 17 patients (82%); risk factors
      were atrial fibrillation (n = 11), previous embolism (n = 6), mitral stenosis (n
      = 6), hypertension (n = 9), and ischemic cardiac disease (n = 7). All patients
      reported persisting pain predominantly from the flank (n = 11), abdomen (n = 4),
      and lower back (n = 2). On admission, elevated serum lactate dehydrogenase was
      found in 16 (94%) patients, and hematuria was found in 12 (71%) of 17 patients.
      After 24 hours all patients showed an elevated serum lactate dehydrogenase, and
      14 (82%) had a positive test for hematuria. Our findings suggest that in all
      patients presenting with the triad--high risk of a thromboembolic event,
      persisting flank/abdominal/lower back pain, elevated serum levels of lactate
      dehydrogenase and/or hematuria within 24 hours after pain onset--contrast
      enhanced CT should be performed as soon as possible to rule out or to prove acute
      renal infarction.

PMID- 10575422
TI  - Henoch-Schonlein purpura in children. Report of 100 patients and review of the
      literature.
AB  - Henoch-Schonlein purpura (HSP) is an acute leukocytoclastic vasculitis that
      primarily affects children. In the current report, the author presents the
      clinical features of 100 children with HSP and reviews the literature, placing
      particular emphasis on new information concerning the etiology,
      immunopathogenesis, and treatment of HSP. The dominant clinical features of HSP
      are cutaneous purpura (100%), arthritis (82%), abdominal pain (63%),
      gastrointestinal bleeding (33%), and nephritis (40%). The etiology of HSP remains
      unknown, but it is clear that IgA plays a critical role in the immunopathogenesis
      of HSP, as evidenced by increased serum IgA concentrations, IgA-containing
      circulating immune complexes, and IgA deposition in vessel walls and renal
      mesangium. There are 2 subclasses of IgA, but HSP is associated with
      abnormalities involving IgA1 exclusively, and not IgA2. This finding may be a
      consequence of abnormal glycosylation of O-linked oligosaccharides unique to the
      hinge region of IgA1 molecules. Although several lines of evidence suggest a
      genetic susceptibility to HSP, the fundamental basis for the abnormalities
      involving IgA remain unclear. In general, HSP is an acute, self-limited illness,
      but one-third of patients will have 1 or more recurrences of symptoms.
      Corticosteroid therapy may hasten the resolution of arthritis and abdominal pain,
      but does not prevent recurrences. To date, no form of therapy has been shown to
      shorten appreciably the duration of HSP. The long-term prognosis of HSP is
      directly dependent on the severity of renal involvement. Corticosteroids in usual
      doses have no effect on established nephritis. Evidence is emerging that
      treatment with high-dose intravenous pulse methylprednisolone coupled with
      azathioprine or cyclophosphamide may be beneficial in patients with severe
      nephritis.

PMID- 10575423
TI  - Screening mammography in women aged 40-49 years.
AB  - Screening mammography in women aged 40-49 years reduces breast cancer mortality
      by 16%-18%, and is recommended by various national organizations. However, one
      must be aware of the recognized limitations of the approach. The actual benefit
      appears to be small (absolute risk reduction, 0.07%; the number of women who need
      to be screened to prevent 1 woman from dying of breast cancer, about 1,500
      2,500), and there are associated risks and costs with this approach. The medical
      and scientific communities, in partnership with advocacy groups, must continue to
      work to improve our breast diagnostic capabilities, especially in younger women.
      Since this is an emotional and controversial issue, each woman will need to
      consider, with the aid of her primary caregiver, whether the risks of screening
      outweigh its potential benefits, and make an informed decision regarding
      screening.

PMID- 10575424
TI  - Measurement of cytogenetic endpoints in women environmentally exposed to air
      pollution.
AB  - The levels of sister chromatid exchanges (SCE), high-frequency cells (HFC) and
      chromosomal aberrations (CA) were studied in lymphocytes of Silesian women
      environmentally exposed to ambient air pollutants. Inhabitants of a less polluted
      but similarly urbanized area, in a rural region of Poland, served as controls.
      The study population was selected to minimize the major confounding factors
      influencing SCE and CA. These factors include age, gender, smoking status, and
      occupation. All donors were 35-46 years old non-smoking City Hall clerks. The
      levels of all three biomarkers were significantly higher in the exposed group
      than in controls as analyzed by the Mann-Whitney U-test. No correlation was found
      between levels of CA and SCE. Additional possible confounders, such as passive
      smoking, ex-smoking and X-ray chest examination did not influence the levels of
      biomarkers. This study builds upon our previous research in a male population but
      better controls for confounders. Thus, the results reveal genetic damage
      resulting from low-dose but chronic environmental exposure.

PMID- 10575425
TI  - The effect of coal stoves and environmental tobacco smoke on the level of urinary
      1-hydroxypyrene.
AB  - The objective of this study was to investigate a relationship between indoor air
      pollution from heating and cooking with coal-burning stoves and from
      environmental tobacco smoke (ETS), and the level of urinary 1-hydroxypyrene (1-OH
      PY). 1-OH-PY was analysed in children living in three areas of Silesia, a
      province in Poland. Urine samples were collected in winter, (1) from children
      exposed to ETS and smoke resulting from indoor coal-burning and (2) from control
      children. Airborne particulates had been sampled by use of stationary samplers by
      the Regional Sanitary-Epidemiological Station, Katowice throughout 12 months
      prior to the urine sampling. The urinary level of 1-OH-PY tended to increase in
      children exposed to ETS, but the increase was not significant. The concentrations
      of 1-OH-PY in urine of passive smokers were significantly elevated only in Bytom
      where an index of smoking parents of the studied children was highest as compared
      to other areas. Exposure to polycyclic aromatic hydrocarbons (PAH) due to
      domestic heating and cooking with coal-burning stoves resulted in significantly
      increased levels of 1-OH-PY. The results of this study indicate that the uptake
      of PAH due to indoor air pollution strongly affected the level of 1-OH-PY and
      that the main source of PAH in indoor air was the household use of coal for
      heating and/or cooking. When the results associated with this kind of exposure
      were excluded, median 1-OH-PY levels from the three examined areas assumed a
      pattern more similar to that of the benzo(a)pyrene (BaP) concentrations in
      ambient air.

PMID- 10575426
TI  - Chromosome damage and aneuploidy detected by interphase multicolour FISH in
      benzene-exposed shale oil workers.
AB  - A multicolour tandem-labelling fluorescence in situ hybridization (FISH)
      procedure was used to detect chromosome alterations in peripheral blood cells of
      a group of Estonian petrochemistry workers. Twelve workers employed in benzene
      production and five cokery workers, together with eight unexposed rural controls,
      were enrolled in the study. The methodology employed, based on the in situ
      hybridization of adjacent centromeric and pericentromeric regions, allowed the
      simultaneous detection of both chromosome breakage, involving damage-prone
      pericentromeric regions, and hyperploidy in interphase cells. Blood smears from
      all subjects were hybridized with chromosome 1 specific probes, in order to
      detect genotoxic damage in circulating lymphocytes and granulocytes. Moreover,
      lymphocyte cultures were established, harvested 48 h following mitogen
      stimulation and hybridized with the tandem chromosomes 1 and 9 probes. No
      significant difference in the incidence of breakage was detected in the nucleated
      cells of blood smears of exposed vs. control subjects. In contrast, modest but
      significantly increased frequencies of breakage affecting both chromosomes 1 and
      9 were observed in the cultured lymphocytes of the benzene-exposed workers
      compared to the unexposed controls, suggesting an expression of premutagenic
      lesions during the S-phase in vitro. Across the entire study group, the
      frequencies of breakage affecting chromosomes 1 and 9 in the stimulated
      lymphocytes were highly intercorrelated (p < 0.001). No significant difference
      was found in the incidence of hyperploidy among the study groups, although a
      tendency to higher values was observed in benzene-exposed workers. Although the
      relatively small size of the study groups does not allow firm conclusions on the
      role of occupational exposure, the observed patterns are suggestive of effects in
      the benzene-exposed workers. This work also shows that tandem labelling FISH can
      be usefully applied in human biomonitoring, allowing the simultaneous detection
      of both hyperploidy and chromosome breakage at interphase in different cell
      types.

PMID- 10575427
TI  - Examination of ras oncoproteins in human plasma from healthy controls and workers
      exposed to petroleum emissions, including benzene-related compounds.
AB  - Ras oncoproteins in blood plasma from workers exposed to petroleum emissions and
      unexposed controls were examined from Polish and Estonian samples. Twenty-four
      workers and 35 unexposed controls were examined from Poland and 97 exposed and 40
      unexposed controls from Estonia. Of the Estonian workers, 50 were exposed to
      benzene in a benzene production plant and 47 to polyaromatic hydrocarbons and
      benzene in a cokery. Blood plasma proteins were separated by gel electrophoresis,
      transferred to a nitrocellulose membrane by Western blotting and detected by
      chemiluminescence using a monoclonal antibody as the primary antibody. There were
      no statistically significant differences between the exposed and the control
      groups in either the Polish or the Estonian samples.

PMID- 10575428
TI  - Biomarkers of carcinogenesis in humans exposed to polycyclic aromatic
      hydrocarbons.
AB  - The frequencies of micronuclei (MN) in cytokinesis-blocked lymphocytes of 91
      steel foundry workers were analysed. On the basis of ambient PAH levels at the
      work stands and 1-hydroxypyrene concentrations in the urine, the coke-oven
      workers were the most exposed as compared to the rollers reference group. The
      difference in results for the two groups studied was not statistically
      significant, although MN were slightly higher for coke-oven workers. The
      frequency of MN did not increase with exposure: after some increase in 1-10
      years, a decreasing tendency was observed.

PMID- 10575429
TI  - Biomonitoring of genotoxic risk in workers in a rubber factory: comparison of the
      Comet assay with cytogenetic methods and immunology.
AB  - Several substances used in rubber processing are known to be genotoxic. Workers
      in a rubber tyre factory, exposed to a broad spectrum of contaminants such as
      benzo[a]pyrene, benzo-fluoranthene, naphthalene, acetonaphthene, alkenes and 1,3
      butadiene have been regularly examined for several years: chromosomal aberrations
      in lymphocytes, mutagenicity of urine (by use of the Ames test) and various
      parameters of blood and urine were assessed. An elevated level of mercapturic
      acid derivatives was found in the urine of employees, which is indicative of
      environmental exposure to toxicants with alkylating activity. We have now
      extended this study by examining genotoxicity with the modified Comet assay in
      parallel with chromosomal aberrations and micronucleus formation as well as
      immunological endpoints. Twenty-nine exposed workers from this factory were
      compared with 22 non-exposed administrative staff working in the same factory, as
      well as with 22 laboratory workers. The absolute numbers of peripheral leukocytes
      were significantly higher in the exposed group than in either of the control
      groups (p < 0.001). The erythrocyte mean cell volume was significantly higher in
      exposed workers in comparison with laboratory controls (p < 0.05). Percentages of
      lymphocytes, polymorphonuclear leukocytes, monocytes and eosinophils were not
      altered. The proliferative response of T- and B-cells to mitogen treatment when
      calculated per number of lymphocytes and adjusted for smoking, age and years of
      exposure did not differ between exposed and control groups. Endogenous strand
      breaks (including alkali-labile sites) and altered bases (formamidopyrimidine
      glycosylase- and endonuclease III-sensitive sites) were measured by the Comet
      assay in lymphocyte DNA. Exposed workers had significantly elevated levels of DNA
      breaks compared with office workers (p < 0.00001) or with laboratory controls (p
      < 0.00001). Micronuclei occurred at significantly higher frequencies in the
      exposed group than in controls (p < 0.00001), though the frequencies were all
      within the normal range. Significant correlations were seen between individual
      values of strand breaks, micronuclei and chromatid/chromosome breaks and certain
      immunological parameters.

PMID- 10575430
TI  - Biomonitoring of human genotoxicity induced by complex occupational exposures.
AB  - Sensitivity, specificity and correlations among several biomarkers for monitoring
      occupational exposure to complex mixtures of genotoxic agents were assessed in
      occupational environments in Hungarian study populations. The studies have been
      focused on DNA adduct formation, urinary metabolites, mutations and micronuclei
      induced by exposures to complex organic mixtures. In two Hungarian aluminium
      plants, increased DNA adduct and 1-hydroxypyrene (1-OH-PY) levels were observed
      in workers as compared to controls. However, no association between the biomarker
      levels was evident on an individual basis. In Hungarian garage mechanics, DNA
      adduct determinations did not show increased genotoxic exposure as compared to
      the controls. However, ambient air measurements, significantly enhanced 1-OH-PY
      levels, and slightly enhanced frequency of micronuclei indicated increased
      polycyclic aromatic hydrocarbon (PAH) exposure in the garages, as compared to the
      general environment. In a Hungarian vulcanizing plant, DNA adduct determinations
      and 1-OH-PY did not show significantly elevated exposure levels as compared to
      controls. The glycophorin A (GPA) somatic mutation assay was also negative for
      this occupational exposure. The results support previous observations of a lack
      of correlation between DNA adducts detectable by 32P-postlabelling and those
      measured by the PAH-DNA immunoassay in the same DNA sample. These studies also
      demonstrate a lack of close correlation between levels of DNA adducts and urinary
      1-OH-PY in the same individual.

PMID- 10575431
TI  - An evaluation of styrene genotoxicity using several biomarkers in a 3-year follow
      up study of hand-lamination workers.
AB  - A study employing several biomarkers of styrene exposure and genotoxicity was
      carried out in a group of lamination (reinforced plastic) workers and controls,
      who had been repeatedly sampled during a 3-year period. Special attention will be
      paid to the last sampling (S.VI), reported here for the first time. Styrene
      concentration in the breathing zone, monitored by personal dosimeters, and
      urinary mandelic acid (MA) were measured as indicators of external exposure.
      Blood samples were assayed for styrene-specific O6-guanine adducts in DNA, N
      terminal valine adducts of styrene in haemoglobin, DNA single-strand breaks
      (SSB), determined by use of the single cell gel electrophoresis (Comet) assay),
      and hypoxanthine guanine phosphoribosyl transferase (HPRT) mutant frequencies
      (MF) in T-lymphocytes. O6-styrene guanine adduct levels were significantly higher
      in the exposed group (5.9 +/- 4.9 adducts/10(8) dNp) as compared to laboratory
      controls (0.7 +/- 0.8 adducts/10(8) dNp; P = 0.001). DNA adduct levels
      significantly correlated with haemoglobin adducts, SSB parameters and years of
      employment. Styrene-induced N-terminal valine adducts were detected in the
      lamination workers (1.7 +/- 1.1 pmol/g globin), but not in the control group
      (detection limit 0.1 pmol/g globin). N-terminal valine adducts correlated
      strongly with external exposure indicators, DNA adducts and HPRT MF. No
      significant correlation was found with SSB parameters. A statistically
      significant difference in HPRT MF was observed between the laminators (22.3 +/-
      10.6/10(6)) and laboratory controls (14.2 +/- 6.5/10(6), P = 0.039). HPRT MF in
      the laminators significantly correlated with styrene concentration in air, MA and
      haemoglobin adducts, as well as with years of employment and age of the
      employees. No significant difference (P = 0.450) in MF between the laminators and
      the factory controls was observed. Surprisingly, we detected differences in MF
      between sexes. When data from all measurements were combined, women showed higher
      MF (geometric mean 15.4 vs. 11.2 in men, P = 0.020). The styrene-exposed group
      exhibited significantly higher SSB parameters (tail moment (TM), tail length (TL)
      and the percentage of DNA in the tail (TP)) than the control group (P < 0.001).
      SSB parameters correlated with indicators of external exposure and with O6
      styrene guanine adducts. No significant correlation was found between SSB
      parameters and haemoglobin adducts or HPRT MF. The data encompassing biomarkers
      from repeated measurements of the same population over a 3-year period are
      discussed with respect to the mechanisms of genotoxic effects of styrene and the
      interrelationship of individual biomarkers.

PMID- 10575433
TI  - The frequency of induced premature centromere division in human populations
      occupationally exposed to genotoxic chemicals.
AB  - Premature (early) centromere division (PCD, i.e., the separation of centromeres
      during the prometaphase/metaphase of the mitotic cycle) seems to be a possible
      manifestation of chromosome instability in human chromosome-breakage syndromes.
      Chromosome instability also frequently occurs in the peripheral blood lymphocytes
      (PBL) of humans occupationally exposed to clastogenic agents, and is considered
      an etiologic factor of neoplastic diseases. In order to investigate the
      importance of PCD in cancer risk assessment, we studied the frequency of PCDs in
      PBL of 400 Hungarian subjects. The various groups comprised 188 control donors
      and 212 subjects occupationally exposed to different genotoxic chemicals, such as
      acrylonitrile (ACN) and/or dimethylformamide (DMF), benzene, cytostatic drugs,
      ethylene oxide (ETO), mixed exposure in the rubber industry, mixed organic
      solvents including CCl4, hot oil-mist, bitumen, and polychlorinated biphenyls
      (PCB). Data were compared with chromosomal aberration frequencies determined in
      the same samples. PCD yields are significantly higher in populations exposed to
      mixed chemicals, crude oil and cytostatic drugs, compared with controls. PCDs
      involving more than three chromosomes are also more frequent in ETO- and oil mist
      exposed groups than in the others. The results indicate that the induction of
      PCDs is neither incidental nor artificial. As a consequence, we suggest that PCD
      can be developed into a new, exposure-related cytogenetic biomarker for a more
      adequate occupational cancer risk assessment. A further, follow-up
      epidemiological and cytogenetic investigation of PCD is in progress.

PMID- 10575432
TI  - Chromosomal aberrations and sister-chromatid exchanges in Lithuanian populations:
      effects of occupational and environmental exposures.
AB  - Cytogenetic analysis of chromosomal aberrations (CA) in 175,229 cells from 1113
      individuals, both unexposed and occupationally or environmentally exposed to
      heavy metals (mercury and lead), organic (styrene, formaldehyde, phenol and
      benzo(a)pyrene) and inorganic (sulfur and nitrogen oxides, hydrogen and ammonium
      fluorides) volatile substances and/or ionizing radiation was performed. In
      addition, 11,250 cells from 225 individuals were scored for the frequency of
      sister-chromatid exchanges (SCE). Increased frequencies of CA were found in all
      occupationally exposed groups. A principal difference between the exposure to
      heavy metals and organic substances was found: increase in the CA frequency was
      dependent on duration of exposure to mercury but not dependent on duration of
      exposure to styrene, formaldehyde and phenol. A higher CA incidence was found in
      lymphocytes of children living in the vicinity of a plant manufacturing phosphate
      fertilizers. This indicates that children are a sensitive study group for the
      assessment of environmental exposure. However, the results of SCE analysis in
      these children were inconclusive. Exposure to ionizing radiation was found to
      cause chromosome breaks and chromatid exchanges in Chernobyl clean-up workers and
      chromatid breaks, chromatid exchanges, dicentric chromosomes and chromosome
      translocations in workers from the Ignalina Nuclear Power Plant. The increased
      frequency of chromatid exchanges in individuals exposed to ionizing radiation was
      quite unexpected. This may be attributed to the action of some unrecognized life
      style or occupational factors, or to be a result of radiation-induced genomic
      instability. Also an increased SCE frequency was found in lymphocytes of
      Chernobyl clean-up workers.

PMID- 10575434
TI  - Chromosomal aberrations in humans as genetic endpoints to assess the impact of
      pollution.
AB  - The chromosomal aberration assay with peripheral blood lymphocytes has been used
      routinely during the last three decades to survey exposure of humans to various
      genotoxic agents. A large number of biomonitoring studies are based on this
      genetic endpoint. A great deal of data exists on occupational, life-style or
      medical exposure situations but less evidence of the validity of the assay is
      available with regards to environmental exposure. In the present paper we report
      our investigations on the impact of pollution in two different populations using
      chromosomal aberrations in human peripheral blood lymphocytes as a biomarker of
      chronic exposure to heavy metals and dioxins/furans for a long period and as a
      biomarker of acute exposure to accidentally released vinyl chloride in the air.
      In order to study genotoxic effects (chromosomal aberrations) of heavy metals and
      dioxins/furans, 52 exposed individuals from a polluted area were compared to 51
      matched controls from a distant non-industrialized area. A statistically
      significant increase was observed in the frequency of chromosomal aberrations in
      peripheral blood lymphocytes from the exposed population (1.90% aberrant cells
      vs. 1.11% for the controls). In the case of the vinyl chloride accident,
      chromosomal aberrations were analyzed in peripheral blood lymphocytes from 29
      potentially exposed and 29 non-exposed individuals (matched controls). The
      exposed group showed a statistically significant increase in the frequency of
      aberrant cells (1.47% vs. 1.07% for the controls).

PMID- 10575435
TI  - Molecular and cellular alterations in tobacco smoke-associated larynx cancer.
AB  - Tumours of head and neck belong to the most frequent types of cancer world-wide.
      In Poland, mortality from larynx cancer among males has been continuously
      increasing during the last decades up to 8.4 deaths per 100,000 men in 1993,
      which exceeds epidemiological records from other countries. The aetiology of
      laryngeal cancer is strongly associated with exposure to carcinogens present in
      tobacco smoke. The review describes a sequence of molecular and cellular events
      from carcinogenic exposure, DNA adduct formation, detection of mutations in the
      p53 gene, loss of heterozygosity (LOH) in chromosomal loci encoding the p53 and
      p16 genes, and loss of control of the cell cycle. The section concerning DNA
      adducts includes a discussion of the role of such confounders as exogenous
      exposure, the age and sex of the subject, and disease progression. The
      significance of genetic factors as individual risk determinants is discussed in
      relation to bleomycin-induced chromosome instability and in connection with the
      occurrence of defects in genes encoding detoxifying enzymes. The question
      concerning the substantial difference between men and women in larynx cancer
      morbidity and mortality remains open, even when the significantly higher adduct
      formation in male DNA compared with female material was taken into account.
      Preliminary experiments suggest a role of the frequently observed loss of the Y
      chromosome.

PMID- 10575436
TI  - In vitro studies on the genotoxicity of the organophosphorus insecticide
      malathion and its two analogues.
AB  - Malathion [S-(1,2-dicarboethoxyethyl)O,O-dimethyl phosphorodithioate] is a
      commonly used organophosphorus insecticide reported to be genotoxic both in vivo
      and in vitro, but the reports are conflicting. In order to elucidate the
      genotoxic potency of the main compounds present in commercial preparations of
      malathion, the DNA-damaging effect of this insecticide, its major metabolite
      malaoxon [S-(1,2-dicarboethoxyethyl)O,O-dimethyl phosphorothiolate] and its
      isomer isomalathion [S-(1,2-dicarboethoxyethyl)O,S-dimethyl phosphorodithioate],
      all at purity of at least 99.8%, was investigated by use of the alkaline single
      cell gel electrophoresis (comet assay). Freshly isolated human peripheral blood
      lymphocytes were incubated with 25, 75 and 200 microM of the chemicals for 1 h at
      37 degrees C. The concentrations used are comparable to those found in blood
      following various non-lethal human exposures to pesticides. Malathion did not
      cause any significant changes in the comet length of the lymphocytes, throughout
      the range of concentrations tested. Malaoxon and isomalathion introduced damage
      to DNA in a dose-dependent manner. The effect induced by malaoxon was more
      pronounced than that caused by isomalathion. Treated cells were able to recover
      within a 60-min incubation in insecticide-free medium at 37 degrees C except the
      lymphocytes exposed to malaoxon at 200 microM, which did not show measurable DNA
      repair. The latter result suggests a considerable cytotoxic effect (cell death)
      of malaoxon at the highest concentration used. The reported genotoxicity of
      malathion might, therefore, be a consequence of its metabolic biotransformation
      to malaoxon or the presence of malaoxon and/or isomalathion as well as other
      unspecified impurities in commercial formulations of malathion. In this regard,
      the results of our study clearly indicate that malathion used as commercial
      product, i.e., containing malaoxon and isomalathion, can be considered as a
      genotoxic substance in vitro. This means that it may also produce DNA
      disturbances in vivo, such as DNA breakage at sites of oncogenes or tumor
      suppressor genes, thus playing a role in the induction of malignancies in
      individuals exposed to this agent. Therefore, malathion can be regarded as a
      potential mutagen/carcinogen and requires further investigation.

PMID- 10575437
TI  - Bioassay-directed chemical analysis and detection of mutagenicity in ambient air
      of the coke oven.
AB  - In the present study, we summarize the results of studies on the mutagenic
      potential of the main fractions and subfractions of extractable organic material
      (EOM) in the ambient air at the workplaces of the coke oven. The objective of our
      experiments was to apply the Bioassay-Directed Chemical Analysis (with the use of
      the Ames test) for the identification of the differences in the mutagenicity of
      these fractions, in relationship to the complex mixture of EOM in occupational
      air. From the evaluation of results, it is possible to deduce the following
      conclusions: (1) The comparison of the mutagenicity in the main fractions (basic,
      acidic, neutral) demonstrates the existence of differences in mutagenic
      potential. Of the total mutagenicity, 20.4% is in the basic fraction, 25.4% in
      the acidic fraction and 54.2% in the neutral fraction. (2) In general, 90.1% of
      the mutagenicity found in the basic, acidic and neutral fractions together was
      associated with the requirement of metabolic activation in vitro (+S9). In the
      case of the neutral fraction, it was 51.8%. (3) These results also suggest that
      frameshift mutations are the major component (53.8%) of the total mutagenicity of
      the main fractions. (4) With regards to the mutagenicity of organic compounds in
      the neutral fraction it appeared that genotoxicants of its subfractions (slightly
      and moderately polar and aromatic) play the main role. Carcinogenic aromatic
      hydrocarbons (PAH) and genotoxic nitrocompounds play an important role as
      determinants of the mutagenic potential of complex mixtures of harmful compounds
      in ambient air. This is confirmed first by the results of short-term bacterial
      tests.

PMID- 10575439
TI  - [Color Doppler-echo in rheumatoid arthritis with extra-articular location.
      Preliminary experience].
AB  - INTRODUCTION: Chronic inflammation in rheumatoid arthritis usually involves
      articular synovia and extends to other joint components such as bursae, tendons
      and sheaths. Conventional US with high frequency transducers is an accurate tool
      for assessing abnormal changes in evolutive rheumatoid arthritis. We investigated
      the role of color and power Doppler imaging in staging extra-articular
      involvement, monitoring local inflammatory changes and drug treatment response.
      MATERIAL AND METHODS: We used a color Doppler unit with a 5-10 Mhz transducer and
      automatic power Doppler switch to examine 23 patients with tenosynovitis of the
      flexor (4/23) and extensor (8/23) tendons of the hand, Achilles (6/23) and
      posterior tibial (3/23) tendons, and long head of biceps (2/23) in acute
      rheumatoid arthritis. Only minimal pressure was exerted with the probe on the
      patients' skin to avoid compression and collapse of blood vessels. Ten normal
      volunteers were also examined as a control group. RESULTS: In all 23 acute
      rheumatoid arthritis patients, conventional US showed tendon involvement with
      intra-articular fluid, thickened tendons with partial tear and markedly
      hypoechoic thickened sheaths. Color signals were shown in all patients. Mid
      caliber vessels were visualized coursing straight from the sheath deep into the
      tendon. Intra-articular signals were seen in 10/12 patients only. Spectral
      analysis showed arterial flow, with RI ranging .40-.70. Power Doppler added no
      important information, but improved vessel depiction relative to color Doppler
      thanks to its higher accuracy in detecting flow signals. There were no color
      signals in the tendons of the 10 healthy volunteers in the control group. No
      color signals were seen in both joints and tendons in 12 patients submitted to
      medical treatment. CONCLUSION: Color and power Doppler can be a necessary and
      useful integration to high resolution US for flow mapping in rheumatoid arthritis
      patients with tendon and extra-articular involvement. These modes depict local
      circulation changes related to disease stage and treatment response.

PMID- 10575438
TI  - [Clinical scientific research with ionizing radiation in Italy. The standards
      setting and legal aspects].
AB  - INTRODUCTION: The paper reviews the laws that regulate the clinical scientific
      research with ionizing radiations in Italy. Although recent (all introduced after
      1990), the laws are a maze of rules sometimes contradictory and unclear, with
      frequent cross-references which make them difficult to disentangle. The aim of
      the paper is to provide the researcher with a technical and legal guide to find
      his/her way in the labyrinth of rules, and to constitute a basis for a possible
      future rationalization of the regulations. MATERIALS AND METHODS: The contents of
      the article n. 108 of the law by decree 230/1995 and of the Minister's Decree
      21/11/1997 together with the ICRP 62 (introduced in Italy by the Minister's
      Decree 21/11/1997) are extensively reviewed. The authors stress the fact that
      these laws apply only to prospective, but not to retrospective studies. The
      procedure to obtain ministerial authorization of the research project is
      illustrated, together with the possibility of a bureaucratic shortcut whereby the
      ethical committee states that the project conforms to ICRP 62. Special attention
      is paid to the cases of contrast between the ICRP 62 and previously promulgated
      laws: dose thresholds in non-therapeutic research, research on pregnant women or
      in child-bearing age and the issue of the preliminary assessment of new
      radiopharmaceuticals on monkeys (recommended by ICRP 62 but strongly restricted
      by the law by decree 116/1992). As for studies with radiopharmaceuticals, the
      problem of the double authorization required by the Minister's Decree 21/11/1997
      and by the memorandum 10/07/1997, n. 8 of the Ministry of Health is also
      discussed. DISCUSSION AND CONCLUSIONS: The authors express the opinion that the
      Minister's Decree 21/11/1997, together with ICRP 62, render invalid all previous
      rules and regulations which contrast with them. The Minister's Decree 21/11/1997
      and ICRP 62 are practical and exhaustive and offer the researchers and ethical
      committees precise and reliable guidelines. The paper aims to offer a
      contribution for the rationalization of the rules that regulate the field. To
      this regard, an accurate design of the future regulations, reflecting Euratom
      Directive 43/97 is expected by May 13, 2000. The authors' conclusion is that laws
      must regulate, not strangulate, clinical scientific research with ionizing
      radiations: incongruities, uncertainties and bureaucratic excesses must be
      corrected.

PMID- 10575440
TI  - [The identification of the criteria of malignancy and the tissue characterization
      of expansive processes in periskeletal soft tissues. The current role of magnetic
      resonance].
AB  - INTRODUCTION: Expansive masses arising from periskeletal soft tissues are a
      frequent challenge for the imaging specialist. Lesion diagnosis and
      characterization, and the assessment of benign/malignant nature are very
      important factors for treatment planning. We investigated MR capabilities in
      distinguishing benign from malignant masses and for histopathologic lesion
      characterization, also in the light of the latest most authoritative literature
      reports. MATERIAL AND METHODS: February 1995 to November 1997, we examined 237
      patients with known space-occupying lesions arising from periskeletal soft
      tissues. T1- and PD/T2-weighted SE images were acquired on the most suitable
      planes. The findings were independently evaluated by two groups of radiologists
      who were asked a benignity/malignancy judgment based on specific morphological
      criteria and then a presumptive histopathologic characterization. The results
      were then compared with pathologic findings. RESULTS: We had high agreement rates
      for benignity/malignancy judgements, with only < or = 3.8% error rates. In
      contrast, rates were quite variable for histopathologic characterization and
      differed greatly by lesion type. The lesions, defined as malignant, could not be
      characterized histologically in approximately 18% of cases by both groups.
      DISCUSSION AND CONCLUSIONS: Our results, which are in substantial agreement with
      the recent authoritative literature, confirm MRI as an extremely reliable tool
      for distinguishing benign from malignant expansive masses arising from
      periskeletal soft tissues. On the contrary, MRI exhibits good specificity in
      histopathologic characterization only for the masses with such development as to
      permit identification of the anatomical compartment of origin, which are usually
      benign, as well as the masses with typical or pathognomonic tissue signal.

PMID- 10575441
TI  - [Atypical ductal hyperplasia of the breast. Its diagnostic imaging and the role
      of percutaneous needle biopsy with a 14-gauge needle].
AB  - PURPOSE: To investigate the yield of core biopsy in the histologic
      characterization of atypical ductal hyperplasia (ADH) and to assess the
      radiological patterns, if any, of this condition. MATERIAL AND METHODS: January
      1993 to October 1997 we studied 553 lesions, 8 of them with a diagnosis of ADH
      made on microhistologic samples obtained with 14G needles. Biopsy was performed
      under US guidance in 81.7% of cases and under mammographic guidance in 18.3%. The
      breast lesions were studied with mammography, US and MRI, the latter in one case.
      ADH was diagnosed by strict application of Page's and lesion extent criteria.
      RESULTS: Seven of 8 lesions with a core biopsy diagnosis of ADH were submitted to
      surgical biopsy. The diagnosis was changed in as many as 6 of 8 cases, into
      typical ductal hyperplasia (1 case) and carcinoma (1 papilliferous, 3 ductal
      infiltrating and 1 in situ lesions). ADH was confirmed in one case only.
      DISCUSSION: In agreement with other authors, we found no specific radiological
      patterns of ADH. Moreover, the core biopsy diagnosis of ADH requires a surgical
      biopsy, because ADH is often associated with carcinoma. CONCLUSIONS: Surgical
      biopsy is needed to diagnose ADH and therefore it is useless to perform more
      invasive procedures than 14G core biopsy.

PMID- 10575442
TI  - [Brain magnetic resonance with magnetization transfer in multiple sclerosis.
      Lesion hyperintensity before and after intravenous gadolinium administration].
AB  - PURPOSE: To evaluate lesion contrast enhancement in brain magnetic resonance (MR)
      images with and without magnetization transfer pulse (MT) in patients affected
      with multiple sclerosis (MS). MATERIAL AND METHODS: Ten patients affected with
      relapsing-remitting MS underwent a 1.5-T (Magnetom Vision, Siemens) MR
      examination with T1-weighted spin-echo sequences without MT (TR/TE = 630/14 ms)
      and with MT (840/14 ms) using the following common parameters: 21 para-axial
      slices (thickness 5 mm, 10% gap); matrix 256 x 256; field of view 25 cm
      (rectangular 5/8); 2 excitations. The postcontrast sequences with and without MT
      were acquired in a randomized order, starting 5 minutes after the intravenous
      injection of 0.1 mmol/kg Gadoteridol (ProHance, Bracco). The images were blindly
      evaluated in four separate sessions: only the postcontrast images with MT (post
      Gd with MT); only the postcontrast images without MT (post-Gd without MT);
      comparing the pre- and postcontrast images with MT (pre/post-Gd with MT);
      comparing the pre- and postcontrast images without MT (pre/post-Gd without MT).
      The number of hyperintense areas referred to contrast enhancement and the
      evaluation time were measured for each session. The Wilcoxon test was used for
      statistical analysis. RESULTS: The number of areas referred to lesion contrast
      enhancement per patient were as follows: post-Gd with MT, 6.9 +/- 6.8 (mean +/-
      standard deviation) (range 1-24); post-Gd without MT, 3.6 +/- 4.3 (0-14);
      pre/post-Gd with MT, 5.2 +/- 6.1 (1-21); pre/post-Gd without MT, 3.6 +/- 4.9 (0
      16). A nonsignificant difference was found for the comparison between post-Gd
      without MT and pre/post-Gd without MT while significant differences were found
      between post-Gd with MT and pre/post-Gd with MT (p = .028), pre/post-Gd without
      MT and pre/post-Gd with MT (p = .012), as well as between post-Gd without and
      post-Gd with MT (p = .008). The mean evaluation time for the different sessions
      was always less than a minute, ranging from 33 seconds for pre/post-Gd without MT
      to 51 seconds for post-Gd with MT. CONCLUSIONS: The postcontrast sequence
      obtained with the MT pulse detects more active lesions than the postcontrast
      sequence without MT. However, the comparison with the plain images with the MT
      pulse is mandatory to exclude pseudoenhancement foci, i.e. hyperintense areas
      already present in the precontrast images with the MT pulse, without disruption
      of the blood-brain barrier. The post-Gd without MT sequence needs not be compared
      with the precontrast images without MT. Differences in evaluation time are
      practically negligible.

PMID- 10575443
TI  - [The clinical efficacy of magnetic resonance with diffusion-weighted sequences in
      the assessment of acute cerebral ischemia].
AB  - PURPOSE: To evaluate the efficacy of diffusion weighted Magnetic Resonance
      Imaging in the diagnosis of acute ischemic infarction and correlate the signal
      changes observed in the acute phase with final brain damage. MATERIAL AND
      METHODS: Fifteen patients (six women and nine men: mean age 68 years) with acute
      ischemic stroke (within 12 hours) underwent diffusion MRI. All the patients were
      selected on the basis of sudden focal neurologic symptoms and CT findings
      excluding other conditions than ischemia. MRI was performed with a 1.5 T magnet
      with echo-planar gradients. All the patients underwent follow-up CT and/or MRI.
      RESULTS: Diffusion MRI, performed in the acute phase, showed signal changes in
      all the patients whose infarction was later confirmed by CT or MRI. In 10 of 12
      patients with positive diffusion imaging, CT was normal. FLAIR sequences showed
      the lesions in 4 of 12 cases. In the 2 patients with transient ischemic attack
      diffusion MRI was normal as well as follow-up examinations. Apparent Diffusion
      Coefficients values in the infarcted area were almost half those of the
      contralateral normal brain. Final damage (as assessed by CT or MRI) was larger
      than observed in acute diffusion images in all cases but one. CONCLUSION: Because
      of its high sensitivity and specificity, diffusion MRI is going to play a more
      important role in the management of acute ischemic stroke patients.

PMID- 10575444
TI  - [The role of computed tomography after functional surgery on the paranasal
      sinuses. Normal findings and an assessment of the surgical failures].
AB  - INTRODUCTION: Functional endoscopic sinus surgery has become the technique of
      choice to treat benign or inflammatory diseases of paranasal sinuses resistant to
      medical therapy. The goal of this type of surgery is to open the obstructed sinus
      ostia and restore normal aeration and mucociliary clearance. Messerklinger's is
      the most widely used technique. PURPOSE: We investigated the role of CT after
      functional endoscopic sinus surgery and describe CT findings of postoperative
      anatomical changes together with frequent complications and surgical failures.
      METHODS AND MATERIALS: Twenty-seven patients with relapsing symptoms were
      examined with CT of paranasal sinuses 8-32 weeks after functional endoscopic
      sinus surgery. In all cases both preoperative CT and surgical reports were
      available: CT and surgical results were compared. RESULTS: In 21/27 patients
      nasosinusal changes were demonstrated with CT. Recurrent disease secondary to
      inflammation and/or fibrosis was observed in 14 cases. Residual disease was seen
      in 5 patients. A major orbital complication was found in 1 patient with diplopia.
      One patient exhibited a large interruption of cribriform plate with CSF fistula.
      CONCLUSION: CT permitted an accurate assessment of extension and results of
      functional endoscopic sinus surgery. CT is indicated in the postoperative study
      of the patients who a) present symptoms of cerebral and ocular complications
      (early after functional endoscopic sinus surgery); and b) do not respond to
      medical treatments 8-32 weeks after unsuccessful functional endoscopic sinus
      surgery. In these patients CT can demonstrate recurrent and/or residual
      nasosinusal disease and bony defects unintentionally caused by the surgeon during
      the procedure.

PMID- 10575445
TI  - [Vascular complications in intestinal obstructions. The role of computed
      tomography].
AB  - INTRODUCTION: We investigated CT capabilities in showing vascular complications
      (ischemia, infarction) secondary to intestinal obstruction. SUBJECTS AND METHODS:
      32 patients with small bowel obstruction, subdivided in two groups, were examined
      with CT. The first group consisted of 12 patients with small bowel obstruction
      complicated by ischemic injury. It was due to loop strangulation in 10 cases and
      loop distension secondary to colon carcinoma in 2 cases. At surgery the loop
      strangulation was caused by adhesions in 9 cases and by jejunal hernia in 1 case.
      Vascular complications were segmentary small bowel infarction in 7 cases, colonic
      infarction in 2 cases and ischemia, which was resolved after loop debridement, in
      3 cases. The second group consisted of 20 patients with intestinal occlusion due
      to adhesions complicated by a closed loop in 4 cases. All patients were examined
      with(out) i.v. contrast agent administration. Filling of the intestinal loops by
      oral contrast agent was never performed. RESULTS: CT identified the vascular
      injury secondary to intestinal obstruction in 11/12 patients (91%). In one case
      it was not possible to diagnose mild ischemia, which was found of surgery. CT
      findings were: loops distention in all the cases; wall thickening in 11 cases
      with intramural gas in 8 cases and slight contrast enhancement in 1 case; ascites
      in 2 cases; mesenteric edema in 9 cases; gas at the mesenteric root in 1 case. In
      the control group, small bowel obstruction was diagnosed with CT in all cases
      based on the presence of distended loops up to the occlusion site. Parietal
      alterations above the lesion were never found. CONCLUSION: CT is a sensitive tool
      for diagnosing small bowel obstruction and for assessing the site and cause of
      obstruction. CT plays a pivotal diagnostic role in vascular complications, giving
      very important indications for a correct treatment.

PMID- 10575446
TI  - [Colonoscopy with computed tomography with volume reconstruction. The results and
      a comparison with endoscopy and surgery].
AB  - PURPOSE: Virtual CT colonoscopy is a novel technique whose diagnostic accuracy
      and clinical yield are currently investigated. Several studies have shown its
      capabilities in detecting colon and rectal cancers. We report the results of a
      preliminary experience with the volume rendering technique and compare CT
      colonoscopy with endoscopy and surgery. MATERIAL AND METHODS: Our series
      consisted of 25 patients with colon cancer confirmed at endoscopy and/or surgery.
      All examinations were carried out with a spiral CT scanner Philips Tomoscan AVE1.
      Intestinal preparation was adequate in all patients, consisting in gas
      insufflated immediately before acquisition, after the injection of 100 mL
      iodinated contrast agent. All examination were performed in prone position using
      axial 5 mm slices with 5 mm table feed (pitch 1) and 2 mm reconstruction index;
      120 kV and 200-250 mA were used. Images were transferred to a workstation (Easy
      Vision, Philips, release 4.2.1.1) for processing. We acquired multiplanar (MPR)
      and virtual endoscopic images with volume rendering; the selected threshold was 
      250 to -600 Hounsfield Units. Virtual endoscopic images could be obtained in 23
      of 25 cases. The results of the radiological study were compared with endoscopic
      and surgical findings in 25 and 17 cases, respectively. RESULTS: Endoscopy and
      surgery detected 46 lesions: 29 were malignant and 17 benign. Axial CT and MPR
      alone detected 35 lesions (76%), 29 of them malignant and 6 benign. The 11 benign
      lesions missed by axial CT ranged 6-8 mm in diameter. There were no false
      positives. CT colonoscopy alone detected 66 lesions, but 22 of them were false
      positive due to residual stool in the colon (21 cases) and to residual barium in
      the colon (1 case). Combining CT colonoscopy and axial and MPR images enabled to
      correct the false positive diagnoses made by CT colonoscopy alone and to decrease
      the false negative ratio of axial and MPR images. Forty-one of 44 lesions (93%)
      were detected. Thirty-seven lesions were found in the 17 surgical patients; 34 of
      them were correctly identified combining CT colonoscopy and axial and MPR
      findings, while endoscopy detected only 31 lesions. Thus, CT had 92% sensitivity,
      versus 83% of fiberoptic endoscopy. CONCLUSION: In this preliminary experience
      volume rendering CT colonoscopy exhibited high sensitivity in detecting colon
      cancers, but their correct evaluation and characterization can be obtained if
      axial and MPR studies are combined. Further investigation and technological
      developments are necessary to define the yield of this new technique.

PMID- 10575447
TI  - [Gunshot wounds of the abdomen studied by computed tomography. The authors'
      personal experience in 30 cases].
AB  - INTRODUCTION: CT plays an important role in depicting gunshot wounds in
      parenchymal and hollow organs in the abdomen. Relative to other techniques and to
      emergency laparotomy, CT permits good assessment of abdominal content, major
      injuries and changes in other districts, such as chest, pelvis and skull. We
      investigated the yield and role of CT in diagnosing abdominal gunshot wounds,
      with their rich and varied radiological signs and associated injuries. MATERIAL
      AND METHODS: We retrospectively reviewed the findings of 30 patients with
      abdominal gunshot wounds examined in 4 years at Loreto-Mare Hospital, Naples. All
      patients were men, age ranging 19-54 years (mean: 35); 6 of them were not from
      the European Union. Examinations were carried out from diaphragm to pubis with
      i.v. contrast injection and the CT angiography technique. CT was integrated with
      chest studies in 6 cases and with skull studies in 5. Subsequent CT follow-ups
      were necessary in 12 cases submitted to conservative treatment. RESULTS: Liver
      was the most damaged parenchyma, with hemorrhage and lacerocontusion in 7 cases
      and mashed in 1 case; spleen was involved in 4 cases; hemoperitoneum was found in
      18 cases. Diaphragm was involved in 5 cases and pancreas in 2; gallbladder,
      stomach and duodenum were involved in 1 case each and jejunum-ileum and colon in
      3 and 6 cases, respectively. CT showed renal injury in 3 cases and bladder injury
      in 2. Eight patients had vertebral gunshot damage. Pneumothorax, hemothorax and
      lacerocontusion were found in 7 cases; brain was injured in 4 cases and limbs in
      16. DISCUSSION AND CONCLUSIONS: Tissue damage extent depends on the speed and
      kinetic energy the bullet carries into the abdomen. Abdominal radiography shows
      the bullet and its site, pneumoperitoneum from gastrointestinal perforation,
      crash bone injuries, vertebral trauma and subcutaneous emphysema. Instead, CT
      depicts early parenchymal damage and vascular injury and thus becomes a complete
      and necessary tool for imaging gunshot wounds. CT provides early diagnostic
      information which help plan emergency treatment and thus decrease mortality. As
      for angiography and US, we suggest they be used subsequently because in emergency
      they may delay the diagnosis. Moreover, vessel rupture and active intraabdominal
      bleeding are easily detected with spiral CT, which appears the best tool for
      prompt assessment of the injuries associated with gunshot wounds in other
      districts such as, the skull. To conclude, CT permits adequate planning of
      emergency surgery and helps select the cases for follow-up, intensive care and
      conservative treatment.

PMID- 10575448
TI  - [The role of computed tomography in assessing subphrenic abscesses after
      posttraumatic splenectomy].
AB  - INTRODUCTION: We studied subphrenic inflammatory abscesses and splenic fluid
      collections after splenectomy for trauma. These complications may appear early or
      late postoperatively; they are easily demonstrated with CT, which permits
      accurate spatial assessment of the lesions and appropriate treatment with
      percutaneous drainage. We investigated the diagnostic accuracy of CT in
      subphrenic inflammatory conditions after emergency splenectomy for traumatic
      spleen rupture and found that CT is a precious tool for rapid and easy diagnosis
      and follow-up of subphrenic abscesses treated with percutaneous drainage.
      MATERIAL AND METHODS: Thirteen patients with left subphrenic inflammatory
      abscesses after splenectomy for trauma were examined from 1994 to 1998. They were
      9 men and 4 women ranging in age 16-67 years (mean: 32). CT demonstrated
      abscesses early postoperatively in 9 patients and late postoperatively (mean: 3
      months) in 4 patients. Abscesses were diagnosed with CT on admission for an
      abdominal emergency in 3 cases; one abscess was found at outpatient US performed
      for persisting left abdominal pain. CT-guided percutaneous drainage was performed
      in all patients with the Trocar technique. RESULTS: A large inflammatory liquid
      collection with the typical "liquid pseudospleen" appearance and characterized by
      tomodensitometric coefficients of corpusculated fluid was seen in 3 cases.
      Multiple confluent lesions with septa were found in 3 cases. Contrastography of
      the abscess cavity with the injection of a water-soluble iodinated contrast agent
      was performed in 2 cases to detect fistulas connecting to the intestinal loops.
      Subphrenic abscesses had the same CT patterns both early and late
      postoperatively, with the collection organizing into thick and corpusculated
      phlogistic material and exhibiting enhanced capsulofibrous differentiation. Air
      bubbles and water-air levels within the collection were found in 7 cases and
      considered a pathognomonic sign of inflammatory abscesses. A periabscessual
      reaction involving intestinal loops and adjacent organs was seen in 4 cases.
      DISCUSSION AND CONCLUSIONS: Splenectomy causes depressed phagocytosis and
      decreases serum levels of IgM and antigen response. This calls for careful
      selection of the patients absolutely requiring splenectomy, such as those with
      decompensated circulation and multiple parenchymal ruptures or spleen detachment
      from its stalk. Subphrenic abscesses after splenectomy account for 2.5% of
      postoperative complications and those after splenectomy for trauma are rarer
      still, with 1.3%. CT is the imaging method of choice in detecting inflammatory
      abscesses in the residual splenic cavity and assessing their extent. CT-guided
      drainage is the first-line treatment, while surgery is reserved to later stages,
      when drainage fails or other complications occur. Finally, CT permits accurate
      positioning of the catheter inserted with the Trocar technique and its immediate
      monitoring, which permits to assess treatment efficacy.

PMID- 10575450
TI  - [Neurolytic block of the celiac plexus and splanchnic nerves with computed
      tomography. The experience in 150 cases and an optimization of the technic].
AB  - INTRODUCTION: CT-guided celiac plexus and splanchnic nerve neurolytic blocks are
      procedures for pain relief in patients with upper abdominal malignancies. In the
      last 20 years, the technique has been modified by the introduction of CT guidance
      providing improved precision and safety. We report our personal experience and
      provide suggestions for technique optimization. MATERIALS AND METHODS: In 1991
      1998 we performed 150 celiac plexus and/or splanchnic nerve neurolytic blocks
      with ethyl alcohol in 144 cancer patients; the procedure was repeated in 6
      patients. In 69% of cases the patient had a pancreatic lesion. We prefer an
      anterior approach with very thin needles (22 Gauge). The sites of alcohol
      injection (celiac plexus, splanchnic nerves or both) are chosen after evaluation
      of anatomy by preliminary CT scans, or during the procedure, depending on alcohol
      (mixed with a contrast agent) spread. RESULTS: The mean duration of the procedure
      ranged 50 min (1991) to 22 min (1998). 48 hours after the block we obtained major
      pain relief in 79% of cases. After 15 days, 21% of patients had no pain (drugs:
      none), 29% had mild pain (therapy: non-steroid anti-inflammatory drugs), 32% had
      marked pain (therapy: non-steroid anti-inflammatory drugs and, occasionally,
      opioids), 18% had severe pain (only opioid therapy). Pain relief was more
      frequent in splanchnic nerve blocks. DISCUSSION: Our experience confirms that
      neurolytic celiac plexus and/or splanchnic nerve block is a good choice in the
      treatment of upper abdominal cancer pain. We would also like to add that: 1)
      celiac plexus block with CT guidance (with the needle tip positioned anterior to
      aorta) and splanchnic nerve block (with the needle tip positioned posterior to
      diaphragmatic crura) are no longer two separated techniques, but they can be
      chosen and combined according to patients needs. 2) All procedures can be
      performed with anterior approach, in supine position, with a single thin needle,
      allowing to reach the target without any complication, even after puncturing
      stomach, liver, bowel, pancreas or aorta. 3) With CT guidance, even splanchnic
      nerve neurolysis is a low-risk technique, which should be adopted in all cases of
      insufficient alcohol spread in the celiac plexus. 4) When the operators are
      skilled and experienced enough, the time required for the block can be
      significantly decreased to nearly the time required for US-guided or fluoroscopic
      guided procedures.

PMID- 10575449
TI  - [An update of B-mode echography in the characterization of nodular thyroid
      diseases. An echographic study comparing 7.5 and 13 MHz probes].
AB  - PURPOSE: We investigated B-mode US capabilities in diagnosis and characterizing
      thyroid nodules and compared our personal findings with those of the few
      analytical studies in the literature. We also compared the diagnostic accuracy of
      conventional 7.5 MHz versus more recent 13 MHz transducers. MATERIAL AND METHODS:
      We examined 136 consecutive patients with a single thyroid nodule: they were 97
      women and 39 men, age ranging 15-87 years (mean: 37.4). The patients were
      submitted to scintigraphy and laboratory tests first and then to US, fine-needle
      biopsy and/or histologic examination. The final diagnosis was made at cytology
      and/or histology: we had 98 follicular hyperplasias, 20 follicular adenomas and
      18 carcinomas. We studied the presence/absence of the halo sign, cystic portions,
      microcalcifications; nodule margins and echogenicity relative to the thyroid
      gland were also studied. RESULTS: The presence of microcalcifications had the
      highest specificity for malignancy. The sensitivity of this parameter was higher
      with 13 MHz than with 7.5 MHz transducers. Relative to microcalcifications,
      absence of cystic portions and irregular margins, 13 MHz US had 64.7-89%
      accuracy. The halo sign and lesion echogenicity did not permit a reliable
      differential diagnosis between benign and malignant nodules with both 7.5 and 13
      MHz transducers. The association of microcalcifications and irregular margins had
      the highest accuracy, scoring 86% at 7.5 MHz and 90.5% at 13 MHz. CONCLUSIONS:
      High frequency US is a sensitive tool for diagnosing thyroid nodes. Accurate
      analysis of the US signs can suggest the benign/malignant lesion nature, which
      must be integrated with color, power and pulsed Doppler findings.

PMID- 10575451
TI  - Complete functional exclusion of lower urinary tract with ureteral occlusion
      prosthesis.

PMID- 10575452
TI  - [A case of myositis ossificans: what is the real diagnostic value of magnetic
      resonance?].

PMID- 10575453
TI  - [The neurophysiopathology of ischemic lesions of the pons. A report of 4 cases].

PMID- 10575454
TI  - [MR and color Doppler-echo of a meningioma of the sphenoid wing with retro
      orbital extension. A case report].

PMID- 10575455
TI  - [Spontaneous dissection of the internal carotid artery. A report of 2 cases].

PMID- 10575456
TI  - [A case of spontaneous dissection of the infrarenal abdominal aorta treated by
      the positioning of a self-expanding metal prosthesis].

PMID- 10575457
TI  - [Bilateral varicocele as a unique sign of azygos-hemiazygos continuation with an
      anomalous intrahepatic connection. A case report].

PMID- 10575458
TI  - [Color Doppler-echo in Wilkie's syndrome. A case report].

PMID- 10575459
TI  - [Hepatic chemoembolization in a patient allergic to iodinated contrast media: the
      use of Gd-DTPA].

PMID- 10575460
TI  - [Pancreatic sarcoidosis. The computed tomographic aspects in a case].

PMID- 10575461
TI  - [Treatment via a covered endoprosthesis in a case of a pseudoaneurysm of the
      thoracic aorta].

PMID- 10575462
TI  - [An up-to-date argument: neonatal necrotizing enterocolitis].

PMID- 10575463
TI  - [The priority of retrograde echocystography].

PMID- 10575464
TI  - 59th Annual Congress of the Swiss Society of Orthopedics. Winterthour, 9-11
      September 1999. Abstracts.

PMID- 10575465
TI  - The International Year of Older Persons: what occupational therapists have to
      celebrate.

PMID- 10575466
TI  - Shoulder supports revisited: a Canadian follow-up survey.
AB  - This paper investigates the use of shoulder supports with stroke patients in
      Canada and compares the results of two survey questionnaires carried out in 1984
      and 1994. It describes which shoulder supports therapists are using with stroke
      patients and which goals they hope to achieve with specific supports. The
      Lapboard, Cuff Type Sling, and Arm Trough Support were the most frequently used
      supports at both time periods. The most frequent goal chosen for each of these
      three most frequently chosen supports was the same at both time periods but were
      chosen significantly less frequently in 1994. There was a significant decrease in
      the use of the Bobath Axial Roll over the ten-year period. This follow up
      questionnaire documents the limited changes which have occurred in the last ten
      years in the management of the shoulder following stroke, raises some questions
      about this area of practice, and outlines some solutions including the need to
      base occupational therapy practice on more evidence.

PMID- 10575467
TI  - Biomechanical analysis of four supports for the subluxed hemiparetic shoulder.
AB  - External support systems, such as slings and lapboards, may reduce shoulder
      subluxation in individuals with hemiplegia. However there is controversy among
      occupational therapists concerning the most appropriate method to support the
      affected arm. The purpose of the present paper is to report the biomechanical
      analysis of four support systems; two shoulder support systems, a Bobath axillary
      roll, and a laptray. Two dimensional static biomechanical analyses determine the
      mechanical characteristics of each of these four support systems. The results of
      the analyses demonstrate the magnitude of the shoulder loading and the
      effectiveness of the various components of each of the systems. The effect of
      changing some of the characteristics of the slings is demonstrated. Slings with
      straps over the unaffected shoulder provide continuous support for the flaccid
      extremity. The Bobath axillary roll may introduce an unwanted lateral force.
      Lapboards must be maintained at an appropriate distance from the subluxed
      shoulder to be effective. This theoretical analysis of supports systems will
      provide therapists information to help them understand effective supports for
      subluxation.

PMID- 10575468
TI  - Opportunity, not prescription: an exploratory study of the experience of
      occupational engagement.
AB  - Occupational therapy practice is based upon the belief that the use of occupation
      as-means can promote the health and sense of well-being of individuals with
      disability. Despite a firm commitment to the construct of occupation by the
      profession, little empirical evidence has been generated which supports the basic
      tenets of practice. In the psychosocial literature, no studies could be located
      which directly investigated the use of occupation-as-means to mental health. An
      exploratory study was conducted with eight participants of an occupation-based,
      women's mental health group. In-depth interviews and participant observation were
      utilized to explore the meaning of occupational engagement for these women. The
      experience of occupational engagement is presented in the form of a conceptual
      model named occupational spin-off. Occupational spin-off represents conceptually
      the experience of occupational engagement for the participants in the research
      study and describes a process of occupation-as-means to mental health. The
      processes of affirmation, confirmation, actualization, and anticipation
      collectively contribute to and maintain occupational spin-off. The process of
      occupational spin-off contributes to an understanding of why these participants
      have remained out of hospital, and why they are feeling better. Implications of
      this process model for clinical practice and future research are suggested.

PMID- 10575469
TI  - Occupational performance needs of a shelter population.
AB  - Practice in shelters for people who are homeless is an exciting and challenging
      opportunity for occupational therapists. However, there is a paucity of knowledge
      about the occupational performance needs of this population. In the present
      study, 25 persons at a shelter were interviewed using the Canadian Occupational
      Performance Measure (COPM). Data were analyzed using both qualitative and
      quantitative methods. Several major themes emerged including spirituality, "we
      want what everyone wants", choosing satisfaction, diverse health concerns, power
      of relationships, the importance of environment to well-being, and poverty.
      Altruism in the midst of adversity and individuality were minor themes.
      Instrumental activities of daily living, such as access to employment, financial
      management, housing, and recreation, were reported as more important than basic
      activities of daily living. Participants and interviewers also responded to
      general questions regarding the use of the COPM in the assessment process. The
      COPM was found to be useful for assessing the occupational performance needs of
      this population, but should be augmented by inquiry about environmental concerns,
      relationships, housing, and spirituality.

PMID- 10575470
TI  - Reflections on ... the art of observation: reflecting on a spiritual moment.
AB  - Spiritual moments can occur at unexpected times and it is often upon reflection
      that the significance of the moment is understood. The author tells a personal
      story about her daughter and herself engaged in the activity of drawing flowers.
      The reflection which follows highlights both the process and outcomes of the
      experience. Exploring spiritual issues using this narrative medium assists health
      care workers to recognize better and understand spirituality in relation to the
      occupation of visual art.

PMID- 10575471
TI  - 12th Congress of the European College of Neuropsychopharmacology. London, United
      Kingdom, September 21-25, 1999. Abstracts.

PMID- 10575472
TI  - Oxygen '99. 6th Annual meeting of the Oxygen Society. New Orleans, Louisiana,
      USA. November 18-22, 1999. Abstracts.

PMID- 10575473
TI  - 12th Annual Congress of the European Society of Intensive Care Medicine. Berlin,
      Germany, 3-6 October 1999. Abstracts.

PMID- 10575474
TI  - The British Human Genetics Conference. September 27-29, 1999. Abstracts.

PMID- 10575475
TI  - XXX Meeting of the Spanish Society of Physiological Sciences. Caceres, 29
      September-2 October 1999. Abstracts.

PMID- 10575476
TI  - 8th Congress of the European Academy of Dermatology and Venereology. Amsterdam,
      The Netherlands, September 29-October 3, 1999. Abstracts.

PMID- 10575477
TI  - 39th American Society for Cell Biology annual meeting. Washington DC, USA.
      December 11-15, 1999. Abstracts.

PMID- 10575478
TI  - European Association for Vision and Eye Research. Palma de Mallorca, Spain,
      October 6-9, 1999. Abstracts.

PMID- 10575479
TI  - XVIIth International Pigment Cell Conference. Nagoya, Japan, October 30-November
      3, 1999. Abstracts.

PMID- 10575480
TI  - Annual meeting of the Swiss Society of Intensive Medicine with the participation
      of the Swiss Society of Medical Informatics. Davos, 23-24 September 1999.
      Abstracts.

PMID- 10575481
TI  - Annual Congress of the Swiss Society of Anesthesia and Resuscitation. Interlaken,
      5-6 November 1999. Abstracts.

PMID- 10575482
TI  - 7th Vienna Shock Forum. Vienna, Austria, November 13-16, 1999. Abstracts.

PMID- 10575483
TI  - [Ultraschall '99. 23rd Three-country meeting of the Swiss, German, and Austrian
      Societies for Ultrasound in Medicine. Berlin, 26-29 September 1999. Abstracts].

PMID- 10575484
TI  - [Endoscopic terminology--guideline of the German Society for Digestive and
      Metabolic Diseases].

PMID- 10575485
TI  - Randomized studies of coronary artery bypass grafting vs. medical or percutaneous
      catheter-based revascularization: a review.

PMID- 10575486
TI  - Myocardial revascularization without cardiopulmonary bypass.

PMID- 10575487
TI  - Transmyocardial laser revascularization.
AB  - TMLR is effective as an isolated procedure in patients with ungraftable vessels
      and is a useful adjunct to CABG in patients with diffuse and small-vessel disease
      requiring endarterectomies. The optimal subset of patients who will benefit from
      isolated TMLR are those primarily with angina rather than congestive failure, who
      have protected myocardium and uncompromised left ventricular function.

PMID- 10575488
TI  - Cardiac cell transplantation: the autologous skeletal myoblast implantation for
      myocardial regeneration.

PMID- 10575489
TI  - The radial artery as a graft for coronary revascularization: techniques and
      follow-up.

PMID- 10575490
TI  - Aortic valve repair for management of aortic insufficiency.

PMID- 10575491
TI  - Scimitar syndrome.

PMID- 10575492
TI  - Staged surgical approach to neonates with aortic obstruction and single ventricle
      pathophysiology.

PMID- 10575493
TI  - Surgical treatment of single ventricle with aortic arch obstruction in early
      life.

PMID- 10575494
TI  - Early and medium-term outcomes after the fenestrated Fontan operation.

PMID- 10575495
TI  - The alternate recipient list for heart transplantation: a model for expansion of
      the donor pool.

PMID- 10575496
TI  - [The anesthesia consultation].

PMID- 10575497
TI  - [Again and always allergy].

PMID- 10575498
TI  - [Anesthesia consultation in cardiovascular and thoracic surgery. A survey of
      patient and physician satisfaction].
AB  - OBJECTIVE: To assess the quality of the preadmission anaesthetic consultation
      prior to cardiovascular and thoracic surgery with a satisfaction inquiry. STUDY
      DESIGN: Prospective study with a questionnaire, extended over a period of two
      months. PERSONS: Patients and anaesthetists of the cardiothoracic surgical
      service. METHODS: The inquiry, which took place after completion of the
      consultation was achieved by a person non member of the staff. Anaesthetists were
      questioned on the medical content, its exhaustive character and its value for the
      patient's perioperative care. RESULTS: Out of the 273 patients included in the
      study, 121 agreed to answer the questionnaire. Participation in the study was
      more significant in older patients (58 +/- 20 vs 51 +/- 24 years) and following
      shorter waiting time (WT) [15 +/- 13 (0-60) vs 25 +/- 18 (0-66) min]. The
      duration of the consultation (DC) was not different between the two groups [29 +/
      12 (8-70) vs 31 +/- 14 (6-75) min]. However patients' participation increased
      when the DC exceeded by 0.6 the sum of DC and WT [DC > 0.6 (DC + WT)]. The
      analogic score (AS) assessing reduction in preoperative anxiety was 8.4 +/- 1.5
      (2-10). Finally, 108 patients out of 121 considered to have been well informed
      about the anaesthetic [AS = 8.7 +/- 1.2 (4-10)], 113 considered the preadmission
      consultation as a useful procedure [AS = 8.6 +/- 1.5 (2-10)]) and for 41 a
      personalized follow-up by the same anaesthetist was valuable. Only three
      operations had to be postponed the day before surgery. One third of the
      anaesthetists considered that the consultation improved the clinical and
      therapeutic management of the patients. CONCLUSION: This inquiry showed that the
      preadmission anaesthesia consultation was considered as benefitful by patients
      and anaesthetists. However the participation of patients in this study was poor.
      Subsequently to the inquiry information forms have been produced and handed to
      the patient prior to the consultation.

PMID- 10575499
TI  - [The value of anesthesia consultation in relation to the single preanesthetic
      visit].
AB  - OBJECTIVE: In France, a preanaesthetic assessment (PAA) several days prior to
      hospital admission for a scheduled surgical or diagnostic procedure under
      anaesthesia, associated with a preanaesthetic visit (PAV) the day before, are
      compulsory. This study aimed at comparing the benefits of PAA with those of a PAV
      not preceded by a PAA. STUDY DESIGN: Prospective, controlled, randomized study.
      PATIENTS: The study included 296 patients undergoing either a urologic, or
      ophthalmologic, or ENT procedure, randomly allocated either to a PAA (followed by
      a PAV) group or a PAV (without previous PAA) group. METHODS: The main criterion
      of comparison was the duration of preanaesthetic hospital stay and the secondary
      criteria were the incidence of procedure postponements and patients' satisfaction
      respectively. RESULTS: In the PAA group, the preanaesthetic hospital stay was
      shorter by 0.4 days (P = 0.001). Out of the 19 postponed procedures (7%), the
      cause of postponement was a medical one in 15 patients: 13 in the PAV group and 2
      in the PAA group respectively (P = 0.009). The PAA was not considered as a
      constraint by most patients. CONCLUSION: The PAA shortens the duration of
      preanaesthetic hospital stay and decreases the incidence of procedures postponed
      for a medical cause.

PMID- 10575500
TI  - [A scale of perioperative satisfaction for anesthesia. I--Construction and
      validation].
AB  - OBJECTIVE: To develop and to validate a scale assessing perioperative patient's
      satisfaction with anaesthesia (Evan). STUDY DESIGN: Descriptive and evaluative
      study. PATIENTS: The study included 742 adults undergoing a surgical or a
      diagnostic procedure under general anaesthesia. Emergency, ambulatory and
      obstetrical cases were excluded. METHODS: A multidisciplinary working party
      produced 85 questions focusing on various pertinent areas describing
      satisfaction. After a validation, 25 out of them were selected for the
      questionnaire. The latter was completed within the 24 hours following anaesthesia
      by 742 inpatients. RESULTS: Item analysis showed a homogeneous distribution of
      the answers to each item. Main component analysis allowed to explain 53% of total
      variance. Six dimensions were isolated by the exploratory analysis: anxiety,
      embarrassment, fear, pain-discomfort, information and physical needs. Scoring
      method followed a simple additive model: for each dimension, the scale scored 0
      100. The global score represented the sum of the six dimensions also scored 0
      100. Acceptability of Evan questionnaire was satisfactory, with a spontaneous non
      response rate of less than 1% and a completion duration at 11 +/- 8 min.
      CONCLUSION: A self-completed questionnaire on patient's satisfaction with
      anaesthetic period was validated, allowing a global and multidimensional
      assessment of patient's satisfaction.

PMID- 10575501
TI  - [A scale of perioperative satisfaction for anesthesia. II--Preliminary results].
AB  - PURPOSE: To assess the patient's experience of anaesthesia in the early
      postoperative period, with a self-completed questionnaire (Evan). STUDY DESIGN:
      Descriptive and evaluative study. PATIENTS: The study included 742 adults
      undergoing an elective surgical or non surgical procedure under anaesthesia.
      METHODS: An Evan questionnaire with 25 questions was completed 24 hours after
      anaesthesia by the patient. The questionnaire explored six areas, each one being
      marked out from 0 to 100, as the visual analogue scale. The marks were compared
      with consideration of age, gender, ASA physical class, type of anaesthesia,
      anaesthesia duration and type of surgery. RESULTS: The mean global mark was 76 +/
      9 (min-max: 34-99). Marks were lower in the youngest patients, in females, in
      ASA 1 patients, in longest surgical procedures, especially with regard to areas
      belonging to "apprehension", "pain-discomfort" and "physical needs". The lowest
      mark was given for the "information" provided during the pre-anaesthetic
      evaluation. Differences in marks occurred also between surgical specialities.
      CONCLUSION: The Evan questionnaire is a valuable tool for assessing the patient's
      opinion on the perioperative period. Further studies are required to extend its
      use to other fields, as ambulatory surgery.

PMID- 10575502
TI  - [Mechanisms of opioid tolerance and opioid dependence].
AB  - OBJECTIVE: Prescription of opiates to non cancer chronic pain patients is
      controversial, partly because of the risk of tolerance and dependence
      development. The two objectives of that review were: a) to identify the factors
      which may explain the variability of tolerance and dependence in clinical
      practice; b) to analyse the cellular mechanisms of occurrence of those
      phenomenons. DATA SOURCES AND EXTRACTION: To our own file, we added articles
      retrieved in the Medline database, using, alone or in combination, following key
      words (opiate, tolerance, dependence, opiate receptor, pain treatment, cAMP,
      cGMP, NO, NMDA, protein kinase, gene). Out of nearly 450 articles, we selected
      less than 200. DATA SYNTHESIS: Tolerance, defined as loss of opioid efficacy with
      time, is extremely variable and depends on pain mechanisms, intrinsic efficacy
      and administration modality of the opioid, as well as co-administration of other
      agents. Physical dependence is a consequence of the intrinsic and extrinsic
      adaptations concerning structures as locus coeruleus, paragigantocellular
      nucleus, spinal cord. Acute and chronic application of opiates and withdrawal
      give rise to cellular adaptations which depend on the nature and efficacy of the
      opiate, the type of receptor and second messengers, as well as the type of cell
      line under study. These cellular mechanisms have consequences on neuronal
      excitability and gene expression. They constitute a model of cellular tolerance
      and dependence, but cannot explain the subtelties encountered in clinical
      practice.

PMID- 10575503
TI  - [Severe anaphylactic reactions after administration of rocuronium].
AB  - The authors report four cases of severe anaphylactic reactions (grade III or IV)
      to rocuronium bromide. In three of them, it was the first contact with a muscle
      relaxant. In three patients the reaction was mediated by IgE anti-bodies. A cross
      reactivity with other muscle relaxants was existing in two cases (suxamethonium,
      vecuronium and atracurium in one patient, suxamethonium, vecuronium and
      pancuronium in the other.

PMID- 10575504
TI  - [Latex allergy: diagnostic pitfalls].
AB  - A 44-year-old woman, native of Martinique, with a history of multiple allergies
      and severe asthma, sustained an unexplained cardiovascular collapse during
      surgery under general anaesthesia. The patient recovered normally.
      Postoperatively, neither additional explorations were undertaken nor informations
      given to the patient. Later on she had to undergo cholecystectomy. Data obtained
      from preanaesthetic assessment (history, analysis of medical files) were in
      favour of a past intraoperative allergic accident. Allergological tests confirmed
      a latex allergy. This case substantiates the importance of a careful
      preanaesthetic consideration of patient's history and the value of a systematic
      allergologic exploration after an unexplained intraoperative event compatible
      with an anaphylactoid reaction. All such events should be clearly explained and a
      written document handed to the patient.

PMID- 10575505
TI  - [Anaphylactic shock after a test-dose of aprotinin in pediatric orthopedic
      surgery].
AB  - A case of severe anaphylactic shock in a 28-month-old child following a testing
      dose of aprotinin during major orthopaedic surgery is reported. Two months
      earlier, aprotinin had been administered during a similar controlateral surgical
      procedure. The grade III anaphylactic accident required a 48 h treatment in an
      intensive care unit. The outcome was favourable. The pin-prick tests were
      positive for aprotinin, substantiating the diagnosis of anaphylactic shock,
      whereas the test with specific IgE was negative. The value of current diagnostic
      tools for aprotinin allergy is discussed. The administration of a testing-dose in
      a patient previously treated with aprotinin cannot be recommended. Considering
      the risk for allergy, aprotinin should only be administered for recognized
      indications such as major orthopaedic surgery. Before any readministration of
      this agent an assessment by an allergist-anaesthetist is essential for
      determination of the risk-benefit ratio.

PMID- 10575506
TI  - [Tracheal rupture initially masked by accidental bronchial intubation].
AB  - We report a case of tracheal rupture complicating a blunt chest trauma. As the
      endotracheal tube had been inadvertently inserted into the right bronchus,
      tracheal rupture was only suspected when increasingly severe subcutaneous
      emphysema occurred after mobilization of the tube. Bronchoscopy confirmed the
      diagnosis. After surgical repair of the lesion the outcome was uneventful.
      Tracheal rupture is an uncommon lesion. All physical and radiological symptoms
      provide useful diagnostic orientation. In the patient of our case report,
      inadvertent bronchial intubation made artificial ventilation possible and
      probably prevented lethal outcome.

PMID- 10575507
TI  - [Intubation using a submental approach].
AB  - Authors report a case of sub-mental approach for endotracheal intubation in
      maxillo-facial surgery. This unusual technique was simple to perform and remained
      uncomplicated.

PMID- 10575509
TI  - [A 5th "therapeutic window" has been opened].

PMID- 10575508
TI  - [Delay in post-anesthetic recovery in neurosurgery: which diagnostic imaging?].

PMID- 10575510
TI  - [Use in the emergency service of short shielded catheters].

PMID- 10575511
TI  - [Laryngoscopy: prevention of contamination of the blade using a condom or a
      plastic bag].

PMID- 10575512
TI  - Is the Singapore-Malaysia Congress of Medicine relevant in an age of
      specialisation?

PMID- 10575513
TI  - 14th Gordon Arthur Ransome Oration: continuity and change.

PMID- 10575515
TI  - 1998 Distinguished Academician Lecture: hepatic resection--a Western perspective.
AB  - During the past two decades, resection of the liver has progressed from a rarely
      to a commonly performed operation with a low morbidity and mortality. The
      description of the functional anatomy of the liver was instrumental in the change
      from non-anatomic to anatomic resections. Major hepatectomies dominated the early
      experience but segment orientated resections now play a more prominent role.
      Resections may be performed for a variety of malignant or benign lesions or as an
      emergency for trauma or other catastrophic event. In the author's institution,
      923 liver resections have been performed. The indications for the 825 elective
      resections were: metastases (46%), primary malignancy (30%) and non-malignant
      disease (24%). Two-thirds of the 98 emergency hepatectomies were for severe liver
      trauma. The 30-day mortality was 3.6% for the total series; 2.9% for elective
      resection, 1.6% for the non-jaundiced patients. In the last 300 elective
      resections, there has been one postoperative death and the median blood
      transfusion was zero. The development of innovative graft reduction techniques
      has made a major contribution to liver transplantation. The lack of suitable
      whole liver grafts for paediatric recipients was addressed by volume of reduction
      of adult donor livers so that the left lateral segment could be implanted safely
      in an infant's abdomen. This technique was the forerunner of split-liver
      transplantation, auxiliary partial orthotopic transplantation and living-related
      liver transplantation.

PMID- 10575514
TI  - 1998 Runme Shaw Memorial Lecture: somatic evolution of cancer.
AB  - The interpretation of cancer as a somatic evolutionary process involving genetic
      mutation followed by selection, traces its origins to the early years this
      century. The dramatic developments in molecular genetics have substantiated these
      early ideas. Through the application of positional cloning and genomic analysis,
      many mutations in particular genes, both dominant oncogenes and tumour suppressor
      genes have now been found in a wide variety of tumours. Other genetic events such
      as non-disjunction leading to haploid expression of a gene and so reduced gene
      dosage, or epigenetic changes following, for example, changes in methylation
      patterns leading to reduced or increased gene expression, may also play critical
      roles in the progression of a cancer. The analysis of mutations at different
      stages of colorectal cancer provides a good model for following the initiation
      and progression of a cancer. Mutations in the APC gene, which explain familial
      adenomatous polyposis, occur in a high proportion of sporadic colorectal
      carcinomas and appear to be the earliest known changes. Patterns of mutation in
      the gene suggest dominant negative or gain of function effects, and also reveal
      important low penetrance subpolymorphic missense mutations that nevertheless may
      have a very significant impact on the genetic contribution to colorectal cancer
      susceptibility. Mutations are also found in related genes in the APC pathway,
      such as beta-catenin and E-cadherin. Mutations in mismatch repair genes (hMLH1
      and hMSH2) have also been shown to occur, as well as reduced expression due to
      methylation changes, in 10% to 20% of sporadic colorectal carcinomas. In
      addition, mutations in the well known oncogenes p53 and ras are commonly found.
      The growth of a cancer is a balance between the rate of cell division and the
      rate of cell death or apoptosis. Thus, genetic changes which reduce the
      probability of apoptosis, such as p53 and probably hMLH1, are as important a
      feature of the evolution of a cancer as those which enhance the independence
      (APC) and rate of cell division (growth factors). Simple models for the evolution
      of a cancer that take into account these two processes, show that cancers evolve
      initially by a series of finite increases in cell population size, following
      which there may be long periods of cell turnover during which there is an
      opportunity for further mutation and selection. This explains the long lag
      periods between the initiation and subsequent progression of most cancers. Our
      rapidly developing understanding of cancers at the fundamental genetic level
      provides new opportunities for developing targeted treatments, as well as novel
      approaches to prevention and early detection.

PMID- 10575516
TI  - 9th Chapter of Surgeons' Lecture: the orthopaedic surgeon: historical
      perspective, ethical considerations and the future.
AB  - From a fishing village with colonial surgeons from the East India Company,
      Singapore is now a medical and business hub servicing the region and beyond in
      trade and medical education. Orthopaedic Surgery is a young specialty and is the
      fastest growing sub-specialty in Surgery. Orthopaedic education in Singapore has
      a structured syllabus and training is coordinated with the Royal Colleges and the
      American Academy of Orthopaedic Surgeons. Part of the training as Fellows is in
      the United Kingdom and USA on an HMDP Fellowship. Ethics and Continuing Medical
      Education need further emphasis. Sub-specialisation in Orthopaedic Surgery is now
      well-established in Trauma, Adult Reconstructive Surgery, Sports Medicine, Spinal
      Surgery, Hand Surgery and Rehabilitation Medicine. Ageing in the next millennium
      with osteoporosis and hip fracture problems of gait and balance need more
      orthopaedic surgeons to be committed to rehabilitation medicine and voluntary
      service in the community. There is a need for good role models and knowledge on
      Quality Assurance, Clinical Pathways and Administration. Appropriate use of high
      technology and care for the aged in the community with dignity is fundamental to
      good ethical practice. Selfish, pecuniary interests will destroy the very soul
      and fabric of medicine.

PMID- 10575517
TI  - 3rd Yahya Cohen Lecture: the role of the myofibroblast-like cell in
      hepatocellular carcinoma--host defence?
AB  - Hepatocellular carcinoma is a common cancer in Asia with a poor prognosis. Tumour
      encapsulation has been shown to be a good, independent prognostic factor. The
      main cell in the liver responsible for extracellular matrix formation is the
      hepatic stellate cell, and this was investigated as the cell type responsible for
      encapsulation. This lecture discusses the role of hepatic stellate cells in
      hepatocellular carcinoma, in particular with tumour encapsulation as a host
      defence mechanism. The study involved four phases: (1) comparing encapsulated
      tumours with non-encapsulated tumours, (2) comparing with metastatic tumours to
      the liver, (3) creation of an animal model, and (4) investigating known cytokines
      with hepatic stellate cell stimulating activity. The results showed that the
      hepatic stellate cells were responsible for tumour encapsulation and that this
      was impaired in non-encapsulated tumours and in metastatic tumours. A successful
      animal model was created which allowed further work. However, the known cytokines
      that normally stimulate hepatic stellate cells were not shown to be involved in
      tumour encapsulation, suggesting that an unknown factor may be involved.

PMID- 10575518
TI  - 8th Seah Cheng Siang Memorial Lecture: new antithrombotic agents.
AB  - For the long-term prevention of thromboembolic events in patients with
      atherosclerotic vascular disease, aspirin is the preferred antiplatelet drug.
      Only clopidogrel was shown to be more effective and at least as safe than medium
      dose aspirin in direct comparative large-scale trials. Aspirin inhibits the
      cyclooxygenase dependent pathway of platelet aggregation while ticlopidine and
      clopidogrel selectively bind to adenosine diphosphate (ADP) receptors on the
      platelet surface. Compounds which inhibit the synthesis of thromboxane synthase,
      block the thromboxane receptor or have the dual activity were effective in
      experimental thrombosis models in animals but not predictive of results in
      humans. Activation of the platelet glycoprotein (GPIIb/IIIa) receptor on the
      platelet surface is the final pathway of platelet aggregation, regardless of the
      initiating stimulus. Inhibitors of GPIIb/IIIa receptors include monoclonal
      antibodies (abciximab) against this receptor and peptidic as well as non-peptidic
      synthetic specific receptor blockers. Abciximab exchanges between and binds to
      platelets for as long as two weeks whereas synthetic GPIIb/IIIa inhibitors
      inhibit ex vivo platelet aggregation for only a few hours after the end of
      infusion but have the advantage of being also orally active. In the secondary
      prevention of atherothrombosis, large scale trials were successfully conducted
      with aspirin, dipyridamole and clopidogrel. In the first large-scale trials with
      GPIIb/IIIa inhibitors with abciximab was investigated. In aggregate, this class
      of platelet inhibitors, combined with aspirin and heparin, was shown to reduce
      ischaemic events in patients with high- and low-risk coronary intervention,
      stents, unstable angina and non-Q-wave infarction with long-term preservation of
      the initial benefit. With synthetic GPIIb/IIIa inhibitors there is no suppression
      of clinical evident restenosis 6 months after the end of treatment. With the
      doses presently used, bleeding occurs more often with the synthetic GPIIb/IIIa
      inhibitors (used for 3 days) than with abciximab (used for 12 hours) but there
      are no direct comparisons between these drugs.

PMID- 10575519
TI  - Young Investigator's Award: induction of apoptosis following traumatic head
      injury in humans.
AB  - Apoptosis or programmed cell death plays an important role in many developmental
      and pathological processes of the central nervous system. In head injury,
      apoptosis has been recently implicated in many studies on animal brain samples
      the phenomenon of apoptotic gene expression (bax and bcl-2). Twenty specimens of
      contused brain tissue (temporal and frontal lobe) from 20 patients who underwent
      emergency craniotomy and removal of mass lesions were obtained from May to
      October 1997. The samples collected were immediately snap frozen in liquid
      nitrogen and stored at -80 degrees C. Immunohistochemical analysis was performed
      to detect the expression of bcl-2, bax and p53 using standard avidin-biotin
      complex second antibody conjugate methodology utilising commercially available
      primary and secondary antibodies. The average age of cohort was 46.24 +/- 22.17
      years, the average Glasgow Coma Scale on admission was 9.19 +/- 4.72, and the
      average duration from injury to collection of the sample was 20.62 +/- 40.57
      hours. There was documented hypoxia and hypotension seen in 5 of the 20 patients
      (25%). Significant levels of bax protein expression were noted in all samples,
      and p53 expression in 30% of samples. No bcl-2 expression was observed. Our study
      showed that for the first time the strong expression of the pro-apoptotic gene
      (bax) and low levels of the anti-apoptotic gene (bcl-2), thus implicating the
      mechanism of apoptosis in brain injury following trauma. The use of agents to
      inhibit apoptosis may be beneficial in head injury patients.

PMID- 10575520
TI  - Magnetic resonance cholangiopancreatography: value of using the half-Fourier
      acquisition single-shot turbo spin-echo (HASTE) sequence.
AB  - The purpose of this study was to evaluate the accuracy of magnetic resonance
      cholangiopancreatography (MRCP) for visualisation and diagnosis of pancreatico
      biliary diseases. Our results of 35 case studies, correlating with results from
      endoscopic, percutaneous cholangiopancreatography or laparotomy, showed that MRCP
      performed using the half-Fourier acquisition single-shot turbo spin echo (HASTE)
      sequences was fast and accurate for depiction of the biliary and pancreatic
      system, with a diagnostic value comparable to that of direct cholangiography. The
      presence of biliary obstruction was accurately diagnosed in all but one patient.
      In hilar strictures, MR cholangiogram was able to depict the intrahepatic biliary
      tree proximal to the level of obstruction which was not readily displayed by
      endoscopic retrograde cholangiopancreatography (ERCP) (Figs. 1 & 2). This
      overview of the entire biliary system was found to be advantageous for
      preprocedural planning. However, the accuracy for stone detection was limited by
      the presence of aerobilia from previous sphincterotomy or biliary-enteric
      anastomosis. Ductal stones less than 3 mm in size within a non-dilated system may
      be missed due to inadequate spatial resolution. This occurred in a patient with
      pancreatic duct stones. It is hoped that the accuracy of HASTE magnetic resonance
      cholangiopancreatography in evaluation of pancreatico-biliary disease would
      obviate the need for diagnostic invasive cholangiography in selected patients.

PMID- 10575521
TI  - Swallowing impairment and feeding dependency in the hospitalised elderly.
AB  - A prospective study was carried out to determine the prevalence of swallowing
      impairment and feeding dependency in an acute geriatric medicine unit in
      Singapore and the co-morbidity associated with it. A total of 211 patients were
      assessed over a 3-month period. Only 7.1% of patients gave a history of
      swallowing impairment prior to hospitalisation. We found that 29.4% of patients
      on admission and 28.2% on discharge had swallowing impairment, with a mortality
      of 8.1%. The prevalence of feeding dependency, as defined by the need for feeding
      assistance or tube feeding, was 26.5% before admission and 27.8% on discharge.
      The mode of feeding between the time of admission and discharge was changed in
      14.9% of patients in response to the evolving medical condition. Swallowing
      impairment was significantly associated with the presence of dehydration (RR =
      2.82, CI = 1.74-4.57), chest infection on admission (RR = 2.85, CI = 1.85-4.41),
      development of nosocomial chest infection (RR = 6.75, CI = 2.60-17.5), discharge
      to institutional care (RR = 2.8, CI = 1.51-3.47) and increased mortality (RR =
      3.77, CI = 1.45-9.70). We concluded that swallowing impairment and feeding
      dependency are common in the elderly admitted to an acute geriatric unit. As
      elderly patients seldom inform clinicians of any underlying swallowing impairment
      and in view of the increased morbidity and mortality associated with this
      disability, it is important to screen for swallowing impairment. The high
      prevalence of feeding dependency adds to the burden of care in the ill elderly.

PMID- 10575522
TI  - Perceived need for community geriatric services: a survey at a regional hospital
      in Singapore in an inpatient setting.
AB  - Our primary aim was to study the need for community services as perceived by the
      elderly and their relatives. A secondary objective was to determine the
      predictive factors of need for these services. This is a survey of 115
      consecutive non-institutionalised patients admitted to a hospital geriatric
      department and their relatives. Twenty-seven elderly patients without cognitive
      impairment and 115 relatives were interviewed as to their need for community
      services after discharge. Services most needed by patients were: 24-hour medical
      helpline (33%), emergency alarm system (19%), social helpline (14%) and day care
      centre (13%). Services most needed by relatives were: 24-hour medical helpline
      (70%), emergency alarm system (40%), home visits by doctors (40%), respite care
      (35%), day care centre (35%) and transport service (33%). There were low levels
      of need for home help service, meal delivery service and the befriender service.
      Important predictive factors of need were: low ECAQ (Elderly Cognitive Assessment
      Questionnaire) score, low Barthel score, and absence of a carer. The development
      of community geriatric services in Singapore should be guided by the perceived
      needs of the elderly and their relatives/care-givers. This study is limited by
      its hospital-based perspective and small numbers. We recommend that further
      community-based studies be carried out to complement our study and extend our
      findings.

PMID- 10575523
TI  - Long-term outcome and disease control in near-fatal asthma.
AB  - Patients who have survived an episode of intubation and mechanical ventilation
      for acute respiratory failure due to a severe and unresponsive asthmatic attack
      are considered to have experienced a near-fatal asthma (NFA) attack. Such
      patients are at a higher risk of similar severe attacks and hence of death in the
      future. The aims of the study were to: (i) evaluate the outcome; (ii) identify
      any persistent deficiencies in asthma management, and (iii) assess self
      management knowledge in survivors of NFA. Ninety-three consecutive patients who
      had been treated for NFA in the Intensive Care Unit of an urban teaching hospital
      in Singapore from 1992 to 1997 were studied. All hospital records were reviewed
      retrospectively. Survivors were then invited to attend a questionnaire interview
      and to have lung function tests performed. Of the original cohort (OC) of 93
      patients with NFA (mean age 55.2 years), 18 (19% OC) patients (mean age 64 years)
      had died while in hospital and 75 (81% OC) patients survived the initial episode
      of NFA and were discharged home (DH). The long-term outcome of this DH group was:
      13 patients had died (17% DH) and 62 (83% DH) survived. Of these survivors, 35
      were interviewed while 27 declined or were not contactable. This interview
      yielded the following information: (i) Hospitalisation in the past year: 66% had
      no hospital admission; of the 31.4% who had 2 or more admissions, most had a
      further NFA attack. (ii) Health care: The majority of patients (71.4%) were
      monitored by a single doctor. (iii) Patient knowledge of disease management was
      deemed good to fair for trigger avoidance (77%), for appropriate drug usage
      (97%). (iv) Satisfactory inhaler skill (80%). NFA is associated with a high
      intrahospital and long-term mortality. Although most survivors of NFA appeared to
      have satisfactory care and a fair understanding of medication usage, a
      significant minority continue to pose much morbidity and risk for death.

PMID- 10575524
TI  - Hospitalised low-risk community-acquired pneumonia: outcome and potential for
      cost-savings.
AB  - Fine et al. from USA have identified a sub-group of patients with community
      acquired pneumonia (CAP) with a low risk of mortality and suggested that it may
      be cost-effective to manage them as outpatients. The aims of this study were: to
      evaluate the outcome of low risk CAP patients that were hospitalised in our local
      setting, and to gauge the number of such patients in order to estimate the
      potential cost-savings by treating them as outpatients, as well as the safety of
      such an approach. All patients with CAP admitted to our hospital from 1 April
      1997 to 1 March 1998 were enrolled into this prospective cohort study. Low-risk
      patients were identified, and their hospital outcome compared with other
      patients. Hospitalisation charges were obtained from the Finance Department.
      There were 226 patients with CAP. The average age was 64 years with a range of 12
      to 96 years. The median hospital stay was 6 days. Mortality was 13.7%. 16.8%
      required admission to the ICU; none of these were low-risk patients. There were
      47 (21%) low-risk patients, and there was no mortality in this group. They had
      significantly shorter hospital stay (6.4 days versus 10 days) and lower
      hospitalisation charges ($2,160 versus $5,770) compared to other CAP patients.
      Only one low-risk patient had a positive blood culture. In conclusion, nearly one
      fifth of our CAP admissions consisted of low-risk patients that experienced no
      mortality, and required a significantly shorter hospitalisation. The management
      of such patients who are young (< or = 50 years), with no serious co-morbidities
      in an outpatient setting may be a cost-effective strategy, and this group of
      patients consumed 9% of the total hospitalisation charges for CAP.

PMID- 10575525
TI  - A preliminary study of the immunohistochemical detection of a novel tumour
      marker, 22-1-1 antigen, in gynaecological cancer specimens.
AB  - A novel tumour associated antigen, 22-1-1, has been recently described in
      association with a cervical adenocarcinoma cell line. The aims of this paper were
      to study the tissue distribution of this antigen in sections of gynaecological
      cancer specimens and to compare it with negative controls. Six cases of cervical
      cancers, 5 cases of endometrial cancers, 4 cases of ovarian cancers and 5 cases
      each of normal endometrium and cervix were studied. Immunohistochemical staining
      using streptoavidin-biotin methodology was used for each tumour specimen. This
      revealed positive staining for the 22-1-1 antigen in 5 out of 6 cases of cervical
      cancer, 3 out of 5 cases of endometrial cancers, and all 4 cases of ovarian
      mucinous cystadenocarcinomas. Importantly, the antigen was expressed in the
      cytoplasm, cell membrane and glandular lumen of adenocarcinoma cells. The 22-1-1
      antigen was not detected in normal uterine tissues except in uterine cervix, in
      which its expression was observed at low levels. This study shows that the 22-1-1
      antigen was expressed in cancer cells derived from the uterus, cervix and the
      ovary and may be a potential tumour marker in the management of gynaecological
      cancer patients.

PMID- 10575527
TI  - Acoustic neuroma: outcome of surgical resection and study on the anatomy of
      facial and cochlear nerves.
AB  - The treatment of acoustic neuroma (vestibular schwannoma) has evolved greatly. In
      this report, we studied the history of acoustic tumour surgery, and documented
      the value of technical advances in benefiting patients. We also present our
      outcome of surgery for this benign tumour in support of its use as the treatment
      of choice. In 611 patients undergoing initial surgery at Johns Hopkins from 1973
      1994, complete resection was obtained in all but one case (intentional), and
      permanent morbidity and mortality rate was 0.3%. Including temporary morbidity,
      the rate was 3.8%. Tumour recurrence was seen in only 0.8% of cases. The facial
      nerve was preserved in 97.6% and function at one-year was House-Brackmann grade 1
      or 2 in 89.7%. Lastly, we present results of an anatomical study localizing the
      nerves and vessels, and the frequency of involvement by tumour, associated with
      acoustic neuromas in 1006 surgical cases. We continue to offer surgery as the
      best treatment option for the majority of our patients, and prefer the
      suboccipital route because of its unrestricted access to all posterior fossa
      structures, and ability to preserve hearing.

PMID- 10575526
TI  - Trends in mortality, incidence, hospitalisation, cardiac procedures and outcomes
      of care for coronary heart disease in Singapore, 1991-1996.
AB  - In this study, we used Singapore population-based data from 1991 to 1996 to
      examine recent trends in mortality, incidence and hospitalisation for acute
      myocardial infarction (AMI), and explored the roles of primary prevention and
      medical care interventions in explaining these trends. We examined trends in
      medical interventions, namely coronary angiography (catheterisation), coronary
      artery bypass graft (CABG), and percutaneous transluminal coronary angioplasty
      (PTCA), length of stay, and payment methods, and explored the roles of
      technological, healthcare financing and delivery, and regulatory factors in
      influencing the diffusion and outcomes of these medical interventions. During the
      period 1991 to 1996, there were parallel declines in resident population rates of
      mortality, incidence and hospitalisation for AMI. The rates of angiograms, CABG
      and PTCA among residents also increased greatly, with the greatest increase among
      elderly aged 60 years and above. The rates of invasive cardiac procedures for AMI
      were all lower in females than in males. The population case-fatality rate of AMI
      declined slightly only for persons below 40 years of age. The case-fatality rate
      was higher in females than in males. The number of hospitalisations and cardiac
      procedures all rose sharply, and was phenomenal for PTCA (247%). The increase in
      volume of resource use was starkly greater in private hospitals than in
      restructured hospitals. The ratios of PTCA to CABG from 1991 to 1996 for private
      and restructured hospitals showed a greater rate of technology substitution in
      restructured hospitals than in private hospitals. The average length of stay
      (LOS, 6.7 days) was fairly constant in restructured hospitals. For private
      hospitals, LOS declined from 7.6 days in 1991 to 5.6 in 1996. LOS varied little
      among individual restructured hospitals, but widely among private hospitals. The
      most common method of payment for AMI hospitalisation was Medisave alone (50%),
      but for CABG surgery, the proportion of payment made through this method was only
      12%. Out-of-pocket payments, Medisave, Medishield and private insurance have
      increased steadily. These data indirectly suggest that primary prevention and
      medical care interventions might have begun to succeed in reducing the rates of
      coronary heart disease in Singapore. The sharp increases in cardiac procedures
      may be explained by changing supply and demand factors for care of AMI and
      chronic ischaemic heart disease, including consumer preference for cardiac
      procedures, overuse of medical intervention, and technological change. More
      studies are needed to test these hypotheses.

PMID- 10575528
TI  - Cancer gene therapy--fantasy or foresight?
AB  - Gene therapy is an exciting new method of treatment that may have far-reaching
      implications on the way we manage diseases in the future. Cancer has become the
      principal focus of this futuristic research. The breathtaking pace of gene
      discovery in the last two decades, coupled with the birth of recombinant DNA
      technology, gave rise to the concept that genes may be manipulated and used as
      drugs. Genetic modification of cells can be carried out in petri dishes (ex vivo)
      or within the living system (in vivo). In order for the therapeutic genes to
      exert their effect, they have to be transported into the cell nucleus where
      transcription takes place. Liposomes and genetically modified viruses have been
      extensively used as gene vectors. The ideal vector remains elusive. It would be
      one that can achieve tumour-specific, sustained, and regulatable gene expression
      without host toxicity. As a result of the past decade of intense gene therapy
      research, we have learned that it is a rational scientific concept that works
      remarkably well in petri dishes and in laboratory animals. However, early
      clinical gene therapy experimentations paled in comparison. This apparent
      disparity between dramatic preclinical successes and the very modest clinical
      results of gene therapy does not in anyway nullify the concept of gene therapy.
      Instead, it exposes the folly of underestimating the technical complexity of gene
      manipulation in human diseases. Fortunately, technical hurdles such as those
      confronting gene therapy today are not insurmountable; they need, however, much
      ingenuity, resolution and time to be overcome. It is reassuring that recent
      advances in gene therapy provide abundant evidence that the premature infant,
      born of unrealistic pressure, is indeed healthy and thriving. With proper
      nurturing and patience, there is no doubt that, in time, it will bear fruit.

PMID- 10575529
TI  - Diagnosing and managing faecal incontinence.
AB  - The aim of this review was to consolidate the impact of recent advances in
      investigation technology on the clinical diagnostic workup for faecal
      incontinence. A literature search was made with emphasis on the recent 15 years.
      The advent of imaging techniques, particularly endoanal ultrasound has improved
      the understanding of anal incontinence. Of particular significance was the much
      higher incidence of anal sphincter injuries after childbirth, than previously
      suspected. Also important was the clarification of the entity of primary
      degeneration of the internal anal sphincter. Although endoanal ultrasound
      provides clear images of anal sphincter defects to guide surgery, some of these
      defects may be false positive findings especially for the inexperienced. Thus,
      anal manometry is still required to correlate imaging with functional impairment.
      Recent data have questioned the correlation of poor surgical outcome after
      sphincter repair with pudendal nerve dysfunction. Although poor pudendal function
      is no longer considered a contraindication for surgery, longer term follow-up
      studies have shown that the late results are poorer probably due to other factors
      such as poorer tissue associated with nerve dysfunction. Furthermore, new
      treatment modalities such as the electrostimulated gracilloplasty, artificial
      anal sphincter, sacral nerve modulation and autologous fat injection into the
      anal mucosa will require detailed precise diagnosis of faecal incontinence such
      that the most suitable technique may be successfully employed.

PMID- 10575530
TI  - Newer thrombolytic agents.
AB  - Several lines of research towards improvement of thrombolytic agents are being
      explored, including the construction of mutants of plasminogen activators,
      chimeric plasminogen activators, conjugates of plasminogen activators with
      monoclonal antibodies, and plasminogen activators from animal or bacterial
      origin. Some of these new thrombolytic agents have shown promise in animal models
      of venous or arterial thrombosis; only those which are being investigated in
      clinical studies are briefly discussed. Monteplase is a modified tissue type
      plasminogen activator (t-PA) constructed by substituting only one amino acid in
      the epidermal growth factor domain (Cys84-->Ser) and expressed in baby Syrian
      hamster kidney cells. It has a prolonged half-life of more than 20 min, as
      compared to 4 min for native t-PA. TNK-t-PA differs from t-PA by 3 mutations.
      This mutant has increased thrombolytic potency, slower clearance and enhanced
      resistance to the inhibitor PAI-1. Reteplase is a non-glycosylated deletion
      mutant of wild-type human t-PA which contains only kringle 2 and the protease
      domain but lacks its kringle 1 and the finger and growth factor domains. The
      structural changes in reteplase translate into a decreased fibrin binding, a
      lower affinity to endothelial and liver cells resulting in an extended half-life.
      Lanoteplase is a deletion mutant of t-PA with a half-life that is circa 10 times
      greater than alteplase, making it suitable for single bolus injection. YM866 is
      another mutant of t-PA in which the aminoacids 92 to 173 of kringle 1 were
      deleted and arginine275 replaced by glutamic acid which confers a longer half
      life to the mutant. Recombinant glycosylated prourokinase has a greater stability
      than recombinant unglycosylated pro-urokinase, is rapid acting and safe in the
      clinical doses used. Staphylokinase (SAK) is produced by Staphylococcus aureus.
      It induces efficient and rapid recanalization, also after bolus injection, but is
      immunogenic. There are only a few large scale clinical trials published directly
      comparing fibrin-selective thrombolytic drugs. In patients with acute myocardial
      infarction, reteplase, administered in bolus injections, is associated with a
      similar mortality and bleeding rate as front loaded t-PA. Bolus TNK-t-PA has a
      similar incidence of cerebral bleeding as front loaded t-PA and is associated
      with the same survival rate after acute myocardial infarction in a large
      mortality trial.

PMID- 10575532
TI  - Retrospective study of Behcet's disease seen at the National Skin Centre,
      Singapore.
AB  - This retrospective study characterises the clinical manifestations and outcome of
      34 patients diagnosed with Behcet's disease seen at the National Skin Centre from
      1990 to 1997. The 2 diagnostic criteria used were the International Study Group
      and the O'Duffy criteria. Seventy-six per cent satisfied both criteria and the
      remaining 24% satisfied only the incomplete form of the O'Duffy criteria. We
      found that the male to female ratio was 1:1.8. The mean age of presentation was
      33 years (range 21 to 63 years). The majority were Chinese (73%). In our series,
      patients had prominent mucocutaneous involvement. These findings may be
      attributed to patient selection to a tertiary dermatology clinic. Oral (100%) and
      genital (99%) ulceration were the 2 commonest symptoms. The other cutaneous
      features included papulo-pustular or acneiform eruption (26%), erythema nodosum
      (14.7%) and positive pathergy test. Five patients (15%) had arthritis, 1 patient
      had recurrent thrombophlebitis and 2 patients had eye complications. The outcome
      of our patients was generally good with minimal functional impairment and no
      mortality detected. Our patients were primarily outpatient referrals and this may
      explain why systemic complications were rare in our series.

PMID- 10575531
TI  - Controversies in anaesthesia--designer drugs.
AB  - In the past, the discovery of new drugs often occurred by chance. Over recent
      years, an increasing knowledge of the mode of drug action and receptor sites has
      improved our ability to design new drugs. While the mode of action of volatile
      and intravenous anaesthetic agents remains unclear, neuromuscular blocking agents
      and opioids have undergone considerable development and design. Drugs are being
      tailored to produce fewer side effects and to improve desirable properties. As a
      result, the introduction of new drugs has helped to improve techniques in
      anaesthesia. The development of remifentanil is an example of this which is
      discussed. The application of modern technology with target controlled infusions
      (TCI) for the administration of remifentanil represents further advancement in
      techniques which may become available to anaesthetists in the future.

PMID- 10575533
TI  - Measurement of obesity by anthropometry and bioelectric impedance analysis:
      correlation with fasting lipids and insulin resistance in an Asian population.
AB  - Obesity is associated with increased coronary artery disease risk. This is at
      least partially mediated by increased prevalence of other risk factors such as
      dyslipidaemia and insulin resistance. Various anthropometric indices have been
      used to quantify generalised and central obesity. Correlations between these
      measurements and risk factors are specific to the population and findings cannot
      be extrapolated to other ethnic groups. Bioelectric impedance analysis (BIA) is a
      simple means of estimating percentage body fat. We compared body mass index
      (BMI), waist circumference, waist-hip ratio (WHR) and percentage body fat measure
      by BIA as predictors of fasting lipid profiles and insulin resistance in 109
      Singaporean Chinese. BMI was significantly correlated with insulin resistance and
      there appeared to be a threshold at 26 kg/m2 above which the regression line
      became more steep. WHR best predicted fasting triglyceride in both men and women.
      In women, it was inversely correlated with high density lipoprotein cholesterol.
      A similar association was seen in men but this did not reach statistical
      significance. We conclude that measurement of BMI and WHR should be part of the
      assessment of cardiovascular risk in our population as they connote different
      aspects of risk. BIA was not found to be a useful tool for the prediction of
      coronary artery disease risk factors in our population.

PMID- 10575534
TI  - Comparison of first carpometacarpal joint arthrodesis with contralateral excision
      arthroplasty in a patient with bilateral saddle joint arthritis: a case report.
AB  - A post-menopausal patient with bilateral primary osteoarthritis of the first
      carpometacarpal joint (CMCJ) was treated by 2 different surgical techniques. The
      non-dominant left CMCJ was arthrodesed in 1992 while excision of trapezium and
      tendon suspensionplasty was done for the dominant right side in 1997. She
      reported good pain relief with both procedures and she was able to fully oppose
      both thumbs at 6 years after arthrodesis and 1 year after arthroplasty. The grip
      and pinch strength was stronger on the arthrodesed side while hand function tests
      revealed the arthroplasty side to be more dexterous. Subjectively, she preferred
      the right thumb. Radiographs showed no peritrapezial arthritis in the arthrodesed
      CMCJ and no proximal migration of the metacarpal on the reconstructed side. Both
      procedures offered excellent relief of symptoms and she was able to return to
      work as a machine operator.

PMID- 10575535
TI  - T wave alternans and acute rheumatic myocarditis: a case report.
AB  - T wave alternans is an uncommonly recorded cardiac rhythm. We report here an
      unusual case of a 13-year-old girl with acute rheumatic carditis and acute
      nephritis, who developed T wave alternans associated with a prolonged QT
      interval. These electrocardiographic changes were evident only after the initial
      acute stage of the disease process and should be borne in mind for patients with
      acute rheumatic carditis as they may be associated with more malignant
      arrhythmias.

PMID- 10575536
TI  - The development of postgraduate training programmes in Singapore.
AB  - Singapore is a small country compared to Pakistan. Being an urban modern
      developed nation with a high population density, adequate doctors (&
      specialists), and good infrastructure, it has one medical school enrolling 200
      students annually, one Graduate School of Medical Studies (GSMS) responsible for
      entry postgraduate examinations (the M Med) and one Academy of Medicine (AM)
      responsible (jointly with the Graduate School) for exit
      certification/examinations (FAMS) into 35 specialties. There is also one College
      of Family Physicians with a significant role in the training of Family Physicians
      jointly with the Graduate School. The Aga Khan University runs 14 residency (3 to
      4 years) and 2 fellowship programmes. It has the College of Physicians and
      Surgeons of Pakistan, which awards fellowships to trained postgraduate doctors.
      Formal postgraduate education in Singapore began in the 1960s with the help of
      the Australasian Royal Colleges. The Graduate School of Medical Studies was born
      in 1969 to conduct Master of Medicine courses and examinations, either alone or
      jointly with overseas colleges. Over the years up till 1996, the M Med covered 11
      disciplines. Programmes are set up based on local needs for a specialty,
      subspecialty, skill or expertise. Both the GSMS and AM have heavy
      responsibilities under the Specialists Accreditation Board (SAB) of the Ministry
      of Health, to administrate the 35 Specialist Training Committees. Syllabus, log
      books, registers, supervisors, mentors, interviews and exit
      certification/examinations are essential components of the specialist training
      programmes which last 6 to 7 years. As new specialties and subspecialties develop
      internationally, they will be introduced locally at the appropriate time. Through
      the local training programmes, doctors become specialists in their early
      thirties. The challenge is to develop systems to ensure that for the next 30
      years of their practice, they remain up-to-date, competent and effective doctors.

PMID- 10575537
TI  - How does biofeedback reduce clinical symptoms and do memories and beliefs have
      biological consequences? Toward a model of mind-body healing.
AB  - Changes in the magnitude and direction of physiological measures (EMG, EEG,
      temperature, etc.) are not strongly related to the reduction of clinical symptoms
      in biofeedback therapy. Previously, nonspecified perceptual, cognitive, and
      emotional factors related to threat perception (Wickramasekera, 1979, 1988, 1998)
      may account for the bulk of the variance in the reduction of clinical symptoms.
      The mean magnitude of these previously nonspecified or placebo factors is closer
      to 70% when both the therapist and patient believe in the efficacy of the
      therapy. This powerful placebo effect is hypothesized to be an elicited
      conditioned response (Wickramasekera, 1977a, 1977c, 1980, 1985) based on the
      memory of prior healings. These memories of healing are more resistant to
      extinction if originally acquired on a partial rather than continuous
      reinforcement schedule. High and low hypnotic ability in interaction with threat
      perception (negative affect) is hypothesized to contribute to both the production
      and reduction of clinical symptoms. High and low hypnotic ability respectively
      are hypothesized to be related to dysregulation of the sympathetic and
      parasympathetic arms of the autonomic nervous system. Biofeedback is hypothesized
      to be most effective for reducing clinical symptoms in people of low to moderate
      hypnotic ability. For people high in trait hypnotic ability, training in self
      hypnosis or other instructional procedures (e.g., autogenic training, progressive
      muscle relaxation, mediation, CBT, etc.) will produce the most rapid reduction in
      clinical symptoms.

PMID- 10575538
TI  - The third therapeutic revolution: behavioral medicine.
AB  - Behavioral medicine--and one of its progenitors, biofeedback--are expanding as
      the Third Therapeutic Revolution, supplementing surgery and pharmacology in
      treating human illnesses. Parallel development of nonscience-based therapies is a
      part of the same revolution. Labeling their positive results as "placebo effects"
      hides a greater truth: faith and trust play an enormous role in therapy. The
      successes of both behavioral medicine and unorthodox complementary medicine are
      the result of the debonafide effect (my Latin for "from good faith"). Readers are
      urged to adopt this better definition of the "unexplicable" and substantial good
      results of both the placebos in research and the ministration of unorthodox
      treatments.

PMID- 10575539
TI  - Phenotypic characterization of immunomagnetically purified umbilical cord blood
      CD34+ cells.
AB  - This study describes the multilineage differentiation pattern of purified CD34+
      stem cells obtained from human umbilical cord blood. CD34+ cells were collected
      from 49 umbilical cord blood samples. Following immunomagnetic purification,
      cells were double stained with anti CD34 and CD71, CD61, CD7, CD19, CD33, CD36
      and triple stained with anti CD34, CD38 and HLA-DR. Analysis were performed using
      a FACScan flow cytometer. After purification, the mean CD34+ cells' purity was
      85.49 +/- 7.08%. Several subpopulations of umbilical cord blood CD34+ cells were
      identified indicating different lineage commitment. The majority of CD34+ cells
      expressed both CD38 and HLA-DR (91.74 +/- 3.76%), while those lacking CD38 were
      3.43 +/- 2.12% (CD38-DR+) and 1.81 +/- 1.54% (CD38-DR-). These data were compared
      to the expression of lineage commitment markers on purified CD34+ cells from 5
      mobilized peripheral blood samples. The percentage of peripheral blood CD34+CD38
      DR+) and CD34+CD38-DR- cells was significantly lower than umbilical cord blood,
      0.24 +/- 0.18% and 0.04 +/- 0.03% respectively. The knowledge and standardized of
      umbilical cord blood CD34+ cells phenotype is critical since umbilical cord blood
      volume is limited. The homogeneity of CD34+ subpopulation phenotype suggests that
      monitoring of lineage differentiation antigens may not be relevant for clinical
      use of umbilical cord blood samples. However, the observed higher percentage of
      pluripotent CD34+38- stem cells in umbilical cord blood compared to peripheral
      blood, that might explain the successful clinical use of umbilical cord blood
      even when low number of cells are used, candidates these antigens as the
      predictive parameter for clinical use of umbilical cord blood samples.

PMID- 10575540
TI  - Two novel missense mutations of the HFE gene (I105T and G93R) and identification
      of the S65C mutation in Alabama hemochromatosis probands.
AB  - Sequencing of HFE exons 2, 3, 4, and 5, and of portions of introns 2, 4, and 5
      revealed novel mutations in four of twenty hemochromatosis probands who lacked
      C282Y homozygosity, C282Y/H63D compound heterozygosity, or H63D homozygosity.
      Probands 1 and 2 were heterozygous for previously undescribed mutations: exon 2,
      nt 314T-->C (314C; I105T), and exon 2, nt 277G-->(277C; G93R), respectively;
      these probands were also heterozygous for H63D and C282Y, respectively. Probands
      3 and 4 were heterozygous for a previously described but uncommon HFE mutation:
      exon 2, nt 193A-->T (193T; S65C). Proband 3 was also heterozygous for C282Y and
      had porphyria cutanea tarda, and Proband 4 had hereditary stomatocytosis. Each of
      these four probands had iron overload. In each proband with an uncommon HFE
      coding region mutation, I105T, G93R, and S65C occurred on separate chromosomes
      from those with the C282Y or H63D mutations. Neither I105T, G93R, nor S65C
      occurred as spontaneous mutations in our probands. The I105T and G93R mutations
      were linked to haplotypes bearing HLA-A3,-B7 and HLA-A2,-B62, respectively. The
      S65C mutation was linked to a haplotype characterized by HLA-32. Sixteen other
      probands did not have an uncommon HFE exon mutation. In 176 normal control
      subjects, two were heterozygous for S65C, but I105T and G93R were not detected.
      Nine of twenty probands were heterozygous and two probands were homozygous for a
      previously described base-pair change at intron 2, nt 3671T-->C. One proband
      without a detectable missense mutation had a previously described intron 5 allele
      (nt 6700G-->A). Heterozygosity for a previously described base-pair change in
      intron 4 (nt 5636T-->C) was detected in all persons we studied who also had the
      S65C mutation. One proband was heterozygous for a previously undescribed base
      pair change at intron 5 (nt 5807A-->G). We conclude that uncommon HFE exon and
      intron mutations may be discovered among hemochromatosis patients who have
      "atypical" HFE genotypes.

PMID- 10575542
TI  - Haplotype analysis of the HFE gene: implications for the origins of
      hemochromatosis related mutations.

PMID- 10575541
TI  - Induction of globin synthesis in K562 cells is associated with differential
      expression of transcription factor genes.
AB  - Globin gene switching may be mediated by proteins expressed during different
      stages of development. Their identification may clarify the mechanisms of the
      conversion from fetal to adult globin production and lead to new approaches to
      reversing or retarding the gamma- to beta-globin gene switch. To explore this
      hypothesis, K562 erythroleukemia cells were induced to differentiate with 1.25,
      2.5, and 5 mM sodium butyrate and gene expression was studied after 24, 48, and
      72 h. Erythroid differentiation was verified by benzidine staining and by
      measuring the activity of a transduced A gamma-globin gene promoter linked to a
      luciferase reporter gene. Using differential display polymerase chain reaction
      (PCR), total mRNA extracted from induced cells at each time point of induction
      was reverse transcribed in the presence of A, G, and C anchored primers and 16
      arbitrary primers, calculated to amplify approximately 50% of expressed genes.
      Amplified mRNAs from induced and uninduced cells were separated in polyacrylamide
      gels and compared. More than 110 cDNA fragments which appeared to represent
      either up- or downregulated mRNA species in induced K562 cells were identified.
      Sixty-four of these fragments had more than 95% homology to known GenBank
      sequences. Seventeen fragments with characteristics of transcription factors were
      cloned. These include differentiation-related gene-1 (drg-1), PAX 3/forkhead
      transcription factor, HZF2 which is a Kruppel-related zinc finger protein, three
      helix-loop-helix proteins (heir-1, Id3, and GOS8), alpha-NAC transcriptional
      coactivator, LIM domain protein, and trophoblast hypoxia regulating factor.
      Differential expression of all 17 fragments over 72 h was confirmed by reverse
      Northern dot blot analysis, semiquantitative PCR using nested primers, and
      Northern analysis. Erythroid maturation in induced K562 cells is associated with
      differential expression of numerous genes. Some encode transcription factors that
      could effect the initiation of HbF synthesis. Almost half of the differentially
      expressed clones contained cDNAs of unidentified open reading frames and these
      are the object of continued study.

PMID- 10575543
TI  - Adenine nucleotide synthesis in human erythrocytes depends on the mode of
      supplementation of cell suspension with adenosine.
AB  - In suspensions of washed human erythrocytes, adenosine added in a single dose to
      concentrations of 0.1-10.0 mmol/l suspension was deaminated at rates ranging from
      10 to 50 mmol/l cells h. The sum of adenosine, inosine, and hypoxanthine
      concentrations in the suspension, as well as the intracellular concentration of
      ATP, remained constant. In the presence of 25-50 mmol/l orthophosphate, addition
      of a single dose of adenosine into erythrocyte suspension increased the ATP
      concentration by up to 280% of the initial level. If the initial adenosine
      concentrations were greater than 5 mmol/l suspension, ATP increased independently
      of adenosine concentration to the level determined only by the concentration of
      orthophosphate. After orthophosphate was returned to its initial level, ATP in
      erythrocytes began to decrease. In the presence of coformycin, erythrocytes
      utilised adenosine at a rate of 0.2-0.3 mmol/l cells h. Their adenylate pool
      increased at a rate of 0.10-0.16 mmol/l cells h for several hours, but
      intracellular ATP increased only slightly. The energy charge of cells decreased
      significantly from 0.86 +/- 0.05 (control) to 0.82 +/- 0.06. Adenosine
      continuously pumped into erythrocyte suspensions at rates of 0.02-5.0 mmol/l
      cells h for several hours caused the adenylate pool of erythrocytes and
      intracellular ATP to increase synchronously at a rate of 0.02-0.35 mmol/l cells
      h. The energy charge of these erythrocytes increased significantly up to 0.91 +/-
      0.03. After pumping of adenosine was stopped, the intracellular ATP and the
      adenylate pool began to decrease, returning sometimes to the initial level in 2-3
      h.

PMID- 10575544
TI  - Hemostasis of tiger prawn Penaeus monodon affected by Vibrio harveyi,
      extracellular products, and a toxic cysteine protease.
AB  - The effects of bacterial cells, extracellular products (ECP) and a purified
      cysteine protease of Vibrio harveyi on hemostasis and plasma components of tiger
      prawn (Penaeus monodon) were studied. The clotting ability of the hemolymph
      withdrawn from moribund prawns pre-injected with the bacteria, ECP, cysteine
      protease of PBS (control) was observed for 2 h at 25 C. Of these, only the
      control group was clottable while all the other groups were unclottable. A
      component of the plasma, previously identified as coagulogen-like protein, was
      further confirmed to be a coagulogen by the comparison of plasma with serum on
      non-reduced SDS-PAGE or using rabbit antiserum to the coagulogen-like protein (R
      alpha coagulogen) to neutralize the clotting ability of normal prawn hemolymph.
      The coagulogen was reduced in amount in plasma of moribund prawns after injection
      with the bacteria, ECP or cysteine protease while it apparently disappeared after
      pre-incubation with the ECP or cysteine protease for 2 h at 25 C compared with
      normal prawn plasma as observed in crossed immunoelectrophoresis (CIE) gels. The
      reduction of the amount of coagulogen in plasma of moribund prawns was also
      evident in CIE gels using R alpha coagulogen. In addition, the apparent
      disapperance of the coagulogen mentioned above was eventually proven to be due to
      the change of its migration rate in CIE gels after pre-incubation with ECP or
      cysteine protease, since the disappeared coagulogen arc (arc 2) (migrated into
      arc 1) could be visualized by using R alpha coagulogen or by reducing the time
      for pre-incubation from 2 h to 30 min. Thus, the effects of cysteine protease on
      plasma coagulogen observed in vitro and in vivo may markedly interfere with
      hemostasis leading to the occurrence of unclottable hemolymph. These complex
      events may significantly contribute to the pathogenicity of V. harveyi in the
      prawn.

PMID- 10575545
TI  - Activation of the delta-globin gene by the beta-globin gene CACCC motif.
AB  - The promoter region of adult beta globin genes in humans and other mammals
      contains conserved regions of pivotal importance for their regulated tissue
      specific expression. These include the CACCC and CAAT motifs. The CACCC motif is
      duplicated in humans and other mammals. The human delta-globin gene lacks these
      conserved regions and its expression in normal individuals is about 3% that of
      the beta globin gene. Previous studies have shown that the introduction of the
      beta-globin CACCC or CAAT can activate the delta-globin gene promoter, but the
      effect of the distal CACCC element has not yet been tested. In the present study,
      using site-specific mutagenesis, we have introduced the consensus sequence for
      the distal and proximal CACCC motif and the CAAT box alone or in combination in
      the wild-type delta-globin gene promoter. The resulting mutants, as well as the
      wild type (wt) delta- and beta-globin gene promoters, have been analyzed in a
      transient expression assay in Cos7, K562, and MEL cell lines. The results show
      that the CACCC boxes can increase the transcription efficiency of the delta
      globin gene promoter in both erythroid and non-erythroid cell systems. The
      contribution of the two CACCC elements is almost equal in the non-erythroid
      (Cos7) and erythroid embryonic-fetal cell lines (K562), while the proximal CACCC
      element is more active in adult erythroid cells (MEL). Nonetheless, duplication
      of this element does not appear to affect the efficiency of the promoter
      synergistically. Furthermore, to assess the competitive ability of the delta
      globin promoter containing the proximal or distal CACCC consensus sequences over
      the wt beta globin gene promoter, we have carried out transient expression
      experiments using DNA constructs in which the delta and beta globin gene
      promoters are linked in cis and are sharing a single enhancer (competitive
      transient expression). The results show that both CACCC elements are able to
      activate the delta globin gene promoter in Cos7 and K562 cells, although to a
      different extent, whereas only the proximal CACCC element is effective in
      increasing the transcription efficiency in MEL cells. These findings are in
      agreement with the more severe clinical phenotype produced by the beta
      thalassemia mutations affecting the proximal CACCC box as compared with those
      within the distal CACCC box. The Erythroid Kruppel Like Factor (EKLF) is a
      nuclear protein restricted to erythroid cells which specifically bind the CACCC
      box sequence and activate the beta-globin gene. In the present study we carried
      out transactivation experiments of the mutagenized delta-globin gene promoter by
      introducing an EKLF expressing construct in erythroid cells. Constructs
      containing the proximal but not those bearing the distal CACCC element are
      transactivated. Our results indicate that the proximal CACCC box and, to a lesser
      extent, also the distal box have a role in the regulated stage specific
      expression of a beta-like globin gene, and show that the insertion of a single
      CACCC motif in the delta-globin gene promoter is sufficient to increase its
      activity. Nevertheless only the delta globin gene promoter containing the
      proximal CACCC element is able to compete with the wt beta globin gene promoter
      in the adult erythroid environment. These findings have potential relevance for
      the future prospective treatment of inherited hemoglobinopathies based on the
      conversion of the low functioning delta-globin gene into a high functioning beta
      like globin gene.

PMID- 10575546
TI  - The consequence of nucleotide substitutions in the triosephosphate isomerase
      (TPI) gene promoter.
AB  - Mutations at -5A-->G, -8-->GA within the cap proximal element (CPE), and -24T-->G
      within the TATA box of the triosephosphate isomerase (TPI) gene promoter have
      been identified in populations with a wide geographical distribution. These
      mutations lie within, or in close proximity to, known cis-active elements in the
      TPI gene promoter. To determine the functional significance of mutation at these
      sites, which remains controversial, their effect on the expression of erythrocyte
      TPI enzyme activity was studied in 110 healthy unrelated subjects. The -5G
      mutation did not alter erythrocyte TPI level, whereas the -8A mutation was
      accompanied by a significant reduction in enzyme activity to around 90% and 76%
      of normal erythrocyte TPI activity in heterozygotes and homozygotes,
      respectively. The -8A -24G genotype was associated with 75% of normal TPI
      activity in a heterozygote studied, implying that substitution of G at position 
      24 within the canonical TATA motif causes an additive decrease in TPI gene
      transcription in erythroid cells. A DNA-protein complex of 125kDa which was
      competitively blocked by specific unlabelled oligomers was demonstrated at the
      CPE and TATA box by electrophoretic mobility shift analysis. These findings
      provide direct evidence that TPI promoter mutations are linked to a reduction of
      TPI enzyme activity in vivo.

PMID- 10575547
TI  - Unique and recurrent WAS gene mutations in Wiskott-Aldrich syndrome and X-linked
      thrombocytopenia.
AB  - Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) are allelic
      phenotypes caused by defects of the WAS gene. Fourteen distinct mutations
      including seven novel gene defects in 16 WAS and four XLT patients were
      identified by single strand conformation polymorphism analysis and DNA sequencing
      of the WAS gene. Eleven (79%) of these mutations are located within exons 1 to 4
      with clustering in exon 2. Carrier detection in 33 at-risk females and prenatal
      diagnosis at 12 weeks gestation in one family with a novel WAS mutation was
      performed by direct mutation analysis. A remarkably high frequency (72%) of point
      mutations involved CpG dinucleotides. C-->T or G-->A transitions at CpG sites
      were identified in all isolated WAS cases (n = 7). Allele frequencies for the
      dinucleotide repeat at locus DXS6940 were determined in Northern European,
      African and Asian populations. Mutation screening alone or in combination with
      analysis of polymorphic loci DXS6940 and DXS255 delineated the germline origin of
      a unique insertion mutation and four recurrent CpG mutations, three of which
      arose spontaneously during maternal gametogenesis.

PMID- 10575548
TI  - Identification of new Fas mutations in a patient with autoimmune
      lymphoproliferative syndrome (ALPS) and eosinophilia.
AB  - Autoimmune lymphoproliferative syndrome (ALPS) is a rare, newly recognized,
      chronic lymphoproliferative disorder in children and is characterized by
      lymphadenopathy, splenomegaly, pancytopenia, autoimmune phenomena and expansion
      of double-negative (DN) T lymphocytes (TCR alpha beta+, CD4-, CD8-). Defective
      lymphocyte apoptosis caused by mutations of the Fas (CD95) gene has been linked
      in the pathogenesis of ALPS, as binding of Fas-ligand to Fas can trigger
      apoptosis. Of the ALPS cases reported to date, point mutations, frameshifts and
      silent mutations in Fas all have been identified. We report two new point
      mutations in Fas in a child with ALPS and eosinophilia; studies on other family
      members established the pattern of inheritance for these mutations. Flow
      cytometric analysis of blood and tissues (spleen, lymph node, bone marrow)
      revealed abnormally expanded populations of DN T lymphocytes. Furthermore,
      activated lymphocytes and IFN gamma-activated eosinophils were resistant to Fas
      mediated apoptosis. Eosinophil resistance to Fas-mediated apoptosis has not been
      previously described in ALPS. Sequencing of Fas revealed two separate mutations
      not previously reported. One mutation, a C to T change at base 836, was a silent
      mutation inherited from the mother, while the second mutation, a C to A change at
      base 916, caused a non-conservative amino acid substitution in the death domain
      of Fas, changing a threonine to a lysine. This mutation is associated with a
      predicted change in the structure of a part of the death domain from a beta
      pleated sheet to an alpha-helix. We speculate that the mutation in the death
      domain prevents the interaction of Fas with intracellular mediators of apoptosis
      and is responsible for the autoimmune manifestations of ALPS and the abnormal
      lymphocytosis and eosinophilia in this patient.

PMID- 10575549
TI  - Analysis of blood coagulation in the zebrafish.
AB  - The zebrafish (Danio rerio) is a unique animal model in which saturation
      mutagenesis has been used to identify genes involved in vertebrate development.
      The relevance of the zebrafish as a genetic model for hemostasis depends, in
      large part, on the degree of similarity between the zebrafish and mammalian
      systems. The diminutive size of the zebrafish poses technical problems for
      analysis of coagulation. This study describes methods to obtain citrated whole
      blood and plasma from the zebrafish, analyze in vitro coagulation in small plasma
      volumes, obtain uniform dosing of zebrafish with oral anticoagulants, and
      demonstrate specific factor activities via chromogenic assays. Analysis of the
      zebrafish system demonstrates the presence of both the intrinsic and extrinsic
      pathways of coagulation, evidence for prothrombin, factor X, protein C,
      antithrombin, and heparin cofactor II activity, and a requirement for vitamin K
      dependent gamma-carboxylation of zebrafish hemostatic proteins. Induction of a
      morphologically recognizable bleeding phenotype by warfarin treatment is also
      demonstrated. Characterization of zebrafish coagulation provides evidence that
      major hemostatic pathways are conserved between zebrafish and man. These
      similarities indicate that the zebrafish is a relevant genetic model for
      identification of novel genes involved in hemostasis and thrombosis.

PMID- 10575550
TI  - Significance of linkage disequilibrium between mutation C282Y and a MseI
      polymorphism in population screening and DNA diagnosis of hemochromatosis.
AB  - An increasing number of studies demonstrate a lack of phenotypic expression in
      subjects found to be homozygous for the common hereditary hemochromatosis (HH)
      mutation, C282Y. In this study the impact of possible overestimation of C282Y
      homozygosity, as a consequence of a MseI polymorphism identified in intron 4 of
      the HFE gene, was investigated in South African subjects. Utilization of a
      modified polymerase chain reaction (PCR)-based assay highlighted the potential
      implications with respect to genotype/phenotype correlation studies, particularly
      in the general population. Mistyping rather than lack of disease association
      provides a plausible explanation for the phenomenon of C282Y homozygosity without
      iron overload. Reassessment of C282Y mutation status in such cases may result in
      justified population screening in HH.

PMID- 10575551
TI  - A combination of hydroxyurea and isobutyramide to induce fetal hemoglobin in
      transgenic mice is more hematotoxic than the individual agents.
AB  - Pharmacologic agents such as hydroxyurea (HU), N, 3-4 trihydroxybenzamide
      (didox), and isobutyramide (ISB) can elevate gamma-globin as a potential
      treatment for the beta-hemoglobinopathies. In these experiments, transgenic mice
      with 5'HS2 from the human beta-globin locus control region, the fetal (A gamma),
      and adult (beta s) globin genes were used. Mice were treated with HU, didox, or
      ISB individually, or with combinations of HU or didox with ISB. The aim was to
      determine whether these drugs have synergistic effects on the induction of fetal
      hemoglobin (HbF) and whether the combination regimens are more hematotoxic. In
      the combination regimens, injections of HU or didox for five weeks were
      concomitant with ISB treatment every other day for the final three weeks of
      treatment. The combination of HU + ISB was more hematotoxic than the individual
      drugs based on significantly increased percentages of reticulocytes and reduced
      hemoglobin, indicating that caution should be taken in treatments involving
      combinations of these types of drugs. The didox + ISB combination was not more
      hematotoxic than the individual drugs. HbF was not induced in the groups treated
      with the combinations of HU or didox with ISB compared to the individual agents.
      There was a negligible effect on the percentage of HbF and an unexpected negative
      effect on the percentage of F cells. The results also have implications for
      future testing of HbF-inducing drugs in mouse models. In control mice that were
      phlebotomized but not treated with any drugs, increased percentages of F cells
      were observed, indicating that blood sampling can cause this effect. In addition,
      increases in the percentage of F cells did not correlate with increases in the
      percentage of HbF, indicating that monitoring F cells alone is not a sufficient
      measure of HbF induction.

PMID- 10575552
TI  - Diagnosis and management of patients with unstable angina.

PMID- 10575553
TI  - Structural and functional studies of UDP-glucuronosyltransferases.
AB  - UDP-Glucuronosyltransferases (UGTs) are glycoproteins localized in the
      endoplasmic reticulum (ER) which catalyze the conjugation of a broad variety of
      lipophilic aglycon substrates with glucuronic acid using UDP-glucuronic acid (UDP
      GIcUA) as the sugar donor. Glucuronidation is a major factor in the elimination
      of lipophilic compounds from the body. In this review, current information on the
      substrate specificities of UGT1A and 2B family isoforms is discussed. Recent
      findings with regard to UGT structure and topology are presented, including a
      dynamic topological model of UGTs in the ER. Evidence from experiments on UGT
      interactions with inhibitors directed at specific amino acids, photoaffinity
      labeling, and analysis of amino acid alignments suggest that UDP-GIcUA interacts
      with residues in both the N- and C-terminal domains, whereas aglycon binding
      sites are localized in the N-terminal domain. The amino acids identified so far
      as crucial for substrate binding and catalysis are arginine, lysine, histidine,
      proline, and residues containing carboxylic acid. Site-directed mutagenesis
      experiments are critical for unambiguous identification of the active-site
      architecture.

PMID- 10575554
TI  - Trichloroethylene activates CD4+ T cells: potential role in an autoimmune
      response.
AB  - Trichloroethylene is an industrial solvent and has become a major environmental
      contaminant. Autoimmune-prone MRL +/+ mice were treated for up to 22 weeks with
      trichloroethylene in the drinking water (0, 2.5, and 5.0 mg/mL) in order to study
      the immunoregulatory effects of this environmental toxicant. After only 4 weeks
      of treatment, trichloroethylene was shown to promote the expansion of CD4+ T
      cells that expressed a memory/activation phenotype (i.e., CD44hi CD45RBlo) and
      secreted high levels of IFN-gamma, but not IL-4. In addition, trichloroethylene
      treatment accelerated the development of an autoimmune response in the MRL +/+
      mice as evidenced by an earlier appearance of antinuclear antibodies and
      increased levels of total IgG2a. MRL +/+ mice treated with trichloroethylene for
      22 weeks also contained antibodies specific for trichloroethylene adducts,
      suggesting the activation of trichloroethylene-specific T cells. The results
      suggest that trichloroethylene can stimulate antigen nonspecific as well as
      specific T cells that are capable of promoting autoimmunity in genetically
      predisposed individuals.

PMID- 10575555
TI  - Interspecies differences in cancer susceptibility and toxicity.
AB  - One of the most complex challenges to the toxicologist represents extrapolation
      from laboratory animals to humans. In this article, we review interspecies
      differences in metabolism and toxicity of heterocyclic amines, aflatoxin B1,
      2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and related compounds, endocrine
      disrupters, polycyclic aromatic hydrocarbons, tamoxifen, and digitoxin. As far as
      possible, extrapolations to human toxicity and carcinogenicity are performed.
      Humans may be more susceptible to the carcinogenic effect of heterocyclic amines
      than monkeys, rats, and mice. Especially, individuals with high CYP1A2 and 3A4
      activities and the rapid acetylator phenotype may be expected to have an
      increased risk. Striking interspecies variation in susceptibility to aflatoxin B1
      carcinogenesis is known, with rats representing the most sensitive and mice the
      most resistant species, refractory to dietary levels three orders of magnitude
      higher than rats. An efficient conjugation with glutathione, catalyzed by
      glutathione S-transferase mYc, confers aflatoxin B1 resistance to mice. Extremely
      large interspecies differences in TCDD-induced toxicity are known. The guinea pig
      is the most susceptible mammal known, with an LD50 in the range 1-2 micrograms
      TCDD/kg, whereas the hamster is the most resistant species with an LD50 greater
      than 3000 micrograms/kg. A number of experts have pointed out to the fact that
      humans appear to be less sensitive to TCDD than most laboratory animals. Human
      exposure to background levels of TCDD is not likely to cause an incremental
      cancer risk. A clear cause--effect relationship has been shown between
      environmental endocrine-disrupting contaminants and adverse health effects in
      wildlife, whereas the effects seem to be less critical for humans. Studies on DNA
      adduct formation and metabolism of the nonsteroidal antiestrogen tamoxifen
      indicate that rats and mice are orders of magnitude more susceptible than humans.

PMID- 10575556
TI  - Oxidant mechanisms in toxic acute renal failure.
AB  - Over the last decade, there is accumulating evidence for a role of reactive
      oxygen metabolites in the pathogenesis of a variety of renal diseases, including
      gentamicin, glycerol, cisplatin, and cyclosporine A models of toxic acute renal
      failure. Gentamicin has been shown both in in vitro and in vivo studies to
      enhance the generation of reactive oxygen metabolites. Iron is important in
      models of tissue injury, presumably because it is capable of catalyzing free
      radical formation. Gentamicin has been shown to cause release of iron from renal
      cortical mitochondria. Scavengers of reactive oxygen metabolites as well as iron
      chelators provide protection in gentamicin-induced nephrotoxicity. In glycerol
      induced acute renal failure, an animal model of rhabdomyolysis, there is enhanced
      generation of hydrogen peroxide, and scavengers of reactive oxygen metabolites
      and iron chelators provide protection. Although the dogma is that the myoglobin
      is the source of iron, recent studies suggest that cytochrome P450 may be an
      important source of iron in this model. In addition, there are marked alterations
      in antioxidant defenses, such as glutathione, as well as changes in heme
      oxygenase. Several recent in vitro and in vivo studies indicate an important role
      of reactive oxygen metabolites in cisplatin-induced nephrotoxicity. Thus,
      catalytic iron is increased both in vitro and in vivo by cisplatin, and iron
      chelators as well as hydroxyl radical scavengers have been shown to be
      protective. Recent studies indicate that cytochrome P450 may also be an important
      source of the catalytic iron in cisplatin nephrotoxicity. Cyclosporine A has been
      shown to enhance generation of hydrogen peroxide in vitro and enhance lipid
      peroxidation in vitro and in vivo. Antioxidants have been shown to be protective
      in cyclosporine A nephrotoxicity. This collective body of evidence suggests an
      important role for reactive oxygen metabolites in toxic acute renal failure and
      may provide therapeutic opportunities of preventing or treating acute renal
      failure in humans.

PMID- 10575557
TI  - Organization and financial aspects of gastrointestinal endoscopy in Hungary.

PMID- 10575558
TI  - Clinician's guide through the tight junctions [editoria; comment].

PMID- 10575559
TI  - Peripheral cholecystokinin A and cholecystokinin B receptors mediate stimulation
      of gastric pepsinogen and acid secretion following intracerebroventricular
      injection of cholecystokinin-8-sulphate.
AB  - BACKGROUND: Peptides of cholecystokinin family regulate various physiological
      actions by acting at level of central nervous system. AIMS: To: 1) investigate
      possible influence of central cholecystokinin pathways on gastric pepsinogen and
      acid secretions; 2) characterize pharmacological profile and location of
      cholecystokinin receptor subtypes involved in gastric effects of centrally
      applied cholecystokinin-8-sulphate (cholecystokinin-8S). METHODS: Urethane
      anaesthetized rats were subjected to continuous perfusion of gastric lumen.
      Pepsin levels in perfusate were determined by enzymatic assay based on
      spectrophotometric measurement of products generated by peptic digestion of
      bovine haemoglobin. Acidity was measured by automatic potentiometric titration of
      hydrogen ions. RESULTS: Following intracerebroventricular injection,
      cholecystokinin-8S increased both pepsinogen and acid output. In addition,
      intravenous cholecystokinin-8S stimulated peptic and acid secretions more
      promptly and at lower doses than after central injection. Stimulant effects of
      centrally applied cholecystokinin-8S were not affected by intracerebroventricular
      injection of devazepide (cholecystokinin A receptor antagonist) or L-365,260
      (cholecystokinin B receptor antagonist) or by bilateral vagotomy. However,
      intravenous devazepide partly antagonized pepsigogue action of
      intracerebroventricular cholecystokinin-8S without affecting its acid
      hypersecretory effect, whereas after intravenous injection of L-365,260 peptic
      hypersecretion evoked by intracerebroventricular cholecystokinin-8S was partially
      prevented and acid response was completely blocked. Similar effects were exerted
      by intravenous devazepide and L-365,260 against intravenous cholecystokinin-8S. A
      complete blockade of pepsigogue effects induced by intracerebroventricular or
      intravenous cholecystokinin-8S was obtained after combined intravenous treatment
      with devazepide plus L-365,260. Gastric hypersecretory effects of intravenous
      cholecystokinin-8S were not modified by bilateral vagotomy. CONCLUSIONS: Increase
      in pepsinogen output evoked by centrally applied cholecystokinin-8S does not
      depend on interaction with central nervous sites. Following central or parenteral
      injection of cholecystokinin-8S, increase in peptic secretion would result from
      activation of both peripheral cholecystokinin A and B receptors presumably
      located at the level of gastric mucosa.

PMID- 10575560
TI  - Incidence of incisional hernia following emergency abdominal surgery.
AB  - BACKGROUND: A retrospective study was conducted to determine incidence and
      predisposing factors of incisional hernia after an emergency midline laparotomy.
      PATIENTS AND METHODS: The study population consisted in 197 patients of whom 138
      were followed-up for 2 years after surgery. RESULTS: An incisional hernia
      developed in 25 (18.1%) patients at a mean follow-up of 11.2 months. Multivariate
      analysis showed the importance of age (> 60 years, p < 0.004), obesity (p <
      0.008) and occurrence of post-operative wound infection (p < 0.00001) for the
      development of an incisional hernia. Univariate analysis showed that intestinal
      occlusion (p < 0.02), peritonitis (p < 0.006), upper abdominal access (p < 0.04)
      and post-operative wound infection (p < 0.003) in older patients and obesity (p <
      0.003) and the presence of a neoplasm (p < 0.006) in younger patients, played a
      significant role. The comparison between young and old patients showed that upper
      abdominal access (p < 0.007), interrupted and layered wound closure (p < 0.02 and
      p < 0.01, respectively) and contamination of the operative field (p < 0.004)
      played a statistically significant role in older patients. CONCLUSIONS: The rate
      of incisional hernia after an emergency midline laparotomy is higher than after
      elective procedures. However, it could be reduced with proper attention to the
      suture technique, i.e. mass and continuous suture, better preparation of the
      operative field and scrupulous sterility throughout the procedure in order to
      decrease the incidence of post-operative wound infection.

PMID- 10575561
TI  - Clinical outcome of chronic hepatitis C in patients treated with interferon:
      comparison between responders and non-responders.
AB  - AIM: To evaluate the prognosis of chronic hepatitis C in relation to interferon
      therapy response and the persistence of therapeutic benefits. PATIENTS/METHODS:
      We studied the clinical outcome of 191 patients with chronic infection (152
      chronic hepatitis C and 39 cirrhosis) treated with recombinant alpha-interferon
      (3-6 MU on alternate days for 1 year) during a mean period of 47 months (range
      22.5-73.8). Control tests were done at 6-month intervals. HCV RNA was determined
      pre- and post-treatment in all participants, but continued yearly in long-term
      responders. The appearance of cirrhosis was estimated using a non-invasive method
      that utilizes a model based on clinical, instrumental and biochemical variables.
      Ascites, encephalopathy, haemorrhage, hepatocellular carcinoma, and death were
      considered liver-disease-related events. RESULTS: A total of 39 patients were
      long-term responders, 36 relapsers, and 116 non-responders; 92% of long-term
      responders cleared HCV RNA and remained negative throughout the study period. The
      3 HCV-RNA-positive long-term responders continued being so. No biochemical
      relapse was observed in long-term responders regardless of virological status.
      New cirrhosis was observed in 3/30 relapsers, in 9/85 non-responders, and in no
      long-term responders. Overall, 9 episodes of severe events occurred in 20% of
      cirrhotics and in 0.6% of chronic hepatitis, all non-responders. CONCLUSIONS:
      Long-term response interrupts the progression to cirrhosis and reduces the
      incidence of severe complications. Multivariate analysis revealed that "baseline
      diagnosis of cirrhosis" was the only independent factor predictive of an
      unfavourable outcome of chronic HCV-related liver disease.

PMID- 10575562
TI  - Long-term outcome of chronic hepatitis C treated with interferon.

PMID- 10575563
TI  - One-year pilot study on tauroursodeoxycholic acid as an adjuvant treatment after
      liver transplantation.
AB  - BACKGROUND: The usefulness of ursodeoxycholic acid after liver transplantation is
      controversial. Tauroursodeoxycholic acid, the natural taurine-amidate, is a
      highly hydrophilic and cytoprotective bile salt currently under investigation.
      AIMS: To investigate the clinical usefulness of tauroursodeoxycholic acid after
      liver transplantation. PATIENTS: Thirty-three patients undergoing liver
      transplantation entered the study. METHODS: Sixteen patients were randomized to
      receive tauroursodeoxycholic acid (250 b.i.d. for 12 months) and 17 served as
      controls. Tauroursodeoxycholic acid was given from day 5 after transplantation
      for one year. RESULTS: Tauroursodeoxycholic acid treatment was safe and well
      tolerated. No drop outs occurred. Among the 29 patients undergoing long-term
      follow-up, five deaths occurred (3 of whom in the tauroursodeoxycholic acid
      group), none of which was related to treatment. The one-year actuarial survival
      was 78.6% in patients treated with tauroursodeoxycholic acid and 86.7% in
      controls (n.s.). No differences were observed with respect to early or late graft
      function and survival, nor to acute cellular rejection. Tauroursodeoxycholic acid
      therapy was associated with lower serum cholesterol levels (p < 0.02) during the
      early postoperative months; with milder cholestasis; with a drop in biliary
      cholates but no changes in endogenous hydrophobic bile salts. CONCLUSIONS: Long
      term treatment with low dose tauroursodeoxycholic acid after liver
      transplantation is safe but does not affect graft function and survival.

PMID- 10575564
TI  - Ursodeoxycholic acid after liver transplantation: does conjugation with taurine
      make the difference?

PMID- 10575565
TI  - Combination treatment of interferon alpha-2b and ribavirin in comparison to
      interferon monotherapy in treatment of chronic hepatitis C genotype 4 patients.
AB  - BACKGROUND AND AIM: Treatment of chronic hepatitis C patients, infected with
      genotype 4 with interferon-alpha yielded a limited response. Our aim was to
      compare the efficacy of interferon-alpha alone and in combination with ribavirin
      in chronic hepatitis C patients infected with genotype 4. PATIENTS: Fifty-two
      chronic hepatitis C patients (all males) infected with genotype 4, who had not
      received interferon, were randomized into 2 equal comparable groups. METHODS:
      Group I received interferon alpha-2b "Schering Plough" 3 MU, tiw combined with
      ribavirin (1000 mg/day). Group II received interferon alpha-2b alone in the same
      dose. Both groups were evaluated monthly, at the end of 24 weeks of treatment and
      24 weeks later. Two patients were dropped from group I and one patient from group
      II. RESULTS: Biochemical response: at the end of treatment, a return to normal of
      ALT was obtained in 16/24 (66.7%) patients on combination therapy vs 8/25 (32%)
      patients on interferon alone (p = 0.0152). At the end of follow-up, a sustained
      response was achieved in 10/24 (41.7%) patients on combination therapy vs 4/25
      (16%) patients on interferon (p = 0.0468). Virologic response: at the end of
      treatment, the rates of virological response were higher in the patients on
      combination therapy 9/24 (37.5%) than in those on interferon 4/25 (16%) (p =
      0.0380). At the end of follow-up, loss of serum HCV RNA was reported in 5/24
      (20.8%) patients on combination therapy vs 2/25 (8%) patients on interferon (p =
      0.1916). Histologic response: mild histologic improvement was shown by a decrease
      in the inflammatory score, which was highest in patients in the combination
      group. CONCLUSIONS: In chronic hepatitis C patients infected with genotype 4,
      combination therapy with interferon-alpha and ribavirin was more effective than
      treatment with interferon monotherapy. At the end of the follow-up, about 50% of
      patients in both groups were still viraemic though their ALT remained normal.

PMID- 10575566
TI  - Clinical and molecular diagnosis of hereditary non-polyposis colorectal cancer:
      problems and pitfalls in an extended pedigree.
AB  - Hereditary non-polyposis colorectal cancer (or Lynch syndrome) is an autosomal
      dominant disease in which early onset colorectal carcinomas aggregate in families
      together with tumours of other organs. The genetic basis of the syndrome has been
      clarified with the identification of mutations in several DNA mismatch repair
      genes (MSH2, MLH1, PMS1, PMS2 and MSH6). We describe the clinical features and
      molecular characterization of a large hereditary non-polyposis colorectal cancer
      family which has been followed for almost 10 years. The kindred showed a striking
      aggregation of colorectal tumours in 3 successive generations; most of these
      neoplasms developed before the age of 50 years and were localized in the proximal
      colon. Molecular tests (carried out in ten individuals) showed specific
      alterations at the MLH1 gene, consisting in the insertion of a T nucleotide
      between bases 2,269 and 2,270; the mutation caused frameshift of the open reading
      frame and synthesis of a polypeptide longer than normal. The only tumour that
      could be analysed was positive for microsatellite instability. Physicians should
      become more confident with hereditary tumours and their implications, which are
      not limited to a single individual but concern all family members at risk of
      cancer. This family approach is different, and requires more expertise than the
      traditional individual approach. Common problems encountered in Hereditary Non
      polyposis Colorectal Cancer families include: A) poor collaboration of subjects
      at risk (a situation which may cause some conflict between the doctor's duty to
      inform patients about their risk of disease and the rights of patients to choose
      and decide about their health); B) definition of the most appropriate
      surveillance programme for a given family (how many investigations to propose to
      the patients, and how often); C) possible interaction between genes and
      environmental factors (for instance, a gene carrier--in this family--developed an
      endometrial carcinoma after standard tamoxifen adjuvant therapy for breast
      cancer).

PMID- 10575567
TI  - Structure and function of tight junctions. Role in intestinal barrier.
AB  - The tight junctions are narrow belts that circumferentially surround the upper
      part of the lateral surfaces of the adjacent epithelial cells to create fusion
      points or "kisses". They are involved in maintaining the cellular polarity and in
      the establishment of compositionally distinct fluid compartments in the body.
      Tight junctions are formed by many specific proteins and are connected with the
      cytoskeleton. In contrast to what might be expected, the intestinal tight
      junctions are highly dynamic areas and their permeability can change in response
      to both external and intracellular stimuli. In fact, the tight junctions play an
      important role in the regulation of the passive transepithelial movement of
      molecules. A number of signalling molecules have been implicated in the
      regulation of tight junction function, including Ca++, protein kinase C, G
      proteins, phospholipase A2 and C. In many intestinal and systemic diseases,
      changes in intestinal permeability are related to alteration of tight junctions
      as an expression of intestinal barrier damage. Moreover, permeability of the
      tight junctions can be modified by bacterial toxins, cytokines, hormones and
      drugs. A better understanding of tight junction structure, biogenesis and
      regulation mechanisms should throw further light on the intestinal barrier
      functions and suggest innovative therapeutic strategies.

PMID- 10575568
TI  - Mother-to-infant transmission of hepatitis C virus.
AB  - Since the programme of the hepatitis B virus vaccination started, hepatitis C
      virus has become the most significant cause of chronic liver disease of
      infectious aetiology in paediatric age. After the introduction of hepatitis C
      virus screening of blood units, vertical transmission seems to now be the most
      common route of hepatitis C virus infection in children. According to studies on
      infants born to anti-hepatitis C virus positive women, the rate of mother-to
      infant transmission is about 5% when the mother is anti-hepatitis C virus
      positive and anti-HIV negative, but the risk is three-five times higher when the
      mother is coinfected with HIV. Both viral and host-related factors are of
      importance as risk factors in vertical hepatitis C virus transmission. Among the
      first, only viral load has been demonstrated by some authors as a relevant risk
      factor while genotype seems not to be influent. The importance of quasispecies
      has been hypothesized but not yet clarified. Among host-related factors, beyond
      maternal HIV coinfection, maternal drug abuse has certainly an important role.
      Other factors such as breast feeding and vaginal delivery do not seem to
      influence the rate of vertical transmission. Progression to chronicity occurs in
      the majority of perinatally infected children, although hepatitis C virus
      associated liver disease is usually mild throughout infancy and childhood.

PMID- 10575569
TI  - From yeast to man--from mitochondria to liver regeneration: a new essential gene
      family.
AB  - The purpose of this review is to bring to the attention of the reader the latest
      developments in research on an important new emerging gene family. The respective
      genes are found in eukaryotes from yeast to man and even on the genome of some
      doubled-stranded DNA viruses. They have essential functions in the biogenesis of
      mitochondria, the cell division cycle and, in higher eukaryotes, in the
      development of organs like liver and testis. The most important medical
      implication is their probable role in liver regeneration that will, therefore, be
      addressed in detail. Aspects of molecular biology, medical implications and
      problems of developmental biology reflect the complexity of the functions of
      these proteins and the subjects of the respective research. This is just the
      beginning of an interdisciplinary effort directed towards the elucidation of the
      precise function of these essential factors inside the eukaryotic cell. In the
      general part of this review, we will concentrate on the history of the discovery
      of these genes and on a summary of their characteristic features. In the more
      specialized section, the specific role as augmenter of liver regeneration will be
      addressed in detail.

PMID- 10575570
TI  - Epidemiology of inflammatory bowel disease in Italy.
AB  - The incidence of inflammatory bowel diseases is similar throughout Italy. Two
      prospective multicentre studies in the same period have shown an incidence very
      similar to Northern Europe. The incidence of ulcerative colitis ranged from 3.4
      to 10.5. The incidence of Crohn's disease ranged from 1.9 to 6.6. The time trends
      seem to indicate an increase in both diseases. The need to set up General
      Registries of disease is underlined. The clinical behaviour and the diagnostic
      approach are homogeneous throughout the country. Compared to Northern Europe,
      surgery was less common in ulcerative colitis. Among the risk factors, familial
      occurrence has been shown to have the same prevalence as in Northern Europe
      suggesting a common genetic background. Studies on other risk factors are
      warranted considering the lack of data. Data on mortality show that there is a
      decrease in deaths in ulcerative colitis and a slight increase in mortality for
      Crohn's disease in the first few years after diagnosis. A retrospective study on
      costs has shown a greater economic burden from ulcerative colitis, however, new
      multicentre prospective studies are necessary.

PMID- 10575571
TI  - Current treatment modalities in active Crohn's disease.
AB  - The aetiology of Crohn's disease is unknown and, therefore, no curative
      treatments are currently available. Crohn's disease treatment requires knowledge
      of several variables affecting patient's responsiveness including:
      characteristics of the disease and of the host, as well as the specific purposes
      of treatment and the characteristics of the effective drugs. Currently available
      drugs for active Crohn's disease include: a) old drugs (oral/topical salicylates,
      conventional steroids); b) old drugs with a new face (immunosuppressives,
      antibacterial drugs); c) new drugs (budesonide, anti-cytokines/cytokines,
      probiotics). Among the old drugs, corticosteroids (1 mg/kg) are the most
      effective, with a 65-85% induction of remission, when compared to high dose
      sulphasalazine (3-5 g/day) (12%) and 5-aminosalicylic acid (4 g/day) (25%). The
      following drugs represent current treatment modalities in steroid/refractory
      active Crohn's disease. Immunosuppressives, including azathioprine (2-2.5 mg/kg)
      and 6-mercaptopurine (1-1.5 mg/kg) are less effective than steroids (30-40% vs 65
      85%), but in chronic active Crohn's disease they show a 76% "steroid-sparing"
      effect and 63% fistula closure. The reported efficacy of methotrexate (25 mg/kg)
      and cyclosporine A in fistulous Crohn's disease needs to be confirmed.
      Antibiotics, such as metronidazole and ciprofloxacin (1 g/day) are effective in
      perianal or colonic active Crohn's disease. Budesonide, a steroid with low
      systemic absorption, shows an efficacy comparable to prednisone in active small
      bowel Crohn's disease. Bowel rest and enteral feeding are effective in active
      Crohn's disease. To summarize, conventional steroids still represent the most
      effective drugs in active Crohn's disease. However, refractory disease, steroid
      dependence, drug-side effects and/or complications may require two main
      alternative management strategies: a) surgical resection in localized or primary
      Crohn's disease; b) alternative drugs in extensive or recurrent Crohn's disease.

PMID- 10575572
TI  - Current treatment for prevention of relapse and recurrence in Crohn's disease.
AB  - Maintenance of remission induced by medical therapy and prevention of recurrence
      after intestinal resection are two of the major goals in Crohn's disease
      treatment. Two main groups of drugs are employed in prevention of relapse and
      recurrence: sulfasalazine and 5-aminosalicylic derivatives and the group of
      azathioprine/6-mercaptopurine. Although most clinical trials on the efficacy of
      sulfasalazine as maintenance therapy of Crohn's disease have given negative
      results, it could probably be favourably used in remission maintenance of Crohn's
      colitis. Controlled studies and two reviews have shown that 5-aminosalicylic
      derivatives are effective in reducing the risk of relapse. Ileitis and
      ileocolitis respond better than colitis. These drugs are also able to reduce the
      severity of lesions and of symptoms after surgery. 6-mercaptopurine and
      azathioprine can be used in more aggressive forms of the disease. The efficacy of
      this immuno-suppressive therapy is reported in over 70% of patients and the
      incidence of associated side effects is acceptable, but 6-mercaptopurine and
      azathioprine act slowly and the long latency period limits the usefulness of
      these drugs in some patients.

PMID- 10575573
TI  - Infliximab (Remicade), a new biological treatment for Crohn's disease.
AB  - Tumour necrosis factor plays a pivotal role in Crohn's disease intestinal
      inflammation. Blocking this cytokine by means of the chimeric monoclonal antibody
      infliximab has led to a rapid reduction in mucosal inflammation. More than 65% of
      refractory Crohn's disease patients treated with infliximab showed a remarkable
      improvement in their symptoms, which was maintained by repeated infusions every 2
      months up to 44 weeks. Patients with draining enterocutaneous fistulae also
      benefited from infliximab treatment, with more than 60% of fistulae healed after
      3 infusions. Adverse events following infliximab infusions were mild and
      transient, occurring with the same frequency in infliximab and placebo-treated
      patients. In conclusion, infliximab appears to offer a promising novel
      therapeutic agent for refractory and fistulizing Crohn's disease. Long-term risks
      and benefits remain to be determined.

PMID- 10575574
TI  - Duodenal perforation as a complication of an endoscopically placed biliary stent.

PMID- 10575575
TI  - Acute pancreatitis after morphine administration.

PMID- 10575576
TI  - The specialist-general practitioner relationship: a new model for primary care
      gastroenterology.

PMID- 10575577
TI  - Preimplantation genetic diagnosis: considerations for use in elective human
      embryo sex selection.

PMID- 10575578
TI  - The role of apoptosis in normal and abnormal embryonic development.
AB  - Programmed cell death or apoptosis is a widespread biological phenomenon.
      Apoptosis is characterized by typical cell features such as membrane blebbing,
      chromatin condensation, and DNA fragmentation. It involves a number of membrane
      receptors (e.g., Fas, TNFR) and a cascade of signal transduction steps resulting
      in the activation of a number of cysteine proteases known as caspases. Disordered
      apoptosis may lead to carcinogenesis and participates in the pathogenesis of
      Alzheimer disease, Parkinson disease, or AIDS. Programmed cell death plays an
      important role in the processes of gamete maturation as well as in embryo
      development, contributing to the appropriate formation of various organs and
      structures. Apoptosis is one of the mechanisms of action of various cytotoxic
      agents and teratogens. Teratogen-induced excessive death of embryonic cells is
      undoubtedly one of the most important events preceding the occurrence of
      structural abnormalities, regardless of their nature. Therefore understanding the
      mechanisms involved in physiological as well as in disturbed or dysregulated
      apoptosis may lead to the development of new methods of preventive treatment of
      various developmental abnormalities. The present review summarizes data on the
      mechanisms of programmed cell death and concentrates on apoptosis involved in
      normal or disturbed gametogenesis and in normal and abnormal embryonic
      development.

PMID- 10575579
TI  - Pregnancy rate in IVF rescue in high responders to human menopausal gonadotropin.
AB  - PURPOSE: In vitro fertilization had been previously suggested by us as a means of
      "rescue" for patients with imminent ovarian hyperstimulation syndrome (OHSS)
      during treatment with human menopausal gonadotropin (hMG). We evaluated the
      pregnancy rate of rescued IVF cycles. METHODS: During the years 1994-1995, women
      treated with hMG and at risk of developing OHSS were referred to our IVF unit.
      Their estradiol level was above 1500 pg/ml, and eight or more follicles were
      observed by ultrasonography in all the patients. These high responders were
      offered the option to undergo ovum aspiration. We report the pregnancy rate in
      this group of patients. RESULTS: Thirty-nine women were referred to our unit for
      rescue IVF. Two were uneligible due to high progesterone concentrations. Thirty
      seven women underwent ovum pickup and 32 had embryo transfer. The clinical
      pregnancy rate was 40% (13/32). Only two women had clinical OHSS. CONCLUSIONS: We
      suggest that rescue IVF may be considered in hMG cycles of high responders with
      imminent OHSS. Rescue IVF offers a high rate of conception, avoids high-order
      multiple pregnancy, and appears not to increase the risk of OHSS in these women.

PMID- 10575580
TI  - Endometrial pattern on the day of oocyte retrieval is more predictive of
      implantation success than the pattern or thickness on the day of hCG
      administration.
AB  - PURPOSE: Multiple studies have confirmed a lower implantation (IR) and pregnancy
      rate (PR) in women who exhibit a homogeneous pattern (pattern II) of the
      endometrium compared to a triple-line pattern (pattern I) on the day of hCG
      administration. However, no data are available to evaluate if patients alter
      their endometrial thickness and pattern between the day of hCG administration
      (DhCG) and the day of oocyte retrieval (DRET) and whether these changes adversely
      affect endometrial receptivity. METHODS: We prospectively evaluated 86 women
      (mean age, 32.9 +/- 3.8 years; range, 24-40 years) undergoing 103 IVF/ET cycles.
      RESULTS: Pattern II was noted in 7 cycles (6.8%) on DhCG, compared to 96 cycles
      with pattern I (93.2%). However, 20 cycles (19.4%) had pattern II on DRET. The
      ongoing IR was 13.0% (3/23) in the pattern II group compared to 20.8% (76/365) in
      the pattern I group on DhCG (P = NS). However, a significant decrease in the
      ongoing IR, to 9.9% (7/71), was noted in pattern II, compared to 23.3% (71/305)
      in pattern I, on DRET (P = 0.019). There was no difference in age, basal FSH,
      peak E2, P4 on the day of hCG, number of oocytes, number of ET, or endometrial
      thickness between pregnant and nonpregnant patients, or between patients with
      pattern I and those with pattern II. A trend toward higher progesterone levels on
      DhCG was noted in women with pattern II (P = 0.078). CONCLUSIONS: Endometrial
      pattern, rather than thickness, on the day of oocyte retrieval appears to be an
      important prognosticator of endometrial receptivity.

PMID- 10575581
TI  - Clinical outcome of day 2 versus day 3 embryo transfer using serum-free culture
      media: a prospective randomized study.
AB  - PURPOSE: The objective was to evaluate whether extending the embryo culture
      period from 2 to 3 days would yield a more optimal selection of viable embryos,
      thereby increasing the implantation and live birth rates. METHODS: Patients
      undergoing in vitro fertilization with at least one oocyte fertilized were
      prospectively randomized to 2 or 3 days of embryo culture in serum-free media. On
      the basis of their morphology and cleavage rate, a maximum of three embryos was
      selected for transfer. RESULTS: Embryos transferred on day 2 or day 3 were
      similar morphologically, however, a higher proportion of retarded embryos was
      observed on day 3. The implantation rate was 15.8 and 14.3% for day 2 and day 3
      transfers, respectively. The increase in live birth rate from 18.5 to 22.6%,
      possibly suggesting a better embryo selection on day 3, was not statistically
      significant. CONCLUSIONS: Extending the embryo culture period from 2 to 3 days
      had no effect on implantation and live birth rates.

PMID- 10575582
TI  - The preovulatory serum estradiol pattern in natural IVF/ICSI cycles.
AB  - PURPOSE: The aim of the study was to find whether inferences to the possible
      success of natural IVF/ICSI cycles could be drawn from the estradiol (E2)
      pattern. METHODS: Sixty-eight women who underwent oocyte recovery in 98 natural
      cycles were recruited for the study. Daily serum E2 was measured in the
      preovulatory phase (-3 to +2 day). The E2 pattern was compared among four groups:
      Group A, unsuccessful egg retrieval; Group B, no fertilization; Group C, no
      implantation; and Group D, implantation. RESULTS: There was no difference in mean
      E2 levels between groups. Only the ratio of E2 on day +1/E2 on day 0 was
      significantly lower in conception cycles in comparison with nonconception cycles.
      In cycles with a decreased E2 level on day +1, only the implantation rate was
      significantly higher in comparison with cycles with an increasing E2 level.
      CONCLUSIONS: From the E2 pattern it is possible to make inferences about the
      likelihood of implantation but not the fertilization or oocyte recovery success.

PMID- 10575583
TI  - Relationship between the sperm motility index assessed by the sperm quality
      analyzer and the outcome of intracytoplasmic sperm injection.
AB  - PURPOSE: Intracytoplasmic sperm injection (ICSI) has been validated as a useful
      treatment in severe male-factor patients who could not achieve fertilization and
      live births by conventional in vitro fertilization treatment. To examine the
      impact of male factors on ICSI outcome, clinical laboratory data were
      retrospectively analyzed. METHODS: One hundred two cycles of ICSI treatment
      indicated by severe male-factor infertility were entered into this study. Sperm
      parameters including sperm motility, sperm concentration, and sperm motility
      index assessed by the Sperm Quality Analyzer were evaluated. RESULTS: Five
      hundred seventy-six metaphase II oocytes retrieved were manipulated. The normal
      fertilization (2 PN) rate per oocyte was 64.9 +/- 26.0% (mean +/- SD). Of the 99
      transfers, 31 clinical pregnancies were obtained, yielding an average pregnancy
      rate of 31.3% per transfer. The mean sperm motility, sperm concentration, and
      sperm motility index were 20.3 +/- 16.1% (range, 0 to 50%), 18.2 +/- 25.1 x
      10(6)/ml (range, < 1 to 150 x 10(6)/ml), and 31.2 +/- 45.0 (range, 0 to 220),
      respectively. Sperm concentration did not have a significant impact on
      fertilization rate by ICSI. In four cases, ICSI was performed using totally
      immotile sperm and the fertilization rate was 43.5%, which was significantly
      lower than that of some of the other sperm motility groups, and no pregnancy
      could be achieved. In 14 cases in which the sperm motility index assessed by the
      Sperm Quality Analyzer was 0, the fertilization rate (50.0%) was significantly
      lower than in most of the other sperm motility index groups. CONCLUSIONS: These
      findings suggest that in severe male-factor cases with totally immotile sperm or
      a sperm motility index of 0, the selection of good-quality sperm should be
      verified before injection.

PMID- 10575584
TI  - Mycoplasma-mediated uptake of the exogenous human BRCA1 gene by hatching
      blastocysts.
AB  - PURPOSE: Biological vectors for cell transfection are mainly viral in origin,
      with inherent shortcomings. Mycoplasmas are ubiquitous organisms that traverse
      cells easily. The objective was to determine if Ureaplasma urealyticum (T
      mycoplasma) would vector exogenous BRCA1 DNA into blastocysts. METHODS: Hatching
      mouse blastocysts (N = 70) were incubated in the presence of either viable or
      dead Ureaplasma urealyticum at 37 degrees C for 1 hr. The blastocysts were
      exposed to human BRCA1 DNA lacking homology in the mouse genome for 2 hr,
      followed by DNase-1 treatment and wash. Polymerase chain reaction and agarose gel
      electrophoresis analysis of amplified products were performed. RESULTS: The BRCA1
      gene was detected in the blastocysts only when viable Ureaplasma was present. PCR
      analyses of control Ureaplasma and untreated blastocysts were negative.
      CONCLUSION: Viable Ureaplasma organisms were shown to mediate the uptake of DNA
      fragments into blastocysts, resulting in transgenic mouse blastocysts with a
      normal human BRCA1 exon 11 gene.

PMID- 10575585
TI  - An accurate and rapid gender determination assay in single cells by the capillary
      polymerase chain reaction method.
AB  - PURPOSE: In preimplantation genetic diagnosis (PGD), a rapid and accurate assay
      has been required. We have therefore developed a capillary polymerase chain
      reaction (PCR) method using rapid thermal cycling programs to determine the
      gender of single amniocytes. METHODS: Single amniocytes from each amniotic fluid
      sample were isolated by micromanipulation and their gender was determined by a
      multiplex PCR assay in a capillary tube, using primers that amplify a 308-bp DXZ1
      and a 154-bp DYZ1 repeat sequence on the X and Y chromosomes, respectively.
      RESULTS: All four thermal cycling programs, which took 180, 150, 120, and 90 min,
      were 100% accurate in diagnosing the gender of single amniocytes. No DNA
      contamination was observed in any samples. CONCLUSIONS: The multiplex PCR assay
      was rapid and accurate in diagnosing gender in single cells and may be clinically
      applicable in PGD.

PMID- 10575586
TI  - Globulins in protein supplements promote the development of preimplantation
      embryos.
AB  - PURPOSE: Our purpose was to investigate the effect of alpha- and beta-globulins
      contained in protein supplements on the development of preimplantation embryos.
      METHODS: Mouse one-cell embryos were cultured in medium supplemented with 4 mg/ml
      human serum albumin (HSA), 4 mg/ml HSA plus human globulins (0.2, 0.4, 0.8, and
      1.6 mg/ml) that consisted predominantly of alpha- and beta-globulins, or 10%
      Plasmanate Cutter (PC). Blastocysts developed in media supplemented with these
      various protein sources were stained with Hoechst 33342 to determine the number
      of cells. RESULTS: Supplementation with 0.4 to 1.6 mg/ml globulins or PC
      significantly increased the rate of blastocyst development compared with that
      observed with the addition of HSA. Supplementation with globulins significantly
      increased the hatching rate in a dose-dependent manner. The number of cells in
      the blastocysts was significantly increased when the embryos were cultured with
      0.8 mg/ml of the globulins or PC. CONCLUSIONS: The present observations suggest
      that alpha- and beta-globulins in protein supplements promote embryo development
      and hatching.

PMID- 10575587
TI  - The response of bone to unloading.
AB  - Skeletal unloading leads to decreased bone formation and decreased bone mass.
      Bone resorption is uncoupled from bone formation, contributing to the bone loss.
      During spaceflight bone is lost principally from the bones most loaded in the 1-g
      environment, and some redistribution of bone from the lower extremities to the
      head appears to take place. Although changes in calcitropic hormones have been
      demonstrated during skeletal unloading (PTH and 1,25(OH)2D decrease), it remains
      unclear whether such changes account for or are in response to the changes in
      bone formation and resorption. Bed rest studies with human volunteers and
      hindlimb elevation studies with rats have provided useful data to help explain
      the changes in bone formation during spaceflight. These models of skeletal
      unloading reproduce a number of the conditions associated with microgravity, and
      the findings from such studies confirm many of the observations made during
      spaceflight. Determining the mechanism(s) by which loading of bone is sensed and
      translated into a signal(s) controlling bone formation remains the holy grail in
      this field. Such investigations couple biophysics to biochemistry to cell and
      molecular biology. Although studies with cell cultures have revealed biochemical
      responses to mechanical loads comparable to that seen in intact bone, it seems
      likely that matrix-cell interactions underlie much of the mechanocoupling. The
      role for systemic hormones such as PTH, GH, and 1,25(OH)2D compared to locally
      produced factors such as IGF-I, PTHrP, BMPs, and TGF-beta in modulating the
      cellular response to load remains unclear. As the mechanism(s) by which bone
      responds to mechanical load with increased bone formation are further elucidated,
      applications of this knowledge to other etiologies of osteoporosis are likely to
      develop. Skeletal unloading provides a perturbation in bone mineral homeostasis
      that can be used to understand the mechanisms by which bone mineral homeostasis
      is maintained, with the expectation that such understanding will lead to
      effective treatment for disuse osteoporosis.

PMID- 10575588
TI  - Tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) stimulate
      osteoclastic bone resorption.
AB  - As both tissue inhibitor of metalloproteinases-1 (TIMP-1) and TIMP-2 have been
      reported to inhibit bone resorption, we examined whether TIMP-1 or TIMP-2 in
      fetal calf serum (FCS), with which culture media were supplemented, affected
      osteoclastic bone resorption in vitro. Contrary to our expectation, almost
      complete suppression of osteoclastic bone resorption was observed when both TIMP
      1 and TIMP-2 were removed from the FCS. Bone resorption was, however, almost
      fully restored by the addition of recombinant TIMPs. TIMPs stimulate bone
      resorption at significantly lower concentrations (approximately ng/ml) than those
      (approximately micrograms/ml) required to inhibit bone resorption. To understand
      the mechanism of TIMP-dependent bone resorption, we counted and compared the
      number of tartrate-resistant acid phosphatase-(TRAP-) positive and multinuclear
      cells in cultures containing either 10% FCS or TIMP-1-free and/or TIMP-2-free
      FCS. There was essentially no difference in number among these, suggesting that
      the TIMP role seems to be related to the functional expression of osteoclasts.
      Metalloproteinase inhibitors, either BE16627B[L-N-(N-hydroxy-2
      isobutylsuccinynamoyl)-seryl-L-val ine] or R94138 ?N-methyl-(3S)-2-[(2R)-2
      hydroxycarbamoylmethylundecanoyl] hexahydropyridazine-3-carboxamide?, could not
      replace TIMPs, suggesting that the osteoclast-stimulating activity of TIMPs
      cannot be ascribed to merely their inhibitory effect on matrix
      metalloproteinases.

PMID- 10575589
TI  - Treatment effects of bisphosphonates on ovariectomy-induced osteopenia in rats:
      comparison between clodronate and etidronate.
AB  - We studied the effects of clodronate and etidronate on bone loss induced by
      ovariectomy (OVX) in rats. Drug administration was initiated 8 weeks after the
      surgery and continued for 12 weeks (twice per week, s.c.). Lumbar (L4-L5) bone
      mineral density (BMD) and femoral BMD in the sham-operated group were increased
      to 113% and 114%, respectively, whereas those in OVX group were suppressed to
      98.8% and 105%. Clodronate significantly restored the suppressed BMD over the
      entire dose range used (4-25 mg/kg). Etidronate restored BMD only at 4 mg/kg. In
      a histomorphometric analysis of lumbar vertebrae, both bisphosphonates depressed
      the amount of labeled surface, which was increased by OVX, to 11.9%-20.1% of the
      OVX group value for clodronate and to 0.23%-9.7% of the OVX group value for
      etidronate. The osteoid area was significantly increased by etidronate treatment
      over the entire dose range (OS/BS, 175%-295%). On the other hand, the osteoid
      area in the clodronate group did not increase at any dose tested (OS/BS, 38.1%
      49.9%). Urinary excretion of deoxypyridinoline and plasma level of osteocalcin
      were elevated in the OVX group (162%-182% and 123%, respectively), suggesting
      that OVX enhanced bone turnover. Both bisphosphonates suppressed the bone
      turnover accelerated by OVX, and the data indicated that both bisphosphonates
      recovered BMD by means of inhibition of bone resorption. These data suggested
      that clodronate and etidronate reversed osteopenia induced by ovariectomy in
      rats. As judged from the dose response of BMD and histomorphometric findings,
      clodronate showed a wider safety margin than etidronate.

PMID- 10575590
TI  - Effects of sciatic neurectomy on the femur in growing rats: application of
      peripheral quantitative computed tomography and Fourier transform infrared
      spectroscopy.
AB  - The effects of unilateral sciatic neurectomy (USN) on the development of the
      femur were studied in 15 growing Wistar-derived rats (age, 5 weeks). The rats
      were divided into four groups: USN-operated group (right femur), USN-nonoperated
      group (left femur), sham-operated group (right femur), and sham-nonoperated group
      (left femur). Bone mineral density (BMD), bone mineral content (BMC), bone area,
      periosteal circumference, and endosteal circumference were measured by peripheral
      quantitative computed tomography (pQCT) and the mineral/matrix ratio was
      evaluated by Fourier transform infrared spectroscopy (FTIR). The USN-operated
      group showed a significant decrease in cortical BMC, bone area, and periosteal
      circumference compared with the other groups (P < 0.05). The cortical BMD did not
      vary significantly between the groups. In the cancellous bone, the USN-operated
      group showed a significant decrease in BMD and BMC at the metaphysis compared
      with the other groups (P < 0.05). The mineral/matrix ratio of the cortical bone
      did not differ significantly between the USN-operated and USN-nonoperated groups.
      These results suggest that in cortical bone, USN inhibits periosteal bone
      formation but has no significant effect on the mineral/matrix ratio of cortical
      bone in femurs. In cancellous bone, USN induces bone loss at the metaphysis.

PMID- 10575591
TI  - Inhibitors of protein synthesis and RNA synthesis protect against okadaic acid
      induced apoptosis in human osteosarcoma cell line MG63 cells but not in Saos-2
      cells.
AB  - In a previous study, we demonstrated that the protein phosphatase inhibitors,
      okadaic acid and calyculin A, induced apoptosis in human osteosarcoma cell lines,
      Saos-2 and MG63 cells. In the present study, to determine if new gene
      transcription and protein synthesis are required for okadaic acid-induced
      apoptosis in Saos-2 and MG63 cells, the cells were treated for 48h with varying
      concentrations of the inhibitors of protein or RNA synthesis, i.e.,
      cycloheximide, actinomycin D, and puromycin, in the presence of a fixed dose of
      okadaic acid. All these reagents in different concentrations prevented the
      okadaic acid-induced apoptosis in MG63 cells in a dose-dependent fashion. The
      same concentrations of cycloheximide, actinomycin D, or puromycin alone did not
      induce any apoptotic features in MG63 cells. However, not all the aforementioned
      reagents affected okadaic acid-induced apoptosis in Saos-2 cells. Okadaic acid
      induced and cycloheximide-prevented apoptosis was shown by phase-contrast
      microscopy, WST-1 assay, direct visualization of nuclear condensation and
      fragmentation of chromatin, and the characteristic DNA ladder formation on
      agarose gel electrophoresis. The present results indicate that the induction of
      new cell death genes and ongoing protein synthesis may have a role in okadaic
      acid-induced apoptosis in MG63 cells and that such proteins are not required in
      Saos-2 cells.

PMID- 10575592
TI  - Immunohistochemical localization of fibroblast growth factor receptors in the rat
      mandibular condylar cartilage and tibial cartilage.
AB  - The fibroblast growth factor receptors (FGFRs), members of the tyrosine-kinase
      receptor family, are known to play a crucial role in the growth and development
      of cartilaginous tissues. The mandibular condylar cartilage has been suggested to
      have a characteristic growth pattern compared with the tibial growth plate
      cartilage, e.g., cell alignment, mode of proliferation and differentiation, and
      response to humoral and mechanical factors. To examine the mRNA expression and
      localization of fibroblast growth factor receptor (FGFR)-1, -2, and -3 in the
      condylar and tibial growth plate cartilages, reversed transcribed polymerase
      chain reaction (RT-PCR) assay and immunohistochemistry were carried out using
      growing rats. The enzymatically isolated rat condylar and tibial chondrocytes
      expressed mRNA of aggrecan and type II collagen, which are together known as the
      major cartilaginous extracellular matrices. Both types of cells expressed mRNA of
      FGFR-1, -2, and -3 by RT-PCR. In the neonatal rat, immunolocalization of FGFR-1, 
      2, and -3 was found in the middle of the condylar cartilage, mainly in the
      hypertrophic zone of the tibial cartilage. At 3 weeks old, the three FGFRs were
      broadly observed in both cartilages. At 8 weeks old, localization of FGFR-3 was
      absent in the hypertrophic cell layer of the condyle, whereas it was still
      broadly observed in the tibial growth plate cartilage. In the same stage, FGFR-1
      and FGFR-2 showed similar localization in both cartilages to that at 3 weeks of
      age. All these observations suggest that FGFRs play an important role in the
      differential growth pattern of the condylar cartilage.

PMID- 10575593
TI  - Microstructure of the trabecula and cortex of iliac bone in primary
      hyperparathyroidism patients determined using histomorphometry and node-strut
      analysis.
AB  - The purpose of this study was to use histomorphometry to compare the
      microstructure of trabecular and cortical bone in patients with primary
      hyperparathyroidism (PH) with that seen in osteoporosis. Histomorphometric and
      node-strut analyses of iliac bones were performed on 11 female patients with PH
      (61.3 +/- 8.0 years old) and 61 age-matched female patients with involutional
      osteoporosis (OP) (63.6 +/- 5.6 years old). Cancellous bone volume (BV/TV),
      trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation
      (Tb.Sp), and wall thickness (W.Th) were not significantly different in these two
      groups. The bone formation rate (BFR) tended to be higher in the PH group than in
      the OP group. The number of nodes (N.Nd/TV) and node-to-node strut length
      (Nd.Nd/TV) were significantly higher in the PH group than in the OP group. The
      number of termini (N.Tm/TV) and terminus-to-terminus strut length/total strut
      length (Tm.Tm/TSL) were significantly lower in the PH group; cortical porosity
      was significantly higher in the PH group than in the OP group. No correlation was
      found between age and N.Nd in the PH group, but there was a negative correlation
      between age and N.Nd in the OP group. Our results show that trabecular
      connectivity was maintained while cortical porosity deteriorated in patients with
      PH compared with OP. These results suggest that there are microstructural
      differences between PH and OP in cancellous and cortical bone that result from
      the bone remodeling sequence in humans.

PMID- 10575594
TI  - Comparison of antiresorptive activities of ipriflavone, an isoflavone derivative,
      and elcatonin, an eel carbocalcitonin.
AB  - Thirty postmenopausal women with reduced bone mineral density were divided
      randomly into two groups based on the chronological sequence of their first visit
      to the Osteoporosis Clinic of Katsuragi Hospital. Group I was given 600 mg
      ipriflavone orally daily and group II was weekly injected intramuscularly with 20
      units elcatonin, Asu1-7 eel calcitonin (carbocalcitonin). Lumbar spine BMD was
      measured by dual-energy X-ray absorptiometry, and trabecular bone mineral density
      at the distal radius, cortical bone density, and relative cortical volume at the
      radial diaphysis by peripheral computed tomography before the beginning of the
      study and at the 4th, 8th, and 12th month. Markers of bone metabolism--serum
      total alkaline phosphatase, bone-specific alkaline phosphatase, tartrate
      resistant acid phosphatase, osteocalcin, intact osteocalcin, PICP and ICTP, and
      urinary pyridinoline, deoxypyridinoline, and calcium/creatinine (Ca/Cr)--were
      also measured at the same interval. Plasma parathyroid hormone (PTH) and
      calcitonin (CT) were measured at the same time. Radial trabecular bone density
      showed a significantly higher rate of increase in group I (ipriflavone group)
      than in group II (elcatonin group) at the 4th month, whereas lumbar spine BMD
      showed more pronounced increase in the elcatonin group than in the ipriflavone
      group throughout the study period. Bone metabolism markers tended to decline in
      both groups. Total and intact osteocalcin showed a significant fall from the
      baseline throughout the study period only in the ipriflavone group. Urine
      pyridinoline and deoxypyridinoline showed a significant fall from the baseline at
      the 12th month only in the ipriflavone group. On comparing bone gainers with
      increase of lumbar spine BMD by 2% or more with bone losers with a decrease by 2%
      or more, only urine Ca/Cr was significantly different, lower in the former than
      in the latter, despite the general tendency for bone resorption markers to
      decrease in bone gainers and to increase in bone losers.

PMID- 10575595
TI  - Bone mineral density in patients with ossification of the posterior longitudinal
      ligament in the cervical spine.
AB  - Bone mineral density (BMD) has not been clearly determined in patients with
      ossification of the posterior longitudinal ligament (OPLL) in the cervical spine.
      BMD in patients with OPLL was measured in the third vertebral body in the lateral
      projection and in the distal part of the radius in the anteroposterior projection
      using dual-energy X-ray absorptiometry (DXA). Patients with OPLL had
      significantly higher BMD than healthy controls in both the lumbar spine and
      radius. Observing BMD by gender and age group, high BMD was recognized especially
      in female patients over 60 years of age. Significantly increased BMD was observed
      in patients with ankylosing spinal hyperostosis (ASH) in addition to OPLL. These
      findings suggest that patients with OPLL may tend to develop systemic
      hyperostosis, leading to the pathological ectopic ossification observed in OPLL.

PMID- 10575596
TI  - Cervical myelopathy caused by destructive kyphotic spine in Cushing's disease.

PMID- 10575597
TI  - ADSA Foundation Scholar Award. Biology of dairy cows during the transition
      period: the final frontier?
AB  - The transition period, from 3 wk before to 3 wk after parturition, is critically
      important to health, production, and profitability of dairy cows. Most health
      disorders occur during this time. Compared with other stages of the lactation
      cycle, relatively little is known about fundamental biological processes during
      the transition period. The regulation and coordination of lipid metabolism among
      adipose tissue, liver, gut, and mammary gland are key components of the
      adaptations to lactation. Lipid accumulation in liver may contribute to health
      disorders and decreased milk production. Knowledge of key control points in
      hepatic metabolism of long-chain fatty acids is lacking, as is an understanding
      of the metabolic effects of hormones, growth factors, and cytokines that mediate
      stress. Recent evidence indicates that supplemental fats or restricted intakes
      before parturition can induce a coordinated set of metabolic changes in
      metabolism of long-chain fatty acids, including peroxisomal beta-oxidation,
      perhaps mediated by peroxisome proliferator-activated receptors. Estimates of the
      mixture of fuels constituting metabolizable energy in cows during the early
      postpartum period suggest that supply of amino acids and glucogenic compounds may
      be under proposed optima, whereas ketogenic and lipogenic compounds and long
      chain fatty acids may be in excess. Because dietary fat does not suppress body
      lipid mobilization, during the early postpartum period supplemental fat may
      further imbalance the mixture of fuels and lead to decreased dry matter intake.
      Increased understanding of the biology of the transition period should decrease
      health problems and increase profitability of dairy cows.

PMID- 10575598
TI  - Increase of intestinal Bifidobacterium and suppression of coliform bacteria with
      short-term yogurt ingestion.
AB  - To determine whether ingestion of yogurt would alter human intestinal bacterial
      composition and whether Bifidobacterium numbers would increase in the intestine,
      34 healthy volunteers were studied. The experimental period was 26 d, including
      an initial 8 d without yogurt, 10 d with three bottles (230 ml each) of AB yogurt
      per day (President Enterprise Corporation, Tainan, Taiwan), and 8 d without
      yogurt. Stool samples were taken at 3- to 4-d intervals. The bacteria of each
      fresh stool sample were promptly analyzed by dilution and culture on blood,
      MacConkey, Center for Disease Control and NNLP agars, the agar contained
      nalidixic acid, neomycin sulfate, LiCl, and paromomycin sulfate for aerobes,
      coliforms, anaerobes, and bifidobacteria, respectively. The number of bacteria
      was determined as colony-forming units per gram of dried stool. Results indicated
      that ingestion of AB yogurt increased the counts of anaerobic bacteria,
      suppressed aerobic bacteria, and significantly elevated the bifidus to coliform
      ratio. Arbitrarily primed polymerase chain reaction was used to differentiate the
      identity of bifidobacteria in four volunteers before and after yogurt ingestion
      and confirmed that B. bifidum ingested from the yogurt survived and proliferated
      in the stool throughout the experiment. However, the elevated bifidus to coliform
      ratio gradually diminished and disappeared after yogurt consumption was
      discontinued. In conclusion, ingestion of yogurt increased the numbers of stool
      bifidobacteria and suppressed coliform bacteria. The ingested bifidobacteria
      survived for more than 8 d after yogurt consumption was discontinued.

PMID- 10575599
TI  - Cholesterol removal from homogenized milk with beta-cyclodextrin.
AB  - This study was carried out to determine optimum conditions of five different
      factors (beta-cyclodextrin concentration, mixing temperature, mixing time,
      centrifugal force, and centrifugation time) in reduction of cholesterol in 3.6%
      fat, homogenized milk by application of beta-cyclodextrin. beta-Cyclodextrin at
      0.5 to 1.5% provided 92.2 to 95.3% removal of cholesterol when mixed at 10
      degrees C for 10 min. Among other factors, mixing time (5 to 20 min) did not
      significantly affect cholesterol removal. Removal was enhanced with increasing
      centrifugal forces up to 166x g (95.9%) but decreased thereafter. Various
      centrifugation times (5 to 20 min) did not have significant effects. Based on
      these results, we suggest that the optimum conditions for the process are
      addition of 1.5% beta-cyclodextrin, mixing temperature of 10 degrees C, 10-min
      mixing time, and centrifugation at 166x g for 10 min.

PMID- 10575600
TI  - Near-infrared spectroscopy for dairy management: measurement of unhomogenized
      milk composition.
AB  - The potential of near-infrared spectroscopy to measure fat, total protein, and
      lactose contents of unhomogenized milk was studied for use in dairy management,
      as a new tool for on-line milk analysis in the process of milking. Influence of
      the spectral region, sample thickness, and spectral data treatment on the
      accuracy of determination was investigated. Transmittance spectra of 258 milk
      samples, collected at different stages of the milking process, were obtained with
      a spectrophotometer (NIRSystems 6500; FOSS-NIRSystems, Silver Spring, MD) in the
      wavelength range from 400 to 2500 nm with sample thicknesses of 1 mm, 4 mm, and
      10 mm. The spectral region and sample thickness were found to be significant
      factors for milk fat and total protein determination but not the lactose
      determination. The best accuracy was obtained with the 1100 to 2400 nm region, 1
      mm sample thickness, and the first derivative data transformation. For the
      spectral region from 700 to 1100 nm, close accuracy was obtained for fat with a
      10-mm sample and for total protein with a 1-mm sample thickness. The sample
      thickness did not change significantly the accuracy of lactose determination.
      Different treatments of spectral data did not improve the calibrations for fat
      and protein. For the region from 700 to 1100 nm, where inexpensive on-line
      sensors could be used, the highest positive coefficients for fat were at 930,
      968, 990, 1026, 1076, and 1092 nm; for lactose were at 734, 750, 786, 812, 908,
      974, 982, and 1064 nm; and for total protein were at 776, 880, 902, 952, and 1034
      nm.

PMID- 10575601
TI  - Effects of bovine somatotropin and evaporative cooling plus shade on lactation
      performance of cows during summer heat stress.
AB  - Thirty-two Holstein cows (8 per treatment) averaging 195 d in milk were assigned
      to 70 d of treatment on the basis of production during a 14-d pretreatment
      period, which was used for covariate analysis. The experiment was a randomized
      block design with a 2 x 2 factorial arrangement of treatments. Factors were
      normal shade or shade plus evaporative cooling with pressurized spray, plus with
      or without the administration of bovine somatotropin (bST). Cows receiving bST
      were injected with 500 mg of bST every 14 d. All cows were fed the same total
      mixed rations twice daily at approximately 10% in excess of appetite, and water
      was offered free choice. There were no interactions between bST and the cooling
      system for any of the variables measured. Milk yield was increased by bST and
      tended to be greater for cooled cows. Fat percentages were increased by bST, and
      yields of fat, protein, and 3.5% fat-corrected milk, and the efficiency of
      conversion of dry matter to milk, whereas evaporative cooling increased body
      weights and protein yields, but decreased SNF and milk protein percentages.
      Rectal temperatures and respiration rates also were lower for cooled cows. And,
      bST increased nonesterified fatty acids in blood serum, suggesting that a part of
      the energy for increased milk production came from mobilization of body fat.
      Administration of bST effectively improved performance of cows under hot summer
      conditions whether evaporatively cooled or not.

PMID- 10575602
TI  - Effect of calcium soaps of fatty acids and administration of somatotropin on milk
      production, preovulatory follicular development, and plasma and follicular fluid
      lipid composition in high yielding dairy cows.
AB  - The effect of fat and bovine somatotropin (bST) on preovulatory follicular
      hormones and lipids was evaluated by feeding cows for 150 d from parturition a
      control diet, a control diet plus 0.55 kg/d of calcium soaps of fatty acids, or a
      control diet with 500 mg of bST injected every 14 d. Fourteen days after a
      synchronized or natural estrus, cows were injected with a PGF2 alpha analogue; 48
      h later, follicular fluid from all ovarian follicles > 8 mm was aspirated. Cows
      fed fat or injected with bST produced more milk and milk solids than did control
      cows, and cows on the bST treatment lost more body condition after calving than
      did cows on the other treatments. Both treatments changed the proportion of
      estradiol-active follicles (> 400 ng of estradiol/ml of follicular fluid) and the
      correlation between follicular fluid estradiol concentration and the total number
      large follicles per cow. In follicles aspirated between 60 and 90 DIM the
      percentage of estradiol-active follicles was 67, 40, and 0 for cows on the
      control, calcium soaps of fatty acids, and bST treatments, respectively. After 90
      DIM, no differences existed between treatments in the percentage of estradiol
      active follicles. Estradiol concentration in follicular fluid was correlated with
      DIM at follicle aspiration (r = 0.51). The proportion of oleic acid in free fatty
      acids in plasma at 50 DIM was lower in control cows and was lower in follicular
      fluid of estradiol-active follicles. Both calcium soaps of fatty acids and bST
      had a considerable effect on follicular development and activity and the
      composition of fatty acids in follicles.

PMID- 10575603
TI  - Efficacy of timed embryo transfer with fresh and frozen in vitro produced embryos
      to increase pregnancy rates in heat-stressed dairy cattle.
AB  - Our objective was to determine whether pregnancy rates in heat-stressed dairy
      cattle could be enhanced by timed embryo transfer of fresh (nonfrozen) or frozen
      thawed in vitro-derived embryos compared to timed insemination. Ovulation in
      Holstein cows was synchronized by a GnRH injection followed 7 d later by PGF2
      alpha and a second treatment with GnRH 48 h later. Control cows (n = 129) were
      inseminated 16 h (d 0) after the second GnRH injection. On d 7, a fresh (n = 133)
      or frozen-thawed (n = 142) in vitro-derived embryo was transferred to cows
      assigned for timed embryo transfer after categorizing the corpus luteum by
      palpation per rectum as 3 (excellent), 2 (good or fair), 1 (poor), and 0
      (nonpalpable). Response to the synchronization treatment, determined by plasma
      progesterone concentration (ng/ml) < or = 1.5 on d 0 and > or = 2.0 on d 7, was
      76.2%. Mean plasma progesterone concentration on d 7 increased as the quality of
      corpus luteum improved from category 0 to 3. Concentrations of progesterone in
      plasma were elevated (> or = 2.0 ng/ml) at 21 d in 64.7 (fresh embryo), 40.3
      (frozen embryo), and 41.4 +/- 0.1% (timed insemination) of cows, respectively.
      Cows that received a fresh embryo had a greater pregnancy rate at 45 to 52 d than
      did cows that received a frozen-thawed embryo or timed insemination (14.3 > 4.8,
      4.9 +/- 2.3%). Body condition (d 0) of cows influenced the pregnancy rate and
      plasma progesterone concentrations. In summary, timed embryo transfer with fresh
      in vitro-produced embryos in heat-stressed dairy cattle improved pregnancy rate
      relative to timed insemination.

PMID- 10575604
TI  - Effect of a monensin-controlled release capsule on cow health and reproductive
      performance.
AB  - Dry cows and pregnant heifers from 25 farms near Guelph, Ontario, Canada were
      enrolled in a large, double-blind, randomized clinical trial designed to evaluate
      the impact of monensin on energy metabolism, health, and production. A total of
      503 cows was given monensin in controlled-release capsules, and 507 cows were
      administered placebo capsules 3 wk before expected calving date. The effects of
      treatment on health were evaluated using a logistic regression model. Treatment
      with monensin significantly reduced the incidence of abomasal displacement (OR =
      0.41-0.84) and multiple illnesses (OR = 0.38-0.89). Monensin treatment tended to
      reduce the incidence of clinical ketosis (P = 0.11) and the risk of being culled
      (P = 0.09) in the first 94 d of lactation. Reproductive performance was analyzed
      with both a logistic regression model for conception rate and a survival analysis
      for days to first breeding and days from calving to conception. Treatment with
      monensin had no significant effect on any measure of reproductive performance.

PMID- 10575605
TI  - Effects of the presence of the mammary gland on expression of neutrophil adhesion
      molecules and myeloperoxidase activity in periparturient dairy cows.
AB  - Neutrophil function is reduced in periparturient dairy cows. Possible factors
      that reduce neutrophil function include endocrine changes associated with
      parturition and metabolic stresses associated with lactogenesis. In this study,
      mastectomized and intact cows were studied to specifically examine the effects of
      lactogenesis on neutrophil function in periparturient cows. Expression of
      adhesion molecules on neutrophils (L-selectin, mediating capture and rolling
      adhesion, and beta 2-integrin, mediating tight adhesion vital to egress) and
      neutrophil myeloperoxidase activity (an index of bactericidal activity) were
      assessed in mastectomized and intact cows. Expression of L-selectin decreased at
      parturition followed by rapid recovery to prepartum values in both intact and
      mastectomized cows. Expression of beta 2-integrins increased in intact cows at
      parturition but not in mastectomized cows. Expression of beta 2-integrins was
      greater in intact cows than in mastectomized cows throughout the study.
      Neutrophil myeloperoxidase activity decreased from baseline prepartum values as
      parturition approached in both intact and mastectomized cows, which suggests the
      endocrine changes associated with the act of parturition are predominant factors
      causing loss of neutrophil function. Myeloperoxidase activity recovered to
      prepartum values within a week of parturition in mastectomized cows; however,
      myeloperoxidase activity remained depressed in neutrophils obtained from intact
      cows throughout the first 20 d of lactation. The presence of the mammary gland
      and its attendant metabolic stresses slowed recovery of neutrophil function,
      which suggests that the metabolic stress of lactation exacerbated periparturient
      immunosuppression.

PMID- 10575606
TI  - Experimental Staphylococcus aureus intramammary challenge in late lactation dairy
      cows: quarter and cow effects determining the probability of infection.
AB  - The purpose of this study was to identify factors at the quarter and cow level
      that determine whether a quarter remains infected after an intramammary challenge
      with Staphylococcus aureus Newbould 305. A total of 135 cows were studied.
      Information on animal characteristics, cow-conformation, cow somatic cell count
      (SCC), and bacteriology, blood vitamin E levels, serology for retro-viral
      infections, bovine leukocyte adhesion deficiency-carrier status, and the presence
      of bovine lymphocyte antigens class I alleles was collected on each animal. All
      quarters of all cows were then challenged with Staphylococcus aureus Newbould
      305. The challenge with S. aureus Newbould 305 resulted in 28 cows (20.7%) that
      did not establish infection in any of the quarters, 21 (15.6%) cows had 1 quarter
      infected, 35 (25.9%) had 2 quarters infected, 24 (17.8%) had 3 quarters infected,
      and 27 (20.0%) had all quarters infected. A higher prechallenge SCC decreased the
      risk of infection. An infection with Corynebacterium bovis prior to challenge
      decreased the risk of S.aureus infection. Of the bovine lymphocyte antigen
      alleles, the presence of the W20A allele proved to be significantly associated
      with a decreased risk of infection. No other factors proved to be significant.

PMID- 10575607
TI  - Changes in milk protein fraction as affected by subclinical mastitis.
AB  - From cows that had both healthy quarters and quarters with subclinical mastitis
      [somatic cell count (SCC) 84,000 vs. 293,000/ml in bucket milk], foremilk, bucket
      milk, and stripping and residual milks were collected. Young milk was obtained
      1.5 h later following a repeated oxytocin injection. Compared with milk from
      healthy quarters, milk from quarters with subclinical mastitis showed elevated
      SCC, plasminogen, and protein and had increased activity of n-Acetyl-beta-D
      glucosaminidase (NAGase) and plasmin, as well as elevated portions of whey
      proteins and gamma-casein in the total protein. The SCC and the other mentioned
      parameters were also higher in the foremilk and the stripping and residual milks
      compared with bucket milk, independent of the udder health status; however,
      decreased values were found for total protein. Young milk showed an increase of
      SCC and n-Acetyl-beta-D-glucosaminidase activity compared with bucket milk.
      Because of lower levels of total plasmin and gamma-casein, we concluded that this
      young milk was newly synthesized milk containing some casein degradation products
      and that proteolysis of casein continued in the udder until the next milking. The
      n-Acetyl-beta-D-glucosaminidase activity was shown to be a better indicator for
      subclinical mastitis and correlated better with protein degradation than did SCC.

PMID- 10575608
TI  - A comparison of profitability and economic efficiencies between management
      intensive grazing and conventionally managed dairies in Michigan.
AB  - A retrospective cohort study was designed to determine differences in
      profitability, asset efficiency, operating efficiency, and labor efficiency
      between Michigan dairy farms implementing management-intensive grazing (MIG) and
      conventionally managed dairy farms. Financial information and labor use data for
      the calendar year 1994 were collected with surveys and personal interviews from
      35 MIG dairies and 18 conventionally managed dairies. Because the geographic
      distribution of MIG and conventionally managed farms in this study did not
      include Michigan's "dairy belt," extrapolation of these results to an average
      Michigan or Midwest dairy should be made with care. Within the areas represented,
      however, multivariate linear regression indicated that MIG dairies had more
      economic profit than conventionally managed dairies. They captured this profit by
      being more efficient in asset use, operating practices, and labor use. These
      results suggest that MIG could provide a sustainable alternate management tool
      for portions of Michigan's dairy industry.

PMID- 10575609
TI  - Monitoring daily milk yields with a recursive test day repeatability model
      (Kalman filter).
AB  - Mixed model methodology and recursive estimation techniques (Kalman filter) were
      combined to detect significant changes in the performance level of both
      individual cows and an entire herd. Yields were predicted for the next time of
      recording using all data available up to that time. Predicted yields were
      compared with actual measurements. If the error of prediction, or innovation,
      exceeded +/- 2 times its standard deviation, the observation was considered to be
      significantly different from the former yield level. The data comprised 30,199
      records for 135 cows and 366 d. Effects fitted in the model were test day, breed,
      and lactation class as fixed effects and cow within lactation number as a random
      effect. A lactation curve was fitted within lactation class. Of the observed milk
      yields, 9.2% deviated significantly from the expected value in a negative
      direction. None of the innovation of the fixed-day effect exceeded the threshold
      of two standard deviations. Compared with the results of rolling average, which
      were calculated as the average of a 10-d period, over 20% of the observations of
      the daily milk yield were classified differently by the two methods. The mixed
      model method for recursive estimation takes better account of environmental and
      lactational effects influencing daily milk yields as the rolling average. The
      mixed-model recursive estimation method was applicable for the detection of
      suspicious (i.e., outside a specified prediction interval) observations of
      individual cows at the time of the actual recording.

PMID- 10575611
TI  - Short communication: the effect of duodenal ammonia infusions on milk production
      and nitrogen balance of the dairy cow.
AB  - We hypothesized that an increased uptake of ammonia from the gut of dairy cows
      would increase the use of amino acids for urea synthesis and decrease the
      availability of amino acids for milk protein production, leading to a reduction
      in milk protein output. To test this hypothesis, four multiparous Holstein
      Friesian dairy cows offered a constant diet based on grass silage were
      continuously infused with ammonium acetate (ammonia) or acetic acid (control)
      into the duodenum for 5 d in each period of a changeover design experiment.
      Silage intake, rumen ammonia, pH and volatile fatty acid concentrations, and
      feces N excretion and whole body N balance were all unaffected by treatment,
      although urinary N excretion increased. Similarly, there was no effect of
      treatment on milk yields or on milk constituent yields. We concluded that ammonia
      absorption represents a loss of protein to the animal, but that it is unlikely to
      result in reduced amino acid availability for productive purposes such as
      lactation.

PMID- 10575610
TI  - Effects of dietary nitrogen manipulation on ammonia volatilization from manure
      from Holstein heifers.
AB  - Decomposition of livestock manure produces gaseous ammonia. Dietary manipulation
      is one means to reduce N in manure and ammonia volatilization. The effects of
      dietary crude protein concentration on N intake, N and urinary urea-N excretion,
      and ammonia volatilization were measured. Eight Holstein heifers (body weight =
      260 to 488 kg) were fed a total mixed ration containing either 9.6 or 11.0% crude
      protein in a crossover design. Oatlage and concentrate were fed at 77:23 (dry
      matter basis), and soybean meal was used to alter total dietary crude protein.
      Seven-day adjustment periods preceded 5-d collection periods. Indwelling urinary
      catheters were inserted 2 d prior to the collection periods. Daily feces and
      acidified urine were collected, stirred, and subsampled for total Kjeldahl N,
      urinary urea N, dry matter, P, K, and ash. Urine collection tubes were split
      during period 2 to allow for collection of unacidified samples for urea N and
      total N determinations. Unacidified urine and fecal samples were combined (1:1.3)
      for collection of volatilized ammonia. Remaining slurries were extracted for
      total and urea N. Increased dietary crude protein concentration increased N
      intake, N excretion, urea-N excretion, and N excreted in the urine by the
      heifers. Dietary manipulation of N intake by reduction of 14.0% (dry matter
      basis) resulted in a 28.1% decrease in ammonia emission and decreases in the urea
      N, total N, and percentage N excreted in the urine of 29.6, 19.8, and 7.4%,
      respectively. Ammonia volatilization was dependent on N quantity and form in the
      urine.

PMID- 10575612
TI  - Effects of rumen energy supply timing on feed intake control in lactating dairy
      cows.
AB  - The aim of this trial was to demonstrate the mechanisms and dynamics of signals
      triggered by digestion in the short-term control of feed intake. Large nylon bags
      containing rolled wheat were placed into the rumens of four fistulated cows-
      either prior to feed distribution or during a feeding period--and left for 4 h.
      To account for bag volume and its effects, bags full of indigestible sawdust were
      used as a control. The four treatments were compared according to a Latin square
      design with three replications. Regardless of their contents, when bags were
      present during the experimental feeding period, intake decreased by 1.2 kg of dry
      matter through a filling effect. Wheat in the bags had no specific effect on
      intake during the experimental intake period. Conversely, on the day after the
      experiment, the presence of wheat during feeding caused a 4.2-kg dry matter
      decrease in intake compared with the saw-dust control. This trial indicated that
      the nutritional feedback signaling effect on intake control during meals is
      delayed, contrary to that of rumen fill. Moreover, the delayed effect on intake
      is only observed when nutrient cues are synchronous with meals, and,
      consequently, could be the result of experience.

PMID- 10575613
TI  - Effects of dietary fiber on intake, milk yield, and digestion by lactating dairy
      cows during cool or hot, humid weather.
AB  - Lactating cows were offered diets with increasing neutral detergent fiber
      concentrations to determine the effects on intake, milk yield and composition,
      blood hormones, and nutrient digestion during cool or hot weather conditions.
      Tifton 85 bermudagrass hay was substituted for corn silage so that the forage
      portion of diets were: 1) 40% corn silage (control), 2) 32.4% corn silage, 7.6%
      bermudagrass, 3) 24.8% corn silage, 15.2% bermudagrass, or 4) 17.2% corn silage,
      22.8% bermudagrass (dry basis). Dietary neutral detergent fiber concentrations (%
      dry matter) were 30.2, 33.8, 37.7, and 42.0, respectively. Intake of dry matter
      declined with increasing dietary neutral detergent fiber during cool and hot
      periods, but intake adjusted for cool weather treatment differences did not
      change further during hot weather. Milk yield declined linearly with increasing
      neutral detergent fiber during cool weather and changed quadratically during hot
      weather. Milk temperature declined with increasing dietary neutral detergent
      fiber for the p.m. milking during the cool period and declined with increasing
      dietary neutral detergent fiber for the a.m. and p.m. milkings during the hot
      period. Digestibility of neutral detergent fiber improved and ruminal turnover of
      particulate digesta was increased with greater dietary neutral detergent fiber
      content. No dietary fiber level by hot weather interaction was observed,
      suggesting that total energy intake may have and a greater effect on milk yield
      than dietary fiber content during hot, humid weather.

PMID- 10575614
TI  - Identification and characterization of Enterococcus species isolated from forage
      crops and their influence on silage fermentation.
AB  - Forty-eight strains of lactic acid bacteria were isolated from forage crops, and
      their identification, characterization and influence on silage fermentation were
      studied. All isolates were Gram-positive, short-chain-forming, catalase-negative,
      and facultatively anaerobic cocci that did not produce gas from glucose, only
      formed L-lactic acid, and were able to grow at pH 9.6%, in 6.5% NaCl, or with 40%
      bile, but not below pH 4.5. These isolates were commonly isolated from forage
      crops, and they were divided into four groups (A, B, C, and D) according to sugar
      fermentation characteristics. Selected strains of FA 5, FA 27, FA 45, and FA 57
      were identified as Enterococcus hirae, E. faecalis, E. casseliflavus, and E.
      mundtii, respectively, on the basis of DNA-DNA homology, Strains FA 5, FA 27, FA
      45, and FA 57 and two strains from commercial inoculants, LC 10 (Lactobacillus
      casei) and LP 15 (L. plantarum), were used as additives to alfalfa and guinea
      grass silages. Alphalfa and guinea grass silages inoculated with LC 10, LP 15, FA
      5 + LC 10, and FA 5 + LP 15-treatments in alfalfa and guinea grass silages had
      significantly lower pH values, contents of butyric acid and ammonia nitrogen, gas
      production, and dry matter losses compared with the control silage after 60 d of
      fermentation. However, the E. hirae FA 5, E. faecalis FA 27, E. casseliflavus FA
      45, and E. mundtii FA 57-inoculated silages gave similar values to the control in
      both types of silage. The FA 27 + LC 10 and FA 27 + LP 15-inoculated silages did
      not differ in fermentation quality from LC 10 and LP 15-inoculated silages alone.
      The results confirmed that Enterococcus species were not able to improve silage
      quality.

PMID- 10575615
TI  - Effect of feeding macerated alfalfa silage on nutrient digestibility and milk
      yield in lactating dairy cows.
AB  - Five feeding studies were conducted with 141 lactating Holstein cows comparing
      macerated and control alfalfa silage harvested at two cuttings in each of 2 yr.
      Overall, silage made from macerated alfalfa contained more ash (suggesting
      improved soil contamination); greater fiber and lower nonprotein nitrogen (NPN)
      content suggested greater fermentation in the silo. In a digestion study, two
      diets were fed containing [dry matter (DM) basis] 72% of either control or
      macerated second-cutting alfalfa. Apparent digestibility of neutral detergent
      fiber and acid detergent fiber (ADF) was increased by maceration, and similar
      changes in digestibility were observed with Yb or indigestible ADF as marker;
      indigestible ADF was used as a marker in later studies. Lactation trials were
      conducted with first- and second-cutting alfalfa from each year. In each study,
      diets were formulated from alfalfa silage plus concentrate based on processed
      high moisture ear corn; mean compositions were (DM basis): negative control (61%
      control alfalfa silage), macerated (61% macerated alfalfa silage), and positive
      control (50% control alfalfa silage). All diets contained 2% crude protein from
      either roasted soybeans or low-solubles fish meal; soybean meal was added to make
      the positive control isonitrogenous (but not equal in ruminal undergraded
      protein). Milk yield was greater on macerated than negative control in two of
      four trials but not different in the other two trials. Yields of milk and milk
      components were not different between macerated and positive control in one of
      four trials. Versus the negative control, milk fat synthesis was depressed on
      macerated alfalfa in one trial. Overall performance on macerated versus negative
      control indicated greater apparent digestibility of organic matter (OM), greater
      yield of milk, protein, and solids not fat, but lower milk fat content. Yields of
      milk and milk components were greater overall on positive control versus
      macerated. Estimation of net energy for lactation (NEL) from maintenance, milk
      yield, and body weight gain indicated that control and macerated alfalfa silage
      contained, respectively, 1.36 and 1.42 Mcal of NEL of OM, an increase of about 5%
      due to maceration of alfalfa in these trials.

PMID- 10575616
TI  - Influence of carbohydrate source and buffer on rumen fermentation
      characteristics, milk yield, and milk composition in early-lactation Holstein
      cows.
AB  - The effects of concentrate to forage ratio and sodium bicarbonate (buffer)
      supplementation on intake, ruminal fermentation characteristics, digestibility
      coefficients, milk yield, and milk composition were examined in 4 cannulated
      Holstein cows (100 +/- 20 d in milk). A 4 x 4 Latin square design with 2 x 2
      factorial arrangement of treatments was implemented for 3-wk experimental
      periods. The 4 treatments were a 50:50 concentrate to forage ratio with 1.2% of
      dry matter (DM) and without added buffer and a 75:25 concentrate to forage ratio
      with (1.2% of DM) and without (0% of DM) buffer. The forage component of the
      ration was a 50:50 mixture of alfalfa and barley and triticale silage, and diets
      were fed ad libitum as a total mixed ration. Although feed intake was not
      influenced by treatments, substantial treatment differences were observed for
      milk yield and milk composition. Cows fed high-concentrate diet had lower ruminal
      pH, ruminal acetate, and butyrate concentrations, whereas propionate
      concentrations were significantly elevated. The addition of buffer, at both
      levels of concentrate inclusion, resulted in elevated total volatile fatty acids
      and acetate concentrations. We concluded that altering the forage concentrate
      ratio in the diet of lactation cows influenced milk yield and milk composition,
      but the addition of buffer to the diet prevented the elevation in trans-C18:1
      fatty acids in milk fat, and related milk fat depression, associated with feeding
      high-concentrate diets.

PMID- 10575617
TI  - Detection of putative loci affecting milk, health, and type traits in a US
      Holstein population using 70 microsatellite markers in a genome scan.
AB  - Quantitative trait loci affecting milk yield, health, and type traits were
      studied for seven large U.S. Holstein grandsire families using the granddaughter
      design. Seventy microsatellite markers located throughout the genome were
      selected for the quantitative trait loci scan. Effects of marker alleles were
      analyzed for 30 traits (21 type traits, 5 milk traits, 2 calving ease triats, and
      somatic cell score and productive life) and 16 canonical traits derived from type
      and production traits. Previously we reported results from 36 of these markers
      but have re-evaluated those results using a more robust analysis method. We
      report results from all 70 markers using permutation tests to calculate
      experiment-wise significance values, replacing the less stringent comparison-wise
      values previously reported. With this new methodology we detected 9 putative
      quantitative trait loci within specific families. Four markers were associated
      with effects on type traits on chromosomes 4, 5, 14, and 23. Two markers were
      associated with effects on protein percentage on chromosomes 6 and 14, and 3
      markers were associated with effects on productive life on chromosomes 2, 21, and
      23. Although these initial 70 microsatellite markers have been completed in the 7
      Holstein families, additional markers will need to be added to allow interval
      analysis of areas where putative QTL have been identified and to increase marker
      density where needed.

PMID- 10575618
TI  - Genetic analysis of herd life in Quebec Holsteins using Weibull models.
AB  - Survival analysis methodologies were used to study herd life in Canadian Holstein
      cows. Herd life was defined as true herd life or the length of time between first
      calving and censoring. True herd life adjusted for 305-d milk production was
      defined as functional herd life. Lifetime record (censored or completed) were
      from 331,147 Holstein cows registered in the Programme d'Analyse des Troupeaux
      Laitiers du Quebec (PATLQ) that calved for the first time between March 1, 1981
      and March 31, 1995. The Weibull (proportional hazards) model used to analyze true
      herd life and functional herd life contained a Weibull baseline hazard function
      and the time-dependent effects of year of first calving, lactation number by
      stage of lactation, annual change in herd size and herd-year (random), and the
      time-independent effects of the milk recording option (supervised or not) and age
      at first calving. The model for functional herd life included also the time
      dependent effect of herd-year-parity class of 305-d milk production. Genetic
      differences between sires with regard to the hazard function of their daughters
      was clearly demonstrated. The hazard rate followed a different pattern in later
      lactations, particularly in the first 240 d in milk. Older age at first calving
      was found to be associated with higher risks of culling. Changes in herd size had
      a small impact on the hazard function of animals. The hazard decreased as
      production of the cow increased. Heritability in the log scale was 0.09 for true
      herd life and 0.08 for functional herd life, but when heritability was expressed
      on the original scale, the estimates for the two traits were 0.19 and 0.15,
      respectively. The difference in the median survival between a bull with an
      estimated transmitting ability of 0.6 and another bull with an estimated
      transmitting ability of 1.3 was 690 d or 1.7 lactations. Rank correlations
      between the official estimated transmitting abilities for true herd life and
      functional herd life and those obtained in this study were 0.62 and 0.66,
      respectively.

PMID- 10575619
TI  - Short communication: quantitative trait loci analysis on 17 nonproduction traits
      in the New Zealand dairy population.
AB  - Seven New Zealand Holstein-Friesian families and two Jersey families, a total of
      274 sires, were analyzed in a granddaughter design for marker-quantitative trait
      loci associations. For 17 nonproduction traits (management, size, and
      conformation traits), an across-family analysis was undertaken using multimarker
      regression procedures. Threshold levels were set empirically by permuting the
      data. A quantitative trait locus for stature was identified on chromosome 14,
      which was significant at the 15% experimentwise level (suggestive linkage). The
      quantitative trait locus was identified to be segregating in three of the nine
      families.

PMID- 10575620
TI  - Clinical mastitis in primiparous Holsteins: comparisons of bovine leukocyte
      adhesion deficiency carriers and noncarriers.
AB  - The objective of this study was to determine the impact of bovine leukocyte
      adhesion deficiency on clinical mastitis incidence, severity, and duration in
      Holstein cows. Genomic DNA from milk of 847 Holstein cows in six Pennsylvania
      herds was used to determine bovine leukocyte adhesion deficiency genotypes (82 or
      9.7% carriers). Data on clinical mastitis incidence, severity, duration, and
      pathogen involved were collected during first lactation for the project cows. One
      hundred ninety-four cows had one or more clinical mastitis episodes; milk samples
      from each quarter with clinical mastitis were collected at discovery of the
      episode and were cultured following National Mastitis Council recommendations.
      The overall incidence of clinical mastitis was significantly affected by sire and
      herd-year-season of calving. In addition, incidence of clinical mastitis tended
      to increase with age at first calving. Severity and duration of clinical mastitis
      were impacted by the pathogen involved. Incidence of clinical mastitis from all
      pathogens, from coagulase-negative staphylococci, and from coliform bacteria was
      not significantly related to bovine leukocyte adhesion deficiency status.
      Carriers tended to have lower rates of mastitis from streptococci other than
      Streptococcus agalactiae when compared with noncarriers, but this result should
      be interpreted with caution because of the low frequency of mastitis from the
      streptococci. Bovine leukocyte adhesion deficiency status was unrelated to
      severity or duration of clinical episodes. Bovine leukocyte adhesion deficiency
      carriers are probably similar to noncarriers in resistance to clinical mastitis.

PMID- 10575621
TI  - Release characteristics of chitosan treated alginate beads: II. Sustained release
      of a low molecular drug from chitosan treated alginate beads.
AB  - The aim of this paper was to investigate the possible applicability of chitosan
      treated alginate beads as a controlled release system of small molecular drugs
      with high solubility. Timolol maleate (mw 432.49) was used as a model drug. The
      beads were prepared by the ionotropic gelation method and the effect of various
      factors (alginate, chitosan, drug and calcium chloride concentrations, the volume
      of external and internal phases and drying methods) on bead properties were also
      investigated. Spherical beads with 0.78-1.16 mm diameter range and 10.8-66.5%
      encapsulation efficiencies were produced. Higher encapsulation efficiencies and
      retarded drug release were obtained with chitosan treated alginate beads. Among
      the different factors investigated such as alginate, drug, chitosan and CaCl2
      concentrations, the volumes of the external and internal phases affected bead
      properties. The drying technique has an importance on the bead properties also.
      The release data was kinetically evaluated. It appeared that chitosan treated
      alginate beads may be used for a potential controlled release system of small
      molecular drugs with high solubility, instead of alginate beads.

PMID- 10575622
TI  - Effect of formulation variables on cis-platin loaded chitosan microsphere
      properties.
AB  - Chitosan microspheres containing cis-platin were prepared using a w/o emulsion
      system. Variables important for microsphere properties were investigated: these
      include; chitosan, cis-platin and glutaraldehyde concentrations, the types of
      chitosan and oil, the cross-linking process and stirring rate. Chitosan and
      glutaraldehyde concentrations, the types of oil and chitosan have a significant
      effect on cis-platin entrapment in chitosan microspheres. In general,
      incorporation efficiency was high and ranged from 28-99%. The type and
      concentration of chitosan affected cis-platin release from microspheres. The type
      of oil was also important for release properties. Cis-platin release from
      microspheres is characterized by an initial burst effect.

PMID- 10575623
TI  - Interaction of sesame oil with soybean phosphatidylcholine and their formation of
      small dispersed particles.
AB  - Stable aqueous dispersions of sesame oil (SO) were obtained by co-sonication with
      soybean phosphatidylcholine (PC) in the SO mole fraction range of 0.1-0.8. In
      order to clarify the dispersal mechanism, the dispersed particles were
      characterized and the interaction of SO with PC was investigated using several
      physicochemical techniques. Dynamic light scattering measurements showed that the
      diameter of the dispersed particles was 40-60 nm. The trapped aqueous volume
      inside the particles was determined fluorometrically using the aqueous space
      marker, calcein. The trapped volume in the SO/PC particles decreased remarkably
      with the addition of SO into small unilamellar vesicles of PC. The decline in
      fraction of vesicular particles was also confirmed by fluorescence quenching of N
      dansylhexadecylamine in the PC membrane by the addition of the quencher CuSO4.
      These results indicate that the excess SO separated from the PC bilayers is
      stabilized as emulsion particles by the PC surface monolayer. Monolayer-bilayer
      equilibrium of SO/PC mixtures was estimated by measurements of spreading and
      collapse pressures. The results showed that the coexistence of emulsion particles
      (surface monolayer of PC + core of SO) with vesicular particles (bilayer) was
      critically important for the formation of stably dispersed particles of the lipid
      mixture.

PMID- 10575624
TI  - Development of oral drug delivery system using floating microspheres.
AB  - Floating acrylic resin microspheres with an internal hollow structure were
      prepared by a solvent diffusion and evaporation method. The yield of microspheres
      depended on the diffusion rate of ethanol and/or isopropanol in the organic
      phase. They were successfully produced when a mixture of ethanol and isopropanol
      was used instead of ethanol alone. The mixing ratio of components in the organic
      phase affected the size and the yield of microspheres and the best results were
      obtained at the volume ratio of ethanol:isopropanol:dichloromethane (8:2:5).
      Direct introduction of the organic phase into the aqueous phase through a glass
      tube also significantly improved the yield by avoiding the contact of organic
      phase with the surface of water. The optimum rotation speed and temperature were
      250 rpm and 25 degrees C, respectively. Several different drugs with various
      physico-chemical properties were used as model drugs for encapsulation and
      release tests. When a drug had low solubility in dichloromethane and high
      solubility in both water and a mixture of ethanol/isopropanol, the loading
      efficiency was the lowest. The release profiles were significantly different
      depending on the solubility of a drug in the release medium and the physico
      chemical properties of an encapsulated drug.

PMID- 10575625
TI  - Niosomal delivery of 5-fluorouracil.
AB  - Non-ionic surfactant vesicles (niosomes) have shown promise as cheap, chemically
      stable alternatives to liposomes. Niosomes of spans (Sorbitan monoesters) have
      shown promise of commercial exploitation. Hence, niosomes were prepared of 5
      fluorouracil (FU) using different spans. Niomsomes were prepared by the hand
      shaking method (HSM), reverse phase evaporation (REV) and ether injection method
      (EIM) using a series of Spans, i.e. Span 20, 40, 60 and 80. HSM giving least
      permeable vesicles were used to study the effect of variables like type of Span,
      composition of lipid and total lipid concentration on entrapment efficiency (EE)
      and release rate. Span 40 and 60 released 40.9 and 37.1% drug in 6 h while Span
      20 and 80 displayed 52.2 and 57.1% release, respectively in the same time.
      Niosomes of Span 40 showed a mean vesicle size of 8.1 microns, EE of 15.3 +/-
      1.3% and released 78.6% drug in 6 h; inclusion of cholesterol reduced the vesicle
      size to 4.8 microns, EE to 12.3 +/- 0.9% and the release to 50.5% (in 6 h), while
      incorporation of dicetyphosphate further reduced the vesicle size to 3.87
      microns, EE to 10.9 +/- 1.1% and reduced release to 40.9% (in 6 h). Increase in
      the amount of lipid used translated into an almost linear increase in EE.
      Biodistribution of drug in rats was modified on encapsulation. The concentration
      of niosomal drug in liver, lung and kidney was increased while it decreased in
      intestine compared to free drug solution following intravenous administration.
      The niosomal formulation displayed higher and sustained plasma drug level profile
      compared to free drug solution. Pharmacokinetic calculations revealed an increase
      in half-life, area under the curve and decrease in volume of distribution of the
      drug on encapsulation. Thus, the study suggests that niosomes can act as
      promising carriers for 5-Fluorouracil.

PMID- 10575626
TI  - 5-fluorouracil loaded chitosan microspheres for chemoembolization.
AB  - In this study, chitosan microspheres were prepared by a suspension cross-linking
      technique. A petroleum ether/mineral oil mixture was used as the suspension
      medium which includes an emulsifier, e.g. Tween-80. Glutaraldehyde was used as
      the cross-linker. 5-Fluorouracil was incorporated in the matrix for the possible
      use of the microspheres in chemoembolization. The size and size distribution of
      the chitosan microspheres varied in the size range of 100-200 microns, by
      changing the emulsifier concentration, stirring rate, chitosan/solvent ratio and
      drug/chitosan solution ratio. In summary, the size and size distribution of the
      microspheres decreased when the emulsifier concentration and stirring rate were
      increased. Smaller microspheres with narrower size distributions were obtained
      when the chitosan/solvent ratio and drug/chitosan ratio were lower. It was
      possible to load the chitosan microspheres with 5-FU to a concentration of 10.4
      mg 5-FU/g chitosan. Around 60% of the loaded drug was released within the first
      24 h, then the release rate became much slower.

PMID- 10575627
TI  - Solid lipid nanoparticles (SLN/Lipopearls)--a pharmaceutical and cosmetic carrier
      for the application of vitamin E in dermal products.
AB  - Solid lipid nanoparticles (SLN, Lipopearls) are nanoparticles made from solid
      lipids by high pressure homogenization. Incorporation of chemically labile active
      ingredients into the solid lipid matrix protects against chemical degradation,
      which is shown for vitamin E. The SLN are physically stable in aqueous
      dispersions and also after incorporation into a dermal cream as proven by photon
      correlation spectroscopy and differential scanning calorimetry. Electron
      microscopy and atomic force microscopy data reveal the spherical shape of the SLN
      and the detailed structure of the particle surface. Ultrafine particles form an
      adhesive film leading to an occlusive effect on the skin. The occlusion promotes
      the penetration of vitamin E into the skin, as shown by the stripping test. In
      addition to chemical stabilization of active ingredients, occlusive effects on
      the skin and subsequent enhanced penetration of compounds, the SLN also possess a
      pigment effect covering undesired colours leading to an increased aesthetic
      acceptance by the customer.

PMID- 10575628
TI  - Protective colloids and polylactic acid co-affecting the polymorphic crystal
      forms and crystallinity of indomethacin encapsulated in microspheres.
AB  - The co-effect of protective colloids and polylactic acid (PLA) on the polymorphic
      crystal forms and crystallinity of indomethacin (IMC) in IMC-loaded PLA
      microspheres was investigated with differential scanning calorimetry, infrared
      spectroscopy and x-ray diffractometry, to evaluate the polymorphic crystal forms
      and crystallinity of IMC encapsulated in PLA microspheres. The surfactant, sodium
      dodecyl sulphate (SDS), was also used as a dispersing agent. The results indicate
      that the polymorphism and crystallinity of IMC encapsulated in IMC-loaded PLA
      microspheres was dependent on the type of protective colloid and PLA used. The
      amorphous state and alpha-form of IMC were found in the IMC-loaded PLA
      microspheres prepared using polysaccharide (pectin or beta-cyclodextrin) as a
      protective colloid or SDS as a dispersing agent. However, the amorphous and
      methylene chloride solvate of IMC seemed to exist in the IMC-loaded PLA
      microspheres prepared with the proteins (gelatin or albumin), synthetic cellulose
      derivative (methyl cellulose or hydroxylpropyl methylcellulose) or the synthetic
      nonionic polymer (polyvinyl alcohol, polyvinyl pyrrolidone or biosoluble polymer)
      as a protective colloid. PLA was found to express a certain crystallinity in
      microspheres and not be affected by the protective colloids, but it played a more
      important role in influencing the crystallization of IMC during
      microencapsulation than the protective colloids. No interaction occurred in the
      physical mixture of IMC and PLA, nor in the IMC-loaded PLA microspheres.

PMID- 10575629
TI  - In vitro and in vivo release properties of brilliant blue and tumour necrosis
      factor-alpha (TNF-alpha) from poly(D,L-lactic-co-glycolic acid) multiphase
      microspheres.
AB  - The dissolution properties of two model compounds, brilliant blue and tumour
      necrosis factor (TNF-alpha), from poly(D,L-lactic-co-glycolic acid) (PLGA)
      multiphase microspheres were investigated. In addition, the in vivo release of
      TNF-alpha from the microspheres, in mice, was studied. The microspheres were
      prepared by an anhydrous multiple emulsion solvent evaporation method. Multiphase
      microspheres containing brilliant blue exhibited a three phase release profile in
      vitro, and displayed a significantly lower level of dye released during the
      initial phase compared to conventional matrix-type microspheres. Slow release of
      the dye was observed during the second phase, which was followed by a
      disintegration of the polymer wall during the third phase of the release process.
      In vitro dissolution profiles of TNF-alpha were calculated by compensation for
      the simultaneous degradation of the protein in the dissolution medium. The
      initial burst release of TNF-alpha was significantly reduced with the multiphase
      microspheres. The three phase release profile, as seen with the dye, was not
      observed for the microspheres containing the TNF-alpha. The rate of release of
      the protein from the microspheres was determined in vivo by analysing the
      residual level of TNF-alpha remaining in the particles following intraperitoneal
      administration of the microspheres to mice. The release of the protein from the
      microspheres in vivo was significantly faster than predicted from the results of
      the in vitro studies. The absence of an initial burst release of TNF-alpha from
      the multiphase microspheres was reflected in a significant reduction in the
      plasma level of TNF-alpha when compared to the matrix-type microspheres and a
      solution of the protein. The controlled release property of the multiphase
      microspheres is expected to overcome the adverse reactions due to dose dumping
      that occurs following the local administration of TNF-alpha.

PMID- 10575630
TI  - ADP-ribosylation of tubulin by chicken NAD-arginine ADP-ribosyltransferase
      suppresses microtubule formation.
AB  - We obtained evidence that tubulin and actin, two major cytoskeletal proteins, are
      preferentially ADP-ribosylated in the bovine brain cytosol by NAD-arginine ADP
      ribosyltransferase purified from chicken polymorphonuclear leukocytes. ADP
      ribosylation of tubulin almost completely blocked self-assembly of the protein.
      The stoichiometry of ADP-ribose incorporation into unassembled and assembled
      tubulin was 6 and 2 mol/mol of tubulin, respectively. These findings suggest that
      sites of ADP-ribosylation in the unassembled tubulin molecule are crucial for
      tubulin assembly, and that covalently attached ADP-ribose moieties interfere with
      tubulin interaction by steric hindrance or conformational change. Thus, ADP
      ribosylation may be involved in cytoskeletal organization in the brain via the
      modification of tubulin.

PMID- 10575631
TI  - Effect of meal timing after resistance exercise on hindlimb muscle mass and fat
      accumulation in trained rats.
AB  - To study the effect of meal timing after exercise on body composition, 20 male
      rats were assigned to either a group fed a meal right after exercise (R) or a
      group fed a meal 4 h after exercise (L). Resistance exercise (squatting) was
      conducted from 6:00 to 7:00, 3 d/wk for 10 wk. Meals were consumed from 7:00 to
      8:00 and from 19:00 to 20:00 for R, and from 11:00 to 12:00 and from 19:00 to
      20:00 for L. The room was lighted from 7:00 to 19:00. After 10 wk, the body
      weight was comparable between the groups. The hindlimb muscle weight was higher
      in R than in L by 6% (p < 0.05), whereas the sum of the weight of perirenal,
      epididymal, and mesenteric adipose tissues was lower in R than in L by 24% (p <
      0.01). The soleus lipoprotein lipase (LPL) activity was higher in R than in L by
      70% (p < 0.01), and the activity negatively correlated with the adipose tissue
      weight (r = -0.49, p < 0.05). These results suggest the possibility that
      ingesting a meal right after resistance exercise may contribute to an increase in
      the muscle mass and to a decrease in the adipose tissue compared to ingesting a
      meal several hours later.

PMID- 10575632
TI  - Effect of dietary seal and fish oils on triacylglycerol metabolism in rats.
AB  - Eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids were distributed mainly in
      the sn-1 and 3 positions of seal oil triacylglycerol and in the sn-2 position of
      fish oil triacylglycerol. Seal oil or fish oil-rich fats having constant
      polyunsaturated/monounsaturated/saturated fatty acids and n-6/n-3 polyunsaturated
      fatty acid (PUFA) ratios were fed to rats for 3 wk. Control rats were fed on a
      fat containing linoleic acid as the sole PUFA. Seal oil more effectively lowered
      serum and liver triacylglycerol concentrations than fish oil. The activities of
      fatty acid synthase (FAS), glucose-6-phosphate dehydrogenase (G6PDH) and hepatic
      triacylglycerol lipase (HTGL) were significantly lower in the seal oil group than
      in the control group, whereas the activity of HTGL was significantly lower and
      the hepatic peroxisomal beta-oxidation and activity of lipoprotein lipase (LPL)
      in adipose tissue were significantly higher in the fish oil group than in the
      control group. These observations suggest that the predominant
      hypotriacylglycerolemic effect of seal oil is caused by the suppression of fatty
      acid synthesis.

PMID- 10575633
TI  - Molecular role of ascorbate in enhancement of NO production in activated
      macrophage-like cell line, J774.1.
AB  - Ascorbate-enhanced nitric oxide (NO) production in lipopolysaccharide (LPS)- and
      interferon-gamma (IFN-gamma)-activated macrophage J774.1 cells through the
      inducible nitric oxide synthase (iNOS) pathway. The iNOS gene was synergistically
      induced by LPS and IFN-gamma. The inductive mechanism of ascorbate on the iNOS
      gene was studied by examining the degradation of I kappa B alpha by Western
      blotting, activation of the nuclear factor kappa B (NF-kappa B) by gel shift
      assays, and protein levels of interferon regulatory factor 1 (IRF-1) in LPS- and
      IFN-gamma-activated cells. Ascorbate had no effect on the onset of either I kappa
      B alpha degradation or the nuclear translocation of NF-kappa B, but it delayed
      the recovery of I kappa B alpha. The prolonged degradation of I kappa B alpha
      caused by ascorbate in LPS- and IFN-gamma-activated cells paralleled elevated NF
      kappa B binding to DNA, which led to an increase in the iNOS protein level.
      Ascorbate alone did not induce I kappa B alpha degradation or NF-kappa B
      activation. Furthermore, ascorbate exerted no effect on the expression of I kappa
      B alpha and ubiquitin genes in the activated cells. Ascorbate could modulate NF
      kappa B DNA binding activity in response to combined LPS and IFN-gamma
      activation, which increases NO production in activated macrophages.

PMID- 10575634
TI  - Effect of dietary sesamin on metabolic fate of an exogenous linolelaidic acid in
      perfused rat liver.
AB  - To estimate the relative significance of exogenous and endogenous fatty acid
      substrates in decreasing hepatic triacylglycerol secretion after sesamin feeding,
      livers from rats fed diets supplemented with and without sesamin (sesamin:
      episesamin, 1:1, w/w) were perfused in the presence and absence of an exogenous
      di-trans isomer of linoleic acid (linolelaidic acid, trans,trans-9,12
      octadecadienoic acid). Both exogenous trans fatty acid and dietary sesamin, as
      compared with respective controls, resulted in a marked increase in hepatic
      ketogenesis; however, the beta-hydroxybutyrate to acetoacetate ratio was elevated
      by exogenous fatty acid and decreased by dietary sesamin. On the other hand,
      hepatic secretions of triacylglycerol, phospholipid and cholesterol were markedly
      lowered in rats fed sesamin, especially when exogenous fatty acid substrate was
      provided. The relative significance of the exogenous fatty acid was observed in
      the dietary sesamin-induced decrease in hepatic secretion of triacylglycerol.
      These results suggest that increased fatty acid oxidation by dietary sesamin, as
      reflected by enhanced ketone body production, leads to decreased partition of
      fatty acid substrates to the esterification pathways, and this in turn reduces
      the synthesis and secretion of triacylglycerol. The altered metabolism of
      exogenous fatty acids in the liver was therefore a major determinant for the
      synthesis and secretion of triacylglycerol.

PMID- 10575635
TI  - Adequacy of maternal pyridoxine supplementation during pregnancy in relation to
      the vitamin B6 status and growth of neonates at birth.
AB  - To evaluate the adequacy of maternal pyridoxine supplementation during pregnancy
      for both maternal and neonatal status at birth, vitamin B6 status, assessed by
      plasma pyridoxal phosphate (PLP), pyridoxal (PL) and total aldehyde vitamer (PLP
      + PL) concentrations, and the growth of neonates, including weight, length, head
      and chest circumferences, were examined for 209 neonates whose mothers were
      supplemented with 0, 1, 2 or 3 mg pyridoxine.HCl (PN.HCl)/d during pregnancy.
      Maternal PN.HCl supplementations were positively correlated to both maternal (r =
      0.62) and cord (r = 0.78) plasma PLP concentrations (p < 0.0001). Mothers
      supplemented with 2 or 3 mg/d PN.HCl had significantly higher plasma
      concentrations of PLP and total B6 aldehyde vitamer in maternal and cord blood
      compared with those receiving 0 or 1 mg PN.HCl/d. A growth benefit for neonates
      whose mothers had maternal and cord plasma PLP concentrations > or = 40 nM was
      revealed by the maternal supplementation of 2 mg PN.HCl/d during pregnancy. Thus,
      in healthy pregnant women, according to our study, a daily supplement of 2 mg
      PN.HCl provides the adequacy of maternal and neonatal vitamin B6 status and the
      satisfactory growth of neonates at birth.

PMID- 10575636
TI  - Tryptophan-niacin metabolism in liver cirrhosis rat caused by carbon
      tetrachloride.
AB  - We investigated the change of tryptophan-niacin metabolism induced by carbon
      tetrachloride (CCl4) in rats with liver cirrhosis. The rats were injected with
      CCl4 (0.5 or 1 mL of 50% olive oil solution/kg body weight) twice a week for 1 or
      2 mo and given phenobarbital water simultaneously. The urinary excretions of
      nicotinamide (Nam) and its metabolites were assayed. As the result, the urinary
      excretion of Nam, N1-methyl-4-pyridone-3-carboxamide (4-Py), Nam + N1
      methylnicotinamide (MNA) + N1-methyl-2-pyridone-5-carboxamide (2-Py) + 4-Py was
      lower in the CCl4-treated groups than in the non-treated group (control)
      regardless of the experimental period (1 mo and 2 mo) or dosing amount of CCl4
      (0.5 and 1 mL). Moreover, we investigated which pathway of tryptophan-niacin
      metabolism was affected in CCl4-treated rat. As the result, the possibility that
      the MNA-->4-Py reaction is inhibited by CCl4 treatment was suggested in this
      experiment.

PMID- 10575637
TI  - Vitamin B6 down-regulates the expression of human GPIIb gene.
AB  - Glycoprotein IIb (GPIIb) is the alpha-subunit of the platelet membrane receptor
      GPIIb/IIIa, which plays a major role in platelet aggregation. Vitamin B6 has been
      reported to be an antiaggregative agent, although its mechanism is not well
      known. To understand the molecular mechanism of vitamin B6 on antiaggregation, we
      analyzed the effects of various forms of vitamin B6 on the expression of human
      GPIIb promoter using chloramphenicol acetyl transferase (CAT) as the reporter
      gene. The GPIIb promoter region was amplified by polymerase chain reaction (PCR),
      cloned into pBLCAT3 to drive the CAT reporter gene and transfected into human
      erythroleukemia (HEL) cells. Transient expression of the GPIIb promoter was
      determined after transfected cells were treated with 1 microM pyridoxine (PN),
      pyridoxal (PL), pyridoxal-5-phosphate (PLP), or 4-deoxypyridoxine (4-dex) for 48
      h. Our results show that the GPIIb promoter activity was down-regulated to 54, 35
      and 63% in the presence of PN, PL and PLP, respectively, as compared to an
      untreated control whose promoter activity was 100%. However, no adverse effect on
      GPIIb promoter was detected by 4-dex, which is an antagonist of vitamin B6. The
      down-regulation effect of vitamin B6 on GPIIb promoter activity may lead to a
      reduction of GPIIb protein expression and thus be detrimental to platelet
      aggregation.

PMID- 10575638
TI  - Effect of dietary protein quality on the brain protein synthesis rate in aged
      rats.
AB  - The purpose of this study was to determine whether the quality of dietary protein
      affects the rate of brain protein synthesis in aged rats. Experiments were
      conducted on three groups of aged rats (30 wk) given diets containing 20 g
      casein, 20 g gluten or 20 g gelatin/100 g for 10 d. The fractional rates of
      protein synthesis in the brain, liver and kidney declined with the decrease in
      quality of dietary protein. In the brain, liver and kidney, the RNA activity [g
      protein synthesized/(g RNA.d)] correlated significantly with the fractional rate
      of protein synthesis. The RNA concentration (mg RNA/g protein) was not related to
      the fractional rate of protein synthesis in any organ. The results suggest that
      the rate of protein synthesis in the brain declines with the decrease in quality
      of dietary protein consumed by aged rats, and that RNA activity is at least
      partly related to the fractional rate of brain protein synthesis.

PMID- 10575639
TI  - Immunochemical characterization of ovomucoid from Japanese quail egg white using
      monoclonal antibodies.
AB  - The ovomucoid of Japanese quail egg white is known as a proteinase inhibitor or
      protein component responsible for egg allergy. In order to characterize the
      antigenic properties of ovomucoid in relation to its molecular structure, we have
      prepared two monoclonal antibodies, E9 (IgG1) and E11 (IgG1), recognizing
      distinct epitopes from each other. These monoclonal antibodies bound to the
      SDS/mercaptoethanol-treated ovomucoid, but not to the reductively
      carboxymethylated and pyridylethylated ovomucoid. By immunoblotting analysis of
      the peptic digests of ovomucoid, it was shown that E9 bound to the fragment
      consisting of two domains, I and II, of the ovomucoid, and that E11 reacted with
      the fragment containing domain III. These results indicate that the antigenic
      activity depends on the conformational structure of domains tightly folded by
      disulfide linkages. Ovomucoids from hen and duck were also recognized by both the
      antibodies, although having less affinity compared to the one from Japanese
      quail. These antibodies proved to be effective in establishing an enzyme-linked
      immunosorbent assay system for quantitative analysis of quail ovomucoid.

PMID- 10575640
TI  - Mechanism in inhibitory effects of vitamin K2 on osteoclastic bone resorption: in
      vivo study in osteopetrotic (op/op) mice.
AB  - Osteoclast deficiency in op/op mice was cured by a single injection of 5
      micrograms recombinant human macrophage colony-stimulating factor (M-CSF). On d
      5, the osteoclast number reached a maximum value. By d 15, the osteoclast number
      had decreased to about 70% of the maximum level. Moreover, by d 20, the
      osteoclast number had decreased to about 30% of its maximum level. On d 5, the
      osteoclast number of vitamin K2 12 h previously had decreased to about 30% of the
      M-CSF-only injected mice. Moreover, on d 5, the osteoclast number of the mice
      receiving a single injection of vitamin K2 24 h previously had decreased to about
      15% that of mice injected only with M-CSF. These results indicate that vitamin K2
      inhibits in vivo osteoclast formation. On d 20, the osteoclast number of the mice
      injected with a single dose of vitamin K2 12 or 24 h previously had decreased to
      0% compared with those receiving only M-CSF. The present results suggest that the
      vitamin K2 "causes cell death" to mature osteoclasts and inhibits in vivo
      osteoclast formation.

PMID- 10575641
TI  - Orthopaedic residency training: a survey of the graduates' perspective.
AB  - STUDY DESIGN: A survey of residency graduates. OBJECTIVES: To establish a profile
      of the typical graduate and to determine the value and influence of residency
      training on professional development, particularly on clinical expertise.
      BACKGROUND: Physical therapists are involved in direct access in some states as a
      result of health care reform. There is increasing interest within the physical
      therapy profession in evaluating residency education as an avenue for providing
      physical therapists with the advanced skills to meet the changing nature of
      providing care. METHODS AND MEASURES: A questionnaire was sent to 98 graduates of
      a year long advanced orthopaedic manual therapy residency program. A response
      rate of 94.9% was obtained. RESULTS: Influence of residency training on clinical
      skills and expertise received high ("major positive") ratings on the abilities to
      logically reason (94%), thoroughly examine (95%), treat effectively (84%) and
      efficiently (79%), and to "diagnose" (85%). Graduates spend 23% of their time
      teaching in some manner. Autonomy of decision making was the primary factor (43%)
      in determining place of work. CONCLUSIONS: The results of this survey suggest
      that residency education assists physical therapists to refine and expand their
      clinical knowledge and skills that are important for health care roles requiring
      increasing autonomy of practice, such as primary care. Our questionnaire may also
      serve as a template for the measurement of outcome in clinical physical therapy
      residency programs.

PMID- 10575642
TI  - Skin pH changes associated with iontophoresis.
AB  - STUDY DESIGN: Randomized controlled trial. The researcher measuring skin pH was
      blinded to group assignment. OBJECTIVES: To compare the skin surface pH changes
      associated with iontophoresis. The investigation was designed to address the
      question of whether significant skin pH changes occur under the cathode on the
      skin surface when performing iontophoresis and assessed the influence of
      different electrode-buffering systems intended to stabilize skin pH (surface).
      BACKGROUND: Whether buffers are needed to stabilize skin pH during iontophoresis
      has not been thoroughly addressed in the literature. The effectiveness of
      immobile resins versus simple phosphate buffers is also unclear. METHODS AND
      MEASURES: Sixty volunteer subjects were administered iontophoresis of normal
      saline using buffered or nonbuffered electrode systems. Each subject participated
      in 1 of the 12 doses by electrode conditions (i.e., 5 subjects per group).
      Surface skin pH was measured before and after iontophoresis with a flat-surface
      pH electrode in concert with an analog pH meter. The independent variables were
      electrode type (4 levels) and dosage (3 levels). The dependent variable was the
      change in skin surface pH. RESULTS: A significant change in skin pH was found
      only when the treatment dose was 80 mA/minute with a nonbuffered electrode (x =
      3.14 +/- 1.09). CONCLUSIONS: The skin pH changes that occur during a properly
      delivered iontophoresis treatment at dosages of 20 and 40 mA/min were small and
      not significantly different with or without the addition of buffers. Those pH
      changes associated with 80 mA/min doses were significantly greater when no buffer
      was employed but were stabilized by each of the buffers used in the study
      (preloaded immobile resins or simple phosphates added at point of treatment).

PMID- 10575643
TI  - Effect of patellar taping on knee kinetics of patients with patellofemoral pain
      syndrome.
AB  - STUDY DESIGN: Single-group repeated measures examining patients with
      patellofemoral pain syndrome. OBJECTIVE: To examine the effect of McConnell
      patellar taping on single-leg vertical jump height and knee extensor moment and
      power during a vertical jump and lateral step-up. BACKGROUND: Patellar taping is
      used by clinicians in an attempt to maximize knee extensor function during
      sporting activities and rehabilitation of patients with patellofemoral pain
      syndrome. No studies have examined the effect of patellar taping on vertical jump
      height and knee extensor moment and power during a maximal vertical jump or
      lateral step-up. METHODS AND MEASURES: Fourteen women (24.4 +/- 5.8 years) with
      unilateral patellofemoral pain performed a single-leg vertical jump and lateral
      step-up during 4 knee conditions: patellar tape, placebo tape, no tape, and the
      uninvolved knee. Maximal knee extensor moment, knee power, and vertical jump
      height were measured for each condition using a force platform and motion
      analysis system. RESULTS: Analysis of variance and post hoc analyses revealed a
      main effect for knee condition. The patellar tape condition resulted in a greater
      knee extensor moment (1.57 +/- 0.32 N.m/kg) and power (3.47 +/- 0.67 W/kg) than
      did the no-tape (1.31 +/- 0.39 N.m/kg and 2.79 +/- 1.21 W/kg) and placebo tape
      (1.33 +/- 0.30 N.m/kg and 2.70 +/- 0.99 W/kg) conditions. Additional analyses
      showed that the vertical-jump height was significantly greater in the uninvolved
      lower extremity (25.69 +/- 2.66 cm) compared with the patellar tape (23.33 +/-
      4.22 cm), placebo tape (23.08 +/- 4.20 cm), and no-tape (23.45 +/- 4.54 cm)
      conditions. The patellar tape condition did not show a different vertical jump
      height than the placebo or no-tape conditions. CONCLUSIONS: These results suggest
      that patellar taping compared with no tape may improve the knee extensor moment
      and power during weight-bearing activities such as the lateral step-up exercise
      and the vertical jump.

PMID- 10575644
TI  - Normalized forces and active range of motion in unilateral radial epicondylalgia
      (tennis elbow).
AB  - STUDY DESIGN: Single group pretest-posttest. BACKGROUND: There is a lack of
      consensus concerning the preferred assessment and treatment for radial
      epicondylalgia. OBJECTIVES: Determine whether deficiencies in muscle force, joint
      range of motion, or painful force threshold are detected when measurements from
      the involved upper extremity are normalized to values from the uninvolved
      extremity. METHODS AND MEASURES: Ten patients (70% men) 42 +/- 7 years in age
      with unilateral radial epicondylalgia participated. The visual analog pain scale
      and 6 measurements involving either muscle force, joint range of motion, or
      painful force threshold were examined. RESULTS: When comparing the initial
      assessments to final assessments, a significant improvement was found for the
      visual analog pain scale (5 +/- 3 vs 1 +/- 3) and for the following normalized
      scores: grip (78 +/- 26% vs 101 +/- 20%) and isometric wrist extension forces (68
      +/- 24% vs 95 +/- 35%), painful force threshold over the lateral epicondyle (49
      +/- 22% vs 94 +/- 14%), and active wrist extension range of motion (83 +/- 13% vs
      96 +/- 10%). CONCLUSIONS: Normalized force and range of motion measurements
      following treatment for unilateral radial epicondylalgia are sensitive
      assessments of patient progress. In comparison with measurements of force and
      range of motion that are not adjusted to a baseline score, normalized
      measurements detect changes in patient responses when baseline scores vary.

PMID- 10575645
TI  - Effects of the forearm support band on wrist extensor muscle fatigue.
AB  - STUDY DESIGN: A crossover experimental design with repeated measures. OBJECTIVE:
      To determine whether the forearm support band alters wrist extensor muscle
      fatigue. BACKGROUND: Fatigue of the wrist extensor muscles is thought to be a
      contributing factor in the development of lateral epicondylitis. The forearm
      support band is purported to reduce or prevent symptoms of lateral epicondylitis
      but the mechanism of action is unknown. METHODS AND MEASURES: Fifty unimpaired
      subjects (36 men, 14 women; mean age = 29 +/- 6 years) were tested with and
      without a forearm support band before and after a fatiguing bout of exercise.
      Peak wrist extension isometric force, peak isometric grip force, and median power
      spectral frequency for wrist extensor electromyographic activity were measured
      before and after exercise and with and without the forearm support band. A 2 x 2
      repeated measures multivariate analysis of variance was used to analyze the data,
      followed by univariate analysis of variance and Tukey's multiple comparison
      tests. RESULTS: Peak wrist extension isometric force, peak grip isometric force,
      and median power spectral frequency were all reduced after exercise. However,
      there was a significant reduction in peak grip isometric force and peak wrist
      extension isometric force values for the with-forearm support band condition
      (grip force 28%, wrist extension force 26%) compared to the without-forearm
      support band condition (grip force 18%, wrist extension force 15%). CONCLUSIONS:
      Wearing the forearm support band increased the rate of fatigue in unimpaired
      individuals. Our findings do not support the premise that wearing the forearm
      support band reduces muscle fatigue in the wrist extensors.

PMID- 10575646
TI  - Skin thickness and VMO:VL ratio.

PMID- 10575647
TI  - An introduction to the cytochrome P450s.

PMID- 10575648
TI  - Pharmacogenetics of cytochromes P450.

PMID- 10575649
TI  - Induction and inhibition of CYPs and implications for medicine.

PMID- 10575650
TI  - Cytochromes P450 in synthesis of steroid hormones, bile acids, vitamin D3 and
      cholesterol.

PMID- 10575651
TI  - Microsomal cytochrome P450 and eicosanoid metabolism.

PMID- 10575652
TI  - Effects of disease on expression and regulation of CYPs.

PMID- 10575653
TI  - Cytochromes P450 and cancer.

PMID- 10575654
TI  - Cytochromes P450 as targets to autoantibodies in immune mediated diseases.

PMID- 10575655
TI  - Suppression of hepatic fatty acid oxidation and food intake in men.
AB  - We investigated the effects of the fatty acid oxidation inhibitor etomoxir (ETO)
      on food intake and on fat and carbohydrate metabolism in two double-blind
      crossover studies in male, normal-weight subjects. In study 1, ETO (75 mg [+]
      racemate) or placebo was given orally 30 min after completion of a standardized,
      fat-enriched (total energy: 2698 kJ, 40% from fat) lunch. The subjects (n = 15)
      were isolated from external time cues and free to choose when to eat dinner from
      an oversized serving (total energy: 6656 kJ, 60% from fat). In study 2, subjects
      (n = 13) were selected for habitually high fat intake (mean: 44% of energy
      intake). ETO (150 mg) or placebo was given after an overnight fast, 2.5 h before
      offering an oversized high fat breakfast (6960 kJ, 72% from fat). In both
      studies, blood samples were taken and the respiratory quotient (RQ) was measured
      several times during each test period. In study 1, ETO (75 mg) did not affect the
      timing and size of the dinner or subjective feelings of hunger and satiety.
      Although ETO (75 mg) did not affect the RQ, it decreased plasma beta
      hydroxybutyrate (BHB) and increased plasma lactate compared with placebo. Plasma
      triacylglycerols (TG), free fatty acids (FFA), glucose, and insulin were not
      affected by ETO. In study 2, ETO (150 mg) enhanced hunger feelings and increased
      the size of the breakfast by 22.7%. ETO did not affect the RQ, but baseline RQ
      was lower in study 2 than in study 1 (0.83 versus 0.89, P < 0.01). Compared with
      placebo, ETO (150 mg) decreased plasma BHB and increased plasma FFA and plasma
      lactate. Baseline plasma concentrations of BHB, FFA, and lactate were higher in
      study 2 than in study 1 (BHB: 242 versus 81 mumol/L, P < 0.001; FFA: 0.674 versus
      0.406 mmol/L, P < 0.01; lactate: 1.08 versus 0.74 mmol/L, P < 0.05). Plasma
      concentrations of TG, glucose, and insulin were not affected by ETO. The results
      suggest that inhibition of hepatic fatty acid oxidation stimulates eating in men
      when baseline fatty acid oxidation is sufficiently high and markedly suppressed
      by the treatment.

PMID- 10575656
TI  - Relationship of serum leptin levels and selected nutritional parameters in
      patients with protein-caloric malnutrition.
AB  - Leptin is a protein hormone produced by adipocytes that reflects the body fat
      content, i.e., its serum concentration in healthy individuals positively
      correlates with the body mass index and body fat content. Serum leptin levels are
      lower in both patients with anorexia nervosa and protein-caloric malnutrition
      caused by chronic non-malignant illnesses. The aim of the present study was to
      compare serum leptin levels and selected, routinely used nutritional parameters
      in women with anorexia nervosa (n = 17), severely malnourished patients with
      short bowel syndrome (n = 13), and control non-obese healthy women (n = 17) to
      clarify the relation between selected nutritional parameters and serum leptin
      levels. We found that serum leptin levels in the anorexia nervosa and short bowel
      syndrome groups were significantly lower than those in the control group (in
      ng/mL: 3.63 +/- 1.64 and 2.59 +/- 1.17 versus 12.06 +/- 7.59, respectively).
      Protein malnutrition expressed by decrease in serum concentrations of total
      protein, albumin, and prealbumin was more pronounced in the short bowel syndrome
      group. Triceps skin fold, arm muscle circumference, and body mass index were
      significantly lower in the patient group than in the control group and did not
      significantly differ between the short bowel syndrome and anorexia nervosa
      groups. No significant difference in serum leptin concentration between the short
      bowel syndrome and anorexia nervosa groups was found. Serum leptin levels
      correlated positively with body mass index and triceps skin fold in the control
      and anorexia nervosa groups but not in the short bowel syndrome group. We
      conclude that serum leptin levels in patients with anorexia nervosa and short
      bowel syndrome are significantly lower than in healthy individuals and have no
      statistically significant relation to serum total protein, abumin, and
      prealbumin.

PMID- 10575657
TI  - Influence of preoperative nutritional state on inflammatory response after
      surgery.
AB  - To investigate whether the preoperative nutritional state influences the
      postoperative inflammatory reaction and immunity, we grouped patients whose
      postoperative nutritional support was performed by total parenteral nutrition
      into the good nutritional state group (group I) and the latent protein-calorie
      malnutrition suggested group (group II) based on the preoperative rapid turnover
      protein (RTP). Nutritional markers markedly decreased after surgery and recovered
      almost to preoperative levels on postoperative day (POD-) 7 in groups I and II.
      Nutritional markers on POD-7 in group II were significantly lower than those in
      group I (RTP, P < 0.001; albumin, P < 0.05). After surgery, levels of interleukin
      6 (IL-6), C-reactive protein (CRP), and polymorphonuclear (PMN-) elastase were
      higher in group II than in group I (P < 0.01). In groups I and II, IL-6 and
      interleukin-8 (IL-8) rose before the remarkable elevation of CRP and PMN
      elastase. In group I, all the nutritional markers showed a negative correlation
      with CRP and PMN-elastase. Further, a positive correlation was observed between
      IL-6 and CRP and between IL-8 and PMN-elastase. In conclusion, evaluation of the
      preoperative nutritional state appears to be very important for the prediction of
      postoperative complication.

PMID- 10575658
TI  - Proinflammatory cytokine production by mitogen-stimulated peripheral blood
      mononuclear cells (PBMCs) in trauma patients fed immune-enhancing enteral diets.
AB  - Widespread metabolic changes associated with injury facilitate the delivery of
      nutrients to the immune system. The effect of specific nutrients administered by
      the enteral route on the immune response in trauma victims is not well
      understood. The purpose of this study was to examine whether the synthesis of
      proinflammatory cytokines (tumor necrosis factor-alpha [TNF-alpha], interleukin-1
      beta [IL-1 beta], and interleukin-6 [IL-6]) by peripheral blood mononuclear cells
      (PBMCs) are influenced by the nature of the dietary fat in critically injured
      trauma victims. We measured plasma TNF-alpha, IL-1 beta, and IL-6 and their
      release stimulated by phytohemagglutinin (PHA) and endotoxin (lipopolysaccharide,
      LPS) from PBMCs of 13 severely injured (injury severity score = 30 +/- 2)
      patients once within 48-60 h after injury and then after 7 d of enteral feeding
      (1.5 g protein[P].kg-1.d-1). Group I (n = 6) received diet A (Crucial) and group
      II (n = 7) received diet B (Impact). The plasma levels of TNF-alpha and IL-1 beta
      in trauma patients are not significantly different from those in healthy
      volunteers, but plasma IL-6 levels are significantly increased (five times) in
      severely injured patients. Stimulation of TNF-alpha and IL-1 beta secretion by
      LPS and PHA were significantly higher in patients than in control subjects; in
      contrast, there was no stimulation of IL-6 because of trauma or nutritional
      support by either of the diets. Stimulation of IL-1 beta by LPS was normalized by
      Crucial but was further enhanced by Impact. The higher fat content in Crucial may
      contribute in part to the apparent immunomodulation. Crucial seems to be a better
      choice in correcting the nutritional deficiency.

PMID- 10575659
TI  - Children's dietary recalls: the salience of entree and liking for foods on
      accuracy and order of reporting.
AB  - This study investigated the impact of entree and liking for foods on the accuracy
      and order of reporting on children's school lunch recalls. Data were collected
      during a series of studies to investigate children's lunch recalls from a
      cognitive processing approach to understand better how children remember what
      they have eaten. Fourth-grade children from four schools were randomly selected,
      observed eating lunch, and interviewed the same (n = 89) or next (n = 148) day.
      Foods were classified as matches (observed and reported eaten), omissions
      (observed but not reported eaten), or phantoms (not observed but reported eaten),
      and corresponding rates were calculated. Statistical analyses included z tests
      and permutation tests. For same- and next-day recalls, children were more likely
      to report entree than other meal components earlier in the interview. For next
      day recalls, the phantom rate for the remaining items was lower for children who
      reported entrees accurately versus inaccurately. For items liked "a lot" compared
      with items "not liked a lot," match rates were higher for next-day recalls, and
      phantom rates were lower for both same- and next-day recalls. Because entree and
      liking for foods appear to play salient roles in children's dietary recalls,
      these results provide guidance regarding the development of specific prompts to
      increase the accuracy of children's dietary recalls.

PMID- 10575660
TI  - Effect of the nucleoside analogs zidovudine, didanosine, stavudine, and
      lamivudine on the sense of taste.
AB  - The purpose of this study was to investigate the taste properties of nucleoside
      analogs, which are among the current medications used to treat human
      immunodeficiency virus (HIV) infection. Eighteen unmedicated HIV-positive
      subjects and 41 healthy control subjects participated in threshold and
      suprathreshold experiments. All of the nucleoside medications tested were
      perceived as predominantly bitter (along with other qualities such as metallic,
      medicinal, sour, astringent, and cooling). The nucleoside analog with the lowest
      detection thresholds was zidovudine; the detection threshold was 1.47 mM for HIV
      infected patients and 2.15 mM for control subjects. Detection thresholds for
      lamivudine were 4.41 mM for HIV-infected patients and 4.36 mM for control
      subjects. Detection thresholds for stavudine were 6.39 mM for HIV-infected
      patients and 5.99 mM for control subjects. Detection thresholds for didanosine
      were 14.29 mM for HIV-infected patients and 24.0 mM for control subjects. The
      nucleoside analogs also modified the taste perception of KCl and CaCl2. There
      were no significant differences between HIV-infected subjects and control
      subjects for detection threshold values for any of the drugs. However, HIV
      infected subjects rated lamivudine, zidovudine, and stavudine as significantly
      more bitter than did the control subjects at concentrations four times higher
      than their detection thresholds. This result was not due to use of medications by
      HIV-infected subjects because none of the subjects (neither HIV-infected nor
      control) were taking medications.

PMID- 10575661
TI  - Glutamine-antioxidant supplementation increases body cell mass in AIDS patients
      with weight loss: a randomized, double-blind controlled trial.
AB  - Loss of body cell mass, the active functioning tissue of the body, commonly
      occurs in patients with human immunodeficiency virus (HIV) infection, and the
      extent of wasting is related to the length of survival. We evaluated the anabolic
      role of the amino acid L-glutamine (GLN) and antioxidants in a double-blind,
      placebo-controlled trial in 26 patients with > 5% weight loss since disease
      onset. Subjects received GLN-antioxidants (40 g/d) in divided doses or glycine
      (40 g/d) as the placebo for 12 wk. Throughout the study, the subjects were seen
      weekly by a nutritionist, and body weight, bioelectric impedance assessment, and
      nutritional counseling were performed. Twenty-one subjects completed the study,
      and the groups were well matched. The 5 patients excluded from analysis all met a
      priori exclusion criteria. Over 3 mo, the GLN-antioxidant group gained 2.2 kg in
      body weight (3.2%), whereas the control group gained 0.3 kg (0.4%, P = 0.04 for
      difference between groups). The GLN-antioxidant group gained 1.8 kg in body cell
      mass, whereas the control group gained 0.4 kg (P = 0.007). Intracellular water
      increased in the GLN-antioxidant group but not in the control group. In
      conclusion, GLN-antioxidant nutrient supplementation can increase body weight,
      body cell mass, and intracellular water when compared with placebo
      supplementation. GLN-antioxidant supplementation provides a highly cost-effective
      therapy for the rehabilitation of HIV+ patients with weight loss.

PMID- 10575662
TI  - Malnutrition and wasting, immunodepression, and chronic inflammation as
      independent predictors of survival in HIV-infected patients.
AB  - To analyze the long-term survival factors associated with HIV infection, a
      prospective follow-up study of 165 HIV-infected patients was performed after a
      clinical, nutritional, and biological evaluation. Survival rate could be
      determined in 129 patients after a follow-up of 42 mo before the use of protease
      inhibitors. After univariate analysis, multivariate analysis was performed with
      the Cox regression proportional-hazard model. Survival curves were calculated and
      compared with the Kaplan, Meier, and log-rank tests. The study also analyzed the
      factors associated with impaired nutritional status at the beginning of the study
      and their effects on the long-term follow-up. Factors that could explain body
      weight loss before the study were the level of intakes, resting energy
      expenditure, chronic diarrhea, and the number of previous opportunistic
      infections. In the long-term follow-up, univariate analysis showed that
      nutritional status could be separated into four classes of body weight loss (BWL)
      by degree of loss (BWL < or = 5%, 5% < BWL < or = 10%, 10% < BWL < or = 20%, BWL
      > 20%); lean body mass (adjusted to height), body cell mass, CD4 count, albumin,
      prealbumin, and C-reactive protein (CRP) were all significant predictors. Age,
      stage of disease, number of previous opportunistic infections, and antiviral
      therapies were not associated with a change in survival. With the multivariate
      model, only CD4 counts, lean body mass/height squared, and CRP remained
      significant independent predictors of survival after controlling for other
      factors.

PMID- 10575663
TI  - Serum 25-hydroxyvitamin D levels in active women of middle and advanced age in a
      rural community in Japan.
AB  - There have been few epidemiologic studies on vitamin D status in Asians. The
      purpose of this study was to investigate the 25-hydroxyvitamin D (25[OH]D) levels
      in active women of middle and advanced age in Japan. We targeted 236 women who
      participated in an annual health check-up program in September 1997. Among them,
      160 women were examined. Serum 25(OH)D2 and 25(OH)D3 levels were determined with
      high-performance liquid chromatography. In addition, the study included survey
      questions regarding age, body weight and height, occupation, use of skin
      protection, clinical and reproductive histories, and lifestyles. The average age
      was 65.6 y (SD = 8.3). The mean concentrations of 25(OH)D2 and 25(OH)D3 were 0.5
      (SD = 3.2) nmol/L and 78.3 (SD = 17.8) nmol/L, respectively. None of the subjects
      showed hypovitaminosis D (25[OH]D < 37.0 nmol/L). Concentrations of 25(OH)D3 did
      not change with age (r = -0.079, P = 0.32), nor did other variables associated
      with 25(OH)D3 concentrations except for "engaging in farming" (P = 0.03) in the
      occupational category. These findings indicate that 25(OH)D levels in active
      middle- and advanced-aged women in Japan have appropriate vitamin-D status.
      Studies to elucidate and assess the dietary intake of vitamin D in Japanese women
      can be of further benefit.

PMID- 10575664
TI  - Bioelectrical impedance methods in clinical research: a follow-up to the NIH
      Technology Assessment Conference.
AB  - In 1994, the National Institutes of Health (NIH) convened a Technology Assessment
      Conference "to provide physicians with a responsible assessment of bioelectrical
      impedance analysis (BIA) technology for body composition measurement." In 1997,
      Serono Symposia USA, Inc., organized an invited panel of scientists and
      clinicians, with extensive research and clinical experience with BIA, to provide
      an update. Panel members presented reviews based on their own work and published
      studies for the intervening years. Updates were provided on the single and
      multifrequency BIA methods and models; continued clinical research experiences;
      efforts toward establishing population reference norms; and the feasibility of
      establishing guidelines for potential diagnostic use of BIA in a clinical
      setting. This report provides a summary of the panel's findings including a
      consensus on several technical and clinical issues related to the research use of
      BIA, and those areas that are still in need of additional study.

PMID- 10575665
TI  - Dietary glutamine enhances cytokine production by murine macrophages.
AB  - To examine the effects of dietary glutamine on cytokine production by
      macrophages, mice were fed for 2 wk on a control diet that included 200.0 g
      casein/kg providing 19.6 g glutamine/kg or a glutamine-enriched diet that
      provided 54.8 g glutamine/kg partly at the expense of casein. There were no
      differences in weight gain between animals fed the two diets. The plasma
      concentrations of a number of amino acids differed according to the diet fed;
      this variation largely reflected the variation in the levels of the different
      amino acids in the diets. Plasma glutamine concentration was not significantly
      affected by dietary glutamine level. The production of three cytokines, tumor
      necrosis factor-alpha, interleukin-1 beta, and interleukin-6, was greater for
      lipopolysaccharide-stimulated macrophages from mice fed the glutamine-enriched
      diet. Thus, increasing the amount of glutamine in the murine diet enhances the
      ability of macrophages to respond to stimulation, at least in terms of cytokine
      production. These observations suggest that increasing the availability of
      glutamine orally could promote immune responses involving macrophage-derived
      cytokines.

PMID- 10575666
TI  - Lipid and lipid-free total parenteral nutrition: differential effects on
      macrophage phagocytosis in rats.
AB  - Lipid emulsions provided with total parenteral nutrition (TPN) have been
      associated with mononuclear phagocytic system functional changes. The aim of the
      present investigation was to assess the influence of TPN with added lipid
      emulsions on macrophage (M phi) phagocytosis. Wistar rats (n = 70) with external
      jugular vein cannulation were randomized into seven groups. The rats received an
      oral diet or six different isocaloric (1.16 kcal/mL), isonitrogenous (1.5 g/mL),
      and isolipidic (30% non-protein calories) TPN regimens: (a) an oral diet with
      intravenous infusion of saline (OS); (b) non-lipid TPN (glucose); (c) TPN with
      10% long chain triacylglycerol emulsions (LCT); (d) TPN with 90% LCT and 10% fish
      oil (FO) emulsion; (e) TPN with 50% LCT and 50% FO; (f) TPN with 10% lipid
      emulsion with 50% medium chain triacylglycerol (MCT) and 50% LCT; and (g) TPN
      with 45% MCT, 45% LCT, and 10% FO. After 96 h of TPN or saline infusion,
      colloidal carbon (Pelikan, Germany) was injected intravenously at 1.0 mL/kg body
      weight, and the rats were killed after 3 h. Liver, spleen, and lung were weighed
      and prepared by immunohistochemistry analyses with the HAM-56 anti-M phi
      antibody. Under light microscopy, the total M phi number (MT) and the colloidal
      carbon phagocytic M phi number (MP) were established, and the phagocytic index
      was calculated as MP/MT x 100. There were no statistical (P < 0.05) differences
      in liver, spleen, or lung weights among the seven groups in comparison with the
      OS group. Non-lipid TPN inhibited spleen and lung M phi phagocytosis when
      compared with the OS and lipid-TPN groups. Lipid TPN supplemented with fish oil
      emulsion increased total liver and lung M phi number and phagocytosis. These
      results indicate that TPN supplemented with fish oil increases M phi phagocytosis
      in rats.

PMID- 10575667
TI  - Marginal copper and high fat diet produce alterations in electrocardiograms and
      cardiac ultrastructure in male rats.
AB  - This study investigated whether a high fat diet in tandem with a marginal copper
      (Cu) diet exerts deleterious effects on copper status, cardiac morphology, and
      electrophysiology compared to a low-fat marginal copper diet. Male weanling Long
      Evans rats were fed diets containing either marginal copper (42.5 mumol/kg) or
      adequate copper (97.6 mumol/kg), and low fat (50.0 g/kg) or high fat (150.0 g/kg)
      diet for 12 wk in a 2 x 2 factorial design. To simulate the western diet, fat was
      composed of a 1:2 polyunsaturated:saturated fatty acids using a coconut and corn
      oil mixture. High dietary fat increased liver Cu concentration. Marginal copper
      diets decreased liver Cu,Zn-superoxide dismutase activity. Dietary copper and fat
      level had no effect on volume densities of mitochondria and myofibril. However,
      lower mitochondrial pathologic scores were observed in the rats consuming the
      high fat diets. Marginal copper high fat diet prolonged atrial electric
      depolarization (PR) and ventricular electric depolarization and repolarization
      (QT) intervals. This study provided direct evidence that a high fat diet can
      exert detrimental effects on cardiac ultrastructure and lead to alterations in
      electrocardiograms. The combination of marginal copper-high fat diet appears to
      alter cardiac electric conductivity. Longer term studies should provide
      information more relevant to clinical situations and morphologic changes.

PMID- 10575668
TI  - Asthma, oxidant stress, and diet.
AB  - It has been suggested that the increased prevalence of atopy and asthma observed
      in many developed countries over the past 30 y is in part the result of a
      decrease in the incidence and severity of early childhood infections. The
      immunologic consequence of this phenomenon has been the expansion of T-lymphocyte
      populations away from the T-helper 1 (Th1) subset and in the direction of the Th2
      subset. This leads to the creation of a cytokine-mediated propensity for the
      development of an intense inflammatory response in the airways, resulting in
      oxidative stress, airway tissue injury, and the development of atopy and
      asthmatic symptomatology. Over this same period, there has been a decreased
      intake of dietary substances that contribute to antioxidant defense, and this
      appears to have contributed to the rise of atopy and asthma. Studies evaluating
      the efficacy of these antioxidant substances in the prevention of asthma and as
      adjuvants in the treatment of asthma are reviewed, and suggestions are made for
      the direction of future studies.

PMID- 10575669
TI  - Metabolic maladaptation: individual and social consequences of medical
      intervention in correcting endemic hypothyroidism.
AB  - Endemic hypothyroidism has been studied in a Central African population in remote
      Congo (ex-Zaire) to investigate the prevalence, severity, causes, and potential
      control of this disorder, with questions as to why this disease is conserved, and
      whether it confers any adaptive advantage in this resource-constrained
      environment. Iodine deficiency, cassava goiterogens, and selenium deficiency were
      found to be the factors implicated in the severe hypothyroidism expressed in
      congenital cretinism and high goiter incidence in this isolated population, which
      continues to be under observation following medical intervention. Profound
      hypothyroidism was encountered in whole village populations as measured by serum
      thyrotropin determinations ranging from very high to over 1000 IU, and thyroxin
      levels ranging from low to undetectable; cretinism rates were as high as 11% and
      goiter incidence approached 100%. Assessment of endocrinologic status, caloric
      requirement, energy output, fertility, and ecologic factors was carried out
      before and during iodine repletion by depot injection. Hypothyroidism was
      corrected and cretinism eliminated in the treatment group, with goiters reduced
      in most instances (with regrowth exhibited in some who escaped control) and some
      symptomatic goiter patients were offered surgical treatment for respiratory
      obstruction. Individual patient benefits, including improved strength and
      increased energy output, were remarkable. The social and developmental
      consequences observed within the collective groups of treated patients were
      remarkable for an increase in caloric requirement and a dramatic increase in
      fertility that led to quantitative as well as qualitative increases in resource
      consumption. Micronutrient iodine repletion was not accompanied by any
      concomitant increase in macronutrient supply, and hunger and environmental
      degradation resulted. The highly prevalent disease of hypothyroidism is found in
      highest incidence in areas of greatest resource constraint. It may be that
      hypothyroidism is conserved in such areas because it may confer adaptive
      advantage in such marginal environments as an effect, as well as a cause, of
      underdevelopment. Hypothyroidism may limit energy requirements, fertility, and
      consumer population pressure in closed ecosystems that could otherwise be
      outstripped. Single factor intervention in a vertical health care program not
      sensitive to the fragile biologic balance and not part of a culture-sensitive
      development program might result in medical maladaptation.

PMID- 10575670
TI  - A glimpse into the process...

PMID- 10575671
TI  - Moral maladaptation? Reflections on a report of research involving the correction
      of endemic hypothyroidism in Africa.

PMID- 10575672
TI  - Medical imperialism in the Congo?

PMID- 10575673
TI  - Informed consent and other ethical issues: a clinician's view.

PMID- 10575674
TI  - Health care advocacy in world health.

PMID- 10575675
TI  - Leptin, anorexia nervosa, and anorexia of acute and chronic disease.

PMID- 10575677
TI  - Worldwide optimal nutrition, disease prevention, and health promotion.

PMID- 10575676
TI  - Tea and health.
AB  - The possible beneficial effects of tea consumption in the prevention of cancer
      and cardiovascular diseases have been demonstrated in animal models and suggested
      by studies in vitro. Similar beneficial effects, however, have not been
      convincingly demonstrated in humans: beneficial effects have been demonstrated in
      some studies but not in others. If such beneficial effects do exist in humans,
      they are likely to be mild, depending on many other lifestyle-related factors,
      and could be masked by confounding factors in certain populations. Another
      concern is that the amounts of tea consumed by humans are lower than the doses
      required for demonstrating the disease-prevention effects in animal models.
      Caution should be applied, however, in the use of high concentrations of tea for
      disease prevention. Ingestion of large amounts of tea may cause nutritional and
      other problems because of the caffeine content and the strong binding activities
      of tea polyphenols, although there are no solid data on the harmful effects of
      tea consumption. More research is needed to elucidate the biologic activities of
      green and black tea and to determine the optimal amount of tea consumption for
      possible health-beneficial effects.

PMID- 10575678
TI  - Early enteral nutrition in acute pancreatitis.

PMID- 10575679
TI  - Immune modulation with OKG supplementation in burn injury.

PMID- 10575680
TI  - Red wine and black grape strengthen blood antioxidant potential.

PMID- 10575681
TI  - Nutritional support of the patient with severe burn injury.

PMID- 10575682
TI  - Aluminium in parenteral nutrition admixtures: an unnecessary risk?

PMID- 10575683
TI  - Obesity in Brazil: an overview.

PMID- 10575684
TI  - Perioperative nutrition in infants and children.

PMID- 10575686
TI  - Healthy employees in healthy organisations: workplace health promotion in Europe.

PMID- 10575685
TI  - The Second International Scientific Symposium on Tea & Human Health, September
      14th, 1998.
AB  - It is fascinating to reflect that tea, the world's most widely consumed beverage
      next to water, began in Chinese antiquity not as a beverage but as a medicine.
      Several millennia later, modern scientific research is confirming that such
      ancient intuition has relevance to contemporary health concerns including cancer,
      heart disease, and antibiotic-resistant bacteria. The timeliness of this message
      as the 20th century concludes could not be better. The importance of a balanced
      diet has been recognized and studied throughout this century. The concept that we
      are what we eat has become a part of popular culture. If tea's health message,
      which future scientific research will continue to articulate, is creatively
      presented and embraces the romantic image that tea affords the industry, there is
      every reason to expect a rebirth and reinvigoration of this ancient beverage as a
      new millennium commences.

PMID- 10575687
TI  - Concept and principles of workplace health promotion.

PMID- 10575688
TI  - Enterprise for health: pushing the agenda forward.

PMID- 10575689
TI  - Worksite health promotion: the European Union perspective.

PMID- 10575690
TI  - WHP interventions and work organisation: the health circle approach.

PMID- 10575691
TI  - The role of WHP in occupational health and safety: lessons learnt in Australia.

PMID- 10575692
TI  - Training for workplace health promotion in Europe.

PMID- 10575694
TI  - The technology corner.

PMID- 10575693
TI  - Workplace health promotion in large enterprises.

PMID- 10575695
TI  - Meeting report: Third European Congress of Protistology and 9th European Congress
      on Ciliate Biology, Helsingor, Denmark, July 26-30, 1999.

PMID- 10575696
TI  - Divergent perspectives on protist species richness.

PMID- 10575697
TI  - Molecular mechanisms of membrane trafficking. What do we learn from Dictyostelium
      discoideum?

PMID- 10575698
TI  - Bacteria and paralytic shellfish toxins.

PMID- 10575699
TI  - Protozoal sequences may reveal additional isoforms of the 14-3-3 protein family.
AB  - The phylogenetic position of eleven 14-3-3 proteins from five protozoal species
      was tested relative to other eukaryotic 14-3-3 versions representing many of the
      previously described isoforms. The protozoal proteins, four from Entodinium
      caudatum, three from Entameoba histolytica and four from apicomplexan parasites
      formed clusters closer to the plant and animal epsilon isoforms than to the
      animal beta, gamma/eta, sigma/theta, and zeta isoforms. This extends the
      preliminary findings of Wang and Shakes (1996) but data from a wider range of
      genera are still required to strengthen our hypothesis that the protozoan
      isoforms may constitute novel isoforms of the 14-3-3 family.

PMID- 10575700
TI  - V-ATPase is a major component of the Golgi complex in the scaly green flagellate
      Scherffelia dubia.
AB  - Highly purified membranes isolated from the Golgi complex of the scaly green
      flagellate Scherffelia dubia (Chlorophyta) were subjected to Triton X-114 two
      phase partitioning. Proteins in the detergent phase were analyzed by 2D gel
      electrophoresis and a major protein of 66 kD (p66) was N-terminally sequenced.
      The complete cDNA sequence of p66 was obtained by 3' RACE-PCR and screening of a
      cDNA library of S. dubia with a PCR probe derived from the 3' RACE. Sequence
      analysis of the cDNA clone identified p66 as subunit A of V-ATPase. Other major
      proteins in the isolated Golgi complex were immunoreactive to heterologous
      antibodies raised against subunit B or the holoenzyme of V-ATPase. A polyclonal
      (anti-p66) antibody raised against a recombinant, bacterially expressed p66
      fusion protein recognized p66 in the isolated Golgi complex in western blots and
      localized the antigen by immunogold electron microscopy mostly to the scale
      reticulum but also to the Golgi stack within the Golgi complex. Concanamycin A
      sensitive (but bafilomycin A1-insensitive) ATPase activity was present in the
      isolated Golgi complex, and monensin at 0.5-1 microM reversibly inhibited
      flagellar regeneration and resulted in swelling of Golgi cisternae. It is
      concluded that a functional V-ATPase is a major protein of the Golgi complex in
      S. dubia and is presumably associated with sorting processes at the
      endocytotic/exocytotic boundary of the Golgi complex.

PMID- 10575701
TI  - The plastid in Plasmodium falciparum asexual blood stages: a three-dimensional
      ultrastructural analysis.
AB  - The plastid in Plasmodium falciparum asexual stages is a tubular structure
      measuring about 0.5 micron x 0.15 micron in the merozoite, and 1.6 x 0.35 microns
      in trophozoites. Each parasite contains a single plastid until this organelle
      replicates in late schizonts. The plastid always adheres to the (single)
      mitochondrion, along its whole length in merozoites and early rings, but only at
      one end in later stages. Regions of the plastid are also closely related to the
      pigment vacuole, nuclear membrane and endoplasmic reticulum. In merozoites the
      plastid is anchored to a band of 2-3 subpellicular microtubules. Reconstructions
      show the plastid wall is characteristically three membranes thick, with regions
      of additional, complex membranes. These include inner and outer membrane
      complexes. The inner complex in the interior lumen is probably a rolled
      invagination of the plastid's inner membrane. The outer complex lies between the
      outer and middle wall membranes. The interior matrix contains ribosome-like
      granules and a network of fine branched filaments. Merozoites of P. berghei and
      P. knowlesi possess plastids similar in structure to those of P. falciparum. A
      model is proposed for the transfer of membrane lipid from the plastid to other
      organelles in the parasite.

PMID- 10575702
TI  - Characterization of Hemiselmis amylosa sp. nov. and phylogenetic placement of the
      blue-green cryptomonads H. amylosa and Falcomonas daucoides.
AB  - The morphology and ultrastructure of a new freshwater blue-green cryptomonad,
      Hemiselmis amylosa sp. nov., is described. In addition, a marine blue-green
      cryptomonad isolate was confirmed as Falcomonas daucoides by electron microscopy
      and phycobilin analysis so that it could be included in molecular sequence
      studies, since the original isolate is no longer available. Complete ssu rRNA
      gene sequences for H. amylosa and F. daucoides were obtained. Our freshwater
      isolate of Hemiselmis possesses the same general features described for blue
      green marine species, but it differs in having an eyespot, and multiple, single
      thylakoids penetrating the pyrenoid; therefore, a new blue-green, freshwater
      species is described. Phylogenetic analyses of H. amylosa and F. daucoides, as
      well as 24 other cryptophyte algae, indicate a monophyletic origin for all blue
      green cryptomonads. Falcomonas forms a sister clade to blue-green cryptomonads,
      indicating that it is the most primitive extant blue-green cryptomonad and
      probably diverged early from other blue-green genera. Furthermore, we suggest
      that the eocyte blue-green cryptomonad may have originated from a Proteomonas
      like progenitor that underwent a pigment change, resulting in a Falcomonas-like
      cell. Based on comparative morphology, the Proteomonas haplomorph may be a likely
      candidate in the evolutionary transformation from red to blue-green in
      cryptomonads; however, phylogenetic analyses neither support nor refute this
      hypothesis. Finally, the current status of cryptomonad classification is
      addressed.

PMID- 10575703
TI  - Reflective properties of different eyespot types in dinoflagellates.
AB  - The reflective properties of different types of dinoflagellate eyespots were
      investigated using confocal laser scanning microscopy in the epireflection
      contrast mode. Although the eyespots studied differed with respect to
      localization (cytosol or plastid) and organization of the globule layer(s), all
      types effectively absorbed and reflected blue-green laser light (principal lines
      of 488/514 nm). The relative orientation of the eyespot surface towards the light
      source strongly influenced the reflective properties. Maximal reflection occurred
      when the eyespot surface was approximately perpendicular to the light source and
      rapidly decreased at increasing angles of light incidence. Horizontal and
      vertical optical sectioning of live and fixed cells resolved differences in the
      reflection patterns. Focusing of reflected light on the basal portion of the
      longitudinal flagellum was observed for the cytosolic eyespot of Glenodinium sp.
      and the triple membrane-bounded eyespot of Peridinium foliaceum, presumably a
      vestige of a host plastid. This flagellum is thought to be mainly involved in
      mediating orientational movement responses. In contrast, the reflection patterns
      obtained from the eyespot of Woloszynskia pascheri, which represents the third
      and most commonly observed dinoflagellate eyespot type within a plastid, point to
      only minor focusing. Reflection signals could be followed a considerable distance
      into the sulcus in all cases, indicating that in dinoflagellate eyespots,
      irrespective of the presumed receptor location (plasma membrane overlying the
      eyespot and/or the basal part of the longitudinal flagellum), back reflection of
      non-absorbed light can enhance the excitation probability of the
      photoreceptor(s). Such a combined reflection/absorption screen allows maximal
      contrast modulation and will, in conjunction with the specialized geometry of the
      dinoflagellate eyespots, increase the directionality of these eyespot aparatuses
      considerably.

PMID- 10575704
TI  - Motile chemosensory behaviour of phagotrophic protists: mechanisms for and
      efficiency in congregating at food patches.
AB  - Phagotrophic protists are capable of congregating at point sources of food within
      a few minutes, from distances of up to several cm in the case of ciliates, or
      several mm in the case of microflagellates. This is exemplified by four ciliate
      species and a heterotrophic flagellate. Congregation is accomplished by the
      combined effect of more than one type of chemosensory motile behaviour including
      "kinetic responses", "temporal-gradient sensing", and "helical klinotaxis". The
      results are discussed in terms of microscale patchiness in nature.

PMID- 10575705
TI  - Modelling of microscale patch encounter by chemotactic protozoa.
AB  - A model of protozoan chemotaxis, based on the rate of change of chemoreceptor
      occupancy, was used to analyse the efficiency of chemotaxis in a variety of
      situations. Simulated swimming behaviour replicated patterns observed
      experimentally. These were classified into three forms of chemosensory behaviour;
      run-tumble, steered turning, and helical klinotaxis. All three could be simulated
      from a basic model of chemotaxis by modifying memory times and rotational
      velocities. In order to steer during helical klinotaxis, the cell must have a
      short term memory for responding to a signal within a fraction of the time period
      of the helix. Steered turning was identified as a form where cells react to
      negative changes in concentration by steering around the turn to swim back up the
      gradient. All 3 forms were quite effective for encountering targets within the
      response radius. A response to negative changes in concentration, experienced
      when the cell is moving away from a target, was found to be important in the
      absence of periodic changes in swimming direction. The frequency of patch
      encounter at a fixed density was calculated to be roughly proportional to
      swimming speed. On the basis of the model, cells are only able to sense point
      sources within a radius of a few mm. However, even a response radius of 1 mm is
      enough to increase encounter probability of otherwise minute targets by 2 orders
      of magnitude. The mean time for patch encounter was calculated to be an
      exponential function of the mean distance between patches. This results in a very
      sharp threshold at approximately 6 cm, above which they are not encountered by
      protozoa within time periods of several days.

PMID- 10575706
TI  - "To have eyes is common--to use them is rare" Ernst Bresslau (1877-1935) as
      protistologist.

PMID- 10575707
TI  - [Use and perception of health systems by children and their families:
      interdisciplinary applied research. History, methodology and trends].

PMID- 10575708
TI  - [Natural histories of disease: a pragmatic approach to multidisciplinary research
      on health care seeking behavior and therapeutic itineraries].
AB  - Public health is determined by the interaction of social, cultural and biological
      factors. Because of this complexity, a multidisciplinary approach is needed when
      doing research on public health problems. Medical anthropology and epidemiology
      share a common interest for human behavior and health, so it is especially
      appropriate for these two disciplines to work together in studying health seeking
      behavior and the use of health systems. In order to better understand social and
      cultural factors associated with health seeking behavior, a suitable qualitative
      research method was needed for use in association with a medical and
      epidemiological approach in the research program "Use and perception of health
      systems by children and their family", carried out in Algeria, the Congo
      (Brazzaville), Morocco, and Togo. Three factors were considered important:
      coordinating the qualitative and quantitative research methods within a single
      time frame, involving all members of the multidisciplinary research teams in each
      country, and producing data accessible and useful to health care professionals
      and others responsible for health system performance. A case study method based
      on "natural histories of illness" was adopted, using home interviews of families
      about a recent illness episode of an under-5 child. There are several advantages
      to this approach: 1) analysis of illness episodes reveals the totality of the
      health seeking process, including therapeutic itineraries; 2) families have
      little difficulty in describing an illness episode in the order events occurred;
      3) these accounts are easily understood by health professionals, resembling as
      they do a "clinical case study" approach; 4) the content is readily available in
      the form of common discourse for use by health program planners and
      administrators. The method is thus able to provide information necessary for
      organizing health services which meet the perceived needs of the population.

PMID- 10575709
TI  - [An epidemiological study of health care seeking behavior of children under 5
      years of age in Algeria: what lessons for improving the health care system?].
AB  - In many developing countries, dissatisfaction with primary health care has been
      accompanied by inappropriate use of university teaching hospitals, frequently for
      benign health problems. This situation is often attributed to the user population
      who supposedly misunderstands the functioning of health systems. This article
      describes the health seeking process and outcome of consultations for under-five
      children in two geographic zones in Algeria (very different in their care
      networks, and in the socioeconomic and educational characteristics of their
      populations), using a representative sample of users of public and private health
      services. During 4 one-week periods in 1991, a cross-sectional study was carried
      out among families of children and the health personnel they consulted, in all
      the health structures in the 2 zones. A Franco-Algerian supervisory team prepared
      consensual definitions of both the seriousness and the urgency of the pathology,
      as well as of the appropriateness of the health care structure chosen for that
      condition. The analysis of 1560 consultations shows dysfunctions in the health
      seeking process: numerous "self-referrals" (94%); unjustified recourse to
      university hospitals in 29% of cases; important delays before consulting (> or =
      1 week in 14% of cases); absence of the mother during the consultation;
      differences in the mode of recourse according to the child's sex (for equivalent
      seriousness and urgency, recourse is more frequent to the emergency room and
      university hospital for boys, but girls are more often hospitalized).
      Nonetheless, the Algerian supervisors of the research consider that the choice of
      the health care facility is appropriate in 91% of cases. At the service level,
      dysfunctions are equally frequent, especially the absence of the transfer of
      information on the child between different health care professionals. The primary
      preoccupation of parents is with accessibility (distance, cost), which leads to
      recommending the revitalizing of small first-line facilities, especially in rural
      areas, the more so because they are used and appreciated by families.

PMID- 10575710
TI  - [Families and children confronting health care practices in Algeria].
AB  - This paper describes results of a study on perceptions and behaviors of families
      concerning care of sick children, within the context of the Algerian health
      system as it functioned in two zones, Ain Taya and Tigzirt, in 1991. One hundred
      twenty families in the two zones were interviewed at home on the health seeking
      process during a recent illness episode of an under-5 child. Results show
      families make extensive use of curative health services for children, with
      apparently little use of traditional medicine, and only initial use of home
      remedies. Access to public services is often difficult due to distance, while
      incompetence, long waiting times, favoritism, lack of material, and poor
      communication with health personnel constitute families' main complaints. Use of
      private physicians, in spite of costs, is considered a gain in time, and rapport
      and communication are better. Results of the research among these families are
      discussed in relation to those from a study carried out at the same time among
      health professionals, results which show deep dissatisfaction on their part as to
      the means put at their disposal and with the quality of relationships maintained
      with the administration on the one hand, and with the client population on the
      other. Improving the public health sector in Algeria will entail greater
      investment in the quality of peripheral services, and training of health
      personnel in better communication skills.

PMID- 10575711
TI  - [Utilization of hospital emergency service for primary care (study at the
      Children's Hospital of Rabat, Morocco)].
AB  - BACKGROUND: Utilisation of emergency department (ED) for non-urgent problems,
      usually dealt with in first line health services (FLHS), has an impact both in
      terms of efficiency (ED care is more expensive than primary health care) and in
      terms of quality of care (due to ED overcrowding). This study describes the
      utilisation pattern of the ED at the Children's Hospital of Rabat (CHR) and
      assesses the appropriateness of ED utilisation. METHODS: During a whole week in
      September 1991, 24 h/24, information about every child admitted in the ED was
      collected by outside investigators, using a questionnaire. This questionnaire was
      divided into two sections. One section, filled out at admission of the child,
      consisted of the following items: time of arrival, health problem, health seeking
      pattern and identification of child (name, age, gender and address). The second
      section was filled out at the medical consultation and consisted primarily of a
      judgement about the relevance of ED utilisation (urgent/non-urgent condition,
      need for hospital-based equipment, subjective assessment of delay). RESULTS:
      During the week under study, 1,544 children were admitted at the ED: 904 at the
      medical ED and 640 at the surgical ED. At the medical ED, the proportion of
      urgent cases was 38%; among them, 65% needed hospital-based equipment and among
      the latter 72% arrived on time. It means that only 18% of the children utilised
      the ED in an appropriate way. At the surgical ED, the proportion of urgent cases
      was 56%; among them, 41% needed hospital-based equipment and among the latter 86%
      arrived on time. It means that only 20% of the children appropriately utilised
      the surgical ED. Appropriate utilisation is not associated with gender. The
      proportion of cases judged as urgent was associated neither to hour of admission-
      at least for the medical ED--nor to distance (less than 15 km). However, the
      proportion of urgent cases varied according to the day of the week. CONCLUSION:
      Results confirmed the opinion of the CHR staff: most children admitted to the ED
      had health problems that should have been cared for at FLHS. Rationalisation of
      ED utilisation will depend on the health system's ability to supply acceptable
      and accessible care at FLHS.

PMID- 10575712
TI  - [Why patients do not comply with reference decision made by general
      practitioners?].
AB  - SUBJECT: A health system's efficacy depends on the efficacy of its different
      components (first-level health services and hospitals). It also depends on the
      system's ability to ensure the continuity of care among the various levels of the
      system. Health care officials in Settat Province, Morocco, found continuity in
      this province to be unsatisfactory. Depending on the health centre involved, only
      31 to 52% of patients referred from the first to the second level of care reached
      the hospital. METHODS: The study was conducted in two rural and two urban health
      centres (HCs) covering a total population of around 94,000. The methodology
      consisted of two steps. First we analysed retrospectively various determinants
      (age, gender, distance, time until appointment) that might influence the
      compliance of patients referred by the four health centres in 1994. Then we
      observed curative medical consultations conducted in each of these health centres
      over a three-day period; the 38 patients referred to the hospital over this
      period were interviewed and the organisation of the hospital used on was
      analysed. RESULTS: The results revealed low compliance: only 43% (782/1807) of
      the patients referred actually consulted the hospital's departments. The
      compliance rates varied from one HC to the other and were lower in rural than
      urban areas taken as a whole (34% (207/607) versus 48% (575/1200), respectively).
      The interviews revealed that patients did not trust the last-year medical
      students who staffed the emergency rooms. Another organisational problem in the
      hospital was identified: patients referred to the hospital to consult a
      specialist were not seen immediately but given appointments at later dates, and
      these waiting times influenced the final success of the referral process. Thus,
      if the patients were seen immediately, compliance increased from 48 to 77% in the
      case of the urban HCs and from 34 to 67% in the case of the rural HCs.
      CONCLUSION: The most important determinants of compliance were above all
      associated with the way health services were organized and the quality of
      communication between health professionals and patients.

PMID- 10575714
TI  - [Health care seeking behavior of children in Togo].
AB  - Epidemiological and anthropological studies were carried out in Togo on health
      seeking behavior for under 5 children to determine causes of dysfunctions in
      health services. This article reports on the main findings of the anthropological
      study. Anthropological literature on health seeking behavior has identified
      labeling and associated explanatory models of illness as important factors for
      making choices in the use of health services. This study, carried out among 100
      families in Togo on health seeking behavior for under-five children, found little
      difference in the signs and symptoms of illness recalled and the health resources
      used. Different causal explanations similarly showed little variation in signs
      and symptoms of illness. The only causal explanation for illness which appeared
      to correspond to place of recourse was related to social causes, where
      traditional practitioners were more often consulted. Families explained choices
      more on the basis of the accessibility and quality of health services
      (geographical and financial accessibility, reception by health personnel,
      organization of services, drug availability) than on the basis of the particular
      signs and symptoms of the illness. Improving the organization and functioning of
      health services should contribute more to appropriate use of the modern health
      care sector than interventions targeting user populations, since the latter
      appear to be aware of the advantages of modern medicine, but find financial,
      social and organizational features of services unsatisfactory.

PMID- 10575713
TI  - [An epidemiological study of health care seeking behavior by children under the
      age of 5 years at hospital emergency services in Togo].
AB  - The functioning and efficacy of pediatric emergency services are currently being
      questioned in many Northern countries, as well as in the South, for example in
      North Africa. Reference is often made to unjustified medical emergencies in the
      face of an influx of patients with benign problems who come from socially
      disadvantaged families. In the university and regional hospitals in three regions
      in Togo, we compared three categories of under-5 patients: children sent to "day
      time" emergency services after triage done by health personnel; those sent to the
      "ordinary consultation"; and children brought after hours by their family
      (without referral by a health professional in 92% of cases) and seen in the
      "after-hours" emergency service. Serious tropical pathology (cerebral malaria,
      malaria, sickle cell disease) is mainly seen in emergency consultations, in which
      high hospitalization rates are noted (83% during the day, 67% at night) and a
      lethality of 3.4%. One cannot therefore use terms such as "false emergencies",
      "felt" and "medically unjustified" and the pediatric supervisor for the research
      considered that recourse to after-hours emergency services was justified in 75%
      of cases. Families using night services have higher educational levels than those
      sent to day emergency services, the mother's educational level being the main
      factor associated with certain characteristics of health seeking behavior
      (duration of symptoms prior to arrival at hospital, recourse to modern medical
      drugs). There is often a long delay before recourse to hospital: only 45% of
      children seen after hours and half of those who died came the 1st or 2nd day of
      the illness. Self-medication at home is usual but recourse to tradi-practitioners
      appears rare (4%). Several solutions can be envisaged and should be linked:
      strengthening of the first level of care, technical improvements in emergency
      services, training of tradi-practitioners in the recognition and referral of
      emergency cases, improvement of reception practices at the hospital level,
      prophylactic and preventive measures for tropical diseases.

PMID- 10575715
TI  - [An epidemiological study of consultations of children under 5 years of age in
      Brazzaville (Congo)].
AB  - In most of the large cities in developing countries, geographic accessibility to
      health care is not a major problem. Thus, indifference to public services and a
      preference for home treatment, recourse to traditional medicine or to the private
      sector may be related to problems in the quality of services. A cross-sectional
      epidemiological study of hospital visits by under-5 children was carried out in
      health centres and hospital out-patient services in Brazzaville (Congo). Sampling
      in these health facilities was done using a systematic random sample with a
      proportion of 25%, during 4 periods chosen according to seasonal factors. An
      exhaustive investigation of the entire public sector serving children was done in
      the study. At the same time, the same data were gathered in a sample of private
      facilities (doctors' and nurses' offices, traditional healers, religious healing
      centres), chosen as a function of their permanence and the numbers of their
      clientele. This article analyses services offered during 2215 visits by children,
      who were under 1 year of age in more than 50% of cases. In the public sector, 75%
      of visits were to first-line health centres. Public services show marked
      dysfunctions: the complexity of internal referrals, clinical examinations which
      are inadequate in relation to symptoms, and poor communication (explanations as
      to cause of illness in less than 2% of cases, and on treatments in less than 50%
      of cases). Communication seems well developed among private physicians and
      traditional healers, the latter engaging in both preventive and curative
      activities. Communication during well-child visits and consultations at health
      centres is especially disappointing, in light of the very young age of the
      parents (1/4 are high-school or college students). There is a two-fold risk in
      this situation: flight towards non-conventional medicine on the one hand, and
      access to private medicine based on socio-economic status on the other. It thus
      appears necessary to standardise procedures and acts in first line public health
      services and to promote training of personnel in communication skills with
      families (training using social science perspectives and participative
      pedagogical techniques).

PMID- 10575716
TI  - [An epidemiologic study of health care seeking behavior of children under 5 years
      of age by sex in developing countries].
AB  - Since the end of the 1970's, excess mortality among girls, from the end of the
      neonatal period until the age of 4 years, has been observed in some South Asian
      countries. Explanatory hypotheses for this situation have in fact noted
      differences by sex in food allocation and in care during illness. In some North
      African and sub-Saharan countries in Africa, mortality data suggest the same type
      of phenomenon, but less reliable statistics and a lack of data analysis by sex on
      use of health services does not really allow clarification of the problem. The
      objective of this study was to analyse health seeking behaviour by sex and to
      identify explanatory factors for any differences found. A cross sectional study
      of 1560 consultations of under-5 children was carried out in 6 university and
      regional hospitals in 3 African countries: Algeria (the zones of Ain Taya and
      Tigzirt); Togo (the zones of Lome, Atakpame and Kara) and the Congo
      (Brazzaville). Results confirm the existence of discrimination against girls. In
      ways which vary according to zones, and in comparison to boys, observations of
      girls show: under-representation among outpatients (29% in Tigzirt, 40% in Kara),
      especially when they have many siblings, of which some are sisters; longer
      duration of the development of symptoms before first resort (leading to increased
      severity of symptoms); less investment in health care; detrimental feeding
      practices. Higher SES of the father plays a favourable role, especially for
      girls, and children of both sexes benefit when the mother has a good educational
      level. The large regional differences demonstrate the complex interaction among
      explanatory factors: rurality, problems of access to the hospital, low economic
      level, low social status of women. This research opens the way so that, in
      Africa, research will no longer be carried out on health seeking behaviour and
      utilisation of health services without examining separately the situation of boys
      and girls, and analysing the possible causes of any differences.

PMID- 10575717
TI  - [Repeated accidents among adolescents. Anxiety traits, depressives and associated
      risk behavior].
AB  - PURPOSE OF THE STUDY: To look for and to assess the psychopathology of
      adolescents with repeated accidents. METHODS: A prospective study of a clinic
      group of adolescents from 12 to 18 years old with two or more accidents in the 18
      months before. This group is compared to a matched control group. The clinical
      evaluation use Scan, Hamilton, C.E.S.D., M.A.D.R.S. and R.S.S. Zuckerman scales.
      RESULTS: The clinic group (boy: 83 p. 100) exhibited a significant improvement in
      severe Anxiety Disorders (83 p. 100) and Depressive Episode Disorder (25 p. 100).
      Improvement also occurred in Dysthymic disorders and Sensation Seeking.
      CONCLUSIONS: Repeated accidents occurred among adolescent with psychopathologic
      features which revealed some psychic difficulties needed an evaluation and an
      appropriated help.

PMID- 10575718
TI  - [Fractures of the intercondylar eminence of the tibia in children. Apropos of 25
      cases with a 1-20 year follow up].
AB  - PURPOSE OF THE STUDY: This study tries to clarify the diagnostic strategy in
      intercondylar eminence fractures of the tibia and aids the deduction of
      therapeutic options based on the analysis of the long-term morbidity of anterior
      laxity. MATERIAL AND METHODS: This retrospective, monocentric study of 25
      children with a mean age of 11.8 years (7-15 years) was performed with an average
      follow-up of 7.2 years (1-20 years). Fractures are itemized with Meyers-McKeever
      modified by Zaricznyj and Zifko-Gaudernak classifications. Conservative treatment
      (16 patients) consisted of hemarthrosis aspiration, ligament examination,
      manipulation into extension and cast immobilization under general anesthesia.
      Surgical treatment (9 patients) consisted of wire suture fixation (4 times), wire
      suture fixation held by a screw (3 times) and direct screw fixation (2 times).
      Four patients were lost to follow-up. Patients were evaluated with the Lysholm
      (21 patients) and IKDC (15 patients) scores systems. Anterior laxity was checked
      with a KT-1000 arthrometer. Antero-posterior and lateral X-rays were performed.
      The statistical analysis was carried out with Mann-Whitney and Fischer tests.
      RESULTS: There are 18 good or very good results and only 3 medium with the
      Lysholm score and 5 knees graded A, 9 graded B and 1 graded C with the IKDC
      score. Mean anterior laxity is 1.86 mm (0 to 4 mm) after conservative treatment
      and 1.5 mm (-1 to 4 mm) after operative treatment. 5 patients have an anterior
      laxity and only 2 an anterior instability. No arthritic lesions, 1 nonunion, and
      11 malunions have been observed, mainly after conservative treatment. DISCUSSION:
      Ligament examination under general anesthesia is useless for displaced fractures
      and dangerous for those were not displaced. Diagnostic arthroscopy is not yet
      allowed. Magnetic Resonance Imaging is useful to explore osteochondral fractures
      and symptomatic meniscal lesions. Laxity is the consequence of anterior cruciate
      ligament elongation. CONCLUSION: The diagnosis of these fractures rests on a
      simple radio-clinical examination to determinate the exact position, the
      displacement and the size of the osteochondral fragment in order to choose the
      best treatment. Conservative treatment will be chosen preferentially because of a
      poor long-term morbidity. Treatment will be surgical, preferably arthroscopic, in
      the others cases.

PMID- 10575719
TI  - [Thoracoscopy versus thoracotomy in spinal surgery: comparison of 2 paired
      series].
AB  - PURPOSE OF THE STUDY: This study was carried out to compare the intraoperative
      and postoperative results of conventional surgery of the thoracic spine by
      thoracotomy with those of the thoracoscopic technique to determine the advantages
      of this new approach. MATERIAL AND METHODS: A series of twenty-nine patients
      operated by thoracoscopy for a spinal disorder was matched regarding the etiology
      of spine disease and type of surgical procedure with twenty-four patients
      operated by thoracotomy. This matching procedure yielded two similar groups of
      twenty patients. The criteria used for evaluation were the duration of the
      procedure, blood loss, intraoperative complications, the duration of stay in
      postoperative intensive care, the duration and yield of pleural drainage, the
      time until return to the upright position, duration of use of WHO grade-three
      analgesics (morphine derivatives), the postoperative complications, and the
      length of hospitalization. RESULTS: There was a significant difference in three
      parameters: the duration of the procedure (thoracotomy, 172 min; thoracoscopy,
      246 min; p < 0.006), intraoperative bleeding (thoracotomy, 837 mL; thoracoscopy,
      447 mL; p < 0.0009), and duration of use of WHO grade-three analgesics
      (thoracotomy, 4.5 days; thoracoscopy, 2.3 days; p = 0.011). There was no
      difference in the intra- or postoperative complication rates of the two methods.
      DISCUSSION: The better view provided by thoracoscopy and its preservation of the
      wall structures probably explain why there was less bleeding and postoperative
      pain with this technique. The insufficiency of the current thoracoscopic
      instrumentation and the learning curve account for the longer duration of these
      interventions. CONCLUSION: These data confirm the usefulness of thoracoscopy
      which is less traumatizing, less hemorrhagic, and causes no more complications
      than thoracotomy. The longer operative duration is currently a minor drawback,
      and should shorten with experience and the development of specific
      instrumentation.

PMID- 10575720
TI  - [Replacement arthroplasty of paralytic hip. Apropos of 18 cases].
AB  - PURPOSE: Frequency of hip impairment, with sub-luxation or dislocation, during
      evolution of neuromuscular diseases depends on intensity and spreading of palsy.
      At the end of growth or at the beginning of adult life, secondary arthritis can
      induce pain and lack of mobility. The importance of the chondropathy and
      irreducible lack of congruence may doom to failure a conservative articular or
      periarticular surgery. Total hip arthroplasty is an alternative, but the risks of
      dislocation, ectopic ossifications and infection make often refute this
      indication. We report our experience of total arthroplasty for paralytic hip,
      about 18 cases. MATERIALS AND METHODS: We reviewed retrospectively 14 consecutive
      patients with neuromuscular disease, who had 18 total arthroplasties of paralytic
      hips. The origin of neuromuscular disease was cerebral for 7 patients (6 cerebral
      palsy: 4 spastic or athetosic tetraplegias, 1 spastic diplegia, 1 hemiplegia; 1
      head trauma), 6 medullar disorders (1 Friedreich disease, 2 acute anterior
      poliomyelitis, 1 vascular injury, 1 malformative spine with sacral agenesis and 1
      cervical spine trauma) and 1 muscular affection (Steinert disease). Mean age of
      the patient was 40 year old (19 to 64). Mean follow up was 5 years. Intensity and
      diffusion of weakness were variables, compatible with gait with or without help
      for 11 patients, and for 3 patients with sitting posture and transfer. The
      coxopathy, with pain stiffness and vicious attitudes, induced the loss of gait or
      sitting posture and transfer. The goal of the arthroplasty was the restitution of
      the initial function. 11 hip had previous surgery, with infection in 2 cases.
      Arthritis was secondary to hip palsy in 14 cases (4 dislocations, 6
      subdislocations, 3 complications of surgery of paralytic hip dislocation in
      childhood, 1 nervous arthropathy), and independent of palsy in 4 cases (1 femoral
      head avascular necrosis ans 3 primary arthritis). The prosthesis were LFA
      Charnley Kerboull in all cases except 1. We used transtrochanteric approach.
      RESULTS: Mean follow-up is 5.6 years. Functional initial goal has been obtain in
      all cases. Ectopic ossifications occurred in 3 cases, without functional
      consequence. One acetabular loosening occurred after 13 years and has been
      reoperated on. There was no polyethylene wear. We noticed 1 mechanical and 2
      chemical femoral loosening. Prosthetic dislocation occurred in 4 cases, always
      during the 4 post-operative months, without recurrence after this critical
      period. There were no infection. DISCUSSION: If gait is possible, there is no
      satisfactory alternative to total hip arthroplasty. In absence of gait, total hip
      arthroplasty gives also the best functional results. Girdlestone procedure is not
      indicated because it will induce the loss of transfer and side effects as
      ascension of proximal femur with recurrence of adduction bringing out pain and
      sometimes scabs. CONCLUSION: Total arthroplasty of paralytic hip induced
      restitution of initial function for all patients and an acceptable rate of
      complication after strict selection of patients and indications, specific
      operative technique and rehabilitation for each patient. This results encourage
      us to carry on with this therapeutic orientation.

PMID- 10575721
TI  - [Computer-assisted preoperative planning of knee replacement arthroplasty].
AB  - The general configuration of replaced knee is difficult to anticipate because of
      the large number of geometrical parameters related to morphology, prosthetic
      implants and pre-operative choices (such as ligament release). This article
      features the studies achieved in order to create a decision aiding computer tool
      dedicated to total knee prosthesis. METHOD AND MODEL: We have built a geometrical
      modelling of the physiological knee and prosthesis elements association. A
      numerical processing through biomechanical laws permitted to simulate the
      geometrical and mechanical behaviour of the whole for different flexing angle.
      RESULTS: A first validation of the model, comparing the numerical simulation
      results and the measuring of the 30 implanted knee X-rays, showed a valid
      matching (86 p.cent of the total cases) between model and real configuration.
      DISCUSSION: This tool allows to realise simulations and optimizations with regard
      to the following issues: decreased risks of the unsealing of the patellar
      component through contact centering with the trochlea, increased mechanical
      efficiency of the force transmission from the quadriceps to the tibia, increased
      maximum flexing angle considering the extension of the quadriceps. CONCLUSION:
      The orthopedic surgeon should be greatly assisted in the future preoperative
      planning by these initial findings.

PMID- 10575722
TI  - [Comparative biomechanical study of 3 types of osteosynthesis of the Duparc grade
      IV fractures of the calcaneus: value of triangular internal fixation].
AB  - PURPOSE OF THE STUDY: We present an in vitro biomechanical study performed to
      evaluate and compare, for an experimentally produced fracture of the calcaneum
      (Duparc grade IV), the reaction of 3 standard models of internal fixation
      commonly used in these fractures and which occupy different volumes. MATERIALS
      AND METHODS: We compared different methods of fixation using fresh human
      calcanei. In two experimental series, we compared triangular internal fixation (3
      1/4 tube AO plates Saragaglia), Y internal fixation (2 1/3 tube AO plates Bezes),
      isolated screw technique (three 3.5 diameter screws, two 4.5 diameter screws).
      The plates and screws were made of identical material (316L). Both series used 8
      pairs of bone (talo-calcaneum system) with the same fracture submitted to a 200N
      to 1000N load. Stiffness and movement were analyzed using 8 references on the
      calcaneum. RESULTS: The stiffness and movement analysis with 8 references points
      demonstrated the superior resistance to bending with the triangular internal
      fixation. Fixation stability was significantly better than with the Y or screw
      technique. DISCUSSION: This study underlined the importance of triangular
      trabecular organization of cancellous bone on calcaneum biomechanics. We showed
      that the 3 (anterior, posterior and inferior) trabeculae must be repaired in
      calcaneum fractures to achieve horizontal and vertical stability of the talar
      joint. CONCLUSION: In our hands, restoration of the triangular architecture of
      calcaneum fractures, to resemble a roof truss, where the talus is fixed to the
      triangle vertex, is fundamental to obtain a rigid and stable internal fixation.

PMID- 10575723
TI  - [Traumatic ruptures of the pectoralis major muscle. Apropos of 3 cases].
AB  - INTRODUCTION: Three ruptures of the pectoralis major are reported. The mechanism
      of injury was excessive external rotation with high muscular tension. Rupture of
      muscle often occurs at the humeral insertion or musculotendinous junction.
      MATERIAL AND METHODS: In the three cases, surgical repair was performed. Suture
      could be made without excessive tension. Patients were immobilized in a sling for
      three weeks. Passive exercises were begun at 3 weeks. RESULTS: All patients
      recovered and had postoperatively the same sport level as before. In late
      surgical repair the consistent fibrosis makes dissection of the ruptured tendon
      difficult and it's retraction hinders the suture. DISCUSSION: The symptoms are
      sometimes initially under evaluated. In limited number of cases the treatment may
      be delayed: functional disability and strength limitation justify surgical
      treatment. The results, however, are usually good according to the score of Mc
      Entire. Surgical repair is recommended in distal ruptures in active patients to
      restore previous muscle strength and contour.

PMID- 10575724
TI  - [A case of isolated avulsion fracture of the posterior cruciate ligament in a
      child].
AB  - PURPOSE OF THE STUDY: The authors report one case of isolated avulsion fracture
      of the tibial attachment of the posterior cruciate ligament. They recommend the
      use of 3D CT Scan to appreciate the size, the displacement of the bone fragment
      or the occurrence of comminuted fracture. MATERIAL AND METHOD: A 12 years old
      girl was admitted for knee pain and swelling secondary to horse's hoof blow on
      the anterior aspect of the proximal tibia. Hemarthrosis, contusion of the
      anterior surface of the proximal tibia were present. Because of pain and
      swelling, the knee could not be examined with accuracy. Roentgenographic
      examination showed isolated avulsion fracture of the tibial attachment of the
      posterior cruciate ligament. 3D CT Scan confirmed the lesion. Bony fragment was
      displaced and was not comminuted. Approach through the popliteal fossa was used
      and bony fragment was screwed back into its bed. RESULTS: Postoperatively, a long
      leg plaster of Paris was applied for 6 weeks. The patient was followed for 1.5
      year. She returned to her previous occupation. There was no residual laxity. X
      ray confirmed fracture union. DISCUSSION: Results of primary repair of
      interstitial posterior cruciate ligament tears were inconsistent. On the
      contrary, good functional results were obtained with surgically treated avulsion
      fracture of the posterior cruciate ligament. Displaced bony fragment will be
      fixed properly to its bed. 3D CT Scan appreciate the size, the displacement or
      the occurrence of comminuted fracture. Those informations help to define surgical
      procedure: screw, wire-suture or staple.

PMID- 10575725
TI  - [Villonodular synovitis of the knee in a 5-year-old child. Apropos of a case].
AB  - PURPOSE OF THE STUDY: Case report of a five-year-old boy presenting with a
      painless swelling of the left knee with decreased range of motion. METHOD: Joint
      aspiration: fluid rich in red blood cells. X-ray--CT-scan--MRI: pigmented
      villonodular synovitis suspected. Arthroscopy with synovectomy and biopsy
      confirmed diagnosis. Because of remaining swelling one month after arthroscopy,
      intra-articular injection of triamcinolone hexacetonide gave a good result which
      has been maintained after 2 years. DISCUSSION: Hypothesis on etiology and
      pathophysiology, differential diagnosis and treatment of Pigmented villonodular
      synovitis are discussed based on a study of the literature. CONCLUSION: Pigmented
      villonodular synovitis is a rare condition in children. Association with other
      congenital disorders such as polyarticular localizations and family-history have
      been described. The diagnosis has to be proved by a biopsy. MRI seems to be the
      examination which gives the best information. Surgical treatment is indicated and
      consists of an arthroscopic synovectomy but which is often incomplete. A
      postoperative injection of triamcinolone hexacetonide may be the solution to
      avoid recurrence of Pigmented villonodular synovitis.

PMID- 10575726
TI  - [Osteopetrosis: diagnostic and therapeutic management. Apropos of 5 cases].
AB  - PURPOSE OF THE STUDY: The purpose of this study was to analyse 5 cases of
      osteopetrosis: 2 dominant and 3 recessive forms. MATERIAL AND METHODS: Among five
      cases of children suffering from osteopetrosis. There were three malignant and
      two benign forms. Three children affected by malignant form, received a bone
      marrow transplantation. RESULTS: Only one child who received a bone marrow
      transplantation was still alive and cured (one died due to transplantation
      complications, the other child died accidentally). The two children presenting a
      benign form were periodically followed for iterative fractures and did not
      present serious complications. DISCUSSION: Our analysis compared to literature
      review allows us to insist on bone marrow transplantation. This is the only
      possibility for these children who were condemned in the past. The frequency of
      iterative fractures on children presenting a dominant form necessitates medical
      and orthopedic follow-up. Narrowness of the medullary canal, bone fragility
      contra indicates intramedullary nailing when fixation is indicated. CONCLUSION:
      Osteopetrosis is an autosomal metabolic bone disease caused by an anomaly of
      osteoclasts action. Two main forms exist: the dominant form which is benign, and
      the recessive form which is malignant. Actually recessive forms can be treated
      and cured by bone marrow transplantation and the children who were in the past
      condemned are saved. Children with dominant form must be followed up by an
      orthopaedic surgeon because of bone weakness. The increase in number of cases
      detected in immigrant populations with a high rate of consanguineous marriages
      led us to present this study.

PMID- 10575727
TI  - [Multiple schwannoma of the sciatic nerve. Apropos of a case].
AB  - A case of multiple neurilemmoma at the sciatic nerve is presented. A 79 years old
      male reported as initial symptom the appearance of a mass at the popliteal fossa
      without any neurological impairment. The MRI showed numerous tumors along the
      that were no previously detected. The tumor was easy to remove without affecting
      the nerve. No neurologic alteration occurred at the postoperative period which
      confirms the good prognosis of this tumor.

PMID- 10575728
TI  - [Tissue reactions to wear debris of joint prostheses. Diagnostic problems.
      Apropos of 2 cases].
AB  - We report two cases of tissue reactions to wear debris after large joint
      prostheses. In the first case, a septic loosening of a hip arthroplasty was
      suspected after emergence of an inguinal mass. In the second case, a patient with
      loose hip prosthesis had surgery for a prostatic adenocarcinoma and pelvic lymph
      nodes were discovered during surgery. They were first suspected to be metastatic
      carcinoma. These two diagnostic problems were resolved by histology which
      revealed sinusal histiocytic reaction to wear debris. The peculiar sign of this
      reaction is the presence of birefringent components such as polyethylene seen
      with polarized light. These problems will become more frequent in the future
      because of the increasing number of elderly patients who have had hip replacement
      and will undergo surgery for pelvic cancer. A close medico-surgical collaboration
      should help pathologists in such cases.

PMID- 10575729
TI  - [Traction-mobilization in 2-stage treatment of infected total knee prosthesis.
      Apropos of 12 cases].
AB  - INTRODUCTION: A two stages reimplantation is advised by most authors in salvage
      of infected total knee arthroplasty. This treatment is more difficult, but seems
      more successful in controlling infection. It set the problem of the attitude
      between the two operative stages: an antibiotic cement spacer is usually used,
      but articular mobilization is not possible, except with an articulating spacer.
      MATERIAL AND METHODS: Since 1989, we use traction-mobilisation between the two
      operative stages, with mobilization under traction up to 50 degrees, and on edge
      of bed up to 70-90 degrees, till the reimplantation. We used this method on 12
      cases of chronic infection in total knee arthroplasty. The reimplantation was
      done 34 to 47 days later. The reimplantation was more easy and more comfortable
      in approach and exposition, and post operative mobilisation easier. RESULTS: We
      did not have any recurrence of infection in this patients, but the follow up is
      too short for some of them. One prosthesis was removed for mechanical failure.
      The mean range of motion is 86 degrees at two months, 96 degrees at one year.
      DISCUSSION: The antibiotic cement spacer presents the disadvantage of leaving
      material in a potentially infected environment. It does not allow mobilisation,
      except using an articulating spacer. Traction-mobilisation keep articular
      flexion, allows mobilization, and does not leave any material in articulation.
      But this method has the disadvantage of requiring an hospital care between the
      two stages: that is reasonable if the delay is short. CONCLUSION: Traction
      mobilization seems to be an alternative to cement spacer. It makes the
      reimplantation easier, facilitates post operative recovery of mobility, and does
      not seem to increase recurrence of infection.

PMID- 10575730
TI  - Electrospray ionization Fourier transform ion cyclotron resonance mass
      spectrometry.
AB  - The basic principles and recent advances in electrospray ionization Fourier
      transform ion cyclotron resonance mass spectrometry are reviewed. A brief history
      of electrospray ionization is provided, along with a complete technical
      description of the technique, electrospray ionization variations, and advantages.
      Next, the fundamental principles of Fourier transform ion cyclotron resonance
      mass spectrometry are covered, including ion cyclotron motion, ion cyclotron
      resonance excitation, and image current detection. Instrumentation and methods
      used to couple these techniques are then described. Topics include ion source
      configuration, ion transport through a strong magnetic field gradient, and ion
      trapping methods. The article concludes with selected applications that highlight
      the strengths of electrospray ionization Fourier transform ion cyclotron
      resonance mass spectrometry.

PMID- 10575731
TI  - Antimicrobial and genotoxic activities of N-(2-hydroxyethyl)-1,2-benzisothiazol
      3(2H)-thione carbamic esters.
AB  - The antimicrobial properties of N-(2-hydroxyethyl)-1,2-benzisothiazol-3(2H)
      thione (1a,b) and its carbamic esters 2a,b-6a,b were tested in vitro against Gram
      positive and Gram negative bacteria, yeasts and dermatophytes. All compounds
      markedly inhibit the growth of Gram positive bacteria exhibiting MIC values
      ranging from 1.25 to 10 micrograms/ml. A strong antifungal activity is exerted
      against dermatophytes with MICs, in general, between 0.7 and 12 micrograms/ml.
      Structure-activity relationship studies show that these compounds are, in most
      cases, more effective than the corresponding benzisothiazolone analogues 7-12.
      None of the tested compounds shows genotoxic properties by Bacillus subtilis rec
      assay and Salmonella-microsome test.

PMID- 10575732
TI  - Inclusion of ketoprofen with skimmed milk by freeze-drying.
AB  - Ketoprofen is a non-steroidal anti-inflammatory drug which is not soluble in
      water and creates gastrointestinal problems. In order to improve the solubility
      of the drug in water and enhance its dissolution rate, physical mixture (PM) and
      inclusion (IC) of ketoprofen with skimmed milk (SM) were prepared and
      investigated. Enhancement of solubility of ketoprofen was obtained by preparing
      its IC with SM which can be used because of its amino acid and surface active
      agents content and can also be used for treatment of gastric disturbance.
      Lyophilization technique was used to prepare the IC. Results obtained showed that
      the solubility of IC of ketoprofen with SM was almost four times greater than the
      solubility of the plain drug. Data from the dissolution rate determination have
      also indicated that IC of ketoprofen with SM significantly improved the
      dissolution rate of the drug compared with PM and the plain form. Differential
      scanning calorimetry (DSC), X-ray powder diffraction and scanning electron
      microscopic (SEM) analysis revealed the formation of IC of ketoprofen with SM.

PMID- 10575733
TI  - Theoretical study of mexiletine and its interaction with cationic and anionic
      receptor sites.
AB  - Theoretical methods are applied to study the antiarrhythmic (AA) mexiletine (1
      (2,6-dimethylphenoxy)-2-aminopropane). The AM1 method is used to construct a
      three-centre binding model for this drug. This model consists of an amine
      nitrogen atom that is protonated to a higher degree at physiological pH, flat
      hydrophobic regions of aromatic rings and additional functional groups with lone
      electron pairs of oxygen. Based on these ideas, a model for the binding of
      mexiletine at the transmembrane protein was constructed. An ab initio SCF method
      was used to study the two-component mexiletine-receptor binding site composed of
      acetate (Glu-, Asp-) and protonated methylamine (Lys+, Arg+). The binding of
      mexiletine to the receptor may be understood by considering a two-step process of
      recognition and binding of AA to its receptor. Within this model the mexiletine
      cation is recognised in the first step and bonded to the negatively-charged part
      of the receptor. In a subsequent step, the interaction between the amide oxygen
      and cationic amine group of the membrane protein may follow.

PMID- 10575734
TI  - Synthesis and X-ray crystal structure of the calcium channel antagonist: dimethyl
      1,4-dihydro-2,6-dimethyl-4-[4'-(4H-4-oxo-1-benzopyran-2-yl)phenyl]- 3,5-pyridine
      dicarboxylate.
AB  - The synthesis of the title compound via the Hantzsch method from 4'-flavone
      carboxaldehyde is described, and its molecular structure was determined by X-ray
      crystallography. The 1,4-dihydropyridine (1,4-DHP) ring adopts a boat
      conformation. The phenyl ring of the flavone is not exactly perpendicular to the
      DHP ring. Calcium antagonistic activity of this compound was evaluated in vitro
      by using BaCl2-stimulated rat ileum.

PMID- 10575735
TI  - New pyridine derivatives as potential antimicrobial agents.
AB  - A set of pyridine derivatives bearing a substituted alkylthio chain or a
      piperidyl ring in position 2 or 4 were synthesized, and their antimycobacterial
      and antifugal activities were evaluated. Chemical structures were confirmed by IR
      and NMR data, and by elemental analysis. Minimum inhibitory concentrations (MIC)
      were used for the evaluation of microbiological activity in vitro. The compounds
      were moderately active against both Mycobacterium tuberculosis and nontuberculous
      mycobacteria. The most active compound was 2-cyanomethylthiopyridine-4
      carbonitrile (7) with MIC against Mycobacterium kansasii in the range of 8-4
      mumol/l. The antifungal activities of the compounds were relatively low.

PMID- 10575736
TI  - psi(SO2NH) transition state isosteres of peptides. Synthesis and bioactivity of
      sulfonamido pseudopeptides related to carnosine.
AB  - This paper reports the synthesis of tauryl dipeptides related to carnosine. In
      particular H-Tau-His-OH (5), H-Tau-His(pi-Me)-OH (6) and H-Tau-His(tau-Me)-OH (9)
      are described. The enzyme carnosinase has been isolated from pig kidney and after
      purification has been used to test the stability and the inhibitory activity of
      the three new analogues. H-Tau-His-OH (5) and H-Tau-His(tau-Me)-OH (9) were found
      to possess weak inhibitory properties towards carnosinase, while H-Tau-His(pi-Me)
      OH (6) proved to be devoid of any significant activity. All the three sulfonamido
      pseudopeptides 5, 6 and 9 show stability to carnosinase activity.

PMID- 10575737
TI  - Synthesis and relative binding affinity to steroid receptors and
      antiproliferative activity on MCF-7 cells of 2,3-disubstituted indenes.
AB  - The study of the relative binding affinity of a set of 2,3-disubstituted indenes
      to the receptors of steroid hormones indicates a weak effect of some derivatives
      on estrogen, progesterone and androgen receptors. The antiproliferative effect on
      human MCF-7 cells also shows a weak activity for three derivatives.

PMID- 10575738
TI  - Non-imidazole histamine H3 ligands. Part I. Synthesis of 2-(1-piperazinyl)- and 2
      (hexahydro-1H-1,4-diazepin-1-yl)benzothiazole derivatives as H3-antagonists with
      H1 blocking activities.
AB  - New 2-(1-Piperazinyl)- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazoles were
      prepared and tested as H1- and H3-receptor antagonists. A number of compounds
      showed weak H1-antagonistic activity, with pA2 values ranging from 5.5 to 6.1.
      The simple alkyl substituted, 2-[1-(4-methyl and 4-ethyl)piperazinyl] analogues
      show increasing, moderate H3-antagonistic activity (pA2 = 6.0, and pA2 = 7.0).
      The compounds with 4-phenylalkyl substitution, for both the piperazinyl and the
      hexahydro-1H-1,4-diazepin-1-yl homologues series, regardless of the different
      physicochemical properties of the para substituents at the phenyl ring, showed
      weak H3-antagonistic activity with pA2 values ranging from 4.4 to 5.6.

PMID- 10575739
TI  - Antioxidant properties of albumin: effect on oxidative metabolism of human
      neutrophil granulocytes.
AB  - The present study aims at investigating the effect of bovine serum albumin (BSA)
      on the trial of oxidative-stress. The antioxidant effects of BSA were determined
      by human neutrophil granulocytes oxygen free radicals and their by-products (O2-,
      H2O2, HOCl) productions. BSA interacts with those reactive oxygen species (ROS)
      in a dose-dependent manner. The 50% inhibitory concentration (IC50) of BSA
      estimated, after phorbol-12-myristate-13-acetate (PMA) stimulation were: 33.5
      mg/ml for O2-, 6.5 mg/ml for H2O2, and 6.85 mg/ml for HOCl. When neutrophils were
      washed after pre-incubation with BSA, there was no significant decrease of ROS
      after stimulation of PMA (maximal: 15 +/- 1.2%). In the free cell experiments,
      IC50 for H2O2 and HOCl were 7.86 mg/ml and 0.67 mg/ml, respectively. The
      mechanism at which BSA acts may result from a simple chemical interaction with
      ROS rather than an intracellular mechanism by intervention in PMA oxidative
      metabolism. These antioxidant activities confer to BSA properties, which might be
      used to prevent damage inflicted by these ROS during inflammatory disorders.

PMID- 10575740
TI  - Voltammetric determination of N-nitrosoderivatives of atenolol and propranolol in
      simulated gastric juice.
AB  - A highly sensitive and simple voltammetric method is proposed for the
      determination of N-nitrosoatenolol (NA) and N-nitrosopropranolol (NP) in
      simulated gastric juice. The method is based on measuring the differential-pulse
      polarographic peak produced by NA and NP in Britton-Robinson buffers of pH 3 and
      4 for NA and NP, respectively. Both compounds yielded diffusion-controlled
      current with diffusion-current constants of 7.23 +/- 0.03 and 9.46 +/- 0.06 for
      NA and NP, respectively. The current-concentration plots were rectilinear over
      the range 0.16-9.6 micrograms ml-1 with minimum detectability (S/N = 2) of 0.015
      microgram ml-1 (5 x 10(-8) M) for NA; for NP the range was 0.08-8.0 micrograms ml
      1 with minimum detectability (S/N = 2) of 0.009 microgram ml-1 (3 x 10(-8) M).
      The proposed method was successfully applied to study the possible in vivo
      production of the nitroso-derivatives under the standard nitrosation reaction
      conditions recommended by WHO. The method is characterized by simplicity and
      higher sensitivity as compared with the reported HPLC method.

PMID- 10575741
TI  - Hypolipidemic properties of a diphenyl-methylen-ethylamine derivative with
      affinity for beta 3-adrenoceptors in a model of hypercholesterolemia.
AB  - beta 3-Adrenergic agonists have been proposed as potential new drugs for the
      treatment of diabetes and/or obesity therapy, because of the hypoglycemic and
      lipolytic effects found with some of these compounds. Moreover, their application
      in other therapeutic areas such as hypercholesterolemia and atherosclerosis has
      been suggested. This experimental trial was conducted to assess the effects of
      Trecadrine, a new molecule with affinity for beta 3-adrenoceptors, on a model of
      hypercholesterolemia in rats, and also to explore a possible beneficial role of
      these agents in lipid disturbances therapy. The results indicated a marked
      reduction in serum triglyceride levels (-40%; P < 0.01) and lipoprotein lipase
      activity in white fat (-49%, P < 0.001) of hypercholesterolemic rats treated with
      Trecadrine for 16 days as compared with hypercholesterolemic non-treated rats.
      Moreover, Trecadrine produced a significant increase in the oxygen consumption in
      brown adipose tissue (+154%, P < 0.01). In relation to cholesterolemia, an
      improvement in total cholesterol (-20%) and total/HDL-cholesterol ratio (-25%) in
      serum was noted in the animals receiving the pharmacological treatment. In
      conclusion, the results of this trial support that Trecadrine administration may
      have a therapeutic potential in disorders associated with hypertriglyceridemia
      such as obesity and some types of hyperlipidaemias.

PMID- 10575742
TI  - [Ambiguous genitalia: what factors should be considered before designating the
      definite sex?].

PMID- 10575743
TI  - [Genetics and dysmorphology in the context of pediatric subspecialties].

PMID- 10575744
TI  - [Pediatricians' opinion on sedation in children].
AB  - OBJECTIVE: Our objective was t evaluate the current knowledge and attitudes of
      pediatricians regarding the issue of pediatric sedation. PATIENTS AND METHODS: In
      October 1996 we conducted a mail survey of all 686 members of the Asturias,
      Cantabria and Castilla y Leon Pediatric Society. Physicians were asked to
      complete and return a confidential 18-item questionnaire. RESULTS: One hundred
      fifty-seven (23%) of the eligible physicians responded. Of the responding
      physicians, 90% agreed that they had insufficient training in pain and sedation
      management. Seventeen percent thought childhood sedation to be very effective,
      76% effective and 7% little effective. Fifty-nine percent thought infant sedation
      was easy and 36% considered it to be difficult. Thirty-six percent of the
      pediatricians who work in hospitals considered the cooperation of children under
      8 to be good versus only 17% of the primary attention pediatricians (p < 0.05).
      Thirty-nine percent thought that it was only necessary on some occasions that the
      parents are present when the child is sedated before surgery. Forty-eight percent
      of the male pediatricians considered that sedation was always or almost always
      indicated versus 67% of the female pediatricians (p < 0.05). The most used
      sedative drugs are midazolam (24%), diazepam (23%) and chloral hydrate (14%).
      Eleven percent indicated that it was necessary to monitor cardiorespiratory
      function and oxygen saturation during sedation. CONCLUSIONS: Pediatricians in
      this Society seem to have a lack of knowledge concerning sedation of their
      patients. Training in childhood sedation is needed.

PMID- 10575745
TI  - [Neutropenia as early manifestation of X-linked agammaglobulinemia. Report on 4
      patients].
AB  - OBJECTIVE: The aim of this study was to determine the frequency of neutropenia
      associated to X-linked agammaglobulinemia (XLA) and to describe the clinical
      characteristics of the children diagnosed in our unit. PATIENTS AND METHODS: A
      revision of the medical records registered in our unit during a 28 year period
      (1970-1998) according to the diagnostic criteria of XLA was performed. We
      included in the study group those patients that expressed a neutropenia.
      Immunological studies by standard techniques were performed. RESULTS: Of the 37
      patients fulfilling the diagnostic criteria of XLA, 4 cases had experienced
      episodes of neutropenia (10.81%). The frequency of neutropenia within the group
      without familiar antecedents was 15% and within the group with familiar
      antecedents 5.88%. In all cases, the neutropenia was present during a serious
      acute infectious disease. The neutropenia was transient and resolved promptly
      after the onset of antibiotic therapy in all patients. None of the patients
      experienced neutropenia while under therapy with intravenous gammaglobulin.
      CONCLUSIONS: The association of XLA and neutropenia seems to be sufficiently
      frequent as to include it in the differential diagnosis of neutropenia during
      infancy. It is important to consider a primary immunodeficiency diagnosis when a
      child presents neutropenia and a serious acute infectious disease. Quantification
      of serum immunoglobulin levels and enumeration of lymphocyte subpopulations can
      lead to an early diagnosis.

PMID- 10575746
TI  - [Inappropriate use of pediatric hospitalization].
AB  - OBJECTIVE: Our aim was to identify the inappropriate utilization of pediatric
      hospitalization, its reasons and associated factors. PATIENTS AND METHODS: Three
      hundred twenty-three medical records were randomly selected among the patients
      aged 6 months to 14 years and hospitalized in 1995 in a public hospital of the
      Community of Valencia. The validated Spanish version of the "Pediatric
      Appropriateness Evaluation Protocol" was retrospectively applied. The proportions
      of inappropriate admissions and stays and their reasons were estimated and their
      association with certain factors analyzed. RESULTS: Of the admissions 17.7% (95%
      CI: 13.5-21.8) and 15.5% of the stays (95% CI: 11.5-19.4) were considered
      inappropriate. The most frequent reason for inappropriate admission was that
      diagnostic and therapeutic needs might have been solved by ambulatory care.
      Inappropriate stays were in mot cases (70%) due to that doctors did not pay
      attention to keeping the patient in the hospital although acute care was no
      longer needed. Female patients, non-elective admissions, admissions by general
      pediatricians or traumatology and weekend stays had significantly higher
      proportions of inappropriate utilization. CONCLUSIONS: A considerable proportion
      of inappropriate admissions and stays was observed, although it is in the lower
      range of those observed in other studies in pediatric patients. The most frequent
      reasons were attributed to an excessively conservative medical practice.

PMID- 10575747
TI  - [Our experience in the management of peritonsillar phlegmon and abscess in
      children].
AB  - OBJECTIVE: Our objective was to evaluate the possible causes of the increased
      incidence of peritonsillar abscess in children during recent years, since up
      until now this condition has been unusual in children. PATIENTS AND METHODS: A
      retrospective study of all cases diagnosed in the Emergency Room between 1983 and
      1998 detected nine children admitted to the hospital with painful swallowing,
      high fever and trismus. All of them underwent fine needle aspiration and
      transcutaneous ultrasound. RESULTS: The mean age was 9.8 years. Eight children
      suffered previous pharyngo-tonsillar infection, although emergency assistance was
      only confirmed in four cases. Six children were treated with macrolides, two with
      amoxicillin and one with cefuroxime. Exploration always diagnosed peritonsillar
      infection and needle aspiration detected an abscess in six cases. Ultrasound did
      not provide new information. In cases with abscess, drainage was performed and in
      three patients under general anesthesia. Bacteriologic cultures showed a lack of
      correlation between the isolates from the tonsillar surface and from pus from the
      abscess or tonsillar core. In the latter two there was a preponderance of
      Haemophilus influenzae and anaerobes. All children received intravenous
      antibiotic therapy and delayed tonsillectomy was done. There were no
      complications. CONCLUSIONS: Infant cases of peritonsillar abscess are increasing
      and there is no clear relationship with acute tonsillar infections, but probably
      with the use of inadequate antibiotics.

PMID- 10575748
TI  - [Non-traumatic cerebral hemorrhage in childhood: etiology, clinical
      manifestations and management].
AB  - OBJECTIVE: Non-traumatic intracranial hemorrhage is a rare occurrence in
      children, with the most frequent etiology being vascular malformation. Our aim
      was to review the etiology and management of spontaneous cerebral hemorrhage in
      children. PATIENTS AND METHODS: We have reviewed the patients admitted to our
      intensive care unit (ICU) with spontaneous intracranial hemorrhage from 1980 to
      1998. The etiology, symptoms and their clinical management were analyzed.
      RESULTS: Forty patients with non-traumatic intracranial hemorrhage were admitted
      during this time period. The mean age was 6.8 years and the male/female ratio was
      2.4/1. This condition presented with a sudden onset in 83%. The most common form
      of presentation was headache, vomiting and altered consciousness. The most
      frequent etiology was vascular malformation (32.2%). Initial management was
      symptomatic and addressed the prevention or treatment of intracranial
      hypertension and seizures. Mortality was 38% and there were sequelae in 35%.
      CONCLUSIONS: Management of critical non-traumatic intracranial hemorrhage
      consists in preventing or treating cerebral hypertension. The monitoring of
      intracranial pressure, jugular oxygen saturation and transcranial Doppler allows
      an indirect measurement of cerebral blood flow. Prompt excision of the hematoma
      improves the outcome. In vascular malformations, endovascular embolization or
      radiosurgery are possible.

PMID- 10575749
TI  - [Effect of apolipoprotein E phenotypes on the response to dietary treatment of
      children with hypercholesterolemia].
AB  - OBJECTIVE: Our objective was to determine if apo E phenotypes have any effect on
      the serum lipoprotein response to dietary intervention in children with
      hypercholesterolemia. PATIENTS AND METHODS: We have selected 76 children with
      total serum cholesterol levels higher than 200 mg/dL. At diagnosis, each patient
      met with a member of our clinic that established dietary recommendations (total
      and saturated fat intake: 30 and 10%, respectively, of total energy intake). At
      diagnosis and after 6 months of therapy we determined a lipoprotein profile.
      RESULTS: After 6 months of therapy, there was only a significant change in
      children with phenotype E3/E4, with significant decreases in serum total
      cholesterol (from 247 +/- 43 to 231 +/- 47 mg/dL, p = 0.002), LDL-cholesterol
      (from 164 +/- 47 to 149 +/- 48 mg/dL, p = 0.002) and triglycerides (from 81 +/-
      36 to 71 +/- 31 mg/dL, p = 0.028) concentrations. Absolute and % delta
      differences in serum lipoprotein concentrations before and after dietary
      treatment do not show significant differences between apo E phenotype groups.
      CONCLUSIONS: In the group studied, apo E phenotypes do not determine the response
      to a low-fat, low-cholesterol diet in children with hypercholesterolemia. To know
      the factors that determine the variability in the response to dietary
      intervention in children with hypercholesterolemia it would be interesting to
      study other familial and genetic factors.

PMID- 10575750
TI  - [Effects of competitive physical exercise on neuroendocrine response and
      interleukin-6 liberation in children].
AB  - OBJECTIVE: The purpose of this study was to evaluate the effects of physical
      activity on the secretion of cortisol, melatonin and interleukin-6 (IL-6) in
      children. PATIENTS AND METHODS: A controlled prospective study was carried out.
      Based on anthropometrical measurements and physical examination, which excluded
      those with an organic pathology or that were further than one standard deviation
      from the 50th percentile, 74 male children aged 6 or 7 years were included in
      this study. Forty-one children from a public school (PS) and 33 children from a
      soccer sport school (SS) were selected and asked to perform three different
      physical activities. A score was made to evaluate their performance and both
      before and after physical activity salivary samples were obtained to measure
      cortisol, melatonin and IL-6 concentrations. RESULTS: The children in the SS
      group had a better global physical performance score than those from the PS.
      There were no statistically significant differences in biochemical parameters
      between the two groups before and after exercise. There was a rise in the
      cortisol, melatonin and IL-6 levels after physical activity in both groups. The
      increment in melatonin levels after exercise was significantly higher in the SS
      group. There was a strong positive correlation between the rise of cortisol and
      IL-6 levels after exercise. CONCLUSIONS: In our study, controlled physical
      competitive activity in children 6 or 7 years of age showed no negative
      repercussion on cortisol secretion or in the liberation of IL-6.

PMID- 10575751
TI  - [Neonatal candidiasis and liposomal amphotericin B treatment: our experience].
AB  - OBJECTIVE: Nosocomial Candidiasis in low birth weight (LBW) infants have
      increased. Toxic side effects limit the use of conventional Amphotericin B for
      treatment of fungal infections. The liposomal forms have lowered this risk
      considerably, even at higher doses. Our aim was to evaluate treatment response to
      liposomal Amphotericin B in neonates with Candidiasis. PATIENTS AND METHODS:
      Fifteen neonates diagnosed both clinically and biologically of Candidiasis
      infection and who were treated with liposomal Amphotericin B from June 1994
      through July 1997 were included. Duration of treatment, when culture became
      negative, secondary effects, complications, other medication, basal pathology and
      clinical course were analyzed. RESULTS: Mean gestational age was 36 +/- 6 weeks
      and 60% were preterm. Mean age at diagnosis was 13.4 days. Eleven patients
      presented sepsis (1 C. Sp., 9 C. albicans and 1 C. parapsilosis). They were
      treated with liposomal Amphotericin B, starting dose 0.5-1 mg/kg/day). One
      patient had associated 5-fluorocytosine. Cultures became negative at
      approximately 13 days and mean duration of therapy was 21.13 days. Seven patients
      showed additional bacterial infections. Side effects during treatment were anemia
      and hypotension. CONCLUSIONS: Liposomal Amphotericin B has been effective in the
      treatment of Candidiasis without toxic signs that can be attributed solely to the
      medication.

PMID- 10575752
TI  - [Usefulness of erythropoietin in the treatment of anemia of prematurity.
      Influence of birth weight].
AB  - OBJECTIVE: Our objective was to analyze the utility of treatment with
      erythropoietin (EPO) plus iron in decreasing the need of late transfusions and
      reaching hematocrit > or = 32% in preterm infants of < or = 32 weeks of
      gestation. PATIENTS AND METHODS: Between March 1996 and October 1998, preterm
      infants of one unit were considered as the control group, while another group in
      another unit in the same hospital were treated with EPO (250 U/Kg, 3 times a
      week, subcutaneously) from day 7 of life until 37 weeks 37 post-conception. Oral
      iron was added to treatment one week later (5 mg/Kg, and increased in order to
      keep ferritin levels > 100 ng/ml). More strict transfusion criteria were
      established. Weights were stratified in < 1,000 g, 1,000-1,249 g and > or = 1,250
      g. RESULTS: Blood losses during the first 2 weeks were higher in the control
      group and that was probably the reason for the increased number of transfusions
      during the first 10 days of life. Late transfusions decreased in the EPO treated
      group (p < 0.0003). This was significant after the 3rd week and in the 1,000
      1,249 g weight group. The EPO-treated group showed lower hematocrit < or = 32% (p
      < 0.001). When EPO-treated infants were separately analyzed it was clear that
      late transfusions were more frequent in infants that were smaller, more immature
      and sicker and with higher blood losses. The reticulocyte count increase was
      similar in both groups of late transfused vs. Not transfused EPO-treated infants,
      being higher at 4 weeks after EPO was started (30/1000). EPO and ferritin values
      were always higher in late transfused EPO-treated infants than in non-transfused
      infants. CONCLUSIONS: The EPO plus iron treated group of preterm infants had a
      40% decrease in the need for late transfusions in comparison with the control
      group. The best results were obtained in the 1000-1249 g group of preterm
      infants.

PMID- 10575753
TI  - [Subgaleal hematoma in a newborn infant with severe hemophilia].

PMID- 10575754
TI  - [Aplasia cutis as a teratogenic effect of methimazole].

PMID- 10575755
TI  - [Gonadoblastoma with transformation to ovarian dysgerminoma. Apropos of 2 cases].

PMID- 10575756
TI  - [Congenital cutaneous candidiasis. Apropos of 2 cases].

PMID- 10575757
TI  - [Recurrent scarlet fever].

PMID- 10575758
TI  - [What is your diagnosis? Acute abdomen].

PMID- 10575759
TI  - [Guidelines on pediatric cardiopulmonary resuscitation: basic, advanced and
      neonatal (I). Spanish Pediatric and Neonatal Cardiopulmonary Resuscitation
      Group].

PMID- 10575760
TI  - [Advances in pediatric immunology. Advances in allergology].

PMID- 10575761
TI  - Annual meeting of the German Pharmaceutical Society. Frankfurt, 6-9 October 1999.
      Abstracts.

PMID- 10575762
TI  - Record linkage--a vision renewed.

PMID- 10575763
TI  - Population-based linkage of health records in Western Australia: development of a
      health services research linked database.
AB  - OBJECTIVES: To introduce the Western Australian Health Services Research Linked
      Database as infrastructure to support aetiologic, utilisation and outcomes
      research. To compare the study population, data resources, technical systems and
      organisational supports with international best practice in record linkage and
      health research. METHOD AND RESULTS: The WA Linked Database systematically links
      the available administrative health data within an Australian State of 1.7
      million people. It brings together, initially, six core data elements (birth
      records, midwives' notifications, cancer registrations, in-patient hospital
      morbidity, in-patient and public out-patient mental health services data and
      death records). It will be updated regularly and is designed, in future
      extensions, to include data on primary, residential and domiciliary care and
      health surveys. Linkage uses probabilistic matching of patient names and other
      identifiers. Geocodes for spatial analysis are assigned using address linkage and
      mapping software. By June 1997, the project had taken 2 1/2 years to develop the
      system and link seven million core data records from 1980 to 1995. CONCLUSIONS:
      The system is consistent with international benchmarks, from four centres of
      excellence, for the study population, core datasets, matching and geocoding, and
      collaborative networks. There are prospects to redress deficiencies in primary
      medical contact and other data resources, validation studies, tracing systems and
      a more supportive legal framework. IMPLICATIONS: The WA Linked Database will be
      used in combination with medical record audits to provide a comprehensive
      evaluation of health system performance.

PMID- 10575764
TI  - First-time hospital admissions with illicit drug problems in indigenous and non
      indigenous Western Australians: an application of record linkage to public health
      surveillance.
AB  - OBJECTIVE: To monitor incidence rates of first-time hospital admission with an
      illicit drug problem in the Indigenous and non-Indigenous populations of Western
      Australia in 1980-95. METHOD: Some 10,533 first admissions among 16,294 total
      admissions mentioning any of 19 groups of illicit drug problems were identified
      using linked hospital separation data from the WA Health Services Research Linked
      Database. RESULTS: Trends in age-standardised rates showed two distinct features:
      a rapid acceleration in first-time admission rates commencing from about 1991;
      and a cross-over of the rates in Indigenous and non-Indigenous people. In 1980,
      the rates were 9.2 per 100,000 PY in Indigenous and 16.4 per 100,000 PY in non
      Indigenous people. By 1995, the respective rates were 180.7 and 95.5 per 100,000
      PY. Largest proportional increases were observed in first-time admissions
      mentioning amphetamine dependence or abuse, although increases were seen also in
      problems due to opiates, hallucinogens, cocaine and cannabis. CONCLUSION: The
      results are consistent with data on the rising use of injectable amphetamines and
      other illicit drugs, especially among Aboriginal people. IMPLICATIONS: Urgent
      attention is required to identify ways of reducing health problems due to illicit
      substance use in both Indigenous and non-Indigenous Australians.

PMID- 10575765
TI  - Validation of linked administrative data on end-stage renal failure: application
      of record linkage to a 'clinical base population'.
AB  - OBJECTIVE: To evaluate the use of record linkage to monitor the occurrence of end
      stage renal failure in Western Australia in 1980-94. METHODS: A clinical base
      population of 1,046 patients was identified from the Western Australian (WA)
      Health Services Research Linked Database. To exclude acute renal failure,
      patients were selected if they received in-hospital renal dialysis on more than
      10 occasions over more than 28 days in 1980-94. Estimates of annual incident and
      prevalent cases were validated against the ANZDATA dialysis and transplant
      register. Reasons for discrepancy were investigated by an ad hoc linkage between
      the two data sources. RESULTS: The WA Linked Database counted slightly fewer
      incident cases (-7%) and slightly more prevalent cases (+7%) than the ANZDATA
      Register. The Linked Database identified 97% of cases on the ANZDATA Register,
      but this fell to 83% post case definition, probably due to patients receiving
      home-based dialysis failing to meet our case definition. ANZDATA correctly
      identified 90% of cases in the linked file. CONCLUSION: Trends in end-stage renal
      failure from 1986 to 1994, based on the Linked Database, were the same as those
      reported from purpose-designed disease registers. IMPLICATIONS: Linked
      administrative data provide a valid and efficient means to plan and evaluate many
      of the routine aspects of renal dialysis and transplant services.

PMID- 10575766
TI  - Suicide rates in psychiatric in-patients: an application of record linkage to
      mental health research.
AB  - OBJECTIVE: To study trends in the rate of suicide in psychiatric patients in
      Western Australia. To examine the associations of suicide with demographic and
      clinical factors. METHODS: A population-based cohort of 52,010 individuals whose
      first psychiatric admission occurred in 1980-95 was identified from the Health
      Services Research Linked Database. There were 471 deaths by suicide by 31
      December 1995. Age standardised suicide rates per 1,000 person-years at risk were
      calculated. Suicide rates in the first year after a patient's first admission
      were also examined and a proportional hazards regression analysis was performed
      to examine risk factors for suicide. RESULTS: Male psychiatric patients were 3.4
      times more likely to commit suicide than female patients (95% CI 2.76-4.24).
      Younger patients were at higher risk than older patients, and patients with
      extended periods of in-patient treatment were at more than double the risk of
      short-stay patients. Over the 16-year period, the rate of suicide in the first
      year after first psychiatric admission was found to increase by 3.4% a year (95%
      CI -0.7-7.6%). CONCLUSIONS: The findings confirm that psychiatric patients are at
      high risk of suicide. Patient outcomes in terms of risk of suicide after hospital
      discharge have deteriorated. IMPLICATIONS: Improvements are needed in the
      provision of community support to high risk psychiatric patients. Further work
      should be done to identify patients at highest risk of suicide.

PMID- 10575767
TI  - Factors associated with analgesic and psychotropic medications use by community
      dwelling older people with chronic pain.
AB  - OBJECTIVE: The present study sought to examine use prevalence and factors
      associated with use of analgesic and psychotropic medications in community
      dwelling older people with chronic non-malignant pain. METHOD: The study group
      comprised 193 community-dwelling older people with daily chronic non-malignant
      pain who were selected from a random sample of 1,000 older people in Melbourne.
      RESULTS: The use prevalence for the study group was 63% for analgesics and 39%
      for psychotropic medications, which is higher than the general older population
      without chronic pain (p < 0.00001). More women with chronic pain used analgesics,
      while psycho-social factors such as problems with sleeping and living at home
      alone were found to be associated with an increased use of psychotropic
      medications. CONCLUSION: A high proportion of community-dwelling older people
      with chronic non-malignant pain use analgesic and psychotropic medications.
      IMPLICATIONS: These findings provide the basis for further investigation into the
      level and appropriateness of analgesic and psychotropic medication use by older
      people with chronic pain.

PMID- 10575768
TI  - Discourse about menopause in selected print media.
AB  - OBJECTIVE: In Western societies, menopause has negative connotations with
      variable effects for women at midlife. To assess the power of the stereotype,
      selected popular print media were surveyed for their depiction of menopause.
      METHOD: Ten years' output of two daily newspapers and four women's magazines was
      surveyed for menopause-related copy. Both content and discourse analyses were
      applied to quantify retrieved copy (using SPSS) and identify dominant discourse
      (using NUD.IST). RESULTS: A database of 302 items was analysed. No consistency in
      reporting trends was found although there were thematic peaks for 'menopause' in
      the late 1980s and 'hormone replacement therapy' three years later. With few
      exceptions, discourse about menopause drew on and reinforced schemata of ill
      health, psychological disturbance, vulnerability, decrepitude, biological
      determinism and disease management. CONCLUSIONS: The limited discourse about
      menopause in the surveyed media was characterised by strong themes of illness,
      medical management and fear. A general perception that menopause affects women's
      health and competence from midlife was reflected by this public discourse.
      IMPLICATIONS: Public health awareness that menopause is not synonymous with
      dysfunction will contribute to a paradigmatic shift in public discourse that
      affords value to all of women's lifespan, not just the procreative.

PMID- 10575769
TI  - A case-control study of Yersinia enterocolitica infections in Auckland.
AB  - OBJECTIVE: To identify major risk factors for Yersinia enterocolitica (YE) and
      identify measures to reduce YE infections. METHODS: A prospective case control
      study, group age matched, using 186 cases of YE identified by community pathology
      laboratories and 379 randomly selected controls. Conducted between April 1995 and
      June 1996 in Auckland, New Zealand. Face-to-face interviews used a standardised
      questionnaire examining exposures to factors potentially associated with YE
      infections including untreated water, unreticulated sewerage, consumption of
      selected foods, selected food handling practices and socio-demographic factors.
      Multivariate logistic regression was used to calculate adjusted odds ratios for
      the potential risk factors. Population attributable risk (PAR) was calculated for
      significant exposures. RESULTS: Having more than two people living in the home
      was more common among cases than controls (OR = 2.2). Town supply water (OR =
      0.2), reticulated sewerage (OR = 0.34) and looking after a young child (OR =
      0.51) were significantly less common. Of the meats, only pork (OR = 1.34) had a
      higher consumption rate, while bacon (OR = 0.75) and smallgoods (OR = 0.73) were
      consumed less frequently by cases than controls. Eating food from a sandwich bar
      was more frequent among cases (OR = 1.18). Fruit and vegetable consumption was
      marginally less (OR = 0.98). The population attributable risk of these factors
      was 0.89, implying that 89% of YE would be eliminated if adverse exposures were
      removed. CONCLUSIONS: The risk of YE illness is increased by contact with
      untreated water, unreticulated sewerage and consumption of pork. Investigation of
      non-town water supply, informal sewerage systems and methods of preparation and
      consumption of pork are recommended to determine how YE enters the human food
      chain.

PMID- 10575770
TI  - Population health environmental indicators: ecologic monitoring of environment
      related health and disease trends.
AB  - BACKGROUND: Current State of the Environment (SoE) reporting focuses primarily on
      indicators directly related to the physical environment such as climate, and air,
      water and soil quality. As the environment has both direct and indirect effects
      on human health, an opportunity exists to include environment-related human
      disease indicators as an SoE indicator theme. OBJECTIVE: To develop a set of
      population health environmental indicators (PHEIs, phi s) that can illustrate
      environment-related disease (ERD) trends at the population level. METHODS: A
      literature review was conducted on environmental health monitoring and the
      current knowledge of environmental effects on human health. Key PHEIs were
      identified and routine health data collections accessed and analysed to
      illustrate temporal and geographic trends. RESULTS: Diseases with an
      environmental aetiology are tabulated and examples are given of the type and
      range of PHEIs that can be developed for an Australian geographic area.
      CONCLUSIONS: Illustrating environmental degradation in terms of resultant human
      diseases is a potent tool for promoting environmental protection measures. This
      paper examines a range of PHEIs that may be used as indicators of both
      environmental disease and environmental quality. IMPLICATIONS: PHEIs could be
      developed as a useful SoE indicator theme, and as a tool to help foster the
      convergence which is occurring between environmental health and public health
      fields.

PMID- 10575771
TI  - Tobacco smoking among fourth form school students in Wellington, New Zealand,
      1991-97.
AB  - OBJECTIVE: To investigate trends in smoking and associated demographic factors
      among fourth form (14-15 years) school students. METHOD: In 1991, all 35
      secondary schools in Wellington, New Zealand, were invited to participate; 15
      took part. Smoking behaviours were assessed biennially by self-report. Trends
      were examined among 5,834 students, using multilevel regression. RESULTS: When
      adjusted for sex, ethnicity and their interaction, the baseline (1991) prevalence
      of smoking within the past month was 18% (95% CI 10-29) rising to 28% (95% CI 15
      46) in 1997. The comparable baseline prevalence of daily smoking was 8% (95% CI 3
      21) rising to 15% (95% CI 4-40) in 1997. Smoking was more common among girls than
      boys and most common among Maori girls, for whom the adjusted odds of current and
      daily smoking were, respectively, 3.40 times (95% CI 2.56-4.52) and 5.00 times
      (95% CI 3.64-6.87) those of Europeans. School socio-economic status and sex
      composition added to the explanatory power of the model for daily smoking, but
      had negligible effect on the odds ratios for sex and ethnic group. CONCLUSIONS
      AND IMPLICATIONS: The suggested rise in the prevalence of smoking has
      implications for future adult smoking rates and health costs. Under
      representation of socio-economically disadvantaged schools may have produced
      conservative estimates. The increased odds of smoking among girls and Maori
      confirm the need to develop interventions appropriate for these groups.

PMID- 10575772
TI  - Establishing safe injecting rooms in Australia: attitudes of injecting drug
      users.
AB  - OBJECTIVE: To investigate the attitudes of injecting drug users (IDUs) towards
      the establishment of safe injecting rooms (SIRs) in Melbourne, Australia.
      METHODS: Multi-site convenience sampling at Needle and Syringe Exchange Programs
      (NSEPs) within six Melbourne suburbs. Four hundred current IDUs were recruited
      directly through NSEP and participant snowballing. Respondents completed either a
      semi-structured interview, anonymous self-report questionnaire, face-to-face
      interview or participated in a focus group. Participants were asked to report on
      their knowledge and attitudes about SIR, their experiences and concerns as
      participants of street-based illicit drug markets, and their willingness to use
      SIRs if established. RESULTS: Participants (91%) were knowledgeable about the SIR
      issue and thought such a strategy had potential to address both personal and
      wider community harms associated with public injecting. Most (77%) indicated they
      would be willing to use a SIR if established in Melbourne. Gender, lifetime non
      fatal overdose episodes and frequency of heroin use were all significantly
      related to a person's willingness to use SIRs. A significant number also reported
      a preference for injecting at their own place of residence due to concerns
      regarding privacy, safety and police presence within street-based market places.
      CONCLUSIONS: This study has identified a number of important issues relating to
      the likely demand and uptake of SIRs that should be addressed when considering
      the feasibility of establishing SIRs within Australia.

PMID- 10575773
TI  - Physical activity initiatives for male factory workers: gatekeepers' perceptions
      of potential motivators and barriers.
AB  - OBJECTIVE: Worksites have been argued to be a key setting for physical activity
      promotion, particularly for lower-paid, less-skilled workers. These occupational
      groups are at increased risk of cardiovascular disease. There is no strong
      evidence in support of the efficacy of worksite fitness and physical activity
      interventions. This study assessed potential motivators and barriers to worksite
      physical activity initiatives for less-skilled workers. METHOD: We conducted
      telephone interviews with 13 Victorian WorkCover insurance providers and 30
      manufacturing industry worksite managers. The manufacturing industry was selected
      as it contains a substantial portion of workers from this high-risk occupational
      group. RESULTS: Most insurers incorporated physical activity elements into injury
      prevention programs. Few worksite managers reported programs to encourage workers
      to be more active; they identified reduced premiums and lower-cost programs
      through insurers as possible motivators. Both groups identified workers'
      reluctance to participate in physical activity, lack of awareness of potential
      benefits and program cost as major barriers for worksite physical activity. Other
      barriers included potential adverse effects on productivity and increased injury
      risk. CONCLUSIONS: Broader occupational health and safety policies and joint
      initiatives between insurers and worksite managers may have the potential to
      provide more opportunities for workers to be more active. However, the barriers
      identified outweighed the perceived benefits. IMPLICATIONS: Without structural
      and regulatory changes or new incentives, the adoption of physical activity
      initiatives in Australian manufacturing-industry workplaces is unlikely.

PMID- 10575774
TI  - A profile of the clients of male sex workers in three Australian cities.
AB  - OBJECTIVE: This paper describes the profile of clients as reported by 186 male
      sex workers in three Australian cities. METHOD: The data were collected using a
      diary which was completed after each commercial sexual encounter with a male
      client over a two-week period. The data reported in this study are based on
      reports from 2,088 sex encounters and a profile of 1,776 clients. RESULTS: The
      findings reveal, for example, that the most common source used for recruiting
      clients was advertisements, followed by escort agencies, although there were
      differences between the three cities; the majority of the clients were in their
      40s but clients of street workers were younger; clients were most often
      classified as 'middle class', with differences by source of client recruitment;
      less than half the clients were identified as being gay and a significant number
      were identified as bisexual or straight; alcohol and drug use took place in a
      small percentage of the encounters; most workers had some information about their
      clients, such as occupation and home number; violence was infrequent; and unsafe
      sex was requested in a minority of the encounters. CONCLUSION: Overall, the
      results reveal that clients of male sex workers are a highly heterogeneous group.
      IMPLICATIONS: The paper highlights a number of issues which can further promote
      safety and public accountability in male sex work.

PMID- 10575775
TI  - Prevalence of illicit drug use among youth: results from the Australian School
      Students' Alcohol and Drugs Survey.
AB  - OBJECTIVE: To estimate the prevalence of illicit drug use among Australian
      secondary school students. METHOD: Data was collected as part of the Australian
      School Student's Alcohol and Drugs Survey, a national survey of 29,447 secondary
      school students. RESULTS: Of all students aged 12-17 years, 39.9% (44.1% of males
      and 35.9% of females) reported having used at least one illicit drug in their
      lifetime. Cannabis was the most widely used illicit drug with 36.4% of all
      students reporting having used cannabis. Substantially fewer students reported
      using other drugs: hallucinogens (8.6%), amphetamines (6.1%), cocaine (3.6%),
      ecstasy (3.6%), opiates (3.7%) and steroids (1.8%). There were clear gender and
      age differences in the prevalence of illicit drug use: more males than females
      reported illicit drug use and the lifetime prevalence of illicit drug use
      increased with age. Most of those who reported illicit drug use had used drugs on
      relatively few occasions although there was a small minority of the sample who
      reported more frequent use. Finally, there were strong association between
      regular cannabis use and the use of other illicit drugs in the past year, and
      moderate associations between illicit drug use and the extent of both tobacco and
      alcohol use. CONCLUSIONS: The findings of this, the first national survey of
      illicit drug use among Australian school students, indicate a high prevalence of
      illicit drug use. Comparisons with previous regionally based surveys suggest
      there may have been a recent increase in the prevalence of cannabis use and
      highlight the need for further monitoring of and prevention efforts aimed at
      reducing illicit drug use among students.

PMID- 10575776
TI  - Public hospital pregnancy termination services: are we meeting demand?
AB  - OBJECTIVES: To identify the socio-demographic characteristics of women seeking
      termination of pregnancy through a public hospital service and explore issues of
      accessibility to the service. METHOD: An audit of the Pregnancy Advisory Service
      (PAS) at the Royal Women's Hospital in Melbourne from January to March 1996. Data
      were collected from 1,088 intake forms of women seeking an abortion. RESULTS: The
      women were of low socio-economic status, with 437 (40.2%) living on a government
      pension or benefit and 55.6% holding a Health Benefits Card. However, only 33.8%
      were given an appointment for an abortion in the public clinic, with most (63.7%)
      referred to private services. CONCLUSIONS: The demand for this public hospital
      abortion service exceeds its capacity and economically disadvantaged women are
      required to seek abortion in private services. IMPLICATIONS: There is a role for
      regional health authorities to ensure adequate distribution of public hospital
      pregnancy termination services.

PMID- 10575777
TI  - Reliability of self-reported behavioural health risk factors in a South
      Australian telephone survey.
AB  - OBJECTIVE: To test the reliability of telephone health survey questions. METHOD:
      A telephone survey on mental health of South Australians in 1997 was re
      administered to a random sub-sample of 102 respondents between 32 and 79 days
      after the original survey. RESULTS: Demographic questions (age, gender, number of
      adults and children in the household) showed the highest reproducibility and were
      almost perfect. Questions regarding health risk factors, such as smoking and
      drinking behaviour, showed substantial to almost perfect agreement. Co-morbidity
      variables were substantially reproducible where prevalence estimates were not
      close to zero. CONCLUSIONS: The results were comparable to findings from similar
      studies associated with the Behavioral Risk Factor Surveillance System (BRFSS) in
      the United States. The study suggests that the telephone health survey instrument
      used in South Australia is reliable for estimating health conditions and
      behaviours in the population.

PMID- 10575778
TI  - Demoralisation, distress and pain in older Western Australians.
AB  - OBJECTIVE: To assess the relationship of psychiatric morbidity, morale, physical
      activity and the presence of pain in older people. METHOD: Older people attending
      senior citizens' clubs were administered the 28-item General Health Questionnaire
      (GHQ-28), the Revised Philadelphia Geriatric Centre Scale (RPGCS) and five self
      report questions from the Brief Disability Questionnaire. They also rated the
      presence of pain on a five-point scale. Multiple and logistic regression were
      used to adjust for socio-demographic factors and identify variables independently
      associated with psychological status and morale. RESULTS: Of 112 people
      approached, 86% agreed to take part (n = 96). The sample showed a wide range in
      total GHQ scores (mean = 2.9, range = 0-19) and RPGCS scores (mean = 2.3, range =
      1.1-3.0). Twenty-one per cent had psychological distress as defined by a score of
      > or = 6 on the GHQ-28 (n = 19). Fifty-four respondents (56%) reported low morale
      as defined by a score < 2 on the RPGCS. There was a close relationship between
      psychological distress, low morale on the RPGCS (OR = 5.5 [1.5-20.5]) and
      moderate to severe pain (OR = 5.3 [1.8-15.9]). When adjusted odds ratios were
      calculated to control for confounding factors, moderate to severe pain remained
      independently associated with psychological distress (OR = 1.6 [1.3-2.4] p =
      0.02), and limitations in daily activities with low morale (OR = 3.64 (1.001-8.4)
      p = 0.05). CONCLUSIONS: There is a close relationship between physical
      disability, low morale and psychological distress. IMPLICATIONS: An increased
      index of suspicion for psychological distress is warranted in all older people
      with physical disability, particularly in the presence of moderate to severe
      pain.

PMID- 10575779
TI  - Estimates of smoking and related behaviour in an immigrant Lebanese community:
      does survey method matter?
AB  - OBJECTIVE: To estimate the prevalence of smoking, stage-of-change and GP advice
      to quit in the Sydney Lebanese community and whether these findings varied by
      survey method. METHOD: Three methods--telephone interviews using sampling from
      the electronic White Pages, personal interviews of a household member selected
      using cluster sampling and a mailed survey using an electoral roll sample--were
      used in separate surveys of persons born in Lebanon living in three postcode
      areas of Sydney in 1997. RESULTS: Smoking prevalence was consistent across the
      three methods, with male smoking averaging 49% and female smoking averaging 29%.
      About two-thirds of smoking respondents across each of the survey methods had no
      plans for quitting. CONCLUSIONS: As smoking prevalence did not vary across the
      three sampling and survey methods used here, the simplest and most inexpensive
      method (the electronic White Pages and telephone surveying of identifiable ethnic
      surnames) should be preferred. IMPLICATIONS: Smoking prevalence in the Sydney
      Lebanese community is determined consistently using a variety of survey methods.

PMID- 10575780
TI  - Population-based cancer control: where is the greatest benefit from proven
      strategies to 'regain' years of life lost prematurely?
AB  - OBJECTIVE: To apply a 'health gain' approach to population-based cancer control.
      METHOD: We calculated the potential years of life otherwise lost prematurely
      which could be 'regained' through implementation of cancer control programs for
      which Level I or Level II evidence already exists for population outcomes.
      RESULTS: More potential years of life lost (PYLLs) would be 'regained' by
      enforcing a 'smoke-free' Australia than by any other possible scenario based on
      proven effectiveness. Even achievable scenarios for tobacco control (17% or 20%
      prevalence) would 'regain' more PYLL than either mammographic screening according
      to national policy or faecal occult blood testing (FOBT) of both men and women
      over 50 years for colorectal cancer. CONCLUSIONS: As few commentators remain
      optimistic that more money will be allocated to health, strategic thinking for
      health gain needs to re-appraise resource allocation for population-based cancer
      control in Australia. IMPLICATIONS: We recommend wider debate in response to our
      finding that, on the basis of best available evidence, the greatest potential for
      health gain lies less in cancer screening than fully funded tobacco control.

PMID- 10575781
TI  - Content analysis and publication outcomes of projects by public health medicine
      registrars.
AB  - OBJECTIVE: To examine the content of the project work of public health medicine
      registrars in New Zealand and identify publication outcomes. METHOD: All projects
      submitted during 1987-97 were examined and key aspects captured on a database.
      Literature searches using Medline, Health Star, Index New Zealand and the NZ
      National Library catalogue were undertaken. RESULTS: A total of 355 registrar
      projects produced by 91 registrars were identified. Only 29% of these projects
      were associated with one or more publications that could be identified in
      electronic databases commonly available to New Zealanders and only 16% of them
      were associated with an article in the Medline-indexed literature. A possible
      cause for concern is the relatively small amount of project work (6% of projects)
      that was directly on Maori and/or Pacific Peoples' health. There also appears to
      be a relative lack of project work on chronic disease epidemiology and control,
      tobacco control and the socio-economic determinants of health. CONCLUSIONS: Given
      the relatively high quality of registrar project work, a publication rate of only
      29% is probably suboptimal. The subject matter of registrar projects appears to
      infrequently address certain major areas of public health importance including
      Maori and Pacific Peoples' health. IMPLICATIONS: Consideration should be given to
      addressing these issues by those involved in public health medicine training.

PMID- 10575782
TI  - A qualitative analysis of parental decision making for childhood immunisation.
AB  - OBJECTIVE: Achieving high rates of childhood immunisation is an important public
      health aim. Currently, however, immunisation uptake in Australia is
      disappointing. This qualitative study investigated the factors that influence
      parental decision making for childhood immunisation, and whether parents'
      experiences were better conceptualised in terms of static subjective expected
      utility models or in terms of a more dynamic process. METHOD: Semi-structured in
      depth interviews were conducted with 20 predominantly middle-class mothers--17
      immunizers and three non-immunizers, in Melbourne, Victoria, in 1997. The data
      were then examined using thematic analysis. RESULTS: The results suggested that
      for these participants the decision regarding childhood immunization was better
      conceptualized as a dynamic process. The decision required initial consideration,
      implementation then maintenance. CONCLUSION: If a better understanding of
      immunization decision making is to be achieved, future studies must look beyond
      static frameworks. IMPLICATION: Clearer insight into the dynamic nature of
      immunization decision making should assist in the identification of more
      effective methods of promoting childhood immunization to groups at risk of non
      compliance.

PMID- 10575783
TI  - Design of cross-sectional surveys using cluster sampling: an overview with
      Australian case studies.

PMID- 10575784
TI  - Cultural safety and work practice.

PMID- 10575785
TI  - Childhood leukaemia and TV towers: the debate continues.

PMID- 10575787
TI  - Infection control guidelines--two new supplements now available.

PMID- 10575786
TI  - Summary report and recommendations of the Expert Working Groups for Strain and
      Laboratory Surveillance of Hepatitis B Virus and Hepatitis C Virus.

PMID- 10575788
TI  - [The treatment of a fracture of proximal end of the femur in own material].
AB  - Results of treatment for fracture of proximal end of the femur in 263 patients
      (86 males and 177 females) aged between 7 and 104 years were analyzed. Ninety
      percent of the patients were older than 60 years. Mean follow-up was 4.6 years
      (range 1 to 9 years). Immediate Austin-Moore hip hemiarthroplasty in the elderly
      and screw fixation in younger patients rendered best results in the femoral neck
      fractures. Ender nailing in the elderly and angular plating or skeletal traction
      in the young proved most successful in trochanteric fractures.

PMID- 10575789
TI  - [The use of the Richard's dynamic hip screw and hip Zespol fixator in the
      treatment of proximal femoral fracture].
AB  - A series of 49 patients (27 females, 22 males) aged 24-82 operated on due to
      proximal end of the femur fracture between 1990 and 1995 were included in this
      study. There were 23 femoral neck fractures and 26 trochanteric fractures. DHS
      was used in 35 patients and Zespol hip fixator in 14 cases. Good results have
      been achieved in 85.7%. Neither method proved superior to the other. Poor results
      occurred in subcapital neck fractures. DHS seems to offer advantage in
      trochanteric fractures and Zespol method in femoral neck fractures.

PMID- 10575790
TI  - [Analysis of the results of peri-trochanteric fracture treated by the Ender
      nails].
AB  - Results of Ender nailing in 140 patients aged between 49 and 99 (mean 81 years)
      with peritrochanteric fracture have been analyzed. Pros and cons of the method
      are discussed and potential complications pointed out. The method proved useful;
      results were good despite advanced age of the patients. In fractures grade I and
      II Kayle scale Ender nailing resulted in least complications. The risk of death
      was doubled by delaying surgical intervention.

PMID- 10575791
TI  - [Supra-acetabular cysts of the hip: results of surgical treatment].
AB  - Results of surgical treatment for supraacetabular cystic changes in 8 middle-aged
      females are presented. Complete excision and filling the defect with iliac
      autografts has been performed, histological examination of the change followed in
      all cases. No inflammatory, systemic or neoplasmatic changes were identified.
      Good results were achieved and hip osteoarthritis delayed. Surgery proved useful
      in treatment for supraacetabular cystic changes in the hip.

PMID- 10575792
TI  - [Comparative assessment of mineral changes in the femoral bone after the Weller
      and Centrament total hip replacement].
AB  - Mineral changes within femoral bone after Weller cemented stem implantation (31
      females, 20 males, mean age 69.6 years) and cemented Centrament stem implantation
      (35 females, 16 males, mean age 65.3 years) were evaluated and compared.
      Densitometry with LUNAR DPX has been performed 4 times in every patient: 8-12
      days after surgery and subsequently in 6-months time span. Orthopedic Auto
      Analysis software has been used to determine BMC and BMD. Decrease of both values
      was observed at every measurement and Gruen zones 7, 6 and 1 were affected most
      despite of the stem type.

PMID- 10575793
TI  - [Factors influencing bone mineral density around the femoral stem after
      cementless total hip arthroplasty].
AB  - Factors influencing bone mineral density around the femoral stem after PM
      cementless total hip arthroplasty were evaluated in longitudinal study of 18 hips
      in 18 patients who had undergone surgery due to unilateral hip osteoarthritis.
      Bone mineral density in the femoral neck was determined by dualenergy X-ray
      absorptiometry measurement performed preoperatively and in periprosthetic femoral
      Gruen's zones prospectively 2 weeks, 3, 6, 12 and 24 months after surgery. The
      concentrations of calcium, magnesium and fluoride were measured in cortical and
      trabecular bone samples taken from resected femoral head and neck. At 12 and 24
      months after the operation the regional bone mineral density measurement showed
      significant, maximum decrease but after 12 months bone mineral density appeared
      to be stabilized. The analysis of preoperative femoral neck density and fluoride
      content in trabecular bone proved that osteopenia and lower fluoride
      concentrations correlated significantly with greater bone density decrease after
      total hip arthroplasty. No other factors (age, sex, weight, calcium and magnesium
      concentrations in bone and fluoride concentration in cortical bone) showed
      significant associations.

PMID- 10575794
TI  - [Transient osteopenia of the hip in children].
AB  - The course and results of treatment of 4 boys with transient osteopenia of the
      hip are presented. Mean age of patients at the onset of symptoms was 9 years 5
      months (range 5 years 3 months-14 years 6 months). Pain at exertion and limp
      dominated in all cases. Quadriceps atrophy was a constant finding and hip
      rotation was restricted in 3 cases. Laboratory findings were normal except for
      the elevated ESR. Radiography and CT showed diffused osteopenia within femoral
      neck and head. Bone scan was abnormal in 3 cases. Weight bearing restriction and
      exercises introduction resulted in ceasing of the symptoms within 3 months.

PMID- 10575795
TI  - [Application of the Ilizarov apparatus in the treatment of knee osteoarthritis].
AB  - Illizarov apparatus has been applied to stabilize "dome" high tibial osteotomy in
      14 cases (11 females and 3 males). The age of patients ranged from 22 to 77 years
      (mean 60.3 years). Varus deformity was present in 12 cases (mean 18 deg) and
      valgus in 2 (mean 20 deg). The Dihlman's classification of knee osteoarthritis
      was used. The patients started full weight bearing on the second postoperative
      day. Primary bone union was achieved in all cases within 6 weeks and at this
      point the fixator was removed. The range of knee motion was good, no
      neurovascular complications occurred. Superficial infection around K-wire was
      found in 4 cases but did not require any replacement. Temporary limitation of the
      ankle motion occurred in 2 cases. Good clinical results and high patients
      satisfaction proved Illizarov apparatus effectiveness in treatment of knec
      osteoarthritis.

PMID- 10575796
TI  - [Application of the Ottawa ankle rules in the ankle and midfoot injuries:
      verification of the method on the basis of own material].
AB  - The aim of study was to verify the specificity and usefulness of the Ottawa Ankle
      Rules in trauma patients. Prospective observations were made on 103 adult
      patients (48 males and 55 females aged 16 to 74 years). Clinical examination was
      subsequently verified by radiography. According to Ottawa Rules pain in the
      posterior aspect of distal 6 cm of tibia or fibula or pain at fifth metatarsal or
      navicular bone occurring immediately after injury suggests bone fracture. In 78
      cases (75%) no fracture was seen on X-ray; ankle sprain and midfoot sprain was
      diagnosed in 49 (63%) and 19 (37%) patients respectively. Fractures have been
      found in 26 patients (25%); 19 in the ankle area and 7 within tuberosity of the
      fifth metatarsal. Diagnosis set according to Ottawa Ankle Rules was confirmed
      radiologically in 89 patients (86%). Clinically diagnosed fracture was ruled out
      radiologically in 14 cases (13%) and only once (1%) radiogram revealed fracture
      missed clinically. In our material specificity of the method was 86% and the risk
      of misdiagnosed fracture was less than 1 percent.

PMID- 10575797
TI  - [Own experience in Partridge fixation method].
AB  - A series of 34 patients (21 males, 13 females aged 16 to 85 years) served to
      assess Partridge fracture stabilization method. The method was employed always
      with some other mode of fixation. Twenty-eight patients had primary long bone
      shaft fracture, in 6 cases refracture occurred in the course of treatment with
      different method or resulted from intraoperative complication. In authors'
      opinion Partridge method is best combined with intramedullar fixation, extends
      indications for the latter and is recommended in atypical surgical situations.
      Good clinical results were achieved and no bony union disturbances were observed.

PMID- 10575798
TI  - [The value of radiological examination in the diagnosis of rotator cuff tear].
AB  - The aim of this paper was to evaluate the correlation between radiological
      changes on a-p radiograph of the shoulder and rotator cuff tear on the ground of
      analysis of 328 patients (360 shoulders) aged between 11 and 73 years suffering
      from different forms of periarthritis humeroscapularis. Sonographic examination
      revealed rotator cuff tear in 54 shoulders; 38 confirmed at surgery and 16 at
      arthrography. There was very strong correlation between rotator cuff tear and
      irregularities of greater tubercle, narrowing of the distance between humeral
      head and acromion to 5 mm or less, greater tubercle recession, osteophytes and
      reverse shape of acromion. Last 3 changes were very strongly correlated with
      medium and large size rotator cuff tear.

PMID- 10575799
TI  - [An attempt to restore protective sensation after a greater omentum flap coverage
      due to circular soft tissue defect in the hand].
AB  - The paper presents method of restoration of protective sensation after major hand
      injuries primarily treated with great omental flap. Existing methods have been
      modified on assumption that free end of transplanted sural nerve might act as
      sensation receptor. Two patients were operated on. Several months after surgery
      patients reported paresthesiae at skin compression. Function improvement is
      seemingly indicated by objects less frequently falling of out of the hand.

PMID- 10575800
TI  - [Thumb replantation after 22 hours of ischemia: a case report and review of
      literature].
AB  - Contemporary views on ischemia time role on finger replantations within the hand
      are presented. Numerous cases of successful replantations after prolonged warm
      ischaemia (up to 42 hours) and cold ischaemia (up to 94 hours) are cited. A case
      of 17 year old male with thumb amputation in zone V who had successful
      replantation done after 22 hours of ischemia is described in details. At 4 months
      follow-up reinervation is progressing and prognosis is good. Intraoperative
      problems and pharmacotherapy are discussed.

PMID- 10575801
TI  - Posterior lumbar interbody fusion and cages.
AB  - The author of the paper presents an overview of posterior lumbar interbody fusion
      (PLIF), including a historical note, a global surgical strategy as well as
      specific indications for this procedure (discogenic low back pain, spondylosis,
      spondylolisthesis, recurrent disc herniation, failed chemonucleolysis, spinal
      stenosis). A short description of surgical technique can also be found in the
      paper. The author also emphasises the possible complications linked with this
      procedure and the need for experienced surgeons in order to decrease the number
      of postoperative complications. Finally the paper contains a short description of
      the most commonly used implants during surgical corrections of lumbar
      biomechanics.

PMID- 10575802
TI  - Use of the hospital anxiety and depression scale as a screening tool for patients
      with headache.
AB  - BACKGROUND: The Hospital Anxiety and Depression Scale (HADS) is becoming widely
      used in medical settings to screen for anxiety or depressive disorders. It has
      been shown to be a good screening instrument in different ethnic and disease
      populations. The objective of this study was to evaluate the validity and
      reliability of HADS in patients with headache at a headache clinic. METHODS:
      Consecutive new patients to a headache clinic at the Taipei Veterans General
      Hospital from September to December, 1998, were recruited in the study. The
      participants completed the HADS questionnaire and underwent a psychiatric
      semistructured interview according to the Diagnostic and Statistical Manual (4th
      revision). The reliability and validity of the HADS were evaluated with respect
      to headache. RESULTS: A total of 62 patients (21 men, 41 women) completed the
      study. The HADS had a good internal consistency when applied to patients
      suffering from headache, with a Cronbach's alpha coefficient of 0.84 and a split
      half reliability of 0.84. Factor analysis in this sample revealed four factors:
      anxiety, depression, panic and somatic factors. A total of 48 patients (77%) had
      a psychiatric diagnosis. The frequency of depressive disorders was 57% and
      anxiety disorders 31%. A total HADS score of 10 or more was the optimal cut-off
      point for depressive disorders. The sensitivity was 85.7%, and the specificity
      33.3%. A total score of at least 13 was the optimal cut-off point for anxiety
      disorder. The sensitivity was 84.2%, while the specificity was 41.9%.
      CONCLUSIONS: Depression and anxiety were quite common among patients with
      headache in a headache clinic. The HADS can be used as a screening instrument for
      depressive and anxiety disorders. Because of the low specificity, the HADS should
      not be used solely as an indicator of psychiatric comorbidity among patients with
      headache in a headache clinic. This is the first study that verifies the use of
      the HADS as a psychiatric screening tool in patients with headache by comparing
      the scores of the HADS with psychiatric diagnoses.

PMID- 10575803
TI  - Lack of association between deletion polymorphism of the ACE gene and ischemic
      vascular diseases in a Chinese population in Taiwan.
AB  - BACKGROUND: The association between deletion/insertion polymorphism of the
      angiotensin I-converting enzyme (ACE) gene and ischemic vascular diseases (IVDs)
      is still unclear. This study was designed to evaluate the role of ACE gene
      polymorphism in the pathogenesis of IVDs in a Chinese population living in
      Taiwan. METHODS: A case-control study was carried out to examine the association
      of the ACE gene genotype and the allele frequency in 400 IVD patients, including
      214 patients with ischemic cerebrovascular disease (ICVD) and 186 patients with
      ischemic heart disease (IHD), compared with 200 control individuals. RESULTS:
      Although the patients with ICVD and IHD were found to have higher frequencies of
      the D/D genotype (22% and 43%) and the D allele (20% and 42%) than the controls
      (16% and 39%), the statistical differences were not significant, as shown by chi
      2 analysis (p > 0.05). Upon further comparison of the frequencies of the D allele
      among the two sexes and different age subgroups, there was still no significant
      association. CONCLUSIONS: Deletion polymorphism of the ACE gene was not
      associated with IVD in a Chinese population in Taiwan. The unique or synergistic
      effect of other genes that might contribute to the pathogenesis of IVDs needs
      further investigation.

PMID- 10575804
TI  - Effects of mutans streptococci, Actinomyces species and Porphyromonas gingivalis
      on collagen degradation.
AB  - BACKGROUND: While Streptococcus mutans and Actinomyces spp are considered to be
      major pathogenic microorganisms of root caries, their roles in the degradation of
      organic matrix components of human root dentin need clarification. METHODS: Ten
      laboratory strains and 11 clinical isolates of mutans streptococci and
      Actinomyces species, and positive bacterial or purified enzyme controls
      (Porphyromonas gingivalis whole cell lysates, trypsin or clostridial collagenase)
      were used to establish the degradation of azocollagen (AC), insoluble type I
      collagen (IC) or human dentin collagen (DC) from dentin powder in two types of
      experiments investigating collagenolytic activity either during or after
      bacterial growth. Ultraviolet-irradiated dentin powder and gamma-irradiated IC
      were used to assess the collagenolytic activity of test strains during bacterial
      growth. AC, IC and acid-treated dentin powder were used to determine the
      collagenolytic activity of sonicated bacterial whole cells and cell-free culture
      supernatants recovered from test strains after growth. Hydroxyproline or
      spectrophotometric assays were used to analyze the level of degraded collagen.
      RESULTS: Data from this study showed that in contrast to the positive controls,
      none of the laboratory strains or clinical isolates elicited significant
      degradation of AC, IC or DC. CONCLUSIONS: Results indicated that mutans
      streptococci and Actinomyces species had no significant collagenolytic activity,
      but may be involved in the root caries process through other mechanisms. In
      addition, proteolytic enzymes from other oral bacteria such as Porphyromonas
      gingivalis or from host cells such as neutrophils may also participate in the
      pathogenesis of root caries.

PMID- 10575805
TI  - Intraoperative neurosurgical ultrasonography.
AB  - BACKGROUND: Ultrasound scanning is a well-established means of evaluating
      intracranial structures in infants and children with open fontanelles. However,
      it remains underutilized in neurosurgical operations. We present our experience
      with the intraoperative use of realtime ultrasonography during 36 neurosurgical
      procedures. METHODS: Thirty-six intraoperative ultrasonography (IOUS) procedures
      were performed over the past two years. Thirty-two patients had intracranial
      lesions and four had intraspinal tumors. A real-time scanner equipped with a 5
      MHz and a 7.5 MHz transducer was used during surgery. RESULTS: IOUS worked well,
      regardless of the location of the craniotomy site. It was useful in localizing
      and characterizing intracranial and intraspinal masses, assuring the completeness
      of tumor removal (22 cases), proper positioning of ventricular shunt catheters (5
      cases), guiding and confirming the decompression of cysts or abscesses (3 cases)
      and real time monitoring of surgical complications (36 cases). CONCLUSIONS: IOUS
      can be helpful in defining intracranial and intraspinal lesions as well as normal
      architecture. It shortens the operative time and decreases the surgical
      morbidity. The expertise of the physician with sonographic equipment facilitates
      its accurate and expedient intraoperative neurosurgical application.

PMID- 10575806
TI  - Outcome of advanced primary fallopian tube adenocarcinoma.
AB  - BACKGROUND: Because of the rarity of primary fallopian tube adenocarcinoma
      (PFTA), the outcome of advanced primary fallopian tube carcinoma has not been
      fully evaluated, especially in Taiwan. METHODS: We retrospectively studied
      patients with proven surgicopathologic stage III PFTA. Thirteen patients from
      1965 to 1995 were identified. All patients received standard staging surgery
      including washing cytology, total abdominal hysterectomy, bilateral salpingo
      oophorectomy, retroperitoneal lymphadenectomy, infracolic omentectomy and
      excisional biopsy of all suspicious lesions. This was followed by adjuvant
      chemotherapy with four to eight courses of CAP or CEP (cyclophosphamide 500
      mg/m2, adriamycin 50 mg/m2, or epirubicin 50 mg/m2, and cisplatin 50 mg/m2
      intravenously, every 3 weeks) regimen. RESULTS: The accumulative disease-free
      survival rate was 15%. The incidence of retroperitoneal lymph node metastases was
      high, up to 69%, and the incidence of para-aortic lymph node metastases was 62%.
      Eighty-five percent of the cases were poorly differentiated carcinoma. Optimal
      debulking surgery was completed in 62% of patients, contributing to long-term
      patient survival (25% vs 0%), compared with those without optimal debulking
      surgery. CONCLUSIONS: The prognosis of stage III PFTA in our study was poor.
      Careful lymph node dissection in the retroperitoneal space including the para
      aortic area is required. Optimal debulking surgery plus postoperative adjuvant
      chemotherapy appears to be the only option for enhancing long-term disease-free
      survival.

PMID- 10575807
TI  - Serum cholesterol levels and prevalence of hypercholesterolemia in school-aged
      Taiwanese children and adolescents: the Taichung Study.
AB  - BACKGROUND: Atherosclerosis has become one of the leading causes of death in
      Taiwan. Hypercholesterolemia is a major risk factor for coronary atherosclerosis.
      To evaluate the mean total cholesterol values and the prevalence of
      hypercholesterolemia in school-aged Taiwanese children and adolescents, an
      epidemiologic survey was conducted. METHODS: After two-stage sampling of 52
      primary schools and 26 junior high schools in Taichung City, we randomly selected
      3,924 children (2,070 boys and 1,854 girls). Blood total cholesterol (TC),
      triglyceride (TG) and high-density lipoprotein (HDL)-cholesterol were measured.
      Response rate was 86.8%. Subjects' ages ranged from seven to 14 years old.
      RESULTS: From this cross-sectional survey, the following characteristics (mean +/
      SD) were documented for boys and girls, respectively: TC, 162 +/- 28 and 165 +/-
      29 mg/dl; TG, 74 +/- 33 and 80 +/- 32 mg/dl; HDL-cholesterol, 61 +/- 13 and 59 +/
      12 mg/dl; and low-density lipoprotein (LDL)-cholesterol, 87 +/- 24 and 90 +/- 25
      mg/dl. The mean TC across all age groups ranged from 149 to 172 mg/dl for boys
      and 157 to 170 mg/dl for girls. In boys, the TC concentration was highest at age
      11 (172 mg/dl), and in girls was highest at age 7 (170 mg/dl). Borderline
      hypercholesterolemia (TC > 170 mg/dl) was found in 36.5% of boys (13.5-53.1%) and
      39.7% of the girls (28.3-48.6%). Hypercholesterolemia (TC > 200 mg/dl) was found
      in 9.7% of males (3.1-16.6%) and 10.3% of the females (5.0-14.9%). CONCLUSIONS:
      The prevalence of borderline hypercholesterolemia was 38.0% for TC and 17.2% for
      LDL-C, and for hypercholesterolemia, it was 9.9% for TC and 5.8% for LDL-C. The
      higher TC levels in Taiwanese children were primarily due to higher HDL-C and TG
      levels.

PMID- 10575808
TI  - Ligament reconstruction and tendon interpositional arthroplasty for degenerative
      arthritis of the thumb trapeziometacarpal joint.
AB  - BACKGROUND: The trapeziometacarpal joint provides important functions for the
      hand. This joint is often involved in primary osteoarthritis. METHODS: From
      November 1982 to December 1995, we encountered 42 patients (47 hands) with
      osteoarthritis (OA). All the patients were Chinese. Thirty-six patients (36
      hands) were treated surgically. Ligament reconstruction and tendon interposition
      arthroplasty were done with total removal of the trapezium or partial removal of
      trapeziometacarpal joint depending on the stage of the disease. These patients
      were monitored for an average of 106 months and evaluated both clinically and
      roentgenographically. RESULTS: Of three stage II cases, the results of two were
      excellent and one was good. Of the 18 stage III patients, 14 had excellent
      (77.8%) and four had good (22.2%) results. In the 15 stage IV patients, 10 had
      excellent (66.6%), four had good (26.7%) and one had fair (6.7%) results. No
      patient had poor results. CONCLUSIONS: Ligament reconstruction and tendon
      interpositional arthroplasty is a good alternative in treating degenerative
      arthritis of the trapeziometacarpal joint of the thumb. Partial removal of the
      diseased joint is indicated for stage II, and total removal of the trapezium is
      indicated for stage III and IV patients. Men seek treatment more often than women
      due to their need to work, even though women are more commonly afflicted with
      this disorder.

PMID- 10575809
TI  - Comparison of recovery characteristics of sevoflurane and halothane for
      outpatient surgery in infants.
AB  - BACKGROUND: Sevoflurane, a newly approved potent inhaled anesthetic in Taiwan,
      provides rapid emergence from anesthesia in adults and children. Clinically, it
      is difficult to accurately assess the rate of recovery from anesthesia in
      infants. This study was designed to compare the emergence characteristics of
      halothane with those of sevoflurane having recourse to a respiratory agent
      monitor in infants undergoing outpatient surgery. METHODS: Forty infants of ASA
      class I, scheduled for day-case urologic surgery were studied. Patients were
      randomly allocated to two groups of 20. Sevoflurane or halothane was used as the
      inhaled anesthetic. Toward the end of surgery, sevoflurane or halothane was
      turned off. The concentrations of exhaled sevoflurane or halothane were read
      every minute after its discontinuation until extubation. The decay curve of the
      exhaled concentration of either agent was recorded minute by minute for 10
      minutes. The time intervals from discontinuation of the inhalation agent to
      spontaneous movement and tracheal extubation were recorded. Untoward side-effects
      during emergence were also compared. RESULTS: Sevoflurane was eliminated faster
      than halothane. Based on the decay curves of the exhaled concentrations of the
      two agents, the time constant for halothane was 2.59 minutes and that for
      sevoflurane was only 1.43 minutes. The time from discontinuation of agent to
      extubation was also shorter for sevoflurane. Postoperative restlessness or
      agitation occurred more frequently in infants who received sevoflurane, although
      the difference was of no statistical significance. CONCLUSIONS: Sevoflurane is
      superior to halothane for rapid elimination in infant outpatient surgery as
      gauged by observation of end-tidal concentration elimination curves recorded with
      a respiratory agent monitor. No other postoperative side-effect was evident in
      sevoflurane anesthesia.

PMID- 10575810
TI  - Differential effects of different cytokines on the tumorigenicity and
      immunogenicity of murine tumors.
AB  - BACKGROUND: Granulocyte-macrophage colony stimulating factor (GM-CSF) or other
      cytokine gene transfer into tumor cells makes an effective tumor vaccine.
      However, this technique is time consuming and it is not possible for routine use
      in every patient. METHODS: The present study was designed to combine use of the
      irradiated B-16 cell line, a C57BL6 mice melanoma cell line, and cytokine (GM
      CSF, interleukin-4 [IL-4], IL-10, or IL-12) manipulation, to enhance
      effectiveness of the tumor vaccine in prevention or reduction of subcutaneous
      tumor formation or pulmonary metastases. RESULTS: The results of in vitro studies
      show that the cytolytic activity of the splenocyte was highest when IL-2 or IL-4
      was added to the culture medium. Immune splenocytes demonstrated the same level
      of cytolytic activity regardless of whether the mice were immunized once, twice
      or thrice. The proliferation assay was higher in immune splenocytes compared with
      normal splenocytes. The results of both the subcutaneous and pulmonary tumor
      growth models showed that immunization alone retarded tumor growth and prolonged
      survival, and this effect was essentially the same regardless of the frequency of
      immunization. However, the effect was much stronger when IL-4 was used during
      immunization in the subcutaneous tumor model, whereas IL-12 was the most optimal
      cytokine in the pulmonary metastases model. CONCLUSIONS: Different cytokines have
      different effects on immunization in different animal models even with the same
      tumor and animal. Careful selection of the appropriate cytokine for tumor vaccine
      immunization must be considered when different patterns of tumor recurrence are
      noted in clinical practice.

PMID- 10575811
TI  - Fatal hemoptysis in dissecting aortic aneurysm and salmonellosis: a case report.
AB  - Hemoptysis is a rare manifestation of dissecting aortic aneurysm and
      aortobronchial fistula may occur when an aortic aneurysm is mycotic,
      atherosclerotic, traumatic or postoperative. Aortobronchial fistulas are
      generally fatal if not treated surgically. An aggressive diagnostic approach to
      patients with hemoptysis and prompt surgical intervention in those suspected of
      aortobronchial fistulas should result in additional survivors. Imaging studies,
      including chest radiography, chest computerized tomography, arteriography and
      bronchoscopy provide useful diagnostic information. However, challenges remain
      when we encounter this condition. Sometimes, the final exsanguinating hemorrhage
      is preceded by a distinct prodromal period of intermittent hemoptysis. This
      allows clinicians time to recognize such fistulas and perform emergency surgery.
      We present a patient with this condition to alert clinicians to this potentially
      deadly cause of hemoptysis.

PMID- 10575812
TI  - Laparoscopic unroofing of hepatic cysts with intraperitoneal drainage: a report
      of three cases.
AB  - Hepatic cysts are not uncommon and are usually asymptomatic, while large cysts
      sometimes show clinical manifestations. The management of large symptomatic
      hepatic cysts includes both percutaneous aspiration and surgical intervention.
      Aspiration has a high recurrence rate and is not a curative treatment. Recently,
      laparoscopic unroofing or "fenestration" in selected patients with hepatic cysts
      has gained popularity, for it shortens hospital stay, involves minimal
      invasiveness and does not result in a high recurrence rate. We report three cases
      of symptomatic hepatic cysts successfully treated with laparoscopic surgery.

PMID- 10575813
TI  - Intracavitary cardiac tumor secondary to carcinoma of the cervix: a case report.
AB  - Carcinoma of the cervix spreading to the paracervical lymphatics is a common
      phenomenon followed by involvement of the para-aortic lymph nodes and subsequent
      distant metastases. The most common extranodal metastases sites are the lungs,
      followed by the liver and bones. The heart is an extremely rare metastatic target
      for carcinoma of the cervix. Furthermore, the majority of cardiac metastases
      involve the pericardium and endocardium and are particularly rare. We present the
      case of a 56-year-old woman with recurrent squamous cell carcinoma of the cervix
      who died after aggressive multimodality treatment including concurrent
      chemoradiotherapy and surgical intervention. The patient died suddenly and the
      autopsy showed disseminated carcinomatosis with portal vein, hepatic vein,
      inferior vena cava and right ventricular tumor emboli.

PMID- 10575814
TI  - Delayed-onset of Pseudomonas infection in a hydroxyapatite orbital implant: a
      case report.
AB  - Hydroxyapatite (HA) orbital implant, a multiple porous coralloid-like material,
      is frequently used in orbital reconstruction after enucleation or evisceration
      surgery. HA implants contain multiple interconnected pores in which rich
      fibrovascular tissue ingrowth could theoretically help to resist infection.
      Infection of hydroxyapatite implants are rare. Most HA implant infections occur
      before complete vascularization. We present this first case in Taiwan of delayed
      onset Pseudomonas infection five years after receiving the HA implant. There was
      not much improvement after intensive medications, so removal of the implant was
      finally performed. The pathology study disclosed diffuse inflammatory cell
      infiltration in the whole implant with a necrotic central core. Rich
      fibrovascular ingrowth was also noted. Once a porous HA implant is infected, the
      infection is difficult to control and becomes more severe due to the dead space
      of the interconnected pores. Removal of the implant seems to be the only
      successful treatment modality.

PMID- 10575815
TI  - Pulmonary alveolar-septal amyloidosis presenting as heart failure with unilateral
      pleural effusion: a case report.
AB  - We report a case of pulmonary alveolar-septal amyloidosis associated with
      chylothorax and paraproteinemia initially presenting as congestive heart failure
      with unilateral pleural effusion. A 72-year-old man was initially diagnosed with
      congestive heart failure based on the correlation of clinical manifestation and
      chest radiography. Concentric left ventricular hypertrophy with mild hypokinesis
      of the left ventricle was found on cardiac echography. Thoracocentesis was
      performed for right-sided pleural effusion, which persisted despite medical
      treatment; chylous exudate was aspirated. Because the etiology of the exudative
      pleural effusion was undetermined, the patient underwent a thoracotomy that
      showed pulmonary alveolar-septal amyloidosis. Immunoglobulin M paraproteinemia
      was identified by serum immunoelectrophoresis. We conclude that it is imperative
      to search for the cause of an undetermined exudative pleural effusion, with
      particular attention to chylothorax and amyloidosis as the differential
      diagnoses.

PMID- 10575816
TI  - [Screening of patients referred to our clinic for odontogenic focal diseases].
AB  - During 1997 and 1998 261 patients suffering from suspected focal diseases were
      investigated for the presence of persisting chronic inflammatory disorders in the
      oral cavity. In 83% of the patients pulp necrosis, chronic inflammation of the
      apical area and the periodontal tissues could be revelated. The most commonly
      diagnosed disorders were pulp necrosis, chronic apical periodontitis and
      periodontitis complicata respectively. Most frequently these diseases could be
      detected in chronic cardiac disorders, uveitis and dermatological diseases. In
      the future follow-up studies parallel with the elimination of the dental
      disorders monitoring of blood and serum parameters will be conducted in order to
      obtain data of th systemic effect of the persisting chronic dental diseases.

PMID- 10575817
TI  - [Marginal adaptation of different esthetic filling materials under the effect of
      heat treatment].
AB  - The aim of the study was to examine the marginal adaptation of six tooth coloured
      restoratives to the tooth hard tissues before and after heat treatment
      considering the filling method and the placement of the cavity margin. The study
      showed that 1) the composite marginal adaptation was better with enamel bonding
      technique than with total bonding technique; 2) the microleakage was less before
      heat treatment; 3) the best fit was at the occlusal surface and the worst at the
      gingival tooth-filling junction with the composites; 4) non-composites showed the
      best adaptation at the approximal enamel-filling junction and the worst at the
      occlusal surface; 5) the best marginal adaptation could be achieved with Charisma
      and SpectrumTPH among the composites, and Dyract among the non-composites.

PMID- 10575818
TI  - [The Hungarian translation of the "Dental Fear Survey" based on the Hungarian
      population].
AB  - Authors translated the "Dental Fear Survey" (DFS) into Hungarian. 196 persons
      have been investigated and the DFS values have been compared to DAS, STAI-S, STAI
      T values. Mean values were: DFS: 46.27; DAS: 12.24; STAI-S: 41.58; STAI-T: 42.68.
      Authors found all values higher in the case of women comparing to men. Positive
      correlation has been found between DAS and DFS, but STAI-S and STAI-T increased
      only moderately comparing to the DAS and DFS values.

PMID- 10575819
TI  - [Microscopic study of dental calculus in cadavers from the 18th-19th centuries].
AB  - The authors studied the dental calculus of 20 mummies with ligth microscopy,
      polarized ligth microscopy and scanning electron microscopy. Gram positive
      bacteria could be detected in all preparates, while Gram negative bacteria in 12
      and fungi only in 3 dental calculus was visible. Animal food remains within five,
      and plant remains in all dental calculus were identified. Anorgic element and
      cell debris were seen in all preparates.

PMID- 10575820
TI  - The fetal development of the human uterine cervix from the 12th to the 31st
      postmenstrual week as revealed by scanning electron microscopy. Anatomical and
      clinical correlations.
AB  - To clarify the differentiation of the human uterine cervix, fetuses of the 12th,
      15th, 18th, 20th, 21st, 22nd, and 31st postmenstrual week were studied by
      Scanning Electron Microscopy. At the 12th week the endocervical epithelium
      consisted of microvillous cells, often showing single cilia and anlages of
      tubular glands. At the 15th week the cervical canal was entirely formed and its
      surface cells appeared columnar. At the 18th week these cells were replaced by
      flat or slightly raised cells, provided with thin microplicae. At the 20th week
      the endocervical epithelium appeared pseudostratified with higher, apically
      convex and shorter basal cells; glands developed in form of tubular invaginations
      of the luminal epithelium. At the 21st week in the lower part of the endocervix
      polymorphic, globose cells with short and stubby microvilli and others elongated,
      having short microplicae, were observed. These latter likely corresponded to the
      so-called columnar cells undergoing squamous metaplasia. Among microvillous
      and/or metaplastic cells, a number of apoptotic cells, as globose elements with a
      ruffled and invaginated surface, were also noted. At the 22nd week evident plicae
      palmatae were found, covered by microvillous secreting cells. These showed smooth
      bulged apices releasing droplets by a "micro-apocrine" mechanism. These features
      increased at the 31st week, when many droplets were noted also around the mouth
      of the cervical glands. Only at this phase of development fully ciliated cells
      were found often contacting secretory material. Mature squamous exfoliating cells
      with complex microplicae covered an hypertrophied portio vaginalis. The squamous
      cells extended toward a squamo-columnar junction in form of flat, tongue-like
      projections. Their tips consisted of immature squamous metaplastic cells, which
      were endocervical columnar progressively becoming elongated elements, exhibiting
      short microvilli. The above features are rather similar to those occurring during
      the adult reproductive age. Therefore, it might be hypothesized that, during
      pregnancy, a common gestational hormonal background may induce somewhat similar
      morpho-dynamic processes in the cells and tissues of the fetal reproductive tract
      mimicking what occurs in the adult female.

PMID- 10575821
TI  - Morphological changes induced by prolonged darkness in the retinal pigment
      epithelium of the turtle (Pseudemys scripta elegans).
AB  - The retinal pigment epithelium of Vertebrates was shown to be sensitive to cyclic
      oscillations of light and darkness. The morphological changes induced by
      prolonged darkness on the retinal epithelial cells of the freshwater turtle were
      studied, with particular regard to their localization and to their reversibility
      if animals are recovered under cyclic light. The eyes were processed for light
      and electron microscopy and a morphological and morphometric analysis was
      performed on the specimens. After 7 days of prolonged darkness, the vitreal
      extremity of some epithelial cells was partially detached; on the basal zone the
      infoldings were missing and vesicles and tubules, often arranged in rows, were
      observed. After 30 days of prolonged darkness, partial or complete double layers
      of epithelial cells were present: the superficial layer was connected, by means
      of the apical fringes, to the photoreceptors, whilst the deepest layer showed
      vesicles and tubules on its basal zone. After 7 days of recovery to L:D = 12:12,
      no cyclic activity was demonstrated and only occasional double layers of cells
      were present; on the basal surface isolated basal infoldings were present where
      two adjacent cells were joined together. It could be concluded that the
      detachment of the apical part of some cells, rapidly covered by the lateral
      sliding of the adjacent cells, and the substitution of the basal infoldings with
      vesicles and tubules could represent the morphological response of the retinal
      epithelium to the functional changes induced by prolonged darkness.

PMID- 10575822
TI  - The spinal cord development in guinea pig: a morphometric study on an image
      analysis system.
AB  - Using an image analysis system, the Authors carried out a morphometric study on
      guinea pig spinal cord in order to determine volumetric changes of white and gray
      matter during development. White and gray matter volumes were determined by
      measuring the area occupied by these matters in 10 micrograms sections of spinal
      cord in 1 day and 90 days old subjects. Several topographic correspondences in
      the localisation of the lowest and highest volumetric values were observed in the
      two groups of subjects. Such correspondences were more marked for white than gray
      matter. Moreover, during growth white matter volume showed an increase double
      that observed in gray matter.

PMID- 10575823
TI  - Measurements of the diameter of the abdominal aorta using C.T.
AB  - The purpose of this study was to verify the difference between diameters of
      abdominal aorta obtained on corpses and on living bodies, using C.T. The Authors
      focused the attention on abdominal aorta, beneath kidney veins. Moreover, a
      linear relationship was found between height and diameter of abdominal aorta. A
      careful examination of the literature has shown discordance among the values of
      the abdominal aorta. The Authors conclude that improved techniques of
      radiological anatomy may offer an important support to obtain important data for
      clinical practice.

PMID- 10575824
TI  - Histomorphometric study on the osteocyte lacuno-canalicular network in animals of
      different species. II. Parallel-fibered and lamellar bones.
AB  - The shape, size and density of osteocyte lacunae in parallel-fibered and lamellar
      bone were histomorphometrically analyzed in relation to the organization of the
      collagen fiber texture and the animal species (frog, sheep, dog, bovine, horse
      and man). The following parameters were measured under the light microscope (LM)
      by a computer-assisted image analyzer: 1) shape, size and distribution of
      osteocyte lacunae; 2) osteocyte lacuno-canalicular density. In close agreement
      with our previous studies, which includes woven bone, it resulted that in all
      animals (even in frog) osteocyte lacunae have a rounded globous shape in woven
      bone and an oval shape in both parallel-fibered and lamellar bone; in the latter,
      however, they are more flattened, only located in loose lamellae and thus
      regularly distributed in rows. Osteocyte lacunar density is higher in woven
      fibered, intermediate in parallel-fibered and lower in lamellar bone, whereas no
      correlation seems to exist with the animal species. In conclusion, these results
      suggest that osteocyte shape, size and density seem to depend mainly on collagen
      fiber texture rather than on the animal species. The role of osteocyte
      recruitment on the spatial organization of collagen fibers in bone tissues is
      discussed.

PMID- 10575825
TI  - Morphological study of the vas deferens of the pigeon (Columba livia).
AB  - A morphological study of the vas deferens of the pigeon was carried out in order
      to determine the electronmicroscopic features of its epithelial lining, and the
      expression of pancytokeratins. The results showed that the epithelium is columnar
      pseudostratified and consists of non-ciliated (principal) cells and basal cells.
      Presence of a predominantly granular endoplasmic reticulum, mitochondria and well
      developed Golgi complexes bearing vesicles on their cis/trans surfaces were
      observed. In addition to these vesicles associated with the Golgi complexes were
      observed membrane-delimited vesicles with a low electron density content or with
      an electrondense content mainly related to the endoplasmic reticulum. Apical
      cytoplasmic expansions with heterogeneous cytoplasmic content were also seen.
      These subcellular features associated to the presence of pancytokeratins, suggest
      the occurrence of a secretory process in principal cells, as well provide a mural
      structural support to the vas deferens.

PMID- 10575826
TI  - Designing interdisciplinary documentation for the continuum of care.
AB  - An increased emphasis on integrated care delivery and the need to access
      information across the care continuum led to an assessment and modification of
      the current documentation system at Summa Health System in Akron, Ohio. The goal
      was to achieve more complete and concise interdisciplinary charting. This article
      describes the process the two-hospital system developed to achieve integrated
      documentation reflecting the patient's progress toward team-defined outcomes.
      Steps in the evaluation and modification of the old system, lessons learned, and
      results/implications for quality improvement are shared.

PMID- 10575827
TI  - Critical pathways as an essential part of a disease management program.
AB  - Disease management is becoming a common tool utilized by health systems for
      managing patients with chronic diseases. Part of the success of disease
      management can be attributed to the use of critical pathways. Critical pathways
      are the tools that prompt decisions to be made based on clinical practice
      guidelines. In addition to allowing nursing case managers to have significant
      input into patient treatment decisions, critical pathways assist disease
      management programs in realizing significant cost savings as well as assisting in
      outcomes management activities.

PMID- 10575828
TI  - Nursing home care quality: a multidimensional theoretical model integrating the
      views of consumers and providers.
AB  - This exploratory study was undertaken to discover the defining dimensions of
      nursing home care quality from the viewpoint of consumers of nursing home care.
      Eleven focus groups were conducted in five Missouri communities. The seven
      dimensions of the consumer multidimensional model of nursing home care quality
      are: staff, care, family involvement, communication, environment, home, and cost.
      The views of consumers and families are compared with the results of a previous
      study of providers of nursing home services. An integrated, multidimensional
      theoretical model is presented for testing and evaluation. An instrument based on
      the model is being tested to observe and score the dimensions of nursing home
      care quality.

PMID- 10575829
TI  - Exploring indicators of telephone nursing quality.
AB  - To explore whether documentation, use of clinical guidelines, and nurse
      competency are the best indicators of quality telephone nursing, this study
      examined the relationship between these commonly cited indicators and the
      characteristics of a telephone nursing call. This study, done at a large health
      maintenance organization (HMO), found: accompanying symptoms played a major role
      in telephone nursing assessment; call length was related to documentation process
      and to number of visits to a health care facility after a call; nurses'
      interpersonal skills and ability to determine urgency of a call are related to
      the documentation process but not to outcomes of the call; time of a call is
      related to disposition; and disposition is related to number of visits after a
      call.

PMID- 10575830
TI  - Consumers' descriptions of quality health care.
AB  - Consumer-oriented health care report cards have emerged as a strategy to
      disseminate information to consumers about the quality of health plans and
      relative costs, with the goal of enabling them to make informed choices. While
      consumers have reported an interest in having access to this information, how
      they actually define quality of care is not yet clear. Despite extensive research
      on defining and measuring health care quality, less attention has been given to
      consumers' perspectives of quality care. In this study, 239 consumers were
      interviewed using four open-ended questions on their descriptions of quality
      health care and quality nursing care. Consumers described quality health care in
      terms of access to care (n = 143), followed by having competent and skilled
      providers (n = 104) and receiving the proper treatment (n = 100). Consumers
      defined quality nursing care as having nurses who were concerned about them and
      demonstrated caring behaviors (n = 148), were competent and skilled (n = 115),
      communicated effectively with them (n = 99), and taught them about their care (n
      = 97).

PMID- 10575831
TI  - Predictors of birth outcome among Hispanic immigrant women.
AB  - Eliminating racial and ethnic disparities in health is a major goal of Healthy
      People 2010. Health care providers and institutions can address the specialized
      cultural expectations and needs of Hispanic Americans by assessing acculturation
      status of the population, an intervening variable in patient compliance, and
      health outcomes. This article reports on maternal acculturation status and the
      relationship to birth outcomes of 382 Hispanic pregnant women in the southwest
      United States. The majority of these women were Mexican-oriented and had healthy
      pregnancies and healthy birth outcomes. Findings support the hypothesis that
      traditional Mexican cultural practices serve protective functions for the
      childbearing woman.

PMID- 10575832
TI  - Dutch nurse clinics for children with asthma: views of professionals and parents.
AB  - In the Netherlands, there are two kinds of nurse clinics for asthmatics.
      Extramural nurse clinics are run under the sole responsibility of a home care
      organization while transmural nurse clinics are run under the joint
      responsibility of a home care organization and a hospital. This article gives
      insight into the opinions of professionals and parents of asthmatic children
      about the care given at these clinics. The conclusion is that organizational
      differences between the clinics do not influence parents' (positive) perceptions
      about the quality and continuity of care provided at the clinics.

PMID- 10575833
TI  - Issues in nurses' practical skill development in the clinical setting.
AB  - Generally, it is assumed that nurses are reasonably skilled in the performance of
      practical nursing actions by the end of their first year of practice. This
      article contests this assumption based on empirical data from a longitudinal
      study of newly graduated nurses. Three issues are discussed: the notion that
      experience (per se) can guarantee a positive development in practical skill
      performance; the failure to relate to inherent complexities in practical skill
      performance during evaluation of skill; and the significance of acknowledging
      differences in skill complexity during skill development. A reinstated focus on
      practical skill in nursing education and collaboration between education and
      practice is needed to secure quality in a nurse's actual performance.

PMID- 10575835
TI  - Aortic regurgitation detected with Doppler echocardiography in apparently healthy
      adolescents.
AB  - In this study, we sought to determine the prevalence and characteristics of
      aortic regurgitation (AR) in apparently healthy adolescent students. A total of
      315 healthy junior high school students underwent echocardiographic examination.
      There were 158 boys and 157 girls, with a mean +/- standard deviation age of 13.3
      +/- 0.9 years (range, 13-15 yr). AR was found in six (2%) students. Five of the
      six (83%) with AR had minimally thickened aortic valves: three (50%) had a
      thickened right coronary cusp and four (67%) had a thickened noncoronary cusp,
      but none had a thickened left coronary cusp. The AR was mild in five (83%)
      students and moderate in one (17%). Two of the six students had aortic valve
      prolapse, both of whom had minimal thickening. One student with AR did not have
      any abnormal structural changes, and one had aortic root dilatation. No cardiac
      chamber dilatation was noted in students with AR. These findings indicate a
      relatively high prevalence of AR in apparently healthy adolescents.

PMID- 10575834
TI  - Heart transplantation with marginal recipients and donors.
AB  - With improvements in surgical techniques and management of postoperative
      complications, heart transplantation can now be performed with donors and
      recipients who were previously considered unsuitable. In this study, we report
      the results of heart transplantation with marginal donors and recipients in our
      hospital. From June 1993 through June 1998, we performed 79 heart
      transplantations. Marginal recipients were defined as those with high pulmonary
      vascular resistance (> 6 Wood units), severe renal impairment (serum creatinine >
      2 mg/dL and creatinine clearance < 50 mL/min), or severe hepatic dysfunction (ALT
      and AST > 100 IU/L or serum bilirubin > 2.5 mg/dL). Marginal donors were those
      with any of the following conditions: old age (> 40 years), size mismatch
      (donor/recipient body weight ratio < 0.8), history of chronic alcohol use,
      previous cardiopulmonary resuscitation and hypotension, hepatitis B or C virus
      positivity, coronary artery disease, high-dose dopamine (> 10 micrograms.kg-1.min
      1), or prolonged allograft ischemic time (> 4 hours). Of the 79 transplantations
      performed, 45 (58%) involved marginal recipients or donors. The 30-day mortality
      rate was 5%, and the 1-year and 5-year survival rates were 87% and 83%,
      respectively. The survival rates did not differ significantly between cases
      involving marginal donors or recipients and those involving nonmarginal donors
      and recipients. There were 27 marginal recipients (34%), only one of whom died
      during surgery. Five of six recipients with severe renal impairment needed short
      term hemodialysis after transplantation. Recipients with high pulmonary vascular
      resistance had a higher incidence of early acute rejection (5/10 vs 22/69).
      Thirty-three (42%) of the patients received transplants from marginal donors,
      four of whom died during surgery; two died of acute vascular rejection, one of
      allograft failure caused by prolonged ischemic time, and one of bleeding
      secondary to preoperative sepsis and coagulopathy. These results show that heart
      transplantation may be performed in marginal recipients and donors, with
      acceptable operative mortality.

PMID- 10575836
TI  - Detection and assessment of circle of Willis aneurysms in acute subarachnoid
      hemorrhage with three-dimensional computed tomographic angiography: correlation
      with digital substraction angiography findings.
AB  - In this retrospective study, we examined the usefulness of computed tomographic
      angiography (CTA) for the detection and assessment of circle of Willis aneurysms
      in patients with acute nontraumatic subarachnoid hemorrhage (SAH), using
      selective digital substraction angiography (DSA) as the gold standard. Thirty
      five patients who presented with acute, nontraumatic SAH, diagnosed on the basis
      of unenhanced computed tomography or lumbar puncture findings or both, underwent
      both CTA and DSA. The CTA images were interpreted for the presence, location,
      size, and shape of the aneurysm, presence of a neck, and relationship of the
      aneurysm to adjacent arterial branches. The CTA and DSA images were then
      compared, with the latter images serving as the gold standard. DSA revealed 37
      aneurysms in 32 patients and ruled out intracranial aneurysms in the remaining
      three. The sensitivity and specificity of CTA for aneurysm detection were 97% and
      100%, respectively. The size of the smallest aneurysm shown was 4 mm, and the
      largest aneurysm was 21 mm. The size and lobularity of the aneurysms estimated
      from CTA images corresponded well with those estimated from DSA images. In
      addition, CTA provided a three-dimensional representation of the aneurysmal
      lesion, which was considered useful for surgical planning. Our results confirm
      the accuracy of CTA in comparison with DSA. Because of its reliability, minimal
      invasiveness, and rapidity, CTA may become the technique of choice for
      neuroradiologic work-up of SAH patients. DSA then would be used to diagnose
      intracranial aneurysms only in selected, questionable cases.

PMID- 10575837
TI  - Tuberculous pleurisy with effusion.
AB  - To assess the clinical features of Taiwanese patients with tuberculous pleurisy
      and their response to treatment, we analyzed the records of patients treated for
      this condition from December 1990 through November 1995, at a regional 100-bed
      referral center for tuberculosis care. Diagnosis of tuberculous pleurisy was
      based on histologic evidence of caseating granulomatous inflammation in the
      pleural biopsy specimen, or evidence of mycobacteria in pleural fluid. Patients
      were also stratified on the basis of parenchymal involvement. Ninety-seven
      patients (79 men, 18 women) with a mean age of 47.5 (range, 15-90) years were
      included in the analysis. The two major symptoms were cough (69%) and shortness
      of breath (57%). Chest roentgenographs showed that the pleural effusion was
      unilateral in 88 (91%) patients, and small to moderate in amount in 74 (76%).
      Laboratory analysis of the pleural fluid showed moderate levels of glucose (4.6
      mmol/L), with no significant difference between patients with and without
      parenchymal involvement. The levels of lactate dehydrogenase and triglycerides
      were significantly higher in patients with parenchymal involvement (172 vs 240.5
      IU and 0.36 vs 0.45 mmol/L, respectively). In 85 of 93 patients (91%) with
      available data, lymphocytes were predominant in the differential count. All
      patients had received short-course chemotherapy for at least 6 months. After
      excluding the defaulters and patients receiving subsequent management in other
      hospitals, the overall rate of successful treatment was 97% (72/74). There was no
      significant difference in the treatment outcome between patients with parenchymal
      involvement and those without. None of the successfully treated patients had a
      relapse within a mean follow-up period of 31.7 +/- 18.4 months. We conclude that
      current patients with tuberculous pleurisy in Taiwan are not young, and short
      course chemotherapy with isoniazid, ethambutol, rifampicin, and pyrazinamide is
      an effective treatment. The presence of parenchymal tuberculous lesions does not
      appear to influence the treatment outcome.

PMID- 10575838
TI  - Imported malaria: successful treatment of 31 patients in the era of chloroquine
      resistance.
AB  - The diagnosis and management of imported malaria presents a continuing challenge
      in developed countries, including Taiwan. We retrospectively analyzed the records
      of all 31 patients with imported malaria treated at National Taiwan University
      Hospital from January 1984 through December 1998. Plasmodium falciparum was
      identified as the causative malarial parasite in 18 patients, P. vivax in 12, and
      P. ovale in one. All 31 patients had fever, but only 13 presented with the
      characteristic fever pattern. The most common initial laboratory abnormalities
      were thrombocytopenia (20/31), mild hyperbilirubinemia (20/31), and leukopenia
      (7/31). The median time from the onset of fever to the correct diagnosis was 4
      days for P. falciparum and 5 days for P. vivax. In 28 cases, the clue that led to
      early diagnosis was the patient's travel history. Quinine, but not chloroquine,
      was effective in 17 out of 18 cases of falciparum malaria. Three patients treated
      with intravenous quinine required a change of regimen because of life-threatening
      quinine toxicity; artesunate served as a safe and effective alternative in this
      situation. While most patients with tertian malaria were cured with the standard
      chloroquine and primaquine regimen, a higher dosage was required for one case
      acquired in Papua New Guinea. All patients, including two with severe malaria,
      survived. We conclude that, the mortality of imported malaria in the chloroquine
      resistance era can be minimized with early recognition by obtaining a thorough
      travel history, and instituting appropriate antimalarial chemotherapy based on
      precise identification of species. Quinine toxicity should be closely monitoried,
      especially when this drug is given intravenously.

PMID- 10575839
TI  - Acute monoblastic leukemia in a child following chemotherapy for neuroblastoma.
AB  - The long-term effects of childhood cancer and its therapy are serious problems
      that deserve attention. One of the most important late effects is the development
      of secondary malignancy. We encountered a girl with neuroblastoma who developed
      acute monoblastic leukemia as a secondary malignancy, 32 months after starting
      treatment for the primary tumor at the age of 4 years and 10 months. For the
      primary tumor, she had received cyclophosphamide, ifosphamide, etoposide,
      epirubicin, cisplatin, and vincristine during a period of 20 months; no
      radiotherapy was given. Cytogenetic analysis of the leukemic cells showed no
      specific changes, but a rearrangement of the mixed lineage leukemia gene
      (chromosome 11q23 translocation) was subsequently found by reverse transcription
      polymerase chain reaction. The survival time after onset of the secondary
      malignancy was brief. The leukemogenic hazards of cancer treatment should be
      weighed against their therapeutic benefits.

PMID- 10575840
TI  - De novo RET proto-oncogene mutation in a patient with multiple endocrine
      neoplasia type 2B.
AB  - We report a case of multiple endocrine neoplasia type 2B (MEN 2B) with de novo
      RET proto-oncogene mutation. The patient, a 23-year-old Taiwanese woman, was
      admitted for treatment of recurrent medullary thyroid cancer (MTC) 7 years after
      a total thyroidectomy. Mucosal neuromas and marfanoid appearance were also noted.
      Because MEN 2B was suspected, the patient and her family members underwent
      genetic analysis. A heterozygous germline mutation at codon 918 (ATG-->ACG) of
      the proto-oncogene RET was detected in the patient. This mutation was considered
      de novo, as it was not detected in either of her parents or her siblings. The
      patient underwent surgery for removal of the recurrent tumor. Although no
      pheochromocytoma was noted, regular follow-up is necessary because of persistent
      hypercalcitoninemia.

PMID- 10575841
TI  - Cardiogenic shock in a patient with glyphosate-surfactant poisoning.
AB  - We present a case of glyphosate-induced cardiogenic shock in a young man. The
      patient a 26-year-old man, presented with nausea and vomiting 4 hours after
      attempting suicide by drinking 150 mL of glyphosate surfactant. Cardiogenic shock
      with accelerated idio-ventricular rhythm on electrocardiography developed after
      admission. Intravenous injection of epinephrine, atropine, and calcium failed to
      improve the condition. Over the next 16 hours, the QRS complex gradually
      narrowed, sinus rhythm returned, and the hemodynamic status improved.
      Echocardiograms revealed diffuse left ventricular hypokinesis with markedly
      reduced ejection fraction while the patient was in shock; normal left ventricular
      function resumed the next day. In this case, the glyphosate surfactant poisoning
      induced shock may have been due to transient suppression of the cardiac
      conduction system and contractility, rather than intravascular hypovolemia.

PMID- 10575842
TI  - Acute respiratory distress syndrome due to tuberculosis in a child after
      allogeneic bone marrow transplantation for acute lymphoblastic leukemia.
AB  - We report the occurrence of tuberculosis in a 10-year-old Taiwanese boy,
      approximately 4 months after he received a matched-related bone marrow
      transplantation from his sister for acute T-cell lymphoblastic leukemia. After
      transplantation, grade III acute graft-versus-host disease developed and the
      patient was treated with prednisolone and cyclosporine. Marrow failure was noted
      on day 77 post-transplantation, however, after an episode of herpes zoster
      infection. Interstitial pneumonia, diagnosed on the basis of chest x-ray and
      computed tomography findings, occurred on day 120. Histologic examination of an
      open-lung biopsy specimen showed caseating granulomas and a few acid-fast
      bacilli. The patient died of acute respiratory distress syndrome, despite
      immediate implementation of antituberculosis therapy. Sputum cultures grew
      Mycobacterium tuberculosis 5 weeks later. This report demonstrates that the
      possibility of tuberculosis needs to be considered in immunocompromised patients,
      and that appropriate prophylaxis should be instituted in areas where tuberculosis
      is endemic.

PMID- 10575843
TI  - A non-radioactive polymerase chain reaction method for diagnosis of Machado
      Joseph disease.
AB  - Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) is caused by
      unstable CAG trinucleotide repeat expansion in the coding region of the MJD gene.
      In this study, we describe a non-radioactive polymerase chain reaction (PCR)
      method to detect the CAG repeat range of the MJD gene. This technique allows
      direct visualization of the PCR products on ethidium bromide-stained agarose gels
      within hours. In this study, genomic DNA samples isolated from peripheral
      lymphocytes, amniotic fluid cells, and chorionic villi were tested with two sets
      of commonly used MJD primers. PCR conditions were optimized, which resulted in
      clear visualization of both the primer sets on 3% agarose gels. Ten out of 25
      candidate MJD patients have been identified with this method to date, with no
      false-positive or false-negative diagnoses. This simple, reliable, and cost
      effective method can be used for patient diagnosis, pre-symptomatic diagnosis,
      and prenatal diagnosis.

PMID- 10575844
TI  - Another house divided: Union Medical Service and sectarians during the Civil War.

PMID- 10575845
TI  - Mary Lincoln's final illness: a medical and historical reappraisal.

PMID- 10575846
TI  - A female malady? Women at the South Carolina Lunatic Asylum, 1828-1915.

PMID- 10575847
TI  - Konstantin M. Bykov and the discovery of the role of the corpus callosum.

PMID- 10575848
TI  - [Even normal drug dosages can induce hepatic injuries. The medical profession is
      often amazingly unaware of this fact].

PMID- 10575849
TI  - [Gunter Blobel the 1999 Nobel Prize-winner in physiology and medicine. Proteins
      are directed in the cell through by built-in "zip-codes"].

PMID- 10575850
TI  - [Physicians' lowered responsibility contributes to the increasing sick-leave].

PMID- 10575851
TI  - [Is stress tolerance of female physicians lower compared to male physicians?].

PMID- 10575852
TI  - [Are you unstable and sensitive to stress, my dear?].

PMID- 10575853
TI  - [A story about School Health Services, Health Control and Neuropsychiatry. (The
      story about unhealthy relations)].

PMID- 10575854
TI  - [The law on involuntary psychiatric commitment is a disaster].

PMID- 10575855
TI  - [Is a 3-day treatment of uncomplicated lower urinary tract infection to be
      recommended?].

PMID- 10575856
TI  - [The health insurance authority should be responsible for prevention of benefit
      misuse].

PMID- 10575857
TI  - [Revolutionary progress is to be expected when health care will be marked by
      genetics].

PMID- 10575858
TI  - [Intensive genome research].

PMID- 10575859
TI  - [Is flucloxacillin-induced liver damage an underreported complication?].

PMID- 10575860
TI  - [Strong connection between malnutrition, inflammation and arteriosclerosis.
      Improved treatment of renal failure if underlying factors are attacked].
AB  - Malnutrition, inflammation and atherosclerotic cardiovascular disease occur at
      high prevalence, and often concomitantly, in conjunction with chronic renal
      failure. Several features of malnutrition (e.g., increased oxidative stress,
      increased plasma levels of fibrinogen, Lp(a), and inflammation) may all, alone or
      in concert, increase the risk of cardiovascular disease. Recent findings suggest
      malnutrition and hypoalbuminaemia in chronic renal failure to be largely the
      consequence of such factors as heart failure, chronic infection and inflammation,
      that simultaneously trigger the development of atherosclerotic cardiovascular
      disease. Central to this scenario is the involvement of proinflammatory cytokines
      which may cause muscle wasting, hypoalbuminaemia, anorexia, and accelerated
      atherosclerosis. It is unlikely that the high mortality due to atherosclerotic
      disease among patients with chronic renal failure can be substantially reduced
      unless new treatment strategies are developed which address the complex
      relationships that exist between malnutrition, inflammation and cardiovascular
      disease.

PMID- 10575861
TI  - [The experience of labor does not improve following Cesarean section].

PMID- 10575862
TI  - [Cesarean section--a woman's choice or physician's responsibility?].

PMID- 10575863
TI  - [Screening for celiac disease in adults].
AB  - This article is a review of literature from Medline and other sources, which
      shows that coeliac disease is far more prevalent than previously considered. The
      clinical picture is very diverse, making diagnosis difficult in many patients and
      calling for great clinical awareness. Even patients with no or few symptoms have
      biochemical signs of malabsorption, e.g. folate, vitamin, and iron deficiency,
      and many exhibit osteopenia. Patients with untreated coeliac disease carry a
      significant risk of developing malignancies. Risk groups for screening are family
      members, patients with coeliac associated disorders, and patients with
      uncharacteristic symptoms. Screening among apparently healthy subjects has been
      carried out for epidemiological purposes, but is not recommended outside
      protocols. Diagnosing coeliac disease is important because lifelong strict
      dietary treatment is effective in alleviating symptoms and preventing longterm
      complications.

PMID- 10575864
TI  - [Orthopedic language 2. Wrong terminology leads to misdirected treatment].

PMID- 10575865
TI  - [Gallstone therapy requires further scrutiny. Important viewpoints in a new
      Danish report].

PMID- 10575867
TI  - [A book and a film about general practitioners is a great success in France].

PMID- 10575866
TI  - [New discoveries on diabetes discussed in the USA. Can glitazones halt
      "epidemics" of the metabolic syndrome?].

PMID- 10575868
TI  - [Proposal by the minister of health and social affairs on family practice.
      Salvation of the Swedish health care or a nostalgic dream?].

PMID- 10575869
TI  - [New demands in future when it comes to competence in emergency medicine].

PMID- 10575870
TI  - [I won't have the attack on the health insurance authority's personnel].

PMID- 10575871
TI  - [Can physicians assess work capacity?].

PMID- 10575872
TI  - [Make difference between political and professional targets!].

PMID- 10575873
TI  - [Unnecessary alarms about "unnecessary heart disease"].

PMID- 10575875
TI  - [Nesidiodysplasia. A rare cause of hyperinsulinemia in an adult patient].
AB  - Adult hyperinsulinaemia is usually caused by benign insulinomas. These tumours
      are often small, and are associated with excellent outcome of surgical removal.
      In cases of negative outcome of surgical exploration, or of persistent
      hyperinsulinaemic hypoglycaemia, the possibility must be considered of some rare
      condition such as the presence of metastatic insulinoma, B-cell hyperplasia,
      multiple micro- or macro-adenomas, hyperinsulinaemia factitia, or
      nesidiodysplasia. The latter is the most common cause of hyperinsulinaemia in
      children but is rare in adults. It is defined as a maldistributed islet cell mass
      within the normal exocrine pancreas, with disturbed control of hormone
      synthesis/secretion resulting in hormone overproduction, usually
      hyperinsulinaemia. In persistent hyperinsulinaemic hypoglycaemia of infancy,
      inactivating mutations of the sulphonylurea receptor gene is one possible cause
      of nesidiodysplasia. Adult nesidiodysplasia is discussed in the article, and
      illustrated by the case of a patient undergoing distal pancreatectomy for
      hyperinsulinaemia, the diagnosis being subsequently established histologically.
      Following spleen- and duodenum-preserving subtotal (95%) pancreatectomy, the
      patient was symptom-free.

PMID- 10575874
TI  - [Self-starvation over 1500 years: the work of God, the devil or weight-control?].
AB  - For centuries self-starvation among young women has been the subject of intensive
      discussion. First and foremost it has been a question of debate over aetiological
      models. During the middle ages, the central issue was whether self-starvation was
      the work of God or the devil. Subsequently the question was whether the
      explanation was scientific or religious. The aim of medical science was to find a
      scientific explanation or debunk the phenomenon as fraudulent. The causes of self
      starvation remain unclear. During the nineteenth century, the focus switched back
      and forth between biological and psychosocial models. Current multifactorial
      aetiological models take into account biological susceptibility, socio-cultural
      factors and psychological vulnerability.

PMID- 10575876
TI  - [Many ethical problems are generated by genomic research].

PMID- 10575877
TI  - [Hypertension plus hypokalemia should direct the line of thoughts toward Liddle's
      syndrome].

PMID- 10575878
TI  - [Anxiety before, under and after being on call duty--what can be done?].

PMID- 10575879
TI  - [Clinical chemistry must be anchored in medicine].

PMID- 10575880
TI  - [Why does illness exist? An evolutionary perspective. I: Health and illness in a
      wider biological context].

PMID- 10575881
TI  - [Why does illness? An evolutionary perspective. II: Evolution-biology and
      psychiatry--an umbrella theory for a divided science].

PMID- 10575882
TI  - [Recommendations by the Swedish lung cancer group. Shorter waiting time is a
      quality requirement in the management of lung cancer].

PMID- 10575883
TI  - [Massage has its place in traditional medicine, but more and better studies are
      required].

PMID- 10575884
TI  - [The child with special needs in school--often with delayed physical development
      and socially disadvantaged].

PMID- 10575885
TI  - [When radioactive water was a gleam of hope for the sick].

PMID- 10575886
TI  - [Palliative treatment of esophageal and cardial carcinoma].
AB  - Recent series reported increasing incidence of esophageal and cardial cancers
      with prognosis still severe in spite of surgical progress. The late diagnosis
      reduces the chance of radical surgery; on the other hand about 80-90% of patients
      develop local or distant recurrence. Therefore the treatment of esophageal and
      cardial cancer is often palliative: surgical resection is reserved only to
      selected cases. Endoscopic palliation was the treatment of choice in a total of
      265 patients 174 of which received laser therapy and 91 prosthesis intubation.
      The results it good in about 80% of cases.

PMID- 10575887
TI  - [Complications of Barrett's esophagus: indications for esophageal resection with
      special reference to high-grade dysplasia].
AB  - BACKGROUND: Columnar lined oesophagus (Barrett's oesophagus) can sometimes be
      associated with complications such as stricture, ulcer and dysplasia. In some
      selected cases there is an indication for oesophageal resection. METHODS: From
      1983 to 1997, 12 patients underwent oesophagectomy for "complicated" Barrett's
      oesophagus. All patients had gastroesophageal reflux and Barrett metaplasia for
      many years. Ten of them were symptomatic, and pH-manometric alterations as well
      as alterations were noted at biliary scintigraphy. Ten patients had intestinal
      metaplasia. Two patients had previous antireflux operations. Four had a long (3-5
      cm) and undilatable stricture. One was affected by a perforating ulcer. One
      patient had an indefinite grade dysplasia but endosonography revealed high
      suspicion of cancer. Six patients had a high-grade dysplasia. Operative technique
      consisted of a transhiatal oesophagectomy in nine cases and a laparotomic and
      right thoracotomic oesophagectomy (Ivor-Lewis) in two. RESULTS: There was no 30
      day mortality; three post operative complications were observed. One of the four
      patients suffering from stricture died four years after intervention due to non
      related causes; the other three are still living and regularly feed per os after
      12, 9 and 7 years. The patient with ulcer is still living after 6 years and
      regularly feeding per os. The patient suffering from an indefinite grade
      dysplasia had an adenocarcinoma (stage IIa) on the operative specimen. The
      patient is still living after 2 years. Three patients operated for high-grade
      dysplasia had an adenocarcinoma on the specimen. Two patients (stage I) are
      living after 3 and 5 years. One patient (stage IIa) died after 19 months with
      recurrence. CONCLUSIONS: In case of non neoplastic "complicated" Barrett's
      oesophagus the indication for the oesophageal resection can be considered as the
      extreme useful therapy only after an accurate selection of patients. Especially
      in case of high-grade dysplasia, the great incidence of unexpected adenocarcinoma
      indicates oesophagectomy for patients who are suitable for surgery.

PMID- 10575888
TI  - [Mallory-Weiss syndrome. Outcome of 160 cases].
AB  - The Mallory-Weiss (M-W) syndrome is responsible for about 7.5% of all bleedings
      of oesophageal origin. Emergency endoscopic treatment allows to obtain a rapid
      diagnosis as well as an effective treatment. Personal experience on 160 cases of
      M-W tears (14.2% of all oesophageal bleeding) is reported. The tears were
      classified in three groups: IA and IB (30 cases); IIA and IIB (48 cases); IIC and
      III (82 cases). In the first two groups a complete haemostasis was obtained in 73
      out of 78 cases (93.6%) with a single session and in 5/78 cases with two sessions
      of sclerotherapy. The third group was treated with medical therapy. There was no
      procedure related mortality. An analysis of etiologic factors, anatomic
      conditions and pathogenetic correlations has highlighted the role of portal
      hypertension in cirrhotic patients in favouring the bleeding in some of these
      patients and the role of hiatal hernia and cardial incontinence in determining
      the site of the lesions.

PMID- 10575889
TI  - [Treatment of acute biliary pancreatitis in the aged in the endolaparoscopic
      era].
AB  - BACKGROUND: Acute biliary pancreatitis (ABP) still retains high morbidity (15
      50%) and mortality (20-35%). Therefore it appears to be crucial to clearly assess
      the aetiological factors (50% of idiopathic are in fact biliary pancreatitis) and
      to establish the severity in order to plan the appropriate treatment. METHODS: In
      this study we have considered 61 patients divided into 2 groups. Group 1 had 29
      ABP patients aging less than 65 years, group 232 patients aging more than 65
      years; the diagnosis was made by ultrasound and serological values in 78.5% of
      cases, while in the remaining 21.5% was only serological. Following Ranson and
      APACHE II scoring 18 cases (29.5%) were classified as severe [6 (20.6%) in group
      1; 12 (37.5%) in group 2: p < 0.01], 43 (70.4%) as mild. All patients with severe
      ABP had emergency ERCP + ES (within 24-48 hrs) followed by LC (< or = 10 days).
      Patients with mild ABP had LC within 10 days; in these cases IOC was always done.
      RESULTS: In severe cases operative endoscopy cured pancreatic inflammation in 13
      cases. Subsequent LC never showed serious morbidity, apart subcutaneous emphysema
      in one case. In 5 cases laparotomy was required since pancreatic necrosis was
      present, with 60% mortality. In patients with mild pancreatitis LC was
      successfully performed in all cases, with 6.9% morbidity. IOC showed choledochal
      stones in 32.5% of cases, while in severe cases stones in the biliary tree were
      showed in 88.8% of cases. No significant differences were detected between group
      1 and 2. CONCLUSIONS: In conclusion ABP treatment is always surgical, and almost
      always with minimally-invasive procedures in severe cases (ERCP + ES with LC < or
      = 10 days) if surgery is performed within 24-48 hrs as well as in mild cases (LC
      + IOC) when surgery is done within 10 days, independently from the age of the
      patients.

PMID- 10575890
TI  - [Biofragmentable anastomosis ring (BAR) in surgery of the digestive system].
AB  - Twenty-six patients submitted to surgery using BAR in intestinal anastomosis have
      been studied. The results were compared with data of the literature concerning
      this device of anastomosis and about mechanical staplers and manual suture. The
      following data were taken into consideration: type of operation, type of
      anastomosis, average time of execution, complications, days of postoperative
      canalization and feeding, costs of three anastomosis types. Postoperative
      complications rate were 23% with a postoperative death rate of 7.6%. There was
      only one intraoperative complication during a colorectal anastomosis. The average
      time, to package an intestinal anastomosis using BAR, was 69.9 minutes. The
      average type of postoperative canalization was 3.7 days and average period in
      hospital was 10.3 days. The costs of manual suture, of mechanical staplers and of
      BAR are respectively L. 50,000, 1,340,000 and 583,000. BAR complications are
      similar to the other techniques; this study shows a reduction of operative time,
      postoperative canalization and period in hospital, with a consequent decreasing
      of global costs. The execution of intestinal anastomosis using BAR is easier then
      the other techniques, the learning time is least and the procedure is uniform.
      The introduction of this technique in the common operative practice together with
      manual suture and stapler is stressed.

PMID- 10575891
TI  - [Thoracic drainage in trauma emergencies].
AB  - A group of 191 cases of emergency tube thoracostomy for acute trauma reviewed
      retrospectively from March 1993 to March 1998 is reported. Of this group 169 were
      men and 22 were women. Their ages ranged from 16 to 73 years. The causes were as
      follows: 89 cases (46%) road accident; 33 cases (17%) accidental trauma; 33 cases
      (17%) someone else violence (assault, gunshot or stab wound); 15 cases (8%) work
      accident; 11 cases (6%) domestic accident and 5 cases (3%) iatrogenic trauma. In
      32 patients a diagnosis of pneumothorax was made (2 tension, 11 for penetrating
      chest injuries, 19 after blunt trauma). In 2 cases of tension pneumothorax and in
      3 cases of open pneumothorax a chest tube (24-28 Fr) in the third space in the
      mid-clavicular line was introduced. In the other patients it was decided to place
      a chest tube in the mid-axillary line in the fifth intercostal space to drain
      pneumothorax. Only in 7 cases suction was necessary. Fifty-four hemothorax (3
      bilateral) were treated in 11 cases using thoracentesis, while the remaining
      cases were treated using the insertion of multiple drainage holes in the
      intercostal space (fifth in the mid-axillary line directed inferiorly and
      posteriorly). One hundred and three were the cases of hemopneumothorax: 24 of
      them received 2 chest tubes, the first (20-26 Fr) apically in the second
      intercostal space in the mid-clavicular line, the second (32-38 Fr) in the fifth
      intercostal space in the mid-axillary line. All the other cases were treated
      using a single thoracostomy. In 14 cases suction was applied. Two cases of
      chylothorax resolved by a large tube positioned in the chest (fifth intercostal
      space in the mid-axillary line) with a constant negative pressure were also
      observed. Duration of tube drainage ranged from 4 and 18 days, with an average of
      11 days. Five infections of thoracostomy site and 1 empyema resolved by
      rethoracotomy were observed. Moreover, there were 3 complications: 2 subcutaneous
      placements and 1 little laceration of the lung. Thirty-one drained patients were
      operated: in 5 cases thoracotomy and laparotomy (2 exitus in tabula); only
      thoracotomy in 8 cases; 19 laparotomy and thoracostomy (1 exitus in tabula).

PMID- 10575892
TI  - [Tension free hernioplasty in the treatment of recurrent inguinal hernia. Our
      experience].
AB  - BACKGROUND: Despite the new surgical approach with "tension free" techniques,
      recurrent inguinal hernia repair remains a difficult surgical problem. METHODS:
      Personal experience in 61 cases of recurrent inguinal hernia is reported; in all
      patients a new hernioplasty with a "tension free" technique was performed. Medium
      follow-up of the study was 27 months (min 6 mm, max 56 mm); 3 recurrences were
      observed, 2 in Lichtenstein "plug" hernioplasty and 1 with the Trabucco
      technique. RESULTS: No recurrences were observed in Lichtenstein "mesh"
      hernioplasty group. CONCLUSIONS: Lichtenstein "mesh" hernioplasty can solve every
      anatomical situation in hernia recurrence and good results, with little or any
      complications, are achievable; "plug" technique is easier but recurrences in
      other sites of a weak inguinal wall are possible.

PMID- 10575893
TI  - [Open versus laparoscopic treatment in inguinal hernia. Our experience].
AB  - The knowledge acquired in recent years in the field of etiopathogenesis of
      materials for prosthesis and of surgical technics regarding inguinal hernias
      together with a renewed interest for local-regional anesthesia has created a real
      revolution in a field that for almost 100 years had been dominated by the same
      uncontrasted ideas. The fundamental stages in the evolution of surgical technics
      are reviewed as well as the most recent discoveries in the field of biochemical
      textiles and prosthesis available today that have contributed to the development
      of new surgical methods. These, distinguishing between "open" and laparoscopic
      technics, are compared on the basis of the data found in the literature
      concerning recurrence, morbidity, period of convalescence and costs. Personal
      experience concerns the last four years with 632 patients treated, some in
      emergency conditions and others in programmed operations, using the foremost
      methods of "open" surgery but preferring, among these, those that are tension
      free. The follow-up involved 84% of the patients for a period of no less than 18
      months. A reduction of complications and of relapses was obtained: 5-9% in
      traditional operations against 0.5% for those that were tension free. With this
      type of operation the postoperative hospitalization was considerably reduced so
      that 35% of them could fit into the "one day surgery" category. On the basis of
      these results it is stressed that both the laparoscopic technics and the tension
      free technics offer advantages as compared to so called traditional methods;
      however, even though the first type seems to assure a shorter postoperative
      period, there is the inconvenience of higher costs and the necessity of general
      anesthesia.

PMID- 10575894
TI  - [Stromal tumors of the small intestine (GIST). Prognostic differences based on
      clinical, morphological and immunophenotypic features].
AB  - Gastro Intestinal Stromal Tumors (GIST) are rare malignant non-epithelial tumors
      arising from gastro-intestinal tract. They represent the 0.2% of all malignancy
      of this site. Three cases, treated in our Department, are an example of the
      anatomo-clinical features of these tumors. In two cases the clinical features on
      admission were similar to those of acute abdominal pain; in the third one a
      palpable mass rapidly growing was observed. All three patients had surgical
      treatment but survival were quite different. The size of tumor mass in the first
      two cases was 5 cm; one patient was alive after ten years without relapse, the
      second one died five years after with liver metastasis. The third one, with a
      mass larger more than ten centimeters, developed 8 months after surgical
      resection a diffuse local relapse of the disease. The microscopic pattern and the
      lack of epithelial markers allowed to classify them as GIST. All cases were
      tested with S100 protein, smooth muscle actine, and CD-34 antigen. Two cases had
      both smooth muscle and nervous markers, the third resembled a malignant
      schwannoma. Prognosis was correlated with the size of tumor at the time of
      surgery and immunophenotype pattern. The tumors with high expression of nervous
      antigens had a worse prognosis.

PMID- 10575895
TI  - [Cervical esophago-visceral anastomosis with an endoscopic linear stapler. Note
      on a surgical technique].
AB  - The incidence of anastomotic fistula in the neck after esophagectomy and
      esophagogastroplasty may be as high as 30%; the incidence of anastomotic stenosis
      may be as high as 10%. To avoid these potential and sometimes serious
      complications, the authors describe a partially mechanical esophago-visceral
      anastomosis. The esophageal stump is brought near the anterior wall of the
      transposed stomach. A small gastrotomy is performed. An endoscopic linear stapler
      is then inserted in the esophageal and gastric lumen, and fired. The anterior
      wall of the anastomosis is fashioned with a running suture.

PMID- 10575896
TI  - [Pectoris major muscle flap in mammaplasty].
AB  - Due to the late postoperative permanent ptosis recurrence in breast reduction
      and/or mastopexy, the senior author has introduced a new surgical technique using
      the inferior third of the pectoralis major muscle which constructed and fashioned
      according to the anatomo-histological variations. Fixation of this muscle flap to
      the inferior pole of the mammary gland will avoid any future breast ptosis.
      Personal experience with 51 consecutive cases of breast reduction and/or
      mastopexy operated between March 1994 and March 1996 is reported. The procedure
      is illustrated in details; the main indications, late results, limitations and
      possible early and late complications are studied and discussed.

PMID- 10575897
TI  - [Intratumor flowmetry in endometrial carcinoma. Correlation with the tumor
      stage].
AB  - BACKGROUND: To assess the value of intra-tumoral (endometrial) flow as detected
      by color Doppler ultrasound in relationship with negative prognostic factors in
      patients with endometrial carcinoma. METHODS: Fifty-three patients with a
      previous histological diagnosis of endometrial carcinoma were included in the
      study. Transvaginal ultrasound with pulsed color Doppler was performed in order
      to record resistance indexes and vascular density (defined as "high" if > or = 3
      vascular spaces were detectable for any given area). All cases were classified
      according to FIGO after surgery and histology. Prognostic bad factors were
      considered: FIGO stage (> I), tumor grade (> 1), myometrial invasion (> 50%)
      involvement of vascular spaces and lymph node metastasis. RESULTS: Both
      resistance indexes and vascular density in the endometrium related well to more
      prognostic signs. No relationship was found for lymph node metastasis, probably
      justified by the small number of positive nodes (2/27). DISCUSSION: Color Doppler
      ultrasound seems to be a promising technique in pre-surgical staging of
      endometrial carcinoma. Detection of vascular spaces rather than low resistance
      indexes is, in personal experience, more significantly related to advanced
      disease. It is hypothesized that long term follow-up of these patients can show a
      predictive value of Doppler ultrasound on the outcome of the disease.

PMID- 10575898
TI  - [Severe preeclampsia. Appropriate management and socio-cultural factors].
AB  - BACKGROUND: Preeclampsia in its severe form is characterized by a high incidence
      of both maternal and fetal morbidity and mortality. Its prevention is therefore
      one of the fundamental goals of modern obstetrics. METHODS: Twenty-two women with
      severe preeclampsia have been perspectively examined and compared with 66 women
      without preeclampsia with the aim to evaluate the effect of the prenatal care and
      the influence of sociocultural variables. RESULTS: Differences between the two
      groups weren't observed with regard to sociocultural features, but the women with
      severe preeclampsia were treated later and less controlled during pregnancy.
      CONCLUSIONS: Preeclampsia requires a careful surveillance and an intense care,
      above all in its severe form, to avoid the high tribute of maternal and fetal
      complications that this syndrome still causes today.

PMID- 10575899
TI  - [Frequency and practice of prescribing prenatal HIV tests during pregnancy].
AB  - BACKGROUND: To assess frequency and practices of antenatal HIV testing. METHODS:
      Cross-sectional study. Site: obstetric units of San Paolo Hospital, Milan
      (teaching, public, 60 beds, 1500 deliveries/years, reference centre for HIV and
      pregnancy) and of Sandro Pertini Hospital, Rome (public, urban, 36 beds, 1500
      deliveries/year). PARTICIPANTS: parturients consecutively admitted for delivery,
      in the last three months of 1997. INTERVENTION: interview by a structured
      questionnaire. Out-comes: frequency and practices of antenatal HIV testing.
      RESULTS: About 79% of the 500 parturients admitted at the San Paolo Hospital and
      57% of the 300 at the Pertini Hospital had been tested for HIV during the current
      pregnancy (p < 0.001). Overall, in 91% of cases (507/555) the test has been
      requested by the woman's gynecologist with other antenatal tests. Discussion on
      HIV testing, infection and pregnancy lasted less than 5 minutes in 92% of San
      Paolo parturients, and in almost all (99.4%) of the Pertini women. Women in the
      San Paolo hospital had HIV information available by leaflets in 47% of cases in
      comparison to 35% of those at the Pertini hospital. CONCLUSIONS: In Italy, HIV
      testing seems to be routinely included in the management of pregnancy, although
      the uptake and practices of offering the test seem not always appropriate. The
      higher uptake and the better practice seem to correlate with the higher
      involvement of San Paolo hospital in the fields of HIV infection in pregnancy.
      However, the reported overall 71% of tested parturients suggests that in Italy we
      are still far away from a universal antenatal HIV testing. Specific guidelines
      should be issued in order to implement and to uniform universal antenatal HIV
      testing, and to optimize the management of infected women.

PMID- 10575900
TI  - [Impact of counseling on the sexual habits and reproductive decisions in HIV-1
      positive subjects].
AB  - BACKGROUND: To assess the results of counselling on sexual behavior and
      reproductive choices of couples discordant for HIV-1, in South-Eastern Italy.
      SETTING: University Hospital, Apulia region, South-Eastern Italy. METHODS: In the
      period March 1985-December 1995, one hundred and forty-four HIV-1 discordant
      couples were enrolled. They were followed up for a median period of 39 months
      (range 12-60 months). Behavioural counselling was performed at each visit of the
      infected case and the sexual partner was periodically tested for HIV-1
      antibodies. RESULTS: Sixty percent of couples pursued in unprotected sex
      intercourse, 30 new infections being diagnosed during the study period
      (cumulative incidence rate = 21%). In addition, 49 pregnancies in 38 women were
      recorded. Termination was very seldom the choice of pregnant women. CONCLUSIONS:
      There is a clear indication for a failure in the counselling process. A change in
      population characteristics is to be pointed out as the main factor of the
      results. More appropriate counselling modalities need to be introduced for the
      different targets of sexual behaviour of our population.

PMID- 10575901
TI  - [Determinant factors for the use of screening for cervical cancer in Friuli
      Venezia Giulia].
AB  - BACKGROUND: To describe the determinants of missed or irregular Pap-test.
      METHODS:  DESIGN: cross-sectional descriptive study. SETTING: Trieste province
      (urban) and San Daniele district (mostly rural). SUBJECTS: 294 (89%) out of 332
      (83%) women interviewed from a simple random sample of 400 women 25 to 64 years
      of age. INTERVENTION: none. DATA COLLECTION: planned telephone interview with a
      pre-tested questionnaire. RESULTS: 256 (87%) women had a Pap-test at least once
      in their life, 169 (57%) in the last two years. The 222 (76%) women with a Pap
      test in the last five years know where and when, but not how often. The
      gynaecologist recommended the test in 63% of cases; only 23 women were informed
      by their general practitioner and only 8 decided the Pap-test based on this
      information. Fifty-three percent had the Pap-test always in the same health
      facility; the decision to change was related mainly with long waiting lists (18%)
      and distance (16%). In San Daniele district private health facilities were
      preferred to public ones more than in Trieste (48% vs 20%; p < 0.0005). Among
      women with regular Pap-test, 36% had higher education vs 23% among women with
      missed or irregular test (p = 0.05). The main reported reason for missed or
      irregular Pap test was inadequate information, followed by deficiencies in the
      quality of services. CONCLUSIONS: The Pap-test rate was higher than expected. The
      small number of women with missed or irregular Pap-test (66/294; 22%) does not
      allow to draw firm conclusions about the reasons for non use, though these seem
      to be similar to those already reported in the literature, i.e. lack of adequate
      information. A regional programme, including standard methods of assessment of
      coverage, would lead to increased regular use of this screening.

PMID- 10575902
TI  - [Phytoestrogen-containing food and prevention of postmenopausal osteoporosis and
      cardiovascular diseases].
AB  - Food phytestrogens and prevention of postmenopausal osteoporotic and
      cardiovascular disease. Phytestrogens are diphenolic compounds, widely found in
      plants and foods, with structural and biological estrogen-like similarities.
      Their anti-estrogenic effects are well known and studied due to the possibility
      to prevent some tumors such as breast and prostate cancer. In menopause they have
      an estrogenic-like action on lipidic and bone metabolism. Phytestrogens rich
      foods can positively affect the postmenopausal osteoporotic and cardiovascular
      pathology.

PMID- 10575903
TI  - Treatment of vaginal vault prolapse with abdominal sacral colpopexy using prolene
      mesh.
AB  - BACKGROUND: We report our experience on abdominal sacral colpopexy (CSP) with a
      prolene mesh in women with vaginal vault prolapse. METHODS: From 1994 to 1997 15
      patients (average 57 years), underwent CSP. All patients suffered from a serious
      vaginal vault prolapse. Eight of them also had a uterine prolapse. Seven patients
      had already been operated for hysterectomy (5 vaginal, 2 abdominal). Four of them
      had already been operated for urinary incontinence: (3 Raz, 1 Burch). In 6 cases
      we have a colposuspension according to Burch associated with CSP. Average follow
      up was 15 months. RESULTS: All the patients have carried a bladder catheter for 4
      12 days (average 5 days). The patients who were sexually active have begun having
      normal sexual intercourse again. Neither relapses of the treated prolapses, no
      infections or rejections of the prosthesis have been verified. In 1 patient
      pollakiuria insensitive to anticholinergics has persisted. Four patients have
      complained of hypogastric "sense of weight", without any clinical evidence of
      pathology. CONCLUSION: Our survey confirms the information and the good result of
      this technique in the treatment of the total vaginal dome prolapse, also in
      comparison with our operations for sacrospinosous ligament fixation. This kind of
      treatment through the vagina, is not always possible, above all after
      hysterectomy with a very short vagina.

PMID- 10575904
TI  - [Use of the TUT (Tension-free Vaginal Tape) in the treatment of female urinary
      stress incontinence. Preliminary results].
AB  - BACKGROUND: The Tension-free Vaginal Tape (TVT) represents the most recent
      technique for the treatment of genuine stress urinary incontinence (GSUI). The
      various number of surgical procedures proposed for the treatment of GSI very
      often do not lead to a complete remission of this pathology. The data from the
      literature show how TVT is a effective procedure for the treatment of female
      urinary incontinence. METHODS: Twenty-nine women with diagnosis of urinary
      incontinence underwent application of polypropilene band (TVT: tension-free
      vaginal tape) underneath the uretra, in order to treat this disorder. The
      procedure has been carried out in peripheral anesthesia. RESULTS: A complete
      remission of the urinary incontinence was obtained in 24 patients. In the
      remaining cases there was an improvement of the symptoms in two patients, whereas
      in two patients remained a secondary detrusor instability. In one case the
      external iliac vein was perforated thus requiring a surgical repair. CONCLUSION:
      The short surgical time, the feasibility of the procedure and the following short
      hospitalization made this technique well accepted either by the surgeons ang the
      patients. Moreover the possibility to carry out the procedure in peripheral
      anesthesia allows to have the collaboration of the patient. However this
      technique is not free of risks, how the serious complication we had can
      demonstrate.

PMID- 10575906
TI  - Vitamin E, a modifier of platelet function: rationale and use in cardiovascular
      and cerebrovascular disease.
AB  - Vitamin E has emerged as a major factor in the prevention and inhibition of
      cardiovascular disease. The inhibition of platelet function, especially adhesion,
      which is an important event in the development and propagation of cardiovascular
      disease, plays a crucial role in the beneficial effect that vitamin E exerts on
      such diseases. Although it is best known for its antioxidant activity, vitamin E
      interferes with platelet adhesion via a mechanism that is independent of this
      action. Vitamin E-induced inhibition of protein kinase C leads to decreased
      platelet pseudopodia formation upon stimulation by agonists, a process that is
      instrumental in reducing platelet adhesion. In conjunction with potent inhibitors
      of platelet aggregation, vitamin E has become a widely applied treatment regimen
      for this group of diseases. Increased bleeding, especially when vitamin E is
      combined with a potent platelet aggregation inhibitor, has to be considered a
      side effect of its mechanism of action, but should not detract from the potential
      benefits for the majority of patients who take this vitamin.

PMID- 10575905
TI  - Plasma homocysteine as a cardiovascular risk factor: causal, consequential, or of
      no consequence?
AB  - Elevated plasma total homocysteine may be causally related to the risk of
      atherosclerotic cardio-vascular diseases. Many significant studies indicate an
      effect by elevated homocysteine on cardiovascular disease occurrence,
      progression, and recurrence that is independent of traditional risk factors.
      However, recent data have cast doubt on the veracity of the relationship between
      elevated plasma total homocysteine and the incidence of cardiovascular disease.
      In general, a stronger relationship has been found in cross-sectional and
      retrospective case-control studies than in nested case-control or prospective
      studies. The issues of study design, bias, and confounding are critical to an
      analysis of this putative relationship, and their effects can only be avoided by
      randomized controlled trials of homocysteine-lowering therapy (folic acid). While
      awaiting the outcome of these trials, there may already be sufficient evidence to
      prescribe homocysteine-lowering therapy in subjects deemed to be at high risk of
      cardiovascular disease.

PMID- 10575907
TI  - Alcohol and ischemic stroke.
AB  - Stroke mortality represents the third leading cause of death after coronary
      artery disease and all cancers. Various studies have reported a protective effect
      of light to moderate alcohol consumption on ischemic stroke risk. The
      relationship between alcohol and ischemic stroke risk appears to be causal.
      Potential mechanisms and recommendations for daily practice are discussed.

PMID- 10575908
TI  - Folate and cancer prevention: a new medical application of folate beyond
      hyperhomocysteinemia and neural tube defects.
AB  - Folate is an important cofactor in the transfer of one-carbon moieties and plays
      a key role in DNA synthesis, repair, and methylation. The role of folate has
      greatly evolved from the prevention of macrocytic anemia to the prevention of
      cardiovascular disease and neural tube defects. More recently, epidemiologic,
      animal, and clinical evidence suggests that folate may also play a role in cancer
      prevention. Two recently published large, prospective epidemiologic studies
      suggest that maintaining adequate levels of serum folate or moderately increasing
      folate intakes from dietary sources and vitamin supplements can significantly
      reduce the risk of pancreatic and breast cancer, respectively. This protective
      effect of folate appears to be operative in subjects at risk for developing these
      cancers, namely, male smokers for pancreatic cancer and women regularly consuming
      a moderate amount of alcohol for breast cancer. Because the expanding role of
      folate nutrition in cancer prevention has major public health implications,
      research is required to clearly elucidate the effect of folate on carcinogenesis.

PMID- 10575909
TI  - Antioxidants and breast cancer.
AB  - A recent prospective study found that consumption of fruits and vegetables high
      in specific carotenoids and vitamins reduced breast cancer risk among
      premenopausal women. This observed protection might not be due to the
      anticarcinogenic mechanism of a single nutrient. Further prospective studies
      relating blood and dietary micronutrients to breast cancer risk are warranted.

PMID- 10575911
TI  - Giving a bad name to a perfectly good nutrient.

PMID- 10575910
TI  - The molecular mechanism of the stimulation of adipocyte differentiation by a
      glucocorticoid.
AB  - The glucocorticoid dexamethasone (dex) stimulates differentiation of cultured
      preadipocytes of the 3T3-L1 cell line to adipocytes. The preadipocytes express a
      gene termed preadipocyte factor 1 (pref-1). The pref-1 gene product is abundant
      in preadipocytes but completely absent in adipocytes. Constitutive expression of
      pref-1 blocks differentiation of adipocytes, as does a soluble 50 kDa fragment of
      the pref-1 protein. It appears that dex mediates adipogenesis by down-regulating
      expression of pref-1.

PMID- 10575912
TI  - [Reinfection with Helicobacter pylori in patients with duodenal ulcer after
      successful eradication].
AB  - The study was performed in 224 patients with exacerbated chronic duodenal ulcer
      and with Helicobater pylori (H. pylori) infection. The infection was confirmed by
      histological techniques and rapid urease test. The patients were treated randomly
      with one of the triple therapies: 1) omeprazole with amoxicillin and
      clarithromycin, 2) omeprazole with clarithromycin and metronidazole or 3)
      colloidal bismuth with amoxicillin and metronidazole and after eradication the
      antiulcer drug was continued for 4 weeks. The control endoscopy was performed 6
      weeks after the beginning of the therapy and during two-year follow-up. The ulcer
      healing, macroscopic and microscopic appearance of the gastric mucosa and H.
      pylori infection was examined. Endoscopy was repeated 1 and 2 years after
      successful eradication. The ulcer was healed in 93%, 95% and 92% of patients from
      groups I, II and III, respectively, and eradication of H. pylori was seen in 83
      90% of cases. The treatment significantly diminished the chronic active
      gastritis. During 1- and 2-year follow-up the ulcer recurrences were observed in
      5.3% and 13% of patients and reinfection in 7.7% and 16.7% of cases. The ulcer
      recurrences appeared in patients with H. pylori infection. The H. pylori
      reinfection rate was higher than observed in western countries.

PMID- 10575913
TI  - [Primary gastrointestinal lymphomas].
AB  - The paper presents clinical signs, diagnosis, treatment and therapeutic results
      in the group of patients with a primary gastrointestinal lymphomas. All of the
      patients had a surgical procedure: 5 of them were operated on according to a
      fixed plan and 3 had an emergency operation. 6 patients were subjected to
      chemotherapy and radiotherapy. The patients were analyzed along with the obtained
      therapeutic results.

PMID- 10575914
TI  - [H"urthle cell thyroid neoplasms].
AB  - The paper presents up to date knowledge about oncocytic neoplasms (Hurtle cell
      tumor). The following paper is based on the biggest study group in Poland. Most
      of these tumors were benign. The histopathological diagnosis was usually very
      difficult. The authors pointed out that the most important problem in the
      treatment process was the histopathological examination. Even intraoperative
      pathological diagnosis is not discriminative for the diagnosis. All diagnoses
      were based on paraffin-embedded samples examination. In the authors' opinion
      treatment process should be individualised according to all clinical and
      histopathological results.

PMID- 10575915
TI  - [The influence of shunt surgery on the improvement of cognitive disorders in
      hydrocephalic patients].
AB  - We present 43 cases with cognitive disorders due to communicating hydrocephalus
      assessed by means of neuropshychological tests before and 4-8 months after shunt
      treatment. The patients were the part of the 95 hydrocephalic cases (45.3%)
      operated on in the period of 1993-98 at the Department of Neurosurgery in Krakow.
      Cognitive functions improvement was detected in 81.4% cases, no changes in 7%,
      and deterioration in 11.6%. Most often the improvement of lingual function, short
      memory and attention was noted. The worst prognosis for the prediction of
      improvement of the cognitive functions had the patients with significant cerebral
      atrophy, and those with symptoms lasting over 1 years.

PMID- 10575916
TI  - [Adaptation of computed tomography and roentgenography to bone density
      measurements].
AB  - The increasing interest in issues connected with osteoporosis has recently caused
      the development of many new diagnostic methods which allow the measurement of
      bone density. The DEXA method, performed by specialised densitometers, is one of
      the most developed and reliable methods. However, the high cost od densitometers
      and DEXA investigation prevent this method from becoming easily accessible for
      everyday diagnosis. The adaptation of computerised tomography and rentgenography
      to densitometric measurements could be one of the methods by which the problem of
      densitometric diagnosis accessibility could be solved. Both methods are usually
      applied in the imaging of human tissues, working on the basis of differences in
      tissue X-ray absorption. X-ray absorption and density are related by linear
      function in the energy range used in rentgenography and tomography; therefore,
      quantitative information concerning density should be easily received. The
      procedure adapting computerised tomography and rentgenography to quantitative
      measurements of bone density in the lumbar spine is outlined in this work. The
      quantitative information is obtained from digitalised tomographic and
      rentgenographic images through use of a personal computer. Both methods were
      tested using a set of phantoms imitating the lumbar spine and the surrounding
      tissues. The precision and accuracy of both methods were assessed and compared to
      the precision and accuracy of the DEXA method. The outlined results confirm the
      usefulness of the described method in diagnosis.

PMID- 10575917
TI  - [Controversies introduced by a modern system of palliative care based on a four
      year experience at the Center of Palliative Care, Care and Treatment Clinic in
      Cracow].
AB  - During four years of activity Palliative Care Centre in Cracow treated 821
      patients. 624 died, mainly at home-482, (75%). During that time patients were
      visited at home 5034 times and in Out patient Clinic 3453 times. Author analysed
      numerous controversies which were met in contact of palliative care with other
      specialisations of medicine.

PMID- 10575918
TI  - [Palliative care as an optimal procedure for terminal neoplastic diseases].
AB  - In about 60% patients of oncological diseases have unfavourable course and
      patients have many serious symptoms. Author tries to present principal directions
      of palliative care which proposes a new model of the treatment of oncological
      patients.

PMID- 10575919
TI  - [Aplastic anemia--contemporary procedures and therapeutic perspectives].
AB  - Severe aplastic anaemia (SAA) state of art is summarised. Currently there are two
      therapeutic possibilities: allogeneic bone marrow transplantation (BMT) and
      immunosuppressive therapy. Decision should be based on disease severity, patient
      performance status, age and the availability of the HLA identical donor.
      Allogeneic BMT is the treatment of choice for the young (less than 25 years) SAA
      patients. It's side effects including graft versus host disease markedly increase
      with age. Immunosuppressive therapy is an option for patients older than 45, or
      younger ones with no HLA compatible donor. Optimisation of the treatment
      protocols is the subject of various ongoing randomised multicentre studies.

PMID- 10575921
TI  - [Hyperhomocysteinemia in chronic renal failure].
AB  - Cardiovascular disease constitute the main cause of death in chronic renal
      failure patients on maintenance dialysis. During the last years one of the
      suspected cause promoting atherosclerotic lesions in this group of patients has
      been increased plasma homocystein level. The following article presents selected
      causes of hyperhomocysteinemia in chronic renal failure patients, mechanism of
      their toxic effect on cardiovascular system and methods of treatment of these
      disturbances.

PMID- 10575920
TI  - [Flow cytometry in hematologic diagnosis].
AB  - The paper presents flow cytometry method in haematology diagnostics. Beside to
      the estimation of blast cells phenotype in acute leukaemia, flow cytometry allows
      to evaluate the presence of minimal residual disease (MRD) and multi drug
      resistance protein (MDR). Flow cytometry plays a crucial role in the estimation
      of DNA profile in cancer cells and evaluation of stem cells. Repeatedly flow
      cytometry is used to estimate platelets and reticulocytes.

PMID- 10575922
TI  - [Pain response and measurement in infants].
AB  - Medical recognition of infant pain has been based on several complex
      misunderstandings. It should be no longer controversial that newborns in manner
      similar to other infants, have the ability to recognize painful insults and
      respond to them. Now it is accepted that a functional response to various stimuli
      by several neuropathways and both anatomic and physiologic, peripheral and
      central connections between sensory neurons and central nervous system occur
      relatively early in fetal life. Incoming painful stimuli may be influenced by
      several different neuromediators. It is accepted that three broad areas of pain
      measurement in the infant can be used. Behavioural responses, i.e. a marked
      change in the facial expression and crying, have been described as part of the
      infant response to noxious stimuli. They are related to the degree of stress and
      pain. The infants have the same as adults neurochemical disturbances associated
      with physiologic stress. Hormonal responses may perturb developmentally fragile
      glucose homeostasis and increase protein catabolism. The physiological
      consequences are changes in heart rate, respiration, blood pressure, peripheral
      and central vascular perfusion and various gastrointestinal functions. Because
      pain is associated with a risk of several physiologic changes these adverse
      effects should be blunted by appropriate analgesia.

PMID- 10575923
TI  - [Imaging of kidney fibro-lipomatosis].
AB  - The purpose of this study is to promote a deeper understanding of problems
      connected with the issue of fibrolipomatosis among a large number of physicians.
      This pathology is of a great importance in the diagnostic process, both due to
      its high incidence rate, and to the fact that in some cases it imitates diseases
      that require surgical intervention. Kidney fibrolipomatosis is well-known to
      radiologists, but other specialists' knowledge of this pathology is rather
      limited. The prevalence of abdominal cavity US examinations, performed by various
      specialists, makes it necessary to draw physicians' attention to this disease.

PMID- 10575924
TI  - [Mediators of the inflammatory response in the course of acute pancreatitis].
AB  - Acute pancreatitis (AP) is one of the most frequent causes of acute inflammatory
      states in the abdominal cave. In majority of cases the disease, if properly
      treated, has a selflimiting course and terminates in several days. However, in
      about 20% of patients with diagnosed AP haemorrhagic and necrotic lesions of the
      pancreas occur what effects in multiple organ injury and high mortality of these
      patients. Early diagnosis of haemorrhagic and necrotizing outcome of the disease
      is difficult, therefore new markers of necrotizing acute pancreatitis are still
      under research. Cytokines mediating inflammatory process may provide some
      specific information on the expected outcome of acute pancreatitis. Article
      reviews the information about the role of inflammatory cytokines in development
      and outcome of acute pancreatitis.

PMID- 10575925
TI  - [Unusual complication in the course of acute pancreatitis].
AB  - Rare neurological complication in course of severe acute pancreatitis was
      described. A 38-year old woman developed Multiple Organ Dysfunction Syndrome
      ((MODS) and neurological complications such as transient encephalopathy and
      polineuropathy in a form of tetraplegy.

PMID- 10575926
TI  - [The development of non-Hodgkin's lymphoma during the course of autoimmune
      diseases. Five case reports].
AB  - The development of five of non-Hodgkin lymphomas during the course of autoimmune
      diseases was presented. The treatment methods of autoimmune disease included:
      irradiation steroids, non-steroidal anti-inflammatory drugs or immuno-suppressive
      drugs. The time interval between diagnosis of autoimmune disease and lymphoma was
      from 2 to 28 years. High-grade lymphoma was observed in all cases. After
      treatment (irradiation with or without combination with multidrug chemotherapy)
      the complete regression was observed and disease-free survival between 16 and 48
      months after treatment was obtained.

PMID- 10575927
TI  - [Acute iatrogenic postrenal failure].
AB  - Urinary tract obstruction is relatively seldom responsible for causing acute
      renal failure. It is also known that the iatrogenic factors account for very
      small percent of all episodes of obstructive renal failure. This report concerns
      a patient with acute renal failure due to improper urinary catheter use. It was
      followed by inattentive and nonchalant examinations taken by urologist in spite
      of the evident symptoms of acute obstructive renal insufficiency. The authors
      emphasize the importance of properly taken patient's history and physical
      examination to prevent patients from fatal courses of diseases. It is also
      sufficient to avoid difficult ethical problems and to protect ourselves from
      unpleasant legal consequences.

PMID- 10575928
TI  - [Christian dimension of suffering].
AB  - Human existence is marked by imperfection, whose expression--among other things-
      is suffering. The problem of answering the question about the meaning of
      suffering for human life in its entirety is of great significance in philosophy
      and theology. In the Old Testament it meant God's punishment for the evil done by
      man. In Christianity this bleak notion of suffering has found a new dimension-
      suffering is creative, redemptive in character; it enables a man to surpass his
      limits. The understanding of suffering and its sense has a profound meaning in
      building a suitable attitude of a sick person towards his own weakness.

PMID- 10575929
TI  - [First trials of inhalation-therapy in Poland].
AB  - The gas-therapy unit was founded by professor Oszacki in Cracow's St. Lazarus
      Hospital in 1937. This was the beginning of the new therapy, well known in West
      Europe. Well equipped and modern provided unit worked nearly two years. In 1939
      the oxygen explosion and subsequent fire completely destroyed it. In this
      accident three young doctors died. The Second World War interrupted further
      development of this new therapy.

PMID- 10575930
TI  - [The history of Jan Gwiazdomorski's "Health House" in Cracow].
AB  - Dr Jan Gwiazdomorski founded the first infirmary that was called Health House in
      Cracow in 1883. In the begining its addresses was No 39 Karmelicka Street, and in
      1889 it was moved to No 1 Siemiradzkiego Street. Surgical, ginecological,
      obstetric and other patients were admitted there except those suffering from
      contagious diseases and mental disorders. After its founder's death, "Dom
      Zdrowia" was taken over by surgeon Maksymilian Rutkowski and gynecologist Bruno
      Wojciechowski who adapted it for new patient's needs. In Health House more than
      30 patients could be hospitalized. Before World War I Rutkowski withdrew from the
      partnerschip. Wojciechowski became the sole owner of the hospital. After his
      death it became the property of the Sedzimir's. During the Nazi occupation it was
      managed by Marian Mossler. After the war it was nationalized in 1950 and turned
      onto the Station of Ambulance Service.

PMID- 10575931
TI  - [XXXV National Congress of the Spanish Society of Cardiology. Seville, 13-16
      October 1999. Abstracts].

PMID- 10575932
TI  - [Secondary prevention of cardiovascular diseases is a priority, yet the results,
      so far, are insufficient].

PMID- 10575933
TI  - [Evolution of epidemiological methods in clinical research in Spain (1975-1994)].
AB  - BACKGROUND: Previous studies have shown a sparing utilization of analytical and
      experimental designs in Spanish clinical research journals. The study aims are to
      compare among countries, the use of epidemiologic method in articles published in
      scientific journals, and to determine the extent to which this research has
      direct funding. METHODS: Cross-sectional study including all original papers
      published during 1994 in Medicina Clinica [(Med Clin (Barc)], Revista Clinica
      Espanola (Rev Clin Esp), The Lancet (Lancet) and New England Journal of Medicine
      (N Engl J Med). They were classified according to epidemiological design and we
      verified the financial support mention. RESULTS: 594 papers were included.
      Epidemiological studies without control group prevailed in Spanish journals. The
      most common designs were descriptive studies in Med Clin (Barc), with 45.5%, and
      clinical series in Rev Clin Esp, with 41.7%. The 33.6% of original papers
      published in Lancet and 28.4% of N England J Med were randomized trials. We found
      information about financial support in 73.7% of papers published in Lancet, in
      77.4% of N Engl J Med, in 23.1% of Med Clin (Barc) papers and not one in the Rev
      Clin Esp studies. CONCLUSIONS: In Spanish clinical journals the use of
      epidemiological methods with control group is limited and direct financial
      support unusual. Wherefore these studies have a limited applicability.

PMID- 10575934
TI  - [Community effectiveness of vaccines against infectious parotiditis (mumps).
      Report of cases].
AB  - BACKGROUND: In our country, there are two types of infectious mumps vaccines
      available. In recent times, doubts have been raised regarding the overall
      effectiveness of these vaccines and the comparative effectiveness of the two
      strains (Rubini strain and Jeryl Lynn strain). In the "East Seville" Primary Care
      district, 245 cases were reported in 1997 (90.1 cases per 100,000 inhabitants).
      This study is aimed at taking advantage of the outbreak of cases of mumps to
      evaluate affected populations and comparative incidence according to type of
      vaccines given during childhood. METHODS: Descriptive analysis of the cases (age,
      territorial spread, inoculation history') and trend analysis (annual incident
      rates) within this health care district and the surrounding area. The overall
      effectiveness of the mumps vaccines. The case incidence rates among those
      inoculated with Rubini strain and those inoculated with Jeryl Lynn strain are
      also estimated. RESULTS: The highest rates of incidence are found among children
      in the 1-4 age range. Overall effectiveness rates for these vaccines have been
      estimated. A significantly higher rate of infection has been found among the
      children inoculated with Rubini strain than those inoculated with the Jeryl Lynn
      strain (relative risk of 6.5 with a Confidence Interval of 95% 3.6-11.8).
      CONCLUSIONS: The effectiveness which follows from this study does not seem as
      good as the theoretical effectiveness anticipated for the mumps vaccines. It thus
      seems advisable for other case studies to be conducted by types of vaccines used.
      The data to be furnished by means of sero-epidemiological studies are also of
      major interest.

PMID- 10575935
TI  - [Validity of the Hospital Emergency Suitability Protocol].
AB  - BACKGROUND: Different studies rate the proportional number of visits unsuited to
      the HER services at 20%-80% of all. This wide range is due, in good part, to no
      consensus existing as to the definition of the term "emergency" and the ideal
      degree of assistance for dealing with each possible situation which leads to the
      use of subjective judgments for evaluating unsuitability. The purpose of this
      study is that of developing and validating an objective tools for pinpointing
      unsuitable hospital emergencies. METHOD: Based on a conceptual framework which
      included as dimensions the seriousness of the clinical condition of the patient
      in question, the intensity of the services rendered and some situations which
      would warrant spontaneous visits being suitable, the Hospital Emergency
      Suitability Protocol (HESP), a tool entailing explicit criteria for assessing the
      suitability of the visits to the HER's, and a random sample of 100 emergency room
      clinical histories, the reliability thereof of observers on an individual and
      group basis and the validity of judgment and predictive validity thereof as
      regarding the opinion of experts having been analyzed. RESULTS: The HESP revealed
      itself to provide an excellent reliability rate of observers on an individual and
      group basis (indexes of agreement fond of 99%-100%; kappa statistic of 0.97
      1.00), and judgment validity on the borderline between moderate and low (index of
      agreement found of 68%, kappa statistic 0.39). This low level of agreement is due
      to the fact that the HESP functions like a highly specific (the inappropriate
      cases accord to the clinical judgment are evaluated as inappropriate) yet not
      highly sensitive tool (solely 59% of the cases which the HESP considered to be
      suitable were evaluated as such by the clinical judgments). CONCLUSIONS: The HESP
      acts as a highly reliable tool capable of pinpointing the most clearly unsuitable
      fraction of the inappropriate visits to the HER's. These characteristics make it
      useful for drawing comparisons among hospitals and for long-range follow-up or
      monitoring of actions for lowering the percentages of unsuitable use.

PMID- 10575936
TI  - [Analysis of the cohort effect on the trend in mortality from motor neuron
      disease in Spain, 19551-1002].
AB  - BACKGROUND: An increase in the mortality due to motor neuron disease (MND) has
      been reported in Spain over the past 30-40 years. It has been suggested that this
      increase is due to the cohort effect, but his hypothesis has not been proven.
      METHODS: The motor neuron disease (MND) mortality statistics by age and by gender
      were furnished from the Spanish National Institute of Statistics. The mortality
      specifically by age and the adjusted age-related rates were calculated. By
      Poisson regression, the cohort effect of birth on the mortality by ages has been
      analyzed, the cohort effect also having been analyzed by graphic methods.
      RESULTS: The mortality adjusted by age was declining up until 1969, as of which
      time it has been on the rise. Each five-year birth cohort increases the risk of
      dying from MND by 8.5%. CONCLUSIONS: The increase in the mortality due to MND in
      Spain is the result of a cohort effect.

PMID- 10575937
TI  - [Knowledge, beliefs and attitudes of the female population towards cancer in
      Mallorca].
AB  - BACKGROUND: To analyze the knowledge of the facts on the part of the female
      population of Mallorca with regard to the causes of cancer, the beliefs regarding
      diagnosis and treatment and their attitude toward prevention. METHODS: A
      descriptive cross-section study of a random population sample (n = 124) of women
      within the 40-69 age range. The questionnaire includes socio-demographic
      variables, risk factors, early warning symptoms and beliefs regarding diagnosis
      and treatment and attitudes toward prevention. RESULTS: Cigarette smoking (92.7%;
      CI:88.1-97.3) and drinking alcoholic (85.7%; CI:79.4-92.0) are the most well
      identified causes. Also the presence of a lump in the breast (92.6%; CI:87.9
      97.2) and changes in a mole or wart on the skin (89.7%; CI:84.2-95.2%). The
      underestimate the role of the diet (44.4%; CI:35.1-53.8) and overestimate the
      environmental factors. The knowledge and use of self-examination procedures on
      the breast are associated directly with the degree of education (p < 0.05). Most
      believe that early diagnosis improves the prognosis (IC:94.2-99.5) and that
      treatment is beneficial (85.2%; CI:78.5-91.9). They consider surgery to be the
      most highly effective method, and in the event of any doubt they would first see
      their primary care physician (41.9%; CI:33.2-50.6). It is mainly older women
      having a low level of completed schooling who get their information regarding
      cancer above all from the television (43.5%; CI:34.8-52.3). Worthy of special
      mention is the very small impact of health care personal as a source of
      information (6.5%; CI:2.1-10.8). CONCLUSIONS: A major knowledge of the facts
      exists regarding the causes and warning signs, although some misconceptions do
      exist. In view of future prevention campaigns, educational measures addressed
      mainly to older women having a low level of completed schooling should be carried
      out.

PMID- 10575938
TI  - [The diet of 13-year-old students in the city of Saragossa].
AB  - BACKGROUND: The importance of diet as a cause of different diseases and the
      possibility of educational involvement during the school-age years leads to it
      being advisable to ascertain the attitudes of young people with regard to
      nutrition and their eating habits. METHODS: Cross-section study. A self-test
      survey was conducted regarding the nutrition-related habits and knowledge on a
      sample randomly taken from among 543 students from the 1st level school-leaving
      certificate studies (age 13) in the city of Saragossa, including an assessment of
      the foods eaten by means of 24-hour recall and a questionnaire regarding how
      often different foods are eaten weekly. A pilot study was conducted on 50
      individuals, with validation by means of personal interviews in 15 cases.
      RESULTS: A total of 516 questionnaires were analyzed. The subjects were found to
      possess an average degree of knowledge regarding nutrition-related matters. A
      total 41.5% of the sample acknowledged advertising having an impact on their
      diet. A greater diet-related impact was found to exist among the females
      analyzed. The eating survey revealed a diet consisting of normal calorie intakes,
      but excessive protein and low carbohydrate intakes, excess fat intake being noted
      among males. An excessive amount of Meat and meat products and Sweets and candies
      was noted, contrasting with the low Grain, Fish and Potato intake. CONCLUSIONS:
      Educational measures must be taken among school-age children with regard to
      informing them concerning the composition of foods and a correct diet, teaching
      them to take a critical stance with regard to food advertising. They must be
      counseled to lessen their intakes of Meats and Sweets and to increase the amount
      of complex carbohydrates and Fish.

PMID- 10575940
TI  - [Eye protection for servicemen under battle conditions by the use of special
      glasses].
AB  - The paper substantiates a possibility of eye protection for military men in
      combat with special glasses and corrective spectacles. It shows that explosive
      shrapnel wounds dominate over the gunshot ones of visual organs. In the
      overwhelming majority of cases they are produced by small splinters with kinetic
      energy less than 18 J. It is found that the high-impact resistant polymeric
      optical material can be used for effective eye protection, which should result in
      a considerable reduction of eye wounds.

PMID- 10575939
TI  - [Adverse reactions and other drug-related problems in an emergency service
      department].
AB  - BACKGROUND: Adverse Drug Reactions (ADR) and Drug-Related Problems (DRP's) are a
      frequency cause of hospital emergency room visits and require better assessment.
      METHOD: An analysis was made of 1097 consecutive admission to the emergency room
      at the Nuestra Senora de los Volcanes, Hospital (currently the General Hospital
      of Lanzarote) in Arrecife de Lanzarote (Canary Islands) over a three-month period
      in order to detect any possible DAR or any other drug-related problems. RESULTS:
      Nineteen (19) of the 1097 admissions were due to Adverse Drug Reactions (ADR)
      (1.73%; 95% IC:0.96%-2.5%). Some of the most outstanding of the other "Drug
      Related Problems" (DRP's) were medication overdose, which was diagnosed in 5
      (0.45%) of the patients; the worsening of the symptoms due to ceasing to take the
      medication was involved in 8 (0.72%), and incorrect treatments which involved
      medical care at the emergency room totaled 11 (1.0%). The number of drug-related
      problems (DRP's) in the sample totaled 43 (3.9%). The drug-related problems
      (DRP's) led to hospitalization in 1.9% of the cases seen in the emergency room
      and led to hospitalization in 9.6% of all of hospital admission through the
      emergency room for the period of time under study. The ADR led to 4.1% of the
      hospital admissions. CONCLUSIONS: Drug-related problems are a frequent, major
      problem which has not been well-analyzed in the emergency rooms. Additionally,
      emergency rooms can function as the first point of detection of a ADR among an
      outpatient population.

PMID- 10575941
TI  - [The role of military medical expertise in preserving the mental health of
      servicemen].
AB  - The authors examine factors of mental dysadaptation, neurotic disorders'
      formation and psychopathy criminal reactions in draftees. An emphasis has been
      made on the clinical and psychological stages of dysadaptation and psycho
      dysadaptation cases of pre-nosolologic levels. Some measures of improvement for
      military-medical panels have been offered.

PMID- 10575942
TI  - [Experience in conducting exercises with a special forces' medical detachment of
      the Urals Military District].

PMID- 10575943
TI  - [Ethical problems in military medical practice].

PMID- 10575944
TI  - [Terrorism: the medical, social and psychological aspects].

PMID- 10575945
TI  - [Surgical care for the wounded in an armed conflict: the organization and support
      of qualified surgical care (2)].

PMID- 10575946
TI  - [Anesthesiological and resuscitation care for the wounded in an armed conflict
      (1)].

PMID- 10575947
TI  - [The organization of the delivery of surgical care to the wounded in a garrison
      hospital reinforced with a specialized surgical team].

PMID- 10575948
TI  - [Noncombat trauma in servicemen in armed conflicts].

PMID- 10575949
TI  - [A comparative analysis and the basic treatment principles in gunshot wounds of
      the face and jaws].

PMID- 10575950
TI  - [The demand for blood transfusion agents and blood substitutes in the treatment
      of wounded patients].
AB  - Modern arms in combat tend to increase sanitary losses, change their structure
      and make combat traumas more severe. Blood transfusion therapy became a necessity
      in the wounds treatment. The recent armed conflicts made military medics move the
      blood transfusion service to the front lines. The authors present some data
      obtained in Afghanistan and Chechnya.

PMID- 10575951
TI  - [The principles of the etiological diagnosis and antibacterial therapy of
      atypical pneumonias].

PMID- 10575952
TI  - [The disinfection of the surgery department of a garrison hospital using a
      neutral anolyte].

PMID- 10575953
TI  - [The laboratory diagnosis of rickettsioses].
AB  - Difficulties in the clinical diagnosis of rickettsiosis and related illnesses
      made it necessary to develop and improve its methods (immunoferment analysis,
      nondirect methods of fluorescent antibodies and polimerase chain reaction).
      Detailed recommendations for diagnosis of Q-fever by the level and growth of
      antibodies of IgG and IgA subclasses.

PMID- 10575954
TI  - [The assessment of age-related limitations in the activities of deep-water
      divers].

PMID- 10575955
TI  - [Citizen, scientist, patriot (on the 150th anniversary of the birth of I. P.
      Pavlov)].

PMID- 10575956
TI  - [Academician A. L. Miasnikov--outstanding Russian therapist (on the centenary of
      his birth)].

PMID- 10575957
TI  - [Outstanding military field therapist (on the centenary of the birth of P. I.
      Egorov)].

PMID- 10575958
TI  - [The 65th anniversary of the military hospital in Komsomol'sk-na-Amure].

PMID- 10575959
TI  - [The 40th anniversary of the Central Medical Laboratory of the Navy].

PMID- 10575960
TI  - Multiplexed automated DNA sequencing directly from single bacterial colonies.
AB  - Sample preparation has been one of the major bottlenecks for large-scale DNA
      sequencing projects in terms of time and cost. To improve sample throughput and
      to integrate the front-end tasks to capillary-array DNA sequencers, protocols for
      directly sequencing the plasmids from a single bacterial colony in fused-silica
      capillaries were developed. After the colony is picked, lysis is accomplished in
      situ in the plastic sample tube using either a thermocycler or a heating block.
      Upon heating, the plasmids are released while chromosomal DNA and membrane
      proteins are denatured and precipitate to the bottom of the tube. After adding
      enzyme and Sanger reagents, the resulting solution was aspirated into the
      reaction capillaries by a syringe pump, and cycle sequencing was initiated. No
      deleterious effect upon the reaction efficiency, the on-line purification system,
      or the capillary electrophoresis separation was observed, even though the crude
      lysate was used as the template. Multiplexed online DNA sequencing data from 8
      parallel channels allowed base calling up to 620 bp with an accuracy of 98%. The
      entire system can be automatically regenerated for repeated operation. By the
      marriage of colony sequencing with the capillary array sequencer, both the front
      end and the back end of DNA sequencing are combined in a miniaturized format.
      This protocol will ultimately reduce the cost of sequencing to well below current
      levels.

PMID- 10575961
TI  - A fiber-optic evanescent wave DNA biosensor based on novel molecular beacons.
AB  - We have prepared a novel optical fiber evanescent wave DNA biosensor using a
      newly developed molecular beacon DNA probe. The molecular beacons (MB) are
      oligonucleotide probes that become fluorescent upon hybridization with target
      DNA/RNA molecules. Biotinylated MBs have been designed and immobilized on an
      optical fiber core surface via biotin-avidin or biotin-streptavidin interactions.
      The DNA sensor based on a MB does not need labeled analyte or intercalation
      reagents. It can be used to directly detect, in real-time, target DNA/RNA
      molecules without using competitive assays. The sensor is rapid, stable, highly
      selective, and reproducible. We have studied the hybridization kinetics of the
      immobilized MB by changing the ionic strength of the hybridization solution and
      target DNA concentration. Our result shows divalent cations play a more important
      role than monovalent cations in stabilizing the MB stem hybrids and in
      accelerating the hybridization reaction with target DNA/RNA molecules. The
      concentration detection limit of the MB evanescent wave biosensor is 1.1 nM. The
      MB DNA biosensor has been applied to the analysis of specific gamma-actin mRNA
      sequences amplified by polymerase chain reaction.

PMID- 10575962
TI  - Characteristics of acoustic plate modes on rotated Y-cuts of quartz utilized for
      biosensing applications.
AB  - Acoustic plate modes (APM) on various quartz substrates have been investigated in
      order to determine their usefulness for liquid-sensing applications. The modes
      have been characterized in terms of their mass sensitivity, mode separation,
      temperature sensitivity, and reproducibility of the experimental results.
      Promising characteristics are found for rotated Y-cuts of quartz with the
      direction of acoustic mode propagation being perpendicular to the X-axis of the
      quartz crystal. Experiments on the detection of immunochemical reactions are
      performed using different quartz APM sensors, and the results are compared to
      similar experiments utilizing APM devices on ZX-LiNbO3.

PMID- 10575963
TI  - Monitoring glutamate and ascorbate in the extracellular space of brain tissue
      with electrochemical microsensors.
AB  - This paper describes electrochemical microsensors for the in vivo measurement of
      glutamate and ascorbate in the extracellular space of brain tissue. To prepare
      glutamate microsensors, carbon fiber microelectrodes (10 microns in diameter and
      300-400 microns long) were modified with a cross-linked redox polymer film
      containing enzymes. The microsensors were coated with a thin Nafion film before
      use. The glutamate microsensors were both selective and sensitive toward
      glutamate, with detection limits in the low micromolar range. Physiologically
      relevant concentrations of several electroactive compounds found in brain tissue
      produced no response at the glutamate microsensors and also did not affect their
      glutamate response, the only exception being glutamine, for which a small
      response was observed in the absence, but not in the presence, of glutamate. The
      ascorbate microsensors were used in conjunction with cyclic voltammetry. They
      were sensitive and selective toward ascorbate, but did exhibit a small
      sensitivity toward the dopamine metabolite, dihydroxyphenylacetic acid. The in
      vivo measurements performed establish the ability of the glutamate microsensors
      to monitor the component of the basal extracellular glutamate level that is
      derived from the neuronal activity of brain tissue.

PMID- 10575964
TI  - Luminol/H2O2 chemiluminescence detector for the analysis of nitric oxide in
      exhaled breath.
AB  - A new instrument for the detection of nitric oxide has been developed and applied
      to the analysis of exhaled breath. The instrument is based on conversion of NO to
      NO2, using the oxidant chromium trioxide, followed by detection of
      chemiluminescence in the reaction of NO2 with an alkaline luminol/H2O2 solution.
      The presence of H2O2 is found to enhance the sensitivity of NO2 detection by a
      factor of approximately 20. A bundle of porous polypropylene hollow fiber
      membranes is used to bring the gaseous sample into contact with the luminol
      solution. Chemiluminescence occurring within the translucent hollow fibers is
      detected using a miniature photomultiplier tube. The limit of detection for NO is
      0.3 ppbv for S/N = 3, and the 1/e response time is 2 s. A large interference
      resulting from the 4-6% CO2 concentration in exhaled breath is removed by use of
      an ascarite scrubber in the air stream. Breath measurements of NO were made using
      a sampling technique developed by Sensor Medics (Yorba Linda, CA) with
      simultaneous detection using the luminol/H2O2 and NO + O3 chemiluminescence
      techniques. The two instruments were found to be in excellent agreement. Nitric
      oxide levels were in the range 6.0-22.0 ppbv for healthy individuals and 40.0
      80.0 ppbv for individuals with asthma or a respiratory infection. This new
      detector offers the advantages of compact size, low cost, and a simple
      configuration compared to NO detectors based on NO + O3 chemiluminescence.

PMID- 10575965
TI  - Carbohydrate analysis of a chimeric recombinant monoclonal antibody by capillary
      electrophoresis with laser-induced fluorescence detection.
AB  - A general method for the analysis of asparaginyl-linked (N-linked) carbohydrate
      moieties of an IgG1 monoclonal antibody is described here. The antibody,
      rituximab, is a mouse/human chimeric antibody to human CD20 antigen. The glycans
      present on rituximab are neutral complex biantennary oligosaccharides with zero,
      one, and two terminal galactose residues (G0, G1, and G2, respectively). To
      monitor the variation of the glycosylation during manufacture, the glycans were
      first enzymatically released from the antibody via digestion with peptide-N
      glycosidase F, then derivatized with a charged fluorophore, 8-aminopyrene-1,3,6
      trisulfonic acid and further separated by capillary electrophoresis with laser
      induced fluorescence detection. All observed glycans were fully resolved,
      including the positional isomers of G1. The exact nature of the isomers in terms
      of the location of the terminal galactose was further characterized via multiple
      enzymatic digestion steps including mannosidase with activity toward specific
      Man(alpha 1,3) linkage. The optimization and several key parameters, i.e.,
      enzymatic digestion and derivatization, in the assay development will be
      discussed. Moreover, to ensure that the assay can be used in routine lot release
      testing, the assay was validated and found to be accurate and precise. The
      analytical approach described is suitable for characterization as well as routine
      testing of the N-linked glycan content in any IgG1 monoclonal antibody and
      glycoproteins in general.

PMID- 10575966
TI  - Column performance and stability for high-speed vacuum-outlet GC of volatile
      organic compounds using atmospheric pressure air as carrier gas.
AB  - The development of lightweight, portable GC instrumentation is handicapped by the
      need for compressed carrier gas to drive the separation. The use of air as
      carrier gas eliminates the need for compressed gas tanks. If a vacuum pump is
      used to pull carrier gas and injected samples through the column, atmospheric
      pressure air can be used as carrier gas. Vacuum outlet operation also improves
      performance for high-speed separations by reducing detector dead time and by
      shifting optimal carrier gas velocity to higher values. Under vacuum outlet
      conditions using atmospheric pressure air as carrier gas, a 6-m-long, 0.25-mm
      i.d. capillary column can generate approximately 12,500 theoretical plates, and a
      12-m-long column can generate approximately 44,000 plates but with a 3-4-fold
      increase in separation time. The principal issues in column selection for high
      speed GC with air as a carrier gas are efficiency and stability. Several bonded
      and nonbonded stationary phases were evaluated for use with air as carrier gas in
      the analysis of volatile organic compounds of interest in airmonitoring
      applications. These include dimethylpolysiloxane, 50% phenyl-50% methyl
      polysiloxane, 50% cycanopropylphenyl-50% methyl polysiloxane, trifluoropropyl
      polysiloxane, poly(ethylene glycol), and dicyanoallyl polysiloxane (nonbonded).
      The dimethyl polysiloxane and the trifluoropropyl polysiloxane columns showed
      good efficiency and no significant deterioration after 5 days of continuous
      operation with air as carrier gas. The 50% phenyl-50% methyl polysiloxane and the
      50% cycanopropylphenyl-50% methyl polysiloxane columns showed poorer efficiency,
      and the poly(ethylene glycol) and dicyanoallyl polysiloxane columns showed
      excessive deterioration in air.

PMID- 10575967
TI  - Synthesis and evaluation of an aromatic polymer-coated zirconia for reversed
      phase liquid chromatography.
AB  - We synthesized a novel aromatic polymer-coated zirconia-based RPLC stationary
      phase by chemical adsorption of a copolymer of chloromethylstyrene and
      diethoxymethylvinylsilane onto zirconia (CMS/VMS-ZrO2). Characterization of the
      pore structure of the support by nitrogen porosimetry and inverse size-exclusion
      chromatography indicates that CMS/VMS-ZrO2 maintains the well-defined pore
      structure of the base material. Flow studies show that CMS/VMS-ZrO2 has good mass
      transfer characteristics. The reversed-phase retention characteristics of the new
      support are comparable to those of conventional silica-bonded phases. We have
      also evaluated the mechanical, thermal, and pH stability of CMS/VMS-ZrO2. The
      results show that CMS/VMS-ZrO2 is stable over a very wide range of pH (pH = 1-13)
      and at temperatures as high as 160 degrees C. Chromatographic separations of some
      low molecular weight aromatic analytes on CMS/VMS-ZrO2 and octadecyl-bonded
      silica phases indicate that there are some subtle but significant differences in
      the chromatographic selectivity of these two types of phases.

PMID- 10575968
TI  - Extraction and isolation of linear alkylbenzenesulfonate and its
      sulfophenylcarboxylic acid metabolites from fish samples.
AB  - Linear alkylbenzenesulfonate (LAS) is the most widely used synthetic surfactant.
      In fish, assessment of the environmental risk and investigation of the
      biotransformation behavior of LAS require compound-specific methods for
      extraction and isolation of LAS and its biotransformation products,
      sulfophenylcarboxylic acids (SPC). Matrix solid-phase dispersion (MSPD)
      extraction with subsequent ion-pair liquid-liquid (IP-LL) partitioning of the
      extract was a time-efficient sample preparation method for analysis of LAS. The
      recovery of parent LAS from spiked fish exceeded 70%, and the limit of
      quantitation ranged around 0.2 mg.kg-1 corresponding to 0.6 mumol.kg-1. In a
      simultaneous determination of LAS and SPC in fish, the analytes were MSPD
      extracted in different fractions. The target compounds were separated from the
      sample matrix by protein precipitation and subsequent isolation of (a) SPC by
      graphitized carbon black solid-phase extraction of the supernatant and (b) parent
      LAS by IP-LL partitioning of the pellet obtained after protein precipitation. The
      recoveries of the model compounds C12-2-LAS and C4-3-SPC were 84 +/- 6 and 65 +/-
      11%, respectively. The use of C3-3-SPC as an internal standard corrected for the
      loss of the biotransformation product during sample workup. The suitability of
      both methods was demonstrated by analyzing fish containing LAS and SPC incurred
      during aqueous exposure.

PMID- 10575969
TI  - Detection of oxygen consumption of cultured adherent cells by bead injection
      spectroscopy.
AB  - This paper describes a method for detecting oxygen consumption of adherent cell
      cultures. The sensing is based on oxygen-dependent quenching of the
      phosphorescence of a Pt-porphyrin complex immobilized on microcarrier beads,
      which are used as the cell culture substrate. Bead injection, a recent variant of
      the flow injection technique, is used to pack an aliquot of the beads into a
      small sensing layer that can be easily and rapidly renewed. The technique is
      tested on a model system of Chinese Hamster Ovary M1 cells grown on Cytodex-3
      microcarrier beads. Cellular respiration is monitored through O2 consumption
      measured across a period of 3 min. The method is validated by detecting the
      impairment of aerobic metabolism caused by 1.5 mM amobarbital. Further, it is
      shown to have enough precision to distinguish even more subtle changes, such as
      the increase in oxygen consumption caused by stimulation of the muscarinic m1
      receptor with 100 microM carbachol.

PMID- 10575970
TI  - High-sensitivity assay for pesticide using a peroxidase as chemiluminescent
      label.
AB  - The application of a newly isolated transgenic tobacco peroxidase (TOP) as a
      chemiluminescent label for immunoassay purposes is described for the first time.
      The enzyme has been oxidized with m-periodate and subsequently coupled to the
      model compound 2,4-dichlorophenoxyacetic acid (2,4-D) using a carbodiimide
      method. As compared to the native horseradish peroxidase used in control
      experiments, the TOP enzyme showed significantly higher efficiency of coupling to
      the antigen and no loss of the specific activity was observed. The obtained 2,4-D
      TOP conjugate demonstrated unique properties in chemiluminescent detection. The
      latter allowed the minimization of the conjugate concentration due to the
      superior chemiluminescent activity of the enzyme. A highly sensitive capillary
      chemiluminescent immunoassay using the 2,4-D-TOP conjugate as labeled competitor
      is reported. Direct competitive ELISA has been performed using a specific
      monoclonal antibody immobilized onto the sol-gel treated glass capillary surface.
      A modified photomultiplier tube with a special holder for a capillary was used
      for the resulting chemiluminescent signal detection. The typical standard
      calibration curve for the 2,4-D pesticide detection is linear between 30 pg and
      500 ng/mL.

PMID- 10575971
TI  - Using the Short Form-36 with multiple sclerosis patients in five countries: a
      cross-cultural comparison.
AB  - Questionnaires measuring health-related quality of life are increasingly used in
      international studies of medical effectiveness. It is important to know if data
      from these instruments are comparable across countries. We initiated a
      collaboration among five research groups--from the USA, The Netherlands, Belgium,
      France, and the UK--in the field of health-related quality of life in multiple
      sclerosis. All groups used the 36-item Short Form Health Survey. The goal of our
      study was to make a cross-cultural comparison. In the five countries under study
      the sample size varied from 50 to 134 patients with multiple sclerosis. The
      survey was completed by a total of 457 patients, who were heterogeneous in
      relation to age, duration of illness, severity and type of multiple sclerosis.
      There appeared to be major differences among the samples in scores on each of the
      eight scales. These findings may be influenced by differences in method of
      recruitment, demographic and disease-related characteristics, administration, and
      cultural factors. After having performed a number of analyses, it appeared that
      the differences were mainly attributable to sampling effects; however, cultural
      influences could not be excluded.

PMID- 10575972
TI  - Rape and physical attractiveness: judgments concerning likelihood of
      victimization.
AB  - Subjects in two studies were shown portraits of 32 young women who varied widely
      in physical attractiveness. Subjects were told that half of these women had been
      victims of a crime and half had not. Their job was to sort the portraits
      correctly into those two categories. In both studies, attractive women were more
      often categorized as victims of rape. In Study 2, attractive women were not more
      likely to be categorized as having been beaten and robbed. Correlation analyses
      showed that the association between physical attractiveness and presumed criminal
      victimization was significantly higher for rape than for being beaten and robbed.

PMID- 10575973
TI  - Manic-depressiveness and its correlates.
AB  - Manic-depressiveness is the name here given to a hypothesized personality
      continuum that has, at one extreme, manic-depressive psychosis. A Manic
      Depressiveness Scale is described, which comprises three scales, Manic
      Experience, Depressive Experience, and the sum of the two, since they are
      correlated. 250 undergraduate psychology students at the University of Adelaide
      and at Goldsmiths' College, London, were administered the Manic-Depressiveness
      Scale along with 12 measures including the Eysenck Personality Questionnaire
      (Revised). Scores on the total Manic-Depressiveness Scale tended (in order of
      size of association) to be correlated with Schizotypal Personality (and three
      subscales), Neuroticism, Magical Ideation, Mystical Experience, Belief in the
      Paranormal, absence of Social Naivete, and Psychoticism. Manic Experience showed
      a pattern of relationships with the above variables broadly similar to that of
      Depressive Experience but included Creative Personality, while Depressive
      Experience included introversion. The relationship between manic-depressiveness
      and schizotypy is discussed.

PMID- 10575974
TI  - The role of social desirability, negative affectivity, and female reproductive
      system symptoms in differences in reporting symptoms by men and women.
AB  - 52 women and 38 men completed the Inventory of Health Status, Version 2, a
      measure of somatic health, and the Cornell Medical Index which provided separate
      scores for somatic and emotional health. The Personal Style Inventory was given,
      from which measures of Social Desirability and Negative Affectivity were
      utilized. Multiple regressions were done separately with scores on the Inventory
      of Health Status and the Cornell Emotional component, and scores on Social
      Desirability, Negative Affectivity, and sex as predictors. Scores on Social
      Desirability and Negative Affectivity were forced into the equation first. For
      the Inventory of Health Status, sex alone contributed significantly to the final
      equation. For scores on the Cornell Index's emotional component both sex and
      scores on negative affectivity had significant beta weights. Analysis of items
      from the Inventory of Health Status was done to examine the role of symptoms
      pertaining to women's reproductive system, and almost all the items that differed
      by sex were either clearly or possibly specific female reproductive items, e.g.,
      "Abnormal menstruation." Similar analyses were not possible for the organic
      component of the Cornell Index, which has different items for reproductive
      systems of men and women. The complexity of the female reproductive system may
      play a central role in sex differences in symptom reporting and perhaps of
      emotional distress, but other interpretations are discussed.

PMID- 10575975
TI  - Alexithymic traits as predictors of difficulties with adjustment in an outpatient
      cohort of expatriates in Tokyo.
AB  - The purpose of this study was to examine whether alexithymic characteristics,
      which are thought to be related to poor coping with stress, would be associated
      with variables thought to reflect adjustment to life abroad. The subjects were 56
      expatriates living in Tokyo, Japan. The Expatriate Adaptation Inventory, the
      Toronto Alexithymia Scale, and the Social Support Questionnaire of the Stress and
      Coping Inventory were given to the subjects. Scores on alexithymia were
      significantly associated with dissatisfaction with life abroad, higher
      satisfaction with life in one's home country prior to departure, and higher
      ratings on the perception of poor social support. An alexithymia variable,
      difficulty identifying feelings, was a significant predictor of dissatisfaction
      with life abroad and satisfaction with life in the home country. The results
      suggest that, because alexithymia was associated with lower satisfaction with
      life abroad and higher satisfaction in the home country prior to departure, it
      may be a predictor of adjustment difficulties when individuals live abroad.
      Empirical confirmation is needed.

PMID- 10575976
TI  - Moderating influence of social support on suicidal ideation in a sample of
      Mexican immigrants.
AB  - The present study explored social support as a moderator in the relationship
      between depression and suicidal ideation in a sample of 104 immigrant Mexican
      American adults. Participants completed the Personal Resource Questionnaire--Part
      2, the Center for Epidemiologic Studies-Depression Scale, and the Adult Suicidal
      Ideation Questionnaire. Ineffective social support and high depression were
      significantly associated with elevated suicidal ideation. Further analyses
      indicated a significant interaction between social support and depression in
      predicting suicidal ideation, thereby suggesting that social support may serve as
      a protective factor against suicidal ideation during the acculturative process.

PMID- 10575977
TI  - Family as a factor in delinquency.
AB  - 50 adjudicated delinquents were given academic and psychological tests and a self
      report of delinquency according to the learning disability/delinquency study of
      the National Criminal Justice Service of 1980. 31 learning disabled delinquents
      were identified. The test of proportions compared learning disabilities in
      delinquent (n = 31) and nondelinquent (ns = 24 and 43) samples. The Mann-Whitney
      U test compared the reported number of categories of delinquent behavior in the
      three groups. A typical delinquent of this rural area tends to be a white male
      with average or above intelligence and a learning disability. His family is
      large; his parents are divorced. He comes from a poorer economic and cultural
      background. A dysfunctional family can be a center wherein delinquency grows; on
      the other hand, a strong family can nurture and protect when peers and school
      fail.

PMID- 10575978
TI  - Measurement of depression in a military sample.
AB  - Using the responses of 250 Navy health care providers, we considered the
      sensitivity and specificity of the SCL-90-R Depression subscale and the Global
      Severity Index in predicting mild, moderate, and severe depression in a deployed
      military sample. Using the 90th percentile norms to identify caseness for both
      measures, each performs with 100% certainty in ascertaining severe depression and
      with less certainty in pinpointing a nonevent (specificity). Results are further
      considered by sex.

PMID- 10575979
TI  - Monitoring and assessing symptoms of chronic fatigue syndrome: use of time series
      regression.
AB  - Chronic Fatigue Syndrome's principal symptoms are severe and include prolonged
      fatigue and a number of other minor symptoms. Behavioral data collection methods
      were used in a case study to show some of the benefits that can be derived from
      monitoring symptoms hourly and daily. Using time series regression, several
      statistically significant correlates of fatigue were found both within days and
      between days. Perceived energy, physical exertion, and mental exertion were
      significantly related to fatigue in both analyses. Collection of such data may
      help resolve a number of theoretical and methodological problems in research on
      the Chronic Fatigue Syndrome.

PMID- 10575980
TI  - Sex differences in self-silencing.
AB  - The construct of self-silencing was proposed to account for women's greater
      vulnerability to developing depression. This study of 1,117 students (795 women
      and 322 men) explored possible explanations for the empirical finding that men
      self-silence to the same or greater extent than women. Analysis showed that men
      reported more self-silencing than women. A factor analysis confirmed the subscale
      structure of the Silencing the Self Scale for women and men, with relatively few
      departures from the originally proposed subscales. Depression and self-silencing
      scores were correlated positively for both men and women. The results of two
      multiple regressions, performed separately for men and women, showed that
      depressive symptomatology accounted for a significant percentage of the variance
      in self-silencing but that social desirability did not account for a significant
      increment in the variance accounted for in silencing the self. The scores on the
      Care as Self-sacrifice and the Divided Self subscales were intercorrelated for
      women, but not for men, indicating that there may be a sex difference in
      perception of self-silencing behavior.

PMID- 10575981
TI  - State and trait depression and suicidality.
AB  - In a sample of 68 undergraduates, current depression scores predicted current
      suicidal ideation while depressive personality scores predicted prior suicidal
      ideation.

PMID- 10575982
TI  - Mexican-American male batterers on the MCMI-III.
AB  - This study examined personality characteristics of Mexican-American male
      batterers. 60 Mexican-American male batterers (M = 33.6 yr.) in the court system
      in South Texas took the MCMI-III and their MCMI-III scores were compared with the
      scores of a community sample of 45 Mexican-American individuals (M = 30.4 yr.).
      The batterers frequently scored higher than the nonbatterers on the Avoidant and
      Passive-Aggressive scales, while nonbatterers frequently scored higher on the
      Histrionic scale. The batterers scored significantly higher on 18 out of 24 MCMI
      III scales, while nonbatterers scored significantly higher on two scales.

PMID- 10575983
TI  - Religion and suicidal ideation in a sample of Latin American immigrants.
AB  - The present study explored the association of measures of religious activities
      and suicidal ideation in a sample of adult Latin American immigrants (145 women,
      56 men). No relationship was found between religious affiliation and suicidal
      ideation. Self-perception of religiosity, influence of religion, and church
      attendance were significantly negatively associated with suicidal ideation. A
      multiple regression analysis showed that influence of religion was a significant
      predictor of suicidal ideation. The present findings lend empirical support to
      the notion that high religiosity may play a protective role against suicide.

PMID- 10575984
TI  - Relationship of arithmetic problem solving and reflective-impulsive cognitive
      styles in third-grade students.
AB  - Different individuals approach mathematical problems in a variety of ways, with
      these different approaches also reflected in over-all cognitive styles. This
      investigation had two purposes, first, to determine whether good and poor
      arithmetic problem solvers differ substantially in cognitive style, and second,
      to determine whether the students, after training in techniques of solving
      arithmetic problems, improve their performance with no significant change in
      cognitive style. A total of 98 third graders participated (mean age 8.1 yr.; 50
      boys, 48 girls). The Matching Familiar Figure Test was used to classify the
      students by cognitive style as either Reflective or Impulsive. Students also were
      given training with different problem-solving exercises for different arithmetic
      problems. The training program in problem-solving strategies did not improve
      performance on arithmetic problems for Reflective students; however, Impulsive
      students' performance did improve after training.

PMID- 10575985
TI  - Sex and the Barnum effect: rationality versus helpfulness.
AB  - In 1998 Piper-Terry and Downey found that women accepted friends' bogus test
      interpretations more readily than did men and the researchers attributed this to
      women's helpfulness. Layne countered that women are more open and thus rationally
      expected their friends' interpretations to be more accurate. Later Downey asked
      participants how accurately they believed their friends could describe their
      personalities. Although this pilot study's sensitivity to differences was low,
      the women's accuracy ratings still tended to exceed those of men (p < .06) as
      Layne predicted. This may suggest that the rationality hypothesis is better
      supported than the female-helpfulness hypothesis.

PMID- 10575987
TI  - Predicting the suicide rate of children in America.
AB  - The time-series regressions for suicide rates by race and sex for those aged 5 to
      14 years in the USA from 1933-1980 were predicted by scores on two factors which
      had high loadings for year and for the marriage rate.

PMID- 10575986
TI  - Endorsements by Mexican-Americans of the Bem Sex-Role Inventory: cross-ethnic
      comparison.
AB  - Gender-related personality traits among Mexican-American men and women were
      examined. The sample consisted of 307 Mexican-Americans (150 women, 157 men) in a
      predominantly Mexican and Mexican-American community in South Texas. Mexican
      American men scored significantly higher than the women on eight masculine items,
      whereas Mexican-American women scored higher than the men on four feminine items.
      A comparison between the scores of Mexican-Americans on the Bem Sex-Role
      Inventory with those of the original sample in the inventory's manual showed that
      the scores for the Masculinity and Femininity subscales for both Mexican-American
      men and women were not significantly different from those of the original sample.
      A significant difference, however, was found on some of the items of the
      inventory. Analysis also indicated that more Mexican-American men were
      categorized as Feminine and Androgynous than were non-Hispanic Euro-American
      males in the original sample. Among Mexican-American women there were more
      individuals classified as Masculine and Undifferentiated and a lower percentage
      as Feminine than among the original sample. Implications and recommendations
      based on the results are discussed.

PMID- 10575988
TI  - How college students' physical health relates to coping.
AB  - The relationship between coping and physical health status was examined for 100
      undergraduate students using the COPE scale and the Medical Index (formerly
      identified as the Cornell Medical Index). Using stepwise multiple regression,
      scores for COPE scales--alcohol or drug use, and focus on and venting of emotions
      accounted for significant amounts of variance (but only 10% and 5%, respectively)
      in the scores for physical health symptoms reported.

PMID- 10575989
TI  - Transmission of risk factors across three generations.
AB  - The present study examined the association between the parent-grandmother
      relationship, the parenting of toddlers, and toddlers' anger. Parent-grandmother
      relations were assessed when the parents were adolescents. Patient-toddler
      relations were examined when the toddlers were two years of age. The sample
      consists of 185 2-yr-old toddlers, one of the parents of each toddler, and the
      corresponding grandmother of each toddler. The findings support our hypothesis
      that there would be an indirect effect of the grandmothers' personalities and
      child-rearing practices on their grandchildren through the influence of the
      grandmothers on the parents. The influence of both the grandmothers' and the
      parents' smoking behaviors on the toddlers' anger was mediated by their child
      rearing practices. The significance of the findings from a multigenerational
      study are discussed with reference to incorporating them into prevention
      programs. The findings are consistent with the notion of the intergenerational
      transmission of risk factors--from grandparents to parents to toddlers.

PMID- 10575990
TI  - Depression and suicidal preoccupation in South African students.
AB  - Xhosa, Zulu, and colored students in South Africa did not differ on depression
      scores, but there was some evidence that the pattern of the symptoms of
      depression differed among the three groups.

PMID- 10575991
TI  - The status of the Beck Anxiety Inventory in contemporary research.
AB  - The author performed a comparative analysis on the research output of 6 popular
      clinical measures of anxiety. The results of a citation analysis of the database
      from PsycINFO for the years 1991-1998 indicated that the Beck Anxiety Inventory
      presently ranks third, behind the State-Trait Anxiety Inventory and the Fear
      Survey Schedule, in terms of use in research.

PMID- 10575992
TI  - Further validation of the shame and guilt scales of the Harder Personal Feelings
      Questionnaire-2.
AB  - Previous research using the Harder Personal Feelings Questionnaire-2 has
      generally supported the validity of its subscales for the measurement of the
      traits of proneness to shame and guilt. This study extended the construct
      validity by investigating hypothesized relationships between scores on the
      questionnaire and several personality constructs not previously examined,
      including attachment style, the five personality factors assessed by the NEO-Five
      Factor Inventory, Sensation Seeking and Positive Affect (both from the Multiple
      Affect Adjective Check List-Revised). Shame and guilt scales were each expected
      to correlate inversely with secure attachment, Extraversion, Openness, Sensation
      Seeking (uninhibitidness), and Positive Affect, while they were predicted to
      correlate positively with Neuroticism from the NEO measure. Shame was expected to
      show stronger relationships than guilt with Extraversion, Openness, and Sensation
      Seeking. For the 41 college students results were mostly as predicted, even after
      shame and guilt scores were partialled for each other, thereby providing further
      evidence for the construct validity of the Personal Feelings Questionnaire-2
      scales.

PMID- 10575993
TI  - Homosexual parents: testing "common sense"--a literature review emphasizing the
      Golombok and Tasker longitudinal study of lesbians' children.
AB  - Counter to claims by the American Psychological Association and the National
      Association of Social Workers as well as numerous reviewers that children raised
      by homosexuals and married heterosexuals do not differ, the elaborate social
      personality theory called "common sense" predicts that because "like produces
      like" and because psychopathy/sociopathy informs the major expressions of social
      deviance including homosexuality, children of homosexuals will (1) be more
      frequently subjected to parental instability (of residence and sexual partners)
      and (2) have poorer peer and adult relationships. Also, as is held to be true of
      their parents, homosexuals' children will be more apt to (3) become homosexual,
      (4) be unstable (have emotional problems and difficulty forming lasting bonds)
      with reduced interest in natality, and (5) be sexually precocious and
      promiscuous. Differences between homosexual and heterosexual comparison groups
      that bore on "common sense" were considered suggestive "bits" of empirical
      evidence. Differences that emerged within studies conducted by sympathetic
      researchers utilizing volunteer samples were considered bits of adverse evidence.
      Of 171 bits, 82 adverse and 55 nonadverse bits supported, while 34 bits fell
      against "common sense." From this tentative method of counting, support was found
      for common sense beliefs that children of homosexuals will be more apt to become
      homosexual and have poorer peer relationships, while weaker support was found for
      some of the other predictions. As assessed in this way, the empirical evidence in
      the literature tended to lean against claims of "no differences" between children
      raised by homosexuals and heterosexuals. In particular, the strongly worded
      official claims of there being "no differences" are overstatements. They amount
      to the organizations and some prominent researchers asserting that they have
      proven the null hypothesis, which is fundamentally impossible. It is likely that
      the nonsignificant statistical findings stressed thus far include Type Two errors
      created by use of volunteer samples, inadequate identification and measurement of
      likely differences, and refusal to interpret results in ways contrary to the
      sympathies of subjects, investigators, and the organizations.

PMID- 10575994
TI  - Pleasure, guilt and secretory immunoglobulin A.
AB  - Before producing saliva samples for Immunoglobulin A assay, 30 subjects listed
      their pleasurable activities and rated them in terms of pleasure and guilt.
      Levels of Immunoglobulin A were higher in those subjects with high ratios of
      pleasure-guilt scores.

PMID- 10575995
TI  - MMPI screening scales for somatization disorder.
AB  - 44 items on the MMPI were identified which appear to correspond to some of the
      symptoms in nine of the 10 groups on the Perley-Guze checklist for somatization
      disorder (hysteria). This list was organized into two scales, one reflecting the
      total number of symptoms endorsed and the other the number of organ systems with
      at least one endorsed symptom. Full MMPIs were then obtained from 29 women with
      primary affective disorder and 37 women with somatization disorder as part of a
      follow-up study of a consecutive series of 500 psychiatric clinic patients seen
      at Washington University. Women with the diagnosis of somatization disorder
      scored significantly higher on the somatization disorder scales created from the
      44 items than did women with only major depression. These new scales appeared to
      be slightly more effective in identifying somatization disorder than the use of
      the standard MMPI scales for hypochondriasis and hysteria. Further development is
      needed.

PMID- 10575996
TI  - Sex differences in self-estimates of lay dimensions of intelligence.
AB  - 260 participants rated themselves on 12 items that made up the three types of
      intelligence as noted by Sternberg, et al. in 1981. There were sex differences on
      two of the three standardized scores with men rating themselves higher than women
      on practical and verbal intelligence. This confirms previous studies of sex
      differences in the ratings of over-all (g) and multiple intelligences.

PMID- 10575997
TI  - Escaping the professional pressure-cooker.

PMID- 10575998
TI  - Frequency of bone densitometry for osteoporosis?

PMID- 10575999
TI  - Self-care tip for diabetic patients.

PMID- 10576000
TI  - Tailoring presentation technology to your audience.

PMID- 10576001
TI  - Where to find practical patient education materials. Empowering your patients
      without spending a lot of time and money.

PMID- 10576002
TI  - Of bugs and drugs. A guide through the labyrinth of antimicrobial therapy for
      respiratory tract infections.
AB  - Choosing appropriate antimicrobial therapy is no longer a simple process. Even
      for the common problems of respiratory tract disease in children and adults,
      selection is complicated by both increasing microbial resistance and the daunting
      number of extended-spectrum antibiotics now on the market. In this article, Drs
      Singh and Arrieta look at the problem from all aspects and give their specific
      recommendations.

PMID- 10576003
TI  - Treatment of Acute MI. Institute for Clinical Systems Improvement.

PMID- 10576004
TI  - Update on urine-based markers for bladder cancer. How sensitive and specific are
      the new noninvasive tests?
AB  - Urine cytology is still the most commonly used noninvasive test to diagnose
      bladder cancer. However, cytology's ability to detect low-grade bladder tumors is
      limited, and its results require interpretation by a pathologist, are not
      available immediately, and are subjective. Several noninvasive urine-based tests
      are now available for detection and follow-up of bladder cancer. At least two of
      these new tests (BTA stat and AuraTek FDP) can easily be performed in the office,
      and the results are available in about 10 minutes. When choosing a test,
      physicians should keep in mind that none of the currently available tests is 100%
      accurate. However, the new urine-based tests are more sensitive than urine
      cytology and hence more reliable in detecting low-grade bladder cancer. They are
      useful tools in patients with urinary symptoms or microscopic hematuria or as
      office-based adjuncts to diagnostic procedures. Some of the markers that are
      being developed could significantly improve and simplify workup, diagnosis, and
      follow-up, and they may allow for detection of disease at an earlier stage, thus
      improving the chances of curative therapy.

PMID- 10576005
TI  - A structured approach to low back pain. Thorough evaluation is the key to
      effective treatment.
AB  - When a patient comes to you seeking relief from low back pain, do you picture
      endless numbers of office visits with no improvement, no matter what you
      prescribe? Your anxiety may be well founded, but there is hope. By understanding
      and applying basic principles for management of low back pain, you can increase
      your comfort level and improve patient outcomes. In this article, Dr. Biewen
      presents a no-nonsense, step-by-step approach to evaluation and treatment that
      can take the worry out of your next low back pain appointment.

PMID- 10576006
TI  - Opioids for chronic nonmalignant pain. Choosing suitable candidates for long-term
      therapy.
AB  - Opioid maintenance analgesia for chronic nonmalignant pain can be successful in
      selected cases, but it is not a panacea for all pain, and management of patients
      using opioids can be an arduous process. A consistent and principle-based
      approach is recommended. Passion and chauvinism exist on both sides of the
      controversy and should be discouraged.

PMID- 10576007
TI  - Following the clues to neuropathic pain. Distribution and other leads reveal the
      cause and the treatment approach.
AB  - Neuropathic pain can seem enigmatic at first because it can last indefinitely and
      often a cause is not evident. However, heightened awareness of typical
      characteristics, such as the following, makes identification fairly easy: The
      presence of certain accompanying conditions (e.g., diabetes, HIV or herpes zoster
      infection, multiple sclerosis) Pain described as shooting, stabbing, lancinating,
      burning, or searing Pain worse at night Pain following anatomic nerve
      distribution Pain in a numb or insensate site The presence of allodynia
      Neuropathic pain responds poorly to standard pain therapies and usually requires
      specialized medications (e.g., anticonvulsants, tricyclic antidepressants, opioid
      analgesics) for optimal control. Successful pain control is enhanced with use of
      a systematic approach consisting of disease modification, local or regional
      measures, and systemic therapy.

PMID- 10576008
TI  - Why is chronic pain so difficult to treat? Psychological considerations from
      simple to complex care.
AB  - The treatment of patients with chronic pain can be difficult and challenging.
      Recent advances in our understanding of the pathophysiologic mechanisms involved
      have led to viewing this condition as a multifactorial problem with interrelated
      structural, functional, and psychophysiologic factors. Treatment of simple
      chronic pain is fundamentally different from that of complex chronic pain. The
      former can be managed by one clinician alone, whereas the latter requires the
      integration of a multidisciplinary team of specialists with a biopsychosocial
      treatment philosophy.

PMID- 10576009
TI  - Neonatal jaundice. Strategies to reduce bilirubin-induced complications.
AB  - Neonatal hyperbilirubinemia is the most common reason for hospital readmission in
      the first 2 weeks of life. Kernicterus is still relatively uncommon but has been
      on the rise with the institution in the 1990's of aggressive early postnatal
      discharge policies. Bilirubin-induced complications can be prevented by
      instituting a neonatal jaundice protocol to identify infants at risk for
      significant hyperbilirubinemia, by ensuring adequate parental education and
      preparedness, and by implementing a good neonatal tracking system for follow-up
      care. Hyperbilirubinemia is easily treated with phototherapy, which can be
      administered at home in selected infants.

PMID- 10576010
TI  - Caring for adults with mental disabilities. Problems tend to be complex among
      this growing population.
AB  - Providing medical care for patients with mental disabilities may be challenging
      and financially unappealing because of the need for extra time and effort.
      Nonetheless, primary care physicians can meet the medical needs of these patients
      and benefit from working with a team approach that fosters open communication and
      documentation of potential barriers and preferences. Development of healthcare
      maintenance guidelines that can be easily individualized is also beneficial.
      Advanced planning and a willingness to learn help the clinician overcome the
      challenges and develop a strong patient-provider relationship that can be very
      rewarding.

PMID- 10576012
TI  - Systemic lupus erythematosus. Measures to keep this unpredictable disease under
      control.
AB  - SLE is a chronic autoimmune disease with an unpredictable history and course. It
      can occur in men or women at any age, but it is most prevalent in women of
      childbearing age. SLE displays a variety of clinical and laboratory
      manifestations that vary from vague constitutional symptoms to findings of end
      organ dysfunction. Early recognition can lead to better treatment and preventive
      care, thereby avoiding the more aggressive renal, cardiovascular, and septic
      manifestations. Recognition and management of lupus flares and of medication side
      effects can markedly reduce morbidity and mortality, allowing patients to live
      more functional lives.

PMID- 10576011
TI  - How to deal with chronic constipation. A stepwise method of establishing and
      treating the source of the problem.
AB  - Chronic constipation is a common medical complaint encountered often in a primary
      care setting. Most patients can be treated successfully with simple measures,
      including education, bowel habit training, increased fluid and fiber intake, and
      use of laxatives. Chronic constipation is usually considered idiopathic, but
      secondary causes should be excluded. In about 1% of patients with severe,
      intractable constipation, further diagnostic testing (e.g., endoscopy, colonic
      transit study) is needed. Patients with colonic inertia can be treated with
      judicious use of laxatives, but surgery may be necessary in a few cases. Patients
      with outlet inertia should be referred for biofeedback treatment.

PMID- 10576013
TI  - Topical corticosteroid-induced acne. Three treatment strategies to break the
      'addiction' cycle.

PMID- 10576014
TI  - Antidepressant drug interactions in the elderly. Understanding the P-450 system
      is half the battle in reducing risks.
AB  - Antidepressant treatment in patients 65 years of age or older carries increased
      risks of adverse drug events because of age-related physiologic changes,
      polypharmacy, and individual variability in drug metabolism (due to genetic
      factors, concurrent disease, diet, and consumption habits). Reduction of total
      drug burden, adjustment of dose levels, and careful selection of an appropriate
      agent are important steps toward avoiding adverse drug interactions, In addition,
      the documented and potential drug interactions of the various classes of
      antidepressants, and specific agents within each class, should be considered.
      Each elderly patient should be treated individually and monitored carefully
      during the initiation and maintenance of antidepressant therapy.

PMID- 10576015
TI  - The case of the curious ripples. Felinization of the esophagus.

PMID- 10576016
TI  - Neuropathic pain.

PMID- 10576017
TI  - [Analysis of risk factors for the formation of internal exposure dose to the
      rural population and effectiveness of preventive actions in agriculture in the
      long-term after the Chernobyl Accident].
AB  - The regularities in the formation of internal exposure doses to the population
      living in the Chernobyl affected areas are described. The factors responsible for
      changes in doses are identified and their significance is assessed. The effects
      of countermeasures on the radiation situation variations are estimated. The need
      for an addressed application of countermeasures is shown with taking into account
      types of rural settlements based on the radioecological factors responsible for
      dose formation in the population.

PMID- 10576018
TI  - [ Delayed effect of prenatal irradiation on the critical organs functional state
      in children after Chernobyl accident].
AB  - Some indexes of a metabolism in 186 children exposed in utero through the
      Chernobyl accident were investigated ten years after the irradiation. All the
      children (basic and control groups) live in the territory with contamination less
      than 15 Ci/km2. It was shown, that the activity of alanine aminotransferase
      (ALT), aspartate aminotransferase (AST), alkaline phosphatase and the level of
      bilirubin (conjugated and unconjugated) differed from the corresponding indexes
      in the control group (p < 0.05). These change depended on sex. The correlation
      between the levels of the total bilirubin, activity of the ACT, ALT in serum and
      absorbed doze to the thyroid of fetus was found (correlation coefficient > -0.8,
      p < 0.05). The linear regression equations for these three indexes are straight
      line: the total bilirubin, ACT and ALT decreased with the increase of the
      absorbed dose to the thyroid of fetus (p < 0.05). The relationship between the
      all indexes in serum and effective doze and levels of cesium accumulation was not
      detected.

PMID- 10576019
TI  - [Embryology of ovules from the second-year-old cones of scotch pine after acute
      irradiation in the zone of Chernobyl nuclear plant].
AB  - The embryological processes after acute irradiation in the zone of Chernobyl
      (radiation level 4-5 Yy) were studied in ovules from the second-year-old cones of
      scotch pine. Four types of anomalies were detected in ovules of all experimental
      pine trees: undeveloped ovules in layer of strobiles; a substitution of female
      gametophit by tissues originaled from tapetal or nucellar cells; death of
      macrogametophytes connected with the interruption of divisions during the
      cenocitic stage in full-fertile pine trees. These anomalies appear during the
      normal development of microgametophytes.

PMID- 10576020
TI  - [Radioecological condition of cleansing structures on the territory contaminated
      with radionuclides as a result of the accident on the Chernobyl Nuclear Power
      Station and the problems handing with the forming precipitates of sewage in
      republic Belarus].
AB  - This article deals with the problems, connected with the formation of radioactive
      deposits in sewage (D.S.). It's shown that the main places of the accumulation of
      D.S. are the fields of filtration, silty sites and biological pools. In order to
      reduce the extent of the risk of the secondary contamination of environment we
      could offer the modernization of the elements of the cleansing structures, the
      development of refining technologies and reduction of mobility of radiocaesium.

PMID- 10576021
TI  - [The topological method of analysis of ground contamination of former nuclear
      test sites].
AB  - The method of topological description of former nuclear tests in demonstrated in
      this paper. The information about the field is extracted from the topology of 2D
      crossections of 3D surfaces constructed on experimental data. The complexity of
      izolines' system for each cross section in estimated by algebraic sum of contours
      bounded the areas where the field is higher then the given level. That gives a
      possibility to do morphological analysis of radionuclide fields using archive
      data and can be used for ecological diagnosis of different contaminations. The
      using of this method is shown on some examples.

PMID- 10576022
TI  - [The study of mechanisms of radioprotective action of indometofen n hematopoietic
      stem cells in mouse long-term bone marrow cultures].
AB  - The influence of indometophen (an analog of tamoxiphen) on the dynamic content
      and the proliferative activity of CFUs (colony-forming units) and CFU-GM
      (granulocyto-macrophages precursors) and the level of colony-stimulating factor
      (GM-CSF) in mouse long-term bone marrow cultures were studied for 4 weeks after
      administration. Five days after indometophen injection the long-term cultures
      were exposed to irradiation with a dose of 2 Gy and on the time course of
      postirradiation recovery haemopoietic precursors cells and dynamic release of GM
      CSF in the culture supernatants were examined. The data of this report suggest
      that the mechanisms responsible for the radioprotective action of indometophen
      may be associated both with its direct effects on the proliferation and
      differentiation of hemopoietic cellular precursors and with the stimulation of
      release of growth-differential factors by hemopoietic microenvironmental
      elements.

PMID- 10576023
TI  - [Structure and functional changes in the gastric intramural nervous plexus in
      emotionally stressed rats exposed to low doses of long-term ionizing irradiation
      and lead].
AB  - Changes in the catecholamine content in adrenergic fibres, acetylcholinesterase
      activity, and in the energy metabolism enzymes lactate dehydrogenase and
      succinate dehydrogenase in neurons of the gastric intramural plexus during
      emotional stress in rats a day after combined exposure to prolonged (30 days)
      ionizing radiation in a total dose 1.0 Gy and 0.6 mg/kg lead were studied. A
      decrease in catecholamines in adrenergic fibres and acetylcholinesterase and
      lactate dehydrogenase activity in neurons was observed. An enhanced sensitivity
      of the gastric intramural plexus after the prolonged exposure to small doses of
      ionizing radiation and lead in conditions of emotional stress was suggested.

PMID- 10576024
TI  - [Effect of somatotropin on the course and result of combined radiation and
      mechanical injury].
AB  - In the experiment on rats it was shown that injection of somatotropin (1 ED/kg,
      i.m. at 1, 3, 5, 7 and 9 days) after combined irradiation and mechanical injury
      (4.5 Gy, LD50/30 and plural fractures) improved the overall condition of the rats
      and increased the survival. The drug accelerated the bone regeneration.

PMID- 10576026
TI  - [Epigenetic cell reactions induced by ionizing radiation].
AB  - The importance of radiation modification of epigenetic activity in the general
      mechanism of radiobiological reactions is proved. The inheritable epigenetic
      changes induced by irradiation are one of the basic reasons of formation of the
      remote radiation pathology. It is noted that epigenetic inheritable changes of
      cells have the determined character distinguishing them from mutation changes,
      being individual and not directed. It is underlined the ability of ionizing
      radiation to modify a level of spontaneous genetic instability inherited in a
      number of cell generations on the epigenetic mechanism.

PMID- 10576025
TI  - [Cellular reactions induced by chronic exposure to 14C beta-rays].
AB  - In V-79 cells the Effects of chronic exposure on induction of chromosome
      aberrations and abnormal metaphases as well as on efficiency of subsequent
      exposure to 2 Gy gamma-rays were investigated. It was found that chronic exposure
      increased the yield of chromosome aberrations as well as abnormal metaphases
      (spread-metaphases and apoptotic metaphases). In spite of the level of damages in
      cells, the chronic beta-exposure protected cells against the additional induction
      of chromosomal aberrations by subsequent exposure to higher acute dose of gamma
      irradiation. Cytogenetic adaptive response was retained in the surviving progeny
      of irradiated cells which were cultured in free medium during 40, 70 days or one
      year after chronic exposure. At this time the level of residual chromosome
      aberrations, colony forming ability and distribution of the cells by the number
      of chromosomes were almost the same as in unirradiated cells. However, the high
      level of abnormal metaphases and half as much of cells in colony in the surviving
      progeny of irradiated cells in comparison with unirradiated cell, allow us to
      suggest that the chronic exposure induced the selection of adaptive forms in
      condition of the higher level of radiation.

PMID- 10576027
TI  - [Effect of external irradiation with different intensity at 1 Gy dose on the DNA,
      RNA and total protein content in the testis and liver of rats].
AB  - The content of DNA, RNA and total protein in the rat testes and liver was studied
      1 and 30 days after external chronic gamma-irradiation (dose rate 1.8 and 5.76
      cGy/day) and acute gamma-irradiation with relatively low dose rate (5.4 cGy/min)
      up to a total dose of 1 Gy. The results obtained pointed to the specific
      metabolic reaction of radiosensitive (testes) and radioresistant (liver) tissues
      of organism at external irradiation at relatively low dose of different intensity
      due to unequal cell capacity for proliferation.

PMID- 10576028
TI  - [Advances and prospects of a combined therapy of acute radiation injury in
      experiments].
AB  - We present the results of a long-standing experimental development of ways and
      means for acute radiation sickness treatment that have been authorized for
      application in medicine and are mostly aimed at large-scale accidental injuries.
      The paper describes means for early treatment (prodigiosan, desoxynate, typhoid
      vaccine, proteus vaccine), a myeolopoiesis stimulant (estradiol dipropionate), a
      detoxication procedure (hemosorption), substitution therapy with bone marrow
      cells and peripheral blood mononuclears, anti-infectious schemes comprising
      antibiotics and polyvitamins.

PMID- 10576029
TI  - [Treatment of infectious complications of experimental acute radiation injury
      with combined antibiotic sulacillin].
AB  - An anti-infectious effect of sulacillin (ampicillin/sulbactam) is higher than
      that of ampicillin in treatment of irradiated mice infected with a beta
      lactamaseproducing strain of Kl. pneumoniae. Involving of sulacillin as a
      principal antibiotic into the therapeutic scheme for acute radiation sickness
      results in 67% dogs survival at LD90/45.

PMID- 10576030
TI  - [Efficiency of polysaccharide translam for early treatment of acute radiation
      illness].
AB  - Antiradiation therapeutic efficiency of translam (1-->3; 1-->6-beta-D-glucan)
      produced by enzymatic synthesis out of laminarin, polysaccharide of Laminaria
      cychorioides, has been studied in four animal species (mice, guinea-pigs, dogs,
      monkeys). A stable curative effect has been observed following its administration
      within first 24 h after radiation exposure at doses that cause acute radiation
      sickness (about LD90). The preparation is nontoxic and has a broad therapeutic
      range which permits its practical application.

PMID- 10576031
TI  - [Experimental assessment of the cardiovascular system functional state in rats
      after chronic gamma-irradiation in various absorbed doses].
AB  - Prolonged anthenatal gamma-irradiation of rats with total doses of 1.25; 1.9 and
      2.5 Gy resulted in discoordination of cardiovascular system function. This study
      confirm our previous data on negative effect of chronic gamma-irradiation on
      forming and development of the functional systems in the anthenatally irradiated
      organism.

PMID- 10576032
TI  - [Biological and ecological aspects of the effects combined electromagnetic rays
      on farm animals].
AB  - The study of a biological effect of ultraviolet, ultrahigh frequency and gamma
      radiation, as well as combinations of these, on the functional status of the
      sheep body systems has made it possible to evaluate the sensitivity of a body
      exposed to these factors and its adaptive potentials. The pattern of variations
      in the body systems when a combined EMR is applied depends on to which extent one
      or another factor dominates the others. It is however possible that the effect of
      the leading factor is modified by that of a less severe radiation, energy
      characteristics of which differ from those of the dominating factor.

PMID- 10576033
TI  - Mechanisms of chronic rejection.

PMID- 10576034
TI  - The role of transforming growth factor-beta in transplant rejection.

PMID- 10576035
TI  - The effects of lipids on graft outcome.

PMID- 10576036
TI  - The future of new immunosuppressive drugs.

PMID- 10576037
TI  - Pharmacokinetics of tacrolimus: clinically relevant aspects.

PMID- 10576038
TI  - Four-year follow-up of the European Tacrolimus Multicenter Renal Study.

PMID- 10576039
TI  - Tacrolimus-based immunosuppression in pediatric renal transplantation.

PMID- 10576040
TI  - Effect of immunosuppressive therapy on graft half-life projections. The
      Collaborative Transplant Study.

PMID- 10576041
TI  - Conversion to tacrolimus for acute corticosteroid- and antibody-resistant
      rejection following kidney transplantation.

PMID- 10576042
TI  - Conversion to tacrolimus in hyperlipidemic patients.

PMID- 10576043
TI  - Conversion from cyclosporine to tacrolimus in renal transplant recipients with
      gum hyperplasia.

PMID- 10576044
TI  - Tacrolimus and glucose metabolism.

PMID- 10576045
TI  - Single-center experience with initial intravenous dosing of tacrolimus after
      kidney transplantation.

PMID- 10576046
TI  - Dosing and management guidelines for tacrolimus in renal transplant patients.

PMID- 10576047
TI  - Report of the first 118 tacrolimus-treated patients at St George's Hospital,
      London.

PMID- 10576048
TI  - Immunological and nonimmunological risk factors with tacrolimus and Neoral in
      renal transplant recipients: an interim report.

PMID- 10576049
TI  - Tacrolimus and mycophenolate mofetil in cadaveric renal transplant recipients.
      The European Multicentre Tacrolimus/MMF Study Group.

PMID- 10576050
TI  - The Benelux experience with the combination of tacrolimus and mycophenolate
      mofetil.

PMID- 10576051
TI  - Tacrolimus, mycophenolate mofetil and corticosteroids as primary
      immunosuppression after renal transplantation at the Hospital 12 de Octubre,
      Madrid.

PMID- 10576052
TI  - Outcome of tacrolimus conversion therapy for renal allograft rejection: 5-year
      follow-up.

PMID- 10576053
TI  - Corticosteroid withdrawal under tacrolimus primary and rescue therapy in renal
      transplantation: the Chicago experience.

PMID- 10576054
TI  - Vascular rejection with tacrolimus and potential long-term graft outcome.

PMID- 10576055
TI  - [Natural interspecific hybrids of transposable phages of Pseudomonas aeruginosa].
AB  - Bacterial viruses of Pseudomonas aeruginosa assigned to two groups, D3112 and B3,
      recombine with very low frequencies. Previous study of the genome structure of
      intergroup hybrids suggested the incompatibility of some genetic modules of these
      bacteriophages. In this work, several natural hybrid transposable phages that had
      the genomes largely consisting of modules of phages from group D3112 and B3, were
      described. The discovery of these phages suggests the continuous genetic exchange
      in nature of these viruses belonging to different species. This model is
      considered as promising from the viewpoint of monitoring virus evolution.

PMID- 10576056
TI  - [A statistical study of the growth and morphogenesis of axillary apparatus and
      notum in the Pth mutants of Drosophila].
AB  - The regularities of morphogenesis of the ventral wing-hinge structures in the Pth
      mutants of Drosophila melanogaster were studied using statistical methods. Our
      views on the vectorial growth of presumptive wing hinge as an entire unity were
      independently confirmed using statistical methods. The expected duplication
      forms, the possibility of their one-dimensional classification, the expected
      number of possible types, and other aspects of duplication were discussed in view
      of other possible suggestions on the growth of the ventral wing hinge. The growth
      of the anterior half of the pteropleurum was shown to have a rigid organization,
      because it can be described as a function of one variable. The growth was shown
      to be exponential. The empirical formula that fits experimental data with a
      significance of 99.99% was chosen. The relationship between the presumptive
      ventral wing hinge and the presumptive notum in respect of growth was shown to be
      statistical (the coefficient of correlation r = 0.37) rather than functional.
      Therefore, such a morphologically united formation as the wing imaginal disk does
      not have a unified growth pattern. The growth pattern is composed from the
      individual growth patterns of its constituents that have a certain degree of
      independence.

PMID- 10576057
TI  - [Insertional mutagenesis of Arabidopsis thaliana: increase of germinating seeds
      transformation efficiency after sonication].
AB  - An efficient procedure of transforming Arabidopsis thaliana germinating seeds was
      elaborated on the basis of the method of Feldmann and Marks. The procedure
      involves microdamaging T1 seeds by sonication before culturing with a vector
      Agrobacterium strain and yields more than 1% T2 transformants. Germinating seeds
      were transformed with Agrobacterium timefaciens hypervirulent strain A281
      carrying plasmid pLD3 derived from pBI121. A collection of 54 A. thaliana T2
      transformants was obtained; some of them showed marked morphological alterations.
      The transgenic nature of plants that acquired resistance to a marker antibiotic
      was confirmed histochemically and by PCR amplification of a T-DNA region.

PMID- 10576058
TI  - [Genetic variation of the mitochondrial DNA gene encoding cytochrome b in the
      Magadan population of sable Martes zibellina L].
AB  - The population of sable Martez zibellina consisting of two subspecies (M. z.
      kamtschadalica and M. z. jacutensis) on the territory of the Magadan oblast was
      analyzed for the variation of the 1300-bp mtDNA gene region encoding cytochrome
      b. Three haplotypes were revealed among the animals studied (n = 52). Six out of
      nine restriction endonucleases that had recognizable sites within the studied
      region of mtDNA genome had polymorphic sites. An index of gene diversity h was
      0.27. The high level of polymorphism is a result of the fact that the population
      studied comprised two clearly differentiated subspecies. The ratio of dominating
      haplotypes corresponds to the percentage of females introduced from Kamchatka and
      Khabarovsk Krai, which suggests that in the period which has elapsed both
      maternal lineages remained fairly unchanged.

PMID- 10576059
TI  - [The coat color mutation in silver foxes (Vulpes vulpes): morphology of guard
      hairs].
AB  - The structure of guard hairs was analyzed in the mottling mutants of silver
      foxes. The mottling mutation occurred in the population of silver foxes which has
      been subjected to domestication. Hairs from the mottling areas were shown to have
      the following distinctions from silvery-black hairs: the lack of clear grana
      shaft separation, a lesser thickness and length, another shape and pattern of
      guard-hair scales, another thickness ratio between cortical and medullar layers,
      a lesser number of melanocytes in hair bulbs, and a lesser number of dendritic
      processes in melanocytes. Putative mechanisms underlying the phenotypic effect of
      the mutant gene that controls mottling are suggested.

PMID- 10576060
TI  - [Correlation between the duration of radiation adaptive response in bone marrow
      cells of mice and the dose of gamma-irradiation in vivo].
AB  - The dependence between the adaptive response and adaptive dose was studied on the
      basis of cytogenetic damage in polychromatic erythrocytes of bone marrow cells in
      mice after a low dose gamma-irradiation in vivo. The adaptive response to doses
      of 0.1 and 0.2 Gy was found to be retained for at least two months after
      irradiation. However, the adaptive dose of 0.4 Gy did not induce prolonged
      adaptive response.

PMID- 10576061
TI  - [Comparative analysis of allele polymorphism of three short tandem repeats in the
      Russian, Uzbek and Georgian populations].
AB  - The allele polymorphism of the AGC short tandem repeat (STR) of exon 1 of the
      androgen receptor (AR) gene located in Xq11-12, ATCT STR of intron 40 of the von
      Willebrand factor (vWF) gene located in chromosome 12p12, and AGAT STR of an
      anonymous DNA sequence (STRX1) from the short arm of the X chromosome was
      analyzed in the Georgian, Uzbek, and Russian populations. Polymerase chain
      reaction (PCR) with DNA of unrelated persons revealed 14 AR, 7 vWF, and 7 STRX1
      alleles in Georgians; 14, 8, and 6 alleles, respectively, in Uzbeks; and 16, 8,
      and 9 alleles, respectively, in Russians. The heterozygosity at these STR was
      0.61, 0.78, and 0.46 in Georgians; 0.60, 0.83, and 0.44 in Uzbeks; and 0.80,
      0.70, and 0.58 in Russians. The correspondence of genotype frequencies to the
      Hardy-Weinberg equilibrium was observed with AR STR in Russians and Uzbeks, STRX1
      STR in Georgians, and vWF in all three populations. A significant deviation from
      the equilibrium was found for STRX1 in Russians and Uzbeks and AR in Georgians.
      The potential of individualization was 0.05 for AR, 0.13 for vWF, and 0.18 for
      STRX1 in Georgians; 0.04, 0.09, and 0.13, respectively in Uzbeks; and 0.05, 0.14,
      and 0.07, respectively, in Russians. The allele and genotype frequency
      distributions of each STR were analyzed in all three populations. Allele
      frequencies in the populations were compared by the Kolmogorov-Smirnov test. The
      Russian population significantly differed in allele frequencies of the three STR
      from Uzbeks and in those of STRX1 and AR from Georgians. Georgians and Uzbeks
      significantly differed in vWF and STRX1 frequencies. The possibility of using the
      three STR in molecular diagnosis of the corresponding monogenic diseases,
      population genetic studies, and personal identification is discussed.

PMID- 10576063
TI  - [An efficient algorithm for estimation of functions of a pedigree with short
      inbred loops].
AB  - The study is a further development of the methods for genetic analysis using
      pedigree data. Methods for approximation of the likelihood based on cutting of
      all loops are often used in analysis of large pedigrees with multiple loops. In
      this study, a fast efficient algorithm for calculating likelihood is proposed.
      This algorithm allows short inbred loops to be processed without cutting them
      and, hence, prevents the loss of genetic information. The approach proposed may
      be important for analysis of the pedigrees of farm and laboratory animals, where
      inbred crosses resulting in short inbred loops are common. The results of a
      stochastic genetic experiment agree with this suggestion: the use of the
      algorithm proposed considerably increases the accuracy of estimation of model
      parameters and testing of genetic hypotheses.

PMID- 10576062
TI  - [Polymorphism of gene encoding vascular angiotensin II receptor and
      microangiopathies in patients with insulin-dependent diabetes mellitus].
AB  - Polymorphism A1166C of the AT1R gene encoding angiotensin vascular receptor
      [replacement of C (cytosine) for A (adenine)) at position 1166] was compared in
      patients with insulin-dependent diabetes mellitus (IDDM) complicated by diabetic
      nephropathy (DN) and in noncomplicated patients (n = 27 and n = 41, respectively)
      and also in patients with IDDM complicated by diabetic retinopathy (DR) and in
      correspondent noncomplicated individuals (n = 30 and n = 44, respectively). The
      frequency of AT1R gene alleles and genotypes in patients with IDDM complicated by
      DN did not differ significantly from that observed in patients with
      noncomplicated IDDM. In contrast, in patients with IDDM complicated by
      retinopathy, a significant decrease in the content of A allele (68.3% against
      82.6%) and a significant increase in the content of C allele (31.7% against
      17.4%) was found as compared with the control group. Thus, in the Moscow
      population, A1166C polymorphism of the AT1R gene is not associated with diabetic
      renal complications but indeed associated with diabetic retinal complications. C
      allele is a risk factor of DR (the relative risk, RR, is equal to 2.17), and A
      allele is, in contrast, a protective factor against early retinopathy development
      (RR is equal to 0.49).

PMID- 10576064
TI  - [Polymorphism of the serotonin transporter gene in populations of the Volga-Ural
      region].
AB  - Polymorphism of the serotonin transporter gene (hSERT) was studied in eight human
      populations of the Volga-Ural region by means of polymerase chain reaction (PCR).
      The populations studied belonged to Turkic (Bashkirs, Tatars, and Chuvashes),
      Finno-Ugric (Maris, Komis, Mordovians, and Udmurts), and Eastern Slavic
      (Russians) ethnic groups. Comparison of the hSERT polymorphisms in these
      populations established the population-specific distribution patterns of the main
      component of this polymorphic system in the region studied and revealed the
      interethnic differences in hSERT allelic and genotypic frequencies.

PMID- 10576065
TI  - [Qualitative and quantitative variation of serum proteins in fluorosis patients].
AB  - Comparison between patients with occupational fluorosis, a group of healthy
      workers, and a sample from the general population revealed differences in
      concentrations of some polymorphic serum proteins. These differences depended on
      phenotypes of patients. TF 1-2, PI 1-2, and HP 2-1 patients exhibited a decreased
      concentration of transferrin (TF), a decreased concentration of proteinase
      inhibitor (PI), and an increased concentration of haptoglobin (HP), respectively.

PMID- 10576066
TI  - [The study of correlation between the K-ras genotype and murine susceptibility to
      chemically induced lung neoplasms].
AB  - The susceptibility of the ICR, DD/He and CC57/BR mice to urethane-induced lung
      tumors was analyzed in comparison with the A/He (highly susceptible) and AKR
      (resistant) lines of mice. Allelic variants of the K-Ras gene intron 2 in these
      lines have been determined. Susceptibility of the ICR mice was similar to that of
      the A mice, and intron 2 of the K-Ras ICR gene carried the 37-bp deletion
      analogous to that described in the A/He line. The DD mice intron 2 also contained
      the deletion, but despite the presence of the "susceptible" K-Ras allele, the
      DD/He mice were resistant to urethane induction of lung tumors. The CC57BR line
      carried the deletion and demonstrated relatively high susceptibility. Our
      findings indicate that the K-Ras gene may be important in the chemical induction
      of lung tumors.

PMID- 10576067
TI  - What role for statins? A review and economic model.

PMID- 10576068
TI  - "Engineering" the wound-healing process.

PMID- 10576069
TI  - Frequency response of evoked potential in normal and diseased nerve muscle.

PMID- 10576070
TI  - Improving geometric model construction for blood flow modeling.

PMID- 10576071
TI  - Automated registration of brain images using edge and surface features.

PMID- 10576072
TI  - Fast and precise positioning of single cells on planar electrode substrates.
AB  - For cell biosensors and for studying neural networks using planar electrode
      substrates, a suitable technique for positioning single cells on electrodes was
      needed. We reported a new method for fast and efficient positioning of single
      cells on ring electrodes by controlled suction through holes. We described the
      microfabrication of electrode substrates with microholes and the cell positioning
      procedure. L929 cells and Neuro 2A cells could be positioned in parallel without
      cell damage.

PMID- 10576074
TI  - Ideas to help break down barriers.

PMID- 10576073
TI  - Micromachined needle arrays for drug delivery or fluid extraction.
AB  - Micromachined needle arrays have been designed, fabricated, and characterized.
      The design includes arrays of 25 needles with fluid coupling channels and dual
      structural supports. Numerical modeling of fluid flow characteristics was
      performed, demonstrating that the needle coupling channels redistribute flow when
      the input or output ports are fully restricted. Micromachining technologies have
      been used to batch fabricate hollow metallic fluid coupled needle arrays. The
      significance of this work includes the development of the hollow metallic
      micromachined needle arrays for biomedical applications, as well as a discussion
      of structural, fluidic, and biological design considerations. The micromachined
      needle array has many advantages, including (a) reduced trauma at penetration
      site (small size), (b) greater freedom of patient movement (minimal penetration),
      (c) a practically pain-free drug delivery device (distribution of force), (d)
      precise control of penetration depth (needle extension length), and (e) they can
      be stacked and packaged into a 3-D device for fluid transfer.

PMID- 10576075
TI  - Synthesis and transformation of three-dimensional facial images.

PMID- 10576076
TI  - A wireless near-infrared energy system for medical implants.

PMID- 10576078
TI  - Reuse of single-use medical devices.

PMID- 10576077
TI  - Estimating complexity from EEG background activity of epileptic patients.

PMID- 10576079
TI  - The Supreme Court sets standards for engineering expert testimony.

PMID- 10576080
TI  - Who was Faraday and what did he do?

PMID- 10576081
TI  - Enabled to care: community mental health care as a virtual organisation.

PMID- 10576083
TI  - Outcome study of English speaking temporary residents in Japan.
AB  - Eighteen factors were examined for their effect on the outcome in 103 English
      speaking temporary residents who received treatment in Japan for a psychiatric
      disorder. Two dimensions extracted by multivariate analysis distinguished
      "premature leave" and "drop out" category respectively. The first "premature
      leave" dimension was composed of mode of therapy, primary diagnosis, accumulated
      stay and experience of past stay in Japan. the second "drop out" dimension was
      composed of mode of therapy and referral source. The treatment outcome was
      influenced by personal psychiatric data, the social adaptation process and the
      treatment process.

PMID- 10576082
TI  - Social factors and first onset schizophrenia among Asians and whites.
AB  - Previous studies from the Indian subcontinent had suggested that the onset and
      outcome of schizophrenia is linked with social factors. We set out to study the
      inception rates and social factors in whites and Asians who were presenting for
      the first time ever to various catchment facilities in Ealing catchment area. A
      total of 62 cases (38 white and 24 Asians) were diagnosed as having
      schizophrenia. Using well established and previously validated standardised
      instruments we collected information on various social factors and inception
      rates of schizophrenia. The inception rates and social factors were largely
      similar in these two groups. By and large the social factors in the two groups
      were broadly similar except that Asians were significantly more likely to show
      increased religious activity compared with their white counterparts. Contrary to
      previous findings Asians were more likely to have had longer duration of symptoms
      prior to seeking help. These findings are discussed in relation to Asian support
      systems and suggestions made for future research.

PMID- 10576084
TI  - Prevalence of depressive symptoms and mood disorders in primary care: a Spanish
      rural study.
AB  - BACKGROUND: 5-10% of primary care patients present a classification diagnosis of
      Major Depression, 5-10% of Dysthymia and 20% "depressive symptoms only". We tried
      to obtain the prevalence of depressive symptoms in a Spanish primary care area
      (11,667 adult inhabitants, Seville). METHODS: a randomized sample of 221 people
      (SE = 0.0025, a = 0.05) was initially examined using the Beck Depression
      Inventory (BDI). The patients with a BDI > 16 were considered as "cases" and were
      extensively examined using the "Schedules for Clinical Assessment in
      Neuropsychiatry" (SCAN). RESULTS AND CONCLUSIONS: Our prevalence of depressive
      symptoms was higher than that reported in international studies with similar BDI
      cutting-scores. Class-linked vulnerability could play an important aetiological
      role. Prevalences of Major Depression and Dysthymia were similar to other reports
      using structured diagnostic interviews. The cases were usually lower-class
      females, and they also presented medium or high psychosocial disability.
      Depressive symptoms and mood disorders in Primary Care represent an unsolved
      health care problem today.

PMID- 10576085
TI  - Diagnoses of children and adolescents on initial presentation to a Nigerian
      outpatient psychiatry clinic.
AB  - Child and adolescent psychiatry is an underdeveloped specialty in Nigeria,
      relegated by more entrenched cultural systems, such as traditional healers and
      syncretic churches, to merely an auxiliary role in child mental health care.
      Little is therefore known about the epidemiology of childhood disorders as
      encountered in psychiatric settings. We reviewed the outpatient psychiatric
      clinic's patient register at the Psychiatric Hospital of Uselu in Benin City,
      Nigeria, over a twenty-four week period. Fifty-three patients who presented in
      the twenty-four week index period had definite diagnoses indicated in the
      register. Of these, 68% had diagnoses denoting significant behavioral
      disturbances that would motivate their visit to allopathic hospitals after other,
      more culturally sanctioned healers were of little help. Our findings are compared
      with similar studies in other cultures.

PMID- 10576086
TI  - Patients who miss initial appointments in community psychiatry? A Spanish
      community analysis.
AB  - OBJECTIVES: To identify factors that predict which patients, when referred by
      their GP, make a first appointment at a Mental Health Centre and then fail to
      attend. METHOD: Sequential observational study in which data was collected for
      one year on all the people (1311) with an arranged date for an initial
      appointment at an urban Community Mental Health Centre. RESULTS: Approximately
      25% of patients who request an initial appointment fail to attend. The variables
      that predict non-attendance are: the lack of a telephone number for contact, the
      time lapse before the appointment, and when drug-addiction is the reason for
      requesting the appointment. One variable that results in a specific kind of
      behaviour is the timing of the initial appointment, since males and females tend
      to miss at different times. We also found that missing the appointment followed a
      seasonal pattern. CONCLUSIONS: In order to optimise the service, it is necessary
      to discover the proportion of probable misses, and aim to arrange the appointment
      with the shortest possible time lapse and to take into consideration the sex of
      the patient when fixing the time of the interview.

PMID- 10576087
TI  - Effects of community mobile team intervention in the Drewnica Hospital catchment
      area. 1. Patient outcome.
AB  - This study measured social functioning, treatment satisfaction and hospital
      utilization of 88 patients with chronic psychoses before and after a 1-year
      community mobile team programme, following most of the principles of assertive
      community treatment. The intervention had a positive impact in all measures. A
      clinically significant improvement of social functioning, as measured by
      Birchwood's Social Functioning Scale, was noted in 56% of patients, and 81% of
      subjects showed a clinically significant increase in satisfaction level. Time
      hospitalized decreased fourfold and number of admissions decreased twofold. To be
      certain that the changes found were due to the intervention and not other
      factors, further prospective studies of mobile community teams versus traditional
      care are indicated.

PMID- 10576088
TI  - The relationship of causal beliefs and contact with users of mental health
      services to attitudes to the 'mentally ill'.
AB  - Programmes to destigmatise 'mental illness' have traditionally been based on the
      'mental illness is an illness like any other' metaphor and have been largely
      unsuccessful. By measuring attitudes towards, and etiology beliefs about, 'mental
      illness' before and after a series of four undergraduate lectures presenting the
      psychosocial causes of, and solutions to, severe mental health problems, this
      study (a) replicated previous studies demonstrating a relationship between
      biogenetic causal beliefs and negative attitudes towards 'mental patients'; (b)
      found that following the lectures attitudes improved, particularly around the key
      variables of dangerousness and unpredictability; and (c) demonstrated that amount
      of contact with people who had received psychiatric treatment was an even
      stronger predictor of positive attitudes than acceptance of a psychosocial
      perspective.

PMID- 10576089
TI  - [Effect of carbon, nitrogen and phosphorus nutrition on the R, S, and M
      dissociants of Pseudomonas aeruginosa in mixed cultures].
AB  - The effect of glucose, nitrate, and phosphate on the stationary-phase growth
      characteristics of R, S, and M dissociants of the hydrocarbon-oxidizing strain P.
      aeruginosa K-2 was studied. The optimal concentrations of glucose and phosphate
      providing for at least 90% of the maximal culture density were found to be 2-7%
      glucose and 0.02-0.12% phosphate. The main factor that determined the proportion
      of dissociants in bacterial populations was the initial concentration of
      phosphate. The fraction of R dissociant in populations increased linearly with
      the concentration of glucose and varied nonlinearly with the concentration of
      phosphate in the growth medium. The fraction of M dissociant depended solely on
      the concentration of phosphate in a manner inverse to that typical of R
      dissociant. In glucose-deficient media containing sufficient amounts of
      phosphorus, S dissociant prevailed over R dissociant.

PMID- 10576090
TI  - [Sensitivity of soil bacteria isolated from the alienated zone around the
      Chernobyl Nuclear Power Plant to various stress factors].
AB  - Seventy strains of chemoorganotrophic bacteria isolated by our group in 1993-1994
      from soil sampled in the zone around the Chernobyl Nuclear Power Plant (ChNPP)
      were studied with respect to their sensitivity to various stress factors damaging
      DNA. Bacillus subtilis, B. cereus (both spores and vegetative cells),
      Methylobacterium extorquens, M. mesophilicum, and unidentified pigmented bacteria
      were found to be the most resistant to ultraviolet (UV) radiation, exhibiting
      LD90 values of 40 to more than 211 J/m2. The same bacteria, as well as Bacillus
      polymyxa, were tolerant to hydrogen peroxide (lethal concentrations of H2O2
      ranged from 0.3 to 1.0 M); i.e., UV-resistant strains were also tolerant to
      hydrogen peroxide and vice versa. Fluorescent pseudomonads were the most
      sensitive to both UV radiation and H2O2, showing LD90 from 6 to 18 J/m2 and a
      lethal concentration of H2O2 lower than 0.1 M. All of the soil samples collected
      in the alienated zone around the ChNPP, where the radioactivity of the soil had
      decreased from 1000 to 2 microCi/kg soil over the period from 1987 to 1995,
      contained not only resistant bacteria but also a small number of bacteria
      sensitive to UV radiation and H2O2.

PMID- 10576091
TI  - [Ultraviolet irradiation of soil samples as a model of the effect of stress
      factors on bacterial diversity in soil ecosystem].
AB  - UV irradiation is proposed for use in studying the effect of radioactive
      irradiation, since radioresistant bacteria are, as a rule, resistant to UV, and
      the mechanisms of repair of cell damage induced by UV and ionizing radiation are
      similar. It was found that the total number of bacteria and the number of
      dominant species in soil samples exposed to UV radiation decreased, indicating
      the unfavorable effect of UV radiation on bacterial diversity in soil ecosystems.
      The percentage of cells of bacteria belonging to dominant species varied
      significantly depending on the intensity of UV irradiation. It can be inferred
      that long-term irradiation of soils must impair the stability of soil ecosystems,
      a phenomenon that was indeed observed in the zone around the Chernobyl Nuclear
      Power Plant. At the same time, the UV irradiation of soil samples made it
      possible to reveal minor species, primarily UV-resistant pigmented bacteria. UV
      irradiation can probably be used as a selective factor for the isolation of
      radioresistant species.

PMID- 10576092
TI  - [Diversity of bacteria at various depths in the southern part of lake Baikal as
      detected by 16S rRNA sequencing].
AB  - Phylogenetic analysis of the bacterial community inhabiting the water of Lake
      Baikal was performed on the basis of 16S rRNA sequencing. The composition of the
      bacterial community was shown to vary significantly with depth. Cyanobacteria
      were dominant species at the surface of the lake. At a moderate depth (400 m),
      actinomycete relatives were most abundant. At a great depth and near the bottom,
      the community was composed mainly of proteobacteria and cyanobacteria (the latter
      are probably brought from the surface layers by vertical near-shore water
      fluxes). Most of the bacterial 16S rRNA sequences detected exhibited low
      similarity to those known and formed separate clusters in the phylogenetic tree,
      which may indicate the endemic nature of the corresponding bacteria.

PMID- 10576093
TI  - [Transfer of cryptic plasmids between Bacillus subtilis cells via spontaneous
      transformation].

PMID- 10576094
TI  - Polycyclic aromatic hydrocarbons in the ambient air of Greek towns in relation to
      other atmospheric pollutants.
AB  - Polycyclic aromatic hydrocarbons (PAHs) were determined in the ambient air of six
      towns in N. Greece. This paper presents the variability of the particle-bound
      PAHs concentrations and the particle PAH content during the cold and the warm
      months. Correlations of total PAHs with other atmospheric pollutants were largely
      different among towns indicating that the relative contribution of emission
      sources is different in each location. In the warm months PAHs were significantly
      correlated with vehicular pollutants thus suggesting traffic as the major PAH
      emmitting source. The same was also deduced from the comparison of the ambient
      PAH profiles to the profiles of particular sources. The contribution of
      residential heating was significant in most towns during winter. Principal
      component analysis of the data did not result in a clear distinction between
      towns thus suggesting that all are influenced by similar source types. Finally,
      the risk associated with the inhallation of carcinogenic PAHs in each town was
      estimated and compared to the risk from more urbanized/industrialized sites in N.
      Greece.

PMID- 10576095
TI  - Polycyclic aromatic hydrocarbons in fuel-oil contaminated soils, Antarctica.
AB  - Where fuel oil spills have occurred on Antarctic soils polycyclic aromatic
      hydrocarbons (PAH) may accumulate. Surface and subsurface soil samples were
      collected from fuel spill sites up to 30 years old, and from nearby control
      sites, and analysed for the 16 PAHs on the USEPA priority pollutants list, as
      well as for two methyl substituted naphthalenes, 1-methylnaphthalene and 2
      methylnaphthalene. PAH levels ranged from 41-8105 ng g-1 of dried soil in the
      samples from contaminated sites and were below detection limits in control site
      samples. PAH were detected in surface soils and had migrated to lower depths in
      the contaminated soil. The predominant PAH detected were naphthalene and its
      methyl derivatives.

PMID- 10576096
TI  - The disposition and metabolism of 1,3-dibromobenzene in the rat.
AB  - The distribution, excretion and metabolism of 1,3-dibromobenzene following a
      single i.p. administration to rats 100 or 300 mg/kg was investigated using
      radiotracer [3H] and GC-MS technique. After 72 hours about 74 to 90% were
      excreted in urine. The highest radioactivity was observed in the liver, kidneys
      and fat tissue. Later on a steady decline of radioactivity was apparent in all
      investigated tissues except for blood cells and the sciatic nerve, where constant
      levels were noted. In urine the following substances were identified and
      quantified by GC peak areas: unchanged 1,3-DBB (18%), dibromophenols (34%),
      dibromothiophenols (28%), dibromothioanisole (1.8%), bromophenol (5.5%),
      bromohydroxythiophenols (5%), and bromohydroxythioanisole (7.5%).

PMID- 10576097
TI  - Photocatalytic oxidation of cyanide in aqueous solutions of poly(sodium
      styrenesulfonate-co-2-vinylnaphthalene).
AB  - Photosensitized by poly (sodium styrenesulfonate-co-2-vinylnaphthalene) (PSSS-VN)
      oxidation of cyanide in an aqueous solution was studied. The reaction was found
      to occur via photoinduced electron transfer from CN- to the polymeric
      chromophores. The process leads to formation of NCO-.

PMID- 10576098
TI  - Interpretation of analytical data on n-alkanes and polynuclear aromatic
      hydrocarbons in Arbacia lixula from the coasts of Tenerife (Canary Islands,
      Spain) by multivariate data analysis.
AB  - The hydrocarbons contents (n-alkanes, polycyclic aromatic hydrocarbons) were
      determined in the sea urchin Arbacia lixula. Multivariate data analysis as
      principal component analysis, factor analysis and, cluster analysis were applied
      to elucidate sources of pollution. PCA and FA were performed to establish the
      relationships between variables (hydrocarbons), samples (sea urchin) and sources
      of pollution.

PMID- 10576099
TI  - Polybrominated diphenyl ethers detected in human adipose tissue from Spain.
AB  - Polybrominated diphenyl ethers (PBDEs) were detected in 13 human adipose tissue
      samples from Spain, 3 women and 10 men. Tetra-, penta- and hexabrominated
      diphenyl ethers were determined at ng/g lipid (ppb) level in all the samples. The
      average TeBDE level was 1.36 ng/g, the average PeBDE was 0.93 ng/g and the HxBDE
      1.83 ng/g. Human adipose tissue levels of PBDE obtained in the current samples
      from Spain are comparable with the tissue levels reported in recent Swedish
      investigations.

PMID- 10576100
TI  - Enhanced decomposition of NO on the alkalized PdO/Al2O3 catalyst.
AB  - Experimentally, decomposition of NO on the alkalized Pd/Al2O3 catalyst is
      remarkably enhanced at 825-1000 K. The enhancement in N2 yield may be due to the
      additional basic sites on the alkalized catalyst that can trap NO molecules.
      However, at T > 1000 K, due to the fact that the absorbed oxygen in subsurface or
      bulk of Pd was involved in the formation and desorption of oxygen molecules,
      yield of oxygen was enhanced.

PMID- 10576101
TI  - Micronucleus assay and lymphocyte mitotic activity in risk assessment of
      occupational exposure to microwave radiation.
AB  - The effects of radiofrequency electromagnetic radiation (RFR) on the cell
      kinetics and genome damages in peripheral blood lymphocytes were determined in
      lymphocytes of 12 subjects occupationally exposed to microwave radiation. Results
      showed an increase in frequency of micronuclei (MN) as well as disturbances in
      the distribution of cells over the first, second and third mitotic division in
      exposed subjects compared to controls. According to previous reports micronucleus
      assay can serve as a suitable indicator for the assessment of exposure to
      genotoxic agents (such as RFR) and the analysis of mitotic activity as an
      additional parameter for the efficient biomonitoring.

PMID- 10576102
TI  - Biodegradation in laboratory activated sludge plants and aquatic toxicity of
      herbicides.
AB  - The biodegradation and the aquatic toxicity of four herbicides (isoproturon,
      terbuthylazine, mecoprop, metamitron) were investigated. Laboratory activated
      sludge plants were used for biodegradation experiments. The biodegradation of
      mecoprop reached nearly 100%, the other herbicides were not eliminated by
      biodegradation. The acute Daphnia magna 24-h assay, the algal 72-h inhibition
      test, and the recently developed lemna growth inhibition 7-d test were applied to
      evaluate the biological effects of herbicides as original substances. EC 50 and
      EC 10 values were determined. Algal and lemna test show that isoproturon and
      terbuthylazine are both much more toxic than mecoprop and metamitron. Daphnids
      are generally less sensitive against herbicides than plants. Biodegradation and
      toxicity test were coupled for mecoprop to assess biological long-term effects of
      possible biodegradation products of this herbicide. The effluents of the
      laboratory activated sludge units were used in toxicity tests (Daphnia magna 21-d
      reproduction test, lemna growth inhibition 7-d test). No inhibiting effect on the
      tested organisms was observed.

PMID- 10576103
TI  - High-rate biodegradation of 3- and 4-nitroaniline.
AB  - A municipal wastewater biosludge was acclimated to the degradation of 4
      nitroaniline (4-NA). The acclimation was achieved by using this compound as the
      sole source of nitrogen during the degradation of succinate as the sole source of
      carbon and energy. The acclimated bacteria were able to eliminate and mineralize
      4-NA as the sole source of carbon and energy. However, in batch tests, the
      degradation process was somewhat instable and only occurred at comparatively low
      rates. A continuously operated miniaturized fixed-bed bioreactor was used in
      order to increase the degradation rates. It was inoculated with the acclimated
      bacteria and fed with 4-NA as the sole substrate. The system enabled high
      bioconversion efficiency, due to the development of a high biomass concentration
      of up to 5.45 g SS L-1. At input concentrations of 4-NA up to 4.5 mM and a
      hydraulic retention time of 3.5 hours a high degradation rate of 1.1 mmol 4-NA L
      1 h-1 and 90 ... 95% DOC removal were achieved. Partial nitrification, also
      occurred. After gradual adaptation, the bacteria also degraded 3-NA and 4-NA
      simultaneously in this system. Additional batch tests showed, that 3-NA can serve
      as the sole source of carbon, nitrogen and energy.

PMID- 10576104
TI  - Evaluation of laboratory-made sludge for an anaerobic biodegradability test and
      its use for assessment of 13 chemicals.
AB  - Laboratory-made sludge for a biogas based anaerobic biodegradability test was
      prepared as an alternative for digested sludge from wastewater treatment plants
      (WWTPs). Biodegradation activities and background gas productions of digested
      sludge from various WWTPs were found to vary significantly depending on the
      source, which adversely affected test reliability. Subsequently, test conditions
      such as sludge concentration and sludge washing were examined with the laboratory
      made sludge and a sludge concentration of 1.0 g-SS/L without washing was
      determined to be most suitable. Under these conditions, biodegradability tests
      were conducted for 13 select chemicals and their relative toxicities to
      methanogenic bacteria were evaluated. The results of biodegradability tests
      showed that chemicals with -OH and -CH2OH radicals were readily biodegraded and
      those with -Cl, -NO2, -NH2, -SO3H and -CH3 had inhibited degradation responses m
      nitriphenol and 2,4,6-trichlorophenol were highly toxic to methanogenic bacteria,
      with m-nitrophenol completely inhibiting methane fermentation as low as 20 mg/L.

PMID- 10576105
TI  - Changes in concentration levels of selected VOCs in newly erected and remodelled
      building in Gdansk.
AB  - Volatile organic compounds such as benzene, toluene, butyl acetate, ethylbenzene,
      m-xylene, styrene and m-dichlorobenzene were measured in three newly erected and
      remodelled dwellings. The present study also attempted to examine the time
      dependence of concentrations of selected VOCs in each investigated dwelling. This
      was accomplished by at least triplicate measurements of the IAQ. To collect a
      series of air samples the active and passive methods were used. In both cases
      activated charcoal was applied as a sorption medium. The samples were recovered
      by solvent extraction, and analysed by capillary column gas chromatography,
      employing a flame ionisation detector. The experimental results showed that MAC
      values for analysed VOCs were exceeded (even a few orders of magnitude) for the
      measurements made before inhabiting of the occupants, in every investigated
      dwelling. The concentrations of the investigated VOCs decreased significantly
      with time, which should be expected, although in some cases the levels of
      selected VOCs remained still high. Our experience indicates that parallel
      application of two different indoor air sampling techniques to determine analytes
      of interest, though more laborious and time consuming, can lead to significant
      conclusions concerning indoor air quality in monitored spaces.

PMID- 10576106
TI  - Environmental behavior of explosives in groundwater from the Milan Army
      Ammunition Plant in aquatic and wetland plant treatments. Uptake and fate of TNT
      and RDX in plants.
AB  - Uptake and fate of TNT and RDX by three aquatic and four wetland plants were
      studied using hydroponic, batch, incubations in explosives-contaminated
      groundwater amended with [U-14C]-TNT or [U-14C]-RDX in the laboratory. Substrates
      in which the plants were rooted were also tested. Plants and substrates were
      collected from a small-scale wetland constructed for explosives removal, and
      groundwater originated from a local aquifer at the Milan Army Ammunition Plant.
      This study demonstrated rapid uptake of [U-14C]-TNT derived 14C, concentration at
      the uptake sites and limited transport in all plants. Per unit of mass, uptake
      was higher in submersed than in emergent species. Biotransformation of TNT had
      occurred in all plant treatments after 7-day incubation in 1.6 to 3.4 mg TNT L-i,
      with labeled amino-dinitrotoluenes (ADNTs), three unidentified compounds unique
      for plants, and mostly polar products as results. Biotransformation occurred also
      in the substrates, yielding labeled ADNT, one unidentified compound unique for
      substrates, and polar products. TNT was not recovered by HPLC in plants and
      substrates after incubation. Uptake of [U-14C]-RDX derived 14C in plants was
      slower than that of TNT, transport was substantial, and concentration occurred at
      sites where new plant material was synthesized. As for TNT, uptake per unit of
      mass was higher in submersed than in emergent species. Biotransformation of RDX
      had occurred in all plant treatments after 13-day incubation in 1.5 mg RDX L-1,
      with one unidentified compound unique for plants, and mostly polar products as
      results. Biotransformation had occurred also in the substrates, but to a far
      lower extent than in plants. Substrates and plants had one unidentified 14C-RDX
      metabolite in common. HPLC analysis confirmed the presence of RDX in most plants
      and in three out of four substrates at the end of the incubation period.

PMID- 10576107
TI  - Biomarker approach to evaluating the impact of scientific stations on the
      Antarctic environment using Trematomus bernacchii as a bioindicator organism.
AB  - A biomonitoring study was performed to evaluate the human impact on two small
      coves adjacent to the Italian Scientific Station at Terra Nova Bay in November
      1995. The study used the fish species Trematomus bernacchii as a bioindicator
      organism for a biomarker analysis based on porphyrin levels, and BPMO
      (Benzo(a)pyrene MonoOxygenase) and EROD (Ethoxyresorufin-O-deethylase)
      activities. Porphyrin levels and EROD and BPMO activities were found to be
      generally low. In contrast to previous years, no statistically significant
      difference was found between the potentially contaminated cove and the control
      cove after the Italian expedition had been active nearby for a period of one
      month. This indicates a marked decrease in certain types of contaminants such as
      organochlorines and trace metals, mainly due to improvements in waste disposal.

PMID- 10576108
TI  - Sorption of copper and nickel by spent animal bones.
AB  - Animal bone is able to adsorb copper and nickel ions from their single aqueous
      solutions. It was noted that a decrease in the sorbent concentration with
      constant copper or nickel concentration, or an increase in the copper or nickel
      concentration with a constant sorbent concentration resulted in a higher metal
      loading per unit weight of the sorbent. Increase in the initial pH of the metal
      solution resulted in an increase in the metals uptake per unit weight of the
      sorbent. Freundlich isotherm model was found to be applicable for the
      experimental data of Cu2+ and Ni2+. The results showed that animals bones can be
      used for the adsorption of the Cu2+ and Ni2+ with higher affinity toward Cu2+
      ions. The new sorbent was able to decrease copper concentration to a limit lower
      than the limit permitted by the environmental regulations.

PMID- 10576109
TI  - Experimental assessment of bio-reduction of di-2-thylhexyl phthalate (DEHP) under
      aerobic thermophilic conditions.
AB  - The reduction of organic contaminants in sewage sludge is of great importance for
      a further sludge disposal or agricultural utilization. Laboratory scale batch
      experiments were performed to assess the potential use of the aerobic
      thermophilic treatment technique to reduce the concentration of difficult to
      degrade organic chemicals. Di-2-ethylhexyl phthalate (DEHP) was chosen as a model
      representative of these chemicals. The effect of the sludge temperature and
      aeration rate on the reduction of DEHP concentration as well as on the reduction
      of the organic dry solid (oDS) was investigated. With a specific air flow rate of
      16 m3/m3.h and a thermophilic temperature of 63 degrees C it was possible to
      achieve up to 70% reduction of the DEHP concentration and 61% of oDS within 96
      hours. The maximum degradation of the oDS matter occurred within the first 24
      hours of operation whereby only little oDS was degraded afterward. During the
      experiments the reactor content was routinely monitored for pH, COD, along with
      the ammonia nitrogen and orthophosphate concentrations.

PMID- 10576111
TI  - Effects of chronic low-level PAH contamination of soil invertebrate communities.
AB  - Soils containing low levels of polycyclic aromatic hydrocarbons (PAHs) were
      collected from an abandoned industrial site. A study was conducted to evaluate
      the effects of these contaminants on soil invertebrates representing three levels
      of ecological hierarchy: the microfauna, mesofauna, and macrofauna. Nematodes
      were studied as representatives of the soil microfauna, microarthropods as
      representatives of the mesofauna, and earthworms as representatives of the
      macrofauna. Six sample plots representing a gradient of PAH contamination ranging
      from 5.28 to 80.46 mg/kg total PAHs were evaluated. Nematode community structure,
      including abundance and diversity of trophic and taxonomic groups; the total
      abundance of microarthropods (orders Collembola and Acarina); and earthworm
      (Eisenia andrei) growth were evaluated. Multiple regression analyses were used to
      evaluate trends in the responses of these target organisms to PAH concentrations
      and habitat variability. Abundance of omnivore/predator nematodes and
      microarthropod order Collembola; nematode taxonomic diversity; and the percent
      difference in earthworm weights exhibited positive associations with PAH
      concentrations. Total abundance of microarthropod order Acarina was negatively
      associated with PAH concentrations.

PMID- 10576110
TI  - Decolorization and biodegradability of photocatalytic treated azo dyes and wool
      textile wastewater.
AB  - The photodegradation and biodegradability have been investigated for four non
      biodegradable commercial azo dyes, Reactive YellowKD-3G, Reactive Red 15,
      Reactive Red 24, Cationic Blue X-GRL, an indicator. Methyl Orange, and one
      industrial wool textile wastewater, using TiO2 suspensions irradiated with a
      medium pressure mercury lamp. The color removal of dyes solution and dyeing
      wastewater reached to above 90% within 20-30 min. of photocatalytic treatment.
      Biochemical oxygen demand (BOD) was found to increase, while chemical oxygen
      demand (COD), total organic carbon (TOC) decreased, so that the ratio of BOD5/COD
      of the wastewater increased from original zero up to 0.75. The result implies
      that photocatalytic oxidation enhanced the biodegradability of the dye-containing
      wastewater and therefore relationship between decolorization and biodegradability
      exists. When the color disappeared completely, the wastewater biodegraded
      normally and could be discharged for further treatment. The experimental results
      demonstrate that it is possible to combine photocatalysis with conventional
      biological treatment for the remedy of wastewater containing generally non
      biodegradable azo dyes.

PMID- 10576112
TI  - The effect of the oil dispersant Omni-Clean on the toxicity of fuel oil no. 2 in
      two bioassays with the sheepshead minnow Cyprinodon variegatus.
AB  - Bioassays (7-day early life stage and 96 h acute bioassays) were conducted with
      the sheepshead minnow, Cyprinodon variegatus, to determine the toxicity of the
      dispersant Omni-Clean by itself and in combination with fuel oil no. 2.
      Performance characteristics of both bioassay types were also compared. Bioassays
      used oil by itself, dispersant by itself, and oil and dispersant in various
      ratios. Omni-Clean was less toxic than many other dispersants, and had a
      relatively small effect on individual biomass. Toxicities of the oil/dispersant
      combinations were generally higher than expected from the toxicities of the oil
      and dispersant by themselves, indicating a more-than-additive effect on toxicity.
      The comparison of performance characteristics between the 7-day and the 96-hour
      bioassays showed that the early life stage test is generally more sensitive, and
      has the added advantage of an additional and sensitive endpoint (fish biomass).

PMID- 10576114
TI  - Nursing and the primacy of technological progress.
AB  - This article identifies assumptions common to interpreting technological progress
      in contemporary nursing practice. Technology is described in terms of its
      characteristics and progress is identified as an ideological assumption
      influencing the way we think about, practice, and explain technology in
      contemporary nursing. Arguments associated with linear development, the
      elimination of scarcity, the technological imperative, the advancement of
      nursing, and technology as a neutral phenomenon are examined. It is argued that
      understanding progress assists us to develop insight into the relationship
      between technology and nursing.

PMID- 10576113
TI  - Physico-chemical characteristics and pollution level of Lake Nainital (U.P.,
      India): role of macrophytes and phytoplankton in biomonitoring and
      phytoremediation of toxic metal ions.
AB  - Lake Nainital is the sole source of drinking water for the local people and even
      to majority of tourists. In background of lake utility and its importance at
      national level, such study is essential which is focused on toxic metal pollution
      and current nutrient status of the lake and their magnification by algae and
      macrophytes. Study has shown that lake water is rich in nutrients which supports
      growth of many aquatic macrophytes and algal blooms. Besides, water is
      contaminated with metals like Cr, Cu, Fe, Mn, Ni, Pb and Zn. Concentration of
      some of them like Fe, Pb and Ni were higher than the recommended maximum
      permissible limits. Concentration of these metals were also found high in lake
      sediments. The level of metals amongst various components of lake varied
      considerably in different season. Plants and algae growing therein accumulated
      appreciable amount of metals and water roots of Salix being more efficient than
      others. High metal removing potential of these plants may be significant for
      biomonitoring studies and could be a useful phytoremediation technology to
      restore water quality by harvesting submerged and floating biomass inhabiting
      littoral zone of the lake.

PMID- 10576115
TI  - Self-care of well adult Canadians and adult Canadians with end stage renal
      disease.
AB  - Empirical support for Orem's Self-Care Deficit Theory of Nursing [Orem, D.E.,
      1995. Nursing: Concepts of practice, 5th. ed. Mosby, Toronto] is accumulating.
      However, little is known about the relative usefulness of the theory with well
      and chronically ill adults. This research examined multiple relationships deduced
      from Orem's Theory in 109 well adults and 141 adults with end stage renal disease
      (ESRD). Relations among personality traits, gender, age, socioeconomic status,
      self-care agency, and self-care were examined. Qualitative and quantitative
      differences were evident for the two samples. For example, self-care agency was a
      stronger predictor of self-care in well adults. Implications for development of
      disease-specific, mid-range theory are explored.

PMID- 10576116
TI  - Cultural competence of measurement scales of menopausal symptoms: use in research
      among Korean women.
AB  - Even though there are advancements in research related to culturally competent
      care, there is an increasing realization that coherent theories and a research
      base to guide health care that is culturally competent is yet to be fully
      developed. In this paper, cultural competence of the scales measuring menopausal
      symptoms are critically analyzed in light of their limitations for Korean women-
      a population other than for whom it was developed. The analyses indicate that
      there are issues of contextuality, relevance, communication style, authenticity,
      power relationships and time constraints.

PMID- 10576117
TI  - Longitudinal effects of an early family intervention programme on the adaptation
      of parents of children with a disability.
AB  - This study assesses the longitudinal effects of an original early intervention
      programme on the adaptation of parents of children with a disability (Down
      syndrome and cleft lip/palate, i.e. DS and CLP). Variations in the effects of the
      programme according to the time of measurement, the type of disability and
      parent's gender are also examined. Globally, the results show a better adaptation
      among parents who participated in the intervention programme compared to those
      who did not participated in the programme. These parents had lower levels of
      parental stress, they had more positive perceptions and attitudes concerning
      their child's disability and their parental situation, they were more confident
      in their own resources and the help they could receive from others, they had
      lower levels of emotional distress, anxiety and depression and they perceived
      more emotional support from their spouse. In general, these gains were maintained
      throughout the year when the children were between six and 18 months of age, they
      were relatively similar for parents of children with DS and parents of children
      with CLP, as well as for mothers and fathers.

PMID- 10576118
TI  - Supporting nursing staff exposed to violence at work.
AB  - An individual nurses risk of experiencing violence will vary related to his or
      her area of practice, role and work setting. The available evidence suggests that
      good practice in environmental design, security management and staff training may
      reduce but will not eliminate the probability of nurses experiencing assault. If
      we cannot prevent all violence then we must consider how we best support those
      who may be exposed to it. This paper thus explores the research on the effects of
      violence on nurses and critically examines the literature on staff support.

PMID- 10576119
TI  - Predictors of care dependency in Alzheimer's disease after a two-year period.
AB  - This paper presents the results from a panel study in the Netherlands of 68
      female in-patients with Alzheimer's disease. The main focus of this study was to
      investigate longitudinal changes and differences in care dependency. Descriptive
      statistics indicated an increase in almost all 15 features of dependency in a two
      year period. A stepwise regression procedure revealed that the loss of social
      relationships, the loss of the ability to communicate, and the degree of care
      dependency at entry to the study were the strongest predictors of the follow-up
      ratings. The pattern of findings reveals that the Care Dependency Scale is
      sensitive to care dependency increase after a two-year period, and that the scale
      has utility in establishing longitudinal patterns of care dependency.

PMID- 10576120
TI  - Patient positioning and the accuracy of pulmonary artery pressure measurements
      (180f).
AB  - The measurement of pulmonary artery pressure (PAP) is a common nursing practice
      in hemodynamic monitoring of patients in the emergency room and intensive care
      unit. Several researchers have proposed that PAP should be measured with the
      patient in a supine position with legs horizontal in order to promote a relaxed
      state. The most widely used reference point is the phlebostatic axis, which is
      located at the intersection of the fourth intercostal space and the midchest
      level. However, this positioning requirement is in conflict with one of the goals
      of nursing care, which is to achieve comfortable positioning of the patient
      without compromising respiratory or cardiovascular function. In addition, since
      frequent readings are necessary, critically ill patients can lose valuable sleep
      time. The existing literature still fails to justify the validity of the
      phlebostatic axis as an external reference point for leveling the pressure
      transducer. In addition, findings on the accuracy of readings obtained in the
      supine, Fowler's and lateral recumbent positions are also in conflict. This paper
      reviewed research related to measurement of PAP in the supine, various Fowler's,
      and lateral positions in order to clarify the major factors which might have
      resulted in the conflicts in data on PAP measurements. Suggestions are also
      provided for nurse clinicians to obtain more accurate PAP measurements.

PMID- 10576121
TI  - Epidemiological study of nephropathia epidemica in Finland 1989-96.
AB  - This study presents data on 33,000 serum samples studied from July 1989 to June
      1996 in Finland, with 6,701 serologically confirmed Puumala virus (PUU)
      infections. In addition, a PUU serosurvey of 8,000 sera from Finland is
      presented. On average, 957 PUU infections were detected annually, resulting in an
      incidence of 19/100,000; mortality was less than 0.1%. The infection was most
      common in the district of Ita-Savo with an incidence of 90/100,000. The seasonal
      peak was in November-December; however, the urban population had its incidence
      peak in August. Local epidemics mirrored bank vole densities, with 3-4-y cycles.
      Males contracted the disease at a mean age of 40 y, females at 44 y (male:female
      ratio 2:1). The disease was relatively rare in children and elderly people. The
      nationwide PUU antibody prevalence for women entering Finnish maternity clinics
      was 3%, suggesting 5% for the total population. The highest prevalences (7% for
      young women) were encountered in eastern Finland. In the district with the
      highest clinical alert, approximately 30% of all PUU infections were estimated to
      lead to clinical disease with serological confirmation.

PMID- 10576122
TI  - Improvement of lymphocyte proliferation in human immunodeficiency virus infection
      after recombinant interleukin-2 treatment.
AB  - In this study, the effect of recombinant interleukin-2 (rIL-2) on the function of
      peripheral blood mononuclear cells (PBMC) from human immunodeficiency virus (HIV)
      infected patients was examined. Using polymerase chain reaction (PCR), an
      impaired ability of PBMC from 8 patients to respond upon mitogen stimulation with
      expression of IL-2 and IL-2 receptor (IL-2R) messenger ribonucleic acid (mRNA)
      was found compared with healthy donors (p = 0.02 and p = 0.05, respectively).
      Flow cytometry was used to determine the expression of p55 interleukin-2 alpha
      receptor (CD25) after phytohaemagglutinin (PHA)-stimulation. Induced CD25
      expression in response to stimulation was lower in patient cells than in donor
      cells (in CD4+ (p = 0.01) and in CD8+ (p = 0.03)). After rlL-2 treatment, the
      functionality of ex vivo expanded PBMC from patients was restored to the level
      found in donors. Finally, the induced gene expressions for IL-2 and IL-2R were
      positively correlated (p < 0.0001), suggesting that the activation of the IL-2
      and IL-2R genes in humans may share a common activation pathway, as has been
      found in monkeys infected by simian immunodeficiency virus (SIV). These results
      indicate the existence of a reversible IL-2 and IL-2R defect at the
      pretranscriptional or transcriptional level in PBMC from patients. This may help
      explain the T-cell anergy found during HIV-infection.

PMID- 10576123
TI  - Report on a long-term study of maternal and congenital cytomegalovirus infection
      in Sweden. Review of prospective studies available in the literature.
AB  - This report summarizes knowledge accumulated in a long-term study of congenital
      and maternal cytomegalovirus (CMV) infection in Sweden. Some new findings are
      included. We considered diagnostic methods, sources of maternal infection
      (including occupational risks), roles of primary and secondary maternal
      infections, transmission to foetuses, incidence, symptoms and prognosis of
      established congenital infection and relative importance of such infection in
      infantile sensorineural deafness, microcephaly and type 1 diabetes mellitus.
      Virus isolation testing was done 1977-1985 on 16,474 newborns. 76 (0.5%)
      congenitally infected infants were found, 22/76 (29%) with transient neonatal
      symptoms and 11/60 (18%) with neurological symptoms by the age of 7 y. Type of
      maternal CMV infection was serologically determined in 62/76 cases (30 primary,
      32 secondary). CNS disturbances in the infants occurred after both primary (all
      trimesters) and secondary maternal infections. The negative potential of
      secondary maternal infections might be an obstacle to preventive vaccination.

PMID- 10576124
TI  - Increased prevalence of retrovirus infections among older women in Africa.
AB  - Recent studies of HIV-2 have suggested an increased incidence and prevalence
      among women older than 45 y compared with younger women. We therefore examined
      whether this phenomenon applied generally to all 3 major retroviruses, HIV-1, HIV
      2 and HTLV-I, among women in Africa. We conducted a MedLine search from 1987 to
      1997, using the keywords Africa and HIV-1, HIV-2 or HTLV, respectively. Community
      studies, national surveys and studies on professional cohorts were selected. Age
      groups > 45/50 y were compared with the age group with the lowest female/male
      prevalence ratio between 20 and 44 y of age. Thirty-one studies had sufficient
      data to be included. The female/male odds ratio (OR) for seropositivity was
      calculated for the old and the young age groups, respectively, providing the
      ratio of odds ratios: OR (old)/OR (young). Summary ratios for studies of all 3
      retroviruses were estimated. In general we found a higher female/male prevalence
      ratio in the age group over 45/50 y than in the younger age group. For HIV-1 the
      odds ratio was 1.82 times [95% confidence interval (CI) 1.19-2.79] higher in the
      old age group than in the young group. For HIV-2 it was 1.97 [95% CI 0.95-4.08],
      and for HTLV-I it was 2.02 [95% CI 0.99-4.14] times higher. For all 3 viruses
      combined, the ratio was 1.88 [95% CI 1.36-2.61]. The few incidence studies of HIV
      1 and HIV-2 indicated a similar tendency. Since differential mortality is
      unlikely to explain the pattern, the increase in the HIV-1, HIV-2 and HTLV-I
      female/male prevalence ratio suggests that older women may have increased
      exposure or susceptibility to all 3 retrovirus infections.

PMID- 10576125
TI  - Initial binding sites of antimicrobial peptides in Staphylococcus aureus and
      Escherichia coli.
AB  - We examined the initial binding sites of magainin 1, cecropin P1 and
      lactoferricin B in Staphylococcus aureus and Escherichia coli. All 3 peptides
      were active against E. coli, whereas only lactoferricin B exerted any activity
      against S. aureus. Soluble lipoteichoic acid and lipopolysaccharide both
      interacted with all 3 peptides, whereas soluble teichoic acid interacted with
      lactoferricin B only. Antibodies against teichoic acid diminished the activity of
      lactoferricin B, while antibodies against lipoteichoic acid had no influence on
      the activity of lactoferricin B. Antibodies against lipopolysaccharide diminished
      the activity of lactoferricin B and magainin 1, but had no effect on the activity
      of cecropin P1 against E. coli. We conclude that the initial binding sites of
      lactoferricin B in S. aureus, and of lactoferricin B and magainin 1 in E. coli,
      are teichoic acid and lipopolysaccharide, respectively. Cecropin P1 seems to
      interact with a different binding site than those of magainin 1 and lactoferricin
      B in E. coli.

PMID- 10576126
TI  - Helicobacter pylori infection in Ethiopian children: a cohort study.
AB  - Risk factors for infection with Helicobacter pylori (HP) were investigated in a
      cohort study of 121 seronegative children in Ethiopia aged 2-4 y, who had
      previously participated in a case-control study. Blood samples were drawn at
      inclusion in the cohort study and again after 12 and 30 months. At 12 months the
      parents were also interviewed about putative risk factors for infection, using a
      structured questionnaire. Analyses were made by comparing risk factors in
      seropositive and seronegative children. The seroconversion rate during the first
      year was 31% (27/87) and during the following 18 months 34% (17/50; corresponding
      to an annual incidence of 24%). After a period of 30 months, 58% (14/24) of the
      children who were 24-29 months old at inclusion in the study had seroconverted,
      compared with 40% (4/10) of those who were 30-35 months old, 73% (22/30) of those
      who were 36-41 months old and 31% (4/13) of those who were 42 months old or more.
      These results indicate that peak age for HP infection is below 6 y in this cohort
      in Ethiopia, and might also reflect a pattern of repeated seroconversion and sero
      reversion in early childhood. Independent predictors of HP-seroconversion were
      the variables 'drinking-water', comparing water from a well with water from
      rivers or pipes (RR = 1.46, 95% CI 1.0-2.15) and 'antibiotic treatment' (RR =
      1.84, 95% CI 1.16-2.92).

PMID- 10576127
TI  - PCR identification of the group A Neisseria meningitidis gene in cerebrospinal
      fluid.
AB  - The aim of this study was to develop a PCR method for direct identification of
      Neisseria meningitidis serogroup A in cerebrospinal fluid. The assay makes use of
      unique sites within the gene cassette responsible for expression of the (alpha1 -
      > 6)-linked N-acetyl-D-mannosamine-1-phosphate serogroup A capsule. A total of 67
      different N. meningitidis strains and 12 clinical samples of CSF, culture
      positive for N. meningitidis, were examined. All the strains and samples of N.
      meningitidis serogroup A were correctly identified by an amplified PCR product of
      519 bp. The PCR method for identification is specific for the group A gene of N.
      meningitidis. The assay may contribute to reducing recurrent, devastating
      epidemics of meningococcal infection by providing a diagnostic tool for grouping
      in developing countries where problems with false negative cultures are common
      and vaccination against serogroup A meningococci may be required.

PMID- 10576128
TI  - Improved recovery of Mycobacterium tuberculosis from pleural aspirates: bedside
      inoculation, heparinized containers and liquid culture media.
AB  - The effects of bedside inoculation, heparinized containers and liquid culture
      media on the recovery of Mycobacterium tuberculosis from pleural aspirates were
      evaluated in this study. Of 155 patients, 63 were diagnosed to have pleural
      effusion tuberculous in origin. The overall recovery of M. tuberculosis was
      57.1%. Bedside inoculation of the specimens produced a significantly higher yield
      than laboratory inoculation using non-heparinized specimens. When the pleural
      aspirates were transported in heparinized containers, the recovery rate was
      comparable to that from bedside inoculation, but lower when non-heparinized
      containers were used. No significant difference was found in recovery rate
      between the two liquid media, but the rate was significantly higher with the use
      of liquid media than conventional solid media. Thus, bedside inoculation of
      pleural aspirates, use of heparinized containers for transport for delayed
      inoculation in the laboratory and use of liquid culture media are recommended.

PMID- 10576129
TI  - Saquinavir hard gel suppresses viral load insufficiently in HIV-infected patients
      naive to anti-retroviral therapy: a retrospective cohort study.
AB  - Protease inhibitors are important components in anti-retroviral regimens. In this
      retrospective study 29 HIV-infected patients treated with a regimen of
      zidovudine, lamivudine and saquinavir hard gel in 1 centre in Denmark were
      compared with 58 patients treated with zidovudine, lamivudine and ritonavir or
      indinavir followed at 5 other centres in Scandinavia. All patients were naive to
      anti-retroviral therapy prior to institution of the actual anti-retroviral
      regimen and were followed for a median of 1.3 and 1.4 y respectively. The 2
      groups did not differ significantly with respect to age, gender, route of
      infection, ethnic background, viral load, CD4 count, AIDS at baseline or
      frequency of clinical controls. Six and 12 months after initiating anti
      retroviral therapy, 31% and 34% of the patients on the saquinavir regimen
      obtained HIV-RNA < or = 500 compared with 76% and 73% in the control group (p <
      0.001). In contrast to viral load, the increase in CD4 count did not differ
      significantly between the 2 groups. In conclusion, we found that with respect to
      suppression of viral load a regimen of saquinavir, zidovudine and lamivudine
      seemed to be inferior to a regimen of zidovudine, lamivudine and ritonavir or
      indinavir.

PMID- 10576130
TI  - Analysis of the discontinuation of protease inhibitor therapy in routine clinical
      practice.
AB  - We evaluated the frequency of and reasons for discontinuation of protease
      inhibitor therapy in a cohort of HIV-infected patients in a prospective
      observational study. We included 230 HIV-infected patients who had started
      protease inhibitor therapy between November 1996 and July 1997. Mean baseline CD4
      count was 138 cells/microl and HIV-RNA 4.5 log10. Forty-five percent of patients
      had prior AIDS and 77% had been treated with nucleoside analogues. Saquinavir
      treated patients were at a less advanced stage of HIV disease. Overall, 41.3% of
      patients discontinued therapy, and their last HIV-RNA measured higher than that
      of patients who continued therapy: 4.07 vs. 2.70 log10 (p < 0.0001). Reasons for
      discontinuation of therapy were poor adherence (including abandonment) (18.6%),
      drug intolerance (12.1%), virological failure (7%) and physician decision (3.5%).
      In a multivariate model, factors associated with drug discontinuation were not
      taking indinavir (OR 0.26, 95% CI 0.12-0.59) and being pretreated with nucleoside
      analogues (OR 3.42, 95% CI 1.58-7.42). We concluded that in routine clinical
      practice a high proportion of patients discontinued protease inhibitors during
      the first 6 months of therapy, the main reason being the patient's own decision
      (abandonment or poor adherence). Psychological support and counselling are
      warranted in patients when initiating protease inhibitor therapy.

PMID- 10576131
TI  - Activity of voriconazole: post-antifungal effect, effects of low concentrations
      and of pretreatment on the susceptibility of Candida albicans to leucocytes.
AB  - This study examined: (i) the post-antifungal effect (PAFE) of Voriconazole (UK
      109,496) on Candida albicans, at 2 concentrations (MIC and 4 x MIC) in the
      presence or absence of 10% human serum; (ii) the activity of low concentrations
      of the drug (1/4 x MIC) on yeasts that had previously been exposed to
      Voriconazole (PAFSE) with or without 10% human serum; and (iii) the effect of
      Voriconazole pretreatment on the fungicidal activity of leucocytes and serum
      against C. albicans (PALE). Two concentrations (0.25 and 1 mg/l) of Voriconazole
      induced no PAFE against C. albicans between -4.3 and -1.4 h, but when the assays
      were performed in the presence of serum, positive and concentration-dependent
      PAFEs were obtained (0.2-4.1 h). Pretreated yeasts were more susceptible than
      untreated yeasts to low concentrations (0.0625 mg/l) of Voriconazole, so the drug
      showed positive PAFSE that was dependent on the concentration used in
      pretreatment without serum (0.3-1.9 h) or with 10% human serum (0.5-2.5 h).
      Pretreatment of the growing C. albicans cells with Voriconazole (0.25 mg/l)
      increased their vulnerability to killing by leucocytes during the last 2 h (p <
      0.05), leading to PALE of 2 h. The results suggest that these effects might be
      used to evaluate the in vivo activity of an antifungal agent. The sum of the
      durations of these effects (PAFE, PAFSES and PALE) cause a considerable delay in
      yeast growth in treated cultures compared with control cultures.

PMID- 10576132
TI  - Oral hairy leukoplakia: a manifestation of primary infection with Epstein-Barr
      virus?
AB  - Oral hairy leukoplakia (OHL) is a characteristic lesion presumably secondary to
      Epstein-Barr virus (EBV) reactivation. It is frequently seen in individuals
      infected with the human immunodeficiency virus (HIV) and less often in other
      immunosuppressed individuals. The frequent association of this lesion with HIV
      infection and its rare occurrence in normal individuals usually motivates the
      search for immunosuppression, particularly secondary to HIV, when this lesion is
      found. We describe here a healthy HIV-negative individual with OHL and clinical
      and laboratory data suggestive of acute EBV infection.

PMID- 10576133
TI  - Encephalitis caused directly by Mycoplasma pneumoniae.
AB  - A case of non-fatal encephalitis in a 21-y-old immunocompetent woman is
      described. High titre serum antibodies against Mycoplasma pneumoniae were found.
      In addition, Mycoplasma pneumoniae DNA was detected in the cerebrospinal fluid by
      polymerase chain reaction. Neuroimaging findings by magnetic resonance and
      computed tomographic scanning of the brain, and laboratory investigations,
      including a search for serum antibodies to gangliosides, did not support an
      immune-mediated mechanism. No other pathogens were found. These results strongly
      suggest that the encephalitis was caused directly by Mycoplasma pneumoniae
      invasion of the central nervous system. They also indicate that such pathogenetic
      mechanism may sometimes be sufficient to explain neurological manifestations
      occurring during the course of Mycoplasma pneumoniae infection. The consequences
      for therapy are discussed.

PMID- 10576134
TI  - Toxic-shock-like-syndrome due to Streptococcus pneumoniae sinusitis.
AB  - We describe a patient with Streptococcus pneumoniae sinusitis associated with a
      severe sepsis syndrome and desquamative rash whose clinical illness strongly
      resembled toxic-shock syndrome. Assay of convalescent serum for antibodies to
      toxic-shock syndrome toxin 1 was negative. This case suggests the possibility of
      an additional bacterial pathogen associated with toxic-shock syndrome.

PMID- 10576135
TI  - Chronic brucellosis in workers in a meat-packing plant.
AB  - We report an outbreak of brucellosis among 9 patients in a meat-packing plant.
      All patients developed chronic brucellosis characterized by severe chronic
      musculoskeletal pains, diffuse arthralgia, myalgia and recurrent bouts of fever,
      which we suggest may be related to a delay in antibiotic treatment. All the
      patients had a prolonged recovery requiring rehabilitation therapy.

PMID- 10576136
TI  - Isolated pyogenic osteomyelitis of the odontoid process.
AB  - A case of isolated pyogenic osteomyelitis of the odontoid process is reported.
      Diagnosis was made using magnetic resonance imaging. Aggressive treatment,
      including transoral drainage of the abscess, antibiotics and cervical
      immobilization, resulted in a successful outcome. A review of the world's
      literature revealed only 15 previous reports of this rare entity.

PMID- 10576137
TI  - Reversible total IgA deficiency associated with phenytoin treatment.
AB  - A 55-y-old male developed long-standing upper respiratory symptoms during
      phenytoin treatment of epileptic fits. Complete lack of serum IgA was noted
      repeatedly. Following replacement of phenytoin, normal IgA levels were found and
      a slow improvement in respiratory symptoms occurred. Immunoglobulin deficiency,
      in particular low levels of IgA, are not uncommon among phenytoin treated
      subjects. The occurrence of frequent respiratory infections in such patients
      justifies the investigation of immunoglobulin levels.

PMID- 10576138
TI  - Abdominal tuberculosis: the problem of diagnostic delay.
AB  - Abdominal tuberculosis can be difficult to diagnose. In order to minimize
      diagnostic delay, an audit study showed that the Mantoux test and/or culture of
      ascitic fluid did not reveal tuberculosis immediately. Laparoscopy/laparotomy
      with Ziel-Nielson staining and culture of tissue biopsy always confirmed the
      diagnosis. It is suggested that biopsy should be the first line in investigating
      patients suspected of having abdominal tuberculosis.

PMID- 10576139
TI  - Cerebrospinal fluid nitric oxide levels in childhood bacterial meningitis.
AB  - The role of nitric oxide (NO) in childhood bacterial meningitis was investigated
      by determining the levels of nitrate/nitrite, stable end products of NO
      metabolism, in cerebrospinal fluid (CSF). Eighteen children with bacterial
      meningitis and 18 as a control group were included in the study. Mean (+/- SD)
      CSF nitrate/nitrite levels were 27.6 +/- 26 micromol/l in the bacterial
      meningitis group and 3.2 +/- 1.8 micromol/l in the control group (p = 0.0005). We
      found no correlation between CSF nitrate/nitrite levels and CSF white blood cell
      count (r = 0.22), protein (r = 0.26) or tumour necrosis factor alpha (TNF-alpha)
      levels (r = 0.046), but a moderate negative correlation between CSF
      nitrate/nitrite and glucose levels (r = -0.46).

PMID- 10576140
TI  - Epidemiology of HIV infection in the Republic of Korea.
AB  - Since the first case of human immunodeficiency virus (HIV) infection in the
      Republic of Korea (ROK) was detected in 1985, 876 HIV-infected patients have been
      reported, as of December 1998. The male to female ratio was 6.8:1, and 87% of the
      patients were between 20 and 49 years of age. The major modes of transmission
      were sexual contacts, accounting for 86% of the cases (65% heterosexuals and 21%
      homosexuals). Transmission through blood and blood products accounted for 28
      cases (3.2%), and vertical transmission for one case. No cases among intravenous
      drug abusers were reported. The seroprevalence among the blood donors was
      approximately one in 100,000. Subtypes A, B, C, D, E, and G of HIV-1 have been
      introduced into the ROK, and subtype B is the most predominant subtype. The
      frequency of the a deletion in the CCR5 gene, a coreceptor of HIV-1, was less
      than 1% among Koreans.

PMID- 10576141
TI  - Evaluation of antibody responses to pneumococcal vaccines with ELISA and
      opsonophagocytic assay.
AB  - Antibodies to a capsular polysaccharide (PS) provide protection against
      Streptococcus pneumoniae which express the homologous capsular serotype, and
      pneumococcal vaccines are designed to induce antibodies in the capsular PS.
      Levels and opsonophagocytic capacity of antibodies to the capsular PS of S.
      pneumoniae serotype 19F were determined by sera from adults immunized with 23
      valent S. pneumoniae capsular PS vaccines. Geometric means of IgG anti-19F
      antibody level and specific opsonic titer rise significantly after immunization.
      The level of anticapsular PS antibodies for S. pneumoniae 19F serotype is fairly
      well correlated (r2=O.63) with the opsonophagocytic activities of sera. However,
      3.7% (1/27) of serum samples display strikingly less opsonophagocytic activity
      than expected on the basis of their antibody level. Thus, antibody level may be
      of general use in predicting vaccine-induced protection among adults for 19F
      serotype. However, the opsonic activity data suggest that antibody levels are not
      always indicative of functional antibody.

PMID- 10576142
TI  - Effects of interleukin-10 on chemokine KC gene expression by mouse peritoneal
      macrophages in response to Candida albicans.
AB  - Chemokine KC has been considered to be a murine homologue of human GRO/MGSA and
      was identified as chemoattractant for monocytes and neutrophils. This study
      examined the expression of KC mRNA in thioglycollate-elicited mouse peritoneal
      macrophages that were stimulated in vitro with Candida albicans (CA). Also
      examined were the inhibitory effects of IL-10 on the CA-induced expression of KC
      gene by Northern blot analysis. CA was found to induce chemokine gene expression
      in a gene-specific manner, CXC chemokine IP-10 mRNA expression was not detected
      in CA-stimulated macrophages. Maximum KC mRNA expression was observed
      approximately 2 hr after adding CA. The inhibitory action of IL-10 to CA-induced
      KC mRNA expression on mouse peritoneal macrophages was independent on
      concentration and stimulation time of IL-10 and was observed approximately one
      hour after adding IL-10 and CA simultaneously. IL-10 produced a decrease in the
      stability of KC mRNA, and CA-stimulated macrophages with cycloheximide blocked
      the suppressive effect of IL-10. These results suggest that CA also induces
      chemokine KC from macrophages, and IL-10 acts to destabilize CA-induced KC mRNA
      and de novo synthesis of an intermediate protein is a part of the IL-10
      suppressive mechanism.

PMID- 10576143
TI  - Angiotensin II stimulates proliferation of adventitial fibroblasts cultured from
      rat aortic explants.
AB  - It has been proposed that the local renin-angiotensin system is activated in the
      adventitia after vascular injury. However, the physiological role of Angiotensin
      II (Ang II) in the adventitia has not been studied at a cellular level. This
      study was designed to assess the role of Ang II in the growth response of
      cultured adventitial fibroblasts (AFs). Adventitial explants of the rat thoracic
      aorta showed outgrowth of AFs within 5-7 days. Ang II caused hyperplastic
      response of AF cultures. The Ang II-induced mitogenic response of AFs was
      mediated primarily by the AT1 receptor. Ang II caused a rapid induction of
      immediate early genes (c-fos, c-myc and jun B). Induction of c-fos expression was
      fully blocked by an AT1 receptor antagonist but not by an AT2 receptor
      antagonist. Epidermal growth factor (EGF), platelet-derived growth factor-BB
      (PDGF-BB) and basic fibroblast growth factor (bFGF) induced DNA synthesis in AFs.
      Co-stimulation of AFs with the growth factors and Ang II potentiated the
      incorporation of 3H-thymidine into DNA. Results from this study indicate that Ang
      II causes mitogenesis of AFs via AT1 receptor stimulation and potentiates the
      responses to other mitogens. These data suggest that the Ang II may play an
      important role in regulating AF function during vascular remodeling following
      arterial injury.

PMID- 10576144
TI  - Augmented expression of cardiac atrial natriuretic peptide system in hypertensive
      rats.
AB  - The present study was aimed at investigating the regulation of atrial natriuretic
      peptide (ANP) system in association with either enhanced or attenuated activity
      of the renin-angiotensin system (RAS). The cardiac tissue mRNA and peptide levels
      of ANP were measured in rats with two-kidney, one clip (2K1C) or
      deoxycorticosterone acetate (DOCA)-salt hypertension. Plasma renin concentration
      was increased in 2K1C hypertension along with increases of renin mRNA and protein
      contents in the clipped kidney. On the contrary, it was suppressed in DOCA-salt
      hypertension along with decreases of renin mRNA and protein contents in the
      remaining kidney. The plasma ANP concentration was similarly increased in both
      models of hypertension. The cardiac tissue ANP contents were not significantly
      changed, but the tissue ANP mRNA levels were upregulated in the hypertrophied
      heart in these two models of hypertension. It is suggested that the cardiac ANP
      system is transcriptionally enhanced by cardiac hypertrophy associated with
      hypertension, independent of the systemic RAS.

PMID- 10576145
TI  - Percutaneous transmyocardial revascularization induces angiogenesis: a histologic
      and 3-dimensional micro computed tomography study.
AB  - The purpose of this study was to visualize the spatial patterns and connection of
      channels created after percutaneous transmyocardial revascularization (PTMR) in
      normal porcine hearts, and to estimate the relative contributions of
      transmyocardial and coronary perfusion. Six pigs underwent PTMR creating channels
      using radiofrequency ablative energy. Three-dimensional computed tomography
      imaging of channels 1 hr after PTMR showed the direct connection of PTMR channels
      to the myocardial capillary network and to epicardial coronary vessels. In the
      heart, examined 28 day after PTMR, there was a fine, extensive, network of
      microvessels originating from the site of the original PTMR channel, also
      connecting the left ventricular cavity to myocardial capillaries. Histopathologic
      examination of the 1-hr specimens showed numerous regions of myocardial
      hemorrhage and associated inflammatory cell infiltration. In the 28-day
      specimens, newly developed new vascular network suggested neovascularization
      within the core of these channel remnants. The immunoreactivity for basic
      fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF)
      were intense within myocardium and neovascular structure surrounding PTMR channel
      remnants. The vascular connections occur by direct communication with existing
      myocardial vasculature acutely, and angiogenesis in these channel remnant
      chronically.

PMID- 10576146
TI  - Left ventricular muscle mass regression after aortic valve replacement.
AB  - Implanting a valve that will reduce left ventricular mass is critical in aortic
      stenosis. Regression of left ventricular hypertrophy in 46 aortic valve
      replacement (AVR) patients receiving a St. Jude Medical (SJM) valve was assessed
      by serial electrocardiographic and echocardiographic studies during the
      preoperative, immediate, and late postoperative periods. The patients were
      divided into three groups according to valve size; 19 mm group (n=9), 21 mm group
      (n=20), and 23+mm group (n=17). There was no surgical mortality. The NYHA
      functional class improved from an average of 2.2+/-0.8 preoperatively to 1.3+/
      0.5 post-operatively. Left ventricular muscle mass index (LVMI) regression failed
      to reach statistical significance in the 19 mm group, whereas in the other two
      groups a steady decrease in the LVMI occurred with follow up. ECG findings were
      less remarkable showing insignificant differences in voltage among the three
      groups (p=0.000). In conclusion, the current data suggest that the 19 mm SJM
      valve may not result in satisfactory left ventricular muscle mass regression
      despite adequate function, even in small patients. Therefore, additional
      procedures to accommodate a larger valve may be warranted in the aortic annulus
      smaller than 21 mm.

PMID- 10576148
TI  - c-Myc expression is related with cell proliferation and associated with poor
      clinical outcome in human gastric cancer.
AB  - We underwent protein assay for Myc expression in 76 human gastric cancer tissues
      using immunohistochemistry. Expression of Myc protein was analyzed according to
      proliferative indices measured by flow cytometry. Levels of Myc protein
      expression was evaluated by correlating with biologic and clinical parameters. In
      36 (47.4%) of 76 primary gastric cancers, overexpression of Myc was observed. We
      could observe expression of Myc protein in a significant portion of early gastric
      cancer (42.9%). Expression of Myc protein was demonstrated to be more frequent in
      poorly differentiated cancer cells (p=0.043). However, expression of Myc protein
      had little influence over progress or extent of the disease. Expression of Myc
      protein was significantly correlated with increased proliferative activity
      (p=0.032) and patients with high levels of Myc expression had poor disease-free
      survival. In a certain proportion of human gastric cancer, Myc protein may
      function as a regulator of cancer cell growth and expression of Myc may represent
      an aggressive phenotype of gastric cancer.

PMID- 10576147
TI  - Comparison of CD34+ subsets and clonogenicity in human bone marrow, granulocyte
      colony-stimulating factor-mobilized peripheral blood, and cord blood.
AB  - To compare the clonogenicity and distribution of CD34+ subsets in bone marrow
      (BM), granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood
      (PB) and cord blood (CB), we analyzed in vitro colony formation and CD34+ cells
      co-expressing differentiation molecules (CD38, HLA-DR), myeloid associated
      molecules (CD13, CD33), a T-cell associated molecule (CD3), and a B-cell
      associated molecule (CD19) from mononuclear cells (MNCs) in the three
      compartments. The proportions of CD34+CD38- cells (BM: 4.4+/-2.8%, PB: 5.3+/
      2.1%, CB: 5.9+/-3.9%) and CD34+HLA-DR cells (BM: 4.7+/-3.4%, PB: 5.5+/-2.3%, CB:
      6.1+/-3.7%) did not differ significantly among the compartments. In contrast, a
      significantly higher proportion of CD34 cells of PB and CB co-expressed CD13
      (75.0+/-11.4%, 77.7+/-17.3%) and CD33 (67.1 +/-5.7%, 56.8+/-10.3%) compared with
      those of BM (43.0+/-6.3%, 27.6+/-5.1%) and a significantly higher number of
      granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming
      units (BFU-E) were detected in MNCs derived from PB and CB compared with those
      from BM (p<0.01). The proportion of CD34+CD19+ cells was higher in BM (34.9+/
      11.9%) than those in PB (5.6+/-3.0%) and CB (4.7=2.1%) (p<0.05). The proportion
      of CD34+CD3+ was comparable in all three compartments. In conclusion, our
      findings show that MNCs of mobilized PB and CB display similar phenotypic
      profiles of CD34+ subsets and clonogenicity, different from those of BM.

PMID- 10576149
TI  - Transforming growth factor-beta1 protein, proliferation and apoptosis of oval
      cells in acetylaminofluorene-induced rat liver regeneration.
AB  - Administering of 2-acetylaminofluorene (2-AAF) before a two-thirds partial
      hepatectomy (PHx) results in suppression of hepatocyte proliferation and
      stimulation of oval cell proliferation. The objectives of this study was to
      examine the oval cell behaviour and associated transforming growth factor-beta1
      (TGF-beta1) protein expression by combining 2-AAF with selective hepatic damage
      caused by PHx. We also studied the temporal relationship between TGF-beta1
      expression, and proliferation and apoptosis of oval cells. Oval cells emerged
      from the portal areas and became more numerous with time fanning out into the
      periportal and midzonal hepatic parenchyma. Both smooth muscle actin (SMA) and
      TGF-beta1 immunostain revealed that TGF-beta1-positive cells were SMA-positive
      hepatic stellate cells (HSCs). Coinciding with the proliferation of oval cells,
      an increase expression of TGF-beta1 produced by SMA-positive HSCs was observed,
      thereafter apoptosis of oval cells reached its peak. This result implicated that
      TGF-beta1 produced by HSCs is intimately associated with proliferation and
      apoptosis of oval cells, and plays a role in the cessation of oval cell
      activation and remodeling of liver parenchyma in 2-AAF induced liver
      regeneration.

PMID- 10576150
TI  - Surgical removal of visceral fat decreases plasma free fatty acid and increases
      insulin sensitivity on liver and peripheral tissue in monosodium glutamate (MSG)
      obese rats.
AB  - In order to evaluate the role of visceral and subcutaneous fat tissue in insulin
      sensitivity and lipid metabolism, we measured the fasting levels of plasma free
      fatty acid (FFA) and insulin, glucose disappearance rate (Rd), and hepatic
      glucose production rate (HGP) after surgical removal of visceral (VF) or
      subcutaneous (SF) fat tissue in monosodium glutamate-obese (MSG-Ob) rats.
      Monosodium glutamate obesity was induced in rats by neonatal injection of MSG.
      Surgery to remove fat was done at 15 weeks of age. The experiments were done four
      weeks after the surgery. MSG-Ob rats showed increased levels of FFA, insulin, and
      HGP and decreased Rd compared to normal rats. In the VF group, the FFA level and
      HGP were decreased to normal values, Rd was partially normalized, but the level
      of insulin did not change significantly compared to MSG-Ob. In the SF group, FFA
      and Rd were partially normalized, but HGP was not suppressed significantly
      compared to MSG-Ob. These results suggest that visceral fat affects the insulin
      sensitivity of liver and FFA concentration more than subcutaneous fat; however,
      no significant difference was shown on whole body insulin sensitivity and fasting
      insulin concentration.

PMID- 10576151
TI  - The relationship between plasma leptin and nutritional status in chronic
      hemodialysis patients.
AB  - Leptin serves an important role in suppressing appetite in mice and is known to
      be elevated in chronic renal failure (CRF) patients. But clinical significance of
      leptin as an appetite-reducing uremic toxin, remains to be determined. So we
      studied the relationship between plasma leptin and nutritional status in 46
      chronic hemodialysis (HD) patients. Pre HD leptin was measured and divided by
      body mass index (BMI) to give adjusted leptin levels. KT/Vurea (K, dialyzer urea
      clearance; T, duration of HD; V, volume of distribution of urea), C-reactive
      protein (CRP), plasma insulin and nutritional parameters such as serum albumin,
      normalized protein catabolic rate (nPCR), subjective global assessment (SGA), BMI
      and mid-arm muscle circumference (MAMC) were also measured. Mean plasma leptin
      levels were 8.13+/-2.91 ng/mL (male 3.15+/-0.70; female 14.07+/-6.14, p<0.05).
      Adjusted leptin levels were positively correlated with nPCR (male r=0.47, p<0.05;
      female r=0.46, p<0.05), SGA (male r=0.43, p<0.05; female r=0.51, p<0.05) and MAMC
      (male r=0.60, p<0.005; female r=0.61, p<0.05). They did not correlate with
      KT/Vurea, serum albumin, hematocrit, bicarbonate, insulin and CRP. Presence of DM
      and erythropoietin therapy had no effect on leptin levels. These results suggest
      that leptin is a marker of good nutritional status rather than a cause of protein
      energy malnutrition in chronic HD patients.

PMID- 10576152
TI  - Induction of c-Jun mRNA without changes of estrogen and progesterone receptor
      expression in myometrium during human labor.
AB  - To elucidate the endocrine mechanism of human parturition, the expression of c
      Jun and c-Fos mRNA were examined in relation to estrogen receptor (ER) and
      progesterone receptor (PR) in human myometrium. c-Jun mRNA was detected in all
      myometrial tissues (n=5) during labor but not before labor (n=5) and in oxytocin
      resistant postterm pregnancy (n=3). c-Fos mRNA was detected in only one
      myometrial tissue from a woman in labor. The distribution and intensity of
      immunostaining for ER and PR were semiquantitatively scored. During the late
      pregnancies, no significant difference was seen in the receptor scores for
      myometrial ER and PR between the patients who experienced labor and those who did
      not. Receptor scores for ER and PR were significantly lower in postterm pregnancy
      than in late pregnancy, regardless of the labor status. These data suggest that
      there are no changes in ER and PR in human myometrium during parturition. On the
      other hand, postterm pregnancy is associated with low ER and PR. c-Jun, induced
      during labor without changes in ER and PR, may play a role as a signaling
      mechanism in human myometrium.

PMID- 10576153
TI  - Chondroblastoma of the temporal bone: a clinicopathologic study of five cases.
AB  - Chondroblastoma is a rare benign bone tumor. It commonly affects the epiphysis of
      long bones during the second and third decades of life. Chondroblastoma of the
      temporal bone is extremely rare. We reviewed five cases of chondroblastoma
      arising in the temporal bone. Four cases were female and one was male. The ages
      ranged from 41 to 60 years (mean, 53.6 years). All cases involved the temporal
      bone. Three involved the left side and two the right. Chief complaints were long
      standing localized pain and hearing difficulty. A sharply demarcated lobulated
      mass was the main radiological finding. Microscopic findings were those of
      chondroblastoma of usual locations. Two cases showed aneurysmal bone cyst-like
      areas. Immunohistochemical studies for CD34, CD99, S-100 protein and cytokeratin
      were performed. Tumor cells were diffusely positive for S-100 protein in three
      cases and weakly positive for cytokeratin in one case. CD34 and CD99 were
      negative in all cases. In summary, chondroblastoma of the temporal bone is rare
      and occurs in older age group than reported cases of chondroblastoma of the usual
      location in the literature.

PMID- 10576154
TI  - Survival improvement with combined radio-chemotherapy in the primary central
      nervous system lymphomas.
AB  - The benefits of radio-chemotherapy in HIV-negative primary central nervous system
      (CNS) lymphomas were analyzed in 40 patients, who received radiotherapy to the
      brain or craniospinal axis with the total dose of 4460-5940 cGy to the primary
      tumor. Radiotherapy was followed by systemic chemotherapy, mainly with the
      cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) regimen, in 16
      of the patients. Follow-up ranged from four to 95 months with a median of 15
      months. The relapse rate was 72.5%, and 83% of the relapses occurred within the
      radiation field. Median survival was 19 months and the two-year survival rate was
      41%. Survival was significantly influenced by treatment method and radiation dose
      when measured by univariate analysis; median survival and the two-year survival
      rate was 29 months and 63% after radio-chemotherapy, while 13.5 month and 29%
      after radiotherapy alone (p= 0.027), and 22 months and 49% with doses of 50 Gy or
      more, but 12.5 months and 13% with doses less than 50 Gy (p=0.009). However,
      statistical significance was lost in multivariate analysis. These results might
      suggest the short-term efficacy of radio-chemotherapy, however, cautious
      observation is needed to confirm long-term effects.

PMID- 10576155
TI  - A case of prominent epicardial fat mimicking a tumor on echocardiography.
AB  - Epicardial fat may anteriorly produce an echo-free space that can be mistaken for
      pericardial fluid. We recently experienced a 67-year-old woman with prominent
      epicardial fat which was presented as an echogenic tumor-like mass. She underwent
      open pericardiostomy to relieve large amount of pericardial effusion. Operative
      findings revealed only prominent epicardial fat. Biopsy of the pericardial and
      fat tissues revealed an inflammation and normal fat cells without any malignant
      cell infiltration.

PMID- 10576156
TI  - Cervical thymic cyst in the elderly: a case report.
AB  - Cervical thymic cyst is uncommon and usually occurs in the first and second
      decades. Cervical thymic cyst after the third decade is so rare that it is very
      difficult to diagnose in spite of its typical location. We present a rare case of
      cervical thymic cyst in the lower left - anterior of the neck in a 50-year-old
      woman. It showed well-defined, anechoic cyst on ultrasonography and non-enhancing
      low attenuation mass on CT. A typical anatomic relationship was noted between the
      mass and carotid sheath.

PMID- 10576158
TI  - Immunoglobulin A nephropathy in patients with non-insulin dependent diabetes
      mellitus.
AB  - The occurrence of immunoglobulin A nephropathy (IgAN) in patients with noninsulin
      dependent diabetes mellitus (NIDDM) is a rare event and of pathogenetic interest.
      It is not clear whether this is merely coincidence. We report here five patients
      with IgAN in NIDDM associated with or without diabetic glomerulosclerosis. All of
      the patients were Korean males. In three patients, diabetes mellitus was
      diagnosed at the same time with diagnosis of IgAN, and the known duration of the
      diabetes in the other two patients were three and seven years, respectively.
      There was no evidence of diabetic retinopathy in four patients, but it was found
      in one patient. In all cases, the diagnosis of IgAN was made by immunohistology.

PMID- 10576157
TI  - Endoscopic retrograde pancreatographic findings of pancreatic lipomatosis.
AB  - Pancreatic lipomatosis is characterized by fatty infiltration or replacement of
      the pancreas, and has been associated with many conditions. We recently
      experienced two cases of pancreatic lipomatosis in patients with pancreatic
      pseudocyst and a case of lipomatosis in diabetes mellitus. In these patients,
      abrupt obstruction of the main pancreatic duct with smooth tapering is a typical
      endoscopic retrograde pancreatography (ERP) finding of pancreatic lipomatosis and
      must be differentiated with pancreatic carcinoma.

PMID- 10576159
TI  - Parosteal osteosarcoma of the scapula.
AB  - Parosteal osteosarcoma is a low-grade osteosarcoma, which occurs on the surface
      of the bone. We had experienced a parosteal osteosarcoma involving the flat bone,
      the scapula of a 21-year-old man. This is an extremely rare location for a
      parosteal osteosarcoma. Plain radiograph showed broad-based, well-defined
      radiodense lesion at the scapula. Computed tomogram demonstrated an intact cortex
      and absence of a medullary involvement. Tumor showed a lobulated, high-density
      lesion, indicating bone formation. Histologically, parosteal osteosarcoma is a
      well-differentiated osteosarcoma. The tumor is composed of a hypocellular
      proliferation of spindle cells, with minimal cytologic atypia. The bone is in the
      form of a well-formed bony trabeculae. Occasional cartilage is present in the
      form of a cap.

PMID- 10576161
TI  - Voyage to the land of developmental enamel mineralization.

PMID- 10576160
TI  - Large subcutaneous calcification in systemic lupus erythematosus: treatment with
      oral aluminum hydroxide administration followed by surgical excision.
AB  - A 32-year-old woman with a long-standing systemic lupus erythematosus had
      multiple subcutaneous nodules on her axillae, iliac crests and limbs. Three years
      ago, these nodules began to appear and slowly became larger. Some of them amassed
      to form a large, fungating, lobulated mass on her right iliac crest.
      Roentgenographic and histological examination showed that they were calcium
      deposits. She was initially treated with aluminum hydroxide administration for
      nine months, which resulted in moderate decrease in size and softening in
      consistency, but not complete resolution. Then, the mass on the right iliac crest
      was excised, with an excellent early result.

PMID- 10576162
TI  - Synthesis and secretion of MCP-1 by dental follicle cells--implications for tooth
      eruption.
AB  - The monocyte chemotactic protein-1 (MCP-1) gene is expressed in the dental
      follicle, a loose connective tissue sac that must be present for eruption to
      occur. The role of MCP-1 may be to recruit mononuclear cells (monocytes) to the
      dental follicle, where these cells, in turn, fuse to form osteoclasts to resorb
      alveolar bone for the formation of an eruption pathway. Thus, it was the aim of
      this study to determine if MCP-1 is secreted by dental follicle cells in culture
      and if its secretion is enhanced by potential tooth eruption molecules. Western
      blotting and a two-site capture enzyme-linked immunoabsorbent assay demonstrated
      that MCP-1 was synthesized and secreted into the medium by the follicle cells.
      Incubation of the cells with either transforming growth factor-beta one (TGF-beta
      1) or interleukin-one alpha (IL-1 alpha) enhanced the secretion of MCP-1 by the
      cells. Measurement of the chemotactic ability of the conditioned medium to
      attract mouse monocytes demonstrated that the chemotaxis of the medium was
      increased if the cells had previously been incubated in IL-1 alpha, although
      there appears to be a threshold concentration of MCP-1 above which chemotaxis is
      not enhanced. These combined results suggest that the critical initial cellular
      event of tooth eruption, an influx of mononuclear cells into the dental follicle
      at an early post-natal age, may be initiated by the secretion of MCP-1 by the
      dental follicle cells.

PMID- 10576163
TI  - Implantation of octacalcium phosphate (OCP) in rat skull defects enhances bone
      repair.
AB  - Synthetic octacalcium phosphate (OCP) enhances bone formation if implanted into
      the subperiosteal region of murine bone. Such implanted OCP may be resorbed and
      replaced by bone with time. We hypothesized that OCP could be used as an
      effective bone substitute. To test this hypothesis, we designed the present study
      to investigate if bone repair in a rat skull defect is enhanced by the
      implantation of OCP. Rats were divided into two groups: OCP-treated animals and
      untreated controls. Six rats from each group were fixed at 4, 12, and 24 weeks
      after implantation. A full-thickness standardized trephine defect was made in the
      parietal bone, and synthetic OCP was implanted into the defect. After being
      examined radiographically, the specimens were decalcified and processed for
      histology. OCP implantation significantly promoted bone repair compared with the
      controls. A statistical analysis showed an increase in the area of radiopacity
      within the skull defect between week 4 and week 12. Histologically, bone was
      formed on the implanted OCP and along the defect margin at week 4. At week 12,
      the implanted OCP was surrounded by newly formed bone. At week 24, the defect was
      almost completely filled with bone. In the control, bone formation was observed
      only along the defect margin. The present results demonstrate that OCP could be
      used as an effective bone substitute.

PMID- 10576164
TI  - Blood circulation as source for osteopontin in acellular extrinsic fiber cementum
      and other mineralizing tissues.
AB  - Osteopontin (OPN) is one of the major non-collagenous proteins in root cementum
      and other mineralized tissues. Although most of this mineral-seeking protein is
      thought to be produced by local tissue cells, some of it might enter the
      mineralizing matrix from the blood. To test this hypothesis, we followed the
      distribution of a single dose of purified porcine or rat 125I-labeled OPN
      injected i.v. in rats, in mineralizing and non-mineralizing tissues and in
      subcutaneously implanted collagenous implants. The animals were killed 30 or 48
      hrs after injection. Tissues (calvaria, tibia, lower and upper jaws) were
      harvested and processed for radioautography and biochemical analysis. Tissues as
      well as calcifying collagenous implants proved to have taken up radiolabel. In
      EDTA extracts of long bones, the majority of the radiolabel was demonstrated to
      be associated with intact OPN. The iodinated protein was also found in the
      acellular extrinsic fiber cementum (acellular cementum) layer investing the
      continuously growing incisors, in laminae limitantes, cement lines, and in
      forming bone near the mineralization front. Further, the label was present in the
      circumpulpal dentin of the incisors, and some of it appeared to have been
      incorporated into developing enamel. It is concluded that OPN in acellular
      cementum and other mineralizing tissues may-at least partially-originate from
      sources outside the direct environment following its transportation via serum.

PMID- 10576165
TI  - Pellicle precursor proteins: acidic proline-rich proteins, statherin, and
      histatins, and their crosslinking reaction by oral transglutaminase.
AB  - Previous studies have demonstrated that whole saliva and pellicle formed in vitro
      from oral fluid contain covalently crosslinked salivary proteins. The purpose of
      this study was to determine which salivary proteins can act as substrates for
      transglutaminase, an enzyme responsible for the covalent crosslink reaction
      between a glutamine residue and a lysine residue. Transglutaminase was prepared
      from the pellet fraction of human whole saliva. Dansyl cadaverine (N-dansyl-1,5
      diaminopentane) was used to study the reactivity of glutamine residues in acidic
      large and small proline-rich proteins, statherin, and the major histatins,
      whereas a glutamine-containing dansylated peptide was used to study the
      reactivity of lysine residues in these proteins. Crosslink formation was measured
      fluorometrically after the addition of fluorescent probe to the salivary protein
      substrate and transglutaminase. The covalent attachment of the fluorescent probe
      to salivary proteins was confirmed by SDS-PAGE. It was found that almost all of
      the lysines present in the acidic PRPs and statherin, and some of the lysines
      present in histatins, could participate in the crosslink reaction. Glutamine
      reactivity was also observed, but a maximum of only 14% of glutamine residues
      present in acidic PRPs and statherin participated in the crosslink formation.
      These results demonstrate that primary pellicle precursor proteins, acidic
      proline-rich proteins, statherin, and the major histatins are capable of
      undergoing crosslink reactions catalyzed by oral transglutaminase. This may
      enable other proteins in the oral cavity to be incorporated into the acquired
      enamel pellicle.

PMID- 10576166
TI  - Reduced in vivo cell-mediated immune responses to mumps, tuberculin, and
      streptokinase/streptodornase but not to Candida albicans in oral lichen planus.
AB  - Oral lichen planus is considered to be a T-cell-mediated disease. The purpose of
      this study was to investigate the capacity of T-lymphocytes in oral lichen planus
      patients to respond to a number of commonly encountered environmental antigens in
      vivo. To do this, we assessed dermal delayed-type hypersensitivity responses to
      mumps, streptokinase/streptodornase, Candida albicans, and purified protein
      derivative of tuberculin (PPD) in 17 oral lichen planus patients and in matched
      controls. Reduced induration in response toward mumps, PPD, and
      streptokinase/streptodornase was demonstrated in oral lichen planus patients
      compared with controls. In addition, the total sum of induration diameters was
      decreased in the patients. However, C. albicans stimulation resulted in similar
      levels of response in both groups. The differences in induration size between
      matched patients and controls for mumps and PPD were thus significantly greater
      than the corresponding differences for the C. albicans antigen. This suggests
      that a selective difference in the response to these antigens exists in oral
      lichen planus patients. The results may point to a loss of memory T-helper
      function to infrequently encountered environmental antigens, represented by
      mumps, PPD, and streptokinase/streptodornase, contrarily to memory function to
      common antigens (C. albicans), which seem to be unaffected.

PMID- 10576167
TI  - Morphological and functional characteristics of acinar atrophy and recovery in
      the duct-ligated parotid gland of the rat.
AB  - Although acinar atrophy occurs frequently in salivary diseases, the relationship
      between structural changes and functional decrements is not well-established, and
      the potential for recovery of histological and functional integrity has not been
      wholly quantified. We aimed, therefore, to develop further our understanding of
      pathological acinar atrophy. Stensen's duct was ligated for periods up to six
      weeks and, in separate experiments, was de-ligated after two weeks and allowed to
      recover for up to two weeks. Qualitative and quantitative histological analyses
      were carried out. Additionally, the ability of enzymatically dispersed cells from
      ligated and de-ligated glands to respond to neurohormonal stimuli was also
      measured. The results confirmed that totally obstructed glands undergo a rapid,
      progressive severe atrophy amounting to absolute losses of over 85% of acinar
      tissue by two weeks. Acinar shrinkage and cell losses through apoptosis accounted
      for the glandular atrophy. Remaining intralobular epithelia consisted of
      extremely atrophic acini and numerous duct-like structures with intermediate
      forms. Dispersed cells from atrophic glands exhibited agonist-induced release of
      chloride similar to normal. Together, these structural-functional results confirm
      the persistent viability of acinar-like cells in the obstructed gland and suggest
      that the duct-like structures are derived from surviving atrophic acini. De
      ligated glands exhibited a near-normal recovery of structure by two weeks. Their
      enzymatically dispersed cells responded normally to agonist stimulation. The
      results support the view that pathological atrophy is largely similar to
      physiological atrophy, providing a mechanism for acinar cell survival under
      adverse conditions, with the possibility of eventual recovery.

PMID- 10576168
TI  - Suppression of jaw-opening and trigemino-hypoglossal reflexes during swallowing
      in the cat.
AB  - Jaw-opening and trigemino-hypoglossal reflexes can be evoked by innocuous as well
      as noxious afferents from intra-oral structures. It has been reported that the
      amplitude of the jaw-opening reflex evoked by weak electrical stimulation of the
      upper lip is subject not only to tonic suppression but also to phase-linked
      modulation during mastication. In this study, we investigated whether the jaw
      opening and trigemino-hypoglossal reflexes are modulated during swallowing. Data
      were obtained from 8 chloralose-anesthetized cats. Reflexes were monitored by
      electromyographic activities recorded from the anterior digastric, genioglossus,
      and styloglossus muscles and, after paralysis, by the efferent discharge in the
      digastric and hypoglossal nerves. Swallowing was elicited either by water dropped
      on the tongue or by repetitive stimulation of the superior laryngeal nerve. Jaw
      opening and trigemino-hypoglossal reflexes were evoked by stimulation of the
      lingual nerve, and the evoked afferent volley was recorded from the Gasserian
      ganglion so that the threshold of the lingual nerve could be determined. The
      following results were obtained: (1) The jaw-opening and trigemino-hypoglossal
      reflexes evoked by stimulation of the low-threshold, but not high-threshold,
      lingual afferents were remarkably suppressed during swallowing; and (2) both the
      jaw-opening and trigemino-hypoglossal reflexes evoked by low-threshold lingual
      afferents were suppressed during fictive swallowing after the animals were
      paralyzed. We conclude that the jaw-opening and trigemino-hypoglossal reflexes
      evoked by low-threshold lingual afferents are suppressed during swallowing by a
      central motor program.

PMID- 10576169
TI  - Cold pressor stimulation effect on hemodynamic changes following sustained
      isometric contraction in human jaw-closure muscles.
AB  - It is postulated that an altered adrenergic response pattern may be associated
      with chronic muscle pain states. To evaluate this hypothesis, one must fully
      understand the effect of an adrenergic activation on masticatory muscle blood
      flow under various conditions. This study evaluated the effect of a 12 degrees C
      cold pressor stimulation (a mild adrenergic activator), applied to the hand
      forearm area, on intramuscular hemodynamics in the human masseter and temporalis
      muscles following a sustained isometric contraction. We assessed hemodynamics by
      measuring intramuscular hemoglobin concentration repeatedly, using a non-invasive
      near-infrared spectroscopy device. Measurements were taken before, during, and
      after a 30-second sustained 50% maximum voluntary contraction task. Fourteen
      healthy subjects, seven males and seven females, with no history of muscle pain
      in the masticatory system participated in this study. This protocol was repeated
      three times, but in the second trial, the cold pressor stimulation was applied to
      the subject during and for 5 min after the sustained contraction task. Repeated
      measure analysis of variance performed on these data revealed that the peak
      hemoglobin concentration levels in the post-contraction recovery period were
      significantly reduced (between 13 and 14%) with cold pressor stimulation, both in
      the masseter (p < 0.001) and in the temporalis (p < 0.001) muscles. The results
      suggest that cold pressor stimulation produced a reduced intramuscular
      vasodilative response in these muscles during the immediate post-contraction
      period. One explanation for these results is that altering the local chemical
      environment of the muscle affects the adrenergic response pattern typically
      induced by a cold pressor stimulation.

PMID- 10576170
TI  - Morphologic and biochemical changes of the masseter muscles induced by occlusal
      wear: studies in a rat model.
AB  - Occlusal alterations may result in changes in the functional performance of
      masticatory muscles. In this study, we set up an experimental model in rats to
      examine whether masticatory muscle abnormalities occur after a malocclusion is
      induced. Rats underwent unilateral amputation of the molar cusps to simulate an
      occlusal wear situation. The masseter muscles ipsilateral and contralateral to
      the amputated molars were excised at different experimental times. Sham-operated
      rats were used as controls. The tissue samples were studied by light and electron
      microscopy and morphometry. Tissue calcium content, a biochemical index of muscle
      injury, was also determined. The results show that occlusal dysfunction leads to
      microvessel constriction and clear-cut morphologic damage of muscular fibers and
      blood capillary endothelium, as well as to elevation of tissue calcium content,
      in the ipsilateral masseter muscle. These changes are likely related to muscle
      fatigue and ischemia. The early signs of injury do not involve the entire muscle
      but are mostly restricted to tissue areas rich in type I (slow) muscle fibers,
      which are characterized by a predominantly aerobic metabolism. The muscle damage
      becomes more extended and severe with time. On the other hand, the contralateral
      muscles show only slight alterations which are reversible with time, possibly due
      to an adaptive response.

PMID- 10576171
TI  - Orthodontists' perceptions of the impact of phase 1 treatment for Class II
      malocclusion on phase 2 needs.
AB  - The most appropriate timing for the treatment of Class II malocclusions is
      controversial. Some clinicians advocate starting a first phase in the mixed
      dentition, followed by a phase 2 in the permanent dentition. Others see no clear
      advantage to that approach and recommend that the entire treatment be done in the
      late mixed or early permanent dentition. This study examines how orthodontists,
      blinded to treatment approach, perceive the impact of phase 1 treatment on phase
      2 needs. The sample consisted of 242 Class II subjects, aged 10 to 15, who had
      completed phase 1 or observation in a randomized clinical trial (RCT). For each
      subject, video orthodontic records, a questionnaire, a fact sheet, and a
      cephalometric tracing were sent to five randomly selected reviewing orthodontists
      blinded to subject group and study purpose. Reviewing orthodontists were asked to
      assess treatment need, general approach, need for extractions, priority,
      difficulty, and determinants. Orthodontists agreed highly on treatment need (95%)
      and moderately on treatment approach (84%) and extraction need (80%). They did
      not perceive differences in need, approach, or extractions between treated and
      control groups. Treated subjects were judged as less difficult (p = 0.0001) and
      to have a lower treatment priority (p = 0.0001) than controls. In ranking
      problems that affect treatment decisions, the orthodontists ranked dental Class
      II (p = 0.005) and skeletal relationships (p = 0.004) more highly in control than
      in treated patients. These data indicate that orthodontists do not perceive phase
      1 treatment for Class II as preventing the need for a second phase or as offering
      any particular advantage with respect to preventing the need for extractions or
      other skeletal treatments in that second phase. They do view early Class II
      treatment as an effective means of reducing the difficulty of and priority for
      phase 2.

PMID- 10576172
TI  - A controlled daytime challenge of motor performance and vigilance in sleep
      bruxers.
AB  - Many etiological factors have been suggested for sleep bruxism. Among these,
      elevated mental and physical alertness has been proposed to characterize sleep
      bruxers. The present study tests the hypothesis that, during the day-time, sleep
      bruxers are more vigilant and more prone to react to a motor command than are
      control subjects. Seven sleep bruxers, diagnosed polysomnographically according
      to validated research criteria, were matched for age and gender to seven control
      subjects. A simple reaction time task was selected to assess daytime vigilance
      and motor responsiveness. The following physiological measures were recorded:
      reaction time, error rate, electroencephalography, electrocardiography,
      electromyography, and video detection of body movements. Analysis of these
      variables showed no differences between groups. During the test, bruxers and
      controls showed a parallel decrease in EEG vigilance and heart rate over time.
      Frequency of orofacial and body movements was the same in both groups, and no
      clenching activity was observed during the experimental test. Subjects' visual
      analog scale ratings revealed that both controls and bruxers were more
      competitive after the test than before, and bruxers were slightly more anxious
      than controls before and after the test. Together, the results indicate that
      sleep bruxers are neither more vigilant nor more prone to react to a motor
      command during the daytime than are control subjects.

PMID- 10576173
TI  - Risk factors for perinatal human immunodeficiency virus transmission in patients
      receiving zidovudine prophylaxis. Pediatric AIDS Clinical Trials Group protocol
      076 Study Group.
AB  - OBJECTIVE: To identify modifiable obstetric factors associated with the failure
      of zidovudine chemoprophylaxis to prevent perinatal human immunodeficiency virus
      type 1 (HIV-1) transmission. METHODS: We analyzed data from Pediatric AIDS
      Clinical Trials Group protocol 076, a randomized, double-masked, placebo
      controlled trial that demonstrated that a zidovudine regimen could prevent
      perinatal HIV-1 transmission. We estimated the zidovudine treatment effect using
      the relative reduction in transmission risk among women randomized to treatment
      with zidovudine compared with women randomized to receive placebo. Univariate and
      multivariate statistical analyses were used to assess whether the treatment
      effect differed in magnitude according to potential antepartum or intrapartum
      risk factors. RESULTS: In the univariate analysis, the zidovudine treatment
      effect was found to differ significantly in magnitude according to quartile of
      maternal weight at the time of study entry (interaction test, P = .03); among
      women in the heaviest-weight quartile (weight more than 82 kg), there was a 26%
      relative reduction in transmission risk, compared with a 79% relative reduction
      among the other three quartiles (interaction test, P = .05). In the zidovudine
      treatment group, women who transmitted HIV-1 were significantly more likely than
      nontransmitters to have had antepartum procedures or conditions associated with
      increased risk of fetal exposure to maternal blood or cervicovaginal secretions
      (43% compared with 19%, P = .04). In the multivariate analysis, adjustment for
      the plasma HIV-1 RNA level and CD4+ cell percentage did not eliminate the
      differential treatment effect according to these factors. CONCLUSION: High
      maternal weight and conditions associated with fetal exposure to maternal blood
      or cervicovaginal secretions may diminish the efficacy of zidovudine
      chemoprophylaxis.

PMID- 10576174
TI  - Prenatal diagnosis of fetal cytomegalovirus infection after primary or recurrent
      maternal infection.
AB  - OBJECTIVE: To determine the reliability of prenatal diagnosis of cytomegalovirus
      infection in women with primary or recurrent infection. METHODS: Amniotic fluid
      (AF) samples from 117 pregnant women were evaluated for cytomegalovirus culture
      and cytomegalovirus-DNA detection. Neonatal and postnatal samples also were
      examined to confirm or exclude transmission of maternal-fetal cytomegalovirus
      infection. RESULTS: Of 25 women with primary cytomegalovirus infection, 13 (52%)
      had cytomegalovirus-positive AF samples by polymerase chain reaction (PCR), nine
      of which also were diagnosed by culture. All eight neonates born to mothers whose
      AF was cytomegalovirus-positive by PCR and culture were cytomegalovirus infected,
      and three were symptomatic. One aborted fetus had cytomegalovirus-DNAemia. Of
      four women with cytomegalovirus-positive AF samples by PCR only, two delivered
      asymptomatic cytomegalovirus-infected neonates and two aborted (one fetus had
      cytomegalovirus encephalopathy). Of 45 mothers with recurrent infection, two with
      AF cytomegalovirus-positive by PCR and culture, and another with cytomegalovirus
      positive AF samples by PCR only, aborted cytomegalovirus-DNA-positive fetuses. Of
      the other seven women with cytomegalovirus-positive AF samples by PCR only, two
      delivered asymptomatic cytomegalovirus-infected neonates, two delivered neonates
      cytomegalovirus-positive by PCR only (one was symptomatic), and three delivered
      infants cytomegalovirus-negative by PCR and culture. All 47 mothers with
      nonactive cytomegalovirus infection and cytomegalovirus-negative AF samples had
      uninfected neonates. Polymerase chain reaction was superior to viral culture in
      sensitivity and negative predictive value (100% compared with 57% and 94%,
      respectively) but was lower in specificity and positive predictive value (97% and
      83%, respectively, compared with 100%). CONCLUSION: Prenatal diagnosis of fetal
      cytomegalovirus infection should include PCR in addition to viral culture,
      particularly for congenital cytomegalovirus infections following maternal
      recurrence.

PMID- 10576175
TI  - Value of perinatal autopsy.
AB  - OBJECTIVE: To determine how often a perinatal autopsy identified the cause of
      death, and how frequently this information changed recurrence risk estimates or
      altered parental counseling. METHODS: We reviewed all autopsies of fetal
      stillbirths and briefly viable neonates performed by one perinatal pathologist at
      the University of Alabama Hospital from 1992 to 1994. RESULTS: Four hundred
      sixteen fetal and early neonatal deaths occurred at our hospital from January 1,
      1992, to June 1, 1994. Consent for an autopsy examination was granted for 139 of
      these (33%), and all autopsies were performed by a single perinatal pathologist.
      Abnormalities likely to be the cause of death were identified in 130 of 139 cases
      (94%). Ninety-one subjects did not have structural anomalies: In 14 cases autopsy
      revealed previously unsuspected pathology that altered parental counseling; in 68
      cases autopsy findings were consistent with the clinical obstetrical diagnosis;
      and in nine cases the cause of death could not be identified. Forty-eight
      subjects were anomalous. Thirty-seven of these (79%) had been evaluated by
      antenatal ultrasonography, and autopsy identified additional abnormalities in 51%
      (19 of 37). In the 11 deaths evaluated neonatally, a previously unsuspected
      diagnosis likely to be the cause of death was identified in three. Overall,
      autopsy findings changed recurrence risk estimates and/or parental counseling in
      36 of 139 cases (26%). CONCLUSION: The cause of fetal or perinatal death was
      determined by autopsy in 94% of cases in our series. Counseling and recurrence
      risk estimates were altered by autopsy findings in 26%.

PMID- 10576176
TI  - Comparison of late-second-trimester nonstress test characteristics between small
      for gestational age and appropriate for gestational age infants.
AB  - OBJECTIVE: To compare electronic fetal heart rate (FHR) monitoring
      characteristics between appropriate for gestational age (AGA) fetuses and small
      for gestational age (SGA) fetuses and to determine whether SGA fetuses have
      specific abnormalities at second-trimester electronic fetal monitoring (EFM),
      using nonstress test. METHODS: Among 953 children born from 1993-1996, we
      identified 500 singleton infants born after 36 weeks' gestation of uncomplicated
      pregnancies in whom second-trimester (24-27 weeks' gestation) EFM records were
      obtained. Individual components of FHR patterns (baseline rate, baseline FHR
      variability, presence of acceleration [at least 10 beats per minute for at least
      10 seconds], and periodic or episodic deceleration [at least 25 beats per minute
      for at least 15 seconds]) and birth characteristics were compared between AGA and
      SGA infants, or between pregnancies with or without second-trimester
      decelerations. RESULTS: Among 500 infants, 443 were AGA and 57 SGA; 105 had and
      395 did not have second-trimester decelerations. Baseline FHR variability (12.9+/
      3.2 beats per minute) in SGA fetuses was significantly higher than variability
      (10.3+/-3.4 beats per minute) in AGA fetuses (P<.001). Small for gestational age
      fetuses were significantly more likely to have second-trimester decelerations
      than AGA fetuses (33.3% vs. 19.4%, P<.05). There were no significant differences
      in baseline rate and accelerations between AGA and SGA infants. Small for
      gestational age infants were more frequent in pregnancies with second-trimester
      decelerations, compared with those without second-trimester decelerations (18.1%
      vs. 9.6%, P<.05). Baseline FHR variability in pregnancies with second-trimester
      decelerations was significantly higher than in pregnancies without second
      trimester decelerations (12.2+/-3.7 vs. 10.0+/-3.1 beats per minute, P<.001).
      CONCLUSION: Periodic or episodic decelerations and increased FHR variability
      during late second-trimester EFM were associated with an increased risk of SGA
      birth weight.

PMID- 10576177
TI  - Clinical implications of atypical chromosome abnormalities diagnosed prenatally.
AB  - OBJECTIVE: To determine the frequency of atypical aneuploidy resulting from
      prenatal testing and assess the implications of these diagnoses on prenatal
      decision making. METHODS: We reviewed all amniotic fluid and chorionic villus
      samples obtained between January 1994 and September 1997 and grouped the abnormal
      cases into typical or atypical subcategories. This distinction was based upon
      whether the diagnosis provided a straightforward range of prognoses or an
      ambiguous clinical implication. Results were stratified by sample source to
      determine whether atypical aneuploidy was more commonly seen in cultures of
      chorionic villi or amniocytes. We also evaluated the influence of ultrasound
      findings on prenatal decision making in atypical aneuploid cases. RESULTS: Of
      2960 samples, 134 were abnormal (4.4%), with 27 of 134 abnormalities (20%)
      representing atypical aneuploidies. The percentages of chorionic villus and
      amniocentesis cases complicated by atypical aneuploidy (22% and 78%,
      respectively) were consistent with the distribution of procedures in the entire
      study. Ultrasound abnormalities did not invariably prompt a decision to terminate
      pregnancy (only two terminations of six fetuses with congenital malformation),
      whereas atypical karyotypes led to termination even in the presence of normal
      appearing fetal anatomy (five terminations of 21 without malformations; P = .63).
      CONCLUSION: The frequency of atypical aneuploidy resulting from prenatal
      diagnosis was approximately 1.0%, and these cases represented 20% of all abnormal
      karyotypes observed. The ambiguity conferred by atypical aneuploidy can influence
      a family's decision making, even in the presence of normal ultrasound findings.

PMID- 10576178
TI  - Adverse obstetric outcome in low- and high- risk pregnancies: predictive value of
      maternal serum screening.
AB  - OBJECTIVE: To determine whether the relationship between adverse pregnancy
      outcome and elevated maternal serum alpha-fetoprotein (MSAFP) and/or maternal
      serum hCG levels in women whose fetuses have no chromosomal abnormalities or
      neural tube defects is restricted to pregnancies with a priori elevated risk for
      pathology or also present in low-risk pregnancies. METHODS: The outcomes of
      pregnancy in two groups of patients with elevated MSAFP and/or maternal serum hCG
      values were compared with the outcomes of a reference group with normal serum
      values. The first study group consisted of 83 women without pre-existing risk for
      poor outcome as defined by the guidelines of the Dutch Society of Obstetrics and
      Gynecology. The second study group consisted of 62 women with a priori elevated
      risk according to these guidelines. RESULTS: Fetal or neonatal death, pregnancy
      induced hypertension, placental abruption, placenta previa, preterm delivery,
      delivery of infants with birth weights in the 2.3rd percentile, and complications
      during the third stage of labor occurred significantly more often in patients
      with elevated values and low a priori risk than in women with normal values and
      without pre-existing risk factors. There was no significant increase in adverse
      pregnancy outcome in women with elevated values and high a priori risk compared
      with women with normal values and elevated a priori risk. CONCLUSION: In women at
      low risk, elevated MSAFP and/or maternal serum hCG values are predictive of
      adverse pregnancy outcome. In women with a priori elevated risk, abnormal serum
      values do not increase this risk.

PMID- 10576179
TI  - General health and psychological symptom status in pregnancy and the puerperium:
      what is normal?
AB  - OBJECTIVE: To identify normative changes in psychological and physiologic health
      status associated with pregnancy and the puerperium. METHODS: Self-administered
      surveys containing Ware's Short Form-36 and Derogatis's Brief Symptom Inventory
      were completed by 393 pregnant women during their third trimester. Of those, 253
      completed the same survey during the puerperium. Results were compared between
      periods and with those of samples of women from standardized community samples.
      RESULTS: On the Short Form-36, pregnant women in the third trimester had
      significantly poorer levels of functioning (P<.01) than community controls with
      regard to bodily pain (51.86 versus 79.61), physical functioning (62.91 versus
      89.12), social functioning (74.0 versus 84.06), vitality (47.24 versus 58.04),
      and functional limitations resulting from physical health problems (45.0 versus
      86.73) subscales. Those differences persisted into the puerperium. Compared with
      pregnancy, scores on social functioning and functional limitations caused by
      emotional problems decreased during the puerperium. Women reported improved
      perceptions of their general health in the puerperium compared with community
      controls (80.22 versus 74.80). On the Brief Symptom Inventory, pregnant women
      reported significantly higher levels of emotional distress on the three global
      measures and on the somatization (0.75 versus 0.35), obsessive-compulsive (0.70
      versus 0.48), and hostility (0.59 versus 0.36) subscales than controls; those
      changes normalized in the puerperium. CONCLUSION: Pregnancy and the puerperium
      are associated with significant changes in psychological and physiologic health
      status. Documentation of those changes is important if the Short Form-36 and
      Brief Symptom Inventory are to be used in health outcomes research with this
      population.

PMID- 10576180
TI  - Serious maternal morbidity after childbirth: prolonged hospital stays and
      readmissions.
AB  - OBJECTIVE: To determine the frequency of and risk factors for serious morbidity
      resulting in a prolonged hospital stay or readmission among women enrolled in
      Tennessee's Medicaid program who delivered live or dead infants in 1991. METHODS:
      This retrospective cohort study included 33,251 women of white or black
      ethnicity. Main outcome measures included childbirth-related medical conditions
      serious enough to result in death, prolonged delivery hospitalization, or
      readmission within 60 days of delivery. RESULTS: Among 25,810 women with vaginal
      (78%) and 7441 (22%) women with cesarean deliveries, 2.6% and 8.9%, respectively,
      had at least one childbirth-related medical condition requiring prolonged
      delivery hospitalization or readmission, including infection (1.8% and 7.9%),
      hypertension-related complications (0.7% and 2.0%), or hemorrhage (0.5% and
      2.4%). After controlling for other risk factors, maternal age over 32 years was
      independently associated with increased rate of serious morbidity among women who
      had vaginal (relative risk [RR] 1.9, 95% confidence interval [CI] 1.4, 2.7) or
      cesarean deliveries (RR 1.6, 95% CI 1.1, 2.2). Black women had approximately
      twice the rate of maternal morbidity with vaginal (RR 1.9, 95% CI 1.5, 2.4) or
      cesarean deliveries (RR 2.3, 95% CI 1.9, 2.9). Primiparous women who had vaginal
      or cesarean deliveries had a 60% (RR 1.6, 95% CI 1.3, 2.0) and 70% (RR 1.7, 95%
      CI 1.4, 2.0), respectively, greater risk of serious maternal morbidity than women
      with 1-3 prior births. CONCLUSION: Predictors of serious maternal morbidity
      included age over 32 years, black ethnicity, and primiparity.

PMID- 10576181
TI  - Induced abortion and subsequent pregnancy duration.
AB  - OBJECTIVE: To examine whether induced abortion influences subsequent pregnancy
      duration. METHODS: Women who had their first pregnancies during 1980, 1981, and
      1982 were identified in three Danish national registries. A total of 15,727 women
      whose pregnancies were terminated by first-trimester induced abortions were
      compared with 46,026 whose pregnancies were not terminated by induced abortions.
      All subsequent pregnancies until 1994 were identified by register linkage.
      RESULTS: Preterm and post-term singleton live births were more frequent in women
      with one, two, or more previous induced abortions. After adjusting for potential
      confounders and stratifying by gravidity, the odds ratios of preterm singleton
      live births in women with one, two, or more previous induced abortions were 1.89
      (95% confidence interval [CI] 1.70, 2.11), 2.66 (95% CI 2.09, 3.37), and 2.03
      (95% CI 1.29, 3.19), respectively. Odds ratios of post-term singleton live births
      in women with one, two, or more previous induced abortions were 1.34 (95% CI
      1.24, 1.44), 1.50 (95% CI 1.26, 1.78), and 1.58 (95% CI 1.09, 2.28),
      respectively. CONCLUSION: The study showed an increase in preterm and post-term
      pregnancies after induced abortions. The risk of post-term delivery was high
      regardless of the interpregnancy interval, whereas increased risk of preterm
      delivery was seen mainly when interpregnancy intervals were longer than 12
      months.

PMID- 10576182
TI  - Vaginal 5-fluorouracil for high-grade cervical dysplasia in human
      immunodeficiency virus infection: a randomized trial.
AB  - OBJECTIVE: To compare the efficacy and toxicity of topical vaginal 5-fluorouracil
      (5-FU) maintenance therapy against the effects of observation after standard
      treatment for high-grade cervical dysplasia in human immunodeficiency virus (HIV)
      infected women and to evaluate the association between baseline CD4 count and
      time to recurrence. METHODS: In a phase III unmasked, randomized, multicenter,
      outpatient clinical trial, 101 HIV-positive women either received 6 months of
      biweekly treatment with vaginal 5-FU cream (2 g) or underwent 6 months of
      observation after standard excisional or ablative cervical treatment for cervical
      intraepithelial neoplasia (CIN). Papanicolaou smears and colposcopy were
      scheduled at regular intervals during the ensuing 18 months, with the primary end
      point being the time at which CIN of any grade recurred. RESULTS: Thirty-eight
      percent of women developed recurrence: 14 (28%) of 50 in the 5-FU therapy group
      and 24 (47%) of 51 in the observation group. Treatment with 5-FU was
      significantly associated with prolonged time to CIN development (P = .04).
      Observation subjects were more likely to have high-grade recurrences, with 31%
      developing CIN 2-3 compared with 8% in the 5-FU treatment arm (P = .014), and
      disease recurred more quickly in observation subjects as well. Baseline CD4 count
      was related significantly to time to recurrence (P = .04), with 46% of subjects
      with CD4 counts less than 200 cells/mm3 developing recurrence compared with 33%
      of subjects with CD4 counts at least 200 cells/mm3. Disease recurred more slowly
      in subjects who had received antiretroviral therapy than in antiretroviral
      therapy-naive subjects. There were no instances of grade 3 or 4 toxicity, and
      compliance with 5-FU treatment was generally good. CONCLUSION: Adjunctive
      maintenance intravaginal 5-FU therapy after standard surgery for high-grade
      lesions safely and effectively reduced recurrence of cervical intraepithelial
      neoplasia in HIV-infected women.

PMID- 10576183
TI  - Factors affecting prophylactic oophorectomy in postmenopausal women.
AB  - OBJECTIVE: Prophylactic oophorectomy performed concomitantly with hysterectomy
      may prevent ovarian cancer. Our goal was to better understand the basis for
      performing concomitant oophorectomy and to determine whether this procedure is
      associated with increased morbidity. METHODS: Our cross-sectional study used a
      hospital discharge database to identify women 50 years and older who, between
      1994-1996, had hysterectomies in Maryland for a benign condition. We used
      multiple logistic regression to examine the independent effect of physician and
      patient factors on the likelihood of receiving a concomitant oophorectomy.
      RESULTS: Concomitant oophorectomy was performed in 61% of the 6227 women in our
      sample. Patients undergoing total abdominal hysterectomy (odds ratio [OR] 11.42;
      95% confidence interval [CI] 9.65, 13.51) and laparoscopically assisted vaginal
      hysterectomy (OR 11.34; 95% CI 8.13, 15.81) were substantially more likely to
      have an oophorectomy than patients treated with vaginal hysterectomy, after
      adjusting for diagnosis and other covariates. We also found significant variation
      in the likelihood of receiving oophorectomy for women undergoing vaginal
      hysterectomy in different geographic regions. Additionally, physicians who
      performed many vaginal hysterectomies were significantly more likely to perform a
      concomitant oophorectomy. After adjusting for type of procedure, diagnosis,
      comorbidities, and age, oophorectomy was not associated with increased surgical
      morbidity. CONCLUSION: These results suggest that there are marked variations in
      physician practice style for concomitant oophorectomy. The variation across
      geographic regions and with case volume suggests the influence of nonclinical
      factors on oophorectomy rates.

PMID- 10576184
TI  - FSH levels in relation to hysterectomy and to unilateral oophorectomy.
AB  - OBJECTIVE: To examine the association between hysterectomy, unilateral
      oophorectomy, and ovarian status, measured by FSH concentrations, in women aged
      35-49 years. METHODS: From the National Health and Examination Survey III, 1716
      women aged 35-49 years were studied. Information on menopausal status, surgical
      history (hysterectomy, single or bilateral oophorectomy), smoking, and other
      characteristics was collected in a structured interview, height and weight were
      measured, and one blood sample was collected. We used logistic regression to
      analyze FSH concentration in relation to hysterectomy and oophorectomy,
      controlling for age, ethnicity, body mass index, smoking, education,
      nulligravidity, and exercise. RESULTS: Hysterectomy with unilateral oophorectomy
      was associated with an increased prevalence of elevated FSH (above 20 IU/L)
      (adjusted odds ratio [OR] 2.4, 95% confidence interval [CI] 1.3, 4.6) compared
      with women who had not had hysterectomies or oophorectomies. Among women with two
      ovaries, hysterectomy was associated with increased prevalence of elevated FSH
      (adjusted OR 1.5, 95% CI 1.0, 2.5). As a comparison of the effect size, the
      observed association between hysterectomy and elevated FSH was smaller than the
      association between FSH and current smoking (OR 2.0), a factor associated with a
      1-2 year decrease in mean age at natural menopause. CONCLUSION: Although the
      differences in FSH levels were small, there was evidence of elevated FSH in women
      who have had hysterectomies, even if at least one ovary remained.

PMID- 10576185
TI  - Anatomy of pelvic arteries adjacent to the sacrospinous ligament: importance of
      the coccygeal branch of the inferior gluteal artery.
AB  - OBJECTIVE: To describe the arterial vascular anatomy in the area of the
      sacrospinous ligament. METHODS: Cadaver pelvises were dissected to reveal the
      anatomy of the sacrospinous ligament with emphasis on vascular and neuroanatomy.
      Flexible rulers were used to measure the coccygeal branch in five hemipelvises.
      RESULTS: The pudendal vessels and nerve pass immediately medial and inferior to
      the ischial spine (within 0.5 cm of the spine) and behind the sacrospinous
      ligament. The pudendal artery lies anterior to the sacrotuberous ligament, which
      passes behind the ischial spine to its attachment at the posterior ischial
      tuberosity. The inferior gluteal artery originates from the posterior or the
      anterior branch of the internal iliac artery to pass behind the sciatic nerve and
      the sacrospinous ligament. There is a 3- to 5-mm window in which the inferior
      gluteal vessel is left uncovered above the top of the sacrospinous ligament and
      below the lower edge of the main body of the sciatic nerve plexus. The coccygeal
      branch of the inferior gluteal artery passes immediately behind the midportion of
      the sacrospinous ligament and pierces the sacrotuberous ligament in multiple
      sites. The main body of the inferior gluteal artery leaves the pelvis by passing
      posterior to the upper edge of the sacrospinous ligament and following the
      inferior portion of the sciatic nerve out of the greater sciatic foramen.
      CONCLUSION: Sutures placed through the sacrospinous ligament at least 2.5 cm from
      the ischial spine along the superior border of the sacrospinous ligament and
      without transgressing the entire thickness are in an area generally free of
      arterial vessels.

PMID- 10576186
TI  - Maternal central hemodynamics in hypertensive disorders of pregnancy.
AB  - OBJECTIVE: To document maternal central hemodynamics during the preclinical and
      clinical phases of nonproteinuric gestational hypertension and preeclampsia.
      METHODS: We conducted a longitudinal study of 400 primigravidas who were
      monitored throughout pregnancy using Doppler echocardiography. Multinomial
      logistic regression was used to identify variables associated with risk of
      hypertension. RESULTS: Gestational hypertension developed in 24 women and
      preeclampsia developed in 20. Compared with normotensive controls, women who had
      preeclampsia had significantly elevated cardiac outputs before clinical
      diagnosis, but total peripheral resistance was not significantly different during
      this latent phase. During the clinical phase of preeclampsia, there was a marked
      reduction in cardiac output and increase in peripheral resistance. All women who
      had gestational hypertension had significantly elevated cardiac outputs before
      and during the clinical course of the condition. CONCLUSION: Our data support the
      concept of a hyperdynamic disease model for preeclampsia, with a subsequent
      hemodynamic crossover to low cardiac output and high resistance circulation
      coinciding with the onset of the clinical syndrome. Women with gestational
      hypertension had no such hemodynamic crossover and maintained hyperdynamic
      circulation throughout pregnancy.

PMID- 10576187
TI  - Vaginal birth after cesarean and uterine rupture rates in California.
AB  - OBJECTIVE: To describe attempted and successful vaginal birth after cesarean
      (VBAC) rates and uterine rupture rates for women with and without prior
      cesareans, and compare delivery outcomes in hospitals with different attempted
      VBAC rates. METHODS: We used California hospital discharge summary data for 1995
      to calculate attempted and successful VBAC rates and uterine rupture rates. We
      used multivariate logistic regression models to evaluate and adjust for age,
      ethnicity, and payment source. We report the relative risk (RR), attributable
      fraction, and 95% confidence intervals (CIs) for uterine rupture. RESULTS: There
      were 536,785 delivery discharges during 1995. The cesarean rate was 20.8%, and
      12.5% of women had histories of cesareans. Of women with histories of cesareans,
      61.4% attempted VBAC and 34.8% were successful. There were 392 uterine ruptures
      (0.07%). Women with prior cesareans were 16.98 (95% CI 13.51, 21.43) times more
      likely to experience uterine rupture, attributable fraction 66% (95% CI 60%,
      73%). Among women with prior cesareans, those who attempted VBAC were 1.88 (95%
      CI 1.45, 2.44) times as likely to have uterine rupture, attributable fraction 34%
      (95% CI 21%, 46%). Women who delivered in hospitals with high attempted VBAC
      rates were less likely to have cesarean deliveries, more likely to have
      successful VBACs, and more likely to experience uterine ruptures. CONCLUSION:
      Uterine rupture occurs at a low rate in women with and without prior cesarean
      delivery. Risk of rupture is increased among women with prior cesarean delivery
      and among those who attempt VBAC.

PMID- 10576188
TI  - Violent maternal deaths in North Carolina.
AB  - OBJECTIVE: To describe the frequency of domestic violence and substance abuse
      among a series of injury-related maternal deaths, determine awareness of the
      obstetric provider of domestic violence in those deaths by intimate partner
      homicide or depression in those deaths by suicide, and examine the relative risk
      of violent maternal death for unmarried status and non-white race. METHODS: A
      follow-up investigation was carried out for a case series of 41 injury-related
      maternal deaths identified from 1992 to 1994 in North Carolina. Death
      certificates, police records, newspapers, and records from medical examiners were
      used to ascertain mechanism and intent, history of alcohol or drug abuse, and, in
      cases of homicide, the relationship of the perpetrator to the victim. The
      obstetric provider was asked about his or her knowledge of domestic violence,
      depression, and drug or alcohol abuse relevant to the deceased victim. RESULTS: A
      total of 21 women (51.2%) were known to have or suspected of having been abused
      by either an intimate partner or an acquaintance. Of the 41 women, 11 (26.8%)
      were known to have abused drugs and/or alcohol. The obstetric provider was aware
      or suspicious of abuse in one third of homicides committed by an intimate
      partner. In three of the five suicide deaths, the obstetric provider was aware of
      depression. CONCLUSION: Domestic violence and drug and alcohol abuse were common
      in this series of injury-related maternal deaths. Domestic violence and
      depression were often unrecognized by the obstetric provider in these severe
      cases.

PMID- 10576189
TI  - Randomized comparison of oral misoprostol and oxytocin for labor induction in
      term prelabor membrane rupture.
AB  - OBJECTIVES: To compare labor induction intervals between oral misoprostol and
      intravenous oxytocin in women who present at term with premature rupture of
      membranes. METHODS: One hundred eight women were randomly assigned to misoprostol
      50 microg orally every 4 hours as needed or intravenous oxytocin. The primary
      outcome measure was time from induction to vaginal delivery. Sample size was
      calculated using a two-tailed alpha of 0.05 and power of 80%. RESULTS: Baseline
      demographic data, including maternal age, gestation, parity, Bishop score, birth
      weight, and group B streptococcal status, were similar. The mean time +/-standard
      deviation to vaginal birth with oral misoprostol was 720+/-382 minutes compared
      with 501+/-389 minutes with oxytocin (P = .007). The durations of the first,
      second, and third stages of labor were similar. There were no differences in
      maternal secondary outcomes, including cesarean birth (eight and seven,
      respectively), infection, maternal satisfaction with labor, epidural use,
      perineal trauma, manual placental removal, or gastrointestinal side effects.
      Neonatal outcomes including cord pH, Apgar scores, infection, and admission to
      neonatal intensive care unit were not different. CONCLUSION: Although labor
      induction with oral misoprostol was effective, oxytocin resulted in a shorter
      induction-to-delivery interval. Active labor intervals and other maternal and
      neonatal outcomes were similar.

PMID- 10576190
TI  - Clinical chorioamnionitis and histologic placental inflammation.
AB  - OBJECTIVE: To estimate the rate of histologic chorioamnionitis in the presence of
      diagnosed clinical chorioamnionitis and determine whether clinical markers of
      maternal and neonatal infection are associated with histologic chorioamnionitis.
      METHODS: We identified singleton pregnancies from 1996 in which discharge
      diagnoses included clinical chorioamnionitis and reviewed maternal and neonatal
      records for clinical evidence of chorioamnionitis and suspected or confirmed
      neonatal infections. Placentas were examined for acute histologic
      chorioamnionitis. RESULTS: One hundred thirty-nine pregnancies with the discharge
      diagnosis of maternal clinical chorioamnionitis were included. Eighty-six (61.9%)
      had the clinical diagnosis supported by histologic chorioamnionitis. Histologic
      chorioamnionitis was associated with an earlier gestational age at delivery
      (35.7+/-6.5 weeks versus 38.6+/-2.9 weeks, P = .002), lower epidural usage (72.1%
      versus 92.5%, P = .004), less internal monitoring (47.7% versus 75.5%, P = .001),
      and possible neonatal sepsis (60.5% versus 35.8%, P = .005). For 19 of 71 (26.8%)
      infants with possible neonatal sepsis, placentas did not show histologic
      chorioamnionitis. CONCLUSION: Clinical chorioamnionitis and possible neonatal
      infection were not supported by histologic evidence for infection in 38.1% and
      26.8% of cases, respectively, suggesting other noninflammatory causes of signs
      and symptoms.

PMID- 10576191
TI  - Outcome of twin pregnancies according to intrapair birth weight differences.
AB  - OBJECTIVE: To assess the clinical significance of twin intrapair birth weight
      differences. METHODS: This was a retrospective study of twin pregnancy outcomes.
      Intrapair birth weight differences were stratified into the following six groups:
      14% or less, 15-20%, 21-25%, 26-30%, 31-40%, and 41% or more using the larger
      infant as the growth standard. Statistical analysis was done using the Mantel
      Haenzel chi2 test. RESULTS: We studied 1370 consecutive women who delivered at
      Parkland Hospital, Dallas, Texas, between January 1, 1988, and December 31, 1996,
      and had twin gestations and live births or fetal deaths within 7 days of
      delivery. Greater birth weight discordance was significantly associated with
      preterm delivery due to intervention (P<.001). Noncephalic-cephalic presentations
      and cesarean delivery were also associated with greater discordance (P = .001 and
      .02, respectively). Neonatal morbidities, including low birth weight, intensive
      care admission, and respiratory distress, were all associated with higher birth
      weight discordance. Fetal abnormalities were more common with increased
      discordance (P<.001). Greater birth weight discordance was also associated with
      intrauterine fetal death. There were no differences in outcome for the smaller
      compared with the larger twin of the twin pair. CONCLUSION: Twin birth weight
      discordance is problematic because severe divergent fetal growth increases the
      risk of fetal death and leads to obstetric intervention and consequent neonatal
      morbidity due to prematurity.

PMID- 10576192
TI  - Central nervous system abnormalities assessed with prenatal magnetic resonance
      imaging.
AB  - OBJECTIVE: To determine the frequency at which magnetic resonance imaging (MRI)
      provides additional information in fetuses with suspected central nervous system
      (CNS) abnormalities on ultrasound. METHODS: Between May 1, 1996, and March 26,
      1999, 83 women with 90 fetuses (including seven sets of live twins) had 91
      ultrasonographic and MRI examinations of the fetal CNS. Eight women were studied
      twice, one for two different indications. If referrals came from outside our
      institution, a confirmatory sonogram was obtained. Indications for examination
      were ventriculomegaly (n = 25), suspected neural tube defect (n = 16), arachnoid
      cyst (n = 12), large cisterna magna (n = 11), and miscellaneous indications (n =
      20). RESULTS: Magnetic resonance imaging findings led to changed diagnoses in 26
      (40%) of 66 fetuses with abnormal confirmatory sonograms. Magnetic resonance
      imaging findings not found by ultrasound included partial or complete agenesis of
      the corpus callosum (n = 11), porencephaly (n = 6), hemorrhage (n = 5), tethered
      cord (n = 3), cortical gyral abnormality (n = 2), cortical cleft (n = 2),
      midbrain abnormality (n = 2), and partial or complete agenesis of the septi
      pellucidi (n = 3), as well as holoprosencephaly, cerebellar hypoplasia,
      subependymal and cortical tubers, vascular malformation, and vermian cysts (one
      case each). Abnormalities better delineated by MRI than ultrasound included three
      cephaloceles, a dural arteriovenous malformation, one distal sacral neural tube
      defect, and the mass effect of three arachnoid cysts. That information was used
      to alter patient counseling and at times management. CONCLUSION: When a CNS
      anomaly is detected by sonography or suspected on ultrasound, MRI findings might
      lead to altered diagnosis and patient counseling.

PMID- 10576193
TI  - Predicting the risk of cystic fibrosis with echogenic fetal bowel and one cystic
      fibrosis mutation.
AB  - OBJECTIVE: To assess fetal risk for cystic fibrosis when echogenic bowel and one
      cystic fibrosis mutation are detected. METHODS: A hypothetical cohort of 1000
      women with singleton pregnancies and echogenic fetal bowel during the second
      trimester was used to determine the probability of cystic fibrosis when one
      cystic fibrosis transmembrane conductance regulator mutation was detected. The
      risk of cystic fibrosis was calculated using the range of prevalence of cystic
      fibrosis in fetuses with echogenic bowel reported in the literature. Risk
      calculations for fetuses of Ashkenazi Jewish, Northern European, African
      American, Hispanic, and Asian descent accounted for carrier frequencies and
      mutation detection rates specific to each ethnic group. RESULTS: As the assumed
      prevalence of cystic fibrosis increases from 1-25%, the probability that a white
      fetus with one mutation and echogenic fetal bowel actually has cystic fibrosis
      increases from 4.8% to 62.5%. Assuming a 2% risk of cystic fibrosis with
      echogenic fetal bowel, an Ashkenazi Jewish fetus and an Asian fetus with
      echogenic bowel and one mutation have a 3.1% and 72% risk of cystic fibrosis,
      respectively. The probability of cystic fibrosis in a nonwhite fetus is between
      those two extremes. CONCLUSION: The probability of cystic fibrosis after
      detection of echogenic bowel and one cystic fibrosis mutation varied among ethnic
      groups. Even at the highest prevalence of cystic fibrosis, most white fetuses
      will not have cystic fibrosis. In nonwhite populations almost half of these
      fetuses will have cystic fibrosis, even at the lowest prevalence of cystic
      fibrosis.

PMID- 10576194
TI  - Amnion-chorion separation after 17 weeks' gestation.
AB  - OBJECTIVE: To evaluate the cause of and perinatal outcomes of amnion-chorion
      separation that is apparent sonographically after 17 weeks' gestation. METHODS:
      We searched our ultrasound database over 7 years for information on pregnant
      women who had live fetuses and complete separation between amnion and chorion
      that persisted beyond 17 weeks' gestation. For inclusion in the study, the women
      had to have amnion separated from chorion on at least three sides of the
      gestational sac. Medical records were reviewed for whether women had
      amniocenteses, results of the amniocenteses, and outcomes of the pregnancies.
      RESULTS: Of 15 pregnant women with live fetuses, ten had amniocenteses before
      identification of amnion-chorion separation and five did not. Three had fetuses
      with Down syndrome, two of whom had amnion-chorion separation evident before
      amniocentesis, and all three had other sonographic findings suggestive of
      aneuploidy. Three fetuses died. The other pregnancies were complicated by one or
      more adverse events, including two fetuses with growth restriction, five preterm
      deliveries, two with oligohydramnios, and one with abruptio placentae. Five
      infants were delivered at term and are alive and well. Overall, ten of 15
      pregnancies resulted in live newborns, one of whom had Down syndrome. CONCLUSION:
      Complete amnion-chorion separation that persisted after 17 weeks' gestation is
      associated with a variety of adverse perinatal outcomes, including aneuploidy.

PMID- 10576195
TI  - Immunohistochemical localization of the prostaglandin E subtype-1 receptor in
      cytokine-stimulated and unstimulated amnion cells.
AB  - OBJECTIVE: To visualize histochemically the prostaglandin EP1 receptor in human
      amnion cells and to study the effect of inflammatory cytokines, which are known
      to stimulate the EP1 receptor, on localization. METHODS: Immortalized amnion
      cells, grown on standard microscope slides and either nonstimulated (control) or
      stimulated by incubation in culture medium containing interleukin-1beta (25
      ng/mL), interleukin-4 (50 ng/mL), or tumor necrosis factor alpha (25 ng/mL), were
      incubated with rabbit anti-human EP1 antibody and stained by a two-step indirect
      immunoperoxidase strepavidin-biotin method using horseradish peroxidase and 3,3'
      diaminobenzidine as the chromogen. The localization was done on ten different
      flasks of cells. Duplicate slides for each cytokine concentration were prepared.
      Negative controls for each reagent, prior blocking with 1% bovine serum albumin
      or 1% milk, or pretreatment with preimmune rabbit immunoglobulin G were run
      simultaneously. Slides were viewed by standard light microscopy with and without
      counterstaining with hematoxylin. RESULTS: Amnion cells incubated in medium alone
      showed receptor localization throughout the cytoplasmic region of the cell
      membrane. The localization was nonuniform; a discrete unipolar region of
      perinuclear nonlocalization was observed. Staining occurred in widely dispersed
      nests. Cytokine stimulation resulted in increased intensity of staining and an
      increase in the size of the positive nests; however, it did not affect the
      discrete unipolar perinuclear region of nonlocalization. CONCLUSION:
      Histochemical localization of the human EP1 receptor confirms a cytoplasmic
      identity and probable plasma membrane localization. Stimulation by inflammatory
      cytokines increases staining by recruitment of new amnion cells and appears to
      increase receptor density per cell.

PMID- 10576196
TI  - Glutathione S-transferase isoenzymes in decidua and placenta of preeclamptic
      pregnancies.
AB  - OBJECTIVE: To investigate a possible involvement of glutathione S-transferases,
      major detoxificating enzymes, in the pathophysiology of preeclampsia. METHODS:
      Levels of glutathione S-transferase isoforms and enzyme activity were assessed in
      placental and decidual tissues in 22 preeclamptic and 21 normotensive women.
      Measured values were analyzed statistically using the Mann-Whitney U test for
      comparison between groups, and the signed-rank test for comparison within groups.
      RESULTS: Glutathione S-transferase pi is the main glutathione S-transferase
      isoform in normal placental and decidual tissue. Lower median placental and
      decidual glutathione S-transferase pi levels were found in preeclamptic women
      compared with controls: 1268 (range: 524-3925) and 2185 (range: 503-6578), P =
      .05, for placenta; 1543 (range: 681-2967) and 2169 (range: 893-3929), P = .02,
      for decidua. The total amount of glutathione S-transferases in control and
      preeclamptic pregnancies was higher in decidua than in placenta. CONCLUSION:
      Reduced levels of glutathione S-transferase class pi in preeclampsia might
      indicate a decreased capacity of the glutathione/glutathione S-transferase
      detoxification system. A higher total amount of glutathione S-transferases in
      decidual tissue might point to a more pronounced protective role of decidua
      compared with placenta.

PMID- 10576197
TI  - Abdominal sacrospinous ligament colposuspension.
AB  - BACKGROUND: When an abdominal approach is chosen for repair of pelvic prolapse, a
      paravaginal repair is often used to correct lateral cystoceles and a retropubic
      urethropexy to correct genuine stress incontinence. If concomitant vaginal vault
      prolapse exists, an approach for vaginal vault support, which can be done through
      the space of Retzius, would be beneficial. We describe an abdominal approach to
      the sacrospinous ligament. TECHNIQUE: The space of Retzius is accessed and
      important anatomic landmarks, including the obturator canal and neurovascular
      bundle, paravaginal veins, bladder, and ischial spine, are identified. The
      sacrospinous ligament complex is palpated and exposed. The superior
      posterolateral vaginal wall is then fixed to the complex. Often a bilateral
      repair is possible. EXPERIENCE: Fifty-five women at two centers had abdominal
      sacrospinous ligament colpopexies for vaginal vault prolapse. All had other
      repairs for pelvic organ prolapse. No follow-up operations were needed for
      recurrent vault prolapse, over an average of 23 months follow-up. CONCLUSION: An
      abdominal approach to the sacrospinous ligament complex can be used, providing
      pelvic reconstruction surgeons with an alternative technique for vaginal vault
      support when other space-of-Retzius procedures are required.

PMID- 10576198
TI  - A method of masking oxytocin infusion rates.
AB  - BACKGROUND: Controversy exists as to the optimum infusion rate of oxytocin during
      labor. A system is described to mask infusion rates, and this may help eliminate
      bias in the study of oxytocin infusion. METHOD: The hardware consists of a
      commercially available infusion pump that has the capability to receive and send
      computer messages and a laptop computer. The pump and a programmed computer are
      attached to a portable stand for bedside use. The display on the pump may be
      masked while the computer displays the level for any one of three actual rates.
      EXPERIENCE: Masked and unmasked simulations were performed without human
      subjects, followed by unmasked bedside testing in 45 patients. The simulation and
      bedside testing confirmed the system had the ability to maintain designated flow
      rates in all manner of increases, decreases, stoppages, and restarts. CONCLUSION:
      This system is a computer-controlled infusion pump with the ability to mask
      infusion rates. This may allow investigators to compare oxytocin infusion rates
      objectively in the induction and augmentation of labor.

PMID- 10576199
TI  - Hepatitis C: screening in pregnancy.
AB  - Hepatitis C virus infection, which is far more prevalent than human
      immunodeficiency virus (HIV)-1, can lead to cirrhosis, hepatocellular carcinoma,
      hepatic failure, and death. Like HIV-1, hepatitis C is transmitted parenterally,
      sexually, and from mother to infant. The American Academy of Pediatrics and the
      Centers for Disease Control and Prevention (CDC) recently recommended that all
      children born to women who are infected with hepatitis C virus or have risk
      factors for infection be screened for hepatitis C. Most infected women are
      asymptomatic and unaware of their infection, so routine prenatal testing is
      needed to fully meet that goal. We do not believe that current data justify
      universal testing, but we believe it is time for all obstetricians to test
      selectively based on risk factors.

PMID- 10576200
TI  - United States Medical Licensure Examination step 1 scores and obstetrics
      gynecology clerkship final examination.
AB  - OBJECTIVE: To determine if scores from first attempts at the United States
      Medical Licensure Examination step 1 correlated with obstetrics-gynecology
      examination scores and identified students at risk of failure. METHODS: All
      students in obstetrics-gynecology clerkships at the University of Illinois at
      Chicago from July 1995 through June 1998 were studied. The clerkship length was 8
      weeks. Six clerkship sites were used, each of which assigned students to
      obstetrics-gynecology for the same length. Only first attempts at the obstetrics
      gynecology clerkship examination and United States Medical Licensure Examination
      step 1 were evaluated. RESULTS: Among 522 students the mean (+/- standard
      deviation [SD]) United States Medical Licensure Examination step 1 score was 205
      (+/-24.4). The mean score (+/-SD) for the standard obstetrics-gynecology
      examination was 69.5 (+/-8.1). The obstetrics-gynecology examination score
      correlated significantly with the United States Medical Licensure Examination
      step 1 score (r = .662, P<.001). Sixty-five students failed their first attempts
      at the United States Medical Licensure Examination step 1 examination, and ten
      failed their first attempts at the clerkship examination. Students who failed
      their first attempts at the United States Medical Licensure Examination step 1
      were more likely to fail their first attempts at the clerkship examination
      (relative risk 18.6; 4.6, 72.6; P<.001). More than half the students who failed
      their initial United States Medical Licensure Examination step 1 examinations
      failed or finished in the lower 25th percentile on their obstetrics-gynecology
      finals. CONCLUSION: United States Medical Licensure Examination step 1 scores
      correlated with obstetric-gynecology clerkship examination scores. Failure on the
      first attempts of the United States Medical Licensure Examination step 1
      examination predicted students at risk of failures of the obstetrics-gynecology
      final examination and those who finished in the lower 25th percentile.

PMID- 10576201
TI  - An ACOG-affiliated medical student obstetrics and gynecology club.
AB  - An ACOG-affiliated obstetrics and gynecology club for medical students was
      developed at the University of Medicine and Dentistry of New Jersey-Robert Wood
      Johnson Medical School to introduce medical students to the specialty early in
      their careers, to educate them about obstetrician-gynecologists effect on women's
      health, and to guide them through exploration of the field. With ACOG District
      III Fellow and Junior Fellow support and collaboration, the club was formed and
      operational within 6 months. Because of this club students feel included in the
      district and national organizations by participating in Junior Fellow and Fellow
      activities. Through Junior Fellow activities, medical students get first-hand
      exposure to numerous obstetrics and gynecology residency programs. Through
      workshops and noncredit electives, medical students receive personal mentoring by
      Fellows and Junior Fellows. Students participate in community projects and from
      those programs can better understand the needs of women, especially women with
      inadequate or no health insurance. The collaboration between Junior Fellows,
      Fellows, and medical students is the most important component in establishing a
      student-run club affiliated with ACOG. This project has effectively introduced
      students to the field of women's health early in their careers and could provide
      a model for implementation at other medical schools.

PMID- 10576202
TI  - Colposcopy in pregnancy: directed brush cytology compared with cervical biopsy.

PMID- 10576203
TI  - Survivin apoptosis: an interloper between cell death and cell proliferation in
      cancer.

PMID- 10576204
TI  - Heparin-binding EGF-like growth factor expression increases selectively in
      bladder smooth muscle in response to lower urinary tract obstruction.
AB  - Heparin-binding epidermal growth factor-like growth factor (HB-EGF), an
      activating ligand for the epidermal growth factor receptor (ErbB1) tyrosine
      kinase and at least one isoform of the ErbB4 receptor tyrosine kinase, is
      synthesized by the smooth muscle of the human bladder wall. In this study we
      tested the hypothesis that HB-EGF plays a role in the bladder-wall thickening
      that occurs in response to obstructive syndromes affecting the lower urinary
      tract, possibly by acting as an autocrine smooth muscle cell (SMC) growth factor.
      HB-EGF was mitogenic for primary culture human bladder SMC, and cell growth in
      serum-containing medium was inhibited more than 70% by [Glu52]-diphtheria
      toxin/CRM197, a specific HB-EGF inhibitor, consistent with a physiologic role for
      HB-EGF as an autocrine bladder SMC mitogen. Human and mouse bladder SMC in vivo
      and cultured human bladder SMC expressed the primary HB-EGF receptor, ErbB1, but
      not mRNA for the secondary HB-EGF receptor, ErbB4, thereby identifying ErbB1 as
      the cognate HB-EGF receptor in the bladder wall. Reverse transcription-polymerase
      chain reaction analysis also demonstrated ErbB2 and ErbB3 expression in human
      bladder muscle tissue, suggesting the possibility of receptor cross-talk after
      ErbB1 activation. Urethral ligation in mice resulted in an increase in steady
      state HB-EGF mRNA expression up to 24 hours in whole bladder tissue in comparison
      with ErbB1 and glyceraldehyde 3-phosphate dehydrogenase mRNA levels, which did
      not change in a demonstrable pattern. HB-EGF protein increased coordinately with
      HB-EGF mRNA levels. Dissection of bladder tissue into muscle and mucosal layers
      demonstrated that the increase in HB-EGF mRNA occurred predominantly in the
      muscle layer, with peak levels (13-fold higher than sham controls) occurring 12
      hours after obstruction. These data support a physiologic role for HB-EGF as a
      mediator of hypertrophic bladder tissue growth.

PMID- 10576205
TI  - Expression of endothelin-1 in rats developing hypobaric hypoxia-induced pulmonary
      hypertension.
AB  - Experimental pulmonary hypertension induced in a hypobaric hypoxic environment
      (HHE) is characterized by structural remodeling of the heart and pulmonary
      arteries. Endothelin-1 (ET-1), a 21-amino acid peptide, is a novel and long
      lasting vasoconstrictor that increases pulmonary arterial pressure in both in
      vivo and in vitro experiments. To study the effects of HHE on ET-1 activity in
      the lungs, 59 male rats were subjected to the equivalent of an altitude of 5500 m
      for 1 to 4 weeks. In rats exposed to HHE, the mean pulmonary arterial pressure
      increased significantly from 15.2+/-0.3 (ground level) to 30.6+/-1.5 mm Hg (5500
      m level) at 4 weeks, whereas their mean systemic arterial pressure remained
      normal. The levels of ET-1 mRNA and protein, measured respectively by Northern
      blot analysis and enzyme immunoassay, increased rapidly in the lungs on exposure
      to HHE. By in situ hybridization and immunohistochemistry, respectively, ET-1
      mRNA and protein were detected in control rats in nonciliated bronchiolar
      epithelial cells and alveolar epithelial cells, as well as in the endothelial
      cells of pulmonary arteries, but minimally in the smooth muscle cells of
      pulmonary arteries. ET-1 mRNA- and protein-reactive smooth muscle cells in
      pulmonary arteries and ET-1 mRNA-reactive airway epithelial cells were
      significantly more abundant in rats exposed to HHE than in ground level controls.
      These results suggest the possibility that in smooth muscle cells in pulmonary
      arteries and airway epithelial cells, ET-1 may play an autocrine or paracrine
      role in the remodeling of blood vessels during the development of the pulmonary
      hypertension that is induced by HHE.

PMID- 10576207
TI  - Trapidil inhibits monocyte chemoattractant protein-1 and macrophage accumulation
      after balloon arterial injury in rabbits.
AB  - Trapidil (triazolopyrimidine) is an antiplatelet agent that acts in part as a
      phosphodiesterase inhibitor and as a competitive inhibitor of the platelet
      derived growth factor (PDGF) receptor. Trapidil has been shown to attenuate
      intimal hyperplasia in rat and hamster models of balloon arterial injury and to
      inhibit restenosis after percutaneous transluminal coronary angioplasty in
      several small clinical trials. Monocyte chemoattractant protein-1 (MCP-1) is a
      PDGF-inducible monocyte chemoattractant that is thought to play a particularly
      important role in recruiting monocyte/macrophages to sites of atherosclerosis and
      vessel injury. We hypothesized that, because of its ability to antagonize PDGF
      mediated events, trapidil would inhibit the synthesis of MCP-1 and decrease
      macrophage accumulation in the injured arterial wall. Hypercholesterolemic
      rabbits were treated with trapidil (60 mg/kg/day subcutaneously) the day before
      and then daily for 6 days after balloon injury of the femoral artery; control
      rabbits received vehicle only. Trapidil resulted in a 75% reduction in MCP-1
      expression and macrophage accumulation in the arterial wall 7 days after injury.
      This study suggests that trapidil has potent anti-inflammatory properties and
      that its activity in attenuating intimal hyperplasia may be in part attributed to
      its effects on macrophage accumulation.

PMID- 10576206
TI  - Mechanisms of photoreceptor cell apoptosis induced by N-methyl-N-nitrosourea in
      Sprague-Dawley rats.
AB  - A single intraperitoneal injection of 75 mg/kg N-methyl-N-nitrosourea (MNU) was
      given to 50-day-old female Sprague-Dawley rats and examined sequentially 12 and
      24 hours, and 3 and 7 days after MNU treatment. Photoreceptor cell death was
      evoked in all treated rats. After MNU treatment, 7-methyldeoxyguanosine DNA
      adduct was detected selectively in photoreceptor cell nuclei at 12 hours,
      followed by photoreceptor cell apoptosis as confirmed by terminal
      deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick
      end labeling signals which peaked at 24 hours and continued until day 7 when
      several layers of photoreceptor cell nuclei were left. In apoptosis cascade, down
      regulation of Bcl-2 was seen at 12 hours and up-regulation of Bax was seen at 24
      hours, and caspase family (caspase 3/CPP32, caspase 6/Mch2, and caspase 8/FLICE
      protease) activities peaked 72 hours after MNU treatment. Therefore MNU-induced
      photoreceptor cell death was attributed to DNA adduct formation restricted to
      photoreceptor cell nuclei leading to photoreceptor cell apoptosis by up
      regulation of Bax protein, down-modulation of Bcl-2 protein, and activation of
      caspases 3, 6, and 8.

PMID- 10576208
TI  - Molecular IgV(H) analysis demonstrates highly somatic mutated B cells in
      synovialitis of osteoarthritis: a degenerative disease is associated with a
      specific, not locally generated immune response.
AB  - In osteoarthritis (OA), the synovial tissue exhibits a nonfollicular inflammatory
      infiltration with a characteristic arrangement of lymphocytes and plasma cells.
      These arrangements are either small perivascular aggregates with plasma cells
      surrounding the lymphocytes or small groups of plasma cells, located in the
      vicinity of small blood vessels. These patterns suggest that B lymphocytes
      directly differentiate into plasma cells. To understand the B-cell response in
      OA, we analyzed the V(H) genes from B cells of synovial tissue of nine OA
      patients (average age, 71.5+/-10.5 years; six female and three male). V(H) gene
      repertoires were determined from RNA prepared from tissue cryosections and from
      DNA of single isolated B lymphocytes and plasma cells. The inflammatory
      infiltrate was analyzed immunohistochemically by detecting CD20, Ki-M4
      (follicular dendritic cells), CD4, IgG, IgM, IgA, Ki-67, and by simultaneous
      demonstration of the plasma-cell-specific antigen CD138 (syndecan-1) and factor
      VIII. The molecular data demonstrate B cells with a high number of somatic
      mutations (average, 16.5 to 19.8), and high ratios of replacement to silent
      mutations in the small lymphocytic/plasmacellular aggregates of OA. In the tissue
      cryosections, the values of the sigmaR/sigmaS at the complementarity determining
      regions were 5.3 and 2.0 in the framework regions. For both the isolated B
      lymphocytes and plasma cells, the value of this ratio in the complementarity
      determining regions was 3.5. In the framework regions, the values of this ratio
      were 2.0 for the isolated B cells and 1.8 for the plasma cells. B lymphocytes and
      plasma cells exhibited a distribution not described thus far. Two patterns of B
      cell distribution could be observed: (a) Centrally located CD20+ B and CD4+ and
      CD8+ T lymphocytes were surrounded directly by IgG (predominantly) or IgA and IgM
      plasma cells. No proliferating Ki-67-positive cells and no follicular dendritic
      cells (germinal centers) could be detected in the aggregates; (b) Plasma cells
      (predominantly IgG) were located directly near endothelial cells of small blood
      vessels. The finding of highly mutated V(H) genes in B lymphocytes and the
      characteristic arrangement of B lymphocytes and plasma cells suggests that B
      cells, which participate in OA synovialitis, have undergone germinal center
      reaction at different sites. This may explain the low inflammatory infiltration
      without germinal centers in OA, which is a feature of this primarily degenerative
      joint disease.

PMID- 10576210
TI  - Rapid appearance of M cells after microbial challenge is restricted at the
      periphery of the follicle-associated epithelium of Peyer's patch.
AB  - M cells within the follicle-associated epithelium (FAE) of the gut play a central
      role in the initiation of mucosal immune responses by transporting antigens to
      the intestinal lymphoid tissue. We have previously demonstrated that the
      instillation into the gut of a nonenteric microorganism, Streptococcus pneumoniae
      R36a, is an excellent experimental model to investigate the highly dynamic nature
      of the FAE in response to microbial challenge. In the present study, S.
      pneumoniae was introduced into rabbit ileal loops, each one containing a Peyer's
      patch (PP), and the number of M cells was assessed by morphological and
      functional characteristics in different areas of the FAE after a short time (1-3
      hours). We report that a marked increase in the number of M cells was detected in
      the periphery, but not in the apical area, of the FAE as early as 1 hour after
      exposure to S. pneumoniae. Furthermore, a variant of this experiment enabled us
      to establish that the increased numbers of M cells led to an improved capability
      of the FAE to transport latex fluorescent microspheres (0.5 microm), highly
      specific to rabbit M cells, from the gut lumen to the intestinal lymphatic
      system. In these animals the cisterna chyli was cannulated, and the
      microparticles were introduced into the intestinal loops after stimulation with
      pneumococci. The microparticles reaching the lymph were then counted by flow
      cytometer. We interpreted these results as showing that only enterocytes located
      within the periphery of the FAE are converted to fully operational M cells by
      certain microbial interaction and the ability of enterocytes to undergo this
      conversion may depend on their stage of differentiation.

PMID- 10576209
TI  - Pulmonary lesions in primary respiratory syncytial virus infection, reinfection,
      and vaccine-enhanced disease in the cotton rat (Sigmodon hispidus).
AB  - Infection of the cotton rat lung with a human strain of respiratory syncytial
      virus results in substantial virus replication and is associated with mild-to
      moderate peribronchiolitis, perivasculitis, and bronchitis. Reinfection after 49
      days did not result in detectable virus replication, but surprisingly, was
      associated with an earlier appearance and accentuation of the three types of
      lesions seen in cotton rats undergoing primary infection. Animals primed with
      formalin-inactivated virus and challenged after 49 days had pulmonary viral
      titers 1/10 to 1/100 of that seen in naive animals, but developed markedly
      accentuated lesions of the same type as in animals undergoing primary or
      secondary infection. In addition, the animals with the vaccine-enhanced disease
      developed alveolitis and interstitial pneumonitis, which seem to be specific
      markers for the vaccine enhancement. These latter markers may be useful in
      determining the safety of nonreplicating vaccines.

PMID- 10576211
TI  - Role of interleukin-8 phosphorylated kinases in stimulating neutrophil migration
      through fibrin gels.
AB  - Interleukin (IL)-8 elicits neutrophil migration in the early inflammatory
      response. This action of IL-8 is believed to involve mitogen-activated protein
      (MAP) kinase p44/42. In the present study, we used specific inhibitors to
      investigate the role of p44/42 kinase in stimulating neutrophil migration. The IL
      8-guided migration through an imitation of inflammatory matrix, a fibrin gel, was
      impaired by 90% after treatment with 7 microM U0126, a specific inhibitor of the
      kinase of p44/42 kinase. Superoxide anion generation induced by high
      concentrations of bacterial signals was not impaired in the absence of functional
      p44/42. This anion generation could be decoupled from the p44/42 independency by
      priming the cells, a pretreatment with IL-8. The addition of U0126 inhibited by
      60% the priming and subsequent superoxide anion generation triggered by low
      concentrations of bacterial signals. An impact on the priming effect and
      migration of neutrophils was found upon blockade (with wortmannin) of a further
      kinase event that converges on the p44/42 phosphorylation. Wortmannin blocked
      phosphatidylinositol 3-kinase and secondarily phosphorylation of p44/42 and of
      the p44/42-related MAP kinase p38. The overlapping functional consequences of a
      specific blockade of p38 MAP kinase (applying in vivo anti-inflammatory pyridinyl
      imidazole) further ascribed a migratory role to those signals culminating in
      p44/42 MAP kinase phosphorylation, and suggests a role in vivo.

PMID- 10576213
TI  - Angiotensin-converting enzyme (CD143) in neoplastic germ cells.
AB  - Angiotensin I-converting enzyme (ACE, CD143, Kininase II, EC 3.4.15.1) occurs in
      two isoforms; whereas the somatic isoform (sACE) appears in certain endothelial
      cells and some other cell types, the testicular isoform (tACE) was found in
      humans and various mammals only during spermiogenesis. An expression of ACE was
      reported formerly in some human seminomas, but its isoform type, cellular
      distribution, and pathogenetic meaning are not known. Therefore we analyzed
      normal human testes, 22 different testicular tumors, and 23 fetal and postnatal
      tissues of different stages of testicular development. By reverse transcriptase
      polymerase chain reaction, ACE mRNA isoforms were assessed in homogenized tissue
      sections and in germ cells selectively isolated by laser-assisted cell picking.
      Immunohistochemistry was performed on consecutive sections using monoclonal
      antibodies specific to the human somatic isoform or both, sACE and tACE. In adult
      men, tACE was detectable in spermatids and spermatozoa, but normal spermatogonia
      and spermatocytes were not found to express ACE in any isoform. By contrast, both
      mRNA and protein of sACE were detectable in the cells of intratubular germ cell
      neoplasm, seminomas, and other testicular tumor types. Because sACE was also
      found in fetal germ cells, our findings point to profound differences in the
      regulation of ACE expression in fetal, mature adult, and neoplastic germ cells.
      They are in agreement with the concept that neoplastic germ cells phenotypically
      reflect an embryonic stage of cellular differentiation. Laser-assisted cell
      picking proved to be a reliable method to investigate differently regulated mRNA
      of cells which reside in close neighborhood within complex tissues.

PMID- 10576212
TI  - Sequence-specific inhibition of gene expression in intact human skin by
      epicutaneous application of chimeric antisense oligodeoxynucleotides.
AB  - Targeted and selective inhibition of keratinocyte gene expression in human
      epidermis could be an efficient and safe pharmacologic approach in many skin
      diseases. In this study we investigated whether topical application of antisense
      oligodeoxynucleotides (ODN) on intact human skin can be used to inhibit
      expression of a gene in the differentiated compartment of the epidermis. We
      applied a variety of 20-mer antisense and control ODN designed to hybridize to
      different regions on the mRNA of the inducible epidermal proteinase inhibitor
      skin-derived antileukoproteinase (SKALP)/elafin that was used as a model target
      gene. When nuclease-resistant fully phosphorothioate ODN were applied to explant
      cultures of human skin, they were found to be either ineffective at low doses or
      severely toxic at higher doses which could be attributed to the extremely high
      degree of protein binding found with this type of ODN. When chimeric ODN with a
      phosphodiester core and phosphorothioate 5' and 3' ends were applied to intact
      skin, no toxicity was noted. One of the tested chimeric ODN, that exhibit only
      minor protein binding, was found to inhibit SKALP expression at the protein level
      in a dose-dependent manner. The observed inhibition on SKALP expression levels
      was specific as evaluated by application of strict criteria. Sequence specificity
      was assessed by the addition of sense and scrambled ODN which were ineffective.
      Furthermore the expression levels of three other differentiation-related genes
      (involucrin, cytokeratin 16, and secretory leukocyte proteinase inhibitor) were
      not affected, indicating that the inhibition was gene specific. Confocal laser
      scanning analysis of fluorescently labeled ODN confirmed that these molecules can
      easily penetrate the epidermis and localize in the cytoplasm of differentiated
      keratinocytes. We conclude that topical application of antisense ODN can be used
      to modulate epidermal gene expression, and could potentially be useful to inhibit
      expression of genes that are relevant in skin diseases.

PMID- 10576214
TI  - Synthesis of deuterium-labeled tetrahydrocortisol and tetrahydrocortisone for
      study of cortisol metabolism in humans.
AB  - A method is described for the preparation of multi-labeled tetrahydrocortisol
      (3alpha,11beta,17alpha,21-tetrahydroxy-5beta-[1, 2,3,4,5-2H5]pregnan-20-one, THF
      d5), allo-tetrahydrocortisol (3alpha,11beta,17alpha,21-tetrahydroxy-5alpha-[1
      ,2,3,4,5-2H5]pregnan-20-one, allo-THF-d5), and tetrahydrocortisone
      (3alpha,17alpha,21-trihydroxy-5beta-[1,2,3,4,5-2H5]pre gnane-11,20-dione, THE-d5)
      containing five non-exchangeable deuterium atoms in the steroid ring A. Reductive
      deuteration at C-1, C-2, C-3, C-4, and C-5 of prednisolone or prednisone was
      performed in CH3COOD with rhodium (5%) on alumina under the deuterium atmosphere.
      The isotopic purities of the labeled compounds as [2H5]-form were estimated to be
      86.17 atom%D for THF-d5, 74.46 atom%D for allo-THF-d5 and 81.90 atom%D for THE
      d5, based on the ion intensities in the region of the molecular ion of methoxime
      trimethylsilyl (MO-TMS) derivatives measured by GC-MS.

PMID- 10576215
TI  - The effect of 4beta and 19 ester functionalities on some electrophilic addition
      reactions of delta5-steroids.
AB  - The reactions of 3beta-acyloxyandrost-5-enes with bromine/silver acetate (Petrow
      reaction) and mercury(II) trifluoroacetate (modified Treibs oxidation) have been
      used previously to effect allylic oxidation on these substrates en route to
      biologically active compounds. In both these reactions, which involve
      electrophilic addition to the delta5-bond, the 3-acyloxy substituent plays a
      significant role. In this report, the effect of introducing other substituents
      proximate to the delta5-bond has been studied by using derivatives of 3beta
      acetoxyandrost-5-en-17-one (1), namely, 3beta,4beta-diacetoxyandrost-5-en-17-one
      (13), 3beta,19-diacetoxyandrost-5-en-17-one (14), 3beta-acetoxyandrost-5-ene-7,17
      dione (15), and 3beta-acetoxy-4,4-dimethylandrost-5-en-17-one (17). Our results
      indicate that in both sets of reactions the effect of the introduced functional
      groups was pronounced. In the Petrow reaction, electrophilic addition rather than
      allylic oxidation on the diacetates was observed. With the Treibs reaction,
      allylic oxidation on the diacetates occurred. The 7-keto and 4,4-dimethyl
      steroids proved to be poor substrates in both reactions.

PMID- 10576216
TI  - Sterols of the marine sponge Petrosia weinbergi: implications for the absolute
      configurations of the antiviral orthoesterols and weinbersterols.
AB  - The marine sponge Petrosia weinbergi was found to contain isofucosterol and
      clionasterol as its major sterols. The rare cyclopropyl sterol (24S,28S)-24,28
      methylenestigmast-5-en-3beta-ol, previously detected as only 0.07% of the total
      sterols of a pelagophytic alga Pulvinaria sp., made up 6.6% of the total sterols.
      These sterols are believed to be the biosynthetic precursors of the antiviral
      orthoesterols and weinbersterols found in the same sponge. Based on the side
      chains of the isolated sterols, the absolute configurations of the antiviral
      steroid side chains are assigned to be (24R,28S)- for orthoesterol B, (24R)- for
      orthoesterol C, and (24S,28S)- for weinbersterols A and B.

PMID- 10576217
TI  - 17Alpha-alkan (or alkyn) amide derivatives of estradiol as inhibitors of steroid
      sulfatase activity.
AB  - To develop inhibitors of steroid sulfatase without residual estrogenic activity,
      we have designed a series of estradiol (E2) derivatives bearing an alkan (or
      alkyn) amide side chain at position 17alpha. A hydrophobic alkyl group was
      selected from our previous study where 17alpha-octyl-E2 was found to inhibit
      strongly the steroid-sulfatase activity. Furthermore, it is known that an
      alkylamide side chain blocks the estrogen-receptor activation. Starting from
      ethynylestradiol, the chemical synthesis of target compounds was short and
      efficient with overall yields of 22-42% (3 or 4 steps). Among these compounds, N
      octyl,N-methyl-3-(3',17'beta-dihydroxy-1',3',5'(10')-estratrien- 17'alpha-yl)
      propanamide (15) was the most potent inhibitor, with an IC50 value of 0.08 microM
      for the transformation of estrone sulfate (E1S) to estrone (E1) by homogenated
      JEG-3 cells. N-butyl, N-hexyl, and N,N-dioctyl propanamide derivatives of E2
      (IC50 values of 6.4, 2.8, and >20 microM, respectively) were less potent
      inhibitors than N-octyl analog 15. Furthermore, the unsaturated propynamide
      analog of 15 gave lower inhibition (four times) than the saturated compound.
      Compound 15 is also about 100-fold more effective in interacting with the enzyme
      than substrate E1S itself. The ability of target compounds to bind the estrogen
      receptor, to stimulate the proliferation of estrogen-sensitive ZR-75-1 cells, or
      to inhibit the E2-stimulation of ZR-75-1 cells was also evaluated. Although a
      mixed estrogenic/anti-estrogenic activity was obtained for tested compounds at 1
      microM, no estrogenic activity was observed at 0.03 microM for 15. In conclusion,
      a promising inhibitor of steroid-sulfatase activity was obtained by introducing a
      hydrophobic octyl group in a 17alpha-propanamide side chain of E2, but further
      structure-activity relationships (SAR) studies are necessary to minimize the
      residual estrogenic activity.

PMID- 10576219
TI  - Synthesis of (25R)-26-hydroxy-15-ketosterols.
AB  - (25R)-3beta,26-Dihydroxy-5alpha-cholest-8(14)-en-15-one (1) and (25R)-3beta,26
      dihydroxy-5alpha,14beta-cholest-16-en-1 5-one (2) were synthesized from (25R)
      3beta,26-dibenzoyloxy-5alpha,14alpha-chole st-16-ene (4). Oxidation of 4 with
      CrO3-3,5-dimethylpyrazole at -20 degrees C gave (25R)-3beta,26-dibenzoyloxy
      5alpha,14alpha-chole st-16-en-15-one (5) along with (25R)-3beta,26-dibenzoyloxy
      5alpha-cholest-16alpha+ ++,17alpha-epoxide (6). Oxidation of 5 with selenium
      dioxide afforded (25R)-3beta,26-dibenzoyloxy-5alpha-cholest-8(14),16-++ +dien-15
      one (7) and (25R)-3beta,26-dibenzoyloxy-5alpha,14beta-choles t-16-en-15-one (8).
      Selective hydrogenation of 7 followed by hydrolysis in alcoholic potassium
      hydroxide yielded (25R)-3beta,26-dihydroxy-5alpha-cholest-8(14)-en-15-one (1).
      Hydrolysis of 5 and 8 in alcoholic potassium hydroxide provided (25R)-3beta,26
      dihydroxy-5alpha,14beta-cholest-16-en-1 5-one (2).

PMID- 10576218
TI  - Steroid transformations with Fusarium oxysporum var. cubense and Colletotrichum
      musae.
AB  - The utility of two locally isolated fungi, pathogenic to banana, for steroid
      biotransformation has been studied. The deuteromycetes Fusarium oxysporum var.
      cubense (IMI 326069, UAMH 9013) and Colletotrichum musae (IMI 374528, UAMH 8929)
      had not been examined previously for this potential. In general, F. oxysporum
      var. cubense effected 7alpha hydroxylation on 3beta-hydroxy-delta5-steroids,
      6beta, 12beta, and 15alpha hydroxylation on steroidal-4-ene-3-ones, side-chain
      degradation on 17alpha,21-dihydroxypregnene-3,20-diones, and 15alpha
      hydroxylation on estrone. Both strains were shown to perform redox reactions on
      alcohols and ketones.

PMID- 10576220
TI  - A novel steroidal spin label for membrane structure studies: synthesis and
      applications.
AB  - 2,2,6,6-Tetramethyl piperidine-N-oxyl nitroxyls are known to partition between
      aqueous and lipid phases, thus serving as probes to study membrane dynamics. The
      synthesis of a novel steroidal spin label, 3alpha-hydroxycholan-24-yl
      (2",2",6",6"-tetramethyl-N-oxyl)p iperidyl butan-1',4'-dioate, containing 2,2,6,6
      tetramethylpiperidine-N-oxyl moiety covalently bonded to the side chain in 3,24
      caprostan-diol has been described. The localization of this spin label in model
      biomembranes has been studied by using electron spin resonance, differential
      scanning calorimetry, and 1H and 31P NMR spectroscopic techniques. Its
      applicability in studying the phase transition properties of model membrane L
      alpha-dipalmitoyl phosphatidyl choline in the presence and absence of drugs has
      been described by using electron spin resonance. The label has also been used to
      study the permeability of epinephrine into membrane. The results have shown the
      applicability of the spin label as a potential spin probe in the study of
      biomembranes.

PMID- 10576221
TI  - Within-person variability of the ratios of urinary 2-hydroxyestrone to 16alpha
      hydroxyestrone in Caucasian women.
AB  - The ratio of urinary 2-hydroxyestrone (2-OHE1) to 16alpha-hydroxyestrone (16alpha
      OHE1) has been suggested as a potential biomarker for breast cancer risk. We
      evaluated within-person variability of this biomarker in ten healthy Caucasian
      women aged 23-58 years. Each study participant was asked to provide an overnight
      fasting morning urine sample once a week for an average of 8 weeks. These urine
      samples were assayed for 2-OHE1 and 16alpha-OHE1 by using competitive enzyme
      immunoassay kits purchased from the ImmunaCare Corporation. The coefficients of
      variation for urinary 2-OHE1/16alpha-OHE1 over the study period ranged from 13.7
      to 59.6% (mean, 33.3%) in our study participants. There was a good correlation
      between the level of the urinary 2-OHE1/16alpha-OHE1 ratio in any single urine
      sample and the average ratio over the 8-week study period from the same woman,
      with the mean correlation coefficient of 0.85. These results indicated that the
      within-person variation of the 2-OHE1 to 16alpha-OHE1 ratio for most women was
      moderate and the level of this ratio in a single urine sample, in general,
      reflects reasonably well the level of this biomarker over a 2-month period.

PMID- 10576222
TI  - Intracranial EEG in temporal lobe epilepsy.
AB  - Intracranial EEG monitoring before epilepsy surgery, while becoming less commonly
      performed in patients with unilateral mesial temporal lobe epilepsy, is still
      widely used when bilateral independent temporal lobe seizures are suspected or
      when extratemporal foci cannot be ruled out by noninvasive means. Additionally,
      many epilepsy centers are reporting excellent surgical outcome in patients with
      neocortical temporal lobe epilepsy, when resections are guided by intracranial
      EEG studies. This article reviews the indications, technical aspects, risks, and
      interpretation of intracranial EEG in patients with temporal lobe seizures. It
      also considers intracranial EEG features predictive of surgical outcome.

PMID- 10576223
TI  - Invasive EEG monitoring in children: when, where, and what?
AB  - With rapid advances in noninvasive technology, the need for chronic intracranial
      monitoring to define the epileptogenic region has diminished significantly. Its
      role in presurgical evaluation has come under scrutiny particularly in adults
      with lesional epilepsy. With the shift in surgical candidacy toward the younger
      age groups, however, invasive monitoring has regained its utility especially in
      children with normal imaging studies and cortical dysplasia. This review
      critically evaluates its continuing role, attempting to assess cost-benefit under
      specific clinical scenarios and proposes how the findings can be incorporated
      into the challenging task of surgical planning in intractable childhood epilepsy.

PMID- 10576224
TI  - Neocortical temporal lobe epilepsy: intracranial EEG features and surgical
      outcome.
AB  - Patients with neocortical temporal lobe epilepsy (NTLE) may have less favorable
      outcome with anterior temporal lobectomy than those with mesial temporal foci.
      The authors analyzed ictal intracranial electroencephalograms (EEGs) in patients
      with NTLE to identify features that predict surgical outcome. The following
      intracranial ictal EEG features in 31 consecutive medically intractable NTLE
      patients were studied: Frequency (i.e., low-voltage fast [>20 Hz], recruiting
      ictal-onset spikes, ictal-onset rhythms less than 5 Hz, ictal-onset rhythms with
      repetitive sharp waves between 5 and 20 Hz); extent of ictal onset (focal,
      sublobar, and lobar); localization within the temporal lobe (anterior, posterior,
      or regional); and the time to seizure spread outside the temporal lobe (rapid,
      intermediate, and slow). The average follow-up period was 36.7 months (range, 18
      to 60 months). Findings between two outcome groups were compared: class I group
      (seizure-free) and class II to IV group (persistent seizures). Twenty-one (66.7%)
      of 31 patients with NTLE were seizure-free. Intracranial EEG features which were
      significantly associated with seizure-free outcome were focal or sublobar onset,
      anterior temporal onset, and slow propagation time (P < 0.05). There was a trend
      for patients with ictal onset morphologies of slow ictal-onset rhythm and
      repetitive sharp waves to be seizure-free (P = 0.07). Intracranial EEG is helpful
      in predicting surgical outcome in NTLE patients.

PMID- 10576225
TI  - Indications and outcome of ictal recording with intracerebral and subdural
      electrodes in refractory complex partial seizures.
AB  - Intracranial electrophysiologic recording has often been used to localize ictal
      onset zones in presurgical evaluation of refractory complex partial seizures.
      Specific indications for intracranial ictal monitoring have not been analyzed in
      detail, however. The authors designed this study to test the utility of
      intracranial monitoring in specific indications and considered six specific
      indications for intracranial monitoring. They compared prospectively determined
      indications and outcomes of chronic intracerebral and subdural electrophysiologic
      recording in 50 consecutive patients whose ictal onset zones had been
      inadequately localized with interictal and ictal EEG using extracranial
      electrodes, magnetic resonance imaging, interictal[18F]fluorodeoxyglucose
      positron emission tomography, and neuropsychological testing. In 47 patients
      ictal onset zones were localized with intracranial recordings, leading to
      resections in 38 patients. Each indication for intracranial monitoring selected a
      group in which the majority went on to have efficacious epilepsy surgery (5-year
      follow-up). Definitive diagnosis of bilateral independent ictal onset zones in
      temporal lobe epilepsy required intracranial ictal EEG. Intracranial EEG
      localization supported efficacious resection in most patients, despite
      contradictory or nonlocalizing extracranial ictal EEG and neuroimaging
      abnormalities. Critical analysis of these specific indications for intracranial
      monitoring may be useful in multicenter evaluation of these techniques.

PMID- 10576226
TI  - Identification of electrocorticogram patterns as the basis for a direct brain
      interface.
AB  - This study reports on the first step in the development of a direct brain
      interface based on the identification of event-related potentials (ERPs) from an
      electrocorticogram obtained from the surface of the cortex. Ten epilepsy surgery
      patients, undergoing monitoring with subdural electrode strips and grid arrays,
      participated in this study. Electrocorticograms were continuously recorded while
      subjects performed multiple repetitions for each of several motor actions. ERP
      templates were identified from action-triggered electrocorticogram averages using
      an amplitude criterion. At least one ERP template was identified for all 10
      subjects and in 56% of all electrode-recording sets resulting from a subject
      performing an action. These results were obtained with electrodes placed solely
      for clinical purposes and not for research needs. Eighty-two percent of the
      identified ERPs began before the trigger, indicating the presence of premovement
      ERP components. The regions yielding the highest probability of valid ERP
      identification were the sensorimotor cortex (precentral and postcentral gyri) and
      anterior frontal lobe, although a number were recorded from other areas as well.
      The recording locations for multiple ERPs arising from the performance of a
      specific action were usually found on close-by electrodes. ERPs associated with
      different actions were occasionally identified from the same recording site but
      often had noticeably different characteristics. The results of this study support
      the use of ERPs recorded from the cortical surface as a basis for a direct brain
      interface.

PMID- 10576227
TI  - Detection of event-related potentials for development of a direct brain
      interface.
AB  - The study presented here is part of an ongoing effort to develop a direct brain
      interface based on detection of event-related potentials (ERPs). In a study
      presented in a companion article, averaged ERP templates were identified from
      electrocorticograms recorded during repetition of voluntary motor actions. Here
      the authors report on the detection of individual motor ERPs within the
      electrocorticogram using cross-correlation. An averaged ERP template was created
      from the first half of each electrocorticogram and then cross-correlated with the
      continuous electrocorticogram from the second half. Points where the cross
      correlation value exceeded an experimentally determined detection threshold were
      considered to be detection points. A detection point was considered to be a valid
      "hit" if it occurred between 1 second before and 0.25 second after the recorded
      time of a voluntary action. The difference between the hit and false-positive
      percentages (HF-difference) was used as a metric of detection accuracy. HF
      differences greater than 90 were found for 5 of 15 subjects, HF-differences
      greater than 75 were found for 8 of 15 subjects, and HF-differences greater than
      50 were found for 12 of 15 subjects. The three other subjects with HF-differences
      less than 50 had electrode locations not well suited for recording movement
      related ERPs. Recordings from sensorimotor and supplementary motor areas produced
      the highest yield of channels with HF-difference greater than 50; however, a
      number of channels with good performance were found in other areas as well. The
      results demonstrate the likely prospect of using ERP detection as the basis of a
      single-switch direct brain interface and that furthermore, there is a good
      possibility of obtaining multiple control channels using this approach.

PMID- 10576228
TI  - Rational use of EEG in adults in clinical practice.
AB  - The electroencephalogram (EEG) is still widely used for the diagnosis of several
      clinical conditions and symptoms. To assess the information provided by the EEG
      in relation to its duration, and to identify the shortest recording providing a
      conclusive report, the tracing was tested in 290 adult patients seen in a
      hospital neurophysiology unit for epilepsy (definite or uncertain), headache,
      head trauma, fainting, syncope, undefined loss of consciousness, vertigo, and
      cerebrovascular disease. Two neurophysiologists participating in the study read
      the same EEG independently. The record was based on a standardized timed sequence
      of montages. At each step any changes from the previous step were noted. Sixty
      seven percent of the EEGs were coded as normal or aspecific, 24.1% were slow, and
      8.6% were epileptiform. Normal tracings ranged from 38.8% (definite epilepsy) to
      87.5% (vertigo), and epileptiform EEG from 0 (uncertain epilepsy) to 28.6%
      (definite epilepsy). The final report was clear in 80% of cases at the end of a 2
      minute reading and almost 90% after 4 minutes. Hyperventilation and intermittent
      photic stimulation contributed little to the final report. Only for definite
      epilepsy were there changes along the whole sequence of montages. Thus, only for
      epilepsy need the EEG recordings last more than 20 minutes, whereas for the other
      clinical indications the total recording time could be limited to 4 minutes at
      most.

PMID- 10576229
TI  - Quantitative thermal perception testing in adults.
AB  - In 225 adults aged 18 to 80 years, normative warm and cold perception thresholds
      were assessed at the volar distal forearm, thenar eminence, lower medial calf,
      and lateral dorsal foot using the method of limits and a Thermotest (Somedic,
      Stockholm, Sweden). A 1.5-cm x 2.5-cm thermode, a 1 degrees C/s stimulus change
      rate, and a 32 degrees C baseline temperature were applied. Thresholds of five
      consecutive stimuli were averaged. At the thenar eminence a 3 degrees C/s
      stimulation was applied in addition to the 1 degree C/s stimulation. Effects of
      spatial summation were studied at the calf and forearm by additional testing with
      a 2.5-cm x 5.0-cm thermode. To evaluate the influence of skin temperature,
      thresholds were correlated with the pretest skin temperature at the tested sites.
      Reproducibility of stimulus perception was determined by comparing the lowest to
      the highest response to five consecutive stimuli. Results showed sufficient
      accuracy of thermal perception thresholds. Thresholds were higher with the 3
      degrees C/s stimulation than with the 1 degree C/s stimulation. Thresholds were
      lower with the large than with the small probe. Skin temperature had only minimal
      influence on thresholds. The use of a 32 degrees C baseline temperature and a 1
      degree C/s stimulus change rate is recommended. The large probe should be used at
      body sites where the entire thermode surface adjusts planely to the skin. Warming
      up the tested skin area is not necessary before thermotesting.

PMID- 10576230
TI  - Analysis of the corneal reflex with air puff: normal controls and patient groups.
AB  - Though there are several reports published about the corneal reflex elicited by
      different methods, a standardized electrophysiologic study with air puff in man
      has not been published. The aim of this study is to standardize the corneal
      reflex elicited by air puff to cornea. The authors studied the corneal reflex
      with air puff and direct touch by using a standardized method in patients with
      thalamic hemorrhage (n = 15), hemispheric infarction (n = 9), brainstem
      infarction (n = 9), multiple sclerosis (n = 12), and Bell's palsy (n = 12) and in
      normal control subjects (n = 21). The conventional blink reflex (BR) was also
      studied. The reflex responses were recorded from both orbicularis oculi muscles
      by air puff and direct touch to cornea in addition to the electrical stimulation
      of the supraorbital nerve. No statistical difference could be detected between
      the responses elicited by air puff or direct touch to cornea (P > 0.05). Corneal
      reflex responses were statistically different from the R2 response of the BR (P <
      0.005). Because the responses elicited by direct touch and air puff to cornea are
      identical, air puff to cornea can be used confidently to study the corneal
      reflex.

PMID- 10576232
TI  - Intracranial EEG. The last word.

PMID- 10576231
TI  - Using frequency domain characteristics to discriminate physiologic and
      parkinsonian tremors.
AB  - The manner in which characteristics of time series in the frequency domain can
      enhance discrimination between physiologic and parkinsonian tremor when tremor
      amplitude is low was examined. Rest tremor and postural tremor with and without
      visual feedback were recorded twice in the two hands of a group of patients with
      Parkinson's disease (PD) (n = 21) and a group of healthy control subjects (n =
      30) using displacement laser systems. Recordings were analyzed quantitatively
      using amplitude and seven frequency domain characteristics. Postural tremor with
      no visual feedback allowed the most efficient discrimination between the two
      groups of subjects especially in velocity and acceleration (derived from
      displacement) and allowed identification of more patients with PD as separate
      from the range observed in the control group. Moreover, the frequency domain
      characteristics that were investigated identified the majority of the patients
      even when amplitude did not. After eliminating redundant (correlated)
      characteristics, it was found that the frequency composition of tremor in PD can
      be described adequately with four characteristics, which are the most reliable,
      independent, and discriminative elements for detecting early or subtle
      modifications in tremor. Also, a series of finger flexions was found to enhance
      physiologic tremor but not tremor in PD. Discrimination of low-amplitude tremor
      in PD from normal physiologic tremor is enhanced by examining the median
      frequency of oscillations, the concentration of power in the power spectrum, and
      the distribution of power in particular ranges. Tremor measurement should not be
      limited to acceleration data as some information is more visible in velocity time
      series.

PMID- 10576233
TI  - Small fetal size: a risk factor for breech birth at term.
AB  - OBJECTIVE: To examine fetal size as a risk factor for breech birth at term.
      METHODS: Singleton breech or cephalic births of gestational age > or = 37 weeks
      in New South Wales (NSW), Australia from 1990 to 1996 were analyzed. Birthweight
      percentile was used as a measure of fetal size at the time of birth. Factors
      associated with breech birth at term were analyzed using logistic regression.
      RESULTS: There were 18914 singleton breech and 540164 cephalic births in the
      study period. The important independent predictors of breech birth at term were
      advancing maternal age, primiparity, female sex and small size for gestational
      age. Infants < 10th percentile had an adjusted odds ratio of 1.33 (95% CI 1.28
      1.38) for breech birth at term compared with 25th-75th percentile infants.
      CONCLUSIONS: Breech birth at term was associated with smaller fetal size for
      gestational age. This was shown directly through an association with birthweight
      for-gestational-age percentiles and indirectly through association with female
      sex, primiparous birth and congenital anomalies.

PMID- 10576234
TI  - Medical management of non-viable early first trimester pregnancy.
AB  - OBJECTIVE: To compare the efficacy of intramuscular methotrexate plus vaginal
      misoprostol to vaginal misoprostol alone in completing abortion in women with non
      viable early first trimester pregnancy. METHOD: Twenty-one women with non-viable
      pregnancy up to 49 days gestation were randomized to receive intramuscular
      methotrexate, followed 2 days later by vaginal misoprostol or misoprostol alone.
      We also collected patient satisfaction information. RESULT: Complete abortion
      occurred in all 12 (100%) women in the combined group and eight of nine (89%, RR
      = 1.13, CI 0.89-1.42) women in the misoprostol only group. Of the women, 75%
      rated their experience as good and would choose medical management again.
      CONCLUSION: Either methotrexate plus misoprostol or misoprostol alone effectively
      completed abortion in women with non-viable early pregnancy and represent
      acceptable medical alternatives to surgery or expectant management.

PMID- 10576235
TI  - Gonadal function in young women with Down syndrome.
AB  - OBJECTIVE: Investigations suggest an increased incidence of gonadal dysfunction
      in patients with Down syndrome. New features, Alzheimer disease and osteoporosis
      emerge in these individuals. Therefore, hormonal investigation in persons with
      Down syndrome is pursued. METHODS: Thirteen females with trisomy 21 (23.65 +/-
      3.23 years old) participated in the study. Ultrasound studies were performed to
      explore the internal genitals. Blood samples were taken for the determination of
      follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2),
      prolactin (PRL), dehydroepiandrosterone sulfate (DHEA-S), testosterone (T) and 17
      hydroxyprogesterone (17-OHP). RESULTS: The patients were at stage V of sexual
      development. Ultrasonography demonstrated normal uterine and ovarian size and
      endometrial thickness as well. The ovaries of all patients contained follicles of
      normal distribution and various sizes. The mean concentrations of FSH, DHEA-S and
      E2 were normal. The level of PRL was significantly higher than that of the
      controls, but within the normal lab range. The levels of LH, T and 17-OHP were
      significantly elevated, compared to those of the control group (P < 0.05, P <
      0.01, P < 0.001, respectively). CONCLUSIONS: Our data produce new information on
      the gonadal function of Down syndrome women. Specific studies on pituitary
      gonadal and pituitary-adrenal axis function are needed.

PMID- 10576236
TI  - Mammographic and ultrasonographic study of changes in the breast related to HRT.
AB  - OBJECTIVE: To determine the frequency and degree of change in mammographic
      densities, and new solid or cystic formations in the breast tissue, during
      different types of hormone replacement therapy (HRT). SUBJECTS AND METHODS: This
      prospective study included 118 postmenopausal women, 88 under hormone replacement
      therapy and 30 control subjects. Four types of hormone therapies were compared
      for their effects on mammograms and sonograms obtained before and during therapy.
      Mean duration of follow-up was 16.92 +/- 7.65 months in the treated and 21.56 +/-
      11.49 months in the control group. Density changes on mammograms were evaluated
      subjectively. RESULTS: Density increase was recorded in 34% of the patients
      receiving HRT and in none of the control subjects (P < 0.01). Highest frequency
      of density increase was found in the groups treated with estrogen plus
      cyproterone acetate (46%) and with estrogen plus medroxyprogesterone acetate
      (43%). Frequencies of density increase in the tibolone users, and in estrogen
      alone users were 28% and 18%, respectively. Degree of density increase was
      evidently minimal in tibolone users, compared to others. New cysts occurred in
      six patients receiving HRT (6%) which was not statistically different from the
      control group (16%) (P > 0.05). New cyst formation was not related to the degree
      of density increase. New solid mass formation was not observed. CONCLUSION: Our
      findings show that mammographic density changes related to HRT are dependent on
      the selected hormone regimen. Formations of breast cysts or solid lesions do not
      seem to be related to HRT.

PMID- 10576238
TI  - Dietary phytoestrogens in the prevention of long-term postmenopausal diseases.
AB  - Phytoestrogens (PEs) are natural compounds, with a biological activity like
      estrogen, which comprise isoflavones, lignans and coumestans. A traditional
      Asiatic phytoestrogen-rich diet is associated with a lower incidence of breast
      cancer and postmenopausal illness, and much evidence indicates that PEs prevent
      bone resorption, increase bone density and reduce cholesterol. The estrogenic
      effects of phytoestrogens can be useful in preventing postmenopausal osteoporosis
      and cardiovascular disease.

PMID- 10576237
TI  - Effect of a half dose of tamoxifen on proliferative activity in normal breast
      tissue.
AB  - OBJECTIVES: To investigate the proliferative activity of the mammary gland
      epithelium and plasma levels of progesterone, estradiol, prolactin, luteinizing
      hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin
      (SHBG) in premenopausal women treated with 10 and 20 mg of tamoxifen (TAM) for 22
      days. PATIENTS AND METHODS: A randomized double-blind study was performed with 43
      premenopausal women with a diagnosis of fibroadenoma of the breast. The patients
      were divided into three groups: A (n = 15, placebo); B (n = 15, TAM 10 mg/day)
      and C (n = 13, TAM 20 mg/day). They started taking an oral dose of TAM or placebo
      on the very first day of the menstrual cycle. Lumpectomy was performed on the
      22nd day of therapy. Normal breast tissue samples were collected during surgery,
      immediately immersed in 10% buffered formalin, processed for routine histology
      and immunohistochemistry for proliferating cell nuclear antigen (PCNA) detection.
      Two peripheral blood samples were collected, both on the 22nd day of the
      menstrual cycle, in order to evaluate the hormone levels. PCNA expressing
      epithelial cells were quantified by using a digital program Kontron Image System
      KS-300 in 1000 cells (400 x ). RESULTS: The percentage of cells expressing PCNA
      was significantly higher in the group receiving placebo (group A, 50.3%) when
      compared to groups receiving TAM 10 or 20 mg/day (group B, 24.1%; and group C,
      23.2%, respectively) (P < 0.001). Differences between groups B and C were not
      significant. Levels of progesterone, estradiol and SHBG were significantly higher
      in B and C groups compared to group A. Increasing concentrations of FSH (P <
      0.0045) and lower levels of prolactin (P < 0.0055) were only found in the group
      receiving 20 mg/day of TAM (group C). CONCLUSIONS: A 22-day TAM therapy, either
      with 10 or 20 mg/day, significantly reduced the PCNA expression and therefore the
      proliferative activity of the normal human breast tissue. Increasing levels of
      estradiol, progesterone and SHBG were associated with TAM therapy at 10 or 20
      mg/day. However, a significant change of the level of FSH and prolactin was
      reached only with a 20-mg/day dose.

PMID- 10576239
TI  - Should laboring parturients with Harrington rods receive lumbar epidural
      analgesia?

PMID- 10576240
TI  - Extra-amniotic prostaglandin-E2 for termination in the second and early third
      trimesters.

PMID- 10576241
TI  - Lipoleiomyoma of the uterus.
AB  - Uterine lipoleiomyoma may associate with certain concomitant metabolic disorders.
      The possible clinical correlates and the potential implications on the
      pathogenesis are elaborated.

PMID- 10576242
TI  - Carcinoma of the cervix: aspects of clinical presentation and management in Benin
      City.
AB  - Carcinoma of the cervix is the most common gynecological cancer in Benin City.
      Late presentation, poverty and grand multiparity featured prominently.
      Multiplicity of sexual partners was rather uncommon.

PMID- 10576243
TI  - The FIGO study group on women's sexual and reproductive rights. International
      Federation of Gynecology and Obstetrics.
AB  - In October 1998, the FIGO Executive Board established a Study Group on Women's
      Sexual and Reproductive Rights to develop specific details regarding observance,
      enforcement and advancement. At its inaugural meeting in April 1999 the Study
      Group reviewed international and national progress in respect of such rights.
      International initiatives had achieved considerable progress towards
      specification and monitoring of rights, particularly through the committee
      receiving reports of national compliance under the Convention on the Elimination
      of All Forms of Discrimination Against Women. National progress was more mixed.
      While some countries had improved women's sexual and reproductive rights, many
      had not, and rights in some had regressed. The Study Group considered actions
      available to FIGO member societies to advance rights in their countries, how
      advancement of rights might be pursued in countries in general, and initiatives
      that FIGO itself might undertake and facilitate to protect and promote women's
      sexual and reproductive rights.

PMID- 10576244
TI  - ACOG committee opinion. Telecommunication in medicine: number 221, September
      1999. Committee on professional liability. American College of Obstetricians and
      Gynecologists.

PMID- 10576245
TI  - Artificial senescence of bovine retinal pigment epithelial cells induced by near
      ultraviolet in vitro.
AB  - RPE cells irradiated by near-ultraviolet (NUV) were characterized at cellular,
      biochemical and molecular levels in order to determine whether light-induced RPE
      changes contribute to the senescence of RPE cells in vitro. Biochemical and
      molecular parameters of cellular senescence were studied by using both bovine RPE
      cells at confluence repeatedly irradiated by NUV (peaking at 365 nm) and RPE
      cells at different levels of population doubling (PDL). After repeated NUV
      irradiation, RPE proliferation was markedly suppressed. In parallel, the BrdU
      index significantly reduced to a minimum level, similar to RPE cells undergoing
      multiple population doublings. NUV irradiation resulted in a decrease in cellular
      alkali-soluble melanin and an increase in lipofuscin-like fluorophores. The
      lipofuscin-like fluorophores, isolated from RPE cells exposing repeated NUV
      irradiation, represented a gradual hyperchromic change and red-shift, reaching
      the wavelength maxima (560-572 nm), at excitation wavelength of 365 nm, a typical
      range of 'age pigment'. These phenomena were substantially eliminated in oxygen
      free conditions. Both the NUV-irradiated RPE cells and RPE cells at 20 Pd
      expressed 4 to 8-fold and 2 to 4-fold less PEDF and TIMP-3 genes, respectively.
      As result of experiments using chronic photochemical treatment, RPE cells
      represented several characteristics of cellular senescence. In addition to
      alterations of the melanin/lipofuscin system, DNA synthesis was greatly
      suppressed in NUV-irradiated RPE cells, indicating replicative senescence. The
      phenomena of downregulation of the possible senescence markers imply that
      photochemical reactions of RPE cells accelerate the process of RPE senescence.

PMID- 10576246
TI  - Augmentation of indices of oxidative damage in life-long melatonin-deficient
      rats.
AB  - The chief pineal secretory product, melatonin, is an efficient free radical
      scavenger and antioxidant. The current study tested whether the life-long
      reduction of endogenous melatonin levels due to pinealectomy would influence the
      accumulation of oxidatively damaged products as the animals aged. Rats were
      either pinealectomized or sham operated when they were 2-months-old. At 25 months
      of age these animals were killed along with 2-month-old controls. Aging in the
      pineal-intact animals was associated with increased levels of lipid peroxidation
      products (malondialdehyde and 4-hydroxyalkenals in the lung, kidney and skin),
      rises in an oxidatively damaged DNA product (8-hydroxy-deoxyguanosine in liver,
      kidney and pancreas), and in the levels of protein carbonyls (in the liver).
      Likewise, advanced age was associated with a significant decrease in membrane
      fluidity (increased membrane rigidity) of hepatic microsomes in pineal-intact
      rats. For all of these parameters and in a number of organs, pinealectomy caused
      further increases in the indices of oxidative damage. Consistent with previous
      suggestions, the implications of these findings is that aging is associated with
      the augmented accumulation of oxidatively damaged macromolecules and that these
      increases are exaggerated when a relative melatonin deficiency is induced by
      pinealectomy. The findings are consistent with the idea that the accelerated
      accumulation of oxidatively damaged products after pinealectomy was due to
      reduction in melatonin since it functions as a free radical scavenger and
      antioxidant. On the other hand, other pineal secretory products that were reduced
      as a consequence of pineal removal may have also been responsible for some of the
      observed changes.

PMID- 10576247
TI  - Telomerase activity in hybrids between telomerase-negative and telomerase
      positive immortal human cells is repressed in the different complementation
      groups but not in the same complementation group of immortality.
AB  - The expression of telomerase is essential for cells to be immortalized, and most
      immortal cell lines possessed telomerase activity. Using the cell fusion
      technique, it has been shown that mortal and telomerase-negative phenotypes of
      normal cells are dominant over immortal and telomerase-positive phenotypes,
      suggesting that the normal cells possessed dominant repressor-type activity for
      telomerase expression. Several telomerase-negative immortal human cell lines were
      reported, in which telomerase-independent mechanisms was supposed to maintain
      telomere length. We aimed at seeing whether the telomerase-negative phenotype of
      these immortal cells is dominant over telomerase-positive phenotype of other
      immortal cells in correlation with cellular mortality. Results showed that, when
      telomerase-positive and -negative immortal parental cell lines belonging to the
      different complementation groups were fused, telomerase-negative mortal hybrid
      clones arose, i.e. telomerase-negative phenotype was dominant as well as mortal
      phenotype. However, when immortal hybrid cells arose from telomerase-positive and
      -negative immortal parents belonging to either the same or different
      complementation groups, they were all telomerase-positive, i.e. telomerase
      negative phenotype appeared to be recessive. Telomerase-negative immortal hybrid
      was never established from any combinations between telomerase-negative and 
      positive immortal parental cells.

PMID- 10576248
TI  - Age-related effects of oxidative metabolism and cyclic AMP signaling on
      neutrophil apoptosis.
AB  - Spontaneous as well as Fas-induced polymorphonuclear cell apoptosis is unchanged
      in the elderly. However, a weak responsiveness to antiapoptotic signals elicited
      by proinflammatory molecules has been reported in neutrophils isolated from aged
      humans. To gain insight into this field, here we have evaluated the role of
      oxidative metabolism and cyclic AMP (cAMP) signaling on age-related neutrophil
      apoptotic cell death. Results show that although superoxide dismutase (SOD),
      added exogenously to cell cultures, is able to prolong neutrophil survival in
      both young and aged individuals, high amounts of the enzyme are further effective
      in cell cultures of young donors only. Notably, the addition of catalase gives
      rise to a more striking, yet comparable, inhibition of neutrophil-programmed cell
      death in both groups of subjects. Furthermore, even low amounts of catalase are
      enough to restore a normal apoptotic outcome in SOD-treated cell cultures of old
      donors. Unlike the oxidative metabolism, cAMP signaling activation does not
      reveal any difference in the apoptotic response of neutrophils isolated from
      young and aged donors. Thus, supplementation of cell cultures with prostaglandin
      E2, dibutyryl cAMP or, to a lesser degree, forskolin results in a dose-dependent
      inhibition of DNA cleavage product appearance in both groups of subjects. The
      data outline that an impairment of neutrophil antioxidant shield, leading to an
      augmented cell oxidative load, is likely to occur as a feature of age. This may
      increase the apoptotic rate of stimulated cells, which may in turn account for
      the increased susceptibility of elderly individuals to life-threatening
      infections.

PMID- 10576249
TI  - Update on psychosocial research on leukaemia for social work practitioners.
AB  - This article describes an Australian initiative that has undertaken the challenge
      of establishing a permanent psychosocial research program on leukaemia and
      associated haematological disorders to inform service provision and policy
      development for patients and their families. The description of this initiative
      is set in the context of a summary of the present research that exists in this
      area. This research indicates that this is a group of patients with a high rate
      of morbidity who, along with their family and carers, are vulnerable to physical,
      social, emotional and spiritual distress. The discussion concludes with a
      description of research projects that are presently being undertaken to extend
      our understanding of the psychosocial issues associated with these diagnostic
      groups.

PMID- 10576250
TI  - The cessation of cancer treatment as a crisis.
AB  - Although it is commonly acknowledged that a diagnosis of cancer can be a form of
      a crisis precipitating a period of disequilibrium, few researchers have examined
      the psychosocial issues associated with the completion of adjuvant cancer
      treatment. This exploratory study examines the responses of women in a community
      based cancer support group to an open-ended question asking them to describe
      their experiences since their treatment ended. Subjects were asked to respond to
      whether they felt the loss of the "safety net" of treatment had caused them any
      type of distress. The narrative responses of the subjects support the notion that
      the period after treatment ceases may be viewed as a crisis that brings with it
      anxiety and uncertainty. The results of this study reinforce the need for
      additional research to better understand the issue so that services and programs
      can be enhanced to better meet patients' needs. Additionally, the results suggest
      that social workers may play a crucial role in helping women make the transition
      from cancer "patient" to cancer "survivor."

PMID- 10576251
TI  - Social work with adult cancer patients: a vote-count review of intervention
      research.
AB  - The meaning of a cancer diagnosis has changed in the past decades, bringing with
      it a myriad of psychosocial interventions to improve the psychological or
      functional status of those coping with the disease. Today, social workers in
      oncology need to be current with research in order to integrate empirical and
      practical knowledge. In an effort to assist in this process, we reviewed
      empirical studies to address the following questions: (1) When are patients
      likely to be willing to accept help? (2) Is there sufficient evidence to show
      that some types of psychosocial treatment are effective in improving
      psychological or physical functioning? (3) Are certain treatments preferable for
      some cancer patients depending on the type of cancer and stage of disease? Using
      a vote-count review of 40 intervention studies in psychosocial oncology, 36
      documented some positive outcomes from treatments, 4 studies exhibited null
      findings, and no studies were found to have clearly negative results. Studies
      revealed the most positive results from interventions during the treatment phase,
      next from interventions at diagnosis, and lastly from interventions during the
      terminal stage. Individual and group formats showed a comparable level of
      efficacy. Interventions that included cognitive behavioral methods had the most
      consistently positive results. Those intervention studies where social workers
      were involved in the research were less successful at demonstrating efficacy.
      This difference was due primarily to the fact that social workers often did not
      include cognitive behavioral interventions in their research. Based on the
      results of this study, social workers might want to reevaluate their intervention
      strategies.

PMID- 10576252
TI  - A comparative study of Jewish and Arab battered women presenting in the emergency
      room of a general hospital.
AB  - Domestic violence has been well documented in the past few years in both social
      work and medical journals. Our study seeks to determine the comparison between
      two cultures regarding this important issue. Five domains regarding demographic
      variables, components of battering, coping skills, social services offered and
      discharge objectives are discussed. Our findings suggest that the differences in
      several areas of battering in the two ethnic groups reflect to a large extent
      differences in the two cultures. Issues that warrant further research are child
      abuse and substance abuse in the Arab culture both on individual issues and in
      relationship to domestic violence.

PMID- 10576253
TI  - Social work practice with transsexuals in Hong Kong who apply for sex
      reassignment surgery.
AB  - There is a dearth of social work literature describing the comprehensive way of
      helping transsexuals who seek sex reassignment surgery. In view of this knowledge
      gap, this paper proposes a practice model to help transsexuals at different
      stages: assessment, surgery, and post-surgical follow-up. The characteristics of
      this practice model, its underlying theoretical framework, its focus of
      intervention, and the intervention at the multiple systems levels (namely
      individual, family and organization) are described. The roles of the social
      worker at different stages of helping are discussed.

PMID- 10576254
TI  - Alpha-gustducin-immunoreactive solitary chemosensory cells in the developing
      chemoreceptorial epithelium of the rat vallate papilla.
AB  - The presence of solitary chemosensory cells was studied in rat vallate papillae
      during the first week of post-natal life by alpha-gustducin immunocytochemistry.
      In 1- to 3-day-old rats, isolated alpha-gustducin-immunoreactive cells were found
      within the epithelium of the vallate papilla. These cells, mainly located in the
      basal layer, were scattered among keratocytes and wrapped in alpha-gustducin
      negative epithelial cells in a glia-like fashion. The alpha-gustducin
      immunoreactive cells were usually round and some of them gave rise to short,
      large processes directed towards the lumen of the oral cavity or the basal
      lamina. Rarely, some cells showed an evident bipolar shape. Small taste buds
      containing either alpha-gustducin-immunoreactive or alpha-gustducin-negative
      cells appeared in the vallate papillae of 4-day-old rats in which isolated,
      bipolar-shaped alpha-gustducin-immunoreactive cells were also found. After the
      first week of post-natal life, the taste buds appeared basically similar to those
      of adult animals. In conclusion, the present study demonstrates that the presence
      of epithelial cells with characteristics of solitary chemosensory cells precedes
      the development of the taste buds.

PMID- 10576255
TI  - Pheromone-triggered orientation flight of male moths can be disrupted by
      trifluoromethyl ketones.
AB  - In a wind tunnel trifluoromethyl ketones (TFMKs) have been found to disrupt the
      orientation flight of male moths to pheromone sources (virgin females or
      synthetic pheromone). This is demonstrated by comparison of the flight parameters
      of the Egyptian armyworm Spodoptera littoralis and the Mediterranean corn borer
      Sesamia nonagrioides, which had been topically treated with TFMKs, with those
      calculated for untreated insects. Inhibition occurred in all types of behavior
      and that of the source contact has been quantified and found to be dose
      dependent. The same effect has also been noticed in Mediterranean corn borer
      males flying to an attraction source consisting of mixtures of (Z)-11-hexadecenyl
      trifluoromethyl ketone (8), a closely related analogue of the major component of
      the pheromone, and the natural pheromone blend. The most active TFMKs are those
      closest in structure to the natural pheromone, along with those chemicals which
      easily hydrate in solution, such as the beta-thiosubstituted derivatives. Along
      with the previously reported reduction of catches in the field, our results
      suggest the possible application of these chemicals in future new pest control
      strategies.

PMID- 10576256
TI  - Odorant binding protein diversity and distribution among the insect orders, as
      indicated by LAP, an OBP-related protein of the true bug Lygus lineolaris
      (Hemiptera, Heteroptera).
AB  - Insect odorant binding proteins (OBPs) are thought to deliver odors to olfactory
      receptors, and thus may be the first biochemical step in odor reception capable
      of some level of odor discrimination. OBPs have been identified from numerous
      species of several insect orders, including Lepidoptera, Diptera, Coleoptera and
      Hymenoptera; all are holometabolous insects belonging to the monophyletic
      division of insects known as the Endopterygota. Recently, an antennal protein
      with OBP-like properties was identified from Lygus lineolaris, a hemipteran
      insect representing the Hemipteroid Assemblage, a sister division to the
      Endopterygota. The full length sequence of Lygus antennal protein (LAP) is
      presented in this report. In situ hybridization analysis revealed LAP expression
      in cell clusters associating with olfactory sensilla; expression was adult
      specific, initiating in developing adult tissue during the transitional period
      that precedes the actual adult molt. Sequence analysis confirmed that LAP is
      homologous with the OBP-related protein family, and most similar to the OS-E and
      OS-F proteins of Drosophila, the ABPX proteins of Lepidoptera and the OBPRP
      proteins of the Coleoptera. Assuming that the OBP-related proteins represent one
      homologous family, the identification of LAP significantly expands the
      phylogenetic depth of that family and its underlying role in odor detection to
      encompass all members of the Endopterygota and Hemipteroid Assemblage, which
      comprise >90% of all insect species.

PMID- 10576257
TI  - A kinetic model of the transient phase in the response of olfactory receptor
      neurons.
AB  - A model is presented that predicts the instantaneous spike rate of an olfactory
      receptor neuron (ORN) in response to the quality and concentration of an odor
      stimulus. The model accounts for the chemical kinetics of ligand-receptor binding
      and activation processes, and implicitly the initiation of second messenger
      cascades that lead to depolarization and/or hyperpolarization of the ORN
      membrane. Both of these polarizing processes are included in the most general
      form of the model, as well as a process that restores the voltage to its negative
      resting state. The spike rate is assumed to be linearly proportional to the level
      of voltage depolarization above a critical negative voltage level. The model
      includes the simplifying assumption that activation of bound ligand-receptor
      complexes by G-proteins and other enabling molecules follows a Monod function
      that has the ratio of enabling molecules to bound unactivated ligand-receptor
      complexes as its argument. Parameters are selected that provide an excellent fit
      of the model to previously published empirical data on the response of cockroach
      ORNs to pulsed 1-hexanol stimuli. The sensitivity of model output to various
      model parameters is investigated and changes to parameters are discussed that
      would improve the ability of ORNs to follow rapidly pulsed stimuli.

PMID- 10576258
TI  - Heterogeneous expression of glycoconjugates among individual glomeruli of the
      hamster main olfactory bulb.
AB  - Glomeruli within the main olfactory bulb (MOB) are known as areas of synapse
      formation between axon terminals of olfactory neurons in the olfactory epithelium
      and dendrites of the first relay neurons (mitral and tufted cells) in the MOB, so
      that they serve as functional units in olfaction. We examined expression patterns
      of glycoconjugates in the glomeruli of the hamster MOB by lectin histochemistry
      using 21 biotinylated lectins. Thirteen lectins, WGA, s-WGA, DSL, DBA, SBA, WA,
      SJA, RCA-I, PNA, ECL, UEA-I, PSA and LCA, showed differential binding patterns
      among the glomeruli. To evaluate these differential binding patterns of lectins,
      we analysed staining intensity of each of the 13 lectins on the level of
      individual glomeruli by image analysis, and classified staining intensity into
      five grades (negative, 1+, 2+, 3+, 4+) on the basis of results obtained. This
      classification enables us to make detailed comparison among individual glomeruli.
      We further analysed the grade of staining intensity of each of the 13 lectins in
      the same glomerulus in adjacent serial sections by image analysis, and found that
      individual glomeruli varied in combination of grades of staining intensity and
      kinds of lectins. These results indicate that glycoconjugates are expressed
      heterogeneously in individual glomeruli, and that heterogeneous expression may
      contribute to the topographic organization of the primary olfactory pathway.

PMID- 10576259
TI  - Nodal shape (S/L) and its combination with size for assessment of cervical
      lymphadenopathy: which cut-off should be used?
AB  - The short axis to long axis (S/L) ratio is commonly used to assess cervical
      lymphadenopathy; however, the cut-off value used has been limited to 0.5. The
      accuracy of the combination of S/L ratio and nodal size has not been documented
      previously. We evaluated 1143 normal cervical nodes from 95 healthy subjects, and
      1441 nodes from 290 patients with proven cervical lymphadenopathy. The optimum
      cut-off value of the S/L ratio was determined in different regions of the neck:
      submental (0.5), submandibular (0.7), parotid (0.5), upper cervical (0.4), middle
      cervical (0.3) and posterior triangle (0.4). In the submandibular and parotid
      regions, the combination of the S/L ratio and short axis shows substantial
      improvement in diagnostic accuracy when compared to the S/L ratio alone.

PMID- 10576260
TI  - Confounding effects of myocardial background intensity and attenuation in
      contrast echocardiography: an in vivo study.
AB  - It has been shown in vitro that the time-intensity data of echo contrast agents
      may be influenced by the background intensity of the myocardium and attenuation
      at high contrast agent concentrations. In the present study, these effects are
      evaluated from in vivo data. An effect of background intensity of the myocardium
      on the determination of the transit rate of the contrast agent could not be
      demonstrated unambiguously. A statistically significant relation between transit
      rate and background intensity was found only for intermediate flows in the
      transmural region. The magnitude of this relation was such that it does not
      provide a serious source of error. Attenuation and shadowing typically
      underestimate the transit rate of the contrast agent, which results in
      overestimation of flow. It is recommended that the lowest doses of contrast agent
      inducing myocardial opacification should be applied.

PMID- 10576261
TI  - Alterations in ultrasonic backscatter during intra-aortic balloon
      counterpulsation support in patients with acute myocardial infarction.
AB  - Alterations of ultrasonic backscatter parameters have been evident in humans with
      myocardial infarction or ischemia. The backscatter variability could be restored
      in ischemic or stunned myocardium after reperfusion. The aims of this study were
      to determinate changes in regional myocardial ultrasonic backscatter during intra
      aortic balloon counterpulsation (IABP) support in patients with acute myocardial
      infarction (AMI), and to evaluate whether backscatter imaging could be a
      functional guide of IABP support. A total of 9 patients with AMI were
      investigated during IABP support with a two-dimensional (2-D) ultrasonic
      backscatter imaging approach for parasternal short-axis view. Coronary
      angiography was performed in 6 of the 9 patients. A total of 21 vessel
      territories were studied in different modes of IABP support: 1:1, 1:2 and
      standby. Restoration of cyclic variation of backscatter after IABP support was
      demonstrated in 10 vessel territories. Failure of restoration of cyclic variation
      of backscatter after IABP support was noted in 6 vessel territories with severe
      coronary lesions (total or nearly total occlusion) or scar tissue. No changes of
      the ultrasonic backscatter were found in nonischemic vessel territories with
      patent coronary arteries or TIMI III coronary flow. In addition, the wall motion
      score did not change significantly with different IABP support. These results
      suggest that IABP could restore the cyclic variation of backscatter in ischemic
      myocardium. Myocardial anisotropy may play an influential role in the alterations
      of ultrasonic backscatter. We propose that ultrasonic backscatter could be a
      noninvasively functional guide of IABP use in patients with AMI.

PMID- 10576262
TI  - Acoustic radiation force in vivo: a mechanism to assist targeting of
      microbubbles.
AB  - The goal of targeted imaging is to produce an enhanced view of physiological
      processes or pathological tissue components. Contrast agents may improve the
      specificity of imaging modalities through selective targeting, and this may be
      particularly significant when using ultrasound (US) to image inflammatory
      processes or thrombi. One means of selective targeting involves the attachment of
      contrast agents to the desired site with the use of a specific binding mechanism.
      Because molecular binding mechanisms are effective over distances on the order of
      nanometers, targeting effectiveness would be greatly increased if the agent is
      initially concentrated in a particular region, and if the velocity of the agent
      is decreased as it passes the potential binding site. Ultrasonic transmission
      produces a primary radiation force that can manipulate microbubbles with each
      acoustic pulse. Observations demonstrate that primary radiation force can
      displace US contrast agents from the center of the streamline to the wall of a
      200-microm cellulose vessel in vitro. Here, the effects of radiation force on
      contrast agents in vivo are presented for the first time. Experimental results
      demonstrate that radiation force can displace a contrast agent to the wall of a
      50-microm blood vessel in the mouse cremaster muscle, can significantly reduce
      the velocity of flowing contrast agents, and can produce a reversible
      aggregation. Acoustic radiation force presents a means to localize and
      concentrate contrast agents near a vessel wall, which may assist the delivery of
      targeted agents.

PMID- 10576263
TI  - Effect of filling gases on the backscatter from contrast microbubbles: theory and
      in vivo measurements.
AB  - Two surfactant-based contrast agents, ST44 and ST68, were produced according to
      US Patent # 5,352,436 and filled with either air, C4F10 (perfluorobutane) or SF6
      (sulfur hexaflouride). Ten rabbits received i.v. injections of each agent/gas
      combination with 5 repetitions of each dose (range: 0.005-0.13 mL/kg). A custom
      made 10-MHz cuff transducer was placed around the surgically exposed distal aorta
      and audio Doppler signals were acquired in vivo. Quantitative in vivo dose
      responses were calculated off-line using spectral power analysis and compared to
      a theoretical model of microbubble dissolution and enhancement. For qualitative
      comparisons, 10 rabbits were imaged pre- and postcontrast administration (dose:
      0.1 mL/kg) in gray-scale and colour. All agent/gas combinations produced marked
      Doppler enhancement with air bubbles enhancing least of all (p < 0.0001) and ST68
      SF6 best of all (maximum: 27.6 +/- 2.04 dB; p < 0.012). There were no significant
      differences between other agent/gas combinations (0.30 < p < 0.70). Theoretical
      enhancement was within 1 order of magnitude of the experimental observations
      (i.e., deviations of up to 10 dB). The duration of contrast enhancement was 1-2
      min for air-filled bubbles, 3-5 min for SF6-filled bubbles and more than 7 min
      for C4F10-filled bubbles. In conclusion, ST68-SF6 microbubbles produced most in
      vivo enhancement of the agent/gas combinations studied. Theory matched the
      measurements within an order of magnitude.

PMID- 10576264
TI  - Contrast-enhanced ultrasound for guidance of local tumor ablation.
AB  - The objective was to assess the efficacy of sonography with and without contrast
      medium enhancement in guiding and monitoring percutaneous ethanol ablation of
      tumors in an animal model. VX-2 carcinoma was implanted into the thighs of New
      Zealand white rabbits and examined by grey-scale ultrasound, color, power, and
      pulse Doppler, before and after injection of 95% ethanol into the tumors.
      Injections of ethanol were guided by ultrasound to sites of tumor vascularity,
      until all tumor vascularity had been obliterated. Microbubble contrast medium or
      saline was injected i.v. prior to each of the ultrasonic interrogations.
      Arteriography was performed before and after ablation. Selected tumor samples
      were submitted for histologic examination. Contrast enhanced tumor vascularity
      over saline controls in all cases. In some, incompletely ablated foci of tumor
      could only be identified with contrast medium enhancement. Arteriography showed
      complete ablation of all but 1 tumor. We conclude that ultrasound enhanced by
      contrast better shows the presence or absence of tumor vascularity. Ultrasound
      enhanced by contrast might offer an accurate means of guiding and monitoring
      percutaneous ethanol injection for tumor ablation.

PMID- 10576265
TI  - Implementation of spectral width Doppler in pulsatile flow measurements.
AB  - In this paper, we present an automatic beam-vector (Doppler) angle and flow
      velocity measurement method and implement it in pulsatile flow measurements using
      a clinical Doppler ultrasound system. In current clinical Doppler ultrasound flow
      velocity measurements, the axis of the blood vessel needs to be set manually on
      the B-scan image to enable the estimation of the beam-vector angle and the beam
      vector angle corrected flow velocity (the actual flow velocity). In this study,
      an annular array transducer was used to generate a conical-shaped and
      symmetrically focused ultrasound beam to measure the flow velocity vectors
      parallel and perpendicular to the ultrasound beam axis. The beam-vector angle and
      flow velocity is calculated from the mode frequency (f(d)) and the maximum
      Doppler frequency (f(max)) of the Doppler spectrum. We develop a spectrum
      normalization algorithm to enable the Doppler spectrum averaging using the
      spectra obtained within a single cardiac cycle. The Doppler spectrum averaging
      process reduces the noise level in the Doppler spectrum and also enables the
      calculation of the beam-vector angle and flow velocity for pulsatile flows to be
      measured. We have verified the measurement method in vivo over a wide range of
      angles, from 52 degrees to 80 degrees, and the standard deviations of the
      measured beam-vector angles and flow velocities in the carotid artery are lower
      than 2.2 degrees and 12 cm/s (about 13.3%), respectively.

PMID- 10576267
TI  - Strain measurements of rabbit Achilles tendons by ultrasound.
AB  - Axial components of tendons' transverse strain fields were successfully measured
      in vitro by ultrasound. Achilles tendons of New Zealand white rabbits were used.
      Tendon inflammation was simulated by artificially inducing ischemia. Strain
      measurements were also correlated with conventional B-mode sonograms and
      histological micrographs. Results showed that strain measurements had reasonable
      agreement with histological examinations and provided better tissue
      differentiation than conventional B-mode imaging. For a given tendon, the strain
      values corresponding to different tissue layers were easily differentiated with
      an elastographic contrast-to-noise ratio ranging from 17 to 43 dB. Such
      differences, however, were not always present in the sonograms. Therefore,
      ultrasonic strain imaging may be a useful tool for assessing tendon disorders
      during the rehabilitation process.

PMID- 10576266
TI  - Tendon displacement assessment by pulsed Doppler tissue imaging: validation with
      a reciprocating string test target.
AB  - After hand trauma and surgery, assessment of tendon excursion is important in
      reconstructive surgery and rehabilitation. Aimed as a more reliable alternative
      to traditional noninvasive methods, a colour Doppler imaging scanner was adapted
      to measure longitudinal tendon displacement. Displacement was quantified by
      integrating the velocity estimated from the zero-crossing rate of the Doppler
      signal. The system was tested by measuring displaced distances of a rubber string
      that was moved back and forth. At a determined optimal receiver gain, 1.5-cm
      string displacements were measured with less than +/- 0.05-cm bias throughout an
      echo-signal dynamic range of 22 dB; standard deviations were around 0.05 cm.
      Regression analysis between measured and true displacements in the range 0.5-2.5
      cm resulted in a best fit straight line with slope 0.927, intercept 0.041 cm and
      residual standard error of 0.06 cm. A transfer technique was conceived to ensure
      accuracy when measuring tendons in the body. This CDI-based pulsed Doppler system
      merits verification for measurement of tendon excursion in patients.

PMID- 10576268
TI  - A rotating torus phantom for assessing color Doppler accuracy.
AB  - A rotating torus phantom was designed to assess the accuracy of color Doppler
      ultrasound. A thin rubber tube was filled with blood analog fluid and joined at
      the ends to form a torus, then mounted on a disk submerged in water and rotated
      at constant speeds by a motor. Flow visualization experiments and finite element
      analyses demonstrated that the fluid accelerates quickly to the speed of the
      torus and spins as a solid body. The actual fluid velocity was found to be
      dependent only on the motor speed and location of the sample volume. The phantom
      was used to assess the accuracy of Doppler-derived velocities during two
      dimensional (2-D) color imaging using a commercial ultrasound system. The Doppler
      derived velocities averaged 0.81 +/- 0.11 of the imposed velocity, with the
      variations significantly dependent on velocity, pulse-repetition frequency and
      wall filter frequency (p < 0.001). The torus phantom was found to have certain
      advantages over currently available Doppler accuracy phantoms: 1. It has a high
      maximum velocity; 2. it has low velocity gradients, simplifying the calibration
      of 2-D color Doppler; and 3. it uses a real moving fluid that gives a realistic
      backscatter signal.

PMID- 10576269
TI  - Measurement accuracy of the flow velocity in pulsed ultrasound Doppler
      velocimeter.
AB  - This paper presents a numerical simulation method for evaluating the measurement
      accuracy of the high-frequency pulsed ultrasound Doppler velocimeter (PUDV). The
      frequency distribution of the Doppler signal from a sample volume is calculated
      by dividing the sample volume into small cells and using the statistics of the
      velocities of the cells. The distribution is used to analyze the accuracy of the
      poststenotic velocity measurements of a 20-MHz 80-channel PUDV. The target flow
      field is obtained by solving Navier-Stokes equations numerically. It was shown
      that the velocities evaluated by the zero-cross and Fourier transform methods
      agreed well with the given velocities, and that flow separation was successfully
      detected. It was also shown that the tube diameter should be at least twice as
      large as the diameter of the sample volume to obtain accurate measurements.

PMID- 10576270
TI  - Ultrasound power deposition model for the chest wall.
AB  - An ultrasound power deposition model for the chest wall was developed based on
      secondary-source and plane-wave theories. The anatomic model consisted of a
      muscle-ribs-lung volume, accounted for wave reflection and refraction at muscle
      rib and muscle-lung interfaces, and computed power deposition due to the
      propagation of both reflected and transmitted waves. Lung tissue was assumed to
      be air-equivalent. The parts of the theory and numerical program dealing with
      reflection were experimentally evaluated by comparing simulations with acoustic
      field measurements using several pertinent reflecting materials. Satisfactory
      agreement was found. A series of simulations were performed to study the
      influence of angle of incidence of the beam, frequency, and thickness of muscle
      tissue overlying the ribs on power deposition distributions that may be expected
      during superficial ultrasound (US) hyperthermia of chest wall recurrences. Both
      reflection at major interfaces and attenuation in bone were the determining
      factors affecting power deposition, the dominance of one vs. the other depending
      on the angle of incidence of the beam. Sufficient energy is reflected by these
      interfaces to suggest that improvements in thermal doses to overlying tissues are
      possible with adequate manipulation of the sound field (advances in ultrasonic
      heating devices) and prospective treatment planning.

PMID- 10576271
TI  - In vitro heating of human fetal vertebra by pulsed diagnostic ultrasound.
AB  - The temperature rise generated at the surface of unperfused human fetal vertebrae
      in vitro by an ultrasound beam with characteristics typical of those used in
      pulsed Doppler examinations has been measured. The bone samples were from fetuses
      that ranged in age from 14 to 39 weeks, dating from the last menstrual period.
      The samples were embedded in agar gel and the temperature rise at their surface
      was measured using a 50-microm diameter K-type thermocouple. The power in the
      ultrasound beam was 50 +/- 2 mW and the -6 dB diameter was 2.9 mm. The
      temperature rise at 295 s ranged from 0.6 degrees C in the youngest sample to 1.8
      degrees C in the oldest. Approximately 70% of the temperature rise occurred in
      the first min.

PMID- 10576272
TI  - Ultrasound-induced cavitation damage to external epithelia of fish skin.
AB  - Transmission electron microscopy was used to show the effects of therapeutic
      ultrasound (< or = 1.0 W/cm2, 1 MHz) on the external epithelia of fish skin.
      Exposures of up to 90 s produced damage to 5 to 6 of the outermost layers.
      Negligible temperature elevations and lack of damage observed when using degassed
      water indicated that the effects were due to cavitation. The minimal intensity
      was determined for inducing cellular damage, where the extent and depth of damage
      to the tissues was correlated to the exposure duration. The results may be
      interpreted as a damage front, advancing slowly from the outer cells inward,
      presumably in association with the slow replacement of the perforated cell
      contents with the surrounding water. This study illustrates that a controlled
      level of microdamage may be induced to the outer layers of the tissues.

PMID- 10576273
TI  - Erosion of artificial endothelia in vitro by pulsed ultrasound: acoustic
      pressure, frequency, membrane orientation and microbubble contrast agent
      dependence.
AB  - The erosion of cells from fibroblast monolayers simulating the vascular
      endothelium by 20 micros pulses of ultrasound at 500 Hz PRF was studied in
      relation to the peak negative acoustic pressure (P-; 0.0-2.5 MPa), ultrasound
      (US) frequency (1.0, 2.1 or 3.5 MHz), orientation of the monolayer (i.e.,
      simulating the sites of ultrasound entry/exit from a blood vessel) and the
      presence or absence of a microbubble contrast agent (3 Vol% Albunex). The a
      priori hypotheses were that erosion of the monolayers would: 1. arise due to
      insonation treatment, 2. arise as a consequence of cavitation activity and, thus,
      increase with increasing P- at constant frequency, and decrease with increasing
      frequency at constant P-, 3. be significantly increased by the presence of a
      microbubble contrast agent, and 4. have a weak dependence on monolayer
      orientation. The data support these hypotheses. Under the most severe exposure
      conditions used, most of the affected cells appeared to have been lysed; however,
      a substantial number of viable cells were dislodged from the monolayer surface.

PMID- 10576274
TI  - Broadband measurement of the scattering-to-attenuation ratio for Albunex at 37
      degrees C.
AB  - The attenuation coefficient and backscatter coefficient of Albunex were measured
      over a wide range of concentrations and frequencies (at a temperature of 37
      degrees C), and were used to calculate the scattering-to-attenuation ratio (STAR)
      value. Each of these quantities exhibited concentration dependence in agreement
      with predictions from simple scattering theory: the backscatter coefficient grew
      linearly with concentration, the power of the transmitted signal decreased
      exponentially with concentration due to attenuation, and the STAR was independent
      of concentration scaling. Because of the markedly differing concentration
      dependence, it is necessary to consider all of these quantities (not just the
      STAR value alone) when evaluating and comparing the potential efficacy of
      ultrasonic contrast agents.

PMID- 10576275
TI  - TB in cattle and badgers: more than a question of science.

PMID- 10576276
TI  - Zoonoses and wildlife: the case for further study.

PMID- 10576278
TI  - Preliminary investigation of the vitamin D status of pet rabbits.
AB  - The plasma concentrations of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3)
      (vitamin D3) were measured in blood samples taken from one wild rabbit and 13 pet
      rabbits at different times of the year. Some pet rabbits had low or undetectable
      plasma concentrations of 1,25-(OH)2D3 especially if they were kept in hutches.
      Rabbits with more access to sunlight had higher concentrations of 1,25-(OH)2D3.

PMID- 10576277
TI  - Equine influenza in the United Kingdom in 1998.
AB  - In 1998, equine influenza was diagnosed by serology and nucleoprotein enzyme
      linked immunosorbent assay as the cause of acute respiratory disease in
      vaccinated and unvaccinated horses in the UK. The signs were generally milder in
      vaccinated horses and completely susceptible animals showed the most severe
      signs, including pyrexia, inappetence, coughing, mucopurulent nasal discharge and
      secondary bacterial pneumonia. In a detailed investigation of an outbreak among
      52 vaccinated thoroughbreds in a flat racing yard, more than 60 per cent of the
      horses seroconverted on the evidence of paired serum samples tested by single
      radial haemolysis (SRH). Preliminary sequencing and characterisation of an
      isolate from this outbreak indicated that it was an 'American-like' strain. In
      addition, in this outbreak there was a larger proportion of horses with
      preinfection SRH titres greater than 140 mm2 that subsequently seroconverted than
      in other recent outbreaks from which 'European-like' strains have been isolated.
      This result suggested that the cross-protectivity between circulating 'American
      like' strains and the 'European-like' strains of A/equine-2 viruses present in
      current vaccines may be decreasing.

PMID- 10576279
TI  - Oestrogen and progesterone receptors in the uterine wall of bitches with cystic
      endometrial hyperplasia/pyometra.
AB  - Fresh samples of uterine wall and peripheral plasma were obtained from 13 bitches
      of different breeds when they were treated for cystic endometrial
      hyperplasia/pyometra by ovariohysterectomy. The plasma samples were assayed for
      progesterone and 17beta-oestradiol, and the tissue samples were examined
      histopathologically and for the presence of oestrogen and progesterone receptors
      by an immunocytochemical method. The immunoreactivity was scored
      semiquantitatively, taking into account both the intensity and distribution of
      the specific staining of the receptors, by using a simplified scoring system. The
      scores for both oestrogen and progesterone receptors in the glandular epithelium
      were much lower, and in the endometrial stroma a mean (sd) score for oestrogen
      receptors was 46.0 (44.7) compared with 0 in comparable endometrial tissues from
      normal bitches at the same stage of the oestrous cycle.

PMID- 10576280
TI  - Efficacy of an inactivated oil emulsion vaccine against hydropericardium syndrome
      in broilers.
AB  - Two inactivated vaccines were prepared against hydropericardium syndrome. The
      vaccine prepared from liver homogenate extracted with chloroform, inactivated
      with formalin and adjuvanted with liquid paraffin was highly effective against
      challenge in chickens aged three, five and seven weeks. Seroconversion following
      vaccination and challenge was assessed by the agar gel immunodiffusion test. The
      inactivated oil emulsion vaccine was highly effective against the syndrome in
      both experimental trials and field trials.

PMID- 10576282
TI  - Suspected tremorgenic mycotoxicosis (ryegrass staggers) in alpacas (Llama pacos)
      in the UK.

PMID- 10576281
TI  - Potential contamination of beef carcases with brain tissue at slaughter.

PMID- 10576283
TI  - Outbreak of salmonellosis in farmed European wild boars (Sus scrofa ferus).

PMID- 10576284
TI  - Symmetrical double aortic arch in a dog.

PMID- 10576285
TI  - Outbreak of malignant catarrhal fever in cattle in Spain.

PMID- 10576286
TI  - Efficacy of an injectable ivermectin/clorsulon combination against Fasciola
      hepatica in sheep.

PMID- 10576287
TI  - Summer mastitis in England and Wales: 1992 to 1997.

PMID- 10576288
TI  - Availability of Large Animal Immobilon and Revivon.

PMID- 10576289
TI  - Opportunities in farm practice.

PMID- 10576290
TI  - UK screening programme for canine autoimmune thyroiditis.

PMID- 10576291
TI  - Inhaled and nasal corticosteroids: factors affecting the risks of systemic
      adverse effects.
AB  - There has been increasing concern in the medical literature about the safety of
      inhaled and nasal corticosteroids, since many patients, both adults and children,
      are increasingly prescribed these drugs for the long-term prophylactic treatment
      of asthma and rhinitis. It is well recognised that systemic absorption occurs
      following inhaled and nasal administration of corticosteroids, but the dose at
      which clinically relevant side effects occurs is controversial. The controversy
      stems from the fact that the degree of systemic absorption depends not only upon
      the prescribed dose, but also upon the mode of delivery and the severity of the
      underlying disease. From a regulatory view, it is essential that the Product
      Information (Summary of Product Characteristics and Patient Information Leaflet)
      reflects the available evidence to enable a doctor to make an informed decision
      when prescribing these medicines. This article assesses the potential for inhaled
      and nasal corticosteroids to cause systemic adverse effects by analysing the
      published literature and spontaneously reported suspected adverse drug reactions
      reported to the Committee on Safety of Medicines and Medicines Control Agency.
      Five main areas of concern were reviewed: hypothalamic-pituitary-adrenal axis
      suppression, osteoporosis or changes in bone mineral density, growth retardation
      in children, cataracts, and glaucoma. Conclusions regarding these side effects at
      licensed doses of inhaled and nasal corticosteroids are reached and the clinical
      relevance is discussed, particularly following long-term therapy. The
      recommendations of the Committee on Safety of Medicines and Medicines Control
      Agency are included.

PMID- 10576292
TI  - Structural studies of atom-specific anticancer drugs acting on DNA.
AB  - The interactions of many important anticancer drugs with DNA play important roles
      in their biological functions. In fact, DNA can be considered as a macromolecular
      receptor for those drugs. There are several classes of DNA-acting anticancer
      drugs. Some form noncovalent complexes with DNA by either intercalation (such as
      daunorubicin and doxorubicin) or groove-binding (such as distamycin A). Others,
      such as cisplatin, mitomycin C, and ecteinascidins, form covalent linkages with
      DNA. Finally, some (e.g., duocarmycin/CC-1065, bleomycin/pepleomycin, and
      enediyne antibiotics) cause DNA backbone cleavages. During the past decade, the
      detailed molecular interactions of several DNA-acting anticancer drugs with DNA
      have been studied with structural tools, including high resolution X-ray
      diffraction and NMR spectroscopy. These results have provided useful insights
      into DNA conformation and drug-DNA interactions. In particular, it was found that
      specific atomic sites on DNA are often the targets for drug covalent actions.
      Here we review the structural aspects of the interactions of several anticancer
      drugs acting on: (1) the N2 amino group of guanine in the minor groove, (2) the
      N3 atom of guanine and adenine in the minor groove, (3) the N7 atom of guanine
      and adenine in the major groove, and finally, (4) the C4', C5', and C1' atoms of
      the deoxyribose in the backbone of B-DNA double-helix. Understanding the
      underlying mechanism of the drug action at the cellular and molecular levels
      through those structural studies should be useful in the development of new
      anticancer drugs.

PMID- 10576293
TI  - Omega-3 fatty acids as cancer chemopreventive agents.
AB  - There is both epidemiologic and experimental evidence that the long-chain omega-3
      fatty acids (FAs), which occur at high levels in some fish oils, exert protective
      effects against some common cancers, notably those of breast, colon, and,
      perhaps, prostate. Multiple mechanisms are involved in this chemopreventive
      activity, including suppression of neoplastic transformation, cell growth
      inhibition and enhanced apoptosis, and antiangiogenicity; however, a common
      feature of most of these biological effects is the inhibition of eicosanoid
      production from omega-6 FA precursors. Several of the known risk factors for
      breast, and colon cancer may be favorably modified by dietary omega-3 FA
      supplementation, and the implementation of clinical chemoprevention trials is now
      feasible.

PMID- 10576294
TI  - A difference that matters: comparisons of structured and semi-structured
      psychiatric diagnostic interviews in the general population.

PMID- 10576295
TI  - Diagnosing mental disorders in the community. A difference that matters?

PMID- 10576296
TI  - Cross validation of a general population survey diagnostic interview: a
      comparison of CIS-R with SCAN ICD-10 diagnostic categories.
AB  - BACKGROUND: Comparisons of structured diagnostic interviews with clinical
      assessments in general population samples show marked discrepancies. In order to
      validate the CIS-R, a fully structured diagnostic interview used for the National
      Survey of Psychiatric Morbidity in Great Britain, it was compared with SCAN, a
      standard, semi-structured, clinical assessment. METHODS: A random sample of 1882
      Leicestershire addresses from the Postcode Address File yielded 1157 eligible
      adults: of these 860 completed the CIS-R; 387 adults scores > or = 8 on the CIS-R
      and 205 of these completed a SCAN reference examination. Neurotic symptoms, in
      the previous week and month only, were enquired about. Concordance was estimated
      for ICD-10 neurotic and depressive disorders, F32 to F42 and for depression
      symptom score. RESULTS: Sociodemographic characteristics closely resembled
      National Survey and 1991 census profiles. Concordance was poor for any ICD-10
      neurotic disorder (kappa = 0.25 (95% CI, 0.1-0.4)) and for depressive disorder
      (kappa = 0.23 (95% CI, 0-0.46)). Sensitivity to the SCAN reference classification
      was also poor. Specificity ranged from 0.8 to 0.9. Rank order correlation for
      total depression symptoms was 0.43 (Kendall's tau b; P < 0.001; N = 205).
      DISCUSSION: High specificity indicates that the CIS-R and SCAN agree that
      prevalence rates for specific disorders are low compared with estimates in some
      community surveys. We have revealed substantial discrepancies in case finding.
      Therefore, published data on service utilization designed to estimate unmet need
      in populations requires re-interpretation. The value of large-scale CIS-R survey
      data can be enhanced considerably by the incorporation of concurrent semi
      structured clinical assessments.

PMID- 10576297
TI  - Pubertal changes in hormone levels and depression in girls.
AB  - BACKGROUND: Throughout their reproductive years, women suffer from a higher
      prevalence of depression than men. Before puberty, however, this is not the case.
      In an earlier study, we found that reaching Tanner Stage III of puberty was
      associated with increased levels of depression in girls. This paper examines
      whether the morphological changes associated with puberty (as measured by Tanner
      stage) or the hormonal changes underlying them are more strongly associated with
      increased rates of depression in adolescent girls. METHODS: Data from three
      annual waves of interviews with 9 to 15-year-olds from the Great Smoky Mountains
      study were analysed. RESULTS: Models including the effects of testosterone and
      oestradiol eliminated the apparent effect of Tanner stage. The effect of
      testosterone was non-linear. FSH and LH had no effects on the probability of
      being depressed. CONCLUSIONS: These findings argue against theories that explain
      the emergence of the female excess of depression in adulthood in terms of changes
      in body morphology and their resultant psychosocial effects on social
      interactions and self-perception. They suggest that causal explanations of the
      increase in depression in females need to focus on factors associated with
      changes in androgen and oestrogen levels rather than the morphological changes of
      puberty.

PMID- 10576298
TI  - Early risk factors and adult person--environment relationships in affective
      disorder.
AB  - BACKGROUND: Lower cognitive ability, higher neuroticism and symptoms of anxiety
      and depression in childhood predict non-psychotic disorder in adulthood. This
      study examined whether these early risk factors act by modifying relationships
      with life events close to disease onset in adulthood. METHODS: Childhood measures
      of neuroticism (N) (including maternal N), cognitive ability (CA) and symptoms of
      anxiety and depression were measured in a national British birth cohort of 5362
      individuals born in the week 3-9 March, 1946. At ages 36 and 43 years, mental
      state examinations were carried out by trained interviewers, and subjects were
      asked about the occurrence of stressful life events in the previous year (SLE).
      RESULTS: The effect of aggregated SLEs on mental health was greater in women, in
      individuals with higher childhood N and poorer childhood mental health. Higher
      maternal N was also associated with greater sensitivity to SLEs, independent of
      subject's N, suggesting possible familial transmission of vulnerability. In
      addition, higher childhood N predicted, independent of later mental health,
      greater likelihood of reported exposure to SLEs. In general, individuals with
      higher childhood CA also reported more SLEs. CONCLUSIONS: The results suggest
      that early risk factors for affective disorder exert effects by modifying person
      environment relationships close to onset of adult symptoms. Sensitivity to life
      events may be transmitted from parents to offspring; psychopathological
      continuity over the life-span may be explained in part by continuity of altered
      stress sensitivity.

PMID- 10576299
TI  - Genetic differences in alcohol sensitivity and the inheritance of alcoholism
      risk.
AB  - BACKGROUND: Substantial evidence exists for an important genetic contribution to
      alcohol dependence risk in women and men. It has been suggested that genetically
      determined differences in alcohol sensitivity may represent one pathway by which
      an increase in alcohol dependence risk occurs. METHODS: Telephone interview
      follow-up data were obtained on twins from male, female and unlike-sex twin pairs
      who had participated in an alcohol challenge study in 1979-81, as well as other
      pairs from the same Australian twin panel surveyed by mail in 1980-82. RESULTS:
      At follow-up, alcohol challenge men did not differ from other male twins from the
      same age cohort on measures of lifetime psychopathology or drinking habits; but
      alcohol challenge omen were on average heavier drinkers than other women. A
      composite alcohol sensitivity measure, combining subjective intoxication and
      increase in body-sway after alcohol challenge in 1979-81, exhibited high
      heritability (60 %). Parental alcoholism history was weakly associated with
      decreased alcohol sensitivity in women, but not after adjustment for baseline
      drinking history, or in men. High alcohol sensitivity in men was associated with
      substantially reduced alcohol dependence risk (OR = 0.05, 95% CI 0.01-0.39).
      Furthermore, significantly decreased (i.e. low) alcohol sensitivity was observed
      in non-alcoholic males whose MZ co-twin had a history of alcohol dependence,
      compared to other non-alcoholics. These associations remained significant in
      conservative analyses that controlled for respondents' alcohol consumption levels
      and alcohol problems in 1979-81. CONCLUSIONS: Men (but not women) at increased
      genetic risk of alcohol dependence (assessed by MZ co-twin's history of alcohol
      dependence) exhibited reduced alcohol sensitivity. Associations with parental
      alcoholism were inconsistent.

PMID- 10576301
TI  - The Thought Control Questionnaire--psychometric properties in a clinical sample,
      and relationships with PTSD and depression.
AB  - BACKGROUND: Recent developments in research suggest that particular attempts to
      control thoughts may contribute to the problem of intrusion. An instrument
      capable of identifying strategies for dealing with unwanted intrusions in
      clinical populations may be used for differentiating between thought control
      strategies that may or may not be helpful. METHODS: The Thought Control
      Questionnaire (TCQ) (Wells & Davies, 1994) developed and validated on a normal
      sample, was administered to a clinical sample in order to investigate the
      consistency of the original factor structure and its psychometric properties. The
      sensitivity of the scale to change associated with recovery was also examined.
      Relationships between individual differences in thought control strategies and
      psychiatric symptoms in patients with DSM-IV major depression, and PTSD with or
      without major depression were investigated. RESULTS: The Scree Test suggested a
      six-factor solution which was rotated. This solution split the original
      distraction subscale into separate behavioural and cognitive distraction,
      otherwise the subscales were almost identical to those obtained in non-clinical
      subjects. As this split has been shown to be unreliable, further analyses in this
      study were based on the five-factor version of the TCQ obtained by Wells & Davies
      (1994). Predictors of recovery and of symptoms in PTSD and depression were
      explored. CONCLUSIONS: Correlations between the TCQ subscales and other measures
      suggest that particular thought control strategies may be associated with the
      symptoms of PTSD and depression. The TCQ scales appear to be sensitive to changes
      associated with recovery. Significant differences emerged in thought control
      strategies between depressed and PTSD patients. Hierarchical regression analysis
      showed distraction, punishment and reappraisal control strategies predicted
      depression scores in depressed patients while use of distraction predicted
      intrusions in PTSD.

PMID- 10576300
TI  - Stimulation of the noradrenergic system enhances and blockade reduces memory for
      emotional material in man.
AB  - BACKGROUND: It is clearly established that emotional events tend to be remembered
      particularly vividly. The neurobiological substrates of this phenomenon are
      poorly understood. Recently, the noradrenergic system has been implicated in that
      beta blockade has been shown to reduce significantly the delayed recall of
      emotional material with matched neutral material being unaffected. METHODS: In
      the present study, 36 healthy young adults were randomly allocated to receive
      either yohimbine, which stimulates central noradrenergic activity, metoprolol
      which blocks noradrenergic activity, or matched placebo. The three groups were
      well matched. All capsules were taken orally, prior to viewing a narrated 11
      slide show described a boy being involved in an accident. RESULTS: Yohimbine
      significantly elevated, and metoprolol reduced mean heart rate during the slide
      show relative to placebo, thus confirming the efficacy of the pharmacological
      manipulation. One week later, in a surprise' test, memory for the slide show was
      tested. As predicted, yohimbine-treated subjects recalled significantly more and
      metoprolol subjects fewer slides relative to placebo. This result was confirmed
      via analysis of multiple-choice recognition memory scores. CONCLUSIONS: We
      conclude that stimulation of the noradrenergic system results in the enhancement
      and blockade in a reduction of recall and recognition of emotional material in
      man.

PMID- 10576302
TI  - Neuroticism and self-esteem as indices of the vulnerability to major depression
      in women.
AB  - BACKGROUND: Neuroticism and self-esteem, two commonly used personality
      constructs, are thought to reflect a person's underlying vulnerability to major
      depression. The relative strength of these predictors is not known. METHOD:
      Information was gathered on 2163 individual women from an epidemiological sample
      of female female twin pairs. Neuroticism was assessed by the Eysenck Personality
      Questionnaire and global self-esteem by the Rosenberg Self-Esteem Scale. Major
      depression (DSM-III-R criteria) and stressful life events were also assessed. The
      personality constructs were studied in relation to major depression by logistic
      regression and structural equation modelling. RESULTS: Both cross-sectionally and
      prospectively, examined individually, neuroticism was a stronger predictor of
      risk for major depression than was self-esteem. When examined together, the
      predictive power of neuroticism remained substantial, while that of self-esteem
      largely disappeared. The same pattern of findings was obtained when a subset of
      subjects who had recently experienced stressful life events was analysed. By
      trivariate twin modelling, we found that the covariation of self-esteem,
      neuroticism and major depression was due largely to genetic factors. When self
      esteem was the 'upstream' variable, a substantial genetic correlation remained
      between neuroticism and major depression. By contrast, when neuroticism was the
      'upstream' variable, the genetic correlation between self-esteem and major
      depression disappeared. CONCLUSIONS: The personality construct of neuroticism is
      a substantially better index of a woman's underlying vulnerability to major
      depression than is self-esteem. These findings suggest that overall emotionality
      or emotional reactivity to the environment reflects risk for depression better
      than does global self-concept.

PMID- 10576303
TI  - The impact of widowhood on depression: findings from a prospective survey.
AB  - BACKGROUND: We investigated the impact of widowhood on depression and how
      resources and contextual factors that define the meaning of loss modified this
      effect. METHOD: In a prospective, nationally representative sample of women in
      the US aged 54 or older we compared 64 women who were widowed in the 3 years
      between data collection waves with 431 women who were stably married over the
      time interval. RESULTS: Those who became widowed reported more depression than
      controls for 2 years following the loss. However, this effect was confined to
      respondents whose husbands were not ill at baseline. Widowed women whose husbands
      were ill at baseline already had elevated depression in the baseline interview
      and did not become significantly more depressed after the death. Consistent with
      this result, women who were not depressed pre-bereavement were most vulnerable to
      depression following the loss of an ill spouse during the first year of
      widowhood. CONCLUSIONS: Results suggest that spouses' illness may forewarn wives
      of their impending loss and these women may begin to grieve before his death.
      Those forewarned women who are not depressed pre-bereavement may experience the
      most post-bereavement depression. Findings are discussed in light of previous,
      more methodologically limited studies.

PMID- 10576304
TI  - Attempted suicide in west London, I. Rates across ethnic communities.
AB  - BACKGROUND: Two previous studies from the United Kingdom have suggested that
      rates of attempted suicide in Asian women are higher than in the native
      population. METHOD: Over a 1-year period we identified 434 patients presenting
      from one catchment area to four hospitals, after episodes of self-harm. These
      patients were assessed using the GHQ, CIS-R, and Life Events Inventory, and by
      collecting details of the attempt itself. RESULTS: Asian women had the highest
      overall rates; 1.6 times those in White women and 2.5 times the rate among Asian
      men. The rates were lowest among older women. Among younger Asian women (less
      than 30 years) the rates were 2.5 times those of White women and seven times
      those of Asian men. The rates among black groups were lower than expected. Self
      poisoning was the commonest method of self-harm. CONCLUSIONS: Younger Asian women
      are vulnerable to increased rates of attempted self-harm and deserve to be
      studied further.

PMID- 10576305
TI  - Attempted suicide in west London, II. Inter-group comparisons.
AB  - BACKGROUND: Previous studies of attempted suicide have suggested that cultural
      and social factors play a significant role in the causation of deliberate self
      harm. METHOD: In order to measure elements of culture conflict two inter-group
      comparisons were undertaken. In the first, 27 Asian women who had presented to
      hospital services following attempted suicide (Asian group) were matched with a
      group of similar age Asian women attending GP surgeries for other reasons (Asian
      GP attenders group). The second comparison was between the Asian and 46 White
      attempters. RESULTS: On comparing Asian attempters with Asian GP attenders group
      the former were more likely to have a history of previous suicidal behaviour, to
      have a psychiatric diagnosis, and be unemployed. Their parents were more likely
      to have arrived in the United Kingdom at an older age. In addition, those who
      attempted suicide were more likely to have been in an inter-racial relationship
      and to have changed religions. In the second inter-group comparison, the
      characteristics of Asian and White suicide attempt patients were examined. White
      attempters were more likely to have mental illness, and were more likely to use
      alcohol as part of the method of attempted suicide. By contrast, Asian attempters
      had experienced life events pertaining to relationships, took fewer tablets and
      yet expressed greater regret at not succeeding in the attempt. CONCLUSIONS:
      Although numbers are small, social stress and other cultural factors play an
      important role in the act of deliberate self-harm.

PMID- 10576306
TI  - Suicide and undetermined death in south east Scotland. A case-control study using
      the psychological autopsy method.
AB  - BACKGROUND: Mental disorders are major risk factors for suicide. Not all those
      who suffer from mental disorders kill themselves. Additional information is
      required to differentiate higher and lesser risk patients. METHODS: Retrospective
      case-control comparison was made of cases of suicide/undetermined death with
      living controls using psychological autopsy in South East Scotland. Cases and
      controls were matched for age, sex and mental disorder. Informants were those
      closest to cases and controls. The subjects were 45 cases of suicide/undetermined
      death and 40 living controls. RESULTS: Cases and controls did not differ
      significantly in severity of mental disorder. The main factors independently
      associated with undetermined death or suicide were: a history of deliberate self
      harm (adjusted OR 4 1); physical ill health (adjusted OR 7.8); and engagement by
      mental health services (adjusted OR 0.01). Other antecedents associated with
      increased risk (criminal record, police involvement, financial problems and
      failure to vote) and those associated with decreased risk (contact with a doctor
      and in-patient care) did not exert effects after controlling for confounding.
      CONCLUSIONS: Controls were receiving more care of whatever kind. Treatment of
      mental disorder comorbid with physical illness and a history of deliberate self
      harm may be especially important. Factors that separate those with mental
      disorder at high risk from those at lesser risk relate to care levels provided,
      which may be a function of engagement by and with health services. The role of
      mental health professionals is beneficial in suicide prevention. The focusing of
      that role towards engaging alienated or 'difficult' patients should be addressed.

PMID- 10576307
TI  - The prevalence of Gilles de la Tourette syndrome in children and adolescents with
      autism: a large scale study.
AB  - BACKGROUND: An earlier small-scale study of children with autism revealed that
      8.1% of such patients were co-morbid for Gilles de la Tourette syndrome (GTS).
      The present study is a large scale test of whether this result replicates.
      METHOD: Four hundred and forty-seven pupils from nine schools for children and
      adolescents with autism were screened for the presence of motor and vocal tics.
      RESULTS: Subsequent family interviews confirmed the co-morbid diagnosis of
      definite GTS in 19 children, giving a prevalence rate of 4.3%. A further 10
      children were diagnosed with probable GTS (2.2%). CONCLUSIONS: These results
      indicate that the rate of GTS in autism exceeds that expected by chance, and the
      combined rate (6.5%) is similar to the rates found in the smaller-scale study.
      Methodological considerations and alternative explanations for an increased
      prevalence are discussed.

PMID- 10576308
TI  - Neuropsychological assessment of young people at high genetic risk for developing
      schizophrenia compared with controls: preliminary findings of the Edinburgh High
      Risk Study (EHRS).
AB  - BACKGROUND: Finding risk indicators for schizophrenia among groups of individuals
      at high genetic risk for the disorder, has been the driving force of the high
      risk paradigm. The current study describes the preliminary results of a
      neuropsychological assessment battery conducted on the first 50% of subjects from
      the Edinburgh High Risk Study. METHODS: One hundred and four high risk subjects
      and 33 normal controls, age and sex matched, were given a neuropsychological
      assessment battery. The areas of function assessed and reported here include
      intellectual function, executive function, perceptual motor speed, mental
      control/ encoding, verbal ability and language, learning and memory measures, and
      handedness. RESULTS: The high risk subjects performed significantly more poorly
      than the control subjects in the following domains of neuropsychological
      function: intellectual function, executive function, mental control/encoding and
      learning, and memory. Controlling for IQ, high risk subjects made significantly
      more errors on the Hayling Sentence Completion Test (HSCT), took longer to
      complete section A of the HSCT, had lower scores on the delayed recall condition
      of the visual reproductions subtest of the Wechsler Memory Scale-Revised, and had
      significantly poorer Rivermead Behavioural Memory Test (RBMT) standardized
      scores. The presence of significant group by IQ interactions for the RBMT and
      time to complete section A of the HSCT suggested that differences among the
      groups were more marked in the lower IQ range. Performance on the HSCT was found
      to be related to the degree of family history of schizophrenia. CONCLUSIONS: High
      risk subjects performed more poorly than controls on all tests of intellectual
      function and on aspects of executive function and memory.

PMID- 10576309
TI  - Different psychopathological models and quantified EEG in schizophrenia.
AB  - BACKGROUND: This study compared the ability of two different models of
      psychopathology in schizophrenia to account for findings in the quantified
      electroencephalogram (qEEG) recorded from midline sites in a group of 40 subjects
      with schizophrenia. The first model was based on the positive and negative
      syndrome dichotomy, the second was a tripartite model that resembled Liddle's
      syndromes of psychomotor poverty, disorganization and reality distortion (Liddle,
      1987a). METHODS: A group of 40 subjects with predominantly chronic schizophrenia
      was assessed with the Positive and Negative Syndrome Scale (PANSS) prior to the
      acquisition of their quantified electroencephalogram. The relationship between
      EEG data and symptomatology was explored, initially with the PANSS positive and
      negative subscales and then with a tripartite model derived From a principal
      component analysis of the 14 positive and negative subscale items. RESULTS: The
      tripartite syndrome model showed a greater concordance with the qEEG of the
      subjects than the dichotomous model. 'Psychomotor poverty' was significantly
      positively correlated with both delta and beta power and 'reality distortion' was
      significantly positively correlated with alpha-2 power. No significant
      correlations between the positive and negative syndrome dichotomy and the qEEG
      were observed. CONCLUSIONS: This study lends support to the factor analysis of
      psychopathology, and specifically the tripartite syndrome model of schizophrenia,
      as a step in explicating the biological dimensions of the disorder.

PMID- 10576310
TI  - To what extent does symptomatic improvement result in better outcome in psychotic
      illness? UK700 Group.
AB  - BACKGROUND: The effectiveness of therapeutic interventions in psychosis is
      increasingly reported in terms of reductions in different symptom dimensions. It
      remains unclear, however, to what degree such symptomatic changes are accompanied
      by improvement in other measures such as service use, quality of life, and needs
      for care. METHODS: A sample of 708 patients with chronic psychotic illness was
      assessed on three occasions over 2 years (baseline, year 1 and year 2). A
      multilevel analysis was conducted to examine to what degree reduction in
      psychopathological scores derived from factor analysis of the Comprehensive
      Psychopathological Rating Scale (CPRS), was associated with improvement in
      service use, disability, subjective outcomes and measures of self-harm. RESULTS:
      Reduction in positive, negative, depressive and manic symptoms over the study
      period were all independently associated with lessening of social disability.
      Reduction in negative symptoms, and to a lesser extent in positive and manic
      symptoms, was associated with less time in hospital and more time living
      independently, whereas changes in positive and manic symptoms resulted in fewer
      admissions. Subjective outcomes such as improvement in quality of life, perceived
      needs for care and dissatisfaction with services showed the strongest
      associations with reduction in depressive symptoms. Reduction in positive
      symptoms was associated with decreased likelihood of parasuicide. Results did not
      differ according to diagnostic category. CONCLUSION: The findings suggest that
      changes in distinct psychopathological dimensions independently and
      differentially influence outcome. Therapeutic interventions aimed at reducing
      symptoms of more than one dimension are likely to have more widespread effects.

PMID- 10576311
TI  - Urbanization and risk for schizophrenia: does the effect operate before or around
      the time of illness onset?
AB  - BACKGROUND: Higher level of urbanicity of place of birth and of place of
      residence at the time of illness onset has been shown to increase the risk for
      adult schizophrenia. However, because urban birth and urban residence are
      strongly correlated, no conclusions can be drawn about the timing of the risk
      increasing effect. The current study discriminated between any effect of
      urbanization before and around the time of illness onset. METHODS: All
      individuals born between 1972 and 1978 were followed up through the Dutch
      National Psychiatric Case Register for first admission for schizophrenia until
      1995 (maximum age 23 years). Exposure status was defined by a combination of
      place of birth and place of residence at the time of illness onset in the three
      most densely populated provinces of the Netherlands (the 'Randstad', exposed) or
      in all other areas (the 'non-Randstad', non-exposed). The risk for schizophrenia
      was examined in four different exposure groups: non-exposed born and non-exposed
      resident (NbNr, reference category), non-exposed born and exposed resident
      (NbEr), exposed born and non-exposed resident (EbNr) and exposed born and exposed
      resident (EbEr). RESULTS: The greatest risk for schizophrenia was found in the
      EbNR group, without evidence for any additive effect of urban residence (rate
      ratio (RR) for narrow schizophrenia in EbNr group, 2.05 (95 % CI 1.18-3-57); in
      EbEr group, 1.96 (95% CI, 1.55-2.46)). Individuals who were not exposed at birth,
      but became so later in life, were not at increased risk of developing
      schizophrenia (RR for narrow schizophrenia in NbEr group, 0.79 (0.46-1.36)).
      CONCLUSION: The results suggest that environmental factors associated with
      urbanization increase the risk for schizophrenia before rather than around the
      time of illness onset.

PMID- 10576312
TI  - Frontal variant of frontotemporal dementia: a cross-sectional and longitudinal
      study of neuropsychiatric features.
AB  - BACKGROUND: The term frontotemporal dementia (FTD) covers both the temporal and
      frontal presentations of this condition. The frontal variant (fv) presents with
      insidious changes in personality and behaviour, with neuropsychological evidence
      of disproportionate frontal dysfunction. Although psychiatric features are well
      recognized, there is little systematic data examining the mental state using
      assessment instruments and no reported studies of the longitudinal progress and
      assessment. METHODS: Fifteen patients with a diagnosis of FTD(fv) were assessed
      using the Comprehensive Psychiatric Rating Scale (CPRS). A subgroup of five
      patients were reassessed annually using the same instrument, generating data over
      a 3-year period. RESULTS: At initial assessment a third of 15 patients had no
      psychiatric symptoms to report. Three patients reported symptoms of sadness, but
      only one patient met criteria for DSM-IV major depressive episode. One patient
      experienced symptoms of elation, but did not meet criteria for manic episode,
      while two patients had hypochondriacal complaints but did not meet DSM-IV
      criteria for hypochondriasis. One of these patients also experienced the
      compulsion to count but did not meet criteria for obsessive compulsive disorder.
      The objective mental state was, on the whole, not congruent with the reported
      symptoms. Five patients assessed over a 3-year period showed no progression of
      their subjectively reported symptoms. CONCLUSIONS: Psychiatric symptoms although
      often present were characterized by their shallowness, lack of elaboration and
      non-development over time.

PMID- 10576313
TI  - Cognitive reserve and mortality in dementia: the role of cognition, functional
      ability and depression.
AB  - OBJECTIVE: This study examined whether dementia patients with greater cognitive
      reserve had increased mortality rates, and whether this association was different
      across strata of cognition, functional ability and depression. METHODS: In the
      community-based Amsterdam Study of the Elderly, 261 non-institutionalized
      dementia patients, identified using the Geriatric Mental State Schedule (GMS),
      were followed for an average of 55.5 months after which mortality data were
      obtained. Cognitive reserve was indicated by years of education and pre-morbid
      intelligence (measured using the Dutch Adult Reading Test). Cognition, functional
      ability and depression were indicated by Mini-Mental State scores, ADL and IADL
      measurements and GMS depressive syndrome, respectively. RESULTS: During the
      follow-up 146 persons (55.9%) died. Cox regression analyses showed that more
      highly educated dementia patients had higher mortality rates, only if they had
      low MMSE scores or if they had a concurrent depression. Pre-morbid intelligence
      was associated with a higher mortality rate, independent of cognition, but this
      association was much stronger among patients with depression. The positive
      association between education or intelligence and mortality was not modified by
      functional disabilities. CONCLUSIONS: The results suggest that dementia patients
      with greater cognitive reserve have increased mortality rates, only if the
      disease has progressed to such an extent that clinical symptoms are more severe.
      In this respect, the reserve hypothesis needs a modification. Depression in
      dementia patients with greater cognitive reserve may reflect a subgroup of
      patients with poor prognosis.

PMID- 10576314
TI  - Impairment of olfactory identification in obsessive-compulsive disorder.
AB  - BACKGROUND: Olfactory identification ability has been associated with processing
      in the orbitofrontal cortex (OFC), an area that has been implicated in the
      pathophysiology of obsessive-compulsive disorder (OCD). Although olfactory
      sensitivity is normal in patients with OCD, no study has investigated olfactory
      identification in this disorder. METHODS: A group of 20 subjects with OCD and 23
      age- and education-matched controls performed a standardized test of olfactory
      identification. They also performed computerized tests of spatial memory span,
      spatial working memory and spatial recognition memory that have been shown
      previously to be sensitive to cognitive deficits in patients with OCD. RESULTS:
      Performance on the olfactory identification task, spatial recognition task and
      spatial span task was significantly worse in the OCD group than controls.
      CONCLUSIONS: While impairment in spatial cognition is consistent with previous
      studies of OCD, its significance for brain-behaviour models of OCD is unclear.
      However, the finding of abnormal olfactory identification in patients with OCD is
      consistent with the hypothesis that there is a disruption to processing at the
      level of the OFC in the disorder.

PMID- 10576315
TI  - Socio-economic factors that predict psychiatric admissions at a local level.
AB  - BACKGROUND: The aim of the study was to confirm the predictive relationship
      between socio-economic factors and psychiatric admissions at a fine grain
      geographical level. The strength of association was compared with those of other
      studies that have looked at separate diagnostic groups. METHOD: Psychiatric
      admissions were from electoral wards of the County of South Glamorgan, which
      encompasses the capital city of Wales, Cardiff. Standardized psychiatric
      admission ratios (SAR) for different diagnostic groups were calculated for a 5
      year period. The ecological association with deprivation indices and with single
      variables at the level of electoral ward was examined. Of a total of 15266
      psychiatric admissions, 11296 were analysed. RESULTS: Psychiatric morbidity,
      reflected in SAR was inversely related to socio-economic deprivation for both
      sexes. This applied to all diagnostic groups except organic disorders. The
      relationship was most marked for schizophrenia, delusional disorders and
      substance abuse, closely followed by personality disorders, and less for
      affective and neurotic disorders. Little difference existed between three
      composite indices of deprivation (Carstairs, Jarman, Townsend), but the
      marginally best predictor was that designed by Jarman. However, low rates of car
      ownership and high unemployment were as good at predicting SAR as any of the
      compound indices. CONCLUSION: Socio-economic factors account for almost 50 % of
      the variance in psychiatric admission rates between electoral wards. The degree
      of association between psychiatric morbidity and deprivation varies between
      diagnostic groups, arguing against a common factor linking deprivation and
      psychiatric admissions generally. Frequently updated unemployment figures provide
      nearly as useful and more immediate information than 10-yearly Census data used
      to calculate the deprivation indices. These figures may be used for needs
      assessment and targeting resources at a local level.

PMID- 10576316
TI  - The association between the high interpersonal sensitivity type of personality
      and a lifetime history of depression in a sample of employed Japanese adults.
AB  - BACKGROUND: Although the 'high interpersonal sensitivity' type of personality has
      repeatedly been shown to be related to depression by case-control studies, no
      studies have confirmed whether this association also exists in a non-clinical
      sample. METHODS: Scores on the Interpersonal Sensitivity Measure (IPSM) were
      compared between employed Japanese adults with and without a lifetime diagnosis
      of major depressive disorder. The diagnosis was provided by the Inventory to
      Diagnose Depression, Lifetime version. A multiple logistic regression analysis
      estimated the odds ratios for having a lifetime diagnosis of depression. RESULTS:
      The scores on the IPSM were higher in the subjects with a lifetime history of
      depression than those without a lifetime history of depression. On the five
      subscales of the IPSM, the subjects with a lifetime history of depression showed
      higher scores on 'interpersonal awareness', 'need for approval', and 'separation
      anxiety' than those without a lifetime history of depression. The multiple
      logistic regression analysis showed that the subjects with the high interpersonal
      sensitivity type of personality had an increased risk for experiencing lifetime
      depression. CONCLUSIONS: The results suggest that high interpersonal sensitivity
      is a risk factor for depression even in a non-clinical sample from non-Western
      culture.

PMID- 10576317
TI  - Bipolar disorder and the serotonin transporter gene: a family-based association
      study.
AB  - BACKGROUND: The human serotonin transporter gene (5-HTT) is a strong candidate
      for involvement in the pathogenesis of mood disorders. Two common polymorphisms
      have been identified in the gene: a VNTR in intron 2 and a functional
      deletion/insertion in the promoter region. In previous studies we proposed that
      allele 12 of the VNTR might increase susceptibility for bipolar disorder.
      METHODS: We have genotyped 122 parent-offspring trios of British Caucasian origin
      where the proband had DSM-IV Bipolar I disorder (BPI). The results were analysed
      with the transmission/ disequilibrium test (TDT), which examines whether
      particular alleles are preferentially transmitted from heterozygous parents to
      affected offspring. RESULTS: The 12 repeat in the VNTR in intron 2 was
      transmitted 72 times and not transmitted 56 times (chi2 = 2.0, 1 df, P = 0.16).
      If we exclude 24 families in which the proband was a case in our published case
      control studies (Collier et al. 1996a; Rees et al. 1997), the excess transmission
      of allele 12 reaches conventional levels of statistical significance: chi2 =
      3.85, 1 df, P < 0.05. The deletion/insertion polymorphism in the promoter region
      was not associated with BPI: 66 parents transmitted the inserted (L) allele and
      59 parents transmitted the deleted (S) allele (chi2 = 0.39, 1 df, P = 0.53).
      CONCLUSIONS: The 12 repeat of the VNTR in intron 2 of the serotonin transporter
      gene might be a susceptibility factor in bipolar affective disorder. The genetic
      effect, if true, is likely to be small, and requires confirmation in further
      studies using parental controls.

PMID- 10576318
TI  - Family climates: family factors specific to disturbed eating and bulimia nervosa.
AB  - More than a decade of research has characterized the families of individuals with
      bulimia and bulimia anorexia (Anorexia Nervosa, Binge/Purging Type) as less
      expressive, less cohesive, and experiencing more conflicts than normal control
      families. This two-part study investigated variables believed more directly
      related to disturbed eating and bulimia as contributing to a "family climate for
      eating disorders." In Study 1. a nonclinical sample of 324 women who had just
      left home for college and a sample of 121 mothers evaluated their families.
      Principal-components analyses revealed the same factor structure for both
      students and mothers, with Family Body Satisfaction, Family Social Appearance
      Orientation, and Family Achievement Emphasis loading together, representing the
      hypothesized family climate for eating disorders: the remaining variables loaded
      with the more traditional family process variables (conflict, cohesion,
      expressiveness), representing a more general family dysfunction. As predicted,
      the family climate for eating disorders factor score was a more powerful
      predictor of disturbed eating. Study 2 extended these findings into a clin ical
      population, examining whether the family climate for eating disorders variables
      would distinguish individuals with bulimia from both depressed and healthy
      controls. Groups of eating-disordered patients (n = 40) and depressed (n = 17)
      and healthy (n = 27) controls completed family measures. The eating-disordered
      group scored significantly higher on family climate variables than control
      groups. Family process variables distinguished clinical groups (depressed and
      eating disordered) from healthy controls, but not from one another. Controlling
      for depression removed group differences on family process variables, but family
      climate variables continued to distinguish the eating-disordered group from both
      control groups. Indications for further research are discussed.

PMID- 10576319
TI  - Disclosure of HIV seropositivity.
AB  - Deciding whether or not to disclose one's HIV-positive status to another person
      is an important decision: the way each person experiences and copes with the
      illness is reflected in this choice. We conducted a study of 174 patients (29.3%
      of women) to examine how the decision to disclose or conceal was made, as well as
      its subjective and social consequences. We discovered that only 3.5% of the
      individuals remained silent about their illness. Most spoke about it, regardless
      of how they had been infected or of the advice they had received to be discrete.
      The confession often did not bring them the relief they sought. Revealing one's
      HIV-positive status is not a sign of social responsibility, or of a special trust
      in someone, but rather a compulsive act to release suppressed tension.
      Individuals who do not confess need attention; their silence is a sign of their
      inability to adapt to their illness, as well as of their self-imposed exclusion
      from society.

PMID- 10576320
TI  - Chinese Frost Multidimensional Perfectionism Scale: a validation and prediction
      of self-esteem and psychological distress.
AB  - Recent research has shown that perfectionism is an important psychological
      variable in explaining various disorders. This study evaluated (a) the factor
      structure and psychometric properties of the Chinese Frost Multidimensional
      Perfectionism Scale (CFMPS) and (b) the relative predictive power of its
      subscales for self-esteem and psychological distress, including depressive,
      anxiety, and stress symptoms. Nine hundred and forty-seven Chinese adolescents
      from Hong Kong between 13 and 18 years of age participated in the study. Results
      indicated that five of the original six factors emerged in the factor analysis.
      The CFMPS and its subscales were found to have satisfactory internal
      consistencies. Replicating and extending previous findings, the factors "Concern
      over Mistakes" and "Doubt about Action" accounted for most of the variances of
      self-esteem and psychological distress. The factor "Organization" might have
      positive value on psychological health. Possible cultural influence on the
      development of perfectionism and limitations of the study are discussed.

PMID- 10576321
TI  - Comparison of the Kaufman Brief Intelligence Test and the Wechsler Intelligence
      Scale for Children-Third Edition in economically disadvantaged African American
      youth.
AB  - The Kaufman Brief Intelligence Test (K-BIT; Kaufman & Kaufman, 1990) and the
      Wechsler Intelligence Scale for Children-Third Edition (WISC-III; Wechsler, 1991)
      are compared in 35 economically disadvantaged African American youth presenting
      for treatment in a community mental health setting. Significant correlations were
      found between K-BIT Composite and WISC-III Full Scale IQ scores. Results revealed
      significant differences between K-BIT and WISC-III scores; K-BIT Composite and
      Matrices mean scores were found to be 6 and 11 points higher than respective WISC
      III Full Scale IQ and Performance IQ mean scores. No significant differences were
      obtained between K-BIT Vocabulary and WISC-III Verbal IQ scores. Our findings
      support the authors' recommendations for use of the Matrices subtest alone with
      African American youth from economically disadvantaged backgrounds (Kaufman &
      Kaufman, 1990).

PMID- 10576322
TI  - The interaction of posttraumatic stress disorder and depression among older
      combat veterans.
AB  - The question whether depression is related to trauma as part of posttraumatic
      stress disorder (PTSD) itself or whether it represents autonomous symptoms
      occurring separately (from PTSD) has not been answered. We addressed two issues:
      (a) What is the relationship between PTSD and depression as measured by
      continuous measures on outcomes? and (b) By removing depression components from
      the PTSD diagnosis, what is the impact on standard outcomes? Older veterans from
      World War II or Korea were interviewed and given self-report measures on PTSD and
      depression. The CAPS-1 and the MMPI-D were used as the continuous measures for
      PTSD and depression. The outcome measures were health status, overall adjustment,
      social support, and physiological status. Results showed that depression
      influenced health status and social support: PTSD did not contribute to the
      equation. The CAPS-1 also was further divided into CAPS-PTSD and CAPS-D
      (depression) based on item content. For adjustment and health status, PTSD
      asserted a greater influence; for social support and heart rate, depression was
      the greater influence. Discussion addressed the fact that depression is an
      important consideration in the expression of PTSD.

PMID- 10576323
TI  - Cognitive deficits in schizophrenia on the WAIS-R NI Sentence Arrangement
      Subtest. Wechsler Adult Intelligence Scale-Revised Neuropsychological Inventory.
AB  - Performance of participants diagnosed with schizophrenia on the Sentence
      Arrangement subtest of the WAIS-R NI and several tests sensitive to frontal lobe
      dysfunction was significantly poorer than that of manic depressive or control
      participants. Several measures of performance of patients diagnosed with
      schizophrenia on the WAIS-R NI Sentence Arrangement subtest appeared to support
      recent interpretations of the cognitive deficit seen in schizophrenia. These data
      represent the first demonstration of deficit performance by patients with
      schizophrenia on the Sentence Arrangement subtest. This is also supportive of the
      prediction that one of the areas whose activity may influence scores on this
      subtest is the prefrontal cortex. In addition, neither positive nor negative
      symptoms systematically correlated with the cognitive deficits reported despite
      specific predictions from the current literature.

PMID- 10576324
TI  - Evaluating the effectiveness of short-term treatment at a university counseling
      center.
AB  - The effectiveness of short-term treatment provided to 55 students treated at a
      university counseling center was evaluated. The Symptom Checklist-90-R was
      administered at intake and at the termination of treatment for 41 clients, and at
      initial intake, again after a 6-week no-treatment waiting list period, and again
      at the termination of treatment, for 14 clients. Statistically and clinically
      significant improvements in SCL-90-R scores were obtained following counseling
      for those receiving immediate treatment. Clients in the waiting list condition
      did not improve until after receiving treatment. This study adds to the existing
      empirical literature suggesting that university counseling centers provide
      effective treatment. experience of caregiving. The measure is useful for
      understanding the close relationship between both the difficult and positive
      aspects of caregiving and also may be used to identify a caregiver's strengths in
      clinical and research settings.

PMID- 10576325
TI  - Finding meaning through caregiving: development of an instrument for family
      caregivers of persons with Alzheimer's disease.
AB  - Systematic assessment of the positive aspects of caregiving has been limited by
      the lack of comprehensive, theoretically based, and psychometrically sound
      measures. This study developed and tested a measure primarily designed to assess
      positive aspects and ways that caregivers find meaning through their experience
      of caring for a person with dementia. The measure has three subscales:
      Loss/Powerlessness, which identifies difficult aspects of caregiving; Provisional
      Meaning, which identifies how caregivers find day-to-day meaning; and Ultimate
      Meaning, which identifies philosophical/religious/spiritual attributions
      associated with the experience of caregiving. The measure is useful for
      understanding the close relationship between both the difficult and positive
      aspects of caregiving and also may be used to identify a caregiver's strengths in
      clinical and research settings.

PMID- 10576326
TI  - Social support and psychopathology in homeless patients presenting for emergency
      psychiatric treatment.
AB  - We compared homeless to domiciled psychiatric patients' symptomatology and
      perceived level of social support (PSS) within hours of psychiatric emergency
      service (PES) arrival. Homeless patients experienced less PSS and more negative
      symptoms, but not more psychosis, than their domiciled counterparts. Domiciled
      patients' PSS was highly related to their clinical presentation: less support
      predicted increased psychopathology. Homeless patients' clinical symptoms,
      although as common and severe, were unassociated with PSS. These findings suggest
      that homeless psychiatric patients may be less reactive to positive environmental
      influences like social support and manifest more severe and refractory symptoms
      than domiciled patients presenting for emergency treatment.

PMID- 10576327
TI  - Clinical trials versus mental health services research: contributions and
      connections.
AB  - The growing emphasis on using empirical data to guide mental health policy
      decision making has contributed, in part, to a developing dichotomy along the
      continuum of research on mental health interventions. At one end of the continuum
      is research on the efficacy of mental health interventions, traditionally
      referred to as clinical trials research. The goal of clinical trials research is
      to determine whether or not a specific intervention can be shown to be
      efficacious for a specific problem. At the other end of the continuum is research
      on the implementation and evaluation of mental health interventions,
      traditionally referred to as mental health services research. The goals of mental
      health services research are to understand the access to, organization and
      financing of, and outcomes of mental health interventions. The conceptual,
      methodological, and measurement features of both types of research are presented
      and suggestions are offered to bridge the gap between the two paradigms. The
      purpose of this article is to highlight each discipline's unique contributions to
      mental health research and, in so doing, facilitate a discussion that fosters
      scientific integration and collaboration between clinical trials and mental
      health services investigators.

PMID- 10576328
TI  - Embarrassing problems for the field of psychotherapy.
AB  - A case is presented that the field of psychotherapy has some embarrassing
      problems that are collectively denied and that it is important for the field to
      admit they exist so that steps can be taken toward their resolution. A
      provisional list of 11 problems is proposed, together with suggested avenues
      toward solution. The invitation is to consider, revise, improve, and extend the
      list of embarrassing problems in a spirit of open debate and discussion to help
      advance the field of psychotherapy by enabling efforts toward resolution of these
      embarrassing problems.

PMID- 10576329
TI  - Weight preoccupation, personality, and depression in university students: an
      interactionist perspective.
AB  - This cross-sectional study investigated whether Beck's (1983, 1987) cognitive
      personality traits of sociotropy and autonomy interacted with weight
      preoccupation in their contribution to depressed mood in women and men. Two
      hundred and fifty-one undergraduates were administered the revised Sociotropy
      Autonomy Scale (SAS), the Beck Depression Inventory (BDI), the Eating Disorders
      Inventory (EDI), and the Restraint Scale (RS). Three separate hierarchical
      multiple regression analyses, with the BDI as the dependent variable, revealed a
      specific congruent interaction between weight preoccupation and personality.
      Specifically, weight-preoccupied women and men experienced depressed mood to the
      extent that they were characterized as more highly sociotropic. Further
      examination of weight preoccupation among men, in the direction of weight or
      muscle gain, revealed that the highest levels of depressed mood were experienced
      by highly sociotropic men who wanted to gain weight and muscle mass.

PMID- 10576330
TI  - Codetype base rates for the "I Mean Business" suicide items on the MMPI-2.
AB  - This study focused on the frequency with which two MMPI-2 suicide items (506 and
      520) were endorsed. These two items can be referred to as the "I Mean Business"
      items, for there is no denying that the client is reporting the recent
      contemplation of actively taking his or her life. A large sample (N = 23,646) of
      well-defined MMPI-2 codetypes was examined from the Caldwell (1997) data set. The
      frequencies with which individuals within a particular codetype endorsed Item
      506, Item 520, or both are provided by gender. Results provide information that
      is consistent with the clinical lore concerning suicidal ideation/intent and
      codetypes. Unexpected findings are also noted. The implications of these base
      rates in psychotherapy are discussed from clinical and risk management
      perspectives.

PMID- 10576331
TI  - Fall in the number of intracardiac neurons in aging rats.
AB  - The neurons of whole cardiac atria were stained using a NADH-diaphorase technique
      in young adult (3 months old) (GI) and aging rats (20 months old) (GII). Light
      microscopy revealed differences in the appearance of the neurons in the two
      groups. In GI, most ganglia contained 50-100 neurons while in GII, most ganglia
      usually contained 20 neurons. The mean total number of neurons in the atria of
      GII was 245+/-31, i.e. only 23% of the mean value in GI (1086+/-203). The mean
      size of the ganglionic neurons (area of maximum cell profile) was 702 microm2 in
      GI and 1065 microm2 in GII. Histological sections of the ganglia revealed that a
      capsule of collagen fibers sheaths each ganglion in both groups. In GII, the
      density of collagen fibers increases in the capsule and in the septa within the
      ganglia; yellow or red, type I collagen fibers predominate in this group. No
      elastic fibers were present in the cardiac ganglia of either group. It is
      suggested that in aging rats, structural changes and reorganization of the
      remnant neurons accompany neuron reduction.

PMID- 10576332
TI  - Dietary supplementation of thyme (Thymus vulgaris L.) essential oil during the
      lifetime of the rat: its effects on the antioxidant status in liver, kidney and
      heart tissues.
AB  - This study aimed not only to identify age-related changes in certain antioxidant
      systems, but to assess whether dietary supplementation of thyme oil could address
      the unfavourable antioxidant-pro-oxidant balance that occurs with age. The
      present study has shown that there were significant declines in the superoxide
      dismutase activities in the liver and heart of old rats, although kidney showed
      no decline. Liver glutathione peroxidase (GSHPx) activity was found to have
      increased significantly in old rats, while a significant decrease was observed in
      kidney. Heart GSHPX activity was not found to differ significantly between young
      and old rats. There were also significant declines in the total antioxidant
      status in each tissue examined. A general feature of these various antioxidant
      parameters measured was that their activities remained higher in rats whose diets
      were supplemented with thyme oil, suggesting that they retained a more favourable
      antioxidant capacity during their life span.

PMID- 10576333
TI  - Nitric oxide synthase in aging rat skeletal muscle.
AB  - The neuronal isoform of nitric oxide synthase (NOS) is expressed at high
      concentrations in skeletal muscle, and NO influences muscle contractility,
      glucose utilization, and free radical damage or protection. NOS activity and
      expression was evaluated in extensor digitorum longus (EDL), soleus, and
      diaphragm of 8 and 24 month old Fisher 344 rats. In 8-month-old animals, NOS
      activity was highest in EDL, which contained the highest percentage of NOS
      containing fibers, and was lowest in soleus. NOS activity and percentage of NOS
      containing fibers was significantly reduced in all muscle groups with age. To
      determine if NOS reduction correlated with free radical injury the level of lipid
      peroxidation, as measured by malonaldehyde equivalents, was determined. With age
      lipid peroxidation increased in EDL, was reduced in diaphragm, and showed a non
      significant change in soleus. Therefore, a straightforward reduction of NOS
      activity does not correlate with lipid peroxidation. The reduction of NOS with
      age in skeletal muscle may be most significant for muscle metabolism and force
      production and be of limited significance for free radical metabolism.

PMID- 10576334
TI  - Differential age effect of oral administration of an antigen on antibody
      response: an induction of tolerance in young mice but enhancement of immune
      response in old mice.
AB  - Sheep red blood cells (SRBC) were orally administered to young (4 months old) and
      old (22 months old) mice, and its effect on the antibody production after
      systemic immunization was compared between young and old mice. The results showed
      that the dose-dependent suppression of antibody response (oral tolerance) was
      observed in young mice which had been previously treated with oral administration
      of SRBC. On the contrary, the enhancement of antibody production was observed in
      old mice which had been treated in the same way. The enhanced level of IgG
      antibody in old mice was higher than that of young mice. The critical age
      determining either suppression or enhancement of antibody response after the oral
      administration of the antigen was present between 6.5 and 10.5 months of age.
      When the oral administration of the antigen was performed in young (3 months old)
      and middle-aged mice (12 months old), the oral tolerance for young and the
      enhanced antibody response for middle-aged mice were observed even at 6 months
      after the treatment. The analysis by in vitro antibody response using T and B
      cells prepared from young and old mice showed that age-related alteration of T
      and B cells is responsible for the suppression and the enhancement of antibody
      response after oral administration of SRBC, respectively.

PMID- 10576335
TI  - Temporal and spatial expression of EmH-3, a homeobox-containing gene isolated
      from the freshwater sponge Ephydatia muelleri.
AB  - Homeoboxes have been particularly valuable in identifying genes involved in
      development. This prompted us to look for homeobox-containing genes in sponges,
      the most primitive metazoans, and to explore the potential role of these genes in
      their development. Using the reverse transcription polymerase reaction (RT-PCR),
      we analyzed the expression of EmH-3 homeobox-containing gene at different stages
      of development, and in different cell-type populations. The patterns of EmH-3
      expression show that this gene is expressed differentially in the course of
      development and in a cell-type specific manner. The level of transcripts
      increases from undetectable levels in resting gemmules to higher levels at the
      moment of hatching and throughout the sponge's life. EmH-3 is strongly expressed
      in the pluripotent archaeocytes, whether isolated from fully differentiated
      sponges (adult archaeocytes) or from HU-treated sponges (embryonic archaeocytes).
      Conversely, in differentiated cells such as pinacocytes and choanocytes, EmH-3
      expression is very weak and similar to that found in the resting gemmules. On the
      other hand, another freshwater sponge homeobox-containing gene, prox1 from
      Ephydatia fluviatilis is expressed almost at the same level at all stages of
      development and in all the investigated cell populations. Together, these results
      suggest that EmH-3 plays a role in cell determination and/or differentiation. In
      particular EmH-3 would determine which archaeocytes will multiply and undergo
      differentiation and which ones will remain undifferentiated.

PMID- 10576336
TI  - New developments in the pathophysiology of inflammatory pancreatic disease.

PMID- 10576337
TI  - The role of calcium in pancreatitis.
AB  - BACKGROUND/AIMS: A large, sustained increase in acinar [Ca2+]i may play a key
      role in the pathogenesis of acute pancreatitis. Many mechanisms which lead to
      cell damage in vitro and pancreatitis in vivo, such as free radicals or
      supraphysiological cerulein concentrations, cause a rapid increase in [Ca2+]i in
      pancreatic acinar cells. Little is known about why [Ca2+]i increases in some
      instances stimulate secretion and in other instances initiate cell death. So far,
      [Ca2+]i increases were thought to represent physiological signals when they
      occurred as oscillations at the single cell level. METHODOLOGY: This paper
      reviews recent literature and our own original research about the role of calcium
      in the function of pancreatic acinar cells and the development of pancreatitis.
      RESULTS: Recent studies showed that exposure of acinar cells to free radicals not
      only caused a bulk increase in [Ca2+]i but also resulted in calcium oscillations
      which had a lower frequency than, but similar amplitude to oscillations occurring
      after physiological stimuli. The absolute increase in [Ca2+]i did not definitely
      determine the cellular response. Instead, the duration of [Ca2+]i increase may
      have been more important. In contrast to previous belief of a direct relationship
      between [Ca2+]i oscillations and exocytosis, recent results show that radicals
      can induce [Ca2+]i oscillations which do not exert exocytosis but inhibit the
      secretory response to physiological stimuli. Further experiments showed that the
      [Ca2+]i release caused by radicals originates from thapsigargin-insensitive,
      ryanodine-sensitive stores. CONCLUSIONS: The origin and duration of [Ca2+]i
      increases rather than their extent or oscillatory nature, determine whether the
      cell will secrete or die. An abnormal [Ca2+]i increase can trigger trypsin
      activation, acinar cell damage and acute pancreatitis. This hypothesis is
      supported by studies which show that calcium chelators inhibit radical-induced
      trypsin activation as well as cell necrosis and apoptosis. Thus, an inhibition of
      pathological [Ca2+]i release may have a therapeutic potential.

PMID- 10576338
TI  - Phospholipase A2 in acute pancreatitis: new biochemical and pathological aspects.
AB  - Phospholipase A2 has been implicated in the pathogenesis and pathophysiology of
      acute pancreatitis. The initial enthusiasm concerning pancreatic group I
      phospholipase A2 as an enzyme responsible for pancreatic necrosis and systemic
      manifestations of acute pancreatitis has gradually waned, as the mechanisms of
      the pathogenesis and the pathophysiology of acute pancreatitis have been
      revealed. The overactive systemic inflammatory response associated with the
      activation of different cascade systems and increased levels of inflammatory
      mediators as seen in severe acute pancreatitis, closely resembles that associated
      with other severe inflammatory diseases such as septic shock. The critical role
      of the non-pancreatic secretory group II phospholipase A2 in the chain of
      inflammatory mediators has been emphasized recently, as new detection methods for
      the enzyme have become available.

PMID- 10576339
TI  - Oxidative stress in acute pancreatitis.
AB  - The present work critically reviews the evidence for an involvement of free
      radicals in the pathophysiology of acute pancreatitis and the potential of
      treatment with antioxidants and scavenger substances. Data originating from
      clinical trials, experimental pancreatitis studies and in vitro investigations
      are included. Enhanced free radical activities and increased concentrations of
      lipid peroxides in plasma and tissue have been found in both patients and
      experimental animals with acute pancreatitis. The individual contribution of
      possible sources of free radicals (e.g., invading inflammatory cells, xanthine
      oxidase, cytochromes P450, nitric oxide synthase) is not yet clear, however.
      Since prophylactic administration of antioxidants diminished, in particular,
      pancreatic edema formation, free radicals seem to play an important role in the
      genesis of edema in acute pancreatitis. An involvement of free radicals in the
      pathogenesis of pancreatic necrosis could not yet be proven. Thus, no antioxidant
      treatment has proven useful for therapy of fulminant pancreatitis in animals to
      date. However, in severe acute pancreatitis characterized by death occurring
      after 12-18 hours, the seleno-organic compound Ebselen, which has a glutathione
      peroxidase-like activity, and the membrane permeable ascorbic acid derivative CV
      3611 have been demonstrated to be effective. To date, controlled clinical studies
      have failed to demonstrate the therapeutic efficacy of antioxidant selenium or
      glutathione precursor supplementation. Therefore, further controlled clinical
      trials are needed to determine whether supplements of antioxidants can alter the
      clinical course of acute pancreatitis. Since the nitric oxide radical may even
      protect the pancreas, a purely negative discussion of the role of free radicals
      on the pancreas is not justified. The actual role of free radicals in acute
      pancreatitis, i.e. serving the body's defense against infection, being an
      epiphenomenon of the inflammatory process without pathophysiological relevance,
      or having true pathogenic significance, is not yet clear. Lipid peroxidation may
      perhaps not be the cause but rather the sequel of pancreatic inflammation and may
      likely reflect the severity of the systemic inflammatory response rather than
      that of pancreatic parenchyma damage. In vitro, exposure of isolated pancreatic
      acinar cells to oxidative stress caused rapid cell damage and death. Such
      knowledge from cellular studies might help to plan therapeutical trials to
      evaluate potentially effective therapies in the experimental animal, as well as
      in patients suffering from pancreatitis. Thus, to further clarify the role of
      oxidative stress in acute pancreatitis, an integrated approach is needed,
      including investigations at various biological levels, from isolated cells or
      even organelles to laboratory animals and, finally, clinical studies in man.

PMID- 10576340
TI  - TGFbeta and the extracellular matrix in pancreatitis.
AB  - Regeneration from cerulein-induced pancreatitis is accompanied by a transient
      synthesis and deposition of extracellular matrix components in the rat pancreas.
      To study the involvement of transforming growth factor beta1 (TGFbeta1), one of
      the most potent modulators of the extracellular matrix, in the process of
      pancreatic regeneration we examined the expression of this gene on the transcript
      and protein level in pancreata of rats sacrificed 0 hours, 24 hours, 2, 3, 5, 7
      days after a 12 hour infusion of maximal doses of cerulein (10 microg kg(-1) h(
      1)). TGFbeta1 protein increased twofold after 24 hours and 48 hours and returned
      to control values 7 days after induction of pancreatitis, while TGFbeta1-mRNA
      reached maximal values (3-fold over controls) after 2 days. The largest amount of
      TGFbeta1 mRNA was found in pancreatic acinar cells and in stromal cells. To
      verify the functional implication of TGFbeta overexpression in regulating
      extracellular matrix remodeling during regeneration from acute pancreatitis, rats
      were treated with 3 injections of neutralizing antibody against TGFbeta1 given 30
      min before, and 24 hours and 48 hours after the start of infusion. In rats
      treated with maximal doses of cerulein and TGFbeta antibodies, pancreatic
      hydroxyproline content and expression of collagens I and III and of TGFbeta1 were
      significantly reduced. These results provide evidence that transforming growth
      factor beta1 among other cytokines is involved in the regulation of extracellular
      matrix remodeling in the rat pancreas during regeneration from cerulein-induced
      acute pancreatitis. In addition, there is evidence in the literature that
      application of recombinant TGFbeta after recurrent episodes of acute cerulein
      induced pancreatitis promotes pancreatic fibrosis (3). Thus, TGFbeta is a
      regulator of extracellular matrix remodeling in the pancreas, and may be an
      important promoting factor in the pathogenesis of chronic pancreatitis. This
      hypothesis is supported by data in the literature showing enhanced TGFbeta
      expression in human chronic pancreatitis (2) and development of fibrosis and
      inflammation in pancreata of transgenic mice overexpressing TGFbeta1 (3).

PMID- 10576341
TI  - Mechanism and role of trypsinogen activation in acute pancreatitis.
AB  - In healthy subjects, the 3 known pancreatic trypsinogens, which are
      endopeptidases belonging to the chymotrypsin superfamily, are activated by
      enterokinase and partial autoactivation in the duodenum. The premature activation
      of trypsinogen in the pancreatic interstitium, with the subsequent activation of
      other pancreatic zymogens, is believed to lead to the autodigestion of the gland,
      this being the first event in acute pancreatitis. The mechanisms that lead to
      trypsinogen, activation in acute pancreatitis are largely unknown. However,
      ischemia, hypercalcemia and the activation of cathepsin B (by cholecystokinin)
      are thought to be of importance. The easiest and most reliable way to assess
      trypsinogen activation is the measurement of the activation peptide, TAP, in
      urine, plasma, pancreatic tissue or ascitic fluid. In the animal model of acute
      pancreatitis, TAP in ascites and pancreatic tissue has been shown to correlate
      with the presence and extent of necroses. It has proven to be a good marker for
      the severity of pancreatitis and is a useful marker in examining the
      pathophysiology and possible treatment modalities in the animal model of acute
      pancreatitis. Studies on TAP in human acute pancreatitis were most commonly
      focused on urinary TAP. Within a 48-hour time frame after the onset of the
      disease, TAP was a good predictor of the severity of acute pancreatitis. The main
      advantage over other markers, such as CRP, is that TAP is the earliest marker of
      necrosis to be increased. Also, increased levels of TAP in ascitic fluid were
      shown to correlate well with pancreatic necroses. In our experience, plasma TAP
      was found to have a "diagnostic window" within the first 3 days predicting
      pancreatic necroses. Positive TAP gave a very good positive prediction and a high
      specificity towards the development of pancreatic necroses, but did not differ
      between necrotizing pancreatitis with systemic complications or uncomplicated
      necrotizing pancreatitis. We therefore think that plasma TAP is a very good
      marker for local complication in acute pancreatitis and its routine measurements
      may help to identify patients at a high risk within the first days of the
      disease.

PMID- 10576342
TI  - Malignant biliary obstruction: management with percutaneous metallic stent
      placement.
AB  - BACKGROUND/AIMS: To report our experience on palliative management of malignant
      biliary obstruction with percutaneous placement of metallic stents. METHODOLOGY:
      During a 3-year period 20 patients with malignant biliary obstruction were
      treated with percutaneous insertion of metallic biliary endoprostheses. RESULTS:
      Stent placement was successful in 19 patients, with significant improvement of
      jaundice in 18 patients. 17 patients have died up to date. In this group survival
      was 4-324 days (mean: 107 days) and mean stent primary and secondary patency 94.3
      and 97.4 days, respectively. Three patients are alive with a follow-up from 20
      195 days. Mean secondary patency is 65.3 days (20-134 days). We encountered
      serious complications in 4 patients (20%). Thirty-day mortality was 15%, while
      procedural mortality was 10%. Four patients presented 13-120 days (mean: 71.5
      days) after the procedure with stent reocclusion (reocclusion rate: 20%).
      CONCLUSIONS: The procedure is relatively easy and safe to perform, yields
      excellent palliation of the patient's symptomatology and, therefore, contributes
      substantially to the maintenance of good quality of life of the patient with
      malignant biliary obstruction.

PMID- 10576343
TI  - Secondary excision of choledochal cysts after previous cyst-enterostomies.
AB  - BACKGROUND/AIMS: Patients with a choledochal cyst previously treated by internal
      drainage should undergo secondary cyst excision. The results of such secondary
      excisions have not yet been reported. METHODOLOGY: Over a 27-year period, 121
      patients underwent excision of a choledochal cyst at our hospitals. Of these, 14
      patients underwent secondary cyst excision following internal drainage. These
      patients were compared retrospectively with the remaining 107 patients who
      underwent primary cyst excision. RESULTS: Blood loss and operative time were
      greater, and early and late post-operative complications were significantly more
      frequent in the secondary excision group. Wound infection (early complication),
      pancreatic stones (late complication), and hepatolithiasis (late complication)
      were significantly more common in the secondary excision group. Histologically,
      inflammation and biliary glands were more frequently seen in the resected bile
      ducts in the secondary excision group. CONCLUSIONS: The long-term results of
      secondary excision of choledochal cysts are worse than after primary excision.
      The frequent late complications may be related to the development of biliary
      glands as a consequence of cyst-enterostomy.

PMID- 10576344
TI  - Results of retrograde transhepatic biliary drainage after a common bile duct
      exploration for choledocholithiasis.
AB  - BACKGROUND/AIMS: The purpose of this study is to assess the benefits of
      retrograde transhepatic biliary drainage (RTBD) and a primary closure after a
      common bile duct (CBD) exploration for patients with choledocholithiasis.
      METHODOLOGY: We analyzed 143 patients with choledocholithiasis who had been
      managed by RTBD after undergoing a CBD exploration retrospectively over a 12-year
      period. The main outcome criteria were frequency of occurrence of post-operative
      complications which needed a relaparotomy and the clinical long-term results. In
      addition, the radiographic diameter changes of the CBD at the site of the primary
      closure and liver function tests after RTBD were also evaluated. RESULTS: The
      frequency of bile peritonitis in the patients undergoing the RTBD procedure was
      only 0.7% (1 out of 143 cases). Cholangiography via the RTBD tube revealed no
      severe stenosis at the site of primary closure. Liver function returned to normal
      on day 3 after RTBD (p<0.05). Recurrence of common bile duct stones developed in
      2 patients in this series during the follow-up (1-12 years). CONCLUSIONS: RTBD
      and a primary closure of the CBD after CBD exploration appears to be a clinically
      safe and effective method for such patients with choledocholithiasis who had
      undergone a complete stone removal intra-operatively.

PMID- 10576345
TI  - Treatment of unresectable hepatic hilar malignancies with self-expanding metallic
      stents.
AB  - BACKGROUND/AIMS: This study assesses the treatment of biliary obstruction in
      patients with hilar malignancies by metallic stents. METHODOLOGY: Twenty-one
      consecutive patients with unresectable malignant biliary obstruction at the
      hepatic hilum (Bismuth type II, III and IV) were treated with percutaneous
      transhepatic placement of self-expandable metallic endoprostheses. The
      endoprostheses were successfully inserted in all patients. In 12 patients all
      segments of the liver were drained and in 9 patients partial segments of the
      liver were drained. RESULTS: Seventeen patients (81%) showed relief from jaundice
      and could be freed of external drainage tubes. Ten patients (48%) showed no
      recurrent symptoms due to stent obstruction until death. Overall survival was
      4.86+/-4.15 (mean+/-SD) months, stent patency was 3.76+/-3.64 months and comfort
      index representing a ratio of well-being was 70.5+/-38.3%. There was no
      significant difference in survival rate, stent patency or comfort index between
      the groups with complete and those with partial drainage. CONCLUSIONS: Even in
      patients with complicated hepatic hilar biliary occlusions, internal drainage
      using metallic stents can relieve jaundice and leave patients free of external
      tubes with a comfortable quality of life.

PMID- 10576346
TI  - The effects of sodium deoxycholate, lactulose and glutamine on bacterial
      translocation in common bile duct ligated rats.
AB  - BACKGROUND/AIMS: Sepsis is a major cause of post-operative morbidity and
      mortality in obstructive jaundice as a result of bacterial translocation from the
      gut. This study was conducted to investigate the effects of glutamine, lactulose,
      and the bile salt Na deoxycholate in preventing bacterial translocation in an
      animal model where obstructive jaundice was developed by common bile duct
      ligation. METHODOLOGY: Fifty Wistar albino rats were divided into 5 groups of 10
      animals each. The animals in groups I-IV underwent common bile duct ligation and
      received, respectively, either saline, Na deoxycholate, lactulose or glutamine,
      orally. Group V had sham ligation and received saline orally. The animals were
      sacrificed at the end of the 7th day, and serum concentrations of bilirubin,
      aspartate aminotransferase (ALT), alanine aminotransferase (ALT), and alkaline
      phosphatase (AP) were measured. In addition, mesenteric lymph nodes were removed
      and cultured together with cecal content. Histopathologic examination of terminal
      ileum specimens was made. RESULTS: Na deoxycholate, lactulose and glutamine all
      reduced bacterial translocation rates to mesenteric lymph nodes (p<0.05), with
      glutamine causing the greatest effect. Na deoxycholate and lactulose prevented
      bacterial translocation by causing a decrease in cecal intraluminal bacterial
      content (p<0.001), while glutamine exerted its effect by preserving intestinal
      mucosal integrity. CONCLUSIONS: The integrity of the intestinal mucosal barrier
      is of paramount importance in preventing bacterial translocation, and the
      measures taken to protect mucosal integrity reduce bacterial translocation to a
      greater extent than those taken to decrease the number of bacteria in the gut.

PMID- 10576347
TI  - Improved acceptability of laparoscopic surgery and increasing rate of
      cholecystectomy implications for surgeon and patients.
AB  - BACKGROUND/AIMS: The aim of our study was to evaluate the impact of introduction
      of laparoscopic cholecystectomy (LC) and reasons for the increase in
      cholecystectomy rate, by a retrospective review of all admissions for gallbladder
      disease before and after the introduction of laparoscopic surgery in our
      department. METHODOLOGY: Chi-squared test was used for statistical analysis of
      the comparisons. RESULTS: Comparing the 2 periods, cholecystectomy rate increased
      by 35% (p<0.01) and patients aged 25-44 years were more likely to undergo LC
      (p<0.001); a 35% decrease in unjustified refusal (p<0.02) was also observed. The
      number of both longstanding disease patients and asymptomatic ones operated upon
      was not different (p=1; p=0.06), while a 46% increase (p=0.02) in cholecystectomy
      rate was shown in patients with low-grade symptoms or at 1st colic episode.
      CONCLUSIONS: An increase in the patient pool due to improved acceptability was
      responsible for the increase in cholecystectomy rate after introduction of
      laparoscopic surgery, rather than lowered surgical threshold, as previously
      suggested by other authors. Judiciousness is required to prevent the increased
      acceptability of LC from leading to its uncontrolled and unrestricted use, as
      alteration of the surgical threshold may occur without surgeon awareness,
      particularly when dealing with low grade symptomatic patients.

PMID- 10576348
TI  - A case of hyperosmolar nonketotic coma occurring during chemotherapy using
      cisplatin for gallbladder cancer.
AB  - A 61 year-old woman was admitted to our hospital because of an abdominal tumor.
      She was diagnosed with recurrent gallbladder cancer, and treated with cisplatin
      (CDDP). On day 6, after the 1st cycle of chemotherapy, she developed confusion
      and suddenly became comatose. She was diagnosed as having hyperosmolar nonketotic
      coma (HNC) on day 7. She had no history of diabetes mellitus. She recovered from
      HNC after 3 days of treatment with continuous infusion of 0.45% saline and
      moderate amounts of insulin. HNC may be a complication of CDDP chemotherapy in
      patients with malignancy. Early diagnosis and appropriate treatment is necessary
      for HNC occurring during chemotherapy for malignant disease.

PMID- 10576349
TI  - Gallbladder tuberculosis (case report and review of the literature).
AB  - The incidence of abdominal tuberculosis is increasing and the familiarity with
      its clinical presentation shortens its diagnostic time and improves its
      management. Gallbladder tuberculosis has unique considerations regarding its
      pathology, diagnosis and surgical management. The authors report a case of
      gallbladder tuberculosis in a 40 year-old female who presented with a clinical
      picture of acute cholecystitis. Abdominal ultrasound showed a dilated gallbladder
      with a large gall stone located in the neck region. Several lymph nodes were seen
      in the hilum of the liver compressing the portal vein which were associated with
      smaller retroperitoneal lymph nodes. The diagnosis of gallbladder tuberculosis
      was reached only during surgery and was proven by histopathology. The gallbladder
      was adherent to the surrounding tissues and covered with multiple tuberculous
      nodules. The patient had a retrograde open cholecystectomy and treated with anti
      tuberculous drugs. The literature on this topic is reviewed.

PMID- 10576350
TI  - The role of epidermal growth factor in gastric epithelial proliferation in portal
      hypertensive rats exposed to stress.
AB  - BACKGROUND/AIMS: This study was designed to determine whether epidermal growth
      factor may have a role in the stomach of portal hypertensive rats after exposure
      to water immersion and restraint stress. METHODOLOGY: Rats with portal
      hypertension (portal vein partial ligation) were studied to determine the
      proliferative response of the gastric epithelium to epidermal growth factor (EGF)
      during stress. The portal hypertensive rats received EGF (0, 10, 25, 50, and 100
      microg/kg/day) subcutaneously for 7 days before water immersion restraint stress.
      Each rat was subjected to water immersion restraint stress for 6 hours, at the
      end of which the stomachs were excised to evaluate gross and microscopic mucosal
      damage, and gastric epithelial proliferation using proliferating cell nuclear
      antigen (PCNA) immunoreactivity. RESULTS: The gross and microscopic mucosal
      damage were significantly greater in control or low dose EGF-pretreated (10 or 25
      microg/kg/day) rats than in high dose EGF-pretreated (50 or 100 microg/kg/day)
      rats (p<0.01). These changes were accompanied by parallel alterations in the PCNA
      labeling index. The PCNA labeling index between high dose EGF-pretreated and
      control or low dose EGF-pretreated rats differed significantly (p<0.01).
      CONCLUSIONS: This study clearly indicates that the influence of EGF on the
      proliferative response of the portal hypertensive (PHT) gastric epithelium to
      stress in rats was dose-dependent, suggesting an important role for EGF in the
      protection of PHT gastric mucosa from stress injury.

PMID- 10576351
TI  - Establishment and characteristics of human hepatocellular carcinoma cells with
      metastasis to lymph nodes.
AB  - BACKGROUND/AIMS: Although the mechanism of cancer metastasis has been gradually
      elucidated, less is known concerning the characteristics of human hepatocellular
      carcinomas (HCCs) with metastatic potential. We examined the expression of
      molecules that mediate cell-cell or cell-substrate interaction, nm23-H1
      expression, and ultrastructural features of several human HCC cell lines.
      METHODOLOGY: Expression of E-cadherin, integrin (alpha3beta1), intracellular
      adhesion molecule-1 (ICAM-1), and nm23-H1 protein was analyzed by
      immunocytochemistry or Western blotting, and ultrastructural features were
      further studied by electron microscopy in 4 human HCC cell lines, PLC/PRF/5, HuH
      7, OCUH-16, and Nuk-1 which were originally established from metastatic cells in
      lymph nodes at our institute. RESULTS: Neither E-cadherin, integrin, nor ICAM-1
      was immunocytochemically detected in any of the 4 cell lines. Expression of nm23
      H1 protein was weakly detected in OCUH-16, Nuk-1, and Huh-7 cells by Western
      blotting, but was clearly detected in PLC/PRF/5 cells by Western blotting.
      Ultrastructurally, metastatic Nuk-1 cells exhibited the intracytoplasmic
      canaliculus-like structures found in fibrolamellar carcinoma and the
      intracytoplasmic glandular lumina found in bile-duct carcinoma, while the other 3
      cell lines did not. In addition, Nuk-1 cells expressed neither cytokeratin 8 nor
      cytokeratin 19. CONCLUSIONS: Nuk-1 cells, which are human HCC cells with
      metastasis to lymph nodes, alone exhibited intracytoplasmic canaliculus-like
      structures and glandular lumina, as well as a marked reduction of nm23-H1
      protein, but did not express E-cadherin, integrin, or ICAM-1. Formation of both
      intracytoplasmic canaliculus-like structures and intracytoplasmic glandular
      lumina is one of the characteristics that may be involved in metastasis of HCC
      cells to lymph nodes, as is reduction of nm23-H1 protein.

PMID- 10576352
TI  - Minimal endoscopic aspects of gastric low-grade malt-lymphoma.
AB  - Low-grade gastric MALT-lymphoma is a neoplasia with a very indolent course and an
      excellent prognosis. Even if the most common endoscopic findings have described
      non-specific aspects, often suggestive for benign conditions, the endoscopy
      reveals a wide range of gastric mucosal changes both at diagnosis and at relapse.
      We report 2 cases of low-grade gastric MALT-lymphoma in which the diagnosis was
      made casually because the endoscopic presentation consisted only in mucosal
      hyperaemia in 1 case and in normal-appearing mucosa of the stomach in the second
      case. The patients were successfully treated with anti-Helicobacter pylori
      therapy. At 18 and 12 months of follow-up, respectively, the patients were
      disease-free. The bland appearance of this disease in some patients may reflect
      the early diagnosis of the tumor. Even if endoscopy and echoendoscopy often
      constitute useful and reliable diagnostic procedures, in the early phases of the
      tumor the histologic evaluation of endoscopic biopsies including
      immunohistochemistry represent the diagnostic procedure more reliably to detect
      this neoplasm.

PMID- 10576353
TI  - Gastrointestinal lesions in an adult patient with Henoch-Schonlein purpura.
AB  - A 28 year-old man was admitted because drug toxication, due to a high dose of
      antipsychotic drugs, presented purpuric rash on both legs, lower abdominal pain,
      arthralgia, and fresh-bloody stool. Colonoscopy observed numerous small ring-like
      petechiae in the rectum and in the sigmoid colon. Upper gastrointestinal
      endoscopy found a few petechiae in the antrum of the stomach and in the duodenal
      second portion. He was treated with coagulation factor X III after admission.
      After 38 days, there was no abnormal mucosa in the colorectum, the duodenal
      second portion, or the antrum of the stomach. The disappearance of
      gastrointestinal lesions correlated with the course of the illness.
      Gastrointestinal tracts should be thoroughly observed in patients with Henoch
      Schonlein purpura.

PMID- 10576354
TI  - Pre-operative radiotherapy in rectal cancer: evaluation of irradiation effects on
      cellular undifferentiation and its influence on prognosis.
AB  - BACKGROUND/AIMS: In spite of the new technology--stapler, antibiotics, anesthesia
      and new surgical and diagnostic procedures--the prognosis on treatment of cancer
      of the rectum has not changed in the last 50 years. Survival rates of 50-55%
      seems immutable in all published series. The main course for those results is the
      high incidence of recurrence, either local or widespread. Local recurrence is
      directly related to the number of undifferentiated cells and to the grade of wall
      invasion. So any kind of treatment that would diminish the number of
      undifferentiated cells and the size or the tumor wall penetration certainly would
      decrease the local recurrence rate, lengthening the interval free from cancer
      and, perhaps, modifying the long-term survival rate. Between 1978-1996, a total
      of 287 patients with rectal adenocarcinoma were treated by pre-operative RTD.
      METHODOLOGY: The same RDT protocol was used in all the patients: 400 cGy, 200
      cGy/day, during 4 consecutive weeks (anterior and posterior pelvic fields).
      Surgery was performed 7-10 days after completion of RDT. RESULTS: Statistical
      analysis of the whole group showed that pre-operative RDT does decrease frequency
      of undifferentiated cells. Moreover, the incidence of local recurrence diminished
      after irradiation by 3.48%. Pre-operative RDT reduces tumor volume and wall
      invasion, as well as the mortality rate due to local recurrence (2.43%) and
      alters long-term survival rate (80.17%). CONCLUSIONS: Pre-operative radiotherapy
      is really effective in reducing the number of undifferentiated cells and in
      diminishing the carcinomatous infiltration of the rectal wall.

PMID- 10576355
TI  - Infrequent activation of mitogen-activated protein kinase in human colon cancers.
AB  - BACKGROUND/AIMS: Mitogen-activated protein kinase (MAPK) is a downstream factor
      of the Ras-Raf-MAPK cascade and it is now considered to be a key molecule in
      signaling processes stimulated by growth factors and differentiation inducers.
      METHODOLOGY: We examined MAPK activity in 21 advanced colon cancers to
      investigate whether the MAPK cascade might play a role in the progression of
      colon cancers. RESULTS: MAPK activation (3.9-10.1-fold) was observed in 4 of 21
      cases (18%), but 3 cases (75%, 3 of 4 cases) showed MAPK activation without ras
      mutation, thus suggesting that MAPK activation did not correlate with the
      presence of Ki-ras mutations in these cases. Other kinds of oncogene activation
      would be involved to MAPK activation in human colon cancers. In other cases MAPK
      activation was not detected or partly down-regulated. CONCLUSIONS: These findings
      suggest that positive and negative regulation of MAPK activity are associated
      with loss of normal growth control and may be involved in carcinogenesis of colon
      cancers.

PMID- 10576356
TI  - Study of long intestinal tube for decompression of obstructive left colon cancer.
AB  - BACKGROUND/AIMS: Recently, several reports have recommended primary resection,
      rather than a staged operation, for obstructive left colon cancer. However pre
      operative decompression is important for reducing complications and improving the
      curability of primary resection. Among the many pre-operative decompression
      strategies reported, we selected the long intestinal tube and evaluated the
      effectiveness of this convenient strategy. METHODOLOGY: A long intestinal tube
      was inserted pre-operatively for decompression in 27 of 29 patients undergoing
      resection for obstructive left colon cancer (1991-1995). We retrospectively
      studied the clinical features (responders vs. non-responders) of the 27 patients.
      We also compared these 27 with 26 other pre-1990 patients, who did not receive
      pre-operative decompression, in term of post-operative morbidity. RESULTS: Twelve
      of the 27 patients were responders; success rate 44.4%. There were no blood
      profile differences between responders and non-responders, but the time from
      bowel movement cessation to intestinal tube insertion was 3 days or less in all
      responders but 4 days or more in non-responders (p<0.001). There was no
      significant difference in the rate of post-operative morbidity between those with
      and without pre-operative decompression. CONCLUSIONS: Decompression is likely to
      be successful, allowing elective primary resection, when initiated within 3 days
      of bowel movement cessation. However, more than 4 days post-onset, other
      decompression methods or emergency surgery is necessary.

PMID- 10576357
TI  - Physiological studies on nitric oxide in the right sided colon of patients with
      diverticular disease.
AB  - BACKGROUND/AIMS: Previously, we reported that non-adrenergic non-cholinergic
      (NANC) inhibitory nerves are decreased in the left-sided colon of patients with
      diverticular disease, contributing to their intraluminal high pressure by
      segmentation (1). It is established that nitric oxide (NO) is released by
      stimulation of NANC inhibitory nerves. Among Oriental people, including the
      Japanese, right-sided diverticular disease has predominated more frequently than
      among Western people. In order to evaluate the function of NO in the right-sided
      colon of patients with diverticular disease, we examined the enteric nerve
      responses in colonic materials from patients with this disease, using the right
      sided normal colon as a control. METHODOLOGY: Colonic tissue specimens were
      obtained from 8 patients with diverticular disease of the right-sided colon, and
      normal segments of the right-sided colon were obtained from 11 patients with
      localized diseases. A mechanograph was used to evaluate in vitro colonic
      responses to electrical field stimulation (EFS) of adrenergic and cholinergic
      nerves before and after treatment with various autonomic nerve blockers, N(G)
      nitro-L-arginine (L-NNA), and L-arginine. RESULTS: 1) Cholinergic nerves were
      more dominant in the diverticular colon than in the normal colon (p<0.01). 2)
      NANC inhibitory nerves were found to act on the normal colon and to a lesser
      extent in the diverticular colon (p<0.05). 3) NO mediates the relaxation reaction
      of NANC inhibitory nerves in the normal colon and to a lesser extent in the
      diverticular colon. CONCLUSIONS: The intrinsic intestinal innervation contains
      excitatory and inhibitory nerves and the former, especially cholinergic nerves,
      are dominant in the right-sided colon with diverticula. In addition, reduction of
      the action of NANC inhibitory nerves by substances such as NO may be largely
      related to the tight intraluminal pressure by colonic segmentation observed in
      the right-sided colon with diverticula.

PMID- 10576358
TI  - Rectal leiomyosarcoma diagnosed by endoscopic ultrasonography.
AB  - A 67 year-old man was admitted to the Tainan Municipal Hospital due to a
      protruding mass, usually noted during defecation. Digital examination revealed a
      single, smooth, large mass over the rectum, occupying almost the entire lumen.
      Colonoscopy, barium enema, and computed tomography (CT) demonstrated a submucosal
      tumor of the rectum. Endoscopic ultrasound (EUS) study showed that the tumor
      originated from the muscle layer. Based on the size, margin and echogenicity of
      the mass, a malignant neoplasm, probably leiomyosarcoma, was diagnosed. Post
      operative histologic examination confirmed that the resected tumor was
      leiomyosarcoma. Existing ancillary procedures like colonoscopy, abdominal CT,
      magnetic resonance image (MRI), and barium enema are neither reliable nor
      accurate in locating which layer the lesion originates. Colonoscopic biopsy is
      disappointing since submucosal tumor is usually inaccessible. EUS study can
      provide us with a more distinct image with regards to tumor origin, size, margin
      and echogenicity. This report emphasizes the important role of EUS in the pre
      operative diagnosis of submucosal tumors of the rectum. Furthermore, this tool
      can aid the surgeons whether wide excision or an abdomino-perineal resection
      should be performed.

PMID- 10576359
TI  - Endoscopic variceal ligation (EVL) combined with partial splenic embolization
      (PSE).
AB  - BACKGROUND/AIMS: The effectiveness of reducing the recurrence rate of esophageal
      varices by combining partial splenic embolization (PSE) with endoscopic variceal
      ligation (EVL) was investigated. METHODOLOGY: Patients with complete eradication
      of esophageal varices were collected as study cases with the following results:
      31 cases with PSE and EVL (PSE+EVL group), 25 cases with EVL alone (EVL group),
      and 33 cases with EIS alone (EIS group). The cumulative recurrence rates were
      obtained by observing new varices. RESULTS: The cumulative recurrence rates at 6
      months were 21.1% in the PSE+EVL group, 58.1% in the EVL group and 32.5% in the
      EIS group. Those at 1 year were 37.0%, 70.7% and 50.2%, respectively, and those
      at 2 years were 58.1%, 80.4% and 73.0%, respectively. For all 3 time periods,
      recurrence rates of the PSE+EVL group were significantly lower than those of the
      EVL group (p=0.042). Cumulative rates in the PSE+EVL group tended to be lower
      than those in the EIS group. Further analysis was made on the comparative
      recurrence rates of the 3 groups, according to Child's classification. The
      cumulative recurrence rates in Child A cases did not significantly differ between
      the 3 groups. Cumulative rates in Child B cases were significantly lower in the
      PSE+EVL group than in the EVL group (p=0.032), and those in the PSE+EVL group
      tended to be lower than those in the EIS group. These trends were observed
      between the PSE+EVL group and the EVL group in Child C cases, while cumulative
      rates did not show differences between the PSE+EVL group and the EIS group.
      CONCLUSIONS: It was inferred that PSE-combined EVL therapy is a very effective
      therapy for achieving long-term complete eradication of esophageal varices.

PMID- 10576360
TI  - Positive impact on surgical treatment for asymptomatic patients with esophageal
      carcinoma.
AB  - BACKGROUND/AIMS: The prognosis of patients with esophageal carcinoma remains
      unsatisfactory. The purpose of this study was to clarify the clinicopathologic
      characteristics of asymptomatic patients. METHODOLOGY: We retrospectively
      compared 78 cases of asymptomatic esophageal carcinoma (AEC) with 341 cases of
      symptomatic esophageal carcinoma (SEC). RESULTS: In 47 of 78 patients with AEC,
      the tumors were discovered by mass screening and in 31 patents by follow-up
      examination for other disease. Nearly 70% of the patients with AEC had a
      carcinoma in situ (Tis) or T1 tumor, whereas nearly 70% of the patients with SEC
      had T3 or T4 tumors. The incidences of lymph node metastasis, lymphatic invasion
      and vascular invasion were significantly lower in patients with AEC than in those
      with SEC. The 5-year survival rate in AEC and SEC were 59.3% and 22.9%,
      respectively. With regard to the cause of death, 26.8% (11/41) of patients with
      AEC and 59.9% (166/277) of patients with SEC died of esophageal carcinoma.
      CONCLUSIONS: In order to improve the prognosis of esophageal carcinoma, an effort
      should be made to detect early esophageal carcinoma among patients at risk for
      tumors when they are still asymptomatic.

PMID- 10576361
TI  - Comparative post-operative study of prostheses, with and without an anti-reflux
      valve system, in the palliative treatment of esophageal carcinoma.
AB  - BACKGROUND/AIMS: Palliative treatment of advanced esophageal carcinoma by
      esophageal tunnelization with a prosthesis allows immediate relief of dysphagia.
      However, the procedure is subject to a high rate of morbidity, including
      gastroesophageal reflux (GER) present in all patients with a prosthesis
      positioned through the gastroesophageal junction, resulting in complications
      (pyrosis, aspiration pneumonias, sleep disorders) and reduced quality of life in
      these patients who already have a lower rate of survival. In an attempt to reduce
      GER and its complications, the authors created a surgical prosthesis coupled to
      an anti-reflux valve system, comparing it to the use of an esophageal prosthesis
      without an anti-reflux valve mechanism. METHODOLOGY: Twenty-two patients were
      allocated to 2 tunnelization groups: esophageal prosthesis without an anti-reflux
      valve mechanism (group 1) and surgical prosthesis coupled to an anti-reflux valve
      system (group 2). The GER was quantified measuring esophageal-gastric pH, and
      using fluoroscopy, contrast radiographs and esophageal emptying scintigraphy.
      Initially, the pH of secretions in S1 (esophagus) and S2 (stomach) was determined
      using reagent strips after aspirating their contents with different syringes.
      First with the patient seated at rest in bed, later performing a Valsalva
      maneuver, deep breathing and forced coughing. The same procedure was performed
      with the patient in left lateral decubitus, right lateral decubitus, and dorsal
      decubitus with the head of the bed lowered to 20 degrees. After finishing these
      maneuvers, 15 ml of 1 molar acetic acid were infused through the catheter
      positioned in the antrum, and, after 5 min, S1 and S2 material sampling was
      repeated in the same positions as mentioned above. RESULTS: The pH values between
      the various positions and maneuvers performed in each group separately were not
      significantly different, but, if we compare the 2 groups, and the secretions
      obtained in S1 and S2, there was a significant difference in pH measures in all
      positions. In the patients in group 1, S1 presented a mean pH ranging from 2.87
      3.62 in the initial measures, and between 2.17 and 3.5 after the infusion of 15
      ml of 1 molar acetic acid. On the other hand, in group 2, the mean pH of S1
      remained between 6.34 and 8.32 in the initial measures and between 4.99 and 7.33
      in the presence of acid infusion. At the level of S2, the pH remained unchanged
      between 2 and 2.7, in both groups. CONCLUSIONS: The authors conclude that the
      association of an esophageal prosthesis with a valve system significantly reduces
      GER, as compared with its use alone. Furthermore, it allows marked reduction of
      the symptoms and resulting complications, and does not interfere clinically with
      esophageal emptying. It thus significantly improves the quality of life of these
      patients.

PMID- 10576362
TI  - Fulminant nonocclusive mesenteric ischemia developing just after esophagectomy.
AB  - Nonocclusive mesenteric ischemia (NOMI) is a poorly understood condition, marked
      by progressive ischemia of the intestine leading to infarction, sepsis and death.
      The mortality rate remains high. Three cases of NOMI occurred after esophagectomy
      at our facility. It was suspected, through investigation of these cases, that
      NOMI occurring after major surgical procedures like esophagectomy has a far more
      rapid and progressive clinical course and high mortality rate. Therefore, it
      should be distinguished from spontaneously developing NOMI. A huge water shift
      between the intravascular space and the extravascular space during and just after
      surgery is suspected to have played a major role in the development of post
      operative NOMI. Diagnosis and treatment of NOMI after a major surgery are quite
      difficult.

PMID- 10576363
TI  - Combined modality therapy for basaloid squamous carcinoma of the esophagus.
AB  - A 61 year-old woman came to our hospital with dysphasia that had persisted for 2
      months. Endoscopy and barium swallow showed a protruding tumor, about 6.0 cm
      long, in the midportion of the esophagus. A biopsy specimen showed squamous cell
      carcinoma of the esophagus. Computed tomography (CT) scan revealed adventitial
      involvement and lymph node metastases beneath the carina. After 2 courses of
      chemotherapy with cisplatin (CDDP) 100 mg for 1 day, 5-Fluorouracil (5-FU) 800 mg
      for 5 days, and leucovorin 30 mg for 5 days, complete regression of the tumor was
      observed by endoscopy and barium esophagography. Transthoracic esophagectomy with
      lymph node dissection was performed. Histologically, the muscle layers of the
      resected esophagus had been replaced by fibrous tissue; however, small foci of
      basaloid squamous carcinoma (BSC) were found in the submucosa. Six months after
      surgery, a CT scan revealed a metastatic lymph node around the right main
      bronchus. Chemotherapy and radiotherapy resulted in the disappearance of the
      metastasis. The patient has survived for more than 3 years since surgery with a
      good quality of life.

PMID- 10576364
TI  - Magnetization transfer contrast imaging of liver cirrhosis.
AB  - BACKGROUND/AIMS: To test the feasibility of magnetization transfer contrast (MTC)
      imaging in the evaluation of liver cirrhosis. METHODOLOGY: Three normal
      volunteers and 22 cirrhotic liver patients (13 of them harbored hepatoma) were
      prospectively studied with on-resonance binomial pulsed MTC imaging using a 1.0
      Tesla MR scanner. Both MTC and non-MTC images were acquired. The magnetization
      transfer (MT) effect (defined as: 1-signal intensity of MTC/signal intensity of
      non-MTC), was used as an indicator and was correlated with different disease
      status. Lesion-to-liver contrast of non-MTC versus MTC imaging was also compared.
      RESULTS: Chronic hepatitis and early fibrosis had a MT effect similar to that of
      the normal group. Frank cirrhosis had the strongest MT effect. Cirrhosis, when
      infiltrated by diffuse hepatoma, showed a significantly weaker MT effect than
      that of the normal group (p<0.05), early cirrhosis (P<0.005), and frank cirrhosis
      (p<0.05). Overall, the MT effects in these 22 patients were widely variable.
      There was no significant improvement in lesion contrast of MTC imaging when
      compared to that of non-MTC imaging due to complex signal attenuation behavior of
      either the background liver tissue or the tumor itself. CONCLUSIONS: The complex
      pathological change of the cirrhotic liver tissue may account for the wide
      variation of the MT effect and the compromised lesion contrast in cirrhotic
      patients. Caution should be taken when cirrhotic tissue has an unusually weak MT
      effect. Then, the possibility of a mixed disease process such as fatty
      metamorphosis or diffuse hepatoma should be highly suspected. Our experience
      shows that MTC imaging plays a potential role in the evaluation of the multi
      facets of cirrhotic tissue change.

PMID- 10576365
TI  - Gastroduodenal perforation in cancer patients.
AB  - BACKGROUND/AIMS: Patients with advanced or metastatic cancer have compromised
      nutritional, metabolic, and immune conditions. Little is known about
      gastroduodenal perforation in cancer patients. METHODOLOGY: Data of 11 cancer
      patients with gastroduodenal perforation were retrospectively reviewed. RESULTS:
      There were 2 females and 9 males with a mean (+/- s.e.) age of 56.7+/-4.7 years
      and a median of 55. The primary malignancies included lung cancers (3 cases),
      hepatocellular carcinomas (2 cases), squamous cell carcinomas of the tongue (2
      cases), malignant lymphoma of the small bowel (1 case), adenocarcinoma of the
      pancreas (1 case), adenocarcinoma of the stomach (1 case), and acute
      lymphoblastic leukemia (1 case). The average duration of symptoms was 36.5+/-10.1
      hours (median: 24 hours). Methods of surgical treatment included simple closure
      of the perforation (6 cases), truncal vagotomy and pyloroplasty (3 cases),
      pyloroplasty (1 case), and subtotal gastrectomy (1 case). Four patients (36.4%)
      had post-operative complications. The post-operative hospital mortality rate was
      18.2%. One patient died of sepsis with gastrointestinal hemorrhage and 1 died of
      hepatic failure and respiratory failure. Pre-operative shock is the only
      significant factor in predicting operative mortality. CONCLUSIONS: Gastroduodenal
      perforation occurring in cancer patients without chemotherapy had favorable short
      term operative results.

PMID- 10576366
TI  - Absorption of bismuth from two bismuth compounds before and after healing of
      peptic ulcers.
AB  - BACKGROUND/AIMS: Previous reports state that there is absorption of bismuth
      through active peptic ulcers. It was therefore of interest to investigate the
      extent of absorption in patients at the ulcer and post-ulcer stages. METHODOLOGY:
      Twenty H. pylori-positive patients with gastroscopically verified gastric or
      duodenal ulcers were randomly allocated to ingest 3000 mg bismuth subnitrate
      (BSN) (10 patients) or 480 mg colloidal bismuth subcitrate (CBS) (10 patients).
      Bismuth serum concentration in 12 samples drawn during the first 4 hours after
      drug intake was analyzed and the area under the curve (Bi-AUC) was calculated.
      Anti-H. pylori therapy with amoxicillin and lanzoprazole eradicated H. pylori in
      10 patients and healed the ulcers in all patients 4 weeks after therapy ended,
      then the bismuth absorption test was repeated. RESULTS: There was no significant
      difference between ulcer- and post-ulcer Bi-AUC for patients receiving BSN or for
      patients receiving CBS. On a molar basis, CBS gave a 17.4-fold greater absorption
      of bismuth compared to BSN. CONCLUSIONS: The presence of an active ulcer does not
      significantly influence the absorption of bismuth from CBS or BSN.

PMID- 10576367
TI  - The investigation of iron deficiency anemia--a hospital based audit.
AB  - BACKGROUND/AIMS: Iron deficiency anemia (IDA) is associated with an increased
      incidence of malignancy. Our aim was to audit the management of patients with IDA
      seen in a teaching hospital gastroenterology unit, and to assess the role of
      upper and lower gastrointestinal endoscopy as well as mesenteric angiography in
      improving the diagnostic yield. METHODOLOGY: A retrospective review of all
      outpatient letters and in-patient discharge summaries in an 11 month period in
      1996 was used to identify anemic patients. All endoscopic and radiological
      procedures were documented on these patients. RESULTS: 98 cases (46 male) of IDA
      were identified. Of these, 94% had upper GI endoscopy with a yield for potential
      bleeding sources of 54% (including 4 malignancies) and 84% had lower GI
      investigation by colonoscopy or barium enema with a diagnostic yield of 37%
      (including 3 malignancies and 10 adenomatous polyps). Combined endoscopic and
      barium examinations provided a positive diagnosis in 69%, and 12.2% had
      significant co-existent upper and lower GI pathology. Thirty-three patients
      underwent visceral angiography (27 of who had no positive endoscopic diagnosis).
      Twenty-seven studies revealed a bleeding source (yield 82%). Overall an
      underlying diagnosis was made in 92% of patients. CONCLUSIONS: The incidence of
      significant dual pathology in patients with IDA was high. Investigation of the
      lower GI tract should be performed in all patients unless a malignancy is found
      on upper GI endoscopy. Mesenteric angiography has a high diagnostic yield, and is
      a useful investigation in patients with resistant or transfusion dependent anemia
      in whom endoscopic or barium studies are normal.

PMID- 10576368
TI  - Recurrent mesenteric desmoid tumors with multiple peritoneal dissemination: a
      case report and review of desmoid in Japan.
AB  - We report, herein, on the first case of a mesenteric desmoid tumor with multiple
      peritoneal dissemination. A 73 year-old Japanese woman, who had a history of
      uterine cancer that was treated with hysterectomy followed by a high dose of
      irradiation 25 years ago, had an unknown stenosis of the sigmoid colon, which was
      treated with partial resection of the stenosed colon 6 years ago, and then
      resulted in multiple small bowel obstructions due to the recurrence of mesenteric
      desmoids. The clinical behavior of this tumor is considered to be unpredictable.
      We emphasize that mesenteric desmoid tumors should be considered as one of the
      causes of stenosis of the colon and small bowel, and patients should receive
      careful follow-up after unknown stenosis.

PMID- 10576369
TI  - Percutaneous microwave coagulation therapy for unresectable hepatocellular
      carcinoma.
AB  - BACKGROUND/AIMS: Percutaneous microwave coagulation therapy (PMCT) has recently
      been introduced as a new treatment for hepatocellular carcinoma (HCC) in Japan.
      This study was performed to evaluate its efficacy and safety. METHODOLOGY:
      Thirteen patients with 17 nodules of unresectable HCC were subjected to PMCT
      under ultrasonic guidance. The tumors ranged from 1.2-4.4 cm in size. Assessment
      of the efficacy of PMCT was made by follow-up with dynamic computed tomography
      (CT). RESULTS: In the patients with small HCC (< or = 2.0 cm), 8 of 10 nodules
      (80%) showed complete remission after PMCT. In small nodules located on the liver
      surface, 3 out of 4 nodules (75%) showed complete remission. However, in the
      patients with larger HCC (> or = 2.1 cm), 5 out of 7 nodules developed local
      recurrence after PMCT. Regarding assessment of the necrotic area after PMCT,
      dynamic CT revealed enhancement that was possibly caused by congestion of the
      liver parenchyma surrounding the area of necrosis due to PMCT in the early phase
      of the treatment. Therefore, the necrotic area must be assessed carefully.
      Although a slight heat sensation and/or pain during microwave irradiation (a
      common effect of PMCT) occurred in all patients, there were no serious adverse
      effects. CONCLUSIONS: Complete remission of small HCC (< or = 2 cm in diameter)
      can be achieved with PMCT alone, but there seem to be limitations to its
      effectiveness with larger HCC (> or = 2.1 cm). There were no serious adverse
      effects from PMCT and the therapy can be safely carried out even in patients with
      poor liver function.

PMID- 10576370
TI  - CT portography and post-lipiodol CT in the preinterventional work-up of primary
      and secondary liver tumors. A single center experience.
AB  - BACKGROUND/AIMS: The evaluation of the clinical use of CT portography (CTp) and
      post-lipiodol CT (CT post-lip) in terms of therapeutic implications in patients
      with liver malignancies, particularly hepatocellular carcinoma (HCC).
      METHODOLOGY: We prospectively evaluated 130 patients with CTp and CT post-lip:
      109 with HCC and underlying cirrhosis (group I) and 21 with liver metastases
      considered for surgical resection (group II). All patients also underwent hepatic
      angiography (hA). Mean lesion size was 4.6 cm and 2.2 cm for group I and II
      respectively. Previous contrast-enhanced CT studies were available for
      comparison. RESULTS: Diagnostic CTp examinations resulted in only 84.4% of group
      I due to enhancement in homogeneities and in all patients from group II. In
      comparison with the referral CT, additional lesions were seen in 83.6% of the HCC
      group and in 66.6% of the metastatic group that implicated treatment alterations
      in 15.21% and in 23.8% of them, respectively. Hepatic angiography revealed
      hypervascularity in 91.3% of HCC lesions and in 33.3% of metastatic ones. CT post
      lip images suitable for evaluation resulted in 104/130 patients (80%). At CT post
      lip false negative results were observed in 33.73% patients with HCC and in
      30.95% patients with liver metastases. Selective lipiodol retention was seen in
      only 50% of the biopsy proved satellites. CONCLUSIONS: CTp reveals additional
      lesions that have therapeutic implications in at least 15% of HCC patients and in
      20% of patients with metastatic disease, and should be routinely included in the
      preinterventional work-up particularly for cases in which intraarterial or
      percutaneous treatment is scheduled. By contrast, CT post-lip seems to be of
      limited value unless it is evaluated in combination with CTp and angiography.

PMID- 10576371
TI  - The effect of intraportal administration of prostaglandin E1 on liver blood flow
      and liver function.
AB  - BACKGROUND/AIMS: Prostaglandin E1 (PGE1) exerts a hepatic cytoprotective action
      directly and indirectly through enhancing hepatic blood flow. Although PGE1 is
      usually administered systemically, more than 60% of PGE1 is inactivated during
      only a single passage through the lung. By administering PGE1 intraportally the
      intrahepatic level of this drug can be increased effectively and liver
      dysfunction might be prevented. In this study, the effect of intraportal
      administration of PGE1 to patients who underwent hepatectomy was estimated.
      METHODOLOGY: Twenty patients who underwent hepatectomy from January 1995 to
      December 1996 were divided into 2 groups, i.e., a PGE1 group (n=8) and a control
      group (n=12). Laboratory data and hepatic portal blood flow were examined before
      and after hepatectomy. In the PGE 1 group, PGE 1 was continuously infused at a
      dose of 120 microg/day for 5 days through a catheter inserted into the portal
      vein via the gastroepiploic vein. RESULTS: There was no difference in the post
      operative change in aspartate aminotransferase (AST) or alanine aminotransferase
      (ALT) between the 2 groups. Elevation of total bilirubin was more significantly
      suppressed in the PG group than in the control group. Total branched-chain amino
      acids and the tyrosine ratio reached their peak on the 5th post-operative day
      (POD) and were significantly higher in the PG group. Post-operative portal blood
      flow was significantly increased in the PG group. CONCLUSIONS: Our results
      indicated that continuous intraportal administration of small doses of PGE1 is
      effective for the protection of hepatic function after hepatectomy.

PMID- 10576372
TI  - Hepatocellular carcinoma: surgical treatment and prognostic variables in 56
      patients.
AB  - BACKGROUND/AIMS: Partial hepatectomy (PH) or total hepatectomy and orthotopic
      liver transplantation (OLT) may be curative in selected patients treated for
      hepatocellular carcinoma (HCC). The analysis of clinical series may help in the
      choice of the more appropriate treatment. METHODOLOGY: During the past 11 years,
      40 patients with HCC were treated by PH and 16 patients underwent total
      hepatectomy and OLT. Selection criteria for transplantation were the liver
      function and the tumor resectability. RESULTS: The actuarial 1-, 3- and 5-year
      survival rates were 67%, 34% and 18%, respectively, after PH and 62%, 54% and 54%
      after OLT. The only prognostic factor after PH was the tumor extension to a
      single or both lobes. Patients with associated cirrhosis had significantly more
      post-operative complications, but a comparable long-term survival. The
      proliferative cell nuclear antigen labeling index (PCNA-LI), evaluated on tumoral
      tissue in 16 patients, showed that an index <30% indicates a better prognosis for
      HCC developing in non-cirrhotic liver. CONCLUSIONS: For patients carefully pre
      operatively evaluated, the presence of an associated cirrhosis does not seem to
      modify the long-term survival after PH, and OLT may offer more than 50% 5-year
      survival. A PCNA-LI <30% appears to be a good prognostic factor in patients
      without cirrhosis.

PMID- 10576373
TI  - Liver regeneration and restoration of liver function after partial hepatectomy:
      the relation of fibrosis of the liver parenchyma.
AB  - BACKGROUND/AIMS: Patients who survive partial hepatectomy sometimes have
      unsatisfactory liver regeneration and restoration of liver function. Although the
      extent of resection should be adjusted to attain favorable liver regeneration and
      restoration of liver function, a guiding principle for this has not been
      established. METHODOLOGY: Seventy patients with hepatic tumors associated with
      liver disorders of various severity who underwent hepatectomy were studied. We
      calculated the removal rate of the liver and the regeneration rate of the remnant
      liver using computed tomography. The liver function was investigated using ICG R
      15 (retention rate of indocyanine green). Liver disorder was classified into 4
      groups, according to the severity of fibrosis. RESULTS: The regeneration rates of
      the remnant liver indicated a significant decline in patients with severe
      fibrosis. In the no fibrosis and mild fibrosis groups, an increased removal rate
      was associated with increased regeneration rate, and post-operative ICG R-15
      improved with time. However, in the moderate fibrosis and severe fibrosis groups,
      an increased removal rate was not associated with increased regeneration rate,
      and post-operative ICG R-15 showed no change or became worse with time.
      CONCLUSIONS: Severe fibrosis of the liver parenchyma is associated with poorer
      regeneration of the remnant liver leading to poor restoration of post-operative
      liver function. The severity of fibrosis is useful as a predictive factor for
      liver regeneration and restoration of liver function after partial hepatectomy.

PMID- 10576374
TI  - Reactivation of hepatitis B but not hepatitis C in patients with malignant
      lymphoma and immunosuppressive therapy. A prospective study in 305 patients.
AB  - BACKGROUNDS/AIMS: The aim of this prospective study was to determine the
      prevalence of hepatitis B (HBV) and hepatitis C viral (HCV) infection as well as
      to study the morbidity and mortality of viral reactivations in patients treated
      with corticosteroid containing chemotherapy. METHODOLOGY: From January 1991 to
      April 1996, 305 patients admitted for treatment of Hodgkin's disease and non
      Hodgkin's lymphoma were tested for HBV, and 181 patients for HCV infection. They
      were followed-up regularly on a monthly basis with liver biochemistry and viral
      serology. RESULTS: The prevalence of HBs antigen and hepatitis C antibody was
      found to be 3.2% and 16% respectively. There were 9 reactivations of HBV among 8
      HBs antigen positive patients (78%), one among 35 HBs antigen negative patients
      (2.8%) and none in HCV positive patients. In 83% of cases, reactivation was
      connected to chemotherapy and corticosteroids. The overall death rate of HBV
      reactivation was 37%; in severe hepatitis it was 60%. All fatal reactivations
      were in anti-HBe positive patients. CONCLUSIONS: The low prevalence of HCV failed
      to demonstrate an association between hepatitis C viral infection and lymphoma in
      Slovenia. Reactivation of HBV infection in HBsAg positive malignant lymphoma
      patients is a common and often fatal complication of treatment.

PMID- 10576375
TI  - Treatment for extrahepatic metastasis of hepatocellular carcinoma following
      successful hepatic resection.
AB  - BACKGROUND/AIMS: Recent advances in both the diagnosis and treatment of
      hepatocellular carcinoma (HCC) have improved its prognosis. Intrahepatic
      recurrence after hepatectomy can be treated with repeated hepatectomy,
      transhepatic arterial embolization (TAE), percutaneous ethanol injection therapy
      (PEIT), or microwave coagulo-necrotic therapy. However, treatment for
      extrahepatic recurrence is also important in prolonging survival in some
      patients. METHODOLOGY: After radical hepatectomy in 155 patients, extrahepatic
      recurrences were found in 15 patients that underwent subsequent treatment. The
      interval between completing treatment for the primary tumor and the discovery of
      metastasis, the location and mode of treatment of the metastasis, and the
      outcomes were analyzed. RESULTS: Distant metastasis was detected at a mean of 7
      months after radical resection of the primary tumor. Location of the metastasis
      included lung, bone, and adrenal gland. Four patients had no intrahepatic
      recurrence and 11 patients had simultaneous intrahepatic recurrence. Six patients
      with intrahepatic and extrahepatic recurrence that underwent systemic
      chemotherapy had poor prognoses, and all died within 12 months as a result of
      progression of the intrahepatic tumor. Five patients with intra- and extrahepatic
      recurrence that underwent systemic chemotherapy combined with hepatic arterial
      infusion chemotherapy had relatively good outcomes; all survived for more than 12
      months. CONCLUSIONS: These results suggest that to obtain a good prognosis for
      extrahepatic metastasis coexisting with intrahepatic recurrence, intrahepatic
      recurrence should be controlled by locoregional therapy, and extrahepatic
      metastasis should be controlled by systemic chemotherapy and/or irradiation
      therapy.

PMID- 10576376
TI  - Liver resection for breast cancer metastases.
AB  - BACKGROUND/AIMS: The prognosis of patients with hepatic metastases (HM) from
      breast cancer receiving no treatment is extremely poor. Results of systemic and
      regional chemotherapy as well as other treatment modalities, such as
      immunotherapy or hormonal therapy, are disappointing in this group of patients,
      with median survival rates hardly exceeding 1 year. METHODOLOGY: We performed a
      retrospective analysis of patients undergoing resection of isolated HM from
      breast cancer to determine the morbidity, mortality and prognosis following this
      procedure. RESULTS: Fifteen female patients underwent liver resection between
      September 1985 and April 1997. Two patients had synchronous and 13 patients had
      metachronous HM. The mean number of HM was 3.3 (1-9) (bilobar in 6 patients) with
      a mean diameter of 5.3 cm (2-11 cm). The following resections were performed:
      wedge resection (4), left lateral segmentectomy (2), right hemihepatectomy (3),
      left hemihepatectomy (1), extended right hemihepatectomy (3) and extended left
      hemihepatectomy (2). There was no hospital mortality. Morbidity (transient
      hepatic failure (n=2) and intra-operative hemorrhage necessitating splenectomy
      (n=1)) occurred in 3 patients. Median follow-up was 12 (1-88) months. Six
      patients developed recurrent liver disease; 2 relapsed elsewhere. Six of these 8
      patients died. Overall median survival following liver resection was 57 months
      with 1-, 2- and 3-year survival rates of 100%, 71.4% and 53.6% respectively.
      CONCLUSIONS: Liver resection is a viable treatment option for selected patients
      with isolated HM from breast cancer that can be performed safely. It should be
      considered in individual patients if the operative risk is low, if no
      extrahepatic disease is present and provided a complete resection with clear
      margins is technically feasible.

PMID- 10576377
TI  - Two-dimensional analysis of production of IL-6 and TNF-alpha can predict the
      efficacy of IFN-alpha therapy.
AB  - BACKGROUND/AIMS: Many patients with chronic hepatitis C are now treated with
      interferon-alpha (IFN-alpha). The increase in the number of patients treated with
      IFN-alpha, however, has resulted in increased reports of adverse drug reactions
      (ADR). This prompted us to investigate for a useful parameter for predicting the
      effects of IFN-alpha treatment before initiating the therapy for the benefit of
      patients. METHODOLOGY: Peripheral blood mononuclear cells (PBMCs) obtained from
      patients with chronic hepatitis C and healthy volunteers were incubated at 37
      degrees C for 24 hours at various concentrations of IFN-alpha (1, 10(2), and
      10(4) IU/ml). The tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL
      6) formed in the culture medium were determined. Also, the binding of 125I
      labeled IFN-alpha to PBMCs and 2', 5'-oligoadenylate synthetase (2-5AS)
      activities were measured. RESULTS: The addition of IFN-alpha to PBMCs at
      concentrations of 1-10(4) IU/ml showed dose-dependent changes in the binding of
      125I-labeled IFN-alpha to PBMCs and 2-5AS activities. There was a strong
      correlation between the production of IL-6 and that of TNF-alpha (r>0.9). The
      production of IL-6 by the PBMCs of the high responders is significantly higher
      than that of the low-responders at the same value of TNF-alpha. A statistically
      significant difference was demonstrated by analysis of covariance. CONCLUSIONS:
      The findings of this study suggest that two-dimensional analysis of the in vitro
      production of TNF-alpha and IL-6 by PBMCs induced by IFN-alpha is useful for
      predicting the outcome of the IFN-alpha treatment in patients.

PMID- 10576378
TI  - The prevalence of gallstones in chronic liver disease is related to degree of
      liver dysfunction.
AB  - BACKGROUND/AIMS: Earlier studies have indicated an elevated risk for gallstone
      disease in patients with cirrhosis. This study aimed to evaluate the prevalence
      of gallstones in patients with chronic liver disease (CLD) with respect to sex,
      etiology, and severity of liver disease. METHODOLOGY: Four hundred and thirteen
      adults (176 women), mean age 51.2+/-14 years, with CLD, who had undergone liver
      biopsy during 1978-1993, and from whom sera were available, were investigated
      retrospectively. The results were compared with a population-based
      ultrasonography study of 556 healthy men and women, in their 40s and 60s.
      RESULTS: The prevalence of gallstones in patients with CLD did not differ from
      that in the control population. An increased frequency was observed in patients
      with CLD initially classified as cryptogenic, of whom the majority (60%) later
      were reclassified as chronic hepatitis C. The frequency of gallstones was also
      high in PiZ-heterozygotes for alpha1-antitrypsin deficiency (5/21, 24%) compared
      to non-PiZ-carriers (17/389, 4.8%), (p<0.001). In 67 patients with histologic
      evidence of cirrhosis, 30% (20/67) had gallstones (vs. 15% in the general
      population, p<0.01). The prevalence of gallstones increased significantly from
      Child's class A (16%) to C (56.2%). The difference was significant in males
      (18.2% vs. 62.5%, p=0.033), but not in females. Fifty percent of the patients
      with gallstones were symptomatic. CONCLUSIONS: Progressive liver dysfunction is a
      risk factor for gallstones particularly in males. HCV infection and PiZ
      carriership may further increase biliary lithogenesis.

PMID- 10576379
TI  - Living-related auxiliary partial orthotopic liver transplantation for primary
      sclerosing chonangitis--subsequent removal of the native liver.
AB  - In Japan, living-related auxiliary partial orthotopic liver transplantation
      (APOLT) is mainly indicated for small-for-size grafts. We present the case of a
      24 year-old patient with primary sclerosing cholangitis (PSC) who underwent a
      living-related auxiliary partial orthotopic liver transplantation for a small-for
      size graft, that was subsequently excised. During the transplantation procedure,
      the native liver was freed from the surrounding tissues, and was only connected
      to the body by the right hepatic artery and right hepatic vein. The auxiliary
      extended left lobe graft, corresponding to 22% of the estimated recipient liver
      volume, was orthotopically transplanted after extended left lobectomy of the
      recipient native liver. Post-transplant CT-volumetry showed rapid increase of the
      graft volume with atrophy of the native liver, and GSA scintigraphy showed
      dominant function of the graft. Although hyper-bilirubinemia was prolonged by the
      removal of the native liver on the 18th post-transplantation day, it gradually
      subsided after plasmapheresis was performed twice, and the patient was discharged
      on the 77th post-transplantation day. We conclude, based on this case, that
      subsequent removal of the native liver is necessary in APOLT for patients with
      potential hepatic malignancies. The optimal timing of the removal of the remnant
      native liver should be determined based on CT-volumetry, GSA scintigraphy, and
      the liver biopsy specimen of the graft.

PMID- 10576380
TI  - Spontaneous hepatocellular adenoma with marked cystic degeneration.
AB  - We report a case of spontaneous hepatocellular adenoma with marked cystic
      degeneration in the non-cirrhotic liver. A 36 year-old Japanese woman with
      neither history of liver diseases nor use of oral contraceptives and steroids,
      complained of a 6 kg weight loss over 6 months. Barium meal study revealed an
      extramural compression along the fornix of the stomach. Abdominal ultrasonography
      (UC) and computed tomography (CT) demonstrated a mass in the left lateral segment
      of the liver that measured 11.6x9.5 cm with cystic lesions. Laboratory data on
      admission showed no significant findings. Celiac angiography revealed a hyper
      vascular mass. Surgical exploration revealed a soft mass arising and protruding
      from the left lateral segment of the liver. Partial resection of the left lateral
      segment was performed. Histologically, the tumor was surrounded by a thin fibrous
      pseudocapsule. The neoplastic cells resembling normal hepatocytes around the
      tumor were large, pale and arranged in thick, irregular cords. Neither mitotic
      figures nor foci of dysplasia were present. The central portions of the tumor
      showed marked cystic degeneration. The tumor was histologically diagnosed as
      hepatocellular adenoma (HCA). HCA with cystic degeneration has been rarely
      reported.

PMID- 10576381
TI  - Inflammatory pseudotumor of the liver treated surgically.
AB  - This report describes the case of an inflammatory pseudotumor of the liver in a
      61 year-old female, diagnosed by an ultrasound scan (USG), computed tomography
      (CT) and needle biopsy. The right hemihepatectomy has been carried out. There
      were no complications in the post-operative course.

PMID- 10576382
TI  - Liver metastasis nineteen years after surgery for typical bronchial carcinoid.
AB  - A resected case of metastatic liver carcinoid is presented. A 62 year-old woman,
      who had undergone removal of a typical bronchial carcinoid 19 years before, was
      found to have a well-defined, oval hepatic tumor on ultrasonography. The resected
      specimen was a hard and solid tumor, which was microscopically diagnosed as a
      carcinoid. Histological review of the previously resected lung tumor revealed
      that the liver tumor was a metastasis from the primary bronchial carcinoid. The
      patient is alive without recurrence 42 months after hepatectomy. This case
      suggests that typical bronchial carcinoid, a slowly growing tumor, may
      metastasize to distant sites after many years, and that re-excision of metastatic
      lesions may prolong survival time.

PMID- 10576383
TI  - A case of extra-hepatic portal vein aneurysm: evaluation by 3-dimensional
      computerized tomography angiogram.
AB  - Portal vein aneurysms (PVAs) are rare lesions associated with congenital vascular
      anomalies or chronic portal hypertension. Although usually benign, they
      occasionally lead to complications such as aneurysmal rupture, porto-systemic
      shunts, mural thrombosis in the portal vein, and compression of the biliary
      tract. So far, the diagnosis of these lesions has been dependent on 2-dimensional
      imaging modalities such as computed tomography (CT) or magnetic resonance imaging
      (MRI), or invasive procedures such as percutaneous transhepatic portography. Here
      we present the first documented case of an extra-hepatic portal vein aneurysm
      evaluated by 3-dimensional CT angiography. This easily performed and accurate
      imaging technique may obviate the need for invasive angiographic procedures in
      the future for the 3-dimensional characterization of deep vascular malformations
      in the portal circulation.

PMID- 10576384
TI  - The role of MIB-1 index in the prognosis of resectable pancreatic head cancer.
AB  - BACKGROUND/AIMS: Cell kinetics are important indicators of the biological
      behavior of various human tumors. In this study, we evaluated the prognostic
      values of the proliferative factors including MIB-1 index, DNA ploidy and S-phase
      fraction, and further determined the independent prognostic factors in pancreatic
      head cancer after pancreatoduodenectomy. METHODOLOGY: Patients with pancreatic
      head cancer undergoing pancreatoduodenectomy were included. Cell proliferative
      parameters including MIB-1 index, DNA ploidy and S-phase fraction measured by
      flow cytometry were evaluated and compared with the conventional
      clinicopathologic factors. RESULTS: There were 21 resectable pancreatic head
      cancers. By univariate analysis MIB-1 index, cell differentiation and
      lymphovascular invasion were significant prognostic factors. The 5-year survival
      rate was 22.2% for overall patients and 29.2% for patients with MIB-1 < or = 11%,
      while it was 0% for MIB-1 index > 11%, p=0.011. Tumors without lymphovascular
      invasion had significantly better prognosis than those with lymphovascular
      invasion (median survival: 38 vs. 10 months, p=0.009). The median survival was
      significantly longer for well-differentiated cancers than for moderately and
      poorly differentiated cancers (44 vs. 11 and 9 months, p=0.038). There was no
      correlation between the MIB-1 index and the other 2 conventional prognostic
      factors. After multivariate analysis, only the MIB-1 index emerged as the
      independent prognostic factor. CONCLUSIONS: MIB-1 index played a significant role
      in the prognosis of the resectable pancreatic head cancer and could potentially
      complement the conventional factors in predicting the prognosis and determining
      the optimal treatment strategy. MIB-1 index was also an important independent
      prognostic factor.

PMID- 10576385
TI  - Peritoneal washings cytology combined with immunocytochemical staining in
      pancreatic cancer.
AB  - BACKGROUND/AIMS: Peritoneal washings from patients with pancreatic cancer
      demonstrate malignant cells in 0-58% of patients. But the significance of their
      potential for implantation and growth after radical surgery has not been
      clarified. METHODOLOGY: Peritoneal washings were collected from 74 consecutive
      pancreatic cancer patients during a 5-year period and studied by conventional
      staining and immunocytochemical staining using anti-CEA and anti-CA 19-9. Fifty
      of the 74 patients were resectable and the others were nonresectable. RESULTS:
      Seven out of 8 patients with macroscopic peritoneal metastasis were positive in
      conventional staining, but all 8 patients were positive in immunocytochemical
      staining. Five of the 66 (8%) patients without macroscopic peritoneal metastasis
      were positive in conventional staining, but the positive rate increased to 14 of
      66 (22%) in immunocytochemical staining. There was no statistically significant
      difference in post-operative cumulative survival rate between the 13 positive
      cytology patients and 37 negative cytology patients without macroscopic
      peritoneal metastasis. CONCLUSIONS: The positive rate of peritoneal washings
      cytology was increased in this study by the use of immunocytochemical staining in
      addition to conventional staining. No statistically significant difference in
      post-operative cumulative survival rate between positive cytology patients and
      negative cytology patients without macroscopic peritoneal metastasis was
      observed.

PMID- 10576386
TI  - Solid papillary-cystic tumor of the pancreas.
AB  - BACKGROUND/AIMS: Clinical diagnosis and histopathological findings of a solid
      papillary-cystic tumor (SCT) of the pancreas may be unrecognized due to difficult
      differentiation between exocrine and endocrine pancreatic neoplasms, such as
      acinar cell carcinoma. Surgeons should be aware of this benign but rather
      uncommon lesion because complete excision is possible and successful.
      METHODOLOGY: The clinical course, surgical treatment and morphological findings
      of 3 patients with SCT are analyzed. The cases comprised 2 females and 1 male
      ranging in age from 49-72 years. The tumors were identified by histopathologic
      examination including immunostaining. RESULTS: The tumors, which were localized
      in the head, body and tail of the pancreas expressed a distinct immunostaining
      such as focal alpha1-antitrypsin in cases 1 and 2, and diffuse vimentin in all 3
      cases. Keratin reactivity appeared positive in case 2 and 3, and neuroendocrine
      markers in case 2. The diversity of immunostaining emphasizes the tumor cell
      phenotype expressing epithelial, mesenchymal, and endocrine lines. After
      pancreatic resection 2 patients recovered successfully and 1 died. No lymph node
      or distal metastases were found at autopsy. CONCLUSIONS: Considering the
      favorable prognosis, the pancreatic SCT should be recognized by clinicians and
      pathologists, and surgically removed.

PMID- 10576387
TI  - Clinicopathological features in misdiagnosed pancreatic carcinoma.
AB  - BACKGROUND/AIMS: There is more potential for misclassification of adenocarcinoma
      of the pancreas than for many other cancers because of the difficulty of accurate
      diagnosis. METHODOLOGY: We analyzed the clinicopathological features of 105
      patients who were suspected of having unresectable adenocarcinoma of the pancreas
      on their 1st visit to our outpatient clinic. RESULTS: Ten of 105 patients (10%)
      had been misdiagnosed as having pancreatic carcinoma. The final diagnoses were
      made mainly using dynamic computed tomography (CT) and/or histologic examination.
      The incidence of weight loss (> or = 7% of total-body weight, within 6 months
      before diagnosis) in the misdiagnosed patients was significantly lower than that
      in pancreatic carcinoma patients (30% vs. 67%, p=0.02). Serum CA19-9 abnormality
      (> 100 U/ml) was observed less frequently in the misdiagnosed patients than in
      the patients with pancreatic carcinoma (40% vs. 77%, p=0.01). The detection of a
      dilated main pancreatic duct and/or pancreatic mass by imaging modalities was
      less frequent in the misdiagnosed patients (p<0.01). CONCLUSIONS: Dynamic CT
      and/or histologic examination may be essential when making a definite diagnosis
      of advanced pancreatic carcinoma. In addition, weight loss, serum CA19-9
      abnormality, detection of a dilated main pancreatic duct and/or pancreatic mass
      may also be useful in making a differential diagnosis of this disease.

PMID- 10576388
TI  - Severe acute pancreatitis associated with hyperlipidemia: report of two cases and
      review of the literature in Japan.
AB  - Two cases of severe acute pancreatitis associated with type V
      hyperlipoproteinemia are reported. A 39-year-old obese woman was hospitalized
      with continuous severe abdominal pain. The diagnosis was made on the day of
      admission to our hospital, and treatment using continuous regional arterial
      infusion of a protease inhibitor and an antibiotic was performed with good
      results. The other patient was a 35 year-old woman in the 35th week of pregnancy,
      and a diagnosis of gestational hyperlipidemic pancreatitis was made on the day of
      onset. She was treated supportively using intravenous hyperalimentation, protease
      inhibitors, and antibiotics. She recovered from the acute pancreatitis and
      delivered a healthy term infant. It is difficult to diagnose acute pancreatitis
      in patients with type V hyperlipoproteinemia, because even when serum amylase
      levels are high, the value is reduced by high serum triglycerides. Early
      diagnosis was achieved in both of the present cases, and early intensive therapy
      was performed, which may be of the utmost importance in saving the life of a
      patient.

PMID- 10576389
TI  - Successful transcatheter embolization of a pancreaticoduodenal artery aneurysm in
      association with celiac axis occlusion: a case report.
AB  - We report a case of a pancreaticoduodenal artery (PDA) aneurysm in association
      with celiac axis occlusion. A 54 year-old female complaining of abrupt onset of
      abdominal pain was admitted to our hospital. On admission, abdominal CT
      examination revealed a hematoma in the retroperitoneal space. Selective superior
      mesenteric artery (SMA) angiography disclosed an aneurysm in the anterior
      inferior pancreaticoduodenal artery (AIPDA). The celiac axis was occluded and
      blood was flowing to the liver and spleen via the enlarged pancreaticoduodenal
      arcade from the SMA. Transcatheter embolization of the aneurysm was performed
      successfully. Up to 1996, there have been 37 reported cases of PDA aneurysm in
      association with celiac axis stenosis or occlusion, including this one.
      Transcatheter embolization was performed successfully in only 5 of these cases.
      The formation of this type of PDA aneurysm is thought to be a result of the
      increased blood flow in the pancreaticoduodenal arcade due to celiac axis
      stenosis or occlusion. The transcatheter embolization performed in our report
      produced a far greater blood flow, which may lead to further aneurysmal
      formation. Careful follow-up is therefore necessary.

PMID- 10576391
TI  - The role of nitric oxide (NO) in the human pyloric sphincter.
AB  - BACKGROUND/AIMS: Nitric oxide (NO) has recently been shown to be a
      neurotransmitter in non-adrenergic non-cholinergic (NANC) inhibitory nerves in
      the gastrointestinal tract. To clarify the role of NO in the human pyloric
      sphincter, enteric nerve responses in pyloric tissue specimens obtained from
      patients with gastric cancer were investigated. METHODOLOGY: Fresh specimens of
      normal pylorus obtained from 18 patients with gastric cancer were used. The
      subjects consisted of 12 men and 6 women, aged from 45-74 years (average: 60.1
      years). A mechanograph was used to evaluate in vitro pyloric sphincter muscle
      responses to electrical field stimulation (EFS) of adrenergic and cholinergic
      nerves before and after treatment with various autonomic nerve blockers, and N(G)
      nitro-L-arginine (L-NNA) and L-arginine. RESULTS: Cholinergic nerves were mainly
      involved in the regulation of enteric nerve responses to EFS in the basal
      condition of the study, and NANC inhibitory nerves acted on human pylorus. L-NNA
      concentration dependently inhibited the relaxation in response to EFS in the
      human pylorus, and this inhibitory effect in the pylorus was reversed by L
      arginine. CONCLUSIONS: These findings suggest that the cholinergic/adrenergic and
      NANC inhibitory nerves play important roles in regulating contraction and
      relaxation of the human pylorus, and that NO plays an important role as a
      neurotransmitter in NANC inhibitory nerves of the human pylorus.

PMID- 10576390
TI  - Long-term effects of distal splenorenal shunt with splenopancreatic and gastric
      disconnection on hypersplenism due to liver cirrhosis.
AB  - BACKGROUND/AIMS: Though the distal splenorenal shunt has been applied for
      gastroesophageal varices caused by liver cirrhosis, many patients develop
      secondary hypersplenism due to the portal hypertension following liver cirrhosis.
      We examined whether this operation could be effective for alleviating secondary
      hypersplenism for a long post-operative period. The subjects were 42 cases with
      gastroesophageal varices following liver cirrhosis in which we had performed
      distal splenorenal shunts with splenopancreatic and gastric disconnection at our
      institution in the period from 1983 1994 and the post-operative survival periods
      had been over 3 years. METHODOLOGY: White blood cell counts, platelet counts and
      spleen volume were measured prior to operation, 1 month after operation and
      during the post-operative period of 3-5 years. Quality of life and clinical
      symptoms were evaluated during the post-operative period of 3-5 years. RESULTS:
      White blood cell counts, platelet counts and spleen volume were improved
      respectively at 1 month and during the 3-5-year period after surgery, compared to
      those prior to operation. None of the clinical symptoms of hypersplenism were
      observed and the long-term performance status was satisfactory. CONCLUSIONS: We
      can conclude that the distal splenorenal shunt with splenopancreatic and gastric
      disconnection alleviated hypersplenism for post-operatively long periods.

PMID- 10576392
TI  - The management of bleeding peptic ulcer in the elderly with heater probe
      thermocoagulation.
AB  - BACKGROUND/AIMS: The aim of this study was to compare the clinical
      characteristics of bleeding peptic ulcers in the elderly with those in younger
      patients, retrospectively. METHODOLOGY: Between 1986 and 1994, 274 patients with
      bleeding peptic ulcers were treated with heater probe endoscopically. They were
      divided into 2 groups: 48 in the elder group (70 years of age or older) and 226
      in the younger group (<70). We evaluated the rate of concomitant disease,
      rebleeding rate, incidence of emergency surgery, mortality and blood transfusion
      requirement between the 2 groups. RESULTS: The incidence of concomitant disease
      was significantly higher in the elderly group (83.3%) than in the younger group
      (33.3%) (p<0.01). The rate of rebleeding (younger group 23.5% vs. elderly group
      31.3%), the incidence of emergency surgery (5.8% vs. 6.3%, respectively) and the
      rate of mortality due to hemorrhage (2.2% vs. 4.2%, respectively) were similar in
      the 2 groups. There was no significant difference in the mean volume of blood
      transfused. CONCLUSIONS: It was revealed that aggressive endoscopic hemostasis
      improved the mortality rate and the incidence of emergency surgery in elderly
      patients as well as in younger patients, provided that their general condition
      was monitored carefully.

PMID- 10576394
TI  - Primary squamous cell carcinoma of the stomach: a case report with a review of
      Japanese and Western literature.
AB  - A case of a 75 year-old male with primary squamous cell carcinoma of the stomach
      is reported. It is extremely rare to see squamous cell carcinoma developing in
      the stomach, without being accompanied by a component of adenocarcinoma. Up to
      the present, 18 Japanese and 62 Western cases of this type of carcinoma have been
      reported in the literature. The origin of this malignancy has not been well
      elucidated yet and thus, several plausible hypotheses have been proposed. In this
      presented case, the tumor consisted of only squamous cell carcinoma and the focus
      of squamous metaplasia was not found histologically in the adjacent mucosa.
      Therefore, it may be considered that the carcinoma arises from misplaced squamous
      cell nests of the stomach.

PMID- 10576393
TI  - Synchronous gastric cancer associated with hepatocellular carcinoma: a study of
      10 patients.
AB  - BACKGROUND/AIMS: Little information regarding synchronous gastric cancer (GC)
      associated with hepatocellular carcinoma (HCC) is available. The aim of this
      study was to clarify the clinicopathologic features of synchronous GC associated
      with HCC, and we also discuss the diagnostic and therapeutic issues regarding
      them. METHODOLOGY: In a series of 396 patients with GC and 340 patients with HCC,
      we investigated the clinicopathologic features of the patients with synchronous
      GC associated with HCC (HCC group; n=10). They were compared to the patients with
      resected GC without HCC (non-HCC group) which was divided into 2 groups: with
      chronic hepatic disease (CHD: CHD group; n=15) and without CHD (Control group;
      n=345). RESULTS: The HCC group consisted of 10 of the 396 patients with GC
      (2.6%), and of 340 with HCC (2.9%). Eight node-negative early GC and 2 advanced
      GC cases were observed in the HCC group. Nine of these GC (90%) were well
      differentiated adenocarcinoma. The tumor sizes of the HCC group were
      significantly smaller than those of the control group (p<0.05). The incidences of
      intestinal type and early GC in the HCC group were significantly higher than
      those in the control group, (p<0.05). However, there were no significant
      differences in any parameters between the HCC group and CHD group. With regard to
      early GC, there were no significant differences in any parameters, excluding the
      site of GC in the CHD group, between the HCC group and non-HCC group. Eight in
      the HCC group were surgically resected, and the post-operative period of these
      patients was uneventful. Although there were no significant differences in
      survival after surgery among the 3 groups, the survival of the patients with
      early GC in the HCC group was significantly worse than that in the control group
      (p<0.01). CONCLUSIONS: The clinicopathologic features of synchronous GC
      associated with HCC are not very aggressive in most patients probably because of
      the early detection, and those of early GC with HCC appeared to resemble that of
      GC with CHD. Since early GC may not influence the clinical outcome of HCC
      patients, limited gastric resection can be recommended even when curative surgery
      for HCC is performed. By contrast, when advanced GC is present, curative
      gastrectomy with lymphadenectomy would be advisable to improve the long-term
      survival.

PMID- 10576395
TI  - On the validity of interblock averaging of P300 in clinical settings.
AB  - The reduction of long-latency auditory ERPs amplitude, including P300, to
      repeated stimuli has been well documented in the literature on habituation. The
      effect of block repetition on auditory ERPs recorded for clinical purposes, where
      interblock intervals are commonly longer than those employed in habituation
      studies, was studied in a sample of 38 adults submitted to two blocks of a
      counting oddball paradigm. Four different experimental conditions were
      considered, differing in target probability, delivery or not of a previous
      passive oddball tone sequence, and the performance or not of other oddball tasks
      requiring more complex discriminative responses between the two blocks. Results
      showed that: (1) N1 amplitude to the frequent non-target stimuli decreased in the
      second block under all the conditions; (2) when the two blocks were consecutive
      (separated by 2-3 min), P300 amplitudes were unaffected by block repetition, this
      whatever the probability of the target (25% vs. 10%) and whether or not a passive
      oddball sequence preceded the two active blocks; (3) P300 amplitude was only
      affected by stimulus repetition in those subjects who performed more complex
      cognitive tasks between the first and second blocks and; (4) latency values were
      unaffected by repetition. It is hypothesised that the N1 amplitude decline may be
      caused by a decrease in alertness or arousal level produced by stimuli
      repetition. Reduction in P3 amplitude only appeared when more difficult tasks had
      to be done between the two oddball blocks and may reflect a decrease in the
      amount of attentional resources allocated to the second block, due either to
      fatigue or over training. The practice of using a grand average of several
      repetitions of the oddball paradigm, as recommended for the clinical use of long
      latency ERPs, seems to be adequate provided that long interblock intervals are
      used and that the subject is not engaged in tasks requiring a high mental
      workload between the trial blocks.

PMID- 10576396
TI  - Sex differences in EEG coherence during a verbal memory task in normal adults.
AB  - Coherence analysis was applied to the EEG of 15 female and 15 male subjects who
      had to memorise dichotically presented lists of concrete nouns. The EEG was
      recorded from 16 scalp electrodes placed in accordance with the 10/20 system. The
      results show significant gender-related differences in total coherence reactivity
      due to a greater increase of rest to task coherence in female than in male
      subjects. Women differed by showing higher coherence reactivity in the right
      hemisphere for all analysed (theta 1, theta 2, alpha 1, and alpha 2) frequency
      bands. They also had more extensive task-induced increases of interhemispheric
      coherence in theta bands in comparison with single changes in male subjects. In
      women these changes were mainly between the frontal electrodes of the left
      hemisphere paired with posterior electrodes of the other hemisphere. These
      findings indicate sex-related differences in functional cortical organisation
      during verbal memory tasks.

PMID- 10576397
TI  - Simultaneous EEG and EDA measures in adolescent attention deficit hyperactivity
      disorder.
AB  - Adolescent unmedicated ADHD males and age- and sex-matched normal control
      subjects were examined simultaneously using EEG and EDA measures in a resting
      eyes-open condition. ADHD adolescents showed increased absolute and relative
      Theta and Alpha1 activity, reduced relative Beta activity, reduced skin
      conductance level (SCL) and a reduced number of non-specific skin conductance
      responses (NS.SCRs) compared with the control subjects. Our findings indicate the
      continuation of increased slow wave activity in ADHD adolescents and the presence
      of a state of autonomic hypoarousal in this clinical group.

PMID- 10576398
TI  - Classical conditioning of the human blood pressure response.
AB  - The object of this experiment was to demonstrate that blood pressure responses
      could be classically conditioned in human subjects and to describe the topography
      of the conditioned response. Despite clear evidence for classical blood pressure
      conditioning in animals there is little evidence concerning a clear demonstration
      of the phenomenon in human subjects, and no description of the form of the
      conditioned response. A 'neutral' 8-s 70-db tone (CS) was paired with a 500-ms
      electric shock (UCS) in a delay conditioning paradigm. Conditioned subjects were
      compared to a control group that received the CS and UCS on a truly random
      schedule. The subjects in the conditioning group showed a conditioned blood
      pressure response that emerged during the last 4 s of the 8-s CS. The results
      differ from those obtained from animals, where the CR typically emerges during
      the first half of the CS. These data may have implications for the role of
      learning in hypertensive disorders.

PMID- 10576399
TI  - Hemodynamic profile of stress-induced anticipation and recovery.
AB  - Systolic and diastolic blood pressure, heart rate, stroke volume, cardiac output,
      and total peripheral resistance were measured in 100 healthy men and women with
      the aim of investigating hemodynamic profile during anticipation of, and recovery
      from, exposure to active and passive laboratory stressors. A 5-min anticipatory
      period preceded two tasks, both of which lasted 2.5 min. The tasks were mental
      arithmetic ('beta-adrenergic' stress) and the cold pressor test ('alpha
      adrenergic' stress). Each task was followed by a 5-min recovery period. Blood
      pressure and heart rate were measured with a FinaPres 2300e, and stroke volume,
      cardiac output, and total peripheral resistance were computed from these
      parameters. Salivary cortisol was measured in relation to both tasks, and
      participants completed tests of state and trait anxiety, locus of control, and
      hostility. As expected, mental arithmetic and the cold pressor test elicited
      myocardial and vascular patterns of reactivity, respectively. However, contrary
      to expectations, anticipatory and recovery hemodynamic profile involved
      essentially vascular responding for both stressors. Salivary cortisol increased
      in response to both tasks but only weakly correlated with hemodynamic changes.
      None of the subjective measurements was a strong predictor of physiological
      reactivity. The findings suggest that stress-induced anticipatory and recovery
      reactivity may be generally vascular rather than myocardial. This could have
      important implications in light of suggestions that anticipatory and recovery
      responses may be better predictors of subsequent cardiovascular disease than
      direct stress-induced reactivity.

PMID- 10576400
TI  - Increased emergence of alpha activity over the left but not the right temporal
      lobe within a dark acoustic chamber: differential response of the left but not
      the right hemisphere to transcerebral magnetic fields.
AB  - The percentages of alpha activity per minute over the left and right temporal
      lobes were measured for the first and second successive 15-min intervals while
      subjects wore opaque goggles within an acoustic chamber. A weak (5 microT), burst
      firing magnetic field was presented during this period for 1 s every 4 s
      primarily over the left or the right cerebral hemisphere. The results indicated
      that the left temporal lobe became less vigilant between the first and second 15
      min while the right temporal lobe did not. When standardized scores for each
      subject's measures over time and across hemispheres were employed, increased
      alpha time over the left temporal lobe relative to the right temporal lobe was
      observed only when the transcerebral magnetic field was applied over the left
      hemisphere. Stimulation of the right hemisphere did not evoke this discrepancy.
      The detection of the effects of this specific complex magnetic field upon
      electroencephalographic activity may be more probable when the subjects are
      exposed to partial sensory deprivation.

PMID- 10576401
TI  - Comparison of P300 from passive and active tasks for auditory and visual stimuli.
AB  - The P300 event-related brain potential (ERP) was elicited with a stimulus
      sequence paradigm for auditory and visual stimuli in separate active and passive
      task response conditions. Auditory stimuli in the passive task yielded P300
      waveforms similar to those obtained from the active task condition. Visual
      stimuli in the passive task yielded much smaller P300 waveforms that were not
      morphologically consistent with those from the active task. The results suggest
      that auditory stimuli produce more robust P300 components than visual stimuli in
      passive task situations.

PMID- 10576402
TI  - The attractiveness of the concept of a prospectively designed two-stage clinical
      trial.

PMID- 10576403
TI  - Clinical equivalence.
AB  - When the classical approach of testing the null hypothesis of equality is used
      and the results are not statistically significant, formal conclusions regarding
      the "closeness" of the treatments cannot be drawn. When the purpose of the
      investigation is to exhibit "closeness," misinterpretations may result in
      inappropriate, or even incorrect, conclusions. Here methodology for use when the
      goal is to exhibit the equivalence (noninferiority) of the treatments is
      discussed. The techniques allow direct conclusions to be drawn regarding the
      equivalence of the treatments. A review is presented.

PMID- 10576404
TI  - Resampling and multiplicity in cost-effectiveness inference.
AB  - We compare published methods for placing statistical confidence limits around
      incremental cost-effectiveness ratio statistics and show that only a
      nonparametric, bootstrap approach using polar angles gives completely reasonable
      results when neither treatment has significant advantages in cost or
      effectiveness. We also discuss alternative ways to report analytical results
      using plots, confidence or tolerance limits, and quadrant acceptability
      fractions. Finally, we use simulation to study the multiplicity bias that can be
      introduced into ICER confidence limits when only the most favorable results are
      reported over several possible choices of numerator cost measure and denominator
      effectiveness measure.

PMID- 10576405
TI  - A novel Bayesian decision procedure for early-phase dose-finding studies.
AB  - Phase I first-in-man studies in normal, healthy volunteers are performed to
      define a maximum safe dose and to identify a range of acceptable doses for later
      drug development studies in patients. Analysis of pharmacokinetic and
      pharmacodynamic data using mixed-effects modeling can be used to fit an overall
      dose-response relationship. By expressing prior information as pseudodata, the
      same methodology can be used to perform a Bayesian analysis and to determine
      posterior modal estimates for the model parameters. Decision theory can then be
      applied to maximize a chosen gain function, utilizing real-time data capture for
      choosing safe doses in a way that will provide more informative responses, thus
      accelerating study completion. The methodology is introduced elsewhere (1). The
      purpose of this paper is to describe software currently in development and to
      illustrate the method using an example from a recent study.

PMID- 10576406
TI  - Statistical methods for monitoring clinical trials.
AB  - Clinical trials are monitored to determine whether a treatment is safe and
      effective. If it becomes clear that treatment is superior to control, ethical
      considerations compel us to stop the study and make the treatment available to
      control patients. On the other hand, if it becomes clear that the treatment will
      not be shown superior to control, we would like to stop the study and save
      valuable resources for more promising agents. But how much evidence is enough to
      declare benefit, and what criteria do we use to stop for lack of benefit? This
      article reviews monitoring procedures designed to answer these two questions. The
      B-value approach of Lan and Wittes (1) and Lan and Zucker (2) is used to unify
      the monitoring of many different kinds of trials, including those with
      continuous, dichotomous, or survival outcomes.

PMID- 10576408
TI  - Approximate sample sizes for testing hypotheses about the ratio and difference of
      two means.
AB  - This article deals with a unifying approach to approximate sample size
      determination for different types of hypotheses formulated in terms of two means
      of normally distributed data. A simple approximation is given to the sample size
      required for testing hypotheses about the ratio of the means. The formula
      includes the situations of testing noninferiority, superiority, or equivalence.
      We present a more general formula that also covers hypotheses formulated in terms
      of the difference of means. We show that over a wide range of parameter values
      the approximation provides reliable sample sizes.

PMID- 10576407
TI  - Cross-study hierarchical modeling of stratified clinical trial data.
AB  - Hierarchical random-effects models can be used to estimate treatment or other
      covariate effects in single-study analyses coordinated over multiple clinical
      units and can also be extended to a wide variety of cross-study applications.
      After reviewing the single-study case, we use data from five trial protocols to
      look for units that tend to have treatment effects consistently above or below
      the study-specific grand mean across several studies. As a first step, we
      summarize the patient-level data as study-specific and unit-specific estimated
      treatment effects and standard errors using independent Cox regression models. We
      then compare the results of a hierarchical model using these data summaries as
      input to those produced by a more fully Bayesian method that uses the actual
      patient-level survival data. We also compare various different models using a
      deviance information criterion, a recent extension of the Akaike information
      criterion designed for hierarchical models. Our procedure appears to be effective
      at answering the question whether certain clinical units of the Terry Beirn
      Community Programs for Clinical Research on AIDS are better than others at
      identifying treatment effects where they exist.

PMID- 10576409
TI  - Establishing equivalence by showing that a specified percentage of the effect of
      the active control over placebo is maintained.
AB  - We propose a procedure for establishing equivalence that determines whether a
      specified percentage of the treatment effect of a known active agent over placebo
      is maintained. This procedure accounts for the error in the estimates from the
      historical studies of the known active agent and placebo as well as the error in
      the estimates from the equivalence study of the new test treatment versus the
      active control. After the procedure is presented, it is compared analytically to
      a procedure in which the equivalence boundary is estimated from historical data
      and then used with a one-sided test. We address sample size requirements for the
      proposed equivalence procedure. We also illustrate the use of the proposed
      procedure with an example from the clinical area of thrombolytic therapy in acute
      myocardial infarction.

PMID- 10576410
TI  - Linear structural equation model in analyzing quality-of-life-data from clinical
      trials.
AB  - Assessment of quality of life (QOL) in clinical trials becomes a challenging task
      from the viewpoint of clinical biostatistics. The responses of the items for
      measuring QOL indices usually vary widely from patient to patient and from time
      to time. Measurement errors might be present in the responses of the items, and
      they might be correlated. Hence, in analyzing QOL data, the usual assumption that
      there are no measurement errors in responses is too liberal. Because the QOL
      indices are likely to be correlated, separate analysis of each index might not be
      efficient from the point of view of statistical methodology. We apply linear
      structural equation modeling (LISREL) in assessing the QOL data obtained from a
      clinical trial. A basic premise of the LISREL approach is that the abstract
      concepts (latent constructs) that are not directly measurable can be studied.
      LISREL is a statistical procedure for conceiving and testing structural
      hypotheses that cannot be tested adequately with other statistical procedures. It
      allows us to specify relations between unobserved and observed variables while
      controlling for measurement errors and correlations among both the measurement
      errors and the latent constructs.

PMID- 10576411
TI  - A simple way to estimate the median time and compare survival distributions in
      analgesic trials under informative censoring.
AB  - We discuss the problem of estimating the median time and comparison of survival
      curves when data are nonrandomly censored in analgesic trials. In these trials
      patients experience post-surgical pain at the time of randomization. Time to
      onset of analgesia is measured by patient-administered stopwatches. An effective
      analgesic is one for which the median time to onset is "short." The study design
      allows patients to remedicate if their pain persists, and this remedication prior
      to pain relief censors the time-to-onset measures. The time to onset for patients
      who remedicate is nonrandomly censored. Assuming noninformative censoring yields
      misleading results with the Kaplan-Meier method (for estimation of median time)
      and the log-rank test (for comparison of survival curves). This assumption can
      also obscure the superior effect of an effective analgesic over an ineffective
      one. We propose a simple and intuitive way to handle the nonrandomly censored
      data in analgesic trials in order to (a) estimate the median time to pain relief
      and (b) compare the survival distributions between treatments. The method
      proposed is applied to data collected from an acute pain clinical trial, and the
      results are discussed.

PMID- 10576412
TI  - Kinetics of doxorubicin handling in the LLC-PK1 kidney epithelial cell line is
      mediated by both vesicle formation and P-glycoprotein drug transport.
AB  - The subcellular distribution of doxorubicin was evaluated in living non-fixed LLC
      PK1 cells, which maintain the structural and functional characteristics of the
      kidney proximal tubule epithelium and also express P-glycoprotein. After 10 min
      incubation, doxorubicin fluorescence was detectable in the nucleus. The intensity
      of nuclear fluorescence progressively increased, reaching the maximum at the end
      of the first hour. Then, the nuclear signal started to decrease and, at 2 h,
      doxorubicin fluorescence disappeared almost completely from the cell nucleus.
      Cytoplasmic fluorescent vesicles first appeared in the perinuclear region after
      10 min doxorubicin exposure and increased in number and size over a period of 2
      h. From 2 to 5 h, fluorescent vesicles moved unidirectionally to the cell
      periphery. Disappearance of doxorubicin punctate fluorescence in LLC-PK1 cells
      treated with methylamine or monensin demonstrated that drug accumulation occurred
      inside acidic compartments. In addition, the cytoplasmic pattern of doxorubicin
      fluorescence was very similar to that observed upon exposure to the acidotropic
      tracer LysoSensor Blue. Involvement of P-glycoprotein in doxorubicin handling by
      LLC-PK1 cells was suggested by modified intracellular doxorubicin distribution
      after cell incubation with verapamil and vinblastine. Moreover, the fluorescent P
      glycoprotein substrate Bodipy FL Verapamil was shown to accumulate in LLC-PK1
      cells in a manner that is quite similar to that observed for doxorubicin. P
      glycoprotein expression was evaluated by immunoblot using the JSB-1 and C219
      monoclonal antibodies. Immunofluorescence analysis was performed using the JSB-1
      monoclonal antibody. P-glycoprotein immuno-reactivity was found both on the
      plasma membrane and intracytoplasmically in a perinuclear position. Reverse
      transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that MDR1 gene
      was expressed. This study indicates that a rapid intracellular redistribution
      accompanies the process of doxorubicin uptake by LLC-PK1 cells. Although these
      cells are non-tumour cells derived from the normal epithelium of the proximal
      renal tubule, they display a model of doxorubicin redistribution which is
      characteristic of doxorubicin-resistant tumour cells.

PMID- 10576413
TI  - Immunohistochemical detection of microsomal epoxide hydrolase in human synovial
      tissue.
AB  - Microsomal epoxide hydrolase catalyses the hydrolysis of epoxides to water
      soluble trans-dihydrodiols. We studied the expression of the hydrolase in
      synovial tissue samples from patients with osteoarthritis (n = 20), rheumatoid
      arthritis (n = 36), ankylosing spondylitis (n = 10) or psoriatic arthritis (n =
      15) by use of immunohistochemistry with videodensitometric quantification of
      staining. Strong immunostaining for microsomal epoxide hydrolase was detected in
      tunica media of synovial blood vessels and moderate staining in synovial lining
      cells. Experiments with antibodies against CD68 and CLA suggested that both type
      A (macrophage-like) and type B lining cells (fibroblast-like synoviocytes)
      express the hydrolase. In addition, some of the subsynovial fibroblast-like
      cells, histiocytes and monocytes were intensively stained for microsomal epoxide
      hydrolase. In general, there were no major differences in the intensity of
      immunostaining for the hydrolase between the diagnostic groups. The enzyme may be
      involved in local hydrolysis of epoxide metabolites of endo- and xenobiotics in
      synovial tissue.

PMID- 10576414
TI  - Immunohistochemical and ultrastructural evidence for myelopoiesis in the
      scid/scid mouse thymus.
AB  - The ultrastructure of scid mouse thymus (a small encapsulated epithelial mass
      within the precardial fat pad) is described. The epithelium did not form cortex
      or medulla and hence remained relatively undifferentiated. Small unmyelinated
      nerves innervated the capsule, the major blood vessels and were distributed
      between the epithelial cells. Fenestrated blood vessels were common. Thymocytes
      were not identified but numerous granulocytes, mast cells and some fibroblasts,
      macrophages and interdigitating cells were present. All stages of granulopoiesis
      were observed in scid thymus. A very small number of immunoreactive ER-MP58 cells
      indicated bone marrow derived myeloid precursor cells, and low numbers of ER
      MP12+ and ER-MP20+ mononuclear cells indicated stages of myeloid cells committed
      to the granulocyte/macrophage lineage. Cells containing proliferating nuclear
      cell antigen (cells in G1, S and G2-M stage) were present throughout the thymic
      mass. BALB/c thymuses contained cortical foci of p53+ cells whereas in scid mice,
      p53 positive cells were scattered singly throughout the thymus. This study
      indicates that the presence of moderately extensive myelopoiesis within the scid
      mouse thymus has potential for the study of extramedullary haematopoiesis, and
      also that it is important to bear this function in mind when using the scid mouse
      as an immunological model for thymus reconstitution and for creating 'organoid'
      cultures.

PMID- 10576415
TI  - Prolactin secretory bypath exposed in cultured lactotrophs.
AB  - In the present report, the prolactin secretory pathways were re-examined in
      cultured lactotrophs submitted to various experimental conditions of stimulation,
      inhibition and/or alteration of the intracellular flow of the synthesis and
      release of prolactin. Primary cultures of rat pituitary cells stimulated with
      thyrotropin-releasing hormone, or inhibited with either cycloheximide or dopamine
      in the presence or absence of 0.1 microg/ml brefeldin A, were used. The
      radioimmunoassay quantification of released and intracellular prolactin was
      correlated with ultrastructural and immunocytochemical studies. Brefeldin A
      diminished significantly the secretion and the intracellular content of prolactin
      4 h after application, while morphological effects were seen starting from 30
      min. The drug did not modify the response to thyrotropin-releasing hormone (120%
      increment). The simultaneous incubation of brefeldin A with cycloheximide or
      dopamine diminished the released prolactin concomitant with a lower
      (cycloheximide) or greater (dopamine) hormonal intracellular prolactin content
      with respect to brefeldin A. The combined treatment cycloheximide-dopamine
      inhibited prolactin secretion. The ultrastructural and immunocytochemical
      features of lactotrophs supported these radioimmunoassay data. These results
      revealed that prolactin release in vitro in the presence or not of brefeldin A is
      dependent on either: the neosynthesized hormone that can be inhibited by
      cycloheximide, and the hormone stored in granules, the exocytosis of which was
      blocked by dopamine, indicates the contribution of both constitutive and
      regulated pathways in the secretory process. The brefeldin A blockade of the
      intracellular transport also disclosed morphological evidence of an alternative
      pathway of prolactin secretion through vesicles originated in the rough
      endoplasmic reticulum bypassing the Golgi complex.

PMID- 10576416
TI  - Effects of estradiol and calcium on gonadotrophic cells in middle-aged female
      rats.
AB  - The effects of multiple treatment with estradiol dipropionate (EDP) or calcium
      glucoheptonate (Ca) or a combination of the two on gonadotrophic cells in the
      pituitary pars distalis of middle-aged female rats were examined. The animals
      were treated daily for two weeks with EDP (0.625 mg i.p./kg body weight) or Ca
      (11.4 mg/kg body weight) or EDP + Ca. Luteinising (LH) and follicle stimulating
      hormone (FSH)-producing cells were examined by immunohistochemistry using
      antisera to the specific (beta) beta-subunits of LH and FSH and a peroxidase-anti
      peroxidase immunohistochemical procedure. Plasma levels of FSH and LH were
      measured by radio-immune assay. A stereological method for determining
      morphometric parameters in immunopositive FSH and LH cells was used. The number
      of gonadotrophs per unit area (mm2), their cellular volume and relative volume
      densities, as well as plasma levels of FSH and LH, were decreased in all treated
      females in comparison with the controls. The most significant decrease of these
      parameters was observed in EDP-treated animals. Such changes were also expressed
      in Ca-treated animals, but the alterations were less distinct. These results
      demonstrate that multiple EDP or Ca application to middle-aged female rats is
      able to inhibit, directly or indirectly, the morphofunctional state of
      gonadotrophic cells in the pituitary pars distalis.

PMID- 10576417
TI  - Expression of TNF-alpha and immunohistochemical distribution of hepatic
      macrophage surface markers in carbon tetrachloride-induced chronic liver injury
      in rats.
AB  - In liver injury induced by carbon tetrachloride, secondary hepatic injury occurs
      from inflammatory processes originating from products released by activated
      Kupffer cells, which play a central role in hepatic inflammation. The purpose of
      our study was to demonstrate, in rats, the relationships between a function of
      the hepatic macrophages, TNF-alpha production and the state of activation of
      these cells, characterized by their phenotype, in the different phases of the
      process and development of fibrosis in a carbon tetrachloride-induced cirrhosis
      model. The immunohistochemical localization of proinflammatory cytokine TNF-alpha
      and surface surface makers (ED1 and ED2) was studied in hepatitis and cirrhosis
      in response to 3 and 9 weeks ingestion of carbon tetrachloride. After carbon
      tetrachloride ingestion, accompanying the increased necrosis, immunohistochemical
      analysis of liver tissue sections demonstrated the significantly increased number
      of cells expressing ED1, ED2 and TNF-alpha, compared to normal. The number of
      cells expressing the surface phenotypic markers of liver macrophages increased
      and this change was concomitantly associated with an increased cellular
      expression of TNF-alpha. Local macrophage proliferation and influx of newly
      recruited blood monocytes resulted in an increase of the macrophage population.
      The populational changes involved difference in functional activity and enhanced
      TNF-alpha expression. This cytokine expressed in the carbon tetrachloride-induced
      inflammatory process is associated with the development of fibrosis and may
      contribute to disease severity.

PMID- 10576418
TI  - Effects of transforming growth factor-beta1 on the gene expression of decorin,
      biglycan, and alkaline phosphatase in osteoblast precursor cells and more
      differentiated osteoblast cells.
AB  - In this study, the effects of incubating two clonal rat osteoblastic cell lines
      at different stages of differentiation, ROB-C26 (C26) and ROB-C20 (C20), with
      transforming growth factor-beta1 (TGF-beta1) on the gene expression of decorin,
      biglycan, and alkaline phosphatase were examined. C26 cells are a potential
      osteoblast precursor cell line that is also capable of differentiating into
      muscle cells and adipocytes and is differentiated into osteoblasts after
      treatment with bone morphogenetic protein-2. C20 cells are a more differentiated
      osteoblastic cell line. Our Northern blot studies demonstrated that after
      treatment with TGF-beta1 (0, 0.1, 1.0, 5.0, and 10 ng/ml), a dose- and time
      dependent decrease in decorin mRNA expression was found in C26 cells. In
      contrast, the effect of decorin mRNA with TGF-beta1 was not determined in C20
      cells, since decorin mRNA expression was extremely low in this cell line even in
      the absence or presence of TGF-beta1. Although TGF-beta1 treatment resulted in no
      appreciable effect on biglycan mRNA expression in both cell lines in a dose- and
      time-dependent manner, it decreased significantly the expression of alkaline
      phosphatase in both cell lines at the gene and protein level. Reverse
      transcriptase-polymerase chain reaction analysis revealed the gene expression of
      decorin, and TGF-beta type I and type II receptors in both cell lines. These
      results indicate that osteoblasts progenitor cells express both decorin and
      biglycan mRNAs. In contrast, more differentiated and mature osteoblastic cells
      express preferentially biglycan mRNA. TGF-beta1 exerts different effects on the
      expression of decorin and biglycan mRNAs, and is a potent inhibitor of the gene
      expression of alkaline phosphatase during osteoblast differentiation.

PMID- 10576419
TI  - Analysis of strain distribution in the medial collateral ligament using a
      photoelastic coating method.
AB  - The strain distribution over the entire medial collateral ligament (MCL) was
      measured using a photoelastic coating method. This new approach utilized a
      polyurethane monomer as a photoelastic coating film. The initial experiments
      investigating MCL strain measurement showed that this film had a high sensitivity
      for strain and good adhesion to the ligament. It was confirmed that strain
      distribution could be obtained qualitatively over the entire ligament using this
      method. The mechanism of MCL injury was studied by applying this polyurethane
      coating film to the entire MCL in a femur-MCL-tibia complex. When simple tension
      was applied to the complex, strain concentrations were centred at the tibial
      insertion site, and all the specimens ruptured at the MCL tibial insertion site.
      With application of a valgus bending moment, increased strain was seen in the MCL
      from the medial femoral condyle to the medial epicondyle. Histological analysis
      demonstrated midsubstance ligament ruptures in this same region. For both tests,
      rupture sites and increased strain concentration sites correlated. In addition,
      an impingement phenomenon of the MCL on the medial femoral condyle can be seen
      during application of valgus force, and this phenomenon may explain the higher
      incidence of MCL injuries on the femoral side seen in the clinical setting. This
      polyurethane coating method allows for direct and visual measurements, and can
      qualitatively measure the strain behaviour over the entire MCL surface. This new
      technique represents a significant improvement over previous point-by-point
      strain measurement methods.

PMID- 10576420
TI  - A new method of assessing the mechanical properties of patient support systems
      (PSS) using a phantom. A preliminary communication.
AB  - Pressure ulcers are a major problem worldwide believed to affect over 5% of all
      hospital in-patients, and countless others in the community at large. Many types
      of Patient Support Systems (PSS) are sold as pressure ulcer prevention equipment,
      but no consensus exists as to their mechanical efficacy. The use of human
      volunteers to assess the mechanical properties of PSS introduces non
      repeatability and variability in results which cannot give a statistically
      significant difference in performance between systems. Mechanical testing without
      human volunteers provides faster evaluations of PSS, with improved precision and
      repeatability. An instrumented articulated anthropometric phantom has been
      developed to investigate the distortion of simulated soft body "tissues" of the
      buttock and sacral areas due to precise and repeatable static loading on a PSS.
      The weight of the phantom can be adjusted to 50, 70 and 90 kg and can be applied
      with the torso inclined at 0 degrees, 45 degrees and 80 degrees. Validation of
      the phantom by measuring interface pressure using a force sensing array mat
      indicates that the phantom represents realistic physiological loading conditions.
      The new method of measuring the distortion of the "artificial tissues" provides a
      highly selective ranking of PSS.

PMID- 10576421
TI  - A hybrid approach to EMG pattern analysis for classification of arm movements
      using statistical and fuzzy techniques.
AB  - In this paper, a hybrid approach is presented for discriminating a few upper limb
      movements by processing the electromyographic (EMG) signals from selected
      shoulder muscles. Statistical techniques, such as the Generalized Likelihood
      Ratio test, the Principal Component Analysis, autoregressive parametric modeling
      techniques and cepstral analysis techniques, combined with a fuzzy logic based
      classifier (the Abe-Lan network) are used to construct low-dimensional feature
      spaces with high classification rates. The experimental results show the ability
      of the algorithm to correctly classify all the EMG patterns related to the
      selected planar arm pointing movements. Moreover, the structure presented offers
      promise for real-time applications because of the low computation costs of the
      overall algorithm.

PMID- 10576422
TI  - Classification of tetraplegics through automatic movement evaluation.
AB  - The general problem of classification of functional movements in humans with
      spinal cord injuries requires the following questions to be answered: what are
      the essential kinematic parameters that we have to observe during the movement?
      Is it possible to estimate preserved motor skills based on kinematics? Which
      computational method for identification is suited to geometric feature analysis?
      To answer these questions we have developed the methodology which has two phases:
      (1) recordings of a series of specified arm movements; and (2) custom made
      software for graphical presentation of arm movements and the design of wavelet
      and neural networks for movement classification. The proposed protocol is
      automated and both graphical presentation and neural networks allow easy
      interpretation of the instrumented assessment to accomplish automatic
      classification of arm movements in tetraplegics. The protocol was evaluated on 16
      spinal cord injury (SCI) patients and seven healthy control subjects for three
      different arm movements. The classification rate yielded results in the range 46
      100% for movement trials that were tested. The application of neural networks for
      classification of arm movements is completed with results using different neural
      networks: backpropagation, radial basis, recurrent (Elman), self-organizing and
      Learning Vector Quantization (LVQ).

PMID- 10576423
TI  - Automatic synthesis of synergies for control of reaching--hierarchical
      clustering.
AB  - In this paper we describe a novel method for determining synergies between joint
      motions in reaching movements by hierarchical clustering. A set of recorded elbow
      and shoulder trajectories is used in a learning algorithm to determine the
      relationships between angular velocities at elbow and shoulder joints. The
      learning algorithm is based on optimal criteria for obtaining the hierarchy of
      descriptions of movement trajectories. We show that this method finds complex
      synergism between optimal joint trajectories for a given set of data and angular
      velocities at the shoulder and elbow joints. Three other machine learning
      techniques (ML) are used for comparison with our method of hierarchical
      clustering of trajectories. These MLs are: (1) radial basis functions (RBF), (2)
      inductive learning (IL), and (3) adaptive-network-based fuzzy inference system
      (ANFIS). Better error characteristics were obtained using the method of
      hierarchical clustering in comparison with the other techniques. The advantage of
      the method of hierarchical clustering with respect to the other MLs is in
      integrating the spatial and temporal elements of reaching movements.
      Determination and analysis of spatio-temporal events of movement trajectories is
      a useful tool in designing control systems for functional electrical stimulation
      (FES) assisted manipulation.

PMID- 10576424
TI  - Toward a portable blood pressure recorder device equipped with an accelerometer.
AB  - The 24-h ambulatory systolic blood pressure (ASBP) recording has become a helpful
      tool in the diagnosis of hypertension and evaluation of the efficiency of anti
      hypertensive drugs. Yet, the very high variability of ASBP makes the analysis of
      the recording rather difficult. A potential solution to reduce ASBP variability
      has been studied and is presented in this article. It consists of equipping the
      portable ASBP recorder device with other sensors, a three axes accelerometer and
      a heart rate recorder, so as to enable an analysis to be undertaken of the
      arterial pressure profile in the light of these concomitant data. A database has
      been collected, and a model linking ASBP variations with body acceleration and
      heart rate measurements is developed. Its performance is tested in prediction and
      the results compared with those obtained from one of the solutions currently used
      by physicians to deal with ASBP variability. The results obtained with 16 young
      subjects from the database, for whom two 24-h recordings are available, are
      significantly improved and very encouraging.

PMID- 10576425
TI  - Modelling evaluation of the testing condition influence on the maximum stress
      induced in a hip prosthesis during ISO 7206 fatigue testing.
AB  - In vivo fatigue failure of hip prosthesis stems has been extensively reported in
      literature. The ISO 7206 international standard has been developed to assess the
      fatigue reliability of hip prostheses. It describes the fatigue testing apparatus
      and procedure and it is currently adopted by several testing laboratories
      throughout the world. In this work we evaluate the maximum stress in a titanium
      alloy commercial stem in different testing conditions, ranging within the
      standard specification, using the finite element method applied to a 3D model of
      the stem. The calculated maximum von Mises stress ranges from +4.5 to -1.5% (for
      different cement constraint levels) and from +6.7 to -6.8% (for different stem
      angular orientations) with respect to that calculated at the nominal testing
      conditions. The results suggest that the ISO 7206 testing specification will give
      experimental data of reasonable accuracy, with probably no more scatter than that
      found in typical specimen test results. This is particularly important in the
      case of components manufactured from materials showing a fatigue resistance
      highly sensitive to stress variations, such as the Ti6A14V alloy, for which a
      small increase of the maximum applied stress corresponds to a significant
      decrease of the statistical fatigue life.

PMID- 10576426
TI  - A study of heart rate and heart rate variability in human subjects exposed to
      occupational levels of 50 Hz circularly polarised magnetic fields.
AB  - The effects of power-frequency magnetic fields on heart rate and heart rate
      variability (HRV) were studied in groups of adult volunteers. Exposure consisted
      of 28 microT (280 mG) at 50 Hz (circularly polarized) for 100 or 150 seconds
      either following or prior to a similar period of sham-exposure. A small but
      significant slowing of heart rate of the order of 2% was observed in two separate
      studies in which the fields were generated by continuous sinusoidal currents.
      Magnetic fields generated by square-wave currents or by currents turned
      alternatively on and off at 15 second intervals during the exposure period
      produced inconsistent effects on heart rate. Analysis of the HRV spectra in
      relation to continuous sinusoidal exposure showed a consistent reduction in the
      ratio of power in the Low Band (0.02-0.15 Hz) to the High Band (0.16-1.0 Hz).
      This reduction in ratio was significant for experiments in which respiration was
      controlled at 0.2 Hz (12 breaths/minute) where the order was actual exposure
      followed by sham exposure (On-->Off). The spectral power in the Low Band was
      significantly reduced for both orders, but the High Band power was significantly
      raised only for the On-->Off order. Although there are some inconsistencies,
      these data indicate that short exposures to magnetic fields at occupational
      levels may influence heart rate control mechanisms.

PMID- 10576427
TI  - Multiple lead recordings improve accuracy of bio-impedance plethysmographic
      technique.
AB  - We have developed the theory and instrumentation of multiple multi-electrode bio
      impedance (BI) measurements based on lead field theoretical approach. To derive
      reliable information based on BI data, a quantity of measurements should be taken
      with electrode configurations possessing regional measurement sensitivity. An
      apparatus has been developed with an eye to the requirements imposed by the
      theoretical aspects of achieving multiple multi-electrode BI measurements. It has
      features compensating electrode-contact related errors and errors due to
      imbalance between the conductive pathways when multiple electrodes are utilised
      for BI measurement. The proposed design allows simultaneous multi-electrode BI
      and bioelectric recording with the same electrode system. Initial operation
      experiences in clinical environment indicate that the device functions as
      intended, and allows user-friendly utilisation of multiple BI measurements.
      Contributions presented to BI methodology and instrumentation improve the
      reliability of BI measurements.

PMID- 10576428
TI  - Stobadine: bellwether of a broader view of drug actions.
AB  - Stobadine was recognized early in its development as having antioxidant
      properties. A number of laboratories found associations between the antioxidant
      properties of stobadine and its potential beneficial effects. We found that
      stobadine acted as an antioxidant in a modification of an oxygen radical
      absorbance capacity (ORAC) assay. Similar results were observed with other drugs,
      including tirilazad and pramipexole. We suggest that stobadine and certain other
      drugs exhibit antioxidant properties in both hydrophilic and hydrophobic
      environments. Other drugs have been developed for their antioxidant properties
      and some currently marketed drugs have antioxidant properties. Although they may
      not have been explicitly sought during development, at least some of the
      beneficial effects may be related to antioxidant properties and/or scavenging of
      free radicals. Because stobadine was one of the first drugs for which useful
      properties were associated with its antioxidant actions, stobadine may be seen as
      a bellwether of a broader view of pharmacological actions--a view that
      encompasses antioxidant properties as a useful basis of therapeutic effects.

PMID- 10576429
TI  - Chemistry, physiology and pathology of free radicals.
AB  - The superoxide anion radical and other reactive oxygen species (ROS) are formed
      in all aerobic organisms by enzymatic and nonenzymatic reactions. ROS arise in
      both physiological and pathological processes, but efficient mechanisms have
      evolved for their detoxification. Similarly, reactive nitrogen intermediates
      (RNI) have physiological activity, but can also react with different types of
      molecules, including superoxide, to form toxic products. ROS and RNI participate
      in the destruction of microorganisms by phagocytes, as in the formation of a
      myeloperoxidase-hydrogen peroxide-chloride/iodide complex which can destroy many
      cells, including bacteria. It is known that the cellular production of ROS and
      RNI is controlled by different mechanisms. These free radicals can react with key
      cellular structures and molecules, thus altering their biological function. An
      imbalance between the systems producing and removing ROS and RNI may result in
      pathological consequences.

PMID- 10576430
TI  - Theoretical study of the reactivity properties of two forms of stobadine.
AB  - The cardio- and neuroprotective effect of the pyridoindole stobadine (S) is
      conditioned mainly by its good radical scavenging properties. It has been showed
      by EPR experiment, that the ultimate product of the reaction of stobadine with
      hydroxyl radical is the nitroxyl radical. However, for the unsaturated
      dehydrostobadine (DHS) the ultimate product was not experimentally determined,
      although its reactivity with a hydroxyl radical has been detected. Using the
      quantum chemical method AM1 we calculated the physico-chemical properties of S,
      DHS and their radicals. For the stobadine alone, the corresponding radical was
      formed by removing the H* from the NH group of indol, while in the case of DHS we
      removed the CH3* from the nitrogen in pyridine ring. For S and DHS we calculated
      the differences in the energies between the parent molecules and the
      corresponding radicals as well as the spin distributions for the radicals. The
      results confirmed the differences in the reactivities of S and DHS.

PMID- 10576431
TI  - EPR spectroscopy of free radical intermediates of antiarrhythmic-antihypoxic drug
      stobadine, a pyridoindole derivative.
AB  - Mechanisms of antioxidant action of stobadine, a pyridoindole derivative with
      cardioprotective and antihypoxic properties, has been probed using EPR
      spectroscopy. Oxidation of stobadine by PbO2/tBuOOH in benzene results in the
      formation of nitroxide radical observable directly by EPR spectroscopy at room
      temperature, indicating conversion of indolic amino group to the corresponding
      nitroxide.

PMID- 10576432
TI  - Elevated oxidative stress in models of normal brain aging and Alzheimer's
      disease.
AB  - Age-associated neurodegenerative disorders are becoming more prevalent as the
      mean age of the population increases in the United States over the next few
      decades. Both normal brain aging and Alzheimer's disease (AD) are associated with
      oxidative stress. Our laboratory has used a wide variety of physical and
      biochemical methods to investigate free radical oxidative stress in several
      models of aging and AD. Beta-amyloid (A beta), the peptide that constitutes the
      central core of senile plaques in AD brain, is associated with free radical
      oxidative stress and is toxic to neurons. This review summarizes some of our
      studies in aging and A beta-associated free radical oxidative stress and on the
      modulating effects of free radical scavengers on neocortical synaptosomal
      membrane damage found in aging and A beta-treated systems.

PMID- 10576433
TI  - Increased oxidative stress brought on by pro-inflammatory cytokines in
      neurodegenerative processes and the protective role of nitrone-based free radical
      traps.
AB  - Nitrone-based free radical traps (NFTs) have been shown to be protective in
      several neurodegenerative models. Our research has strongly implicated that: A)
      several neurodegenerative conditions exhibit increased levels of pro-inflammatory
      cytokines which consequently result in increased levels of oxidative stress and
      B) that NFTs act in part by suppressing oxidative stress through suppression of
      the action of the cytokine cascade. Acquired Immune Deficiency Syndrome (AIDS)
      dementia complex (ADC) is one of several conditions where the data collected
      helped to develop these concepts. Novel observations include demonstration that
      IL-1beta acts on cultured brain glia cells to invoke protein nitration and
      oxidative stress and that low levels of PBN (alpha-phenyl tert-butyl nitrone)
      inhibit this effect. We interpret these data as indicating that PBN prevents IL
      1beta mediated peroxynitrite formation. Additionally, we have found that the AIDS
      viral envelope protein gp120 upregulates mRNA for the cytokines TNF alpha and TNF
      beta in rat neonatal brain, and that PBN prevents this. Western blots of protein
      extracts showed upregulation of inducible nitric oxide synthase (iNOS) in gp120
      treated neonatal rat brains, and that PBN prevented induction of this enzyme as
      well. These observations underscore the general concept that PBN inhibits the
      induction of genes which produce neurotoxic products, one of which is
      peroxynitrite formed by the reaction of nitric oxide with superoxide, and may act
      also by inhibiting the induction of cytokines which mediate pro-inflammatory
      conditions in the brain.

PMID- 10576434
TI  - 4-Hydroxynonenal as a second messenger of free radicals and growth modifying
      factor.
AB  - Immunohistochemical analysis of the distribution of the lipid peroxidation
      product 4-hydroxynonenal (HNE) in the brain of baboons exposed to experimental
      hemorrhagic traumatic shock or sepsis showed that systemic oxidative stress and
      the thereby generated HNE affect the blood:brain barrier and the regulation of
      cerebral blood flow determining secondary brain damage. Similarly, HNE was
      determined during ischemia in the brain blood vessels of rats exposed to
      ischemia/reperfusion injury of the brain. After reperfusion, HNE disappeared from
      the blood vessels but remained in neurones and in glial cells. Since HNE
      modulates cell proliferation and differentiation (including proto-oncogene
      expression), it is postulated that HNE might have prominent local and systemic
      effects that are not only harmful but beneficial, too, determining the outcome of
      various pathophysiological conditions based on oxidative stress.

PMID- 10576436
TI  - Reactive oxygen species induced smooth muscle responses in the intestine, vessels
      and airways and the effect of antioxidants.
AB  - Numerous experimental data confirm the importance of reactive oxygen species
      (ROS) in physiological activities of smooth muscles and in the pathogenesis of
      various diseases with altered function of smooth muscles. The present study shows
      that smooth muscles of the intestine, airways and vessels, as well as their
      epithelium, endothelium and innervations, might be important targets of the ROS
      action. We demonstrated differences among the actions of various ROS (endogenous,
      exogenous, produced enzymatically, non-enzymatically) as well as among their
      actions in different smooth muscle tissues. Our results indicate that ROS are
      involved in changes in muscle tone, membrane conductance, calcium homeostasis,
      calcium-dependent processes, as well as in eicosanoid and nitric oxide
      metabolism. The effects of antioxidative enzymes (superoxide dismutase,
      catalase), of several drugs of natural origin (e.g. Kampo Medicines) and
      synthetic agents (e.g. stobadine, nitrosopine, ACE inhibitors) suggest that
      smooth muscle tissues are useful models to study ROS action and drug intervention
      in ROS induced injuries.

PMID- 10576435
TI  - Stobadine inhibits lysosomal enzyme release in vivo and in vitro.
AB  - This study investigated the ability of stobadine, an effective cardioprotective
      drug with antiarrhythmic, antihypoxic and oxygen free radical scavenging
      properties, to protect cells against cyclophosphamide-induced toxic and cytotoxic
      damage in vivo and in vitro. Cyclophosphamide-induced toxic damage in female ICR
      mice was accompanied by marked increase in the activity of lysosomal enzymes in
      the spleen and kidney. Administration of stobadine prior to cyclophosphamide
      inhibited these biochemical changes. The in vivo protective effect of stobadine
      was comparable with its in vitro effect established in HeLa cells.

PMID- 10576437
TI  - Protective effect of stobadine in experimental colitis.
AB  - To assess the possible role of reactive oxygen species in inflammatory bowel
      disease, the effect of the antioxidant and free radical scavenger stobadine was
      studied in acetic acid-induced experimental colitis. Stobadine administered
      locally into the colon was found to reduce the extent of colonic mucosal injury,
      abolish the increase in myeloperoxidase activity, attenuate the enhanced vascular
      permeability, and prevent the depletion of reduced glutathione. The attempt to
      reduce pharmacologically excessive free radical production and oxidative damage
      in the inflamed colonic mucosa may be regarded as a complementary treatment of
      ulcerative colitis.

PMID- 10576438
TI  - Mucolytics and antioxidant activity.
AB  - We investigated effects of the mucolytics ambroxol and N-acetylcysteine on
      airways reactivity evoked by histamine in guinea pigs exposed to toluene vapors.
      We did not find significant changes in reactivity of tracheal smooth muscle from
      animals treated with mucolytics compared to the control group. However, the
      administration of ambroxol and N-acetylcysteine caused a significant decrease in
      lung tissue reactivity. The effect of ambroxol was more pronounced after
      intraperitoneal injection than after inhalation, while N-acetylcysteine was only
      effective after inhalation. The protective effects of mucolytics in the lung
      tissue may be due to their antioxidant activity together with other mechanisms.

PMID- 10576439
TI  - Free oxygen radicals contribute to high incidence of reperfusion-induced
      arrhythmias in isolated rat heart.
AB  - Early period of reperfusion of ischemic myocardium is associated with a high
      incidence of severe tachyarrhythmias including ventricular tachycardia and
      fibrillation (VT and VF). Free oxygen radicals (FOR) have been identified as one
      of the principal factors responsible for reperfusion-induced events. However,
      their role in arrhythmogenesis is not clear. In the present study, in isolated
      Langendorff-perfused rat hearts subjected to 30 min global ischemia, the onset of
      reperfusion induced 100% incidence of both VT and VF with their gradual cessation
      over 5 min of reperfusion. Generation of H2O2 in the myocardium in the first
      minutes of reperfusion was visualized by means of cerium cytochemistry and
      confirmed by X-ray microanalysis. The mechanism of the arrhythmogenic effect of
      FOR may involve inhibition of the sarcolemmal Na+/K+-ATPase, as demonstrated in
      the rat heart sarcolemmal fraction subjected to FOR-generating system (H2O2 +
      FeSO4).

PMID- 10576440
TI  - Effect of stobadine on cardiac injury induced by ischemia and reperfusion.
AB  - The aim of this work was to evaluate the effect of the antioxidant stobadine on
      ischemia/reperfusion-induced injury of the isolated rat heart. Experiments were
      performed according to Langendorff. Ischemia was induced by stop-flow lasting 30
      minutes and the duration of repefusion was 30 minutes. Reperfusion of the
      ischemic heart induced dysrhythmias, with the most severe ones occurring in the
      first minutes of reperfusion. A significant increase in coronary perfusion
      pressure was observed starting after 15 min of reperfusion. Stobadine (10(-6) M
      applied 3 minutes before onset of ischemia and during reperfusion) prevented the
      deleterious effects to develop fully. The protective effect of stobadine observed
      in our experiments seems to be a consequence of its antioxidant properties.

PMID- 10576441
TI  - Stobadine and heart mitochondria.
AB  - Previous work has shown, that stobadine-hydrochloride (-)cis-2,8-dimethyl
      2,3,4,4a,5,9b-hexahydro-14-pyrido(4,3b) indole administered in a single dose 2
      mg/kg of body weight reduces cardiotoxic effect of isoproterenol (1 mg/kg) as
      shown by lowered serum enzyme activities of AST, CPK, LDH and ALT. We studied the
      effect of stobadine in vivo on respiration, the level of ATP, malondialdehyde
      (MDA) and superoxiddismutase (SOD) in heart mitochondria. Serum enzyme activities
      of AST, CPK and LDH after stobadine application were significantly decreased. In
      mitochondria, respiration and activity of SOD were inhibited, level of MDA was
      increased and level of ATP was unchanged. The cardioprotective effect of
      stobadine is not linked to preservation of mitochondrial function. This effect is
      probably more complex and mediated on the level of the whole organism.

PMID- 10576442
TI  - Stobadine is a potent modulator of endogenous endothelin-1 in human fibroblasts.
AB  - Binding of endothelin (ET) peptides to their respective receptors with resulting
      proliferation of vascular smooth muscle has been implicated in the pathogenesis
      of arterial hypertension and atherosclerosis. Recently it was hypothesized that
      endothelin- (ET-1) bound to its two membrane receptors (ET(A) and ET(B))
      continues to activate signal transducing proteins in cells. It was also shown
      that pyridoindole stobadine stabilized lysosomal membranes in myocardium in early
      ischemia. Therefore we decided to study the effects of stobadine on specific,
      subtype-selective binding and subsequent degradation of human, synthetic [125I]
      ET-1 in human fibroblasts (HF). Our results indicate that stobadine significantly
      potentiated ET-1 binding by reductive ET(B) selective degradation of ET-1 in HF.
      Hence, it is very plausible that stobadine may modulate endogenous endothelin and
      its intracellular mitogenic and chemotactic factors, principally by affecting two
      presumably related processes, participating in the proliferative and mitogenic
      response, (1) potentiation of signal trasduction from ET(A) receptors, and (2)
      subtype-ET(B) selective intracellular processing.

PMID- 10576443
TI  - Indole derivatives as neuroprotectants.
AB  - It seems to be satisfactorily proved that reactive oxygen species (ROS)
      participate in numerous pathological processes in the nervous system (NS).
      Compounds able to interfere with the action of ROS might be useful in prevention
      and treatment of these pathologies. The search is focused on compounds with a
      suitable spectrum of pharmacological and pharmacokinetic properties, among which
      indole derivatives are distinct group with great potential to be further
      developed. The paper presents an overview of indole derived compounds in which
      protective action has been demonstrated in the NS in situations in which ROS are
      excessively generated, such as chemically induced oxidative stress,
      hypoxia/reoxygenation, ischemia/reperfusion. These compounds include indoleamines
      (melatonin), carbazoles (carvedilol), carbolines (tetrahydrocarbolines,
      pyrimidoindoles, vinpocetine). Special attention is paid to the gamma-carboline
      stobadine. A range of effects which seem to be associated with its
      neuroprotective actions (antioxidant and ROS scavenging effects, capability to
      pass the hematoencephalic barrier, pharmacokinetic properties, etc.) are
      considered. A novel compound with pyrimidoindole structure (U-101033E) is
      mentioned. Attention is drawn also to the neurotoxic potential demonstrated in
      some carbolines (2-amino-alpha-carboline, halogenated tetrahydro-beta-carboline
      "TaClo", harmane, norharmane). The indole nucleus seems to be a promising basis
      for design and synthesis of new derivatives able to protect the NS against
      oxidative stress in a variety of acute and chronic NS pathologies.

PMID- 10576444
TI  - Membrane ion transport systems during oxidative stress in rodent brain:
      protective effect of stobadine and other antioxidants.
AB  - The effect of oxidative stress in vitro induced by radical generating systems
      (RGS) (Fe2+-EDTA and Fe2+-EDTA plus H2O2) on synaptosomal and microsomal ion
      transport systems as well as on the membrane fluidity was investigated. Oxidative
      insult reduced Na+, K+-ATPase activity by 50.7% and Na+-dependent Ca2+ uptake
      measured in choline media by 46.7%. Membrane fluidity was also significantly
      reduced as observed with the fluorescent probe. Stobadine (ST) prevented the
      decrease in membrane fluidity and Na+-dependent Ca2+ uptake, however Na+, K+
      ATPase activity was only partially protected, indicating a more complex mechanism
      of inhibition. Incubation of microsomes with RGS led to the loss of ability of
      membranes to sequester Ca2+, as well as to the decrease of Ca2+-ATPase activity
      and to the increase of Ca2+ permeability to 125.1%. The relative potency of the
      two RGS to decrease membrane fluidity correlated well with the system's potencies
      to induce lipid peroxidation. The extent of protection against depression of Ca2+
      uptake values and Ca2+-ATPase activity by membrane soluble antioxidants (U
      74500A, U-83836E, t-butylated hydroxytoluene-BHT and ST) was dependent on the
      experimental conditions and on the dose and nature of antioxidant used. ST seems
      to be at least as affective as BHT and 21-aminosteroids, and more potent than
      tocopherol acetate. Water soluble glutathione had no significant effect on the
      RGS induced inhibition of Ca2+-ATPase activity. Combination of ST with
      glutathione enhanced ST antioxidant efficacy, so drug combination might be
      beneficial therapeutically.

PMID- 10576445
TI  - Effect of stobadine on lipid peroxidation in brain and heart after ischemia and
      reperfusion of the brain.
AB  - Stobadine (ST), a novel drug with pyridoindol structure, was recently found to
      prevent reperfusion injury in rat brain. The aim of the present study was to
      reveal whether ST may prevent peroxidative changes in the heart and brain that
      were triggered by postischemic reperfusion of the brain. In the brain,
      reperfusion significantly increased the contents of malondialdehyde (MDA) by
      43.8% and conjugated diens (CD) by 24.5% when compared with the end of ischemia.
      In the heart, contents of MDA and CD in reperfusion became elevated three fold
      and by 41.7%, respectively, when comparing to the values at the end of ischemia.
      In the heart, no significant changes in activities of the superoxide dismutase
      (SOD) and glutathione peroxidase (GPx) induced by ischemia or reperfusion were
      detected. In contrast, reperfusion induced a slight decrease in GPx activity in
      the brain. In accordance with our previous results, an application of ST (2
      mg/kg) to the femoral artery shortly prior to reperfusion of the ischemic brain,
      prevented significantly MDA and CD accumulation in brain. Nevertheless, ST was
      not able to prevent the brain-ischemia/reperfusion-induced elevation of MDA and
      CD contents in the heart.

PMID- 10576446
TI  - Stobadine protects against ischemia-reperfusion induced morphological alterations
      of cerebral microcirculation in dogs.
AB  - Vascular diseases of the CNS are a major medical, social and economic problem.
      From the number of causes leading to nervous malfunction and damage, ischemia is
      most prominent. Thus, neuronal protection from ischemic damage may provide
      significant preventive and treatment potential. This study was designed to test
      possible protective effects of stobadine in a canine model of global cerebral
      ischemia. Seven minute ischemia was induced by four vessel ligation and
      maintained using a controlled systemic hypotension. Stobadine pretreated animals
      were infused with 2 mg/kg stobadine 30 minutes prior to ischemia, while control
      animals received vehicle. After a 24 hour reperfusion phase, animals were
      perfusion-fixed and evaluated using electron microscopy. Stobadine pretreated
      dogs showed much less damage to both endothelial lining and pericapillary
      structures of the blood-brain barrier. This included preservation of cellular
      shape of the endothelium, patency of microvessels, lack of intraluminal blebs
      material, near normal cytoplasmic osmiophilia, decreased thickness of endothelial
      basement membrane, significantly less edema of astrocyte end-feet, and
      preservation of fine mitochondrial structure compared to the control group.
      Ischemic neuronal changes were observed less frequently in the stobadine
      pretreated group. In summary, we conclude that stobadine protects both cerebral
      microcirculation and neurons from injury induced by global cerebral ischemia and
      reperfusion.

PMID- 10576447
TI  - Effect of stobadine, U-74389G, trolox and melatonin on resistance of rat
      hippocampal slices to oxidative stress.
AB  - Reactive oxygen species have been suggested to participate in the impairment of
      nervous tissue by oxidative stress, induced by hypoxia (HYP) followed by
      reoxygenation (ROX). Although the mechanisms of such injury are rather complex,
      antioxidants might exert some protective action under such circumstances. This
      study tested the effect of a series of compounds interfering with the generation
      and action of reactive oxygen species on impairment of synaptic transmission in
      the CA1 region of rat hippocampal slices exposed to HYP followed by ROX in vitro.
      Shortlasting HYP (typically 4.5-7.5 min under the conditions used) resulted in
      fast decay of the amplitude of population spikes evoked in the CA1 neurons by
      stimulation of Schaffer collaterals. The impairment was mostly irreversible.
      However, in the presence of the antioxidants stobadine, 21-aminosteroid U-74389G,
      melatonin and trolox (with optimal concentrations of 10-30 micromol/l, 10
      micromol/l, 30-100 micromol/l and 200 micromol/l, respectively), the irreversible
      damage of the transmission was significantly diminished. The decay of the
      synaptic transmission failure during HYP was also delayed by stobadine, U-74389G
      and melatonin. The results demonstrated that compounds with antioxidant activity
      may effectively protect nervous tissue during HYP and ROX.

PMID- 10576448
TI  - Iron as catalyst for oxidative stress in the pathogenesis of Parkinson's disease?
AB  - The mechanisms leading to degeneration of melanized dopaminergic neurons in the
      brain stem, and particularly in the substantia nigra zona compacta (SNZC) in
      patients with Parkinson's disease (PD) are still unknown. Demonstration of
      increased iron Fe(III) in SNZC of PD brain has suggested that Fe-melanin
      interaction may contribute to oxidative neuronal damage. Energy dispersive X-ray
      electron microscopic analysis of the cellular distribution of trace elements
      revealed significant Fe-peaks, similar to those of a synthetic melanin-Fe(III)
      complex in intracytoplasmic electron-dense neuromelanin granules of SNZC neurons,
      with highest levels in a case of PD and Alzheimer's disease (AD). No Fe increase
      was found in Lewy bodies or in SN neurons of control specimens. The relevance of
      chemical reactions of dopamine (DA), 5-hydroxydopamine (5-OHDA), and 6
      hydroxydopamine (6-OHDA) with Fe(III) and with dioxygen for the pathogenesis of
      PD was investigated. An initiating mechanism related to interaction between Fe
      and neuromelanin is suggested which results in accumulation of Fe(III) and a
      continuous production of cytotoxic species inducing a cascade of pathogenic
      reactions ultimately leading to neuronal death.

PMID- 10576449
TI  - Amyloid beta-peptide inhibits Na+-dependent glutamate uptake.
AB  - The purpose of this review is to summarize much of the work on the inhibition of
      the astroglial glutamate transporter in relation to excitotoxic
      neurodegeneration, in particular, inhibition of uptake by the beta-amyloid
      peptide (A beta) found in the Alzheimer's disease (AD) brain. There is evidence
      for oxidative stress in the AD brain, and A beta has been found to generate
      reactive oxygen species (ROS), thus adding to the stress or possibly initiating
      it. The oxidative inhibition of the glutamate transporter protein by A beta
      increases the vulnerability of glutamatergic neurons, and by rendering them
      susceptible to the excitotoxic insult that results from impaired glutamate
      uptake, A beta can be directly connected to the neurodegeneration that follows.

PMID- 10576450
TI  - Aggregation of human blood platelets in the presence of the pyridoindole
      stobadine.
AB  - The antiarrhythmic and cardioprotective drug stobadine, possessing antioxidant
      and neuroprotective properties, was studied as to its in vitro effect on
      aggregation of human blood platelets. Pretreatment of platelets with stobadine
      for 30 s inhibited stimulated platelet aggregation in a dose-dependent way.
      Depending on the aggregation stimulus used, the minimal effective concentrations
      of the drug were 1 micromol/l (adrenaline), 200 micromol/l (ADP), and 1,000
      micromol/l (PMA). Aggregation induced with thrombin or Ca2+-ionophore A23187 was
      not changed in the presence of stobadine even in the concentration of 1,000
      micromol/l. Addition of stobadine 30 s after adrenaline was also effective and
      terminated aggregation (100 and 1,000 micromol/l) or prolonged onset of its
      second phase (10 micromol/l). The presented experiments showed stobadine as a
      potent inhibitor of adrenaline-induced aggregation, indicating its involvement in
      the observed antithrombotic and cytoprotective activity.

PMID- 10576451
TI  - Effect of stobadine on oxygen free radical generation in stimulated human
      polymorphonuclear leukocytes.
AB  - The generation both superoxide and a mixture of reactive oxygen species was
      recorded in a suspension of human polymorphonuclear leukocytes stimulated with
      phorbol myristate acetate. While stobadine dose-dependently decreased
      chemiluminescence, only its highest concentration used reduced significantly
      superoxide generation. The results suggest that stobadine is a more effective
      scavenger of free radicals rather than a quencher of superoxide anion.

PMID- 10576453
TI  - Oxidative modification of serum albumin in an experimental glycation model of
      diabetes mellitus in vitro: effect of the pyridoindole antioxidant stobadine.
AB  - Under conditions of an experimental in vitro glycation model, the pyridoindole
      antioxidant stobadine significantly inhibited glycation-related fluorescence
      changes of bovine serum albumin as well as the yield of 2,4
      dinitrophenylhydrazine-reactive carbonyls with an efficacy comparable to that of
      the reference antioxidants Trolox C and 2-keto-4-methiolbutyric acid, and more
      efficiently than did aminoguanidine. Since stobadine did not affect the covalent
      binding of glucose, the protective effect may be explained by the ability of the
      drug to eliminate free radical intermediates of glyco-oxidation reactions,
      operative after the preceding glycation steps.

PMID- 10576452
TI  - Inhibition of nonenzymatic protein glycation and lipid peroxidation by drugs with
      antioxidant activity.
AB  - We studied the effects of aminoguanidine (AG), beta-resorcylidene aminoguanidine
      (RAG), DL-penicillamine (PNCA) and captopril on early and advanced glycation of
      human serum albumin (HSA). We also assessed inhibition of lipid peroxidation by
      AG and RAG in erythrocytes. Incubation of HSA with D-glucose (20 mM, 37 degrees C
      for 21 days) led to the formation of Amadori products and fluorescent advanced
      glycation end-products (AGE). Only PNCA markedly reduced the formation of Amadori
      products, while all tested compounds markedly reduced the formation of AGE. AG
      and RAG also inhibited malondialdehyde formation in erythrocytes incubated with
      hydrogen peroxide. Addition of AG at concentrations from 1 microM to 1 mM caused
      a 10-80% inhibition of lipid peroxidation. Thus, AG and RAG inhibit toxic
      oxidative processes and may have therapeutic potential in a number of human
      diseases.

PMID- 10576455
TI  - Pharmacokinetic study of stobadine.
AB  - The aim of this paper is to provide a brief overview of most important results of
      stobadine kinetic studies in rats, dogs, and human volunteers. In these studies,
      stobadine dihydrochloride and stobadine dipalmitate was used for intravenous and
      oral administration, respectively. To evaluate kinetic properties of stobadine
      and its metabolites, TLC, HPLC, GLC, GC-MS, radiometric, and fluorometric methods
      were developed and used.

PMID- 10576454
TI  - Prevention of processes coupled with free radical formation prevents also the
      development of calcium-resistance in the diabetic heart.
AB  - Recently it was shown that besides their negative role in pathogenesis of
      diabetes, reactive oxygen species (ROS) and particularly the products of non
      enzymatic glycation of proteins (NEGP) may also participate in some processes of
      adaptation of the myocardium to diabetes, such as in the mechanism of development
      of calcium resistance of the heart. Our study revealed that the hearts of rats
      with experimentally induced diabetes (single dose of streptozotocin, 45 mg/kg
      i.v., 6 U/kg insulin daily) develop considerable resistance against calcium
      overload (induced by means of Ca-paradox). On the day 63 after the beginning of
      experiment, when the diabetic cardiomyopathy became fully developed but the
      hearts were still not failing, their calcium resistance was increased to 83.33%.
      Our results provide evidence that, when applied in a special regimen,
      resorcylidene aminoguanidine (RAG, 4 mg/kg) prevented both, the formation of
      fructosamine (a source of ROS generation), and also that of the advanced Maillard
      products, in the heart sarcolemma of diabetic rats. The effect of RAG was
      accompanied by a decrease in calcium resistance in the group of rats with chronic
      diabetes (63 days) from 83.3 to 46.7%. It is concluded that NEGP and ROS
      formation are inevitably needed for development of calcium resistance in the
      diabetic hearts.

PMID- 10576456
TI  - Kinetics of hydrolysis of acetyl, valeroyl and nicotinoyl acyl derivatives of
      stobadine.
AB  - The present work deals with the kinetics of hydrolysis of the acyl derivatives of
      stobadine, an originally synthesized potential antiarrhythmic and antihypoxic
      drug, which was found to have also an excellent scavenging effect on reactive
      oxygen species. The acyl derivatives of stobadine, which possess high
      lipophilicity, represent model blood-brain barrier penetrating agents. It is
      assumed that the acyl derivatives of stobadine may act as prodrugs which are
      hydrolysed in different biological tissues to release the active drug. The
      decomposition of three acyl derivatives of stobadine was studied in acidic, basic
      and neutral buffer solutions at constant ionic strength (0.1 mol/L) at 25 degrees
      and 70 degrees C using UV spectrophotometric method. The pseudo first-order rate
      constants and the pH-rate profile for the degradation of acetyl-, valeroyl- and
      nicotinoyl-derivatives of stobadine were determined. Confirmation that stobadine
      was the first degradation product was provided by thin-layer chromatography.

PMID- 10576457
TI  - Placental transfer of stobadine in rabbits.
AB  - Stobadine, a pyridoindole antioxidant, was investigated for its placental
      transfer and distribution in New Zealand white rabbits on the 27th day of
      gestation. The concentrations of stobadine were determined in maternal and foetal
      organs (plasma, brain, heart) at 30, 60, 120, and 360 minutes after oral
      administration of the drug in a dose of 5 mg/kg. The results obtained proved that
      after oral stobadine intake by rabbits at the stage of advanced pregnancy both
      maternal and foetal organs were under a certain drug level which could act
      protectively against oxidative stress--frequently occurring during late
      organogenesis, foetal stages and delivery, as well as during early postnatal
      development.

PMID- 10576458
TI  - Antimutagenic effects of stobadine: review of results.
AB  - The paper summarizes the results of our previously published studies testifying
      the hypothesis of the antimutagenic effect of stobadine (STB) in vivo and in
      vitro. The micronucleus test was used in in vivo experiments with ICR mice. Oral
      pretreatment with STB significantly decreased the mutagenic effect of
      cyclophosphamide (CP) in a concentration-dependent way. The protective effect of
      STB was confirmed in fetuses of CP-treated mice. STB pretreatment exerted also a
      radioprotective effect in Co60-irradiated mice. The ineffectiveness of STB
      posttreatment is indicative of its effect operative in the initiation of
      mutagenesis and of its radical-scavenging mechanism. The ability of STB to reduce
      N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)induced gene mutations and MNNG
      induced calcinosis/Raynaud's phenomenon/esophageal
      dysmotility/sclerodactyly/telangiectasia variant of scleroderma (CREST)-positive
      and CREST-negative micronuclei in V79 cells was tested in in vitro experiments.
      We found that this drug reduced the level of both gene mutations and CREST
      negative micronuclei mainly if given as pretreatment before exposure of cells to
      MNNG. We conclude that STB may have inhibited mutagenesis not only by scavenging
      reactive oxygen species, but also as a result of induction of metabolic enzymes,
      which reduced the level of DNA lesions.

PMID- 10576459
TI  - Patient advocacy at risk: ethical, legal and political dimensions of adverse
      reimbursement practices in brain injury rehabilitation in the US.
AB  - This article examines the relationship between the growing challenge of securing
      reimbursement for delivering traumatic brain injury rehabilitation in the US and
      the health providers' duty to advocate for the welfare of patients. Following a
      discussion of five impediments or barriers to reimbursement--namely, the erosion
      of private insurance, the insurer's refusal to pay, lack of empirical data to
      justify rehabilitation as 'medically necessary', financial incentives to
      abbreviate care, and the ERISA preemption--the article offers a series of
      recommendations aimed at enhancing patient advocacy. A prominent theme of this
      article is that health providers cannot forsake their advocacy role and so must
      be protected from potential penalties imposed by payers for doing so. The degree
      to which this protection occurs, however, may largely depend on a willingness to
      agitate for health reform on the state and federal levels.

PMID- 10576460
TI  - Cognitive indicators of vocational outcome after severe traumatic brain injury
      (TBI) in childhood.
AB  - Recent studies suggest that plasticity does not benefit outcome when diffuse
      cerebral pathology of the young child's brain is concerned. Thirty-three patients
      with severe traumatic brain injury (TBI) at preschool age were followed-up until
      adulthood. After the age of 18 years, a thorough neurological, neuropsychological
      and social evaluation, including detailed patient history and assessment of
      identity, was made by the team. When the youngest patients were 21 years old, the
      study was completed, with a questionnaire assessing employment status and ability
      to live independently. Twenty-seven per cent of the patients worked full time,
      21% had subsidised work, 37% lived independently at home and 15% needed help with
      every-day functions. Tests measuring speed, executive and memory functions were
      significantly associated with vocational outcome, as was the sense identity,
      which was independent of the test scores. The results support the recent reports
      on the vulnerability of a young child's brain to early trauma. The study also
      strongly suggests that the final assessment of outcome after childhood TBI should
      be done in adulthood.

PMID- 10576461
TI  - Traumatic brain injury: influence of blood alcohol level on post-acute cognitive
      function.
AB  - Alcohol intoxication frequently contributes to the occurrence of traumatic brain
      injury. Few studies, however, have examined whether acute pre-injury alcohol
      intoxication or premorbid history of alcohol abuse exacerbate cognitive
      impairments that commonly result from traumatic brain injury. This study examined
      the influence of blood alcohol level at time of hospital admission on cognitive
      functioning during the post-acute stage of recovery from traumatic brain injury.
      After controlling for pre-injury history of alcohol abuse, hospital admission
      blood alcohol level was predictive of poorer delayed verbal memory, greater
      decrement in verbal memory over time, and poorer visuospatial functioning.
      Moreover, there were non-significant trends for higher blood alcohol levels to
      predict poorer performance on measures of immediate verbal memory and
      perseveration.

PMID- 10576462
TI  - Rearranged marriages: marital relationships after head injury.
AB  - An in depth study of 18 heterosexual couples investigated the quality of the
      marital and sexual relationships 1-7 years after the male partner had suffered a
      severe head injury. Both quantitative and qualitative methods were employed and
      the focus was on the perspective of the uninjured female partner. The female
      partners reported both marital and sexual satisfaction as lower following injury.
      They rated their current marital satisfaction as significantly less than their
      brain injured partners. The quantitative part of the study revealed major role
      changes experienced by the women, with many comparing their new role to that of a
      parent with total decision making responsibility. The incompatibility of this
      role with that of sexual partner was mentioned by many. A tendency for the males
      to express gratitude but not to communicate their feelings was described by many
      women. Most women were resigned to the expectation that there would be little
      change in the future and, for most, the only positive aspect of the relationship
      was a sense of commitment and continuing companionship. The implications of the
      findings for rehabilitation and couple therapy are discussed.

PMID- 10576463
TI  - Carbamazepine in agitation and aggressive behaviour following severe closed-head
      injury: results of an open trial.
AB  - Ten patients presenting agitation and anger outbursts at various stages following
      a severe closed head injury, were treated in a prospective open trial with
      carbamazepine, with doses ranging from 400 to 800 mg per day, during 8 weeks.
      Group analysis demonstrated a statistically significant improvement of a score
      made up from six target items from the neurobehavioural rating scale. Improvement
      mainly concerned irritability and disinhibition. A statistically significant
      improvement was also found with the Agitated Behaviour Scale. Social functioning,
      as assessed by family or staff ratings of the Katz Adjustment Scale, also
      significantly improved. No modification of global cognitive functioning was found
      with the Mini Mental Status Examination. Individual analysis demonstrated that
      the beneficial effect was important in five cases, moderate in three patients and
      negligible in two cases. It is concluded that carbamazepine might help to reduce
      agitated behaviour in brain-injured patients. However, response to treatment
      demonstrated an important inter-individual variability.

PMID- 10576464
TI  - Paroxetine versus citalopram treatment of pathological crying after brain injury.
AB  - Selective serotonin reuptake inhibitors (SSRIs) are the treatment of choice for
      pathological crying after brain injury, independent of accompanying depression.
      In a series of 26 consecutive patients with acquired brain damage and episodes of
      involuntary crying, the efficacy and tolerability of paroxetine and citalopram
      were compared. The severity of pathological crying or laughing was rated based on
      clinical interviews with symptom provocation. The first 13 patients were treated
      with paroxetine and another 13 patients received citalopram in single daily doses
      of 10 to 40 mg. Rapid onset (within 1-3 days) and highly significant (p < 0.001)
      improvements of emotionalism were observed after both paroxetine and citalopram.
      There were no efficacy differences, despite the longer symptom duration in the
      citalopram group. The only adverse effect after paroxetine was nausea, which was
      reversible, in two patients, and nausea with vomiting in another two patients,
      who were switched to citalopram. Citalopram was tolerated without adverse
      effects.

PMID- 10576465
TI  - Detecting malingering in head injury litigation with the Word Memory Test.
AB  - The Word Memory Test (WMT) is a relatively new computer-based test that is
      designed to measure both verbal memory and biased responding (i.e. malingering).
      The purpose of this study was to examine the performance of a large sample of
      patients involved in head injury litigation on the WMT measures of biased
      responding. The patients were divided into two groups, those with relatively mild
      head injuries (n = 234) and those with moderate or severe brain injuries (n =
      64). The patients with less severe injuries performed significantly poorer on the
      WMT measures of biased responding.

PMID- 10576466
TI  - Neuropsychological, MRI and EEG findings after very mild traumatic brain injury.
AB  - Neuropsychological performance, magnetic resonance imaging (MRI) and
      electroencephalography (EEG) were investigated in 12 consecutive patients with
      very mild traumatic brain injury (MTBI) (Glasgow coma score 15) within 24 hours
      and 6 weeks after injury. The data were compared to 14 control subjects. There
      was a significant impairment in neuropsychological performance (verbal memory,
      arithmetic abilities and psychomotor reaction time) at onset and after 6 weeks,
      whereas verbal fluency and non-verbal memory test revealed no significant
      differences matching the control values. In MRI scans, three patients showed
      traumatic lesions (slight epidural haematoma, haemorrhagic contusions and white
      matter lesions indicating diffuse axonal injury). In the EEG recordings, no
      generalized slowing or focal changes were found. Structural and functional
      impairment can be identified using neuroimaging and neuropsychological
      examination, even in very MTBI patients.

PMID- 10576467
TI  - Assessment of minimally responsive patients: clinical difficulties of single-case
      design.
AB  - Improved management of very severely central nervous system (CNS) injured
      individuals has given rise to an increasing number of patients in a minimally
      responsive state. There is a growing literature stressing the importance of
      accurately determining these patients' level of cognitive functioning and its
      role in appropriate rehabilitation and long term management. The single case
      design model appears to be the intervention of choice, with its great flexibility
      and tailored approach to each individual case. The recent literature has focused
      on the technical aspects of the assessment, offering clear procedural guidelines.
      Unfortunately, there is a dearth of information about clinical factors such as
      clinical setting and family involvement, which may interfere with or prevent a
      planned intervention. The case of MT is presented, who was the subject of a
      single case intervention 9 months following an extremely severe traumatic brain
      injury. The planned intervention was to examine the effects of a psychostimulant
      on MT's level of arousal, in order to improve his participation in the
      rehabilitation programme. Beyond the results (which were equivocal), the clinical
      difficulties in conducting single case study designs in rehabilitation are
      discussed. Ways to minimize these difficulties are proposed.

PMID- 10576468
TI  - The development of illness beliefs.
AB  - This article is concerned with the factors that might lead to the development of
      illness fears. The hypothesis of a somatosensory amplification style (i.e, an
      augmented sensitivity in some people to both internal and external stimulation),
      and the hypothesis of inadequate concepts of health and illness, are presented as
      the two main explanations that scientific literature presents. The main scales
      that are used to diagnose illness fears are reviewed and the questions that
      presently challenge researchers are examined. Finally, suggestions for future
      studies are indicated.

PMID- 10576469
TI  - From gut to brain and back--a new perspective into functional gastrointestinal
      disorders.

PMID- 10576470
TI  - Models and measurements of depression in chronic pain.
AB  - The main aspects of the most common models describing depression in chronic pain
      patients are reviewed. It is suggested that dualistic thinking provides neither a
      satisfactory model of chronic pain, nor of depression, and relies on questionable
      assumptions of homogeneous, diagnostically defined entities. Models of depression
      based in cognitive psychology, although apparently more suitable, cannot be
      applied to populations of pain patients without clarifying the relationship
      between pain and depression. Furthermore, commonly used depression measurement
      instruments are criticized for criterion contamination, lack of external
      reference, and lack of sensitivity when applied to these groups, all of which
      further obscure the relationship. Finally, we suggest more promising directions
      for research in this area.

PMID- 10576471
TI  - Differences between bulimia nervosa and binge-eating disorder in females with
      type 1 diabetes: the important role of insulin omission.
AB  - This study explored the differences between bulimia nervosa ("BN," n=22) and
      binge-eating disorder ("BED," n=11) in type 1 diabetic females and the factors
      most predictive of poor glycemic control in patients suffering from these
      disorders. These two groups and a control group without eating disorders (n=32)
      were compared across a number of demographic, psychological, and medical
      variables. BN manifested significantly more severe disturbances related to eating
      disorders, depression, anxiety, a higher rate of co-occurring mental disorders,
      and poorer psychosocial functioning compared with BED. BN also showed poorer
      glycemic control. Multivariate analysis indicated that higher serum glycosylated
      hemoglobin (HbA1c) levels were most associated with the presence of severe
      insulin omission in type 1 diabetic females with binge eating. Clinicians may be
      able to determine the psychological/medical severity of illness in these patients
      by identifying the presence of compensatory behaviors to prevent weight gain such
      as severe insulin omission, as described in the DSM-IV.

PMID- 10576473
TI  - What's in a name: mortality and the power of symbols.
AB  - One's attitude about oneself, and the treatment one receives from others, might
      be affected, in some small but measurable way, by stigmatic or salutary labeling
      due to one's name. If names affect attitudes and attitudes affect longevity, then
      individuals with "positive" initials (e.g., A.C.E., V.I.P.) might live longer
      than those with "negative" initials (e.g., P.I.G., D.I.E.). Using California
      death certificates, 1969-1995, we isolated 2287 male decedents with "negative"
      initials and 1200 with "positive" initials. Males with positive initials live
      4.48 years longer (p<0.0001), whereas males with negative initials die 2.80 years
      younger (p<0.0001) than matched controls. The longevity effects are smaller for
      females, with an increase of 3.36 years for the positive group (p<0.0001) and no
      decrease for the negative. Positive initials are associated with shifts away from
      causes of death with obvious psychological components (such as suicides and
      accidents), whereas negative initials are associated with shifts toward these
      causes. However, nearly all disease categories display an increase in longevity
      for the positive group and a decrease for the negative group. These findings
      cannot be explained by the effects of death cohort artifacts, gender, race, year
      of death, socioeconomic status, or parental neglect.

PMID- 10576472
TI  - Neurotic butterflies in my stomach: the role of anxiety, anxiety sensitivity and
      depression in functional gastrointestinal disorders.
AB  - This study examined the prevalence of functional gastrointestinal (FGI)
      disorders, and the association between FGI disorders and measures of affective
      distress, among a sample of 127 university students. Subjects completed a
      questionnaire battery including Research Diagnostic Questions for Functional
      Gastrointestinal Disorders, the Beck Anxiety Inventory, the Anxiety Sensitivity
      Index, the Beck Depression Inventory, and a medical utilization questionnaire.
      FGI disorders were diagnosed in 51.2% of the sample. Functional dyspepsia
      (22.8%), dyschezia (20.5%), functional heartburn (19.7%), functional chest pain
      (18.1%), and globus (12.6%) were the most frequently diagnosed disorders.
      Participants experiencing globus, functional dyspepsia, or functional heartburn
      showed significant differences in terms of anxiety, anxiety sensitivity,
      depression, and/or physician visits, when compared with participants without
      these disorders. Our results suggest that FGI disorders are strikingly prevalent
      among young adults, and specific FGI disorders are associated with affective
      distress. Implications of the observed association between psychological factors
      and FGI disorders are discussed.

PMID- 10576474
TI  - Cardiovascular changes during induced emotion: an application of lang's theory of
      emotional imagery.
AB  - Studies of emotion have provided occasional support for physiological
      differentiation of affective states; however, the evidence has been inconsistent.
      The aims of the present study were to investigate cardiovascular changes
      associated with relived experiences of happiness, sadness, anger, fear, and
      disgust and to examine the utility of methods designed to optimize the induction
      of emotional responses. Thirty-four undergraduates who scored 0.5 sd above the
      mean on Larsen and Diener's Affect Intensity Measure described their most intense
      experiences of five emotions. These descriptions were then used to induce those
      emotions while blood pressure and other hemodynamic measures were monitored.
      Systolic blood pressure, diastolic blood pressure, and stroke volume
      differentiated among emotions. The results support the suggestion that
      cardiovascular activity differentiates emotional states and provide some insight
      into the physiological adjustments subserving such effects. The study
      demonstrates a method that may be applied to studies of discrete emotions.

PMID- 10576475
TI  - The measurement of irritable bowel syndrome (IBS)-related misconceptions in
      people with IBS.
AB  - Irritable bowel syndrome (IBS) is a common chronic disorder affecting between 15%
      and 22% of Western populations; core symptoms include abdominal pain and
      disturbed bowel function. Adjusting to living with IBS may entail considerable
      coping effort and, because medical treatments are largely ineffective, people
      with IBS must learn to manage the condition themselves. Self-management programs
      that include an increased awareness of and information relating to chronic
      illness have been shown to lead to positive benefits. The present article
      describes the development of the IBS misconceptions scale, an instrument designed
      to measure the misconceptions held by people with IBS. The final 17-item
      questionnaire was able to differentiate between three groups expected to differ
      in terms of IBS-related misconceptions, and showed good validity and reliability.
      The IBS-MS may be a useful tool in patient education programs, because it should
      be sensitive to changes in illness-related knowledge gained during intervention
      programs, and it is hoped that further research will lend further support to its
      reliability, validity, and usefulness.

PMID- 10576476
TI  - Short-term outcome of rhinoplasty for medical or cosmetic indication.
AB  - Psychological effects of rhinoplastic operations were evaluated in male and
      female patients who had sought surgical correction because of psychological
      distress caused by the appearance of the nose or because of a medical referral to
      correct functional disorders. Seventy-two patients selected by gender and
      operation motivation were asked to fill out the MPI and the IPAT Anxiety scale 2
      3 months before and 8 months after the operation. Results at follow-up
      highlighted a significant decrease of the mean Neuroticism and Anxiety scores and
      an increase in Extroversion scores in the group as a whole. The psychological
      benefits gained by the female patients were greater than those of the males.
      Patients whose motivation was exclusively aesthetic were, overall, more
      psychologically distressed than those with a functional motivation.

PMID- 10576477
TI  - Five-year follow-up of cosmetic rhinoplasty.
AB  - The psychological impact of rhinoplasty for aesthetic reasons on psychological
      well-being is controversial. The aim of the present study is to assess short- and
      long-term psychological changes in patients who underwent rhinoplasty. Seventy
      nine patients, without traumatic lesions, who presented for cosmetic surgery,
      completed the MPI scales for Neuroticism and Extroversion and the IPAT scale for
      Anxiety, 3 months before and 6 months and 5 years after surgery. Results showed a
      significant decrease of anxiety and neuroticism in both postoperative evaluations
      and an increase on the Extroversion scale only at the 6-month follow-up.
      Psychological distress persisted in most patients after the operation.

PMID- 10576478
TI  - Herbert Henry Jasper M.D., Ph.D., 1906-1999.

PMID- 10576479
TI  - Event-related EEG/MEG synchronization and desynchronization: basic principles.
AB  - An internally or externally paced event results not only in the generation of an
      event-related potential (ERP) but also in a change in the ongoing EEG/MEG in form
      of an event-related desynchronization (ERD) or event-related synchronization
      (ERS). The ERP on the one side and the ERD/ERS on the other side are different
      responses of neuronal structures in the brain. While the former is phase-locked,
      the latter is not phase-locked to the event. The most important difference
      between both phenomena is that the ERD/ERS is highly frequency band-specific,
      whereby either the same or different locations on the scalp can display ERD and
      ERS simultaneously. Quantification of ERD/ERS in time and space is demonstrated
      on data from a number of movement experiments.

PMID- 10576480
TI  - Roles of a potassium afterhyperpolarization current in generating neuromagnetic
      fields and field potentials in longitudinal CA3 slices of the guinea-pig.
AB  - OBJECTIVES: Roles of a calcium-dependent potassium conductance of slow
      afterhyperpolarization (AHP) type (gK(AHP)) in generating magnetoencephalographic
      (MEG) signals were studied in hippocampal longitudinal CA3 slices of the guinea
      pig. METHODS: The roles of gK(AHP) were experimentally inferred from effects of
      its blocker, carbamylcholine-chloride (carbachol, CCh), on MEG signals. The MEG
      signals were compared with extracellular field potentials and intracellular
      potentials of the pyramidal cells in the slice. RESULTS: CCh profoundly affected
      MEG waveforms. CCh reduced the initial spike of the evoked MEG signals
      independently of stimulation of the cell layer and apical dendrites. The slow
      wave of the evoked MEG signals was reduced by the somatic stimulation, but was
      enhanced by the apical stimulation. Elevated extracellular calcium and bath
      applied tetraethylammonium (TEA) enhanced the CCh effects. CCh also increased
      spontaneous MEG signals. These effects on MEG and field potentials could be
      interpreted on the basis of synaptic and intracellular effects of CCh.
      CONCLUSIONS: Our results indicate that abnormality in this subtle calcium
      dependent potassium channel may profoundly influence MEG and EEG signals.

PMID- 10576481
TI  - Decomposition and mapping of generalized spike-wave complexes.
AB  - OBJECTIVE: To delineate more precisely the electrical fields of spikes versus
      waves during absence seizures. METHODS: Five children with 25 absence seizures
      were investigated with an expanded electrode array. Spikes were separated from
      waves by appropriate filtering and current source density maps were obtained from
      different portions of the waves as well as spikes. In order to detect
      commonalities for spread of activity, averaging of the complexes was also carried
      out. RESULTS: The anterior head regions (prefrontal and fronto-polar) show
      independent activity from the posterior ones (parieto-occipital) for spikes as
      well as waves. Voltage maps give a simplified and therefore misleading picture.
      The complexity of the process and propagation of events is best appreciated when
      current source densities (CSD) are mapped and several head views are available.
      Spike 1 becomes clearly visible upon filtering, even when it is not apparent from
      raw tracings, and can be mapped. CONCLUSIONS: Future topographic investigations
      of the SW complex should utilize CSD maps rather than rely entirely on voltages.
      This applies also to seemingly focal spikes--especially in children--in order to
      differentiate them from a partial expression of a generalized seizure tendency.

PMID- 10576482
TI  - Determinants of motor unit action potential duration.
AB  - OBJECTIVE: Motor unit action potential (MUAP) recordings are modeled by means of
      a single muscle fiber simulation program, to define two key subcomponents
      comprising the complete physiologic MUAP duration. A number of defining
      properties of these subcomponents are further developed. METHODS: A single muscle
      fiber simulation program is utilized with various muscle fiber lengths and
      conduction velocities to generate near-field and far-field waveforms. RESULTS:
      Two key subcomponents to the total physiologic single muscle fiber and hence MUAP
      duration are identified. One, defined as the near-field component, is directly
      dependent upon muscle fiber hemi-length. The other, defined as the far-field
      component, is independent of fiber length, but matches the internal action
      potential in duration. Both the near-field and far-field components are inversely
      dependent upon intracellular action potential conduction velocity. Additionally,
      temporal dispersion among the individual fibers contributing to a MUAP must be
      included in the overall MUAP duration calculation. CONCLUSIONS: It is hoped that
      this approach to MUAP duration may allow a more complete appreciation of the
      components contributing to the MUAP, than permitted by the empirically derived
      values for MUAP duration presently under clinical use.

PMID- 10576483
TI  - Corticomotor excitability and perception of effort during sustained exercise in
      the chronic fatigue syndrome.
AB  - OBJECTIVE: We have investigated the possibility of a central basis for the
      complaints of fatigue and poor exercise tolerance in subjects with chronic
      fatigue syndrome (CFS). METHODS: Transcranial magnetic stimulation of the motor
      cortex was used to measure sequential changes in motor evoked potential (MEP)
      amplitude, post-excitatory silent period (SP) duration and twitch force of the
      biceps brachii muscle during a 20% maximum isometric elbow flexor contraction
      maintained to the point of exhaustion. Ten patients with post-infectious CFS and
      10 age- and sex-matched control subjects were studied. Results were analysed
      using non-parametric repeated measures analysis of variance (Friedman's test) and
      Mann-Whitney U-tests for intra- and inter-group comparisons respectively.
      RESULTS: Mean endurance time for the CFS group was lower (13.1+/-3.2 min, mean +/
      SEM) than controls (18.6+/-2.6 min, P < 0.05) and CFS subjects reported higher
      ratings of perceived exertion. During the exercise period MEP amplitude and SP
      duration increased in both groups but to a lesser extent in CFS subjects.
      Interpolated twitch force amplitude also increased during exercise, being more
      pronounced in CFS subjects. CONCLUSION: The findings are in keeping with an
      exercise-related diminution in central motor drive in association with an
      increased perception of effort in CFS.

PMID- 10576484
TI  - Electroencephalographic analysis of cortico-muscular coherence: reference effect,
      volume conduction and generator mechanism.
AB  - OBJECTIVE: To measure the synchrony between cortical and muscle oscillatory
      activities, the coherence estimate between EEG and EMG was computed. METHODS: The
      multichannel electroencephalogram (EEG) and electromyogram (EMG) of the right
      abductor pollicis brevis muscle were recorded in 5 normal volunteers. Various
      types of EEG derivation methods were systematically compared to establish a
      standard method to study cortico-muscular coupling. RESULTS: The use of a
      reference-free EEG derivation (current source density) greatly improved cortico
      muscular coherence. In all subjects, EEGs over the left sensorimotor cortex were
      coherent with EMG (mean peak frequency: 18.7 Hz, mean highest coherence: 0.124).
      The time lag from cortex to muscle in 14-50 Hz was 14.3 ms. EEG source derivation
      revealed that both radial and tangential generators in the precentral cortex
      might contribute to this phenomenon. In the EEG signals using common average
      reference, an artifactual coherence peak over the medial frontal area was
      observed, which might largely be explained by volume conduction from the primary
      sensorimotor cortex. CONCLUSIONS: We conclude that the current source density or
      its approximation is preferable to estimate the cortico-muscular coherence and
      that the interpretation of such coherence using referenced EEGs should be taken
      with care.

PMID- 10576485
TI  - Comparison between concentric needle EMG and macro EMG in patients with a history
      of polio.
AB  - OBJECTIVES: Acute poliomyelitis causes degeneration of anterior horn cells,
      followed by denervation. Reinnervation and muscle fibre hypertrophy are
      mechanisms that compensate this loss of neurones. Concentric needle EMG (CNEMG)
      and macro EMG are two methods to assess the magnitude of initial involvement and
      the compensatory reinnervation. The aim of this study is to explore the
      difference between CNEMG and macro EMG describing the status of the motor unit in
      patients previously affected by polio. METHODS: Macro and concentric needle EMG
      investigations were performed in 261 muscles in 121 patients with a remote
      history of polio. RESULTS: CNEMG was abnormal in 211 muscles, macro EMG was
      abnormal in 246 muscles. The macro amplitude was 3-4 times 'more abnormal' than
      CNEMG amplitude relative to the reference values. CNEMG duration was less
      abnormal and showed only weak correlation with macro amplitudes. The most likely
      explanation for the difference in magnitude of deviation from reference values
      for CNEMG and macro EMG, is a more pronounced 'phase cancellation' between single
      fibre action potentials in CNEMG. This is supported by simulation studies
      reported here. CONCLUSIONS: In conclusion macro EMG better reflects the size of
      the motor unit than the CNEMG. For detection of concomitant disorders, CNEMG is
      the method of choice.

PMID- 10576486
TI  - Comparison of different modalities for detection of small fiber neuropathy.
AB  - OBJECTIVES: In general, large fiber sensory function is easier to assess than
      small fiber function both clinically and electrophysiologically. Therefore, small
      fiber sensory neuropathies are more difficult to diagnose. The relative
      sensitivities of different electrodiagnostic tests for small fiber neuropathy are
      not known. We sought to determine and compare the sensitivities of quantitative
      thermal sensory testing (QST), quantitative sudomotor axon reflex testing
      (QSART), and cardiovascular autonomic testing for diagnosis in patients with
      clinically suspected small fiber neuropathy. METHODS: 15 adult patients with
      clinically suspected small fiber sensory neuropathy underwent neurologic
      examination, QST, and QSART. Twelve also underwent cardiovascular autonomic
      testing. RESULTS: 80% had an abnormal neurologic examination consistent with
      small fiber neuropathy, while 93% had at least one abnormal quantitative test.
      QSART was most sensitive with 12 of 15 (80%) having abnormal studies while 10 of
      15 (67%) had abnormal thermal thresholds by QST. Abnormal heart rate with deep
      breathing was detected in 9 of 12 (75%) patients. CONCLUSION: Of the modalities
      tested, QSART was most sensitive in confirming the clinical suspicion of a small
      fiber neuropathy. Autonomic cardiovascular abnormalities were also common in our
      patients. Clinical examination and QSART may be optimal for screening patients
      for small fiber neuropathy.

PMID- 10576487
TI  - Processing of affective pictures modulates right-hemispheric gamma band EEG
      activity.
AB  - The present study was designed to test differential hemispheric activation
      induced by emotional stimuli in the gamma band range (30-90 Hz). Subjects viewed
      slides with differing emotional content (from the International Affective Picture
      System). A significant valence by hemisphere interaction emerged in the gamma
      band from 30-50 Hz. Other bands, including alpha and beta, did not show such an
      interaction. Previous hypotheses suggested that the left hemisphere is more
      involved in positive affective processing as compared to the right hemisphere,
      while the latter dominates during negative emotions. Contrary to this
      expectation, the 30-50 Hz band showed relatively more power for negative valence
      over the left temporal region as compared to the right and a laterality shift
      towards the right hemisphere for positive valence. In addition, emotional
      processing enhanced gamma band power at right frontal electrodes regardless of
      the particular valence as compared to processing neutral pictures. The extended
      distribution of specific activity in the gamma band may be the signature of cell
      assemblies with members in limbic, temporal and frontal neocortical structures
      that differ in spatial distribution depending on the particular type of emotional
      processing.

PMID- 10576488
TI  - Cortical auditory dysfunction in children with oral clefts: relation with cleft
      type.
AB  - OBJECTIVE: Up to 46% of individuals with oral clefts suffer from language
      learning disabilities. The degree of these disabilities varies according to cleft
      type. The pathogenesis of cognitive malfunctioning or its relationship with cleft
      type is not known. We investigated persistence of auditory short-term memory
      (STM) that is implicitly involved in language-specific perception in children
      with clefts, grouped using fine-graded cleft classification. METHODS: Cortical
      evoked potentials were recorded in 78 children with non-syndromic oral clefts and
      in 32 healthy peers. A mismatch negativity (MMN) potential that indexes
      preattentive detection of change in auditory input was obtained in response to
      tone sounds. In order to test durability of short-term memory traces, sounds were
      presented with three stimulation rates. RESULTS: With slowest stimulation, MMN
      amplitudes were reduced in cleft children as compared to the healthy peers (P <
      0.00065). Only cleft-lip children did not significantly differ from controls.
      Among isolated palatal clefts, the more posteriorly delimited the cleft was, the
      smaller was the amplitude of MMN. MMNs of smallest amplitudes were obtained in
      the subgroup of complete unilateral cleft of lip and palate. CONCLUSIONS: Reduced
      MMN amplitudes, found in cleft children, imply deficiency in auditory STM trace
      maintenance. This dysfunction is likely to contribute to their language and
      learning disabilities. The MMN diminution with shorter/more posterior clefts
      suggests that differences in auditory cortex function are one of the underlying
      mechanisms of the cleft type-malcogniton association.

PMID- 10576489
TI  - Auditory associative cortex dysfunction in children with autism: evidence from
      late auditory evoked potentials (N1 wave-T complex).
AB  - OBJECTIVES: Auditory processing at the cortical level was investigated with late
      auditory evoked potentials (N1 wave-T complex) in 4-8-year-old autistic children
      with mental retardation and compared to both age-matched normal and mentally
      retarded children (16 children in each group). METHODS: Two negative peaks which
      occurred in the 80-200 ms latency range were analyzed according to stimulus
      intensity level (50 to 80 dB SPL): the first culminated at fronto-central sites
      (N1b) and the second at bitemporal sites (N1c, equivalent to Tb of the T
      complex). The latter wave was the most prominent and reliable response in normal
      children at this age. RESULTS: Our results in autistic children indicated
      abnormalities of this wave with markedly smaller amplitude at bitemporal sites
      and pronounced peak latency delay (around 20 ms). Moreover, in both reference
      groups the intensity effect was found on both sides whereas in autistic children
      it was absent on the left side but present on the right. CONCLUSION: These
      findings in autistic children showing very disturbed verbal communication argue
      for dysfunction in brain areas involved in N1c generation i.e., the auditory
      associative cortex in the lateral part of the superior temporal gyrus, with more
      specific left side defects when auditory stimulus have to be processed.

PMID- 10576490
TI  - The prognostic value of intraoperative BAEP patterns in acoustic neurinoma
      surgery.
AB  - Based on a consecutive series of 70 hearing patients with unilateral acoustic
      neurinomas and intraoperative monitoring of brain-stem auditory evoked potentials
      (BAEP), 4 dynamic BAEP patterns could be characterized. These patterns correspond
      with early and late postoperative hearing outcome. All patients with stable wave
      V (pattern 1) showed definite hearing preservation, all patients with
      irreversible abrupt loss of BAEP (pattern 2) lost their hearing, despite early
      hearing preservation in two cases. All patients with irreversible progressive
      loss of either wave I or wave V (pattern 3) eventually suffered from definite
      postoperative hearing loss, despite early hearing preservation in two cases.
      Those cases with intraoperative reversible loss of BAEP (pattern 4) showed
      variable short and long term hearing outcome. In 34% hearing was preserved, 44%
      suffered from postoperative hearing loss, the remaining 22% showed postoperative
      hearing fluctuation, either as a delayed hearing loss or as reversible hearing
      loss. Postoperative hearing fluctuation indicates anatomical and functional
      preservation of the cochlear nerve during surgery and is suggestive of a
      pathophysiological mechanism initiated during the surgical procedure and
      continuing thereafter. Patients at risk for delayed hearing loss can be
      identified during surgery by a characteristic BAEP pattern and may benefit from
      vasoactive treatment.

PMID- 10576491
TI  - Impaired preconscious auditory processing and cognitive functions in Alzheimer's
      disease.
AB  - OBJECTIVE: To study whether preconscious auditory processing is deteriorated in
      patients with Alzheimer's disease (AD) having mild to moderate cognitive
      symptoms. To investigate whether auditory processing correlates with the
      impairment of the higher cortical functions. METHODS: P50m and N100m responses
      elicited by a sequence of repetitive tones were recorded with a whole-head
      magnetometer from 22 patients with probable AD and from 18 healthy age-matched
      controls. In addition, an extensive neuropsychological test battery assessing
      main cognitive domains was administered to all subjects. RESULTS: The patients
      with AD had significantly delayed N100m responses in the left hemisphere that
      correlated with the impairment of the language functions. CONCLUSIONS: N100m
      auditory responses measured with magnetoencephalography may be useful in
      evaluating the severity and progression of the cortical dysfunction in dementia.

PMID- 10576492
TI  - Comparison of somatosensory evoked high-frequency oscillations after posterior
      tibial and median nerve stimulation.
AB  - OBJECTIVE: We compared the high-frequency oscillations (HFOs) evoked by posterior
      tibial nerve (PTN) and median nerve (MN) stimulation. METHODS: Somatosensory
      evoked potentials (SEPs) were recorded with a filter set at 10-2000 Hz to right
      PTN and to right MN stimulation in 10 healthy subjects. The HFOs were obtained by
      digitally filtering the wide-band SEPs with a band-pass of 300-900 Hz. RESULTS:
      HFOs were recorded in 8 of the 10 subjects for PTN, and in all subjects for MN
      stimulation. The HFOs after both PTN and MN stimulation started approximately at
      or after the onset of the primary cortical response (P37 and N20) and ended
      around the middle of the second slope. HFO amplitudes and area after PTN
      stimulation were significantly smaller than those after MN stimulation. HFO
      duration after PTN stimulation was markedly longer than that after MN
      stimulation. However, HFO interpeak latencies did not differ between the two
      nerves. CONCLUSIONS: The present findings suggest that the HFOs after PTN and MN
      stimulation reflect a neural mechanism common to the hand and foot somatosensory
      cortex.

PMID- 10576493
TI  - Steady-state vibration somatosensory evoked potentials: physiological
      characteristics and tuning function.
AB  - OBJECTIVE: The steady-state somatosensory evoked potentials (S-SEPs) to vibratory
      stimulation were recorded to characterize their physiological properties.
      METHODS: Vibratory stimuli were applied to the right palmar surface in 10 normal
      subjects. A total of 200 responses were recorded from electrodes at 2 cm
      posterior to C3, Cz and C4 and 2 cm anterior to C3. All responses were Fourier
      analyzed and the amplitudes of the first (1F) and second (2F) harmonic components
      were thus obtained. The effects of modulation frequency (5-30 Hz) and stimulus
      intensity (0.001-0.1 Newton (N)) on S-SEPs were studied. RESULTS: The amplitudes
      of 1F and 2F were greatest at the electrode 2 cm posterior to C3, 1F being
      predominant. The mean 1F amplitudes as a function of modulation frequency showed
      a bimodal distribution with a trough at 14 Hz and a peak at 21 Hz. The mean 1F
      amplitudes showed a linear increase of up to 0.05 N and thereafter reached a
      plateau against the logarithmic stimulus intensity axis. CONCLUSION: Vibratory S
      SEPs may originate from the primary somatosensory cortex and provide information
      on the fast-adapting mechanoreceptive afferents. The temporal resonance at 21 Hz
      places the somatosensory system between the visual and auditory systems.

PMID- 10576494
TI  - The effect of spatial frequency on chromatic and achromatic steady-state visual
      evoked potentials.
AB  - OBJECTIVE: Little is known about the physiological properties of the major
      components of steady-state visual evoked potentials (VEPs). Based on the
      hypothesis that isoluminant color and high contrast pattern differentially
      activate the parvo- and magnocellular pathways, we studied difference in spatial
      frequency function between chromatic and achromatic VEPs to sinusoidal gratings.
      METHODS: Steady-state VEPs to isoluminant chromatic (red-green) and high contrast
      (90%) achromatic (black-white) sinusoidal gratings with nine spatial frequencies
      (0.5 to 8.0 cycles/degrees (cpd)) at 4 Hz (8 reversals/s) were recorded in 13
      normal subjects. VEPs were Fourier analyzed to obtain phase and amplitude of the
      second (2F) and fourth (4F) harmonic responses. RESULTS: The 2F amplitude of
      chromatic VEPs decreased above 4.0 cpd in a low-pass function while that of
      achromatic VEPs showed a band-pass function with a peak at 4.0 cpd. The 4F
      amplitude of chromatic VEPs was not affected significantly by spatial frequency
      whereas that of achromatic VEPs exhibited a high-pass function. The phases of 2F
      and 4F showed a non-monotonic function of spatial frequency in both chromatic and
      achromatic stimuli with peaks at middle spatial frequencies. CONCLUSION:
      Chromatic and achromatic visual stimuli differently affected 2F and 4F
      components, which thus suggests that 2F and 4F components are generated from
      different neuronal subgroups largely in the parvocellular pathway.

PMID- 10576495
TI  - Independent sleep EEG slow-wave and spindle band dynamics associated with 4 weeks
      of continuous application of short-half-life hypnotics in healthy subjects.
AB  - OBJECTIVES: Habituation and adverse withdrawal reactions after prolonged
      medication with benzodiazepine (BZ) hypnotics are believed to play a role in dose
      escalation and the development of dependence. METHODS: In the current sleep EEG
      study in 43 healthy male subjects, the known property of BZ- and similar
      hypnotics to change the NREM sleep EEG spectrum is utilized for a detailed
      quantitative analysis across 4 weeks of continuous medication and a subsequent
      two-week withdrawal period. The BZ hypnotic triazolam and the non-BZ hypnotics
      zopiclone and zolpidem, differing in pharmacological properties and reported
      adverse effects, were examined in parallel to a placebo group. RESULTS: Reliably
      occurring spectral effects in the sleep stage 2 EEG were found in the 3 frequency
      bands 0.8-5 Hz, 5-10 Hz and 10-15 Hz. All 3 hypnotics showed the typical
      'benzodiazepine signature', a 10-15 Hz increase and lower-frequency (<10 Hz)
      suppression relative to the preceding drug-free night. However, these effects
      developed differently across the first medication night, across the 4 medication
      weeks and after withdrawal: While the 5-10 Hz effect covaried with the blood
      presence of the drugs as estimated from the known plasma half-lifes, showed
      habituation and a rebound after withdrawal, the 10-15 Hz power increased across
      medication days and showed no rebound. Effects in the 0.8-5 Hz band in the first
      medication night correlated with the decrease of sleep efficiency at later
      withdrawal for triazolam and zolpidem.

PMID- 10576496
TI  - Changes in long-latency reflexes onset latencies across full-wave rectified and
      non-rectified recordings.
AB  - Electrically elicited long-latency reflexes (LLRs) were obtained from thenar
      muscles by either fully rectified or non-rectified raw recordings in 10 healthy
      volunteers. The LLR II onset latencies were significantly (P < 0.0001) delayed on
      rectified (mean +/- SD: 49.8+/-2.9 ms) compared to raw (45.3+/-2.3 ms)
      recordings, with a mean difference of 4.4 ms. These data show that, according to
      the recording technique employed, the LLR II onset latencies can change
      considerably. The possible implications on cortical relay time (CRT) calculation
      and the understanding of the intracortical connections physiology are discussed.

PMID- 10576497
TI  - Identification of hemifield single trial PVEP on the basis of generalized dynamic
      neural network classifiers.
AB  - This paper is concerned with the application of generalized dynamic neural
      networks for the identification of hemifield pattern-reversal visual evoked
      potentials. The identification process is performed by different networks with
      time-varying weights using signals from different electrode positions as external
      inputs. Since dynamic neural networks are able to process time-varying signals,
      the identification of the stimulated hemiretinae is performed without feature
      extraction. The performance of the method presented is compared with a reference
      method based on the values of instantaneous frequency at the occipital electrode
      positions at P100 latency.

PMID- 10576498
TI  - The RULER model. Is this how the somatosensory cortex works?
AB  - Despite a wealth of information, it is still not known how neurones in the
      different neocortical layers interact to produce a conscious perception. We now
      put forward a model for the somatosensory cortex in which a touch is perceived
      whenever superficial cortical pyramidal cells (in layers II and III) are made to
      discharge by a recurrent input from deep pyramidal neurones (in layer V). The
      superficial cells act as biological amplifiers and the number discharging will
      depend both on the strength of the message from the thalamus and on the variable
      background depolarisation of their apical dendrites. The recurrent volley arises
      in the layer V neurones at the end of an IPSP (inhibitory postsynaptic
      potential), which itself follows an excitatory response induced by the incoming
      thalamic signal; the IPSP is generated by local basket cells. The duration of the
      initial excitation--IPSP--late excitation sequence corresponds to a time chunk,
      that is, the period over which neural activity is integrated to produce a
      perception. During the time chunk, the superficial cortical pyramids, unlike the
      deeper ones, can accumulate information as subthreshold excitatory postsynaptic
      potentials (EPSPs). The relative time at which the information arrived in the
      cortex is roughly coded by the gradient of EPSPs among cells in an axis
      perpendicular to the cortical surface. Although developed for the somatosensory
      cortex, the basic features of the model may well apply to other sensory receiving
      areas of the cortex.

PMID- 10576499
TI  - Bilateral centrotemporal spikes triggered by blinking: an unusual form of sensory
      input with related cortical EEG activity.
AB  - OBJECTIVE: To investigate the morphology, scalp topography and temporal
      relationship with orbicularis oculi muscle contraction of bilateral blink related
      spikes (BRS) in a 7-year-old boy with chromosomopathy, mild mental retardation
      and left spontaneous centrotemporal spikes (SS). METHODS: The patient underwent
      video-polygraphic recordings with off-line analysis of SS and BRS by means of
      spike-averaging and orbicularis oculi contraction-locked averaging techniques
      respectively. EEG activity related to reflex blinking (evoked by glabellar
      tapping) was also studied. RESULTS: SS and BRS presented the same morphology,
      characterised by four peaks (P1, N1, P2, N2). SS were located over the left
      centroparietal regions, while BRS were placed over both left and right
      centrotemporoparietal regions and constantly followed the contraction of
      orbicularis oculi with overlapping peak latencies over C3 and C4 electrodes (P1
      72 ms; N1 115 ms; P2 164 ms; N2 236 ms). Reflex blinking evoked a small waveform
      with the same features as BRS. CONCLUSIONS: Our findings suggest that both
      involuntary and reflex blinking can act as a form of sensory stimulation probably
      engaging similar nervous pathways and cortical sources in generating EEG
      abnormalities: the trigeminal system.

PMID- 10576500
TI  - Genotype of glutathione S-transferase and other genetic configurations in
      myelodysplasia.
AB  - We examined polymorphisms of glutathione S-transferase (GST) genes in 159
      Japanese patients with myelodysplasia and compared the incidence with that in 43
      normal individuals to clarify their pathogenetic significance in myelodysplasia.
      In individuals with the GSTT1 null genotype, the odds ratios for disease risk
      were elevated to 2.65 (95%CI; 1.27-5.52) in de novo MDS, 4.62 (1.48-14.4) in
      therapy-related AML, and 2.94 (1.07-8.07) in AML with triliniage dysplasia. Other
      representative polymorphisms of GSTs had a similar incidence among patients with
      myelodysplasia, and those of the controls and other hematological disorders. To
      further investigate the genetic pathway of myelodysplasia, the association
      between GST genotype and karyotype or configurations of TP53 and NRAS was
      evaluated, but no relationship was noted. These results suggest that the GSTT1
      null genotype may play a role in an increased risk of myelodysplasia unrelated to
      other mechanisms of myelodysplasia, such as chromosomal alterations or mutation
      of TP53 or NRAS.

PMID- 10576501
TI  - Resident bone marrow macrophages in idiopathic (primary) myelofibrosis (IMF): a
      histochemical and morphometric study on sequential trephine biopsies.
AB  - A histochemical and morphometric study was performed on sequential bone marrow
      biopsies in 65 patients with idiopathic (primary) myelofibrosis (IMF) to quantify
      the resident-mature CD68+ macrophages and a peculiar, so-called activated
      subpopulation. Statistical analysis revealed no significant correlations between
      number of macrophages, density of argyrophilic fibers and degree of myeloid
      metaplasia. Our results are reflecting in vitro findings on cytokine release,
      macrophage activation and their complex functional associations with
      myelofibrotic matrix formation. Macrophage growth is assumed to be related to a
      number of putative pathomechanisms including abnormal (upregulated) cytokine
      expression (PDGF, TGF-beta, IL-1), enhancement and activation by CSF-1 (M-CSF)
      and possibly also phagocytic stimulation. The latter feature may be triggered by
      increased degradation of senescent megakaryocytes, frequently occurring as
      endstages of growth factors-releasing fibrogenetic megakaryopoiesis.

PMID- 10576502
TI  - Kinetic characteristics of de novo and secondary AML cells influence their
      response to haemopoietic growth factor (HGF) priming and correlate with clinical
      outcome.
AB  - This study has assessed the effect of in vitro haemopoietic growth factor (HGF)
      priming on the S phase activity of cells from patients with de novo AML and AML
      secondary to MDS. The occurrence of receptors for G-CSF, GM-CSF, IL-3 and SCF on
      marrow cells was assessed using immunofluorescent ligand binding assays.
      Additionally, patients responses to first phase induction chemotherapy was
      recorded to examine whether in vitro kinetic data might correlate with clinical
      outcome. All kinetic and receptor assays were performed in normal marrow cells to
      ascertain their response to priming. Incubation of AML cells in serum free medium
      (SFM) +/- G + GM-CSF, IL-3, SCF, G + GM-CSF + SCF or IL-3 + SCF prior to S phase
      assessment revealed that priming permutations inclusive of SCF were most
      effective but also that the baseline level of S phase activity with SFM alone
      influenced the subsequent response to priming. Regardless of AML group, samples
      with low baseline S phase activity (< 10%) were significantly more responsive
      than those with high (> 10%) SFM S phase levels. However there was no
      corresponding difference in the percentages of cells bearing receptors. In both
      AML groups, low baseline S phase activity was observed more frequently in samples
      from patients who achieved CR. Normal samples possessed receptors for all HGFs
      and were responsive to all priming permutations except SCF alone. This study
      raises four points: (a) it may be prudent to reserve the use of priming HGFs for
      those patients with low baseline S phase activity whose cells respond in vitro
      and to use SCF in these priming cocktails; (b) the presence of receptors capable
      of ligand binding in AML samples did not guarantee kinetic response; (c) normal
      progenitors were responsive to priming which may have implications for
      haemopoietic reconstitution post therapy; and (d) the kinetic characteristics of
      AML progenitors may influence clinical outcome regardless of whether treatment
      includes HGFs.

PMID- 10576503
TI  - Amphotericin B lipid complex for the treatment of patients with acute leukemia
      and hepatosplenic candidiasis.
AB  - Hepatosplenic candidiasis (HSC) is an emerging complication of the treatment of
      patients with acute leukemia. Treatment of this infection can be very difficult
      and data on the duration of antifungal therapy are not available. We evaluated
      the efficacy of amphotericin B lipid complex (ABLC) for the treatment of five
      patients with acute leukemia and HSC. The dose of the administered ABLC ranged
      between 5 and 11 mg/kg per day and the median duration of therapy was 4.3 months.
      Four patients had complete response to the above treatment with resolution of
      fever and improvement in the radiologic findings. One patient refused to continue
      treatment and subsequently died with relapsed leukemia and disseminated Candida
      infection. Preliminary data suggest that ABLC is a well-tolerated and effective
      treatment for HSC and should be considered for phase II trials as front line
      treatment for this type of deep seated fungal infections.

PMID- 10576504
TI  - A new complex variant Philadelphia chromosome, t(1;9;22)ins(17;22), characterized
      by fluorescence in situ hybridization in an adult ALL.
AB  - A new complex variant Philadelphia chromosome was detected in a 65-year-old man
      with acute, pre-B, lymphoblastic leukemia (ALL). The classic cytogenetic analysis
      identified an apparently balanced three-way translocation
      t(1;9;22)(q25;q34;q11.2). Fluorescence in situ hybridization (FISH) studies
      confirmed the translocation and showed bcr/abl fusion on the der(22). However,
      these studies revealed that the distal part of the bcr gene was not translocated
      onto chromosome 1 at 1q25, but inserted into chromosome 17 at 17p12-13. This
      complex variant translocation was described as a
      t(1;9;22)(q25;q34;q11.2)ins(17;22)(p12-13;q11.2q11.2). Secondary changes
      including +8, an inversion of the derivative chromosome 9, a translocation
      t(14;20)(q11;q13), and an additional derivative 22 were also identified in most
      of the abnormal cells. The patient died from systemic fungemia and multiorgan
      failure 9 months after the diagnosis of ALL. The clinical significance of complex
      variant Philadelphia chromosomes in ALL is reviewed and discussed.

PMID- 10576505
TI  - Pleiotropic drug resistance in B-cell chronic lymphocytic leukaemia--the role of
      Bcl-2 family dysregulation.
AB  - B-cell chronic lymphocytic leukaemia (B-CLL) is an incurable clonal disease which
      shows initial responsiveness to a number of chemotherapeutic drugs. However, most
      treated patients become resistant to treatment and this represents a major
      problem in the successful management of the condition. Experimental evidence
      points to the fact that most chemotherapeutic drugs ultimately exert their cell
      killing effect through the process of apoptosis. In this study we compared the
      apoptotic responses of B-CLL cells in vitro following exposure to several
      chemotherapeutic drugs. We found that there was a correlation between ID50 values
      for all the drugs under investigation; particularly between Chlorambucil and
      Fludarabine (P = 0.0002). In addition, we analysed the expression of Bcl-2 and
      Bax, two proteins pivotal to the regulation of apoptosis, both immediately ex
      vivo and in viable and apoptotic sub-populations following exposure to drug. Our
      data suggest that high Bcl-2/Bax ratios may be predictive of a drug resistant
      phenotype in B-CLL cells and that modulation of these proteins is essential for
      the induction of cell death. Furthermore, it seems likely that the superior
      potency that has been ascribed to Fludarabine is due to it being administered in
      a more optimised dose. A recently reported clinical trial of Fludarabine against
      high-dose Chlorambucil supports this view since it showed that both treatment
      modalities were comparable in terms of response rate and survival times.

PMID- 10576506
TI  - Differential activity of glycosaminoglycans on colony-forming cells from cord
      blood. Preliminary results.
AB  - Heparin, heparan sulfate and chondroitin sulfate were evaluated for their
      possible role on proliferation and differentiation of hematological precursor
      cells from cord blood. For these purposes, different concentrations of
      glycosaminoglycans were added to methyl-cellulose in colony assay performed with
      human cord blood derived cells. A volume of 10 microg/ml heparin induces a
      significant increase of both granulocyte-monocyte and granulocyte colonies, and a
      decrease of erythroid-colonies, more evident in the presence of 100 microg/ml.
      Heparan sulfate-treatment induces a significant increase of all granulocyte
      monocyte colonies derived from CFU-granulocyte-monocyte, CFU-granulocyte and CFU
      monocyte precursors. A significant decrease of multipotent cells was also
      observed. On the other hand, chondroitin sulfate induces an increase of
      granulocyte-colonies and a decrease of erythroid-colonies. Glycosaminoglycans
      with different structure may be useful to increase the number of specific
      colonies. The selective and differential binding of glycosaminoglycans with
      several growth factors and the regulation of their activities is discussed.

PMID- 10576507
TI  - Cytotoxic and antiproliferative effects of heptaacetyltiliroside on human
      leukemic cell lines.
AB  - The peracetylated derivative of kaempferol-3-O-beta-D-(6''-E-p-coumaroyl)
      glycopyranoside (tiliroside) (1a) was tested for its cytotoxic and cytostatic
      activity against several human leukemic cell lines. The significant cytotoxic
      activity of this derivative, prompted to an additional examination on some of the
      cell lines used. The effect on the uptake of [3H]thymidine as a marker of DNA
      synthesis and on the cell proliferation, was investigated as well as the
      morphology of the cells and the kind of death induced, using the Wright-Giemsa
      dye and horizontal agarose-gel electrophoresis. Flow cytometric experiments of 1a
      on some leukemic cell lines was also performed. Compound 1a showed a significant
      antiproliferative effect as soon as 1 h of continuous incubation at all cell
      lines tested. Cells were killed, through the process of apoptosis and the
      appearance of the apoptotic signs was time and dose-dependent, while from the
      flow cytometric experiments, a synchronisation (through a delay probably in the
      G(0/1) phase) of the cells seems to take place.

PMID- 10576508
TI  - Ex-vivo expansion and maturation of CD34-positive hematopoietic progenitors
      optimization of culture conditions.
AB  - The aim of this study was to look for an ex vivo culture system for clinical
      application. We evaluated the ex vivo expansion of peripheral blood CD34+ cells
      in gas-permeable bags and whether or not an exogenous protein source would be
      required in these kind of cultures. We also evaluated maturation of the cells
      during culture. Cells were cultured for 15 days in medium supplemented with SCF,
      G-CSF, IL3 and IL6. The bags supported the expansion of hematopoietic cells in a
      similar manner to small scale flasks system: (a) the expansion means of total
      nucleated cells on day +5 were 12.5-fold for bag versus 5-fold for flask, on day
      +10 were 44.12-fold for bag versus 41-fold for flask and on day +15 were 67.7
      fold for bag versus 84.2-fold for flask, (b) the peak values of CFU-GM were
      reached on day +10 (9.2-fold for bag vs. 12-fold for flask), and (c) maximal
      expansion of CD15+/CD11b- population occurred on day +10 (517.5-fold for bag vs.
      2959.2-fold for flask). So, we did not find any advantages by culturing further
      than day +10. We subsequently investigated the use of serum-free medium. The
      study showed better results when we used medium supplemented with autologous
      plasma versus serum-free system. In summary, these data described a strategy of
      culture clinically feasible and safe, using gas-permeable bags, and the kinetics
      and differentiation of neutrophils and neutrophil precursors from selected CD34+
      cells in liquid cultures. Ex vivo expansion of this population might result in
      earlier engraftment as compared with that for selected stem cells alone.

PMID- 10576509
TI  - p53 gene deletion and trisomy 12 in hairy cell leukemia and its variant.
AB  - The deletion or mutation of the p53 tumour suppressor gene on chromosome 17p13 is
      known to be associated with aggressive disease in several B-cell malignancies.
      The present study describes the p53 gene status in 20 cases of hairy cell
      leukemia (HCL) and in 12 cases of its morphological variant (HCL-V) by
      fluorescence in situ hybridization (FISH). A high incidence of p53 deletion was
      found in both diseases (75-100% of cases). However, a significant difference was
      observed between the proportion of cells with p53 deletion in HCL-V cases (mean
      31%) and HCL cases (mean 12%) P value < 0.01. The observed difference correlates
      with the well known tendency for transformation and poor response to therapy in
      HCL-V and seven cases of HCL-V with greater than 22% of cells with p53 deletion
      showed features of disease progression and transformation. Trisomy 12 was present
      in 8.5% of the cells in one case of HCL-V and in 6-8% of cells in three cases of
      HCL.

PMID- 10576510
TI  - Transfer of the cytidine deaminase cDNA into hematopoietic cells.
AB  - In order to investigate whether transfer of the cytidine deaminase (CDD) cDNA
      would increase chemotherapy resistance to cytosine arabinoside (ara-C) we used a
      retroviral vector expressing both, neomycin phosphotransferase and the CDD cDNA,
      to transduce hematopoietic cells from cell lines and from murine bone marrow
      (BM). After coculture on producer clones with a viral titer of 1 x 10(5) CFU/ml
      and up to 3-fold increased CDD enzymatic activity, WEHI-3 cell line and primary
      hematopoietic cells were exposed to ara-C in clonogenic assays. A transduction
      efficiency of 34.8 +/- 6.2% could be determined for BM clonogenic progenitor
      cells by G418 resistance. We could observe significantly more colonies (77 +/-
      3.1%) surviving from transduced primary BM cells than from mock cells (51.7 +/-
      9.3%) at 10(-8) mol/l ara-C. At 10(-7) mol/l ara-C 8.7% of BM cells became
      absolutely resistant after retroviral transduction. Our data confirm that CDD
      represents another candidate gene for increasing resistance to cytotoxic drugs in
      hematopoietic cells.

PMID- 10576511
TI  - ABL-BCR expression in BCR-ABL-positive human leukemia cell lines.
AB  - Expression of normal ABL and BCR and of reciprocal fusion genes BCR-ABL and ABL
      BCR was examined in a panel of 53 BCR-ABL-positive cell lines by RT-PCR to
      determine the influence of the various transcripts on leukemogenesis. Seventeen
      out of 18 lymphoid cell lines expressed ABL1a and/or ABL1b, whereas only 16 out
      of 35 myeloid cell lines expressed one or both normal ABL transcripts. Normal BCR
      was expressed in seven lymphoid cell lines; all cell lines from the m-bcr group
      (n = 9) were BCR-negative. Among the myeloid cell lines, 77% expressed the BCR
      gene. The M-bcr and m-bcr translocations were equally distributed among cell
      lines with lymphoid phenotype. The m-bcr translocation was not found in myeloid
      cell lines. b3-a2 constitutes the predominant form of fusion gene in myeloid cell
      lines with an incidence of about 68%. One myeloid cell line exhibited the mu-bcr
      variant. An ABL-BCR transcript of the 1a splice variant was not detected in any
      of the cell lines. ABL1b-BCR was expressed in all varieties of cell types and
      translocation forms: 56 and 66% in the lymphoid and myeloid cell lines,
      respectively; similar distributions were found for the fusion gene types: 67%
      among e1-a2, 73% among b2-a2, and 61% among b3-a2 translocations. Except for the
      lack of expression of normal BCR in m-bcr cell lines and of ABL1a-BCR expression
      in all cell lines, no consistent correlation of expression or lack of expression
      of BCR and ABL or of ABL-BCR reciprocal fusion genes could be found with cell
      lineages and translocation types. Further work is required to determine the exact
      role of the reciprocal fusion gene transcripts on the pathophysiological
      mechanisms of leukemogenesis.

PMID- 10576512
TI  - Pre-clinical evaluation of SN-38 and novel camptothecin analogs against human
      chronic B-cell lymphocytic leukemia lymphocytes.
AB  - The topoisomerase I inhibitor camptothecin and its analogs have potent activity
      against a wide range of solid tumors and several hematologic malignancies.
      Previous studies with these compounds using the MTT metabolic inhibition assay
      have shown significant cytotoxicity against lymphocytes from patients with
      chronic B-cell lymphocytic leukemia (B-CLL). Yet the water soluble analogue,
      topotecan, which was inhibitory at > 1 microM in vitro, had no clinical activity
      in vivo. In the present study, we evaluated the in vitro cytotoxicities of SN-38,
      the active form of irinotecan, and two newer water soluble camptothecin
      derivatives 10,11-methylenedioxy-20(S)-camptothecin glycinate (MDCG) and 7
      chloromethyl-10,11-methylenedioxy-20(S)-camptothecin glycinate (CMMDCG). These
      two glycinate esters are prodrugs for 10,11-methylenedioxy-20(S)-camptothecin
      (MDC) and 7-chloromethyl-10,11-methylenedioxy-20(S)-camptothecin (CMMDC),
      respectively. Effects on cellular metabolism, induction of apoptosis, and overall
      cell survival were used to evaluate chemosensitivity. We report that the relative
      cytotoxic potency for these compounds is MDC > or = CMMDC > or = SN-38 >> TPT >
      CPT-11, where MDC, CMMDC, and SN-38 were over an order of magnitude more
      cytotoxic than TPT and CPT-11. We also investigated potential mechanisms
      underlying the unexpected cytotoxicity of these camptothecin derivatives in B-CLL
      cells that are known to be arrested in G0/G1 of the cell cycle, and found that
      this class of compounds inhibited [3H]uridine incorporation. We therefore
      postulate that the inhibition of RNA rather than DNA synthesis may be responsible
      for the observed cytotoxicity in non-cycling B-CLL cells.

PMID- 10576513
TI  - EBV infection induced transformation of benign T lymphoproliferative state in
      patient with chronic active EBV infection into malignant lymphoma: implication of
      EBV infection as additive oncogenic factor in tumorigenesis.
AB  - An 11-year-old girl with chronic EBV (Epstein-Barr virus) infection, who later
      developed malignant lymphoma in the lung, is reported. She had an increased
      number of V alpha2, V beta8, CD3, CD4, and HLADR positive activated lymphocytes
      (20-30% of total lymphocytes) in peripheral blood. One year later, she developed
      lymphoma in the lung, which was V alpha2, V beta8, CD3, CD4, HLADR and IL2Rbeta
      positive. At that time, the population in the peripheral blood increased up to
      40%, but there was no evidence of lymphoma in the bone marrow. In situ
      hybridization revealed lymphoma cells were EBER-1 positive but gp350/220 and LMP
      mRNA negative. The EBV genome was detected in the tumor, but not in the
      peripheral T cells. Clonal analysis of the lymphoma cells revealed monoclonal
      rearrangement of the TcRbeta and gamma gene, however, investigation of the
      terminal repeat of EBV gene did not show the monoclonal pattern. These results
      indicate that infection of EBV into clonally activated T cells was related with
      transformation from benign lymphoproliferative disease to malignant lymphoma in
      this patient.

PMID- 10576514
TI  - Trisomy 21 as the sole acquired karyotypic abnormality in acute myeloid leukemia
      and myelodysplastic syndrome.
AB  - We report five cases of myeloid disorders in which trisomy 21 (+21) was found as
      the sole acquired karyotypic abnormality, comprising two cases of acute myeloid
      leukemia (AML) and three cases of myelodysplastic syndrome (MDS). In this series,
      MDS patients with +21 presented as high grade disease, which included two cases
      of refractory anemia with excess of blasts (RAEB) and one case of refractory
      anemia with excess of blasts in transformation (RAEBt), and showed rapid disease
      progression. Significant thrombocytopenia was observed in all three patients, and
      bone marrow examination showed a marked reduction in megakaryocytes. AML patients
      with +21 included one case each of AML-M2 and M4. Despite the poor prognosis
      reported in AML patients with +21 as the sole abnormality, the patient in our
      series who was able to complete intensive treatment was cured of disease. The
      role of +21 in leukemogenesis is reviewed.

PMID- 10576515
TI  - New diabetes criteria and clinical implications.

PMID- 10576516
TI  - Measurement of insulin resistance in vivo.
AB  - Insulin sensitivity, which can be impaired in both glucose-intolerant and non
      glucose-intolerant individuals, is a valuable parameter because of its potential
      as a marker for the future development of diabetes and increased cardiovascular
      risk. Techniques available for the determination of insulin sensitivity include
      the glucose clamp, insulin tolerance test, insulin suppression test, the
      frequently sampled intravenous glucose tolerance test and the regional artero
      venous balance. Model assessment methods are also available for the measurement
      of insulin sensitivity at steady-state plasma glucose and insulin levels or after
      a standardised glucose infusion. Methods vary in their complexity, and the choice
      between them depends on the nature of the information required. There is also
      evidence for a strong genetic contribution to insulin sensitivity; although
      identification of the relevant gene(s) has not yet been successful, accurate
      phenotyping should still be carried out as part of the assessment of a patient's
      clinical status.

PMID- 10576517
TI  - General characteristics of the insulin resistance syndrome: prevalence and
      heritability. European Group for the study of Insulin Resistance (EGIR).
AB  - It has recently been recommended by a WHO expert committee that the insulin
      resistance syndrome, a cluster of cardiovascular risk factors linked to insulin
      resistance, should be termed 'the metabolic syndrome'. Characterisation with data
      from 2 large databases [the European Group for the study of Insulin Resistance
      (EGIR) and the Danish Twin Register] has shown that insulin resistance correlates
      closely with the various components of the metabolic syndrome, and that the
      prevalence of the syndrome is approximately 16% among Caucasians. Both
      genetically determined and environmentally induced insulin resistance may
      precipitate onset of the metabolic syndrome, and increased levels of abdominal
      fat may be of primary importance in its development.

PMID- 10576518
TI  - Pathogenesis of insulin resistance in type 2 diabetes: a collision between
      thrifty genes and an affluent environment.

PMID- 10576519
TI  - Visceral obesity and diabetes.
AB  - Visceral obesity is a strong predictor of type 2 (non-insulin-dependent) diabetes
      and is associated with insulin resistance. In addition, research has indicated
      that the accumulation of visceral fat is regulated by endocrine mechanisms. Data
      suggest that progressive malfunction of the hypothalamic-pituitary-adrenal (HPA)
      axis, with elevation of levels of cortisol and reductions in levels of sex
      steroids and growth hormone, is associated with visceral accumulation of fat that
      contributes to circulating levels of free fatty acids, and that these factors are
      implicated in the development of insulin resistance. Furthermore, failure of
      central feedback control of the HPA axis by glucocorticoid receptors (GR) appears
      to be correlated with polymorphisms near the first exons of the GR gene. The HPA
      axis disturbances are similar to those seen after prolonged exposure to
      environmental stress. Psychosocial and socioeconomic factors, alcohol, depressive
      traits and anxiety are linked to HPA axis abnormalities.

PMID- 10576520
TI  - Syndrome X: 10 years after.

PMID- 10576521
TI  - Clinical efficacy of metformin against insulin resistance parameters: sinking the
      iceberg.
AB  - It has been increasingly recognised in recent years that type 2 (non-insulin
      dependent) diabetes is part of a cluster of cardiovascular risk factors known as
      the metabolic syndrome, but also endorsed with such names as the deadly quartet,
      syndrome X and the insulin resistance syndrome. Atherosclerosis is the most
      common complication of type 2 diabetes among Europeans, and coronary artery,
      cerebrovascular and peripheral vascular disease are 2 to 5 times more common in
      people with this condition than in those without diabetes. These observations
      indicate that the treatment of type 2 diabetes requires agents that do more than
      simply lower blood glucose levels, and a therapy with both antihyperglycaemic
      effects and beneficial effects on dyslipidaemia, hypertension, obesity,
      hyperinsulinaemia and insulin resistance is likely to be most useful. In this
      respect, metformin has an important and established role: this drug has been
      shown to lower blood glucose and triglyceride levels, and to assist with weight
      reduction and to reduce hyperinsulinaemia and insulin resistance. Studies in the
      Israeli sand rat, Psammomys obesus, have indicated hyperinsulinaemia/insulin
      resistance to be the initial and underlying metabolic disorder in obesity and
      type 2 diabetes. Thus, the well established effect of metformin in reducing
      insulin resistance makes this drug an excellent candidate for the prevention of
      progression of impaired glucose tolerance to type 2 diabetes, and for the
      reduction of mortality associated with cardiovascular disease.

PMID- 10576522
TI  - Pathogenesis of type 2 diabetes: implications for metformin.

PMID- 10576523
TI  - The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms.
AB  - Metformin is regarded as an antihyperglycaemic agent because it lowers blood
      glucose concentrations in type 2 (non-insulin-dependent) diabetes without causing
      overt hypoglycaemia. Its clinical efficacy requires the presence of insulin and
      involves several therapeutic effects. Of these effects, some are mediated via
      increased insulin action, and some are not directly insulin dependent. Metformin
      acts on the liver to suppress gluconeogenesis mainly by potentiating the effect
      of insulin, reducing hepatic extraction of certain substrates (e.g. lactate) and
      opposing the effects of glucagon. In addition, metformin can reduce the overall
      rate of glycogenolysis and decrease the activity of hepatic glucose-6
      phosphatase. Insulin-stimulated glucose uptake into skeletal muscle is enhanced
      by metformin. This has been attributed in part to increased movement of insulin
      sensitive glucose transporters into the cell membrane. Metformin also appears to
      increase the functional properties of insulin- and glucose-sensitive
      transporters. The increased cellular uptake of glucose is associated with
      increased glycogen synthase activity and glycogen storage. Other effects involved
      in the blood glucose-lowering effect of metformin include an insulin-independent
      suppression of fatty acid oxidation and a reduction in hypertriglyceridaemia.
      These effects reduce the energy supply for gluconeogenesis and serve to balance
      the glucose-fatty acid (Randle) cycle. Increased glucose turnover, particularly
      in the splanchnic bed, may also contribute to the blood glucose-lowering
      capability of metformin. Metformin improves insulin sensitivity by increasing
      insulin-mediated insulin receptor tyrosine kinase activity, which activates post
      receptor insulin signalling pathways. Some other effects of metformin may result
      from changes in membrane fluidity in hyperglycaemic states. Metformin therefore
      improves hepatic and peripheral sensitivity to insulin, with both direct and
      indirect effects on liver and muscle. It also exerts effects that are independent
      of insulin but cannot substitute for this hormone. These effects collectively
      reduce insulin resistance and glucotoxicity in type 2 diabetes.

PMID- 10576524
TI  - Insulin resistance, polycystic ovary syndrome and metformin.
AB  - Polycystic ovary syndrome (PCOS) is the most common disorder of ovarian function
      in premenopausal women. PCOS is characterised by chronic anovulation and androgen
      excess with clinical manifestation of irregular menstrual cycles, hirsutism
      and/or acne. Insulin resistance with resultant hyperinsulinaemia, irrespective of
      excess weight or frank obesity, has been reported in patients with PCOS, and, as
      insulin has a direct effect on ovarian androgen production in vitro, insulin
      resistance may play a crucial role in the physiopathology of PCOS. Although the
      molecular mechanism(s) of insulin resistance in PCOS is unclear, excessive
      insulin-independent serine phosphorylation of the beta subunit of the insulin
      receptor, as reported in some patients with PCOS, has been put forward as a new
      mechanism for insulin resistance. Insulin-sensitising agents have recently been
      investigated for their role in the short term treatment of insulin resistance in
      PCOS. Controlled studies have shown that metformin administration, by promoting
      bodyweight loss, can decrease fasting and stimulated plasma insulin levels.
      However, other studies have shown metformin 500 mg 3 times daily to decrease
      insulin secretion and to reduce ovarian production of 17alpha-hydroxyprogesterone
      with recovery of spontaneous or clomifene-induced ovulation, independently of
      weight loss. These findings suggest a new indication for metformin and present
      insulin-sensitising agents as a novel approach in the treatment of ovarian
      hyperandrogenism and abnormal ovulation in PCOS. They also suggest that long term
      administration of metformin might be helpful in treating insulin resistance, thus
      reducing risks of type 2 (non-insulin-dependent) diabetes and cardiovascular
      disease in these patients.

PMID- 10576526
TI  - Metformin prevents weight gain by reducing dietary intake during insulin therapy
      in patients with type 2 diabetes mellitus.

PMID- 10576525
TI  - Strategies for the management of diabetic dyslipidaemia.
AB  - Atherosclerosis, the complication most prominently associated with type 2
      diabetes and cardiovascular disease, represents a major burden for both
      individuals and society. Mortality rates associated with cardiovascular disease
      among patients with type 2 diabetes are at least 3 times those in the general
      population, and although 'traditional' cardiovascular risk factors affect
      patients with this disorder as they do other individuals, they do not account for
      the excess risk attached to type 2 diabetes. There is a growing body of evidence
      to show that hyperglycaemia and dyslipidaemia are connected with this excess
      cardiovascular risk: hypertriglyceridaemia has been implicated in several
      prospective clinical studies, and available data suggest that low density
      lipoprotein (LDL)-cholesterol is more atherogenic in patients with type 2
      diabetes than in other individuals. It is possible that this increased
      atherogenicity is associated with a preponderance of small, dense LDL particles
      that are more prone to oxidation and glycation than larger fractions and that may
      be involved in endothelial dysfunction. These findings lead to the recommendation
      of mandatory global risk assessment, accompanied by good glycaemic control,
      aggressive lowering of serum levels of LDL-cholesterol and maintenance of serum
      levels of triglyceride at the lowest possible level in patients with type 2
      diabetes.

PMID- 10576527
TI  - Lactic acidosis in metformin therapy.
AB  - The biguanide drugs metformin and phenformin have been linked in the past to
      lactic acidosis, a metabolic condition associated with high rates of mortality.
      Although concern over the hyperlactataemic effect of phenformin led to the
      withdrawal of this drug from clinical practice in the 1970s, the situation with
      metformin has been less clear. Retrospective data indicate that, in metformin
      treated patients with lactic acidosis, neither the degree of hyperlactataemia nor
      accumulation of metformin is of prognostic significance. Furthermore, the lowest
      rates of mortality were seen in patients with high plasma concentrations of
      metformin, which has led to the hypothesis that the drug may confer some benefit,
      linked to an increase in vasomotility, in such cases. Overall, it appears that
      mortality in patients receiving metformin who develop lactic acidosis is linked
      to underlying disease rather than to metformin accumulation, and that metformin
      can no longer be considered a toxic drug in this respect. These findings are
      likely to be of considerable relevance to the management of patients with type 2
      (non-insulin-dependent) diabetes mellitus, especially where such patients are
      elderly.

PMID- 10576529
TI  - Prevention of type 2 diabetes: role of metformin.
AB  - Metformin lowers moderate (nondiabetic) fasting hyperglycaemia in individuals at
      risk for type 2 diabetes without causing hypoglycaemia. In addition, it has
      demonstrated favourable action on several cardiovascular risk factors that are
      often present in these individuals: it favours the maintenance of diet-induced
      weight loss and its associated improvement in fibrinolysis; and it lowers plasma
      concentrations of fasting insulin, total and low density lipoprotein-cholesterol,
      free fatty acids, and of two markers of endothelial damage--tissue plasminogen
      activator antigen and von Willebrand factor. These effects together with the good
      tolerability profile of the drug position metformin as a first-line agent for the
      prevention of type 2 diabetes.

PMID- 10576528
TI  - Strategies for better diabetes control in the US.
AB  - Recent surveys in the US have indicated that 71% of the total diabetes care is
      delivered by primary care physicians, and that current management practices in
      terms of the point of initiation of pharmacological treatment fall considerably
      short of the American Diabetes Association's recommendations. In part, this delay
      in initiating treatment is due to a fear of provoking hypoglycaemia, which in
      itself results from a general avoidance of blood glucose monitoring on the part
      of patients. As a consequence of this apparent disregard for diabetes care, blood
      glucose concentrations are not adequately controlled in the US and this is
      reflected in a high incidence of chronic complications, particularly diabetic
      neuropathy. This is likely to have major cost implications in the future. In an
      effort to improve the standard of diabetes care, a number of US authorities have
      begun producing guidelines for primary care physicians, and in the State of
      Texas, treatment algorithms that incorporate recommendations based on the current
      US registration trial data have been developed. These recommendations, which have
      now been adopted by the State of Texas and form part of the minimum standard of
      care mandated by the State Department of Health's Diabetes Council, provide
      guidance on the selection and use of oral antidiabetic drugs (including
      sulphonylureas, metformin, troglitazone, repaglinide and acarbose) in patients
      with type 2 diabetes, both for glycaemic control and for prevention of
      cardiovascular complications. It is hoped that organised implementation of these
      treatment algorithms will produce better control of diabetes and its
      complications than the current ad hoc strategies used by individual
      practitioners.

PMID- 10576530
TI  - Annotation: Outcomes in long-term foster family care.

PMID- 10576531
TI  - School refusal: issues of conceptualisation, assessment, and treatment.
AB  - Developments in the assessment and treatment of school refusal have often been
      hampered by a failure to recognise its essentially heterogeneous nature. This
      paper provides a review of major conceptual complexities that have helped to
      undermine developments in clinical practice. In particular, it considers the
      distinction between school refusal and truancy, and school phobia and separation
      anxiety. Common approaches to the assessment and treatment of school refusal are
      outlined. Although behavioural and cognitive behavioural approaches are now
      widely accepted as central to treatment, it is increasingly recognised that
      individually tailored programmes, utilising a range of approaches, are most
      likely to prove successful. An approach focusing upon the functions, rather than
      the symptoms, of school refusal is advocated as having most promise for
      assessment and the subsequent formulation of individual prescriptive treatment.

PMID- 10576532
TI  - A longitudinal study of maternal labour force participation and child academic
      achievement.
AB  - The associations between maternal labour force participation and child academic
      achievement were examined in a birth cohort of New Zealand children who have been
      studied from birth to age 18. The results of this analysis suggested the presence
      of small associations between the extent of maternal labour force participation
      and scores on standardised tests of word recognition, reading comprehension, and
      mathematical reasoning. Similar associations were found between maternal labour
      force participation and success in school leaving examinations. These
      associations arose predominantly because children whose mothers worked had better
      performance than children whose mothers who had not worked in paid employment.
      However, patterns of maternal labour force participation were also related to a
      series of family and child factors including: maternal education, family
      socioeconomic status, race, birth order, family composition, early mother-child
      interaction, and child IQ. Adjustment for these factors reduced associations
      between maternal labour force participation and academic achievement to the point
      of practical and statistical nonsignificance. These results were found to be
      robust and similar conclusions were found for (1) a range of measures of maternal
      labour force participation, and (2) subgroups of the cohort defined by gender,
      socioeconomic status, ethnicity, or family type.

PMID- 10576533
TI  - Siblings, parents, and partners: family relationships within a longitudinal
      community study. ALSPAC study team. Avon Longitudinal Study of Pregnancy and
      Childhood.
AB  - Links between sibling relationships, mother-partner, and parent-child
      relationships were studied in a longitudinal community sample of 3681 sibling
      pairs. Individual differences in sibling relationship quality were related to
      mother-partner affection and hostility assessed 4 years earlier, to contemporary
      parent-child negativity, and to indices of social adversity. Evidence for both
      direct and indirect pathways (via parent-child relations) linking mother-partner
      and sibling relations were found. Comparisons of prediction for non-stepfamilies
      and stepfather families showed similarities in patterns of association, but also
      differences: In stepfather families, mother-partner hostility was unrelated to
      parent-child negativity and sibling relationship quality. Both positivity and
      negativity towards young siblings decreased with the age of older siblings, and
      older sisters were more positive than older brothers.

PMID- 10576534
TI  - Hyperactivity and reading disability: a longitudinal study of the nature of the
      association.
AB  - In order to investigate the possible causal relationships between hyperactivity
      and educational underachievement that might account for their frequent co
      occurrence, four groups of boys, defined by the presence or absence of
      hyperactivity and specific reading retardation, were identified in an
      epidemiological study of 7 8-year-old children. They were examined in detail by
      means of parental interviews and psychological tests and reassessed 9 years later
      at the age of 16-18 years on a similar range of measures. The findings provided
      little support for the idea that persistent reading disabilities either lead to
      the development of hyperactivity de novo or increased the likelihood that
      hyperactivity, when present, would persist. Similarly, although features of
      hyperactivity persisted to follow-up, there was little evidence that they either
      lead to the development of reading disabilities or increased the likelihood that
      reading disabilities, when present, would persist. Socioeconomic adversity and a
      history of speech therapy were more common in the group with both hyperactivity
      and reading disability, but the strength of these associations made it unlikely
      that these factors could account for the frequent co-occurrence of the two
      conditions.

PMID- 10576535
TI  - Helping children adjust--a Tri-Ministry Study: I. Evaluation methodology.
AB  - This report describes the evaluation methodology of the Tri-Ministry Study--a
      school-based trial evaluating the effectiveness of three universal programs: (a)
      a classwide social skills program (SS), (b) a partner reading program (RE); and,
      (c) a combination of both (SS & RE), to reduce and prevent behavioural
      maladjustment among children in the primary division (up to grade 3) of Ontario
      schools. The trial was done between 1991 and 1995. Sixty schools in 11 boards of
      education took part and were assigned randomly to program(s) during the study.
      Contributing to the evaluation database are detailed follow-up assessments
      (observations, ratings, and standard tests) on 2439 children. Three-level growth
      trajectory models are used to evaluate program effects. The analysis presented
      for illustration in this report focuses on reading achievement measured by the
      Wide Range Achievement Test. A companion paper presents the results of the study
      and discusses important methodological and programmatic issues applicable to this
      and other prevention studies in the field.

PMID- 10576536
TI  - Helping children adjust--a Tri-Ministry Study: II. Program effects.
AB  - This report describes program effects of the Tri-Ministry Study a school-based,
      longitudinal trial carried out over a 5-year period to assess the effectiveness
      of classwide social skills training (SS), partner reading (RE), and a combination
      of both (SS & RE) to reduce maladjustment among children in the primary division
      (up to grade 3) of Ontario schools. It also places these effects in the context
      of other school-based prevention studies and discusses them in view of important
      methodological and programmatic issues. The incremental effects attributable to
      the intervention programs were small and sporadic. There were statistically
      significant increases in prosocial behaviour observed in the playgrounds of
      intervention schools with no differentiation by program type. Furthermore, there
      was some evidence--a reduction in teacher and parent-rated externalising problems
      -that the combination of SS & RE and SS alone may have had modest beneficial
      effects. A review of nine other school-based studies, which evaluated universally
      delivered mental health prevention programs in general populations of students,
      revealed similar mixed results. There are both methodologic and programmatic
      issues implicated in the weak findings that have been reported to date. These
      issues need to be addressed to advance knowledge about the potential impact of
      mental-health prevention initiatives delivered universally through school-based
      programs. A companion paper gives the specific details on the programs,
      randomisation of schools, selection of subjects, measurements, and analysis.

PMID- 10576537
TI  - Psychological screening of children for post-traumatic stress disorder.
AB  - One hundred and seventy children attending a hospital accident and emergency
      department following everyday trauma were interviewed and completed the Post
      traumatic Stress Disorder (PTSD) screening battery suggested by Yule and Udwin
      (1991). Diagnostic interviews (CAPS-C) confirmed that 39 (22.9%) fulfilled the
      DSM-IV criteria for PTSD. There were significant differences between children
      with and without PTSD on each individual component of the screening battery.
      Various criteria for caseness were evaluated and at 6 weeks post trauma the
      screen identified up to 90% of children diagnosed with PTSD and 73% with
      borderline conditions. A subset of 36 children were reassessed 8 months post
      trauma and all children with persistent PTSD were correctly identified by initial
      screen scores. The limitations of the study and the role of screening for PTSD in
      the absence of proven psychological interventions are discussed.

PMID- 10576538
TI  - Maternal expressed emotion and adjustment in children with epilepsy.
AB  - Epilepsy in childhood may alter family relationships but the relevance of these
      changes for the increased rates of psychopathology has been little investigated.
      This study uses maternal expressed emotion (EE) to examine family relationships
      of children with epilepsy and the association with high risk for psychiatric
      disorder. EE was assessed using the Camberwell Family Interview carried out with
      the mothers of 22 schoolchildren with chronic epilepsy who were attending a
      general hospital outpatient clinic. Sixteen of these children had similarly aged
      healthy siblings who served as controls. High risk for psychiatric disorder in
      the children and mothers was assessed using behavioural, mood, and self-esteem
      questionnaires completed by mothers, teachers, and children. It was found that
      mothers showed significantly more emotional overinvolvement and a trend for more
      hostility towards their children with epilepsy than towards sibling controls. For
      the 22 children with epilepsy, maternal emotional overinvolvement was not
      associated with child behavioural deviance. High levels of criticism and, to a
      lesser extent, hostility did show associations with child behavioural deviance,
      and the strongest links were between maternal criticism and maternal rated
      antisocial and overactive behaviour in the child. Fewer positive comments by
      mothers towards the children were associated with child emotional symptoms and
      lower self-esteem in a number of areas. This study suggests that further research
      could consider the appropriateness of psychological intervention for families in
      which mothers are critical and hostile and whose children show antisocial
      behaviour.

PMID- 10576539
TI  - Syndrome dimensions of the child behavior checklist and the teacher report form:
      a critical empirical evaluation.
AB  - The construct representation of the cross-informant model of the Child Behavior
      Checklist (CBCL) and the Teacher Report Form (TRF) was evaluated using
      confirmatory factor analysis. Samples were collected in seven different
      countries. The results are based on 13,226 parent ratings and 8893 teacher
      ratings. The adequacy of fit for the cross-informant model was established on the
      basis of three approaches: conventional rules of fit, simulation, and comparison
      with other models. The results indicated that the cross-informant model fits
      these data poorly. These results were consistent across countries, informants,
      and both clinical and population samples. Since inadequate empirical support for
      the cross-informant syndromes and their differentiation was found, the construct
      validity of these syndrome dimensions is questioned.

PMID- 10576540
TI  - Predictors of cognitive test patterns in autism families.
AB  - In a case-control study of cognitive performance, tests of intelligence, reading,
      spelling, and pragmatic language were administered to the parents and siblings of
      90 community-ascertained probands with autism (AU group) and to the parents and
      siblings of 40 similarly ascertained probands with trisomy 21 Down syndrome (DS
      group). The two samples were comparable for age and parents' education; both
      groups were well-educated and had above-average intelligence. AU parents scored
      slightly but significantly lower on the WAIS-R Full Scale and Performance IQ, on
      two subtests (Picture Arrangement and Picture Completion), and on the Word Attack
      Test (reading nonsense words) from the Woodcock-Johnson battery. There were no
      differences between AU and DS siblings. As in earlier studies, AU parents, more
      often than DS parents, reported a history of early language-related cognitive
      difficulties; we were not able to replicate this in siblings. AU parents who
      reported such difficulties scored significantly lower on Verbal IQ, spelling, and
      the nonsense reading test. AU parents without a history of early language-related
      cognitive difficulties often had a Verbal IQ that exceeded Performance IQ by more
      than one standard deviation. AU siblings with early language-related difficulties
      had similar findings: lower Verbal IQ, poorer spelling, and poorer reading
      scores, compared to AU siblings without such a history. Parents with a positive
      history also scored worse on a measure of pragmatic language,the Pragmatic Rating
      Scale, but not on measures of social-related components of the broader autism
      phenotype. We propose that cognitive differences in a subset of autism family
      members are manifestations of the language-related component of the broader
      autism phenotype, and separate from the social-related component. This is
      consistent with the hypothesis that there are several genes that may interact to
      cause autism which segregate independently and have distinguishable
      manifestations in family members. The hypothesis would be further supported by
      finding different patterns of genetic loci linked to autism in families where one
      or both parents has language difficulties.

PMID- 10576541
TI  - A visually impaired savant artist: interacting perceptual and memory
      representations.
AB  - In this single case study, paintings by a visually impaired and cognitively
      handicapped savant artist are evaluated. He paints his pictures exclusively from
      memory, either after having looked at a natural scene through binoculars, or
      after studying landscape photographs in brochures, catalogues, and books. The
      paintings are compared with the models from which they were derived, and the
      resulting generative changes are accounted for by an interaction between impaired
      visual input and memory transformations.

PMID- 10576542
TI  - Brain dopamine D2 receptor mRNA levels are elevated in young spontaneously
      hypertensive rats.
AB  - Levels of brain dopamine D2 receptor expression were compared between
      spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY)
      controls by quantitative in situ hybridisation, using a complementary RNA probe
      for D2 receptor mRNA. In SHR which were 6 weeks of age, significantly higher
      levels of D2 receptor mRNA were found in the caudate-putamen (42%), nucleus
      accumbens (23%), olfactory tubercle (17%) and substantia nigra (38%) compared to
      age-matched WKY controls. D2 receptor mRNA levels were also higher in the
      substantia nigra (27%) of 12-14-week old SHR compared to WKY. The increased
      levels of dopamine D2 receptor gene expression displayed in young prehypertensive
      SHR could implicate altered central dopaminergic activity in the pathogenesis of
      hypertension.

PMID- 10576543
TI  - Morphological differentiation of microglial cells in culture: involvement of
      insoluble factors derived from astrocytes.
AB  - It is believed that ramified resting microglial cells in the brain are
      differentiated from macrophage-like ameboid cells, although the mechanism for the
      differentiation is not fully understood. In the present study, we investigated
      whether the differentiation of microglial cells is observable in mixed brain cell
      culture prepared from newborn rat forebrains. In confluent mixed brain cell
      culture, both ramified and ameboid microglial cells were simultaneously present.
      The ramified cells were located in or under the astrocyte monolayer, while the
      ameboid cells were over the layer as revealed by confocal laser scan microscopy.
      The majority of ramified cells appeared after the astrocyte layer was completely
      formed and they downregulated the expression of the major histocompatibility
      complex antigen. Fibronectin was detected around ramified microglial cells, and
      laminin was also present in the astrocyte monolayer in mixed brain cell culture,
      while both proteins were not distributed near ameboid cells over the monolayer.
      When purified microglial cells were cultured on astrocyte-derived extracellular
      matrix in serum-free medium, they ramified. These results show that the
      differentiation of microglial cells is observable in culture and that astrocytes
      may play pivotal roles in the differentiation mainly by secreting insoluble
      factors.

PMID- 10576544
TI  - In vivo upregulation of the blood-brain barrier GLUT1 glucose transporter by
      brain-derived peptides.
AB  - Glucose is the critical metabolic fluid for the brain, and the transport of this
      nutrient from blood to brain is limited by the blood-brain barrier (BBB) GLUT1
      glucose transporter. The expression of the BBB-GLUT1 gene is augmented in brain
      endothelial cultured cells incubated with brain-derived trophic factors and the
      brain-derived peptide preparation Cerebrolysin (C1, EBEWE, Austria). The aim of
      the present investigation was to determine if C1 induces similar changes in the
      expression of the BBB-GLUT1 gene following its administration to rats in vivo.
      The BBB glucose transporter activity was investigated with the intracarotid
      artery perfusion technique using [3H]diazepam as cerebral blood flow marker. The
      acute or chronic administration of C1 markedly increased the brain permeability
      surface area of D-[14C]glucose compared to controls (D-[14C]glucose/[3H]diazepam
      ratio, 1.6- to 1.9-fold increase in frontal cortex, P < 0.05). Increased activity
      of the BBB glucose transporter was correlated with a significant rise in the
      abundance of the BBB-GLUT1 protein measured by both Western blot analysis and
      immunocytochemistry, and with a decrease in the transcript levels of this
      transporter. Data presented here demonstrate that the in vivo administration of
      Cl increases the transport of glucose from blood to brain via BBB-GLUT1 gene
      expression.

PMID- 10576545
TI  - Neural cell line-specific regulatory DNA cassettes harboring the murine D1A
      dopamine receptor promoter.
AB  - Transcription in the human and rat D1A dopamine receptor genes proceeds from two
      distinct promoters in neuronal cells while only the downstream intronic promoter
      is active in renal cells. To investigate the utility of these promoters in the
      brain cell-specific expression of transgenes, we now studied the 5' flanking
      region of the murine D1A gene. We confirmed the presence of two functional
      promoters utilized for the tissue-specific regulation of this gene similar to its
      human and rat homologues. The cloned 1.4-kb genomic fragment spans nucleotides -
      967 to + 384 relative to the first ATG codon and includes intron 1 between bases 
      534 to -420. Transient expression analyses using various chloramphenicol
      acetyltransferase constructs revealed that the murine D1A upstream promoter fused
      with the human D1A gene activator sequence ActAR1 has potent transcriptional
      activity in a D1A-expressing neuronal cell line but not in other cell lines
      tested including renal (OK cells), glial (C6) and hepatic (HepG2), suggesting
      that this hybrid construct harbors neural cell-specific elements. The
      availability of potent regulatory DNA cassettes harboring the murine D1A gene
      promoter could aid testing the neuronal-specific expression of transgenes in
      vivo.

PMID- 10576546
TI  - Regulation of dopamine uptake by basic fibroblast growth factor and epidermal
      growth factor in cultured rat astrocytes.
AB  - We examined the characteristics of dopamine (DA) uptake and its regulation by
      neurotrophic factors such as basic fibroblast growth factor (bFGF) and epidermal
      growth factor (EGF) in cultured rat astrocytes. In the presence of inhibitors of
      monoamine oxidase (MAO) and catechol-O-methyl-transferase (COMT), astrocytes took
      up DA by Na(+)-dependent and Na(+)-independent mechanisms that were sensitive to
      a reduction in temperature. The Na(+)-dependent and Na(+)-independent components
      increased linearly with increasing [3H]DA concentration (1-1000 microM), and
      showed no saturation. Na(+)-dependent DA uptake was significantly inhibited by
      ouabain, a Na(+)-K+ ATPase inhibitor. In bFGF-treated astrocytes, [3H]DA uptake
      increased in a time-dependent manner until 48 h, and declined after 72 h in both
      the presence and absence of Na+. In EGF-treated astrocytes, [3H]DA uptake
      increased in a time-dependent manner until 72 h in both the presence and absence
      of Na +. This enhancement of DA uptake induced by EGF or bFGF was significantly
      inhibited when the cells were cultured with actinomycin D, cycloheximide, or
      brefeldin A. Actinomycin D and brefeldin A also significantly inhibited the basal
      uptake of [3H]DA into astrocytes. These results suggest the existence of Na(+)
      dependent and Na(+)-independent DA uptake in cultured rat astrocytes, and that
      EGF or bFGF might stimulate the expression and translocation of the extraneuronal
      DA transporter.

PMID- 10576547
TI  - CEPU-1, an immunoglobulin superfamily molecule, has cell adhesion activity and
      shows dynamic expression patterns in chick embryonic spinal cord.
AB  - In an attempt to isolate novel molecules involved in motoneuron differentiation
      and target muscle innervation during embryogenesis, we performed mRNA
      differential display analysis by comparing cDNAs of motoneurons purified by
      immunopanning from different portions along the rostro-caudal axis of chick
      embryonic spinal cord, and cloned an immunoglobulin superfamily protein named
      C30. By sequence comparison, C30 was shown to be an alternatively spliced isoform
      of CEPU-1, which was formerly reported as a member of the immunoglobulin
      superfamily specifically expressed in cerebellar Purkinje cells (Spaltmann and
      Brummendorf, 1996, J. Neurosci. 16, 1770-1779). We analyzed the expression
      pattern of CEPU-1 both at the mRNA and protein levels in the spinal cord of the
      chick embryo. Until stage 23, CEPU-1 was expressed faintly in the ventral part of
      the neural tube but gradually it became localized to a specific group of cells.
      In the motor column, CEPU-1 was expressed transiently in many columnar layers. A
      C30-transfected cell line showed Ca(2+)-independent cell-cell binding activity.
      These results suggest a role for CEPU-1 in specific axon guidance and/or
      fasciculation of motoneurons during development.

PMID- 10576548
TI  - Anatomical re-evaluation of the corticostriatal projections to the caudate
      nucleus: a retrograde labeling study in the cat.
AB  - The distribution of cortical neurons projecting to the cat caudate nucleus (CN)
      was examined using retrograde labeling methods. Single injections of either
      horseradish peroxidase conjugated with wheat germ agglutinin (HRP-WGA), or the
      fluorescent tracers Fast Blue (FB) or Diamidino Yellow (DY) were made into
      different regions of the CN. This study confirms the following previous findings.
      (1) Labeled neurons were observed in the frontal and parieto-temporal cortices.
      (2) The corticocaudate cells were mainly located in layer V, although some cells
      were also observed in layer III and occasionally in layers II and VI. (3) Dorsal
      injections into the rostral CN yielded more dorsal labeling in the cerebral
      cortex. However, ventral cortical areas such as the ventral part of the prelimbic
      (PL) cortical area and the insular cortex (sylvian anterior (SA), agranular and
      disgranular insular areas) presented retrograde labeling after both dorsal and
      ventral injections into the CN. (4) Dorsal injections into the CN labeled all
      subdivisions of areas 4 and 6 whereas the ventral ones labeled only the areas
      4delta, 6alphabeta, 6aalpha, 6iffu. The novel findings of this study are as
      follows. (1) The cortical area 6betabeta and the dorsolateral prefrontal area
      (PfDl) were labeled in all our cases. In addition, PL, anterior limbic, SA and
      rostral part of cingulate (Cg) cortical areas were also labeled in most of our
      cases. (2) Ventral injections into the CN elicited a higher number of
      retrogradely labeled neurons in the ventral prefrontal area than dorsal
      injections. (3) A topographical relationship was found between the caudal CN and
      the dorsomedial prefrontal area so that dorsal injections in the caudal CN
      elicited retrograde labeling in the rostral PfDl, whereas ventral injections
      labeled the caudal PfDl. (4) A topography from dorsal to rostral and ventral to
      caudal was also observed between injections into the CN and PL and Cg. (5) A
      mediolateral topography was observed in the presylvian, cruciate and splenial
      sulci.

PMID- 10576549
TI  - The role of astrocytes in the development of hepatic encephalopathy.
AB  - Thioacetamide (TAA), a hepatotoxin used to ascertain the role of astrocytes in
      hepatic encephalopathy, was administered to prepare four experimental groups of
      rats. (The TAA1D, TAA1.5D, TAA2D, and TAA2.5D group rats were perfusion fixated
      with formalin at 1, 1.5, 2, and 2.5 days, respectively, after initial
      administration of TAA. In addition, TAA was readministered to the TAA2D and
      TAA2.5D rats 24 h after the first dose.) Abnormalities of higher brain function
      and equilibrium that progressed with time were apparent in the rats receiving
      TAA. On the other hand, innate reflexes (e.g. pupillary reflex) were similar to
      those in the normal control group. Astrocyte cell areas in the hippocampus,
      neocortex, hypothalamus, cerebellum, and basal ganglia (striatum) from the TAA
      rats were significantly larger than in corresponding sites from the normal rats
      (maximum in TAA1D and TAA1.5D groups). However, there were no differences with
      respect to the midbrain. Any morphological difference was not observed in neurons
      between the hepatic encephalopathy and normal rats. Administration of TAA caused
      hepatic tissue injury that progressed over time. Surprisingly, encephalopathy was
      apparent even when hepatic injury was mild. These findings suggest that
      abnormalities in astrocytes, which precede any abnormal change in neurons, play a
      role in the development of hepatic encephalopathy.

PMID- 10576550
TI  - Interaction of the C-terminal domain of delta glutamate receptor with spectrin in
      the dendritic spines of cultured Purkinje cells.
AB  - The interaction of neurotransmitter receptors with the underlying cytoskeleton
      via subsynaptic proteins is an important mechanism for the targeting of the
      receptors to synapses in the central nervous system. We show that delta glutamate
      receptors (delta receptors), expressed predominantly in the dendritic spines of
      cerebellar Purkinje cells, directly interact with spectrin, a member of the actin
      binding family of proteins. Moreover, the interaction between spectrin and C
      terminal domain of the delta receptor is 50% inhibited by 1 microM of Ca2+ in
      vitro, compared with that in the absence of Ca2+. These results suggest that
      delta receptors on the postsynaptic membrane of the dendritic spines of
      cerebellar Purkinje cells are anchored to the actin cytoskeleton via spectrin,
      and that Ca2+ elevation in the dendritic spines causes delta receptor
      declustering by dissociation of the receptors from spectrin. This mechanism for
      receptor anchoring at postsynaptic sites may regulate synaptogenesis and/or
      synaptic plasticity.

PMID- 10576551
TI  - Human parathyroid hormone (1-34) increases urinary excretion of lysosomal enzymes
      in rats.
AB  - The kidney is the major target of parathyroid hormone (PTH), and PTH influences
      the urinary excretion of calcium, phosphate and hydrogen ions. It was previously
      reported that the urinary, excretion of N-acetyl-beta-D-glucosaminidase (NAG), a
      lysosomal enzyme, transiently increases after human PTH (hPTH) (1-34) infusion in
      normal subjects and idiopathic hypoparathyroidism patients, but not in
      pseudohypoparathyroidism type I patients. Here we report that intravenous
      infusion of hPTH(1-34) to rats transiently increased the urinary excretion of
      various lysosomal enzymes, such as beta-glucuronidase and acid phosphatase as
      well as NAG. However, it did not affect the urinary excretion of tubular brush
      border membrane enzymes, i.e. alkaline phosphatase, leucine aminopeptidase and
      gamma-glutamyl transpeptidase. Human PTH(1-34) dose-dependently increased the
      urinary excretion of NAG in rats with a peak at 30 min, which returned to a
      baseline within 60 min. The increase in the urinary NAG excretion caused by
      hPTH(1-34) positively correlated with the increase in the urinary cAMP excretion
      (r = 0.844, p < 0.01), and infusion of dibutyryl cAMP at a dose of 20 mg/kg
      similarly increased the urinary excretion of NAG. These results suggested that
      the increase in the urinary excretion of lysosomal enzymes caused by hPTH(1-34)
      may be a functional response to hPTH(1-34) occurring in the renal tubules via PTH
      signaling pathway.

PMID- 10576552
TI  - Purine pathway enzymes in a cyst forming strain of Toxoplasma gondii.
AB  - The activities of purine salvage enzymes in tachyzoites from a cyst-forming
      strain of Toxoplasma gondii were determined using HPLC. Six enzymes were assayed
      both in vitro and in vivo: adenosine deaminase, guanine deaminase, purine
      nucleoside phosphorylase, xanthine oxidase, hypoxanthine-guanine
      phosphoribosyltransferase and adenine phosphoribosyltransferase. In vitro, the
      tachyzoites were cultured in the human myelomonocytic cell line THP-1, for 24 h
      to 96 h. Neither guanine deaminase nor hypoxanthine-guanine
      phosphoribosyltransferase activity was detected in 24 and 96 h cultures. In vivo,
      in controls and infected animals, the purine nucleoside phosphorylase and
      adenosine deaminase activities were the most important activities both in sera
      and cerebral tissue in comparison with the other activities. It was also noted
      that the infection modified the enzymatic activities of this purine salvage
      pathway, in particular, the guanine deaminase cerebral activity of infected mice
      was 20-fold lower than the value of controls. The treatment of mice with 2',3'
      dideoxyinosine, a purine analog, at the dose of 100 mg.kg(-1).d for 30 days,
      induced an important increase of all enzymatic activities in the brains in
      comparison with control animals. These data suggest that one target of 2',3'
      dideoxyinosine is the purine metabolism.

PMID- 10576553
TI  - Immunotherapy for experimental rat autoimmune thyroiditis using a novel
      immunosuppressant, FTY720.
AB  - While autoimmune disease needs to be continuously treated via long term,
      administration of immunosuppressants conventional immunotherapy using drugs such
      as cyclosporin and tacrolimus may cause adverse effects. Recently, a novel agent,
      FTY720, which was structurally modified from a natural product, has been shown to
      have a moderate and different immunosuppressive effect from conventional drugs.
      In this study, we examined the effect of FTY720 on experimental autoimmune
      thyroiditis (EAT), which was induced in rats by neonatal thymectomy, followed by
      subsequent sublethal irradiation. Thyroid stimulating hormone (TSH) was measured
      before and at the end of drug therapy. Histological and hematological
      examinations were performed using the samples from sacrificed animals. High TSH
      levels in the animals returned to the normal range following treatment with
      FTY720. The severity of the thyroiditis was lower in the FTY720 group than in the
      control group. FTY720 markedly decreased the number of circulatory lymphocytes,
      and no infections episodes were observed under this treatment. Thus, FTY720
      treatment might be preferred for continuous immunotherapy for autoimmune disease
      without adverse effects.

PMID- 10576554
TI  - Dehydroepiandrosterone (DHEA) facilitates liver regeneration after partial
      hepatectomy in rats.
AB  - In this study we investigated whether or not liver regeneration is facilitated by
      dehydroepiandrosterone (DHEA) after partial (70%) hepatectomy in rats. Treatment
      with DHEA (300 mg/kg body weight) did not cause any significant increase in the
      expression ratio of proliferating cell nuclear antigen (PCNA) in sham-operated
      controls; however, in partially hepatectomized rats it caused a significant
      increase in the ratio in hepatocytes 24 and 36 hr after hepatectomy. In partially
      hepatectomized rats, DHEA treatment significantly accelerated the restoration of
      liver 48, 60, and 72 hr after partial hepatectomy. The restoration rate in DHEA
      treated hepatectomized rats at 72 hr was 1.3-fold greater than in partially
      hepatectomized controls. Treatment with androstenedione (300 mg/kg body weight),
      the first metabolite of DHEA, did not cause any significant increase in the
      expression of PCNA in either sham-operated controls or partially hepatectomized
      rats. These results indicate that DHEA itself promotes the liver regenerative
      process after partial hepatectomy in rats.

PMID- 10576555
TI  - Lack of protection of monoamine oxidase B-deficient mice from age-related spatial
      learning deficits in the Morris water maze.
AB  - Monoamine oxidase B (MAO-B) increases in brain in response to aging and
      neurodegeneration. Whether such increases represent a risk factor to further
      neuronal damage or simply represent epiphenomena remains unclear. L-deprenyl, an
      inhibitor of MAO-B, has been shown to improve learning in aged rodents. However,
      recent data suggests this may occur through mechanisms independent of its
      enzymatic inhibition. This study investigates visualspatial learning of MAO-B
      deficient mice and examines what effects absence of MAO-B has on age-related
      cognitive decline. Learning was tested in the Morris Water Maze in male
      transgenic MAO-B knockout mice (KO) ages 2 months (n = 9), 7 months (n = 7), and
      17 months (n = 8). Performance was compared to that of wild type (WT)
      littermates. Animals were given four 60 second trials per day with the submerged
      platform in the "North" position. Animals received 7 days of learning in which
      they were introduced into the pool facing the wall, alternating between the
      "East" and "West" positions. A single probe trial followed on day 8, followed by
      continuation of the original learning paradigm on days 9 and 10. Subsequently,
      the platform position was changed to the diagonally opposite quadrant and
      learning continued on days 11-13, followed by a cue phase in which the platform
      was made visible. Total distance traveled and latency to the platform was
      increased in 7- and 17- month old mice, most significantly at the beginning of
      the acquisition phase. This effect reappeared again in 17- month old mice during
      the reversal phase. No predominant genotypic differences in latency or distance
      were observed during any phase of the experiment. Our results show that presence
      or absence of MAO-B does not appear to alter performance in the Morris water
      maze. Furthermore, presence or absence of MAO-B does not provide protection from
      the age-dependent deficits in spatial learning.

PMID- 10576556
TI  - Validation of the internal reference technique for microdialysis measurements of
      interstitial histamine in the rat.
AB  - The internal reference technique (IRT) was compared with the no net flux method
      (NFM) as a microdialysis calibration technique for sampling of interstitial
      histamine in the rat. Microdialysis catheters (polyacrylonitrile, 50 kD cut off)
      were inserted in liver, muscle, subcutaneous tissue and in an induced
      adenocarcinoma. Estimated relative recovery with IRT ranged from 23+/-2% in liver
      to 30+/-3% in subcutaneous tissue with and without tumor (p<0.05). By using the
      NFM-technique we found similar recovery as compared to the IRT in all tissues
      studied. Interstitial histamine was up to 3-fold higher than the mean plasma
      histamine concentration (54+/-2 nmol/l). Subcutaneous tissue (177+/-39 nmol/l)
      and subcutaneous tumor (165+/-29 nmol/l) exhibited high histamine while liver
      (65+/-14 nmol/l) and liver tumor (75+/-7 nmol/l) had low interstitial histamine
      concentrations. In conclusion, the IRT was validated against the NFM as a rapid
      method for histamine measurements in situ in the rat.

PMID- 10576557
TI  - Differential effect of chronic antidepressant treatments on lipopolysaccharide
      induced depressive-like behavioural symptoms in the rat.
AB  - In the present study we observed that lipopolysaccharide (LPS) administration
      provoked a characteristic reduction in body weight gain, food consumption,
      saccharin (but not water) consumption and nocturnal locomotor activity. It has
      been previously suggested that the ability of LPS to suppress the consumption of,
      and preference for, a palatable solution such as saccharin without altering water
      consumption, may represent an anhedonic response. The results of the present
      study demonstrate that chronic treatment with the tricyclic antidepressant (TCA)
      desipramine (7.5 mg/kg; i.p.) prevented LPS-induced anorexia, loss of body
      weight, the antidipsogenic effect and hypoactivity. In contrast, chronic
      treatment with the antidepressants paroxetine (7.5 mg/kg; i.p.) and venlafaxine
      (10 mg/kg; i.p.) failed to alter any of the LPS-induced behavioural responses.
      Furthermore, chronic treatment with desipramine (and to a lesser extent
      paroxetine) reduced the consumption of, and preference for, saccharin suggesting
      that these antidepressant treatments induce an "anhedonic" response in their own
      right. In conclusion, chronic desipramine treatment attenuated LPS-induced
      depressive-like behavioural symptoms in the rat. However, chronic treatment with
      paroxetine and venlafaxine did not significantly alter LPS-induced behavioural
      responses. The results of the present study support the hypothesis that TCA's may
      exert part of their anti-depressive efficacy through their effects on the immune
      system. However, this property does not appear to be shared by newer
      antidepressants which possess a better side effect profile than the TCA's. The
      suppressive effect of TCA's on proinflammatory cytokine secretion is discussed as
      a mechanism by which these agents alter LPS-induced behavioural responses.

PMID- 10576558
TI  - Exogenous nitric oxide modulates cytokine production in human leukocytes.
AB  - Exogenous nitric oxide was found to modify the pattern of cytokine secretion from
      human leukocytes, with similar outcome in 11 different healthy blood donors.
      Peripheral blood mononuclear cells (PBMC) were stimulated with
      phytohaemagglutinin (PHA) in the presence of increasing amounts of the NO donor S
      nitroso-N-acetyl-penicillamine (SNAP). The NO donor dose-dependently enhanced IL
      4 secretion into the supernatant (p<0.01). In contrast, IFNgamma production was
      not affected while IL-10 levels were slightly decreased. Comparable changes were
      observed when analysing cytokine mRNA levels by semiquantitative RT-PCR. The
      differential effect of the NO donor on IL-4 versus IL-10 and IFNgamma gene
      expression suggests an immunomodulatory potential of NO, which may serve to limit
      inflammatory responses.

PMID- 10576560
TI  - Effects of transforming growth factor beta1 on cell growth and parathyroid
      hormone-related protein in Walker 256 tumor cells.
AB  - Hypercalcemic strains of the rat Walker 256 (W256) tumor synthesize parathyroid
      hormone-related protein (PTHrP) and at least one of them produces an ill-defined
      transforming growth factor activity. We tested the production of transforming
      growth factor (TGF) beta by a hypercalcemic W256 tumor strain, and assessed its
      effects on tumor cell growth and PTHrP expression. We found that addition of TGF
      beta1 for 7 days inhibited cell growth ([3H]thymidine incorporation and cell
      number) dose dependently, between 0.04-20 pM. The antiproliferative effect of TGF
      beta1 on W256 tumor cell growth was likely mediated by binding to high affinity
      receptors (Kd = 14 pM) in these cells. At different tumor cell growth stages,
      acidified cell-conditioned medium contained immunoreactive TGF beta1. However,
      the nonacidified tumor cell-conditioned medium was found to contain neither
      immunoreactive nor bioactive TGF beta. Moreover, exposure of W256 tumor cells to
      a neutralizing anti-TGF beta1 antibody failed to affect tumor cell proliferation.
      Thus, W256 tumor cells appear to secrete TGF beta in an inactive form. Using
      reverse transcription followed by PCR, we found that addition of 20 pM TGF beta1
      increased its own mRNA expression, apparently by stimulating gene transcription,
      within 6-12 h in W256 tumor cells. In addition, 20 pM TGF beta1 stimulated PTHrP
      mRNA in these cells at 24 h; an effect which was mediated, at least in part, by
      increasing PTHrP mRNA stability. Immunoreactive PTHrP decreased in the W256 tumor
      cell-conditioned medium after treatment with 20 pM TGF beta1 for 24-48 h. These
      results support the validity of this W256 tumor strain for in vivo studies to
      clarify the relative role of TGF beta and PTHrP in the pathogenesis of humoral
      hypercalcemia of malignancy.

PMID- 10576559
TI  - New opioid affinity labels containing maleoyl moiety.
AB  - Opioid receptor binding properties and pharmacological profiles of novel peptides
      containing maleoyl function were determined in order to develop new affinity
      labels. Based on the enkephalin structure peptide ligands were synthesized and
      tested. Both in in vitro receptor binding experiments and pharmacological
      studies, all ligands showed agonist character with relatively high affinity (Ki
      values in the nanomolar range) and good to moderate selectivity. Replacement of
      Gly2 in the enkephalin frame with D-Ala led to higher affinities with a small
      decrease in selectivity. The longer peptide chains resulted in compounds with
      high percentage (up to 86%) of irreversible binding. The selectivity pattern of
      the ligands is in good agreement with the data obtained from the pharmacological
      assays (guinea pig ileum and mouse vas deferens bioassays). The newly synthesized
      peptides could be used in further studies in order to determine more detailed
      characteristics of the ligand-receptor interaction.

PMID- 10576561
TI  - Studies on the cardiovascular action of TPY-beta: an antihypertensive agent with
      antiplatelet activity.
AB  - 1-Pyrrolidinylmethyl-2-naphthol hydrochloride (TPY-beta) has been reported to
      have hypotensive and bradycardiac effects in anesthetized rats. Whether
      administration of atropine or bilateral vagotomy affects mean arterial pressure
      or heart rate was examined. The percentage difference in hypotensive and
      bradycardiac effect of TPY-beta (0.5 mg/kg) was 63 +/- 5% and 68 +/- 9%,
      respectively, in unpretreated rats compared to control levels. Atropine
      pretreatment (0.1 mg/kg, i.v.) significantly reduced the depressant effect of TPY
      beta, although heart rate and mean arterial pressure remained 21 +/- 3% and 31 +/
      4%, respectively, as compared to control levels. Vagotomy decreased heart rate
      and mean arterial pressure response but moderate bradycardiac (13 +/- 2%) and
      hypotensive (10 +/- 3%) effects still remained as compared to control levels.
      Unilateral microinjection of 1, 3.3 and 10 nM TPY-beta into the nucleus tractus
      solitarri elicited a dose-dependent depressor (-10 +/- 2; -20 +/- 3; -25 +/- 3
      mmHg) and bradycardiac activities (-20 +/- 4; -26 +/- 5; -55 +/- 10 beats/min).
      TPY-beta also relaxed the isolated rat aortic rings preconstracted with high
      extracellular K+ (80 mM) and Ca2+ (1.9 mM). The above findings suggest that the
      suppressive effects of TPY-beta may involve activation of vagus nerve and a
      direct inhibition of Ca2+ channel. In addition, TPY-beta inhibited the
      aggregation of washed rabbit platelets (aggregated by arachidonic acid and
      collagen) and adhesiveness on fibrinogen-coated surface. The results suggest that
      TPY-beta possesses antihypertensive and antiplatelet activity.

PMID- 10576562
TI  - Agonist-induced release of nitric oxide during acute exposure to nicotine.
AB  - While we have shown that acute infusion of nicotine impairs agonist-induced
      dilatation of resistance arterioles (Am. J. Physiol. 272:H2337-H2342, 1997), no
      studies have examined the release of nitric oxide in response to these agonists
      before and during treatment with nicotine. Thus, the first goal of the present
      study was to examine agonist-induced release of nitric oxide by the hamster cheek
      pouch microcirculation under control conditions and during acute infusion of
      nicotine. We measured the release of nitric oxide (Sievers NO analyzer) in
      response to repeated topical application of acetylcholine (1.0 microM) and 5'
      adenosine diphosphate (ADP; 1.0 microM) during infusion of vehicle and during
      infusion of nicotine (2.0 microg/kg/min i.v. for 30 minutes followed by a
      maintenance dose of 0.35 microg/kg/min). In hamsters treated with vehicle,
      topical application of acetylcholine and ADP elicited reproducible increases in
      nitric oxide release. In contrast, in hamsters treated with nicotine, there was a
      marked inhibition of nitric oxide release in response to acetylcholine and ADP.
      In a previous study (J. Appl. Physiol. 85:1292-1298, 1998) we found that
      treatment of the hamster cheek pouch microcirculation with superoxide dismutase
      restored impaired agonist-induced vasodilatation during acute infusion of
      nicotine. Thus, our second goal was to examine whether superoxide dismutase would
      restore agonist-induced release of nitric oxide during infusion of nicotine. We
      found that treatment of the hamster cheek pouch microcirculation with superoxide
      dismutase prior to infusion of nicotine prevented nicotine-induced impairment of
      nitric oxide release in response to acetylcholine and ADP. We suggest that
      nicotine alters dilatation of arterioles via an increased release of superoxide
      anion and subsequent inactivation of nitric oxide.

PMID- 10576563
TI  - The effect of a neuropeptide Y antagonist, BIBP 3226, on short-term arterial
      pressure control in conscious unrestrained rats with congestive heart failure.
AB  - The effects of a neuropeptide Y (NPY) Y1-receptor antagonist (BIBP 3226) on mean
      arterial pressure (MAP) and heart rate were investigated in conscious
      unrestrained rats with chronic congestive heart failure. The rats were randomly
      assigned to 2 groups, and received either BIBP 3226 or its inactive enantiomer
      (BIBP 3435) as an intravenous infusion (6 mg/kg/h for 1.5 h, respectively).
      Before, during and after the infusion, rats were stressed with a jet of air and
      received a bolus injection of NPY (2 nmol/kg iv.). There was no difference
      between the 2 groups in resting MAP and heart rate before, during or after
      infusion (BIBP 3226 vs. BIBP 3435). The effects of exogenous NPY on MAP were
      significantly attenuated in BIBP 3226 group during and 1 h after the infusion
      (p<0.05). The tissue NPY levels in heart, adrenal gland and kidney in heart
      failure rats were not different from those in sham-operated rats. The results
      suggest that Y1-receptor mechanisms are of minor importance in the short-term
      control of basal MAP and heart rate in conscious unrestrained rats with
      congestive heart failure.

PMID- 10576564
TI  - Trp-Lys-Tyr-Met-Val-Met activates mitogen-activated protein kinase via a PI-3
      kinase-mediated pathway independent of PKC.
AB  - Trp-Lys-Tyr-Met-Val-Met (WKYMVM) is a novel potent peptide which can stimulate
      phosphoinositide hydrolysis in U937 as well as U266 and HL-60 cells (Baek et al.,
      J. Biol. Chem. 271, 8170 (1996)). The peptide also induces superoxide generation
      in human neutrophils (Seo et al., J. Immunol. 158, 1896 (1997)). However, the
      signaling pathway down-stream of PLC set in motion by the peptide is not yet
      completely understood. We studied the signaling pathway of the peptide with the
      goal of elucidating the mechanism of the peptide's action. WKYMVM induced a rapid
      and transient activation of the ERKs in human histiocytic lymphoma cells, U937.
      The ERK1 activation peaked at 5 min and returned to the basal level after 30 min.
      The ERK1 stimulation by the peptide was partially inhibited by pretreatment of
      the cells with pertussis toxin (PTX), implicating G-protein involvement in the
      peptide's action. Pretreatment of staurosporine, protein kinase C (PKC)
      inhibitor, or PKC down-regulating PMA had no impact on the ERK1 activation by the
      peptide, indicating that the signaling pathway is independent of PKC activation.
      Pretreatment of the cells with neomycin and intracellular Ca2+ mobilizing
      reagents had also no effect on the ERK1 activation by the peptide. However,
      pretreatment with wortmannin or LY294002, the inhibitor of phosphatidylinositol 3
      kinase (PI-3K), strongly inhibited peptide-stimulated ERK1 activation. Our
      results suggest that PI-3K may be an important participant in the ERK cascade
      induced by the peptide. Furthermore, the treatment of U937 cells with the peptide
      activated p74Raf-1, an upstream kinase of ERK. Taken together, our results
      suggest that the peptide activate ERK via a G-protein/PI-3K/Ras/Raf-1 mediated
      signaling pathway in U937 cells.

PMID- 10576565
TI  - COST-action 820: vaccines against animal coccidioses. Proceedings of a workshop.
      Toledo, Spain, 22-25 October 1998.

PMID- 10576566
TI  - Molecular epidemiology and evolutionary genetics of Leischmania parasites.
AB  - In order to illustrate the relevance of the concepts and methods of evolutionary
      genetics in the understanding of the epidemiology of pathogenic agents, we
      develop in this paper the case of the Leishmania, a genus of parasitic protozoa.
      An extensive study of various natural populations of Leishmania in different
      countries (Old and New World) was carried out by using Multilocus Enzyme
      Electrophoresis (MLEE) and Random Amplified Polymorphic DNA fingerprinting (RAPD)
      as genetic markers. The data have been interpreted in evolutionary genetic terms.
      The main benefit of this approach has been to better define the concept of
      species in the genus Leishmnania, on rigorous phylogenetic bases. As a matter of
      fact, a sound taxonomical background is a prerequisite for any epidemiological
      approach. Since the biological concept of species is difficult or impossible to
      apply for most pathogenic microorganisms, we recommend relying on criteria of
      both phylogenetic discreteness and of epidemiological/medical relevance to
      describe new species of Leishmania. Through this approach, for example, we have
      shown that the species status of L. ( V.) perzzl.ianza can be supported. On the
      contrary, we have been unable to clearly distinguish L. (V.) panamensis from L.
      (V.) guyanensis with genetic tools. Additionally, we have shown that the
      epidemiological inferences based on a limited set of genetic markers can be
      misleading. As a matter of fact, we have demonstrated that a collection of L.
      (L.) infantum stocks identified as zymodeme 'MON 1' by other authors present
      additional genetic heterogeneity and do not correspond to a distinct 'Discrete
      Typing Unit' DTU, and are actually polyphyletic. Lastly, in the samples that were
      conveniently designed, we have confirmed that Leishmania parasites have a
      basically clonal population structure. As the clonal model specifies it,
      occasional bouts of genetic exchange remain nevertheless possible. Telling
      comparisons are drawn with the evolutionary genetics of other pathogens
      Trypanosoma cruzi and Trypanosoma congolense.

PMID- 10576567
TI  - DNA vaccination strategies against infectious diseases.
AB  - DNA immunisation represents a novel approach to vaccine and immunotherapeutic
      development. Injection of plasmid DNA encoding a foreign gene of interest can
      result in the subsequent expression of the foreign gene products and the
      induction of an immune response within a host. This is relevant to prophylactic
      and therapeutic vaccination strategies when the foreign gene represents a
      protective epitope from a pathogen. The recent demonstration by a number of
      laboratories that these immune responses evoke protective immunity against some
      infectious diseases and cancers provides support for the use of this approach. In
      this article, we attempt to present an informative and unbiased representation of
      the field of DNA immunisation. The focus is on studies that impart information on
      the development of vaccination strategies against a number of human and animal
      pathogens. Investigations that describe the mechanism(s) of protective immunity
      induced by DNA immunisation highlight the advantages and disadvantages of this
      approach to developing vaccines within a given system. A variety of systems in
      which DNA vaccination has resulted in the induction of protective immunity, as
      well as the correlates associated with these protective immune responses, will be
      described. Particular attention will focus on systems involving parasitic
      diseases. Finally, the potential of DNA immunisation is discussed as it relates
      to veterinary medicine and its role as a possible vaccine strategy against animal
      coccidioses.

PMID- 10576568
TI  - Comparison of the IFAT and Iscom-ELISA response in bovine foetuses with Neospora
      caninum infection.
AB  - The study was carried out to evaluate the efficacy of foetal serology in the
      diagnosis of Neospora-associated bovine abortions. Fluids from 14 foetuses of
      cows with confirmed neosporosis (Group A), seven foetuses with confirmed bovine
      viral diarrhoea virus (BVD infection) (Group B) and 11 aborted foetuses without
      demonstrable infection (Group C) were examined. The age of the foetuses ranged
      from 4.5 months to 9 months. Albumin concentration (measured by Rocket
      Immunoelectrophoresis) was not significantly different in Group A compared with
      that in both Groups B and C, while that in Group B was significantly lower than
      in Group C. Levels of total IgG ranged from 0.01 to 1.78 (mg IgG) ml(-1) measured
      by single radial immunodiffusion technique. A measurable level of total IgG was
      found in all foetuses from Groups A and B, with no significant difference between
      levels in the two groups. Only one foetus in Group C had a detectable level of
      IgG. All foetuses in Group A had a specific IgG response (titre> or = 20) against
      Neospora caninum using the IFAT, while no positive responses in IFAT were found
      in Groups B and C. Measurement of specific IgG1 and IgG2 by Iscom-ELISA showed
      one and three false-negative results, respectively, in Group A. The IgG1 and IgG2
      response in Group A was correlated according to the Spearman test (r = 0.66).
      Increasing age of the foetuses correlated significantly with the foetal IgG
      concentration, the specific IgG and IgG1 + IgG2. On the basis of the results
      obtained, it was concluded that the IFAT with a cut-off titre of 1:20, was a
      specific method for diagnosis of neosporosis in foetuses older than 4.5 months.
      The Iscom-ELISA also showed promising results as a method for screening specific
      antibodies against N. caninum in foetal fluid.

PMID- 10576569
TI  - The antigenic composition of Neospora caninum.
AB  - Neospora caninum is an apicomplexan parasite which causes neosporosis, namely
      stillbirth and abortion in cattle, and neuromuscular disease in dogs. Although N.
      caninum is phylogenetically and biologically closely related to Toxoplasma
      gondii, it is antigenically clearly distinct. In analogy to T. gondii, three
      stages have been identified. These are: (i) asexually proliferating tachyzoites;
      (ii) tissue cysts harbouring slowly dividing bradyzoites; and (iii) oocysts
      containing sporozoites. The sexually produced stage of this parasite has only
      recently been identified, and has been shown to be shed with the faeces from dogs
      orally infected with N. caninum tissue cysts. Thus dogs are definitive hosts of
      N. caninum. Tachyzoites can be cultivated in vitro using similar techniques as
      previously described for T. gondii. Methods for generating tissue cysts
      containing N. caninum bradyzoites in mice, and purification of these cysts, have
      been developed. A number of studies have been undertaken to identify and
      characterise at the molecular level specific antigenic components of N. caninum
      in order to improve serological diagnosis and to enhance the current view on the
      many open questions concerning the cell biology of this parasite and its
      interactions with the host on the immunological and cellular level. The aim of
      this paper is to provide an overview on the approaches used for detection of
      antigens in N. caninum. The studies discussed here have had a great impact in the
      elucidation of the immunological and pathogenetic events during infection, as
      well as the development of potential new immunotherapeutic tools for future
      vaccination against N. caninum infection.

PMID- 10576570
TI  - Significance of Neospora caninum in British dairy cattle determined by estimation
      of seroprevalence in normally calving cattle and aborting cattle.
AB  - A case control study was conducted to evaluate the significance of Neospora
      caninum infections in cattle in England and Wales. The prevalence of N. caninum
      in normally calving cattle (the control group; n = 418) and aborting cattle (n =
      633) was estimated using a commercial antibody-detection ELISA. Prevalence
      estimates for bovine virus diarrhoea virus, infectious bovine rhinotracheitis
      virus and Leptospira hardjo were also obtained by serology. The prevalence of N.
      caninum was significantly higher (P < 0.0001) in the aborting group (18%; 95%
      confidence interval: 15%, 21%) than in the control group (6%; 95% confidence
      interval: 4%, 8%); the latter is the first estimate, to date, of the national
      seroprevalence of N. caninum in dairy cattle in England and Wales. Prevalence
      estimates for bovine virus diarrhoea virus, infectious bovine rhinotracheitis
      virus and L. hardjo were not found to be higher in the aborting cattle than in
      the control group. With N. caninum, a strong association between seropositivity
      and abortion was found, with seropositive cows being 3.5-times more likely to
      abort than seronegative cows (odds ratio = 3.49; 95% confidence interval: 2.16,
      5.69). Furthermore, 12.5% of abortions in dairy cattle in England and Wales may
      be attributable to N. caninum, as indicated by estimation of the population
      aetiological fraction.

PMID- 10576571
TI  - Towards evaluating the economic impact of bovine neosporosis.
AB  - In spite of the global importance of neosporosis as a cause of bovine abortion,
      there is very little information about its economic consequences. The economic
      costs are a product of estimations of the quantity of the effects attributable to
      Neospora infection, and the particular unit costs of those effects. In this brief
      review, which arose from a workshop on the economics of coccidiosis held at the
      COST 820 meeting, Toledo 1998, we discuss the possible effects of neosporosis
      which are of economic significance and summarise the available estimates of their
      magnitude to provide a basis for further economic analysis. Neospora infection
      has been associated with abortion, increased culling and reduced milk yield. In
      addition, it has been diagnosed in cases of stillbirth and neonatal mortality, it
      is likely to contribute to early foetal death and resorption and it is
      responsible for a reduction in the value of female breeding cattle. In
      quantifying the role of Neospora, it is important that epidemiologically based,
      case-controlled studies are conducted because, given the extreme efficiency with
      which bovine Neospora infection is vertically transmitted, demonstration of
      prevalence of infection in affected animals (including foetuses) is not a true
      indicator of the significance of this disease. Relatively few epidemiological
      studies have been conducted, but in investigations in the USA, Holland and
      Britain, infected cows have been shown to be about three times more likely to
      abort than non-infected cattle. In the UK this approach has been used to estimate
      the proportion of abortions in the national dairy population which may be
      attributable to Neospora caninum.

PMID- 10576572
TI  - Seroprevalence of Neospora caninum infection in dairy and beef cattle in Spain.
AB  - In recent years, neosporosis has been identified as a major cause of abortion in
      dairy and beef cattle. Although the disease has been described worldwide, there
      is a Jack of information concerning the prevalence of this infection in different
      cattle production systems. The aim of this study was to investigate the
      seroprevalence of Neospora caninum infection in a representative area of beef and
      dairy cattle production in Spain. A cross-sectional study was undertaken in which
      herds constituted the initial sampling unit and two strata (dairy and beef herds)
      were considered. Using a 95% level of confidence and setting 5% (beef) and 5.4%
      (dairy) error limits, 216 beef and 143 dairy herds were randomly selected and
      sampled. Nine animals (> 1 year old) were randomly sampled in each herd to detect
      the presence of the infection. A herd was considered infected when at least one
      animal was seropositive. In total, serum samples from 1121 dairy and 1712 beef
      animals were collected and tested for specific anti-N. caninum IgG using an
      ELISA. Specific antibodies were detected in 55.1% (119/216) beef and 83.2%
      (119/143) dairy herds. Individual prevalences obtained were 17.9% (306/1712) for
      beef and 35.9% (402/1121) for dairy animals. Presence of N. caninum infection was
      higher in dairy than in beef herds and the association between infection and the
      cattle production system (dairy or beef) was statistically significant [(chi2)Y=
      29.21, P < 0.001, OR = 4.04 (2.35-6.99)]. Herd size of dairy cattle did not
      appear to be associated with N. caninum infection. On the contrary, infection was
      associated with herd size in beef cattle (chi2 = 12.79, P < 0.01). Finally, no
      association was found between replacement or pasture management and infection in
      beef herds.

PMID- 10576573
TI  - A compartmentalised model for the estimation of the cost of coccidiosis to the
      world's chicken production industry.
AB  - A compartmentalised model is presented for the estimation of the monetary losses
      suffered by the world's poultry industry resulting from coccidiosis of chickens
      and costs of its control. The model is designed so that the major elements of
      loss may be separately quantified for any chicken-producing entity, e.g., a farm,
      a poultry company, a country, etc. Examples are presented and the sources,
      reliability and geographical relevance of the data used for each parameter are
      provided. Loss elements for specific geographical areas should be recalculated at
      appropriate intervals to take into account local and international fluctuations
      in costs of chicks feed, labour, financial inflation and world currency exchange
      rates. Equations are given for relationships among numbers of chickens,
      liveweights, weights of carcasses, feed consumptions, feed conversion ratio
      (FCR), prices of feeds, prices of anticoccidial therapeutic and prophylactic
      drugs, values of chickens, chicken rearing costs; and effects of coccidiosis on
      mortality, weight gain and FCR. Using these equations, it is theoretically
      possible for an international team of representatives, each using reliable local
      data, to calculate simultaneously each relevant loss element for their respective
      countries. Addition of these elements could give, for the first time, an accurate
      global estimate of the losses due to chicken coccidiosis. The total cost of
      coccidiosis in chickens in the United Kingdom in 1995 is estimated to have been
      at least GB pound silver 38 588 795, of which 98.1% involved broilers (80.6% due
      to effects on mortality, weight gain and feed conversion, and 17.5% due to the
      cost of chemoprophylaxis and therapy). The costs of poor performance due to
      coccidiosis and its chemical control totalled 4.54% of the gross revenue from UK
      sales of live broilers. This model includes a new method for comparing the
      profitabilities of different treatments in commercial trials. providing actual
      costs rather than the arbitrary numerical scores of other methods. Although
      originally designed for the study of coccidiosis, the model is equally applicable
      to any disease. It should be of value to agricultural economists, the animal feed
      and poultry industries, animal health companies, and to research scientists
      (particularly for preparing grant applications).

PMID- 10576574
TI  - Vaccination against Eimeria tenella infection using a fraction of E. tenella
      sporozoites selected by the capacity to activate T cells.
AB  - At 8 days after a primary Eimeria tenella infection, a subset of T cells, of
      which the protective role is as yet unclear, circulates in the peripheral blood.
      In order to investigate this, the in vitro cellular responsiveness of these
      peripheral blood lymphocytes has been used as selection criterion to identify
      potentially protective E. tenella sporozoite antigens. The hydrophilic protein
      phase of purified E. tenella sporozoite homogenates obtained by Triton X-114
      extraction was fractionated using preparative gel electrophoresis. Nine
      fractions, separated according to different molecular weight, were tested for
      their ability to stimulate T-cell responses. Both the proliferation of peripheral
      blood lymphocytes and the macrophage activating activity released in the culture
      supernatants were measured. On the basis of this responsiveness, four fractions
      were selected and used to vaccinate chickens. All vaccine preparations induced
      strong T-cell responses. One fraction immunised chickens against subsequent
      challenge infection, in that the caecal lesion scores were significantly lower as
      compared with that of the unvaccinated controls. This fraction contained
      hydrophilic polypeptides with a molecular mass that ranged from 26 to 30 kDa.

PMID- 10576575
TI  - The identification of Cryptosporidium species and Cryptosporidium parvum directly
      from whole faeces by analysis of a multiplex PCR of the 18S rRNA gene and by
      PCR/RFLP of the Cryptosporidium outer wall protein (COWP) gene.
AB  - A multiplex polymerase chain reaction (PCR) procedure to amplify 18S rRNA gene
      fragments has been developed. Amplified DNA fragments of the expected size were
      obtained which were specific for Cryptosporidium parvum and Cryptosporidium
      wrairi (422 bp), Cryptosporidium baileyi (11106 bp) and Cryptosporidium muris
      (1346 bp). Criptosporidium parvum and C. wrairi can be distinguished using a
      PCR/restriction fragment length polymorphism (RFLP) analysis of the
      Cryptosporidium outer wall protein (COWP) gene, and these two techniques were
      applied to DNA extracted from whole faeces using a simple and rapid procedure.
      Cryptosporidium parvum DNA was detected in the faeces of 72 humans and 24 calves
      where cryptosporidial oocysts were demonstrated using conventional light
      microscopy. The specific DNA fragments were not amplified using extracts of
      material containing other lower eukaryotic parasites.

PMID- 10576576
TI  - Ultrastructure, fractionation and biochemical analysis of Cryptosporidium parvum
      sporozoites.
AB  - Sporozoites of the apicomplexan parasite Cryptosporidium parvum were subjected to
      cell disruption and subcellular fractionation using a sucrose density step
      gradient. With this procedure, highly enriched preparations of the parasite
      membrane, the micronemes, dense granules and amylopectin granules were produced.
      No separate fraction containing rhoptries was obtained, however this organelle
      was found in defined fractions of the gradient, still associated with the apical
      tip of the sporozoites. Using negative staining, the internal structure of the
      micronemes was revealed by transmission electron microscopy. Micronemes and dense
      granules showed characteristic protein compositions by sodium dodecyl sulfate
      polyacrylamide gel electrophoresis. The micronemes contained three major proteins
      of approximately 30, 120 and 200 kDa and the dense granules contain five major
      proteins in the 120-180 kDa range.

PMID- 10576577
TI  - Role of adult sheep in transmission of infection by Cryptosporidium parvum to
      lambs: confirmation of periparturient rise.
AB  - In sheep farms, oocyst shedding by asymptomatic adult carriers is one of the
      mechanisms which may explain maintenance of infections by Cryptosporidium parvum
      between lambing periods. The objective of this work was to investigate this
      hypothesis and the existence of a periparturient rise in oocyst shedding.
      Fourteen pregnant sheep were randomly selected from two farms with a history of
      neonatal diarrhoea caused by C. parvum and samples were collected from the 6th
      week before birth until 2 weeks after birth. Faecal samples were filtered,
      concentrated and examined for oocysts using an indirect immunofluorescence assay.
      The kinetics of anti-C. parvum antibodies (IgG and IgA) were studied using an
      indirect enzyme-linked immunosorbent assay. All except one animal excreted C.
      parrum oocysts at some time during the experimental period. The percentage of
      animals passing oocysts increased in the first week post-partum (farm 1) and in
      the first week before birth (farm 2). The numbers of oocysts excreted ranged from
      20-440 oocysts g(-1) of faeces. In contrast, no significant changes in the anti
      C. parvum immunoglobulin levels were observed over the sampling period. Finally,
      a high percentage of lambs (71%) born to these ewes acquired infection in the
      first 2 weeks of life.

PMID- 10576578
TI  - A review of the importance of cryptosporidiosis in farm animals.
AB  - Cryptosporidium species are coccidian parasites with a large capacity to
      reproduce and to disseminate. Several species are known to infect farm animals,
      although the economic importance of cryptosporidiosis is highly host species
      dependent. This paper reviews the impact of cryptosporidial infections in
      livestock and poultry. For different farm animals, the Cryptosporidium spp. that
      occur, as well as their clinical and pathological features, and their
      interactions with other pathogens, are described. In addition, data concerning
      the prevalence, the transmission and the epidemiology of the disease are
      mentioned and a description of the economic losses associated with
      cryptosporidiosis in each of the hosts is given. Cryptosporidiosis seems to be
      mainly a problem in neonatal ruminants. Cryptosporidium parvum is considered to
      be an important agent in the aetiology of the neonatal diarrhoea syndrome of
      calves, lambs and goat kids, causing considerable direct and indirect economic
      losses. Avian cryptosporidiosis is an emerging health problem in poultry,
      associated with respiratory disease in chickens and other Galliformes, and with
      intestinal disease in turkeys and quails. Because of limited availability of
      effective drugs, the control of cryptosporidiosis relies mainly on hygienic
      measures and good management.

PMID- 10576579
TI  - Speculation on whether a vaccine against cryptosporidiosis is a reality or
      fantasy.
AB  - In this paper the authors question whether the development of a vaccine against
      cryptosporidiosis could be taken into consideration. The necessity and
      feasibility of such a vaccine for human and veterinary application is discussed.
      Developmental stages within the life cycle of the parasite that might act as
      possible targets for vaccine development are summarised, as well as the target
      antigens offered by molecular biology and immunology studies. Vaccination trials
      against cryptosporidiosis carried out so far, including the active and passive
      immunisation approach, are also overviewed. It seems that with respect to a
      Cryptosporidium vaccine two target groups can be considered: children of the
      developing world and neonatal ruminants. Antigens representing possible
      candidates for a subunit vaccine were identified based on their function,
      location and/or the immune response they evoke. While the active vaccination of
      newborn calves, lambs and goat kids has to face a number of important
      limitations, the passive immunisation approach, where dams were immunised to
      protect their progeny by colostral transfer, was proven to be a valuable
      alternative. Finally, a number of points of action for the near future are put
      forward.

PMID- 10576580
TI  - Pathogenicity of selected Toxoplasma gondii isolates in young pigs.
AB  - The pathogenicity in 7-week-old pigs to five different Toxoplasma gondii strains
      of various host species origin was compared after i.v. inoculation of 10(4)
      tachyzoites. Additionally, one group of pigs was inoculated i.v. with 10(6)
      tachyzoites of the reference strain, SSI 119. In response to the infection a
      significant effect of T. gondii tachyzoite inoculation dose as well as
      differences among strains could be observed in several parameters. The 10(6)-dose
      inoculated pigs showed variable degrees of clinical illness and recurrent
      episodes of fever 4-17 days p.i., while pigs of four of the 10(4) tachyzoite
      inoculated groups experienced a short-lived rise in body temperature from day 6-8
      p.i. without any apparent illness or inappetence. Control pigs and pigs infected
      with the least pathogenic strain had normal body temperature throughout the
      experiment. In all inoculated pigs, T. gondii-specific IgM and IgG antibodies
      appeared from day 8-10 and 10-17 p.i., respectively. Serum levels of alkaline
      phosphatase and the acute phase protein haptoglobin were decreased or increased,
      respectively, in response to the infection. Differential leukocyte count on
      peripheral blood revealed a significant lymphocytopenia on day 6 p.i. equal to
      both CD4+ and CD8+ T-cells, but shifting towards a reduced ratio of CD4+/CD8+ T
      cells from day 8-14 p.i. In the 10(6)-dose inoculated pigs a considerable
      increase in zymosan induced and spontaneous oxidative burst capacity of
      peripheral blood leukocytes was observed from 6 days p.i. compared with control
      pigs. Oxidative burst capacity was not examined for other pigs. In conclusion,
      several useful parameters to identify differences in T. gondii pathogenicity
      other than mortality were identified. Furthermore, even at low doses, significant
      differences between recently collected Danish T. gondii field isolates were
      demonstrated after i.v. inoculation in young pigs.

PMID- 10576581
TI  - Biological control of rodents using Sarcocystis singaporensis.
AB  - Parasites have been identified as an important factor in regulating vertebrate
      populations. In replicated field experiments (plots up to 4 ha) performed in
      Thailand we tested whether commensal and field rodents could be artificially
      infected and controlled with the host-restricted apicomplexan protozoon
      Sarcocystis singaporensis which is endemic in Southeast Asia. When bait-pellets
      containing high numbers of these parasites were consumed by rodents of three
      species (Rattus norvegicus, Rattus tiomanicus, Bandicota indica) in different
      agricultural habitats (chicken farm, oil palm plantation, ricefield), we observed
      a parasite-induced mortality ranging from 58% to 92%. Detection of merozoites of
      S. singaporensis in lung tissue samples of rats collected dead at the
      experimental sites using a species-specific monoclonal antibody confirmed that S.
      singaporensis was the causative agent of mortality. As observed with brown rats,
      the parasite's effect on the host was not related to sex. These experiments
      demonstrate for the first time that artificial infection of rodents with an
      endemic protozoon has the potential for effective population control.

PMID- 10576582
TI  - Development and validation of species-specific nested PCRs for diagnosis of acute
      sarcocystiosis in sheep.
AB  - Sheep may be infected by four species of Sarcocystis. Two of these species,
      Sarcocystis tenella and Sarcocystis arieticanis, are pathogenic. They may cause
      abortion or acute disease during the early phase of infection, and chronic
      disease during the late phase of infection. Thus far, diagnosis of sarcocystiosis
      in sheep has been limited, because traditional diagnostic tests based on the
      detection of Sarcocystis-specific antibodies are only genus-specific and, thus,
      cannot differentiate between pathogenic and non-pathogenic species. In addition,
      most of these tests show a reasonable sensitivity only for the late phase of
      infection. Therefore, diagnosis of acute sarcocystiosis has been based mainly on
      post-mortem examination, i.e. after the animal had succumbed to the disease. Here
      we established species-specific nested PCR assays based on unique small subunit
      ribosomal RNA gene sequences of S. tenella and S. arieticanis. These PCR assays
      specifically detect DNA of the homologous species in blood samples of sheep. No
      cross-reactions were observed with the heterologous pathogenic species, the non
      pathogenic species Sarcocystis gigantea, or the closely related coccidia
      Toxoplasma gondii and Neospora caninum. In sheep experimentally infected with S.
      tenella or S. arieticanis, positive PCR results were correlated with the early
      phases of multiplication (endopolygeny) of the parasites. By contrast,
      Sarcocystis-specific antibodies were detected by an enzyme-linked immunosorbent
      assay only during the terminal phase of endopolygeny or thereafter. Thus, the
      nested PCR assays developed here enable, for the first time, the diagnosis and
      differentiation of infections with S. tenella and S. arieticanis in living sheep
      during the acute phase of the disease and facilitate comprehensive studies on the
      epidemiology and importance of infections with pathogenic Sarcocystis species in
      sheep.

PMID- 10576583
TI  - Low convulsive activity of a new carbapenem antibiotic, DK-35C, as compared with
      existing congeners.
AB  - Since carbapenems and cephalosporins have been suggested to induce convulsive
      side effects through an inhibitory action on the central gamma-aminobutyric acid
      (GABA)-mediated inhibitory transmission, the present study evaluated the
      convulsive activity of a new carbapenem antibiotic (1R,5S,6S)-6[(R)-1
      hydroxyethyl]-2-[(3S,5S)-5(S-methyl-4thiomorpholin  ylcarbonyl)pyrrolidin-3-thio]
      l-methylcarbapen-2-em-3- carboxylic acid (DK-35C) in in vitro and in vivo
      experiments, in comparison with cefazolin, imipenem and meropenem. In in vitro
      experiments, their abilities to inhibit [3H]muscimol (5 nM) binding to GABA(A)
      receptors were measured using crude synaptic membranes prepared from the rat
      cerebral cortex. The concentrations (mM) of the antibiotics which inhibit 50% of
      the specific binding, were 0.6 for imipenem, 1.8 for cefazolin, 15.4 for DK-35C
      and 27.6 for meropenem. In in vivo experiments, intracerebroventricular (i.c.v.)
      injections of cefazolin, imipenem and DK-35C induced convulsions in a dose
      dependent manner in rats. The doses (nmol/rat) of the antibiotics which induce
      convulsions in 50% of rats, were 57 for imipenem, 96 for cefazolin, 377 for DK
      35C and >3000 for meropenem. In the mouse pentylenetetrazole (PTZ) convulsive
      model, intravenous pretreatment with cefazolin (800 mg/kg) or imipenem (200
      mg/kg) shifted the dose-response curve of PTZ (i.p.) to the left, indicating
      enhancement of the convulsive activity of PTZ. However, pretreatment with
      cefazolin, meropenem or DK-35C at a dose of 400 mg/kg did not produce any marked
      effects on the convulsive activity of PTZ compared with the saline vehicle
      pretreated control. The results clearly demonstrate a good correlation between in
      vitro GABA(A) receptor binding assay and in vivo i.c.v. convulsive model using
      rats, and suggest that DK-35C may possess a relatively weak convulsive activity
      mediated through an interaction with GABA(A) receptors.

PMID- 10576584
TI  - The relative estrogenic activity of technical toxaphene mixture and two
      individual congeners.
AB  - Toxaphene is the most abundant persistent organic pollutant in the Arctic and in
      the Great Lakes. Toxaphene technical mixture (Tox) applied as a pesticide
      consists of over 800 congeners. Through processes of environmental degradation,
      selected metabolism, and bioaccumulation, two congeners are prominent in humans;
      2-exo,3-endo,5-exo,6-endo,8,8,10,10-octachlorobornane (T2 or Parlar 26) and 2
      exo,3-endo,5-exo,6-endo,8,8,9,10, 10-nonachlorocamphene (T12 or Parlar 50). The
      MCF7-E3 human breast cancer cell model was used to screen for the estrogenic
      activities of Tox, T2, and T12. A concentration of 10 microM was required by all
      three compounds to elicit an estrogenic response as indicated by a proliferative
      effect (PE) upon the cells. The congeners, however, showed significantly
      different PEs from Tox. Both T2 and T12 had a lower PE (16 and 30%) and than Tox,
      and T2 had a higher PE than T12 (19%). Results from binary combination studies
      showed that the effects of Tox, T2, and T12 were additive. Tox, T2, and T12 had
      no significant effects on estrogen receptor and progesterone receptor levels. Our
      results suggest that the two environmental prevalent congeners had lower
      estrogenic activities than Tox and there is no synergistic effect.

PMID- 10576585
TI  - Meso-2,3-dimercaptosuccinic acid induces calcium transients in cultured rhesus
      monkey kidney cells.
AB  - The maintenance of intracellular Ca2+ homeostasis is critical to many cellular
      functions that rely on the calcium ion as a messenger. While attempting to
      characterize the effects of lead on intracellular calcium levels ([Ca2+]i) in LLC
      MK2 Rhesus Monkey kidney cells, we observed that treatment with the metal
      chelating drug, meso-2,3-dimer-captosuccinic acid (DMSA) evoked transient
      increases in [Ca2+]i. Changes in [Ca2+]i were monitored using the Ca2+ indicator
      dye Fura-2 and a dual wavelength fluorescence imaging system. In the presence of
      2 mM extracellular Ca2+, DMSA treatment caused a concentration-dependent (15-500
      microM) transient increase in [Ca2+]i returning to baseline levels within 30-60
      s. Pharmacologic concentrations of DMSA (30 microM) stimulated a three-fold
      increase in [Ca2+]i, which was spatiotemporally comparable to Ca2+ transients
      induced by other calcium agonists. Depletion of inositol trisphosphate (IP3)
      sensitive [Ca2+]i stores with the smooth endoplasmic reticulum calcium-ATPase
      (SERCA) inhibitor thapsigargin did not prevent DMSA-elicited increases in
      [Ca2+]i, suggesting that Ca2+ mobilized by DMSA was either extracellular or from
      an non-IP3 releasable Ca2+ pool. Treatment with glutathione, cysteine, or 2
      mercaptoethanol caused similar but not identical calcium transients. Adenosine-5'
      trisphosphate (ATP) also elicited transient increases in [Ca2+]i similar to those
      of DMSA. No transient increases in [Ca2+]i were elicited by DMSA or ATP in the
      absence of extracellular calcium. These data indicate that DMSA and other
      sulfhydryl compounds trigger an influx of extracellular calcium, suggesting a
      previously unobserved and unanticipated interaction between DMSA and the Ca2+
      messenger system.

PMID- 10576587
TI  - Pathophysiological mechanisms of TNF during intoxication with natural or man-made
      toxins.
AB  - Intoxication with different natural toxins or man-made toxicants has been
      associated with the induction of tumor necrosis factor alpha (TNF). These include
      endotoxin, superantigens, Pseudomonas aeruginosa exotoxin A, bacterial DNA, T
      cell stimulatory agents such as agonistic anti-CD3 mAbs or concanavalin A, alpha
      amanitin, paracetamol, ethanol, carbon tetrachloride, dioxin, and
      dimethylnitrosamine. In this paper we compile and discuss the current knowledge
      on the pathophysiological role of TNF during intoxication with all mentioned
      toxins and toxicants. A possible role of gut-derived endotoxin in several TNF
      dependent toxic events has been considered. The development of pharmaceuticals
      that selectively interfere with the detrimental pathways induced by TNF during
      intoxication with bacteria, viruses, drugs, or other chemicals requires detailed
      knowledge of the signaling pathways originating from the two TNF receptors (TNFR1
      and TNFR2). Major characteristics of these signaling pathways are described and
      put together.

PMID- 10576586
TI  - Short-term moderate aflatoxin B1 exposure has only minor effects on the gut
      associated lymphoid tissue of Brown Norway rats.
AB  - Aflatoxin B1 (AFB1) is toxic to the systemic immune system in various animal
      species, whereas little is known about its effect on the gut-associated lymphoid
      tissue (GALT). It may be hypothesized that the toxicity of AFB1 and its locally
      generated metabolites in the intestinal tissue may result in a disturbed
      intestinal integrity and, subsequently, in an impaired immune response towards
      dietary proteins. The objective of our study was to investigate the toxic effect
      of short-term moderate AFB1 exposure on the intestinal epithelium and on the
      immune cells associated with the intestinal tract. The toxicological potential of
      AFB1 and its metabolites to the intestinal epithelium was determined by measuring
      viability and genotoxic damage in isolated jejunal epithelial cells (comet assay)
      after 30 min incubation in vitro. In vivo toxicology studies were carried out
      with Brown Norway (BN) rats, which were exposed orally once a week with AFB1 (1 x
      100 microg/kg body weight (b.w.)/week) for 5 consecutive weeks. Viability and
      genotoxicity were measured in explanted jejunal epithelial cells. For studying
      the effectiveness of AFB1 on immunological parameters BN rats were treated with a
      high (study 1: 1 x 1 mg/kg b.w./week) or a low (study 2: 1 x 100 microg/kg
      b.w./week) AFB1 dose for 5 consecutive weeks with or without ovalbumin (OVA).
      Mesenteric lymphocytes were isolated and proliferative responsiveness, secretion
      of interferon-gamma, and changes in lymphocyte subpopulations as well as mucosal
      mast cell specific protease and anti-OVA specific antibody concentrations were
      measured. In vitro, AFB1 ( >30 microM) induced genotoxicity in rat jejunal
      epithelial cells. The oral administration of AFB1 (1 x 100 microg/kg b.w./week)
      did not induce DNA damage in jejunal epithelial cells. The high AFB1 dose
      increased the number of CD8+ and CD8/CD71 + cells in mesenteric lymph nodes. The
      immune response towards OVA was not affected. The low AFB1 dose only reduced the
      proliferative responsiveness of mesenteric lymphocytes (P < 0.05). Serum
      concentrations of anti-OVA specific IgE antibody, of RMCPII, and the capacity of
      mesenteric lymphocytes to produce interferon-gamma were not impaired by AFB1. In
      conclusion, exposure to moderate doses of AFB1 does not damage the intestinal
      epithelium and has only minor effects on the GALT. The low exposure, as it may
      predominantly occur in western countries, does not appear to increase the risk
      for sensitization to dietary antigens.

PMID- 10576588
TI  - New insights into nitric oxide and coronary circulation.
AB  - Since its discovery over 20 years ago as an intercellular messenger, nitric oxide
      (NO), has been extensively studied with regard to its involvement in the control
      of the circulation and, more recently, in the prevention of atherosclerosis. The
      importance of NO in coronary blood flow control has also been recognized. NO
      independent vasodilation causes increased shear stress within the blood vessel
      which, in turn, stimulates endothelial NO synthase activation, NO release and
      prolongation of vasodilation. Reactive hyperemia, myogenic vasodilation and
      vasodilator effects of acetylcholine and bradykinin are all mediated by NO.
      Ischemic preconditioning, which protects the myocardium from cellular damage and
      arrhythmias, is itself linked with NO and both the first and second windows of
      protection may be due to NO release. Exercise increases NO synthesis via
      increases in shear stress and pulse pressure and so it is likely that NO is an
      important blood flow regulatory mechanism in exercise. This phenomenon may
      account for the beneficial effects of exercise seen in atherosclerotic
      individuals. Whilst NO plays a protective role in preventing atherosclerosis via
      superoxide anion scavenging, risk factors such as hypercholesterolemia reduce NO
      release leading the way for endothelial dysfunction and atherosclerotic lesions.
      Exercise reverses this process by stimulating NO synthesis and release. Other
      factors impacting on the activity of NO include estrogens, endothelins,
      adrenomedullin and adenosine, the last appearing to be a compensatory pathway for
      coronary control in the presence of NO inhibition. These studies reinforce the
      pivotal role played by the substance in the control of coronary circulation.

PMID- 10576589
TI  - Polyamine deprivation alters formalin-induced hyperalgesia and decreases morphine
      efficacy.
AB  - Although the exact functions of polyamines in the nervous system remain still
      unclear, they are thought to have a physiological role in intracellular signal
      processing and neurotransmission. Polyamine deprivation which consists in the
      reduction of both the endogenous and exogenous sources of polyamines is a
      promising treatment for cancer. In a previous study we have shown that this
      treatment provokes an analgesic effect in rats submitted to brief phasic
      nociceptive tests. The present study examined the effect of polyamine deprivation
      on pain-related behaviors and spinal c-fos expression evoked in the formalin test
      presumed to better reflect clinical pain, using morphine as analgesia control.
      Polyamine deprivation per se altered the characteristic pain-related behaviors,
      reducing the interphase depression of pain, without inducing changes in the
      spinal Fos staining. In addition this treatment prevented the antinociceptive
      effect of morphine both on behavioral responses and on spinal c-fos expression.
      In polyamine-deprived rats, despite morphine injection, nociceptive scores
      remained dramatically high during the intermediate and the late phases of the
      response and the number of Fos immunoreactive neurons remained largely higher in
      deeper layers than in morphine control rats. Altogether these data support a
      modulatory role of polyamines both on the neuronal circuitry mediating sensory
      information, and on mechanisms underlying morphine analgesia.

PMID- 10576590
TI  - Existence of a bioactive lipid, cyclic phosphatidic acid, bound to human serum
      albumin.
AB  - A novel bioactive lipid, cyclic phosphatidic acid (cPA), was identified in lipids
      bound to human serum albumin. A cPA fraction was extracted and purified from
      human serum albumin by use of a combination of preparative TLC and HPLC.
      Electrospray ionization mass spectrometry of the purified fraction showed
      molecular ions corresponding to cPA, which was composed of some different fatty
      acid species. The most abundant component was identified as palmitoyl-cPA by
      tandem mass spectrometry using collision-induced dissociation. These data have
      established that cPA is a naturally occurring lipid bound to human serum albumin.

PMID- 10576591
TI  - Gene suture--a novel method for intramuscular gene transfer and its application
      in hypertension therapy.
AB  - In this report, reporter gene beta-galactosidase (LacZ) was chosen to compare two
      different intramuscular gene transfer methods, direct injection and gene suture.
      Evidence showed that gene suture can produce a higher foreign gene express
      efficiency in skeletal muscle compared with the direct injection method. The
      highly efficient eukaryotic expressing vectors of human atrial natriuretic factor
      (ANF) were constructed (pcD2/pAdVAntage/hANF and pcDNA3/hANF), and in vivo ANF
      gene delivery was performed by intramuscular gene suture. The effects of ANF gene
      transfer on blood pressure and renal sodium and water excretion were studied in
      three models of hypertensive animals. Results showed that a marked decrease of
      mean arterial pressure (MAP) and a significant increase of urine volume and
      urinary sodium excretion was produced in rats receiving the hANF construct due to
      the local expression of ANF and its secretion into plasma. Taken together, these
      results indicate that gene suture may represent a novel gene delivery modality in
      gene therapy.

PMID- 10576592
TI  - Alternative exon splicing of cyclic AMP response element-binding protein in
      peripheral sensory and sympathetic ganglia of the rat.
AB  - Alternative splicing patterns of cyclic AMP response element-binding protein
      (CREB) in dorsal root ganglia, lumbar sympathetic ganglia and several peripheral
      tissues of the rat have been investigated by an exon-flanking polymerase chain
      reaction strategy. A series of RT-PCR with primer pairs flanking all possible
      alternative splicing sites (corresponding to a genomic region with at least one
      full exon and two flanking introns) has revealed multiple tissue specific splice
      variants. These include some novel transcripts that lack the phosphorylation site
      and part of the leucine zipper region which is crucial for dimerization and DNA
      binding. Some isoforms previously reported as testis-specific were also detected
      in rat peripheral ganglia and other tissues. Notably, splicing patterns are
      specific for some regions. Some of the splice variants indicate inhibitory
      functions due to lacking phosphorylation sites or partially missing DNA-binding
      or leucine zipper domains. These findings suggest a complex expression and
      functional regulation of CREB in peripheral tissues including dorsal root and
      sympathetic ganglia.

PMID- 10576593
TI  - Comparison of A68 levels in Alzheimer diseased and non-Alzheimer's diseased brain
      by two ALZ50 based methods.
AB  - A total of 61 human brain specimens were analyzed with both ELISA and Western
      Blot using the ALZ50 monoclonal antibody. The brain specimens included:
      Alzheimer's Disease (AD, n=31), AD/Down's (n=2), Normal (n=14), Parkinson's
      Disease (n=7), Huntington's chorea (n=2), Wernicke-Korsakov's Encephalopathy
      (n=3), and Motor Neuron Disease (n=2). The non-AD cases (n=28) had no detectable
      A68 by ELISA, and showed no A68 bands by Western blot. The AD cases (n=33), all
      were positive for A68 by the ELISA, but only 31 of 33 had visible A68 band by
      Western blot. Additionally, a method for solubilization of A68 is reported.

PMID- 10576594
TI  - Increased expression of peripheral benzodiazepine receptors and diazepam binding
      inhibitor in human tumors sited in the liver.
AB  - The peripheral benzodiazepine receptor system triggers intracellular metabolic
      events and has been associated with cell proliferation. Its endogenous ligand,
      the diazepam binding inhibitor, contributes to steroidogenesis by promoting
      cholesterol delivery to the inner mitochondrial membrane. The present study was
      undertaken to verify whether this system is altered in tumors sited in the liver.
      Peripheral benzodiazepine receptors and diazepam binding inhibitor were studied
      using immunocytochemistry and in situ hybridization in 9 human tumors sited in
      the liver, in liver hyperplasia, cirrhotic nodular regeneration, intestinal
      adenocarcinoma and in surrounding non-tumoral tissue. Immunocytochemical staining
      and in situ hybridization demonstrated that peripheral benzodiazepine receptors
      and diazepam binding inhibitor were more prominently expressed in neoplastic
      cells than in non-tumoral tissue. They were present in the same cells, suggesting
      that diazepam binding inhibitor may act in an intracrine manner in these cells.
      Higher peripheral benzodiazepine receptors and diazepam binding inhibitor
      expression in tumor cells suggest an implication of this system in the metabolism
      of neoplastic cells. Furthermore the evaluation of peripheral benzodiazepine
      receptor and diazepam binding inhibitor expression might be useful in evaluating
      malignancy and in diagnostic approaches of tumors in liver tissue.

PMID- 10576595
TI  - PD 102807, a novel muscarinic M4 receptor antagonist, discriminates between
      striatal and cortical muscarinic receptors coupled to cyclic AMP.
AB  - In membranes of Chinese hamster ovary cells expressing the cloned human M1-M4
      muscarinic receptor subtypes, PD 102807, a novel M4 selective antagonist, was
      found to counteract the M4 receptor-induced stimulation of [35S]-GTPgammaS
      binding to membrane G proteins with a pK(B) of 7.40, a value which was 63-, 33-
      and 10-fold higher than those displayed at M1 (pK(B) = 5.60), M2 (pK(B) = 5.88)
      and M3 (pK(B) = 6.39) receptor subtypes, respectively. In rat striatal membranes,
      PD 102807 antagonized the muscarinic inhibition of dopamine (DA) D1 receptor
      stimulated adenylyl cyclase with a pK(B) value of 7.36. In contrast, in membranes
      of rat frontal cortex, PD 102807 displayed lower potencies in antagonizing either
      the muscarinic facilitation of corticotropin releasing hormone (CRH)-stimulated
      adenylyl cyclase (pK(B) = 5.79) or inhibition of Ca2+/calmodulin (Ca2+/CaM)
      stimulated enzyme activity (pK(B) = 5.95). In each response investigated, PD
      102807 interacted with muscarinic receptors in a manner typical of a simple
      competitive antagonist. These data provide additional evidence that PD 102807 is
      a M4-receptor preferring antagonist and that this compound can discriminate the
      striatal muscarinic receptors inhibiting DA D1 receptor activity from the
      cortical receptors mediating the potentiation of CRH receptor signalling and the
      inhibition of Ca2+/CaM-stimulated adenylyl cyclase activity.

PMID- 10576596
TI  - Regulation of cardiac adrenomedullin-mRNA in different stages of experimental
      heart failure.
AB  - Adrenomedullin (AM) is a peptide hormone with vasodilating and natriuretic
      properties. AM plasma concentrations are elevated in heart failure. Whether
      cardiac AM-mRNA synthesis is increased in heart failure is not known. We measured
      AM-mRNA/GAPDH-mRNA in all four heart chambers in compensated and overt heart
      failure in rats with two different sizes of aortocaval shunt. Left and right
      atrial AM-mRNA expressions were unchanged in both heart failure models.
      Similarly, left and right ventricular AM-mRNA expressions were unchanged in
      compensated heart failure. In overt heart failure, however, the AM-mRNA
      expression was significantly increased in the left ventricle (145+/-20 vs. 100+/
      3% of control, p<0.05). The right ventricular AM-mRNA expression was
      significantly increased only in a subgroup of animals with pulmonary congestion
      (lung weight >2.0 g, 141+/-16 vs. 100+/-11% of control, p<0.05). Ventricular AM
      concentrations were elevated in both ventricles in overt heart failure. AM plasma
      concentrations were significantly higher in the subgroup with pulmonary
      congestion than in rats with compensated heart failure (496+/-95 vs. 143+/-7
      pmol/l, p<0.01). These data indicate that ventricular AM-mRNA expression and AM
      concentrations were upregulated only in advanced stages of heart failure.
      However, the exact contribution of cardiac AM synthesis to the increased AM
      plasma levels remains to be established.

PMID- 10576597
TI  - Phorbol ester inhibits DNA damage-induced apoptosis in U937 cells through
      activation of protein kinase C.
AB  - The effects of phorbol 12-myristate 13-acetate (PMA) on DNA damage-induced
      apoptosis were examined in promyelocytic leukemia cells, U937, in comparison with
      other differentiation-inducing agents to clarify the role of protein kinase C
      (PKC) vis-a-vis cellular differentiation in apoptosis. The apoptosis of U937
      cells was observed at as early as 1-1.5 h following UV irradiation, with most
      cells being in apoptotic state at 3 h. Pretreatment with PMA for as short as 5
      min was sufficient to inhibit apoptosis induced by UV irradiation, whereas
      apparent changes in cell cycle distributions and expression of differentiation
      markers by PMA were not observed until 12 h and 48 h, respectively. The
      inhibition of apoptosis by PMA was completely abolished by the pretreatment with
      calphostin C, a PKC inhibitor, and 4 alpha-phorbor 12,13-didecanoate, which is
      unable to activate PKC, did not protect U937 cells against apoptosis induced by
      UV irradiation. Other differentiation inducers, such as cyclic AMP and active
      vitamin D3, did not affect the UV-induced apoptosis of U937 cells. Taken
      together, it was suggested that PMA inhibits DNA damage-induced apoptosis through
      the activation of PKC rather than as a result of differentiation of U937 cells.

PMID- 10576598
TI  - Nitric oxide synthesis inhibition suppresses implantation and decreases cGMP
      concentration and protein peroxidation.
AB  - The effect of Nw-nitro-L-arginine on embryonic implantation and cGMP carbonyl
      group concentration was assessed at the rat implantation site (IS) and non
      implantation site (NIS). The intraluminal administration of 25 microg (2.3 mM) of
      Nw-nitro-L-arginine inhibited implantation in 34.7% and embryo survival (100%),
      while in addition, decreasing cGMP concentration both at the site (1664.2 +/-
      333.8 pmoles/mg of protein for the control and 1321 +/- 384.3 for those treated),
      as well as at the NIS (1203.7 +/- 200 to 780.2 +/- 168.5). Carbonyl group
      concentration was considerably less at the implantation site treated with Nw
      nitro-L-arginine than in the control (0.062 +/- 0.012 nmoles/mg of protein and
      0.45 +/- 0.1, respectively). Nonetheless, the NIS was not significantly different
      (0.12 +/- 0.04 and 0.15 +/- 0.05). Our results show that a nitric oxide (NO)
      dependent system parallel to the formation of cGMP and protein peroxidation
      products is important at the blastocyst implantation site in order for the
      endometrium to acquire the necessary properties for an adequate receptivity.

PMID- 10576599
TI  - Inhibition of tyrosinase by green tea components.
AB  - The pigment melanin in human skin is a major defense mechanism against
      ultraviolet light of the sun, but darkened skin color, which is the result of
      increased and redistributed epidermal melanin, could be a serious aesthetic
      problem. Epidemiologically, it is well known that the consumption of green tea
      may help prevent cancers in humans and also reduce several free radicals
      including peroxynitrite. In the present study, to assess the efficacy of the
      inhibition of mushroom tyrosinase (monophenol monooxygenase EC 1.14.18.1), ten
      kinds of Korean traditional teas were screened for their tyrosinase inhibitory
      activity. Green tea was the strongest inhibitor, and the major active
      constituents in the tea are (-)-epicatechin 3-O-gallate (ECG), (-)-gallocatechin
      3-O-gallate (GCG), and (-)-epigallocatechin 3-O-gallate (EGCG). All are catechins
      with gallic acid group as an active site. The kinetic analysis for inhibition of
      tyrosinase revealed a competitive nature of GCG with this enzyme for the L
      tyrosine binding at the active site of tyrosinase.

PMID- 10576600
TI  - Stimulatory effect of enkephalins on calcium efflux from bovine adrenal
      chromaffin cells in culture.
AB  - The effects of leucine- and methionine-enkephalin, opiate peptides, on Ca2+
      efflux from cultured bovine adrenal chromaffin cells were examined. These
      enkephalins stimulated the efflux of 45Ca2+ from cells in a concentration
      dependent manner (10(-8) M-10(-6) M). Leucine-enkephalin did not increase the
      intracellular free Ca2+ level, 45Ca2+ uptake, catecholamine secretion, cAMP level
      or cGMP level. The peptide-stimulated 45Ca2+ efflux was not inhibited by
      incubation in Ca2+-free medium, but was inhibited by incubation in Na+-free
      medium. These results indicate that enkephalins stimulate extracellular Na+
      dependent 45Ca2+ efflux from cultured bovine adrenal chromaffin cells, probably
      by stimulating membrane Na+/Ca2+ exchange.

PMID- 10576601
TI  - Force spectroscopy between acetylcholinesterase molecule and its natural
      substrate to study the effects of inhibitors and reactivators on enzyme activity.
AB  - The force spectrum (FS) between acetylcholinesterase (AChE) molecule and its
      natural substrates acetylcholine (ACh) and the influences of AChE inhibitors and
      reactivators have been investigated with atomic force microscopy (AFM) at single
      molecule level in real-time. AChE and ACh were covalently immobilized onto the
      surfaces of gold-plated mica and Si3N4 tip of the atomic force microscope
      respectively. First, AChE was imaged in image mode of AFM and one of AChE
      molecules was selected as the center of the scanning. Then scanning mode was
      changed into force scanning mode and FS was recorded in a frequency of 5 x s(-1).
      Solutions of drugs or toxicants can be injected from the fluid-in tube of the
      fluid cell at any desired time. The FS between ideally immobilized normal AChE,
      Inhibited AChE or aged AChE and ACh each had their own shape features. The
      influences of drugs or toxicants on these features could be observed in real-time
      on the screen of the computer. These results demonstrated that AFM force
      spectroscopy could be used as a new method to study the effects of drugs and
      toxicants on the activity of the enzyme in pharmacology and toxicology.

PMID- 10576602
TI  - Dose-dependent hyperlipidemia in rabbits following administration of poloxamer
      407 gel.
AB  - Poloxamer 407 (P-407) is a tri-block polymer that exhibits concentration
      dependent reverse thermal gelation, a characteristic potentially useful for
      developing sustained release injectable drugs. While some reports suggest that P
      407 is 'non-toxic', rodent studies demonstrate that P-407 induces hyperlipidemia,
      an action that makes this polymer a questionable drug delivery vehicle.
      Unfortunately, the majority of earlier studies employed supra-physiologic doses
      of P-407. The present study examined if lower, clinically useful, doses of gel
      forming concentrations of P-407 induced hyperlipidemia in rabbits. Male and
      female rabbits were injected with 5.5 mg/kg (0.025 mL/kg), 27.5 mg/kg (0.125
      mL/kg), or 137.5 mg/kg (0.625 mL/kg) of 22% P-407 and the actions of this polymer
      on blood chemistry were assessed at 6 h, 1 d, 2 d, 7 d, and 14 d following
      injection. Control rabbits received no injection. The highest dose of P-407
      (137.5 mg/kg) significantly increased serum triglycerides and cholesterol in both
      male and female rabbits with the maximum increase observed at 2 d after
      injection. Male rabbits were more sensitive to P-407 than females following
      injection of 137.5 mg/kg P-407. The lower doses of P-407 did not alter serum
      triglycerides or cholesterol. In all groups, serum triglycerides and cholesterol
      were at baseline levels by 14 d. P-407 did not affect other blood chemistry
      parameters. Although P-407 induces a dose-dependent hyperlipidemia in rabbits,
      low doses of this polymer may be used in controlled release drug delivery
      applications without the untoward hyperlipidemic effect.

PMID- 10576603
TI  - Immunological enhancement with a low dose of cyclophosphamide in aged mice.
AB  - Aged mice treated with a low dose of cyclophosphamide (CY) showed significantly
      enhanced immune capacity in cellular proliferation and antibody response. In
      these mice, total cell numbers were increased both in the thymus and spleen,
      compared to those in non-treated mice. Treatment with a low dose of CY induced
      apoptosis of thymocytes in the atrophic thymus of the aged mice, being followed
      by an increase of proliferation of thymocytes and leading to an increase of
      thymocytes and splenic T cells. Treatment with a high dose of CY also induced
      apoptosis in the thymus, but suppressed the proliferative capacity, therefore not
      leading to an enhancement of immune capacity. In young mice, however, CY
      suppressed immune capacity regardless of the dose. Thymocytes and splenic T cells
      of young mice were more susceptible to CY than those of old mice and were
      decreased in number after the treatment with even a low dose of CY.

PMID- 10576604
TI  - Sex steroids modulate the synthesis and phosphorylation of proteins in the brain
      cortex of aging mice.
AB  - We have analysed the synthesis and phosphorylation of total cellular proteins and
      their modulation by sex steroids (testosterone and 17beta-estradiol) in the brain
      cortex of adult (25-28 weeks) and old (54-58 weeks) male and female AKR mice. The
      level of (35S) methionine incorporation in total proteins is comparatively higher
      in males than females. It declines significantly in older males but shows no
      difference with age in females. After gonadectomy, the extent of (35S) methionine
      incorporation decreases in adults but not in the old. The incorporation is
      induced remarkably by estradiol in males and by both sex steroids in females.
      Further analysis by fluorography shows several proteins, but only a few (66, 45
      and 29 kDa) vary in levels significantly with age, sex and hormonal treatment.
      The data on phosphorylation of total cellular proteins by (32P) orthophosphate
      incorporation exhibit no age-dependent variation. However, it is reduced
      drastically by gonadectomy in adults. After the addition of testosterone, the
      extent of phosphorylation is enhanced significantly in adults but remains the
      same in the old of both sexes. Estradiol also increases this modification
      remarkably in males of both ages and adult females, but shows no effect in old
      females. These results suggest that both testosterone and estradiol modulate the
      synthesis and phosphorylation of brain cortex proteins in age- and sex-dependent
      manner. This leads to alterations in physiological activities of the animal.

PMID- 10576605
TI  - Influence of circadian time, ageing, and hypertension on the urinary excretion of
      nitric oxide metabolites in rats.
AB  - Urinary excretion of NO metabolites (NOx) was measured in male spontaneously
      hypertensive rats (SHR) and their normotensive Wistar-Kyoto controls (WKY) in two
      age groups: young (11 weeks) and old (58 weeks). Urine was collected every 6 h
      throughout 24 h with and without injection interperitoneally of N(G)-nitro-L
      arginine-methyl-ester (L-NAME), 30 mg/kg, at 7:00 or 19:00 h. In addition, blood
      pressure changes by L-NAME were evaluated using radiotelemetry. In both strains
      of rats, injection of L-NAME abolished almost completely the urinary excretion of
      NOx, indicating that urinary NOx indeed reflect the endogenous rate of NO
      synthesis. Time-dependent variation in urinary NOx excretion was observed in WKY
      rats of both ages (analysis of variance, P<0.05), with higher excretion in the
      dark period. In SHR rats, time-dependent variation in NOx excretion was lost, and
      the overall amount of NOx excreted within 24 h was significantly lower in young
      SHR than in age-matched WKY rats. Moreover, blood pressure increases by L-NAME
      were significantly smaller in SHR than in WKY rats. In old rats of both strains,
      NOx excretion was reduced, and the difference between the strains disappeared.
      Our findings demonstrate that ageing is accompanied by a loss in NOx excretion,
      and suggest that hypertension in SHR leads to a reduction in NO synthesis already
      at young age.

PMID- 10576606
TI  - Mitochondrial respiratory chain activity in the human brain as a function of age.
AB  - Age-associated changes in mitochondrial respiratory chain activity were
      investigated in human brain tissue collected at autopsy. Four brain regions, the
      frontal cortex, superior temporal cortex, cerebellum and putamen, were studied to
      map any regional variation. A significant decrease in cytochrome c oxidase
      activity was seen in all regions studied with increasing age (P<0.05). Although a
      small decrease in succinate dehydrogenase-cytochrome c oxidoreductase and NADH:
      ubiquinone oxidoreductase activities was observed, this was not statistically
      significant. This study has shown that the age-related fall in cytochrome c
      oxidase activity affects the frontal cortex, superior temporal cortex, cerebellum
      and putamen. The variation in the extent of age-related oxidative phosphorylation
      decline was striking. We hypothesize that individuals with more severe age
      related decline may be predisposed to neuronal dysfunction, whereas individuals
      with well preserved oxidative phosphorylation may enjoy some degree of neuronal
      protection.

PMID- 10576607
TI  - Age-related impairments in TCR/CD3 activation of ZAP-70 are associated with
      reduced tyrosine phosphorylations of zeta-chains and p59fyn/p56lck in human T
      cells.
AB  - The expression and catalytic activity of the protein tyrosine kinase (PTK) ZAP-70
      are needed for normal intracellular signaling through the T-cell receptor
      (TCR)/CD3 complex. However, the possible effect of aging on the catalytic
      activity of ZAP-70 in human peripheral blood T cells stimulated via the TCR/CD3
      complex is unknown. The current studies show that T cells from a substantial
      proportion of elderly humans (12) exhibit significant reductions in the catalytic
      activity, but not expression of ZAP-70 when stimulated by ligation of the TCR/CD3
      with cross-linked anti-CD3epsilon monoclonal antibody OKT3. In addition, the
      reduced catalytic activity of ZAP-70 in T cells from elderly subjects was not
      restored to the normal levels in response to ligation of CD4 receptors,
      suggesting defects in PTKs linked to both CD3 and CD4 receptors. Other
      experiments demonstrated that the age-related impairments of ZAP-70 activation in
      anti-CD3-stimulated T cells were accompanied by decreased tyrosine
      phosphorylations of zeta-chains and autophosphorylations of the PTKs
      p561ck/p59fyn. Moreover, the age-related defects in these early TCR/CD3-mediated
      phosphorylation events were readily detectable in both CD45RO+ memory and CD45RA+
      naive T cells. Thus, these results suggest that defects in early TCR/CD3-mediated
      phosphorylation events among CD45RO+ memory and CD45RA+ naive T cells from
      certain elderly humans may con tribute to impaired induction of ZAP-70 catalytic
      activity.

PMID- 10576608
TI  - Mass hearing screening in kindergarten students.
AB  - OBJECTIVE: To determine the types of hearing losses identified by mass hearing
      screenings in the public school system. DESIGN: Prospective observational.
      PARTICIPANTS: Students enrolled in kindergarten in the public school system.
      SETTING: Major metropolitan area. MAIN OUTCOME MEASURES: (1) hearing screening
      tests performed by speech pathologists using an audiometer in a quiet room; (2)
      formal audiologic testing including pure tone audiometry, tympanograms, speech
      discrimination, and acoustic impedance testing in a sound proof booth. RESULTS:
      140 students failed hearing screening on two separate occasions; 91(65%)
      underwent formal audiologic testing at Milwaukee Public School, 43% demonstrated
      conductive hearing losses, 14% demonstrated sensorineural losses and 43%
      demonstrated normal hearing. CONCLUSION: Mass hearing screening in the school
      system (1) is useful for detecting transient conductive hearing losses, (2)
      detects a significant number of sensorineural hearing losses and (3) has a very
      poor follow-through by the families of those students identified with hearing
      loss through the screening program.

PMID- 10576609
TI  - Supratubal recess in neonates and infants.
AB  - OBJECTIVE: The fetal development of the supratubal recess and of the tensor fold
      was described by Hammar in 1902. Recent studies claim that neither structure is
      regularly present in neonates and controversial views have been presented of the
      separation of the anterior attic and supratubal recess. The objective of this
      study is to clarify these issues. METHODS: Twenty temporal bones, 13 neonate and
      seven infant, were studied either by microdissection of fresh (five bones) or
      formalin stored (two) specimens, or by serial sectioning after formalin fixation
      and decalcification (13 bones). The serial sections were cut to 20 microm, every
      tenth section saved and stained by hematoxylin eosin. RESULTS: In all specimens
      the separating structure between the anterior attic and supratubal recess was the
      tensor fold. It was intact in 15 bones while five showed a membrane defect. In
      vertically oriented folds the recess was deep and in horizontally oriented folds
      shallow. In 19 bones the tensor fold inserted superiorly to a soft tissue
      insertion ring of varying thickness and only once directly to a shallow
      transverse crest. The breadth of the tensor fold near the tensor tendon showed
      only little variation, whereas its height, and the distance from the tensor
      tendon to the supratubal tegmen varied in larger limits. CONCLUSIONS: The tensor
      fold and the supratubal recess are present already in the neonate and thus
      develop during the fetal period. The shape of the recess is determined by the
      fold direction and its size grows in conjunction with the other middle ear
      spaces. The transverse crest has no apparent influence on the position of the
      tensor fold. The easiest method to study the integrated whole of the anterior
      attic and supratubal recess is to view them alternatively from the anterior and
      superior microdissection approaches. Clinically, removal of the tensor fold
      creates an efficient additional aeration route from the supratubal recess to the
      anterior attic.

PMID- 10576610
TI  - Endoscopic drainage of pediatric paranasal sinus mucoceles.
AB  - Paranasal sinus mucoceles are rare in children. The traditional treatment is to
      perform surgical drainage via an external incision. In adults endonasal surgical
      techniques are increasingly being used to treat mucoceles. A series of seven
      children is reported. All cases were successfully treated with endoscopic
      intranasal surgical drainage without complication or recurrence. When used by
      surgeons familiar with endoscopic sinus surgery this has proved a safe and
      successful procedure that avoids facial scarring. Despite previous reports
      suggesting cystic fibrosis is the major aetiological factor in pediatric
      mucoceles, no child in this series had been diagnosed as suffering from cystic
      fibrosis.

PMID- 10576611
TI  - Acute mastoiditis in children--our experience.
AB  - The incidence of acute mastoiditis and the number of complications has changed
      since the 1950s, despite the increasing antibiotic effectiveness. Other series
      concluded that the incidence of acute mastoiditis is rising in the recent years,
      which can be justified by the antibiotic resistance of the microorganisms and the
      absence of paracentesis in the treatment of acute otitis media. Our aim is to
      approach risk factors, clinical presentation, diagnosis and treatment of acute
      mastoiditis. We reviewed 62 clinical records of patients in pediatric age,
      observed in D. Estefania Hospital Lisbon, between January 1993 and December 1997.
      There was a relative homogenous distribution during the 5 years of the study
      period. The patient age ranged from 5 months to 14 years. They all were treated
      with intravenous antibiotics. The mean duration of treatment was 7.4 days. We
      registered 15 complications: 14 retroauricular subperiosteal abscesses and one
      subdural empyema. The most common isolated microorganism was Streptococcus
      pneumoniae. We found no statistic difference (P > 0.1) in the incidence of acute
      mastoiditis between the 5 years of the study.

PMID- 10576612
TI  - Microalbuminuria as renal marker in recurrent acute tonsillitis and tonsillar
      hypertrophy in children.
AB  - Raised levels of microalbuminuria pointing out glomerular abnormality and
      indicate renal damage. Glomerulonephritis is caused by immune reaction leading to
      the formation of circulating immune complexes that are deposited on the basal
      membrane of the glomerulus. The time course and the appearance of antibodies
      against infectious agents both play very important roles in its clinical
      presentation. Antibodies against streptococci have not a protective role, but
      offers a useful marker of the presence or absence of recent infection. This work
      studies the presence of microalbuminuria and circulating anti-streptococcal
      antibodies, namely, anti-streptolysin O and anti-deoxyribonuclease B antibodies
      in ninety children which underwent tonsillectomy due to infectious and
      obstructive tonsillar pathology. These children were divided in recurrent acute
      tonsillitis (n= 34), recurrent tonsillitis with tonsillar hypertrophy (n = 26),
      and tonsillar hypertrophy (n = 30). It was found in recurrent acute tonsillitis a
      moderate correlation between microalbuminuria and anti-streptolysin O, and a weak
      correlation between microalbuminuria and anti-deoxyribonuclease B antibodies. It
      was also found significant differences of the levels of anti-streptococcal
      antibodies between the three groups of pathologies. It is proposed the
      determination of microalbuminuria, an inexpensive and harmless test, as an
      indicator of possible renal damage in recurrent acute tonsillitis.

PMID- 10576613
TI  - Gender and intra-observer agreement about laryngoscopy of papilloma.
AB  - BACKGROUND: The gender of the observer may bias data. OBJECTIVE: Compare the
      intra-observer agreements of male and female pediatric otolaryngologists about
      videotaped images of laryngeal papilloma. DESIGN: Five male and six female
      pediatric otolaryngologists independently viewed videotapes of ten children
      undergoing treatment for laryngeal papilloma. Each of 12 anatomic sites was
      categorized as disease present, absent, or indeterminate. Each observer estimated
      the percent overall airway obstruction. 5-24 weeks later, each observer repeated
      his/her assessments. RESULTS: The mean intra-observer agreements for both male
      and female pediatric otolaryngologists were good, and identical (kappa 0.63;
      proportion of positive agreement 0.82; proportion of negative agreement 0.72).
      Females more frequently categorized a site as indeterminate. Males more
      frequently categorized a site oppositely on repeat assessment. The males'
      indeterminate/opposite ratio was less than that of the females' (P = 0.03). Intra
      observer estimates of overall airway obstruction have wide variability: for male
      pediatric otolaryngologists, differences exceeding 30% are significant; for
      females, 40%. CONCLUSION: Male and female pediatric otolaryngologists had equally
      good and identical intra-observer kappa scores and proportions of positive and
      negative agreement. However, males used the indeterminate category less than did
      the females, and males more often gave an opposite categorization at the second
      viewing session. Estimates of overall airway obstruction have much intra-observer
      variability.

PMID- 10576614
TI  - The surgical management of the pars tensa retraction pocket in the child--results
      following simple excision and ventilation tube insertion.
AB  - Retraction pockets of the pars tensa formed due to poor mesotympanic ventilation
      can result in chronic infection, ossicular damage and even acquired
      cholesteatoma. A diversity in opinion exists as to the best surgical treatment of
      an established retraction pocket. This paper presents a consecutive prospective
      series of 39 ears managed over the last 4 years by means of simple excision and
      insertion of a middle ear ventilation tube. The retraction pockets were graded
      according to Sade's 1979 classification. There were 23 grade II and sixteen grade
      III retractions. All 39 pockets were successfully excised. Thirty-four of the
      perforations healed, with the remaining five failing to heal at the time of
      analysis. In 13 cases the pockets recurred, but in five of these cases the
      recurrence is minimal and has required no further surgical intervention. Of the
      eight remaining significant recurrences, four have undergone a repeat procedure
      with no further recurrence in three cases. Following initial surgery, 67% of the
      ears operated upon had either minimal or no recurrence. Following further surgery
      this figure increased to 75%. The air conduction threshold improved by an average
      of thirteen decibels in those ears that healed with no recurrence.

PMID- 10576615
TI  - Alagille syndrome with cavernous carotid artery aneurysm.
AB  - We present a case of right sided blindness caused by a cavernous carotid artery
      aneurysm in a 17-year-old patient presenting with an Alagille syndrome. The
      diagnosis was made by magnetic resonance imaging and confirmed by angiography.
      This aneurysm was treated successfully with endovascular placement of detachable
      balloons. Cerebral vascular malformations are rarely reported in association with
      this syndrome. We discuss the clinical presentation, diagnosis, treatment and
      detection of this type of abnormality.

PMID- 10576616
TI  - Laryngeal hamartoma: surgical management.
AB  - A newborn female infant with severe inspiratory stridor was found to have a
      laryngeal non-encapsulated hamartoma in the supraglottic area, medial to the
      hyoid bone and extending into the petiole of the epiglottis. Histologic
      examination revealed an extremely uncommon glandular hamartoma. Surgical
      management in the newborn period consisted of conservative endoscopic excision
      combined with open laryngofissure. The hamartoma was removed in the newborn
      period to avoid tracheostomy, because decanulation after tracheostomy in infants
      can be difficult.

PMID- 10576617
TI  - Effects of the phosphodiesterase inhibitor rolipram on streptococcal cell wall
      induced arthritis in rats.
AB  - The phosphodiesterase-IV (PDE-IV) inhibitor, rolipram, is antiinflammatory in a
      number of animal models and inhibits the release of a variety of cytokines,
      including TNFalpha. Arthritis induced in rats by systemic reactivation with
      streptococcal cell walls (SCW) following intraarticular sensitization is a
      TNFalpha-dependent, delayed-type hypersensitivity (DTH) reaction. Rolipram
      administered during the reactivation phase dose-dependently inhibited hind paw
      edema through day 24, the day of peak swelling. PMN and T-cell recruitment to the
      arthritic joint were also attenuated in rolipram-treated rats. Histologic
      examination of ankle sections from rolipram-treated animals showed a marked
      attenuation of synovial inflammation. Mechanistic studies to determine the role
      of glucocorticoids in mediating rolipram action showed that the inhibitory effect
      of rolipram on swelling was not reversed by RU 486, a glucocorticoid antagonist.
      In contrast, RU 486 reversed the inhibitory effects of rolipram on TNFalpha
      secretion. To further evaluate the role of cAMP in the model, the beta-adrenergic
      receptor (betaAR) agonist isoproterenol was tested, and found to inhibit swelling
      but not the release of TNFalpha. These results are consistent with the view that
      the inhibitory effects of rolipram may be partially mediated by cAMP-dependent,
      but TNFalpha-independent, mechanisms. The betaAR antagonists propranolol and
      nadolol had no appreciable affect on the antiinflammatory effect of rolipram.
      However, rolipram reversed the lethal effects of the antagonists observed when
      either was administered alone. Apparently, beta-adrenergic mechanisms moderate
      the response to challenge, and rolipram treatment, presumably as a result of its
      effects on cAMP levels, reverses the toxic effect of the antagonists.

PMID- 10576618
TI  - Effects of tramadol and its enantiomers on Concanavalin-A induced-proliferation
      and NK activity of mouse splenocytes: involvement of serotonin.
AB  - The centrally acting analgesic drug tramadol is a 1:1 racemic mixture of two
      enantiomers, with different pharmacological properties. The (-)-tramadol
      preferentially inhibits noradrenaline uptake, whereas the (+)-tramadol inhibits
      serotonin uptake and binds to opioid receptors. Since tramadol has been shown to
      stimulate some immune responses in mice, in the present work we analyzed the
      effects of its enantiomers on the same parameters, with the aim to better
      characterize the mechanisms involved in such action of tramadol. The acute
      administration of 20 and 40 mg/kg of racemic tramadol and of 10 and 20 mg/kg of
      (+)-tramadol induced a significant and comparable stimulation of Concanavalin-A
      (Con-A) induced proliferation and of Natural Killer (NK) activity of splenocytes.
      On the contrary, the (-)-tramadol was devoid of any effect. The pretreatment with
      the serotoninergic antagonist metergoline (3.0 mg/kg) completely blocked the
      effects of both tramadol and (+)-tramadol. We suggest that the enhancement of the
      serotoninergic tone could be at the basis of the stimulatory effects exerted by
      tramadol on Con-A induced lymphoproliferation and NK activity.

PMID- 10576619
TI  - Immunotoxicological effects of repeated combined exposure by cypermethrin and the
      heavy metals lead and cadmium in rats.
AB  - The immunotoxic effect of a 28 days oral exposure by 55.4, 22.2, and 11.1 mg/kg
      cypermethrin (CY) was investigated in 4 weeks old male Wistar rats. The applied
      test system involved the determination of general toxicological parameters (body
      weight gain, organ weight of thymus, heart, lung, liver, spleen, kidneys,
      adrenals and the popliteal lymph node), haematological parameters (white blood
      cell count, red blood cell count, haematocrit, mean cell volume of red blood
      cells, cellularity of the femoral bone marrow), as well as immune function assays
      (splenic plaque forming cell assay, delayed type hypersensitivity reaction). The
      highest dose resulted in a significant increase of the relative liver weight, and
      all three doses resulted in (although inconsistent) changes in the haematocrit
      and MCV values. The maximum of DTH reaction decreased at all three doses. On
      combination of the highest CY dose with non-effective doses of lead or cadmium
      the immunotoxic effects of the former were modified. When immunotoxic doses of Cd
      or Pb were combined with the lowest CY dose, further interactions were observed
      on the examined parameters. The alterations of the immunotoxic effects of CY by
      simultaneous exposure with Cd or Pb, as described here, can lead to unexpected
      health consequences and/or can lead to false positive or negative results in
      human epidemiological studies.

PMID- 10576620
TI  - Curcuma longa inhibits TNF-alpha induced expression of adhesion molecules on
      human umbilical vein endothelial cells.
AB  - Identification of non-steroidal anti-inflammatory small molecules is very
      important for the development of anti-inflammatory drugs. We demonstrate here
      that out of three compounds, viz diferuloylmethane, p-coumaroylferuloylmethane
      and di-p-coumaroylmethane, present in the ethyl acetate extract of Curcuma longa,
      diferuloylmethane is most potent in inhibiting TNF-alpha induced expression of
      ICAM-1, VCAM-1 and E-selectin on human umbilical vein endothelial cells. The
      inhibition by diferuloylmethane is time dependent and is reversible. By using RT
      PCR, we demonstrate that it inhibits the induction of steady state transcript
      levels of ICAM-1, VCAM-1 and E-selectin, and therefore it may interfere with the
      transcription of their genes. As diferuloylmethane significantly blocks the
      cytokine induced transcript levels for the leukocyte adhesion molecules, it may
      be interfering at an early stage of signalling event induced by TNF-alpha.

PMID- 10576621
TI  - Effect of endothelin-1 on alpha-smooth muscle actin expression and on alveolar
      fibroblasts proliferation in interstitial lung diseases.
AB  - Endothelin-1 (ET-1) is a potent constrictor and mitogen peptide which is
      expressed in several pulmonary diseases. To elucidate the involvement of ET-1 in
      lung interstitial pathologic events, we assessed ET-1 secretion by alveolar
      macrophages (AM) and fibroblasts recovered from the bronchoalveolar lavage (BAL)
      of patients with idiopathic pulmonary fibrosis (IPF), sarcoidosis (SA) and from
      control subjects. We characterized in vitro alveolar fibroblasts of all subjects
      using monoclonal antibody specific to alpha-smooth muscle actin (alpha-SM actin)
      and human fibroblast marker. We also examined the effect of ET-1 on the
      fibroblasts' mitogenesis and on their cytoskeletal phenotype. The AM recovered
      from IPF patients showed increased spontaneous secretion of ET-1 compared with
      cells from SA and control subjects. The expression of alpha-SM actin in the
      fibroblasts from IPF patients was significantly higher than in SA fibroblasts and
      normal lung fibroblasts. Assessing alveolar fibroblasts purity revealed a
      negative staining for alpha-SM actin in all SA and control fibroblasts, while
      alveolar fibroblasts recovered from IPF were 100% positive for alpha-SM actin, a
      reliable differentiation marker of myofibroblastic cells. Exposure of SA alveolar
      fibroblasts to ET-1 resulted in an increased expression of alpha-SM actin.
      Addition of exogenous ET-1 to alveolar fibroblasts culture stimulated DNA
      synthesis and proliferation in all groups. Moreover, neutralization of ET-1 by
      monoclonal antibody was shown to decrease 3H-thymidine incorporation in
      fibroblasts cultured with AM supernatants. These results suggest possible
      interactions between AM, myofibroblasts and fibroblasts in interstitial lung
      diseases (ILD). By modulating alpha-SM actin expression and exertion of the
      mitogenic effect on alveolar fibroblasts, ET-1 might play an important role in
      the fibrogenesis of ILD.

PMID- 10576623
TI  - Veterinary medicines: a shrinking choice, and a shrinking line of supply.

PMID- 10576622
TI  - Immunoregulatory effects of N9-benzyl- and N7-benzyl-8-bromoguanines.
AB  - In this study we investigated the effects of two guanine derivatives, 9-benzyl-
      (I) and 7-benzyl-8-bromoguanines (II) on the proliferation of human T-cell
      leukemia and T-cell lymphoma, normal human peripheral blood mononuclear cells
      (PBMC), and mouse Th1 (pGL10) and Th2 (D10.G4.1) clones. We also assessed their
      effects on cytokine production (IL-3, IL-10 and IFN-gamma) in PBMC, T-cell
      lymphoma, HUT78 (IL-2), and murine Th1 (IL-2) and Th2 (IL-4 and IL-5) clones.
      These compounds were synthesize as analog of known inhibitors of purine
      nucleoside phosphorylase (PNP) 8-amino-9-benzylguanine. These compounds
      suppressed proliferation of human leukemia MOLT-4 cells, human cutaneous lymphoma
      HUT78 cells and normal PMBC. Compound II was a significantly more potent
      inhibitor than compound I. Exogenous recombinant human IL-2 reversed the anti
      proliferative effects of both compounds on HUT78 cells. These compounds had low
      toxicity to human EBV-transformed B-lymphocytes. Both compounds suppressed the
      production of IL-2 by activated human HUT78 cells, IFN-gamma by PBMC and did not
      affect IL-3 and IL-10 production in PBMC. Compound I inhibited anti-CD3-activated
      IL-2 secretion from the murine Th1 clone. The murine Th2 clone was less sensitive
      to both compounds as compared with Thl. The production of IL-4 and IL-5 by this
      clone was not suppressed. Thus, it has been shown that not only 9-substituted
      guanines but also their 7-isomers selectively inhibit T-cell functions and both
      selectively inhibit Th1-related cytokines secretion.

PMID- 10576624
TI  - Serological surveillance of equine viral arteritis in the United Kingdom since
      the outbreak in 1993.
AB  - Serological analysis of blood samples submitted to the Animal Health Trust showed
      that during 1995, 185 of 9203 unvaccinated horses (2.0 per cent) tested positive
      for antibodies to equine arteritis virus (EAV), and that during 1996, 46 of 8851
      unvaccinated horses (0.52 per cent) tested positive. During both years
      thoroughbreds were the predominant breed tested and only a small proportion of
      these (<0.3 per cent), consisting predominantly of imported mares, were
      seropositive. In contrast, among standardbred horses, from which samples were
      actively solicited in 1995, 84 of 454 (18.5 per cent) were seropositive. Among
      standardbreds there was a difference in prevalence between types of horses, with
      3.7 per cent of racing horses, 25 per cent of non-racing horses and 41 per cent
      of stallions testing seropositive. Investigations of seropositive stallions
      identified during 1994 and 1995 demonstrated that clinically inapparent equine
      viral arteritis (EVA) had occurred previously in the UK. Of 50 seropositive
      stallions, nearly half were standardbreds and nearly all had been imported from
      either North America or the European Union. Whether 34 seropositive stallions
      were shedding virus in their semen was established either by test mating, by the
      serology of the covered mares, or by investigation by MAFF following the
      introduction of the Equine Viral Arteritis Order 1995. Nine of the stallions
      (26.5 per cent) were identified as presumptive shedders of EAV in semen and among
      specific breeds, viral shedding was identified in six of 15 (40 per cent)
      standardbreds and three of nine (33 per cent) warmbloods. In contrast with the
      outbreak of EVA in the UK in 1993, no signs of disease typical of EAV infection
      were reported during these investigations, even in mares test mated to stallions
      shedding the virus.

PMID- 10576625
TI  - Development of a gonadotrophin-releasing hormone and prostaglandin regimen for
      the planned breeding of dairy cows.
AB  - Four studies were carried out to determine the ovarian responses of dairy cows
      undergoing natural oestrous cycles to sequential injections of gonadotrophin
      releasing hormone (GnRH), followed seven days later by prostaglandin and, 48 to
      72 hours later, by a second injection of GnRH. In study 1, of 60 cows so treated,
      47 were in the intended periovulatory phase when a fixed-time insemination was
      given 72 hours after the prostaglandin. In study 2, detailed observations were
      made in 32 cows treated as in study 1, using ultrasound to determine the optimum
      time to administer the second dose of GnRH. Ovulation was most effectively
      synchronised by giving GnRH 56 to 60 hours after the prostaglandin. Study 3
      investigated the timing of ovulation when no initial dose of GnRH was given. Six
      cows were injected with prostaglandin on day 12 of the oestrous cycle, followed
      by GnRH 60 hours later. Five of the six cows ovulated 24 to 36 hours after GnRH,
      an equivalent timing and synchrony to that in study 2, in which a dose of GnRH
      had been given seven days before prostaglandin. In study 4, an initial dose of
      GnRH was given to six cows late (day 17) in the oestrous cycle, and prostaglandin
      seven days later. The GnRH treatment delayed luteolysis in five of the cows so
      that they were responsive to the prostaglandin and ovulated 24 to 36 hours after
      the second dose of GnRH. The use of GnRH (day 0) - prostaglandin (day 7) - GnRH
      (day 9.5) appears to be an effective means of synchronising ovulation in most
      cows.

PMID- 10576626
TI  - Atypical outbreak of caprine cryptosporidiosis in the Sultanate of Oman.
AB  - An outbreak of cryptosporidiosis occurred in goats ranging in age from two days
      to adult, on a well-managed closed farm. None of the other animals on the farm,
      including sheep, cows and buffalo, were affected. Morbidity approached 100 per
      cent in goats less than six months of age. Despite intensive supportive care, 238
      goats died, ranging in age from two days to over one year. Cryptosporidia were
      detected in large numbers in the intestinal contents of dead animals and in
      faecal smears of animals with diarrhoea. Massive numbers of the organisms were
      also demonstrated histopathologically and by electronmicroscopy, and no other
      significant pathogens were detected. The outbreak was unique in terms of the
      extreme virulence of the organism, its apparent species-specificity, and the
      shedding of the organism by animals over four weeks of age.

PMID- 10576627
TI  - Immunohistochemical evaluation of tonsillar tissue for preclinical screening of
      scrapie based on surveillance in Belgium.

PMID- 10576628
TI  - Absence of trypanosomes in polar bears (Ursus maritimus) from Svalbard.

PMID- 10576629
TI  - Pathological changes in free-ranging African ungulates during a rinderpest
      epizootic in Kenya, 1993 to 1997.

PMID- 10576630
TI  - Shigellosis in a squirrel monkey: a clinical history.

PMID- 10576631
TI  - Opportunities in farm practice.

PMID- 10576632
TI  - Pig assurance scheme.

PMID- 10576633
TI  - Quarantine and rabies.

PMID- 10576634
TI  - Microchip identification.

PMID- 10576635
TI  - Problems for the child with epilepsy.

PMID- 10576636
TI  - Neuropsychological and behavioral status of children with complex partial
      seizures.
AB  - Neuropsychological and behavioral status were examined in 57 children aged 7 to
      16 years with complex partial seizures (CPS) and compared with 27 sibling control
      children of the same age. Epilepsy had a significant effect on both cognitive and
      behavioral adjustment measures. Children with CPS had significant impairment
      across all seven cognitive domains assessed, reflective of a profile of
      relatively diffuse and generalized cognitive dysfunction. Age at onset of
      recurrent seizures was the strongest and most consistent predictor of adequacy of
      cognitive functioning; earlier age at onset was associated with poorer cognitive
      status. Children with CPS also had more problems compared with sibling control
      children on measures of social and school competence and internalizing behavior
      problems, but not externalizing behaviors. Further, frequency of seizure activity
      in the past year, rather than age at seizure onset, emerged as the strongest
      predictor of these behavioral difficulties. These findings are discussed in the
      context of understanding the impact of CPS on cognition and behavioral
      adjustment, and identifying the contribution of various aspects of the
      neurodevelopmental course of CPS to these issues.

PMID- 10576637
TI  - Behavioral and neuropsychological correlates of hyperactivity and inattention in
      Brazilian school children.
AB  - Attempts at subtyping attention-deficit-hyperactivity disorder (ADHD) along the
      hyperactivity dimension are considered controversial. This study addresses this
      issue by dividing a non-clinical sample of Brazilian children (mean age, 9.4
      years; SD, 2.9), who were attending a mainstream school in the Greater Rio de
      Janeiro area, into four behavioral domain groups (normal [NO, N=324],
      hyperactive/impulsive [HI, N=17], inattentive [IA, N=48], and combined [C, N=13])
      on the basis of teacher ratings on an ADHD scale. The groups did not differ in
      intellectual level as determined by the Human Figure Drawing test. Comparisons
      were made between groups along the factorial dimensions extracted from the
      Composite Teacher Rating Scale, academic performance and neuropsychological
      measures were then performed. Our data showed that IA and C children are less
      independent and more prone to socialization problems than NO children, and that
      HI and C children are less anxious and fearful than IA children. Furthermore, the
      groups differed in academic and neuropsychological performance. The results could
      be considered consistent with the hypothesis that ADD with hyperactivity (ADD/+)
      and ADD without hyperactivity (ADD/-) represent singular nosological entities.

PMID- 10576638
TI  - Brain activity and language assessment using event-related potentials:
      development of a clinical protocol.
AB  - To test the validity of a new computerized task to assess children's receptive
      vocabulary, event-related potentials (ERPs) were recorded from 56 typically
      developing children ranging in age from 5 to 12 years. This ERP-computerized
      vocabulary task does not require a child to give a verbal or motor (i.e.
      pointing) response. Single pictures, from an existing standardized test of
      receptive vocabulary, were presented on a computer screen and simultaneously
      named either correctly (congruent) or incorrectly (incongruent) via a computer.
      As predicted, the N400 amplitude was found to be significantly higher to the
      incongruent picture-word pair (i.e. the child knew it was an incorrect pairing)
      than to the congruent picture-word pair (i.e. the child knew it was a correct
      pairing). This effect was found for each of the four age groups (5 to 6 years, 7
      to 8 years, 9 to 10 years, 11 to 12 years). This task accurately estimated
      current receptive vocabulary in typically developing children. Although still in
      the development stage, it may eventually serve as an adjunct to a thorough
      neurological and neurodevelopmental assessment of some children presenting with
      moderate to severe cerebral palsy.

PMID- 10576639
TI  - Stance balance control with orthoses in a group of children with spastic cerebral
      palsy.
AB  - Although ankle-foot orthoses (AFOs) are frequently prescribed to correct skeletal
      malalignment in children with spastic diplegia, their effect on standing balance
      abilities has not been documented. This study investigated balance differences
      related to the presence of pathology and orthotic conditions during conditions of
      unexpected stance perturbation by comparing four children aged between 3 1/2 and
      15 years with spastic cerebral palsy and four control children matched for years
      of independent walking experience. Electromyographic and kinematic data were
      collected and compared between groups and in three orthotic conditions (no AFOs,
      solid AFOs, dynamic AFOs). Results revealed that balance responses of children
      with spasticity were characterized by: increased coactivation of muscles as
      opposed to distal to proximal recruitment, decreased presence of upright posture
      in stance, increased use of 'on-toes' strategies, and different sway
      characteristics compared with the typically developing children. In both groups
      of children, the use of solid AFOs during perturbed stance resulted in: decreased
      activation of gastrocnemius muscles, disorganized muscle-response patterns,
      decreased use of ankle strategies, and increased joint angular velocities at the
      knee compared with conditions without AFOs or with dynamic AFOs. These
      preliminary results support the use of dynamic AFOs to correct skeletal
      malalignment in children with spastic diplegia.

PMID- 10576640
TI  - Bone age and linear skeletal growth of children with cerebral palsy.
AB  - The aim of this study was to compare the linear growth of children with cerebral
      palsy (CP) with that of children without CP. The segmental lengths (humerus,
      ulna, femur, tibia, and spine), recumbent length, body weight, and bone age of 62
      children with CP (age range 2.25 to 14 years, mean 7.13 years) were measured and
      compared with 68 children without CP (age range 1.50 to 12.67 years, mean 6.73
      years). The results show that bone-age delay is common in children with CP (68%
      with a delay of more than 1 year). The linear growth of children with CP is
      similar to that of children without CP when bone age is used instead of
      chronological age. There is a strong correlation between segmental lengths and
      body height. Hence, this study favours using segmental lengths for estimating
      height in children with CP and using the comparison group as a reference for this
      purpose. Nutritional and non-nutritional factors on bone-age delay are discussed.

PMID- 10576641
TI  - Development of postural adjustments during reaching in infants with CP.
AB  - The development of postural adjustments during reaching movements was
      longitudinally studied in seven infants with cerebral palsy (CP) between 4 and 18
      months of age. Five infants developed spastic hemiplegia, one spastic
      tetraplegia, and one spastic tetraplegia with athetosis. Each assessment
      consisted of a simultaneous recording of video data and surface EMGs of arm,
      neck, trunk, and leg muscles during reaching in various lying and sitting
      positions. The basic organization of postural adjustments of the children
      developing spastic CP was intact. Their main problem was a deficient capacity to
      modulate the postural adjustments to task-specific constraints - a deficit which
      was attributed to a combination of an impaired motor coordination and deficits in
      sensory integration. The child with spastic-dyskinetic CP showed distinct
      abnormalities in the basic organization of postural adjustments.

PMID- 10576642
TI  - Homozygous factor-V mutation as a genetic cause of perinatal thrombosis and
      cerebral palsy.
AB  - A 5-year old girl with cerebral palsy (CP), preterm birth, postnatal aortic
      thrombus, and cerebellar venous infarction who is homozygous for the
      thrombophilic factor-V Leiden (fVL) mutation is reported. The role of hereditary
      thrombophilic disorders in the development of perinatal vascular lesions such as
      aortic thrombi, renal-vein thrombosis, venous-sinus thrombosis, and cerebral
      infarction is unknown. This case report brings into question a potential
      association between fVL, perinatal vascular lesions, perinatal stroke, and CP.

PMID- 10576643
TI  - Factor-V Leiden: a risk factor for cerebral palsy.

PMID- 10576644
TI  - Episodic dyscontrol syndrome.

PMID- 10576645
TI  - 'A National UK Audit into epilepsy-related deaths'.

PMID- 10576646
TI  - 'A woman with Prader-Willi syndrome gives birth to a healthy baby girl'.

PMID- 10576647
TI  - Effect of ploidy, recruitment, environmental factors, and tamoxifen treatment on
      the expression of sigma-2 receptors in proliferating and quiescent tumour cells.
AB  - Recently, we demonstrated that sigma-2 receptors may have the potential to be a
      biomarker of tumour cell proliferation (Mach et al (1997) Cancer Res 57: 156
      161). If sigma-2 receptors were a biomarker of tumour cell proliferation, they
      would be amenable to detection by non-invasive imaging procedures, thus
      eliminating many of the problems associated with the flow cytometric measures of
      tumour cell proliferation presently used in the clinic. To be a good biomarker of
      tumour cell proliferation, the expression of sigma-2 receptors must be
      essentially independent of many of the biological, physiological, and/or
      environmental properties that are found in solid tumours. In the investigation
      reported here, the mouse mammary adenocarcinoma lines, 66 (diploid) and 67
      (aneuploid), 9L rat brain tumour cells, and MCF-7 human breast tumour cells were
      used to study the extent and kinetics of expression of sigma-2 receptors in
      proliferative (P) and quiescent (Q) tumour cells as a function of species, cell
      type, ploidy, pH, nutrient depletion, metabolic state, recruitment from the Q
      cell compartment to the P-cell compartment, and treatment with tamoxifen. In
      these experiments, the expression of sigma-2 receptors solely reflected the
      proliferative status of the tumour cells. None of the biological, physiological,
      or environmental properties that were investigated had a measurable effect on the
      expression of sigma-2 receptors in these model systems. Consequently, these data
      suggest that the proliferative status of tumours and normal tissues can be non
      invasively assessed using radiolabelled ligands that selectively bind sigma-2
      receptors.

PMID- 10576648
TI  - A comparative evaluation of various invasion assays testing colon carcinoma cell
      lines.
AB  - Various colon carcinoma cell lines were tested in different invasion assays, i.e.
      invasion into Matrigel, into confluent fibroblast layers and into chicken heart
      tissue. Furthermore, invasive capacity and metastatic potential were determined
      in nude mice. The colon carcinoma cells used were the human cell lines Caco-2, SW
      480, SW-620 and HT-29, and the murine lines Colon-26 and -38. None of the human
      colon carcinoma cells migrated through porous membranes coated with Matrigel; of
      the murine lines, only Colon-26 did. When incubated in a mixture of Matrigel and
      culture medium non-invading cells formed spheroid cultures, whereas invading
      cells showed a stellate outgrowth. Only the heterogeneously shaped (epithelioid
      and stellate) cells of SW-480 and SW-620 and the spindle-shaped cells of Colon-26
      invaded clearly confluent skin and colon fibroblasts as well as chicken heart
      tissue. However, when transplanted into the caecum of nude and syngeneic mice,
      all the lines tested were invasive with the exception of Caco-2 cells. We
      conclude that the outcome of in vitro tests measuring the invasive capacity of
      neoplastic cells is largely dependent on the test system used. Invasive capacity
      in vitro is strongly correlated with cells having a spindle cell shape, vimentin
      expression and E-cadherin down regulation. In contrast, HT-29 and Colon-38 cells
      having an epithelioid phenotype were clearly invasive and metastatic in vivo, but
      not in vitro.

PMID- 10576649
TI  - The acridonecarboxamide GF120918 potently reverses P-glycoprotein-mediated
      resistance in human sarcoma MES-Dx5 cells.
AB  - The doxorubicin-selected, P-glycoprotein (P-gp)-expressing human sarcoma cell
      line MES-Dx5 showed the following levels of resistance relative to the non-P-gp
      expressing parental MES-SA cells in a 72 h exposure to cytotoxic drugs: etoposide
      twofold, doxorubicin ninefold, vinblastine tenfold, taxotere 19-fold and taxol 94
      fold. GF120918 potently reversed resistance completely for all drugs. The EC50s
      of GF120918 to reverse resistance of MES-Dx5 cells were: etoposide 7+/-2 nM,
      vinblastine 19+/-3 nM, doxorubicin 21+/-6 nM, taxotere 57+/-14 nM and taxol 91+/
      23 nM. MES-Dx5 cells exhibited an accumulation deficit relative to the parental
      MES-SA cells of 35% for [3H]-vinblastine, 20% for [3H]-taxol and [14C]
      doxorubicin. The EC50 of GF120918, to reverse the accumulation deficit in MES-Dx5
      cells, ranged from 37 to 64 nM for all three radiolabelled cytotoxics. [3H]
      vinblastine bound saturably to membranes from MES-Dx5 cells with a KD of 7.8+/
      1.4 nM and a Bmax of 5.2+/-1.6 pmol mg(-1) protein. Binding of [3H]-vinblastine
      to P-gp in MES-Dx5 membranes was inhibited by GF120918 (K = 5+/-1 nM), verapamil
      (Ki = 660+/-350 nM) and doxorubicin (Ki = 6940+/-2100 nM). Taxol, an allosteric
      inhibitor of [3H]-vinblastine binding to P-gp, could only displace 40% of [3H]
      vinblastine (Ki = 400+/-140 nM). The novel acridonecarboxamide derivative
      GF120918 potently overcomes P-gp-mediated multidrug resistance in the human
      sarcoma cell line MES-Dx5. Detailed analysis revealed that five times higher
      GF120918 concentrations were needed to reverse drug resistance to taxol in the
      cytotoxicity assay compared to doxorubicin, vinblastine and etoposide. An
      explanation for this phenomenon had not been found.

PMID- 10576650
TI  - Effects of the glucolipid synthase inhibitor, P4, on functional and phenotypic
      parameters of murine myeloma cells.
AB  - This study describes the effects of the glucolipid synthase inhibitor P4, (DL
      threo-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol ), on various functional
      and phenotypic parameters of 5T33 murine myeloma cells. Cell recovery was reduced
      by >85% following incubation of the cells for 3 days in the presence of 4 microM
      P4 (the IC50 concentration). Both cytostatic and cytotoxic inhibition was
      observed with tumour cell metabolic activity and clonogenic potential reduced to
      42% and 14% of controls, respectively, and viability reduced to 52%. A dose
      dependent increase in cells undergoing apoptosis (from 7% to 26%) was also found.
      P4 induced a decrease in the number of cells expressing H-2 Class I and CD44, and
      a large increase in cells expressing H-2 Class II and the IgG2b paraprotein. It
      did not affect surface expression of CD45 or CD54 (ICAM-1). Based on these
      alterations in tumour cell growth, adhesion molecule expression and potential
      immunogenicity, it is anticipated that P4 will provide a novel therapeutic
      approach for the treatment of multiple myeloma. In addition, given that
      essentially all tumours rely heavily on overexpressed or abnormal
      glucosphingolipids for growth, development and metastasis, glucolipid synthase
      inhibitors may prove to be universally effective anti-cancer agents.

PMID- 10576652
TI  - Targeted cytotoxic analogue of bombesin/gastrin-releasing peptide inhibits the
      growth of H-69 human small-cell lung carcinoma in nude mice.
AB  - Recently, we developed a powerful cytotoxic analogue of bombesin AN-215, in which
      the bombesin-like carrier peptide Gln-Trp-Ala-Val-Gly-His-Leu-psi(CH2-NH)-Leu-NH2
      (RC-3094) is conjugated to a potent derivative of doxorubicin, 2
      pyrrolinodoxorubicin (AN-201). Small-cell lung carcinomas (SCLCs) are known to
      express high levels of bombesin receptors. We evaluated whether these receptors
      could be used for targeting cytotoxic bombesin analogue to H-69 SCLC cells. H-69
      cells were xenografted into male nude mice, which then received an intravenous
      injection of AN-215, cytotoxic radical AN-201, the carrier peptide RC-3094 alone
      or unconjugated mixture of RC-3094 and AN-201. The levels of mRNA for bombesin
      receptor subtypes were evaluated by reverse transcription-polymerase chain
      reaction. In vitro, both the analogue AN-215 and the radical AN-201 showed strong
      antiproliferative effects on H-69 cells, AN-215 requiring more time to exert its
      action at 10(-8) M concentration than AN-201. In vivo, the growth of H-69 SCLC
      tumours was significantly inhibited by the treatment with 200 nmol kg(-1) of AN
      215, while equimolar doses of the cytotoxic radical AN-201 or the mixture of AN
      201 and the carrier peptide were toxic and produced only a minor tumour
      inhibition as compared with control groups. mRNA for bombesin receptor subtypes 2
      (BRS-2) and 3 (BRS-3) was detected in H-69 tumours. The mRNA levels for BRS-3,
      but not for BRS-2, were lower in the AN-215-treated tumours as compared with
      controls. Our results demonstrate that the cytotoxic bombesin analogue AN-215
      could be considered for targeted therapy of tumours, such as SCLC, that express
      bombesin receptors.

PMID- 10576651
TI  - Effects of the protein kinase inhibitors wortmannin and KN62 on cellular
      radiosensitivity and radiation-activated S phase and G1/S checkpoints in normal
      human fibroblasts.
AB  - Wortmannin is a potent inhibitor of phosphatidylinositol (PI) 3-kinase and PI 3
      kinase-related proteins (e.g. ATM), but it does not inhibit the activity of
      purified calmodulin-dependent protein kinase II (CaMKII). In the present study,
      we compared the effects of wortmannin and the CaMKII inhibitor KN62 on the
      response of normal human dermal fibroblast cultures to gamma radiation. We
      demonstrate that wortmannin confers a phenotype on normal fibroblasts remarkably
      similar to that characteristic of cells homozygous for the ATM mutation. Thus
      wortmannin-treated normal fibroblasts exhibit increased sensitivity to radiation
      induced cell killing, lack of temporary block in transition from G1 to S phase
      following irradiation (i.e. impaired G1/S checkpoint), and radioresistant DNA
      synthesis (i.e. impaired S phase checkpoint). Wortmannin-treated cultures display
      a diminished capacity for radiation-induced up-regulation of p53 protein and
      expression of p21WAF1, a p53-regulated gene involved in cell cycle arrest at the
      G1/S border; the treated cultures also exhibit decreased capacity for enhancement
      of CaMKII activity post-irradiation, known to be necessary for triggering the S
      phase checkpoint. We further demonstrate that KN62 confers a radioresistant DNA
      synthesis phenotype on normal fibroblasts and moderately potentiates their
      sensitivity to killing by gamma rays, without modulating G1/S checkpoint, p53 up
      regulation and p21WAF1 expression following radiation exposure. We conclude that
      CaMKII is involved in the radiation responsive signalling pathway mediating S
      phase checkpoint but not in the p53-dependent pathway controlling G1/S
      checkpoint, and that a wortmannin-sensitive kinase functions upstream in both
      pathways.

PMID- 10576653
TI  - Dosimetric evaluation and radioimmunotherapy of anti-tumour multivalent Fab'
      fragments.
AB  - We have been investigating the use of cross-linked divalent (DFM) and trivalent
      (TFM) versions of the anti-carcinoembryonic antigen (CEA) monoclonal antibody
      A5B7 as possible alternatives to the parent forms (IgG and F(ab')2) which have
      been used previously in clinical radioimmunotherapy (RIT) studies in colorectal
      carcinoma. Comparative biodistribution studies of similar sized DFM and F(ab')2
      and TFM and IgG, radiolabelled with both 131I and 90Y have been described
      previously using the human colorectal tumour LS174T nude mouse xenograft model
      (Casey et al (1996) Br J Cancer 74: 1397-1405). In this study quantitative
      estimates of radiation distribution and RIT in the xenograft model provided more
      insight into selecting the most suitable combination for future RIT. Radiation
      doses were significantly higher in all tissues when antibodies were labelled with
      90Y. Major contributing organs were the kidneys, liver and spleen. The extremely
      high absorbed dose to the kidneys on injection of 90Y-labelled DFM and F(ab')2 as
      a result of accumulation of the radiometal would result in extremely high
      toxicity. These combinations are clearly unsuitable for RIT. Cumulative dose of
      90Y-TFM to the kidney was 3 times lower than the divalent forms but still twice
      as high as for 90Y-IgG. TFM clears faster from the blood than IgG, producing
      higher tumour to blood ratios. Therefore when considering only the tumour to
      blood ratios of the total absorbed dose, the data suggests that TFM would be the
      most suitable candidate. However, when corrected for equitoxic blood levels,
      doses to normal tissues for TFM were approximately twice the level of IgG,
      producing a two-fold increase in the overall tumour to normal tissue ratio. In
      addition RIT revealed that for a similar level of toxicity and half the
      administered activity, 90Y-IgG produced a greater therapeutic response. This
      suggests that the most promising A5B7 antibody form with the radionuclide 90Y may
      be IgG. Dosimetry analysis revealed that the tumour to normal tissue ratios were
      greater for all 131I-labelled antibodies. This suggests that 131I may be a more
      suitable radionuclide for RIT, in terms of lower toxicity to normal tissues. The
      highest tumour to blood dose and tumour to normal tissue ratio at equitoxic blood
      levels was 131I-labelled DFM, suggesting that 131I-DFM may be best combination of
      antibody and radionuclide for A5B7. The dosimetry estimates were in agreement
      with RIT results in that twice the activity of 131I-DFM must be administered to
      produce a similar therapeutic effect as 131I-TFM. The toxicity in this therapy
      experiment was minimal and further experiments at higher doses are required to
      observe if there would be any advantage of a higher initial dose rate for 131I
      DFM.

PMID- 10576654
TI  - N-substituted benzamides inhibit NFkappaB activation and induce apoptosis by
      separate mechanisms.
AB  - Benzamides have been in clinical use for many years in treatment against various
      disorders. A recent application is that as a sensitizer for radio- or
      chemotherapies. We have here analysed the mechanism of action of N-substituted
      benzamides using an in vitro system. We found that while procainamide was
      biologically inert in our system, the addition of a chloride in the 3' position
      of the benzamide ring created a compound (declopramide) that induced rapid
      apoptosis. Furthermore, declopramide also inhibited NFkappaB activation by
      inhibition of IkappaBbeta breakdown. An acetylated variant of declopramide, N
      acetyl declopramide, showed no effect with regard to rapid apoptosis induction
      but was a potent inhibitor of NFkappaB activation. In fact, the addition of an
      acetyl group to procainamide in the 4' position was sufficient to convert this
      biologically inactive substance to a potent inhibitor of NFkappaB activation.
      These findings suggest two potential mechanisms, induction of early apoptosis and
      inhibition of NFkappaB mediated salvage from apoptosis, for the biological effect
      of N-substituted benzamides as radio- and chemo-sensitizers. In addition it
      suggests that N-substituted benzamides are potential candidates for the
      development of anti-inflammatory compounds using NFkappaB as a drug target.

PMID- 10576655
TI  - Association between tissue hypoxia and elevated non-protein sulphydryl
      concentrations in human cervical carcinoma xenografts.
AB  - A double staining technique was developed for the simultaneous measurement of
      tissue hypoxia and the concentration of non-protein sulphydryls (NPSH), based on
      the fluorinated nitroimidazole EF5 and the fluorescent histochemical NPSH stain 1
      (4-chloromercuriphenoylazo)-naphthol-2 (mercury orange). Cryostat sections of
      tumour tissue were examined by fluorescence image analysis, using a computer
      controlled microscope stage to generate large tiled field images of the cut
      tumour surface. This method was applied to the human cervical squamous cell
      carcinoma lines ME180 and SiHa, grown as xenografts in severe combined
      immunodeficient (SCID) mice, in order to determine if there is a systematic
      relationship between tissue hypoxia and NPSH levels. Hypoxic regions of the
      tumours, defined by EF5 labelling, were found to show greater NPSH concentrations
      relative to better oxygenated regions. This is probably due to increases in
      glutathione, since the ME180 and SiHa xenografts contained low levels of cysteine
      and metallothionein; the other major cellular thiols that can bind to mercury
      orange. Because the effects of glutathione on radiation and chemotherapy
      resistance are likely to be greater under hypoxic conditions, these results have
      potentially important implications for the study of resistance mechanisms in
      solid tumours.

PMID- 10576656
TI  - Altered expression of the suppressors PML and p53 in glioblastoma cells with the
      antisense-EGF-receptor.
AB  - Gene amplification and enhanced expression of the epidermal growth factor
      receptor (EGFR) represent the major molecular genetic alteration in glioblastomas
      and it may play an essential role in cell growth and in the carcinogenic process.
      On the other hand, the nuclear suppressor proteins PML and p53 are also known to
      play critical roles in cancer development and in suppressing cell growth. Here we
      report that, in glioblastoma cells with defective EGFR function, the expressions
      of both promyelocytic leukaemia (PML) and p53 were altered. Cells that were
      transfected with the antisense-cDNA of EGFR were found to have more cells in G1
      and fewer cells in S phase. In addition, the transfected cells were found to be
      non-responsive to EGF-induced cell growth. Interestingly, the expression of the
      suppressors p53 and PML were found to be significantly increased by
      immunohistochemical assay in the antisense-EGFR cells. Moreover, the PML
      expression in many of the cells was converted from the nuclear dot pattern into
      fine-granulated staining pattern. In contrast, the expressions of other cell
      cycle regulated genes and proto-oncogene, including the cyclin-dependent kinase 4
      (cdk4), retinoblastoma, p16INK4a and p21H-ras, were not altered. These data
      indicate that there are specific inductions of PML and p53 proteins which may
      account for the increase in G1 and growth arrest in antisense-EGFR treated cells.
      It also indicates that the EGF, p53 and PML transduction pathways were linked and
      they may constitute an integral part of an altered growth regulatory programme.
      The interactions and cross-talks of these critical molecules may be very
      important in regulating cell growth, differentiation and cellular response to
      treatment in glioblastomas.

PMID- 10576657
TI  - The potential role for prolactin-inducible protein (PIP) as a marker of human
      breast cancer micrometastasis.
AB  - The prolactin-inducible protein (PIP/GCPD15) is believed to originate from a
      limited set of tissues, including breast and salivary glands, and has been
      applied as a clinical marker for the diagnosis of metastatic tumours of unknown
      origin. We have investigated the potential role of PIP mRNA as a marker of human
      breast cancer metastasis. Using reverse transcription polymerase chain reaction
      and Southern or dot blot analysis, PIP mRNA was detected in 4/6 breast cell
      lines, independent of oestrogen receptor (ER) status. In breast primary tumours
      (n = 97), analysed from histologically characterized sections, PIP mRNA was
      detected in most cases. Higher PIP mRNA levels correlated with ER+ (P = 0.0004),
      progesterone receptor positive (PR+) (P = 0.0167), low-grade (P = 0.0195)
      tumours, and also PIP protein levels assessed by immunohistochemistry (n = 19, P
      = 0.0319). PIP mRNA expression was also detectable in 11/16 (69%) of axillary
      node metastases. PIP mRNA expression, however, was also detected in normal breast
      duct epithelium, skin, salivary gland and peripheral blood leucocyte samples from
      normal individuals. We conclude that PIP mRNA is frequently expressed in both
      primary human breast tumours and nodal metastases. However, the presence of PIP
      expression in skin creates a potential source of contamination in venepuncture
      samples that should be considered in its application as a marker for breast
      tumour micrometastases.

PMID- 10576658
TI  - Phase I clinical study applying autologous immunological effector cells
      transfected with the interleukin-2 gene in patients with metastatic renal cancer,
      colorectal cancer and lymphoma.
AB  - Natural killer-like T lymphocytes termed cytokine-induced killer (CIK) cells have
      been shown to eradicate established tumours in a severe combined immune deficient
      (SCID) mouse/human lymphoma model. Recently, we demonstrated that CIK cells
      transfected with cytokine genes possess an improved proliferation rate and a
      significantly higher cytotoxic activity as compared to non-transfected cells.
      Here, in a phase I clinical protocol, autologous CIK cells were generated from
      peripheral blood obtained by leukapheresis in patients with metastatic renal cell
      carcinoma, colorectal carcinoma and lymphoma. CIK cells were transfected with a
      plasmid containing the interleukin-2 (IL-2) gene via electroporation. Transfected
      cells generated IL-2 in the range of 330-1800 pg 10(-6) cells 24 h(-1) with a
      mean of 836 pg 10(-6) cells 24 h(-1). Ten patients received 1-5 intravenous
      infusions of IL-2-transfected CIK cells; five infusions with transfected CIK
      cells were given. In addition, the same patients received five infusions with
      untransfected CIK cells for control reasons. In three patients, WHO grade 2 fever
      was observed. Based on polymerase chain reaction of peripheral blood transfected
      cells could be detected for up to 2 weeks after infusion. There was a significant
      increase in serum levels of interferon gamma (IFN-gamma), granulocyte-macrophage
      colony-stimulating factor (GM-CSF) and transforming growth factor beta (TGF-beta)
      during treatment. Interestingly, there was also an increase in CD3+ lymphocytes
      in the blood of patients during therapy. In accordance, a partial increase in
      cytotoxic activity in peripheral blood lymphocytes (PBLs) was documented when
      patient samples before and after therapy were compared. Concerning clinical
      outcome, six patients remained in progressive disease, three patients showed no
      change by treatment, and one patient with lymphoma developed a complete response.
      In conclusion, we were able to demonstrate that CIK cells transfected with the IL
      2 gene can be administered without major side-effects and are promising for
      future therapeutic trials.

PMID- 10576659
TI  - A high proliferation rate measured by cyclin A predicts a favourable chemotherapy
      response in soft tissue sarcoma patients.
AB  - A small but not insignificant number of patients experience a prolonged survival
      after treatment of metastatic soft tissue sarcoma. This must be weighed against
      the majority of the patients who benefit little from the therapy, but
      nevertheless experience its side-effects. It would therefore be of utmost
      importance to be able to screen for those patients who respond to the treatment.
      Since proliferating cells are more sensitive to chemotherapy than non
      proliferative cells, we measured the proliferation rate of the primary tumour of
      55 soft tissue sarcoma patients with locally advanced or metastatic disease by
      determining the flow cytometric S phase fraction and immunohistochemical Ki-67
      and cyclin A scores. S phase fraction or Ki-67 score did not predict chemotherapy
      response or progression-free survival. A high cyclin A score, however, correlated
      with a better chemotherapy response (P = 0.02) and longer progression-free
      survival time (P = 0.04). Our results suggest that a high cyclin A score predicts
      chemotherapy sensitivity.

PMID- 10576660
TI  - Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for
      refractory or relapsing malignancies.
AB  - Temozolomide, an oral cytotoxic agent with approximately 100% bioavailability
      after one administration, has demonstrated schedule-dependent clinical activity
      against highly resistant cancers. Thirty patients with minimal prior chemotherapy
      were enrolled in this phase I trial to characterize the drug's safety,
      pharmacokinetics and anti-tumour activity, as well as to assess how food affects
      oral bioavailability. To determine dose-limiting toxicities (DLT) and the maximum
      tolerated dose (MTD), temozolomide 100-250 mg m(-2) was administered once daily
      for 5 days every 28 days. The DLT was thrombocytopenia, and the MTD was 200 mg m(
      2) day(-1). Subsequently, patients received the MTD to study how food affects the
      oral bioavailability of temozolomide. When given orally once daily for 5 days,
      temozolomide was well tolerated and produced a non-cumulative, transient
      myelosuppression. The most common non-haematological toxicities were mild to
      moderate nausea and vomiting. Clinical activity was observed against several
      advanced cancers, including malignant glioma and metastatic melanoma.
      Temozolomide demonstrated linear and reproducible pharmacokinetics and was
      rapidly absorbed (mean Tmax approximately 1 h) and eliminated (mean t1/2 = 1.8
      h). Food produced a slight reduction (9%) in absorption of temozolomide.
      Temozolomide 200 mg m(-2) day(-1) for 5 days, every 28 days, is recommended for
      phase II studies.

PMID- 10576661
TI  - Ifosfamide, cisplatin and etoposide combination in locally advanced inoperable
      non-small-cell lung cancer: a phase II study.
AB  - From March 1993 to February 1997, 43 eligible patients with inoperable stage IIIA
      (ten patients) and stage IIIB (33 patients), histologically confirmed NSCLC
      received 3 courses of the ICE combination (ifosfamide 1.5 g m(-2) and mesna 750
      mg m(-2) two times a day, cisplatin 25 mg m(-2) and etoposide 100 mg m(-2), all
      administered intravenously (i.v.) on days 1-3 every 3 weeks) with G-CSF support.
      After three cycles, patients were submitted to radical surgery or received two
      additional courses of the ICE regimen and/or curative radiotherapy. Grade 3-4
      neutropenia occurred in 21% of 114 evaluable courses, but was of short duration,
      leading to neutropenic fever in 5% of the courses. Severe thrombocytopenia and
      anaemia were observed in 13% and 3% of the courses respectively. Non
      haematological toxicity was generally mild with only two episodes of reversible
      renal impairment. The overall response rate after three chemotherapy courses was
      69% (28 partial responses, one complete response). Ten patients (8/10 patients in
      stage IIIA, 2/33 patients in stage IIIB) underwent radical surgery. Median TTP
      for patients not undergoing surgery (n = 33) was 8 months (range 3-34+); median
      DFS for patients rendered NED by surgery (n = 10) was 26 months (range 1-54+).
      Median OS for the entire group was 12.5 months (range 2-57+). The ICE regimen is
      active in locally advanced NSCLC with acceptable toxicity and warrants further
      exploration as induction chemotherapy in larger series.

PMID- 10576662
TI  - Serosal complications of single-agent low-dose methotrexate used in gestational
      trophoblastic diseases: first reported case of methotrexate-induced peritonitis.
AB  - Methotrexate (MTX) is a folate antagonist widely used both as an anticancer drug
      and as an immunosupressant. Administration of an 8-day methotrexate and folinic
      acid regime may be associated with pleuritic chest pain and pneumonitis. We have
      reviewed the toxicity seen in 168 consecutive patients treated with low-dose MTX
      for persistent trophoblastic disease. Twenty-five per cent of patients developed
      serosal symptoms, pleurisy was the commonest complaint. The majority of patients
      had mild to moderate symptoms which were controlled with simple analgesia and did
      not necessitate a change in treatment; 11.9% had severe symptoms which
      necessitated a change in treatment. One patient developed a pericardial effusion
      and a second patient developed severe reversible peritoneal irritation. The
      possible aetiology and pathophysiology of methotrexate-induced serosal toxicity
      is discussed.

PMID- 10576663
TI  - High level expression of differentially localized BAG-1 isoforms in some
      oestrogen receptor-positive human breast cancers.
AB  - Sensitivity to oestrogens and apoptosis are critical determinants of the
      development and progression of breast cancer and reflect closely linked pathways
      in breast epithelial cells. For example, induction of BCL-2 oncoprotein
      expression by oestrogen contributes to suppression of apoptosis and BCL-2 and
      oestrogen receptor (ER) are frequently co-expressed in tumours. BAG-1/HAP is a
      multifunctional protein which complexes with BCL-2 and steroid hormone receptors
      (including the ER), and can suppress apoptosis and influence steroid hormone
      dependent transcription. Therefore, analysis of expression of BAG-1 in human
      breast cancer is of considerable interest. BAG-1 was readily detected by
      immunostaining in normal breast epithelial cells and most ER-positive tumours,
      but was undetectable or weakly expressed in ER-negative tumours. BAG-1 positive
      cells showed a predominantly cytoplasmic or cytoplasmic plus nuclear distribution
      of staining. A correlation between ER and BAG-1 was also evident in breast cancer
      derived cell lines, as all lines examined with functional ER expression also
      expressed high levels of BAG-1. In addition to the prototypical 36 kDa BAG-1
      isoform, breast cancer cells expressed higher molecular weight isoforms and, in
      contrast to BCL-2, BAG-1 expression was independent of oestrogens. BAG-1 isoforms
      were differentially localized to the nucleus or cytoplasm and this was also
      independent of oestrogens. These results demonstrate a close association between
      BAG-1 and functional ER expression and suggest BAG-1 may be useful as a
      therapeutic target or prognostic marker in breast cancer.

PMID- 10576664
TI  - Predictive value of decreased p27Kip1 protein expression for the recurrence-free
      and long-term survival of prostate cancer patients.
AB  - The p27Kip1 gene has been identified as inductor of cell cycle arrest at the G1
      checkpoint to prevent entry of somatic cells into the S phase of the cell cycle
      when substantial DNA damage has occurred. It has been suggested that decreased
      expression of the p27Kip1 protein may contribute to the development of human
      malignancies due to loss of critical antiproliferative mechanisms. In the present
      study, 95 specimens (T1-T4) from 95 randomly selected patients undergoing radical
      prostatectomy at the Urological Department of Hannover University (82 patients)
      as well as in the Josef Hospital Regensburg (13 patients) between 1981 and 1992
      for whom tissue blocks for immunohistochemical investigation were available, were
      investigated for different biological and clinical characteristics as possible
      predictors for recurrence-free and long-term survival: age, depth of tumour
      infiltration, histological grade, lymph node status, as well as decreased
      expression of the p27Kip1 protein. After a median follow-up up of 56 months (24
      151 months), seven of 21 (33%) patients (Group 1) with loss of p27Kip1 protein
      expression or a relative amount of <10% of positively stained tumour cells
      developed recurrent disease in contrast to 17 of 74 (23%) patients (Group 2) with
      retained p27Kip1 protein expression (> or =10% of positively stained tumour
      cells). The median recurrence-free survival was 14 months (5-40 months) for
      patients from Group 1 and 31 months (7-133 months) for Group 2 patients (P =
      0.02). In multivariate analysis, loss of p27Kip1 protein expression was
      identified as the only independent prognostic parameter for recurrence-free
      survival. In contrast, neither the univariate nor the multivariate analysis
      showed a correlation between loss of p27Kip1 protein expression and the long-term
      survival of the patients. Prospective studies are urgently needed to confirm the
      independent prognostic value of decreased p27Kip1 protein expression together
      with overexpression of the p53 tumour suppressor protein in patients with
      localized prostate cancer. The availability of more refined prognostically
      important biological variables in addition to established prognostic factors like
      tumour stage or Gleason score might help decision making in patients at high risk
      for the development of local recurrence or systemic tumour progression.

PMID- 10576666
TI  - Melanoma-inhibiting activity (MIA) mRNA is not exclusively transcribed in
      melanoma cells: low levels of MIA mRNA are present in various cell types and in
      peripheral blood.
AB  - The detection of minimal amounts of melanoma cells by tyrosinase reverse
      transcription polymerase chain reaction (RT-PCR) is seriously hampered by false
      negative reports in blood of melanoma patients with disseminated melanoma.
      Therefore, additional assays which make use of multiple melanoma markers are
      needed. It has been shown that introduction of multiple markers increases the
      sensitivity of detection. Melanoma inhibitory activity (MIA) is one such melanoma
      specific candidate gene. To test the specificity of MIA PCR, we performed 30 and
      60 cycles of PCR with two different sets of MIA specific primers on 19 melanoma
      and 16 non-melanoma cell lines. MIA mRNA was detected in 16 out of 19 melanoma
      cell lines and in seven out of 16 non-melanoma cell lines after 30 cycles of PCR.
      However, MIA mRNA could be detected in all cell lines after 60 cycles of PCR.
      Also, in 14 out of 14 blood samples of melanoma patients, five out of six blood
      samples of non-melanoma patients and in seven out of seven blood samples of
      healthy volunteers, MIA mRNA was detected after 60 cycles of PCR, whereas no MIA
      PCR product could be detected in any of the blood samples after 30 cycles of PCR.
      We conclude that low levels of MIA transcripts are present in various normal and
      neoplastic cell types. Therefore, MIA is not a suitable marker gene to facilitate
      the detection of minimal amounts of melanoma cells in blood or in target organs
      of the metastatic process.

PMID- 10576665
TI  - Evaluation of seven tumour markers in pleural fluid for the diagnosis of
      malignant effusions.
AB  - Carcinoembryonic antigen (CEA), carbohydrate antigens 15-3, 19-9 and 72-4 (CA 15
      3, CA 19-9 and CA 72-4), cytokeratin 19 fragments (CYFRA 21-1), neuron-specific
      enolase (NSE) and squamous cell carcinoma antigen (SCC) were evaluated in pleural
      fluid for the diagnosis of malignant effusions. With a specificity of 99%,
      determined in a series of 121 benign effusions, the best individual diagnostic
      sensitivities in the whole series of 215 malignant effusions or in the subgroup
      of adenocarcinomas were observed with CEA, CA 15-3 and CA 72-4. As expected, a
      high sensitivity was obtained with SCC in squamous cell carcinomas and with NSE
      in small-cell lung carcinomas. CYFRA and/or CA 15-3 were frequently increased in
      mesotheliomas. Discriminant analysis showed that the optimal combination for
      diagnosis of non-lymphomatous malignant effusions was CEA + CA 15-3 + CYFRA +
      NSE: sensitivity of 94.4% with an overall specificity of 95%. In malignant
      effusions with a negative cytology, 83.9% were diagnosed using this association.
      The association CYFRA + NSE + SCC was able to discriminate adenocarcinomas from
      small-cell lung cancers. Regarding their sensitivity and their complementarity,
      CEA, CA 15-3, CYFRA 21-1, NSE and SCC appear to be very useful to improve the
      diagnosis of malignant pleural effusions.

PMID- 10576668
TI  - Expression of MAGE-1 and -3 genes and gene products in human hepatocellular
      carcinoma.
AB  - MAGE gene family encodes peptides recognized by autologous cytotoxic T
      lymphocytes in a major histocompatibility complex (MHC) class-I restricted
      fashion. In the present study, we have performed reverse-transcription polymerase
      chain reaction (RT-PCR) for the genes, as well as immunohistochemical analysis
      and Western blotting of MAGE-1 and -3 proteins in 33 surgically resected
      hepatocellular carcinomas (HCCs). MAGE-1 and -3 mRNAs were constitutively
      expressed exclusively in 78 and 42% of HCCs respectively. On immunohistochemistry
      with monoclonal antibodies, 77B for MAGE-1 and 57B for MAGE-3, MAGE-1 and -3
      proteins were recognized in cytoplasm of only six among 33 (18%) and two of 29
      HCCs (7%) respectively. The distribution pattern was mostly focal in HCC nodules.
      By contrast, the Western blot analysis revealed that the MAGE-1 (46 kDa) and -3
      proteins (48 kDa) were expressed in 80 and 60% of 15 HCCs examined respectively.
      The proteins of MAGE-1 and -3 were also expressed exclusively in HCCs regardless
      of the histological grading and clinical staging. Our results indicate that the
      detection of the genes by RT-PCR or the proteins by Western blotting is useful
      for differentiating early HCCs from non-cancerous lesions, and that the peptides
      derived from MAGE-1 and -3 proteins might be suitable targets for immunotherapy
      of human HCC.

PMID- 10576667
TI  - Distribution of laminin and fibronectin isoforms in oral mucosa and oral squamous
      cell carcinoma.
AB  - The expression of laminin and fibronectin isoforms varies with cellular
      maturation and differentiation and these differences may well influence cellular
      processes such as adhesion and motility. The basement membrane (BM) of fetal oral
      squamous epithelium contains the laminin chains, alpha2, alpha3, alpha5, beta1,
      beta2, beta3, gamma1 and gamma2. The BM of adult normal oral squamous epithelium
      comprises the laminin chains, alpha3, alpha5, beta1, beta3, gamma1 and gamma2. A
      re-expression of the laminin alpha2 and beta2 chains could be shown in adult
      hyperproliferative, dysplastic and carcinomatous lesions. In dysplasia and oral
      squamous cell carcinoma (OSCC), multifocal breaks of the BM are present as
      indicated by laminin chain antibodies. These breaks correlate to malignancy grade
      in their extent. Moreover, in the invasion front the alpha3 and gamma2 chain of
      laminin-5 can immunohistochemically be found outside the BM within the cytoplasm
      of budding carcinoma cells and in the adjacent stroma. The correlation between
      the morphological pattern of invasive tumour clusters and a laminin-5
      immunostaining in the adjacent stroma may suggest, first, that a laminin-5
      deposition outside the BM is an immunohistochemical marker for invasion and
      second, that OSCC invasion is guided by the laminin-5 matrix. Expression of
      oncofetal fibronectins (IIICS de novo glycosylated fibronectin and ED-B
      fibronectin) could be demonstrated throughout the stromal compartment. However,
      the ED-B fibronectin synthesizing cells (RNA/RNA in situ hybridization) are
      confined to small stroma areas and to single stroma and inflammatory cells in the
      invasion front. A correlation of the number of ED-B fibronectin synthesizing
      cells to malignancy grade could not be seen. ED-B fibronectin mRNA-positive cells
      seem to be concentrated in areas of fibrous stroma recruitment with a linear
      alignment of stromal fibro-/myofibroblasts (desmoplasia). Double staining
      experiments (ED-B fibronectin in situ hybridization and alpha-smooth muscle actin
      immunohistochemistry) indicated that the stroma myofibroblasts are a preferential
      source of ED-B fibronectin. In conclusion, in OSCC, a fetal extracellular matrix
      conversion is demonstrable. Tumour cells (laminin alpha2 and beta2 chain) and
      recruited stromal myofibroblasts (oncofetal ED-B fibronectin) contribute to the
      fetal extracellular matrix milieu.

PMID- 10576669
TI  - Reproducibility of microvessel counts in breast cancer specimens.
AB  - Assessment of tumour vascularity in core biopsy specimens may be a useful
      predictor of response to primary therapy. This study addresses practical
      methodological issues regarding accuracy of tumour vascularity assessments in
      different breast cancer specimens. Issues addressed in the study are variation
      caused by (i) inherent observer variation in the method, (ii) tumour
      heterogeneity and (iii) previous surgical manipulation of tumours. Microvessel
      counts were performed by two observers on separate occasions and by two different
      observers. Counts were performed on core biopsies and tumour sections taken
      simultaneously (n = 16) and with an intervening time interval (n = 21). In
      addition core biopsies were obtained from the same tumour on two separate
      occasions (n = 10). A highly significant correlation was found in counts
      performed by the same observers at different times and between two different
      observers. No significant correlation was found in counts of core biopsies and
      tumour sections taken either simultaneously or subsequently. No correlation was
      found between counts of sequential core biopsies. Study findings suggest that,
      although microvessel counts may be assessed reproducibly by the same and
      different observers, counts performed in core biopsies do not accurately reflect
      those of overall tumour, limiting their potential as predictive or prognostic
      markers.

PMID- 10576670
TI  - Reasons it is doubtful that preconceptional paternal irradiation with plutonium
      239 had any effect on cancer induction by methyl-nitroso-urea.

PMID- 10576671
TI  - Does a threat appeal moderate reckless driving? A terror management theory
      perspective.
AB  - A series of two studies examined the effects of threat appeals on reckless
      driving from a terror management theory perspective. In both studies, all the
      participants (N = 109) reported on the relevance of driving to their self-esteem,
      and, then, half of them were exposed to a road trauma film and the remaining to a
      neutral film. In Study 1, the dependent variable was the self-report of
      intentions to drive recklessly in hypothetical scenarios. In Study 2, the
      dependent variable was actual behavior (driving speed) in a driving simulator.
      Findings indicated that a road trauma film led to less reported intentions of
      reckless driving, but to higher driving speed than a neutral film. These effects
      were only found among participants who perceived driving as relevant to their
      self-esteem. The discussion emphasized the self-enhancing mechanisms proposed by
      the terror management theory.

PMID- 10576672
TI  - The effects on safety, time consumption and environment of large scale use of
      roundabouts in an urban area: a case study.
AB  - An experiment with small roundabouts-as speed reducing measures-was carried out
      in a Swedish city. The purpose of the study was to test the large scale and long
      term effects of the roundabouts. The results showed that the roundabouts reduced
      the speed considerably at the junctions and on links between roundabouts. The
      lateral displacement the roundabout forces the driver to has a great importance
      for the speed of approaching cars to a roundabout. The speed-reducing effect is
      large already at a 2 m deflection. A larger deflection does not result in a
      larger effect. Conflict studies indicated an overall decrease in accident risk by
      44%. Vulnerable road-users' risk was reduced significantly, while there was no
      reduction for car occupants. There is a relation between the reduction of
      approach speed and the reduction of injury accident risk. The time consumption at
      a time operated signal was reduced heavily by the instalment of a roundabout at a
      signalised intersection. On average, emissions (CO and NOx) at roundabouts
      replacing non-signalised junctions increased by between 4 and 6%, while a
      roundabout replacing a signalised intersection led to a reduction by between 20
      and 29%. The noise level was reduced at junctions that were provided with
      roundabout. Car drivers were less positive to the roundabouts than bicyclists. In
      the long term, the unchanged roundabouts worked almost as good as they did
      shortly after the rebuilding. The study showed that details in the design are of
      decisive importance for road-users' safety. Special attention has to be paid to
      the situation of bicyclists. The transition between the cycle path/lane and the
      junction has to be designed with care-the bicyclists should be integrated with
      motorised traffic before they enter the roundabout. There should be only one car
      lane both on the approach, in the circulating area and on the exit. The size of
      the roundabout shall be as small as possible.

PMID- 10576673
TI  - Sixteen years age limit for learner drivers in Sweden--an evaluation of safety
      effects.
AB  - Through a reform implemented in Sweden, September 1993, the age limit for
      practising car driving was lowered from 17 1/2 to 16 years while the licensing
      age remained 18. The purpose of lowering the age limit was to give the learner
      drivers an opportunity to acquire more experience as drivers before being allowed
      to drive on their own. The primary aim of this study was to evaluate the effect
      of the reform in terms of accident involvement and data were therefore obtained
      from the national register of police reported accidents. The results show that
      after the reform there was a general reduction in the accident risk (accidents
      per 10 million km) of novice drivers with approximately 15%. Additional analyses
      show that the reduction of accident risk in the group who utilised the new age
      limit was approximately 40%, whereas those who did not utilise the prolonged
      training period did not benefit at all. Between 45 and 50% of the age population
      were found to utilise the reform. The accident reduction does not seem to be just
      an initial first year effect since the results were similar over 3 years of
      novice drivers during their first 2 years with a licence. These results suggest
      that the reform has been beneficial for the safety of novice drivers in Sweden.
      The results also suggest a potential for additional safety improvements if more
      young learner drivers can be brought to utilise the low age limit.

PMID- 10576674
TI  - Which are the relevant costs and benefits of road safety measures designed for
      pedestrians and cyclists?
AB  - This paper discusses the current state-of-the-art with respect to impact
      assessment and cost-benefit analysis of measures designed to improve safety or
      mobility for pedestrians and cyclists. The study concludes that a number of
      impacts that are likely to regarded as important for pedestrians and cyclists are
      not included in current impact assessments and cost-benefit analyses as these are
      made in Norway. Impacts that are not currently included in impact assessments and
      cost-benefit analyses are: (a) changes in the amount of walking and cycling; (b)
      changes in travel time for pedestrians and cyclists; (c) changes in road user
      insecurity (feeling of safety); and (d) changes in road user health state. In
      order to include these effects in impact assessments and cost-benefit analyses,
      more needs to be known about their occurrence and monetary value. Hypothetical
      examples of ideally designed cost-benefit analyses are given, based on highly
      preliminary monetary values for travel time, insecurity and generalised costs of
      travel for pedestrians and cyclists. These analyses indicate that inclusion of
      these effects in cost-benefit analyses could make a major difference for the
      results of those analyses.

PMID- 10576675
TI  - A comparison of different ways to approximate time-to-line crossing (TLC) during
      car driving.
AB  - Three experiments are presented in which the accuracy of different methods to
      approximate time-to-line crossing is assessed the first experiment TLC was
      computed, using a trigonometric method, during normal driving while the vehicle
      stayed in lane. The minima of TLC were compared with two approximations and it
      was found computing TLC as lateral distance divided by lateral velocity gave poor
      results. It was concluded that this simple approximation is not suitable for
      measuring TLC minima in studies of driver behaviour. A way of computing TLC that
      takes account of the curved path of the vehicle resulted in a good fit of TLC
      minima. In two other experiments the vehicle exceeded the lane boundary, either
      intentionally as a result of a lane change manoeuvre, or unintentionally as a
      result of impaired driving. In these cases no TLC minima exists since these only
      occur as a result of correcting steering actions to stay within the lane. In
      contrast to normal lane keeping, it was found that prior to crossing the lane
      boundary, the simple approximation resulted in more accurate estimation of
      available time before the lane boundary is exceeded compared to the more complex
      approximation. This indicates that for lane keeping support systems and systems
      that detect when the driver has fallen asleep and drifts out of lane, a simple
      algorithm for TLC estimation may give reliable results, while this algorithm is
      not accurate enough for more fundamental studies of driver behaviour. However,
      the reliability of the approximation is only satisfactory over a very short time
      range before the lane boundary is actual exceeded. This may result in warnings
      that come too late and result in too little time to respond for the driver.

PMID- 10576676
TI  - Hispanics, Blacks and White driving under the influence of alcohol: results from
      the 1995 National Alcohol Survey.
AB  - OBJECTIVE: To report nationwide survey data on patterns of driving under the
      influence of alcohol among Whites, Blacks and Hispanics. METHOD: Data were
      obtained from a probability sample consisting of 1582 Blacks, 1585 Hispanics and
      1636 Whites in the US household population. Interviews averaging 1 h in length
      were conducted in respondents' homes by trained interviewers. RESULTS: Self
      reported rates of driving a car after having drunk enough 'to be in trouble if
      stopped by the police' were highest among White and Hispanic men (22 and 21%,
      respectively), as were lifetime arrest rates for driving under the influence of
      alcohol (13% for White men, 19% for Hispanic men). Additionally, our analyses
      suggest that drinkers who drive under the influence of alcohol are more likely to
      be men (regardless of ethnicity), consume more alcohol, and be alcohol dependent
      than drinkers who do not engage in alcohol-impaired driving.

PMID- 10576677
TI  - Regional mortality from motor vehicle traffic injury: relationships among place
      of-occurrence, place-of-death, and place-of-residence.
AB  - Regional mortality data, which are compiled according to place-of-residence of
      the decedent, are an important reference for regional health planning and
      resource allocation. However, it would be inappropriate to apply these data to
      studies of environmental risk factors if a large proportion of fatal motor
      vehicle traffic injuries (MVTI) in fact occur outside the resident county. The
      aim of this study was to determine the proportion and characteristics of
      residents of a rural area of Taiwan who died from MVTIs that occurred outside the
      county of residence. We also explored the relationships among the place-of
      occurrence, place-of-death, and place-of-residence of these decedents. The
      families or neighbors of residents of Huatung Area (eastern Taiwan) who died from
      MVTIs in 1994 or 1995 were interviewed to identify the place-of-occurrence of the
      MVTI. Of the 882 Huatung Area residents who died as a result of an MVTI during
      the study period and for whom relevant data were available, the MVTI occurred
      outside the resident county in 207 (23%) cases. Residents whose MVTI occurred
      outside the county of residence were more likely to be youths (aged 15-24) or
      young adults (aged 25-44) and driving automobiles or trucks. Of the 866 cases in
      which the exact place was known, the place-of-occurrence and the place-of-death
      (recorded on the death certificate) were in the same county in 849 (98%). Because
      a high proportion of fatal MVTIs occurred outside the resident county, the
      mortality rate calculated according to place-of-residence does not accurately
      reflect the environmental risk factors in this area. The finding that the
      characteristics of those whose MVTI occurred outside the county differed from
      those decedents whose MVTI occurred within the county indicates that there are
      two target groups for prevention programs. In addition, at least in Huatung Area,
      the place-of-death recorded on the death certificate could serve as a surrogate
      for the place-of-occurrence in epidemiologic studies.

PMID- 10576678
TI  - Globalization in road safety: explaining the downward trend in road accident
      rates in a single country (Israel).
AB  - A theoretical model is proposed in which road safety in a single country depends
      upon parochial considerations, such as police enforcement, and upon global
      considerations, such as international road safety technology. We show that there
      is a non-spurious relationship between the downward trend in the rate of road
      accidents in Israel and the road accident rate abroad. We suggest that this
      reflects the international propagation of road safety technology as it is
      embodied in motor vehicles and road design, rather than parochial road safety
      policy. Recent developments in the econometric analysis of time series are used
      to estimate the model using data for Israel. We make no direct attempt to explain
      the downward trend in the rate of road accidents outside Israel.

PMID- 10576679
TI  - Assessment of university students' coping strategies and reasons for driving in
      high-risk drinking-driving situations.
AB  - A total of 116 students (87 women; 29 men) enrolled at a large, public Midwestern
      university in the United States were recruited to complete a set of demographic
      questionnaires and drinking-driving episode surveys. The latter surveys assessed
      participants' reported motivations for driving or not driving during four recent
      drinking episodes. Content analyses were used to develop lists of commonly
      reported reasons for not driving (e.g. found alternate transportation), reasons
      for driving after drinking (e.g. perceived need to go to destination), potential
      alternatives to driving after drinking (e.g. walking to destination), and
      strategies used to avoid detection or arrest by police (e.g. driving more slowly,
      using back roads or side streets). Participants made both situational and self
      coping attributions to explain why they did not, on occasion, drive after
      drinking. These results may be used as a foundation for prevention and education
      programs that are designed to: (a) encourage use of coping strategies and
      alternatives to driving while disputing peer-generated justifications for driving
      after drinking, and (b) challenge the value of potentially unsafe strategies for
      avoiding detection and arrest when driving under the influence.

PMID- 10576680
TI  - Accident reduction factors and causal inference in traffic safety studies: a
      review.
AB  - Accident reduction factors are used to predict the change in accident occurrence
      which a countermeasure can be expected to cause. Since ethical and legal
      obstacles preclude the use of randomized experiments when evaluating traffic
      safety improvements, empirical support for the causal effectiveness of accident
      countermeasures comes entirely from observational studies. Drawing on
      developments in causal inference initiated by Donald Rubin, it is argued here
      that the mechanism by which sites are selected for application of a
      countermeasure should be included as part of a study's data model, and that when
      important features of the selection mechanism are neglected, existing methods for
      estimating accident reduction factors become inconsistent. A promising, but
      neglected, way out of these difficulties lies in developing rational
      countermeasure selection methods which also support valid causal inference of
      countermeasure effects.

PMID- 10576681
TI  - Exploration of the barriers to bicycle helmet use among 12 and 13 year old
      children.
AB  - Despite the fact that bicycle helmet usage reduces the risk of bicycle-related
      head injuries, only a small percentage of children routinely wear helmets. The
      aim of this study was to qualitatively explore the barriers to bicycle helmet
      usage among 12 and 13 year old children. The study is based on four focus groups
      with 31 children from schools is an urban New York City area. A majority of both
      boys and girls did not perceive a need for wearing helmets for routine riding or
      short trips, and felt that helmet usage was uncomfortable and made them appear
      dumb. Also, students could not recall any health promotion efforts by a variety
      of health providers and felt local legislation had little impact on usage rates.
      The qualitative findings of this study provide valuable material for researchers
      seeking to understand the factors associated with non-use of bicycle helmets.

PMID- 10576682
TI  - Factors affecting the severity of motor vehicle traffic crashes involving elderly
      drivers in Ontario.
AB  - A population-based cross-sectional study was conducted to examine factors
      affecting the severity of motor vehicle traffic crashes (MVTCs) involving elderly
      drivers in Ontario. The study population included drivers aged 65 and over
      involved in injury-producing MVTCs between 1988 and 1993 on Ontario public roads.
      Information was obtained from the Canadian Traffic Accident Information Databank
      (TRAID) compiled from police reports. The severity of MVTC was classified as
      fatal, major, minor or minimal. Comparisons between fatal-, major-, minor- and
      minimal-injury crashes were conducted. Percentage distributions of crashes at
      each level of severity involving elderly drivers were examined according to
      specific factors and tested using the X2 test. Multivariate unconditional
      logistic regression was used to calculate the estimated relative risk as odds
      ratios (ORs) while controlling for confounding factors. A number of factors were
      significantly related to the increased risk of fatal-injury in crashes compared
      with a reference category for each variable. These included age (OR = 1.4 for 70
      79 and OR = 2.3 for 80 + ), sex (OR = 1.4 for males), failing to yield right-of
      way/disobeying traffic signs (OR = 1.7), non-use of seat belts (OR = 4.0),
      ejection from vehicle (OR = 11.3), intersection without traffic controls (OR =
      1.7), roads with higher speed limits (OR = 7.9 for 70-90 km/h; OR= 5.8 for 100
      km/h), snowy weather (OR= 1.6), head-on collisions (OR=55.1), two-vehicle turning
      collisions (OR = 3.1 for left-turn, OR = 8.7 for right-turn), overtaking (OR =
      5.6), and changing lanes (OR = 2.1). Adverse medical/physical conditions
      increased the risk of fatality by a factor of 5 for drivers 75-79 years of age
      and a factor of 3.5 for those 80 years and over. However, in the age group 65-74,
      medical/physical condition did not appear to be related to risk of fatality.
      Similar but weaker associations between these factors and risk of major- and
      minor-injury in crashes were also observed. To reduce the severity of crashes
      involving elderly drivers, strategies could target specific factors such as head
      on collisions, single-vehicle collisions, and traffic controls at intersections.
      Driver conditions such as medical/physical conditions and driver actions such as
      failing to yield right-of-way/disobeying traffic signs should be examined
      further.

PMID- 10576683
TI  - Preventing vehicle crashes with trains at grade crossings: the risk seeker
      challenge.
AB  - A formative evaluation for a communication campaign to decrease rail-automobile
      accidents was conducted with a survey of 891 randomly selected residents in
      Michigan, USA. The formative evaluation was theoretically grounded in the
      extended parallel process model. The results of the study suggest that the
      majority of respondents engage in safe driving behaviors around railways.
      However, 10-20% reported extremely risky behaviors such as trying to 'beat the
      train' (labeled 'risk seekers'). Further analyses revealed that the risk seekers
      were disproportionately male with strong sensation seeking tendencies to engage
      in new and novel experiences and to avoid boredom. The results suggest that high
      sensation seeking tendencies cause one to experience greater frustration and
      exhibit greater judgment distortions around rail crossings, which in turn, cause
      one to try and beat the train. Specific recommendations are given for campaign
      developers and limitations to the study are addressed.

PMID- 10576684
TI  - A new structural variation on the methanesulfonylphenyl class of selective
      cyclooxygenase-2 inhibitors.
AB  - By inserting an oxygen link between the 3-fluorophenyl and the lactone ring of
      5,5-dimethyl-3-(3fluorophenyl)-4-(4-methanesulfonylphenyl)-2 (5H)-furanone 1
      (DFU), analogs with enhanced in vitro COX-2 inhibitory potency as well as in vivo
      potency in models of inflammation were obtained.

PMID- 10576685
TI  - Synthesis and biological evaluation of 3-heteroaryloxy-4-phenyl-2(5H)-furanones
      as selective COX-2 inhibitors.
AB  - A series of 3-heteroaryloxy4-phenyl-2-5H)-furanones were prepared and evaluated
      for their potency and selectivity as COX-2 inhibitors. This led to the
      identification of L-778,736 as a potent, orally active and selective inhibitor of
      the COX-2 enzyme.

PMID- 10576686
TI  - Inhibition of macrophage migration inhibitory factor (MIF) tautomerase activity
      by dopachrome analogs.
AB  - A macrophage migration inhibitory factor (MIF) dopachrome tautomerization assay
      was employed for identification of MIF inhibitors. One group of dopachrome
      analogs was identified which inhibits MIF tautomerase activity. In particular,
      the analogs with a leaving group at beta position displayed activity at a
      concentration of tenfold less than that of the MIF-substrate. These findings
      could lead to a better understanding of MIF biological activities and the
      development of agents for the treatment of MIF related diseases.

PMID- 10576687
TI  - Synthesis of Tc-D,D-HMPAO and Tc-L,L-HMPAO and their comparison of chemical and
      biological properties.
AB  - Tc-D,D- and TC-L,L-HMPAO were synthesized. The stability of Tc-D,D- and TC-L,L
      HMPAO in vitro is similar to that of d,l-isomers by the spectrophotometric and
      three strips methods. Cerebral uptake (%D in brain) for the L,L-isomer is higer
      than the D,D- and d,l-isomer in rats. Delayed studies shows that T-L,L-HMPAO
      reveals less washout and reflects a higher cerebral deposition properties than
      the D,D- and d,l-isomer.

PMID- 10576688
TI  - Synthesis and in vitro cytotoxicity of hexacyclic camptothecin analogues.
AB  - A series of C(7)-N-alkylaminoethyl-C(10), C(11)-methylenedioxy- and ethylenedioxy
      camptothecin (3a-g, 4a-b) were prepared. Their syntheses and in vitro
      cytotoxicity were reported. Among 15 derivatives, 3a and 3b showed more potent
      cytotoxicity than Camptothecin, especially in CAOV-3 cell line.

PMID- 10576689
TI  - A novel method for preparation of optically active alpha-monobenzoyl glycerol via
      lipase-catalyzed asymmetric transesterification of glycerol.
AB  - One-step synthesis of optically active alpha-monobenzoyl glycerol is described by
      lipasecatalyzed transesterification of benzoate derivatives with glycerol in 1,4
      dioxane.

PMID- 10576690
TI  - Synthesis and biological evaluation of two novel DAT-binding technetium complexes
      containing a piperidine based analogue of cocaine.
AB  - Two new technetium complexes containing a piperidine template have been
      synthesized and evaluated as possible leads for the development of dopamine
      transporter (DAT) imaging agents. Binding data for the corresponding rhenium
      complexes containing either a monoaminomonoamide (MAMA') or a diaminodithiol
      (DADT) chelating unit exhibited significant affinity for the DAT. Initial
      biodistribution studies in rats revealed only a low brain uptake.

PMID- 10576691
TI  - Unsymmetrical cyclic ureas as HIV-1 protease inhibitors: novel biaryl indazoles
      as P2/P2' substituents.
AB  - The preparation of unsymmetrical cyclic ureas bearing novel biaryl indazoles as
      P2/P2' substituents was undertaken, utilizing a Suzuki coupling reaction as the
      key step. Compound 6i was equipotent to the lead compound of the series SE063.

PMID- 10576692
TI  - Synthesis and evaluation of benzoxazinones as HIV-1 reverse transcriptase
      inhibitors. Analogs of Efavirenz (SUSTIVA).
AB  - Two series of benzoxazinones differing in the aromatic substitution pattern were
      prepared and evaluated as HIV-1 reverse transcriptase inhibitors. The 5-fluoro
      (5a-d) and 6-nitro (5e-h) substituted compounds displayed activity comparable or
      better than Efavirenz, the lead structure of the series.

PMID- 10576693
TI  - Dicationic 2-fluorenonylcarbapenems: potent anti-MRS agents with improved
      solubility and pharmacokinetic properties.
AB  - The synthesis and biological evaluation of a series of dicationic-substituted 2
      fluorenonylcarbapenems is described. This class of compounds showed enhanced
      water solubility while maintaining potent activity against MRS. Introduction of a
      1-beta-methyl substituent was found to improve pharmacokinetics.

PMID- 10576694
TI  - Fluorescent molecular probes V: a sensitive caspase-3 substrate for fluorometric
      assays.
AB  - (Z-Asp-Glu-Val-Asp)-Rhodamine 110 [(Z-DEVD)2-Rh 110] was prepared and
      characterized as a sensitive fluorogenic substrate for the determination of
      caspase-3 activity.

PMID- 10576695
TI  - Acyclic structural variants of growth hormone secretagogue L-692,429.
AB  - Systematic investigation of acyclic analogs of L-692,429, the prototype
      benzolactam growth hormone secretagogue, has helped to further define the
      structural requirements for the release of growth hormone from rat pituitary
      cells for this class of secretagogues.

PMID- 10576696
TI  - Parallel synthesis of 3-aryloxy-2-propanolamines and evaluation as dual affinity
      5-HT(1A) and 5-HT re-uptake ligands.
AB  - A solution phase synthesis for the preparation of 3-aryloxy-2-propanolamine
      libraries has been developed. This resulted in the identification of 5 as a
      ligand with dual affinity for 5-HT1A and serotonin reuptake receptors which shows
      excellent pharmacokinetic parameters.

PMID- 10576697
TI  - Further hypotensive metabolites from Verbesina caracasana.
AB  - After the isolation of caracasanamide and caracasandiamide, further hypotensive
      components of Verbesina caracasana were shown to be N3-prenylagmatine, N1-3',4'
      dimethoxycinnamoylagmatine, agmatine and galegin (prenylguanidine). The
      structures were assigned on the basis of the spectral data of both metabolites
      and products from their alkaline hydrolyses. A pharmacological analysis of these
      products is also presented.

PMID- 10576698
TI  - Peroxides as oxidative enzyme inhibitors: mechanism-based inhibition of a
      cysteine protease by an amino acid ozonide.
AB  - A stable ozonide derived from Cbz-L-Phe accomplishes rapid and stoichiometric
      inhibition of papain at less than 100 microM concentration under conditions where
      formation of the corresponding aldehyde is negligible. Oxidation of the active
      site thiolate by the bound peroxide is believed to lead to formation of an
      inactive sulfenate or sulfenic acid. Reduction of the ozonide in excess DMSO
      provides a convenient method for in situ generation of a peptide aldehyde.

PMID- 10576699
TI  - Quantitation of Bacteroides forsythus in subgingival plaque comparison of
      immunoassay and quantitative polymerase chain reaction.
AB  - Our objective was to compare three methods (enzyme-linked immunosorbent assay
      [ELISA], endpoint and quantitative polymerase chain reaction [E-PCR and Q-PCR])
      for detection and quantitation of Bacteroides forsythus in 56 plaque samples from
      seven subjects with progressive periodontal disease. Samples collected in buffer
      were pelleted and resuspended in 500 microl of water. Fifty microl aliquots were
      removed for an ELISA performed on bacteria or plaque immobilized on 96-well
      plates and probed with B. forsythus specific antibody. An occurrence of 3.7+/-0.6
      x 10(4) or more bacteria were detected by ELISA in pure culture; 26 of 54 plaque
      samples were positive, two samples could not be analyzed. Samples for PCR were
      autoclaved for 10 min prior to use. The detection level of E-PCR using primers
      specific for B. forsythus 16S rRNA was 200 cells and 42 out of 56 samples were
      positive based on ethidium bromide stained agarose gels. Q-PCR using the same
      primers combined with a nested fluorescent oligonucleotide probe detected 10+/
      0.32 bacteria in pure culture; 43 of 56 plaque samples were positive. The ELISA
      and Q-PCR obtained identical results with 36 of the 54 samples assayed; there
      were one false positive and 17 false negative ELISA results using Q-PCR as
      standard. The positive proportions of plaque samples were almost the same for E
      PCR and Q-PCR. We conclude that the PCR methods are more appropriate for a
      multicenter study because of greater sensitivity and convenience of sample
      transportation from clinics to a central laboratory.

PMID- 10576700
TI  - Quantifying biofilm structure using image analysis.
AB  - We have developed and implemented methods of extracting morphological features
      from images of biofilms in order to quantify the characteristics of the inherent
      heterogeneity. This is a first step towards quantifying the relationship between
      biofilm heterogeneity and the underlying processes, such as mass-transport
      dynamics, substrate concentrations, and species variations. We have examined two
      categories of features, areal, which quantify the relative magnitude of the
      heterogeneity and textural, which quantify the microscale structure of the
      heterogeneous elements. The feature set is not exhaustive and has been restricted
      to two-dimensional images to this point. Included in this paper are the methods
      used to extract the structural information and the algorithms used to quantify
      the data. The features discussed are porosity, fractal dimension, diffusional
      length, angular second moment, inverse difference moment and textural entropy. We
      have found that some features are better predictors of biofilm behavior than
      others and we discuss possible future directions for research in this area.

PMID- 10576701
TI  - A polymerase chain reaction based method for detecting Mycoplasma/Acholeplasma
      contaminants in cell culture.
AB  - A detection system that utilizes a primer mixture in a nested polymerase chain
      reaction for detecting Mycoplasma contaminants in cell cultures is described.
      Primers were designed to amplify the spacer regions between the 16S and 23S
      ribosomal RNA genes of Mycoplasma and Acholeplasma. This detection system was
      able to detect 20-180 colony forming units per milliliter of sample. Eight
      commonly encountered Mycoplasma and Acholeplasma contaminants, which include
      Mycoplasma (M.) arginini, M. fermentans, M. hominis, M. hyorhinis, M. orale, M.
      pirum, M. salivarium, and Acholeplasma laidlawii, were consistently amplified.
      Mycoplasma contaminants generated a single DNA band of 236-365 base pairs (bp),
      whereas A. laidlawii produced a characteristic two-band pattern of 426 and 219 bp
      amplicons. Species identification could be achieved by size determination and
      restriction enzyme digestion. Minor cross-reactions were noted with a few closely
      related gram positive bacteria and DNA from rat cell lines. A Mycoplasma
      Detection Kit for detecting Mycoplasma contaminants in cell cultures has been
      developed based on this approach.

PMID- 10576702
TI  - Evaluation of a new system for the fixation, concentration, and staining of
      intestinal parasites in fecal specimens, with critical observations on the
      trichrome stain.
AB  - Proto-fix (Alpha-Tec Systems, Inc., Vancouver, WA) is a new single vial,
      environmentally safe, parasitology (pathogenic and nonpathogenic protozoans and
      helminths) fixative and transport solution. It is used in conjunction with a new
      concentration/sedimentation reagent, CONSED, (Alpha-Tec Systems, Inc. Vancouver,
      WA) as a replacement to the formalin-ethyl acetate (FEA) concentration procedure
      using Lugol's iodine. The newly adopted procedure was tested against the FEA
      concentration samples using split proficiency testing samples supplied by the
      American Association of Bioanalysts (AAB). Routinely, patient samples collected,
      fixed, and transported in Proto-Fix were processed and tested at Diagnostic Labs,
      Inc. (DLI), Phoenix, AZ. Detected parasites were documented using a video camera
      printer system attached to the optical equipment. The quality of the fixative and
      stain were found to be superior to that of the FEA-Lugol's method and the yield
      of detected parasites was considerably higher. Eighty-five percent of 39 unknown
      parasite species tested were correctly detected using the Proto-fix-CONSED system
      compared to 46% using the FEA-Lugol's method. Of all the other methods and stains
      used at DLI, the trichrome stain (a popular modification of Gomori's trichrome
      stain for tissue sections) was found to be least reliable.

PMID- 10576703
TI  - A sensitive method to detect initiation of growth in Streptococcus gordonii using
      ribosomal RNA operon-reporter gene fusions.
AB  - A system for studying the early growth response of Streptococcus gordonii to
      environmental stimuli has been developed. A reporter gene, encoding alpha
      amylase, has been integrated into an rRNA operon to monitor changes in cellular
      physiology associated with the initiation of growth. Two such strains with single
      integrants have been characterized during the transition from lag phase to
      exponential growth. Synthesis of the reporter is correlated to growth initiation
      in both strains, and the reporter enzyme is detectable with sufficient
      sensitivity. Comparison of the expression profiles of the two rrn operons
      containing the reporter gene suggests that they are differentially expressed over
      the course of growth.

PMID- 10576704
TI  - Resolution of high-molecular-weight components in lipopolysaccharides of
      Escherichia coli, Morganella morganii, Citrobacter freundii and Citrobacter
      diversus strains with sodium dodecyl sulfate polyacrylamide gels.
AB  - The use of 0.5% sodium dodecyl sulfate in polyacrylamide separation gels allowed
      the resolution in several bands of high-molecular-mass components in smooth
      lipopolysaccharide of bacterial outer membrane from Escherichia coli, Morganella
      morganii, Citrobacter freundii and Citrobacter diversus. With or without 0.1%
      SDS, however, such a result was not possible.

PMID- 10576705
TI  - Extraction and recovery of organochlorine pesticides from fungal mycelia.
AB  - An extraction method was developed to recover organochlorine pesticides (OCPs)
      associated with live and mercuric chloride-treated fungal mycelia. A Cladosporium
      sp. was inoculated into potato dextrose broth, DDT (90 mg/l) added and incubated
      for seven days. The combination of a microextraction procedure for aqueous-phase
      associated DDT and a sonication extraction for mycelia-bound DDT, using
      dichloromethane as the extracting solvent, resulted in the recovery of 31-51% of
      added DDT. DDT recovery was increased to 62-65% by grinding the fungal mycelia
      before sonication. Alkali and nitric acid pretreatments were tested to increase
      the recovery of DDT associated with fungal mycelia, however, these treatments
      resulted in the production of unidentified DDT transformation products.
      Pretreating mycelia containing DDT in concentrated hydrochloric acid at 60
      degrees C for 2, 4 and 6 h resulted in DDT recoveries of 90-91%, 99% and 101-102%
      respectively without the production of transformation products. When an OCP
      mixture (DDT, DDD and DDE) was added to fungal mycelia, between 89% and 96% of
      DDT, DDD and DDE were recovered from live cultures compared to 85-91% in mercuric
      chloride-treated cultures using the microextraction/hydrochloric acid
      pretreatment (60 degrees C/6 h) sonication extraction method.

PMID- 10576706
TI  - Miniprep DNA isolation from unicellular and filamentous cyanobacteria.
AB  - A rapid miniprep method for isolation of DNA from 12 strains of cyanobacteria
      belonging to groups I, III, IV and V is described. The protocol is a modification
      of the methods of Boyle and Lew [Boyle, J.S., Lew, A.M., 1995. An inexpensive
      alternative to glassmilk for DNA purification. Trends Genet. 11, 8] and the
      cetyltrimethyl ammonium bromide (CTAB) extraction method of Sahgai-Maroof et al.
      [Sahgai-Maroof, M.A., Soliman, K.M., Jorgensen, R.A., Allard, R.W., 1984.
      Ribosomal DNA spacer-length polymorphisms in barley: Mendelian inheritance,
      chromosomal location and population dynamics. Proc. Natl. Acad. Sci. USA 81, 8014
      80181. The new method is especially useful for obtaining cyanobacterial DNA from
      unicellular, filamentous and filamentous branched species. The method does not
      require phenol extraction and the product can be used directly for PCR
      amplification and restriction digestion.

PMID- 10576707
TI  - A simple, rapid and non-destructive procedure to extract cell wall-associated
      proteins from Frankia.
AB  - A simple cell fractionation procedure was developed to extract cell wall
      associated proteins from the nitrogen-fixing actinomycete Frankia. The method was
      based on washing Frankia mycelia in 62.5 mM Tris-HCl (pH 6.8) buffer supplemented
      with 0.1% Triton X-100 as solubilizing agent. Cell wall-associated proteins were
      efficiently extracted in less than 10 min, recovering approximately 94.5+/-7.44
      microg protein per extraction procedure from exponentially growing cells
      corresponding to 50 ml of culture. The amount of cell lysis occurring during the
      cell wall extraction was estimated to be 1.50+/-0.51%. Three peptidoglycan
      hydrolases with apparent molecular masses of 4.7, 12.1, and 17.8 kDa were
      detected by zymography in the cell wall-associated protein fraction. On the
      contrary, no cell wall lytic enzyme was detected in the cytoplasmic protein
      fraction. These results indicate that the present method enables a specific
      extraction of cell wall-associated proteins. Moreover, fluorescein isothiocyanate
      (FITC) labelling of the cell surface proteins showed an efficient removal of cell
      wall-associated proteins. Growth of the treated Frankia cells (i.e. cells from
      which the cell wall-associated proteins were removed) in semi-solid media
      suggested that these cells were still viable. This technique is of importance for
      functionality studies of cell wall-associated proteins, particularly for bacteria
      where traditional cell fractionation methods are difficult to be applied.

PMID- 10576708
TI  - Functional MRI of the human motor cortex using single-shot, multiple gradient
      echo spiral imaging.
AB  - In this study, we combined the advantages of a fast multi-slice spiral imaging
      approach with a multiple gradient-echo sampling scheme at high magnetic field
      strength to improve quantification of BOLD and inflow effects and to estimate T2*
      relaxation times in functional brain imaging. Eight echoes are collected with
      echo time (TE) ranging from 5 to 180 ms. Acquisition time per slice and echo time
      is 25 ms for a nominal resolution of 4 x 4 x 4 mm3. Evaluation of parameter
      images during rest and stimulation yields no significant activation on the inflow
      sensitive spin-density images (rho or I0-maps) whereas clear activation patterns
      in primary human motor cortex (M1) and supplementary motor area (SMA) are
      detected on BOLD sensitive T2*-maps. The calculation of relaxation times and
      rates of the activated areas over all subjects yields an average T2* +/- standard
      deviation (SD) of 46.1+/-4.5 ms (R2* of 21.8+/-2.2 s(-1)) and an average increase
      (deltaT2* +/- SD) of 0.93+/-0.47 ms (deltaR2* of -0.4+/-0.14 s(-1)). Our findings
      demonstrate the usefulness of a multiple gradient echo data acquisition approach
      in separating various vascular contributions to brain activation in fMRI.

PMID- 10576709
TI  - Choledocolithiasis: diagnostic accuracy of MR cholangiopancreatography. Three
      year experience.
AB  - The purpose of this study was to evaluate the diagnostic accuracy of MR
      cholangiopancreatography (MRCP) in the detection of common bile duct stones. A
      series of 286 consecutive patients were referred for MRCP, that was performed
      with a 1.5 T MR unit, through a non-breath-hold, respiratory-triggered, fat
      suppressed, two-dimensional, heavily T2-weighted fast spin-echo sequence in the
      coronal plane. Axial T1 and T2-weighted sequences were first obtained. Axial,
      coronal, and Maximum Intensity Projection images were evaluated by three
      independent readers, who were asked to determine whether stones were present or
      not inside the biliary tract. The findings of MRCP images were compared with
      endoscopic retrograde cholangiopancreatography, percutaneous trans-hepatic
      cholangiography, intra-operative cholangiography, surgical, or imaging follow-up
      findings. Two-hundred and seventy-eight out of 286 MRCP examinations were judged
      diagnostic by the three reviewers. Among the 278 patients included in our study
      group, biliary tract lithiasis was proved in 76 cases (27%). On the basis of
      reviewers' reading, MRCP had sensitivity 92-93%, specificity 97-98%, positive
      predictive value 91-93%, negative predictive value 97-98%, and the diagnostic
      accuracy ranged between 95% and 96% in the detection of calculi. Interobserver
      agreement was excellent (K = 0.84, kappa statistic). MRCP showed a high
      diagnostic accuracy and an excellent inter-observer agreement in the detection of
      common bile duct stones.

PMID- 10576710
TI  - Magnetic resonance cholangiopancreatography: comparison between respiratory
      triggered turbo spin echo and breath hold single-shot turbo spin echo sequences.
AB  - The purpose of this study was to compare the relative conspicuity of the
      pancreaticobiliary tree on respiratory-triggered three-dimensional turbo spin
      echo (3D TSE RT) and breath hold single-shot turbo spin echo (SSTSE BH)
      acquisitions respectively in MRCP imaging. Both techniques were applied to 61
      patients with clinically suspected pancreaticobiliary disease using a 1.0 T MR
      system. All images were reviewed blindly. Qualitative comparison was made by
      grading subjectively the conspicuity of extrahepatic, intrahepatic, and main
      pancreatic ducts. Quantitative comparison included calculations of signal-to
      noise ratio of the common bile duct, main pancreatic duct, gallbladder, liver,
      and contrast-to-noise ratio, relative contrast between common bile duct,
      gallbladder, and liver. 3D TSE RT provided significantly higher signal-to-noise
      ratio of the common bile duct (mean value 163.19) and main pancreatic duct (mean
      value 95.37) compared to SSTSE BH (mean values 76.24 and 26.22, respectively). 3D
      TSE RT was inferior to SSTSE BH for the depiction of intrahepatic ducts and
      pancreatic duct (head portion). 3D TSE RT and SSTSE BH sequences provide
      complimentary information in the visualization of the biliary and pancreatic
      ducts. Further comparative clinical studies are needed to redefine the
      sensitivity, specificity, and accuracy of MRCP using both sequences.

PMID- 10576711
TI  - Distinct patterns of active and non-active plaques using texture analysis on
      brain NMR images in multiple sclerosis patients: preliminary results.
AB  - The benefits of texture analysis of magnetic resonance images have been assessed
      in multiple sclerosis (MS) patients. Out of thirty-two lesions identified in
      eight MS patients, nine were considered active, judging from their gadolinium
      uptake. Texture analysis allowed to obtain forty-two characterizing parameters
      for each lesion. Using discriminant analysis as a statistical method allowed to
      classify the lesions into two groups: active or non-active. An attempt to
      classify their level of activity by using only co-occurrence matrices was
      unsuccessful. Alternately, the same type of analysis performed on runlength
      analysis criteria allowed the accurate classification of 88% of active lesions
      and 96% of non-active lesions. Using incremental discriminate analysis can reduce
      the number of useful parameters. This method showed that among the 42 parameters,
      8 only were highly significant and permitted an accurate classification. Five of
      these parameters are runlength parameters, and three others are more directly
      related to the global distribution. The main interest of runlength parameters is
      that they allowed to demonstrate that the lesion structure was different in
      active and non-active plaques. This preliminary work suggests that using texture
      analysis could be of interest in the follow-up of MS patients because it provides
      an opportunity to identify active lesions without frequent gadolinium injections.

PMID- 10576712
TI  - Reduced anisotropy of water diffusion in structural cerebral abnormalities
      demonstrated with diffusion tensor imaging.
AB  - We used diffusion tensor imaging (DTI) to investigate the behavior of water
      diffusion in cerebral structural abnormalities. The fractional anisotropy, a
      measure of directionality of the molecular motion of water, and the mean
      diffusivity, a measure of the magnitude of the molecular motion of water, were
      measured in 18 patients with longstanding partial epilepsy and structural
      abnormalities on standard magnetic resonance imaging and the results compared
      with measurements in the white matter of 10 control subjects. Structural
      abnormalities were brain damage (postsurgical brain damage, nonspecific brain
      damage, perinatal brain damage, perinatal infarct, ischemic infarct, perinatal
      hypoxia, traumatic brain damage (n = 3), mitochondrial cytopathy and
      mesiotemporal sclerosis), dysgenesis (cortical dysplasia (n = 2) and heterotopia)
      and tumors (meningioma (n = 2), hypothalamic hamartoma and glioma). Anisotropy
      was reduced in all structural abnormalities. In the majority of abnormalities
      this was associated with an increased mean diffusivity; however, 30% of all
      structural abnormalities (some patients with brain damage and dysgenesis) had a
      normal mean diffusivity in combination with a reduced anisotropy. There was no
      correlation between fractional anisotropy and mean diffusivity measurements in
      structural abnormalities (r = -0.1). Our findings suggest that DTI is sensitive
      for the detection of a variety of structural abnormalities, that a reduced
      anisotropy is the common denominator in structural cerebral abnormalities of
      different etiologies and that mean diffusivity and fractional anisotropy may be,
      in part, independent. Combined measurements of mean diffusivity and fractional
      anisotropy are likely to increase the specificity of DTI.

PMID- 10576713
TI  - MR assessment of the brain maturation during the perinatal period: quantitative
      T2 MR study in premature newborns.
AB  - The purpose of our study is to trace in vivo and during the perinatal period, the
      brain maturation process with exhaustive measures of the T2 relaxation time
      values. We also compared regional myelination progress with variations of the
      relaxation time values and of brain signal. T2 relaxation times were measured in
      7 healthy premature newborns at the post-conceptional age of 37 weeks, using a
      Carr-Purcell-Meiboom-Gill sequence (echo time 60 to 150 ms), on a 2.35 Tesla
      Spectro-Imaging MR system. A total of 62 measures were defined for each subject
      within the brain stem, the basal ganglia and the hemispheric gray and white
      matter. The mean and standard deviation of the T2 values were calculated for each
      location. Regional T2 values changes and brain signal variations were studied. In
      comparison to the adult ones, the T2 relaxation time values of both gray and
      white matter were highly prolonged and a reversed ratio between gray and white
      matter was found. The maturational phenomena might be regionally correlated with
      a T2 value shortening. Significant T2 variations in the brainstem (p < 0.02), the
      mesencephalon (p < 0.05), the thalami (p < 0.01), the lentiform nuclei (p < 0.01)
      and the caudate nuclei (p < 0.02) were observed at an earlier time than they were
      visible on T2-weighted images. In the cerebral hemispheres, T2 values increased
      from the occipital white matter to parietal, temporal and frontal white matter (p
      < 0.05) and in the frontal and occipital areas from periventricular to
      subcortical white matter (p < 0.01). Maturational progress was earlier and better
      displayed with T2 measurements and T2 mapping. During the perinatal period, the
      measurements and analysis of T2 values revealed brain regional differences not
      discernible with T2-weighted images. It might be a more sensitive indicator for
      assessment of brain maturation.

PMID- 10576714
TI  - Cerebral tissue water spin-spin relaxation times in human neonates at 2.4 tesla:
      methodology and the effects of maturation.
AB  - Using a 4-echo spin-echo sequence, cerebral T2 was measured in specific anatomic
      regions in eleven healthy newborn infants, whose gestational plus postnatal ages
      (GPAs) lay between 37 and 42 weeks. For a region in the pons, T2 was 141+/-9 ms
      (mean +/- standard deviation), and no significant dependence upon GPA was seen.
      In the thalamus mean T2 was 136+/-13 ms, and T2 demonstrated a significant
      negative linear dependence upon age (r = 0.690; p < 0.02). In periventricular and
      frontal regions, mean T2 were 217+/-33, and 228+/-32 ms respectively, and more
      marked negative linear correlations with age were observed (r = 0.833; p < 0.001
      and r = 0.722; p < 0.02). For these regions, the rate of T2 decrease with age
      appeared to be related to known patterns of myelination. For the parietal region
      studied, mean T2 was 204+/-34 ms, no significant dependence upon GPA being seen.
      T2 shows promise as an objective measure of cerebral development in the perinatal
      period.

PMID- 10576716
TI  - Flow and oxygenation dependent (FLOOD) contrast MR imaging to monitor the
      response of rat tumors to carbogen breathing.
AB  - Gradient recalled echo (GRE) images are sensitive to both paramagnetic
      deoxyhaemoglobin concentration (via T2*) and flow (via T1*). Large GRE signal
      intensity increases have been observed in subcutaneous tumors during carbogen (5%
      carbon dioxide, 95% oxygen) breathing. We term this combined effect flow and
      oxygenation-dependent (FLOOD) contrast. We have now used both spin echo (SE) and
      GRE images to evaluate how changes in relaxation times and flow contribute to
      image intensity contrast changes. T1-weighted images, with and without outer
      slice suppression, and calculated T2, T2* and "flow" maps, were obtained for
      subcutaneous GH3 prolactinomas in rats during air and carbogen breathing. T1
      weighted images showed bright features that increased in size, intensity and
      number with carbogen breathing. H&E stained histological sections confirmed them
      to be large blood vessels. Apparent T1 and T2 images were fairly homogeneous with
      average relaxation times of 850 ms and 37 ms, respectively, during air breathing,
      with increases of 2% for T1 and 11% for T2 during carbogen breathing. The
      apparent T2* over all tumors was very heterogeneous, with values between 9 and 23
      ms and localized increases of up to 75% during carbogen breathing. Synthesised
      "flow" maps also showed heterogeneity, and regions of maximum increase in flow
      did not always coincide with maximum increases in T2*. Carbogen breathing caused
      a threefold increase in arterial rat blood PaO2, and typically a 50% increase in
      tumor blood volume as measured by 51Cr-labelled RBC uptake. The T2* increase is
      therefore due to a decrease in blood deoxyhaemoglobin concentration with the
      magnitude of the FLOOD response being determined by the vascular density and
      responsiveness to blood flow modifiers. FLOOD contrast may therefore be of value
      in assessing the magnitude and heterogeneity of response of individual tumors to
      blood flow modifiers for both chemotherapy, antiangiogenesis therapy in
      particular, and radiotherapy.

PMID- 10576715
TI  - Dynamic contrast-enhanced MRI of Implanted VX2 tumors in rabbit muscle:
      comparison of Gd-DTPA and NMS60.
AB  - We studied the dynamics of injected contrast enhancement in implanted VX2 tumors
      in rabbit thigh muscle. We compared two contrast agents Gd-DTPA and NMS60, a
      novel gadolinium containing trimer of molecular weight 2.1 kd. T1-weighted spin
      echo images were acquired preinjection and at 5-60 min after i.v. injection of
      0.1 mmol/kg of agent. Dynamic T1-weighted SPGR images (1.9 s/image) were acquired
      during the bolus injection. Male NZW rabbits (n = 13) were implanted with
      approximately 2 x 10(6) VX2 tumor cells and grew tumors of 28+/-27 mL over 12 to
      21 days. NMS60 showed significantly greater peak enhancement in muscle, tumor
      rim, and core compared to DTPA in both T1-weighted and SPGR images. NMS60 also
      showed delayed peak enhancement in the dynamic scans (compared to Gd-DTPA) and
      significantly reduced leakage rate constant into the extravascular space for
      tumor rim (K21 = 5.1 min(-1) vs. 11.5 min(-1) based on a 2 compartment kinetic
      model). The intermediate weight contrast agent NMS60 offers greater tumor
      enhancement than Gd-DTPA and may offer improved regional differentiation on the
      basis of vascular permeability in tumors.

PMID- 10576717
TI  - In vivo measurements of multi-component T2 relaxation behaviour in guinea pig
      brain.
AB  - Multi-echo Carr-Purcell-Meiboom-Gill (CPMG) imaging sequences were implemented on
      1.5 T and 4.0 T imaging systems to test their ability to measure in vivo multi
      component T2 relaxation behavior in normal guinea pig brain. The known dependence
      of accurate T2 measurements on the signal-to-noise ratio (SNR) was explored in
      vivo by comparing T2 decay data obtained using three methods to increase SNR
      (improved RF coil design, signal averaging and increased magnetic field
      strength). Good agreement between T2 values of nickel-doped agarose phantoms was
      found between imaging and spectroscopic methods. T2 values were determined for
      gray matter (GM) and white matter (WM) locations from images of guinea pig brain
      in vivo. T2 measurements of GM were found to be monoexponential at both field
      strengths. The mean T2 times for GM were 71 ms at 1.5 T, and 53 ms at 4.0T. The
      highest average SNR was achieved using an improved RF coil at 4.0T. In this case,
      two peaks were extracted in WM, a "short" T2 peak at approximately 6 ms, and a
      "medium" T2 peak at approximately 48 ms. T2 values in GM and the major component
      of WM were significantly decreased at 4.0T compared to 1.5 T. The improved SNR
      attained with this optimized imaging protocol at 4.0T has allowed for the first
      time extraction of the myelin-sensitive T2 component of WM in animal brain in
      vivo.

PMID- 10576718
TI  - Magnetic resonance imaging in the evaluation of inflammatory lesions in muscular
      and soft tissues: an experimental infection model induced by Candida albicans.
AB  - We have developed an experimental model to monitor inflammatory lesions in muscle
      and soft-tissues during the different stages of the disease by means of Magnetic
      Resonance Imaging (MRI). MRI of mice legs infected with Candida albicans was
      performed by standard two-dimensional spin echo and fast spin echo (RARE) using
      customized coils. The MRI findings were compared with pathologic examinations at
      the initial acute and established acute inflammatory stages, which provided
      accurate and detailed information on the evolution of the processes involved. The
      yeast caused inflammation within the first hours post-inoculation, appearing on
      T2-weighted images as an inhomogeneous mass with increased signal intensity. The
      presence of fungal hyphae was observed as hypointense signal areas in both T2 and
      T1 weighted images, with histologic confirmation. Areas of decreased signal
      intensity on T2 weighted images were apparent on the last experimental day and
      were attributed to the granulation tissue located within the capsule surrounding
      the abscess. The close correlation found between MRI and histopathology suggests
      that MRI is an ideal radiologic technique for monitoring the clinical and
      therapeutic follow-up of fungal infections in muscle and soft tissues.

PMID- 10576720
TI  - Two-point method for T1 estimation with optimized gradient-echo sequence.
AB  - Relaxation times estimation methods play a central role in various problems, such
      as magnetic resonance (MR) hardware calibration, tissue characterization, or
      temperature measurement. Previous studies have proposed optimization criteria to
      estimate the relaxation time T1 faster than with a multipoint method leading to
      two-point methods. In this paper, the class of optimized two-point methods is
      extended to gradient-echo (GE) sequence offering new advantages over spin-echo
      (SE) or inversion recovery (IR) sequences. Two GE acquisitions, with optimal flip
      angles theta1 and theta2 minimizing both the total scan time and the variance in
      the computed T1 image were applied to estimate T1, and the results were compared
      with those of SE sequence with optimized paired repetition times T(R1) and T(R2).
      First, phantom studies were carried out with five tissue-like samples on a 0.5T
      scanner. Then in vivo, human brain T1 image were calculated using both optimized
      GE and SE two-point methods. More precise T1 GE estimates than those for SE were
      found thanks to high signal-to-noise ratio (SNR) per unit of time, but with a
      small bias. These results also concern the temperature variation measurement
      methods, based on T1 estimation. Preliminary experimental data for temperature
      measurement are given.

PMID- 10576719
TI  - Mapping eddy current induced fields for the correction of diffusion-weighted echo
      planar images.
AB  - Diffusion-weighted echo-planar magnetic resonance imaging is potentially of great
      importance as a diagnostic imaging tool; however, the technique currently suffers
      a number of limitations, including the image distortion caused by the eddy
      current induced fields when the diffusion-weighting magnetic field gradient
      pulses are applied. The distortions cause mis-registration between images with
      different diffusion-weighting, that then results in artifacts in quantitative
      diffusion images. A method is presented to measure the magnetic fields generated
      from the eddy currents for each of three orthogonal gradient pulse vectors, and
      then to use these to ascertain the image distortion that occurs in subsequent
      diffusion-weighted images with arbitrary gradient pulse vector amplitude and
      direction, and image plane orientation. The image distortion can then be
      reversed. Both temporal and spatial dependence of the residual eddy current
      induced fields are included in the analysis. Image distortion was substantially
      reduced by the correction scheme, for arbitrary slice position and angulation.
      This method of correction is unaffected by the changes in image contrast that
      occur due to diffusion weighting, and does not need any additional scanning time
      during the patient scan. It is particularly suitable for use with single-shot
      echo planar imaging.

PMID- 10576721
TI  - MRI image plane nonuniformity in evaluation of ferrous sulphate dosimeter gel
      (FeGel) by means of T1-relaxation time.
AB  - MR image nonuniformity can vary significantly with the spin-echo pulse sequence
      repetition time. When MR images with different nonuniformity shapes are used in a
      T1-calculation the resulting T1-image becomes nonuniform. As shown in this work
      the uniformity TR-dependence of the spin-echo pulse sequence is a critical
      property for T1 measurements in general and for ferrous sulfate dosimeter gel
      (FeGel) applications in particular. The purpose was to study the characteristics
      of the MR image plane nonuniformity in FeGel evaluation. This included studies of
      the possibility of decreasing nonuniformities by selecting uniformity optimized
      repetition times, studies of the transmitted and received RF-fields and studies
      of the effectiveness of the correction methods background subtraction and
      quotient correction. A pronounced MR image nonuniformity variation with
      repetition and T1 relaxation time was observed, and was found to originate from
      nonuniform RF-transmission in combination with the inherent differences in T1
      relaxation for different repetition times. The T1 calculation itself, the
      uniformity optimized repetition times, nor none of the correction methods studied
      could sufficiently correct the nonuniformities observed in the T1 images. The
      nonuniformities were found to vary considerably less with inversion time for the
      inversion-recovery pulse sequence, than with repetition time for the spin-echo
      pulse sequence, resulting in considerably lower T1 image nonuniformity levels.

PMID- 10576722
TI  - Post-registration spatial filtering to reduce noise in functional MRI data sets.
AB  - Image registration is commonly performed in the analysis of functional magnetic
      resonance imaging data sets. However, the nature of artifacts introduced in the
      process of alignment has not been well described. In this manuscript, high
      frequency losses inherent in image registration are discussed, together with a
      conceptual division into acquisition- and resampling-related artifacts. Simulated
      and experimental data are presented to illustrate these artifacts. In simulations
      comparing corrected and reference images, root mean square (RMS) difference
      errors of 0.74% and 2.62% were observed following the correction of one degree of
      rotation for images registered with frequency regridding and bilinear
      interpolation, respectively. In human experiments, regression of RMS difference
      error as a percentage of mean brain signal yielded slopes of 0.69 to 1.31% per
      degree corrected by regridding. A post-registration spatial filtering technique
      is presented to reduce noise introduced during registration by selectively
      attenuating high frequencies near the corners of k-space. Filtering following
      regridding resulted in reductions in RMS error of 49.6% for simulated data and of
      17.4% to 32.5% in human experiments, demonstrating the effectiveness of the
      filtering technique.

PMID- 10576723
TI  - Restoration of MR-induced artifacts in simultaneously recorded MR/EEG data.
AB  - During a Magnetic Resonance sequence, simultaneously acquired
      ElectroEncephaloGraphy (EEG) data are compromised by severe pollution due to
      artifacts originating from the switching of the magnetic field gradients. In this
      work, it is shown how these artifacts can be strongly reduced or even removed
      through application of an adaptive artifact restoration scheme. The method has
      proved to be fully automatic and to retain high frequency EEG information, which
      is indispensable for many EEG applications.

PMID- 10576724
TI  - Comparison of automated and visual texture analysis in MRI: characterization of
      normal and diseased skeletal muscle.
AB  - Automated magnetic resonance imaging (MRI) texture analysis was compared with
      visual MRI analysis for the diagnosis of skeletal muscle dystrophy in 14 healthy
      and 17 diseased subjects. MRI texture analysis was performed on 8 muscle regions
      of interest (ROI) using four statistical methods (histogram, co-occurrence
      matrix, gradient matrix, runlength matrix) and one structural (mathematical
      morphology) method. Nine senior radiologists assessed full leg transverse slice
      images and proposed a diagnosis. The 59 extracted texture parameters for each ROI
      were statistically analyzed by Correspondence Factorial Analysis. Non-parametric
      tests were used to compare diagnoses based on automated texture analysis and
      visual analysis. Texture analysis methods discriminated between healthy
      volunteers and patients with a sensitivity of 70%, and a specificity of 86%.
      Comparison with visual analysis of MR images suggests that texture analysis can
      provide useful information contributing to the diagnosis of skeletal muscle
      disease.

PMID- 10576725
TI  - MRI appearance of cervical incompetence in a pregnant patient.
AB  - Ultrasonography is currently the principal imaging modality for diagnosing
      cervical incompetence during pregnancy. Various technical factors, both patient
      and technologist/transducer related, may limit its evaluation for cervical
      incompetence. MRI is not dependent on these technical considerations. MRI may
      demonstrate a higher degree of soft tissue contrast than ultrasonography for
      depicting uterine anatomy. MRI may, in some instances, be more accurate in
      depicting cervical incompetence in the gravid patient. We present the first case
      of cervical incompetence in a pregnant patient diagnosed by MRI, in which
      ultrasonography failed to provide conclusive evidence of extra-uterine herniation
      of the amniotic sac.

PMID- 10576726
TI  - Relating to classification and etiology of Chiari I malformation.

PMID- 10576727
TI  - Interacting minds--a biological basis.
AB  - The ability to "mentalize," that is to understand and manipulate other people's
      behavior in terms of their mental states, is a major ingredient in successful
      social interactions. A rudimentary form of this ability may be seen in great
      apes, but in humans it is developed to a high level. Specific impairments of
      mentalizing in both developmental and acquired disorders suggest that this
      ability depends on a dedicated and circumscribed brain system. Functional imaging
      studies implicate medial prefrontal cortex and posterior superior temporal sulcus
      (STS) as components of this system. Clues to the specific function of these
      components in mentalizing come from single cell recording studies: STS is
      concerned with representing the actions of others through the detection of
      biological motion; medial prefrontal regions are concerned with explicit
      representation of states of the self. These observations suggest that the ability
      to mentalize has evolved from a system for representing actions.

PMID- 10576728
TI  - The male determinant of self-incompatibility in Brassica.
AB  - In the S locus-controlled self-incompatibility system of Brassica, recognition of
      self-related pollen at the surface of stigma epidermal cells leads to inhibition
      of pollen tube development. The female (stigmatic) determinant of this
      recognition reaction is a polymorphic transmembrane receptor protein kinase
      encoded at the S locus. Another highly polymorphic, anther-expressed gene, SCR,
      also encoded at the S locus, fulfills the requirements for the hypothesized
      pollen determinant. Loss-of-function and gain-of-function studies prove that the
      SCR gene product is necessary and sufficient for determining pollen self
      incompatibility specificity, possibly by acting as a ligand for the stigmatic
      receptor.

PMID- 10576729
TI  - Molecular architecture of the rotary motor in ATP synthase.
AB  - Adenosine triphosphate (ATP) synthase contains a rotary motor involved in
      biological energy conversion. Its membrane-embedded F0 sector has a rotation
      generator fueled by the proton-motive force, which provides the energy required
      for the synthesis of ATP by the F1 domain. An electron density map obtained from
      crystals of a subcomplex of yeast mitochondrial ATP synthase shows a ring of 10 c
      subunits. Each c subunit forms an alpha-helical hairpin. The interhelical loops
      of six to seven of the c subunits are in close contact with the gamma and delta
      subunits of the central stalk. The extensive contact between the c ring and the
      stalk suggests that they may rotate as an ensemble during catalysis.

PMID- 10576730
TI  - First-principles determination of elastic anisotropy and wave velocities of MgO
      at lower mantle conditions
AB  - The individual elastic constants of magnesium oxide (MgO) have been determined
      throughout Earth's lower mantle (LM) pressure-temperature regime with density
      functional perturbation theory. It is shown that temperature effects on seismic
      observables (density, velocities, and anisotropy) are monotonically suppressed
      with increasing pressure. Therefore, at realistic LM conditions, the isotropic
      wave velocities of MgO remain comparable to seismic velocities, as previously
      noticed in athermal high-pressure calculations. Also, the predicted strong
      pressure-induced anisotropy is preserved toward the bottom of the LM, so lattice
      preferred orientations in MgO may contribute substantially to the observed
      seismic anisotropy in the D" layer.

PMID- 10576731
TI  - Core rotational dynamics and geological events
AB  - A study of Earth's fluid core oscillations induced by lunar-solar tidal forces,
      together with tidal secular deceleration of Earth's axial rotation, shows that
      the rotational eigenfrequency of the fluid core and some solar tidal waves were
      in resonance around 3.0 x 10(9), 1.8 x 10(9), and 3 x 10(8) years ago. The
      associated viscomagnetic frictional power at the core boundaries may be converted
      into heat and would destabilize the D" thermal layer, leading to the generation
      of deep-mantle plumes, and would also increase the temperature at the fluid core
      boundaries, perturbing the core dynamo process. Such phenomena could account for
      large-scale episodes of continental crust formation, the generation of flood
      basalts, and abrupt changes in geomagnetic reversal frequency.

PMID- 10576732
TI  - Eight centuries of north atlantic ocean atmosphere variability
AB  - Climate in the tropical North Atlantic is controlled largely by variations in the
      strength of the trade winds, the position of the Intertropical Convergence Zone,
      and sea surface temperatures. A high-resolution study of Caribbean sediments
      provides a subdecadally resolved record of tropical upwelling and trade wind
      variability spanning the past 825 years. These results confirm the importance of
      a decadal (12- to 13-year) mode of Atlantic variability believed to be driven by
      coupled tropical ocean-atmosphere dynamics. Although a well-defined interdecadal
      mode of variability does not appear to be characteristic of the tropical
      Atlantic, there is evidence that century-scale variability is substantial. The
      tropical Atlantic may also have been involved in a major shift in Northern
      Hemisphere climate variability that took place about 700 years ago.

PMID- 10576733
TI  - van der waals interactions in the Cl + HD reaction
AB  - The van der Waals forces in the entrance valley of the Cl + HD reaction are shown
      here to play a decisive role in the reaction's dynamics. Exact quantum mechanical
      calculations of reactive scattering on a potential energy surface without Cl-HD
      van der Waals forces predict that the HCl and DCl products will be produced
      almost equally, whereas the same calculations on a new ab initio potential energy
      surface with van der Waals forces show a strong preference for the production of
      DCl. This preference is also seen in crossed molecular beam experiments on the
      reaction. The study of chemical reaction dynamics has now advanced to the stage
      where even comparatively weak van der Waals interactions can no longer be
      neglected in calculations of the potential energy surfaces of chemical reactions.

PMID- 10576734
TI  - Ordered bicontinuous nanoporous and nanorelief ceramic films from self assembling
      polymer precursors
AB  - Three-dimensional ceramic nanostructured films were produced from silicon
      containing triblock copolymer films exhibiting the double gyroid and inverse
      double gyroid morphologies (space group Ia3d). A one-step room-temperature
      oxidation process that used ozonolysis and ultraviolet irradiation effected both
      the selective removal of the hydrocarbon block and the conversion of the silicon
      containing block to a silicon oxycarbide ceramic stable to 400 degrees C.
      Depending on the relative volume fraction of the hydrocarbon block to the silicon
      containing block, either nanoporous or nanorelief structures were fabricated
      with calculated interfacial areas of approximately 40 square meters per gram and
      pore or strut sizes of approximately 20 nanometers.

PMID- 10576735
TI  - Single-bond formation and characterization with a scanning tunneling microscope
AB  - A scanning tunneling microscope (STM) was used to manipulate the bonding of a
      carbon monoxide (CO) molecule and to analyze the structure and vibrational
      properties of individual products. Individual iron (Fe) atoms were evaporated and
      coadsorbed with CO molecules on a silver (110) surface at 13 kelvin. A CO
      molecule was transferred from the surface to the STM tip and bonded with an Fe
      atom to form Fe(CO). A second CO molecule was similarly transferred and bonded
      with Fe(CO) to form Fe(CO)(2). Controlled bond formation and characterization at
      the single-bond level probe chemistry at the spatial limit.

PMID- 10576736
TI  - Mechanical rotation of the c subunit oligomer in ATP synthase (F0F1): direct
      observation.
AB  - F0F1, found in mitochondria or bacterial membranes, synthesizes adenosine 5'
      triphosphate (ATP) coupling with an electrochemical proton gradient and also
      reversibly hydrolyzes ATP to form the gradient. An actin filament connected to a
      c subunit oligomer of F0 was able to rotate by using the energy of ATP
      hydrolysis. The rotary torque produced by the c subunit oligomer reached about 40
      piconewton-nanometers, which is similar to that generated by the gamma subunit in
      the F1 motor. These results suggest that the gamma and c subunits rotate together
      during ATP hydrolysis and synthesis. Thus, coupled rotation may be essential for
      energy coupling between proton transport through F0 and ATP hydrolysis or
      synthesis in F1.

PMID- 10576737
TI  - Visualization of dioxygen bound to copper during enzyme catalysis.
AB  - X-ray crystal structures of three species related to the oxidative half of the
      reaction of the copper-containing quinoprotein amine oxidase from Escherichia
      coli have been determined. Crystals were freeze-trapped either anaerobically or
      aerobically after exposure to substrate, and structures were determined to
      resolutions between 2.1 and 2.4 angstroms. The oxidation state of the quinone
      cofactor was investigated by single-crystal spectrophotometry. The structures
      reveal the site of bound dioxygen and the proton transfer pathways involved in
      oxygen reduction. The quinone cofactor is regenerated from the iminoquinone
      intermediate by hydrolysis involving Asp383, the catalytic base in the reductive
      half-reaction. Product aldehyde inhibits the hydrolysis, making release of
      product the rate-determining step of the reaction in the crystal.

PMID- 10576738
TI  - A breakdown of Brassica self-incompatibility in ARC1 antisense transgenic plants.
AB  - Self-incompatibility, the rejection of self pollen, is the most widespread
      mechanism by which flowering plants prevent inbreeding. In Brassica, the S
      receptor kinase (SRK) has been implicated in the self-incompatibility response,
      but the molecular mechanisms involving SRK are unknown. One putative downstream
      effector for SRK is ARC1, a protein that binds to the SRK kinase domain. Here it
      is shown that suppression of ARC1 messenger RNA levels in the self-incompatible
      Brassica napus W1 line is correlated with a partial breakdown of self
      incompatibility, resulting in seed production. This provides strong evidence that
      ARC1 is a positive effector of the Brassica self-incompatibility response.

PMID- 10576739
TI  - Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme.
AB  - The hallmark of rheumatoid arthritis (RA) is specific destruction of the synovial
      joints. In a mouse line that spontaneously develops a disorder with many of the
      features of human RA, disease is initiated by T cell recognition of a
      ubiquitously expressed self-antigen; once initiated, pathology is driven almost
      entirely by immunoglobulins. In this study, the target of both the initiating T
      cells and pathogenic immunoglobulins was identified as glucose-6-phosphate
      isomerase, a glycolytic enzyme. Thus, some forms of RA or related arthritides may
      develop by a mechanism fundamentally different from the currently popular
      paradigm of a joint-specific T cell response.

PMID- 10576740
TI  - Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses,
      leukocyte homeostasis, and to preclude autoimmunity.
AB  - Apoptosis can be triggered by members of the Bcl-2 protein family, such as Bim,
      that share only the BH3 domain with this family. Gene targeting in mice revealed
      important physiological roles for Bim. Lymphoid and myeloid cells accumulated, T
      cell development was perturbed, and most older mice accumulated plasma cells and
      succumbed to autoimmune kidney disease. Lymphocytes were refractory to apoptotic
      stimuli such as cytokine deprivation, calcium ion flux, and microtubule
      perturbation but not to others. Thus, Bim is required for hematopoietic
      homeostasis and as a barrier to autoimmunity. Moreover, particular death stimuli
      appear to activate apoptosis through distinct BH3-only proteins.

PMID- 10576741
TI  - Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt.
AB  - Extracellular signals often result in simultaneous activation of both the Raf-MEK
      ERK and PI3K-Akt pathways (where ERK is extracellular-regulated kinase, MEK is
      mitogen-activated protein kinase or ERK kinase, and PI3K is phosphatidylinositol
      3-kinase). However, these two signaling pathways were shown to exert opposing
      effects on muscle cell hypertrophy. Furthermore, the PI3K-Akt pathway was shown
      to inhibit the Raf-MEK-ERK pathway; this cross-regulation depended on the
      differentiation state of the cell: Akt activation inhibited the Raf-MEK-ERK
      pathway in differentiated myotubes, but not in their myoblast precursors. The
      stage-specific inhibitory action of Akt correlated with its stage-specific
      ability to form a complex with Raf, suggesting the existence of differentially
      expressed mediators of an inhibitory Akt-Raf complex.

PMID- 10576742
TI  - Phosphorylation and regulation of Raf by Akt (protein kinase B).
AB  - Activation of the protein kinase Raf can lead to opposing cellular responses such
      as proliferation, growth arrest, apoptosis, or differentiation. Akt (protein
      kinase B), a member of a different signaling pathway that also regulates these
      responses, interacted with Raf and phosphorylated this protein at a highly
      conserved serine residue in its regulatory domain in vivo. This phosphorylation
      of Raf by Akt inhibited activation of the Raf-MEK-ERK signaling pathway and
      shifted the cellular response in a human breast cancer cell line from cell cycle
      arrest to proliferation. These observations provide a molecular basis for cross
      talk between two signaling pathways at the level of Raf and Akt.

PMID- 10576743
TI  - Building neural representations of habits.
AB  - Memories for habits and skills ("implicit or procedural memory") and memories for
      facts ("explicit or episodic memory") are built up in different brain systems and
      are vulnerable to different neurodegenerative disorders in humans. So that the
      striatum-based mechanisms underlying habit formation could be studied, chronic
      recordings from ensembles of striatal neurons were made with multiple tetrodes as
      rats learned a T-maze procedural task. Large and widely distributed changes in
      the neuronal activity patterns occurred in the sensorimotor striatum during
      behavioral acquisition, culminating in task-related activity emphasizing the
      beginning and end of the automatized procedure. The new ensemble patterns
      remained stable during weeks of subsequent performance of the same task. These
      results suggest that the encoding of action in the sensorimotor striatum
      undergoes dynamic reorganization as habit learning proceeds.

PMID- 10576744
TI  - [The concept of "certainty" in science].

PMID- 10576745
TI  - [Quality assessment of drug use in the elderly].
AB  - INTRODUCTION: The objective is to evaluate the quality of medication utilization
      through the analysis of the pattern of usage, the degree of compliance to
      essential drug lists, therapeutic value and by drug interactions found among
      women over 60 years of age. METHODS: Six hundred thirty-four women enrolled at
      the Open University of the Third Age were studied. Data was collected through
      pattern-oriented, tested questionnaires. The variables examined were related to
      drugs and to drug utilization. The units of analysis used were the drugs and the
      individual. RESULTS: Of 634 women that participated in the study, 9,1% did not
      use drugs. The number of medications taken vary from 1 to 17. The average is 4,0
      drugs/woman. Among the 2.510 pharmaceutical specialties mentioned by the
      interviewed, 538 different substances were identified. About 26% of the
      medications were in agreement with the recommendations of the World Health
      Organization and 17% with recommendations of the "Relacao Nacional de
      Medicamentos Essenciais". Seventeen percent of the drugs are inappropriate for
      use in seniors; 14,1% of the women may suffer consequences for taking drugs of
      the same therapeutic class, and 15, 5% are exposed to interactions. CONCLUSIONS:
      The data suggest that the pattern of the medication utilization is considerably
      influenced by the medical prescription and that their quality is harmed by the
      low selectiveness of the pharmaceutical market

PMID- 10576746
TI  - [Epidemiology of ageing in Northeastern Brazil: results of a household survey].
AB  - INTRODUCTION: The population of Brazil is ageing very rapidly, and the care of
      the elderly is an emerging priority. Up to this date, there is no comprehensive
      study addressing the profile of the elderly in Northeastern Brazil. The objective
      is to compile the multidimensional profile of the elderly residents in a
      metropolitan area of Northeastern Brazil. METHODS: Six hundred sixty-seven
      elderly (60 years and over), residents in the city of Fortaleza, Ceara, Brazil,
      constituting a multistage random sample stratified by socioeconomic status. The
      data was gathered by household survey using a multidimensional functional
      assessment questionnaire. RESULTS: The majority of the elderly were living in
      multigenerational households (75,3%). More than half (51,9%) lived without the
      spouse; 92,4% mentioned at least one disease; 26,4% were considered psychiatric
      cases; 47,7% showed loss of autonomy; 6,6% were hospitalized, and 61,4% used
      health services within the twelve and six months preceding the interview,
      respectively. The prevalence of multigenerational households, loss of autonomy
      and psychiatric morbidity were higher in the poorest areas. CONCLUSIONS: The
      elderly population in the city of Fortaleza lives mainly in multigenerational
      households, with physical and mental morbidity rates particularly high in poor
      areas, they represent special concern in terms of burden for the social and
      health services in the next decades

PMID- 10576747
TI  - [Dynamics of institutionalization of older adults in Belo Horizonte, Brazil].
AB  - INTRODUCTION: Epidemiological and social changes related to population aging in
      Brazil will probably increase the need for nursing homes (NH). The study analyses
      the dynamics of institutionalization in Belo Horizonte, a 3 million inhabitant
      city of whom 8.0% are aged 60 or more. METHODS: Age and length of stay of 1,128
      NH residents (92.5% of the estimated population) was registered and occupancy and
      institutionalization rates were determined. RESULTS: Among women aged 65+ in Belo
      Horizonte, 0.88% were living in NH; among men, 0.26%. Occupancy rates were 92%.
      Women (81%) were older than men (76.4 x 70.4 years; two-tailed t test = 6. 4;
      p=0.00) and lived there for a longer period (5.6 x 4.5 years; two-tailed t test =
      2.6; p=0.01). Almost 1/3 of the men were aged < 65. CONCLUSIONS: High occupancy
      rates, long waiting lists and hard criteria for admission (half reject demented
      or dependent individuals) insinuates that these low institutionalization rates
      are related to scarcity of beds. The preponderance of women reflects the
      proportion of those widowed or separated in the community (66% of those aged 65
      +, versus 76% of married man). The high frequency of institutionalized men aged
      <65 suggests lower capacity of maintaining themselves after widowhood. High death
      rates (24% during a 20 month follow-up of a 263 random sample) determines the
      small median length of stay (3 years). These data unveil the anachronism of a
      system which is not directed towards the maintenance of the Brazilian older
      people among their families and homes.

PMID- 10576748
TI  - [Years of life lost by mortality: a component of the burden of disease].
AB  - INTRODUCTION: The register of death by cause, sex and age groups of residents in
      1994 in Rio Grande do Sul (RS) and Santa Catarina (SC), two Brazilian southern
      states, were studied to calculate the years of life lost (YLL), one of the two
      components that summarize disability adjusted life years (DALY), in RS, SC and
      Brazil. METHODS: The methodology employed is the same used in the Global Burden
      of Disease study to quantify the mortality component (YLL) of DALY in the world.
      RESULTS: The results show that the greatest proportion and rates caused by Group
      II (Noncommunicable diseases), linked with more advanced stages of the
      epidemiological transition, in RS, SC and Brazil. But in both states and
      especially in Brazil, Group I (Communicable, maternal, perinatal and nutritional
      conditions) causes an important proportion of YLL. The Group III (Injuries) was
      the second more important group in RS and SC and the third in Brazil. Road
      traffic accidents are particularly important in SC, where the intentional injury
      rate is half than the one in RS. The leading causes of YLL were road traffic
      accidents, ischemic heart disease and cerebrovascular disease in SC, and ischemic
      heart disease, cerebrovascular disease and road traffic accidents in RS.
      CONCLUSIONS: Death certification in the southern region of Brazil has a complete
      coverage and miscoded death proportion is small, providing a reliable mortality
      information. DALY allow comparing fatal and nonfatal health outcomes to determine
      the importance of different diseases and to establish health priorities. DALY are
      also an useful tool to identify disadvantaged groups, target health interventions
      and provide information for social control of resource allocation.

PMID- 10576749
TI  - [Mental health policies and changes in emergency service demand].
AB  - OBJECTIVE: To verify the modifications observed in a school hospital psychiatric
      emergency unit in Ribeirao Preto - SP, Brazil (EP-RP), due to alterations in the
      mental health policies implemented in this region. METHODS: Data about
      attendances was collected from university hospital files of the EP-RP, from 1988
      to 1997. The following variables were studied: sex, age, origin and main
      diagnosis. Data about changes in mental health policies of the region was
      obtained from documents of the city and state departments of health. RESULTS: The
      yearly increase in the number of attendances followed the progressive involvement
      of EP-RP with the mental health service network, as the number of patients who
      looked for the service in 1995 was 2.3 times greater than in 1988. During this
      period, attendance at the EP-RP gave support to the modifications in the mental
      health policies in this region, resulting in a reduction of 654 psychiatry beds.
      In 1996 and 1997, a reduction of about 20% was observed in the total of
      attendance, as compared to 1995, result from an increase in the attendance
      capacity and number of the extra-hospital services. Since 1990, the EP-RP started
      to attend a higher proportion of older, male patients, with drug dependency and
      psychotic disorders and a lower proportion of non-psychotic patients.
      CONCLUSIONS: The changes observed in the EP-RP are related to modifications in
      the Ribeirao Preto region mental health policies, like the psychiatric beds
      control, installed in 1990, the reduction of psychiatric beds after 1993, and the
      creation and/or amplification of extra-hospital services, in 1995.

PMID- 10576750
TI  - [Mental disorders as risk factors for the development of cocaine
      abuse/dependence: case-control study].
AB  - OBJECTIVE: To evaluate the role of psychiatric disorders and alcohol dependence
      as possible risk factors for cocaine abuse/dependence. METHODS: The case-control
      study used the "snowball" technique in order to select untreated cocaine users
      (cases) and to match sex, age and friendship. Information was gathered using the
      Composite International Diagnostic Interview (CIDI), and computer diagnosis were
      generated according to the DSM-III-R criteria. The analysis was performed through
      the logistic conditional regression. RESULTS: The study included 208 subjects.
      The main results showed that having a history of alcohol dependence was
      independently associated with an increased risk of cocaine abuse/dependence
      (OR=15,1; 95% CI 3,8-60, 2); no other psychiatric disorder was significantly
      associated with an increase in this risk after the multivariate analysis. An
      increased risk of cocaine abuse/dependence was also found for those who related
      suicide thoughts (OR=3,1; 95% CI 0,91-10,8), suggesting an association between
      more severe manifestations of depression and cocaine abuse. CONCLUSIONS: These
      findings suggest that programs directed towards the treatment and prevention of
      cocaine abuse must be prepared to address issues related to comorbidity of drug
      abuse with alcohol and other psychiatric disorders

PMID- 10576751
TI  - [Diagnostic reliability in mental disorders of the International Classification
      of Diseases in primary care].
AB  - INTRODUCTION: The objective is to evaluate the test version of Chapter V -
      "Mental and Behavioral Disorders reliability", of the 10th revision of the
      International Classification of Diseases, Version for Primary Care (ICD -10 PC),
      prepared by the Division of Mental Health of the World Health Organization (WHO).
      METHODS: During September and October of 1994, Community General Physicians (CGP)
      from the Health and Environment Department of the State of Rio Grande do Sul were
      trained in the use of this version, prepared for the field trial, according to
      the design proposed by WHO. RESULTS: The results refer to a study about
      reliability of diagnosis attributed by 9 pairs of CGP to 460 patients in their
      first appointments. Cohen's Kappa for Mental Health Disorder, present or absent,
      was 0,79 (CI 95%: 0,69 - 0,88). CONCLUSION: The use of ICD-10 CP will give more
      specificity to the information and will allow a better communication between
      health workers at the level of primary care

PMID- 10576752
TI  - [Occurrence of encephalic and cardiac cysticercosis (Cysticercus cellulosae) in
      necropsy].
AB  - OBJECTIVE: To review the incidence and pathologic findings of cysticercosis
      diagnosed at autopsies, with emphasis on the most common organs affected.
      METHODS: Reports of 1.596 autopsies performed between 1974 and 1997 at a school
      hospital in Uberaba, MG, Brazil were studied. The following data were obtained:
      age, sex, ethnic group, body mass index, and the site of the cysticercosis.
      RESULTS: The study found diagnosis of cysticercosis in 53 autopsies (3.3%). The
      average age of patients with cysticercosis was 50 (range: 15 to 86 years); 62.3%
      were male, and 64.1% Caucasian. The most affected organs were: brain (79.2%),
      heart (22.6%), skeletal muscle (11.3%), and other organs (5.7%). No statistical
      differences were found comparing age, gender, ethnic group, and body mass index
      of the affected and the non-affected patients. In two cases of neurocysticercosis
      the lesions were located in the ventromedial nucleus of the hypothalamus.
      CONCLUSION: Both the overall incidence of cysticercosis and the incidence of
      cardiac cysticercosis were greater in the study than in other autopsy series from
      the same geographic areas. In two cases there was an association between
      hypothalamic cysticercosis and obesity

PMID- 10576753
TI  - [Female mortality in the Municipality of Sao Paulo: quality of medical death
      certificates].
AB  - OBJECTIVE: To evaluate the quality of the medical certification of deaths of 10
      49 year-old women, resident in the Southern region of the city of S. Paulo
      METHODS: The Puffer methodology was utilized to investigate the causes of death
      of all 10-49 year-old women, resident in the region, and deceased in the year
      1989 (664 deaths in the total). The main causes of death in the original death
      certificates and the "new" causes of death arisen from the research were
      compared. The sensitivity and the kappa index were calculated. RESULTS: In some
      chapters of the International Classification of Diseases and Causes of Death, 9th
      Revision (CID-9), a high sensitivity was found: "Diseases of the Circulatory
      System" (91.9%), "Neoplasms" (89.7%) and "External Causes" (84.1 %). In some
      others, a very low sensitivity was found. The chapter "Mental Illnesses", with a
      34.3 percent sensitivity only, must be mentioned. From 11 deaths originally
      classified in this chapter, 32 cases were found. In most of these "new" cases,
      the main cause of death was found to be alcoholism. The chapter "Complications of
      Pregnancy, Delivery and the Puerperium", also showed a low sensitivity (44.9%).
      The kappa index was found to be 0.63, which indicated a regular concordance.
      DISCUSSION: The quality of the medical certification of causes of death is still
      unsatisfactory in the studied area. This poor quality may affect negatively the
      interventions in the area of women's health, masking the severity of important
      problems

PMID- 10576754
TI  - [Risk factors for injuries caused by traffic accidents and the impact of an
      intervention on the road].
AB  - OBJECTIVE: To evaluate the effect of interventions at a highway, in the
      occurrence and severity of injuries by traffic accidents. METHOD: It was made a
      comparative analysis of two cross-sectional studies in 1994 and 1996. RESULTS: In
      1994 the rate was 7.96 accidents/ 100,000 vehicles and in 1996 8.49 / 100,000
      vehicles. The increase was not significant (p>0.05). The rate of injured drivers
      in 1994 was of 2.10 / 100,000 vehicles and of 1.35 / 100,000 vehicles in 1996,
      which was a significant decrease (p<0.000). The self-report of use of seat belt
      (63.46% versus 76.6%), the small vehicles involved in accidents (7.9% versus
      37.7%), nocturnal schedule (23.7% versus 31.8%) and in Mexico-Cuernavaca
      direction (45% versus 66.7%), were more frequent in 1996 (p<0.05). The risk of
      injury, using a logistic regression model, between drivers exposed to the
      interventions (1996) and those that were not exposed (1994) adjusted by: age,
      speed, use of seat belt, alcohol intake and external cause, showed a protective
      effect of the interventions at the highway (OR 0.42 CI95% 0.27-0.66). CONCLUSION:
      There is an evident need of multisectorial approaches in the study and evaluation
      of the interventions in the field of the traffic accidents. The present research
      is a clear example of the repercussions over health of interventions developed by
      the transportation sector at the highway.

PMID- 10576755
TI  - [Eye health promotion and early visual problem detection in the public health
      services].
AB  - INTRODUCTION: The main purpose of the study was to verify knowledge about eye
      health care attention of the pediatricians and nurses at public health centers in
      the city of Campinas, state of Sao Paulo, Brazil. METHODS: Knowledge, attitudes
      and practices regarding eye health on behalf of pediatricians and nurses who
      worked at health centers in Campinas were studied through questionnaires and
      forms. RESULTS: The implementation of primary health care actions in children
      wasn't usual in the public services due to the little knowledge that both
      pediatricians and nurses had about it. Of 61% pediatricians, 82,0% (50) and 91,0%
      of the 22 nurses didn't know the age at which visual development is finished;
      86,3% (53) of the pediatricians and 100,0% the nurses didn't know what was
      amblyopia. CONCLUSIONS: Therefore, the eye health promotion and the early visual
      problem detection in children were not run by the professionals from the public
      health services in the city of Campinas.

PMID- 10576756
TI  - [Changes in susceptibility of Aedes aegypti to organophosphates in municipalities
      in the state of Sao Paulo, Brazil].
AB  - Baseline data on susceptibility of Aedes aegypti to organophosphates detected
      alterations in cities of the state of S. Paulo, Brazil

PMID- 10576757
TI  - [Dioxins and furans: origins and risks].
AB  - A bibliographic review is presented with the objective of describing the origin
      and the risks to the public health of dioxins and furans and getting familiar
      with some research areas about these compounds. The review has considered 16
      selected references covering a period of approximately twelve years (1986 to
      1997). The main conclusions were: a) These compounds are from nonnatural origin,
      considered highly toxic, extremely persistent in the environment, and they have
      been detected in all environmental matrices like: soil, sediments, air, water,
      animals and plants; b) emissions of these compounds to the atmosphere come
      primarily from combustion processes; c) atmospheric dispersion, deposition and
      subsequent accumulation in the food chain seem to be the major exposure pathway
      to the general population; d) due to their lipophilic characteristic and
      persistence in the environment, these compounds accumulate in adipose tissues,
      being food of animal origin those which present higher concentrations; e) in
      Brazil, the few studies conducted, with the measurement of concentrations of
      these compounds in the environment have showed levels comparable to those
      obtained in Germany. The authors recommend the development of further studies
      about these compounds in Brazil, specially about their accumulation in food and
      in human tissue

PMID- 10576758
TI  - [Traumatic brain injury].

PMID- 10576760
TI  - Autoimmune diabetes: is GAD the culprit?

PMID- 10576759
TI  - Sodium/iodide symporter: a key transport system in thyroid cancer cell
      metabolism.
AB  - The recent cloning of the gene encoding the sodium/iodide symporter (NIS) has
      enabled better characterization of the molecular mechanisms underlying iodide
      transport, thus opening the way to clarifying its role in thyroid diseases.
      Several studies, at both the mRNA and the protein expression levels, have
      demonstrated that TSH, the primary regulator of iodide uptake, upregulates NIS
      gene expression and NIS protein abundance, both in vitro and in vivo. However,
      other factors, including iodide, retinoic acid, transforming growth factor-beta,
      interleukin-1alpha and tumour necrosis factor alpha, may participate in the
      regulation of NIS expression. Investigation of NIS mRNA expression in different
      thyroid tissues has revealed increased levels of expression in Graves' disease
      and toxic adenomas, whereas a reduction or loss of NIS transcript was detected in
      differentiated thyroid carcinomas, despite the expression of other specific
      thyroid markers. NIS mRNA was also detected in non-thyroid tissues able to
      concentrate radioiodine, including salivary glands, stomach, thymus and breast.
      The production of specific antibodies against the NIS has facilitated study of
      the expression of the symporter protein. Despite of the presence of high levels
      of human (h)NIS mRNA, normal thyroid glands exhibit a heterogeneous expression of
      NIS protein, limited to the basolateral membrane of the thyrocytes. By
      immunohistochemistry, staining of hNIS protein was stronger in Graves' and toxic
      adenomas and reduced in thyroid carcinomas. Measurement of iodide uptake by
      thyroid cancer cells is the cornerstone of the follow-up and treatment of
      patients with thyroid cancer. However, radioiodide uptake is found only in about
      67% of patients with persistent or recurrent disease. Several studies have
      demonstrated a decrease in or a loss of NIS expression in primary human thyroid
      carcinomas, and immunohistochemical studies have confirmed this considerably
      decreased expression of the NIS protein in thyroid cancer tissues, suggesting
      that the low expression of NIS may represent an early abnormality in the pathway
      of thyroid cell transformation, rather than being a consequence of cancer
      progression. The relationship between radioiodine uptake and NIS expression by
      thyroid cancer cells require further study. New strategies, based on manipulation
      of NIS expression, to obtain NIS gene reactivation or for use as NIS gene therapy
      in the treatment of radiosensitive cancer, are also being investigated.

PMID- 10576761
TI  - Non-suppressed thyrotropin and elevated thyroglobulin are independent predictors
      of recurrence in differentiated thyroid carcinoma.
AB  - OBJECTIVE: Although in most cases differentiated thyroid carcinoma (DTC) responds
      to surgery and radioiodine (RaI) therapy, some patients will have recurrence and
      eventually cancer-related death. However, although various prognostic factors of
      DTC have been identified (e.g. staging, suppressed thyrotropin), none of the
      previous studies have assessed simultaneously their role in multivariate
      analysis. DESIGN AND METHODS: In this retrospective population-based study, we
      reviewed the clinicopathological data of 254 DTC patients treated in eastern
      Finland during the years 1976-1995, for clinical characteristics, primary
      treatment, follow-up and cancer recurrence. Tumor stage was based on pathological
      tumor-node-metastasis (pTNM) classification, and histopathological specimens were
      re-evaluated. RESULTS: DTC recurrence occurred in 33 patients (13%). In
      univariate analyses, the predictors of recurrence were older age (>60 years,
      P<0.05), follicular tumor type (P<0.01), pTNM classification system (P<0.05) and
      post-ablative radioiodine uptake outside the neck (P<0.05). Non-suppressed serum
      thyrotropin (TSH) and elevated serum thyroglobulin (>3 microg/l) measured one
      year after operation were both related to tumor recurrence (P<0.05 and P<0.001
      respectively). In multivariate analysis the independent predictors for recurrence
      were both elevated thyroglobulin (P<0.001) and non-suppressed TSH (P<0.05)
      independent of histology, pTNM stage and RaI uptake. Adjusted risk ratio for
      recurrence of DTC for unsuppressed thyrotropin was 2.3, for elevated
      thyroglobulin 14.0 and, if both conditions were present, the risk ratio increased
      to 45.1. CONCLUSION: Our results suggest that both non-suppressed serum TSH and
      elevated serum thyroglobulin are related to an increased risk of DTC recurrence
      independent of tumor type and pTNM stage.

PMID- 10576762
TI  - Early or prophylactic thyroidectomy in MEN 2/FMTC gene carriers: results in 71
      thyroidectomized patients. The French Calcitonin Tumours Study Group (GETC).
AB  - BACKGROUND: Once genetic testing accurately identifies MEN 2 gene carriers,
      affected children are given the opportunity to undergo thyroidectomy at the
      earliest stages of the C-cell disease. OBJECTIVE: To define reliable parameters
      by which to identify the best moment for thyroidectomy in patients who are
      carriers of the MEN 2 gene. PATIENTS AND METHODS: Seventy-one MEN 2/FMTC gene
      carriers, collected through the national register of the French Calcitonin
      Tumours Study Group, were evaluated. All the patients included were younger than
      20 years of age and underwent total thyroidectomy. Basal and pentagastrin
      stimulated calcitonin were assayed using an immunoradiometric method (sensitivity
      less than 2pg/ml). Calcitonin measurement was evaluated on the basis of
      histopathological findings in surgical thyroid specimens. RESULTS: We found C
      cell hyperplasia or medullary thyroid carcinoma in all the 71 gene carriers -
      even for the youngest patients - and nodal metastases were present in four cases.
      Calcitonin measurement (basal or pentagastrin-stimulated) detected C-cell disease
      preoperatively in all patients. Six of the 71 patients were not surgically cured:
      one had nodal metastases, one had an advanced staged disease and four had an
      incomplete nodal dissection or had not undergone lymph node surgery. CONCLUSIONS:
      Determination of calcitonin forms an integral part of the management of MEN 2
      gene carriers. Thyroidectomy is undisputably indicated when basal calcitonin is
      abnormal. When basal calcitonin is undetectable, a pentagastrin-stimulated
      increase in calcitonin to more than 10 pg/ml indicates an early thyroidectomy to
      cure the patient.

PMID- 10576763
TI  - Germline MEN1 mutations in sixteen Japanese families with multiple endocrine
      neoplasia type 1 (MEN1).
AB  - OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is a syndrome of endocrine
      tumors involving the parathyroids, anterior pituitary and enteropancreatic
      neuroendocrine tissues, and is inherited in an autosomal dominant manner.
      Recently, the gene responsible for this syndrome, MEN1, was positionally cloned
      in 11q13. We aimed to assess the significance of MEN1 gene diagnostics in
      families with MEN1. DESIGN: Sixteen probands of familial MEN1 and their 40 family
      members were subjected to the study. METHODS: Full-length sequencing of the open
      reading frame and exon-intron boundaries in the MEN1 gene was performed with
      probands of familial MEN1. Family members were examined for the identified
      mutation in the proband. RESULTS: We identified heterozygous germline mutations
      of the MEN1 gene in all of 16 Japanese MEN1 families examined, achieving the
      highest detectability of MEN1 mutations in familial MEN1 among studies that
      examined more than 10 families. Eleven kinds of the identified MEN1 germline
      mutations were novel. More than half were nonsense or frameshift mutations
      resulting in a premature stop codon (9/15; 60%), and no mutation hot spots or no
      apparent genotype-phenotype relationships were observed, in support of the
      results of other studies. We identified 40 mutant MEN1 gene carriers and 16 non
      carriers in the course of the present study in those families. CONCLUSIONS:
      Analysis of the germline mutations in the MEN1 gene, providing significantly
      useful clinical information to probands and family members of MEN1, should be
      considered as a standard procedure and categorized as belonging to Group 1 cancer
      predisposition testing by the American Society of Clinical Oncology.

PMID- 10576764
TI  - Observational study in adult hypopituitary patients with untreated growth hormone
      deficiency (ODA study). Socio-economic impact and health status. Collaborative
      ODA (Observational GH Deficiency in Adults) Group.
AB  - OBJECTIVE: The aim of the present study was to assess the socio-economic impact
      at baseline and after one year of follow-up of clinical and health status
      characteristics and laboratory tests of adult-onset GH deficiency (AGHD), a well
      known clinical entity, in a large group of Spanish hypopituitary patients with
      untreated AGHD. DESIGN AND METHODS: A total of 926 eligible patients with GHD (GH
      </= 5 ng/ml after stimulation) and at least one further pituitary hormone
      deficiency were retrospectively studied; 356 of these were followed for one year.
      Complete physical examination, IGF-I, lipid and routine biochemistry measurements
      and health-related quality of life (HRQoL) with the specific QoL-Assessment of
      Growth Hormone Deficiency in Adults (AGHDA) questionnaire were assessed at
      baseline and at 12 months in the prospective study. Health status and health
      economic evaluation were measured by a specific questionnaire and a patient diary
      and compared with Spanish population study results. RESULTS: Clinical
      characteristics and laboratory tests of AGHD showed a higher incidence of
      cardiovascular risk factors and mortality compared with the general population
      (hypercholesterolaemia in 29% vs 18% and hypertension in 22.1% vs 14. 9%). QoL
      AGHDA scores for patients were significantly worse (P<0.01) and direct health
      costs were higher than in the general population. CONCLUSIONS: Hypopituitary GHD
      adults had more cardiovascular risk factors, higher mortality, worse HRQoL and
      higher absolute health costs than the general population in Spain.

PMID- 10576765
TI  - Amino acid variants of the vitamin D-binding protein and risk of diabetes in
      white Americans of European origin.
AB  - BACKGROUND: Genetic variants of vitamin D-binding protein (DBP) have been
      reported to be associated, not only with diabetes, but also with prediabetic
      traits, in several populations. There are two known polymorphisms in exon 11 of
      the DBP gene that result in amino acid variants: at codons 416 GAT-->GAG (Asp-
      >Glu) and 420 ACG-->AAG (Thr-->Lys). OBJECTIVE: To examine the association of
      these polymorphisms with diabetes in white Americans of European origin. METHODS:
      We studied unrelated individuals: 181 with type 1 diabetes, 215 with type 2
      diabetes, and 163 healthy controls. Exon 11 was amplified using polymerase chain
      reaction and the two alleles were determined by digestion with specific
      endonucleases: HaeIII and StyI, respectively. RESULTS: At codon 416, Asp/Glu
      allele frequencies were 45%/55% in patients with type 1 diabetes, 43%/57% in
      patients with type 2 diabetes, and 46%/54% in controls (chi(2)=0.69, 2 d.f.,
      P<0.71). At codon 420, corresponding Lys/Thr frequencies were 27%/73%, 30%/70%,
      and 30%/70% (chi(2)=1.25, 2 d.f., P=0.53). Distributions of genotypes at both
      loci, and the haplotypes defined by the two loci, were also very similar in all
      groups. CONCLUSION: DNA polymorphisms in the DBP gene are not associated with
      diabetes in white Americans of European origin.

PMID- 10576766
TI  - Effect of insulin sensitivity on pulsatile insulin secretion.
AB  - OBJECTIVE: The aim of the study was to determine whether derangements in insulin
      pulsatility are related to the presence of insulin resistance or whether these
      changes occur only in non-insulin-dependent diabetes mellitus (NIDDM). DESIGN AND
      METHODS: The study included 26 obese, 11 NIDDM and 10 control subjects. The obese
      group was divided into a low insulin (plasma insulin <20 mU/l, OLI, 14 subjects)
      and a high insulin (OHI, 12 subjects) group. For pulsatility analysis blood was
      sampled every 2 min for 90 min. Pulsatility analysis was carried out using the
      PulsDetekt program. The insulin secretion randomness was quantified using
      interpulse interval deviation (IpID) and approximate entropy (ApEn). ApEn and
      ApEn normalized by s.d. of the individual insulin time series (nApEn) were
      calculated. Lower values of ApEn and IpID indicate more regular secretion.
      Homeostasis model assessment (HOMA) was used to quantify insulin sensitivity.
      RESULTS: Insulin pulses were significantly less regular in the OHI and the NIDDM
      groups compared with the control and the OLI groups (control: ApEn 0.54+/-0.16,
      nApEn 0.69+/-0.19, IpID 2.53+/-0.99; OLI: ApEn 0.64+/-0.12, nApEn 0. 79+/-0.15,
      IpID 2.92+/-1.09; OHI: ApEn 0.88+/-0.07, nApEn 0.92+/-0. 07, IpID 3.95+/-0.84;
      NIDDM: ApEn 0.92+/-0.16, nApEn 0.99+/-0.09, IpID 4.41+/-0.53; means +/- s.d.).
      There was no difference in the pulse regularity between the OHI and the NIDDM
      groups. CONCLUSIONS: Decrease in insulin sensitivity was correlated with the
      reduction of insulin secretion regularity. Therefore irregular insulin secretion
      is related to a reduction in insulin sensitivity, and it is not unique to NIDDM.

PMID- 10576767
TI  - Acquired lipoprotein lipase deficiency associated with chronic urticaria. A new
      etiology for type I hyperlipoproteinemia.
AB  - Type I hyperlipoproteinemia (type I HLP) is a rare disorder of lipid metabolism
      characterized by fasting chylomicronemia and reduced postheparin plasma
      lipoprotein lipase (LPL) activity. Most cases of type I HLP are due to genetic
      defects in the LPL gene or in its activator, the apolipoprotein CII gene. Several
      cases of acquired type I HLP have also been described in the course of autoimmune
      diseases due to the presence of circulating inhibitors of LPL. Here we report a
      case of type I HLP due to a transient defect of LPL activity during puberty
      associated with chronic idiopathic urticaria (CIU). The absence of any
      circulating LPL inhibitor in plasma during the disease was demonstrated. The LPL
      genotype showed that the patient was heterozygous for the D9N variant. This
      mutation, previously described, can explain only minor defects in the LPL
      activity. The presence of HLP just after the onset of CIU, and the elevation of
      the LPL activity with remission of the HLP when the patient recovered from CIU,
      indicate that type I HLP was caused by CIU. In summary, we report a new etiology
      for type I HLP - a transient decrease in LPL activity associated with CIU and
      with absence of circulating inhibitors. This is the first description of this
      association, which suggests a new mechanism for type I HLP.

PMID- 10576768
TI  - Fas and Fas ligand gene expression in autoimmune thyroiditis in BB/W rats.
AB  - OBJECTIVE: Apoptosis via the Fas pathway is a potential mechanism for thyroid
      tissue destruction leading to clinical hypothyroidism in Hashimoto's thyroiditis
      (HT). Recent studies reported contradictory results regarding the regulation of
      Fas/Fas ligand (FasL) expression by cytokines in vitro. We therefore determined
      the Fas and FasL gene expression in the BioBreeding/Worcester (BB/W) rat
      thyroiditis model, which can be regarded as a model for HT. METHODS: In order to
      obtain BB/W rats with spontaneous, iodine-induced or without lymphocytic
      thyroiditis (LT), rats were divided into 3 groups: 55-day-old rats after 24 days
      of iodine administration, 75-day-old rats after 45 days of iodine administration,
      and 101-day-old rats respectively. The gene expression of Fas, FasL, and
      interleukin (IL)-1beta was determined by Genescan fragment analysis using reverse
      polymerase chain reaction. Serum thyroglobulin (TG) antibody concentrations were
      measured and the extent of lymphocytic infiltration of one thyroid lobe was
      histologically graded. RESULTS: Fas and FasL gene expression was significantly
      higher in rats with LT and correlated with the extent of lymphocytic infiltration
      and the TG antibody level. There was no evidence that the expression of IL-1beta
      or other cytokines is related to the expression of Fas or its ligand.
      CONCLUSIONS: The increased expression of Fas and FasL in LT of BB/W rats suggests
      the involvement of the Fas pathway in the pathogenesis of LT in BB/W rats.
      However, in contrast to results of recent in vitro studies, in the BB/W rat
      Fas/FasL expression is not regulated by IL-2, -4, -6, -10, -12, interferon gamma,
      and tumor necrosis factor alpha.

PMID- 10576769
TI  - In vitro basal and GnRH-stimulated secretion of gonadotrophins reflects long
      lasting modulatory effects, and peripheral levels are not predicted by pituitary
      responsiveness to GnRH.
AB  - OBJECTIVE: Production of the appropriate pattern of gonadotrophin levels is
      crucial to proper functioning of the female reproductive system. We aimed to
      establish whether the pituitary has invariant secretory characteristics when
      isolated from in vivo controls. We aimed to obtain information during both the
      rising and declining phases of the gonadotrophin surge. DESIGN: This study
      investigated factors that are directed at the pituitary by isolating it from the
      acute influences of the in vivo environment and studying gonadotrophin secretion
      in vitro. METHODS: Pituitaries of adult female rats were collected at selected
      times during the day of pro-oestrus and incubated in vitro, and at the same time
      blood was collected. Peripheral levels of LH and FSH were measured over the whole
      day of pro-oestrus, basal in vitro secretions of LH and FSH from pituitaries were
      measured, GnRH-stimulated LH and FSH secretion were assessed, and the
      responsiveness of LH and FSH secretion to GnRH were calculated. RESULTS:
      Peripheral levels of LH peaked at 1800 h (P<0.02) followed by a subsequent
      decline. In contrast, although FSH had a peak at 1800 h (P<0.01), serum levels
      were also high at the end pro-oestrus. The profile of basal LH and FSH secretion
      from the pituitary in vitro, in the absence of added secretagogue, resembled that
      of the peripheral blood levels of each gonadotrophin. Pituitaries collected at
      1800 h secreted most LH (P<0. 02). FSH secretion was low early on the day of pro
      oestrus and then increased to and was maintained at high levels in the last
      quarter of the day (P<0.01). When the pituitaries were stimulated with GnRH the
      patterns of LH release and FSH release approximated those observed for basal
      release. Responsiveness of the pituitaries to GnRH was calculated by determining
      the ratio of GnRH-stimulated release to basal release. However, low levels of
      gonadotrophin were secreted even from pituitaries which were highly responsive as
      determined from consideration of percentage increase in secretion induced by
      GnRH. CONCLUSIONS: The secretory activity was dependent on the time of day the
      pituitaries were collected. Since the secretion occurred after the tissue had
      been removed from the direct influence of the in vivo environment, the variations
      in secretion must reflect long-lasting components of the mechanism that regulate
      gonadotrophin concentrations. There were changes in both LH and FSH
      responsiveness to GnRH stimulation over the day of pro-oestrus. Delineation of
      the time courses and changing predominance of multiple processes is needed to
      assist understanding the mechanisms underlying the female reproductive cycle.

PMID- 10576770
TI  - Absence of regular pulsatile LH secretion during pre- and post-implantation
      periods in sheep.
AB  - Two experiments were conducted to determine the patterns of LH secretion and to
      evaluate the LH responses to pulsatile administration of GnRH during early
      pregnancy in ewes. In experiment 1, pregnant ewes (n=16) were used to determine
      the concentration of LH in plasma of jugular blood samples collected every 15 min
      for 6h before (day 10 post-mating) and after (days 20 and 30 post-mating)
      implantation. In experiment 2, the pituitary LH responses to exogenous pulsatile
      administration of GnRH were examined on day 10 post-mating in 4 pregnant ewes. A
      small dose of GnRH (200 ng/ml saline) was injected (i.v.) every 3h and jugular
      blood samples were collected every 15 min for 12h beginning at the onset of GnRH
      administration and continuing through the 4th GnRH pulse. During the frequent
      sample bleeding at any of the stages of pregnancy examined, LH concentrations
      oscillated in a pulsatile manner. However, pulsatile LH release occurred
      irregularly and infrequently. Overall mean LH concentrations, frequency and
      amplitude of LH pulses were not significantly different between any of the stages
      of pregnancy examined. Pulsatile administration of GnRH on day 10 post-mating
      induced regular pulses of LH. In conclusion, these data demonstrate that: (i)
      pulsatile LH secretion occurs irregularly during early pregnancy, and (ii) the
      absence of regular pulsatile LH release during early pregnancy is not attributed
      to a lack of pituitary responsiveness to GnRH.

PMID- 10576771
TI  - Co-localization of neuroendocrine hormones in the human fetal pancreas.
AB  - OBJECTIVE AND DESIGN: Co-localization of the four major pancreatic hormones, and
      also of islet amyloid polypeptide (IAPP), peptide tyrosine tyrosine (PYY),
      secretin and neurotensin, has been studied in the endocrine pancreas of human
      fetuses at 16, 18 and 22 weeks of gestation. METHODS: Double and triple
      immunofluorescence stainings have been used. RESULTS: All three fetal pancreata
      contained cells that showed insulin, glucagon, somatostatin, pancreatic
      polypeptide (PP), IAPP, secretin and PYY immunoreactivity. Neurotensin cells were
      found in the youngest fetus and gastric inhibitory polypeptide (GIP) in the two
      older fetuses. Co-localization of two hormones occurred in most of the endocrine
      cell types in the three fetuses examined, but three hormones occurred in only a
      few cells and especially in the youngest fetus. Somatostatin cells were the only
      cell type which was largely monohormonal. Our findings showed that there are two
      different co-localization patterns: insulin was co-localized mainly with IAPP and
      glucagon, while secretin and PYY occurred together with glucagon and PP.
      CONCLUSIONS: These data are the first to describe secretin and neurotensin in the
      fetal pancreas. Two different co-localization patterns could be distinguished:
      insulin, IAPP and glucagon, and glucagon, secretin, PP and PYY.

PMID- 10576772
TI  - Effect of leptin on ACTH-stimulated secretion of cortisol in rhesus macaques and
      on human adrenal carcinoma cells.
AB  - OBJECTIVE: Because glucocorticoids stimulate leptin release and, at least in
      vitro, leptin inhibits cortisol secretion, a feedback system between
      glucocorticoids and leptin has been proposed. However, in humans and non-human
      primates there are no in vivo studies to support any role for leptin in the
      control of the hypothalamic-pituitary-adrenal axis. In this study, we
      investigated the effect of leptin on (i) ACTH-stimulated secretion of cortisol in
      six male rhesus monkeys and (ii) basal and forskolin (FSK)-stimulated cortisol
      secretion by the human adrenal carcinoma cell H295R in vitro. DESIGN AND METHODS:
      In vivo studies: after suppression of endogenous ACTH with either dexamethasone
      (n=6) or a corticotropin-releasing factor (CRF) antagonist (d-Phe CRF(12-41))
      (n=3), 1 microg bolus of human ACTH(1-24) was administered to stimulate adrenal
      cortisol release. Blood samples were collected every 15 min for 3 h. Leptin (1
      mg) was infused over 4 h, starting 1 h before ACTH bolus. IN VITRO STUDIES: NCI
      H295R cells were incubated for 6, 12, 24 and 48 h in the absence or presence of
      20 micromol/l FSK in combination with leptin (100 ng/ml medium). Cortisol levels
      in serum and medium were measured by solid phase radioimmunoassay. RESULTS: Acute
      leptin infusion to rhesus monkeys did not change basal cortisol levels, peak
      cortisol levels after ACTH(1-24) or the area under the curve when compared with
      studies in which leptin was not given. FSK increased cortisol levels in medium at
      24 and 48 h, but leptin did not change cortisol release in either control or FSK
      stimulated cells. CONCLUSIONS: Short-term leptin infusion affected neither the
      cortisol response to ACTH in non-human primates in vivo nor cortisol release
      (basal or FSK stimulated) by H295R cells, in vitro. These data suggest that
      leptin may not be an acute regulator of primate adrenal cortisol secretion.

PMID- 10576773
TI  - Effects of basic fibroblast growth factor and nerve growth factor on lactate
      production, gamma-glutamyl transpeptidase and aromatase activities in cultured
      Sertoli cells.
AB  - Sertoli cells are under the control of FSH and androgens and also respond to
      polypeptidic factors locally produced. Basic fibroblast growth factor (bFGF) and
      nerve growth factor (NGF) have been proposed to belong to the large set of
      intratesticular regulators. The aim of the present investigation was to analyze
      the effects of bFGF and NGF on lactate production, gamma-glutamyl transpeptidase
      (gamma-GTP) and aromatase activities. Cultured Sertoli cells dose-dependently
      responded to bFGF by increasing lactate production and gamma-GTP activity under
      basal conditions. In FSH-stimulated cultures, a synergistic effect of FSH with
      bFGF for lactate production was observed. NGF did not produce changes in lactate
      production or gamma-GTP activity at any dose tested. Both peptides decreased FSH
      stimulated aromatase activity. These results provide additional evidence for the
      participation of bFGF and NGF in the complex network of intratesticular
      regulators. bFGF has pleiotropic effects on Sertoli cell function while the
      actions of NGF seem to be more limited.

PMID- 10576775
TI  - Research in Medical Education. Proceedings of the 38th annual conference.
      Washington, DC, USA. October 25-27, 1999.

PMID- 10576774
TI  - Distinct glucose lowering and beta cell protective effects of vanadium and food
      restriction in streptozotocin-diabetes.
AB  - Vanadium is an oral insulin-mimetic agent that diminishes hyperglycemia, improves
      beta-cell insulin store and secretory function, and can reverse the diabetic
      state chronically after withdrawal from treatment. As food restriction has been
      reported to enhance insulin sensitivity and reduce insulin demand, we assessed
      the contribution of a reduced food intake to the glucose lowering and beta-cell
      protective effects of vanadium. Streptozotocin (STZ)-diabetic rats were untreated
      (D) or administered vanadyl sulfate in the drinking water (DT) at one week prior
      to and for 5 weeks following the administration of STZ. An additional group was
      pair-fed (DP) with an equal amount of food as that consumed by the DT group.
      Shortly after the induction of diabetes, hyperglycemic D rats demonstrated a
      significant rise in plasma insulin to levels that initially exceeded that of the
      controls. This was followed by a steady reduction over several weeks, suggesting
      a gradual depletion of functional beta-cells. Both vanadium treatment and pair
      feeding abolished the insulin hypersecretory response following STZ
      administration. Glucose lowering was enhanced in DT animals when administered
      higher concentrations of vanadium, despite no further reduction in food intake,
      and all DT animals (10/10) were normoglycemic by 5 weeks. Mean pancreatic insulin
      content in DT rats was improved fourfold and was associated with a greater number
      of granulated beta-cells. Conversely, food restriction only modestly improved
      glycemia and the pancreatic insulin store and, unlike DT, DP rats remained highly
      glucose-intolerant. At 5 weeks of diabetes, fed circulating glucose and insulin
      levels were strongly correlated (P=0.0002) in the D and DP groups, supporting the
      notion that glucose lowering with food restriction is dependent on improved
      plasma insulin levels. A separate correlation was observed in DT animals within a
      lower range of plasma insulin, suggesting that vanadium, unlike food restriction,
      reduced plasma glucose by enhancing insulin sensitivity. Thus, vanadium preserves
      beta-cells in STZ-diabetes at least partially by abolishing the insulin
      hypersecretory response and the eventual exhaustion of residual insulin stores
      following a moderate dose of STZ. This property of vanadium would appear to be
      useful in the treatment of prediabetic and newly diagnosed insulin-dependent
      diabetes mellitus.

PMID- 10576776
TI  - Synthesis, structural elucidation and pharmacological properties of some 5-acetyl
      3,4-dihydro-6-methyl-4-(substituted phenyl)-2(1H) -pyrimidinones.
AB  - In this study, the synthesis of some new 5-acetyl-3,4-dihydro-6-methyl-4
      (substituted phenyl)-2(1H)-pyrimidinones has been reported. The compounds were
      prepared by the Biginelli reaction of acetylacetone with aromatic aldehydes and
      urea. The structures of the compounds were characterized by UV, IR, 1H NMR, 13C
      NRM, mass spectra and elementary analysis. The calcium antagonistic activity of
      these compounds was tested in vitro on rat ileum precontracted with 4 x 10(-3) M
      barium chloride.

PMID- 10576778
TI  - Tumour immunotherapy: developments and strategies.

PMID- 10576777
TI  - Benzodiazepine receptor ligands. III. Synthesis and biological evaluation of 2-
      and/or 3-substituted pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides.
AB  - A new series of 2- and/or 3-substituted pyrazolo [5,1-c][benzotriazine 5-oxides
      and their 8-chloro derivatives were synthesized, and their benzodiazepine
      receptor (BZR) affinities were evaluated in vitro in comparison to lead compound
      3-ethoxycarbonyl-8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide (29) [1,2].
      None of the new compounds showed significant affinity for BZR. On the basis of a
      pharmacophore/receptor model suggested for lead compound 29, some hypotheses to
      explain the inactivity of new derivatives are discussed.

PMID- 10576779
TI  - [Prevention of S. pneumoniae infections in Italy. Roma, Italy, 2 July 1999.
      Proceedings].

PMID- 10576780
TI  - [Usefulness of chloride serum concentrations in being treated with potassium
      bromide].

PMID- 10576781
TI  - [Seizure exacerbation by the use of leuprorelin acetate for treatment of central
      precocious puberty in a female patient with symptomatic localization-related
      epilepsy].

PMID- 10576782
TI  - [Oligohidrosis caused by zonisamide: retrospective study].

PMID- 10576783
TI  - [Values of cerebrospinal fluid neopterin and IL-6 in patients with acute
      encephalopathy].

PMID- 10576784
TI  - Chaos and complexity.

PMID- 10576785
TI  - Chaos and complexity.

PMID- 10576786
TI  - Chaos and complexity.

PMID- 10576787
TI  - Tonics.

PMID- 10576788
TI  - [Helicobacter pylori infection: a single microorganism with many consequences].

PMID- 10576789
TI  - Proceedings of the Intensive Care Society and Riverside Group "State of the Art"
      Meeting. London, United Kingdom, December 17-18, 1998.

PMID- 10576790
TI  - Carbon dioxide and the cerebral circulation.

PMID- 10576791
TI  - Blood pressure and renin angiotensin system responses to initiation of treatment
      with captopril or losartan in heart failure.

PMID- 10576792
TI  - Subtherapeutic levels of phenytoin with standard doses in infants: need to review
      dosage schedule.

PMID- 10576793
TI  - Primary vesicoureteric reflux diagnosed in the 1st month of life.

PMID- 10576794
TI  - Successful treatment of post-renal transplant erythrocytosis with losartan.

PMID- 10576795
TI  - Posterior vertical bite opening: a new paradigm in dentofacial orthopedic /
      orthodontic therapy.

PMID- 10576796
TI  - Worldwide Transplant Center Directory. Islet transplants.

PMID- 10576797
TI  - Worldwide Transplant Center Directory. Small bowel transplants.

PMID- 10576799
TI  - Papers presented at the 6th Southeast European Symposium of Pediatric Surgery.
      Graz, Austria, May 22-23, 1998.

PMID- 10576798
TI  - [Embryogenesis of blood and vascular endothelium].

PMID- 10576800
TI  - Countdown to contract. Is NHS orthodontics finished?

PMID- 10576801
TI  - Meeting of the Israel Society for Auditory Research. Tel Aviv, October 5, 1999.
      Abstracts.

PMID- 10576802
TI  - Methods for Health Impact Assessment in Environmental and Occupational Health.
      Geneva, Switzerland, 9-11 July 1997.

PMID- 10576803
TI  - Commentary on Hallermann-Streiff Syndrome: experience with 15 patients and review
      of the literature.

PMID- 10576804
TI  - From Foundations to the Future: Building a New Era in DVT Management. Proceedings
      of a meeting. Barcelona, Spain, 26-27 June 1998.

PMID- 10576805
TI  - [Rupture of the ligamenta alaria between dens axis and atlas and condylus of the
      right os occipitale].

PMID- 10576807
TI  - [Genes & cancer. Card no. 28: PTEN (MMAC, TEP-1) (phosphatase and tensin homolog
      deleted on chromosome 10)].

PMID- 10576808
TI  - [Programmed cell death, it is a matter of channels].

PMID- 10576806
TI  - Large cell non-Hodgkin's lymphoma and Hodgkin's disease arising synchronously in
      a patient with chronic lymphocytic leukemia: importance of immunocytochemistry.

PMID- 10576809
TI  - [Heparanase cloned at last: a new target for antimetastatic drugs].

PMID- 10576810
TI  - [Empiric antibiotic therapy of febrile neutropenias in cancer patients treated
      with chemotherapy: oral trial?].

PMID- 10576811
TI  - [The goals and limits of the debate].

PMID- 10576812
TI  - [Under what conditions should we propose a prophylactic mastectomy for a woman at
      risk?].

PMID- 10576813
TI  - [For what reasons should we avoid suggesting a prophylactic mastectomy for a
      woman at risk?].

PMID- 10576814
TI  - [35th annual meeting of the ASCO. American Society of Clinical Oncology].

PMID- 10576815
TI  - [Second annual meeting of the American Society of Gene Therapy (ASGT)].

PMID- 10576816
TI  - [Decision making in biology: ROC analysis].

PMID- 10576817
TI  - Glucocorticoid induced osteoporosis: pathogenesis, diagnosis and treatment. Lake
      Garda, Italy, April 8-10, 1999. Abstracts.

PMID- 10576819
TI  - Proceedings of European Congress on Osteoporosis. Berlin, September 11-15, 1998.

PMID- 10576818
TI  - Exercise and the Skeleton. London, United Kingdom, 17 November 1998. Abstracts.

PMID- 10576820
TI  - 4th International Congress of the World Muscle Society. Antalya, Turkey, 14-16
      October 1999. Abstracts.

PMID- 10576821
TI  - Minimising the impact of visual impairment. Many visual aids to help people with
      diabetes are no longer available.

PMID- 10576822
TI  - Minimising the impact of visual impairment. Training in use of low vision aids is
      important.

PMID- 10576823
TI  - Psychotherapy for severe personality disorder. Article did not do justice to
      available research data.

PMID- 10576824
TI  - Psychotherapy for severe personality disorder. Author should have got the facts
      right.

PMID- 10576825
TI  - Psychotherapy for severe personality disorder. Randomised controlled trials may
      not be best for studies of clinical situations.

PMID- 10576826
TI  - Commentary: Competencies for informed shared decision making.

PMID- 10576827
TI  - Commentary: proposals based on too many assumptions.

PMID- 10576828
TI  - Antidepressants for old people. Elderly people are particularly prone to develop
      side effects.

PMID- 10576829
TI  - Antidepressants for old people. Lack of evidence of efficacy is not evidence of
      lack of efficacy.

PMID- 10576830
TI  - Antidepressants for old people. Research on antidepressants in the elderly
      population is scarce.

PMID- 10576831
TI  - General practitioners' experiences of patients' complaints. Mentoring should be
      more widespread.

PMID- 10576832
TI  - Differences in death rates in English hospitals. Data are inadequate basis for
      drawing conclusion of paper.

PMID- 10576833
TI  - Managing patients with deliberate self harm who refuse treatment in accident and
      emergency departments. No case law supports sectioning under the Mental Health
      Act in these circumstances.

PMID- 10576834
TI  - Managing patients with deliberate self harm who refuse treatment in accident and
      emergency departments. Mental health professionals would be wary of detaining
      someone simply to impose treatment for overdose.

PMID- 10576835
TI  - Benzodiazepine use in pregnancy and major malformations or oral clefts. Pooled
      results are sensitive to zero transformation used.

PMID- 10576836
TI  - Benzodiazepine use in pregnancy and major malformations or oral clefts. Quality
      of primary studies must influence inferences made from meta-analyses.

PMID- 10576837
TI  - Choosing the right antibiotic. Antibiotic choice may affect risk of Clostridium
      difficile infection.

PMID- 10576838
TI  - Naturalistic treatment study of depression in general practice. Antidepressants
      are overrated.

PMID- 10576839
TI  - Reasons for not seeing drug representatives. But doctors do see them: "freebies"
      seem disproportionately important.

PMID- 10576840
TI  - Reasons for not seeing drug representatives. Companies have to encourage doctors
      to prescribe their products.

PMID- 10576841
TI  - Reasons for not seeing drug representatives. Drug representatives have much to
      offer.

PMID- 10576842
TI  - DEC methods for appraising new drugs. Are justified.

PMID- 10576843
TI  - DEC methods for appraising new drugs. Horizon scanning is important for emerging
      health technologies.

PMID- 10576844
TI  - DEC methods for appraising new drugs. Paper has errors and omissions.

PMID- 10576845
TI  - Diminishing returns to aggregate level studies.

PMID- 10576847
TI  - Commentary: a new script for nursing home care in the United Kingdom?

PMID- 10576846
TI  - Two pathways, but how much do they diverge?

PMID- 10576848
TI  - Sunlight and health. Article did not help informed debate.

PMID- 10576849
TI  - Sunlight and health. Not all sunlight is dangerous, just ultraviolet radiation.

PMID- 10576850
TI  - Sunlight and health. Severity of effect depends on where you live.

PMID- 10576851
TI  - Sunlight and health. Exposure to sunlight may reduce cancer risk.

PMID- 10576852
TI  - Design of CRASH trial. Trial is best way to elucidate effectiveness of
      corticosteroids in acute severe head injury.

PMID- 10576853
TI  - Routine antenatal HIV testing. Is acceptable to women.

PMID- 10576854
TI  - Fungal infections of skin and nails of feet. Authors of meta-analysis defend
      their view.

PMID- 10576855
TI  - The coroner service. Inquests often facilitate grief.

PMID- 10576856
TI  - The coroner service. All sudden infant deaths must be investigated thoroughly.

PMID- 10576857
TI  - The coroner service. A national service would be more consistent.

PMID- 10576858
TI  - The coroner service. Culturally sensitive care for the dying is basic human
      right.

PMID- 10576859
TI  - [The parasite-host relations in the system of Ligula intestinalis (L.) (Cestoda,
      Pseudophyllidae)--the bream].
AB  - Proteins and reducing sugars were assayed. The total proteolytic and amylolytic
      activities were determined in flushes of body cavity of the breams infected and
      noninfected by plerocercoids Ligula intestinalis. Infection with L. intestinalis
      markedly affected the composition of the medium and the activity of enzymes
      functioning in the body cavity of the bream: protein content increased, total
      proteolytic activity remained practically unchanged, while the content of
      reducing sugars and total amylolytic activity decreased. The strength of fixation
      of amylolytic enzymes on the surface of L. intestinalis tegument was tested. The
      dynamics of desorption of these enzymes from the tegument of plerocercoids and
      adult cestodes parasitizing in the fish intestine. The contents of protein and
      glycogen do not depend on the cestode length and strobile region.

PMID- 10576860
TI  - Dictyostelium discoideum: a promising centrosome model system.
AB  - The centrosome of the slime mould Dictyostelium discoideum displays a morphology
      markedly different from centriolar centrosomes or yeast spindle pole bodies,
      while fulfilling the same conserved functions in the organization of the
      microtubule cytoskeleton. Recent advances suggest that the Dictyostelium
      centrosome may offer an interesting model system, usefully complementing other
      well-studied centrosome models. The establishment of an isolation procedure and
      the generation of a range of monoclonal antibodies have been achieved, which are
      important pre-requisites for biochemical investigation. Furthermore, the role of
      the centrosome in cell motility and centrosome duplication process have been
      investigated using cells with GFP-labelled centrosomes.

PMID- 10576861
TI  - Identification and function of the centrosome centromatrix.
AB  - Centrosomes direct the organization of microtubules in animal cells. However, in
      the absence of centrosomes, cytoplasm has the potential to organize microtubules
      and assemble complex structures such as anastral spindles. During cell
      replication or following fertilization, centrioles that are incapable of
      organizing microtubules into astral arrays are introduced into this complex
      cytoplasmic environment. These centrioles become associated with pericentriolar
      material responsible for centrosome-dependent microtubule nucleation, and thus
      the centrosome matures to ultimately become a dominant microtubule organizing
      center that serves as a central organizer of cell cytoplasm. We describe the
      identification of a novel structure within the pericentriolar material of
      centrosomes called the centromatrix. The centromatrix is a salt-insoluble
      filamentous scaffold to which subunit structures that are necessary for
      microtubule nucleation and abundant in the cytoplasm bind. We propose that the
      centromatrix serves to concentrate and focus these subunits to form the
      microtubule organizing center. Since binding of these subunits to the
      centromatrix does not require nucleotides, we propose a model for centrosome
      assembly which predicts that the assembly of the centromatrix is a rate-limiting
      step in centrosome assembly and maturation.

PMID- 10576862
TI  - Proceedings of the 5th Brazilian Symposium on Extracellular Matrix. SIMEC 98.
      Angra dos Reis, RJ, Brasil. September 7-10, 1998.

PMID- 10576863
TI  - Magnesium, zinc, and copper status in women involved in different sports.
AB  - The dietary intake, serum levels, and urinary excretion of magnesium, zinc, and
      copper were studied in 78 women involved in different sports (karate, handball,
      basketball, and running) and in 65 sedentary women. Seven-day, weighed-food
      dietary reports revealed that no group of female athletes reached the minimal
      intake recommended for magnesium (280 mg/day) and zinc (12 mg/day), although
      their values were superior to those of the control group. The estimated safe and
      adequate minimal intake of copper (1.5 mg/day) was amply surpassed by the
      basketball players and runners but was not reached by the handball players. Serum
      levels and urinary excretion of magnesium, zinc and copper di not seem related
      either to their intake or to the type of physical activity performed. The
      influence of other factors such as nutritional status, bioavailability,
      intestinal absorption mechanisms, and muscle-level modifications might explain
      the differences between the different groups of female athletes.

PMID- 10576864
TI  - Factors affecting the efficiency of introducing precise genetic changes in ES
      cells by homologous recombination: tag-and-exchange versus the Cre-loxp system.
AB  - The introduction of genetic modifications in specific genes by homologous
      recombination provides a powerful tool for elucidation of structure-function
      relationships of proteins of biological interest. Presently, there are several
      alternative methods of homologous recombination that permit the introduction of
      small genetic modifications in specific loci. Two of the most widely used methods
      are the tag-and-exchange, based on the use of positive-negative selection
      markers, and the Cre-loxP system, based on the use of a site-specific
      recombinase. The efficiency of detection of targeting events at different loci
      using the two systems was compared. Additionally, we analysed how the distance
      between two gene markers placed within the region of homology of a targeting
      vector affects the rate at which both markers are introduced into the locus
      during the homologous recombination event. Our results indicate that the method
      based on the use of positive-negative selection markers was less efficient than
      the Cre-loxP based system, irrespective of locus or type of positive-negative
      selection. It was also determined that as the distance between the selectable
      marker and the genetic modification being introduced increases, there is a
      progressive reduction in the efficiency of detecting events with the desired
      genetic modification.

PMID- 10576865
TI  - Milken's crusade. Venture science.

PMID- 10576866
TI  - Psychiatric care. Shrinking benefits.

PMID- 10576867
TI  - Drug costs. Double your measure.

PMID- 10576868
TI  - Job loyalty. Battle in the Bronx.

PMID- 10576869
TI  - Child immunization. Stuck on service.

PMID- 10576870
TI  - Should the FDA regulate alternative medicines?

PMID- 10576872
TI  - Online services. No call waiting.

PMID- 10576871
TI  - Immigrant outreach. Hola, health care.

PMID- 10576873
TI  - Fairness and nurses' pay.

PMID- 10576874
TI  - Rape treatment. A SANE (sexual assault nurse examiner) approach.

PMID- 10576875
TI  - Outcomes data. Generous gesture.

PMID- 10576876
TI  - Son also rises. Interview by Chris Serb.

PMID- 10576878
TI  - OR planning. Suite success.

PMID- 10576877
TI  - Public relations. The word on Y2K.

PMID- 10576879
TI  - Alternative medicine. Drumming--and then some.

PMID- 10576880
TI  - Healing decor. Screen savers.

PMID- 10576881
TI  - Trauma staff. Working wounded.

PMID- 10576882
TI  - Referrals. Low-tech connect.

PMID- 10576883
TI  - Should doctors bargain collectively with HMOs?

PMID- 10576884
TI  - Should you toss Medicaid when it's losing money?

PMID- 10576885
TI  - Glass ceiling. Learning to lead.

PMID- 10576886
TI  - 12th International Symposium on High Performance Capillary Electrophoresis and
      Related Microscale Techniques. Palm Springs, California, USA. 23-28 January 1999.
      Proceedings.

PMID- 10576887
TI  - Short-lasting primary headaches: focus on trigeminal automatic cephalgias and
      indomethacin-sensitive headaches.
AB  - Short-lasting primary headache syndromes provides both a diagnostic challenge and
      considerable therapeutic reward. Primary short-lasting headaches broadly divide
      themselves into those associated with auto nomic symptoms, trigeminalautonomic
      cephalgias and those with little autonomic syndromes. The trigeminal-autonomic
      cephalgias include cluster headache and paroxysmal hemicranias, in which head
      pain and cranial autonomic symptoms are prominent. Consideration of short-
      lasting headaches, particularly in the context of the differential diagnosis
      between cluster headache and paroxysmal hemicrania leads to a consideration of
      indomethacin-sensitive headaches. There are a group of headaches, such as
      paroxysmal hemicrania and hemicrana continua , which have a curious and a very
      robust response to indomethacin. These headaches tend to be referred to
      neurologists as they are refractory to other treatments and thus are useful to
      know about.

PMID- 10576888
TI  - Induction of electrical excitability by NGF requires autocrine action of a CNTF
      like factor.
AB  - The overlapping expression of neurotrophin and neural cytokine receptors
      indicates that most neuronal populations are responsive to both classes of
      factors, yet relatively little is known about how these two trophic signaling
      systems interact to regulate neuronal phenotype. We report here that one hallmark
      of NGF's effects on target cells, the induction of membrane electrical
      excitability, requires the intermediary action of a CNTF-like factor. We found
      that NGF's regulation of voltage-gated potassium channels, unlike its regulation
      of voltage-gated sodium and calcium channels, involves a CNTF-like
      autocrine/paracrine loop. We showed that NGF induces secretion of a soluble
      factor that mimics the action of exogenous CNTF in regulating voltage-gated
      potassium channels and that NGF's ability to regulate this potassium channel is
      blocked by three independent reagents that inhibit the signaling of CNTF and/or
      related factors. The identity of this autocrine factor does not appear to be CNTF
      itself. Thus, a CNTF-like autocrine/paracrine factor is both necessary and
      sufficient for the regulation of potassium channels by NGF and is a key
      determinant of the type of electrical excitability that NGF induces in target
      cells.

PMID- 10576889
TI  - Autophagy is activated by apoptotic signalling in sympathetic neurons: an
      alternative mechanism of death execution.
AB  - Autophagy is a mechanism whereby cells digest themselves from within and so may
      be used in lieu of apoptosis to execute cell death. Little is known about its
      role in neurons. In newly isolated sympathetic neurons, two independent apoptotic
      stimuli, NGF-deprivation or cytosine arabinoside added in the presence of NGF,
      caused a 30-fold increase in autophagic particle numbers, many autophagosomes
      appearing before any signs of DNA-fragmentation. The anti-autophagic drug 3
      methyladenine also delayed apoptosis, its neuroprotection correlating with
      inhibition of cytochrome c release from mitochondria and prevention of caspase
      activation. In contrast, autophagic activity remained elevated in neurons treated
      with the pan-caspase inhibitor Boc-Asp(OMe)fmk, which inhibited morphological
      apoptosis but did not inhibit cytochrome c release nor prevent cell death. We
      propose that the same apoptotic signals that cause mitochondrial dysfunction also
      activate autophagy. Once activated, autophagy may mediate caspase-independent
      neuronal death.

PMID- 10576890
TI  - Laminin-2/integrin interactions enhance myelin membrane formation by
      oligodendrocytes.
AB  - To examine the role of extracellular matrix (ECM)/integrin interactions in
      myelination we have analyzed oligodendrocyte differentiation and myelin membrane
      formation in oligodendrocytes grown in cell culture. We have found that the ECM
      substrates fibronectin, vitronectin, and laminin-2 (merosin) have no effect on
      differentiation, as measured by the appearance of myelin basic protein-expressing
      cells, but that laminin-2 substrates dramatically enhance myelin membrane
      formation. Blocking antibody and immunolocalization studies suggest that this
      effect is mediated via 1 integrins. The v integrins expressed on
      oligodendrocytes, in contrast, are less effective at promoting membrane
      formation. These results show that the interaction between laminin-2 expressed in
      white matter tracts and oligodendrocyte laminin-binding integrins may be an
      important part of the signalling mechanisms that stimulate oligodendrocytes to
      elaborate the extensive myelin membrane required to wrap the axon and form the
      myelin sheath. The results also provide a logical explanation for the
      abnormalities of myelination observed in humans with merosin-deficient congenital
      muscular dystrophy.

PMID- 10576891
TI  - A novel neuron-specific DNA end-binding factor in the murine brain.
AB  - To characterize the distribution of transcription factor AP-1 and YY1 DNA-binding
      activities in the rat brain, the labeled target oligonucleotides were loaded on
      brain sections and after incubation and washing, the residual signal was
      registered by autoradiography. The binding was predominantly associated with
      neurons and was regionally specific with highest levels in the cerebellum,
      hippocampus, and piriform cortex. The identified binding factor was not, however,
      sequence-specific, but apparently recognized DNA ends and was activated by long
      double-stranded DNA. UV cross-linking identified the molecular mass of the factor
      to be about 80 kDa. The factor was not found in soluble brain extracts,
      suggesting its association with membranes or the nuclear matrix. Despite apparent
      similarities with Ku protein, which targets DNA-ends, the DNA end-binding
      activity was present in brains of Ku86- and Ku70-deficient mice. Since DNA end
      binding factors are generally involved in DNA repair, the same function may be
      suggested for the novel factor identified in the present study.

PMID- 10576892
TI  - Identification of genes induced by neuregulin in cultured myotubes.
AB  - The formation of the neuromuscular junction (NMJ) involves a series of inductive
      interactions between motor neurons and muscle fibers. The neural signals proposed
      to induce the mRNA expression of acetylcholine receptors in muscle include
      neuregulin (NRG). In the present study, we have employed RNA fingerprinting by
      arbitrarily primed PCR analysis to identify the differentially expressed
      transcripts following NRG treatment in cultured myotubes. Nine partial cDNA
      fragments were isolated; the mRNA expression of eight of these genes was found to
      be up-regulated by NRG. The spatial and temporal expression profiles of these NRG
      regulated genes in rat tissues during development suggest potential functional
      roles during the formation of NMJ in vivo. Our findings not only allowed the
      identification of novel genes, but also suggested possible functions for some
      known genes that are consistent with their potential roles at the NMJ.
      Furthermore, the identification of G-protein beta1 subunit and G-protein-coupled
      receptor as NRG-regulated genes has provided the first demonstration that
      activation of the NRG signaling pathway can induce the expression of components
      in the G-protein signaling cascade.

PMID- 10576893
TI  - UNFPA's technical support services system. United Nations Population Fund.

PMID- 10576894
TI  - Clinical significance of telomerase activity in the non-cancerous epithelial
      region of oesophageal squamous cell carcinoma.

PMID- 10576895
TI  - Colonic motility is abnormal before surgery for rectal prolapse.

PMID- 10576896
TI  - Effect of training on the incidence of nerve damage in thyroid surgery.

PMID- 10576897
TI  - Experimental study of the effect of intraperitoneal heparin on tumour
      implantation following laparoscopy.

PMID- 10576898
TI  - Current management of acute leg ischaemia: results of an audit by the Vascular
      Surgical Society of Great Britain and Ireland.

PMID- 10576899
TI  - Leucocyte count and C-reactive protein in the diagnosis of acute appendicitis.

PMID- 10576900
TI  - Interstitial laser coagulation for hepatic tumours.

PMID- 10576901
TI  - Risk scoring in surgical patients.

PMID- 10576902
TI  - Intraoperative lymphatic mapping and the sentinel node concept in colorectal
      carcinoma.

PMID- 10576903
TI  - Randomized clinical trial of laparoscopic versus open inguinal hernia repair.

PMID- 10576904
TI  - Randomized clinical trial of laparoscopic versus open inguinal hernia repair.

PMID- 10576905
TI  - Special issue in memory of Professor Sir Derek H. R. Barton (1918-1998).

PMID- 10576906
TI  - Toxic effect of synthetic pyrethroid permethrin on the enzyme system of the
      freshwater fish Channa striatus.
AB  - Treatment with 40% and 80% of the LC50 (24h) of the pyrethroid permethrin after
      24h exposure causes significant reduction in the activity of lactate
      dehydrogenase and cytochrome oxidase and enhanced the succinate dehydrogenase
      activity in the tissues of the freshwater fish Channa striatus. The results
      indicate that permethrin blocks aerobic as well as anaerobic metabolism in the
      exposed fishes.

PMID- 10576907
TI  - Evolutionary game theory.

PMID- 10576908
TI  - Ignorance: the only thing more expensive than education.

PMID- 10576909
TI  - Effects of age and gender on the cardiovascular responses to isoproterenol.

PMID- 10576910
TI  - Neisseria meningitidis subtype nomenclature.

PMID- 10576912
TI  - A new MHC locus that influences class I peptide presentation.

PMID- 10576911
TI  - Increased circulating levels of lipopolysaccharide binding protein in children
      with Escherichia coli O157:H7 hemorrhagic colitis and hemolytic uremic syndrome.

PMID- 10576913
TI  - Commotio cordis: a precordial thump?

PMID- 10576914
TI  - Commotio cordis: sudden death due to chest wall impact in sports.

PMID- 10576915
TI  - Contrast echocardiography during pericardiocentesis.

PMID- 10576916
TI  - Prevalence of hibernating myocardium in patients with severely impaired ischaemic
      left ventricles.

PMID- 10576917
TI  - Prognostic significance of electrical alternans v signal averaged ECG in
      predicting the outcome of electrophysiological testing and arrhythmia-free
      survival.

PMID- 10576918
TI  - Stenting for middle aortic syndrome.

PMID- 10576919
TI  - Epidemiology and control of bovine theileriosis. Proceedings of an international
      colloquium. Antwerp, Belgium, 10-12 December 1997.

PMID- 10576920
TI  - Botterell the leader.

PMID- 10576921
TI  - "The Second Ice Age".

PMID- 10576922
TI  - Proceedings of the American Cancer Society 2nd National Conference on Cancer
      Genetics. San Francisco, California, USA. June 26-28, 1998.

PMID- 10576923
TI  - Competitive inhibitors of yeast phosphoglucose isomerase: synthesis and
      evaluation of new types of phosphorylated sugars from the synthon D
      arabinolactone-5-phosphate.
AB  - Designed as competitive inhibitors of the isomerization reaction catalyzed by the
      potential chemotherapeutic target phosphoglucose isomerases (PGI), D
      arabinonamide-5-phosphate and D-arabinohydrazine-5-phosphate were synthesized and
      fully characterized. These new types of phosphorylated sugar derivatives were
      easily and efficiently obtained in a one-step procedure from the promising
      synthon D-arabinono-1,4-lactone 5-phosphate. These two compounds proved to be new
      good competitive inhibitors of yeast PGI with the substrate D-fructose-6
      phosphate, though not as strong as D-arabinohydroxamic acid-5-phosphate. Overall,
      our results are in accord with the postulated 1,2-cis-enediolate species as a
      probable high-energy intermediate of the PGI-catalyzed reaction.

PMID- 10576924
TI  - Cartilage degradation by hyaluronate lyase and chondroitin ABC lyase: a MALDI-TOF
      mass spectrometric study.
AB  - Matrix-assisted laser desorption ionization and time-of-flight mass spectrometry
      (MALDI-TOF MS) has been used to investigate degradation products of two selected
      polysaccharides of cartilage (chondroitin sulfate and hyaluronic acid).
      Testicular hyaluronate lyase and chondroitin ABC lyase were used for enzymic
      digestion of both polysaccharides as well as of cartilage specimens.
      Polysaccharide solutions and cartilage supernatants were assayed by positive and
      negative MALDI-TOF MS. Especially chondroitin ABC lyase produced high amounts of
      digestion products (unsaturated di- and tetrasaccharides) from polysaccharides as
      well as from cartilage, clearly monitored by MALDI-TOF MS. It is concluded that
      MALDI-TOF MS provides a precise and fast tool for the determination of
      oligosaccharides since no previous derivatization is required.

PMID- 10576926
TI  - Copper associated liver diseases in infancy and childhood.

PMID- 10576925
TI  - Re: Aortoiliac aneurysm with arteriocaval fistula treated by a bifurcated
      endovascular stent-graft.

PMID- 10576927
TI  - Spotlight on molecular biology of ion channels and electrical remodeling. Special
      issue dedicated to Edouard Coraboeuf.

PMID- 10576928
TI  - Proceedings of TeleMed 98: From research to service delivery. 6th International
      Conference on Telemedicine and Telecare. London, United Kingdom, 25-26 November
      1998.

PMID- 10576930
TI  - Delirium in the elderly: epidemiological, pathogenetic, diagnostic and treatment
      aspects. Proceedings of the 3rd Symposium on Aging and Aging Disorders.
      Stockholm, Sweden, September 3-4, 1998.

PMID- 10576931
TI  - [Abstracts of work presented at the 48th Pharmacology Seminar in Prague, 9-12
      September 1998].

PMID- 10576929
TI  - Cloning of fish enzymes and other fish protein genes.
AB  - Fish metabolism needs special enzymes that have maximum activity at very
      different conditions than their mammalian counterparts. Due to the differences in
      activity, these enzymes, especially cold-adapted proteases, could be used
      advantageously for the production of some foods. In addition to the enzymes, this
      review describes some other unique fish polypeptides such as antifreeze proteins,
      fluorescent proteins, antitumor peptides, antibiotics, and hormones, that have
      already been cloned and used in food processing, genetic engineering, medicine,
      and aquaculture. Recombinant DNA technology, which allows these biological
      molecules to be cloned and overexpressed in microorganisms is also described,
      highlighting innovative applications. The expected impact of cloning fish
      proteins in different fields of technology is discussed.

PMID- 10576932
TI  - Report from the American Lung Association/American Thoracic Society (ALA/ATS)
      Conference, San Diego, California, April 1999.

PMID- 10576933
TI  - Furby does not interfere with medical devices.

PMID- 10576934
TI  - Lingual technique--top or flop?

PMID- 10576935
TI  - Futalosine and its derivatives, new nucleoside analogs.
AB  - Futalosine, a new nucleoside analog, was isolated from a fermentation broth of
      Streptomyces sp. MK359-NF1. Some chemical derivatives of futalosine were
      prepared. 6-O-Methylfutalosine methylester inhibited growth of HeLa-S3 cells in
      vitro (IC50 = 19.5 micrograms/ml) in contrast to the weak activity of futalosine.
      6-O-Methylfutalosine methylester at concentrations higher than 10 micrograms/ml
      inhibited incorporation of 3H-TdR and 3H-UR but not 3H-Leu in the acid-soluble
      fractions of HeLa-S3 cells.

PMID- 10576936
TI  - Photobiology: The molecular mechanisms of light-induced damage and the effects of
      light on human skin diseases. Proceedings of the 47th Montagna Annual Symposium
      on the Biology of Skin. Snowmass, Colorado, USA. August 19-23, 1998.

PMID- 10576937
TI  - Plication of diaphragmatic eventration.

PMID- 10576939
TI  - Web alert. Analytical techniques. Mechanisms.

PMID- 10576938
TI  - I am a 46-year-old man with hypertension. I recently started taking Inderal for
      my blood pressure. I feel fine and my pressure is way down, but I can no longer
      get my pulse up when I work out on my treadmill or bike. Does that mean I won't
      benefit from exercise anymore?

PMID- 10576940
TI  - Analytical techniques.

PMID- 10576941
TI  - Microbial genomes III: Sequencing, functional characterization, and comparative
      genomics.

PMID- 10576942
TI  - Complementary medicine for disease and illness prevention? A research
      perspective.

PMID- 10576943
TI  - L-ornithine aspartate - a rationale for its use in combination with chemotherapy,
      radiation, and hyperthermia in oncology.

PMID- 10576944
TI  - Selected bibliography.

PMID- 10576945
TI  - Acute altitude sickness in children.

PMID- 10576946
TI  - Antimalarials for visitors to Kruger National Park?

PMID- 10576947
TI  - Egocentric localization: visually directed alignment to projected head landmarks
      in binocular and monocular observers.
AB  - PURPOSE: To determine the accuracy and precision with which humans align moving,
      non-moving, point-like and linear stimuli to three head landmarks projected to a
      frontal plane. Monocularly enucleated and binocularly normal subjects, performing
      monocularly, were tested. METHODS: Experimental tasks consisted of aligning the
      stimulus, a luminescent target, using a remote steering wheel control, to three
      projected landmarks; the nose, and the outside edge of each ear. Experiments were
      performed with a fixed [static] linear stimulus and a small dynamic stimulus, and
      then with a fixed stimulus at both a very close and an intermediate distance.
      RESULTS: The data from the monocular enucleated observers showed better accuracy
      in some conditions but their variable errors were larger than those of the
      controls. CONCLUSIONS: We propose that, for the alignments of the enucleated
      monocular subjects, a) the increase in accuracy is consistent with a shift of the
      egocenter in the direction of the remaining eye, and b) the decrease in precision
      may be due to the fact that the egocenter does not correspond to the mid-sagittal
      or median plane. This disparity would require adjustments to be learned in order
      to perform tasks involving visually directed alignments to the self.

PMID- 10576948
TI  - Strabology Report of the 25th Annual Meeting of the American Association for
      Pediatric Ophthalmology and Strabismus. The Westin Harbour Castle Hotel, Toronto,
      Ontario, Canada. April 15-18, 1999.

PMID- 10576950
TI  - 5th International Symposium on Insulin-Like Growth Factors. Brighton, United
      Kingdom, 31 October-4 November, 1999. Abstracts.

PMID- 10576949
TI  - Shock-induced figure-of-eight reentry in the isolated rabbit heart.
AB  - The patterns of transmembrane potential on the whole heart during and immediately
      after fibrillation-inducing shocks are unknown. To study arrhythmia induction, we
      recorded transmembrane activity from the anterior and posterior epicardial
      surface of the isolated rabbit heart simultaneously using 2 charge-coupled device
      cameras (32,512 pixels, 480 frames/second). Isolated hearts were paced from the
      apex at a cycle length of 250 ms. Two shock coils positioned inside the right
      ventricle (-) and atop the left atrium (+) delivered shocks at 3 strengths (0.75,
      1.5, and 2.25 A) and 6 coupling intervals (130 to 230 ms). The patterns of
      depolarization and repolarization were similar, as is evident in the uniformity
      of action potential duration at 75% repolarization (131.4?8.3 ms). At short
      coupling intervals (<180 ms), shocks hyperpolarized a large portion of the
      ventricles and produced a pair of counterrotating waves, one on each side of the
      heart. The first beat after the shock was reentrant in 90% of short coupling
      interval episodes. At long coupling intervals (>180 ms), increasingly stronger
      shocks depolarized an increasingly larger portion of the heart. The first beat
      after the shock was reentrant in 18% of long coupling interval episodes.
      Arrhythmias were most often induced at short coupling intervals (98%) than at
      long coupling intervals (35%). The effect and outcome of the shock were related
      to the refractory state of the heart at the time of the shock. Hyperpolarization
      occurred at short coupling intervals, whereas depolarization occurred at long
      coupling intervals. Consistent with the "critical point" hypothesis, increasing
      shock strength and coupling interval moved the location where reentry formed
      (away from the shock electrode and pacing electrode, respectively).

PMID- 10576951
TI  - Circumcision.

PMID- 10576952
TI  - Religious circumcision: a Moslem view.

PMID- 10576953
TI  - Management of renal angiomyolipoma: a report of 53 cases.

PMID- 10576954
TI  - Can the triple-threat academic physician exist in the new millennium?

PMID- 10576955
TI  - Results from new test compared with results from "Radiation dose from DXA
      Scanning to reproductive tissues of females", Journal of Clinical Densitometry,
      Vol. 1:379-83, 1998.

PMID- 10576956
TI  - USAN Council. List No. 419. New names. Pexiganan acetate.

PMID- 10576957
TI  - USAN Council. List No. 419. New names. Mecasermin.

PMID- 10576958
TI  - USAN Council. List No. 419. New names. Pramlintide acetate.

PMID- 10576959
TI  - USAN Council. List No.420. New names. Nesiritide.

PMID- 10576960
TI  - USAN Council. List No.420. New names. Sacrosidase.

PMID- 10576961
TI  - Recent drug-related adverse events with inhaled corticosteroids that should be
      considered in patients at risk.

PMID- 10576962
TI  - Long- and short-term blood pressure and RR-interval variability and psychosomatic
      distress in chronic fatigue syndrome.

PMID- 10576963
TI  - Erythrocyte Na+/Li+ countertransport and Na+/K+ -2Cl- co-transport in essential
      hypertension.

PMID- 10576964
TI  - Proceedings of the 3rd International Conference on Farm Animal Endocrinology--The
      Somatotropic Axis. Brussels, Belgium, 7-10 December 1998.

PMID- 10576965
TI  - Health-care policy: quo vadis?

PMID- 10576966
TI  - Lyme disease vaccine--LYMErix.

PMID- 10576967
TI  - EMBO Workshop Molecular Biology of Chromosome 21 and Down Syndrome. Israel, June
      1999. Abstracts.

PMID- 10576968
TI  - [Dr. Paul Borner, founder of the Deutsche Medizinische Wochenschrift].

PMID- 10576969
TI  - [Future-oriented clinical research in Germany. Biostatistics].

PMID- 10576970
TI  - [Sarcoidosis with emphysema].

PMID- 10576971
TI  - Neurontin: expanding the clinical experience. Proceedings of a symposium. Cannes,
      France, June 5, 1998.

PMID- 10576972
TI  - 6th Annual Conference of the American Society for Neural Transplantation.
      Clearwater, Florida, USA. April 29-May 2, 1999. Abstracts.

PMID- 10576973
TI  - [45th Meeting of the French Association for the Study of the Liver. Montpellier,
      29 September-1 October, 1999. Abstracts].

PMID- 10576974
TI  - Hepatic oxygen supplementation as therapy in cirrhotic liver disease.

PMID- 10576975
TI  - Pain in alcoholic chronic pancreatitis.

PMID- 10576976
TI  - Gastroenterologists of the new millennium.

PMID- 10576977
TI  - Identification of multiple candidate genes for IBD susceptibility using high
      density transcript mapping in the IBD2 locus on chromosome 12q.

PMID- 10576978
TI  - Dimethylsulfoxide for renal dysfunction caused by systemic amyloidosis
      complicating Crohn's disease.

PMID- 10576979
TI  - Metronidazole susceptibility in Helicobacter pylori.

PMID- 10576980
TI  - Image of the month. Porcelain gallbladder.

PMID- 10576981
TI  - Training and education in gastroenterology. List of available training programs.

PMID- 10576982
TI  - Effectiveness of polyethylene glycol antegrade gut lavage bowel preparation for
      colonoscopy--timing is the key?

PMID- 10576983
TI  - Photodynamic therapy of nenresectable cholangiocarcinoma.

PMID- 10576984
TI  - Octreotide in the prevention of pancreatic injury associated with endoscopic
      cholangiopancreatography.

PMID- 10576985
TI  - Trans-silencing by P elements inserted in subtelomeric heterochromatin involves
      the Drosophila polycomb group gene, Enhancer of zeste.

PMID- 10576986
TI  - Is multiple paternity necessary for the evolution of genomic imprinting?

PMID- 10576987
TI  - Angina pectoris and oesophageal angina.

PMID- 10576988
TI  - Intrahepatic HCV levels in chronic HCV infection.

PMID- 10576989
TI  - Is exposure to a patient with Crohn's disease an environmental factor for
      developing the disease.

PMID- 10576990
TI  - [Respiratory tract diseases and apoptosis].

PMID- 10576991
TI  - Methods and conclusions in the clinical study of TT virus.

PMID- 10576992
TI  - Intragenic polymorphic missense mutations in the XLRS1 gene in families with
      juvenile X-linked retinoschisis.

PMID- 10576994
TI  - Cornea and blindness.

PMID- 10576995
TI  - Current perspectives in infectious keratitis.

PMID- 10576996
TI  - Single-plate Molteno implants in complicated glaucomas: results, survival rates,
      and complications.
AB  - Sixty-two single-plate single-stage Molteno implantations for complicated
      glaucomas were performed between March 1991 and November 1992. The charts of all
      these patients were reviewed to determine the intraocular pressure (IOP) control
      success rate (< 21 mm Hg with or without medications), visual success rate
      (retention or improvement of visual acuity from preoperative level) and the rate
      of complications encountered. A Kaplan-Meier life-table (survival) analysis was
      also performed. IOP control was obtained in 74.2% of cases. Mean postoperative
      IOP was 16.97 +/- 8.07 mm Hg (Mean +/- SD). Visual success was obtained in 51.6%
      of the eyes. Eyes with aphakia/pseudophakic glaucomas showed the best response
      with 80% of them achieving IOP control and 60% achieving visual success. The
      survival plot for IOP control revealed 75.81% and 74.19% success rates at 48 and
      72 weeks, respectively. Complications encountered were either due to the early
      postoperative hypotony or were tube-related. These results were gratifying
      considering the severity of the glaucoma in these cases and they reaffirm the
      usefulness of the Molteno implant in the management of difficult glaucomas.

PMID- 10576997
TI  - A review of childhood admission with perforating ocular injuries in a hospital in
      north-west India.
AB  - A retrospective study of perforating ocular injuries in children below the age of
      fifteen years was conducted. Eighty patients (eighty-nine eyes) were included in
      this study. Male children were more susceptible to ocular injury as compared to
      females (p = < 0.01). Children of the school-going age were the most affected
      (73.8%). Majority of the injuries occurred in the sports field (p = < 0.01).
      Playing with bow and arrow, and gillidanda* accounted for majority of the sport
      injuries (47.2%). Sixty-eight percent of the perforated eyes had no light
      perception at the end of treatment. Health education on the preventive aspects of
      ocular injuries in schools as well as through mass media should reduce the
      incidence of visual loss due to ocular injuries.

PMID- 10576998
TI  - Postequatorial horizontal rectus recession in the management of congenital
      nystagmus.
AB  - Postequatorial (12 mm) recession of all four horizontal recti was done in nine
      patients with congenital nystagmus. Fifteen of 18 eyes showed decreased amplitude
      of nystagmus while 12 eyes also showed an increase in visual acuity.
      Functionally, significant limitation of ocular motility was not encountered
      despite unconventionally large recessions.

PMID- 10576999
TI  - Computerised tomography in Tolosa-Hunt syndrome.
AB  - Twelve patients who satisfied the clinical criteria of Tolosa-Hunt syndrome
      (THS), underwent axial computerised tomography (CT) scan of the head. Two
      patients had abnormalities detected in the cavernous sinus on the affected side
      which supported the clinical diagnosis. This coupled with steroid responsiveness
      and long-term asymptomatic follow-up firmly established the diagnosis of THS. We
      discuss the computerised tomographic findings seen in THS and the relevance of
      using accurate imaging techniques as the first line of investigation in these
      cases.

PMID- 10577000
TI  - Alport's syndrome: a case report.

PMID- 10577001
TI  - Ping pong gaze (periodic alternating gaze): a case report.

PMID- 10577002
TI  - Orbital apex syndrome: a rare complication of septorhinoplasty.

PMID- 10577003
TI  - Postoperative management of corneal graft.

PMID- 10577004
TI  - Insurance for all Americans.

PMID- 10577005
TI  - The Bancroft-Mackerras Medal of the Australian Society for Parasitology.

PMID- 10577006
TI  - [Classification and therapy of aortic valve stenosis].

PMID- 10577007
TI  - [Dangerous drug intolerance].

PMID- 10577008
TI  - [Poisoning with ecstasy or cocaine. Why no beta blockers?].

PMID- 10577009
TI  - [Secondary coronary heart disease prevention by red wine?].

PMID- 10577011
TI  - Symposium: Use of Imaging in Drug R&D. Bethesda, Maryland, USA. September 11-13,
      1998. Proceedings and abstracts.

PMID- 10577012
TI  - The laryngeal mask airway: routine, risk or rescue?

PMID- 10577010
TI  - Lack of causal link between muscle [H+] and ventilation during exercise.

PMID- 10577013
TI  - Is vasopressin an ideal vasopressor to treat hypotension in septic shock?

PMID- 10577014
TI  - Professing a new discipline through a new chair in nursing development.

PMID- 10577015
TI  - Apology. Triangulation in nursing research: issues of conceptual clarity and
      purpose.

PMID- 10577016
TI  - Nurses in war zones are facing growing danger.

PMID- 10577017
TI  - Cancer nursing study.

PMID- 10577018
TI  - New BHF research reveals inadequate rehabilitation for heart patients. British
      Heart Foundation.

PMID- 10577019
TI  - Research shows persistent bedwetting can affect the psychological development of
      children.

PMID- 10577020
TI  - Young offenders and substance misuse: the cost to us and them--tackling the
      problems.

PMID- 10577021
TI  - The journal 150 & 100 years ago. August 1849 and 1899.

PMID- 10577022
TI  - Case 7. Radicular cyst.

PMID- 10577023
TI  - Graphic representation of the results of kinetic analyses.

PMID- 10577024
TI  - Which model is best? Let the data decide.

PMID- 10577025
TI  - Forces determining ion permeation.

PMID- 10577026
TI  - Test of Poisson-Nernst-Planck theory in ion channels.

PMID- 10577027
TI  - Ion permeation and chemical kinetics.

PMID- 10577028
TI  - Theories of ion permeation: a chaser.

PMID- 10577029
TI  - Familial hydrocephalus.

PMID- 10577030
TI  - Branchial plexopathy related to alcohol intoxication.

PMID- 10577032
TI  - Isolated infarction in the territory of lateral posterior choroidal arteries.

PMID- 10577031
TI  - Positive response to therapy in a patient with a seropositive paraneoplastic
      cerebellar degeneration and an endometrioid carcinoma of the vesicovaginal
      septum.

PMID- 10577033
TI  - Neurostimulation of the ventral intermediate thalamic nucleus alleviates
      hereditary essential myoclonus.

PMID- 10577034
TI  - Invasive intracranial aspergillosis secondary to intranasal corticosteroids.

PMID- 10577036
TI  - Catatonia due to central pontine and extrapontine myelinolysis: case report.

PMID- 10577035
TI  - Magnetic resonance imaging and vertebral artery dissection.

PMID- 10577037
TI  - Association between butyrylcholinesterase K variant and the Alzheimer type
      neuropathological changes in apolipoprotein E epsilon4 carriers older than 75
      years.

PMID- 10577038
TI  - Ideomotor prosodic apraxia.

PMID- 10577039
TI  - Vocal cord abductor paralysis in spinocerebellar ataxia type 1.

PMID- 10577040
TI  - Lateral gaze synkinesis on downward saccade attempts with paramedian thalamic and
      midbrain infarct.

PMID- 10577041
TI  - Botulinum toxin is a useful treatment in excessive drooling in saliva.

PMID- 10577042
TI  - Extensive brain calcifications in systemic sclerosis: two cases.

PMID- 10577043
TI  - All tibial foot: an electrophysiological artifact.

PMID- 10577044
TI  - Shortened length of stay for hospitalized cardiovascular patients.

PMID- 10577045
TI  - CLA and PPARgamma activation.

PMID- 10577046
TI  - [Outpatient surgery for patients with peritonsillar abscess].

PMID- 10577047
TI  - [Outpatient surgery--tympanoplasty].

PMID- 10577048
TI  - [Ambulatory surgical procedures for congenital ear fistula or earlobe
      hemangioma].

PMID- 10577049
TI  - Canadian Palliative Care Conference. London, Ontario, Canada. October 3-6, 1999.
      Abstracts.

PMID- 10577050
TI  - Electric magnetic resonance and spectrophotometry evidence on the photodynamic
      activity of a new perylenequinonoid pigment.
AB  - Di-cysteine substituted hypocrellin B (DCHB) is a new water-soluble
      photosensitizer with significantly enhanced red absorption at wavelengths longer
      than 600 nm over the parent compound hypocrellin B (HB). The photosensitizing
      properties (Type I and/or Type II mechanisms) of DCHB have been investigated in
      dimethylsulfoxide (DMSO) and aqueous solution (pH 7.4) using electron
      paramagnetic resonance (EPR) and spectrophotometric methods. In anaerobic DMSO
      solution, the semiquinone anion radical of DCHB (DCHB-) is predominantly
      photoproduced via self-electron transfer between excited- and ground-state DCHB
      species. The presence of an electron donor significantly promotes the formation
      of the reduced form of DCHB. When a deoxygenated aqueous solution of DCHB and an
      electron door are irradiated with 532 nm light, the hydroquinone of DCHB (DCHBH2)
      is formed via the disproportionation of the first-formed DCHB- and second
      electron transfer to DCHB- and second electron transfer to DCHB- from the
      electron donor. When oxygen is present, singlet oxygen (1 O2), superoxide anion
      radical (O2-) and hydroxyl radical (OH) are produced. The quantum yield of 1 O2
      generation by DCHB photosensitization is estimated to be 0.54 using Rose Bengal
      as a reference, a little lower than that of HB (0.76). The superoxide anion
      radical is also significantly enhanced by the presence of electron donors.
      Moreover, O2- upon disproportionation generated H2O2 and ultimately the highly
      reactive OH via the Haber-Weiss reaction pathway. The efficiency of O2-
      generation by DCHB is obviously enhanced over that of HB. These findings suggest
      that the photodynamic actions of DCHB may proceed via type I and Type II
      mechanisms and that this new photosensitizer retains photosensitizing activity
      after photodynamic therapy-oriented chemical modification.

PMID- 10577051
TI  - Oxygen depletion during in vitro photodynamic therapy: structure-activity
      relationships of sulfonated aluminum phthalocyanines.
AB  - Photodynamically induced oxygen depletion has been measured in an Ehrlich ascites
      mouse tumor cell line using a Clark-type electrode. Cells are loaded with
      aluminum phthalocyanines, sulfonated to different degrees (A1PcS(n), n = 0,2,3,4)
      and consisting of various isomeric species. Different cell lines and incubation
      procedures are used in order to investigate the cellular uptake mechanism. Uptake
      (in units of molecules/cell), post-irradiation redistribution and A1PcS(n)
      photodegradation are measured using spectroscopic techniques. For a given
      sensitizer, the oxygen depletion rate per cell increases sublinearly with uptake
      and superlinearly with cell density. In order to compare oxygen depletion rates
      of different compounds, we have defined the biological quantum yield (BQY) as the
      number of oxygen molecules that disappear per absorbed photon. The BQY is
      independent of uptake and cell density; therefore, it denotes the intrinsic
      photoactivity of a sensitizer. Sensitizers with high BQY show efficient post
      irradiation intracellular redistribution. Photodegradation during irradiation is
      similar for all sensitizers (20-30%).

PMID- 10577052
TI  - Preventing injuries in children: cluster randomized controlled trial in primary
      care.

PMID- 10577053
TI  - The mode of delivery and the risk of vertical transmission of human
      immunodeficiency virus type I--a meta-analysis of 15 prospective cohort studies.

PMID- 10577054
TI  - Efficacy of home-based peer counseling to promote exclusive breast-feeding: a
      randomized controlled trial.

PMID- 10577055
TI  - Advising parents of asthmatic children on passive smoking: randomized controlled
      trial.

PMID- 10577056
TI  - Pediatric gastroenterology and the AGA.

PMID- 10577058
TI  - NICE.

PMID- 10577057
TI  - Cortical spreading depression in the gyrencephalic feline brain studied by
      magnetic resonance imaging.
AB  - 1.Time-lapse diffusion-weighted magnetic resonance imaging (DWI) was used to
      detect and characterize complex waves of cortical spreading depression (CSD)
      evoked with KCL placed upon the suprasylvian gyrus of anaesthetized cats. 2. The
      time-lapse representations successfully demonstrated primary CSD waves that
      propagated with elliptical wavefronts selectively over the ipsilateral cerebral
      hemispheres with a velocity of 3.8 +/- 0.70 mm min(-1) (mean +/- S.E.M. of 5
      experiments). 3. In contrast, the succeeding secondary waves often remained
      within the originating gyrus, were slower (velocity 2.0 +/- 0.18 mm min(-1), more
      fragmented and varied in number. 4. Computed traces of the apparent diffusion
      coefficients (ADCs) showed negative deflections followed by monotonic decays
      (amplitudes: primary wave, -19.9 +/- 2.8%; subsequent waves, -13.6 +/- 1.9%
      duration at half-maximal decay, 150-200 s) when determined from regions of
      interest (ROIs) through which both primary and succeeding CSD waves propagated.
      5. The passage of both the primary and the succeeding waves often correlated with
      transient DC potential deflections recorded from the suprasylvian gyrus. 6. The
      detailed waveforms of the ADC and the T2*-weighted (blood oxygenation level
      dependent: BOLD) traces showed a clear reciprocal correlation. These imaging
      features that reflect disturbances in cellular water balance agree closely with
      BOLD measurements that followed the propagation velocities of the first and
      subsequent CSD events. They also provide a close physiological correlate for
      clinical observations of cortical blood flow disturbances associated with human
      migraine.

PMID- 10577059
TI  - The consultation in art.

PMID- 10577060
TI  - Beating heart disease with engineering. A meeting organized by the Royal Academy
      of Engineering and held at the Royal Society of Medicine, London, on Thursday 7
      May 1998.

PMID- 10577061
TI  - The Last Universal Common Ancestor and Beyond. Proceedings of a workshop. France,
      July, 1996.

PMID- 10577062
TI  - Incorrect us of "immortalization" for B-lymphoblastoid cell lines transformed by
      Epstein-Barr virus.

PMID- 10577063
TI  - This month in investigative urology: Immunotherapy of bladder cancer.

PMID- 10577064
TI  - Genetically enhanced rice to help fight malnutrition.

PMID- 10577065
TI  - From the Centers for Disease Control and Prevention. Publication of survey
      results of assessment of state health agencies' readiness for 2000.

PMID- 10577066
TI  - A look back: the electrocardiogram.

PMID- 10577067
TI  - 12th Annual Research Meeting of the Kind-Philipp-Foundation for Leukemia
      Research. Wilsede/Luneburger Heide, 2-5 June 1999. Abstracts.

PMID- 10577068
TI  - [Chronic fatigue syndrome is not medically explained. Biomedical explanation is
      confusing for the patient].

PMID- 10577069
TI  - The integrase family of recombinase: organization and function of the active
      site.
AB  - The integrase family of site-specific recombinases (also called the tyrosine
      recombinases) mediate a wide range of biological outcomes by the sequential
      exchange of two pairs of DNA strands at defined phosphodiester positions. The
      reaction produces a recombinant arrangement of the DNA sequences flanking the
      cross-over region. The crystal structures of four integrase family members have
      revealed very similar three-dimensional protein folds that belie the large
      diversity in amino acid sequences among them. The active sites are similar in
      organization to those seen in structures of eukaryotic type IB topoisomerases,
      and conservation of catalytic mechanism is expected. The crystal structures,
      combined with previous biochemical knowledge, allow the refinement of models for
      recombination and the assignment of catalytic function to the active site
      residues. However, each system has its own peculiarities, and the exact sequence
      of events that allows the reaction to proceed from the first exchange reaction to
      the second is still unclear for at least some family members.

PMID- 10577070
TI  - [Type II diabetes mellitus. Rosiglitazone is effective against insulin
      resistance].

PMID- 10577071
TI  - The Third International Conference on Environmental Mutagens in Human
      Populations.

PMID- 10577072
TI  - The departure of Jerome P. Kassirer.

PMID- 10577073
TI  - The departure of Jerome P. Kassirer.

PMID- 10577074
TI  - The departure of Jerome P. Kassirer.

PMID- 10577075
TI  - The departure of Jerome P. Kassirer.

PMID- 10577076
TI  - The departure of Jerome P. Kassirer.

PMID- 10577077
TI  - The departure of Jerome P. Kassirer.

PMID- 10577078
TI  - The departure of Jerome P. Kassirer.

PMID- 10577079
TI  - The departure of Jerome P. Kassirer.

PMID- 10577080
TI  - Cardioversion of atrial fibrillation.

PMID- 10577081
TI  - Estimating the risk of cerebral palsy after assisted conceptions.

PMID- 10577082
TI  - Case 1-1999: Acute hemorrhagic leukoencephalitis.

PMID- 10577083
TI  - Case 1-1999: Acute hemorrhagic leukoencephalitis.

PMID- 10577084
TI  - Case 1-1999: Acute hemorrhagic leukoencephalitis.

PMID- 10577085
TI  - More on deglutition syncope.

PMID- 10577086
TI  - The freezing of time as a presenting symptom of Parkinson's disease.

PMID- 10577087
TI  - Long-term survival after bone marrow transplantation.

PMID- 10577088
TI  - Long-term survival after bone marrow transplantation.

PMID- 10577089
TI  - Hydrogenated fats and serum cholesterol levels.

PMID- 10577090
TI  - Hydrogenated fats and serum cholesterol levels.

PMID- 10577091
TI  - Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs.

PMID- 10577092
TI  - Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs.

PMID- 10577093
TI  - Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs.

PMID- 10577094
TI  - Spinal epidural lipomatosis in a patient with the ectopic corticotropin syndrome.

PMID- 10577095
TI  - More about parkinsonism after taking ecstasy.

PMID- 10577096
TI  - More about parkinsonism after taking ecstasy.

PMID- 10577097
TI  - More about parkinsonism after taking ecstasy.

PMID- 10577098
TI  - Mitral-valve prolapse.

PMID- 10577099
TI  - Mitral-valve prolapse.

PMID- 10577100
TI  - A grade 6 systolic murmur.

PMID- 10577101
TI  - Replacement of the aortic root in Marfan's syndrome.

PMID- 10577102
TI  - Replacement of the aortic root in Marfan's syndrome.

PMID- 10577103
TI  - Association between actinic keratoses and potentially photosensitizing drugs.

PMID- 10577104
TI  - A serologic marker of paraneoplastic limbic and brain-stem encephalitis in
      patients with testicular cancer.

PMID- 10577105
TI  - Infants with CMV and HIV-1.

PMID- 10577106
TI  - Occult gastrointestinal bleeding.

PMID- 10577107
TI  - Munchausen's syndrome by proxy identified with an implantable
      electrocardiographic recorder.

PMID- 10577108
TI  - Prevention of neural-tube defects.

PMID- 10577109
TI  - Fluoroquinolone resistance in Streptococcus pneumoniae.

PMID- 10577110
TI  - Fluoroquinolone resistance in Streptococcus pneumoniae.

PMID- 10577112
TI  - An increase in the number of deaths in the United States in the first week of the
      month.

PMID- 10577111
TI  - Mother-to-infant transmission of the human immunodeficiency virus during primary
      infection.

PMID- 10577113
TI  - An increase in the number of deaths in the United States in the first week of the
      month.

PMID- 10577114
TI  - What's the price of a research subject?

PMID- 10577115
TI  - What's the price of a research subject?

PMID- 10577116
TI  - What's the price of a research subject?

PMID- 10577117
TI  - What's the price of a research subject?

PMID- 10577118
TI  - Students' knowledge of and attitudes about female circumcision in Egypt.

PMID- 10577119
TI  - Medical professionalism in society.

PMID- 10577120
TI  - Authors' conflicts of interest: a disclosure and editors' reply.

PMID- 10577121
TI  - Reimbursement for evaluation and management services.

PMID- 10577122
TI  - Reimbursement for evaluation and management services.

PMID- 10577123
TI  - Reimbursement for evaluation and management services.

PMID- 10577124
TI  - Reimbursement for evaluation and management services.

PMID- 10577125
TI  - Reimbursement for evaluation and management services.

PMID- 10577126
TI  - Reimbursement for evaluation and management services.

PMID- 10577127
TI  - Reimbursement for evaluation and management services.

PMID- 10577128
TI  - Reimbursement for evaluation and management services.

PMID- 10577129
TI  - Neostigmine for acute colonic pseudo-obstruction.

PMID- 10577130
TI  - Neostigmine for acute colonic pseudo-obstruction.

PMID- 10577131
TI  - Neostigmine for acute colonic pseudo-obstruction.

PMID- 10577132
TI  - Neostigmine for acute colonic pseudo-obstruction.

PMID- 10577133
TI  - DNA vaccines.

PMID- 10577134
TI  - The effects of vancomycin and beta-lactam antibiotics on vancomycin-resistant
      Staphylococcus aureus.

PMID- 10577135
TI  - Priming with human chorionic gonadotropin before retrieval of immature oocytes in
      women with infertility due to the polycystic ovary syndrome.

PMID- 10577136
TI  - Should the proposed changes in the OPTN regulations include kidneys?

PMID- 10577137
TI  - [Blood platelets in children too few and too large: the giant platelet
      syndromes].
AB  - In 4 children, two boys aged 15 and two girls aged 17 years, thrombocytopenia was
      found with thrombocyte size of about the diameter of an erythrocyte, so called
      giant platelets. In 3 of the patients no signs of increased bleeding tendency
      were present, while the fourth had bruises, small stature and subnormal hearing.
      The 50-year-old father of 2 of the patients (a brother and sister) had
      thrombocytopenia with giant platelets as well. The patients without an increased
      bleeding tendency were advised to carry a 'medical alert.' Thrombocytopenia with
      giant platelets can be part of a hereditary syndrome in which other organ systems
      may be involved, e.g., kidneys, ears (hearing loss) or eyes (cataract).
      Morphological assessment of thrombocytes in children with chronic
      thrombocytopenia can contribute to the prevention of ineffective therapy
      (corticosteroids, gammaglobulin, splenectomy).

PMID- 10577138
TI  - Clinical Immunology Symposium. Amsterdam, The Netherlands. 4 March 1999.
      Abstracts.

PMID- 10577139
TI  - Special issue dedicated to Dr. Nico M. van Gelder.

PMID- 10577140
TI  - [Improved measurement of knee-joint stability. The Michael-Jager Prize for a
      Stuttgart research group].

PMID- 10577141
TI  - UCN-01-mediated G1 arrest in normal but not tumor breast cells is pRb-dependent
      and p53-independent.
AB  - In this study we investigated the growth inhibitory effects of UCN-01 in several
      normal and tumor-derived human breast epithelial cells. We found that while
      normal mammary epithelial cells w were very sensitive to UCN-01 with an IC(50) of
      10nM tumor cells displayed little to no inhibition of growth with any measurable
      IC(50) at low UCN-01 concentrations (i.e. 0-80 nM). The UCN-01 treated normal
      cells arrested in G1 phase and displayed decreased expression of most key cell
      cycle regulators examined, resulting in inhibition of CDK2 activity due to
      increased binding of p27 to CDK2. Tumor cells on the other hand displayed no
      change in any cell cycle distribution or expression of cell cycle regulators.
      Examination of E6- and E7-derived strains of normal cells revealed that pRb and
      not p53 function is essential for UCN-01-mediated G1 arrest. Lastly, treatment of
      normal and tumor cells with high doses of UCN-01 (i.e. 300 nM) revealed a
      necessary role for a functional G1 checkpoint in mediating growth arrest. Normal
      cells, which have a functional G1 checkpoint, always arrest in G1 even at very
      high concentrations of UCN-01. Tumor cells on the other hand have a defective G1
      checkpoint and only arrest in S phase with high concentrations of UCN-01. The
      effect of UCN-01 on the cell cycle is thus quite different from staurosporine, a
      structural analogue of UCN-01, which arrests normal cells in both G1 and G2,
      while tumor cells arrest only in the G2 phase of the cell cycle. Our results show
      the different sensitivity to UCN-01 of normal compared to tumor cells is
      dependent on a functional pRb and a regulated G1 checkpoint.

PMID- 10577142
TI  - An outcomes study of cochlear implants in deaf patients.

PMID- 10577143
TI  - Some problems with wind-up and its calculation.

PMID- 10577144
TI  - The role of sex hormones in pain response.

PMID- 10577145
TI  - Weaning from gastrostomy tube feeding: commentary on oral aversion.

PMID- 10577146
TI  - Etiology and clinical signs of serious infections in young infants in developing
      countries: a WHO collaborative study.

PMID- 10577147
TI  - Sedation in emergency situations.

PMID- 10577148
TI  - Child advocates.

PMID- 10577149
TI  - Role of hypothermia in asphyxia.

PMID- 10577150
TI  - Developmental care does not alter sleep and development of premature of infants.

PMID- 10577151
TI  - Palivizumab (Synagis)--cohorting babies to reduce waste.

PMID- 10577152
TI  - Useful mnemonic for remembering the AAP's suggestions for clinical violence
      prevention and management. American Academy of Pediatrics.

PMID- 10577153
TI  - A new vision for collective bargaining.

PMID- 10577154
TI  - Index of suspicion. Case 2. Diabetes insipidus.

PMID- 10577155
TI  - Index of suspicion. Case 3. Perforated appendix with purulent peritoneal fluid.

PMID- 10577156
TI  - Academic challenge: teacher burnout...

PMID- 10577157
TI  - Current awareness in prenatal diagnosis.

PMID- 10577158
TI  - [Lucien Leger, 1912-1999].

PMID- 10577159
TI  - Proceedings of the 3rd meeting on the Critical Assessment of Techniques for
      Protein Structure Prediction. Asilomar, December 1998.

PMID- 10577160
TI  - Sperm mobility determines the outcome of sperm competition in the domestic fowl.
AB  - The aim of this study was to establish whether the mobility of sperm of the
      domestic fowl, as measured by an in vitro assay, predicted the outcome of sperm
      competition. Thirteen pairs of New Hampshire roosters, comprising one male
      categorized as having high-mobility sperm and the other as having average
      mobility sperm, were used. Each male provided 25 x 10(6) sperm, which were mixed
      and artificially inseminated into between four and seven New Hampshire hens, each
      of which produced 2-11 offspring. The experiment was conducted twice, such that
      the same pair of males inseminated the same females. Paternity was assigned by
      using microsatellite markers. There was a clear effect of sperm-mobility
      phenotype on the outcome of sperm competition: in all 13 pairs the high-mobility
      male fathered the majority of offspring (75.3% overall; p < 0.0001). The
      proportion of offspring fathered by the high-mobility male within pairs varied
      significantly between male pairs (p < 0.0005). This effect was associated with
      the difference in sperm-mobility scores between males within pairs; there was a
      significant positive relationship between the proportion of offspring fathered by
      the high-mobility male and the ratio of mobility scores between males (p < 0.05).
      In addition, compared with their success predicted from the non-competitive
      situation, in the competitive situation high-mobility males were
      disproportionately successful in fertilizing eggs compared with average-mobility
      males. This may occur because female sperm storage is limited in some way and a
      greater proportion of high-mobility sperm gain access to the female's sperm
      storage tubules. There was no evidence that female effects accounted for any of
      the variation in paternity.

PMID- 10577161
TI  - Proceedings of the 1st International Conference on Inhibitors of Protein Kinases.
      Warsaw, Poland, September 15-20, 1998.

PMID- 10577162
TI  - Guide to Physical Therapist Practice: revisions.

PMID- 10577163
TI  - The electronic Plant Gene Register.

PMID- 10577164
TI  - Is a paradigm shift occurring in brief psychological treatments?

PMID- 10577165
TI  - Does repair of radiation damage play a role in breast cancer?

PMID- 10577166
TI  - [2nd International meeting on human and animal infections due to Chlamydia,
      Mycobacteria, Brucella and Borrelia. Buenos Aires, Argentina, 25 June-4 July
      1997. Proceedings].

PMID- 10577167
TI  - Acute Renal Failure Satellite Symposium. International Society of Nephrology,
      Chilean Society of Nephrology. Santiago, Chile, May 7-8, 1999. Abstracts.

PMID- 10577168
TI  - The pelvic-pulmonary connection.

PMID- 10577169
TI  - Obesity and the respiratory system: new methods to examine an old question.

PMID- 10577170
TI  - How to manage the low-risk patient with lower respiratory tract infection?

PMID- 10577171
TI  - New definitions of sleep disordered breathing--not yet a mandate in clinical
      practice.

PMID- 10577172
TI  - [Taking responsibility for the small child. A report of the 16th Annual Meeting
      of the Association Suisse de Pedodontie (ASP), 21 January 1999 in Bern].

PMID- 10577173
TI  - [The annual meeting of the Societe suisse d'orthopedie dento-faciale on the
      accumulated experience of Swiss university professors].

PMID- 10577174
TI  - ["He who knows the truth and does not speak it, remains a dishonorable wretched
      creature" (Daniel August von Binzer 1793-1868, at the 1817 Wartburg fete).
      "Honesty is the greatest of mischiefs for it is the only thing that the cunning
      do not anticipate" (Alexandre Dumas fils, 1824-1895)].

PMID- 10577175
TI  - [Quality standards and the European TQM model in dental practice (1)].

PMID- 10577176
TI  - [The determination of the status of oral implantology in 2000. The St. Moritz
      Dental Continuing Education week of 21-27 March 1999].

PMID- 10577177
TI  - [Anonymous: "Saint Apollonia and Saint Dorothea". The BonaDent Collection].

PMID- 10577178
TI  - [Quality guidelines: the trump for us dentists].

PMID- 10577179
TI  - [A consensus on basal osseointegrated implants (BOI). The Implantoral-Club
      Germany (ICD)].

PMID- 10577180
TI  - [Comments on the reader's letter "The fluoride content in children's
      toothpastes"].

PMID- 10577181
TI  - [The patient's right to information].

PMID- 10577182
TI  - Groups race to sequence and identify New York virus.

PMID- 10577183
TI  - Nuclear accident. Special treatment set for radiation victim.

PMID- 10577184
TI  - Possible new anti-inflammatory agent.

PMID- 10577185
TI  - Mouse genome added to sequencing effort.

PMID- 10577186
TI  - Philanthropy's rising tide lifts science.

PMID- 10577187
TI  - A new finger on the protein destruction button.

PMID- 10577188
TI  - First components found for new kidney filter.

PMID- 10577189
TI  - Stevenson's fingers.

PMID- 10577190
TI  - Support for structural genomics and synchrotrons.

PMID- 10577191
TI  - Microbial ecology. How to avoid oxygen.

PMID- 10577192
TI  - Proton pump caught in the act.

PMID- 10577193
TI  - Kourilsky takes helm at the Pasteur Institute.

PMID- 10577194
TI  - Varmus to leave NIH in December to run Sloan-Kettering...

PMID- 10577196
TI  - Policing of science. A misconduct definition that finally sticks.

PMID- 10577195
TI  - New insights into cystic fibrosis ion channel.

PMID- 10577197
TI  - Are genetic tests adequately regulated?

PMID- 10577198
TI  - Keeping calm about Kansas.

PMID- 10577199
TI  - Keeping calm about Kansas.

PMID- 10577200
TI  - Evolution flies.

PMID- 10577201
TI  - Evolution flies.

PMID- 10577202
TI  - Evolution flies.

PMID- 10577203
TI  - Defensins and host defense.

PMID- 10577205
TI  - Sequencing. Gels and genomes.

PMID- 10577204
TI  - Neurobiology. The constant junction.

PMID- 10577206
TI  - PEG antibodies.

PMID- 10577207
TI  - Do-it-yourself gene watching.

PMID- 10577208
TI  - Keeping genome databases clean and up to date.

PMID- 10577210
TI  - Enzymes point way to potential Alzheimer's therapies.

PMID- 10577209
TI  - Genome maps 10. Comparative genomics. Mammalian radiations. Wall chart.

PMID- 10577211
TI  - Science supporter John Porter to leave Congress.

PMID- 10577212
TI  - On the track of Ebola's hideout?

PMID- 10577213
TI  - PNAS to joint PubMed Central--on condition.

PMID- 10577214
TI  - Transgenic food debate. The Lancet scolded over Pusztai paper.

PMID- 10577215
TI  - Scientists strike back against creationism.

PMID- 10577216
TI  - Prions: a lone killer or a vital accomplice?

PMID- 10577217
TI  - Aging research. Do mitochondrial mutations dim the fire of life?

PMID- 10577218
TI  - A new blocker for the TGF-beta pathway.

PMID- 10577219
TI  - Protein ZIP codes make Nobel journey.

PMID- 10577220
TI  - New online tools for scholars: 3.

PMID- 10577221
TI  - Science and scripture.

PMID- 10577222
TI  - Science and scripture.

PMID- 10577223
TI  - Science and scripture.

PMID- 10577224
TI  - Documenting speciation.

PMID- 10577225
TI  - Perspectives: neurobiology. Cranking it up a notch.

PMID- 10577226
TI  - Do proteins predate DNA?

PMID- 10577227
TI  - Following the scent of avian olfaction.

PMID- 10577228
TI  - Salmon follow watery odors home.

PMID- 10577229
TI  - Paleontology. Siberian mammoth find raises hopes, questions.

PMID- 10577230
TI  - Evolutionary genetics. The why behind the Y chromosome.

PMID- 10577231
TI  - Obesity research. Leptin not impressive in clinical trial.

PMID- 10577232
TI  - Scientific misconduct. Shalala takes watchdog office out of the hunt.

PMID- 10577233
TI  - Molecular biology. Candidate 'gene silencers' found.

PMID- 10577234
TI  - Fetal cells help Parkinson's patients.

PMID- 10577235
TI  - Scientific publishing. Researchers plan free global preprint archive.

PMID- 10577236
TI  - Turning thoughts into actions.

PMID- 10577237
TI  - A long season puts Catalhoyuk in context.

PMID- 10577238
TI  - Genetic disease. Sweden takes steps to protect tissue banks.

PMID- 10577239
TI  - Quoting the Hippocratic Oath.

PMID- 10577240
TI  - Silent scientists.

PMID- 10577241
TI  - Assessing the spread of engineered TMV.

PMID- 10577242
TI  - New tools for the antimitotic toolbox.

PMID- 10577243
TI  - Perspectives: neurobiology. PrP's double causes trouble.

PMID- 10577244
TI  - [Allogenic hand transplantation. A case report of the first 6 months].

PMID- 10577245
TI  - [Abstracts of the presentations delivered at the 12th World AIDS Conference].

PMID- 10577246
TI  - [Improved survival rate by postoperative radiotherapy in postmenopausal high risk
      patients with breast carcinoma].

PMID- 10577248
TI  - Notice of duplicate publication.

PMID- 10577247
TI  - Pseudo-steroid resistant asthma.

PMID- 10577249
TI  - The frontiers of sleep.

PMID- 10577250
TI  - Channel-linked receptors--from subunits to novel drug targets.

PMID- 10577251
TI  - One wheel on my wagon: lysolipid phosphate signalling.

PMID- 10577252
TI  - Peptide autoreceptors: does an autoreceptor for substance P exist?
AB  - The presence of autoreceptors for simple neurotransmitters at synapses in the
      mammalian nervous system is well established. By contrast, the evidence for such
      receptors modifying neuropeptide transmission is less obvious. Probably the most
      well characterized of the neuropeptides is substance P (SP), which appears to
      play a major role as a primary afferent modulator. This article highlights
      evidence to support the existence of autoreceptors that might modulate the
      release of this neuropeptide and which, therefore, could be important in the
      design of drugs affecting SP function, not only in sensory processing, but also
      elsewhere in the brain.

PMID- 10577254
TI  - [Trends in the treatment of ovarian neoplasm. Proceedings of a meeting].

PMID- 10577253
TI  - The EGF receptor as central transducer of heterologous signalling systems.
AB  - The cross-talk between heterologous signalling systems of the cell represents a
      new dimension of complexity in the molecular communication network that governs a
      great variety of physiological processes. In pathophysiologically transformed
      cells, key elements of this network could offer unique opportunities for
      pharmacological intervention. In this article, the current state of knowledge
      regarding the role of epidermal growth factor (EGF) in such a network is
      described and the recent advances made in the elucidation of the mechanism
      underlying EGF receptor transactivation are discussed.

PMID- 10577255
TI  - Proceedings of the 2nd Conference of the Australian Veterinary Virology Group.
      Melbourne, September 24-26, 1998.

PMID- 10577256
TI  - [The 1st Congress of Transfusion Specialists of Russia and a meeting of blood
      service specialists of the Armed Forces].

PMID- 10577257
TI  - [An instructional-methodological meeting of the medical staff of military
      sanatoria].

PMID- 10577258
TI  - [Dissertations defended in 1999].

PMID- 10577260
TI  - Proceedings of the 4th International Symposium on Viruses of Lower Vertebrates.
      United Kingdom, 12-15 May 1998.

PMID- 10577259
TI  - Haemovigilance systems.

PMID- 10577261
TI  - Current awareness on yeast.

PMID- 10577262
TI  - [The antinociceptive action of the poison of the spotted salamander Salamandra
      salamandra].

PMID- 10577263
TI  - [The conformational-correlational aspects of the substrate specificity of the
      cholinesterases in the Pacific Ocean squid Todarones pacificus and in mammals].

PMID- 10577264
TI  - [Mechanisms for formation and maintenance of synapses mediated by biogenic
      amines: pathogenesis and therapy of mental retardation and developmental
      disabilities by genetic and epigenetic factors].
AB  - Fibers of the global projection system ramify tremendously and distribute in the
      diverse region of the brain. Biogenic amines in the global projection system have
      been shown to facilitate formation and maintenance of synapses in the developing
      and adult brain. In terms of serotonin 5-HT2A receptor was shown to mediate the
      function of serotonin. We raised specific antibodies against 5-HT2A receptor
      protein. Virtually all the neurons in the cerebral cortex expressed 5-HT2A
      receptor. By using the function of biogenic amines to facilitate synapse
      formation and maintenance a novel approach can be developed in the neuroscience.
      That is to perturb biogenic amines, to change synaptic density, and to examine
      changes in the ability of learning and memory. Removing serotonin and
      acetylcholine for a week, at the maximum 58% of synapses are decreased in the
      hippocampus. The animals losing synapses spent a longer latency compared to
      intact animals in Morris water maze. The level of biogenic amines in the
      developing brain has been known to decrease tremendously by genetic diseases such
      as phenylketonuria, Down syndrome and autism as well as environmental factors
      such as nutrition and stress. In those situations synapses in the brain are
      suggested to be decreased. Synaptic mechanism for mental retardation and
      developmental disability by the cascade appears to contribute for understanding
      pathophysiology and a new therapy.

PMID- 10577265
TI  - Early predictors of intractability in childhood epilepsy: a community-based case
      control study in Copparo, Italy.
AB  - OBJECTIVES: To identify early predictors of intractability in childhood and
      adolescence epilepsy. MATERIALS AND METHODS: We carried out a community-based
      case-control study using the incidence cohort of epileptic patients living in the
      district of Copparo, in the province of Ferrara, Italy. The comparative study was
      performed in 31 cases and 95 controls. Cases were patients who averaged at least
      1 unprovoked seizure per month during an observational period of at least 2
      years. Controls were subjects having achieved remission for at least 5 years
      regardless of current therapy. RESULTS: Onset at age <1 year, remote symptomatic
      etiology and high frequency of seizures before therapy were found to be
      independent early predictors of intractability. CONCLUSION: Our study suggested
      that the risk of developing intractable epilepsy may, to some extent, be
      predicted at the time of initial diagnosis in children with early-onset epilepsy
      of remote symptomatic etiology, especially if seizure propensity is initially
      high.

PMID- 10577266
TI  - Verbal semantic memory in temporal lobe epilepsy.
AB  - OBJECTIVES: Temporal lobe epilepsy (TLE) may determine memory difficulties not
      explained by episodic memory impairment. The present study was aimed to verify
      the presence of specific semantic memory dysfunctions in TLE and to explore their
      relations to epilepsy variables. SUBJECTS AND METHODS: Forty-seven patients with
      lateralized temporal (n = 26) or extra-temporal lobe epilepsy (n = 21) and 23
      healthy subjects were compared. Picture Naming and Pointing to a Picture were
      used to explore expressive and receptive vocabulary and the Semantic
      Questionnaire evaluated semantic judgment of verbally presented items. The
      Selective Reminding Procedure for word list learning and Story Recall were used
      to assess episodic memory. Spontaneous speech and the Token Test controlled for
      language disturbances, and Raven's Coloured Progressive Matrices were used to
      evaluate abstract reasoning ability. RESULTS: Multivariate analysis of variance
      of test scores showed significant impairment of semantic memory in patients with
      left TLE compared to healthy controls, whereas episodic memory was impaired in
      left temporal and extra-temporal epilepsy (as measured by word learning) and all
      epilepsy groups (as measured by Story Recall). In the TLE groups, naming
      abilities were more compromised than single-word comprehension and semantic
      judgment - which were not significantly affected. No deficits in language
      abilities or in abstract reasoning were found in any patient group. Factor
      analysis of memory tests scores in the patients produced two factors, one
      semantic and the other episodic. Regression analysis revealed that the semantic
      factor was related to abstract reasoning, left hemisphere lateralization of
      seizures, and age of seizure onset; while the episodic factor was related to age.
      CONCLUSIONS: Left TLE may determine significant verbal semantic memory
      compromise, maybe due to impaired access to the semantic-lexical storage. In non
      aphasic epilepsy patients, comparison of performance on semantic and episodic
      memory tests may be useful for assessing the nature of memory failures, and may
      complement clinical and neurophysiological means for defining the epileptic
      center.

PMID- 10577268
TI  - Clinical evaluation of the driving ability in stroke patients.
AB  - OBJECTIVES: Stroke often causes physical, cognitive and psychomotor dysfunction,
      which markedly decreases the driving ability of stroke patients. The aim of this
      study was to evaluate the driving ability of stroke patients using
      multidisciplinary clinical evaluation and driving-related laboratory tests.
      MATERIALS AND METHODS: A neurologist evaluated the driving ability of 20 male
      stroke patients on the basis of his own clinical examination and the observations
      and measurements of a neurological multidisciplinary rehabilitation team. After
      that a traffic psychologist evaluated the patients' driving ability on the basis
      of the driving-related cognitive and psychomotor laboratory tests. The patients
      themselves also evaluated their driving ability, as did their spouses. All the
      evaluations were carried out independently using the same 10-point scale. The
      control group consisted of 20 healthy males, matched by age and driving
      experience, who went through the same laboratory test package as the patients
      did. RESULTS: The stroke patients had more deficiencies in all tested driving
      related cognitive and psychomotor functions than the controls. The neurologist
      and the psychologist together evaluated 12 (60%) of the 20 stroke patients being
      unable to drive; 8 patients out of 11 with non-dominant hemisphere lesion and 4
      in the dominant group. The patients themselves and their spouses had a clear
      tendency to overestimate driving ability compared to the estimates of the
      neurologist and the psychologist. The hit-rate of the evaluations of the
      neurologist and traffic psychologist (75%) was high. CONCLUSION: Stroke patients
      form a risk group as drivers due to their decreased cognitive and psychomotor
      abilities, and driving ability should always be evaluated after stroke. The
      results suggest that multidisciplinary neurological teams are able to evaluate
      the driving ability of stroke patients reliably. A careful evaluation of driving
      ability without a driving test requires assessment of cognitive and psychomotor
      functions critical in driving, which is not feasible for physicians without the
      support of a multidisciplinary team and/or traffic-related laboratory tests.

PMID- 10577267
TI  - Outcome for patients with carotid stenosis undergoing carotid endarterectomy, the
      cerebral condition followed by extra/intracranial ultrasound examinations.
AB  - Seventy-six patients undergoing carotid endarterectomy were studied to estimate
      the effect of operation, evaluate the accessible methods of examination and
      disclose the complications owing to the operation. In addition, the hypothesis
      that the pulsatility index in MCA measured by the Doppler method could disclose
      severe ischemia and risk of complications during endarterectomy was tested. The
      study was a prospective study of patients operated at the University Hospital in
      Odense in the years 1991-1996. Data collected included demographics, operative
      indications, complications, follow-up extra/transcranial Doppler examinations,
      cerebrovascular reactivity investigations, recurrent symptoms and deaths.
      Concerning the carotid stenosis, a fairly good correlation was found between the
      results of extracranial Doppler examinations, Duplex and carotid angiography.
      Serious complications after surgery were few. One patient, who had a coronary by
      pass operation consecutive to the endarterectomy, died 3 weeks after the
      operation, owing to a hematothorax. Five patients (7%) suffered a stroke. Only 2
      patients needed rehabilitation, and they came out with minor disturbances in the
      use of a hand. Recurrent stenosis in excess of 69% emerged in 3% of the patients.
      All were hemodynamically insignificant. One patient had a new TIA during the
      observation time of 3-60 months. After the operation she had a thrombosis in the
      operated carotid artery. Thus our results, a perioperative stroke rate of 7% and
      a mortality rate of 1%, are in line with the average results in multicenter
      trials. In addition a PI below 0.60 in the MCA seemed to be a warning of the risk
      of postoperative cerebral hyperemia.

PMID- 10577269
TI  - Cerebral microembolism, a disease marker for ischemic cerebrovascular events in
      the antiphospholipid syndrome of systemic lupus erythematosus?
AB  - OBJECTIVES: We investigated whether the detectability of microembolic Doppler
      signals (MES) in the intracranial circulation may help to define the individual
      cerebrovascular risk in systemic lupus erythematosus (SLE) with antiphospholipid
      syndrome (APS). MATERIAL AND METHODS: Retrospective cross-sectional study of 70
      patients with SLE with or without APS, and 30 controls with a history of cerebral
      ischemia of unknown cause. Of all patients, 38 had a clinical history of APS and
      32 did not. RESULTS: 15 patients with APS (39%) showed MES. In contrast, all
      patients without APS and 29 of 30 controls were microemboli-negative. MES were
      more strongly associated with cerebrovascular symptoms than with APS,
      antiphospholipid antibodies, or cardiac pathology. The time elapsed since the
      last ischemic cerebrovascular symptom was significantly shorter in microemboli
      positive patients than in microemboli-negative patients (P<0.001). CONCLUSION:
      MES may be related to disease activity in patients with SLE and APS. Their
      detection may help to assess individual cerebrovascular risk and contribute to
      therapeutic decision making and therapeutic monitoring.

PMID- 10577270
TI  - Visual hallucinations, white matter lesions and disease severity in Parkinson's
      disease.
AB  - OBJECTIVES: To determine if visual hallucinations in patients with Parkinson's
      disease are associated with an increased prevalence of white matter lesions.
      PATIENTS AND METHODS: Fifteen patients with (group 1) and 15 patients without
      (group 2) a history of visual hallucinations were studied. Both groups were
      matched for age. Magnetic resonance imaging was performed in all patients using
      standard T2 weighted Fast-Spin-Echo sequences. Assessment of cerebral white
      matter changes was performed using a modification of established criteria, with
      semiquantitative evaluation of periventricular and deep white matter changes.
      RESULTS: There was no significant group difference with regard to the total
      amount of white matter changes, nor was a group difference found between the
      amount or extent of periventricular hyperintensities or deep white matter
      lesions. Group 1 was significantly (P = 0.001) more disabled as evaluated by
      Hoehn/Yahr stage controlling for age and duration of disease. Mean increases in
      Hoehn/Yahr stage were not significantly greater in group 1 compared with group 2
      at a 2-year follow-up examination (0.6 vs. 0.3, P = 0.166). CONCLUSION: Our data
      suggest that visual hallucinations are an indicator of a more aggressive course
      of the disease, but are not associated with a higher prevalence of global or
      occipital white matter lesions.

PMID- 10577271
TI  - Development of REM sleep atonia.
AB  - OBJECTIVES: To study the functional development of neuronal systems that suppress
      muscle activity, we quantified the chronological change of atonia in rapid-eye
      movement sleep (REMS). METHODS: REMS atonia was quantified by the tonic and
      phasic inhibition indices (TII and PII). TII indicates the shortness of chin
      muscle activity, whereas PII standardizes the simultaneous occurrence of chin
      muscle activity and bursts of rapid eye movements. TII and PII were calculated in
      REMS of 135 polysomnographical recordings obtained in healthy humans from
      premature babies to a 77-year-old man. RESULTS: TII increased significantly with
      age, while PII decreased significantly. TII reached an adult level at
      preadolescence, while PII at early infancy. CONCLUSION: Human nervous systems
      involved in both tonic and phasic inhibition in REMS raise their activities with
      age. Since TII and PII reach adult levels at different ages, suppression of
      muscle activity is hypothesized to be mediated through at least 2 independent
      systems in humans.

PMID- 10577272
TI  - Hybrid survival motor neuron genes in Japanese patients with spinal muscular
      atrophy.
AB  - Spinal muscular atrophy (SMA) is a frequently occurring autosomal recessive
      disease, characterized by the degeneration of spinal cord anterior horn cells,
      leading to muscular atrophy. Most SMA patients carry homozygous deletions of the
      telomeric survival motor neuron gene (SMN) exons 7 and 8. In the study presented
      here, we examined 20 Japanese SMA patients and found that 4 of these patients
      were lacking in telomeric SMN exon 7, but retained exon 8. In these 4 patients,
      who exhibited all grades of disease severity, direct sequencing analysis
      demonstrated the presence of a hybrid SMN gene in which centromeric SMN exon 7
      was adjacent to telomeric SMN exon 8. In an SMA family, a combination of
      polymerase chain reaction and enzyme-digestion analysis and haplotype analysis
      with the polymorphic multicopy marker Agl-CA indicated that the patient inherited
      the hybrid gene from her father. In conclusion, hybrid SMN genes can be present
      in all grades of disease severity and inherited from generation to generation in
      an SMA family.

PMID- 10577273
TI  - Impaired ascendant central pathways conduction in impotent diabetic subjects.
AB  - OBJECTIVES: Diabetic impotence is generally due to peripheral neuropathy, but a
      central pathway impairment has also been suggested. We evaluated somatosensory
      transmission in a group of impotent diabetic men to assess the role of central
      nervous system (CNS) involvement. MATERIALS AND METHODS: Somatosensory evoked
      potentials (SEPs) of pudendal (pdn) and posterior tibial (ptn) nerves were
      recorded in 74 patients. Type and duration of diabetes, severity of sexual
      dysfunction, medium term metabolic control, occurrence of microangiopathic
      chronic complications and autonomic neuropathy were evaluated. RESULTS: Our data
      show an impairment of central conduction times in pdn (25.7%) and ptn (39.2%)
      greater than peripheral nervous impairment (pdn 12.2%, ptn 8.1%), in impotent
      diabetic patients without any further major complication. Central nervous
      conduction delay resulted to be correlated with poor glycemic control.
      Significant evident autonomic dysfunction was found only in a minority of cases.
      CONCLUSION: Our data might suggest that altered conduction along CNS and somatic
      peripheral neuropathy might develop independently. We confirm the hypothesis of a
      "central diabetic neuropathy" and suggest that central sensory pathways
      involvement, not related to peripheral impairment, could play a role in the
      pathogenesis of erectile dysfunction in diabetic patients.

PMID- 10577275
TI  - Proceedings of the 3rd International Symposium on Paget's Disease. Napa,
      California, USA. November 29-30, 1998.

PMID- 10577274
TI  - Cerebrospinal fluid levels of biotin in various neurological disorders.
AB  - OBJECTIVES: To analyse biotin concentrations in human cerebrospinal fluid (CSF)
      and serum from controls without evidence of nutritional or neurological disorders
      and patients with common neurological disorders. PATIENTS AND METHODS:
      Cerebrospinal fluid was obtained from patients by lumbar puncture, serum was
      prepared from freshly drawn whole blood and biotinidase in samples was inhibited
      before being analysed for biotin by radioligand assay. RESULTS: Assay
      characteristics were within an acceptable range (intra-and interassay coefficient
      of variations were 8.8 and 12.0 respectively, recovery: 91-114% and sensitive,
      lowest standard concentration 15 ng/l). Significantly lower values for biotin
      were found in patients with multiple sclerosis (both CSF and serum) in comparison
      to the controls. Significantly reduced values for cerebrospinal fluid biotin were
      found in epileptics compared to controls, whereas, in serum the difference was
      approaching significance. No significant differences were observed in other
      groups of patients. CONCLUSION: There is a significant reduction in cerebrospinal
      fluid biotin in epileptics and patients with multiple sclerosis compared to
      controls. In epileptics this may be related to competition between biotin and
      anticonvulsants bearing carbamide ring for absorption. Reduction of biotin levels
      in patients with multiple sclerosis could be attributed to intestinal
      malabsorption caused by the underlying disease or a biotin-binding immunoglobulin
      which may be involved in multiple sclerosis pathogenesis.

PMID- 10577276
TI  - Gender, race, and class in organizational contexts.
AB  - Creating settings that support diversity has been a long-standing concern of
      community psychology. In this paper, I propose two qualities as important aspects
      of organizational contexts that support the meaningful participation of diverse
      groups: (a) a culture of connection and (b) recognition of multiple "realities."
      For each theme, I first examine countervailing values that can undermine
      meaningful participation of nondominant groups. I suggest that organizational
      values for independence and a press for sameness can contribute to settings where
      members of traditionally oppressed groups will be prevented from meaningful
      participation. I also suggest that fostering a culture of connectedness that
      actively legitimizes multiple realities is a constructive alternative. To
      illustrate these points, I share observations based on experiences in
      manufacturing, educational, and community-based settings. Then, I explore two
      dynamics that are important when confronting the countervailing values and
      building more inclusive contexts: (a) accountability for impact and (b) privilege
      dynamics. Last, I turn to some possibilities for change through a stance of
      connected disruption.

PMID- 10577277
TI  - Further dialogue on indirect bonding.

PMID- 10577278
TI  - Does root morphology change?

PMID- 10577279
TI  - A novel mutation of the erythroid-specific gamma-Aminolevulinate synthase gene in
      a patient with non-inherited pyridoxine-responsive sideroblastic anemia.
AB  - A novel missense mutation, G663A, in exon 5 of the erythroid-specific delta
      aminolevulinate synthase gene (ALAS2) was identified in a Japanese male with
      pyridoxine-responsive sideroblastic anemia. Activity of the mutant delta
      aminolevulinate synthase protein expressed in vitro was 15.1% compared with the
      normal control, but was increased up to 34.5% by the addition of pyridoxal 5'
      phosphate, consistent with the clinical response of the patient to pyridoxine
      treatment. The same mutation was also detected in genomic DNa from the oral
      mucosal membrane of the patiet; however, it was not detected in other family
      member. These findings suggest that this G663A mutation is responsible for
      sideroblastic anemia in the proband, and may be an index mutation in this
      pedigree.

PMID- 10577280
TI  - Acquired pure megakaryocytic aplasia report of two cases with long-term responses
      to antithymocyte globulin and cyclosporine.
AB  - Acquired pure megakaryocytic aplasia is a rare disorder defined by severe
      thrombocytopenia with no other hematologic abnormalities and absent, or severely
      decreased marrow megakaryocytes. The etiology may be immune suppression of
      megakaryocyte development. Two patients are described who both responded rapidly
      to a combination of antithymocyte globulin and cyclosporine and who remain in
      remission 13-20 months after discontinuation of cyclosporine. This regimen is
      well described for treatment of aplastic anemia and may also be effective for
      acquired pure megakaryocytic aplasia.

PMID- 10577282
TI  - Reactive oxygen species production of neutrophils in patients with acute
      promyelocytic leukemia during treatment with all-trans retinoic acid.
AB  - We measured N-formyl-methionyl-leucyl-phenylalanine-induced reactive oxygen
      species production by neutrophils from three patients with acute promyelocytic
      leukemia during treatment with all-trans retinoic acid using a luminol-enhanced
      chemiluminescence assay. The maximum level of reactive oxygen species production
      during all-trans retinoic acid treatment was 58.8 +/- 2.3 x 10(4) (mean +/- SEM)
      counted photons per seconds (cps), which was significantly higher (p<0.0001) than
      that of neutrophils from health volunteers (13.3 +/- 2.3 x 10(4) cps).

PMID- 10577281
TI  - Decreased expression of p33ING1 mRNA in lymphoid malignancies.
AB  - The ING1 is a newly cloned putative tumor-suppressor gene, which is involved in
      the p53 signaling pathway. We found decreased expression of ING1 mRNA in 4 of 5 T
      cell lines and 5 of 11 B-cell lines including two Burkitt lymphomas and two
      myelomas. These observations suggest that decreased ING1 expression might play an
      important role in the development or progression of some lymphoid tumors.
      Polymerase chain reaction-SSCP and sequencing analyses found neither point
      mutations nor small deletions in the ING1 gene, suggesting that decreased
      expression is due to transcriptional or post-transcriptional mechanisms.

PMID- 10577283
TI  - Proceedings of the 7th Joint Science Symposium on Occupational Safety and Health.
      Hidden Valley, Pennsylvania, USA. October 26-29, 1998.

PMID- 10577284
TI  - Patience for Terrence.

PMID- 10577285
TI  - Determinants of abdominal circumference.

PMID- 10577286
TI  - Gender and heart rate regulation.

PMID- 10577287
TI  - Ventricular fibrillation during spinal surgery.

PMID- 10577288
TI  - [12th Congress of Virology of Versailles-Le Chesnay. 20, 21 May 1999].

PMID- 10577289
TI  - Metabolic acidosis and coma after acetaminophen ingestion.

PMID- 10577290
TI  - Effect of magnesium hydroxide on iron absorption after ferrous sulfate.

PMID- 10577291
TI  - Cardioversion of paroxysmal atrial fibrillation.

PMID- 10577292
TI  - Leukocyte count in diagnosis of acute appendicitis.

PMID- 10577293
TI  - XX Meeting of Micromolecular Evolution, Systematics, and Ecology. Rio de Janeiro,
      Brazil, 19-21 August 1998. Proceedings.

PMID- 10577294
TI  - Older age, aggressiveness of care, and survival for seriously ill, hospitalized
      adults. SUPPORT Investigators. Study to Understand Prognoses and Preferences for
      Outcomes and Risks of Treatments.
AB  - BACKGROUND: Older age is associated with less aggressive treatment and higher
      short-term mortality due to serious illness. It is not known whether less
      aggressive care contributes to this survival disadvantage in elderly persons.
      OBJECTIVE: To determine the effect of age on short-term survival, independent of
      baseline patient characteristics and aggressiveness of care. DESIGN: Secondary
      analysis of data from a prospective cohort study. SETTING: Five academic medical
      centers participating in SUPPORT (Study to Understand Prognoses and Preferences
      for Outcomes and Risks of Treatments). PATIENTS: 9105 adults hospitalized with
      one of nine serious illnesses associated with an average 6-month mortality rate
      of 50%. MEASUREMENTS: Survival through 180 days of follow-up. In Cox proportional
      hazards modeling, adjustment was made for patient sex; ethnicity; income;
      baseline physical function; severity of illness; intensity of hospital resource
      use; presence of do-not-resuscitate orders on study day 1; and presence and
      timing of decisions to withhold transfer to the intensive care unit, major
      surgery, dialysis, blood transfusion, vasopressors, and tube feeding. RESULTS:
      The mean (+/- SD) patient age was 63 +/- 16 years, 44% of patients were female,
      and 16% were black. Overall survival to 6 months was 53%. In analyses that
      adjusted for sex, ethnicity, income, baseline functional status, severity of
      illness, and aggressiveness of care, each additional year of age increased the
      hazard of death by 1.0% (hazard ratio, 1.010 [95% CI, 1.007 to 1.013]) for
      patients 18 to 70 years of age and by 2.0% (hazard ratio, 1.020 [CI, 1.013 to
      1.026]) for patients older than 70 years of age. Adjusted estimates of age
      specific 6-month mortality rates were 44% for 55-year-old patients, 48% for 65
      year-old patients, 53% for 75-year-old patients, and 60% for 85-year-old
      patients. Similar results were obtained in analyses that did not adjust for
      aggressiveness of care. Acute physiology and diagnosis had much larger relative
      contributions to prognosis than age. CONCLUSIONS: We found a modest independent
      association between patient age and short-term survival of serious illness. This
      age effect was not explained by the current practice of providing less aggressive
      care to elderly patients.

PMID- 10577295
TI  - Prophylactic fluconazole in liver transplant recipients. A randomized, double
      blind, placebo-controlled trial.
AB  - BACKGROUND: Among persons who receive solid organ transplants, liver transplant
      recipients have the highest incidence of invasive fungal infection; however, no
      antifungal prophylaxis has been proven to be effective. OBJECTIVE: To evaluate
      the efficacy and safety of prophylactic fluconazole in liver transplant
      recipients. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING:
      University-affiliated transplantation center. PATIENTS: 212 liver transplant
      recipients who received fluconazole (400 mg/d) or placebo until 10 weeks after
      transplantation. MEASUREMENTS: Fungal colonization, proven superficial or
      invasive fungal infection, drug-related side effects, and death. RESULTS: Fungal
      colonization increased in patients who received placebo (from 60% to 90%) but
      decreased in patients who received fluconazole (from 70% to 28%). Proven fungal
      infection occurred in 45 of 104 placebo recipients (43%) but in only 10 of 108
      fluconazole recipients (9%) (P < 0.001). Fluconazole prevented both superficial
      infection (29 of 104 placebo recipients became infected [28%] compared with 4 of
      108 fluconazole recipients [4%]; P < 0.001) and invasive infection (24 of 104
      placebo recipients became infected [23%] compared with 6 of 108 fluconazole
      recipients [6%]; P < 0.001). Fluconazole prevented infection by most Candida
      species, except C. glabrata. However, infection and colonization by organisms
      intrinsically resistant to fluconazole did not seem to increase. Fluconazole was
      not associated with any hepatotoxicity. Patients receiving fluconazole had higher
      serum cyclosporine levels and more adverse neurologic events (headaches, tremors,
      or seizures in 13 fluconazole recipients compared with 3 placebo recipients; P =
      0.01). Although the overall mortality rate was similar in both groups (12 of 108
      [11%] in the fluconazole group compared with 15 of 104 [14%] in the placebo
      group; P > 0.2), fewer deaths related to invasive fungal infection were seen in
      the fluconazole group (2 of 108 patients [2%]) than in the placebo group (13 of
      104 patients [13%]) (P = 0.003). CONCLUSIONS: Prophylactic fluconazole after
      liver transplantation decreases fungal colonization, prevents superficial and
      invasive fungal infections, and has no appreciable hepatotoxicity. Although
      fluconazole prophylaxis is associated with fewer deaths from fungal infection, it
      does not improve overall survival. Patients receiving prophylactic fluconazole
      require close monitoring of serum cyclosporine levels to avoid neurologic
      toxicity.

PMID- 10577296
TI  - Malignant neoplasms in long-term survivors of bone marrow transplantation. Late
      Effects Working Party of the European Cooperative Group for Blood and Marrow
      Transplantation and the European Late Effect Project Group.
AB  - BACKGROUND: Patients who receive bone marrow transplants have increased risk for
      new malignant conditions because of several risk factors, including conditioning
      with radiation and chemotherapy, immune stimulation, and malignant primary
      disease. The occurrence of and risk factors for malignant neoplasm in long-term
      survivors must be assessed. OBJECTIVE: To determine the risk and define potential
      risk factors for new malignant conditions in long-term survivors after marrow
      transplantation. DESIGN: Retrospective multicenter study. SETTING: Study of the
      Late Effects Working Party with 45 transplantation centers cooperating in the
      European Cooperative Group for Blood and Marrow Transplantation. PATIENTS: 1036
      consecutive patients who underwent transplantation for leukemia, lymphoma, inborn
      diseases of the hematopoietic and immune systems, or severe aplastic anemia.
      Transplantation was done before December 1985, and patients had survived more
      than 5 years. MEASUREMENTS: Reports on malignant neoplasms were evaluated, and
      the incidence was compared to that in the general population. Patient age and
      sex, primary disease and status at transplantation, histocompatibility of the
      donor, conditioning regimen, type of prophylaxis of graft-versus-host disease,
      development of acute and chronic graft-versus-host disease, and treatment of
      chronic graft-versus-host disease were evaluated as variables. RESULTS: Median
      follow-up since transplantation was 10.7 years (range, 5 to 22.1 years).
      Malignant neoplasms were seen in 53 patients; the actuarial incidence (+/- SE)
      was 3.5% +/- 0.6% at 10 years and 12.8% +/- 2.6% at 15 years. The rate of new
      malignant disease was 3.8-fold higher than that in an age-matched control
      population (P < 0.001). The most frequent malignant diseases were neoplasms of
      the skin (14 patients), oral cavity (7 patients), uterus (including cervix) (5
      patients), thyroid gland (5 patients), breast (4 patients), and glial tissue (3
      patients). Median age of patients and their donors was 21 years. Malignant
      neoplasms were more frequent in older patients and in patients with chronic graft
      versus-host disease. Older patient age and treatment of chronic graft-versus-host
      disease with cyclosporine were significant risk factors for new malignant
      neoplasms after bone marrow transplantation. CONCLUSIONS: The spectrum of
      neoplasms and immunosuppressive treatment with cyclosporine for chronic graft
      versus-host disease as dominant risk factors indicate that immunosuppression is
      the major cause of malignant neoplasms in patients receiving marrow transplants.

PMID- 10577297
TI  - Influence of patient education on profiles of physician practices.
AB  - BACKGROUND: Few data are available about the effect of patient socioeconomic
      status on profiles of physician practices. OBJECTIVE: To determine the ways in
      which adjustment for patients' level of education (as a measure of socioeconomic
      status) changes profiles of physician practices. DESIGN: Cross-sectional survey
      of patients in physician practices. SETTING: Managed care organization in western
      New York State. PARTICIPANTS: A random sample of 100 primary care physicians and
      50 consecutive patients seen by each physician. MEASUREMENTS: Ranks of physicians
      for patient physical and mental health (Short Form 12-Item Health Survey) and
      satisfaction (Patient Satisfaction Questionnaire), adjusted for patient age, sex,
      morbidity, and education. RESULTS: Physicians whose patients had a lower mean
      level of education had significantly better ranks for patient physical and mental
      health status after adjustment for patients' level of education level than they
      did before adjustment (P < 0.001); this result was not seen for patient
      satisfaction. After adjustment for patients' level of education, each 1-year
      decrease in mean educational level was associated with a rank that improved by
      8.1 (95% CI, 6.6 to 9.6) for patient physical health status and by 4.9 (CI, 3.9
      to 5.9) for patient mental health status. Adjustment for education had similar
      effects for practices with more educated patients and those with less educated
      patients. CONCLUSIONS: Profiles of physician practices that base ratings of
      physician performance on patients' physical and mental health status are
      substantially affected by patients' level of education. However, these results do
      not suggest that physicians who care for less educated patients provide worse
      care. Physician profiling should account for differences in patients' level of
      education.

PMID- 10577298
TI  - Influence of the vitamin D receptor gene polymorphism on bone loss in men after
      liver transplantation.
AB  - BACKGROUND: Bone loss is a frequent complication after liver transplantation.
      OBJECTIVE: To investigate whether vitamin D receptor gene polymorphism influences
      bone loss in men after liver transplantation. DESIGN: Prospective cohort study.
      SETTING: University hospital. PATIENTS: 55 male candidates for liver
      transplantation. MEASUREMENTS: Lumbar spine bone mineral density was measured
      before and 3, 6, 12, and 24 months after liver transplantation. Vitamin D
      receptor genotype was determined by restriction endonuclease Bsml. RESULTS:
      Vitamin D receptor genotypes were significantly associated with post
      transplantation changes in bone mineral density (P = 0.028). Within 3 months
      after transplantation, patients with the genotypes Bb or BB showed a vertebral
      bone loss substantially greater than that in patients with the bb genotype
      (between-group difference in the percentage change with respect to baseline bone
      mineral density, 3.7% [95% CI, 0.6% to 6.9%1). In 3 to 24 months after
      transplantation, bone mineral density increased steadily in the three allelic
      groups. CONCLUSIONS: Vitamin D receptor gene polymorphism influences bone loss
      after liver transplantation. Patients with the bb genotype are, to some extent,
      protected against post-transplantation bone loss.

PMID- 10577299
TI  - Synovial fluid analysis for diagnosis of intercritical gout.
AB  - BACKGROUND: The diagnosis of gout in the intercritical phase can be difficult.
      OBJECTIVE: To determine whether synovial fluid analysis allows the diagnosis of
      intercritical gout. DESIGN: Cross-sectional study. SETTING: Outpatient
      rheumatology clinics. PATIENTS: 101 patients with gout. INTERVENTION:
      Arthrocentesis of 80 knees and 21 first metatarsophalangeal joints (each joint
      from a different patient) that had been inflamed but were currently asymptomatic.
      MEASUREMENTS: Frequency with which arthrocentesis yielded synovial fluid;
      presence of monosodium urate crystals in the synovial fluid sample; and, for
      synovial fluid with crystals, the number of microscope fields that had to be
      scanned before crystals were found. RESULTS: Synovial fluid was obtained from 91
      of 101 joints. The fluid from all 43 patients not receiving hypouricemic agents
      contained monosodium urate crystals. These crystals were found in the synovial
      fluid of only 34 of 48 patients receiving hypouricemic agents. In 90% of the
      synovial fluid samples that contained crystals, crystals were seen in the first
      five microscope fields examined. CONCLUSIONS: Arthrocentesis of asymptomatic
      knees and first metatarsophalangeal joints and synovial fluid analysis are simple
      procedures that facilitate the diagnosis of gout during intercritical periods.

PMID- 10577300
TI  - Update in oncology.

PMID- 10577301
TI  - Combination therapy with multiple disease-modifying antirheumatic drugs in
      rheumatoid arthritis: a preventive strategy.
AB  - The traditional "pyramid" or sequential approach to treatment of patients with
      rheumatoid arthritis involved use of a nonsteroidal anti-inflammatory drug for
      months to years while seeking to avoid use of second-line antirheumatic drugs
      until evidence of joint damage was seen. This approach led to short-term
      reduction of inflammation and a few remissions. However, long-term remissions
      were rare, and most patients experienced poor long-term outcomes, including joint
      destruction, severe functional declines, considerable economic losses, work
      disability, and premature mortality. At this time, a "preventive" strategy is
      evolving in which early aggressive treatment with disease-modifying antirheumatic
      drugs is used, seeking to minimize long-term joint damage. When residual
      inflammation remains after maximum doses of single agents, as is usually the
      case, combinations of disease-modifying antirheumatic drugs appear to be a
      reasonable consideration for many patients. Methotrexate is the most commonly
      used "anchor drug" in combination therapy. Evidence from randomized, controlled
      clinical trials and observational studies have indicated increased efficacy and
      acceptable (and often lower) toxicity for combinations of methotrexate plus
      cyclosporine, hydroxychloroquine, sulfasalazine, leflunomide, etanercept, and
      infliximab. Further studies lasting 5 years or more are needed to determine the
      long-term effectiveness, toxicities, and optimal clinical use of disease
      modifying antirheumatic drug combinations. At this time, such combinations are
      taken by at least some patients under care of almost all rheumatologists, and it
      appears likely that they will be used increasingly in the coming decades.

PMID- 10577303
TI  - The legacy of SUPPORT. Study to Understand Prognoses and Preferences for Outcomes
      and Risks of Treatments.

PMID- 10577302
TI  - Name-based surveillance and public health interventions for persons with HIV
      infection. Multistate Evaluation of Surveillance for HIV Study Group.
AB  - Name-based surveillance of HIV infection is the law in 31 U.S. states but remains
      controversial. This policy can be advocated solely to support surveillance of the
      epidemic, but a frequent argument is that it also provides a public health
      benefit by allowing follow-up of HIV-infected persons. These persons can then
      receive timely medical care and can be assisted with notifying sex and needle
      sharing partners. Few comparative data are available to evaluate the outcomes of
      these interventions. In five states with name-based surveillance of HIV
      infection, the Multistate Evaluation of Surveillance for HIV Study Group surveyed
      a cross-sectional probability sample of persons with AIDS who tested positive for
      HIV before the date of their AIDS diagnosis. Health department follow-up of a
      reported HIV infection was not associated with more timely receipt of medical
      care after a positive HIV test result. Only 8.6% of persons who delayed medical
      care after their first positive HIV test result gave concern about being reported
      by name as a reason; no person gave it as the main reason. Persons who were
      tested anonymously and those who were tested confidentially did not differ in the
      mean number of sex and needle-sharing partners notified: Those tested anonymously
      reported personally notifying 3.85 sex and needle-sharing partners, and those
      tested confidentially reported notifying-personally and through the health
      department-3.80 partners. Many researchers and policymakers believe that name
      based surveillance of HIV infection will have positive or negative effects on
      partner notification and access to health care. These results suggest that the
      potential for such effects has been exaggerated.

PMID- 10577304
TI  - Roxanne.

PMID- 10577305
TI  - An entirely benign disorder.

PMID- 10577306
TI  - Risk factors for thromboembolism.

PMID- 10577307
TI  - Risk factors for thromboembolism.

PMID- 10577308
TI  - Hormone replacement therapy in postmenopausal U.S. women.

PMID- 10577309
TI  - Thrombolytic predictive instrument.

PMID- 10577310
TI  - The Park Nicollet experience.

PMID- 10577311
TI  - Sigmoidoscopy reimbursement.

PMID- 10577312
TI  - Splenectomy-induced portal hypertension and pulmonary hypertension.

PMID- 10577313
TI  - False-positive HIV diagnosis by HIV-1 plasma viral load testing.

PMID- 10577314
TI  - Nosocomial transmission of hepatitis C virus.

PMID- 10577315
TI  - Renin-secreting adenocarcinoma of the colon.

PMID- 10577316
TI  - Famotidine-induced erythema multiforme: cross-sensitivity with cimetidine.

PMID- 10577317
TI  - Tropheryma whippelii in synovial tissue and fluid.

PMID- 10577318
TI  - Sudden jaundice with isolated atypical perinuclear antineutrophil cytoplasmic
      antibodies.

PMID- 10577319
TI  - Retroperitoneal hematoma and enoxaparin.

PMID- 10577320
TI  - Long QT syndrome and torsade de pointes in a patient receiving fluconazole.

PMID- 10577321
TI  - Treatment of parathyroid cysts with fine-needle aspiration.

PMID- 10577322
TI  - "Catastrophic" diagnosis of the antiphospholipid syndrome.

PMID- 10577323
TI  - Posterior pituitary sigma receptors and drug-induced syndrome of inappropriate
      antidiuretic hormone release.

PMID- 10577324
TI  - Computational genomics: the medicine of the future?

PMID- 10577325
TI  - Clinical utility of blood cultures drawn from indwelling central venous catheters
      in hospitalized patients with cancer.
AB  - BACKGROUND: Because of concern about low specificity, the American College of
      Physicians guidelines and expert opinion discourage the use of a central venous
      catheter when obtaining blood for culture for bacteremia or fungemia. However,
      data on the reliability of cultures done with blood obtained from a central
      venous catheter are conflicting. OBJECTIVE: To determine the sensitivity,
      specificity, and positive and negative predictive values of cultures done with
      blood obtained through a central venous catheter compared with peripheral
      venipuncture. DESIGN: Retrospective cohort study of hospitalized patients with
      cancer in whom samples for paired cultures were drawn through a central venous
      catheter and peripheral venipuncture. SETTING: Tertiary care, university
      affiliated medical center. PATIENTS: 185 patients hospitalized on a hematology
      oncology ward between August 1994 and June 1996. MEASUREMENTS: Blinded
      assessments of culture results done by infectious disease experts were used as
      the gold standard. Sensitivity, specificity, and positive and negative predictive
      values were compared for culture of blood from central catheters and culture of
      blood from peripheral venipuncture. RESULTS: Of 551 paired cultures, 469 (85%)
      were catheter-negative/venipuncture-negative, 32 (6%) were catheter
      positive/venipuncture-positive, 17 (3%) were catheter-negative/venipuncture
      positive, and 33 (6%) were catheter-positive/venipuncture-negative pairs. For the
      82 paired cultures with at least one positive result, blinded determination of
      true bacteremia or fungemia was made by two infectious disease specialists. For
      catheter draw compared with peripheral venipuncture, sensitivity was 89% (95% CI,
      79% to 98%) and 78% (CI, 65% to 90%) (difference, 11 percentage points [CI, -6 to
      28 percentage points]), specificity was 95% (CI, 93% to 97%) and 97% (CI, 96% to
      99%) (difference, -2 percentage points [CI, -5 to 0.2 percentage points]),
      positive predictive value was 63% (CI, 50% to 75%) and 73% (CI, 60% to 86%)
      (difference, -10 percentage points [CI, -26 to 5 percentage points]), and
      negative predictive value was 99% [CI, 97% to 100%]) and 98% (CI, 96% to 100%)
      (difference, 1 percentage point [CI, -0.5 to 3 percentage points]). CONCLUSIONS:
      In hospitalized hematology-oncology patients, culture of blood drawn through
      either the central catheter or peripheral vein shows excellent negative
      predictive value. Culture of blood drawn through an indwelling central venous
      catheter has low positive predictive value, apparently less than from a
      peripheral venipuncture. Therefore, a positive result from a catheter needs
      clinical interpretation and may require confirmation. However, the use of a
      catheter to obtain blood for culture may be an acceptable method for ruling out
      bloodstream infections.

PMID- 10577326
TI  - Early beta-blocker therapy for acute myocardial infarction in elderly patients.
AB  - BACKGROUND: Despite the evidence supporting the importance of early beta-blocker
      therapy, this intervention has received little attention as an indicator of
      quality of care. OBJECTIVES: To determine how often beta-blockers are
      administered as early treatment of acute myocardial infarction in patients 65
      years of age or older, to identify predictors of the decision to use beta
      blockers, and to evaluate the association between the early use of beta-blockers
      and in-hospital mortality. DESIGN: Observational study. SETTING: Nongovernment,
      acute care hospitals in the United States. PATIENTS: Medicare beneficiaries who
      were 65 years of age or older, were hospitalized with an acute myocardial
      infarction in 1994 and 1995, and did not have a contraindication to beta-blocker
      therapy. MEASUREMENTS: Medical chart review to obtain information about the use
      of beta-blockers, contraindications to these drugs, patient demographics, and
      clinical factors. RESULTS: Of the 58 165 patients (from a total of 4414
      hospitals), 28 256 (49%) received early beta-blocker therapy. Patients with the
      highest risk for in-hospital death were the least likely to receive therapy.
      Patients who received beta-blockers had a lower in-hospital mortality rate than
      patients who did not receive beta-blockers (odds ratio, 0.81 [95% CI, 0.75 to
      0.87]), even after adjustment for baseline differences in demographic, clinical,
      and treatment characteristics between the two groups. CONCLUSIONS: Early beta
      blocker therapy was not used for 51% of elderly patients who were hospitalized
      with an acute myocardial infarction and did not have a contraindication to this
      therapy. Increasing the early use of beta-blockers for these patients would
      provide an excellent opportunity to improve their care and outcomes.

PMID- 10577327
TI  - Is history of squamous-cell skin cancer a marker of poor prognosis in patients
      with cancer?
AB  - BACKGROUND: Nonmelanoma skin cancer is associated with increased occurrence of
      subsequent cancer and death from cancer, but it is not known whether a history of
      skin cancer is associated with poor prognosis after a second diagnosis of cancer.
      OBJECTIVE: To determine whether history of squamous-cell skin cancer is a marker
      of poor prognosis in patients with cancer. DESIGN: Population-based cohort study.
      SETTING: Sweden, 1958 to 1996. PATIENTS: All patients in the Swedish Cancer
      Registry with or without a first diagnosis of squamous-cell skin cancer and a
      subsequent or first diagnosis of non-Hodgkin lymphoma (including chronic
      lymphocytic leukemia) or cancer of the colon, breast, prostate, or lung.
      MEASUREMENTS: Relative risk (RR) for death determined by using Cox proportional
      hazards regression analysis. RESULTS: Patients with a history of squamous-cell
      skin cancer had a significantly greater risk for death than those with no such
      history after receiving a diagnosis of non-Hodgkin lymphoma (RR, 1.33), colon
      cancer (RR, 1.24), breast cancer (RR, 1.19), or prostate cancer (RR, 1.17).
      Patients with lung cancer and a history of squamous-cell skin cancer who survived
      for 1 year after diagnosis of lung cancer also had an increased risk for death
      (RR, 1.29). CONCLUSION: Patients with a registered history of squamous-cell skin
      cancer have a poor prognosis after diagnosis of subsequent cancer and warrant
      careful medical attention.

PMID- 10577328
TI  - The cost-effectiveness of treating all patients with type 2 diabetes with
      angiotensin-converting enzyme inhibitors.
AB  - BACKGROUND: Although guidelines recommend angiotensin-converting enzyme
      inhibitors for diabetic patients with microalbuminuria, this strategy requires
      that providers adhere to screening recommendations. In addition, the benefit of
      angiotensin-converting enzyme inhibitors in normoalbuminuric patients was
      recently demonstrated. OBJECTIVE: To evaluate the cost-effectiveness of treating
      all patients with type 2 diabetes. DESIGN: Markov model simulating the
      progression of diabetic nephropathy. DATA SOURCES: Randomized trials estimating
      the progression of diabetic nephropathy with and without angiotensin-converting
      enzyme inhibitors. TARGET POPULATION: Patients 50 years of age with newly
      diagnosed type 2 diabetes (fasting plasma glucose level > or = 7.8 mmol/L [140
      mg/dL]). TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTIONS: Patients
      received angiotensin-converting enzyme inhibitors, screening for
      microalbuminuria, or screening for gross proteinuria. OUTCOME MEASURES: Lifetime
      cost, quality-adjusted life expectancy, and marginal cost-effectiveness. RESULTS
      OF BASE-CASE ANALYSIS: Screening for gross proteinuria had the highest cost and
      the lowest benefit. Compared with screening for microalbuminuria, treating all
      patients was more expensive ($15240 and $14940 per patient) but was associated
      with increased quality-adjusted life expectancy (11.82 and 11.78 quality-adjusted
      life-years). The marginal cost-effectiveness ratio was $7500 per quality-adjusted
      life-year gained. RESULTS OF SENSITIVITY ANALYSIS: Results were sensitive to the
      cost, effectiveness, and quality of life associated with angiotensin-converting
      enzyme inhibitor therapy, as well as age at diagnosis. The model was relatively
      insensitive to adherence with screening and costs of treating end-stage renal
      disease. CONCLUSIONS: Treating all middle-aged diabetic patients with angiotensin
      converting enzyme inhibitors is a simple strategy that provides additional
      benefit at modest additional cost. The strategy assumes that patients meet the
      older diagnostic criteria for diabetes and makes sense only for those who are not
      bothered by treatment.

PMID- 10577329
TI  - Reversal of iron deficiency anemia after Helicobacter pylori eradication in
      patients with asymptomatic gastritis.
AB  - BACKGROUND: Iron deficiency anemia is the most common form of anemia worldwide.
      Recent studies have suggested an association between Helicobacter pylori
      infection and iron deficiency. OBJECTIVE: To investigate the effects of
      eradicating H. pylori with combination antibiotic therapy on iron deficiency
      anemia in patients with H. pylori-associated gastritis. DESIGN: Case series.
      SETTING: University hospital. PATIENTS: 30 patients with a long history of iron
      deficiency anemia in whom H. pylori-associated gastritis was the only pathologic
      gastrointestinal finding detected. INTERVENTION: Eradication therapy with two
      antibiotics and discontinuation of iron replacement therapy. MEASUREMENTS:
      Complete blood count, ferritin levels, and gastroscopy with biopsy to evaluate H.
      pylori status. RESULTS: At 6 months, 75% of patients had recovered from anemia
      (P<0.001), ferritin values increased from 5.7+/-0.7 microg/L to 24.5+/-5.2
      microg/L (95% CI, 8.85 to 29.97). After 12 months, 91.7% of patients had
      recovered from anemia. CONCLUSIONS: Cure of H. pylori infection is associated
      with reversal of iron dependence and recovery from iron deficiency anemia.

PMID- 10577330
TI  - Noninvasive imaging for the diagnosis of coronary artery disease: focusing the
      development of new diagnostic technology.
AB  - BACKGROUND: New tests, such as magnetic resonance imaging (MRI) and electron-beam
      computed tomography (CT), are being developed for the diagnosis of coronary
      artery disease. OBJECTIVE: To determine the conditions that a new test must meet
      to be a cost-effective alternative to established imaging tests. DESIGN: Decision
      model and cost-effectiveness analysis. DATA SOURCES: Literature review and meta
      analysis. TARGET POPULATION: 55-year-old men and 65-year-old women presenting
      with chest pain. TIME HORIZON: Lifetime of the patient. PERSPECTIVE: Health care
      policy. INTERVENTIONS: MRI, electron-beam CT, exercise echocardiography, exercise
      single-photon emission CT, and coronary angiography. OUTCOME MEASURES: Target
      sensitivity and specificity values for a new noninvasive test. RESULTS OF BASE
      CASE ANALYSIS: Assuming that society is willing to pay $75000 per quality
      adjusted life-year (QALY) gained, a new test that costs $1000 would need a
      sensitivity of 94% and a specificity of 90% to be cost-effective. RESULTS OF
      SENSITIVITY ANALYSIS: Assuming that society is willing to pay $50000 per QALY
      gained, a new test that costs $1000 or more would never be cost-effective. For a
      test that costs $500, the sensitivity and specificity must each be 95%.
      CONCLUSIONS: New imaging techniques, such as MRI and electron-beam CT, must be
      relatively inexpensive and have excellent sensitivity and specificity to be cost
      effective compared with other techniques for the diagnosis of coronary artery
      disease. Similar analyses in other areas of health care may help to focus the
      development of new diagnostic technology.

PMID- 10577331
TI  - Update in preventive medicine.

PMID- 10577332
TI  - Atrial fibrillation and thromboembolism: a decade of progress in stroke
      prevention.
AB  - Atrial fibrillation is associated with a sixfold increased risk for stroke. More
      than a dozen published randomized trials of anticoagulants or antiplatelet agents
      for stroke prevention provide solid evidence on which to base antithrombotic
      prophylaxis. Adjusted-dose warfarin reduces risk for stroke by about 60% compared
      with placebo, aspirin reduces this risk (primarily for nondisabling stroke) by
      about 20% compared with placebo, and warfarin reduces it by about 40% compared
      with aspirin. Warfarin provides maximal protection against stroke at
      international normalized ratios of 2.0 to 3.0. Risk stratification of patients
      with atrial fibrillation identifies those who potentially benefit most or least
      from anticoagulation; this is important because a substantial percentage of
      patients with atrial fibrillation have relatively low rates of stroke if they are
      given aspirin. Many elderly patients with recurrent intermittent atrial
      fibrillation experience high rates of stroke and benefit from anticoagulation.
      The value of precordial or transesophageal echocardiography in addition to
      clinical risk stratifiers for stratifying stroke risk is controversial. Altered
      hemostasis favoring thrombosis may contribute to formation of atrial appendage
      thrombus, but these conditions remain ill defined. The past decade has brought
      unprecedented progress toward understanding thromboembolism in patients with
      atrial fibrillation and has changed the clinical perspective of a prevalent
      cardiac arrhythmia into an important opportunity for stroke prevention. Making
      the most of this promise calls for appreciation of the epidemiology of atrial
      fibrillation and the concept of risk specificity in the face of diverse
      therapeutic options.

PMID- 10577333
TI  - Use of interferon for prevention of hepatocellular carcinoma in cirrhotic
      patients with hepatitis B or hepatitis C virus infection.
AB  - The incidence of hepatocellular carcinoma in North America is increasing. Current
      debate focuses on whether interferon administered to cirrhotic patients-with or
      without biochemical or virologic response-delays or prevents cancer of the liver.
      Review of the literature revealed several studies that showed improvement in or
      delay in progression of histologic fibrosis in patients with hepatitis C virus
      (HCV) infection. In patients with hepatitis B virus (HBV) infection, conversion
      to the nonreplicative stage may be associated with histologic improvement.
      However, only 11 studies (6 of HCV, 3 of HBV, and 2 of HCV and HBV) compared
      development of hepatocellular carcinoma in interferon-treated patients with
      cirrhosis and cirrhotic patients who were not treated with interferon. Although
      no firm statistical conclusions could be drawn, the literature suggests that
      interferon therapy may prevent hepatocellular carcinoma in patients with
      cirrhosis, particularly those infected with HCV. Interferon treatment cannot be
      recommended for all persons with cirrhosis and HBV or HCV infection because the
      current evidence is only suggestive. Long-term randomized, controlled trials may
      provide definitive data; however, it will be difficult, if not impossible, to
      conduct such trials because of the improved efficacy of combination therapy with
      interferon and ribavirin in patients with chronic HCV infection and the
      development of new therapies for patients with HBV infection.

PMID- 10577334
TI  - Henry Harrower and the turbulent beginnings of endocrinology.
AB  - The emergence of new medical science in the mid-19th century was usually greeted
      with derision by "practical men" who saw their academic colleagues as elitist
      intellectuals whose work bore little or no relation to the rough-and-tumble
      aspects of patient care. This schism, which was nowhere greater than in the field
      of endocrinology, widened in 1891 when a myxedematous patient was dramatically
      restored to health after the administration of a thyroid extract. On the one
      hand, academicians-who saw this result as a triumphal example of the transference
      of laboratory studies to the bedside--were encouraged to pursue further studies
      in endocrine pathophysiology and pharmacology. On the other hand, medical
      practitioners began to believe that crude extracts from glands or other organs,
      when prescribed as orally administered mixtures, were effective for the treatment
      of most human ailments. The organotherapeutic forces were ably championed by
      Henry R. Harrower, MD, a manufacturer as well as a dispenser of organotherapeutic
      products. For some years, the claims of the organotherapists remained
      unchallenged. Finally, in 1921, Harvey Cushing, pioneer neurosurgeon and
      endocrinologist, launched a crushing assault on the purveyors of pluriglandular
      therapy. These attacks continued over ensuing years, and organotherapy fell into
      disrepute. Nevertheless, the assertions of "practical men" have not subsided;
      rather, we are now confronted by insistent claims for a bewildering array of
      herbal remedies, over-the-counter hormonal products, and alternative therapies.

PMID- 10577336
TI  - On being a doctor. Harry James.

PMID- 10577335
TI  - Interpreting, integrating, and individualizing evidence about the prevention of
      diabetic nephropathy.

PMID- 10577337
TI  - Famciclovir and postherpetic neuralgia.

PMID- 10577338
TI  - Theophylline therapy for near-fatal Cheyne-Stokes respiration.

PMID- 10577339
TI  - Theophylline therapy for near-fatal Cheyne-Stokes respiration.

PMID- 10577340
TI  - Improving preventive care guidelines.

PMID- 10577341
TI  - Delayed treatment of bacterial meningitis.

PMID- 10577342
TI  - Elevated estradiol and testosterone levels and risk for breast cancer.

PMID- 10577343
TI  - Impaired glucose tolerance in HIV-infected patients.

PMID- 10577344
TI  - Treatment of chronic lead intoxication.

PMID- 10577345
TI  - Hepatitis B virus genotypic resistance to lamivudine.

PMID- 10577346
TI  - Left coronary ostial stenosis caused by focal intimal fibrosis.

PMID- 10577347
TI  - Medical writings. W;t.

PMID- 10577348
TI  - [Clinical case for the experts].

PMID- 10577349
TI  - [Sinus mucoceles and surgery in iatrogenic diseases].
AB  - The increasing number of mucocele cases treated by the authors during the past
      ten years coincide with the expansion of functional endoscopic sinus surgery
      (FESS). The aim of this study is to evaluate the iatrogenic characteristics of
      this surgery by analysing the locations, time of development and the potential
      pathogenic factors of sinus mucoceles. Forty-two sinus mucoceles were operated in
      our department. These mucoceles were most frequently found in the anterior
      ethmoido-frontal system. Eleven patients had a history of endonasal ethmoidectomy
      mainly due to nasal polyposis. The time of mucocele formation after initial FESS
      (< 22 months) seems to be shorter than after exonasal sinus surgery or trauma (<
      10 years). Endoscopic and CT-scan revealed different types of sinus obstruction
      findings: nasofrontal duct occlusion due to a fibrosis and osteogenic scar tissue
      process, or anterior ethmoid synechia in the case of ethmoido-frontal sinus
      mucocele, uncinate process fragment or scar tissue duct occlusion as far as
      maxillary sinus mucocele were concerned. We conclude that there seems to be a
      correlation between the expansion of FESS and the increasing number of mucocele
      cases. However, in this context it has to taken into consideration, that our
      department treats a considerable number of sinus pathology. Anterior ethmoid
      seems to be a favourable area for sinus mucocele formation. In order to prevent
      mucocele, it is essential to carry out FESS with great precaution. If endonasal
      surgery is performed, particularly in the anterior ethmoid, a close endoscopic
      follow-up, completed by radiological examinations, where necessary, must be
      ensured.

PMID- 10577350
TI  - Aminoglycoside and macrolide resistance in Burkholderia pseudomallei.

PMID- 10577351
TI  - Mechanisms of quinolone resistance in clinical isolates of Shigella dysenteriae.

PMID- 10577352
TI  - Incidence of mefA and mefE genes in viridans group streptococci.

PMID- 10577353
TI  - Comparison of E test to microdilution for determining in vitro activities of
      antibiotics against Brucella melitensis.

PMID- 10577354
TI  - Proceedings of the 6th symposium on lactic acid bacteria: genetics, metabolism
      and applications. Veldhoven, The Netherlands, 19-23 September 1999.

PMID- 10577355
TI  - Registration, licensure, and accountability.

PMID- 10577356
TI  - Locating a home page and journal source; hypothermia and the perioperative
      patient.

PMID- 10577357
TI  - Substrate specificity of human glycinamide ribonucleotide transformylase.
AB  - The nucleotide substrate specificity of human glycinamide ribonucleotide
      transformylase, a chemotherapeutic target, has been examined. The enzyme accepts
      the sarcosyl analog of glycinamide ribonucleotide, carbocyclic glycinamide
      ribonucleotide, and two phosphonate derivatives of carbocyclic glycinamide
      ribonucleotide with V/K values, relative to that obtained for beta-glycinamide
      ribonucleotide, of 1, 27, 1.4, and 2.9%, respectively. Several other analogs of
      carbocyclic glycinamide ribonucleotide, namely a truncated phosphonate and 2',3'
      dideoxy- and 2',3'-dideoxy-2',3'-didehydro-carbocyclic glycinamide
      ribonucleotide, were inhibitors of the enzyme, competitive against glycinamide
      ribonucleotide, with Ki values approximately 100 times higher than the Km for 
      glycinamide ribonucleotide. Although the results of the present study parallel
      those obtained previously with the avian enzyme (V. D. Antle, D. Liu, B. R.
      McKellar, C. A. Caperelli, M. Hua, and R. Vince (1996) J. Biol. Chem. 271, 6045
      6049), quantitative differences between the two enzyme species have been
      uncovered.

PMID- 10577358
TI  - Overlapping distribution of the 130- and 110-kDa myosin I isoforms on rat liver
      membranes.
AB  - The biochemical and mechanochemical properties and localization of myosin I
      suggest the involvement of these small members of the myosin superfamily in some
      aspects of intracellular motility in higher cells. We have determined by
      quantitative immunoblotting with isoform-specific antibodies that the 130-kDa
      myosin I (myr 1 gene product) and 110-kDa myosin I (myr 2 gene product) account
      for 0.5 and 0.4%, respectively, of total rat liver protein. Immunoblot analyses
      reveal that the 130- and 110-kDa myosins I are found in several purified
      subcellular fractions from rat liver. The membrane-associated 130-kDa myosin I is
      found at the highest concentration in the plasma membrane (28 ng/microg plasma
      membrane protein) followed by the endoplasmic reticulum-like mitochondria
      associated membrane fraction (MAM; 10 ng/microg MAM protein), whereas the 110-kDa
      myosin I is found at the highest concentration in Golgi (50 ng/?g Golgi protein)
      followed by plasma membrane (20 ng/microg) and MAM (7 ng/microg). Our analyses
      indicate that myosin I is peripherally associated with Golgi and MAM and its
      presence in these fractions is not a consequence of myosin I bound to
      contaminating actin filaments. Although found in relatively low concentrations in
      microsomes, because of the abundance of microsomes, in liver most of the membrane
      associated myosin I is associated with microsomes. Neither myosin I isoform is
      detected in purified mitochondria. This is the first quantitative analysis
      addressing the cellular distribution of these mammalian class I myosins.

PMID- 10577359
TI  - Biosynthesis and inactivation of N-arachidonoylethanolamine (anandamide) and N
      docosahexaenoylethanolamine in bovine retina.
AB  - N-Arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG),
      the two proposed endogenous agonists of cannabinoid receptors, and the putative
      AEA biosynthetic precursor, N-arachidonoylphosphatidylethanolamine (NArPE), were
      identified in bovine retina by means of gas chromatography-electron impact mass
      spectrometry (GC-EIMS). This technique also allowed us to identify N
      docosahexanoylethanolamine (DHEA) and 2-docosahexanoylglycerol (2-DHG), two
      derivatives of docosahexaenoic acid (DHA), one of the most abundant fatty acids
      esterified in retina phospholipids and necessary for optimal retinal function. N
      Docosahexaenoylphosphatidylethanolamine (NDHPE), the potential biosynthetic
      precursor for DHEA, was also found. The fatty acid composition of the sn-1 and sn
      2 positions of bovine retina's most abundant phospholipid classes, also
      determined here, were in agreement with a phospholipid-dependent mechanism for 2
      AG, 2-DHG, AEA, and DHEA biosynthesis, as very high levels of polyunsaturated
      fatty acids, including DHA, were found on the sn-2 position of
      phosphatidylcholine (PC) and -ethanolamine (PE), and measurable amounts of di
      docosahexanoyl-PC and -PE, two potential biosynthetic precursors of NDHPE, were
      detected. Accordingly, we found that isolated particulate fractions from bovine
      retina could release AEA and DHEA in a time-dependent fashion. Finally, a fatty
      acid amide hydrolase (FAAH)-like activity with subcellular distribution and pH
      dependency similar to those reported for the brain enzyme was also detected in
      bovine retina. This activity was inhibited by FAAH inhibitors,
      phenylmethylsulfonyl fluoride and arachidonoyltrifluoromethylketone, and appeared
      to recognize DHEA with a lower efficiency than AEA. These data indicate that AEA
      and its congeners may play a physiological role in the mammalian eye.

PMID- 10577360
TI  - Acute appendicitis in children after renal transplantation.

PMID- 10577361
TI  - Difficult asthma: beyond the guidelines.

PMID- 10577362
TI  - Effect of environmental tobacco smoke on peak flow variability.

PMID- 10577363
TI  - Mothering to death.

PMID- 10577364
TI  - Reduced bone mineral density at completion of chemotherapy for a malignancy.

PMID- 10577365
TI  - Rheumatic heart disease in school children in Samoa.

PMID- 10577366
TI  - The vitamin K debacle: cut the Gordian knot.

PMID- 10577367
TI  - Polysomnography and home documented monitoring of cardiorespiratory pattern.
AB  - Polysomnographic findings were compared with data obtained subsequently from home
      documented monitoring in order to study the diagnostic value of both techniques.
      Polysomnography was performed in 1274 infants born prematurely and in 422
      patients admitted because of apparent life threatening events (ALTEs). In 72 of
      the infants, home documented monitoring of the cardiorespiratory pattern,
      including QRS complexes, was performed. Subsequent documented episodes of heart
      rate < 50 beats/min were considered as "serious life threatening events". It was
      confirmed that polysomnographic findings correlated well with subsequent events
      as registered by home documented monitoring. Especially in the ALTE group where
      both infants with and without abnormal polysomnography were home monitored, the
      single polysomnography significantly predicted subsequent life threatening
      events. Home documented monitoring of the cardiorespiratory pattern has a
      distinctive advantage over simple cardiorespiratory monitoring as a means to
      identify and document life threatening events, in addition to its value as a
      rescue device.

PMID- 10577368
TI  - Investigation of hypertension and the recognition of monogenic hypertension.

PMID- 10577369
TI  - Cladribine in the treatment of systemic lupus erythematosus nephritis.

PMID- 10577370
TI  - Leg bone pain syndrome in a kidney transplant patient treated with tacrolimus
      (FK506)

PMID- 10577371
TI  - Spleen haemorrhagic infarction and hazards of anticoagulation in Wegener's
      granulomatosis.

PMID- 10577372
TI  - Amiodarone induced lupus.

PMID- 10577373
TI  - Antinuclear antibodies in relapsing polychondritis.

PMID- 10577374
TI  - There is no association between polymyalgia rheumatica and acute parvovirus B19
      infection.

PMID- 10577375
TI  - Neutrophil chemotaxis in Behcet's syndrome.

PMID- 10577376
TI  - Neuropsychiatric systemic lupus erythematosus.

PMID- 10577377
TI  - A man with intermittent fever and arthralgia.

PMID- 10577378
TI  - Ear, ear, what's going on in Norfolk?

PMID- 10577379
TI  - Outcomes '99. Conference on cardiac and vascular surgery: neurobehavioral
      assessment, physiological monitoring and cerebral protective strategies. Key
      West, Florida, USA. May 26-30, 1999. Proceedings and abstracts.

PMID- 10577381
TI  - 1st European Meeting of Vascular Biology and Medicine. Nurnberg, Germany,
      September 29-October 1, 1999. Abstracts.

PMID- 10577380
TI  - [Paul Davis (1919-1999)].

PMID- 10577382
TI  - Newborns as clients: net resources of interest.

PMID- 10577383
TI  - Comment on Laurila and colleagues' article.

PMID- 10577384
TI  - Interactions between nitric oxide and endothelin-1 in vessels from
      hypercholesterolaemic rabbits.

PMID- 10577385
TI  - Platelet glycoprotein IIIa polymorphisms, plasma lipoprotein(a) concentration and
      early coronary disease.

PMID- 10577386
TI  - Antisense DNA-targeting protein kinase A-RIA subunit: a novel approach to cancer
      treatment.
AB  - Enhanced expression of the RIa subunit of cAMP-dependent protein kinase type I
      (PKA-I) has been shown during carcinogenesis, in human cancer cell lines and in
      primary tumors. We demonstrate that the sequence-specific inhibition of RIa gene
      expression by antisense oligonucleotides results in the differentiation of
      leukemia cells and growth arrest of cancer cells of epithelial origin and tumors
      in mice. The loss of RI by the antisense results in rapid increase in the half
      life of the competitor molecule, RII protein, via its stabilization in a
      holoenzyme complex (PKA-II) that insures depletion of PKA-I and sustained
      inhibition of tumor growth. RI antisense, which restrains tumor cell growth by
      turning on the signals for blockade of tumor cell survival, namely blockade of
      the tyrosine kinase signaling, cell cycle deregulation and apoptosis, provides a
      single gene-targeting approach to treatment of cancer.

PMID- 10577387
TI  - Cell cycle regulation of DNA replication initiation proteins in mammalian cells.
AB  - Genomic DNA has to be replicated completely and only once during a single cell
      cycle in order to maintain integrity. Eukaryotes have developed highly regulated
      machinery for precisely replicating genomic DNA that is fragmented into multiple
      chromosomes. Our knowledge of such mechanisms largely depends on findings with
      budding yeast, since identification of specific DNA sequences acting as
      replication origins, autonomously replicating sequences, has allowed extensive
      analyses of the initiation of DNA replication. Several factors essential for
      regulation of initiation have been identified, including ORC, CDC6 and MCM.
      Subsequent work has suggested that the fundamental machinery for DNA replication
      may be conserved in metazoan embryonic cells in which replication occurs sequence
      independently, and also in mammalian nonembryonic cells, where replication
      origins are more specific. However, there are specific differences. In this
      review, information on function and regulation of mammalian initiation factors,
      ORC, CDC6 and MCM, is summarized, and yeast and embryonic systems are compared. A
      hypothetical model for the state of prereplication chromatin in mammalian cell
      nuclei and regulation during the cell cycle is also proposed.

PMID- 10577388
TI  - Plasma membrane calcium ATPases as critical regulators of calcium homeostasis
      during neuronal cell function.
AB  - The plasma membrane calcium ATPases (PMCAs) are ubiquitously expressed proteins
      that couple the extrusion of calcium across the plasma membrane with the
      hydrolysis of ATP. In mammals, four separate genes encode distinct PMCA isoforms.
      Complex patterns of alternative RNA splicing generate additional isoform
      variability. Functionally, the PMCAs were originally assigned the role of
      maintaining basal levels of intracellular calcium. Recent evidence, however, is
      expanding the role of the PMCAs as important participants in dynamic Ca2+
      regulation and as crucial players of Ca2+ export during normal and pathological
      conditions. This review highlights recent advances made on the biology of the
      PMCAs within the context of neuronal development, cellular responses to external
      stimuli and cell survival. Particular emphasis is placed on the role of the PMCAs
      in vestibular and auditory functions, localized calcium signaling in
      photoreceptor synaptic terminals and calcium-mediated cell death.

PMID- 10577390
TI  - CDC7 kinase complex as a molecular switch for DNA replication.
AB  - Cdc7 kinase and its activator Dbf4 protein, originally identified in budding
      yeast Saccharomyces cerevisiae, are widely conserved in eukaryotes including
      fission yeast and human. Dbf4-related activators bind and stimulate kinase
      activity of Cdc7-like catalytic subunit. Its kinase activity is cell cycle
      regulated, mainly through availability of the activation subunit whose level
      increases at G1/S boundary and is maintained at a high level throughout S phase.
      MCM2 protein is among physiologically important substrates. Genetic studies in
      fission yeast indicate that Cdc7-related kinase complex also functions in
      meiosis, uninduced mutagenesis, DNA replication checkpoint signaling and
      maintenance of chromatin structures during S phase.

PMID- 10577391
TI  - Transcription factors in DNA replication.
AB  - Accumulating evidence suggests the involvement of transcription factors in the
      regulation of DNA replication in eukaryotic cells. Almost all eukaryotic DNA
      viruses contain binding sites for transcription factors which function as
      auxiliary elements for DNA replication initiation at replication origins, and,
      indeed, the binding of transcription factors to these elements has been shown to
      stimulate DNA replication. Transcription factors also regulate some of the
      chromosome DNA replication origins of budding yeast, indicating that
      transcription factor involvement in DNA replication is not restricted to viruses.
      Consistent with this notion, recently determined replication origins of higher
      eukaryotes have been found occasionally to associate with transcription factor
      binding sites, although there is no direct evidence for the involvement of the
      factors that bind to these sequences in DNA replication. Analyses using viral and
      yeast systems have suggested that transcription factors stimulate the formation
      of the replication initiation complex by engaging in specific interactions with
      proteins of the initiation complex and/or by modulating the repressive chromatin
      structure around origins of replication. These mechanisms are analogous to those
      advanced to explain stimulation of transcription by transcription factors. The
      accumulated data suggests that transcription factors play a general role in the
      formation of functional complexes on chromosomes.

PMID- 10577389
TI  - Induction of S phase by G1 regulatory factors.
AB  - The first gap phase (G1) in the mammalian cell cycle plays a pivotal role in
      determining whether or not cells are to initiate DNA replication. Progression
      through G1 phase and transition into S phase are positively and negatively
      regulated by a series of factors, collectively termed G1 regulators. Among them,
      D-type G1 cyclins and a Cdk inhibitor, p27Kip1, function as the target of growth
      factors to integrate extracellular signals into cell cycle regulators. Another G1
      cyclin, cyclin E, and a transcription factor E2F are situated the furthest
      downstream of known G1 regulators and seem to be directly involved in the
      initiation of chromosomal DNA replication. Alterations in G1 regulator genes are
      often present in human tumors, indicating that G1 regulators participate in tumor
      suppressive mechanisms as well as in cell proliferation.

PMID- 10577392
TI  - Implication of transcription factor E2F in regulation of DNA replication.
AB  - The transcription factor E2F plays crucial roles in induction of S phase in
      mammalian cells by regulating the expression of genes that encode molecules
      involved in cell cycle progression. E2F exerts a repressive effect on E2F
      responsive genes in G0/G1 phase by associating with the retinoblastoma tumor
      suppressor gene product pRb and the related protein p130. This repression is
      relieved by phosphorylation of the pRb family proteins by G1 cyclin (cyclin D and
      cyclin E) -dependent kinases, resulting in expression of E2F-responsive genes in
      late G1 with a peak at the G1/S boundary. One group of genes influenced by E2F
      encode cell cycle regulatory molecules, including members of the E2F family and
      cyclin E, demonstrating a loop-type regulation of activities of E2F and cyclin E
      dependent kinase at this stage in the cell cycle. Another group is involved in
      DNA replication, including genes for molecules regulating initiation of DNA
      replication. Overexpression of E2F is sufficient to induce DNA synthesis in serum
      starved fibroblasts. In addition, overexpression of cyclin E, which is essential
      for entry into S phase, overcomes G1 arrest caused by inhibition of E2F activity
      without resuming E2F mediated transcription, suggesting the mergence of the two
      pathways. Thus, E2F target-gene products and cyclin E-dependent kinase activity
      apparently co-operate to initiate replication of DNA.

PMID- 10577393
TI  - The effect of nicotine on developing brain catecholamine systems.
AB  - Biochemical studies have confirmed that nicotinic acetylcholine receptor mRNA and
      protein are expressed early in the development of the fetal central nervous
      system. Perinatal administration of nicotine produces a broad spectrum of effects
      on brain development, including inhibition of DNA synthesis, altered ornithine
      decarboxylase activity, altered neurotransmitter function, and significant
      alterations in cortical morphogenesis. Catecholamine systems, both in the brain
      and in the periphery, are particularly sensitive to prenatal nicotine exposure.
      Acute and chronic nicotine administered to pregnant dams causes alterations in
      dopamine and its metabolites in male and female rat fetuses. These changes can
      persist into adulthood. Prenatal nicotine exposure also causes locomotor
      disturbances in pups, which can have long-lasting effects. The effect of nicotine
      on developing noradrenergic neurons is less clear. Some effects may include
      increases in noradrenergic neuronal activity in the pup and aberrant central
      release of norepinephrine in response to neonatal hypoxia after nicotine exposure
      in utero. Catecholamine neurons develop early in ontogeny, so nicotine induced
      alterations have the potential to induce permanent changes. Hence, more research
      is needed to get a clearer picture of the effect of nicotine on developing
      catecholamine systems. The affects of nicotine on catecholamine systems in the
      adult are discussed for comparison.

PMID- 10577394
TI  - The metazoan origin recognition complex.
AB  - Regulated initiation of DNA replication relies on the firing of initiator
      proteins that bind specifically to origin DNA. The discovery of the first
      eukaryotic initiator, the Saccharomyces cerevisiae Origin Recognition Complex
      (ORC) has allowed us to discern some aspects of how the onset of replication is
      regulated. However, understanding the specifics of replication in metazoan
      organisms can only be achieved by directly addressing these questions in animal
      cells. This review deals with the current state of knowledge on the metazoan
      Origin Recognition Complex, its composition and regulation in higher eukaryotes,
      its role in the initiation of replication and beyond replication, and its
      possible connection with human pathology.

PMID- 10577395
TI  - Replication origins of mammalian chromosomes: the happy few.
AB  - Replication of eukaryotic cell genomes is a tightly controlled process occurring
      once and only once per cell cycle. Replication initiates at several thousand
      origins, whose cis-acting sequences and trans-acting proteins have been partially
      characterized in the yeast S. cerevisiae in the last few years. In contrast,
      identification of origins of DNA replication in mammalian cells have proven much
      more difficult. Currently, less then 20 bona fide mammalian origins have been
      identified, of which only few characterized in detail. Here we discuss the
      available methods for origin identification in mammalian DNA and the main
      results, sometimes controversial, so far generated by their application. In
      particular, we review the currently available information concerning the three
      best characterized origins, namely those in the lamin B2 and b-globin gene
      domains in human cells and the one located downstream of the dihydrofolate
      reductase gene in hamster cells.

PMID- 10577396
TI  - PCNA binding proteins.
AB  - PCNA (proliferating cell nuclear antigen), originally characterized as a DNA
      polymerase accessory protein, functions as a DNA sliding clamp for DNA polymerase
      delta and is an essential component for eukaryotic chromosomal DNA replication.
      Recent studies have revealed a striking feature of PCNA in its ability to
      interact with multiple partners, involved, for example, in Okazaki fragment
      joining, DNA repair, DNA methylation and chromatin assembly. Since these
      reactions take place mainly on replicating DNA, PCNA has applications as a marker
      for DNA synthesis. It is of interest that proteins involved in cell cycle
      regulation may also exhibit PCNA binding activity. For example, the CDK
      inhibitor, p21 (Cip1/Waf1) interacts with PCNA blocking its activity necessary
      for DNA replication and also affecting interactions with other PCNA binding
      proteins. The available data indicate that DNA sliding clamps have generated
      additional functions with evolution of eukaryotes from simple prokaryotes. In
      mammalian cells, they play key roles in controlling DNA synthesis reactions and
      the reorganization of replicated DNA at replication forks. Several cell cycle
      regulation proteins target these processes by affecting PCNA actions

PMID- 10577397
TI  - Is a pressor necessary during aortic perfusion and oxygenation therapy of cardiac
      arrest?
AB  - STUDY OBJECTIVE: Occlusion of the descending aorta and infusion of oxygenated
      ultrapurified polymerized bovine hemoglobin may improve the efficacy of advanced
      cardiac life support (ACLS). Because selective aortic perfusion and oxygenation
      (SAPO) directly increases coronary perfusion pressure, exogenous epinephrine may
      not be required. The purpose of this study was to determine whether exogenous
      epinephrine is necessary during SAPO by comparing the rate of return of
      spontaneous circulation and aortic and coronary perfusion pressures during ACLS
      SAPO in animals treated with either intra-aortic epinephrine or saline solution.
      METHODS: A prospective, randomized, interventional before-after trial with a
      canine model of ventricular fibrillation cardiac arrest and ACLS based on
      external chest compression was performed. The ECG, right atrial, aortic arch, and
      esophageal pulse pressures were measured continuously. A descending aortic
      occlusion balloon catheter was placed through the femoral artery. Ventricular
      fibrillation was induced, and no therapy was given during the 10-minute arrest
      time. Basic life support was then initiated and normalized by standardization of
      esophageal pulse pressure and central aortic blood gases. After 3 minutes of
      basic life support, the aortic occlusion balloon was inflated, and 0.01 mg/kg
      epinephrine or saline solution was administered through the aortic catheter
      followed by 450 mL of ultrapurified polymerized bovine hemoglobin over 2 minutes.
      Defibrillation was then attempted. The outcomes and changes in intravascular
      pressures were compared. RESULTS: Aortic pressures were higher during infusions
      in animals treated with epinephrine. During infusion, the mean aortic relaxation
      pressure increased by 58+/-5 mm Hg in animals that had received epinephrine
      versus 20+/-11 mm Hg in those that had received saline placebo. The coronary
      perfusion pressure during infusion increased by 52+/-8 mm Hg in animals that had
      received epinephrine versus 26+/-10 mm Hg in those that had received saline. Only
      2 of 7 animals in the placebo group had return of spontaneous circulation versus
      7 of 8 in the epinephrine group. CONCLUSION: The addition of epinephrine to ACLS
      SAPO increases vital organ perfusion pressures and improves outcome from cardiac
      arrest. There appears to be a profound loss of arterial vasomotor tone after
      prolonged arrest. This loss of vasomotor tone may make exogenous pressors
      necessary for resuscitation after prolonged cardiac arrest.

PMID- 10577398
TI  - Rate of change of serial beta-human chorionic gonadotropin values as a predictor
      of ectopic pregnancy in patients with indeterminate transvaginal ultrasound
      findings.
AB  - STUDY OBJECTIVE: To determine the predictive value of the rate of change of
      serial beta-human chorionic gonadotropin (hCG) values in patients with symptoms
      suggestive of ectopic pregnancy but who have indeterminate transvaginal
      ultrasound findings, and to determine whether the predictive value was enhanced
      depending on whether the endometrial cavity was empty at ultrasound examination.
      METHODS: A retrospective study was performed on consecutive emergency department
      patients from August 1, 1991, through August 1, 1998, presenting with abdominal
      pain or vaginal bleeding, a positive beta-hCG test result, and indeterminate
      transvaginal ultrasound findings. Patients were eligible for the study if they
      had a second beta-hCG assay performed within 7 days of the initial visit and
      before either a diagnostic dilation and evacuation or laparoscopy. Patients were
      excluded if they were lost to follow-up. Patients were divided into 4 groups
      based on the rate of change of beta-hCG values over a 48-hour interval (increase
      by >66%, increase by <66%, decrease by <50%, decrease by >50%). In addition, the
      4 main groups were further subdivided depending on whether the endometrial cavity
      was empty at ultrasound examination. Intergroup differences in the frequency of
      ectopic pregnancy based on the rate of change of the beta-hCG value were compared
      using logistic regression. Logistic regression also was used to determine whether
      addition of the ultrasound result improved predicative accuracy. A P value of
      less than.05 was considered significant. Odds ratios (ORs) were determined for
      each subgroup. RESULTS: Three hundred thirty-one eligible patients were
      identified; of these, 24 were excluded. Of the 307 enrolled patients, 33 (10.7%)
      had a final diagnosis of ectopic pregnancy. Intergroup differences in the
      frequency of ectopic pregnancy based on the beta-hCG rate of change were
      significant (P<.0001). Addition of the ultrasound result to this model further
      improved predicative accuracy (P<.0001). Overall, patients with increasing beta
      hCG values were at increased risk compared with those with decreasing beta-hCG
      values, and patients with empty uteri at ultrasound were at increased risk
      compared with those with uteri that were not empty. Combining the beta-hCG rate
      of change with the ultrasound result identified 3 high-risk groups: patients with
      beta-hCG values that increased by less than 66% and an empty uterus at ultrasound
      (OR 24.8); patients with beta-hCG values that decreased by less than 50% and an
      empty uterus at ultrasound (OR 3.7); and patients with beta-hCG values that
      increased by more than 66% and an empty uterus at ultrasound (OR 2.6). Patients
      with beta-hCG values that decreased by more than 50% were found to be at low risk
      for ectopic pregnancy irrespective of the specific endometrial findings at
      ultrasound. CONCLUSION: The rate of change of serial beta-hCG values, in patients
      with an indeterminate pelvic ultrasound examination, is predictive of ectopic
      pregnancy. Addition of whether the endometrial cavity is empty at ultrasound
      leads to a further improvement in predictive accuracy.

PMID- 10577399
TI  - Ultrasound-guided brachial and basilic vein cannulation in emergency department
      patients with difficult intravenous access.
AB  - STUDY OBJECTIVE: Emergency department patients who require intravenous access but
      lack peripheral intravenous sites frequently require central line placement.
      Blind percutaneous brachial vein cannulation has been proposed as an alternative
      in these patients but is associated with high failure and complication rates. We
      evaluated an ultrasound-guided approach to percutaneous deep brachial vein or
      basilic vein cannulation in ED patients with difficult intravenous access.
      METHODS: We prospectively enrolled ED patients who required intravenous access in
      whom there had been 2 unsuccessful attempts at establishing a peripheral
      intravenous line. Using a 7.5-MHz ultrasound probe, the deep brachial vein or
      basilic vein was identified and then cannulated with a 2-in, 18- to 20-gauge
      intravenous catheter. Time from probe placement to cannulation, number of
      attempts, and complications were recorded. RESULTS: One hundred one patients were
      enrolled, of whom 50 were injection drug users and 21 were obese. Cannulation was
      successful in 91 patients (91%) and accomplished on the first attempt in 73
      (73%). The mean (+/-SD) time required for cannulation was 77 seconds (+/-129,
      range 4 to 600 seconds). The line infiltrated or fell out within 1 hour of
      cannulation in 8 (8%) patients. One patient reported severe pain. There were 2
      (2%) cases of brachial artery puncture. CONCLUSION: Ultrasound-guided brachial
      and basilic vein cannulation is safe, rapid, and has a high success rate in ED
      patients with difficult peripheral intravenous access.

PMID- 10577400
TI  - Emergency department documentation in cases of intentional assault.
AB  - STUDY OBJECTIVE: Emergency department records are an important source of injury
      surveillance data. However, documentation regarding intentional assault has not
      been studied and may be suboptimal. The purpose of this study was to analyze
      physician documentation of assailant, site, and object used in intentional
      assault. METHODS: The ED log of an urban Level I trauma center was
      retrospectively reviewed to identify eligible patients presenting consecutively
      in November 1996. All acutely injured patients not involved in a motorized
      vehicle crash were identified. RESULTS: From the ED log, 1, 483 patients were
      identified as possible study subjects; 1,457 (98%) charts were located and
      reviewed and 971 (67%) met inclusion criteria. Of these, 288 (30%) cases resulted
      from intentional assault. In 67% of patients, there was no documentation of the
      identity of the assailant. For 13% of cases, there was no documentation regarding
      the object or force used in the assault. In 79% of cases there was no
      documentation regarding the site of assault. For 24 cases (8%), the assailant was
      documented as an intimate partner or ex-partner. Police involvement in these
      cases was documented 54% of the time, despite the fact that this state mandates
      police reports for cases of acute partner violence. Social service involvement
      and shelter referrals were documented in less than one fourth of domestic
      violence cases. CONCLUSION: Although the ED commonly treats patients who have
      been assaulted, basic surveillance data are often omitted from the chart.
      Structured charting may provide more complete data collection.

PMID- 10577401
TI  - Checking for breathing: evaluation of the diagnostic capability of emergency
      medical services personnel, physicians, medical students, and medical laypersons.
AB  - STUDY OBJECTIVE: International guidelines for cardiopulmonary resuscitation (CPR)
      recommend determination of unconsciousness, breathlessness, and absence of pulse
      to diagnose cardiorespiratory arrest. Thus far, there have been no scientifically
      proven data available regarding the quality of assessing breathlessness. The
      study objective was to evaluate the effectiveness of checking for breathing in an
      emergency situation, to determine the necessary amount of time until diagnosis,
      and to document used techniques. METHODS: Four different populations were tested
      for their ability to assess breathlessness: emergency medical services (EMS)
      personnel, physicians, medical students, and laypersons. Each participant was
      asked to perform the diagnostic procedure twice, first with a breathing or not
      breathing unresponsive test person and then with a modified megacode manikin
      (with the possibility of simulated respiratory function). The order of testing
      and the respiratory status were strictly randomized. Diagnostic accuracy, time
      interval to diagnosis, and used techniques were documented. RESULTS: A total of
      261 persons were tested in 522 trials, with a median time interval of 12 seconds
      for obtaining a diagnosis. Regarding all participants, the correct diagnosis was
      achieved in 81.0% (EMS personnel, 89.7%; physicians, 84.5%; medical students,
      78.4%; laypersons, 71.5%). Only 55.6% of all participants showed correct
      diagnostic skills (EMS personnel, 91.3%; physicians, 51.5%; medical students,
      61.9%; laypersons, 18.5%). CONCLUSION: Checking for breathing was shown to be
      mostly inaccurate and unreliable. This diagnostic procedure takes more time than
      recommended in international guidelines. Therefore CPR training should focus more
      on the determination of breathlessness. Also, the guidelines for CPR should be
      revised.

PMID- 10577402
TI  - Simple CPR: A randomized, controlled trial of video self-instructional
      cardiopulmonary resuscitation training in an African American church
      congregation.
AB  - STUDY OBJECTIVE: Despite the proven efficacy of cardiopulmonary resuscitation
      (CPR), only a small fraction of the population knows how to perform it. As a
      result, rates of bystander CPR and rates of survival from cardiac arrest are low.
      Bystander CPR is particularly uncommon in the African American community.
      Successful development of a simplified approach to CPR training could boost rates
      of bystander CPR and save lives. We conducted the following randomized,
      controlled study to determine whether video self-instruction (VSI) in CPR results
      in comparable or better performance than traditional CPR training. METHODS: This
      randomized, controlled trial was conducted among congregational volunteers in an
      African American church in Atlanta, GA. Subjects were randomly assigned to
      receive either 34 minutes of VSI or the 4-hour American Heart Association
      "Heartsaver" CPR course. Two months after training, blinded observers used
      explicit criteria to assess CPR performance in a simulated cardiac arrest
      setting. A recording manikin was used to measure ventilation and chest
      compression characteristics. Participants also completed a written test of CPR
      related knowledge and attitudes. RESULTS: VSI trainees displayed a comparable
      level of performance to that achieved by traditional trainees. Observers scored
      40% of VSI trainees competent or better in performing CPR, compared with only 16%
      of traditional trainees (absolute difference 24%, 95% confidence interval 8% to
      40%). Data from the recording manikin confirmed these observations. VSI trainees
      and traditional trainees achieved comparable scores on tests of CPR-related
      knowledge and attitudes. CONCLUSION: Thirty-four minutes of VSI can produce CPR
      of comparable quality to that achieved by traditional training methods. VSI
      provides a simple, quick, consistent, and inexpensive alternative to traditional
      CPR instruction, and may be used to extend CPR training to historically
      underserved populations.

PMID- 10577403
TI  - A quality control program for acute pain management in out-of-hospital critical
      care medicine.
AB  - STUDY OBJECTIVE: This study was conducted to evaluate a quality control program
      for improving pain treatment in the out-of-hospital setting. METHODS: Pain was
      evaluated for all patients at the beginning (T(0)) and the end (T(end)) of out-of
      hospital management. During the first part of the study (part 1, n=108), the
      administration and choice of analgesics was left to the physician's discretion.
      Pain protocols were then modified to encourage the use of opioids. The
      effectiveness of this new pain management was analyzed (part 2, n=105) using pain
      scales and quality of relief. RESULTS: Seventy percent of patients who expressed
      meaningful pain did not request analgesia, and 36% did not receive any analgesia
      in part 1 in contrast to 7% in part 2 of the study. The verbal rating scale and
      visual analog scale scores were substantially improved at T(end) versus T(0) in
      both periods, but the improvement was greater in part 2 (mean visual analog scale
      score at T(end) was 29.3+/-23 mm [+/-SD]) than in part 1 (38.6+/-25 mm). The
      percentage of patients who expressed satisfactory relief increased in part 2 (67%
      versus 49% in part 1). The mean dose of intravenous morphine was 7.2+/-6 mg.
      Adverse effects were rare and minor. CONCLUSION: This program focusing on pain
      treatment plus implementation of pain protocols (with intravenous morphine)
      improved pain management in the field.

PMID- 10577404
TI  - Out-of-hospital violence injury surveillance: quality of data collection.
AB  - STUDY OBJECTIVE: The recognized need to improve data collection for violence
      prevention may be met, in part, by using out-of-hospital data for injury
      surveillance. The purpose of the Prehospital Violence Injury Surveillance project
      was to examine the extent to which paramedics can adequately collect information
      about injuries, particularly intentional injuries, at emergency scenes. METHODS:
      Paramedics in a large Midwestern metropolitan area were trained to assess
      violence-related events and collect relevant data using a modified ambulance run
      report form. Data collected from 8 violence-related training scenarios and from
      13 ride-along observations were analyzed to estimate paramedic interrater
      reliability using the kappa statistic. Data from 7,363 run report forms, filed
      during a 3-month study period, were abstracted and analyzed for completeness and
      quality. RESULTS: Paramedics demonstrated fair to good, and sometimes excellent,
      interrater agreement when documenting the training scenarios. Paramedics revealed
      barriers to collecting violence-related out-of-hospital data. The paramedics and
      the observer disagreed in documenting 77% of the ride-along observations.
      Overall, 73% of abstracted run report forms showed documentation errors, with
      more than 99% of these reports containing errors of omission and 29% showing
      internal documentation inconsistencies. Despite the emphasis on violence-related
      data, documentation of domestic abuse screening was missing from more than 99% of
      run reports from female patients. CONCLUSION: Significant barriers to quality out
      of-hospital data collection were identified during study implementation and in
      abstracted run reports. These barriers included the following: lack of
      organizational support; characteristics of the violence-related data elements;
      design of the ambulance run report form; and paramedic knowledge, attitudes, and
      behaviors regarding data collection.

PMID- 10577405
TI  - Emergency Medical Services for Children managed care white paper series:
      introduction.
AB  - The introduction of managed care principles profoundly changed the delivery of
      health care in the United States. The Emergency Medical Services for Children
      (EMSC) program has developed a series of white papers to address the impact of
      managed care on the emergency care system for children and adolescents. We hope
      that these white papers will focus discussions among managed care organizations,
      health care providers, and the public in ways that will lead to improvement in
      the system of care available to children and adolescents.

PMID- 10577406
TI  - Quality and accountability: Children's emergency services in a managed care
      environment.
AB  - The fast pace of change in the health care system has sparked growing interest
      among purchasers, consumers, providers, health plans, and others in evaluating
      and improving the quality of health services. The Emergency Medical Services for
      Children Program's Managed Care Task Force recommended the development of a white
      paper to focus on issues related to quality and accountability in children's
      emergency medical services in a managed care environment. A literature review was
      conducted, and a panel reviewed and discussed relevant materials. The panelists
      then developed recommendations as a resource for managed care organizations,
      providers of care, professional associations, and federal, state, and local
      policymakers.

PMID- 10577407
TI  - Twenty-four-hour access to emergency care for children in managed care.
AB  - Children's medical emergencies occur around the clock. In years past, the
      emergency department, open 24 hours a day, was a familiar site for treating these
      emergencies. However, in today's health care environment, the scenario can be
      more confusing. As many families move from a fee-for-service system into a
      managed care organization (MCO), they may be unclear about what they should do in
      an emergency involving their child. MCOs want to provide appropriate care, and at
      the same time, operate within a system designed to contain costs through the
      establishment of effective health care delivery systems. Providers of emergency
      services, including specialists in pediatric medicine and emergency medical
      services responders, also must contend with a different set of problems,
      including administrative entanglements and concerns about reimbursement for their
      services. This article continues the white paper series by the Emergency Medical
      Services for Children Managed Care Task Force.

PMID- 10577408
TI  - New-generation anticoagulants: the low molecular weight heparins.
AB  - Heparin has been the mainstay of acute anticoagulation therapy for decades.
      Within the past 20 years, several different heparin fractions-collectively known
      as low molecular weight heparins (LMWHs)-have been evaluated in various medical
      and surgical settings in which anticoagulation is routinely warranted. The LMWHs
      are efficacious, safe, cost-effective, and easier to administer and monitor than
      standard, unfractionated heparin. As LMWH use becomes more widespread, emergency
      physicians will use these new agents instead of unfractionated heparin for
      unstable angina, non-Q-wave myocardial infarction, or thromboembolic disease.
      This review focuses on the pharmacologic properties of unfractionated heparin and
      LMWH, associated complications, and the use of these agents in acute ischemic
      coronary syndromes, thromboembolic disease, and other selected clinical
      situations.

PMID- 10577409
TI  - Cardiopulmonary resuscitation techniques and instruction: when does evidence
      justify revision?

PMID- 10577410
TI  - Acute pain management in the field.

PMID- 10577411
TI  - Reference listing of international emergency medicine journals and Web sites.

PMID- 10577412
TI  - The Costa Rican emergency medicine residency: design and implementation of a new
      specialty training program in Central America.
AB  - A program of physician training in the specialty of emergency medicine was
      developed in Costa Rica, Central America, during the years 1993 and 1994. The
      program involved 2 phases: a faculty preparation course, and the residency
      itself. The preparation of faculty members for the residency was undertaken in
      Costa Rica, with a US emergency faculty physician residing in the host country to
      assist in the development of the program. Twenty-one faculty members were
      prepared to teach the residency curriculum. A core group of Costa Rican physician
      educators with assistance from the US emergency medicine specialist developed a
      curriculum suitable for the needs of the region. A selection process for
      prospective applicants to the residency program is described. The first residents
      began training in February 1994, just before completion of the faculty program.
      The first emergency medicine specialists graduated from the 3-year training
      program in 1997. The residency program continues to function at the time of this
      publication. This description is offered as one model for the initiation of
      emergency medicine specialty training in a developing country.

PMID- 10577413
TI  - Ventricular tachycardia in an adolescent with arrhythmogenic right ventricular
      dysplasia.
AB  - We report the case of an adolescent boy with exertional syncope and ventricular
      tachycardia caused by arrhythmogenic right ventricular dysplasia. Diagnosis was
      determined by transthoracic echocardiography and definitive management with an
      automatic internal cardiac defibrillator. Emergency physicians must be aware of
      this serious but treatable cause of adolescent exertional syncope.

PMID- 10577414
TI  - National Highway Traffic Safety Administration (NHTSA) Notes. Speeding and other
      unsafe driving actions.

PMID- 10577415
TI  - NHTSA Notes Commentary: strategies to combat aggressive driving. National Highway
      Traffic Safety Administration.

PMID- 10577416
TI  - The resuscitation.

PMID- 10577417
TI  - Excess case reports in the emergency medicine literature.

PMID- 10577418
TI  - Serotonin syndrome after a single dose of fluvoxamine.

PMID- 10577419
TI  - Parenteral methylprednisolone in the emergency department.

PMID- 10577421
TI  - Parenteral methylprednisolone in the emergency department

PMID- 10577420
TI  - Parenteral methylprednisolone in the emergency department

PMID- 10577422
TI  - Translation of clinical evidence into medical practice.

PMID- 10577423
TI  - No time to wait.

PMID- 10577424
TI  - Tailored treatment for heart failure: An emerging concept.

PMID- 10577425
TI  - Is there still a future for neutral endopeptidase inhibitors?

PMID- 10577426
TI  - Heart failure after myocardial infarction: A good heart is hard to find.

PMID- 10577427
TI  - Primary intervention in acute myocardial infarction: Do bankers' hours suffice,
      or should we invest our resources elsewhere?

PMID- 10577428
TI  - Hemostasis of the femoral vasculature: Shouldn't we have an answer by now?

PMID- 10577429
TI  - Radiofrequency atrioventricular junction ablation for atrial fibrillation: how
      can we make it better?

PMID- 10577430
TI  - Stress testing: national patterns and predictors of test ordering.
AB  - OBJECTIVE: To determine predictors of ordering of exercise stress tests.
      BACKGROUND: Because exercise stress testing is routinely used and widely
      available and may have an effect on subsequent evaluation of and therapy for
      heart disease, understanding current patterns of ordering exercise stress tests
      may have important implications for national health care costs. We hypothesized
      that factors other than clinical condition exert an influence on ordering of
      exercise stress tests. METHODS: Data from the 1991 and 1992 National Ambulatory
      Medical Care Surveys conducted by the National Center for Health Statistics were
      analyzed by means of multivariate logistic regression. RESULTS: In an estimated
      1.12 billion adult visits to office-based physicians in the United States (95%
      confidence interval [CI], 1.07-1.16 billion), 6.2 million (95% CI, 4.8-7.6
      million) exercise stress tests were ordered. After adjustment for clinical and
      nonclinical variables associated with the office visit, cardiologists were 3.7
      (95% CI, 2.7-5.1) times more likely to order exercise stress tests than were
      internists, who were more likely to order an exercise stress test than were
      family and general practitioners (0.5, 95% CI, 0.3-0.7). Nonclinical factors
      associated with increased ordering of exercise stress tests included male sex
      (odds ratio 2.5; 95% CI, 2.0-3.2), white race (odds ratio 1.6; 95% CI, 1.1-2.3),
      new referral status (odds ratio 3.8; 95% CI, 2.5-5.8), and private insurance
      (odds ratio 1.4; 95% CI, 1.1-1.8). Medicare recipients were about half (95% CI,
      0.4-0.9) as likely as other patients to have an exercise stress test ordered.
      CONCLUSIONS: Factors other than clinical condition exert an influence on ordering
      of exercise stress tests and may represent modifiable elements associated with
      appropriate practice.

PMID- 10577431
TI  - Incremental prognostic value of myocardial perfusion single photon emission
      computed tomography in patients with diabetes mellitus.
AB  - BACKGROUND: Previous studies have shown that myocardial perfusion single photon
      emission computed tomography (SPECT) provides incremental prognostic information
      in the general population, but the prognostic efficacy of nuclear testing in
      patients with diabetes mellitus is unclear. METHODS: We conducted a study with
      1271 consecutively registered patients with diabetes and 5862 patients without
      diabetes with known or suspected coronary artery disease undergoing rest thallium
      201/stress technetium 99m sestamibi dual-isotope myocardial perfusion SPECT with
      exercise or adenosine pharmacologic testing. Patients were followed up for at
      least 1 year. The successful follow-up rate was 92.4% for patients with diabetes
      and 94.0% for subjects without diabetes. The mean follow-up period was 23.7 +/-
      7.7 months for the former group and 21.5 +/- 6.1 months for the latter. RESULTS:
      Over the follow-up period, patients with diabetes had significantly higher rates
      of hard events (cardiac death or nonfatal myocardial infarction) (4.3% per year
      versus 2.3% per year, P <.001) and higher total event rates (hard events and late
      revascularization) (9.0% per year versus 5.3% per year, P <. 001) compared with
      rates among patients without diabetes. Cox proportional hazards analysis revealed
      that nuclear testing added incremental value over clinical and historical
      variables among patients with diabetes (global chi(2) increased 46% for the
      exercise group [n = 619] and 88% for the adenosine group [n = 461]; both P <.
      001). The event rates rose significantly as a function of summed stress score and
      summed difference score among both patients with diabetes and patients without
      diabetes (P <.001). The patients with diabetes with normal scans had relatively
      low hard event rates (1% to 2% per year), those with mildly abnormal scans had
      intermediate hard event rates (3% to 4% per year), and those with moderately to
      severely abnormal scans had relatively high hard event rates (>7% per year).
      CONCLUSIONS: The results of this study indicated that exercise and adenosine
      stress myocardial perfusion SPECT are valuable for risk stratification and
      management of patients with diabetes.

PMID- 10577432
TI  - Exercise testing: improving performance with a ramped Bruce protocol.
AB  - BACKGROUND: The standard Bruce protocol was compared with a ramped Bruce protocol
      in stress testing of a general population of patients. METHODS: We examined
      hemodynamic responses, test duration, and patient comfort with each exercise
      protocol. Twenty-three patients completed the study, 14 men and 9 women with a
      mean age of 51 +/- 12 years. Each patient completed the 2 treadmill protocols in
      a random manner. RESULTS: Mean peak heart rate, systolic blood pressure, and
      rating of perceived exertion according to the revised Borg scale were equivalent
      in both protocols, measuring 157 +/- 15 beats/min, 170 +/- 22 mm Hg, and 8 +/- 1
      for the Bruce and 158 +/- 17 beats/min, 175 +/- 20 mm Hg, and 8 +/- 1 for the
      ramp protocol (P = NS). Duration of test and metabolic equivalents (METs) were
      greater with the ramp than with the Bruce protocol. For the Bruce duration and
      METs were 8:25 +/- 3:00 min and 9.6 +/- 3.1, and for the ramp 10:01 +/- 2:32 min
      and 11.4 +/- 2.7 (P <.0001 for both). Subjective rating of difficulty was
      assessed on a scale of 1 to 5, 1 being the most difficult and 5 being the
      easiest. Rating for the Bruce protocol was 2.5 +/- 0.9 and for the ramp 4.1 +/-
      0.9 (P <.0001). CONCLUSION: We propose that a ramped modification of the Bruce
      protocol achieves equivalent hemodynamic goals but with better duration. Patients
      preferred the ramp with respect to comfort, and exercise data can be correlated
      easily with standard protocols.

PMID- 10577433
TI  - Recognition of infarct localization by specific changes in intramural myocardial
      mechanics.
AB  - BACKGROUND: After transmural myocardial infarction (MI), changes occur in
      intramural myocardial function. This has been described in anterior MI only. The
      aim of this study was to determine the relation between variable infarct
      locations and intramural deformation in patients with a first MI. METHODS: Forty
      patients (33 men and 7 women aged 57 +/- 11 years) with different infarct-related
      coronary arteries (25 left anterior descending, 7 circumflex, and 8 right
      coronary) were studied 6 +/- 3 days after infarction with magnetic resonance
      tissue tagging and 2-dimensional finite element analysis of myocardial
      deformation. Short-axis tagged images were acquired at base, mid, and apical
      level. Intramural deformation was measured in 6 circumferential segments per
      level. Results were compared with 9 age-matched healthy controls. RESULTS: Each
      infarct area demonstrated a significant reduction of intramural deformation. At
      mid-ventricular level, segments with maximum impaired intramural function were
      the anteroseptal segment for left anterior descending-related MI (stretch: 16% vs
      33% for controls, P <.001), the posterolateral segment for related MI (stretch:
      20% vs 34%, P <. 01); and the inferior segment for right coronary artery related
      MI (stretch: 18% vs 25%, P =.082). In these infarct segments, the intramural
      regional systolic stretch was more circumferentially oriented compared with
      radially oriented stretch in the same segments in controls (P <.05). CONCLUSION:
      The infarct area can be recognized by a specific spatial pattern of intramural
      deformation. In infarcted compared with noninfarcted myocardium, deformation is
      significantly reduced and systolic stretch deviates from the radial direction.
      Left anterior descending related infarcts were found to have larger regional
      differences in intramural deformation than circumflex or right coronary artery
      related MI of enzymatically the same size.

PMID- 10577434
TI  - Prehospital delay in patients hospitalized with heart attack symptoms in the
      United States: the REACT trial. Rapid Early Action for Coronary Treatment (REACT)
      Study Group.
AB  - BACKGROUND: The use of thrombolytic therapy for patients with myocardial
      infarction has been limited by patient delay in seeking care. We sought to
      characterize prehospital delay in patients hospitalized for evaluation of heart
      attack symptoms. METHODS AND RESULTS: The Rapid Early Action for Coronary
      Treatment (REACT) is a multicenter, randomized community trial designed to reduce
      patient delay. At baseline, data were abstracted from the medical records of 3783
      patients hospitalized for evaluation of heart attack symptoms in 20 communities.
      The median prehospital delay was 2.0 hours; 25% of patients delayed longer than
      5.2 hours. In a multivariable analysis, delay time was longer among non-Hispanic
      blacks than among non-Hispanic whites, longer at older ages, longer among
      Medicaid-only recipients and shorter among Medicare recipients than among
      privately insured patients, and shorter among patients who used an ambulance.
      CONCLUSIONS: The observed pattern of differences is consistent with the
      contention that demographic, cultural, and/or socioeconomic barriers exist that
      impede rapid care seeking.

PMID- 10577435
TI  - Very early assessment of risk for in-hospital death among 11,483 patients with
      acute myocardial infarction. GISSI investigators.
AB  - BACKGROUND: The efficacy of reperfusion therapy after acute myocardial infarction
      is time dependent. The risk profile of every patient should be available as soon
      as possible. Our aim was to determine whether collection of simple clinical
      markers at hospital admission might allow reliable risk stratification for in
      hospital mortality. METHODS: The subjects were 11,483 patients with acute
      myocardial infarction from the GISSI-2 cohort. The GISSI-1 and GISSI-3
      populations were selected to validate the classification. To stratify patients,
      the tree-growing method called recursive partitioning and amalgamation (RECPAM)
      was used. This method is used to identify homogeneous and distinct subgroups with
      respect to outcome. RESULTS: The RECPAM algorithm provided 6 classes. RECPAM
      class I included Killip class 3 to class 4 patients (516 deaths/1000). RECPAM
      class II included Killip 2 patients older than 66 years and with anterior
      infarction or sites of infarction that could not be evaluated (314 deaths/1000).
      Killip 1 patients older than 75 years and with anterior or multiple sites or
      sites that could not be evaluated were included in RECPAM class III with Killip
      class 2 patients younger than 66 years and with systolic blood pressure less than
      120 mm Hg or older than 66 years and with any other infarction site (207
      deaths/1000). The other classes showed lower mortality rates (91, 32, and 12
      deaths/1000 for RECPAM classes IV, V, and VI). In the GISSI 1 and GISSI 3 samples
      the 6 classes ranked in the same order in terms of mortality rate. With respect
      to low-risk strata, patients belonging to RECPAM class VI without serious
      clinical events in the first 4 days had a very low incidence of in-hospital death
      (0.9%) or morbidity. Cumulative 6-month mortality for the 6 RECPAM classes was
      59.6%, 41.2%, 26.4%, 12.9%, 4. 8%, and 2.2%. CONCLUSIONS: Four simple clinical
      markers readily available at admission of patients with myocardial infarction
      allow a quick, reliable, and inexpensive prediction of risk for in-hospital and 6
      month mortality. The RECPAM classification also helped identify a large subgroup
      of patients fit for early hospital discharge.

PMID- 10577436
TI  - Racial differences in the management of unstable angina: results from the
      multicenter GUARANTEE registry.
AB  - BACKGROUND: Prior studies, usually conducted with the use of insurance databases,
      have shown differences in the use of cardiac procedures between black patients
      and white patients hospitalized with various types of coronary artery disease.
      However, few data are available in prospectively collected cohorts of patients
      with unstable angina or on the use of appropriate medications or interventions.
      METHODS AND RESULTS: We evaluated 2948 consecutive patients with unstable angina
      admitted to 35 hospitals across the United States in 1996, comparing nonwhite and
      white patients. Seventy-seven percent of patients were white, 14% were black, 4%
      were Hispanic, 1% were Asian, and 3% were other or unknown race. Differences were
      seen in coronary risk profile, with a higher incidence of hypertension and
      diabetes mellitus in nonwhites. Cardiac catheterization was performed less often
      in nonwhites compared with whites (36% vs 53%, P =.001). Even in patients meeting
      the criteria for appropriate catheterization in the Agency for Health Care Policy
      Research unstable angina guidelines, fewer nonwhites underwent catheterization
      (44% vs 61%, P =.001), but among these, fewer nonwhites had significant coronary
      stenosis (72% vs 90%, P =.001). However, among patients catheterized who had
      indications for revascularization, angioplasty and coronary artery bypass
      grafting were performed equally often in nonwhites and whites. CONCLUSIONS:
      Current guidelines would recommend more aggressive use of cardiac catheterization
      for nonwhite patients. However, our findings suggest that racial differences may
      need to be included in the diagnostic and interventional algorithms.

PMID- 10577437
TI  - Insights into the pathophysiology of atherosclerosis and prognosis of black
      Americans with acute coronary syndromes.
AB  - BACKGROUND: Disparities in prognosis for black and white patients with coronary
      heart disease have been widely reported. For several reasons it is unclear to
      what extent biologic factors contribute to these differences. METHODS: The
      current medical literature regarding the pathophysiologic characteristics of
      cardiovascular disease is reviewed with emphasis on how racially mediated
      biologic differences may affect the manifestation, treatment, and prognosis of
      patients with coronary heart disease, particularly patients with acute coronary
      syndromes. RESULTS: Black patients with coronary heart disease have a higher
      prevalence of ischemic heart disease risk factors, including hypertension, left
      ventricular hypertrophy, diabetes, and tobacco use. Other factors related to
      atherosclerosis, vascular reactivity, and thrombolysis that quantitatively and
      functionally differ among racial groups are identified. Prospective, randomized
      trials comparing outcomes among patients with acute coronary syndromes have
      included only a fraction of the available black population, although they reveal
      a similar short-term mortality rate for black and white patients. Several
      factors, including enhanced fibrinolysis among black patients with acute
      myocardial infarction, may in part counterbalance better understood and more
      prevalent comorbidities to equalize short-term (30-day) survival. All-cause, long
      term (1-year) mortality appears worse for black patients compared with white
      patients with similar cardiovascular risk profiles. CONCLUSION: As racially
      mediated biologic differences between black and white patients become better
      understood, targeted interventions to prevent coronary heart disease and treat
      acute coronary syndromes in black patients can be developed.

PMID- 10577438
TI  - Niacin treatment increases plasma homocyst(e)ine levels.
AB  - BACKGROUND: Studies have reported high levels of plasma homocyst(e)ine as an
      independent risk factor for arterial occlusive disease. The Cholesterol Lowering
      Atherosclerosis Study reported an increase in plasma homocyst(e)ine levels in
      patients receiving both colestipol and niacin compared with placebo. Thus the
      objective of this study was to examine the effect of niacin treatment on plasma
      homocyst(e)ine levels. METHODS: The Arterial Disease Multiple Intervention Trial,
      a multicenter randomized, placebo-controlled trial, examined the effect of niacin
      compared with placebo on homocyst(e)ine in a subset of 52 participants with
      peripheral arterial disease. RESULTS: During the screening phase, titration of
      niacin dose from 100 mg to 1000 mg daily resulted in a 17% increase in mean
      plasma homocyst(e)ine level from 13.1 +/- 4.4 micromol/L to 15.3 +/- 5.6
      micromol/L (P <.0001). At 18 weeks after randomization, there was an absolute 55%
      increase from baseline in mean plasma homocyst(e)ine levels in the niacin group
      and a 7% decrease in the placebo group (P =.0001). This difference remained
      statistically significant at the end of follow-up at 48 weeks. CONCLUSIONS:
      Niacin substantially increased plasma homocyst(e)ine levels, which could
      potentially reduce the expected benefits of niacin associated with lipoprotein
      modification. However, plasma homocyst(e)ine levels can be decreased by folic
      acid supplementation. Thus further studies are needed to determine whether B
      vitamin supplementation to patients undergoing long-term niacin treatment would
      be beneficial.

PMID- 10577439
TI  - Relation between aerobic capacity and extent of myocardial ischemia in patients
      with normal cardiac function.
AB  - BACKGROUND: The relation between aerobic capacity and extent of exercise-induced
      myocardial ischemia has not been investigated. Fifty patients with coronary
      artery disease (>/=50% stenosis) without myocardial infarction underwent
      cardiopulmonary exercise testing followed by quantitative thallium perfusion
      imaging. Results were compared with those of age- and sex-matched healthy
      controls with a low likelihood of coronary artery disease. Patients with Q-wave
      infarction, pulmonary disease, and peripheral vascular disease were excluded.
      Cardiopulmonary exercise testing and thallium perfusion imaging parameters were
      correlated for extent of global ischemia, occurrence of increased pulmonary
      thallium uptake, and transient ventricular dilatation during exercise. RESULTS:
      Patients with global ischemia <20% (group 1, n = 25) had normal cardiopulmonary
      exercise testing results, similar to the control group, except for workload and
      maximal predicted heart rate, which were reduced. However, patients with ischemia
      >/=20% (group 2, n = 25) had poor cardiopulmonary exercise testing results
      compared with the controls. The ventilatory anaerobic threshold showed the most
      significant decrease of all cardiopulmonary exercise testing parameters (48% +/-
      6% vs 57% +/- 6%, P <.0001), and it was the only parameter to correlate with
      extent of ischemia (r = -0.5; P <.003) as well as frequency of increased
      pulmonary uptake and transient ventricular dilatation (r = -0.33, P =.03).
      CONCLUSIONS: Ventilatory anaerobic threshold is significantly related to extent
      of myocardial ischemia and signs of heart failure during exercise. However,
      patients with mild to moderate exercise-induced ischemia may have normal
      cardiopulmonary exercise testing performance.

PMID- 10577440
TI  - Development of eptifibatide.
AB  - BACKGROUND: The primary cause of acute coronary syndromes is the development of a
      thrombus, a pathologic manifestation of platelet aggregation that occurs as part
      of the normal process of hemostasis. The discovery that the final common step in
      platelet aggregation, through the binding of fibrinogen to the activated platelet
      integrin glycoprotein (GP) IIb/IIIa, has opened the door to the development of
      novel and potentially more effective antithrombotic therapies. Abciximab, a human
      murine chimeric Fab fragment of a monoclonal antibody against the GP IIb/IIIa
      receptor, was the first agent of this class to demonstrate clinical
      effectiveness. Several of the specific properties of abciximab, such as its long
      half-life, lack of receptor-blocking specificity, and some tendency for
      antigenicity, have prompted the development of alternative GP IIb/IIIa inhibitors
      with distinct pharmacologic profiles. METHODS AND RESULTS: One of these newer
      agents is eptifibatide, which was developed by mimicking the GP IIb/IIIa blocker
      barbourin, found in the venom of the southeastern pigmy rattlesnake. Eptifibatide
      is a small, cyclic heptapeptide that has shown high specificity and high affinity
      for GP IIb-IIIa, a short plasma half-life, and rapid onset of antiplatelet action
      accompanied by a rapid reversibility of platelet inhibition once treatment is
      stopped. CONCLUSIONS: In clinical trials, culminating in the phase III IMPACT II
      (Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis) and PURSUIT
      (Platelet GP IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin
      Therapy) trials, eptifibatide was found to reduce coronary events significantly
      in a broad range of low-, medium-, and high-risk patients with acute coronary
      syndromes without significantly increasing the risk of bleeding or other
      complications. These results suggest that eptifibatide may prove to be an
      effective addition to currently available antithrombotic therapies.

PMID- 10577441
TI  - Clinical outcome after multivessel coronary stent implantation.
AB  - BACKGROUND: Percutaneous transluminal coronary angioplasty (PTCA) has been shown
      to be an effective therapy for multivessel coronary artery disease, although more
      frequent acute complications and an increased need to repeat revascularization
      than with single-vessel PTCA continue to be limitations. Intracoronary stent
      placement has been shown to reduce the rate of acute complications and the need
      for subsequent revascularization. We sought to evaluate the outcome among
      patients undergoing successful multivessel coronary intervention with stents.
      METHODS: The participants were 175 patients without coronary artery bypass grafts
      who underwent multivessel coronary revascularization in which stent placement was
      attempted in all treated segments from January 1992 through March 1998 at our
      institution. Clinical and angiographic characteristics and outcomes were
      analyzed. RESULTS: Stent placement was attempted for 428 coronary lesions. The
      angiographic success rate was 100%. Modified American College of Cardiology
      American Heart Association type B2 and C lesions accounted for 74.5% of the
      lesions. Three patients (1.7%) died in the hospital. No patient had Q-wave
      myocardial infarction or needed coronary artery bypass grafting. Procedural
      success was achieved for 172 patients (98.3%). The Kaplan-Meier probability of
      freedom from death or myocardial infarction at 12 months was 96.6%, of any
      revascularization was 81. 7%, and of death, myocardial infarction, and any
      revascularization combined was 79.8%. The use of long-acting nitrates at 12
      months was reduced (34.3% versus 19.1%, P =.01). CONCLUSIONS: Multivessel
      coronary stent placement is associated with an excellent procedural success rate
      despite a high rate of adverse lesion characteristics and a high event-free
      survival rate during the follow-up period. The likelihood that revascularization
      will not have to be repeated during the first follow-up year is significantly
      better than that for historic controls of multivessel PTCA.

PMID- 10577442
TI  - Daytime and nighttime differences in patterns of performance of primary
      angioplasty in the treatment of patients with acute myocardial infarction.
      Maximal Individual Therapy in Acute Myocardial Infarction (MITRA) Study Group.
AB  - BACKGROUND: Concern exists regarding the results of primary angioplasty for acute
      myocardial infarction when the procedure is performed during night hours. METHODS
      AND RESULTS: Between June 1994 and January 1997, 491 patients with acute
      myocardial infarction who underwent primary angioplasty procedures were
      consecutive registered in the Maximal Individual Therapy in Acute Myocardial
      Infarction (MITRA) study. Three hundred seventy-eight patients (77%) were treated
      during the day and 113 (23%) at night. Baseline characteristics showed no major
      differences between the 2 groups. Prehospital delay time was 60 minutes shorter
      during the night (median value 180 minutes for day, 120 minutes for night, P
      =.005), and in-hospital time to treatment was 9 minutes longer (median value 85
      minutes day, 94 minutes night, P =.037). Patients treated during the night more
      often received angiotensin-converting enzyme blockers (61.4% day, 76.1% night, P
      =.004) and the so-called optimal adjunctive therapy (54% day, 64.6% night, P
      =.045). There were no differences concerning clinical events between the 2
      groups. Hospital mortality was 8.7% during the day and 5.3% during the night
      (univariate analysis P =.238; logistic regression P =.653). CONCLUSIONS: In a
      clinical setting, primary angioplasty for acute myocardial infarction can be
      performed safely during the night with a clinically insignificant prolongation of
      in-hospital time to reperfusion compared with practice during the day.

PMID- 10577443
TI  - Randomized comparison of hemostasis techniques after invasive cardiovascular
      procedures.
AB  - BACKGROUND: The arterial access required during most invasive vascular procedures
      provides a common source of complications and morbidity. This problem has been
      made worse by recent trends in earlier ambulation and more aggressive
      antihemostatic drug regimens. Despite these trends, no randomized trials have
      been reported comparing the 3 most commonly used techniques in achieving
      hemostasis at the arterial puncture site. METHODS: A cohort of 400 patients
      undergoing catheterization laboratory procedures were randomly assigned to 1 of 3
      groups of arterial compression: manual compression, mechanical clamp, and
      pneumatic compression device. Standard requirements of the trial included
      uniformity in initial compression times, patient instructions, nursing follow-up,
      and timing of ambulation as well as a structured interview and physical
      examination at 24 hours. RESULTS: Prolonged compression was required in 13% of
      the manual group, 20% of the clamp group, and 35% of the pneumatic group (P
      <.0001). In-lab bleeding was more common in the pneumatic group (3%, 4%, and 16%,
      respectively, P <.0001), as was the need for an alternate compression technique
      (1%, 1%, and 27%, P <.0001). The groups also differed in respect to mean hematoma
      size (3.9 cm(2), 7.8 cm(2), and 19.8 cm(2), P =.036) and level of discomfort
      during compression (1.9, 2.2, and 3.1 on a 1- to 10-point scale, P <.0001).
      Comparable findings were observed in the subgroup of patients eligible for
      outpatient procedures. CONCLUSIONS: Use of the pneumatic compression device leads
      to longer compression times, greater discomfort, more bleeding, and larger
      hematomas. Differences between manual compression and the mechanical clamp were
      more subtle but tend to favor use of the manual technique.

PMID- 10577444
TI  - Titration of vasodilator therapy in chronic heart failure according to plasma
      brain natriuretic peptide concentration: randomized comparison of the hemodynamic
      and neuroendocrine effects of tailored versus empirical therapy.
AB  - BACKGROUND: Most patients with chronic heart failure (CHF) receive the same dose
      of angiotensin-converting enzyme (ACE) inhibitors because there is currently no
      measure of treatment efficacy. We sought to determine whether titration of
      vasodilator therapy according to plasma brain natriuretic peptide (BNP)
      concentration may be of value in the individual optimization of vasodilator
      therapy in CHF. METHODS AND RESULTS: Twenty patients with mild to moderate CHF
      receiving stable conventional therapy including an ACE inhibitor were randomly
      assigned to titration of ACE inhibitor dosage according to serial measurement of
      plasma BNP concentration (BNP group) or optimal empirical ACE inhibitor therapy
      (clinical group) for 8 weeks. Only the BNP-driven approach was associated with
      significant reductions in plasma BNP concentration throughout the duration of the
      study and a significantly greater suppression when compared with empiric therapy
      after 4 weeks [-42.1% (-58.2, -19.7) vs -12.0% (-31.8, 13.8), P =.03]. Both
      treatment strategies were well tolerated and associated with favorable
      neurohormonal and hemodynamic effects; however, in comparison between groups,
      mean heart rate fell (P =.02) and plasma renin activity rose (P =.03) in the BNP
      group when compared with the clinical group. CONCLUSIONS: Plasma BNP
      concentration may be chronically reduced by tailored vasodilator therapy in CHF.
      Furthermore, titration of vasodilator therapy according to plasma BNP was
      associated with more profound inhibition of the renin-angiotensin-aldosterone
      system and significant fall in heart rate when compared with empiric therapy.

PMID- 10577445
TI  - Clinical predictors of heart failure in patients with first acute myocardial
      infarction.
AB  - BACKGROUND: The occurrence of heart failure associated with an acute myocardial
      infarction has a strong adverse effect on long-term morbidity and mortality. The
      prediction and prevention of heart failure could influence these adverse events.
      METHODS AND RESULTS: We studied 483 consecutive patients who had their first
      acute myocardial infarction and who were admitted within 24 hours of the onset of
      symptoms. Heart failure was defined as the presence of pulmonary rales or an S3
      gallop, or the presence of alveolar or interstitial edema by radiograph. Baseline
      demographic data, determination of peak creatine phosphokinase level,
      echocardiographic left ventricular ejection fraction, blood pressure, and pulse
      were obtained. Heart failure occurred in 41.6% (201 of 483) of the patients. We
      observed a bimodal occurrence of heart failure with an early occurrence at
      admission in 4% (20 of 483) followed by a second increase beginning after the
      fourth day of admission in 39% of the remaining patients (181 of 463). Predictors
      of early heart failure were older age, diabetes mellitus, or previous cardiac
      symptoms, whereas the predictors of heart failure after the fourth day included
      the same demographic predictors in addition to a history of hypertension, male
      sex, increased peak creatine phosphokinase level and heart rate, and decrease in
      left ventricular ejection fraction. In-hospital death occurred in 5.3% compared
      with 1.4% (P =.012) in patients who did and did not have heart failure,
      respectively. The occurrence of heart failure during hospital admission also
      adversely affected the 18-month follow-up, with 14.9% deaths in the patients with
      heart failure and 6.4% in those without heart failure (P =.002). CONCLUSION:
      Heart failure is frequently associated with acute myocardial infarction and
      occurs with a bimodal distribution and is associated with increased risk of death
      during hospitalization and during 18 months of follow-up. Predictors of early
      heart failure include previous medical conditions and age. The second peak
      occurrence can be predicted by similar characteristics in addition to increased
      peak creatine phosphokinase level, decreased left ventricular ejection fraction,
      and increased heart rate.

PMID- 10577446
TI  - A randomized trial of ecadotril versus placebo in patients with mild to moderate
      heart failure: the U.S. ecadotril pilot safety study.
AB  - OBJECTIVE: To determine the short-term safety and tolerability of the addition of
      ecadotril to conventional therapy in patients with mild to moderate heart
      failure. METHODS: Fifty ambulatory patients, 18 to 75 years of age, with mild to
      moderate heart failure, left ventricular ejection fraction </=35%, taking stable
      doses of angiotensin-converting enzyme inhibitor, diuretics, and optionally
      digoxin were enrolled in a randomized, double-blind, placebo-controlled dose
      escalation study of ecadotril 50 to 400 mg twice daily versus conventional
      therapy alone. RESULTS: No increases in deaths, serious adverse events, or
      dropouts from adverse events were observed for the ecadotril group compared with
      placebo. The serum measures of neurohormonal activation were highly variable.
      Changes in signs and symptoms of heart failure, New York Heart Association class,
      and patient self-assessment of symptoms were not observed with ecadotril therapy;
      however, the study was not designed to detect differences in these parameters.
      CONCLUSION: In this small pilot study, ecadotril in doses of 50 to 400 mg twice
      daily was generally well-tolerated and without severe short-term adverse effects
      in patients with mild to moderate heart failure. Evaluation of the clinical
      efficacy and long-term safety of ecadotril and other neutral endopeptidase
      inhibitors in patients with heart failure requires further study.

PMID- 10577447
TI  - Comparison of the short-term effects of candoxatril, an orally active neutral
      endopeptidase inhibitor, and frusemide in the treatment of patients with chronic
      heart failure.
AB  - BACKGROUND: Candoxatril is a novel neutral endopeptidase inhibitor that increases
      plasma concentrations of atrial natriuretic factor and thereby produces
      natriuresis, diuresis, and vasorelaxation. This profile of action offers
      theoretical advantages over standard diuretic therapy in the treatment of
      patients with heart failure. The aims of the study were to compare the effects of
      candoxatril with those of frusemide in the treatment of patients with mild heart
      failure. METHODS: Male patients with mild heart failure were randomly assigned to
      9 days of therapy with 20 mg frusemide twice a day, 200 mg candoxatril twice a
      day, or 400 mg candoxatril twice a day (n = 10 per group) after a 14-day placebo
      washout phase. Systemic hemodynamic measurements, exercise tolerance, and urinary
      and plasma hormone concentrations were assessed during the placebo run-in and at
      the beginning and end of the double-blind therapy. RESULTS: Frusemide and
      candoxatril caused similar diuresis and natriuresis. Candoxatril caused a slight
      decrease in systolic blood pressure and a dose-dependent increase in plasma and
      urinary concentrations of atrial natriuretic factor without elevating plasma
      renin activity. Frusemide reduced plasma concentrations of atrial natriuretic
      factor and increased plasma renin activity. Treadmill exercise capacity decreased
      30 +/- 26 seconds after use of frusemide, compared with increases of 12 +/- 35
      seconds after use of 200 mg candoxatril twice a day and 35 +/- 31 seconds after
      use of 400 mg candoxatril twice a day (P =.13; frusemide versus 400 mg
      candoxatril twice a day). CONCLUSIONS: In the treatment of patients with mild
      heart failure, candoxatril has diuretic effects equivalent to those of 20 mg
      frusemide twice a day without the associated and potentially detrimental
      activation of the renin-angiotensin-aldosterone system. The trend for improved
      exercise capacity with candoxatril warrants further investigation.

PMID- 10577448
TI  - Metoprolol CR/XL in patients with heart failure: A pilot study examining the
      tolerability, safety, and effect on left ventricular ejection fraction.
AB  - BACKGROUND: This study was designed to investigate the tolerability, safety, and
      effect on left ventricular function of a new long-acting preparation of
      metoprolol, metoprolol succinate (CR/XL). METHODS AND RESULTS: Sixty patients
      were randomly assigned with a 2:1 ratio, drug versus placebo, administered with a
      gradually increasing dose of 12.5 to 150 mg of blinded medication during an 8
      week period and continued for 6 months. The average peak dose achieved was 99 mg
      and 132 mg in the metoprolol succinate and placebo groups, respectively. The drug
      was well tolerated and there was no significant difference in drug withdrawals,
      New York Heart Association class, or quality of life assessment. The increase in
      left ventricular ejection fraction measure at baseline and 6 months measured by
      radioisotopic ventriculography was greater in the metoprolol succinate group (27.
      5% to 36.3%) than in the placebo group (26% to 27.9%) (P <.015). Examination of
      serial Holter electrocardiographic recordings indicate that metoprolol succinate
      therapy was associated with a significant (P <.05) decrease in total ventricular
      ectopy at 8 weeks of therapy and a decrease in ventricular couplets and
      nonsustained ventricular tachycardia at 8 through 26 weeks of therapy. No changes
      were observed in plasma norepinephrine during therapy except a transitory
      significant (P <.05) increase in N terminal proatrial natriuretic factor at 8
      weeks in the metoprolol succinate group. CONCLUSIONS: This study indicates that
      treatment with metoprolol succinate for a 6-month period is safe and well
      tolerated and is associated with an increase in left ventricular ejection
      fraction and a decrease in ventricular ectopic beats.

PMID- 10577449
TI  - Mitral regurgitation after atrioventricular node catheter ablation for atrial
      fibrillation and heart failure: acute hemodynamic features.
AB  - BACKGROUND: Radiofrequency catheter ablation of the atrioventricular node and
      pacemaker insertion have been associated with occasional development of mitral
      regurgitation (MR). Ventricular pacing might result in MR if (1) left ventricular
      (LV) compliance is decreased and/or (2) mitral valve leaflet apposition is
      disturbed. We studied acute hemodynamic changes resulting from initiation of
      ventricular pacing in patients undergoing ablation. METHODS AND RESULTS: Thirteen
      patients (10 men and 3 women) with a mean age of 73.4 +/- 8. 6 years, with
      chronic atrial fibrillation and congestive heart failure, had permanent
      ventricular pacemaker insertion with lead placement at the right ventricular (RV)
      apex. The following hemodynamic recordings were obtained before ablation (during
      atrial fibrillation) and then immediately after ablation (during RV pacing):
      heart rate, mean arterial pressure, LV end-diastolic pressure (LVEDP), mean
      pulmonary capillary wedge pressure, V-wave amplitude, and cardiac index. Presence
      of MR was assessed by V-wave amplitude and the results of LV angiography. In
      patients who had MR, recordings were also obtained during temporary ventricular
      pacing from the RV outflow tract (RVOT). As a group there were no significant
      changes in any hemodynamic measurement. Before ablation, mild MR by LV angiogram
      was present in 5 patients, but none had large V-wave amplitude. After ablation,
      mild MR was present by LV angiogram in 6 patients, and in 3 of these patients
      large V-wave amplitude developed (mean amplitude 42.7 +/- 2.2 mm Hg; assigned to
      group 1). This was associated with a rise in LVEDP in 1 patient (consistent with
      reduced LV compliance), but LVEDP was unchanged in the other 2 patients
      (suggesting abnormal mitral valve leaflet apposition). All patients in group 1
      exhibited a fall in V-wave amplitude when the pacing site was moved to the RVOT.
      CONCLUSIONS: Both reduced LV compliance and disturbed mitral valve leaflet
      apposition contribute to MR after ablation. MR is reduced by pacing from the
      RVOT.

PMID- 10577450
TI  - Transcatheter closure of patent ductus arteriosus with the use of Rashkind
      occluders and/or Gianturco coils: long-term follow-up in 123 patients and special
      reference to comparison, residual shunts, complications, and technique.
AB  - BACKGROUND: This report describes the long-term follow-up of transcatheter
      closure of patent ductus arteriosus (PDA) with 2 different modalities in 123
      patients of diverse ages. METHODS AND RESULTS: Between October 1990 and August
      1997, 123 patients underwent transcatheter PDA (1.9 to 7.5 mm) closure at a mean
      age of 6.8 +/- 8.9 years (range 0.06 to 52) and mean weight of 20.9 +/- 17. 6 kg
      (range 2.7 to 83). In the initial procedure, the Rashkind device was used in 60,
      the Gianturco coil(s) in 60, and the Rashkind device with a coil in 3 patients.
      Six-month closure rate for the Rashkind group was 77% versus 90% for the coil
      group. The second procedure was carried out for residual shunt in 19 (14 in the
      Rashkind group and 5 in the coil group) and a third procedure in 1 patient from
      the Rashkind group. A balloon wedge catheter was used in 50 of 78 coil procedures
      to prevent coil embolization. One device and 11 coils (8 without balloon aid)
      embolized to the pulmonary arteries. The device and all coils except 2 were
      retrieved successfully. Overall, 122 (99%) patients showed complete PDA closure.
      The mean uneventful follow-up period was 44.11 +/- 23.77 months (range 8.7 to
      90.28). CONCLUSIONS: Transcatheter closure of PDA is feasible in infants as well
      as in patients >50 years of age without significant complications. The coils are
      easy to implant, less expensive, and multiple coils may be used in moderately
      large (>3.5 mm) ducts more effectively than with the Rashkind device. The use of
      a balloon wedge catheter prevents immediate coil embolization. Multiple
      procedures are feasible and safe to achieve complete closure.

PMID- 10577451
TI  - Straddling tricuspid valve as a sign of ventriculoatrial malalignment: A
      morphometric study of 19 postmortem cases.
AB  - BACKGROUND: Straddling tricuspid valve, despite extensive investigation, remains
      an incompletely understood form of complex congenital heart disease. METHODS: A
      morphometric study of 19 postmortem cases of straddling tricuspid valve was
      performed, and the results were compared with 32 normal control heart specimens.
      RESULTS: In straddling tricuspid valve, marked malalignment of the ventricles was
      always found relative to the atria. The angle between the ventricular septum and
      the atrial septum in the short-axis projection averaged 61 degrees +/- 24
      degrees, the normal ventriculoatrial septal angle averaging 5 degrees +/- 2
      degrees (P <. 001). The right ventricular sinus (inflow tract) was significantly
      smaller than the left (P <.01). A ventricular septal defect was present in 79%:
      atrioventricular canal type in 42%, atrioventricular canal type confluent with a
      conoventricular defect in 26%, and a conoventricular defect in 11%. When the
      straddling tricuspid valve adhered to the crest of the muscular ventricular
      septum (n = 4 cases, 21%), the 2 salient findings were (1) an intact ventricular
      septum and (2) double-outlet right atrium. The nonstraddling part of the
      tricuspid valve opened into the small right ventricle. The straddling part of the
      tricuspid valve opened into the larger left ventricle. The mitral valve also
      opened into the left ventricle. Hence hearts with double-outlet right atrium had
      3 atrioventricular valves. Congenital mitral stenosis was present in 26% of this
      series. CONCLUSION: Straddling tricuspid valve was always characterized by marked
      ventriculoatrial malalignment, indicated by an abnormally large ventriculoatrial
      septal angle, best seen in the short-axis projection.

PMID- 10577452
TI  - Confusion in geography.

PMID- 10577454
TI  - People's Republic of China.

PMID- 10577456
TI  - Defining risk in unstable angina.

PMID- 10577458
TI  - Observer-related variability in IVUS measurements after stenting.

PMID- 10577460
TI  - Effectiveness of heparin in preventing thrombin generation and thrombin activity
      in patients undergoing coronary intervention.

PMID- 10577461
TI  - Telemedicine in cardiology.

PMID- 10577463
TI  - Newer antithrombin agents in acute coronary syndromes.
AB  - Thrombin, through its procoagulant and prothrombotic actions, plays a central
      role in the pathogenesis of unstable angina and acute myocardial infarction.
      Antithrombin therapy with unfractionated heparin has several important
      disadvantages, such as a variable anticoagulant effect, sensitivity to platelet
      factor 4, an inability to inhibit clot-bound thrombin, and the potential to cause
      thrombocytopenia. Alternative approaches have focused on novel anticoagulants,
      including direct antithrombins (eg, hirudin) and low-molecular-weight heparins
      (eg, enoxaparin). Direct antithrombins bind tightly to thrombin without requiring
      the cofactor antithrombin. Low-molecular-weight heparins display enriched anti
      factor Xa activity, improved bioavailability, and facilitated administration
      versus unfractionated heparin. Recent trials demonstrate that direct
      antithrombins reduce rates of death and myocardial infarction early in patients
      without ST elevation, but the treatment effect diminishes over time. In contrast,
      treatment with enoxaparin shows superiority versus unfractionated heparin, and
      the treatment effect is durable over time. Whether thrombolysis with adjunctive
      treatment with low-molecular-weight heparins will show efficacy in patients with
      ST-segment elevation is the subject of ongoing trials.

PMID- 10577464
TI  - Newer antiplatelet agents in acute coronary syndromes.
AB  - Aspirin is accepted as standard therapy in the management of acute coronary
      syndromes, but has significant limitations, including intolerance, allergy,
      resistance, peptic ulceration, and intracranial hemorrhage. Recent trials
      involving approximately 18,000 patients with unstable angina have investigated
      the efficacy and safety of glycoprotein IIb/IIIa receptor antagonists, which
      block the final common pathway of platelet aggregation. The Platelet Receptor
      Inhibition in Ischemic Syndrome Management (PRISM) trial compared tirofiban with
      heparin and found a 33% reduction in the composite end point of death, myocardial
      infarction, or refractory ischemia at 48 hours. In the Platelet Receptor
      Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs
      and Symptoms (PRISM-PLUS) trial, patients were randomly assigned to receive
      either heparin, tirofiban, or both. At 7 days, the patients who had received
      heparin and tirofiban had a 34% lower incidence of the composite end point of
      death, myocardial infarction, or refractory ischemia than those treated with
      heparin alone. The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor
      Suppression Using Integrilin Therapy (PURSUIT) trial randomly assigned patients
      to receive either eptifibatide or placebo. At 30 days, the rate of death or
      myocardial infarction was reduced by 9.6% in the eptifibatide group compared with
      the placebo group. In the Platelet IIb/IIIa Antagonism for the Reduction of Acute
      Coronary Syndrome Events in a Global Organization Network (PARAGON) trial,
      patients were randomly assigned to receive either low- or high-dose lamifiban
      with or without heparin, or heparin alone. There were no differences between the
      treatment groups at 30 days, but at 6 months the patients randomly assigned to
      receive low-dose lamifiban had a 23% lower incidence of death or myocardial
      infarction, perhaps because of long-term passivation of the plaque. Overall,
      IIb/IIIa antagonists have been shown to be safe and beneficial in patients with
      unstable angina, particularly during the infusion period. However, there remain a
      number of unanswered questions concerning treatment with these agents, such as
      the appropriate dosing regimens and the safety and efficacy of combining
      intravenous antiplatelet therapy with other agents such as low-molecular-weight
      heparin, thrombolytic agents, and oral agents.

PMID- 10577465
TI  - The emerging role of low-molecular-weight heparin and antiplatelet therapies in
      the cardiac catheterization laboratory.
AB  - The advent of new pharmacotherapies and interventional devices has exponentially
      increased the breadth of coronary procedures in a variety of clinical settings.
      The low-molecular-weight heparins, a new class of antithrombins, offer several
      advantages over unfractionated heparin as anticoagulants. New antiplatelet agents
      have also been developed that block components of the platelet aggregation
      pathway not inhibited by aspirin. The use of these new therapies has the
      potential to significantly improve the outcome of percutaneous coronary
      interventions. One low-molecular-weight heparin, enoxaparin, was shown in the
      ESSENCE trial to be significantly superior to unfractionated heparin in the
      medical management of unstable angina. Evidence from ESSENCE suggests that
      enoxaparin used in conjunction with percutaneous revascularization and stenting
      does not cause increased bleeding. Trials directly comparing the safety and
      efficacy of heparin and enoxaparin as adjunctive therapies in percutaneous
      interventions are in progress. In addition, intramural delivery of enoxaparin to
      achieve a locally high concentration is being investigated for the prevention of
      restenosis after coronary stenting. Aspirin together with ticlopidine, which
      inhibits adenosine diphosphate-induced platelet activation, has been shown to be
      superior to aspirin plus anticoagulation in trials of patients undergoing
      percutaneous revascularization with stenting. Clopidogrel has emerged as a
      possible alternative to ticlopidine. Antiplatelet therapies directed against the
      glycoprotein IIb/IIIa receptor, which plays a critical role in aggregation, have
      been tested in several clinical trials in patients undergoing percutaneous
      intervention. The combination of new antiplatelet and new anticoagulant therapies
      may offer added benefit not seen with the individual agents alone. The safety and
      effectiveness of such new regimens is currently being investigated in a number of
      clinical trials.

PMID- 10577467
TI  - Adsorptive control of water in esterification with immobilized enzymes.
      Continuous operation in a periodic counter-current reactor.
AB  - A periodic counter-current adsorptive-reactor system is developed to carry out
      continuous esterifications in organic solvents with immobilized enzymes. The
      system comprises a number of fixed-beds distributed between a reaction-adsorption
      zone and a regeneration zone and operated in a "merry-go-round" sequence. Water
      formed in the reaction is adsorbed preventing the formation of a free-water phase
      and deactivation of the biocatalyst. The adsorbed water is, in turn, recovered by
      desorption in the regeneration zone. The concept is tested experimentally on a
      laboratory-scale using, as a model, the esterification of isoamyl alcohol and
      propionic acid in hexane catalyzed by an immobilized lipase. Pure isoamyl alcohol
      is used as a regenerant to remove excess water from the biocatalyst. In the
      periodic steady-state, improvements in ester productivity greater than 50% over
      that achievable with a conventional fixed-bed reactor are demonstrated
      experimentally with just two beds in a series arrangement. Use of a water
      selective adsorbent in conjunction with the biocatalyst provides further
      improvements by reducing accumulation of water on the enzyme. A mathematical
      model is also developed to predict the thermodynamic activity of water along the
      reactor and describe the dynamic behavior of the system. The model, based on
      independently developed rate and equilibrium parameters, successfully predicts
      the experimental behavior and provides an effective tool for scale-up and
      optimization.

PMID- 10577466
TI  - Should the emergence of new agents change the management of patients with acute
      coronary syndromes without ST-segment elevation?
AB  - Cardiac catheterization for diagnostic angiography and revascularization, if
      indicated, plays an increasing role in the management of acute coronary syndromes
      in the absence of ST elevation. The disagreement between those who favor a
      conservative approach to intervention and those who favor an aggressive approach
      centers on whether interventions should be routinely performed in all patients.
      New pharmacotherapies have emerged that reduce the incidence of death and
      myocardial infarction in this group of patients. At the same time, the success
      rate of percutaneous revascularizations has been improved by the widespread use
      of stenting, and a reduction in complications has been achieved with new
      pharmacologic agents. As therapies are rapidly evolving, it is difficult to
      extrapolate the results of earlier clinical trials to the most current practices.
      Until evidence is available comparing optimal medical management with the most
      successful interventional techniques, the best approach to intervention is likely
      to remain the subject of discussion.

PMID- 10577468
TI  - A simple structured model for maintenance, biomass formation, and ajmalicine
      production by nondividing Catharanthus roseus cells.
AB  - The stoichiometry of maintenance and carbohydrate storage as well as ajmalicine
      production kinetics of non-dividing Catharanthus roseus cells in the second stage
      of a two-stage batch process were investigated. For the mathematical description
      of these processes, a simple structured model with 5 parameters is proposed. In
      the model the biomass is divided in two compartments: active biomass and storage
      carbohydrates. In induction medium (standard medium without phosphate, nitrogen
      and hormones), biomass formation, glucose consumption, and CO(2) production
      appeared to be constant in time. Therefore, it is assumed that the active biomass
      level is constant. The maintenance coefficient m(S), and the yield of storage
      carbohydrates on glucose Y(SC) were optimized by fitting the model on
      experimental data: 0.003 C-mol/C-mol/h and 0.82 C-mol/C-mol, respectively.
      Production kinetics were incorporated in this model and related to the active
      biomass fraction. The maximum specific ajmalicine production rate q(p)(max) was
      fitted on the data: 7.5 micromol/C-mol/h. The model was tested at several
      different experimental conditions, and proved to describe the experimental
      results adequately. An independent experiment at a very high cell density in
      order to obtain maximum product formation was used to validate the model. It
      provided a satisfactory description of the results, but the final ajmalicine
      concentration (198 micromol/L after 18 days) was lower than the calculated
      maximum, due to accumulation of inhibiting gaseous metabolites.

PMID- 10577470
TI  - Genetically structured modeling of protein production in filamentous fungi.
AB  - A general framework for a genetically structured model is presented. The
      framework allows description of the interactions in a system of regulatory and
      structural genes. The model assumes equilibrium kinetics for the binding of
      regulatory proteins to the promoter regions of the genes and includes the
      possible activation of proteins following their synthesis. The model is evaluated
      by simulating the alcA-expression (alcohol dehydrogenase I) in Aspergillus
      nidulans which is an inducible system subject to glucose repression. The
      intracellular enzyme levels in strains with different regulatory mutations are
      simulated during various growth conditions. The model gives a good description of
      the experimental data with changes in only a few parameter values which have a
      mechanistic interpretation.

PMID- 10577469
TI  - Preliminary study of real-time fiber optic based protein C biosensor.
AB  - Deficiency of protein C (PC), one of the human body's key anticoagulants, can
      lead to massive thrombotic complications. There is a diagnostic need to perform
      real-time assays, in order to quickly identify and treat this disease. An immuno
      optical biosensor for the diagnosing of PC deficiencies and monitoring of PC
      concentrations is being developed for this purpose. Monoclonal antibody against
      PC (anti-PC) is immobilized on the surface of a tapered quartz fiber that is
      enclosed in a glass tube (capacity approximately 200 microL). Following sample
      injection, PC within a sample binds to the anti-PC in a highly specific reaction.
      The system is then probed with a fluorophore-tagged secondary antibody against
      PC. Excitation light is applied through the fiber, and the fluorescence intensity
      is correlated with the PC concentration in the sample. This study presents (1) a
      feasibility, direct binding assay, (2) a comparison of methods to immobilize anti
      PC upon the fiber (direct immobilization vs an avidin-biotin bridge), and (3)
      effectiveness of an elution step to regenerate the fiber. PC-deficient patients
      typically have a concentration range less than 2.5 microg/mL. It was found that
      the sensor could detect PC levels down to 0.1 microg/mL in pure buffer with
      minimal optimization. Avidin-biotin immobilization of the primary antibody
      produced enhanced signals, up to 470% of the original intensities. Preliminary
      fiber regeneration tests achieved nearly a 50% increase in fiber lifetime with
      the use of a CaCl(2) elution step. Ultimately, further development may lead to
      automation and the use of the system as a multi-blood factor analyzer.

PMID- 10577471
TI  - Control of pH in large-scale, free suspension animal cell bioreactors: alkali
      addition and pH excursions.
AB  - It is likely that, in the future, animal cell cultures of a higher cell density
      and/or cell lines with higher specific oxygen demands will be available. Such
      developments will lead to the need for improved homogeneity in the bioreactor and
      a greater supply of nutrients. The accompanying significant increase in CO(2)
      production and accumulation and the resulting reduction in pH are also important
      implications for process engineering. Such pH reduction is typically controlled
      by the addition of sodium carbonate. Previous studies using flow visualization
      mimicking the operating conditions in a typical plant-scale reactor showed
      potentially cell-damaging regions within it due to pH excursions. This paper
      confirms the existence of these excursions by pH measurements in the alkali
      addition zone. It also identifies the accumulation of alkali in a region of poor
      local liquid homogenization as a serious scale-up problem and shows how a change
      in the addition point significantly reduces it.

PMID- 10577472
TI  - Prolonging cell-free protein synthesis with a novel ATP regeneration system.
AB  - A new approach for the regeneration of adenosine triphosphate (ATP) during cell
      free protein synthesis was developed to prolong the synthesis and also to avoid
      the accumulation of inorganic phosphate. This approach was demonstrated in a
      batch system derived from Escherichia coli. Contrary to the conventional methods
      in which exogenous energy sources contain high-energy phosphate bonds, the new
      system was designed to generate continuously the required high-energy phosphate
      bonds within the reaction mixture, thereby recycling the phosphate released
      during protein synthesis. If allowed to accumulate, phosphate inhibits protein
      synthesis, most likely by reducing the concentration of free magnesium ion.
      Pediococcus sp. pyruvate oxidase, when introduced in the reaction mixture along
      with thiamine pyrophosphate (TPP) and flavin adenine dinucleotide (FAD),
      catalyzed the generation of acetyl phosphate from pyruvate and inorganic
      phosphate. Acetyl kinase, already present with sufficient activity in Escherichia
      coli S30 extract, then catalyzed the regeneration of ATP. Oxygen is required for
      the generation of acetyl phosphate and the H(2)O(2) produced as a byproduct is
      sufficiently degraded by endogenous catalase activity. Through the continuous
      supply of chemical energy, and also through the prevention of inorganic phosphate
      accumulation, the duration of protein synthesis is extended up to 2 h. Protein
      accumulation levels also increase. The synthesis of human lymphotoxin receives
      greater benefit than than that of chloramphenicol acetyl transferase, because the
      former is more sensitive to phosphate inhibition. Finally, through repeated
      addition of pyruvate and amino acids during the reaction period, protein
      synthesis continued for 6 h in the new system, resulting in a final yield of 0.7
      mg/mL.

PMID- 10577473
TI  - Analysis and use of endogenous nuclease activities in Escherichia coli lysates
      during the primary isolation of plasmids for gene therapy.
AB  - Two important issues in the downstream processing of plasmids for gene therapy
      are the stability of plasmids in the process streams, and the presence of
      contaminating host RNA. Results with a 4.8-kb plasmid harbored in a non-nuclease
      deficient strain of Escherichia coli show that, in spite of the harsh conditions
      during alkaline lysis, a fraction of endogenous nucleases remains active,
      degrading both RNA and genomic and plasmid DNA. Although it is possible to
      minimize plasmid degradation by decreasing temperature and reducing processing
      times, the presence of endogenous nucleases can be used advantageously to purify
      the plasmid streams. The kinetics of nucleic acid degradation showed that, by
      controlling the incubation at 37 degrees C, it was possible to degrade RNA
      selectively, while maintaining plasmid integrity. A reduction of 40% in RNA
      content was obtained, corresponding to a 1.5-fold increase in plasmid purity
      using high-performance liquid chromatography (HPLC). This strategy is simple and
      straightforward, and the increase in processing time and the associated plasmid
      loss (9%) are fully justified by the purity increase. Furthermore, the use of
      endogenous RNase activity is clearly advantageous over alternative procedures,
      such as the addition of external RNase, in terms of cost, validation, and
      compliance with guidelines from regulatory agencies.

PMID- 10577474
TI  - Rapid quantitation and monitoring of plasmid DNA using an ultrasensitive DNA
      binding dye.
AB  - A sensitive fluorescence-based method for monitoring plasmid DNA during
      production was investigated. This simple method of assaying for plasmid DNA
      allows rapid monitoring of plasmid yields from a recombinant Escherichia coli fed
      batch fermentation. The assay has several advantages over traditional methods of
      plasmid DNA measurement. The fluorescent dye is highly specific and can measure
      total plasmid DNA concentration in about 5 min. The assay is sensitive over a
      wide range of plasmid concentrations of between 15 and 280 ng/mL, even in the
      presence of impurities that occur within alkaline lysate preparations. The
      technique can also be applied to monitoring fermentation and downstream
      purification steps.

PMID- 10577483
TI  - Phage DNA transport across membranes.
AB  - Phage nucleic acid transport is atypical in bacterial membrane transport: it is
      unidirectional and concerns a unique molecule the size of which may represent 50
      times that of the bacterium. The rate of DNA transport, although it varies from
      one phage to another, can reach values as high as 3000 bp s(-1). This raises the
      following questions which will be discussed in this review. Is there a single
      mechanism of transport for all types of phages? Does the phage genome cross the
      outer and inner membranes by a unique mechanism? Is it transported as a free
      molecule or in association with proteins? How does it avoid periplasmic
      nucleases? Is such transport dependent on phage and/or host cell components? What
      is the driving force for transport? Recent cryoelectron microscopy experiments
      will be presented which show that it is possible to encapsulate a phage genome
      (121000 bp) into unilamellar liposomes. The interest of such a model system in
      gene delivery and in the study of the mechanisms of DNA compaction will be
      discussed.

PMID- 10577484
TI  - Membrane topology of CadA homologous P-type ATPase of Helicobacter pylori as
      determined by expression of phoA fusions in Escherichia coli and the positive
      inside rule.
AB  - The only experimental data available on the membrane topology of transition metal
      ATPases are from in vitro studies on two distinct P-type ATPases (CadA and CopA)
      of a gastric bacterium, Helicobacter pylori, both postulated to contain eight
      transmembrane domains (H1 to H8). In this study, H. pylori CadA ATPase was
      subjected to analysis of membrane topology in vivo by expression of ATPase
      alkaline phosphatase (AP) hybrid proteins in Escherichia coli using a novel
      vector, pBADphoA. This vector contains an inducible arabinose promoter and unique
      restriction sites for fusion of DNA fragments to phoA. The phoA gene lacking
      sequences encoding its N-terminal signal peptide was linked to the C-terminal
      regions of the postulated five cytoplasmic and four periplasmic segments of the
      H. pylori pump. The results obtained by heterologous expression of ATPase-AP
      hybrid proteins showed consistence with a model of eight transmembrane domains.
      They also demonstrated that the H. pylori ATPase sequences are well assembled in
      the cytoplasmic membrane of E. coli, a neutralophilic bacterium. Cloning and
      amino acid sequence analysis of the homologous ATPase of Helicobacter felis
      further verified the topological model for the H. pylori pump analyzed here,
      although the degree of amino acid sequence identity varied between the
      corresponding transmembrane segments, from 25% for H1 up to 100% for H6. It was
      found that the topology of ATPase follows the 'positive inside rule'. With
      respect to the bioenergetic capacities of H. pylori, we discuss here the membrane
      potential as a possible factor directing insertion of ATPases in the cytoplasmic
      membrane of gastric bacteria.

PMID- 10577485
TI  - Trehalose hydrolysis is not required for human serum-induced dimorphic transition
      in Candida albicans: evidence from a tps1/tps1 mutant deficient in trehalose
      synthesis.
AB  - Exponential yeast-like cells of a Candida albicans wild-type strain exhibited
      strong capacity for germ tube formation in a glucose-containing medium (YPD)
      after induction with human serum at 37 degrees C, whereas the isogenic double
      disruptant tps1/tps1 mutant, which is deficient in trehalose synthesis, failed to
      produce germ tubes. In a medium without glucose (YP), the morphological
      transition fraction was roughly equivalent in both strains. Substitution of
      glucose by galactose or glycerol increased the number of wild-type proliferating
      cells able to enter the dimorphic program with no noticeable change in their
      trehalose content, while stationary cells, which accumulate a large amount of
      trehalose, did not form germ tubes. When fresh medium was added, a high
      proportion of these resting cells recovered their ability to carry out dimorphic
      transition. The tps1/tps1 mutant followed the same pattern of hyphae formation,
      despite the fact that it was unable to accumulate trehalose either during
      dimorphism induction or after several stress challenges. Furthermore, trehalose-6
      phosphate synthase activity was barely detectable in the mutant. These results
      strongly suggest that serum-induced dimorphic transition does not require
      trehalose mobilization; they also support the idea that TPS1 is the only activity
      involved in trehalose biosynthesis in C. albicans.

PMID- 10577486
TI  - Distribution of Staphylococcus sciuri subspecies among human clinical specimens,
      and profile of antibiotic resistance.
AB  - The distribution of three subspecies comprising Staphylococcus sciuri was
      determined for a collection of 30 clinical isolates originating from Morocco, the
      United Kingdom, and France. The sources of these isolates were principally
      wounds, skin, and soft tissue infections. At the species level, the isolates were
      identified according to biochemical characteristics and at the subspecies level
      by the ribotyping technique. PCR analysis performed with the 16S-23S ribosomal
      DNA intergenic spacer was less powerful for subspecies differentiation. S. sciuri
      subsp. sciuri was the most frequent subspecies (21 isolates) found in the
      collection, whereas S. sciuri subsp. rodentium (seven isolates) and S. sciuri
      subsp. carnaticus (two isolates) were less common. mecA or a mecA-related gene
      was detected by PCR and Southern blot in all 30 S. sciuri isolates, supporting
      the suggestion that S. sciuri species are the natural reservoir of the mecA gene.
      While the linA/linA' gene coding for lincomycin resistance was present in five
      isolates, an uncharacterized gene for this resistance was suspected in seventeen
      other isolates.

PMID- 10577487
TI  - Identification of Shigella serotypes by restriction of amplified O-antigen gene
      cluster.
AB  - Due to the scarcity of distinctive biochemical reactions for differentiation of
      Shigella-Escherichia coli, antigenic analysis has long been used for
      identification and typing of Shigella isolates. Nevertheless, several intra- and
      interspecific cross-reactions have been reported to disturb serotyping assays.
      Shigella serotyping is also occasionally affected by the transition from the
      smooth (S) form to the rough (R) form. Thus, there is a need for the development
      of novel robust and discriminating methods for Shigella identification and
      typing. Characteristically, all genes specifically involved in O-antigen
      synthesis are clustered in E. coli, Shigella, and Salmonella. Published
      oligonucleotide sequences complementary to JUMPstart and gene gnd, the conserved
      flanking sequences upstream and downstream of O-antigen gene clusters, were used
      to amplify the O-antigen gene cluster of representative strains of each Shigella
      serotype. A unique, amplified fragment was generally observed for each serotype
      (size ranging from 6 kbp to 17 kbp). Clearly identifiable and reproducible
      patterns were obtained for each serotype after MboII digestion of the products,
      except for S. boydii 12 which showed two distinct patterns, and S. flexneri
      serotypes 1 to 5 and X and Y which showed a single pattern. A database was built
      with the Taxotron package allowing automated identification of clinical Shigella
      isolates to all known serotypes.

PMID- 10577488
TI  - Energy conservation in aerobically grown Staphylococcus aureus.
AB  - The present studies provide new data on the involvement of menaquinol oxidases in
      substrate oxidation and energy conservation in aerobically grown, resting cells
      of Staphylococcus aureus 17810R, starved of endogenous energy reserves and
      supplemented with glutamate or L-lactate. These cells were energetically
      competent, since they oxidized both substrates, generated an electrochemical
      proton gradient (deltamuH+) and synthesized ATP via oxidative phosphorylation.
      Studies with KCN showed that: (i) L-lactate oxidation occurred via two terminal
      menaquinol oxidases - the ba3-type sensitive to low KCN and the bo-type
      insensitive to cyanide, (ii) glutamate oxidation proceeded via the bo-type
      oxidase, and (iii) ATP synthesis with glutamate or L-lactate was coupled only to
      the bo-type oxidase. Also in glucose-grown cells oxidizing L-lactate, ATP
      synthesis was coupled to the highly repressed bo-type oxidase. It is suggested
      that in the respiratory chain of strain 17810R two energy coupling sites may be
      present: in the complex of NADH-menaquinone oxidoreductase and in the complex of
      the bo-type menaquinol oxidase. The rate of ATP synthesis was similar with both
      substrates, but the rate of their oxidation differed significantly: the P/O
      ratios were 1.5 and 0.03 with glutamate and L-lactate, respectively. CCCP
      accelerated glutamate oxidation by 50% but was without effect on L-lactate
      oxidation. In cell lysates, the rates of NADH and L-lactate oxidation were equal.
      It is concluded that in whole cells of S. aureus 17810R oxidation of NADH derived
      from glutamate breakdown is tightly coupled to phosphorylation, while L-lactate
      oxidation seems to be rather loosely coupled.

PMID- 10577489
TI  - Reptile-associated salmonellosis--selected states, 1996-1998.
AB  - During 1996-1998, CDC received reports from approximately 16 state health
      departments of Salmonella infections in persons who had direct or indirect
      contact with reptiles (i.e., lizards, snakes, or turtles). Salmonella infection
      can result in invasive illness including sepsis and meningitis, particularly in
      infants. Despite educational efforts, some reptile owners remain unaware that
      reptiles place them and their children at risk for salmonellosis. This report
      summarizes clinical and epidemiologic information in four cases and provides
      information about state regulations to prevent transmission of Salmonella spp.
      from reptiles to humans.

PMID- 10577490
TI  - Assessment of laboratory tests for plasma homocysteine--selected laboratories,
      July-September 1998.
AB  - Cardiovascular disease, including coronary heart disease and stroke, is the
      leading cause of death in the United States. Elevated plasma homocysteine (Hcy),
      generally defined as fasting plasma Hcy levels >15 micromol/L, is an independent
      risk factor for vascular diseases (1,2). It is unknown whether Hcy is a cause of
      or a marker for atherosclerosis. A recent statement by the Nutrition Committee of
      the American Heart Association concluded that until results of clinical trials
      are available, population-wide Hcy screening is not recommended (3). However, Hcy
      tests are used in the clinical setting and information on interlaboratory
      variation, on method variation, is limited. To assess the status of
      interlaboratory and intralaboratory variation for Hcy analysis, CDC conducted a
      study of selected laboratories during July-September 1998. This report summarizes
      findings from the study, which indicates a need to improve analytic precision and
      to decrease analytic differences among laboratories (4).

PMID- 10577491
TI  - Surveillance for acute pesticide-related illness during the Medfly eradication
      program--Florida, 1998.
AB  - The Mediterranean fruit fly (Medfly) (Ceratitis capitata, Wiedemann) is an exotic
      insect that can damage approximately 250 fruit and vegetable plant species and is
      a serious threat to domestic agriculture. During the spring and summer of 1998,
      pesticides were used by federal and state agriculture authorities to eradicate
      Medfly infestations that had been detected in portions of five Florida counties
      (Table 1). This report summarizes surveillance data, describes probable and
      possible cases of illness associated with the eradication effort, and provides
      recommendations for future Medfly-eradication programs.

PMID- 10577492
TI  - Tobacco use--United States, 1900-1999.
AB  - Smoking--once a socially accepted behavior--is the leading preventable cause of
      death and disability in the United States. During the first decades of the 20th
      century, lung cancer was rare; however, as cigarette smoking became increasingly
      popular, first among men and later among women, the incidence of lung cancer
      became epidemic (Figure 1). In 1930, the lung cancer death rate for men was 4.9
      per 100,000; in 1990, the rate had increased to 75.6 per 100,000 (1). Other
      diseases and conditions now known to be caused by tobacco use include heart
      disease, atherosclerotic peripheral vascular disease, laryngeal cancer, oral
      cancer, esophageal cancer, chronic obstructive pulmonary disease, intrauterine
      growth retardation, and low birthweight. During the latter part of the 20th
      century, the adverse health effects from exposure to environmental tobacco smoke
      also were documented. These include lung cancer, asthma, respiratory infections,
      and decreased pulmonary function (2).

PMID- 10577493
TI  - Cigarette smoking among adults--United States, 1997.
AB  - In the United States, cigarette smoking is the leading cause of preventable
      morbidity and mortality and results in approximately 430,000 deaths each year
      (1). One of the national health objectives for 2000 is to reduce the prevalence
      of cigarette smoking among adults to no more than 15% (objective 3.4) (2). To
      assess progress toward meeting this objective, CDC analyzed self-reported data
      about cigarette smoking among U.S. adults from the 1997 National Health Interview
      Survey (NHIS) Sample Adult Core Questionnaire. This report summarizes the
      findings of this analysis, which indicate that, in 1997, 24.7% of adults were
      current smokers and that the overall prevalence of current smoking in 1997 was
      unchanged from the overall prevalence of current smoking from the 1995 NHIS.

PMID- 10577494
TI  - Recommendations regarding the use of vaccines that contain thimerosal as a
      preservative.
AB  - On October 20, 1999, the Advisory Committee on Immunization Practices (ACIP)
      reviewed information about thimerosal in vaccines and received updates from CDC's
      National Immunization Program and several vaccine manufacturers on the current
      and anticipated availability of vaccines that do not contain thimerosal as a
      preservative. The review was prompted by a joint statement about thimerosal
      issued July 8, 1999, by the American Academy of Pediatrics (AAP) and the Public
      Health Service (PHS) (1) and a comparable statement released by the American
      Academy of Family Physicians (2). These statements followed a Congressionally
      mandated Food and Drug Administration (FDA) review of mercury in drugs and food,
      which included a reassessment of the use of thimerosal in vaccines.

PMID- 10577495
TI  - Withdrawal of rotavirus vaccine recommendation.
AB  - In July 1999, CDC recommended that health-care providers and parents postpone use
      of the rhesus rotavirus vaccine-tetravalent (RRV-TV) (RotaShield, Wyeth
      Laboratories, Inc., Marietta, Pennsylvania), for infants, at least until November
      1999. This action was based on reports to the Vaccine Adverse Event Reporting
      System of intussusception (a type of bowel obstruction that occurs when the bowel
      folds in on itself) among 15 infants who received rotavirus vaccine. Also at that
      time, the manufacturer, in consultation with the Food and Drug Administration,
      voluntarily ceased further distribution of the vaccine.

PMID- 10577496
TI  - Migration of leukocytes across endothelium and beyond: molecules involved in the
      transmigration and fate of monocytes.
AB  - Passage of leukocytes across the endothelial lining into sites of inflammation
      has been shown to be regulated largely by platelet/endothelial cell adhesion
      molecule-1 (PECAM/CD31). We summarize recent work from our laboratory documenting
      that PECAM is involved both in diapedesis and the subsequent step of migration
      across the basal lamina. The former process involves a homophilic interaction
      between the amino-terminal extracellular domains of PECAM on the leukocyte and on
      the endothelial cell. The latter process involves a heterophilic interaction
      between the membrane-proximal extracellular domain of PECAM and an unknown
      ligand(s) in the subendothelial basal lamina. These findings are demonstrated in
      both in vitro and in vivo models. For monocytes, however, transmigration is just
      the first step in the next phase of their lives. In addition to their specific
      recruitment during the inflammatory response, many monocytes constitutively leave
      the bloodstream to enter tissues. However, only a fraction of these become tissue
      macrophages. In an in vitro model of monocyte emigration, approximately half of
      the leukocytes that initially transmigrate an endothelial monolayer migrate back
      out in the basal-to-apical direction within the next 2 days. This reverse
      transmigration cannot be blocked by anti-PECAM reagents, but involves p
      glycoprotein and tissue factor expressed on the leukocytes. The reverse
      transmigrating cells are phenotypically dendritic cells (DC). Their maturation to
      mature DC can be accelerated by inclusion of inflammatory stimuli in the co
      culture. The cells that remain behind in the subendothelial collagen are
      phenotypically macrophages. We postulate that a major source of DC in lymph nodes
      is cells derived from monocytes that enter a tissue via the blood and leave
      several days later via afferent lymphatic channels.

PMID- 10577497
TI  - Sialic acid binding receptors (siglecs) expressed by macrophages.
AB  - Sialic acids are structurally and topographically well-suited to function as
      ligands in cellular recognition events. Sialoadhesin (Sn) is a sialic acid
      binding receptor uniquely expressed by macrophage subsets. It is a member of the
      immunoglobulin (Ig) superfamily with 17 extracellular domains. Sn is a
      prototypical member of the siglec family of sialic acid binding proteins, which
      includes CD22, myelin-associated glycoprotein, CD33, and siglec-5. These membrane
      proteins are involved in discrete functions in the hemopoietic, immune, and
      nervous systems. The sialic acid binding region of siglecs is localized within
      the membrane-distal, amino-terminal domain and in the case of Sn, it has been
      characterized in atomic detail by X-ray crystallography, nuclear magnetic
      resonance, and site-directed mutagenesis. Our studies on Sn indicate that this
      receptor is likely to function as a macrophage accessory molecule in a variety of
      cell-cell and cell-extracellular matrix interactions. CD33 and siglec-5 are also
      expressed on macrophage subsets as well as other myeloid cells. However, unlike
      Sn, the properties of these molecules indicate a predominant role in signaling
      functions rather than in cell-cell interactions.

PMID- 10577498
TI  - Modular components of phagocytosis.
AB  - Phagocytosis is an evolutionarily ancient host cell endocytic response to
      particulate stimuli. Phagocytic leukocytes utilize highly conserved programs of
      signaling and motility to engulf foreign pathogens. Particle ingestion requires
      actin assembly and pseudopod extension, two cellular events that coincide
      spatially and temporally. This review presents evidence that phagocytosis
      proceeds in discrete but coordinated stages. In the case of receptors for the Fc
      portion of IgG (FcgammaRs), engagement of the IgG ligands results in receptor
      aggregation and recruitment of cytosolic tyrosine kinases, most notably Syk.
      Phosphorylation of tyrosine residues occurs within immunoreceptor tyrosine
      activation motif (ITAM) consensus sequences found in FcgammaR subunits, which
      leads to further recruitment and activation of Syk via its SH2 domains. Syk
      tyrosine kinase activity is required for FcgammaR-mediated actin assembly, which
      is controlled by several GTPases, including Rac1 and Cdc42. Phagocytosis and Rac
      mediated cytoskeletal alterations also require the participation of another low
      molecular GTPase, ARF6. Simultaneously, phosphatidylinositol 3-kinase is
      recruited to the plasma membrane, which triggers exocytosis from an intracellular
      membrane source that is required for pseudopod extension. The source of this
      membrane is as yet unknown. This review focuses on individual components of
      phagocytosis and emphasizes that the signaling requirements for each of these is
      distinct.

PMID- 10577499
TI  - Inhibitory and activating receptors involved in immune surveillance by human NK
      and myeloid cells.
AB  - We review the structure, cellular distribution, ligand specificity, and function
      of two emerging types of receptors involved in natural killer (NK) and myeloid
      cell recognition of other cells: ILT/LIR/MIR and 2B4 receptors. ILT/LIR/MIR
      receptors are differentially expressed on lymphoid and myeloid cells and two of
      them, ILT2 and ILT4, recognize HLA class I molecules. Whereas some receptors
      inhibit, others induce cell activation. 2B4 is broadly expressed on leukocytes,
      binds CD48, and mediates non-MHC-restricted cytotoxicity by NK cells.

PMID- 10577500
TI  - ATP receptors and giant cell formation.
AB  - We have investigated the role of the purinergic P2X7 receptor in the formation of
      multinucleated giant cells in human monocyte/macrophage cultures stimulated with
      either concanavalin A or phytohemagglutinin. Macrophage fusion can be blocked by
      a P2X7-selective pharmacological antagonist or by a mAb directed against the
      extracellular P2X7 domain. Furthermore, macrophage cell clones expressing high
      P2X7 levels spontaneously fuse in culture, whereas macrophage clones lacking P2X7
      are unable to fuse. Our findings suggest that the newly identified purinergic
      P2X7 receptor plays a central role in the complex chain of events leading to
      generation of macrophage-derived giant cells.

PMID- 10577501
TI  - The transcription factor PU.1 does not regulate lineage commitment but has
      lineage-specific effects.
AB  - PU.1 is a transcription factor shown to regulate the expression of many important
      genes in myeloid and B cells. At birth, mice homozygous for the disruption of the
      PU.1 gene have erythrocytes, megakaryocytes, and T cells, but no mature myeloid
      or B cells. Cells with an inability to develop to maturity were found in this
      mouse for B cells, neutrophils, eosinophils, mast cells, and monocytes. Rescue of
      early monocytic cells by transfection with the PU.1 gene results in renewed
      development to macrophages. These results demonstrate that PU.1 is an important
      regulator in the development of cells in the hematopoietic system.

PMID- 10577502
TI  - The peroxisome proliferator-activated receptor(PPARgamma) as a regulator of
      monocyte/macrophage function.
AB  - Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent
      transcription factors of the nuclear hormone receptor super-family, which
      includes the steroid, retinoid, and thyroid hormone receptors. The PPARs can be
      activated by fatty acids and their eicosanoid metabolites, and have until
      recently been considered primarily to regulate genes involved in glucose and
      lipid homeostasis. In the past year there has been an explosive increase in
      research implicating PPARgamma in macrophage biology, cell cycle regulation, and
      atherosclerosis. This review describes recent insights into the role of PPARgamma
      in the macrophage lineage, and its potential function in the regulation of
      inflammatory responses and atherosclerosis.

PMID- 10577504
TI  - Lung surfactant proteins (SP-A and SP-D) in non-adaptive host responses to
      infection.
AB  - The lung surfactant proteins A and D (SP-A and SP-D) are collectins composed of C
      type lectin domains attached to collagen regions. SP-A and SP-D are mainly found
      in the surfactant covering the pulmonary epithelial cells, but are also produced
      by cells lining the gastrointestinal tract. The main role of SP-A and SP-D is to
      interact directly with carbohydrate on the surface of microbial pathogens,
      thereby initiating a variety of effector mechanisms. This review focuses on the
      non-adaptive host responses of SP-A and SP-D to infection. Interaction of SP-A
      and SP-D with phagocytes is discussed and the structure and function of the
      putative receptors for SP-A and SP-D is presented. SP-A and SP-D seem to be
      regulated in a way similar to acute-phase proteins in the course of inflammation
      and evidence for the involvement of SP-A and SP-D as immunomodulators as well as
      their role in clearing allergens and modulating effector mechanisms in allergic
      reactions is discussed.

PMID- 10577503
TI  - Macrophage scavenger receptors and foam cell formation.
AB  - Scavenger receptors bind and internalize modified low-density lipoprotein (LDL)
      and high-density lipoprotein (HDL). Because the expression of scavenger receptors
      is not down-regulated by cholesterol, macrophages (Mphi) expressing scavenger
      receptors can internalize substantial quantities of cholesteryl ester from
      oxidized LDL and HDL, leading to foam cell formation. Mphi express several
      different classes of the growing scavenger receptor family on their cell surface
      and their relative contribution to Mphi cholesterol physiology and atherogenesis
      is the subject of intense investigation. We focus on the potential role of two
      scavenger receptors, macrosialin and SR-BI/II in Mphi cholesterol metabolism.
      Macrosialin is a predominantly Mphi-specific oxidized LDL-binding protein and an
      atherogenic diet markedly up-regulates its hepatic expression in atherosclerosis
      susceptible and atherosclerosis-resistant mouse strains. The HDL receptor, SR-BI
      and its splicing variant SR-BII, colocalize with caveolin in caveolae in Mphi.
      Caveolae are initial acceptor sites for cholesteryl esters and these findings
      indicate a possible role for caveolae and SR-BI in Mphi-selective lipid uptake
      and in regulating Mphi cholesterol flux in the vascular wall.

PMID- 10577505
TI  - Intracellular niches for extracellular bacteria: lessons from Helicobacter
      pylori.
AB  - Helicobacter pylori colonizes the gastric epithelium of humans and plays a
      causative role in peptic ulcer disease and perhaps gastric cancer. H. pylori
      proliferates in the mucus layer over the epithelium and is not cleared by the
      host immune response. Although the mucus layer is the major reservoir of H.
      pylori in vivo, a growing body of evidence suggests that H. pylori can persist in
      multiple intracellular locales. Clinical isolates of H. pylori invade epithelial
      monolayers at least as well as Shigella. The intracellular organisms are
      cytotoxic, and bacterial microcolonies form on the exposed basement membrane.
      Both mononuclear phagocytes and neutrophils phagocytose unopsonized H. pylori.
      However, the internalized organisms are not killed efficiently and our recent
      data suggest that H. pylori disrupts phagosome maturation. Collectively, the data
      support the hypothesis that intracellular H. pylori represent a reservoir of
      organisms that contributes to bacterial persistence, host tissue damage, and
      treatment failure.

PMID- 10577506
TI  - Nramp1: a link between intracellular iron transport and innate resistance to
      intracellular pathogens.
AB  - Nramp1 (natural resistance-associated macrophage protein one) regulates
      intracellular pathogen proliferation and macrophage inflammatory responses.
      Murine Nramp1 exhibits a natural polymorphism with alleles termed resistant and
      susceptible. Alleles restrict or allow the proliferation of intracellular
      pathogens, respectively. Structural predictions suggest that Nramp1 encodes the
      prototypic member of a transporter family. Nramp1 exhibits sequence identity to
      Nramp2, which regulates intestinal and reticulocyte iron uptake. Based on this
      sequence identity we have initiated experiments for Nramp1 to investigate its
      role in macrophage iron homoeostasis and using a transfection approach in the
      RAW264.7 murine macrophage-like cell line, which lacks a functional Nramp1 gene.
      Nramp1 expression supports increased acute cytoplasmic influx of iron, detected
      using the fluorescent iron sensor dye calcein. Analysis of the endogenous iron
      sensors, iron regulatory protein 1 and 2, reveals a greater flux of iron in
      Nramp1-expressing cells and in its exclusion from the cytoplasm. Other work
      supports the prediction that Nramp1 is a phosphoprotein and the extent of
      phosphorylation changes in response to inflammatory cytokines. Together these
      data support the hypothesis that control of intracellular iron homoeostasis is a
      vital element used by phagocytes to control the proliferation of intracellular
      pathogens.

PMID- 10577507
TI  - Macrophage apoptosis in mycobacterial infections.
AB  - Mycobacterial diseases are a major public health concern. In the case of
      tuberculosis, the problem has been acerbated due to the emergence of drug
      resistant strains of Mycobacterium tuberculosis, and Mycobacterium avium is the
      major opportunistic pathogen in HIV-1 infection in the United States. M.
      tuberculosis and M. avium replicate in human macrophages and induce apoptosis.
      Incubation of freshly added uninfected autologous macrophages with apoptotic M.
      avium-infected macrophages results in 90% inhibition of bacterial growth.
      Apoptosis also prevents the release of intracellular components and the spread of
      mycobacterial infection by sequestering the pathogens within apoptotic bodies.
      Consistent with the model that host cell apoptosis is a defense mechanism against
      mycobacteria is the finding that the virulent M. tuberculosis strain H37Rv
      induces substantially less macrophage apoptosis than the attenuated strain H37Ra.
      Evasion of apoptosis by this pathogen is achieved by enhanced release of sTNFR2
      by H37Rv-infected macrophages and subsequent formation of inactive TNF-alpha
      TNFR2 complexes. These observations contribute to the hypothesis that apoptosis
      of the host macrophage is an important defense mechanism in mycobacterial
      infections, which prevents the spread of the infection.

PMID- 10577508
TI  - Macrophages: important accessory cells for reproductive function.
AB  - Macrophages are found throughout reproductive tissues. To determine their
      role(s), we have studied mice homozygous for a null mutation (Csfm(op)) in the
      gene encoding the major macrophage growth factor, colony-stimulating factor-1
      (CSF-1). Both male and female Csfm(op)/Csfm(op) mice have fertility defects.
      Males have low sperm number and libido as a consequence of dramatically reduced
      circulating testosterone. Females have extended estrous cycles and poor ovulation
      rates. CSF-1 is the principal growth factor regulating macrophage populations in
      the testis, male accessory glands, ovary, and uterus. However, analyses of CSF-1
      nullizygous mice suggest that the primary reproductive defect is in the
      development of feedback regulation of the hypothalamic-pituitary axis. Although
      not correlating with deficiencies of microglia populations, electrophysiological
      investigations indicate an impairment of neuronal responses. This suggests that
      microglia, under the influence of CSF-1, act to organize neuronal connectivity
      during development and that the absence of this function results in a
      perturbation of the hypothalamic-pituitary-gonadal axis. Macrophages also appear
      to have functions in the differentiated tissues of the reproductive system,
      including having a positive influence on steroidogenic cells. These data suggest
      that macrophages, through their trophic functions, can be considered as essential
      accessory cells for normal reproductive functioning.

PMID- 10577509
TI  - Heat shock response: presence and effects in burn patient neutrophils.
AB  - Heat shock proteins (HSPs) are present in neutrophils (PMNs) from critically ill
      patients. We investigated whether HSPs were present in PMNs from burn patients
      and whether heat shock contributed to the functional defects observed in burn
      PMNs. Using both flow cytometry and Western blot techniques it was observed that
      inducible HSP72 (iHSP72) was present in PMNs and leukocytes from burn patients,
      especially in patients with inhalation injury. Similar to burn PMNs, and in
      contrast to normal cells, heat shocked PMNs (43 degrees C incubation) expressed
      iHSP72 and were unable to increase the expression of CD11b/CD18 in response to
      pro-inflammatory stimuli. Degranulation after pro-inflammatory stimuli was
      decreased for both burn- and heat-shocked PMNs when compared to normal controls.
      In burn PMNs these functional abnormalities were mainly due to decreased
      quantities of proteins (CD11b, albumin, B12 binding protein, beta-glucuronidase)
      present within cytoplasmic granules. However, in heat-shocked PMNs the
      abnormalities were primarily related to abnormal exocytosis. In conclusion, our
      data show that decreased quantities of cytoplasmic granule proteins and, to a
      smaller degree, defective exocytosis are involved in the functional abnormalities
      observed in burn PMNs.

PMID- 10577510
TI  - Respective involvement of TGF-beta and IL-4 in the development of Langerhans
      cells and non-Langerhans dendritic cells from CD34+ progenitors.
AB  - In vivo, dendritic cells (DC) form a network comprising different populations. In
      particular, Langerhans cells (LC) appear as a unique population of cells
      dependent on transforming growth factor beta(TGF-beta) for its development. In
      this study, we show that endogenous TGF-beta is required for the development of
      both LC and non-LC DC from CD34+ hematopoietic progenitor cells (HPC) through
      induction of DC progenitor proliferation and of CD1a+ and CD14+ DC precursor
      differentiation. We further demonstrate that addition of exogenous TGF-beta
      polarized the differentiation of CD34+ HPC toward LC through induction of
      differentiation of CD14+ DC precursors into E-cadherin+, Lag+CD68-, and Factor
      XIIIa-LC, displaying typical Birbeck granules. LC generated from CD34+ HPC in the
      presence of exogenous TGF-beta displayed overlapping functions with CD1a+
      precursor-derived DC. In particular, unlike CD14(+)-derived DC obtained in the
      absence of TGF-beta, they neither secreted interleukin-10 (IL-10) on CD40
      triggering nor stimulated the differentiation of CD40-activated naive B cells.
      Finally, IL-4, when combined with granulocyte-macrophage colony-stimulating
      factor (GM-CSF), induced TGF-beta-independent development of non-LC DC from CD34+
      HPC. Similarly, the development of DC from monocytes with GM-CSF and IL-4 was TGF
      beta independent. Collectively these results show that TGF-beta polarized CD34+
      HPC differentiation toward LC, whereas IL-4 induced non-LC DC development
      independently of TGF-beta.

PMID- 10577511
TI  - Differential effects of B7-1 and B7-2 on the costimulation of mouse nonspecific
      cytotoxic T lymphocyte development in response to anti-CD3 antibody.
AB  - Despite extensive study, the relative contribution of B7-1 and B7-2 molecules to
      the costimulation of cytotoxic T lymphocyte (CTL) activation remains
      controversial. We used blocking mAbs to B7-1 and B7-2 molecules to determine the
      role of these B7 family members in the in vitro induction of mouse nonspecific
      CTL in response to soluble anti-CD3 mAb. Optimal induction of anti-CD3-activated
      killer-T (AK-T) cells was found to require interactions with B7-2 on residual
      accessory cells in nylon wool-nonadherent spleen cell preparations during the
      first 12 h of culture in the presence of anti-CD3 mAb. Because B7-1 is not
      expressed at high enough levels on residual accessory cells in primary T cell
      cultures to be an effective ligand for CD28, we used LPS-stimulated B cells,
      which express substantial B7-1, in addition to B7-2, to determine the
      contribution of B7-1 to AK-T cell development. Compared with B7-2, the
      contribution of B7-1 to the costimulation of AK-T cells in this system was modest
      because anti-B7-1 mAb had only a minimal inhibitory effect on the generation of
      cytotoxicity, whereas anti-B7-2 mAb strongly inhibited AK-T cell development.
      Anti-CD3-induced cytotoxicity of T cells from CD4 knockout mice and CD4-depleted
      nylon wool-nonadherent spleen cells from wild-type mice was inhibited by anti-B7
      2 mAb, implying that B7-2 is able to bind directly to CD28 on CD8+ T cells and
      costimulate their activation. B7-1 blockade, on the other hand, did not affect
      the costimulation of CD8+ T cells. Blockade of B7-2/ CD28 interactions with anti
      B7-2 mAb strongly inhibited granzyme B, but not perforin or Fas ligand gene
      expression, suggesting an explanation for the inhibitory effect of anti-B7-2 mAb
      on AK-T cell development. These data indicate that B7-2 is superior to B7-1 as a
      costimulator of mouse AK-T cell induction.

PMID- 10577512
TI  - A phagocytic challenge with IgG-coated erythrocytes depresses macrophage
      respiratory burst and phagocytic function by different mechanisms.
AB  - A phagocytic challenge with IgG-coated erythrocytes (EIgG) previously has been
      shown to cause impaired macrophage respiratory burst capacity and FcgammaR
      mediated phagocytic function. Because both the respiratory burst and FcgammaR
      mediated phagocytosis are dependent on the release of arachidonate (AA), we
      evaluated the effects of impaired AA release on the depression of macrophage
      function caused by a phagocytic challenge. Challenge with EIgG caused a
      depression of A23187-stimulated AA release that was associated with impaired
      phorbol myristate acetate (PMA)-stimulated H2O2 production and FcgammaR-mediated
      phagocytic function. In contrast, challenge with IgG-coated glass beads (BIgG)
      had no effect on either AA release or H2O2 production but did depress phagocytic
      function. Exogenous AA prevented the depression of H2O2 production but had no
      effect on phagocytic function. Phospholipase A2 (PLA2) activity was depressed
      under conditions where AA release was impaired. The depression of phagocytic
      function was correlated with a depression of both EIgG binding and FcgammaR
      expression. Thus, a phagocytic challenge with EIgG results in macrophage
      dysfunction by depressing PLA2 activity and depleting FcgammaR.

PMID- 10577513
TI  - alpha9beta1 integrin is expressed on human neutrophils and contributes to
      neutrophil migration through human lung and synovial fibroblast barriers.
AB  - Accumulation of leukocytes in inflamed tissue involves their migration through
      vascular endothelium and then in the connective tissue. Recently we utilized a
      barrier of human synovial, dermal, and lung fibroblasts (HSF, HDF, and HLF) grown
      on polycarbonate filters as a model of human polymorphonuclear leukocyte (PMN)
      migration through connective tissue. The beta2 integrins (CD 11/ CD18) and
      alpha4, alpha5, and alpha6beta1 (VLA-4, -5, and -6) integrins each contributed to
      this PMN migration. Here we report that on human blood leukocytes, alpha9beta1
      (VLA-9) is expressed only on PMNs and that it is up-regulated after PMN
      activation. Based on monoclonal antibody (mAb) blocking studies, alpha9beta1
      integrin contributed to C5a-induced PMN migration through fibroblast (HLF and
      HSF) barriers. This role was apparent only when alternate mechanisms such as
      CD18, alpha4, alpha5, and alpha6beta1 integrins were blocked and then mAb to
      alpha9beta1 integrin inhibited the residual PMN migration (by 40-50%) through the
      HLF or HSF barrier, resulting in > or = 75% inhibition overall. In contrast, PMN
      migration across interleukin-1-activated endothelium (HUVEC) in response to a C5a
      gradient, which is partly (30-40%) via CD11/CD18-independent mechanisms, was not
      inhibited by adhesion blocking by mAbs to alpha4, alpha5, alpha6, and alpha9beta1
      even in combination. These results indicate that alpha9beta1 integrin on PMN may
      have a special role, in conjunction with other beta1 integrins, in mediating PMN
      migration in the extravascular space, and may contribute to differential
      neutrophil function within tissues.

PMID- 10577514
TI  - CpG-oligodeoxynucleotide-resistant variant of WEHI 231 cells.
AB  - Bacterial DNA and synthetic single-stranded oligonucleotides having unmethylated
      CpG motifs (CpG-ODN) powerfully stimulate cellular immune responses by an unknown
      mechanism. There is evidence that internalization of the nucleotide is required
      for activity. Both CpG-ODN and engagement of CD40 protects WEHI-231 murine B
      lymphoma cells from apoptosis induced by antibody to surface IgM, and both agents
      induce interleukin-6 (IL-6) production by these cells. We now report the
      isolation of CpG-ODN-resistant subclones (designated CR) from WEHI 231 cells, as
      well as subclones that are sensitive to CpG-ODN (designated CS). CR clones
      completely fail to respond to CpG-ODN but they retain the capacity to respond
      normally to engagement of CD40. CR cells incorporate CpG-ODN into small,
      acidified perinuclear vesicles in the same way as do the parent WEHI 231 cells.
      The CR, CS, and WEHI 231 cells all had identical cytogenetics. The described CR
      clones have a stable and specific defect in the mechanism responsible for the
      intracellular recognition and response to CpG-ODN, suggesting that they harbor a
      mutation that disables the CpG-ODN detection mechanism. These clones may be
      useful to determine at a molecular level which proteins and cell components are
      required for immune cells to detect and respond to CpG-ODN.

PMID- 10577515
TI  - Modulatory effects of human herpes virus-7 on cytokine synthesis and cell
      proliferation in human peripheral blood mononuclear cell cultures.
AB  - Human herpes virus-7 (HHV-7) infects cells of the immune system and thus may
      modulate their function. To investigate the potential immunomodulatory effects of
      this virus, we performed an in vitro study in which we investigated effects of
      HHV-7 on the synthesis of several key immunomodulatory cytokines, i.e. tumor
      necrosis factor alpha (TNF-alpha), interleukin-2 (IL-2), interferon-gamma (IFN
      gamma), IL-4, IL-6, and transforming growth factor beta (TGF-beta). This was
      examined after in vitro infection of human peripheral blood mononuclear cells
      (PBMC) with HHV-7. We found elevated levels of TNF-alpha, TGF-beta, and IFN-gamma
      in the supernatants of HHV-7-infected cells. By reverse transcriptase-polymerase
      chain reaction (RT-PCR) analysis, using cytokine-specific primers, we found that
      levels of TNF-alpha, TGF-beta, and IFN-gamma mRNA were increased in the infected
      cells. The HHV-7 infection also significantly (P < 0.05) decreased the production
      of IL-2 from activated, IL-2-producing PBMC. Furthermore, mitogen- and cytokine
      induced cellular proliferative responses of human PBMC were found to be
      significantly (P < 0.05) down-regulated by this virus. On the other hand, HHV-7
      did not affect IL-4 and IL-6 synthesis. Overall, our results indicate that HHV-7
      infection causes significant immunomodulatory effects with regard to cytokine
      synthesis in these cells as well as inhibiting lymphocyte proliferation by
      various stimuli.

PMID- 10577516
TI  - Interleukin-1 production by mouse macrophages is regulated in a feedback fashion
      by nitric oxide.
AB  - The pleiotropic cytokine interleukin-1 (IL-1) is an inducer of the inducible
      nitric oxide synthase (iNOS). It was surprising to find that treatment of normal
      mice with an iNOS inhibitor resulted in detectable IL-1beta mRNA in colon and
      spleen, suggesting feedback regulation. When mouse peritoneal exudate cells (PEC)
      or RAW 264.7 cells were stimulated with lipopolysaccharide (LPS), concomitant
      inhibition of iNOS resulted in an increase of IL-1beta and IL-1alpha protein
      secretion. Conversely, after addition of the NO-generating compound NOC-18, IL
      1beta and IL-1alpha concentrations in supernatants were dose-dependently reduced.
      Costimulation with interferon-gamma (IFN-gamma) reversed the NOC-18-mediated
      suppression of IL-1alpha protein concentration into an almost fivefold increase
      in RAW 264.7 cells. This effect was specific for IL-1alpha and was also seen in
      PEC. The mRNA expression for IL-1beta and IL-1alpha in RAW 264.7 cells correlated
      with the protein levels, suggesting transcriptional regulation by NO.
      Dysregulated IL-1/NO cross-regulation may play a role in inflammatory diseases.

PMID- 10577517
TI  - Down-regulation of the beta-chemokine receptor CCR6 in dendritic cells mediated
      by TNF-alpha and IL-4.
AB  - Chemokines are involved in the control of dendritic cell (DC) trafficking, which
      is critical for the immune response. We have generated DC from human umbilical
      cord blood CD34+ progenitors cultured with granulocyte-macrophage colony
      stimulating factor, tumor necrosis factor alpha (TNF-alpha), and stem cell
      factor. Using an anti-CCR6 monoclonal antibody, we observed that these cells
      showed maximum expression of this beta-chemokine receptor when they were
      immature, as determined by their relatively low expression of several DC
      maturation markers such as CD1a, CD11c, CD14, CD40, CD80, and CD83. Immature DC
      responded strongly to macrophage inflammatory protein-3alpha (MIP-3alpha), the
      CCR6 ligand, in migration and calcium mobilization assays. CCR6 expression
      decreased in parallel with the DC maturation induced by prolonged TNF-alphaq
      treatments. Interleukin-4 was also able to decrease CCR6 protein levels. Our
      findings suggest that the MIP-3alpha/CCR6 interaction plays an important role in
      the trafficking of immature DC to chemokine production sites such as injured or
      inflamed peripheral tissues, where DC undergo maturation on contact with
      antigens.

PMID- 10577518
TI  - Annexins VII and XI are present in a human macrophage-like cell line.
      Differential translocation on FcR-mediated phagocytosis.
AB  - We have studied the divalent cation-dependent association of proteins to
      subcellular fractions of human macrophage-like cells before and after FcR
      mediated phagocytosis. Among these proteins we have identified annexins VII and
      XI for the first time in these cells, along with annexins I, III, and VI.
      Although all of these annexins are present in the cytosolic fraction, the extent
      of their association to membrane and phagosome fractions from resting and
      stimulated cells is variable. Annexin VII translocates from cytosolic to membrane
      fractions after phagocytic stimulation, along with annexin I, III, and VI.
      Annexins VII and XI are found associated with purified phagosomes along with I,
      III, and VI, and this association is greater after a 24-h chase period. Our
      results show differences in the intracellular distribution of different annexins
      in macrophage-like cells on phagocytosis. Annexins VII, VI, III, and I respond to
      particle ingestion by translocating to phagosomes and other cell membrane
      structures, whereas annexin XI translocates predominantly to phagosomes,
      suggesting dissimilarities in their function.

PMID- 10577519
TI  - Phosphorylation of p40-phox during activation of neutrophil NADPH oxidase.
AB  - NADPH oxidase, a superoxide-producing enzyme in phagocytic cells, consists of
      membrane-associated cytochrome b558 and cytosolic components (p47-phox, p67-phox,
      p40-phox, rac 1/2). Activation of NADPH oxidase is accompanied by the
      phosphorylation of cytosolic components (p47-phox and p67-phox). In this study,
      we have examined whether p40-phox, a newly identified cytosolic component, is
      phosphorylated during neutrophil activation, and the relationship between p40
      phox phosphorylation and NADPH oxidase activation. When 32P-labeled guinea pig
      neutrophils were stimulated by phorbol 12-myristate 13-acetate, p40-phox was
      phosphorylated as p47-phox. It is interesting that phosphorylation of p40-phox
      was markedly inhibited by protein kinase C inhibitor, H-7, but not by casein
      kinase II inhibitor, A-3, and H-7 inhibited translocation of p40-phox and
      activation of NADPH oxidase. Furthermore, purified protein kinase C but not
      casein kinase II directly phosphorylated p40-phox of p40-phox/p47-phox/p67-phox
      complex. Together these observations suggest that p40-phox is phosphorylated by
      protein kinase C during neutrophil activation, and phosphorylation of p40-phox
      may be important for the activation of NADPH oxidase.

PMID- 10577520
TI  - Regulation of CD 163 on human macrophages: cross-linking of CD163 induces
      signaling and activation.
AB  - CD163 is a member of the group B scavenger receptor cysteine-rich (SRCR)
      superfamily. This study describes aspects of the tissue distribution, the
      regulation of expression, and signal transduction after cross-linking of this
      receptor at the cell surface of macrophages. CD163 showed an exclusive expression
      on resident macrophages (e.g., red pulp macrophages, alveolar macrophages). The
      expression was inducible on monocyte-derived macrophages by glucocorticoids but
      not by interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor (GM
      CSF), and interferon-gamma. The combination of IL-4 or GM-CSF with
      glucocorticoids resulted in a further increase. Subcellular analysis of alveolar
      macrophages by immunoelectron microscopy showed a plasma membrane localization of
      the antigen. Cross-linking of CD163 with monoclonal antibody induced a protein
      tyrosine kinase-dependent signal that resulted in (1) slow-type calcium
      mobilization, (2) inositol triphosphate production, and (3) secretion of IL-6 and
      GM-CSF. The data suggest a function for the SRCR-superfamily receptor CD163 in
      the regulation of inflammatory processes by macrophages.

PMID- 10577521
TI  - Comparison of central and peripheral visual field properties in the optic
      neuritis treatment trial.
AB  - PURPOSE: To compare the results of peripheral kinetic visual field testing and
      central static perimetry for patients enrolled in the Optic Neuritis Treatment
      Trial to determine (1) whether loss and recovery of visual field sensitivity in
      the far periphery was different from that observed in the central visual field
      and (2) whether the far peripheral visual field provided additional useful
      information that was not available in the central visual field results. METHODS:
      Both affected and fellow eyes of 448 patients with optic neuritis in the Optic
      Neuritis Treatment Trial were evaluated according to the trial protocol during
      the patients' first 3 years in the study. Central static visual field tests were
      performed with program 30-2 on the Humphrey Field Analyzer, and peripheral
      kinetic testing consisted of plotting the I3e and II4e isopters on the Goldmann
      perimeter. Both test procedures were conducted according to the trial protocols,
      and quality control assessments and clinical evaluations were performed on all
      the visual fields. RESULTS: For both affected and fellow eyes at all 11 visits,
      there was a greater number of abnormal visual fields in the central static
      perimetry results than in the peripheral kinetic data. Only 2.9% of affected eyes
      had an abnormal peripheral visual field with a normal Humphrey mean deviation
      during year 1. At baseline, 97.1% of affected eyes had an abnormal Humphrey mean
      deviation on central static testing, whereas only 69.9% had abnormal peripheral
      kinetic visual fields. Approximately 80% of the I3e and II4e isopters for
      affected eyes that were abnormal at baseline were within normal limits at 30
      days, but it took until week 19 for even 70% of the Humphrey mean deviations to
      return to normal. In addition, the II4e isopters (more peripheral than the I3e
      isopters) that were abnormal at baseline showed a somewhat greater percentage of
      improvement from baseline through day 30 than the abnormal I3e isopters. Although
      this difference is statistically significant, it is probably not clinically
      significant. For visits after week 19, approximately 25% to 30% of affected eyes
      had an abnormal Humphrey mean deviation, whereas only 10% to 15% of peripheral
      kinetic fields were abnormal. CONCLUSIONS: For the affected eye in optic
      neuritis, the central visual field shows greater abnormalities than the far
      peripheral visual field. When the results obtained through Humphrey automated
      central static visual fields and Goldmann peripheral kinetic isopters are
      compared, the far periphery appears to recover more rapidly and more completely
      than the central field, at least in more severe cases of optic neuritis. In most
      cases, recovery in optic neuritis can probably be monitored effectively with
      automated perimetry of the central visual field alone. However, in cases of
      severe loss of the central visual field, a peripheral kinetic visual field
      obtained with a Goldmann perimeter may provide additional information about the
      patient's vision in the far periphery.

PMID- 10577522
TI  - Global visual field involvement in acute unilateral optic neuritis.
AB  - PURPOSE: To quantify automated visual field defects seen at entry in the Optic
      Neuritis Treatment Trial (ONTT) to determine whether particular areas of the
      field are preferentially affected and to determine the extent of visual field
      involvement in patients having "localized" field defects. METHODS: Review of
      Humphrey 30-2 Visual Field (Allergan-Humphrey, Inc, San Leandro, CA) data from
      the involved and fellow eyes of 440 patients who were enrolled in the ONTT. Field
      defects were evaluated by comparing the involved eye to the fellow eye. RESULTS:
      Patients with diffuse visual field defects had a relatively equal diminution of
      visual threshold throughout the tested 30-2 field. Patients with localized
      central and cecocentral scotomas had their greatest depression of threshold
      centrally; however, even those patients with mild defects (mean defect, <6 dB)
      had diminution of visual threshold throughout the entire tested 30-degree field.
      Patients with moderate (mean defect, 6 to 20 dB) and severe (mean defect, >20 dB)
      central and cecocentral defects had even greater peripheral depression. Patients
      with altitudinal or quadrant defects had involvement of the "unaffected" field
      that also varied with the mean defect. The overall average depression of visual
      threshold for all patients averaged 36%+/-4% and was relatively uniform
      throughout the tested field. CONCLUSIONS: Optic neuritis affects the entire
      central 30-2 field, even in patients who appear to have localized depression of
      visual threshold. Optic neuritis does not appear to have a predilection for any
      particular area of the visual field.

PMID- 10577523
TI  - Recovery of visual field function in the optic neuritis treatment trial.
AB  - PURPOSE: To assess the pattern of recovery of the visual field of patients with
      optic neuritis and to determine whether all affected portions of the visual field
      recover similarly or certain portions of the visual field have greater recovery.
      METHODS: We reviewed the Humphrey Visual Field (Allergan-Humphrey Inc, San
      Leandro, California) data from the initial and 6-month examination for the
      involved and fellow eyes of patients enrolled in the Optic Neuritis Treatment
      Trial (ONTT). The average threshold for each patient was calculated for the
      entire tested field and for locations within concentric rings having a radius 3,
      9, 15, 21, and 27 degrees from fixation. The absolute amount of improvement and
      percentage improvement in average threshold between entry and the 6-month follow
      up examination were determined for each patient. These measurements were compared
      within the concentric rings to assess patterns of recovery. RESULTS: Patients
      with localized defects recovered 86%+/-20% of their initial defect in average
      threshold, whereas those having diffuse defects recovered an average of 85%+/
      23%. The area about fixation had the greatest relative recovery of threshold
      (87%+/-21% at 3 degrees); the relative recovery decreased with increasing
      eccentricity from fixation (P<.01). CONCLUSIONS: Patients with optic neuritis
      have a marked return of visual field function that does not appear to differ
      between patients with diffuse or localized field defects. The reduced redundancy
      of axons in the periphery of the field compared with near fixation may be
      responsible for the greater relative recovery of threshold near fixation.

PMID- 10577524
TI  - Surgical treatment of children blinded by Stevens-Johnson syndrome.
AB  - PURPOSE: The surgical treatment of severe Stevens-Johnson syndrome is considered
      to be very difficult, especially in children. However, ocular surface
      reconstruction is possible in certain cases. METHODS: We have performed ocular
      surface reconstruction by allogeneic corneal epithelial stem cell transplantation
      in four children blinded by Stevens-Johnson syndrome. RESULTS: Two cases failed,
      and the other two had excellent results. The successful cases had good lacrimal
      function and conjunctival epithelium, with clear corneal stroma and pathology
      limited to the superficial ocular tissue, whereas the failures did not.
      CONCLUSIONS: The successful ocular surface reconstruction has been stable for
      more than 1 year in two cases, suggesting that some patients with Stevens-Johnson
      syndrome are very good candidates for ocular surface reconstruction, especially
      when the patients have good tear function and healthy conjunctival epithelium.

PMID- 10577525
TI  - Improvement of visual function with glare testing after photorefractive
      keratectomy and radial keratotomy.
AB  - PURPOSE: To evaluate the effect of a glare source on visual function in patients
      after photorefractive keratectomy and radial keratotomy. METHODS: Thirteen
      patients (22 eyes) who underwent photorefractive keratectomy and 20 patients (40
      eyes) who underwent radial keratotomy were evaluated in this cross-sectional
      study. LogMAR visual acuity and contrast sensitivity were measured. Pupils were
      measured with the Rosenbaum card. A halogen/tungsten glare source approximated
      the luminance of headlights of an oncoming car at 100 feet. RESULTS: In the
      photorefractive keratectomy and radial keratotomy groups, pupils were
      significantly smaller (P<.01) and the pupillary clearance of the ablation zone in
      photorefractive keratectomy and the clear zone in radial keratotomy were
      significantly larger under the glare condition (P<.01). In the photorefractive
      keratectomy group, visual acuity and contrast sensitivity under the glare
      condition were significantly higher than in the no-glare condition (P = .02). In
      the radial keratotomy group, contrast sensitivity under the glare condition was
      significantly higher than under the no-glare condition (P = .001 to .003).
      CONCLUSIONS: After photorefractive keratectomy or radial keratotomy, the
      traditional glare source constricted the pupil and partially masked the optical
      aberrations, which resulted in an improvement in visual function. A "pupil
      sparing" aberration test is needed for evaluation of visual function after
      refractive surgery.

PMID- 10577526
TI  - Retinal detachment in myopic eyes after laser in situ keratomileusis.
AB  - PURPOSE: To analyze the incidence and characteristics of retinal detachment in
      myopic patients treated by laser-assisted in situ keratomileusis. METHODS: We
      retrospectively studied the retinal detachments observed in 1,554 consecutive
      eyes (878 patients) undergoing laser-assisted in situ keratomileusis for the
      correction of myopia (follow-up, 30.34+/-10.27 months; range, 16 to 54). Mean
      patient age was 33.09+/-8.6 years (range, 20 to 60). Before treatment with laser
      assisted in situ keratomileusis, all patients had a comprehensive examination,
      and detected lesions predisposing to retinal detachment were treated before
      performing the laser-assisted in situ keratomileusis procedure. RESULTS: Retinal
      detachment occurred in four (0.25%) of 1,554 eyes of four (0.45%) of 878
      patients. All four patients who developed retinal detachment in one eye were
      women. Degree of preoperative myopia was -13.52+/-3.38 diopters (range, -8.00 to 
      27.50). The time interval between refractive surgery and retinal detachment was
      11.25+/-8.53 months (range, 2 to 19 months). In all cases retinal detachment was
      spontaneous. In all eyes the retina was reattached successfully at the first
      retinal detachment surgery. Mean best-corrected visual acuity after laser
      assisted in situ keratomileusis and before retinal detachment development was
      20/43 (range, 20/50 to 20/30). After retinal detachment repair, best-corrected
      visual acuity was 20/45 (range, 20/50 to 20/32). Differences between best
      corrected visual acuity before and after reattachment were not statistically
      significant (P = .21, paired Student t test). A myopic shift was induced in three
      eyes that had retinal detachment repaired by scleral buckling, from -0.58+/-0.72
      diopter (range, +0.25 to -1.00) before retinal detachment and -2.25+/-1.14
      diopters (range, -1.00 to -3.25) after retinal detachment surgery (P = .03,
      paired Student t test). CONCLUSIONS: Laser-assisted in situ keratomileusis for
      correction of myopia is followed by a low incidence of retinal detachment.
      Conventional scleral buckling surgery was successful in most cases and did not
      cause significant changes in the final best-corrected visual acuity. A
      significant increase in the myopic spherical equivalent was observed after
      scleral buckling in these patients.

PMID- 10577527
TI  - Parapapillary atrophy in patients with focal visual field loss.
AB  - PURPOSE: To examine parapapillary atrophy in normal subjects and patients with
      primary open-angle glaucoma with focal visual field loss. METHODS: Twenty-nine
      patients with repeatable early focal visual field loss according to standard
      automated perimetry (Humphrey program 24-2) and 29 matched (age and disk area)
      normal subjects were included. Parapapillary atrophy area and optic disk
      topography were evaluated with a confocal scanning laser ophthalmoscope. The
      difference in parapapillary atrophy area between normal subjects and patients
      with glaucoma was examined. Optic disk topography was evaluated by means of the
      rim-disk area ratio in 36 10-degree sectors and classified into diffuse and focal
      patterns of neuroretinal rim thinning. In patients with a focal pattern, the
      locations of rim thinning and parapapillary beta zone atrophy were compared.
      RESULTS: Beta zone atrophy was detected more frequently in patients with glaucoma
      (45% [13/29]) than in normal subjects (7% [2/29]), and it was located both
      superiorly and inferiorly in 92% (12/13) of the glaucoma patients. Alpha zone
      atrophy was significantly larger in patients with glaucoma than normal subjects
      (P = .009) but not more frequent (97% [28/29] in both groups). Sixty-one percent
      (8/13) of glaucoma patients with beta atrophy had diffuse thinning and 31% (4/13)
      had focal thinning. Eight percent (1/13) did not have neuroretinal rim thinning.
      In the four patients with both focal rim thinning and beta zone atrophy, the
      location of rim thinning corresponded to the location of the beta zone atrophy
      (100% [4/4]). CONCLUSIONS: In patients with early focal glaucomatous visual field
      loss, the presence and location of parapapillary beta zone atrophy and
      neuroretinal rim thinning are in good correspondence. Observation of localized
      parapapillary beta zone atrophy in clinical practice should direct one to more
      closely examine the optic disk in this region, as it may reveal localized rim
      thinning in a disk previously considered to be normal. Moreover, diffuse
      structural change in an eye with only focal functional change, as determined by
      standard automated perimetry, is consistent with the possibility that structural
      damage may be more widespread than functional damage in these patients.

PMID- 10577529
TI  - Ocular and optic nerve head ischemic disorders and hearing loss.
AB  - PURPOSE: To investigate in an exploratory study whether any evidence suggests
      that ophthalmic ischemic disorders, particularly of the optic nerve head, are
      associated with hearing loss. METHODS: We investigated prospectively 583
      consecutive patients in eight primary ocular diagnostic groups for associated
      hearing loss: nonarteritic anterior ischemic optic neuropathy (n = 81), normal
      tension glaucoma (n = 36), primary open-angle glaucoma (n = 138), other types of
      glaucoma (n = 142), ocular arterial occlusive disorders (n = 22), retinal vein
      occlusion (n = 89), ocular vasculitis (n = 42), and a miscellaneous group (n =
      33). The patients and their relatives were questioned in detail for any evidence
      of hearing loss in the patients. RESULTS: In the logistic regression model, with
      presence or absence of hearing loss as the dependent variable and gender, age,
      and diagnosis as independent variables, gender (P = .003) and age (P<.0001) were
      found to be significantly associated with hearing loss. No significant
      association was found with any of the ophthalmic disease groups evaluated in this
      study. Whenever any significant association with any ophthalmic disease group was
      seen, this result could be explained by examination of the association between
      diagnosis and age, which showed a significant (P<.001) association. CONCLUSIONS:
      This study showed that there is a significant (P<.001) relationship between
      hearing loss and aging-the older the population, the higher the incidence of
      hearing loss-but the study showed that there is no association between hearing
      loss and ocular and optic nerve head ischemic disorders. The two represent
      unrelated and independent disorders.

PMID- 10577528
TI  - Effect of brimonidine on optic nerve blood flow in rabbits.
AB  - PURPOSE: Brimonidine is a highly selective alpha2-adrenoreceptor agonist that
      lowers intraocular pressure. The aim of the present study was to analyze in vivo
      the vasomotor effects and the influence of brimonidine on blood flow within the
      optic nerve, by means of intraluminal microvascular corrosion casting technique
      and intravascular injection of colored microspheres. METHODS: New Zealand white
      rabbits received either brimonidine tartrate 0.2% or placebo (vehicle) topical
      drops in one eye for 4 weeks. Intraocular pressures were measured at baseline and
      4 weeks. The anterior optic nerve microvasculature of four rabbits was examined
      with corrosion castings for regions of focal vasoconstriction. Optic nerve blood
      flow was determined in 16 rabbits by means of nonradioactive colored
      microspheres. RESULTS: The vasoconstriction values of the short posterior ciliary
      arterial branches in the brimonidine eyes were 16.7%+/-3.7%. In the fellow
      untreated eyes, the mean vasoconstriction was 16.6%+/-2.4%. In the placebo
      treated eyes, the average constriction was 15.9%+/-3.2%; the fellow eyes showed a
      mean constriction value of 16.1%+/-5.3%. There was no statistical difference
      between any of the groups (P = .2). The optic nerve blood flow in the brimonidine
      treated rabbits was 0.18+/-0.06 ml/mg/min and 0.17+/-0.04 ml/mg/min in the
      treated and the fellow eyes, respectively. The difference between the optic nerve
      blood flow in the brimonidine-treated eyes and the optic nerve blood flow in all
      of the untreated eyes (0.19+/-0.06 ml/mg/min) also was not statistically
      different (P = .82). CONCLUSIONS: Long-term application of brimonidine 0.2% does
      not affect the blood flow or vasomotor activity of the anterior optic nerve.

PMID- 10577530
TI  - Impaired color vision associated with diabetic retinopathy: Early Treatment
      Diabetic Retinopathy Study Report No. 15.
AB  - PURPOSE: To report color vision abnormalities associated with diabetic
      retinopathy. METHODS: Color vision function was measured at baseline in 2,701
      patients enrolled in the Early Treatment Diabetic Retinopathy Study, a randomized
      trial investigating photocoagulation and aspirin in the treatment of diabetic
      retinopathy. Hue discrimination was measured by the Farnsworth-Munsell 100-Hue
      test, and errors in color vision were reported as the square root of the total
      100-Hue (SQRT 100-Hue) score. RESULTS: Approximately 50% of the Early Treatment
      Diabetic Retinopathy Study population had color vision scores (SQRT 100-Hue
      score) worse than 95% of the normal population reported by Verriest and
      associates. The factors most strongly associated with impaired hue discrimination
      were macular edema severity, age, and presence of new vessels. A tritan-like
      defect was prominent and increased in magnitude with increasing severity of
      macular edema. However, many patients had color discrimination impairment without
      macular edema. CONCLUSIONS: Impaired color vision is a common observation among
      participants enrolled in the Early Treatment Diabetic Retinopathy Study. Compared
      with published data on normal subjects, approximately 50% of the patients in the
      Early Treatment Diabetic Retinopathy Study had abnormal hue discrimination.
      Macular edema severity, age, and the presence of new vessels were the factors
      most strongly associated with impaired color discrimination. A tritan-like defect
      was prominent and increased in magnitude with increasing severity of macular
      edema. Impaired color vision should be considered in the evaluation and
      counseling of patients with diabetic retinopathy.

PMID- 10577531
TI  - Anatomic and visual results in asymptomatic clinical rhegmatogenous retinal
      detachment repaired by scleral buckling.
AB  - PURPOSE: To report presenting characteristics as well as anatomic and visual
      results in asymptomatic clinical rhegmatogenous retinal detachment repaired by
      scleral buckling. METHODS: Review of 28 eyes of 27 patients with an asymptomatic
      clinical retinal detachment-defined as a rhegmatogenous retinal detachment with
      subretinal fluid extending more than 2 disk diameters posterior to the equator
      which were repaired by scleral buckling from January 1989 through December 1996
      with follow-up of 6 months or longer. RESULTS: With a single scleral buckling
      procedure, anatomic reattachment of the retina occurred in all eyes; one eye
      redetached 14 months after the initial surgery secondary to a new retinal break
      and was successfully reattached. All eyes had best-corrected presenting and final
      visual acuity of 20/50 or better. Final best-corrected Snellen visual acuity was
      within 1 line of best-corrected presenting visual acuity in 82% of eyes; three
      eyes improved more than 1 line of Snellen visual acuity and two eyes lost more
      than 1 line. CONCLUSION: Anatomic and visual results in asymptomatic clinical
      rhegmatogenous retinal detachment after scleral buckling surgery are excellent.
      Strong consideration should be given to repair of these detachments.

PMID- 10577532
TI  - Optical coherence tomography of successfully repaired idiopathic macular holes.
AB  - PURPOSE: To present the cross-sectional retinal imaging results of optical
      coherence tomography in eyes with successfully repaired idiopathic macular hole
      and their relevance to visual recovery. METHODS: We studied 33 eyes with
      successful repair of an idiopathic macular hole through vitrectomy and fluid-gas
      exchange from 32 patients (11 men and 21 women) with ages ranging from 48 to 78
      years, with a median age of 66 years. Preoperative conditions in eyes with
      primary surgery disclosed nine eyes with stage 2, 14 eyes with stage 3, and four
      eyes with stage 4 macular hole. An additional six eyes underwent a second surgery
      because the previous surgery was unsuccessful. Measurement of best-corrected
      visual acuity, slit-lamp biomicroscopy with fundus contact lens, fundus
      photographs, and optical coherence tomographic examination were performed between
      6 and 9 months after surgery in 29 eyes and between 15 and 36 months after
      surgery in four eyes. RESULTS: Optical coherence tomographic images of the
      repaired macular holes were categorized into three patterns. U-type (normal
      foveal contour; 13 eyes) showed mildly to moderately backscattering layers with a
      smooth circular surface covering retinal pigment epithelium and choriocapillaris
      layers. In eyes with V-type (steep foveal contour; 13 eyes), the retinal pigment
      epithelium and choriocapillaris layers were covered with moderately
      backscattering layers with a notch. W-type (foveal defect of neurosensory retina;
      seven eyes) showed abruptly or gradually terminating sensory retinal layers to
      expose the surface of the retinal pigment epithelium and choriocapillaris layers.
      Postoperative acuity was well correlated with these patterns of optical coherence
      tomographic images. CONCLUSION: Assessment of successfully repaired idiopathic
      macular holes with optical coherence tomographic images provides a useful
      correlation with postoperative visual recovery.

PMID- 10577533
TI  - Timing of retinal redetachment after removal of intraocular silicone oil
      tamponade.
AB  - PURPOSE: To evaluate the interval between removal of intraocular silicone oil
      tamponade and retinal redetachment after pars plana vitrectomy, and to
      investigate factors influencing the length of the interval. PATIENTS AND METHODS:
      The retrospective study included 42 eyes of 42 consecutive patients who
      experienced a retinal redetachment after silicone oil had been removed 8.0+/-6.2
      months after an initial pars plana vitrectomy including intraocular silicone oil
      (5,000 centistokes) tamponade. Pars plana vitrectomy had been performed for
      proliferative vitreoretinopathy caused by complicated rhegmatogenous retinal
      detachment. RESULTS: The retina redetached 2 days to 5.5 months after silicone
      oil removal (mean +/- SD, 1.3+/-1.4 months; median, 18 days). Thirteen (30%) of
      all 42 redetachments occurred in the first 9 days, 21 (50%) of all 42 retinal
      redetachments occurred in the first 18 days, and 32 (75%) of all 42 retinal
      redetachments occurred in the first 50 days. The interval between silicone oil
      removal and retinal redetachment was statistically (by analysis of variance)
      independent of the method of silicone removal (transpupillary drainage vs via
      pars plana sclerotomies), refractive error of the eye (P = .62), time between
      initial pars plana vitrectomy and silicone oil removal (P = .99), visual acuity
      before silicone oil removal (P = .26), type of anesthesia (P = .69), gender (P =
      .80), and age (P = .48) of the patients. CONCLUSION: The risk of retinal
      redetachment decreases steeply with increasing time after silicone oil removal.
      Three to 5 months after oil removal, retinal redetachment becomes unlikely. The
      time of retinal redetachment is statistically independent of the method of
      silicone oil removal, refractive error, time between the preceding pars plana
      vitrectomy and silicone oil removal, visual acuity before silicone oil removal,
      type of anesthesia, and gender and age of the patents. These data may be
      important for scheduling reexaminations and for counseling patients in their
      planned activities after removal of intraocular silicone oil tamponade.

PMID- 10577535
TI  - Eyelid tumors: accuracy of clinical diagnosis.
AB  - PURPOSE: To determine the accuracy, specificity, and sensitivity of the clinical
      diagnosis of malignant tumor of the eyelid. METHOD: Analysis of consecutively
      submitted biopsy specimens of the eyelid for 1 year to a regional ophthalmic
      pathology laboratory. RESULTS: Agreement was noted between clinical and
      histopathologic diagnoses on 72 (84%) of 86 eyelid biopsy specimens received over
      12 months. Ten (11.6%) clinical diagnoses of suspected malignant eyelid tumor
      showed benign skin conditions, and four (4.6%) clinical diagnoses of presumed
      benign conditions proved to be malignant. CONCLUSIONS: The clinical assessment of
      eyelid malignancy by ophthalmologists is reasonably good when evaluated in terms
      of sensitivity (87.5%) and specificity (81.5%) of diagnosis. Lesions giving rise
      to the false-negative diagnosis of malignancy tend to be nodules with
      unremarkable surface features.

PMID- 10577534
TI  - Visual field defects in the optic neuritis treatment trial: central vs
      peripheral, focal vs global.

PMID- 10577536
TI  - Central bump-like opacity as a complication of high hyperopic photorefractive
      keratectomy.
AB  - PURPOSE: A new complication is reported in association with high hyperopic
      excimer laser photorefractive keratectomy. METHODS: One thousand consecutive eyes
      were treated with a Meditec MEL-60 excimer laser (Meditec Inc, Heroldsberg,
      Germany) for hyperopic refractive error between +1 diopters and +7 diopters.
      RESULTS: Three eyes with high hyperopic corrections between +5 and +6 diopters
      had a central, round bump-like subepithelial scar develop 1 month after hyperopic
      photorefractive keratectomy, which reduced the uncorrected and spectacle
      corrected visual acuity. CONCLUSION: Central bump-like opacity is a new, visually
      significant complication of unknown origin associated with high hyperopic
      photorefractive keratectomy. Possible causes of this complication include drying
      and edema of the cornea as a result of prolonged exposure, interruption of the
      peripheral superficial nerve plexus affecting the central anterior stroma, and
      abnormal epithelial or tear film function resulting from excessive central
      steeping.

PMID- 10577537
TI  - Treatment of recurrent conjunctival papillomatosis with mitomycin C.
AB  - PURPOSE: To report an effective treatment for recurrent squamous papillomas of
      the conjunctiva with excision and application of mitomycin C. METHOD: Case
      report. RESULTS: A 5-year-old African-American girl with recurrent squamous
      papillomas of the right bulbar and palpebral conjunctiva was treated with
      multiple therapies, including excision, cryotherapy, and conjunctival injection
      of alpha-interferon; all therapies were followed by recurrence. After treatment
      with excision followed by intraoperative application of mitomycin C to the
      involved conjunctiva, the patient had no recurrence in a 30-month period.
      CONCLUSIONS: Excision with application of mitomycin C was successful in managing
      a case of squamous papillomatosis that was resistant to traditional therapy.

PMID- 10577538
TI  - Conjunctival mucoepidermoid carcinoma in a young HIV-infected man.
AB  - PURPOSE: To report a case of conjunctival mucoepidermoid carcinoma occurring in a
      long-standing pterygium in a 33-year-old Cambodian man infected with the human
      immunodeficiency virus (HIV). METHODS: Review of clinical history and
      histopathologic findings. RESULTS: A pterygium that was present for 8 years
      suddenly became highly inflamed and underwent rapid growth. After the initial
      diagnostic conjunctival and corneal biopsy showed mucoepidermoid carcinoma,
      subsequent additional deep excisions of the adjacent sclera and cornea were
      necessary to completely excise the tumor. Cytokeratin and mucicarmine stains were
      used to confirm the pathologic diagnosis of mucoepidermoid carcinoma.
      CONCLUSIONS: Unique features of this case include the extremely young age of the
      patient (perhaps rendered susceptible by his HIV infection), the tumor
      masquerading as a pterygium, and the use of a hybrid lamellar and full-thickness
      corneoscleral resection requiring a complementary graft. Seventeen months after
      the resection, the patient is free of tumor; this was histopathologically
      confirmed with multiple random conjunctival biopsies.

PMID- 10577539
TI  - Congenital smooth muscle hamartoma of the conjunctival fornix.
AB  - PURPOSE: Congenital smooth muscle hamartomas are benign tumors composed of
      proliferating smooth muscle cells. They are usually seen as abnormal patches of
      skin. Ocular involvement of congenital smooth muscle hamartomas is unusual, with
      rare reports of patients with external eyelid involvement or proptosis resulting
      from orbital tumors. We describe a patient with a congenital smooth muscle
      hamartoma that involved the tarsal conjunctival fornix. METHODS: Review of the
      patient's medical records, including the results of ophthalmologic, radiologic,
      and histologic examinations. RESULTS: A healthy 2-year-old boy was initially seen
      with a conjunctival mass. He had a discrete, gray, cystic-appearing lesion in the
      inferior fornix of the left eye. A magnetic resonance imaging study revealed no
      signs of extension of the lesion into the orbit. The lesion was surgically
      excised. Histologic sections showed large bundles of smooth muscle with a
      fibrotic background and interdigitating fat, consistent with a diagnosis of a
      congenital smooth muscle hamartoma. CONCLUSION: To our knowledge, this is the
      first report of a patient with a congenital smooth muscle hamartoma arising from
      the conjunctival fornix. It presumably originated from either the smooth muscle
      of the vascular endothelium or from the capsulopapebral muscle. Congenital smooth
      muscle hamartoma should be considered in the differential diagnosis of cystic
      appearing conjunctival fornix lesions.

PMID- 10577540
TI  - Double-knot transscleral suture fixation technique for displaced intraocular
      lenses.
AB  - PURPOSE: To describe a simplified new technique for repositioning and attaching a
      suture to the haptic of a displaced posterior chamber intraocular lens (IOL).
      METHODS: We describe a double-knot technique for repositioning and transscleral
      suture fixation of a subluxed posterior chamber IOL after penetrating
      keratoplasty. Two 10-0 Prolene transscleral sutures on straight needles are
      passed around the IOL haptic, tied extraocularly, and used to secure the
      repositioned haptic of the IOL. A second knot ties the transscleral suture in the
      scleral bed, stabilizing the haptic in the ciliary sulcus. RESULTS: In the case
      described, the IOL was stable and well positioned 2 months after surgery.
      CONCLUSION: The double-knot technique for intraocular repositioning and
      transscleral suture fixation of displaced posterior chamber IOLs reduces the
      extensive intraocular manipulation and scleral incisions required for IOL
      exchange and may reduce chronic irritation associated with iris fixation.

PMID- 10577541
TI  - Blurred vision during sexual arousal associated with narrow-angle glaucoma.
AB  - PURPOSE: To describe three women with narrow-angle glaucoma who had transient
      blurred vision during sexual arousal. METHOD: Case reports. RESULTS: Three women,
      aged 37, 45, and 55 years, were seen with bilateral narrow-angle glaucoma and
      were treated with bilateral laser iridotomy. In each patient, additional surgery
      was required to control the glaucoma. After establishing a rapport with her
      physician, each patient described transient blurred vision, from a few minutes to
      several hours in duration, which began during sexual arousal. This symptom
      resolved after peripheral iridotomy and, in one patient, after laser iridoplasty.
      CONCLUSION: The association of transient blurred vision with sexual activity may
      delay presentation of patients with symptomatic narrow-angle glaucoma.

PMID- 10577543
TI  - Purtscher-like retinopathy associated with pancreatic adenocarcinoma.
AB  - PURPOSE: To investigate a case of Purtscher-like retinopathy that occurred in
      association with pancreatic adenocarcinoma. METHOD: Case report. RESULTS: A 63
      year-old woman presented with multiple gray patches in the central vision of both
      eyes. Visual acuity was 20/20 in both eyes. Funduscopy showed large peripapillary
      yellow-white patches within the superficial retina and small superficial retinal
      hemorrhages in both eyes. The patient subsequently had abdominal pain. Computed
      tomography of the abdomen demonstrated a large pancreatic mass with extension
      into the liver. Histologic examination of a percutaneous needle biopsy specimen
      showed mucinous pancreatic adenocarcinoma. CONCLUSION: Pancreatic adenocarcinoma
      should be added to the list of systemic diseases that can be associated with
      Purtscher-like retinopathy.

PMID- 10577542
TI  - Endophthalmitis from Mycobacterium bovis-bacille Calmette-Guerin after
      intravesicular bacille Calmette-Guerin injections for bladder carcinoma.
AB  - PURPOSE: To present clinical and histologic findings of intraocular infection
      with Mycobacterium bovis-bacille Calmette-Guerin after intravesicular bacille
      Calmette-Guerin injections for treatment of bladder carcinoma. METHODS: A 77-year
      old man was initially seen with visual acuity of 20/200, focal retinitis,
      vasculitis, and progressive vitreous opacity in the right eye and visual acuity
      of light perception, intraocular inflammation, and a dense cataract in the left
      eye 14 months after intravesicular injection of live bacille Calmette-Guerin
      organisms. RESULTS: Vitreous cultures in the right eye demonstrated growth of
      bacille Calmette-Guerin organisms. Bilateral loss of light perception occurred
      despite systemic antimy-cobacterial therapy. Histopathologic examination
      demonstrated nongranulomatous inflammation and acid-fast bacilli in both eyes.
      CONCLUSION: Delayed endogenous endophthalmitis may develop after intravesicular
      bacille Calmette-Guerin injection that may not respond to systemic agents.
      Intravitreal therapy may be indicated.

PMID- 10577544
TI  - Is serum cholesterol associated with progression of diabetic retinopathy or
      macular edema in persons with younger-onset diabetes of long duration?
AB  - PURPOSE: To quantitate the relationships of total cholesterol and high-density
      lipoprotein cholesterol to the incidence and progression of diabetic retinopathy
      and macular edema 5 years later in those with younger-onset diabetes of long
      duration. METHODS: Casual serum specimens for lipid values and fundus photography
      at the time of the lipid determinations were evaluated with regard to retinal
      lesions in photographs taken 5 years later during the course of a population
      based cohort study. RESULTS: Univariable associations were significant for
      associations of incident retinal lesions with total cholesterol/high-density
      lipoprotein cholesterol, but multivariable associations considering covariates
      were not significant. CONCLUSION: Our data suggest that lowering cholesterol by
      therapeutic means may not be indicated for the sole purpose of decreasing the
      incidence or progression of these retinal lesions.

PMID- 10577545
TI  - Retinal detachment associated with a macular hole in severely myopic eyes.
AB  - PURPOSE: To investigate factors associated with extensive retinal detachment in
      severely myopic eyes with a macular hole. METHOD: Fifty-two consecutive eyes with
      a macular hole and severe myopia were retrospectively studied. RESULTS: An
      extensive retinal detachment, defined as extending beyond the cuff of subretinal
      fluid, was observed in 37 eyes (71%). Extensive retinal detachment developed in
      36 (95%) of 38 eyes with a posterior staphyloma and in one (7%) of 14 eyes
      without a posterior staphyloma (P<.0001). Extensive retinal detachment also
      developed in 32 (89%) of 36 eyes with complete posterior vitreous detachment and
      in five (31%) of 16 eyes without posterior vitreous detachment (P<.0001).
      CONCLUSION: Posterior staphyloma rather than anteroposterior vitreomacular
      traction may contribute to the development of retinal detachment associated with
      a macular hole in severely myopic eyes.

PMID- 10577546
TI  - Analysis of vitrectomy for idiopathic macular hole by optical coherence
      tomography.
AB  - PURPOSE: To evaluate foveal structure after vitrectomy for idiopathic macular
      hole in relation to postoperative visual outcome. METHODS: Optical coherence
      tomography was performed postoperatively to assess retinal thickness at the
      foveal center in patients who underwent vitrectomy, posterior hyaloid membrane
      removal, and perfluoropropane gas tamponade for idiopathic macular hole. Thirty
      seven eyes of 36 patients documented to have achieved anatomic hole closure by
      optical coherence tomography were included in the study. RESULTS: Increased
      visual acuity significantly correlated with greater foveal thickness assessed at
      a median of 5 months postoperatively (Spearman analysis; R = .453, P = .005).
      CONCLUSION: Visual outcome after anatomic closure of macular holes by vitrectomy
      is closely related to the structure of the center of the fovea postoperatively.

PMID- 10577547
TI  - Optic nerve avulsion from a golfing injury.
AB  - PURPOSE: To describe a patient with optic nerve avulsion after being struck in
      the eye with a golf club. METHODS: A 10-year-old male was hit in the left eye by
      a golf club. The patient underwent full ophthalmoscopic evaluation and
      neuroimaging. RESULTS: The patient had no light perception in the left eye when
      first seen. Avulsion of the optic nerve with vitreous hemorrhage was apparent on
      examination. Computed tomographic imaging of the brain and orbits revealed no
      abnormalities. CONCLUSIONS: Optic nerve avulsion from golf-related injury is more
      likely to occur when the impact site is between the globe and the orbital rim.
      Rupture of the globe is more likely to occur with direct impact to it.

PMID- 10577548
TI  - Oculomotor nerve schwannoma associated with ophthalmoplegic migraine.
AB  - PURPOSE: To describe a patient with an oculomotor nerve schwannoma who had
      symptoms of ophthalmoplegic migraine. METHODS: Case report. RESULTS: A 23-year
      old woman had a history of recurrent headache accompanied by transient right
      oculomotor palsy since age 7 years. Ophthalmoplegic migraine was diagnosed. She
      was subsequently found to have a structural lesion of her right oculomotor nerve
      on magnetic resonance imaging. The magnetic resonance image characteristics were
      consistent with schwannoma originating from the oculomotor nerve. CONCLUSIONS:
      This case illustrates that an intrinsic lesion of the oculomotor nerve
      (schwannoma) may be associated with a painful relapsing-remitting oculomotor
      palsy mimicking the clinical syndrome of ophthalmoplegic migraine.

PMID- 10577549
TI  - Retinal detachment in phakic eyes with anterior chamber intraocular lenses to
      correct severe myopia.

PMID- 10577550
TI  - Ketorolac tromethamine 0.5% ophthalmic solution in the treatment of moderate to
      severe ocular inflammation after cataract surgery: a randomized, vehicle
      controlled clinical trial.

PMID- 10577551
TI  - Optic nerve blood flow in glaucoma: effect of systemic hypertension.

PMID- 10577552
TI  - 50th anniversary historical article. The hemodynamic basis of diastology.

PMID- 10577553
TI  - Catheter-based percutaneous myocardial laser revascularization in patients with
      end-stage coronary artery disease.
AB  - OBJECTIVES: This study evaluates the feasibility and safety of a catheter-based
      laser system for percutaneous myocardial revascularization and analyses the first
      clinical acute and long-term results in patients with end-stage coronary artery
      disease (CAD) and severe angina pectoris. BACKGROUND: In patients with CAD and
      intractable angina who are not candidates for either coronary artery bypass
      grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA),
      transmyocardial laser revascularization (TMR) has been developed as a new
      treatment that results in reduced angina pectoris and increased exercise
      capacity. However, surgical thoracotomy is required for TMR with considerable
      morbidity and mortality. METHODS: A catheter-based system has been developed that
      allows creation of laser channels in the myocardium from within the left
      ventricular cavity. Laser energy generated by a Holmium: YAG (Cardiogenesis
      Corporation, Sunnyvale, California) laser was transmitted to the myocardium via a
      flexible optical fiber capped by an optic lens. The optical fiber was maneuvered
      to the target area under biplane fluoroscopy through a coaxial catheter system
      permitting movement in three dimensions. RESULTS: Thirty-four patients with
      severe CAD not amenable to either CABG or PTCA and refractory angina pectoris
      (Canadian Cardiologic Society [CCS] Angina Scale Class III-IV) were included in
      the study. Ischemic regions were identified by coronary angiography and confirmed
      by thallium scintigraphy. The percutaneous myocardial revascularization (PMR)
      procedure was successfully completed in all patients. In 29 patients, one
      vascular territory of the left ventricle and in 5 patients, two vascular
      territories were treated. Eight to fifteen channels were created in each ischemic
      region. Major periprocedural complications were limited to an episode of arterial
      bleeding requiring surgical repair. There was one death early after PMR, due to a
      myocardial infarction (MI) in a nontreated region. Clinical follow-up at 6 months
      (17 patients) demonstrated significant improvement of angina pectoris (CCS class
      before PMR: 3.0+/-0.0, six months after PMR: 1.3+/-0.8, p<0.0001) and increased
      exercise capacity (exercise time on standard bicycle ergometry before PMR: 384+/
      141 s, six months after PMR: 514+/-158 s, p<0.05), but thallium scintigraphy
      failed to show improved perfusion of the laser treated regions. CONCLUSIONS:
      Percutaneous myocardial revascularization is a new safe and feasible therapeutic
      option in patients with CAD and severe angina pectoris not amenable to either
      CABG or PTCA. Initial results show immediate and significant improvement of
      symptoms and exercise capacity but evidence of improved myocardial perfusion is
      still lacking.

PMID- 10577554
TI  - A tunnel at the end of the light?

PMID- 10577555
TI  - Long-term endothelial dysfunction after coronary artery stenting.
AB  - OBJECTIVES: We assessed the endothelial-dependent vasomotor function in
      nonrestenotic coronary arteries more than six months following stent
      implantation, balloon angioplasty (BA), and directional atherectomy (DCA).
      BACKGROUND: Catheter-based coronary interventions are associated with extensive
      arterial injury. Endothelial function has been shown to remain chronically
      abnormal after vascular injury. The long-term effects of different percutaneous
      coronary interventions on endothelial function are not known. METHODS: Thirty
      nine patients treated at least six months earlier with a coronary intervention
      for isolated proximal left anterior descending (LAD) stenosis, with no evidence
      of restenosis, were studied. Twelve patients had been stented, 15 had been
      treated with BA, and 12 had undergone DCA. Changes in diameter of the intervened
      LAD, and the unintervened circumflex coronary artery (Cx), in response to
      intracoronary acetylcholine infusions were assessed by quantitative angiography.
      RESULTS: The groups had similar angiographic characteristics and risk factors for
      endothelial dysfunction. The LAD constricted significantly more (p = 0.02) in
      previously stented patients (-21.8+/-4.3%), as compared to patients previously
      treated with BA (-9.5+/-2.8%) or with DCA (-9.1+/-3.6%). In contrast,
      acetylcholine infusion resulted in mild constriction in the Cx, which was similar
      in the three groups (p = 0.47). By multiple regression analysis, previous implant
      of a stent was the only significant predictor of LAD constriction (p = 0.008).
      CONCLUSIONS: More severe endothelial dysfunction was observed long term after
      stenting as compared to BA or DCA. These findings may have implications with
      respect to the progression of atherosclerosis in coronary arteries subjected to
      percutaneous interventions.

PMID- 10577556
TI  - Can stents damage coronary arteries remote from the stent?

PMID- 10577557
TI  - The renal effect of low-dose dopamine in high-risk patients undergoing coronary
      angiography.
AB  - OBJECTIVES: The purpose of the study was to examine the potential renal
      protective effect of low-dose dopamine in high-risk patients undergoing coronary
      angiography. BACKGROUND: Contrast nephropathy is prevalent in patients with
      chronic renal failure (CRF) and/or diabetes mellitus (DM). Decreased renal blood
      flow due to vasoconstriction was suggested as a contributory mechanism. Low-dose
      dopamine has a dilatory effect on the renal vasculature. METHODS: Sixty-six
      patients with mild or moderate CRF and/or DM undergoing coronary angiography were
      prospectively double-blindedly randomized, to either 120 ml/day of 0.9% saline
      plus dopamine 2 microg/kg/min (Dopamine group) or saline alone (Control group)
      for 48 h. RESULTS: Thirty-three Dopamine-treated (30 diabetics and 6 with CRF)
      and 33 Control (28 diabetics and 5 with CRF) patients were compared. Plasma
      creatinine (Cr) level increased in the Control group from 100.6+/-5.2 before to
      112.3+/-8.0 micromol/liter within five days after angiography (p = 0.003), and in
      the Dopamine group from 100.3+/-5.4 before to 117.5+/-8.8 micromol/liter after
      angiography (p = 0.0001), respectively. There was no significant difference in
      the change of Cr level (deltaCr) between the two groups. However, in a subgroup
      of patients with peripheral vascular disease (PVD), deltaCr was -2.4+/-2.3 in the
      Control group and 30.0+/-12.0 micromol/liter in the Dopamine group (p = 0.01). No
      significant difference occurred in deltaCr between Control and Dopamine in
      subgroups of patients with preangiographic CRF or DM. CONCLUSIONS: Contrast
      material caused a small but significant increase in Cr blood level in high-risk
      patients. There is no advantage of dopamine over adequate hydration in patients
      with mild to moderate renal failure or DM undergoing coronary angiography.
      Dopamine should be avoided in patients with PVD exposed to contrast medium.

PMID- 10577558
TI  - Clinical practice guidelines in unstable angina improve clinical outcomes by
      assuring early intensive medical treatment.
AB  - OBJECTIVES: To determine the influence of clinical practice guidelines on
      treatment patterns and clinical outcomes in unstable angina and the effectiveness
      of guideline reminders on implementing practice guidelines, two groups of medium
      and high risk patients with unstable angina were compared. BACKGROUND: New
      guidelines have been published by the Agency for Health Care Policy and Research
      (AHCPR) for evaluating and managing patients with unstable angina. The impact of
      these guidelines to improve the quality of care has never been tested. METHODS:
      Group 1 included 338 consecutive medium or high risk patients admitted before
      publication of the AHCPR guidelines, and group 2 consisted of 181 consecutive
      similar risk patients admitted after institution of the AHCPR guideline reminders
      at this institution. Dissemination of clinical practice guidelines was ensured by
      a grand rounds lecture and by posting guideline reminders on all group 2
      patients' charts within 24 h of admission. RESULTS: The two groups were similar
      in terms of most baseline characteristics, including hypercholesterolemia,
      diabetes, hypertension, smoking history, baseline ST segment depression and
      previous coronary artery bypass graft surgery. Group 1 patients were older (68+/
      13 vs. 63+/-16 years, p = 0.001) and more frequently had a previous myocardial
      infarction (39% vs. 22%, p = 0.001). Group 2 patients more frequently required
      intravenous nitroglycerin to control the index episode of chest pain (43% vs.
      34%, p = 0.003). Group 2 patients more frequently received aspirin (96% vs. 88%,
      p = 0.009) during admission and underwent coronary angiography (71% vs. 58%, p =
      0.006). More importantly, group 2 patients received oral beta-blockers (p =
      0.008), aspirin and coronary angiography (p = 0.001) earlier than group 1
      patients and experienced recurrent angina (29% vs. 54%) and myocardial infarction
      or death less frequently (3% vs. 9%, p = 0.028). CONCLUSIONS: In unstable angina,
      clinical practice guidelines were associated with greater use of aspirin and
      coronary angiography and greater use and earlier administration of beta-blockers.
      Variation in drug use over time was also reduced. Objective improvement in
      clinical outcome was also noted. Thus, practice guidelines improve the quality of
      care of patients with unstable angina.

PMID- 10577559
TI  - Enhanced inflammatory response in patients with preinfarction unstable angina.
AB  - OBJECTIVES: We assessed the extent and the time course of the acute phase
      response following myocardial cell necrosis and its relationship with the
      presence of preinfarction unstable angina (UA). BACKGROUND: Elevated levels of
      acute phase proteins have been reported in patients with UA and in patients with
      acute myocardial infarction (MI). METHODS: C-Reactive Protein (CRP), serum
      amyloid A protein (SAA) and interleukin-6 (IL-6) were measured in 36 patients
      with MI admitted within 3 h from symptoms onset. All patients had normal levels
      of creatine kinase and of troponin T on admission, rising above diagnostic levels
      within 6 to 12 h. Blood samples for CRP, SAA and IL-6 measurements were taken on
      admission, at 6, 24, 48, 72 h and at discharge. RESULTS: Twenty of the 36
      patients studied presented an unheralded MI (Group 1); the remaining 16 patients
      had symptoms of unstable angina in the preceding 7 days (Group 2). Group 2
      patients have much higher levels of CRP and SAA on admission (median values 8.8
      vs. 3 mg/L and 28 vs. 3.4 mg/L, respectively, all p<0.001). Following the
      necrotic insult, despite similar infarct size and clinical signs of reperfusion,
      Group 2 patients had strikingly higher peaks of IL-6 (median values 85.2 vs. 19
      pg/ml, p<0.05), CRP (50 vs. 31.4 mg/L, p<0.05) and SAA (228 vs. 45 mg/L,
      p<0.001). CONCLUSIONS: Our data demonstrated that the acute phase response is
      greatly enhanced in patients with preinfarction UA compared with those presenting
      with an unheralded MI. The significant differences in acute phase response
      observed in these two clinical presentations of MI indicate a major difference in
      their underlying pathogenetic components.

PMID- 10577560
TI  - Cardiac troponin I levels and clinical outcomes in patients with acute coronary
      syndromes: the potential role of early percutaneous revascularization.
AB  - OBJECTIVES: To establish the role of early catheter-based coronary intervention
      among patients sustaining acute coronary syndromes (ACS) stratified according to
      admission plasma troponin I (Tn-I) levels. BACKGROUND: The impact of early
      revascularization strategy on the clinical outcomes in patients with ACS
      stratified by plasma Tn-I levels has not been established. METHODS: In-hospital
      complications and long-term outcomes were assessed in 1,321 consecutive patients
      with non-ST elevation ACS undergoing early (within 72 h) catheter-based coronary
      interventions. Patients were grouped according to admission Tn-I levels. Group I
      (n = 1,099) had no elevated plasma Tn-I (<0.15 ng/ml), Group II (n = 95) had Tn-I
      level between 0.15 to 0.45 ng/ml and Group III (n = 127) had Tn-I >0.45 ng/ml. In
      hospital composite cardiac events (death, Q-wave MI, urgent in-hospital
      revascularization) and 8 months clinical outcomes (death, MI, repeat
      revascularization or any cardiac event) were compared between the three groups.
      RESULTS: The rate of in-hospital composite cardiac events was 6.1% among patients
      with Tn-I >0.45 ng/ml, 1.0% in patients with Tn-I between 0.15-0.45 ng/ml and
      3.1% in patients without elevated admission Tn-I (p = 0.09 between groups). There
      was no difference in hospital mortality (p = 0.25). At eight months of follow-up,
      there was no difference in out-of-hospital death (3.5%, 3.8% and 1.8%, p = 0.17,
      respectively), MI (2.6%, 3.8% and 2.9%, p = 0.94) or target lesion
      revascularization (9.0%, 8.3% and 11.5%, p = 0.47), and cardiac event-free
      survival was also similar between groups (p = 0.66). By multivariate analysis, Tn
      I >0.45 ng/ml was independently associated with in-hospital composite cardiac
      events [odds ratio (OR) = 2.4, p = 0.04] but not with out-of-hospital clinical
      events up to eight months. CONCLUSIONS: In patients with ACS, early (within 72 h)
      catheter-based coronary intervention may attenuate the adverse prognostic impact
      of admission Tn-I elevation during eight months of follow-up despite a trend
      towards increased in-hospital composite cardiac events.

PMID- 10577562
TI  - Complete atrioventricular block complicating acute myocardial infarction in the
      thrombolytic era. SPRINT Study Group and the Israeli Thrombolytic Survey Group.
      Secondary Prevention Reinfarction Israeli Nifedipine Trial.
AB  - OBJECTIVES: We assessed the incidence, associated clinical parameters and
      prognostic significance of complete atrioventricular block (CAVB) complicating
      acute myocardial infarction (AMI) in the thrombolytic era and compared them to
      data from the prethrombolytic era. BACKGROUND: The introduction of new
      therapeutic modalities to treat AMI, aimed to enhance coronary reperfusion and to
      limit myocardial necrosis, was expected to decrease the incidence of CAVB and to
      improve prognosis. However, there are only limited data regarding the incidence
      and the prognosis of AMI patients with CAVB in the thrombolytic era. METHODS:
      Data from 3,300 patients from the Israeli Thrombolytic Surveys (prospective,
      nationwide surveys of consecutive patients with AMI in all 25 coronary-care units
      in Israel in 1992 and 1996) were analyzed and compared with data from 5,788
      patients included in the SPRINT (Secondary Prevention Reinfarction Israeli
      Nifedipine Trial) Registry (1981 to 1983). RESULTS: During the 1990s, the
      incidence of CAVB was 3.7% compared with 5.3% in the 1980s, p = 0.0007. In the
      1990s, mortality of patients with CAVB was significantly higher than in those
      without CAVB at 7 days (odds ratio [OR] = 4.05 95% CI [confidence interval] 2.34
      to 6.82, 30 days OR = 3.98 [95% CI 2.44 to 6.43] and one-year hazard ratio [HR] =
      2.36, [95% CI 1.68 to 3.30]) and similar in thrombolysis-treated and not-treated
      patients. Mortality of patients with CAVB has not changed significantly between
      the two periods; seven-day OR = 0.82 (95% CI 0.46 to 1.43); 30-day OR = 0.78 (95%
      CI 0.45 to 1.33) and one-year HR = 0.79 (95% CI 0.54 to 1.56), respectively, in
      the 1990s as compared to a decade earlier. CONCLUSIONS: The incidence of CAVB
      complicating AMI is lower in the thrombolytic era than in the prethrombolytic
      era. Mortality among patients with CAVB is still high and has not declined within
      the last decade. The AMI patients who develop CAVB in the thrombolytic era have
      significantly worse prognosis than do patients without CAVB.

PMID- 10577561
TI  - Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction:
      results of a multicenter, randomized, placebo-controlled trial: the Acute
      Myocardial Infarction STudy of ADenosine (AMISTAD) trial.
AB  - OBJECTIVES: The Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial
      was designed to test the hypothesis that adenosine as an adjunct to thrombolysis
      would reduce myocardial infarct size. BACKGROUND: Reperfusion therapy for acute
      myocardial infarction (MI) has been shown to reduce mortality, but reperfusion
      itself also may have deleterious effects. METHODS: The AMISTAD trial was a
      prospective, open-label trial of thrombolysis with randomization to adenosine or
      placebo in 236 patients within 6 h of infarction onset. The primary end point was
      infarct size as determined by Tc-99 m sestamibi single-photon emission computed
      tomography (SPECT) imaging 6+/-1 days after enrollment based on multivariable
      regression modeling to adjust for covariates. Secondary end points were
      myocardial salvage index and a composite of in-hospital clinical outcomes (death,
      reinfarction, shock, congestive heart failure or stroke). RESULTS: In all, 236
      patients were enrolled. Final infarct size was assessed in 197 (83%) patients.
      There was a 33% relative reduction in infarct size (p = 0.03) with adenosine.
      There was a 67% relative reduction in infarct size in patients with anterior
      infarction (15% in the adenosine group vs. 45.5% in the placebo group) but no
      reduction in patients with infarcts located elsewhere (11.5% for both groups).
      Patients randomized to adenosine tended to reach the composite clinical end point
      more often than those assigned to placebo (22% vs. 16%; odds ratio, 1.43; 95%
      confidence interval, 0.71 to 2.89). CONCLUSIONS: Many agents thought to attenuate
      reperfusion injury have been unsuccessful in clinical investigation. In this
      study, adenosine resulted in a significant reduction in infarct size. These data
      support the need for a large clinical outcome trial.

PMID- 10577563
TI  - Outcome of Hispanic patients treated with thrombolytic therapy for acute
      myocardial infarction: results from the GUSTO-I and III trials. Global
      Utilization of Streptokinase and TPA for Occluded Coronary Arteries.
AB  - OBJECTIVES: We sought to describe the differences in the process of care and
      clinical outcomes between Hispanics and non-Hispanics receiving thrombolytic
      therapy for myocardial infarction (MI). BACKGROUND: Hispanics are the fastest
      growing and second largest minority in the U.S. but most cardiovascular disease
      data on Hispanics has been derived from retrospective studies and vital
      statistics. Despite their higher cardiovascular risk-factor profile, better
      outcomes after MI have been reported in Hispanics. METHODS: We studied the
      baseline characteristics, resource use and outcomes of 734 Hispanics and 27,054
      non-Hispanics treated for MI in the GUSTO-I and -III trials. The primary end
      point of both trials was 30-day mortality. RESULTS: Hispanics were younger,
      shorter, lighter and more often diabetic and began thrombolysis 9 min later,
      compared with non-Hispanics. Measures of socioeconomic status (educational level,
      employment and health insurance) were lower among Hispanics. Fewer Hispanics than
      non-Hispanics underwent in-hospital angiography (70% vs. 74%, p = 0.013) or
      bypass surgery (11% vs. 13.5%, p = 0.04). Hispanics received more angiotensin
      converting enzyme (ACE) inhibitors and less calcium-channel blockers,
      prophylactic lidocaine and inotropic agents. Mortality at 30 days and at one year
      did not differ significantly between Hispanics and non-Hispanics (6.4% vs. 6.7%
      and 9.0% vs. 9.7%, respectively). We noted no interactions between thrombolytic
      strategy and Hispanic status on major outcomes (30-day death, stroke and major
      bleeding). CONCLUSIONS: The care of Hispanics with MI differed slightly from that
      of non-Hispanics. Nevertheless, these differences in care did not affect long
      term outcomes.

PMID- 10577564
TI  - Cytomegalovirus in the pathogenesis of atherosclerosis: the role of inflammation
      as reflected by elevated C-reactive protein levels.
AB  - OBJECTIVES: We hypothesized that cytomegalovirus (CMV) infection: 1) stimulates
      an inflammatory response, reflected by elevated C-reactive protein (CRP) levels,
      and 2) predisposes to coronary artery disease (CAD), in part, through CMV-induced
      inflammation. BACKGROUND: Although some studies show an association between CMV
      and atherosclerosis, others do not. We believed that CMV exerted an atherogenic
      effect by inducing inflammation, and the disparate results may derive partly from
      individual variability in the capacity to control CMV inflammatory activity.
      METHODS: Blood samples were tested for CMV seropositivity and CRP levels from 238
      individuals being evaluated for CAD by coronary angiography. RESULTS: An elevated
      CRP level (>0.5 mg/dl) was a significant CAD determinant even after adjustment
      for traditional CAD risk factors (odds ratio [OR] = 2.4; p = 0.02). Moreover, CMV
      seropositivity was significantly associated with increased CRP levels (p = 0.04
      after adjustment for CAD risk factors), suggesting that CMV could evoke a
      subclinical inflammatory response. However, considerable host variation existed
      in this response to CMV. When adjusted for CAD risk factors, the OR for CAD were
      1.3 in the subgroup with CMV seropositivity alone (p = 0.7), 2.3 in the subgroup
      with elevated CRP levels alone (p = 0.2), and 4.3 in the subgroup with combined
      CMV seropositivity and elevated CRP levels (p = 0.01). CONCLUSIONS: Our results
      suggest that 1) CMV elicits a subclinical inflammatory response, but only in
      certain individuals, and 2) individuals with an inflammatory response appear
      susceptible to the atherogenic effects of CMV, whereas those without appear
      resistant. These results may partly explain the disparate results of studies
      attempting to relate CMV to atherogenesis.

PMID- 10577565
TI  - Nocturnal ischemic events in patients with obstructive sleep apnea syndrome and
      ischemic heart disease: effects of continuous positive air pressure treatment.
AB  - OBJECTIVES: To investigate the occurrence of nocturnal ischemic events in
      patients with obstructive sleep apnea syndrome (OSAS) and ischemic heart disease
      (IHD). BACKGROUND: Although previous reports documented nocturnal cardiac
      ischemic events among OSAS patients, the exact association between obstructive
      apneas and ischemia is not yet clear. It is also not known what differentiates
      between patients showing nocturnal ischemia and those that do not. METHODS: Fifty
      one sleep apnea patients (age 61.3+/-8.3) with IHD participated in the study
      (after withdrawal of beta-adrenergic blocking agents and anti-anginotic
      treatment). All patients underwent whole-night polysomnography including
      ambulatory blood pressure recordings (30 min interval) and continuous Holter
      monitoring during sleep. A control group of 17 OSAS patients free from IHD were
      also similarly studied. Fifteen of the 51 patients were also recorded under
      continuous positive airway pressure (CPAP). RESULTS: Nocturnal ST segment
      depression occurred in 10 patients (a total of 15 events, 182 min), of whom six
      also had morning ischemia (06-08 am). Five additional patients had only morning
      ischemia. No ischemic events occurred in the control group. Age, sleep
      efficiency, oxygen desaturation, IHD severity and nocturnal-double product (DP)
      values were the main variables that significantly differentiated between patients
      who had ischemic events during sleep and those who did not. Nocturnal ischemia
      predominantly occurred during the rebreathing phase of the obstructive apneas,
      and it is characterized by increased heart rate (HR) and DP values. Treatment
      with continuous positive airway pressure significantly ameliorated the nocturnal
      ST depression time from 78 min to 33 min (p<0.001) as well as the maximal DP
      values (14,137+/-2,827 vs. 12,083+/-2,933, p<0.001). CONCLUSIONS: Exacerbation of
      ischemic events during sleep in OSAS may be explained by the combination of
      increased myocardial oxygen consumption as indicated by increased DP values and
      decreased oxygen supply due to oxygen desaturation with peak hemodynamic changes
      during the rebreathing phase of the obstructive apnea. Treatment with CPAP
      ameliorated the nocturnal ischemia.

PMID- 10577566
TI  - Relationship of extent of revascularization with angina at one year in the Bypass
      Angioplasty Revascularization Investigation (BARI).
AB  - OBJECTIVES: To determine the relative degree of revascularization obtained with
      bypass surgery versus angioplasty in a randomized trial of patients with
      multivessel disease requiring revascularization (Bypass Angioplasty
      Revascularization Investigation [BARI]), one-year catheterization was performed
      in 15% of patients. BACKGROUND: Complete revascularization has been correlated
      with improved outcome after coronary artery bypass grafting (CABG) but not with
      percutaneous transluminal coronary angioplasty (PTCA). Relative degrees of
      revascularization after PTCA and surgery have not been previously compared and
      correlated with symptoms. METHODS: Consecutive patients at four BARI centers
      consented to recatheterization one year after revascularization. Myocardial
      jeopardy index (MJI), the percentage of myocardium jeopardized by > or =50%
      stenoses, was compared and correlated with angina status. RESULTS: Angiography
      was completed in 270 of 362 consecutive patients (75%) after initial CABG (n =
      135) or PTCA (n = 135). Coronary artery bypass grafting patients had 3+/-0.9
      distal anastomoses and PTCA patients had 2.4+/-1.1 lesions attempted at initial
      revascularization. At one year, 20.5% of CABG patients had > or =1 totally
      occluded graft and 86.9% of vein graft, and 91.6% of internal mammary artery
      distal anastomotic sites had <50% stenosis. One year jeopardy index in surgery
      patients was 14.1+/-11%, 46.6+/-20.3% improved from baseline. Initial PTCA was
      successful in 86.9% of lesions and repeat revascularization was performed in
      48.4% of PTCA patients by one year. Myocardial jeopardy index one year after PTCA
      was 25.5+/-22.8%, an improvement of 33.8+/-26.1% (p<0.01 for greater improvement
      with CABG than PTCA). At one year, 29.6% of PTCA patients had angina versus 11.9%
      of surgery patients, p = 0.004. One-year myocardial jeopardy was predictive of
      angina (odds ratio 1.28 for the presence of angina per every 10% increment in
      myocardial jeopardy, p = 0.002). Randomization to PTCA rather than CABG also
      predicted angina (odds ratio 2.19, p = 0.03). CONCLUSIONS: In this one-year
      angiographic substudy of BARI, CABG provided more complete revascularization than
      PTCA, and CABG likewise improved angina to a greater extent than PTCA.

PMID- 10577567
TI  - Worse clinical outcome but similar graft patency in women versus men one year
      after coronary artery bypass graft surgery owing to an excess of exposed risk
      factors in women. CABADAS. Research Group of the Interuniversity Cardiology
      Institute of The Netherlands. Coronary Artery Bypass graft occlusion by Aspirin,
      Dipyridamole and Acenocoumarol/phenoprocoumon Study.
AB  - OBJECTIVES: This retrospective study sought to assess differences in graft
      patency and clinical outcome between women and men after coronary artery bypass
      graft surgery (CABG). BACKGROUND: A less favorable clinical outcome has been
      reported in women as compared with men. Its relation to graft patency has not
      been studied. METHODS: We analyzed one-year follow-up data of 912 patients (120
      women) who entered a randomized clinical drug trial. All patients received vein
      grafts; in 494 patients (56 women) internal mammary artery (IMA) grafts were also
      used. Graft patency was assessed by coronary angiography at one year. Primary
      clinical end points were myocardial infarction, revascularization procedures and
      death; secondary clinical end points included recurrent angina, heart failure and
      arrhythmias. RESULTS: Occlusion rates of vein grafts were 16.7% in women and
      12.4% in men (odds ratio [OR] 1.62, 95% confidence interval [CI] 0.88 to 3.00, p
      = 0.12); occlusion rates of IMA grafts were 3.4% and 5.7% in women and men,
      respectively (OR 0.56, 95% CI 0.08 to 3.96, p = 0.56). Primary clinical end
      points were observed in 16.7% of women and 9.2% of men (OR 1.97, 95% CI 1.10 to
      3.34, p = 0.022), and any clinical end point in 41.7% of women and 25.8% of men
      (OR 2.06, 95% CI 1.39 to 3.04, p = 0.0004). Myocardial infarction (15% vs. 7.6%,
      OR 2.15, 95% CI 1.24 to 3.75, p = 0.013) and recurrent angina (26.7% vs. 15.4%,
      OR 2.00, 95% CI 1.28 to 3.11, p = 0.004) occurred most frequently. Multivariate
      regression analysis did not identify gender as an independent risk factor for
      graft occlusion or the clinical end points. Graft occlusion was an independent
      predictor of the composite primary clinical end point (OR 2.75, 95% CI 1.59 to
      4.75, p = 0.0003) and each of the secondary clinical end points. The observed
      differences were due to an imbalance of risk factors at baseline and to surgical
      and graft characteristics. CONCLUSIONS: One-year occlusion rates of vein and IMA
      grafts were comparable in women and men. Clinical outcome was related to graft
      patency and was less favorable in women owing to their uneven distribution of
      risk factors among both groups.

PMID- 10577568
TI  - Prognostic value of pharmacological stress echocardiography in patients with
      known or suspected coronary artery disease: a prospective, large-scale,
      multicenter, head-to-head comparison between dipyridamole and dobutamine test.
      Echo-Persantine International Cooperative (EPIC) and Echo-Dobutamine
      International Cooperative (EDIC) Study Groups.
AB  - OBJECTIVES: The study compared the prognostic value of dipyridamole and
      dobutamine stress echocardiography in patients with known or suspected coronary
      artery disease. BACKGROUND: Extensive information is available on the relative
      diagnostic accuracy of the two tests assessed in a head-to-head fashion, whereas
      comparative data on their prognostic yield are largely preliminary to date.
      METHODS: Dipyridamole (up to 0.84 mg/kg over 10 min) atropine (up to 1 mg over 4
      min) (DIP) and dobutamine (up to 40 microg/kg/min)-atropine (1 mg over 4 min)
      (DOB) stress tests were performed in 460 patients with known or suspected
      coronary artery disease. Patients were followed up for 38+/-21 months. RESULTS:
      The DIP was negative in 253 and positive in 207 patients. The DOB was negative in
      242 and positive in 218 patients. During the follow-up, there were 80 cardiac
      events. For all cardiac events, the negative and positive predictive value were
      83% and 17% for DOB, 84% and 19% for DIP, respectively (p = NS). Considering only
      cardiac death, by univariate analysis Wall-Motion Score Index (WMSI) at DIP peak
      dose (chi-square 13.80, p<0.0002) was the strongest predictor, followed by WMSI
      DOB (chi2 = 8.02, p<0.004) and WMSI at rest (chi2 = 6.85, p<0.008). By stepwise
      analysis, WMSI at DIP peak dose was the most important predictor (RR [relative
      risk] 7.4, p<0.0001). CONCLUSIONS: In patients at low-to-moderate risk of cardiac
      events, pharmacological stress echocardiography with either dobutamine or
      dipyridamole allows effective and grossly comparable, risk stratification on the
      basis of the presence, severity and extension of the induced ischemia.

PMID- 10577569
TI  - Lack of association of a common polymorphism of the plasminogen activator
      inhibitor-1 gene with coronary artery disease and myocardial infarction.
AB  - OBJECTIVES: The study was done to assess whether the common polymorphic allele
      (4G) of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with
      coronary artery disease (CAD) or myocardial infarction (MI). BACKGROUND: Impaired
      fibrinolytic function has been associated with CAD and MI. Plasminogen activator
      inhibitor-1 plays a central role in intravascular thrombosis and thrombolysis;
      the common insertion/deletion polymorphism (4G/5G) of PAI-1 has been correlated
      with altered PAI-1 levels and proposed as a coronary risk factor. METHODS: Blood
      was drawn and DNA extracted from 1,353 consenting patients undergoing coronary
      angiography. The 4G and 5G alleles of PAI-1 were amplified using specific
      primers. Amplified products were visualized by staining with ethidium bromide
      after electrophoresis in 1.5% agarose. RESULTS: Patient age averaged 63.5 (SD
      11.7) years; 70% were men, 28% had a history of MI, 66% had severe CAD (>60%
      stenosis), and 23% had no CAD or MI. Overall, the frequency of the 4G allele was
      54.2%, and 78% of patients were 4G carriers. Genotypic distributions were: 4G/4G
      = 30.1%, 4G/5G = 47.9%, and 5G/5G = 21.8%. Neither carriage of 4G (CAD odds ratio
      [OR] = 1.08 [0.80 to 1.46], MI OR = 1.11 [0.83 to 1.49]) nor 4G/4G homozygosity
      (CAD OR = 1.07, MI OR = 0.98) was associated with CAD or MI. In multivariate
      analyses, risk factors associated with CAD were (in order): gender, age, smoking,
      diabetes, cholesterol, and hypertension; for MI, they were gender, smoking, and
      cholesterol. CONCLUSIONS: A common PAI-1 polymorphism (4G) was not importantly
      associated with angiographic CAD or history of MI in a Caucasian population.
      Modest risk (i.e., OR <1.5), especially for MI, or risk in association with other
      factors, cannot be excluded.

PMID- 10577570
TI  - Smokeless tobacco as a possible risk factor for myocardial infarction: a
      population-based study in middle-aged men.
AB  - OBJECTIVES: To explore whether the use of snuff affects the risk of myocardial
      infarction (MI). BACKGROUND: Snuff and other forms of smokeless tobacco are
      widely used in some populations. Possible health hazards associated with the use
      of smokeless tobacco remain controversial. METHODS: In a population-based study
      within the framework of the Northern Sweden center of the World Health
      Organization Multinational Monitoring of Trend and Determinants in Cardiovascular
      Disease (WHO MONICA) Project, tobacco habits were compared in 25- to 64-year-old
      men with first-time fatal or nonfatal MI and referent subjects matched for age
      and place of living (687 cases, 687 referents). RESULTS: The unadjusted odds
      ratio (OR) for MI in regular cigarette smokers as compared with men who never
      used tobacco was 3.65 (95% confidence interval [CI] 2.67 to 4.99). When
      nonsmoking regular snuff dippers were compared with never-users of tobacco, the
      unadjusted OR was 0.96 (0.65 to 1.41). After adjustment for multiple
      cardiovascular risk factors, the OR was 3.53 (95% CI 2.48 to 5.03) for regular
      smoking and 0.58 (95% CI 0.35 to 0.94) for regular snuff dipping. Restricting the
      analyses to fatal cases of myocardial (including sudden death) showed a tendency
      towards increased risk among snuff dippers 1.50 (95% CI 0.45 to 5.03).
      CONCLUSIONS: The risk of MI is not increased in snuff dippers. Nicotine is
      probably not an important contributor to ischemic heart disease in smokers. A
      possible small or modest detrimental effect of snuff dipping on the risk for
      sudden death could not be excluded in this study due to a limited number of fatal
      cases.

PMID- 10577571
TI  - Snuff, nicotine and cardiovascular disease: implications for tobacco control.

PMID- 10577572
TI  - Hemodynamic and neuroendocrine effects for candoxatril and frusemide in mild
      stable chronic heart failure.
AB  - OBJECTIVES: The study aimed to assess the hemodynamic and neuroendocrine effects
      of candoxatril and frusemide compared with placebo in patients with mild chronic
      heart failure. BACKGROUND: Candoxatril is an atriopeptidase inhibitor. It
      increases circulating levels of atrial natriuretic peptide leading to natriuresis
      and diuresis, which alleviate the symptoms of a failing heart. METHODS: This was
      a multicenter, randomized, double-blind study. Forty-seven patients with mild
      stable chronic heart failure received candoxatril 400 mg/day, frusemide 40 mg/day
      or placebo for up to six weeks. Cardiac indices were determined at rest and
      during exercise, and blood samples were taken for laboratory analysis.
      Assessments were performed at baseline (day 0) and after six weeks (day 42).
      RESULTS: In comparison with placebo, both drugs significantly reduced mean
      pulmonary capillary wedge pressure following the first dose administration. Only
      candoxatril significantly reduced pulmonary capillary wedge pressure during
      exercise on day 0, while both drugs significantly reduced this parameter on day
      42. Changes in the remaining hemodynamic parameters were comparable for both
      drugs relative to placebo. Frusemide significantly increased mean plasma renin
      activity (days 0 and 42), and the mean aldosterone concentration (day 42) in
      comparison with placebo, whereas candoxatril caused no significant changes in any
      of the hormonal parameters assessed. CONCLUSIONS: These results show that
      candoxatril, 400 mg/day, has a similar hemodynamic profile to frusemide, 40
      mg/day, but it does not induce adverse neuroendocrine effects. Candoxatril
      therefore appears to offer a clinically significant advantage over frusemide,
      providing an alternative therapeutic approach to the treatment of patients with
      mild stable chronic heart failure.

PMID- 10577573
TI  - Pulmonary hypertension and exercise intolerance in patients with heart failure.
AB  - OBJECTIVES: This study was undertaken to investigate the relationship between
      pulmonary hypertension and exercise performance in patients with heart failure.
      BACKGROUND: The exercise capacity of patients with heart failure is frequently
      reduced. Pulmonary hypertension may contribute to this exercise intolerance by
      impairing blood flow through the pulmonary circulation. METHOD: Three hundred
      twenty patients with heart failure underwent upright treadmill exercise testing
      with hemodynamic monitoring. The incidence of pulmonary hypertension and the
      relationship between pulmonary vascular resistance (PVR) and exercise cardiac
      output and minute oxygen consumption (VO2) were examined. RESULTS: Pulmonary
      vascular resistance was normal (<1.5 Wood Units; Group 1) in 28% of the patients,
      mildly elevated (1.5 to 2.49 Wood Units; Group 2) in 36%, moderately elevated
      (2.5 to 3.49 Wood Units; Group 3) in 17% and severely elevated (>3.5 Wood Units;
      Group 4) in 19%. Increasing PVR was associated with significantly lower peak
      exercise VO2 (Group 1: 13.9+/-3.7; 2:13.7+/-3.4; 3: 11.8+/-2.4; 4: 11.5+/-2.6
      L/min, p<0.01 Groups 3 and 4 vs. 1) and lower peak exercise cardiac output (Group
      1: 10.0+/-2.8, 2:9.0+/-3.0; 3: 7.4+/-2.1; 4: 6.3+/-2.0 L/min, p<0.05, Groups 2, 3
      and 4 vs. 1). The pulmonary wedge pressure decreased during exercise, consistent
      with impaired left ventricular filling, in 36% of patients with severe pulmonary
      hypertension (Group 4) versus only 13% of patients with normal PVR (p<0.01).
      CONCLUSIONS: Pulmonary vascular resistance is frequently increased in heart
      failure and is associated with a reduced cardiac output response to exercise,
      suggesting that pulmonary hypertension impairs exercise performance in heart
      failure.

PMID- 10577574
TI  - Slowed glycogen utilization enhances exercise endurance in patients with heart
      failure.
AB  - OBJECTIVES: The objective of the study was to investigate the impact of
      alteration of glycogen stores and metabolism on exercise performance in patients
      with heart failure. BACKGROUND: In normal subjects, muscle glycogen depletion
      results in increased exertional fatigue and reduced endurance. Skeletal muscle
      biopsies have revealed reduced glycogen content in patients with congestive heart
      failure (CHF). Whether glycogen depletion contributes to reduced endurance and
      abnormal ventilation in these patients is unknown. METHODS: Bicycle exercise
      tests with measurement of respiratory gases were performed following dietary
      manipulations to induce glycogen depletion (60% protein, 40% fat) and slow
      glycogen utilization (60% carbohydrate, 30% fat, 10% protein) in 13 patients with
      CHF (left ventricular ejection fraction 22+/-6%; age 48+/-9 years) and 7 control
      subjects (age 45+/-5 years). Maximal exercise, exercise at 75% of peak workload
      until exhaustion and 1-min cycles of supramaximal exercise at 133% of peak were
      performed on three occasions over a two-week period. RESULTS: Significant changes
      in resting respiratory quotients (RQs) in normal (Baseline: 0.78+/-0.03;
      Depleted: 0.69+/-0.05) and CHF subjects (Baseline: 0.84+/-0.05; Depleted: 0.72+/
      0.05) were observed (both p<0.05). Peak Vo2 (oxygen consumption) in both groups
      was unchanged. The ventilatory response to exercise was analyzed by correlating
      CO2 production (V(CO2)) to minute ventilation (VE) in each test. The slopes of
      these correlations were not affected in either group. With glycogen depletion,
      exercise endurance was reduced from 17 to 6.1 min (57+/-19%) in normal subjects
      versus a reduction of 9.4 to 8.1 min (11+/-19%) in patients (p<0.05). With slowed
      glycogen use, CHF patients increased exercise endurance from 9.4 to 16.5 min
      (65%) versus 17 to 20.6 min (18%) in normal subjects (p<0.05). CONCLUSIONS:
      Glycogen depletion minimally affects maximal exercise performance, endurance or
      ventilation in CHF patients, whereas slowed glycogen utilization markedly
      enhances exercise endurance. Therapeutic interventions that increase or slow use
      of glycogen stores may have clinical benefit.

PMID- 10577575
TI  - A cohort study of childhood hypertrophic cardiomyopathy: improved survival
      following high-dose beta-adrenoceptor antagonist treatment.
AB  - OBJECTIVES: The study analyzed factors, including treatment, affecting disease
      related death in patients with hypertrophic cardiomyopathy (HCM) presenting in
      childhood. BACKGROUND: Previous smaller studies suggest that mortality is higher
      in patients with HCM presenting in childhood compared with presentation in
      adulthood, but these studies have all originated from selected patient
      populations in tertiary referral centers, and reported no significant protection
      by treatment. METHODS: Retrospective comparisons of mortality were done in total
      cohort of patients presenting to three regional centers of pediatric cardiology.
      There were 66 patients (25 with Noonan's syndrome) with HCM presenting at age <19
      years; mean follow-up was 12.0 years. RESULTS: Among risk factors for death were
      congestive heart failure (p = 0.008), large electrocardiogram voltages (Sokolow
      Lyon index p = 0.0003), and degree of septal (p = 0.004) and left ventricular (p
      = 0.028) hypertrophy expressed as percent of 95th centile value. The only
      treatment that significantly reduced the risk of death on multifactorial analysis
      of variance was high-dose beta-adrenoceptor antagonist therapy (propranolol 5 to
      23 mg/kg/day or equivalent; p = 0.0001). Nineteen out of 40 patients managed
      conventionally (no treatment, 0.8 to 4 mg/kg of propranolol, or verapamil) died,
      median survival 15.8 years, with no deaths among 26 patients on high-dose beta
      blockers (p = 0.0004); survival proportions at 10 years were 0.65 (95% confidence
      interval 0.49-0.80) and 1.0, respectively (p = 0.0015). Survival time analysis
      shows better survival in the high-dose beta-blocker group compared with the "no
      specific therapy" group (p = 0.0009) and with the conventional-dose beta-blocker
      group (p = 0.002). Hazard ratio analysis suggests that high-dose beta-blocker
      therapy produces a 5-10-fold reduction in the risk of disease-related death.
      CONCLUSIONS: High-dose beta-blocker therapy improves survival in childhood HCM.

PMID- 10577576
TI  - Transthoracic echocardiography using second harmonic imaging: diagnostic
      alternative to transesophageal echocardiography for the detection of atrial right
      to left shunt in patients with cerebral embolic events.
AB  - OBJECTIVES: We sought to evaluate whether transthoracic contrast echocardiography
      using second harmonic imaging (SHI) is a diagnostic alternative to
      transesophageal contrast echocardiography (TEE) for the detection of atrial right
      to left shunt. BACKGROUND: Paradoxic embolism is considered to be the major cause
      of cerebral ischemic events in young patients. Contrast echocardiography using
      TEE has proven to be superior to transthoracic echocardiography (TTE) for the
      detection of atrial shunting, SHI is a new imaging modality that enhances the
      visualization of echocardiographic contrast agents. METHODS: We evaluated 111
      patients with an ischemic cerebral embolic event for the presence of atrial right
      to left shunt using an intravenous (IV) contrast agent in combination with three
      different echocardiographic imaging modalities: 1) TTE using fundamental imaging
      (FI); 2) TTE using SHI; and 3) TEE. The severity of atrial shunting and the
      duration of contrast visibility within the left heart chambers were evaluated for
      each imaging modality. Image quality was assessed separately for each modality by
      semiquantitative scoring (0 = poor to 3 = excellent). Presence of atrial right to
      left shunt was defined as detection of contrast bubbles in the left atrium within
      the first three cardiac cycles after contrast appearance in the right atrium
      either spontaneously or after the Valsalva maneuver. RESULTS: A total of 57
      patients showed evidence of atrial right to left shunt with either imaging
      modality. Fifty-one studies were positive with TEE, 52 studies were positive with
      SHI, and 32 were positive with FI (p<0.001 for FI vs. SHI and TEE). The severity
      of contrast passage was significantly larger using SHI (61.6+/-80.2 bubbles)
      compared to FI (53.7+/-69.6 bubbles; p<0.005 vs. SHI) but was not different
      compared to TEE (43.9+/-54.3 bubbles; p = NS vs. SHI). The duration of contrast
      visibility was significantly longer for SHI (17.4+/-12.4 s) compared to FI
      (13.1+/-9.7 s; p<0.001) and TEE (11.9+/-9.6 s; p<0.02). Mean image quality
      improved significantly from FI (1.5+/-0.8) to SHI (2.0+/-0.8; p<0.001 vs. FI) and
      TEE (2.5+/-0.7; p<0.001 vs. SHI). CONCLUSIONS: In combination with IV contrast
      injections, TEE and SHI have a comparable yield for the detection of atrial right
      to left shunt. Both modalities may miss patients with atrial shunting. In young
      patients with an unexplained cerebrovascular event and no clinical evidence of
      cardiac disease, a positive SHI study may obviate the need to perform a TEE study
      to search for cardiac sources of emboli.

PMID- 10577577
TI  - Epidemiological approach to quality assessment in echocardiographic diagnosis.
AB  - OBJECTIVES: This study sought to determine whether statistical analysis of a
      computerized clinical diagnostic database can be used as a tool for quality
      assessment by determining the contribution of reader bias to variance in
      diagnostic output. BACKGROUND: In industry, measurement of product uniformity is
      a key component of quality assessment. In echocardiography, quality assessment
      has focused on review of small numbers of cases, or prospective determination of
      reader variability in selected and relatively small subsets. However, diagnostic
      biases in clinical practice might be discerned utilizing large computerized
      databases to determine interreader differences in diagnostic prevalence and, with
      use of appropriate statistical methods, to determine the association of reader
      selection with diagnostic prevalence independently of other covariates. METHODS:
      We analyzed 6,026 echocardiograms in a computerized database, read by one of
      three level 3 (American Society of Echocardiography) readers, for differences in
      frequency among four coded echocardiographic diagnoses: mitral valve prolapse,
      valvular vegetations, left ventricular (LV) thrombus, and LV regional wall-motion
      abnormality. RESULTS: Significant differences (up to fourfold) were found between
      readers, which persisted after statistical adjustment for those population
      characteristics, which differed slightly between readers. The low population
      prevalence of these conditions would have made it unlikely that these interreader
      differences could be detected by nonstatistical methods. Additionally, chamber
      dimensions differed between readers and were not normally distributed.
      CONCLUSIONS: Statistically based quality assessment analysis of computerized
      clinical databases facilitates ongoing monitoring of interreader bias despite low
      diagnostic prevalence, and targets opportunities for subsequent quality
      improvement.

PMID- 10577578
TI  - Assessing the quality of medical diagnosis.

PMID- 10577579
TI  - Gated blood-pool SPECT evaluation of changes after radiofrequency catheter
      ablation of accessory pathways: evidence for persistent ventricular preexcitation
      despite successful therapy.
AB  - OBJECTIVES: This study was designed to prospectively evaluate the effects of
      radiofrequency ablation in Wolff-Parkinson-White (WPW) syndrome by scintigraphic
      analysis. BACKGROUND: The functional changes triggered by radiofrequency current
      ablation of atrioventricular accessory pathways are not fully known. METHODS:
      Forty-four patients with WPW syndrome were consecutively investigated before and
      48 h after radiofrequency therapy. Fourteen patients had right sided
      atrioventricular pathways and 30 patients had left sided bypass-tracts. Planar
      gated imaging and gated blood pool tomography were performed in all of these
      patients. RESULTS: A significant increase in the left ventricular ejection
      fraction (LVEF) was demonstrated in patients with left preexcitation (62.2+/-7.9%
      before ablation against 64.4+/-6.3% after ablation, p = 0.02) but not for those
      with right sided anomalous pathway. Phase analysis only gave significant
      differences following ablation of right sided pathways (left-to-right phase
      difference = 14.4+/-13.8 degrees before ablation versus 7.5+/-7.2 degrees after
      ablation, p<0.05). Early abnormal ventricular contraction persisted in 12
      patients with right accessory pathways and in 8 patients with left accessory
      pathways despite the complete disappearance of any abnormal conduction as proven
      electrophysiologically. CONCLUSIONS: Following catheter ablation of
      atrioventricular accessory pathways: 1) an improvement of left ventricular
      function may be seen, particularly in patients with left sided accessory
      pathways, and 2) unexpected persistence of local ventricular preexcitation at the
      site of successful ablation may be detected.

PMID- 10577580
TI  - Serologic evaluation of patients with primary and recurrent ocular toxoplasmosis
      for evidence of recent infection.
AB  - PURPOSE: To identify the frequency of recently acquired vs chronic systemic
      Toxoplasma gondii infections in patients with ocular toxoplasmosis. METHODS:
      Serum samples from 22 patients with primary ocular toxoplasmosis (not from scars)
      and 42 patients with recurrent ocular toxoplasmosis were tested for the presence
      of anti-T. gondii IgM, IgG, and IgA antibodies and compared with samples from 24
      patients with other causes of uveitis. Intraocular production of anti-T. gondii
      IgG and IgA, and the presence of T. gondii DNA was determined in patient s and
      control subjects from whom ocular fluid was available. RESULTS: Serologic
      evidence of recently acquired infection was found for 11 (50%) of 22 patients
      with primary ocular toxoplasmosis and for one (2%) of 42 with recurrent ocular
      toxoplasmosis. In the uveitis control group, anti-T. gondii IgM antibodies could
      be detected in two (8%) of 24 patients, but anti-T. gondii IgA antibodies were
      not detectable. Patients with primary ocular toxoplasmosis and serologic markers
      of recently acquired systemic infection were significantly older than those with
      chronic infection (P = .008). Intraocular production of anti-T. gondii IgG was
      more frequently noted in patients with recurrent than primary ocular
      toxoplasmosis (81% vs 41%; P < .001), but intraocular T. gondii DNA was more
      frequently found in patients with primary ocular toxoplasmosis than in those with
      recurrent ocular toxoplasmosis (37% vs 4%; P < .01). CONCLUSIONS: Primary ocular
      toxoplasmosis can be seen in either recently acquired or chronic T. gondii
      infection. Patients with ocular disease and recently acquired infection were
      older and more likely to have T. gondii DNA in intraocular fluids.

PMID- 10577581
TI  - Intraocular inflammatory reactions without focal necrotizing retinochoroiditis in
      patients with acquired systemic toxoplasmosis.
AB  - PURPOSE: To describe the occurrence of intraocular inflammatory reactions as the
      sole ophthalmic manifestation of acquired systemic toxoplasmosis. METHODS: Review
      of medical records for 10 patients with uveitis and evidence of recent Toxoplasma
      gondii infection. RESULTS: Patient ages ranged from 3 to 51 years. Ocular
      symptoms were present in each of eight adult patients. Inflammation was
      unilateral in nine patients; it manifested as vitreous humor cells and haze (10
      patients), anterior chamber cells (seven patients), and retinal vasculitis (seven
      patients). No patient had necrotizing retinochoroiditis upon initial examination.
      Inflammation resolved in each of nine patients who had follow-up examinations.
      Foci of retinitis or inactive retinochoroidal scars were seen in four of these
      nine patients during follow-up examinations, at intervals of 2.0 weeks to 2.5
      years after initial examination. CONCLUSIONS: Retinal vasculitis and associated
      inflammatory reactions may be the only ophthalmic disorder during the early
      stages of a newly acquired T. gondii infection. Later development of retinitis or
      scars consistent with toxoplasmic retinochoroiditis in the same eyes suggests
      that the initial, isolated inflammation may be caused by the presence of
      parasites in retinal tissue. These cases may have implications for understanding
      the original source of retinal infection in patients who have recurrent
      toxoplasmic retinochoroiditis and for treatment of newly acquired T gondii
      infection.

PMID- 10577582
TI  - Recurrent ocular disease in postnatally acquired toxoplasmosis.
AB  - PURPOSE: Although recurrences are typical of congenital toxoplasmosis, the long
      term ocular manifestations in postnatally acquired toxoplasmosis have never been
      systematically studied. We report on the ocular manifestations complicating the
      chronic phase of postnatally acquired toxoplasmosis. METHODS: Review of the
      clinical data of 14 patients who presented with active ocular toxoplasmosis not
      associated with scars and who had serologic characteristics of recently acquired
      systemic toxoplasmosis. RESULTS: Mean follow-up was 4.6 years. Recurrent ocular
      disease developed in eight (57%) of 14 cases. The number of patients with
      recurrences increased with the follow-up time: four (29%) of 14 during the first
      year of follow-up; eight (57%) of 14 during the second year; and eight of nine
      during the third follow-up year. No risk factors for the development of
      recurrences were identified. Satellite lesions developed in five of eight
      patients with recurrences, whereas lesions not adjacent to old scars, located in
      areas of previously unaffected retina, developed in three patients. CONCLUSIONS:
      In postnatally acquired toxoplasmosis, frequent recurrences of ocular disease can
      be seen during the chronic phase of infection.

PMID- 10577583
TI  - Cost considerations of medical therapy for glaucoma.
AB  - PURPOSE: To determine the calculated daily patient cost (cost minimization) of
      medical glaucoma therapy. METHODS: The actual volume of various glaucoma
      medications was determined for all commercially available sizes of the tested
      products. The drops per ml on the basis of the actual volume and the daily costs
      of the dosage schedules recommended by the manufacturers were compared. The cost
      of each bottle of medication was determined from the average wholesale price in
      the United States. RESULTS: The generic timolol products dosed twice daily and
      the once-daily gel-forming solutions (range, $0.30 to $0.46/day) were similar on
      a cost-per-day basis compared with the brand name metipranolol (Optipranolol;
      Bausch & Lomb Pharmaceuticals, Tampa, Florida, at $0.43/day) and timolol
      (Timoptic; Merck, West Point, Pennsylvania, at $0.46/day and Timoptic XE at
      $0.38/ day). Betaxolol (Betoptic S; Alcon Laboratories, Fort Worth, Texas, at
      $0.65/day), carteolol (Ocupress; CibaVision, Duluth, Georgia, at $0.57/day),
      levobunolol ($0.61/day), and brand name levobunolol (Betagan; Allergan, Irvine,
      California, at $0.81/day) all were dosed twice daily and were more costly on a
      per-day basis. The topical carbonic anhydrase inhibitors brinzolamide (Azopt;
      Alcon, at $0.96/day) and dorzolamide (Trusopt; Merck, at $1.02/day) were dosed
      three times daily and were similar on a cost-per-day basis. The combination
      product Cosopt (timolol 0.5% + dorzolamide 2.0%, Merck, at $1.12/day) was less
      costly than separate bottles of a topical carbonic anhydrase inhibitor (three
      times daily dosing) and a beta-blocker ($1.26 to $1.83/day), often even if the
      topical carbonic anhydrase inhibitor was dosed two times daily ($0.94 to $1.49).
      The selective alpha2-agonist brimonidine (Alphagan; Allergan, at $0.90/day) twice
      daily and the prostaglandin analog latanoprost (Xalatan; Pharmacia & Upjohn,
      Kalamazoo, Michigan, at $0.92/day) once daily were similarly priced. CONCLUSIONS:
      All generic timolol, Optipranolol, Timoptic, and Timoptic XE ranged between $0.30
      and $0.46 per day. Betaxolol, Ocupress, generic levobunolol, and Betagan were
      more costly, ranging between $0.57 and $0.81 per day. Cosopt ($1.12/day) was less
      costly than separate bottles of a topical beta-blocker and a topical carbonic
      anhydrase inhibitor dosed three times daily ($1.26 to $1.83/day) and often twice
      daily ($0.94 to $1.49). Alphagan and Xalatan were similarly priced ($0.90/day and
      $0.92/day, respectively). This study is based on a best-case scenario for all
      medicines and does not account for wasted doses, the frequency of refills, or a
      medication's success or failure rate. New adjunctive glaucoma regimens exhibit
      similar costs per day compared with more traditional regimens.

PMID- 10577584
TI  - Long-term follow-up of trabeculectomy without antimetabolites in patients with
      uveitis.
AB  - PURPOSE: To determine the long-term success rate after trabeculectomy without
      antimetabolites in patients with uveitis. METHODS: Review of data from all
      patients with uveitis who underwent trabeculectomy for uncontrolled intraocular
      pressure secondary to intraocular inflammation between May 1990 and December
      1994. Results were compared with those from a group of patients with primary open
      angle glaucoma matched for sex and surgeon. RESULTS: The uveitis group consisted
      of 32 eyes (20 patients). Maximum control of intraocular inflammation was
      achieved for a minimum of 2 months before surgery. Mean (+/-SD) age was 40.0 +/-
      12.5 years (range, 14 to 67 years), with a median (+/-SE) follow-up of 53.0 +/-
      1.8 months (range, 33 to 84 months). The primary open-angle glaucoma group
      consisted of 33 eyes (23 patients), with a mean age of 62.0 +/- 13.7 years
      (range, 26 to 81 years) and a median follow-up of 63.0 +/- 12.0 months (range, 34
      to 299 months). The overall 5-year success rate (intraocular pressure < or =21 mm
      Hg with or without topical medication) for the uveitis group was 78% compared
      with 82% for the primary open-angle glaucoma group (P = .7). The absolute 5-year
      success rate (intraocular pressure < or =21 mm Hg with no medication) for the
      uveitis group was 53% compared with 67% for the primary open-angle glaucoma group
      (P = .87). CONCLUSIONS: In the absence of other risk factors, such as Afro
      Caribbean race and previous intraocular surgery, and with adequate preoperative
      control of inflammation, trabeculectomy without antimetabolites may be considered
      the primary surgical procedure for increased intraocular pressure in patients
      with uveitis.

PMID- 10577585
TI  - High intraocular pressure and survival: the Framingham Studies.
AB  - PURPOSE: To examine whether high intraocular pressure (greater than or equal to
      25 mm Hg) or a history of treatment for glaucoma is associated with decreased
      survival and, if so, how such ocular markers might be explained. METHODS: Eye
      examinations, including applanation tonometry, were conducted on members of the
      Framingham Eye Study cohort from February 1, 1973, to February 1, 1975.
      Participants who reported a history of treatment for glaucoma were identified.
      Survival data, including information on the date of death, were available from
      the time of the Eye Study through March 31, 1990. RESULTS: Of the 1,764 persons
      under the age of 70 years at the baseline eye examination, 1,421 persons had low
      intraocular pressure (< or =20 mm Hg), 264 persons had medium intraocular
      pressure levels (20 to 24 mm Hg), and 79 persons had high intraocular pressure (>
      or =25 mm Hg) or history of glaucoma treatment. During the follow-up period, 29%,
      30%, and 47% died in the groups with low, medium, and high intraocular pressure
      (or history of glaucoma treatment), respectively. In an age-and-sex adjusted Cox
      proportional hazards analysis, the death rate ratio for the group with medium
      intraocular pressure relative to the group with low intraocular pressure was
      1.04. The corresponding death rate ratio for the group with high intraocular
      pressure was 1.56 with a 95% confidence interval of 1.11 to 2.19 (P < .001).
      After adjustment for age, sex, hypertension, diabetes, cigarette smoking, and
      body mass index, a positive relationship remained, but at a borderline level of
      significance (P = .075). CONCLUSIONS: High intraocular pressure or the presence
      of glaucoma is a marker for decreased life expectancy in the Framingham Eye Study
      cohort. The relationship is present even after adjustment for risk factors known
      to be associated with higher mortality such as age, sex, hypertension, diabetes,
      cigarette smoking, and body mass index. Special attention to the general health
      status of patients with high intraocular pressure or glaucoma seems warranted.

PMID- 10577586
TI  - The epidemiology of cataract in Australia.
AB  - PURPOSE: To describe the prevalence and risk factors for cataract in an
      Australian population aged 40 years and older. METHODS: Participants were
      recruited by a household census and stratified, random cluster sampling to
      represent residents of Victoria, Australia, aged 40 years and older. The
      following information was collected: initial visual acuity and best-corrected
      visual acuity, demographic details, health history, dietary intake of
      antioxidants, lifetime ocular ultraviolet B exposure, and clinical eye
      examination, including lens photography. Cortical opacities were measured in
      sixteenths. Cortical cataract was defined as opacity greater than or equal to
      4/16 of pupil circumference. Nuclear opacities were graded according to the
      Wilmer cataract grading scheme, and cataract was defined as greater than or equal
      to nuclear standard 2.0 of four standards. The height and width of any posterior
      subcapsular opacity was measured and recorded. Posterior subcapsular cataract was
      defined as posterior subcapsular opacity greater than or equal to 1 mm2. The
      worse eye was selected for analysis. Backward stepwise logistic regression was
      used to quantify independent risk factors for cataract. RESULTS: A total of 3,271
      (83% of eligible) of the urban residents, 403 (90% of eligible) nursing home
      residents, and 1,473 (92% of eligible) rural residents participated. The urban
      residents ranged in age from 40 to 98 years (mean, 59 years), and 1,511 (46%)
      were men. The nursing home residents ranged in age from 46 to 101 years (mean, 82
      years), and 85 (21%) were men. The rural residents ranged in age from 40 to 103
      years (mean, 60 years), and 701 (47.5%) were men. The overall weighted rate of
      cortical cataract was 11.3% (95% confidence limits, 9.68%, 13.0%) excluding
      cataract surgery and 12.1% (95% confidence limits, 10.5%, 13.8%) including
      cataract surgery. The risk factors for cortical cataract that remained in the
      multivariate logistic regression model were age, female gender, diabetes duration
      greater than 5 years, gout duration greater than 10 years, arthritis diagnosis,
      myopia, use of oral beta-blockers, and increased average annual ocular
      ultraviolet B exposure. Overall, 12.6% (95% confidence limits, 9.61%, 15.7%) of
      Victorians aged 40 years and older had nuclear cataract including previous
      cataract surgery, and 11.6% (95% confidence limits, 8.61%, 14.7%) had nuclear
      cataract excluding previous cataract surgery. In the urban and rural cohorts,
      age, female gender, rural residence, brown irides, diabetes diagnosed 5 or more
      years earlier, myopia, age-related maculopathy, having smoked for greater than 30
      years, and an interaction between ocular ultraviolet B exposure and vitamin E
      were all risk factors for nuclear cataract. The rate of posterior subcapsular
      cataract excluding previous cataract surgery was 4.08% (95% confidence limits,
      3.01%, 5.14%), whereas the overall rate of posterior subcapsular cataract
      including previous cataract surgery was 4.93% (95% confidence limits, 3.68%,
      6.17%) . The independent risk factors for posterior subcapsular cataract in the
      urban and rural cohorts that remained were age in years, rural location, use of
      thiazide diuretics, vitamin E intake, and myopia. CONCLUSIONS: The expected
      increase in the prevalence of cataract with the aging of the population
      highlights the need to plan appropriate medical services and public health
      interventions for primary and secondary prevention. Many of the identified risk
      factors for cataract in the population have the potential for being modified
      through public health interventions.

PMID- 10577587
TI  - Ultrasound biomicroscopy for detection of breaks and detachment of the ciliary
      epithelium.
AB  - PURPOSE: To elucidate details of the pathologic changes in the ciliary epithelium
      associated with atopic dermatitis and blunt ocular trauma. METHODS: We examined
      prospectively 52 eyes of 42 patients with detachment of the nonpigmented
      epithelium of the ciliary body associated with atopic dermatitis and blunt ocular
      trauma. All the eyes underwent ultrasound biomicroscopic examination as an
      adjunct to binocular indirect ophthalmoscopy with scleral depression and slit
      lamp biomicroscopy. RESULTS: Of the 52 eyes examined, high-resolution ultrasound
      biomicroscopy and conventional diagnostic methods (that is, binocular indirect
      ophthalmoscopy with scleral depression and slit-lamp biomicroscopy) disclosed
      breaks at the anterior vitreous base border in 40 eyes, at the pars plicata of
      the ciliary body in 27 eyes, and at the white midline (that is, the line located
      in the mid pars plana anterior to the anterior vitreous base border) in four
      eyes. In 40 eyes the breaks at the anterior vitreous base border could be
      detected with conventional methods but in only 28 eyes could they be diagnosed
      with ultrasound biomicroscopy. Conversely, in 27 eyes the breaks of the pars
      plicata could be observed with ultrasound biomicroscopy but in 25 eyes they were
      detected with conventional methods. In 21 eyes with breaks only at the anterior
      vitreous base border, the detachment of the nonpigmented ciliary epithelium was
      limited posterior to the white midline. In all 27 eyes with the nonpigmented
      ciliary epithelial detachment anterior to the white midline, the breaks of the
      pars plicata were identified by ultrasound biomicroscopy. CONCLUSION: Because of
      the minimum deformation of the globe during examination, ultrasound biomicroscopy
      contributed to the diagnosis of detailed structural change in the ciliary body
      associated with atopic dermatitis and blunt ocular trauma in relation to the
      white midline. In our sample of patients, the white midline may act as a barrier
      against ciliary nonpigmented epithelial detachment, and detachment of the
      nonpigmented epithelium anterior to the white midline indicated the presence of
      the pars plicata break in most cases.

PMID- 10577588
TI  - Foveal retinoschisis and retinal detachment in severely myopic eyes with
      posterior staphyloma.
AB  - PURPOSE: To evaluate the tomographic features of the retina in patients with
      severe myopia and posterior staphyloma. METHODS: In a prospective study of 32
      eyes of 19 consecutive patients with severe myopia and posterior staphyloma, we
      performed complete ophthalmic examinations and studied cross-sectional images of
      the macula with optical coherence tomography. Patients' age ranged from 41 to 83
      years (average, 62.7 years). Best-corrected visual acuity ranged from 20/500 to
      20/40 (average, 20/120). The study included 26 phakic and six pseudophakic eyes.
      The refractive errors of 26 phakic eyes ranged from -8 to -31 diopters (average, 
      16.7 diopters). Although refractive errors were within -8 diopters in six
      pseudophakic eyes, the eyes had apparent posterior staphyloma. The axial lengths
      measured by A-mode ultrasonography ranged from 25.7 to 32.7 mm (average, 29.2
      mm). Slit-lamp examination with contact lens showed that none of the eyes had a
      macular hole. RESULTS: In nine eyes with shallow retinal elevation on slit-lamp
      examination, optical coherence tomography disclosed a foveal retinal detachment
      with retinoschisis in eight eyes and a foveal retinal detachment in one eye. Two
      of the remaining 23 eyes had retinoschisis. CONCLUSIONS: Foveal retinal
      detachment and retinoschisis are common features in severely myopic eyes with
      posterior staphyloma. Retinal detachment may precede the formation of a macular
      hole in severely myopic eyes.

PMID- 10577589
TI  - The effect of pregnancy on retinal hemodynamics in diabetic versus nondiabetic
      mothers.
AB  - PURPOSE: To investigate retinal circulatory changes that occur during the third
      trimester of pregnancy in diabetic patients and control subjects. METHODS:
      Bidirectional laser Doppler velocimetry and monochromatic fundus photography were
      used to assess the retinal circulation in seven pregnant diabetic patients and 13
      age-matched pregnant control subjects. Retinal venous diameter (D), maximum
      erythrocyte velocity (Vmax), and retinal volumetric blood flow rate (Q) were
      measured in one eye of each subject during the third trimester of pregnancy
      (DPREG, VmaxPREG, and QPREG, respectively). These measurements were repeated
      during the postpartum period for both diabetic patients (11+/-7 weeks postpartum)
      and control subjects (16+/-6 weeks postpartum; P = .203; DPOST, VmaxPOST, and
      QPOST). RESULTS: In control subjects, DPREG was significantly reduced by -4.5%+/
      4.4% (mean percent difference +/-1 standard deviation; paired t test, P =.006)
      relative to DPOST. In diabetic women, DPREG was also significantly reduced by 
      8.1%+/-3.2% compared with DPOST (P = .001), a change that was significantly
      larger than that seen in control subjects (unpaired t test; P = .035). Compared
      with QPOS T, QPREG was reduced by -7.1%+/-14.2% (P = .123), in control subjects.
      In diabe tic women, QPREG was significantly decreased by -18.4%+/-9.3% compared
      with QPOST (P = .012). This reduction in QPREG was significantly greater in
      diabetic patients than in nondiabetic control subjects (unpaired t test, P =
      .040). No significant differences between VmaxPREG and VmaxPOST were observed in
      either diabetic patients (-3.1%+/-12.9%; P =.400) or control subjects (+1.9%+/
      14.4%; P = .787). CONCLUSIONS: Retinal venous diameter is decreased during the
      third trimester of pregnancy in both diabetic and nondiabetic mothers. This
      decrease is significantly larger in diabetic than in nondiabetic mothers. In
      addition, we observed a reduction in retinal volumetric blood flow in diabetic
      patients during pregnancy that was significantly larger than that present in
      nondiabetic women. This fall in retinal volumetric blood flow in diabetic
      patients may exacerbate retinal ischemia and hypoxia and thus may be associated
      with the progression of diabetic retinopathy.

PMID- 10577590
TI  - Anatomic variations of the inferior oblique muscle: a potential cause of failed
      inferior oblique weakening surgery.
AB  - PURPOSE: To document the variations in normal anatomy that occur at the insertion
      of the inferior oblique muscle and in the vicinity of its surgical capture site
      (10 to 12 mm from the insertion). METHODS: One hundred intact cadaver orbits with
      no history of eye muscle or orbital disorders during life were carefully
      dissected to expose the entire length of the inferior oblique muscle. The number
      of divisions of muscle at the insertion, total width of the muscle belly, and
      variations in anatomy 10 and 12 mm from the insertion were recorded. RESULTS:
      Seventeen (17%) of the 100 inferior oblique muscles had multiple divisions at the
      insertion. Eight muscles (8%) had two bellies at 10 or 12 mm from the insertion.
      Among these eight, four had two distinct (bifid) bellies extending to the
      insertion, and four had dehiscences in the muscle. The mean muscle width among
      these eight specimens was 0.5 and 0.7 mm larger than the mean width of the other
      92 specimens at the 10 mm and 12 mm positions, respectively. Neither difference
      was significant at the .05 level. CONCLUSIONS: Multiple insertions were found in
      17% of inferior oblique muscles examined; duplications of the inferior oblique
      muscle at the surgical capture site were found in 8%. These duplications may
      account for some cases of recurrence or persistence of inferior oblique
      overaction after weakening surgery, owing to inadvertent incomplete capture of
      the muscle during surgery.

PMID- 10577591
TI  - Volumetric determination of enucleation implant size.
AB  - PURPOSE: To determine whether volumetric calculation of enucleation implant size
      improves the results of the enucleation procedure. METHODS: The volume of the
      enucleated globe was measured in 33 eyes of 33 patients, allowing intraoperative
      calculation of implant size. The degree of postoperative anophthalmic volume
      deficit was evaluated by determining the relative enophthalmic position of the
      implant using Hertel exophthalmometry. These results were compared with those
      obtained from two groups of historical control patients who had previously
      undergone enucleation with the insertion of standard size 18-mm or 20-mm
      implants. RESULTS: There was significant variability in the volume of "normal"
      size globes (range, 7.0 to 9.0 ml; mean, 7.9 ml; standard deviation [SD], 0.7),
      resulting in the placement of implants between 18 to 22 mm in diameter. Study
      patients undergoing volumetric determination of implant size demonstrated less
      implant enophthalmos (mean, 5.9 mm) than historical control patients who received
      18-mm (mean, 8.5 mm; P =.0001) or 20-mm (mean, 6.8 mm, P = .0332) implants.
      CONCLUSIONS: Volumetric determination and individualization of enucleation
      implant size appears to reduce postoperative anophthalmic volume deficit.

PMID- 10577592
TI  - Wrapping hydroxyapatite orbital implants with posterior auricular muscle complex
      grafts.
AB  - PURPOSE: To report the use of posterior auricular muscle complex grafts as a
      wrapping material for hydroxyapatite orbital implants in enucleation surgery.
      METHOD: In a retrospective multicenter study, autogenous posterior auricular
      muscle complex grafts were used to cover hydroxyapatite orbital implants in 83
      patients with a mean age of 38.6 years (range, 1 to 85 years), of whom 63 had
      primary unilateral enucleation and 20 had secondary orbital implants following
      enucleation. The mean follow-up period after posterior auricular muscle complex
      grafts was 36 months (range, 14 to 60 months). RESULTS: Of the 83 patients, two
      (2.4%) developed limited orbital implant exposure, which was treated with a
      second posterior auricular muscle complex "patch graft." No patient developed
      postoperative orbital infection or implant extrusion. All patients were fitted
      with an acceptable prosthesis and had satisfactory cosmetic and functional
      results. No patient developed vascular compromise or a wound defect associated
      with the posterior auricular donor site. CONCLUSION: Autogenous posterior
      auricular muscle complex grafts should be considered as an appropriate wrapping
      material for hydroxyapatite orbital implants for primary enucleation and for
      secondary orbital implants after enucleation.

PMID- 10577593
TI  - Reconsidering the pathogenesis of ocular toxoplasmosis.
AB  - PURPOSE: To review recent observations regarding the sources of Toxoplasma gondii
      infection and rates of ocular involvement in cases of infection acquired after
      birth, and to reconcile them with older observations and widely held beliefs
      about the pathogenesis of ocular toxoplasmosis. METHOD: A review of pertinent
      reports from the medical literature. RESULTS: There are several potential sources
      and routes of infection, including inhalation of spores and ingestion of
      contaminated drinking water, that were previously unrecognized. Ocular
      involvement in cases of acquired infection appears to be more common than
      heretofore believed. A variety of host and parasitic factors may influence rates
      of ocular infection and the characteristics of ocular disease. CONCLUSIONS: The
      scars from which recurrent toxoplasmic retinochoroiditis arise may be the result
      of remote, acquired infections in many cases, rather than the residua of
      congenital infections, as commonly assumed. A better understanding of the
      epidemiology of T. gondii infection, as well as the host and parasitic factors
      that influence disease presentation, is important for developing strategies for
      prevention and management of ocular toxoplasmosis.

PMID- 10577594
TI  - Delayed mustard gas keratopathy: clinical findings and confocal microscopy.
AB  - PURPOSE: To describe the clinical manifestations and confocal microscopic
      findings in a patient with delayed mustard gas keratopathy. METHOD: Case report.
      A 32-year-old veteran who had participated in the Iran Iraq conflict was exposed
      to mustard gas in 1988. Ocular abnormalities in 1996 and 1998 and corneal
      confocal microscopic findings in 1998 are presented. RESULTS: In 1996, slit-lamp
      examination disclosed bilateral limbal changes with tortuous blood vessels and
      full-thickness corneal alterations. In 1998, the right eye had porcelain-white
      episcleral changes and adjacent peripheral ulcerative keratopathy. Confocal
      microscopy demonstrated irregular-appearing epithelial and basal epithelial
      cells. The anterior stroma was remarkable for spindle-like keratocytes, diffuse
      fibrillar inhomogeneities and the presence of highly reflective material.
      CONCLUSIONS: Mustard gas keratopathy is a uncommon cause of ocular damage, but it
      may lead to delayed ocular damage.

PMID- 10577595
TI  - Iatrogenic cataract after laser-assisted in situ keratomileusis.
AB  - PURPOSE: To report a case of corneal opacity and iatrogenic cataract after laser
      assisted in situ keratomileusis. METHOD: Case report. A 44-year-old man was
      initially seen with a traumatic cataract, corneal stromal opacity, and defect of
      the endothelium in the right eye after laser-assisted in situ keratomileusis
      performed by a plastic surgeon who had no ophthalmologic training. RESULTS: It
      was speculated that repeated ablations resulted in corneal perforation. We
      immediately performed phacoemulisification to remove the cataract and to prevent
      phacolytic glaucoma. However, visual acuity remained 20/200 because of the
      corneal stromal opacity, and penetrating keratoplasty was performed 2 months
      later, which improved best-corrected visual acuity to 20/30. CONCLUSIONS: This
      case demonstrated that laser-assisted in situ keratomileusis can cause
      devastating damage to the eye.

PMID- 10577596
TI  - Emerging ciprofloxacin-resistant Pseudomonas aeruginosa.
AB  - PURPOSE: To report a clinical series of ciprofloxacin-resistant ocular isolates
      of Pseudomonas aeruginosa from a tertiary care ophthalmic center. METHODS: Review
      of in vitro sensitivities of all ocular isolates of P. aeruginosa be tween July
      1991 and September 1998. In vitro resistance was defined as a minimum inhibitory
      concentration of 4 or more microg per ml. RESULTS: Nine of 423 ocular isolates of
      P. aeruginosa showed in vitro resistance to ciprofloxacin. From 1991 to 1994,
      0.44% (1/227) of ocular isolates were resistant to ciprofloxacin, whereas from
      1995 to 1998, 4.1% (8/ 196) of ocular isolates showed in vitro resistance (P =
      .014). CONCLUSIONS: Ciprofloxacin-resistant P. aeruginosa has been identified in
      recent clinical ocular specimens. Ciprofloxacin resistance among ocular isolates
      of P. aeruginosa is a local and worldwide concern.

PMID- 10577597
TI  - Identification of bacterial pathogens in patients with endophthalmitis by 16S
      ribosomal DNA typing.
AB  - PURPOSE: To determine whether sequence analysis of 16S ribosomal DNA (rDNA) can
      be used to detect bacterial pathogens in patients with postoperative
      endophthalmitis. METHODS: In 10 eyes of 10 patients, vitreous specimens were
      collected for culture and rDNA typing. Variable segments of each ribosomal DNA
      specimen were amplified by polymerase chain reaction (PCR), sequenced, and
      aligned by BLAST, a computer alignment program, against sequences in GenBank at
      the National Institutes of Health. RESULTS: Specimens were available from five
      eyes with bacterial endophthalmitis diagnosed by Gram stain or culture. Amplified
      16s rDNA sequences from the eyes of three patients were identical to
      microbiologic results. Polymerase chain reaction results were negative in two
      cases in which unusual organisms were detected. All five control specimens from
      patients with nonbacterial endophthalmitis or uveitis were PCR negative.
      Approximately 48 to 72 hours are required under ideal conditions for final
      species identification with this ribosomal typing technique. CONCLUSIONS: 16S
      rDNA typing shows potential as a relatively rapid technique for identifying
      bacteria in vitreous samples.

PMID- 10577598
TI  - Exophiala jeanselmei causing late endophthalmitis after cataract surgery.
AB  - PURPOSE: To report two cases of late endophthalmitis caused by Exophiala
      jeanselmei after cataract surgery. METHODS: Case reports, including clinical
      evaluation, direct examination, and culture of the aqueous humor. RESULTS: In
      each case, samples from the anterior chamber had positive growth of yeasts with
      toruloid hyphae and pseudohyphae. Intravitreal and anterior chamber amphotericin
      B were used in both cases. Apparent clinical resolution was achieved, but after 3
      months in one case and 6 months in the other the infection recurred more
      aggressively, with severe endophthalmitis leading to ocular atrophy. CONCLUSION:
      E. jeanselmei causes a severe intraocular infection and isolation, and
      identification of the agent ensures proper diagnosis and treatment. After
      clinical resolution of the infection, careful and long-term follow-up is
      recommended to promptly detect relapse and immediately reintroduce treatment.

PMID- 10577599
TI  - Periocular abscess and cellulitis from Pasteurella multocida in a healthy child.
AB  - PURPOSE: To examine an unusual cause of periorbital cellulitis, Pasteurella
      multocida. METHODS: Case report, review of the literature. RESULTS: We treated a
      13-year-old previously healthy child who developed Pasteurella preseptal
      cellulitis secondary to a cat bite and cat scratch. After receiving a dose of
      intravenous antibiotics and starting oral antibiotics, the child had delayed
      onset of several abscesses around the right eye, with marked pain and erythema.
      After incision and drainage, he improved. CONCLUSION: Pasteurella multocida is a
      rare but potentially serious cause of ocular infection. All cases of potential
      exposure should be treated promptly and followed until complete resolution of
      infection.

PMID- 10577600
TI  - Optic disk size in open-angle glaucoma: the Blue Mountains Eye Study.
AB  - PURPOSE: To compare optic disk size in eyes of subjects classified as normal with
      the eyes of subjects with open-angle glaucoma, ocular hypertension, or
      pseudoexfoliation syndrome in an older population-based sample. METHODS: The Blue
      Mountains Eye Study examined 3,654 subjects. Vertical disk diameter was measured
      from stereoscopic disk photographs, and we used spherical equivalent refraction
      to correct for magnification. Analyses used all eyes in a general estimating
      equation model. RESULTS: Mean disk diameter was 1.556 mm in glaucomatous eyes,
      significantly different (P <.05) than normal eyes (1.506 mm) and eyes with ocular
      hypertension (1.494 mm) or pseudoexfoliation (1.501 mm). CONCLUSIONS: Patients
      with glaucoma have slightly larger optic disks than nonglaucomatous subjects.

PMID- 10577601
TI  - Macular fibrosis associated with talc retinopathy.
AB  - PURPOSE: To investigate a patient with talc retinopathy who developed macular
      fibrosis with resultant visual loss. METHODS: A 64-year-old intravenous drug
      abuser was evaluated for bilateral peripheral retinal neovascularization. He
      admitted to abusing oral methylphenidate intravenously. Funduscopy showed
      numerous intravascular talc particles in the macular area of both eyes. Over a
      period of next 4 years, visually significant macular fibrosis gradually developed
      in both eyes, the left eye more than the right eye. RESULTS: Fluorescein
      angiography confirmed the presence of bilateral peripheral retinal
      neovascularization with adjacent areas of ischemic retina. The patient was
      treated with peripheral laser treatment to the ischemic retina with resultant
      regression of peripheral retinal neovascularization. Bilateral macular fibrosis
      accounted for the reduced vision in our patient. CONCLUSION: Talc retinopathy can
      be associated with macular fibrosis with resultant visual loss.

PMID- 10577602
TI  - Optical coherence tomography images of spontaneous macular hole closure.
AB  - PURPOSE: To investigate optical coherence tomography images of spontaneous
      macular hole closure. METHOD: Case report. In a 60-year-old woman with full
      thickness macular hole, posterior vitreous detachment, and previous branch
      retinal vein occlusion, we observed the entire course of spontaneous macular hole
      closure by use of optical coherence tomography. RESULTS: Spontaneous macular hole
      closure began as the inward protrusion of the tissue around the margin of the
      macular hole. The protruding tissue then connected to bridge the macular hole,
      which mimicked a foveal retinal detachment. The bridged tissue gradually
      thickened, and the foveal detachment and perifoveal cysts resolved. The fovea
      eventually regained its normal configuration. CONCLUSIONS: The bridging of the
      protruding retinal tissue over the macular hole plays a key role in spontaneous
      macular hole closure.

PMID- 10577603
TI  - Bilateral scleral pit associated with systemic sclerosis.
AB  - PURPOSE: To describe a case of a bilateral scleral pit in a patient with systemic
      sclerosis. METHODS: Case report. RESULTS: A bilateral scleral pit with
      surrounding scleral ischemia overlying the pars plana was noted in a 72-year-old
      woman with known systemic sclerosis. CONCLUSIONS: Scleral pits should be added to
      the list of ocular findings associated with systemic sclerosis.

PMID- 10577604
TI  - Residual ethanol content of donor sclera after storage in 95% ethanol and saline
      rinse of various durations.
AB  - PURPOSE: Some surgeons are wary of using alcohol-preserved sclera for allografts
      because they fear a toxic effect on surrounding tissue after placement. We set
      out to determine the amount of ethanol remaining in scleral allograft material
      after storage in 95% ethanol. METHODS: Sixty half scleras from 30 donors were
      preserved in 95% ethanol for an average of 31+/-14 days (range, 11 to 50 days).
      Rehydration was performed by soaking each half sclera in 4 ounces of balanced
      salt solution. Half scleras were randomly assigned to six groups of 10 each.
      Assays for ethanol were performed on the following groups: no balanced salt
      solution soak and balanced salt solution soak for 10 minutes, 20 minutes, 30
      minutes, 40 minutes, and 50 minutes. Ethanol assay was performed by Headspace Gas
      Space Chromatography at ChemaTox Laboratory, Inc, Boulder, Colorado. RESULTS: The
      10 half scleras without balanced salt solution soak had a mean ( SD) ethanol
      level of 175+/-14.1 mg per g of sclera. After 10 minutes of balanced salt
      solution s oak, the level decreased to 7.57+/-1.56 mg per g, then 3.77+/-3.02 mg
      per g at 20 minutes, 1.59+/-0.61 mg per g at 30 minutes, 1.07+/-0.30 mg per g at
      40 minutes, and 0.96+/-0.26 mg per g at 50 minutes. Approximately 96% of the
      ethanol is leeched out of the half sclera by 10 minutes and 98% by 20 minutes.
      CONCLUSIONS: For sclera preserved in 95% ethanol, soaking in balanced salt
      solution for 20 minutes or longer leeches approximately 98% of the ethanol from
      the preserved donor sclera.

PMID- 10577605
TI  - Discordant retinoblastoma in monozygotic twins.
AB  - PURPOSE: We report cases of discordant retinoblastoma in twins confirmed to be
      monozygotic by DNA analysis. METHODS: Twin A demonstrated severe, bilateral,
      multifocal retinoblastoma, which was recalcitrant to external beam irradiation
      and chemoreduction. Twin B has not demonstrated retinoblastoma. DNA analysis was
      performed with polymorphic microsatellite markers to confirm monozygosity. Single
      stranded conformation polymorphism and Southern blot analysis of the
      retinoblastoma gene were performed. RESULTS: Molecular genetic analyses confirmed
      monozygosity but failed to disclose a retinoblastoma gene mutation in either
      twin. CONCLUSIONS: The extreme phenotypic discordance may best be explained by an
      unidentified, postzygotic retinoblastoma gene mutation in early embryonic
      development of the affected twin.

PMID- 10577606
TI  - Penetrating ocular injury with a fetal scalp monitoring spiral electrode.
AB  - PURPOSE: To report a penetrating ocular injury resulting from inadvertent
      placement of a fetal scalp monitoring spiral electrode into the right eye of a
      preterm male with a face presentation. METHODS: Case report and review of the
      literature. RESULTS: A spiral electrode was screwed clockwise into the right eye,
      tearing the inferior retina and creating two inferior iridotomies. Severe myopic
      astigmatism resulted from gradual lens dislocation combined with elongation of
      the eye. Despite persistent occlusive therapy and aggressive optical correction,
      before and after lensectomy at age 3 years, visual acuity was only 20/200 at age
      8 years. CONCLUSIONS: Although complications from spiral monitoring electrodes
      are uncommon, this case emphasizes that before inserting a spiral monitoring
      electrode during labor, face presentation must be excluded to prevent inadvertent
      ocular injury.

PMID- 10577607
TI  - Intact sensory fusion in a child with divergence paresis caused by a pontine
      glioma.
AB  - PURPOSE: To describe a child with divergence paresis esotropia caused by a brain
      tumor with intact sensory and motor fusion. METHOD: Case report. RESULTS: A 9
      year-old boy who had one episode of double vision was initially seen with a
      small, variably present esophoria at near vision, an intermittent 10 prism
      diopter esotropia at distance, and stereopsis of 80 arc seconds. A magnetic
      resonance imaging examination disclosed a 4.0 x 4.5-cm pontine glioma.
      CONCLUSIONS: Ophthalmologists should recognize that the presence of intact
      sensory and motor fusion in a child with acute, comitant esotropia of the
      divergence paresis type does not preclude intracranial abnormality. If immediate
      neuroimaging is deferred, repeated thorough ocular motility examinations are
      warranted to detect progression.

PMID- 10577608
TI  - Akinetopsia from nefazodone toxicity.
AB  - PURPOSE: To investigate two cases of selective impairment of motion perception
      (akinetopsia) induced by toxicity from the antidepressant nefazodone, a new drug
      that blocks serotonin reuptake and antagonizes 5-HT2 receptors. METHODS: Case
      reports. RESULTS: A 47-year-old man receiving nefazodone (Serzone; Bristol-Meyers
      Squibb, New York, N.Y.) (100 mg twice daily), reported a bizarre derangement of
      motion perception. Moving objects were followed by a trail of multiple "freeze
      frame" images, which dissipated promptly when motion ceased. A 48-year-old woman
      receiving nefazodone (400 mg daily at bedtime) reported a similar phenomenon,
      with visual trails following moving objects. In both patients, vision returned to
      normal after the dosage of nefazodone was reduced or eliminated. CONCLUSIONS:
      Nefazodone toxicity can result in akinetopsia, characterized by the inability to
      perceive motion in a normal, smooth fashion; persistence of multiple, strobelike
      images; and visual trails behind moving objects. In this rare syndrome,
      stationary elements are perceived normally, indicating that nefazodone causes
      selective impairment of pathways involved in motion processing in the visual
      system.

PMID- 10577609
TI  - Cerebrospinal fluid leakage during endscopic forehead lifting.
AB  - PURPOSE: To report a case of endoscopic brow lift in which cerebrospinal fluid
      leakage was encountered. METHOD: A 69-year-old otherwise healthy man underwent
      endoscopic forehead lifting. RESULTS: An area of strong adherence was encountered
      in the area of the left superior paracentral scalp incision. As the adherence was
      released, clear fluid extruded (cerebrospinal fluid) and a burr hole was
      discovered. Absorbable gelatin sponge was placed over the dural defect and burr
      hole, and closure of the endoscopic scalp incisions was accomplished. CONCLUSION:
      Caution is suggested in performing this procedure when a patient has any history
      of a head trauma.

PMID- 10577610
TI  - New endocrine tumor markers of gynecologic malignancies. A review.

PMID- 10577611
TI  - Use of maternal care in a rural area of Zimbabwe: a population-based study.
AB  - PURPOSE: Our aim was to determine the coverage of antenatal and delivery care and
      the determinants of non-compliance in a rural area of Zimbabwe in order to
      improve the quality and efficiency of maternal health care services. METHODS: A
      community-based, cross-sectional study was carried out in the catchment area of
      Gutu Mission Hospital, in rural Zimbabwe, from January to June 1996. Two hundred
      and thirty-five women, aged 16 to 54 years, who had delivered a child in the past
      three years were interviewed on general characteristics (age, marital status,
      religion, education, work), obstetric history, use of family planning, pregnancy
      complications, number of antenatal visits, and use of maternity waiting shelters.
      Associations of these factors to non-use of antenatal care facilities and
      hospital delivery were studied. In the Gutu district, guidelines exist to
      identify women at high risk of complications during pregnancy and to indicate
      where women should give birth (hospital, rural clinic or at home). We evaluated
      which factors were important for non-compliance to these guidelines. The analyses
      were performed using a logistic regression model. RESULTS: Ninety-seven percent
      of the pregnant women attended the antenatal care facilities at least once.
      Seventy-three percent came at least five times or more. Belonging to certain
      religious groups proved to be the strongest explanatory factor for not attending
      antenatal care facilities. Use of maternity waiting shelters and complications
      during the pregnancy were important factors for hospital delivery, whereas
      unemployment and being without a husband were associated with deliveries outside
      the hospital. Identification as high risk of a complicated pregnancy by
      application of the existing guidelines was not associated with place of delivery.
      Delivery at a location that did not conform to the existing guidelines was
      associated with non-use of maternity waiting shelters, unemployment or being
      without a husband and use of traditional care. CONCLUSIONS: Our study showed a
      high attendance rate at antenatal care facilities in the Gutu District. By
      analyzing determinants of non-use of antenatal care facilities, of hospital
      delivery and of inappropriate location of delivery according to local guidelines,
      we identified certain risk factors which are suitable for modification and may
      help to improve antenatal and perinatal care in the Gutu District in Zimbabwe.

PMID- 10577612
TI  - The effect of antenatal steroid administration on the fetal response to
      vibroacoustic stimulation.
AB  - BACKGROUND: Betamethasone transiently suppresses multiple fetal biophysical
      activities, including breathing movements, limb and trunk movements, heart rate
      variability, and heart rate accelerations. Unnecessary iatrogenic delivery of
      preterm fetuses due to the false diagnosis of fetal compromise has been described
      in this setting. The sonographically observed startle response of the fetus to
      vibroacoustic stimulation has been described as another modality to provide
      reassurance about fetal well-being. It is unknown, however, whether the startle
      response is also suppressed by betamethasone. The purpose of this study was to
      examine the effect of betamethasone on this biophysical parameter. METHODS: A
      prospective cohort study. Vibroacoustic stimulation was applied to the maternal
      abdomen and fetal movement responses were sonographically observed prior to (0
      hours), 48 hours after, and 96 hours after betamethasone administration. We
      recorded the presence or absence of the fetal startle response, and, if a
      response was present, graded semi-quantitatively the intensity of the movements
      (vigorous versus sluggish). RESULTS: Twenty-two of 26 fetuses (84.6%) displayed a
      vigorous vibroacoustic startle response prior to betamethasone administration, in
      comparison to three of 26 fetuses (11.5%) at 48 hours after exposure (p<0.0001).
      Eleven fetuses and eight fetuses displayed no startle response at all (p<0.0005),
      or a sluggish response only (p<0.0005) at 48 hours, respectively. At 96 hours
      after betamethasone exposure, no differences in the number of fetuses with a
      vigorous, sluggish, or absent response were observed in comparison to 0 hours.
      Stratification of cases by gestational age groups of 28-30 weeks versus 31-34
      weeks showed similar response patterns. CONCLUSION: Antenatal betamethasone
      exposure transiently suppresses the sonographically observed fetal startle
      response to vibroacoustic stimulation. Accordingly, this modality cannot be used
      for the ascertainment of fetal well-being of steroid exposed fetuses.
      Betamethasone seems to suppress central nervous system dependent biophysical
      activities. including the brain-stem dependent vibroacoustic startle reflex.

PMID- 10577613
TI  - Blood lead and cadmium and birth weight among sub-arctic and arctic populations
      of Norway and Russia.
AB  - BACKGROUND: Delivering women and their newborns in the Kola Peninsula of Russia
      and the neighboring arctic area of Norway were studied to explore relationships
      between maternal cadmium and lead status and birth weight as a pregnancy outcome.
      METHODS: Life-style information, maternal blood and cord blood specimens were
      collected from 50 consecutive mother-infant pairs from hospital delivery
      departments in three Russian and three Norwegian communities. Pregnancy outcomes
      were verified by consulting medical records. Lead and cadmium were determined in
      the blood samples by electrothermal atomic absorption spectrometry. RESULTS: The
      median blood-cadmium concentration for the Russian mothers was 2.2 nmol/L (n =
      148) versus 1.8 nmol/L in the Norwegian group (n = 114, p = 0.55). A weak
      association was observed between maternal cadmium and amount smoked (r = 0.30,
      p<0.001); no correlation was found between maternal blood cadmium and birth
      weight. The corresponding maternal lead values were 0.14 (Russia) and 0.06
      micromol/L (Norway), p<0.001. The latter lead concentration constitutes one of
      the lowest adult population values reported to date. Maternal and cord blood lead
      levels were strongly correlated (r = 0.88, p<0.001). In a multivariate linear
      regression model, maternal blood lead was recognized as a negative explanatory
      variable (p<0.05) for birth weight and child's body mass index (BMIC), with or
      without adjustment for gestational age. A similar association was suggested by
      ANOVA-analysis of maternal blood lead by quartiles. CONCLUSION: Maternal blood
      lead level as an environmental factor is an apparent predictor of low birth
      weight and BMIC. It reduced substantially the contribution of a country factor in
      explaining the observed differences in birth weight.

PMID- 10577614
TI  - Prediction of cervical response to prostaglandin E2 using fetal fibronectin.
AB  - BACKGROUND: To determine whether presence of fetal fibronectin in cervico-vaginal
      secretions at term will predict the cervical response to prostaglandin E2 (PGE2)
      pessaries and successful induction of labor amongst subjects with unfavorable
      cervices. METHODS: Cervico-vaginal secretion was tested for the presence of fetal
      fibronectin prior to cervical ripening with PGE2 pessaries in women with a
      singleton term or post-term pregnancy undergoing induction of labor. The total
      number of PGE2 pessaries, interval from induction to labor and induction to
      delivery, latent phase and active phase of labor and cesarean section rate were
      compared. RESULTS: Women with fetal fibronectin in their cervico-vaginal
      secretion had better cervical response to PGE2 pessaries and required fewer doses
      for induction of labor and they took a shorter time interval from induction to
      delivery. They tend to have a lower cesarean section rate but the figures did not
      reach statistical significance. CONCLUSIONS: The presence of fetal fibronectin
      from cervico-vaginal secretions in subjects with a Bishop score <5 is predictive
      of a favorable response to induction by prostaglandin pessary

PMID- 10577615
TI  - Late onset postpartum thrombocytosis in preeclampsia.
AB  - BACKGROUND: During pregnancy, changes in blood coagulation and fibrinolysis
      create a hypercoagulable state. In the puerperium this thrombogenicity is even
      higher, and the chance of developing thromboembolism is 3-5 times higher in this
      period than during pregnancy. In preeclampsia, platelets are activated and play a
      substantial role in the pathogenesis of the disease. Systematic information on
      longitudinal changes in platelet number and size postpartum after normotensive
      and preeclamptic pregnancies is not available. METHODS: We measured platelet
      number, mean platelet volume and the median volume of the 20% largest platelets
      in eleven preeclamptic and eleven normotensive pregnant women matched for mode of
      delivery. The blood samples were taken antepartum and every 2-3 days in the
      postpartum period until the platelet count decreased/normalized. RESULTS: In the
      preeclamptic group, the platelet count increased significantly from 240x10(9)/l
      antepartum to 621x10(9)/l on day 6-14 postpartum (p<0.01). In the control group,
      the platelet count increased from 214x10(9)/l antepartum to 251x10(9)/l on day 2
      5 (p<0.01) and 351x10(9)/l on day 6-14 postpartum (p<0.01). The platelet count
      was significantly higher in the preeclamptic than in the control group 6-14 days
      postpartum (p<0.01). Antepartum, mean platelet volume and the median of the 20%
      largest platelets were significantly higher in the preeclamptic than in the
      control group. CONCLUSION: The platelet count is significantly increased
      postpartum both after normotensive, and 2-3 fold more after preeclamptic
      pregnancies. The time to peak values is between 6-14 days, usually at a time when
      patients are discharged from hospital.

PMID- 10577616
TI  - The usefulness of initial risk assessment as a predictor of pregnancy
      complications and premature delivery.
AB  - BACKGROUND: Risk assessment is an essential component of all programs for
      surveillance of pregnancy. The objective of the study is to assess the usefulness
      of initial risk status as predictor for pregnancy complications and premature
      delivery. METHODS: A retrospective, area-based study including all women giving
      birth at Vasteras Central Hospital, Sweden in 1990 (2,008) and 1992 (1,874). Data
      was collected before and after the introduction of a reduced routine surveillance
      program. The study populations were classified in a low-risk group and three risk
      groups according to presence of risk factors at booking (initial risk factors),
      development of pregnancy complications (later risk factors) or a combination of
      both. Relative risk for premature delivery and predictive value of initial risk
      factors for pregnancy complications were analyzed. RESULTS: The relative risk for
      premature delivery was significantly increased in all three risk categories both
      years except for the group with only initial risk factors in 1990. Risk factors
      were present at booking in 27% (1990) and 26% (1992). Pregnancy complications
      developed in 35% and 28%, respectively. The positive predictive value of initial
      risk factors for pregnancy complications was 40% and 33%, adding little useful
      information. CONCLUSION: The relative risk for premature delivery was correlated
      to obstetric risk but was moderately increased with initial risk factors only.
      The initial risk status is a poor predictor of pregnancy complications and cannot
      alone be used for individual planning of surveillance during pregnancy. Even for
      low risk women routine programs must be structured to secure adequate
      identification of current complications.

PMID- 10577617
TI  - Eclampsia in Finland in 1990-1994.
AB  - BACKGROUND: Eclampsia is a serious threat to both maternal and fetal well-being.
      We started the present study because no recent data are available on the
      incidence of eclampsia and the outcome of patients with this serious disorder in
      Finland. METHODS: The incidence of eclampsia in Finland in 1990-1994 was studied
      retrospectively. The data were retrieved from the National Birth Register and the
      Finnish Hospital Discharge Register. Patient records were reviewed. RESULTS:
      Seventy-seven cases of eclampsia were found in the hospital records, which gave
      an eclampsia incidence of 2.4 per 10,000 deliveries (95% confidence intervals 1.9
      to 2.9). Eclampsia was preceded by severe pre-eclampsia in 84% and by mild pre
      eclampsia in 8% of the patients. Ten mothers suffered from severe eclampsia
      related complications but, fortunately, none of the mothers died. Perinatal
      mortality was 5%, and 33% of the newborns were small for gestational age.
      CONCLUSIONS: Eclampsia is rare in Finland. Its low incidence is probably due to
      improved neonatal care that allows earlier deliveries before the progress of
      preeclampsia to eclampsia.

PMID- 10577618
TI  - Endometrial polyps during menopause: characterization and significance.
AB  - BACKGROUND: To characterize postmenopausal women with endometrial polyps and to
      evaluate their significance. METHODS: The study population included all
      consecutive postmenopausal patients with a diagnosis of endometrial polyp,
      treated at our center over a two-year period. Demographic, medical and
      gynecological data were assessed with regard to the endometrial histologic
      findings. RESULTS: Of the 146 eligible patients, 15 had endometrial hyperplasia
      (four with atypia); there were no cases of endometrial carcinoma. The 20 patients
      (13.7%) using hormone replacement therapy had a significantly higher rate of
      endometrial hyperplasia than non-hormone users (p<0.006). No differences were
      observed among the endometrial histological categories for any of the presenting
      symptoms and signs, ultrasonographic findings, or medical histories. CONCLUSIONS:
      Postmenopausal endometrial polyp is a common, mostly benign entity. However, the
      relatively high rate of concomitant endometrial hyperplasia, especially in
      patients receiving hormone replacement therapy, dictates a thorough histological
      evaluation in all cases.

PMID- 10577619
TI  - Laparoscopic management of bladder endometriosis.
AB  - BACKGROUND: To assess the methods, indications and results of operative
      laparoscopy for patients presenting with bladder endometriosis. METHODS:
      Descriptive retrospective study. All the patients presenting with bladder
      endometriosis infiltrating the bladder muscularis between January 1, 1993 and
      June 30, 1998 were included in this series. RESULTS: It was possible to treat
      bladder endometriosis in all the patients by performing a laparoscopic partial
      cystectomy. With an average follow-up of 31.6 months (range 6-61) the results are
      satisfactory. Neither per- nor postoperative complications were observed. The
      patients experienced an improvement in their condition, with complete
      disappearance of the urinary symptoms in every case. No recurrence of the
      functional urological symptoms occurred. CONCLUSIONS: Provided the surgeons are
      skilled and the lesions require no ureteral reimplantation, operative laparoscopy
      is a valid alternative to laparotomy for partial cystectomy.

PMID- 10577620
TI  - Treatment of premenstrual syndrome with gonadotropin-releasing hormone agonist in
      a low dose regimen.
AB  - BACKGROUND: GnRH agonists constitute a well-documented treatment for premenstrual
      syndrome (PMS). However, the hypo-estrogenic state induced by the treatment
      renders it less suitable for long-term clinical use. The aim of the current study
      was to investigate the efficacy of a low dose GnRH agonist with respect to its
      ability to relieve premenstrual symptoms and maintain regular ovulatory cycles.
      METHODS: The effect of a low dose GnRH agonist (buserelin) on luteal phase
      symptomatology was evaluated in 27 women with severe premenstrual syndrome. The
      design was doubleblind, placebo-controlled and cross-over. Patients were
      randomized to either GnRH-agonist intranasally in a dosage of 100 microg once
      daily for two months or placebo for two months before the cross-over was made.
      The primary outcome measure consisted of daily symptom ratings for mood and
      physical symptoms made by the patients throughout the study. Adverse events and
      hormone concentrations were assessed at visits every second week. RESULTS:
      Premenstrual irritability and depression were significantly relieved by low dose
      GnRH agonist. Positive symptoms such as friendliness and cheerfulness were also
      improved during the premenstrual week. Likewise physical symptoms of swelling and
      headache displayed a significant improvement during buserelin treatment, whereas
      breast tenderness scores were unaffected by the treatment. The low dose GnRH
      agonist treatment regimen induced anovulation in as much as 56% of patients, but
      these subjects were significantly older than those women who maintained ovulatory
      cycles throughout the study. CONCLUSION: GnRH treatment significantly reduced
      premenstrual depression and irritability. However, low dose GnRH therapy is prone
      to induce anovulation, particularly with increasing age.

PMID- 10577621
TI  - Loop diathermy or laser excisional conization for cervical intraepithelial
      neoplasia.
AB  - BACKGROUND: Cervical intraepithelial neoplasia (CIN) can be managed by ablative
      or excisional procedures. We have compared the excision time, effectiveness, and
      safety of loop diathermy (loop) against laser conization. METHODS: In a
      prospective study in two hospital departments 222 women were randomized to loop
      or laser conization. Data were collected by questionnaires after operation and at
      two follow-up examinations. RESULTS: At department A (122 women), two physicians
      performed 27% of the loop and 35% of the laser excisions; at department B (100
      women), the corresponding figures were 69% and 59%. Loop was quicker than laser
      conization in both departments (median 3-4 min versus 10-20 min), while laser
      conization was more time consuming in department A (median A/B = 20/10 min).
      Peroperative bleeding dominated during the laser procedure in both departments
      and complicated the loop procedure more frequently in department A. Postoperative
      bleeding occurred with equal frequency in the four groups (41.8%, 52.7%, 59.2%,
      64.7%). At both departments, bleeding for more than two weeks was reported twice
      as often after laser conization (A:13.8%, B:24.2%), when compared to loop
      excision (A:7.1%, B:13.7%). Residual CIN was found in all of three re-conizations
      and in one of eight hysterectomy specimens. CONCLUSIONS: Loop was quicker than
      laser excision, per- and postoperative bleeding diminished, and the success rates
      were comparable. Physicians mastered Loop excision after a few attempts. However,
      the results improved, when performed by a restricted number of physicians.
      Histological incomplete excision indicates close colposcopic and cytologic follow
      up to identify residual CIN.

PMID- 10577622
TI  - Prospectively detected cancer in familial breast/ovarian cancer screening.
AB  - BACKGROUND: Early diagnosis and treatment are shown to improve survival of breast
      and ovarian cancer. Identification and medical follow-up of high-risk groups may
      be important for early diagnosis. METHODS: A prospective study of 845 women from
      breast/ovarian- and ovarian cancer kindreds who were classified according to pre
      set inclusion criteria (Table I), were offered genetic counseling and annual
      medical examinations of breasts and ovaries. The material consisted of three
      series: 1) 754 unaffected women, 2) 49 women with breast cancer, and 3) 42 women
      with ovarian cancer. RESULTS: In series 1) nine ovarian cancers and 20 breast
      cancers, in series 2) seven ovarian cancers, and in series 3) three breast
      cancers were found. All but one of the ovarian cancers were 40 years or older,
      and 4/16 (25%) were Borderline cancer. All breast cancers were 30 years or older,
      and 89% were detected before spread. CONCLUSIONS: This is to our knowledge the
      first prospective report of the combined breast/ovarian cancer findings in
      breast/ovarian cancer kindreds. A woman with both breast and ovarian cancer is
      the hallmark of inherited breast/ovarian cancer, and 50% of the ovarian cancers
      were detected in these families. Borderline ovarian cancer may represent a
      manifestation of this syndrome. If prophylactic oophorectomy prevents ovarian
      cancer, oophorectomy at age 45 would have prevented 75% of such cancers. Based on
      these results we revised our protocol for annual follow-up in these kindreds: 1)
      clinical breast examination and mammography (ultrasound/cytology if indicated)
      from 30 years of age, 2) gynecologic examination (including vaginal ultrasound,
      serum-CA125) from 35 years of age, and 3) discuss oophorectomy at 45 years of
      age.

PMID- 10577623
TI  - Landry Guillian-Barre Strohl syndrome in pregnancy: use of high-dose intravenous
      immunoglobulin.

PMID- 10577624
TI  - Elevated serum alpha-fetoprotein levels as a presenting sign of epidural
      recurrence from cervical cancer.

PMID- 10577625
TI  - Unilateral pulmonary edema as a life-threatening complication of ritodrine.

PMID- 10577626
TI  - Three-dimensional sonographic visualization of fetal facial anomaly.

PMID- 10577627
TI  - Fluid absorption and the long term outcome after transcervical resection of the
      endometrium.

PMID- 10577628
TI  - Care of patients and subterfuge, in equal parts.

PMID- 10577629
TI  - Conventional versus newer antihypertensive therapies--a draw.

PMID- 10577630
TI  - Symptoms of reproductive-tract infection--not all that they seem to be.

PMID- 10577631
TI  - Understanding the Y chromosome.

PMID- 10577632
TI  - Platelet activation with exercise and risk of cardiac events.

PMID- 10577633
TI  - Spinal-cord stimulation in management of angina.

PMID- 10577634
TI  - Prevention of the abdominal compartment syndrome.

PMID- 10577635
TI  - Randomised trial of old and new antihypertensive drugs in elderly patients:
      cardiovascular mortality and morbidity the Swedish Trial in Old Patients with
      Hypertension-2 study.
AB  - BACKGROUND: The efficacy of new antihypertensive drugs has been questioned. We
      compared the effects of conventional and newer antihypertensive drugs on
      cardiovascular mortality and morbidity in elderly patients. METHODS: We did a
      prospective, randomised trial in 6614 patients aged 70-84 years with hypertension
      (blood pressure > or = 180 mm Hg systolic, > or = 105 mm Hg diastolic, or both).
      Patients were randomly assigned conventional antihypertensive drugs (atenolol 50
      mg, metoprolol 100 mg, pindolol 5 mg, or hydrochlorothiazide 25 mg plus amiloride
      2.5 mg daily) or newer drugs (enalapril 10 mg or lisinopril 10 mg, or felodipine
      2.5 mg or isradipine 2-5 mg daily). We assessed fatal stroke, fatal myocardial
      infarction, and other fatal cardiovascular disease. Analysis was by intention to
      treat. FINDINGS: Blood pressure was decreased similarly in all treatment groups.
      The primary combined endpoint of fatal stroke, fatal myocardial infarction, and
      other fatal cardiovascular disease occurred in 221 of 2213 patients in the
      conventional drugs group (19.8 events per 1000 patient-years) and in 438 of 4401
      in the newer drugs group (19.8 per 1000; relative risk 0.99 [95% CI 0.84-1.16],
      p=0.89). The combined endpoint of fatal and non-fatal stroke, fatal and non-fatal
      myocardial infarction, and other cardiovascular mortality occurred in 460
      patients taking conventional drugs and in 887 taking newer drugs (0.96 [0.86
      1.08], p=0.49). INTERPRETATION: Old and new antihypertensive drugs were similar
      in prevention of cardiovascular mortality or major events. Decrease in blood
      pressure was of major importance for the prevention of cardiovascular events.

PMID- 10577636
TI  - Troponin concentrations for stratification of patients with acute coronary
      syndromes in relation to therapeutic efficacy of tirofiban. PRISM Study
      Investigators. Platelet Receptor Inhibition in Ischemic Syndrome Management.
AB  - BACKGROUND: A major challenge for physicians is to identify patients with acute
      coronary syndromes who may benefit from treatment with glycoprotein-IIb/IIIa
      receptor antagonists. We investigated whether troponin concentrations can be used
      to stratify patients for benefit from treatment with tirofiban. METHODS: We
      enrolled 2222 patients of the Platelet Receptor Inhibition in Ischemic Syndrome
      Management study with coronary artery disease and who had had chest pain in the
      previous 24 h. All patients received aspirin and were randomly assigned treatment
      with tirofiban or heparin. We took baseline measurements of troponin I and
      troponin T. We recorded death, myocardial infarction, or recurrent ischaemia
      after 48 h infusion treatment and at 7 days and 30 days. FINDINGS: 629 (28.3%)
      patients had troponin I concentrations higher than the diagnostic threshold of
      1.0 microg/L and 644 (29.0%) troponin T concentrations higher than 0.1 microg/L.
      30-day event rates (death, myocardial infarction) were 13.0% for troponin-I
      positive patients compared with 4.9% for troponin-I-negative patients (p<0.0001),
      and 13.7% compared wth 3.5% for troponin T (p<0.001). At 30 days, in troponin-I
      positive patients, tirofiban had lowered the risk of death (adjusted hazard ratio
      0.25 [95% CI 0.09-0.68], p=0.004) and myocardial infarction (0.37 [0.16-0.84],
      p=0.01). This benefit was seen in medically managed patients (0.30 [0.10-0.84],
      p=0.004) and those undergoing revascularisation (0.37 [0.15-0.93] p=0.02) after
      48 h infusion treatment. By contrast, no treatment effect was seen for troponin-I
      negative patients. Similar benefits were seen for troponin-T-positive patients.
      INTERPRETATION: Troponin I and troponin T reliably identified high-risk patients
      with acute coronary syndromes, managed medically and by revascularisation, who
      would benefit from tirofiban.

PMID- 10577637
TI  - Efficacy of cervical-smear collection devices: a systematic review and meta
      analysis.
AB  - BACKGROUND: Few randomised controlled trials have sufficient power to show clear
      advantages of different designs of cervical-smear collection devices. We studied
      by systematic review whether the design of cervical-smear devices affects rates
      of inadequate smears and detection of disease and whether the presence of
      endocervical cells in the smear affects detection of disease. METHODS: We sought
      relevant randomised controlled trials by computer literature review by MEDLINE
      backed up by a manual search of 16 journals. Each trial was classified according
      to methodological quality criteria. Odds ratios were calculated where data
      allowed. FINDINGS: 34 randomised controlled trials investigating cervical
      Papanicolaou smear collection devices were identified. All 34 trials compared the
      ability of devices to collect endocervical cells, and 19 compared the ability of
      devices to detect dyskaryosis. Meta-analyses showed that compared with other
      collection devices, the Ayre's spatula is an ineffective device for collecting
      endocervical cells (for example, odds ratio for comparison of extended-tip
      spatulas vs Ayre's spatula 2.25 [95% CI 2.06-2.44]) and also gives a lower yield
      of dyskaryosis (odds ratio for comparison of extended-tip spatulas vs Ayre's
      spatula 1.21 [1.20-1.33]). Devices that effectively collect endocervical cells
      also detect a higher proportion of abnormal cytology than those that do not.
      INTERPRETATION: The widely used Ayre's spatula is the least effective device for
      cervical sampling and should be superseded by extended-tip spatulas for primary
      screening and investigation of women before and after treatment for cervical
      intraepithelial neoplasia. The presence of endocervical cells is a valid and
      convenient surrogate for the ability to detect dyskaryosis.

PMID- 10577638
TI  - Prevalence of progressive supranuclear palsy and multiple system atrophy: a cross
      sectional study.
AB  - BACKGROUND: The prevalence of progressive supranuclear palsy (PSP) and multiple
      system atrophy (MSA) in the general population is unknown. Clinicopathological
      studies of patients diagnosed as having Parkinson's disease suggest that the two
      disorders may be underdiagnosed. We investigated the population prevalence of
      these disorders. METHODS: We screened computerised records of 15 general
      practices in London, UK, for patients with specific diagnostic labels suggestive
      of Parkinson's disease or parkinsonism and all patients who had ever received
      antiparkinsonian medication. We assessed eligible patients by review of records,
      interview, physical examination, and video recordings of neurological signs for
      independent diagnostic confirmation. We diagnosed parkinsonian disorders
      according to published criteria and further reviewed patients with atypical
      features after 1 year. FINDINGS: The participation rate was 84%. The age-adjusted
      prevalence for PSP was 6.4 per 100,000 (five probable and one possible case [95%
      CI 2.3-10.6]) and for MSA 4.4 per 100,000 (two probable and two possible cases
      [1.2-7.6]). An additional four atypical patients were identified at 1 year but
      did not fulfil criteria for PSP or MSA. INTERPRETATION: Our results suggest that
      the true prevalence of PSP and MSA has been underestimated, since many patients
      in the community remain undiagnosed or misdiagnosed.

PMID- 10577640
TI  - Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large
      volume plasma apheresis.
AB  - BACKGROUND: In chronic HIV-1 infection, dynamic equilibrium exists between viral
      production and clearance. The half-life of free virions can be estimated by
      inhibiting virion production with antiretroviral agents and modelling the
      resulting decline in plasma HIV-1 RNA. To define HIV-1 and hepatitis C virus
      (HCV) dynamics, we used plasma apheresis to increase virion clearance temporarily
      while leaving virion production unaffected. METHODS: Plasma virus loads were
      measured frequently before, during, and after apheresis in four HIV-1-infected
      patients, two of whom were also co-infected with HCV. Rates of virion clearance
      were derived by non-linear least-square fitting of plasma virus load to a model
      of viral dynamics. FINDINGS: Virion clearance rate constants were 0.0063/min
      (9.1/day) to 0.025/min (36.0/day; half-life 28-110 min) for HIV-1 and 0.0038/min
      (5.5/day) to 0.0069/min (9.9/day; half-life 100-182 min) for HCV. These values
      provided estimates of daily particle production of 9.3 log10-10.2 log10 particles
      for HIV-1 and 11.6 log10-13.0 log10 particles for HCV. INTERPRETATION: Our
      findings confirm that HIV-1 and HCV are produced and cleared extremely rapidly.
      New estimates for HIV-1 clearance are up to ten times higher than previous ones,
      whereas HCV clearance is similar to previous estimates.

PMID- 10577639
TI  - Reproductive-tract infections in women in low-income, low-prevalence situations:
      assessment of syndromic management in Matlab, Bangladesh.
AB  - BACKGROUND: In the control of reproductive-tract infections, including sexually
      transmitted infections (STIs), in low-income and middle-income countries, WHO
      recommends syndromic management for individuals with symptoms. This intervention
      was initially developed in areas where prevalence of such infections is high. We
      investigated the clinical effectiveness and cost of this approach among a group
      of women with a low prevalence of infection. METHODS: During a 5-month period, we
      investigated all women complaining of abnormal vaginal discharge and seeking care
      at maternal and child health/family-planning centres in Matlab, Bangladesh, for
      the presence of laboratory-diagnosed reproductive-tract infections and STIs.
      Syndromic diagnoses made by trained health-care workers were compared with
      laboratory diagnosis of infection. We then calculated the costs of treating women
      by means of the recommended WHO algorithm and an adapted algorithm incorporating
      use of a speculum and simple diagnostic tests. FINDINGS: The prevalence of
      endogenous infections among 320 women seen was 30%. Cervical infections
      (Neisseria gonorrhoeae and Chlamydia trachomatis) were found in only three women.
      The WHO algorithm had a high sensitivity (100%) but a low specificity (zero for
      bacterial vaginosis, candida, and Trichomonas vaginalis). The speculum-based
      algorithm had a low sensitivity (between zero and 59%) but a higher specificity
      (79-97%). Between 36% and 87% of costs would have been spent on uninfected women.
      INTERPRETATION: The high rate of overtreatment in the population studied carries
      both financial and social costs--the latter in potentially exposing women
      misdiagnosed as having an STI to threats of domestic disruption or even violence.
      We make recommendations for management programmes in areas of low STI prevalence
      and low income.

PMID- 10577641
TI  - A 51-year-old woman with disorientation and amnesia.

PMID- 10577642
TI  - Low oestrogen receptor alpha expression in normal breast tissue underlies low
      breast cancer incidence in Japan.
AB  - Among white Australians without breast cancer, the median of the percentage of
      oestrogen receptor alpha positive cells was 12% for women younger than 50 years
      and 17% for those 50 years or older; among Japanese women who had no breast
      cancer and are generally at low risk for this disease, the corresponding values
      were both significantly lower and around 9%.

PMID- 10577643
TI  - Early-onset drunk driving, violent criminality, and mental disorders.
AB  - We examined an association between the onset age for drunk driving, psychiatric
      morbidity and/or violent criminality. Almost half of violent offenders with
      mental disorder committed their first drunk driving before 18 years of age. The
      younger the drunk driver was, the greater the probability was of being violent
      and mentally ill.

PMID- 10577644
TI  - Effect of growth hormone on growth delay in burned children: a 3-year follow-up
      study.
AB  - Children with severe burns benefit from acute therapy with recombinant human
      growth hormone by maintaining their original stature after injury. This effect is
      particularly apparent in children injured outside growth-spurt years.

PMID- 10577645
TI  - Acute pancreatitis induced by magnetic-resonance-imaging contrast agent.
AB  - We present a case of acute pancreatitis induced by magnetic-resonance-imaging
      (MRI) contrast agent. We suggest that the use of MRI with this agent early in
      acute pancreatitis should be reconsidered.

PMID- 10577646
TI  - Contralateral thalamic perfusion in patients with reflex sympathetic dystrophy
      syndrome.
AB  - Iodine-123-labelled iodoamphetamine single-photon emission computed tomography of
      patients with reflex sympathetic dystrophy syndrome showed substantial variation
      in thalamic perfusion of the side contralateral to the painful limb. The
      variations are related to time from the onset of symptoms, which suggests that
      the thalamus undergoes adaptive changes in the course of this neurological
      disorder.

PMID- 10577648
TI  - Clindamycin and nicotinic neuromuscular transmission.
AB  - Upon clindamycin treatment a patient with Parkinson's disease showed marked
      tremor improvement which may be explained by clindamycin's ability to inhibit in
      vitro nicotinergic, but not muscarinic signal transmission.

PMID- 10577647
TI  - Reduced bone formation after exposure to organophosphates.
AB  - Bone histomorphometric analysis in 24 agricultural workers with chronic
      organophosphate exposure showed significantly lower bone formation at tissue and
      cellular level than in healthy controls.

PMID- 10577649
TI  - pH dependency of serum ionised calcium.
AB  - Measurement by ion selective electrode showed that the pH dependency of serum
      ionised calcium is better described by an inversely S-shaped third-degree
      function than by the conventionally used logarithmic function.

PMID- 10577650
TI  - Oesophageal involvement in pemphigus vulgaris.
AB  - Oesophageal involvement of pemphigus vulgaris had been considered an exceptional
      event. However, our endoscopic study found oesophageal lesions in seven of eight
      (87.5%) patients with pemphigus vulgaris.

PMID- 10577651
TI  - ACE inhibitors still the drug of choice for heart failure--and more.

PMID- 10577652
TI  - Studies on rare genetic diseases: a good use of funds?

PMID- 10577653
TI  - Health-care reform back on the US political agenda.

PMID- 10577654
TI  - Chinese AIDS experts call for more education to halt HIV epidemic.

PMID- 10577655
TI  - Commonwealth commits to HIV/AIDS problem.

PMID- 10577656
TI  - Further restrictions on mentally ill in UK.

PMID- 10577657
TI  - Glaucoma.
AB  - In 2000 an estimated 66.8 million people worldwide will have glaucoma, 6.7
      million of whom will be bilaterally blind from irreversible optic-nerve damage.
      Yet even in developed countries with public educational programmes that target
      glaucoma, half of the individuals with glaucoma remain undiagnosed. Patients with
      even mild visual impairment secondary to glaucoma may have difficulties with
      mobility, driving, and social interactions. Although glaucoma may be associated
      with increased eye pressures, its diagnosis does not rely on a specific level of
      eye pressure. Diagnosis of glaucoma often relies on examination of the optic disc
      and assessment of the visual field. The two most common types of glaucoma-
      primary open-angle glaucoma and primary angle-closure glaucoma--have different
      risk factors. Although similar medications can be used to treat these two types
      of glaucoma, the overall management of patients differs in important ways. Until
      recently, there were no randomised clinical trials that showed the effectiveness
      of lowering eye pressures with medications or surgery in patients with glaucoma.
      However, in 1998 a randomised clinical trial showed the benefit of lowering eye
      pressure in patients with glaucoma who had eye pressures of 24 mm Hg or less.
      Because glaucoma is treatable, and because the visual impairment from glaucoma is
      irreversible, early detection of the disease is critically important.

PMID- 10577658
TI  - The dustbin of history, and why so much of modern medicine should end up there.

PMID- 10577659
TI  - Male circumcision and HIV infection: 10 years and counting.

PMID- 10577660
TI  - HIVNET nevirapine trials.

PMID- 10577661
TI  - HIVNET nevirapine trials.

PMID- 10577662
TI  - HIVNET nevirapine trials.

PMID- 10577663
TI  - Tenecteplase and alteplase in acute myocardial infarction.

PMID- 10577664
TI  - Preconceptional paternal exposure to pesticides and increased risk of childhood
      leukaemia.

PMID- 10577665
TI  - Preoperative imaging of parathyroid glands.

PMID- 10577666
TI  - Preoperative imaging of parathyroid glands.

PMID- 10577667
TI  - Microchimerism in a human hand allograft.

PMID- 10577668
TI  - Albert Einstein's brain.

PMID- 10577669
TI  - Albert Einstein's brain.

PMID- 10577670
TI  - Albert Einstein's brain.

PMID- 10577671
TI  - Contaminated surgical instruments and variant Creutzfeldt-Jakob disease.

PMID- 10577672
TI  - Contaminated surgical instruments and variant Creutzfeldt-Jakob disease.

PMID- 10577673
TI  - CTLA-4 and HLA gene susceptibility to thyroid-associated orbitopathy.

PMID- 10577674
TI  - Safety of raltitrexed.

PMID- 10577675
TI  - Safety of raltitrexed.

PMID- 10577676
TI  - Chocolate contains additional flavonoids not found in tea.

PMID- 10577677
TI  - Brazilian public hospitals.

PMID- 10577678
TI  - Mortality in Herculaneum before volcanic eruption in 79 AD.

PMID- 10577679
TI  - The Nobel chronicles. 1981: Roger Wolcott Sperry (1913-94); David Hunter Hubel (b
      1926); Torsten N Wiesel (b 1924).

PMID- 10577680
TI  - Radiotherapy in bladder cancer.
AB  - In the present review, we have evaluated the outcome of radiotherapy in patients
      with bladder cancer. The exact value of radical radiotherapy is difficult to
      establish because changes in treatment techniques and selection of patients have
      biased the results. The 5-year survival rates are reported to be 35-71% in T1
      tumors, 27-59% in T2 tumors, 10-38% in T3 tumors and 0-16% in T4 tumors. Several
      other factors, like performance status and hemoglobin level, are important for
      the outcome. Morbidity of radical radiotherapy depends on several treatment and
      patient related factors, but 50-75% experience acute intestinal or urological
      symptoms and 10-20% may develop severe late toxicity, depending on the kind of
      registration. The importance of field size or overall treatment time cannot be
      established from available data. Hyperfractionation with dose escalation has
      proven effective in one study. Preoperative radiotherapy with cystectomy has not
      proven better than cystectomy alone or better than radiotherapy alone. The
      addition of systemic chemotherapy has increased disease-free survival, but has
      not significantly reduced the rate of distant metastases or improved overall
      survival. Presently, the standard radiation regimen is a conventional dose and
      fractionation schedule to a total dose of 60-66 Gy with a three- or four-field
      technique covering the bladder and tumor. The efficacy of additional irradiation
      of regional lymph nodes is questionable. New treatment possibilities with
      advanced techniques of radiotherapy, hyperfractionation and dose escalation
      and/or the addition of systemic chemotherapy may improve outcome. These options
      should be further explored in clinical trials.

PMID- 10577681
TI  - Radiotherapy in the management of cutaneous B-cell lymphoma. Our experience in 25
      cases.
AB  - PURPOSE: To report our results in the treatment with radiation therapy of 25
      patients affected by B-cell lymphoma with initial cutaneous presentation.
      MATERIALS AND METHODS: From October 1978 to June 1997, we have treated 25
      patients with cutaneous B-cell lymphoma (CBCL) by cutaneous irradiation. There
      were 17 males and eight females, aged from 23 to 89 years (median age 50 years).
      The mean follow-up time for the series was 3.9 years (range from 0.2 to 15 years)
      from the completion of radiation therapy. All patients were staged as follows: in
      group 1, single lesion; group 2, multiple lesions; group 3, disseminated lesions.
      There were six (24%) patients in group 1, 15 (60%) patients in group 2, and four
      (16%) in group 3. There were nine patients with head and neck lesions, 11
      patients with trunk lesions, and five patients with leg lesions. Thirteen
      patients (52%) had previously received chemotherapy for CBCL. Extended field
      irradiation was used to treat six patients (24%). Localized field irradiation
      (LFI) was performed for the other 19 patients (76%). RESULTS: The overall
      survival rate at 5 years was 73%. The complete response (CR) to the treatment for
      our series was 92%. The length of complete remission ranged from 2 to 180 months.
      There were three patients (8%) who obtained partial response (PR). Disease-free
      survival (DFS) at 1 year was 91% and at 5 years was 75%. Radiotherapy was
      generally well tolerated. CONCLUSIONS: Localized field irradiation is an
      effective treatment for some localized forms of primary cutaneous B-cell lymphoma
      and can obtain prolonged remissions. The patients with wide-spread skin
      involvement are usually candidates for extended field irradiation and/or
      chemotherapy. For the advanced stages of cutaneous B-cell lymphoma, where the
      chemotherapy is the treatment of choice, some good palliation can be achieved
      using local field irradiation.

PMID- 10577682
TI  - Radiotherapy of pelvic malignancies: impact of two types of rigid immobilisation
      devices on localisation errors.
AB  - BACKGROUND AND PURPOSE: To determine the distribution of set-up errors for
      patients treated with and without two rigid partial immobilisation devices for
      pelvic malignancies. MATERIALS AND METHODS: 30 patients receiving pelvic
      irradiation with a four field technique underwent a total of 524 portal films.
      The patients are divided into 3 cohorts of 10 patients. The first cohort is
      treated on a standard treatment couch without immobilisation device (NI); the
      second and third cohorts are treated with a custom-made immobilisation device
      used in an attempt to improve set-up accuracy: an Alpha-Cradle mattress (AM) or
      an Orfit cast (OC). Set-up deviations are analysed in the X, Y, Z directions of a
      fixed coordinate system, corresponding to the lateral, cranio-caudal and antero
      posterior direction, respectively. RESULTS: Considering the percentage of
      discrepancies < or = 5 mm between the simulation films and the portal films as a
      measure of set-up accuracy, immobilisation devices seem to increase accuracy:
      88.5% (X) 79% (Y) and 100% (Z) with AM; 84% (X-Y), 97.5% (Z) with OC and only
      76.5% (X), 40% (Y) and 65.5% (Z) for NI. The distribution of the systematic set
      up errors for the three patient cohorts, defined as the mean patient displacement
      for the treatment course, had a mean and a standard deviation of (0.7 +/- 2.7) mm
      in the X-axis, (-5.5 +/- 2.6) mm in the Y-axis and (-0.9 +/- 2.2) mm in the Z
      axis when no immobilisation is added; (0.8 +/- 1.7) mm, (-2 +/- 2.7) mm and (0.3
      +/- 0.4) mm for the Alpha-Cradle group; (0.3 +/- 1.4) mm, (0.5 +/- 1.1) mm and
      (0.5 +/- 0.6) mm for the Orfit cast group. The distribution of random errors
      about the mean approximated a normal distribution and the standard deviations are
      4.4 mm (X), 4.2 mm (Y) and 4.8 mm (Z) for NI; 3.3, 3.5 and 2.5 mm for the AM;
      3.4, 3.3 and 2.7 mm for the OC. CONCLUSIONS: The two rigid immobilisation devices
      improve the reproducibility of a given pelvic field but there is a small benefit
      comparative to the cost and the cumbersome place of the devices.

PMID- 10577683
TI  - Impact of the filling status of the bladder and rectum on their integral dose
      distribution and the movement of the uterus in the treatment planning of
      gynaecological cancer.
AB  - PURPOSE: Determination of the impact of the filling status of the organs at risk
      (bladder and rectum) on the uterus mobility and on their integral dose
      distribution in radiotherapy of gynaecological cancer. METHODS: In 29 women
      suffering from cervical or endometrial cancer two CT scans were carried out for
      treatment planning, one with an empty bladder and rectum, the second one with
      bladder and rectum filled. The volumes of the organs at risk were calculated and
      in 14 patients, receiving a definitive radiotherapy, the position of the uterus
      within the pelvis was shown using multiplanar reconstructions. After generation
      of a 3D treatment plan the dose volume histograms were compared for empty and
      filled organs at risk. RESULTS: The mobility for the corpus uteri with/without
      bladder and rectum filling was in median 7 mm (95%-confidence interval: 3-15 mm)
      in cranial/caudal direction and 4 mm (0-9 mm) in posterior/anterior direction.
      Likewise, cervical mobility was observed to be 4 mm (-1-6 mm) mm in
      cranial/caudal direction. A full bladder led to a mean reduction in organ dose in
      median from 94-87% calculated for 50% of the bladder volume (P < 0.05, Wilcoxon's
      matched-pairs signed-ranks test). For 66% of the bladder volume the dose could be
      reduced in median from 78 to 61% (P < 0.005) and for the whole bladder from 42 to
      39% (P < 0.005), respectively. No significant contribution of the filling status
      of the rectum to its integral dose burden was noticed. CONCLUSIONS: Due to the
      mobility of the uterus increased margins between CTV and PTV superiorly,
      inferiorly, anteriorly and posteriorly of 15, 6 and 9 mm each, respectively,
      should be used. A full bladder is the prerequisite for an integral dose
      reduction.

PMID- 10577684
TI  - A simplified CT-based definition of the lymph node levels in the node negative
      neck.
AB  - INTRODUCTION AND PURPOSE: Using three dimensional (3D) conformal radiotherapy
      (CRT) techniques for elective neck irradiation (ENI) may allow for local disease
      control to be maintained while diminishing xerostomia by eliminating major
      salivary glands (or parts thereof) from the treatment portals. The
      standardization of CT based target volumes for the clinically negative (elective)
      neck is a prerequisite for 3DCRT. The aim of the present study was to
      substantially modify an existing ('original') CT-based protocol for the
      delineation of the neck target volume, into a more practical ('simplified')
      protocol. This will allow for rapid contouring and the implementation of
      conformal ENI in routine clinical procedures. MATERIAL AND METHODS: An earlier
      ('original') version of the CT-based definition for elective neck node regions 2
      5 was re-evaluated, using 15 planning CT scans of previously treated patients.
      The contouring guidelines were simplified by (1) using a smaller number of easily
      identifiable soft tissue- and bony anatomical landmarks, which in turn had to be
      identified in only a limited number of CT slices, and (2) by subsequently
      interpolating the contoured lymph node regions. The adequacy of target coverage
      and the sparing using both 'original' and 'simplified' delineation protocols was
      evaluated by DVH analysis after contouring the primary tumor, the neck and the
      major salivary glands in a patient with supraglottic laryngeal (SGL) carcinoma
      who was treated using a 3DCRT technique. RESULTS: The BEV projections of the
      'original' and the 'simplified' versions of the 3D elective neck target showed
      good agreement and were found to be reproducible. The DVH's of the target and
      parotid glands were not significantly different using both contouring protocols.
      CONCLUSIONS: The 'simplified' protocol for the delineation of the 3D elective
      neck target produced both comparable target coverage and sparing of the major
      salivary glands. When used together with an interpolation program, this
      'simplified' protocol substantial reduced the contouring time and makes ENI with
      sparing of the major salivary glands a practical and achievable goal.

PMID- 10577685
TI  - Animation and radiobiological analysis of 3D motion in conformal radiotherapy.
AB  - PURPOSE: To allow treatment plans to be evaluated against the range of expected
      organ motion and set up error anticipated during treatment. METHODS: Planning
      tools have been developed to allow concurrent animation and radiobiological
      analysis of three dimensional (3D) target and organ motion in conformal
      radiotherapy. Surfaces fitted to structures outlined on CT studies are projected
      onto pre-treatment images or onto megavoltage images collected during the patient
      treatment. Visual simulation of tumour and normal tissue movement is then
      performed by the application of three dimensional affine transformations, to the
      selected surface. Concurrent registration of the surface motion with the 3D dose
      distribution allows calculation of the change in dose to the volume. Realistic
      patterns of motion can be applied to the structure to simulate inter-fraction
      motion and set-up error. The biologically effective dose for the structure is
      calculated for each fraction as the surface moves over the course of the
      treatment and is used to calculate the normal tissue complication probability
      (NTCP) or tumour control probability (TCP) for the moving structure. The tool has
      been used to evaluate conformal therapy plans against set up measurements
      recorded during patient treatments. NTCP and TCP were calculated for a patient
      whose set up had been corrected after systematic deviations from plan geometry
      were measured during treatment, the effect of not making the correction were also
      assessed. RESULTS: TCP for the moving tumour was reduced if inadequate margins
      were set for the treatment. Modelling suggests that smaller margins could have
      been set for the set up corrected during the course of the treatment. The NTCP
      for the rectum was also higher for the uncorrected set up due to a more rectal
      tissue falling in the high dose region. CONCLUSION: This approach provides a
      simple way for clinical users to utilise information incrementally collected
      throughout the whole of a patient's treatment. In particular it is possible to
      test the robustness of a patient plan against a range of possible motion
      patterns. The methods described represent a move from the inspection of static
      pre-treatment plans to a review of the dynamic treatment.

PMID- 10577686
TI  - In vivo dosimetry during conformal radiotherapy: requirements for and findings of
      a routine procedure.
AB  - PURPOSE: Conformal radiotherapy requires accurate knowledge of the actual dose
      delivered to a patient. The impact of routine in vivo dosimetry, including its
      special requirements, clinical findings and resources, has been analysed for
      three conformal treatment techniques to evaluate its usefulness in daily clinical
      practice. MATERIALS AND METHODS: Based on pilot studies, routine in vivo
      dosimetry quality control (QC) protocols were implemented in the clinic. Entrance
      and exit diode dose measurements have been performed during two treatment
      sessions for 378 patients having prostate, bladder and parotid gland tumours.
      Dose calculations were performed with a CT-based three-dimensional treatment
      planning system. In our QC-protocol we applied action levels of 2.5% for the
      prostate and bladder tumour group and 4.0% for the parotid gland patients. When
      the difference between the measured dose at the dose specification point and the
      prescribed dose exceeded the action level the deviation was investigated and the
      number of monitor units (MUs) adjusted. Since an accurate dose measurement was
      necessary, some properties of the on-line high-precision diode measurement system
      and the long-term change in sensitivity of the diodes were investigated in
      detail. RESULTS: The sensitivity of all diodes decreased by approximately 7%
      after receiving an integrated dose of 10 kGy, for 4 and 8 MV beams. For 34 (9%)
      patients the difference between the measured and calculated dose was larger than
      the action level. Systematic errors in the use of a new software release of the
      monitor unit calculation program, limitations of the dose calculation algorithms,
      errors in the planning procedure and instability in the performance of the
      accelerator have been detected. CONCLUSIONS: Accurate in vivo dosimetry, using a
      diode measurement system, is a powerful tool to trace dosimetric errors during
      conformal radiotherapy in the range of 2.5-10%, provided that the system is
      carefully calibrated. The implementation of an intensive in vivo dosimetry
      programme requires additional staff for measurements and evaluation. The patient
      measurements add only a few minutes to the total treatment time per patient and
      guarantee an accurate dose delivery, which is a prerequisite for conformal
      radiotherapy.

PMID- 10577687
TI  - Verification of electron field positioning.
AB  - The difficulties in verification of electron fields are due to the limited range
      of electrons within the human body. Modern linacs provide a special mode of
      operation (film mode), so that electron fields can be irradiated with a small
      photon dose. Thus, the images obtained can be used for comparison with the
      corresponding simulator images or DRRs to determine the electron field position
      and to detect positioning errors.

PMID- 10577688
TI  - Tangential breast irradiation: a multi-centric intercomparison of dose using a
      mailed phantom and thermoluminescent dosimetry.
AB  - PURPOSE: To measure the accuracy of radiation therapy of the breast planned with
      2D and 3D algorithms. MATERIALS AND METHODS: The accuracy of radiation therapy of
      the breast with 2D and 3D algorithms was investigated as a national
      intercomparison using a semi-anatomical breast phantom. The dose was measured
      with thermoluminescent (TL) dosemeters. RESULTS: The mean deviation of measured
      to planned dose at isocentre was -2.7%. The influence of some planning and
      irradiation factors is evaluated. CONCLUSION: The study demonstrates that beam
      energy and the use of CT have no marked influence on the accuracy of dose
      calculations, care has to be exercised when wedges are used and even with
      sophisticated 3D algorithms there is a systematic error in the dose received by
      the patient.

PMID- 10577689
TI  - Dosimetric evaluation of a commercial 3-D treatment planning system using Report
      55 by AAPM Task Group 23.
AB  - BACKGROUND AND PURPOSE: A relevant part of radiotherapy treatment planning system
      QA concerns dose calculation verification. Report 55 by AAPM TG-23 is an
      instrument for performing dosimetric evaluation of treatment planning systems in
      case of external photon beams. It was employed by different groups in three
      radiotherapy departments for controlling performances of RTPS CadPlan Varian
      Dosetek, versions 2.7.9, 3.0.6 and 3.1.1. MATERIALS AND METHODS: Once the basic
      data of the AAPM 4 MV and 18 MV X-ray units had been converted into the CadPlan
      format and the AAPM units configured, the whole set of TG23 tests were carried
      out on three different systems. According to Report 55, comparisons between
      values measured by TG-23 and calculated by RTPS were made in terms of dose at
      selected points and radiological field width at different depths. RESULTS: As far
      as dose is concerned, 266 data were compared for 4 MV and 297 for 18 MV. Ninety
      five-point-nine percent of dose deviations for 4 MV and 92.6% for 18 MV are less
      than 2%. Most of the relevant discrepancies for both energies occur in a test
      case where dose has to be calculated under a long narrow block centred on the
      beam axis. Deviations as much as 6.1% for 4 MV and -7.5% for 18 MV were observed
      in points at 1 cm depth under the block. Poor results were also observed in the
      rectangular field 25 x 5, in points outside the field edges under collimators. As
      regards radiological field width, 58 out of 64 comparisons for 4 MV occurred in
      the range +/- 2 mm. For 18 MV the biggest deviation was -2.2 mm. CONCLUSIONS: The
      TG-23 tests demonstrated that the accuracy of the RTPS in dose calculation is
      good in most of the typical radiotherapy applications. Our results are better
      than those recently published for other RTPS. The TG-23 package turned out to be
      an effective instrument for QA and calculation verification, as well as being a
      powerful method for training purpose in configuring and using a RTPS.

PMID- 10577690
TI  - Radiation therapy in Africa: distribution and equipment.
AB  - BACKGROUND AND PURPOSE: Africa is the least developed continent as regards
      radiation oncology resources. The documented ASR of cancer is of the order of 1
      to 2 per 1000. With improving health care this is becoming more significant. This
      review was undertaken to help develop priorities for the region. MATERIALS AND
      METHODS: Radiation Oncology departments in Africa were identified and a survey of
      their equipment performed. These were compared to the reported situation in 1991.
      Population tables for the year 2000 were compared to available megavoltage
      machines. RESULTS: Of 56 countries in Africa, only 22 are confidently known to
      have megavoltage therapy concentrated in the southern and northern extremes of
      the continent. The 155 megavoltage machines operating represents over 100%
      increase over the past 8 years. The population served by each megavoltage machine
      ranges from 0.6 million to 70 million per machine. Overall, only 50% of the
      population have some access to Radiation Oncology services. CONCLUSION: Progress
      has been made in initiating radiation oncology in Ghana, Ethiopia and Namibia.
      There has been some increase in machines in Algeria, Egypt, Libya, Morocco and
      Tunisia. However, a large backlog exists for basic radiation services.

PMID- 10577691
TI  - On the appropriateness of the probability model for series type complications.

PMID- 10577692
TI  - Time requirements in conformal radiotherapy treatment planning.

PMID- 10577693
TI  - Palliative radiotherapy of bone metastases: there is now evidence for the use of
      single fractions.

PMID- 10577694
TI  - Accelerated radiation therapy in non-small cell lung cancer.

PMID- 10577695
TI  - The effect of a single fraction compared to multiple fractions on painful bone
      metastases: a global analysis of the Dutch Bone Metastasis Study.
AB  - PURPOSE: To answer the question whether a single fraction of radiotherapy that is
      considered more convenient to the patient is as effective as a dose of multiple
      fractions for palliation of painful bone metastases. PATIENTS: 1171 patients were
      randomised to receive either 8 Gy x 1 (n = 585) or 4 Gy x 6 (n = 586). The
      primary tumour was in the breast in 39% of the patients, in the prostate in 23%,
      in the lung in 25% and in other locations in 13%. Bone metastases were located in
      the spine (30%), pelvis (36%), femur (10%), ribs (8%), humerus (6%) and other
      sites (10%). METHOD: Questionnaires were mailed to collect information on pain,
      analgesics consumption, quality of life and side effects during treatment. The
      main endpoint was pain measured on a pain scale from 0 (no pain at all) to 10
      (worst imaginable pain). Costs per treatment schedule were estimated. RESULTS: On
      average, patients participated in the study for 4 months. Median survival was 7
      months. Response was defined as a decrease of at least two points as compared to
      the initial pain score. The difference in response between the two treatment
      groups proved not significant and stayed well within the margin of 10%. Overall,
      71% experienced a response at some time during the first year. An analysis of
      repeated measures confirmed that the two treatment schedules were equivalent in
      terms of palliation. With regard to pain medication, quality of life and side
      effects no differences between the two treatment groups were found. The total
      number of retreatments was 188 (16%). This number was 147 (25%) in the 8 Gy x 1
      irradiation group and 41 (7%) in the 4 Gy x 6 group. It was shown that the level
      of pain was an important reason to retreat. There were also indications that
      doctors were more willing to retreat patients in the single fraction group
      because time to retreatment was substantially shorter in this group and the
      preceding pain score was lower. Unexpectedly, more pathological fractures were
      observed in the single fraction group, but the absolute percentage was low. In a
      cost-analysis, the costs of the 4 Gy x 6 and the 8 Gy x 1 treatment schedules
      were calculated at 2305 and 1734 Euro respectively. Including the costs of
      retreatment reduced this 25% cost difference to only 8%. The saving of
      radiotherapy capacity, however, was considered the major economic advantage of
      the single dose schedule. CONCLUSION: The global analysis of the Dutch study
      indicates the equality of a single fraction as compared to a 6 fraction treatment
      in patients with painful bone metastases provided that 4 times more retreatments
      are accepted in the single dose group. This equality is also shown in long term
      survivors. A more detailed analysis of the study is in progress.

PMID- 10577696
TI  - 8 Gy single fraction radiotherapy for the treatment of metastatic skeletal pain:
      randomised comparison with a multifraction schedule over 12 months of patient
      follow-up. Bone Pain Trial Working Party.
AB  - AIM: To compare a single fraction of 8 Gy with a course of multifraction
      radiotherapy in terms of long-term benefits and short-term side effects in
      patients with painful skeletal metastases. METHODS: Seven hundred and sixty-five
      patients with painful skeletal metastases requiring palliative radiotherapy were
      entered into a prospective randomised clinical trial comparing 8 Gy single
      fraction with a multifraction regimen (20 Gy/5 fractions or 30 Gy/10 fractions).
      Patients recorded pain severity and analgesic requirements on self-assessment
      questionnaires before treatment, at 2 weeks and at 1, 2, 3, 4, 5, 6, 8, 10 and 12
      months after radiotherapy. Pain relief was the primary endpoint of treatment
      benefit. Short-term side-effects were compared in a subset of 133 consecutive
      patients who graded nausea, vomiting and antiemetic usage prior to treatment and
      at daily intervals from days I to 14. RESULTS: Overall survival at 12 months was
      44%, with no statistically significant difference apparent between randomised
      groups. There were no differences in the time to first improvement in pain, time
      to complete pain relief or in time to first increase in pain at any time up to 12
      months from randomisation, nor in the class of analgesic used. Retreatment was
      twice as common after 8 Gy than after multifraction radiotherapy, although
      retreatment for residual or recurrent pain did not reflect a difference between
      randomised groups in the probability of pain relief. The difference in the rate
      of retreatment is thought to reflect a greater readiness to prescribe
      radiotherapy after a single fraction, not a greater need. There were no
      significant differences in the incidence of nausea, vomiting, spinal cord
      compression or pathological fracture between the two groups. CONCLUSIONS: A
      single fraction of 8 Gy is as safe and effective as a multifraction regimen for
      the palliation of metastatic bone pain for at least 12 months. The greater
      convenience and lower cost make 8 Gy single fraction the treatment of choice for
      the majority of patients.

PMID- 10577697
TI  - Single 4 Gy re-irradiation for painful bone metastasis following single fraction
      radiotherapy.
AB  - PURPOSE: to investigate effectiveness of a single-fraction of 4 Gy given for re
      treatment of bone metastasis after previous single-fraction radiotherapy (RT).
      MATERIAL AND METHODS: Of 135 patients retreated, 109 patients were retreated
      because of pain relapsing after 4 Gy (group I, n = 34), 6 Gy (group II, n = 39),
      or 8 Gy (group III, n = 36), while 26 patients were re-irradiated after initial
      non-response (group I, n = 12; group II, n = 8; group III, n = 6). RESULTS: Of
      the 109 patients that were re-irradiated for pain relapse, 80 (74%) patients
      responded (complete response (CR) = 31%; partial response PR) = 42%). Among the
      26 patients that initially did not respond, there were 12 (46%) responses.
      Patients with previous CR were more likely to achieve CR than were patients with
      previous PR (P = 0.042). No such finding was observed for obtaining PR, which was
      achieved in 45% each of patients previously having either CR or PR (P = 0.99).
      Patients with previous CR had similar chance to obtain either CR or PR (P =
      0.65), while previous PR influenced subsequent response in the way of achieving
      more PRs than CRs (P = 0.00054). Combined, these data showed that patients with
      initial CR were more likely to respond than those with previous PR (85% vs. 67%,
      P = 0.037). There were no difference between the three initial treatment groups
      regarding the efficiency (CR or CR + PR) of second RT. Toxicity was low and only
      gastrointestinal. CONCLUSIONS: Single-fraction RT consisting of 4 Gy was
      effective and little toxic treatment that could be administered after previous
      single-fraction RT.

PMID- 10577698
TI  - A randomised phase III study of accelerated or standard fraction radiotherapy
      with or without concurrent carboplatin in inoperable non-small cell lung cancer:
      final report of an Australian multi-centre trial.
AB  - PURPOSE: To investigate the effects separately and together of (a) shortening
      overall treatment time and (b) giving concurrent carboplatin in patients having
      radical radiotherapy for inoperable non-small-cell lung cancer (NSCLC). PATIENTS
      AND METHODS: Between April 1989 and May 1995, 204 patients with medically
      inoperable or technically unresectable NSCLC localised to the primary site and
      regional lymph nodes were randomised to receive one of four treatments using a 2
      x 2 factorial design: standard radiotherapy, 60 Gy in 30 fractions in 6 weeks
      (R6); accelerated radiotherapy, 60 Gy in 30 fractions in 3 weeks (R3); standard
      radiotherapy as in R6 with carboplatin 70 mg/m2/day for 5 days during weeks 1 and
      5 of radiotherapy (R6C); accelerated radiotherapy as in R3 with carboplatin 70
      mg/m2/day for 5 days during week 1 of radiotherapy (R3C). RESULTS: The estimated
      median survival of all randomised patients was 15.7 months and estimated 2-year
      survival was 31%. The longest survival was seen in patients randomised to R6C
      (median 20.3 months, 41% surviving at 2 years) but there were no statistically
      significant differences between treatment arms or treatment factors (carboplatin
      versus no carboplatin, accelerated versus conventional radiotherapy).
      Haematological toxicity was significantly greater in patients treated with
      carboplatin and oesophageal toxicity was significantly greater and more
      protracted in patients treated with accelerated radiotherapy. CONCLUSIONS: This
      study failed to show a significant survival advantage for any of the treatment
      arms or factors. Halving overall treatment time resulted in significantly greater
      oesophageal toxicity with no suggestion of a survival advantage.

PMID- 10577699
TI  - Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus
      conventional radiotherapy in non-small cell lung cancer: mature data from the
      randomised multicentre trial. CHART Steering committee.
AB  - BACKGROUND AND METHOD: A randomised controlled trial in locally advanced non
      small cell lung cancer (NSCLC), compared CHART which employs 36 fractions of 1.5
      Gy 3 times per day to give 54 Gy in 12 consecutive days with conventional
      radiotherapy-30 fractions of 2 Gy to a total dose of 60 Gy in 6 weeks. A total of
      563 patients were entered between April 1990 and April 1995. This report is based
      upon the data updated to 1 April 1998. RESULTS: The analysis of the mature data
      shows that the benefits previously reported have been maintained. Overall there
      was a 22% reduction in the relative risk of death, which is equivalent to an
      absolute improvement in 2 year survival of 9% from 20 to 29% (P = 0.008) and a
      21% reduction in the relative risk of local progression (P = 0.033). In the large
      subgroup of patients with squamous cell cancer which accounted for 81% of the
      cases, there was a 30% reduction in the relative risk of death, which is
      equivalent to an absolute improvement in 2 year survival of 13% from 20 to 33% (P
      = 0.0007) and a 27% reduction in the relative risk of local progression (P =
      0.012). Furthermore, in squamous carcinoma there was a 25% reduction in the
      relative risk of local and/or distant progression (P = 0.025) and 24% reduction
      in the relative risk of metastasis (P = 0.043). There was no evidence that CHART
      gave more or less benefit in any other subgroup. CONCLUSION: This analysis of
      mature data confirms that CHART is superior to conventional radiotherapy in
      achieving local tumour control and survival in locally advanced NSCLC. This
      demonstrates the importance of cellular repopulation as a cause of failure in the
      radiotherapy of NSCLC. The reduction in the risk of metastasis confirms that
      improved local tumour control, even in lung cancer, can reduce the incidence of
      metastasis. This trial shows that control of local tumour can lead to an
      improvement in long term survival.

PMID- 10577700
TI  - ARCON: accelerated radiotherapy with carbogen and nicotinamide in non small cell
      lung cancer: a phase I/II study by the EORTC.
AB  - BACKGROUND: Non small cell lung cancers (NSCLC) are rapidly proliferating
      tumours, which are characterized by the presence of extensive hypoxic components,
      especially in patients with advanced loco-regional disease. Previous studies
      suggest a deleterious impact of acute (perfusion-limited) hypoxia on the outcome
      of radiotherapy for these tumours. AIM: This pilot study was aimed at determining
      the feasibility and tumour response rates that can be achieved with an ARCON
      regime in patients with locally advanced, staged IIIA or B, NSCLC tumours.
      METHODS: The phase I/II study included three steps: accelerated fractionation
      (AF) combined with carbogen (ten analysable patients), AF together with the daily
      administration of nicotinamide (n = 11 ) and AF with both carbon and nicotinamide
      (n = 14). Radiotherapy was based on a large daily dose per fraction (2.75 Gy up
      to 55 Gy in 4 weeks). Nicotinamide was administered at a dose of 6 g per patient
      per treatment day and carbogen was inhaled for 5 min before and during
      radiotherapy. RESULTS: The incidence of grade 3 + acute toxicity during the
      irradiation did not exceed 10%, neither in the lung parenchyma nor in the
      mediastinum. No significant difference was found in loco-regional, radio-induced
      toxicity among the three study steps. Although a similar fraction of patients
      showed grade 2 or 3 emesis in all the steps, of the 25 patients entered in the
      two Nicotinamide containing steps 10 (40%) developed grade 2 or greater reactions
      which significantly detracted from their quality of life. There was no
      significant difference in tumour clearance rate among the three steps. The
      percentage of objective responses at 2 months was 60, 54 and 57% in steps 1, 2
      and 3, respectively. CONCLUSION: The feasibility of this ARCON protocol, using
      2.75 Gy doses per fraction over 4 weeks, is good as regards radiotherapy-related
      side effects but it appears necessary in future to reduce the dose of
      Nicotinamide to reduce the incidence of nausea and vomiting. There was no
      significant difference in time to progression among the three study steps.

PMID- 10577701
TI  - Do acute mucosal reactions lead to consequential late reactions in patients with
      head and neck cancer?
AB  - BACKGROUND AND PURPOSE: The relationship between acute and late mucosal reactions
      remains ill defined but is of considerable relevance to efforts to produce
      therapeutic gains through the use of altered fractionation schemes and concurrent
      chemotherapy. We therefore investigated whether acute mucosal reactions in
      patients treated with an accelerated and a conventionally fractionated
      radiotherapy regime predicted the severity of late mucosal reactions. PATIENTS
      AND METHODS: The study population consisted of 191 patients randomised on a
      prospective trial comparing conventional fractionation at 2 Gy/fraction per day,
      70 Gy over 47 days with an accelerated regimen of 59.4 Gy, 1.8 Gy b.i.d over 24
      days for Stage III-IV carcinoma of the head and neck. Acute and late mucosal
      reactions were scored according to RTOG/EORTC criteria and analyzed using
      multiple regression techniques. RESULTS: The duration of time spent by patients
      at the acute confluent mucositis grade 3 level was inversely related to the time
      to onset of the reaction for both fractionation schedules. Time to onset was more
      rapid for patients treated on the accelerated schedule but time spent at the
      reaction grade did not differ significantly between the schedules. After
      correction for treatment and patient related factors, anatomical site (oral
      cavity/oropharynx versus hypopharynx/larynx) and increasing duration of confluent
      mucositis emerged as independent predictors of the hazard of late mucosal
      reactions with the latter effect being more pronounced in the accelerated
      treatment arm. The expected reduction in late mucosal effects in the accelerated
      fractionation arm, predicted by the LQ model for late effects was identified only
      in patients whose acute confluent mucosal reactions lasted less than 20 days.
      CONCLUSIONS: The presence of individual patient susceptibility factors that
      determine the severity of acute mucosal reactions is suggested. A link between
      severe and prolonged acute reactions and the risk of developing late mucosal
      reactions that is independent of biological dose, has also been found. Purpose
      designed prospective studies of these issues are necessary.

PMID- 10577703
TI  - Role of radiotherapy in sarcoma of the breast--a retrospective review of the M.D.
      Anderson experience.
AB  - BACKGROUND: The role of adjuvant radiotherapy for sarcoma of the breast, based on
      local extension of disease and patterns of failure, remains undefined because of
      the rarity of the disease presentation. METHODS: Fifty-nine cases of soft tissue
      sarcoma of the breast were retrospectively reviewed. Cystosarcoma phylloides was
      excluded from analysis. Surgical intervention consisted of segmental resection (n
      = 16) or mastectomy (n = 38); five patients underwent excisional biopsy. Adjuvant
      radiotherapy was administered in four patients following segmental resection and
      in 13 patients after mastectomy. Doses totaled 50 Gy in the majority of patients,
      and conventional criteria and radiotherapy techniques for adjuvant breast
      irradiation were used. RESULTS: None of the dissected axillary nodes contained
      metastatic tumor on pathologic review. Patterns of failure were evaluated. Tumor
      size (P < 0.03) and surgical margins (P < 0.002) were predictive of local failure
      (LF). Due to limited patient numbers, no statistical significance was identified
      with any treatment modality. Following mastectomy alone, LF occurred in 13
      patients (34%) versus the 13% rate of LF with mastectomy and radiotherapy (P =
      NS). Distant metastases developed concurrently with the two local failures in the
      group that underwent mastectomy and radiation. After segmental mastectomy, LF
      occurred in 3 cases (25%) concurrent with distant metastases: no LF were noted
      after segmental mastectomy and radiation (P = 0.27). For all treatment groups,
      local recurrences were characterized as multiple and involved the chest wall.
      Local failure occurred in 60% of patients with positive surgical margins who did
      not receive adjuvant irradiation. Irrespective of surgical margins, over 75% of
      local recurrences developed among patients treated by surgery alone. CONCLUSIONS:
      The role of radiotherapy for breast sarcoma remains undefined due to the rarity
      of this disease presentation. This retrospective review failed to demonstrate a
      statistical benefit for the administration of adjuvant irradiation in sarcoma of
      the breast, probably because of limited patient numbers. Because large tumor size
      and positive surgical margins incur a higher risk for LF, radiotherapy is
      probably indicated in these cases. Axillary dissection obligates the
      radiotherapist to treat the axilla in order to include all tissues in the
      surgical bed, and should be avoided to reduce potential treatment related
      morbidity. Established therapeutic principles and techniques used for both soft
      tissue sarcoma and breast cancer should continue to be applied.

PMID- 10577702
TI  - Postoperative irradiation of minor salivary gland malignancies of the head and
      neck.
AB  - OBJECTIVES: (1) To review the Stanford experience with postoperative radiotherapy
      for minor salivary gland carcinomas of the head and neck. (2) To identify
      patterns of failure and prognostic factors for these tumors. MATERIALS AND
      METHODS: Fifty-four patients with localized tumors were treated with curative
      intent at Stanford University between 1966 and 1995. The 1992 AJCC staging for
      squamous cell carcinomas was used to retrospectively stage these patients.
      Thirteen percent had stage I, 22% stage II, 26% stage III, and 39% stage IV
      neoplasms. Thirty-two patients (59%) had adenoid cystic carcinoma, 15 (28%) had
      adenocarcinoma, and seven (13%) had mucoepidermoid carcinoma. Thirty (55%) had
      positive surgical margins and seven (13%) had cervical lymph node involvement at
      diagnosis. The median follow-up for alive patients was 7.8 years (range: 25
      months-28.9 years). RESULTS: The 5- and 10-year actuarial local control rates
      were 91 and 88%, respectively. Advanced T-stage (T3-4), involved surgical
      margins, adenocarcinoma histology, and sinonasal and oropharyngeal primaries were
      associated with poorer local control. The 5- and 10-year actuarial freedom from
      distant metastasis were 86 and 81%, respectively. Advanced T-stage (T3-4), lymph
      node involvement at diagnosis, adenoid cystic and high-grade mucoepidermoid
      histology were associated with a higher risk of distant metastases. The 10-year
      cause-specific survival (CSS) and overall survival (OS) were 81 % and 63%,
      respectively. On multivariate analysis, prognostic factors affecting survival
      were T-stage (favoring T1-2), and N-stage (favoring NO). When T- and N-stage were
      combined to form the AJCC stage, the latter became the most significant factor
      for survival. The 10-year OS was 86% for stage I-II vs. 52% for stage III-IV
      tumors. Late treatment-related toxicity was low (3/54); most complications were
      mild and no cranial nerve damage was noted. CONCLUSIONS: Surgical resection and
      carefully planned post-operative radiation therapy for minor salivary gland
      tumors is well tolerated and effective with high local control rates. AJCC stage
      was the most significant predictor for survival and should be used for staging
      minor salivary gland carcinomas.

PMID- 10577704
TI  - An assessment of the number of CT slices necessary to plan breast radiotherapy.
AB  - AIMS: The aim of this study was to evaluate the number of CT slices required to
      produce satisfactory dose distribution for tangential field irradiation of the
      chest wall and breast and to assess correlation of this with the volume of breast
      tissue treated. Forty-six patients underwent a CT scan of the thorax. An
      optimized plan was produced by assessing dose distribution on the central axis
      (CAX) slice only. This plan was then recalculated using the entire CT data set
      without any changes to the beam parameters. A separate optimized plan was
      generated using the CAX slice and two slices indicative of the upper and lower
      level of the field. This three-slice plan was then calculated using the entire CT
      data set. Finally an optimized 3D plan was generated using the entire CT data
      set. The different planning methods were compared using dose-volume histograms
      (DVH). Dose inhomogeneity was defined as any treatment volume outside the ICRU 50
      dose distribution recommendations. RESULTS: Fifty-two percent of single-slice
      plans and 21% of three-slice plans (when assessed volumetrically) had greater
      volumes of breast tissue outside the ICRU 50 report guidelines suggesting that
      better homogeneity could be achieved by assessing a greater number of slices.
      Seventy-nine percent of three-slice plans showed no homogeneity improvement if
      the plan was calculated with the entire 3D data set. CONCLUSIONS: We conclude
      that a single-slice plan is unsatisfactory in providing sufficient information
      about the dose variation across the treatment volume and that ideally a 3D plan
      with DVHs should be produced. If the required data is unavailable then a minimum
      of three slices should be used as an approximation. We also propose a software
      tool for treatment planning systems, which calculates the percentage of the total
      PTV having dose outside the ICRU 50 radiation dose distribution homogeneity
      guideline range.

PMID- 10577705
TI  - Hypnosis instead of general anaesthesia in paediatric radiotherapy: report of
      three cases.
AB  - PURPOSE: This report proposes hypnosis as a valid alternative to general
      anaesthesia for immobilisation and set-up in certain cases in paediatric
      radiotherapy. METHODS: We report three cases of children who underwent
      radiotherapy in 1994 and were treated using hypnosis for set-up during
      irradiation. The first and the second were two cases of macroscopic resection of
      cerebellar medulloblastoma in which craniospinal irradiation was necessary, while
      the third patient suffered of an endorbitary relapse of retinoblastoma previously
      treated with bilateral enucleation, radiotherapy and chemotherapy; in this last
      situation the child needed radiation as palliative therapy. Hypnosis was used
      during treatment to obtain the indispensable immobility. Hypnotic conditioning
      was obtained by our expert psychotherapist while the induction during every
      single treatment was made by the clinician, whose voice was presented to the
      children during the conditioning. RESULTS: Every single fraction of the radiation
      therapy was delivered in hypnosis and without the need for narcosis. CONCLUSIONS:
      Hypnosis may be useful in particular situations to prepare paediatric cancer
      patients during irradiation, when lack of child collaboration might necessitate
      the use of general anaesthesia and when anaesthesia itself is not possible.

PMID- 10577706
TI  - Single fraction radiotherapy for bone metastases: are all questions answered?
AB  - All randomized trials show comparable pain relief rates with single or
      fractionated radiotherapy (RT) in selected patients. Further studies are required
      to determine the optimal single dose (our analysis suggests 6-8 Gy), its efficacy
      in preventing fractures/cord compression and defining criteria for recommending
      fractionated RT for a select few. Besides this, a 'lingua franca' for pain
      assessment tools is urgently required.

PMID- 10577707
TI  - Prediction of overall pulmonary function loss in relation to the 3D dose
      distribution for patients with breast cancer and malignant lymphoma.

PMID- 10577708
TI  - First Gordon Research Conference on Neurovirology and Second International
      NeuroVirology Symposium 1999.

PMID- 10577709
TI  - The fatty acid and monosaccharide compositions of three neutral and three
      phosphorylated glycolipids isolated from Leishmania donovani promastigotes grown
      in a chemically defined medium.
AB  - Several lipids and macromolecular lipoconjugates of Leishmania spp. have now been
      well characterized; however, the glycolipids of L. donovani have not been
      thoroughly examined. In the present study, 3 neutral and 3 phosphorylated
      glycolipids were detected in promastigote forms of the organism grown in a
      chemically defined medium. The fatty acid and sugar compositions of these
      glycolipids, isolated and purified by adsorption column chromatography and thin
      layer chromatographic procedures, were identified and quantified by gas-liquid
      chromatography and mass spectrometry. Myristate (14:0), palmitate (16:0),
      palmitoleate (16:1), stearate (18:0), oleate (18:1), and linoleate (18:2) were
      the major fatty acids in all 6 glycolipids. Arabinose, mannose, glucose, and
      galactose were detected in the glycolipids. The biochemical nature of these
      lipids suggested that the major components in the isolated preparations of the 6
      glycolipids are diacylglycerophospholipids, distinct from the major precursors of
      macromolecular lipoconjugates such as the lipid anchors of cell surface antigens
      that have been reported. These appear to be terminal products of lipid
      biosynthesis in this parasite.

PMID- 10577710
TI  - Developmental arrest and pregnancy-induced transmammary transmission of
      Ancylostoma caninum larvae in the murine model.
AB  - Pregnancy is associated with reactivation of latent infections of many protozoal
      and helminthic parasites. To facilitate in vivo studies on the process of
      transmammary transmission of hookworm infection to nursing newborns, we
      established an experimental model of infection of BALB/c mice with infective
      larvae of the canine nematode Ancylostoma caninum. To establish latency with a
      significant reservoir of tissue larvae and achieve acceptable pregnancy success
      rates, mice were subcutaneously infected at day 5 postimpregnation; similar
      larval distribution profiles were observed at the end of the gestational period
      for bred compared to correspondingly infected unbred animals. No larvae were
      detected in fetuses or neonatal pups. Significant numbers of larvae were not
      detected in mammary tissue during the periparturient or postpartum lactational
      periods although about 8% of a dam's reservoir of tissue larvae was transferred
      to her nursing pups; this suggests that larvae reaching the mammary glands are
      rapidly transmitted through the milk sinuses, as was documented by
      histopathological analyses. Comparison of BALB/c with C57BL/6 mice that typically
      display divergent immune responses to infection showed no difference in tissue
      larval burden or in numbers transferred to pups. A hypothesis for the molecular
      mechanism of larval reactivation and transmission is discussed.

PMID- 10577711
TI  - Enteric helminths of perch (Perca fluviatilis L.) and yellow perch (Perca
      flavescens Mitchill): stochastic or predictable assemblages?
AB  - Component communities of perch (Perca fluviatilis L) in Eurasia and the North
      American yellow perch (Perca flavescens Mitchill) were examined to determine the
      nature of their parasite communities. The scale of this investigation is
      continental and includes data collected across the distribution of each host
      species. Data were compiled from the literature and from 5 sample sites in North
      America. Four parasite species were found to occur frequently in the helminth
      component communities of P. flavescens. The cestodes Bothriocephalus cuspidatus
      and Proteocephalus pearsei, the digenean Crepidostomum cooperi, and the nematode
      Dichelyne cotylophora comprised a suite of species of which some or all occurred
      in most samples. Similarly, a group of 4 predictable parasite species was
      identified for P. fluviatilis in Eurasia, the digenean Bunodera luciopercae, the
      nematode Camallanus lacustris, the cestode Proteocephalus percae, and the
      acanthocephalan Acanthocephalus lucii. Specificity was not a requirement for
      predictability. Despite geographical isolation for millions of years, and
      different fish species interactions within and between continents, the
      predictability of these parasite assemblages indicates they are shaped by a
      biology, especially feeding patterns, common to both perch species. This is
      evidence that parasite assemblages comprised of nonhost-specific parasites in
      freshwater fishes are not merely stochastic assemblages but have key components
      that are predictable at this broad continental scale.

PMID- 10577712
TI  - Factors influencing the fecal egg and oocyst counts of parasites of wild European
      rabbits Oryctolagus cuniculus (L.) in Southern Western Australia.
AB  - Abundance of intestinal parasites was monitored by fecal egg and oocyst counts
      for samples of wild rabbits Oryctolagus cuniculus with different levels of
      imposed female sterility from 12 populations in southwestern Australia.
      Differences in egg counts of Trichostrongylus retortaeformis between seasons and
      age groups were dependent on the sex of the host. Pregnancy may have been
      responsible for these differences because egg counts were consistently higher in
      intact females than in females surgically sterilized by tubal ligation. Egg
      counts for Passalurus ambiguus were influenced by season and host age but there
      were no differences between sexes or between intact and sterilized female
      rabbits. No differences were detected in the oocyst counts of the 8 species of
      Eimeria between male and female rabbits or between intact and sterilized females.
      Seasonal differences were detected in oocyst counts of Eimeria flavescens and
      Eimeria stiedai. The overwhelming determinant of coccidian oocyst counts was host
      age, with 6 species being much more abundant in rabbits up to 4 mo of age. There
      was a suggestion that egg counts of T. retortaeformis and oocyst counts of
      several species of Eimeria were reduced in populations where rabbit numbers had
      been depressed for at least 2 yr, but there was no evidence that short-term
      variations in rabbit numbers had a measurable effect on parasite abundance.

PMID- 10577713
TI  - Evaluation of the association of parasitism with mortality of wild European
      rabbits Oryctolagus cuniculus (L.) in southwestern Australia.
AB  - Abundances of the parasitic nematodes Trichostrongylus retortaeformis and
      Passalurus ambiguus, and 8 Eimeria species were estimated by fecal egg and oocyst
      output in 12 discrete free-ranging populations of wild rabbits (Oryctolagus
      cuniculus) in southwestern Australia. Comparisons of parasite egg and oocyst
      counts were made between those rabbits known to have survived at least 2 mo after
      fecal samples were collected and those rabbits that did not survive. There were
      significant negative relationships between parasite egg and oocyst counts and
      survival when all age groups and collection periods were pooled for several
      species of coccidia and for T. retortaeformis. However, when the same comparisons
      were made within rabbit age groups and within collection periods, there were very
      few significant differences even where sample sizes were quite large. The
      differences indicated by the pooled analysis for coccidia were most likely due to
      an uneven host age distribution with respect to survival, combined with an uneven
      distribution of the oocyst counts with rabbit age. The result for T.
      retortaeformis was similarly affected but by a seasonal pattern. Parasitism by
      nematodes and coccidia did not appear to be an important mortality factor in
      these rabbit populations, at least at the range of host densities we examined.
      This suggests that other factors must have been responsible for the observed
      pattern of density-dependent regulation in these rabbits.

PMID- 10577714
TI  - New host and ocean records and remarks on the morphology and behavior of Jusheyus
      shogunus (Copepoda: Siphonostomatoida: Eudactylinidae.
AB  - Jusheyus shogunus Deets and Benz, 1987 (Copepoda: Eudactylinidae) is reported
      from wreckfish, Polyprion americanus (Schneider, 1801) collected from widely
      separated locations in the north Atlantic. This represents a new host record and
      new ocean report for this parasite. Examination of male and female copepods
      allowed some confusion regarding the morphology of J. shogunus to be eliminated.
      Jusheyus shogunus possesses a cephalothorax rather than a cephalosome and its
      dorsal styliform processes are connected by an internal bridging sclerite and an
      external dorsal plate that is hinged to its cephalothorax. Each process also
      articulates with its own internal ventral sclerite. A series of muscles services
      these structures, and comparisons of the dorsal styliform processes of J.
      shogunus with the dorsal stylets of Kroyeria spp. revealed some morphological
      similarities. Adult female J. shogunus in the study collection varied in size
      from 2.16 to 4.97 mm total length, and smaller and larger specimens presented
      somewhat different body forms. Most egg sacs contained multiseriately arranged
      eggs; however, several specimens possessed a sac whose distal portion contained
      uniseriately arranged eggs and whose proximal portion contained 2 rows of eggs.
      Jusheyus shogunus attaches to the gill filament lamellae of its hosts using its
      second antennae and maxillipeds. The dorsal styliform processes can be erected by
      either directly raising them or by flexing the cephalothorax at its junction with
      the first free thoracic segment. In either case the tips of the processes can
      engage 1 to several lamellae on the adjacent gill filament to help secure the
      parasite.

PMID- 10577715
TI  - Phylogeny of the leech family Glossiphoniidae based on mitochondrial gene
      sequences and morphological data.
AB  - The phylogenetic relationships of the Glossiphoniidae (Rhynchobdellida) were
      investigated using morphological characters and the mitochondrial genes
      cytochrome c oxidase subunit I and nicotinamide adenine dinucleotide
      dehydrogenase subunit 1. Thirty-five taxa representing 10 of the 23 currently
      recognized glossiphoniid genera were sampled, including more than 70% of known
      North American species, as well as others from Europe, South America, Africa, and
      a species endemic to Lake Baikal. Outgroup taxa included species from the
      Piscicolidae and Ozobranchidae. Cladistic analysis resulted in 1 most
      parsimonious tree. Subfamily distinctions, i.e., Haementeriinae, Theromyzinae,
      and Glossiphoniinae, that have been based on eye morphology and reproductive
      biology are not corroborated. Results also provide insights into several
      problematic genus-level classifications. For example, relationships of
      Placobdella and Haementeria are clarified and elimination of Desserobdella may be
      necessary. Bloodfeeding from vertebrates is seen to be a primitive characteristic
      that has been lost twice within the clade. The hypothesis that the biannulate
      leech, Oligobdella biannulata, represents an important transitional form is re
      evaluated in a phylogenetic context.

PMID- 10577716
TI  - Variation in the density of questing Ixodes pacificus (Acari:Ixodidae) nymphs
      infected with Borrelia burgdorferi at different spatial scales in California.
AB  - The density of, and prevalence of infection with Borrelia burgdorferi in, Ixodes
      pacificus nymphs as well as the density of infected nymphs were compared at 12
      properties at a small rural community at high risk for Lyme disease (CHR) and at
      12 areas at the University of California Hopland Research and Extension Center
      (HREC), Mendocino County, California. The mean infection prevalence and density
      of infected nymphs were 1.7% (range, 0-4.2%) and 0.10 infected nymphs per 100 m2
      (range, 0-0.23 per 100 m2) at the HREC, and 12.4% (range, 3.9-41.3%) and 1.83
      infected nymphs per 100 m2 (range, 0.29-22.17 per 100 m2) at the CHR. Thus, the
      mean density of infected nymphs differed 18-fold between CHR and HREC and 76-fold
      between properties at the CHR. Also, there was up to 10-fold variation in
      infection prevalence and 16-fold variation in density of infected nymphs between
      discrete areas within properties at the CHR. The high densities of infected
      nymphs recorded at the CHR suggest that, despite the low statewide incidence of
      Lyme disease, the medical community should be alerted that Lyme disease can be
      highly endemic in rural areas of northwestern California. The prevalence of
      spirochetal infection was higher for nymphs collected in southern/western, as
      compared to northern/eastern, exposures at both HREC and CHR. Infection
      prevalence and nymphal density were negatively associated at the HREC, whereas
      they tended to be associated positively at the CHR. A positive association was
      observed between nymphal density and density of infected nymphs when data from
      CHR and HREC were combined, and when data from the CHR were considered alone, but
      not for data from the HREC alone.

PMID- 10577717
TI  - Spermatogenesis and spermiogenesis in Microcotyle sp. (Microcotylidae,
      Monogenea).
AB  - Ultrastructural observations of spermatogenesis and spermiogenesis in Microcotyle
      sp. a microcotylid monogenean parasite from the gills of Hypostomus sp., are
      described. The spermatogonia were irregularly shaped, forming a peripheral layer
      of cells; spermatocytes were larger than spermatogonia and a nuclear synaptonemal
      complex was observed; young spermatids were joined by a central cytophore forming
      rosettes. Spermiogenesis was characterized by the outgrowth of a cytoplasmic
      protuberance, the zone of differentiation, containing the basal bodies, separated
      by an intercentriolar body, from which flagella grow out and fuse posteriorly
      with the median process. Cross sections of the anterior and the middle regions of
      spermatozoa revealed nuclei, mitochondria, peripheral microtubules, and paired
      axonemes each with a 9+1 pattern.

PMID- 10577718
TI  - Cryptosporidium parvum: structural components of the oocyst wall.
AB  - Cryptosporidium parvum, an enteropathogenic parasite, infects a wide range of
      mammals including man and constitutes a substantial veterinary and medical threat
      due to its ubiquitous distribution and the stability of the oocyst stage. The
      oocyst wall of C. parvum is known to be extremely resistant to chemical and
      mechanical disruption. Isolated oocyst walls are shown by both thin sectioning
      and negative staining transmission electron microscopy to possess a filamentous
      array on the inner surface. This filamentous array can be greatly depleted by
      digestion with proteinase K and trypsin, but pepsin has less effect.
      Ultrasonication of the untreated oocyst walls produced almost no fragmentation,
      but extension of the suture resulted in inward spiraling of the wall to generate
      ellipsoid and cigar-shaped multilayer bodies, with the filamentous array still
      present. When ultrasonicated, proteinase K-digested oocyst walls progressively
      fragmented into small sheets. These wall fragments, depleted of filaments, are
      shown by negative staining to possess a pronounced linearity, indicative of an
      integral highly complex lattice structure.

PMID- 10577719
TI  - A revised arithmetic model of long slender to short stumpy transformation in the
      African trypanosomes.
AB  - An arithmetic model that closely approximates an African trypanosome infection in
      immunosuppressed mice is presented. The final model was based on an examination
      of the following parameters: the rate of long slender to short stumpy transition,
      the maximum percentage of long slender to short stumpy stages that can be
      induced, the survival time or half life of the short stumpy stage in vivo, and
      the rate (%) of long slender to short stumpy stage transition following the peak
      in transformation. The model is based on the assumption that the long slender to
      short stumpy transition is parasite population dependent and that in mice the
      long slender to short stumpy transition only begins when the trypanosome
      population reaches a density of 1 x 10(7) trypanosomes/ml. The model predicts
      that the parasitemia during the first several days of an infection is controlled
      solely by the kinetics of the transition of the dividing long slender stage to
      the nondividing short stumpy stage. It was not necessary to include in the model
      the host's immune response in order to simulate the early growth kinetics of
      pleomorphic trypanosomes in infected mice.

PMID- 10577720
TI  - A field trial of the effectiveness of a feline Toxoplasma gondii vaccine in
      reducing T. gondii exposure for swine.
AB  - A 3-yr field trial was conducted on 8 commercial swine farms in Illinois to
      determine the effectiveness of a feline Toxoplasma gondii vaccine in reducing the
      exposure of swine to T. gondii. A vaccine consisting of live bradyzoites of the
      mutant T-263 strain, capable of preventing oocyst shedding by cats, was used in
      this study. Each farm was visited 3 times in 1994, 3 times in 1995, and once in
      1996. Cats were trapped and inoculated with the T-263 oral vaccine during 1994
      and 1995. On each visit, the following samples were collected: blood from pigs,
      cats, and mice for detection of serum antibodies to T. gondii, feces from cats to
      detect oocysts, and heart and brain tissues from rodents to determine the
      presence of T. gondii tissue cysts. The modified agglutination test (MAT), with a
      positive titer set at the 1:25 dilution, was used to determine serum antibodies.
      At first capture, 72.6% (61/84) of juvenile cats and 32.6% (31/95) of adult cats
      had no detectable antibodies (seronegative), indicating no prior exposure to T.
      gondii when they received their first vaccine. Of these first-time seronegative
      cats, 58.1% (18/31) of adult and 45.9% (28/61) of juvenile cats were recaptured
      and received a second dose of vaccine. Changes in the prevalence of T. gondii
      infection were evaluated from the prevaccination (1992, 1993) to the
      postvaccination (1996) period. Eleven cats (5%) were detected shedding oocysts
      between 1994 and 1996, of which 10 (90.1%) shed during 1994. The last detection
      of oocyst shedding by cats was during the first farm visit in 1995. There was a
      significant decrease in T. gondii seroprevalence for finishing pigs (P < 0.05,
      Wilcoxon sign rank test). There was a positive correlation (Spearman's p = 1.0, P
      < 0.0001) between the change in prevalence in juvenile cats and the change in
      prevalence in finishing pigs. The seropositivity rate (MAT > or = 1:25) in mice
      among all farms decreased from 4% in 1992-1993 to 0% in 1996. The mean prevalence
      of T. gondii tissue cyst isolation for mice on all farms decreased from 1.1% in
      1994, to 0.8% in 1995, and to 0.5% in 1996. The results of this study suggest
      that the reduced exposure of pigs to T. gondii was due to the administration of
      the T. gondii vaccine to cats.

PMID- 10577722
TI  - One fate of bloodstream trypomastigote forms of Trypanosoma cruzi after immune
      clearance: an ultrastructural study.
AB  - The fate of bloodstream forms of Trypanosoma cruzi in tissues of mice was studied
      after immune elimination from circulation. Observations using transmission
      electron microscopy showed platelet thrombi occluding small vessels in the lung,
      liver, and spleen, and phagocytosed parasites in different stages of destruction
      within macrophages, neutrophils, and eosinophils. It is suggested that no
      particular cell population is a potential effector, but that different cells act
      in concert to destroy the parasites. The mechanism of this destruction might be
      related to intra- and extracellular mechanisms with trypanolytic activity.

PMID- 10577721
TI  - Longitudinal cellular immune responses in asymptomatic and symptomatic Brugia
      malayi-infected Indian leaf monkey Presbytis entellus.
AB  - To investigate the cell-mediated immune (CMI) responses of the host during the
      development of acute filarial disease manifestations, we studied the sequential
      changes in CD4+ and CD8+ T-cell subsets, leukocyte migration inhibition (LMI)
      response to Brugia malayi adult worm antigen, and concanavalin-A (ConA) and
      filarial antigen-induced lymphocyte transformation (LT) in the Indian leaf monkey
      (Presbytis entellus)-B. malayi model. Filarial infection was established in
      monkeys by subcutaneous inoculations of infective larvae (L3) (700-1,250
      L3/monkey) in multiple doses, and the infected monkeys were categorized as
      symptomatic (Sym) and asymptomatic (Asym) depending on whether or not acute
      clinical manifestations were shown by them. In Sym monkeys, LMI response to
      homologous adult parasite antigen was significantly suppressed as compared to
      Asym monkeys. In Asym monkeys, LMI response varied among the animals; 2 showed an
      increase throughout the study period and 2 showed suppression at different time
      points. When compared with Asym monkeys, CD8+ T cells in Sym monkeys showed a
      trend of significant increase after day 180 postinoculation (PI). CD4+ T cells
      remained within the normal range till day 300 (PI), after which they showed a
      marginal increase. ConA-stimulated LT was suppressed in Asym monkeys from day 60
      PI. Antigen-stimulated LT was unresponsive in both Asym and Sym animals. Thus,
      the host's LT response to ConA is suppressed in Asym animals, and alteration in
      CD8+ T-cell number and LMI response in Sym monkeys may be involved in the
      development of the acute disease manifestations in this model.

PMID- 10577723
TI  - Cross-transmission studies with Eimeria arizonensis, E. arizonensis-like oocysts
      and Eimeria langebarteli: host specificity at the genus and species level within
      the Muridae.
AB  - Cross-transmission experiments were done using sporulated oocysts of Eimeria
      arizonensis from Peromyscus truei and Peromyscus maniculatus, and oocysts of 2
      putative species that resemble E. arizonensis, i.e., Eimeria albigulae from
      Neotoma albigula, and Eimeria onychomysis from Onychomys leucogaster. Oocysts of
      each species were inoculated into representatives of P. maniculatus and the
      latter 2 rodent species. Other experiments were conducted wherein oocysts of
      Eimeria langebarteli from Peromyscus leucopus were given to P. truei and P.
      maniculatus. Oocysts of E. arizonensis from P. truei and P. maniculatus could be
      transmitted only to P. maniculatus; likewise, oocysts of E. albigulae and E.
      onychomysis produced patent infections only in N. albigula and O. leucogaster,
      respectively. Oocysts of E. langebarteli from P. leucopus could be transmitted to
      P. truei, but not P. maniculatus. These results indicate that E. arizonensis, and
      the morphologically similar E. albigulae and E. onychomysis, are distinct species
      that are not transmissible between the genera of their respective hosts
      (Peromyscus, Neotoma, Onychomys), and that some isolates of E. langebarteli,
      reported from 6 species of Peromyscus and Reithrodontomys megalotis, may not
      always be infective to P. maniculatus.

PMID- 10577724
TI  - Cold stress-induced modulation of inflammatory responses and intracerebral
      cytokine mRNA expression in acute murine toxoplasmosis.
AB  - The effects of a physical stressor, cold water stress (CWS), within the central
      nervous system were investigated in the acute phase of infection with Toxoplasma
      gondii. Female BALB/c mice were subjected to CWS for 5 min each day for 8 days
      prior to oral infection with 20 cysts of the low virulent ME 49 strain. Animals
      were killed at 10-day intervals to detect inflammation, gliosis, and expression
      of intracerebral cytokine mRNAs. Zones of inflammation were detected by Nissl
      staining and gliosis by immunoreactivity to glial fibrillary acidic protein.
      Larger zones of inflammation and reactive astrogliosis were consistently observed
      in mice subjected to CWS and infected (CWS +INF) compared to control infected
      (INF) mice. Expression of interleukin (IL)-1beta, IL-2, IL-12, interferon (IFN)
      gamma, tumor necrosis factor (TNF)-alpha, and inducible nitric oxide synthase
      (iNOS) were decreased in CWS+INF mice at 10 days postinoculation (PI), followed
      by a gradual increase after day 20 PI. This was in contrast to increased
      expression of these cytokines at 10 days PI in INF mice with a gradual decline
      thereafter. Inflammation and astrogliosis in CWS+INF mice were associated with an
      increased expression of IL-1beta, IL-6, IL-12, and TNF-alpha between 20 and 30
      days PI. These findings correlated with the continuous gene expression of
      tachyzoite surface antigen (SAG)-1 mRNA in CWS+INF mice compared to its sharp
      decline in INF mice after 20 days PI. These results suggest that CWS delays
      regulation and control of intracerebral Toxoplasma gondii during acute infection
      in BALB/c mice by decreasing the early expression of IFN-gamma, IL-2, TNF-alpha,
      iNOS, IL-1beta, and IL-12, while increasing the expression of IL-6, a
      counterregulatory cytokine.

PMID- 10577725
TI  - Tissue damage in the male murine reproductive system during experimental Taenia
      crassiceps cysticercosis.
AB  - Chronic infection with Taenia crassiceps cysticerci in male mice increases the
      level of estradiol in serum, whereas it reduces that of testosterone. In
      addition, male mice lose their typical male reproductive behavior. The effects of
      cysticerci infection on the histomorphology of male reproductive tissues are
      unknown. The present study was undertaken to determine the histological changes
      in testes, seminal vesicles, and prostate of male mice infected with T.
      crassiceps cysticerci. At 16 wk of infection, all tissues exhibited high
      inflammatory infiltrate. Tissue lesions included marked dilation and peripheral
      fibrosis. In the testes, a diminution of spermiogenesis was observed. The overall
      results indicated that the histological changes in chronically parasitized male
      mice occurred with changes in hormone levels, simultaneously with the high
      inflammatory immune response.

PMID- 10577726
TI  - Allopodocotyle chiliticorum n. sp. (Digenea: Opecoelidae) from redlip shiners,
      Notropis chiliticus, in Basin Creek, North Carolina.
AB  - Allopodocotyle chiliticorum n. sp. is described from the intestines of redlip
      shiners (Notropis chiliticus) from Basin Creek, North Carolina. The new species
      is characterized by circumcecal vitelline fields that are not confluent in the
      post-testicular space, which distinguishes it from the 3 previously known species
      of this genus described from freshwater fishes. The new species is characterized
      further by an elongate vitelline reservoir lying dorsal to the ovary, an ovary as
      large or larger than the testes, and an excretory vesicle not reaching the
      posterior testis. A. chiliticorum n. sp. most closely resembles Allopodocotyle
      lepomis (Dobrovolny, 1939) in body shape, testes shape, and terminal genitalia
      but is distinguished further from this species by the extent of the intestinal
      ceca. The new species is the fourth species of Allopodocotyle known from
      freshwater fishes in North America.

PMID- 10577727
TI  - Two new species of Oochoristica Luhe, 1898 (Eucestoda: Cyclophyllidea:
      Anoplocephalidae: Linstowiinae) parasitic in Ctenosaura spp. (Iguanidae) from
      Costa Rica and Mexico.
AB  - Five species of Oochoristica, Oochoristica osheroffi, Oochoristica gracewileyae,
      Oochoristica whitentoni, and 2 new species described herein have strobilae longer
      than 200 mm, many secondary ovarian lobes, and testes extending anteriorly to
      midovarian level. A combination of 3 characters distinguishes the 5 species from
      each other. Oochoristica osheroffi has an average of 68 testes per proglottid,
      ovarian lobes wider than long, and osmoregulatory canals not forming an
      anastomosing plexus; O. gracewileyae has an average of 113 testes per proglottid,
      ovarian lobes longer than wide, and osmoregulatory canals not forming an
      anastomosing plexus; O. whitentoni has an average of 125 testes per proglottid,
      ovarian lobes wider than long, and osmoregulatory canals forming an anastomosing
      plexus; a new species in Ctenosaura similis from Costa Rica has an average of 62
      testes per proglottid, ovarian lobes longer than wide, and osmoregulatory canals
      forming an anastomosing plexus; and a new species in Ctenosaura pectinata from
      Mexico has an average of 122 testes per progottid, ovarian lobes longer than
      wide, and osmoregulatory canals forming an anastomosing plexus. Oochoristica
      gracewileyae differs from the other 4 species by having genital pores 10-15%
      rather than 25-35% of proglottid length from the anterior end and by having
      convoluted rather than straight or sinuous transverse osmoregulatory canals. The
      new species from Mexico differs from the other 4 species and apparently from all
      described species of Oochoristica thus far by possessing darkly staining granules
      throughout the parenchyma of the scolex.

PMID- 10577728
TI  - Spauligodon ovifilus n. sp. (Nematoda: Pharyngodonidae) and other helminths from
      Diplodactylus stenodactylus (Reptilia: Gekkonidae) from Australia.
AB  - Spauligodon ovifilus n. sp. (Nematoda: Pharyngodonidae) from the large intestines
      of the gecko Diplodactylus stenodactylus is described and illustrated. Prevalence
      of infection was 50% (mean intensity 5.9 +/- 6.3, range 1-21). Spauligodon
      ovifilus n. sp. represents the thirty-fifth species to be assigned to this genus
      and is distinguished by the extremely long filament of the egg. This is the first
      report of species of Spauligodon from Australia. In addition, 1 gecko harbored 1
      female of Wanaristrongylus papangawurpae, a new host record; 1 gecko harbored 1
      encapsulated larva of Abbreviata sp. Review of species assigned to Spauligodon
      caused the reclassification of Spauligodon azerbajdzanicus to Skrjabinodon
      azerbajdzanicus n. comb.

PMID- 10577729
TI  - Sarcocystis speeri N. sp. (Protozoa: Sarcocystidae) from the opossum (Didelphis
      virginiana).
AB  - The North American opossum (Didelphis virginiana) is host to at least 3 species
      of Sarcocystis: Sarcocystisfalcatula, Sarcocystis neurona, and a recently
      recognized Sarcocystis sp. A new name, Sarcocystis speeri, is proposed for the
      third unnamed Sarcocystis. Immunodeficient mice are an experimental intermediate
      host for S. speeri. Sarcocystis speeri sporocysts are 12-15 x 8-10 microm in
      size, and its schizonts are found in many organs of mice. Sarcocysts of S. speeri
      are found in skeletal muscles and they are up to 5 mm long and filiform. By light
      microscopy, the sarcocyst wall is thin (<1 microm thick); ultrastructurally, the
      cyst wall is up to 1.8 microm thick and has characteristic steeple-shaped villar
      protrusions surmounted by a spire. Sarcocystis speeri schizonts are
      morphologically and antigenically distinct from schizonts of S. neurona, and S.
      speeri sporocysts were not infective to budgerigars (Melopsittacus undulatus).

PMID- 10577730
TI  - Structure, biodiversity, and historical biogeography of nematode faunas in
      holarctic ruminants: morphological and molecular diagnoses for Teladorsagia
      boreoarcticus n. sp. (Nematoda: Ostertagiinae), a dimorphic cryptic species in
      muskoxen (Ovibos moschatus).
AB  - Discovery of the ostertagiine nematode Teladorsagia boreoarcticus n. sp. in
      muskoxen, Ovibos moschatus, from the central Canadian Arctic highlights the
      paucity of knowledge about the genealogical and numerical diversity of nematode
      faunas characteristic of artiodactyls at high latitudes across the Holarctic.
      Teladorsagia boreoarcticus is a dimorphic cryptic species distinguished from
      Teladorsagia circumcincta/Teladorsagia trifurcata in domestic sheep by a 13%
      divergence in the ND4 region of mitochondrial DNA, constant differences in the
      synlophe, and significantly longer esophageal valve, spicules, gubernaculum, and
      bursa. Teladorsagia boreoarcticus represents an archaic component of the North
      American fauna and may have a Holarctic distribution in muskoxen and caribou.
      Recognition of T. boreoarcticus in muskoxen, in part, corroborates hypotheses for
      the existence of a cryptic species complex of Teladorsagia spp. among Caprinae
      and Cervidae at high latitudes and indicates the importance of climatological
      determinants during the late Tertiary and Pleistocene on diversification of the
      fauna. Also reinforced is the concept of the North American fauna as a mosaic of
      endemic and introduced species. Discovery of a previously unrecognized species of
      Teladorsagia has additional implications and clearly indicates that (1) our
      knowledge is incomplete relative to potentially pathogenic nematodes that could
      be exchanged among domestic and wild caprines; (2) we do not have sufficient
      knowledge of the fauna to understand the ecological control mechanisms
      (limitations) on dissemination and host range; and (3) an understanding of
      historical and geographical influences on the genealogical diversity and
      distribution of nematode faunas in domestic and wild ruminants is requisite to
      define the interface between agricultural and natural ecosystems across the
      Holarctic.

PMID- 10577731
TI  - Differentiation of Mexican species of Haematoloechus looss, 1899 (Digenea:
      Plagiorchiformes): molecular and morphological evidence.
AB  - Molecular evidence is interpreted in the light of morphology to examine the
      validity of several species of Haematoloechus described as Mexican endemics.
      Internal transcribed spacers 1 and 2 and 28S ribosomal genes were sequenced for
      11 isolates. Phylogenetic analysis of separate partitions and combined databases
      was conducted. Results were analyzed, in the light of morphological evidence.
      Haematoloechus macrorchis is proposed as a junior synonym of Haematoloechus
      longiplexus. Haematoloechus pulcher is a sibling species with Haematoloechus
      complexus in Lerma wetlands. In Mexico, Haematoloechus medioplexus is distributed
      along the east coast coinciding with the distribution of Rana berlandieri. The
      sister species of H. medioplexus is Haematoloechus coloradensis, sharing the
      distribution of the uterus as a synapomorphic character. Haematoloechus illimis
      is more closely related to H. medioplexus and H. coloradensis than to H.
      complexus. It can be distinguished by the distribution of the uterus, lobed
      ovary, and testes.

PMID- 10577732
TI  - Detection of Toxoplasma gondii parasitemia in experimentally inoculated cats.
AB  - Toxoplasma gondii B1 gene polymerase chain reaction (PCR) amplification utilizing
      a flanking and nesting reaction was compared to mouse bioassay on feline whole
      blood samples collected before and after experimental inoculation with T. gondii.
      Samples were collected from 5 cats prior to inoculation with T. gondii and on
      days 3, 7, 10, 14, 21, 28, 35, 42, 49, 56, 63, 70, 84, 112, 140, 143, 147, 150,
      154, 161, 168, 175, and 182 after inoculation. Cats were challenged with T.
      gondii orally on day 140. Bioassay was found to be less effective for detection
      of parasitemia than B1 gene PCR. Parasitemia was detected in all 5 cats by PCR
      multiple times after primary and challenge inoculation. Detection of T. gondii
      parasitemia by PCR utilizing the flanking reaction described here may be useful
      in predicting the oocyst shedding period in individual cats. As none of the cats
      developed signs of systemic illness, yet were chronically parasitemic, T. gondii
      whole-blood PCR is not helpful as a diagnostic test for clinical feline
      toxoplasmosis.

PMID- 10577733
TI  - Oral dosing of neonatal mice with sucrose reduces infection with Cryptosporidium
      parvum.
AB  - Cryptosporidium parvum is a significant cause of diarrheal disease in humans and
      economically important livestock species. There is no effective treatment
      available for this protozoan parasite. Mechanisms of intestinal colonization by
      C. parvum are not well understood, but it has been suggested that the parasite
      may utilize a lectin-like receptor. We used an infant mouse model to test whether
      high sugar concentrations in the intestine would affect in vivo colonization with
      C. parvum. We found that a single oral dose of sucrose, administered to mice at
      the time of, or 24 hr before, challenge with C. parvum significantly reduced
      infection. Significant reduction of infection was also seen in mice given
      isomaltose. Histologic examination of intestinal sections of mice treated with
      sucrose or isomaltose, but not other sugars, showed marked vacuolation of the
      small intestinal epithelium 1 day after treatment. Three days after treatment,
      tissue appeared normal. Thus, sucrose and, to a lesser extent, isomaltose reduced
      in vivo colonization with C. parvum and altered epithelial cell morphology in
      intestines of mice.

PMID- 10577734
TI  - The effect of chloroquine on the production of interferon-gamma, interleukin (IL)
      4, IL-6, and IL-10 in Plasmodium chabaudi chabaudi in infected C57BL6 mice.
AB  - The effect of chloroquine (CQ) on the production pattern of interferon (IFN)
      gamma, interleukin (IL)-4, IL-6, and IL-10 in female C57BL6 mice infected with
      Plasmodium chabaudi chabaudi AS was evaluated during a period of 35 days. Our
      data confirm that there is a switch from a T helper cell (Th)1 to a Th2 response
      during malaria infection in this model. Proliferation assays showed a decreased
      stimulation index in infected mice that was further reduced in infected mice
      treated with CQ. Noninfected control mice treated with CQ showed an increase
      production of IFN-gamma. However, no detectable changes in IL-4, IL-6, and IL-10
      production were observed in this group. CQ treatment of infected mice resulted in
      parasite clearance that was associated with an earlier production of IL-4, IL-6,
      and IL-10 when compared with nontreated infected mice. We suggest that this
      earlier switch to a Th2 response is a consequence of parasite killing rather than
      CQ interference with cytokine production.

PMID- 10577735
TI  - Recovery of Trichuris tenuis Chandler, 1930, from camelids (Lama glama and
      Vicugna vicugna) in Argentina.
AB  - A survey of whipworms was conducted in llamas and vicunas in northwestern
      Argentina. Fecal examinations of a group of 14 llamas (April 1995-March 1996) and
      69 vicunas (November 1996) indicated a high prevalence (usually >50%) of
      Trichuris sp. in these hosts. Prevalence was highest during July-November 1995
      that also coincided with the highest mean fecal egg count. During postmortem
      examinations of 1 llama and 1 vicuna, specimens of Trichuris tenuis were
      recovered from the cecum/large intestine of each camelid. This is the first
      report of T. tenuis in South America, and the first report in the vicuna. It is
      suggested that T. tenuis is the typical whipworm of aboriginal camelids.

PMID- 10577736
TI  - Cipangopaludina chinensis malleata (Gastropoda: Viviparidae): a new second
      molluscan intermediate host of a human intestinal fluke Echinostoma cinetorchis
      (Trematoda: Echinostomatidae) in Korea.
AB  - Two species of the viviparid snails have been reported in Korea, e.g.,
      Cipangopaludina chinensis malleata and Cipangopaludina japonica. Cipangopaludina
      chinensis malleata collected at 3 of 12 localities were found to be infected with
      metacercariae of Echinostoma cinetorchis, one of the snail-borne human intestinal
      trematodes in Korea. Metacercariae from these snails were fed to rats (S/D
      strain), and adult worms of E. cinetorchis, characterized by 37-38 collar spines
      on the head crown, were recovered from the ileocecal regions. However, no C.
      japonica collected from 2 localities harbored the metacercariae. In experiments
      with laboratory-bred viviparid snails, all viviparids were not susceptible to
      miracidia of E. cinetorchis. To confirm the identity of second intermediate hosts
      of E. cinetorchis experimentally, 2 species of viviparid snails were exposed to
      the cercariae from Segmentina hemisphaerula that had been infected with miracidia
      of E. cinetorchis. Both species of snails were susceptible to cercariae of E.
      cinetorchis. This is the first report of Cipangopaludina spp. serving as the
      second intermediate host of E. cinetorchis and as a potential source of human
      infection.

PMID- 10577737
TI  - Hepatic sarcocystosis in a horse.
AB  - Hepatic sarcocystosis was diagnosed in a horse in association with refractory
      bacterial osteomyelitis and plasma cell tumor of the maxilla and hepatic
      salmonellosis. Gross lesions included pleural, pericardial, and peritoneal
      effusions, hepatomegaly, gastric ulceration, colonic edema, and proliferative
      tissues filling 2 maxillary dental alveoli. Histologically, liver was
      characterized by severe suppurative, necrotizing, periportal hepatitis, and
      severe periacinar necrosis. Hepatocytes frequently contained protozoal schizonts
      in various stages of development. In mature schizonts, merozoites were often
      arranged radially around a central residual body, consistent with asexual
      division by endopolygeny. Ultrastructural features of merozoites included an
      apical conoid and polar ring, anterior micronemes, central nuclei, and absence of
      rhoptries. These protozoa did not react to antisera raised against Neospora
      caninum, Sarcocystis neurona, Toxoplasma gondii, or Hammondia hammondi. The
      microscopic and ultrastructural characteristics and immunoreactivity of this
      organism are consistent with a Sarcocystis sp. other than S. neurona. This is the
      first report of Sarcocystis-associated hepatitis in a horse. The life cycle of
      this organism and source of infection are unknown.

PMID- 10577738
TI  - Prevalence of antibodies to Neospora caninum in horses in North America.
AB  - Serum samples from 296 horses slaughtered for food in the United States were
      tested for antibodies to Neospora caninum by the Neospora-agglutination test
      (NAT). Antibodies were found in 69 (23.3%) horses with titers of 1:40 (19
      horses), 1:80 (19 horses), 1:100 (3 horses), 1:200 (7 horses), 1:400 (4 horses),
      and 1:800 (17 horses). This is the first serologic survey for N. caninum
      antibodies in horses.

PMID- 10577739
TI  - Trypanosoma cruzi: increased 5'-nucleotidase activity associated with dysfunction
      of adrenergic receptors in acutely infected albino Swiss mice.
AB  - Adenosine, derived from hydrolysis of 5'-AMP by 5'-nucleotidase activity, may be
      involved in coupling coronary blood flow to cardiac function and metabolism; it
      has been postulated as a cardioprotective substance in ischemic myocardium. The
      stimulation of beta-adrenergic receptors produces an increase in adenosine by 5'
      AMP hydrolysis. In addition, it has been demonstrated that in Chagas' disease
      there is decreased cardiac perfusion. We show in this paper by histochemical and
      densitometric procedures that ecto-5'-nucleotidase activity increases in
      ventricles of acutely Trypanosoma cruzi-infected mice and that the density of
      beta-adrenergic receptors is significantly diminished with affinity similar to
      controls, showing that a compensatory mechanism was absent. The increase of ecto
      5'-nucleotidase in heart myocytes from infected mice may produce cardioprotective
      adenosine that may be independent of beta-adrenergic function, based on the
      hypoperfusion conditions of acute chagasic cardiomyopathy.

PMID- 10577740
TI  - Toxoplasma gondii: difference of invasion into tissue of digestive organs between
      susceptible and resistant strain and influence of IFN-gamma in mice inoculated
      with the cysts perorally.
AB  - Because it is widely accepted that there is a significant difference in
      susceptibility to chronic infection by Toxoplasma gondii among inbred mouse
      strains with different genetic backgrounds, we compared the distribution of the
      protozoa in digestive organs at early stages of infection between resistant
      (BALB/c) and susceptible (C57BL/ 6) mice after peroral infection with Fukaya
      strain cysts. Furthermore, to determine the influence of interferon gamma (IFN
      gamma) on the infectivity of the cysts to the digestive tract, homozygous IFN
      gamma knockout mice were utilized. Quantitative competitive polymerase chain
      reaction (QC-PCR) was employed to assess the distribution of T. gondii in
      different organs at various times after ingestion of cysts. SAG1, a T. gondii
      specific gene, was detected in the small intestine and the caecum in wild-type
      C57BL/6 mice and in the whole digestive tract in IFN-gamma knockout C57BL/6 at 24
      hr after infection. No detectable reaction in QC-PCR was observed in BALB/c mice
      at 24 hr after ingestion of the cysts. Destruction of the IFN-gamma gene showed
      less effect on the resistance to infection in BALB/c mice, but remarkable
      augmentation of infectivity of T. gondii to the rectum and peripheral blood was
      observed in C57BL/6 mice.

PMID- 10577741
TI  - Resolution of six chromosomes of Trichomonas vaginalis and conservation of size
      and number among isolates.
AB  - The electrophoretic karyotype of Trichomonas vaginalis isolates was determined by
      contour-clamped homogeneous electric field electrophoresis. Six chromosomal bands
      ranging between 50 kbp and 6 Mbp were reliably resolved by our separation method.
      Trichomonad chromosomes fell into 3 distinct size classes. The 3 maxichromosomes
      were approximately 5,700, 4,700, and 3,500 kbp. Two intermediate-sized
      chromosomes were approximately 1,200 kbp and 1,100 kbp. A minichromosome was
      approximately 75 kbp. The same size and number of chromosomes were present in 15
      T. vaginalis isolates obtained from different geographic regions, reinforcing the
      idea of a highly conserved karyotype among trichomonal isolates worldwide.

PMID- 10577742
TI  - Simplified technique for isolation, excystation, and culture of Sarcocystis
      species from opossums.
AB  - Sarcocystis neurona is a protozoan parasite that causes a neurological disease in
      horses called equine protozoal myeloencephalitis. The route of transmission is
      speculated to be by fecal-oral transfer of sporocysts shed from opossums.
      Controversy exists regarding both the natural life cycle for this parasite as
      well as the species identity of opossum Sarcocystis. To provide stage-specific
      material for species comparison, 27 opossums from southern Michigan were screened
      for Sarcocystis spp. sporocysts. Seven opossums were positive for Sarcocystis
      sporocysts by fecal flotation. A simplified, effective technique for isolation,
      excystation, and culture of opossum Sarcocystis sp. from mucosal scrapings was
      developed. All 7 Sarcocystis sp. isolates were successfully cultured to grow long
      term in equine dermal cells to the merozoite stage. Merozoites were observed
      between 5 and 15 days after inoculation. In conclusion, opossums shed Sarcocystis
      sp. sporocysts that may be manipulated to excyst and grow in vitro in equine
      dermal cell lines to the merozoite stage using the simplified technique
      described.

PMID- 10577743
TI  - Conserved polymerase chain reaction primers fail in diagnosis of parasitic
      infections.
AB  - We demonstrate that a set of previously described polymerase chain reaction
      primers used for detection of hemogregarines in reptiles will also amplify the
      same region of the 18S rRNA gene of reptiles, amphibians, mammals, and insects
      and thus should not be used for molecular diagnosis. These same primers have also
      been used to differentiate 2 species of Plasmodium that infect lizards. We
      provide evidence that the observed variance may have been dependent on
      parasitemia and not representative of actual molecular differences between the 2
      parasite species.

PMID- 10577744
TI  - Helminth communities in Audouin's gulls, Larus audouinii from Chafarinas Islands
      (western Mediterranean).
AB  - A survey of intestinal helminth communities of Audouin's gulls Larus audouinii,
      from their breeding colonies in Chafarinas Islands, western Mediterranean, Spain
      was conducted to determine the abundance and species diversity of intestinal
      parasites of these birds. The sample of 58 gulls harbored intestinal helminth
      infracommunities composed of species that are gull generalists, including the
      digeneans Cardiocephalus longicollis, Knipowitschiatrema nicolai, Condylocotyla
      pilodora, and Aporchis massiliensis, and the cestode Tetrabothrius cylindraceus.
      Two nematodes are waterfowl generalists (Cosmocephalus obvelatus and Paracuaria
      adunca), whereas the digenean Acanthotrema armata is an Audouin's gull
      specialist. The relative high values of species richness and diversity of the
      helminth infracommunities are comparable to those of other gulls (Larus
      philadelphia, Larus canus), probably reflecting the specialized, nonselective
      fish diet of L. audouinii.

PMID- 10577745
TI  - Polymorphisms in the beta-tubulin gene of Cryptosporidium parvum differentiate
      between isolates based on animal host but not geographic origin.
AB  - Polymerase chain reaction primers were designed to target a region of the
      Cryptosporidium parvum beta-tubulin gene spanning an intron. Amplification
      products contained 11 polymorphic positions, representing a sequence divergence
      of 1.8%, which discriminated between isolates of C. parvum found solely in humans
      (genotype 1) and those found in humans and animals (genotype 2). Seven of the
      polymorphic sites were located outside of the intron and the polymorphism between
      isolates was readily demonstrated by HaeIII restriction digestion. However, all
      of the sequences from genotype 1 human-derived oocysts isolated in the United
      States and Australia were conserved. Also, there were no sequence differences
      between bovine isolates obtained from both continents. Therefore, isolates could
      not be differentiated based on geographic source of origin.

PMID- 10577746
TI  - Attempted chemoprophylaxis of cryptosporidiosis in chickens, using diclazuril,
      toltrazuril, or garlic extract.
AB  - Three battery tests were conducted to study the anticryptosporidial efficacy of
      the 2 commercially available anticoccidial triazinone derivates, diclazuril and
      toltrazuril, and a garlic extract. At the recommended level, diclazuril reduced
      the oocyst output of birds by 14.6%. The efficacy of toltrazuril was 52.1% at the
      recommended level, which could be moderately increased using 5 or 10 times the
      recommended dose. However, these doses resulted in significant weight gain
      reduction. The efficacy of garlic extract was 24.4%. It is concluded that none of
      the drugs can be recommended for chemoprophylaxis or therapy of cryptosporidiosis
      in chickens.

PMID- 10577747
TI  - Clinical management of oral lichen planus.
AB  - Oral lichen planus is a relatively common chronic disease of the mucous membranes
      which may have more transient cutaneous manifestations. It has a number of well
      recognized clinical signs and a wide range of symptoms from none through mild
      discomfort to severe debilitating intra-oral erosions and ulceration. It often
      does not respond to treatment and, in a small proportion of cases, undergoes
      malignant transformation to squamous cell carcinoma. Although there is an array
      of treatments, they are palliative rather than curative. Corticosteroids in
      various forms remain the mainstay of treatment but newer immunomodulatory agents
      have an increasing role. In this paper, we review current thinking about the
      management of oral lichen planus and summarize a recent European consensus
      protocol.

PMID- 10577748
TI  - Evaluation of the long-term effect of function on rhBMP-2 regenerated
      hemimandibulectomy defects.

PMID- 10577749
TI  - Stereoscopic lithography: customized titanium implants in orofacial
      reconstruction. A new surgical technique without flap cover.
AB  - Head and neck surgery may involve complex methods of composite reconstruction
      that do not replicate the volume and contour of the normal anatomy. 'Functional'
      reconstruction implies replication of the normal volume and contour of both hard
      and soft tissues to produce normal form and function of the face, mouth and jaws.
      Techniques such as stereoscopic lithography and computer-assisted design, and
      manufacture (CAD-CAM) have been successfully used with computer-numerized control
      (CNC) milling to manufacture customized titanium implants for single-stage
      reconstruction of the maxilla, hemimandible and dentition without the use of
      composite flap cover after the removal of tumours. Reduction in theatre time and
      personnel, less need for intensive care, and earlier discharge from hospital,
      indicate possible savings of Pound Sterling 17,000-Pound Sterling 19,000 per
      patient. There are implications for surgery in general, and further research and
      development is advocated.

PMID- 10577750
TI  - Emerging role of nitric oxide in cancer.
AB  - The small molecule nitric oxide has generated an exponential amount of research
      since its identification as a biological messenger in 1987. It is a free radical,
      the actions of which are diverse, and many are still poorly understood. An area
      of great interest is the role of nitric oxide in the growth and metastasis of
      solid tumours, where it seems to have a complex action including both inhibitory
      and tumour-promoting activity. Over 28,000 research papers have been written on
      nitric oxide, with only a minority concentrating on the head and neck. In this
      review, we give a brief history of this fascinating molecule, concentrating on
      its possible interest to oral and maxillofacial surgeons.

PMID- 10577751
TI  - Oral cancer, smoking and alcohol: the patients' perspective.
AB  - Although the roles of smoking and drinking alcohol in the aetiology of oral
      cancer are common knowledge among the medical community, those who have the
      disease are often less well informed. To quantify this potential lack of
      knowledge, 152 patients being reviewed after treatment for oral cancer were
      questioned about their smoking habits, alcohol consumption, and their
      understanding of the part these factors play in the development of malignancy. At
      least six months after the diagnosis of their malignancy, 72 (47%) still smoked
      and 55 (36%) drank alcohol to excess. Only one-third were aware that these habits
      were important in the development of oral cancer. These results indicate
      widespread ignorance and suggest that education about the causes of oral cancer
      is required in the population as a whole and particularly among those with the
      disease.

PMID- 10577752
TI  - Mapping dynamic epithelial cell proliferative activity within the oral cavity of
      man: a new insight into carcinogenesis?
AB  - Our aim was to characterize epithelial cell proliferative activity within the
      oral cavity and to find out if there were differences between sites with high and
      low incidence of cancer. A total of 105 samples of clinically normal mucosa were
      harvested from various intra-oral sites. Excised specimens were incubated in
      vitro with tritiated thymidine and bromodeoxyuridine to 'double label' cells
      undergoing DNA synthesis, and enable calculation of the duration of S phase and
      estimation of variables of cell flux to and from S. Mean labelling indices
      (percentage of cells within the S phase of the cell cycle) were highest in the
      floor of mouth (12.3%) and ventral tongue (10.1%), while activity was lowest in
      the dorsum of tongue (4.3%) and the palate (7.2%), P<0.001. In general, both cell
      influx and the duration of S increased proportionally to the labelling index.
      Sites with a high incidence of cancer were characterized by high labelling
      indices, increased cell influx and a prolonged S phase.

PMID- 10577753
TI  - Characterization of epithelial cell activity in patients with oral cancer.
AB  - Accurate, predictive assessment of the clinical behaviour and progression of
      individual oral cancers and premalignant lesions requires reproducible and
      quantitative analyses of diseased tissue. In this paper we describe the use of in
      vitro double labelling (sequential tritiated thymidine and bromodeoxyuridine
      staining of proliferating epithelial cells) to calculate S phase labelling
      indices (LIs), estimation of S phase duration (tS), and measurement of variables
      of flux to and from S for excised specimens of oral squamous cell carcinoma,
      premalignant lesions, and clinically normal mucosa from patients with oral
      cancer. There was a significant increase in mean LIs in buccal mucosa
      leukoplakias (14.5%) compared with normal mucosa (10.3%); P = 0.03. LIs were also
      increased in patients with cancers of the floor of mouth and ventral tongue but
      neither these changes nor alterations in flux parameters or S Phase durations
      were significant. Twenty-one kinetic profiles of dysplastic and malignant tissue
      were compared with conventional histopathological results, however, and these
      showed a 2.2% increase in LIs with each increase in grade of dysplasia (P =
      0.004) and a 12% increase in LIs with each reduction in tumour differentiation (P
      = 0.02).

PMID- 10577754
TI  - Use of intra-articular morphine for postoperative analgesia following TMJ
      arthroscopy.
AB  - Recent studies have suggested that giving opioids locally into inflamed tissue
      may cause analgesia. This antinociceptive effect has been attributed to the
      interaction of the drug with opioid receptors upregulated by inflammation in the
      peripheral tissues. We have compared the analgesic effect of intra-articular
      morphine with that of normal saline and a combination of morphine and its
      antagonist naloxone after arthroscopy of the temporomandibular joint (TMJ).
      Twenty-one patients took part in a randomized controlled double-blind trial and
      received one of these three solutions at the end of operation. The pain scores,
      time to the first request for analgesia, and the analgesic consumption of the
      patients in the three groups did not differ significantly at any time during the
      study period.

PMID- 10577755
TI  - Arthroscopic surgery of the temporomandibular joint: comparison of two successful
      techniques.
AB  - We have compared two techniques of arthroscopic surgery for advanced internal
      derangement of the temporomandibular joint (TMJ). Patients with stage III or
      above TMJ internal derangement, who had not responded to three months of non
      surgical treatment, were prospectively and randomly assigned to one of two types
      of treatment. One group had arthroscopic lysis and lavage (ALL) and the other had
      ALL plus arthroscopic anterolateral capsular release (AALCR). All patients were
      assessed preoperatively, and at 1, 3, 6, and 12 months postoperatively. Thirty
      five patients (41 joints) had ALL and 66 patients (73 joints) had AALCR. The only
      significant difference was at 1 month, when the ALL group could not open their
      mouths as far as the AALCR group (P < 0.01). Both groups had significantly less
      pain in the joint and better jaw opening one year postoperatively. The stage of
      disease did not affect the outcome. Both ALL and AALCR gave good results in the
      management of advanced internal derangement of the TMJ. Unless early wide mouth
      opening is required, the less invasive procedure of lysis and lavage should be
      chosen.

PMID- 10577756
TI  - Effect of unilateral condylectomy on the sheep temporomandibular joint.
AB  - Unilateral condylectomy was performed on five young adult sheep. The animals were
      killed at three months and both joints and the excised condyles were examined
      macroscopically and histologically. All five showed pronounced regeneration of
      the condylar head on the operated side. The articular surface was fibrous and
      fused to the disc. Four of the five opposite joints showed medial remodelling.
      Young sheep have a higher regenerative capability than human adults of equivalent
      age, and similar reactions to those of children.

PMID- 10577757
TI  - Masseteric hypertrophy?: preliminary report.
AB  - We report radiological and histological investigations of a patient who presented
      with the masseteric hypertrophy. Sections of the patient's masseter muscles were
      also investigated using a series of histological techniques. The histological and
      morphometric analysis of the patient's masseter muscle showed numerous small
      fibres, which indicated that the masseteric enlargement was not the result of
      classic fibre hypertrophy. We suggest that the use of the term 'hypertrophy' in
      this condition may be misleading.

PMID- 10577758
TI  - Levandoski panographic analysis in the diagnosis of hyperplasia of the coronoid
      process.
AB  - The Levandoski panographic analysis of routine panoramic radiographs was
      developed to improve the diagnosis of hyperplasia of the coronoid process. The
      ratio of the length of the coronoid process to the condylar process in the
      Levandoski panographic analysis has a linear relationship with that in the
      cephalometric analysis (r = 0.75, n = 59). The ratio in patients with hyperplasia
      of the bilateral coronoid process was significantly greater than that of the
      control on both sides (P < 0.01). Although the minimum value of ratio in the
      patients was 1.15, the maximum value of the controls was 1.07. These results show
      that the Levandoski panographic analysis is useful in the evaluation of
      hyperplasia of the coronoid process in adults. When a patient complains of
      limited mouth-opening and the ratio is more than 1.1, further investigations
      should be made to verify the diagnosis of hyperplasia of the coronoid process.

PMID- 10577759
TI  - Influence of folic acid on pregnant women.

PMID- 10577760
TI  - Re: Baur & Butler. Electrocautery-ignited endotracheal tube fire: case report.

PMID- 10577761
TI  - Re: Jones. Intermaxillary fixation using intraoral cortical bone screws.

PMID- 10577762
TI  - Temporary intermaxillary fixation: a quick reliable method.

PMID- 10577763
TI  - Re: Filippi et al. Sensory disorders after separation of the nasopalatine nerve
      during removal of palatal displaced canines: prospective investigation.

PMID- 10577764
TI  - Head injuries, assaults, ethnicity, Stephen Lawrence and all that: the emerging
      role of maxillo-facial units.

PMID- 10577766
TI  - Pediatric ear, nose and throat services' demands and resources: a global
      perspective.
AB  - Global population trends, health care economics and disease patterns are
      reviewed. The world's population has doubled twice in the twentieth century, and
      will grow by at least a further 2 billion before stabilizing in the middle of the
      next century. There is gross maldistribution of wealth and health care
      expenditures: 20% of the population control 80% of the gross domestic product,
      the same 20% of the population spend 87% of the total global health care funds.
      Extreme poverty facilitates all manner of diseases. Globally, infections remain
      the most important causes of disease. Of these, upper respiratory infections are
      an important cause of hearing loss and learning handicap in children world-wide.
      Epidemic meningitis in Africa and parts of Asia is a preventable major cause of
      death and deafness. There are about 80,000 otolaryngologists in the world and
      they too are maldistributed, with most in Europe and the Americas. This is
      exacerbated when looked at from the standpoint of children, most children live
      where there are fewest otolaryngologists: the differences are greater than two
      orders of magnitude. This greatly affects the role and scope of paediatric
      otolaryngology. The discipline is small and rapidly evolving. Suggestions are
      made for sharing training.

PMID- 10577765
TI  - Aspergillosis with calcification of the maxillary sinus.

PMID- 10577767
TI  - Pediatric otorhinolaryngology in Europe.
AB  - Nowadays Europe encompasses more than 30 countries. These countries differ in
      climate, in culture, in population density, in history, in socio-economic system
      and in the organization of medical care. Despite these differences there is a
      general trend of unification in politics, in industry and in science. In the
      field of medicine, medical faculties and professional organizations try to
      harmonize medical curricula and training programmes for medical specialists.

PMID- 10577768
TI  - Management of acute otitis media in an era of increasing antibiotic resistance.
AB  - Development of resistance to available antimicrobial agents has been identified
      in every decade since the introduction of the sulfonamides in the 1930s. Current
      concerns for management of acute otitis media (AOM) are multi-drug resistant
      Streptococcus pneumoniae and beta-lactamase producing Haemophilus influenzae and
      Moraxella catarrhalis. In the USA, amoxicillin remains the drug for choice for
      AOM. Increasing the current dose to 80 mg/kg/day in two doses provides increased
      concentrations of drug in serum and middle ear fluid and captures additional
      resistant strains of S. pneumoniae. For children who fail initial therapy with
      amoxicillin an expert panel convened by the Centers for Disease Control and
      Prevention suggested amoxicillin-clavulanate, cefuroxime axetil or intramuscular
      ceftriaxone. To protect the therapeutic advantage of antimicrobial agents used
      for AOM, it is important to promote judicious use of antimicrobial agents and
      avoid uses if it is likely that viral infections are the likely cause of the
      disease, to implement programs for parent education and to increase the accuracy
      of diagnosis of AOM. Conjugate polysaccharide pneumococcal vaccines are currently
      in clinical trial; early results indicate protective levels of antibody can be
      achieved with a three dosage schedule beginning at 2 months of age. Finally,
      alternative medicine remedies may be of value for some infectious diseases
      including AOM; garlic extract is bactericidal for the major bacterial pathogens
      of AOM but is heat- and acid-labile and loose activity when cooked or taken by
      mouth.

PMID- 10577769
TI  - Growth factor therapy to the damaged inner ear: clinical prospects.
AB  - Most hearing loss results from lesions of the sensory cells and/or of the neurons
      of the auditory part of the inner ear. There is currently no treatment able to
      stop the progression of a hearing loss or to restore a lost auditory function. In
      this paper, we review the progress which has been made with respect to the
      regeneration and the protection of the hair cells and of the auditory neurons in
      the cochlea. In particular, we emphasize the control by growth factors of the
      protection/repair mechanisms of the neurosensory structures within the inner ear,
      in the prospect of the possible clinical use of these molecules. Finally, we
      discuss the different approaches which can be used to deliver these therapeutic
      agents to the inner ear.

PMID- 10577770
TI  - Cochlear gene therapy: current perspectives.
AB  - Gene therapy has the potential to revolutionize therapy for hearing disorders.
      Advances in our understanding of the molecular basis of hearing combined with
      techniques for intracochlear gene transfer are leading us closer to clinical
      applications. Potential areas of interest are reviewed and experimental success
      using adeno-associated virus to effect intracochlear gene transfer is discussed.

PMID- 10577771
TI  - Update of microbial problems in pediatric otorhinolaryngology: plenary session.
AB  - The bacteria to consider in upper respiratory tract infections in children are
      pneumococci, Haemophilus influenzae, group A streptococci and Moraxella
      catarrhalis.

PMID- 10577772
TI  - Redefining the survival of the fittest: communication disorders in the 21st
      century.

PMID- 10577773
TI  - The development of communication and language in deaf and severely hard of
      hearing children: implications for the future.
AB  - Severe hearing impairment is seldom detected in children before the age of 6-12
      months as parent-infant interaction is similar to that of a normal parent-child
      interaction. This is probably due to an innate capacity of infants to take
      information in one sensory modality and translate it into another, called amodal
      perception. The roots of language are traced to early proto-conversations, as
      well as to early pretend play. Relationships are viewed as the context in which
      socialisation takes place, basic competences emerge, regulations of emotions
      develop and communication skills are acquired. If habilitation after diagnosis of
      a severe hearing impairment primarily is focused on an oral-aural approach,
      natural patterns of communication between parent and child will gradually
      disappear, which will have negative implications on the development of these
      children. If, instead, they are allowed to develop those means of communication
      that are easy for them to produce and to perceive, positive consequences have
      been registered on the development of communication and language, as well as on
      their socio-emotional and cognitive development. When these children have been
      given opportunities to become bilingual with a signed and a written and/or spoken
      language, it has enabled them to attend higher education, to have a qualified job
      and thereby a good life in the future.

PMID- 10577774
TI  - Communications disorders and the interactions and relation(s) to other disorders
      susceptibility.
AB  - Communication is the action and process of transmitting a message and the way in
      which this message is received and interpreted. We observe the social character
      of this action and its effectiveness. Evidently, in order to make communication
      effective, it is necessary for the attitude of the receiver to be socially,
      ideologically and psychologically receptive. Communication and language are
      practically two indistinguishable terms. In the case of a deaf child, the
      learning of cognitive abilities depends absolutely on how his environment
      educates him. Today we depend on new communication skills and their particular
      mission and meaning with reference to otolaryngology. In the age of communication
      in the 21st century, society will direct its resources toward strategy of
      preventive and medical care that will optimize the population's health
      communication. Otolaryngology will continue to grow and prosper by responding to
      these pressing human and social needs and building upon communications, and by
      incorporating them in this new domain, of language, thus we will be able to find
      the medical and surgical cures for communication disorders.

PMID- 10577775
TI  - The impact of hearing impairment: a global health problem.
AB  - Hearing impairment is a substantial worldwide problem mainly affecting the adult
      population. The prevalence of permanent childhood hearing impairment (PCHI) is
      relatively small (1 in 752) but the effects of PCHI are substantial. Children
      with PCHI (aged 4-12 years; n = 100) who use spoken English as their first
      language were assessed for cognitive and behaviour performance (controls included
      hearing children and children with otitis media with effusion). There was a trend
      in performance across severity for all assessments, with about a 2 SD difference
      for IQ between hearing controls and PCHI, causing concern for the pervasiveness
      and impact of even moderate PCHI.

PMID- 10577776
TI  - Accessibility for the hearing impaired.
AB  - The social anthropology of mild hearing loss is gradually being accepted, as it
      affects both children and adults. With this comes the understanding that
      effective aural communication requires adequate sound sources and a good
      transmission medium as well as good hearing. If the first two conditions are met,
      much hearing disability might be avoided without resorting to a hearing aid. A
      plea is made for better accessibility for the hearing impaired by improving
      environmental conditions for acoustic signals, especially speech.

PMID- 10577777
TI  - Management of obstructive sleep apnea syndrome in children with craniofacial
      malformation.
AB  - Children with craniofacial syndromes, especially those with midfacial hypoplasia,
      micrognathia, or deformation of the cranial base, are frequently suffering from
      obstructive sleep apnea syndrome (OSAS). It is important to recognize this
      condition. Diagnostic methods and therapeutic developments are discussed.
      Experience with 31 patients in the Sophia Children's Hospital is presented. The
      majority of these infants suffered from moderate or severe OSAS. Treatment varied
      from symptomatic (e.g. continuous positive airway pressure) to curative. These
      therapies could often prevent a tracheotomy. Still more curative treatment
      options are needed.

PMID- 10577778
TI  - Nasal obstruction in children with craniofacial malformations.
AB  - The etiology, patient evaluation and management of nasal obstruction in children
      with craniofacial malformations is broadly discussed. Specific reference is made
      to the experience by the senior author (WSC) with respect to nasal surgery in 29
      of these patients during the 12 years from 1987 to January 1st, 1998.

PMID- 10577779
TI  - Cholesteatoma in children, predictors and calculation of recurrence rates.
AB  - The aim of the study was to evaluate the long-term recurrence rate after surgery
      for acquired cholesteatoma in children, to search for predictors of recurrency
      and to analyse the impact of the applied statistical method on the outcome of the
      results. During a 15-year period, 114 children underwent first-time surgery for
      acquired cholesteatoma. The patients were re-evaluated with a median observation
      time of 5.8 years, range 1-16 years. Recurrence of cholesteatoma developed in 27
      ears. The cumulated total recurrence rate was 24% using standard incidence rate
      calculation, applying Kaplan-Meier survival analysis the recurrence rate was 33%.
      Recurrent disease occurred significantly more frequent in children < 8 years,
      with negative preoperative Valsalva, ossicular resorption and with large
      cholesteatomas. In conclusion, young children with poor Eustachian tube function,
      large cholesteatoma and erosion of the ossicular chain, are at special risk of
      recurrence and should be observed several years after surgery.

PMID- 10577780
TI  - Cholesteatomatous chronic otitis media.

PMID- 10577781
TI  - Cholesteatoma in children.
AB  - Cholesteatoma in children is generally considered to be more aggressive and
      destructive than in adults. Each otologic surgeon has experienced widely extended
      cholesteatomas in children with large pneumatized mastoid processes. In this
      paper, we want to present clinical and experimental observations which imply that
      the destructive potential in children is similar to that in adults. Factors and
      observations that have led to the assumption that cholesteatoma in children is
      more aggressive will be discussed. Based on our experience and the literature, we
      tried to distill the current and leading thoughts concerning this intriguing
      entity.

PMID- 10577782
TI  - Pediatric one-stage cholesteatoma surgery: long term results.
AB  - The long-term results of pediatric cholesteatoma are dispersed and there is no
      consensus on operation methods and on factors affecting outcome of surgery. We
      analyzed the independently evaluated long-term results and possible reasons for
      recholesteatoma. Eighty-four consecutive pediatric (age < 16 years) cholesteatoma
      operations were undertaken in the Helsinki University Central Hospital ENT
      Department. The operations were not staged; all mastoids were obliterated and
      bony ear canals reconstructed without open cavities. The pre- and perioperative
      and annual control data were recorded in a database. The last control was
      independently performed (J.S.) with an average follow-up of 4.8 years and 87%
      attendance. The total recholesteatoma rate was 29% (24/84), and it was not
      dependent on the size of cholesteatoma, mastoid status, cholesteatoma in the
      window niches or stapedial erosion. A retraction process developed in 25% (21/84)
      of the ears and 42% (9/21) of these turned into retraction pocket cholesteatomas
      as late as 13 years postoperatively. Retractions and postoperative discharge,
      especially in combination, predisposed to recholesteatoma. Of the healed ears,
      37% became atelectatic. Hearing was maintained on the preoperative level. Reduced
      middle ear and attic ventilation led to retractions, and atelectasis and a
      tendency to discharge accelerated the process. Pitfalls in mastoid obliteration
      and attic reconstruction and the failure to create new ventilation routes were
      important reasons for recholesteatoma.

PMID- 10577783
TI  - A scheme for challenging cholesteatoma in children.
AB  - In order to secure both long-lasting carefree ears and hearing
      preservation/restoration, the best method to apply is the closed-method
      tympanoplasty, especially for cholesteatomatous otitis media in children. We
      agree with this method, in spite of the high percentages of postoperative
      residual cholesteatoma in children. Until a better way of irradicating
      cholesteatoma becomes available, either staged operations or periodical check-ups
      for many years are mandatory. While postoperative attic retraction/cholesteatoma
      formation seems to be preventable in most cases, the rate of residual
      cholesteatoma is very high in our data and in other reports. Looking for a
      reason, the differences between the cholesteatoma in children and those in adults
      are to be investigated in macro-, micro- and ultramicroscopic observations. In
      addition, basic rather than clinical studies on cholesteatoma in children are
      requested.

PMID- 10577784
TI  - Management of rhinosinusitis in children.
AB  - The authors provide definitions for the different forms of pediatric
      rhinosinusitis, with an enumeration of the main symptoms and signs. They also
      provide the indications for CT scan examination and microbiological
      investigations. In addition, they emphasize the importance of concomitant
      systemic disease, such as allergy and immunological disorders. The adequate
      medical management, which is mandatory before any surgery, is considered and
      discussed, and the indications for surgery are provided.

PMID- 10577785
TI  - Epidemiology and prevalence of aspecific chronic sinusitis.
AB  - The problems inherent in the gathering of epidemiologic and prevalence data for
      aspecific chronic sinusitis are outlined. The need for a better understanding of
      the natural history of chronic sinusitis in children is stressed.

PMID- 10577786
TI  - Paroxysmal vertigo in children--an epidemiological study.
AB  - BACKGROUND: Little is currently known about the prevalence of vertigo in
      children. METHODS: In a questionnaire designed to examine the prevalence of
      migraine and migraine equivalents in children of school age, we included an item
      on 'attacks of dizziness in the past year'. The questionnaire was applied to 2165
      children (10% of the school population in the city of Aberdeen, Scotland).
      RESULTS: 314 children had experienced at least one episode of dizziness in the
      previous year, unexplained in 44% of cases. A total of 57 children with three
      attacks, either unexplained or attributed to migraine, were interviewed and
      examined. Forty-five fulfilled our criteria for benign paroxysmal vertigo. Other
      symptoms suggestive of migraine were found in a small majority, but in 47%
      paroxysmal vertigo was an isolated symptom. The age of onset peaked at 12 years,
      but it was seen in all age groups. Paroxysmal vertigo was commonly accompanied by
      features that are common in migraine, i.e. pallor, nausea, phonophobia and
      photophobia, and migraine was twice as common in first degree relatives compared
      to controls. CONCLUSIONS: Paroxysmal vertigo is common in children and although
      it is seldom diagnosed, it appears to cause few major problems to the affected
      children. In common with previous studies, we found that it appears to be related
      to migraine.

PMID- 10577787
TI  - Intratemporal and intracranial complications of acute suppurative otitis media in
      children: renewed interest.
AB  - In recent years, a rise in the incidence of intratemporal and intracranial
      complications of acute otitis media (AOM) has been mentioned in the literature.
      Lack of a well-developed immune system and difficulties in diagnosing AOM, can
      account for part of the rise in the incidence of complications of purulent middle
      ear infections in young children. Antibiotic treatment of AOM is certainly not an
      absolute safeguard against the development of complications. Antibiotic therapy
      may have a masking effect on significant signs and symptoms of complications,
      causing delay in diagnosis. Myringotomy, especially in young children, should not
      be forgotten for drainage and to provide material for culture. Increased
      virulence of the causative pathogens cannot be ruled out, but to date there is no
      evidence suggesting it. We have to maintain a high level of clinical awareness.
      If there is insufficient improvement of the patient with the appropriate
      conservative treatment, radioimaging followed by the necessary surgical
      procedures should be performed.

PMID- 10577788
TI  - Persistency of an effect: otitis media during the first year of life with nine
      years follow-up.
AB  - A cohort of lower socioeconomic-economic children who experienced multi and
      prolonged episodes of otitis media during their first year of life and followed
      for 9 years showed that all of the children had poorer performance in linguistic
      tasks than did the control group. Differences were found in all of the OM +
      children at all ages. The effect of the otitis media and its accompanying hearing
      loss was noted in eight measures throughout the 9-year period of observation.

PMID- 10577789
TI  - Uncommon and unusual complications of otitis media with effusion.
AB  - Some complications of otitis media with effusion (OME) are not obvious and not
      always associated with otitis media by physicians and patients; the authors
      propose to call them 'unusual complications', although they may be quite
      frequent. Complications such as dizziness, clumsiness and behavioural disorders
      are classified in this group. Other complications are rare and uncommon such as
      sensorineural hearing loss and cholesteatoma. Some of these sequelae are
      structural, others more functional. The impact of OME on complex functions such
      as language, learning or behaviour is still controversial but seems to have been
      underestimated until now. Not only withholding treatment in children with OME may
      cause complications but also the treatment of OME may lead to sequelae, although
      serious side effects caused by the treatment of OME are rare. In this literature
      review, the epidemiology, importance and diagnosis of the uncommon and unusual
      complications of OME will be discussed.

PMID- 10577790
TI  - Waldeyer's ring and otitis media: the nasopharyngeal tonsil and otitis media.
AB  - This overview of the relationship between the nasopharyngeal tonsil and otitis
      media will review three important concepts: (1) Adenoid inflammation leads to
      inflammatory obstruction of the Eustachian tube; (2) early colonization of the
      adenoid with the three major bacterial pathogens of otitis media is the most
      important factor in the early pathogenesis of otitis media; (3) the local immune
      system in the adenoid particularly specific secretory IgA directed against both
      viruses and bacterial pathogens are probably genetically controlled and represent
      the immunological factor in protecting the host against invasion of these agents
      in the Eustachian tube and middle ear. This overview of the relationship between
      the adenoid and the development of otitis media emphasizes that nasopharyngeal
      colonization with the three major middle ear pathogens is among the most
      important risk factors in the pathogenesis of otitis media. Inasmuch as these
      pathogens normally reside in the nasopharynges of most healthy children, the
      factors which trigger development of otitis media need to be carefully evaluated.
      Among these two triggers are viral infections and upper respiratory tract
      allergy.

PMID- 10577791
TI  - What is wrong in chronic adenoiditis/tonsillitis anatomical considerations.
AB  - Waldeyer's ring is most prominent during childhood, when the size of the oro
      nasopharyngeal space is not yet fully developed, but decreases spontaneously with
      age. In the child, enlarged tonsils and/or adenoids may cause Eustachian tube
      dysfunction/otitis media, rhinosinusitis, obstructive sleep apnea, voice changes,
      change in facial growth, swallowing problems and can affect overall quality of
      life. Consequently, tonsillectomy and/or adenoidectomy are among the most common
      surgical procedures in children. The size of the oro- and nasopharynx has been
      investigated in normal children with and without tonsil/adenoid hyperplasia, to
      assess whether or not it is the adenoid and tonsillar tissue that are enlarged
      and not the dimensions of the anatomic space that are reduced. Studies have
      supported that the nasopharyngeal space is not smaller in children with
      hyperplastic adenoids when compared to normal children. However, children with
      large obstructing tonsils have a smaller oropharyngeal diameter compared to
      children with small tonsils. Tonsil/adenoid hyperplasia appears to be due to an
      increase in the lymphoid elements. The size of the tonsil has been shown to be
      directly proportional to aerobic bacterial load and absolute number of B and T
      cells. Bacteria have been suggested in the etiology of the development of
      hyperplasia. Of interest is that of the different pathogens, Haemophilus
      influenzae in particular, has been associated with tonsil/adenoid hyperplasia.
      The distribution of dendritic cells, antigen presenting cells, is altered during
      disease, with fewer dendritic cells in the surface epithelium and more in the
      crypts and extrafollicular areas.

PMID- 10577792
TI  - What is wrong in chronic adenoiditis/tonsillitis immunological factor.
AB  - The local immune response in adenoid and tonsil tissue can be visualized and the
      complexity of the cytokine network and effector molecule expression has not been
      illustrated in several different tonsillar entities. Many factors still remain to
      be learned in order to help us to understand the interactions between
      microorganisms and host in peripheral lymphatic tissue.

PMID- 10577793
TI  - Development of the child's voice: premutation, mutation.
AB  - Voice range profile (VRP) measurement was used to evaluate the vocal capabilities
      of 180 children aged between 4 and 12 years without voice pathology. There were
      10 boys and 10 girls in each age group. Using an automatic VRP measurement
      system, F0 and SPL dB (lin) were determined and displayed two-dimensionally in
      real time. The speaking voice, the shouting voice and the singing voice were
      investigated. The results show that vocal capabilities grow with advancing age,
      but not continuously. The lowering of the habitual pitch of the speaking voice as
      well as of the entire speaking pitch range occurs for girls between the ages of 7
      and 8, for boys between 8 and 9. A temporary restriction of the minimum vocal
      intensity of the speaking voice (the ability to speak softly) as well as of the
      singing voice occurs for girls and for boys at the age of 7-8. A decrease of the
      maximum speech intensity is found for girls at the age of between 7 and 8, for
      boys between 8 and 9. A lowering of the pitch as well as of the intensity of the
      shouting voice occurs for both sexes from the age of 10. In contrast to earlier
      general opinion we note for girls a stage of premutation (between the age of 7
      and 8) with essentially the same changes seen among boys, but 1 year earlier. The
      beginning of the mutation can be fixed at the age of 10-11 years.

PMID- 10577794
TI  - The role of the adenoid in allergic sensitisation.
AB  - Allergic sensitisation of the airways occurs in the mucosa of the shock organ, or
      in the lymphatic stations draining these structures. The lymphatic structure
      closest to the nasal mucosa in humans is the adenoid and in mice the nasal mucosa
      associated lymphoid tissue (NALT). In this study we tried to find evidence for
      our hypothesis that allergic sensitisation can occur in the adenoid (NALT). The
      first part of the investigation was set up to determine possible cellular changes
      in the adenoid of allergic children compared to non-allergic controls using
      immunohistochemical staining techniques. We found CD1a (Langerhans cells) and
      eosinophils to be more numerous in the adenoid of allergic children. In the
      second part of this study we used a murine model to determine if an intranasally
      applied 'allergen' is processed in the NALT and/or cervical lymph nodes (CLN). An
      auto fluorescent dye (Di I) was applied into the nasal cavity of mice. At
      subsequent time intervals mice were terminated. NALT and CLN tissue sections were
      placed under fluorescent microscopy. We found that Di I transported to both the
      NALT and CLN. However, the dye remained in the NALT at least 2 days longer than
      in the CLN. In these studies we found evidence that the lymphoid compartment in
      the upper respiratory tract (adenoid and NALT) are involved in the processes of
      allergic diseases.

PMID- 10577795
TI  - The bacteriology of the nasopharynx in childhood.
AB  - Non-typeable Haemophilus influenzae and Streptococcus pneumoniae (Pnc) are
      frequently isolated from the nasopharynx (NP) of young healthy children.
      Colonization of the NP may be detected in early infancy with peaks toward the
      second year of life. NP carriage of Pnc and especially of antibiotic-resistant
      Pnc is common and plays an important role in its spread in children, its
      prevalence increases in those coming into close contact, such as children
      attending day-care facilities. Several studies show that the presence of older
      siblings, antibiotic treatment during the month preceding the culture and the
      attendance at a large day-care center are associated with carriage of drug
      resistant Pnc. Significant changes may occur early during antibiotic treatment,
      and these changes may vary with the use of different antibiotics. Also new
      strains of Pnc not detected initially emerge, and newly detected organisms are
      most often resistant to the administered drug. Nasopharyngeal colonization with
      resistant bacteria was shown to be associated with an increased incidence of
      acute otitis media with resistant organisms and growing incidence of unresolved
      otitis media. Preliminary studies show that conjugate pneumococcal vaccine might
      reduce the nasopharyngeal pneumococcal carriage in general, and of resistant
      organisms in particular.

PMID- 10577796
TI  - Achievements of the European Working Group on Genetics of Hearing Impairment.
AB  - Three years ago an European Working Group for the study of genetics of hearing
      impairment was founded with the aim to standardise terminology and protocols in
      order to collect families with genetic hearing impairments for a European-based
      epidemiological, clinical and genetic analysis. Hereditary hearing impairments
      include a large variety of genetic causes. The occurrence of the different forms
      is rare, but the overall genetic aetiology is thought to account for up to 50% of
      newborns' hearing impairment as well as several late onset, progressive cases. In
      the later years, several locations associated with non-syndromal hearing
      impairments and different mutations for the syndromic diseases have been
      identified. Five subgroups have been formed: Definitions and protocols,
      Epidemiology, Vestibular involvement, Otological and cranial malformations,
      Molecular biology. Meetings were organised for discussion and establishment of
      common ground work. Application of the agreed documents was performed to verify
      protocols. Final agreements were circulated by Infoletter (1-5). Informatic
      working tools on the Internet have been designed. Standardised definitions,
      audiological and vestibular protocols have been defined. Pilot studies using
      experimental protocols to identify informative carriers or to help clinical
      differentiation between non-syndromic forms have also been performed. Two web
      sites related to the work have been created. A description of phenotypes of
      locations identified has been defined. Joining forces to standardise definitions
      and protocols and collaboration between clinicians and geneticists has
      contributed considerably to progress in this field.

PMID- 10577797
TI  - Non-syndromic hearing impairment: gene linkage and cloning.
AB  - Non-syndromic hearing impairment (NSHI) affects approximately 1:2000 newborns and
      is a significant cause of hearing loss in the elderly. Although the phenotype is
      quite similar, NSHI is extremely heterogeneous, with over 40 genetic loci now
      known. A number of the relevant genes have been cloned. These advances are
      impacting clinical practice and revolutionizing our understanding of the biology
      of hearing.

PMID- 10577798
TI  - Otitis media in Inuit children in the Eastern Canadian Arctic--an overview--1968
      to date.
AB  - Clinical observations made on the Inuit in the Eastern Canadian Arctic during the
      past three decades support that the current high prevalence of chronic otitis
      media among their children is a relatively new phenomenon. It is a
      social/economic disease related to their urbanization that occurred following
      World War II when the vast majority of the Inuit abandoned their isolated nomadic
      way of life and moved into permanent settlements. The disease, in a great many,
      runs a natural course with spontaneous healing. There is evidence that as the new
      millennium approaches the prevalence of the disease among the children is
      decreasing.

PMID- 10577799
TI  - Present aspects of otitis media among children in Greenland.

PMID- 10577800
TI  - Otitis media in Australian Aboriginal children: an overview.
AB  - Remote and rural Australian Aboriginal children achieve lower standards of
      numeracy and literacy than their non-Aboriginal peers. The reasons are complex,
      but extraordinarily high rates of conductive hearing loss (> 50%) are, in part,
      responsible for poor classroom success. In addition to the burden of acute
      bacterial respiratory illness (highest rates of invasive pneumococcal disease in
      the literature), chronic disease affects virtually every young child. In the
      Aboriginal community studied, otitis media commenced within 3 months of birth for
      all infants, progressed to chronic suppurative otitis media in 60% and did not
      resolve throughout early childhood. Our findings, supported by mathematical
      modelling, show that the vicious cycle of endemic chronic otitis media is
      perpetuated by high carriage rates of multiple species and multiple types of
      respiratory bacterial pathogens, by high cross-infection rates and thus, by early
      age of pathogen acquisition and prolonged carriage. Long-term damage to
      respiratory mucosa, possibly linked to later chronic bronchitis and
      bronchiectasis, follows a constant series of infections by each of the
      concurrently held pathogens, without periods of recovery. Overcrowding and poor
      hygiene promote this vicious cycle. Medical and social options for intervention
      are limited by poor resources, low expectations for health and a complex biology
      that includes antibiotic resistant pneumococci.

PMID- 10577801
TI  - Sensorineural hearing loss in children.
AB  - Sensorineural hearing loss in children, either congenital or acquired, has an
      incidence of 2-4 per million. Molecular diagnosis of early childhood deafness
      became available for some types of syndromal and non-syndromal forms and will
      offer different treatment modalities in the future. Severe to profound
      sensorineural hearing loss can be effectively treated with cochlear implants.
      There is evidence of cerebral auditory plasticity under electrical stimulation of
      the auditory nerve with better performance in early implanted children. Other
      predicting factors are related to the type of schooling, family support and
      residual hearing. In the long-term, prelingually deafened children will develop
      considerable speech perception and production. Children with marginal benefit
      from hearing aid amplification show significant improvements in speech perception
      following implantation. Implantation is also possible in cases of cochlear
      malformation. However, special attention has to be given to the facial nerve, a
      possible CSF leak and electrode misplacement. Apart from hearing improvement
      cochlear implants have a positive impact on the family situation, schooling and
      personal well-being.

PMID- 10577802
TI  - Cochlear implantation in deaf children and adolescents: effects on family
      schooling and personal well-being.
AB  - The paper is an attempt to answer the main questions raised by that part of the
      deaf community which still consider cochlear implants (CI) an attack against the
      psychophysical integrity of the pre-lingually deaf. METHODS: The psychological
      well-being of six adolescents and six children was assessed pre- and post
      implantation using various tools, i.e. projective tests, assessment scales (AS),
      and structured interviews with parents and teachers. The analysis of post-implant
      findings shows a reduction of stereotype elements, more dynamic modes of
      figurative expression, quite good relationships within their own social
      environment and gradual, positive integration both at home and at school.
      Cochlear implantation would seem to cause no psychological disruption. Our sample
      group show an improvement in their modes of expression--more consistent with the
      mental and effective age--and a greater awareness of personal limits, together
      with the ability to judge the appropriateness of their own behavior.

PMID- 10577803
TI  - The development of auditory perception in children following cochlear
      implantation.
AB  - The time course for the development of auditory perception in prelingually deaf
      children following cochlear implantation may extend over many years, thus making
      long-term studies necessary to evaluate any such outcome. However, few such
      studies exist in the literature. We prospectively followed-up a consecutive group
      of 133 prelingually deaf children up to 6 years following implantation. All
      children were prelingually deaf with age at onset of deafness < 3 years and age
      at implantation < 8 years. The aetiology of deafness was meningitis for 45
      children (34%), congenital deafness for 77 children (58%) and other causes for 11
      children (8%). All were implanted with a Nucleus-22 multi-channel cochlear
      implant and followed the same rehabilitation programme. No child was lost to
      follow-up and there were no exclusions from the study. Prelingually deaf children
      showed significant improvement in the auditory perception with implant
      experience. 82% of children who reached the 6-year interval could understand
      conversation without lip-reading. The respective percentage in the 4-year
      interval was 70%. The long-term results of cochlear implantation reveal that the
      majority of prelingually deaf children, when implanted before the age of 8 years,
      will develop significant auditory perception.

PMID- 10577804
TI  - Cerebral auditory plasticity and cochlear implants.
AB  - Previous animal research and clinical experiences in humans suggest the existence
      of an auditory critical period in language acquisition. We review the literature
      and present the changes within the cochlear nuclei in bilaterally deafferentated
      adult non-human primates. We also present and analyse the results of 98
      prelingually deaf children and teenagers who underwent a cochlear implantation at
      the University of Navarra. Patients received a Nucleus 22 or 24 multichannel
      cochlear implant (CI). They were grouped in five categories according to their
      age at surgery. Performance is compared with a control group of 58 postlinguals.
      Only early-implanted prelingual children (before 6 years of age) achieved a
      complete open-set speech recognition, even with better performance than
      postlinguals. These results clearly demonstrate the existence of a period of high
      neural auditory plasticity within the first 6 years of life. The introduction of
      auditory stimulation with a CI can not restore the loss of neural plasticity out
      of this period. Prelingual children under 6 years of age should receive a CI as
      soon as there is a reliable diagnosis of bilateral sensorineural hearing loss.

PMID- 10577805
TI  - Monitoring methods of nasal pathology.
AB  - The importance of correct clinical and therapeutic monitoring of allergic
      rhinitis is understandable in the light of the social and economic impact of this
      pathology: its prevalence is over 10% of the total population all over the world.
      For the evaluation of the local nasal pathology we include: (1) anterior
      rhinoscopy, (2) active anterior rhinomanometry, (3) positioned acoustic
      rhinometry, (4) determination of mucociliary transport time, (5) specific nasal
      provocation test. Active anterior rhinomanometry allows reliable assessment of
      the nasal respiratory function, acoustic rhinometry shows the geometry of nasal
      cavity, mucociliary transport time is an indicator of the mucosa eutrophism. In
      our experience, the specific nasal provocation test is one of the most important
      tests in this field. It is more sensitive than the skin test and the
      radioallergosorbent test (RAST) in the asymptomatic phase and it is able to show
      organ allergies. In this study we review the importance of this test and the
      methodology we commonly use.

PMID- 10577806
TI  - Use of corticosteroids for nasal allergy in children.
AB  - A literature review is presented regarding studies of systemic and side effects
      of corticosteroids for topical treatment in the airways. Systemic effects studied
      are plasma and urine cortisol, with and without cosyntropin stimulation test.
      Generally, doses lower than 400 microg had no discernible effects. All studies
      found were performed on adults. Side effects are, e.g. cataract, septal
      perforation, and bone growth retardation. The latter side effect is studied in
      children with asthma, e.g. with knemometry. Generally, doses of 400 microg a day
      or less of 'modern' corticosteroids did not reduce the growth rate. No report is
      found concerning septal perforation in children.

PMID- 10577807
TI  - Local and systemic immunotherapy in nasal allergy.
AB  - Two assays have been done to evaluate the effect of immunotherapy in nasal
      allergy. First, a trial of nasal immunotherapy and second, the study of mediator
      release after vaccines. Local immunotherapy, applied directly, triggers different
      response mechanisms. Specific nasal immunotherapy started before seasonal or
      perennial symptoms peak, has been done by increasing the doses of allergen three
      times a week during a 3-month period and a manutention period of a weekly nasal
      puff of the same allergen. Symptom scores and drug consumption have been
      registered. The results have been compared with the scores obtained in the same
      patients over the same period of the same year before immunotherapy. In perennial
      rhinitis blockage, rhinorrea, sneezing and itching scores all decreased. In
      seasonal rhinitis, a similar score decrease was obtained for blockage, rhinorrea,
      sneezing and itching. Pharmacological scores also decreased. These data point to
      a short-term effect of nasal immunotherapy. Tryptase release has been evaluated
      in nasal washings after nasal challenge with a Parietaria (Pellitory wall)
      extract before and after specific systemic immunotherapy, in order to evaluate
      changes in mast cells reactivity. Eight patients were studied, all allergic to
      Parietaria. Nasal provocation tests have been done before the season with
      increasing doses of 10, 100 and 1000 PNU and tryptase assayed in nasal washings
      at 10, 20 and 30 min after provocation. Immunotherapy decreased tryptase release
      after nasal challenge. The data point to the effect of systemic specific
      immunotherapy on mast cell reactivity.

PMID- 10577808
TI  - Modern imaging of petrous bone malformations: improvement for clinical
      embryological correlations.
AB  - The rapid perfecting of modern diagnostic imaging during the past decade has
      provided several new ways to explore ear malformations. Helical computed
      tomography, three-dimensional (3D) reformations, virtual endoscopy and thin
      sliced 3D magnetic resonance imaging constitute the most important recent
      progress. In parallel, conventional morphologic studies and modern teratologic
      experimentation give rise to new concepts relative to ear development. The
      molecular and genetic control of ear morphogenesis is becoming better known, and
      several malformations can be considered as a consequence of a disruption of
      genetic or morphogenetic processes. The role of the homeobox genes is
      particularly important in normal and abnormal development. The field in which
      radio-embryologic correlations are possible is presently very wide and includes:
      the association of vestibular defects and lenticulo-stapedial malformations;
      abnormalities in cochlear coiling; complex ossicular abnormalities; and
      'branchial' syndromes. Several experimental models in animals can reproduce this
      variety of malformations.

PMID- 10577809
TI  - Non-specific and specific immunity to bacterial invasion of the middle ear
      cavity.
AB  - The role of the non-specific (mucociliary clearance, mucus, lactoferrin,
      lysozyme, fibronectin, lactoperoxidase, complement, phagocytosis) and specific
      (immunoglobulins) immune systems in combating bacterial pathogens invading the
      middle ear cavity is discussed. The non-specific system is present from birth,
      acts promptly against a broad spectrum of microorganisms, has no memory, and is
      present for life. In contrast, immunoglobulins act specifically. Secretory IgA
      antibody prevents bacteria from attaching to the epithelium, has no pro
      inflammatory effect and does not activate complement. IgG antibodies can opsonize
      the bacteria for phagocytosis and eventually prevent the bacteria from
      penetrating the epithelium. IgG is pro-inflammatory and can activate a complement
      cascade.

PMID- 10577810
TI  - Effects of intranasal immunization on protective immunity against otitis media.
AB  - It has been reported that intranasal immunization can induce mucosal immune
      responses. However, the efficacy of intranasal immunization on otitis media
      caused by non-typeable Haemophilus influenzae (NTHi) is not yet elucidated. Mice
      were intranasally, orally, intratracheally or intraperitoneally immunized with
      outer membrane protein (OMP) isolated from NTHi, and antigen-specific immune
      responses were determined by enzyme-linked immunosorbent assay (ELISA) and enzyme
      linked immuno-spot assay (ELISPOT). Cytokine production from splenic CD4+ T cells
      was examined by ELISA. Following the immunization, the clearance of NTHi from the
      nasal and nasopharyngeal cavity was examined. OMP-specific IgA antibody titers in
      nasal washes and the numbers of specific IgA-producing cells in nasal passages
      were significantly increased in intranasally immunized mice. Cytokine analysis
      showed that interferon-gamma (IFN-gamma) and interleukins IL-6 and IL-10 were
      predominantly produced from CD4+ T cells. The clearance of NTHi was significantly
      enhanced in the intranasal immunization group. Intranasal immunization is an
      effective vaccination regimen for the induction of OMP-specific mucosal immune
      responses.

PMID- 10577811
TI  - Neurogenic tumors of the head and neck in children.
AB  - Soft tissue tumors make up 63% of all tumors in children. Tumors of the
      sympathetic chain make up 7.4% of tumors arising in children (nine new cases a
      year for every million children in USA) while neurofibrosarcomas make up 3.4%
      (2.4 new cases per year for every million children). There is a certain
      difference between the frequency of benign forms (rather elevated) and that of
      malignant forms (rather low). Diagnosis is possible by echo-scan, computed
      tomography, magnetic resonance imaging and fine-needle aspiration biopsy. As
      regards therapy, surgical resection represents the treatment of choice. In our
      experience, 35 neurogenic tumors in pediatric patients (8-16 years), arising in
      head and neck spaces, were observed and treated in the period 1976 and 1995.
      Twenty-six cases were schwannomas, six were neurofibromas and three were
      olfactory neuroblastomas. All the patients underwent surgery. Sacrifice of the
      affected nerve was necessary in 12 cases (all neurofibromas and eight
      neurinomas). In one case of olfactory aesthesioneuroblastoma a combined approach
      (extra-intracranial approach) was employed. Two patients are alive and disease
      free with 5 and 7 years follow-up. As regards dysfunctional pathology following
      surgical resection, we report definitive facial nerve palsy in two cases,
      permanent laryngeal palsy in six cases, tongue dysfunction in one case and cheek
      hypoaesthesia in one case.

PMID- 10577812
TI  - Salivary gland neoplasia in childhood.
AB  - Salivary gland tumours, benign or malignant, are rare in childhood and as a
      result may be misdiagnosed and treated inappropriately. Ten children with
      salivary gland tumours have been treated by the author over a period of 18 years.
      Four tumours were benign and six malignant. Treatment in all cases was by
      surgical excision. There has been one recurrence, treated by further surgery, in
      an acinic cell carcinoma. Three cases had inadequate surgery or biopsy before
      referral. These findings reflect other series, which demonstrate that a solid
      tumour in a salivary gland in childhood is more likely to be malignant than to be
      benign.

PMID- 10577813
TI  - Surgical treatment of chronic otitis media with effusion.
AB  - Otitis media with effusion is the most frequent reason for admission to hospital
      for surgery in children. There are worldwide differences in the management of the
      condition. Recent studies have evaluated indications for surgery, surgical
      treatment methods, outcome measures following surgery and sequelae. The present
      report defines the increased risk of behavioural problems in pre-school children
      with persistent disease. Factors affecting the outcome of surgery with
      ventilation tubes are discussed. Assessment is made of the complications due to
      the disease and those resulting from treatment with ventilation tubes. Finally, a
      review is made of the various international guidelines for the management of
      persistent disease as a basis for good clinical practice.

PMID- 10577814
TI  - Evaluation of factors affecting outcome of surgery for otitis media with effusion
      in clinical practice.
AB  - In discussing surgery for otitis media with effusion (OME), tympanostomy tubes
      and adenoidectomy are important. Sinus surgery is less important and cleft palate
      surgery needs to be mentioned for completeness sake. There is no evidence
      supporting the value of tonsillectomy in the treatment of OME. Tympanostomy tubes
      are possibly best regarded as artificial eustachian tubes, which remain in
      position for a variable amount of time. It is therefore apparent that resolution
      of OME from tympanostomy tube placement largely depends on whether underlying
      aetiological factors have either resolved or been corrected when the tympanostomy
      tube was in position.

PMID- 10577815
TI  - Assessment of complications of the condition and of the treatment of otitis media
      with effusion.
AB  - Persistent otitis media with effusion (OME) may cause long-term changes of the
      tympanic membrane and middle ear, resulting in some degree of hearing loss. One
      of the traditional aims of treatment with ventilation tubes is to prevent these
      complications from developing. Ventilation tubes themselves, however, are also
      known to induce changes of the tympanic membrane. Several recent studies have
      addressed the questions: what are the effects of the disease, and what are the
      result of its treatment? The object of this study was to present the state of the
      art, by literature review, regarding structural and functional complications of
      OME and treatment with ventilation tubes. In both observational and experimental
      studies tympanosclerosis is reported to occur in 39-65% of ears treated with
      ventilation tubes as opposed to 0-10% of untreated ears. For segmental atrophy
      these percentages are 16-73 and 5-31, respectively. Regarding the prevalence of
      atelectasis and attic retraction, the difference between ventilated and untreated
      ears is less: 10-37% as opposed to 1-20% for atelectasis, and 10-52% as opposed
      to 29-40% for attic retraction. The average hearing loss associated with these
      tympanic membrane abnormalities is less than 5 dB. Although ventilation tubes
      have proven very effective in improving hearing in the short term, they have not
      proven effective in preventing long-term changes of the tympanic membrane related
      to OME, nor in keeping some degree of hearing loss from developing.

PMID- 10577816
TI  - Environmental ear, nose and throat problems in children. IFOS Standing Committee
      for Pediatric ORL.

PMID- 10577817
TI  - Nasal allergy and atmospheric pollution.
AB  - Among the effects that pollution of the air causes on human health, irritation of
      the exposed mucosa is the earliest and the most obvious one. Pollutants damage
      the anatomical and functional integrity of the primary airways, in particular
      they cause alteration of the mucociliary system. The mucosa undergoing continuous
      aggression by an aerosol loaded with pollutants assumes the characteristics of a
      tissue with chronic inflammatory processes with dysepithelialised areas that
      could be an easy entrance for airborne allergens. The loss of integrity of
      epithelial lining, the interference with the repulsion of extraneous particles
      trapped in the mucus, the infiltration of the inflammatory cells and lymphocytes
      called into action by the phlogistic reaction multiply the occasion of meeting
      between environmental allergens and the immunological system of the host and
      basically of setting in motion the process of sensitisation. So there is a strict
      relationship between nasal allergy and pollution, that should not be ignored:
      allergy is the cause of considerable disturbances interfering with study, work
      and social activity and can lead to local and distal complications.

PMID- 10577818
TI  - Correlation between respiratory alterations and respiratory diseases due to urban
      pollution.
AB  - BACKGROUND: Air pollution is strongly correlated with allergic and infectious
      diseases. Chronicity of the stimulation and immaturity of the defense system make
      children prone to respiratory diseases. The aim of this study was to assess the
      adverse effects of urban levels of air pollution, correlating children's
      respiratory diseases and ultrastructural studies in rats, compared to controls in
      a clean area. METHODS: An epidemiological survey was conducted with 2000 school
      children (age range 7-14 years old), divided into two groups of 1000 children
      each: the Red group from Sao Paulo city (17,000,000 inhabitants) and the Green
      group from a rural area around the city of Tupa with no air pollution at all. A
      questionnaire was given to the children's parents in order to estimate history of
      respiratory diseases and predisposing factors. A total of 69 rats were housed for
      6 months in the center of Sao Paulo, and ultrastructural studies of the
      epithelium of the airways were done and compared to 56 control animals in the
      rural area. RESULTS: The Red group of children had a statistically significant (P
      < 0.005) high prevalence of respiratory diseases such as rhinitis, sinusitis, and
      upper respiratory infections (URI). Rats exposed to air pollution developed
      ultrastructural ciliary alterations. CONCLUSION: The results obtained in the
      present investigation suggest that chronic exposure to urban levels of air
      pollution may cause respiratory diseases in children and ultrastructural ciliary
      alterations in the epithelium of the airways in rats, when compared to controls
      in a pollution-free rural area.

PMID- 10577819
TI  - Air pollution and the etiology of laryngitis in children.

PMID- 10577820
TI  - Relationship between passive smoking, recurrent respiratory tract infections and
      otitis media in children.
AB  - The cause of upper respiratory tract infections (URTI) are multifactorial
      (enlarged adenoid, environmental conditions, staying at the care centers, smoking
      parents, allergy). Directly, viral infection causes damage to the ciliary cells
      and mucociliary clearance in the nasopharynx and Eustachian tube, promotes tubal
      occlusion and provokes otitis media. Enlarged adenoids reduce ventilation to the
      nasopharynx, increase accumulation of the secretion and provide a good condition
      for bacteria. AIMS OF THE STUDY: Evaluation of the factors playing a role in
      recurrent URTI and otitis media in children. Clinical and histopathological
      examination of adenoid tissue of children who were passive smokers and children
      who were not exposed to cigarette smoke. Evaluation of the difference between
      ciliary-mucous transport among passive smokers and children not exposed to
      cigarette smoke. METHODS: The analysis of interview questionnaires in 1000
      children aged 3-14 years. Histopathological examinations of adenoid tissue
      excised in the group of children of recurrent upper respiratory tract infections
      and serous otitis media exposed and not exposed to cigarette smoke. CONCLUSIONS:
      Among the risk factors for URTI, the most important are: (1) socio-economic
      conditions; (2) staying at day care centers; and (3) passive smoking. Allergy was
      confirmed in 35-38% of URTI children. Surgical treatment was undertaken in 11.4
      32.5% of URTI children (tonsilloadenoidectomy). Histopathological and
      ultrastructural evaluation of adenoid tissue in passive smoking children
      indicates significant differences to children not exposed to cigarette smoke.

PMID- 10577821
TI  - Posterior glottic stenosis.
AB  - Posterior glottic stenosis in children is not uncommon and must be differentiated
      from vocal cord paralysis when there is posterior glottic fixation. Procedures
      aimed at increasing the airway lumen by tissue excision have not been uniformly
      successful. Chronic aspiration and poor voice results have been reported.
      Expansion of the posterior glottis yields excellent results. Tracheotomy
      decannulation without aspiration and return of vocal cord mobility in children
      who have vocal cord fixation with achievement of a functional voice can be
      expected from widening the laryngeal framework. Scar incision without excision
      reduces the denuded laryngeal surface. The laryngeal framework is widened by
      anterior and posterior cricoid split and by stenting. Posterior cartilage
      grafting reduces scar tissue build-up and the duration of stenting.

PMID- 10577822
TI  - Cricotracheal resection for pediatric subglottic stenosis.
AB  - Until recently, cricotracheal resection (CTR) has not been commonly accepted as a
      treatment modality for severe subglottic stenosis in the pediatric age group. The
      reasons have included the risk of a possible dehiscence at the site of the
      anastomosis, the likelihood of injury to the recurrent laryngeal nerves, and the
      interference with normal growth of the larynx. Thirty-eight infants and children
      with a severe subglottic stenosis underwent a partial cricoid resection with
      primary thyrotracheal anastomosis. Thirty-three patients were tracheotomy
      dependent at the time of surgery and 34 were referred cases; 27 were classified
      as grade III, and 10 as grade IV stenoses according to new Cotton's
      classification. Nineteen patients were younger than 3 years of age at the time of
      surgery. The tracheotomy was resected during the surgical procedure in 21 cases.
      Decannulation was achieved in 36/38 cases after an open procedure. There is one
      complete restenosis and one good result awaiting decannulation after further
      surgery for a Pierre Robin syndrome. The authors experienced no lesion of the
      recurrent laryngeal nerves and no fatality. Thirty-one patients show no
      exertional dyspnea, three a slight stridor while exercising, and two patients are
      not decannulated. The postoperative follow-up in longer than 10 years in eight
      cases. All patients show a normal growth of the larynx and trachea. Compared to
      laryngotracheoplasties, CTR gives better results for severe subglottic stenosis.
      This operation should become the treatment of choice for severe (grade III and
      IV) subglottic stenosis in infants and children.

PMID- 10577823
TI  - Hearing screening--aspects of epidemiology and identification of hearing impaired
      children.
AB  - Mass screening of hearing in children is based on the concept of secondary
      prevention. In recognition of the importance of an early identification and
      intervention in children with congenital or early-acquired (i.e. neonatal period)
      hearing disability, numerous hearing screening programs have been introduced
      throughout the world. The devastating consequences of a congenital/early acquired
      hearing disability upon the speech, language, and social development of a child,
      and the estimated prevalence rates of at least 1-1.5/1000 live births of
      congenital permanent hearing impairment, represent an important health problem.
      The increase in the estimated prevalence of permanent hearing impairment in
      childhood, reaching at least 3.6-8.2% of live births at 5-9 years of age further
      emphasizes the importance of the problem. The delayed identification of children
      with congenital/early acquired hearing disability should result in the
      implementation of universal neonatal hearing screening, and the negative impact
      on the learning processes during school age from hearing impairment acquired
      throughout childhood seems to justify the introduction or maintenance of a
      hearing screening at school entrance. Implementation of efficient hearing
      screening programs throughout the neonatal period, infancy, or childhood should
      result in secondary prevention of this important health problem.

PMID- 10577824
TI  - Dysphonia in infants.
AB  - The definition of infant dysphonia is difficult because the physiological
      phonation itself may be extremely variable in newborns. In a wider sense, all
      voice utterings can be interpreted as dysphonia which deviate continuously in any
      of the parameters (timbre, pitch, intensity, or noise) from the normal. We
      differentiated 20 types of such pathological phonation. The most characteristic
      are: the hoarse (caused by inflammation or tumor of the vocal cords); the hollow
      (indicative of tracheal stenosis); the shrill (suggesting a CNS damage); the
      bleating (pathognostic of Down syndrome); the faint (a result of myogenic
      diseases); and the mewing cry (etiology: cri-du-chat syndrome). In a narrower
      sense dysphonia in infants is a kind of pathological phonation without evidence
      of neurological alteration or chromosomal aberration and without a verified
      laryngeal lesion. These infants utter pressed, harsh, or very high voice
      (hyperfunctional form) or a weak, inert cry (hypofunctional form). The dysphonic
      voice may be characterized also by sudden change in melody or in pitch (glide,
      shift, break, bitonality) and by turbulent noises. This type of newborn dysphonia
      is a result of the immature innervation of the larynx, it gradually improves and
      lateron spontaneously disappears. Perceptual evaluation, endoscopy, and acoustic
      analysis yield useful diagnostic information.

PMID- 10577825
TI  - Phonation in the newborn, infant cry.
AB  - Sound spectrographic studies have shown that the crying of newborn infants has a
      fundamental frequency of about 400-600 cycles per second, and mostly a slightly
      rising-falling melody contour. In sick infants, and especially those with
      diseases affecting the central nervous system, abnormal cry characteristics
      occur. The fundamental frequency has been increased, and the melody contour is
      unstable. Various cry characteristics, which rarely occur in cries of healthy
      infants, are more often present in cries of the sick ones. Studies of cries in
      newborn infants have been especially aimed to determine whether cry analysis
      could be successful in diagnostics and in the early detection of the infant at
      risk for developmental difficulties.

PMID- 10577826
TI  - Vocal fold nodules in children: preferable therapy.
AB  - BACKGROUND: The purpose of this paper is to know the preferable treatment for
      vocal fold nodules in children. METHODS: Two hundred and fifty nine patients with
      vocal fold nodules (176 males and 83 females) were retrospectively reviewed. Age
      ranged from 2 to 18 years with a mean age of 9 years. In addition, questionnaire
      survey was carried out, asking about their present voice. RESULTS: Sixteen
      percent of the patients showed improvement by vocal hygiene advice. Fifty two
      percent of patients receiving voice therapy showed some improvement. Eighty nine
      percent of patients showed some improvement by endolaryngeal microsurgery. With
      respect to the influence of puberty upon the voice, there was no significant
      difference among vocal hygiene, voice therapy, and no-treatment for pre-puberty
      cases. Surgical treatment was the only reliable method to acquire voice
      improvement for pre-puberty cases. In contrast, following puberty there was no
      significant difference in voice improvement among treatment modalities.
      CONCLUSION: If the patient needs immediate improvement of voice, surgery is
      preferable. If they need the improvement of voice but do not hurry up, voice
      therapy should be carried out. If patients have no motivation, vocal hygiene is
      recommended.

PMID- 10577827
TI  - Velopharyngeal insufficiency.
AB  - Velopharyngeal insufficiency (VPI) refers to the mobility of the velopharyngeal
      sphincter to adequately separate the nasal cavity from the oral cavity during
      speech. The auditory result of this structural problem is hyperrhinophy, abnormal
      resonance and the production of distracting noises during speech created by
      turbulent airflow escaping from the nasal cavity.

PMID- 10577828
TI  - Voice problems in children: pathogenesis and diagnosis.
AB  - Voice problems seem to concern more than one child out of twenty, and may concern
      quality (hoarseness), resonance (nasality), pitch (mutation) and loudness. The
      main etiological categories are defined as organic (congenital/acquired),
      functional/habitual (especially due to voice abuse and misuse), and psychogenic
      (especially mutation disorders). Flexible transnasal endoscopes of small diameter
      (2.3 mm) are optimally suited for accurate endoscopic diagnosis, especially if
      combined with video-recording and stroboscopy.

PMID- 10577829
TI  - Mast cells and tryptase in the middle ear of children with otitis media with
      effusion.
AB  - OBJECTIVES: This is the first report of the presence of tryptase, a reflection of
      mast cell activity, in chronic middle ear effusion of patients in whom atopic
      status was characterized. DESIGN AND METHODS: Mediator activity of mast cells and
      eosinophils was measured prospectively from effusion of 33 random patients and
      five controls with chronic otitis media with effusion (OME). Atopy was determined
      by enzyme-linked immunosorbent assay testing. Middle ear biopsies from a second
      group of eight OME patients and four controls were fixed in plastic and stained
      immunohistochemically for mast cells. RESULTS: Sixty-one percent of patients had
      extensive activation of mast cells in their middle ears. Among those with
      elevated tryptase in their effusion, 95.6% were atopic and 94.7% also had
      elevated effusion eosinophilic cationic protein. Tryptase was elevated only in
      the effusion of atopic patients as compared with controls (P < 0.01). Mast cells
      were present in six of eight OME ears and absent in all four normals. CONCLUSION:
      Mast cells and its mediator tryptase, both indicators of a Th2-driven immune
      response, are present in the majority of ears which have chronic effusion,
      suggesting that the inflammation within the middle ear of most OME patients is
      allergic in nature.

PMID- 10577830
TI  - Prevention of accidental childhood strangulation: where is the site of
      obstruction?
AB  - BACKGROUND: Accidental strangulation is a preventable problem with limited
      scientific understanding in children. Children's clothing and household furniture
      have the potential to cause strangulation. Localizing the site of obstruction
      would provide understanding and insight to preventing this unfortunate event.
      METHODS: While undergoing the application of pressure to the submental and
      suprahyoid region in eight patients flexible endoscopy was performed to evaluate
      the location of obstruction. RESULTS: Submental pressure occluded the nasopharynx
      and oropharynx. Suprahyoid pressure occluded the larynx. CONCLUSIONS: In
      suspension strangulation, airway obstruction appears to occur at the level of the
      larynx involving the epiglottis and the arytenoids. Increased knowledge regarding
      site of airway occlusion may help to decrease the hazard of accidental
      strangulation.

PMID- 10577831
TI  - Discovery of the role of dihydrotestosterone in androgen action.

PMID- 10577833
TI  - Separation by thin-layer chromatography of the most common androgen-derived C19
      steroids formed by mammalian cells.
AB  - Several methods have been developed in the past for the separation and
      identification of closely related steroid hormones. Although these methods are
      effective, most of them use HPLC-derived systems and are expensive, laborious, or
      time-consuming. In the course of our studies of the metabolism of
      dehydroepiandrosterone and androstenedione in tissues, we have modified a
      previously published technique in such a way that in one TLC step we can separate
      most of the androgen C19 steroid derivatives produced by mammalian cells. We have
      used this modified technique for the past 2 years with considerable success and
      reproducible results, and we find it to be rapid and relatively inexpensive.

PMID- 10577832
TI  - Progesterone receptor is not required for progesterone action in the rat corpus
      luteum of pregnancy.
AB  - In this study, we investigated whether progesterone exerts a local action
      regulating the function of the corpus luteum of pregnancy in rats. The luteal
      activities of the enzymes 3beta-hydroxysteroid dehydrogenase (3beta-HSD),
      involved in progesterone biosynthesis, and 20alpha-hydroxysteroid dehydrogenase
      (20alpha-HSD), that catabolizes progesterone and reduces progesterone secretion
      by the corpus luteum, were evaluated after intrabursal ovarian administration of
      progesterone in pregnant rats that had received a luteolytic dose of
      prostaglandin F2alpha (PGF2alpha). Luteal 3beta-HSD activity decreased and
      20alpha-HSD activity increased after PGF2alpha treatment (100 microg x 2
      intraperitoneally on Day 19 of pregnancy at 12:00 p.m. and 4:00 p.m.) when
      compared with controls sacrificed at 8:00 p.m. on Day 20 of pregnancy. This
      effect of PGF2alpha on the luteal 3beta-HSD and 20alpha-HSD activities was
      abolished in animals that also received an intraovarian dose of progesterone (3
      microg/ovary on Day 19 of pregnancy at 8:00-9:00 a.m.). In a second functional
      study, luteal cells obtained from 19-day pregnant rats responded to the synthetic
      progestin promegestone (R5020) in a dose-dependent manner, with an increase in
      the progesterone output. In addition, the glucocorticoid agent hydrocortisone did
      not affect progesterone accumulation in the same luteal cell culture. We also
      examined by immunocytochemistry the expression of progesterone receptors (PR) in
      the corpora lutea during pregnancy and demonstrated the absence of PR in this
      endocrine gland in all the days of pregnancy studied. In the same pregnant rats,
      positive staining for PR was observed in cells within the uteroplacental unit,
      such as cells of the decidua basalis and trophoblast giant cells of the
      junctional zone. In addition, positive PR staining was observed in the ovarian
      granulosa and theca cells of growing follicles, but not in corpora lutea of
      ovaries obtained from cycling rats at proestrus. In summary, this report provides
      further evidence of a local action of progesterone regulating luteal function in
      the rat despite the absence of a classic PR.

PMID- 10577834
TI  - Steroid transformations with Exophiala jeanselmei var. lecanii-corni and
      Ceratocystis paradoxa.
AB  - The fungi Exophiala jeanselmei var. lecanii-corni [IMI (International Mycological
      Institute) 312989, UAMH (University of Alberta Microfungus Collection and
      Herbarium) 8783] and Ceratocystis paradoxa (IMI 374529, UAMH 8784) have been
      examined for their potential in steroid biotransformation. The study has
      determined that E. jeanselmei var. lecanii-corni effected overall anti
      Markovnikov hydration on dehydroisoandrosterone, and side-chain degradation on a
      variety of pregnanes. Both ascomycetes were found to carry out redox reactions of
      alcohols and ketones as well as 1,4 reduction of alpha,beta-unsaturated carbonyl
      systems.

PMID- 10577835
TI  - A convenient synthesis of dinorbile acids: oxidative hydrolysis of norbile acid
      nitriles.
AB  - We report a convenient method for the synthesis of dinorbile acids (23,24-dinor
      5beta-cholan-22-oic acids, pregnane-20-carboxylic acids) in fair to good yields
      from norbile acid nitriles in one step by oxidative hydrolysis with oxygen in the
      presence of potassium-t-butoxide. The method results in stepwise overall removal
      of two carbon atoms in bile acid side chains in two steps. Dinorbile acids
      corresponding to several common bile acids have been prepared and their
      structures confirmed by spectroscopic methods. This simple method for synthesis
      of dinorbile acids may facilitate their study metabolically.

PMID- 10577836
TI  - Novel steroid constituents of the soft coral Sinularia dissecta.
AB  - Chemical examination of the soft coral Sinularia dissecta furnished five steroids
      (1-5), which include four new polyhydroxy steroids (2-5). The structures of new
      compounds have been established by the study of their spectral data. Steroid 5
      was a novel polyoxygenated epoxy steroid.

PMID- 10577837
TI  - Effect of organic anions and bile acid conjugates on biliary excretion of taurine
      conjugated bile acid sulfates in the rat.
AB  - Biliary organic anion excretion is mediated by an ATP-dependent primary active
      transporter, canalicular multispecific organic anion transporter/multidrug
      resistance protein 2. On the other hand, a multiplicity of canalicular organic
      anion transporter/multidrug resistance protein 2 has been suggested. Therefore,
      to examine the effect of hydrophobicity on the substrate specificity of
      canalicular multispecific organic anion transporter/multidrug resistance protein
      2, we examined the effect of organic anions and bile acid conjugates on biliary
      excretion of three taurine-conjugated bile acid sulfates with different
      hydrophobicity, taurolithocholate-3-sulfate, taurochenodeoxycholate3-sulfate, and
      taurocholate-3-sulfate in rats. Biliary excretions of these bile acid conjugates
      were delayed in Eisai hyperbilirubinemic rats. Biliary excretion of these bile
      acid conjugates was inhibited by sulfobromophthalein, whereas biliary excretion
      and taurocholate-3-sulfate was not inhibited by phenolphthalein glucuronide.
      Taurolithocholate-3-sulfate and ursodeoxycholate-3-glucuronide decreased biliary
      excretion of taurochenodeoxycholate-3-sulfate and taurocholate-3-sulfate, but
      ursodeoxycholate-3,7-disulfate did not affect biliary excretion of
      taurochenodeoxycholate-3-sulfate and taurocholate-3-sulfate. These findings
      indicate that very hydrophilic organic anions are not good substrates of
      canalicular multispecific organic anion transporter/multidrug resistance protein
      2.

PMID- 10577838
TI  - Effect of dehydroepiandrosterone and its sulfate and fatty acid ester derivatives
      on rat brain membranes.
AB  - The effects of dehydroepiandrosterone (DHEA) as well as its sulfate and fatty
      acid ester derivatives on rat brain membrane fluidity was investigated by
      fluorescence depolarization of a lipid probe 1,6-diphenyl-1,3,5-hexatriene and
      compared to its effect on phospholipid conformation investigated by Fourier
      transform infrared spectroscopy. In rat brain, membrane fluidity varied rostro
      caudally, the frontal cortex showing the highest fluidity compared to the
      hypothalamus, hippocampus, striatum, thalamus, and hindbrain. As previously
      reported, it was observed that cholesteryl hemisuccinate and stearic acid
      rigidify striatal membrane whereas linoleic acid and L-alpha-phosphatidylcholine
      increase the membrane fluidity. Striatal fluidity was increased in vitro with
      increasing concentrations of DHEA, this effect was greater with the DHEA fatty
      acid ester derivatives (DHEA-L), DHEA-undecanoate, and DHEA-stearate, whereas no
      effect was observed with DHEA-sulfate (DHEA-S). In the frontal cortex only the
      two DHEA-L derivatives increased membrane fluidity, whereas DHEA and DHEA-S were
      without effect. The effect of DHEA-L on synthetic dimyristoylphosphatidylcholine
      d54 phospholipid membranes indicates a disordering effect of DHEA-undecanoate and
      DHEA-stearate as reflected by increased trans-gauche isomerization of the acyl
      chains of the lipid. Hence, DHEA-L increase the disorder and/or fluidity of brain
      membranes; interestingly, these compounds are abundant in the brain where they
      are generally considered as storage compounds that slowly release the active
      unconjugated steroid hormone.

PMID- 10577839
TI  - DNA replication checkpoint control.
AB  - The eukaryotic cell cycle comprises two critical phases, DNA replication (S
      phase) and the subsequent distribution of an equivalent genome to each of two
      daughter cells at mitosis (M phase). A signal transduction cascade called the
      replication checkpoint has evolved to ensure that M phase does not occur prior to
      the completion of S phase. The mitotic regulators targeted by this checkpoint
      have recently been identified in the fission yeast Schizosaccharomyces pombe. As
      was the case for the DNA damage checkpoint, studies on the replication checkpoint
      in fission yeast promise to provide an excellent framework for analogous studies
      in mammalian cells.

PMID- 10577840
TI  - Soft tissue sarcoma: apples, oranges, and passion fruit.

PMID- 10577841
TI  - Prognostic factors for children and adolescents with surgically resected
      nonrhabdomyosarcoma soft tissue sarcoma: an analysis of 121 patients treated at
      St Jude Children's Research Hospital.
AB  - PURPOSE: The rarity and heterogeneity of pediatric nonrhabdomyosarcoma soft
      tissue sarcoma (NRSTS) has precluded meaningful analysis of prognostic factors
      associated with surgically resected disease. To define a population of patients
      at high risk of treatment failure who might benefit from adjuvant therapies, we
      evaluated the relationship between various clinicopathologic factors and clinical
      outcome of children and adolescents with resected NRSTS over a 27-year period at
      our institution. PATIENTS AND METHODS: We analyzed the records of 121 consecutive
      patients with NRSTS who underwent surgical resection between August 1969 and
      December 1996. Demographic data, tumor characteristics, treatment, and outcomes
      were recorded. Univariate and multivariate analyses of prognostic factors for
      survival, event-free survival (EFS), and local and distant recurrence were
      performed. RESULTS: At a median follow-up of 9.2 years, 5-year survival and EFS
      rates for the entire cohort were 89% +/- 3% and 77% +/- 4%, respectively. In
      univariate models, positive surgical margins (P =.004), tumor size > or = 5 cm (P
      <.001), invasivene (P =.002), high grade (P =.028), and intra-abdominal primary
      tumor site (P =.055) adversely affected EFS. All of these factors except
      invasiveness remained prognostic of EFS and survival in multivariate models.
      Positive surgical margins (P =.003), intra-abdominal primary tumor site (P
      =.028), and the omission of radiation therapy (P =.043) predicted local
      recurrence, whereas tumor size > or = 5 cm (P <.001), invasiveness (P <.001), and
      high grade (P =.004) predicted distant recurrence. CONCLUSION: In this largest
      single-institution analysis of pediatric patients with surgically resected NRSTS,
      we identified clinicopathologic features predictive of poor outcome. These
      variables should be prospectively evaluated as risk-adapted therapies are
      developed.

PMID- 10577842
TI  - Results of treatment for soft tissue sarcoma in childhood and adolescence: a
      final report of the German Cooperative Soft Tissue Sarcoma Study CWS-86.
AB  - PURPOSE: The goal of the second German Soft Tissue Sarcoma Study CWS-86 (1985 to
      1990) was to improve the prognosis in children and adolescents with soft tissue
      sarcoma by means of a clinical trial comprising intensive chemotherapy and risk
      adapted local therapy. PATIENTS AND METHODS: There were 372 eligible patients. A
      staging system based on the postsurgical extent of disease was used. Chemotherapy
      consisted of vincristine, dactinomycin, doxorubicin, and ifosfamide. Radiotherapy
      was administered early at 10 to 13 weeks simultaneously with the second
      chemotherapy cycle (32 Gy or 54. 4 Gy). The single dose was reduced to 1.6 Gy and
      given twice daily (accelerated hyperfractionation). RESULTS: The event-free
      survival (EFS) and overall survival rates at 5 years were 59% +/- 3% and 69% +/-
      3%, respectively. The 5-year EFS rate according to stage was as follows: stage I,
      83% +/- 5%; stage II, 69% +/- 6%; stage III, 57% +/- 4%; and stage IV, 19% +/-
      6%. The outcome for patients with stage III disease who required radiotherapy was
      much better in the CWS-86 study compared with the CWS-81 study (5-year EFS, 60%
      +/- 5% v 44% +/- 6%; P =.053). The most common treatment failure was isolated
      local relapse, with 14% of patients relapsing at the primary tumor site.
      CONCLUSION: The improved design of the study incorporating risk-adapted
      radiotherapy allowed treatment to be reduced for selected groups of patients
      without compromising survival.

PMID- 10577843
TI  - Survival and neurodevelopmental outcome of young children with medulloblastoma at
      St Jude Children's Research Hospital.
AB  - PURPOSE: Young children treated for medulloblastoma are at especially high risk
      for morbidity and mortality from their disease and therapy. This study sought to
      assess the relationship, if any, between patient outcome and M stage.
      Neuropsychologic and endocrine outcomes were also assessed. PATIENTS AND METHODS:
      Twenty-nine consecutively diagnosed infants and young children were treated for
      medulloblastoma at St Jude Children's Research Hospital between November 1984 and
      December 1995. All patients were treated with the intent of using postoperative
      chemotherapy to delay planned irradiation. RESULTS: The median age at diagnosis
      was 2.6 years. Six patients completed planned chemotherapy without progressive
      disease and underwent irradiation at completion of chemotherapy. Twenty-three
      children experienced disease progression during chemotherapy and underwent
      irradiation at the time of progression. The 5-year overall survival rate for the
      entire cohort was 51% +/- 10%. The 5-year progression-free survival rate was 21%
      +/- 8%. M stage did not impact survival. All patients lost cognitive function
      during and after therapy at a rate of -3.9 intelligence quotient points per year
      (P =.0028). Sensory functions declined significantly after therapy (P =.007). All
      long-term survivors required hormone replacement therapy and had growth
      abnormalities. CONCLUSION: The majority of infants treated for medulloblastoma
      experienced disease progression during initial chemotherapy. However, more than
      half of these patients can be cured with salvage radiation therapy, regardless of
      M stage. The presence of metastatic disease did not increase the risk of dying
      from medulloblastoma. All patients treated in this fashion have significant
      neuropsychologic deficits. Our experience demonstrates that medulloblastoma in
      infancy is a curable disease, albeit at a significant cost.

PMID- 10577844
TI  - Total-body irradiation and melphalan is a safe and effective conditioning regimen
      for autologous bone marrow transplantation in children with acute myeloid
      leukemia in first remission. The Italian Association for Pediatric Hematology and
      Oncology-Bone Marrow Transplantation Group.
AB  - PURPOSE: To evaluate the safety and efficacy of a preparative regimen consisting
      of fractionated total-body radiation (9.9 to 12 Gy) and melphalan (140 mg/m(2) in
      a single dose) in children with acute myeloid leukemia in first complete
      remission (CR) given autologous bone marrow transplantation (ABMT). PATIENTS AND
      METHODS: Fifty-three children (30 males and 23 females; age range, 1.5 to 18
      years) were enrolled onto the study. The median time from first CR to ABMT was
      3.5 months (range, 1.4 to 13 months), with 45 patients (85%) undergoing
      transplantation within 6 months from the diagnosis. Forty-five patients received
      in vitro marrow purging with standard-dose mafosfamide (100 microg/mL), seven
      patients were treated with interleukin-2 before marrow collection, and in the
      remaining child, the marrow was unmanipulated. The median infused cell dose was
      1.8 x 10(8)/kg (range, 0.4 to 5.8 x 10(8)/kg). RESULTS: All patients but one
      achieved hematopoietic engraftment, with a median time to neutrophil recovery of
      24 days (range,11 to 66 days). Treatment-related toxicity was moderate and
      consisted mainly of mucositis. One patient died from cytomegalovirus interstitial
      pneumonia, and one died from pulmonary hemorrhage. Fourteen patients (26%)
      relapsed at a median time of 6 months after ABMT (range, 2 to 17 months), with a
      cumulative relapse probability of 29% (95% confidence interval, 16% to 42%). The
      5-year Kaplan-Meier estimate of survival for all 53 patients was 78% (range, 65%
      to 90%), whereas the overall 5-year disease-free survival was 68% (range, 55% to
      81%), with a median follow-up duration of 40 months (range, 7 to 130 months).
      CONCLUSIONS: These data suggest that, in our cohort of patients, the combination
      of total-body irradiation and melphalan is safe and associated with good
      antileukemia activity, making ABMT an appealing alternative for postremission
      therapy in children with acute myeloid leukemia in first CR.

PMID- 10577845
TI  - High cure rates and reduced long-term toxicity in pediatric Hodgkin's disease:
      the German-Austrian multicenter trial DAL-HD-90. The German-Austrian Pediatric
      Hodgkin's Disease Study Group.
AB  - PURPOSE: To further reduce therapy-related late effects in patients with
      pediatric Hodgkin's disease (HD) while maintaining the high cure rates achieved
      with vincristine, prednisone, procarbazine, and doxorubicin (OPPA) or
      OPPA/cyclophosphamide, vincristine, prednisone, and procarbazine (COPP)
      chemotherapy and involved-field radiotherapy. The risk of testicular dysfunction
      was addressed by substituting etoposide for procarbazine (OEPA) in the induction
      therapy for boys. Radiation doses and fields were further reduced. PATIENTS AND
      METHODS: Three hundred nineteen boys and 259 girls younger than 18 years with
      previously untreated HD, enrolled onto the study between 1990 and 1995, were
      allocated to treatment group (TG)1 (early stages), TG2 (intermediate stages), or
      TG3 (advanced stages). All groups underwent two cycles of OEPA (boys) or OPPA
      (girls) for induction chemotherapy. TG2 and TG3 continued on additional two or
      four cycles, respectively, of COPP. Low-dose radiotherapy was given to the
      initially involved sites, ie, reduced involved fields. RESULTS: Initial response
      to OPPA or OEPA induction was virtually identical. Eight of 578 patients
      experienced early progression of HD. Thirty-seven relapses, three secondary
      tumors, and no secondary leukemias have been recorded, with a median follow-up
      duration of 5.1 years (maximum, 8.1 years). Thirteen of 578 patients died. The
      probability of 5-year event-free survival/overall survival is 91%/98% in the
      total group, 94%/97% with OPPA, and 89%/98% with OEPA induction therapy. Risk
      factor analysis showed two significant prognostic factors: histologic subtype NS2
      and "B" symptoms. OEPA induction therapy, large mediastinal tumor, and age were
      not significant. Preliminary studies of testicular function indicate a lower risk
      of germ cell damage than previously documented with OPPA. CONCLUSION: OEPA is a
      satisfactory alternative to OPPA. Radiotherapy can be confined to involved sites
      when combined with appropriate chemotherapy. The DAL-HD-90 regimen represents a
      comprehensive treatment program for all stages of pediatric HD and offers a
      favorable benefit/risk ratio, combining excellent disease control, moderate acute
      toxicity, and reduced long-term toxicity.

PMID- 10577846
TI  - Improved survival of children with isolated CNS relapse of acute lymphoblastic
      leukemia: a pediatric oncology group study .
AB  - PURPOSE: Isolated meningeal relapse in children with acute lymphoblastic leukemia
      (ALL) usually has been followed by bone marrow relapse and limited survival. The
      purpose of this study was to prevent marrow relapse by administering intensive
      therapy before delayed craniospinal radiation. PATIENTS AND METHODS: Eighty-three
      patients with ALL in first bone marrow remission with an isolated CNS relapse
      were treated with systemic chemotherapy known to enter into the CSF and
      intrathecal chemotherapy for 6 months. Craniospinal irradiation (24 Gy cranial/15
      Gy spinal) was then administered, followed by 1.5 years of maintenance
      chemotherapy. RESULTS: All 83 patients achieved a second remission. The 4-year
      event-free survival (EFS) rate was 71.1% +/- 5.3%. There was a fourfold increased
      risk of relapse for children whose initial remission was less than 18 months. The
      4-year EFS rate for patients with a first complete remission >/= 18 months was
      83.3% +/- 5.3%, and for those with a first complete remission less than 18
      months, it was 46.2% +/- 10.2% (P =.0002.) There was a low incidence of
      neurologic toxicity and an unexpectedly high rate of allergic reactions to L
      asparaginase. Five patients developed secondary malignancies: two with acute
      nonlymphoblastic leukemia during therapy, one with myelodysplasia after therapy,
      and two with brain tumors 1.5 to 2 years after cessation of therapy. CONCLUSION:
      For children with ALL and an isolated CNS relapse, treatment that delays
      definitive craniospinal irradiation by 6 months to allow for more intensive
      systemic and intrathecal chemotherapy results in better EFS than has been
      previously reported. Using this approach, the long-term prognosis for children
      with first complete remission >/= 18 months is comparable to that at the time of
      original diagnosis of ALL.

PMID- 10577847
TI  - Expression of aberrantly spliced oncogenic ikaros isoforms in childhood acute
      lymphoblastic leukemia.
AB  - PURPOSE: We sought to determine if molecular abnormalities involving the Ikaros
      gene could contribute to the development of acute lymphoblastic leukemia (ALL) in
      children. PATIENTS AND METHODS: We studied Ikaros gene expression in normal human
      bone marrow, normal thymocytes, normal fetal liver-derived immature lymphocyte
      precursor cell lines, eight different ALL cell lines, and leukemic cells from 69
      children with ALL (T-lineage ALL, n = 18; B-lineage ALL, n = 51). Expression of
      Ikaros protein and its subcellular localization were examined by immunoblotting
      and confocal laser-scanning microscopy, respectively. Polymerase chain reaction
      (PCR) and nucleotide sequencing were used to identify the specific Ikaros
      isoforms expressed in these cells. Genomic sequencing of splice junction regions
      of the Ikaros gene was performed in search for mutations. RESULTS: In each of the
      ALL cases, we found high-level expression of a non-DNA-binding or aberrant DNA
      binding isoform of Ikaros with abnormal subcellular compartmentalization
      patterns. In contrast, only wild-type Ik-1 and Ik-2 isoforms with normal
      subcellular localization were found in normal bone marrow cells and thymus
      derived or fetal liver-derived normal lymphocyte precursors. In leukemic cells
      expressing the aberrant Ikaros coding sequences with the 30-base-pair deletion,
      genomic sequence analysis of the intron-exon junctions between exons 6 and 7
      yielded the wild-type sequence. We identified a single nucleotide polymorphism
      (SNP) affecting the third base of the triplet codon for a proline (CCC or CCA) in
      the highly conserved bipartite activation region (viz, A or C at position 1002
      numbering from the translation start site of Ik-1) within our Ikaros clones. Bi
      allelic expression of truncated and/or non-DNA-binding isoforms along with wild
      type isoforms was observed in leukemic cells, which implicates trans-acting
      factor(s) affecting splice site recognition. CONCLUSION: Our findings link
      specific molecular defects involving the Ikaros gene to childhood ALL.
      Posttranscriptional regulation of alternative splicing of Ikaros RNA seems to be
      defective in leukemic lymphocyte precursors from most children with ALL.
      Consequently, leukemic cells from ALL patients, in contrast to normal lymphocyte
      precursors, express high levels of non-DNA-binding Ikaros isoforms that are
      reminiscent of the non-DNA-binding Ikaros isoforms that lead to lymphoblastic
      leukemia in mice.

PMID- 10577848
TI  - Patients with t(8;21)(q22;q22) and acute myeloid leukemia have superior failure
      free and overall survival when repetitive cycles of high-dose cytarabine are
      administered.
AB  - PURPOSE: To examine the effect of single compared with repetitive (at least
      three) cycles of high-dose cytarabine after induction therapy for patients with
      acute myeloid leukemia (AML) who have the t(8;21)(q22;q22) karyotype. PATIENTS
      AND METHODS: Patients entered onto the study had AML and t(8;21) and attained a
      complete remission on four successive Cancer and Leukemia Group B studies. In
      these studies, either > or = three cycles of high-dose cytarabine or one cycle of
      high-dose cytarabine was administered, followed by sequential
      cyclophosphamide/etoposide and mitoxantrone/diaziquone with or without filgrastim
      support. Outcomes of these two groups of t(8;21) patients were compared. RESULTS:
      A total of 50 patients with centrally reviewed AML and t(8;21) were assigned to
      receive one (n = 29) or > or = three cycles (n = 21) of high-dose cytarabine as
      postinduction therapy. The clinical features of these two groups of patients were
      similar. Initial remission duration for t(8;21) patients assigned to one cycle of
      high-dose cytarabine was significantly inferior (P =.03), with 62% of patients
      experiencing relapse with a median failure-free survival of 10.5 months, compared
      with the group of patients who received > or = three cycles, in which only 19%
      experienced relapse and failure-free survival is estimated to be greater than 35
      months. Furthermore, overall survival was also significantly compromised (P =.04)
      in patients assigned to one cycle of high-dose cytarabine, with 59% having died
      as a consequence of AML, compared with 24% of those who received > or = three
      cycles of high-dose cytarabine. CONCLUSION: These data demonstrate that failure
      free survival and overall survival of patients with t(8;21)(q22;q22) may be
      compromised by treatment approaches that do not include sequential high-dose
      cytarabine therapy.

PMID- 10577849
TI  - Ifosfamide, carboplatin, and etoposide: a highly effective cytoreduction and
      peripheral-blood progenitor-cell mobilization regimen for transplant-eligible
      patients with non-Hodgkin's lymphoma.
AB  - PURPOSE: To evaluate a chemotherapy regimen that consisted of ifosfamide
      administered as an infusion with bolus carboplatin, and etoposide (ICE) supported
      by granulocyte colony-stimulating factor (G-CSF) for cytoreduction and stem-cell
      mobilization in transplant-eligible patients with primary refractory or relapsed
      non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: One hundred sixty-three
      transplant-eligible patients with relapsed or primary refractory NHL were treated
      from October 1993 to December 1997 with ICE chemotherapy at Memorial Sloan
      Kettering Cancer Center. Administration of three cycles of ICE chemotherapy was
      planned at 2-week intervals. Peripheral-blood progenitor cells were collected
      after cycle 3, and all patients who achieved a partial response (PR) or complete
      response (CR) to ICE chemotherapy were eligible to proceed to transplantation.
      Event-free and overall survival, ICE-related toxicity, and the number of CD34(+)
      cells collected after treatment with ICE and G-CSF were evaluated. RESULTS: All
      163 patients were assessable for response, and there was no treatment-related
      mortality. A major response (CR/PR) was evident in 108 patients (66.3%); 89% of
      the responding patients underwent successful transplantation. Patient who
      underwent transplantation and achieved a CR to ICE had a superior overall
      survival to that of patients who achieved a PR (65% v 30%; P =.003). The median
      number of CD34(+) cells/kg collected was 8.4 x 10(6). The dose-limiting toxicity
      of ICE was hematologic, with 29.4% of patients developing grade 3/4
      thrombocytopenia. There were minimal nonhematologic side effects. CONCLUSION: ICE
      chemotherapy, with ifosfamide administered as a 24-hour infusion to decrease CNS
      side effects, and the substitution of carboplatin for cisplatin to minimize
      nephrotoxicity, is a very effective cytoreduction and mobilization regimen in
      patients with NHL. Furthermore, the quality of the clinical response to ICE
      predicts for posttransplant outcome.

PMID- 10577850
TI  - Gemcitabine as a single agent in the treatment of relapsed or refractory
      aggressive non-Hodgkin's lymphoma.
AB  - PURPOSE: A multicenter phase II trial was conducted to evaluate the efficacy and
      toxicity of gemcitabine in patients with relapsed or refractory aggressive non
      Hodgkin's lymphomas (NHL). PATIENTS AND METHODS: Thirty-one patients with B-cell
      intermediate or high-grade NHL (Working Formulation) were enrolled onto the
      study. The median age was 61 years, with a Karnofsky performance status of </=
      80% in 65% of patients. Forty-eight percent had stage III or IV (Ann Arbor
      Classification) at study entry. Pretreatment consisted of one, two, or three
      chemotherapeutic regimens in nine, 11, and 11 patients, respectively. Gemcitabine
      1,250 mg/m(2) was administered intravenously over 30 minutes on days 1, 8, and 15
      of a 28-day schedule. RESULTS: Thirty patients were assessable for efficacy, and
      31 were assessable for toxicity. No complete responses were observed, but six
      patients showed a partial response, 11 stable disease, and 13 progressive
      disease. The overall response rate was 20% (95% confidence interval, 8% to 39%)
      for assessable patients and 19% (95% confidence interval, 8% to 34%) for the
      intent-to-treat analysis. The median duration of partial response was 6 months
      (range, 3.7 to 15+ months). Nonhematologic World Health Organization grade 3
      toxicity included hepatic toxicity in four patients and infection in two.
      Hematologic toxicity was observed as grade 3 anemia in three patients, grade 3
      leukopenia in two patients, grade 3/4 neutropenia in two patients, and grade 3/4
      thrombocytopenia in six patients. CONCLUSION: The present schedule of gemcitabine
      displays modest efficacy and mild toxicity in pretreated aggressive NHL.

PMID- 10577851
TI  - Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or
      refractory CD20(+) B-cell non-Hodgkin's lymphoma.
AB  - PURPOSE: Yttrium-90 ibritumomab tiuxetan (IDEC-Y2B8) is a murine immunoglobulin
      G1 kappa monoclonal antibody that covalently binds MX-DTPA (tiuxetan), which
      chelates the radioisotope yttrium-90. The antibody targets CD20, a B-lymphocyte
      antigen. A multicenter phase I/II trial was conducted to compare two doses of
      unlabeled rituximab given before radiolabeled antibody, to determine the maximum
      tolerated single dose of IDEC-Y2B8 that could be administered without stem-cell
      support, and to evaluate safety and efficacy. PATIENTS AND METHODS: Eligible
      patients had relapsed or refractory (two prior regimens or anthracycline if low
      grade disease) CD20(+) B-cell low-grade, intermediate-grade, or mantle-cell non
      Hodgkin's lymphoma (NHL). There was no limit on bulky disease, and 59% had at
      least one mass > or = 5 cm. RESULTS: The maximum-tolerated dose was 0.4 mCi/kg
      IDEC-Y2B8 (0.3 mCi/kg for patients with baseline platelet counts 100 to
      149,000/microL). The overall response rate for the intent-to-treat population (n
      = 51) was 67% (26% complete response [CR]; 41% partial response [PR]); for low
      grade disease (n = 34), 82% (26% CR; 56% PR); for intermediate-grade disease (n =
      14), 43%; and for mantle-cell disease (n = 3), 0%. Responses occurred in patients
      with bulky disease (> or = 7 cm; 41%) and splenomegaly (50%). Kaplan-Meier
      estimate of time to disease progression in responders and duration of response is
      12.9+ months and 11.7+ months, respectively. Adverse events were primarily
      hematologic and correlated with baseline extent of marrow involvement with NHL
      and baseline platelet count. One patient (2%) developed an anti-antibody response
      (human antichimeric antibody/human antimouse antibody). CONCLUSION: These phase
      I/II data demonstrate that IDEC-Y2B8 radioimmunotherapy is a safe and effective
      alternative for outpatient therapy of patients with relapsed or refractory NHL. A
      phase III study is ongoing.

PMID- 10577852
TI  - Classical Hodgkin's disease and follicular lymphoma originating from the same
      germinal center B cell.
AB  - PURPOSE: Classical Hodgkin's disease and non-Hodgkin's B-cell lymphoma
      occasionally occur in the same patient. To clarify whether these different
      diseases share a common precursor cell, we analyzed the immunoglobulin
      rearrangements in tumor cells of the classical Hodgkin's disease and the
      follicular lymphoma that developed in the same patient 2 years apart. PATIENTS
      AND METHODS: Polymerase chain reaction (PCR) for the detection of rearranged
      immunoglobulin genes was carried out on single Reed-Sternberg cells and on whole
      tissue DNA extracted from the follicular lymphoma. PCR products were sequenced
      and compared with each other and with germ line immunoglobulin variable segments.
      Immunoglobulin heavy- and light-chain transcripts were analyzed by radioactive in
      situ hybridization. RESULTS: The same monoclonal immunoglobulin gene
      rearrangement was found in both neoplasms. The variable region of the
      immunoglobulin heavy-chain genes of the Reed-Sternberg and of the follicular
      lymphoma cells were differently mutated, but six somatic mutations were shared by
      both lymphoma cells. Although the coding capacity of the immunoglobulin genes was
      preserved in both neoplastic cell populations, immunoglobulin heavy- (mu) and
      light- (kappa) chain expression was restricted to the follicular lymphoma cells,
      except for small amounts of kappa light-chain mRNA in some Reed-Sternberg cells.
      CONCLUSIONS: The neoplastic cells of the Hodgkin's disease and the follicular
      lymphoma that occurred in this patient derived from a common precursor B cell.
      Its differentiation stage could be identified as that of a germinal center B
      cell. Thus, transforming events can be more important than the cell of origin in
      determining a disease entity.

PMID- 10577853
TI  - Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with
      resected stage III gastric cancer.
AB  - PURPOSE: The efficacy of adjuvant chemotherapy in gastric cancer is
      controversial. We conducted a phase III, randomized, multicentric clinical trial
      with the goal of assessing the efficacy of the combination of mitomycin plus
      tegafur in prolonging the disease-free survival and overall survival of patients
      with resected stage III gastric cancer. PATIENTS AND METHODS: Patients with
      resected stage III gastric adenocarcinoma were randomly assigned, using sealed
      envelopes, to receive either chemotherapy or no further treatment. Chemotherapy
      was started within 28 days after surgery according to the following schedule:
      mitomycin 20 mg/m(2) intravenously (bolus) at day 1 of chemotherapy; 30 days
      later, oral tegafur at 400 mg bid daily for 3 months. Disease-free survival and
      overall survival were estimated using the Kaplan-Meier analysis and the Cox
      proportional hazards model. RESULTS: Between January 1988 and September 1994, 148
      patients from 10 hospitals in Catalonia, Spain, were included in the study. The
      median follow-up period was 37 months. The tolerability of the treatment was
      excellent. The overall survival and disease-free survival were higher in the
      group of patients treated with chemotherapy (P =.04 for survival and P =.01 for
      disease-free survival in the log-rank test). The overall 5-year survival rate and
      the 5-year disease-free survival rate were, respectively, 56% and 51% in the
      treatment group and 36% and 31% in the control group. CONCLUSION: Our positive
      results are consistent with the results of recent studies; which conclude that
      there is a potential benefit from adjuvant chemotherapy in resected gastric
      cancer.

PMID- 10577854
TI  - Combination chemotherapy with carboplatin, docetaxel, and gemcitabine in advanced
      non-small-cell lung cancer: a phase II study.
AB  - PURPOSE: To evaluate the efficacy and toxicity of the combination of carboplatin,
      docetaxel, and gemcitabine in patients with advanced non-small-cell lung cancer
      (NSCLC). PATIENTS AND METHODS: Forty-five chemotherapy-naive patients with NSCLC
      were treated on an out-patient basis with carboplatin area under the curve 5
      intravenous (IV) and gemcitabine 800 mg/m(2) IV on day 1 and docetaxel 75 mg/m(2)
      IV and gemcitabine 800 mg/m(2) IV on day 8. Granulocyte colony-stimulating factor
      (150 ug/m(2) subcutaneously) was given prophylactically from day 3 to day 6 and
      day 10 to day 16. Chemotherapy was repeated every 4 weeks. Patients were
      evaluated for response every two cycles of treatment. RESULTS: The median age of
      the patients was 58 years (range, 24 to 75 years). The performance status was 0
      for 16 patients, 1 for 17 patients, and 2 for 12 patients. Nine patients (20%)
      had stage IIIB disease, and 36 (80%) had stage IV; histology was mainly squamous
      cell carcinoma (51.2% of patients) that was poorly differentiated (37.8%). All 45
      patients were assessable for toxicity, and 41 were assessable for response. On an
      intent-to-treat analysis, the objective response rate was 46. 5% (21 out of 45
      patients; 95% confidence interval [CI], 31.7% to 62. 5%). Of the 45 patients,
      four (8.8%) achieved a complete response (95% CI, 2.5% to 21.2%); 17 (37.7%)
      achieved a partial response (95% CI, 23.8% to 53.5%); seven (15.5%) had stable
      disease; and 14 (31. 1%) had progressive disease. The median survival time was
      13.5 months, and the actuarial 1-year survival rate was 51.11%. The median
      duration of response was 7.6 months, and the time to tumor progression was 8.1
      months. Grade 3/4 anemia and thrombocytopenia occurred in 17.7% and 28.8% of
      patients, respectively. Twenty-one patients (46.6%) developed grade 3/4
      neutropenia, and six patients (13.3%) were complicated with fever. Alopecia was
      universal. Grade 3 diarrhea occurred in four patients (8.8%); grade 3/4
      neurotoxicity occurred in 10 patients (22.2%); and grade 2/3 allergic reaction
      occurred in three patients (16.6%). There were no treatment-related deaths. Six
      patients (13.3%) required a dose reduction, two of which required two reductions.
      CONCLUSIONS: The combination of carboplatin, docetaxel, and gemcitabine is an
      effective regimen for the treatment of chemotherapy-naive patients with advanced
      NSCLC, causing only moderate toxicity.

PMID- 10577855
TI  - Phase II study of oral platinum drug JM216 as first-line treatment in patients
      with small-cell lung cancer.
AB  - PURPOSE: This multicenter phase II trial was performed to determine tumor
      efficacy and tolerance of the oral platinum drug JM216 in patients with small
      cell lung cancer (SCLC). PATIENTS AND METHODS: Patients with SCLC limited disease
      unfit for intensive chemotherapy or those with extensive disease received JM216
      120 mg/m(2)/d for 5 consecutive days every 3 weeks. Individual dose escalation to
      140 mg/m(2)/d was allowed if toxicity was </= grade 2 according to the National
      Cancer Institute Common Toxicity Criteria. Tumor response was evaluated according
      to World Health Organization criteria. RESULTS: Twenty-seven patients were
      assessable for toxicity and 26 for tumor response. Eighty-eight cycles were
      administered. Common Toxicity Criteria grade 3 and 4 hematologic toxicities were
      neutropenia in 15.9% and 3.7%, lymphocytopenia in 47.6% and 17.1%, and
      thrombocytopenia in 19.5% and 10.3% of cycles, respectively. One patient suffered
      from neutropenic fever. Nausea, vomiting, and diarrhea were the most common
      nonhematologic toxicities. Except for grade 4 diarrhea in one patient, no grade 4
      nonhematologic toxicity was observed. No severe neurotoxicity or nephrotoxicity
      was observed. Tumor response rate was 10 of 26 (38%; 95% confidence interval, 19%
      to 58%), excluding five unconfirmed partial responses. No complete responses were
      observed. Median overall time to progression was 110 days (range, 5 to 624 days).
      Median overall survival time was 210 days (range, 5 to 624 days). CONCLUSION:
      Oral JM216 is active in previously untreated patients with SCLC and shows mild
      toxicities.

PMID- 10577856
TI  - Phase II trial of doxorubicin and paclitaxel plus granulocyte colony-stimulating
      factor in metastatic breast cancer: an Eastern Cooperative Oncology Group Study.
AB  - PURPOSE: Several groups have reported that the combination of doxorubicin plus
      paclitaxel given as a 3-hour intravenous (IV) infusion for up to eight cycles
      produces a high response rate (> 80%) and complete response rate (> 20%) in
      metastatic breast cancer, but is also complicated by a 20% incidence of
      congestive heart failure (CHF). The purpose of this phase II trial was to
      evaluate the antineoplastic activity of the regimen in a multi-institutional
      setting and to reduce the incidence of cardiotoxicity by limiting treatment to a
      maximum of six cycles. PATIENTS AND METHODS: Fifty-two patients with advanced
      breast cancer received doxorubicin (60 mg/m(2) by IV injection) followed 15
      minutes later by paclitaxel (200 mg/m(2) by IV infusion over 3 hours) every 3
      weeks for four to six cycles. RESULTS: Objective responses occurred in 25 of 48
      assessable patients (52%; 95% confidence interval [CI], 38% to 66%), including
      four complete responses (8%; 95% CI, 0% to 16%). The median cumulative
      doxorubicin dose given was 240 mg/m(2) (range, 132 to 360 mg/m(2)). Eleven
      patients (21%) were documented as having a decrease in the LVEF below normal,
      including three patients (6%; 95% CI, 0% to 12%) who developed CHF. CONCLUSION:
      The doxorubicin/paclitaxel regimen that we used is unlikely to produce an
      objective response rate of more than 70% and a complete response rate of more
      than 20% in patients with metastatic breast cancer, and proved to be excessively
      cardiotoxic for use in the adjuvant setting.

PMID- 10577857
TI  - World Health Organization classification of neoplastic diseases of the
      hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee
      meeting-Airlie House, Virginia, November 1997.
AB  - PURPOSE: The European Association of Hematopathologists and the Society for
      Hematopathology have developed a new World Health Organization (WHO)
      classification of hematologic malignancies, including lymphoid, myeloid,
      histiocytic, and mast cell neoplasms. DESIGN: Ten committees of pathologists
      developed lists and definitions of disease entities. A clinical advisory
      committee (CAC) of international hematologists and oncologists was formed to
      ensure that the classification would be useful to clinicians. The CAC met in
      November 1997 to discuss clinical issues related to the classification. RESULTS:
      The WHO uses the Revised European-American Lymphoma (REAL) classification,
      published in 1994 by the International Lymphoma Study Group, to categorize
      lymphoid neoplasms. The REAL classification is based on the principle that a
      classification is a list of "real" disease entities, which are defined by a
      combination of morphology, immunophenotype, genetic features, and clinical
      features. The relative importance of each of these features varies among
      diseases, and there is no one gold standard. The WHO Neoplasms recognizes
      distinct entities defined by a combination of morphology and cytogenetic
      abnormalities. At the CAC meeting, which was organized around a series of
      clinical questions, participants reached a consensus on most of the questions
      posed. They concluded that clinical groupings of lymphoid neoplasms were neither
      necessary nor desirable. Patient treatment is determined by the specific type of
      lymphoma, with the addition of grade within the tumor type, if applicable, and
      clinical prognostic factors, such as the International Prognostic Index.
      CONCLUSION: The WHO classification has produced a new and exciting degree of
      cooperation and communication between oncologists and pathologists from around
      the world, which should facilitate progress in the understanding and treatment of
      hematologic malignancies.

PMID- 10577858
TI  - Malignant skin lesions. Case 1: nevoid malignant melanoma of the breast
      presenting as a contralateral breast metastasis.

PMID- 10577859
TI  - Malignant skin lesions. Case 2: lymphoepithelioma-like carcinoma of the skin.

PMID- 10577860
TI  - Computed tomography in febrile neutropenia.

PMID- 10577861
TI  - Telomerase activity in fine-needle aspirates of breast lesions.

PMID- 10577862
TI  - Prognosis of metastatic melanoma: where are the details?

PMID- 10577863
TI  - Glucocorticoids and prostate cancer in castrate men.

PMID- 10577864
TI  - Quality improvement: carrots or sticks?

PMID- 10577865
TI  - Letrozole: updated duration of response.

PMID- 10577866
TI  - Behavioral health care parity and string quartets.

PMID- 10577867
TI  - Economic grand rounds: the high costs of care for four patients with mania who
      were not compliant with treatment.

PMID- 10577868
TI  - Personal accounts: family talk.

PMID- 10577869
TI  - Practical geriatrics: psychiatric consultation to nursing homes.

PMID- 10577870
TI  - Emergency psychiatry: contemporary practices in managing acutely violent patients
      in 20 psychiatric emergency rooms.

PMID- 10577872
TI  - Web Sites Worth Watching.

PMID- 10577871
TI  - Datapoints: prescription patterns for mood and anxiety disorders in a community
      sample.

PMID- 10577873
TI  - Daniel Blain: Founder of This Journal.
AB  - Editor's Note: On the masthead page of every issue, under the Taking Issue
      commentary, we state that this journal was established in 1950 by Daniel Blain,
      M.D. Next month we begin our year-long 50th anniversary celebration with a series
      of historical articles highlighting some of the important developments in
      psychiatry over that period. This month we set the stage with this article by
      Lucy Ozarin, M.D., who has been closely associated with the journal from its
      inception.

PMID- 10577875
TI  - Use of the balanced scorecard to improve the quality of behavioral health care.
AB  - As the debate over managed care continues, measuring quality has increasingly
      become a focus in health care. One approach to measuring quality is the use of a
      scorecard, which summarizes a critical set of indicators that measure the quality
      of care. The author describes the Balanced Scorecard (BSC), a tool developed for
      use in businesses to implement strategic plans for meeting an organization's
      objectives, and shows how the BSC can be adapted for use in behavioral health
      care. The scorecard addresses quality of care at five levels: financial,
      customer, outcomes, internal processes, and learning and growth. No more than
      four or five realistic objectives are chosen at each level, and an indicator for
      the achievement of each objective is designed. The BSC integrates indicators at
      the five levels to help organizations guide implementation of strategic planning,
      report on critical outcomes, and offer a report card for payers and consumers to
      make informed choices.

PMID- 10577876
TI  - Outcomes of four treatment approaches in community residential programs for
      patients with substance use disorders.
AB  - OBJECTIVE: Treatment approaches used in community residential facilities for
      patients with substance use disorders were identified, and patients'
      participation in treatment and case-mix-adjusted one-year outcomes for substance
      use, symptoms, and functioning in facilities with different treatment approaches
      were examined. METHODS: A total of 2,376 patients with substance use disorders
      treated in a representative sample of 88 community residential facilities were
      assessed at entry to and discharge from the facility and at one-year follow-up.
      The community residential facilities were classified into four types based on the
      major emphasis of the treatment program: therapeutic community, psychosocial
      rehabilitation, 12-step, and undifferentiated. RESULTS: Patients in programs that
      used the therapeutic community, psychosocial rehabilitation, and 12-step
      approaches had comparable one-year outcomes in symptoms and functioning that were
      better than those of patients in undifferentiated programs. A more directed
      treatment orientation, a longer episode of care, and completion of care were
      independently related to better one-year outcomes. These findings held for
      patients with only substance use disorders and for patients with both substance
      use and psychiatric disorders. CONCLUSIONS: Community residential programs that
      have a more directed treatment orientation and that motivate patients to complete
      treatment have better substance use outcomes. As an increasingly important locus
      of specialized care, community residential facilities need to develop and
      maintain more differentiated and distinctive treatment orientations.

PMID- 10577877
TI  - Adequacy of prenatal care among women with psychiatric diagnoses giving birth in
      California in 1994 and 1995.
AB  - OBJECTIVE: Although poor prenatal care is detrimental to maternal and infant
      health, few studies have assessed the adequacy of prenatal care among women with
      psychiatric diagnoses. This investigation examined the association between chart
      recorded psychiatric and substance use diagnoses at the time of delivery and
      adequacy of prenatal care among all women delivering babies in California
      hospitals during 1994 and 1995. METHODS: The authors undertook an archival
      analysis of data from the California Health Information for Policy Project
      (CHIPP), which consists of linked hospital discharge and birth certificate data
      for 1,094,178 deliveries in 1994 and 1995. The associations between International
      Classification of Diseases, 9th Revision, Clinical Modification psychiatric and
      substance abuse diagnoses and level of prenatal care were examined. Logistic
      regression analyses were conducted to assess the association between maternal
      diagnostic category and inadequate prenatal care while controlling for payment
      source, age, education, race, marital status, and parity (previous births).
      RESULTS: Women who received psychiatric and substance use diagnoses demonstrated
      significantly increased risk of inadequate prenatal care compared with women
      without those diagnoses. CONCLUSIONS: Psychiatric diagnoses were associated with
      an increased risk of inadequate prenatal care; the association between
      psychiatric and substance use diagnoses and poor prenatal care persisted even
      after the analysis controlled for known risk factors. Future investigations will
      need to elucidate the processes of prenatal care for women with psychiatric
      disorders so that preventive interventions can be developed.

PMID- 10577878
TI  - Child psychiatrists as leaders in public mental health systems: two surveys of
      state mental health departments.
AB  - OBJECTIVE: The purposes of the study were to document the administrative roles
      that child psychiatrists play in the development of policy in state departments
      of mental health and to identify barriers to their participation. METHODS: A
      survey was sent to the director of the department of mental health in each U.S.
      state and territory to determine the administrative duties of child psychiatrists
      who work in the department's central administration. A follow-up survey was sent
      to directors of children's services in state departments of mental health to
      determine what skills child psychiatrists would need to develop to increase their
      likelihood of being selected for administrative leadership positions. RESULTS:
      Nine of the 31 departments of mental health that responded to the first survey
      had formalized central administrative roles for child psychiatrists as either an
      administrative consultant or a children's medical director. The 19 respondents to
      the second survey indicated that to play a role in the central administration of
      state departments of mental health, most child psychiatrists needed improved
      knowledge in cultural competency, organizational dynamics, how government
      functions, the use of an asset-based approach to dealing with families, and use
      of interventions other than inpatient units, outpatient medication, or
      psychotherapy. CONCLUSIONS: To improve the leadership role of child psychiatrists
      in public-sector systems, training opportunities should be developed to increase
      their knowledge and skills in areas needed for effective participation in policy
      development. Training should include formal didactic instruction and clinical
      experiences that focus on the wide range of interventions used in public-sector
      systems and on the administrative skills needed for leadership positions.

PMID- 10577879
TI  - Offenders with mental disorders: a call to action.

PMID- 10577880
TI  - An outpatient psychiatry program for offenders with mental disorders found not
      guilty by reason of insanity.
AB  - OBJECTIVE: Rehospitalization and criminal recidivism were examined among a group
      of offenders with mental disorders adjudicated as not guilty by reason of
      insanity and mandated to receive treatment in a forensic psychiatric outpatient
      program as a condition of release. METHODS: A retrospective chart review was
      conducted for 43 offenders with mental disorders who were acquitted as being not
      guilty by reason of insanity for the index offense and were active in the
      outpatient treatment program in 1996. Data were abstracted on sociodemographic,
      psychiatric, and criminal characteristics predating the index offense;
      rehospitalizations and new crimes and rearrests after the offense; and clinical
      and psychosocial functional outcomes after enrollment in the outpatient program.
      RESULTS: For the 43 patients, the mean length of stay in the program was 68
      months, with a range of 4.9 months to 18.4 years. Almost two-thirds of the
      patients were diagnosed as having schizophrenia, schizoaffective disorder, or a
      nonaffective psychotic disorder; 58 percent had a comorbid substance use
      disorder, and 63 percent had an axis II diagnosis. Since program enrollment, 20
      patients (47 percent) were rehospitalized at least once, and eight (19 percent)
      were rearrested or had committed a new crime. At the end of 1996, only nine (24
      percent) were in full remission, and 26 (68 percent) showed at least one
      indicator of difficulty reintegrating into the community. CONCLUSIONS: Even after
      treatment in a specialized forensic program, this sample of offenders with
      serious mental disorders remained impaired symptomatically and functionally.
      Although avoidance of rehospitalization is considered a successful outcome,
      rehospitalization is preferable to rearrest for this forensic population.

PMID- 10577881
TI  - Pathways into prostitution among female jail detainees and their implications for
      mental health services.
AB  - OBJECTIVE: To explore the service needs of women in jail, the authors examined
      three pathways into prostitution: childhood sexual victimization, running away,
      and drug use. Studies typically have explored only one or two of these pathways,
      and the relationships among the three points of entry remain unclear. METHODS:
      Data on 1,142 female jail detainees were used to examine the effects of childhood
      sexual victimization, running away, and drug use on entry into prostitution and
      their differential effects over the life course. RESULTS: Two distinct pathways
      into prostitution were identified. Running away had a dramatic effect on entry
      into prostitution in early adolescence, but little effect later in the life
      course. Childhood sexual victimization, by contrast, nearly doubled the odds of
      entry into prostitution throughout the lives of women. Although the prevalence of
      drug use was significantly higher among prostitutes than among nonprostitutes,
      drug abuse did not explain entry into prostitution. CONCLUSIONS: Running away and
      childhood sexual victimization provide distinct pathways into prostitution. The
      findings suggest that women wishing to leave prostitution may benefit from
      different mental health service strategies depending on which pathway to
      prostitution they experienced.

PMID- 10577882
TI  - A collaborative community-based treatment program for offenders with mental
      illness.
AB  - OBJECTIVE: The paper describes initial results of collaboration between a mental
      health treatment program at a community mental health center in Baltimore and a
      probation officer of the U.S. federal prison system to serve the mental health
      needs of offenders on federal probation, parole, supervised release, or
      conditional release in the community. METHODS: A forensic psychiatrist in the
      treatment program and a licensed social worker in the probation office facilitate
      the close working relationship between the agencies. Treatment services provided
      or brokered by the community mental health center staff include psychiatric and
      medical treatment, intensive case management, addictions treatment, urine
      toxicology screening, psychosocial or residential rehabilitation services,
      intensive outpatient care, partial hospitalization, and inpatient treatment.
      RESULTS: Among the 16 offenders referred for treatment during the first 24 months
      of the collaborative program, 14 were male and 14 were African American. Three of
      the 16 violated the terms of their release due to noncompliance with stipulated
      mental health treatment; only one of the three had been successfully engaged in
      treatment. One patient died, two completed their terms of supervision, and ten
      remained in treatment at the time of the report. CONCLUSIONS: The major strength
      of this collaboration is the cooperation of the treatment and monitoring agencies
      with the overall goal of maintaining the offender in the community. Further
      research is needed to confirm the effectiveness of the clinical model in reducing
      recidivism and retaining clients.

PMID- 10577883
TI  - A SAMHSA research initiative assessing the effectiveness of jail diversion
      programs for mentally ill persons.
AB  - For nearly 30 years jail diversion programs have had wide support as a way to
      prevent people with mental illnesses and substance use disorders from
      unnecessarily entering the criminal justice system by providing more appropriate
      community-based treatment. Although these programs have had wide support, very
      few systematic outcomes studies have examined their effectiveness. This paper
      discusses findings on rates of incarceration of persons with serious mental
      illness and co-occurring substance use disorders in U.S. jails, summarizes
      recently completed research on jail diversion programs, and describes a three
      year research initiative begun in 1997 by the Substance Abuse and Mental Health
      Services Administration that uses a standardized protocol to examine the
      characteristics and outcomes of various types of jail diversion programs in nine
      sites throughout the U.S.

PMID- 10577884
TI  - Planning to meet the needs of offenders with mental disorders in the United
      Kingdom.
AB  - During the last decade the planning of services for offenders with mental
      disorders in the United Kingdom has been geared toward diverting them from the
      criminal justice system to appropriate levels of psychiatric and social care.
      Although a seamless service system is yet to be developed, the central government
      has made a concerted effort to promote a better understanding of the needs of
      offenders with mental disorders and encourage collaboration between the relevant
      agencies. A major program of research has been initiated, and local health
      authorities have been encouraged to use a consortium approach to planning and
      delivery of specialist services. The authors discuss the activities of the Wessex
      consortium, composed of five local health authorities and a social services
      department serving a catchment area with a population of 2.5 million in southern
      England. The consortium has commissioned needs assessments for all offenders with
      mental illness from the catchment area and a survey of the resources for secure
      residential treatment in the region. Based on data from this research, the
      consortium is planning the development of two long-stay secure units to
      accommodate offenders with a history of repeated inpatient and prison stays and
      poor response to previous treatment and rehabilitation efforts.

PMID- 10577885
TI  - Psychiatric illness and comorbidity among adult male jail detainees in drug
      treatment.
AB  - The prevalence of psychiatric disorders was examined in a sample of 204 pretrial
      jail detainees receiving standard drug treatment. More than half of the sample
      had at least one lifetime DSM-III-R axis I diagnosis, and the lifetime rates of
      serious mental illness were higher than reported prevalence rates for arrestees
      in general jail populations. Detainees with comorbid disorders were more likely
      than others to have more than one co-occurring psychiatric disorder, to have been
      arrested for property crimes, and to be dependent on alcohol, marijuana, or PCP.
      The findings argue for the expansion of integrated treatment services within
      criminal justice drug treatment settings.

PMID- 10577886
TI  - Mental health benefit limits and cost sharing under managed care: a national
      survey of employers.
AB  - Mental health services experts suggest that managed care diminishes the need for
      arbitrary benefit limits and consumer cost-sharing. Data from 577 health plans
      were used to test the hypotheses that health maintenance organizations (HMOs) and
      carve-out plans are less likely to use benefit limits or service exclusions, have
      more generous limits, and have lower cost-sharing requirements than non-HMOs and
      non-carve-out plans. The results show that HMOs were more likely to use service
      exclusions and did not make less use of benefit limits. Carve-outs were less
      likely to use some coverage exclusions. Comparisons of the stringency of limits
      and cost-sharing provisions did not show consistent differences.

PMID- 10577887
TI  - Initial treatment engagement in a rural community mental health center.
AB  - The charts of patients who received an initial assessment at a rural mental
      health center were reviewed to identify patient, system, and clinical
      characteristics that predicted return to the center for at least one treatment
      visit in the following three months. Among 112 patients, the overall rate of
      return was 46 percent. Patients who were seen for assessment within one week of
      their initial request for services were significantly more likely to return, as
      were those who had lower scores on the Global Assessment of Functioning scale.
      Patients referred for assessment by agencies of social control were the least
      likely to return for treatment.

PMID- 10577888
TI  - The use of physical restraints in Polish psychiatric hospitals in 1989 and 1996.
AB  - The use of physical restraints in 11 locked psychiatric wards in Warsaw, Poland,
      was examined in 1989 and 1996 to determine whether the implementation of the
      Mental Health Act in 1995 and other political transformations changed this
      psychiatric practice. All episodes of restraint were documented during a one
      month period in both years. Significantly more episodes of restraint occurred in
      1996, but the average duration of each episode decreased, the number of episodes
      per patient fell, and the proportion of episodes due to patient aggression
      increased. Findings indicate that use of restraint was less arbitrary in 1996,
      which is likely attributable to the replacement of local institutional rules by
      national regulations controlling the use of restraint in psychiatric practice.

PMID- 10577890
TI  - A Flawed Study Design?

PMID- 10577889
TI  - A flawed study design?

PMID- 10577891
TI  - Employment and disability.

PMID- 10577892
TI  - An ACT program for co-occurring disorders.

PMID- 10577901
TI  - The size distribution of homozygous segments in the human genome.

PMID- 10577902
TI  - Long homozygous chromosomal segments in reference families from the centre
      d'Etude du polymorphisme humain.
AB  - Using genotypes from nearly 8,000 short tandem-repeat polymorphisms typed in
      eight of the reference families from the Centre d'Etude du Polymorphisme Humain
      (CEPH), we identified numerous long chromosomal segments of marker homozygosity
      in many CEPH individuals. These segments are likely to represent autozygosity,
      the result of the mating of related individuals. Confidence that the complete
      segment is homozygous is gained only with markers of high density. The longest
      segment in the eight families spanned 77 cM and included 118 homozygous markers.
      All individuals in family 884 showed at least one segment of homozygosity: the
      father and mother were homozygous in 8 and 10 segments with an average length of
      13 and 16 cM, respectively, and covering a total of 105 and 160 cM, respectively.
      The progeny in family 884 were homozygous over 5-16 segments with average length
      11 cM. The progeny in family 102 were homozygous over 4-12 segments with average
      length 19 cM. Of the 100 individuals in the other six families, 1 had especially
      long homozygous segments, and 19 had short but significant homozygous segments.
      Our results indicate that long homozygous segments are common in humans and that
      these segments could have a substantial impact on gene mapping and health.

PMID- 10577903
TI  - Phenotypes in three pedigrees with autosomal dominant obesity caused by
      haploinsufficiency mutations in the melanocortin-4 receptor gene.
AB  - Recently, haploinsufficiency mutations in the melanocortin-4 receptor gene (MC4
      R) were detected which were assumed to lead to the phenotype of extreme obesity.
      Previously, we detected three obese carriers among 306 index patients. Here we
      describe the detection of one haploinsufficiency carrier in an additional study
      group of 186 obese individuals. We subsequently genotyped and phenotyped 43
      family members of these four index patients, two of whom were second-degree
      cousins. A total of 19 carriers were identified. Extreme obesity was the
      predominating phenotype. However, moderate obesity occurred in three of the
      carriers. No other specific phenotypic abnormalities were detected. Female
      haploinsufficiency carriers were heavier than male carriers in the respective
      families, a finding similar to findings in MC4-R-knockout mice. In conclusion,
      our data fully support the etiologic role of MC4-R haploinsufficiency mutations
      in obesity.

PMID- 10577904
TI  - Loss-of-function mutations in a human gene related to Chlamydomonas reinhardtii
      dynein IC78 result in primary ciliary dyskinesia.
AB  - Primary ciliary dyskinesia (PCD) is a group of heterogeneous disorders of unknown
      origin, usually inherited as an autosomal recessive trait. Its phenotype is
      characterized by axonemal abnormalities of respiratory cilia and sperm tails
      leading to bronchiectasis and sinusitis, which are sometimes associated with
      situs inversus (Kartagener syndrome) and male sterility. The main ciliary defect
      in PCD is an absence of dynein arms. We have isolated the first gene involved in
      PCD, using a candidate-gene approach developed on the basis of documented
      abnormalities of immotile strains of Chlamydomonas reinhardtii, which carry
      axonemal ultrastructural defects reminiscent of PCD. Taking advantage of the
      evolutionary conservation of genes encoding axonemal proteins, we have isolated a
      human sequence (DNAI1) related to IC78, a C. reinhardtii gene encoding a dynein
      intermediate chain in which mutations are associated with the absence of outer
      dynein arms. DNAI1 is highly expressed in trachea and testis and is composed of
      20 exons located at 9p13-p21. Two loss-of-function mutations of DNAI1 have been
      identified in a patient with PCD characterized by immotile respiratory cilia
      lacking outer dynein arms. In addition, we excluded linkage between this gene and
      similar PCD phenotypes in five other affected families, providing a clear
      demonstration of locus heterogeneity. These data reveal the critical role of
      DNAI1 in the development of human axonemal structures and open up new means for
      identification of additional genes involved in related developmental defects.

PMID- 10577906
TI  - Digenic junctional epidermolysis bullosa: mutations in COL17A1 and LAMB3 genes.
AB  - Junctional epidermolysis bullosa (JEB), a genetically heterogeneous group of
      blistering skin diseases, can be caused by mutations in the genes encoding
      laminin 5 or collagen XVII, which are components of the hemidesmosome-anchoring
      filament complex in the skin. Here, a family with severe nonlethal JEB and with
      mutations in genes for both proteins was identified. The index patient was
      compound heterozygous for the COL17A1 mutations L855X and R1226X and was
      heterozygous for the LAMB3 mutation R635X. As a consequence, two functionally
      related proteins were affected. Absence of collagen XVII and attenuated laminin 5
      expression resulted in rudimentary hemidesmosome structure and separation of the
      epidermis from the basement membrane, with severe skin blistering as the clinical
      manifestation. In contrast, single heterozygotes carrying either (1) one or the
      other of the COL17A1 null alleles or (2) a double heterozygote for a COL17A1 and
      a LAMB3 null allele did not have a pathological skin phenotype. These
      observations indicate that the known allelic heterogeneity in JEB is further
      complicated by interactions between unlinked mutations. They also demonstrate
      that identification of one mutation in one gene is not sufficient for
      determination of the genetic basis of JEB in a given family.

PMID- 10577905
TI  - Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at
      CpG hotspots.
AB  - Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of
      acquired skills after a period of normal development in infant girls. The
      responsible gene, encoding methyl-CpG binding protein 2 (MeCP2), was recently
      discovered. Here we explore the spectrum of phenotypes resulting from MECP2
      mutations. Both nonsense (R168X and R255X) and missense (R106W and R306C)
      mutations have been found, with multiple recurrences. R168X mutations were
      identified in six unrelated sporadic cases, as well as in two affected sisters
      and their normal mother. The missense mutations were de novo and affect conserved
      domains of MeCP2. All of the nucleotide substitutions involve C-->T transitions
      at CpG hotspots. A single nucleotide deletion, at codon 137, that creates a L138X
      stop codon within the methyl-binding domain was found in an individual with
      features of RTT and incontinentia pigmenti. An 806delG deletion causing a V288X
      stop in the transcription-repression domain was identified in a woman with motor
      coordination problems, mild learning disability, and skewed X inactivation; in
      her sister and daughter, who were affected with classic RTT; and in her
      hemizygous son, who died from congenital encephalopathy. Thus, some males with
      RTT-causing MECP2 mutations may survive to birth, and female heterozygotes with
      favorably skewed X-inactivation patterns may have little or no involvement.
      Therefore, MECP2 mutations are not limited to RTT and may be implicated in a much
      broader phenotypic spectrum.

PMID- 10577907
TI  - Complement factor H gene mutation associated with autosomal recessive atypical
      hemolytic uremic syndrome.
AB  - Atypical hemolytic uremic syndrome (HUS) presents with the clinical features of
      hypertension, microangiopathic hemolytic anemia, and acute renal failure. Both
      dominant and recessive modes of inheritance have been reported. This study
      describes the genetic and functional analysis of a large Bedouin kindred with
      autosomal recessive HUS. The kindred consists of several related nuclear families
      in which all parent unions of affected children are consanguineous. A previous
      report demonstrated that a dominant form of HUS maps to chromosome 1q and that
      complement factor H (CFH), a regulatory component of the complement system, lies
      within the region and is involved in the dominant disorder. Early-onset and
      persistent hypocomplementemia in this Bedouin kindred prompted us to evaluate the
      CFH gene. Linkage analysis was performed, demonstrating linkage between the
      disorder and the markers near the CFH gene. Mutation analysis of the CFH coding
      region revealed a single missense mutation. Functional analyses demonstrate that
      the mutant CFH is properly expressed and synthesized but that it is not
      transported normally from the cell. This is the first study reporting that a
      recessive, atypical, early-onset, and relapsing HUS is associated with the CFH
      protein and that a CFH mutation affects intracellular trafficking and secretion.

PMID- 10577908
TI  - The molecular basis of Sjogren-Larsson syndrome: mutation analysis of the fatty
      aldehyde dehydrogenase gene.
AB  - Sjogren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized
      by ichthyosis, mental retardation, spasticity, and deficient activity of fatty
      aldehyde dehydrogenase (FALDH). To define the molecular defects causing SLS, we
      performed mutation analysis of the FALDH gene in probands from 63 kindreds with
      SLS. Among these patients, 49 different mutations-including 10 deletions, 2
      insertions, 22 amino acid substitutions, 3 nonsense mutations, 9 splice-site
      defects, and 3 complex mutations-were found. All of the patients with SLS were
      found to carry mutations. Nineteen of the missense mutations resulted in a severe
      reduction of FALDH enzyme catalytic activity when expressed in mammalian cells,
      but one mutation (798G-->C [K266N]) seemed to have a greater effect on mRNA
      stability. The splice-site mutations led to exon skipping or utilization of
      cryptic acceptor-splice sites. Thirty-seven mutations were private, and 12
      mutations were seen in two or more probands of European or Middle Eastern
      descent. Four single-nucleotide polymorphisms (SNPs) were found in the FALDH
      gene. At least four of the common mutations (551C-->T, 682C-->T, 733G-->A, and
      798+1delG) were associated with multiple SNP haplotypes, suggesting that these
      mutations originated independently on more than one occasion or were ancient SLS
      genes that had undergone intragenic recombination. Our results demonstrate that
      SLS is caused by a strikingly heterogeneous group of mutations in the FALDH gene
      and provide a framework for understanding the genetic basis of SLS and the
      development of DNA-based diagnostic tests.

PMID- 10577910
TI  - Mutation rates in humans. I. Overall and sex-specific rates obtained from a
      population study of hemophilia B.
AB  - A population-based study of hemophilia B mutations was conducted in the United
      Kingdom in order to construct a national confidential database of mutations and
      pedigrees to be used for the provision of carrier and prenatal diagnoses based on
      mutation detection. This allowed the direct estimate of overall (micro), male
      (v), and female (u) mutation rates for hemophilia B. The values obtained per
      gamete per generation and the 95% confidence intervals are micro;=7.73 (6. 29
      9.12&parr0;x10-6; v=18.8 (14.5-22.9&parr0;x10-6; and u=2.18 (1. 44-3.16&parr0;x10
      6. The ratio of male-to-female mutation rates is 8. 64, with a 95% confidence
      interval of 5.46-14.5. The higher male rate was not caused by a much higher rate
      of transition at CpG sites in the male. Attempts to detect evidence of gonadal
      mosaicism for hemophilia B mutation in suitable families did not detect any
      instances of ovarian mosaicism in any of 47 available opportunities. This
      suggests that the risk of a noncarrier mother manifesting as a gonadal mosaic by
      transmitting the mutation to a second child should be <0.062.

PMID- 10577909
TI  - Mutation detection of PKD1 identifies a novel mutation common to three families
      with aneurysms and/or very-early-onset disease.
AB  - It is known that several of the most severe complications of autosomal-dominant
      polycystic kidney disease, such as intracranial aneurysms, cluster in families.
      There have been no studies reported to date, however, that have attempted to
      correlate severely affected pedigrees with a particular genotype. Until recently,
      in fact, mutation detection for most of the PKD1 gene was virtually impossible
      because of the presence of several highly homologous loci also located on
      chromosome 16. In this report we describe a cluster of 4 bp in exon 15 that are
      unique to PKD1. Forward and reverse PKD1-specific primers were designed in this
      location to amplify regions of the gene from exons 11-21 by use of long-range
      PCR. The two templates described were used to analyze 35 pedigrees selected for
      study because they included individuals with either intracranial aneurysms and/or
      very-early-onset disease. We identified eight novel truncating mutations, two
      missense mutations not found in a panel of controls, and several informative
      polymorphisms. Many of the polymorphisms were also present in the homologous
      loci, supporting the idea that they may serve as a reservoir for genetic
      variability in the PKD1 gene. Surprisingly, we found that three independently
      ascertained pedigrees had an identical 2-bp deletion in exon 15. This raises the
      possibility that particular genotypes may be associated with more-severe disease.

PMID- 10577911
TI  - Mutation rates in humans. II. Sporadic mutation-specific rates and rate of
      detrimental human mutations inferred from hemophilia B.
AB  - We estimated the rates per base per generation of specific types of mutations,
      using our direct estimate of the overall mutation rate for hemophilia B and
      information on the mutations present in the United Kingdom's population as well
      as those reported year by year in the hemophilia B world database. These rates
      are as follows: transitions at CpG sites 9.7x10-8, other transitions 7.3x10-9,
      transversions at CpG sites 5.4x10-9, other transversions 6.9x10-9, and small
      deletions/insertions causing frameshifts 3.2x10-10. By taking into account the
      ratio of male to female mutation rates, the above figures were converted into
      rates appropriate for autosomal DNA-namely, 1.3x10-7, 9.9x10-9, 7.3x10-9, 9.4x10
      9, 6.5x10-10, where the latter is the rate for all small deletion/insertion
      events. Mutation rates were also independently estimated from the sequence
      divergence observed in randomly chosen sequences from the human and chimpanzee X
      and Y chromosomes. These estimates were highly compatible with those obtained
      from hemophilia B and showed higher mutation rates in the male, but they showed
      no evidence for a significant excess of transitions at CpG sites in the spectrum
      of Y-sequence divergence relative to that of X-chromosome divergence. Our data
      suggest an overall mutation rate of 2.14x10-8 per base per generation, or 128
      mutations per human zygote. Since the effective target for hemophilia B mutations
      is only 1.05% of the factor IX gene, the rate of detrimental mutations, per human
      zygote, suggested by the hemophilia data is approximately 1.3.

PMID- 10577912
TI  - A 28-kb deletion spanning D15S63 (PW71) in five families: a rare neutral variant?
AB  - Methylation analysis with probe PW71 (D15S63) is an established procedure to test
      patients suspected of having Prader-Willi syndrome or Angelman syndrome. Using
      this test, we have identified a 28-kb deletion spanning D15S63 in five
      independent families. Sequence analysis revealed identical breakpoints in all the
      families. The haplotype data are compatible with a common ancestral origin of the
      deletion in at least two families. The deletion was not found in 1, 000 unrelated
      controls. Although the deletion maps within the imprinting-center region, neither
      maternal nor paternal inheritance of the deletion appears to affect imprinting in
      proximal 15q. We conclude that the deletion is a rare neutral variant that can
      lead to false-positive results in the PW71-methylation test.

PMID- 10577913
TI  - Clustered 11q23 and 22q11 breakpoints and 3:1 meiotic malsegregation in multiple
      unrelated t(11;22) families.
AB  - The t(11;22) is the only known recurrent, non-Robertsonian constitutional
      translocation. We have analyzed t(11;22) balanced-translocation carriers from
      multiple unrelated families by FISH, to localize the t(11;22) breakpoints on both
      chromosome 11 and chromosome 22. In 23 unrelated balanced-translocation carriers,
      the breakpoint was localized within a 400-kb interval between D22S788 (N41) and
      ZNF74, on 22q11. Also, 13 of these 23 carriers were tested with probes from
      chromosome 11, and, in each, the breakpoint was localized between D11S1340 and
      APOA1, on 11q23, to a region </=185 kb. Thus, the breakpoints on both chromosome
      11 and chromosome 22 are clustered in multiple unrelated families. Supernumerary
      der(22)t(11;22) syndrome can occur in the progeny of balanced-t(11;22) carriers,
      because of malsegregation of the der(22). There has been speculation regarding
      the mechanism by which the malsegregation occurs. To elucidate this mechanism, we
      have analyzed 16 of the t(11;22) families, using short tandem-repeat-polymorphism
      markers on both chromosome 11 and chromosome 22. In all informative cases the
      proband received two of three alleles, for markers above the breakpoint on
      chromosome 22 and below the breakpoint on chromosome 11, from the t(11;22)
      carrier parent. These data strongly suggest that 3:1 meiosis I malsegregation in
      the t(11;22) balanced-translocation-carrier parent is the mechanism in all 16
      families. Taken together, these results establish that the majority of t(11;22)
      translocations occur within the same genomic intervals and that the majority of
      supernumerary-der(22) offspring result from a 3:1 meiosis I malsegregation in the
      balanced-translocation carrier.

PMID- 10577914
TI  - A common breakpoint on 11q23 in carriers of the constitutional t(11;22)
      translocation.
AB  - Structural chromosomal rearrangements occur commonly in the general population.
      Individuals that carry a balanced translocation are at risk of having unbalanced
      offspring; therefore, the frequency of translocations in couples with recurrent
      spontaneous abortions is higher than that in the general population. The
      constitutional t(11;22) translocation is the most common recurrent non
      Robertsonian translocation in humans and may serve as a model to determine the
      mechanism that causes recurrent meiotic translocations. We previously localized
      the t(11;22) translocation breakpoint to a region on 22q11 within a low-copy
      repeat, termed "LCR22." To define the breakpoint on 11q23 and to ascertain
      whether this region shares homology with LCR22 sequences, we performed haplotype
      analysis on patients with der(22) syndrome. We found that the breakpoint on 11q23
      occurred between two genetic markers, D11S1340 and APOC3-tetra, both being
      present within a single bacterial-artificial-chromosome clone. To determine
      whether the breakpoint occurred within the same region among a larger set of
      carriers, we performed FISH mapping studies. The breakpoints were all within the
      same clone, suggesting that this region may harbor sequences that are prone to
      breakage. We narrowed the breakpoint interval, in both derivative chromosomes
      from two unrelated carriers, to a 190-bp, AT-rich repeat, which indicates that
      this repeat may mediate recombination events on chromosome 11. Interestingly, the
      LCR22s harbor AT-rich repeats, suggesting that this sequence motif may mediate
      recombination events in nonhomologous chromosomes during meiosis.

PMID- 10577915
TI  - Accelerated telomere shortening in the human inactive X chromosome.
AB  - Telomeres are nucleoprotein complexes at the end of eukaryotic chromosomes, with
      important roles in the maintenance of genomic stability and in chromosome
      segregation. Normal somatic cells lose telomeric repeats with each cell division
      both in vivo and in vitro. To address a potential role of nuclear architecture
      and epigenetic factors in telomere-length dynamics, the length of the telomeres
      of the X chromosomes and the autosomes was measured in metaphases from blood
      lymphocytes of human females of various ages, by quantitative FISH with a peptide
      nucleic-acid telomeric probe in combination with an X-chromosome centromere
      specific probe. The activation status of the X chromosomes was simultaneously
      visualized with antibodies against acetylated histone H4. We observed an
      accelerated shortening of telomeric repeats in the inactive X chromosome, which
      suggests that epigenetic factors modulate not only the length but also the rate
      of age-associated telomere shortening in human cells in vivo. This is the first
      evidence to show a differential rate of telomere shortening between and within
      homologous chromosomes in any species. Our results are also consistent with a
      causative role of telomere shortening in the well-documented X-chromosome
      aneuploidy in aging humans.

PMID- 10577916
TI  - Variation in short tandem repeats is deeply structured by genetic background on
      the human Y chromosome.
AB  - Eleven biallelic polymorphisms and seven short-tandem-repeat (STR) loci mapping
      on the nonrecombining portion of the human Y chromosome have been typed in men
      from northwestern Africa. Analysis of the biallelic markers, which represent
      probable unique events in human evolution, allowed us to characterize the stable
      backgrounds or haplogroups of Y chromosomes that prevail in this geographic
      region. Variation in the more rapidly mutating genetic markers (STRs) has been
      used both to estimate the time to the most recent common ancestor for STR
      variability within these stable backgrounds and to explore whether STR
      differentiation among haplogroups still retains information about their
      phylogeny. When analysis of molecular variance was used to study the
      apportionment of STR variation among both genetic backgrounds (i.e., those
      defined by haplogroups) and population backgrounds, we found STR variability to
      be clearly structured by haplogroups. More than 80% of the genetic variance was
      found among haplogroups, whereas only 3.72% of the genetic variation could be
      attributed to differences among populations-that is, genetic variability appears
      to be much more structured by lineage than by population. This was confirmed when
      two population samples from the Iberian Peninsula were added to the analysis. The
      deep structure of the genetic variation in old genealogical units (haplogroups)
      challenges a population-based perspective in the comprehension of human genome
      diversity. A population may be better understood as an association of lineages
      from a deep and population-independent gene genealogy, rather than as a complete
      evolutionary unit.

PMID- 10577917
TI  - Localization of a gene for Duane retraction syndrome to chromosome 2q31.
AB  - Duane retraction syndrome (DRS) is a congenital eye-movement disorder
      characterized by a failure of cranial nerve VI (the abducens nerve) to develop
      normally, resulting in restriction or absence of abduction, restricted adduction,
      and narrowing of the palpebral fissure and retraction of the globe on attempted
      adduction. DRS has a prevalence of approximately 0.1% in the general population
      and accounts for 5% of all strabismus cases. Undiagnosed DRS in children can lead
      to amblyopia, a permanent uncorrectable loss of vision. A large family with
      autosomal dominant DRS was examined and tested for genetic linkage. After
      exclusion of candidate regions previously associated with DRS, a genomewide
      search with highly polymorphic microsatellite markers was performed, and
      significant evidence for linkage was obtained at chromosome 2q31 (D2S2314 maximum
      LOD score 11.73 at maximum recombination fraction. 0). Haplotype analysis places
      the affected gene in a 17.8-cM region between the markers D2S2330 and D2S364. No
      recombinants were seen with markers between these two loci. The linked region
      contains the homeobox D gene cluster. Three of the genes within this cluster,
      known to participate in hindbrain development, were sequenced in affected and
      control individuals. Coding sequences for these genes were normal or had genetic
      alterations unlikely to be responsible for the DRS phenotype. Identifying the
      gene responsible for DRS may lead to an improved understanding of early cranial
      nerve development.

PMID- 10577918
TI  - Linkage of inflammatory bowel disease to human chromosome 6p.
AB  - Inflammatory bowel disease (IBD) is characterized by a chronic relapsing
      intestinal inflammation. IBD is subdivided into Crohn disease and ulcerative
      colitis phenotypes. Given the immunologic dysregulation in IBD, the human
      leukocyte-antigen region on chromosome 6p is of significant interest. Previous
      association and linkage analysis has provided conflicting evidence as to the
      existence of an IBD-susceptibility locus in this region. Here we report on a two
      stage linkage and association analysis of both a basic population of 353 affected
      sibling pairs (ASPs) and an extension of this population to 428 white ASPs of
      northern European extraction. Twenty-eight microsatellite markers on chromosome 6
      were genotyped. A peak multipoint LOD score of 4.2 was observed, at D6S461, for
      the IBD phenotype. A transmission/disequilibrium test (TDT) result of P=.006 was
      detected for D6S426 in the basic population and was confirmed in the extended
      cohort (P=.004; 97 vs. 56 transmissions). The subphenotypes of Crohn disease,
      ulcerative colitis, and mixed IBD contributed equally to this linkage, suggesting
      a general role for the chromosome 6 locus in IBD. Analysis of five single
      nucleotide polymorphisms in the TNFA and LTA genes did not reveal evidence for
      association of these important candidate genes with IBD. In summary, we provide
      firm linkage evidence for an IBD-susceptibility locus on chromosome 6p and
      demonstrate that TNFA and LTA are unlikely to be susceptibility loci for IBD.

PMID- 10577919
TI  - Localization of a gene for autosomal recessive distal renal tubular acidosis with
      normal hearing (rdRTA2) to 7q33-34.
AB  - Failure of distal nephrons to excrete excess acid results in the "distal renal
      tubular acidoses" (dRTA). Early childhood features of autosomal recessive dRTA
      include severe metabolic acidosis with inappropriately alkaline urine, poor
      growth, rickets, and renal calcification. Progressive bilateral sensorineural
      hearing loss (SNHL) is evident in approximately one-third of patients. We have
      recently identified mutations in ATP6B1, encoding the B-subunit of the collecting
      duct apical proton pump, as a cause of recessive dRTA with SNHL. We now report
      the results of genetic analysis of 13 kindreds with recessive dRTA and normal
      hearing. Analysis of linkage and molecular examination of ATP6B1 indicated that
      mutation in ATP6B1 rarely, if ever, accounts for this phenotype, prompting a
      genomewide linkage search for loci underlying this trait. The results strongly
      supported linkage with locus heterogeneity to a segment of 7q33-34, yielding a
      maximum multipoint LOD score of 8.84 with 68% of kindreds linked. The LOD-3
      support interval defines a 14-cM region flanked by D7S500 and D7S688. That 4 of
      these 13 kindreds do not support linkage to rdRTA2 and ATP6B1 implies the
      existence of at least one additional dRTA locus. These findings establish that
      genes causing recessive dRTA with normal and impaired hearing are different, and
      they identify, at 7q33-34, a new locus, rdRTA2, for recessive dRTA with normal
      hearing.

PMID- 10577920
TI  - Homozygosity mapping in families with Joubert syndrome identifies a locus on
      chromosome 9q34.3 and evidence for genetic heterogeneity.
AB  - Joubert syndrome is a rare developmental defect of the cerebellar vermis, with
      autosomal recessive inheritance. The phenotype is highly variable and may include
      episodic hyperpnea, abnormal eye movements, hypotonia, ataxia, developmental
      delay, and mental retardation. Even within sibships the phenotype may vary,
      making it difficult to establish the exact clinical diagnostic boundaries of
      Joubert syndrome. To genetically localize the gene region, we have performed a
      whole-genome scan in two consanguineous families of Arabian/Iranian origins, with
      multiple affected probands. In one family, we detected linkage to the telomeric
      region of chromosome 9q, close to the marker D9S158, with a multipoint LOD score
      of Z=+3.7. The second family did not show linkage to this region, giving a first
      indication of genetic heterogeneity underlying Joubert syndrome. These findings
      were supported by subsequent analysis of two smaller families-one compatible with
      linkage to 9q; the other, unlinked. We conclude that Joubert syndrome is
      clinically and genetically heterogeneous and that one locus maps to chromosome
      9q.

PMID- 10577921
TI  - Delineation of the critical interval of Bardet-Biedl syndrome 1 (BBS1) to a small
      region of 11q13, through linkage and haplotype analysis of 91 pedigrees.
AB  - Bardet-Biedl syndrome (BBS) is a genetically heterogeneous recessive disease
      characterized primarily by atypical retinitis pigmentosa, obesity, polydactyly,
      hypogenitalism, and mental retardation. Despite the presence of at least five
      loci in the human genome, on chromosomes 2q, 3p, 11q, 15q and 16q, as many as 50%
      of the mutations appear to map to the BBS1 locus on 11q13. The recessive mode of
      inheritance and the genetic heterogeneity of the syndrome, as well as the
      inability to distinguish between different genetic loci by phenotypic analyses,
      have hindered efforts to delineate the 11q13 region as a first step toward
      cloning the mutated gene. To circumvent these difficulties, we collected a large
      number of BBS pedigrees of primarily North American and European origin and
      performed genetic analysis, using microsatellites from all known BBS genomic
      regions. Heterogeneity analysis established a 40.5% contribution of the 11q13
      locus to BBS, and haplotype construction on 11q-linked pedigrees revealed several
      informative recombinants, defining the BBS1 critical interval between D11S4205
      and D11S913, a genetic distance of 2.9 cM, equivalent to approximately 2.6 Mb.
      Loss of identity by descent in two consanguineous pedigrees was also observed in
      the region, potentially refining the region to 1.8 Mb between D11S1883 and
      D11S4944. The identification of multiple recombinants at the same position forms
      the basis for physical mapping efforts, coupled with mutation analysis of
      candidate genes, to identify the gene for BBS1.

PMID- 10577922
TI  - A founder effect in the newfoundland population reduces the Bardet-Biedl syndrome
      I (BBS1) interval to 1 cM.
AB  - Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive disorder; major
      phenotypic findings include dysmorphic extremities, retinal dystrophy, obesity,
      male hypogenitalism, and renal anomalies. In the majority of northern European
      families with BBS, the syndrome is linked to a 26-cM region on chromosome 11q13.
      However, the finding, so far, of five distinct BBS loci (BBS1, 1q; BBS2, 16q;
      BBS3, 3p; BBS4, 15q; BBS5, 2q) has hampered the positional cloning of these
      genes. We use linkage disequilibrium (LD) mapping in an isolated founder
      population in Newfoundland to significantly reduce the BBS1 critical region.
      Extensive haplotyping in several unrelated BBS families of English descent
      revealed that the affected members were homozygous for overlapping portions of a
      rare, disease-associated ancestral haplotype on chromosome 11q13. The LD data
      suggest that the BBS1 gene lies in a 1-Mb, sequence-ready region on chromosome
      11q13, which should enable its identification.

PMID- 10577923
TI  - Paroxysmal kinesigenic choreoathetosis locus maps to chromosome 16p11.2-q12.1.
AB  - Paroxysmal kinesigenic choreoathetosis (PKC), the most frequently described type
      of paroxysmal dyskinesia, is characterized by recurrent, brief attacks of
      involuntary movements induced by sudden voluntary movements. Some patients with
      PKC have a history of infantile afebrile convulsions with a favorable outcome. To
      localize the PKC locus, we performed genomewide linkage analysis on eight
      Japanese families with autosomal dominant PKC. Two-point linkage analysis
      provided a maximum LOD score of 10.27 (recombination fraction [theta] =.00;
      penetrance [p] =.7) at marker D16S3081, and a maximum multipoint LOD score for a
      subset of markers was calculated to be 11.51 (p = 0.8) at D16S3080. Haplotype
      analysis defined the disease locus within a region of approximately 12.4 cM
      between D16S3093 and D16S416. P1-derived artificial chromosome clones containing
      loci D16S3093 and D16S416 were mapped, by use of FISH, to 16p11.2 and 16q12.1,
      respectively. Thus, in the eight families studied, the chromosomal localization
      of the PKC critical region (PKCR) is 16p11.2-q12.1. The PKCR overlaps with a
      region responsible for "infantile convulsions and paroxysmal choreoathetosis"
      (MIM 602066), a recently recognized clinical entity with benign infantile
      convulsions and nonkinesigenic paroxysmal dyskinesias.

PMID- 10577924
TI  - Mapping of a gene determining familial partial epilepsy with variable foci to
      chromosome 22q11-q12.
AB  - We identified two large French-Canadian families segregating a familial partial
      epilepsy syndrome with variable foci (FPEVF) characterized by mostly nocturnal
      seizures arising from frontal, temporal, and occasionally occipital epileptic
      foci. There is no evidence for structural brain damage or permanent neurological
      dysfunction. The syndrome is inherited as an autosomal dominant trait with
      incomplete penetrance. We mapped the disease locus to a 3. 8-cM interval on
      chromosome 22q11-q12, between markers D22S1144 and D22S685. Using the most
      conservative diagnostic scheme, the maximum cumulative LOD score was 6.53 at
      recombination fraction (straight theta) 0 with D22S689. The LOD score in the
      larger family was 5.34 at straight theta=0 with the same marker. The two families
      share an identical linked haplotype for >/=10 cM, including the candidate
      interval, indicating a recent founder effect. A severe phenotype in one of the
      probands may be caused by homozygosity for the causative mutation, as suggested
      by extensive homozygosity for the linked haplotype and a bilineal family history
      of epilepsy. An Australian family with a similar phenotype was not found to link
      to chromosome 22, indicating genetic heterogeneity of FPEVF.

PMID- 10577925
TI  - Genetic linkage of autosomal-dominant Alport syndrome with leukocyte inclusions
      and macrothrombocytopenia (Fechtner syndrome) to chromosome 22q11-13.
AB  - Fechtner syndrome is an autosomal-dominant variant of Alport syndrome, manifested
      by nephritis, sensorineural hearing loss, cataract formation,
      macrothrombocytopenia, and polymorphonuclear inclusion bodies. As opposed to
      autosomal-recessive and X-linked Alport syndromes, which have been genetically
      well studied, the genetic basis of Fechtner syndrome remains elusive. We have
      mapped the disease-causing gene to the long arm of chromosome 22 in an extended
      Israeli family with Fechtner syndrome plus impaired liver functions and
      hypercholesterolemia in some individuals. Six markers from chromosome 22q yielded
      a LOD score >3.00. A maximum two-point LOD score of 7.02 was obtained with the
      marker D22S283 at a recombination fraction of 0. Recombination analysis placed
      the disease-causing gene in a 5.5-Mb interval between the markers D22S284 and
      D22S1167. No collagen genes or genes comprising the basement membrane have been
      mapped to this region.

PMID- 10577926
TI  - Y-Chromosome evidence for a northward migration of modern humans into Eastern
      Asia during the last Ice Age.
AB  - The timing and nature of the arrival and the subsequent expansion of modern
      humans into eastern Asia remains controversial. Using Y-chromosome biallelic
      markers, we investigated the ancient human-migration patterns in eastern Asia.
      Our data indicate that southern populations in eastern Asia are much more
      polymorphic than northern populations, which have only a subset of the southern
      haplotypes. This pattern indicates that the first settlement of modern humans in
      eastern Asia occurred in mainland Southeast Asia during the last Ice Age,
      coinciding with the absence of human fossils in eastern Asia, 50,000-100,000
      years ago. After the initial peopling, a great northward migration extended into
      northern China and Siberia.

PMID- 10577927
TI  - The genetic epidemiology of early-onset epithelial ovarian cancer: a population
      based study.
AB  - We conducted a population-based study to determine the contribution of germline
      mutations in known candidate genes to ovarian cancer diagnosed at age <30 years.
      Women with epithelial ovarian cancer were identified through cancer registries.
      DNA samples were analyzed for mutations in BRCA1, the "ovarian cancer-cluster
      region" (nucleotides 3139-7069) of BRCA2, and the mismatch-repair genes hMSH2 and
      hMLH1. Probable germline mutations in hMLH1 were identified in 2 (2%; 95%
      confidence interval 1%-8%) of 101 women with invasive ovarian cancer diagnosed at
      age <30 years. No germline mutations were identified in any of the other genes
      analyzed. There were no striking pedigrees suggestive of families with either
      breast/ovarian cancer or hereditary nonpolyposis colorectal cancer (HNPCC). There
      was a significantly increased incidence of all cancers in first-degree relatives
      of women with invasive disease (relative risk [RR] = 1.6, P=.01) but not in
      second-degree relatives or in relatives of women with borderline cases. First
      degree relatives of women with invasive disease had increased risks of ovarian
      cancer (RR = 4.8, P=.03), myeloma (RR = 10, P=.01), and non-Hodgkin lymphoma (RR
      = 7, P=.004). Germline mutations in BRCA1, BRCA2, msh2, and mlh1 contribute to
      only a minority of cases of early-onset epithelial ovarian cancer. Our data
      suggest that early-onset ovarian cancer is not associated with a greatly
      increased risk of cancer in close relatives.

PMID- 10577928
TI  - An optimal algorithm for automatic genotype elimination.
AB  - In an effort to accelerate likelihood computations on pedigrees, Lange and
      Goradia defined a genotype-elimination algorithm that aims to identify those
      genotypes that need not be considered during the likelihood computation. For
      pedigrees without loops, they showed that their algorithm was optimal, in the
      sense that it identified all genotypes that lead to a Mendelian inconsistency.
      Their algorithm, however, is not optimal for pedigrees with loops, which continue
      to pose daunting computational challenges. We present here a simple extension of
      the Lange-Goradia algorithm that we prove is optimal on pedigrees with loops, and
      we give examples of how our new algorithm can be used to detect genotyping
      errors. We also introduce a more efficient and faster algorithm for carrying out
      the fundamental step in the Lange-Goradia algorithm-namely, genotype elimination
      within a nuclear family. Finally, we improve a common algorithm for computing the
      likelihood of a pedigree with multiple loops. This algorithm breaks each loop by
      duplicating a person in that loop and then carrying out a separate likelihood
      calculation for each vector of possible genotypes of the loop breakers. This
      algorithm, however, does unnecessary computations when the loop-breaker vector is
      inconsistent. In this paper we present a new recursive loop breaker-elimination
      algorithm that solves this problem and illustrate its effectiveness on a pedigree
      with six loops.

PMID- 10577929
TI  - Linkage detection adaptive to linkage disequilibrium: the disequilibrium maximum
      likelihood-binomial test for affected-sibship data.
AB  - It has been demonstrated in the literature that the transmission/disequilibrium
      test (TDT) has higher power than the affected-sib-pair (ASP) mean test when
      linkage disequilibrium (LD) is strong but that the mean test has higher power
      when LD is weak. Thus, for ASP data, it seems clear that the TDT should be used
      when LD is strong but that the mean test or other linkage tests should be used
      when LD is weak or absent. However, in practice, it may be difficult to follow
      such a guideline, because the extent of LD is often unknown. Even with a highly
      dense genetic-marker map, in which some markers should be located near the
      disease-predisposing mutation, strong LD is not inevitable. Besides the genetic
      distance, LD is also affected by many factors, such as the allelic heterogeneity
      at the disease locus, the initial LD, the allelic frequencies at both disease
      locus and marker locus, and the age of the mutation. Therefore, it is of interest
      to develop methods that are adaptive to the extent of LD. In this report, we
      propose a disequilibrium maximum-binomial-likelihood (DMLB) test that
      incorporates LD in the maximum-binomial-likelihood (MLB) test. Examination of the
      corresponding score statistics shows that this method adaptively combines two
      sources of information: (a) the identity-by-descent (IBD) sharing score, which is
      informative for linkage regardless of the existence of LD, and (b) the contrast
      between allele-specific IBD sharing score, which is informative for linkage only
      in the presence of LD. For ASP data, the proposed test has higher power than
      either the TDT or the mean test when the extent of LD ranges from moderate to
      strong. Only when LD is very weak or absent is the DMLB slightly less powerful
      than the mean test; in such cases, the TDT has essentially no power to detect
      linkage. Therefore, the DMLB test is an interesting approach to linkage detection
      when the extent of LD is unknown.

PMID- 10577930
TI  - A general conditional-logistic model for affected-relative-pair linkage studies.
AB  - Model-free LOD-score methods are often employed to detect linkage between marker
      loci and common diseases, with samples of affected sib pairs. Although extensions
      of the basic one-disease-locus model have been proposed that allow separate
      inclusion of other types of affected relative pairs, discordant relative pairs,
      covariates, or additional disease loci, a unified framework that can handle all
      of these features has been lacking. In this report, I propose a conditional
      logistic parameterization that generalizes easily to include all of these
      features. Two data examples, one using simulated data and one using type 1
      diabetes, illustrate applications of the models.

PMID- 10577931
TI  - Modeling the probability that Ashkenazi Jewish women carry a founder mutation in
      BRCA1 or BRCA2.

PMID- 10577933
TI  - The importance of a family history of breast cancer in predicting the presence of
      a BRCA mutation.

PMID- 10577934
TI  - DNA sequence variants of p53: cancer and aging.

PMID- 10577936
TI  - Elevated frequency and allelic heterogeneity of congenital nephrotic syndrome,
      Finnish type, in the old order Mennonites.

PMID- 10577935
TI  - P53 codon 72 polymorphism and longevity: additional data on centenarians from
      continental Italy and Sardinia.

PMID- 10577937
TI  - Complete inactivation of the TSC2 gene leads to formation of hamartomas.

PMID- 10577938
TI  - Stratification analysis of an osteoarthritis genome screen-suggestive linkage to
      chromosomes 4, 6, and 16.

PMID- 10577939
TI  - Evidence for interaction between psoriasis-susceptibility loci on chromosomes
      6p21 and 1q21.

PMID- 10577940
TI  - Founder BRCA1/2 mutations among male patients with breast cancer in Israel.

PMID- 10577942
TI  - A First Comparison of the Surface Brightness Fluctuation Survey Distances with
      the Galaxy Density Field: Implications for H0 and Omega.
AB  - We compare the peculiar velocities measured in the surface brightness fluctuation
      survey of galaxy distances with the predictions from the density fields of the
      IRAS 1.2 Jy flux-limited redshift survey and the optical redshift survey (ORS) to
      derive simultaneous constraints on the Hubble constant H0 and the density
      parameter beta=Omega0.6&solm0;b, where b is the linear bias. We find that
      betaI=0.42+0.10-0.06 and betaO=0.26+/-0.08 for the IRAS and ORS comparisons,
      respectively, and that H0=74+/-4 km s-1 Mpc (with an additional 9% uncertainty
      due to the Cepheids themselves). The match between predicted and observed
      peculiar velocities is good for these values of H0 and beta, and although there
      is covariance between the two parameters, our results clearly point toward low
      density cosmologies. Thus, the unresolved discrepancy between the "velocity
      velocity" and "density-density" measurements of beta continues.

PMID- 10577941
TI  - Heterogenous point mutations in the mitochondrial tRNA Ser(UCN) precursor
      coexisting with the A1555G mutation in deaf students from Mongolia.

PMID- 10577943
TI  - Reobserving the Extreme-Ultraviolet Emission from Abell 2199: In Situ Measurement
      of Background Distribution by Offset Pointing.
AB  - The EUV excess emission from the clusters A2199 and A1795 remains an unexplained
      astrophysical phenomenon. There has been many unsuccessful attempts to
      "trivialize" the findings. In this Letter, we present direct evidence proving
      that the most recent of such attempts, which attributes the detected signals to a
      background nonuniformity effect, is likewise excluded. We address the issue by a
      reobservation of A2199 that features a new filter orientation, usage of a more
      sensitive part of the detector, and, most crucially, the inclusion of a
      background pointing at approximately 2 degrees offset-the first in situ
      measurement of its kind. We first demonstrate quantitatively two facts: (1) the
      offset pointing provides an accurate background template for the cluster
      observation, while (2) data from other blank fields do not. We then performed a
      point-to-point subtraction of the in situ background from the cluster field, with
      an appropriate propagation of errors. The resulting cluster radial profile is
      consistent with that obtained by our original method of subtracting a flat
      asymptotic background. The emission now extends to a radius of 20&arcmin;; it
      confirms the rising prominence of EUV excess beyond approximately 5&arcmin; as
      previously reported.

PMID- 10577944
TI  - The Mass Function of Young Star Clusters in the "Antennae" Galaxies.
AB  - We determine the mass function of young star clusters in the merging galaxies
      known as the "Antennae" (NGC 4038/9) from deep images taken with the Wide Field
      Planetary Camera 2 on the refurbished Hubble Space Telescope. This is
      accomplished by means of reddening-free parameters and a comparison with stellar
      population synthesis tracks to estimate the intrinsic luminosity and age, and
      hence the mass, of each cluster. We find that the mass function of the young star
      clusters (with ages less, similar160 Myr) is well represented by a power law of
      the form psi&parl0;M&parr0;~M-2 over the range 104 less, similarM less,
      similar106 M middle dot in circle. This result may have important implications
      for our understanding of the origin of globular clusters during the early phases
      of galactic evolution.

PMID- 10577945
TI  - X-Ray Detection of SN 1994W in NGC 4041?
AB  - Optical spectra of SN 1994W in NGC 4041 revealed the presence of a dense (Ne>108
      cm-3) circumstellar shell. An observation with the ROSAT High-Resolution Imager
      detected a source, with a luminosity of approximately 8x1039 ergs s-1, coincident
      with the position of SN 1994W to within 1&farcs;4. The positional coincidence
      plus the optical evidence for a dense circumstellar shell support the
      identification of the X-ray source as SN 1994W.

PMID- 10577947
TI  - Neutrino Event Rates from Gamma-Ray Bursts.
AB  - We recalculate the diffuse flux of high-energy neutrinos produced by gamma-ray
      bursts in the relativistic fireball model. Although we confirm that the average
      single burst produces only approximately 10-2 high-energy neutrino events in a
      detector with a 1 km2 effective area, i.e., about 10 events yr-1, we show that
      the observed rate is dominated by burst-to-burst fluctuations that are very
      large. We find event rates that are expected to be larger by 1 order of
      magnitude, likely more, which are dominated by a few very bright bursts. This
      greatly simplifies their detection.

PMID- 10577946
TI  - Chandra Detection of Massive Black Holes in Galactic Cooling Flows.
AB  - Anticipating forthcoming Chandra X-ray observations, we describe the continuation
      of interstellar cooling flows deep into the cores of elliptical galaxies.
      Interstellar gas heated to T>1 keV in the potential of massive black holes (r
      less, similar50 pc) should be visible unless thermal heating is diluted by
      nonthermal pressure. Since our flows are subsonic near the massive black holes,
      distributed cooling continues within approximately 300 pc. Dark, low-mass stars
      formed in this region may be responsible for some of the mass attributed to
      central black holes.

PMID- 10577948
TI  - Delayed Detonation at a Single Point in Exploding White Dwarfs.
AB  - Delayed detonation in an exploding white dwarf, which propagates from an off
      center transition point rather than from a spherical transition shell, is
      described and simulated. The differences between the results of two-dimensional
      simulations and the one-dimensional case are presented and discussed. The two
      dimensional effects become significant in transition density below 3rho7, where
      the energetics, the production of Fe group elements, and the symmetry of the
      explosion are all affected. In the two-dimensional case, the explosion is less
      energetic and less Ni is produced in the detonation phase of the explosion. For
      low transition density, the reduction in Ni mass can reach 20%-30%. The asymmetry
      in abundances between regions close to the transition point and regions far from
      that point is large and could be a source of polarization patterns in the emitted
      light. We conclude that the spatial and temporal distribution of transition
      locations is an important parameter that must be included in delayed detonation
      models for Type Ia supernovae.

PMID- 10577950
TI  - BRI 0021-0214: Another Surprise at the Bottom of the Main Sequence.
AB  - We report the detection of an Halpha flare on the low-luminosity M9.5 dwarf BRI
      0021-0214. This star has rapid rotation, vsin&parl0;i&parr0; approximately 40 km
      s-1, but generally shows no significant chromospheric emission. Our detection of
      the flare shows that a magnetic field is present, although the level of activity
      at maximum is 3 times lower than the mean quiescent level in early- and mid-type
      M dwarfs. Based on data available in the literature, we estimate that the star is
      in outburst for no more than 7% of the time.

PMID- 10577949
TI  - Upper Limits on the Continuum Emission from Geminga at 74 and 326 MHz.
AB  - We report a search for radio continuum emission from the gamma-ray pulsar
      Geminga. We have used the VLA to image the location of the optical counterpart of
      Geminga at 74 and 326 MHz. We detect no radio counterpart. We derive upper limits
      to the pulse-averaged flux density of Geminga, taking diffractive scintillation
      into account. We find that diffractive scintillation is probably quenched at 74
      MHz and does not influence our upper limit, S<56 mJy (2 sigma), but that a 95%
      confidence level at 326 MHz is S<5 mJy. Owing to uncertainties on the other low
      frequency detections and the possibility of intrinsic variability or extrinsic
      variability (refractive interstellar scintillation) or both, our nondetections
      are nominally consistent with these previous detections.

PMID- 10577951
TI  - Thermal Stability of Cold Clouds in Galaxy Halos.
AB  - We consider the thermal properties of cold, dense clouds of molecular hydrogen
      and atomic helium. For cloud masses below 10-1.7 M middle dot in circle, the
      internal pressure is sufficient to permit the existence of particles of solid or
      liquid hydrogen at temperatures above the cosmic microwave background
      temperature. Optically thin thermal continuum emission by these particles can
      balance cosmic-ray heating of the cloud, leading to equilibria that are thermally
      stable even though the heating rate is independent of cloud temperature. For the
      Galaxy, the known heating rate in the disk sets a minimum mass of order 10-6 M
      middle dot in circle necessary for survival. Clouds of this type may in principle
      comprise most of the dark matter in the Galactic halo. However, we caution that
      the equilibria do not exist at redshifts z greater, similar1 when the temperature
      of the microwave background was substantially larger than its current value;
      therefore, the formation and the survival of such clouds to the present epoch
      remain open questions.

PMID- 10577952
TI  - Enhanced Cloud Disruption by Magnetic Field Interaction.
AB  - We present results from the first three-dimensional numerical simulations of
      moderately supersonic cloud motion through a tenuous, magnetized medium. We show
      that the interaction of the cloud with a magnetic field perpendicular to its
      motion has a great dynamical impact on the development of instabilities at the
      cloud surface. Even for initially spherical clouds, magnetic field lines become
      trapped in surface deformations and undergo stretching. The consequent field
      amplification that occurs there and, in particular, its variation across the
      cloud face then dramatically enhance the growth rate of Rayleigh-Taylor unstable
      modes, hastening the cloud disruption.

PMID- 10577953
TI  - Shock-heated NH3 in a Molecular Jet Associated with a High-Mass Young Star.
AB  - We present the discovery of shock-excited NH3 in a well-collimated jet associated
      with the extremely young high-mass star IRAS 20126+4104. The NH3 (3, 3) and (4,
      4) emission is dominated by three clumps along the SiO jet. At the end of the
      jet, there exists strong and broad (+/-10 km s-1) NH3 (3, 3) emission. With
      typical brightness temperatures greater than 500 K, the overall emission
      indicates a weakly inverted population and appears in an arc, consistent with the
      excitation by bow shocks. There are two bright spots in the NH3 (3, 3) emission
      with brightness temperatures of approximately 2000 K. The narrow line width (1.5
      km s-1 FWHM), the small sizes (<0&farcs;3), and the unusually high brightness
      temperature of the features are indicative of maser emission. Our observations
      provide clear evidence that NH3 (3, 3) masers are excited in shock regions in
      molecular outflows.

PMID- 10577954
TI  - TRACE and Yohkoh Observations of High-Temperature Plasma in a Two-Ribbon Limb
      Flare.
AB  - The ability of the Transition Region and Coronal Explorer (TRACE) to image solar
      plasma over a wide range of temperatures (Te approximately 104-107 K) at high
      spatial resolution (0&farcs;5 pixels) makes it a unique instrument for observing
      solar flares. We present TRACE and Yohkoh observations of an M2.4 two-ribbon
      flare that began on 1999 July 25 at about 13:08 UT. We observe impulsive
      footpoint brightenings that are followed by the formation of high-temperature
      plasma (Te greater, similar10 MK) in the corona. After an interval of about 1300
      s, cooler loops (Te<2 MK) form below the hot plasma. Thus, the evolution of the
      event supports the qualitative aspects of the standard reconnection model of
      solar flares. The TRACE and Yohkoh data show that the bulk of the flare emission
      is at or below 10 MK. The TRACE data are also consistent with the Yohkoh
      observations of hotter plasma (Te approximately 15-20 MK) existing at the top of
      the arcade. The cooling time inferred from these observations is consistent with
      a hybrid cooling time based on thermal conduction and radiative cooling.

PMID- 10577955
TI  - Building towards a consensus for the use of tumour necrosis factor blocking
      agents.

PMID- 10577956
TI  - Rheumatoid arthritis: a synovial disease?

PMID- 10577957
TI  - Asthma and epididymitis: the calm before the storm.

PMID- 10577959
TI  - Recurrent lung shadowing in adult juvenile idiopathic arthritis.

PMID- 10577958
TI  - Two forms of reactive arthritis?
AB  - Inflammatory arthritides developing after a distant infection have so far been
      called reactive or postinfectious, quite often depending on the microbial trigger
      and/or HLA-B27 status of the patient. For clarity, it is proposed that they all
      should be called reactive arthritis, which, according to the trigger, occurs as
      an HLA-B27 associated or non-associated form. In addition to the causative agents
      and HLA-B27, these two categories are also distinguished by other
      characteristics. Most important, HLA-B27 associated arthritis may occur identical
      to the Reiter's syndrome with accompanying ureteritis and/or conjunctivitis,
      whereas in the B27 non-associated form this has not been clearly described.
      Likewise, only the B27 associated form belongs to the group of
      spondyloarthropathies.

PMID- 10577960
TI  - Parasympathetic failure does not contribute to ocular dryness in primary
      Sjogren's syndrome.
AB  - OBJECTIVE: To investigate the sympathetic and parasympathetic cardiovascular
      function in primary Sjogren's syndrome (SS) and to investigate the possible
      relation with ocular dryness. METHODS: 41 (40 women) patients with primary SS,
      mean age 50 years (range 20-80) with a mean disease duration of eight years
      (range 1-30), were studied. In each patient direct arterial blood pressure (BP),
      heart rate (HR) and respiration were measured continuously for two hours. The
      function of the autonomic circulatory regulation was evaluated by measuring the
      heart rate response to deep breathing (6 cycles/min) and by means of the Valsalva
      manoeuvre and the responses of BP, HR and plasma noradrenaline (norepinephrine)
      concentrations to a 10 minute 60 degree head up tilt test. Pupillography was done
      to evaluate ocular autonomic function. RESULTS: The HR-Valsalva ratio was
      abnormal in 24% of the patients, and the HR variability during forced respiration
      was abnormal in 56% of the patients. The HR responses to both the Valsalva
      manoeuvre and deep breathing, as indicators of parasympathetic function, were
      abnormally low in 6 of 41 (15%) patients. In only two patients the decrease in
      systolic BP in response to the head up tilt test, as indicator of sympathetic
      function, was more than 20 mm Hg. However, increment of plasma noradrenaline
      concentration during head up tilt test and the overshoot of BP in phase IV of the
      Valsalva manoeuvre, as indicators of sympathetic function, were normal in both
      patients. Thus, no evidence for sympathetic dysfunction was found, whereas
      evidence for parasympathetic failure occurred sometimes. Autonomic pupillary
      function in patients with primary SS and healthy controls, as well as the
      Schirmer test in patients with or without evidence for parasympathetic
      dysfunction as based on the results of the Valsalva and deep breathing tests,
      were not significantly different. CONCLUSION: Parasympathetic, but not
      sympathetic dysfunction seems to occur in a subgroup of primary SS. Results show
      that this does not necessarily contribute to the typical ocular dryness in this
      condition.

PMID- 10577961
TI  - Changes in the incidence and prevalence of rheumatoid arthritis in Kamitonda,
      Wakayama, Japan, 1965-1996.
AB  - OBJECTIVE: To evaluate secular trends in the incidence and prevalence of
      rheumatoid arthritis (RA) in Japan. METHODS: The incidence and prevalence of RA
      were determined in a longitudinal population based study in the Kamitonda
      district, Wakayama, Japan, from 1965 to 1996. RESULTS: In the study area
      consisting of about 3000 inhabitants, 16 incident cases, satisfying definite RA
      by the Rome criteria were detected during the study period. The age and sex
      adjusted incidence in both men and women combined and the age adjusted incidence
      in women significantly decreased (p<0.025 and p<0. 01, respectively). The age and
      sex adjusted prevalence in all inhabitants tended to decrease (p<0.1), and the
      age adjusted prevalence in women significantly declined (p<0.025). In men,
      however, neither incidence nor prevalence showed significant change. CONCLUSIONS:
      The decline of incidence and prevalence of female RA may be reducible to some
      environmental changes preferentially occurring more obviously in Japanese women
      than in men. Because the use of oral contraceptives has been extremely low in
      Japan, the decline should be explained by other factors.

PMID- 10577962
TI  - Increased IgA rheumatoid factor and V(H)1 associated cross reactive idiotype
      expression in patients with Lyme arthritis and neuroborreliosis.
AB  - OBJECTIVE: To investigate whether autoreactive mechanisms occur in Lyme disease
      (LD) by determining IgA, IgG and IgM rheumatoid factor (RF) concentrations and RF
      associated cross reactive idiotype (CRI) expression in the serum of LD patients,
      with comparison to patients with rheumatoid arthritis (RA). METHODS: The RF
      isotype profiles were determined in 59 patients with LD; erythema migrans (EM)
      (n=19), neuroborreliosis (NB) (n=20) and Lyme arthritis (LA) (n=20). Mouse
      monoclonal antibodies (mAbs) G6 and G8 (V(H)1 gene associated), D12 (V(H)3 gene
      associated) and C7 (V(kappa)III gene associated) were then used to determine the
      RF associated CRI expression on IgM antibodies in 16 of these LD patients (eight
      seropositive for RF); (EM (n=3), NB (n=6), LA (n=7)). RESULTS: Seven (18%)
      patients with either NB or LA had increased concentrations of IgA RF compared
      with none with EM. Significant differences in the number of patients with raised
      concentrations of IgG RF or IgM RF were not found between the LD patient groups.
      Five (3NB, 1LA and 1 EM) (31%) and three (2NB and 1LA) (19%) of LD patients had
      raised concentrations of the CRIs recognised by mAbs G6 and G8, respectively.
      These CRIs were detected in LD sera both with and without raised concentrations
      of RF and were not demonstrated on anti-Borrelia burgdorferi antibodies using
      ELISA. No LD sera tested had raised concentrations of the determinants recognised
      by mAbs C7 or D12. CONCLUSION: Significantly raised concentrations of IgA RF and
      increased use of V(H)1 germline gene associated CRIs are found on IgM antibodies
      in the serum of LD patients. These data indicate the recruitment of autoreactive
      B lymphocytes in some patients with the later stages of LD.

PMID- 10577963
TI  - Controlled study of the prevalence of radiological osteoarthritis in clinically
      unrecognised juxta-articular Paget's disease.
AB  - BACKGROUND: Paget's disease of bone is common and often undiagnosed in the
      population. The association of Paget's disease and osteoarthritis is well
      described but only in cases ascertained in secondary and tertiary care centres to
      which they have been referred largely because of pain. This study represents an
      attempt to confirm the association between Paget's disease and osteoarthritis in
      a population previously unknown to have Paget's disease. METHODS: Radiographs of
      people over 55 years that included the entire pelvis, sacrum, femoral heads and
      lumbar spine (mostly plain abdominal radiographs) were obtained from hospital
      records for the period 1993-95. Films were screened by a trained observer and the
      positive films were reviewed by a consultant radiologist who also examined a 1 in
      10 sample of the negative films. A sub-sample of 153 confirmed positive cases
      were matched for age and sex using cases without Paget's disease and these pairs
      were assessed by two observers working in tandem. The hip joints were scored 0-5
      using a modification of the original descriptive classification of Kellgren and
      Lawrence and minimum joint space of the hip was also measured. RESULTS: Not all
      cases were available for assessment. A total of 248 films were included (137
      without Paget's, 89 with unilateral and 22 with bilateral disease). The mean age
      of the cases and controls was 78.4 years and 77.4 years respectively with 66/45
      male/female cases and 78/59 male/female controls. One hundred and twenty nine
      affected hips were available for comparison with 352 unaffected hips. Median
      joint space narrowing for the affected hip was 3 mm (range, 0-5 mm) and for the
      unaffected hip 4 mm (range, 0-6 mm, Mann-Whitney U test, p=0.00001). Median
      Kellgren and Lawrence grade for both groups was 0, with no statistical difference
      between the groups (Mann-Whitney U test, p=0.74). In terms of severity of
      osteoarthritis, there were 19 instances of grades 2+ in the unaffected hips, and
      only five in the affected hips. CONCLUSIONS: Pagetic coxopathy is characterised
      by loss of joint space, which may represent a secondary chondropathy. Although
      joint failure may result from this secondary chondropathy progression may be
      dependent on non-Pagetic factors. It is also possible that the usual radiological
      features of osteoarthritis may be modified or obscured by the Paget's disease.

PMID- 10577964
TI  - Perceptual variation in grading hand, hip and knee radiographs: observations
      based on an Australian twin registry study of osteoarthritis.
AB  - OBJECTIVE: The radiographic diagnosis of osteoarthritis (OA) in the peripheral
      skeleton is dependent on the skilled examination of several morphological
      characteristics of the condition as visualised on plain radiographs. However, the
      process is perceptual and generally enhanced by comparison against photographic
      standards. This study assessed the intra-rater and inter-rater reliability of
      radiologists experienced in reporting hand, hip and knee films derived from a
      community-based sample when using the photographic atlas recently developed by
      Burnett et al. METHODS: This study was part of a multifaceted diagnostics
      protocol, evaluating methodological issues, in the conduct of genetic research in
      osteoarthritis. From a cohort of 118 twin pairs, registered with the Australian
      Twins Registry (ATR), standard clinical examinations were performed on 74
      complete and 11 incomplete pairs of twins over age 50 years, followed by standard
      AP hand, AP pelvis and AP standing radiographs of the knees. The pairs were
      selected both to represent twin pairs who had previously self reported a
      diagnosis of OA, as well as those who had not. Radiologists read the films blind
      to the original self reported diagnosis and without reference to their pairing.
      The films were read by comparison against photographic standards and were scored
      according to specific features. All films were read independently by two
      consultant radiologists blind to one another's assessments, and selected films
      were thereafter assigned for rereading. Inter-rater and intra-rater agreement
      were different for different features, different anatomic areas, and, for the
      former, were different for the two radiologists. RESULTS: Inter-rater agreement
      was different for different anatomic areas, different radiographic features, and
      the two radiologists. Intra-rater agreement for the presence or absence of OA was
      as follows: actual observed agreement = 0.79 to 0.97 and 0.83 to 0.98; adjusted
      kappa statistic = 0.58 to 0.94 and 0.67 to 0.96; inter-rater agreement was as
      follows: actual observed agreement = 0. 77 to 0.97; adjusted kappa statistic =
      0.54 to 0.94. Agreement was generally high in most of the principal target joints
      for OA: DIP, PIP, 1st CMC, hip and knee. CONCLUSIONS: Although assessor agreement
      was not perfect, it is concluded that for genetic epidemiology purposes, while
      duplicate assessments may be advantageous, it is possible for radiographs to be
      examined accurately by a single experienced assessor. However, for less
      experienced assessors independent examinations should be made by at least two
      assessors and either a consensus reached on disparate examinations or an
      algorithm developed to adjudicate any discrepancies.

PMID- 10577965
TI  - Detection of anti-ADAM 10 antibody in serum of a patient with pulmonary fibrosis
      associated with dermatomyositis.
AB  - OBJECTIVES: It has been suggested that the humoral immune system plays a part in
      the pathogenesis of pulmonary fibrosis. Although circulating autoantibodies to
      lung protein(s) have been suggested, few lung proteins have been characterised.
      The purpose of this study is to determine the antigen recognised by serum of a
      patient with pulmonary fibrosis associated with dermatomyositis. METHODS: To
      accomplish this, anti-small airway epithelial cell (SAEC) antibody in a patient's
      serum was evaluated using a western immunoblot. RESULTS: An autoantibody against
      SAEC was found, and the antigen had a molecular weight of 62 kDa. Using the
      patient's serum, clones from the normal lung cDNA library were screened and
      demonstrated that anti-SAEC antibody in the patient's serum was against ADAM (A
      disintegrin and metalloprotease) 10. CONCLUSION: This is the first report that
      demonstrates the existence of anti-ADAM 10 antibody in a patient with pulmonary
      fibrosis associated with dermatomyositis.

PMID- 10577968
TI  - DAP kinase and DAP-3: novel positive mediators of apoptosis.

PMID- 10577967
TI  - Signal transduction by tumour necrosis factor and tumour necrosis factor related
      ligands and their receptors.

PMID- 10577969
TI  - Tumour necrosis factor gene polymorphisms as severity markers in rheumatoid
      arthritis.

PMID- 10577970
TI  - The rationale for the current boom in anti-TNFalpha treatment. Is there an
      effective means to define therapeutic targets for drugs that provide all the
      benefits of anti-TNFalpha and minimise hazards?
AB  - Progress in understanding mechanisms of disease are necessary to usher in major
      changes in treatment. A new era in rheumatoid arthritis (RA) and related chronic
      autoimmune/inflammatory diseases is now beginning, with a variety of anti
      TNFalpha treatments licensed for use in both RA and Crohn's disease. The
      rationale for this new treatment lies in an understanding that cytokines are
      critical, rate limiting molecules lying at the heart of the chronic
      autoimmune/inflammatory disease process. This understanding was developed from
      the critical evaluation of a hypothesis that was proposed linking cytokines,
      antigen presentation and autoimmunity in 1983. Detailed analysis focusing on the
      major site of the disease, the rheumatoid synovium was essential to developing
      indications that blockade of TNFalpha might be efficacious. This clue was
      validated using anti-TNFalpha treatment of an animal model of RA, murine collagen
      induced arthritis, and by immunohistochemical demonstration of upregulated TNF
      and TNF-R expression in the synovium. With this three pronged rationale, the
      authors were able to convince Centocor, Inc, which had developed a chimaeric anti
      TNFalpha antibody for use in sepsis, to work with them to test the concept that
      TNFalpha blockade would be beneficial in RA. With the success of that first
      trial, other companies have subsequently tested their anti-TNF strategies
      successfully. Current interests extend to understanding the processes that
      regulate TNF production in the rheumatoid joint. Progress in this area is
      discussed, using adenoviruses to infect normal macrophages and rheumatoid
      synovium.

PMID- 10577972
TI  - Role of tumour necrosis factor alpha in experimental arthritis: separate activity
      of interleukin 1beta in chronicity and cartilage destruction.
AB  - Chronic arthritis is characterised by persistent joint inflammation and
      concomitant joint destruction. Using murine arthritis models and neutralising
      antibodies as well as cytokine specific knockout conditions, it was found that
      tumour necrosis factor alpha (TNFalpha) is important in early joint swelling.
      Membrane bound TNFalpha is sufficient to drive this aspect of inflammation as
      well as the acute cellular infiltrate in the synovial tissue. Interleukin 1 (IL1)
      is not necessarily a dominant cytokine in early joint swelling, but has a pivotal
      role in sustained cellular infiltration and erosive cartilage damage. TNFalpha
      independent IL1 production is a prominent feature in murine arthritis models.
      These observations provide evidence for potential uncoupling of joint
      inflammation and erosive changes, implying that both cytokines need to be
      targeted to achieve optimal treatment.

PMID- 10577971
TI  - The function of tumour necrosis factor and receptors in models of multi-organ
      inflammation, rheumatoid arthritis, multiple sclerosis and inflammatory bowel
      disease.
AB  - There is now good evidence to demonstrate that aberrations in tumour necrosis
      factor (TNF) production in vivo may be either pathogenic or protective and
      several plausible mechanisms may explain these contrasting activities. According
      to the classic pro-inflammatory scenario, failure to regulate the production of
      TNF at a site of immunological injury may lead to chronic activation of innate
      immune cells and to chronic inflammatory responses, which may consequently lead
      to organ specific inflammatory pathology and tissue damage. However, more cryptic
      functions of this molecule may be considered to play a significant part in the
      development of TNF mediated pathologies. Direct interference of TNF with the
      differentiation, proliferation or death of specific pathogenic cell targets may
      be an alternative mechanism for disease initiation or progression. In addition to
      these activities, there is now considerable evidence to suggest that TNF may also
      directly promote or down regulate the adaptive immune response. A more complete
      understanding of the temporal and spatial context of TNF/TNF receptor (TNF-R)
      function and of the molecular and cellular pathways leading to the development of
      TNF/TNF-R mediated pathologies is necessary to fully comprehend relevant
      mechanisms of disease induction and progression in humans. In this paper, the
      potential pathogenic mechanisms exerted by TNF and receptors in models of multi
      organ inflammation, rheumatoid arthritis, multiple sclerosis and inflammatory
      bowel disease are discussed. Elucidating the nature and level of contribution of
      these mechanisms in chronic inflammation and autoimmunity may lead to better
      regulatory and therapeutic applications.

PMID- 10577974
TI  - Anti-tumour necrosis factor specific antibody (infliximab) treatment provides
      insights into the pathophysiology of rheumatoid arthritis.

PMID- 10577973
TI  - Tumour necrosis factor and other cytokines in murine lupus.

PMID- 10577975
TI  - Summary of clinical trials in rheumatoid arthritis using infliximab, an anti
      TNFalpha treatment.

PMID- 10577977
TI  - Preliminary results of early clinical trials with the fully human anti-TNFalpha
      monoclonal antibody D2E7.

PMID- 10577976
TI  - Etanercept: therapeutic use in patients with rheumatoid arthritis.
AB  - Tumour necrosis factor (TNF) plays a central part in the pathophysiology of
      rheumatoid arthritis (RA). TNF initiates signal transduction by interacting with
      surface bound TNF receptors. Soluble tumour necrosis factor receptors (sTNFRs)
      act as natural inhibitors of TNF activity. Etanercept, recombinant p75 sTNFR:Fc
      fusion protein, has received approval from the US Food and Drug Administration
      for patients with RA and juvenile RA (JRA) who have failed treatment with at
      least one other drug. Etanercept has demonstrated excellent safety and efficacy
      in large scale, randomised, double blind, placebo controlled trials of patients
      with RA and JRA who are refractory to other disease modifying anti-rheumatic
      drugs. The therapeutic effects mediated by etanercept are rapid and sustained.
      Combining etanercept with methotrexate was found to be safe and more effective
      than treatment with methotrexate alone in the treatment of RA. These clinical
      findings demonstrate that etanercept can result in symptomatic improvement in
      patients with RA and JRA. Etanercept is an important new addition to the
      treatment of these diseases.

PMID- 10577978
TI  - PEGylated recombinant human soluble tumour necrosis factor receptor type I (r-Hu
      sTNF-RI): novel high affinity TNF receptor designed for chronic inflammatory
      diseases.
AB  - The proinflammatory cytokine, tumour necrosis factor alpha (TNFalpha) has been
      shown to play a pivotal part in mediating acute and chronic inflammation. The
      activities of TNFalpha are modulated by the proteolytic shedding of the soluble
      extracellular domains of the two TNF receptors, p55 sTNF-RI and p75 sTNF-RII.
      Amgen Inc has cloned and expressed a recombinant form of a natural inhibitor of
      TNFalpha, referred to as recombinant human soluble TNF receptor type I (r-Hu-sTNF
      RI, sTNF-RI). sTNF-RI is an E coli recombinant, monomeric form of the soluble TNF
      type I receptor. A high molecular weight polyethylene glycol (PEG) molecule is
      attached at the N-terminus position to form the molecule intended for clinical
      evaluations (PEG sTNF-RI). Preclinical studies to date demonstrate that PEG sTNF
      RI is efficacious in rodent models of chronic inflammatory disease including
      rheumatoid arthritis and Crohn's disease at doses as low as 0.3 mg/kg given every
      other day. This dose results in plasma concentrations of 0.3 to 0.5 microg/ml.
      Higher doses with correspondingly higher plasma concentrations yield higher
      efficacy. It has also demonstrated efficacy in E coli lipopolysaccharide, and
      Staphylococcus enterotoxin B mediated models of acute inflammation in rodents and
      primates. Pharmacokinetic studies in mice, rats, cynomolgus monkeys, baboons, and
      chimpanzees have been conducted with PEG sTNF-RI. Absorption from a subcutaneous
      dose was slow, with the time to reach maximal plasma concentrations of 24-48
      hours in rats, and in monkeys, and 3-29 hours in chimpanzees. The initial volume
      of distribution of PEG sTNF-RI was essentially equivalent to that of plasma (40
      ml/kg). This suggests the protein does not appear to extensively distribute from
      the systemic circulation with a volume of distribution at steady state (Vss) less
      than 200 ml/kg in all species studied. These results are consistent with previous
      experience with PEGylated proteins in which PEGylation decreases both the rate of
      absorption and the plasma clearance of human recombinant proteins in animals and
      humans. The use of a PEG molecule will probably provide a more advantageous
      dosing schedule (that is, less frequent dosing) for the patient compared with a
      non-PEG sTNF-RI.

PMID- 10577979
TI  - Pharmacoeconomic evaluation of new treatments: efficacy versus effectiveness
      studies?
AB  - The juxtaposition of economic and clinical evaluation raises new issues in the
      design of clinical trials. Recent pharmacoeconomic guidelines provide some
      direction, but do not deal with the appropriate timing of economic evaluations in
      the drug developmental process. Ideally, pharmacoeconomic data should be
      available at the time of the regulatory and formulary decision making. Current
      pivotal phase III trials do not provide these data; they are designed to test
      safety and efficacy (does the drug work under optimal circumstances?) and not to
      answer questions about the effectiveness of a drug, the more relevant question
      for economic analysis (does the drug work in usual care?). The use of more
      "naturalistic" designs for some phase III randomised trials has been suggested.
      These so called "effectiveness trials" more closely reflect routine clinical
      practice. They use a more flexible dosage regimen, and a "usual care" instead of
      a placebo comparator. Patients randomised are more representative of actual
      practice and outcomes include quality of life and utility measures. They are more
      suited to provide the data needed to estimate the real benefit of the treatment
      in actual care. When costs are applied and compared with these benefits, you can
      estimate the efficiency of allocating resources to this new drug. Increasing the
      use of effectiveness trials in phase III would decrease the need for economic
      modelling.

PMID- 10577980
TI  - Safety, cost and effectiveness issues with disease modifying anti-rheumatic drugs
      in rheumatoid arthritis.

PMID- 10577981
TI  - FDA perspective on anti-TNF treatments.

PMID- 10577982
TI  - European regulatory aspects on new medicines targeted at treatment of rheumatoid
      arthritis.

PMID- 10577983
TI  - Treatment of rheumatoid arthritis with interleukin 1 receptor antagonist.

PMID- 10577985
TI  - Clinical implications of tumour necrosis factor alpha antagonism in patients with
      congestive heart failure.

PMID- 10577984
TI  - Interleukin 10 treatment for rheumatoid arthritis.

PMID- 10577986
TI  - Immunomodulation by thalidomide and thalidomide analogues.

PMID- 10577987
TI  - Anti-TNF antibody treatment of Crohn's disease.

PMID- 10577990
TI  - Circulation online only : november 30, 1999

PMID- 10577989
TI  - Access to disease modifying treatments for rheumatoid arthritis patients.

PMID- 10577991
TI  - Exercise tolerance as a guide to therapeutic efficacy for heart failure : the
      potential for angiotensin receptor blockers.

PMID- 10577988
TI  - The role of TNFalpha and lymphotoxin in demyelinating disease.

PMID- 10577992
TI  - Opposing effects of beta(1)- and beta(2)-adrenergic receptors on cardiac myocyte
      apoptosis : role of a pertussis toxin-sensitive G protein.
AB  - BACKGROUND: beta-Adrenergic receptor (beta-AR) stimulation increases apoptosis in
      adult rat cardiac (ventricular) myocytes (ARVMs) via activation of adenylyl
      cyclase. beta(2)-ARs may couple to a G(i)-mediated signaling pathway that can
      oppose the actions of adenylyl cyclase. METHODS AND RESULTS: In ARVMs, beta-AR
      stimulation for 24 hours increased the number of apoptotic cells as measured by
      flow cytometry. beta-AR-stimulated apoptosis was abolished by the beta(1)-AR
      selective antagonist CGP 20712A (P<0.05 versus beta-AR stimulation alone) but was
      potentiated by the beta(2)-AR-selective antagonist ICI 118,551 (P<0.05 versus
      beta-AR stimulation alone). The muscarinic agonist carbachol also prevented beta
      AR-stimulated apoptosis (P<0.05 versus beta-AR stimulation alone), whereas
      pertussis toxin potentiated the apoptotic action of beta-AR stimulation (P<0.05
      versus beta-AR stimulation alone) and prevented the antiapoptotic action of
      carbachol. CONCLUSIONS: In ARVMs, stimulation of beta(1)-ARs increases apoptosis
      via a cAMP-dependent mechanism, whereas stimulation of beta(2)-ARs inhibits
      apoptosis via a G(i)-coupled pathway. These findings have implications for the
      pathophysiology and treatment of myocardial failure.

PMID- 10577993
TI  - Joint effects of an aldosterone synthase (CYP11B2) gene polymorphism and classic
      risk factors on risk of myocardial infarction.
AB  - BACKGROUND: The -344C allele of a 2-allele (C or T) polymorphism in the promoter
      of the gene encoding aldosterone synthase (CYP11B2) is associated with increased
      left ventricular size and mass and with decreased baroreflex sensitivity, known
      risk factors for morbidity and mortality associated with myocardial infarction
      (MI). We hypothesized that this polymorphism was a risk factor for MI. METHODS
      AND RESULTS: We used a nested case-control design to investigate the
      relationships between this polymorphism and the risk of nonfatal MI in 141 cases
      and 270 matched controls from the Helsinki Heart Study, a coronary primary
      prevention trial in dyslipidemic, middle-aged men. There was a nonsignificant
      trend of increasing risk of MI with number of copies of the -344C allele.
      However, this allele was associated in a gene dosage-dependent manner with
      markedly increased MI risk conferred by classic risk factors. Whereas smoking
      conferred a relative risk of MI of 2.50 (P=0.0001) compared with nonsmokers in
      the entire study population, the relative risk increased to 4.67 in -344CC
      homozygous smokers (relative to nonsmokers with the same genotype, P=0.003) and
      decreased to 1.09 in -344TT homozygotes relative to nonsmokers with this
      genotype. Similar joint effects were noted with genotype and decreased HDL
      cholesterol level as combined risk factors. CONCLUSIONS: Smoking and dyslipidemia
      are more potent risk factors for nonfatal MI in males who have the -344C allele
      of CYP11B2.

PMID- 10577994
TI  - Effect of potential confounding factors on the thrombolysis in myocardial
      infarction (TIMI) trial frame count and its reproducibility.
AB  - BACKGROUND: The potential factors that introduce variability into TIMI frame
      count (TFC) have not been systematically investigated. The goal of this study was
      to determine if nitrate use, dye injection rate, catheter size, the phase of the
      cardiac cycle in which dye is injected, or heart rate affect the TFC and to
      investigate the reproducibility of the TFC. METHODS AND RESULTS: The dye
      injection rate was increased 1 mL/s, and angiography was repeated. A coronary
      angiogram was taken first with an 8F catheter and then with a 6F catheter. After
      taking angiograms, intracoronary nitrate was given to the patient, and the second
      angiography was performed. Basal heart rate was increased 20 beats/min, and
      angiography was repeated. Dye injection was performed at the beginning of systole
      and diastole. The TFC was not significantly changed by increasing the dye
      injection rate (P=0.467) or by changing catheter size (P=0.693). Nitrate
      administration significantly increased the TFC from 26.4+/-11.9 to 32.8+/-13.3
      frames (P<0.001). Dye injection at the beginning of diastole significantly
      decreased the TFC from 30.1+/-8.8 to 24.4+/-7.9 frames (P<0.001) for the left
      coronary artery and from 24.16+/-4.49 to 21. 24+/-4.45 frames (P<0.001) for the
      right coronary artery. Increasing heart rate significantly decreased the TFC from
      30.4+/-6.1 to 25. 3+/-7.2 frames (P<0.001). Intraobserver and interobserver
      reproducibility of the TFC was good (mean difference, 1.33+/-1.24 and 2.57+/-1.72
      frames, respectively). CONCLUSIONS: Nitrate use, heart rate, and the phase of the
      cardiac cycle in which dye is injected had significant effects on the TFC.
      Therefore, studies comparing TFC need to consider these factors, and the use of
      nitrates should be either standardized or randomized.

PMID- 10577996
TI  - Human prostacyclin synthase gene and hypertension : the Suita Study.
AB  - BACKGROUND: Prostacyclin (prostaglandin I(2)) is a strong vasodilator that
      inhibits the growth of vascular smooth muscle cells and is also the most potent
      endogenous inhibitor of platelet aggregation. Therefore, it has been considered
      to play an important roles in cardiovascular disease. On the basis of the
      hypothesis that variations of the prostacyclin synthase gene may also play an
      important role in human cardiovascular disease, we performed a screening for
      variations in the human prostacyclin synthase gene. METHODS AND RESULTS: We have
      detected a repeat polymorphism in the promoter region of the human prostacyclin
      synthase gene. The number of 9-bp (CCGCCAGCC) repeats in the promoter region,
      which encodes a tandem repeat of Sp1 transcriptional binding sites, varied
      between 3 and 7 in Japanese subjects. Luciferase reporter analysis indicated that
      the alleles of 3 and 4 repeats (R3 and R4, respectively) had less promoter
      activity in cultured human umbilical vein endothelial cells. We then investigated
      the possible association of this repeat polymorphism with blood pressure in a
      large population-based sample (the Suita Study), which consisted of 4971 Japanese
      participants. Multivariate models indicated that participants with the R3R3,
      R3R4, or R4R4 genotype (SS genotype, n=80) had significantly higher systolic
      pressure (P=0.0133) and pulse pressure (P=0.0005). The odds ratio of hypertension
      (140/90 mm Hg) for the SS genotype was 1.942 (95% confidence interval 3.20 to
      1.19, P=0.0084). CONCLUSIONS: Repeat polymorphism of the human prostacyclin
      synthase gene seems to be a risk factor for higher pulse pressure and is
      consequently a risk factor for systolic hypertension in the Japanese population.

PMID- 10577995
TI  - Improvement in exercise tolerance and symptoms of congestive heart failure during
      treatment with candesartan cilexetil. Symptom, Tolerability, Response to Exercise
      Trial of Candesartan Cilexetil in Heart Failure (STRETCH) Investigators.
AB  - BACKGROUND: The renin-angiotensin system plays an important part in the
      pathogenesis of congestive heart failure (CHF). This study evaluated the effect
      of an angiotensin II type 1 receptor antagonist on exercise tolerance and
      symptoms of CHF. METHODS AND RESULTS: In this multicenter, double-blind, parallel
      group study, 844 patients with CHF were randomized to 12 weeks' treatment with
      placebo (n=211) or candesartan cilexetil 4 mg (n=208), 8 mg (n=212), or 16 mg
      (n=213) after a 4-week placebo run-in period. Changes in exercise time, Dyspnea
      Fatigue Index score, NYHA functional class, and cardiothoracic ratio were
      determined. Candesartan cilexetil produced a dose-related improvement in exercise
      time. For the intention-to-treat population, the increase produced by candesartan
      cilexetil 16 mg was significantly greater than that produced by placebo (47.2
      versus 30.8 seconds, P=0.0463). All doses of candesartan cilexetil significantly
      improved the Dyspnea Fatigue Index score relative to placebo. NYHA class improved
      more frequently in the candesartan cilexetil groups; the differences relative to
      placebo were not significant. The decrease in cardiothoracic ratio with
      candesartan 4 to 16 mg was small but statistically significant compared with
      placebo (all P<0.05). In all candesartan cilexetil groups, plasma renin activity
      and angiotensin II levels increased from baseline and aldosterone levels
      decreased in the 8- and 16-mg treatment groups. Candesartan cilexetil was well
      tolerated at all doses. CONCLUSIONS: In summary, treatment with candesartan
      cilexetil demonstrated significant improvements in exercise tolerance,
      cardiothoracic ratio, and symptoms and signs of CHF and was well tolerated.

PMID- 10577997
TI  - Alterations of heart rate variability after radiofrequency catheter ablation of
      focal atrial fibrillation originating from pulmonary veins.
AB  - BACKGROUND: Transient sinus bradycardia and hypotension have been reported as
      complications during radiofrequency (RF) ablation of focal atrial fibrillation
      (AF) originating from pulmonary veins (PVs). This study used heart rate
      variability (HRV) to evaluate the effects of focal PVs ablation on autonomic
      function. METHODS AND RESULTS: Thirty-seven patients with paroxysmal AF were
      referred for ablation. The study group included 30 patients who underwent
      transseptal ablation of PVs, and the control group included 7 patients who
      underwent the transseptal procedure without ablation. The mean sinus rate and
      time-domain (standard deviation of RR intervals and root-mean-square of
      differences of adjacent RR intervals) and frequency-domain (low frequency, high
      frequency, and low-frequency/high-frequency ratio) analyses of HRV were obtained
      by use of 24-hour Holter monitoring before and 1 week, 1 month, and 6 months
      after ablation. All the triggering points of AF were from PVs, and they were
      successfully ablated. Severe bradycardia and hypotension were noted during
      ablation of PVs in 6 patients (group IA); 24 patients without the above
      complication belonged to group IB. Compared with preablation values, a
      significant increase in mean sinus rate and low-frequency/high-frequency ratio
      and a significant decrease in standard deviation of RR intervals, root-mean
      square of differences of adjacent RR intervals, low frequency, and high frequency
      were noted in groups IA and IB patients 1 week after ablation. The changes in HR
      and HRV recovered spontaneously in the 2 subgroups by 1 month later. These
      parameters of HRV did not change in the control group after the transseptal
      procedure. CONCLUSIONS: Transient autonomic dysfunction with alterations in HR
      and HRV occurred after ablation of focal AF originating from PVs.

PMID- 10577998
TI  - Serum glutathione in adolescent males predicts parental coronary heart disease.
AB  - BACKGROUND: Traditional risk factors account for only half of the morbidity and
      mortality from coronary heart disease (CHD). There is substantial evidence that
      oxidative injury plays a major role in the atherosclerotic process. Thus,
      antioxidants may protect against development of atherosclerosis. Glutathione, an
      intracellular tripeptide with antioxidant properties, may be protective. METHODS
      AND RESULTS: This case-control study compared total serum glutathione (tGSH) in
      81 adolescent male offspring of parents with premature CHD (ie, before 56 years
      of age) and 78 control male offspring of parents without known or suspected CHD.
      Case offspring had significantly lower tGSH than control offspring. In multiple
      logistic regression with parental CHD status as the dependent variable, age
      entered as a covariate, and other CHD risk factors competing to enter the model
      as significant independent predictor variables, LDL cholesterol (odds ratio [OR],
      2.15 [units=1.5 SD]; 95% CI, 1.21 to 3.82), tGSH (OR, 0.40; 95% CI, 0.22 to
      0.71), HDL cholesterol (OR, 0.42; 95% CI, 0.22 to 0.78), and total serum
      homocysteine (OR, 2.6; 95% CI, 1.35 to 5.02) entered the model as significant
      predictors of parental CHD status. CONCLUSIONS: Low tGSH in adolescent boys is a
      significant independent predictor of parental CHD, in addition to elevated LDL
      cholesterol, low HDL cholesterol, and elevated total serum homocysteine
      concentrations.

PMID- 10577999
TI  - Arrhythmias and conduction defects as presenting symptoms of fatty acid oxidation
      disorders in children.
AB  - BACKGROUND: The clinical manifestations of inherited disorders of fatty acid
      oxidation vary according to the enzymatic defect. They may present as isolated
      cardiomyopathy, sudden death, progressive skeletal myopathy, or hepatic failure.
      Arrhythmia is an unusual presenting symptom of fatty acid oxidation deficiencies.
      METHODS AND RESULTS: Over a period of 25 years, 107 patients were diagnosed with
      an inherited fatty acid oxidation disorder. Arrhythmia was the predominant
      presenting symptom in 24 cases. These 24 cases included 15 ventricular
      tachycardias, 4 atrial tachycardias, 4 sinus node dysfunctions with episodes of
      atrial tachycardia, 6 atrioventricular blocks, and 4 left bundle-branch blocks in
      newborn infants. Conduction disorders and atrial tachycardias were observed in
      patients with defects of long-chain fatty acid transport across the inner
      mitochondrial membrane (carnitine palmitoyl transferase type II deficiency and
      carnitine acylcarnitine translocase deficiency) and in patients with
      trifunctional protein deficiency. Ventricular tachycardias were observed in
      patients with any type of fatty acid oxidation deficiency. Arrhythmias were
      absent in patients with primary carnitine carrier, carnitine palmitoyl
      transferase I, and medium chain acyl coenzyme A dehydrogenase deficiencies.
      CONCLUSIONS: The accumulation of arrhythmogenic intermediary metabolites of fatty
      acids, such as long-chain acylcarnitines, may be responsible for arrhythmias.
      Inborn errors of fatty acid oxidation should be considered in unexplained sudden
      death or near-miss in infants and in infants with conduction defects or
      ventricular tachycardia. Diagnosis can be easily ascertained by an acylcarnitine
      profile from blood spots on filter paper.

PMID- 10578000
TI  - Red wine inhibits monocyte chemotactic protein-1 expression and modestly reduces
      neointimal hyperplasia after balloon injury in cholesterol-Fed rabbits.
AB  - BACKGROUND: Wine consumption decreases the risk of myocardial infarction. Intimal
      hyperplasia contributes to restenosis after angioplasty. Local ethanol delivery
      inhibits intimal hyperplasia after balloon injury in rabbit iliac and pig
      coronary arteries. The effects of wine consumption on intimal response and
      monocyte chemotactic protein-1 (MCP-1) expression were studied in cholesterol-fed
      rabbits. METHODS AND RESULTS: Male rabbits were fed a 2% cholesterol diet
      together with red wine (12.5% vol, 5 mL/kg body wt per day; n=7), white wine
      (13.3% vol, 5 mL/kg body wt per day; n=7), or no wine as a control (n=8) for 6
      weeks. A balloon injury of the abdominal aorta was performed at the end of the
      third week. Abdominal aortas were harvested at the end of 6 weeks. Neointimal
      hyperplasia was measured morphometrically. MCP-1 expression was determined by
      Northern blot, in situ hybridization, and immunohistochemistry. Rabbits fed red
      wine had significantly less neointimal hyperplasia than did control rabbits
      (intima/media area ratio 0.59+/-0.05 [red wine group] versus 0.79+/-0.07 [control
      group], P<0.05). However, rabbits fed white wine showed a trend (but not
      significant) toward less intimal response compared with control rabbits
      (intima/media area ratio 0.65+/-0.04 [white wine group] versus 0.79+/-0.07
      [control group], P=0.165). Both red wine and white wine significantly reduced MCP
      1 mRNA and protein expression in the aorta. CONCLUSIONS: Long-term consumption of
      red wine and white wine inhibits MCP-1 expression, and in the small number of
      animals studied, red wine modestly reduces neointimal hyperplasia. Since red wine
      exhibits higher antioxidant capacity than does white wine, the decreased intimal
      response might be partly attributed to its antioxidant effects.

PMID- 10578001
TI  - Classic preconditioning decreases the harmful accumulation of nitric oxide during
      ischemia and reperfusion in rat hearts.
AB  - BACKGROUND: The role of NO in the mechanism of preconditioning is not understood.
      Therefore, we studied the effect of preconditioning and subsequent
      ischemia/reperfusion on myocardial NO content in the presence of an NO synthase
      (NOS) inhibitor. METHODS AND RESULTS: Isolated working rat hearts were subjected
      to preconditioning protocols of 3 intermittent periods of rapid pacing or no-flow
      ischemia of 5 minutes' duration each followed by a test 30 minutes of global no
      flow ischemia and 15 minutes of reperfusion. Test ischemia/reperfusion resulted
      in a deterioration of myocardial function and a considerable increase in cardiac
      NO content as assessed by electron spin resonance. Preconditioning improved
      postischemic myocardial function and markedly decreased test ischemia/reperfusion
      induced NO accumulation. In the presence of 4.6 micromol/L N(G)-nitro-L-arginine
      (LNA), basal cardiac NO content decreased significantly, although test
      ischemia/reperfusion-induced functional deterioration and NO accumulation were
      not affected in nonpreconditioned hearts. However, the protective effects of
      preconditioning on both test ischemia/reperfusion-induced functional depression
      and NO accumulation were abolished. When 4.6 micromol/L LNA was administered
      after preconditioning, it failed to block the effect of preconditioning. In the
      presence of 46 micromol/L LNA, ischemia/reperfusion-induced NO accumulation was
      significantly decreased and postischemic myocardial function was improved in
      nonpreconditioned hearts. CONCLUSIONS: Our results show that (1) although NO
      synthesis by the heart is necessary to trigger classic preconditioning,
      preconditioning in turn attenuates the accumulation of NO during
      ischemia/reperfusion, and (2) blockade of ischemia/reperfusion-induced
      accumulation of cardiac NO by preconditioning or by an appropriate concentration
      of NOS inhibitor alleviates ischemia/reperfusion injury as demonstrated by
      enhanced postischemic function.

PMID- 10578002
TI  - Resistance artery mechanics, structure, and extracellular components in
      spontaneously hypertensive rats : effects of angiotensin receptor antagonism and
      converting enzyme inhibition.
AB  - BACKGROUND: Altered vascular mechanics resulting from changes in collagen and
      integrins may influence resistance artery structure and function and, therefore,
      peripheral resistance and blood pressure in spontaneously hypertensive rats
      (SHR). METHODS AND RESULTS: Effects of age, angiotensin-converting enzyme
      inhibition (fosinopril, 10 to 30 mg/kg per day), and AT(1)-receptor antagonism
      (irbesartan, 50 mg/kg per day) on vascular structure, mechanics, and composition
      were assessed in SHR. Systolic blood pressure was elevated in young SHR (130+/-2
      mm Hg) compared with Wistar-Kyoto (WKY) rats (106+/-2 mm Hg). In adult SHR, the
      rise in systolic blood pressure (44+/-3 mm Hg) was blunted by fosinopril (18+/-1
      mm Hg) and irbesartan (9+/-3 mm Hg). Lumen diameter of mesenteric resistance
      arteries was smaller and media/lumen ratio was greater in young and adult SHR
      versus WKY rats. Growth index was 24% in untreated adult SHR versus WKY rats;
      these values were -35% for fosinopril-treated and -29% for irbesartan-treated SHR
      versus untreated SHR. Isobaric wall stiffness was normal despite increased
      stiffness of wall components in adult SHR vessels. Irbesartan partially prevented
      stiffening of wall components in SHR. The collagen/elastin ratio was greater in
      adult SHR vessels (6.5+/-1.3) than in WKY (3.2+/-0.4) vessels. Expression of
      alpha(v)beta(3) and alpha(5)beta(1) integrins was increased in SHR aged 20 versus
      6 weeks. Expression of alpha(5)beta(1) integrins was lower in young SHR, and
      alpha(v)beta(3) integrins were overexpressed in adult SHR versus WKY rats.
      Irbesartan and fosinopril attenuated differences in the collagen/elastin ratio
      and integrin expression. CONCLUSIONS: Wall components of mesenteric resistance
      arteries stiffen with age in SHR. Interrupting the renin-angiotensin system has
      normalizing effects on integrin expression and composition, stiffness, and growth
      of the arterial wall.

PMID- 10578003
TI  - Electrophysiological effects of dronedarone (SR33589), a noniodinated benzofuran
      derivative, in the rabbit heart : comparison with amiodarone.
AB  - BACKGROUND: To overcome the side effects of amiodarone (AM), its noniodinated
      analogue, dronedarone (SR), was synthesized. In this study, its
      electrophysiological effects were compared with those of AM in rabbit hearts.
      METHODS AND RESULTS: Five animal groups (n=7 each) for 3 weeks received daily
      oral treatment of 1 of these regimens: (1) control, vehicle only; (2) AM 50 mg/kg
      (AM50); (3) AM 100 mg/kg (AM100); (4) SR 50 mg/kg (SR50); and (5) SR 100 mg/kg
      (SR100). ECGs were recorded before drug and at 3 weeks of drug before euthanasia.
      Action potentials were recorded from isolated papillary muscle and sinoatrial
      node by microelectrode techniques. The short-term effects were studied in
      controls (n=5) at various concentrations of SR (0 to 10 micromol/L) in tissue
      bath. Action potential duration at 50% (APD(50)) and 90% (APD(90)) repolarization
      and upstroke dV/dt (V(max)) at various cycle lengths were compared by ANOVA with
      repeated measures. Compared with control, AM and SR increased RR, QT, and QTc
      intervals (P<0.0001 for all). Ventricular APD(50) and APD(90) were lengthened by
      20% to 49% as a function of dose (P<0.005 to <0.0001) and cycle length (P<0.001).
      SR100 effects were greater than those of AM100 (P<0.002). V(max) was decreased by
      both AM100 (P<0.0001) and SR100 (P<0.01). Sinoatrial node automaticity was slowed
      in treated groups compared with that of the control group (P<0.0001 for all).
      CONCLUSIONS: The electrophysiological effects of dronedarone are similar to those
      of AM but more potent, despite deletion of iodine from its molecular structure, a
      finding of importance for the development of future class III antiarrhythmic
      compounds.

PMID- 10578004
TI  - Images in cardiovascular medicine. Evolution of rapid middle cerebral artery
      recanalization during intravenous thrombolysis for acute ischemic stroke.

PMID- 10578005
TI  - AHA scientific statement. Magnetic resonance angiography : update on applications
      for extracranial arteries.

PMID- 10578006
TI  - Glucose-insulin-potassium use in acute myocardial infarction.

PMID- 10578007
TI  - Glucose-insulin-potassium use in acute myocardial infarction.

PMID- 10578008
TI  - Optimal dosage of insulin and glucose in glucose-insulin-potassium treatment of
      acute myocardial infarction remains to Be established

PMID- 10578009
TI  - Myocardial gene transfer for patients with myocardial ischemia.

PMID- 10578010
TI  - Angiogenesis for treatment of ischemic heart disease: should we worry about
      progression of atherosclerosis?

PMID- 10578011
TI  - Recovery of coronary flow and left ventricular function after abciximab.

PMID- 10578012
TI  - Volume-sensitive K(+)/Cl(-) cotransport in rabbit erythrocytes. Analysis of the
      rate-limiting activation and inactivation events.
AB  - The kinetics of activation and inactivation of K(+)/Cl(-) cotransport (KCC) have
      been measured in rabbit red blood cells for the purpose of determining the
      individual rate constants for the rate-limiting activation and inactivation
      events. Four different interventions (cell swelling, N-ethylmaleimide [NEM], low
      intracellular pH, and low intracellular Mg(2+)) all activate KCC with a single
      exponential time course; the kinetics are consistent with the idea that there is
      a single rate-limiting event in the activation of transport by all four
      interventions. In contrast to LK sheep red cells, the KCC flux in Mg(2+)-depleted
      rabbit red cells is not affected by cell volume. KCC activation kinetics were
      examined in cells pretreated with NEM at 0 degrees C, washed, and then incubated
      at higher temperatures. The forward rate constant for activation has a very high
      temperature dependence (E(a) approximately 32 kCal/mol), but is not affected
      measurably by cell volume. Inactivation kinetics were examined by swelling cells
      at 37 degrees C to activate KCC, and then resuspending at various osmolalities
      and temperatures to inactivate most of the transporters. The rate of transport
      inactivation increases steeply as cell volume decreases, even in a range of
      volumes where nearly all the transporters are inactive in the steady state. This
      finding indicates that the rate-limiting inactivation event is strongly affected
      by cell volume over the entire range of cell volumes studied, including normal
      cell volume. The rate-limiting inactivation event may be mediated by a protein
      kinase that is inhibited, either directly or indirectly, by cell swelling, low
      Mg(2+), acid pH, and NEM.

PMID- 10578013
TI  - Activation of Ca(2+)-dependent K(+) channels contributes to rhythmic firing of
      action potentials in mouse pancreatic beta cells.
AB  - We have applied the perforated patch whole-cell technique to beta cells within
      intact pancreatic islets to identify the current underlying the glucose-induced
      rhythmic firing of action potentials. Trains of depolarizations (to simulate
      glucose-induced electrical activity) resulted in the gradual (time constant: 2.3
      s) development of a small (<0.8 nS) K(+) conductance. The current was dependent
      on Ca(2+) influx but unaffected by apamin and charybdotoxin, two blockers of
      Ca(2+)-activated K(+) channels, and was insensitive to tolbutamide (a blocker of
      ATP-regulated K(+) channels) but partially (>60%) blocked by high (10-20 mM)
      concentrations of tetraethylammonium. Upon cessation of electrical stimulation,
      the current deactivated exponentially with a time constant of 6.5 s. This is
      similar to the interval between two successive bursts of action potentials. We
      propose that this Ca(2+)-activated K(+) current plays an important role in the
      generation of oscillatory electrical activity in the beta cell.

PMID- 10578014
TI  - Evidence that the product of the human X-linked CGD gene, gp91-phox, is a voltage
      gated H(+) pathway.
AB  - Expression of gp91-phox in Chinese hamster ovary (CHO91) cells is correlated with
      the presence of a voltage-gated H(+) conductance. As one component of NADPH
      oxidase in neutrophils, gp91-phox is responsible for catalyzing the production of
      superoxide (O(2).(2)). Suspensions of CHO91 cells exhibit arachidonate
      activatable H(+) fluxes (Henderson, L.M., G. Banting, and J.B. Chappell. 1995. J.
      Biol. Chem. 270:5909-5916) and we now characterize the electrical properties of
      the pathway. Voltage-gated currents were recorded from CHO91 cells using the
      whole-cell configuration of the patch-clamp technique under conditions designed
      to exclude a contribution from ions other than H(+). As in other voltage-gated
      proton currents (Byerly, L., R. Meech, and W. Moody. 1984. J. Physiol. 351:199
      216; DeCoursey, T.E., and V.V. Cherny. 1993. Biophys. J. 65:1590-1598), a lowered
      external pH (pH(o)) shifted activation to more positive voltages and caused the
      tail current reversal potential to shift in the manner predicted by the Nernst
      equation. The outward currents were also reversibly inhibited by 200 microM zinc.
      Voltage-gated currents were not present immediately upon perforating the cell
      membrane, but showed a progressive increase over the first 10-20 min of the
      recording period. This time course was consistent with a gradual shift in
      activation to more negative potentials as the pipette solution, pH 6.5,
      equilibrated with the cell contents (reported by Lucifer yellow included in the
      patch pipette). Use of the pH-sensitive dye 2'7' bis-(2-carboxyethyl)-5(and 6)
      carboxyfluorescein (BCECF) suggested that the final intracellular pH (pH(i)) was
      approximately 6.9, as though pH(i) was largely determined by endogenous cellular
      regulation. Arachidonate (20 microM) increased the amplitude of the currents by
      shifting activation to more negative voltages and by increasing the maximally
      available conductance. Changes in external Cl(-) concentration had no effect on
      either the time scale or the appearance of the currents. Examination of whole
      cell currents from cells expressing mutated versions of gp91-phox suggest that:
      (a) voltage as well as arachidonate sensitivity was retained by cells with only
      the NH(2)-terminal 230 amino acids, (b) histidine residues at positions 111, 115,
      and 119 on a putative membrane-spanning helical region of the protein contribute
      to H(+) permeation, (c) histidine residues at positions 111 and 119 may
      contribute to voltage gating, (d) the histidine residue at position 115 is
      functionally important for H(+) selectivity. Mechanisms of H(+) permeation
      through gp91-phox include the possible protonation/deprotonation of His-115 as it
      is exposed alternatively to the interior and exterior faces of the cell membrane
      (see Starace, D.M., E. Stefani, and F. Bezanilla. 1997. Neuron. 19:1319-1327) and
      the transfer of protons across an "H-X-X-X-H-X-X-X-H" motif lining a conducting
      pore.

PMID- 10578015
TI  - Rapid activation of the cardiac ryanodine receptor by submillisecond calcium
      stimuli.
AB  - The local control concept of excitation-contraction coupling in the heart
      postulates that the activity of the sarcoplasmic reticulum ryanodine receptor
      channels (RyR) is controlled by Ca(2+) entry through adjoining sarcolemmal single
      dihydropyridine receptor channels (DHPRs). One unverified premise of this
      hypothesis is that the RyR must be fast enough to track the brief (<0.5 ms)
      Ca(2+) elevations accompanying single DHPR channel openings. To define the
      kinetic limits of effective trigger Ca(2+) signals, we recorded activity of
      single cardiac RyRs in lipid bilayers during rapid and transient increases in
      Ca(2+) generated by flash photolysis of DM-nitrophen. Application of such Ca(2+)
      spikes (amplitude approximately 10-30 microM, duration approximately 0.1-0.4 ms)
      resulted in activation of the RyRs with a probability that increased steeply
      (apparent Hill slope approximately 2.5) with spike amplitude. The time constants
      of RyR activation were 0.07-0.27 ms, decreasing with spike amplitude. To fit the
      rising portion of the open probability, a single exponential function had to be
      raised to a power n approximately 3. We show that these data could be adequately
      described with a gating scheme incorporating four sequential Ca(2+)-sensitive
      closed states between the resting and the first open states. These results
      provide evidence that brief Ca(2+) triggers are adequate to activate the RyR, and
      support the possibility that RyR channels are governed by single DHPR openings.
      They also provide evidence for the assumption that RyR activation requires
      binding of multiple Ca(2+) ions in accordance with the tetrameric organization of
      the channel protein.

PMID- 10578016
TI  - Cystic fibrosis transmembrane conductance regulator. Physical basis for lyotropic
      anion selectivity patterns.
AB  - The cystic fibrosis transmembrane conductance regulator (CFTR) Cl channel
      exhibits lyotropic anion selectivity. Anions that are more readily dehydrated
      than Cl exhibit permeability ratios (P(S)/P(Cl)) greater than unity and also bind
      more tightly in the channel. We compared the selectivity of CFTR to that of a
      synthetic anion-selective membrane [poly(vinyl chloride)-tridodecylmethylammonium
      chloride; PVC-TDMAC] for which the nature of the physical process that governs
      the anion-selective response is more readily apparent. The permeability and
      binding selectivity patterns of CFTR differed only by a multiplicative constant
      from that of the PVC-TDMAC membrane; and a continuum electrostatic model
      suggested that both patterns could be understood in terms of the differences in
      the relative stabilization of anions by water and the polarizable interior of the
      channel or synthetic membrane. The calculated energies of anion-channel
      interaction, derived from measurements of either permeability or binding, varied
      as a linear function of inverse ionic radius (1/r), as expected from a Born-type
      model of ion charging in a medium characterized by an effective dielectric
      constant of 19. The model predicts that large anions, like SCN, although they
      experience weaker interactions (relative to Cl) with water and also with the
      channel, are more permeant than Cl because anion-water energy is a steeper
      function of 1/r than is the anion-channel energy. These large anions also bind
      more tightly for the same reason: the reduced energy of hydration allows the net
      transfer energy (the well depth) to be more negative. This simple selectivity
      mechanism that governs permeability and binding acts to optimize the function of
      CFTR as a Cl filter. Anions that are smaller (more difficult to dehydrate) than
      Cl are energetically retarded from entering the channel, while the larger (more
      readily dehydrated) anions are retarded in their passage by "sticking" within the
      channel.

PMID- 10578018
TI  - Changes in weight, fluid balance and serum albumin in patients referred for
      nutritional support.
AB  - BACKGROUND AND AIMS: Starvation and injury impair the excretion of an excess
      sodium and water load, resulting in oedema and hypoalbuminaemia, which may have
      adverse effects on gastrointestinal physiology. We have retrospectively assessed
      clinical signs and fluid balance in 44 adult patients referred for nutritional
      support for >== 10 days. METHODS: Clinical evidence of oedema was noted.
      Oedematous patients were managed with a low sodium (0-50 mmol/day), low volume (2
      l/day) feed. Some also received albumin and a diuretic. Body weight was recorded
      daily and serum albumin three times weekly. The lowest recorded weight during
      nutritional support and the weight at the time of discharge were correlated with
      serum albumin concentration. RESULTS: The 21 patients with oedema had acute
      surgical conditions and complications such as sepsis while the 23 non-oedematous
      patients had chronic conditions with gradual nutritional depletion. During
      nutritional support the mean (SEM) weight in kg of the oedematous patients fell
      from 79.3 (2.9) to 69.2 (3.2) (P>> 0.00001) and subsequently rose to 70.1 (3.2)
      (P= 0.005). Corresponding values for the non-oedematous patients were 61.4 (4.0),
      60.2 (3.9) (P>> 0.05) and 61.2 (3.7) (P= 0.002) respectively. Weight reduction
      reflected negative salt and water balance and correlated with a rise in serum
      albumin (r = -0.61 for oedematous and r = -0.65 for non-oedematous patients)
      largely reflecting reversal of previous dilution. CONCLUSION: These findings have
      important implications for the salt and water content of perioperative fluid and
      nutritional prescriptions. They also emphasize the dilutional component of
      hypoalbuminaemia in these patients.

PMID- 10578019
TI  - Observations in energy and macronutrient intake during prolonged bed-rest in a
      head-down tilt position.
AB  - OBJECTIVE: to report observations in energy and macronutrient intakes, and body
      weight during prolonged bed-rest in a head down tilt (HDT) position. DESIGN: open
      study, each subject was his own control, and was studied during 14 days of
      baseline, 42 days of -6 degrees HDT bed-rest, and 12 days of recovery. SUBJECTS:
      eight healthy young man were recruited, one dropped out. METHODS: energy and
      macronutrient content of the diet were calculated from weighed amounts of food
      consumed and French food composition tables. RESULTS: body weight declined during
      HDT (74.0+/-3.2 to 71.8+/-3.2 kg, P<< 0.001) and increased during recovery
      (72.7+/-3.2 kg, P<< 0. 001). Energy intake decreased during HDT (by 17% after 4-5
      weeks) and increased during recovery but remained lower than during baseline (P<<
      0.001). During HDT fat intake, expressed by a percentage of energy, decreased
      (P<< 0.01) while carbohydrate increased (P= 0.04); protein intake did not change
      (P= 0.08). The reverse trends were observed during recovery. CONCLUSIONS: the
      present study reports a spontaneous reduction in energy and relative fat intake
      during prolonged HDT bed rest. We believe that these findings have implications
      for the clinical setting.

PMID- 10578020
TI  - Substrate fuel kinetics in enterally fed trauma patients supplemented with
      ornithine alpha ketoglutarate.
AB  - BACKGROUND: Ornithine-alpha-ketoglutarate (OKG) is a promising anticatabolic
      agent and the mechanisms of its potential use in trauma patients are not clearly
      understood. AIM: To determine the altered whole-body protein, lipid and glucose
      substrate kinetics in trauma victims in the early flow-phase of injury when they
      were fed enterally with or without OKG. METHODS: Fourteen adult, multiple trauma
      patients who were highly catabolic and hypermetabolic were studied. Whole-body
      protein ((15)N glycine), fat (2 stage glycerol infusion) and glucose
      ((3H)glucose) kinetics (t/o) and plasma parameters were measured (A) within 48-60
      h after injury before starting nutritional support and then (B) after 4 days of
      enteral feeding. Group A (n=7, control) received a defined enteral formula (Two
      Cal HN, 1.4 times BEE calories) and Group B (n=7, OKG) received same
      isonitrogenous diet replacing 2.62gN/d from the enteral diet by OKG-N (20g
      OKG/d). RESULTS (Mean+/-SEM): Protein turnover is significantly (P<==0.05)
      increased in OKG treated patients (4.68+/-0. 15 vs 3.90+/-0.23, gP/kg/day) and
      glycerol turnover is decreased (0. 87+/-0.16 vs 1.46+/-0.16, micro mole/kg/min).
      Glucose turnover is not changed. Significant (P<== 0.05) increases in circulating
      plasma levels of hormones (insulin, 44.2+/-8.4 vs 15.7+/-5.0 ulU/ml, growth
      hormone 1.68+/-0.33 vs 0.92+/-0.16, ng/ml and IGF-1, 106+/-13 vs 75+/-18, ng/ml)
      and free amino acids (glutamine, 383+/-20 vs 306+/-25, Proline, 203+/-18 vs 146+/
      13 and ornithine, 164+/-27 vs 49+/-5 micro mole/l) are found in OKG treated
      patients, compared to non OKG patients. CONCLUSION: Increased hormone secretion
      due to OKG and the rapid interaction between the metabolites of OKG at the
      intermediary metabolism level may be responsible for altered substrate fuel
      kinetics.

PMID- 10578017
TI  - pH-dependent inhibition of voltage-gated H(+) currents in rat alveolar epithelial
      cells by Zn(2+) and other divalent cations.
AB  - Inhibition by polyvalent cations is a defining characteristic of voltage-gated
      proton channels. The mechanism of this inhibition was studied in rat alveolar
      epithelial cells using tight-seal voltage clamp techniques. Metal concentrations
      were corrected for measured binding to buffers. Externally applied ZnCl(2)
      reduced the H(+) current, shifted the voltage-activation curve toward positive
      potentials, and slowed the turn-on of H(+) current upon depolarization more than
      could be accounted for by a simple voltage shift, with minimal effects on the
      closing rate. The effects of Zn(2+) were inconsistent with classical voltage
      dependent block in which Zn(2+) binds within the membrane voltage field. Instead,
      Zn(2+) binds to superficial sites on the channel and modulates gating. The
      effects of extracellular Zn(2+) were strongly pH(o) dependent but were
      insensitive to pH(i), suggesting that protons and Zn(2+) compete for external
      sites on H(+) channels. The apparent potency of Zn(2+) in slowing activation was
      approximately 10x greater at pH(o) 7 than at pH(o) 6, and approximately 100x
      greater at pH(o) 6 than at pH(o) 5. The pH(o) dependence suggests that Zn(2+),
      not ZnOH(+), is the active species. Evidently, the Zn(2+) receptor is formed by
      multiple groups, protonation of any of which inhibits Zn(2+) binding. The
      external receptor bound H(+) and Zn(2+) with pK(a) 6.2-6.6 and pK(M) 6.5, as
      described by several models. Zn(2+) effects on the proton chord conductance
      voltage (g(H)-V) relationship indicated higher affinities, pK(a) 7 and pK(M) 8.
      CdCl(2) had similar effects as ZnCl(2) and competed with H(+), but had lower
      affinity. Zn(2+) applied internally via the pipette solution or to inside-out
      patches had comparatively small effects, but at high concentrations reduced H(+)
      currents and slowed channel closing. Thus, external and internal zinc-binding
      sites are different. The external Zn(2+) receptor may be the same modulatory
      protonation site(s) at which pH(o) regulates H(+) channel gating.

PMID- 10578021
TI  - Multivitamin administration before ischemia reduces ischemia-reperfusion injury
      in rabbit skeletal muscle.
AB  - This study investigated the effect of a multivitamin preparation administered
      before ischemia or before reperfusion, on ischemia-reperfusion (I/R) injury of
      skeletal muscle. An in vivo hindlimb skeletal muscle I/R model (2.5 h/2 h) was
      carried out on adult New Zealand white rabbits. Animals used as I/R models were
      treated with a multivitamin preparation (0.4 ml/kg bw i.v. bolus), containing
      alpha-tocopherol, ascorbic acid, retinol, vitamin B complex, 30 min before
      starting ischemia (group MV(isc)) or 5 min before reperfusion (group MV(rep)) and
      compared to animals with I/R without treatment (group IR) and sham operated
      animals (group SHAM). Interstitial edema (muscle interfiber area, %MIFA) and
      changes in microvessel size (microvessel cross sectional area, MVCSA, microm(2))
      were measured. Plasma malondialdehyde concentrations (MDA-TBA, nmol/ml) served as
      a measure of lipid peroxidation. After 2h of reperfusion, ischemia-reperfusion
      developed a significant microvascular constriction and an interstitial edema (IR,
      vs SHAM;P<< 0.01), but administration of antioxidative vitamins before the onset
      of ischemia reduced microvascular constriction and edema formation (P<< 0.05 vs
      IR group). In a similar manner, administration of vitamins before ischemia
      lowered plasma MDA-TBA levels as compared to the untreated group during
      reperfusion (p<< 0. 05). In animals treated with vitamins before reperfusion, the
      biochemical and morphological results showed no differences as compared to the
      untreated group. Antioxidative treatment with a multivitamin preparation exerted
      a beneficial effect on I/R injury of skeletal muscle when the aforementioned
      vitamins were administered before ischemia but not before the onset of
      reperfusion.

PMID- 10578022
TI  - Improvement in lipid and haemostasis patterns after Helicobacter pylori infection
      eradication in type 1 diabetic patients.
AB  - Helicobacter pylori has been implicated in the cardiovascular risk of diabetic
      patients. The aim of our study was to investigate whether the Helicobacter pylori
      infection plays a role in the lipid and haemostasis patterns of type 1 diabetic
      patients. Twenty nine patients with type 1 diabetes mellitus and H. pylori
      infection were enrolled (Chlamydia pneumoniae negative). The H. pylori infection
      status was assessed by serology and urease breath test. In all patients levels of
      total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol, lipoprotein
      (a) (Lpa) C reactive protein (CRP), fibrinogen, thrombin/antithrombin III complex
      (TAT), plasminogen activator inhibitor type 1(PAI-1), tissue plasminogen
      activator (t-PA) and von Willebrand antigen were measured. All patients were
      evaluated before and after H. pylori eradicating treatment with amoxicillin,
      clarithromycin and omeprazole. Twenty two patients were eradicated and seven
      remained infected. In H. pylori eradicated patients, HDL cholesterol increased
      (59.7+/-18.9 mg/dl vs 65.2+/-15. 9 mg/dl, P << 0.05), after treatment. After H.
      pylori eradication, the levels of CRP and TAT decreased (48+/-0.7 ng/l vs 3.3+/
      0.4 ng/l;P << 0.05), (27.7+/-44.7 microg/ml vs 2.1+/-1.4 microg/ml, P << 0.05),
      respectively. The decrease in TAT was higher in the group of H. pylori (+)
      patients with higher levels of TAT (TAT >> 20 ng/ml, 92.8+/-41.6 ng/ml vs 1.9+/
      2.0 ng/ml, P << 0.005; TAT 4Eth 20 ng/ml; 10.1+/-5.2 ng/ml vs 2.2+/-0.6 ng/ml, P
      << 0.05). These changes did not occur in patients without H. pylori eradication.
      Eradication of H. pylori infection in type 1 diabetic patients modifies some
      parameters of lipid and haemostasis patterns, (increase of HDL-cholesterol,
      reduction of Lpa and decrease of CRP and TAT) and so contributes to improvement
      of cardiovascular risk factors in these patients.

PMID- 10578023
TI  - Prospective audits of quality of PEM recognition and nutritional support in
      critically ill elderly patients.
AB  - BACKGROUND AND AIMS: Undereating is a frequent concern in acute care geriatric
      settings and is supposed to worsen the outcomes of the underlying diseases, while
      the quality of nutritional support could be improved. METHODS: Two consecutive
      and prospective audits (A and B) with team training over a 1 year period
      investigated the quality of malnutrition recognition and nutritional support and
      outcomes in immobilized, critically ill elderly subjects. RESULTS: Audit A
      included 170 patients (86.3+/-6.1 years old) and audit B, 232 patients (86.3+/
      6.3), respectively 20.6% and 31.4% of the hospitalized population.
      Misclassifications occurred in A in 54.0% compared to 34.05% in B (P < 0.001).
      32.6% in A versus 86.9% in B adequately received oral supplements (P = 0.02).
      Significant risk factors for the adverse outcomes in the combined two audits
      were: dementia (RR: 1.8, 95%CI: 1.0 to 3.0, P= 0.04) and dehydration (RR: 2.0,
      95%CI:1.0 to 4.1, P= 0.05) for pressure ulcer incidence; stroke (RR: 8.8, 95%CI:
      4.8 to 16.0, P < 0.001) for pressure ulcer prevalence at discharge; neoplasms
      (RR: 1.1, 95%CI: 1.0 to 1.2, P = 0.02) for nosocomial infections; bladder
      indwelling for urinary tract infections (RR: 4.8, 95%CI: 2.9 to 7.7, P<< 0.001);
      swallowing problems for pulmonary infections (RR: 5.4, 95%CI: 2.8 to 10.5, P <
      0.001); venous indwelling for septicaemia (RR: 5.4, 95%CI: 1.3 to 23. 3, P=
      0.02). However, after adjustment on significant risk factors, the outcome rate
      was similar in audit B: death rate: A (15.6%), B (14.2%); length of stay: A
      (17.3+/-10.4 days), B (17.4+/-10.0); pressure ulcer incidence: A (26.4%), B
      (20.2%), (83% were erythema); pressure ulcer prevalence at discharge: A (14.7%),
      B (10.3%), (40% were erythema); nosocomial infections: A (26.4%), B (19.0%).
      CONCLUSION: The improvement of malnutrition recognition and nutritional support
      was not followed by a perceptible decrease in adverse outcome rate, this latter
      being mainly related to the underlying conditions of these critically ill elderly
      patients.

PMID- 10578024
TI  - Nutritional status, insulin-like growth factor-1 and quality of life in elderly
      women with hip fractures.
AB  - AIM: To evaluate nutritional status and its relation to cognitive and physical
      function and quality of life in elderly female patients with hip fractures.
      METHODS: Nutritional status was assessed in 42 women (80+/-7 years old) using the
      body mass index (BMI), triceps skin fold, arm muscle circumference and serum
      levels of insulin-like growth factor (IGF-1) and its binding protein (BP) IGFBP
      1. Handgrip strength was measured. The Short Portable Mental Status Questionnaire
      was used to assess cognitive function and the Nottingham Health Profile to asses
      quality of life. RESULTS: Low BMI (<== 20) and reduced IGF-1 and IGFBP-1 levels
      were detected in 50% of the patients. BMI correlated with IGF-1 (p<< 0.02) and
      with hand grip strength (P<< 0.001). Hand grip strength correlated with arm
      muscle circumference (P<< 0.05). Cognitive dysfunction was detected in 18% of the
      patients, and a correlation was found between cognitive function and BMI (P<<
      0.01). The Nottingham Health Profile assessment indicated a lower quality of life
      in underweight patients as compared to others (P<< 0.05). CONCLUSIONS: Half of
      the elderly women with hip fractures displayed signs of protein-energy
      malnutrition. Underweight was associated with reduced serum levels of IGF-1,
      muscle fatigue, cognitive dysfunction and a low quality of life rating, i.e. a
      cluster of factors which may unfavourably influence the postoperative course in a
      large proportion of hip fracture patients.

PMID- 10578025
TI  - Nutritional assessment in head injured patients through the study of rapid
      turnover visceral proteins.
AB  - BACKGROUND & AIMS: Nutritional monitoring of rapid turnover visceral protein is
      important in the recognition of malnutrition in patients admitted to the
      Intensive Care Unit (ICU). We studied prealbumin and retinol-binding protein in
      patients who received three different kinds of artificial nutrition in order to
      evaluate the appropriateness of artificial nutrition. METHODS: 45 consecutive
      head injury patients received enteral (Group A), parenteral (Group B) or both
      enteral and parenteral nutrition (Group C) at random. We considered these
      parameters: prealbumin, retinol binding protein and nitrogen balance before (T1),
      after 3 (T2), 7 (T3) and 11 (T4) days after the beginning of study. Statistical
      analysis was performed with Kruskal-Wallis test and Bonferroni's t -test.
      RESULTS: Plasma prealbumin and Retinol binding protein (RBP) showed an increasing
      of basal values during the study period in all groups (<< 0.0001) and more
      significantly in group A (Enteral nutrition P < 0. 001 vs Total parenteral
      nutrition (TPN) and Enteral P<< 0.01 vs Enteral and parenteral nutrition).
      CONCLUSION: Data obtained in the present study indicate that a laboratory is
      essential for monitoring nutritional assessment and for checking the
      appropriateness of nutritional therapy. We found prealbumin to be the most
      sensitive measure and found it to be the test of choice for early assessment and
      intervention.

PMID- 10578026
TI  - Scalability problems of simple genetic algorithms.
AB  - Scalable evolutionary computation has become an intensively studied research
      topic in recent years. The issue of scalability is predominant in any field of
      algorithmic design, but it became particularly relevant for the design of
      competent genetic algorithms once the scalability problems of simple genetic
      algorithms were understood. Here we present some of the work that has aided in
      getting a clear insight in the scalability problems of simple genetic algorithms.
      Particularly, we discuss the important issue of building block mixing. We show
      how the need for mixing places a boundary in the GA parameter space that,
      together with the boundary from the schema theorem, delimits the region where the
      GA converges reliably to the optimum in problems of bounded difficulty. This
      region shrinks rapidly with increasing problem size unless the building blocks
      are tightly linked in the problem coding structure. In addition, we look at how
      straightforward extensions of the simple genetic algorithm-namely elitism,
      niching, and restricted mating are not significantly improving the scalability
      problems.

PMID- 10578027
TI  - FDA - a scalable evolutionary algorithm for the optimization of additively
      decomposed functions.
AB  - The Factorized Distribution Algorithm (FDA) is an evolutionary algorithm which
      combines mutation and recombination by using a distribution. The distribution is
      estimated from a set of selected points. In general, a discrete distribution
      defined for n binary variables has 2(n) parameters. Therefore it is too expensive
      to compute. For additively decomposed discrete functions (ADFs) there exist
      algorithms which factor the distribution into conditional and marginal
      distributions. This factorization is used by FDA. The scaling of FDA is
      investigated theoretically and numerically. The scaling depends on the ADF
      structure and the specific assignment of function values. Difficult functions on
      a chain or a tree structure are solved in about O(n radical n) operations. More
      standard genetic algorithms are not able to optimize these functions. FDA is not
      restricted to exact factorizations. It also works for approximate factorizations
      as is shown for a circle and a grid structure. By using results from Bayes
      networks, FDA is extended to LFDA. LFDA computes an approximate factorization
      using only the data, not the ADF structure. The scaling of LFDA is compared to
      the scaling of FDA.

PMID- 10578028
TI  - Linkage identification by non-monotonicity detection for overlapping functions.
AB  - This paper presents the linkage identification by non-monotonicity detection
      (LIMD) procedure and its extension for overlapping functions by introducing the
      tightness detection (TD) procedure. The LIMD identifies linkage groups directly
      by performing order-2 simultaneous perturbations on a pair of loci to detect
      monotonicity/non-monotonicity of fitness changes. The LIMD can identify linkage
      groups with at most order of k when it is applied to O(2(k)) strings. The TD
      procedure calculates tightness of linkage between a pair of loci based on the
      linkage groups obtained by the LIMD. By removing loci with weak tightness from
      linkage groups, correct linkage groups are obtained for overlapping functions,
      which were considered difficult for linkage identification procedures.

PMID- 10578029
TI  - Scaling of program fitness spaces.
AB  - We investigate the distribution of fitness of programs concentrating on those
      represented as parse trees and, particularly, how such distributions scale with
      respect to changes in the size of the programs. By using a combination of
      enumeration and Monte Carlo sampling on a large number of problems from three
      very different areas, we suggest that, in general, once some minimum size
      threshold has been exceeded, the distribution of performance is approximately
      independent of program length. We proof this for both linear programs and simple
      side effect free parse trees. We give the density of solutions to the parity
      problems in program trees which are composed of XOR building blocks. Limited
      experiments with programs including side effects and iteration suggest a similar
      result may also hold for this wider class of programs.

PMID- 10578032
TI  - Introduction to the special issue: scalable evolutionary computation

PMID- 10578030
TI  - On the scalability of parallel genetic algorithms.
AB  - This paper examines the scalability of several types of parallel genetic
      algorithms (GAs). The objective is to determine the optimal number of processors
      that can be used by each type to minimize the execution time. The first part of
      the paper considers algorithms with a single population. The investigation
      focuses on an implementation where the population is distributed to several
      processors, but the results are applicable to more common master-slave
      implementations, where the population is entirely stored in a master processor
      and multiple slaves are used to evaluate the fitness. The second part of the
      paper deals with parallel GAs with multiple populations. It first considers a
      bounding case where the connectivity, the migration rate, and the frequency of
      migrations are set to their maximal values. Then, arbitrary regular topologies
      with lower migration rates are considered and the frequency of migrations is set
      to its lowest value. The investigationis mainly theoretical, but experimental
      evidence with an additively-decomposable function is included to illustrate the
      accuracy of the theory. In all cases, the calculations show that the optimal
      number of processors that minimizes the execution time is directly proportional
      to the square root of the population size and the fitness evaluation time. Since
      these two factors usually increase as the domain becomes more difficult, the
      results of the paper suggest that parallel GAs can integrate large numbers of
      processors and significantly reduce the execution time of many practical
      applications.

PMID- 10578033
TI  - Detecting and estimating signals in noisy cable structure, I: neuronal noise
      sources.
AB  - In recent theoretical approaches addressing the problem of neural coding, tools
      from statistical estimation and information theory have been applied to quantify
      the ability of neurons to transmit information through their spike outputs. These
      techniques, though fairly general, ignore the specific nature of neuronal
      processing in terms of its known biophysical properties. However, a systematic
      study of processing at various stages in a biophysically faithful model of a
      single neuron can identify the role of each stage in information transfer. Toward
      this end, we carry out a theoretical analysis of the information loss of a
      synaptic signal propagating along a linear, one-dimensional, weakly active cable
      due to neuronal noise sources along the way, using both a signal reconstruction
      and a signal detection paradigm. Here we begin such an analysis by quantitatively
      characterizing three sources of membrane noise: (1) thermal noise due to the
      passive membrane resistance, (2) noise due to stochastic openings and closings of
      voltage-gated membrane channels (NA+ and K+), and (3) noise due to random,
      background synaptic activity. Using analytical expressions for the power spectral
      densities of these noise sources, we compare their magnitudes in the case of a
      patch of membrane from a cortical pyramidal cell and explore their dependence on
      different biophysical parameters.

PMID- 10578034
TI  - Detecting and estimating signals in noisy cable structures, II: information
      theoretical analysis.
AB  - This is the second in a series of articles that seek to recast classical single
      neuron biophysics in information-theoretical terms. Classical cable theory
      focuses on analyzing the voltage or current attenuation of a synaptic signal as
      it propagates from its dendritic input location to the spike initiation zone. On
      the other hand, we are interested in analyzing the amount of information lost
      about the signal in this process due to the presence of various noise sources
      distributed throughout the neuronal membrane. We use a stochastic version of the
      linear one-dimensional cable equation to derive closed-form expressions for the
      second-order moments of the fluctuations of the membrane potential associated
      with different membrane current noise sources: thermal noise, noise due to the
      random opening and closing of sodium and potassium channels, and noise due to the
      presence of "spontaneous" synaptic input. We consider two different scenarios. In
      the signal estimation paradigm, the time course of the membrane potential at a
      location on the cable is used to reconstruct the detailed time course of a
      random, band-limited current injected some distance away. Estimation performance
      is characterized in terms of the coding fraction and the mutual information. In
      the signal detection paradigm, the membrane potential is used to determine
      whether a distant synaptic event occurred within a given observation interval. In
      the light of our analytical results, we speculate that the length of weakly
      active apical dendrites might be limited by the information loss due to the
      accumulated noise between distal synaptic input sites and the soma and that the
      presence of dendritic nonlinearities probably serves to increase dendritic
      information transfer.

PMID- 10578035
TI  - Natural gradient learning for over- and under-complete bases In ICA.
AB  - Independent component analysis or blind source separation is a new technique of
      extracting independent signals from mixtures. It is applicable even when the
      number of independent sources is unknown and is larger or smaller than the number
      of observed mixture signals. This article extends the natural gradient learning
      algorithm to be applicable to these overcomplete and undercomplete cases. Here,
      the observed signals are assumed to be whitened by preprocessing, so that we use
      the natural Riemannian gradient in Stiefel manifolds.

PMID- 10578036
TI  - Combined 5 x 2 cv F test for comparing supervised classification learning
      algorithms.
AB  - Dietterich (1998) reviews five statistical tests and proposes the 5 x 2 cv t test
      for determining whether there is a significant difference between the error rates
      of two classifiers. In our experiments, we noticed that the 5 x 2 cv t test
      result may vary depending on factors that should not affect the test, and we
      propose a variant, the combined 5 x 2 cv F test, that combines multiple
      statistics to get a more robust test. Simulation results show that this combined
      version of the test has lower type I error and higher power than 5 x 2 cv proper.

PMID- 10578037
TI  - Adaptive neural coding dependent on the time-varying statistics of the somatic
      input current.
AB  - It is generally assumed that nerve cells optimize their performance to reflect
      the statistics of their input. Electronic circuit analogs of neurons require
      similar methods of self-optimization for stable and autonomous operation. We here
      describe and demonstrate a biologically plausible adaptive algorithm that enables
      a neuron to adapt the current threshold and the slope (or gain) of its current
      frequency relationship to match the man (or dc offset) and variance (or dynamic
      range or contrast) of the time-varying somatic input current. The adaptation
      algorithm estimates the somatic current signal from the spike train by way of the
      intracellular somatic calcium concentration, thereby continuously adjusting the
      neurons' firing dynamics. This principle is shown to work in an analog VLSI
      designed silicon neuron.

PMID- 10578038
TI  - A reinforcement learning approach to online clustering.
AB  - A general technique is proposed for embedding online clustering algorithms based
      on competitive learning in a reinforcement learning framework. The basic idea is
      that the clustering system can be viewed as a reinforcement learning system that
      learns through reinforcements to follow the clustering strategy we wish to
      implement. In this sense, the reinforcement guided competitive learning (RGCL)
      algorithm is proposed that constitutes a reinforcement-based adaptation of
      learning vector quantization (LVQ) with enhanced clustering capabilities. In
      addition, we suggest extensions of RGCL and LVQ that are characterized by the
      property of sustained exploration and significantly improve the performance of
      those algorithms, as indicated by experimental tests on well-known data sets.

PMID- 10578039
TI  - Replicator equations, maximal cliques, and graph isomorphism.
AB  - We present a new energy-minimization framework for the graph isomorphism problem
      that is based on an equivalent maximum clique formulation. The approach is
      centered around a fundamental result proved by Motzkin and Straus in the mid
      1960s, and recently expanded in various ways, which allows us to formulate the
      maximum clique problem in terms of a standard quadratic program. The attractive
      feature of this formulation is that a clear one-to-one correspondence exists
      between the solutions of the quadratic program and those in the original,
      combinatorial problem. To solve the program we use the so-called replicator
      equations--a class of straightforward continuous- and discrete-time dynamical
      systems developed in various branches of theoretical biology. We show how,
      despite their inherent inability to escape from local solutions, they
      nevertheless provide experimental results that are competitive with those
      obtained using more elaborate mean-field annealing heuristics.

PMID- 10578040
TI  - Independent component analysis: A flexible nonlinearity and decorrelating
      manifold approach.
AB  - Independent component analysis (ICA) finds a linear transformation to variables
      that are maximally statistically independent. We examine ICA and algorithms for
      finding the best transformation from the point of view of maximizing the
      likelihood of the data. In particular, we discuss the way in which scaling of the
      unmixing matrix permits a "static" nonlinearity to adapt to various marginal
      densities. We demonstrate a new algorithm that uses generalized exponential
      functions to model the marginal densities and is able to separate densities with
      light tails. We characterize the manifold of decorrelating matrices and show that
      it lies along the ridges of high-likelihood unmixing matrices in the space of all
      unmixing matrices. We show how to find the optimum ICA matrix on the manifold of
      decorrelating matrices, and as an example we use the algorithm to find
      independent component basis vectors for an ensemble of portraits.

PMID- 10578041
TI  - On the design of BSB neural associative memories using semidefinite programming.
AB  - This article is concerned with the reliable search for optimally performing BSB
      (brain state in a box) neural associative memories given a set of prototype
      patterns to be stored as stable equilibrium points. By converting and/or
      modifying the nonlinear constraints of a known formulation for the synthesis of
      BSB-based associative memories into linear matrix inequalities, we recast the
      synthesis into semidefinite programming problems and solve them by recently
      developed interior point methods. The validity of this approach is illustrated by
      a design example.

PMID- 10578042
TI  - How to design a connectionist holistic parser.
AB  - Connectionist holistic parsing offers a viable and attractive alternative to
      traditional algorithmic parsers. With exposure to a limited subset of grammatical
      sentences and their corresponding parse trees only, a holistic parser is capable
      of learning inductively the grammatical regularity underlying the training
      examples that affects the parsing process. In the past, various connectionist
      parsers have been proposed. Each approach had its own unique characteristics, and
      yet some techniques were shared in common. In this article, various dimensions
      underlying the design of a holistic parser are explored, including the methods to
      encode sentences and parse trees, whether a sentence and its corresponding parse
      tree share the same representation, the use of confluent inference, and the
      inclusion of phrases in the training set. Different combinations of these design
      factors give rise to different holistic parsers. In succeeding discussions, we
      scrutinize these design techniques and compare the performances of a few parsers
      on language parsing, including the confluent preorder parser, the backpropagation
      parsing network, the XERIC parser of Berg (1992), the modular connectionist
      parser of Sharkey and Sharkey (1992), Reilly's (1992) model, and their
      derivatives. Experiments are performed to evaluate their generalization
      capability and robustness. The results reveal a number of issues essential for
      building an effective holistic parser.

PMID- 10578043
TI  - A unified analysis of value-function-based reinforcement- learning algorithms.
AB  - Reinforcement learning is the problem of generating optimal behavior in a
      sequential decision-making environment given the opportunity of interacting with
      it. Many algorithms for solving reinforcement-learning problems work by computing
      improved estimates of the optimal value function. We extend prior analyses of
      reinforcement-learning algorithms and present a powerful new theorem that can
      provide a unified analysis of such value-function-based reinforcement-learning
      algorithms. The usefulness of the theorem lies in how it allows the convergence
      of a complex asynchronous reinforcement-learning algorithm to be proved by
      verifying that a simpler synchronous algorithm converges. We illustrate the
      application of the theorem by analyzing the convergence of Q-learning, model
      based reinforcement learning, Q-learning with multistate updates, Q-learning for
      Markov games, and risk-sensitive reinforcement learning.

PMID- 10578044
TI  - Neuronal regulation: A mechanism for synaptic pruning during brain maturation.
AB  - Human and animal studies show that mammalian brains undergo massive synaptic
      pruning during childhood, losing about half of the synapses by puberty. We have
      previously shown that maintaining the network performance while synapses are
      deleted requires that synapses be properly modified and pruned, with the weaker
      synapses removed. We now show that neuronal regulation, a mechanism recently
      observed to maintain the average neuronal input field of a postsynaptic neuron,
      results in a weight-dependent synaptic modification. Under the correct range of
      the degradation dimension and synaptic upper bound, neuronal regulation removes
      the weaker synapses and judiciously modifies the remaining synapses. By deriving
      optimal synaptic modification functions in an excitatory-inhibitory network, we
      prove that neuronal regulation implements near-optimal synaptic modification and
      maintains the performance of a network undergoing massive synaptic pruning. These
      findings support the possibility that neural regulation complements the action of
      Hebbian synaptic changes in the self-organization of the developing brain.

PMID- 10578045
TI  - Comparison of SOM point densities based on different criteria.
AB  - Point densities of model (codebook) vectors in self-organizing maps (SOMs) are
      evaluated in this article. For a few one-dimensional SOMs with finite grid
      lengths and a given probability density function of the input, the numerically
      exact point densities have been computed. The point density derived from the SOM
      algorithm turned out to be different from that minimizing the SOM distortion
      measure, showing that the model vectors produced by the basic SOM algorithm in
      general do not exactly coincide with the optimum of the distortion measure. A new
      computing technique based on the calculus of variations has been introduced. It
      was applied to the computation of point densities derived from the distortion
      measure for both the classical vector quantization and the SOM with general but
      equal dimensionality of the input vectors and the grid, respectively. The power
      laws in the continuum limit obtained in these cases were found to be identical.

PMID- 10578046
TI  - Diverse glycosylation of MUC1 and MUC2: potential significance in tumor immunity.
AB  - Mucins are major epithelial luminal surface proteins and function as a physical
      and biological barrier protecting mucous epithelia. Diverse glycosylation of
      mucins potentially provides a basis for tissue-specific interaction with the
      milieu. When mucins are associated with malignant epithelial cells, they not only
      protect these cells from a host environment during metastatic dissemination but
      also generate immunogenic epitopes which are used by the host in the detection
      and immunological elimination of carcinoma cells potentially depending upon their
      status of glycosylation. Diverse mucin structures are generated by the
      combination of different core peptides, of which 10 have been reported so far,
      multiple types of UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases (pp
      GalNAc-Ts), and the consequences of stepwise glycosylation events. For example,
      the mucin 1 (MUC1) associated with malignant cells was previously believed to
      exhibit unique features with a lower percentage of threonine and serine residues
      attached to N-acetylgalactosamine and/or without extension through core 2
      structures. Some of MUC1-specific monoclonal antibodies and cytotoxic lymphocytes
      recognize the peptide sequences PDTR within the tandem repeat portion exposed by
      decreased degree of glycosylation. The specific arrangement of N
      acetylgalactosamine residues is shown to be generated by a combination of pp
      GalNAc-Ts with different specificities. The role of core 2 branching is somewhat
      confusing because well-known carcinoma-associated carbohydrate epitopes such as
      sialyl-Le(X), sialyl-Le(a), Le(Y), and others are often expressed when O-glycans
      are extended through core 2 branching. The other series of well-known carcinoma
      associated carbohydrate structures are truncated O-glycans, conventionally called
      Tn and sialyl-Tn antigens. Interestingly, these are often found to be aligned on
      core polypeptides, resulting in three or more consecutive truncated O-glycans.
      MUC2 and other mucins, but not MUC1, have unique tandem repeats containing three
      or more consecutive serine or threonine residues, which potentially serve as a
      scaffold for trimeric Tn and sialyl-Tn epitopes. We recently found, using the
      MUC2 tandem repeat, that trimeric Tn is a high-affinity receptor for a calcium
      type lectin expressed on the surface of histiocytic macrophages. The biosynthesis
      of trimeric Tn was strictly regulated by the acceptor specificity of pp-GalNAc
      Ts. These results strongly suggest that variation in both glycan structures and
      distribution of glycans on the core polypeptides give mucins unique and diverse
      biological functions that play essential roles in carcinoma-host and other
      cellular interactions.

PMID- 10578047
TI  - Crystal structure of Thermus thermophilus HB8 UvrB protein, a key enzyme of
      nucleotide excision repair.
AB  - In the nucleotide excision repair system, UvrB plays a central role in damage
      recognition and DNA incision by interacting with UvrA and UvrC. We have
      determined the crystal structure of Thermus thermophilus HB8 UvrB at 1.9 A
      resolution. UvrB comprises four domains, two of which have an alpha/beta
      structure resembling the core domains of DNA and RNA helicases. Additionally,
      UvrB has an alpha-helical domain and a domain consisting of antiparallel beta
      sheets (beta-domain). The sequence similarity suggests that the beta-domain
      interacts with UvrA. Based on the distribution of the conserved regions and the
      structure of the PcrA-DNA complex, a model for the UvrB-DNA complex is proposed.

PMID- 10578048
TI  - Detection of a variety of Ser/Thr protein kinases using a synthetic peptide with
      multiple phosphorylation sites.
AB  - A novel peptide with multiple phosphorylation sites, which we designated as
      multide, was developed to detect a wide variety of protein kinases in crude cell
      extracts. Multide, KKRKSSLRRWSPLTPRQMSFDC, has been designed to contain consensus
      sequences for various Ser/Thr protein kinases including cAMP-dependent protein
      kinase, protein kinase C, MAP kinases, and Ca(2+)/calmodulin-dependent protein
      kinases in a single peptide. In-gel protein kinase assay using multide was found
      to be very useful for analyzing the activities of protein kinases that are
      altered in response to various extracellular stimuli. The substrate specificities
      of the protein kinases thus detected were further determined by using five
      multide analogs with different phosphorylation sites.

PMID- 10578049
TI  - Identification of functionally important residues of Arabidopsis thaliana S
      adenosylmethionine decarboxylase.
AB  - The Arabidopsis thaliana S-adenosylmethionine decarboxylase (AdoMetDC) cDNA
      (GenBank(TM) U63633) was cloned, and the AdoMetDC protein was expressed,
      purified, and characterized. The K(m) value for S-adenosylmethionine (AdoMet) is
      23.1 microM and the K(i) value for methylglyoxal bis-(guanylhydrazone) (MGBG) is
      0.15 microM. Site-specific mutagenesis was performed on the AdoMetDC to introduce
      mutations at conserved cysteine (Cys(50), Cys(83), and Cys(230)) and lysine(81)
      residues, chosen by examination of the conserved sequence and proved to be
      involved in enzymatic activity by chemical modification. The AdoMetDC mutants
      K81A and C83A retained up to 60 and 10% of wild type activity, respectively,
      demonstrating that lysyl and sulfhydryl groups are required for full catalytic
      activity. However, changing Cys(50) and Cys(230) to alanine had minimal effects
      on the catalytic activity. Changing Lys(81) to alanine produced an altered
      substrate specificity. When lysine was used as a substrate instead of AdoMet, the
      substrate specificity for lysine increased 6-fold. The K(m) value for AdoMet is
      11-fold higher than that of the wild type, but the V(max) value is more than 60%.
      Taken together, the results suggest that the lysine(81) residue is critical for
      substrate binding.

PMID- 10578050
TI  - Characterization of human serum mannan-binding protein promoter.
AB  - Serum mannan binding protein (MBP), a mannose/N-acetylglusosamine-specific
      lectin, is important in innate immunity. In order to elucidate the mechanism
      underlying the wide intra- and interracial variety in the MBP serum level, we
      have studied the transcriptional regulation of human MBP. Rapid amplification of
      cDNA ends (5' RACE) analysis of Hep G2 RNA indicated the presence of a novel
      exon, designated as "exon 0," upstream of previously identified exon 1 [Taylor,
      M.E. et al. (1989) Biochem. J. 262, 763-771]. Two MBP mRNAs with different sized
      5'-noncoding regions were detected: the longer transcript starts at exon 0 and
      the shorter one at exon 1. Promoter analysis involving a luciferase assay vector
      revealed that the transcript starting from exon 1 predominates over that starting
      from exon 0. In addition, a hepatocyto-specific nuclear factor, (HNF)-3, which is
      known to control the expression of hepatocyto-specific genes, up-regulates the
      transcription of human MBP from exon 1, while a glucocorticoid, which is known to
      up-regulate acute phase proteins, markedly suppresses MBP transcription.
      Recently, polymorphisms were found to occur in the promoter region at two
      positions [Madsen, H.O. et al. (1995) J. Immunol. 155, 3013-3020]. Functional
      promoter analysis indicated that three haplotype variants as to these positions,
      HY, LY, and LX, exhibit high, medium and low promoter activity, respectively, in
      accordance with the results of a previous population study.

PMID- 10578051
TI  - Purification, molecular cloning, and genomic organization of human brain long
      chain acyl-CoA hydrolase.
AB  - An acyl-CoA hydrolase, referred to as hBACH, was purified from human brain
      cytosol. The enzyme had a molecular mass of 100 kDa and 43-kDa subunits, and was
      highly active with long-chain acyl-CoAs, e.g. a maximal velocity of 295
      micromol/min/mg and K(m) of 6.4 microM for palmitoyl-CoA. Acyl-CoAs with carbon
      chain lengths of C(8-18) were also good substrates. In human brain cytosol, 85%
      of palmitoyl-CoA hydrolase activity was titrated by an anti-BACH antibody, which
      accounted for over 75% of the enzyme activity found in the brain tissue. The cDNA
      isolated for hBACH, when expressed in Escherichia coli, directed the expression
      of palmitoyl-CoA hydrolase activity and a 44-kDa protein immunoreactive to the
      anti-BACH antibody, which in turn neutralized the hydrolase activity. The hBACH
      cDNA encoded a 338-amino acid sequence which was 95% identical to that of a rat
      homolog. The hBACH gene spanned about 130 kb and comprised 9 exons, and was
      mapped to 1p36.2 on the cytogenetic ideogram. These findings indicate that the
      long-chain acyl-CoA hydrolase present in the brain is well conserved between man
      and the rat, suggesting a conserved role for this enzyme in the mammalian brain,
      and enabling genetic studies on the functional analysis of acyl-CoA hydrolase.

PMID- 10578052
TI  - Effects of removal and reconstitution of myosin regulatory light chain and
      troponin C on the Ca(2+)-sensitive ATPase activity of myofibrils from scallop
      striated muscle.
AB  - In order to examine the involvement of troponin-linked Ca(2+)-regulation, in
      addition to well-known myosin-linked Ca(2+)-regulation, in the contraction of
      molluscan striated muscle, myofibrils from Ezo-giant scallop striated muscle were
      desensitized to Ca(2+) by removing both myosin regulatory light chain and
      troponin C by treatment with a strong divalent cation chelator, CDTA. The ATPase
      level in the desensitized myofibrils was about half the maximum level in intact
      myofibrils regardless of the Ca(2+)-concentration at 25 and 15 degrees C. In the
      absence of Ca(2+), the ATPase of the desensitized myofibrils was suppressed by
      myosin regulatory light chain but not affected by troponin C at either
      temperature. The ATPase was activated at higher Ca(2+)-concentrations by both
      myosin regulatory light chain and troponin C, but the activating effects of these
      two proteins were affected differently by temperature. The activation of ATPase
      by myosin regulatory light chain was much greater than that by troponin C at 25
      degrees C, whereas the activation by troponin C was much greater than that by
      myosin regulatory light chain at 15 degrees C. The maximum activation was only
      obtained in the presence of both myosin regulatory light chain and troponin C at
      these temperatures. These findings strongly suggest that the contraction of
      scallop striated muscle is regulated through both myosin-linked and troponin
      linked Ca(2+)-regulation, and that the troponin-linked Ca(2+)-regulation is more
      significant at lower temperature.

PMID- 10578053
TI  - Identification of heat shock protein 90-associated 84-kDa phosphoprotein.
AB  - In eukaryotic cells, HSP90 is associated with several protein kinases and
      regulates their activities. HSP90 was also reported to possess an
      autophosphorylase activity. In this study, we examined in vitro
      autophosphorylation of HSP90, which was purified from chick muscle. We show that
      HSP90 was not phosphorylated in vitro, but an 84-kDa protein (p84) was highly
      phosphorylated. P84 was neither HSP90 nor its degradative product, as it was not
      detected by an antibody (BF4) specific to HSP90 in denaturing immunoprecipitation
      and Western blot analysis. Phosphorylation of a protein similar to p84 was also
      detected with purified human brain and HeLa HSP90, indicating that p84 is present
      in many different types of cells. P84 appeared to exist as large complexes, as
      determined by HPLC and native gel electrophoresis. Native immunoprecipitation
      using anti-HSP90 (BF4)-conjugated Affi-gel revealed that this phosphoprotein is
      specifically associated with HSP90. The interaction of p84 and HSP90 was not
      affected by p84 phosphorylation. In addition, p84 phosphorylation was prevented
      by the presence of divalent cations such as Mg(2+) and Mn(2+). In contrast, p84
      phosphorylation was significantly activated by addition of exogenous Ca(2+)
      between 100 and 500 microM, although it was blocked by higher concentrations (>1
      mM) of Ca(2+). HSP90, but not p84, could be phosphorylated by casein kinase II.
      Finally, p84 phosphorylation was specifically prevented by hemin, but not by
      other kinase inhibitors, indicating that p84 phosphorylation may be regulated by
      heme-regulated protein kinase.

PMID- 10578054
TI  - Molecular cloning and splicing isoforms of mouse p144, a homologue of CA150.
AB  - We previously characterized p144 bearing N-acetylglucosamine residues in a rat
      liver nuclear matrix fraction. Based on partial amino acid sequences of rat p144,
      mouse p144 cDNA was cloned and sequenced, and its amino acid sequence was
      predicted. The sequence revealed that p144 is a rat homologue of CA150, which is
      a transcription factor involved in Tat-activated human immunodeficiency virus
      type 1 transcription. The reported human CA150 consists of 1098 amino acids and
      has a leucine zipper-like motif in its carboxyl-region. However, a clone of mouse
      p144 cDNA encoded a CA150 consisting of 1,034 amino acids. The mouse CA150 was
      shorter by 64 amino acids than hitherto known human CA150 and lacked the leucine
      zipper-like motif. We designated the longer and shorter CA150 species as CA150a
      and CA150b, respectively. The partial nucleotide sequences of other mouse p144
      cDNA clones were examined and it was found that some clones encode CA150a having
      a leucine zipper-like motif. It was suggested that CA150a and CA150b are splicing
      isoforms. All rat and mouse tissues examined contained transcripts for both
      CA150a and CA150b. Both transcripts were detected in human blood and Jurkat cells
      as well as mouse CD4(+) T-cells, which are the HIV-1-sensitive counterpart in
      humans.

PMID- 10578055
TI  - Molecular cloning of cDNA encoding a novel microphthalmia-associated
      transcription factor isoform with a distinct amino-terminus.
AB  - Microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix
      leucine zipper protein, and plays an important role in the development of various
      cell types, such as neural-crest-derived melanocytes and optic-cup-derived
      retinal pigment epithelium. Three isoforms of MITF with distinct amino-termini
      have been described. These include melanocyte lineage-specific MITF-M, heart-type
      MITF-H, and the recently identified MITF-A. Here we identify a fourth isoform,
      MITF-C, with a unique amino-terminus of 34 amino acid residues, which shares
      about 43% sequence identity with putative transactivation segments of two
      previously identified leukemogenic factors, ENL and AF-9. Reverse transcription
      polymerase chain reaction analysis revealed that MITF-C mRNA is expressed in many
      cell types, including retinal pigment epithelium, but is undetectable in
      melanocyte-lineage cells. In contrast, MITF-A and MITF-H mRNAs are coexpressed in
      all cell types examined. Transient cotransfection assays suggested that MITF-C,
      like other MITF isoforms, functions as a transcriptional activator of certain
      target genes, but its transactivation specificity for the target promoters is
      different from those of other MITF isoforms. Therefore, isoform multiplicity
      provides MITF with differential expression patterns as well as functional
      diversity.

PMID- 10578056
TI  - 5-Bromodeoxyuridine induces senescence-like phenomena in mammalian cells
      regardless of cell type or species.
AB  - 5-Bromodeoxyuridine was found to induce flat and enlarged cell shape,
      characteristics of senescent cells, and senescence-associated beta-galactosidase
      in mammalian cells regardless of cell type or species. In immortal human cells,
      fibronectin, collagenase I, and p21(wafl/sdi-1) mRNAs were immediately and very
      strongly induced, and the mortality marker mortalin changed to the mortal type
      from the immortal type. Human cell lines lacking functional p21(wafl/sdi-1),
      p16(ink4a), or p53 behaved similarly. The protein levels of p16(ink4a) and p53
      did not change uniformly, while the level of p21(wafl/sdi-1) was increased by
      varying degrees in positive cell lines. Telomerase activity was suppressed in
      positive cell lines, but accelerated telomere shortening was not observed in
      tumor cell lines. These results suggest that 5-bromodeoxyuridine activates a
      common senescence pathway present in both mortal and immortal mammalian cells.

PMID- 10578057
TI  - The effect of phospholipase A(2) immobilization upon calcium interaction: a
      kinetic study.
AB  - In this work we studied the effect of Ca(2+) on the ability of immobilized PLA(2)
      to hydrolyze phospholipid substrates either in aggregate or monomeric forms. We
      use a kinetic methodology for the determination of dissociation constants of
      soluble and immobilized PLA(2)-Ca(2+) complexes. This approach allows us to
      obtain the values of the dissociation constants of enzyme-Ca(2+) (K(x)) and
      enzyme-Ca(2+)-substrate (K'(x)) complexes from the kinetic data obtained at
      different substrate and Ca(2+) concentrations. Results using mixed micelles of
      phospholipid-Triton X-100 showed that, in most cases, productive complexes were
      destabilized by immobilization of PLA(2). However, a correct analysis of the
      interaction must be independent of the classical modes of PLA(2) action toward
      lipid surfaces. Thus, a substrate in monomeric form was also employed to analyze
      the effect of immobilization on hydrolysis rate in the absence of interfacial
      activation. Kinetic data showed that the immobilization affected severely the
      mode of PLA(2) action. The kinetic data also suggested that immobilization
      promoted conformational alterations in the Ca(2+)-binding site, destabilizing the
      productive complex enzyme-Ca(2+)-phospholipid.

PMID- 10578058
TI  - Regulation of natural killer cell-mediated swine endothelial cell lysis through
      genetic remodeling of a glycoantigen.
AB  - The effect of remodeling of a glycoantigen such as the alpha-Gal epitope,
      Galalpha1,3Galbeta1,4GlcNAc-R, by the introduction of glycosyltransferase genes
      on natural killer (NK) cell-mediated direct cytotoxicity was investigated using
      human peripheral blood mononuclear cells (PBMC) or an NK-like cell line, YT
      cells, as an effector, and swine endothelial cells (SEC) as a target. Several SEC
      transfectants were established by transfection with the genes for beta1,4-N
      acetylglucosaminyltransferase III, alpha2, 3-sialyltransferase and alpha1,2
      fucosyltransferase. These transfections led to dramatic reductions in both direct
      and indirect NK cell-mediated cytotoxicity, by 72-94% in the case of PBMC and 27
      72% in that of YT cells, in addition to an effective reduction in
      xenoantigenicity, which is substantially caused by the alpha-Gal epitope, to
      human natural antibodies. The NK cell-mediated direct cytotoxicity was remarkably
      blocked by an anti-alpha-Gal epitope monoclonal antibody or GSI lectin which
      preferentially binds to the epitope. Furthermore, treatment of the parental cells
      with alpha-galactosidase resulted in a significant reduction in cytotoxicity.
      These results suggest that the alpha-Gal epitope is involved not only in
      hyperacute rejection and acute vascular rejection, but also in NK cell-mediated
      direct cytotoxicity. Thus, the genetic remodeling of the alpha-Gal epitope and
      probably other glycoantigens as well can be expected to represent a new approach
      for overcoming not only indirect but also direct immunity to xenografts.

PMID- 10578059
TI  - Fatty acid alcohol ester-synthesizing activity of lipoprotein lipase.
AB  - The fatty acid alcohol ester-synthesizing activity of lipoprotein lipase (LPL)
      was characterized using bovine milk LPL. Synthesizing activities were determined
      in an aqueous medium using oleic acid or trioleylglycerol as the acyl donor and
      equimolar amounts of long-chain alcohols as the acyl acceptor. When oleic acid
      and hexadecanol emulsified with gum arabic were incubated with LPL, palmityl
      oleate was synthesized, in a time- and dose-dependent manner. Apo-very low
      density lipoprotein (apoVLDL) stimulated LPL-catalyzed palmityl oleate synthesis.
      The apparent equilibrium ratio of fatty acid alcohol ester/oleic acid was
      estimated using a high concentration of LPL and a long (20 h) incubation period.
      The equilibrium ratio was affected by the incubation pH and the alcohol chain
      length. When the incubation pH was below pH 7.0 and long chain fatty acyl
      alcohols were used as substrates, the fatty acid alcohol ester/free fatty acid
      equilibrium ratio favored ester formation, with an apparent equilibrium ratio of
      fatty acid alcohol ester/fatty acid of about 0.9/0.1. The equilibrium ratio
      decreased sharply at alkaline pH (above pH 8.0). The ratio also decreased when
      fatty alcohols with acyl chains shorter than dodecanol were used. When a
      trioleoylglycerol/fatty acyl alcohol emulsion was incubated with LPL, fatty acid
      alcohol esters were synthesized in a dose- and time-dependent fashion. Fatty acid
      alcohol esters were easily synthesized from trioleoylglycerol when fatty alcohols
      with acyl chains longer than dodecanol were used, but synthesis was decreased
      with fatty alcohols with acyl chain lengths shorter than decanol, and little
      synthesizing activity was detected with shorter-chain fatty alcohols such as
      butanol or ethanol.

PMID- 10578060
TI  - Misfolded membrane-bound cytochrome P450 activates KAR2 induction through two
      distinct mechanisms.
AB  - Using the mRNA differential display technique and Western blot analysis, the
      present study demonstrates that induction of KAR2 occurs when misfolded membrane
      bound cytochrome P450, mutated in its cytosolically exposed domain, is expressed
      in Saccharomyces cerevisiae. Using various KAR2 promoter constructs in front of
      the Escherichia coli beta-galactosidase reporter gene, we found a fast and strong
      induction through the heat shock element (HSE), which was enhanced several fold
      by its adjacent GC-rich region. Additionally, a less pronounced induction was
      detected for the UPR element (UPRE). As expected, this response was absent in the
      ire1 disruptant strain. However, the HSE-mediated induction was enhanced upon
      disruption of IRE1 suggesting that the HSE pathway can compensate for the lack of
      a functional UPR pathway. Western blotting confirmed that Kar2p levels were
      increased to the same extent in the ire1 disruptant and in the non-disruptant
      strain. Removal of the P450 membrane-spanning region also abolished the UPRE
      mediated induction of KAR2 transcription, but the HSE-mediated response remained.
      The data show for the first time that the transcription of KAR2 is significantly
      induced in response to a misfolded membrane-bound endoplasmic reticulum protein,
      and identifies the HSE and UPRE regions as KAR2 promoter elements responding to
      the misfolded cytosolic P450 domain and to the membrane-integrated mutant P450,
      respectively.

PMID- 10578061
TI  - Kinetics of interactions of sendai virus envelope glycoproteins, F and HN, with
      endoplasmic reticulum-resident molecular chaperones, BiP, calnexin, and
      calreticulin.
AB  - Sendai virus envelope glycoproteins, F and HN, mature during their transport
      through the endoplasmic reticulum (ER) and Golgi complex. To better understand
      their maturation processes in the ER, we investigated the time course of their
      interactions with three ER- resident molecular chaperones, BiP, calnexin (CNX),
      and calreticulin (CRT), in Sendai virus-infected HeLa cells. Pulse-chase and
      immunoprecipitation analyses using antibodies against each virus glycoprotein or
      ER chaperone revealed that F precursor interacted with CNX transiently (t(1/2)=8
      min), while HN protein displayed longer and sequential interactions with BiP
      (t(1/2)=8 min), CNX (t(1/2)=15 min), and CRT (t(1/2)=20 min). HN interacted with
      the three ER chaperones not only as a monomer but also as a tetramer for several
      hours, suggesting mechanism(s) to undergo chaperone-mediated quality control of
      an assembled HN oligomer in the ER. The kinetics of dissociation of the HN
      chaperone complexes exhibited a marked delay in the presence of proteasome
      inhibitors, suggesting that a part of HN associated with BiP, CNX, and CRT is
      destined to be degraded in the proteasome-dependent pathway. Further, the
      associations between virus glycoproteins and CNX or CRT were impaired by
      castanospermine, an inhibitor of ER glucosidase I and II, confirming that these
      interactions require monoglucosylated oligosaccharide on F(0) and HN peptides.
      These findings together suggest that newly synthesized F protein undergoes rapid
      maturation in the ER through a transient interaction with CNX, whereas HN protein
      requires more complex processes involving prolonged association with BiP, CNX,
      and CRT for its quality control in the ER.

PMID- 10578062
TI  - Phosphatidylserine-mediated phagocytosis of anticancer drug-treated cells by
      macrophages.
AB  - Apoptotic cells are rapidly phagocytosed and eliminated from the organism.
      Although cancer cells apoptose when treated with anticancer drugs, how those
      cells are recognized by phagocytic cells has remained unclear. The human leukemia
      cell line Jurkat was cultured with doxorubicin or bufalin and induced to undergo
      apoptosis accompanied by phosphatidylserine externalization. When apoptotic
      Jurkat cells were mixed with mouse peritoneal macrophages, efficient phagocytosis
      was observed. Apoptosis and phagocytosis of Jurkat cells were both inhibited by Z
      VAD-FMK, and phagocytosis was significantly reduced in the presence of
      phosphatidylserine-containing liposomes. These results suggest that anticancer
      drugs induce apoptosis-dependent and phosphatidylserine-mediated phagocytosis in
      cancer cells.

PMID- 10578063
TI  - Indispensability of transmembrane domains of Golgi UDP-galactose transporter as
      revealed by analysis of genetic defects in UDP-galactose transporter-deficient
      murine had-1 mutant cell lines and construction of deletion mutants.
AB  - UDP-galactose transporter is a membrane protein localized in the Golgi apparatus.
      It translocates UDP-galactose from the cytosol into the Golgi lumen, thus
      providing galactosyltransferases with their substrate. We characterized murine
      UDP-galactose transporter through molecular cloning for the following purposes:
      (i) to elucidate the molecular bases underlying the genetic defects of murine Had
      1 mutants, which are deficient in UDP-galactose transporting activity, and (ii)
      to obtain information that would help us in planning rational approaches to
      identify functionally essential regions, based on comparison of primary
      structures between human and murine UDP-galactose transporters. We identified
      five nonsense mutations, one missense Gly178Asp mutation, and two aberrant
      splicing mutations. Although glycine178 is highly conserved among nucleotide
      sugar transporters, a Gly178Ala variant was functional. The species-differences
      between human and murine UDP-galactose transporters were largely confined to the
      N- and C-terminal regions of the transporters. Substantial deletions in the N-
      and C-terminal regions did not lead to loss of UDP-galactose transporting
      activity, indicating that these cytosolic regions are dispensable for the
      transporting activity. The transporter was fused with green-fluorescent protein
      at the C-terminal cytosolic tail without impairing the functions of either
      protein. Our results demonstrate the importance of the transmembrane core region
      of the UDP-galactose transporter protein.

PMID- 10578064
TI  - Enhancement of secretion of human procollagen I in mouse HSP47-expressing insect
      cells.
AB  - We previously demonstrated that insect cells were able to synthesize recombinant
      human procollagen I as triple-helical heterotrimers when transfected with cDNAs
      of both proalpha1(I) and proalpha2(I) chains. However, most of the heterotrimers
      were retained within the cells, unlike in the case of mammalian cells [Tomita,
      M., Kitajima, T., and Yoshizato, K. (1997) J. Biochem. 1061-1069]. In an attempt
      to improve the secretion of the heterotrimers, we introduced the putative
      collagen-specific chaperone HSP47 into this insect expression model. Mouse HSP47
      produced by the insect cells bound intracellularly to both human proalpha1(I) and
      proalpha2(I) chains and enhanced the secretion of procollagen I heterotrimers.
      HSP47 was also coexpressed with either proalpha1(I) chains or proalpha2(I)
      chains, which showed that it enhanced the secretion of the former but not the
      latter. This selective effect of HSP47 was similarly observed in the cells
      treated with inhibitors of procollagen triple helix formation, indicating that
      HSP47 can also accelerate the secretion of non-helical procollagens. HSP47 did
      not change the intracellular solubility of proalpha1(I) and proalpha2(I) chains
      in 1% NP-40, eliminating the possibility that it prevents proalpha chains from
      aggregating into insoluble forms within the insect cells. We concluded that HSP47
      can play a role in the secretion of alpha1(I)-procollagen chains in the insect
      cell model. The present study also demonstrated the dissimilarity in the
      mechanism of folding and secretion of the expressed procollagen I between the
      insect and mammalian cells.

PMID- 10578065
TI  - Studies on functions of the 63-kDa A- and 74-kDa B'(delta)-regulatory subunits in
      human erythrocyte protein phosphatase 2A: dissociation and reassociation of the
      subunits.
AB  - A heterodimeric form, CA, of protein-serine/threonine phosphatase (PP) 2A
      purified from human erythrocytes was dissociated into a 34-kDa catalytic subunit
      C and 63-kDa inactive subunit A by Sephacryl S-200 gel filtration in the presence
      of 6 M urea. Reassociation of the C- and A-subunits in the absence of urea
      suppressed the PP activity of the C subunit toward phosphorylase a, P-H2B
      histone, and P-H1 histone in the presence or absence of 20 mM MnCl(2) or 50 mM
      Mg(CH(3)COO)(2), but stimulated the PP activity toward P-H1 histone in the
      presence of 200 mM NaCl and the Mn(2+)-dependent protein-tyrosine phosphatase
      (PTP) activity toward P-Tyr-Glu copolymers. The 74-kDa inactive B'(delta) subunit
      was isolated from a heterotrimeric form, CAB'(delta), of PP2A partially purified
      from human erythrocytes, by heparin-Sepharose column chromatography. The
      B'(delta) subunit reassociated with CA and suppressed the PP- and PTP-activities
      of CA. The B'(delta) subunit did not associate with the isolated C subunit
      directly, and had no effect on the activities of the C subunit, indicating that
      the A subunit is essential for the association of the B'(delta) subunit with CA
      and the resulting suppression of the PP- and PTP-activities.

PMID- 10578066
TI  - Activation of protein kinase B induced by H(2)O(2) and heat shock through
      distinct mechanisms dependent and independent of phosphatidylinositol 3-kinase.
AB  - Protein kinase B (PKB) is a downstream target of phosphatidylinositol (PI) 3
      kinase in the signaling pathway of growth factors, and is activated by cellular
      stress such as H(2)O(2) and heat shock. To study the mechanism of the stress
      induced activation of PKB, PI 3-kinase products were measured in stress
      stimulated cells. Both PI 3,4-bisphosphate and PI 3,4, 5-trisphosphate increased
      in H(2)O(2)-treated cells, and the elevation of these phospholipids and
      activation of PKB were concurrently blocked by wortmannin, a potent inhibitor of
      PI 3-kinase. In heat-shocked cells, the level of PI 3,4-bisphosphate did not
      change while that of PI 3,4,5-trisphosphate increased slightly, and an
      association between PKB molecules was observed. Two active PKB fractions,
      presumably monomeric and oligomeric forms, were resolved from heat-shocked cells
      by gel filtration column chromatography. Activation of the former was suppressed
      by pretreatment with wortmannin, whereas the generation and activation of the
      latter were not blocked by the PI 3-kinase inhibitor. Only the monomeric form,
      but not the oligomeric form, was recovered from H(2)O(2)-treated cells, and its
      activation was prevented by wortmannin. These results indicate that PKB is
      activated by two distinct mechanisms that are dependent and independent of PI 3
      kinase in stress-stimulated cells.

PMID- 10578067
TI  - Identification of the hemidesmosomal 500 kDa protein (HD1) as plectin.
AB  - HD1 is a 500 kDa hemidesmosomal plaque protein recognized by monoclonal antibody
      mAb-121. Recent research on inherited skin disease has suggested that it might be
      identical to plectin or an isoform. To cast light on this question, we have
      prepared several monoclonal antibodies that recognize a 500 kDa protein in the
      hemidesmosome fraction. Unexpectedly, some staining pattern heterogeneity was
      observed on immunofluorescence microscopy. Attention was focused on two
      monoclonal antibodies which gave different localization in bovine skin and
      retinal pigment epithelial cells. Determination of the amino-terminal sequence of
      an antigenic 100 kDa polypeptide fragment derived from the 500 kDa component of
      an insoluble fraction of bovine hepatocytes revealed it was identical to that of
      plectin. Using the two antibodies, we screened a cDNA library derived from
      BMGE+H, a bovine mammary gland epithelial cell line. The isolated cDNA clones
      corresponded to the rod domain of bovine plectin, with two separate epitope
      regions for each of the antibodies. From these results we conclude that the
      hemidesmosomal 500 kDa component HD1 is identical to plectin. As judged on rough
      estimation of molar ratios on this basis, hemidesmosomes are composed of plectin,
      BP230, the integrin beta4 subunit, and alpha6 in a 1:1:1:1 ratio.

PMID- 10578069
TI  - beta1-4Galactosyltransferase activity of mouse brain as revealed by analysis of
      brain-specific complex-type N-linked sugar chains.
AB  - We previously reported two brain-specific agalactobiantennary N-linked sugar
      chains with bisecting GlcNAc and alpha1-6Fuc residues, (GlcNAcbeta1
      2)(0)(or)(1)Manalpha1-3(GlcNAcbeta1-2M analpha1-6)(GlcNA cbeta1-4)Manbeta1
      4GlcNAcbeta1-4(Fucalpha1-6)Glc NAc [Shimizu, H., Ochiai, K., Ikenaka, K.,
      Mikoshiba, K., and Hase, S. (1993) J. Biochem. 114, 334-338]. Here, the reason
      for the absence of Gal on the sugar chains was analyzed through the detection of
      other complex type sugar chains. Analysis of N-linked sugar chains revealed the
      absence of Sia-Gal and Gal on the GlcNAc residues of brain-specific
      agalactobiantennary N-linked sugar chains. We therefore investigated the
      substrate specificity of galactosyltransferase activities in brain using
      pyridylamino derivatives of agalactobiantennary sugar chains with structural
      variations in the bisecting GlcNAc and alpha1-6Fuc residues as acceptor
      substrates. While the beta1-4galactosyltransferases in liver and kidney could
      utilize all four oligosaccharides as substrates, the beta1
      4galactosyltransferase(s) in brain could not utilize the agalactobiantennary
      sugar chain with both bisecting GlcNAc and Fuc residues, but could utilize the
      other three acceptors. Similar results were obtained using glycopeptides with
      agalactobiantennary sugar chains and bisecting GlcNAc and alpha1-6Fuc residues as
      substrates. The beta1-4galactosyltransferase activity of adult mouse brain thus
      appears to be responsible for producing the brain-specific sugar chains and to be
      different from beta1-4galactosyltransferase-I. The agalactobiantennary sugar
      chain with bisecting GlcNAc and alpha1-6Fuc residues acts as an inhibitor against
      "brain type" beta1-4galactosyltransferase with a K(i) value of 0.29 mM.

PMID- 10578068
TI  - Characterization of a novel fungal protein, p15, which induces neuronal
      differentiation of PC12 cells.
AB  - In our previous paper, we reported that a 15 kDa protein (p15) produced by a
      fungus, genus Helicosporium, enhanced NGF-induced neurite outgrowth from PC12
      cells. Here we further characterized the actions of p15. The complete amino acid
      sequence of p15 was determined and it was shown to be a hydrophilic protein
      composed of 118 amino acid residues with two intramolecular disulfide bridges.
      p15-induced neurite outgrowth was blocked by the depletion of extracellular
      Ca(2+) in the culture medium and was significantly inhibited by L-type Ca(2+)
      channel inhibitor nicardipine. p15 stimulated Src kinase and MAPK activities, and
      neurite outgrowth was not observed in srcDN2, a dominant negative c-src(K295R)
      expressing cell line, and was significantly reduced in RasN17-expressing cells.
      These results suggest that p15 stimulates neurite outgrowth through the
      potentiation of L-type Ca(2+) channels, thereby activating the Src-Ras-MAPK
      cascade.

PMID- 10578070
TI  - Glutaraldehyde (GA)-hapten adducts, but without a carrier protein, for use in a
      specificity study on an antibody against a GA-conjugated hapten compound:
      histamine monoclonal antibody (AHA-2) as a model.
AB  - In our recent study on monoclonal antibodies (mAbs AHA-1-5) against
      glutaraldehyde (GA)-conjugated histamine (HA), we identified one mAb (AHA-2)
      which can detect neuronal HA in the rat brain with an immunocytochemistry method
      (ICC) [Fujiwara et al. (1999) J. Biochem. 126, 503-509]. In the present study the
      specificity of AHA-2 mAb for use for ICC has been examined by means of
      competitive experiments involving HA and analogs, all of which had been allowed
      to react with GA followed by sodium borohydride, but not allowed to couple with
      the carrier protein. It was demonstrated that the antibody distinguished
      alterations in the chemical structure of the molecule, showing decreased
      immunoreactivity with all the GA-adducts of (R)-(-)-alpha-methylhistamine, 1- and
      3-methylhistamine, L-histidine, and 1- and 3-methyl-L-histidine. On the other
      hand, AHA-1 mAb only reacted with GA-adducts of 3-MeHA (3-MeHA-GA) and HA (HA
      GA), to almost the same degree, in relatively high concentration ranges. AHA-3,
      4, and 5 mAbs reacted about 10-times more strongly with 1-MeHA-GA than with HA
      GA, but reacted very little or not at all with the other analogs. These results
      may suggest that AHA-2 mAb recognized both the non-substituted imidazole and
      alpha-methine groups of a HA molecule in addition to the conjugation site of GA
      including the part(s) reduced with NaBH(4), and especially the imidazole group
      more strictly than the other mAbs. This may partly explain why AHA-2, among the
      five AHA mAbs, can detect neuronal HA with an ICC method. The present ELISA
      method for GA-hapten adducts should be applicable to other antibodies against GA
      conjugated biologically active amines or amino acids, thus allowing the study of
      antibody specificity for ICC more easily and accurately than was previously
      possible with hapten-protein conjugates as antigens.

PMID- 10578071
TI  - Studies on cytogenesis in adult rat adrenal cortex: circadian and zonal
      variations and their modulation by adrenocorticotropic hormone.
AB  - Circadian rhythms and zonal variations in the cell proliferation of adult rat
      adrenal cortex were studied by following the cells in the DNA-synthesizing stage
      (S-phase) as assessed by 5-bromo-2'-deoxyuridine incorporation into the cell
      nuclei and/or by visualizing proliferating cell nuclear antigen. The S-phase
      cells were observed throughout the day in two regions of the adrenal cortex: (i)
      a region from the inner half of the zona glomerulosa to near the outer margin of
      the zona fasciculata, and (ii) the outer one-fourth portion of the zona
      fasciculata. Very little change in number was observed in the former region
      between day and night, while a burst of cell proliferation occurred in early
      morning at 3-4 a.m. in the latter region. A prominent rise in the plasma
      adrenocorticotropic hormone (ACTH) concentration preceded the burst of cell
      proliferation by about 4 h. Upon raising the plasma ACTH concentration by
      administration of ACTH or metyrapone, prominent cell proliferation also occurred
      in the same portion of the zona fasciculata 4-6 h after the provoked ACTH surge.
      Thus at least two sites in rat adrenal cortex are responsible for cytogenesis in
      this endocrine organ, and respond differentially to day/night cycles and
      circulating ACTH levels.

PMID- 10578072
TI  - Health education: new perspectives.

PMID- 10578075
TI  - Linking teaching and research: establishing a proposal for training polytechnic
      school faculty.
AB  - Based on the experience of a teacher training program entitled Program for
      Continuing Education of Polytechnic Faculty (PAETEC) developed by the Escola
      Politecnica de Saude Joaquim Vemancio (EPSJV/FIOCRUZ), this article is intended
      to contribute to the discussion of alternatives for continuing vocational teacher
      education programs. In the search for new on-the-job teacher training models
      fostering interaction between the educational process and research activity, the
      experience employs a strategy based on the construction of an integrated
      methodology allowing teachers to reflect on their own practices and turn them
      into the object of their research.

PMID- 10578073
TI  - [Popular education, community health, and social support in a context of
      globalization].
AB  - The author discusses difficulties experienced by working-class groups in a crisis
      context, relating to the demands they make on authorities. Popular participation
      has traditionally referred to activities resulting in pressure on authorities for
      improved basic services. One can contend that activities commonly known as
      popular education and community health are currently at a stalemate. The social
      support theory is proposed as a form of not only discussing the crisis in health
      services, but also the health model as being basically curative. In this sense,
      concepts such as "control over one's life", "life making sense", and "solidarity"
      are discussed as important factors for prevention and maintenance in the field of
      health education. Although it was a context of crisis which led to the discussion
      of the social support theory, the latter's value does not depend on such a
      context.

PMID- 10578074
TI  - [Education and health services: evaluating professional training].
AB  - This paper analyzes the results of a follow-up study and evaluation of the
      Specialization Course in Public Health administered from 1993 to 1995 by the
      Department of Preventive and Social Medicine at the School of Medical Sciences,
      Universidade de Campinas, Brazil. The study was conducted during the course and
      with a follow-up several months later. Students reported on their professional
      activities, difficulties and facilities in performing them, and their commitment
      to the public health services in which they worked. They also expounded on their
      needs and expectations regarding specialized training in public health. At the
      end of the required course load (first semester) and the optional courses (second
      semester), students evaluated the course content's relevance, their own
      understanding, and the strengths and weaknesses of the respective teaching
      strategies. Finally, six and eight months after the courses, the professionals
      evaluated how they were able to apply their new knowledge to their work. Various
      research instruments were used, including group dynamics, individual
      questionnaires, and focal groups, comprising a broad methodological approach. A
      single sample of individuals was thus studied at different moments with regard to
      this experience.

PMID- 10578076
TI  - [Integration of health into the school curriculum in Botucatu, Sao Paulo].
AB  - This study focuses on the drafting and development of a public health program
      aimed at strategies to integrate health activities and the school curriculum. The
      program is based on three main lines of activity: full health care for
      schoolchildren, with special emphasis on the public school system; training of
      personnel in the fields of health and education by means of internships allowing
      participants to experience, work, and reflect critically on the activities with
      an interdisciplinary team; and work with teachers from the public elementary
      school system to implement and develop innovative measures in the fields of
      health and education to respond to the demand by schools and the community.

PMID- 10578077
TI  - [Multiprofessional demand and clientele: influences and challenges for a Master's
      degree course in educational technology in the health sciences].
AB  - This article aims to identify the key characteristics of individuals pursuing a
      Master's degree in Health Education, discussing relevant issues concerning the
      objectives and content of their training. The analysis is based on data for
      Master's applicants selected during the four years since the program on
      Educational Technology in Health Sciences was created by the Unit of Educational
      Technology in Health, under the Health Sciences Center at the Federal University
      of Rio de Janeiro. The study showed that the applicants came from various
      professions and belonged to both teaching faculty and health care teams. The
      profile identified by the study has provided the material for discussing key
      aspects related to the Master's course characteristics and the challenges
      involved in achieving its social role and meeting the clientele's needs.

PMID- 10578078
TI  - [Analysis of dental students' knowledge and concepts in oral health: evaluation
      by concept maps].
AB  - This study sought to analyze senior dental students' cognitive structure
      concerning the topic of "enamel", which is fundamentally important for
      understanding oral health, since it offers basic scientific concepts for clinical
      and preventive practices and is the main subject of several courses during
      dentistry training. The strategy used to analyze students' cognitive structures
      was Novak's Concept Maps, based on Ausubel's Meaningful Learning theory. Analysis
      of students' maps allowed for a study of students' cognitive structure and
      concepts concerning oral health. It also fostered a diagnosis of students'
      knowledge in several important aspects of scientific and professional training.
      The results highlighted the need for rethinking the teaching/learning process in
      dentistry training.

PMID- 10578079
TI  - [Sexuality and the human body: the subject's view through video images].
AB  - This study analyzes images of the body linked to sexual and reproductive behavior
      found in the communication processes mediated by so-called educational videos. In
      the relationship between subject and technology, the paper is intended to
      characterize the discourses and the view or perspective currently shaping health
      education practices. Focusing on the potential in the relationship between the
      enunciator and subjects represented in the text and the interaction between
      health professionals and messages, the study attempts to characterize the
      discourses and questions providing the basis for a given view of the body and
      sexuality. The study was conducted in the years 1996-1997 and focused on health
      professionals from the public health system. The results show a concept of
      sexuality that tends to generalize the meaning ascribed to sexual experience,
      ignoring the various ways by which different culturally defined groups attribute
      meaning to the body.

PMID- 10578080
TI  - [Lessons from health education for HIV/AIDS prevention: theoretical elements for
      the construction of a new integrated practice].
AB  - There is an evident contrast between health education practices and theoretical
      reflection concerning them as models. Health education practices have undergone
      considerable development in terms of strategies, methods, and modalities, while
      theoretical models have remained deficient, reductionist, fragmentary, and
      focused on behavior rather than social practices. Major problems include
      individualism, asymmetrical "teacher-student" relationships, students as passive
      objects of practices, lack of social and cultural contextualism, and excessive
      focus on factual behavior. We propose a praxis based on ten levels of integration
      regarding different human dimensions: 1) complexity requires interdisciplinarity;
      2) holism; 3) combined perceptual and expressive dimensions in a integrated
      language; 4) framing of practices in real contexts; 5) realization of the
      continuity between the individual and collective realms; 6) symmetrical, dialogic
      and active educational practice; 7) integration of both intellectual-cognitive
      and affective-volitional processes; 8) risks as vulnerabilities of social groups
      that are capable of organization; 9) use of imagination in role-playing games;
      10) recognition of others and diversity. Political aspects of education are
      emphasized as promoting citizenship and social change.

PMID- 10578081
TI  - General population and HIV prevention: from risk to action.
AB  - Since knowledge about AIDS transmission now appears to be very good, many
      observers are surprised that more people do not practice behavior, like safer
      sex, designed to minimize risk of contracting the disease. Still, previous
      studies have not shown that there is a direct link between knowledge and
      behavior. New models, based on people's concrete experiences, are therefore
      needed. The goal of this qualitative research, based on 61 in-depth interviews
      conducted in France, is to describe how people understand the threat of AIDS and
      how they face the risk of transmission in their sex lives. In order to understand
      preventive actions, we must study how information is interpreted and how
      knowledge is integrated, so that people perceive general or personal risk. We
      must also specify the way in which people distinguish between aspects of risk
      perception and vulnerability; feelings of personal control, constructed on the
      basis of social experiences; characteristics of situations; and finally, the
      dynamics of action. The proposed risk management model accounts for these diverse
      factors in elucidating the great diversity of actions reported. This dynamic, non
      linear model is designed to capture both the impact of perceptive and cognitive
      elements on action and vice versa.

PMID- 10578082
TI  - Evaluation of the ZIG-ZAIDS game: a playful-educative resource for HIV/AIDS
      prevention.
AB  - This article presents the evaluation process for the ZIG-ZAIDS game,
      investigating the material's applicability in formal and informal educational
      contexts, i.e., how the game has been used by health professionals, parents, and
      the target population (pre-adolescents, or children over 9 years old). The study
      involved evaluation questionnaires sent to a list of schools and institutions
      using the game, plus interviews and visits to places where the game was used and
      tested with groups of students. It also includes an analysis of evaluation
      previously sent by the authors to people who had requested the game. The results
      showed that the population's level of information is more relevant than age in
      relation to the game's impact. Another important aspect relates to ZIG-ZAIDS'
      applicability to different situations: training of health and teaching
      professionals; activities with street children; municipal institutions and
      events, schools, companies, communities, and health care centers. In summary, ZIG
      ZAIDS was found to be an entertaining, creative, and innovative alternative for
      providing information on AIDS and sexuality.

PMID- 10578083
TI  - [Evaluation of counseling activities: analysis of a person-centered prevention
      perspective].
AB  - This paper evaluates STD/HIV/AIDS counseling activities provided by the Brazilian
      National Health Care System (SUS). The following institutional health services
      were assessed: four anonymous testing and counseling centers, one clinic
      specializing in treatment for people with HIV, and five STD clinics. All the
      above are recognized as training centers by the Brazilian Ministry of Health
      (National STD/AIDS Control Program). The data were collected from March to
      September 1997. The counseling activities from these health services was compared
      with guidelines developed by the National STD/AIDS Control Program using a
      qualitative evaluation methodology. The main categories analyzed were: a)
      approaching the patient; b) active listening; c) effective communication; d) risk
      assessment and discussion of alternatives for risk reduction; and e) orientation
      concerning clinical aspects and treatment (treatment compliance and improved
      quality of life). The paper concludes by suggesting changes to improve
      counseling.

PMID- 10578084
TI  - [Health education and environmental education: an integrated experience].
AB  - This paper reports on work with elementary school teachers from different types
      of Brazilian municipalities, from the coast to the interior and from capitals to
      small towns. With the larger purpose of facilitating teachers' perception of the
      identity between environmental education and health education, the study focuses
      on local issues related to quality of life, as well as local teachers' concepts
      concerning health and the environment. Finally, the study analyzes the importance
      of intersectorial cooperative programs facilitating long-term educational
      projects.

PMID- 10578085
TI  - [Nutritional education in public health services].
AB  - The purpose of this study was to discuss the implementation of nutritional
      education in public health services from the perspective of health professionals
      (physicians and nurses) working in them. The study was conducted in the
      Municipality of Campinas, Sao Paulo State, Brazil, from October 1993 to July
      1995, using action-based research methodology. The results describe the
      construction of nutritional knowledge in training and professional institutions;
      behavior towards food-related problems in daily professional experience as
      compared to personal life; the contradiction between the apparently trivial act
      of eating and the complexity of dietary problems; the interface between the
      acceptance of this work and the incorporation of nutritional education activities
      and their actual institutionalization; and health professionals' opinions
      concerning situations permeating the implementation of activities. The paper
      concludes by referring to the need to implement nutritional education activities,
      difficulties experienced by physicians and nurses in approaching nutritional
      problems, and the importance of including nutrition in the curricula of health
      courses.

PMID- 10578086
TI  - [Literacy embodied: the pioneering work of Hortensia de Hollanda in health
      education].

PMID- 10578087
TI  - [Marijuana, health, disease, and freedom: analysis of an Internet forum].
AB  - This paper takes a Health Education perspective to analyze a debate forum on the
      Brazilian Internet site entitled "Universo On-Line", in which the following
      questions were addressed: "Do you believe that marijuana is harmful to one's
      health?" "In your opinion, should marijuana use be decriminalized?" By applying
      qualitative discourse analysis techniques to responses from the forum, we were
      able to identify six main types of discourse, reflecting the opinions of six
      "collective subjects" concerning drugs, health, disease, and freedom and existing
      as social representations in the current Brazilian collective imagination.
      Research on these social representations allows one to establish criteria for
      intervention in the field of Health Education.

PMID- 10578088
TI  - [Teaching and health: a biological view].
AB  - Living systems are structure determined systems. Teaching is never feasible, but
      learning is inevitable, a comment by an observer about some aspect of the
      constant changes occurring while life goes on. Teachers are all those who open up
      spaces for conviviality and allow congruent changes to take place. There are no
      instructive interactions in nature. Health and the biology of living systems are
      phenomena studied in different domains. What is healthy or unhealthy for humans,
      is defined by human culture. As biological phenomena, health and disease are
      relational configurations of the organism and its medium. From this perspective,
      individual health is a social phenomenon.

PMID- 10578089
TI  - [Health promotion and health education at the school of governance in health,
      National School of Public Health, Brazil].
AB  - Schools of public health should define their teaching, research, and technical
      cooperative programs on the basis of epidemiological, epistemological, and health
      care parameters, which are heavily affected by the socioeconomic context of their
      countries. Brazil's demographic and epidemiological transition has been
      characterized by an increasing prevalence of diseases and risk factors associated
      with life styles, thus requiring an extensive and in-depth change in the
      country's health care model, with a greater supply of evidence-based services and
      preventive and health promotion measures, including new initiatives in
      information, education, and communications. This article approaches the recent
      experience at the Brazilian National School of Public Health, which has added to
      its long-standing academic tradition with a strategic reorientation known as the
      School of Governance in Health, including distance education as one of its main
      teaching options. Given Brazil's prevailing social and health situation, we
      conclude by highlighting the importance of training health professionals and
      promoting research and technological development in the fields of health
      promotion and education within the context of the School of Governance in Health
      at the National School of Public Health.

PMID- 10578090
TI  - Effect of organic acids on the growth and fermentation of ethanologenic
      Escherichia coli LY01.
AB  - Hemicellulose residues can be hydrolyzed into a sugar syrup using dilute mineral
      acids. Although this syrup represents a potential feedstock for biofuel
      production, toxic compounds generated during hydrolysis limit microbial
      metabolism. Escherichia coli LY01, an ethanologenic biocatalyst engineered to
      ferment the mixed sugars in hemicellulose syrups, has been tested for resistance
      to selected organic acids that are present in hemicellulose hydrolysates.
      Compounds tested include aromatic acids derived from lignin (ferulic, gallic, 4
      hydroxybenzoic, syringic, and vanillic acids), acetic acid from the hydrolysis of
      acetylxylan, and others derived from sugar destruction (furoic, formic,
      levulinic, and caproic acids). Toxicity was related to hydrophobicity.
      Combinations of acids were roughly additive as inhibitors of cell growth. When
      tested at concentrations that inhibited growth by 80%, none appeared to strongly
      inhibit glycolysis and energy generation, or to disrupt membrane integrity.
      Toxicity was not markedly affected by inoculum size or incubation temperature.
      The toxicity of all acids except gallic acid was reduced by an increase in
      initial pH (from pH 6.0 to pH 7.0 to pH 8.0). Together, these results are
      consistent with the hypothesis that both aliphatic and mononuclear organic acids
      inhibit growth and ethanol production in LY01 by collapsing ion gradients and
      increasing internal anion concentrations.

PMID- 10578091
TI  - Novel polymer-polymer conjugates for recovery of lactic acid by aqueous two-phase
      extraction.
AB  - A new family of polymer conjugates is proposed to overcome constraints in the
      applicability of aqueous two-phase systems for the recovery of lactic acid.
      Polyethylene glycol-polyethylenimine (PEI) conjugates and ethylene oxide
      propylene oxide-PEI (EOPO-PEI) conjugates were synthesized. Aqueous two-phase
      systems were generated when the conjugates were mixed with fractionated dextran
      or crude hydrolyzed starch. With 2% phosphate buffer in the systems, phase
      diagrams with critical points of 3.9% EOPO-PEI-3.8% dextran (DEX) and 3.5% EOPO
      PEI-7.9% crude starch were obtained. The phase separation temperature of 10% EOPO
      PEI solutions titrated with lactic acid to pH 6 was 35 degrees C at 5% phosphate,
      and increased linearly to 63 degrees C at 2% phosphate. Lactic acid partitioned
      to the top conjugate-rich phase of the new aqueous two-phase systems. In
      particular, the lactic acid partition coefficient was 2.1 in 10% EOPO-PEI-8% DEX
      systems containing 2% phosphate. In the same systems, the partitioning of the
      lactic acid bacterium, Lactococcus lactis subsp. lactis, was 0.45. The
      partitioning of propionic, succinic, and citric acids was also determined in the
      new aqueous two-phase systems.

PMID- 10578092
TI  - Development of a bioartificial pancreas: I. long-term propagation and basal and
      induced secretion from entrapped betaTC3 cell cultures.
AB  - Bioartificial pancreatic constructs based on immunoisolated, insulin-secreting
      cells have the potential for providing effective, long-term treatment of type I
      (insulin-dependent) diabetes. Use of insulinoma cells, which can be amplified in
      culture, relaxes the tissue availability limitation that exists with normal
      pancreatic islet transplantations. We have adopted mouse insulinoma betaTC3 cells
      entrapped in calcium alginate/poly-L-lysine/alginate (APA) beads as our model
      system for a bioartificial pancreas, and we have characterized the effects of
      long-term propagation and of glucose concentration step changes on the
      bioenergetic status and on the metabolic and secretory activities of the
      entrapped cells. Cell bioenergetics were evaluated nonivasively by phosphorus-31
      nuclear magnetic resonance ((31)P NMR) spectroscopy, and metabolic and secretory
      parameters by assaying cell culture medium. Data indicate that net cell growth
      occurred between days 3 and 10 of the experiment, resulting in an approximate
      doubling of the overall metabolic and secretory rates and of the intracellular
      metabolite levels. Concurrently, a reorganization of cell distribution within the
      beads was observed. Following this growth period, the measured metabolic and
      secretory parameters remained constant with time. During glucose step changes in
      the perfusion medium from a high concentration of 12 to 15 mM to 0 mM for 4.5 h
      to the same high glucose concentration, the oxygen consumption rate was not
      affected, whereas insulin secretion was always glucose-responsive. Intracellular
      nucleotide triphosphates did not change during 0 mM glucose episodes performed
      early in culture history, but they declined by 20% during episodes performed
      later in the experiment. It is concluded that the system of APA-entrapped betaTC3
      cells exhibits several of the desirable characteristics of a bioartificial
      pancreas device, and that a correlation between ATP and the rate of insulin
      secretion from betaTC3 cells exists for only a domain of culture conditions.
      These findings have significant implications in tissue engineering a long-term
      functional bioartificial endocrine pancreas, in developing noninvasive methods
      for assessing construct function postimplantation, and in the biochemical
      processes associated with insulin secretion.

PMID- 10578093
TI  - Development of a bioartificial pancreas: II. Effects of oxygen on long-term
      entrapped betaTC3 cell cultures.
AB  - Tissue-engineered pancreatic constructs based on immunoisolated, insulin
      secreting cells are promising in providing an effective, relatively inexpensive,
      long-term treatment for type I (insulin-dependent) diabetes. An in vitro
      characterization of construct function under conditions mimicking the in vivo
      environment is essential prior to any extensive animal experimentation.
      Encapsulated cells may experience hypoxic conditions postimplantation as a result
      of one or more of the following: the design of the construct; the environment at
      the implantation site; or the development of fibrosis around the construct. In
      this work, we studied the effects of 3- and 4-day-long hypoxic episodes on the
      metabolic and secretory activities and on the levels of intracellular metabolites
      detectable by phosphorus-31 nuclear magnetic resonance ((31)P NMR) of
      alginate/poly-L-lysine/alginate entrapped betaTC3 mouse insulinomas continuously
      perfused with culture medium. Results show that, upon decreasing the oxygen
      concentration in the surrounding medium, the encapsulated cell system reached a
      new, lower metabolic and secretory state. Hypoxia drove the cells to a more
      anaerobic glycolytic metabolism, increased the rates of glucose consumption (GCR)
      and lactate production (LPR), and reduced the rates of oxygen consumption (OCR)
      and insulin secretion (ISR). Furthermore, hypoxia reduced the levels of
      intracellular nucleotide triphosphates (NTP) and phosphorylcholine (PC) and
      caused a rapid transient increase in inorganic phosphate (P(i)). Upon restoration
      of the oxygen concentration in the perfusion medium, all parameters returned to
      their prehypoxic levels within 2 to 3 days following either gradual
      unidirectional changes (ISR, NTP, PC) or more complicated dynamic patterns (OCR,
      GCR, LPR). A further increase in oxygen concentration in the perfusion medium
      drove OCR, ISR, NTP, PC, and P(i) to new, higher levels. It is concluded that
      (31)P NMR spectroscopy can be used for the prolonged noninvasive monitoring of
      the bioenergetic changes of encapsulated betaTC3 cells occurring with changes in
      oxygen tension. The data also indicate that the oxygen-dependent states might be
      related to the total number of viable, metabolically active cells supported by
      the particular oxygen level to which the system is exposed. These findings have
      significant implications in developing and non-invasively monitoring a tissue
      engineered bioartificial pancreas based on transformed beta cells, as well as in
      understanding the biochemical events pertaining to insulin secretion from betaTC3
      insulinomas.

PMID- 10578094
TI  - Improvement of the primary metabolism of cell cultures by introducing a new
      cytoplasmic pyruvate carboxylase reaction.
AB  - Continuous mammalian cell lines are important hosts for the production of
      biological pharmaceuticals. However, these cell lines show some severe disorders
      in primary metabolism, which they have in common with many cancer cells. This
      leads to a high throughput of substrates giving a low energy yield and ample
      toxic side products such as lactate and ammonia. Because the enzymatic connection
      between glycolysis and the tricarboxylic acid cycle (TCA) is very poor, glucose
      is mainly degraded via oxidative glycolysis. It will be shown that introducing a
      pyruvate carboxylase gene expressed in the cytoplasma into a continuous BHK-21
      cell line, and thus reconstituting the missing link between glycolysis and TCA,
      can reduce this problem. Thus, glucose consumption could be reduced by a factor
      of four and glutamine utilization up to a factor of two, compared with control.
      Moreover, a 1.4-fold-higher adenosine triphosphate (ATP) content was achieved.
      The flux of labeled [(14)C]-glucose into the TCA is shown to be enhanced,
      indicating a higher rate of oxidative glucose degradation. Host cell lines with
      an improved energy metabolism will therefore result in better exploitation of
      substrates, an increasing yield by the more efficient use of carbon source, and
      higher product integrity combined with lower production costs.

PMID- 10578095
TI  - Thermoseparating water/polymer system: a novel one-polymer aqueous two-phase
      system for protein purification.
AB  - In this study we show that proteins can be partitioned and separated in a novel
      aqueous two-phase system composed of only one polymer in water solution. This
      system represents an attractive alternative to traditional two-phase systems
      which uses either two polymers (e.g., PEG/dextran) or one polymer in high-salt
      concentration (e.g., PEG/salt). The polymer in the new system is a linear random
      copolymer composed of ethylene oxide and propylene oxide groups which has been
      hydrophobically modified with myristyl groups (C(14)H(29)) at both ends (HM
      EOPO). This polymer thermoseparates in water, with a cloud point at 14 degrees C.
      The HM-EOPO polymer forms an aqueous two-phase system with a top phase composed
      of almost 100% water and a bottom phase composed of 5-9% HM-EOPO in water when
      separated at 17-30 degrees C. The copolymer is self-associating and forms
      micellar-like structures with a CMC at 12 microM (0.01%). The partitioning
      behavior of three proteins (lysozyme, bovine serum albumin, and apolipoprotein A
      1) in water/HM-EOPO two-phase systems has been studied, as well as the effect of
      various ions, pH, and temperature on protein partitioning. The amphiphilic
      protein apolipoprotein A-1 was strongly partitioned to the HM-EOPO-rich phase
      within a broad-temperature range. The partitioning of hydrophobic proteins can be
      directed with addition of salt. Below the isoelectric point (pI) BSA was
      partitioned to the HM-EOPO-rich phase and above the pI to the water phase when
      NaClO(4)was added to the system. Lysozyme was directed to the HM-EOPO phase with
      NaClO(4), and to the water phase with Na-phosphate. The possibility to direct
      protein partitioning between water and copolymer phases shows that this system
      can be used for protein separations. This was tested on purification of
      apolipoprotein A-1 from human plasma and Escherichia coli extract. Apolipoprotein
      A-1 could be recovered in the HM-EOPO-rich phase and the majority of
      contaminating proteins in the water phase. By adding a new water/buffer phase at
      higher pH and with 100 mM NaClO(4), and raising the temperature for separation,
      the apolipoprotein A-1 could be back-extracted from the HM-EOPO phase into the
      new water phase. This novel system has a strong potential for use in biotechnical
      extractions as it uses only one polymer and can be operated at moderate
      temperatures and salt concentrations and furthermore, the copolymer can be
      recovered.

PMID- 10578096
TI  - Modeling and simulation of competition between two microorganisms for a single
      inhibitory substrate in a biofilm reactor.
AB  - A simple biofilm model was developed to simulate the competition between two
      microorganisms for a common inhibitory substrate. The following assumptions were
      made for the simulations: (1) the biofilm has a uniform thickness and is composed
      of 5 segments, (2) growth of two microorganisms A and B which utilize the common
      substrate is expressed by the Haldane kinetics with a spatial limitation term and
      is independent of the other microorganism in the biofilm reactor, and (3)
      diffusion of the substrate, movement of the microorganisms, and continuous loss
      of the biomass by shearing are expressed by Fick's Law-type equations. The
      qualitative behavior of the biofilm reactor is characterized by five regions, I
      V, depending on the operation conditions, the substrate concentration in feed,
      and the dilution rate. In region I, both microorganisms are washed out of the
      biofilm reactor. In region II, microorganism B is washed out, and in region III,
      microorganism A is washed out of the biofilm. In region IV, both microorganisms
      coexist with one another. In region V, both microorganisms coexist with a
      sustained oscillatory behavior. Convergence to regions I-V depends on the initial
      conditions. In regions II-V, washout of either or both microorganisms is also
      observed with initial conditions too far away.

PMID- 10578098
TI  - Passages 2000

PMID- 10578097
TI  - Catalytic activity and conformation of chemically modified subtilisin Carlsberg
      in organic media.
AB  - Subtilisin Carlsberg, an alkaline protease from Bacillus licheniformis, was
      modified with polyoxyethylene (PEG) or aerosol-OT (AOT), and the solubility,
      conformation, and catalytic activity of the modified subtilisins in some organic
      media were compared under the same conditions. The solubility of modified
      subtilisins depended on the solubility of the modifier. On the other hand, the
      conformational changes depended on the solubility, rather than the property, of
      the modifier. When the modified subtilisin was dissolved in water-miscible polar
      solvents such as dimethylsulfoxide, acetonitrile, and tetrahydrofuran,
      significant conformational changes occurred. When modified subtilisin was
      dissolved in water-immiscible organic solvents, such as isooctane and benzene,
      the solvent did not induce significant conformational changes. The catalytic
      activity in the transesterification reaction of the N-acetyl-L-phenylalanine
      ethylester of the modified subtilisin in organic solvents was higher than that of
      native subtilisin. The high activity of modified subtilisin was thought to be due
      to a homogeneous reaction by the dissolved enzymes.

PMID- 10578100
TI  - Synaptic connections of DB3 diffuse bipolar cell axons in macaque retina.
AB  - In primate retinas, the dendrites of DB3 diffuse bipolar cells are known to
      receive inputs from cones. The goal of this study was to describe the synaptic
      connections of DB3 bipolar cell axons in the inner plexiform layer. DB3 bipolar
      cells in midperipheral retina were labeled with antibodies to calbindin, and
      their axons were analyzed in serial, ultrathin sections by electron microscopy.
      Synapses were found almost exclusively at the axonal varicosities of DB3 axon
      terminals. There were 2.14 synaptic ribbons per varicosity. There were 33
      varicosities per DB3 cell, giving an average of 71 ribbons per axon terminal.
      Because there were 1.5 postsynaptic ganglion cell dendrites per DB3 axonal
      varicosity, we estimate that there is at least 1 synapse per varicosity onto a
      parasol ganglion cell dendrite. There were 3.4 input synapses from amacrine cells
      per axonal varicosity. Among these were feedback synapses to the DB3 bipolar cell
      axon varicosities, which were made by 47% of the postsynaptic amacrine cell
      processes. Some of the feedback synapses could be from amacrine cells
      immunoreactive for cholecystokinin precursor or choline acetyltransferase,
      because both types of amacrine cells costratify with parasol cells and are known
      to be presynaptic to bipolar cells. AII amacrine cells were both presynaptic and
      postsynaptic to DB3 axons, a finding consistent with the large rod input to
      parasol ganglion cells reported in physiological experiments. DB3 bipolar cell
      axons also made frequent contacts with neighboring DB3 axons, and gap junctions
      were always found at these sites.

PMID- 10578099
TI  - Diffuse bipolar cells provide input to OFF parasol ganglion cells in the macaque
      retina.
AB  - Parasol retinal ganglion cells are more sensitive to luminance contrast and
      respond more transiently at all levels of adaptation than midget ganglion cells.
      This may be due, in part, to differences between bipolar cells that provide their
      input, and the goal of these experiments was to study these differences. Midget
      bipolar cells are known to be presynaptic to midget ganglion cells. To identify
      the bipolar cells presynaptic to parasol cells, these ganglion cells were
      intracellularly injected with Neurobiotin, cone bipolar cells were immunolabeled,
      and the double-labeled material was analyzed. In the electron microscope, we
      found that DB3 diffuse bipolar cells labeled by using antiserum to calbindin D
      28k were presynaptic to OFF parasol cells. In the confocal microscope, DB3
      bipolars costratified with OFF parasol cell dendrites and made significantly more
      appositions with them than expected due to chance. Flat midget bipolar cells were
      labeled with antiserum to recoverin. Although they made a few appositions with
      parasol cells, the number was no greater than would be expected when two sets of
      processes have overlapping distributions in the inner plexiform layer. DB2
      diffuse bipolar cells were labeled with antibodies to excitatory amino acid
      transporter 2, and they also made appositions with OFF parasol cells. These
      results suggest that DB2 bipolar cells are also presynaptic to OFF parasol
      ganglion cells, but midget bipolar cells are not. We estimate that midperipheral
      OFF parasol cells receive approximately 500 synapses from 50 DB3 bipolar cells
      that, in turn, receive input from 250 cones.

PMID- 10578102
TI  - Induction of c-fos-like and fosB-like immunoreactivity reveals forebrain neuronal
      populations involved differentially in pup-mediated maternal behavior in juvenile
      and adult rats.
AB  - Juvenile rats can exhibit maternal behavior after being exposed continuously to
      rat pups, a process called sensitization. Maternal behavior in juveniles is
      robust and is similar to adult maternal behavior (Mayer and Rosenblatt [1979]
      Dev. Psychobiol. 12:407-424; Gray and Chesley [684] J. Comp. Psychol. 98:91-99).
      In this study, immunocytochemical detection of the protein products of two
      immediate-early genes, c-fos and fosB, was used as a tool to identify forebrain
      neuronal populations involved in the maternal behavior of 27-day-old juvenile
      rats compared with 60-day-old adults. To sensitize them, rats were exposed
      continuously to foster pups. Once they were maternal, they were isolated from
      pups overnight, reexposed to pups for 2 hours, and then killed. Nonmaternal
      control animals also were isolated overnight and were either reexposed to pups
      for 2 hours or kept isolated from pups before killing. The lateral habenula (LH)
      was the only area in which both maternal juveniles and maternal adults had more c
      Fos-immunoreactive (-Ir) neurons compared with controls. In maternal adults, the
      number of neurons that expressed c-Fos and FosB immunoreactivity increased in the
      medial preoptic area (MPO) and the ventral bed nucleus of the stria terminalis
      (BSTv), whereas the dorsal bed nucleus of the stria terminalis (BSTd) and the
      medial and cortical nuclei of the amygdala (MEA and COA, respectively) had
      increases only in the number of neurons that expressed c-Fos immunoreactivity. In
      contrast, juveniles, whether or not they were maternal, had the same number of c
      Fos-IR and FosB-Ir neurons in all these areas. The adult-like increase in the
      number of c-Fos-Ir neurons found in maternal juveniles suggests that the juvenile
      LH participates in the neural circuit that supports maternal behavior in an adult
      like manner. The lack of c-fos or fosB induction in the MPO, BSTv, BSTd, COA, or
      MEA of maternal juveniles compared with maternal adults may reflect the
      immaturity of these brain regions in juvenile rats. Exactly what this immaturity
      consists of and when the responses of these regions become adult-like remain to
      be determined.

PMID- 10578101
TI  - Identification of a subpopulation of substantia nigra pars compacta gamma
      aminobutyric acid neurons that is regulated by basal ganglia activity.
AB  - In this report, the authors provide a novel description of a population of gamma
      aminobutyric acid-containing neurons in the substantia nigra, pars compacta
      (SNC). By using metabolic mapping of the immediate-early gene, c-fos, the
      activation pattern of these cells was characterized with respect to basal ganglia
      stimulation. Dopaminergic stimulation with d-amphetamine or apomorphine induced
      Fos expression in the central region of the SNC. However, lesions of the
      nigrostriatal dopamine pathway significantly reduced d-amphetamine- and
      apomorphine-induced Fos expression in the ipsilateral and contralateral SNC,
      respectively. Suppression of stimulant-induced Fos expression in the striatum,
      using antisense oligodeoxynucleotides, also eliminated Fos expression in the
      ipsilateral SNC, indicating that striatal efferent projections are involved in
      the activation of these cells. Double-labeling immunohistochemistry revealed that
      the Fos-positive cells did not express tyrosine hydroxylase but were
      immunoreactive for glutamic acid decarboxylase. Retrograde labeling of
      nigrostriatal neurons, combined with Fos immunofluorescence, revealed that these
      Fos-positive cells did not project to the striatum. Thus, these neurons do not
      appear to comprise a nondopaminergic nigrostriatal circuit but likely represent
      locally-projecting interneurons of the substantia nigra.

PMID- 10578103
TI  - Auditory cortex on the human posterior superior temporal gyrus.
AB  - The human superior temporal cortex plays a critical role in hearing, speech, and
      language, yet its functional organization is poorly understood. Evoked potentials
      (EPs) to auditory click-train stimulation presented binaurally were recorded
      chronically from penetrating electrodes implanted in Heschl's gyrus (HG), from
      pial-surface electrodes placed on the lateral superior temporal gyrus (STG), or
      from both simultaneously, in awake humans undergoing surgery for medically
      intractable epilepsy. The distribution of averaged EPs was restricted to a
      relatively small area on the lateral surface of the posterior STG. In several
      cases, there were multiple foci of high amplitude EPs lying along this
      acoustically active portion of STG. EPs recorded simultaneously from HG and STG
      differed in their sensitivities to general anesthesia and to changes in rate of
      stimulus presentation. Results indicate that the acoustically active region on
      the STG is a separate auditory area, functionally distinct from the HG auditory
      field(s). We refer to this acoustically sensitive area of the STG as the
      posterior lateral superior temporal area (PLST). Electrical stimulation of HG
      resulted in short-latency EPs in an area that overlaps PLST, indicating that PLST
      receives a corticocortical input, either directly or indirectly, from HG. These
      physiological findings are in accord with anatomic evidence in humans and in
      nonhuman primates that the superior temporal cortex contains multiple
      interconnected auditory areas.

PMID- 10578104
TI  - Mushroom bodies of vespid wasps.
AB  - Mushroom bodies are higher centers in the brains of insects. Studies on honey
      bees and species of ants suggest that these centers are particularly prominent in
      social insects. The present study confirms the presence of large mushroom bodies
      in five subfamilies of vespid wasps, while at the same time showing significant
      departures from the mushroom body organization that typifies bees and ants.
      Although the basic organizational plan of the insect mushroom body into calyces,
      peduncle, and lobes is maintained, as is the arrangement of axons of intrinsic
      neurons, the size and arrangements of the vespid mushroom body lobes differ
      markedly from those known from other Hymenoptera. Furthermore, considerable
      variation is found both between and within vespid subfamilies. The present
      results are discussed with respect to current hypotheses about functional
      attributes of mushroom bodies and the phylogeny of the Vespidae.

PMID- 10578105
TI  - Comparison of cortically and subcortically controlled motor systems. II.
      Distribution of anterogradely labeled terminal boutons on intracellularly filled
      rubrospinal neurons in rat and turtle.
AB  - The present study examined the circuitry of the red nucleus of the Sprague-Dawley
      rat and the freshwater pond turtle, Chrysemys picta, by using intracellular cell
      filling combined with anterograde tract tracing. Although both species have a
      well-developed cerebellorubral system, they differ in that the red nucleus of
      rats receives direct input from the motor areas of the cerebral cortex, whereas
      turtles do not. However, a direct descending projection from the hypothalamus to
      the red nucleus of turtles has been described. The aim of this study was to
      elucidate the relative functional contributions of the cerebellum and descending
      inputs to motor signal generation in the red nucleus. The results show that the
      cellular distribution of cerebellar inputs on rubrospinal neurons is similar
      between the rat and turtle; these projections are observed on the soma and the
      proximal and distal dendrites. In contrast, the hypothalamic inputs in turtles
      occupy mainly the more distally located dendrites, similar to the position of the
      cortical inputs in rats. These findings suggest that, first, the cerebellar
      inputs are not spatially segregated from the cortical or hypothalamic inputs in
      rats or turtles, as far as can be determined by light microscopy. Second, there
      is specificity of input from the cortex in rats and hypothalamus in turtles onto
      the distal portions of the dendrites. The similarity in the organizational
      features of the mammalian and non-mammalian cerebellorubrospinal systems has
      implications for interpretations of the relative roles of the cerebellum and
      cerebral cortex in motor control.

PMID- 10578106
TI  - Differential vulnerability of oculomotor, facial, and hypoglossal nuclei in G86R
      superoxide dismutase transgenic mice.
AB  - In recent years, several mouse models of amyotrophic lateral sclerosis (ALS) have
      been developed. One, caused by a G86R mutation in the superoxide dismutase-1 (SOD
      1) gene associated with familial ALS, has been subjected to extensive
      quantitative analyses in the spinal cord. However, the human form of ALS includes
      pathology elsewhere in the nervous system. In the present study, analyses were
      extended to three motor nuclei in the brainstem. Mutant mice and control
      littermates were evaluated daily, and mutants, along with their littermate
      controls, were killed when they were severely affected. Brains were removed after
      perfusion and processed for Nissl staining, the samples were randomized, and the
      investigators were blinded to their genetic status. Stereologic methods were used
      to estimate the number of neurons, mean neuronal volumes, and nuclear volume in
      three brainstem motor nuclei known to be differentially involved in the human
      form of the disease, the oculomotor, facial, and hypoglossal nuclei. In the
      facial nucleus, neuron number consistently declined (48%), an effect that was
      correlated with disease severity. The nuclear volume of the facial nucleus was
      smaller in the SOD-1 mutant mice (45.7% difference from control mice) and
      correlated significantly with neuron number. The oculomotor and hypoglossal
      nuclei showed less extreme involvement (<10% neuronal loss overall), with a trend
      toward fewer neurons in the hypoglossal nucleus of animals with severe facial
      nucleus involvement. In the oculomotor nucleus, neuronal loss was seen only once
      in five mice, associated with very severe disease. There was no significant
      change in the volume of individual neurons in any of these three nuclei in any
      transgenic mouse. These results suggest that different brainstem motor nuclei are
      differentially affected in this SOD-1 mutant model of ALS. The relatively
      moderate and late involvement of the hypoglossal nucleus indicates that, although
      the general patterns of neuronal pathology match closely those seen in ALS
      patients, some differences exist in this transgenic model compared with the
      progression of the disease in humans. However, these patterns of cellular
      vulnerability may provide clues for understanding the differential susceptibility
      of neural structures in ALS and other neurodegenerative diseases.

PMID- 10578107
TI  - Development and evolutionary origin of feathers.
AB  - Avian feathers are a complex evolutionary novelty characterized by structural
      diversity and hierarchical development. Here, I propose a functionally neutral
      model of the origin and evolutionary diversification of bird feathers based on
      the hierarchical details of feather development. I propose that feathers
      originated with the evolution of the first feather follicle-a cylindrical
      epidermal invagination around the base of a dermal papilla. A transition series
      of follicle and feather morphologies is hypothesized to have evolved through a
      series of stages of increasing complexity in follicle structure and follicular
      developmental mechanisms. Follicular evolution proceeded with the origin of the
      undifferentiated collar (stage I), barb ridges (stage II), helical displacement
      of barb ridges, barbule plates, and the new barb locus (stage III),
      differentiation of pennulae of distal and proximal barbules (stage IV), and
      diversification of barbule structure and the new barb locus position (stage V).
      The model predicts that the first feather was an undifferentiated cylinder (stage
      I), which was followed by a tuft of unbranched barbs (stage II). Subsequently,
      with the origin of the rachis and barbules, the bipinnate feather evolved (stage
      III), followed then by the pennaceous feather with a closed vane (stage IV) and
      other structural diversity (stages Va-f). The model is used to evaluate the
      developmental plausibility of proposed functional theories of the origin of
      feathers. Early feathers (stages I, II) could have functioned in communication,
      defense, thermal insulation, or water repellency. Feathers could not have had an
      aerodynamic function until after bipinnate, closed pennaceous feathers (stage IV)
      had evolved. The morphology of the integumental structures of the coelurisaurian
      theropod dinosaurs Sinosauropteryx and Beipiaosaurus are congruent with the
      model's predictions of the form of early feathers (stage I or II). Additional
      research is required to examine whether these fossil integumental structures
      developed from follicles and are homologous with avian feathers. J. Exp. Zool.
      (Mol. Dev. Evol.) 285:291-306, 1999.

PMID- 10578108
TI  - Modularity in animal development and evolution: elements of a conceptual
      framework for EvoDevo.
AB  - For at least a century biologists have been talking, mostly in a black-box sense,
      about developmental mechanisms. Only recently have biologists succeeded broadly
      in fishing out the contents of these black boxes. Unfortunately the view from
      inside the black box is almost as obscure as that from without, and developmental
      biologists increasingly confront the need to synthesize known facts about
      developmental phenomena into mechanistic descriptions of complex systems. To
      evolutionary biologists, the emerging understanding of developmental mechanisms
      is an opportunity to understand the origins of variation not just in the
      selective milieu but also in the variability of the developmental process, the
      substrate for morphological change. Ultimately, evolutionary developmental
      biology (EvoDevo) expects to articulate how the diversity of organic form results
      from adaptive variation in development. This ambition demands a shift in the way
      biologists describe causality, and the central problem of EvoDevo is to
      understand how the architecture of development confers evolvability. We argue in
      this essay that it makes little sense to think of this question in terms of
      individual gene function or isolated morphometrics, but rather in terms of higher
      order modules such as gene networks and homologous characters. We outline the
      conceptual challenges raised by this shift in perspective, then present a
      selection of case studies we believe to be paradigmatic for how biologists think
      about modularity in development and evolution. J. Exp. Zool. (Mol. Dev. Evol.)
      285:307-325, 1999.

PMID- 10578109
TI  - The evolutionary challenges of extreme environments (Part 1).

PMID- 10578110
TI  - Molecular evolution of the synapsin gene family.
AB  - Synapsins, a family of synaptic vesicle proteins, play a crucial role in the
      regulation of neurotransmission and synaptogenesis. They have been identified in
      a variety of invertebrate and vertebrate species, including human, rat (Rattus
      norvegicus), cow (Bos taurus), longfin squid (Loligo pealei), and fruit fly
      (Drosophila melanogaster). Here, synapsins were cloned from three additional
      species: frog (Xenopus laevis), lamprey (Lampetra fluviatilis), and nematode
      (Caenorhabditis elegans). Synapsin protein sequences from all these species were
      then used to explore the molecular phylogeny of these important neuronal
      phosphoproteins. The ancestral condition of a single synapsin gene probably gave
      rise to the vertebrate synapsin gene family comprised of at least three synapsin
      genes (I, II, and III) in higher vertebrates. Synapsins possess multiple domains,
      which have evolved at different rates throughout evolution. In invertebrate
      synapsins, the most conserved domains are C and E. During the evolution of
      vertebrates, at least two gene duplication events are hypothesized to have given
      rise to the synapsin gene family. This was accompanied by the emergence of an
      additional conserved domain, termed A. J. Exp. Zool. ( Mol. Dev. Evol. ) 285:360
      377, 1999.

PMID- 10578111
TI  - Gene duplication and recruitment of a specific tropomyosin into striated muscle
      cells in the jellyfish Podocoryne carnea.
AB  - Cnidaria are the most basal animal phylum in which smooth and striated muscle
      cells have evolved. Since the ultrastructure of the mononucleated striated muscle
      is similar to that of higher animals, it is of interest to compare the striated
      muscle of Cnidaria at the molecular level to that of triploblastic phyla. We have
      used tropomyosins, a family of actin binding proteins to address this question.
      Throughout the animal kingdom, a great diversity of tropomyosin isoforms is found
      in non-muscle cells but only a few conserved tropomyosins are expressed in muscle
      cells. Muscle tropomyosins are all similar in length and share conserved termini.
      Two cnidarian tropomyosins have been described previously but neither of them is
      expressed in striated muscle cells. Here, we have characterized a new tropomyosin
      gene Tpm2 from the hydrozoan Podocoryne carnea. Expression analysis by RT-PCR and
      by whole mount in situ hybridization demonstrate that Tpm2 is exclusively
      expressed in striated muscle cells of the medusa. The Tpm2 protein is shorter in
      length than its counterparts from higher animals and differs at both amino and
      carboxy termini from striated muscle isoforms of higher animals. Interestingly,
      Tpm2 differs considerably from Tpm1 (only 19% identity) which was described
      previously in Podocoryne carnea. This divergence indicates a functional
      separation of cytoskeletal and striated muscle tropomyosins in cnidarians. These
      data contribute to our understanding of the evolution of the tropomyosin gene
      family and demonstrate the recruitment of tropomyosin into hydrozoan striated
      muscles during metazoan evolution. J. Exp. Zool. (Mol. Dev. Evol.) 285:378-386,
      1999.

PMID- 10578112
TI  - Isolation and identification of terpenoid sex pheromone components from extracts
      of hemolymph of males of the Caribbean fruit fly.
AB  - Extracts obtained from hemolymph of sexually mature males of the Caribbean fruit
      fly Anastrepha suspensa contained four biologically important terpenoid
      components of the sex pheromone. The four components were identified as
      farnesene, bisabolene, anastrephin, and epianastrepin based on their relative
      retention indexes from capillary gas chromatography analysis, using both apolar
      and polar phase columns and their chemical ionization (isobutane) mass spectra.
      The ratio of the components in extracts of hemolymph was the same as the ratio
      present in the volatile blend of pheromone released by sexually mature males
      during the reproductive period. Studies conducted to determine the effect of age
      on amounts of these components in hemolymph indicated that they increased from
      undetectable levels on the day of adult emergence to maximum levels on day eight.
      The increases in amounts of the components present in hemolymph with increasing
      age were correlated with increases in amounts of volatile pheromone released by
      males. Time of day studies showed that the amounts of these components in
      hemolymph followed the daily pattern of release of volatile pheromone components.
      Other components of the sex pheromone including ocimene, (Z)-3-nonen-1-ol, (Z,Z)
      3,6-nonadien-1-ol and suspensolide were not found in extracts of hemolymph. The
      data suggest that the hemolymph plays a role in the transport of these pheromone
      components during sexual signalling. Arch. Insect Biochem. Physiol. 42:225-232,
      1999. Published 1999 Wiley-Liss, Inc.

PMID- 10578113
TI  - Hormonal activation of phosphorylase in cockroach fat body trophocytes: A
      correlation with trans-membrane calcium flux.
AB  - This study is an investigation of the temporal relationship between transmembrane
      Ca(2+) fluxes, and glycogen phosphorylase activation in dispersed trophocytes
      from the fat body of the cockroach, Periplaneta americana. Phosphorylase is
      maximally activated within 5 min after treating the trophocytes with either of
      the hypertrehalosemic hormones, Pea-HTH-I and Pea-HTH-II. Activation caused by
      Pea-HTH-II is sustained for a longer period than that produced by Pea-HTH-I.
      Chelation of extracellular Ca(2+) with EGTA blocks the activation of
      phosphorylase by HTH. Similarly, chelation of intracellular Ca(2+) with Quin 2
      greatly diminishes the phosphorylase activating effect of both HTHs. The data
      support the view that an increase in the intracellular Ca(2+ )concentration is
      required for the activation of phosphorylase and that extracellular Ca(2+) is an
      essential, although not necessarily sole, source of Ca(2+) for this purpose.
      Using (45)Ca(2+) to trace the movement of Ca(2+) following a challenge with
      either Pea-HTH-I or -II, it was shown that (45)Ca(2+)influx nearly doubled during
      the first 30 s. At this time, the trophocytes begin to expel Ca(2+) at a rate
      higher than that of untreated cells and this state persists for approximately 4
      min. The Ca(2+) fluxes are consistent with its postulated role in the activation
      of phosphorylase. Arch.

PMID- 10578114
TI  - Analysis of an insect neuropeptide, Schistocerca gregaria ion transport peptide
      (ITP), expressed in insect cell systems.
AB  - We have produced an active form of Schistocerca gregaria ion transport peptide
      (ITP) in an insect cell expression system. Transformed Drosophila Kc1 cells
      secreted a form of ITP into the cell culture medium that was proteolytically
      cleaved correctly at the amino (N)-terminus. Concentrated culture supernatant
      from transformed Kc1 and Hi5 cells had high biological activity when tested on
      isolated locust ilea. Conversely, ITP expressed by baculovirus-infected Sf9 cells
      was larger in size and had decreased specific activity compared to ITP produced
      by Kc1 cells due to incorrect cleavage of the peptide at the N-terminus in the
      baculovirus system. This demonstrates how processing of the secreted foreign
      protein (ITP) expressed under the late polyhedrin promoter is compromised in a
      baculovirus-infected cell. Transient transformation of Kc1 cells results in
      supernatants containing two forms of ITP; one form (A) co-elutes with synthetic
      ITP and the other form (B) has reduced electrophoretic mobility. In contrast, in
      stably transformed Kc1 cell supernatant, ITP is expressed in a single form, which
      has the same electrophoretic mobility and specific biological activity as form A
      produced by transiently transformed Kc1 cells. Arch.

PMID- 10578115
TI  - Physiological control of pheromone production in Choristoneura fumiferana and C.
      rosaceana.
AB  - The diel periodicity of calling behavior and pheromone production are synchronous
      in virgin females of both Choristoneura fumiferana and C. rosaceana (Lepidoptera:
      Tortricidae). Newly emerged females decapitated prior to scotophase produced no
      or very little pheromone 24 h later. However, injection of PBAN or Br-SEG
      homogenates, obtained from donors of the same or the other species, stimulated
      pheromone production to normal levels. Transection of the ventral nerve cord
      (VNC) or extirpation of the terminal abdominal ganglion (TAG) did not affect
      pheromone production in control females. Similarly, injections of PBAN or Br-SEG
      homogenates into decapitated females reactivated pheromone production to normal
      levels, whether or not the VNC was intact or the TAG present. Furthermore,
      octopamine was not effective in stimulating pheromone production in decapitated
      females. Taken together, these results indicate that the regulation of pheromone
      production is not neurally mediated in either Choristoneura species. However,
      there was no evidence that hemolymph collected from pheromone-producing females
      contained pheromonotropic activity. Similarly, isolated glands incubated with
      PBAN did not produce pheromone. The presence of the bursa copulatrix was required
      to produce pheromone in both tortricids as production was not restored in
      decapitated bursa-less females injected with PBAN or a Br-SEG homogenate.
      However, an extract of the bursa copulatrix did not elicit pheromonotropic
      activity in decapitated females or incubated glands of either species. The bursa
      copulatrix is only involved in pheromone production of some species of tortricids
      but our results do not support the current explanation for such interspecific
      differences. We postulate that the relative importance of a bursa factor may be
      related to the evolution of different desaturation systems used for pheromone
      biosynthesis in the Tortricidae. Arch.

PMID- 10578116
TI  - Destruction of smallpox stocks.

PMID- 10578117
TI  - The relation of prophylactic inoculations to the onset of poliomyelitis. 1950.

PMID- 10578118
TI  - Active and passive immunisation against respiratory syncytial virus.
AB  - RSV is a major cause of respiratory illness in infants under 2 years of age.
      Evidence is accumulating that it is also underestimated as a cause of respiratory
      infection in adults, the elderly and immunocompromised individuals. Active
      interventions to control the impact of RSV infection have been hampered by a lack
      of understanding of the immune response to RSV in different age groups. A number
      of different strategies for developing RSV vaccines have been pursued, including
      live attenuated vaccines, genetically engineered live and subunit vaccines and
      peptide vaccines with varying degrees of success. The target populations for RSV
      vaccines include infants, the elderly and women of childbearing age, but the
      efficacy of different vaccines may differ according to age. Desirable immune
      responses and immune correlates of protection to RSV in humans remain uncertain
      and determining these is critical for introduction of any vaccines. Prophylaxis
      and treatment of RSV in infants using human immunoglobulin containing high titres
      of RSV specific neutralising antibody (RSV-Ig) has shown limited success in
      different infant populations. Prophylaxis of premature infants with RSV-Ig,
      particularly those with bronchopulmonary dysplasia, has demonstrated limited
      clinical efficacy against RSV. In contrast, there are significant safety concerns
      for use of this preparation for prophylaxis in infants with congenital heart
      disease and no demonstrable efficacy in treatment of RSV disease in healthy
      infants. The cost of the preparation will limit use to highly selected infant
      groups. Production of humanized monoclonal antibodies to RSV offers another
      potential passive immunotherapy intervention for RSV, with increased specific
      activity and reduced side effects, although its use remains experimental.

PMID- 10578120
TI  - Human herpesvirus 7.
AB  - Human herpesvirus 7, reported in 1990 is a lymphotropic member of the
      betaherpesvirus subfamily of herpesviruses. The virus is highly seroprevalent,
      primary infection usually occurs during childhood, and it has been associated
      with cases of exanthem subitum, pityriasis rosea, neurological manifestations and
      transplant complications. The latter two may warrant antiviral intervention, in
      vitro studies have shown that HHV-7 is susceptible to several nucleoside
      phosphonate compounds. In vitro, the virus has approximately a 5 day growth cycle
      in cultured lymphocytes; in vivo, latency is established in peripheral blood T
      cells and a persistent infection is established in salivary gland tissue from
      which infectious virus is constitutively shed in saliva. The HHV-7 genome is
      approximately 145 kb and encodes at least 84 different proteins. Studies
      characterising HHV-7 gene products and the required interactions between viral
      and cellular genes necessary for virus replication, persistence and latency are
      in their infancy. HHV-7 infection has a variety of effects on host cells
      including upregulation of interleukin 15 and down-modulation of the cell surface
      molecule CD4; the latter serves as the cellular membrane receptor for HHV-7.
      Since HIV also infects T-cells via the CD4 molecule, the interactions of these
      viruses within T-cells during the course of AIDS are important areas of
      investigation.

PMID- 10578119
TI  - The development of live attenuated cold-adapted influenza virus vaccine for
      humans.
AB  - A procedure to attenuate live influenza virus of type A and type B was developed
      using adaptation of the virus to grow at 25 degrees C (cold adaptation; ca).
      Through a series of stepwise passages, two stable mutants were obtained and
      designated as 'Master' strains, one for type A influenza virus (A/Ann Arbor/6/60
      H2N2) and one for type B influenza virus (B/Ann Arbor/1/66). These mutants were
      used in genetic reassortment using either the classical method or more recently
      described reverse genetics to update the relevant surface antigens of the
      circulating strains of influenza virus. The derivation is based on the concept of
      6/2 where 6 signifies the six internal genes of the master strain and 2 refers to
      the two genes coding for the two surface glycoproteins HA and NA of the
      circulating influenza virus. The advantages of this vaccine were demonstrated to
      be (1) proper level of attenuation, (2) non-transmissibility, (3) genetic
      stability, (4) presence of the ca and ts markers and (5) immunogenicity involving
      both local and the cell-mediated immune responses. The clinical trials in
      infants, children, adults and elderly have provided the necessary data for
      eventual licensing of this vaccine. The ease of administration (intranasal)
      safety and high efficacy make this vaccine suitable to prevent influenza virus
      infection in all age groups.

PMID- 10578121
TI  - In vivo models for Epstein-Barr virus (EBV)-associated B cell lymphoproliferative
      disease (BLPD).
AB  - EBV infects B lymphocytes in vivo and establishes a life-long persistent
      infection in the host. The latent infection is controlled by EBV-specific MHC
      class 1-restricted CTL. Immunosuppression reduces CTL activity, and this
      facilitates outgrowth of EBV+ve B cell lymphoproliferative disease (BLPD). BLPD
      are aggressive lesions with high mortality. This review presents some key facets
      in the development of EBV-associated BLPD and in vivo studies on its
      pathogenesis. The animal models used to date include the common marmoset
      (Callithrix jacchus), the cottontop tamarin (Saguinus oedipus oedipus), rhesus
      monkey, murine herpesvirus 68 (MHV68), and the severe combined immunodeficient
      (scid) mouse, each of which has been used to address particular aspects of EBV
      biology and BLPD development. Scid mice inoculated i.p. with PBMC from EBV
      seropositive individuals develop EBV+ve BLPD-like tumours. Thus this small animal
      model (hu-PBMC-scid) is currently used by many laboratories to investigate EBV
      associated diseases. We and others have studied BLPD pathogenesis in the hu-PBMC
      scid model and shown that EBV+ve B cells on their own do not give rise to tumours
      in this model without inclusion of autologous T cell subsets in the inoculum.
      Based on the findings that (1) established tumours do not contain T cells and (2)
      tumour cells express a variety of B cell growth factors, a stepwise model of
      lymphomagenesis in the scid mouse model can be defined. Additionally, the hu-PBMC
      scid model can be used to assess novel therapeutic regimes against BLPD before
      introduction into a clinical setting.

PMID- 10578122
TI  - Antiviral developments. Three new drugs approved for treatment of HIV infection.

PMID- 10578124
TI  - Contractile 5-HT1B receptors in human cerebral arteries: pharmacological
      characterization and localization with immunocytochemistry.
AB  - 1 The cerebrovascular receptor(s) that mediates 5-hydroxytryptamine (5-HT)
      induced vasoconstriction in human cerebral arteries (HCA)has proven difficult to
      characterize, yet these are essential in migraine. We have examined 5-HT receptor
      subtype distribution in cerebral blood vessels by immunocytochemistry with
      antibodies selective for human 5-HT1B and human 5-HT1D receptors and also studied
      the contractile effects of a range of 5-HT receptor agonists and antagonists in
      HCA. 2 Immunocytochemistry of cerebral arteries showed dense 5-HT1B receptor
      immunoreactivity (but no 5-HT1D receptor immunoreactivity) within the smooth
      muscle wall of the HCA. The endothelial cell layer was well preserved and weak 5
      HT1B receptor immunoreactivity was present. 3 Pharmacological experiments on HCA
      with intact endothelium showed that 5-carboxamidotryptamine was significantly
      more potent than alpha-methyl-5-HT, 2-methyl-5-HT and 5-HT in causing
      vasoconstriction. The 5-HT1B/1D receptor agonists naratriptan, sumatriptan,
      zolmitriptan and 181C91 (N-desmethyl zolmitriptan), all induced equally strong
      contractions and with similar potency as 5-HT. The maximum contractile response
      was significantly less for avitriptan and dihydroergotamine. There was a
      significant correlation between vasoconstrictor potency and 5-HT1B- and 5-HT1D
      receptor affinity, but not with 5-HT1A-, 5-ht1F or 5-HT2- receptor affinity. 4
      The 5-HT1B/1D-receptor antagonist GR 55562 (10-7 - 10-6 M) inhibited the
      contractile responses to sumatriptan and 5-CT in a competitive manner with a pKB
      value for GR 55562 of 7.4. Furthermore, ketanserin (10-7 M), prazosin (10-7 M),
      and sulpiride (10-7 M) were devoid of significant antagonistic activity of 5-HT
      induced contraction in the HCA. 5 The results are compatible with the hypothesis
      that the 5-HT1B receptors play a major role in 5-HT-induced vasoconstriction in
      HCA.

PMID- 10578123
TI  - Cyclo-oxygenase-2: pharmacology, physiology, biochemistry and relevance to NSAID
      therapy.
AB  - Cyclo-oxygenase is expressed in cells in two distinct isoforms. Cyclo-oxygenase-1
      is present constitutively whilst cyclo-oxygenase-2 is expressed primarily after
      inflammatory insult. The activity of cyclo-oxygenase-1 and -2 results in the
      production of a variety of potent biological mediators (the prostaglandins) that
      regulate homeostatic and disease processes. Inhibitors of cyclo-oxygenase include
      the nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin, ibuprofen and
      diclofenac. NSAIDs inhibit cyclo-oxygenase-2 at the site of inflammation, to
      produce their therapeutic benefits, as well as cyclo-oxygenase-1 in the gastric
      mucosa, which produces gastric damage. Most recently selective inhibitors of
      cyclo-oxygenase-2 have been developed and introduced to man for the treatment of
      arthritis. Moreover, recent epidemiological evidence suggests that cyclo
      oxygenase inhibitors may have important therapeutic relevance in the prevention
      of some cancers or even Alzheimer's disease. This review will discuss how the new
      advancements in NSAIDs research has led to the development of a new class of
      NSAIDs that has far reaching implications for the treatment of disease.

PMID- 10578125
TI  - Chronic and acute effects of thiazolidinediones BM13.1258 and BM15.2054 on rat
      skeletal muscle glucose metabolism.
AB  - 1 New thiazolidinediones BM13.1258 and BM15.2054 were studied with regard to
      their PPARgamma-agonistic activities and to their acute and chronic effects on
      glucose metabolism in soleus muscle strips from lean and genetically obese rats.
      2 Both BM13.1258 and BM15.2054 revealed to be potent PPARgamma-activators in
      transient transfection assays in vitro. 3 In insulin-resistant obese rats, but
      not in lean rats, 10 days of oral treatment with either compound increased the
      stimulatory effect of insulin on muscle glycogen synthesis to a similar extent
      (insulin-induced increment in micromol glucose incorporated into glycogen g-1 h
      1: control, +1.19+/-0.28; BM13.1258, +2.50+/-0.20; BM15.2054, +2.55+/-0.46;
      P<0.05 vs control each). 4 In parallel to insulin sensitization, mean glucose
      oxidation increased insulin-independently in response to BM13.1258 (to 191 and
      183% of control in the absence and presence of insulin, respectively; P<0.01
      each), which was hardly seen in response to BM15.2054 (to 137 and 124% of
      control, respectively; ns). 5 Comparable effects on PPARgamma activation and on
      amelioration of insulin resistance by BM13.1258 and BM15.2054 were therefore
      opposed by different effects on glucose oxidation. 6 In contrast to chronic oral
      treatment, acute exposure of muscles to BM13.1258 or BM15.2054 in vitro elicited
      a distinct catabolic response of glucose metabolism in specimens from both lean
      and obese rats. 7 The results provide evidence that BM13.1258 and BM15.2054 can
      affect muscle glucose metabolism via more than one mechanism of action. 8 Further
      efforts are required to clarify, to what extent other mechanisms besides insulin
      sensitization via the activation of PPARgamma are involved in the antidiabetic
      actions of thiazolidinediones.

PMID- 10578128
TI  - Increased hindrance on the chiral carbon atom of mexiletine enhances the block of
      rat skeletal muscle Na+ channels in a model of myotonia induced by ATX.
AB  - 1 The antiarrhythmic drug mexiletine (Mex) is also used against myotonia.
      Searching for a more efficient drug, a new compound (Me5) was synthesized
      substituting the methyl group on the chiral carbon atom of Mex by an isopropyl
      group. Effects of Me5 on Na+ channels were compared to those of Mex in rat
      skeletal muscle fibres using the cell-attached patch clamp method. 2 Me5 (10
      microM) reduced the maximal sodium current (INa) by 29.7+/-4.4 % (n=6) at a
      frequency of stimulation of 0.3 Hz and 65.7+/-4.4 % (n=6) at 1 Hz. At same
      concentration (10 microM), Mex was incapable of producing any effect (n=3). Me5
      also shifted the steady-state inactivation curves by -7. 9+/-0.9 mV (n=6) at 0.3
      Hz and -12.2+/-1.0 mV (n=6) at 1 Hz. 3 In the presence of sea anemone toxin II
      (ATX; 5 microM), INa decayed more slowly and no longer to zero, providing a model
      of sodium channel myotonia. The effects of Me5 on peak INa were similar whatever
      ATX was present or not. Interestingly, Me5 did not modify the INa decay time
      constant nor the steady-state INa to peak INa ratio. 4 Analysis of ATX-induced
      late Na+ channel activity shows that Me5 did not affect mean open times and
      single-channel conductance, thus excluding open channel block property. 5 These
      results indicate that increasing hindrance on the chiral atom of Mex increases
      drug potency on wild-type and ATX-induced noninactivating INa and that Me5 might
      improve the prophylaxis of myotonia.

PMID- 10578127
TI  - Effects of glibenclamide on glycylsarcosine transport by the rat peptide
      transporters PEPT1 and PEPT2.
AB  - 1 Glibenclamide is a widely used sulphonylurea for the treatment of non-insulin
      dependent diabetes mellitus (NIDDM). This agent has been reported to inhibit the
      activities of various ion channels and transporters. In the present study, we
      examined the effects of glibenclamide on the function of the H+/peptide
      cotransporters PEPT1 and PEPT2 by using stable transfectants. 2 Uptake of [14C]
      glycylsarcosine, a typical substrate for peptide transporters, by PEPT1- or PEPT2
      expressing transfectant was inhibited by glibenclamide as well as other
      sulphonylureas including tolbutamide. 3 Kinetic analysis revealed that the
      inhibition by glibenclamide was noncompetitive. Dixon plot analyses showed that
      the Ki values of this agent were 25 and 7.8 microM for PEPT1 and PEPT2,
      respectively. 4 Glibenclamide did not inhibit Na+-coupled alanine and alpha
      methyl-D-glucoside transport, suggesting that the inhibitory effects of
      glibenclamide on peptide transporters were not due to nonspecific interactions. 5
      There was little uptake of [3H]-glibenclamide by PEPT-expressing transfectants as
      compared to mock-transfected cells, suggesting that glibenclamide was not a
      substrate for these peptide transporters. 6 In summary, glibenclamide inhibited
      the [14C]-glycylsarcosine transport by PEPT1 and PEPT2 in a noncompetitive
      fashion, although glibenclamide per se was not transported through these
      transporters. These findings would provide important information for clinical,
      physiological and biochemical aspects of peptide transporters.

PMID- 10578126
TI  - 'Outside-in' signalling mechanisms underlying CD11b/CD18-mediated NADPH oxidase
      activation in human adherent blood eosinophils.
AB  - 1 Incubation of human eosinophils in BSA-coated tissue culture plates resulted in
      time-dependent adhesion and attendant activation of the NADPH oxidase that were
      both inhibited (by >85%) by blocking antibodies raised against CD11b and CD18. 2
      SB 203580, an inhibitor of p38 mitogen-activated protein (MAP) kinase, did not
      influence adhesion but inhibited superoxide anion generation (pIC50=-6.57). 3
      PP1, an inhibitor of the src-family of protein tyrosine kinases, inhibited
      adhesion and CD11b/CD18-mediated superoxide anion generation with similar
      potencies (pEC50s=-5.53 and -5.99 respectively) suggesting that inhibition of the
      NADPH oxidase was a direct consequence of blocking adhesion. 4 The protein kinase
      C (PKC) inhibitors Ro-31 8220 (broad spectrum inhibitor), GF 109203X (inhibitor
      of conventional and novel isoforms) and Go 6976 (inhibitor of conventional
      isoforms) suppressed adhesion-dependent NADPH oxidase activation (pIC50s=-6.61, 
      6.05 and -4.89 respectively) without affecting adhesion. Based upon the
      selectivity of these drugs PKCdelta and PKCepsilon are implicated in the
      suppression of oxidant production. 5 Wortmannin, an inhibitor of
      phosphatidylinositol 3-kinase (PtdIns 3-kinase), abolished superoxide anion
      production in adherent eosinophils (pEC50=-9.06). Similarly, CD11b/CD18-dependent
      adhesion was suppressed with the same potency (pEC50=-9.29) although the maximum
      effect did not exceed 50% implying that wortmannin also had an affect on those
      processes that govern adhesion-driven oxidase activation. 6 PD 098059 and
      piceatannol, inhibitors of MAP kinase kinase-1 and the syk tyrosine kinase
      respectively, had no effect on CD11b/CD18-mediated adhesion or NADPH oxidase
      activation. 7 The results of this study demonstrate that human eosinophils adhere
      to BSA-coated plastic by a CD11b/CD18-dependent mechanism, which is responsible
      for activation of the NADPH oxidase. Although the signalling pathway(s) utilized
      by CD11b/CD18 is still to be elucidated, the data presented herein implicate p38
      MAP kinase, novel PKCs and PtdIns 3-kinase.

PMID- 10578129
TI  - The sulphonylurea glibenclamide inhibits voltage dependent potassium currents in
      human atrial and ventricular myocytes.
AB  - 1 It was the aim of our study to investigate the effects of the sulphonylurea
      glibenclamide on voltage dependent potassium currents in human atrial myocytes. 2
      The drug blocked a fraction of the quasi steady state current (ramp response)
      which was activated positive to -20 mV, was sensitive to 4-aminopyridine (500
      microM) and was different from the ATP dependent potassium current IK(ATP). 3
      Glibenclamide dose dependently inhibited both, the peak as well as the late
      current elicited by step depolarization positive to -20 mV. The IC50 for
      reduction in charge area of total outward current was 76 microM. 4 The double
      exponential inactivation time-course of the total outward current was accelerated
      in the presence of glibenclamide with a tau(fast) of 12.7+/-1.5 ms and a
      tau(slow) of 213+/-25 ms in control and 5.8+/-1.9 ms (P<0.001) and 101+/-20 ms
      (P<0.05) under glibenclamide (100 microM). 5 Our data suggest, that both
      repolarizing currents in human atrial myocytes, the transient outward current
      (Ito1) and the ultrarapid delayed rectifier current (IKur) were inhibited by
      glibenclamide. 6 In human ventricular myocytes glibenclamide inhibited Ito1
      without affecting the late current. 7 Our data suggest that glibenclamide
      inhibits human voltage dependent cardiac potassium currents at concentrations
      above 10 microM.

PMID- 10578130
TI  - Efficient functional coupling of the human D3 dopamine receptor to G(o) subtype
      of G proteins in SH-SY5Y cells.
AB  - 1 The D3 dopamine receptor presumably activates Gi/Go subtypes of G-proteins,
      like the structurally analogous D2 receptor, but its signalling targets have not
      been clearly established due to weak functional signals from cloned receptors as
      heterologously expressed in mostly non-neuronal cell lines. 2 In this study,
      recombinant human D3 receptors expressed in a human neuroblastoma cell line, SH
      SY5Y, produced much greater signals than those expressed in a human embryonic
      kidney cell line, HEK293. Quinpirole, a prototypic agonist, markedly inhibited
      forskolin-stimulated cyclic AMP production and Ca2+-channel (N-type) currents in
      SH-SY5Y cells, and enhanced GTPgamma35S binding in isolated membranes, nearly ten
      times greater than that observed in HEK293 cell membranes. 3 GTPgamma35S-bound
      Galpha subunits from quinpirole-activated and solubilized membranes were
      monitored upon immobilization with various Galpha-specific antibodies. Galphao
      subunits (not Galphai) were highly labelled with GTPgamma35S in SH-SY5Y, but not
      in HEK293 cell membranes, despite their abundance in the both cell types, as
      shown with reverse transcription-polymerase chain reaction and Western blots. N
      type Ca2+ channels and adenylyl cyclase V (D3-specific effector), on the other
      hand, exist only in SH-SY5Y cells. 4 More efficient coupling of the D3 receptor
      to Go subtypes in SH-SY5Y than HEK293 cells may be attributed, at least in part,
      to the two D3 neuronal effectors only present in SH-SY5Y cells (N-type Ca2+
      channels and adenylyl cyclase V). The abundance of Go subtypes in the both cell
      lines seems to indicate their availability not a limiting factor.

PMID- 10578131
TI  - Roles of atypical protein kinase C in lysophosphatidic acid-induced type II
      adenylyl cyclase activation in RAW 264.7 macrophages.
AB  - 1 Lysophosphatidic acid (LPA) has been widely studied as a naturally occurring
      and multifunctional phospholipid messenger in diverse tissue and cell types and
      shown to inhibit adenylyl cyclase (AC) by a G protein-mediated mechanism. 2 In
      type II AC-expressing mouse RAW 264.7 macrophages, we showed that LPA at 3-50
      microM increased cyclic AMP formation in a concentration-dependent manner, the
      effect being additive with that of forskolin or cholera toxin, and synergistic
      with that of prostaglandin E1 (PGE1) or isoproterenol. 3 The potentiation effect
      of LPA was unaffected by the removal of serum or pertussis toxin treatment. 4
      Both colchicine and cytochalasin B potentiated the cyclic AMP response to PGE1,
      the effect being additive to that of LPA. 5 On studying the regulation of type II
      AC by protein kinase C (PKC), phorbol 12-myristate-13 acetate (PMA) potentiated
      the PGE1-elicited cyclic AMP response, this effect being non-additive to that of
      LPA, suggesting that PKC activation was the common mechanism involved in AC
      potentiation by LPA and PMA. 6 PKC inhibitor Ro 31-8220, but not Go 6976,
      significantly inhibited the LPA-induced cyclic AMP potentiation. 7 The
      potentiation effect of LPA was unaffected by long-term treatment with PMA, which
      resulted in the down-regulation of PKCalpha, betaI, betaII and PKCdelta, but not
      PKCepsilon, mu, lambda and zeta. 8 By in situ kinase assay, we found a marked
      increase in atypical PKC activity after LPA treatment. 9 Taken together, we
      conclude that LPA can elicit a unique signalling cascade in RAW 264.7 macrophages
      and increase type II AC activity via the activation of atypical PKC.

PMID- 10578132
TI  - Pharmacological characterization of the human P2Y11 receptor.
AB  - 1 The human P2Y11 receptor is coupled to both the phosphoinositide and the cyclic
      AMP pathways. A pharmacological characterization of the recombinant human P2Y11
      receptor has been conducted following stable expression in two different cell
      lines: the 1321N1 astrocytoma cells for inositol trisphosphate measurements and
      the CHO-K1 cells for cyclic AMP assays. The rank order of potency of a series of
      nucleotides was almost identical for the two pathways: ATPgammaS approximately
      BzATP > dATP > ATP > ADPbetaS > 2MeSATP. 2 ADPbetaS, AMPalphaS and A3P5PS behaved
      as partial agonists of the human P2Y11 receptor. At high concentrations, these
      three nucleotides were able to partially inhibit the ATP response. 3 Suramin was
      a more potent antagonist than reactive blue 2, whereas pyridoxal-phosphate-6
      azophenyl-2',4'-disulphonic acid was completely inactive. The P2Y11 receptor
      proved to be sensitive to suramin in a competitive way with an apparent Ki value
      of 0.82+/-0. 07 microM. 4 The ATP derivative AR-C67085 (2-propylthio-beta, gamma
      dichloromethylene-D-ATP), a potent inhibitor of ADP-induced platelet aggregation,
      was the most potent agonist of the P2Y11 receptor, among the various nucleotides
      tested. 5 The pharmacological profile of the recombinant human P2Y11 receptor is
      closely similar to that of the cyclic AMP-coupled P2 receptor recently described
      in HL-60 cells, suggesting that it is the same receptor.

PMID- 10578133
TI  - S 15535, a benzodioxopiperazine acting as presynaptic agonist and postsynaptic 5
      HT1A receptor antagonist, prevents the impairment of spatial learning caused by
      intrahippocampal scopolamine.
AB  - 1 The effect of S 15535 (4-benzodioxan-5-yl)1-(indan-2-yl)piperazine), an agonist
      at presynaptic and antagonist at postsynaptic 5-HT1A receptors, on the impairment
      of spatial learning caused by intrahippocampal scopolamine in a two-platform
      spatial discrimination task was studied. 2 Scopolamine (4.0 microg microl-1),
      injected bilaterally into the CA1 region of the dorsal hippocampus 10 min before
      each training session, impaired choice accuracy with no effect on choice latency
      and errors of omission. 3 Administered subcutaneously 30 min before each training
      session, S 15535 1.0 (but not 0.3) mg kg-1 did not modify choice accuracy but
      prevented its impairment by intrahippocampal scopolamine. 4 WAY 100635, a 5-HT1A
      receptor antagonist, injected into the dorsal raphe at 1.0 microg 0.5 microl-1 5
      min before scopolamine, had no effect on choice accuracy and latency or errors of
      omission and did not modify the effect of scopolamine but completely antagonized
      the effect of S 15535 (1.0 mg kg-1) on scopolamine-induced impairment of choice
      accuracy. 5 The results confirm a previous report (Carli et al., 1998) that
      stimulation of presynaptic 5-HT1A receptors in the dorsal raphe counteracts the
      deficit caused by intrahippocampal scopolamine, probably by facilitating the
      transfer of facilitatory information from the entorhinal cortex to the
      hippocampus. 6 Drugs that stimulate action on presynaptic 5-HT1A receptors, such
      as S 15535 and other partial 5-HT1A receptors agonists, may be useful in the
      symptomatic treatment of human memory disturbances associated with loss of
      cholinergic innervation to the hippocampus.

PMID- 10578134
TI  - Non-adrenergic binding of [3H]atipamezole in rat kidney--regional distribution
      and comparison to alpha2-adrenoceptors.
AB  - 1 Atipamezole (4-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole) was first
      introduced as a potent and specific alpha2-adrenoceptor antagonist, but in some
      tissues [3H]atipamezole identifies an additional population of binding sites,
      distinct from both classical alpha2-adrenoceptors and I1- and I2-imidazoline
      receptors identified with [3H]para-aminoclonidine or [3H]idazoxan. 2 In the
      present study we have characterized [3H]atipamezole binding sites in rat kidney
      by receptor autoradiography and membrane binding assays and determined whether
      they are pharmacologically identical with the previously described binding sites
      for [3H]para-aminoclonidine and [3H]idazoxan. [3H]RX821002 and [3H]rauwolscine
      were used to compare the regional distribution of alpha2-adrenoceptors to that of
      non-adrenergic binding sites of [3H]atipamezole. 3 Comparative autoradiographic
      experiments demonstrated the differential localisation of [3H]atipamezole,
      [3H]RX821002 and [3H]rauwolscine binding sites in rat kidney. The pattern of
      distribution of non-adrenergic [3H]atipamezole binding sites is clearly distinct
      from that of alpha2-adrenoceptors. 4 The non-adrenergic binding of
      [3H]atipamezole in rat kidney does not fall into any of the previously identified
      three classes of imidazoline receptors studied with [3H]para-aminoclonidine,
      [3H]idazoxan and [3H]RX821002. 5 Atipamezole had no inhibitory effect on MAO-A or
      MAO-B activity in renal membranes, which speaks against the involvement of MAOs
      in the observed radioligand binding.

PMID- 10578135
TI  - The anticonvulsant effects of the enantiomers of losigamone.
AB  - 1 Losigamone is a novel anticonvulsant undergoing phase III clinical trials in
      patients with partial and secondary generalized seizures. This study investigated
      the effects of the S(+)- and R(-)- enantiomers of losigamone on endogenous amino
      acid release from BALB/c mouse cortical slices, spontaneous depolarizations in
      the cortical wedge preparation of the DBA/2 mouse and audiogenic seizures in
      DBA/2 mice. 2 S(+)-losigamone (100 and 200 microM) significantly reduced both
      potassium- and veratridine-elicited release of glutamate and aspartate from
      cortical slices. R(-)-losigamone had no effect on release at concentrations up to
      400 microM. 3 Cortical wedges exhibit spontaneous depolarizations when perfused
      with magnesium-free artificial cerebrospinal fluid. S(+)-losigamone significantly
      reduced these depolarizations at 50-200 microM whilst R(-)-losigamone had a
      significant effect at 200-800 microM. 4 DBA/2 mice are susceptible to audiogenic
      seizures and S(+)-losigamone dose-dependently (5, 10 and 20 mg kg-1, i.p.)
      significantly inhibited clonic/tonic convulsions with 91% of the mice protected
      at 20 mg kg-1. There was no protection at 20 mg kg-1 with R(-)-losigamone. 5
      These results, from both in vitro and in vivo experiments, confirm that the
      pharmacological activity profiles of the two losigamone enantiomers are not
      identical and suggest further that excitatory amino acid-mediated processes are
      involved in the mode of action of S(+)-losigamone whereas R(-)-losigamone does
      not possess such properties. For the treatment of neurological conditions
      involving exaggerated excitatory amino acid function the use of S(+)-losigamone
      might therefore be more effective clinically than losigamone or its R(-)
      enantiomer.

PMID- 10578136
TI  - Endothelin alters the reactivity of vasa vasorum: mechanisms and implications for
      conduit vessel physiology and pathophysiology.
AB  - 1 The walls of certain large blood vessels are nourished by the vasa vasorum, a
      network of microvessels that penetrate the adventitia and media of the vessel
      wall. The purpose of this study was to characterize endothelin-1 (ET-1)-mediated
      contraction of vasa and to investigate whether threshold concentrations of ET-1
      alters the sensitivity to constrictors. Arterial vasa were dissected from the
      walls of porcine thoracic aorta and mounted in a tension myograph. 2 ET-1 and ETB
      selective agonist, sarafotoxin 6c (S6c), produced concentration-dependent
      contraction. ETA receptor antagonist, BQ123 (10 microM), caused a biphasic
      rightward shift of ET-1 response curves. ETB receptor antagonist, BQ788 (1
      microM), produced a rightward shift of response curves to ET-1 and S6c of 5- and
      80 fold respectively. 3 ET-1 responses were abolished in Ca2+-free PSS but
      unaffected by selective depletion of intracellular Ca2+ stores. Nifedipine (10
      microM), an L-type Ca2+ channel blocker, attenuated ET-1 responses by 44%.
      Inhibition of receptor-operated Ca2+ channels or non-selective cation entry using
      SKF 96365 (30 microM) and Ni2+ (1 mM) respectively, attenuated ET-1 contractions
      by 60%. 4 ET-1 (1-3 nM) enhanced responses to noradrenaline (NA) (4 fold) but not
      to thromboxane A2-mimetic, whilst K+ (10-20 mM) sensitized vasa to both types of
      constrictor. 5 Therefore, ET-1-induced contraction of isolated vasa is mediated
      by ETA and ETB receptors and involves Ca2+ influx through L-type and non-L-type
      Ca2+ channels. Furthermore elevation of basal tone of vasa vasorum alters the
      profile of contractile reactivity. These results suggest that ET-1 may be an
      important regulator of vasa vasorum reactivity.

PMID- 10578137
TI  - Pharmacological activation of the ryanodine receptor in Jurkat T-lymphocytes.
AB  - 1 Recently, we provided evidence for cyclic adenosine 5'-diphosphate-ribose, cADP
      ribose, as a second messenger in Jurkat T-lymphocytes upon stimulation of the T
      cell receptor/CD3- complex (Guse et al., 1999). cADP-ribose mobilizes Ca2+ from
      an intracellular Ca2+ store which is sensitive to caffeine and gated by the
      ryanodine receptor/Ca2+ release channel. In the present study we investigated the
      ability of the trypanocidal drug, suramin, to activate the ryanodine receptor of
      T-cells. Since suramin cannot permeate the plasma membrane, it was necessary to
      microinject the drug into Fura-2 loaded T-lymphocytes. 2 In a dose dependent
      manner suramin increased the intracellular Ca2+ concentration. The dose-response
      curve is very steep and calculates for an EC50 of 7. 6+/-2.9 mM suramin in the
      injection pipette. 3 Co-injection of the selective ryanodine receptor inhibitor
      ruthenium red completely abolished the suramin induced Ca2+ transient. This
      finding allows for the conclusion that the IP3-receptor sensitive Ca2+ pool is
      not the primary target of the suramin induced Ca2+ transient. 4 Furthermore,
      Ins(1,4,6)PS3, an antagonist of the InsP3-receptor could not suppress the suramin
      induced Ca2+ signal. The suramin induced Ca2+ transients declined very slowly;
      however, in the presence of Ins(1,4,6)PS3 this decay was accelerated. In
      addition, suramin did not interact with the cADP-ribose binding site of the
      ryanodine receptor of T-cells. 5 In conclusion, suramin is found to be an agonist
      for the T-cell ryanodine receptor as previously found for the cardiac and
      skeletal muscle isoform. Therefore, suramin can be designated a universal
      ryanodine receptor agonist.

PMID- 10578138
TI  - Beneficial effects of Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), a
      superoxide dismutase mimetic, in zymosan-induced shock.
AB  - 1 The therapeutic efficacy of Mn(III)tetrakis (4-benzoic acid) porphyrin
      (MnTBAP), a novel superoxide dismutase mimetic which scavenges peroxynitrite, was
      investigated in rats subjected to shock induced by peritoneal injection of
      zymosan. 2 Our data show that MnTBAP (given at 1, 3 and 10 mg kg-1
      intraperitoneally, 1 and 6 h after zymosan injection) significantly reduce in
      dose dependent manner the development of peritonitis (peritoneal exudation, high
      nitrate/nitrite and peroxynitrite plasma levels, leukocyte infiltration and
      histological examination). 3 Furthermore, our data suggest that there is a
      reduction in the lung, small intestine and liver myeloperoxidase (MPO) activity
      and lipid peroxidation activity from MnTBAP-treated rats. 4 MnTBAP also reduced
      the appearance of nitrotyrosine immunoreactivity in the inflamed tissues. 5
      Furthermore, a significant reduction of suppression of mitochondrial respiration,
      DNA strand breakage and reduction of cellular levels of NAD+ was observed in ex
      vivo macrophages harvested from the peritoneal cavity of zymosan-treated rat. 6
      In vivo treatment with MnTBAP significantly reduced in a dose-dependent manner
      peroxynitrite formation and prevented the appearance of DNA damage, the decrease
      in mitochondrial respiration and the loss of cellular levels of NAD+. 7 In
      conclusion our results showed that MnTBAP was effective in preventing the
      development of zymosan-induced shock.

PMID- 10578139
TI  - Nociceptin and the ORL-1 ligand [Phe1psi (CH2-NH)Gly2]nociceptin(1-13)NH2 exert
      anti-opioid effects in the Freund's adjuvant-induced arthritic rat model of
      chronic pain.
AB  - 1 Stimulation of the opioid receptor-like1 (ORL-1) receptor by nociceptin (NC)
      produces hyperalgesia and reverses the antinociceptive effects induced by
      opioids. Most studies concerning the central effects of NC were conducted using
      acute pain models. The role NC may play in chronic inflammation remains
      unelucidated. 2 The present study was undertaken to assess the action of NC in
      the Freund's adjuvant-induced monoarthritic rat model. The effects of drugs known
      to act as analgesics in this model were evaluated. The effects of NC, NCNH2, and
      the ORL-1 ligand, [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 ([F/G]NC(1-13)NH2), were also
      studied alone or in association with morphine. 3 NC (1 - 30 nmol, i. c.v.) was
      inactive, whilst NCNH2 (10 nmol, i.c.v.) exerted hyperalgesic effects (-4.5+/-0.9
      vs -0.7+/-0.8 s of vehicle-treated animals). [F/G]NC(1-13)NH2 (0.01 - 10 nmol,
      i.c.v.) induced hyperalgesia in the arthritic paw (-3.3+/-0.6 vs -0.3+/-0.5 s of
      vehicle-treated animals; 10 nmol). 4 Both NC (0.01 - 10 nmol, i.c.v. ) and
      [F/G]NC(1-13)NH2 (0.01 - 1 nmol, i.c.v), 30 min after morphine (3 mg kg-1, s.c.)
      induced an immediate and short-lived reversal of morphine effects (2.6+/-0.3 vs
      10.4+/-1.0 and 1.2+/-1.5 vs 9.3+/-1.1 s of morphine alone, respectively),
      therefore displaying anti-opioid activity. 5 In the Freund's adjuvant-induced rat
      model of arthritis, both NC and [F/G]NC(1-13)NH2 act as anti-opioid peptides.
      Furthermore, NCNH2 and [F/G]NC(1-13)NH2 induce hyperalgesia when given alone.
      Further investigations and the identification of a centrally acting ORL-1
      antagonist are necessary to better understand the role of NC in pain mechanisms.

PMID- 10578140
TI  - Voltage-dependent block of normal and mutant muscle sodium channels by 4-Chloro-m
      Cresol.
AB  - 1 The effects of 4-Chloro-m-Cresol (4-CmC) were examined on heterologously
      expressed wild type (WT), Paramyotonia Congenita (R1448H) and Hyperkalemic
      Periodic Paralysis (M1360V) mutant alpha-subunits of human muscle sodium
      channels. 2 Block of rested sodium channels caused by 4-CmC was concentration
      dependent with an ECR50 of 0.40 mM in WT, 0.45 mM in R1448H and 0.49 mM in
      M1360V. 3 Inactivation significantly promoted 4-CmC-induced sodium channel block
      in all clones indicated by 4-CmC-induced shifts of steady-state availability
      curves, reflecting a higher proportion of channel block at depolarized membrane
      potentials. Channel block was almost complete (>90%) at concentrations close to
      the ECR50 (0.5 mM) on application of an inactivating prepulse before the test
      pulse. 4 4-CmC accelerated the current decay following depolarization and
      prolonged recovery from inactivation in all clones. Of these, R1448H, the mutant
      which displayed severely impaired inactivation in the controls, responded to 4
      CmC with the most pronounced acceleration of inactivation. Control experiments
      revealed enhanced recovery from inactivation in the mutants, which was restored
      to normal in 0.1 mM 4-CmC. 5 4-CmC induced no additional frequency-dependent
      block. 6 Our results clearly demonstrate that 4-CmC is as effective as lidocaine
      (Fan et al., 1996) in blocking muscle sodium channels. Low concentrations of the
      compound (</=ECR50) were able to restore pathologically accelerated recovery from
      inactivation and impaired inactivation in the mutants to the WT value.

PMID- 10578141
TI  - The involvement of protein kinase C in nitric oxide-induced damage to rat
      isolated colonic mucosal cells.
AB  - 1 The role of protein kinase C (PKC) in colonic cellular injury in response to
      high concentrations of nitric oxide (NO) released from the donor, S-nitroso-N
      acetyl-DL-penicillamine (SNAP) was investigated. 2 Addition of SNAP (0.1-1000
      microM) to the cellular suspension resulted in a dose-dependent increase in the
      extent of damage to isolated colonic mucosal cells as assessed by Trypan blue dye
      uptake and release of the lysosmal enzyme, N-acetyl-beta-glucosaminidase. SNAP
      treatment also resulted in an increase in cellular total PKC activity. These
      increases were reduced or eliminated by pretreatment of the cells with the PKC
      antagonists staurosporine or GF 109203X or the NO scavenger, phenyl-4,4,5,5,
      tetramethylimidazoline-1-oxyl 3-oxide (PTIO). 3 PKC-alpha, PKC-delta, PKC-epsilon
      and PKC-zeta were detected in colonic cellular lysates by immunoblotting.
      However, only PKC-epsilon protein was increased in response to SNAP treatment.
      Furthermore, SNAP treatment resulted in activation of PKC-epsilon by causing
      translocation of the enzyme from the cytosolic to membrane fraction of the cell.
      This effect was eliminated if cells were preincubated with the NO scavenger,
      PTIO. 4 The extent of cellular damage in response to addition of SNAP to the
      incubation medium was enhanced by coincubation with the PKC activator, phorbol 12
      myristate 13-acetate (PMA; 1 and 10 microM). 5 PKC activity and the extent of
      cell damage in response to SNAP were reduced by preincubation of the cells with
      the peroxyl scavenger, ebselen (0.01-10 microM). 6 These data suggest that the
      PKC-epsilon isoform of the enzyme mediates NO-induced damage to colonic mucosal
      cells. This response may occur, at least in part, due to peroxynitrite formation.

PMID- 10578142
TI  - Early increases in renal kallikrein secretion on administration of potassium or
      ATP-sensitive potassium channel blockers in rats.
AB  - 1 This study aimed to examine whether administration of potassium or ATP
      sensitive potassium channel (KATP channel) blockers caused early increases in
      renal kallikrein (KK) secretion. To clarify this mechanism, the effect on renal
      KK secretion of a KATP channel blocker was compared with the effect resulting
      from use of an osmotic diuretic or volume load. Furthermore, the effect on
      potassium-induced increases in renal KK secretion by an additional treatment
      using a KATP channel blocker was examined. Lastly, the effect of a KATP channel
      blocker on renal KK secretion was also examined in superfused slices of kidney
      cortex. 2 Intravenous infusion of potassium augmented renal KK secretion within
      30 min while urine volume increased gradually in both the potassium loading and
      control groups. 3 Administration of the KATP channel blocker, 4
      morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydr ochloride (PNU-37883A) or
      glibenclamide, caused a dose-dependent increase in renal KK secretion. 4 The
      concentration of KK in urine was higher in the PNU-37883A group as compared to
      the osmotic-diuretic or volume-load group. 5 PNU-37883A had no additive effect on
      the potassium-induced increase in renal KK secretion. 6 Renal KK secretion
      increased in slices of kidney cortex incubated with PNU-37883A within 10 min of
      superfusion. 7 In conclusion, administration of both potassium and KATP channel
      blockers induced early increases in renal KK secretion in the absence of the
      washout phenomenon. Potassium loading may have increased renal KK secretion
      through the same mechanism as the KATP channel blocker.

PMID- 10578143
TI  - Inhibition by genistein of the hyperpolarization-activated cation current in
      porcine sino-atrial node cells.
AB  - 1 The hyperpolarization-activated cation current (If) was recorded in single
      pacemaker cells of the porcine sino-atrial node, and the effects of genistein, an
      isoflavone inhibitor of tyrosine-specific protein kinases was investigated by the
      whole-cell patch clamp technique. 2 Genistein (20-500 microM) decreased If in a
      dose-dependent manner with an IC50 value of 62.3 microM and a maximum inhibition
      of 45.3%. 3 The effect on If appeared without altering the half-activation
      potential (control, -88.3+/-2.8 mV; genistein, -87.0+/-1.8 mV) and the slope
      factor (control, 8.0+/-0.3 mV; genistein, 8.6+/-0.7 mV) of the steady-state
      activation curve. No significant voltage-dependency was detected in the fully
      activated current-voltage relation measured by the double-pulse protocols. 4 The
      inactive form of genistein analogue, daidzein (500 microM) or genistin (200
      microM), were without effect. If was not affected by another tyrosine kinase
      inhibitor, tryphostin-47 (100 microM), but tyrphostin-25 (100-200 microM)
      suppressed If in an irreversible manner. 5 Neither bath nor intracellular
      application of the tyrosine phosphatase inhibitor, orthovanadate, affected If,
      and subsequent application of genistein inhibited If significantly. 6 These data
      indicate that the inhibition of If by genistein is not mediated through tyrosine
      kinase inhibition but through nonselective block of the If channels.

PMID- 10578144
TI  - Pharmacological similarities between native brain and heterologously expressed
      alpha4beta2 nicotinic receptors.
AB  - 1 We studied the pharmacological properties of native rat brain and
      heterologously expressed rat alpha4beta2 nicotinic receptors immunoprecipitated
      onto a fixed substrate with the anti-alpha4 antibody mAb 299. 2 Immunodepletion
      with the anti-beta2 antibody mAb 270 showed that 89% of the mAb-299-precipitated
      rat brain receptors contained beta2. 3 The association and dissociation rate
      constants for 30 pM +/-[3H]-epibatidine binding to alpha4beta2 receptors
      expressed in oocytes were 0.02+/-0.01 and 0.03+/-0.01 min-1 (+/-standard error,
      degrees of freedom=7 - 8) at 20 - 23 degrees C. 4 The Hill coefficients for +/
      [3H]epibatidine binding to the native brain, alpha4beta2 receptors expressed in
      oocytes, and alpha4beta2 receptors expressed in CV-1 cells (using recombinant
      adenovirus) were 0.69 - 0.70 suggesting a heterogeneous receptor population. Fits
      of the +/-[3H]-epibatidine concentration-binding data to a two-site model gave KD
      s of 8 - 30 and 560 - 1,200 pM. The high-affinity sites comprised 73 - 74% of the
      native brain and oocyte alpha4beta2 receptor population, 85% of the CV-1
      alpha4beta2 receptor population. 5 The expression of rat alpha4beta2 receptors in
      CV-1 cells using vaccinia viral infection-transfection resulted in a more
      homogeneous receptor population (Hill coefficient of 1. 0+/-0.2). Fits of the +/
      [3H]-epibatidine binding data to a single-site model gave a KD of 40+/-3 pM. 6
      DHbetaE (IC50=260-470 nM) and the novel nicotine analogue NDNI (IC50=7-10 microM)
      inhibited 30 pM+/-[3H]-epibatidine binding to the native brain and heterologously
      expressed alpha4beta2 receptors equally well. 7 The results show that alpha4beta2
      containing nicotinic receptors in the rat brain and heterologously expressed rat
      alpha4beta2 receptors have similar affinities for +/-[3H]-epibatidine, DHbetaE,
      and NDNI.

PMID- 10578145
TI  - Identification of the G-protein-coupled ORL1 receptor in the mouse spinal cord by
      [35S]-GTPgammaS binding and immunohistochemistry.
AB  - 1 Although the ORL1 receptor is clearly located within the spinal cord, the
      functional signalling mechanism of the ORL1 receptor in the spinal cord has not
      been clearly documented. The present study was then to investigate the guanine
      nucleotide binding protein (G-protein) activation mediated through by the ORL1
      receptor in the mouse spinal cord, measuring the modulation of guanosine-5'-o-(3
      [35S]-thio) triphosphate ([35S]-GTPgammaS) binding by the putative endogenous
      ligand nociceptin, also referred as orphanin FQ. We also studied the anatomical
      distribution of nociceptin-like immunoreactivity and nociceptin-stimulated [35S]
      GTPgammaS autoradiography in the spinal cord. 2 Immunohistochemical staining of
      mouse spinal cord sections revealed a dense plexus of nociceptin-like
      immunoreactive fibres in the superficial layers of the dorsal horn throughout the
      entire length of the spinal cord. In addition, networks of fibres were seen
      projecting from the lateral border of the dorsal horn to the lateral grey matter
      and around the central canal. 3 In vitro [35S]-GTPgammaS autoradiography showed
      high levels of nociceptin-stimulated [35S]-GTPgammaS binding in the superficial
      layers of the mouse dorsal horn and around the central canal, corresponding to
      the areas where nociceptin-like immunoreactive fibres were concentrated. 4 In
      [35S]-GTPgammaS membrane assay, nociceptin increased [35S]-GTPgammaS binding of
      mouse spinal cord membranes in a concentration-dependent and saturable manner,
      affording maximal stimulation of 64.1+/-2.4%. This effect was markedly inhibited
      by the specific ORL1 receptor antagonist [Phe1Psi (CH2-NH) Gly2] nociceptin (1 -
      13) NH2. None of the mu-, delta-, and kappa-opioid and other G-protein-coupled
      receptor antagonists had a significant effect on basal or nociceptin-stimulated
      [35S]-GTPgammaS binding. 5 These findings suggest that nociceptin-containing
      fibres terminate in the superficial layers of the dorsal horn and the central
      canal and that nociceptin released in these areas may selectively stimulate the
      ORL1 receptor to activate G-protein. Furthermore, the unique pattern of G-protein
      activation in the present study provide additional evidence that nociceptin is
      distinct from the mu-, delta- or kappa-opioid system.

PMID- 10578146
TI  - Characterization of the in vitro effects of 5-hydroxytryptamine (5-HT) on
      identified neurones of the rat dorsal motor nucleus of the vagus (DMV).
AB  - 1 Whole cell patch clamp techniques were used on thin brainstem slices to
      investigate the effects of 5-hydroxytryptamine (5-HT) on gastrointestinal
      projecting dorsal motor nucleus of the vagus (DMV) neurones. Neurones were
      identified as projecting to the stomach (n=122) or intestine (n=84) if they
      contained the fluorescent tracer Dil after it had been applied to the gastric
      fundus, corpus or antrum/pylorus or to the duodenum or caecum. 2 A higher
      proportion of intestinal neurones (69%) than gastric neurones (47%) responded to
      5-HT with a concentration-dependent inward current which was antagonized fully by
      the 5-HT2A receptor antagonist ketanserin (1 microM). 3 Stimulation of the
      nucleus tractus solitarius (NTS) induced inhibitory synaptic currents that were
      reduced in amplitude by application of the 5-HT1A receptor agonist 8-OHDPAT (1
      microM) or the 5-HT1A/1B receptor agonist TFMPP (1 microM) in 61% and 52% of
      gastric- and intestinal-projecting neurones, respectively. 5-HT also
      significantly reduced the frequency but not the amplitude of spontaneous
      inhibitory currents. 4 These data show that 5-HT excites directly a larger
      proportion of intestinal projecting neurones than gastric-projecting neurones, as
      well as inhibiting synaptic transmission from the NTS to the DMV. These data
      imply that the response to DMV neurones to 5-HT may be determined and classified
      by their specific projections.

PMID- 10578147
TI  - Release of nitric oxide from endothelial cells stimulated by YC-1, an activator
      of soluble guanylyl cyclase.
AB  - 1 In this study we examined the endothelium-dependent effect of YC-1 - a benzyl
      indazole derivative which directly activates soluble guanylyl cyclase (sGC) - on
      vascular relaxation and nitric oxide (NO) and guanosine-3',5'-cyclic
      monophosphate (cyclic GMP) in endothelial cells. 2 In preconstricted rat aortic
      rings with intact endothelium, YC-1 produced a concentration-dependent
      relaxation. However, the concentration response curve was shifted rightward to
      higher concentrations of YC-1, when (i) the aortas were pre-treated with L-NG
      nitroarginine methylester (L-NAME) or (ii) the endothelium was removed. 3
      Incubation of bovine aortic endothelial cells (BAEC) with YC-1 produced a
      concentration-dependent NO synthesis and release as assessed using a porphyrinic
      microsensor. Pre-incubating cells with L-NAME or with 8-bromo-cyclic GMP
      decreased this effect indicating that the YC-1 stimulation of NO synthesis is due
      to an activation of nitric oxide synthase, but not to an elevation of cyclic GMP.
      No direct effect of YC-1 on recombinant endothelial constitutive NO synthase
      activity was observed. 4 The YC-1 stimulated NO release was reduced by 90%, when
      extracellular free calcium was diminished. 5 In human umbilical vein endothelial
      cells (HUVEC), YC-1 stimulated intracellular cyclic GMP production in a
      concentration- and time-dependent manner. Stimulation of cyclic GMP was greater
      with a maximum concentration of YC-1 compared to calcium ionophore A23187.
      Similar effects were observed in BAEC and rat microvascular coronary endothelial
      cells (RMCEC). 6 When HUVEC and RMCEC were pre-treated with L-NG-nitroarginine (L
      NOARG), the maximum YC-1 stimulated cyclic GMP increase was reduced by >/=50%. 7
      These results indicate, that beside being a direct activator of sGC, YC-1
      stimulates a NO-synthesis and release in endothelial cells which is independent
      of elevation of cyclic GMP but strictly dependent on extracellular calcium. The
      underlying mechanism needs to be determined further.

PMID- 10578148
TI  - Investigation of the subtypes of alpha1-adrenoceptor mediating contractions of
      rat vas deferens.
AB  - 1 The subtypes of alpha1-adrenoceptor mediating contractions of rat vas deferens
      to endogenous and exogenous noradrenaline and to the exogenous agonists
      methoxamine, phenylephrine and A61603 have been examined. 2 The effects of
      antagonists on the shape of concentration-response curves, both tonic and phasic,
      to the four agonists were analysed. Prazosin produced parallel shifts in all
      cases. Particularly for RS 17053 against noradrenaline, there was some evidence
      for a resistant component of the agonist response. High concentrations of RS
      17053 (1-10 microM) virtually abolished tonic contractions but phasic
      contractions were resistant. 3 A series of nine antagonists (the above and
      WB4101, benoxathian, phentolamine, BMY 7378, HV 723, spiperone) were investigated
      against contractions to noradrenaline. The correlation with the potency of the
      series of alpha1-adrenoceptor antagonists against contractions to noradrenaline
      was significant only for the alpha1A-adrenoceptor ligand binding site (r=0.88,
      n=9, P<0.01). 4 In epididymal portions (nifedipine 10 microM), the isometric
      contraction to a single electrical pulse is alpha1-adrenoceptor mediated. The
      correlation with ligand binding sites for 11 antagonists (the above plus ARC 239
      and (+)-niguldipine) was significant only for the alpha1D-adrenoceptor subtype
      (r=0.65, n=11, P<0.05). 5 In conclusion, tonic contractions of rat vas deferens
      produced by exogenous agonists are mediated predominantly by alpha1A
      adrenoceptors, although a second subtype of receptor may additionally be involved
      in phasic contractions. Nerve-stimulation evoked alpha1-adrenoceptor mediated
      contractions seem to predominantly involve non-alpha1A-adrenoceptors, and the
      receptor involved resembles the alpha1D-receptor.

PMID- 10578149
TI  - Studies on the acute and chronic effects of reboxetine on extracellular
      noradrenaline and other monoamines in the rat brain.
AB  - 1 The effect of reboxetine, a novel antidepressant drug that potently and
      selectively inhibits neuronal noradrenaline (NA) uptake, on brain extracellular
      monoamines was studied by microdialysis. 2 Fifteen mg kg-1 i.p. reboxetine raised
      extracellular NA in the frontal cortex (by 242%) and dorsal hippocampus (by
      240%). 3 Idazoxan (1 mg kg-1 s.c.), given 60 min after 15 mg kg-1 reboxetine,
      markedly potentiated the effect on extracellular NA in the frontal cortex (by
      1580%) and dorsal hippocampus (by 1360%), but had no effect by itself. 4 Twenty
      four hours after the last injection of a chronic schedule (15 mg kg-1 i.p. once
      daily for 14 days) reboxetine had no effect on basal extracellular concentrations
      of NA in the dorsal hippocampus and a challenge dose of reboxetine (15 mg kg-1)
      raised extracellular NA similarly in rats treated chronically with reboxetine (by
      353%) and saline (by 425%). 5 Ten and 20 microg kg-1 i.p. clonidine dose
      dependently reduced hippocampal extracellular NA similarly in rats given chronic
      reboxetine (by 32% and 57%) and saline (by 42% and 56%). 6 Extracellular
      concentrations of dopamine and 5-HT in the striatum were similar in rats treated
      chronically with reboxetine and saline. A challenge dose of reboxetine (15 mg kg
      1) had no effect on striatal extracellular dopamine and slightly increased
      striatal extracellular 5-HT to a similar extent in rats treated chronically with
      reboxetine (by 137%) and saline (by 142%). 7 The results suggest that combining
      reboxetine with an alpha2-adrenoceptor antagonist may facilitate its
      antidepressant activity. Repeated treatment confirmed that reboxetine is fairly
      selective for the noradrenergic system but provided no evidence of adaptive
      changes in that system that could facilitate its effect on extracellular NA.

PMID- 10578150
TI  - Effects of inhibitors of the activity of poly (ADP-ribose) synthetase on the
      organ injury and dysfunction caused by haemorrhagic shock.
AB  - 1 Poly (ADP-ribose) synthetase (PARS) is a nuclear enzyme activated by strand
      breaks in DNA, which are caused by reactive oxygen species (ROS). Here we
      investigate the effects of the PARS inhibitors 3-aminobenzamide (3-AB),
      nicotinamide and 1,5-dihydroxyisoquinoline (ISO) on the circulatory failure and
      the organ injury/dysfunction caused by haemorrhage and resuscitation in the
      anaesthetized rat. 2 Haemorrhage (sufficient to lower mean arterial blood
      pressure to 50 mmHg for 90 min) and subsequent resuscitation with shed blood
      resulted (within 4 h after resuscitation) in a delayed fall in blood pressure to
      66+/-4 mmHg (control, n=13). This circulatory failure was not affected by
      administration (5 min prior to resuscitation) of 3-AB (10 mg kg-1 i.v., n=7),
      nicotinamide (10 mg kg-1 i.v., n=6) or ISO (3 mg kg-1 i.v., n=6). 3 Haemorrhage
      and resuscitation also resulted in rises in the serum levels of urea and
      creatinine. This renal dysfunction was attenuated by 3-AB and nicotinamide, but
      not by nicotinic acid (n=7), an inactive analogue of nicotinamide. Although ISO
      (n=6) also attenuated the renal dysfunction caused by haemorrhage and
      resuscitation, its vehicle (10% DMSO, n=4) had the same effect. 4 Haemorrhagic
      shock resulted in enhanced serum levels of aspartate aminotransferase (AST),
      alanine aminotransferase (ALT) and lipase, indicating the development of
      hepatocellular and pancreatic injury, respectively. Similarly, haemorrhagic shock
      also resulted in an increase in the serum levels of creatine kinase (CK)
      indicating the development of neuromuscular injury. This was attenuated by 3-AB
      and nicotinamide, but not by nicotinic acid. Although ISO also attenuated the
      liver, pancreatic and neuromuscular injury caused by haemorrhagic shock, its
      vehicle had the same effect. 5 Thus, activation of PARS contributes to the organ
      injury and dysfunction caused by haemorrhage and resuscitation in the rat.

PMID- 10578151
TI  - Evidence that somatostatin sst2 receptors mediate striatal dopamine release.
AB  - 1 Somatostatin (SRIF) is a cyclic tetradecapeptide present in medium-sized aspiny
      interneurones in the rat striatum. We have previously shown that exogenous SRIF
      potently stimulates striatal dopamine (DA) release via a glutamate-dependent
      mechanism. We now report the ability of the selective sst2 receptor agonist, BIM
      23027, to mimic this effect of SRIF. 2 In vivo microdialysis studies were
      performed in anaesthetized male Wistar rats. In most experiments, compounds were
      administered by retrodialysis into the striatum for 15 min periods, 90 min and
      225 min after sampling commenced, with levels of neurotransmitters being measured
      by HPLC with electrochemical and fluorescence detection. 3 BIM-23027 (50 and 100
      nM) stimulated DA release with extracellular levels increasing by up to 18 fold.
      4 Prior retrodialysis of BIM-23027 (50 nM) abolished the effects of subsequent
      administration of SRIF (100 nM). 5 The agonist effects of both BIM-23027 and SRIF
      were abolished by the selective sst2 receptor antagonist, L-Tyr8-CYN-154806 (100
      nM). 6 The AMPA/kainate receptor antagonist, DNQX (100 microM), abolished the
      agonist effects of BIM-23027 as previously shown for SRIF. 7 This study provides
      evidence that the sst2 receptor mediates the potent dopamine-releasing actions
      observed with SRIF in the rat striatum. Dopamine release evoked by both peptides
      appears to be mediated indirectly via a glutamatergic pathway. Other subtype
      specific somatostatin receptor ligands were unable to elicit any effects and
      therefore we conclude that no other somatostatin receptor types are involved in
      mediating the dopamine-releasing actions of SRIF in the striatum.

PMID- 10578153
TI  - Herpes simplex thymidine kinase (HStk) transgenic donor lymphocytes.
AB  - Patients with recurrent leukemia after an allogeneic hematopoietic stem cell
      transplant may be treated with donor lymphocyte infusions (DLI). The transfusion
      of lymphocytes from the original hematopoietic stem cell donor induces remission
      in approximately one third of relapsed AML cases and 80% of relapsed CML. DLI may
      be complicated by delayed and sometimes lethal graft-versus-host disease (GVHD).
      In an attempt to avoid this complication, several centers have initiated DLI
      trials in which the infused lymphocytes carry a suicide gene, herpes simplex
      thymidine kinase (HStk), which confers sensitivity to ganciclovir (GCV). In the
      event of severe GVHD, administration of GCV should terminate or ameliorate GVHD.

PMID- 10578152
TI  - Effect of vasoactive intestinal peptide (VIP)-related peptides on cholinergic
      neurogenic and direct mucus secretion in ferret trachea in vitro.
AB  - 1 We investigated whether vasoactive intestinal peptide (VIP) and its related
      peptides, pituitary adenylate cyclase activating peptide (PACAP) and secretin,
      regulate cholinergic neural mucus secretion in ferret trachea in vitro, using
      35SO4 as a mucus marker. We also studied the interaction between VIP and secretin
      on cholinergic mucus output. 2 VIP (1 and 10 microM) increased secretion, whereas
      neither PACAP1 - 27, PACAP1 - 38 nor secretin (up to 10 microM) increased mucus
      output. In contrast, VIP, PACAP1 - 27 and PACAP1 - 38 concentration-dependently
      inhibited cholinergic neural secretion, with an order of potency of VIP>PACAP 1 -
      38>PACAP1 - 27. Neither PACAP1 - 27 nor PACAP1 - 38 altered the secretion induced
      by acetylcholine (ACh). 3 Secretin increased cholinergic neural secretion with a
      maximal increase of 190% at 1 microM. This potentiation was blocked by VIP or
      atropine. Similarly, secretin (1 microM) potentiated VIP (1 microM)-induced mucus
      output by 160%. Secretin did not alter exogenous ACh-induced secretion. VIP vs
      secretin competition curves suggested these two peptides were competing
      reversibly for the same receptor. 4 We conclude that, in ferret trachea in vitro,
      VIP and PACAPs inhibit cholinergic neural secretion via pre-junctional modulation
      of cholinergic neurotransmission. VIP and secretin compete for the same receptor,
      possibly a VIP1 receptor, at which secretin may be a receptor antagonist.

PMID- 10578154
TI  - Practical considerations in the use of tacrolimus for allogeneic marrow
      transplantation.
AB  - Tacrolimus has been shown to be more effective than cyclosporine for prevention
      of acute graft-versus-host disease (GVHD). A number of transplant centers have
      therefore adopted tacrolimus as standard prophylaxis, but with additional
      experience, current management of tacrolimus differs from that in the clinical
      studies. Therefore, a consensus conference was convened to assess the current
      practices. For prevention of GVHD, conference participants recommended
      administering tacrolimus at 0.03 mg/kg/day (by lean body weight) i.v. by
      continuous infusion from day -1 or -2 pretransplant, with day -2 used especially
      for pediatric patients. Therapeutic drug monitoring was considered essential in
      the management of patients on tacrolimus. The consensus target range for the
      whole blood concentration was 10-20 ng/ml. Doses were modified for blood levels
      outside the target range or for nephrotoxicity, and tacrolimus was discontinued
      for intolerable tremor, hemolytic uremic syndrome, leukoencephalopathy or other
      serious toxicity. Tacrolimus was employed most frequently in combination with
      minimethotrexate (5 mg/m2 i.v. days 1, 3, 6 and 11). Tapering was individualized
      according to center practice. No patient category was excluded from use of
      tacrolimus based on age, extent of disease, patient-donor histocompatibility or
      stem cell source. Tacrolimus was also used successfully for treatment of chronic
      GVHD. The responsiveness of steroid-refractory acute GVHD was marginal, so it was
      deemed more prudent to use tacrolimus for prophylaxis instead.

PMID- 10578155
TI  - Treatment of chronic myelogenous leukemia with autologous bone marrow
      transplantation followed by roquinimex.
AB  - Unmanipulated autologous bone marrow transplant (ABMT) offers patients with
      chronic myelogenous leukemia (CML) a long-term survival of 10%, at best.
      Immunotherapy has a role in the myeloid leukemias, and there is increasing
      evidence that of all hematopoietic neoplasms, CML may be the most susceptible to
      immune regulation. Roquinimex is known to enhance T cell, NK cell and macrophage
      activity. A phase II study was initiated in March 1992 to evaluate the role of
      roquinimex in Ph chromosome-positive CML post ABMT. Patients were conditioned
      with busulfan/ cyclophosphamide followed by reinfusion of unmanipulated Ph
      positive bone marrow stem cells (>1 x 108 NBC/kg). When engraftment of
      neutrophils (ANC) reached 100/microl, patients received oral roquinimex twice
      weekly, escalating to a maximal dose of 0.2 mg/kg in 2 weeks. Seventeen patients
      have entered the study; 11 in first chronic phase (CP1); two in second chronic
      phase (CP2) and four in accelerated phase (AP). All required significant
      myelosuppressive therapy prior to ABMT to maintain stable blood counts and most
      had also received prior interferon therapy. All patients survived the transplant.
      Subsequent toxicity consisted mainly of musculoskeletal aches and peripheral
      edema. Additionally, specific skin changes were observed including graft-versus
      host-like disease and eccrine sweat gland necrosis. Eight out of 17 patients are
      alive 28-60 months post ABMT. Of the nine patients who died, two were in CP2 and
      three in AP. All patients in CP1 went into a complete hematological remission
      post ABMT and seven of the 11 patients had at least a major cytogenetic response
      (greater than 65% Ph-negative metaphases) at 1 year or beyond and four of the 11
      patients had a complete cytogenetic response at 2 years or beyond. Cytogenetic
      response post transplant often developed over time and did not simply represent
      post ABMT engraftment with Ph-negative cells. The clinical and cytogenetic data
      in these patients are encouraging and suggest that roquinimex may have
      significant activity when given post ABMT to patients with Ph-positive CML.

PMID- 10578157
TI  - Cyclosporine-induced autologous graft-versus-host disease in patients with acute
      myeloid leukemia undergoing non-myeloablative chemotherapy without progenitor
      cell reinfusion.
AB  - To determine the incidence and severity of cyclosporine-induced graft-versus-host
      disease following non-myeloablative chemotherapy without progenitor cell
      reinfusion in patients with acute leukemia, 17 adults with refractory acute
      myeloid leukemia (14) or blastic phase of chronic myeloid leukemia (3) were
      treated with etoposide 2400 mg/m2 and cyclophosphamide 120 mg/kg followed by
      cyclosporine (CsA) 2.5 mg/kg i.v. daily and interferon gamma 0.025 mg/m2
      subcutaneously every other day until day 28. Skin biopsies were obtained on days
      14 and 28, or on the appearance of a skin rash, and graded for GVHD. Blood
      samples were examined at baseline and weekly starting on day 14 for natural
      killer (NK) cell and T cell lymphocytic changes. Post-treatment lymphocytes from
      select patients were assessed for allogeneic NK cell and autologous leukemic cell
      cytolytic activity. Four patients developed pathologic grade 2 cutaneous acute
      GVHD. Of the three patients who achieved a complete remission, two had evidence
      of GVHD. Post-treatment, three patients (two with GVHD) in whom adequate numbers
      of lymphocytes could be obtained showed NK cell cytolytic activity against
      allogeneic tumor cells (K562), but none had cytolytic activity against their own
      cryopreserved leukemic cells. These data suggest that in patients with AML
      treated with subablative doses of chemotherapy without autotransplant, autologous
      GVHD can be induced, although at an incidence lower than that reported for CsA
      induced GVHD following marrow transplantation. An enhancement of T cell and NK
      cell activity levels similar to experiences in syngeneic models of autologous
      GVHD was seen, but no direct autologous leukemic cell cytotoxicity could be
      demonstrated.

PMID- 10578156
TI  - Peripheral blood stem cell mobilization and apheresis: analysis of adverse events
      in 94 normal donors.
AB  - Adverse events were analyzed in 94 normal donors who underwent PBSC harvest with
      G-CSF. The median dose of G-CSF was 9.7 microg/kg/day (range, 2.0-16.7), and the
      duration of administration was 4-6 days. Frequent symptoms were bone pain (71%),
      general fatigue (33%), headache (28%), insomnia (14%), anorexia (11%), nausea
      and/or vomiting (11%). One donor (1%) developed grade 3 toxicity bone pain (WHO
      criteria). WBC counts and ANC increased during G-CSF administration. After
      leukapheresis, three donors (3%) developed grade 3 toxicity neutropenia. Platelet
      counts decreased after leukapheresis. Three donors (3%) developed grade 3
      thrombocytopenia. The means of both ALP and LDH increased approximately 1.9-fold
      compared with pretreatment levels. In one pediatric donor (1%), ALP was elevated
      to the grade 3 toxicity level. From multivariate analysis, the incidence of bone
      pain increased when G-CSF was given at a dose of 8.8 microg/kg/day or more,
      headaches were frequent in donors younger than 35 years, and the incidence of
      nausea and/or vomiting was high in female donors. The peak levels of WBC counts
      and ANC and post-treatment level of LDH increased in correspondence with the
      escalation of G-CSF dose. All adverse events normalized on follow-up evaluation.
      In conclusion, although PBSC harvest for normal donors is acceptable, care must
      be taken for all donors in terms of their sex and age as well as the G-CSF dose.
      We recommend less than 8.8 microg/kg/day as the G-CSF dose for PBSC mobilization
      in normal donors.

PMID- 10578158
TI  - Infectious complications after autologous peripheral blood progenitor cell
      transplantation followed by G-CSF.
AB  - Infectious complications after autologous peripheral blood progenitor cell
      transplantation (PBPCT) have been reported in a few studies including small
      patient numbers. The present study was performed to assess the incidence, types,
      outcome and factors affecting early and late infections in 150 patients aged 18
      to 68 years (median 46.5) who underwent high-dose therapy, with G-CSF. Patients
      were kept in reverse isolation rooms and received antimicrobial chemoprophylaxis
      with oral quinolone and fluconazole. One hundred and fifteen patients (76.7%)
      developed fever (median 3 days, range 1-29); 20 patients (55.5%) had Gram
      positive and 13 (36. 2%) Gram-negative bacterial infections. There were no fungal
      infections or infection-related deaths. Mucositis grade II-IV (P = 0. 0001; odds
      ratio 3.4) and >5 days on ANC <100/microl (P = 0.0001; odds ratio 2.3) correlated
      with development of infection. Only days with ANC <100/microl affected infection
      outcome (P = 0.0024) whereas the antibiotic regimen did not. After day +30 there
      were four cases of bacterial pneumonitis (2.7%), one case of fatal CMV pneumonia
      (0. 8%) and 20 of localized VZV infection (13.3%). Reduction of neutropenia
      duration with PBPCT and G-CSF is not enough to prevent early infectious
      complications since only a few days of severe neutropenia and mucositis are
      related to development of early infections. However, no infection-related deaths
      were seen. Although Gram-positive organisms were the major cause of bacteremia, a
      glycopeptide in the empirical antibiotic regimen did not affect infection
      outcome. In PBPCT recipients, early and late opportunistic infections were
      notably absent, which was at variance with what was seen with bone marrow
      recipients. Efforts should be made to prevent mucositis and neutropenia and
      identify new strategies of antibacterial prophylaxis.

PMID- 10578159
TI  - Itraconazole oral solution as antifungal prophylaxis in children undergoing stem
      cell transplantation or intensive chemotherapy for haematological disorders.
AB  - This was an open study of oral antifungal prophylaxis in 103 neutropenic children
      aged 0-14 (median 5) years. Most (90%) were undergoing transplantation for
      haematological conditions (77% allogeneic BMT, 7% autologous BMT, 6% PBSC
      transplants and 10% chemotherapy alone). They received 5.0 mg/kg itraconazole/day
      (in 10 mg/ml cyclodextrin solution). Where possible, prophylaxis was started at
      least 7 days before the onset of neutropenia and continued until neutrophil
      recovery. Of the 103 who entered the study, 47 completed the course of
      prophylaxis, 27 withdrew because of poor compliance, 19 because of adverse events
      and 10 for other reasons. Two patients died during the study and another five
      died within the subsequent 30 days. No proven systemic fungal infections
      occurred, but 26 patients received i.v. amphotericin for antibiotic-unresponsive
      pyrexia. One patient received amphotericin for mycologically confirmed
      oesophageal candidosis. Three patients developed suspected oral candidosis but
      none was mycologically proven and no treatment was given. Serious adverse events
      (other than death) occurred in 21 patients, including convulsions (7), suspected
      drug interactions (6), abdominal pain (4) and constipation (4). The most common
      adverse events considered definitely or possibly related to itraconazole were
      vomiting (12), abnormal liver function (5) and abdominal pain (3). Tolerability
      of study medication at end-point was rated as good (55%), moderate (11%), poor
      (17%) or unacceptable (17%). Some patients had poor oral intakes due to
      mucositis. No unexpected problems of safety or tolerability were encountered. We
      conclude that itraconazole oral solution may be used as antifungal prophylaxis
      for neutropenic children.

PMID- 10578160
TI  - Prophylaxis and treatment of chemo- and radiotherapy-induced oral mucositis - are
      there new strategies?
AB  - Oral mucositis is a major dose-limiting toxic effect of intensive cancer
      chemotherapy. Oral complications may lead to dose reduction or delay in further
      cancer treatment. Mucositis can be caused directly by cytotoxic effects and
      indirectly by sustained neutropenia after cytostatic therapy. An impaired mucosal
      barrier predisposes to life-threatening septic complications during aplasia. The
      prevalence of an oral focus in febrile neutropenia has been reported in up to 30%
      of cases and also reduces quality of life. The basic strategies aim at pain
      relief and prevention of bacterial and fungal infectious complications. However,
      no effective causal prophylaxis or treatment of oral mucositis is widely
      accepted. The introduction of cytokines, eg granulocyte-macrophage colony
      stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) for
      oral mucositis may be particularly effective and offer a new and hopeful
      approach. At present, the optimal growth factor, best schedule, effective dosage
      and best mode of application is not known.

PMID- 10578161
TI  - Psychological risk factors and early complications after bone marrow
      transplantation in adults.
AB  - Complications of bone marrow transplantation can compromise its effectiveness,
      and often it is not possible to predict who is at greatest risk. In a previous
      study we reported that certain psychological factors correlated with a high
      incidence of post-transplant mortality, and here we analyze the associated
      complications and causes of death. Prior to receiving high-dose chemotherapy and
      bone marrow transplantation, 112 patients underwent a psychodynamically oriented
      psychiatric assessment (the 'FIT' assessment). Mortality and associated
      complications were ascertained by a retrospective chart review. The results of
      the 'FIT' assessment correlated with the incidence of complications and death,
      whether or not the transplant was performed for hematologic or solid organ
      cancers, or was from an allogeneic or autologous source. Most individuals with a
      high risk profile died of progressive major organ dysfunction or
      recurrent/refractory neoplastic disease in the first year after transplant. We
      propose that such a psychiatric assessment might identify a subgroup of
      individuals in whom pre-emptive therapeutic interventions could be most
      effective.

PMID- 10578162
TI  - Patients' psychosocial concerns following stem cell transplantation.
AB  - Information regarding the nature, frequency, correlates and temporal trajectory
      of concerns of stem cell transplantation (SCT) recipients is critical to the
      development of interventions to enhance quality of life (QOL) in these
      individuals. This study examined psychosocial concerns in 110 SCT (87%
      autologous) recipients drawn from two SCT centers. Participants were a mean of 46
      years of age and 17 months post-SCT (range 3-62 months). Information regarding
      current and past SCT-related concerns, performance status, and demographic
      characteristics was collected by telephone interview or questionnaire. Recipients
      reported a wide variety of psychosocial concerns following SCT. Recipients who
      were younger, female and evidenced a poorer performance status reported a larger
      number of post-SCT concerns. Examination of the temporal trajectory of concerns
      suggests that some concerns are salient throughout the course of post-SCT
      recovery (eg disease recurrence, energy level, 'returning to normal'), some are
      salient early in the course of recovery (eg quality of medical care,
      overprotectiveness by others), and others emerge later in the course of recovery
      (eg feeling tense or anxious, sexual life, sleep, relationship with
      spouse/partner, ability to be affectionate). Implications for the development of
      interventions to enhance post-SCT QOL are identified.

PMID- 10578163
TI  - Growth in children with poor-risk neuroblastoma after regimens with or without
      total body irradiation in preparation for autologous bone marrow transplantation.
AB  - Impaired growth after TBI prior to BMT has been a constant finding in children
      with leukemia. The growth of poor-risk neuroblastoma (NBL) survivors treated with
      myeloablative preparative regimens and ABMT at the Hospital for Children and
      Adolescents, University of Helsinki, since 1982 is reported. Two separate groups
      were analyzed: (1) The TBI- patients (n = 15) were conditioned with high-dose
      chemotherapy only. They had been treated at the age of 1.0-6.3 (mean 3.0) years
      and the post-ABMT follow-up time was 1.5-14.5 (mean 7.7) years. (2) The TBI+
      patients (n = 16) had received TBI in addition to high-dose chemotherapy. They
      had been treated at the age of 1.3-4. 8 (mean 3.0) years, and the post-ABMT
      follow-up time was 1.5-8.0 (mean 4.7) years. The height standard deviation score
      (SDS) was similar for the two groups at the time of diagnosis, -0.3 +/- 1.2 (mean
      +/- s.d.), and at the time of ABMT, -0.7 +/- 1.1. After transplantation, the
      height SDS continued to decrease in the TBI+ group, the mean being -2.0 SDS at 5
      years after ABMT. In the TBI-group, the mean height SDS remained within -0.7 to 
      0.9 to the 10 years of follow-up. Five patients received growth hormone (GH)
      therapy starting 2-6 years after ABMT. They all had low GH secretion in
      provocative tests. All showed some response to GH therapy. The mean height SDS
      increased 0.4 SDS during the 3 years following the start of GH therapy, while in
      the untreated patients a decrease of 0. 8 SDS during the corresponding time (P =
      0.009) was observed. We conclude that NBL patients grow poorly following ABMT
      when TBI is included in the conditioning regimen, but close to normally when
      treated without TBI. The need for GH therapy should be evaluated early to avoid
      an unnecessary decrease in final height.

PMID- 10578164
TI  - Isolated extramedullary relapse of acute lymphoblastic leukaemia after allogeneic
      bone marrow transplantation.
AB  - Isolated extramedullary relapse of acute lymphoblastic leukaemia (ALL) with
      sparing of the marrow after allogeneic bone marrow transplantation (BMT) is a
      rare occurrence, and the mechanisms underlying the selective involvement of
      extramedullary sites remain undefined. These might be due to relapse in sanctuary
      sites where the leukaemic cells are resistant to chemotherapy, or a stronger
      putative graft-versus-leukaemia (GVL) effect in the marrow as compared with
      peripheral tissues. We report two ALL patients with repeated episodes of
      extramedullary relapse after BMT in whom both mechanisms might be operating. In
      the first patient, the marrow was in morphologic and molecular remission before
      isolated leukaemic relapse in the central nervous system (CNS) occurred.
      Subsequent secondary infiltration of leukaemic cells into the marrow was only
      evident molecularly but not morphologically, implying that the relapse had arisen
      in a sanctuary CNS site. In the second patient, a first relapse in the marrow,
      which was induced into morphologic and molecular remission by chemotherapy and
      donor lymphocyte infusion, was followed by extramedullary relapses without any
      subsequent involvement of the marrow. This suggested that factors, likely to be
      due to a GVL effect, were stronger in the marrow than in peripheral tissues.

PMID- 10578165
TI  - Encephalopathy complicating high-dose melphalan.
AB  - High-dose melphalan (HDM) with peripheral blood stem cell transplant (PBSCT) is a
      common treatment for patients with multiple myeloma (MM) and more recently also
      with AL amyloidosis (ALA). We report two female patients with severe renal
      failure who underwent treatment with HDM for MM (patient 1) and ALA (patient 2).
      Both patients developed severe encephalopathy with generalised tonic-clonic
      seizures and a Glasgow Coma Scale (GCS) of 3/15. Causes for coma such as
      infections, metabolic disturbances, cerebral ischaemia or haemorrhage were
      excluded. Patient 1 died on day 25 post transplant while comatose. Patient 2
      recovered from her comatose state 18 days after transplantation. To our knowledge
      this is the first report on a possible role of high-dose melphalan in the
      development of encephalopathy.

PMID- 10578166
TI  - Aspergillus tracheobronchitis after allogeneic bone marrow transplantation.
AB  - We describe a patient who developed Aspergillus tracheobronchitis after BMT. She
      complained of progressive dyspnea on day +165 and her respiratory function
      deteriorated rapidly. Although neither early chest X-rays nor CT scans were
      negative, bronchoscopy revealed formation of a pseudomembrane around the
      bronchial walls. Based upon pathological and microbiological examinations, she
      was diagnosed as having invasive Aspergillus tracheobronchitis. Retrospectively
      analyzed, the Aspergillus circulating antigen detection tests became positive
      before clinical symptoms developed, and may be beneficial for early diagnosis of
      Aspergillus tracheobronchitis. This form of aspergillosis should be regarded as
      one of the serious complications after BMT.

PMID- 10578167
TI  - In vivo expansion of reinfused autologous peripheral blood stem cells after a
      myeloablative regimen, as an alternative to ex vivo expansion pretransplantation:
      an intriguing observation in apatient autografted twice.

PMID- 10578168
TI  - Comparison of the antigenemia assay and screening bronchoscopy for detection of
      cytomegalovirus infection after bone marrow transplantation.

PMID- 10578169
TI  - Stem cell transplantation

PMID- 10578170
TI  - Caspases: a decade of death research.

PMID- 10578171
TI  - Caspase structure, proteolytic substrates, and function during apoptotic cell
      death.
AB  - Caspases play an essential role during apoptotic cell death. These enzymes define
      a new class of cysteine proteases and comprise a multi-gene family with more than
      a dozen distinct mammalian family members. The discrete and highly limited subset
      of cellular polypeptides that are cleaved by these proteases is sufficient to
      account for the majority of cellular and morphological events that occur during
      cell death. In some cases, caspases also play a contributory role in escalating
      the propensity for apoptosis, and in doing so may exacerbate disease
      pathogenesis.

PMID- 10578172
TI  - Caspase knockouts: matters of life and death.
AB  - Apoptosis, the seemingly counter-intuitive act of physiological cell suicide, is
      accomplished by an evolutionarily conserved death program that is centered on the
      activation of a group of intracellular cysteine proteases known as caspases. It
      is now clear that both extra- and intra-cellular stimuli induce apoptosis by
      triggering the activation of these otherwise latent proteases in a process that
      culminates in caspase-mediated disintegration of cellular contents and their
      subsequent absorption by neighboring cells. While many elegant in vitro studies
      have demonstrated the requirement of caspase activities for the execution of
      most, if not all, apoptosis, the precise contribution of individual caspases in
      vivo and how they functionally relate to each other remain poorly elucidated.
      Fortunately, the generation of various caspase deficient mice through gene
      targeting has provided a unique window of opportunity to definitely examine the
      physiological function of these caspases in vivo. As the list of caspase
      knockouts grows, we considered it was time to review what we have been learned,
      from these studies about the exact role of individual caspases in mediating
      apoptotic events. We will also provide our prediction on the direction of future
      studies in this ever-growing field of caspases.

PMID- 10578173
TI  - Catalytic properties of the caspases.
AB  - Caspase stands for cysteine-dependent aspartate specific protease, and is a term
      coined to define proteases related to interleukin 1beta converting enzyme and CED
      3.1 Thus their enzymatic properties are governed by a dominant specificity for
      substrates containing Asp, and by the use of a Cys side-chain for catalyzing
      peptide bond cleavage. The use of a Cys side chain as a nucleophile during
      peptide bond hydrolysis is common to several protease families. However, the
      primary specificity for Asp turns out to be very rare among protease families
      throughout biotic kingdoms. Of all known mammalian proteases only the caspase
      activator granzyme B, a serine protease, has the same primary specificity. In
      addition to this unusual primary specificity, caspases are remarkable in that
      certain of their zymogens have intrinsic proteolytic activity. This latter
      property is essential to trigger the proteolytic pathways that lead to apoptosis.
      Here we review the known enzymatic properties of the caspases and their zymogens
      within the broad context of structure:mechanism:activity relationships of
      proteases in general.

PMID- 10578174
TI  - Mechanisms mediating caspase activation in cell death.
AB  - The initial activation of a caspase in a caspase cascade is a crucial event that
      determines whether a cell will ultimately undergo cell death. Although each cell
      contains a number of different caspases, only a small subset may be required for
      apoptosis in response to a specific stimulus. It now seems that each caspase
      cascade has two types of caspases involved, the upstream or class I caspases, and
      the downstream or class II caspases. Class I caspases are characterised by long
      amino-terminal prodomains that carry specific protein - protein interaction
      domains which mediate oligomerisation of caspases, often assisted by specific
      adaptor molecules. Oligomerisation appears to be sufficient for autocatalytic
      activation of class I caspases. Once the first caspase in the pathway has been
      activated, it processes downstream caspases initiating a cascade of amplifying
      events that lead to the apoptotic death of a cell. This article reviews our
      current understanding of mechanisms that mediate the activation of caspases.

PMID- 10578175
TI  - Serial killers: ordering caspase activation events in apoptosis.
AB  - Caspases participate in the molecular control of apoptosis in several guises; as
      triggers of the death machinery, as regulatory elements within it, and ultimately
      as a subset of the effector elements of the machinery itself. The mammalian
      caspase family is steadily growing and currently contains 14 members. At present,
      it is unclear whether all of these proteases participate in apoptosis. Thus,
      current research in this area is focused upon establishing the repertoire and
      order of caspase activation events that occur during the signalling and
      demolition phases of cell death. Evidence is accumulating to suggest that
      proximal caspase activation events are typically initiated by molecules that
      promote caspase aggregation. As expected, distal caspase activation events are
      likely to be controlled by caspases activated earlier in the cascade. However,
      recent data has cast doubt upon the functional demarcation of caspases into
      signalling (upstream) and effector (downstream) roles based upon their prodomain
      lengths. In particular, caspase-3 may perform an important role in propagating
      the caspase cascade, in addition to its role as an effector caspase within the
      death programme. Here, we discuss the apoptosis-associated caspase cascade and
      the hierarchy of caspase activation events within it.

PMID- 10578176
TI  - Caspase activation without death.
AB  - Since molecular cloning of the C. elegans ced-3 gene revealed its homology with
      mammalian IL-1beta-converting enzyme,1 14 members of the caspase family have been
      identified, which have often been involved as mediators of one or more phases of
      the apoptotic process. 2,3 However, an over-simplified role of these proteases
      may be insufficient to explain the usually constitutive expression of such a
      large and complex family of enzymes, many of which display overlapping
      specificity. In addition to the well-established role of caspase-1 in the
      production of active IL-1beta and IL-18 in inflammation,4 an increasing number of
      reports has recently suggested that caspases may have a function outside of
      apoptosis. In this review, the situations in which cells survive despite the
      presence of activated caspases in their cytoplasm will be examined and discussed,
      with the intent to gather all recent advances in this new field that promises to
      be a focus for caspase research in the near future.

PMID- 10578177
TI  - Caspase inhibitors.
AB  - Caspases are the key effector molecules of the physiological death process known
      as apoptosis, although some are involved in activation of cytokines, rather than
      cell death. They exist in most of our cells as inactive precursors (zymogens)
      that kill the cell once activated. Caspases can be controlled in two ways. The
      processing and activation of a caspase can be regulated by molecules such as
      FADD, APAF-1, Bcl-2 family members, FLIP and IAPs. Active caspases can be
      controlled by a variety of inhibitors that directly interact with the protease.
      This review describes the later direct caspase inhibitors that have been
      identified, products of both viral and cellular genes, and artificial caspase
      inhibitors that have been developed both as research tools and as pharmaceutical
      agents to inhibit cell death in vivo.

PMID- 10578178
TI  - Apaf1 and the apoptotic machinery.
AB  - The molecular characterization of the Caenorhabditis elegans cell death genes has
      been crucial in revealing some of the biochemical mechanisms underlying apoptosis
      in all animals. Four C. elegans genes, egl-1, ced-9, ced-4 and ced-3 are required
      for all somatic programmed cell death to occur. This genetic network is highly
      conserved during evolution. The pro-death gene egl-1 and the anti-death gene ced
      9 have structural and functional similarities to the vertebrate Bcl2 gene family.
      The killer gene ced-3 encodes a cystein-aspartate protease (caspase), which is
      the archetype of a family of conserved proteins known as effectors of apoptosis
      in mammals. Zou and collaborators1 reported the biochemical identification of an
      apoptotic protease activating factor (Apaf1), a human homolog of C. elegans CED
      4, providing important clues to how CED-4 and its potential relatives could work.
      A number of proteins have been shown to interact with Apaf1 or to be determinant
      for its activity as an apoptotic adapter. The aim of this review is to provide an
      overview of the recent progress made in the field of developmental apoptosis by
      means of the murine Apaf1 targeted mutations. The central role of Apaf1 in the
      cell death machinery (apoptosome) and its involvement in different apoptotic
      pathways will also be discussed.

PMID- 10578179
TI  - Ultrarapid caspase-3 dependent apoptosis induction by serine/threonine
      phosphatase inhibitors.
AB  - The protein phosphatase (PP) inhibitors nodularin and microcystin-LR induced
      apoptosis with unprecedented rapidity, more than 50% of primary hepatocytes
      showing extensive surface budding and shrinkage of cytoplasm and nucleoplasm
      within 2 min. The apoptosis was retarded by the general caspase inhibitor Z
      VAD.fmk. To circumvent the inefficient uptake of microcystin and nodularin into
      nonhepatocytes, toxins were microinjected into 293 cells, Swiss 3T3 fibroblasts,
      promyelocytic IPC-81 cells, and NRK cells. All cells started to undergo budding
      typical of apoptosis within 0.5 - 3 min after injection. This was accompanied by
      cytoplasmic and nuclear shrinkage and externalization of phosphatidylserine.
      Overexpression of Bcl-2 did not delay apoptosis. Apoptosis induction was slower
      and Z-VAD.fmk independent in caspase-3 deficient MCF-7 cells. MCF-7 cells stably
      transfected with caspase-3 showed a more rapid and Z-VAD.fmk dependent apoptotic
      response to nodularin. Rapid apoptosis induction required inhibition of both PP1
      and PP2A, and the apoptosis was preceded by increased phosphorylation of several
      proteins, including myosin light chain. The protein phosphorylation occurred even
      in the presence of apoptosis-blocking concentrations of Z-VAD.fmk, indicating
      that it occurred upstream of caspase activation. It is suggested that phosphatase
      inhibiting toxins can induce caspase-3 dependent apoptosis in an ultrarapid
      manner by altering protein phosphorylation.

PMID- 10578180
TI  - BMP-4 and retinoic acid synergistically induce activation of caspase-9 and cause
      apoptosis of P19 embryonal carcinoma cells cultured as a monolayer.
AB  - In monolayer cultures of P19 EC cells treated with both all-trans retinoic acid
      (RA) and bone morphogenetic protein (BMP)-4 (RA/BMP-4 treatment), many non
      adherent apoptotic cells and activated caspase-3-positive cells were observed,
      but they were not observed in cells treated with RA or BMP-4 alone. Consistent
      with the appearance of activated caspase-3-positive cells, BMP-4 and RA together
      induced processing of caspase-9, Ac-DEVD-MCA cleavage activity and DNA
      fragmentation. These three activities were observed infrequently or not at all
      when cells were treated with RA or BMP-4 alone. In the RA/BMP-4 treatment-induced
      apoptosis, caspase-9 was upstream of caspase-3 in the enzyme cascade, and the
      caspase-9 to -3 step was key in the apoptotic pathway. Bcl-xL inhibited
      processing of caspase-9, Ac-DEVD-MCA cleavage activity and DNA fragmentation
      induced by RA/BMP-4 treatment. However, unlike staurosporine-induced apoptosis,
      cytochrome c, which activates caspase-9, was not detected in the cytosol of
      RA/BMP-4-treated cells. RA and BMP-4 may activate caspase-9 through an apoptotic
      pathway other than the Apaf-1/cytochrome c pathway. The prominent decrease of X
      chromosome-linked inhibitory apoptosis protein (XIAP) in the cytosol may explain
      the activation of caspase-9 induced by RA and BMP-4 treatment.

PMID- 10578181
TI  - The proteolytic procaspase activation network: an in vitro analysis.
AB  - In general, apoptotic stimuli lead to activation of caspases. Once activated, a
      caspase can induce intracellular signaling pathways involving proteolytic
      activation of other caspase family members. We report the in vitro processing of
      eight murine procaspases by their enzymatically active counterparts. Caspase-8
      processed all procaspases examined. Caspase-1 and -11 processed the effector
      caspases procaspase-3 and -7, and to a lesser extent procaspase-6. However, vice
      versa, none of the caspase-1-like procaspases was activated by the effector
      caspases. This suggests that the caspase-1 subfamily members either act upstream
      of the apoptosis effector caspases or else are part of a totally separate
      activation pathway. Procaspase-2 was maturated by caspase-8 and -3, and to a
      lesser extent by caspase-7, while the active caspase-2 did not process any of the
      procaspases examined, except its own precursor. Hence, caspase-2 might not be
      able to initiate a wide proteolytic signaling cascade. Additionally, cleavage
      data reveal not only proteolytic amplification between caspase-3 and -8, caspase
      6 and -3, and caspase-6 and -7, but also positive feedback loops involving
      multiple activated caspases. Our results suggest the existence of a hierarchic
      proteolytic procaspase activation network, which would lead to a dramatic
      increase in multiple caspase activities once key caspases are activated. The
      proteolytic procaspase activation network might allow that different apoptotic
      stimuli result in specific cleavage of substrates responsible for typical
      processes at the cell membrane, the cytosol, the organelles, and the nucleus,
      which characterize a cell dying by apoptosis.

PMID- 10578182
TI  - Solution structure and mutagenesis of the caspase recruitment domain (CARD) from
      Apaf-1.
AB  - Activation of procaspase-9, a key component of the apoptosis mechanism, requires
      the interaction of its caspase recruitment domain (CARD) with the CARD in the
      adaptor protein Apaf-1. Using nuclear magnetic resonance spectroscopy and
      mutagenesis we have determined the structure of the CARD from Apaf-1 and the
      residues important for binding the CARD in procaspase-9. Apaf-1's CARD contains
      seven short alpha-helices with the core six helices arranged in an antiparallel
      manner. Residues in helix 2 have a central role in mediating interaction with
      procaspase-9 CARD. This interaction surface is distinct from that proposed based
      on the structure of the CARD from RAIDD, but is coincident with that of the
      structurally similar FADD death effector domain and the Apaf-1 CARD interface
      identified by crystallographic studies.

PMID- 10578183
TI  - A comparison of the cytoplasmic domains of the Fas receptor and the p75
      neurotrophin receptor.
AB  - The p75 neurotrophic receptor (p75) shares structural features with the Fas
      receptor (FasR). Both receptors contain extracellular cysteine-rich repeats, a
      single transmembrane domain, and intracellular death domains. However, it has not
      been clearly established whether their death domains are equivalent in their
      ability to mediate apoptosis. To understand better the role of p75 during
      apoptosis, we constructed chimeric receptors that contained the extracellular
      portion of the FasR and the intracellular portion of p75. These chimeric
      receptors, one containing the p75 transmembrane domain and the other containing
      the FasR transmembrane portion, as well as wild-type p75 and Fas receptors, were
      transiently transfected into human U373 glioma cells and human embryonic kidney
      293 cells (293 cells), which are both responsive to Fas-mediated apoptosis.
      Whereas expression of FasR was sufficient to induce apoptosis in U373 and 293
      cells, expression of p75 and the chimeric receptors induced only minimal levels
      of cell death compared to FasR. The results indicate that the magnitudes of FasR-
      and p75-induced killing are different and suggest that the death domain of p75
      does not function in the same manner as the FasR death domain.

PMID- 10578184
TI  - Digital quantitative radiography: tools and toys.

PMID- 10578185
TI  - Magnetic resonance imaging of experimentally-induced sialadenitis in rat
      submandibular glands.
AB  - OBJECTIVES: To correlate the features of magnetic resonance (MR) images of
      experimentally induced obstructive sialadenitis in rat submandibular glands with
      the histopathological changes. METHODS: Changes in MR images of ligated and non
      ligated rat submandibular glands were compared with the histopathological changes
      and wet weight ratios. Spin echo T1 weighted images (SE T1WI), fast spin echo T2
      weighted images (FSE T2WI), and gradient echo T2 weighted images (GE T2WI) were
      obtained at 1, 2, 3, 4, 5, 7 and 21 days after duct ligation with a 0.3 T MR
      imaging system. RESULTS: There was a significant difference (P<0.05) between the
      signal intensity ratios of both ligated and non-ligated glands on each day,
      except at 21 days on GE T2WI. On SE T1WI, small interval changes of signal
      intensity ratios were observed on both glands, whereas there were large interval
      changes at 1 - 2 days, 4 - 7 days and 21 days after duct ligation with FSE T2WI.
      These three periods correlated highly with three phases of histopathological
      changes, swelling of acinar cells at 1 - 2 days, atrophy of acinar cells and
      increase of duct-like structures at 3 - 7 days, and proliferation of connective
      tissue at 21 days, and the changes in wet weight ratios. A similar tendency was
      observed on GE T2WI to FSE T2WI. CONCLUSIONS: As FSE T2WI showed large changes in
      signal intensity that correlated highly with histopathological three phases, it
      is recommended as the MR sequence of choice for diagnosing the degree of damage
      in obstructive sialadenitis.

PMID- 10578186
TI  - The role of computed tomography in the preoperative assessment and follow-up of
      oromandibular reconstruction with microvascular osteomyocutaneous free flaps.
AB  - OBJECTIVE: To investigate the capacity of helical CT in the pre- and post
      operative management of oromandibular reconstruction of patients with
      oropharyngeal carcinoma using microvascular composite free flaps.
      MATERIALS/METHODS: Thirty-four patients with oropharyngeal cancer were examined
      by helical CT and nine (six men and three women) submitted to oromandibular
      reconstruction. The osteomyocutaneous flaps used for reconstruction were taken
      from the iliac crest in six cases and from the fibula in three cases. All
      patients were examined by CT 1 - 4 days postoperatively and then at 6 monthly
      intervals. Double helical scans were performed in all cases, with slices of 2 - 3
      mm for primary lesion studies and 5 mm for lymph node staging, pitch >/=1 and
      RI=1. Multiplanar (MPR) and 3D reconstructions were obtained from pre- and
      postoperative CT examinations. RESULTS: Preoperative CT showed massive bone
      infiltration in six of the nine surgical patients and marginal infiltration in
      three. These findings were confirmed histologically. There were no false
      negatives. The immediate postoperative examination showed correct flap
      positioning in eight of nine cases. The flap underwent ischemic necrosis in two
      cases; CT showed very early signs of bone ischemia in both. CT detected two cases
      of recurrence after about 1 year. CONCLUSIONS: Axial CT permitted adequate
      assessment of the extent of mandibular infiltration and detected early ischemic
      complications and distant recurrences. Integration with MPR and 3D
      reconstructions simplified the choice of flap type and size and enabled the
      postoperative assessment of correct flap positioning. This helped the surgeon
      plan subsequent rehabilitation with osseo-integrated implants.

PMID- 10578187
TI  - An electronic survey of opinions on the compatibility of current X-ray generators
      with intra-oral digital X-ray systems.
AB  - OBJECTIVES: To assess opinions on the compatibility of current X-ray generators
      with intra-oral digital X-ray systems. METHODS: A questionnaire was posted in
      both English and in Japanese on oral and maxillofacial radiology electronic
      bulletin boards. The questionnaire was also mailed to selected researchers and
      manufacturers in oral and maxillofacial radiology. The replies were evaluated to
      determine opinion on the current and future status of digital intra-oral imaging
      with special reference to their compatibility with current X-ray generators.
      RESULTS: Seventy-one replies were received from 19 countries: 39% from Japan and
      Korea, 27% from North America, 25% from Europe and 8% from the rest of the world.
      Eighty per cent of respondents were from academia, 15% from industry and the
      remainder largely in private practice. Respondents' experience was equally
      divided between solid state, mainly charge-coupled devices (CCDs) and
      photostimulable phosphor (IP) technologies. Sixty-eight per cent considered that
      current X-ray generators are compatible with intra-oral digital systems and many
      believed this was due to their gray scale flexibility. Twenty-eight per cent
      believed that existing X-ray generators are inconsistent with low exposure times.
      Many of the replies suggested that in future pixel size would decrease and bit
      depth and receptor sensitivity increase. CONCLUSIONS: Most respondents are happy
      to use existing X-ray generators with digital X-ray systems. However, they also
      believe that increased sensitivity of receptors could lead to more stringent
      designs of X-ray generators to ensure more reliable outputs in the low exposure
      range.

PMID- 10578188
TI  - Carotid artery calcification in the black population: a retrospective study on
      panoramic radiographs.
AB  - OBJECTIVES: To determine the prevalence of carotid artery calcification on
      panoramic radiographs in the Black population. METHODS: Panoramic radiographs of
      700 adult male and female Black dental outpatients from the Medical Center of
      Louisiana Charity Hospital were examined for any unusual radiopacity adjacent to
      or just below the intervertebral space between C3 and C4. RESULTS: Three (0.43%)
      of the 700 patients, with ages ranging from 46 - 77-years-old, had one or more
      unusual radiopacities in the region of interest. All three were female.
      CONCLUSION: It is uncommon to find radiopacities adjacent to or just below the
      intervertebral space between C3 and C4 in the general Black population.

PMID- 10578189
TI  - Detection of bone invasion by gingival carcinoma of the mandible: a comparison of
      intraoral and panoramic radiography and computed tomography.
AB  - OBJECTIVE: To assess the diagnostic accuracy of panoramic radiography (PR),
      panoramic radiography combined with intraoral radiography (PR+IR), and CT in
      detecting the supero-inferior extent of tumor invasion of the mandible by
      gingival carcinoma. METHOD: PR, PR+IR, and CT images of the mandible in 37
      patients with gingival carcinoma were evaluated by five oral radiologists for the
      supero-inferior extent of bone invasion using ROC analysis. The mean ROC curve
      area (Az) of each observer for the different imaging modalities was analysed by
      nonparametric two-way ANOVA. P<0.05 was considered statistically significant.
      RESULTS: The mean Az for the detection of bone invasion were 0.88+/-0.03 for PR,
      0.77+/-0.12 for PR+IR, and 0.87+/-0.03 for CT (P=0.0907). The mean Az for the
      detection of bone invasion beyond the alveolus was 0.89+/-0.07 for PR, 0.85+/
      0.08 for PR+IR, and 0.83+/-0.06 for CT (P=0.5438). The mean Az for the detection
      of bone invasion beneath the mandibular canal were 0.94+/-0.04 for PR, 0.94+/
      0.02 for PR+IR, and 0.91+/-0. 04 for CT (P=0.2466). No statistically significant
      differences were observed in Az between PR, PR+IR, and CT. CONCLUSION: We
      consider that PR+IR should be adopted as the initial imaging modality to
      determine the extent of supero-inferior invasion of the mandible in gingival
      carcinoma.

PMID- 10578190
TI  - Idiopathic osteosclerosis in the jaws of Britons and of the Hong Kong Chinese:
      radiology and systematic review.
AB  - AIM: To compare the prevalence of idiopathic osteosclerosis in the jaws in Hong
      Kong and Britain. METHODS: The panoramic radiographs of consecutive patients who
      attended the primary care departments of the dental hospitals in Hong Kong in
      1981 and 1990 and London in 1990 and of Edinburgh in 1993 were reviewed. The size
      of the Hong Kong lesions was measured. The literature was subjected to systematic
      review. RESULTS: The prevalence of idiopathic osteosclerosis in Hong Kong in 1981
      and 1990, London and Edinburgh was 6.7, 5.5, 2.7 and 4.1% respectively. The
      prevalence of idiopathic osteosclerosis was greater in the Oriental (Chinese and
      Japanese) than in Western surveys. The lesions in the 1990 Hong Kong survey in
      the third decade were significantly smaller than those in the 1981 survey. The
      decrease in size in Hong Kong 1990 was also accompanied by a reduction in overall
      prevalence. The predilection for the mandible, especially in the premolar area,
      was observed in the Chinese and London series; this feature was also common to
      all other reports. CONCLUSION: The Chinese have a greater prevalence of
      idiopathic osteosclerosis than Western populations.

PMID- 10578191
TI  - Dependency of dose response of five charge-coupled device-based digital intra
      oral radiographic systems on tube voltage.
AB  - OBJECTIVE: To compare the dependency of dose response of five CCD-based digital
      intra-oral radiographic systems on tube voltage. METHODS: Characteristic curves
      for Sens-A-Ray (old and new generations; Regam Medical Systems, Sundsvall,
      Sweden), Computed Dental Radiography (Schick Technologies, Long Island City, NY,
      USA), CompuRay (Yoshida, Tokyo, Japan), and VIXA (Dentsply/Gendex, Des Plaines,
      IL, USA) were generated between 60 and 90 kVp at intervals of 10 kVp and
      corrected by subtraction of dark current. Their sensitivities were compared.
      RESULTS: The sensitivity of the old generation Sens-A-Ray decreased with increase
      in tube voltage whereas in the other systems it increased. CONCLUSION: In the
      newer systems using a rare earth intensifying screen as a scintillator, the
      sensitivity increases with increase in tube voltage, thus reducing the radiation
      dose to the patient.

PMID- 10578192
TI  - Reproducible X-ray projection geometry in edentulous patients.
AB  - OBJECTIVE: To evaluate a novel fixation system for reproducible radiography in
      edentulous patients. METHODS: A conventional extra-oral fixation system was
      modified with a filmholder and adjustable scales. For measuring reproducibility
      and angulation errors two rods and two balls were fixed on the alveolar crests of
      the maxilla and the mandible and angular variations were measured. One hundred
      radiographs of a conventional phantom were taken by one of the authors and by ten
      dental students. The angular disparity was calculated and intra- and
      interoperator precision determined. RESULTS: The average time taken to assemble
      the fixation system was 4 min. The 95% confidence interval for precision of the
      single operator was less than 2.5 degrees in both the maxilla and mandible. The
      95% confidence interval for precision of the ten students was less than 2.2
      degrees for the maxilla and 2.7 degrees for the mandible. There was no
      significant difference (P>0.05) in interoperator precision. CONCLUSION: The novel
      extra-oral fixation system appears to be a potential means of obtaining
      reproducible radiographs of edentulous patients.

PMID- 10578193
TI  - Cyclopia and exadactyly: CT and MRI findings.
AB  - Cyclopia is a congenital abnormality consisting of fused orbits and a single eye
      and is the most extreme form of alobar holoprosencephaly. The present case
      describes the CT and MRI findings in the skull of a 33-week-old cadaver with
      alobar holoprosencephaly and exadactyly.

PMID- 10578194
TI  - Bone formation in a carcinoma of the maxillary antrum.
AB  - Malignant tumors of the paranasal sinuses are rare: about 80% are found in the
      maxillary sinus123. The presence of dense radiopaque masses in combination with
      destruction of the bone margins suggests osteosarcoma or aspergillosis4 rather
      than carcinoma. We present a unique mucoepidermoid carcinoma of the maxillary
      antrum containing new bone formation and discuss the differential diagnosis.

PMID- 10578195
TI  - Noma: report of a case resulting in bony ankylosis of the maxilla and mandible.
AB  - Noma, or cancrum oris, has been described as a gangrenous infection of the soft
      and hard tissues of the oronasal region. Prior to the advent of antibiotics the
      disease was commonly fatal. Now many survive the acute phase of the disease and
      present the surgeon with formidable problems of repair. This is a report of a
      presumed case of noma that resulted in bony ankylosis of the maxilla and
      mandible. Three-dimensional shaded surface CT reconstruction images were
      especially useful in demonstrating the architecture of the abnormal bone.

PMID- 10578196
TI  - Implantation-type epidermoid cyst of the mandible.
AB  - The documented cases of epidermoid implantation cysts affecting the oral tissues
      are reviewed. A unique case involving the ramus of the mandible is presented.

PMID- 10578197
TI  - Diagnostic imaging of pigmented villonodular synovitis of the temporomandibular
      joint associated with condylar expansion.
AB  - Pigmented villonodular synovitis (PVNS) is a rare lesion of the temporomandibular
      joint. We report a case which was initially misdiagnosed as a parotid tumor. CT
      revealed a well-defined mass demonstrating higher attenuation than the adjacent
      soft tissue with marked expansion of the mandibular condyle. MRI clearly
      delineated the extent of the lesion which had very low signal intensity on both
      T1W and T2W sequences due to the effect of hemosiderin. The usefulness of these
      imaging procedures in diagnosis of PVNS is discussed.

PMID- 10578198
TI  - Review of Impotence Literature.

PMID- 10578199
TI  - Gluttony and thermogenesis revisited.
AB  - The evolutionary and biological significance of adaptive, homeostatic forms of
      heat production (thermogenesis) is reviewed. After summarizing the role and
      selective value of thermogenesis in body temperature regulation (shivering and
      non-shivering thermogenesis) and the febrile response to infection (fever), the
      review concentrates on diet-induced thermogenesis (DIT). Animal studies indicate
      that DIT evolved mainly to deal with nutrient-deficient or unbalanced diets, and
      re-analysis of twelve overfeeding studies carried out between 1967 and 1999
      suggests the same may be so for humans, particularly when dietary protein
      concentration is varied. This implies that the role of DIT in the regulation of
      energy balance is secondary to its function in regulating the metabolic supply of
      essential nutrients. However, individual differences in DIT are much more marked
      when high- or low-protein diets are overfed, and this could provide a very
      sensitive method for discriminating between those who are, in metabolic terms,
      resistant and those who are susceptible to obesity.

PMID- 10578200
TI  - Low-protein overfeeding: a tool to unmask susceptibility to obesity in humans.
AB  - In search for an approach to identify physiological targets for therapeutic
      intervention in obesity management, we have revisited the classic human
      overfeeding studies of the 1960s, with new emphasis on a 'subgroup' of volunteers
      who were shifted between overfeeding on a typical affluent (normal-protein) diet
      and overfeeding on a low-protein diet. Following a re-analysis of these data, the
      arguments are put forward that since low-protein overfeeding is not only a potent
      stimulus of thermogenesis, but also an amplifier (or magnifier) of the small
      inter-individual variations in thermogenesis on the affluent (normal-protein)
      diet, it can be used as a tool to unmask some of the genetic and metabolic basis
      underlying human susceptibility to leanness and fatness.

PMID- 10578201
TI  - Fat balance and hepatic mitochondrial function in response to fat feeding in
      mature rats.
AB  - OBJECTIVE: To study the effects of fat feeding on fat balance and hepatic
      mitochondrial function in postpubertal male rats. DESIGN: Rats were fed low fat,
      medium fat or high fat diet for 15 days. MEASUREMENTS: Energy balance, body
      composition, resting metabolic rate (RMR), mitochondrial state 3 and state 4
      oxygen consumption rates, succinic dehydrogenase (EC 1.3.99.1) and mitochondrial
      alpha-glycerophosphate dehydrogenase (EC 1.1.1.8) activities. RESULTS: Rats fed
      medium fat or high fat diet, in comparison with rats fed low fat diet, showed a
      significantly greater metabolisable energy intake and energy expenditure. In
      addition, body energy and lipid gains were significantly higher in rats fed
      medium fat or high fat diet than in rats fed low fat diet. Mitochondrial
      respiration and enzymatic activities were not affected by fat feeding.
      CONCLUSION: These results indicate that in postpubertal rats fed high fat diets,
      the increase in energy expenditure counteracts only in part the excess fat
      deposition. This is probably due to the impairment in regulatory responses, and
      enhances thermogenesis.

PMID- 10578202
TI  - The role of central fat distribution in coronary artery disease in obesity:
      comparison of nondiabetic obese, diabetic obese, and normal weight subjects.
AB  - OBJECTIVE: To investigate the degree of coronary artery disease (CAD) in relation
      to obesity and fat distribution in obese patients with normal glucose tolerance,
      in comparison with CAD of diabetic obese patients and of normal weight subjects
      with CAD. DESIGN: Patients listed for coronary angiography with different body
      mass index (BMI) with or without diabetes: study of the correlation between
      severity of coronary damage and fat distribution. SUBJECTS: 92 patients
      subdivided into: 30 normal glucose tolerant obese (BMI 31.7+/-0.5, aged 53+/-1.7
      y), 28 type 2 diabetic obese (BMI 30.7+/-0. 3, aged 57+/-1.2 y), and 34 normal
      weight patients (BMI 23.1+/-0.3, aged 54+/-1.7 y). MEASUREMENTS: CAD assessed by
      angiography and evaluated according to the method of Gensini. Fat mass and fat
      distribution assessed by bioelectrical impedance and anthropometry. Clinical,
      biochemical and hormonal variables, as well as smoking habits and alcohol intake.
      RESULTS: The angiographic coronary scores were similar in nondiabetic obese and
      in diabetic obese patients, and were significantly higher than those of normal
      weight subjects. In the entire population coronary score correlated with indices
      of abdominal fat distribution. In the stepwise analysis of each group separately,
      waist hip ratio (WHR) correlated with coronary score only in normal weight
      nondiabetic patients. CAD was inversely associated with BMI only in nondiabetic
      obese patients. CONCLUSION: CAD of obese patients: 1) is similar to that of
      diabetic obese patients; 2) is more severe than that of normal weight
      individuals; and 3) is inversely correlated with BMI. CAD appears to be
      associated with WHR, not with BMI, only in nondiabetic patients with normal body
      weight. On the contrary, CAD of diabetic obese patients is unrelated to BMI and
      parameters of fat distribution, but is associated with smoking habits.

PMID- 10578203
TI  - Prediction of hypertension, diabetes, dyslipidaemia or albuminuria using simple
      anthropometric indexes in Hong Kong Chinese.
AB  - OBJECTIVE: It is important to determine what values of simple anthropometric
      measurements are associated with the presence of adverse cardiovascular risk
      factors such as diabetes or hypertension to provide an indication for further
      detailed investigations. In this analysis, we aimed to assess which
      anthropometric cutoff values are best at predicting the likelihood of diabetes,
      hypertension, dyslipidaemia and albuminuria in Hong Kong Chinese. DESIGN AND
      SETTING: The data were obtained from a previously reported prevalence survey for
      glucose intolerance in a representative Hong Kong Chinese working population.
      SUBJECTS: 1513 subjects (910 men and 603 women) with mean age+/-s.d. 37.5+/-9.2
      y. MEASUREMENTS: We examined the likelihood ratios of having diabetes,
      hypertension, dyslipidaemia and albuminuria in subjects with various cutoff
      values of the four simple anthropometric indexes, namely, body mass index, waist
      hip ratio, waist circumference and the ratio of waist-to-height. RESULTS: We
      developed a nomogram to show the predictive values of different indexes for the
      cardiovascular risk factors using likelihood ratio analysis. Using Caucasian mean
      levels of the simple anthropometric indexes to predict diabetes or hypertension
      in Hong Kong Chinese gave a high likelihood ratio of 2:3:5. CONCLUSION: Higher
      levels of body mass index, waist-hip ratio, waist circumference and the ratio of
      waist-to-height are associated with risk of having diabetes mellitus or
      hypertension in Hong Kong Chinese as in Caucasians. However, the cutoff values of
      those anthropometric indexes to define obesity used in Caucasians may not be
      applicable to Chinese.

PMID- 10578204
TI  - Prevalence of overweight and obesity among school children in Jena (Germany).
AB  - OBJECTIVES: To examine the prevalence and changes in the prevalence of overweight
      and obesity among school children in Jena (Germany) in the last twenty years and
      to identify factors associated with childhood overweight. DESIGN: Cross-sectional
      surveys in 1975, 1985, 1995 and a household questionnaire in 1995. SUBJECTS:
      Children from schools in Jena, aged 7-14 y, participated (1975 : 1002 boys and
      1000 girls; 1985 : 781 boys and 753 girls; 1995 : 989 boys and 912 girls).
      MEASUREMENTS: Prevalence of overweight or obesity based on the 90th or 97th age-
      and sex-specific percentile of the body mass index (BMI) developed for French
      children. In 1995 factors examined in relation to overweight included birth
      weight, birth length, age-class, number of children in household, occupation of
      the father, education of the mother and size of flat (apartment). RESULTS: In
      boys the prevalence of overweight increased from 10.0 to 16.3% and in girls from
      11.7 to 20.7% between 1975 and 1995. The prevalence of obesity increased from 5.3
      to 8.2% in boys and from 4.7 to 9.9% in girls between 1975 and 1995. However, the
      peak in the increase of overweight as well as of obesity lie for both sexes
      between 1985 and 1995. Using logistic regression, statistically significant
      associations with overweight were found for occupation of the father, birth
      weight in both sexes and additionally, for size of flat in girls. CONCLUSIONS:
      Overweight and obesity are increasing health problems among Jena children.
      Further investigations are needed to explore the influence of factors such as
      feeding pattern, food habits and physical activity on overweight. Special
      attention should be paid to the further social development in the society and to
      the link between low social class and overweight. Through such investigations
      effective preventive strategies could be developed.

PMID- 10578205
TI  - Acute appetite reduction associated with an increased frequency of eating in
      obese males.
AB  - OBJECTIVE: To investigate the effects of altered feeding frequencies on the
      relationship between perceived hunger and subsequent food intake and appetite
      control in obese men. DESIGN: Obese men reported in a fasted state in the morning
      to the laboratory where an isoenergetic pre-load (4100+/-234 kJ, which was 33%
      average daily energy requirement (ADER) of each subject) comprising 70%
      carbohydrate, 15% protein, and 15% fat was given. This was administered either as
      a SINGLE meal, or divided evenly over 5 meals given hourly as a MULTI feeding
      pattern. Five hours after the first pre-load, an ad libitum test meal was given
      to determine whether there was a difference in the amount of energy that was
      consumed between the two eating patterns. SUBJECTS: Seven non-diabetic, non
      smoking, unrestrained obese men (age 37.4+/-18.5; BMI 40.02+/-10. 93 kg/m-2) were
      recruited for this study. Subjects were not told the precise reasons for this
      study but rather were informed that changes in blood glucose, insulin and free
      fatty acids with meal frequency were to be monitored. MEASUREMENTS: Blood
      glucose, serum insulin and free fatty acid (FFA) concentrations, and visual
      analogue scales (VAS) were measured prior to commencing the feeding regime and
      thereafter hourly for 5 h. Thereafter an ad libitum meal was given. The weight
      (and energy content) of the food consumed, and the time taken to eat lunch were
      recorded. Following this ad libitum lunch, the same variables were determined
      again (15, 45, and 75 min post-test meal). RESULTS: When given a SINGLE pre-load,
      27% more (t=2.651; P<0.05) energy was consumed in the ad libitum test meal
      (5261+/-1289 kJ) compared to that eaten after the MULTI pre-load (3763+/-1986
      kJ). This increase in food intake occurred despite no significant change in
      subjective hunger ratings. Over the 315 min pre-load period, peak insulin
      concentrations were significantly higher (F6,72=7.95, P<0.01) on the SINGLE
      treatment (171.2+/-129.8 microU ml-1) than on the MULTI treatment (133.7+/-70.2
      microU ml-1). Serum insulin remained elevated for longer on the MULTI meal
      treatment, resulting in no difference in the area under the insulin curves
      between the two feeding treatments. There was a positive correlation (r=0.87)
      between the amount of energy consumed at lunch and insulin concentration before
      lunch in the SINGLE group. However, this relationship was not apparent when
      subjects were given the MULTI meal preload. CONCLUSION: Obese males fed an
      isoenergetic pre-load sub-divided into a multi-meal plan consumed 27% less at a
      subsequent ad libitum test meal than did the same men when given the pre-load as
      a single meal. Prolonged but attenuated increases in serum insulin concentration
      on the multi-meal programme may facilitate this acute reduction in appetite.

PMID- 10578206
TI  - Attitudes towards food containing fats in subjects of different body size.
AB  - OBJECTIVE: The present study was aimed at verifying the hypothesis that
      individuals belonging to different classes of BMI could show diversities in
      attitudes and beliefs toward the consumption of food containing fat within the
      Fishbein and Ajzen framework. SUBJECTS AND METHODS: Nine hundred and seventy-five
      families out of 1200 participated in a study aimed at assessing attitudes towards
      the consumption of foods containing fats. Only subjects over 17 years of age with
      BMI values over 18.5 kg/m2 were included in the present study. The recruited
      families were asked to record their food consumption for 7 days according to a
      mixed technique including the weighed inventory method and the individual daily
      record of food consumption. Each individual also completed a questionnaire
      containing questions on belief, attitude and intention items based on Ajzen and
      Fishbein's model. All questions were related to the consumption of eight foods
      containing fats. RESULTS: The main finding was an absence of differences in
      attitudes and beliefs towards foods containing fats between the two groups of
      normal weight and overweight subjects, obtained by the regression analysis. The
      subjective measure of habit outweighed attitude in the impact on intention of
      consuming. Evidence of something to be further investigated comes from the first
      Principal Component that showed the cognitive 'Beliefs on gaining weight and
      getting fat' was the best summary of information in relation to the choice of red
      meat for the group of normal weight subjects, whereas the same belief was the
      best summary of information in relation to the choice of butter and cheese for
      the group of overweight subjects. CONCLUSION: Attitudes and beliefs play a
      similar role in the choice of foods containing fats in the two groups of people
      considered. Habit was found to be an important predictor of behaviour for both
      the two groups of subjects. With attempts to modify diet, habit may serve as a
      barrier to change. Thus, elucidating the roles played by these variables is
      crucial to developing effective future intervention strategies. However, the
      slight difference found in the cognitive belief on gaining weight and getting fat
      for red meat, butter and cheese suggests that further investigations on opinions
      about the role of certain foods will be useful.

PMID- 10578207
TI  - Changes in renal function during weight loss induced by high vs low-protein low
      fat diets in overweight subjects.
AB  - BACKGROUND: Due to the high satiating effect of protein, a high-protein diet may
      be desirable in the treatment of obesity. However the long-term effect of
      different levels of protein intake on renal function is unclear. OBJECTIVE: To
      assess the renal effects of high vs low protein contents in fat-reduced diets.
      DESIGN: Randomized 6 months dietary intervention study comparing two controlled
      ad libitum diets with 30 energy (E%) fat content: high-protein (HP; 25 E%) or low
      protein, (LP, 12 E% protein). All food was provided by self-selection in a shop
      at the department, and high compliance to the diet composition was confirmed by
      measurements of urinary nitrogen excretion. SUBJECTS: 65 healthy, overweight and
      obese (25<body mass index (BMI)<34 kg/m2). RESULTS: Dietary protein intake
      changed from 91.1 g/d to a 6 months intervention average of 70.4 g/d (P<0.05) in
      the LP group and from 91.4 g/d to 107.8 g/d (P<0.05) in the HP group, producing
      changes in glomerular filtration rate (GFR) of -7.1 ml/min in the LP group and
      +5. 2 ml/min in the HP group (group effect: P<0.05). Kidney volume decreased by 
      6.2 cm3 in the LP group and increased by +9.1 cm3 in the HP group (P<0.05),
      whereas albuminuria remained unchanged in all groups. CONCLUSION: Moderate
      changes in dietary protein intake cause adaptive alterations in renal size and
      function without indications of adverse effects.

PMID- 10578208
TI  - Body size and composition in Polynesians.
AB  - OBJECTIVES: To compare the relationship between body size and body composition in
      New Zealanders of Polynesian and European descent and to develop specific
      regression equations for fat mass for Polynesians. SUBJECTS: 189 Maori (93 males,
      96 females), 185 Samoans (88 males, 97 females) and 241 Europeans (89 males, 152
      females) aged 20-70 y. MEASUREMENTS: Height, weight, four skinfold thicknesses,
      bioelectrical impedance analysis (BIA) and dual energy X-ray absorptiometry
      (DXA). RESULTS: At higher body mass index levels, Polynesians (Maori and Samoans
      combined) had a significantly higher ratio of lean mass:fat mass compared with
      Europeans. Four multiple regression equations incorporating resistance and
      reactance, height and weight, sum of four skinfolds or sum of two skinfolds were
      developed in two-thirds of the Polynesian participants using DXA fat mass as the
      dependent variable. In the remaining one-third of participants, the mean
      difference between fat mass predicted by these equations (r2 range 0.89-0.93) and
      DXA fat mass ranged from -0. 06 to +0.25 kg (s.d. -3.67 to +3.71 kg). CONCLUSION:
      At higher BMI levels, Polynesians were significantly leaner than Europeans,
      implying the need for separate BMI definitions of overweight and obesity for
      Polynesians. The regression equations using BIA, height and weight or skinfold
      thicknesses were good predictors of body composition in Polynesians.

PMID- 10578209
TI  - The influence of abdominal obesity and chronic work stress on ambulatory blood
      pressure in men and women.
AB  - OBJECTIVE: To assess the influence of abdominal obesity and work stress
      (operationalised as low control over work) on ambulatory blood pressure on a
      working day and evening. PARTICIPANTS AND METHODS: 156 school teachers (58 men
      and 98 women) carried out ambulatory blood pressure and heart rate monitoring on
      a work day and evening. Cardiovascular activity was also measured under baseline
      conditions on another occasion, when body weight, height, waist and hip
      circumference were assessed. Perceived control over work was assessed by
      questionnaire, along with mental health, anger expression and social support. 126
      participants repeated the protocol after 12 months. Waist/hip ratio was used as
      the index of abdominal obesity. RESULTS: Baseline blood pressure was positively
      associated with waist/hip ratio in men, but ambulatory blood pressure and heart
      rate were not independently related to waist/hip ratio or job control. However,
      blood pressure and heart rate recorded during the working day and evening were
      elevated in men with high waist/hip ratio who experienced low job control,
      independently of age and body weight. Effects for diastolic blood pressure and
      heart rate were replicated after 12 months. Body mass index was not related to
      blood pressure or heart rate during the day or evening after adjustment for age
      and waist circumference. Low job control was associated with poor psychological
      well-being, negative mood and lack of social support. CONCLUSIONS: The results
      are consistent with the hypothesis that abdominal obesity in men is characterised
      by a tendency towards heightened stress-induced physiological activation, but
      that this tendency will only be manifest in the presence of appropriate
      environmental challenges such as chronic work stress.

PMID- 10578210
TI  - Physical inactivity, sedentary lifestyle and obesity in the European Union.
AB  - BACKGROUND: Diverging trends of decreasing energy intake and increasing
      prevalence of obesity suggest that physical inactivity and sedentary lifestyle
      may be one of the key determinants of the growing rates of overweight/obesity in
      Western populations information about the impact of physical inactivity and
      sedentary lifestyles on the prevalence of obesity among the general adult
      population in the European Union is sparse. OBJECTIVES: To estimate the
      association of leisure-time sedentary and non-sedentary activities with body mass
      index (BMI, kg/m2) and with the prevalence of obesity (BMI>30 kg/m2) in a sample
      of the 15 member states of the European Union. METHODS: Professional interviewers
      administered standardized in-home questionnaires to 15,239 men and women aged 15
      years upwards, selected by a multi-stage stratified cluster sampling with quotas
      applied to ensure national and European representativeness. Energy expenditure
      during leisure time was calculated based on data on frequency of and amount of
      time participating in various physical activities, assigning metabolic
      equivalents (METS) to each activity. Sedentary lifestyle was assessed by means of
      self-reported hours spent sitting down during leisure time. Multiple linear
      regression models with BMI as the dependent variable, and logistic regression
      models with obesity (BMI>30 kg/m2) as the outcome, were fitted. RESULTS:
      Independent associations of leisure-time physical activity (inverse) and amount
      of time spent sitting down (direct) with BMI were found. The adjusted prevalence
      odds ratio (OR) for obesity was 0.52 [95% confidence interval (CI): 0.43-0.64,
      P<0.001] for the upper quintile of physical activity (>30 METS) compared with the
      most physically inactive quintile (<1.75 METS). A positive independent
      association was also evident for the time spent sitting down, with an adjusted
      OR= 1.61(95% CI: 1.33-1.95, P<0.001) for those who spent more than 35 h of their
      leisure time sitting down compared with those who spent less than 15 h.
      CONCLUSIONS: Obesity and higher body weight are strongly associated with a
      sedentary lifestyle and lack of physical activity in the adult population of the
      European Union. These results, however, need to be interpreted with caution due
      to the cross-sectional design. Nonetheless, they are consistent with the view
      that a reduction in energy expenditure during leisure time may be the main
      determinant of the current epidemic of obesity.

PMID- 10578211
TI  - High protein vs high carbohydrate hypoenergetic diet for the treatment of obese
      hyperinsulinemic subjects.
AB  - OBJECTIVE: To test the hypothesis that hyperinsulinemic obese subjects would
      respond differently to changes in the composition of hypoenergetic diets. DESIGN:
      A 4-week randomized dietary intervention trial. SUBJECTS: Thirteen male obese
      hyperinsulinemic normoglycemic subjects were divided into two groups and fed
      hypoenergetic diets providing 80% of their resting energy expenditure (REE). One
      group received a high-protein diet (HP; 45% protein, 25% carbohydrates, and 30%
      fat as percent of dietary energy) and the other a high-carbohydrate diet (HC; 12%
      protein, 58% carbohydrates and 30% fat). MEASUREMENTS: Anthropometry, body
      composition, fasting serum insulin and lipids, and REE were performed before and
      after the feeding period. RESULTS: Weight loss was higher in the HP than HC group
      (8.3+/-0.7 vs 6.0+/-0.6 kg, P<0. 05). There was a decrease in body fat in both
      groups, whereas body water decreased significantly more in the HP group. REE
      decreased more in the HC than the HP group (-384.3+/-84.6 vs -132.3+/-51.0 kcal,
      P<0.05). Serum total cholesterol, triglycerides and LDL cholesterol decreased
      significantly to a similar extent in both diet groups, while HDL cholesterol was
      decreased significantly only in the HP group. Mean fasting insulin decreased
      significantly in both diet groups and reached the normal range only in the HP
      group. CONCLUSION: A low-carbohydrate (LC), HP hypoenergetic diet could be the
      diet composition of choice for a weight-reducing regimen in obese
      hyperinsulinemic subjects.

PMID- 10578212
TI  - Acute effects of leptin on glucose metabolism of in situ rat perfused livers and
      isolated hepatocytes.
AB  - OBJECTIVE: To investigate whether leptin interferes directly with glycogenolysis
      and gluconeogenesis in isolated rat hepatocytes and also in in situ rat perfused
      livers. ANIMALS: Male albino rats (200-250 g) were used in all experiments.
      MEASUREMENTS: D-glucose, L-lactate and pyruvate production. RESULTS: In the
      present study, no differences were found for the rates of glycolysis, as
      expressed by the areas under the curves, among control (24.2+5.0 mmol?g), leptin
      (32.0+4.5 mmol?g), glucagon (24.7+3.0 mmol?g), and the leptin + glucagon
      (23.8+3.4 mmol?g) groups. No difference was found for the rates of glycogenolysis
      between the control and the leptin perfused livers (15.2+3.9 and 15.0+3.2 mmol?g,
      respectively). In the presence of glucagon, the areas under the curves for the
      rate of glycogenolysis rose to 108.6+3.8 mmol?g. When leptin was combined with
      glucagon, the area under the curve for glycogenolysis was 43. 7+4.3 mmol?g. In
      fact, leptin caused a reduction of almost 60% (P<0. 001) in the rate of glucagon
      stimulated glycogenolysis. Under basal conditions, the addition of leptin (100
      ng?ml) to the incubation medium did not elicit any alteration in glucose
      production by isolated hepatocytes. However, in the presence of leptin, the
      production of glucose from glycerol (2 mM), L-lactate (2 mM). L-alanine (5 mM)
      and L-glutamine (5 mM) by the isolated hepatocytes was significantly reduced
      (30%, 30%, 23% and 25%, respectively). The rate of glucose production
      (glycogenolysis) by isolated hepatocytes was not different between the control
      and the leptin incubated groups (445.0+/-91.0 and 428.0+/-72.0 nmol?106 cells?h,
      respectively). CONCLUSION: We conclude that leptin per se does not directly
      affect either liver glycolysis or its glucose production, but a physiological
      leptin concentration is capable of acutely inducing a direct marked reduction on
      the rate of glucagon-stimulated glucose production in in situ rat perfused liver.
      Leptin is also capable of reducing glucose production from different
      gluconeogenic precursors in isolated hepatocytes.

PMID- 10578213
TI  - The 'number need to treat': does it help clinical decision making?
AB  - The number needed to treat (NNT) is an increasingly popular way of presenting the
      effects of treatment. However, the NNT varies markedly depending on the baseline
      risk of patients, the outcome considered, and the clinical setting. Furthermore
      geographic and secular trends make the NNT unstable between places and over time.
      Particular caution is needed in deriving the NNT from pooled absolute risk
      differences in meta-analysis. In general, the NNT should be calculated by
      applying the relative risk reduction on treatment estimated by trials or meta
      analysis to populations of specified absolute high, average or low risk to
      illustrate a range of possible NNTs.

PMID- 10578214
TI  - Simple blood pressure guidelines for primary health care.
AB  - Four simple pragmatic rules are proposed to facilitate the management of
      essential hypertension in the context of primary care. Rule 1: Abandon diastolic
      blood pressure measurement and rely on systolic blood pressure values for
      decisions on treatment thresholds and goals. Rule 2: Assess overall
      cardiovascular risk by history taking, physical examination and simple
      investigation (urine dipsticks, serum creatinine, glucose, lipids and ECG). Rule
      3: As a generality, apply a systolic threshold of 150 mm Hg for the introduction
      of drug treatment when repeated measures of blood pressure following a trial of
      non-pharmacological treatment, remain persistently above this level. This
      threshold may be reduced to 140 mm Hg for higher risk patients (eg, those with
      target organ damage or diabetes) or raised to 160 mm Hg for low risk patients and
      the elderly. Rule 4: Modify therapy if initial drug treatment is ineffective,
      partially effective or poorly tolerated. If blood pressure does not fall below
      the treatment threshold, drug dosage should be increased (except diuretics),
      treatment changed or combinations used to achieve goal pressures.

PMID- 10578215
TI  - The long-term effect of advice to eat more fish on blood pressure in men with
      coronary disease: results from the diet and reinfarction trial.
AB  - BACKGROUND: Systematic reviews of fish and fish oil supplements have reported
      modest reductions in blood pressure (BP). Many of the trials included in these
      reviews used high doses of fish oil and most were of short duration. METHOD:
      Between 1983 and 1987 2033 men under the age of 70, who had recently suffered a
      myocardial infarction, were enrolled in a 2-year trial of dietary advice-the Diet
      and Reinfarction Trial (DART). Participants were randomised in a factorial design
      to receive intensive advice to eat more fish, less fat or more fibre. Those men
      randomised to receive fish advice were encouraged to eat two portions of fatty
      fish each week. Intake of eicosapentaenoic acid was 0.33 g per day in the fish
      advice arm and 0.10 g per day in men not given fish advice. RESULTS: The
      difference in systolic BP in the fish advice arm, adjusted for age and BP at
      baseline, was -0.61 mm Hg (95% CI -2.15, 0.92) at 6 months and 0.40 mm Hg (95% CI
      -1.33, 2.13) at 2 years. The difference in diastolic BP in the fish advice arm,
      adjusted for age and BP at baseline, was -0.50 mm Hg (95% CI -1.47, 0.46) at 6
      months and 0.19 mm Hg (95% CI -0.88, 1.26) at 2 years. CONCLUSIONS: Advice to eat
      modest amounts of fish has little effect on BP in men with coronary disease.

PMID- 10578216
TI  - Trends in blood pressure and urinary sodium and potassium excretion in Japan:
      reinvestigation in the 8th year after the Intersalt Study.
AB  - Using the identical protocol of an Intersalt Study previously conducted, we
      undertook a new study (Intersalt-2) 8 years later. We measured changes in various
      factors affecting blood pressure (BP) including urinary sodium and potassium
      excretion in three districts of Japan: Osaka, Tochigi, and Toyama. Also we
      evaluated the trends in the relationships of those factors to BP. The Intersalt
      Study revealed that the average sodium excretion of all three study centres was
      high (particularly in Toyama) while potassium excretion was relatively low. The
      sodium/potassium ratio was therefore relatively high. The body mass index (BMI)
      was favourable, but the prevalence of heavy alcohol drinkers was high. Comparing
      the first to the second study reveals a decrease in sodium excretion in Toyama,
      although that area still had the highest value of the three study centres. The
      average potassium excretion increased only in Osaka. Sodium/potassium ratio
      decreased in all centres. BMI and the prevalence of heavy drinkers among the
      subjects of both studies were nearly the same. The trend of the relationship of
      sodium to BP in Osaka changed from negative to positive. In Toyama, it changed
      from positive to negative. It is thought that this negative relationship might
      occur in conjunction with a reduction in salt consumption in a population. In
      conclusion this study reveals that average sodium consumption in Japan remains
      high while potassium consumption is still low. As a factor in the prevention of
      hypertension, further efforts to reduce salt consumption and increase potassium
      intake are still needed.

PMID- 10578217
TI  - Ambulatory blood pressure monitoring: a criticism.

PMID- 10578218
TI  - Improvement in treatment of hypertension has not reduced incidence of end-stage
      renal disease.
AB  - Hypertension is an important cause of end-stage renal disease (ESRD) in the USA
      and in Sub-Saharan Africa. Antihypertensive therapy has led to a substantial
      decrease in incidence of stroke (42%) and to a lesser extent of myocardial
      infarction (16%), yet there has been an increase in hypertension related ESRD. In
      1991, about 190 000 persons in the USA either underwent dialysis or received a
      transplant for ESRD. Hypertension was found to be the underlying cause in 29% of
      these patients, second only to diabetes mellitus (36%). Both in the USA and South
      Africa hypertension was found to be the most common cause of ESRD, but it is not
      clear whether this is related to the higher incidence and severity of
      hypertension in black people. Moreover blood pressure (BP) control in black
      patients does not necessarily lead to improved renal function. These findings
      suggest that factors other than BP elevation participate in the progression of
      nephrosclerosis. They include misdiagnosis, black race (socio-economic status,
      physiologic differences, severity of hypertension), BP control (adequate control
      of BP and type of antihypertensive therapy), and possibly other factors like
      genetics. The lack of reduction in ESRD may be that currently accepted standards
      for BP control are not adequate and that different antihypertensive agents affect
      glomerular haemodynamics in different ways. These factors need an in-depth
      analysis to improve the important public health issue of increasing morbidity and
      mortality from ESRD.

PMID- 10578219
TI  - The effect of age on vascular compliance in man: which are the appropriate
      measures?
AB  - Vascular compliance declines rapidly with age and measures of arterial compliance
      may help understanding of the aging process. Of the different measures of
      vascular compliance, those more closely related to chronological age need to be
      identified. These measures may help in the estimation of 'biological age'. We
      measured pulse wave velocity as the carotid-finger interval, carotid-toe interval
      and QKD interval (time between the Q wave and the arrival of the diastolic
      Korotkoff sound (K) over the brachial artery in diastoly (D)); central aortic
      compliance (CAC) and SV/PP (the stroke volume divided by pulse pressure in the
      brachial artery). Thirty-six volunteers were studied (30 men), ages 20 to 84,
      mean 49 years, to give the relationship of these measurements with age. CAC, the
      QKD interval and the carotid-toe interval were most closely related to age (r = -
      0.51, -0.60 and -0.58 respectively). After adjustment for age, the only measure
      related to blood pressure was the carotid-finger interval; b for diastolic blood
      pressure = -0.83 (P = 0.01), the higher the pressure the shorter the interval.
      Measurements of CAC, QKD interval and carotid-toe interval may be employed to
      assess the impact of age on vascular compliance. Measures of peripheral vascular
      compliance, such as the carotid-finger interval, may prove useful in assessing
      the relationship between blood pressure and vascular compliance.

PMID- 10578220
TI  - Comparison of arbitrary definitions of circadian time periods with those
      determined by wrist actigraphy in analysis of ABPM data.
AB  - Determining blood pressure (BP) values at different daily time periods is a well
      recognised measure to assess the risk of end-organ damage. However, the use of
      various definitions of these periods, eg, day vs night, sleep vs wake or
      arbitrary definitions, makes clinical decisions based on available data
      difficult. In the present study, we compared BP loads in actual sleep-wake
      periods to default day-night definition provided by the ambulatory BP monitoring
      (ABPM) software (day 06.00 to 22.00; night 22.00 to 06.00) as well as to an
      arbitrary definition of sleep-wake periods in children published in Soergel et al
      (J Pediatr 1997; 130: 178-184)1 (awake 08.00 to 20.00 and sleep 00.00 to 06.00.
      We used an actigraphy, an accelerometer, to define the actual sleep-wake periods
      in 46 patients with essential hypertension who are on various treatment regimens.
      BP data was obtained by using Spacelabs 90207 monitors for a full 24 h. There
      were significant differences between actual sleep-wake and default definition for
      BP load. No similar finding was noted when arbitrary definition was used. The
      proportion of hypertensives was not significantly different when default and
      arbitrary definitions were used. Classification of dippers and non-dippers is
      greatly affected by the definition of sleep interval using the default method.
      Although some of the misclassifications were not statistically significant, their
      clinical importance must be considered. Determination of sleep and wake periods
      for analysis of ABPM data should be based on careful determination of actual
      periods. Using other definitions may not provide complete information or
      accommodate for individual variation.

PMID- 10578222
TI  - Urinary levels of tissue kallikrein in the South African Black and Indian
      hypertensives.
AB  - It is accepted that Black subjects differ from White and Indian hypertensives in
      their response to hypotensive agents. Black hypertensives in the USA have a lower
      urinary tissue kallikrein (TK) excretion levels compared to White hypertensives.
      It has been suggested that Black patients respond better to thiazide diuretics
      compared to beta-blockers because thiazides increase whereas beta-blockers
      decrease tissue kallikrein excretion. This study compares the excretion of
      urinary TK in Black and Indian hypertensive and normotensive subjects. Urinary TK
      levels were measured with the selective, synthetic peptic substrate with the
      sequence of H-D-Val-Leu-Arg-pNA. Ten hypertensive patients on placebo therapy and
      10 normotensive Black and Indian subjects provided three samples at weeks 0, 2
      and 4 for the determination of urinary TK. The results were analysed using
      analysis of variance to compare the two racial groups. There were no significant
      differences in urinary TK values of the three bi-weekly individual samples.
      Urinary tissue kallikrein values (ng TK/microg protein) in Indian hypertensives
      were in general lower than Black hypertensives.

PMID- 10578221
TI  - Prior antihypertensive treatment and admission blood pressure correlated with
      clinical outcome and early morning presentation in hypertensive ischaemic stroke
      patients.
AB  - Blood pressure (BP) reduction of 5-6 mm Hg reduces the relative risk of stroke by
      30-40%. This effect does not appear to depend on the antihypertensive agent used
      to bring about the required reduction in BP. Patients with acute ischaemic stroke
      often exhibit an elevated BP. These patients, who previously suffered from
      hypertension, have significantly higher levels of BP readings on admission with
      increased incidence of stroke immediately after arising. The aim of this study
      was to compare antihypertensive agents, especially short and long acting drugs
      with the measurement of BP on admission, the time of the ischaemic stroke and its
      clinical severity. This was studied retrospectively in 109 patients (55 females
      and 54 males). The mean age was 69.7 +/- 10.4 years. All the patients admitted
      between 1 July 1996 and 30 June 1997 for ischaemic stroke as established by brain
      CT scan, were studied. Of the stroke subjects not treated or treated with short
      acting calcium blockers, 40.8% and 44.4% of them respectively appeared to have an
      ischaemic stroke in the early morning hours in contrast to 20% of those treated
      with long acting calcium blockers (P < 0.05). The last group of patients also
      experienced less clinical severity. These results emphasise the need for proper
      24-h control of BP and by comparison to other antihypertensive agents, the long
      acting calcium blockers with these subjects may prevent a sudden early morning
      rise in BP, which is instrumental in stroke prevention.

PMID- 10578223
TI  - Effect of a mineral salt diet on 24-h blood pressure monitoring in elderly
      hypertensive patients.
AB  - The influence of a mineral salt on 24-h ambulatory blood pressure (BP) monitoring
      was studied in 20 elderly hypertensive subjects residing in an old peoples home.
      Ordinary table and cooking salt was substituted with a special Na-reduced, K-, Mg
      , and l-lysine HCl-enriched mineral salt (Pansalt(R)) for 6 months.
      Antihypertensive therapy was uninterrupted. An ambulatory BP monitor (Suntech
      Accutracker) measured BP every 20 min during the day and every 30 min at night,
      before and 6 months after starting the diet. Nine patients (45%) decreased both
      systolic and diastolic BP significantly: systolic BP fell from 154.92 +/- 33.67
      mm Hg to 143. 45 +/- 53.1 mm Hg (P < or = 0.01) during the daytime from 6 am to
      midnight; and from 139.80 +/- 32.84 mm Hg to 137.87 +/- 31.17 mm Hg (P < or =
      0.01) from midnight to 6 am. Diastolic BP fell from 85.34 +/- 24.85 mm Hg to
      70.29 +/- 18.31 mm Hg (P < or = 0.01) during the daytime from 6 am to midnight;
      and from 77.1 +/- 22.92 mm Hg to 67.76 +/- 15. 63 mm Hg (P < or = 0.01) at night.
      Blood pressure in the other 11 subjects showed no improvement. Heart rate also
      fell in the subjects, from 69.44 +/- 21.62 beats per minute (bpm) to 66.94 +/-
      11.51 bpm (< or = 0.01) during the day, and from 61.28 +/- 12.82 bpm to 60.43 +/-
      10.33 bpm (P < or = 0.01) during the night. It is concluded that decreased intake
      of Na and increased intake of both K and Mg can be useful in controlling high BP.

PMID- 10578224
TI  - The effect of moxonidine on plasma lipid profile and on LDL subclass
      distribution.
AB  - Moxonidine is a new antihypertensive agent whose mechanism of action appears to
      involve specific stimulation of imidazoline receptors resulting in an inhibition
      of the activity of the central and peripheral sympathetic nervous system. The
      drug seems to behave neutrally with respect to plasma lipid parameters. However,
      there are no data on the effects of moxonidine on the low-density lipoprotein
      (LDL) subclass pattern or on the LDL oxidation susceptibility, both of which are
      known to play a prominent role in the pathogenesis of atherosclerosis. Thus, we
      undertook the present study to examine the influence of moxonidine on the LDL
      subspecies profile and their susceptibility to copper-induced oxidative
      modification in 20 hypertensive patients (11 men, 9 women) aged 38-61 years.
      Moxonidine administered at a dose of 0.4 mg daily for 8 weeks produced a
      significant decrease in both systolic and diastolic blood pressure (from 147 +/-
      10 to 131 +/- 11 mm Hg, P < 0.001, and from 98 +/- 4.5 to 86 +/- 5 mm Hg, P <
      0.001, respectively). No significant change in plasma lipid profile was observed
      after moxonidine administration. Additionally, no change in the susceptibility of
      LDL subclasses to copper-induced oxidative modification was noticed. Finally,
      drug therapy was not followed by any change in either LDL phenotype or in mass
      and composition of the three LDL subfractions. We conclude, that unlike other
      antihypertensive drugs, such as beta-blockers which may predispose to expression
      of a relatively atherogenic lipoprotein subclass pattern, moxonidine does not
      affect either plasma lipid parameters or lipoprotein composition.

PMID- 10578225
TI  - Effectiveness and metabolic effects of perindopril and diuretics combination in
      primary hypertension.
AB  - The effectiveness as well as the metabolic effects of the combination of
      diuretics [hydrochlorothiazide (HCT) vs indapamide (IND)] and perindopril (P) in
      14 patients (7 male, 7 female) aged 37-62 years with mild idiopathic hypertension
      were studied. Following a 4-week wash-out period and a 4-week period of
      monotherapy with P (4 mg/daily), IND (2.5 mg/daily) or HCT (25 mg/daily) was
      added for 4 weeks. Selection of the diuretic agent was random. Following a 4-week
      wash-out period from the diuretic, in which only P was given, the alternative
      diuretic was administered for another period of 4 weeks. P decreased blood
      pressure levels significantly. However, the drug was more efficacious in patients
      with higher plasma renin activity (PRA). Combination treatment induced an
      additional decrease in the blood pressure levels, mainly in patients with lower
      PRA. The combination of P + HCT was more effective than the combination P + IND.
      The addition of either HCT or IND evoked a small but statistically significant
      increase in serum glucose levels while fasting as well as during the 75 g oral
      glucose challenge. However, insulin levels did not change significantly during
      the study. Small but not statistically significant changes in serum electrolytes
      and lipid parameters were observed during the various phases of the study, while
      a statistically significant increase in the serum uric acid was noticed when the
      combination P + HCT was given. We conclude: (1) P in small doses is an effective
      and safe antihypertensive agent, (2) PRA has a predictive value in determining
      the effectiveness of P treatment, (3) the combination of P with small doses of
      HCT or IND is more efficacious than P alone, (4) the combination treatment has
      adverse effects in the carbohydrate tolerance, while there are not significant
      changes in serum electrolyte and lipid parameters.

PMID- 10578227
TI  - No acute additive effect of losartan in a patient already on an ACE inhibitor for
      heart failure.

PMID- 10578226
TI  - Increased weight and blood pressure in adolescent male offspring to mothers with
      pre-pregnancy diabetes-a genetic link?
AB  - Adverse factors acting in foetal or early life have been proposed to be causally
      related to the development of hypertension and glucose intolerance in adult life.
      This might be caused by the influence of foetal malnutrition and impaired foetal
      growth. Another explanation would be that genetic factors can cause a chain of
      events, leading from disease in the mother, to impaired placental function and
      later development of disease in the offspring. We investigated the pregnancy
      outcome in male offspring of 368 diabetic and 38 hypertensive mothers, all
      diagnosed before pregnancy, compared to the offspring of 143254 mothers without a
      corresponding pre-pregnancy diagnosis. The offspring were reinvestigated at the
      age of 18 years, at the time of a conscript test for military service. Offspring
      to diabetic mothers were shorter, but not thinner, and born after a shorter
      gestational time, than offspring to non-diabetic mothers. The former also showed
      increased weight and blood pressure at the conscript testing. This supports the
      notion of a genetic influence on birth variables as well as bodily development in
      the late adolescence. Thus, not only foetal malnutrition but also genetic
      programming seem to be factors of importance for the relationship between
      impaired foetal growth and adult health.

PMID- 10578228
TI  - Prevalence of cardiovascular risk factors in the republic of georgia

PMID- 10578229
TI  - Activation of the nuclear factor kappa B (NF-kappaB) and cyclooxygenase-2 (COX-2)
      genes in cerebral blood vessels in response to systemic inflammation.

PMID- 10578230
TI  - What is the cellular source of prostaglandins in the brain in response to
      systemic inflammation? Facts and controversies.
AB  - Circulating inflammatory mediators can signal neurons through a pathway in which
      cytokine activation of the cells of the blood-brain barrier causes the induction
      of the nuclear factor kappa B (NF-kappaB), leading to the transcription of target
      genes, such as the one encoding cyclooxygenase 2 (COX-2), the enzyme that
      initiates prostaglandin formation. These active products of the arachidonate
      metabolism produced by the cerebral microvasculature have critical roles in
      initiating the neuronal responses and the neurophysiological outcomes that take
      place during immunogenic stimuli, including sickness behaviors, fever and
      increase in the hypothalamic-pituitary adrenal axis. Whether there is more than a
      single cell type in the blood-brain barrier responsible for the synthesis of
      prostanoids in the presence of circulating proinflammatory cytokines is an
      interesting debate that will be summarized here.

PMID- 10578231
TI  - Functional segregation within the human hippocampus.
AB  - Recent evidence suggests that the functions of the brain region critical for long
      term memory, the hippocampus, may be segregated along its anterior-posterior
      axis.

PMID- 10578232
TI  - Neurobiological basis of relapse prediction in stimulant-induced psychosis and
      schizophrenia: the role of sensitization.
AB  - A number of consistent clinical observations provide direction for the hypothesis
      that pathological sensitization of neuronal systems may be an important factor
      for relapse or the onset of stimulant-induced psychosis (eg, methamphetamine or
      amphetamine psychosis, cocaine psychosis and phencyclidine psychosis) and
      schizophrenia. First, psychotic symptoms can be produced in normal subjects by
      stimulants. Secondly, a large portion of schizophrenic patients exhibit
      exacerbation of psychotic symptoms in response to stimulants at doses which would
      not be psychotogenic in normal subjects. Lastly, the ability of stress to
      precipitate the onset and relapse of schizophrenia is well documented. In this
      regard, acute responses to stimulants provide useful information for relapse
      prediction of schizophrenia and substance abuse. This paper addresses the nature
      and role of pathological sensitization in relapse of stimulant- and phencyclidine
      induced psychosis and schizophrenia, and its relation to pathophysiology of
      schizophrenia.

PMID- 10578233
TI  - It all sticks together--the APP-related family of proteins and Alzheimer's
      disease.
AB  - In the present review, we shall discuss the pros and cons of a possible
      functional relationship and contribution of the APP family members (APP, APLP1
      and APLP2) to the development of Alzheimer's disease: (1) APP, APLP1 and APLP2
      are highly homologous proteins with similar protein domain organization. (2) All
      APP family proteins have been found to be aggregated in typical Alzheimer's
      disease lesions. (3) Several other proteins have been implied to provide a
      functional link among the APP-related proteins. In normal adult brain APP, APLP1
      and APLP2 are involved in synaptic processes important for memory function. We
      hypothesize that the functional loss of members of the APP family contributes to
      the gradual cognitive decline in Alzheimer's disease patients.

PMID- 10578234
TI  - Dopamine D4 receptors: significance for molecular psychiatry at the millennium.
AB  - Extraordinary progress has been made in the molecular, genetic, anatomical, and
      pharmacological characterization of dopamine D4 receptors in animal and human
      brain. Clarification of the neurochemical and physiological roles of these
      cerebral receptors is emerging. Postmortem neuropathological studies have
      inconsistently linked D4 receptors to psychotic disorders, and genetic studies
      have failed to sustain conclusive associations between D4 receptors and
      schizophrenia. However, associations are emerging between D4 receptors and other
      neuropsychiatric disorders, including attention deficit hyperactivity disorder,
      mood disorders, and Parkinson's disease, as well as specific personality traits
      such as novelty-seeking. Selective D4 agonists and antagonists have been
      developed as useful experimental probes. D4antagonists, so far, have proved
      ineffective in treatment of schizophrenia, but testing in a broader range of
      disorders may yield clinically useful drugs. D4 receptors appear to have broad
      implications for the pathophysiology of neuropsychiatric illnesses and their
      improved treatment.

PMID- 10578235
TI  - Association between variants at the GABAAbeta2, GABAAalpha6 and GABAAgamma2 gene
      cluster and alcohol dependence in a Scottish population.
AB  - A role for the GABA/benzodiazepine receptor complex in alcohol dependence
      syndrome has been suggested by several lines of evidence. To elucidate the role
      of GABAA subunits in human alcohol dependence syndrome, we identified
      polymorphisms in the GABAAbeta2 and GABAAalpha6 receptor subunit genes on 5q33
      and assessed their potential contribution in an association study, together with
      a NciI RFLP at the GABAAgamma2 receptor subunit gene. One hundred and eight
      alcohol-dependent subjects and 54 unrelated controls were recruited from
      Scotland. Two novel genetic markers were identified at the GABAAbeta2 and
      GABAAalpha6 receptor subunit genes and examined for association with the alcohol
      dependence syndrome and subgroups of subjects with Korsakoff's psychosis and
      without Korsakoff's psychosis, together with a NciI RFLP at the GABAAgamma2
      receptor subunit gene. The chi2 tests demonstrated associations between all
      alcohol-dependent subjects (not stratified) and the BanI RFLP at the GABAAbeta2
      receptor subunit gene (P = 0.015), and the AlwNI RFLP at the GABAAalpha6 receptor
      gene (P = 0.013). Significant associations were also found between the alcohol
      dependent subjects with Korsakoff's psychosis and the BanI RFLP (P = 0.039) and
      the AlwNI RFLP (P = 0.003). Haplotype analysis also provided evidence of
      association when all alcohol-dependent subjects (P = 0.013) and the subjects with
      Korsakoff's psychosis (P = 0.007) were compared with controls. Our findings
      provide evidence for a role for the GABAA receptor subunit cluster on chromosome
      5q33 in susceptibility to the alcohol dependence syndrome and Korsakoff's
      psychosis.

PMID- 10578236
TI  - Two novel variants in the DOPA decarboxylase gene: association with bipolar
      affective disorder.
AB  - DOPA decarboxylase (DDC), also known as aromatic L-amino acid decarboxylase
      (AADC), is an enzyme involved in the synthesis of the important neurotransmitters
      dopamine, norepinephrine, and serotonin. In addition, it participates in the
      synthesis of trace amines; compounds suggested to act as endogenous modulators of
      central neurotransmission. Thus, DDC is regarded as a potential susceptibility
      gene for a variety of neuropsychiatric disorders. The aim of the present study
      was to examine the role of DDC in bipolar affective disorder (BPAD). By screening
      10 individuals for sequence variations in the coding region of the DDC gene as
      well as in the neuron-specific promoter and 5' untranslated regions we were able
      to identify two fairly frequent variants: a 1-bp deletion in the promoter and a 4
      bp deletion in the untranslated exon 1. Both deletions affect putative binding
      sites for known transcription factors, suggesting a possible functional impact at
      the level of expression. The two variants were applied in an association study
      including 80 Danish bipolar patients, 112 English bipolar patients, 223 Danish
      controls, and 349 English controls. Analyzing the combined material, a
      significant association was found between the 1-bp deletion and BPAD with P
      values of 0.037 (allelic) and 0.021 (genotypic). The frequency of the 1-bp
      deletion was 13.3% in patients and 9.4% in controls with a corresponding odds
      ratio of 1. 48 (95% CI: 1.02-2.15). The results presented suggest that DDC may
      act as a minor susceptibility gene for bipolar affective disorder.

PMID- 10578237
TI  - Identification of a novel polymorphism of the human dopamine transporter (DAT1)
      gene and the significant association with alcoholism.
AB  - Human dopamine transporter gene (DAT1) has a variable number of tandem repeats
      (VNTR) in its 3'-untranslated region (UTR). The association between the VNTR
      polymorphism and neuropsychiatric disorders has been studied, but their
      relationship is still unclear. Here we identified a novel polymorphism in the 3'
      UTR of the DAT1 gene, G2319A, and a significant association between the
      polymorphism and alcoholism was observed in both genotypic and allelic
      frequencies (P = 0.040 and 0.019, extended Fisher's exact test, respectively).
      There was a significant gene dose effect on the risk for alcoholism associated
      with the 2319-A allele (chi2 = 6.16, df = 2, P = 0.046, linearity tendency test:
      Cochranq-Armitage analysis). Moreover, in the haplotype analysis with G2319A- and
      VNTR-polymorphisms, a positive gene dose efffect on the risk with the A10 allele
      (P = 0.044, linearity tendency test) and a negative gene dose effect with the G10
      allele (P = 0.010, linearity tendency test) for alcoholism were significantly
      detected. Odds ratio for alcoholism with the A10 and G10 alleles were 1.76 (1.12
      2.76) and 0.53 (0.32-0.79), respectively. These results indicate that the DAT1
      gene may confer vulnerability to alcoholism.

PMID- 10578238
TI  - Family-based association studies of bipolar disorder with candidate genes
      involved in dopamine neurotransmission: DBH, DAT1, COMT, DRD2, DRD3 and DRD5.
AB  - The dopaminergic system has been implicated in the aetiology of mood disorders.
      We conducted family-based association studies for polymorphisms at three genes
      involved in the metabolism of dopamine: dopamine transporter (DAT1), dopamine
      beta-hydroxylase (DBH) and catechol-O-methyl transferase (COMT); and three
      dopamine receptors: DRD2, DRD3 and DRD5. We used a sample of 122 parent-offspring
      trios of British Caucasian origin where the proband had bipolar disorder I (BPI),
      and analysed the results with the transmission/disequilibrium test (TDT) which is
      robust to hidden population stratification. No statistically significant
      differences were found between transmitted and not transmitted alleles for any of
      the polymorphisms studied.

PMID- 10578239
TI  - Detection of Borna disease virus RNA from peripheral blood cells in schizophrenic
      patients and mental health workers.
AB  - Accumulating evidence suggests that Borna disease virus (BDV), a neurotropic,
      negative-stranded RNA virus, might be associated with certain human mental
      disorders. Several research groups reported that psychiatric patients had a
      significantly higher prevalence of BDV serum antibodies than normal controls. In
      addition, a significantly higher presence of BDV RNA from peripheral blood cells
      was identified in mental patients than in controls. In our previous study, we
      first identified the presence of BDV serum antibodies in a cohort of Chinese
      schizophrenic patients from Taiwan, and we also demonstrated a significantly
      higher seroprevalence of BDV antibodies among schizophrenic patients than in non
      psychiatric controls. Prompted by the positive seroepidemiological result, we set
      out to investigate the detection of BDV RNA from the peripheral blood cells of
      our schizophrenic patients. By using the reverse transcription-polymerase chain
      reaction (RT-PCR) method, 10 out of 74 Chinese schizophrenic patients from Taiwan
      were found to have BDV RNA in their blood cells, whereas only one out of 69
      controls was positive. The BDV RNA detection rate among schizophrenic patients
      was significantly higher than that in controls (14% vs 1.4%, P < 0.01).
      Furthermore, we studied the BDV RNA detection rate among mental health workers,
      and seven out of 45 mental health workers were found to have positive results.
      The prevalence rate was significantly higher than that in normal controls (15% vs
      1.4%, P < 0.001), which lends further support to our previous finding that mental
      health workers have a significantly higher presence of BDV serum antibodies. In
      summary, our data support the finding that BDV infection might be a contributory
      factor to the pathogenesis of schizophrenia in the Chinese population.

PMID- 10578241
TI  - The DRD2 TaqI polymorphism and symptoms of attention deficit hyperactivity
      disorder.
AB  - The relationship of the DRD2 TaqI-A1 allele to hyperactive/impulsive and
      inattentive symptoms of attention deficit hyperactivity disorder (ADHD) in
      children and adolescents was examined in a sample of clinic-referred children and
      their siblings, and control children and their siblings (n = 236). The
      contribution of genetic dominance and additivity to mean differences among the
      A2A2, A1A2, and A1A1 genotypes was estimated using structural equation modeling.
      The effect of genetic additivity was statistically significant for both traits in
      an analysis of all children. The heritability from the DRD2 locus was estimated
      at 4.27% for hyperactive-impulsive symptoms and 2.12% for inattentive symptoms.
      Children with the A2A2 genotype had the highest mean level of symptoms. To
      control for any possible effects of population stratification, this analysis was
      repeated with parental genotypes as controls. In this smaller sample, although
      the direction of the effect was the same as that in the whole sample, the
      genotypic differences failed to reach conventional significance levels and the
      effect sizes were smaller (h2 = 1.62% and 0.79%, respectively). Furthermore, a
      genotype relative risk test of children who had questionnaire-based diagnoses of
      ADHD also failed to yield evidence of either association or linkage. Given that
      the A1 allele was expected to be the high risk allele, and that results were non
      significant in tests that controlled for population heterogeneity, we doubt that
      this DRD2 polymorphism influences symptoms of ADHD in childhood.

PMID- 10578240
TI  - (+) 3,4-methylenedioxymethamphetamine ('ecstasy') transiently increases striatal
      5-HT1B binding sites without altering 5-HT1B mRNA in rat brain.
AB  - (+) 3,4-Methylenedioxymethamphetamine (MDMA) is a psychedelic drug of abuse that
      causes selective degeneration of serotonergic fibers of dorsal raphe neurons that
      project throughout the forebrain. Previous studies using pharmacological and
      behavioral approaches suggested that MDMA treatment leads to desensitization of 5
      HT1B receptors. We proposed to test whether this occurs by downregulation of 5
      HT1B messenger RNA in dorsal raphe, striatum or CA1 hippocampal neurons and/or 5
      HT1B binding site density in hippocampus and basal ganglia. In Experiment I, rats
      were treated with MDMA using several dosing protocols (2.5 or 10 mg kg-1 day-1
      s.c. given a single time or twice daily for 4 days). The animals were killed 24 h
      after the last dose. [3H]-citalopram binding to serotonin transporters in
      hippocampus was reduced in the high dose protocol, indicating degeneration of
      forebrain serotonergic fibers. Despite the extensive reduction in serotonergic
      content, 5-HT1B mRNA did not change from control levels in any region when
      measured by in situ hybridization. [125I]-Iodocyanopindolol binding to 5-HT1B
      sites in hippocampus was also not changed. In Experiment II, high dose MDMA had
      no effect on 5-HT1B mRNA in any brain region either 1 or 14 days after treatment.
      However, [125I]-iodocyanopindolol binding more than doubled in striatum 1 day
      after MDMA treatment but returned to control levels by 14 days. This may have
      been a transient compensation to early neuronal damage caused by MDMA exposure.
      These results suggest that previously described changes in 5-HT1B function
      following MDMA treatment involve only posttranscriptional changes in receptor
      regulation and do not alter 5-HT1B mRNA levels.

PMID- 10578242
TI  - Evidence for the segregation of a major gene for human plasma GABA levels.
AB  - Gamma-aminobutryic acid (GABA) is a major neurotransmitter in the central nervous
      system, and plasma levels of GABA may reflect brain GABA activity. In 35-40% of
      patients with mood disorders, plasma GABA levels are low compared to
      psychiatrically normal controls. Low plasma GABA in this subgroup of patients has
      characteristics of a biological trait marker for mood disorders. Low plasma GABA
      is also found in a subset of patients with alcohol dependence, but not in
      schizophrenia, anxiety, or eating disorders, suggesting some diagnostic
      specificity. Previous data from a small study of monozygotic twins are consistent
      with the hypothesis that plasma GABA levels are under genetic control. To better
      understand these mechanisms, we conducted a segregation analysis of plasma GABA
      levels in a sample of 157 individuals from 50 nuclear families. Analysis using
      the Class D regressive model indicated that the familial transmission of plasma
      GABA levels is compatible with the segregation of a recessive major gene. Our
      results suggest that plasma GABA levels are under single gene control. Future
      research should address the precise mechanisms which may account for the
      abnormality in GABA levels seen in a subset of patients with mood disorders.

PMID- 10578243
TI  - The myth of chronic whiplash syndrome.

PMID- 10578244
TI  - Recurrent functional and anatomical subvesical obstruction as urological
      complication in a tetraplegic patient.

PMID- 10578245
TI  - Ependymomas of the spinal cord and cauda equina: An analysis of 26 cases and a
      review of the literature.
AB  - STUDY DESIGN: Retrospective review. OBJECTIVES: To clarify the clinical features
      of patients with spinal ependymomas and to compare the clinical results between
      the patients in whom microsurgical technique and spinal cord monitoring were used
      intraoperatively and the patients in whom they were not used. SETTING: Keio
      University Hospital, Tokyo, Japan. METHODS: Twenty-six consecutive patients with
      spinal ependymomas were treated surgically between 1958 and 1995. All patients
      underwent tumor resection through a posterior approach. Complete tumor resection
      was possible in 15 patients (57. 7%), and subtotal tumor resection (more than
      90%) was done in two patients (7.7%). Only a partial tumor resection (less than
      90%) was performed in the remainder of the patients (34.6%). The operative
      results of the patients were evaluated by the Japanese Orthopaedic Association
      Scoring System (JOA score) and its recovery rate. RESULTS: The overall average
      recovery rate was 18.3%. The mean recovery rate was 14.4% in cervical lesion,
      11.1% in thoracic lesion and 40% in lumbar lesion. The recovery rate of eight
      patients with cervical ependymomas who underwent tumor resection under both
      microscopic surgical procedure and intraoperative spinal cord monitoring was
      37.1% although the recovery rate of the rest of the patients was -1.6%. There was
      a statistical difference between the two groups (P<0.02). The survival rate of
      patients following complete excision was statistically better compared to that of
      patients after incomplete resection. CONCLUSION: Both microsurgical technique and
      spinal cord monitoring are indispensable to achieve total removal of ependymomas
      and to obtain improvement of neurological recovery.

PMID- 10578246
TI  - Immunohistochemical study of parathyroid hormone-related protein in vesical
      transitional epithelium of patients with spinal cord injury.
AB  - INTRODUCTION: Parathyroid hormone-related protein (PTHrP), in addition to the
      well-established role in endochrondral bone development, is believed to be an
      important mediator of cellular growth and differentiation in a number of non-bony
      tissues. OBJECTIVES: To compare the immunohistochemical staining of vesical
      transitional epithelium to antibodies raised to synthetic peptides of PTHrP
      composed of amino acid sequences 43 - 52 and 127 - 138 in patients with spinal
      cord injury (SCI) and neuropathic bladder (n=14), and control patients with
      intact neuraxis and no history of bladder cancer (n=10). SETTING: Male SCI
      patients registered with Regional Spinal Injuries Centre, Southport, England.
      INTERVENTION: Endoscopic cold cup biopsy from the trigone of the urinary bladder
      was taken from patients with SCI while they were undergoing a therapeutic
      procedure in the urinary bladder. The control samples of bladder biopsies were
      taken from the archives of the Department of Histopathology, District General
      Hospital, Southport. Immunohistochemistry was performed using rabbit antibodies
      raised against synthetic peptides of human PTHrP (43 - 52) and PTHrP (127 - 138).
      The biopsies were examined for immunostaining of transitional epithelium.
      RESULTS: Of the 14 biopsies of SCI patients, positive immunostaining using
      antibodies to both the PTHrP peptides was found in four cases; five biopsies
      showed positive immunostaining only to anti-PTHrP (43 - 52); and five biopsies
      showed no immunostaining with either of the PTHrP peptides. In contrast,
      transitional epithelium in the biopsy specimens of ten control subjects with no
      history of bladder cancer showed no immunostaining with either of the PTHrP
      peptides. CONCLUSION: This study revealed that the transitional epithelium of
      neuropathic urinary bladder exhibits increased predilection for positive
      immunohistochemical staining for PTHrP (43 - 52), and to a lesser extent, to
      PTHrP (127 - 138), as compared to the vesical transitional epithelium of able
      bodied individuals with no history of vesical malignancy. The possible role of
      PTHrP in the cellular differentiation of urothelium of neuropathic bladder, and
      thereby, in the pathogenesis of cystitis in SCI patients, needs to be explored.

PMID- 10578247
TI  - The effect of residual neurological deficit on oral glucose tolerance in persons
      with chronic spinal cord injury.
AB  - STUDY DESIGN: Oral glucose tolerance testing was performed prospectively in 201
      subjects with spinal cord injury (SCI). The dependent variables included the
      values from the oral glucose tolerance test (glucose and insulin) and diagnostic
      classification (i.e., diabetes mellitus, impaired glucose tolerance, normal
      glucose tolerance); the independent variables consisted of study group, gender,
      ethnic group, age, age at onset of SCI, duration of injury, and anthropometric
      measurements. OBJECTIVE: To determine the potential effects of level and
      completeness of SCI on oral glucose tolerance testing. In addition, the effects
      of gender ethnicity, age, age at onset of SCI, duration of injury, and
      anthropometric measurements on glucose tolerance were investigated. SETTING:
      Subjects with chronic SCI were recruited during their annual physical examination
      at the Comarr Spinal Injury Clinic at Rancho Los Amigos Medical Center, Downey,
      California. METHODS: An oral 75 g glucose load was administered after an
      overnight fast. Serum glucose was determined by autoanalyzer and plasma insulin
      levels, by radioimmunoassay. The results are reported as mean plus or minus
      standard error of the mean (mean+/-SEM). Analysis of variance (ANOVA) applying a
      Scheffe' post hoc F ratio was used for the continuous variables. Chi-squared
      analyses were performed to determine differences between the groups and among the
      subgroups for per cent distribution. Linear regression analyses were performed
      between variables of interest. Stepwise regression analyses were used to predict
      peak serum glucose concentration and peak plasma insulin level from potential
      determinants. RESULTS: The total group consisted of 169 men with a mean age of
      38+/-0.80 (range=20 - 73) years and 32 women with a mean age of 44+/-2.13 (range
      =20 - 72) years. The distribution by ethnicity for the total group with SCI
      consisted of 114 (57%) Latino, 54 (27%) white, and 28) 14%) African American
      individuals. There was no significant difference in ethnic distribution among the
      subgroups for neurological deficit. Subjects were grouped by tetraplegia (Tetra;
      n=81) or paraplegia (Para; n=120) and by subgroup for degree of neurological
      deficit: complete Tetra (n=56), incomplete Tetra (n=25), complete Para (n=84),
      and incomplete Para (n=36). Of the total group, 27 subjects (13.4%) had diabetes
      mellitus and 56 (28.8%) had impaired glucose tolerance. Significantly more
      subjects in the complete Tetra group were classified with a disorder of
      carbohydrate metabolism than in the other neurological deficit subgroups (73 vs
      44%, 24% and 31%, respectively for level of decreasing neurological deficit;
      X2=36.9, P<0.0001). The complete Tetra group had significantly higher serum
      glucose concentrations at 60 min, 90 min, and 120 min and serum insulin
      concentration at 90 and 120 min compared with the other neurological subgroups
      (P<0.05 for each time point). No differences for plasma glucose were evident
      between men and women, however, plasma insulin levels were significantly higher
      for men at the intermediate time points (30 min, 60 min and 90 min), suggesting a
      relative state of insulin resistance in men. By stepwise regression analyses,
      higher peak serum glucose concentrations were associated with increased total
      body %fat, highest level of lesion (complete Tetra vs other neurological
      subgroups), older age at time of injury, and male gender; higher peak plasma
      insulin was associated with increased total body %fat and male gender.
      CONCLUSIONS: This study is the first to report that those individuals with the
      greatest levels of neurological deficit have increased risk of developing
      disorders of carbohydrate metabolism. Males with SCI are more insulin resistant
      than females. Glucose tolerance appears to be independent of the effects of
      ethnicity.

PMID- 10578248
TI  - Thermoregulatory responses of spinal cord injured and able-bodied athletes to
      prolonged upper body exercise and recovery.
AB  - STUDY DESIGN: Single trial, two factor repeated measures design. SETTING:
      England, Cheshire. OBJECTIVES: To examine the thermoregulatory responses of able
      bodied (AB) athletes, paraplegic (PA) athletes and a tetraplegic (TP) athlete at
      rest, during prolonged upper body exercise and recovery. METHODS: Exercise was
      performed on a Monark cycle ergometer (Ergomedic 814E) adapted for arm exercise
      at 60% VO2 peak for 60 min in cool conditions ('normal' laboratory temperature;
      21.5+/-1.7 degrees C and 47+/-7.8% relative humidity). Aural and skin
      temperatures were continually monitored. RESULTS: Mean (+/-S.D.) peak oxygen
      uptake values were greater (P<0. 05) for the AB when compared to the PA (3.45+/
      0.45 l min-1 and 2. 00+/-0.46 l min-1, respectively). Peak oxygen uptake for the
      TP was 0.91 l min-1. At rest, aural temperature was similar between groups
      (36.2+/-0.3 degrees C, 36.3+/-0.3 degrees C and 36.3 degrees C for AB, PA and TP
      athletes, respectively). During exercise, aural temperature demonstrated
      relatively steady state values increasing by 0.6+/-0.4 degrees C and 0.6+/-0.3
      degrees C for the AB and PA athletes, respectively. The TP athlete demonstrated a
      gradual rise in aural temperature throughout the exercise period of 0.9 degrees
      C. Thigh skin temperature increased by 1.3+/-2.5 degrees C for the AB athletes
      (P<0.05) whereas the PA athletes demonstrated little change in temperature (0.1+/
      3.4 degrees C and -0.7 degrees C respectively). Calf temperature increased for
      the PA athletes by 1.0+/-3.6 degrees C (P<0.05), whereas a decrease was observed
      for the AB athletes of -1.0+/-2.0 degrees C (P<0.05) during the exercise period.
      During 30 min of passive recovery, the AB athletes demonstrated greater decreases
      in aural temperatures than those for the PA athletes (P<0. 05). Aural temperature
      for the TP increased peaking at 5 min of recovery remaining elevated until the
      end of the recovery period. Fluid consumption and weight losses were similar for
      the AB and PA athletes (598+/-433 ml and 403+/-368 ml; 0.38+/-0.39 kg and 0.38+/
      0. 31 kg, respectively), whereas changes in plasma volume were greater for the AB
      athletes (-9.8+/-5.8% and 4.36+/-4.9%, respectively; P<0. 05). CONCLUSION: The
      results of this study suggest that under the experimental conditions PA athletes
      are at no greater thermal risk than AB athletes. A relationship between the
      available muscle mass for heat production and sweating capacity appears evident
      for the maintenance of thermal balance. During recovery from exercise, decreases
      in aural temperature, skin temperature and heat storage were greatest for the AB
      athletes with the greatest capacity for heat loss and lowest for the TP athlete
      with the smallest capacity for heat loss. Initial observations on one TP athlete
      suggest substantial thermoregulatory differences when compared to AB and PA
      athletes.

PMID- 10578249
TI  - Weight bearing through flexed upper limbs in quadriplegics with paralyzed triceps
      brachii muscles.
AB  - STUDY DESIGN: A biomechanical analysis of lifting through flexed and extended
      elbows in C5 and C6 quadriplegics. OBJECTIVE: To determine the mechanisms used by
      C5 and C6 quadriplegics to prevent elbow collapse when bearing weight through
      flexed upper limbs. SETTING: A biomechanics laboratory. METHODS: Six motor
      complete C5 and C6 quadriplegic subjects with paralysis of their triceps brachii
      muscles were recruited. A three dimensional kinematic and kinetic analysis of the
      upper limbs was performed whilst subjects attempted to lift their body weight
      through their upper limbs under four different conditions. In one condition
      subjects lifted with their hands placed at the same height as the seat upon which
      they were sitting, whilst in the other three conditions subjects lifted with
      their hands placed on blocks of various heights. The four different conditions
      required subjects to bear weight through their upper limbs with their elbows
      initially flexed between 15 and 40 degrees. MAIN OUTCOME MEASURES: Angular
      displacements and corresponding moments about the shoulder, elbow and wrist
      joints. In addition, EMG data were collected from the upper pectoralis, anterior
      deltoid and biceps brachii muscles during all lifts and expressed as a percentage
      of maximal isometric voluntary contractions. RESULTS: As block height and initial
      elbow flexion increased, subjects lifted progressively less weight. However, even
      under the high block conditions when subjects' elbows were initially flexed up to
      40 degrees, subjects lifted a mean+/-SD of 43%+/-20.4 of their seated body weight
      with one subject lifting 76% of his seated body weight. Subjects lifted by
      generating shoulder and wrist flexor moments. CONCLUSION: Quadriplegics with
      paralyzed triceps brachii muscles can bear moderate and sometimes substantial
      weight through flexed elbows. This is largely achieved by the generation of
      shoulder flexor moments.

PMID- 10578250
TI  - The impact of spinal cord injury on men's time use.
AB  - BACKGROUND: Despite evidence of the relationship between time use and health and
      well-being, and the World Health Organization's recognition of activity
      limitation as a measure of dis-ability, there has been limited investigation into
      the activity patterns of persons with disabilities. METHODS: Interviews and time
      diaries to provide preliminary descriptive and analytical information about the
      daily time use patterns of men with a spinal cord injury (SCI) living in the
      community (n=312) compared with the time use data of able-bodied men (n=3617)
      collected as part of the 1992 Canadian General Social Survey. The study also
      examined relationships between time use by men with SCI and selected factors
      (severity of disability and socioeconomic status). FINDINGS: Statistically
      different time use patterns between the SCI and able-bodied subjects. The men
      with spinal cord injury spent on average 7.2 h in leisure activities (able-bodied
      men=6.0 h); 4.7 (7.7) h in productivity; 3.7 (2.3) h in personal care; and 8.5
      (8.0) h sleeping. The SCI men's lesser productivity time was accounted for
      largely by the lack of time spent in paid work. The average time use of the SCI
      sample showed the most time spent in passive leisure pursuits such as watching TV
      and listening to the radio. The sample rated their satisfaction with their time
      use as mediocre, but levels of adjustment to disability were moderate to high.
      Regression analysis revealed that severity of disability (lesion level,
      functional independence, environment) did not predict the amount of time spent in
      personal care, productivity, leisure, or sleep. Socioeconomic status had a mild
      predictive relationship with time allocation. IMPLICATIONS: The findings suggest
      men with SCI are socially isolated relative to their able-bodied peers.
      Recommendations are made and include both methodological considerations for
      further time use studies with persons with SCI, and policy recommendations. The
      latter focus on the need for rehabilitation, education and resources that go
      beyond functional independence such that persons with SCI can expand both their
      leisure and productivity roles and become better socially and economically
      integrated into society.

PMID- 10578251
TI  - Complete cervical or thoracic spinal cord transections delay gastric emptying and
      gastrointestinal transit of liquid in awake rats.
AB  - STUDY DESIGN: To determine the changes on gastric emptying and gastrointestinal
      transit of liquid throughout the first week after spinal cord transection (SCT)
      in rats. METHODS: Male Wistar rats (n=121) were fasted for 16 h and a complete
      SCT or laminectomy was performed between C7 and T1 (cervical group) or between T4
      and T5 (thoracic group). Dye recovery in the stomach, proximal, mid and distal
      small intestine was determined 30 min, 6 h, 1, 3 or 7 days after surgery. The
      test meal (1.5 ml of a phenol red solution, 0.5 mg/ml in 5% glucose) was
      intragastrically administered and the animals sacrificed by cervical dislocation
      10 min later. RESULTS: Cervical SCT increased dye recovery in the stomach
      (P<0.05) by 70.1, 78.7, 34.2, 41.3 and 50.9% while it decreased recovery in the
      mid small intestine (P<0.05) by 87.1, 85.1, 74.8, 59.5 and 80.1%, respectively 30
      min, 6 h, 1, 3 and 7 days after SCT. Thoracic SCT increased gastric recovery
      (P<0.05) by 43.5, 67.6, 51.2, 75.4 and 38. 9% while it decreased recovery in the
      mid small intestine (P<0.05) by 100, 100, 45.6, 100 and 66.6%, respectively 30
      min, 6 h, 1, 3 and 7 days after SCT. A separate group was submitted to
      laminectomy+bilateral sciatic nerve transection (paraplegic sham). Gastric
      emptying and gastrointestinal transit were not inhibited in this group.
      CONCLUSION: In summary, gastric emptying and gastrointestinal transit of liquid
      are inhibited throughout the first week after high SCT in awake rats.

PMID- 10578252
TI  - Walking with a hybrid orthosis system.
AB  - OBJECTIVE: The purpose of this case study was to determine the functional
      effectiveness of the hybrid orthosis system (HOS) for sit-to-stand and walking
      compared with the reciprocal gait orthosis (RGO) alone in a subject with
      significant orthopedic abnormalities. DESIGN: A subject with complete T7
      paraplegia and a 13 cm leg length discrepancy was implanted with 14 intramuscular
      electrodes and fitted with a custom isocentric RGO. The subject was instructed in
      the use of the HOS and a two wheeled walker in the home and community settings.
      MAIN OUTCOME MEASURES: Using the Functional Independence Measure (FIM), and the
      Borg exertion scale the subject's level of independence and his perceived
      exertion was determined as well as the safety and efficacy of system use in the
      community. RESULTS: Results show that the HOS provided safe, independent
      ambulation with a two wheeled walker and met established criteria for limited
      community use. Walking in the RGO alone was feasible, however, the addition of
      functional electrical stimulation (FES) allowed this subject to walk farther and
      with less perceived exertion. CONCLUSION: This case study suggests that a hybrid
      orthosis system can be an effective clinical option for individuals with
      significant orthopedic complications that might otherwise contra-indicate the
      prescription of either conventional braces or FES alone.

PMID- 10578254
TI  - Culture of human parathyroid cells for transplantation.

PMID- 10578253
TI  - Controlled Fas ligand gene expression by Cre/loxP-mediated switching system: high
      levels of FasL expression result in lethal hepatitis.

PMID- 10578255
TI  - Cytokine analysis of cerebrohepatic organ interaction in porcine liver
      transplantation from brain-dead donors.

PMID- 10578256
TI  - Immunological characteristics of intragraft NKR-P1+ TCR alpha beta + T (NKT)
      cells in rat hepatic allografts.

PMID- 10578258
TI  - FasL expression on pig cells suppresses human natural killer cell mediated
      cytotoxicity.

PMID- 10578257
TI  - Changes in natural killer cell activity before and after living-related donor
      liver transplantation.

PMID- 10578259
TI  - Characterization of B cells producing xenoreactive natural antibodies in humans.

PMID- 10578260
TI  - The expression of nonmuscle myosin heavy chain in rat renal transplantation.

PMID- 10578261
TI  - Hepatocyte growth factor in renal transplantation.

PMID- 10578262
TI  - Pathophysiology of chronic renal allograft rejection.

PMID- 10578263
TI  - The relative influence of antigen-dependent and independent factors for
      development and progression of chronic rejection.

PMID- 10578264
TI  - Inhibitory effect of triptolide on platelet derived growth factor-A and coronary
      arteriosclerosis after heart transplantation.

PMID- 10578265
TI  - Upregulated transforming growth factor-beta 1 mRNA expression in endomyocardial
      biopsies during the development of graft vascular disease after clinical heart
      transplantation.

PMID- 10578266
TI  - The macrophage-derived T-cell growth factor interleukin-15 is present in
      interleukin-2-independent rejection after clinical heart and liver
      transplantation.

PMID- 10578267
TI  - Does peripheral blood eosinophilia predict allograft rejection in living-related
      liver transplantation?

PMID- 10578268
TI  - Role of endothelial apoptosis in delayed xenograft rejection in pig-to-baboon
      cardiac transplantation.

PMID- 10578269
TI  - Induction of transplantation tolerance in humans using stem cell transplants
      prenatally or postnatally.

PMID- 10578270
TI  - Dendritic cells and the outcome of organ transplantation: a contemporary view.

PMID- 10578271
TI  - FK 506 versus cyclosporine in combination with anti-CD4/CD8 monoclonal
      antibodies.

PMID- 10578272
TI  - Proliferation of donor-derived NKR-P1+TCR alpha beta + (NKT) cells in the
      nonrecurrent spontaneous diabetic BB rats transplanted with pancreaticoduodenal
      grafts of Wistar-Furth donors.

PMID- 10578273
TI  - Islet transplantation with mesenteric lymph node cells could induce tolerance in
      a "low-responder" rat combination with class I MHC disparity.

PMID- 10578274
TI  - Reduced expression of NF-AT and NF-kappa B transcription factors in tolerant
      recipients treated with tolerogenic allochimeric donor/recipient class I MHC
      protein.

PMID- 10578275
TI  - A successful induction of tolerance by perioperative intrathymic injection in rat
      "high-responder" heart transplantation.

PMID- 10578276
TI  - Chronopharmacology of tacrolimus in rats: toxicity and efficacy in a mouse-to-rat
      intestinal transplant model and its pharmacokinetic profile.

PMID- 10578277
TI  - Comparative efficacy of liposomal FK 506 with FK 506 (tacrolimus) with and
      without anti-CD4/CD8 monoclonal antibodies.

PMID- 10578278
TI  - Cyclosporine inhibits transport of bile acid in rats: comparison of bile acid
      composition between liver and bile.

PMID- 10578279
TI  - Different effects of cyclosporine and tacrolimus on the activation of mesangial
      metalloproteinases and their inhibitors.

PMID- 10578280
TI  - Pharmacokinetic characteristics of methylprednisolone in Korean renal transplant
      recipients.

PMID- 10578281
TI  - Elimination of the adverse effects of tacrolimus-based induction therapy by a 5
      day exposure of optimal steady-state blood concentration in renal transplant
      patients in the early postoperative period.

PMID- 10578282
TI  - Oral vs intravenous tacrolimus-based induction therapy in renal transplantation.

PMID- 10578283
TI  - Chronotoxicity of mizoribine under repeated administration in the rat.

PMID- 10578284
TI  - Effect of fluconazole on blood levels of tacrolimus.

PMID- 10578285
TI  - Isolated pancreatic graft of swine: development of a model for drug studies.

PMID- 10578286
TI  - Effect of Tranilast on chronic graft vascular disease and tracheal proliferation
      in a rat allograft model.

PMID- 10578287
TI  - Mycophenolate mofetil.
AB  - MMF has taken its place in our immunosuppressive armamentarium. It has proven
      efficacy in preventing AR in a variety of types of transplantation.

PMID- 10578288
TI  - FTY720: mechanisms of action and its effect on organ transplantation (review).

PMID- 10578289
TI  - A short-course therapy with FTY720 prolongs allograft survival after canine
      kidney transplantation.

PMID- 10578290
TI  - Combination effect of tacrolimus and FTY720 in liver transplantation in rats.

PMID- 10578291
TI  - Prolonged graft survival induced by CTLA4IG-gene transfection combined with
      FTY720 administration in rat heart grafting.

PMID- 10578292
TI  - Effects of tacrolimus on small and large bowel anastomoses in the rat.

PMID- 10578293
TI  - Study of graft-infiltrating cells in the rat small bowel allograft using low-dose
      FK 506.

PMID- 10578294
TI  - Potent immunosuppressive effects by a newly synthesized compound KF20444.

PMID- 10578295
TI  - The role of triple immunosuppressive treatment in the successful implantation of
      islet grafts.

PMID- 10578296
TI  - Effect of donor-specific transfusion in combination with FK 506 in rat cardiac
      allotransplantation.

PMID- 10578297
TI  - Experimental intestinal transplantation using mouse fetal intestine in the rat:
      combination effect of FK 506 with cyclophosphamide.

PMID- 10578298
TI  - Dose- and time-related acceleration of chronic graft vascular disease caused by
      cyclosporine in a rat cardiac isograft model.

PMID- 10578299
TI  - Selection criteria for mothers of future donor candidates for xenotransplantation
      (pigs to baboon).

PMID- 10578300
TI  - Selection criteria of donors and recipients in pig-to-baboon orthotopic liver
      xenotransplantation.

PMID- 10578301
TI  - Expression of PI-anchored mini-factor H on porcine endothelial cells: potential
      use in xenotransplantation.

PMID- 10578302
TI  - Study of xenograft rejection in a model of liver xenotransplantation from
      unmodified pig to primate.

PMID- 10578303
TI  - Extracorporeal circulation with an anticomplement synthetic polymer prolongs
      guinea pig-to-rat cardiac xenograft survival.

PMID- 10578304
TI  - Management and nutrition of newborn piglets from hysterectomy to donation.

PMID- 10578305
TI  - Enzyme-assisted synthesis of disaccharides to inhibit binding of human anti-alpha
      Gal antibody.

PMID- 10578306
TI  - Prolongation of concordant xenograft survival by a newly developed drug, FTY720.

PMID- 10578307
TI  - Normal coagulation parameters after ex vivo perfusion of pig livers and kidneys
      with human plasma, aimed at depletion of xenoantibodies.

PMID- 10578308
TI  - Comparison of outcome in renal transplant recipients with respect to arterial
      anastomosis: the internal versus the external iliac artery.

PMID- 10578309
TI  - Clinical impact of slow recovery of renal function in renal transplantation.

PMID- 10578310
TI  - Usage of high-risk donors in non-heart-beating cadaveric kidney transplantation:
      is an older donor available?

PMID- 10578311
TI  - Long-term outcome of kidney transplants from non-heart-beating donors:
      multivariate analysis of factors affecting graft survival.

PMID- 10578312
TI  - Efficacy of tacrolimus in ABO-incompatible kidney transplantation:
      clinicopathological aspect of humoral rejection.

PMID- 10578313
TI  - Tacrolimus rescue for resistant rejection, chronic rejection, and immunoglobulin
      A nephropathy of renal allografts under primary cyclosporine A immunosuppression.

PMID- 10578314
TI  - Long-term results of living unrelated renal transplantation.

PMID- 10578315
TI  - Risk factors affecting the long-term results of renal retransplantation.

PMID- 10578316
TI  - Long-term outcome in renal transplant recipients with focal and segmental
      glomerulosclerosis.

PMID- 10578318
TI  - A case report of kidney transplantation after abdominal surgery for
      neuroblastoma.

PMID- 10578317
TI  - Long-term results of kidney transplantation in preformed antibody-positive highly
      sensitized recipients.

PMID- 10578319
TI  - Kidney transplantation from a hepatitis B surface antigen-positive donor to a
      HBSAG-negative recipient.

PMID- 10578320
TI  - Impact of OKT3 treatment for steroid resistant rejection of renal allografts: the
      long-term outcome at a single center.

PMID- 10578321
TI  - Posttransplant antidonor antibodies and chronic rejection in renal
      transplantation.

PMID- 10578322
TI  - Influence of donor renal reserve on the long-term results of living kidney
      transplantation from elderly donors.

PMID- 10578323
TI  - Long-term results in mizoribine-treated renal transplant recipients: a
      prospective, randomized trial of mizoribine and azathioprine under cyclosporine
      based immunosuppression.

PMID- 10578324
TI  - Donor specific hyporesponsiveness in a clinically tolerant renal transplant
      recipient.

PMID- 10578325
TI  - Comparative study of helical CT scan angiography and conventional arteriography
      for evaluation of living renal transplant donors.

PMID- 10578326
TI  - Two cases of tacrolimus-induced alopecia following kidney transplantation.

PMID- 10578327
TI  - Effect of interferon-alpha treatment in hemodialysis patients and renal
      transplant recipients with chronic hepatitis C.

PMID- 10578329
TI  - Changes in graft volume after living-related liver transplantation.

PMID- 10578328
TI  - Initial experience with 40 cases of living-related donor liver transplantation at
      the University of Tokyo.

PMID- 10578330
TI  - Ursodeoxycholic acid in serum and liver tissue in patients with end-stage
      cholestatic liver cirrhosis.

PMID- 10578331
TI  - A preliminary report on heterotopic segmental living-related and/or split-liver
      cadaveric transplantation.

PMID- 10578332
TI  - Successful living-related heterotopic auxiliary liver transplantation for chronic
      Budd-Chiari syndrome.

PMID- 10578333
TI  - Recovery of renal function after living-related liver transplantation in a case
      of hepatitis B virus liver cirrhosis with renal failure.

PMID- 10578334
TI  - Is splenic artery ligation effective for thrombocytopenia early after liver
      transplantation?

PMID- 10578335
TI  - Retrospective analysis of 30 patients who underwent liver transplantation without
      use of steroids.

PMID- 10578336
TI  - Effects of subzero nonfreezing storage in UW solution on isolated hepatocytes and
      cultured sinusoidal endothelial cells of rat liver.

PMID- 10578337
TI  - Oral administration of geranylgeranylacetone protects rat livers from warm
      ischemic injury.

PMID- 10578338
TI  - Usefulness of high-risk renal graft conditioning; functional improvement of high
      risk grafts by drug addition to continuous hypothermic perfusion preservation
      solution.

PMID- 10578339
TI  - Diagnostic value of noninvasive near-infrared spectroscopy to assess liver
      viability of brain-dead donors.

PMID- 10578340
TI  - Delayed onset of apoptosis following ischemia/reperfusion in rat liver:
      downregulation of bax gene.

PMID- 10578341
TI  - Repetitive ischemia/reperfusion potentiates hepatocellular death by apoptosis.

PMID- 10578342
TI  - The evolution of transplantation societies in Latin America.

PMID- 10578343
TI  - The tenth report of the Latin American Transplant Registry.

PMID- 10578344
TI  - Some landmarks in the evolution of transplantation.

PMID- 10578345
TI  - Searching for history in transplantation: early modern attempts at surgical
      kidney grafting.

PMID- 10578346
TI  - Transplantation in the 21st century.

PMID- 10578347
TI  - Factors influencing kidney graft survival in Latin America. Collaborative
      Transplant Study.

PMID- 10578348
TI  - Transplant tolerance: facts and future.

PMID- 10578349
TI  - Organ commerce.

PMID- 10578350
TI  - Double transplant of marginal kidneys.

PMID- 10578351
TI  - Marginal donors.

PMID- 10578352
TI  - Nonimmunologic factors in the progression of chronic dysfunction in renal
      allografts.

PMID- 10578353
TI  - Enumeration of CD34+ hematopoietic precursor cells: current status.

PMID- 10578354
TI  - Flow cytometric analysis of lymphocyte subsets as a predictive factor for GVHD in
      allogeneic bone marrow transplantation.

PMID- 10578355
TI  - Allo- and autoantibodies in human cardiac allograft recipients.

PMID- 10578356
TI  - Chemokine profile during allogeneic heart transplant rejection.

PMID- 10578357
TI  - Clinical significance of skin crossmatch in kidney transplantation.

PMID- 10578358
TI  - Immunoglobulin A, G, and M levels in pre- and posttransplant sera of cardiac
      allograft recipients.

PMID- 10578359
TI  - Clinical significance of donor-specific alloantibodies in liver transplant
      recipients.

PMID- 10578360
TI  - Influence of pretransplant allosensitization in cardiac transplant outcome.

PMID- 10578361
TI  - Standardization of cellular immunoenzyme assay for anti-HLA class I antibodies
      evaluation: comparison with complement-dependent cytotoxicity methods.

PMID- 10578362
TI  - Relevance of positive B-cell crossmatch in renal transplantation with living
      donors.

PMID- 10578363
TI  - Posthemodialysis human sera inhibit proliferation and enhance granulosities and
      nitric oxide generation in U-937 cells.

PMID- 10578364
TI  - Immunomodulatory effects of vitamin D analog KH1060 on an experimental skin
      transplantation model.

PMID- 10578365
TI  - Value of pre-heart-transplant psychological evaluation: long-term follow-up.

PMID- 10578366
TI  - Pancreas-kidney transplantation in Brazil: current difficulties and perspectives.

PMID- 10578367
TI  - Mycophenolate mofetil with lower cyclosporine dose in high-risk renal transplant
      recipients.

PMID- 10578368
TI  - Duplex Doppler ultrasonography in the dysfunction of early renal allografts:
      correlation with renal histopathology.

PMID- 10578369
TI  - Audiometric changes in patients undergoing hemodialysis and renal
      transplantation.

PMID- 10578370
TI  - Long-term evaluation of two protocols of elective cyclosporine withdrawal in
      renal transplant recipients.

PMID- 10578371
TI  - The fate of renal allografts treated with OKT3 for steroid-resistant rejection.

PMID- 10578372
TI  - Interpretation of surveillance kidney allograft biopsies according to the Banff
      criteria.

PMID- 10578373
TI  - The influence of race on kidney graft survival.

PMID- 10578374
TI  - The mortality of liver failure after kidney transplantation.

PMID- 10578375
TI  - High efficiency kidney transplantation: concept, technique, results, and cost
      analysis.

PMID- 10578376
TI  - Assessment of the nutritional status in patients referred for kidney
      transplantation.

PMID- 10578377
TI  - Cytomegalovirus antigenemia and renal function post-kidney-transplantation.

PMID- 10578378
TI  - Limited nephrectomy in high-efficiency kidney transplantation.

PMID- 10578379
TI  - Transoperative renal intraarterial verapamil in kidney transplantation decreases
      acute tubular necrosis.

PMID- 10578380
TI  - Kidney graft failure due to noncompliance.

PMID- 10578381
TI  - Bone disease after renal transplantation.

PMID- 10578382
TI  - Statistical profile of the Nephrology Institute of Mogi Das Cruzes.

PMID- 10578383
TI  - Renal transplant waiting list exclusion causes: hepatitis C virus infection and
      liver disease prevalence.

PMID- 10578384
TI  - A new method for ureteral implantation: the procedure of choice for kidney
      recipients with very small, defunctionalized bladders.

PMID- 10578385
TI  - Liver transplantation today: situation in Chile.

PMID- 10578386
TI  - Diabetes mellitus and liver transplantation in adults.

PMID- 10578387
TI  - Prevalence of high blood pressure in patients submitted to liver transplantation
      at the ISCMPA.

PMID- 10578388
TI  - Neurological complications in liver transplantation.

PMID- 10578389
TI  - Risk factors for postoperative acute renal failure at a new orthotopic liver
      transplantation program.

PMID- 10578390
TI  - Evaluation of predictive weaning indices for mechanical ventilation in liver
      transplantation.

PMID- 10578391
TI  - Efficacy of a recombinant hepatitis B vaccine (Euvax-B) in adult patients
      awaiting liver transplantation: preliminary results.

PMID- 10578392
TI  - Evaluation of the results of surgical psychoprophylaxis in liver transplant
      recipients at low psychosocial risk.

PMID- 10578393
TI  - Improvement of transthyretin familial amyloidotic polyneuropathy after liver
      transplantation in Argentinian patients.

PMID- 10578394
TI  - Evolution of liver transplant patients at high psychosocial risk.

PMID- 10578395
TI  - Evaluation of prognostic factors for early infection in liver transplantation.

PMID- 10578396
TI  - Tuberculosis in liver transplant patients.

PMID- 10578397
TI  - Pulmonary evolution in conventional liver transplantation with venovenous bypass
      and the piggyback method.

PMID- 10578398
TI  - Early extubation in liver transplantation.

PMID- 10578399
TI  - Acute normovolemic intraoperative hemodilution in liver transplantation.

PMID- 10578400
TI  - Organ donation in Porto Alegre, southern Brazil: attitudes and practices of
      physicians working in intensive care units.

PMID- 10578401
TI  - Recipient death in a live-related transplantation: what should I do with the
      graft? An ethical and medical problem.

PMID- 10578402
TI  - Transplants with cadaveric organs in the State of Sao Paulo, Brazil: the new
      organizational model and first results.

PMID- 10578403
TI  - Evaluation of the arteriovenous fistulae for hemodialysis with duplex scan:
      preliminary report.

PMID- 10578404
TI  - Which is the best type of vascular anastomosis for hemodialysis? A preliminary
      report.

PMID- 10578405
TI  - Sleep disorders in hemodialysis patients.

PMID- 10578406
TI  - Renal replacement therapy in Latin America during 1991-1995. Latin American
      Registry Committee.

PMID- 10578407
TI  - The birth of the Transplantation Society of Latin America and the Caribbean

PMID- 10578408
TI  - [Fournier's gangrene].
AB  - Fournier's gangrene is a rapidly progressive, necrotizing fasciitis of the
      perineal, genital or perianal regions. Despite increasing knowledge about
      aetiology, diagnostic procedures and treatment, the gangrene is still a
      destructive and potentially lethal disease. In two patients, men aged 54 and 63
      years, Fournier's gangrene was diagnosed. The first one died of septic shock 12
      hours after admission. Surgical debridement had been performed immediately. He
      had a latent promyelocytic leukaemia. The second patient recovered fully after
      extensive surgical and antimicrobial therapy. Fournier's gangrene appears to be
      caused by the synergistic pathogenic action of various individually non
      pathogenic commensal bacteria. Virtually all patients have an underlying systemic
      disorder, mainly chronic alcoholism or diabetes mellitus. Immunosupression is a
      predisposing factor. The gangrene requires an aggressive approach, treatment
      being based on the combination of haemodynamic stabilisation, antibiotic triple
      therapy and radical surgical debridement.

PMID- 10578409
TI  - [Cytostatic treatment of ovarian carcinoma].
AB  - Shortly after treatment with the cytostatic combination of cisplatin and
      paclitaxel was generally accepted as the standard therapy for patients with
      epithelial ovarian carcinoma, many have come to regard the combination of
      carboplatin and paclitaxel as a better choice. The latter combination causes
      fewer side effects and may be used in the outpatient clinic. Conceivably, the
      carboplatin-paclitaxel scheme will shortly have to be adjusted again owing to
      results of current research. The intensive basic research of recent years,
      namely, is beginning to yield benefits for the therapeutic arsenal against
      ovarian carcinoma. Possibilities are inhibitors of the breakdown of extracellular
      matrix (such as marimastat) and inhibitors of signal transduction (such as
      trastuzumab).

PMID- 10578410
TI  - [Hypertensive crisis: definition, pathophysiology and treatment].
AB  - Hypertensive crises are currently subdivided into hypertensive emergencies and
      urgencies depending on the acuteness with which the elevated blood pressure has
      to be lowered. Malignant hypertension, defined as severe hypertension and a
      hypertensive fundus grade III or IV, can present itself as an emergency or an
      urgency. For a hypertensive emergency intravenously acting blood pressure
      lowering agents are almost always required, whereas an urgency can usually be
      treated with oral agents. In view of the danger of cerebral hypoperfusion, blood
      pressure reduction during the initial treatment phase of a hypertensive crisis
      should not be more than 20 to 25%. Agents that exert a controllable blood
      pressure lowering action are preferred. Controllable blood pressure lowering
      cannot be achieved with nifedipine capsules. The practice of biting and
      swallowing a nifedipine capsule for the treatment of a hypertensive crisis
      therefore is to be discouraged.

PMID- 10578411
TI  - [Clinical thinking and decision making in practice. An elderly patient with
      vertigo and high sedimentation rate].
AB  - A 77-year-old woman was admitted because of progressive vertigo, nausea and a
      dysarthric speech disorder. The patient's history of diabetes mellitus,
      hypertension and hypercholesterolaemia, and the finding of murmurs over
      peripheral arteries at physical examination led to a presumptive diagnosis of
      cerebellar ischaemia in the context of generalized atherosclerosis. However, the
      diagnosis was revised when bilateral cerebellar infarction was demonstrated
      radiologically, and a biopsy of a temporal artery revealed giant cell arteritis.
      Despite treatment with prednisone (60 mg daily) the patient's neurological
      condition deteriorated, and she succumbed several months later to pneumonia. The
      case illustrates the pitfalls in the diagnostic approach of elderly patients with
      multiple pathology and it also emphasizes that in an elderly person with high
      erythrocyte sedimentation rate (> 100 mm in the first hour) temporal arteritis
      should be ruled out as soon as possible to prevent further neurological damage.

PMID- 10578412
TI  - [Survival and impact of bronchiolitis obliterans syndrome after lung
      transplantation at the Academic Hospital Groningen, 1990/'98].
AB  - OBJECTIVE: To describe the results of the lung transplantation programme in
      Groningen in relation to the bronchiolitis obliterans syndrome (BOS), in the
      first 118 consecutive patients. DESIGN: Retrospective. METHOD: Data were
      collected on the 118 patients subjected to lung transplantation in November 1990
      to June 1998 in the University Hospital Groningen, the Netherlands, regarding the
      prevalence of chronic transplant dysfunction (BOS) and survival. RESULTS: 117
      lung transplantations (95 bilateral lung transplantations including 2
      retransplants, and 22 single lung transplantations) and 1 heart-lung
      transplantation had been performed. The patients were 70 males and 48 females
      with a mean age of 42 years (range: 9-64). The mean (SD) survival at 1, 2, 3 and
      5 years post transplantation was 83% (3), 70% (4), 66% (5) and 61% (5)
      respectively. The median survival amounted to 2447 days. The mean (SD) prevalence
      of BOS at respectively 1, 2, 3 and 5 years post transplantation was 32% (5), 36%
      (5), 44% (5) en 54% (6). After a diagnosis of BOS stage I the median survival was
      649 days. CONCLUSION: The survival of the lung transplant programme of the
      University Hospital Groningen is considered to compare favourably with other
      centres. The prevalence of BOS is considerable, and comparable with the
      prevalence of BOS reported by other programmes. BOS is associated with a
      decreased life expectancy.

PMID- 10578413
TI  - [Incidence and risk factors for eye injuries sustained at fairs: metal particles
      in the eye after a ride of dodg'em cars].
AB  - OBJECTIVE: To determine the incidence of fair eye and its determinants. DESIGN:
      Inventory and case referent study. METHOD: All general practices (370) in the
      middle and south of Limburg, the Netherlands, were asked to report patients with
      a 'faireye' after having visited a fair in this region (population approximately
      866,000) in a 6-week period during the late summer of 1997. Personal data of
      these patients were obtained by telephone interview. A case referent study was
      performed to establish the potential protectiveness of wearing glasses, lenses or
      a cap. RESULTS: 88% of the general practices responded. These reported a total of
      40 patients with a fair eye. There were 41 fairs with dodgem cars during the
      observation period (a relation between dodgem cars and faireyes has been
      suggested). In the study area the incidence of fair eye was 5 per 100,000
      inhabitants per year. Of the 36 responding patients 26 (72%) were male, 97% were
      10-19 years old, and 69% had had 11-20 rides in dodgem cars. Glasses (3%), lenses
      (0%), or a cap (6%) were rarely worn during the rides. The complaints related to
      the fair eye were: pain in the eye (64%), an irritated eye (42%), a red eye
      (41%), an inflamed eye (17%), tears (11%) and photophobia (8%). The odds ratio
      for wearing glasses or lenses in comparison with a sample of the general Dutch
      population, standardised for age and sex, was 0.1 (95% confidence interval: 0.01
      0.69). CONCLUSION: With 5 per 100,000 inhabitants per year fair eye is a regular
      complaint in general practice in South and Middle Limburg. The metal particles
      involved probably come from dodgem attractions, which usually move weekly to
      another town or village between March and November. Wearing glasses or lenses is
      rare in patients with fair eyes. It is advisable to wear protective goggles when
      riding dodgem cars.

PMID- 10578414
TI  - [Nutrition science and disease in the medical history of the 20th century].
AB  - In the twentieth century Dutch physicians provided major contributions to the
      development of the science of nutrition. Before the Second World War research was
      centred around vitamins and infant food, while at the same time the people's
      nutrition became a topic. Shortage of foodstuffs and nutrients had characterized
      the Dutch diet in the beginning of the century, but in the fifties the balance
      shifted towards an abundance of choice, nutrients and energy intake. Improvement
      of the optimum nutrient concentration pro energy unit became the main scientific
      challenge in order to prevent chronic degenerative diseases. Today, an unbalanced
      nutrition pattern is once more an issue as a relative nutrient shortage occurs in
      case of low energy intake and a limited variation of foodstuffs leading to
      chronic degenerative diseases. In addition, the difference between food
      components and medical drugs is decreasing by the advent of 'nutriceuticals'.
      Considering the variety of nutrition-related diseases the science of nutrition
      needs a more prominent place in medical academic education.

PMID- 10578415
TI  - [In Process Citation]

PMID- 10578416
TI  - [Clinical researchers and pharmaceutical industry].

PMID- 10578417
TI  - [A cluster of patients with puerperal fever in Gouda; a reiteration of the lesson
      by Semmelweis].

PMID- 10578418
TI  - [New diagnostic imaging technology often offers no advantage in the differential
      diagnosis of acute abdomen].
AB  - Imaging techniques may lead to better insight in the diagnosis of the acute
      abdomen, and in specific cases to a more rapid diagnosis, especially in the upper
      abdomen. However, frequently the only result of the accessory diagnostic methods
      is delay of the necessary treatment. The yield of CT scanning in acute abdomen is
      too small to justify routine use. Ultrasonography is useful in selected cases,
      but not for routine application. Laparoscopic examination in acute abdomen in
      certain conditions facilitates making the correct diagnosis, but it constitutes
      an aggressive method for patients found free of abnormalities. Skillful history
      taking and adequate performance of physical examination still constitute the
      basis of correct diagnosing. Technical aids may be of value. Good systematical
      studies of the clinical results and the cost effectiveness of physical
      examination and of the technological aids are still largely lacking.

PMID- 10578419
TI  - [Conditions for introduction and financing of new technologies].
AB  - Introduction and application of new technologies in the Dutch health care system
      will be less straightforward in the future than they were in the past. The
      pressure to contain health care expenditure has increased, also because of
      European agreements about adequate financing of collective spending. This will
      make initiators and producers of new technologies more critical towards
      technologies currently in development and urge them to specifically introduce
      technologies with a relatively favourable cost effectiveness profile. Whether new
      technologies will be used to a large extent will increasingly depend on the
      parties in health care at the regional and practice levels, who will assume a
      more important role in resource allocation in health care. On the other hand,
      they will be made more accountable for their decisions and will have to
      demonstrate their contribution to efficiency in health care.

PMID- 10578420
TI  - [Reading screening mammograms with the help of neural networks].
AB  - With digital mammography it is possible to assist radiologists in breast cancer
      screening with computers to improve their reading performance. The need for this
      has been demonstrated by studies showing a large variability in skill of
      radiologists reading mammograms. Moreover, retrospective studies show that a
      significant number of cancers are clearly visible on earlier screening
      mammograms, even for 'trained' computers. Methods for automated detection of
      breast cancer in mammograms often use artificial neural networks. These are
      'trained' to recognize abnormal mammographic areas using a large database of
      known cases. For detection of microcalcification clusters very reliable
      algorithms exist, with such high sensitivity that radiologists can limit their
      search to areas that have been marked 'suspect' by the computer. The development
      of methods to recognize malignant masses is much more difficult, but ample
      progress has been achieved in recent years.

PMID- 10578421
TI  - [Heart transplants in infants: an estimate of need and restrictions].
AB  - The need for cardiac transplantation in children in the Netherlands can be
      estimated at 5-14 per year, including 1-3 in newborns. This treatment can only be
      successful in close cooperation with an existing programme for adult cardiac
      transplantation and in a centre where the surgery for congenital heart disease is
      performed to its complete extent. Heart transplantation should not be the primary
      treatment for hypoplastic left heart syndrome as the Norwood operation
      constitutes a good alternative. Donor shortage is a problem for children also. In
      the treatment of endstage heart disease in newborns, owing to ethical dilemmas,
      surgical treatment is not a matter of course.

PMID- 10578422
TI  - [Acute coronary syndrome: technological improvements in diagnostics and therapy].
AB  - Unstable angina pectoris and non-Q wave infarction are difficult to distinguish
      clinically and electrocardiographically and currently are often called 'acute
      coronary syndrome'. In the technology of diagnosis and treatment there have been
      a number of innovations. The early diagnosis can be improved by means of plasma
      assays of the highly sensitive and specific cardiac markers troponin I and T.
      Both the pharmacotherapy (new platelet aggregation inhibitors) and the invasive
      treatment (use of coronary stents and arterial bypasses) have undergone major-
      expensive--innovations. Randomized trials have not yet made it clear whether
      invasive or conservative therapy is the optimal initial treatment. Both invasive
      treatment and pharmacotherapy are changing rapidly, so that the results of the
      randomized trials are already less relevant to the cardiological practice of
      1999.

PMID- 10578423
TI  - [Role of spirometry in primary practice].
AB  - Spirometry is increasingly used in general practice and improves the
      possibilities regarding mainly the early detection and treatment of obstructive
      pulmonary diseases. However, spirometry performed in general practice is less
      reliable than that performed in lung function laboratories and primary care
      laboratories, so that spirometry performed by the GP personally appears to be
      less suitable for monitoring purposes. Spirometry is a useful and feasible tool
      for GP's, providing that test results are adequately integrated within the GP's
      management of patients with obstructive lung disease. If sufficient attention on
      quality assurance of spirometry cannot be guaranteed in general practice, lung
      function laboratories and primary care laboratories may play an important
      supportive role.

PMID- 10578424
TI  - [Cytokines and immunotherapy in infectious diseases].
AB  - Cytokines are essential mediators in infection and inflammation. Almost all
      cytokines have not only positive but also noxious effects: the proinflammatory
      cytokines released during severe infections in high concentrations lead to organ
      damage and death. The antagonistic anti-inflammatory cytokines inhibit the
      defense against infections. Immunotherapy through modulation of the cytokine
      response may aim at inhibition of the proinflammatory and reinforcement of the
      anti-inflammatory cytokine response, so as to limit the damage of inflammation.
      In patients with sepsis this has so far been little successful, probably owing to
      the multiple effects of the cytokines. Inhibition of proinflammatory cytokines
      was successful, on the other hand, in patients with rheumatoid arthritis or
      Crohn's disease. Another possibility is to aim, on the contrary, at reinforcement
      of the proinflammatory and inhibition of the anti-inflammatory cytokine response,
      to strengthen the resistance of the host. This has given favourable results in a
      limited number of infections.

PMID- 10578425
TI  - [Immunology in the medical practice. XXIV. Expression of antibodies on
      bacteriophages; possibilities for in vitro production of human antibodies for any
      desired application].
AB  - Although poly- and monoclonal antibodies are successfully applied in research, an
      expected clinical breakthrough of these reagents so far has not occurred. This
      can mainly be explained by the animal origin of antibodies, which may lead to a
      deleterious immune response upon therapeutic use in humans. Moreover, it has been
      technically demanding to alter the desired affinity, format and effector
      functions of existing antibodies. Currently, antibody phage-display technology,
      through construction of large and highly diverse antibody libraries, completely
      by-passing the immune system, enables the isolation of human antibodies, which
      can be engineered for every desired application.

PMID- 10578426
TI  - [Genetics in medical practice after 2000].
AB  - Within a few years the 80,000 human genes will be identified which will increase
      our understanding of the genetic aspects of a large number of diseases, not only
      the relatively rare monogenic diseases but also the more frequent multifactorial
      diseases such as atherosclerosis, thrombosis and schizophrenia. Pharmacogenomics
      will lead to particular medication that is tuned to the genetic variations of the
      patient. Presently this increase in knowledge in the area of DNA diagnosis and
      genetic counselling will lead to a continuous increase in requests for assays.
      The possibilities for application will depend on new technological developments
      such as the DNA array technology and automation. To meet the increasing number of
      requests for genetic counselling, genetic nurses will have to play an important
      role. Moreover, collaboration between clinical geneticists and other specialists
      will have to be further intensified.

PMID- 10578427
TI  - [Fluorescence in situ hybridization in the study of chromosomal abnormalities].
AB  - Classical cytogenetics has a low resolving power and allows analysis of dividing
      cells only. In fluorescence in situ hybridization (FISH), a DNA fragment is
      stained with a fluorescent marker, after which this fragment is brought into
      contact with a patient's DNA. The stained fragment can bind to a corresponding
      fragment, revealing its presence or absence. Using FISH, every desired DNA
      sequence (from a whole chromosome to one gene) can be stained. In this way it is
      also possible to diagnose microdeletion syndromes, such as the Williams syndrome,
      the DiGeorge syndrome and submicroscopic chromosome anomalies that play a part in
      mental handicaps. FISH also allows analysis of non-dividing cells. In this way it
      is possible for instance rapidly to examine uncultured amniotic fluid cells for
      the commoner trisomies or to find foetal erythrocytes in a pregnant woman's
      blood. It is also possible to demonstrate tumour-specific breaking points. By
      application of FISH to microarrays it is possible to study a large number of
      genes simultaneously for the presence of a particular number of DNA sequences
      linked to a clinical abnormality.

PMID- 10578428
TI  - [Molecular pathology: intersection of morphology, biochemistry and genetics].
AB  - Molecular analysis of samples of cells and tissues plays an important part in
      clinical pathology, as a supplement to classical morphological examination. This
      holds true without reserve for immunohistochemistry, by now indispensable for
      clinical pathology. It was only recently that molecular genetic analysis was
      introduced into the pathological laboratory and it may be expected that this
      technique will play an important part, especially in cancer diagnostics. Where
      haemato-oncological malignancies and soft tissue sarcomas are concerned, this is
      already the case. Molecular tumour analysis will gain momentum due to advanced
      automated analysis using DNA arrays. Morphological aspects will long remain the
      foundation of tumour classification, but in the future not without major support
      from molecular analysis.

PMID- 10578429
TI  - [Beneficial effects of cryosurgical treatment in benign and low-grade-malignant
      bone tumors in 120 patients].
AB  - BACKGROUND: Benign and low-grade malignant bone tumours are generally treated
      with intralesional curettage. At microscopic level tumour cells are left behind
      and may be responsible for a recurrence. Therefore adjuvant local treatment is
      necessary. METHOD: By spraying liquid nitrogen into the remaining cavity, tumour
      cells are frozen very rapidly. Ice crystals formed in the (tumour) cell will
      mechanically damage the cell resulting in cell necrosis. This combined treatment
      of surgery and freezing is called cryosurgery. RESULTS: In 120 patients with a
      follow-up of at least 1 year the treatment results were good. The tumours were:
      aneurysmatic bone cyst (n = 32), simple bone cyst (n = 13), chondroid tumour (n =
      43), giant-cell tumour (n = 13), eosinophilic granuloma (n = 7) and monostotic
      fibrous dysplasia (n = 12). There were 10 recurring tumours, some of them very
      small; 6 recurrences were treated successfully by cryosurgery again; in 2
      recurrences marginal resection was carried out; 2 recurrences remained (as yet)
      untreated. CONCLUSION: Cryosurgery as a therapy of benign and low-grade malignant
      bone tumours yields results nearly as good as marginal resection, and has the
      advantage that segmental bone resections, which need extensive reconstructions
      are avoided.

PMID- 10578430
TI  - [High-flow transcranial bypass for prevention of brain ischemia].
AB  - In patients in whom the internal carotid artery has to be occluded because of the
      presence of an intracranial giant aneurysm or an infiltrating skull base tumour
      and in patients with brain ischaemia, whose internal carotid artery has been
      occluded spontaneously on the basis of atherosclerosis, a transcranial bypass can
      be created. Since the beginning of the seventies 'low-flow bypasses' are made in
      which a branch of the superficial temporal artery is connected with a cortical
      branch of the middle cerebral artery. Because of the small calibre of the blood
      vessels involved the desired effect on the brain circulation is limited. Thanks
      to the nonocclusive Excimer laser-assisted anastomosing technique, developed by
      Tulleken et al. in the last fifteen years, it is now possible to create a high
      flow bypass in a safe way. A donor vessel, e.g. the V. saphena magna, is
      connected at one end to the external carotid artery and at the other to the
      intracranial part of the internal carotid artery beyond the pathological lesion.
      The mean flow through the bypass was 140 ml/min in about 90 patients. For
      example, in three patients, a woman aged 45 with rightsided progressive
      ophthalmoplegia due to a giant aneurysm, a woman aged 31 years with an aneurysm
      in the right middle ear and a man with a chemodectoma at the base of the skull, a
      transcranial high-flow bypass was created nonocclusively, after which the
      internal carotid artery was closed without any problems.

PMID- 10578431
TI  - [A femoral neck fracture and a kidney transplantation in Egypt].
AB  - The mother of an Egyptian friend of the author is admitted to Asyut University
      Hospital after breaking her hip. A number of direct relatives spend the night in
      her hospital room and discuss the situation with the surgeon the next day. They
      are subsequently sent out to buy an artificial joint, and to bring the fee for
      the operation. The 2000 Egyptian Pounds which is claimed for this is later,
      during the operation, increased by 500 Egyptian Pounds, equivalent to about 150
      US dollars. This is relatively cheap compared with the kidney transplant of
      another relative, which amounted to 40,000 Egyptian Pounds. Most of this money
      was used to pay the donor, since Egyptian law only allows the transplantation of
      organs from living donors.

PMID- 10578432
TI  - The 1999 Eleanor Clarke Slagle Lecture. Defining lives: occupation as identity:
      an essay on competence, coherence, and the creation of meaning.
AB  - This article presents a view of occupation as the principal means through which
      people develop and express their personal identities. Based on a review of theory
      and research, it proposes that identity is instrumental to social life because it
      provides a context for deriving meaning from daily experiences and interpreting
      lives over time. The article proposes that identity also provides a framework for
      goal-setting and motivation. It is asserted that competence in the performance of
      tasks and occupations contributes to identity-shaping and that the realization of
      an acceptable identity contributes to coherence and well-being. Within this
      framework, it is postulated that performance limitations and disfigurement that
      sometimes result from illness or injury have identity implications that should be
      recognized by occupational therapy practitioners. By virtue of their expertise in
      daily living skills, occupational therapy practitioners are well positioned to
      help address the identity challenges of those whom they serve. In so doing, they
      make an important contribution to meaning and well-being.

PMID- 10578433
TI  - The Village AIDS Day Treatment Program: a model of interdisciplinary and
      interdependent care.
AB  - This article describes the Village AIDS Day Treatment Program, a program for
      people living with HIV/AIDS that provides health care by using a full range of
      interdependent services. Opened in 1988, this program was the first of its kind
      in the country. It has provided leadership in developing a model of care that
      addresses the full spectrum of health care--promotion, prevention, maintenance,
      and treatment. Along with describing the program and its services, this article
      includes the program's history and its influencing philosophies.

PMID- 10578434
TI  - Wellness works: community service health promotion groups led by occupational
      therapy students.
AB  - OBJECTIVE: In the context of a group process course, occupational therapy
      students learned health promotion skills through working on personal wellness
      goals and leading community-based health promotion groups. The groups targeted
      topics such as smoking cessation, improving diet, reducing stress through yoga,
      meditation, tai chi chuan, ROM (Range of Motion) Dance, aerobics, and a variety
      of other activities. METHOD: After identifying a personal wellness goal and
      developing it in a Wellness Awareness Learning Contract, each student used a Goal
      Attainment Scale (GAS) to predict an expected outcome for achieving the goal and
      to measure his or her progress toward attaining the goal. Students also used the
      GAS to measure progress in attaining group leadership skills within the community
      groups, which they outlined in a separate Group Skills Contract. Students kept
      weekly logs to foster reflective thinking, and the logs were used for interactive
      dialogue with the instructor. To further evaluate lifestyle change, students
      compared pretest and posttest scores on a Self-Assessment Scorecard, which
      surveyed six areas of health and human potential in body, mind, and spirit.
      RESULTS: Students monitored their own change process on both their personal
      health lifestyle goals and their group leadership skills while developing a
      richer appreciation of the dynamics of working for change with clients in
      community and traditional settings. Differences on the Self-Assessment Scorecard
      indicated improvement on two of the six scales for physical health and choices.
      CONCLUSION: Students experienced firsthand the challenges of developing healthier
      lifestyles on the basis of their personal goals as well as through fostering
      group changes. The two GAS learning contracts provided them with concrete
      evidence of their growth and learning. This experience--embedded in the context
      of a group process course with a community service learning group practicum-
      provided most students with a positive initial experience with group leadership
      as they began to explore roles as agents for lifestyle and health change.
      Suggestions for expanding health promotion roles in practice in the changing
      health care environment are also examined.

PMID- 10578435
TI  - Standards for an accredited educational program for the occupational therapist.
      Accreditation Council for Occupational Therapy Education of The American
      Occupational Therapy Association, Inc.

PMID- 10578436
TI  - Standards for an accredited educational program for the occupational therapy
      assistant. Accreditation Council for Occupational Therapy Education of The
      American Occupational Therapy Association, Inc.

PMID- 10578437
TI  - Guide for supervision of occupational therapy personnel in the delivery of
      occupational therapy services. The American Occupational Therapy Association,
      Inc.

PMID- 10578438
TI  - Guidelines for the use of aides in occupational therapy practice. The American
      Occupational Therapy Association, Inc.
AB  - Aides may have a role in extending or supplementing the services provided by
      occupational therapy practitioners by being assigned non-client-related tasks or
      client-related tasks. Client-related tasks delegated to aides must be carefully
      selected and supervised. Supervision for non-client-related tasks is determined
      by the supervisor and may range from routine to minimal. For client-related
      tasks, continuous supervision is recommended for best practice and incorporates
      the concepts of aide training, competency and return demonstration, review of
      each case, and accountability.

PMID- 10578439
TI  - Standards for continuing competence. The American Occupational Therapy
      Association, Inc.

PMID- 10578440
TI  - Management of occupational therapy services for persons with cognitive
      impairments (statement). The American Occupational Therapy Association, Inc.
AB  - In summary, occupational therapy practitioners play a critical role in helping
      persons with cognitive impairments establish or maintain meaningful and
      productive lives within their social and cultural environment. Occupational
      therapy practitioners effectively address a wide range of cognitive difficulties
      in clients with a variety of ages and diagnoses. Intervention may be directed
      toward the individual with cognitive impairments or toward persons who care for
      or interact with them (e.g., family members, significant others, employers,
      school personnel, other health care workers). Treatment includes changing the
      person's skills or behaviors or adapting the task and/or environment to maintain
      function, ease care-giving, reduce safety hazards, and maximize independence.

PMID- 10578441
TI  - Are doing and being dimensions of holism?

PMID- 10578442
TI  - Alcohol dependence in a client with a work-related injury.

PMID- 10578443
TI  - Goal setting and functional outcomes in rehabilitation.

PMID- 10578444
TI  - [Homicides--the sociodemographic background of the offender and the behavioral
      symptoms].
AB  - The authors examined 261 forensic-psychiatric reports to determine whether
      persons convicted of criminal homicide differed from persons convicted of other
      crimes with regard to personal biography, sociodemographic milieu, and character
      traits. Both groups were found to come from similarly disadvantaged social
      backgrounds. Murderers could not be distinguished on the basis of biographical
      data alone. The parameters found to be distinctive of murderers were: site of the
      crime, criminal-victim relationship, motive for the act, intoxication at the time
      of the crime, and the perpetrator's opinion regarding the purpose and intent of
      the homicide. The present findings confirm some of the results obtained by other
      authors on this topic.

PMID- 10578445
TI  - [Lethal child abuse (through the use of physical force) in the German Democratic
      Republic during the period 1 January 1985 to 2 October 1990. Results of a
      multicenter study].
AB  - No reliable data are available on cases of lethal child abuse (by active force)
      in the area of the former German Democratic Republic. In a multicenter study we
      therefore examined the police and court records for such cases occurring in the
      period 1 January 1985 to 2 October 1990 in the entire area of the former German
      Democratic Republic. RESULTS: The study center received information on 39 cases
      of lethal child abuse which correspond to approximately 7 cases per year.
      However, a low percentage of undetected crimes which cannot be determined more
      precisely has to be taken into consideration. Almost 40% of the victims were
      younger than 1 year, 73% of the victims showed indications of repeated ill
      treatment. The effects caused by using direct blunt forces, against the head in
      particular, were by far the most frequent causes of death. The male contact
      person (the victim's father, brother or stepfather as well as the life companion
      of the child's mother in particular) killed the child in most of the cases. As
      far as it is known, 37% of the male/female offenders suffered from chronic
      alcoholism; 32% of the male/female offenders were under the influence of alcohol
      when the crime happened. 83% of the male/female offenders who were found guilty
      made a confession shortly after the crime had happened or during the
      interrogations. Almost all the male/female offenders were sentenced to prison
      (the duration of the imprisonment varied between one year and for life). Due to
      the considerably lower section rate compared to the one in the German Democratic
      Republic, it is to fear that each second fatal child abuse is not detected in the
      new federal states.

PMID- 10578446
TI  - [The significance of linguistic characteristics within the framework of proof of
      authorship: attempts and goals in forensic linguistics].
AB  - The paper reflects the current state of the art in forensic linguistics and
      discusses the fundamental problem of the determination of the significance of
      linguistic features that are the basis of linguistic reports. A method is
      proposed that supplements the computer-assisted method of the BKA.

PMID- 10578447
TI  - [Practice of forensic entomology. Part 1: Insect collection at the site of
      discovery of the corpse].
AB  - The life cycle of a fly illustrates that the late immature stages of necrophagous
      insects frequently leave the body, and are therefore not found on the corpse
      itself. Taking into account these stages (i.e. pupae) while investigating a death
      scene is very important. Two case histories demonstrate the effects of not taking
      that fact into consideration when determining the post-mortem interval. Since
      there is no standardized method in Germany for collecting insects at a death
      scene, an entomological collection kit with a short instruction is introduced.

PMID- 10578448
TI  - Treatment of schizophrenia and spectrum disorders: pharmacotherapy, psychosocial
      treatments, and neurotransmitter interactions.

PMID- 10578449
TI  - Ziskind-Somerfeld Research Award. Protein kinase C signaling in the brain:
      molecular transduction of mood stabilization in the treatment of manic-depressive
      illness.
AB  - Understanding the biology of the pharmacological stabilization of mood will
      undoubtedly serve to provide significant insight into the pathophysiology of
      manic-depressive illness (MDI). Accumulating evidence from our laboratories and
      those of other researchers has identified the family of protein kinase C isozymes
      as a shared target in the brain for the long-term action of both lithium and
      valproate. In rats chronically treated with lithium, there is a reduction in the
      hippocampus of the expression of two protein kinase isozymes, alpha and epsilon,
      as well as a reduction in the expression of a major PKC substrate, MARCKS, which
      has been implicated in long-term neuroplastic events in the developing and adult
      brain. In addition, we have been investigating the down-stream impact of these
      mood stabilizers on another kinase system, GSK-3 beta and on the AP-1 family of
      transcription factors. Further studies have generated promising preliminary data
      in support of the antimanic action of tamoxifen, and antiestrogen that is also a
      PKC inhibitor. Future studies must address the therapeutic relevance of these
      protein targets in the brain using innovative strategies in both animal and
      clinical investigations to ultimately create opportunities for the discovery of
      the next generations of mood stabilizers for the treatment of MDI.

PMID- 10578450
TI  - A.E. Bennett Research Award. Anatomic basis for differential regulation of the
      rostrolateral peri-locus coeruleus region by limbic afferents.
AB  - BACKGROUND: Neurochemical and electrophysiological studies indicate that the
      locus coeruleus (LC)-norepinephrine system is activated by physiological and
      external stressors. This activation is mediated in part by corticotropin
      releasing factor (CRF), the hypothalamic neurohormone that initiates the
      endocrine response to stress. We have previously shown that the central nucleus
      of the amygdala (CNA) provides CRF afferents to noradrenergic processes in the
      peri-LC area that may serve to integrate emotional and cognitive responses to
      stress. The bed nucleus of the stria terminalis (BNST) shares many anatomical and
      neurochemical characteristics with the CNA, including a high density of CRF
      immunoreactive cells and fibers; however, recent studies have suggested that the
      CNA and the BNST may differentially regulate responses to conditioned and
      unconditioned fear, respectively, suggesting divergent neuroanatomical circuits
      underlying these processes. METHODS: In the present study, neuroanatomical
      substrates subserving regulation of the LC by the BNST were examined. Anterograde
      tract-tracing was combined with immunoelectron microscopy to test the hypotheses
      that BNST efferents target noradrenergic neurons of the LC and that these
      efferents exhibit immunolabeling for CRF. RESULTS: Ultrastructural analysis of
      sections that were dually labeled for the anterograde tracer biotinylated dextran
      amine (BDA) injected into the BNST and tyrosine hydroxylase (TH)-immunoreactivity
      demonstrated that BDA-labeled axon terminals formed synaptic specializations
      (primarily inhibitory) with TH-labeled dendrites and dendrites that lacked TH
      immunoreactivity. In contrast to CNA efferents that exhibited substantial
      immunolabeling for CRF, far fewer BDA-labeled terminals from the BNST in the
      rostrolateral peri-LC contained CRF. CONCLUSIONS: The present results indicate
      that the BNST may provide distinct neurochemical regulation of the peri-LC as
      compared to other limbic afferents such as the CNA. These data are interesting in
      light of behavioral studies showing that the CNA and BNST may be differentially
      involved in fear versus anxiety, respectively.

PMID- 10578451
TI  - Baseline cerebral hypermetabolism associated with carbamazepine response, and
      hypometabolism with nimodipine response in mood disorders.
AB  - BACKGROUND: Positron emission tomography (PET) studies have reported baseline
      (medication free) differences between mood disorder patients and healthy control
      subjects, but relatively little is known about relationships between baseline PET
      scans and treatment responses. Carbamazepine (CBZ) and to a more limited extent
      nimodipine (NIMO) seem useful in mood disorders. We explored whether baseline
      regional cerebral glucose metabolism (rCMRglu) could discriminate CBZ and NIMO
      responders from nonresponders and healthy control subjects. METHODS: In
      refractory mood disorder patients, we examined relationships between responses to
      these drugs, assessed by Clinical Global Impression-Improvement scores, and
      baseline rCMRglu, determined with fluorine-18 deoxy-glucose and PET. RESULTS: CBZ
      responders had baseline left insular hyper-metabolism compared to healthy control
      subjects and nonresponders, whereas nonresponders had widespread (including left
      insular) hypometabolism. Degree of CBZ response correlated with baseline
      paralimbic (including insula) and prefrontal hypermetabolism. In responders but
      not nonresponders, CBZ decreased widespread metabolism, with the degree of
      decrease in left insula correlating with response. In contrast, NIMO responders
      but not nonresponders had baseline widespread (including left insular)
      hypometabolism. Left prefrontal and left insular baseline hypometabolism, but not
      metabolic changes with treatment correlated with degree of NIMO response.
      CONCLUSIONS: These data suggest that baseline anterior paralimbic and prefrontal
      hypermetabolism may be associated with CBZ response, and hypometabolism with NIMO
      response. Based on these preliminary data, further exploration of relationships
      between baseline PET scans and treatment responses is indicated.

PMID- 10578452
TI  - PET imaging of serotonin 1A receptor binding in depression.
AB  - BACKGROUND: The serotonin-1A (5HT1A) receptor system has been implicated in the
      pathophysiology of major depression by postmortem studies of suicide victims and
      depressed subjects dying of natural causes. This literature is in disagreement,
      however, regarding the brain regions where 5HT1A receptor binding differs between
      depressives and controls and the direction of such differences relative to the
      normal baseline, possibly reflecting the diagnostic heterogeneity inherent within
      suicide samples. PET imaging using the 5HT1A receptor radioligand, [11C]WAY
      100635, may clarify the clinical conditions under which 5HT1A receptor binding
      potential (BP) is abnormal in depression. METHODS: Regional 5HT1A receptor BP
      values were compared between 12 unmedicated depressives with primary, recurrent,
      familial mood disorders and 8 healthy controls using PET and [carbonyl-11C]WAY
      100635. Regions-of-interest (ROI) assessed were the mesiotemporal cortex
      (hippocampus-amygdala) and midbrain raphe, where previous postmortem studies
      suggested 5HT1A receptor binding is abnormal in depression. RESULTS: The mean
      5HT1A receptor BP was reduced 41.5% in the raphe (p < .02) and 26.8% in the
      mesiotemporal cortex (p < .025) in the depressives relative to the controls. Post
      hoc comparisons showed the abnormal reduction in 5HT1A receptor BP was not
      limited to these regions, but extended to control ROI in the occipital cortex and
      postcentral gyrus as well. The magnitude of these abnormalities was most
      prominent in bipolar depressives (n = 4) and unipolar depressives with bipolar
      relatives (n = 4). CONCLUSIONS: Serotonin-1A receptor BP is abnormally decreased
      in the depressed phase of familial mood disorders in multiple brain regions. Of
      the regions tested, the magnitude of this reduction was most prominent in the
      midbrain raphe. Converging evidence from postmortem studies of mood disorders
      suggests these reductions of 5HT1A receptor BP may be associated with
      histopathological changes involving the raphe.

PMID- 10578453
TI  - Neurotransmitter interactions in schizophrenia--therapeutic implications.
AB  - The search for new and improved antipsychotic agents has escalated during the
      past five years. The era of searching for non-toxic copies of clozapine has been
      followed by several different lines of research, some of which pursue the
      traditional dopamine track, although at a higher level of sophistication, whereas
      others focus on other neurotransmitters, such as serotonin and glutamate.
      Emerging knowledge about the interactions between different neurotransmitters in
      complex neurocircuits opens up possibilities for achieving antipsychotic activity
      by interfering with many different neurotransmitters. Most intriguing is the
      finding in animal experimental models, indicating that it should be possible to
      alleviate psychotic conditions by stabilizing rather than paralyzing
      neurocircuits, thus avoiding the risk of motor and mental side effects of the
      currently used drugs. Among these new classes dopaminergic stabilizers and 5-HT2A
      receptor antagonists seem to offer most promise at present. In a longer
      perspective, drugs interfering with glutamate function via different mechanisms
      may also turn out to be useful, especially in the control of negative symptoms.

PMID- 10578454
TI  - Pharmacologic treatment of schizophrenia.
AB  - The pharmacologic treatment of schizophrenia remains a critical component in the
      short- and long-term management of this disease. Considerable progress has been
      made in delineating different domains of this illness, ranging from positive and
      negative symptoms to cognitive dysfunction and psychosocial vulnerabilities.
      Increasingly, treatments are being studied in relation to a variety of different
      outcome measures with functional ability and quality of life achieving
      appropriate emphasis. The introduction of a new generation of antipsychotic drugs
      has helped to raise optimism and expectations. Overall, second-generation drugs
      do provide clear advantages in terms of reducing adverse effects (particularly
      drug-induced Parkinsonism, anesthesia, and, hopefully, tardive dyskinesia).
      Advantages in alleviating refractory symptoms, negative symptoms, depression, and
      suicidal behavior are found in some reports; however, much remains to be done
      methodologically in establishing the relative merits of specific drugs in the
      multiple domains of interest.

PMID- 10578455
TI  - A critical review of research on psychosocial treatment of schizophrenia.
AB  - In the following review, the evidence for the effectiveness of the psychosocial
      treatments of schizophrenia are evaluated. Although most studies focus on relapse
      and hospitalization, when available, we present information on other domains of
      outcome (e.g., social adjustment and employment). We begin with family treatments
      for schizophrenia, then intensive case management, followed by social skills
      training, supported employment programs, and finally, individual psychotherapy.
      The topics have been chosen in descending order of available critical supportive
      studies. Recommendations for specific psychosocial interventions (including
      target populations) are discussed. Overall psychosocial treatments have been
      shown to reduce schizophrenic relapses but have not convincingly generalized to
      improving other facets of the illness. Despite this, psychosocial treatments
      should be supported and further research to improve them is necessary.

PMID- 10578456
TI  - Childhood-onset schizophrenia: rare but worth studying.
AB  - Childhood-onset schizophrenia (defined by an onset of psychosis by age 12) is a
      rare and severe form of the disorder that is clinically and neurobiologically
      continuous with the adult-onset disorder. There is growing evidence for more
      salient risk or etiologic factors, particularly familial, in this possibly more
      homogeneous patient population. For the 49 patients with very early onset
      schizophrenia studied to date at the National Institute of Mental Health, there
      were more severe premorbid neuro-developmental abnormalities, a higher rate of
      cytogenetic anomalies, and a seemingly higher rate of familial schizophrenia and
      spectrum disorders than later onset cases. There was no evidence for increased
      obstetric complications or environmental stress. These data, while preliminary,
      suggest that a very early age of onset of schizophrenia may be secondary to
      greater familial vulnerability. Consequently, genetic studies of these patients
      may be particularly informative and may provide important etiologic information.

PMID- 10578457
TI  - Olanzapine safety and efficacy in patients with borderline personality disorder
      and comorbid dysthymia.
AB  - BACKGROUND: Numerous medications have been tested in patients with borderline
      personality disorder (BPD) and/or schizotypal personality disorder (SPD).
      Although many of the medications tested have been demonstrated to be useful, no
      clear main treatment for BPD has emerged. Despite the efficacy of some of the
      medicines, acceptability and side effects have proven to be barriers to the use
      of medication. Therefore, an open-label olanzapine trial utilizing objective
      ratings was performed. METHODS: Patients suffering from BPD and dysthymia were
      included in an 8-week, open-label study of olanzapine monotherapy. The first 4
      weeks of the trial allowed for flexible dosing; during the last 4 weeks,
      olanzapine dose was held constant. Patients were rated on Hopkins Symptoms
      Checklist 90 (SCL-90), Brief Psychiatric Rating Scale (BPRS), Global Assessment
      of Function (GAF), Barratt Impulsivity Scale (BIS 11), and Buss-Durkee Hostility
      Inventory (BDHI). RESULTS: Eleven patients completed at least 2 weeks; nine of
      the patients finished the entire trial. There was a robust and statistically
      significant reduction in the five global ratings. Within the global ratings,
      symptoms of psychoticism, depression, interpersonal sensitivity, and anger were
      among the symptoms to be reduced. No movement disorder symptoms were noted for
      any of the patients. CONCLUSIONS: In this open-label pilot study, patients
      treated with olanzapine showed statistically significant reduction in self-rated
      and clinician-rated scales. Symptoms associated with BPD and dysthymia were among
      those to be substantially reduced. Further studies to explore olanzapine's
      efficacy versus placebo, as well as comparison to other potential treatments for
      BPD, are important next steps.

PMID- 10578458
TI  - Qualitative MRI findings in adults with 22q11 deletion syndrome and
      schizophrenia.
AB  - BACKGROUND: A genetic syndrome associated with schizophrenia, 22q11 deletion
      syndrome (22qDS), may represent a genetic subtype of schizophrenia (22qDS-Sz).
      Structural brain changes are common in schizophrenia and may involve
      developmental anomalies, but there are no data yet for 22qDS-Sz. The objective of
      this study was to assess brain structure in adults with 22qDS-Sz using magnetic
      resonance imaging (MRI). METHODS: Brain and arterial MRI scans of 11 adults with
      22qDS-Sz (mean age = 28.4 years, SD = 6.5) were systematically assessed by a
      neuroradiologist for qualitative anomalies. RESULTS: A high frequency of
      abnormalities were found: T2 white matter bright foci (BF), 90%; developmental
      midline anomalies, 45%; cerebral atrophy or ventricular enlargement, 54%; mild
      cerebellar atrophy, 36%; skull base abnormalities, 55%; and minor vascular
      abnormalities, 36%. CONCLUSIONS: BF and skull base abnormalities, especially in
      association with neurodevelopmental midline abnormalities, may be distinguishing
      MRI features for a genetic subtype of schizophrenia involving a deletion on
      chromosome 22.

PMID- 10578459
TI  - Selective alpha 7 nicotinic receptor stimulation normalizes chronic cocaine
      induced loss of hippocampal sensory inhibition in C3H mice.
AB  - BACKGROUND: A physiological alteration associated with schizophrenic and manic
      psychoses is diminished inhibition of the electrophysiological response to
      repeated auditory stimuli. This deficit also occurs in cocaine addicts. Studies
      in animals show that such inhibition is decreased by noradrenergic receptor
      stimulation and that the inhibition is enhanced by nicotinic cholinergic receptor
      stimulation. METHODS: C3H mice were treated for 7 days with cocaine. They were
      then prepared for electrophysiological recording. After the effects of cocaine
      treatment were observed, they were treated with nicotine agonists. RESULTS:
      Chronic cocaine administration markedly diminished inhibition of the hippocampal
      evoked response to repeated auditory stimuli. The loss of inhibition was reversed
      by acute treatment with either nicotine or the selective alpha 7 nicotinic
      agonist 3-(2,4)-dimethoxybenzylidine anabaseine (DMXB; GTS21). The effects of
      nicotine showed tachyphylaxis, whereas those of DMXB did not. CONCLUSIONS: This
      reversal of cocaine's effect by nicotinic agonists is consistent with previous
      pharmacological studies of the inhibition of auditory response. Additionally, the
      ability of nicotinic agonists to reverse a physiological defect associated with
      psychosis may have therapeutic implications for the neuropsychiatric sequelae of
      cocaine addiction in humans.

PMID- 10578460
TI  - Right prefrontal slow repetitive transcranial magnetic stimulation in
      schizophrenia: a double-blind sham-controlled pilot study.
AB  - BACKGROUND: The aim of this study was to extend our previous work on the
      therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) in
      major depression to patients with schizophrenia. METHODS: Thirty-five inpatients
      with schizophrenia were randomly assigned to either right prefrontal rTMS or sham
      treatment and were rated before and after treatment for positive, negative, and
      depressive symptoms. RESULTS: Thirty-one subjects (rTMS = 16, sham = 15)
      completed a 2-week treatment protocol. No serious adverse effects were reported;
      however, rTMS was not superior to sham treatment on any of the clinical ratings.
      CONCLUSIONS: In contrast to our previous positive findings in major depression,
      right prefrontal slow rTMS does not appear to have a beneficial effect for
      actively psychotic patients with schizophrenia.

PMID- 10578461
TI  - [Third generation of plasminogen activators. New directions in research].
AB  - Recent information on the development of new plasminogen activators (PA) is
      reviewed. The results of studies of PA mutant derivatives synthesized by
      recombinant DNA techniques are discussed. Data on chimeric (hybrid) forms of PAs
      and their chemically synthesized conjugates are presented. The trends in the
      search for PAs are analyzed. A new direction in the study of third-generation PAs
      for combined plasminogen activation and in the further development of the methods
      of thrombolytic therapy is outlined.

PMID- 10578462
TI  - [Synthesis of arginine-containing peptides and their conjugates with protohemin
      IX and tetraphenylporphyrin].
AB  - Arg-containing peptides and their conjugates with protohemin IX were synthesized
      by the solid phase method using Merrifield resin. The conjugates of Arg
      containing peptides with tetraphenylporphyrin were obtained by using phosphorus
      trichloride as an activating agent.

PMID- 10578463
TI  - [Novel chromophore substrates of aspartyl proteinases].
AB  - Chromophore substrates Dnp-Ala-Glu-Phe-Ala-Arg-NH2 and Dnp-Ala-Ala-Phe-Nle-Ala
      Arg-NH2 of aspartic proteases were synthesized by a combination of chemical and
      enzymic methods. The kinetic parameters of their hydrolysis with pepsin,
      aspergyllopepsin, and chymosin were determined. The introduction of Nle in the
      P1' position gives stable enzyme-substrate complexes with pepsin and chymosin. A
      Glu residue at the P2 position contributes significantly to an increase in kcat
      for the chymosin hydrolysis.

PMID- 10578464
TI  - [Peptide synthesis catalyzed by subtilisin-72 in organic solvents].
AB  - The solubility, stability, and activity of native subtilisin 72 and of its
      complex with SDS were comparatively studied in a number of polar organic
      solvents. Subtilisin was found to catalyze peptide bond formation when suspended
      in acetonitrile or solubilized as a complex with SDS in ethanol and isopropanol.
      Tripeptide Z-Ala-Ala-Leu-pNA, tetrapeptides A-Ala-Ala-P1-P1'-B, where A = Z or
      Abz; P1 = Leu, Phe, Met, Trp, Ile, Tyr, Phe(NO2), or Glu(OMe), P1' = Leu, Phe,
      Glu, Ala, Ile, Val, or Arg; B = NH2, pNA, or 2-(2,4-dinitrophenyl)aminoethylamine
      residue (Ded); pentapeptides Z-Ala-Ala-Leu-Ala-Ala-pNA and Z-Ala-Ala-Leu-Ala-Phe
      pNA; and hexapeptide Abz-Val-Ala-Phe-Phe-Ala-Ala-Ded were synthesized using the
      SDS-subtilisin complex. The complex also efficiently catalyzed the
      oligomerization of tripeptide H-Phe-Ala-Leu-OCH3 in ethanol, which resulted in a
      63:37 mixture of trioligomer and tetraoligomer. It was demonstrated that SDS
      subtilisin is a much more efficient catalyst than the suspension of native
      enzyme.

PMID- 10578465
TI  - [Mechanism of action of aspartic proteinases. V. Conformational characteristics
      of fragments of substrate-binding sites in rhizopuspepsin and HIV-1 proteinase].
AB  - The conformational states of side chains of catalytic Asp residues in active
      sites of HIV-1 protease and rhizopuspepsin in the potential field of free enzymes
      were studied by using theoretical conformational analysis. Structural factors
      that stabilize the conformation of these residues in free enzymes were revealed.
      Methods of molecular mechanics were used to estimate the stabilization energy of
      the Met46-Phe53 labile fragments of HIV-1 protease in the potential field of
      their nearest surrounding amino acid residues for the conformations
      characteristic of the free protein and similar to that of the protein in enzyme
      inhibitor complexes. In solution, the conformational state of the fragments of
      the free enzyme was concluded to be similar to that observed in the enzyme
      complex with the ligand and different from that determined by X-ray diffraction
      analysis. This difference was ascribed to the effect of crystal packing.

PMID- 10578466
TI  - [Enzymatic acetylation of xenobiotics: its efficacy and role in side effects].
AB  - Quantum-chemical calculations of a series of molecules with primary amino groups
      were carried out, and the results were compared with experimental data on the in
      vivo acetylation degree. A criterion of the interaction efficiency of primary
      amines with arylamine N-acetyltransferase was suggested. An analysis of the known
      data and the results of our calculations showed that the interaction
      peculiarities of xenobiotics containing primary amino groups with the acetylating
      system of an organism largely define the spectrum of side effects of these
      xenobiotics.

PMID- 10578467
TI  - [Production of recombinant hIL-4delta2-a native isoform of human interleukin-4 in
      Escherichia coli cells].
AB  - Expression plasmids containing the synthetic gene hil-4 delta 2 was constructed
      to produce human interleukin-4 in Escherichia coli cells. Strains TG1 (pBTIL-4
      delta 2) and BL21 (DE3) (pETIL-4 delta 2) produced the recombinant protein as
      inclusion bodies, and its production level was up to 30% of the total cell
      protein. The renatured hIL-4 delta 2 inhibited IL-4-stimulated T cell
      proliferation, and this effect was enhanced by cyclosporin A.

PMID- 10578468
TI  - [DNA methyltransferases for detection of the level of methylation of cytosine in
      the DNA CCWGG sequence].
AB  - An assay for the cytosine methylation level in the eukaryotic DNA CCWGG sequence
      is proposed. The method is based on the ability of DNA methylase BstNI to
      methylate DNA containing in a CCWGG site a nonmodified or 5-methylated cytosine
      to yield N4-methyl- or N4,5'-dimethylcytosine, respectively.

PMID- 10578469
TI  - [Mass spectrometry MALDI TOF for rapid qualitative evaluation of recombinant
      proteins production in E. coli].
AB  - The possible use of MALDI TOF MS for the analysis of Escherichia coli strains
      producing recombinant proteins was studied. It was shown that the target
      chimerical proteins might be rapidly detected in the strains.

PMID- 10578470
TI  - Auditory evoked responses to single tones and closely spaced tone pairs in
      children grouped by reading or matrices abilities.
AB  - Long latency auditory evoked responses (AER) were formed to single tones and
      rapid tone pairs. Using the t-statistic SPM technique, children with poorer WIAT
      reading scores demonstrated group difference overlying the left parietal and
      frontal language regions but just for AER to tone pair stimuli. Variables derived
      from these regions were not significantly different when the same subjects were
      grouped by K-BIT Matrices scores. When the same children were regrouped by
      Matrices scores and compared using the SPM technique, differences were now seen
      over the right hemisphere, especially in the parietal and frontotemporal regions,
      for both single and two-tone derived AERs. Variables derived from these regions
      were not significantly different for children when grouped by reading score. AER
      data support a specific deficit in two-tone stimulation for poorer reading
      children over the left hemisphere and also a deficit to both single and two-tone
      stimulation over the right hemisphere for children with poorer Matrices scores.

PMID- 10578471
TI  - QEEG and traumatic brain injury: rebuttal of the American Academy of Neurology
      1997 report by the EEG and Clinical Neuroscience Society.

PMID- 10578472
TI  - The burst-suppression electroencephalogram.
AB  - The burst-suppression (BS) pattern of the EEG occurs in a rather limited number
      of conditions. It has been observed in deep stages of general anesthesia and in
      conjunction with sedative overdoses. It is also known to occur in the wake of
      cardiorespiratory arrest. Undercutting of the cortex has been found to result in
      BS activity. Rare neonatal epileptic encephalopathies also give rise to BS. Our
      personal interest was prompted by the consistent finding of BS activity in rats
      following cerebral anoxia (nitrogen inhalation, airway obstruction): after
      periods of EEG flatness, BS activity developed, followed by periodic bursts and
      diffuse slowing. On the other hand, earlier literature (before 1960) showed
      virtually no observation of BS, neither in anoxic patients, nor in animal
      experiments. It is likely that the introduction of modern intensive care
      treatment has engineered episodes of BS activity, probably due to modifications
      of the anoxic cerebral pathology.

PMID- 10578473
TI  - Eye closure related spike and wave discharges: clinical and syndromic
      associations.
AB  - Precipitation of spike and wave (SW) discharges in some epileptic patients by eye
      closure (EC) has rarely been reported. To disclose the clinical characteristics
      and classification of syndromes of epileptic patients with SW discharges induced
      by EC, we investigated 10 patients (1 M, 9 F) showing this peculiar EEG feature.
      The patients aged between 9-39 years (mean 20.6 +/- 9.058), underwent short-term
      (1-3.5 hr) video-EEG investigations in order to document the appearance of the SW
      discharges within 3 seconds of the act of EC, in at least two occasions. Clinical
      analysis showed that 5 female patients who had the syndrome of juvenile myoclonic
      epilepsy (JME) had a later onset of epilepsy (13-15 years) than the 3 patients (3
      girls) with eyelid myoclonia with absences (EMA) (3-8 years of age at onset). The
      remaining 2 patients who were diagnosed as childhood absence epilepsy (CAE) and
      juvenile absence epilepsy (JAE) according to the international classification,
      did not show photosensitivity on the video-EEG. All but one of the 5 JME patients
      had experienced myoclonic seizures in intermittent photic stimulation (IPS) at
      the time of EC, associated with multiple spike and wave discharges. Two of the 3
      EMA patients exhibited typical absences with eyelid myoclonia during the act of
      EC. The high rate of family history of epilepsy in first degree relatives of our
      patients was an outstanding feature, which could have future implications in
      research of the genetic basis of epilepsy patients with ECS.

PMID- 10578474
TI  - Relationship between 3/sec component and 6/sec spike and wave complexes: a case
      report.
AB  - The EEG in this patient shows bilateral spike and wave complexes with a 3/sec
      component (anteriorly) simultaneously with the 6/sec form (posteriorly). The well
      established 3/sec form as an epileptiform pattern seen in absence seizures lends
      support for a significant relationship with the 6/sec form, which should not be
      dismissed as a "normal variant."

PMID- 10578475
TI  - Slow sharp waves.
AB  - Slow sharp waves (SSHW) are of longer duration (around 200 msec and longer) than
      typical sharp wave discharges (70 to 200 msec). This pattern is not merely of
      academic interest, as the electroclinical correlation showed that SSHW were found
      in 23 patients, mostly above age 50 years, with serious illnesses of various
      etiologies. Epileptic seizures occurred in a minority of the cases. The
      electrophysiological basis remains unclear and there is no answer to the
      question, "what causes the relatively long duration of these discharges?"

PMID- 10578476
TI  - Circling seizures in a case with Wilson's disease.
AB  - We report a case of Wilson's disease with circling seizures. Because of the
      existence of other types of frontal automatism and the EEG focus on the frontal
      regions, circling seizures of the patient were thought to originate from the
      frontal lobe. Magnetic resonance imaging demonstrated large cavitary lesions on
      bilateral frontal lobes. The mechanisms of circling behavior are discussed in
      association with Wilson's disease.

PMID- 10578477
TI  - Auditory and visual P300 cognitive evoked responses in patients with COPD:
      relationship to degree of pulmonary impairment.
AB  - Twenty-two subjects with documented COPD and no other significant illnesses were
      studied to assess the effect of varying degrees of COPD on cognitive P300
      auditory and visual evoked potentials. The severity of COPD was determined by
      spirometry with assessment of FEV1, FVC, and FEV1/FVC. Auditory P300 latency was
      significantly correlated with the FEV1/FVC ratio (Pearson Product Moment
      correlations r = -.56, N = 20, probability level = 0.1), indicating that
      increasingly severe airflow impairment is associated with longer auditory P300
      latencies. There was no significant association of FEV1/FVC with visual P300
      latency or with auditory or visual evoked potential amplitude measures.
      Progressive impairment of the auditory P300 evoked potential latency occurs with
      increasing severity of COPD. This impairment is present even in patients with
      mild COPD, suggesting some degree of accompanying cognitive decline early in the
      course of COPD with worsening as the disease progresses.

PMID- 10578478
TI  - N-(4-hydroxyphenyl)retinamide activation of transforming growth factor-beta and
      induction of apoptosis in human breast cancer cells.
AB  - N-(4 hydroxyphenyl)retinamide (4-HPR), a synthetic derivative of all-trans
      retinoic acid, induces DNA synthesis arrest and apoptosis in human breast cancer
      cells in a dose- and time-dependent manner. MDA-MB-435 cells treated with 3
      microM 4-HPR exhibited 58% and 75% DNA synthesis arrest after 1 and 2 days of
      treatment and 31%, 39%, 48%, and 56% apoptosis after 3, 4, 5, and 6 days of
      treatment, respectively. Conditioned media from 4-HPR-treated MDA-MB-435 cells
      contained 63 and 57 pg of active transforming growth factor-beta (TGF-beta) per
      10(6) cells after 1 and 2 days of treatment, whereas conditioned media from
      control cells contained only 9 pg/10(6) cells. TGF-beta involvement in 4-HPR
      induced apoptosis, but not DNA synthesis arrest, in MDA-MB-435 cells was
      demonstrated by 1) blockage of 4-HPR-induced apoptosis by 66-75% after treatment
      of cells with neutralizing antibodies to TGF-beta s, 2) blockage of 4-HPR-induced
      apoptosis by 64-67% after transient transfection of cells with antisense
      oligomers to TGF-beta 1 or TGF-beta type II receptor, 3) blockage of 4-HPR
      induced apoptosis by approximately 50% after inhibition of latent TGF-beta
      activation, and 4) demonstration that human breast cancer cells (T47D) defective
      in TGF-beta signaling were refractive to 4-HPR-induced apoptosis. These data
      indicate that 4-HPR is a potent activator of TGF-beta and that TGF-beta
      participates in 4-HPR-induced apoptosis of human breast cancer cells.

PMID- 10578479
TI  - Effects of soy intake on sex hormone metabolism in premenopausal women.
AB  - Studies suggest that phytoestrogens in soy products may impart hormonal effects
      that protect women against breast cancer. Limited research suggests that intake
      of soy products high in isoflavonoid phytoestrogens affects sex hormone
      metabolism, but it is unknown whether phytoestrogens in soy have any effect on
      menstrual function or serum sex hormones in women on common hormone therapies,
      such as oral contraceptives (OC). We studied the effects of soy in 36
      premenopausal women, 20 of whom used OC. Subjects consumed their normal diet for
      two menstrual cycles and added a soy beverage containing 20 g of protein and 38
      mg of total isoflavones to their usual diet for another two menstrual cycles. No
      significant differences were observed in serum estrone, estradiol, sex hormone
      binding globulin, dehydroepiandrosterone sulfate, prolactin, or progesterone
      concentrations with soy feeding in the non-OC or the OC group. No changes in
      menstrual cycle length or the urinary estrogen metabolite ratio of 2
      hydroxyestrone to 16 alpha-hydroxyestrone were seen with soy feeding in the non
      OC or the OC group. Levels of urinary estrogen metabolites were significantly
      different between the non-OC and the OC group. Thus soy consumption had no
      significant effect on the menstrual cycle, serum sex hormones, or urinary
      estrogen metabolite ratio in premenopausal OC or non-OC users.

PMID- 10578480
TI  - Mammary cancer promotion and MAPK activation associated with consumption of a
      corn oil-based high-fat diet.
AB  - Our earlier work has shown a selective promotional effect on the genesis of
      mammary carcinomas bearing a wild-type, but not mutant, Ha-ras codon 12 in a 1
      methyl-1-nitrosourea (MNU)-induced carcinogenesis model by high-fat diets (Nutr
      Cancer 23, 283-290, 1995). To test the hypothesis that activation of the mitogen
      activated protein kinase (MAPK) pathway is associated with this promotional
      effect, we compared the in vivo MAPK phosphorylation state of carcinomas from
      rats consuming a low-fat (5% corn oil, modified AIN-93G) with that from rats
      consuming a high-fat (25% corn oil) diet. Specifically, 21-day-old female Sprague
      Dawley rats were given an intraperitoneal injection of MNU and one week later
      were randomized to the two diets for six weeks. The number of mammary carcinomas
      per rat was 68% greater in the high-fat group, and Ha-ras mutation was rare in
      this short-term model. The levels of the phosphorylated MAPK2 (active) and of
      proliferating cell nuclear antigen (PCNA) were significantly higher in carcinomas
      from the high-fat group, and the two parameters were substantially correlated (r2
      = 0.43, p < 0.01). The expression level of c-Raf was fourfold higher in the high
      fat group but was only modestly associated with MAPK activation (r2 = 0.35, p <
      0.05). The levels of the total MAPK1 and MAPK2, guanosine triphosphatase
      activating protein, Ha-Ras, and MAPK kinase did not change. These results suggest
      that an upregulation of c-Raf expression by high fat may in part account for the
      in vivo MAPK activation, which in turn may enhance cell proliferation and mammary
      carcinogenesis.

PMID- 10578481
TI  - Effects of marinating with Asian marinades or western barbecue sauce on PhIP and
      MeIQx formation in barbecued beef.
AB  - Heterocyclic aromatic amines (HAAs), a group of chemicals formed during high
      temperature cooking of meat and fish, are potent mutagens and are suspected to
      play a role in colorectal cancer. A recent study suggested that marinating meat
      may offer a way to reduce HAA formation. Hawaii's diverse ethnic populations,
      which are at various risks of colorectal cancer, often use traditional marinades
      when cooking meat. We compared the HAA content of beef steaks marinated overnight
      with teriyaki sauce, turmeric-garlic sauce, or commercial honey barbecue sauce
      with that of unmarinated steaks. The levels of 2-amino-1-methyl-6-phenylimidazo
      [4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)
      were determined by liquid-liquid extraction and gas chromatography-mass
      spectrometry. Beef steaks marinated with teriyaki sauce had 45% and 67% lower
      PhIP level at 10 minutes (p = 0.002) and 15 minutes (p = 0.001) of cooking time
      as well as 44% and 60% lower MeIQx levels at 10 minutes (p = 0.008) and 15
      minutes (p = 0.001), respectively, than unmarinated meat. Lower levels of PhIP
      and MeIQx were also observed in meat marinated with turmeric-garlic sauce. In
      contrast, marinating with barbecue sauce caused a 2.9- and 1.9-fold increase in
      PhIP (p < or = 0.005) and a 4- and 2.9-fold increase in MeIQx (p < or = 0.001) at
      10 and 15 minutes, respectively. Differences in the mutagenic activities of
      marinated and unmarinated steaks, as measured by the Ames assay, paralleled the
      differences in PhIP and MeIQx levels. Future studies should test the effects of
      specific ingredients, including the water content of marinades, and the effect of
      reapplying barbecue sauce during cooking (to reduce charring) on HAA formation.

PMID- 10578482
TI  - Effect of dietary lycopene on N-methylnitrosourea-induced mammary tumorigenesis.
AB  - Epidemiological studies suggest protective effects of lycopene-rich foods on
      several types of cancer, including prostate and gastrointestinal tract. Moreover,
      an inverse association between serum lycopene concentrations and several types of
      cancer has been reported. However, few studies have focused on breast cancer, and
      they have shown little association between lycopene consumption and cancer risk.
      In this report, we used the N-methylnitrosourea (NMU)-induced rat mammary tumor
      model to compare the effects of pure lycopene with a lycopene-rich tomato
      carotenoid oleoresin (TCO) on NMU-induced mammary tumorigenesis. Rats were fed
      diets supplemented with 250 and 500 ppm crystalline lycopene or TCO beginning
      seven days before initiation with NMU (55 days of age) to termination (18 wk
      after NMU). Neither pure lycopene nor lycopene in the form of a mixed carotenoid
      oleoresin exerted an inhibitory effect on tumor incidence, latency, multiplicity,
      volume, or total tumors per group compared with unsupplemented controls. Weight
      gains in all groups were similar. Assay of serum lycopene concentrations in
      lycopene-supplemented groups indicated that median levels of 7,12,60, and 87
      ng/ml were attained in blood of groups supplemented with 250 and 500 ppm lycopene
      and 250 and 500 ppm TCO, respectively. The results of this animal study are
      consistent with epidemiological reports indicating that lycopene does not protect
      against breast cancer.

PMID- 10578483
TI  - Protection by the flavonoids myricetin, quercetin, and rutin against hydrogen
      peroxide-induced DNA damage in Caco-2 and Hep G2 cells.
AB  - Flavonoids are reported to exhibit a wide variety of biological effects,
      including antioxidant and free radical-scavenging activities. Reactive oxygen
      species have been implicated in a range of human pathological diseases such as
      atherosclerosis and certain cancers. The aims of this present study were 1) to
      investigate the effect of the flavonoids myricetin, quercetin, and rutin on cell
      viability, endogenous antioxidant enzyme activities, and DNA integrity in Caco-2
      and Hep G2 cells and 2) to determine whether these flavonoids could protect
      against H2O2-induced DNA damage. Both cell lines were supplemented with various
      concentrations (0-200 microM) of myricetin, quercetin, and rutin for 24 hours or
      H2O2 (50 microM) for 30 minutes, and cell viability was assessed. Over the
      concentration range tested, neither the flavonoids nor H2O2 significantly
      affected cell viability. The effect of the flavonoids on the activities of the
      antioxidant enzymes catalase (EC 1.11.1.6) and superoxide dismutase (EC 1.15.1.1)
      and on DNA integrity was assessed. The flavonoids did not significantly affect
      catalase or superoxide dismutase activity and did not induce DNA damage in either
      cell line. Exposure to 50 microM H2O2 for 30 minutes at 37 degrees C resulted in
      significant DNA damage, and preincubation with the flavonoids before H2O2
      exposure significantly (p < 0.05) protected Caco-2 and Hep G2 cells against H2O2
      induced DNA damage.

PMID- 10578484
TI  - Dietary antioxidant supplementation and DNA damage in smokers and nonsmokers.
AB  - Deficiencies of antioxidant nutrients have been implicated in the etiology of
      lung and other cancers. However, most intervention trials with antioxidant
      nutrients have not shown beneficial effects, and some have indicated that beta
      carotene may be deleterious. This randomized, double-blind, placebo-controlled
      study evaluated the effects of five short-term (4-wk) antioxidant nutrient
      supplement regimens [ascorbic acid (350 mg), RRR-alpha-tocopherol (250 mg), beta
      carotene (60 mg), selenium (80 micrograms as sodium selenite), ascorbic acid (350
      mg) + RRR-alpha-tocopherol (250 mg)] on plasma antioxidants and mononuclear
      leukocyte DNA damage in male smokers (n = 9) and nonsmokers (n = 12). Plasma
      concentrations of ascorbic acid and tocopherol were significantly increased by
      supplementation, but there was no significant change in plasma beta-carotene or
      blood glutathione peroxidase activity after supplementation with beta-carotene or
      selenium. DNA damage in mononuclear leukocytes, as assessed by comet assay, was
      not affected by any supplementation regimen. DNA damage, as assessed by 8
      hydroxydeoxyguanosine in mononuclear leukocytes, was not influenced by ascorbic
      acid, alpha-tocopherol, or selenium supplementation in smokers or nonsmokers, but
      beta-carotene supplementation resulted in significant differences between smokers
      and nonsmokers in the level of oxidative DNA damage, with decreases in smokers
      and increases in smokers. This is a further indication of the differential
      effects of supplemental beta-carotene in smokers and nonsmokers.

PMID- 10578485
TI  - Plant foods, antioxidants, and prostate cancer risk: findings from case-control
      studies in Canada.
AB  - Epidemiological data on most cancer sites suggest that consumption of plant
      foods, which contain high levels of antioxidants, might slow or prevent the
      appearance of cancer. We used data from three case-control studies to test this
      hypothesis. The total study population consisted of 617 incident cases of
      prostate cancer and 636 population controls from Ontario, Quebec, and British
      Columbia. Dietary information was collected by an in-person interview with a
      detailed quantitative dietary history. Unconditional logistic regression analyses
      were performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs).
      A decreasing, statistically significant association was found with increasing
      intakes of green vegetables (OR = 0.54, 95% CI = 0.40-0.71 for 4th quartile),
      tomatoes (OR = 0.64, 95% CI = 0.45-0.91), beans/lentils/nuts (OR = 0.69, 95% CI =
      0.53-0.91), and cruciferous vegetables (OR = 0.69, 95% CI = 0.52-0.91 for 3rd
      quartile). Higher intakes of fruit were associated with higher ORs (OR = 1.51,
      95% CI = 1.14-2.01 for 4th quartile), an effect that was seen for total fruit and
      citrus fruit, as well as for all other noncitrus fruits. Among the grains,
      refined-grain bread intake was associated with a decrease in risk (OR = 0.65 for
      4th quartile), whereas whole-grain breakfast cereals were associated with a
      higher risk for prostate cancer. Of all the antioxidant nutrients studied, the
      ORs were higher with higher intakes of cryptoxanthin (OR = 1.44, 95% CI = 1.09
      1.89 for 4th quartile). Exposure to certain dietary components of plant origin,
      which are potentially modifiable, indicates the theoretical scope for reducing
      the risk from prostate cancer. Future experimental studies or trials are
      warranted for further understanding.

PMID- 10578486
TI  - Inhibitory effect of 12-O-tetradecanoylphorbol-13-acetate-caused tumor promotion
      in benzo[a]pyrene-initiated CD-1 mouse skin by baicalein.
AB  - The effects of topical application of baicalein on 12-O-tetradecanoylphorbol-13
      acetate (TPA)-induced promotion of skin tumors, hyperplasia, ornithine
      decarboxylase activity, and inflammation were evaluated in female CD-1 mice.
      Topical application of baicalein (0.08, 0.16, or 0.2 mumol) with TPA (5 nmol)
      twice weekly for 24 weeks to mice previously initiated with benzo[a]pyrene
      inhibited the number of TPA-induced tumors per mouse significantly.
      Preapplication of the same amount of baicalein also afforded significant
      protection against TPA-induced hyperplasia in the ear skin. Topical application
      of baicalein inhibited tumor promoter-caused induction of epidermal ornithine
      decarboxylase activity by TPA (5 nmol). The topical application of baicalein
      (0.008, 0.016, or 0.02 mumol) inhibited TPA-induced edema of mouse ears by 88%,
      96%, or 97%, respectively. Pretreatment of mouse skin with various amounts of
      baicalein caused inhibition of H2O2 and myeloperoxidase formation by TPA. These
      results indicate that baicalein can be a potential cancer-chemopreventive agent
      against tumor promotion.

PMID- 10578487
TI  - Lack of effect of dietary alpha-tocopherol on chemically induced
      hepatocarcinogenesis in rats.
AB  - We investigated the effects of alpha-tocopherol on diethylnitrosamine (DEN)
      initiation-phenobarbital (PB) promotion of hepatic foci in female Sprague-Dawley
      rats. Groups of eight rats were initiated with DEN (15 mg/kg) at 24 hours of age.
      After weaning, they received diets containing 500 ppm PB and various
      concentrations of alpha-tocopherol, deficient (0 ppm), adequate (100 ppm), and
      supplemented (5,000 ppm), for 24 weeks. Rats fed alpha-tocopherol-supplemented
      diets had significantly greater hepatic alpha-tocopherol levels than those fed
      alpha-tocopherol-deficient or -adequate diets (p < 0.05). Liver lipid
      peroxidation (measured as thiobarbituric acid-reactive substances) was
      significantly greater in rats fed alpha-tocopherol-deficient diets than in those
      fed alpha-tocopherol-adequate or -supplemented diets (p < 0.05). The dietary
      alpha-tocopherol level had no significant effect on the ratios of reduced
      glutathione (GSH) to oxidized GSH or reduced GSH to total GSH in the liver or on
      the plasma prostaglandin E2 concentration or on the activities of hepatic
      cytosolic and particulate protein kinase C. Rats fed alpha-tocopherol-adequate or
      -supplemented diets had significantly greater hepatic glutathione S-transferase,
      GSH reductase, and GSH peroxidase activities than those fed alpha-tocopherol
      deficient diets (p < 0.05). The dietary alpha-tocopherol level did not
      significantly affect the formation of hepatic gamma-glutamyl transpeptidase- and
      placental glutathione S-transferase-positive foci. These results suggest that
      alpha-tocopherol does not influence hepatic foci formation and that reactive
      oxygen species may not be the underlying mechanism of hepatic foci formation in
      this DEN initiation-PB promotion model of hepatocarcinogenesis.

PMID- 10578488
TI  - Antiapoptotic activity of the Bowman-Birk inhibitor can be attributed to
      copurified phospholipids.
AB  - Previous studies have shown that extracts from soy possess potent antiapoptotic
      activity in in vitro and in vivo models. We recently reported that this
      antiapoptotic activity can be attributed to the presence of specific
      phospholipids. In this study, a conventional preparation of the soy-derived
      Bowman-Birk inhibitor (BBI) was tested for antiapoptotic activity in a C3H/10T1/2
      cell serum deprivation assay. The BBI preparation was separated into lipid- or
      protein-containing fractions by organic extraction. The lipid fraction contained
      only antiapoptotic activity; the protein fraction contained only enzyme
      inhibition activity. We therefore conclude that the antiapoptotic activity of the
      BBI preparation is due to specific phospholipids that copurify with BBI. These
      phospholipids retain their antiapoptotic activity after autoclave treatment,
      whereas autoclave treatment of the protein fraction results in a loss of its
      enzyme inhibition activity.

PMID- 10578489
TI  - Eicosapentaenoic acid inhibits the growth of liver preneoplastic lesions and
      alters membrane phospholipid composition and peroxisomal beta-oxidation.
AB  - The purpose of this study was to determine whether individual administration of
      highly purified eicosapentaenoic acid (EPA), one of the main components of the n
      3 polyunsaturated fatty acid family, would alter the growth of focal lesions
      during hepatocarcinogenesis. The protocol used to induce chemical carcinogenesis
      in liver was the Solt-Farber model (diethylnitrosamine as initiator and 2
      acetylaminofluorene and carbon tetrachloride associated with partial hepatectomy
      as promoters). Proliferative lesions were quantified with the histochemical
      marker gamma-glutamyltranspeptidase at partial hepatectomy and at sacrifice. The
      number and size of the gamma-glutamyltranspeptidase-positive foci observed were
      significantly lower in rats supplemented with EPA. Fatty acid treatment increased
      EPA and docosapentaenoic acid content in membrane total phospholipids, in
      phosphatidylethanolamine, and in phosphatidylcholine. The content of arachidonic
      acid decreased significantly only in total phospholipids and in
      phosphatidylethanolamine. Fatty acid content of phosphatidylinositol was not
      modified. Moreover, we observed an increase in the activity of palmitoyl-CoA
      oxidase, the limiting enzyme of peroxisomal beta-oxidation, the preferential
      metabolic pathway of n-3 polyunsaturated fatty acid. Conversely, unmodified
      levels of alpha-tocopherol and unchanged production of lipid peroxidation
      products (malondialdehyde) were observed. These results suggest that the EPA
      inhibitory effect on preneoplastic foci development may be related to alteration
      of fatty acid composition in phospholipid classes and to enhancement of
      peroxisomal beta-oxidation and H2O2 production.

PMID- 10578490
TI  - Influence of a high-calcium carbonate diet on the incidence of experimental colon
      cancer in rats.
AB  - This study was done to determine whether a high dietary calcium carbonate
      concentration could protect against colon tumors in rats. Female Wistar rats were
      randomly assigned to one of four groups and maintained on an 8% lipid diet for an
      adaptation period of four weeks. All groups were then fed a 24% lipid diet
      (sunflower oil), with (Groups 2 and 4) or without (Groups 1 and 3) a 1.5% calcium
      carbonate supplement. They were intrarectally instilled with saline (Groups 1 and
      2) or nitrosomethylurea (NMU) (Groups 3 and 4). Fecal sterol output and pH were
      analyzed for one week each month. Histological analysis was done at the end of
      the 32-week experiment. No tumors were found in the non-NMU-treated animals. The
      NMU-treated rats had tumors: 31% in Group 3 and 30% in Group 4. The calcium
      carbonate supplement had no effect on this incidence. The lipid and cholesterol
      excretions of the calcium carbonate-supplemented rats were significantly
      enhanced. The coprostanol output was not altered, although its fecal
      concentration of the calcium-supplemented rats was decreased. Although neither
      lipid overload nor NMU treatment altered the fecal pH, it was significantly
      increased in both calcium carbonate-supplemented groups. These findings suggest
      that additional calcium as carbonate has no effect on colon tumor incidence,
      although the fecal composition is altered. The increased pH of the feces due to
      the carbonate could have the opposite effect to calcium.

PMID- 10578491
TI  - Low-dose-dependent carcinogenic potential of 2-amino-3-methylimidazo[4,5
      f]quinoline in the immunodeficient (SCID) mouse colon.
AB  - The carcinogenic potential of 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ), one
      of the most potent mutagenic heterocyclic aromatic amines in food, for the colon
      was assessed in mice with severe combined immunodeficiency (SCID). In Experiment
      I, 60 male animals, 7-8 weeks old, were administered 300, 100, or 0 ppm IQ in the
      diet for 20 weeks. The incidence of aberrant crypt foci (ACF), preneoplastic
      lesions, was 100% in the two IQ-administered groups, whereas no ACF were found in
      the controls. Larger lesions, at least four aberrant crypts per focus, were noted
      in the colons of both treated groups. Most ACF were located in the proximal
      colon, and the bromodeoxyuridine-labeling indexes were elevated in a dose
      dependent manner, especially in this region. In Experiment II, IQ was
      administered in the diet at 50, 10, 2, or 0 ppm to 60 female and male 7- to 8
      week-old SCID mice for 30 and 23 weeks, respectively. The incidence of ACF was
      dose dependent in both sexes: 100%, 100%, and 63% in the females administered 50,
      10, and 2 ppm, respectively, and 100%, 83%, and 38%, respectively, in the males.
      Lesions of at least four aberrant crypts per focus were again evident with the 50
      ppm dose. The long-term or higher dose administration of IQ in the diet might
      thus be applied to elucidate colon carcinogenesis in the SCID mouse.

PMID- 10578492
TI  - Low levels of serum vitamins A and E in blood and subsequent risk for cervical
      cancer: interaction with HPV seropositivity.
AB  - Nutritional factors have been associated with risk of cervical cancer, but it is
      unclear whether the associations are of etiological significance or secondary to
      human papillomavirus (HPV) exposure. A delineation of this question requires a
      prospective study with invasive cancer as the end point. We conducted a nested
      case-control study in Finland and Sweden within a joint cohort of 405,000 women
      followed up for, on average, 4 years. Blood samples from 38 prospective cases of
      invasive cervical cancer diagnosed between 1985 and 1994 and 116 controls matched
      for age, country, and sample storage time were available for the study. Levels of
      retinol or unoxidized alpha-tocopherol in the blood were not risk factors for
      cervical cancer. However, joint-effect analysis of low levels of retinol
      disclosed statistically significant (p = 0.023) synergistic (more than
      multiplicative) interaction with HPV (HPV16, HPV18, or HPV33) seropositivity
      (observed relative risk = 2.6, 95% confidence interval = 0.7-8.8, expected
      relative risk = 0.3). Retinol might act as an effect modifier of the HPV
      associated risk for cervical cancer; exposed women may require adequate levels
      for immunologic surveillance of HPV.

PMID- 10578493
TI  - Dietary vitamin E and beta-carotene sources influence vitamin A and E storage in
      young rats fed marginal and adequate vitamin E.
AB  - The effects of two vitamin E levels (30 and 75 IU/kg diet) and the interrelation
      of two vitamin E sources [dl-alpha-tocopheryl acetate (dl-alpha-TA) and d-alpha
      tocopheryl acid succinate (d-alpha-TAS)] and three vitamin A sources [retinyl
      palmitate (RP), all-trans synthetic beta-carotene (SBC), and natural beta
      carotene (NBC)] were studied. Dietary vitamin A sources provided 4,000 IU/kg.
      Twelve groups of Fischer 344 rats (10/group) were fed designated diets for eight
      weeks. For RP, SBC, and NBC, the increase in each vitamin E source from a
      marginal to an adequate dietary level caused a significant increase in liver and
      heart alpha-tocopherol. Among rats fed diets with an adequate level of vitamin E,
      d-alpha-TAS was not as effective as dl-alpha-TA in increasing liver alpha
      tocopherol levels. Plasma retinol was lower in rats fed d-alpha-TAS than in those
      fed dl-alpha-TA. Among rats fed diets with an adequate level of dl-alpha-TA,
      those fed SBC had significantly higher liver and heart alpha-tocopherol
      concentrations than did all other groups (p < 0.05). Liver retinol equivalents
      for rats fed NBC were approximately 66% lower than those in rats fed SBC or RP (p
      < 0.05). The roles of the two vitamin E sources in alpha-tocopherol metabolism
      are not equivalent. These data indicate that vitamin A source influences the
      magnitude of the tissue vitamin A and E changes in response to the two vitamin E
      sources.

PMID- 10578494
TI  - Adding "value" to managing urinary tract infections in children.

PMID- 10578495
TI  - Diagnostic testing strategies in childhood urinary tract infections.

PMID- 10578496
TI  - Imaging of the urinary tract in children.

PMID- 10578497
TI  - Treatment of urinary tract infections.

PMID- 10578498
TI  - The long-term consequences of urinary tract infections: a historic and
      contemporary perspective.
AB  - The long-term adverse consequences of UTI in childhood are hypertension, impaired
      renal function, end-stage renal disease, and complications during pregnancy.
      These adverse effects of UTIs are a result of renal parenchymal damage.
      Currently, these complications are unusual among patients in industrialized
      countries, unless kidney damage is present at birth. VUR, the most common
      abnormality encountered in infants and young children with UTIs, is not a
      diagnostic entity, but reflects a spectrum of underlying conditions. There may be
      nonobstructive VUR with no other urinary tract abnormality. VUR may be associated
      with voiding dysfunction and frequent UTIs. It may be present with bladder outlet
      obstruction, hydronephrosis, and intrauterine renal damage. Children with
      intrauterine renal damage are those most likely to develop hypertension and those
      at greatest risk for progression to end-stage renal disease. Acquired renal
      injury as a cause of adverse long-term consequences due to UTI is much less
      common than it was early in this century, probably as a result of improved health
      care.

PMID- 10578499
TI  - The effect of humidity on samples of microcrystalline cellulose taken from the
      extrusion/marumerization process.
AB  - The purpose of this work was to examine the sorption and desorption of water by
      various samples of microcrystalline cellulose, MCC (Avicel PH-101), taken from
      the extrusion/marumerization process, and to provide data that may explain how
      water affects the MCC polymer matrix during the formation of beads. Two
      isopiestic (humidity) studies were conducted: the first used samples exposed
      directly to controlled humidity conditions, whereas the second used samples that
      were freeze-dried before being exposed to controlled humidity conditions. Water
      sorption and desorption were determined gravimetrically. When both sets of
      samples were initially exposed to low-humidity conditions, they reached
      equilibrium by desorbing water. When these samples were initially exposed to high
      humidity conditions, the high moisture content samples desorbed water, whereas
      the low moisture content and the freeze-dried samples sorbed water to reach
      equilibrium. When the first set of samples was initially exposed to high- and
      then to low-humidity conditions, they reached the same water content achieved by
      being equilibrated directly at the low-humidity condition. However, samples that
      were initially exposed to low- and then to high-humidity conditions had
      equilibrium water contents that were lower than those achieved by being
      equilibrated directly at the high-humidity condition. The original MCC systems
      exhibit a hysteretic effect above 85%, whereas the freeze-dried systems have a
      broader range hysteretic effect starting at 20% relative humidity. The results
      suggest that the internal structure of the MCC polymer fibers must change with
      the sorption and desorption of water, supporting the autohesion theory.

PMID- 10578500
TI  - Developing an injectable formula containing an oxygen-sensitive drug: a case
      study of danofloxacin injectable.
AB  - The purpose of this study was to assess the impact of impurities in formulation
      components, antioxidants, formulation pH, and processing/packaging on the extent
      of color change associated with oxidation of danofloxacin injectable. The methods
      used in this study include reversed-phase HPLC, UV-VIS spectrophotometry, atomic
      absorption spectroscopy, visual observation, and iodimetric titration for
      quantification of the antioxidant. The results from this study revealed that
      trace impurities from two different excipients significantly contributed to color
      change associated with oxidation. Polyvinyl pyrrolidone (PVP) introduced trace
      levels of peroxides into the solution. A second excipient also had a significant
      impact on stability because it introduced trace metal impurities into the
      product. The minimization of oxygen levels alone in the solution and headspace
      was not sufficient to completely eliminate the product instability. The addition
      of an antioxidant, monothioglycerol (MTG), resulted in a formulation less
      sensitive to processing variables. The impact of pH on the performance of MTG was
      also studied. At pH 7.5, MTG resulted in significant improvement in stability;
      however, at pH 6.0 it was not effective as an antioxidant. Process modifications
      alone may not be sufficient to prevent oxidation. Chemical approaches, such as pH
      control, addition of an antioxidant, and control of components should be
      considered first as means of enhancing stability of oxygen-sensitive solutions.

PMID- 10578501
TI  - Drug release from film-coated chlorpheniramine maleate nonpareil beads: water
      influx and development of a new drug release model.
AB  - The purpose of this work was to investigate drug release from film-coated
      chlorpheniramine maleate (CPM) nonpareils (sugar spheres) and the effect of water
      influx on the drug release mechanism. The methods used in the study involved the
      layering of CPM onto nonpareil cores using a fluid-bed apparatus. These CPM cores
      were then coated with an aqueous ethylcellulose dispersion, which was blended
      with a solution of hydroxylpropylmethylcellulose (HPMC) at different
      concentrations. The net water influx was determined by measuring water uptake
      during dissolution. The film surface area was calculated from bead diameters
      measured with an optical microscope. Drug release profiles were measured using
      USP dissolution method I (basket). The results showed that significant water
      influx occurred, which produced an internal liquid phase ranging from 0 to 1.8 x
      10(3) mm3/g of sample. As a result of the water uptake, an increase in bead size
      was observed. The bead surface area varied over the range of 40-80 x 10(3) mm2/g
      sample because of a combined effect of the water uptake and the release of the
      bead contents. A bead geometry parameter was proposed as the ratio of the bead
      surface area to the volume of the internal liquid phase. This bead geometry
      parameter was measured as a function of time and fit to an equation using a
      computer curve-fitting technique. This equation was substituted into an existing
      drug release model to give a more appropriate mathematical model describing drug
      release from this system. The conclusion drawn from these results is that the
      influx of water during drug dissolution creates a progressive increase in the
      liquid phase within the nonpareil bead; this causes a corresponding increase in
      the bead surface area which influences the drug release rate.

PMID- 10578502
TI  - Stability of poly(L-lysine)-complexed plasmid DNA during mechanical stress and
      DNase I treatment.
AB  - The aim of this study was to investigate the formation and stability of complexes
      between plasmid DNA (pDNA) and poly(L-lysine) (PLL). Formation of pDNA/PLL
      complexes with various ratios was determined by a fluorescence spectrophotometric
      method using fluorescamine. The effects of sonication, vortexing, and exposure to
      DNase I on the stability of free pDNA and pDNA/PLL complexes are discussed. A
      linear correlation between PLL added and PLL bound was obtained with overall
      reaction efficiency of 84.2-92.6%. Sonication degraded both free and PLL
      complexed pDNA within 15 sec of vortexing. However, vortexing did not alter the
      stability of free and complexed pDNA. Dramatic increase in the protection of pDNA
      in pDNA/PLL complexes was observed in the DNase I digestion experiment; 68.1
      89.0% of total pDNA in the pDNA/PLL complexes was protected from DNase I
      digestion compared to only 19.2% of total pDNA that remained undegraded after
      DNase I treatment of free pDNA. An increase in the PLL/pDNA ratio led to an
      increase in the protection of supercoiled pDNA; 15.5-38.2% of supercoiled pDNA
      pin PLL/pDNA complexes was protected after DNase I treatment. The results show
      that complexation of pDNA with PLL can stabilize the supercoiled structure of
      pDNA for the development of biodegradable microspheres as a delivery system for
      pDNA. Stability of pDNA/PLL complex can be monitored by PicoGreen dye and
      fluorescence densitometric assay methods.

PMID- 10578503
TI  - Formulation of ranitidine pellets by extrusion-spheronization with little or no
      microcrystalline cellulose.
AB  - The present study was concerned with the feasibility of formulating ranitidine
      into pellets with a range of alternative excipients in place of microcrystalline
      cellulose (MCC). Eight ranitidine formulations employing two or more of the
      excipients lactose, barium sulfate, glyceryl monostearate, and MCC were processed
      by extrusion-spheronization, and characterized according to a series of physico
      mechanical and dissolution criteria. Formulations containing lactose produced
      unsatisfactory pellets of wide size distribution and irregular shape, whereas
      formulations incorporating barium sulfate and glyceryl monostearate with or
      without MCC resulted in relatively spherical pellets of narrow size distribution
      and good mechanical properties. Ranitidine release was found to be rapid and
      virtually complete within 15 min, regardless of the pellet formulation. A direct
      relationship was observed between the concentration of MCC in the formulation and
      the properties of the pellets. In general, the higher the concentration of MCC,
      the rounder, stronger, and less friable the pellets. However, even pellets
      without MCC were also successfully prepared with a superior size distribution and
      shape over those with MCC. Overall, these results confirm that ranitidine can be
      formulated into pellet dosage forms with little or no MCC by the extrusion
      spheronization process.

PMID- 10578504
TI  - The preparation of soft gelatin capsules for a radioactive tracer study.
AB  - Clinical doses are developed for the oral coadministration of radiolabeled and
      nonlabeled forms of a poorly soluble investigational compound: OPC-41061. The
      release rates of the labeled and nonlabeled forms are equated and matched to the
      release rate of the polymer spray-dried form of the drug in the proposed market
      product. The study involves the physicochemical characterization of the powders
      using thermal analysis and dissolution testing, development and extemporaneous
      manufacture of liquid-filled soft gelatin capsules, and dissolution and stability
      testing of the final dosage form. Thermal analysis indicated that the labeled
      powder was amorphous and that the nonlabeled powder, which had been jet-milled,
      was crystalline. Dissolution testing of the jet-milled and spray-dried powders
      indicated that the former was released at a significantly slower rate. A liquid
      formulation containing 25% dimethyl acetamide and 75% polyethylene glycol 400
      (PEG 400) solubilized the desired dose of 60 mg and exhibited a drug profile that
      was similar to the spray-dried formulation. The final formulation was a soft
      gelatin capsule containing 60 mg of drug, including 100 microCi radioactivity,
      dissolved in 0.8 ml of a 25% dimethyl acetamide/75% PEG 400 solution. The
      formulation was chemically and physically stable for a period greater than the
      duration of the study.

PMID- 10578505
TI  - In vitro properties of an in situ forming gel for the parenteral delivery of
      macromolecular drugs.
AB  - The purpose of this research was to (i) formulate a solution of a water-insoluble
      interpolymeric complex (IPC) containing poly(methacrylic acid) (PMA), 15 kDa, and
      poly(ethylene glycol) (PEG), 20 kDa, in a biocompatible cosolvent system; (ii)
      demonstrate that the IPC solution can transform into a gel, in situ, at
      physiological pH; and (iii) determine the ability of the gel to entrap, protect,
      and control the release of macromolecular drugs such as proteins and
      oligonucleotides. Ternary phase diagrams were prepared to identify cosolvent
      composition containing N-methylpyrrolidone (NMP), ethanol, and water that
      dissolve the IPC. IPC solutions (40, 50, or 60% w/v) each containing 1 mg of
      either model proteins, fluorescein isothiocyanate (FITC)-insulin and FITC
      albumin, or 24-mer phosphorothioate oligonucleotides, were placed in containers
      that were immersed in buffer, pH 7.4. Aliquots of the buffer were sampled
      periodically and analyzed for the macromolecular content. In addition, in vitro
      bioactivity of another model protein, alpha-amylase, contained in the IPC
      solution was also determined. The studies demonstrated that a cosolvent
      containing 1:1:2 ratio of NMP/ethanol/water was most suitable for dissolving the
      IPC. Concentrations > 30% w/v IPC were required to form the gel, however, those
      mixtures containing > 60% w/v IPC could not be easily injected via 18-22 gauge
      needle. The gel can entrap and control the release of the model macromolecules
      for up to 6 days, in vitro. In addition, the gel can maintain the bioactivity of
      the protein, alpha-amylase, for 6 days. Therefore, an IPC gel can entrap,
      protect, and control the release of macromolecular drugs over a period of 6 days,
      in vitro, and therefore can be considered for in vivo investigation.

PMID- 10578506
TI  - Dry plant extracts loaded on fumed silica for direct compression: preparation and
      preformulation.
AB  - This paper describes the development of a method to load fumed silica with
      vegetal material (solid residue) from a liquid extract to obtain a solid loaded
      silica product (LSP) with satisfactory flow properties and compressibility to be
      processed by direct-compression technology. Extracts of Melissa officinalis L.
      (M.o.), Cardus marianus L. (C.m.), and Peumus boldus L. (P.b.) were used to load
      silica support. The release of boldine from LSP (P.b.) reached 100% in HCl 0.1 N
      solution and only approximately 70% in water. Some physical-mechanical properties
      of LSP (M.o. and C.m.) alone and LSP-excipient mixtures were determined. The
      densities (bulk and tap) of LSP were higher than those of fumed silica alone.
      Consequently, good flow properties of LSP products were observed. On the other
      hand, flowability, densities, and compactibility of directly compressible
      excipients (lactose, dicalcium phosphate dihydrate, and microcrystalline
      cellulose) were not adversely affected when mixed with LSP.

PMID- 10578507
TI  - Starch gelatinization under thermal stress.
AB  - The behavior under thermal stress of starch dispersed in water was studied by
      differential scanning calorimetry (DSC) to estimate the heat transported through
      the aqueous medium in gelatinization, and to characterize the range of
      gelatinization temperatures. In DSC scanning mode, the endotherm of 10% starch in
      aqueous dispersion showed the tracing of gelatinization at between 67 and 80
      degrees C, having an onset at approximately 69 degrees C. In the isothermal mode,
      characteristically distinct isothermal heat flow profiles were revealed. It was
      hypothesized that the thermal influx proposed as being analogous to the diffusion
      process may affect the profiles. The profiles were transformed and nonlinearly
      fitted according to the square root of time model to characterize a so-called t
      parameter, which was related to mean square displacement of molecular
      distribution. The t-parameter of starch in excess of water decreased compared to
      that of water only. The plot of difference in these t-parameters, expressed as
      delta, against temperature showed a dramatically decreased delta at the
      temperature between 66.7 and 75.2 degrees C, which coincided with the findings
      from scanning mode DSC. It was further hypothesized that the decreased delta may
      be due to the gelatinizing process. According to the theory of polymer solution,
      the critical temperature (theta) at 75.2 degrees C, where the free energy became
      theoretically negative, i.e., the starch became spontaneously dissolved, was
      drawn. This theta was located within the range of gelatinizing temperatures. It
      was deduced that starch polymer may have dissolved during gelatinization. The
      dissolution from acetaminophen tablets prepared by starch paste was lower
      compared with that of negative controls (without paste). Moreover, the paste
      prepared at gelatinizing temperature (70 degrees C) seemed to inhibit
      acetaminophen dissolution from tablet matrices more than that prepared at
      subgelatinizing temperature (50 degrees C).

PMID- 10578508
TI  - Enzymatic degradation of leuprolide in rat intestinal mucosal homogenates.
AB  - The purpose of this study was to evaluate in vitro enzymatic degradation and
      protection of leuprolide acetate in the mucosal homogenates of rat small
      intestine. When leuprolide was incubated at 37 degrees C with the homogenates, it
      was degraded quickly. The apparent Michaelis-Menten constant, K(m), and the
      maximal reaction velocity, Vmax, for leuprolide were 898 mM and 3.4 nmol/min/mg
      protein, respectively. At least four metabolites of leuprolide were observed in
      HPLC chromatograms, which were related to cleavages by some serine proteases. In
      the presence of protease inhibitors in the incubation medium, degradation of
      leuprolide was significantly suppressed by antipain and 3,4-dichloroisocoumarin
      (DCI), whereas bestatin and p-hydroxymercuribenzoic acid (PCMB) showed weaker
      protection than antipain and DCI, and alpha 2-macroglobulin (MG) exhibited no
      protection. When a w/o/w emulsion formulation was used, rapid degradation of the
      drug in intestinal homogenates was also inhibited. Therefore, the present study
      with representative protease inhibitors and a w/o/w formulation revealed that the
      enzymatic degradation of leuprolide is preventable in the rat intestinal mucosal
      homogenates.

PMID- 10578509
TI  - A novel percolation method for determining solubilities of pharmaceutical agents
      in semisolid vehicles.
AB  - A novel technique was developed to quantify the solubility of pharmaceutical
      actives in semisolid formulations. Ointments and emulsions of increasing
      potencies were sheared to disrupt their internal microcrystalline networks. These
      sheared materials were held in taut cheesecloth pouches, and the bleed that
      percolated out was collected and assayed for active potency. The solute
      concentration in the bleed was proportional to the concentration of the solute in
      solution in the formulation. Plots of bleed active potency against total
      formulation potency rose linearly to the point of formulation saturation. Above
      saturation, bleed potencies remained constant, producing plateaus on the
      solubility plots. The formulation potency at the onset of plateau quantified the
      saturation solubility of the active in each formulation. This technique was
      demonstrated with butylparaben in three ointment bases, and with hydrocortisone
      in an emulsion formulation. The solubility estimates thus obtained were confirmed
      experimentally by optical microscopy. This novel technique permits saturation
      solubilities to be determined for a range of semisolid formulations, with much
      greater accuracy than was previously possible.

PMID- 10578510
TI  - Development and evaluation of a laboratory-scale apparatus to simulate the scale
      up of a sterile semisolid and effects of manufacturing parameters on product
      viscosity.
AB  - The purpose of this study was to develop a benchtop apparatus to simulate the
      scale-up of the moist-heat sterilization process of sodium carboxymethylcellulose
      (CMC) gel and identify critical process parameters that affect the sterilized gel
      viscosity. A 600-ml benchtop Parr reactor was modified and used to achieve good
      correlation with a previously established heating profile using different
      equipment at the manufacturing site. The Parr reactor is constructed with 316
      stainless steel, pressure rated to 2000 psig, and temperature rated to 350
      degrees C. After several trials, a low-wattage heater (300 W) was determined to
      be suitable for this sterilization process (122 degrees C for 20 min). An anchor
      stirrer was installed for more efficient mixing while the gel was being
      sterilized. Evacuation and nitrogen flushing of the vessel could easily be
      performed through the gas inlet valves. The temperature controller (model 4843)
      has a microprocessor-based control module that provides a temperature profile
      control with adjustable tuning parameters. This apparatus was used to mimic the
      full-scale sterilization process by simulating the production sterilization
      temperature profile. Using this device, we found that the critical process
      parameters that affected final product viscosity were heating time, the starting
      pressure, residual oxygen concentration in the vessel, and the inherent viscosity
      of the CMC raw material. This study indicated that it is possible to use the Parr
      reactor to simulate the scale-up sterilization process of a semisolid product. A
      product with a consistent viscosity range could be manufactured by controlling
      critical process parameters during sterilization.

PMID- 10578511
TI  - Mixed polymer coating for modified release from coated spheroids.
AB  - Modified-release drug spheroids coated with an aqueous mixture of high-viscosity
      hydroxypropylmethylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC)
      were formulated. The preparation of core drug spheroids and the coating
      procedures were performed using the rotary processor and a bottom-spray fluidized
      bed, respectively. Dissolution studies indicated that incorporation of suitable
      additives, such as poly(vinylpyrrolidone) (PVP) and poly(ethylene glycol) 400
      (PEG) improved the flexibility and integrity of the coat layer by retarding the
      drug release. An increase in coating levels applied generally retarded the
      release rate of the drug. However, the ratio of HPMC to NaCMC in the mixed,
      plasticized polymeric coat played a more dominant role in determining the
      dissolution T50% values. The optimal ratio of HPMC to NaCMC for prolonged drug
      release was found to be 3:1, whereas an increase in the amount of NaCMC in the
      mixed polymer coat only increased drug release. The synergistic viscosity effect
      of HPMC and NaCMC in retarding drug release rate was greater in distilled water
      than in dissolution media of pH 1 and 7.2. Cross-sectional view of the scanning
      electron micrograph showed that all of the coated spheroids exhibited a well
      fused, continuous, and distinct layer of coating film. The drug release kinetics
      followed a biexponential first-order kinetic model.

PMID- 10578512
TI  - The effects of pH and mixed solvent systems on the solubility of oxytetracycline.
AB  - The solubility of oxytetracycline (OTC) in aqueous and mixed solvent systems was
      studied. The effects of pH and cosolvent composition on the solubility and
      apparent dissociation constants (pKa') of OTC were determined by a solubility
      method. The pKa' values of OTC in each mixed solvent system were estimated and
      used to generate expressions for predicting drug solubility in each cosolvent as
      a function of pH. Cosolvent systems of PEG 400, propylene glycol, glycerin, and 2
      pyrrolidone were studied in the pH range of 2.5-9. Solubility results showed
      increased solubility with increased cosolvent concentration, especially in 2
      pyrrolidone solvent systems. These results also showed that cosolvents enhanced
      drug solubility through either their effects on polarity of the solvent medium or
      complex formation with OTC. Aqueous and mixed solvent systems at lower pH values
      resulted in higher OTC solubilization because the drug existed primarily in its
      cationic form. A mass balance equation including all ionic species of OTC allowed
      for estimation of the intrinsic solubilities and pKa' values in each solvent
      system. pKa' values and intrinsic solubility of the OTC zwitterion increased with
      increasing cosolvent content. These parameters allowed prediction of drug
      solubility within the pH range and cosolvent concentrations used in this study.

PMID- 10578513
TI  - The interaction between oxytetracycline and divalent metal ions in aqueous and
      mixed solvent systems.
AB  - The effects of pH, mixed solvent systems, and divalent metal ions on
      oxytetracycline (OTC) solubility and the interactions between OTC and metal ions
      in aqueous and mixed solvent systems were investigated. OTC solubility profiles
      were obtained for pH 4-9. The cosolvents studied were glycerin, propylene glycol,
      PEG 400, and 2-pyrrolidone with the following metal ions: magnesium, calcium, and
      zinc. OTC and its interactions with these metal ions were evaluated by
      solubility, NMR, circular dichroism (CD), and electron diffraction (ED) methods.
      At pH 5.6, no complexation occurred with these metal ions, but OTC zwitterion
      formed aggregates in aqueous solutions as shown by NMR spectra. The hydration of
      the metal ions was observed to affect OTC aggregation, with Mg+2 causing the
      greatest OTC aggregation. At pH 7.5, OTC aggregation and metal-OTC complexation
      were observed in solutions with Ca+2 and Mg+2. Zinc ion was found to decrease OTC
      solubility because of zincate formation, which caused anionic OTC to precipitate.
      Electron diffraction revealed a relationship between OTC and metal-OTC complex
      crystallinity and solubility behavior. The zinc-OTC complex exhibited the highest
      crystallinity and lowest solubility at pH 8.0. Various cosolvents generally
      enhanced OTC solubility, with 2-pyrrolidone having the best solubility power. In
      OTC-metal-2-pyrrolidone and OTC-Zn(+2)-PEG 400 systems, circular dichroism
      provided evidence for the formation of soluble ternary complexes.

PMID- 10578514
TI  - Modeling methods for mixture-of-mixtures experiments applied to a tablet
      formulation problem.
AB  - During the past few years, statistical methods for the experimental design,
      modeling, and optimization of mixture experiments have been widely applied to
      drug formulation problems. Different methods are required for mixture-of-mixtures
      (MoM) experiments in which a formulation is a mixture of two or more "major"
      components, each of which is a mixture of one or more "minor" components. Two
      types of MoM experiments are briefly described. A tablet formulation optimization
      example from a 1997 article in this journal is used to illustrate one type of MoM
      experiment and corresponding empirical modeling methods. Literature references
      that discuss other methods for MoM experiments are also provided.

PMID- 10578515
TI  - Optimization of sustained-release tablet formulations: a four-component mixture
      experiment.

PMID- 10578516
TI  - Recombinant human bone morphogenetic protein-2 binding and incorporation in PLGA
      microsphere delivery systems.
AB  - The objective of this research was to determine the binding capacity and
      kinetics, and total incorporation of recombinant human bone morphogenetic protein
      2 (rhBMP-2) in microspheres made from hydrophilic and hydrophobic poly(lactide-co
      glycolide) (PLGA). Polymers were characterized by molecular weight,
      polydispersity, and acid number. Microspheres were produced via a water-in-oil-in
      water double emulsion system and characterized for bulk density, size, specific
      surface area, and porosity. Protein concentrations were determined by reversed
      phase HPLC. Protein was loaded by soaking microspheres in a buffered solution, pH
      4.5, of rhBMP-2, decanting excess liquid, and vacuum drying the wetted particles.
      Total loading and binding were determined by comparing protein concentration
      remaining to non-microsphere containing samples. Polymer acid number was the
      dominant polymer feature affecting the binding. Higher acid values correlated
      with increased rhBMP-2 binding. The amount of non-bound incorporated rhBMP-2
      linearly correlated with the concentration of protein used in binding. High rhBMP
      2 concentrations inhibit binding to PLGA microspheres. Binding was also inhibited
      by increased lactide content in the PLGA polymer. The polymer characteristics
      controlling rhBMP-2 binding to PLGA microspheres are acid value foremost followed
      by molecular weight and lactide/glycolide ratio. The total amount of rhBMP-2
      incorporated depends on the bound amount and on the amount of free protein
      present.

PMID- 10578517
TI  - Solid-state phase transitions of AG337, an antitumor agent.
AB  - The object of this investigation was to perform detailed solid-state
      characterization studies on the different solid forms of AG337 and to determine
      the conditions of their interconversions. Solid-state characterization was done
      using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA),
      hot stage microscopy, Karl Fischer titrimetry, ambient and variable temperature X
      ray powder diffractometry (XRD) and TGA coupled with FTIR (TGA/FTIR). In addition
      to five polymorphic forms of the anhydrate (I alpha to I epsilon), a hemihydrate
      (C14H12N4OS.2HCl.0.5H2O, II), a monohydrate (C14H12N4OS.2HCl.H2O; III), as well
      as a dihydrate (C14H12N4OS.2HCl.2H2O; IV) were identified. The 'as is' anhydrate,
      I alpha, resisted water uptake until stored at 98% RH (room temperature), where
      it transformed directly to IV, II and III transformed to IV at RH values > or =
      7.6 and 84% respectively. Heating II and III to 130 degrees C in the variable
      temperature XRD resulted in the formation of I beta and I gamma respectively. On
      the other hand, I delta and I epsilon were obtained when II and III were
      respectively stored at 60 degrees C under vacuum. Variable temperature XRD, by
      providing information about the solid-state as a function of temperature,
      assisted in the interpretation of the DSC and TGA results. TGA/FTIR provided
      direct evidence that the thermal events observed in the temperature ranges of 25
      150 degrees C and 200-250 degrees C were due to loss of water and loss of
      hydrogen chloride respectively. In addition to the conventional analytical
      techniques such as XRD, DSC, TGA and KFT, two other techniques, (variable
      temperature XRD and TGA/FTIR), were very useful in these solid-state
      characterization studies.

PMID- 10578518
TI  - Stabilization of pH-induced degradation of porcine insulin in biodegradable
      polyester microspheres.
AB  - The purpose of this research project was to stabilize the pH-induced degradation
      of porcine insulin encapsulated within biodegradable polyester microspheres
      through the incorporation of a basic additive. Insulin microspheres fabricated
      using Poly(L-lactide) (L-PLA) and Poly(DL-lactide-co-glycolide) (50:50 DL-PLGA)
      were subjected to in vitro release studies and the stability of unreleased
      insulin encapsulated within microspheres was investigated. The intramicrosphere
      pH was estimated by encapsulating acid-base indicators covering a wide pH
      transition range within 50:50 DL-PLGA microspheres. Finally, a basic excipient
      sodium bicarbonate was incorporated in 50:50 DL-PLGA microspheres to minimize
      acid-induced insulin degradation. The in vitro release was slow and incomplete (<
      30% in 30 days). Extraction and analyses of the unreleased insulin within the
      microspheres revealed that an average of approximately 11% remained intact. The
      degradation products observed consisted of approximately 15% of three distinct
      deamidated hydrolysis products including A-21 Desamido insulin, approximately 22%
      Covalent Insulin Dimer and trace amounts of High Molecular Weight Transformation
      Products. Comparison of the degradation profile of unreleased insulin contained
      in various microsphere formulations with the in vitro release kinetics indicated
      that an increase in covalent dimer formation within the microspheres prior to
      release is associated with a decrease in the cumulative percent insulin released
      during a 30-day incubation period. In an attempt to correlate insulin degradation
      with the drop in intra-microsphere pH due to polymer hydrolysis, it was
      determined that the pH within a degrading microsphere reaches a value of
      approximately 1.8 after 4 weeks. The incorporation of a basic excipient, sodium
      bicarbonate, in 50:50 DL-PLGA microspheres resulted in an improved in vitro
      release profile (cumulative release approximately 47.3% in 30 days) as well as a
      significant reduction in covalent dimerization of the unreleased insulin to
      barely detectable levels. The low pH microenvironment within a degrading
      microsphere is one of the major factors leading to protein instability, and the
      degradation of proteins encapsulated within polyester microspheres can be
      minimized by the incorporation of a basic excipient.

PMID- 10578519
TI  - Gap junction communication and the modulation of cardiac neural crest cells.
AB  - The analyses of transgenic and knockout mice with perturbations in alpha 1
      connexin (Cx43) function have revealed an important role for gap junctions in
      cardiac development. This likely involves the modulation of cardiac crest
      migration and function. Studies carried out with these mouse models suggest that
      clinically there may be a novel category of cardiac defects involving crest
      perturbations that do not include outflow septation defects, but rather involve
      more subtle defects in the pulmonary outflow tract.

PMID- 10578520
TI  - Extracellular matrix-driven matrix metalloproteinase production in endothelial
      cells: implications for angiogenesis.
AB  - The process of new blood vessel growth, angiogenesis, involves orchestrated
      alterations in endothelial cell interactions with adjacent cells and with
      components of the underlying basement membrane matrix. The activity of matrix
      metalloproteinases (MMPs), proteases that can cleave basement membrane and
      interstitial matrix molecules, has been shown to be necessary for angiogenesis as
      it occurs in several different in vivo and in vitro models. This review discusses
      the potential roles of two particular MMPs, MMP-2 and MT1-MMP, in angiogenesis,
      with emphasis on current understanding of how endothelial cell-extracellular
      matrix interactions may regulate the production of these MMPs via matrix-induced
      signaling leading to transcriptional activation and subsequent formation of
      active multiprotease complexes on the cell surface.

PMID- 10578521
TI  - Exploring the role of the beta-adrenergic receptor kinase in cardiac disease
      using gene-targeted mice.
AB  - The beta-adrenergic receptor signaling system plays a fundamental role in heart
      function. Signaling through beta ARs can be dampened by the actions of the beta
      AR kinase, a kinase whose expression and activity are elevated in chronic human
      heart failure. In this review we highlight studies that have used genetically
      engineered mice to understand how perturbations in myocardial beta AR signaling
      could adversely impact the pathogenesis of cardiac disease. Interrupting this
      process may provide novel therapeutic strategies in the treatment of human heart
      failure.

PMID- 10578522
TI  - Type-I protein-C deficiency caused by disruption of a hepatocyte nuclear factor
      (HNF)-6/HNF-1 binding site in the human protein-C gene promoter.
AB  - The level and tissue specificity of eukaryotic gene transcription is determined
      by the binding of specific transcription factors to DNA sequence elements located
      around the transcription start site. The availability and activity of specific
      transcription factors depends on a variety of developmental and environmental
      cues and, therefore, varies from cell type to cell type. For instance, liver
      tissue, the principal site of expression of the coagulation inhibitor protein C,
      expresses a heterogeneous group of transcription factors called hepatocyte
      nuclear factors (HNFs). Some of these HNFs are essential players in protein-C
      gene expression. This review discusses the significance of HNF-1 and HNF-6 in
      regulating the transcription of the protein-C gene and gives directions for
      future research.

PMID- 10578523
TI  - Decorin links low-density lipoproteins (LDL) to collagen: a novel mechanism for
      retention of LDL in the atherosclerotic plaque.
AB  - A process central to the initiation of atherosclerosis is retention of plasma
      derived low-density lipoprotein (LDL) particles in the extracellular matrix of
      the arterial intima. In this process, the apolipoprotein B-100 component of LDL
      binds to various components of the extracellular matrix, notably the negatively
      charged proteoglycans. In addition to proteoglycans, the intimal matrix contains
      large amounts of collagen. LDL also accumulates in collagen-rich areas of the
      arterial intima. The mechanism of this accumulation has remained obscure, because
      experiments in vitro have shown that LDL binds poorly to collagen. Our recent
      data provide evidence that the ability of collagen to bind LDL in vitro is
      greatly enhanced by decorin, a collagen-binding small proteoglycan that also is
      present in atherosclerotic lesions. This result provides a novel mechanism for
      retention of LDL in collagen-rich regions of the arterial intima.

PMID- 10578524
TI  - Role of annexin II tetramer in plasminogen activation.
AB  - The enzymatic cascade triggered by activation of plasminogen has been implicated
      in a variety of normal and pathologic events, such as fibrinolysis, wound
      healing, tissue remodeling, embryogenesis, and the invasion and spread of
      transformed tumor cells. Recent data established that the Ca(2+)- and
      phospholipid-binding protein, annexin II heterotetramer (AIIt) binds tissue-type
      plasminogen activator (tPA), plasminogen, and plasmin, and dramatically
      stimulates the tPA-dependent conversion of plasminogen to plasmin in vitro.
      Interestingly, the binding of plasmin to AIIt can inhibit the activity of the
      enzyme, suggesting that plasmin bound to the cell surface is regulated by AIIt.
      The existing experimental evidence suggests that AIIt is the key physiological
      receptor for plasminogen on the extracellular surface of endothelial cells.

PMID- 10578525
TI  - Lipoproteins containing apolipoprotein B-100 are secreted by the heart.
AB  - It generally is assumed that lipoproteins containing apolipoprotein B (apo B) are
      secreted only by the intestine and the liver. However, we recently demonstrated
      that the human apo-B gene also is expressed in the hearts of human apo-B
      transgenic mice and in human heart tissue. Using metabolic labeling techniques,
      we showed that heart tissue from human apo-B transgenic mice and nontransgenic
      mice, as well as human heart tissue, synthesize and secrete apo-B-containing
      lipoproteins. The reason why the heart makes lipoproteins is unknown, but we
      hypothesized that the heart may use lipoprotein synthesis to unload surplus
      cellular lipids, particularly triglycerides, which are not immediately required
      for mitochondrial beta-oxidation.

PMID- 10578526
TI  - [Algesic phenomena in panic disorders].
AB  - There were examined 35 patients with panic disorders (PD) which were divided into
      2 groups. In patients of the 1-st group there were observed headaches of tension
      type (17 individuals), meanwhile in the patients of the 2-nd group (18 cases)
      there weren't observed any algesic syndromes. A "saturation" of the life of a
      patient with the different algesic phenomena were estimated as well as the level
      of a depression according to Beck's scale and the manifestations of
      psychopathologic symptoms according to SCL scale were also studied. To estimate
      neurophysiologic parameters there were used a method of a contingent negative
      deviation (CND) and nociceptive flexor reflex. For the patients of the 1-st group
      there was quite characteristic a "saturation" of life with algesic events, an
      atypicity of the algesic attacks and more pronounced connection of PD debut with
      biologic but not with emotional factors. Psychometric observation revealed a
      significantly higher levels of both the depression according to Beck's and the
      somatization according to SCL scales as compared with the 2-nd group. Alterations
      in CND parameters (a decrease of the amplitude of the late wave, increase of
      postimperative negative wave) and an increase of a subjective algesic perception
      in the patients of the 1-st group had testified the pronounced desadaptive
      disorders. In the patients of the 2-nd group these indices were normal. Thus, on
      the PD model there were studied some psychophysiologic factors, which caused a
      formation of chronic algesic syndromes in the patients.

PMID- 10578527
TI  - [Mental disorders in basaloma].
AB  - There were observed 70 patients (21 men, 49 women) with basaliomas (cancer of the
      skin). Mental disorders were observed in form of affective disorders (depression,
      hypothymic colour of the surrounding), syndrome of dismorphophobia
      dismorphomania, relatively short cancerophobic feelings, somatogenic asthenia and
      a development of personality disorders. A forming of the mental disorders were
      conditioned at basaliomas by a complex influence of both somatogenic and
      psychogenic factors. An influence of the psychogenic factors was relatively
      transitory and psychologically comprehending (dysmorphophobia, cancerophobia,
      depression). An influence of the somatogenic factors predetermined a stability, a
      duration and a small reversibility of mental disorders (asthenia, irritative
      weakness, pathological development of the personality).

PMID- 10578528
TI  - [Prognostic criteria of speech rehabilitation in patients with sequelae after
      ischemic stroke].
AB  - Structural analysis concerning a complex of both neuropsychologic and clinical
      data of the patients with sequelae of ischemic stroke was performed. It was
      revealed, that a character of the local alterations of electric activity (EA) on
      EEG, testifying a functional state of cerebral structures, was an important
      prognostic criterion of the efficiency of neurorehabilitation. The local EA
      changes in form of groups of theta-waves and sharp waves of alpha- and theta
      activities were prognostically favourable signs; meanwhile polymorphic slow-wave
      was unfavourable background for performing a restorative education. An analysis
      of the speech disorders revealed that both semantic and dynamic aphasias occur
      more frequently after ischemic stroke. A semantic aphasia was always accompanied
      by the dynamic one and each form may be both leading and secondary. It may be
      dependent on location of a focus (according to EEG) as well as on the character
      and manifestation of the accompanying neuropsychologic symptomatology.

PMID- 10578529
TI  - [Hypnotic effect in individuals with varying degree of suggestibility].
AB  - The paper presents the results of the investigation concerning time and space
      organization of brain cortex electric activity and peculiarities of autonomic
      regulation of cardiac functions in 19 healthy individuals, which had a pronounced
      intention to counteract of hypnotic influence. Taking into consideration the
      reactions to hypnosis, these individuals were divided into three groups:
      predisposed to hypnotic suggestion, sensitive (intermediate group) and resistant
      to hypnotic suggestion. In predisposed individuals there were more pronounced
      sympathetic influences on cardiac functions and less spectral power of all EEG
      rhythms, except beta 2-rhythm. In individuals resistant to hypnotic suggestion
      there was more pronounced alpha-rhythm in brain cortex, while sympathetic
      influences on the cardiac functions were not so pronounced. All individuals
      reacted to hypnotic suggestion by a decreasing of the representation of alpha
      rhythm and by diminishing initial interhemispheric asymmetry. However, a share of
      beta-rhythm was increased in predisposed individuals and of theta-rhythm in
      resistant individuals. In posthypnotic state in resistant persons the
      correlations of initial EEG rhythms were completely recovered, while in the
      individuals from the other groups a recovery was observed only in separate EEG
      frequencies.

PMID- 10578530
TI  - [Doppler ultrasonography in children with sequelae of acute neuroinfections].
AB  - Transcranial dopplerography was performed in 125 children with late (1-3 years)
      neurologic sequelae of acute neuroinfections. Decreased blood flow velocity (BFV)
      in middle cerebral arteries of (0.61 of the value in control group) was found in
      patients with movement disorders. Impairment of the intracranial venous outflow
      together with both acceleration and asymmetry of blood flow in basal veins was
      prevalent in children with intracranial hypertension and hydrocephaly syndrome.
      Hyperconstriction of cerebral vessels together with a low BFV (30% of the initial
      value) was observed during hyperventilation on the side of the lesion in patients
      with epileptic syndrome. In children with cerebrasthenic syndrome the effect of
      cavinton treatment depended on the type of changes in cerebral blood flow:
      positive effect was found in patients with asymmetric decrease of BFV in anterior
      cerebral arteries.

PMID- 10578531
TI  - [Changes in immune status indicators in patients with supratentorial
      meningiomas].
AB  - The immune status was investigated in 38 patients with STM before and after
      surgery. Phasic changes were found: T-lymphopenia and elevated level of antibrain
      antibodies--before the operation, laboratory equivalents of immunodeficient state
      -on day 3-5, and signs of autoimmune cerebral damage--on day 15-18 after the
      operation. Preoperative neurosensibilization potentiated brain edema and
      complicated the course of postoperative period in patients with supratentorial
      meningiomas.

PMID- 10578532
TI  - [Cerebral hemodynamics in fetuses and newborns developing with impaired uterine
      and fetoplacental blood circulation].
AB  - By means of dopplerometry there were examined the blood flows in uterine
      arteries, funic arteries, internal carotid arteries of fetuses of 34 women in III
      trimester of a pregnancy with a threat of a premature birth. Cerebral blood flow
      in newborns was estimated on the 1-st and the 5-th days of life in anterior and
      middle cerebral arteries. Control group included 20 women with the physiologic
      pregnancies and their 20 newborns. In all children developed under the conditions
      of insufficiency of uterine and fetoplacental blood circulation there were
      observed the disorders of cerebral blood circulation, which became manifested
      clinically in birth by the disorders of cerebral circulation of light (in 16),
      average (in 13) and severe (in 5) degree.

PMID- 10578533
TI  - [The status of serotonin protein -- a serotonin transporter in thrombocytes in
      patients with somatoform disorders].
AB  - The role of serotonin transporter (SERT) protein in the development of somatoform
      disorders (SD) was investigated. An association study was performed in terms of
      the evaluation of the level of SERT immunoreactive (IR-SERT) protein using site
      specific antibodies directed at SERT C-terminus fragment, poorly conserved among
      the other cotransporters. The level of the anxious symptomatology was also
      estimated in the patients with SD. 22 patients, who met DSM-IV criteria for
      somatoform disorders, and 32 normals were examined. In platelets from normals, IR
      SERT protein migrated as a difuse band between 68 and 105 kDa, and a major
      sharper band at 43 kDa. Almost complete disappearance of platelet 43 kDa IR-SERT
      protein band was observed in most of the patients with SD. These findings
      permitted to suggest a possibility of either biosynthetic or processing
      abnormality of SERTs in the affected population, that might reflect a dysfunction
      of serotonin neurotransmission in CNS of the patients with SD.

PMID- 10578534
TI  - [Methodological approaches to the evaluation of neuropsychological development of
      children living in regions contaminated with ecological toxins].
AB  - A prevalence of some neurotoxicants, the salts of the heavy metals in particular,
      in the environment of many Russian towns is threatening. The aim of this paper
      was to work out the separate epidemiologic tests for the estimation of neuro
      psychic development in children of 2-5 years old on the basis of the native
      elaborations as well as the determination of their reproductivity and
      informativity in terms of neurotoxic influence. There were examined 155 children
      which lived in the region of a tractor plant with intensive polymetallic
      contamination or in a relatively "clean" central part of a town (Lypetsk). There
      was estimated a reproductivity of the methods used. Good and satisfactory indices
      of the reproductivity were obtained about questionnaire concerning the level of
      intellectual and social-psychologic maturity (85%), about the test concerning the
      behavorial-emotional peculiarities (76.9%), a transitory memory. A test
      concerning a reciprocal coordination of the movements revealed low
      reproductivity, but it was informative in the comparative study of the regions
      investigated. The following approbation of the tests is necessary, especially of
      those, characterising cognitive peculiarities of children, their validity by
      means of the analysis of contents of metals in biological fluids of the children
      examined.

PMID- 10578535
TI  - [A case of primary brain lymphoma].

PMID- 10578536
TI  - [Polymorphism in neuroradiological manifestations of tuberous sclerosis].

PMID- 10578537
TI  - [Cavinton and mydocalm in combined therapy of anxiety disorders and tension
      headaches].

PMID- 10578538
TI  - [The administration of mydocalm and donalgin in vertebro-radicular syndromes].

PMID- 10578539
TI  - [Cerebral ischemia and calcium overload].

PMID- 10578540
TI  - [Clinical syndromes and changes in cerebral hemodynamics and metabolism in
      subcortical stroke].

PMID- 10578541
TI  - [Positive placebo effect in some mental and neurological disorders].

PMID- 10578542
TI  - [Embryonal nerve tissue transplantation in the therapy of Parkinson's disease:
      current issues].

PMID- 10578543
TI  - [Comment on the article by A.L. Bratsun "Risk factors for the Alzheimer's type of
      dementia"].

PMID- 10578544
TI  - Test all diarrhoeal stools for VTEC O157; sensitive methods are available if
      suspicion is high and yield likely to be low.

PMID- 10578545
TI  - Who writes the articles in CDR Weekly?

PMID- 10578546
TI  - Pneumomediastinum: retroperitoneal pathway.
AB  - This is the first in vivo demonstration of the pathway of the gaseous column
      arising from an intra-abdominal source, traveling in the retroperitoneal space
      alongside the great vessels into the mediastinum, resulting in a
      pneumomediastinum.

PMID- 10578547
TI  - Low-dose vincristine-associated bilateral vocal cord paralysis.
AB  - BACKGROUND: Vincristine-associated peripheral neuropathy is a well-described
      entity. We describe a case of vincristine-induced vocal cord paralysis, which is
      a rare complication of this drug. We report herein the second case of bilateral
      vocal cord paralysis in a patient receiving conventional doses of vincristine.
      OBJECTIVE: To present a case report of vincristine-associated vocal cord
      paralysis and to review the relevant English language literature on this subject.
      DESIGN: Report and review of the literature. SETTING: Outpatient community cancer
      center. PATIENT: A 58-year-old female with a diffuse large cell lymphoma stage IV
      receiving cyclophosphamide, doxorubicin, vincristine, and prednisone. RESULTS:
      Bilateral vocal cord paralysis occurred in this patient receiving vincristine as
      part of her chemotherapy regimen. In addition to this case there have been a
      total of 25 prior reports, which are reviewed in the text. CONCLUSION: The
      incidence of bilateral vocal cord paralysis in patients receiving vincristine on
      the usual low-dose schedule is low. Prompt withdrawal of the offending agent
      results in prompt recovery without untoward long-lasting sequela.

PMID- 10578548
TI  - Cytomegalovirus pneumonitis as an initial presentation in an HIV-infected
      patient.
AB  - Human immunodeficiency (HIV) infection often presents with an unusual symptom
      complex. Although cytomegalovirus (CMV) is a frequent opportunistic infection in
      the late stage of acquired immunodeficiency syndrome (AIDS), CMV pneumonitis as
      an initial manifestation of HIV infection is not documented in the medical
      literature. We report a previously healthy patient with bilateral interstitial
      pulmonary infiltrates who was found to have CMV pneumonitis; only later was HIV
      virus infection diagnosed. Cytomegalovirus is a frequently isolated pathogen from
      respiratory secretions in AIDS patients. The role of CMV as a sole pulmonary
      pathogen is controversial. After exclusion of other pathogens, CMV was
      demonstrated by histological changes and viral culture in our case. This case
      indicates that pulmonary infiltrates presenting as the first manifestation of HIV
      infection can be caused by CMV infection.

PMID- 10578549
TI  - Lyme disease: disparity between culture and polymerase chain reaction detection
      of Borrelia burgdorferi after exposure to ceftriaxone in vitro.
AB  - Polymerase chain reaction is often used for detection of Borrelia burgdorferi in
      biological specimens. It has been suggested that polymerase chain reaction may be
      used as a surrogate marker of cell viability. To test this premise, B.
      burgdorferi cultures were treated with the antibiotic, ceftriaxone, and aliquots
      were cultured for cell viability and tested by polymerase chain reaction.
      Ceftriaxone treatment abrogated the ability to subculture B. burgdorferi by three
      days post-treatment. In contrast, positive polymerase chain reaction results were
      obtained for up to 56 days after antibiotic treatment. These findings indicate
      that positive polymerase chain reaction results do not provide proof of bacterial
      cell viability in vitro.

PMID- 10578550
TI  - The economics of catastrophic health insurance.
AB  - Currently over 41 million Americans lack health insurance and would experience
      severe financial stress if faced with a major illness. Catastrophic health
      insurance has been proposed as a means of addressing this problem. This study
      utilizes the National Medical Expenditures Survey of 34,400 households to
      calculate the cost of catastrophic medical coverage under a number of different
      assumptions. Estimates of the annual cost range from $109.2 billion to $149
      billion, depending upon the size of the deductible, and whether a means test is
      used to determine degree of coverage. Given the current antideficit climate in
      Washington, an expense of this magnitude cannot simply be added to the Federal
      budget. Instead, a simple funding proposal is suggested that provides more than
      adequate resources to finance the program. Specifically, universal catastrophic
      coverage would provide insurance companies with relief from approximately $175
      billion in medical bills, more than enough to fund even the most ambitious of the
      proposals.

PMID- 10578551
TI  - The future of managed care: integration of financing, risk management, and
      delivery.
AB  - The most significant transformation of health-care delivery and the health
      insurance industry is under way in the United States. It will change forever, and
      for the better, the way the delivery and financing of our nation's health-care is
      structured. We are witnessing the industrialization and consolidation of what was
      once a fragmented cottage industry. The new system--we call it wave III--will
      result in the re-establishment of the physician/providers as the key decision
      makers in our health-care system of the future. In this next phase of change,
      organized groups of physicians and hospitals will replace the current HMO
      insurance structure. This Third Wave will witness the integration of technology,
      managerial skills, marketing, sales, and negotiating acumen that were previously
      in the domain of health insurance companies (HMOs) into a delivery system where
      physicians and hospitals become partners focusing their coordinated efforts in
      managing health-care and the associated premiums.

PMID- 10578552
TI  - Congress must do more to protect patients' rights.

PMID- 10578553
TI  - Matters of life and death.

PMID- 10578554
TI  - Commercialized, assembly line medicine.

PMID- 10578555
TI  - Loss of dental support increases risk for ischemic stroke.

PMID- 10578556
TI  - Managing asthmatic patient requires examination of the somatic system.

PMID- 10578557
TI  - Asthma article ignores role of allergy and immunotherapy.

PMID- 10578558
TI  - Osteopathic unity must continue.

PMID- 10578559
TI  - Standardized medical record: a new outpatient osteopathic SOAP note form:
      validation of a standardized office form against physician's progress notes.
AB  - The accuracy and efficiency of recording information on a one-page standardized
      Outpatient Osteopathic SOAP Note Form (SNF) was compared with that obtained using
      the physician's progress notes (PPN). Use of the SNF in lieu of the PPN would
      assure the physician that proper clinical data were recorded to ensure proof of
      need and care in any instances of refused reimbursement. Moreover, standardized
      SNFs could be used to document and analyze present treatment protocols, enabling
      medical advances. Ten osteopathic physicians, who were skilled in osteopathic
      manipulative treatment (OMT), enrolled 300 patients. Initial and follow-up
      examinations totaled 959 visits (statistical cases); 76 statistical variables
      were compared. Essentially all information recorded in the PPN was recorded on
      the SNF. A significant difference (P < .05) was found between the PPN data set
      and the SNF data set in all but 17 of the 76 variables. Greater content of
      information almost always was found with the SNF data set. In addition, the SNF
      contained information not found in the PPN, most notably the severity and
      response to treatment of detected somatic dysfunctions. Participating physicians
      stated that the SNF takes about the same amount of time to fill in as the PPN.
      This makes the SNF a practical instrument for accurately and efficiently
      obtaining patient data in all physicians' offices. The validation study conducted
      demonstrated that the Outpatient Osteopathic SOAP Note Form easily and accurately
      reflected information recorded in the PPN and that data recorded may be used by
      physicians in their individual practices or for the conduct of osteopathic
      research.

PMID- 10578560
TI  - Preoperative ultrasound examination interpreted to represent a small contracted
      gallbladder with stones.
AB  - Agenesis of the gallbladder is a relatively rare congenital anomaly with an
      incidence of only 0.01% to 0.04%. Yet it continues to occur. The patient
      described in this case study was symptomatic and received a clinical diagnosis of
      cholecystitis after having an ultrasound examination that was read as indicating
      a small contracted gallbladder with stones. Only after an open surgical procedure
      and cholangiography was it discovered tht the patient actually had a congenital
      absence of the gallbladder. Clinicians need to be aware of the potential for
      congenital absence of the gallbladder when interpreting tests and when findings
      are questionable, and to ensure no surprises, they should consider ordering other
      diagnostic tests before doing surgery.

PMID- 10578561
TI  - Gastric leiomyosarcoma presenting as a sentinel hemorrhage.
AB  - A 43-year-old Asian woman who was initially seen because of hematemesis later had
      a gastric leiomyosarcoma diagnosed. Epigastric palpation, computed tomography,
      and magnetic resonance imaging assisted in determining the size, borders, and
      location of the tumor while a second esophagogastroduodenoscopy revealed friable
      gastric mucosa with erosions. Biopsy specimens taken for frozen section during
      surgical abdominal exploration revealed a malignant gastric stromal tumor. An en
      bloc excision of the mass then followed, with the final pathologic diagnosis a
      gastric leiomyosarcoma. Metastases were later found in the liver, peritoneum, and
      mesentery. Differentiation of gastric leiomyosarcoma from other stromal tumors is
      difficult and requires standardized nuclear and cellular evaluation of atypia,
      necrosis, mitosis, and tumor doubling time. The most common symptoms at initial
      presentation are abdominal pain and gastrointestinal bleeding. Abdominal computed
      tomography remains more specific in suggesting gastric stromal tumors than
      esophagogastroduodenoscopy and upper gastrointestinal barium series. Lymph node
      involvement in gastric leiomyosarcoma is rare and affords the first-line therapy
      of laparoscopic wedge gastrectomy with a good prognosis in tumors less than 6 cm
      in diameter. The prognostic factors include metastasis, size of the tumor,
      histologic grade, DNA ploidy of the tumor, and ulceration of overlying gastric
      mucosa.

PMID- 10578562
TI  - Testicular cysts: management and literature review.
AB  - Simple testicular cysts are extremely rare; only 20 cases have been reported in
      the literature. Sites include the tunica albuginea, tunica vaginalis, and
      testicular epidermis. Conservative enucleation is an effective treatment for
      these lesions once ultrasound examination establishes that the mass is cystic.
      Such Enucleation salvages testicular tissue. In the cases discussed, two patients
      were initially evaluated for vague testicular discomfort and one patient for male
      infertility. All were subsequently found to have benign testicular cysts. All the
      cysts were excised, and all patients remain disease-free. Included is a case
      series report of simple testicular cysts and a review of the literature.

PMID- 10578563
TI  - [Place of laparoscopic surgery in the treatment of gastroesophageal reflux].
AB  - 62 patients (57 females and 5 males, mean age 42.3 years) with gastroesophageal
      reflux disease were treated and followed up in the A.V. Vishnevsky Institute of
      Surgery. The diagnosis was established at endoscopic examination, which revealed
      esophagitis of the 1st degree in 39 patients, of the 2nd--in 20, of the 3d--in 2
      and of the 4th--in 1. Roentgenologic examination of the esophagus and the stomach
      revealed manifestations of the reflux in 43 patients, hernia of the esophageal
      orifice (of the diaphragm)--in 27. According to esophageal manometry data, basal
      pressure in the area of the lower esophageal sphincter made up 9.8 +/- 5.7 mm Hg;
      in 24-hour pH-metry the index of the De Meester exceeded normal 4-5 times and
      made up 61.1 +/- 33.8. All the patients have undergone a course of conservative
      antireflux therapy which in the majority of patients resulted in temporary
      improvement. Laparoscopic operations were carried out in 41 patients
      (fundoplication by Nissen--in 32, Toupet procedure--in 4 and--by Dor--in 5). In
      23 patients cruroraphy and in 32 cholecystectomy have been performed. The
      patients were followed up from 1 to 36 months. In the majority of them the
      results were good and favourable.

PMID- 10578564
TI  - [Microsurgical autotransplantation of organs and tissues in oncologic patients].
AB  - 402 patients with tumors of the head, neck and gastrointestinal tract as well as
      of the locomotor system underwent microsurgical autotransplantation of tissues
      during the treatment and rehabilitation. 483 microsurgical autografts from fascio
      cutaneous, muscular and osseous tissues were used as well as from visceral organs
      (the stomach, omenthum, the bowels). Successful outcomes of plastic and
      reconstructive operations were obtained in 95% of all the cases. Successful
      microsurgical plastics favoured timely application of combined antitumor
      treatment. In 50-60% of oncological patients a complete social and labour
      rehabilitation was achieved. The method proved to be perspective for further
      development and implementation in oncology.

PMID- 10578565
TI  - [Esophago-intestinal anastomosis in gastrectomy].
AB  - The method for application of the esophago-intestinal anastomosis after total
      gastrectomy for cancer of the stomach has been developed. Over 400 patients were
      operated on by this method. Substantial decrease of postoperative complications'
      rate was observed, particularly--faibure of sutures of the anastomoses have been
      developed only in 0.9% of patients. Reflux-esophagitis in long-term postoperative
      period was detected only in 2.2% of patients due to the usage of afferent loop of
      the bowel for the creation of valvular mechanism. Regarding the simplicity of the
      procedure, high reliability and favourable functional abilities of this
      anastomosis, the authors recommend it for wide application in surgical practice.

PMID- 10578566
TI  - [Hepatopancreatoduodenal resection in locally advanced cancer of gallbladder].
AB  - A case of hepatopancreatoduodenectomy in advanced cancer of the gall bladder is
      presented as well as literature data on indications for this operation, technical
      peculiarities of its performance, postoperative complications, follow up results
      and advisability of carrying out such a complicated surgical intervention.

PMID- 10578567
TI  - [Thoracoscopic splanchnic sympathectomy in pancreatic diseases].
AB  - Thoracoscopic splanchnicsympathectomy (TSSE) was performed in 8 patients with
      inoperable tumors of the corpus and tail of the pancreas and in 3 patients with
      painful syndrome of chronic pancreatitis. Severe painful syndrome in the upper
      abdominal region was the main indication for ISSE. Thoracoscopic resection of the
      lower thoracic sympathetic ganglia and splanchnic nerves was performed.
      Postoperative complications were detected in 3 patients: in one case it was
      pneumothorax, in two--pains in the thorax due to the injury of intercostal nerve
      by thoracoport. There were no lethal outcomes accounted for surgical procedure.
      The effectiveness of the operation was evaluated by the use of descriptive and
      visual analogue scales of pain sensitiveness and changes of the amplitude of
      somatosensor provoked potentials of the brain. Favourable and satisfactory
      results were obtained in 9 cases.

PMID- 10578568
TI  - [Resection of spleen with plastics by muscular pedicled flap in experiment].
AB  - Operation for resection of the lower pole segment (lobe) of the spleen with
      plastics of resected surface by pedicled flap from external oblique muscle of the
      abdomen has been developed in experiments on 25 dogs. The animals were followed
      up for 12 months. It was established, that muscular flap covered wound surface
      and promoted hemostasis as well as fixed the spleen in physiological posture.

PMID- 10578569
TI  - [Substantiation of wound retractors choice for median approach in various
      abdominal trauma].
AB  - Clinical and morphological experimental examination for assessment of
      advisability of the use of wound retractor by Sigal-Kabanov in median celiotomy
      has been carried out. The results of anatomical experiments in 28 cadavers of
      adult persons and the application of wound retractors for surgical operations in
      124 patients with injuries of abdominal organs have evidenced the advantages of
      proposed version for retraction of the wound over the other methods.

PMID- 10578570
TI  - [Surgical management in complicated sigmoid cancer].
AB  - The results of operative treatment of 242 patients aged from 30 to 85 years with
      complicated cancer of the sygmoid colon have been analyzed. It is shown that in
      the choice of the method for surgical intervention essential are the character of
      complications, peculiarities of tumor growth, as well as the stage of the disease
      and general condition of the patient. The removal of the tumor followed by
      forming of decompression colostomy, without restoration of bowel continuity
      results in achievement of better initial results. Resection of the tumor with one
      stage placement of the anastomosis is advisable as an elective procedure, after
      elimination of acute symptoms of complications and substantial preoperative
      preparation. The application of U-shaped terminolateral anastomosis allows to
      form a primary colonic anastomosis in acute bowel obstruction due to the tumor of
      the sygmoid colon.

PMID- 10578571
TI  - [Elimination of large fenestrated tracheal defects with use of microsurgical
      technique].
AB  - Operations on the trachea usually entail cutting or dissection of its wall, which
      requires further elimination of the developed defects. The application of a
      primary tracheal anastomosis is not always feasible. A number of methods for
      elimination of large defects of the trachea are not devoid of shortcomings. An
      original method for elimination of the defects of respiratory ways with the use
      of revascularized osteo-cutaneous radial complex flap has been developed and used
      in 8 patients. The sizes of the eliminated defects varied from 8.0 x 2 to 4 x 1.5
      cm. The vessels of the grafts were anastomozed with facial vessels by
      microsurgical technique. This procedure allowed to avoid multistaged treatment
      mode and the newly formed tracheal wall possessed adequate regidity for
      breathing. The cutaneous part of the flap was quite fit for substitution of the
      tracheal mucosa. The method of harvesting the autograft is quite safe, the damage
      to the donor site in the arm is negligible.

PMID- 10578572
TI  - [Surgical treatment of bronchial fistulas after pneumonectomy].
AB  - The results of surgical treatment of 9 patients with bronchial fistulas after
      pneumonectomy have been analysed. During the reoperation the bronchial stump was
      wrapped by the omental flap with vascular pedicle (omentoplasty). In 6 patients
      omentoplasty was used in urgent repeated transpleural operations, in 3--during
      the late operations from transsternal transpericardial approach. Wedge resection
      of the tracheal bifurcation with omentoplasty from transsternal transpericardial
      approach was performed in 2 patients with a short bronchial stump. 2 patients
      died after surgery: one--from cardiopulmonary failure, the other one--from the
      relapse of bronchial fistula. Omentoplasty in patients with primary bronchial
      fistulas proved to be effective. It is advisable to perform reoperations during
      the 1st day after complications developed.

PMID- 10578573
TI  - [Video-assisted thoracoscopy in treatment of pleural empyema].
AB  - The experience of treatment for 609 patients with empyema of the pleura with the
      use of videothoracoscopy technique has been summarized. 436 (71.6%) patients were
      at stage 1 of the disease, 126 (20.7%)--stage 2 and 47 (7.7%)--stage 3. All
      complications of intrapleural bleedings arisen in 3 (0.5%) patients, have been
      controlled through thoracoscope. There were no postoperative complications.
      Transformation of videothoracoscopic operation into the open one has been
      required in 11 (1.8%) patients: in 4--due to extensive destruction of the lung
      tissues, in 4--due to atelectasis of the lung, and in 3--because of the danger of
      endoscopical injury to the mediastinal organs. Feasibility of videothoracoscopic
      decortication of the lung and pleurectomy at stage 3 of chronic empyema of the
      pleura was demonstrated. 37 (78.7%) patients were cured by this method.

PMID- 10578574
TI  - [Hyperbaric oxygenation for treatment of extremities major arteries].
AB  - The results of hyperbaric oxygenation therapy in surgical treatment of 44
      patients with traumatic injuries of major arteries of the extremities were
      analysed. Associated injuries of the veins were observed in 27 (61.4%) patients,
      damages to the nerves--in 32 (72.7%), to the bones and joints--in 5 (11.4%), and
      to the soft tissues--in all of the patients. The indications for the hyperbaric
      therapy were: severe acute ischemia, major soft tissue damages and bone
      fractures, wound infection (purulent, anaerobic) complications and emergency
      ligation procedures on arteries. The use of hyperbaric oxygenation procedure
      together with extracorporeal methods for detoxication and reconstructive
      operations on vessels gives us possibility to broaden the indications for
      reconstructive operations and to prevent and control ischemic and infectious
      complications, endotoxicosis, increase the effectiveness of surgical treatment in
      victims with the injuries of major arteries of the extremities.

PMID- 10578575
TI  - [Giant myxoma of stomach mimicking pancreatic cyst].

PMID- 10578576
TI  - [Venous thromboembolic complications in oncological surgery].

PMID- 10578577
TI  - [Diagnosis and surgical treatment of diffuse toxic goiter].

PMID- 10578578
TI  - [Evolution of surgical treatment for bronchial asthma].

PMID- 10578579
TI  - [Surgical treatment of ulcerogenic pyloroduodenal stenoses].

PMID- 10578580
TI  - [Ambroise Pare'--reformer of surgery].

PMID- 10578581
TI  - Therapeutics, diagnostics and prophylactic agents for military personnel in
      adverse environment.

PMID- 10578582
TI  - Malaria in the Mojave.

PMID- 10578583
TI  - Gender differences in subjective distress attributable to anticipation of combat
      among U.S. Army soldiers deployed to the Persian Gulf during Operation Desert
      Storm.
AB  - This study compares perceptions of stress, cohesion, and psychological well-being
      among 856 male soldiers and 169 female soldiers from combat support and combat
      service support units deployed to the Persian Gulf during Operation Desert Storm.
      Three different types of stressors were measured: anticipation of combat,
      operational stress, and personal stress. Female soldiers scored higher than male
      soldiers on all three measures of stress but scored lower than males on
      horizontal and vertical cohesion. In a stepwise discriminant function analysis,
      anticipation of combat was the most significant discriminator between the
      genders, followed by horizontal cohesion. Anticipation of combat was a
      significant predictor of increased psychological symptoms for both genders, but
      it had a greater effect on the psychological symptoms of female soldiers compared
      with male soldiers.

PMID- 10578584
TI  - Don't know, don't care. III.
AB  - The knowledge of and interest in Department of Defense programs to help medical
      students with their educational expenses in exchange for military service as a
      physician was studied at three medical schools representing the eastern
      (University of Medicine and Dentistry of New Jersey/New Jersey Medical School
      [UMDNJ/NJMS]), midwestern (University of Missouri at Kansas City), and western
      (University of Utah) United States. Despite staggering indebtedness (40% of the
      class of 1998 at the University of Medicine and Dentistry of New Jersey were in
      debt in excess of $100,000 at graduation), surprisingly few students were aware
      of programs such as the Health Professions Scholarship Program, the Health
      Professionals Loan Repayment Program, and the Specialized Training Assistance
      Program. Even fewer were interested when made aware of such financial assistance.
      Hostility to military service as a physician was common. "Patriotism" was
      seemingly anathema. Dwindling recruitment and retention of medical corps officers
      in the reserve components of our nation's armed forces is of grave concern to
      national security and flies in the face of medical students', hence young
      physicians', indebtedness for their education. Clearly Department of Defense
      programs must become more imaginative, certainly more financially appealing.

PMID- 10578585
TI  - Development of a core curriculum in professional growth: practice management
      military model.
AB  - Military medicine has faced some big challenges in recent years. Military
      treatment facilities have not been exempt from these alterations, as the American
      public has sought to reinvent government practices with regard to medicine. Until
      recently, professional education consisted almost entirely of emphasis in the
      particular content of the chosen field. Obstetrics and gynecology was one of the
      first medical specialties to recognize the importance of practice management,
      professional growth and development, and to require exposure to it as part of the
      residency process. The Department of Obstetrics and Gynecology's instructional
      objectives dealing with professional growth and development originated as part of
      the military-unique curriculum for physicians implemented at Tripler Army Medical
      Center in Hawaii. Later, these objectives were used at Madigan Army Medical
      Center in Tacoma, Washington. Recent changes in the health care environment,
      coupled with an increasing awareness of professional liability and the newer
      specter of managed care, force physicians to learn the cost of each health
      encounter and to be more familiar with the business aspects of health care. As
      medicine in general is changing, the curricula have been revised and tailored to
      the needs of our physicians with the addition of ethics, managed care,
      utilization, and practice management.

PMID- 10578586
TI  - Acute dermatitis from oak processionary caterpillars in a U.S. military community
      in Germany.
AB  - One hundred sixty-five soldiers and civilians from the U.S. military community in
      Heidelberg, Germany, sought treatment for acute dermatitis from June 26 through
      July 2, 1995. This was 144 more than the expected number of 21 cases based on a
      background rate of 3 cases per day. Cases consisted of individuals who presented
      with a painful, itching rash distributed widely about the body but concentrated
      in the upper half. Urticarial hairs from oak processionary caterpillars
      (Thaumetopoea processionea L.) (Lepidoptera: Thaumetopoeidae) were eventually
      identified as the cause. This article is the first published report that
      documents the military medical importance of these caterpillars in Europe. The
      implications and measures needed to resolve future outbreaks quickly and
      effectively are discussed.

PMID- 10578587
TI  - Laboratory animal medicine education and training in the uniformed services: a
      brief history.
AB  - The history of laboratory animal medicine education and training for uniformed
      (U.S. Army, U.S. Air Force, and U.S. Public Health Service) veterinarians is
      reviewed from the beginnings in 1961 at the U.S. Air Force School of Aerospace
      Medicine. Of the 636 currently listed diplomates of the American College of
      Laboratory Animal Medicine, at least 208 (32.7%) received specialty training or
      experience in this discipline while on extended active duty in one of the
      uniformed services. The evolving "climate" has led to the establishment of the
      most recent program within the uniformed services at the Uniformed Services
      University of the Health Sciences in Bethesda, Maryland.

PMID- 10578588
TI  - Penetrating eye injury in war.
AB  - The percentage of penetrating eye injuries in war has increased significantly in
      this century compared with the total number of combat injuries. With the
      increasing use of fragmentation weapons and possibly laser weapons on the battle
      field in the future, the rate of eye injuries may exceed the 13% of the total
      military injuries found in Operations Desert Storm/Shield. During the Iran-Iraq
      War (1980-1988), eye injuries revealed that retained foreign bodies and posterior
      segment injuries have an improved prognosis in future military ophthalmic surgery
      as a result of modern diagnostic and treatment modalities. Compared with the
      increasing penetrating eye injuries on the battlefield, advances in ophthalmic
      surgery are insignificant. Eye armor, such as visors that flip up and down and
      protect the eyes from laser injury, needs to be developed. Similar eye protection
      is being developed in civilian sportswear. Penetrating eye injury in the civilian
      sector is becoming much closer to the military model and is now comparable for
      several reasons.

PMID- 10578589
TI  - Blood type discrepancies on military identification cards and tags: a readiness
      concern in the U.S. Army.
AB  - Current policy allows the use of identification cards and tags for transfusion
      purposes during contingency operations. The purpose of this study was to
      determine the percentage of soldiers having the wrong blood type on their
      identification card or dog tag and the effects that these findings could have
      during wartime. Thirty-four of 923 soldiers (3.7%) demonstrated at least one
      discrepancy during testing. Of these 34 discrepancies, 22 (2.3%) involved ABO
      group errors, 10 (1.1%) involved Rh type errors, and 2 (0.2%) involved both ABO
      group and Rh type errors. These errors could lead to transfusion of the wrong
      blood type during wartime. The interface of computer systems in the near future
      may decrease the blood type error rate on identification cards and dog tags.
      Quality improvement programs to increase the accuracy of the blood type on
      identification cards and dog tags are suggested.

PMID- 10578590
TI  - International survey of military mental health professionals.
AB  - This paper reports on data from a survey of international military mental health
      professionals. In a series of open-ended questions, respondents were asked to
      describe their country in terms of the field of military psychology, the role of
      mental health professionals on deployment, the degree to which the field of
      mental health is accepted in the military, and their contact with their
      international counterparts. The survey was mailed to 44 different countries from
      July 1995 through July 1996. The data are based on 30 individual responses from
      23 different countries. Cultural differences included the role of psychologists
      in the military and on deployment, the degree of professional isolation, and
      specific services provided by psychologists. Cultural similarities included the
      ambivalent response to the mental health field by military leaders, the use of
      psychology as a prevention tool, and the degree of interest in international
      contact and exchange. The discussion focuses on three obstacles to the acceptance
      of the mental health field and possible avenues for greater exchange of
      information among military professionals working in psychology-related fields.

PMID- 10578591
TI  - Impact of the Ottawa Ankle Rules in a U.S. Army troop medical clinic in South
      Korea.
AB  - The impact of the Ottawa Ankle Rules on radiograph-ordering behavior was
      assessed. Medical records and radiology reports for 80 consecutive patients who
      presented with the complaint of acute ankle pain were retrospectively reviewed
      for 18 variables. Twenty-two patients met the rules criteria and 45 did not.
      There were 10 fractures in the study group (N = 67), 3 of which were missed by
      the rules. All 3 fractures were 1-mm avulsion fractures of the fibula and are
      considered not clinically significant. Application of the Ottawa Ankle Rules by
      all clinic providers would have decreased the number of radiographs at our
      facility by 68%. The rules had sensitivity and specificity of 70% and 73%, and
      positive and negative predictive values of 31.8% and 93.3%, respectively.
      Providers at our facility did not routinely use the rules. Although the
      incorporation of these rules into our practice would have been significant, we
      recommend their use cautiously for a military population, which maintains a high
      intensity of physical training.

PMID- 10578592
TI  - Changing patterns of care for war-related post-traumatic stress disorder at
      Department of Veterans Affairs medical centers: the use of performance data to
      guide program development.
AB  - This study traces the development of services for war-related post-traumatic
      stress disorder (PTSD) provided at Department of Veterans Affairs (VA) medical
      centers. During the 1980s, long-stay inpatient programs were the major source of
      specialized VA treatment for PTSD, and an initial effort at development of
      specialized outpatient clinics resulted in incomplete implementation. In 1988, a
      full continuum of inpatient and outpatient services was designed and a national
      program of performance monitoring and outcome assessment was implemented to
      standardize program structure, monitor delivery, and evaluate outcomes. A series
      of multisite outcome studies showed significant but modest improvement in
      association with specialized outpatient treatment; they also showed that
      traditional long-term inpatient programs were no more effective and were far more
      costly than short-term specialized inpatient programs. Since 1995, the VA has
      shifted the emphasis of care substantially from inpatient to outpatient settings.
      National monitoring efforts have documented maintenance of specialized PTSD
      treatment capacity, increased access, improvement on available administrative
      measures of quality of care, and improved inpatient outcomes. Although there have
      been major changes in the treatment of mental illness in most health care systems
      in recent years, change in the treatment of PTSD at VA medical centers is unique
      in that it has been guided by the results of multisite outcome studies conducted
      in a "real-world" setting and has been supported by ongoing nationwide
      performance monitoring.

PMID- 10578593
TI  - Surgical treatment of 1,211 patients at the Vinkovci General Hospital, Vinkovci,
      Croatia, during the 1991-1992 Serbian offensive in east Slavonia.
AB  - The work of the Vinkovci General Hospital in the 1991-1992 war in Croatia is
      described. Because the hospital was only 400 m from the front line and the enemy
      shelled it incessantly (it is estimated that the hospital was hit by 5,000-7,000
      heavy artillery shells), the surgical services worked in the cellar. Between May
      1, 1991, and July 1, 1992, 1,211 patients were admitted and subsequently operated
      on. Of these, 51 died (4.3%), 12 of them on admission. Bullet wounds were found
      in 41 patients (3%), and 1,092 (90%) were wounded by shell explosions, 53 (4%) by
      mine explosions, and 25 (2%) contracted burns. Most of the patients were adults,
      but 50 children, half of them with serious wounds, were also treated. Almost two
      thirds of our patients were soldiers or policemen, and one-third were civilians.
      Four of the patients were prisoners of war. The proportions of heavy and light
      wounds among the soldiers and civilians were almost exactly 50%. At almost all
      sites, the ratio of penetrating to nonpenetrating injuries was rather high. With
      regard to wounds to the head, 38% of the wounds were penetrating. We operated on
      181 patients with thorax injuries, of which 80 were penetrating. A high
      proportion of the injuries were on the arms and legs, the latter accounting for
      more than 45% of all wounds. A relatively high proportion of traumatic
      amputations, as well as blast contusions and fractures, were attributable to the
      fact that most of the wounds were caused by explosions (90%). Their seriousness
      required a total of 70 surgical amputations on upper extremities and 156
      amputations on lower extremities. There were many more vessel injuries on lower
      extremities than on upper extremities. In our work, we applied the war medical
      doctrine used through-out the country, which essentially adhered to the NATO
      doctrine. The differences with NATO doctrine stemmed from the fact that Croatian
      military medicine emerged from civilian prewar medicine and worked fully
      integrated with it throughout the war. Yet, our results correspond to the results
      and experiences of other authors belonging to developed military medical
      services.

PMID- 10578594
TI  - Confederate Navy medicine.
AB  - The Confederate Navy's Office of Medicine and Surgery was a small organization
      within the Confederate Navy Department. The physicians, surgeon's stewards, and
      nurses provided medical care to sick and injured sailors from both sides of the
      conflict. The provision of health care often took place under trying
      circumstances, including shortages of medicines, money, and food. Members of the
      medical department served in all major and many minor naval engagements and
      worked long hours treating the wounded after battle. Many of the physicians
      served in the U.S. Navy before the Civil War. Their sacrifices and achievements
      are lost in the maelstrom of the larger conflict on land. This article is an
      effort to call attention to their story.

PMID- 10578595
TI  - Effects of a composite Indian herbal preparation on combat effectiveness in low
      intensity-conflict operations.
AB  - The efficacy of a composite Indian herbal preparation (CIHP) in sustaining the
      mental performance of soldiers engaged in prolonged low-intensity-conflict
      operations has been evaluated. For this purpose, a cohort of 56 soldiers acted as
      volunteers in combat situations. After recording their initial responses to
      psychological tests such as the d2 test, the trail-making test, the serial
      addition test, the short-term memory test, and the Institute for Personality and
      Ability Testing Anxiety Scale, they were randomly given either CIHP or placebo in
      a double-blind fashion for 8 days while they performed their usual combat duties.
      The final 3 days of assignments included physically exhausting and life
      threatening events. On day 8, they were withdrawn from combat duties and the
      psychological tests were readministered immediately. After 7 days of rest, the
      tests were repeated once again. The results indicate comparatively better
      performance immediately after the mission by the CIHP group. CIHP was effective
      at sustaining the mental abilities of soldiers in a low-intensity-conflict
      environment.

PMID- 10578596
TI  - Hypoxemia in young asthmatics with mild airway obstruction by methacholine
      challenge.
AB  - We studied 12 asymptomatic conscripts affected by bronchial asthma to evaluate
      the level of hypoxemia and its relationship with bronchial obstruction induced by
      methacholine (Mch) challenge. Arterial blood samples were obtained before and
      immediately after bronchial challenge. The range of decrease of forced expiratory
      volume/forced vital capacity x 100 in 1 second of expiration (FEV1), the absolute
      value reported as a percentage of the baseline value, after Mch challenge was
      from 21% to 36%. The mean decrease of arterial oxygen tension was 27 mm Hg (from
      11.4 to 39.8 mm Hg), the mean decrease of hemoglobin saturation was 3.53% (from
      0.4 to 7.2), and the mean increase of alveolar-arterial gradient for oxygen was
      28.2 mm Hg. We found a significant correlation between the prechallenge and
      postchallenge differences of arterial oxygen tension and FEV1 (DFEV1P), which was
      expressed as a percentage of the predicted value. In conclusion, the Mch
      challenge seems to be a safe test, and the decrease of arterial oxygen tension
      can be sufficiently predicted by DFEV1P.

PMID- 10578597
TI  - Influence of strict regulations on the use of hearing protectors in the Finnish
      Defence Forces.
AB  - The regulations concerning hearing protection during military training in the
      Finnish Defence Forces were renewed in 1989. The material of this prospective
      study concerns 912 consecutive conscripts (463 before and 449 after the new
      regulations) who were referred to the Central Military Hospital for acute
      acoustic trauma (AAT). We focused on three issues: (1) general habits regarding
      the use of hearing protection during shooting drills and combat training; (2)
      hearing protection at the moment of AAT; and (3) the cause of AAT. In combat
      training, the use of any hearing protectors was only 50% before the new
      regulations, but after they came into force the proportion was greater than 90%,
      and more effective protectors were used. However, at the time of AAT the hearing
      protection was absent in more than 80% of cases in both groups. The most common
      cause of AAT was small arms in both groups (83%).

PMID- 10578598
TI  - Irreducible dislocation of the knee.
AB  - Irreducible knee dislocation is a rare injury. This case report describes a knee
      dislocation in a 39-year-old male U.S. Army noncommissioned officer who was
      injured while playing in a softball game. Arthroscopy showed the medial
      collateral ligament and capsule to be locked in the intercondylar notch, covering
      the medial femoral condyle. Arthrotomy and open reduction were required. Staged
      posterior cruciate ligament reconstruction using patellar tendon autograft was
      later performed. Review of the magnetic resonance imaging scan showed the
      irreducible lesion. The diagnostic clinical and radiographic features of this
      unusual injury are described.

PMID- 10578599
TI  - Effort-related chronic compartment syndrome of the lower extremity.
AB  - Effort-related chronic compartment syndrome (ERCCS) of the lower extremity is
      often misdiagnosed, requiring repeated visits to the physician and subsequent
      delay in definitive treatment. The most significant causes of chronic leg pain in
      physically active individuals are stress fractures, shin splints, and "exercise
      induced" or effort-related chronic compartment syndrome. In patients susceptible
      to ERCCS, the fascial compartments are too small to accommodate the associated
      20% increase in muscle mass that typically occurs with heavy exercise. The
      increased pressure within a small unyielding compartment limits circulation and
      subsequent muscle function. The only appropriate conservative treatment is
      cessation of the offending activity. Early suspicion of the condition is
      paramount, because the definitive treatment is fasciotomy. ERCCS has only
      recently been recognized, and therefore it may be underdiagnosed. Family
      physicians and general medical officers caring for otherwise healthy soldiers and
      athletes should be aware of ERCCS so that prompt orthopedic referral for
      evaluation and definitive treatment will not be delayed.

PMID- 10578600
TI  - [Nutriceuticals].

PMID- 10578601
TI  - [The discovery of cerebral localization].

PMID- 10578602
TI  - [the epidemiology of HIV infection].
AB  - By the end of 1998, estimates indicate that 33.4 millions people were infected
      with Human Immunodeficiency Virus. Over two-thirds of these people live in Sub
      Saharian Africa, where HIV has mostly spread through sex between men and women.
      Today, the epidemic is spreading rapidly in the southern countries of Africa. One
      fifth of infected people live in South and South-East Asia, where the epidemic
      was identified from 1992, mostly in intra-venous drug injectors, sex workers and
      their clients. In Latin America (4% of infected people), men who have sex with
      men and drug injectors are the transmission categories mostly concerned.
      Countries of North America and western Europe concentrated 2.7% of infected
      people. HIV incidence is stable and AIDS cases in many industrialized countries
      are falling. AIDS is one of the ten first causes of death in the world; early
      testing and prevention should remain a high priority in all countries over the
      world.

PMID- 10578604
TI  - [Diagnosis and virologic monitoring of HIV infection].
AB  - The new challenge of the diagnosis of HIV infection concerns the treatment since
      an early diagnosis permits to start antiretroviral therapy with the aim to block
      the evolution to aids. The virological diagnosis may be done easily using new
      sensitive and specific techniques. Using the test of detection of p24 antigenemia
      and HIV-RNA in plasma, it is easy to approach the diagnosis of primary infection.
      The tests for HIV viral load are now largely available and they must be
      systematically included in the follow-up of infected persons.

PMID- 10578603
TI  - [Immunologic and viral mechanisms implicated in HIV infection: the impact of
      treatment].
AB  - HIV-infection leads to the destruction of the immune system, mainly of the
      subgroup of CD4 lymphocytes. The main cell surface receptor for the VIH is the
      CD4 molecule. However the virus can penetrate into the cell through the CCR5
      chemokine receptor that represents a new avenue for antiviral therapy. The early
      phase of HIV infection is characterised by an active viral replication mainly in
      lymph nodes. During the development of the infection, persistent viral
      replication leads to the destruction of CD4 lymphocytes and inhibits their
      turnover. Highly active antiretroviral therapy inhibits viral replication but can
      not eradicate the virus. However this treatment can efficiently restore immune
      function and allows to avoid opportunistic infections. Antiretroviral therapy
      could be associated with an immunotherapy (interleukin-2, therapeutic
      vaccination) in order to achieve a more satisfying T-cell specific response
      directed against the virus, which appears to be lost early in the course of the
      disease, except in the subgroup of patients with a low progression of the
      disease.

PMID- 10578605
TI  - [Primary HIV-1 infection].
AB  - Primary HIV-1 infection occurs soon after HIV contamination while the virus
      invades the organism. It can be accompanied by clinical signs, varying in
      duration and intensity. The understanding of the pathophysiology of primary
      infection has considerably improved since a few years with the study of
      immunological and virological markers. Dramatic changes in prognosis could soon
      happen with the advent of new molecules and (or) new regimens.

PMID- 10578606
TI  - [Pregnancy and HIV].
AB  - The issues raised have evolved over the last few years. The rate of mother-to
      child transmission has decreased, mostly as a consequence of antiretroviral
      therapies. However, these drugs can have toxicity such as mitochondrial diseases
      in the infant, whose incidence and long term consequences are still unknown. The
      choice of therapy should be based on an estimate of benefit on risk on a case-to
      case basis. If the patient requires an effective antiretroviral combination, it
      should not be withheld because of the pregnancy. If the mother does not require
      therapy for her own health, prevention of vertical transmission is based on
      zidovudine monotherapy beginning in the third trimester, which is most effective
      when combined with elective caesarean delivery. Interdisciplinary care must
      include clear information in a climate of dialogue with the mother.

PMID- 10578607
TI  - [Anti-HIV drugs].
AB  - Anti-HIV drugs act by blocking intracellular replication of the virus by
      inhibiting viral enzyme either reverse transcriptase or protease. Reverse
      transcriptase inhibitors belong to 3 different categories: nucleoside analogues,
      which active forms are the triphosphorylated intracellular compound, non
      nucleoside inhibitors and the more recent nucleotide analogues. Protease
      inhibitors are very active in vitro but besides their digestive side effects,
      have numerous drug interactions because they are metabolised through P450 liver
      cytochromes, and are associated with long-term toxicity.

PMID- 10578609
TI  - [The chronicity of HIV infection].
AB  - The widespread use of highly active antiretroviral therapy led to a substantial
      decrease of HIV related-morbidity and mortality in industrialized countries.
      These recent advances allow to envisage a chronicity of HIV infection and led HIV
      infected people to set up a familial or professional life-project, difficult to
      imagine until now. The increase in life-expectancy is nevertheless closely
      dependent on the prolonged adherence of the patients to therapy, which justifies
      the development of strategies to increase medication compliance. The side-effects
      of long-term taken drugs often impair the quality of life of HIV infected people:
      abnormal fat distribution and atherogen hyperlipidemia and insulin resistance,
      mainly described with protease inhibitors, are new worrying concerns. Chronicity
      of HIV infection favours also the development of co-morbidity (HIV-HCV co
      infection). The necessity of a more global and varied case management of people
      living with HIV is emerging simultaneously with a new dynamic of clinical
      research whose ultimal goal still remains the achievement of HIV eradication
      strategies.

PMID- 10578608
TI  - [Treatment strategies and surveillance of chronic HIV infection in adults].
AB  - An improved knowledge of HIV disease pathogenesis, the availability of viral load
      determination and the increasing numbers of available agents have led to major
      advances in the field of antiretroviral therapy. Antiviral therapy has to be
      potent while allowing patient adherence to complex regimens and minimizing long
      term toxicity. Beyond highly active antiretroviral therapy combining two
      nucleosides and a protease inhibitor, other triple-drug combinations have been
      validated or are under study. Therapeutic strategy in case of virological failure
      depends on the choice of the initial combination option, due to the cross
      resistance between drugs from the same class. Viral sensitivity testing on one
      hand, and adjunctive immunotherapy on the other hand, are two interesting
      perspectives that may improve the management of HIV-infected patients.

PMID- 10578610
TI  - [The curriculum of medical studies].

PMID- 10578611
TI  - [Ankylosing spondylitis. Etiology, diagnosis, prognosis, principles of
      treatment].

PMID- 10578612
TI  - [Interpretation of epidemiologic studies. Type of study, elements of bias,
      causality].

PMID- 10578613
TI  - [Acute adrenal insufficiency in adults. Etiology, diagnosis, prevention,
      management in an urgent situation with drug posology].

PMID- 10578614
TI  - [Lengthening of the kaolin or activated cephalin time (KCT, ACT), Quick's time,
      bleeding time. Diagnostic direction].

PMID- 10578615
TI  - [Calcium inhibitors, nitrate derivatives. Principles and indications of use].

PMID- 10578616
TI  - [Autism in children. Diagnosis].

PMID- 10578617
TI  - Is it good medicine?

PMID- 10578618
TI  - Hospitalist programs are acceptable if they are voluntary.

PMID- 10578619
TI  - MedBytes.

PMID- 10578620
TI  - TMA at the table.

PMID- 10578621
TI  - Back to the border.

PMID- 10578622
TI  - Mercy missions.

PMID- 10578623
TI  - New waiting game rules.

PMID- 10578624
TI  - Taking the last train.

PMID- 10578625
TI  - Life-and-death decisions.

PMID- 10578626
TI  - A practice-based rural health fellowship: an innovative approach to support for
      rural care.
AB  - Efforts to support recruitment and retention of rural providers have sometimes
      included local postgraduate training. An innovative approach that includes
      training fellows entirely in a rural area with most of the costs supported
      locally was found to be cost-effective and to produce the expected positive
      effects. Training goals and objectives were accomplished in the areas of rural
      health and advanced maternity care, and the community gained an experienced
      provider as well as a new continuing education activity. This model may be
      applicable to many rural sites that have adequate clinical volume, experienced
      and motivated local faculty, and connection to a supportive regional medical
      center.

PMID- 10578627
TI  - Reversing the tide: emerging options for treating overactive bladder symptoms in
      women.
AB  - The symptom complex of urinary urgency, frequency, nocturia, and urge
      incontinence, also known as the "overactive bladder" syndrome, affects the lives
      of millions of American women. As the symptoms are nonspecific, several different
      etiologies may be responsible. In many women, however, no discernible source can
      be identified. If a basic evaluation, including history, physical examination,
      urinalysis, and postvoid residual determination, fails to identify a source for
      the complaints, empiric treatment with behavioral intervention or a trial of
      medication may be offered to control symptoms. Certain patients will require a
      more detailed evaluation, particularly if conservative measures fail to provide
      relief. The role of advanced diagnostic strategies and the emergence of new
      treatment modalities are discussed.

PMID- 10578628
TI  - HIV tests in developing world communities.

PMID- 10578629
TI  - Community-informed consent for HIV testing and a continuum of confidentiality.

PMID- 10578630
TI  - Human rabies in India: epidemiological features, management and current methods
      of prevention.
AB  - In most endemic countries stray dogs are the main source of rabies infection in
      humans. In India 95-97% of rabies patients are infected by dogs. Most pet dogs do
      not regularly receive booster doses of vaccine. In Thailand, most rabies patients
      develop the disease within 1 month of exposure. Rabies immunoglobulin is costly
      and usually not available. So in India nervous tissue vaccine is commonly used-
      it is inexpensive and freely available despite frequent neurological
      complications. The cost of immunization by tissue culture vaccines may be reduced
      by nearly 60% by intradermal vaccination.

PMID- 10578631
TI  - Neonatal discharge and follow up.
AB  - Increased intensive care for low birth weight and premature infants has made it
      essential to establish a well-organized plan for neonatal discharge and follow
      up. The preventive medical goal is improved care and outcome and in this article
      the organization of such a plan is discussed.

PMID- 10578633
TI  - Establishing and monitoring a control programme to reduce the impact of eye
      disease in sub-Saharan Africa.

PMID- 10578632
TI  - A clinical and histopathological study of macular type of post-kala-azar dermal
      leishmaniasis.
AB  - Post-kala-azar dermal leishmaniasis (PKDL) is an uncommon sequel seen in patients
      with a previous attack of kala-azar (KA). It is characterized by hypopigmented
      macules and erythematous eruptions leading to the formation of papules, plaques
      and nodules. Little attention has been paid to the rare group of patients who
      present with only hypopigmented macules. The present study has described the
      distribution of lesions in macular PKDL and their histopathology.

PMID- 10578634
TI  - Remote village survey for agents causing hepatosplenic disease in the Republic of
      Yemen.
AB  - The objective of this study was to epidemiologically describe potential
      infectious agents among rural people in the Republic of Yemen. This would aid
      clinicians in designing empirical therapy and public health officials in planning
      disease prevention. We sought to examine evidence for the geographical
      distribution of pathogens causing human hepatic and splenic disease among
      villagers and domestic animals living in three remote areas with differing
      altitudes. In June 1992, a cross-sectional survey was conducted at three survey
      sites of differing altitudes: 3080, 1440 and 250 m above sea level.
      Questionnaires, parasitic and serological tests were administered to 627 human
      volunteers. Additionally 317 domestic animals were studied. Malaria,
      schistosomiasis, and hepatitis B and C infections were found to be likely causes
      of human hepatic or splenic disease. Additionally, evidence of human and animal
      infections with the agents of brucellosis and Q fever was found: IgG antibodies
      against hepatitis E virus were discovered in two (2.0%) of the 100 volunteers.
      The prevalence of markers for human and animal disease was often lowest at the
      village of highest elevation, suggesting that increasing altitude, as a surrogate
      or a true independent risk factor, was protective against infection with the
      agents studied.

PMID- 10578635
TI  - Accuracy of chest radiograph diagnosis for smear-negative pulmonary tuberculosis
      suspects by hospital clinical staff in Malawi.

PMID- 10578636
TI  - A nutritional profile of non-pregnant women from the slums of Dinajpur,
      Bangladesh.
AB  - The health and nutritional status of many urban slum dwellers in the developing
      world is said to be deteriorating. The nutritional profile of 328 adult, non
      pregnant women from the slums of Dinajpur, Bangladesh, confirms this. Results of
      a cross-sectional survey showed that approximately half the women were acutely
      malnourished and all but six were anaemic. This, despite the fact that the slums
      of Dinajpur are considered relatively 'better-off' than many in the developing
      world; most families having permanent land tenureship, and access to basic
      education and health services.

PMID- 10578637
TI  - Drastic performance improvement of hand-operated sterilizers.
AB  - In a great number of low-income countries, hand-operated sterilizers are commonly
      used for the sterilization of medical supplies, including porous loads and hollow
      instruments. Due to the socio-economic situation in these countries the
      introduction of fully automatic sterilizers is not (yet) feasible. During a
      course on sterilization technology for hospital technicians at the Polytechnic in
      Mombasa, Kenya, some performance tests have been done with locally used
      sterilizers with standard test loads and loads as are common in the hospitals
      that were visited. The results for porous loads were alarming due to poor air
      removal. Immediately, a number of modifications in the processes were made and
      tested, based on a method of steam pulsing. This resulted in a significant
      improvement of performance and can be introduced at a very low cost.

PMID- 10578638
TI  - Iron status of pregnant women at first antenatal booking in Mbarara University
      Teaching Hospital.
AB  - An assessment of iron status was made on 96 pregnant women and 29 non-pregnant,
      non-lactating menstruating women of comparable age group as controls. Anaemia
      (haemoglobin < 110 g/l) was present in 84.4% of the pregnant women and in 48.3%
      of the control group. Iron deficiency (serum ferritin < 12.0 micrograms/l) was
      present in 51.1% of the pregnant group and 37.9% of the control group. Prevalence
      of anaemia with iron deficiency was 54.7% in anaemic pregnant women. Serum
      ferritin correlated significantly with low haemoglobin (P < 0.05). Median serum
      ferritin declined progressively until 31 weeks of gestation. Preliminary studies
      on their dietetics showed that low animal protein consumption and poor dietary
      iron bioavailability were associated with anaemia.

PMID- 10578639
TI  - Improvised equipment for indwelling suprapubic bladder catheterization.

PMID- 10578640
TI  - Otorrhoea: a management protocol for a tropical doctor.
AB  - Ear discharge is a common symptom encountered in clinical practice in the
      tropics. The aim of this paper is to highlight the practical management of
      otorrhoea from a general practitioner's perspective with special reference to the
      tropics and developing countries.

PMID- 10578641
TI  - Neural tube defects.

PMID- 10578642
TI  - Managing gastrointestinal parasite infections in AIDS.

PMID- 10578643
TI  - Orogastric versus nasogastric feeding of newborn babies.
AB  - Oxygen saturations were compared, 10 min before and 10, 20 and 30 min after
      orogastric and nasogastric feeds, in 10 stable newborns. The mean saturations
      were significantly lower with mere passage of nasogastric tube and continued to
      be so during feeds. There was no difficulty in securing the orogastric tube and
      no baby aspirated milk.

PMID- 10578644
TI  - Monitoring rifampicin compliance by visual inspection of urine colour.

PMID- 10578645
TI  - Traditional herbal preparations and acute renal failure in south west Nigeria.
AB  - Fifty-three cases (36 men; mean age 30.2 +/- 9.5 years) of acute renal failure
      (ARF) in which traditional herbal ARF could have been prevented by proper
      education and awareness.

PMID- 10578646
TI  - Violence suffered by psychotic patients seen at a rural hospital in northeast
      Zaire.

PMID- 10578647
TI  - 27 symphysiotomies.

PMID- 10578648
TI  - Unusual tubercular abscesses in two elderly women.

PMID- 10578649
TI  - Subconjunctival and intraocular cysticercosis in Nepal.

PMID- 10578650
TI  - Technique of vaginal delivery of a dead fetus in transverse lie with hand
      prolapse.

PMID- 10578651
TI  - Measurement of resting metabolic rate in Egyptian males.

PMID- 10578652
TI  - [Genetic technologies in medicine].

PMID- 10578653
TI  - [New and special technologies in medical radiology and radiation medicine].

PMID- 10578654
TI  - [Stages of development and some problems of current intensive care for critical
      conditions].

PMID- 10578655
TI  - [Strategy of search for artificial blood substitutes].

PMID- 10578656
TI  - [New principles and methods of designing immunobiological agents].

PMID- 10578657
TI  - [Interferon: psychotropic, anti-stress and anti-nociceptive effects].

PMID- 10578658
TI  - [New medical technologies by using biocompatible super-elastic materials and
      implants with shape memory].

PMID- 10578659
TI  - [Experience with interdepartmental integration in development and introduction of
      new medical technologies].

PMID- 10578660
TI  - [Virtual reality technology and physiological functions].

PMID- 10578661
TI  - [Russian collection of hybridomas].

PMID- 10578662
TI  - [Functional organization and mechanisms of human intrinsic regulation of natural
      cytotoxicity system].
AB  - The paper gives a detailed account of the specific features and mechanisms of
      natural cytotoxicity (NCT) reactions in health and in disease. The assumption
      that the system autonomically functions has been substantiated and experimentally
      verified. There is evidence for that it is able to self regulate and to be
      controlled by endogenous or exogenous factors. If there is a biological
      expediency for NCT to be limited, which would prevented the intrinsic unchanged
      cells from lesions when they interact with the system's activated cells is first
      discussed. It has been found that there are three organizational levels of the
      mechanisms that rationally limit NCT. These include intra-systemic, extra
      systemic endogenous and exogenous. The theoretical result of the studies is a
      basically new methodology of fundamental developments in the area of
      immunobiological surveillance. It assumes that environmental microbial factors
      have a limiting rather inducing influence on NCT, which prevents intact cells
      from lesions in cytotoxic reactions.

PMID- 10578663
TI  - [Molecular analysis of hereditary nervous system diseases].
AB  - The molecular genetic basis of a large group of monogenic hereditary neurological
      diseases is analyzed. Emphasis is laid on different types of mutations causing
      Huntington's chorea, autosomal dominant ataxias, Friedreich's disease, dopa
      responsive and nondopa-responsive forms of torsion dystonia: the frequencies of
      these mutations and their molecular characteristics have been first investigated
      in the Russian population. Relationships between particular genotypes and various
      clinical variants of these disorders are analyzed. Genetic loci for two novel
      hereditary diseases of the nervous system, such as X-linked congenital cerebellar
      hypoplasia and an atypical form of autosomal recessive muscular dystrophy are
      characterized. Nosological entities of these clinical forms are substantiated in
      accordance with molecular genetic findings. DNA diagnostic techniques have been
      developed, which allows medical genetic counselling and prevention of relapses to
      be made in genetically burden families.

PMID- 10578664
TI  - [Monoamine oxidase, tribulin, isatin: basic and applied medical aspects].
AB  - Monoamine oxidase (MAO) catalyzes the biological degradation of the
      neurotransmitters monoamines. The altered substrate specificity of MAO may be of
      pathogenic importance in some cases and MAO inhibitors showed a therapeutical
      effect in the experimental setting. Analyzing the efficacy of various compounds
      in inhibiting MAO A and B revealed new approaches to designing new-generation MAO
      inhibitors. Tribulin is a fraction of endogenous MAO inhibitors that are present
      in human and animal tissues and biological fluids. Isatin is an endogenous indole
      which was initially derived from a tribulin fraction. An investigation of the
      biological properties of tribulin revealed its heterogeneity and some chemical
      components were identified. It was shown that deficiency of tribulin components
      that selectively inhibited MAO A long with a larger number of molecules of this
      enzyme might be of great importance for the development of alcoholism. In
      addition to MAO inhibition, the physiological concentrations of isatin inhibited
      the receptor-binding of atrial natriuretic peptides and ANP-stimulated guanylate
      cyclase (GC). The sensitivity of ANP-GC to isatin might be allosterically
      regulated. Selective antagonists of natriuretic peptide receptors were found
      among isatin analogues which may be an effective pharmacological tool for further
      studies of the role of natriuretic peptides in the body.

PMID- 10578665
TI  - [Views on development of immunology in the first half of 21-st century].

PMID- 10578666
TI  - [Atherosclerosis as a problem of general biology: cell adaptation to deficiency
      of essential fatty acids].
AB  - It is suggested that intracellular deficiency of polyenic fatty acids (FA) is the
      biochemical basis of atherosclerosis. Its cause in the presence of abundant blood
      polyenic FA as cholesterol esters (cholesterol-esterified polyenic FA) is
      blockade of apoB-100-receptor endocytosis. The occurrence of polyenic FA
      deficiency in phylo- and ontogenesis and the cell adaptation reactions which
      accomplish the cell transfer and receptor absorption of polyenic FA are
      considered. The pathogenesis of atherosclerosis is a long-term adaptation to
      deficient cellular essential FA. At the same time the cells form a plasma
      membrane, synthesize thromboxanes, prostaglandins, and leukotrienes from omega-9
      dihomo-Y-linolenic FA rather than from essential omega-6-arachidonic and omega-3
      eicosapentaenic acids. This adaptation process determines all metabolic
      disturbances which are peculiar to atherosclerosis.

PMID- 10578667
TI  - Storm warnings over Oregon.

PMID- 10578668
TI  - Graduate medical education should not be overtaken by managed care.

PMID- 10578669
TI  - Terminal sedation for intractable distress.

PMID- 10578670
TI  - The future of hospice.

PMID- 10578671
TI  - Hospital staff do not know how much drugs cost.

PMID- 10578672
TI  - Traditional case reports still have a role.

PMID- 10578673
TI  - Demonstrated benefit of glucocorticoids does not mean prednisone is beneficial in
      the routine office setting.

PMID- 10578674
TI  - Pharmaceutical advertising revenue and physician organizations: how much is too
      much?
AB  - OBJECTIVE: To determine if revenue generated from pharmaceutical advertisements
      in medical journals creates potential financial conflicts of interest for
      nonprofit physician organizations that own those journals. DESIGN: Convenience
      sample of six professional medical societies and their respective journals.
      Calculation of pharmaceutical advertising revenue generated by these journals for
      their respective professional medical societies. METHODS: Random selection of
      each journal for one month per quarter in calendar year 1996 and tabulation per
      edition of the average number of pharmaceutical advertising pages for each
      journal. OUTCOME MEASURES: Published advertising rates were used to estimate
      pharmaceutical advertising revenue for calendar year 1996 and compared with each
      organization's gross revenue and membership dues and assessments, based on
      Internal Revenue Service documents for the last available fiscal year (1995).
      RESULTS: Estimated pharmaceutical advertising revenue ranged from $715,000 to
      $18,630,000. Five organizations raised more than 10% of their gross income (range
      2% to 30%) from a single journal's pharmaceutical advertising. Four organizations
      raised as much or more from pharmaceutical advertising as from members (range 17%
      to 790%). CONCLUSIONS: Potential financial conflicts of interest arising from
      pharmaceutical advertisements in medical journals may be substantial. The impact
      on professional societies' financial independence and behavior is unknown.

PMID- 10578675
TI  - Don't bite the hand that feeds you.

PMID- 10578676
TI  - Cognitive behavioral group therapy and phenelzine both effective in social
      phobia.

PMID- 10578677
TI  - Befriending can lead to remission in women with chronic depression.

PMID- 10578678
TI  - How do Oregon psychologists view their role in physician-assisted suicide?

PMID- 10578679
TI  - Osteoma cutis (cutaneous ossification).

PMID- 10578680
TI  - Care of dying patients: beyond symptom management.

PMID- 10578681
TI  - Just say yes: the use of opioids for managing pain at the end of life.

PMID- 10578682
TI  - Beyond breaking bad news: how to help patients who suffer.

PMID- 10578683
TI  - Pattern recognition--shades of red.

PMID- 10578684
TI  - Dutch euthanasia: could it happen here?

PMID- 10578685
TI  - The historical feud over polio vaccine: how could a killed vaccine contain a
      natural disease?

PMID- 10578686
TI  - Academic health centers: a future of struggles and new identities.

PMID- 10578687
TI  - A dying patient: shared intimacies and some questions about physician-assisted
      suicide.

PMID- 10578688
TI  - Debates on physician-assisted suicide are a barrier to real reforms in caring for
      patients.

PMID- 10578689
TI  - [Everybody talks about allergy, but who is doing anything against it?].

PMID- 10578690
TI  - [A reference program for children with urinary tract infection. A proposal for
      diagnosis and treatment of children with urinary tract infection].

PMID- 10578691
TI  - [Apoptosis--programmed cell death].
AB  - The health of multicellular organisms depends not only on the body's ability to
      produce new cells but also on controlled cell death. Apoptosis, or programmed
      cell death, is the opposite of mitosis. It is an active process for destruction
      of unwanted and superfluous cells. Changes in cell survival contribute to the
      pathogenesis of such varied disorders as cancer, many viral infections,
      neuropathies and immunopathies. The growing understanding of apoptosis forms the
      basis for development of new therapeutic strategies controlling cell death. This
      article describes mechanisms involved in the programmed cellular suicide.

PMID- 10578692
TI  - [Making ill and "medicalization". An attempt to clarify the concepts based on
      literature study].
AB  - In Denmark, "medicalization" and "making ill" are words that are used at random.
      The first describes a process where normal reactions and parts of life are
      defined as medical problems and are subsequently dealt with by the health care
      system. The second word is used in Nordic languages to describe the process of a
      healthy person being given the feeling of being ill, e.g. as a result of a
      screening. In the health care debate in Denmark you often find that doctors,
      researchers and lay people use the words "medicalization" and "making ill" in
      different ways. The purpose of this paper is to clarify and define these
      concepts. Based on the literature, different definitions and use of the words are
      examined. A definition is suggested, and it is argued, that "medicalization" and
      "making ill" are not synonymous, but that "making ill" is a result of
      "medicalization". The most notable difference is that "medicalization" is a
      process going on in the society, whereas "making ill" is a process affecting the
      individual.

PMID- 10578693
TI  - [Use of new materials results in improved prostheses. Metals, polymers, ceramics
      and composite materials extend durability].
AB  - Advances in our knowledge of multifactorial host-biomaterial interactions have
      improved the outcome of joint replacement surgery. Fixation and aseptic loosening
      are the principal foci of research. Wear debris from articulating parts is a
      major cause of prosthetic loosening. Tri-biological analysis, and the development
      of new materials and surface finishes have reduced wear particle production. The
      use of modular implants increases flexibility and facilitates surgical fit, but
      also introduces new problems such as dissociation of components, corrosion and
      wear. In the future, as design, biomaterials and surgical technique become
      further optimized, arthroplasty may also become an alternative for use in younger
      patients.

PMID- 10578694
TI  - [Self-assessment of clinical skills among medical trainees when entering
      internship during the spring seasons 1998].
AB  - The aim of this study is to identify medical trainees' level of self-reported
      clinical skills when entering internship. A questionnaire was sent to 124
      trainees, who were about to enter their internship. The questionnaire included 88
      questions on clinical skills, asking the trainees to rate their level of
      mastership on a Visual Analogue Scale from zero to ten, 0 = not mastering and 10
      = mastering. In total one hundred (81%) returned the questionnaire. There is
      considerable variation in the self reported acquisition of clinical skills in
      many of the procedures. In some basic procedures most trainees showed a rather
      high level of mastership, above 7.5, but in other basic procedures about half of
      the candidates report a level of mastership below 5.0. A more thorough
      specification of objectives for practical skills would make it easier to plan an
      effective and efficient training during internship.

PMID- 10578695
TI  - [Mineralocorticoid-like hypertension. "Apparent mineralocorticoid excess". A
      hereditary type of hypertension?].
AB  - The syndrome of apparent mineralocorticoid excess is a form of hypertension
      inherited in an autosomal recessive manner. It results from mutations in the gene
      encoding the kidney isoenzyme of 11 beta-hydroxysteroid dehydrogenase. A number
      of different mutations have been described. Affected patients present with
      hypertension, hypokalemia and low levels of plasma renin and aldosterone. The
      severity of cases vary according to the degree of reduced activity of the enzyme.
      Treatment with potassium-sparing diuretics is effective. Four young adults with
      moderate hypertension are presented. They all had hypokalemia, low renin and low
      aldosterone. The THF + allo-THF/THE ratio was normal or slightly elevated.
      Treatment with amiloride was effective. They are suspected to be mild cases of
      the syndrome of apparent mineralocorticoid excess.

PMID- 10578696
TI  - [Injuries of bus passengers in an area of Copenhagen].
AB  - Medical records from the emergency rooms in an area of Copenhagen with 250,000
      inhabitants were collected. Accidents in buses were counted and the injuries
      graded according to ISS. Over three months 37 casualties were found ranging in
      age from two to 94 years old. About half the accidents happened because of
      braking and about one-third happened when boarding or alighting, primarily among
      the elderly. The injuries were graded from ISS 1 to 18 with three injuries graded
      higher than 11. Of all the casualties, 17 had the treatment concluded in the
      emergency department, while 12 had to be admitted to hospital. Eight had
      ambulatory treatment afterwards. Comparing our results with other investigations
      made in Denmark and abroad we found a higher incidence of casualties. We found
      about three times as many accidents per inhabitant as in Odense and far more
      accidents per driven kilometre than an English investigation. In conclusion, more
      seats in the buses, precautions when braking and a less tight time schedule in
      order to allow enough time for passengers to get on and off could be recommended.

PMID- 10578698
TI  - [C1q deficiency in systemic lupus erythematosus].

PMID- 10578697
TI  - [Adenoma of the nipples. A rare, but essential differential diagnosis].
AB  - A case is presented, where a 52 year-old woman with a two month history of nipple
      discharge was diagnosed with adenoma of the nipple. A total excision of the
      nipple was performed. Adenoma of the nipple is a rare, but benign condition,
      which clinically can be confused with Paget's disease of the nipple, intraductal
      papilloma and adenocarcinoma of the breast. Complete excision of the nipple is an
      adequate treatment of this condition.

PMID- 10578699
TI  - [A prestigious European award to a Danish urologist].

PMID- 10578701
TI  - [Research in Denmark].

PMID- 10578700
TI  - [Clinical forensic medicine].

PMID- 10578702
TI  - [About "Literature searching"].

PMID- 10578704
TI  - Kidney transplantation: state of the art.
AB  - Despite ever-improving health care and new advances in medical technology, the
      number of Americans who develop end-stage renal disease continues to increase.
      Diabetes remains the leading cause of new cases, followed by hypertension and
      glomerulonephritis. More than 200,000 patients require dialysis and more than
      40,000 are awaiting kidneys for transplantation. Kidney transplantation has been
      extremely successful with 1-year patient and graft survival rates at 95% and 90%,
      respectively. The advantages of kidney transplantation are reversal of many of
      the pathophysiologic changes associated with renal failure as normal kidney
      function is restored, elimination of dependence on dialysis and the associated
      dietary restrictions, the opportunity to return to normal life activities, and
      lower medical costs than dialysis after the first year. The shortage of donor
      kidneys is the major limiting factor. Because of the supply and demand
      discrepancy, maximum use of donors from all sources, appropriate recipient
      selection, and equitable allocation are critical.

PMID- 10578703
TI  - [Antimicrobial effects of anesthetics and analgesics].
AB  - Drugs, not designed as antibiotics, and whose primary mode of action is
      modulation of active and passive ionic transport-mechanisms in the eucaryotic
      cell, also act on procaryotic cell-walls, and the action is antimicrobial. The
      drugs may be classified, non-antibiotics. Anaesthetic gases are bactericidal in
      the fluid state, and in the vaporous state at high concentrations. Local
      anaesthetics of the ester type have stronger antimicrobial actions than the
      amidetype, and synergy is found between local anaesthetics and antibiotics.
      Barbiturates show antimicrobial action at high concentrations, and there is a
      possible synergy with antibiotics. Synthetic analogs of morphine have stronger
      antimicrobial action than the natural derivatives. Aspirin (ASA) inhibits the
      growth of Klebsiella pneumoniae at concentrations within the range of that in
      plasma in normal clinical usage; but induces non-genetical resistance to
      antibiotics. Increasing problems of bacterial resistance to common antibiotics
      might render non-antibiotics subject to development into antibiotics, and to be
      utilized in combination treatment of resistant infectious diseases.

PMID- 10578705
TI  - The current state of pancreas transplantation.
AB  - The first pancreas transplant in 1966 demonstrated that a pancreas allograft
      could reestablish euglycemia independent of exogenous insulin in patients with
      type 1 diabetes mellitus. Early outcomes were poor, and application of the
      procedure was limited. In the 1980s, innovations in immunosuppression therapy and
      surgical management of pancreatic exocrine secretions combined with careful
      candidate selection resulted in dramatic improvements in patient and graft
      survival. In the 1990s, the incorporation of additional new anti-rejection agents
      into immunosuppression protocols resulted in a further decrease in the incidence
      of acute rejection, affording more freedom in surgical management of exocrine
      drainage. The vision for the future of transplantation for the treatment of
      diabetes is focused on the percutaneous infusion of pancreatic islets, thus
      eliminating the need for surgical revascularization of a pancreas allograft, yet
      reestablishing regulation of glucose metabolism.

PMID- 10578706
TI  - An overview of liver transplantation.
AB  - Liver transplantation has evolved into an accepted therapy for those with end
      stage liver disease. Since the late 1960s when Dr. Thomas Starzl pioneered the
      first successful human liver transplantation, it has become a surgical specialty
      requiring a multidisciplinary approach. Currently, more than 11,000 patients are
      awaiting liver transplantation. The donor shortage has led to development of
      techniques for reduction in size of liver grafts, split liver grafts, and living
      related grafts. Despite these developments, more than 1,000 patients died in 1997
      while awaiting transplantation. The increasing demand has led to maximal use of
      potential organ donors. The complexity of problems and complications that arise
      during the waiting period and after the transplantation require continued and
      diligent care. The nurse is an integral part of the transplantation team and can
      provide ongoing assessment and education throughout the transplantation process
      to facilitate the patient's return to an independent lifestyle.

PMID- 10578707
TI  - Heart transplantation: state of the art.
AB  - Outcomes in cardiac transplantation have improved during the past 30 years
      because of advances made in medicine and surgery. Patients referred for cardiac
      transplantation are examined through a rigorous evaluation process that involves
      a multidisciplinary approach to determine candidacy. The list for candidates
      awaiting transplantation has grown more rapidly than the donor pool, resulting in
      a need to expand the criteria for donors. Some centers now extend criteria to
      include older donors, those with prolonged periods of ischemia, donor-recipient
      mismatches, and donors requiring bypass surgery. Long-term outcomes from the
      expanded donor pool are under evaluation. Studies are currently in progress to
      explore inducing tolerance through bone marrow infusion and rejection detection
      with the use of a pacemaker. Future alternatives to transplantation include the
      left ventricular assist device as a bridge to recovery, xenotransplantation, and
      the totally artificial heart.

PMID- 10578708
TI  - The state of pediatric heart transplantation.
AB  - Heart transplantation is now an accepted method for treatment of heart disease in
      children, but transplantation in pediatric recipients continues to present unique
      challenges. The differences in indications and the complexity of surgery for
      congenital heart disease are only two of those challenges. A successful means of
      mechanical support is not available, which puts children at special risk of dying
      while waiting for transplantation. In addition, physiologic differences produce
      issues about management after transplantation, including use of immunosuppressive
      agents, control of infection, identification of transplant coronary artery
      disease, and posttransplant lymphoproliferative disease. Because of the longer
      life expectancy desired from pediatric transplantation, measurement of quality of
      life must be more comprehensive. This broad range of special demands means that
      although the state of pediatric heart transplantation is positive, there are
      areas for continued improvement.

PMID- 10578709
TI  - The ventricular assist device as a bridge to cardiac transplantation.
AB  - Congestive heart failure is occurring in the United States at an increasing rate.
      Transplantation remains the treatment of choice for end-stage heart failure.
      Prolonged waiting time and decreased availability of suitable organs has
      increased the necessity for a device to act as a bridge to transplantation to
      keep patients alive during the waiting period. Ventricular assist devices have
      become an accepted and proven option for patients whose condition deteriorates to
      the point that waiting for an available donor organ is a mortal risk. With proper
      patient selection and timely device insertion, these patients can remain stable
      until a donor organ becomes available.

PMID- 10578710
TI  - The current status of lung transplantation: a nursing perspective.
AB  - Since the first lung transplantation was attempted in 1963, the use of the
      procedure has gradually increased. The first successful operation was performed
      in 1983, and during the past decade the number of lung transplantations and heart
      lung transplantations has increased rapidly, with 75% of recipients surviving
      past the first year. Chronic rejection is the greatest obstacle to long-term
      survival. In this article, a brief history of lung transplantation is provided.
      Recipient selection criteria are reviewed, together with the listing process and
      donor organ criteria. Recommendations for care of patients before and after lung
      transplantation are outlined, with a description of the postoperative course,
      including complications, pain control, rehabilitation, discharge procedures, and
      outpatient treatment.

PMID- 10578711
TI  - Indications, evaluations, and postoperative care of the combined liver-heart
      transplant recipient.
AB  - Multiorgan transplantation is now possible because of improvements in
      immunosuppression and surgical techniques. Combined liver-heart transplantation
      (CLHT) is a new option with initial 1-year data reporting 80% 1-year survival
      rates. Organs transplanted with the liver appear to have less allograft
      rejection. Within the United States, fifteen CLHTs have been performed. Three
      CLHTs have been performed at the University of Chicago and are discussed in this
      article. Guidelines for evaluation and listing criteria for CLHT recipients have
      not been established in the medical community. Postoperative care of this patient
      group is demanding and requires a thorough understanding of multiorgan
      pathophysiology, management of high-incidence acute renal dysfunction, tight
      intravascular volume regulation, and an experienced multidisciplinary approach to
      care.

PMID- 10578712
TI  - Overview of transplantation immunology and the pharmacotherapy of adult solid
      organ transplant recipients: focus on immunosuppression.
AB  - A review of transplantation immunology is discussed with emphasis on alloantigen
      presentation, T-lymphocyte activation and proliferation, and the immune effector
      mechanisms responsible for allograft rejection. Immunosuppressive pharmacology is
      introduced beginning with conventional medications (cyclosporine, azathioprine,
      and corticosteroids) followed by a discussion of drugs recently approved by the
      US Food and Drug Administration (mycophenolate mofetil, tacrolimus, and the
      interleukin-2 receptor antagonists). In addition, drugs that are used in the
      treatment of transplant rejection or as rescue therapy are discussed (muromonab
      CD3, antithymocyte globulin, mycophenolate mofetil, tacrolimus, and
      corticosteroids). Throughout, implications for nurses involved in the
      pharmacotherapy of transplant recipients are discussed.

PMID- 10578713
TI  - Development of a renal transplant clinical pathway: one hospital's journey.
AB  - Mounting pressures to resolve multiple challenges related to quality, cost, and
      access in a resource-driven, customer-focused health care environment have
      compelled clinicians to develop innovative strategies to provide cost-effective,
      state-of-the-art care. Targeted patient groups include those associated with high
      cost, high volume, or high resource use. Patients undergoing renal
      transplantation fall into one or more of these categories. Recently, the
      management of patients with end-stage renal disease (ESRD) has come under
      national focus, as evidenced by the fact that Health Care Financing
      Administration (HCFA) has commissioned an ESRD managed care demonstration
      project. The purpose of this article is to describe how one case management tool-
      the clinical pathway--can be used to decrease costs and improve outcomes
      associated with renal transplantation. This discussion will include a review of
      the origins and components of clinical pathways and a description of how one
      institution developed, implemented, evaluated, and refined a renal
      transplantation clinical pathway.

PMID- 10578714
TI  - Organ transplantation: the role of the acute care nurse practitioner across the
      spectrum of health care.
AB  - Organ transplantation has become an accepted treatment method for a multitude of
      conditions once deemed untreatable. Increasing numbers of patients are treated by
      nurse practitioners before and after transplantation in a variety of settings,
      such as primary and specialty care clinics, urgent care, critical care units, and
      long-term care facilities. This article outlines the role of the acute care nurse
      practitioner in the management of adult transplant recipients in a variety of
      health care settings and reviews the problems and interventions specific to this
      patient group. Emphasis is placed on the referral process and collaboration with
      the transplantation team in patient management.

PMID- 10578715
TI  - Non-heart-beating organ donation: process and review.
AB  - To combat the national shortage of donor organs and meet the needs of more than
      60,000 patients awaiting transplant, many organ procurement organizations have
      reevaluated non-heart-beating organ donation (NHBD) as one solution. Non-heart
      beating donation is the process by which organs are recovered from patients after
      the pronouncement of death by cardiopulmonary criteria. Recent media reports have
      misled health care providers to believe that this is a new donation procedure;
      however, NHBD provided the foundation for modern clinical transplantation. This
      article describes non-heart-beating donor evaluation criteria, the donation
      process, associated ethical considerations and the role of the advance practice
      nurse in assisting families with this end-of-life decision. A case study will be
      presented followed by a summary of transplant recipient patient and graft
      survival outcomes.

PMID- 10578716
TI  - Electrical burn injuries.
AB  - This article examines electrical burn injuries, how they occur and the nature of
      the injuries caused when people come into contact with electrical currents. The
      aetiology of tissue damage is discussed along with the pathophysiology of such
      encounters. The management of patients presenting with such injuries is explored
      including the vital role of the nurse in stabilizing and reassuring the patient.
      Careful handling of patients is needed in order to minimize further damage and
      this is discussed along with the resuscitation measures required and fluid
      replacement protocols. Pain management requires careful consideration as does the
      nursing care the patient receives. These are explored along with the support
      required by the family at such a time. The importance of communication is also
      stressed. Conclusions are drawn along with preventative measures to help avoid
      electrical burn injuries occurring.

PMID- 10578717
TI  - Focusing on the faculty. Interview by Alex Mathieson.
AB  - Few things have exercised the minds of Accident and Emergency nurses as much as
      the Faculty of Emergency Nursing. Yet misunderstandings about its aims and
      purpose remain widespread. Alex Mathieson caught up with leading Faculty
      advocate, Rob Crouch, to find out more.

PMID- 10578718
TI  - Ambulance services: could the UK learn from the French?
AB  - Ambulance services, as part of Accident and Emergency provision, are once again
      under scrutiny. This article reflects on a recent visit to a SAMU (Service d'Aide
      Medicale Urgente) unit in France, and considers those issues that could be
      explored in terms of effective UK provision. Recommendations will be proposed for
      future provision.

PMID- 10578719
TI  - The Sacred Space Foundation. Interview by Lynn Sbaih.

PMID- 10578720
TI  - An admission avoidance team: its role in the Accident & Emergency department.
AB  - The recent problems and pressures felt by Accident and Emergency departments
      around the country led a team at Newham Hospital, London, to develop a scheme to
      prevent frail elderly and vulnerable younger patients being unnecessarily
      admitted, thus blocking acute hospital beds. This paper outlines the creation of
      the scheme, its aims and practice, and early results.

PMID- 10578721
TI  - Home accidents in elderly patients presenting to an emergency department.
AB  - A prospective study was carried out in an Accident and Emergency department (A&E)
      to (1) examine the pattern of home accidents in elderly patients presenting to
      the A&E; (2) determine the nature and mechanisms of the accidents; and (3)
      investigate the associated factors in these accidents. All patients aged 65 or
      above with a history of injury at home within one week were included. Patients
      who needed immediate resuscitation and patients with mental illness or violent
      behaviour were excluded. A convenient sample was chosen during an 8-week period.
      A standardized questionnaire was used to collect data on (1) demographics; (2)
      nature of the accident and injury; and (3) health status. Health status
      assessment involved three components: physical status, drug history and past
      health. A total of 100 subjects were included giving an average occurrence of 3.3
      cases per shift. The mean age of the group was 75 with female patients (66)
      outnumbering the males by about two to one. The toilet was the most common site
      (29%) of home accident, followed by the sitting room (18%), the kitchen (14%),
      the bedroom (11%) and the dining room (10%). In 79 cases the patient was alone at
      home during the accident. Falls were the most common (75%) type of accident. The
      remaining 25% of injuries were categorized as sharps injury (8%), foreign body
      ingestion (6%), crush injury (4%), burns/scald (3%), hit by/onto fallen objects
      (3%) and finally, electric shock (1%). Eighteen fractures were recorded. Thirty
      two patients were admitted, 16 to the surgical ward and 16 to the orthopedic
      ward. In the functional assessment only 34 patients could perform the get-up-and
      go test satisfactorily and only 61 patients had good hand grasp. Visual and
      hearing impairment were common. Over 45% of the patients had more than one
      disease and the majority of patients (80) were taking some medication. The roles
      of A&E staff in the prevention of home accidents in the elderly are discussed.

PMID- 10578722
TI  - Dilemma. A familiar face.

PMID- 10578723
TI  - Triage decision making: educational strategies.
AB  - Patient triage in Accident and Emergency departments requires emergency nurses to
      make rapid decisions based on their knowledge and experiences. The development of
      triage decision-making skills can be addressed through the use of simulations,
      'thinking aloud' technique, reflection and the decision rules of experienced
      emergency nurses. Clinical educators and experienced emergency nurse mentors are
      encouraged to recognize that skill acquisition in triage decision making requires
      practice before registered nurses can engage fully in the process of triaging
      patients in the emergency department. It is essential to experience the process
      of triage decision making in order to develop an understanding of the clinical
      information attended to, the sequence in which the information is processed and
      the rules used to combine information leading to a decision on the triage
      category for each patient. By using triage simulations developed from 'real
      triage cases' the process of decision making can be experienced by nurses.
      Further, if these simulations are accompanied by the collection of verbal
      protocols, nurses have opportunities retrospectively to explore their decision
      making with reflection. In addition, the presentation and use of decision rules
      used by experienced triage nurses can enhance the development of skills in novice
      triage nurses.

PMID- 10578724
TI  - Helping students convert assignments into articles: tips for teachers.
AB  - The student may spend a lot of time and effort on an assignment or essay, and
      when the lecturer makes this comment about the finished product, may go ahead and
      submit it to a journal editor. If the editor returns the work with the comment
      'our readers would be most interested in your work but it needs to be presented
      as a journal article', the student rarely feels able to spare the time or make
      the effort to rewrite and resubmit, and the work is never published. The article
      and the assignment could, however, be produced simultaneously, and below are some
      suggestions as to how this could be achieved.

PMID- 10578725
TI  - Resuscitation: a personal perspective, a dual approach.
AB  - Resuscitation is a subject of topical interest and sometimes of controversy. This
      paper has been written following the personal experiences of the author who,
      although an academic also works in and has clinical links with Accident and
      Emergency, together with a specialist interest in resuscitation. Its aim is to
      promote discussion and reflection in order that clinical practice may be
      enhanced, rather than it being used as a tool to prevent the presence of
      relatives at resuscitation. The first incident reported relates to the writer
      delivering resuscitative care, whilst the second records the writer as a
      recipient of resuscitation. In the first instance the emotions experienced by the
      author are recorded together with an account of her subsequent resuscitative
      actions. Mention is made of the hospitalization of the casualty and the reactions
      to this incident by the wife of the casualty. In the second instance it is
      demonstrated how formed opinions can be changed due to experiential
      circumstances, 'do not resuscitate' instructions and the presence of relatives at
      resuscitation. Reflection has been introduced as an integral part of the article,
      to illustrate its value as a tool that can be supportive, positive, an initiator
      of change and that should lead to improved clinical care.

PMID- 10578726
TI  - Mentorship/facilitation for student nurses in Accident and Emergency, making a
      difference.

PMID- 10578727
TI  - Partnership in care: a critical exploration of how this may be applied to
      children attending the Accident and Emergency department.
AB  - Partnership in care is an emerging theme within children's nursing. There has,
      however, been much debate in the literature about what partnership in care is,
      but little consensus has been achieved as to its meaning. Partnership in care has
      been examined from the perspectives of both the parents and the nurses, although
      principally the work to date has focused on children's wards. More recently the
      work on partnership in care has examined how this may work in the children's out
      patient department and also within community children's nursing. Little appears
      to have been written about partnership in care in the Accident and Emergency
      (A&E) environment, and some possible reasons for this have been postulated. Three
      aspects of partnership in care: negotiation and equality of care, parents as
      equal partners, and responsibility for care being shifted have all been examined
      and applied to the A&E setting. Suggestions for research are offered throughout
      the discussion. Finally, the role of the registered children's nurse is examined
      in view of the analysis.

PMID- 10578728
TI  - The basics on bundled services.

PMID- 10578729
TI  - Tracking down elusive patients.

PMID- 10578730
TI  - Evolving legal trends affect NPs.

PMID- 10578731
TI  - Phytoestrogens and the management of menopause.
AB  - Phytoestrogens are plant compounds that are structurally or functionally similar
      to steroidal estrogens produced by the body, such as estradiol. Phytoestrogens
      are derived from dietary precursors. Methodologically rigorous studies
      demonstrate the benefit of phytoestrogens in addressing the climacteric syndrome-
      including vasomotor symptoms--and postmenopausal health risks. Studies suggest
      that phytoestrogen supplementation offers a potential alternative or complement
      to conventional HRT for osteoporosis prevention. Whether these effects will
      translate into reduced fracture rates or enhanced function and well-being remains
      for further study. The majority of evidence about the impact of plant estrogen
      consumption on the risk of cancer is epidemiologic. Rates of breast, endometrial
      and ovarian cancers are low in Asian cultures, where the diet is rich in soy
      isoflavones.

PMID- 10578732
TI  - Perinatal substance abuse and the drug-exposed neonate.
AB  - Tobacco and alcohol are the substances most abused during pregnancy. Alcohol
      (ethanol) is the human teratogen that produces the most serious neurobehavioral
      effects on the fetus. Cocaine is associated with spontaneous abortions, premature
      labor, precipitous labor, stillbirths, meconium staining and abruptio placentae.
      Heroin use during pregnancy has been associated with low birth weight,
      miscarriage, prematurity, microcephaly and intrauterine growth retardation.
      Marijuana is not scientifically linked to significant teratogenic effects. Since
      most substance abusers use multiple drugs, a positive screen for marijuana may
      indicate a high-risk patient. Cigarette smoking has been associated with
      spontaneous abortions, premature rupture of membranes, preterm delivery,
      perinatal death, low birth weight infants, and deficits in learning and behavior.

PMID- 10578733
TI  - Building barriers to HIV.
AB  - The AIDS epidemic has an increasingly female face, and the need for women to use
      effective contraceptive and infection prevention methods has taken on a new
      urgency. Consistent, proper condom use is the most effective method of preventing
      sexually transmitted disease. Research shows that condom breakage most commonly
      results from latex deterioration or incorrect use. Spermicidal cream or gel
      containing nonoxynol 9 is effective in preventing sexually transmitted diseases
      that cause genital ulcers and cervicitis. Spermicides cause genital tract
      irritation in some people, however, increasing their risk of STD infection.
      Diaphragms can protect against pregnancy, but since the devices only protect the
      cervix and a small area of the vagina, HIV or STD transmission may still occur.
      Oral contraceptives do not protect against STDs, nor do injectable and
      implantable contraceptives.

PMID- 10578734
TI  - Attention deficit-hyperactivity disorder not just for children anymore.

PMID- 10578735
TI  - Migraine management. New approaches focus on serotonin receptors.

PMID- 10578736
TI  - Patient information. Basic facts about childhood asthma.

PMID- 10578737
TI  - Hear me roar. How gender affects NP success.

PMID- 10578738
TI  - Raising awareness. Answering the call for better pain management.

PMID- 10578739
TI  - Journey through time. Respect for the past is integral to Native American health
      care.

PMID- 10578740
TI  - NPs need reflection, not blame.

PMID- 10578741
TI  - Parental presence during induction: the role parents play is it valid?

PMID- 10578742
TI  - Michael's surgical experience.

PMID- 10578743
TI  - Intraoperative progress reports to families of surgical clients: a missed
      opportunity.
AB  - The wait while a family member or loved one is undergoing surgery is stressful
      and anxiety-producing. Perioperative nursing contact during this period can
      result in positive outcomes of decreased anxiety, increased receptivity to
      postoperative information, and increased awareness of the professional practice.
      Perioperative nurses have the skills and the opportunity to provide progress
      reports to the client's family, at least once during surgery. Characteristics
      important to this role include motivation and commitment to be informative;
      caring; sensitivity and perceptivity; sense of humour; and education. Possible
      barriers to intraoperative communications include various lacks--of time;
      attention (related to monitoring requirements in the operating room); support
      from management, peers, and doctors; and therapeutic communication skills to
      alleviate anxiety. Progress reports to the family can decrease their physical
      stress and add to their satisfaction with the hospital.

PMID- 10578744
TI  - IFPN--a new organization for perioperative nurses: new partnerships for ORNAC.

PMID- 10578745
TI  - Psychosocial recovery from adult kidney transplantation: a literature review.
AB  - Kidney transplantation is the preferred treatment for patients with end-stage
      chronic renal disease. There appears to be no recent and extensive review of the
      literature on psychosocial recovery from adult kidney transplantation. This
      comprehensive review considers literature on six aspects of patient recovery and
      rehabilitation: psychiatric sequelae, functional recovery, stress and coping, the
      psychological impact of failed kidney transplants, quality of life (QOL), and
      adherence with medications. We conclude that although studies have become both
      more ambitious and rigorous, there is a pressing need to move away from
      descriptive research toward carefully designed multidisciplinary psychological
      intervention studies with kidney transplant patients.

PMID- 10578746
TI  - An investigation of interprofessional collaboration in stroke rehabilitation team
      conferences.
AB  - The aim of this paper is to report a study examining the team processes occurring
      in team conferences in a stroke unit. Team conferences provide an opportunity for
      all members of the rehabilitation team to report patients' progress and establish
      patients' rehabilitation goals. The findings suggest that little discussion or
      consideration of alternative intervention plans are undertaken and that team
      conferences serve to disseminate decisions rather than establish patients'
      rehabilitation goals. Core members of the rehabilitation team have developed
      specific roles. The physiotherapist 'proposes' decisions which are 'seconded' by
      the occupational therapist. The doctor acts to sanction decisions and the nurses
      action them. Team conferences are effective for dissemination of decisions and
      for giving rise to a sense of team collaboration.

PMID- 10578747
TI  - Looking out for the patient and ourselves--the process of family integration into
      the ICU.
AB  - As more intensive care units (ICU) are adopting the policy of unrestricted family
      visiting, families are playing an increasing role in the unit. This role may be
      restricted to being involved in discussions and decisions related to the patient
      or may entail a caregiving role. This study examined how families and nurses
      interact to increase or decrease the family's involvement in the ICU, how nurses
      maintain control, how families remain on guard, endure and find their niche in
      the ICU. The techniques of grounded theory were used to develop a model of the
      process of family integration into the ICU. This model was developed around the
      core variable of 'looking out for the patient-looking out for ourselves'. The
      perspectives of ICU nurses, families and ICU patients in the process of looking
      out for the patient while they look out for themselves are discussed, as well as
      nurses maintaining the position of power and families remaining on guard and
      enduring the ICU experience.

PMID- 10578748
TI  - The psychological impact of working in emergencies and the role of debriefing.
AB  - It has been suggested that there are three major disasters each week world-wide
      of such a magnitude that local services are overwhelmed. Nurses are frequently
      involved in assisting in emergencies. This paper reviews current work looking at
      the impact of working in emergency settings and overseas humanitarian aid work.
      There is evidence that being at a disaster site or overseas humanitarian
      operation can be psychologically damaging. Strategies aimed at reducing this
      damage, such as debriefing, are poorly evaluated but often carried out as an act
      of faith. This is an area that needs to be addressed as nurses will increasingly
      be involved in this work.

PMID- 10578749
TI  - Teaching sociology to nurses: exploring the debate.
AB  - This article reviews literature on the current debate concerning teaching
      sociology to nurses. The debate is limited because it does not take into account
      the work of Donald Schon, or Anthony Giddens. The article also discusses theories
      of adult education which support teaching sociology in nurse education. Sociology
      is essential for nurses, because it can help to develop an understanding and
      analysis of the context and substance of nursing practice.

PMID- 10578750
TI  - Hope in multiple chemical sensitivity: social support and attitude towards
      healthcare delivery as predictors of hope.
AB  - This paper examines hope, as measured by the Herth Hope Scale, and its predictors
      in a sample of 305 people self-identified with multiple chemical sensitivity. The
      sample had relatively low levels of hope with scores unrelated to gender,
      severity or length of illness, income loss as a result of illness, or reported
      iatrogenic harm. Hope scores were positively correlated with perceived social
      support, having found personal growth through illness, age, reported level of
      supportiveness from a partner, an improved course of illness and level of
      reported safety of the home environment in regard to chemical exposures. Negative
      correlations were found with attitude toward healthcare delivery, fatigue and
      reported abuse/ostracism from family members other than partner. Social support,
      Healthcare Orientation, growth through illness, fatigue and age predicted hope
      scores accounted for 55% of the variance. Implications and suggestions for future
      research are discussed.

PMID- 10578751
TI  - Intensive care unit psychosis, the therapeutic nurse-patient relationship and the
      influence of the intensive care setting: analyses of interrelating factors.
AB  - It has been estimated that between 12.5% and 38% of conscious patients admitted
      to critical care settings experience Intensive Care Unit psychosis, a condition
      which seems to resolve upon transfer to the ward. This phenomenon was
      traditionally recognized when the patient outwardly exhibited abnormal behaviours
      and signs in the form of confusion, delirium, anxiety, depression, delusions and
      audiovisual hallucinations, yet it has been argued that due to the illness of the
      patient and their suppressed ability to communicate, such overt displays of
      unusual behaviour are the tip of the iceberg. In recognizing this phenomenon, it
      is felt that a relationship exists between Intensive Care Unit Psychosis, the
      therapeutic nurse-patient relationship, and the environment in which nurses'
      interactions with their clients occur. This paper will explore the interaction
      between these three elements while considering the implications for contemporary
      nursing practice.

PMID- 10578752
TI  - The role of the paediatric nurse in promoting paediatric right to consent.
AB  - This article examines the processes involved in obtaining informed consent
      focusing on the abilities and legalities related to a child's right to consent.
      Most authors who have researched when a child may be considered competent to give
      a valid consent propose that the child must be 14 years old and thus able to
      think abstractly and consider the risks and benefits of the planned treatment.
      Qualitative research on this topic reveals that a child's previous life
      experiences can influence their ability to comprehend the intervention. This
      suggests children under 14 years of age may be regarded as competent. The
      confusion around the prevailing legal situation is examined. The role of the
      paediatric nurse is explored to distinguish areas in which the nurse could
      potentially make a contribution to the process of gaining consent from children.
      The paediatric nurse's role as an assessor, educator and evaluator are
      identified.

PMID- 10578753
TI  - How big is a drop? A volumetric assay of essential oils.
AB  - There has been an increase in the use of aromatherapy in nursing, and many issues
      are now being raised which need addressing in order to maintain professional
      credibility and safe practice. These issues include: who can safely practise
      aromatherapy, what qualifications are required to practise, who provides
      indemnity, and other issues, including the safety and toxicity of essential oils.
      A small study was undertaken to examine the differences in drop size of bergamot
      essential oil. Drop size was determined by weighing different manufacturers'
      essential oil of bergamot and it was found that drop size did differ, resulting
      in unequal doses of essential oil. It is important to be aware of this, because
      there are implications for the size of the dose administered in an aromatherapy
      treatment. This paper raises the issue of standardizing the measurement of
      essential oils, to ensure that there are no problems regarding safety in their
      administration.

PMID- 10578754
TI  - Facilitating critical reflection in mothers of chronically ill children.
AB  - The hybrid model, developed by Schwartz-Barcott & Kim guided the conduct of a
      study of empowerment in mothers of chronically ill children. Integral to the
      model of empowerment that emerged from the study was an ongoing process of
      critical reflection. Through this process, mothers became aware of their
      strengths, abilities and resources. This paper is an in-depth analysis of the
      process of critical reflection, which corroborates recent theory on women's
      development. The process of critical reflection is illuminated by women's ways of
      knowing, as exemplified in the story of one mother, and by elements of maternal
      thinking. Implications for nursing practice in working with mothers of
      chronically ill children are highlighted.

PMID- 10578755
TI  - Nurses' perceptions of sexuality relating to patient care.
AB  - This paper presents a research study which explores the perceptions of nurses
      regarding sexuality related to patient care. A qualitative approach was taken to
      the research. The methodology used was grounded theory. The findings illustrate
      that nurses had difficulty dealing with issues of sexuality, and the reasons for
      this were complex and interrelated. Patient care was influenced by nurses'
      perceptions of sexuality. Nurses in the study did not, generally, provide patient
      care relating to sexuality. Nurses were reluctant to discuss sexuality with their
      patients. Stereotyped images of nurses, males and homosexuals were common. Nurses
      dealt with issues of patient sexuality by employing a variety of coping
      strategies.

PMID- 10578756
TI  - The management of wandering in older people with dementia.

PMID- 10578757
TI  - Increasing the uptake of cervical screening amongst Hong Kong Chinese women: the
      contribution of the nurse practitioner.

PMID- 10578758
TI  - Cautions about nurse staffing standards for nursing homes.

PMID- 10578759
TI  - The Mini-Mental State Examination (MMSE).

PMID- 10578760
TI  - Institutionalized older adults' perceptions of nurse caring behaviors. A pilot
      study.
AB  - The purpose of this article is to identify which behaviors performed by nursing
      staff were important indicators of caring as perceived by older adults residing
      in institutional settings. Using Watson's Theory of Transpersonal Care as the
      framework for the study, the Caring Behavior Assessment (CBA) instrument, which
      is congruent with Watson's carative factors, was used to interview residents. A
      convenience sample of 21 residents residing in long-term care and assisted-living
      facilities answered the 63-item CBA. Descriptive statistics were used to analyze
      the importance of each identified behavior. The analyses revealed that the
      highest indicator of nurse caring focused on the nurses' technical competency
      (instrumental activities). This study noted a significant gender-specific
      perception of caring. This may reflect differences in gender communication styles
      and interpersonal processes which may affect connotations of caring expressions.
      Humanistic caring (expressive activities) was the second most important indicator
      of care. Older adults desired care which preserved and enhanced individual
      dignity.

PMID- 10578761
TI  - Is cognitive impairment a guide to use of Video Respite? Lessons from a special
      care unit.
AB  - The goal of this study was to examine the usefulness of Video Respite (VR) in
      relation to the abilities of cognitively impaired older adults. Three VR
      videotapes were shown to residents of a special care unit. Older adults were
      videotaped as they viewed the VR videotapes to observe their levels of
      involvement. Analyses of the videotapes of the older adults confirmed that
      participation varies considerably between and within residents and, further, that
      cognitive status is not a useful guide in predicting levels of participation.
      Some residents showed no interest in television in general or in VR, while the
      elimination of distractions resulted in more sustained viewing for those inclined
      to participate. The authors' observations suggest ways to optimize the usefulness
      of VR for formal and informal caregivers.

PMID- 10578762
TI  - Activities of daily living. Old-fashioned or still useful?
AB  - 1 The Index of Activities of Daily Living (ADL) is used by many nurses to assess
      function in older adults, but there is debate regarding the scoring, wording of
      questions, and validity in diverse populations. 2 Older adults may give
      inaccurate answers to ADL questions because they misunderstand the questions,
      have personal reasons for underreporting or overreporting difficulty in ADL, or
      fail to recognize difficulty because they have adapted to changes in function. 3
      Physical performance tests, especially of the lower extremities, may be an
      alternative method of assessing function, especially in high-functioning older
      adults who report no difficulty in ADL.

PMID- 10578763
TI  - A comparative study of nurses' and elderly patients' ratings of pain and pain
      tolerance.
AB  - The purpose of this study was to compare elderly patients' and nurses' ratings of
      pain and pain tolerance. Data were collected through structured interviews with
      the patients. The attending nurses completed a questionnaire after conducting a
      pain assessment. Independent of each other, patients and nurses were asked to
      rate on a VAS when pain should be treated (pain tolerance) and pain intensity.
      The VAS has been used both by patients and nurses. The initial selection
      consisted of 43 patients; however, 9% (n = 4) were unable to complete the VAS.
      These patients were not significantly older than those who completed the study (n
      = 39). The results shows that nurses tend to overestimate mild pain and
      underestimate severe pain. Nurses rated pain tolerance significantly lower than
      patients. The results also suggest that nurses with training beyond basic nursing
      education tend to assess patients' pain more accurately than those without
      additional training. For patients who reported that they had pain prior to
      hospitalization, the nurses' pain ratings showed a higher agreement than for
      those who reported that they did not have pain before being hospitalized. At the
      time of the interviews, 21% (n = 8) of patients felt that their pain was so great
      they needed treatment. Those patients also were recognized by the attending
      nurses as being in pain. To improve elderly patients' pain management, practicing
      nurses must collaborate with researchers to develop specific empirical research
      nursing knowledge within geriatric pain management. This research-based knowledge
      should be incorporated into nurses' clinical practice regarding pain management.
      Specific guidelines must be developed for the assessment, treatment, and
      documentation of elderly patients' pain.

PMID- 10578764
TI  - Geriatric mental health education in Canada SKIPs into the 21st century.
AB  - The Skills Immersion Program (SKIP) provides an educational opportunity for staff
      nurses who face the challenge of caring for residents who present with
      psychiatric and behavioral problems in long-term care (LTC) facilities within
      British Columbia, Canada. With the aging population and an increase in the number
      of individuals waiting for placement in care facilities, care providers are in
      substantial need of advanced education and training in the field of geriatric
      psychiatry nursing. Nurses working in LTC facilities in Canada are not prepared
      to manage the changing acuity levels and complex needs of their residents. The
      SKIP was developed by nurses, primarily for nurses, at St. Vincent's Hospital in
      Vancouver, British Columbia, Canada. Nurses who participate in the SKIP acquire
      an enhanced knowledge base in geriatric psychiatry nursing and gain access to
      assessment tools that will assist staff to increase the quality of care for their
      residents.

PMID- 10578765
TI  - Preventing cerumen impaction in nursing facility residents.

PMID- 10578766
TI  - How do you ensure your clients drink the amount of fluid calculated by the
      dietitian?

PMID- 10578767
TI  - Managing long-term care facilities. Three myths about nurse aide work.

PMID- 10578768
TI  - Trust: our most valuable asset.

PMID- 10578769
TI  - Does human milk DHA level affect functional outcome in infants?

PMID- 10578770
TI  - Promoting exclusive breastfeeding for 4-6 months in Honduras: attitudes of
      mothers and barriers to compliance.
AB  - Prospective and retrospective data on maternal attitudes and obstacles to
      exclusive breastfeeding (EBF) were collected from Honduran mothers of low
      birthweight (1500-2500 g), term infants who were enrolled in an intervention
      study to compare infant outcomes in those who were randomly assigned to
      breastfeed exclusively for either 4 or 6 months. Perceived advantages of EBF were
      that it was easier, more practical and economical, and resulted in better infant
      health and growth. Disadvantages included the perceived time demand, concerns
      that the infant would accept solids less readily, and fears that breast milk
      alone was insufficient. The majority of study participants said that they would
      choose to exclusively breastfeed their next infant to 6 months. Although there
      were many obstacles to EBF, particularly in the first few weeks, women who
      persevered became enthusiastic proponents of EBF. Messages to promote EBF need to
      target the entire community, not just mothers, and should focus on addressing
      common misconceptions and alerting women to potential problems before they occur.

PMID- 10578771
TI  - The effect of a peer counseling program on breastfeeding initiation and longevity
      in a low-income rural population.
AB  - Breastfeeding rates among low-income women in the east-south-central United
      States are among the lowest in the country. This study examined the effect of a
      peer counseling program on breastfeeding initiation and duration in a low-income
      rural population in West Tennessee. A postpartum survey and chart review were
      conducted with WIC clients at nine health departments. Response rate was 99%
      (291/293). Breastfeeding initiation and duration at 6 weeks were increased in the
      peer counselor group (n = 156) compared with women in the no-peer counselor group
      (n = 135) (53% vs. 33%, p < 0.001, and 26% vs. 13%, p = 0.006, respectively).
      Multivariate analysis revealed that women in the peer counselor group were
      significantly more likely to initiate breastfeeding (OR = 2.43, 95% CI = 1.23
      4.67) and to be breastfeeding at 6 weeks (OR = 2.78, 95% CI = 2.08-9.51), than
      those in the no-peer counselor group.

PMID- 10578772
TI  - Sources of influence on intention to breastfeed among African-American women at
      entry to WIC.
AB  - To examine how individuals within a woman's life influence her infant feeding
      intention, we interviewed 441 African-American women on the breastfeeding
      attitudes and experiences of their friends, relatives, mother, and the baby's
      father. Women were interviewed at entry into prenatal care at clinics associated
      with one of four Baltimore WIC clinics chosen for a breastfeeding promotion
      project. Qualitative data were also collected among 80 women. Friends and "other"
      relatives were not influential. Grandmothers' opinions and experiences were
      important, but their influence was reduced after considering the opinion of the
      baby's father. The opinion of the woman's doctor was an independent predictor of
      infant feeding intention. Breastfeeding promotion programs should recognize the
      separate influence of fathers, health providers, and grandmothers in women's
      infant feeding decisions.

PMID- 10578773
TI  - Evaluating the association of two breastfeeding assessment tools with
      breastfeeding problems and breastfeeding satisfaction.
AB  - This pilot study evaluated how the scores from each of two breastfeeding
      assessment tools correlated with breastfeeding satisfaction and problems. A
      convenience sample of 30 first-time breastfeeding mothers participated. Mothers
      were randomly assigned to use either the LATCH or Infant Breastfeeding Assessment
      Tool (IBFAT). The Maternal Breastfeeding Evaluation Scale (MBFES) and Potential
      Early Breastfeeding Problem Tool (PEBPT) were used to evaluate the association of
      the scores of each assessment tool with breastfeeding satisfaction and
      breastfeeding problems. As scores on the both the LATCH and IBFAT increased,
      maternal satisfaction scores tended to increase, but not significantly, and
      breastfeeding problem scores tended to decrease (r = -0.5, p = 0.06 and r = 
      0.49, p = 0.06; respectively.

PMID- 10578774
TI  - Induced lactation in an adoptive mother.
AB  - This case report describes the experiences of an gravida 3 para 0 adoptive mother
      who initiated the use of bilateral pumping, metoclopramide, syntocinon nasal
      spray, and a supplemental nursing system to induce lactation. Lactogenesis was
      initiated within 10 days of the adoption. No measurable milk was pumped until the
      baby was 4 months old at which time the mother began pumping 4 ounces per breast
      within 1 week. The mother stopped pumping, taking metoclopramide (Regian) and
      syntocinon, and using the supplementer system at this time. She continued to
      breastfeed without the use of bottles throughout the fourth and fifth months with
      the baby maintaining adequate weight gain.

PMID- 10578775
TI  - Always handy.

PMID- 10578776
TI  - Consulting with the bereaved mother.
AB  - This paper describes approaches that may be used in consulting with the bereaved
      mother about engorgement and involution. The physical and emotional facets of
      this experience are intricately interwoven and lactation consultants should be
      aware that mothers may need a number of health care professionals to meet their
      needs. Suggestions for milk suppression, communication enhancement, and emotional
      support are offered.

PMID- 10578777
TI  - Donor milk banking in Scandinavia.

PMID- 10578778
TI  - Accountability: the IBLCE discipline process. International Board of Lactation
      Consultant Examiners.

PMID- 10578779
TI  - Antiepileptic drug use during breastfeeding.

PMID- 10578780
TI  - Competing interests and scientific publication.

PMID- 10578781
TI  - Computerized breast measurement from conception to weaning: clinical
      implications.
AB  - The CBM system has enabled our laboratory to measure breast growth and
      demonstrate the importance of the short-term local control of milk synthesis in
      lactating women. Although the specific mechanism by which the short-term control
      of milk synthesis occurs has yet to be fully understood, it is now apparent that
      the interaction between storage capacity, degree of fullness, and frequency of
      milk removal plays a significant role. These factors demonstrate that the
      breastfeeding mother can take comfort in the individuality of her breast
      development and feeding pattern, which is uniquely adapted to suit the physiology
      of her breasts and the developmental requirements of her infant.

PMID- 10578782
TI  - Short-term neonatal breastfeeding.

PMID- 10578783
TI  - Breast pain during lactation that resolved with fluconazole: two case studies.

PMID- 10578784
TI  - "Let us have more mother-fed babies": early twentieth-century breastfeeding
      campaigns in Chicago and Minneapolis.

PMID- 10578785
TI  - Does delayed perception of the onset of lactation shorten breastfeeding duration?
AB  - This longitudinal study evaluated the impact of the timing of maternal perception
      of the onset of lactation on breastfeeding duration. Breastfeeding mothers who
      delivered a full-term infant were interviewed daily from day 1 postpartum until
      the onset of lactation. Women were recontacted to determine the duration of any
      breastfeeding at 6.7 months postpartum, and if necessary, at 16.2 months
      postpartum. Cox survival multivariate analyses indicated that among women
      planning to breastfeed for at least 6 months, those with onset of lactation < 72
      hours postpartum were likely to breastfeed longer than their counterparts with a
      delayed onset of lactation. Median breastfeeding durations were 11.7 months and
      3.4 months, respectively (p < 0.00001). Among women who intended to breastfeed
      for less than 6 months, the timing of the onset of lactation did not influence
      breastfeeding duration. All analyses controlled for body build, delivery method,
      employment status, education, parity, and maternal age. These findings suggest
      that a delayed onset of lactation is likely to be associated with a shorter
      breastfeeding duration. This relationship, however, was modified by the mother's
      intended breastfeeding duration.

PMID- 10578786
TI  - Content of lipid nutrients in the milk of Fulani women.
AB  - Little is known about the nutrition of the infants of the Fulani, migratory
      nomads of the western Sahel of Africa. Milk was collected from 18 Fulani women 10
      to 30 days postpartum and the fatty acid compositions of the triacylglycerol and
      phospholipid fractions were determined by capillary gas-liquid chromatography. De
      novo fatty acids (10:0-14:0) comprised 36.3 +/- 12.7% of fatty acids of the
      triacylglycerols. Compared to the milk of various populations worldwide, the milk
      of the Fulani women contained adequate proportions of alpha-linolenic acid (0.50
      +/- 0.16%) and arachidonic acid (0.42 +/- 0.22%), but relatively low amounts of
      linoleic acid (9.95 +/- 2.13%) and docosahexaenoic acid (DHA) (0.15 +/- 0.08%).
      In addition, the milk of the Fulani women contained adequate concentrations of
      beta-carotene (1.58 +/- 0.69 micrograms/dl) and vitamin A (42.7 +/- 40.3
      micrograms/dl), but very low levels of vitamin E (0.11 +/- 0.10 mg/dl). These
      data indicate that exclusively breasted infants of Fulani women were receiving
      relatively low amounts of critical fatty acids and vitamin E.

PMID- 10578787
TI  - Effects of parity on breastfeeding: a study in the rural setting in northern
      Thailand.
AB  - This analysis was undertaken to see whether or not previous successful
      breastfeeding has any influence on subsequent breastfeeding behavior. Lactational
      outcomes were compared between those with and without breastfeeding experience.
      METHODS: Amount of breast milk transferred, frequency of breastfeeding, and time
      spent on the breast, as well as infant's weight, were recorded on days 15, 45,
      90, 180, 270, and 360 postpartum in 30 primiparae and 30 multiparae. Outcomes of
      the primiparae were found to be similar to those of the more experienced
      breastfeeding multiparous mothers with respect to infant growth, amount of breast
      milk transferred, and the frequency of breastfeeding or number of attachments to
      the breast. Though primiparae took somewhat longer to transfer similar amounts of
      breast milk to their infants during the initial 45 to 90 days postpartum, feed
      duration after 90 days was similar to that of the multiparae. Lactation
      performance of the rural northern Thai mothers in our sample was highly
      successful with or without previous breastfeeding experience. It may be that a
      cultural pattern of breastfeeding on demand, strong family support, and
      traditional practices that encourage close contact between mother and her newborn
      compensate for the absence of lactational experience. Unlike reports from Western
      countries, previous breastfeeding does not appear to be an important predictor of
      successful and prolonged breastfeeding in our population.

PMID- 10578788
TI  - Nipple care, sore nipples, and breastfeeding: a randomized trial.
AB  - Sore and cracked nipples are common and may represent an obstacle to successful
      breastfeeding. In Italy, it is customary for health professionals to prescribe
      some type of ointment to prevent or treat sore and cracked nipples. The efficacy
      of these ointments is insufficiently documented. The incidence of sore and
      cracked nipples was compared between mothers given routine nipple care, including
      an ointment (control group), and mothers instructed to avoid the use of nipple
      creams and other products (intervention group). Breastfeeding duration was also
      compared between the two groups. Eligible mothers were randomly assigned, after
      informed consent, to one of the two groups. No difference was found between the
      control (n = 96) and the intervention group (n = 123) in the incidence of sore
      and cracked nipples and in breastfeeding duration. However, several factors were
      associated with sore nipples and with breastfeeding duration. The use of a
      pacifier and of a feeding bottle in the hospital were both associated with sore
      nipples at discharge (p = 0.02 and p = 0.03, respectively). Full breastfeeding up
      to 4 months postpartum was significantly associated with the following early
      practices: breastfeeding on demand, rooming-in at least 20 hours/day, non-use of
      formula and pacifier, no test-weighing at each breastfeed. The incidence of sore
      and cracked nipples and the duration of breastfeeding were not influenced by the
      use of a nipple ointment. Other interventions, such as providing the mother with
      guidance and support on positioning and latching, and modifications of hospital
      practices may be more effective in reducing nipple problems.

PMID- 10578789
TI  - Breastfeeding in public places.
AB  - This study reports the results of a survey of restaurant and shopping center
      managers concerning breastfeeding in their facilities. Managers from 66
      restaurants and 27 shopping centers were interviewed by telephone. One-third of
      the restaurant managers and 48% of the shopping center managers stated that a
      mother could breastfeed anywhere in their facility regardless of what other
      customers might say. The remaining managers would either discourage breastfeeding
      anywhere in their facility, suggest a mother move to a more secluded area if she
      wished to breastfeed, or were unsure how they would react. The variability in
      support for breastfeeding by managers of restaurants and shopping centers will
      continue to create uncertainty for mothers wishing to breastfeed in these public
      places.

PMID- 10578790
TI  - Implementing breastfeeding education in the academic setting.
AB  - It is well known in the lactation community that many of our generalist health
      care providers are inadequately prepared to manage breastfeeding dyads. In
      response to the need for skilled health care providers, a breastfeeding course
      was developed and implemented. The course was offered within a school of nursing,
      but open to all interested participants. Course content included the physiology
      of the mammary glands and related anatomy, breastfeeding support, medical
      complications, research, legislation, and technologies. In addition to obtaining
      critical-thinking skills to manage breastfeeding mothers and infants, students
      also developed a supportive network of colleagues with whom they can collaborate
      and to whom they can refer families. In the future we are considering expanding
      the curriculum to include more practical and community experiences.

PMID- 10578791
TI  - Donating human milk as part of the grieving process.

PMID- 10578792
TI  - Statistical report of the 1998 IBLCE examination. International Board of
      Lactation Consultant Examiners.

PMID- 10578793
TI  - Herbal medications and breastfeeding.

PMID- 10578794
TI  - Recent references.

PMID- 10578795
TI  - Evidence-based practice: art versus science?

PMID- 10578796
TI  - Anesthetic medications in breastfeeding mothers.

PMID- 10578797
TI  - Theoretical underpinnings of breastfeeding confidence: a self-efficacy framework.

PMID- 10578798
TI  - Effects of pumping style on milk production in mothers of non-nursing preterm
      infants.
AB  - Milk production was examined in 39 lactating mothers of non-nursing preterm
      infants from 2 tertiary care centers. The purposes of this study were (1) to
      compare milk production of those using sequential single (SEQ) or simultaneous
      double (SIM) breast-pumping regimen, and (2) to examine the relationship of
      selected variables to inadequate (< 3500 g/week) and adequate (> or = 3500
      g/week) milk production. In multivariate analysis, mothers using SIM produced a
      similar amount of milk by weight during weeks 2 to 5 postpartum compared to those
      using SEQ. A logistic regression model including frequency of kangaroo care,
      frequency of pumping, high versus low income, and previous breastfeeding
      experience was predictive of mothers producing adequate versus inadequate milk
      volume 79% of the time. All of the mothers producing > 3500 g at week 2 produced
      adequate amounts of milk at weeks 4 and 5. None of the mothers producing < 1700 g
      at week 2 reached adequate production by weeks 4 and 5. Of the remaining mothers
      who produced 1700 g to 3500 g at week 2, 54% achieved adequate production during
      weeks 4 and 5 postpartum.

PMID- 10578799
TI  - You can make a difference: increasing breastfeeding rates in an inner-city
      clinic.
AB  - Breastfeeding is endorsed in the United States as the ideal infant feeding
      method, but initiation rates are far behind U.S. national goals, and are
      generally lower in poorer socioeconomic groups. The goal of the project described
      was to increase breastfeeding rates in an inner-city clinic. The intervention
      consisted of prenatal breastfeeding education for all pregnant women, postpartum
      gift packs, and support groups. During the study, the breastfeeding initiation
      rate rose from 36% to 66% (p < 0.05) and the proportion still breastfeeding at 2
      weeks postpartum increased from 35% to 57% (p < 0.05). The cost of the project
      was minimal. The biggest expense was the discharge packets. We conclude that
      relatively inexpensive interventions can have a significant impact on
      breastfeeding initiation, even in a population at high risk of not breastfeeding.

PMID- 10578800
TI  - An audit of mastitis in the emergency department.
AB  - A medical audit was conducted in 1997 of hospital records of women attending the
      emergency department of the Royal Women's Hospital in Melbourne, Australia, in
      1996 with a diagnosis of "mastitis." One hundred and seven women were diagnosed
      with mastitis; approximately half were primiparous (53%) and the median age of
      the baby was 14 days. Most women (69%) attended the emergency department after
      normal working hours. Thirty-nine percent of the women were afebrile, and only
      27% had a temperature of 38.5C or higher. The majority of women were prescribed
      flucloxacillin. Milk culture was obtained in only 15 cases, and Staphylococcus
      aureus was the most common pathogen.

PMID- 10578801
TI  - Breastfeeding practices among employed Thai women in Chiang Mai.
AB  - In many developing countries, labor force participation by women in the
      childbearing years has increased rapidly. Social and economic changes present new
      challenges for women attempting to combine their roles as workers and mothers.
      Little is known about how these challenges affect infant feeding choices. This
      multidisciplinary study investigated work and infant feeding decisions among 313
      employed women in Chiang Mai, Thailand. Resumption of employment generally had
      negative affects on breastfeeding rates and duration. At 6 months postpartum,
      women who worked inside the home breastfed more than those working in the formal
      sector at jobs with inflexible hours (home, 80%; public sector, 37%; private
      sector, 39%). Women who were working outside the home for a long period or had
      shift jobs encountered many obstacles to maintaining breastfeeding, and most gave
      it up within 1 month after resuming employment. There is a need for multisectoral
      policies that address obstacles to breastfeeding among women in the paid labor
      force in Thailand.

PMID- 10578802
TI  - Determinants of the breastfeeding pattern among working women in Sao Paulo.
AB  - The needs of breastfeeding women who work away from home differ from those of
      other women, particularly those who breastfeed exclusively. Sixty-nine factory
      workers were interviewed in Sao Paulo, both during pregnancy and when they
      returned to work. Median durations of exclusive (EBF), predominant (PBF), and any
      breastfeeding (BF) were found to be 10 days, 70 days, and 150 days, respectively.
      Despite having used the 4-month leave to which they were entitled, by 1 month,
      86% of the respondents had given tea, 50% water, and 42% artificial baby milk.
      Only 2 women were still exclusively breastfeeding when they returned to work.
      Various personal characteristics were associated with longer duration of
      breastfeeding. Maternity ward routines were generally not supportive, but
      duration of PBF was longer where better support was received. Duration of EBF was
      longer among women with support for breastfeeding at work, and shorter for those
      working on weekends or doing shift work. Thus, women may have adjusted their
      feeding patterns based on whether or not they anticipated workplace support. Only
      weekend work and socioeconomic status were linked to shorter duration of
      breastfeeding. Stronger social and health care support for EBF may be needed
      before the full impact of workplace support can be usefully studied in Brazil.

PMID- 10578803
TI  - The treatment of Staphyloccocus aureus infected sore nipples: a randomized
      comparative study.
AB  - Sore, cracked nipples are commonly experienced by breastfeeding mothers. We have
      previously reported a strong correlation between sore, cracked nipples and S.
      aureus colonization. A prospective, randomized clinical trial was performed to
      compare four treatment regimes for S. aureus infected sore nipples. Eighty-four
      breastfeeding mothers were enrolled in the study. After 5 days to 7 days of
      treatment, only 8% of mothers showed improvement in the "optimal breastfeeding
      technique alone" group, 16% improved with topical mupiricin, 29% improved with
      topical fusidic acid, yet 79% improved with oral antibiotics (p < .0001). Optimal
      breastfeeding techniques and topical antibiotics ointment failed to heal most
      infected, sore, cracked nipples. Mastitis developed in 12% to 35% of mothers not
      treated with systemic antibiotics compared to 5% of mothers treated with systemic
      antibiotics (p < .005). In conclusion, S. aureus infected sore, cracked nipples
      should be diagnosed as a potentially widespread impetigo vulgaris and treated
      aggressively with systemic antibiotics in order to improve healing and decrease
      the risk of developing mastitis due to an ascending lactiferous duct bacterial
      infection.

PMID- 10578804
TI  - Every drop counts: news from the United Kingdom Association for Milk Banking.

PMID- 10578805
TI  - Anticoagulant use during lactation.

PMID- 10578806
TI  - Recent references.

PMID- 10578807
TI  - A service in crisis? Reflections on the shortage of nurses in the British
      National Health Service.

PMID- 10578808
TI  - Patients' views on quality of care: a comparison of men and women.
AB  - AIM: This study set out to explore gender differences among medical and surgical
      acute care inpatients regarding their perceptions of actual care conditions as
      well as their evaluation of the subjective importance of various care conditions.
      BACKGROUND: Firstly, the literature reports inconsistent findings regarding male
      and female patients' views on care. Secondly, the instruments used in most
      previous research are not derived from a patient perspective. METHODS: The sample
      consisted of 831 patients (48% were women and 52% were men) at two Swedish
      hospitals. Data were collected using the questionnaire 'Quality from the
      Patient's Perspective'. FINDINGS: Male and female patients tended to evaluate the
      actual care received similarly. However, women tend to assign the different care
      aspects higher subjective importance. CONCLUSION: More research is needed to
      illuminate the reasons why men and women hold these different values. Until these
      issues are better understood, there is no valid basis on a group (gender) level
      to give specific practical recommendations to nursing managers.

PMID- 10578809
TI  - Competition to co-operation in national health services: evidence of social and
      cultural effects as management issues.
AB  - AIMS: This review examines how the management of health and health services is
      affected by the context of historical, social and scientific developments.
      BACKGROUND: The paper was prepared for the author's inaugural lecture as
      Professor of Health Services Research at Canterbury Christ Church University
      College. METHODS: The review had the benefit of being conducted during a 3-year
      NHS research and development study of decision-making in the nursing profession.
      A systematic literature review was conducted, yielding bibliographical data for
      analysis of health service issues. CONCLUSION: There is a case for including
      management decisions on appropriate research measures in the health service.
      Another finding of this analysis is that the management of common needs-based
      budgets, for example through co-operative purchasing, is a way forward to
      reconfigure services and reallocate funds, in a context of anomalies and
      inequalities in health care.

PMID- 10578810
TI  - An exploration of the services provided by the clinical nurse specialist within
      one NHS trust.
AB  - AIM: This study examines the services provided by clinical nurse specialists
      within one acute and community NHS Trust. BACKGROUND: The title 'clinical nurse
      specialist' (CNS) is used widely within health care services and describes a
      multitude of roles and service provision. Lack of role clarity impacts upon human
      resources, service delivery and the post holder. METHODS: Patients, carers and
      health care professionals were invited to participate in focus groups. Groups
      sought information about the services provided by the CNS. The research adopted a
      grounded theory approach in order to generate a locally recognizable description
      of the services. FINDINGS: From the data analysis eight technical services
      carried out by the CNSs emerged. Analysis also identified three areas where the
      CNS provided added value. The findings are discussed in relation to relevant
      literature. CONCLUSIONS: Recommendations are made concerning effective and
      efficient use of this important staff resource.

PMID- 10578811
TI  - The impact of clinical experiences during pre-registration diploma in nursing
      courses on initial career choice.
AB  - AIM: The aim of this study was to evaluate the impact of clinical learning
      experiences during the Pre-registration Diploma in Nursing (Adult) course on
      immediate career choice for qualifying nurses. BACKGROUND: Changes in nurse
      education has reduced the exposure of students to some client groups,
      particularly in critical care areas. In recent years trusts are experiencing
      difficulties in recruiting 'D' grade staff nurses to theatres and critical care
      units which may be a direct consequence of this change. METHODS: A questionnaire
      was distributed to 47 pre-registration adult branch students, followed by two
      focus group discussions using a sample of the same students. FINDINGS: Students
      appeared to use preconceived images and expectations about nursing which they
      relied on for job selection, unless changed by personal experience during their
      course. These students held generally negative images about theatre and critical
      care nursing, and as they had little experience to test these images during their
      training, the negative view remained dominant when choosing a job. CONCLUSION: A
      model describing these influencing factors on career decision making was
      developed. The discussion outlines some possible management solutions to address
      the problem of recruitment.

PMID- 10578812
TI  - Political participation in Hong Kong: a study.
AB  - AIMS: The aim of this study was to investigate nurses' level of political
      participation and their perception of political efficacy. METHODOLOGY: This is a
      descriptive study. A self-completed questionnaire survey was conducted. Some
      items in the adopted questionnaire were modified to suit the Hong Kong situation.
      SAMPLES: A convenience sample was used. Three hundred and fifty registered nurses
      that were studying nursing degree programmes in the three universities in Hong
      Kong were invited to participate in the study. FINDINGS: Three hundred and eleven
      registered nurses completed the questionnaire. The findings showed that there
      were some positive signs of both political awareness and participation in nurses.
      However, political activities were mainly confined to voting in general
      elections. Attempts to influence politicians were not evident. Subjects generally
      have low political efficacy, and they did not feel that nurses had the power to
      influence the government's policy. The results of this study are discussed in
      terms of the barriers to nurses' political participation and the recommendations
      for nursing professional development.

PMID- 10578813
TI  - Clinical supervision in nursing in the 1990s--current state of concepts, theory
      and research.
AB  - AIM: The aim of this article is to explore the current state and challenges of
      clinical supervision with regard to its research. BACKGROUND: Clinical
      supervision in nursing has been debated extensively, but also accepted officially
      as part of nursing practice. However, it has been claimed that the subject is
      conceptually vague, theoretically ambiguous and lacking in empirical research
      evidence. METHODS: A computer-based search was carried out in an international
      journal database of nursing. Of the published articles on effectiveness, 11 were
      chosen for a closer examination. FINDINGS: It can be argued that the present
      studies have failed to show actual effects of clinical supervision reliably and
      convincingly enough. CONCLUSION: Research into supervisory effectiveness is still
      in its infancy. To increase the scientific rigour of future research, it would be
      necessary to expand and clarify the scope of these studies as well as to
      diversify the range of research methods on the basis of ontological and
      epistemological analyses.

PMID- 10578814
TI  - Texas revises licensing rules for dialysis facilities.

PMID- 10578815
TI  - Implementation of NKF-DOQI: a progress report.

PMID- 10578816
TI  - How to prepare your dialysis facility for Y2K.

PMID- 10578817
TI  - Violence in the dialysis unit revisited.

PMID- 10578818
TI  - Moving toward the future in access management.

PMID- 10578819
TI  - CDC: reports of VRE cases increasing; hepatitis vaccinations improving.

PMID- 10578820
TI  - Internet interest grows at Northwest Kidney Centers.

PMID- 10578821
TI  - Transplantation on the Web: case study provides hands-on approach.

PMID- 10578823
TI  - Managing transplant care.

PMID- 10578822
TI  - Infection control can help keep VRE in check.

PMID- 10578824
TI  - Presumed consent: the only scheme that works.

PMID- 10578825
TI  - Developing a work-based learning philosophy.

PMID- 10578826
TI  - Respecting and breaking confidences: conceptual, ethical and educational issues.
AB  - Issues of confidentiality are an integral part of professional nursing practice,
      hence reflection on these issues is an integral part of nurse education.
      'Respecting and breaking confidences: conceptual, ethical and educational issues'
      argues that reflection must take account of at least two conceptual issues,
      namely, what is confidential information? and what constitutes a breach of
      confidentiality? An answer to these questions is logically presupposed by the
      ethical questions considered, i.e. what should clients be told about the
      parameters of confidentiality at the first point of contact? and what would
      justify a breach of confidence? The discussion is anchored in a critique of the
      Advisory Paper (1987) on confidentiality, published by the United Kingdom Central
      Council for Nursing, Midwifery and Health Visiting. It concludes by drawing out
      some implications for nurse education.

PMID- 10578827
TI  - Problem-based learning in a competency-based world.
AB  - This article addresses the needed shift in nursing education from an information
      driven approach in teaching to a process that promotes higher level thinking and
      clinical judgement. Strengths and weaknesses of problem-based learning and
      competency-based education in nursing are presented. Whereas the former focuses
      on critical thinking and clinical judgement, the latter's emphasis is on clinical
      competency. The appropriateness of the philosophies in both academic and practice
      settings is discussed.

PMID- 10578828
TI  - The part-time student role: implications for the emotional experience of managing
      multiple roles amongst Hong Kong public health nurses.
AB  - The study investigated the contribution of the added part-time student role on
      the emotional experience of managing multiple roles of Hong Kong public health
      nurses (PHNs) who have children by comparing PHNs with and without the part-time
      student role. The research design employed the experience sampling method.
      Convenience sampling was used to recruit 20 subjects of which nine were
      undertaking part-time degree programmes. A watch was worn that gave a signal at
      six random times each day for 7 days to complete an experience sampling diary.
      PHNs on average responded to 34 signals (80%) and therefore completed 34 diaries,
      which collected data on work, college-work and family juggling and their effects
      on mood states. Results indicate that PHNs with an added part-time student role,
      although having fewer juggling occasions and higher emotional spouse support, had
      fewer family-related activities as well as a lower positive effect and a higher
      negative effect than PHNs without this role. These results suggest that taking up
      an added part-time student role creates additional role strain to nurses with
      children, and lend support to the argument that the stress of managing multiple
      roles is greatest and benefits least when work and non-work role responsibilities
      are both heavy.

PMID- 10578829
TI  - The development of a system for accrediting prior learning of nurses.
AB  - This paper chronicles the experience of applying an action research methodology
      to a research project which developed systems and procedures for the
      accreditation of prior learning in the context of nursing education. Structures
      and methods adopted in implementing this approach are outlined; the outcomes,
      issues and recommendations are discussed.

PMID- 10578830
TI  - The nurse teacher's clinical role now and in the future.
AB  - The role of the nurse teacher in relation to the clinical setting has been
      debated for 20 years, yet it has been the subject of relatively few large
      studies. Recent studies led to inconclusive results, hence the nurse lecturer's
      clinical role remains an area of long-standing dispute. Changes in nurse
      education United Kingdom Central Council (UKCC) and the amalgamation of nurse
      education into higher education as part of the Strategy for Nursing, as well as
      the expansion of supernumerary status for student nurses, gave impetus to the
      search for a new clinical role for nurse lecturers. Research suggests that nurse
      teachers wish to maintain clinical contact, but the nature of this contact is
      vigorously debated at present. Lee, in reviewing the literature, concluded that
      this topic is highly contentious in terms of its nature, extent and purpose. She
      goes as far as to suggest that there is a need for empirical research to address
      the question as to whether there is a role for nurse lecturers in the clinical
      area. This paper examines some of the factors which influence the development of
      the clinical aspect of the role of nurse lecturers, explains how the author
      performed this role and the perceived benefits to students, mentors and the
      lecturer. It proposes a clinical role model based on the literature and the
      author's own personal experience as a 'clinical liaison lecturer' since the
      integration of nursing education into higher education. Key points The clinical
      role of the nurse teacher remains an area of long standing dispute Nurse
      lecturers wish to maintain clinical contact and maintain clinical competence, but
      in reality no consensus exists as to its meaning The mentor's role can be
      complemented by a clinically competent nurse lecturer who arguably should be able
      to teach in the classroom and the practice settings Using a triangular approach
      to reviewing student's experience, lecturers can update their clinical knowledge,
      demonstrate credibility, promote education-practice relations and ensure
      classroom teaching is relevant to current practice The establishment of guiding
      principles (recognized and agreed upon by service and educational managers)
      serves as a framework which nurse teachers can use to establish their own
      clinical role for each of their 'link' areas The nurse lecturer is in a good
      position to influence and maintain standards in nursing practice.

PMID- 10578831
TI  - The biosciences in the pre-registration nursing curriculum: staff and students'
      perceptions of difficulties and relevance.
AB  - This paper considers the problematic position of the biological sciences in pre
      registration nurse education--'The Bioscience Question'. There is no consensus
      and little research on the appropriate content and depth of bioscience knowledge
      required by nurses. Attempts to apportion curriculum time for the biosciences are
      confounded by the difficulty experienced by nursing students with this area.
      Within one university department, a survey was undertaken to investigate the
      perceptions of pre-registration students, and their teachers, of the teaching and
      learning of biological science, in comparison with other areas of the curriculum.
      Our findings concur with others that the biosciences are a source of
      disproportionate difficulty and anxiety to nursing students. Among the students,
      but not the lecturers, there was some, by no means universal, support for the
      suggestion that these problems could be reduced by a reallocation of curriculum
      time in favour of the biosciences. Although it was agreed that bioscience theory
      should be related more closely to nursing practice, there was no evidence that
      this lessened the students' difficulties with the subject. In contrast to
      lecturers, students felt the biosciences to be one of the areas of the pre
      registration curriculum most relevant to clinical practice.

PMID- 10578832
TI  - The selection of students for children's nursing: the qualities expected of
      candidates.
AB  - The knowledge, skills and attitudes which institutions expected of applicants for
      pre-registration Diploma programmes in children's nursing were investigated.
      Criteria were derived through an examination of nursing literature related to
      activities undertaken to meet the needs of children, when they are ill. Specific
      qualities, such as observational, psychomotor and interpersonal skills, combined
      with a desire to work with children and their families, were considered as being
      important in the selection of potential children's nurses. These criteria were
      compared with the expectations of those involved in the selection of students for
      children's nursing. Surprisingly, psychomotor skills were not mentioned by
      respondents and only around one-third of institutions clearly stated that they
      expected some understanding of children and their families. There was no mention
      of observational skills. These data supported the notion that there are a number
      of inherent qualities which selectors might look for in candidates; however, not
      all respondents have the same expectations of their candidates for the Child
      Branch. This raises the question of whether those offering programmes which leads
      to a qualification, acceptable throughout the UK, should be encouraged to work
      towards greater agreement on the qualities of those suitable to be taken into
      education as a children's nurse.

PMID- 10578833
TI  - Nursing to care or caring to nurse: a qualitative investigation of perceptions of
      new recruits.
AB  - This article discusses the perceptions of nine student nurses at the commencement
      of a 3-year diploma programme in nursing. In particular, it focuses on new
      recruits' perceptions of nursing. As part of a larger longitudinal study which
      examines the impact of the nursing curriculum on perceptions of health, data were
      collected from a sample of students concerning their perceptions of nursing,
      health, illness and the course. Content analysis of indepth interviews identified
      four themes concerning perceptions of nursing. These were caring, nurture,
      healing and self-development. These themes are discussed in relation to the
      student nurses life experiences and in the context of a notion of health as a
      central goal for nurse education. The students' perceptions of nursing at the
      commencement of the course suggest that nursing may be a moral choice as an
      occupation underpinned by the desire to do something worthwhile, whilst the
      relationship between nursing and health was not explicit.

PMID- 10578834
TI  - Moral guidance, moral philosophy, and moral issues in practice.
AB  - Approaches to teaching ethics to nurses have been debated in literature for some
      years. Three issues in particular are commonly addressed: the intentions of such
      teaching; the value of examples and case studies; and the compatibility of
      philosophical approaches with the clinical reality experienced by students. It is
      argued here that moral guidance as a strategy is unacceptable, and that a basic
      introduction to philosophical methods is the key to effective learning of the
      skills required for autonomous analysis and decision making. A means for
      including the use of personal experiences and case study material is presented
      which relies upon the provision of a framework of analysis to facilitate
      structured thinking and the pursuit of justifiable arguments. The approach
      suggested is compatible with students' existing experiences and work-context, and
      enhances the integration of ethical reasoning into the multi-faceted totality of
      clinical practice.

PMID- 10578836
TI  - Understanding gallstone formation

PMID- 10578835
TI  - The development of empathy in students on a short, skills based counselling
      course: a pilot study.
AB  - This paper reports on a pilot study to measure the development of empathy in
      students on a short skills-based counselling course. Thirty-eight students from a
      total population of 56 produced mean empathy scores prior to and following the
      counselling training. The results indicate that changes in levels of student
      empathy occurred in all but one of the students with a wide variation in the
      degree of change. Whilst the results obtained in this study in no way allow any
      firm conclusions to be drawn, they do provide tentative evidence that student
      empathy levels can increase as a consequence of undertaking a short skills-based
      counselling course and, further more, comprehensive research in this area is
      indicated. This apparent increase in students' empathy appears to be a positive
      development, yet it could also create difficulties for the nurse due to the
      possibility of increased emotional demands created by this empathy. Despite the
      arguments for attempting to develop empathy in students being robust, there may
      be some individuals who would argue that short skills-based counselling training
      does not enable empathic development in the students. Whilst the authors argue
      that there is a need to demystify counselling training, they in no way suggest
      that there is no need for lengthy, more intensive counselling training. There
      appears to be a case for having both forms of counselling training.

PMID- 10578837
TI  - Neisseria meningitidis

PMID- 10578839
TI  - Easy as PIE

PMID- 10578838
TI  - Reducing risks with antiseptic catheters

PMID- 10578840
TI  - Proper hand-washing technique

PMID- 10578841
TI  - Furazolidone and mood disorder

PMID- 10578842
TI  - Nutritional supplements: good or bad for your surgical patient?

PMID- 10578843
TI  - Listen to the music

PMID- 10578844
TI  - How to reduce your legal risks in an emergency

PMID- 10578845
TI  - Closing in on mitral valve disease

PMID- 10578846
TI  - Actionstat: altitude sickness

PMID- 10578847
TI  - Conscious sedation: guarding your patient against complications

PMID- 10578848
TI  - Taking the tension out of traumatic pneumothoraxes

PMID- 10578849
TI  - Hearing the need: lessons from the bedside

PMID- 10578850
TI  - Gastrointestinal. Emergency!

PMID- 10578851
TI  - Shocking facts about semiautomatic defibrillation

PMID- 10578852
TI  - Herbel medicines: getting beyond the hype

PMID- 10578853
TI  - 7 ways to rise to the top

PMID- 10578854
TI  - Rachel's legacy

PMID- 10578855
TI  - Preventing falls at home

PMID- 10578856
TI  - Myths & facts ... about menopause

PMID- 10578857
TI  - Avoiding rebound injuries from Huber needles

PMID- 10578858
TI  - In memory of Granny

PMID- 10578859
TI  - What a difference a day makes

PMID- 10578860
TI  - Managed care creates ethical dilemmas for oncology nurses.

PMID- 10578861
TI  - Advance directives require much more than just a piece of paper.

PMID- 10578862
TI  - Debate in Washington heats up regarding physician-assisted suicide, pain
      management issues.

PMID- 10578863
TI  - Computerized health care presents confidentiality issues.

PMID- 10578864
TI  - High ethical standards contribute to quality cancer care.

PMID- 10578865
TI  - Rural nursing presents challenges, provides rewards.

PMID- 10578867
TI  - [The present and future of nursing] [In Process Citation]

PMID- 10578866
TI  - Off-broadway play shows how nurse addresses end-of-life needs. Interview by
      Suzanne Gordon.

PMID- 10578868
TI  - [May 12th--day of nursing] [In Process Citation]

PMID- 10578869
TI  - [100 years of International Council of Nurses. A little history].

PMID- 10578870
TI  - [The disposing of the humane. Euthanasia in its historical and current meanings].

PMID- 10578872
TI  - [Multimedia in nursing].

PMID- 10578871
TI  - [Forced measures in psychiatry].

PMID- 10578873
TI  - [With a clear aim towards the future. 10 years of geriatric nursing in 1999.
      Geriatric fair and congress].

PMID- 10578874
TI  - [Setting and pulling of a port needle. Fachgruppe Onkologie im DBfK,
      Landesrerband Bayern].

PMID- 10578876
TI  - [What kind of nursing education will we have?].

PMID- 10578875
TI  - [Depression: a frequent disease. According to WHO every 6th person suffers from
      depression of various causes and severity].

PMID- 10578877
TI  - [New structures for nursing education].

PMID- 10578878
TI  - [Development of nursing education for care of the elderly in Europe].

PMID- 10578879
TI  - [Public relations. II. Some important measures].

PMID- 10578880
TI  - [The variety of relaxation techniques].

PMID- 10578881
TI  - ["Bioethics" justifies the killing of newborns].

PMID- 10578882
TI  - [German nursing society: 100 days of the new board of directors].

PMID- 10578883
TI  - [Under what circumstances is work fun].

PMID- 10578884
TI  - [Day of ambulatory care. Time is money--relationship is quality].

PMID- 10578885
TI  - [The senior as a customer: producers and providers of services are discovering
      the seniors].

PMID- 10578886
TI  - [Nursing is getting a chance to present itself].

PMID- 10578887
TI  - [Care of the severely burned. 1219 minutes of care are needed every day].

PMID- 10578888
TI  - [Care of a patient with total endoprosthesis: discharge is possible after 2
      weeks].

PMID- 10578889
TI  - [Respiration-stimulating massage: calming and regular respiration of the patient
      are the aim].

PMID- 10578890
TI  - [Teaching project: prevention of decubitus ulcers: students learn to take
      responsibility for their own learning].

PMID- 10578891
TI  - [Didactic concepts in practice mentoring: practical teaching goals should be made
      transparent].

PMID- 10578892
TI  - ["Psychological health promotion": nurses can do something for themselves].

PMID- 10578893
TI  - [Primary nursing as an organizational model: primary care needs cooperative
      guidance].

PMID- 10578894
TI  - ["Against the loss of humaneness"--part 1: Care must not be reduced to daily
      routine].

PMID- 10578895
TI  - [Resuscitation: is the nursing service prepared for emergencies?].

PMID- 10578896
TI  - [Intercultural communication in the hospital: what is foreign in this case?].

PMID- 10578897
TI  - [Nursing categories as a basis for the determination of the expenditures for
      intensive care nursing. A model from the intensive care unit of the neurosurgery
      department of the Heidelberg University Hospital].

PMID- 10578899
TI  - [Hilde Steppe] [In Process Citation]

PMID- 10578898
TI  - [Expert opinions by nurses].

PMID- 10578900
TI  - [State of development and challenges of federal German nursing science].
AB  - Nursing care in the Federal Republic of Germany has taken an unexpected, major
      developmental leap in recent years: numerous new study programs for nursing have
      been established over a very short period. Additionally we have also seen the
      advent of nursing science in our universities, and the development of nursing
      research is essential in making this field a true scientific discipline. This
      paper takes stock of what has been achieved so far, reviewing nursing as it is
      practised, study programs, and the development of the scientific discipline and
      nursing research. It will show that, in spite of the numerous achievements in the
      recent past, there are still many more tasks that need to be addressed. Just one
      of these is to fill the continuing vacuum by building up the science, pushing
      ahead with the development of nursing research, and creating appropriate
      conditions for promising researchers from the next generation.

PMID- 10578901
TI  - [What kind of science is required by nursing?].
AB  - This article represents a slightly modified paper presented at the symposium on
      Nursing Science held by the University of Basel in December 1998. It involves a
      topic analysis of the requirements for nursing science of a nursing service of a
      University Hospital. On the basis of this analysis a possible identity of Nursing
      Science is derived. It appears to be compatible both with the ethos and goals of
      the nursing profession and with the present system of the sciences.

PMID- 10578902
TI  - [Development of nursing science in Germany].
AB  - This essay investigates the following two questions: Why did it take so long to
      become apparent that nursing has an important role in our society? What
      influenced the growing importance of nursing? Since this essay was part of a
      habilitation process, it begins with a review of the first German habilitation in
      nursing in 1895. In retrospect, this document reveals ideas of nursing that are
      important and still valid today, even though it was written by a physician.
      However, nursing as a profession practised by nurses or nuns was hidden in the
      invisible corners of health care and developed as a marginal category. For
      religious reasons nurses, as women, were encouraged to obey and not think for
      themselves. Only during the last few decades did nursing acquire a new meaning
      due to structural changes in morbidity and population, as well as a belated new
      sense of self-confidence in a profession still predominantly female. Within these
      new demands, nursing science also gained in significance. Its first substantial
      ideas came from North America. The difficulties in developing the nursing science
      lie in the nature of nursing, which often seems to be near omnipotence.

PMID- 10578903
TI  - [Suggestions for the health care system of the future: family-oriented primary
      health care].
AB  - This paper will describe one of the major trends in health care delivery: family
      oriented primary care. Implications and future directions for practice, education
      and research in the United States and Germany will be described and contrasted.
      The paper is a result of an ongoing dialogue between the first author, a
      Fulbright Professor at the University of Witten/Herdecke, and the second and
      third authors. The authors believe that, contextualizing emerging trends in
      health care delivery in this way, helps to clarify both what is unique to each
      country and what is actually or potentially shared in common.

PMID- 10578904
TI  - [Concepts of pain in preschoolers and children of early school age and their
      parents after painful interventions during hospitalization].
AB  - Subject of the present study are individual pain concepts of preschoolers and
      children of early school age. Their parents' concepts of pain were considered as
      well. In a qualitative study interviews were performed with 9 children and their
      parents in a children's hospital to investigate their individual concepts of
      pain, their methods of pain assessment, and self-initiated strategies of pain
      alleviation. Already 4-6 year old children are able to remember painful
      experiences and to communicate about pain. Strategies of pain alleviation used by
      children are distraction methods as well as methods of physical relief. The
      child's parents play an important role concerning pain assessment and coping. The
      parents' presence is also very important to communicate the child's needs to
      nurses. Parents want nurses to consider physiological as well as behavioral
      aspects in the assessment of the child's pain. Besides, they expect nurses to
      have competences concerning prevention, assessment and alleviation of pain. To
      perform a trustful relationship to children and parents, more intensified
      counselling by nurses seems necessary.

PMID- 10578905
TI  - [Quality criteria for qualitative research].
AB  - In this article criteria for quality in qualitative research will be described,
      discussed, and compared with the usual criteria for quantitative research. This
      paper will focus on Lincoln & Guba's concept of trustworthiness (1985). We hope
      to support novice qualitative researchers and to stimulate further discussion.

PMID- 10578906
TI  - [Quality assurance in nursing: self evaluation and peer review of nursing
      standards. Review of 2 years' experience].
AB  - Within the quality assurance programme of nursing in a teaching hospital in
      Switzerland two steps are considered to be essential: the evaluation of standards
      by the authors themselves (self-evaluation) and the evaluation by peers from the
      hospital (peer review). These evaluations are part of a decentralized model of
      quality assurance. This paper describes the systematic control of the standards
      of care over a period of two years. In particular the author reviews the
      development of the instruments for self-evaluation and peer review; the education
      and allocation of peers: the selection of standards for the control process;
      finally the first results of the evaluations and the ensuing measures. The author
      goes on to describe her experience with the instruments of control. Conformity
      with a preestablished policy and continuity within the group of peers are
      considered to be important prerequisites for the quality of the evaluations.
      Development and control of mainly monodisciplinary standards are considered to be
      a transition and preparation for an eventually interdisciplinary quality
      assurance programme.

PMID- 10578907
TI  - [Nursing diagnoses: questions and controversies].
AB  - This article analyses the issues and controversies surrounding nursing diagnoses.
      In particular, NANDA's attempt to have their nursing diagnosis taxonomy included
      in the WHO's 10th Revision of the International Classification of Diseases, which
      ultimately would have made the NANDA taxonomy the definitive nursing
      classification world wide. A critical analysis and discussion about nursing
      diagnoses within German-speaking nursing society is long overdue.
      Internationally, the nursing environment differs in aspects such as culture,
      philosophy, socio-economic status and legal context--all of which have to be
      taken account of when developing an international nursing classification system.
      In this light, the "fit" of the NANDA taxonomy has to be questioned within a
      European context. Further, the consequences that importing these diagnoses might
      have on the "profession's" development are usually neglected within the
      literature.

PMID- 10578909
TI  - [Psychosocial nursing diagnosis: an interpretative-phenomenological perspective].
AB  - Nursing diagnoses and other nomenclatures of this kind belong to the category of
      technological knowledge, developed for the sake of domination (Scheler 1974
      1928). Nomenclatures can be used as base for the recording of nursing services.
      However, the body of knowledge represented by nursing diagnoses cannot serve the
      profession as a foundation for clinical decision making nor as inspiration for
      professional conversations with patients. Selected psycho-social nursing
      diagnoses are critiqued by comparing them with the description of a patient's
      illness experiences.

PMID- 10578908
TI  - [The complex relationship between nursing diagnosis and nursing management].
AB  - To begin with the meaning nursing diagnostic has upon nursing management is being
      emphasised. Contents and depths are being illustrated on the changements of
      "adjustment" and "development". Adjustment as adaption into the specific
      organisational rationality or development as analysis of organisational norms and
      values as well as reconstructing the context of a new frame of relations. The
      outcome of nursing diagnostics can be shown and discussed on the following four
      dimensions: 1. Task, goals and productivity, 2. Management of personnel , 3.
      Cooperation and integration, 4. Inner and outer flexibility. In addition to the
      elucidations of each dimension sample aspects are picked out to show the outcomes
      on the social and on the whole system. The necessity of the development of
      nursing and its context in a dialectical manner are being stressed. The meaning
      thereof for nursing management is being led by basic importance and the creation
      of jobs which further the personal development. In part two the meaning of
      nursing management for nursing diagnostics is stressed. It is discussed which
      aspects of leadership are essential, the network between them and the
      introduction of a process of development, such as nursing diagnostics. Finally,
      it is made clear to which degree the way changes are handled depends on the
      system of leadership and which norms and values in an organisation further or
      hinder learning and changing processes. This speech bases on the one hand on
      experiences in connection with a pilot project of the Department of Health of the
      State of Zurich under whose partonage the nursing model of DDr. Silvia Kappeli
      has been introduced in five hospitals. It was intended to integrate the planned
      changes into a process of conversion and development of the systems. On the other
      hand it depends on my long-term experiences as an instructor and adviser in the
      health care system.

PMID- 10578910
TI  - [Becoming partners: the meaning of caring for patients with HIV and AIDS].
AB  - The purpose of this study was to understand and describe what constitutes caring
      as experienced by persons living with HIV and AIDS (PLWAs) along their illness
      trajectory. Interpretative phenomenology was employed. Six men and one woman
      living with HIV or AIDS participated in open-ended interviews. Interviews were
      analyzed according to Benner (1994) through paradigm cases, thematic analyses,
      and analyses of examples. Convenience sampling was used to select participants.
      Two distinct categories were interpreted: Letting go step by step and becoming
      partners. Letting go step by step encompasses the entire time people are living
      with HIV/AIDS illness trajectory. Becoming partners describes the relationship
      and commitments between PLWAs and families, friends, and health care providers.
      These findings reinforce the need for families, friends, and health care
      providers to become partners with PLWASs and to work on this partnership along
      the entire illness trajectory.

PMID- 10578911
TI  - [Focal points in operating room nursing].
AB  - This research investigated with which thoughts and nursing problems patients
      undergo surgery without general anaesthetic were preoccupied during their
      operation. In addition, information was collected on those aspects of nursing
      care which the patients appreciated or missed during this time. Both sets of data
      were collected from nurses and patients. Comparative analysis showed that
      patients on average list less problems than nurses. Conclusions with respect to
      nursing care of patients who are awake during surgery is discussed.

PMID- 10578912
TI  - [Decisions and attitudes of nurses caring for severely ill elderly patients: a
      culture-comparing study].
AB  - Results of a comparative investigation in Swedish and German nurses are
      presented. Based on a case-vignette with three levels of available information
      about patient wishes the subjects were asked about their decisions. Generally,
      the Swedish nurses showed a tendency towards less aggressive treatment-options
      and to perform less frequent cardio-pulmonary resuscitation (CPR) against the
      patient written will compared with the Germans. The compliance with patient
      wishes among nurses from both countries was related with the valuation of the
      patient directive as a useful tool in their decision-making process. Furthermore,
      the "level of dementia" emerged as a significant predictor of the treatment
      decision in both groups. The results point to the necessity of continuous
      education and training of nurses aiming at the issues of ethical attitudes and
      coping with ethically problematic situations in the treatment of the elderly in
      order to improve patient autonomy.

PMID- 10578914
TI  - [The WHO comes to Spain].

PMID- 10578913
TI  - [Randomized clinical trials and systemic reviews in nursing literature: a
      comparison between German and international nursing research].
AB  - OBJECTIVES: To ascertain whether there are randomised-controlled trials (RCTs)
      and systematic reviews on nursing care, written in German language, which need to
      be identified for inclusion in systematic reviews of the effects of health care.
      Quantitative comparison of German-language and international nursing research.
      METHODS: Searches by Medline and CINAHL (1988-1997) and searches by hand of seven
      nursing journals, published in German language, to identify RCTs and systematic
      reviews. MAIN MEASURES: Total number of RCTs identified and number of RCTs
      published in German language journals. RESULTS: 15 RCTs related to nursing care
      have been identified. No RCTs have been found by hand search of nursing journals.
      There were no nurse researchers as first authors for RCTs. CONCLUSIONS: German
      nurse researchers need to adapt high quality study designs to nursing
      interventions studies to achieve international research standard.

PMID- 10578915
TI  - [Nursing and the prevention of biological risks: from education to professional
      activity].
AB  - OBJECTIVE: To discover the training nursing students receive regarding prevention
      and control of infection inside hospital settings and the means of self
      protection as well as making people aware of the need to improve this training if
      deemed necessary. METHODS: This is a transversal descriptive study which took
      place in the nursing schools in Spain. Data was gathered by means of a
      questionnaire each respondent filled in by themselves. The lack of a response was
      also studied. A followup meeting was held with those who participated in this
      study to seek consensus in the search for solutions to those necessary changes
      detected. RESULTS: 86% responded to the questionnaire. During the course of
      career preparation, these were the average number of hours dedicated to various
      areas of study: 34.5 to Biological Statistics, 40 to Epidemiology, 28 to
      Infectious Diseases, 29 to Microbiology, 9 to Infection Control, 11 to Concepts
      of Aspesis and Antisepsis, and 36 to Methods of Research and Investigation. More
      than 50% of the professors teaching these classes are licensed nurses. Student
      followup during their clinical practice was carried out basically by nurses in
      university hospitals. 39% of nursing schools teach the concept and content for
      universal precautions prior to clinical practice. In the majority of public
      nursing schools, the followup of a student after a biological accident is carried
      out by the preventive medicine service, whereas this is done by the school
      insurance company in private nursing schools. Therefore, significant differences
      exist. COMMENTS: The theoretical knowledge taught is adequate; the number of
      hours dedicated to each subject varies among the schools; it is necessary to come
      to an agreement on the minimum levels of training required before engaging in
      clinical practice in a safe manner. Universal precautions should be taught in all
      schools before clinical practice occurs.

PMID- 10578916
TI  - [Cutaneous nerves of the right lower extremity].

PMID- 10578917
TI  - [The nursing process. Perspectives of teachers and alumnae].
AB  - A qualitative investigation has been carried out whose objective has been to
      explore the real impact of the Nursing Care Attention Process in an educational
      setting by means of compiling the opinions/perspectives from professors and
      students. The type of qualitative study used is the case study. To this end, a
      nursing school having experience in the teaching of Nursing Care Attention
      Process and having a minimal integration of this topic in its curriculum was
      selected. The selection of the sample professors and students took place
      according to pre-established criteria. The sample total included 8 professors and
      7 students. Data were collected by means of structurally flexible interviews and
      with an itemized study of the documents of the center. The content analysis of
      the data gathered shows that the Nursing Care Attention Process is considered to
      be an adequate instrument in nursing education but one which requires from the
      students an early development in a series of knowledge, abilities and capacities
      so as to be able to use it in practice. Bearing in mind the importance of the
      teaching setting for the appropriate use of this method, this project concludes
      with a series of recommendations which should be carefully weighed when designing
      a curriculum. This article summarizes the author's master' thesis at the
      University of Manchester.

PMID- 10578919
TI  - [IV. National congress of History of Nursing. Nursing on the Jacobean pathway]
      [In Process Citation]

PMID- 10578918
TI  - [Attitude of nurses towards patients with Alzheimer's disease].

PMID- 10578920
TI  - [Cardiopulmonary resuscitation. Electric stimulation of the heart].
AB  - Due to the alteration in contractions coordinated and organized by miocardiac
      fibers, various types of cardiac stimulation have been designed which became
      acceptable standard clinical procedures starting in 1947 after the first
      successful electrical defibrilation was carried out on a human heart. This
      article includes techniques such as precordial fist percussion, repetitive
      precordial beating on the thorax, synchronized cardioversion, non-synchronized
      electrical shocks and pacemakers. Electrical therapy is used in the treatment of
      potentially fatal cardiac arrhythmia, especially for ventricular tachycardia,
      ventricular fibrilation, complete heart block, and asystolia.

PMID- 10578921
TI  - [Enteral nutrition and the critically ill patient].
AB  - Critically ill patients often suffer from malnutrition y loss of muscle weight
      throughout the whole time they are ill, even when they receive nutritional
      therapy, due to the tremendous amount of stress they undergo accompanied by a
      high degree of hypercatabolism. The most recent theories all coincide in the
      importance of the intestine as the preferred way for nutrients to enter the
      bodies of these patients because besides fulfilling its function to absorb and
      digest nutrients, the intestine plays an important role as a barrier to bacteria
      and their toxins. For these reasons, enteral nutrition should be the first option
      to consider whenever we must feed a critically ill patient by artificial means.

PMID- 10578922
TI  - [Intraaortic counterpulsation balloon].
AB  - The pumping or counterpulsation with an intraaortic balloon is currently the most
      widely used circulatory support technique due to the fact that it fulfills a
      unique role in the treatment of patients suffering from serious cardiovascular
      problems. No medication currently available can combine the two basic effects of
      the Intraaortic Counterpulsation Balloon Pump: reduction of the left ventricle
      aftercharge and of the increased diastolic arterial pressure. Since this
      procedure is a vital support for these patients, this challenges nurses'
      abilities and performance; therefore, continuous monitoring is necessary along
      with am immediate evaluation of the signs or symptoms of a patient's clinical and
      hemodynamic state and a precocious detection of possible complications.

PMID- 10578923
TI  - [Peptic ulcer].

PMID- 10578924
TI  - [Children's health and their rights threatened by violence].
AB  - The purpose of this study is to analyze the follow-up of police reports
      concerning domestic violence against children aged 0-5, from 1990 to 1995, held
      in the city of Rio de Janeiro. Based on a descriptive study, initially, on a
      database, the accusations in general were characterized. Soon after, 18 police
      stations were visited to analyze the follow-up of the police reports. Out of 105
      occurrences, only 25 were regarded as investigatory cases and just 01 was going
      to be analyzed in court. In sum, violence against child reflects cultural
      subjects.

PMID- 10578925
TI  - [Prostitution: causes and future perspectives in a group of young girls].
AB  - This is a descriptive exploratory study developed at the city of Natal/RN,
      through interviews with 10 young girls that made sexual programs at the Meio and
      Ponta Negra beaches. The purpose was to identify the reasons that made young
      girls to opt for this activity and the future perspectives of this group. Authors
      identified that the principal cause that leads these kids to become prostitutes
      was the lack of financial conditions, and, also, that they believe in future, to
      be able to work, to leave the prostitution, to have a profession and a better
      life. Therefore, there is a need for decisions by the responsible agencies and
      for society in general to give alternatives to these young kids to leave
      prostitution and mainly to prevent the ingress of new adolescents in this
      activity.

PMID- 10578926
TI  - [Social representations by a nursing team about undernourished children and their
      families].
AB  - The present study derived from our interest in nursing practice with the
      undernourished children and their families. Our objectives were: to understand
      the social representations of the nursing team about undernourished children and
      their families and to analyze how these representations can interfere in the
      process of taking care. Based on qualitative research principles, authors adopted
      the social representations theoretical method. For data collection and analysis,
      authors used the projective techniques and speech subject analysis, respectively.
      Results showed an innocent conception by nursing professionals, that reproduces
      in the practical field a strong moral code and hygienic habits to the family and
      it does not propitiate the formation of a critical conscience about their
      citizenship rights.

PMID- 10578927
TI  - [Transitional care in the course of nursing].
AB  - The present paper addresses human beings' transitionary events which permeate
      their vital cycle, as well as the conductive conditions to the transition
      processes and their care relations. It focuses on the several distinguishing
      types of transition and their conceptualizations throughout the scope of
      transitional care. Such care is concerned with the features of the events which
      derive change, as well as the individual variables and the context interacting
      with those features, facilitating the understanding of the interaction process
      and assimilation of the change. From that conceptualization, it targets the
      development of nursing interventions facing the transitional processes in the
      light of nursing theories, which can be re-stated in transition terms. Due to the
      variety of focuses, transition is related to nursing care and it aims at the
      prevention and intervention for each specific case, providing nurses with an
      innovative focus of care. It points out that care is somehow tied up to each
      developmental stage, favouring maturity and growth in the search for a larger
      balance and stability. Care facing transition brings about answers to the valuing
      of the being.

PMID- 10578928
TI  - [Care of patients with psychiatric disorders].
AB  - Nursing care to the human being in psychical suffering is the theme of this
      investigation, developed in a psychiatric hospital, in the west region of the
      Parana State. This is a qualitative research with the aim of finding out nurses'
      understanding about their work in psychiatric nursing. Authors used open
      interview to all the nurses of the institution. Then, data were grouped in
      thematic unities and analysed through the analysis of the content.

PMID- 10578929
TI  - [Needs of chronic degenerative diseases among adults in a basic health unit in
      Sao Carlos--SP].
AB  - The purpose of this study was to find out the profile of the larger clientele
      more than 12 years old of a Basic Health Unit (BHU), according to socio
      demographic variables such as sex,, age group, color, marital status, origin and
      to characterize the diseases profile according to the chapters of the
      International Classification of Diseases (ICD X-Revision) and group specific
      diagnoses standing out the group of the chronic-degenerative diseases, searching
      for its its characterization in the context of the demographic-epidemiology
      transition. The study was of the transversal type and the population was
      constituted by the clientele registered in the BHU until August 31, 1996.
      Individuals in situation of abandonment, the ones transferred to another units
      and those who died were excluded. The population studied was formed by 1013
      individuals. Data were processed in the software FOXPRO vs 2.0 and the analysis
      developed in EPIINFO vs 6.04. Authors verified that the studied population was
      basically formed by women (87.1%). Regarding age, 69.6% were between 12 and 40
      years old, 95.6% were of white color, 57.2% were married and 97% coming from the
      urban zone. The classification according to ICD chapters showed disturbances of
      the urinary tract and of the genital system (35.5%), breathing system (11.5%) and
      symptoms and signs (9.9%). The classification according to specific groups of
      causes showed similar proportions among the infect-parasitic diseases (24.8%) and
      the chronic-degenerative diseases (24.5%). In the group of chronic-degenerative
      diseases 50% of ICD chapters were formed by the groups: circulatory, endocrine
      causes and mental-behaviour. Authors observed that the profile of diseases at the
      BHU resembles the polarized model of transition where the chronic-degenerative
      diseases coexist with the infect-parasitic ones. The traditional model of care of
      the unit that focuses the maternal infant health seems not to adapt to the
      population progressive aging when prioritizing a clientele that although still
      young need collective actions for primary and secondary prevention of the chronic
      degenerative diseases.

PMID- 10578930
TI  - [Evaluation of patients with chronic pain in nursing consultations: Proposal of
      an instrument for nursing diagnosis].
AB  - This article describes the tool used to collect data for nursing evaluation of
      patients with chronic pain patient in the League Against Pain of the University
      of Sao Paulo at Ribeirao Preto Faculty of Medicine, Brazil. The aim is to
      identify the patients' nursing care needs. The nursing diagnoses proposed by the
      North American Nursing Diagnosis Association (NANDA) were used to point out the
      patients' nursing care needs. The Human Response Patterns, in which the nursing
      diagnoses are classified by NANDA, were used as a framework to construct the
      tool. The way it is used by nursing undergraduate students, members of the League
      Against Pain, is also described.

PMID- 10578931
TI  - [Profile of women with myocardial infarction according to the health field
      model].
AB  - The research aimed at finding out the profile of 49 women with myocardial
      infarction hospitalized in two hospitals at Sao Paulo state. The following
      results were analysed according to the "Health Field Model": a) human biology:
      79.6% of them were from 50 to 80 years old; 71.4% hypertension; 57.2% overweight;
      42.4% diabetes mellitus; 57.1% had a positive family history of hypertension; b)
      socioeconomic characterization: 63.2% housewives; 53% married; 55.1% with a
      salary lower than 3 minimum wages and 51% illiterate; c) life style: 93.8% lived
      a sedentary life; 79.6% referred to daily stress and 34.7% are smokers; d)
      attention to health: 53.1% knew about their diagnosis and 48.9% were being
      treated in primary health services. According to the model there are risk factors
      to infarction in the four elements.

PMID- 10578932
TI  - [The practice of breastfeeding in a group of Brazilian women: a movement of
      accommodation and resistance].
AB  - Actions to stimulate breastfeeding are directed to assist children's needs and do
      not contemplate woman in her specificities. The present study aimed at
      understanding the meanings women give to their experiences and demands in the
      practice of breastfeeding. 20 women that were experiencing breastfeeding for the
      first time were interviewed. Data analysis were based on the feminist theory.
      Authors found breast feeding as a feminine process socially determined. Women
      showed accommodation as they felt the act of breast feeding as donation, a
      sacrifice and dedication as well as resistance when they justified weaning
      affirming the lack of physiological capacity for breastfeeding.

PMID- 10578933
TI  - [Initiation to science in the undergraduate nursing program at the University of
      Sao Paolo (1993-1996): critical analysis].
AB  - This study search to delineate the profile of the scientific production of the
      undergraduate nursing programme of the University of Sao Paulo from 1993 to 1996,
      identifying its main lines and tendencies. In order to characterize it, the
      summaries of the proceedings of the Scientific Initiation Symposium of USP were
      analyzed (SICUSP) and of the Symposum of the University of Sao Paulo at Ribeirao
      Preto College of Nursing (SICEERP), through a classification in research types,
      themes and departments of origin. We observed a prevalence of descriptive
      research and an expressive number of investigations directed to the study of
      socio-cultural aspects among other results.

PMID- 10578934
TI  - [Memories and history for a new view of nursing in Brazil].
AB  - This study aims at evidencing the involvement of the historic knowledge to
      nursing, regarding to development of a critical conscience and new ways of
      perception and appreciation of the profession. Authors emphasize the potential of
      the subject to integrate teaching and research as well as to articulate the
      undergraduate and graduate programmes and in the consolidation of a research line
      of brazilian nursing history (HEB), demanding the preservation in the whole
      country of data sources, and the interchange between HEB researchers and
      historians who have interests on studies like this.

PMID- 10578935
TI  - 9 steps to effective restraint use.

PMID- 10578936
TI  - Ethics on the job: A survey. When caregivers endanger patients.

PMID- 10578937
TI  - A new procedure for prostate patients.

PMID- 10578938
TI  - A Christmas tribute.

PMID- 10578939
TI  - Trauma! Head injuries.

PMID- 10578940
TI  - Pins and pinning--the traditions continue.

PMID- 10578941
TI  - Near death. Back from beyond.

PMID- 10578942
TI  - Natural tranquilizers?

PMID- 10578943
TI  - Too few staff, too much risk.

PMID- 10578944
TI  - Vitamin/herb combos pose dangers.

PMID- 10578945
TI  - The breast cancer myth.

PMID- 10578946
TI  - Buying a computer on the Internet.

PMID- 10578947
TI  - It's on paper, but do they understand it?

PMID- 10578948
TI  - Ischemic stroke pathway relies on ED order sheets.

PMID- 10578949
TI  - How to spot this catheter complication.
AB  - Although it's most commonly seen in cancer patients, superior vena cava syndrome
      is an easily overlooked threat to anyone who has a central venous access device
      in place. Carefully piecing together vague patient complaints with data from a
      chest X-ray and other diagnostic tests will allow prompt treatment.

PMID- 10578950
TI  - A practical approach to problem solving.

PMID- 10578951
TI  - Monitoring the gut to prevent MODS.

PMID- 10578952
TI  - Iatrogenic injuries. Acute tubular necrosis.

PMID- 10578953
TI  - What makes a great nurse?

PMID- 10578954
TI  - 1999 earnings survey. Bedside care is paying off.

PMID- 10578955
TI  - Safer needle devices.

PMID- 10578956
TI  - Using designer margarines to control lipid levels.

PMID- 10578957
TI  - Off-duty doesn't mean off the hook.

PMID- 10578958
TI  - [Why teach sick children and adolescents?].

PMID- 10578959
TI  - [A school in a hospital].

PMID- 10578960
TI  - [School in the neurosurgery department].

PMID- 10578961
TI  - [Home schooling].

PMID- 10578962
TI  - [New technologies helping in the schooling of children].

PMID- 10578963
TI  - [Caring for newborns in neonatology].

PMID- 10578964
TI  - [Dental caries and nutrition in children].

PMID- 10578966
TI  - [School nurses are angry] [In Process Citation]

PMID- 10578965
TI  - [Clinical history of a supposedly epileptic child].

PMID- 10578967
TI  - Thoughts on the cytopathologist and cell culture.

PMID- 10578968
TI  - Fine needle aspiration as a tool to establish primary human breast cancer
      cultures in vitro.
AB  - OBJECTIVE: To verify the potential role of fine needle aspiration (FNA) cytology
      in obtaining malignant cells from primary breast cancer for establishment of a
      primary breast cancer cell line. STUDY DESIGN: In four patients with primary
      breast cancer subjected to FNA for diagnostic purposes, we attempted to establish
      primary cultures. We successfully obtained one primary cell line, originating in
      micropapillary invasive breast carcinoma. FNA material obtained under sterile
      conditions was centrifuged, and the cell pellet was washed with Dulbecco Modified
      Medium. The resulting suspension was seeded in 25-cm2 tissue culture flasks. The
      flasks were maintained with released caps in a 37 degrees C incubator with a
      humidified atmosphere of 5% CO2 in air. After one week, cells attached to the
      bottom of the flasks and began proliferating. When a culture became confluent,
      the cells were treated with 0.05% trypsin/0.02% EDTA in a PBS solution and
      subcultured. The flasks were observed daily with an inverted microscope, and
      culture passages were performed weekly. RESULTS: The cell line obtained was named
      I2FPRW and exhibited morphologic and immunohistochemical features of epithelial
      cells of mammary origin. The cells were positive for cytokeratins (AE1/AE3 and CK
      7), EMA and c-erbB-2. At this writing, this cell line was in the 15th passage of
      subculturing in the flasks with 10% FBS. CONCLUSION: In the present study we
      demonstrated that is possible to establish a breast cancer cell line from
      material obtained by FNA cytology. FNA seems to be a valuable method of obtaining
      malignant cells from breast cancer able to grow free of fibroblasts in cell
      cultures.

PMID- 10578969
TI  - Fine needle aspiration of the testis. Correlation between cytology and histology.
AB  - OBJECTIVE: To determine the diagnostic value, reliability, safety and patient
      discomfort of testicular fine needle aspiration (FNA) as a cytologic sampling
      technique. All cases were divided into three groups: group A (control group), 15
      patients with normal testes undergoing orchiectomy for prostatic carcinoma
      treatment; group B, 17 cases who had presented with oligoazoospermia for
      evaluation of male infertility; group C, 20 cases who had presented mainly with
      scrotal swelling with or without pain. The patients' ages ranged between 22 and
      83 years. Older patients entered group A. Younger patients entered group B. A
      wide range in age occurred in group C. STUDY DESIGN: Fine needle aspirates from
      98 testes in 52 patients, 46 bilaterally punctured, were assessed. RESULTS: All
      fine needle results on group A and most on B and C were correlated with
      histologic results of biopsy specimens. In 88.5% of cases an excellent
      correlation was found between the results of the two methods, and the cytologic
      diagnosis was absolutely precise. The specificity and sensitivity of the method
      were 100% in this series. CONCLUSION: The procedure was well tolerated, reliable
      and simple, with no serious complications. Testicular FNA is a useful and safe
      investigative modality in the evaluation of testicular function and disease.

PMID- 10578970
TI  - Simple BASIC program for calculating the cervicovaginal FNP and for estimating
      the sample size of the number of cervicovaginal smears to be rescreened.
AB  - OBJECTIVE: To guide cytotechnologists and pathologists in calculating the false
      negative proportion, or rate, and the number of Papanicolaou smears to be
      reevaluated for a meaningful assessment of screening performance, a computer
      program written in BASIC was prepared, based on several recent publications in
      the field of cytopathology. RESULTS: A complete program listing and sample runs
      to help users be cognizant of the necessary inputs to run the program. The output
      from the program gives the results of the various calculations. CONCLUSION: Since
      the tedious manual calculations are handled by the computer program, it is more
      likely for those involved in the interpretation of Papanicolaou smears to follow
      the approaches suggested by experts in these two areas.

PMID- 10578971
TI  - Determining the cost-effectiveness of mass screening for cervical cancer using
      common analytic models.
AB  - OBJECTIVE: To estimate the cost per life-year saved (cost-effectiveness ratio
      [CER]) for cervical cancer and to evaluate the influence of the decreased
      incidence upon the cost per life-year saved. STUDY DESIGN: We established
      hypothetical cohorts at 10-year intervals between 30 and 79 years of age, each of
      which consisted of 100,000 asymptomatic female subjects, and estimated the cost
      and effect of single mass screening for cervical cancer. To investigate the
      influence on CER, we performed a sensitivity analysis of each item, including the
      consultation rate for further examination, prevalence rate and cost of medical
      treatment. RESULTS: The estimated CER per one expected life-year of survival was
      lowest for subjects in their 30s and highest for those in their 70s. The
      difference between the two was more than five-fold. Sensitivity analysis was
      rarely affected by changes in the cost of medical treatment and the prevalence
      rate, but the effectiveness rate could be fairly affected by the consultation
      rate for closer examination. CONCLUSION: Mass screening for cervical cancer is
      acceptable in terms of economic effectiveness. Moreover, mass screening for
      cervical cancer could decrease the morbidity rate for scores of years thereafter.

PMID- 10578972
TI  - Preclinical feasibility study of NMP179, a nuclear matrix protein marker for
      cervical dysplasia.
AB  - OBJECTIVE: To evaluate, in a preclinical feasibility study, the efficacy of
      NMP179, a monoclonal antibody recognizing a cervical tumor-associated nuclear
      matrix antigen, for the early detection of high and low grade cervical
      intraepithelial neoplasia. STUDY DESIGN: In a blind study involving two clinical
      sites, NMP179 immunocytochemical staining data from 261 cervicovaginal Thin-Prep
      specimens were evaluated. Assay sensitivity and specificity were calculated based
      upon a positive threshold of > 10 immunostained cells per case, using cytologic
      diagnosis as an end point. RESULTS: Based upon the examination of squamous
      epithelial cells, NMP179 detected 96.7% of cases with cytologically diagnosed
      high grade squamous intraepithelial lesions (HSIL) and 70.5% of low grade
      squamous intraepithelial lesions. The antibody also reacted with 29.6% of normal
      (within normal limits or benign cellular changes) smears. CONCLUSION: The NMP179
      assay detected HSIL with very high accuracy (96.7%). The assay was 79.3%
      sensitive for the detection of low and high grade cervical intraepithelial
      neoplasia (grades 1-3), with a specificity of 70.4%. NMP179 may be an effective
      marker for the early detection of preneoplastic squamous intraepithelial lesions
      of the cervix and may be useful as an adjunctive tool for better management of
      cervical intraepithelial neoplasia.

PMID- 10578973
TI  - Comparative evaluation of seven cell collection devices for cervical smears.
AB  - OBJECTIVE: To compare the most commonly used cervical sampling devices. STUDY
      DESIGN: We examined seven cytology sampling devices (Cytobrush, Cervex brush,
      Szalay spatula, Papex spatula, WrGKK spatula [main social security agency in
      Vienna], cotton swab and loop). Eight hundred smears were assessed for even
      distribution of cells, percentage of slide surface covered with cells, and
      presence and number of endocervical cells. RESULTS: Even distribution of cells
      was best with the WrGKK spatula. Percentage of slide surface covered with
      evaluable cells was best with the Cytobrush. Highest ranking for the presence of
      endocervical cells was found for the Cytobrush. Cotton swabs and loop showed
      inferior results in all categories. CONCLUSION: The use of cervical cell sampling
      devices showing the best cytologic results improves the interpretation and
      validity of cervical smears. Our results suggest that cotton swabs and loops
      should not be used for cervical cell sampling.

PMID- 10578974
TI  - Effects of chemotherapy and tamoxifen on cervical and vaginal smears in bone
      marrow transplant recipients.
AB  - OBJECTIVE: To clarify the importance of squamous and glandular atypia in the
      genital tracts of women undergoing high-dose chemotherapy and receiving
      tamoxifen. STUDY DESIGN: The pathology records of 769 female bone marrow
      transplant recipients from a five-year period at Duke University Medical Center
      were reviewed. One hundred fifteen cervicovaginal smears from 78 patients were
      available for evaluation; of these, 85 smears from 61 patients were selected.
      Only cases from patients with a complete medical history, including menopausal
      status and therapeutic regimen, were included in this study. Forty-five cases
      were from patients treated with chemotherapy alone, and 40 were from patients
      treated with a combination of chemotherapy and tamoxifen. RESULTS: A normal
      cellular pattern was the most common finding. Reactive cellular changes
      associated with therapy effect were identified in 21% of cases. In patients
      treated with chemotherapy alone, an atrophic smear pattern in a premenopausal
      woman was identified in 27% of cases. Squamous epithelial cell abnormalities were
      identified in approximately the same proportion of patients whether they received
      chemotherapy alone or with tamoxifen. Glandular changes were uncommon.
      CONCLUSION: The most common finding was a normal smear pattern. An atrophic smear
      was more commonly found in patients treated with chemotherapy alone than in those
      treated with both chemotherapy and tamoxifen. Squamous epithelial cell
      abnormalities are most probably independent of treatment effect. Glandular
      changes were rare in patients treated with chemotherapy, alone or in combination
      with tamoxifen.

PMID- 10578975
TI  - Rapid detection of HSV from cytologic specimens collected into ThinPrep fixative.
AB  - OBJECTIVE: Herpes simplex virus (HSV) infection is associated with substantial
      morbidity and mortality in neonates. A diagnosis of HSV on cervical cytologic
      studies could lead to a cesarean section, with an increase in the risk of
      maternal morbidity. The identification of viral lesions in sexually active women
      has medical and social implications. There have been reports of false positive
      diagnoses of HSV in patients with altered endocervical cells and with cervical
      intraepithelial neoplasia 3. We evaluated a polymerase chain reaction (PCR)-based
      assay to detect HSV-1 and HSV-2 in routinely collected cervical cytology
      specimens in ThinPrep fixative (Cytyc Corp., Marlborough, Massachussets, U.S.A.).
      STUDY DESIGN: DNA was extracted from five cases that demonstrated cytologic
      changes suggestive of an HSV infection. PCR amplification with subsequent gel
      electrophoresis was performed to detect the presence of HSV. RESULTS: HSV DNA was
      detected in three of five cases that were cytologically diagnosed as suspicious
      or strongly suspicious for HSV infection. CONCLUSION: The combination of the
      ThinPrep liquid-based method for cervical cytology with PCR allows prompt
      confirmation of the diagnosis of HSV without sacrificing the diagnostic
      morphology on the slide.

PMID- 10578976
TI  - Prognostic significance of p53, bcl-2 and EGFR in carcinoma of the endometrium.
AB  - OBJECTIVE: To evaluate the part played by several parameters in the prognosis of
      patients with endometrial carcinoma. STUDY DESIGN: Eighty imprint smears from
      fresh endometrial tumor specimens were studied immunocytochemically for the
      expression of p53, bcl-2 and epidermal growth factor receptor. Also, the presence
      of estrogen receptor (ER) and progesterone receptor (PR) in the tumor tissue was
      measured. The data obtained were related to survival, and associations were
      sought between the parameters studied. RESULTS: Strong associations were found
      between advanced stage, high grade, lymph node metastases at diagnosis,
      nonendometrioid histology and p53 expression with poor survival. Bcl-2 expression
      was associated with good five-year survival. ER expression was associated
      marginally with good five-year survival, but PR expression was not. A strong
      association was found between p53 and advanced disease, stage and lymph node
      metastases at diagnosis. An association between EGFR positivity and survival was
      not found. CONCLUSION: p53 Expression of uterine tumors is an independent and
      strong indicator of poor prognosis. Even patients with stage I and II disease at
      surgery who have p53-positive tumors must be considered at high risk.

PMID- 10578977
TI  - CytoView. A prototype computer image-based Papanicolaou smear proficiency test.
AB  - OBJECTIVE: To develop and assess CytoView, a prototype computer image-based
      cytology proficiency testing (PT) system, as an alternative to glass-slide
      cervical cytology PT. STUDY DESIGN: The computer-based PT consists of 10 cases
      taken from 10 Pap smears, each of which had received a consensus Clinical
      Laboratory Improvement Amendments-category diagnosis from three pathologists.
      Each CytoView "case" was the digital representation of > 8,000 microscopic
      fields, captured from a selected 5 x 10-mm rectangle of a Pap smear. The 5 x 10
      mm capture rectangle was selected from the slide's most representative area for
      its diagnostic category. The CytoView project team developed each case through a
      multistep process that included image capture, image alignment, correlation of
      10x and 40x images, and image display. The 10-slide CytoView PT prototype was
      then assessed by groups of cytopathologists and cytotechnologists. RESULTS: The
      CytoView prototype PT system was developed and assessed. CONCLUSION: Preliminary
      evaluation of CytoView indicated potential for this format as a valid and
      logistically feasible alternative to the traditional glass slide PT format.

PMID- 10578978
TI  - Association of mast cells with Warthin's tumor in fine needle aspirates of the
      salivary gland.
AB  - OBJECTIVE: To determine the significance of the presence of mast cells in
      Warthin's tumor by evaluating the occurrence of these cells in cellular and
      immunohistochemical preparations. STUDY DESIGN: Specimens derived from five cases
      of FNAC were examined. A total of four slides from five cases were prepared from
      each: two air-dried smears were stained with May-Grunwald-Giemsa (MGG) stain and
      two with Hansel's stain. The other two were alcohol fixed and stained using the
      Papanicolaou method. The smears were evaluated for the presence of mast cells,
      especially associated with oxyphilic cells. In order to investigate the location
      of mast cells, we also counted those cells by means of immunohistochemistry using
      anti-mast cell monoclonal antibody AA1. RESULTS: The Hanselstained cellular
      sample from Warthin's tumor contained numerous mast cells, associated mainly with
      large, oxyphilic cell sheets. The number of AA1-positive cells (mast cells)
      stained with immunohistochemistry was greater in epithelial component than in
      lymphoid stroma. CONCLUSION: Mast cells in a salivary gland aspirate might be
      indicative of Warthin's tumor; therefore, MGG-stained slides offer the advantage
      of ease of preparation, particularly when the typical cytologic features are not
      present.

PMID- 10578979
TI  - FNAC of malignant lymphoma in an area with a high incidence of T-cell lymphoma.
      Correlation of accuracy of cytologic diagnosis with histologic subtype and
      immunophenotype.
AB  - OBJECTIVE: To analyze the usefulness of fine needle aspiration cytology on
      malignant lymphoma in an area with a high incidence of T-cell lymphoma and to
      correlate the accuracy of cytologic diagnosis with histologic subtype and
      immunophenotype. STUDY DESIGN: We retrospectively studied the usefulness of fine
      needle aspiration cytology in the diagnosis of 49 cases of nodal and extranodal
      non-Hodgkin's lymphoma (NHL) and seven cases of Hodgkin's disease in a total of
      56 patients in whom subsequent excisional biopsy revealed lymphoid malignancy.
      Slides showing the results of cytologic investigation were reviewed together with
      the information on which histologic diagnosis was based. On the basis of
      pathologic variables, such as prognostic groups based on the Working Formulation,
      so-called grade, cell size based on the modified Rappaport classification, and-
      in cases of NHL--immunophenotype, the accuracy of original and reviewed cytologic
      diagnoses was compared. RESULTS: Of the 49 cases of NHL, 8 (16.3%) were
      inadequate for cytologic diagnosis, and malignant lymphoma was diagnosed or
      suspected in 36 (73.5%), excluding inadequate specimens; the diagnostic accuracy
      for NHL was 87.8%. In high grade cases, malignant lymphoma was more easily
      diagnosed or suspected than in those that were low or intermediate grade. The
      rate of inadequate cases was highest in the "mixed small and large cell"
      category, and cases that were "false negative" were either composed entirely of
      small cells or contained a small cell component. Cytologic diagnosis or suspicion
      of malignant lymphoma was easily obtained in the "large cell" category, followed
      by mixed small and large cell and "small cell." Aspirates from non-B-cell type
      were more frequently acellular than those of B-cell type; with regard to
      diagnostic accuracy, however, there was no noticeable difference between the two
      immunophenotypes. CONCLUSION: In many cases in the mixed small and large cell
      category or where the immunophenotype was non-B, the aspirate was inadequate, and
      no definitive diagnosis was possible. Many of our cases of T-cell lymphoma were
      mixed small and large cell, and in Korea, where the incidence of extranodal and T
      cell lymphoma is high, the usefulness of FNAC for the initial diagnosis of
      malignant lymphoma is limited. For a definitive diagnosis, biopsy is required.

PMID- 10578980
TI  - Cytodiagnosis of lymphoid proliferations by fine needle aspiration biopsy.
      Adjunctive value of flow cytometry.
AB  - OBJECTIVE: To determine the accuracy of fine needle aspiration biopsy (FNAB)
      complemented by flow cytometry (FC) for the diagnosis of reactive and neoplastic
      lymphoid proliferations and subclassification of malignant lymphomas. STUDY
      DESIGN: Forty-one FNABs of lymphoid lesions on which FC had been performed were
      evaluated retrospectively. All cases were correlated with histology or clinical
      follow-up. RESULTS: Twelve FNABs were diagnosed as reactive. Eleven of the 12
      were confirmed as reactive on follow-up. One was a case of posttransplant
      lymphoproliferative disorder. Twenty-five FNABs diagnosed as lymphoma were
      confirmed by histology. In 22 of these 25 cases, there was 100% correlation
      between the subclassification given on FNAB with FC and that given on histology.
      Two of the remaining cases, which were correctly called follicular center cell
      lymphoma, showed discrepancies in grading. One case called Hodgkin's disease on
      FNAB was T-cell lymphoma on histology. Of four FNABs given an inconclusive
      diagnosis, two were lymphoma on follow-up, and two were reactive. CONCLUSION:
      FNAB examination, when it includes immunophenotyping by FC, is a useful technique
      for distinguishing reactive lymphoid proliferations from malignant lymphomas and
      for the subclassification of lymphomas.

PMID- 10578981
TI  - Diagnostic utility of sialosyl-Tn in discriminating carcinomatous cells from
      benign mesothelium in body cavity effusions.
AB  - OBJECTIVE: Detecting malignant cells in the setting of reactive mesothelium can
      be difficult. Several techniques have been tried but without widespread
      acceptance. Sialosyl-Tn (STn) is an aberrantly glycosylated precursor of the MN
      blood group antigen frequently expressed in carcinomas and dysplastic epithelium.
      We investigated the STn monoclonal antibody for its clinical utility as an
      isolated stain to discriminate benign mesothelium from malignant cells. STUDY
      DESIGN: Cell block material from 72 cases of body cavity fluids were
      immunostained for STn using the avidin-biotin complex method without antigen
      retrieval. Slides were incubated overnight at 4 degrees C in a humidified
      chamber. RESULTS: Strong immunoreactivity was noted in 31/40 (77%) carcinomatous
      cases. Only moderate staining was noted in 1 of 28 (4%) benign effusions and weak
      staining in 5 (18%) additional benign cases. Specificity was 100%, sensitivity
      78%, positive predictive value 100% and negative predictive value 76%. No
      staining was noted in four noncarcinomatous malignant effusions. CONCLUSION: STn
      may have diagnostic value in this cytologic setting as part of a diagnostic panel
      but not as an isolated stain.

PMID- 10578982
TI  - Esophageal tuberculosis. Endoscopic cytology as a diagnostic tool.
AB  - OBJECTIVE: To study the utility of endoscopic cytology in the diagnosis of
      esophageal tuberculosis in clinically unsuspected cases. STUDY DESIGN: During a
      period of four years, endoscopic cytology of esophageal lesions was performed on
      228 patients. In eight (3.5%) the cytologic diagnosis of esophageal tuberculosis
      was suggested on smears. Upon endoscopic examination, the sites of involvement
      were mid esophagus (five cases), upper esophagus (two cases) and lower esophagus
      (one case). Linear ulcer was seen in six cases; growth and narrowing of the lumen
      were seen in one case each. Endoscopic brush smears in seven cases and fine
      needle aspiration cytology smear in one case were collected. Air-dried smears
      stained by Giemsa stain were reviewed for detailed cytologic assessment. RESULTS:
      Smears showed well-defined granulomas with necrosis in five cases and granulomas
      without necrosis in three. Cytologic evidence of concurrent poorly differentiated
      squamous cell carcinoma was observed in one case. Tubercle bacilli were
      demonstrated in five cases. Endoscopic biopsy showed granulomas in three cases
      and tubercle bacilli in one case. In six cases there was no clinical or
      radiologic evidence of tuberculosis at other sites, thereby suggesting the
      possibility of primary esophageal tuberculosis. The remaining two cases had a
      past history of tuberculosis; one presented with cervical lymphadenopathy and one
      mediastinal lymphadenopathy. All patients received antitubercular treatment, and
      the patient with concurrent malignancy also received radiotherapy. All but one of
      the patients who succumbed to aspiration pneumonia responded to treatment.
      CONCLUSION: Endoscopic cytology is a useful modality in the diagnosis of
      esophageal tuberculosis in clinically unsuspected cases.

PMID- 10578983
TI  - Cytology of primary pulmonary mucoepidermoid and adenoid cystic carcinoma. A
      report of four cases.
AB  - BACKGROUND: Mucoepidermoid and adenoid cystic carcinomas are very rare primary
      pulmonary neoplasms that can be classified under the broader heading of salivary
      gland-like neoplasms (SGN). Both entities need to be considered in the cytologic
      differential diagnosis of lung tumors. We reviewed cytologic findings in primary
      pulmonary neoplasms diagnosed at our institution during the time period 1981 to
      the present along with outside consultation cases. CASES: Three cases of primary
      mucoepidermoid carcinoma and one case of primary adenoid cystic carcinoma of the
      lung were diagnosed based on cytology during the period examined. Patient ages
      were 16, 25, 47 and 78 years, respectively. The mucoepidermoid cytology specimens
      were composed of three cell types, mucinous, squamous and intermediate cells, at
      times associated with extracellular mucin. The adenoid cystic carcinoma consisted
      of small, uniform cells with dark nuclei, scant cytoplasm and associated,
      acellular balls of basement membrane material. CONCLUSION: The differential
      diagnosis for primary pulmonary neoplasms needs to include the rare SGN.
      Cytologic features of adenoid cystic carcinoma are diagnostic; those of
      mucoepidermoid carcinoma are at least suggestive.

PMID- 10578984
TI  - Cytologic diagnosis of vaginal metastasis from renal cell carcinoma. A case
      report.
AB  - BACKGROUND: Metastasis of renal cell carcinoma to the vagina is rare, although it
      may be the first evidence of the existence of the primary tumor. CASE: A
      metastatic deposit of renal cell carcinoma in the vagina was diagnosed by
      cytology as clear cell adenocarcinoma, which was confirmed by biopsy.
      Radiographic and ultrasound examinations confirmed the renal site of origin,
      which was corroborated by immunohistochemistry of the biopsy specimen.
      CONCLUSION: When a cytologic diagnosis of vaginal clear cell adenocarcinoma is
      made, metastasis of renal cell carcinoma should be considered in the differential
      diagnosis.

PMID- 10578985
TI  - Papillary thyroid carcinoma with exuberant nodular fasciitis-like stroma in a
      fine needle aspirate. A case report.
AB  - BACKGROUND: Papillary thyroid carcinoma (PTC) with exuberant nodular fasciitis
      like stroma (PTC-ES) is a new morphologic variant of conventional PTC. It is
      characterized by extensive reactive stromal proliferation, which may occupy 60
      80% of the tumor. CASE: A 42-year-old female developed a tender, left-sided
      thyroid mass. The fine needle aspiration biopsy specimen contained, besides
      diagnostic epithelial features of PTC, many cohesive tissue fragments of cellular
      stroma. CONCLUSION: A correct cytopathologic diagnosis of PTC-ES can be
      established if both epithelial and stromal components are present in needle
      aspirates.

PMID- 10578986
TI  - Cytology of recurrent ameloblastoma with malignant change. A case report.
AB  - BACKGROUND: Ameloblastoma is a rare tumor of the jaw that arises from the
      odontogenic epithelium. Ameloblastomas have a propensity for local recurrence
      and, rarely, for metastasis. The term malignant ameloblastoma is reserved for
      those metastasizing tumors that retain the typical morphology of ameloblastoma.
      Fine needle aspiration (FNA) reports on ameloblastomas are scant, and those on
      malignant ameloblastomas are still more so. CASE: In a case of malignant
      ameloblastoma diagnosed by FNA cytology, the clinical presentation was that of a
      malignant neoplasm. FNA smears were highly cellular and showed isolated,
      scattered cells and small groups of basaloid cells and polygonal squamous
      epithelial cells. Stellate and spindle-shaped cells were also seen in the
      background. The cytologic diagnosis was subsequently confirmed on histopathology.
      CONCLUSION: The characteristic combination of cells in FNA smears facilitated the
      diagnosis of ameloblastoma. Since the biologic behavior of the tumor was that of
      a malignant neoplasm, the slides were reviewed. The cytologic smears did not
      exhibit sufficient features of malignancy to label the lesion malignant.

PMID- 10578987
TI  - Signet ring adenocarcinoma metastatic to the bronchus and mimicking goblet cell
      hyperplasia. A case report.
AB  - BACKGROUND: Goblet cells in the lower respiratory tract are metaplastic bronchial
      epithelial cells usually associated with asthma or chronic bronchitis. Goblet
      cells acquire their name by a tendency to distend with mucus, with subsequent
      distortion in cell shape. Due to similarity of shape, metaplastic goblet cells
      and signet ring cells can be easily confused in cytologic samples. CASE: A 55
      year-old male with a history of gastrointestinal adenocarcinoma underwent
      brushing, washing and biopsy of a bronchial lesion. The bronchial wash and brush
      samples showed a very cellular specimen, with large aggregates of distended
      columnar cells. These were arranged in long strips, thick bundles and occasional
      three-dimensional aggregates. Some aggregates contained numerous rounded cells
      with markedly distended cytoplasm. The rounded cells were slightly larger than
      the distended columnar cells. These cells had a relatively large but innocuous
      appearing nucleus displaced to the periphery of the cell. The corresponding
      bronchial biopsy revealed signet ring adenocarcinoma, presumably metastatic from
      the gastrointestinal primary. CONCLUSION: Signet ring adenocarcinoma, either
      primary or metastatic, can be difficult to diagnose in cytologic and histologic
      specimens. There are numerous mimics of signet ring cells, both benign and
      neoplastic. In respiratory cytologic specimens, one of the benign imposters is
      goblet cell metaplasia.

PMID- 10578988
TI  - Epithelial-myoepithelial carcinoma of the parotid. A case of ductal-predominant
      presentation with cytologic, histologic and ultrastructural correlations.
AB  - BACKGROUND: The cytologic features of the usual type of epithelial-myoepithelial
      carcinoma (EMC) of the parotid, with myoepithelial cell predominance, is well
      described in the cytology literature. In contrast, the cytologic features of
      ductal-predominant-type EMC has not yet been reported. CASE: An 82-year-old male
      presented with a 2.7-cm parotid mass of two years' duration. Fine needle
      aspiration smears stained with Diff-Quik showed cohesive tissue fragments
      outlined by metachromatic fibrils scattered in abundant, smooth, bluish
      background material. Ultrafast Papanicolaou stain revealed sharply outlined,
      large ductal cells with smooth, round to oval nuclei, prominent nucleoli and
      abundant vacuolated cytoplasm; the cells were arranged tridimensionally in
      occasional follicles that contained thick secretions. Neoplastic myoepithelial
      cells were occasionally seen at the periphery of tissue fragments, most commonly
      hidden underneath the neoplastic ductal epithelium at a slightly different focal
      plane; the cells had small, oval, dark nuclei and inconspicuous cell borders. The
      nuclear area and cell size of the neoplastic ductal cells was two and three
      times, respectively, that of neoplastic myoepithelial cells. CONCLUSION: EMC,
      depending on the ratio of ductal to myoepithelial cell components, has different
      cytologic presentations. This case illustrates the ductal-predominant
      presentation of EMC.

PMID- 10578989
TI  - Multilocular thymic cyst with follicular lymphoid hyperplasia in a male infected
      with HIV. A case report with fine needle aspiration cytology.
AB  - BACKGROUND: Multilocular thymic cyst with follicular lymphoid hyperplasia is a
      rare complication in HIV-infected patients, causing pseudotumorous enlargement of
      the anterior mediastinum. There have been six reported cases, all with only
      histologic findings. This paper reports another such case and includes perhaps
      the first cytologic findings on this rare entity. CASE: A 35-year-old, HIV
      infected male intravenous drug abuser, who complained of worsening central chest
      discomfort and pain on deep inspiration, was found to have a large, septated
      anterior mediastinal mass. Computed tomography-guided fine needle aspiration
      biopsy was performed. The cytologic presentation mimicked that of thymoma, with
      cystic degeneration and a dual population of epithelial cells and lymphocytes as
      well as large aggregates of "epithelial" cells intermixed with lymphocytes in a
      background of macrophages and cyst fluid. Histologic examination of the resected
      mass revealed a multilocular thymic cyst with follicular lymphoid hyperplasia.
      HIV-1 core protein p24 was localized immunohistochemically in the dendritic
      follicular cells of the germinal centers. In retrospect, the quantity of
      epithelium derived from the cyst lining was too scanty for thymoma, and the
      presence of plasma cells and lymphohistiocytic aggregates suggested follicular
      lymphoid hyperplasia. CONCLUSION: Multilocular thymic cyst with follicular
      lymphoid hyperplasia should be considered in the differential diagnosis of an
      anterior mediastinal mass in HIV-infected patients after lymphoma and
      tuberculosis.

PMID- 10578990
TI  - Acute myelogenous leukemia relapsing as granulocytic sarcoma of the cervix. A
      case report.
AB  - BACKGROUND: Granulocytic sarcoma of the uterine cervix is an unusual
      manifestation of acute myeloid leukemia, representing soft tissue masses of
      leukemic myeloblasts. An often misdiagnosed entity, it is often confused with
      other inflammatory or neoplastic conditions, including large cell lymphoma. CASE:
      A 67-year-old female presented with acute myelogenous leukemia and a normal
      karyotype. After eight years in complete remission, abdominal pain and an
      ulcerated mass in the uterine cervix developed, with a normal peripheral blood
      smear. Vaginal cytology examination revealed myeloid blasts, which, on subsequent
      cervical biopsy, stained positive for leukocyte common antigen, Kp-1 (CD68),
      antimyeloperoxidase, lysozyme and chloroacetate esterase, confirming the
      cytologic diagnosis. K-ras was not mutated at codon 12 or 13. Chemotherapy
      induced a complete remission, followed nine months later by central nervous
      system and then systemic relapse. The patient died 13 months after being
      diagnosed with granulocytic sarcoma of the cervix. CONCLUSION: This case
      illustrates the value of vaginal cytology and histologic biopsy evaluation in
      patients with acute myelogenous leukemia, including those without evidence of
      systemic disease. The characteristic cytologic features of granulocytic sarcoma
      led to the correct diagnosis. Histologic biopsy evaluation, including
      immunohistochemistry for myeloid markers, proved of value in confirming the
      diagnosis.

PMID- 10578991
TI  - Fine needle aspiration of primary pleomorphic liposarcoma of the breast. A case
      report.
AB  - BACKGROUND: Primary liposarcoma of the breast is an extremely rare lesion. Only
      two cases describing the aspiration biopsy findings have been reported in the
      literature. We report the cytologic findings in an additional case, stressing the
      cytologic clues necessary to distinguish this neoplasm from a primary
      adenocarcinoma. CASE: A 53-year-old female presented to the emergency room with
      bleeding from a 20-cm, ulcerating mass in the right breast. Four months earlier
      she had been seen at another institution, where a diagnosis of poorly
      differentiated carcinoma was made by aspiration biopsy. Computed tomography had
      been negative for metastatic disease, and the patient refused further evaluation.
      Aspiration biopsy of the breast mass was repeated at our institution and
      interpreted as consistent with a poorly differentiated carcinoma. Histologic,
      immunophenotypic and ultrastructural evaluation of the mastectomy specimen
      revealed a pleomorphic liposarcoma. CONCLUSION: With increasing utilization of
      fine needle aspiration to evaluate breast lesions, it can be anticipated that
      unusual entities, including liposarcomas, will be encountered increasingly in
      breast aspirates. Therefore, it is important to consider liposarcoma in the
      differential diagnosis of aspirates showing isolated spindle and polygonal cells
      with vacuolated cytoplasm, nuclear scalloping and pleomorphism to avoid a
      misdiagnosis of carcinoma.

PMID- 10578992
TI  - Cytologic features of ovarian granulosa cell tumor metastatic to the lung. A case
      report.
AB  - BACKGROUND: Granulosa cell tumor (GCT) of the ovary is an uncommon but not rare
      tumor, and the adult type usually affects postmenopausal women. The adult type of
      GCT has several characteristic clinicopathologic features, including a
      composition of small, uniform cells with Call-Exner bodies and an ability to
      metastasize to extrapelvic organs, even several decades after the initial
      operation. CASE: A 62-year-old female was incidentally found to have multiple
      shadows in the peripheral portions of both lung fields on roentgenography. She
      had a past history of oophorectomy for an ovarian carcinoma more than 20 years
      earlier. A transbronchial lung biopsy series was nondiagnostic. An aspirate
      obtained by transthoracic fine needle aspiration (FNA) biopsy revealed clusters
      of rather uniform, small cells with nuclear grooves, suggestive of a metastatic
      lung tumor. Histologic examination of the lung tissue in comparison with the
      previous oophorectomy specimen confirmed the impression of GCT metastatic to the
      lung. CONCLUSION: A preoperative diagnosis of metastatic lung tumor was
      established by transthoracic FNA cytology. The important cytologic criteria for
      the differential diagnosis are uniformity of tumor cells, coffee bean-like
      nuclear grooves and Call-Exner bodies. The possibility of late recurrence of this
      kind of tumor, even two or three decades after surgical resection, should be kept
      in mind.

PMID- 10578993
TI  - Intraductal papilloma of the salivary gland. A report of two cases with diagnosis
      by fine needle aspiration biopsy.
AB  - BACKGROUND: Intraductal papillomas are rare, benign tumors most commonly
      encountered in minor salivary glands. They are cystic, solitary neoplasms that
      arise from ductal epithelium and produce painless swellings. CASES: Two cases
      arose in major salivary glands. The first case was a superficial, firm mass at
      the superior edge of the parotid, cytologically evocative of an adnexal tumor. A
      firm, submandibular mass in the second case was diagnosed as a papillary
      neoplasm. Fluid was aspirated from both cases. Three-dimensional epithelial
      clusters, some with a papillary configuration and histiocytes, were the main
      cellular components. The majority of cells showed oncocytic differentiation;
      however, benign-appearing ductal cells in honeycomb sheets were also present. The
      first case also had occasional cells suggestive of sebaceous differentiation. The
      excised lesions were unilocular cystic papillary neoplasms consistent with
      intraductal papilloma; focal sebaceous differentiation was noted in the first
      case. CONCLUSION: Awareness of the cytologic features of intraductal papilloma of
      the salivary glands should prompt its inclusion in the differential diagnosis of
      papillary lesions of the head and neck.

PMID- 10578994
TI  - Fine needle aspiration cytology of mammary pseudoangiomatous stromal hyperplasia.
      A case report.
AB  - BACKGROUND: Pseudoangiomatous stromal hyperplasia (PASH) is an unusual benign
      breast lesion that may occasionally present as a palpable mass. CASE: This report
      describes the fine needle aspiration cytology (FNAC) features of a case of
      mammary PASH that presented as a palpable mass. This is the second description of
      the FNAC features of this lesion and the first reported case in which a diagnosis
      of phyllodes tumor was considered. The aspirate was cellular and contained
      cohesive groups of cells in which there was a dual population of epithelial and
      myoepithelial cells. Occasional cellular stromal fragments were present, as were
      typical, bipolar, bare nuclei. Admixed with the bare nuclei were large numbers of
      plump, spindle-shaped cells, some with intact cytoplasm. Histologic examination
      of the excised mass showed features typical of PASH. CONCLUSION: Mammary PASH may
      present as a palpable mass and is likely to be encountered in FNAC specimens.
      This diagnosis should be considered when one is confronted with an aspirate
      containing cohesive epithelial groups, cellular stromal fragments and large
      numbers of single, spindle-shaped cells. These features on FNAC may result in
      consideration of a phyllodes tumor. The single, spindle-shaped cells may be a
      characteristic cytologic feature of PASH.

PMID- 10578995
TI  - Oral leiomyosarcoma in childhood. Report of a case with fine needle aspiration
      cytology.
AB  - BACKGROUND: Leiomyosarcomas are rare tumors in the pediatric age group, and
      occurrence of this neoplasm in the oral cavity is exceedingly rare. This article
      highlights the fine needle aspiration (FNA) cytology diagnosis of a case of
      recurrent oral leiomyosarcoma in childhood. CASE: An 11-year-old male noticed a
      swelling in the oral cavity near the left lower jaw. It was excised and diagnosed
      as leiomyosarcoma on histopathology. Four months later the patient presented with
      a progressive swelling in the oral cavity that extended to the lower jaw. The
      recurrent swelling was subjected to FNA, and its cytologic features were
      consistent with leiomyosarcoma. There was a very good initial response to
      chemotherapy and radiation therapy. However, because of noncompliance with advice
      for further therapy, the patient had a second local recurrence and dissemination
      of the disease to the skeletal system, abdomen and thorax. FNA cytology diagnosis
      of the second locally recurrent lesion and abdominal mass were consistent with
      leiomyosarcoma. Immunocytochemical staining revealed a positive reaction in the
      cytoplasm of tumor cells for vimentin and desmin in the FNA smear and paraffin
      section, respectively. CONCLUSION: Fine needle aspiration cytology is a useful
      technique for detection of recurrence and metastasis during follow-up of
      childhood oral leiomyosarcoma.

PMID- 10578996
TI  - Fine needle aspiration diagnosis of lymphangiomyomatosis. A case report.
AB  - BACKGROUND: Lymphangiomyomatosis is a rare disease of females, usually of
      reproductive age. There is a proliferation of lymphatic smooth muscle in
      mediastinal, retroperitoneal and often pulmonary lymphatics and lymph nodes.
      CASE: A 45-year-old female presented with a right pleural effusion and increasing
      retroperitoneal adenopathy with palpable left inguinal adenopathy. Three months
      previously she had undergone a right salpingo-oophrectomy for an ovarian fibroma
      with concomitant left ovarian wedge biopsy, myomectomy for leiomyomas and partial
      omentectomy. Three years previously, at age 42, she had experienced two transient
      episodes of chylous pleural effusion with no sequelae. She underwent computed
      tomography-guided fine needle aspiration of a 4-cm inguinal lymph node to rule
      out lymphoma. CONCLUSION: Fine needle aspiration of lymphangiomyomatosis yields
      distinctive cytologic morphology. This characteristic morphology, in combination
      with the appropriate history, permits a minimally invasive, timely and in this
      particular case, entirely unexpected diagnosis.

PMID- 10578997
TI  - Giant lamellar bodies in pulmonary MALT lymphoma. A case report.
AB  - BACKGROUND: Giant lamellar bodies are laminated, scroll-like whorls seen within
      alveolar spaces and have been occasionally observed in sclerosing hemangioma of
      the lung. However, to the best of our knowledge, the cytologic findings of giant
      lamellar bodies have not been reported. We describe cytologic findings of giant
      lamellar bodies associated with pulmonary mucosa-associated lymphoid tissue
      (MALT) lymphoma. CASE: A 72-year-old male had a pulmonary mass measuring 2.0 x
      1.4 x 1.5 cm. Cytologic smears imprinted from a cut surface of the resected mass
      revealed a large number of concentrically laminated structures, giant lamellar
      bodies, measuring 15-40 microns in diameter. Necrotic cellular remnants were
      occasionally observed in the center of the structures. In the background, small
      to medium-sized lymphoid cells and plasmacytoid cells were observed. Histologic
      diagnosis of the tumor was IgG, kappa type, MALT lymphoma. An aggregate of giant
      lamellar bodies was observed within entrapped, dilated alveolar spaces lined with
      hypertrophied, type II pneumocytes. Immunohistochemically, the giant lamellar
      bodies were positive for KL-6. CONCLUSION: Giant lamellar bodies may be derived
      from surfactant and necrotic type II pneumocytes and may be observed
      cytologically in cases of pulmonary MALT lymphoma.

PMID- 10578998
TI  - Granulomatous reaction to silicone in axillary lymph nodes. A case report with
      cytologic findings.
AB  - BACKGROUND: Silicone lymphadenopathy is a rare complication in patients with
      breast implants and is often confused with metastases from breast carcinoma.
      CASE: A 36-year-old female who had undergone bilateral breast augmentation six
      years earlier was referred for a mass in the left axilla. Fine needle aspiration
      showed a granulomatous reaction to birefringent material with predominance of
      foreign body giant cells in a lymphoid background. CONCLUSION: This report
      illustrates the usefulness of fine needle aspiration in axillary nodes of
      patients with breast implants in ruling out malignancy and diagnosing implant
      disruption.

PMID- 10578999
TI  - Recurrent synovial cyst of deep soft tissues. A case report.
AB  - BACKGROUND: Cystic lesions of deep soft tissues are rare and usually are composed
      of a mesenchymal tumor undergoing necrosis or regressive changes. Benign cysts
      arising de novo are even more rare and may show features of different morphology,
      potentially leading to an inexact diagnosis. CASE: A 68-year-old male presented
      with a deep, firm mass in the upper part of the back from which a dense liquid
      was aspirated, with an inconclusive diagnosis. A second fine needle aspiration
      was performed, and the lesion was surgically biopsied. Immunohistochemical
      studies were also inconclusive, while ultrastructural studies suggested an origin
      in the synovia of the scapular bursa. CONCLUSION: The cytologic picture was
      suspicious for malignancy due to the presence of numerous pseudopapillary
      structures, reminding us of a secondary deposit from a renal or thyroid primary
      or mesenchymal neoplasm. However, the bland nuclear aspect suggested the
      benignity of the lesion, and the electron microscopic features confirmed the
      synovial origin.

PMID- 10579000
TI  - Nodular sarcoid myositis of skeletal muscle diagnosed by fine needle aspiration
      biopsy. A case report.
AB  - BACKGROUND: Symptomatic striated muscle involvement in sarcoidosis is rare.
      Muscle biopsy is usually required for the diagnosis. Fine needle aspiration
      biopsy (FNAB) has been successfully used in diagnosing soft tissue lesions. To
      the best of our knowledge, FNAB of sarcoid myositis has not been reported. CASE:
      A 31-year-old, black female with a history of sarcoidosis presented with an
      enlarging, painful, left calf mass. Infected thrombi were suspected. FNAB showed
      numerous loosely arranged epithelioid histiocytes, multinucleated giant cells and
      skeletal muscle cells. The overall cytologic picture was that of granulomatous
      myositis. The cytologic features coupled with the patient's history and magnetic
      resonance imaging findings suggested sarcoid myositis. Subsequent muscle biopsy
      showing noncaseating granulomata and negative stains for organisms confirmed the
      diagnosis of nodular sarcoid myositis. CONCLUSION: Nodular sarcoid myositis can
      be suggested by FNAB cytology in a patient with a past history of sarcoidosis.

PMID- 10579001
TI  - FNAC in the diagnosis of recurrent dermatofibrosarcoma protuberans of the
      forehead. A case report.
AB  - BACKGROUND: Dermatofibrosarcoma protuberans is a rare cutaneous soft tissue tumor
      of intermediate malignant potential with a characteristic tendency for
      recurrence. Metastases are unusual. This tumor usually occurs in the trunk and
      extremities and, infrequently, on the face and scalp. Its cytologic appearance on
      fine needle aspiration has only been rarely reported. It is characterized by
      numerous fibroblastlike cells that arrange as single cells or in clusters of
      spindle cells arrayed in a storiform pattern. CASE: A 42-year-old male presented
      with a one-year history of an enlarging left forehead mass (lateral brow) that
      was adjacent to an old surgical scar. Fine needle aspiration revealed a low grade
      spindle cell neoplasm morphologically identical to a dermatofibrosarcoma
      protuberans excised 15 years earlier, indicating tumor recurrence. CONCLUSION:
      Distinguishing dermatofibrosarcoma protuberans from other spindle cell tumors and
      fibrohistiocytic lesions may pose significant challenges to the pathologist.
      However, in the appropriate clinical setting and applying strict diagnostic
      criteria, fine needle aspiration cytology is a reliable tool in establishing the
      diagnosis of this neoplasm.

PMID- 10579002
TI  - Extramedullary hematopoiesis of the thyroid gland diagnosed by FNA cytology. A
      case report.
AB  - BACKGROUND: Extramedullary hematopoiesis (EMH) is the production of elements of
      erythroid and myeloid series at ectopic sites; when concomitant with agnogenic
      myeloid metaplasia, it is invariably seen in advanced disease. In EMH,
      involvement of the thyroid gland is extremely rare. CASE: An 82-year-old male
      with thyroid enlargement underwent fine needle aspiration (FNA) cytology with a
      diagnosis of malignancy. A month later another FNA cytology was performed and was
      consistent with EMH. A complete hematologic workup subsequently allowed the
      diagnosis of agnogenic myeloid metaplasia. CONCLUSION: The presence of EMH in the
      thyroid gland is an unusual finding, and, due to the presence of numerous giant
      cells, the cytologic presentation might be mistaken for anaplastic thyroid
      carcinoma. The differential diagnosis is based on the recognition of giant cells
      as megakaryocytes.

PMID- 10579003
TI  - Squamous cell carcinoma of the bladder with metastasis diagnosed cytologically in
      a pleural effusion.

PMID- 10579004
TI  - Exact Touch: a new single sampler for the uterine cervix.

PMID- 10579005
TI  - Alternaria in esophageal brushing smears.

PMID- 10579006
TI  - Fine needle aspiration biopsy of primary squamous cell carcinoma of the thyroid
      gland.

PMID- 10579007
TI  - Fine needle aspiration diagnosis of a classic-type pelvic seminoma.

PMID- 10579008
TI  - Basal cell adenoma, solid variant, diagnosed by fine needle aspiration cytology.

PMID- 10579009
TI  - Criteria for cytologic reporting of breast fine needle aspiration.

PMID- 10579010
TI  - Detecting abnormal cells from primary serous peritoneal carcinoma by Pap smear.

PMID- 10579011
TI  - Put this in your pipe and smoke it.

PMID- 10579012
TI  - The neglected epidemic.

PMID- 10579013
TI  - 'Like taking a vitamin'. Why patients don't mention their daily medications.

PMID- 10579014
TI  - Treating injuries with hyperbaric oxygen.

PMID- 10579015
TI  - Enlightening patients and practitioners.

PMID- 10579016
TI  - Enlightening patients and practitioners.

PMID- 10579017
TI  - Opioids by the rectal route.

PMID- 10579018
TI  - Treatment for nocturnal enuresis.

PMID- 10579019
TI  - Ethnic representation. ANA advocates more diversity in nursing.

PMID- 10579020
TI  - The mirror. Seeing the future under the exam room lights.

PMID- 10579021
TI  - The last smoke. Your patients can quit smoking--for life.

PMID- 10579022
TI  - Emergency! Prochlorperazine-induced dystonia.

PMID- 10579023
TI  - Migraine in children.

PMID- 10579024
TI  - To have and have not.

PMID- 10579025
TI  - Clinical snapshot. Postdural puncture headache.

PMID- 10579026
TI  - ANA calls for Medicare reform.

PMID- 10579027
TI  - Abdominal compartment syndrome.

PMID- 10579028
TI  - Which straw will break the camel's back?

PMID- 10579029
TI  - Toward a latex-safe workplace.

PMID- 10579030
TI  - Two approaches to multiple specular echo detection using split spectrum
      processing: moving bandwidth minimization and mathematical morphology.
AB  - A split spectrum processing technique using a novel moving bandwidth minimization
      (MBM) method was developed to detect multiple specular targets having different
      spectral characteristics. Mathematical morphology (MM) algorithms were also
      implemented in order to compare the results. An experimental approach to optimal
      parameter determination is described. These non-linear filtering methods are
      applied to medical in vivo imaging to illustrate specular detection and signal to
      noise ratio (SNR) enhancement.

PMID- 10579031
TI  - Maximum a posteriori deconvolution of sparse ultrasonic signals using genetic
      optimization.
AB  - Deconvolution of sparse spike sequences has received much attention in the field
      of seismic exploration. In certain situations in ultrasonic non-destructive
      testing (NDT) of materials, similar conditions as those found in seismic
      exploration occur. One example is the problem of detecting disbonds in layered
      aluminum structures. The reflection sequence convolved with the impulse response
      of the transducer results in masking closely spaced reflections. Deconvolution of
      these signals may reveal the reflection sequence and thus make the interpretation
      easier. In this paper we use the Bernoulli-Gaussian (BG) distribution for
      modeling the signal generation. This relatively simple model allows maximum a
      posteriori (MAP) estimation of the reflection sequence. A derivation of the MAP
      criterion is given for clarity. We propose a genetic algorithm for optimizing the
      MAP criterion. The genetic algorithm approach is motivated by the fact that the
      criterion is non-convex, implying that the criterion may have more than one local
      minimum point. The probability of obtaining the global optimal solution is
      increased by using the proposed genetic algorithm. One of the key features in
      genetic algorithms, the so-called cross-over operator, has been modified and
      adapted to the structure of the BG deconvolution problem to improve the
      efficiency of the search. The algorithm is tested on simulated data using the
      probability of detection (PD) and probability of false alarm (PFA) as evaluation
      criteria. The algorithm is also tested on real ultrasonic data from a layered
      aluminum structure. The results show considerable improvements in the possibility
      of interpreting the signals.

PMID- 10579032
TI  - Ultrasonic slow waves in air-saturated cancellous bone.
AB  - This paper describes preliminary observations of ultrasonic wave propagation in
      air-saturated defatted cancellous bone from the human vertebra. Using a broadband
      pulse transmission system, attenuation and phase velocity were measured over a
      wide frequency range (100 kHz-1 MHz). The observed behaviour was consistent with
      that expected for the decoupled slow wave predicted by Biot's theory. Velocity
      was lower than that of free air, and there was marked frequency-dependent
      attenuation and velocity dispersion. The tortuosity (alpha) of the trabecular
      microstructure was estimated from the high frequency limit of the dispersion
      curve, with a mean value of alpha = 1.040 +/- 0.004 obtained in five specimens.
      Ultrasonic measurements in air represent a valuable new approach, capable of
      yielding parameters that directly characterise bone structure. Furthermore, they
      may give useful insights into wave propagation in bone in vivo, where the
      trabecular framework is saturated with marrow fat rather than air.

PMID- 10579033
TI  - Veterinarians key to discovering outbreak of exotic encephalitis.

PMID- 10579034
TI  - What is your diagnosis? Pneumoperitoneum.

PMID- 10579035
TI  - Perceptions of fourth-year veterinary students about the human-animal bond in
      veterinary practice and in veterinary college curricula.
AB  - OBJECTIVE: To assess veterinary students' perceptions regarding the importance of
      addressing the human-animal bond in veterinary practice and their perceptions
      about the adequacy of curricula on the human-animal bond as presented in US
      veterinary colleges. DESIGN: Survey. PROCEDURE: Data were collected via a brief
      questionnaire mailed during the summer of 1996. Questionnaires were returned by
      552 senior veterinary students representing 21 of 27 veterinary colleges in the
      United States. RESULTS: Senior veterinary students believed that the human-animal
      bond should be a concern of practicing veterinarians, but most did not believe
      they were receiving adequate instruction about the human-animal bond in their
      veterinary colleges. Gender was significantly related to differences in
      perceptions; female students appeared to have more interest in addressing the
      human-animal bond than male students. Students in small animal programs viewed
      the human-animal bond differently than those in large animal programs. Finally,
      students attending schools with extensive human-animal bond or human relations
      curricula were more likely to believe they were receiving adequate instruction in
      this area than students in other schools. CONCLUSIONS AND CLINICAL IMPLICATIONS:
      Curricula addressing the human-animal bond need to be developed and implemented
      in veterinary colleges in the United States.

PMID- 10579036
TI  - Survey of occupational hazards in large animal practices.

PMID- 10579037
TI  - Fringe benefits received by veterinarians, 1997.

PMID- 10579038
TI  - Survey of veterinary extension in the United States.
AB  - OBJECTIVE: To assess veterinary extension in the United States as perceived by
      veterinary extension personnel. DESIGN: Cross-sectional survey. SAMPLE
      POPULATION: Extension veterinarians in the United States. PROCEDURE: 2 surveys
      were designed and mailed to extension veterinarians listed by the USDA and the
      American Association of Extension Veterinarians. RESULTS: 34 states had > or = 1
      extension veterinarian. The majority (> 60%) of extension veterinarians did not
      commit time to resident education and were not involved in research activities.
      Paradoxically, 23% of responding extension veterinarians did not report extension
      work. Programs for food animal producers, horse owners, and companion animal
      owners were provided by 100, 63, and 37% of states, respectively. Continuing
      education (CE) programs were provided for food animal veterinarians, equine
      veterinarians, and companion animal veterinarians by 96, 63, and 52% of states,
      respectively. Challenges facing veterinary extension included limited recognition
      of veterinary extension activities by universities, lack of university personnel
      to support CE programs, and decreased support for companion animal extension
      programs. CONCLUSIONS AND CLINICAL RELEVANCE: Extension veterinarians need to
      identify and clearly articulate the mission of veterinary extension, develop more
      collaborative programs across regions, and continue to serve as catalysts to
      bring diverse constituents together. Extension veterinarians must distinguish
      their mission not solely as information transfer, which can be accomplished in a
      variety of ways outside of extension, but as a coherent and consistent program of
      education and policy developed on a national level and distributed locally.

PMID- 10579039
TI  - Recommendations of a national working group on prevention and control of rabies
      in the United States. Article II: Laboratory diagnosis of rabies. The National
      Working Group on Rabies Prevention and Control.

PMID- 10579040
TI  - Diarrhea associated with trichomonosis in cats.
AB  - OBJECTIVE: To establish clinical features, course of illness, and treatment
      outcome of cats with diarrhea and concurrent infection with Trichomonas
      organisms. Prevalence of fecal trichomonads in a geographically comparable
      population of healthy indoor and feral cats also was assessed. DESIGN:
      Longitudinal study and a cohort study. ANIMALS: 32 cats with diarrhea and
      naturally acquired trichomonosis that were native to North Carolina, Virginia,
      Connecticut, and Tennessee; 20 healthy indoor cats; and 100 feral cats.
      PROCEDURE: Trichomonosis was diagnosed in 32 cats by identification of organisms
      in fresh feces or by protozoal culture of feces. RESULTS: Diarrhea associated
      with the large intestine and trichomonosis were diagnosed in 32 cats. Median age
      of the cats was 9 months; 23 cats were < or = 1 year old at the time of
      diagnosis. Two cats developed diarrhea accompanied by infection with Trichomonas
      organisms after the addition of an infected kitten into the home. Duration of
      diarrhea ranged from 2 days to 3 years. Six cats had a coexisting enteric
      infection. Treatment with antimicrobials improved fecal consistency and reduced
      the number of flagellates in the feces, but did not eliminate infection. Diarrhea
      (with microscopically detectable flagellates) was observed shortly after
      antibiotics were discontinued. Trichomonads were not recovered from feces of any
      healthy indoor or feral cats. CONCLUSIONS AND CLINICAL RELEVANCE: Our findings
      suggest that trichomonosis may be a cofactor in development of diarrhea in young
      cats. Trichomonas organisms were not identified as part of the indiginous fauna
      of healthy indoor or feral cats.

PMID- 10579041
TI  - Serum total and ionized magnesium concentrations and urinary fractional excretion
      of magnesium in cats with diabetes mellitus and diabetic ketoacidosis.
AB  - OBJECTIVE: To determine magnesium (Mg) status in cats with naturally acquired
      diabetes mellitus (DM) and diabetic ketoacidosis (DKA), evaluate changes in Mg
      status after treatment for DKA, and correlate Mg status with systemic blood
      pressure and degree of glycemic control. DESIGN: Case series and cohort study.
      ANIMALS: 12 healthy cats (controls), 21 cats with DM, and 7 cats with DKA.
      PROCEDURE: Serum total magnesium (tMg) and ionized magnesium (iMg) concentrations
      and spot urinary fractional excretion of magnesium (FEmg) were determined, using
      serum and urine samples obtained from all cats when they were entered in the
      study and from cats with DKA 12, 24, and 48 hours after initiating treatment.
      Indirect blood pressure and degree of glycemic control were determined in 10 and
      21 cats with DM, respectively. RESULTS: Initially, 2 and 13 cats with DM and 1
      and 4 cats with DKA had serum tMg and iMg concentrations, respectively, less than
      the low reference limit (mean-2 SD) determined for controls. In cats with DKA,
      serum tMg concentration decreased significantly over time after initiating
      treatment. Urinary FEmg was significantly higher in cats with DM or DKA, compared
      with controls. Systemic hypertension was not detected nor was there a correlation
      between Mg status and degree of glycemic control in cats with DM. CONCLUSIONS AND
      CLINICAL RELEVANCE: Hypomagnesemia was a common finding in cats with DM and DKA
      and was more readily identified by measuring serum iMg concentration than tMg
      concentration. The clinical ramifications of hypomagnesemia in such cats remain
      to be determined.

PMID- 10579042
TI  - Premature closure of the proximal physis of the humerus in a dog as a result of
      harvesting a cancellous bone graft.
AB  - A 5-month-old castrated male mixed-breed dog was evaluated because of lameness of
      the right forelimb. Physical examination revealed pain on manipulation of the
      right elbow joint, and radiography revealed premature closure of the distal
      physis of the radius with subluxation of the right elbow joint. Corrective
      osteotomy of the radius was performed to increase the length of the radius and
      establish congruity of the elbow joint. Cancellous bone was obtained from the
      proximal portion of the humerus and used as a graft at the osteotomy site. The
      dog did well after surgery. Four months after surgery, the dog again was lame on
      the right forelimb. Physical examination revealed instability of the right
      shoulder, and manipulation of that area elicited signs of pain. Radiography
      revealed caudomedial subluxation of the right shoulder as well as deformity of
      the humeral head and hypoplasia of the greater tubercle. It was presumed that
      these changes were associated with collection of the cancellous bone graft during
      the initial surgery, which resulted in premature closure of the proximal physis
      of the humerus. To our knowledge, this is the first report of premature closure
      of the proximal physis of the humerus as a result of procurement of a bone graft.

PMID- 10579043
TI  - Clinical findings, treatment, and outcome of dogs with status epilepticus or
      cluster seizures: 156 cases (1990-1995).
AB  - OBJECTIVE: To report clinical findings, treatments, and outcomes of dogs admitted
      to the hospital for status epilepticus or cluster seizures and evaluate factors
      associated with outcome. DESIGN: Retrospective study. ANIMALS: 156 dogs admitted
      for status epilepticus or cluster seizures. PROCEDURE: Medical records were
      reviewed for seizure and medication history, diagnostic test results, types of
      treatment, hospitalization costs, and outcome of hospital visits. RESULTS: Dogs
      were admitted for seizures on 194 occasions. Of 194 admissions, 128 (66%), 2
      (1%), 32 (16.5%), 2 (1%), and 30 (15.5%) were of dogs with a history of clusters
      of generalized seizures, clusters of partial complex seizures, convulsive status
      epilepticus, partial status epilepticus, and > 1 type of seizure, respectively.
      Underlying causes of seizures were primary epilepsy (26.8%; 52/194), secondary
      epilepsy (35.1%; 68), reactive epileptic seizures (6.7%; 13), primary or
      secondary epilepsy with low serum antiepileptic drug concentrations (5.7%; 11),
      and undetermined (25.8%; 50). One hundred and eighty-six hospital visits resulted
      in admission to the intensive care unit (ICU). Treatments with continuous i.v.
      infusions of diazepam or phenobarbital were initiated during 66.8% (124/186) and
      18.7% (35) of ICU hospital stays for 22.3 +/- 16.1 hours (mean +/- SD) and 21.9
      +/- 15.4 hours, respectively. Of 194 admissions, 74.7% (145) resulted in
      discharge from the hospital, 2.1% (4) in death, and 23.2% (45) in euthanasia. A
      poor outcome (death or euthanasia) was significantly associated with
      granulomatous meningoencephalitis, loss of seizure control after 6 hours of
      hospitalization, and the development of partial status epilepticus. CONCLUSIONS
      AND CLINICAL RELEVANCE: Granulomatous meningoencephalitis, loss of seizure
      control after 6 hours of hospitalization, or the development of partial status
      epilepticus may indicate a poor prognosis for dogs with seizures.

PMID- 10579044
TI  - Combined cycloablation and gonioimplantation for treatment of glaucoma in dogs:
      18 cases (1992-1998).
AB  - OBJECTIVE: To evaluate a combined cycloablative and gonioimplantation technique
      for treatment of glaucoma in dogs. DESIGN: Retrospective study. ANIMALS: 18 adult
      dogs with glaucoma. PROCEDURE: Medical records of dogs that received a valved
      gonioimplant and a cyclodestructive procedure (cyclocryoablation or diode laser
      cyclophotocoagulation) during a 6-year period were reviewed. Retention of vision
      and intraocular pressure control were assessed, as well as number and nature of
      complications. RESULTS: 19 eyes of 18 dogs received a valved gonioimplant and
      either cyclocryoablation (n = 12) or diode laser cyclophotocoagulation (7). At >
      or = 1 year after surgery, 11 of 19 eyes had vision and 14 of 19 eyes had
      intraocular pressure < 25 mm Hg. Two dogs (2 eyes) were lost to follow-up 3 and 6
      months after surgery. Despite the alternative route for aqueous humor flow
      created by the gonioimplant, 7 eyes had increased intraocular pressure (27 to 61
      mm Hg) < 24 hours after surgery. Other complications included excessive
      intraocular fibrin, focal retinal detachment, corneal ulcer, retinal hemorrhage,
      cataract, and implant migration. CONCLUSIONS AND CLINICAL RELEVANCE: Combined
      cycloablation and gonioimplantation appears to be a promising technique for
      retention of vision and control of intraocular pressure in dogs with glaucoma.

PMID- 10579045
TI  - Repeated manual evacuation for treatment of rectal tears in four horses.
AB  - Horses with tears that involve all layers of the rectum except the mesocolon
      (grade IIIb) have a poor prognosis for survival because of the difficulty in
      treating these wounds and the propensity for them to progress to full
      perforations (grade IV). Most treatments for grade-IIIb rectal tears involve
      surgery of some kind, but not all grade-IIIb rectal tears require surgical
      intervention. We report on 4 horses with grade-IIIb rectal tears that were
      evaluated via palpation per rectum and endoscopy. Two of 4 horses were admitted
      with signs consistent with shock and endotoxemia, and evaluation of all
      peritoneal fluid samples was indicative of nonseptic peritonitis. Horses were
      treated via administration of antibiotics and anti-inflammatory drugs and
      repeated manual evacuation of the terminal portion of the small colon and rectum.
      Treatment centered on preventing further enlargement of the rectal tear by
      eliminating the storage function of the terminal portion of the small colon and
      rectum. None of our horses had worsening of the original injury, and horses were
      discharged within 2 weeks of admission with full resolution of the rectal tear.
      Outcomes in the horses of our report indicate that repeated manual evacuation can
      be successful for treatment of horses with grade-IIIb rectal tears.

PMID- 10579046
TI  - High intraosseous pressure as a cause of lameness in a horse with a degloving
      injury of the metatarsus.
AB  - A 6-year-old Paint mare undergoing treatment for a degloving injury of the right
      metatarsus developed a non-weight-bearing lameness 19 days after admission.
      Diagnostic nerve blocks localized the source of pain to the area between the
      tarsus and the metatarsophalangeal joint. Radiography of the metatarsus and
      metatarsophalangeal joint, arthrocentesis of the metatarsophalangeal joint, and
      ultrasonography of the flexor tendons, flexor tendon sheath, and suspensory
      ligament failed to identify the cause of the lameness. The horse was anesthetized
      and intraosseous pressure was measured in the left and right third metatarsal
      bones, using a self-tapping cannulated screw attached to a pressure transducer.
      Pressure in the affected limb (46 mm Hg) was 3.5 times as high as pressure in the
      unaffected limb (13 mm Hg). The day after pressures were measured and
      fenestration was performed, signs of lameness were substantially improved. High
      intraosseous pressure in the affected limb was most likely secondary to edema,
      inflammation, and partial venous thrombosis, in combination with bone
      neovascularization, that impaired intraosseous venous drainage from the medullary
      cavity. Fenestration of the affected bone relieved the excessive pressure and
      allowed for resolution of pain.

PMID- 10579047
TI  - Treatment response and athletic outcome of foals with tarsal valgus deformities:
      39 cases (1988-1997).
AB  - OBJECTIVE: To evaluate the response to various treatments and long-term outcome
      of foals with tarsal valgus deformities. DESIGN: Retrospective study. ANIMALS: 39
      foals with tarsal valgus deformities. PROCEDURE: Data collected from medical
      records, included signalment, history, reason for admission, and clinical
      findings. Radiographic views of the tarsus were evaluated for incomplete
      ossification of tarsal bones and were classified as normal in appearance, type-I
      incomplete ossification, or type-II incomplete ossification. Treatment and
      athletic outcome were documented for each foal. RESULTS: Radiographic assessment
      revealed that 22 of 39 foals (56%) had concomitant tarsal valgus deformities and
      incomplete ossification of the tarsal bones. Eight of 19 foals with tarsal valgus
      deformities that were treated with periosteal stripping responded favorably.
      Foals < or = 60 days old were significantly more likely to respond to periosteal
      stripping than older foals. Five of 8 foals with tarsal valgus deformities that
      were treated with growth plate retardation responded favorably. Eleven of 21
      foals with long-term follow-up performed as intended. Compared with foals with
      type-II incomplete ossification, foals with tarsal bones that had a normal
      radiographic appearance or type-I incomplete ossification were significantly more
      likely to perform as intended. CONCLUSIONS AND CLINICAL RELEVANCE: Foals with
      tarsal valgus deformities should have lateromedial radiographic views of the
      tarsus obtained to assess the tarsal bones for incomplete ossification, which
      will affect athletic outcome. Because foals with type-II incomplete ossification
      of the tarsal bones respond poorly to periosteal stripping alone, treatment by
      growth-plate retardation is recommended.

PMID- 10579048
TI  - Outbreak of abortion associated with Neospora caninum infection in a beef herd.
AB  - Abortion outbreaks caused by infection with Neospora caninum in beef cattle have
      not been well documented. Neospora caninum infection was confirmed in 4 fetuses
      that were aborted by cattle in a 350-head beef herd; an additional 58 cattle
      aborted during the next 2.5 months. Overall, 44.4% (157/354) of the cattle in the
      herd did not become pregnant or experienced fetal loss during this period.
      Initially, 81.3% (282/347) of the herd was seropositive for antibodies to N
      caninum, and seropositive cows were 6.2 times as likely to not be pregnant as
      were seronegative cows. Other potential causes of abortion were not identified in
      this herd. Following the outbreak, few cattle in the herd or in a second exposed
      herd seroconverted, but high antibody titers persisted in most seropositive
      cattle through the end of the calving season. Evidence of cow-to-fetus
      transmission of the organism was detected in > 82% of seropositive cows.

PMID- 10579049
TI  - Brucellosis induced by RB51 vaccine in a pregnant heifer.
AB  - Brucellosis developed in a 14.5-month-old Gelbvieh heifer after the animal was
      vaccinated with the calfhood dose of strain RB51 Brucella abortus vaccine s.c.
      during the fourth month of its first pregnancy. The heifer experienced dystocia
      and was euthanatized during cesarean section because of a large uterine tear. The
      fetus was dead at delivery. Suppurative placentitis and fetal pneumonia were
      evident at necropsy. Brucella abortus strain RB51 was isolated from the placenta
      and the fetus' lung.

PMID- 10579050
TI  - Properties of intra- and intercellular Ca(2+)-wave propagation elicited by
      mechanical stimulation in cultured RPE cells.
AB  - Membrane deformation induced by a mechanical stimulus increases the [Ca2+]i in
      cultured retinal pigment epithelial (RPE) cells, and in many other cell types. In
      this study, confocal microscopy and Ca(2+)-measurements using the fluorescent dye
      fluo-3 were used to measure the spatiotemporal characteristics of the Ca(2+)-wave
      propagation during a mechanical stimulation in Long Evans (LE) RPE cells or
      dystrophic Royal College of Surgeons (RCS) RPE cells. Ca2+ signals were recorded
      in the mechanically stimulated cell and in the neighboring cells. A regenerative
      Ca(2+)-wave with a decreasing rate of propagation was found in the stimulated
      cells. The rate of propagation was significantly slower in RCS-RPE cells compared
      to LE-RPE cells. Incubation with thapsigargin significantly lowered the
      propagation rate in both LE- and RCS-RPE cells. The amplitude of the [Ca2+]i-rise
      in the nucleus and cytoplasm was differentially modulated by protein kinase C in
      RCS-RPE cells, but not in LE-RPE cells. It is concluded that RCS-RPE cells have
      intracellular Ca(2+)-regulating properties which are different from those of LE
      RPE cells.

PMID- 10579051
TI  - Regulation of GATA-4 and AP-1 in transgenic mice overexpressing cardiac
      calsequestrin.
AB  - Transgenic mouse hearts overexpressing the Ca(2+)-binding protein calsequestrin
      (CSQ) have an accompanying 10-fold increase in the sarcoplasmic reticulum (SR)
      Ca2+ load, however, exhibits slow and small Ca(2+)-induced Ca2+ release. Such
      slow kinetics of Ca2+ release may have activated excitation-transcription
      coupling as CSQ overexpressing hearts have induced levels of NFAT and GATA-4
      activities and higher levels of c-fos mRNA and cFos protein compared to those of
      non-transgenic littermates. Adaptive responses, however, appear to downregulate
      transcriptional regulators controlling c-fos gene including serum response factor
      and Ca2+/cAMP response element-binding protein. CSQ-overexpressing hearts also
      had decreased levels of cJun protein, resulting in downregulated AP-1 activity.
      The mRNA levels of angiotensin II type1a receptor which requires AP-1 and GATA-4
      for gene transcription was suppressed in CSQ overexpressing hearts. These results
      demonstrate that CSQ can regulate GATA-4- and AP-1-dependent transcriptional
      events, indicating the existence of SR-nuclear circuits of signal transduction in
      adult cardiac muscle.

PMID- 10579052
TI  - Overshooting cytosolic Ca2+ signals evoked by capacitative Ca2+ entry result from
      delayed stimulation of a plasma membrane Ca2+ pump.
AB  - The effect of capacitative Ca2+ entry on cytosolic free Ca2+ concentration
      ([Ca2+]c) was examined in calf pulmonary artery endothelial cells treated with
      thapsigargin. Restoration of extracellular Ca2+ evoked an overshoot in [Ca2+]c:
      the initial rate of Ca2+ influx was 12.4 +/- 0.5 nM/s as [Ca2+]c rose
      monoexponentially (time constant, tau = 36 +/- 2 s) to a peak (322 +/- 16 nM)
      before declining to 109 +/- 14 nM after 2000 s. Rates of Ca2+ removal from the
      cytosol were measured throughout the overshoot by recording the monoexponential
      decrease in [Ca2+]c after rapid removal of extracellular Ca2+. The time constant
      for recovery (tau rec decreased from 54 +/- 4 s when Ca2+ was removed after 10 s
      to its limiting value of 8.8 +/- 1.0 s when it was removed after 2000 s. The time
      dependence of the changes in tau rec indicate that an increase in [Ca2+]c is
      followed by a delayed (tau = 408 s) stimulation of Ca2+ removal, which fully
      reverses (tau approximately 185 s) after Ca2+ entry ceases. Numerical simulation
      indicated that the changes in Ca2+ removal were largely responsible for the
      overshooting pattern of [Ca2+]c. Because prolonged (30 min) Ca2+ entry did not
      increase the total 45Ca2+ content of the cells, an increased rate of Ca2+
      extrusion across the plasma membrane most likely mediates the Ca2+ removal, and
      since it persists in the absence of extracellular Na+, it probably results from
      stimulation of a plasma membrane Ca2+ pump. We conclude that delayed stimulation
      of a plasma membrane Ca2+ pump by capacitative Ca2+ entry may protect cells from
      excessive increases in [Ca2+]c and contribute to oscillatory changes in [Ca2+]c.

PMID- 10579053
TI  - Recovery of neuronal protein synthesis after irreversible inhibition of the
      endoplasmic reticulum calcium pump.
AB  - In the physiological state, protein synthesis is controlled by calcium
      homeostasis in the endoplasmic reticulum (ER). Recently, evidence has been
      presented that dividing cells can adapt to an irreversible inhibition of the ER
      calcium pump (SERCA), although the mechanisms underlying this adaption have not
      yet been elucidated. Exposing primary neuronal cells to thapsigargin (Tg, a
      specific irreversible inhibition of SERCA) resulted in a complete suppression of
      protein synthesis and disaggregation of polyribosomes indicating inhibition of
      the initiation step of protein synthesis. Protein synthesis and ribosomal
      aggregation recovered to 50-70% of control when cells were cultured in medium
      supplemented with serum for 24 h, but recovery was significantly suppressed in a
      serum-free medium. Culturing cells in serum-free medium for 24 h already caused
      an almost 50% suppression of SERCA activity and protein synthesis. SERCA activity
      did not recover after Tg treatment, and a second exposure of cells to Tg, 24 h
      after the first, had no effect on protein synthesis. Acute exposure of neurons to
      Tg induced a depletion of ER calcium stores as indicated by an increase in
      cytoplasmic calcium activity, but this response was not elicited by the same
      treatment 24 h later. However, treatments known to deplete ER calcium stores
      (exposure to the ryanodine receptor agonists caffeine or 2-hydroxycarbazole, or
      incubating cells in calcium-free medium supplemented with EGTA) caused a second
      suppression of protein synthesis when applied 24 h after Tg treatment. The
      results suggest that after Tg exposure, restoration of protein synthesis was
      induced by recovery of the regulatory link between ER calcium homeostasis and
      protein synthesis, and not by renewed synthesis of SERCA protein or development
      of a new regulatory system for the control of protein synthesis. The effect of
      serum withdrawal on SERCA activity and protein synthesis points to a role of
      growth factors in maintaining ER calcium homeostasis, and suggests that the ER
      acts as a mediator of cell damage after interruption of growth factor supplies.

PMID- 10579054
TI  - Functional characterization of thapsigargin and agonist-insensitive acidic Ca2+
      stores in Drosophila melanogaster S2 cell lines.
AB  - The role of acidic intracellular calcium stores in calcium homeostasis was
      investigated in the Drosophila Schneider cell line 2 (S2) by means of free
      cytosolic calcium ([Ca2+]i) and intracellular pH (pHi) imaging together with
      measurements of total calcium concentrations within intracellular compartments.
      Both a weak base (NH4Cl, 15 mM) and a Na+/H+ ionophore (monensin, 10 microM)
      evoked cytosolic alkalinization followed by Ca2+ release from acidic
      intracellular Ca2+ stores. Pretreatment of S2 cells with either thapsigargin (1
      microM), an inhibitor of endoplasmic reticulum Ca(2+)-ATPases, or with the Ca2+
      ionophore ionomycin (10 microM) was without effect on the amplitude of Ca2+
      release evoked by alkalinization. Application of the cholinergic agonist
      carbamylcholine (100 microM) to transfected S2-DM1 cells expressing a Drosophila
      muscarinic acetylcholine receptor (DM1) emptied the InsP3-sensitive Ca2+ store
      but failed to affect the amplitude of alkalinization-evoked Ca2+ release. Glycyl
      L-phenylalanine-beta-naphthylamide (200 microM), a weak hydrophobic base known to
      permeabilize lysosomes by osmotic swelling, triggered Ca2+ release from internal
      stores, while application of brefeldin A (10 microM), an antibiotic which
      disperses the Golgi complex, resulted in a smaller increase in [Ca2+]i. These
      results suggest that the alkali-evoked calcium release is largely attributable to
      lysosomes, a conclusion that was confirmed by direct measurements of total
      calcium content of S2 organelles. Lysosomes and endoplasmic reticulum were the
      only organelles found to have concentrations of total calcium significantly
      higher than the cytosol. However, NH4Cl (15 mM) reduced the level of total
      calcium only in lysosomes. Depletion of acidic Ca2+ stores did not elicit
      depletion-operated Ca2+ entry. They were refilled upon re-exposure of cells to
      normal saline ([Ca2+]o = 2 mM), but not by thapsigargin-induced [Ca2+]i elevation
      in Ca(2+)-free saline.

PMID- 10579055
TI  - Age-related alterations in caffeine-sensitive calcium stores and mitochondrial
      buffering in rat basal forebrain.
AB  - The properties of caffeine- and thapsigargin-sensitive endoplasmic reticulum
      calcium stores were compared in acutely dissociated basal forebrain neurons from
      young and aged F344 rats by ratiometric microfluorimetry. The ability of these
      stores to sequester and release calcium resembles that observed in other central
      neurons, with an important role of mitochondrial calcium buffering in regulating
      the response to caffeine. An age-related reduction in the filling state of the
      stores in resting cells appears to be mediated by increased rapid calcium
      buffering, which reduces the availability of calcium for uptake into the stores.
      An age-related decrease in the amplitude of maximal caffeine-induced calcium
      release was attributed to increased mitochondrial buffering. There were no age
      related differences in the sensitivity to caffeine or in the calcium
      sequestration/release process at the level of the endoplasmic reticulum per se.
      These findings demonstrate the importance of interactions between cellular
      calcium buffering mechanisms and provide details regarding age-related changes in
      calcium homeostasis which have been thought to occur in these and other neurons
      associated with age-related neuronal dysfunctions.

PMID- 10579056
TI  - Effects of bone fracture and surgery on plasma myosin heavy chain fragments of
      skeletal muscle.
AB  - OBJECTIVE: Myosin heavy chain (MHC) fragment is part of a structural or force
      bearing protein expressed in the thick filament of muscle fibres. Since MHC
      fragment is a contractile protein, an increase in plasma MHC concentrations after
      muscle injury indicates degradation of the contractile apparatus. This study was
      conducted to determine whether MHC concentrations could be a tool in the
      assessment of tissue damage in patients with myoskeletal injuries. DESIGN:
      Prospective, controlled study. SETTING: A UK University National Health Service
      Centre. PATIENTS: Thirty-eight orthopedic patients, of whom 14 received surgical
      treatments within the 2-day study period. Patients were compared with 16
      nonorthopedic control subjects. OUTCOME MEASURES: Serum levels of MHC, creatine
      kinase, cardiac troponin I (cTnI), and myoglobin were measured at the time of
      admission and 24 hours later. Data from patients undergoing surgical repairs were
      obtained 24 hours after surgery. A competitive radio-immunoassay for beta-type
      MHC was used. RESULTS: Plasma MHC concentration was higher in the patients than
      in the controls. The peak levels were observed 24 hours after injury or surgery
      (p < 0.05). cTnI concentrations were consistently below the assay detection limit
      of 0.3 microgram/L, thus excluding protein release from the heart muscle (cardiac
      beta-type MHC). Creatine kinase and myoglobin concentrations were significantly
      higher on admission in the non-surgical patients than in the surgically treated
      cases. CONCLUSIONS: Serum MHC levels could be a useful supplementary
      retrospective, prognostic or diagnostic tool in the study of myoskeletal
      disturbances involving muscle injury or bone fractures that result in membrane
      leakage of myoskeletal cells.

PMID- 10579057
TI  - Predictors of failure of Helicobacter pylori eradication and predictors of ulcer
      recurrence: a randomized controlled trial.
AB  - OBJECTIVE: In light of evidence that Helicobacter pylori treatment fails 5% to
      20% of the time, the objective of this study was to determine predictors of
      unsuccessful H. pylori eradication and of duodenal ulcer recurrence. DESIGN:
      Randomized, double-blind, placebo-controlled trial. SETTING: Gastroenterology
      services of 2 general hospitals in Montreal, Que. PATIENTS: All patients (aged 16
      to 90) with an endoscopically proven duodenal ulcer within the previous year and
      H. pylori infection detected on antral biopsy were asked to participate; 85 were
      included. INTERVENTIONS: Patients were randomized in double-blind fashion to 1 of
      2 eradication therapies, consisting of metronidazole, bismuth subcitrate and
      either amoxicillin or placebo. Endoscopy was performed at follow-up every 3
      months for 12 months. OUTCOME MEASURES: Demographic data, characteristics of
      patients and disease, previous history and family history of ulcer disease,
      compliance at day 10 and day 28 of therapy; in vitro metronidazole resistance of
      H. pylori; eradication of H. pylori (determined by endoscopic biopsy 3 months
      after therapy); and ulcer recurrence within 12 months after therapy. RESULTS:
      Metronidazole resistance (odds ratio [OR] 0.11, 95% confidence interval [CI]
      0.017 to 0.69) was the only independent predictor of eradication. Compliance (as
      defined in the study), density of organisms on culture, as well as several other
      factors examined, were not significant predictors. Treatment group, although a
      significant factor on univariate analysis, was not an independent predictor on
      multivariate analysis, as there were relatively good eradication rates (82% and
      97% among compliant patients) in both groups. With regard to ulcer recurrence, 3
      independent predictors were identified: failed H. pylori eradication (OR 86.5,
      95% CI 4.2 to 1769), unemployment (OR 13.2, 95% CI 1.8 to 95) and a family
      history of ulcer disease (OR 12.2, 95% CI 1.2 to 128). CONCLUSIONS: The best
      predictor of ulcer recurrence is failure of H. pylori eradication, which, in
      turn, depends on metronidazole resistance. Hence, treatments containing
      metronidazole should be avoided in populations with high rates of metronidazole
      resistance. A family history of ulcer disease and unemployment were also
      predictors of ulcer recurrence, which suggests a potential role for treatment of
      contacts.

PMID- 10579059
TI  - Henry Friesen Lecture. Clinical relevance of convertases: atherosclerosis,
      Alzheimer's disease, obesity, diabetes and HIV.

PMID- 10579058
TI  - Regulation and intracellular localization of the epithelial isoforms of the
      Na+/H+ exchangers NHE2 and NHE3.
AB  - The Na+/H+ exchangers (NHE) are a ubiquitous family of membrane proteins that
      catalyze the counter-transport of extracellular Na+ for intracellular H+ and are
      important for intracellular pH and cell volume regulation. The major epithelial
      isoforms, NHE2 and NHE3, are thought to have more specialized roles in regulating
      Na+ and water absorption and are differentially expressed in epithelial tissues.
      NHE2 and NHE3 not only differ with respect to their response to various
      endogenous and exogenous factors but exhibit different intracellular localization
      as well. NHE2 is primarily located at the plasma membrane, whereas NHE3 is mostly
      sequestered in an intracellular compartment corresponding to the recycling
      endosome. Furthermore, NHE3 is localized to the apical pole, whereas polar
      localization of NHE2 has been controversial. The author has recently localized
      NHE2 to the apical membrane of a renal epithelial cell line and identified a 45
      residue-long region of the cytosolic domain (corresponding to residues 731-777 of
      the rat NHE2) to be critical for apical targeting. Although SH3 domains of
      various proteins were found to bind to this and a more carboxy-terminal proline
      rich region in vitro, the functional significance of these interactions appears
      inconsequential. Deletion of both proline-rich regions did not affect Na+/H+
      exchange nor its response to hypertonicity and metabolic depletion. However, loss
      of residues 731-777, which bound specifically in vitro to the SH3 domain of the
      cytoskeletal protein, alpha-spectrin, mistargets NHE2 to the basolateral surface.

PMID- 10579060
TI  - The added value of simultaneous myocardial perfusion and left ventricular
      function.
AB  - The focus of this review is the advantages of simultaneously assessing myocardial
      perfusion and left ventricular function. Nuclear cardiology imaging techniques as
      well as the development of technetium-labeled perfusion tracers now permit
      combined myocardial-perfusion and left-ventricular function studies at a single
      testing interval. Radionuclide angiography as well as electrocardiographic-gated
      images of the perfused myocardium are the two well-established techniques for
      that purpose with a single injection of a technetium-labeled perfusion tracer.
      Recent data have demonstrated the impact and clinical role of these studies, when
      combined, in the diagnosis as well as prognosis and risk stratification of
      patients with suspected or known coronary artery disease. The addition of
      functional information to perfusion data has shown to improve the detection of
      multivessel disease. Most recent data have also demonstrated the ability of these
      combined measurements to improve the prediction of hard events. It appears that
      the role of each of these tests may differ, depending on the patient population,
      particularly in relation to gender and type of stress test performed. Finally, a
      third area of potential application of these combined techniques would be in the
      assessment of myocardial viability using pharmacologic stress tests in
      combination with wall-motion analysis by gated images of the perfused myocardium.

PMID- 10579061
TI  - Pharmacologic stress echocardiography in the assessment of coronary artery
      disease.
AB  - Pharmacologic stress echocardiography has gained widespread popularity in recent
      years because it is more feasible for the patient and less technically demanding
      for the echocardiographer than exercise stress testing. The two most popular
      pharmacologic stresses are dobutamine and dipyridamole. These agents provide
      similar prognostic value and diagnostic accuracy for angiographically assessed
      coronary artery disease; dobutamine has marginally higher sensitivity in single
      vessel disease, and dipyridamole has marginally higher specificity in patients
      with normal coronary arteries. Both stresses are safe, but a physician should
      always be in attendance when they are administered: Life-threatening reactions
      can occur in one of 300 to 500 cases with dobutamine and in one of 700 to 1500
      cases with dipyridamole. For dipyridamole and dobutamine echocardiography,
      outcome data are available from multicenter, international, observational,
      prospective studies, such as the EPIC (Echo Persantine International Cooperative)
      and EDIC (Echo Dobutamine International Cooperative).

PMID- 10579062
TI  - Intravascular ultrasonography in the evaluation of results of coronary
      angioplasty and stenting.
AB  - The main advantage of intravascular ultrasonography (IVUS) over angiography in
      assessing the effect of coronary interventions is the ability of IVUS to directly
      visualize the vessel wall. IVUS often reveals a high residual plaque burden after
      angiographically successful angioplasty, and this can motivate the operator to
      use additional, more aggressive measures in an attempt to increase lumen
      dimensions. Studies using IVUS imaging before and after balloon angioplasty have
      shown that luminal gain after percutaneous transluminal coronary angioplasty
      (PTCA) results from a combination of plaque reduction and vessel wall stretch.
      Minimal luminal area and residual area stenosis after PTCA and stent deployment,
      as measured by IVUS, have been shown to be predictors of restenosis. IVUS studies
      have pointed to vessel shrinkage, not intimal hyperplasia, as the main mechanism
      of restenosis after PTCA. IVUS guidance of stent deployment has often revealed
      inadequate stent expansion despite optimal results on angiography, leading to
      high-pressure stent deployment with significant additional luminal gain.
      Restenosis rates may be lower with IVUS-guided stent deployment.

PMID- 10579063
TI  - Magnetic resonance imaging in acute myocardial infarction.
AB  - Advances in magnetic resonance imaging (MRI) have led to more widespread
      utilization of this diagnostic imaging modality in the diagnosis of coronary
      artery disease. With MRI, the complexity and heterogeneity of myocardial infarcts
      can be demonstrated. By using this technique, much insight has been gained into
      the pathophysiologic mechanisms of acute coronary thrombosis and reperfusion. MRI
      has significant diagnostic potential, particularly if one can combine studies of
      myocardial function, perfusion, and sodium metabolism with the noninvasive
      assessment of coronary anatomy and epicardial coronary artery blood flow.

PMID- 10579064
TI  - Screening for occult coronary artery disease with radiographic detection of
      coronary calcification.
AB  - Coronary atherosclerosis is ubiquitous among adults, yet many afflicted persons
      will suffer no coronary events. Atherosclerotic plaque formation in the coronary
      arteries is a dynamic process, and the onset of a coronary event is often
      unheralded, sudden, and lethal. In addition, it is known that the amount of
      calcification in the coronary arteries correlates with the amount of
      atherosclerosis in different persons and, to a lesser degree, in segments of the
      coronary tree in the same person. Radiographic imaging methods, including
      fluoroscopy, electron-beam computed tomography, and helical computed tomography,
      can detect coronary calcium and seem to be able to diagnose coronary
      atherosclerosis. However, data on the relationship between quantity of coronary
      calcium and event likelihood are limited. Thus, the diagnostic value and,
      particularly, the prognostic value of calcium detection are controversial and may
      be applicable only to certain subgroups of patients.

PMID- 10579065
TI  - Targets for gene therapy of vein grafts.
AB  - Poor long-term patency and a lack of suitable systemic pharmacologic therapy for
      the prevention of vein graft failure have prompted the search for effective local
      gene therapy. Vein grafts are particularly well suited for gene transfer in the
      clinic because direct access to vein is available during surgical preparation for
      grafting. In this review, the available animal models are discussed and a new
      mouse model is highlighted. Recent advances in gene transfer technology are
      reviewed, including the use of adeno-associated virus and modified adenoviruses
      that can prolong in vivo transgene expression for months. Gene therapy is
      intended to reduce early thrombosis, reduce neointima formation, and prevent
      atherosclerosis in vein grafts. Promising antithrombotic targets include tissue
      plasminogen activator and thrombomodulin. Nitric oxide synthase, prostacyclin
      synthase, and tissue inhibitors of metalloproteinases have been used to reduce
      neointima formation, and vein graft atheroma remains a challenge for the future.

PMID- 10579066
TI  - Polarization and myocardial protection.
AB  - Heart surgery or transplantation generally involve global ischemia, and
      techniques have been developed to protect the myocardium from ischemic and
      reperfusion injury. Hyperkalemic cardioplegia has been the gold standard for
      myocardial protection for years, but patients undergoing surgery almost
      invariably have some postoperative dysfunction. One factor may be the
      depolarizing nature of hyperkalemia, which results in continuing transmembrane
      fluxes and metabolism, even during hypothermic ischemia. A potentially beneficial
      alternative to hyperkalemic (depolarizing) cardioplegia is arrest in a
      "hyperpolarized" or "polarized" state, which maintains the myocardial membrane
      potential at or near the resting potential. This should minimize transmembrane
      fluxes and metabolic demand and improve myocardial protection. These alternative
      concepts have recently been investigated by using adenosine and potassium-channel
      openers (which are thought to induce hyperpolarized arrest) or the sodium-channel
      blocker tetrodotoxin (which induces polarized arrest), and results have been
      beneficial compared with the results of hyperkalemia. Additional studies are
      needed before experimental promise can become clinical reality.

PMID- 10579067
TI  - Multiple arterial grafts and survival.
AB  - Limitations in the long-term patency of saphenous veins for bypass grafts have
      encouraged interest in the use of arterial conduits. The positive effect of an
      internal thoracic artery graft on survival has been accepted for more than a
      decade, but it has proven difficult to show additional benefit from additional
      arterial conduits; this is probably due to multiple factors, including
      inappropriate choice of target vessels, short follow-up, and inadequate numbers
      of patients. Recently, however, the positive effect of a second arterial graft
      was confirmed. It will probably be difficult to show a survival benefit from a
      third or fourth arterial graft, but we believe that complete arterial
      revascularization will result in improved long-term freedom from reintervention.
      Interest in arterial conduits for coronary artery bypass was primarily limited to
      the left internal thoracic artery until the mid-1980s, when enthusiasm for the
      use of bilateral internal thoracic arteries grew. More recently, the
      gastroepiploic artery, the inferior epigastric artery, and especially the radial
      artery have all found advocates. However, the original conduit--and the standard
      against which all others are compared--is the greater saphenous vein.

PMID- 10579068
TI  - Myocardial revascularization for the treatment of post-ischemic heart failure.
AB  - Heart failure due to coronary artery disease is a major public health problem.
      Medical treatment ameliorates symptoms and prognosis, although mortality remains
      high. Heart failure occurs when a sizeable number of myocytes do not contract.
      This may be due to irreversible myocyte loss (infarct) and/or dysfunctional but
      viable myocytes (hibernating), which can resume function following coronary
      artery bypass surgery. The presence of hibernating myocardium can be predicted by
      noninvasive nuclear imaging using both single photon (SPECT) and positron
      emission tomography, and also by stress echocardiography. A number of
      uncontrolled studies have demonstrated a promising role for coronary artery
      bypass surgery in patients with heart failure in whom a substantial amount of
      hibernating myocardium is present. These findings, particularly the magnitude of
      the benefits reported, justify the need for a randomized trial in this patient
      population.

PMID- 10579069
TI  - Has laser revascularization found its place yet?
AB  - Transmyocardial laser revascularization (TMR) is a relatively new therapy for
      atherosclerotic coronary artery disease. Unlike well established surgical and
      percutaneous revascularization procedures, TMR is reserved for patients with
      advanced and severe forms of coronary artery disease that is unsuitable for other
      forms of revascularization. The results of TMR so far have been controversial
      with a bias toward steady and incremental adoption as sole therapy or in
      combination with coronary artery bypass graft surgery. The controversy
      surrounding TMR is related to the fact that its mechanism of action is not proven
      beyond a reasonable doubt. It is believed that angiogensis stimulation by the
      laser beam may be responsible for the relief of angina. However, the marked
      discrepancy in the symptomatic relief of angina and the increase in myocardial
      perfusion is not well understood. Other mechanisms proposed include direct
      perfusion through the laser channels, myocardial damage, denervation of ischemic
      myocardium and a placebo effect. It is possible that one or more of these
      mechanism may be responsible at various time intervals for the relief of angina.
      The challenge of TMR is related to improvement in perioperative outcomes, and
      long-term survival without worsening of left ventricular function. The
      achievement of these goals makes TMR an alternative therapy to what was formerly
      the only therapeutic option for these patients, namely: failed maximum medical
      therapy.

PMID- 10579070
TI  - Cardiac angiogenesis and gene therapy: a strategy for myocardial
      revascularization.
AB  - Angiogenesis, the de novo formation of new vasculature, is a critical response to
      ischemia that provides neovascularization of ischemic tissues. In therapeutic
      angiogenesis, an angiogen--a mediator that induces angiogenesis--is delivered to
      targeted tissues, augmenting the native angiogenic process and enhancing
      reperfusion of ischemic tissues. Gene transfer is a novel means of providing
      therapeutic angiogenesis: the cDNA coding for specific angiogens, rather than the
      proteins themselves, is administered to the tissues in which angiogenesis is
      desired. This review is focused on therapeutic angiogenesis based on gene
      transfer strategies for the provision of myocardial revascularization.

PMID- 10579072
TI  - Bibliography. Current world literature. Coronary artery surgery.

PMID- 10579071
TI  - Bibliography. Current world literature. Imaging and echocardiography.

PMID- 10579073
TI  - The necessity of a second prostate biopsy cannot be predicted by PSA or PSA
      derivatives (density or free:total ratio) in men with prior negative prostatic
      biopsies.
AB  - Serum prostate specific antigen, prostate specific antigen density and free:total
      prostate specific antigen are known to be useful for determining the risk of
      prostate cancer in patients undergoing prostate cancer screening. The patient
      with a positive biopsy presents no future prostate specific antigen dilemma.
      Those with negative biopsies often go on to numerous repeat biopsies. Our goal
      was to establish criteria that could be used to identify patients who will
      require repeat prostate biopsies (possibly false negative initial biopsy), while
      not exposing the low risk population (probable true negative initial biopsy) to
      additional invasive procedures. Between March 1991 and March 1998, 148 patients
      who had a biopsy for an elevated prostate specific antigen value (4.1-10.0) or an
      altered digital rectal examination, had no cancer found in the specimen. From
      these, 51 (34.4%) had repeated biopsies, while the others persisted on close
      follow-up. We examined their serum prostate specific antigen, prostate specific
      antigen density and free:total prostate specific antigen value, as well as their
      age and histology results of the initial and repeat biopsy, to determine if any
      predictor of the need for a repeat biopsy could be identified. Eight (15.7%) from
      51 men who had repeat biopsy had prostate cancer detected. Forty three (84.3%)
      patients persisted with a negative biopsy, despite filling the criteria for re
      biopsy. Multivariate analysis failed to identify any significant predictors of
      prostate cancer in the repeat biopsy group. Despite initial success, the prostate
      specific antigen derivatives and free:total prostate specific antigen have not
      safely limited the number of biopsies performed for an abnormal prostate specific
      antigen (4.1-10.0). Neither prostate specific antigen density nor free:total
      prostate specific antigen predicted the need for repeat biopsy in this specific
      group. The results of this ongoing study demonstrate that to date, prostate
      specific antigen and prostate specific antigen derivatives can not be utilized to
      determine which patients will be at high risk for requiring repeat prostate
      biopsy. All patients must be closely monitored for evidence of a change in status
      from benign to malignant disease, and new markers for this purpose are urgently
      needed.

PMID- 10579074
TI  - Renal cell carcinoma: should radical nephrectomy be performed in the presence of
      metastatic disease?
AB  - Metastatic renal cell carcinoma is associated with an unfavorable prognosis and
      the treatment options are limited. Adjunctive radical nephrectomy, performed
      either before or after the administration of systemic immunotherapy, has been
      proposed as a means of improving outcome. The role of nephrectomy for patients
      with metastatic disease remains controversial. This article reviews the role of
      nephrectomy in metastatic renal cell carcinoma and the optimal timing for surgery
      relative to immunotherapy.

PMID- 10579075
TI  - Is open surgery for partial nephrectomy an obsolete surgical procedure?
AB  - During the past few years, the indications for laparoscopic surgery in urology
      have extended from simple ablative procedures towards more complex reconstructive
      and organ-preserving interventions. Among them, transperitoneal and
      extraperitoneal laparoscopic partial nephrectomy have been successfully performed
      for both benign and malignant lesions. However, this approach raises specific
      problems because in contrast to other laparoscopic procedures the techniques and
      tools used during open surgery can not be simply transposed to laparoscopy. The
      absence of surface hypothermia, the lack of manual palpation, difficulties of
      vascular control and reconstruction of the collecting system necessitate new
      solutions readily adaptable to laparoscopic surgery. However, the available
      series comprise only a few cases, and there are differences in techniques and
      instrumentation in almost every operation. In these circumstances, it is too
      early to consider this new approach as reproducible and ready to be used
      elsewhere than in specialized centres. Although the feasibility and good results
      of partial nephrectomy for benign conditions and small exophitic tumours is now
      well documented, the development of new surgical tools and standardization of
      methodology are required for more complex cases within the scope of well
      conceived prospective studies.

PMID- 10579076
TI  - Monoclonal antibodies: will they become an integral part of the evaluation and
      treatment of prostate cancer--focus on prostate-specific membrane antigen?
AB  - Over the past two decades, monoclonal antibody technology has had an increasing
      impact on clinical diagnostic and therapeutic options, and this is true in the
      realm of managing prostate cancer. Several targets such as prostate-specific
      antigen and prostatic acid phosphatase as well as, more recently, angiogenic
      antigens such as vascular endothelial growth factor have been examined for
      therapy. Prostate-specific membrane antigen, a type II integral membrane
      glycoprotein initially characterized by the monoclonal antibody 7E11, has shown
      promise. Recent evidence suggests that prostate-specific membrane antigen is also
      expressed in tumor-associated neovasculature of a wide variety of malignant
      neoplasms. With its expression in prostate secretory-acinar epithelium and the
      prostate and in the neovasculature associated with tumors, prostate-specific
      membrane antigen represents an excellent antigenic target for monoclonal antibody
      diagnostic and therapeutic options. As research continues, the role of monoclonal
      antibody imaging and therapy will become increasingly important in the management
      of prostate cancer.

PMID- 10579077
TI  - Markers for recurrence of superficial bladder cancer: what is valid?
AB  - The management of superficial bladder cancer is characterized by early
      recognition of recurrences and the prevention of progression. Several clinical
      markers are used to divide patients into risk groups determining treatment and
      follow-up schemes. Although only a small fraction of patients will progress to
      invasive disease, survival of these patients is largely dictated by their bladder
      cancer. Whether early aggressive treatment of 'high-risk' superficial bladder
      cancer improves survival is not the issue of this article. Here we discuss the
      markers available for predicting tumour recurrence and progression. Clinical
      markers remain the most practical in decision-making and can identify high-risk
      patients. Molecular markers may be useful, but as yet insufficient evidence
      exists on their efficacy for daily use.

PMID- 10579078
TI  - Recent perspectives in topical therapy in superficial bladder cancer.
AB  - With regard to side-effects in intravesical bacillus Calmette-Guerin instillation
      therapy and the limited efficacy of intravesical chemotherapy, there is still a
      need for improvement of these standard therapies. Recently, technical adjuvant
      means or the modification of cytostatic drugs have been undertaken to improve the
      efficacy of intravesical chemotherapy. Prognostic indicators of the response to
      bacillus Calmette-Guerin immunotherapy have been identified, but indicators of
      side-effects are needed in order to improve the benefit-to-risk ratio of bacillus
      Calmette-Guerin instillation therapy. Many innovative treatment options, however,
      still require a definition of their clinical value.

PMID- 10579079
TI  - Surgery for invasive bladder tumors: technique and outcome.
AB  - The operative management of invasive transitional cell carcinoma has advanced
      significantly in the past year, particularly with respect to continent urinary
      diversion. The long term safety and efficacy of this form of urinary
      reconstruction is being established in terms of both operative and metabolic
      complications. The availability of continent diversion can decrease the interval
      to cystectomy and therefore may impact positively on survival. It has also been
      shown that continent diversion can safely be offered to patients at high risk for
      local recurrence. The importance of urethral sensory threshold on postoperative
      continence is being established. These findings and others continue to enhance
      the survival and quality of life of patients undergoing cystectomy for invasive
      bladder cancer.

PMID- 10579080
TI  - Neo-adjuvant and adjuvant treatment of locally invasive bladder cancer.
AB  - Since Sternberg et al. in 1985 first published preliminary results of
      polychemotherapy in patients with metastatic bladder cancer, it became apparent
      that transitional carcinoma of the bladder is highly responsive to chemotherapy.
      Response rates up to 70% with combination therapy regimens like methotrexate,
      vinblastine, doxorubicin or adriamycin and cisplatin promised that transitional
      carcinoma might be able to cure even in advanced stages. Chemotherapy has either
      been applied prior to the local treatment (such as radical cystectomy or
      radiotherapy) in a neo-adjuvant regimen, or after local therapy in an adjuvant
      regimen. Although a large number of studies have been published in the past 20
      years, the role of the different chemotherapeutic approaches has not been clearly
      defined. Therefore, neither neo-adjuvant nor adjuvant chemotherapy can be
      recommended as 'gold standard' treatment for advanced bladder cancer.

PMID- 10579081
TI  - Health-related quality of life in patients treated for testicular cancer.
AB  - Cross-sectional studies have shown that long-term health-related quality of life
      is satisfactory in the majority of testicular cancer patients, in spite of slight
      to moderate physical morbidity (sexual dysfunction, infertility) in at least a
      third of them. Modern risk-adapted treatment of testicular cancer patients will
      hopefully decrease the long-term sequelae furthermore. Prospective studies are
      needed to identify those patients at increased risk of developing major physical
      or psychosocial problems, and to study the role of medical and psychological
      intervention at an early phase of the clinical course in these patients. The long
      term investigation and follow-up of testicular cancer survivors provide useful
      information on survivorship problems in cured cancer patients in general.

PMID- 10579082
TI  - Treatment of testicular tumours based on risk factors.
AB  - Germ cell cancer is highly sensitive to cisplatinum-based chemotherapy, resulting
      in cure rates of over 90% for patients with minimal metastatic disease or low
      tumour markers, 70% for patients with intermediate prognosis features, and 50%
      for patients with poor prognosis criteria. Whereas current clinical studies aim
      to improve the survival of patients with poor prognosis by means of high-dose
      chemotherapy, or the survival of intermediate prognosis patients by more
      intensive chemotherapy, for patients with good prognosis the reduction of doses,
      number of drugs or cycles is investigated to reduce the short-term and, in
      particular, long-term treatment sequelae. However, apart from these clinical
      studies, the current treatment standard of three cycles of
      platinum/etoposide/bleomycin for good prognosis patients and four cycles for
      intermediate and poor prognosis patients with advanced germ cell cancer has not
      been changed by recent trial results. The excellent cure rate with cisplatinum
      based chemotherapy in the case of early metastatic disease with three cycles of
      platinum/etoposide/bleomycin as well as the high efficacy of adjuvant
      chemotherapy with two cycles of platinum/etoposide/bleomycin in the case of
      microscopic disease did change the treatment standards in stage I and II non
      seminomatous germ cell cancer, with defined treatment options depending on
      prognostic factors. The treatment of testicular cancer based on prognostic
      factors is mandatory in all stages of seminoma and non-seminoma; however,
      molecular biological factors might make a major contribution to a more precise
      determination of prognosis and therefore enable a tailored selection of an
      individual treatment in the future.

PMID- 10579083
TI  - The current role of surgery in the management of residual disease.
AB  - The increasing interest in surveillance rather than primary retroperitoneal lymph
      node dissection for clinical stage I testis cancer has led to retroperitoneal
      lymph node dissection being performed mostly after chemotherapy for stage II-IV
      disease. In most centres residual masses of 2-3 cm or more are removed; those
      smaller than this are most likely to be necrotic. The aim is to remove all
      residual disease even if this necessitates nephrectomy or excision of adjacent
      vascular structures. Laparoscopic approaches are hazardous in these
      circumstances. Thoraco-abdominal surgical approaches enable excellent access to
      retroperitoneal masses and synchronous excision of ipsilateral pulmonary
      metastases and thoracic lymph nodes. Retroperitoneal lymph node dissection also
      appears to be worthwhile in chemotherapy-resistant disease ('desperation
      retroperitoneal lymph node dissection'), although the relapse rate is higher in
      this group.

PMID- 10579084
TI  - Secondary tumors after initial successful treatment of metastatic testis cancer.
AB  - Most patients who present with testicular cancer are cured. Because this is a
      disease of predominantly young men, after curative therapy these men survive for
      many years. In other cancers, treatment-related disease has been noted to appear
      many years after successful therapy. Therefore, the question of whether or not
      therapy-related cancers occur in testicular cancer is especially pertinent.

PMID- 10579085
TI  - Bibliography. Current world literature. Oncology: prostate and renal.

PMID- 10579086
TI  - Bibliography. Current world literature. Oncology: bladder and testis.

PMID- 10579087
TI  - Reassessment of the routine anaerobic culture and incubation time in the
      BacT/Alert FAN blood culture bottles.
AB  - A total of 9,130 blood cultures were collected from adult patients with suspected
      bloodstream infections. The recommended 20 mL sample of blood was divided equally
      between the aerobic and anaerobic FAN bottles and monitored in the BacT/Alert
      Microbial Detection System for a total of 5 days. There were 757 clinically
      significant positive culture pairs from 291 patients. Significant differences
      were found with greater recovery of Pseudomonas aeruginosa (p < 0.001),
      Acinetobacter spp. (p = 0.002), coagulase-negative staphylococci other than
      Staphylococcus epidermidis (p = 0.002), and Candida spp. (p < 0.001) from the
      aerobic bottle and greater recovery of anaerobic bacteria (p < 0.001) from the
      anaerobic bottle. Significantly more episodes of P. aeruginosa bacteremia (p <
      0.003) and candidemia (p < 0.001) were detected by the aerobic FAN bottle and
      significantly more episodes of anaerobic bacteremia (p < 0.001) were detected by
      the anaerobic FAN bottle (Table 2). No other significant differences between
      systems in their detection of bacteremias were noted. Anaerobic bacteremias were
      encountered in diverse and often unpredictable clinical settings. All clinically
      significant episodes of bloodstream infection were detected within 4 days of
      incubation of their cultures. We conclude routine, rather than selective, use of
      the anaerobic FAN bottle in the blood culture set and a 4-day incubation of blood
      cultures in the BacT/Alert aerobic and anaerobic FAN bottles is an appropriate
      routine procedure.

PMID- 10579088
TI  - DNA probe analysis for the carriage of enterotoxigenic Clostridium perfringens in
      feces of a Mexican subpopulation.
AB  - Clostridium perfringens has been implicated as a causative agent of foodborne
      poisoning, infectious diarrhea (not associated with foods), gas gangrene, and
      several veterinary diseases. Fecal carriage of enterotoxigenic strains of this
      bacterium appears to be important in the development of infectious diarrhea and
      as a source of C. perfringens contamination of foods. In this work, carriage of
      this bacterium in feces of a Mexican population was analyzed. C. perfringens was
      found in 126 of the 200 fecal samples obtained from healthy individuals from
      northern Mexico. The samples had an average of 7.4 x 10(3) spores per gram, with
      the elderly population showing the highest levels. Dot blot analyses using a dig
      labeled probe specific for the enterotoxin gene showed that 7% of the samples had
      isolates with toxigenic potential.

PMID- 10579089
TI  - Multiplex PCR for rapid and differential diagnosis of Mycoplasma pneumoniae and
      Chlamydia pneumoniae in respiratory infections.
AB  - A duplex polymerase chain reaction (PCR) was developed for the simultaneous
      detection of Chlamydia pneumoniae and Mycoplasma pneumoniae. A study of 163
      respiratory specimens from in-patients of the "Centre Hospitalier et
      Universitaire de Nancy" showed the good sensitivity of this duplex PCR allowing
      the detection of C. pneumoniae and M. pneumoniae from 8 and 13 patients,
      respectively, whereas the culture was negative for C. pneumoniae for all the
      samples and positive for M. pneumoniae only in 9 cases. The value of these
      results has been confirmed by running on the same samples specific nested PCRs
      for these two microorganisms that gave the same results. Thus, the proposed
      duplex amplification technique may facilitate the diagnosis of infection by these
      two agents that are difficult to isolate.

PMID- 10579090
TI  - In vitro activity of antituberculous agents against Mycobacterium tuberculosis
      isolates from Bogota, DC (Colombia) evaluated by the ETest.
AB  - Tuberculosis tests for antimicrobial susceptibility takes weeks. However, delayed
      therapy, can compromise the patient, as well as lead to an increase in disease
      incidence. Among infectious diseases, tuberculosis continues to be a leading
      cause of death in the world. The E-test is a new concept for Minimal Inhibitory
      Concentrations (MIC) determinations for antimicrobial agents that is based on a
      predefined antibiotic gradient on a plastic strip calibrated with a continuous
      logarithmic MIC scale covering 15 two-fold dilutions. MICs of rifampin,
      isoniazid, and ethambutol were determined by using the E-test (AB BIODISK, Solna,
      Sweden) for 30 clinical strains of Mycobacterium tuberculosis isolated from four
      hospitals, and were compared with the Bactec method. To make the inoculum with a
      turbidity equivalent to a McFarland 3.0 standard, we obtained a sample from an
      agar surface and the Bactec 460, as described by the manufacturer. Excellent
      agreement (100% for rifampin, 96.8% for ethambutol, and 90% for isoniazid) was
      demonstrated between the E-test MIC distributions and the Bactec interpretive
      criteria for all clinical isolates of M. tuberculosis tested. The E-test appears
      to be a good alternative method for testing the susceptibility of M. tuberculosis
      isolates to the three, most-commonly-used therapeutic agents.

PMID- 10579091
TI  - Molecular characterization by PCR-fingerprinting of Candida dubliniensis strains
      isolated from two HIV-positive patients in Spain.
AB  - Six Candida dubliniensis isolates were recovered from two HIV-infected
      individuals in the course of a prospective study of recurrent oral candidosis
      among HIV-positive patients in Spain. Candida albicans strains as well as non
      albicans strains were also obtained from these two patients. C. dubliniensis
      strains were germ-tube-positive and produced abundant chlamydospores.
      Fingerprinting the genomic DNAs of these six C. dubliniensis with the C. albicans
      specific probe 27A as well as karyotyping was performed to confirm the
      identification of these isolates. Further analysis of their genomic DNAs was
      performed by PCR-fingerprinting with the core sequence of phage M13, and they
      exhibited species-specific multilocus band patterns, clearly distinct from those
      of C. albicans isolates analyzed in this study and in a previous one (Diaz-Guerra
      1997). Intraspecies variation was also seen among PCR patterns yielded by C.
      dubliniensis isolates from different patients. Although few strains have been
      analyzed, the use of this PCR-fingerprinting procedure is a promising tool for
      further epidemiologic studies with C. dubliniensis. The isolation of C.
      dubliniensis from Spanish HIV-infected patients contributes to the idea of
      widespread geographic distribution of this species.

PMID- 10579092
TI  - In-vitro activity of cefepime and other broad-spectrum antimicrobials against
      several groups of gram-negative bacilli and Staphylococcus aureus.
AB  - The in vitro activity of cefepime was compared with that of amikacin,
      ceftazidime, imipenem, ciprofloxacin, and piperacillin-tazobactam by using the E
      test against five groups of carefully selected organisms: Klebsiella pneumoniae
      (68 isololates), Pseudomonas aeruginosa (62), methicillin-susceptible
      Staphylococcus aureus (MSSA) (60), and two groups of Enterobacteriaceae (60 and
      62 isolates, respectively). The bacteria were subdivided according to whether the
      infection was nosocomial or community-acquired, applying accepted and predefined
      criteria. These isolates were obtained from patients admitted to our medical
      center throughout 1998. We retrospectively compared antimicrobial
      susceptibilities of the study sample with those of the +/- 3000 bacterial strains
      isolated from blood stream infections since 1990: the study sample appeared to
      represent adequately the clinical databank. Presence of extended-spectrum beta
      lactamase (ESBL) was determined in all groups of Enterobacteriaceae with the ESBL
      screening E-test strip. Of the 252 Gram-negative bacilli tested, 242 (96%) were
      susceptible to cefepime, whereas only 168 (67%) were susceptible to ceftazidime,
      211 (84%) to amikacin, and 220 (87%) to piperacillin-tazobactam (p < 0.001).
      Imipenem was slightly superior to cefepime with only seven isolates resistant
      (3%), six of which were P. aeruginosa. Cefepime was more active against
      Enterobacteriaceae than ceftazidime (93% vs. 72%, p < 0.001). This superiority
      was most evident against nosocomial strains of K. pneumoniae, against which
      cefepime was > three times more active than ceftazidime. The high level of
      resistance seen in nosocomial isolates of K. pneumoniae is consistent with high
      rates of ESBL production (69%, compared with 15-26% in other Enterobacteriaceae).
      The MIC90 of cefepime to methicillin-sensitive S. aureus was 1.5 micrograms/mL,
      whereas that of ceftazidime was 4 micrograms/mL; the susceptibility rate of both
      was 100%. In conclusion, cefepime possesses in vitro potencies against MSSA and
      current clinical strains of Gram-negative bacilli, many of which harbor
      resistance to other antimicrobial agents. Hence, it seems very suitable for
      empiric coverage of serious nosocomial infections.

PMID- 10579093
TI  - In vitro activity of moxifloxacin, a new 8-methoxyquinolone, against gram
      positive bacteria.
AB  - The in vitro activity of moxifloxacin, formerly BAY 12-8039, against gram
      positive bacteria was tested by the agar dilution method. A total of 189 isolates
      that included Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium,
      streptococci, rhodococci, leuconostocs, pediococci, lactobacilli, and
      diphtheroids were tested. Moxifloxacin showed greater potency than ciprofloxacin
      against S. aureus, streptococci, and enterococci, having Minimal Inhibitory
      Concentrations (MICs) lower than those of ciprofloxacin by 2- to 64-fold. This
      improved activity was most prominent for S. aureus. Moxifloxacin was active
      against Leuconostoc and Rhodococcus species. Time-kill studies using moxifloxacin
      at a concentration of 3 micrograms/mL against one isolate each of methicillin
      resistant S. aureus (MSSA) (MIC, 0.031 microgram/mL), MRSA (MIC, 1 microgram/mL),
      two isolates of E. faecalis (MICs, 0.25 and 2 micrograms/mL), and two isolates of
      vancomycin-resistant E. faecium (MICs, 0.25 and 2 micrograms/mL) revealed an
      average decrease in colony forming unit (CFU) by 3.8, 0.4, 4.0, 2.0, 4.2, and 1.8
      log10 CFU/mL at 24 h, respectively. Moxifloxacin is a new 8-methoxyquinolone with
      improved in vitro activity against gram-positive bacteria. Further studies of the
      in vivo activity of this compound appear warranted.

PMID- 10579094
TI  - Evaluation of the in vitro antimicrobial activity of cefepime compared to other
      broad-spectrum beta-lactams tested against recent clinical isolates from 10
      Chinese hospitals. Chinese Antimicrobial Resistance Study Group.
AB  - A surveillance study was initiated in China in 1998 in which 10 medical centers
      participated. The susceptibility profiles of 996 commonly occurring pathogens
      belonging to 10 different species groups were tested by the Etest (AB BIODISK,
      Solna, Sweden) against six broad-spectrum beta-lactam antimicrobial agents
      (cefepime, ceftazidime, ceftriaxone, imipenem, cefoperazone/sulbactam and
      piperacillin or oxacillin). Quality control was closely monitored and cefepime-
      and/or imipenem-resistant Enterobacteriaceae were referred to the reference
      laboratory (University of Iowa College of Medicine, Iowa City, IA) for
      confirmation. The isolates of Citrobacter spp. and Enterobacter spp. were
      generally inhibited by imipenem (100% susceptible) and cefepime (89-94%), but
      were more resistant to the other drugs tested (< or = 74% susceptible). The
      indole-positive Proteus spp. and Serratia spp. isolates were > 94% susceptible to
      all tested beta-lactams except piperacillin. Organisms capable of producing
      extended spectrum beta-lactamases (ESBLs), which included Klebsiella spp. and
      Escherichia coli, were most susceptible to imipenem (100%) and cefepime (> 90%).
      Among the non-enteric Gram-negative bacilli, all drugs were marginally active
      against Pseudomonas aeruginosa (MIC90s, 32-> 256 ug/mL) and the Acinetobacter
      spp. were rather resistant to all the compounds, except imipenem (96%
      susceptible). All strains of Staphylococcus spp. were susceptible to the tested
      antimicrobials except for ceftazidime, which had a low potency (MIC90, 12-16
      micrograms/mL) against Chinese isolates with MICs that fell into the intermediate
      category. Cefepime, the fourth-generation cephalosporin, showed a very broad
      spectrum of activity against Gram-negative pathogens as well as oxacillin
      susceptible Staphylococcus spp. that was comparable with imipenem (widest
      spectrum) and superior to the other tested beta-lactams overall. Continued
      monitoring of clinical strains in China seems necessary to guide chemotherapy.

PMID- 10579095
TI  - United States geographic bacteria susceptibility patterns. 1997 ASCP
      Susceptibility Testing Group.
AB  - Antimicrobial drug resistance in bacterial pathogens continues, with 1997 seeing
      reports of Staphylococcus aureus no longer fully susceptible to vancomycin
      occurring in the United States. To better deal with this rapidly developing
      problem, we present the third year of United States national data that highlights
      the geographic nature of increasing resistance to antimicrobial agents. In 1997,
      we observed increasing numbers of vancomycin-resistant Enterococcus faecium, more
      methicillin-resistant Staphylococcus aureus (MRSA), and an apparent spreading of
      penicillin resistance in pneumococci. The majority of reporting sites now
      indicates that over 20% of Pseudomonas aeruginosa are fully resistant to
      ciprofloxacin, the only oral agent available for treating this pathogen. With
      increasing resistance coming at a time of decreasing available resources, it is
      more clear than ever before that the future of infectious diseases and clinical
      microbiology remains filled with challenge.

PMID- 10579096
TI  - Multicenter evaluation of the antimicrobial activity for six broad-spectrum beta
      lactams in Venezuela: comparison of data from 1997 and 1998 using the Etest
      method. Venezuelan Antimicrobial Resistance Study Group.
AB  - The minimum inhibitory concentrations of six broad-spectrum beta-lactam
      antimicrobial agents were determined in 1998 by use of the Etest versus a total
      of 502 bacteria in seven Venezuelan hospital laboratories. These data were
      compared with results of a similar study performed in 1997. The organisms tested
      included 309 recent clinical isolates of Enterobacteriaceae, 70 Pseudomonas
      aeruginosa, 54 Acinetobacter species, and 69 oxacillin-susceptible Staphylococcus
      aureus. Extended spectrum beta-lactamase production was noted among 30% of
      Klebsiella pneumoniae isolates. Hyperproduction of Amp C cephalosporinase
      producing resistance to ceftazidime and cefotaxime was observed with 10 to 37% of
      isolates of Enterobacter spp., Serratia spp., and Citrobacter freundii. The
      overall rank order of activity of the six beta-lactams tested in this study
      against all clinical isolates was imipenem (96.6% susceptible) > cefepime (90.4%)
      > piperacillin/tazobactam (85.7%) > ceftazidime (73.5%) > cefotaxime (70.5%) >
      piperacillin (55.0%). These findings were very similar to those reported for
      1997.

PMID- 10579097
TI  - An unusual site of chigger bite in a patient with scrub typhus.
AB  - A 70-year-old female farmer was admitted to the hospital because of fever,
      headache, and diarrhea for 7 days. Hypotension, right-sided pleural effusion with
      respiratory distress and leukocytosis were noted. She was initially treated as
      systemic bacterial infection by i.v. administration of ampicillin/sulbactam and
      amikacin. Because fever persisted in spite of aggressive treatment, a repeat
      thorough physical examination was done. An eschar was found over the left-sided
      labium majus and an enlarged lymph node was noted over the left inguinal region.
      Under the impression of scrub typhus, minocycline was administered. The patient's
      clinical condition improved dramatically within 3 days. The diagnosis was later
      confirmed by a serologic test for Rickettsia tsutsugamushi.

PMID- 10579098
TI  - In vitro antifungal activity of BMS-207147 and itraconazole against yeast strains
      that are non-susceptible to fluconazole.
AB  - The activities of itraconazole and the new triazole BMS-207147 were determined
      against Candida strains that were susceptible-dose dependent (fluconazole MICs 16
      to 32 micrograms/mL) or resistant (MICs > or = 64 micrograms/mL) to fluconazole.
      These strains included clinical isolates of Candida krusei, Candida glabrata, and
      Candida albicans. In addition, 16 isogenic, genetically characterized isolates of
      C. albicans, with progressively decreased susceptibility to fluconazole, were
      tested. BMS-207147 MICs to C. krusei, a species considered intrinsically
      resistant to fluconazole, were at 0.13 to 0.5 microgram/mL. The population
      distribution of the fluconazole-nonsusceptible C. glabrata was bimodal with BMS
      207147/itraconazole MICs at 0.5 to 2 micrograms/mL and > or = 16 micrograms/mL.
      The BMS-207147 MICs to the majority of fluconazole-nonsusceptible C. albicans
      strains tested were < or = 1 microgram/mL. The activity of BMS-207147 was
      minimally affected by overexpression of the gene encoding the efflux pump MDR1,
      but MIC increases were observed with changes in ERG11 and with overexpression of
      the CDR transporter gene. Nonetheless, BMS-207147 can be active against C.
      albicans mutants containing cumulative resistance mechanisms to azoles. In other
      words, fluconazole-resistant candidal strains may be susceptible to BMS-207147.

PMID- 10579099
TI  - Schizophrenia: a review of genetic studies.
AB  - Despite the complexities of schizophrenia, notable progress has been achieved in
      its diagnosis and treatment over the last 25 years. In this article we review the
      genetic research that provides the foundation for continued advances. One of the
      bases of our current understanding involves the observation that schizophrenia
      often runs in families. The development and utilization of stringent, reliable
      diagnostic criteria, together with the advent of modern family, twin, and
      adoption paradigms, demonstrate the importance of genetic factors in
      understanding the familial basis of the disorder. Refinements in diagnostic
      criteria have also enabled advances in understanding the likely mode--or modes-
      of genetic transmission of both schizophrenia and related disorders. After
      reviewing representative studies in these areas, we examine genetic linkage
      studies and our progress toward identifying the genes that cause schizophrenia.
      Although consistent results have been difficult to obtain and much work remains
      to be done, evidence for areas of vulnerability has been converging at particular
      chromosomal sites (e.g., 6p, 8p, and 22q), allowing for cautious optimism.
      Finally, we discuss challenges and prospects for the new millennium, including
      the clinical and ethical implications of genetic investigations.

PMID- 10579100
TI  - Mental health services reform in Japan.
AB  - Economic and social pressures are driving Japan to reform its mental health
      services. Traditionally, psychiatric services in Japan have been custodial.
      Reimbursement has been principally fee-for-service, with incentives that
      encourage hospital-based care. Reform measures are beginning to promote the
      concept of "normalization," in which the mentally ill are seen to be disabled,
      like persons with physical disabilities. New practices including
      deinstitutionalization, differentiation of services, revisions in payment, and
      quality assessment are being introduced. This article provides an overview of the
      current status of Japanese mental health services, summarizes policy dilemmas,
      and identifies priority areas for intervention.

PMID- 10579101
TI  - The organization of community health programs: a prospective view from Cambridge.

PMID- 10579102
TI  - Psychopharmacologist as family doctor: complications in the joint treatment of a
      husband and wife.

PMID- 10579103
TI  - Clinical practice guidelines: the Massachusetts experience in psychiatry.

PMID- 10579104
TI  - Continuum thinking in psychiatry.

PMID- 10579105
TI  - No excuses: televised pornography harms children.
AB  - All youngsters are at some risk from exposure to televised pornography, as
      described above. At particular risk for harm, however, are the most vulnerable
      children in our society--children in single-parent homes, children with mental
      and emotional disturbances, mentally challenged children, children who have been
      physically and/or sexually abused, and children in dysfunctional families.
      Youngsters for whom television serves as a babysitter or parental surrogate
      unfortunately are exposed to few competing influences to television viewing. In
      addition, parents in such homes are least likely to know what their children are
      viewing and to be able to pass on their own values about sex and sexual behavior.
      The main possible effects of televised pornography that must concern us as
      clinicians, educators, and parents are modeling and imitation of language heard
      and behaviors observed in televised pornography; negative interference with
      children's normal sexual development; emotional reactions such as nightmares and
      feelings of anxiety, guilt, confusion, and/or shame; stimulation of premature
      sexual activity; development of unrealistic, misleading, and/or harmful attitudes
      toward sex and adult male-female relationships; and undermining of family values
      with resultant conflict between parents and children. Much more research is
      clearly needed on this topic. Because of the ethical and procedural problems
      surrounding research on children exposed to pornography, ideal research designs
      may never be possible. Nonetheless, we hope that this article will stimulate
      further discussion and work. To devise public policy that protects children from
      potentially harmful material while at the same time respecting the media's First
      Amendment rights, such public discourse and responsible research are essential.

PMID- 10579106
TI  - Some aspects of psychodynamic response to novel atypical antipsychotics.

PMID- 10579107
TI  - Oral flora and pathogenic organisms.
AB  - Oral microbial flora consist of numerous bacterial taxa, ranging from aerobes
      through fastidious anaerobes, and fungi, viruses, and protozoa. Many of these
      bacteria are unique to the oral cavity. The organisms exist in a complex
      interrelationship that is regulated and maintained by physical and metabolic
      microbial interactions, and by environmental factors, such as saliva and diet.
      Many of these organisms are relatively harmless, although others are significant
      pathogens, producing local and systemic diseases in healthy and compromised
      individuals.

PMID- 10579108
TI  - Use of the clinical microbiology laboratory for the diagnosis and management of
      infectious diseases related to the oral cavity.
AB  - Our knowledge regarding the pathogenesis of infections relative to the oral
      cavity is rapidly expanding, similar to our overall understanding of how
      infectious diseases impact our daily lives. The complexity of the flora within
      the oral cavity is quite unique and often makes diagnosis difficult; however, it
      is becoming more apparent that accurate diagnostic testing is important from the
      standpoint of focusing appropriate therapy on pathogens within this crucial body
      site, and avoiding overuse of antimicrobial agents in settings of infection where
      they have no demonstrated benefit. New diagnostic methods are being developed to
      detect pathogens and rapidly delineate resistance patterns. Many will be based on
      new genetic assays, but they must be cost effective, sensitive, and specific.
      Another growing challenge is to provide adequate lab support to outpatient
      offices and clinics, without compromising the specimen culture or turnaround
      times. So many patients are being seen away from hospital laboratories that we
      need ways to diagnose sinusitis, pharyngitis, abscess, and other infections of
      the oral cavity without killing the anaerobes and other significant facultative
      bacteria, and without ruining the direct stains by overgrowth or inflammatory
      cell degradation during specimen transport. These results need to be available
      quickly enough to give useful information for office diagnosis in order to effect
      therapy. To optimize both diagnosis and treatment, a key to the future will be
      better communication between the clinical practitioner and laboratory, with an
      increasing emphasis on training expertise in medical microbiology and infectious
      diseases.

PMID- 10579109
TI  - Bacterial and protozoal infections.
AB  - The oral cavity is a common site for manifestations of systemic microbial
      diseases. Oral lesions may be typical of those seen elsewhere on the body, or the
      lesions may be modified by the local environment. The ease of examination within
      the oral cavity, however, and any site-specific features facilitates diagnosis of
      the systemic condition.

PMID- 10579110
TI  - Viral and fungal infections of the oral cavity in immunocompetent patients.
AB  - Oral lesions are easily visualized and often are signs of systemic diseases.
      Clinical diagnosis of viral and fungal infections can sometimes be confusing
      because many lesions will have similar clinical presentations. This article
      reviews the more common viral- and fungal-associated lesions found in the oral
      cavity in immunocompetent individuals. Differential diagnoses for the oral
      lesions are discussed and treatment options are proposed.

PMID- 10579112
TI  - Principles and practice of antibiotic therapy.
AB  - The oral cavity and surrounding structures harbor an extremely complex array of
      microorganisms. As a result, when structures become acutely or chronically
      infected, diseases can present very differently. Surgical and pharmacologic
      management decisions become equally complex, depending on the source site of the
      infection and the areas to which it spreads. This article first reviews the
      various domains of the oral and maxillofacial structures, and then reviews each
      class of antibiotics, describing how the antibiotics are likely to be used.

PMID- 10579111
TI  - Oral microflora as a cause of endocarditis and other distant site infections.
AB  - Bacteremia originating from the oral cavity is common, but the role of bacteremia
      in the genesis of infective endocarditis and other distant site infections is
      unclear. Only a small percentage of oral flora have been associated with distant
      site infection. Important issues remain unresolved concerning the identification
      of patients at risk, the relative risk from invasive dental procedures versus
      naturally occurring bacteremia, and the impact of prophylactic antibiotics on the
      incidence, nature, magnitude, and duration of bacteremia from the oral cavity.
      This article addresses the controversies in infection management in patients at
      risk for distant site infection.

PMID- 10579113
TI  - Is antibiotic prophylaxis necessary for preventing prosthetic device infection?
AB  - Preventing bacteremia in patients with implanted prostheses is a logical concern,
      but whether the danger of infection is real, and whether people actually benefit
      from antibiotic prophylaxis for dental procedures is not clear. This article
      examines and discusses currently available data concerning the use of antibiotic
      prophylaxis to prevent infection associated with prosthetic devices.

PMID- 10579114
TI  - Oral infections and other manifestations of HIV disease.
AB  - Oral lesions are important in the clinical spectrum of HIV/AIDS, arousing
      suspicion of acute seroconversion illness (aphthous ulceration and candidiasis),
      suggesting HIV infection in the undiagnosed individual (candidiasis, hairy
      leukoplakia, Kaposi's sarcoma, necrotizing ulcerative gingivitis), indicating
      clinical disease progression and predicting development of AIDS (candidiasis,
      hairy leukoplakia), and marking immune suppression in HIV-infected individuals
      (candidiasis, hairy leukoplakia, necrotizing periodontal disease, Kaposi's
      sarcoma, long-standing herpes infection, major aphthous ulcers). In addition,
      oral lesions are included in staging systems for HIV disease progression and as
      entry criteria or endpoints in clinical trials of antiretroviral drugs.
      Recognition and management of these oral conditions is important for the health
      and quality of life of the individual with HIV/AIDS. In keeping with this, the
      U.S. Department of Health Services Clinical Practice Guideline for Evaluation and
      Management of Early HIV Infection includes recommendations that an oral
      examination, emphasizing oral mucosal surfaces, be conducted by the primary care
      provider at each visit, a dental examination by a dentist should be done at least
      two times a year, and patients should be informed of the importance of oral care
      and educated about common HIV-related oral lesions and associated symptoms.

PMID- 10579115
TI  - Oral complications associated with immunosuppression and cancer therapies.
AB  - The oral manifestations of oropharyngeal infection in immunocompromised patients
      present a particular challenge for both medical and dental professionals because
      clinical signs and symptoms may be minimal and accurate diagnosis and appropriate
      treatment may be difficult. Effective control of infection and management of oral
      symptoms are important and may be achieved by the judicious use of topical and
      systemic agents and by maintaining good oral hygiene. Prevention of mucosal
      breakdown, suppression of microbial colonization, control of viral reactivation,
      and effective management of severe xerostomia are all critical steps to reduce
      the overall morbidity and mortality of oromucosal infections in the severely
      immunocompromised patient.

PMID- 10579116
TI  - Combination therapy with oral tacrolimus (FK506) and azathioprine or 6
      mercaptopurine for treatment-refractory Crohn's disease perianal fistulae.
AB  - Our aim was to report the clinical experience with combination treatment using
      tacrolimus and either azathioprine (AZA) or 6-mercaptopurine (6MP) in patients
      with Crohn's disease (CD) perianal fistulae. The medical records of all patients
      with Crohn's disease perianal fistulae seen at the Mayo Clinic from 1996-1998 who
      were treated with tacrolimus were reviewed. Clinical response was classified as:
      complete response, partial response, and nonresponse. Eleven patients were
      treated with oral tacrolimus for a mean duration of 22 weeks. The initial oral
      dose of tacrolimus ranged from 0.15 to 0.31 mg/kg/day. Azathioprine or 6MP was
      continued in combination with tacrolimus in seven patients and initiated
      simultaneously with tacrolimus in four patients. All patients improved
      clinically, seven had a complete response, and four had a partial response. The
      mean time to initial improvement was 2.4 weeks, and the mean time to complete
      response was 12.2 weeks. The most frequent adverse events were nausea,
      paresthesias, nephrotoxicity, and tremor. Patients with nephrotoxicity had a
      significantly higher mean initial tacrolimus dose (0.31 mg/kg/day) compared with
      patients who did not have nephrotoxicity (0.25 mg/kg/day) (p = 0.035); however,
      there was not a statistically significant association between the starting dose
      or mean blood level and clinical response. Combination therapy with oral
      tacrolimus and AZA or 6MP may be effective treatment for CD perianal fistulae.
      Higher initial tacrolimus doses increase the risk of nephrotoxicity without
      improving clinical response.

PMID- 10579117
TI  - The prevalence and clinical significance of alpha 1-antitrypsin deficiency (PiZ)
      and ANCA specificities (proteinase 3, BPI) in patients with ulcerative colitis.
AB  - Our aim was to determine the prevalence of the PiZ allele for alpha 1-antitrypsin
      (AAT) deficiency and some relevant antineutrophil cytoplasmic antibody (ANCA)
      specificities in patients with ulcerative colitis (UC), and explore a possible
      association between these markers. In addition, we studied the relation to
      disease extension and activity. Sera from 141 patients with UC (72 women) were
      analyzed while 50 blood donors and 54 patients with acute myocardial infarction
      served as controls. Serum samples were screened for PiZ with ELISA and phenotyped
      by isoelectric focusing. BPI-ANCA and PR3-ANCA were detected by ELISA. Results
      were that 8.5% (12/141) of the patients with UC were PiZ carriers, higher than
      expected in the general Swedish population (4.7%) (p = 0.03). There was a
      significant difference between PiZ-carriers and non-PiZ-carriers in the extension
      and severity of colitis (odds ratio = 4.1, confidence interval = 1.1, 14.9; p =
      0.028, and odds ratio = 9.0, confidence interval = 1.1, 73.3; p = 0.015;
      respectively). BPI-ANCA and PR3-ANCA were detected in 20.5% (29/141) and 12%
      (17/141) (p < 0.05 compared with controls for all parameters). Occurrence of BPI
      ANCA and PR3-ANCA was not related to extension or severity of colitis (p > 0.05
      for both variables). We observed no association between PiZ-carrier status and
      occurrence of BPI-ANCA or PR3-ANCA. The increased frequency of heterozygosity for
      the PiZ variant of AAT deficiency among patients with UC might imply a role
      played by protease inhibitors for regulation of inflammation and immunologic
      response in UC.

PMID- 10579118
TI  - Deferiprone, an oral iron chelator, ameliorates experimental colitis and gastric
      ulceration in rats.
AB  - Iron is pivotal is producing tissue-damaging reactive oxygen metabolites. Our aim
      is to determine the antiinflammatory activity of deferiprone, an oral iron
      chelator, in experimental colitis and gastritis. Colitis was induced by
      intraceccal administration of 2 ml 5% acetic acid or by intracolonic
      administration of 0.1 ml 3% iodoacetamide, with or without cotreatment with
      deferiprone. Gastritis was induced by intragastric administration of ethanol or
      hydrochloric acid (HCl) and by subcutaneous injection of indomethacin, with and
      without deferiprone. Rats were killed 24 hours after acetic acid and
      iodoacetamide, 30 minutes after ethanol, one hour after HCl, and three hours
      after indomethacin administration. The colon or stomach was isolated, macroscopic
      damage was measured, and mucosal samples were obtained for determination of
      eicosanoid generation, myeloperoxidase (MPO), and nitric oxide synthase (NOS)
      activities. Deferiprone decreased iodoacetamide and acetic acid-induced
      macroscopic colonic damage by 67% and 69%, respectively, and macroscopic gastric
      damage by 91%, 68%, and 46% induced by ethanol, HCl, and indomethacin,
      respectively. The effect of deferiprone was accompanied by significant decrease
      in colonic and gastric, MPO and NOS activities, and colonic prostaglandin E2
      (PGE2) generation, in acetic acid, ethanol, and indomethacin models, whereas in
      the iodoacetamide and HCl models attenuation of the decrease in PGE2 generation
      was seen. Deferiprone is protective in experimental colitis and gastritis,
      probably due to decreased production of iron-dependent oxygen-free radicals. Oral
      iron chelators may constitute a novel approach to ameliorate gastrointestinal
      inflammatory disorders.

PMID- 10579119
TI  - Interleukin-10 gene-deficient mice develop a primary intestinal permeability
      defect in response to enteric microflora.
AB  - The normal intestinal epithelium provides a barrier relatively impermeable to
      luminal constituents. However, patients with inflammatory bowel disease
      experience enhanced intestinal permeability that correlates with the degree of
      injury. IL-10 gene-deficient mice were studied to determine whether increased
      intestinal permeability occurs as a primary defect before the onset of mucosal
      inflammation or is secondary to mucosal injury. At 2 weeks of age, IL-10 gene
      deficient mice show an increase in ileal and colonic permeability in the absence
      of any histological injury. This primary permeability defect is associated with
      increased mucosal secretion of interferon-gamma and tumor necrosis factor-alpha,
      and does not involve an increase in nitric oxide synthase activity. Colonic
      permeability remains elevated as inflammation progresses, while ileal
      permeability normalizes by 6 weeks of age. IL-10 gene-deficient mice raised under
      germ-free conditions have no inflammation, and demonstrate normal permeability
      and cytokine levels. This data suggests that the intestinal permeability defect
      in IL-10 gene-deficient mice occurs due to a dysregulated immune response to
      normal enteric microflora and, furthermore, this permeability defect exists prior
      to the development of mucosal inflammation.

PMID- 10579120
TI  - A genome-wide search identifies potential new susceptibility loci for Crohn's
      disease.
AB  - Chronic inflammatory bowel disease (IBD) presents as two major clinical forms,
      Crohn's disease (CD) and ulcerative colitis (UC). Genetic epidemiological studies
      and animal models suggest that inherited factors play significant roles in the
      susceptibility to both forms of IBD. From four genome-wide scans, putative
      susceptibility loci on chromosome 16 (IBD1 for CD), and on chromosomes 1, 3, 4,
      6, 7, 10, and 12 for IBD, have been identified. Several other groups, including
      ours, have confirmed linkage to the loci on chromosomes 12 and 16. The aim of
      this study is to identify other potential susceptibility loci for CD with a
      genome-wide search approach. In our sample of 222 individuals from 46 families
      (20 Jewish and 26 non-Jewish), with a total of 65 sibpairs diagnosed with CD, we
      observed a novel locus with suggestive linkage [multipoint logarithm of the odds
      score (Mlod) > 2] at chromosome 14q11.2 (Mlod = 2.8, p = 0.0002). In addition,
      suggestive linkage was observed in our Jewish families at chromosome 17q21-q23
      (Mlod = 2.1, p = 0.01) and chromosome 5q33-q35 (Mlod = 2.2, p = 0.0003). The
      syntenic regions of the latter locus are mapped within two putative loci on mouse
      chromosomes 11 and 18, which were identified in a mouse IBD model induced by
      dextran sulfate sodium (29). Our preliminary results provide potential evidence
      for several susceptibility loci contributing to the risk of CD. The observation
      of man-mouse synteny may accelerate the identification of CD susceptibility
      gene(s) on human chromosome 5.

PMID- 10579121
TI  - Treatment of severe esophageal Crohn's disease with infliximab.
AB  - Esophageal ulceration with fistula is an uncommon manifestation of Crohn's
      disease. Typical presentation of symptomatic esophageal Crohn's disease may
      include dysphagia, odynophagia, weight loss, and chest discomfort. We present a
      patient with severe esophageal and skin involvement of Crohn's disease that was
      progressive despite conventional therapy including prednisone and 6
      mercaptopurine. The diagnosis of Crohn's was based on the presence of typical
      clinical, endoscopic, and pathologic findings, including granulomas in the skin
      ulcer and the absence of infectious etiologies. The patient had a nearly complete
      resolution of her esophageal disease with a single infusion of infliximab.

PMID- 10579122
TI  - Measurement of pANCA (antineutrophil cytoplasmic antibodies) and ASCA (anti
      saccharomyces cerevisiae) in screening for IBD in young children.

PMID- 10579123
TI  - Th1/Th2 cells.
AB  - A large body of evidence indicates the existence of functionally polarized CD4+ T
      cell responses based on their profile of cytokine secretion. Type 1 T helper
      (Th1) cells produce interferon-gamma, interleukin (IL)-2, and tumour necrosis
      factor (TNF)-beta, which activate macrophages and are responsible for cell
      mediated immunity and phagocyte-dependent protective responses. By contrast, type
      2 Th (Th2) cells produce IL-4, IL-5, IL-10, and IL-13, which are responsible for
      strong antibody production, eosinophil activation, and inhibition of several
      macrophage functions, thus providing phagocyte-independent protective responses.
      Th1 cells mainly develop following infections by intracellular bacteria and some
      viruses, whereas Th2 cells predominate in response to infestations by
      gastrointestinal nematodes. Polarized Th1 and Th2 cells not only exhibit
      different functional properties, but also show the preferential expression of
      some activation markers and distinct transcription factors. Several mechanisms
      may influence the Th cell differentiation, which include the cytokine profile of
      "natural immunity" evoked by different offending agents, the nature of the
      peptide ligand, as well as the activity of some costimulatory molecules and
      microenvironmentally secreted hormones, in the context of the individual genetic
      background. In addition to playing different roles in protection, polarized Th1
      type and Th2-type responses are also responsible for different types of
      immunopathological reactions. Th1 cells are involved in the pathogenesis of organ
      specific autoimmune disorders, Crohn's disease, Helicobacter pylori-induced
      peptic ulcer, acute kidney allograft rejection, and unexplained recurrent
      abortions. In contrast, allergen-specific Th2 responses are responsible for
      atopic disorders in genetically susceptible individuals. Moreover, Th2 responses
      against still unknown antigens predominate in Omenn's syndrome, idiopathic
      pulmonary fibrosis, and progressive systemic sclerosis. Finally, the prevalence
      of Th2 responses may play some role in a more rapid evolution of human
      immunodeficiency virus infection to the full-blown disease. The Th1/Th2 paradigm
      also provides the rationale for the development of new types of vaccines against
      infectious agents and of novel strategies for the therapy of allergic and
      autoimmune disorders.

PMID- 10579124
TI  - Postoperative recurrence of Crohn's disease: pathophysiology and prevention.
AB  - Postoperative recurrence of Crohn's disease is often inevitable. Certain risk
      factors such as smoking, young age, and a perforating disease behavior have been
      identified. Patients running an enhanced risk should be treated with mesalamine
      or, with higher success rates, with azathioprine. An endoscopic evaluation of the
      neoterminal ileum 6 to 12 months after surgery provides relevant information
      predicting the further clinical course and can be used as a guide to adjust
      medical therapy.

PMID- 10579125
TI  - Adenomas in ulcerative colitis: endoscopic polypectomy or colectomy?

PMID- 10579126
TI  - The significance of "adenomas" in ulcerative colitis: deciding when a colectomy
      should be performed.

PMID- 10579127
TI  - Gut permeability in Crohn's disease: the chicken/egg question revisited

PMID- 10579128
TI  - Rectal budesonide for ulcerative colitis: bottoms up!

PMID- 10579129
TI  - Revalidation of A&E specialists.

PMID- 10579130
TI  - Continuing professional development.

PMID- 10579131
TI  - The millennium....

PMID- 10579132
TI  - [Is Palmaz-Schatz stenting effective for second restenosis?].
AB  - The long-term outcome after coronary stent placement in restenotic lesions after
      balloon angioplasty (percutaneous transluminal coronary angioplasty: PTCA)may be
      less favorable compared to stent treatment of de novo lesions, but the role of
      stents in restenotic lesions after 2 prior PTCA procedures is unknown. Elective
      Palmaz-Schatz stent placement was performed in 124 consecutive patients. Stents
      were placed in 70 patients(56%) in the native coronary arteries for de novo
      lesions(de novo group), in 33 patients (27%)for restenotic lesions after one
      prior PTCA(restenosis group), and 21 patients(17%)for restenotic lesions after 2
      prior PTCA(second restenosis group). The 3 groups were well matched with respect
      to lesion type, lesion length, and reference diameter. Stent size was similar in
      the 3 groups. Follow-up angiograms taken about 6 months after stenting were
      available for all patients. The restenosis rate after stenting was similar for
      the de novo group and restenosis group(19% vs 27%, NS). The second restenosis
      group tended to have a higher restenosis rate after stenting than the de novo
      group(38% vs 19%, p = 0.06). The frequency of diffuse type in-stent restenosis of
      the second restenosis group tended to be higher than that of the de novo
      group(63% vs 13%, p = 0.08). Our results suggest that the restenosis rate after
      stenting was higher in patients with repeated restenosis. Therefore, other
      therapeutic methods should be considered.

PMID- 10579133
TI  - [Assessing the physiologic significance of intermediate coronary lesions:
      comparison of coronary flow measurements with exercise electrocardiography].
AB  - Angiography may provide limited assessment of intermediate coronary stenoses.
      Doppler coronary flow reserve has been applied to determine the physiologic
      significance of such lesions. This study compared coronary flow reserve derived
      from intracoronary Doppler flow wire with the results of the exercise tolerance
      test to evaluate the validity of intracoronary flow measurements in the
      assessment of intermediate stenoses. Sixty eight patients with 91 vessels
      harboring angiographically mild-to-severe coronary stenoses in the left anterior
      descending or right coronary artery were studied. All patients had single-vessel
      disease, and angiography showed the target vessel. Distal coronary flow reserve
      was measured with the Doppler guide wire during cardiac catheterization. Exercise
      tolerance tests by bicycle ergometer were performed the day before
      catheterization. Quantitative coronary angiography showed a mean percentage
      diameter stenosis of 44 +/- 21%(range 0-90%). Forty seven of 91 vessels combined
      intermediate lesions(40% to 70%). Percentage diameter stenosis and coronary flow
      reserve were linearly correlated in both overall and intermediate lesions(r = 
      0.52 vs -0.42; both p < 0.0001). Percentage diameter stenosis of overall lesions
      was significantly higher in the positive exercise test group than the negative
      group(59.8 +/- 17.2% vs 37.7 +/- 18.1%, p < 0.0001), but not significantly
      different in intermediate lesions(49.1 +/- 7.8% vs 54.7 +/- 6.6%, p = 0.03). The
      positive exercise test group showed significantly lower coronary flow reserve
      compared to the negative group in both overall and intermediate lesions(overall:
      1.6 +/- 0.5 vs 2.6 +/- 0.9, p < 0.0001; intermediate: 1.6 +/- 0.5 vs 2.5 +/- 0.7,
      p < 0.0001). Coronary flow reserve < 2.0 and positive exercise test agreed in 38
      of 46 intermediate lesions(83%), and percentage diameter stenosis > or = 50% and
      positive exercise test agreed in 34 of these 46 lesions(74%). Coronary flow
      reserve, more than percentage diameter stenosis, correlated with the results of
      the exercise tolerance test, and is considered to be useful to evaluate the
      functional severity of intermediate stenosis.

PMID- 10579134
TI  - [Association between chlamydial infection and coronary artery disease].
AB  - Recent epidemiological studies have demonstrated the association between
      Chlamydia pneumoniae infection and coronary atherosclerosis. However, the
      relationship is less clear in the Japanese population. Serum IgA and IgG
      antibodies to Chlamydia-specific lipopolysaccharide were measured by enzyme
      linked immunosorbent assay in 152 consecutive patients(112 males, 40 females,
      mean age 57 years)who underwent coronary angiography. Patients(n = 123)with
      coronary artery disease(CAD)were defined as having more than 50% diameter
      stenosis in at least one major coronary artery. The control group(n = 29) had
      normal coronary angiograms. In the CAD group, there was a high tendency of
      prevalence of IgA(20% vs 7%, p = 0.08)and IgG(54% vs 34%, p = 0.052). Prevalence
      of either IgA or IgG was significantly higher (59% vs 38%, p = 0.045) compared
      with the control group. Although the index of IgA antibody was not significantly
      different between the CAD and control groups(median 0.52 vs 0.36, p = 0.19), the
      index of IgG antibody was significantly higher in the CAD group than in the
      control group(median 1.29 vs 0.82, p = 0.026). The odds ratios for CAD were
      3.4[95% confidence interval(CI)0.6-18.7]for the prevalence of IgA, 2.3(95% CI 0.9
      5.2)for the prevalence of IgG, and 2.3(95% CI 1.0-5.2)for the prevalence of
      either IgA or IgG. Patients with CAD tended to have high prevalence of antibodies
      to Chlamydia spp, and these findings suggest an association between chlamydial
      infection and coronary atherosclerosis in the Japanese population.

PMID- 10579135
TI  - [Effect of exercise therapy on oxygen consumption in patients with chronic heart
      failure].
AB  - The effect of exercise training on delta Vo2/delta WR was studied in 12
      patients(11 men, one woman, mean age 62 +/- 9 yr)with chronic heart failure(old
      myocardial infarction, dilated cardiomyopathy, patients after coronary arterial
      bypass graft surgery and patients after aortic valve replacement).
      Cardiopulmonary exercise testing was performed to decide the exercise tolerance
      and assess the delta Vo2/delta WR. Patients underwent physical training at the
      anaerobic threshold for 3 months. Cardiopulmonary exercise testing was performed
      after the second week and after the third month. The anaerobic threshold
      increased at the third month compared with before exercise testing and the second
      week(p < 0.05, respectively) (before exercise testing: 13.6 +/- 2.0 ml/min/kg,
      the second week: 14.7 +/- 2.5 ml/min/kg, the third month: 16.2 +/- 2.1
      ml/min/kg). The delta Vo2/delta WR increased at the second week compared with
      before exercise testing(before exercise testing: 8.9 +/- 1.9 ml/min/W, the second
      week: 10.6 +/- 1.9 ml/min/W, p < 0.05), but significantly decreased at the third
      month compared with the second week(the third month: 9.4 +/- 1.7 ml/min/W, p <
      0.05). Serial increase of the anaerobic threshold and the peak Vo2/heart rate
      suggests that the exercise tolerance and cardiac function of the patients
      improved significantly. The increase of the delta Vo2/delta WR after the first 2
      weeks seemed to depend on the luxury blood supply to both working and non-working
      muscles. The decrease of delta Vo2/delta WR at the third month may be due to the
      redistribution of the blood flow to the working muscles.

PMID- 10579137
TI  - Left coronary artery-left ventricular fistula with acute myocardial infarction,
      representing the coronary steal phenomenon: a case report.
AB  - A 59-year-old man presented with a left anterior descending coronary artery to
      left ventricular fistula manifesting as myocardial infarction, representing the
      coronary steal phenomenon. Electrocardiography showed poor R progression in leads
      V1 through V3. The biochemical markers of myocardial injury were elevated.
      Creatine kinase level was 509 IU/l, creatine kinase MB isoenzyme (CK-MB)47 IU/l,
      cardiac troponin T 0.62 ng/ml, myosin light chain 6.1 ng/ml, and myoglobin 142
      ng/ml. Thallium-201 myocardial perfusion imaging with dobutamine stress showed a
      dobutamine-induced perfusion deficit of the anteroseptal wall of the left
      ventricle with 0.1 mV ST-segment depression in II, III, aVF, V5, and V6. The mean
      left anterior descending blood flow measured with the Doppler guidewire was
      increased from 211 to 378 ml/min. Selective coronary arteriography showed
      dominant left coronary artery with the contrast medium streaming into the left
      ventricle via a maze of fine vessels from the distal left anterior descending
      coronary artery. No critical stenosis of the left anterior descending coronary
      artery was observed. Administration of acetylcholine 100 micrograms into the left
      coronary artery did not induce vasoconstriction of that artery. The fistula
      terminating in the left ventricle was ligated surgically and the patient became
      free of chest pain. Thallium-201 myocardial perfusion imaging with dobutamine
      stress revealed no perfusion deficit of the anteroseptal wall of the left
      ventricle. The presence of coronary steal phenomenon was detected by dobutamine
      stress myocardial imaging.

PMID- 10579136
TI  - Hypertrophic cardiomyopathy with mid-ventricular obstruction and splenic
      infarction associated with paroxysmal atrial fibrillation: a case report.
AB  - A 54-year-old woman had been treated for hypertrophic cardiomyopathy and
      paroxysmal atrial fibrillation since 1992. She was admitted with paroxysmal
      atrial fibrillation which was resolved by medical treatment. However, on the next
      day, left lateral chest pain appeared. Computed tomography disclosed a low
      density area in the spleen. She received anticoagulant therapy under a diagnosis
      of splenic infarction, and the pain disappeared. Echocardiography showed
      hypertrophic cardiomyopathy with mid-ventricular obstruction. She was treated
      with cibenzoline to prevent paroxysmal atrial fibrillation attack and attenuate
      the hemodynamic load. After treatment, the pressure gradient decreased from 41 to
      7 mmHg. This patient with hypertrophic cardiomyopathy suffered a rare isolated
      splenic infarction associated with paroxysmal atrial fibrillation.

PMID- 10579138
TI  - [A 65-year-old woman presenting with a left hilar mass].

PMID- 10579139
TI  - [A 59-year-old man with giant negative T waves].

PMID- 10579140
TI  - Are the elderly underrepresented in clinical drug trials?
AB  - In many industrialized nations, the elderly comprise the fastest growing
      subpopulation and constitute an increasing proportion of the total population
      compared to other age groups. The elderly use a disproportionately larger amount
      of health care resources since they experience a higher incidence of disease
      related morbidities, consume more drugs, are subject to more extensive multiple
      medication regimens, and account for more adverse drug events. In response to the
      great demand for geriatric pharmacotherapy, the pharmaceutical industry has
      targeted more drugs to the elderly. However, the elderly are too often excluded
      from clinical trials on drugs primarily destined for their consumption.
      Comprehensive analyses to assess participation of elderly subjects in clinical
      drug trials are needed to design and implement trials that will enhance the
      safety and efficacy of drugs intended for this pharmacologically sensitive
      subpopulation.

PMID- 10579142
TI  - Use of a mail-out continuing education article to teach health professionals
      about drug-induced disease.
AB  - A U.S. Food and Drug Administration (FDA)/Georgetown University Medical Center
      conference was the basis for "Clinical Therapeutics and the Recognition of Drug
      Induced Disease," the first MEDWATCH continuing education (CE) mail-out article.
      Developed as a major component of FDA MEDWATCH post-marketing surveillance
      outreach, the article used a clinical therapeutic approach to discuss topics
      including adverse drug events (ADEs) pharmacology and ADE reporting. Distributed
      nationwide through the MEDWATCH Partners, health professionals applied for CE
      credit by completing a self-assessment examination. With the overall response
      rate slightly more than 2%, 15,260 health professionals (55% physicians and 37%
      pharmacists) received CE credit. Evaluation of the initial approximately two
      thirds (N = 10,021) of successfully completed exams found 99% agreement that
      stated learning objectives were met, and the article relevant to their clinical
      practice; spontaneous comments/letters were also very positive. The highest
      percentage responding specialists were internists (28%) and psychiatrists (17%),
      with notable differences found among specialties for response rate versus
      relative article distribution (such as relatively low response rates among
      surgeons and radiology/radiation physics specialists). The number of health
      professionals receiving CE credit, coupled with examination performance and
      overall response, indicates that "Clinical Therapeutics and the Recognition of
      Drug-Induced Disease" was well received and fulfilled learning objectives. The
      results provide encouragement for this continuing educational approach.

PMID- 10579141
TI  - Pharmacokinetic and pharmacodynamic consequences of metabolism-based drug
      interactions with alprazolam, midazolam, and triazolam.
AB  - This review was conducted to identify the current data on drug interactions with
      alprazolam, midazolam, and triazolam to guide practitioners in the use of these
      drugs. The Medline electronic database from 1966 through 1998 was used to
      identify clinical studies of the pharmacokinetic effect of drugs on these three
      benzodiazepines. Of a total of 491 literature reports identified, 59 prospective
      studies met our selection criteria. The pharmacokinetic parameters of AUC, Cmax,
      t1/2, and tmax were evaluated for changes following an interaction. To allow
      comparison between studies, changes in the parameters were normalized relative to
      the control values. Pharmacodynamic effects and measures, when reported in the
      original studies as statistically significant, were classified as a strong
      interaction, and when the interaction was present but not statistically
      significant, they were classified as mild in this review. As a result, clinically
      significant drug interactions were noted for all three benzodiazepines, although
      it is clear that statistically significant pharmacokinetic changes do not always
      translate into clinically significant pharmacodynamic consequences. All three
      benzodiazepines were susceptible to drug interactions, but oral dosing of
      midazolam and triazolam resulted in greater alterations in the pharmacokinetic
      parameters than alprazolam due to their larger presystemic extraction.
      Ketoconazole and itraconazole were found to be the most potent metabolic
      inhibitors that prolonged the duration of or intensified the magnitude of the
      dynamic response produced by the three benzodiazepines. Rifampin, carbamazepine,
      and phenytoin were noted to be potent metabolic inducers, and their treatments
      result in loss of benzodiazepine therapeutic efficacy. In conclusion, potent
      metabolic inhibitors and inducers can either significantly prolong or diminish
      the dynamic effects of benzodiazepines via their influence on the
      pharmacokinetics of benzodiazepines.

PMID- 10579143
TI  - Pharmacokinetics of S- and R-enantiomers of aminoglutethimide following oral
      administration of racemic drug in breast cancer patients.
AB  - This study was undertaken to examine the pharmacokinetics of both enantiomers of
      AG--that is, (R-AG) and (S-AG) and respective acetyl metabolites, R-AcAG and S
      AcAG--in breast cancer patients. Six patients received a single dose (500 mg) of
      the racemic drug, and serial plasma samples and urine were collected over a 48
      hour period. R-AG, S-AG, R-AcAG, and S-AcAg were measured simultaneously by high
      performance liquid chromatography using two serial chiral separation columns with
      ultraviolet detection. The plasma concentrations of R-AG were about 1.5 times
      higher than those of S-AG, and the data for both enantiomers exhibited the
      characteristics of the one-compartment open model. There were no significant
      differences between R- and S-AG in ka, tmax, V/F, and t1/2. The formation of R-
      and S-AcAG was rapid, and no correlation was found between the t1/2 values of the
      AG enantiomers with that of their acetylated metabolites. Overall, 41% of the
      dose was excreted in urine as AG (15% R-AG and 26% S-AG) and 5.1% as AcAG (2.9% R
      AcAG and 2.2% S-AcAG). Renal clearance of S-AG was significantly greater (i.e.,
      2.3-fold) than that of R-AG and appears to be most likely the cause for the other
      pharmacokinetic differences observed. Both enantiomers had low renal extraction
      ratios, suggesting extensive tubular reabsorption of the compounds. However,
      based on the data obtained, it was concluded that the main factor contributing to
      the therapeutic effectiveness of racemic AG is the large potency difference
      between the R- and S- forms (R > S). The pharmacokinetic differences between R-AG
      and S-AG appear to contribute only marginally to the activity of this drug as an
      aromatase inhibitor.

PMID- 10579144
TI  - Pharmacokinetics of clinafloxacin enantiomers in humans.
AB  - The pharmacokinetics of R-clinafloxacin and S-clinafloxacin enantiomers of the
      broad-spectrum fluoroquinolone antibiotic, clinafloxacin, were characterized in
      selected volunteer subjects and patients after the administration of oral and
      intravenous doses of racemic drug. The absorption of each enantiomer was rapid
      and nearly complete after a single, oral 400 mg racemic dose. The mean (+/- SD)
      bioavailability of R-clinafloxacin was 87.5% +/- 4.8% compared to 86.2% +/- 5.8%
      for S-clinafloxacin. The mean Cmax of each enantiomer was 1.19 micrograms/mL,
      with plasma concentrations of each enantiomer remaining above 0.1 microgram/mL
      for at least 12 hours. No notable differences in the disposition of R
      clinafloxacin and S-clinafloxacin were observed. After a single 400 mg
      intravenous dose of racemic drug, mean (+/- SD) t1/2 was 5.6 +/- 0.3 hours and
      5.7 +/- 0.4 hours, plasma Cl was 329 +/- 49 mL/min and 314 +/- 45 mL/min, and
      Vdss was 138 +/- 18 L and 134 +/- 16 L for R- and S-clinafloxacin, respectively.
      Two healthy volunteers each received a single 400 mg oral dose of racemic
      clinafloxacin (alone) and with oral administration of 1 gm probenecid separated
      by a 1-week washout period between treatments. With probenecid coadministration,
      the increase in AUC0-infinity was 75% and 83% for R-clinafloxacin and was 71% and
      75% for S-clinafloxacin in each subject, respectively. Probenecid increased the
      total exposure (AUC) of both R-clinafloxacin and S-clinafloxacin, although it had
      no stereo-selective effects on the disposition of either enantiomer. The
      antimicrobial potency of the isomers was also evaluated. In vitro susceptibility
      testing showed that the two compounds were comparable in their inhibitory
      activities, as all MICs were within twofold for each organism tested. These
      results demonstrate that in addition to their similar antimicrobial potency, R-
      and S-clinafloxacin have nearly identical disposition characteristics and are
      eliminated by similar mechanisms that display no apparent enantioselectivity in
      man.

PMID- 10579145
TI  - Pharmacokinetics of calcium absorption from two commercial calcium supplements.
AB  - This study was conducted to compare pharmacokinetic indices of calcium absorption
      after a single oral (500 mg calcium) load of Citracal (calcium citrate) and Os
      Cal (calcium carbonate). In 18 postmenopausal normal women, venous blood samples
      were obtained for the measurement of calcium before and hourly for 6 hours after
      an oral ingestion of Citracal, Os-Cal, or placebo with a breakfast meal. The
      change in area under the curve (delta AUC) in serum calcium from preload was 2.5
      fold greater for Citracal than Os-Cal, and the peak-basal variation in serum
      calcium was 76% higher for Citracal than Os-Cal. The increment in serum calcium
      from preload after Citracal administration was significantly higher than that
      obtained after placebo load during most time periods and significantly higher
      than that of Os-Cal at 1, 4, and 5 hours after load. In contrast, delta AUC and
      peak basal variation of Os-Cal did not differ significantly from placebo and
      increment in serum calcium was significantly increased from placebo only at 6
      hours. In conclusion, Citracal is much more bioavailable than Os-Cal.

PMID- 10579146
TI  - The effect of a high-fat meal on the oral bioavailability of the
      immunosuppressant sirolimus (rapamycin).
AB  - The bioavailability of an oral nonaqueous solution of sirolimus was compared
      under fasting conditions and after a high-fat meal in a randomized, two-way
      crossover pharmacokinetic study. Healthy volunteers were administered a 15 mg
      single dose of sirolimus on two occasions, once while fasting and once after
      consumption of a high-fat breakfast. Whole blood concentrations of sirolimus were
      assayed by using a validated method with high-performance liquid
      chromatography/tandem mass spectrometric detection. Sirolimus was absorbed more
      slowly when administered after a high-fat meal than when administered after
      fasting, as shown by statistically significant reductions in peak concentration
      (Cmax) and the ratio of Cmax to the area under the curve (AUC), and lengthening
      of the time to peak concentration. The oral availability of sirolimus was
      increased to a modest extent (35%) and in a uniform manner when administered with
      a high-fat meal; the geometric mean ratio of the fed/fasting AUC values was 1.35,
      with a 90% confidence interval of 1.26 to 1.46. Food had no effect on the
      terminal half-life of sirolimus (mean values of 67 to 68 hours). The 35% increase
      in AUC obtained after a high-fat meal appears small relative to the intersubject
      and intrasubject variabilities observed in clinical trials. However, to minimize
      unnecessary fluctuations in trough whole blood sirolimus concentrations, it is
      advisable that sirolimus be administered consistently in individual patients,
      either with or without meals.

PMID- 10579147
TI  - Single-dose oral pharmacokinetics of three formulations of thalidomide in healthy
      male volunteers.
AB  - Thalidomide was recently approved in the United States for the treatment of
      erythema nodosum leprosum, a complication of leprosy. The present study
      determined the bioequivalence and pharmacokinetics of Celgene's commercial and
      clinical trial thalidomide formulations and the Brazilian Tortuga formulation in
      an open-label, single-dose, three-way crossover design. Seventeen healthy
      subjects were given 200 mg of thalidomide on three occasions, and blood samples
      were collected over 48 hours. Pharmacokinetic parameters were determined using
      compartmental methods for the two Celgene formulations and using noncompartmental
      methods for all three formulations. All subjects reported adverse events, none of
      which was serious or unexpected. Celgene formulations were bioequivalent when
      comparing Cmax, tmax, and AUC. There was significant variability in plasma levels
      from the Tortuga formulation, giving a mean profile that was distinctly different
      from the two Celgene formulations with a lower Cmax value and a longer terminal
      phase. The lower Cmax was probably due to slower absorption. The terminal rate
      constant for the Tortuga formulation was significantly less, giving rise to a
      terminal half-life of 15 hours compared to about 5 to 6 hours for the Celgene
      formulations. Confidence intervals for Cmax between the Tortuga and the Celgene
      formulations were outside the 80% to 125% range, indicating a lack of
      bioequivalence. Extent of absorption, as measured by AUC0-infinity, was
      approximately equal for all three formulations. Terminal half-life for Tortuga
      was two to three times longer compared to the Celgene formulations and is clear
      evidence for absorption rate limitations. The two Celgene formulations showed
      similar pharmacokinetic parameters with profiles that were best described by a
      one-compartment model with first-order absorption and elimination. The authors
      conclude that Celgene's clinical trial and commercial thalidomide formulations
      are similar to each other and distinctly different from the Tortuga formulation
      and that all three formulations exhibited absorption rate-limited elimination.

PMID- 10579148
TI  - Pharmacokinetics of a recombinant modified amino terminal fragment of
      bactericidal/permeability-increasing protein (rBPI21) in healthy volunteers.
AB  - Phase I pharmacokinetic and safety studies were conducted in healthy volunteers
      with rBPI21, a recombinant protein derived from the amino terminal domain of
      human bactericidal/permeability-increasing protein. rBPI21 was administered as a
      30-minute infusion at doses of 0.25 to 4 mg/kg or as a 24- to 48-hour infusion at
      doses of 2 to 8 mg/kg. For the 30-minute infusions, the clearance of rBPI21
      decreased with increasing dose from 8.4 mL/min/kg at 0.25 mg/kg to 3.3 mL/min/kg
      at 4 mg/kg. For rBPI21 infused over 24 to 48 hours the clearance was 10 to 11
      mL/min/kg. The concentration-time profile of rBPI21 was well described by a three
      compartmental model with parallel first-order and Michaelis-Menten (saturable)
      elimination. This model for the clearance of rBPI21 has been useful in estimating
      starting doses for therapeutic clinical trials.

PMID- 10579149
TI  - Effect of disulfiram-mediated CYP2E1 inhibition on the disposition of
      vesnarinone.
AB  - Vesnarinone is an orally administered inotropic agent that is metabolized in
      vitro by the cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1. The purpose of
      this study was to assess the contribution of CYP2E1 activity to the disposition
      of vesnarinone in humans by characterizing the pharmacokinetics before and after
      disulfiram-mediated CYP2E1 inhibition. The pharmacokinetics of vesnarinone 60 mg
      were determined in normal healthy volunteers (N = 7) before and after daily
      disulfiram administration (250 mg). Chlorzoxazone 250 mg was also administered
      before, during, and after disulfiram administration to serve as a positive
      control for CYP2E1 inhibition. Disulfiram treatment decreased 6
      hydroxychlorzoxazone formation clearance by nearly 95% but effected only a modest
      decrease in vesnarinone apparent oral clearance (5.7 +/- 1.0 vs. 5.0 +/- 0.5
      ml/min; p = 0.022). In contrast to the modest effect on the parent drug,
      disulfiram treatment substantially increased plasma concentrations of the primary
      metabolite OPC-18692. The Cmax of OPC-18692 was increased approximately 7-fold,
      and the area under the plasma concentration-time curve was increased 18-fold (2.9
      +/- 0.9 vs. 53.7 +/- 33.2 micrograms.h/ml; p = 0.006). The results indicate that
      CYP2E1 inhibition has only a modest, clinically insignificant effect on
      vesnarinone disposition but markedly increases plasma concentrations of the OPC
      18692 metabolite. The pharmacological properties of this metabolite have not been
      fully defined; thus, the clinical importance of this observation depends on
      whether this metabolite contributes to any of the toxicity associated with
      vesnarinone administration.

PMID- 10579150
TI  - Lack of effect of cimetidine on the pharmacokinetics of sustained-release
      bupropion.
AB  - The objective of this study was to assess whether cimetidine affects the
      pharmacokinetics of sustained-release (SR) bupropion hydrochloride and the active
      metabolite, hydroxybupropion. This randomized, open-label, two-period crossover
      study was conducted in 24 healthy volunteers 18 to 45 years of age. ANOVA showed
      that administration of two 150 mg bupropion SR tablets with one 800 mg cimetidine
      tablet following an overnight fast did not change values for AUC infinity, Cmax,
      tmax, t1/2, and CL/F (CL/F calculated for bupropion only) for either bupropion or
      hydroxybupropion as compared with two 150 mg bupropion SR tablets alone. In this
      study, it appears that there is no effect of cimetidine on the pharmacokinetics
      of bupropion SR.

PMID- 10579151
TI  - Rosiglitazone has no clinically significant effect on nifedipine
      pharmacokinetics.
AB  - To examine the effects of repeat oral dosing of rosiglitazone on the
      pharmacokinetics of nifedipine, a prototype CYP3A4 substrate, a randomized, open
      label, crossover study was performed with two treatment phases separated by a
      washout period of at least 14 days. Twenty-eight healthy male volunteers received
      either a single 20 mg oral nifedipine dose or rosiglitazone 8 mg orally once
      daily for 14 days with a single 20 mg oral nifedipine dose administered on day
      14. Plasma nifedipine concentrations were determined over the 24-hour period
      following administration of the nifedipine doses. Lack of effect was defined as
      the demonstration that the 90% CI was contained entirely within a symmetrical 30%
      range either side of unity on the loge-scale. Following rosiglitazone +
      nifedipine administration, the area under the nifedipine concentration-time curve
      from time zero to infinity (AUC(0-infinity)) was 13% lower than that after
      administration of nifedipine alone. This difference in nifedipine AUC(0-infinity)
      was not deemed to be clinically significant since the 90% CI was contained within
      the protocol-defined 30% range (point estimate for ratio of geometric means 0.87;
      90% CI: 0.79, 0.96). Rosiglitazone had no marked effect on nifedipine peak plasma
      concentration (point estimate: 0.99; 90% CI: 0.73, 1.34) or time to peak
      concentration compared with nifedipine alone. Rosiglitazone coadministration
      produced a small decrease in the mean nifedipine half-life (point estimate: 
      0.77; 90% CI: mean difference -1.29 h, -0.25 h). Both treatment regimens were
      well tolerated and associated with a favorable safety profile. Rosiglitazone, at
      the highest dose used in clinical studies, produced a small, clinically
      insignificant decrease in nifedipine exposure. The very small effect on
      nifedipine pharmacokinetics suggests that rosiglitazone is an extremely weak
      inducer of CYP3A4, a characteristic that distinguishes rosiglitazone from
      troglitazone.

PMID- 10579152
TI  - Role of definitive radiation therapy for larynx preservation in patients with
      advanced laryngeal cancer.
AB  - OBJECTIVE: Recently, neoadjuvant chemotherapy (CT) and radiation therapy (RT)
      have been advocated as a standard treatment for laryngeal preservation in
      patients with locally advanced laryngeal cancer. However, it is still being
      debated whether adding neoadjuvant CT to conventional RT makes an effective
      contribution to laryngeal preservation. The current study was designed to resolve
      this controversy. DESIGN: Retrospective clinical study. SETTING: The Severance
      Hospital, Yonsei Cancer Center, Yonsei University, Seoul, Korea. METHOD: Eighty
      patients (stages III, IV) with squamous cell carcinoma of the larynx were divided
      into two groups according to treatment modalities, which consisted of RT alone (N
      = 40, Group 1) and neoadjuvant CT plus RT (N = 40, Group 2). Comparative analysis
      was undertaken to investigate the differences in the organ preservation rate and
      treatment results between the two groups. RESULTS: There was no significant
      difference in the response rate and patterns of treatment failure between the two
      groups. The 5-year survival rate was similar between Group 1 (24%) and Group 2
      (31%) (p = .1556). In addition, the larynx was almost equally preserved in Group
      1 (62%) versus Group 2 (63%). CONCLUSIONS: Radiation therapy without neoadjuvant
      CT seems to be a valid alternative treatment for the purpose of laryngeal
      preservation in locally advanced laryngeal cancer.

PMID- 10579153
TI  - Endoscopic orbital decompression with preservation of an inferomedial bony strut:
      minimization of postoperative diplopia.
AB  - With the increasing sophistication and safety of endoscopic orbital
      decompression, the technique is seen by many as an attractive and less morbid
      alternative to traditional open techniques. This rationale also makes the
      procedure more acceptable for individuals considering decompression for cosmetic
      reasons. As a result, complications such as postoperative diplopia assume greater
      significance. Preservation of an inferomedial bony strut has been postulated to
      reduce the incidence of postoperative diplopia in transconjunctival, but not
      endoscopic, orbital decompression for dysthyroid ophthalmopathy. We present a
      consecutive series of 11 subjects (21 eyes) who underwent transnasal endoscopic
      medial and inferior decompression of the orbits bilaterally. All patient charts
      were reviewed in a retrospective fashion and ophthalmologic, surgical, and
      cosmetic data were recorded, with callback of patients with incomplete data sets.
      All cases were performed under general anaesthesia. Preservation of the strut was
      possible in 15 of 21 eyes. Visual acuity was preserved or improved in all 21
      eyes. Average ocular recession based on Hertel measurements was 3.6 mm and there
      were no surgical complications. New-onset or worsening diplopia was noted
      postoperatively in 2 of 11 subjects. However, in patients where both struts were
      preserved, there was zero incidence of postoperative diplopia (0/6). These
      results indicate that preservation of an inferomedial bony strut is not only
      technically feasible but also does not compromise the adequacy of decompression.
      The results also suggest that preservation of the inferomedial bony strut during
      endoscopic orbital decompression can reduce the incidence of postoperative
      diplopia.

PMID- 10579154
TI  - Augmentation of the nasal spine area with tissue bone matrix sponge.
AB  - OBJECTIVE: High-density tissue bone matrix (TBM) sponge is a homograft derived
      from human cadaver. It is reported to be osteoinductive. The objective of this
      paper is to measure the bone formation and cosmetic effect of TBM sponge
      implanted in the nasal spine area of patients undergoing rhinoplasty with
      retraction of this region and loss of nasal tip support. DESIGN: The study was
      designed as a prospective trial. SETTING: Patients were selected from private
      facial cosmetic practice and from public otolaryngology practice. PATIENTS: Six
      patients were selected who had retraction of the nasal spine area and loss of tip
      support. INTERVENTION: Patients had implantation of the TBM sponge in the nasal
      spine area either as a sole procedure or in conjunction with other rhinoplasty
      maneuvers. MAIN OUTCOME MEASURES: Palpation was used to assess position, size and
      consistency of the implant. Cosmetic effect was assessed by computer imaging,
      which was used to measure nasolabial angle and tip projection. Bone formation was
      assessed by computed tomography scanning. RESULTS: The implant could be palpated
      in all six patients at 1 month postoperatively, but at 3 months was either
      smaller or could not be felt. Nasolabial angle and tip projection were improved
      in all patients initially, but 3 months following surgery this cosmetic
      improvement was maintained in only two patients. At 3 months, CT scanning showed
      no evidence of bone formation. CONCLUSION: The TBM sponge was not found to be
      osteoinductive or permanent when implanted in the nasal spine area and therefore
      is not a good implant in that region.

PMID- 10579155
TI  - New method for packing the external auditory canal, middle ear space, and mastoid
      cavities after otologic surgery.
AB  - Since its introduction in 1945, an absorbable gelatin sponge, Gelfoam, has long
      been a staple used for packing in otologic surgery. The present method commonly
      employed at the University of Manitoba teaching hospitals requires that operating
      room nurses carefully prepare extremely small pieces of both compressed and
      noncompressed Gelfoam. These pieces are then selectively soaked in an antibiotic
      solution and carefully placed, one by one, into the appropriate position. We
      describe a new paste preparation of Gelfoam powder, Thrombostat, acetic acid, and
      Bacitracin ointment, which can very quickly be injected from a syringe into the
      operated cavity. Our preliminary study indicates that this preparation reduces
      operating time, while making the process of packing easier for the surgeon. In
      addition, it ensures a more evenly packed cavity while still fulfilling the
      requirements of middle ear packing. Postoperatively, it was found to be easier to
      debride from the operative cavity in the office, decreasing patient discomfort
      and procedure time. Reported below is a preliminary clinical patient series
      report comparing this new method to the old method.

PMID- 10579156
TI  - Langerhans' cell histiocytosis: paediatric head and neck study.
AB  - OBJECTIVE: This study presents the experience of the Montreal Children's Hospital
      (MCH) with Langerhans' cell histiocytosis (LCH) and reviews the new advances in
      diagnosis and therapy of this disorder. DESIGN: Retrospective study of 20
      patients seen between July 1986 and July 1997 diagnosed with LCH. METHODS: All of
      the 20 charts were examined for variables including age, sex, area involved,
      treatment modalities, and complications. RESULT: Sixty-five percent of patients
      presented with localized lesions and 35% with multisystem involvement. The most
      common involved area was the skull, and 57% of skull lesions involved frontal
      bone. The temporal bone was involved in 25% of cases. The most common ear symptom
      was otorrhea. CONCLUSION: Langerhans' cell histiocytosis is a rare paediatric
      disorder. Head and neck involvement occurs frequently in both localized and
      multisystem disease. The prognosis is highly dependent on the age and number of
      systems involved.

PMID- 10579157
TI  - Assessment of the caloric-induced tilt in the perceived visual vertical:
      preliminary report.
AB  - OBJECTIVE: The perceived visual vertical (PVV) has been shown to be abnormal in
      patients with acute vestibular lesions but reverts to normal in compensated
      patients. The objectives of this study are to ascertain whether the PVV can be
      modulated by caloric stimulation and whether this modulation diminishes in
      compensated patients with unilateral vestibular lesions. DESIGN: Prospective.
      SETTING: Tertiary care facility. METHOD: Sixty-eight patients referred for
      vestibular testing had an electronystagmography and a PVV. MAIN OUTCOME MEASURES:
      Tilt in PVV, in degrees after caloric stimulation. RESULTS: Cold caloric
      stimulation resulted in a mean tilt in the PVV toward the irrigated ear and warm
      irrigation had the reverse effect. The mean modulation (amplitude of the angular
      distance in degrees between cold and warm tilts) was 4.3 degrees. In a subgroup
      of patients with severe unilateral vestibular dysfunction, this modulation of the
      PVV with caloric stimulation was diminished on the side of the lesion (p =
      .0001). CONCLUSION: Further study is required to assess the potential of the
      caloric PVV as a test of otolith function.

PMID- 10579158
TI  - Ventilation tube in adults with middle-ear effusion.
AB  - OBJECTIVE: This study was conducted to analyze the data concerning otitis media
      with effusion (OME) to configure its etiology, symptomatology, and outcome in
      adults. METHOD: A retrospective study of 198 consecutive cases (260 ears) of OME
      was conducted between July 1988 and June 1996. All of the patients were older
      than 16 years and were diagnosed for the first time. Tympanograms, initial
      symptoms, underlying diseases, extrusion of the ventilation tube, and recurrence
      rate of effusion were analyzed. RESULTS: Sinusitis was usually seen in patients
      16 to 29 and over 60 years old, whereas nasopharyngeal carcinoma was prevalent in
      patients 30 to 59 years old. Ear stuffiness (75.3%) was the most prevalent
      initial symptom, followed by hearing impairment (74.2%). One hundred seventy-five
      ears from 132 patients had been followed up for more than 2 years. In four ears,
      ventilation tubes were removed by instrument; the ventilation tubes in the
      remaining 171 ears of 128 patients extruded spontaneously within 20 months (8.6
      months on average). Recurrence of effusion within 2 years was noted in 78.8%
      (78/99 ears) of patients with head and neck tumours and in 27.3% (12/44 ears) of
      patients with sinusitis. CONCLUSION: Nasopharyngeal carcinoma and sinusitis were
      the main etiologies of OME in adults. In addition to treatment of sinusitis,
      nasopharyngeal check-up is mandatory in adults with OME.

PMID- 10579159
TI  - Endoscopic-powered rhinoplasty.
AB  - OBJECTIVE: To present a new method for sculpting the bony nasal dorsum in
      rhinoplasty surgery. MATERIALS AND METHODS: Fifteen patients underwent powered
      dissection of the nasal dorsum during cosmetic and reconstructive rhinoplasty.
      The precise technique is described and its benefits are discussed. RESULTS: All
      patients had acceptable postoperative results using this technique.
      Intraoperative bleeding and postoperative ecchymosis appeared to be reduced. No
      complications were noted. CONCLUSIONS: Endoscopic-powered rhinoplasty provides an
      excellent approach to the bony dorsum. It allows sculpting to be completed under
      direct vision, permitting precise contouring and easy visualization by
      associates. It can be completed easily and safely with standard microdebrider
      equipment. Its use should be considered in situations requiring precise
      contouring of the bony nasal dorsum.

PMID- 10579160
TI  - Nasal gliomas.

PMID- 10579161
TI  - Aggressive fibromatosis of the neck in two brothers: diagnostic and therapeutic
      implications.

PMID- 10579162
TI  - Leiomyosarcoma of the larynx.

PMID- 10579163
TI  - Fetal scarless wound healing.
AB  - Advances in fetal monitoring and open fetal surgery for life-threatening
      congenital diseases have provided us with the unique opportunity to examine fetal
      surgical wound healing. Fetal wounds heal rapidly and without scarring. The exact
      mechanisms of fetal scarless healing remain unknown. This article illustrates the
      most current understanding of the fetal wound healing process by examining the
      intrinsic properties of fetal skin, fetal fibroblasts, wound matrix, fetal
      environment, and various cytokines. In fetal wound, transforming growth factor
      beta and hyaluronic acid-rich wound matrix play pivoting roles in scarless
      repair. Different experimental strategies to manipulate the healing of adult
      wounds will be presented. These therapeutic measures are based on the scarless
      fetal wound repair model. We will also briefly comment on the current status of
      fetal surgery.

PMID- 10579164
TI  - Battlefield analgesia: an advanced approach.
AB  - We present an advanced battlefield analgesia protocol that is designed to provide
      the maximum benefit for the greatest number of patients using the minimum of
      resources. During the development we considered logistics, drug pharmacology and
      safety, aetiology of the pain and the experience of the expected administrator.
      Analgesia is only considered after the "ABCD" criteria of the Primary Survey have
      been satisfied. The analgesics administered range from enteral nonopioids through
      to intravenous opioids based dynamically upon the Visual Analogue Score (VAS). We
      suggest this protocol could be used by healthcare workers who may not have been
      trained in acute pain management but are called to administer analgesia to the
      serviceman in pain.

PMID- 10579165
TI  - J97 as a tool to investigate the effects of the Southeast Asia smog.
AB  - This paper describes the use of the J97 Health Surveillance System to monitor the
      effects of exposure to atmospheric pollution on the health of the Army population
      in Brunei. It shows that the J97 Health Surveillance tool is adaptable and can be
      used to rapidly set up a population-based health surveillance system.

PMID- 10579166
TI  - Imaging of the rotator cuff and biceps tendon.
AB  - Several different imaging techniques are available for evaluating the rotator
      cuff and biceps tendon. The common disorders of impingement, rotator cuff tears
      and biceps tendonitis are discussed along with the role which the various imaging
      modalities can play in establishing their diagnosis. Plain radiographs can be
      helpful particularly with a history of trauma but give limited information on the
      soft tissues. Ultrasound is a useful and inexpensive means of assessing the
      rotator cuff and biceps tendon but has a number of limitations and varying
      reports on its accuracy. Computed tomography (CT) is most helpful in the
      evaluation of shoulder trauma but gives limited information on the soft tissues.
      Magnetic resonance imaging (MRI) is an accurate imaging modality for evaluating
      the rotator cuff and biceps tendon, allowing visualisation of the soft tissues
      and the adjacent bony structures.

PMID- 10579167
TI  - A unified emergency care system from first aid to definitive care.
AB  - The Unified Emergency Care System (UECS) provides an integrated system of medical
      support from point of injury to the time a casualty is handed over to specialist
      care within hospital. It enables personnel at all skill levels to deliver life
      saving support to casualties with a broad range of acute injuries and illness.
      The UECS facilitates standardised training with each level building upon the
      previous, yet it retains an inherent flexibility to adapt to specific operational
      and service requirements.

PMID- 10579168
TI  - The treatment of snoring in the armed forces.
AB  - Snoring is a common problem, which may have widespread medical and social
      implications. This is particularly true in the setting of the armed forces where
      snoring may have significant effects in terms of personal performance, social
      interaction and security. This paper discusses the general management of snoring
      in the military environment and in particular the clinical effectiveness of one
      surgical procedure, uvulopalatopharyngoplasty. In this study, the procedure
      proves to be an effective surgical option in the management of snoring.

PMID- 10579169
TI  - A method of assigning socio-economic status classification to British Armed
      Forces personnel.
AB  - The objective of this paper was to develop and evaluate a socio-economic status
      classification method for British Armed Forces personnel. Two study groups
      comprising of civilian and Armed Forces families were identified from livebirths
      delivered between 1 January-30 June 1996 within the Northallerton Health district
      which includes Catterick Garrison and RAF Leeming. The participants were the
      parents of babies delivered at a District General Hospital, comprising of 436
      civilian and 162 Armed Forces families. A new classification method was
      successfully used to assign Registrar General's social classification to Armed
      Forces personnel. Comparison of the two study groups showed a significant
      difference in social class distribution (p = 0.0001). CONCLUSION: This study has
      devised a new method for classifying occupations within the Armed Forces to
      categories of social class thus permitting comparison with Registrar General's
      classification.

PMID- 10579171
TI  - Ganglion of the hip joint--we present a logical approach to the exploration of a
      mass in the femoral triangle.
AB  - Hip joint ganglion is a rare cause of a mass in the femoral triangle. Our patient
      presented with a swelling in the groin and a history of femoral hernia repair 5
      years previously. Pre-operative assessment with ultrasound suggested a possible
      femoral artery aneurysm. We propose that safe exploration of a mass closely
      related to the femoral vessels must include vascular control.

PMID- 10579170
TI  - An audit of positive findings in flexible and rigid check cystoscopy.
AB  - Both flexible and rigid cysto-urethroscopy are routinely used in the surveillance
      of transitional cell bladder tumours. This study addressed the issue of patient
      selection for either rigid or flexible cystoscopy. What proportion of positive
      findings at flexible cystoscopy and negative findings at rigid cystoscopy are
      acceptable? Standards were set of 10% for the former and 50% for the latter and
      our practice was then audited. A retrospective analysis of 800 patients
      undergoing check cystoscopy revealed a positive finding rate of 8.3% using the
      flexible instrument and 48.1% using the rigid instrument.

PMID- 10579172
TI  - The duff, no duff casualty.
AB  - A patient who presented with "hyperventilation syndrome" was initially mis
      treated as severe crush injury, illustrating the need for thorough assessment of
      all casualties whilst on exercise prior to arranging casualty treatment and
      evacuation.

PMID- 10579174
TI  - The military practice of chiropody.

PMID- 10579173
TI  - The influence of military surgeons in the development of vascular surgery.
AB  - Surgical attention to major blood vessels has been necessary for as long as man
      has been involved in armed combat. A brief resume of the history of vascular
      surgery is outlined with special reference to the contribution made by the
      military surgeon in battle. The role of modern specialist techniques in vascular
      injuries in present day operations will be briefly discussed.

PMID- 10579175
TI  - Italy 1945.

PMID- 10579176
TI  - [Conformational aspects of phosphorylation].

PMID- 10579177
TI  - [DNA polymerase alpha-DNA primase: structure and function].

PMID- 10579178
TI  - [Stability of normal and hyperacetylated chromatin in the cell free system of
      Drosophila embryos].

PMID- 10579179
TI  - [Corrective role of autonomous 3'--->5'-exonuclease in synthesis of DNA,catalyzed
      by DNA polymerase beta from rat liver].

PMID- 10579180
TI  - [Specific DNA binding and endoribonuclease activity is strongly connected with
      small RNP chromatin].

PMID- 10579181
TI  - [Computer analysis of regulatory signals in complete bacterial genomes.
      Participation of LexA and DinR binding].

PMID- 10579182
TI  - [Design, synthesis, and expression of a gene coding for a protein with two DNA
      binding motifs].

PMID- 10579183
TI  - [Creation of NotI-STS markers for human chromosome 3].

PMID- 10579184
TI  - [In vivo analysis of the proteolytic activity and effects of "sequestering" and
      negative domination of Escherichia coli lon-mutants using the lux regulon of
      Vibrio fischeri].

PMID- 10579186
TI  - [Crystallographic temperature B-factors and intramolecular mobility of
      ribonuclease A].

PMID- 10579185
TI  - [Study of sequence-specificity of complex-formation of the antibiotic daunomycin
      with isomeric deoxytetranucleotides 5'-d(ACGT), 5'-d(AGGT), and 5'-d(TGCA) by NMR
      spectroscopy].

PMID- 10579187
TI  - [Study of the binding of the diaqua-forms of cis-dichlorodiamminplatinum (II)
      with single-chain and dual-chain polynucleotides by quantum chemistry and
      molecular mechanics methods].

PMID- 10579188
TI  - [Hydrogen exchange in ribonuclease A. Heterogeneity of the tertiary structure by
      exchangeability of peptide H-atoms, dynamic properties and evolutionary
      conservation].

PMID- 10579189
TI  - [Possible A-conformation and conformation intermediate between the A- and B-forms
      of DNA fragments with alternating purine-pyrimidine sequences].

PMID- 10579190
TI  - [Proteins with varied levels of photoactive groups of anthracene structure for
      studying their structural organization by various luminescence methods].

PMID- 10579191
TI  - [Analysis of expression of ets-1 and fli-1 proto-oncogenes in murine embryonic
      stem cells, induced to differentiation by retinoic acid].

PMID- 10579192
TI  - [Features of tRNA hydrolysis by autoantibodies from blood serum of patients with
      certain autoimmune and virus diseases].

PMID- 10579193
TI  - [Network version of the protein family pattern bank PROF_PAT 1.1].

PMID- 10579194
TI  - [Localization of the influenza virus M1 matrix protein in the virion].

PMID- 10579195
TI  - [Structure of the 5'-terminal region of the 19S rRNA gene and promoter region of
      rDNA from Astasia longa].

PMID- 10579196
TI  - [Quantitative competitive PCR--diagnostic method for monitoring cytomegalovirus
      infection and antiviral therapy].

PMID- 10579197
TI  - [Structure and properties of the gene for 4-alpha-glucanotransferase from
      Thermotoga neapolitana].

PMID- 10579198
TI  - Human anticipatory eye movements may reflect rhythmic central nervous activity.
AB  - To investigate the possibility that rhythmic activity originating in the central
      nervous system may modulate human eye movements, anticipatory eye movements were
      generated by tracking an intermittently obscured sinusoidally moving target.
      Eight subjects tracked intermittently obscured sinusoids of three different
      frequencies and of two different amplitudes. Eye movements were recorded by an
      infra-red reflection technique. The eye velocity records were analysed in the
      frequency domain by power spectral estimates. During periods where the target was
      obscured, eye movements consisted of a staggered series of anticipatory saccades
      with intervening smooth anticipatory eye movements or relatively stationary
      periods. In sections where the intervening smooth components of anticipatory
      tracking were of high velocity (above 15 deg/s), a superimposed smooth tremulous
      oscillation at around 10 Hz was sometimes present. Coherence analysis showed that
      this 10 Hz range oscillation of smooth anticipatory movement was not derived from
      head tremor and that the same oscillation was present in both eyes. This
      oscillation was not generally observed during smooth tracking of pseudorandom
      waveforms. Investigation of anticipatory eye movements has revealed a 10-Hz range
      oscillation or "tremor" superimposed upon smooth movements that might in other
      circumstances be inhibited by direct visual feedback. This smooth eye movement
      oscillation is thought to originate from the central nervous system and may
      reflect a widespread frequency modulation of motor commands.

PMID- 10579199
TI  - Monkey insular cortex neurons respond to baroreceptive and somatosensory
      convergent inputs.
AB  - To investigate possible convergence of autonomic and somatosensory input in the
      insula of the non-human primate, extracellular single-unit recordings were
      obtained from 81 neurons (43 insular and 38 in surrounding cortex) during
      application of cutaneous nociceptive stimuli (pinch) and baroreceptor challenge
      in six anesthetized monkeys (Macaca fascicularis). All cells were also tested
      with light touch (brush) stimulation. Twenty-six units responded to blood
      pressure changes; 20 (80%) were identified within the insula (P < 0.001). The
      majority of these insular units (16/20) also responded to nociceptive pinch
      (convergent units). More units responsive to changes in blood pressure (unimodal
      and convergent) were found in the right (18/29, 62%) than in the left insular
      cortex (2/14, 14%)(P = 0.004). Twenty-nine insular neurons responded to
      nociceptive stimuli; 16 of these were convergent units and 13 showed unimodal
      responses to somatosensory stimuli alone. These cells had wide bilateral
      receptive fields including face, hand, foot and tail. Ten insular neurons were
      unresponsive to both sets of stimuli (non-responsive cells); significantly more
      of these cells (28/38) were identified in extrainsular locations (P < 0.01). We
      suggest that the primate insular cortex may be involved in the integration of
      cardiovascular function with somatosensory (principally nociceptive) input. This
      view supports the emerging role of the insular cortex as an important forebrain
      site of viscerosomatosensory regulation with clinical implications for
      cardiovascular regulation under conditions of stress and arousal.

PMID- 10579200
TI  - Inhibition of cyclic AMP-dependent protein kinase in the acute phase of focal
      cerebral ischemia in the rat.
AB  - Binding of cyclic AMP to the regulatory subunit of cyclic AMP-dependent protein
      kinase is an essential step in cyclic AMP-mediated intracellular signal
      transduction. In the present study, the binding capacity of cyclic AMP-dependent
      protein kinase for cyclic AMP was examined by autoradiography with local cerebral
      blood flow in focal cerebral ischemia in the rat, which was induced by occlusion
      of the middle cerebral artery using the intraluminal suture method. The binding
      capacity of cyclic AMP-dependent protein kinase and local cerebral blood flow
      were assessed by the in vitro [3H]cyclic AMP binding and the [14C]iodoantipyrine
      methods, respectively. At 3 h of occlusion, a significant reduction in the
      binding of cyclic AMP-dependent protein kinase to cyclic AMP was already noted in
      the lateral region of the caudate-putamen and the parietal cortex. Between three
      and five hours of occlusion, the area with reduced cyclic AMP binding was
      significantly expanded to the peri-ischemic regions including the frontal cortex
      and the medial region of the caudate-putamen. The threshold in local cerebral
      blood flow for reduced cyclic AMP binding was clearly noted at 5 h of ischemia,
      and was 45 ml/100 g per min in the cerebral cortices, and 38 ml/100 g per min in
      the caudate-putamen, respectively. No threshold was noted at 3 h of ischemia,
      since cyclic AMP binding showed a large variation ranging from reduced to normal
      values even when local cerebral blood flow was below 20 ml/100 g per min.
      Recirculation for 3.5 h following 1.5 h of ischemia restored the normal cyclic
      AMP binding in the cerebral cortices, but failed to normalize cyclic AMP binding
      in the caudate-putamen despite good recovery of local cerebral blood flow.
      Western blot analysis suggested that this reduction in cyclic AMP binding was not
      due to loss or degradation of the subunit protein of cyclic AMP-dependent protein
      kinase, and may therefore have resulted from conformational changes in the
      protein. A significant increase in cyclic AMP binding was noted after
      recirculation in the non-ischemic regions such as the frontal and the cingulate
      cortices on the occluded side and in the contralateral cortices. These data
      indicate that cyclic AMP-mediated signal transduction in the brain tissue may be
      very susceptible to ischemic stress, and the region of disrupted signal
      transduction may expand progressively from the ischemic core to peri-ischemic
      regions in the acute phase of ischemia. Such impairment of signal transduction
      may not be restored in the caudate-putamen even when cerebral circulation is
      fully recovered after short-term ischemia, suggesting that a regional
      vulnerability to ischemic stress may also exist in cyclic AMP-mediated signal
      transduction. A significant increase in cyclic AMP binding after recirculation in
      regions outside of ischemic area may be closely related with the protective
      mechanisms of brain tissue, since cyclic AMP has been reported to exert various
      neuroprotective actions.

PMID- 10579201
TI  - The effects of subdural haematoma on spatial learning in the rat.
AB  - Although memory deficits are one of the most persistent consequences of human
      subdural haematoma, cognitive functioning has hardly been investigated in the rat
      subdural haematoma model. In the present study, the effects on spatial learning
      of right- and left-sided unilateral subdural haematoma and of bilateral subdural
      haematoma induced above the sensorimotor cortical areas were evaluated. Spatial
      learning was assessed by standard acquisition in the Morris water escape task
      (five sessions). Additional issues addressed were sensorimotor functioning
      (footprint analysis), recovery of cognitive functioning (tested by an
      overtraining and a reversal training) and replicability of induced cognitive
      deficits. Following unilateral subdural haematoma surgery, hardly any impairments
      in the Morris water escape task were observed: rats with a unilateral right-sided
      subdural haematoma showed very mild, transient deficits, whereas rats with left
      sided subdural haematoma were indistinguishable from controls. Bilateral subdural
      haematoma surgery led to a clear, although transient, performance deficit. We
      conclude that animals with bilateral subdural haematoma may provide a promising
      cognitive deficit model for investigating recovery of function.

PMID- 10579202
TI  - Changes in synaptic expression of clathrin assembly protein AP180 in Alzheimer's
      disease analysed by immunohistochemistry.
AB  - Clathrin assembly protein AP180 plays a regulatory role in clathrin-mediated
      synaptic vesicle recycling in synapses. Previously, using immunoblot analysis, we
      observed a significant reduction of AP180 protein in Alzheimer's disease
      neocortex. In this study, we examined immunohistochemically the expression of
      AP180 in post mortem brains with Alzheimer's disease (n = 5) in comparison with
      neurologically normal controls (n = 5). Overall, AP180 was revealed as
      immunoreactive punctate granules located in the neuropil, and around neuronal
      cell bodies and their processes, consistent with the typical expression of
      synaptic proteins. Reduced density of AP180 immunoreactive puncta was seen
      throughout all layers of the superior frontal gyrus in Alzheimer's disease, but
      the loss of AP180 immunoreactivity was not as prominent in the cerebellum. This
      regional difference is in agreement with our previous results from immunoblot
      analyses. In the hippocampus, cell body AP180 immunoreactivity normally seen in
      the hilus and the CA3 regions of control brains was completely lost in
      Alzheimer's disease. In addition, AP180 immunoreactivity in the molecular layer
      of the dentate gyrus showed several changes in Alzheimer's disease. These
      appeared to be expansion of the inner molecular layer and relative changes in
      immunoreactivity that resulted in clearer delineation of the inner and outer
      molecular layers. These results provide anatomical and spatial information on
      AP180 expression in Alzheimer's disease brains. The variations in altered AP180
      immunoreactivity in different brain regions of Alzheimer's disease may underlie
      the dysfunction of the corresponding synapses.

PMID- 10579203
TI  - Anomalous expression of microtubule-associated protein 1B in the hippocampus and
      cortex of aged rats treated with pentylenetetrazole.
AB  - The aim of the present study was to assess the age-dependent response of
      microtubule-associated protein 1B, a plasticity-associated protein deriving from
      a late gene, following administration of an epileptogenic stimulus. The effect of
      a single administration of the convulsant pentylenetetrazole on microtubule
      associated protein 1B expression in the hippocampal formation and cortex of three
      , 18- and 28-month-old rats was assessed using northern blot analysis, in situ
      hybridization and immunohistochemistry. In three-month-old rats, we detected
      initial increases in microtubule-associated protein 1B messenger RNA at 15 h
      following pentylenetetrazole administration in the granule cells of the dentate
      gyrus, in the CA3 region of the hippocampus and in layers II/III of the
      entorhinal cortex, and these reached a maximum at 44 h. However, in the
      hippocampus and cortex of 18-month-old rats, the peak occurred at 15 h, and in
      the brains of 28-month-old rats a blunted peak was reached at 3 h.
      Pentylenetetrazole treatment in young rats resulted in a robust induction of
      microtubule-associated protein 1B immunoreactivity in the granule cells of the
      dentate gyrus and in layers II/III of the entorhinal cortex, but also produced a
      large decrease in the retrosplenial cortex. However, following pentylenetetrazole
      treatment in older rats, the granule cells of the dentate gyrus were nearly
      devoid of microtubule-associated protein 1B immunoreactivity, whereas the
      retrosplenial cortex showed no changes at all, and the entorhinal cortex had an
      expression pattern similar to that of young rats. Aberrant immunolabeling of
      microtubule-associated protein 1B occurred in cortical layer VI of the aged rats
      where, unlike in young rats, there was heavy staining of neuronal somata. These
      results suggest that the regulation of the plasticity-associated protein
      microtubule-associated protein 1B is altered in the ageing rat brain, with the
      peak of expression shifted to earlier times in 18-month-old rats and blunted,
      variable increases at even earlier times in 28-month-old rats.

PMID- 10579204
TI  - Sphingosine-1-phosphate induces apoptosis of cultured hippocampal neurons that
      requires protein phosphatases and activator protein-1 complexes.
AB  - In this study, we report that mobilization of internal Ca2+ by sphingosine-1
      phosphate, a metabolite of ceramide, induces apoptosis in cultured hippocampal
      neurons. This sphingosine-1-phosphate-induced apoptosis is dependent upon the
      activation of protein phosphatases, possibly calcineurin and phosphatase 2A (or a
      related phosphatase). In addition, pretreatment of neurons with double-stranded
      oligonucleotides containing the metallothionein phorbol-12-myristate-13-acetate
      response element sequence as transcription factor decoys suppressed apoptosis. In
      contrast, double-stranded oligonucleotides containing either the c-jun or SV40
      phorbol-12-myristate-13-acetate response element sequences were ineffective.
      Electrophoretic mobility shift assays and supershift assays revealed that c-Fos
      containing activator protein- complexes preferentially bound the metallothionein
      phorbol-12-myristate-13-acetate response element sequence-containing
      oligonucleotides. Furthermore, antisense oligonucleotides to c-fos and c-jun were
      also protective. The apoptotic death of hippocampal neurons has been hypothesized
      to contribute to the cognitive impairments observed following insults to the
      brain. While increases in intracellular calcium are thought to be key mediators
      of neuronal apoptosis, the biochemical cascade(s) activated as a result of
      increased Ca2+ which mediates apoptosis of hippocampal neurons is (are) not well
      understood. The findings presented in this study suggest that mobilization of
      internal calcium via prolonged exposure of sphingosine-1-phosphate induces
      apoptosis of hippocampal neurons in culture. Sustained increases in intracellular
      calcium activate a phosphatase cascade that includes calcineurin and a
      phosphatase 2A-like phosphatase, and leads to the expression of genes containing
      metallothionein phorbol-12-myristate-13-acetate response element (TGAGTCA)-type
      enhancer sequences. The expression of genes containing TGAGTCA-type enhancer
      sequences appears to be essential for sphingosine-1-phosphate-induced apoptosis
      of hippocampal neurons.

PMID- 10579205
TI  - Glutamate in synaptic terminals is reduced by lack of glucose but not hypoxia in
      rat hippocampal slices.
AB  - Although excessive release of the neurotransmitter glutamate contributes to
      ischemic neuronal damage, immunocytochemical studies have not found a loss of
      glutamate from ischemic axon terminals. We examined the effects of two components
      of ischemia, hypoxia and hypoglycemia, on glutamate loss from rat hippocampal
      slices. In vitro hypoglycemia induced by incubation for 1 h without glucose
      depleted 50% of glutamate from slices when ATP levels were about 5 nmol/mg
      protein. Hypoxic slices aerated with N2 reached similar ATP levels without
      significant glutamate depletion. To induce 50% glutamate losses with chemical
      hypoxia, ATP had to be depleted to < 1 nmol/mg protein. Immunocytochemical
      staining indicated that glutamate-like immunoreactivity was reduced throughout
      slices by hypoglycemia. Hypoxia decreased glutamate-like immunoreactivity in
      neuronal perikarya and dendrites of pyramidal cells and granule cells. However,
      in contrast to hypoglycemia, hypoxia maintained or increased glutamate-like
      immunoreactivity in many terminals. Hypoxia and hypoglycemia induced similar, ATP
      dependent releases of glutamate into supernatants, which could account for only
      part of the hypoglycemic losses. The additional hypoglycemic losses were
      consistent with increased catabolism of glutamate. Glutamate losses from
      hypoglycemic terminals were reduced by blockade of aspartate aminotransferase or
      the tricarboxylic acid cycle. Exogenous glutamate increased glutamate in
      hypoglycemic slices to hypoxic levels and returned glutamate-like
      immunoreactivity to terminals, suggesting that terminals maintained glutamate
      uptake during metabolic insults. Hypoglycemia induces a large loss of glutamate
      that does not occur during hypoxia. The greater loss of glutamate from terminals
      during hypoglycemia is consistent with increased metabolism of glutamate via
      aspartate aminotransferase and not increased release of glutamate. Continued
      uptake of glutamate by hypoxic terminals may help to maintain their levels of
      glutamate. Hypoglycemic metabolism of glutamate may decrease pathologic glutamate
      release and contribute to the prolonged neurologic abnormalities associated with
      recovery from hypoglycemia.

PMID- 10579206
TI  - Chronic intermittent ethanol exposure alters CA1 synaptic transmission in rat
      hippocampal slices.
AB  - We investigated the neuroadaptive changes in synaptic transmission in the CA1
      region of the hippocampus as a result of chronic intermittent ethanol exposure.
      Male Wistar rats were exposed daily (14 h) to ethanol vapors (blood alcohol
      levels = 150-200 mg%) for 12-14 days, and synaptic field potentials elicited by
      Schaffer collateral stimulation were compared in hippocampal slices from control
      and chronic ethanol-treated rats. Excitatory postsynaptic responses of slices
      were recorded under three conditions: (i) normal physiological saline; (ii)
      continued presence of 33 mM (150 mg%) ethanol (chronic ethanol-treated rats
      only); (iii) acute exposure to 33 mM ethanol. When recorded in ethanol-free
      physiological saline, the mean amplitude of the dendritic synaptic potential and
      the somatic population spike were significantly smaller in slices from chronic
      ethanol-treated rats compared to slices from control rats. Under conditions of
      continuous ethanol exposure, somatic and dendritic synaptic responses of slices
      taken from chronic ethanol-treated rats were further depressed, suggesting that
      neural pathways in area CA1 remained sensitive to ethanol. Acute application of
      ethanol led to a more pronounced reduction of the mean somatic population spike
      amplitude in slices from chronic ethanol-treated rats than in slices from control
      rats. However, dendritic synaptic responses were unaffected by acute ethanol in
      slices from both control and chronic ethanol-treated rats. In addition, we
      examined the involvement of presynaptic mechanisms in the effects of chronic
      intermittent ethanol using paired-pulse protocols. When recorded in the continued
      presence of ethanol, slices from chronic ethanol-treated rats exhibited a
      significant reduction in paired-pulse facilitation of the dendritic synaptic
      response compared to slices from control rats, indicating a presynaptic component
      to the neuroadaptive effects of chronic intermittent ethanol exposure.
      Conversely, acute ethanol exposure resulted in an enhancement of paired-pulse
      facilitation of the dendritic synaptic response, an effect that was similar in
      slices from both control and chronic ethanol-treated rats. Paired-pulse
      facilitation of the somatic population spike amplitude was not altered by chronic
      ethanol treatment. However, acute ethanol exposure significantly enhanced paired
      pulse facilitation of the somatic population spike in slices from chronic ethanol
      treated rats. This effect of acute ethanol was not observed in slices from
      control rats. Paired-pulse inhibition was not significantly altered in slices
      from chronic ethanol-treated rats, suggesting that GABAergic inhibitory
      mechanisms were not involved in the neuroadaptive effects of chronic intermittent
      ethanol exposure. We suggest that chronic intermittent ethanol exposure can
      induce multiple neuroadaptive changes in synaptic transmission of CA1 pyramidal
      neurons that are detectable at both the pre- and postsynaptic levels. Alterations
      in paired-pulse facilitation indicate presynaptic changes involving the release
      of the excitatory neurotransmitter glutamate, whereas changes in dendritic
      synaptic responses suggest postsynaptic changes in the responsiveness of neurons
      to synaptic input. Moreover, differential effects of chronic ethanol treatment on
      synaptic responses recorded in the dendrites versus the somatic region implicate
      additional effects of ethanol on somatically located mechanisms of CA1 pyramidal
      neurons. Furthermore, we suggest that complete tolerance to ethanol does not
      occur in the CA1 region of the hippocampus following chronic intermittent ethanol
      exposure.

PMID- 10579207
TI  - Early polysynaptic potentiation recorded in the dentate gyrus during an
      associative learning task.
AB  - In this report, we investigated the electrophysiological dynamics of the neuronal
      circuit including the dentate gyrus during an associative task. A group of rats
      was trained to discriminate between a patterned electrical stimulation of the
      lateral olfactory tract, used as an artificial cue associated with a water
      reward, and a natural odor associated with a light flash. Polysynaptic field
      potential responses, evoked by a single electrical stimulation of the same
      lateral olfactory tract electrode, were recorded in the molecular layer of the
      ipsilateral dentate gyrus prior to and just after each training session. An
      increase in this response was observed when a significant discrimination of the
      two cues began. A positive correlation was found between the change in the
      polysynaptic potentiation and behavioral performances. The onset latency of the
      potentiated polysynaptic response was 35-45 ms. When a group of naive animals was
      pseudoconditioned, no change in field potential was observed. These results are
      consistent with the hypothesized dynamic activation of the dentate gyrus early in
      the making of association, allowing gradual storage of associative information in
      a defined set of synapses. Moreover, the onset latency of the potentiated
      response suggests the existence of reactivating hippocampal loops during the
      processing of associative information.

PMID- 10579208
TI  - Neuronal activity of the septal pacemaker of theta rhythm under the influence of
      stimulation and blockade of the median raphe nucleus in the awake rabbit.
AB  - The control of theta rhythm in neuronal activity of the medial septal area and
      hippocampal electroencephalogram by the brainstem structures was investigated in
      waking rabbits. In the first series of experiments stimulating electrodes were
      implanted into the midbrain reticular formation and median raphe nucleus. The
      standard frequency of theta-bursts in medial septal area neurons and in the
      electroencephalogram was uniformly and chronically decreased in all rabbits with
      electrodes implanted into the median raphe nucleus (4.7 +/- 0.5 Hz versus 5.2 +/-
      0.19 Hz in animals without electrodes in median raphe nucleus). Weak electrical
      stimulation of the median raphe nucleus resulted in additional decrease of theta
      expression in the medial septal area neurons and its disappearance from the
      hippocampal electroencephalogram, where it was substituted by delta-waves and
      spindles. Stimulation of the reticular formation had the opposite effect, with an
      increase in theta frequency, regularity and expression in medial septal area
      neuronal activity and hippocampal electroencephalogram. In the second series of
      experiments reversible functional blockade of the median raphe nucleus by local
      microinjection of lidocaine was performed. This resulted in expression of theta
      bursts in an additional group of medial septal area neurons, an increase in theta
      burst frequency (by 0.5-2 Hz) and regularity with concomitant changes in the
      electroencephalogram. The effects of sensory stimuli on the background of
      increased theta activity were suppressed or significantly decreased. It is
      concluded that, in accordance with the data of other authors, the median raphe
      nucleus can be regarded as a functional antagonist of the reticular formation,
      powerfully suppressing theta-bursts of the medial septal area neurons and
      hippocampal theta rhythm. It is suggested that, in combination with the theta
      enhancing influences of reticular formation, the median raphe nucleus may
      participate in termination of attention, its switching to other stimuli and
      stabilization of the effects of learning.

PMID- 10579210
TI  - Status epilepticus-induced neuronal damage in the rat amygdaloid complex:
      distribution, time-course and mechanisms.
AB  - The present study was designed to elucidate the distribution, time-course and
      mechanism(s) of status epilepticus-induced neuronal damage in the rat amygdaloid
      complex. Status epilepticus was induced with kainate (9 mg/kg, i.p.), and the
      behavioral and electrographic seizure activity of each rat was monitored via
      cortical electrodes attached to a continuous video electrocorticogram system.
      Rats were subsequently perfused 1, 2, 4, 8, 16, 24 or 48 h after kainate
      injection. The first signs of amygdaloid damage were seen in rats perfused 4 h
      after kainate injection, though the severity and temporal appearance of damage
      varied substantially between the different amygdaloid nuclei and their
      subdivisions. Second, terminal transferase dUTP nick-end labeling (TUNEL)
      positive nuclei and laddering of DNA in gel electrophoresis appeared in the
      amygdala 8 and 16 h after kainate, respectively. The distribution and density of
      TUNEL-positive nuclei in the different amygdaloid nuclei correlated with the
      distribution of neuronal damage in Thionin- and silver-stained sections. Third,
      the immunoreactivity of Bax protein, a promoter of apoptotic neuronal death,
      increased in the vulnerable medial division of the lateral nucleus prior to the
      appearance of argyrophilic neurons and TUNEL-positive nuclei. Fourth, the
      severity of neuronal damage progressed in some, but not all, amygdaloid regions
      throughout the 48-h follow-up, even though the occurrence of high-amplitude and
      frequency discharges, which are typically associated with behavioral seizure
      activity, extinguished after 7 h. These data show that status epilepticus-induced
      neuronal damage in the amygdala is a dynamic region-specific process, the
      severity of which depends on the duration of seizure activity. At least one
      mechanism underlying the damage involves apoptosis, which continues long after
      the behavioral and electrographic seizures have subsided.

PMID- 10579209
TI  - Loss of dynorphin-mediated inhibition of voltage-dependent Ca2+ currents in
      hippocampal granule cells isolated from epilepsy patients is associated with
      mossy fiber sprouting.
AB  - The endogenous kappa receptor selective opioid peptide dynorphin has been shown
      to inhibit glutamate receptor-mediated neurotransmission and voltage-dependent
      Ca2+ channels. It is thought that dynorphin can be released from hippocampal
      dentate granule cells in an activity-dependent manner. Since actions of dynorphin
      may be important in limiting excitability in human epilepsy, we have investigated
      its effects on voltage-dependent Ca2+ channels in dentate granule cells isolated
      from hippocampi removed during epilepsy surgery. One group of patients showed
      classical Ammon's horn sclerosis characterized by segmental neuronal cell loss
      and astrogliosis. Prominent dynorphin-immunoreactive axon terminals were present
      in the inner molecular layer of the dentate gyrus, indicating pronounced
      recurrent mossy fiber sprouting. A second group displayed lesions in the temporal
      lobe that did not involve the hippocampus proper. All except one of these
      specimens showed a normal pattern of dynorphin immunoreactivity confined to
      dentate granule cell somata and their mossy fiber terminals in the hilus and CA3
      region. In patients without mossy fiber sprouting the application of the kappa
      receptor selective opioid agonist dynorphin A ([D-Arg6]1-13, 1 microM) caused a
      reversible and dose-dependent depression of voltage-dependent Ca2+ channels in
      most granule cells. These effects could be antagonized by the non-selective
      opioid antagonist naloxone (1 microM). In contrast, significantly less dentate
      granule cells displayed inhibition of Ca2+ channels by dynorphin A in patients
      with mossy fiber sprouting (Chi-square test, P < 0.0005). The lack of dynorphin A
      effects in patients showing mossy fiber sprouting compares well to the loss of
      kappa receptors on granule cells in Ammon's horn sclerosis but not lesion
      associated epilepsy. Our data suggest that a protective mechanism exerted by
      dynorphin release and activation of kappa receptors may be lost in hippocampi
      with recurrent mossy fiber sprouting.

PMID- 10579211
TI  - Maternal separation and early social deprivation in Octodon degus: quantitative
      changes of nicotinamide adenine dinucleotide phosphate-diaphorase-reactive
      neurons in the prefrontal cortex and nucleus accumbens.
AB  - The influence of postnatal socio-emotional deprivation on the development of
      nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase-reactive neurons
      in prefrontal cortical areas and in subdivisions of the nucleus accumbens was
      quantitatively investigated in the precocious rodent Octodon degus. Forty-five
      days-old O. degus from two animal groups were compared: (i) degus which were
      repeatedly separated from their mothers during the first three postnatal weeks
      and after weaning reared in complete isolation; and (ii) degus which were reared
      under normal undisturbed social conditions. Socially-deprived animals displayed a
      significant decrease of NADPH-diaphorase-containing neurons in anterior cingulate
      cortex (85.5%), the same tendency was observed in the infralimbic, precentral
      medial and prelimbic prefrontal areas. Similarly, the core region of nucleus
      accumbens expressed reduced NADPH-diaphorase-reactive neuron numbers in deprived
      animals (70%), whereas the shell region remained unchanged. Since during normal
      postnatal development the number of NADPH-diaphorase-reactive neurons gradually
      decreases in all prefrontal cortical and accumbal regions, the observed
      deprivation-induced changes may reflect either an excessive reduction of NADPH
      diaphorase-positive neurons or a down-regulation of the enzyme in neurons that
      normally express it. Since some NADPH-diaphorase-containing neurons in the
      prefrontal cortex have been shown to be GABAergic, it is tempting to speculate
      that a reduction of these inhibitory neurons in the anterior cingulate cortex may
      result in an enhanced excitatory output activity of disinhibited projection
      neurons in this cortical region, including those that project to the core region
      of the nucleus accumbens. Our results indicate a link between early adverse socio
      emotional experience and the maturation of NADPH-reactive neurons and further
      studies are required to analyse the functional implication for this experience
      induced brain pathology.

PMID- 10579212
TI  - Prior D1 dopamine receptor stimulation is required to prime D2-mediated striatal
      Fos expression in 6-hydroxydopamine-lesioned rats.
AB  - Repeated dopamine agonist administration to rats with unilateral 6
      hydroxydopamine lesions of the nigrostriatal pathway potentiates behavioral and
      neuronal activation in response to subsequent dopamine agonist treatment. This
      response sensitization has been termed "priming" or "reverse-tolerance". Our
      prior work has shown that three pretreatment injections of the mixed D1/D2
      agonist apomorphine (0.5 mg/kg) into 6-hydroxydopamine-lesioned rats permits a
      previously inactive dose of the D2 agonist quinpirole (0.25 mg/kg) to induce
      robust contralateral rotation and striatal Fos expression in
      striatoentopeduncular "direct" pathway neurons. These striatal neurons typically
      express D1 but not D2 receptors. Because apomorphine acts as an agonist at both
      D1 and D2 receptors, the present study sought to determine whether D1, D2, or
      concomitant D1/D2 receptor stimulation was required to prime D2-mediated
      contralateral rotation and striatal Fos expression. Twenty-one days following
      unilateral stereotaxic injection of 6-hydroxydopamine into the medial forebrain
      bundle, rats received three pretreatment injections, at three- to six-day
      intervals, with either: the mixed D1/D2 agonist apomorphine, the D1 agonist
      SKF38393, the D2 agonist quinpirole, or a combination of SKF38393 + quinpirole.
      Ten days following the third pretreatment injection, 6-hydroxydopamine-lesioned
      rats were challenged with the D2 agonist quinpirole (0.25 mg/kg). Pretreatment
      with SKF38393 (10 mg/kg), quinpirole (1 mg/kg) or SKF38393 (1 mg/kg) + quinpirole
      (0.25 mg/kg) permitted an otherwise inactive dose of quinpirole (0.25 mg/kg) to
      induce robust contralateral rotation which was similar in magnitude to that
      observed following apomorphine priming. However, only pretreatment with SKF38393
      (10 mg/kg) or SKF38393 (1 mg/kg) + quinpirole (0.25 mg/kg) permitted the same
      dose of quinpirole (0.25 mg/kg) to induce striatal Fos expression. These results
      demonstrate that while prior stimulation of D1, D2 or D1/D2 receptors can
      effectively prime D2-mediated contralateral rotation, prior stimulation of D1
      receptors is required to prime D2-mediated striatal Fos expression. This study
      demonstrates that priming of 6-hydroxydopamine-lesioned rats with a D1 agonist
      permits a subsequent challenge with a D2 agonist to produce robust rotational
      behavior that is accompanied by induction of immediate-early gene expression in
      neurons that comprise the "direct" striatal output pathway. These responses are
      equivalent to the changes observed in apomorphine-primed 6-hydroxydopamine
      lesioned rats challenged with D2 agonist. In contrast, D2 agonist priming was not
      associated with D2-mediated induction of striatal immediate-early gene expression
      even though priming of D2-mediated rotational behavior was not different from
      that observed following priming with apomorphine or D1 agonist. Therefore, while
      priming-induced alterations in D2-mediated immediate early gene expression in the
      "direct" striatal output pathway may contribute to the enhanced motor behavior
      observed, such changes in striatal gene expression do not appear to be required
      for this potentiated motor response in dopamine-depleted rats.

PMID- 10579213
TI  - Changes in the regional and compartmental distribution of FosB- and JunB-like
      immunoreactivity induced in the dopamine-denervated rat striatum by acute or
      chronic L-dopa treatment.
AB  - This study was carried out in order to examine the effects of acute or chronic L
      DOPA treatment on striatally expressed FosB- and JunB-like proteins in a rat
      model of Parkinson's disease. Rats with a unilateral, near-total 6
      hydroxydopamine lesion of the ascending mesostriatal projection received either
      an acute challenge or a one-week treatment with 10 mg/kg/day methyl L-DOPA
      (combined with 15 mg/mg benserazide), and were killed at either 3 h or two days
      post-injection. Both acute and chronic L-DOPA treatment caused a pronounced,
      persistent increase in the number of FosB-like immunoreactive cells in the
      dopamine-denervated striata (five- and seven-fold increase, respectively, above
      the levels found in lesioned but non-drug-treated controls), but the two
      treatment groups differed markedly with respect to both the average amount of
      staining per cell, which was two-fold larger in the chronic L-DOPA cases, and the
      anatomical distribution of the labeled cells. After an acute injection of L-DOPA,
      FosB-positive cells were distributed rather uniformly across all striatal
      subregions, whereas chronic L-DOPA treatment induced discrete clusters of
      strongly FosB-like immunoreactive cells within medial and central striatal
      subregions, as well as in a large, yet sharply defined portion of the lateral
      caudate-putamen. Strongly labeled cell clusters that appeared in the medial and
      central caudate-putamen were preferentially located within calbindin-poor, mu
      opioid receptor-rich striosomes, whereas the lateral area displaying FosB
      activation encompassed both striosomal and matrix domains. In both the medial and
      the lateral striatum a near-total overlap was found between strongly FosB-like
      immunoreactive cell groups and areas showing pronounced dynorphin expression.
      NADPH-diaphorase-positive striatal interneurons did not express FosB-like
      immunoreactivity after a 6-hydroxydopamine lesion alone, a negligible proportion
      of them did after an acute L-DOPA challenge, but about 8% of these interneurons
      were FosB positive following chronic L-DOPA treatment. Like FosB, JunB was
      induced in the DA-denervated striatum by both acute and chronic L-DOPA treatment,
      and exhibited similar distribution patterns. However, JunB did not exhibit
      prolonged expression kinetics, and was somewhat down-regulated in the chronically
      compared with the acutely L-DOPA-treated rats. The present results show that L
      DOPA administration produces a long-lasting increase in the levels of FosB-, but
      not JunB-like immunoreactivity in the dopamine-denervated striatum. More
      importantly, these data show that striatal induction of FosB- and JunB-like
      proteins by chronic L-DOPA treatment exhibits both regional and compartmental
      specificity.

PMID- 10579214
TI  - Characterization of the extent of pontomesencephalic cholinergic neurons'
      projections to the thalamus: comparison with projections to midbrain dopaminergic
      groups.
AB  - We sought to determine whether pontomesencephalic cholinergic neurons which we
      have been shown previously to project to the substantia nigra and ventral
      tegmental area also contribute to the thalamic activation projection from the
      pedunculopontine and laterodorsal tegmental nuclei. Retrograde tracing,
      immunohistochemical localization of choline acetyltransferase and statistical
      methods were used to determine the full extent of the cholinergic projection from
      the pedunculopontine and laterodorsal tegmental nuclei to the thalamus.
      Progressively larger Fluoro-Gold injections in to the thalamus proportionally
      labeled increasing numbers of pontomesencephalic cholinergic cells both ipsi- and
      contralaterally in the pedunculopontine and laterodorsal tegmental nuclei.
      Multiple large thalamic injections left only a small fraction of the ipsilateral
      pontomesencephalic cholinergic group unlabeled. This small remainder did not
      correspond to the populations which project to the substantia nigra and ventral
      tegmental area, thereby indicating that substantia nigra- and ventral tegmental
      area-projecting cholinergic neurons must also project to the thalamus. We
      examined whether there existed any set of cholinergic neurons in the
      pedunculopontine and laterodorsal tegmental nuclei which did not innervate a
      thalamic target. The distribution of descending projections of the
      pedunculopontine and laterodorsal tegmental nuclei demonstrated that the
      unlabeled remainder cannot correspond to a purely descending group. We also show
      that substance P-positive cholinergic cells in the laterodorsal tegmental nucleus
      project to the thalamus. Further studies demonstrated that the small population
      of cholinergic cells left unlabeled from the thalamus were the smallest sized
      cholinergic cells, and included two groups of small, light-staining cholinergic
      cells located in the parabrachial area and central gray, adjacent to the main
      pedunculopontine and laterodorsal tegmental nuclei cholinergic groups. These
      small cells, in contrast to thalamic-projecting cholinergic cells, did not stain
      positively for reduced nicotinamide adenine dinucleotide phosphate-diaphorase.
      Taken together, these results indicated that all of the reduced nicotinamide
      adenine dinucleotide phosphate diaphorase-positive/choline acetyltransferase
      positive neurons of the pedunculopontine/laterodorsal tegmental nuclei ascend to
      innervate some portion of the thalamus, in addition to the other targets they
      innervate. These findings indicate that the diverse physiological and behavioral
      effects attributed to the activity of pontomesencephalic cholinergic neurons
      should not be dissociated from their activating effects in the thalamus.

PMID- 10579215
TI  - Platelet-activating factor and group I metabotropic glutamate receptors interact
      for full development and maintenance of long-term potentiation in the rat medial
      vestibular nuclei.
AB  - In rat brainstem slices, we investigated the interaction between platelet
      activating factor and group I metabotropic glutamate receptors in mediating long
      term potentiation within the medial vestibular nuclei. We analysed the N1 field
      potential wave evoked in the ventral portion of the medial vestibular nuclei by
      primary vestibular afferent stimulation. The group I metabotropic glutamate
      receptor antagonist, (R,S)-1-aminoindan-1,5-dicarboxylic acid, prevented long
      term potentiation induced by a platelet-activating factor analogue [1-O-hexadecyl
      2-O-(methylcarbamyl)-sn-glycero-3-phosphocholine], as well as the full
      development of potentiation, induced by high-frequency stimulation under the
      blocking agent for synaptosomal platelet-activating factor receptors (ginkolide
      B), at drug washout. However, potentiation directly induced by the group I
      glutamate metabotropic receptor agonist, (R,S)-3,5-dihydroxyphenylglycine, was
      reduced by ginkolide B. These findings suggest that platelet-activating factor,
      whether exogenous or released following potentiation induction, exerts its effect
      through presynaptic group I metabotropic glutamate receptors, mediating the
      increase of glutamate release. In addition, we found that this mechanism, which
      led to full potentiation through presynaptic group I metabotropic glutamate
      receptor activation, was inactivated soon after application of potentiation
      inducing stimulus. In fact, the long-lasting block of the platelet-activating
      factor and metabotropic glutamate receptors prevented the full potentiation
      development and the induced potentiation progressively declined to null.
      Moreover, ginkolide B, given when high-frequency-dependent potentiation was
      established, only reduced it within 5 min after potentiation induction. We
      conclude that to fully develop vestibular long-term potentiation requires
      presynaptic events. Platelet-activating factor, released after the activation of
      postsynaptic mechanisms which induce potentiation, is necessary for coupling
      postsynaptic and presynaptic phenomena, through the activation of group I
      metabotropic glutamate receptors, and its action lasts only for a short period.
      If this coupling does not occur, a full and long-lasting potentiation cannot
      develop.

PMID- 10579216
TI  - Activity of voltage-operated calcium channels in rat cerebellar granule neurons
      and neuronal survival.
AB  - Neuronal activity and Ca2+ channel activation play important roles in neuronal
      survival and development. In cerebellar granule neurons, the culture conditions
      can induce differential expression of various membrane receptor proteins. To test
      the hypothesis that culture conditions might affect the activity of voltage
      operated Ca2+ channels, the present study analysed the differences in Ca2+
      signalling between granule neurons grown in the presence of normal (5 mM) or high
      (25 mM) KCl. The Ca2+ transients evoked by 50 mM KCl developed similarly in both
      cultures, as a function of age. In contrast, when compared with neurons grown in
      25 mM KCl, a proportion of the neurons grown in normal KCl showed, between days
      in vitro 4 and 6, a higher Ca2+ transient in response to 12.5 mM KCl. These
      neurons were less sensitive to the effect of 10 microM nifedipine and,
      conversely, more sensitive to the effects of 10 microM omega-conotoxin MVIIC when
      stimulated with 50 mM KCl, indicating that they express preferentially, at this
      stage, the N- and/or Q-type Ca2+ channels. This period of maximal activity of the
      N/Q-type Ca2+ channels was associated with a significant increase in the rate of
      neuronal apoptosis. The present study also shows, by comparing the rates of
      neuronal apoptosis, that the long-term maintenance in 25 mM KCl appears to
      "synchronize" and sensitize the neuronal population to the apoptotic process.
      These results illustrate the differential effect the culture conditions can have
      on the expression and activity of Ca2+ channels, which, in turn, can modulate
      neuronal survival.

PMID- 10579217
TI  - Carnosine protects against excitotoxic cell death independently of effects on
      reactive oxygen species.
AB  - The role of carnosine, N-acetylcarnosine and homocarnosine as scavengers of
      reactive oxygen species and protectors against neuronal cell death secondary to
      excitotoxic concentrations of kainate and N-methyl-D-aspartate was studied using
      acutely dissociated cerebellar granule cell neurons and flow cytometry. We find
      that carnosine, N-acetylcarnosine and homocarnosine at physiological
      concentrations are all potent in suppressing fluorescence of 2',7'
      dichlorofluorescein, which reacts with intracellularly generated reactive oxygen
      species. However, only carnosine in the same concentration range was effective in
      preventing apoptotic neuronal cell death, studied using a combination of the DNA
      binding dye, propidium iodide, and a fluorescent derivative of the
      phosphatidylserine-binding dye, Annexin-V. Our results indicate that carnosine
      and related compounds are effective scavengers of reactive oxygen species
      generated by activation of ionotropic glutamate receptors, but that this action
      does not prevent excitotoxic cell death. Some other process which is sensitive to
      carnosine but not the related compounds is a critical factor in cell death. These
      observations indicate that at least in this system reactive oxygen species
      generation is not a major contributor to excitotoxic neuronal cell death.

PMID- 10579218
TI  - Physiological and ventral medullary surface activity during hypovolemia.
AB  - The objective was to determine ventral medullary surface responses to blood loss
      sufficient to induce shock. We examined changes in scattered light from rostral
      and intermediate areas of the ventral medullary surface in four intact, drug-free
      cats during acute hypovolemia. Scattered light images, collected during 660 and
      560 nm illumination to measure cellular activity and hemodynamic aspects,
      respectively, were digitized at 50 frames/s during baseline, and during
      withdrawal of 20-30% blood volume. Hypovolemia elicited a profound hypotension
      and eventual bradycardia. In all cats, a modest increase in ventral medullary
      surface reflectance (activity decline) accompanied initial blood loss; as
      hypovolemia continued, and blood pressure declined, reflectance switched to a
      decline (activity increase), with the lowest reflectance occurring at maximal
      blood loss. Hypovolemia elicited multiple transient physiologic behaviors,
      including tachycardia, tachypnea, intermittent isolated and sustained bursts of
      enhanced inspiratory efforts, and extensor activation of the somatic musculature.
      The phasic physiological behaviors during hypovolemia were accompanied by partial
      recovery of medullary surface reflectance and blood pressure towards baseline
      values; however, reflectance continued to decrease as blood pressure
      progressively fell after these recovery efforts. Patterns of reflectance were not
      uniform over areas examined; isolated regions of enhanced or diminished
      reflectance appeared upon the overall images. Optical signals indicating
      hemodynamic changes followed the neural activity patterns, but not precisely.
      Regions within the ventral surface are responsive to hypovolemia, and to
      transient behaviors associated with momentary restoration of blood pressure;
      these ventral surface areas may assume essential roles in the systemic response
      to hypovolemic-induced shock.

PMID- 10579219
TI  - Hyperalgesia due to nerve injury: role of prostaglandins.
AB  - The hypothesis that prostaglandins contribute to hyperalgesia resulting from
      nerve injury was tested in rats in which the sciatic nerve was partially
      transected on one side. Subcutaneous injection of indomethacin (a classic
      inhibitor of cyclo-oxygenase) into the affected hindpaw relieved mechanical
      hyperalgesia for up to 10 days after injection. Subcutaneous injection of
      meloxicam or SC-58125 (selective inhibitors of cyclo-oxygenase-2) into the
      affected hindpaw also relieved mechanical hyperalgesia, but with a shorter time
      course. Subcutaneous injection of SC-19220 (an EP1 prostaglandin receptor
      blocker) into the affected hindpaw produced significant relief of mechanical and
      thermal hyperalgesia. Comparable injections into the contralateral paw or abdomen
      had no effect on mechanical or thermal hyperalgesia, suggesting that the effects
      we observed were local rather than systemic. We conclude that prostaglandins,
      probably prostaglandin E1 or E2, contribute to the peripheral mechanisms
      underlying hyperalgesia following nerve injury. These data provide further
      evidence that inflammatory mediators contribute to neuropathic pain, and may
      warrant further study of peripherally administered non-steroidal anti
      inflammatory drugs as a possible treatment for such pain in patients.

PMID- 10579220
TI  - Metabolic activity changes in the rat spinal cord during adjuvant monoarthritis.
AB  - The development of chronic pain is associated with activity-dependent plastic
      changes in neuronal structures in the peripheral and central nervous system. In
      order to investigate the time-dependent processing of afferent noxious stimuli in
      the spinal cord we employed the quantitative autoradiographic 2-deoxyglucose
      technique in a model of chronic monoarthritic pain in the rat. Spinal metabolic
      activity was determined at various time-points (two, four and 14 days) after the
      injection of complete Freund's adjuvant into the left tibiotarsal joint. In
      addition, the effect of acute noxious mechanical stimulation of the arthritic
      joint was investigated at 14 days of monoarthritis. Local glucose utilization was
      determined in lumbar segments L2-L5, ipsi- and contralateral to the inflamed
      hindpaw, and compared with saline-injected controls. In general, monoarthritic
      animals had bilaterally increased metabolic activity in all laminae of the spinal
      cord. Detailing the time-course showed that in rats with two days of
      monoarthritis metabolic activity was significantly increased to a similar extent
      on both sides of all spinal laminae. In contrast, at four days, glucose
      utilization in deep laminae of the dorsal horn (laminae V-VI), the central gray
      area (laminae X) and the ventral horn (laminae VII-IX) tended to return to
      control levels. At 14 days of monoarthritis, however, metabolic activity showed a
      further increase in all laminae of the spinal cord. This increase was more
      pronounced on the side ipsilateral to inflammation, reaching 65% above
      corresponding control levels in laminae V, VI. Animals with 14 days of
      monoarthritis which were subjected to mechanical noxious stimulation of the
      arthritic joint displayed clear behavioral signs of acute pain. Although in this
      group metabolic activity was above control levels, it was lower than in animals
      with 14 days of monoarthritis that were not additionally stimulated. The data
      show not only a general increase of spinal cord metabolic activity during the
      time-course of the development of a chronic pain state, but also show a region
      specific non-linear time profile. This may reflect the complexity of transducing
      and suppressive transmitter systems involved in the central processing of ongoing
      pain.

PMID- 10579222
TI  - Ciliary neurotrophic factor promotes the regrowth capacity but not the survival
      of intraorbitally axotomized retinal ganglion cells in adult hamsters.
AB  - Ciliary neurotrophic factor has recently been shown to promote the axonal
      regrowth of retinal ganglion cells into a peripheral nerve graft following an
      intracranial transection of the optic nerve (approximately 7 mm from the optic
      disc). It is unclear whether the enhancement of axonal regrowth by ciliary
      neurotrophic factor application correlates with the enhancement of survival of
      retinal ganglion cells and/or the up-regulation of expression of growth
      associated protein-43 messenger RNA in retinas. The present study evaluated the
      regenerative capacity of retinal ganglion cells following intraorbital
      transection of the optic nerve (approximately 1.5 mm from the optic disc) and the
      attachment of a peripheral nerve to the ocular stump of the optic nerve. In
      addition, we have determined the survival of retinal ganglion cells and the
      expression of growth-associated protein-43 messenger RNA in ciliary neurotrophic
      factor-treated retinas following optic nerve transection. The results showed that
      in the ciliary neurotrophic factor-treated retinas, the number of retinal
      ganglion cells which had regrown axons into a peripheral nerve is about four
      times more than the control. In the axotomized retinas, ciliary neurotrophic
      factor initiated sprouting of axon-like processes at 14 and 28 days post-axotomy
      and up-regulated the expression level of growth-associated protein-43 messenger
      RNA at 7, 14 and 28 days post-axotomy. However, ciliary neurotrophic factor did
      not prevent the death of axotomized retinal ganglion cells. We suggest that one
      possible mechanism for the axonal regeneration of axotomized retinal ganglion
      cells by ciliary neurotrophic factor could be mediated by the up-regulation of
      growth-associated protein-43 gene expression and not by increasing the pool of
      surviving retinal ganglion cells after axotomy.

PMID- 10579221
TI  - Supraspinal metabolic activity changes in the rat during adjuvant monoarthritis.
AB  - Pain is a multi-dimensional experience including sensory-discriminative and
      affective-motivational components. The attribution of such components to a
      corresponding cerebral neuronal substrate in the brain refers to conclusions
      drawn from electrical brain stimulation, lesion studies, topographic mappings and
      metabolic imaging. Increases in neuronal metabolic activity in supraspinal brain
      regions, suggested to be involved in the central processing of pain, have
      previously been shown in various animal studies. The present investigation is the
      first to describe supraspinal structures which show increased metabolic activity
      during ongoing monoarthritic pain at multiple time-points. Experimental chronic
      monoarthritis of a hindlimb induced by complete Freund's adjuvant is one of the
      most used models in studies of neuronal plasticity associated with chronic pain.
      Such animals show typical symptoms of hyperalgesia and allodynia for a prolonged
      period. Metabolic activity changes in supraspinal brain regions during
      monoarthritis were assessed using the quantitative [14C]-2deoxyglucose technique
      at two, four, 14 days of the disease and, furthermore, in a group of 14-day
      monoarthritic rats which were mechanically stimulated by repeated extensions of
      the inflamed joint. Local glucose utilization was determined ipsi- and
      contralateral to the arthritic hindpaw in more than 50 brain regions at various
      supraspinal levels, and compared with saline-injected controls. At two and 14
      days of monoarthritis significant bilateral increases in glucose utilization were
      seen in many brain structures, including brainstem, thalamic, limbic and cortical
      regions. Within the brainstem, animals with 14-day monoarthritis showed a higher
      number of regions with increased metabolic activity compared with two days. No
      differences between ipsi- and contralateral sides were detected in any of the
      experimental groups. Average increases ranged from 20 to 40% compared with
      controls and maximum values were detected in specific brain regions, such as the
      anterior pretectal nucleus, the anterior cingulate cortex and the nucleus
      accumbens. Interestingly, at four days of monoarthritis, the glucose utilization
      values were in the control range in almost all regions studied. Moreover, in
      monoarthritic rats receiving an additional noxious mechanical stimulation, the
      rates of glucose utilization were also comparable to controls in all brain areas
      investigated. Such patterns of brain metabolic activity agreed with concomitant
      changes in the lumbar spinal cord, described in the accompanying report. The
      present data show that a large array of supraspinal structures displays elevated
      metabolic activity during painful monoarthritis, with a non-linear profile for
      the time-points investigated. This observation most probably reflects mechanisms
      of transmission and modulation of nociceptive input arising from the
      monoarthritis and accompanying its development.

PMID- 10579223
TI  - In vivo regulation of glial cell line-derived neurotrophic factor-inducible
      transcription factor by kainic acid.
AB  - A putative transcription factor induced in vitro by glial cell line-derived
      neurotrophic factor (GDNF) and transforming growth factor-beta was recently
      cloned and characterized [Yajima S. et al. (1997) J. Neurosci. 17, 8657-8666].
      The messenger RNA of this protein, termed murine GDNF-inducible transcription
      factor (mGIF, hereafter referred to as GIF), is localized within cortical and
      hippocampal regions of brain, suggesting that GIF might be regulated by
      perturbations of these brain regions. In an effort to learn more about the role
      of GIF in vivo, we examined GIF messenger RNA in the brains of rats treated with
      the glutamatergic agonist kainic acid. This treatment is known to induce seizures
      and alter the messenger RNA expression of several growth factors, including GDNF,
      in several brain regions. Rats were given intraperitoneal saline (1 ml/kg) or
      kainic acid (15 mg/kg) and were killed at various time-points for in situ
      hybridization of brain sections with a GIF messenger RNA riboprobe. In saline
      treated rats, GIF messenger RNA was present at low levels in cerebral cortex,
      hippocampus and hippocampal remnants such as the taenia tecta. Kainic acid
      treatment induced robust increases in GIF messenger RNA in several brain regions,
      including cerebral cortex, hippocampus, caudate-putamen, nucleus accumbens, and
      several nuclei of the amygdala and hypothalamus. Most brain regions showed the
      greatest increase in GIF messenger RNA 4-6 h after kainic acid administration and
      a return towards normal levels at 48 h. The CA3 region of hippocampus, however,
      showed a more rapid increase in GIF messenger RNA that was also evident 48 h
      after kainic acid administration. These results demonstrate that GIF messenger
      RNA can be regulated in vivo, and that this novel factor warrants further study
      as a central mediator of GDNF and perhaps other neurotrophic factors.

PMID- 10579224
TI  - Characterization of CArG-binding protein A initially identified by differential
      display.
AB  - While investigating differences in the pattern of gene expression in functionally
      distinct areas of the rat caudate-putamen employing differential display, we
      identified a gene that is highly enriched in tissue adjacent to the lateral
      ventricle. To characterize the gene, a complementary DNA containing the complete
      coding sequence was obtained and sequenced. In addition, radiolabelled DNA and
      riboprobes were generated to examine the expression levels and anatomical
      distribution of the identified gene in the brain. The sequencing data suggests
      that the identified gene is a member of the heterogeneous nuclear
      ribonucleoprotein family and likely represents the rat homolog of CArG-binding
      protein A initially isolated from mouse C2 myogenic cells. CArG-binding protein A
      is widely distributed and moderately expressed in the rat brain and present
      within both neurons and astrocytes. Since the CArG box motif forms the core of
      the serum response element and the serum response element is involved in
      immediate early gene regulation, the expression level of CArG-binding protein A
      was examined following treatment of PC12 cells with nerve growth factor and
      correlated with changes in c-fos and zif268 expression. The results show that
      CArG-binding protein A is up-regulated following nerve growth factor treatment
      and that the up-regulation of CArG-binding protein A can be correlated with the
      down-regulation of c-fos and zif268. The results of the current study leads us to
      suggest that CArG-binding protein A may be involved in brain development and the
      regulation of the serum response element.

PMID- 10579225
TI  - Mu and kappa1 opioid-stimulated [35S]guanylyl-5'-O-(gamma-thio)-triphosphate
      binding in cynomolgus monkey brain.
AB  - Agonist-stimulated [35S]GTPgammaS binding allows the visualization of receptor
      activated G-proteins, thus revealing the anatomical localization of functional
      receptor activity. In the present study, agonist-stimulated [35S]GTPgammaS
      binding was used to demonstrate mu and kappa1 opioid-stimulated [35S]GTPgammaS
      binding in tissue sections and membranes from cynomolgus monkey brain using DAMGO
      and U50,488H, respectively. Concentrations of agonists required to produce
      maximal stimulation of [35S]GTPgammaS binding were determined in membranes from
      the frontal poles of the brain. Receptor specificity was verified in both
      membranes and sections by inhibiting agonist-stimulated [35S]GTPgammaS binding
      with the appropriate antagonist. Mu opioid-stimulated [35S]GTPgammaS binding was
      high in areas including the amygdala, ventral striatum, caudate, putamen, medial
      thalamus and hypothalamus. Dense mu-stimulated [35S]GTPgammaS binding was also
      found in brainstem nuclei including the interpeduncular nucleus, parabrachial
      nucleus and nucleus of the solitary tract. Kappa1 opioid-stimulated
      [35S]GTPgammaS binding was high in limbic and association cortex, ventral
      striatum, caudate, putamen, globus pallidus, claustrum, amygdala, hypothalamus
      and substantia nigra. These results demonstrate the applicability of
      [35S]GTPgammaS autoradiography to examine receptor-activated G-proteins in the
      primate brain and reveal functional mu and kappa1 opioid receptor activity that
      may contribute to the reported central nervous system effects of opiates.

PMID- 10579226
TI  - Distribution of Fos-like immunoreactivity in guinea-pig brain following
      administration of the neurokinin-1 receptor agonist, [SAR9,MET(O2)11]substance P.
AB  - The tachykinins are a family of peptides with putative neurotransmitter roles in
      the nervous system. They mediate their effects via neurokinin-1, neurokinin-2 and
      neurokinin-3 receptors. There has been increasing interest in the therapeutic
      application of the tachykinin neurokinin-1 receptor antagonists in the treatment
      of pain and emesis, and more recently in depression. However, the central role of
      neurokinin-1 receptors is not well understood. The aims of the present study were
      to determine the behavioural responses of guinea-pigs, and the distribution of
      Fos-like immunoreactivity in the guinea-pig brain, following
      intracerebroventricular administration of the neurokinin-1 receptor-selective
      agonist, [Sar9,Met(O2)11]substance P. The effects of pretreatment with the
      neurokinin-1 receptor antagonist, SR 140333, were also investigated.
      Administration of [Sar9,Met(O2)11]substance P induced increased locomotor
      activity, as well as face washing, grooming and wet-dog shake behaviours, all of
      which were inhibited by the neurokinin-1 receptor antagonist, SR 140333,
      indicating the involvement of neurokinin-1 receptors. In order to localize the
      brain regions activated by [Sar9,Met(O2)11]substance P, the distribution of
      neurons expressing Fos-like immunoreactivity was examined.
      [Sar9,Met(O2)11]substance P induced increased Fos-like immunoreactivity in
      widespread areas, including the frontal cortex, hippocampus, amygdala, thalamus,
      hypothalamus, periaqueductal gray, area postrema and nucleus of the solitary
      tract. SR 140333 reduced Fos-like immunoreactivity induced by
      [Sar9,Met(O2)11]substance P in most areas. Thus, brain regions associated with
      emotion, sensation, learning and memory, autonomic regulation and emesis were
      activated by stimulation of neurokinin-1 receptors. The present data have added a
      functional domain to previous neurokinin-1 receptor localization studies by
      describing the extensive regions of the CNS that may be activated by stimulation
      of these receptors, and the potential of neurokinin-1 receptor antagonists to
      inhibit activation of these regions.

PMID- 10579228
TI  - Pharyngeal pouch carcinoma: real or imaginary risks?
AB  - Pharyngeal pouch or Zenker's diverticulum presents to the otolaryngologist with
      symptoms of dysphagia. As supported by the published literature, the condition is
      more frequently seen in Northern Europe, especially the United Kingdom, than
      elsewhere in the world. The cause of the reported increased incidence in the
      United Kingdom is not known, but may be dietary. Surgical management is the
      treatment of choice and is directed at the cricopharyngeus muscle by either an
      external or an internal approach. There is a real risk of carcinoma or carcinoma
      in situ developing in a treated or untreated pharyngeal pouch. Excision of the
      pouch sac is recommended in younger patients, less than 65 years, and in patients
      who have a large pouch. If endoscopic diverticulotomy is performed, then long
      term patient symptom follow-up is to be advocated.

PMID- 10579227
TI  - Complications of pediatric laryngotracheal reconstruction: prevention strategies.
AB  - A retrospective chart review was performed to quantify the postoperative
      complications and outcomes of 82 consecutive cases of laryngotracheal
      reconstruction (LTR) and cricotracheal resection (CTR) performed at a pediatric
      tertiary care hospital over the last 9 years. Six cases of respiratory syncytial
      virus (RSV) bronchiolitis and 8 cases of cervical pseudomonal wound abscess (PWA)
      were identified in a total of 12 patients. All of these infections occurred after
      single-stage LTR or CTR. Both RSV bronchiolitis and PWA were associated with
      significantly more unexpected days of intubation and admission to the intensive
      care unit, as well as higher rates of failure of LTR. Ossification of the cricoid
      cartilage, grade IV subglottic stenosis, and untreated gastroesophageal reflux
      disease (GERD) were also associated with restenosis. Trisomy 21 did not
      significantly influence the success rate of pediatric LTR. Both RSV bronchiolitis
      and PWA are potentially preventable complications of pediatric LTR and CTR. We
      propose strategies to prevent these infections. We also advocate the treatment of
      GERD during the healing phase of LTR.

PMID- 10579229
TI  - Identification of posterior cricoarytenoid motoneurons in the rat.
AB  - The posterior cricoarytenoid (PCA) muscle is the sole abductor of the larynx and
      is controlled by motoneurons located in the nucleus ambiguus. These motoneurons
      receive inputs from a variety of interneurons, including those that impart
      respiratory modulation, and are responsible for the phasic inspiratory activity
      of the PCA muscle. Identification of PCA motoneurons is therefore an essential
      initial step in understanding the mechanisms responsible for coordinated vocal
      cord abduction. We identified PCA motoneurons in the rat model by retrograde
      labeling, and following antidromic activation. A total of 194 neurons were
      identified by retrograde labeling with cholera toxin B subunit (CTB). Labeling
      was exclusively ipsilateral where the contralateral vagus and superior laryngeal
      nerves had been divided. The neurons were multipolar, with dimensions of 33.2 +/-
      6.4 microm (mean +/- standard deviation) in length and 22.4 +/- 3.4 microm in
      width. The neurons were located within a range of 0.6 to 2.4 mm caudal to the
      caudal pole of the facial nerve, 1.2 to 1.7 mm lateral to the midline, and 1.5 to
      2.3 mm deep to the dorsal surface of the medulla. The PCA motoneurons were
      antidromically activated by focal stimulation of the PCA muscle. The
      extracellular field was recorded in 5 rats, and the PCA motoneurons were found
      within a range of 0.8 to 1.7 mm caudal to the caudal pole of the facial nerve,
      1.5 to 2.0 mm lateral to the midline, and 1.9 to 2.4 mm deep to the dorsal
      surface of the medulla. The mean conduction velocity ranged from 37.0 +/- 5.8 to
      68.6 +/- 5.0 m/s. An extracellular antidromic field potential, which corresponds
      to the distribution of the PCA motoneuron pool demonstrated by retrograde
      labeling with CTB, can be reliably obtained in a rat model following focal PCA
      muscle stimulation.

PMID- 10579230
TI  - The otolaryngologist as a role model.
AB  - Throughout our daily interactions with medical students and residents, each of
      us, whether we like it or not, functions as a role model. Since role modeling is
      primarily a passive function - teaching by example - we may not be acutely aware
      of this role and its importance. In what respect is the concept of the role model
      important to otolaryngology-head and neck surgery? In addition to the function of
      specific training - teaching the trade - most of the literature on role modeling
      cites 2 major areas of significance: 1) influencing medical students' career
      choices and 2) facilitating socialization into the world of medicine with the
      establishment of an appropriate professional identity. This brief article reviews
      some of the current literature, catalogs those attributes that have been
      identified as those of excellent role models, and offers some thoughts as to what
      our specialty might consider in response to the challenges to medical education
      in the changing health care environment.

PMID- 10579231
TI  - Education in laryngology: rising to old challenges.
AB  - Education in laryngology has been a subject of interest at least since Louis
      Elsberg's address to the first meeting of the American Laryngological Association
      in 1879. Remarkable scientific, technological, and clinical advances during the
      1980s and 1990s have elevated the standard of laryngological care. It is
      essential for training programs to promulgate these important advances through
      well-planned, comprehensive curricula. Such training should also foster an
      appreciation for the kinds of creative thought, interdisciplinary collaboration,
      and imaginative clinical practice that have been responsible for many of the
      recent dramatic advances in the field of laryngology.

PMID- 10579232
TI  - Inhibition of subglottic stenosis with mitomycin-C in the canine model.
AB  - The objective of this randomized, prospective study was to study the efficacy of
      topical mitomycin-C in the inhibition of subglottic stenosis in a canine model.
      Subglottic stenosis was elicited with the carbon dioxide laser in 10 mongrel
      dogs. Radial incision and serial dilation of the subglottic airway were then
      carried out. The animals were randomized to receive a topical solution of 1%
      mitomycin-C to the dilated area for a 5-minute duration or no further treatment.
      Weekly direct microlaryngoscopy and photodocumentation were performed during the
      6-week study. Airway distress developed in 4 of the 5 control dogs, requiring
      early sacrifice, while all treatment group animals survived the duration of the
      study (p < or = .006). Morphometric analysis of the subglottic photographs
      confirmed a greater than 100% increase in the percentage of relative airway at
      sacrifice in the treatment group (p < or = .049). A statistically significant (p
      < or = .015) decrease in collagen formation in the subglottic scar of dogs
      treated with topical mitomycin-C was documented. Mitomycin-C favorably altered
      the clinical progression of subglottic stenosis, improved quantified airway
      patency, and reduced the amount of subglottic collagen formation in the canine
      model.

PMID- 10579233
TI  - Videolaryngostroboscopy following vertical partial laryngectomy.
AB  - Phonation after partial laryngeal ablative surgery has not often been examined.
      Videolaryngostroboscopic recordings made after vertical partial laryngectomy
      (VPL) were retrospectively reviewed and correlated with patient historical and
      operative factors. Among VPL patients (n = 42), the most common site of vibration
      during phonation was the contralateral false vocal fold (17/42 patients or
      40.5%), followed by the contralateral arytenoid mucosa (10/42 or 23.8%) and the
      contralateral true vocal fold (8/42 patients or 19.0%). There was no overall
      difference in vocal quality judgment with respect to site of vibration (ANOVA, p
      = .373). Vocal quality scores were similar with use of the pyriform mucosal flap
      versus other reconstructive methods (Student's t-test, p = .568). This study
      highlights the fact that reconstruction of a new vibratory source after VPL is
      important for voice production. Because VPL patients infrequently demonstrated
      true vocal fold vibration, alternative sites (ie, false vocal fold, arytenoid
      mucosa) must be considered as new phonatory sources after VPL.

PMID- 10579234
TI  - Electron microscopic and immunohistochemical investigation of Reinke's edema.
AB  - Examination was made of the vocal fold mucosa of Reinke's edema
      immunohistochemically and electron microscopically, with special attention to
      blood vessels in Reinke's space (RS). Ten surgical specimens of Reinke's edema
      were used, and the results obtained are summarized as follows. There were
      subepithelial vascularization and many dilated vessels in RS. The vessels had
      thin endothelium with many fenestrae, many vesicles, and a thickened basement
      membrane. Plasma exuded from the capillaries into surrounding tissue via
      fenestrae. These findings demonstrate increased permeability of the vessels. The
      vascular walls were thin, with few pericytes. The pericytes were situated away
      from the endothelial cells. Some endothelial cells and pericytes had degenerated,
      and vessel occlusion was apparent in some cases. These findings indicate the
      vessels had become fragile. Interstitial cells and/or inflammatory cells in RS
      showed stained cytoplasm with vascular endothelial growth factor. This growth
      factor may possibly enhance capillary permeability and form fragile vessels in
      RS. Fragility and alteration in permeability of the vessels are presumed to cause
      edema of RS, which may progress to Reinke's edema.

PMID- 10579235
TI  - Characterization of human papillomavirus in airway papillomas by histologic and
      biochemical analysis.
AB  - The role of human papillomavirus (HPV) in airway papillomas has been well defined
      in recent literature. The chronicity and recurrence of papillomas has been
      postulated to be a result of residual viral genome in tissue treated with
      standard laser techniques. Thirteen patients with airway papillomas were selected
      for study with polymerase chain reaction (PCR) methods to detect viral DNA.
      Specimens taken prior to laser therapy and specimens taken at laser margins were
      consistently positive for HPV DNA by PCR. The HPV DNA is apparently present in
      tissues after macroscopic disease has been ablated by laser techniques.
      Histologic analysis of laser biopsies demonstrated fragments of squamous
      epithelium with cytologic features of HPV infection. Laser treatment is
      ineffective in eradicating HPV-infected tissues from airway papillomas, and this
      finding supports the notion that recurrence is a product of HPV incorporated into
      tissue not ablated by laser irradiation. Specific methods, results, and clinical
      correlation will be discussed.

PMID- 10579237
TI  - Local corticosteroid treatment of caustic injuries of the esophagus. A
      preliminary report.
AB  - So far, no therapy has been shown to reduce the incidence of strictures in the
      esophagus after ingestion of caustic agents. Two patients with pronounced caustic
      ingestion injuries were treated locally with solutions of corticosteroids
      normally used for inhalation therapy in lung diseases. Serious strictures did not
      appear, and their swallowing returned to normal. Further studies are needed.

PMID- 10579236
TI  - Effect of pharmacological sympathectomy on osteoclastic activity in the
      gerbilline auditory bulla in vivo.
AB  - Bone destruction causes hearing loss in various middle ear disorders. The
      mechanisms of such pathological remodeling are unknown. Unilateral surgical
      sympathectomy is known to induce resorption within mandibular and auditory bulla
      bone. Explanation of the cause of this effect, however, may be confounded by
      hemodynamic changes induced by hemicranial sympathectomy and by uncertainty as to
      the neuroanatomical origins of sympathetic fibers. In this study, gerbils were
      infused with guanethidine sulfate (GS) to evaluate the in vivo effects of
      systemic sympatholysis on auditory bone remodeling. In addition, to discount any
      direct osteolytic effect, GS was assessed of its bone resorbing activity in vitro
      by means of the calvarial calcium release assay. The in vitro study revealed GS
      to have no effect on calcium release. The in vivo study revealed GS to increase
      both the osteoclast surface and number. Guanethidine-induced sympathectomy has
      thus been shown to increase remodeling in gerbilline auditory bone, while no
      direct osteolytic effect could be measured in vitro.

PMID- 10579238
TI  - Developmental changes in the antrum of a child with chronic maxillary
      atelectasis.

PMID- 10579239
TI  - Review of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman
      disease) of head and neck.
AB  - The entity known as sinus histiocytosis with massive lymphadenopathy (SHML), or
      Rosai-Dorfman disease (RD disease), is an uncommon benign proliferation of
      hematopoietic and fibrous tissue that often presents in the head and neck region.
      Its initial manifestations most often include a roughly symmetric, painless,
      bilateral cervical adenopathy, although extranodal disease may develop in a
      minority of patients. The key histologic feature of SHML is the presence of
      various numbers of large, pale histiocytic cells that contain within their
      cellular borders apparently engulfed lymphocytes ("emperipolesis"); these
      distinctive large, pale cells - RD cells - are S-100 protein-positive by
      immunostaining and so differ from ordinary histiocytes. Despite its sometimes
      impressive clinical presentation, SHML is a benign and self-limited disease,
      whose treatment is aimed largely at controlling its local manifestations (most
      often by surgical therapy). The microscopic differential diagnosis, particularly
      in extranodal disease, is at times challenging and can include Langerhans' cell
      histiocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, metastatic carcinoma,
      and metastatic malignant melanoma.

PMID- 10579240
TI  - Role of dopamine receptors and the changes of the tyrosine hydroxylase mRNA in
      acupuncture analgesia in rats.
AB  - Previous studies have shown that dopamine (DA) is involved in electroacupuncture
      analgesia (EAA). L-tetrahydropalmatine (l-THP), a DA receptor antagonist was
      proved to potentiate EAA in both laboratory research and clinical practice. In
      the present study SK&F-38393 and quinpirole (Qui), selective agonists of D1 or D2
      receptors respectively were injected into nucleus (N.) accumbens of rats to
      investigate the roles of D1 and D2 receptors in the potentiation of EAA induced
      by l-THP. The injection of D1 agonist SK&F-38393 (5 microg or 10 microg)
      attenuated the potentiation of EAA induced by l-THP, 10 microg SK&F-38393
      attenuated EAA as well, while the injection of D2 agonist Qui (10 microg or 20
      microg) had no effect on EAA and the potentiation of EAA induced by l-THP. DA
      release was shown to increase in EAA in previous work, however, whether the
      synthesis of DA was influenced is still unknown. In the present study, dot blot
      technique was applied to observe the effect of noxious stimulation or
      electroacupuncture on the level of tyrosine hydroxylase (TH) mRNA in rat brain.
      Noxious electric stimulation was found to elevate the TH mRNA level in substantia
      nigra (SN) and hypothalamus, while electro-acupuncture attenuated the effect of
      noxious stimulation on TH mRNA. The results indicate that D1 but not D2 receptor
      in N. accumbens plays an important role in EAA. EA might regulate the
      biosynthesis of DA by altering the TH gene transcription.

PMID- 10579241
TI  - Effects of Kampo formulations (Chinese herbal medicine traditionally used in
      Japan) on event-related electric potentials.
AB  - Contingent negative variation (CNV) is a brain function test of the central
      nervous system in reference to attention, will preparation and motivation. We
      compared the neuropharmacological effects of 6 main Kampo formulations (1. Mao
      to: MA HUANG TANG; 2. Shimbu-to: ZHEN WU TANG; 3. Ninjin-to: REN SHEN TANG; 4.
      Shigyaku-san: SI NI SAN; 5. Keishi-to: GUI ZHI TANG; and 6. Shimotsu-to: SI WU
      TANG) on CNV. Mao-to induced significant decrease of CNV in 90 minutes after oral
      administration. Shimbu-to showed a tendency to increase CNV in 90 minutes after
      oral administration. Shimotsu-to also induced a transient tendency to increase
      CNV in 60 minutes after oral administration. Keishi-to showed a decrease of CNV
      in the early stage of the experiment, while Ninjin-to and Shigyaku-san showed no
      changes of CNV. From these, it may be concluded that Mao-to and Keishi-to induce
      sedation of brain function, but Shimbu-to and Shimotsu-to show activation, while
      Ninjin-to and Shigyaku-san show no changes of brain function regarding CNV
      related brain function. Furthermore, the time courses of CNV changes were
      different within the same group (sedation or activation) of Kampo formulations.

PMID- 10579242
TI  - A review of current research in microwave resonance therapy: novel opportunities
      in medical treatment.
AB  - Microwave Resonance Therapy (MRT) is a novel medical treatment, which represents
      a synthesis of the ancient Chinese traditional knowledge in medicine
      (acupuncture) and recent breakthroughs in biophysics. By affecting the
      appropriate acupuncture points by the generation of high frequency microwaves (52
      78 GHz), remarkable clinical results are being achieved in surgery, orthopedic
      and traumatology, cardiovascular disorders, urology, gynecology, dermatology,
      gastroenterology, pulmology, upper respiratory tract, cardiology, neurology, and
      oncology during the last decade--the MRT being contraindicated only in the cases
      of acute pain in the abdomen demanding an operation, pregnancy, and menstruation
      cycle. In this paper the quantum-like macroscopic biophysical basis of the MRT
      and its technical details are elaborated too, offering a new insight in the
      mechanisms of the assembling gap junction hemichannels upon the internal
      microwave (MW) electromagnetic field spatio-temporal maximums at the temporary
      position of the acupuncture system, and, hence, the very biophysical nature of
      the temporary psychosomatic health or disease. The quantum-like coherent
      characteristics of the MRT (sharply-resonant sensory response of the disordered
      organism, extremely low-intensity and low-energy non-thermal biologically
      efficient MW radiation, and negligible MW energy losses down acupuncture
      meridians) might be viewed as a consequence of the existence of biological
      nonlocal selfconsistent macroscopic quantum potentials, which can give rise to
      nonlinear coherent EM MW long-range maser-like excitations of biological
      nonlinear absorption medium with the cells as active centers--with acupuncture
      meridians related to eigenfrequencies and spatio-temporal eigenwaves
      distributions of every individual biological quantum system. This suggests that a
      healthy condition might be considered as an absolute minimum (ground state) of
      the nonlocal selfconsistent macroscopic quantum potential of the organism. Some
      disorders of an acupuncture system correspond to higher minimums of the (spatio
      temporally changeable) potential hypersurface in energy-configuration space,
      which possibly explains the higher sensory responses of the more excited (more
      disordered) acupuncture system and the poor MRT sensory response of the healthy
      acupuncture system being already in the ground state. Such a picture also
      supports the EM/ionic "optical" ultralowfrequency modulated MW quantum
      holographic neural network-like function of the acupuncture system (similar to
      complex-valued oscillatory holographic Hopfield-like neural networks), and its
      essential relation to consciousness, as strongly suggested from biophysical
      modeling of altered states of consciousness. Finally, the ionic aspects of the
      acupuncture system are considered, too, as well as the relation of ultradian
      (approximately 2-hour) nasal rhythm recognized in Indian swara yoga and circadian
      (approximately 24-hour) acupuncture rhythm recognized in Chinese traditional
      medicine, and their significance for maintaining the ionic balance within
      acupuncture system, as related to overall health.

PMID- 10579243
TI  - Effects of acupuncture on peripheral T lymphocyte subpopulation and amounts of
      cerebral catecholamines in mice.
AB  - The aim of this study was to investigate the effects of acupuncture on peripheral
      lymphocyte subpopulations and cerebral catecholamines. In order to examine the
      effects of acupuncture, two experiments were performed. Experiment 1: Eighteen
      female mice (strain; C57BL/6) at the age of 7 weeks were divided three groups,
      (a) sham operated (control; n=6), (b) ovariectomized (OVX; n=6), and (c)
      ovariectomized and stimulated by subcutaneous needles on acupuncture point,
      Shenshu (BL23) at the both sides of the back for 20 days (OVX+Acu; n=6). These
      animals were sacrificed at 20 days after needle insertion, and the splenic
      lymphoid cells were examined by two-color flow cytometry, using monoclonal
      antibodies (mAb) to the cell surface antigens, CD3, CD4, CD8a and NK1.1 (CD56).
      In the ovariectomized (OVX) group, the peripheral CD4/CD8 ratio was significantly
      increased and the ratio of natural killer (NK) cells (CD3-NK1.1+; CD3 negative,
      NK1.1 positive) to T lymphocytes was decreased compared to the sham control
      group. In the ovariectomized with needle insertion (OVX+Acu) group, the CD4/CD8
      ratio was reduced, but the NK cells ratio was not changed compared to the OVX
      group. Experiment 2: To investigate the acute effects of subcutaneous needle
      insertion, male C57BL/6 mice (7 weeks old) were used (n=6, each group). The
      acupuncture points Shen-shu (BL23) on the backs of the male mice were also
      stimulated by subcutaneous needles for 3 and 7 days. As a result, the CD4/CD8
      ratio was significantly decreased at day 3 and day 7, compared to the control
      group. On the other hand the NK cells ratio and activated T-cells were increased
      at day 7. The mitogenic activities in the splenic lymphocytes were also increased
      by acupuncture stimulation at day 3. Catecholamine contents in the hippocampus
      were measured by high performance liquid chromatography with the electro-chemical
      detector (ECD-HPLC) method. No significant change was observed in either dopamine
      contents or norepinephrine; however, dopamine metabolite, homovanillic acid (HVA)
      and DOPAC (3,4-dihydroxyphenylacetic acid) were increased at day 3. The study
      suggests that acupuncture has effects on peripheral lymphocyte subpopulations and
      may modulate mitogenic activity. In addition, acupuncture may stimulate dopamine
      turnover.

PMID- 10579244
TI  - Is there a preferred technique for weaning the difficult-to-wean patient? A
      systematic review of the literature.
AB  - OBJECTIVE: To answer the following question: In difficult-to-wean patients, which
      of the three commonly used techniques of weaning (T-piece, synchronized
      intermittent mandatory ventilation, or pressure support ventilation) leads to the
      highest proportion of successfully weaned patients and the shortest weaning time?
      DATA SOURCES: Computerized literature searches in MEDLINE (1975-1996), Cinahl
      (1982-1996), and Healthplan (1985-1996), exploding all Mesh headings pertaining
      to Mechanical Ventilation and Weaning. Searches were restricted to the English
      language, adults, and humans. Personal files were hand searched, and references
      of selected articles were reviewed. STUDY SELECTION: a) POPULATION: Patients
      requiring a gradual weaning process from the ventilator (either requiring
      prolonged initial ventilation of >72 hrs or a failed trial of spontaneous
      breathing after >24 hrs of ventilation); b) INTERVENTIONS: At least two of the
      following three modes of weaning from mechanical ventilation must have been
      compared: T-piece, synchronized intermittent mandatory ventilation, or pressure
      support ventilation; c) OUTCOMES: At least one of the following: weaning time
      (time from initiation of weaning to extubation) or successful weaning rate
      (successfully off the ventilator for >48 hrs); and d) STUDY DESIGN: Controlled
      trial. DATA EXTRACTION: Two reviewers independently reviewed the articles and
      graded them according to their methodologic rigor. Data on the success of weaning
      and the time to wean were summarized for each study. DATA SYNTHESIS: The search
      strategy identified 667 potentially relevant studies; of these, 228 had weaning
      as their primary focus, and of these, 48 addressed modes of ventilation during
      weaning. Only 16 of these 48 studies had one of the specified outcomes, and only
      ten of these were controlled trials. Of the ten trials, only four fulfilled all
      our selection criteria. The results of the trials were conflicting, and there was
      heterogeneity among studies that precluded meaningful pooling of the results.
      CONCLUSIONS: There are few trials designed to determine the most effective mode
      of ventilation for weaning, and more work is required in this area. From the
      trials reviewed, we could not identify a superior weaning technique among the
      three most popular modes, T-piece, pressure support ventilation, or synchronized
      intermittent mandatory ventilation. However, it appears that synchronized
      intermittent mandatory ventilation may lead to a longer duration of the weaning
      process than either T-piece or pressure support ventilation. Finally, the manner
      in which the mode of weaning is applied may have a greater effect on the
      likelihood of weaning than the mode itself.

PMID- 10579245
TI  - Comparison of jugular venous oxygen saturation and brain tissue Po2 as monitors
      of cerebral ischemia after head injury.
AB  - OBJECTIVE: To compare the characteristics of jugular venous oxygen saturation
      (Sjvo2) and brain tissue Po2 (Pbto2) as monitors for cerebral ischemia after
      severe head injury. Sjvo2 has been useful as a monitor for cerebral ischemia, but
      it is limited by its inability to identify regional cerebral ischemia. Pbto2 may
      be superior to Sjvo2 for this purpose, because oxygenation in localized areas of
      the brain can be monitored. DESIGN: Sjvo2 and Pbto2 were successfully monitored
      in 58 patients with severe head injury. The changes in Sjvo2 and Pbto2 were
      compared during ischemic episodes. SETTING: Neurosurgical intensive care unit of
      a level I trauma center. MEASUREMENTS AND MAIN RESULTS: During the monitoring
      period, which averaged 90 hrs/patient, there were 54 episodes during which Sjvo2
      decreased to <50% and/or Pbto2 decreased to <8 torr. Two of these episodes were
      caused by an infarction in the area of the Po2 probe, leaving 52 episodes of
      global hypoxia/ischemia that were identified by one of the two monitors. The
      sensitivities of the two monitors for detecting ischemia, using the thresholds of
      50% and 8 torr for Sjvo2 and Pbto2, respectively, were similar. The Sjvo2
      catheter detected 69.7% of the episodes and the Pbto2 catheter detected 63.5% of
      the episodes. In most of the remaining episodes, both probes reflected a decrease
      in oxygenation, but not to levels below the defined thresholds. The major
      differences in the two measures of oxygenation included the following: a) Sjvo2
      more consistently reflected a reduction in oxygenation during hyperventilation;
      b) Pbto2 was affected more by changes in arterial Po2; and c) during severe
      global ischemia, Pbto2 decreased to 0 and remained at 0, whereas Sjvo2 initially
      decreased but then increased again as cerebral blood flow ceased, and the only
      blood in the jugular bulb was of extracerebral origin. CONCLUSIONS: The two
      monitors provide complimentary information, and neither monitor alone identifies
      all episodes of ischemia. The best strategy for using these monitors is to take
      advantage of the unique features of each monitor. Sjvo2 should be used as a
      monitor of global oxygenation; but Pbto2 should be used as a monitor of local
      oxygenation, ideally with the catheter placed in an area of the brain that is
      vulnerable to ischemia but that may be salvageable with appropriate treatment.

PMID- 10579246
TI  - Efficacy of recombinant human erythropoietin in the critically ill patient: a
      randomized, double-blind, placebo-controlled trial.
AB  - OBJECTIVE: To determine whether the administration of recombinant human
      erythropoietin (rHuEPO) to critically ill patients in the intensive care unit
      (ICU) would reduce the number of red blood cell (RBC) transfusions required.
      DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter
      trial. SETTING: ICUs at three academic tertiary care medical centers. PATIENTS: A
      total of 160 patients who were admitted to the ICU and met the eligibility
      criteria were enrolled in the study (80 into the rHuEPO group; 80 into the
      placebo group). INTERVENTIONS: Patients were randomized to receive either rHuEPO
      or placebo. The study drug (300 units/kg of rHuEPO or placebo) was administered
      by subcutaneous injection beginning ICU day 3 and continuing daily for a total of
      5 days (until ICU day 7). The subsequent dosing schedule was every other day to
      achieve a hematocrit (Hct) concentration of >38%. The study drug was given for a
      minimum of 2 wks or until ICU discharge (for subjects with ICU lengths of stay >2
      wks) up to a total of 6 wks (42 days) postrandomization. MEASUREMENTS AND MAIN
      RESULTS: The cumulative number of units of RBCs transfused was significantly less
      in the rHuEPO group than in the placebo group (p<.002, Kolmogorov-Smirnov test).
      The rHuEPO group was transfused with a total of 166 units of RBCs vs. 305 units
      of RBCs transfused in the placebo group. The final Hct concentration of the
      rHuEPO patients was significantly greater than the final Hct concentration of
      placebo patients (35.1+/-5.6 vs. 31.6+/-4.1; p<.01, respectively). A total of 45%
      of patients in the rHuEPO group received a blood transfusion between days 8 and
      42 or died before study day 42 compared with 55% of patients in the placebo group
      (relative risk, 0.8; 95% confidence interval, 0.6, 1.1). There were no
      significant differences between the two groups either in mortality or in the
      frequency of adverse events. CONCLUSIONS: The administration of rHuEPO to
      critically ill patients is effective in raising their Hct concentrations and in
      reducing the total number of units of RBCs they require.

PMID- 10579247
TI  - Outcomes of critically ill elderly patients: is high-dependency care for
      geriatric patients worthwhile?
AB  - OBJECTIVES: To study the outcomes of elderly patients in a high-dependency care
      unit and to evaluate the costs and benefits of a geriatric high-dependency unit
      (GHDU). DESIGN: Prospective data collection and analysis. SETTING: Geriatric high
      dependency unit. PATIENTS: One hundred fifty patients > or =70 yrs of age who had
      been admitted to the GHDU over a 10-month period were investigated during their
      treatment and rehabilitation. MEASUREMENT AND MAIN RESULTS: The patients' Acute
      Physiology and Chronic Health Evaluation (APACHE) II scores and Simplified Acute
      Physiology Scores (SAPS) were recorded. The APACHE II scores and SAPSs provided a
      close correlation with the patients' mortality (correlation coefficients were
      0.97 and 0.92, respectively). The SAPS proved to have a better linear
      relationship with the elderly patients' mortality in comparison with APACHE II
      scores. Most of the elderly patients included in the study were suffering from
      multiple premorbid medical problems. Overall, the mortality rate up to 1 month
      after discharge from the hospital was 48%. For patients ranging in age from 70 to
      84 yrs, the 1-month mortality was 39.6%; however, for patients > or =85 yrs of
      age, the 1-month mortality was 68.1%. The mortality ratio was 0.96 (for all
      patients), 0.88 (for those ages 70-84 yrs), and 1.05 (for those age 85 yrs and
      above). For patients with nil organ system failure, the mortality rate was 32%.
      For patients with one organ system failure, the mortality increased to 48%. For
      patients with two organ system failures, the mortality rate was 86%. Survival for
      patients with three or more organ system failures was unprecedented. Survivors
      and nonsurvivors were compared. Three poor-prognosis groups were identified:
      group 1, patients who had received preadmission cardiopulmonary resuscitation;
      group 2, patients with a recent history of malignant diseases; and group 3,
      patients who had been mechanically ventilated. All three groups had a
      significantly higher mortality than those without these factors (p<.05). Patients
      in the 85 yrs and above group had a significantly higher mortality rate than
      those in the 70- to 84-yr age group (p<.05). Patients with SAPS and APACHE II
      scores >20 and >30, respectively, had a poor prognosis. The geriatric outcome
      scoring system (GOSS) was used as the functional outcome test for the survivors.
      The GOSS has three components: activities of daily living, mobility status, and
      social condition. At 1 month after discharge, 66.7% of the survivors returned to
      their premorbid activities of daily living abilities, 79.5% maintained their
      mobility status, and 91.7% remained at the same social environment. No survivors
      deteriorated more than one grade in any of the three components measured by the
      GOSS. The severity-of-illness scores, percentage of mechanical ventilation
      utilization, mortality rate, length of GHDU stay, and total hospital stay were
      comparable with those of other intensive care units (ICUs). The cost of 1 GHDU
      bed-day was equivalent to 24% of 1 ICU bed-day. CONCLUSION: The prognostic
      information that we gathered from an unselected group of critically ill elderly
      patients is useful. The GHDU achieved treatment results similar to those achieved
      by an ICU and is therefore seen as an innovative way of treating critically ill
      elderly patients. High-dependency care for the elderly patient is worthwhile.

PMID- 10579248
TI  - Exploring intermittent transcutaneous CO2 monitoring.
AB  - OBJECTIVE: To explore the accuracy of a continuous transcutaneous CO2 (T(CCO2))
      monitor, used in an intermittent rather than a continuous fashion, to obtain
      quick (<5 mins) CO2 readings. DESIGN: Prospective study. SETTING: An urban
      pediatric intensive care unit in a university teaching hospital. PATIENTS: A
      convenience sample of pediatric patients with indwelling arterial catheters.
      INTERVENTION: Transcutaneous monitoring was done simultaneous with arterial blood
      gas monitoring. MEASUREMENTS AND MAIN RESULTS: There were 49 simultaneous
      readings on 19 patients, age 5 days to 16 years, with 13 different diagnoses. The
      T(CCO2) was related to the PCO2 by a Pearson product coefficient of 0.79
      (p<.0005), with a mean difference of 1.94 (T(CCO2)>P(CO2) and 95% confidence
      interval of -0.12 to 4.07. The scatterplot produces a regression line
      characterized by the following equation: PCO2 = (T(CCO2)x1.05)-4.08. CONCLUSIONS:
      Further study to evaluate intermittent TCCO2 as a practical clinical variable is
      warranted. This study should encourage refinement of the technology to be more
      accurate for this use.

PMID- 10579249
TI  - A prospective study of the use of a dobutamine stress test to identify outcome in
      patients with sepsis, severe sepsis, or septic shock.
AB  - OBJECTIVE: To more clearly define the relationship between an oxygen flux test,
      oxygen supply dependency, and outcome in patients with sepsis, severe sepsis, or
      septic shock. DESIGN: Prospective, interventional clinical trial. SETTING: A
      teaching hospital general intensive care unit in London, UK. PATIENTS: A total of
      36 patients with sepsis, severe sepsis, or septic shock were studied during a 10
      month period. INTERVENTIONS: After resuscitation, patients were given an
      intravenous infusion of dobutamine at 10 microg/kg/min for 1 hr. Cardiac and
      respiratory variables were measured before the infusion and then while the
      infusion was in progress. Any patient who was able to increase his or her oxygen
      consumption by >15% was designated a responder to the test. MEASUREMENTS AND MAIN
      RESULTS: Hemodynamic, oxygen transport, and lactate measurements were made at
      baseline and after 1 hr of the dobutamine infusion. All patients were then
      followed up until hospital discharge. Responders to this test had a hospital
      mortality of 14%, whereas nonresponders had a mortality of 91% (p<.01). The
      responders were characterized by being younger (p<.05), having higher Acute
      Physiology and Chronic Health Evaluation III scores (p<.05), and having a greater
      requirement for inotropic support (p<.05). After the test, the responders had
      significantly higher oxygen delivery (p<.01) and oxygen consumption (p<.05) than
      the nonresponders, as well as a significantly greater temperature increase as a
      result of the infusion (p<.05). The nonresponders were unable to increase either
      oxygen delivery or oxygen consumption to the dobutamine. This test was highly
      predictive of outcome (p<.0001). The identification of an increase in both oxygen
      delivery and oxygen consumption (oxygen supply dependency) was not associated
      with a poor outcome. CONCLUSION: A dobutamine oxygen flux test provides evidence
      of the intrinsic function of cells. The inability of these cells to increase
      oxidative metabolism during sepsis, as indicated by the dobutamine test, is
      associated with a high mortality.

PMID- 10579250
TI  - Acute respiratory distress syndrome: frequency, clinical course, and costs of
      care.
AB  - OBJECTIVE: To define the occurrence rate of acute respiratory distress syndrome
      (ARDS) using established criteria in a well-defined general patient population,
      to study the clinical course of ARDS when patients were ventilated using a "lung
      protective" strategy, and to define the total costs of care. DESIGN: A 3-yr (1993
      through 1995) retrospective descriptive analysis of all patients with ARDS
      treated in Kuopio University Hospital. SETTING: Intensive care unit in the
      university hospital. PATIENTS: Fifty-nine patients fulfilled the definition of
      ARDS: Pao2/Fio2 <200 mm Hg (33.3 kPa) during mechanical ventilation and bilateral
      infiltrates on chest radiograph. INTERVENTIONS: None. MEASUREMENTS AND MAIN
      RESULTS: With a patient data management system, the day-by-day data of
      hemodynamics, ventilation, respiratory mechanics, gas exchange, and organ
      failures were collected during the period that Pao2/Fio2 ratio was <200 mm Hg
      (33.3 kPa). The frequency of ARDS was 4.9 cases/100,000 inhabitants/yr. Pneumonia
      and sepsis were the most common causes of ARDS. Mean age was 43+/-2 yrs. At the
      time of lowest Pao2/Fio2, the nonsurvivors had lower arterial and venous oxygen
      saturations and higher arterial lactate than survivors, whereas there were no
      differences between the groups in other parameters. Multiple organ dysfunction
      preceded the worst oxygenation in both the survivors and nonsurvivors. The
      intensive care mortality was 37%; hospital mortality and mortality after a
      minimum 8 months of follow-up was 42%. The most frequent cause of death was
      multiple organ failure. The effective costs of intensive care per survivor were
      US $73,000. CONCLUSIONS: The outcome of ARDS is unpredictable at the time of
      onset and also at the time of the worst oxygenation. Keeping the inspiratory
      pressures low (30-35 cm H2O [2.94 to 3.43 kPa]) reduces the frequency of
      pneumothorax, and might lower the mortality. Most patients are young, and
      therefore the costs per saved year of life are low.

PMID- 10579251
TI  - Intermittent prone positioning in the treatment of severe and moderate
      posttraumatic lung injury.
AB  - OBJECTIVE: Severe posttraumatic lung injury is characterized by impairment of gas
      exchange and pulmonary densities. The influence of intermittent prone positioning
      on pulmonary gas exchange and parenchymal densities was investigated
      prospectively in patients with pulmonary injury after multiple trauma with blunt
      chest trauma. SETTING: A six-bed trauma intensive care unit in a university
      hospital. DESIGN: Prospective, descriptive study. PATIENTS: Twenty-two
      consecutive patients with pulmonary injury after multiple trauma with blunt chest
      trauma and acute lung injury (n = 11) or severe acute respiratory distress
      syndrome (ARDS) (n = 11) according to the definitions of the consensus conference
      on ARDS. INTERVENTIONS: Pulmonary densities were calculated planimetrically from
      computed tomographic scans of the chest before the first and after the last cycle
      of prone positioning. Indications for prone positioning were a) mechanical
      ventilation with FIO2 >0.5 at positive end-expiratory pressure >10 cm H2O for >24
      hrs; or b) pulmonary densities in two or more quadrants being constant or
      increasing within 48 hrs. Arterial blood gas analysis was performed every 2 hrs.
      Intrapulmonary right-to-left shunt (Qs/Qt) and alveolar-arterial PO2 difference
      were calculated 2 hrs after the beginning and end of every prone and supine
      cycle, respectively. Patients were ventilated in the prone position for 8 hrs
      each day. MEASUREMENTS AND MAIN RESULTS: Every single posture change from the
      supine to the prone position resulted in a significant average increase in the
      oxygenation index of 28+/-8 torr (3.7+/-1.1 kPa) (p<.0001). There was a
      significant improvement in oxygenation (4.3+/-0.8 torr [0.57+/-0.11 kPa]) with
      time between two consecutive measurements in the prone as well as the supine
      position (p<.0001). Alveolar-arterial PO2 difference and Qs/Qt showed a
      significant decrease of 25+/-7 torr (3.3+/-0.9 kPa) and 1.1+/-0.46%,
      respectively, for every cycle of prone positioning. Statistical analysis revealed
      no significant alteration of gas exchange within every prone and supine cycle.
      Total static lung compliance improved significantly over time (p<.001). However,
      ventilation of patients in the prone position demonstrated a mean decrease in
      compliance of 2.1+/-0.72 mL/cm H2O. The response to prone positioning was similar
      in patients with ARDS and acute lung injury and revealed no significant
      difference. In both groups, the course of the oxygenation index and Qs/Qt over
      time was almost parallel. Posture changes were continued for 9.0+/-1.1 days. The
      oxygenation index showed an overall increase of 129+/-20 torr (17.2+/-2.7 kPa)
      from baseline supine at the end of prone positioning (p<.0001). Pulmonary
      densities were reduced significantly from 31.1+/-2.5% to 3.8+/-0.81%, Qs/Qt was
      reduced from 24.9+/-1.5% to 11.7+/-0.32%, and FIO2 was reduced from 0.43+/-0.04
      to 0.26+/-0.02 (p<.01). Gas exchange improved in all patients, and no patient
      died immediately as a result of respiratory failure. CONCLUSION: Repeated prone
      positioning recruits collapsed lung tissue and improves gas exchange in trauma
      patients with blunt chest trauma and severe ARDS as well as in trauma patients
      with acute lung injury.

PMID- 10579252
TI  - Hepatic and splanchnic oxygenation during liver transplantation.
AB  - OBJECTIVE: To evaluate hepatic and splanchnic oxygenation during liver
      transplantation. DESIGN: Prospective study. SETTING: University hospital.
      PATIENTS: Ten adult patients undergoing liver transplantation. INTERVENTIONS:
      Standardized surgery and anesthesia without venovenous bypass. MEASUREMENTS AND
      MAIN RESULTS: Hepatic oxygenation was assessed by analyzing oxygen tension,
      oxygen saturation, and lactate concentration in hepatic venous blood. Splanchnic
      oxygenation was assessed by analyzing oxygen tension, oxygen saturation, and
      lactate concentration in portal venous blood and by gastric tonometry. Before
      reperfusion, the grafts were flushed with 1000 mL of acetated Ringer's solution
      and 400 mL of portal venous blood. The effluent blood from the graft was wasted
      and showed a mean pH of 6.86 and a lactate concentration of 9.4 mmol/L. Five
      minutes after portal reperfusion, most of the grafts produced lactate. Portal
      hepatic venous P(CO2) difference ranged from 3 to 16 torr (0.4-2.1 kPa). By the
      time of restoration of the infrahepatic caval flow mean 24 mins later, eight of
      the grafts had stopped producing lactate. Mean hepatic venous oxygen tension was
      47 torr (6.3 kPa), stabilizing to 41 torr (5.5 kPa) at the end of surgery.
      Acidosis resolved without pharmacologic interventions. Mean gastric mucosal pH
      was 7.29 during the anhepatic phase and 7.40 at the end of surgery. One of the
      patients developed hepatic arterial thrombosis intraoperatively. Her data were
      analyzed separately. Later, the other patients recovered with good liver
      function, whereas the patient with hepatic arterial thrombosis was successfully
      retransplanted. CONCLUSIONS: The liver grafts received well-oxygenated portal
      venous blood during reperfusion, despite the low values of gastric mucosal pH
      immediately before reperfusion. Hepatic oxygenation became adequate soon after
      reperfusion. In the patient with hepatic arterial thrombosis, the recovery of
      hepatic oxygenation was impaired and lactic acidosis persisted.

PMID- 10579253
TI  - Effects of low-dose dopexamine on splanchnic oxygenation during major abdominal
      surgery.
AB  - OBJECTIVE: To study the influence of low-dose dopexamine on splanchnic
      oxygenation during major abdominal surgery. DESIGN: Prospective, randomized,
      placebo-controlled study. SETTING: University hospital. PATIENTS: Eighteen adult
      patients undergoing elective major abdominal surgery. INTERVENTIONS: The patients
      received either dopexamine at 1 microg/kg/min (group A, n = 9) or 0.90% saline as
      control (group B, n = 9). MEASUREMENTS AND RESULTS: To assess the splanchnic
      oxygenation, intestinal tissue PO2 (PtissO2) and gastric intramucosal Pco2
      (PmucCO2) were measured, and the PCO2 gap (PmucCO2 - PaCO2) was calculated at
      baseline (T1) and after an infusion period of 60 mins (T2). There was no
      difference between the groups in the global oxygen transport parameters. Low-dose
      dopexamine increases PtissO2 on the serosal side of the small bowel
      (deltaPtissO2, 17+/-24 mm Hg in group A vs. -5+/-10 in group B). The changes in
      PtissO2 at the serosal side of the colon after dopexamine demonstrated a
      nonsignificant increase (deltaPtissO2, 7+/-11 mm Hg in group A vs. -11+/-23 mm Hg
      in group B). In both groups, the Pco2 gap (group A, 6+/-7 mm Hg [T1] and 5+/-6 mm
      Hg [T2], vs. group B, 9+/-10 mm Hg [T1] and 12+/-10 mm Hg [T2]) remained
      unchanged compared with the baseline. CONCLUSION: It is concluded that low-dose
      dopexamine improves PtissO2 at the serosal side of the gut, preferably at the
      small bowel. However, low-dose dopexamine did not improve gastric PmucCO2.

PMID- 10579254
TI  - Dialysis and central venous catheter infections in critically ill patients:
      results of a prospective study.
AB  - OBJECTIVE: To determine the incidence of dialysis catheter (DC)-related
      infections in intensive care unit (ICU) patients, and to compare the frequency of
      DC and central venous catheter (CVC) infections in an ICU setting. DESIGN:
      Prospective, descriptive survey. SETTING: An adult, 10-bed medical/surgical ICU
      at a university hospital. PATIENTS: A total of 151 DCs and 230 CVCs placed in 170
      patients were evaluated. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS:
      Catheter colonization was defined by a quantitative catheter tip culture yielding
      > or =10(3) colony-forming units/mL, catheter-related bacteremia was defined as
      catheter colonization and blood culture positive for the same organism, and site
      infection was defined as the presence of pus at the insertion site. The mean
      duration of catheterization was 6.8+/-6 days for DCs and 5.9+/-4.6 for CVCs (p =
      .52). There was no difference between DCs and CVCs in catheter colonization and
      catheter-related bacteremia incidence rates per 1000 days of catheter use (24.2
      vs. 19.8 [p = .46] and 0.96 vs. 1.5 [p = .60], respectively). Site infection was
      observed in one patient (CVC placement). For DCs and CVCs the duration of
      catheterization was associated with catheter infection (p = .0007 and p = .04,
      respectively), but when the catheters were examined over 5-day intervals, the
      incidence of catheter infections did not increase with duration of catheter use
      (p = .23 and p = .10, respectively). CONCLUSIONS: DC-related infections are
      associated with DC longevity. As shown by the 5-day-interval analysis, the
      incidence of DC-related infections did not increase with DC duration, suggesting
      that the risk for DC-related infections remained unchanged with time. The
      characteristics of DC-related infections in ICU patients were comparable to those
      previously reported for CVC-related infections.

PMID- 10579255
TI  - The effect of acidified enteral feeds on gastric colonization in critically ill
      patients: results of a multicenter randomized trial. Canadian Critical Care
      Trials Group.
AB  - OBJECTIVE: To evaluate the effect of acidified enteral feeds on gastric
      colonization in critically ill patients compared with a standard feeding formula.
      DESIGN: Randomized, double-blind, multicenter trial. SETTING: Eight mixed
      intensive care units at tertiary care hospitals. PATIENTS: We recruited
      mechanically ventilated critically ill patients expected to remain ventilated for
      >48 hrs. We excluded patients with gastrointestinal bleeding, acidemia, and renal
      failure requiring dialysis. We enrolled 120 patients; 38% were female, age (mean
      +/- SD) was 57.6+/-19.3 yrs, and Acute Physiology and Chronic Health Evaluation
      II score (mean +/- SD) was 21.6+/-7.6. INTERVENTIONS: Vital High Nitrogen (Abbott
      Laboratories, Ross Products Division, Columbus, OH) was used as the standard
      feeding formula for the control group (pH = 6.5). Hydrochloric acid was added to
      Vital High Nitrogen to achieve a pH of 3.5 in the experimental group.
      MEASUREMENTS AND MAIN RESULTS: The main outcome measure was gastric colonization.
      Secondary outcomes included gastric pH, pneumonia, and mortality. The mean
      gastric pH in patients receiving acid feeds was lower (pH = 3.3) compared with
      controls (pH = 4.6; p<.05). One patient (2%) on acid feeds was colonized in the
      stomach with pathogenic bacteria, compared with 20 patients (43%) in the control
      group (p<.001). There was no difference in the incidence of pneumonia (6.1% in
      the acid feeds group vs. 15% in the control group; p = .19). Overall, there were
      15 deaths in the acid feeds group and seven in the control group (p = .10); four
      patients in the acid feeds group and three in the control group died during the
      study period (p not significant). CONCLUSIONS: Acidified enteral feeds preserve
      gastric acidity and substantially reduce gastric colonization in critically ill
      patients. Larger studies are needed to examine its effect on ventilator
      associated pneumonia and mortality.

PMID- 10579256
TI  - Continuous cardiac output by femoral arterial thermodilution calibrated pulse
      contour analysis: comparison with pulmonary arterial thermodilution.
AB  - OBJECTIVE: To compare two thermodilution methods for the determination of cardiac
      output (CO)-thermodilution in the pulmonary artery (COpa) and thermodilution in
      the femoral artery (COa)-with each other and with CO determined by continuous
      pulse contour analysis (COpc) in terms of reproducibility, bias, and correlation
      among the different methods. Good agreement between the methods would indicate
      the potential of pulse contour analysis to monitor CO continuously and at reduced
      invasiveness. DESIGN: Prospective criterion standard study. SETTING: Cardiac
      surgical intensive care unit in a university hospital. PATIENTS: Twenty-four
      postoperative cardiac surgery patients. INTERVENTIONS: Without interfering with
      standard hospital cardiac recovery procedures, changes in CO as a result of the
      postsurgical course, administration of vasoactive substances, and/or fluid
      administration were recorded. CO was first recorded after a 1-hr stabilization
      period in the intensive care unit and hourly thereafter for 6 hrs, and by
      subsequent determinations at 9, 12, and 24 hrs. MEASUREMENTS AND MAIN RESULTS:
      There were 216 simultaneous determinations of COpa, COa, and COpc. COpc was
      initially calibrated using COa, and no further recalibration of COpc was
      performed. COpa ranged from 3.0 to 11.8 L/min, and systemic vascular resistance
      ranged from 252 to 2434 dyne x sec/cm5. The mean difference (bias) +/-2 SD of
      differences (limits of agreement) was -0.29+/-1.31 L/min for COpa vs. COa, 0.07+/
      1.4 L/min for COpc vs. COpa, and -0.22+/-1.58 L/min for COpc vs. COa. In all but
      four patients COpc correlated with COa after the initial calibration. Correlation
      and precision of COpc vs. COa was stable for 24 hrs. CONCLUSIONS: Femoral artery
      pulse contour CO correlates well with both COpa and COa even during substantial
      variations in vascular tone and hemodynamics. Additionally, CO determined by
      arterial thermodilution correlates well with COpa. Thus, COa can be used to
      calibrate COpc.

PMID- 10579257
TI  - Ceramide concentrations in septic patients: a possible marker of multiple organ
      dysfunction syndrome.
AB  - OBJECTIVES: To investigate the concentrations of mononuclear cell-associated
      ceramide and serum tumor necrosis factor-alpha (TNF-alpha) in patients with
      sepsis and to assess their predictive value for the development of multiple organ
      dysfunction syndrome (MODS). DESIGN: Prospective, cohort study. SETTING:
      Intensive care unit and two research laboratories at a university hospital.
      PATIENTS: Twenty-three adult patients admitted to an intensive care unit meeting
      the criteria for diagnosis of sepsis. INTERVENTIONS: Blood samples were collected
      at the time when diagnosis of sepsis was made. MEASUREMENTS AND MAIN RESULTS:
      Mononuclear cell-associated ceramide and serum TNF-alpha were significantly
      elevated in the samples from the septic patients compared with the control
      individuals (318.01+/-270.15 pmol/10(6) cells vs. 99.90+/-52.75 pmol/10(6) cells;
      p<.001, and 28.52+/-18.77 pg/mL vs. 10.43+/-3.37 pg/mL; p<.0001, respectively),
      and a direct correlation linked ceramide and TNF-alpha concentrations (r2 = .90,
      p<.00001). In the septic patients who went on to develop MODS, ceramide and TNF
      alpha were significantly higher compared with the no MODS patients (489.22+/
      264.93 pmol/10(6) cells vs. 131.23+/-99.02 pmol/10(6) cells; p<.0001, and 40.96+/
      18 pg/mL vs. 14.95+/-5.60 pg/mL; p<.001, respectively). The receiver operating
      characteristic curves demonstrated that both TNF-alpha and ceramide were
      prognostic of MODS, but ceramide concentrations were more efficient predictors.
      CONCLUSIONS: These observations suggest that mononuclear cells of peripheral
      blood from patients with sepsis are committed to undergo apoptosis, because there
      is evidence that ceramide acts as an endogenous mediator of apoptosis. The strong
      correlation we found between cell-associated ceramide and serum TNF-alpha
      supports the hypothesis that this cytokine plays an important role in activating
      the sphingomyelin pathway and ceramide generation in patients with sepsis. In
      addition, this study provides evidence that consistent concentrations of
      mononuclear cell-associated ceramide may predict progression toward MODS in
      septic patients.

PMID- 10579258
TI  - Hypotestosteronemia in chronically critically ill men.
AB  - OBJECTIVE: To determine the prevalence of hypotestosteronemia in chronically
      critically ill (CCI) men. DESIGN: Prevalence survey. SETTING: Step-down
      respiratory care unit (RCU) at a tertiary care teaching hospital. PATIENTS:
      Thirty ventilator-dependent CCI men transferred from intensive care units (ICUs)
      within the same institution. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS:
      Total testosterone and bioavailable testosterone (bioT) concentrations were
      measured within 48 hrs of RCU admission. Patients were hospitalized a median of
      40 days (range, 9-185 days) before RCU admission, with a median ICU length of
      stay of 25 days (range, 9-177 days). At RCU admission, total testosterone
      concentrations averaged 104+/-96 ng/dL, with average bioT concentrations of 19+/
      20 ng/dL (16+/-9% of total testosterone). Twenty-nine of the 30 patients (96%)
      had bioT concentrations well below the lower limit of normal for their age range.
      bioT concentrations, expressed as a percentage of the normal mean for each
      patient's age range, were positively correlated with the number of days that the
      patient was in the ICU before transfer to the RCU (n = 30, r2 = .17, p = .025).
      However, if the single patient who remained in the ICU for 177 days was excluded,
      this correlation disappeared (n = 29, r2 = .07, p = .09). No other relationship
      was found between bioT concentrations and any other variable, including type of
      patient, ICU length of stay, reason for either initial admission to the ICU or
      prolonged mechanical ventilation, type of nutritional support, or use of
      dopamine. CONCLUSIONS: CCI men have a very high prevalence of
      hypotestosteronemia, which may impede their recuperation and rehabilitation.
      Further studies are needed to determine whether additional pharmacologic
      treatment with testosterone can improve the recovery of these patients.

PMID- 10579259
TI  - Beneficial effects of helium:oxygen versus air:oxygen noninvasive pressure
      support in patients with decompensated chronic obstructive pulmonary disease.
AB  - OBJECTIVE: To test the hypothesis that, in decompensated chronic obstructive
      pulmonary disease (COPD), noninvasive pressure support ventilation using 70:30
      helium:oxygen instead of 70:30 air:oxygen could reduce dyspnea and improve
      ventilatory variables, gas exchange, and hemodynamic tolerance. DESIGN:
      Prospective, randomized, crossover study. SETTING: Medical intensive care unit,
      university tertiary care center. PATIENTS: Nineteen patients with severe COPD
      (forced 1-sec expiratory volume of 0.83+/-0.3 l) hospitalized in the intensive
      care unit for noninvasive pressure support ventilation after initial
      stabilization with noninvasive pressure support for no more than 24 hrs after
      intensive care unit admission. INTERVENTIONS: Noninvasive pressure support
      ventilation was administered in the following randomized crossover design: a) 45
      min with air:oxygen or helium:oxygen; b) no ventilation for 45 min; and c) 45 min
      with air:oxygen or helium:oxygen. MEASUREMENTS AND MAIN RESULTS: Air:oxygen and
      helium:oxygen decreased respiratory rate and increased tidal volume and minute
      ventilation. Helium:oxygen decreased inspiratory time. Both gases increased total
      respiratory cycle time and decreased the inspiratory/total time ratio, the
      reduction in the latter being significantly greater with helium:oxygen. Peak
      inspiratory flow rate increased more with helium:oxygen. PaO2 increased with both
      gases, whereas PaCO2 decreased more with helium:oxygen (values shown are mean+/
      SD) (52+/-6 torr [6.9+/-0.8 kPa] vs. 55+/-8 torr [7.3+/-1.1 kPa] and 48+/-6 torr
      [6.4+/-0.8 kPa] vs. 54+/-7 torr [7.2+/-0.9 kPa] for air:oxygen and helium:oxygen,
      respectively; p<.05). When hypercapnia was severe (PaCO2 >56 torr [7.5 kPa]),
      PaCO2 decreased by > or =7.5 torr (1 kPa) in six of seven patients with
      helium:oxygen and in four of seven patients with air:oxygen (p<.01). Dyspnea
      score (Borg scale) decreased more with helium:oxygen than with air:oxygen (3.7+/
      1.6 vs. 4.5+/-1.4 and 2.8+/-1.6 vs. 4.6+/-1.5 for air:oxygen and helium:oxygen,
      respectively; p<.05). Mean arterial blood pressure decreased with air:oxygen
      (76+/-12 vs. 82+/-14 mm Hg; p<.05) but remained unchanged with helium:oxygen.
      CONCLUSION: In decompensated COPD patients, noninvasive pressure support
      ventilation with helium:oxygen reduced dyspnea and PaCO2 more than air:oxygen,
      modified respiratory cycle times, and did not modify systemic blood pressure.
      These effects could prove beneficial in COPD patients with severe acute
      respiratory failure and might reduce the need for endotracheal intubation.

PMID- 10579260
TI  - Potassium concentrations and ventricular ectopy: a prospective, observational
      study in post-cardiac surgery patients.
AB  - OBJECTIVE: To determine whether a correlation exists between concentrations of
      intracellular and extracellular potassium and to determine the frequency of
      ventricular ectopy in patients after cardiac operations. DESIGN: Prospective,
      observational clinical evaluation. SETTING: Surgical-respiratory intensive care
      unit of a university-affiliated tertiary care center. PATIENTS: Continuous 24-hr
      electrocardiographic monitoring was performed, and serum (extracellular) and
      erythrocyte (intracellular) potassium concentrations ([K+]e and [K+]i) were
      determined, before cardiopulmonary bypass, immediately postoperatively, and at 2,
      4, 12, and 20 hrs after elective coronary bypass grafting in 31 patients.
      INTERVENTIONS: None. Potassium replacement was left to the discretion of the
      attending physicians. MEASUREMENTS AND MAIN RESULTS: Although the mean [K+]e
      varied significantly during the postoperative 24-hr period (p<.0001), the [K+]i
      did not (p = .953). No significant correlations were found between premature
      ventricular beats and [K+]i, [K+]e, or [K+]i/[K+]e (all p>.05). However, among
      the few patients who had one or more episodes of ventricular tachycardia (VT)
      within 30 mins of a study K+ sample, the mean [K+]e was significantly lower
      during the episode(s) of VT compared with the mean [K+]e in the absence of VT
      (p<.01). CONCLUSIONS: Although it is clear that over the clinically acceptable
      range of [K+]e and [K+]i concentrations seen in this population, there is no
      correlation between potassium concentrations and the occurrence of premature
      ventricular beats, the infrequent association of more serious ventricular ectopy,
      VT, with lower [K+]e concentrations supports the practice of using serum
      potassium to guide potassium replacement in patients after cardiac operations.

PMID- 10579261
TI  - Blood volume determination by the carbon monoxide method using a new delivery
      system: accuracy in critically ill humans and precision in an animal model.
AB  - OBJECTIVE: To evaluate accuracy and repeatability of blood volume determinations
      made by the carbon monoxide method, using a ventilator-driven administration
      system. DESIGN: Prospective within-patient comparison, using simultaneous
      measurements by two methods to determine accuracy. Prospective laboratory
      investigation in animals to estimate repeatability. SUBJECTS: For accuracy:
      Nineteen ventilated critically ill patients in a university hospital intensive
      care unit. For repeatability: Six anesthetized, mechanically ventilated
      normovolemic pigs because this is impossible to perform in humans. INTERVENTIONS:
      In the accuracy study, a small mass of carbon monoxide was administered via a
      closed breathing system and arterial blood samples were taken from existing
      cannulas. In the repeatability study, an intramuscular sedative was given,
      followed by an inhalational anesthetic induction and mechanical ventilation via a
      tracheal tube. Left axillary artery and external jugular vein cannulas were
      sited. Anesthesia was maintained using an intravenous infusion. Five sequential
      circulating hemoglobin and blood volume estimations were made using the carbon
      monoxide method. MEASUREMENTS AND MAIN RESULTS: The small carboxyhemoglobin
      increase produced by uptake of a small, known mass of carbon monoxide was used to
      estimate the circulating blood volume. Simultaneous measurement, using 51Cr
      labeled red blood cells, was performed. Twenty measurements were made in 19
      patients. The bias (mean difference between blood volume measurements by the two
      methods) was 397 mL (5.53 mL x kg(-1)) +/-415 mL (+/-5.95 mL x kg(-1)); the
      limits of agreement (mean difference +/-2 SD) were -433 mL and 1227 mL (-6.36 mL
      x kg(-1) and 17.42 mL x kg(-1)). Therefore, 95% of expected differences will lie
      between these limits. The mean blood volume was 75.8 mL x kg(-1) in the animals.
      The coefficient of variation of repeated estimates was 9.49%. Mean circulating
      hemoglobin mass was 7.31 mmol with a coefficient of variation of 10.18%. The mean
      hemoglobin concentration, by co-oximetry, was 5.014 mmol x L(-1), coefficient of
      variation, 2.99%. CONCLUSION: This arrangement is a potential bedside method of
      estimating blood volume and circulating hemoglobin mass. We have rendered the
      technique more acceptable clinically by creating a ventilator-driven
      administration system.

PMID- 10579262
TI  - Hydrocortisone-induced inhibition of reactive oxygen species by polymorphonuclear
      neutrophils.
AB  - OBJECTIVE: To determine whether hydrocortisone given intravenously inhibits
      reactive oxygen species (ROS) generation by polymorphonuclear neutrophils (PMNLs)
      in vivo and, if so, to describe the pharmacodynamics of this effect. DESIGN: A
      prospective, open label study in normal subjects. SETTING: A clinical research
      unit of a tertiary referral center for diabetes and endocrinology. PATIENTS:
      Eight normal subjects (age range, 2450 yrs). INTERVENTION: An indwelling cannula
      was inserted into the antecubital vein. Sequential blood samples were obtained
      from the cannula just before, and after, the intravenous injection of
      hydrocortisone (100 mg) at 1, 2, 4, 8, and 24 hrs. MEASUREMENTS AND MAIN RESULTS:
      ROS generation by PMNLs and mononuclear cells (MNCs) was assayed as previously
      observed in a chemiluminometer. ROS generation by PMNLs and MNCs was inhibited by
      hydrocortisone at 1 hr; this effect peaked at 2 hrs and began to recover by 4
      hrs; ROS generation had recovered to the baseline by 24 hrs. Although the
      pharmacodynamic effect of hydrocortisone on PMNLs and MNCs was similar, the peak
      inhibition was significantly greater for PMNLs (26% of basal vs. 43% of basal,
      p<.02) than MNCs. CONCLUSIONS: There is a marked, consistent, inhibition of ROS
      generation by PMNLs, which parallels that of MNCs after intravenous
      hydrocortisone. The pharmacodynamics of this effect are consistent with our
      current clinical practices.

PMID- 10579263
TI  - Hypoxemia after coronary bypass surgery modeled by resistance to oxygen
      diffusion.
AB  - OBJECTIVE: To evaluate a model describing postoperative hypoxemia after cardiac
      surgery by using two variables, i.e., shunt and resistance to oxygen diffusion
      (Rdff). DESIGN: Estimation of these two variables in normal subjects and
      postoperative cardiac patients. SETTING: The pulmonary function laboratory for
      the normal subjects and the intensive care unit for the cardiac patients.
      PATIENTS/SUBJECTS: Nine postoperative cardiac patients and six healthy subjects.
      INTERVENTIONS: Inspired oxygen fraction was varied in normal subjects and in
      cardiac patients 3-6 hrs after surgery. This variation occurred in four to seven
      steps to achieve arterial oxygen saturations in the range 0.90-1.00. MEASUREMENTS
      AND MAIN RESULTS: Measurements were taken of arterial oxygen saturation, cardiac
      output, ventilation, and end-tidal gases at each inspired oxygen fraction. These
      measurements gave the following estimates for the normal subjects: shunt = 3.9+/
      5.4% (mean +/- SD) and Rdiff = -5+/-16 torr/(L/min) [-0.7+/-2.2 kPa/(L/min)]; for
      the cardiac patients: shunt = 7.7+/-1.8% and Rdiff = 212+/-230 torr/(L/min)
      [28.2+/-30.6 kPa/(L/min)]. The increase in Rdiff (P = .01) was sufficient to
      explain the observed hypoxemia in these patients. The value for shunt was not
      significantly increased in the patients (p = .09). The two-variable model (shunt
      and Rdff) gave a better prediction of arterial oxygen saturation than a model
      with shunt as the only variable (p = .02). CONCLUSIONS: In cardiac patients
      requiring supplementary oxygen, the respiratory abnormality could, in our model,
      be best described by an increased Rdiff, not by an increased shunt value.

PMID- 10579264
TI  - Continuous infusions of lorazepam, midazolam, and propofol for sedation of the
      critically ill surgery trauma patient: a prospective, randomized comparison.
AB  - OBJECTIVE: To compare the efficacy, safety, and cost of continuous infusions of
      lorazepam, midazolam, and propofol in a critically ill trauma/surgery patient
      population. DESIGN: A prospective, randomized, nonblinded, single center.
      SETTING: A 16-bed intensive care unit. PATIENTS: A total of 30 ventilated
      patients who were 18-70 yrs of age and required pharmacologic sedation. Patients
      with renal and/or liver failure, a history of alcohol abuse, a head injury, or in
      a coma were excluded. INTERVENTIONS: Patients were randomized by block design to
      receive lorazepam, midazolam, or propofol. Initial boluses and infusion rates
      were as follows: lorazepam 0.05 mg/kg, then 0.007 mg/kg/hr; midazolam 0.05 mg/kg,
      then 0.003 mg/kg/hr; and propofol 0.25 mg/kg, then 0.06 mg/kg/hr. Sedation was
      assessed and agents titrated every 5-10 mins to achieve > or =2 and <5 on the
      modified Ramsay scale. Once adequate response was achieved, agents were titrated
      to maintain the desired level of sedation. MEASUREMENTS AND MAIN RESULTS:
      Maintenance doses of lorazepam 0.02+/-0.01 mg/kg/hr, midazolam 0.04+/-0.03
      mg/kg/hr, and propofol 2.0+/-1.5 mg/kg/hr achieved the desired level of sedation
      68%, 79%, and 62% of the time, respectively. Oversedation occurred most often
      with lorazepam, compared with midazolam and propofol, at 14%, 6%, and 7% of the
      assessment times, respectively. Undersedation occurred most frequently with
      propofol compared with lorazepam and midazolam, at 31%, 18%, and 16% of the
      assessment times, respectively. The mean number of dosage changes per day was
      7.8+/-4.3 for lorazepam, 4.4+/-2.9 for midazolam, and 5.6+/-6.0 for propofol (p =
      .91). Sedation costs per patient day (mean +/- SD) were $48+/-$76 (lorazepam),
      $182+/-$98 (midazolam), and $273+/-$200 (propofol) (p = .005). The potential
      savings, if all study patients had received lorazepam, is $14,208 compared with
      $8,808 if all received midazolam. CONCLUSIONS: The data suggest that lorazepam
      appears to be a cost-effective choice for sedation; however, oversedation may be
      problematic. Midazolam is the most titratable drug in our population, avoiding
      excessive oversedation or undersedation. Trauma patients may respond inadequately
      to propofol even at higher doses. Lorazepam may be the sedative of choice in
      critically ill trauma/surgery patients.

PMID- 10579265
TI  - Mechanisms for the diminished neutrophil exudation to secondary inflammatory
      sites in infected patients with a systemic inflammatory response (sepsis).
AB  - OBJECTIVE: To determine the mechanism for the reduced polymorphonuclear
      neutrophil exudation to secondary inflammatory sites in critically ill patients
      with infection and systemic inflammatory response (sepsis). DESIGN: Prospective
      cohort study. SETTING: Research laboratory and integrated intensive care unit of
      a tertiary care university-affiliated teaching hospital. PATIENTS: Healthy
      subjects or critically ill patients with confirmed infection and a systemic
      inflammatory response (septic patients). MEASUREMENTS AND MAIN RESULTS: We found
      that polymorphonuclear neutrophil delivery to a secondary inflammatory site (skin
      window blisters) is reduced by >70% in humans with sepsis, defined as serious
      infection and a systemic inflammatory response compared with healthy controls.
      The expression of the endothelial adhesion molecules intercellular adhesion
      molecule-1, E-selectin and P-selectin in microvessels from skin biopsies was
      comparable in the two study groups. Also, CD11a and CD11b levels were equal in
      circulating polymorphonuclear neutrophils (PMNs) from both study groups. Both
      adhesion molecules were markedly and equally up-regulated during exudation.
      Circulating PMNs from septic patients showed marked shedding of L-selectin
      compared to those of healthy controls, with a corresponding increase in their
      plasma L-selectin levels. An increased concentration gradient between plasma and
      exudate fluid was found for tumor necrosis factor-alpha and interleukin-8 in
      septic patients, but not for C5a. The phagocytic and bactericidal capacity of
      septic patient circulating PMNs was higher then in healthy control patients, but
      these differences were lost after exudation. There were no major differences in
      oxidative burst or intracellular calcium flux of circulating PMNs from the two
      study groups. Polymorphonuclear neutrophil exudation primed both responses to
      different extents. CONCLUSIONS: Septic patients deliver fewer PMNs to secondary
      inflammatory sites. In addition, neutrophil exudation results in loss of the
      small priming effect for phagocytosis and bactericidal function induced by
      sepsis. Failure to produce a gradient to C5a and intravascular shedding of L
      selectin may be responsible for this sepsis-induced reduction in neutrophil
      exudation to secondary inflammatory sites.

PMID- 10579266
TI  - Pulmonary lactate release in patients with acute lung injury is not attributable
      to lung tissue hypoxia.
AB  - OBJECTIVE: To determine whether pulmonary lactate production in patients with
      acute lung injury is attributable to lung tissue hypoxia. DESIGN: Prospective,
      controlled, clinical study. SETTING: A multidisciplinary university intensive
      care unit in a general hospital. PATIENTS: Seventy consecutive critically ill
      patients requiring mechanical ventilation and invasive hemodynamic monitoring. Of
      these patients, 18 had no acute lung injury (no ALI); 33 had acute lung injury
      (ALI) (Lung Injury Score [LIS] < or =2.5); and 19 had acute respiratory distress
      syndrome (ARDS) (LIS >2.5). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS:
      After hemodynamic measurements, lactate and pyruvate concentrations were assessed
      in simultaneously drawn arterial (a) and mixed venous (v) blood samples.
      Pulmonary lactate release was calculated as the product of transpulmonary a-v
      lactate difference (L[a-v]) times the cardiac index. Two indices of anaerobic
      metabolism of the lung, i.e., the transpulmonary a-v difference of lactate
      pyruvate ratio (L/P[a-v]) and excess lactate formation across the lungs (XL),
      were calculated. L(a-v) and pulmonary lactate release were higher in patients
      with ARDS than in the other groups (p<.001), and they were also higher in
      patients with ALI compared with patients with no ALI (p<.001). In patients with
      ALI and ARDS (n = 52), pulmonary lactate release correlated significantly with
      LIS (r2 = .14, p<.01) and venous admixture (r2 = .13, p<.01). When all patients
      were lumped together (n = 70), pulmonary lactate release directly correlated with
      LIS (r2 = .30, p<.001), venous admixture (r2 = .26, p<.001), and P(A-a)O2 (r2 =
      .14, p<.01). Neither L/P(a-v) nor XL was significantly different among the three
      groups. CONCLUSION: The lungs of patients with ALI produce lactate that is
      proportional to the severity of lung injury. This lactate production does not
      seem to be attributable to lung tissue hypoxia.

PMID- 10579268
TI  - Does gastric tonometry monitor splanchnic perfusion?
AB  - OBJECTIVE: To define whether the gastric mucosal-arterial PCO2 gradient (PCO2
      gap) reliably reflects hepatosplanchnic oxygenation in septic patients. DESIGN:
      Prospective observational clinical study. SETTING: An adult, 31-bed
      medical/surgical department of intensive care of a university hospital. PATIENTS:
      A total of 36 hemodynamically stable, invasively monitored, mechanically
      ventilated, sedated, paralyzed patients with severe sepsis. INTERVENTIONS: In
      each patient, hepatosplanchnic blood flow was determined by the continuous
      indocyanine green infusion technique and gastric mucosal PCO2 by the saline
      tonometry technique. Suprahepatic venous blood oxygen saturation and PCO2 also
      were measured. The mesenteric veno-arterial PCO2 gradient was determined as the
      difference between the suprahepatic venous blood PCO2 and the arterial blood
      PCO2. MEASUREMENTS AND MAIN RESULTS: There were significant correlations between
      the hepatosplanchnic blood flow and the suprahepatic venous blood oxygen
      saturation (r2 = .56; p<.01), between the hepatosplanchnic blood flow and the
      mesenteric veno-arterial PCO2 gradient (r2 = .55; p<.01), and also between the
      suprahepatic venous blood oxygen saturation and the mesenteric veno-arterial PCO2
      gradient (r2 = .64; p<.01). There was no statistically significant correlation
      between the PCO2 gap and the hepatosplanchnic blood flow, the suprahepatic venous
      blood oxygen saturation or the mesenteric veno-arterial PCO2 gradient.
      CONCLUSIONS: In stable septic patients, the PCO2 gap is not correlated with
      global indexes of gut oxygenation. The interpretation of PCO2 gap is more complex
      than previously thought.

PMID- 10579267
TI  - Modulation of systemic hemodynamics by exogenous L-arginine in normal and
      bacteremic sheep.
AB  - OBJECTIVE: To investigate whether exogenous L-arginine, the substrate for nitric
      oxide synthase, modulates systemic hemodynamics in sepsis. DESIGN: Prospective,
      controlled study in a sheep model of sepsis. SETTING: Animal research facility in
      a university hospital. SUBJECTS: Adult sheep weighing between 35 and 55 kg.
      INTERVENTIONS: Adult sheep sedated and mechanically ventilated, were monitored
      with a pulmonary arterial catheter and an ileal tonometer. Four groups of sheep
      were studied: nonseptic, septic, nonseptic treated with L-arginine, and septic
      treated with L-arginine. Sepsis was induced by the intravenous administration of
      Escherichia coli (1.5x10(8) colony-forming units/kg for 30 mins). L-arginine was
      administered as an intravenous bolus (200 mg/kg for 10 mins) before the septic
      challenge followed by 200 mg/kg/hr for 300 mins. MEASUREMENTS AND MAIN RESULTS:
      Sepsis induced a state of acidosis, hyperlactatemia, hypoxemia, and gastric
      intramucosal acidosis. During the first 30 mins after the septic challenge, there
      was a decrease in cardiac index and blood pressure, and an increase in systemic
      vascular resistance. Thereafter, blood pressure returned to baseline values, and
      systemic vascular resistance fell. Treatment with L-arginine in nonseptic sheep
      did not induce any biochemical or hemodynamic effect. In septic sheep, treatment
      with L-arginine was associated with a greater increase in systemic vascular
      resistance during the first 30 mins, and a more marked decrease in blood pressure
      and systemic vascular resistance after 180 mins. CONCLUSIONS: Exogenous
      administration of L-arginine does not induce hemodynamic effects in normal
      animals, exacerbates the acute vasoconstriction associated with the intravenous
      infusion of E. coli and potentiates the sepsis-induced vasodilation. Our results
      suggest that a) nitric oxide production is not constitutively modulated by
      exogenous L-arginine, b) L-arginine probably enhances the sepsis-induced
      sympathetic discharge, and c) L-arginine becomes rate-limiting for the formation
      of nitric oxide at approximately 3 hrs after the initiation of the septic
      challenge.

PMID- 10579269
TI  - Platelet-activating factor and arachidonic acid metabolites mediate tumor
      necrosis factor and eicosanoid kinetics and cardiopulmonary dysfunction during
      bacteremic shock.
AB  - OBJECTIVE: Platelet-activating factor (PAF) and eicosanoids are putative
      mediators of septic shock that are associated with release of tumor necrosis
      factor (TNF). The purpose of this investigation was to a) examine temporal
      patterns of TNF and arachidonic acid metabolite release in a porcine model of
      bacteremic shock and b) selectively block PAF, thromboxane A2, prostacyclin, and
      leukotrienes to determine the relationships among these inflammatory response
      mediators and the alterations in cardiorespiratory dysfunction for which they are
      required. DESIGN: Prospective, nonrandomized, controlled trial. SETTING:
      Laboratory at a university medical center. SUBJECTS: Thirty-four female Yorkshire
      swine. INTERVENTIONS: Animals were divided into six experimental groups: five
      septic groups receiving an infusion of Aeromonas hydrophila at 0.2 mL/kg/hr,
      gradually increasing to 0.4 mL/kg/hr over 4 hrs. Each of four septic groups was
      pretreated with a specific mediator inhibitor (PAF receptor antagonist, n = 6;
      prostacyclin antibody, n = 5; leukotriene synthesis inhibitor, n = 5; and
      thromboxane receptor antagonist, n = 6). One septic group (n = 6) received no
      mediator inhibitor and served as a septic control, and one anesthesia control
      group (n = 6) received no intervention. MEASUREMENTS AND MAIN RESULTS: PAF
      receptor blockade significantly increased systemic hypotension and mixed venous
      oxygen saturation and decreased pulmonary artery pressure, oxygen extraction and
      consumption, hemoconcentration, and levels of TNF and eicosanoids. Leukotriene
      inhibition increased mean arterial pressure, pulmonary and systemic vascular
      resistance indices, and arterial and mixed venous oxygen saturation and reduced
      pulmonary hypertension, oxygen delivery, oxygen extraction, oxygen consumption,
      and all measured mediators. Thromboxane receptor blockade lowered TNF and
      leukotriene levels, ameliorated systemic and pulmonary vasoconstriction, and
      significantly increased arterial and tissue oxygenation compared with septic
      controls. Prostacyclin antagonism reduced prostacyclin plasma concentrations,
      arterial hypoxemia, and oxygen consumption during sepsis and increased
      circulating leukotriene B4. CONCLUSIONS: Elevations in plasma TNF predictably
      precede peak levels of eicosanoids in this model. PAF, leukotrienes, and
      thromboxane A2 are necessary for pulmonary hypertension during bacteremia.
      Systemic hypotension and increased vascular permeability are mediated by both
      leukotrienes and PAF. There are complex interactions among mediators during
      sepsis and further studies are required to define these relationships.

PMID- 10579270
TI  - Accuracy of intramucosal pH calculated from arterial bicarbonate and the
      Henderson-Hasselbalch equation: assessment using simulated ischemia.
AB  - OBJECTIVES: To determine the accuracy of intramucosal pH (pHi) calculated using
      arterial bicarbonate instead of mucosal capillary bicarbonate in the Henderson
      Hasselbalch equation. DESIGN: Simulation of progressive ischemia in mucosal
      capillary blood. SETTING: University research laboratory. SUBJECTS: Normal human
      blood diluted with plasma. INTERVENTIONS: Three venous blood specimens were
      heparinized and diluted to a mean hemoglobin concentration of 5.0 (+/-0.9) g/dL
      by addition of plasma (2:1, vol:vol). Mucosal capillary aerobic flow stagnation
      was simulated by multiple exposures of each cooled specimen to a gas mixture
      containing 90% nitrogen and 10% CO2. When PCO2 measured at 37 degrees C (98.6
      degrees F) was approximately 120 torr (16 kPa), the assigned anaerobic threshold,
      subsequent anaerobic flow stagnation was simulated by mixing the hypercapnic
      specimens in sealed syringes with five to six successive small aliquots (<100
      microL) of lactic acid (10 g/L). MEASUREMENTS AND MAIN RESULTS: The relationship
      between Pco2 and pH in the specimens was compared with the relationship between
      the same PCO2 values and pHi calculated by substituting bicarbonate
      concentrations of 22 and 26 mmol/L in the Henderson-Hasselbalch equation. As PCO2
      rose from 50 torr (8 kPa), conventionally calculated pHi increasingly
      underestimated simulated mucosal capillary pH, with bias >0.1 pH unit at the
      simulated anaerobic threshold of 120 torr (16 kPa). As PCO2 rose further the
      values converged, becoming equivalent at PCO2 approximately 150 torr (20 kPa).
      From PCO2 > or =200 torr (26.7 kPa), conventional pHi progressively overestimated
      simulated mucosal pH. The difference was >0.3 pH units at PCO2 = 250 torr (33.3
      kPa). CONCLUSIONS: In the mucosal PCO2 range usually encountered clinically, the
      arterial bicarbonate substitution causes underestimation of mucosal capillary pH.
      With moderate mucosal capillary lactic acidosis the error becomes small, and in
      severe regional ischemia there is significant overestimation of mucosal capillary
      pH.

PMID- 10579271
TI  - High-frequency oscillatory ventilation of the perfluorocarbon-filled lung:
      preliminary results in an animal model of acute lung injury.
AB  - OBJECTIVE: To examine the efficiency of gas exchange, hemodynamic function, and
      histopathologic evidence of lung protection using high-frequency oscillation of
      the perfluorocarbon-filled lung in a model of acute lung injury. SETTING: An
      animal research laboratory. DESIGN: A prospective, randomized animal study
      comparing animals randomized to high-frequency oscillation or high-frequency
      oscillation and perfluorocarbon administration (perfluoro-octyl bromide,
      perfubron, or LiquiVent). SUBJECTS: Ten healthy swine (mean weight, 24.6 kg) with
      saline lavage-induced acute lung injury. INTERVENTIONS: Animals were treated with
      repetitive saline lavage to achieve a uniform degree of acute lung injury (Pao2
      of <90 torr [11.9 kPa] on a Fio2 of 1.0). After lung injury, subjects were
      changed to high-frequency oscillatory ventilation and stabilized for 1 hr. High
      frequency oscillation of the perfiuorocarbon-filled lung was initiated in five
      animals with the instillation of 30 mUkg perflubron and five animals continued
      receiving high-frequency oscillation for a total duration of 2 hrs after the
      dosing period. Histopathologic evidence of lung injury was quantified by a
      pathologist using an eight-variable lung injury scoring system to generate a lung
      injury score. MEASUREMENTS AND MAIN RESULTS: Administration of perflubron did not
      produce acute alterations of gas exchange. After the dosing period, there were no
      differences in gas exchange, hemodynamic function, or pulmonary vascular
      resistance between the two groups. The perfluorocarbon-treated animals had a
      significantly lower histopathologic total lung injury score, primarily manifested
      by significantly less atelectasis. CONCLUSIONS: The combination of high-frequency
      oscillatory ventilation and partial liquid ventilation with perfiubron was well
      tolerated hemodynamically, was not associated with deterioration of gas exchange
      during dosing, and did not produce significant differences in either gas exchange
      or hemodynamic variables over a 2-hr period. There was histopathologic evidence
      that the combination of high-frequency oscillation and perfiubron administration
      produces improved recruitment in both dependent and nondependent lung regions.

PMID- 10579272
TI  - Effect of AR-R 17477, a potent neuronal nitric oxide synthase inhibitor, on
      infarction volume resulting from permanent focal ischemia in rats.
AB  - OBJECTIVE: We tested whether AR-R 17477, a selective inhibitor of neuronal nitric
      oxide synthase, reduces brain injury in rats subjected to permanent focal
      ischemia. DESIGN: Randomized within cohort; nonblinded study. SETTING: University
      basic science laboratory. SUBJECTS: Halothane-anesthetized male Wistar rats (n =
      53). INTERVENTIONS: Rats were treated with either intravenous saline (diluent) or
      AR-R 17477 (1 or 3 mg/kg) 30 mins before or 60 mins after the onset of permanent
      focal cerebral ischemia. Infarction volume was determined at 18 or 48 hrs of
      ischemia. MEASUREMENTS AND MAIN RESULTS: Pretreatment with 1 mg/kg AR-R 17477 was
      associated with a decreased infarct volume (2,3,5-triphenyltetrazolium chloride
      staining) in the striatum (saline, 81+/-7 mm3; AR-R 17477, 55+/-3 mm3) but not in
      the cortex at 18 hrs of occlusion (saline, 302+/-29 mm3; AR-R 17477, 237+/-36
      mm3). However, this therapeutic effect of AR-R 17477 was no longer evident if the
      rats were allowed to survive for 48 hrs before analysis of infarction volume. In
      fact, in this separate cohort of animals, three of eight AR-R 17477-treated and
      five of eight saline-treated rats died before completing 48 hrs of ischemia.
      Efficacy of AR-R 17477 was completely absent (even at 18 hrs of ischemia) when
      drug treatment was delayed until 1 hr after the onset of ischemia. Infarction
      volume at 18 hrs of ischemia was similar between rats treated with saline, 1
      mg/kg (cortex, 229+/-43 mm3; striatum, 67+/-8 mm3) or 3 mg/kg AR-R 17477 (cortex,
      284+/-34 mm3; striatum, 75+/-5 mm3). In addition, only one of eight rats treated
      with 3 mg/kg AR-R 17477 at 1 hr of ischemia survived 48 hrs of occlusion,
      compared with three of eight rats treated with saline. CONCLUSIONS: Neuronally
      generated nitric oxide is a mediator of brain injury during permanent focal
      ischemia in rats. However, severity of the ischemic insult appears to limit the
      therapeutic efficacy of the specific neuronal nitric oxide synthase inhibitor, AR
      R 17477.

PMID- 10579273
TI  - Cerebral hemodynamic effects of phenylephrine and L-arginine after cortical
      impact injury.
AB  - OBJECTIVE: To determine the effects of a pressor agent (phenylephrine and L
      arginine) on the abnormal cerebral hemodynamics and on neurologic outcome after a
      severe cortical impact injury in rats. DESIGN: Prospective, randomized study.
      SETTING: University laboratory. SUBJECTS: Male Long-Evans rats, weighing 300 to
      400 g, fasted overnight. INTERVENTIONS: The animals were anesthetized with
      isoflurane, and a severe cortical impact injury (velocity, 5 m/sec; deformation,
      3 mm) was produced in the right parietal cortex. Five minutes after impact
      injury, one of the following three treatments were infused: 1 mL saline
      intravenously for 10 mins, 300 mg/kg L-arginine in 1 mL saline intravenously for
      10 mins, or 0.3 microg/kg/min phenylephrine intravenously for 3 hrs. Mean
      arterial pressure, intracranial pressure (ICP), cerebral perfusion pressure
      (CPP), and laser Doppler flow (LDF) at the impact site and in the contralateral
      parietal cortex were monitored for 3 hrs after the impact injury. Histologic
      examination of the brain was performed at 2 wks after injury in a separate group
      of L-arginine- and saline-treated animals. MEASUREMENTS AND MAIN RESULTS: The
      immediate response to the impact injury was an increase in ICP, and a decrease in
      mean arterial pressure, CPP, and LDF. In the saline-treated animals, LDF
      decreased to <25% of the baseline values at the impact site and stayed at that
      level for the entire 3-hr monitoring period. On the contralateral side, LDF
      decreased initially and recovered gradually to approximately 50% of the preimpact
      baseline value. Infusion of both phenylephrine and L-arginine increased LDF back
      to near-baseline levels. However, phenylephrine increased ICP significantly,
      whereas ICP with L-arginine did not change. L-arginine treatment reduced the
      contusion volume from a median value of 5.28 mm3 to 0.63 mm3. CONCLUSIONS:
      Phenylephrine increased cerebral blood flow (CBF) by increasing CPP. L-arginine,
      however, increased CBF without changing CPP. The improvement in CBF was
      accompanied by a decrease in neurologic injury. Although the pressor agents are
      used currently to increase CBF after traumatic brain injury, other strategies may
      also increase CBF without the potential adverse effects of induced hypertension.

PMID- 10579274
TI  - Ileal mucosal oxygen consumption is decreased in endotoxemic rats but is restored
      toward normal by treatment with aminoguanidine.
AB  - OBJECTIVE: We sought to test the hypothesis that ileal mucosal oxygen consumption
      is impaired in endotoxemic rats. METHODS: Male Sprague-Dawley rats were injected
      intravenously with either Escherichia coli lipopolysaccharide (5 mg/kg) or a
      similar volume of vehicle. A segment of ileum was excised 8 hrs later, and the
      serosal and muscular layers of the bowel were stripped away from the mucosa. A
      strip of mucosa was mounted in a polarographic chamber containing air-saturated
      Krebs-Henseleit buffer plus 20 mM glucose, PO2 being monitored during a 10-min
      period. Some rats were injected intraperitoneally with the inducible nitric oxide
      synthase inhibitor, aminoguanidine (30 mg/kg per dose), or a similar volume of
      vehicle, at 1, 3 and 6 hrs after injection of lipopolysaccharide. RESULTS: In an
      initial experiment, the rate of oxygen consumption was significantly lower for
      mucosal samples from endotoxemic rats as compared with control rats (0.76+/-0.11
      ng-atoms vs. 1.42+/-0.22 ng-atoms of 0/min per microg dry weight, respectively; n
      = 8 per group; p<.05). The rate of mucosal oxygen consumption was higher in
      aminoguanidine-treated as compared with vehicle-treated endotoxemic rats (1.25+/
      0.11 ng-atoms and 0.73+/-0.07 ng-atoms of 0/min per microg, respectively; n = 7
      and n = 6, respectively; p<.05). CONCLUSION: Endotoxemia is associated with
      diminished intestinal mucosal oxygen utilization due to an intrinsic acquired
      derangement in cellular respiration that is caused, at least in part, by an
      aminoguanidine-inhibitable mechanism.

PMID- 10579275
TI  - Prospective, randomized, controlled trial to determine the effect of early
      enhanced enteral nutrition on clinical outcome in mechanically ventilated
      patients suffering head injury.
AB  - OBJECTIVE: To determine the effect of early enhanced enteral nutrition (EN) on
      clinical outcome of head-injured patients. DESIGN: Prospective, randomized,
      controlled trial. SETTING: Tertiary neurosurgical and trauma center. PATIENTS:
      Eighty-two patients suffering head injury and requiring mechanical ventilation.
      INTERVENTIONS: Patients were randomized to receive standard EN (gradually
      increased from 15 mL/hr up to estimated energy and nitrogen requirements) or
      enhanced EN (started at a feeding rate that met estimated energy and nitrogen
      requirements) from day 1. Good neurologic outcome (Glasgow Outcome Scale score of
      4 or 5) was determined at 3 and 6 months after injury, and the incidence of
      infective and total complications was determined during the hospital stay up to 6
      months. MEASUREMENTS AND MAIN RESULTS: Disease severity assessed by best
      preintubation Glasgow Coma Scale score, pupillary responses, Injury Severity
      Score, Acute Physiology and Chronic Health Evaluation II score, computed
      tomographic scan categorization, and age was similar in both groups. Intervention
      patients had a higher percentage of energy (p = .0008) and nitrogen (p<.0001)
      requirements met by EN in the first week after injury. Neurologic outcome at 6
      months was similar between groups, but there was a tendency for more intervention
      patients to have a good neurologic outcome at 3 months than control patients (61%
      vs. 39%, p = .08). Fewer intervention patients had an infective complication (61%
      vs. 85%, p = .02) or more than one total complication (37% vs. 61%, p = .046)
      compared with control patients. Enhanced EN was associated with a reduction in
      the ratio of serum concentration of C-reactive protein to albumin up to day 6
      after injury (p = .004). CONCLUSIONS: Enhanced EN appears to accelerate
      neurologic recovery and reduces both the incidence of major complications and
      postinjury inflammatory responses.

PMID- 10579276
TI  - Continuous flow peritoneal dialysis as a method to treat severe anasarca in
      children with acute respiratory distress syndrome.
AB  - OBJECTIVE: To describe a method of rapid fluid removal in children with anasarca
      and the acute respiratory distress syndrome (ARDS) secondary to sepsis or the
      systemic inflammatory response syndrome. DESIGN: Consecutive case series.
      SETTING: Pediatric Intensive Care Unit of a children's hospital. PATIENTS: Six
      patients with ARDS secondary to sepsis or systemic inflammatory response
      syndrome, who had persistent anasarca complicating their respiratory course
      despite intravenous diuretic therapy. INTERVENTIONS: Continuous flow peritoneal
      dialysis (CFPD) was instituted after percutaneously inserting two Tenckhoff
      dialysis catheters into the peritoneal cavity of each patient and tunneling them
      through the subcutaneous tissue to exit from opposite lower abdominal quadrants.
      A dialysis solution with 2.5% dextrose was administered continuously via one of
      the catheters at a rate ranging from 10-30 mL/kg/hr, and concomitantly drained
      via the other catheter. The concentration of the dialysis solution and rate of
      inflow were adjusted as needed to achieve the desired peritoneal outflow rate.
      CFPD was discontinued when adequate weight loss had occurred and the patient's
      daily urine output exceeded their daily fluid intake. The patient's overall fluid
      balance and change in weight were recorded daily. The PaO2/FiO2 ratio, alveolar
      arterial oxygen gradient, and oxygenation index were also calculated daily.
      MEASUREMENTS AND MAIN RESULTS: Six patients with ARDS, mean age 18.7+/-37.0
      months were mechanically ventilated for 8.0+/-4.0 days before CFPD, during which
      time average body weight increased to 63%+/-22% above admission body weight,
      despite the use of intravenous diuretic therapy. They underwent CFPD for 126.7+/
      60.0 hrs, during which time their body weight decreased to 30%+/-12% above
      admission weight (p<.05). During dialysis, the dialysis outflow rate exceeded the
      inflow rate by 4.2+/-0.9 mL/kg/hr. When compared with values calculated
      immediately before starting CFPD, post-CFPD PaO2/FiO2 increased from 97.0+/-32.0
      to 215.0+/-40.4 mm Hg (12.9+/-4.3 to 28.7+/-5.4 kPa) (p<.05), post-CFPD alveolar
      arterial oxygen gradient decreased from 390.7+/-85.8 to 206.7+/-72.8 mm Hg
      (52.1+/-11.4 to 27.6+/-9.7 kPa) (p<.05), and post-CFPD the oxygenation index
      decreased from 29.6+/-9.8 to 11.8+/-5.6 (p<.05). There were no complications
      associated with dialysis catheter insertion or CFPD therapy. Four patients
      survived. Two patients had an irreversible course of infections and septic shock
      and died. CONCLUSION: Severe anasarca in the course of ARDS can be effectively
      treated in pediatric patients with continuous flow peritoneal dialysis, resulting
      in a significant improvement in respiratory status.

PMID- 10579277
TI  - Blind protected specimen brush and bronchoalveolar lavage in ventilated children.
AB  - OBJECTIVE: To determine whether nonbronchoscopic protected specimen brush (PSB)
      and bronchoalveolar lavage (BAL) are contributive for diagnosing ventilator
      associated pneumonia in mechanically ventilated children. DESIGN: Prospective
      study. SETTING: Fifteen-bed pediatric intensive care unit in a university
      hospital. PATIENTS: A total of 103 mechanically ventilated children, ranging in
      age from 7 days to 8.8 yrs, most with a high clinical suspicion for bacterial
      pneumonia. INTERVENTIONS: All the children underwent nonbronchoscopic PSB and
      BAL. Nonbronchoscopic PSB was performed with a plugged double-sheathed brush and
      BAL with a double-lumen plugged catheter. Endotracheal secretions and blood
      cultures were also collected. Open-lung biopsy was performed for any child who
      died within 7 days after the inclusion in the study, according to the parental
      consent. MEASUREMENTS AND MAIN RESULTS: The PSB specimens were submitted for
      bacteriologic quantitative culture (positive threshold, 10(3) colony-forming
      units [cfu]/mL). The BAL samples were processed for microscopic quantification of
      the polymorphonuclear cells containing intracellular bacteria (positive
      threshold, 1%) and quantitative culture (positive threshold, 10(4) cfu/mL).
      According to diagnostic categories based on clinical, biological, radiologic, and
      pathologic criteria, 29 children had bacterial pneumonia and 64 did not Ten
      children were classified as having an uncertain status. Of the 29 children with
      bacterial pneumonia, 26 (90%) met one of the following three criteria: a) PSB
      specimen culture, > or =10(3) cfu/mL; b) intracellular bacteria in cells
      retrieved by BAL, > or =1%; and c) BAL fluid culture, > or =10(4) cfu/mL. In
      contrast, 56 (88%) of the 64 patients without pneumonia did not. CONCLUSION: The
      results of this study indicate the following: a) nonbronchoscopic PSB and BAL
      were feasible in a large population of mechanically ventilated children; b)
      nonbronchoscopic techniques were contributive for diagnosing ventilator
      associated pneumonia in children; and c) a combined diagnostic approach, using
      nonbronchoscopic PSB and BAL, was superior to using either test alone.

PMID- 10579278
TI  - Myopathy in critically ill patients.
AB  - OBJECTIVE: To review myopathic changes occurring during intensive care treatment
      in the light of recent information about manifestation, clinical settings,
      pathophysiology, and histomorphologic changes. DATA SOURCES: The computerized
      MEDLINE database, bibliography of pertinent articles, and the author's personal
      files. STUDY SELECTION: Studies were selected according to their relevance to
      myopathic complications in critically ill patients. DATA EXTRACTION: All
      applicable data were extracted. DATA SYNTHESIS: Myopathic changes occur
      frequently in patients treated in the intensive care unit (ICU). Three main types
      have been identified: critical illness myopathy, myopathy with selective loss of
      myosin filaments, and acute necrotizing myopathy of intensive care. These
      histologic types probably represent variable expressions of a toxic effect not
      yet identified. Candidates for such myotoxic effects are the mediators of the
      systemic response in sepsis and high-dose administration of corticosteroids and
      muscle relaxants. The influence of these latter agents appears to be particularly
      important in the pathogenesis of myosin loss and myonecrosis. Experimental
      studies suggest that axonal damage attributable to critical illness neuropathy
      can be an additional factor triggering myopathies in the ICU. Muscle membrane
      inexcitability was recently identified as an alternative mechanism of severe
      weakness in ICU patients. CONCLUSIONS: Myopathic changes are surprisingly
      frequent in critically ill patients. The clinical importance of this finding is
      still unknown, but it is likely that weakness caused by myopathy prolongs ICU
      stay and rehabilitation. Because corticosteroids and muscle relaxants appear to
      trigger some types of ICU myopathy, they should be avoided or administered at the
      lowest doses possible. Sepsis, denervation, and muscle membrane inexcitability
      may be additional factors. Studies addressing the pathophysiology of myopathy in
      critically ill patients are urgently needed.

PMID- 10579279
TI  - Protected specimen brush or bronchoalveolar lavage to diagnose bacterial
      nosocomial pneumonia in ventilated adults: a meta-analysis.
AB  - OBJECTIVE: We conducted a meta-analysis by using summary receiver operating
      characteristic curves to compare the diagnostic value for bacterial nosocomial
      pneumonia of the following: a) quantitative culture (colony-forming units per
      milliliter or CFU/mL) of respiratory secretions collected with a bronchoscopic
      protected specimen brush (PSB); b) quantitative culture of a bronchoscopic
      bronchoalveolar lavage (BAL); and c) the percentage of infected cells (IC) in
      BAL. DATA SOURCES: All studies published in the English or the French language,
      through January 1, 1995, on the evaluation of PSB or BAL for the diagnosis of
      pneumonia were considered for analysis. The relevant literature was identified
      through computer and reference searching and by experts in the field. STUDY
      SELECTION: A study was included if at least two of three independent readers
      regarded its purpose as the evaluation of CFU-PSB, CFU-BAL, or IC-BAL for the
      diagnosis in human beings of bacterial nosocomial pneumonia in ventilated adults
      and if the study was prospective and published in a peer-reviewed journal. DATA
      EXTRACTION: Three readers reviewed all published articles and decided whether to
      include each study; consensus was defined as agreement by at least two readers.
      The authors of each original article included in the meta-analysis were asked to
      complete a questionnaire in which they were asked to check and to correct the
      data extracted by one of the independent readers. DATA SYNTHESIS: Summary
      receiver operating characteristic curves were used to compare the efficacy of
      three diagnostic tests. Eighteen studies on CFU-PSB (795 patients) were included,
      as well as 11 studies on CFU-BAL (435 patients) and 11 on IC-BAL (766 patients).
      The accuracy of these tests was not different. However, it seems that
      administration of previous antibiotics markedly decreased accuracy of CFU-PSB (p
      = .0002) but not the accuracy of CFU-BAL and that of IC-BAL. CONCLUSION: Both PSB
      and BAL are reliable to diagnose bacterial nosocomial pneumonia. Because CFU-BAL
      and IC-BAL seemed more resistant to the effects of antibiotics, we recommend BAL
      rather than PSB if the patient is already receiving antibiotics.

PMID- 10579280
TI  - Accurate and precise delivery of nitric oxide during high-frequency oscillatory
      ventilation.
AB  - BACKGROUND: We have previously described a method for the precise delivery of
      inhaled nitric oxide (iNO) via a conventional, continuous-flow, pressure-limited,
      time-cycled ventilator. Because of the augmented effect of iNO decreasing
      pulmonary vascular resistance with high-frequency oscillatory ventilation (HFOV),
      we developed and bench tested a system that permits easy and accurate iNO
      delivery during HFOV. METHOD: The system uses a mass flow controller to deliver
      fixed volumes of iNO to the HFOV circuit in the range 0 to 20 ppm iNO. The
      accuracy of the delivery system is based on a comparison of the difference
      between iNO measured at strategic points in the circuit and the calculated true
      value. RESULTS: The mean difference between the measured and calculated value for
      iNO (n = 360) was -0.2+/-1.74 ppm (2 SD) (range, 0 to 20 ppm, 0 to 15 Hz). The
      formation of nitrogen dioxide was <1 ppm at the level of the endotracheal tube.
      CONCLUSION: The method tests the accuracy of iNO measurements and provides an
      assessment of the uncertainty over the range of iNO and HFOV settings used
      clinically.

PMID- 10579281
TI  - Nitric oxide successfully used to treat acute chest syndrome of sickle cell
      disease in a young adolescent.
AB  - OBJECTIVES: To report a case of acute chest syndrome (ACS) of sickle cell disease
      treated successfully with nitric oxide and to review the physiologic effects of
      nitric oxide and its potential ability to improve outcome in ACS. DESIGN:
      Descriptive case report. SETTING: Eighteen-bed pediatric intensive care unit in a
      university children's hospital. PATIENT: A 15-yr-old black male with sickle cell
      disease, bilateral pulmonary infiltrates, refractory hypoxemia, and unstable
      hemodynamics. INTERVENTION: In addition to exchange transfusion, invasive
      hemodynamic monitoring, and aggressive ventilatory support, inhaled nitric oxide
      was administered in the gas mixture in a concentration of 20 ppm for 72 hrs.
      MEASUREMENTS AND MAIN RESULTS: Cardiac output, pulmonary arterial pressure,
      pulmonary artery occlusion pressure, systemic vascular resistance, pulmonary
      vascular resistance, shunt fraction, and alveolar-arterial oxygen gradient were
      compared with and without inhaled nitric oxide. Marked reductions in pulmonary
      arterial pressure and pulmonary vascular resistance were noted. Cardiac output
      improved, and shunt fraction and alveolar-arterial oxygen gradient were markedly
      reduced. The patient required decreased ventilator and hemodynamic support and
      rapidly made a complete recovery. CONCLUSIONS: Nitric oxide may be beneficial for
      patients with ACS because of its ability to ameliorate pulmonary hypertension and
      ventilation/perfusion mismatch. Nitric oxide may confer some protection against
      polymerization of sickle hemoglobin and exert a reversible antiplatelet effect
      that may be beneficial in ACS. Further study is necessary to determine the safety
      and efficacy of inhaled nitric oxide as a treatment for ACS.

PMID- 10579282
TI  - Local monitoring of cerebral oxygenation: a new and useful tool?

PMID- 10579283
TI  - All my possessions for a moment of time!

PMID- 10579284
TI  - The dobutamine oxygen flux test: a road map to outcome in sepsis?

PMID- 10579285
TI  - On patients and patience.

PMID- 10579286
TI  - Prone position in ARDS: what do we know, and what do we need to know?

PMID- 10579287
TI  - Increasing splanchnic perfusion.

PMID- 10579288
TI  - Acidified enteral feeds: is it physiologic?

PMID- 10579289
TI  - In search of a better watch.

PMID- 10579290
TI  - Tumor necrosis factor-alpha, sphingosine, ceramide: which is the appropriate
      marker of inflammation?

PMID- 10579291
TI  - Potassium replacement after cardiac surgery: it is not time to change practice,
      yet.

PMID- 10579292
TI  - Corticosteroids and the neutrophil: cutting both ways.

PMID- 10579293
TI  - A new day is coming: sedation issues in critical care.

PMID- 10579294
TI  - Lung injury and lactate production: a hypoxic stimulus?

PMID- 10579295
TI  - Can nitric oxide production be modulated by altering L-arginine levels?

PMID- 10579296
TI  - Investigations into the polydeterminant nature of sepsis.

PMID- 10579297
TI  - Partial liquid ventilation combined with high frequency gas ventilation: clinical
      breakthrough or two treatments looking for a home?

PMID- 10579299
TI  - Good fare lessens care.

PMID- 10579298
TI  - Ameliorating cerebral hypoperfusion after traumatic brain injury.

PMID- 10579300
TI  - Peritoneal dialysis.

PMID- 10579301
TI  - Why can't I see clearly now? I have a meta-analysis!

PMID- 10579302
TI  - When knowing is not understanding.

PMID- 10579303
TI  - Intriguing on first sight.

PMID- 10579304
TI  - Gastric intramucosal acidosis in mechanically ventilated patients: role of
      mucosal blood flow.

PMID- 10579305
TI  - Steroids in sepsis: which p value is correct?

PMID- 10579306
TI  - Withdrawal syndrome and tolerance to sedatives and analgesics in intensive care
      unit patients.

PMID- 10579307
TI  - Pediatric gastric tonometry: lessons from the adult experience.

PMID- 10579308
TI  - Mcl-1--just another antiapoptotic Bcl-2 Homolog?

PMID- 10579309
TI  - Characterization of the antiapoptotic Bcl-2 family member myeloid cell leukemia-1
      (Mcl-1) and the stimulation of its message by gonadotropins in the rat ovary.
AB  - The majority of ovarian follicles undergo atresia mediated by apoptosis. Bcl-2
      related proteins act as regulators of apoptosis via the formation of dimers with
      proteins inside and outside the Bcl-2 family. Previous studies have identified
      BAD as a proapoptotic Bcl-2 family member expressed in the ovary. It is known
      that BAD phosphorylation induced by survival factors leads to its preferential
      binding to 14-3-3 and suppression of the death-inducing function of BAD. To
      identify ovarian binding partners for hypophosphorylated BAD, we performed a
      yeast two-hybrid screening of a rat ovary complementary DNA library using as bait
      a mutant BAD incapable of binding to 14-3-3. Screening of yeast transformants
      yielded positive clones encoding the rat ortholog of Mcl-1 (myeloid cell leukemia
      1), an antiapoptotic Bcl-2 protein. Amino acid sequence analysis revealed that
      rat and human Mcl-1 showed a complete conservation of the Bcl-2 homology domains
      BH1, BH2, and BH3. In the yeast two-hybrid system, Mcl-1 binds to the
      hypophosphorylated mutant of BAD and interacts preferentially with different
      proapoptotic (Bax, Bak, Bok, Bik, and BOD) compared with antiapoptotic Bcl-2
      family members (Bcl-2, Bcl-xL, Bcl-w, Bfl-1, CED-9, and BHRF-1). Northern blot
      hybridization demonstrated expression of Mcl-1 transcripts of 2.3 and 3.7 kb in
      the ovary and diverse other rat tissues. In immature rats, PMSG treatment led to
      a transient increase in the 2.3-kb Mcl-1 transcript, peaking at 6 h after
      injection and returning to baseline levels after 24 h. Moreover, the same
      transcript was induced in the PMSG-primed preovulatory rat ovary 6 h after the
      administration of ovulatory doses of either hCG or FSH. In situ hybridization
      studies revealed that the gonadotropin stimulation of ovarian Mcl-1 message
      occurs in both granulosa and thecal cells. In conclusion, rat Mcl-1 was
      identified as an ovarian BAD-interacting protein and the message for the
      antiapoptotic Mcl-1 protein was induced after treatment with gonadotropins in
      granulosa and thecal cells of growing follicles.

PMID- 10579310
TI  - Postnatal growth responses to insulin-like growth factor I in insulin receptor
      substrate-1-deficient mice.
AB  - Organ weight was compared in adult mice with deletion of one (IRS-1-/+) or both
      (IRS-1-/-) copies of the insulin receptor substrate-1 (IRS-1) gene and IRS-1+/+
      littermates. IRS-1-/+ mice showed modest reductions in weight of most organs in
      proportion to a decrease in body weight. IRS-1-/- mice showed major reductions in
      weight of heart, liver, and spleen that were directly proportional to a decrease
      in body weight. In IRS-1-/- mice, kidney and particularly small intestine and
      brain exhibited proportionately smaller weight reductions, and gastrocnemius
      muscle showed a proportionately greater weight reduction than the decrease in
      body weight. Growth deficits in IRS-1-/- mice could reflect impaired actions of
      multiple hormones or cytokines that activate IRS-1. To assess the requirement for
      IRS-1 in insulin-like growth factor I (IGF-I)-dependent postnatal growth, IRS-1
      /+ mice were cross-bred with mice that widely overexpress a human IGF-I transgene
      (IGF+) to generate IGF+ and wild-type mice on an IRS-1+/+, IRS-1-/+, and IRS-1-/-
      background. IGF-I overexpression increased body weight and weight of brain, small
      intestine, kidney, spleen, heart, and gastrocnemius muscle in IRS-1+/+ mice. IGF
      I overexpression could not completely reverse the body growth retardation in IRS
      1-/- mice. Absolute or partial IRS-1 deficiency impaired IGF-I-induced body
      overgrowth more in females than in males. In males and females, IGF-I stimulated
      similar overgrowth of brain regardless of IRS-1 status, and intestine and spleen
      showed dose dependence on IRS-1 for IGF-I-induced growth. IGF-I-induced growth of
      gastrocnemius muscle had an absolute requirement for IRS-1. IGF-I-induced growth
      of kidney and heart was impaired by IRS-1 deficiency only in females. In vivo,
      therefore, most organs do not require IRS-1 for IGF-I-induced growth and can use
      alternate signaling molecules to mediate IGF-I action. Other organs, such as
      gastrocnemius muscle, require IRS-1 for IGF-I-induced growth in vivo.

PMID- 10579311
TI  - Overexpression of insulin-like growth factor-binding protein-2 in transgenic mice
      reduces postnatal body weight gain.
AB  - Insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) has been shown to
      inhibit IGF-dependent cell proliferation in a number of in vitro studies.
      However, no in vivo model of IGFBP-2 overexpression has been established so far.
      Therefore, we have generated transgenic mice, in which expression of a mouse
      IGFBP-2 complementary DNA is controlled by the cytomegalovirus (CMV) promoter. In
      two independent transgenic strains, transgene expression was highest in pancreas
      and stomach, followed by skeletal muscle, heart, colon, spleen, adipose tissue,
      brain, and kidney. Within the pancreas, IGFBP-2 expression was found in the
      islets but not in the exocrine part. Serum IGFBP-2 levels of CMV-IGFBP-2
      transgenic mice were about 3-fold (P < 0.05) increased, compared with controls,
      whereas serum levels of IGF-I and IGF-II were unaffected by IGFBP-2
      overexpression. Fasted serum glucose and fasted insulin levels were slightly
      reduced in transgenic mice, compared with controls. Postprandial serum glucose
      insulin levels were not affected by the genotype. At days later than 23, body
      weights of transgenic mice were significantly (P < 0.05) reduced in both sexes,
      compared with nontransgenic littermates. This reduction in body weight was mainly
      attributable to significantly (P < 0.05) lower carcass weights of CMV-IGFBP-2
      transgenic vs. control mice. In contrast, absolute organ weights were not (or
      only as a tendency) reduced, except for the weight of the spleen, which was
      significantly (P < 0.05) lower in male transgenic than in control mice. Our data
      suggest that IGFBP-2 represents a negative regulator of postnatal growth in mice,
      potentially by reducing the bioavailability of IGF-I.

PMID- 10579312
TI  - Partial characterization of circulating inhibin-B and pro-alphaC during
      development in the male rhesus monkey.
AB  - Gel filtration chromatography and ELISAs for inhibin-B and pro-alphaC were used
      to examine the circulating forms of inhibin in the neonatal (age 2-6 weeks),
      juvenile (age 1-2 yr), and adult male rhesus monkey. In all samples, isoforms of
      inhibin-B of 26-36K and 150K were found. Both forms were significantly greater in
      the adult. The alpha-subunit assay detected major peaks at 45-60 and 29-31K, and
      a minor peak of greater than 100K. As for inhibin-B, the major forms of inhibin
      pro-alphaC were highest in adulthood. Inhibin-B and pro-alphaC were measurable in
      peripheral plasma at age 1 week, increased with the neonatal rise in plasma FSH,
      and then decreased but remained detectable through age 1 yr. Values in adult
      males were higher than at any time during the first year of life. Finally, mean
      values of plasma inhibin-B and pro-alphaC in five monkeys, based on multiple
      blood samples drawn between age 1 week and 1 yr, were rank ordered and were found
      to be highly positively correlated (r = 0.96), suggesting that inhibin levels in
      the first year of life may be a marker of Sertoli cell number, and may predict
      the spermatogenic capacity of the testis in adulthood.

PMID- 10579313
TI  - Endotoxin-induced inhibition of growth hormone receptor signaling in rat liver in
      vivo.
AB  - The bacterial lipopolysaccharide endotoxin induces a catabolic response
      characterized by resistance to multiple anabolic hormones. The objective of this
      study was to determine the effects of endotoxin on the GH signaling pathway in
      rat liver in vivo. After the iv injection of Escherichia coli endotoxin (1
      mg/kg), there was a progressive decrease in liver STAT5 (signal transducer and
      activator of transcription-5) tyrosine phosphorylation in response to GH (40%
      decrease 6 h after endotoxin), which occurred in the absence of a change in
      abundance of the STAT5 protein. Endotoxin resulted in a rapid 40-fold increase in
      liver Janus family kinase-2 (JAK2) messenger RNA, followed by a 2-fold increase
      in JAK2 protein abundance. This was associated with a 50% decrease in
      phosphorylated/total JAK2 after GH stimulation. GH receptor abundance was
      unchanged, suggesting a postreceptor site of endotoxin-induced GH resistance. Rat
      complementary DNAs for three members of the suppressor of cytokine signaling gene
      family were cloned [cytokine-inducible sequence (CIS), suppressor of cytokine
      signaling-2 (SOCS-2), and SOCS-3] and, using these probes, messenger RNAs for
      SOCS-3 and CIS were shown to be increased 10- and 4-fold above control values,
      respectively, 2 h after endotoxin infusion. The finding of endotoxin inhibition
      of in vivo STAT5 tyrosine phosphorylation in response to a supramaximal dose of
      GH in the absence of a change in GH receptor abundance or total GH-stimulated
      JAK2 tyrosine phosphorylation provides the first demonstration of acquired
      postreceptor GH resistance. We hypothesize that this may occur through a
      specificity-spillover mechanism involving the induction of SOCS genes by
      cytokines released in response to endotoxin and subsequent SOCS inhibition of GH
      signaling.

PMID- 10579314
TI  - Ca2+/calmodulin inhibition and phospholipase C-linked Ca2+ Signaling in clonal
      beta-cells.
AB  - Neurotransmitters and hormones, such as arginine vasopressin (AVP) and bombesin,
      evoke frequency-modulated repetitive Ca2+ transients in insulin-secreting HIT-T15
      cells by binding to receptors linked to phospholipase C (PLC). The role of
      calmodulin (CaM)-dependent mechanisms in the generation of PLC-linked Ca2+
      transients was investigated by use of the naphthalenesulfonamide CaM antagonists
      W-7 and W-13 and their dechlorinated control analogs W-5 and W-12. W-7 (10-30
      microM) and W-13 (30-100 microM), but not W-5 (100 microM) and W-12 (300 microM),
      reversibly inhibited the AVP- and bombesin-induced Ca2+ transients. As the
      generation of PLC-linked Ca2+ transients requires mobilization of internal Ca2+
      and Ca2+ influx through voltage-sensitive (VSCC) and -insensitive (VICC) Ca2+
      channels, the effects of the W compounds on these processes were further
      investigated. First, W-7 dose dependently diminished K+ (45 mM)-induced Ca2+
      signals (IC50, approximately 25 microM), and W-13 (100 microM) reduced the K+ (45
      mM)-induced [Ca2+]i rise by about 40-60%, whereas W-5 (100 microM) and W-12 (300
      microM) had no effect. In addition, W-7 (100 microM) inhibited whole cell Ca2+
      currents in mouse beta-cells by about 60%. Second, pretreatment of cells (5 min)
      with W-7 (30 microM), but not W-5 (30 microM), inhibited agonist-induced internal
      Ca2+ mobilization by about 75% in Ca2+-free medium. Neither W-7 (30 microM) nor W
      5 (30 microM) affected AVP (100 nM)-stimulated formation of IP3. Third,
      capacitative Ca2+ influx through VICC activated by thapsigargin (2 microM) in the
      presence of verapamil (50 microM) was inhibited by W-7 (30 microM) but not by W-5
      (30 microM). As all of the W compound effects corresponded well to their reported
      anticalmodulin activity, a specific anticalmodulin action can be assumed. Thus,
      Ca2+ via activation of CaM-dependent processes could provide positive feedback on
      the generation of PLC-linked Ca2+ transients in HIT-T15 cells. This appears to
      involve CaM-dependent regulation of both mobilization of internal Ca2+ and Ca2+
      influx through VSCC and VICC.

PMID- 10579315
TI  - Ca2+ signaling in mouse pancreatic polypeptide cells.
AB  - Ca2+ signaling was studied in pancreatic polypeptide (PP)-secreting cells
      isolated from mouse islets of Langerhans. After measuring the cytoplasmic Ca2+
      concentration ([Ca2+]i), the cells were identified by immunocytochemistry. Most
      PP-cells reacted to carbachol and epinephrine with prompt and reversible
      elevation of [Ca2+]i, often manifested as slow oscillations. The carbachol effect
      was muscarinic, because it was inhibited by atropine. Beta-adrenergic elevation
      of cAMP explains the epinephrine stimulation, which was mimicked by an activator
      of adenylate cyclase and blocked by an inhibitor of protein kinase A. The
      responses to carbachol and epinephrine apparently involve depolarization with
      opening of voltage-dependent Ca2+ channels, because the effects were prevented by
      the Ca2+ channel antagonist methoxyverapamil and by diazoxide, which activates
      ATP-dependent K+ (K(ATP)) channels. Being equipped with K(ATP) channels, the PP
      cells often responded to tolbutamide or high concentrations of glucose with
      elevation of [Ca2+]i. Somatostatin reversed the [Ca2+]i elevation obtained by
      carbachol, epinephrine, tolbutamide, and glucose. These preliminary studies
      support the idea that glucose has a direct stimulatory effect on the PP-cells,
      which can be masked by locally released somatostatin. Expressing both K(ATP)
      channels and voltage-dependent Ca2+ channels, the PP-cells share fundamental
      regulatory mechanisms with other types of islet cells.

PMID- 10579316
TI  - Molecular and functional characterization of pituitary adenylate cyclase
      activating polypeptide (PACAP-38)/vasoactive intestinal polypeptide receptors in
      pancreatic beta-cells and effects of PACAP-38 on components of the insulin
      secretory system.
AB  - It has been previously demonstrated that pituitary adenylate cyclase-activating
      polypeptide (PACAP) regulates insulin secretion. PACAP exerts its biological
      action by binding to at least three different receptor subtypes coupled to
      different signal transduction mechanisms. The signaling pathways underlying the
      insulinotropic effect of PACAP involve mainly the activation of adenylate cyclase
      to form cAMP, which directly and indirectly, through increased intracellular
      Ca2+, stimulates insulin exocytosis. In the present study we have characterized
      the functional and molecular expression of PACAP/vasoactive intestinal
      polypeptide receptors isoforms and subtypes and its isoforms in a beta-cell line
      and in isolated rat pancreatic islets. Although insulinoma cells express the
      messenger RNA encoding PAC1 (-R and -hop variants), VPAC1 and VPAC2, binding
      experiments indicate the preponderance of PAC1 over VPAC 1-2 receptors. We have
      also shown that the main signaling pathway of PACAP in beta-cells is mediated by
      adenylate cyclase, whereas the inositol 1,4,5-trisphosphate pathway is almost
      inactive. Furthermore, we have demonstrated that PACAP exerts long-term effects
      on beta-cells, such as transcriptional regulation of the insulin gene and genes
      of the glucose-sensing system (GLUT1 and hexokinase 1).

PMID- 10579317
TI  - UGT2B23, a novel uridine diphosphate-glucuronosyltransferase enzyme expressed in
      steroid target tissues that conjugates androgen and estrogen metabolites.
AB  - Glucuronidation is widely accepted as a mechanism involved in the catabolism and
      elimination of steroid hormones from the body. However, relatively little is
      known about the enzymes involved, their specificity for the different steroids,
      and their site of expression and action. To characterize the pathway of steroid
      glucuronidation, a novel uridine diphosphate glucuronosyltransferase (UGT) enzyme
      was cloned and characterized. A 1768-bp complementary DNA, encoding UGT2B23 was
      isolated from a monkey liver library. Stable expression of UGT2B23 in human HK293
      cells and Western blot analysis demonstrated the presence of a 51-kDa protein.
      The UGT2B23 transferase activity was tested with 62 potential endogenous
      substrates and was demonstrated to be active on 6 steroids and the bile acid,
      hyodeoxycholic acid. Kinetic analysis yielded apparent Michaelis constant (Km)
      values of 0.9, 13.5, 1.6, and 5.7 microM for the conjugation of androsterone
      (ADT), 3alpha-Diol, estriol, and 4-hydroxyestrone, respectively. RT-PCR analysis
      revealed that UGT2B23 transcript is expressed in several tissues, including the
      prostate, mammary gland, epididymis, testis, and ovary. Primary structure
      analysis shows that UGT2B23 is in the same family of enzymes as the previously
      characterized monkey isoforms UGT2B9 and UGT2B18, which are active on
      hydroxyandrogens. The characterization of UGT2B23 as a functional enzyme active
      on 3alpha-hydroxysteroids, and its expression in extrahepatic tissues, indicate
      that it may potentially play an important role in estrogen and androgen
      catabolism in peripheral steroid target tissues.

PMID- 10579318
TI  - Mechanisms by which blood levels of interleukin-6 (IL-6) are elevated after
      intracerebroventricular injection of IL-1beta in the rat: neural versus humoral
      control.
AB  - Intracerebroventricular (icv) injection of interleukin-1beta (IL-1beta) in rats
      induces elevated IL-6 levels in peripheral blood, exceeding those induced by iv
      or ip injection. Two hypotheses postulated to explain this phenomenon were
      tested. Mediation by peripheral sympathetic activation was excluded by showing
      that agents that blocked preganglionic cholinergic synapses (chlorisondamine),
      beta-adrenergic receptors (propanalol, butoxamine), and alpha-adrenergic
      receptors (phentolamine) did not prevent the IL-6 response. That the peripheral
      response was due to passage of the injected IL-1beta into blood from the brain
      was supported by several observations. Immunoreactive IL-1beta appeared in
      peripheral blood by 10 min after icv injection and remained constant between 10
      100 min after injection; values after icv injection were virtually identical to
      those after iv injection at 60 and 80 min. Radioiodine-labeled IL-1beta appeared
      in blood as early as 5 min, and by phamacokinetic analysis was found to be
      transferred from the brain at a rate greater than 2% of brain content per min(
      1). IL-1beta infused iv in a pattern mimicking brain to blood transfer induced IL
      6 levels that were more than double the values induced by a single bolus
      injection and were not significantly different from the values observed after icv
      injection. Sustained levels of IL-1beta in blood over time contribute to the high
      peripheral IL-6 response. This was shown by administering the same total dose iv
      as a single bolus of 100 ng or in two doses of 50 ng 1 h apart. Rats given a
      divided dose had 6-10 times higher blood IL-6 levels at 2 h than those given a
      single injection. The high levels of IL-6 in blood after icv injection of IL
      1beta are best explained by the reservoir function of the brain IL-1beta pool and
      the self-priming effect of IL-1beta in peripheral tissues.

PMID- 10579319
TI  - Metabolic and secretory interactions between D-glucose and D-fructose in islets
      from GK rats.
AB  - The metabolism of D-glucose and/or D-fructose was investigated in both pancreatic
      islets and parotid cells of control and hereditarily diabetic Goto-Kakizaki (GK)
      rats. In the islets from GK rats, a preferential alteration of the oxidative
      response to D-glucose coincided with an impaired secretory response to the
      aldohexose. Such a metabolic alteration was not found in the parotid cells of GK
      rats. Whether in islet or parotid cells, D-fructose little affected the
      catabolism of glucose in either control or GK rats. The metabolism of D-fructose
      and the effect of D-glucose thereupon were essentially comparable in control and
      GK rats in both pancreatic islets and parotid cells. In both cell types, the
      comparison between the metabolism of D-glucose and D-fructose in cells
      simultaneously exposed to the two hexoses suggested a far from negligible
      contribution of fructokinase to the phosphorylation of D-fructose. Although the
      catabolism of the ketohexose and its modulation by D-glucose were closely
      comparable in islets from control and GK rats, the insulinotropic action of the
      ketohexose, relative to that of the aldohexose, was severely impaired in the GK
      rats. The present work thus emphasizes the specificity of the alteration in D
      glucose metabolism in islets, as opposed to extrapancreatic cells, of GK rats. It
      also reveals in the islets of GK rats a further secretory anomaly apparently not
      attributable to the impairment of nutrient catabolism in the islet cells of these
      diabetic animals.

PMID- 10579320
TI  - The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor
      modulates ERalpha transcriptional activity and is a key regulator of the cellular
      response to estrogens and antiestrogens.
AB  - The human estrogen receptor alpha (ERalpha) and the recently identified ERbeta
      share a high degree of amino acid homology; however, there are significant
      differences in regions of these receptors that would be expected to influence
      transcriptional activity. Consequently, we compared the mechanism(s) by which
      these receptors regulate target gene transcription, and evaluated the cellular
      consequences of coexpression of both ER subtypes. Previously, it has been
      determined that ERalpha contains two distinct activation domains, ERalpha-AF-1
      and ERalpha-AF-2, whose transcriptional activity is influenced by cell and
      promoter context. We determined that ERbeta, like ERalpha, contains a functional
      AF-2, however, the ERbeta-AF-2 domain functions independently within the
      receptor. Of additional significance was the finding that ERbeta does not contain
      a strong AF-1 within its amino-terminus but, rather, contains a repressor domain
      that when removed, increases the overall transcriptional activity of the
      receptor. The importance of these findings was revealed when it was determined
      that ERbeta functions as a transdominant inhibitor of ERalpha transcriptional
      activity at subsaturating hormone levels and that ERbeta decreases overall
      cellular sensitivity to estradiol. Additionally, the partial agonist activity of
      tamoxifen manifest through ERalpha in some contexts was completely abolished upon
      coexpression of ERbeta. In probing the mechanisms underlying ERbeta-mediated
      repression of ERalpha transcriptional activity we have determined that 1) ERalpha
      and ERbeta can form heterodimers within target cells; and 2) ERbeta interacts
      with target gene promoters in a ligand-independent manner. Cumulatively, these
      data indicate that one role of ERbeta is to modulate ERalpha transcriptional
      activity, and thus the relative expression level of the two isoforms will be a
      key determinant of cellular responses to agonists and antagonists.

PMID- 10579321
TI  - Effects of androgens on the insulin-like growth factor system in an androgen
      responsive human osteoblastic cell line.
AB  - Although androgens have significant effects on bone metabolism, the mediators of
      their effects are still unclear. As the insulin-like growth factors (IGFs) and
      IGF-binding proteins (IGFBPs) have important effects on osteoblast proliferation
      and differentiation, we examined androgen effects on the IGF system in a
      conditionally immortalized human fetal osteoblastic cell line, hFOB/AR-6, which
      displays a mature osteoblastic phenotype and physiological levels of functional
      androgen receptors. The nonaromatizable androgen, 5alpha-dihydrotestosterone
      (5alphaDHT), and testosterone, but not dehydroepiandrosterone, increased IGF-I
      messenger RNA (mRNA) levels up to 4-fold in a dose (10(-12)-10(-6) M)- and time
      (2-72 h)-dependent fashion. These changes were prevented by the specific androgen
      receptor antagonist, hydroxyflutamide. In addition, 5alpha-DHT decreased IGFBP-4
      mRNA and protein levels by 2- and 4-fold, respectively, and increased IGFBP-2 and
      -3 mRNA and protein levels by 6- and 7-fold (for mRNA) and 3- and 5-fold (for
      protein), respectively. hFOB/AR-6 cells expressed the type-I IGF receptor, but
      this was not regulated by 5alphaDHT. 5alphaDHT and IGFBP-3 specifically increased
      hFOB/AR-6 cell proliferation, and a monoclonal antibody specific for IGF-I
      blocked this effect. Thus, androgens increase the expression of IGF-I, IGFBP-2,
      and IGFBP-3, but decrease levels of the inhibitory IGFBP-4 in an androgen
      responsive human osteoblastic cell line. Our data are consistent with the
      hypothesis that the effects of androgen on bone cells may be mediated at least in
      part by increases in IGF-I production and by differential regulation of IGFBPs.

PMID- 10579322
TI  - Expression of growth hormone and its receptor in the placental and feto-maternal
      environment during early pregnancy in sheep.
AB  - In a previous study we showed the existence of GH in the ovine placenta. We now
      supplement the information available on placental GH and describe the presence
      and distribution of GH receptor (GH-R) messenger RNA (mRNA) in uterine, fetal,
      and placental tissues during early pregnancy. GH mRNA was not detected in the
      placenta before day 27 (d27). Its expression peaked between d40 and d45 and fell
      after d55. GH mRNA was localized in the trophectoderm and syncytium. During the
      d35-d50 period, concentrations of GH in the maternal circulation were not
      increased. In umbilical blood, however, GH was detected from d35 and was presumed
      to be of placental origin, because GH mRNA was not detected in the fetal
      pituitary gland on d40. We report on GH-R mRNA expression in the placenta between
      d20-d120. The relative abundance of GH-R transcripts increased significantly
      between d25-d43. In the endometrium, GH-R mRNA was detected from d8-d120 of
      pregnancy and from d4-d16 of the cycle. GH-R mRNA was localized in the
      trophectoderm, fetal mesoderm, and maternal uterine stroma. In the fetal liver,
      GH-R mRNA was first detectable on d35. The results of this study indicate that
      between d35-d50 of pregnancy, the endometrium, placenta, and fetus are all
      potential targets for the placental GH.

PMID- 10579323
TI  - Cloning of the mouse somatostatin receptor subtype 5 gene: promoter structure and
      function.
AB  - Somatostatin is a peptide hormone whose actions are mediated by five somatostatin
      receptor subtypes (sstl-5). In the pituitary, somatostatin inhibits TSH release
      from thyrotropes and GH release from somatotropes. We have shown that sst5
      transcripts and protein are induced by thyroid hormone in TtT-97 thyrotropic
      tumors. To map sequences responsible for promoter activity in pituitary cells, we
      cloned the mouse sst5 coding region of 362 amino acids and 12 kb of upstream DNA.
      Initial transfection studies in TtT-97 or GH3 cells mapped high levels of basal
      promoter activity to a 5.6-kb fragment upstream of the translational start,
      whereas shorter genomic fragments had low activity. To identify the
      transcriptional start site we used 5' RACE with TtT-97 poly A+ RNA and a sst5
      antisense coding region primer. Sequence comparison between the complementary DNA
      and the gene revealed that the mouse sst5 gene contains 3 exons and 2 introns.
      The entire coding region was contained in exon 3. Two differently sized RACE
      products demonstrated alternate exon splicing of two untranslated exons in TtT-97
      cells. A promoter fragment from -290/+48 linked to a luciferase reporter
      demonstrated 600- and 900-fold higher activity over a promoterless control in GH3
      mammosomatotropes and TtT-97 thyrotropes, respectively, whereas a larger fragment
      extending to -6400 exhibited no additional promoter activity. Cloning of the sst5
      gene will facilitate the mapping of basal and regulated responses at the
      transcriptional level.

PMID- 10579324
TI  - Tissue-specific, hormonal, and developmental regulation of SCC-LacZ expression in
      transgenic mice leads to adrenocortical zone characterization.
AB  - We report here the study of the human CYP11A1 promoter in driving tissue
      specific, developmentally and hormonally regulated reporter gene expression. A
      4.4-kb fragment containing all known regulatory elements is more efficient than a
      short basal promoter fused to an upstream adrenal enhancer in driving reporter
      LacZ gene expression both in cell culture and in transgenic mice. The LacZ gene
      controlled by the 4.4- and 2.3-kb promoters was expressed in the adrenal cortex,
      testicular Leydig cells, ovarian corpora lutea, and granulosa cells. Transgene
      expression in the adrenals was stimulated by ACTH, indicating the presence of
      ACTH-responsive sequence. Beta-galactosidase activity was first detected in the
      adrenal primordia at 11.5 days postcoitum. Its expression continued throughout
      all stages of adrenal development in a pattern similar to that of the endogenous
      CYP11A1, which was expressed in all zones of the adrenal cortex, but was
      strongest in the X zone. The X zone grew before puberty but regressed afterward,
      as did the levels of CYP11A1 and LacZ gene expression in the X zone. Our study of
      the CYP11A1 promoter in transgenic mice led to characterization of the
      adrenocortical zones.

PMID- 10579325
TI  - Bovine growth hormone transgenic mice display alterations in locomotor activity
      and brain monoamine neurochemistry.
AB  - Recent clinical and experimental data indicate a role for GH in mechanisms
      related to anhedonia/hedonia, psychic energy, and reward. In the present study we
      have investigated whether bovine GH (bGH) transgenic mice and nontransgenic
      controls differ in spontaneous locomotor activity, a behavioral response related
      to brain dopamine (DA) and reward mechanisms, as well as in locomotor activity
      response to drugs of abuse known to interfere with brain DA systems. The animals
      were tested for locomotor activity once a week for 4 weeks. When first exposed to
      the test apparatus, bGH transgenic animals displayed significantly more locomotor
      activity than controls during the entire registration period (1 h). One week
      later, after acute pretreatment with saline, the two groups did not differ in
      locomotor activity, whereas at the third test occasion, bGH mice were
      significantly more stimulated by d-amphetamine (1 mg/kg, ip) than controls. At
      the fourth test, a tendency for a larger locomotor stimulatory effect of ethanol
      (2.5 g/kg, ip) was observed in bGH transgenic mice. bGH mice displayed increased
      tissue levels of serotonin and 5-hydroxyindoleacetic acid in several brain
      regions, decreased DA levels in the brain stem, and decreased levels of the DA
      metabolite 3,4-dihydroxyphenylacetic acid in the mesencephalon and diencephalon,
      compared with controls. In conclusion, bGH mice display more spontaneous
      locomotor activity than nontransgenic controls in a novel environment and
      possibly also a disturbed habituation process. The finding that bGH mice were
      also more sensitive to d-amphetamine-induced locomotor activity may suggest that
      the behavioral differences observed are related to differences in brain DA
      systems, indicating a hyperresponsiveness of these systems in bGH transgenic
      mice. These findings may constitute a neurochemical basis for the reported
      psychic effects of GH in humans.

PMID- 10579326
TI  - Epidermal growth factor and insulin-induced deoxyribonucleic acid synthesis in
      primary rat hepatocytes is phosphatidylinositol 3-kinase dependent and
      dissociated from protooncogene induction.
AB  - The mitogenic response to insulin and epidermal growth factor (EGF) was studied
      in subconfluent and confluent cultures of primary rat hepatocytes. In
      subconfluent cultures, wortmannin, LY294002, and rapamycin reversed insulin- and
      EGF-induced [3H]thymidine incorporation into DNA. The mitogen-activated protein
      kinase (MAPK) kinase 1 (MEK1) inhibitor PD98059 was without significant effect on
      either insulin- or EGF-induced [3H]thymidine incorporation. Insulin treatment did
      not alter levels of messenger RNAs (mRNAs) for c-fos, c-jun, and c-myc. EGF
      induced an increase in c-myc, but not c-fos or c-jun, mRNA levels in subconfluent
      hepatocyte cultures. This increase in c-myc mRNA was abolished by PD98059. In
      confluent cells that could not be induced to synthesize DNA, EGF treatment also
      promoted an increase in c-myc mRNA to levels seen in subconfluent cultures. This
      increase was also abrogated by PD98059. These data indicate that in primary rat
      hepatocyte cultures, 1) the phosphoinositol 3-kinase pathway, perhaps through
      p70s6k activation, regulates DNA synthesis in response to insulin and EGF; 2) the
      MAPKpathway is not involved in insulin- and EGF-induced DNA synthesis; and 3)
      p44/42 MAPKs are involved the induction of c-myc mRNA levels, although this
      induction is not required for DNA synthesis. These studies define two distinct
      signal transduction pathways that independently mediate growth-related responses
      in a physiologically relevant, normal cell system.

PMID- 10579327
TI  - Regulation of components of the ubiquitin system by insulin-like growth factor I
      and growth hormone in skeletal muscle of rats made catabolic with dexamethasone.
AB  - To investigate whether the anabolic effects of insulin-like growth factor I (IGF
      I) and GH are mediated through regulation of the ubiquitin (Ub) pathway, we
      examined the effect of IGF-I (0.35 microg/100 g) and/or GH (0.3 mg/100 g BW) on
      the expression of Ub and Ub-conjugating (E2) enzyme messenger RNAs (mRNAs) in
      skeletal muscle of rats made catabolic by treatment with dexamethasone (Dex; 0.5
      mg/100 g BW) for 3 days. Dex caused a significant loss of body and gastrocnemius
      weight (14% and 25%, respectively) concurrent with an increase in the 2.8- and
      1.2-kb transcripts of Ub (14.3- and 12-fold increases, respectively), the 1.8-
      and 1.2-kb transcripts of 14-kDa Ub-conjugating enzyme (E2-14 kDa; 5.6- and 7.7
      fold increases, respectively), the 4.4- and 2.4-kb transcripts of Ub-E2G (6.5-
      and 8.2-fold increases, respectively), and the 2E isoform of the 17-kDa E2 mRNA
      (3.5-fold increase). Injections of IGF-I in Dex-treated animals ameliorated the
      body weight loss, and the gastrocnemius tended to be heavier. This improvement
      was also accompanied by a significant suppression of transcripts for Ub (58% and
      66% decreases), E2-14 kDa (58% and 68% decreases), and Ub-E2G (78% decrease),
      whereas the 2E isoform of the 17-kDa E2 was only modestly affected (20%
      decrease). GH restored serum IGF-I levels to normal in Dex-treated rats, but had
      no effect on the body weight loss or on any of the studied components of the Ub
      pathway. Administration of IGF-I to the Dex/GH-treated animals decreased the
      activated mRNAs of the Ub pathway in a manner and degree similar to those
      observed in the Dex/ IGF-I group. In summary, these results provide evidence that
      IGF-I regulates the expression of mRNAs encoding components of the Ub pathway
      during catabolism and suggest a possible mechanism for the antiproteolytic
      actions of IGF-I. On the other hand, GH, which is believed not to affect
      proteolysis but only protein synthesis, had no effect on any of the mRNAs
      studied.

PMID- 10579328
TI  - Differential regulation of corticotropin-releasing hormone and vasopressin
      transcription by glucocorticoids.
AB  - CRH and vasopressin (VP), the main regulators of pituitary ACTH secretion, co
      exist in parvocellular cells of the PVN, but their levels of expression are
      regulated differentially during manipulations of the hypothalamic pituitary
      adrenal (HPA) axis. The effects of glucocorticoids on this system was studied
      using in situ hybridization with intronic and exonic probes to measure changes in
      CRH and VP messenger RNA (mRNA) and heteronuclear (hn) RNA in 48-h
      adrenalectomized (ADX) rats receiving injections of corticosterone (2.8 mg/100 g,
      ip) or vehicle. We also determined the time course of changes in VP expression
      following the first 72 h of ADX. Levels of VP heteronuclear (hn) RNA and the
      number of parvocellular cells containing VP hnRNA remained very low in sham
      operated rats, whereas biphasic changes were observed after ADX. Grain density
      levels increased 11.5-fold over sham-operated controls by 6 h, declined to 2-fold
      by 18 h, to increase again to 10- and 20-fold by 48 and 72 h, respectively. In 48
      h ADX rats, vehicle injection increased CRH hnRNA levels transiently (11-fold the
      basal by 15 and 30 min), returning to basal at 60 min, whereas VP hnRNA levels
      increased progressively up to 28-fold the basal by 2 h. Corticosterone injection
      had no significant effect on vehicle-induced increases in CRH hnRNA, in spite of
      marked elevations in circulating corticosterone. In contrast to CRH, VP hnRNA
      levels increased only transiently by 15 min, and then decreased below basal (near
      sham-ADX levels) by 2 h. The data show that in normal conditions the
      responsiveness of parvocellular neurons to stress is under marked inhibition by
      the low resting levels of glucocorticoids, and that the sensitivity of CRH and VP
      transcription to glucocorticoid feedback is markedly different.

PMID- 10579329
TI  - Urocortin messenger ribonucleic acid: tissue distribution in the rat and
      regulation in thymus by lipopolysaccharide and glucocorticoids.
AB  - Urocortin (Ucn), a new mammalian member of the CRF family, is a candidate
      endogenous ligand for type 2 CRF receptors. In a survey of peripheral tissues
      from adult male rats, we found that Ucn messenger RNA (mRNA) was abundant in the
      gastrointestinal tract and immune tissues such as thymus and spleen. We next
      tested the hypothesis that levels of Ucn mRNA levels in thymus and spleen would
      be altered after immune activation. As measured by ribonculease protection assay,
      lipopolysaccharide (LPS) induced a 2-fold time-dependent increase in thymic Ucn
      mRNA levels within 6 h. By contrast, splenic Ucn mRNA levels decreased after LPS.
      Because LPS activates the hypothalamus-pituitary-adrenal (HPA) axis, we examined
      whether the effects of LPS on Ucn mRNA might be mediated through changes in HPA
      axis hormones. Ucn mRNA in thymus, but not spleen, was significantly increased
      after ACTH injection; however, LPS did not increase Ucn expression in the thymus
      of adrenalectomized rats with corticosterone replacement, despite substantial
      increases in ACTH. Finally, sc injection of corticosterone stimulated Ucn mRNA
      comparably to that of LPS. Together, these results suggest that Ucn mRNA
      expression can increase after immune activation in a corticosterone-dependent
      manner, and that such changes in Ucn mRNA may be an additional consequence of HPA
      axis activation.

PMID- 10579330
TI  - Prolactin regulation of pim-1 expression: positive and negative promoter
      elements.
AB  - The lactogen-dependent rat Nb2 lymphoma is a useful model to investigate PRL
      signaling pathways that lead to regulation of gene transcription. A primary
      mechanism coupled to PRL receptor (PRLR) activation in Nb2 cells involves
      phosphorylation by Jak-family tyrosine kinases of one or more signal transducers
      and activators of transcription (Stat) factors which subsequently bind to gamma
      interferon activation sequences (GAS) within promoter regions of target genes.
      However, it is presently unclear whether this mechanism is operative as a means
      for regulating PRL-induced gene expression to the exclusion of other signaling
      pathways. Previously, we reported that PRL directly stimulated rapid expression
      of the protooncogene, pim-1, at the mRNA and protein levels in lactogen-dependent
      Nb2-11 cells. In the present study, experiments were conducted to evaluate
      signaling mechanisms by which PRL regulates transcription of pim-1. Toward this
      end, a 1,268-bp segment upstream of the transcription initiation site of the 5'
      pim-1 promoter and a series of deletion mutants were ligated upstream of the
      chloramphenicol acetylase transferase (CAT) gene in an expression vector that was
      introduced into FDC/Nb2 cells, a premyeloid line that stably expresses the
      intermediate form of the PRLR. Analysis of PRL-treated cultures indicated that
      two elements [distal (DE), -427 to -336 bp and proximal (PE), - 104 to -1] but
      not several GAS or GAS-like sequences were required for hormone activation of the
      pim-1 promoter. Moreover, treatment of Nb2-11 cells with PRL activated protein
      binding to these elements assessed by gel mobility shift assay. Deoxyribonuclease
      I (DNase I) protection experiments revealed a motif containing a nuclear factor-1
      (NF-1, -224 to -217 bp) half-site that was hydrolyzed when exposed to extracts
      from PRL-treated cells but protected by proteins from unstimulated cells. Gel
      mobility shift analysis of this sequence showed decreased protein binding after
      PRL stimulation. It is concluded that the PRLR initiates pim-1 transcription by a
      mechanism that involves transcriptional activation by factors that stimulate the
      DE- and PE-sites and derepress a NF-1-containing element. Moreover, this
      mechanism appears to be independent of an interaction between Stat transcription
      factors and GAS-like elements present within the promoter.

PMID- 10579331
TI  - Sterol regulatory element-binding protein-1a binds to cis elements in the
      promoter of the rat high density lipoprotein receptor SR-BI gene.
AB  - The high density lipoprotein (HDL) receptor, or scavenger receptor class B type I
      (SR-BI), is critical for cholesterol transport and a potential target for
      hypercholesterolemic drugs. Thus, elucidation of the mechanism underlying
      regulation of the HDL receptor SR-BI gene is essential. It has been previously
      shown that there is a correlation between depletion in ovarian cholesteryl ester
      content and increased HDL receptor SR-BI expression in response to hormonal
      stimulation. We wanted to determine whether the levels of mature sterol response
      element-binding protein-1a (SREBP-1a), a key protein in the transcriptional
      regulation of several genes by sterols, are affected under these conditions.
      Thus, Western blot analysis was carried out. Consistent with the possibility that
      SREBP-1a may be involved in the regulation of the HDL receptor SR-BI gene, we
      found that mature SREBP-1a levels increased up to 11-fold in the ovary after
      treatment with 50 U hCG. This increase in mature SREBP-1a protein levels
      correlated with a 30% decrease in ovarian cholesterol levels. These changes in
      both SREBP-1a and cholesterol levels preceded a 2-fold induction of HDL receptor
      SR-BI protein levels. To determine whether SREBP-1a could directly regulate the
      expression of the rat HDL receptor SR-BI gene, approximately 2.2 kb of the
      receptor SR-BI promoter were cloned and sequenced, and deletion analysis and
      mobility shift assays were performed. The results of these studies demonstrate
      that the rat HDL receptor SR-BI promoter contains two sterol response elements
      (pSRE and dSRE) through which SREBP-1a can bind and activate transcription of
      this gene. These motifs are similar to known SRE motifs reported for sterol
      sensitive genes, and the pSRE is located between two Sp1 sites, similar to the
      SRE-1 motif in the low density lipoprotein receptor. The cysteine protease
      inhibitor N-acetyl-leucyl-leucyl-norleucinal, which inhibits SREBP degradation,
      enhanced the effect of SREBP-1a on the regulation of the rat HDL receptor SR-BI
      gene. It has previously been shown that tropic hormones such as hCG can also
      influence gene expression by increasing cAMP levels. Consistent with this fact,
      we have recently shown that steroidogenic factor-1 (SF-1) mediates cAMP
      activation of the HDL receptor SR-BI gene. Thus, we decided to examine whether
      SREBP-1a could cooperate with SF-1 to enhance transcription this gene. The
      results confirm that indeed both SF-1 and SREBP-1a synergize to induce HDL
      receptor SR-BI gene expression.

PMID- 10579332
TI  - Ceramide inhibits L-type calcium channel currents in rat pinealocytes.
AB  - In rat pinealocytes, ceramide can inhibit the KCl- and BayK 8644-mediated
      potentiation of cAMP and cGMP accumulation, suggesting that the L-type Ca2+
      channel is a target of ceramide action. This was examined in the present study
      using intracellular Ca2+ measurement and patch-clamp studies. In fura-2-loaded
      pinealocytes, C2- and C6-ceramide inhibited the Ca2+ increase caused by BayK 8644
      and KCl, but not that caused by norepinephrine, suggesting an inhibitory effect
      of ceramide on the L-type Ca2+ channels. Patch-clamp analysis confirmed that C2-
      and C6-ceramide, but not C2-dihydroceramide (the inactive analog) inhibited the L
      type Ca2+ channel current. Furthermore, treatments known to increase cellular
      ceramide levels, including a glucosylceramide synthase inhibitor and
      sphingomyelinase, also inhibited this current. The inhibitory effect of ceramide
      on the current was attenuated by lavendustin A, a tyrosine kinase inhibitor, but
      not by H7, a serine/threonine kinase inhibitor. The effect of ceramide was
      mimicked by interleukin-1beta, a cytokine highly expressed in the pineal that is
      known to activate the sphingomyelin pathway. These results indicate that the
      sphingomyelin pathway is another important signaling mechanism that regulates the
      L-type Ca2+ channel, and tyrosine kinase appears to be involved in the effect of
      ceramide.

PMID- 10579333
TI  - Ceramide enhances growth hormone (GH)-releasing hormone-stimulated cyclic
      adenosine 3',5'-monophosphate accumulation but inhibits GH release in rat
      anterior pituitary cells.
AB  - In this study, the effect of ceramide on GH-releasing hormone (GHRH)-stimulated
      cAMP accumulation and GH release in rat anterior pituitary cells was
      investigated. C2-, C6-, and C8-ceramide were found to enhance GHRH-stimulated
      cAMP accumulation. In contrast, their effects on GHRH-stimulated GH release were
      inhibitory. Treatment with a glucosylceramide synthase inhibitor produced a
      similar enhancing effect on cAMP accumulation and an inhibitory effect on GH
      release. To identify the pathway through which ceramide mediated its effect, it
      was found that ceramide inhibited GH release stimulated by KCl, BayK 8644, and a
      GH-releasing peptide, but not that stimulated by ionomycin or an activator of
      protein kinase C. Direct measurement of intracellular Ca2+ revealed that C2
      ceramide inhibited GHRH- and KCl-mediated increases in intracellular Ca2+,
      suggesting that ceramide probably inhibits GH release through inhibition of the L
      type Ca2+ channels. As for its mechanism on cAMP accumulation, the enhancing
      effect of ceramide on GHRH-stimulated cAMP accumulation was abolished in the
      presence of a phosphodiesterase inhibitor, isobutylmethylxanthine, suggesting
      that ceramide enhances the cAMP response through inhibition of its metabolism.
      Taken together, our results suggest that ceramide plays an important role in the
      regulation of GHRH-stimulated responses in somatotrophs. By reducing GH secretion
      while enhancing cAMP accumulation, ceramide may promote the synthesis and storage
      of GH in rat anterior pituitary cells.

PMID- 10579334
TI  - Alterations in the growth hormone/insulin-like growth factor I pathways in feline
      GM1 gangliosidosis.
AB  - Cats affected with feline GM1 gangliosidosis, an autosomal, recessively
      inherited, lysosomal enzymopathy, have progressive neurological dysfunction,
      premature thymic involution, stunted growth, and premature death. Although
      increased membrane GM1 gangliosides can result in increased apoptosis of
      thymocytes, there is not a direct correlation between thymocyte surface GM1 and
      thymic apoptosis in vivo, suggesting that other factors may be important to the
      pathogenesis of thymic involution in affected cats. Because GH and insulin-like
      growth factor I (IGF-I) are important hormonal peptides supporting thymic
      function and affecting growth throughout the body, particularly in the
      prepubescent period, several components of the GH/IGF-I pathway were compared in
      GM1 mutant and normal age-matched cats. GM1 mutant cat serum IGF-I concentrations
      were reduced significantly compared with those in normal cats by 150 days of age,
      and GM1 mutant cats had no peripubertal increase in serum IGF-I. Additionally,
      IGF-binding protein-3 was reduced, and IGF-binding protein-2 was elevated
      significantly in GM1 mutant cats more than 200 days of age. Liver IGF-I messenger
      RNA and pituitary GH messenger RNA both were reduced significantly in GM1 mutant
      cats. After stimulation by exogenous recombinant canine GH, serum IGF-I levels
      increased significantly in GM1 mutant cats, indicating that GH/IGF-I signaling
      pathways within the liver remain intact and suggesting that alterations are
      external to the liver.

PMID- 10579335
TI  - Estradiol increases proliferation and down-regulates the sodium/iodide symporter
      gene in FRTL-5 cells.
AB  - Goiter (increased thyroid gland size) is more prevalent in women than men, even
      in areas where iodine levels in the diet are sufficient. We investigated a
      possible role of estrogen on thyroid follicular cell growth using rat FRTL-5
      thyroid follicular cells as a model. Estrogen receptor-alpha (ERalpha) messenger
      RNA was present in FRTL-5 cells using a RT-PCR assay and was confirmed by Western
      blot analysis. An estrogen-responsive reporter gene was transfected into FRTL-5
      cells to test the functionality of the endogenous ERs. Estradiol increased the
      activity of the reporter gene, and the antagonist, ICI182780, inhibited ER
      dependent transcription. To extend this analysis, we examined the effect of
      estradiol on FRTL-5 cell growth. Estradiol increased FRTL-5 cell growth in a time
      and concentration-dependent manner in either the absence or presence of TSH.
      Because iodine is known to inhibit thyroid cell growth, the effect of estradiol
      on the expression of the sodium/iodide symporter (NIS) was assessed as a
      potential target of estrogen action. Estradiol blocked TSH-induced NIS
      expression, and treatment of cells with estradiol and ICI182780 restored TSH
      induced NIS expression to normal levels. These data demonstrate that FRTL-5 cells
      contain functional ERs that enhance cell growth and inhibit expression of the
      NIS. The demonstration of a direct effect of estradiol on thyroid follicular
      cells raises the possibility that it may play a role in the sexually dimorphic
      prevalence of goiter.

PMID- 10579336
TI  - Differential expression of myometrial oxytocin receptor and prostaglandin H
      synthase 2, but not estrogen receptor alpha and heat shock protein 90 messenger
      ribonucleic acid in the gravid horn and nongravid horn in sheep during
      betamethasone-induced labor.
AB  - In the present study, we characterized four myometrial contraction-associated
      proteins (mCAPs): oxytocin receptor (OTR), prostaglandin H synthase 2 (PGHS2),
      estrogen receptor alpha (ERalpha), and heat shock protein 90 (Hsp90) messenger
      RNA (mRNA) expression in the nongravid horn of pregnant sheep and compared them
      with their expression in the gravid horn that is exposed to a greater degree of
      stretch. We also examined the regulatory effects of estrogen and progesterone on
      OTR mRNA expression in ovariectomized nonpregnant sheep. In addition, we
      determined the ontogeny of mCAP expression in the gravid horn throughout late
      pregnancy and during spontaneous term labor. Gravid horn and nongravid horn
      myometria were removed under general anesthesia from control ewes not in labor at
      130-140 days gestational age (dGA; n = 3) and during betamethasone-induced labor
      (n = 6) at the same gestational age. Gravid horn myometrium was also collected
      from ewes not in labor at 95 dGA (n = 3), 101-110 dGA (n = 3), 111-120 dGA (n =
      3), 121-130 dGA (n = 3), 131-140 dGA (n = 3), and 141-145 dGA (n = 4) and from
      ewes in spontaneous term labor (n = 4). All ewes were carrying single fetuses.
      Myometrium was also collected from ovariectomized nonpregnant ewes treated with
      saline (n = 5), estradiol (50 microg/day; n = 5), progesterone (0.3 g,
      intravaginally; n = 5), and estradiol plus progesterone (n = 5). Myometrial RNA
      was extracted and analyzed by Northern blot for OTR, PGHS2, ERalpha, and Hsp90
      mRNA, normalized for 18S ribosomal RNA or beta-actin. ERalpha, Hsp90, OTR, and
      PGHS2 mRNA were all significantly up-regulated during betamethasone-induced labor
      (P < 0.01) in gravid and nongravid horn myometrium. The level of gravid horn OTR
      mRNA during labor was 3 times the level of nongravid horn OTR mRNA (P < 0.0001).
      Gravid horn PGHS2 mRNA was also higher than nongravid horn PGHS2 (P < 0.02). In
      contrast, in spontaneous term labor nongravid horn, ERalpha and Hsp90 mRNA were
      similar to gravid horn. Myometrial ERalpha and Hsp90 mRNA remained unchanged
      throughout late pregnancy and increased at spontaneous term labor (P < 0.05). In
      contrast, myometrial OTR increased around 130 dGA (P < 0.01) and further
      increased at spontaneous term labor (P < 0.02). Progesterone significantly
      inhibited myometrial OTR mRNA expression in nonpregnant sheep and estradiol
      antagonized progesterone's inhibitory effect. Mechanical stretch differentially
      regulated mCAP mRNA expression in the ovine gravid horn and nongravid horn.
      Mechanical stretch appears largely responsible for increased OTR mRNA and to a
      lesser degree PGHS2 mRNA. In addition, endocrine factors may be required for full
      activation of OTR and PGHS2 mRNA associated with labor. ERalpha and Hsp90 mRNA
      are not under the control of uterine stretch in keeping with our previous
      results, indicating that systemic hormones such as estradiol, are prime
      regulators for these two mCAP mRNA expression during labor.

PMID- 10579337
TI  - Effects of recombinant insulin-like growth factor-binding protein-4 on bone
      formation parameters in mice.
AB  - Insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4), one of the most
      abundant IGFBPs produced by bone cells, is a potent inhibitor of IGF actions in
      vitro. To evaluate the modulation of IGF actions on bone formation in vivo by
      IGFBP-4, we produced intact and fragment (50- to 100-fold reduced IGF affinity)
      forms of BP-4 and examined their local and systemic effects using biochemical
      markers. Local administration of IGF-I over the right parietal bone significantly
      increased bone extract alkaline phosphatase activity; this was completely blocked
      by an equimolar dose of intact IGFBP-4, but not IGFBP-4 fragment. A single sc
      administration of IGF-I (2 microg/g BW) significantly increased bone formation
      markers in both serum and skeletal extracts; surprisingly, so did intact IGFBP-4,
      but not fragment IGFBP-4. Subcutaneous administration of an equimolar dose of
      IGFBP-4 along with IGF-I did not significantly block the IGF-I effect.
      Administration of intact IGFBP-4 significantly increased the serum 50-kDa IGF
      pool and decreased the 150-kDa IGF pool without significantly changing total IGF
      I. We postulate that the increase in the 50-kDa IGF pool might enhance IGFs
      bioavailability via a mechanism involving IGFBP-4-specific protease. This study
      demonstrates for the first time that a single local administration of IGFBP-4
      inhibits IGF-I-induced increases in bone formation, whereas systemic
      administration of IGFBP-4 alone increases serum levels of bone formation markers.

PMID- 10579338
TI  - Insulin-like growth factor signaling pathways in rat hepatic stellate cells:
      importance for deoxyribonucleic acid synthesis and hepatocyte growth factor
      production.
AB  - It has been shown recently that insulin-like growth factor 1 (IGF-1) increases
      both DNA synthesis and hepatocyte growth factor (HGF) production in cultured
      hepatic stellate cells. In this study, we used selective blockers to investigate
      crucial signaling pathways for these effects of IGF-1 in cultured rat hepatic
      stellate cells. Both LY 294002 [a phosphatidylinositol 3-kinase (PI3-K)
      inhibitor], and rapamycin [a blocker of activation of the serine/threonine p70 S6
      kinase (p70S6K), a molecule downstream from PI3-K] completely reversed the IGF-1
      induced stimulation of DNA synthesis. Mitogen-activated protein kinase (MAPK)
      inhibition by PD 98059 had a less pronounced suppressory effect, although the
      used PD 98059 dose was fully effective in inhibiting MAPK phosphorylation. Both
      LY 294002 and PD 98059 lowered the IGF-1-induced increase of HGF in the medium by
      about 40%, but LY 294002 was 10 times more potent than PD 98059. Inhibition of
      p70S6K activation by rapamycin blocked IGF-1-induced DNA synthesis but not the
      increase in HGF. In conclusion, PI3-K (and, to some extent, MAPK) signaling
      pathways seem to be important for IGF-1-stimulated DNA synthesis and HGF
      production. DNA synthesis also seems to be dependent on rapamycin-sensitive
      activation of the PI3-K effector p70S6K.

PMID- 10579339
TI  - Anatomical distribution of prolactin-releasing peptide and its receptor suggests
      additional functions in the central nervous system and periphery.
AB  - A recently identified neuropeptide with PRL-releasing capabilities binds to and
      activates a previously known orphan G protein-coupled receptor, GPR10. We
      initiated a study to define the pharmacology of the peptide/receptor interaction
      and to identify the distribution of the peptide and its receptor in the central
      nervous system to elucidate sites of action of the peptide. The PRL-releasing
      peptide (PrRP) is a C-terminally amidated, 31-amino acid peptide derived from a
      98-amino acid precursor. Radioiodinated PrRP-(1-31) binds to its receptor with
      high affinity (1 nM) and stimulates calcium mobilization in CHOK1 cells stably
      transfected with the receptor. A series of N-terminal deletions reveals that the
      PrRP-(12-31) amino acid is equipotent to PrRP-(1-31). Further N-terminal
      deletions reduce the affinity of the ligand considerably, although PrRP-(25-31)
      is still able to compete for binding and behaves as an agonist. The arginine
      residues at position 26 and 30 are critical for binding, as substitution with
      either lysine or citrulline reduces the affinity substantially. In situ
      hybridization reveals a distinct tissue distribution for both the peptide and
      receptor messenger RNAs. The receptor is expressed abundantly in the reticular
      thalamic nucleus, periventricular hypothalamus, dorsomedial hypothalamus, nucleus
      of the solitary tract, area postrema, anterior pituitary, and adrenal medulla.
      The peptide messenger RNA is expressed in the dorsomedial hypothalamus, nucleus
      of the solitary tract, ventrolateral reticular nucleus, and intestine. This
      tissue distribution suggests an alternative function of PrRP than its purported
      hypophysiotropic function, such as a potential role for PrRP in the central
      feedback control of neuroendocrine and autonomic homeostasis. Further work using
      selective agonists and antagonists should help define additional physiological
      roles of this novel mammalian neuropeptide.

PMID- 10579340
TI  - Differential interaction of the methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)
      1,1,1-trichloroethane with estrogen receptors alpha and beta.
AB  - Concern that some chemicals in our environment may affect human health by
      disrupting normal endocrine function has prompted research on interactions of
      environmental contaminants with steroid hormone receptors. We compared the
      activity of 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), an estrogenic
      metabolite of the organochlorine pesticide methoxychlor, at estrogen receptor
      alpha (ERalpha) and estrogen receptor beta (ERbeta). Human hepatoma cells (HepG2)
      were transiently transfected with either human or rat ERalpha or ERbeta plus an
      estrogen-responsive, complement 3-luciferase construct containing a complement 3
      gene promoter sequence linked to a luciferase reporter gene. After transfection,
      cells were treated with various concentrations of HPTE in the presence (for
      detecting antagonism) or absence (for detecting agonism) of 17beta-estradiol.
      HPTE was a potent ERalpha agonist in HepG2 cells, with EC50 values of
      approximately 5 x 10(-8) and 10(-8) M for human and rat ERalpha, respectively. In
      contrast, HPTE had minimal agonist activity with either human or rat ERbeta and
      almost completely abolished 17beta-estradiol-induced ERbeta-mediated activity.
      Moreover, HPTE behaved as an ERalpha agonist and an ERbeta antagonist with other
      estrogen-responsive promoters (ERE-MMTV and vtERE) in HepG2 and HeLa cells. This
      study demonstrates the complexity involved in determining the mechanism of action
      of endocrine-active chemicals that may act as agonists or antagonists through one
      or more hormone receptors.

PMID- 10579341
TI  - Messenger ribonucleic acids encoding a serotonin receptor and a novel gene are
      induced in Sertoli cells by a secreted factor(s) from male rat meiotic germ
      cells.
AB  - Using Sertoli cell-germ cell cocultures and messenger RNA (mRNA) differential
      display, we have identified a complementary DNA of 355 nucleotides that is up
      regulated in Sertoli cells by pachytene spermatocytes. The mRNA differential
      display pattern was confirmed by Northern blotting. Sequence analysis revealed a
      homology of 91% (nt) and 86% (aa) to a serotonin receptor. The mRNA encoding the
      serotonin receptor was detected in Sertoli cells after 18 h of coculture. Its
      induction did not require cell contact, as germ cell-conditioned medium also
      induced the mRNA. The germ cell factor(s) inducing the serotonin receptor mRNA is
      more than 10 kDa, survives freezing and thawing, and is heat sensitive. A high
      dose of serotonin (10 microM) or the serotonin receptor agonists (+/-)-1-(2,5
      dimethoxy-4-iodophenyl)-2-aminopropane HCl and quipazine induce the serotonin
      receptor mRNA in Sertoli cells after 24 h. The antagonists, ketanserin and
      spiperone, inhibit the serotonin-mediated mRNA induction but fail to inhibit the
      germ cell-mediated induction, suggesting that the germ cell factor(s) up
      regulates the serotonin receptor by a distinct pathway. A second clone of 380
      nucleotides, induced in Sertoli cells by pachytene spermatocytes or germ cell
      conditioned medium, did not show homology to database sequences. The germ cell
      factor(s) inducing the second clone is larger than 10 kDa, but is inactivated by
      freezing/thawing and boiling. The induction of a serotonin receptor mRNA and a
      second novel mRNA in Sertoli cells by pachytene spermatocytes demonstrates that
      meiotic germ cells induce mRNA encoding an important receptor in Sertoli cells.

PMID- 10579342
TI  - The pattern of inhibin/activin alpha- and betaB-subunit messenger ribonucleic
      acid expression in rat testis after selective Leydig cell destruction by ethylene
      dimethane sulfonate.
AB  - To further investigate the regulatory mechanisms responsible for the control of
      testicular inhibin/activin subunit gene expression, inhibin-alpha, -betaA, and 
      betaB messenger RNA (mRNA) levels were assessed after ethylene dimethane
      sulfonate (EDS)-induced destruction of Leydig cells (LC) in different animal
      models: the intact rat, the rat treated with high doses of testosterone, and the
      unilaterally cryptorchid rat. In intact rats, EDS selectively eliminates the
      mature adult-type LCs, activating the proliferation and differentiation of
      preexisting LC precursors into a new population of functionally active LCs. In
      this model, a single dose of EDS (75 mg/kg BW, ip) induced a significant increase
      in testicular inhibin-alpha and -betaB mRNA levels 5 days after treatment (5.0-
      and 5.5-fold increases, respectively), whereas inhibin-betaA mRNA remained
      undetectable upon Northern hybridization in control and EDS-treated testes.
      Moreover, in situ hybridization analysis demonstrated that the increased
      expression of inhibin-alpha and -betaB mRNAs observed 5 days after EDS takes
      place mainly in Sertoli cells. Along with LC repopulation, the expression level
      of inhibin-alpha and -betaB messages declined, and inhibin-alpha mRNA returned to
      control values on day 40 after EDS. This treatment, however, failed to alter the
      pattern of testicular expression of FSH receptor and androgen-binding protein
      mRNAs, thus suggesting selectivity for the above effects. In EDS-treated rats
      supplemented with high doses of testosterone, the preexisting mature LCs are
      destroyed, but, due to elevated testosterone concentrations, disruption of
      spermatogenesis is attenuated, and the post-EDS rise in serum gonadotropins is
      blocked; the latter prevents LC regeneration. In this model, a 5.0-fold increase
      in inhibin-alpha mRNA levels, similar to that found in intact animals, was
      detected 5 days after EDS administration, but the rise in inhibin-betaB levels
      was partially delayed. In addition, the blockade of LC repopulation resulted in
      permanent elevation of inhibin-alpha and -betaB messages throughout the study
      period. In unilaterally cryptorchid rats, the abdominal testis shows disrupted
      spermatogenesis and altered paracrine environment that expedites LC repopulation
      after EDS treatment. In this model, the abdominal testes showed a significant 2.5
      fold increase in inhibin-alpha mRNA levels 5 days after EDS, but no effect was
      found in those of inhibin-betaB. Further, the faster rate of LC repopulation
      resulted in precocious decline of inhibin-alpha mRNA levels. Finally, the
      expression of inhibin/activin subunit mRNAs was monitored during postnatal
      testicular development, specifically at the time of regression of fetal-type LCs
      and appearance of those of the adult type. High levels of expression of inhibin
      alpha and -betaB mRNAs were detected in neonatal and infantile testes. A sharp
      decline in both messages took place between days 15-20, i.e. at the time when
      fetal-type Leydig cells are replaced by adult-type cells. From this time point
      onward, inhibin-alpha and -betaB mRNA levels remained low, ranging between 15-30%
      of the maximum. In conclusion, our results suggest that the adult-type LCs
      differentially modulate the expression of inhibin/activin subunit genes and point
      to a major inhibitory role in this cell type on expression of the inhibin-alpha
      gene.

PMID- 10579343
TI  - Parathyroid hormone activates mitogen-activated protein kinase in opossum kidney
      cells.
AB  - Many G protein-coupled receptor agonists activate p42/p44 mitogen-activated
      protein kinase (MAPK), using signaling pathways that are a function of receptor,
      G protein-coupled, and effector complement. In opossum kidney (OK) cells,
      activation of endogenous PTH receptors caused a time- (peak within 15-30 min,
      sustained for approximately 2 h) and dose-dependent (EC50 approximately 3 x 10(
      10) M) activation of MAPK. Immunoblot analysis with an activation- specific MAPK
      antibody indicated that PTH activated both p42 and p44 MAPK. Epidermal growth
      factor (EGF) also activated p42 and p44MAPK in a time- (peak at 5 min, return to
      basal within 2 h) and dose-dependent (EC50 approximately 3 ng/ml) fashion. PTH
      dependent MAPK activation was mimicked by the protein kinase C activator (PKC)
      phorbol myristate acetate (PMA), and the protein kinase A activators 8 bromo-cAMP
      (8-Br-cAMP) and forskolin but was not affected by pertussis toxin pretreatment.
      PMA or 8-Br-cAMP pretreatment blocked MAPK activation by reexposure to each
      kinase activator but caused no significant reduction in MAPK activation by PTH.
      MAPK activation by PTH, EGF, and 8-Br-cAMP was inhibited by the MAPK kinase
      inhibitor PD98059 and an EGF receptor (EGFR)-selective inhibitor tyrphostin
      AG1478. AG1478 also blocked MAPK activation by insulin-like growth factor-1 and
      platelet-derived growth factor. EGF and PTH caused time- and AG1478-sensitive
      phosphorylation of the EGFR, but EGFR desensitization did not affect MAPK
      activation by PTH. EGF, PMA, and low doses of PTH (10(12) to 10(-9) M) stimulated
      while 8-Br-cAMP and high doses of PTH (10(-8) to 10(-6) M) inhibited
      [3H]thymidine uptake. These data demonstrate that PTH activates MAPK and suggest
      that PKC, protein kinase A, and the EGFR play roles in PTH signaling. The
      biphasic effect of PTH on DNA synthesis suggests that MAPK activation by the
      hormone leads to distinct cellular responses.

PMID- 10579344
TI  - Bone anabolic effects of basic fibroblast growth factor in ovariectomized rats.
AB  - The purpose of this study was to characterize the bone anabolic effects of basic
      fibroblast growth factor (bFGF) in ovariectomized (OVX) rats. Female Sprague
      Dawley rats were subjected to ovariectomy or sham surgery at 3 months of age and
      maintained untreated for 2 months post surgery. Groups of OVX rats were then
      treated iv with bFGF at doses of 100 or 200 microg/kg day for 7 or 14 days.
      Another group of OVX rats and a group of sham-operated control rats were treated
      iv with vehicle alone for 14 days. Certain groups of bFGF-treated OVX rats were
      killed at 7 or 14 days after withdrawal of treatment. The right tibiae were
      processed undecalcified for quantitative bone histomorphometry. Vehicle-treated
      OVX rats were characterized by decreased cancellous bone volume associated with
      increased bone turnover. Treatment of OVX rats with bFGF strongly stimulated bone
      formation, as indicated by marked increases of at least a factor of 10 in
      osteoblast surface, osteoid surface, and osteoid volume. Furthermore, new osteoid
      spicules were observed within the marrow cavity of these animals. Osteoclast
      surface was markedly decreased in bFGF-treated OVX rats, but this finding may be
      secondary to the extensive osteoid surface. The strongest bone anabolic effects
      occurred in OVX rats treated with the higher dose of bFGF for 14 days, but these
      animals exhibited a bone mineralization defect, as evidenced by abundant osteoid
      and a lack of double fluorochrome labeling, despite markedly increased osteoblast
      surface. However, the newly-formed osteoid rapidly calcified after withdrawal of
      bFGF treatment. The data indicate that bFGF not only stimulates bone formation on
      pre-existing bone surfaces but also induces de novo formation of bone spicules
      within the marrow cavity, which results in partial restoration of lost cancellous
      bone mass in osteopenic OVX rats after only 14 days of treatment with the growth
      factor. These findings suggest that bFGF merits consideration for development as
      a potential treatment for patients with severe osteopenia who are unresponsive to
      conventional osteoporosis therapies.

PMID- 10579345
TI  - Control of primordial follicle recruitment by anti-Mullerian hormone in the mouse
      ovary.
AB  - The dimeric glycoprotein anti-Mullerian hormone (AMH) is a member of the
      transforming growth factor-beta superfamily of growth and differentiation
      factors. During male fetal sex differentiation, AMH is produced by Sertoli cells
      and induces degeneration of the Mullerian ducts, which form the anlagen of part
      of the internal female genital system. In females, AMH is produced by the ovary,
      but only postnatally. The function of AMH in the ovary is, however, still
      unknown. Female AMH null mice were reported to be fertile, with normal litter
      size, but this does not exclude a more subtle function for ovarian AMH. To
      investigate the function of AMH in the ovary, the complete follicle population
      was determined in AMH null mice, in mice heterozygous for the AMH null mutation,
      and in wild-type mice of different ages: 25 days, 4 months, and 13 months. In the
      present study we found that ovaries of 25-day- and 4-month-old AMH null females,
      compared to those of wild-type females, contain more preantral and small antral
      follicles. In addition, in 4- and 13-month-old AMH null females, smaller numbers
      of primordial follicles were found. Actually, in 13-month-old AMH null females,
      almost no primordial follicles could be detected, coinciding with a reduced
      number of preantral and small antral follicles in these females. In almost all
      females heterozygous for the AMH null mutation the number of follicles fell in
      between the numbers found in wild-type and AMH null females. In 4-month-old AMH
      null females serum inhibin levels were higher and FSH levels were lower compared
      to those in wild-type females. In contrast, inhibin levels were lower in 13-month
      old AMH null females, and FSH levels were unchanged compared to those in wild
      type females. Furthermore, the weight of the ovaries was twice as high in the 4
      month-old AMH null females as in age-matched wild-type females. We conclude that
      AMH plays an important role in primordial follicle recruitment, such that more
      primordial follicles are recruited in AMH null mice than in wild-type mice; the
      mice heterozygous for the AMH null mutation take an in-between position.
      Consequently, the ovaries of AMH null females and those of females heterozygous
      for the AMH null mutation will show a relatively early depletion of their stock
      of primordial follicles. The female AMH null mouse may thus provide a useful
      model to study regulation of primordial follicle recruitment and the relation
      between follicular dynamics and ovarian aging.

PMID- 10579346
TI  - In utero exposure of female lambs to testosterone reduces the sensitivity of the
      gonadotropin-releasing hormone neuronal network to inhibition by progesterone.
AB  - Exposure of the female ovine fetus to exogenous androgens during early gestation
      permanently masculinizes the reproductive anatomy, physiology, and behavior of
      the adult ewe. In utero testosterone exposure has been shown to act centrally on
      the GnRH neuronal network to alter the response to both the stimulatory and
      inhibitory actions of estrogen. It is currently unknown whether fetal androgens
      alter other mechanisms that are critical for the regulation of GnRH release and,
      specifically, other important regulatory steroid feedback loops. Three studies
      were performed on gonadectomized postpubertal sheep to determine whether the
      inhibitory actions of progesterone on episodic LH release are also sex-specific
      and engendered by early in utero exposure to testosterone. In each study, the
      pulsatile pattern of LH release was determined both before and after the sc
      implantation of a progesterone releasing CIDR device. The studies involved 7
      female, 7 male, and 12 androgenized female sheep (T60 (n = 7) and T30 (n = 5)
      groups; 200 mg testosterone propionate/week im to the mother for 60 or 30 days,
      respectively, from day 30-90 or 60-90 of pregnancy). The first two studies were
      performed in the anestrous season in the presence (Exp 1) or absence (Exp 2) of a
      low circulating concentration of estradiol. Exp 3 was carried out in the breeding
      season in the absence of exogenous estrogen. In all three studies progesterone
      inhibited LH pulse frequency only in the females. Progesterone had no action on
      mean LH concentrations or the frequency or amplitude of LH pulses in the males or
      either group of androgenized ewes. We conclude that the inhibition of episodic LH
      release by progesterone is sexually differentiated in the sheep, males being less
      responsive than females to steroid negative feedback. Further, these sex
      differences are a consequence of in utero exposure to androgens for a period as
      short as 30 days between days 60 and 90 of a 147-day pregnancy.

PMID- 10579347
TI  - Potential mechanisms for the plasmin-mediated release and activation of latent
      transforming growth factor-beta1 from the extracellular matrix of growth plate
      chondrocytes.
AB  - Chondrocytes produce latent transforming growth factor-beta1 (TGF-beta1) in a
      small, circulating form of 100 kDa and also store latent TGF-beta1 in their
      matrix in a large form of 290 kDa containing the latent TGF-beta1 binding protein
      1. As growth plate cartilage cells are exceptionally sensitive to TGF-beta1 and
      are known to produce plasminogen activator, the role of plasmin in the activation
      of soluble and matrix-bound latent TGF-beta1 was examined. As is true for other
      cell types, low-dose plasmin (0.01 U/ml) was found to release both active and
      latent TGF-beta1 from chondrocyte matrix in a time-dependent manner over 3 h.
      However, high-dose plasmin (1.0 U/ml) was found to release active TGF-beta1 more
      rapidly than low-dose plasmin, and this release ceased within 30 min; latent
      complex continued to be released over time (3 h). When high-dose plasmin was
      titrated against the serine protease inhibitors, aprotinin and alpha-(2
      aminoethyl)benzenesulfonyl fluoride, results similar to low-dose plasmin were
      obtained, indicating that the effects of high-dose plasmin could be altered to
      mimic those of low-dose plasmin. No differences were observed on the effects of
      plasmin on the release of TGF-beta1 from the matrices of either growth zone or
      resting zone chondrocytes. We examined whether plasmin could further activate the
      truncated large latent TGF-beta1 complex of 230 kDa that was released into the
      media by plasmin. It is known that plasmin will activate the small latent
      complex, so this was compared with the truncated form. Plasmin completely
      activated the small latent complex, whereas a smaller, but significant,
      activation of the truncated form of latent TGF-beta1 also occurred. These studies
      may have relevance to normal physiological conditions, where plasminogen and/or
      plasmin is present in very small amounts in the cartilage and, therefore, small
      amounts of active TGF-beta1 would be present, and to pathological conditions such
      as fractures, where chondroprogenitor cells would be exposed to high
      concentrations of plasmin and, therefore, to short-term high concentrations of
      this potent chondrogenic growth factor.

PMID- 10579348
TI  - Posttranslational processing of progrowth hormone-releasing hormone.
AB  - The prepro-GH-releasing hormone (prepro-GHRH; 12.3 kDa) precursor, like other
      neuropeptide precursors, undergoes proteolytic cleavage to give rise to mature
      GHRH, which is the primary stimulatory regulator of pituitary GH secretion. In
      this study we present the first model of in vitro pro-GHRH processing. Using
      pulse-chase analysis, we demonstrate that at least five peptide forms in addition
      to GHRH are produced. The pro-GHRH (after removal of its signal peptide, 10.5
      kDa) is first processed to an 8.8-kDa intermediate form that is cleaved to yield
      two products: the 5.2-kDa GHRH and GHRH-related peptide (GHRH-RP; 3.6 kDa). GHRH
      RP is a recently described peptide derived from proteolytic processing of pro
      GHRH that activates stem cell factor, a factor known to be essential for
      hemopoiesis, spermatogenesis, and melanocyte function. Further cleavage results
      in a 3.5-kDa GHRH and a 2.2-kDa product of GHRH-RP. Like GHRH, there is GHRH-RP
      immunostaining in hypothalamic neurons in the median eminence as detected by
      immunohistochemistry and immunoelectron microscopy. Based on deduced amino acid
      sequences of the pro-GHRH processing products, several peptides were synthesized
      and tested for their ability to stimulate the cAMP second messenger system. GHRH,
      GHRH-RP, and one of these peptides [prepro-GHRH-(75-92)-NH2] all significantly
      stimulated the PKA pathway. This work delineates a new model of pro-GHRH
      processing and demonstrates that novel peptides derived from this processing may
      have biological action.

PMID- 10579349
TI  - Comparative analyses of mechanistic differences among antiestrogens.
AB  - Antiestrogens such as tamoxifen are one of the most effective methods of treating
      estrogen receptor (ERalpha) positive breast cancers; however, the effectiveness
      of this therapy is limited by the almost universal development of resistance to
      the drug. If antiestrogens are recognized differently by the cell as it has been
      suggested, then in disease conditions where tamoxifen fails to function
      effectively, a mechanistically different antiestrogen might yield successful
      results. Although many antiestrogens have been developed, a direct comparison of
      their mechanisms of action is lacking, thus limiting their utility. Therefore, to
      determine if there are mechanistic differences among available antiestrogens, we
      have carried out a comprehensive analysis of the molecular mechanisms of action
      of 4-hydroxy-tamoxifen (40HT), idoxifene, raloxifene, GW7604, and ICI 182,780.
      Using a novel set of peptides that recognize different surfaces on ERalpha, we
      have found that following binding to ERalpha, each ligand induces a distinct
      ERalpha-ligand conformation. Furthermore, transcriptional assays indicate that
      each ERalpha-ligand complex is recognized distinctly by the transcription
      machinery, and consequently, antiestrogens vary in their ability to inhibit
      estradiol- and 40HT-mediated activities. Relative binding assays have shown that
      the affinity of these ligands for ERalpha is not always representative of their
      inhibitory activity. Using this assay, we have also shown that the pharmacology
      of each antiestrogen is influenced differently by hormone binding proteins.
      Furthermore, GW7604, like ICI 182,780, but unlike the other antiestrogens
      evaluated, decreases the stability of the receptor. Overall, our results indicate
      that there are clear mechanistic distinctions among each of the antiestrogens
      studied. However, GW7604 and ICI 182,780 differ more significantly from tamoxifen
      than idoxifene and raloxifene. These data, which reveal differences among
      antiestrogens, should assist in the selection of compounds for the clinical
      regulation of ERalpha function.

PMID- 10579350
TI  - Selective cloning of cell surface proteins involved in organ development:
      epithelial glycoprotein is involved in normal epithelial differentiation.
AB  - Coordinating the activities of neighboring cells during development in
      multicellular organisms requires complex cellular interactions involving
      secreted, cell surface, and extracellular matrix components. Although most
      cloning efforts have concentrated on secreted molecules, recent work has
      emphasized the importance of membrane-bound molecules during development. To
      identify developmental genes, we raised antibodies to normal embryonic pancreatic
      epithelial cell surface proteins. These antibodies were characterized and used to
      clone the genes coding for the proteins by a panning strategy. Using this
      approach, we cloned the rat homologue of the mouse epithelial glycoprotein (EGP).
      Our immunohistochemistry data, describing the expression of EGP during rat
      development, as well as our in vitro data, looking at the effect of the anti-EGP
      antibody and the extracellular domain of EGP on embryonic pancreatic epithelial
      cell number and volume, strongly suggest a role for EGP during pancreatic
      development.

PMID- 10579351
TI  - Prevention of the polycystic ovarian phenotype and characterization of ovulatory
      capacity in the estrogen receptor-alpha knockout mouse.
AB  - Ovarian-derived estradiol plays a critical endocrine role in the regulation of
      gonadotropin synthesis and secretion from the hypothalamic-pituitary axis. In
      turn, several para/autocrine effects of estrogen within the ovary are known,
      including increased ovarian weight, stimulation of granulosa cell growth,
      augmentation of FSH action, and attenuation of apoptosis. The estrogen receptor
      alpha (ERalpha) is present in all three components of the hypothalamic-pituitary
      ovarian axis of the mouse. In contrast, estrogen receptor-beta (ERbeta) is easily
      detectable in ovarian granulosa cells but is low to absent in the pituitary of
      the adult mouse. This distinct expression pattern for the two ERs suggests the
      presence of separate roles for each in the regulation of ovarian function.
      Herein, we definitively show that a lack of ERalpha in the hypothalamic-pituitary
      axis of the ERalpha-knockout (alphaERKO) mouse results in chronic elevation of
      serum LH and is the primary cause of the ovarian phenotype of polycystic
      follicles and anovulation. Prolonged treatment with a GnRH antagonist reduced
      serum LH levels and prevented the alphaERKO cystic ovarian phenotype. To
      investigate a direct role for ERalpha within the ovary, immature alphaERKO
      females were stimulated to ovulate with exogenous gonadotropins. Ovulatory
      capacity in the immature alphaERKO female was reduced compared with age-matched
      wild-type (14.5+/-2.9 vs. 40.6+/-2.6 oocytes/animal, respectively); however,
      oocytes collected from the alphaERKO were able to undergo successful in vitro
      fertilization. A similar discrepancy in oocyte yield was observed after
      superovulation of peripubertal (42 days) wild-type and alphaERKO females. In
      addition, ovaries from immature superovulated alphaERKO females possessed several
      ovulatory but unruptured follicles. Investigations of the possible reasons for
      the reduced number of ovulations in the alphaERKO included ribonuclease
      protection assays to assess the mRNA levels of several markers of follicular
      maturation and ovulation, including ERbeta, LH-receptor, cyclin-D2, P450-side
      chain cleavage enzyme, prostaglandin synthase-2, and progesterone receptor. No
      marked differences in the expression pattern for these mRNAs during the
      superovulation regimen were observed in the immature alphaERKO ovary compared
      with that of the wild-type. Serum progesterone levels just before ovulation were
      slightly lower in the alphaERKO compared with wild-type. These studies indicate
      that treatment of alphaERKO females with a GnRH antagonist decreased the serum LH
      levels to within the wild-type range and concurrently prevented development of
      the characteristic ovarian phenotype of cystic and hemorrhagic follicles.
      Furthermore, a lack of functional ERalpha within the ovary had no effect on the
      regulation of several genes required for follicular maturation and ovulation.
      However, the reduced numbers of ovulations following the administration of
      exogenous gonadotropins in the alphaERKO suggests an intraovarian role for
      ERalpha in follicular development and ovulation.

PMID- 10579352
TI  - Amphiregulin is coordinately expressed with heparin-binding epidermal growth
      factor-like growth factor in the interstitial smooth muscle of the human
      prostate.
AB  - Peptide growth factors have been proposed as mediators of smooth muscle
      epithelial cell interactions in the human prostate; however, the identity of
      these molecules has not been established. In this study, we compared expression
      levels of messenger RNAs (mRNAs) encoding the epidermal growth factor (EGF)
      receptor-related receptor tyrosine kinases (ErbB1 through 4), the six EGF
      receptor ligands, EGF, transforming growth factor (TGF)-alpha, amphiregulin
      (ARG), HB-EGF, betacellulin, and epiregulin, and the related molecule heregulin
      alpha, in a series of 10 prostate tissue specimens. Only EGF showed a disease
      specific association, with increased mRNA levels in four of five PCa specimens in
      comparison to matched normal tissue from the same subject. In contrast, ARG and
      HB-EGF mRNAs showed a coordinate pattern of expression in 7/10 specimens that was
      distinct from all other growth factor or receptor genes examined and from mRNAs
      for prostate specific antigen, the androgen receptor and GAPDH, a house-keeping
      enzyme. Analysis of an additional series of benign prostatic hyperplasia and
      prostate cancer specimens from 60 individuals confirmed that ARG and HB-EGF mRNA
      levels varied in a highly coordinate manner (r = 0.93; P < 0.0001) but showed no
      association with disease. ARG was immunolocalized largely to interstitial smooth
      muscle cells (SMC), previously identified as the site of synthesis of HB-EGF in
      the prostate, while the cognate ARG and HB-EGF receptor, ErbB1, was localized
      exclusively to ductal epithelial cells and carcinoma cells. Although ARG was a
      relatively poor mitogen for Balb/c3T3 cells in comparison to HB-EGF, it was
      similar in potency to HB-EGF in stimulating human prostate epithelial cell
      growth, suggesting that prostate epithelia may be a physiologic target for ARG in
      vivo. Expression of both ARG and HB-EGF mRNAs was induced in cultured prostate
      SMC by fibroblast growth factor-2, a human prostate SMC mitogen linked to
      prostate disease. These findings indicate that ARG and HB-EGF are likely to be
      key mediators of directional signaling between SMC and epithelial cells in the
      human prostate and appear to be coordinately regulated.

PMID- 10579353
TI  - Insulin-like growth factor (IGF) II induced changes in expression of IGF binding
      proteins in lymphoid tissues of hIGF-II transgenic mice.
AB  - Overexpression of human insulin-like growth factor II (IGF-II) in transgenic mice
      does not result in increased overall body growth. The IGF-II overexpression,
      however, specifically causes growth of the thymus and not of the spleen. We
      address the question whether the observed differences in growth induction in
      lymphoid tissues by IGF-II can be related to differences in local IGF binding
      protein (IGFBP) production, using nonradioactive in situ hybridization and
      Northern blot analysis. IGFBP-2, -4, and -5 are expressed in both lymphoid
      tissues of normal mice. The spleen additionally expresses IGFBP-3 and IGFBP-6.
      IGFBP-1 expression was not detected. Although the expression pattern of the
      IGFBPs did not change upon IGF-II overexpression, the level of expression changed
      in a specific manner for each IGFBP. In both the thymus and the spleen of
      transgenic mice, IGFBP-2 and -5 gene expression was slightly increased, whereas
      the level of IGFBP-4 expression was not altered. In the spleen, IGFBP-6
      expression was not altered by IGF-II overexpression, whereas IGFBP-3 expression
      was strongly increased. The differences in IGFBP expression, and the difference
      in response of these IGFBPs to IGF-II overexpression in thymus and spleen
      suggests an important role of these proteins in growth regulation of both
      lymphoid tissues. We speculate that an increase of IGFBP-3 expression together
      with changes in expression of other IGFBPs, inhibits IGF-II stimulated growth in
      the spleen by an autocrine-/paracrine pathway.

PMID- 10579354
TI  - Expression and signal transduction of calcium-sensing receptors in cartilage and
      bone.
AB  - We previously showed that Ca2+-sensing receptors (CaRs) are expressed in
      chondrogenic RCJ3.1C5.18 (C5.18) cells and that changes in extracellular
      [Ca2+]([Ca2+]o) modulate nodule formation and chondrogenic gene expression. In
      the present study, we detected expression of CaRs in mouse, rat, and bovine
      cartilage and bone by in situ hybridization, immunocytochemistry, immunoblotting,
      and RT-PCR; and we tested the effects of CaR agonists on signal transduction in
      chondrogenic and osteogenic cell lines. In situ hybridization detected CaR
      transcripts in most articular chondrocytes and in the hypertrophic chondrocytes
      of the epiphyseal growth plate. Expression of CaR transcripts was weak or absent,
      however, in proliferating and maturing chondrocytes in the growth plate. In bone,
      CaR transcripts were present in osteoblasts, osteocytes, and bone marrow cells,
      but rarely in osteoclasts. A complementary DNA was amplified from mouse growth
      plate cartilage, which was highly homologous to the human parathyroid CaR
      sequence. Immunocytochemistry of cartilage and bone with CaR antisera confirmed
      these findings. Western blotting revealed specific bands (approximately 140-190
      kDa) in membrane fractions isolated from growth plate cartilage, primary cultures
      of rat chondrocytes, and several osteogenic cell lines (SaOS-2, UMR-106, ROS
      17/2.8, and MC3T3-E1). InsP responses to high [Ca2+]o were evident in C5.18 cells
      and all osteogenic cell lines tested except for SaOS-2 cells. In the latter, high
      [Ca2+]o reduced PTH-induced cAMP formation. Raising [Ca2+]o also increased
      intracellular free [Ca2+] in SaOS-2 and C5.18 cells. These studies confirm
      expression of CaRs in cartilage and bone and support the concept that changes in
      [Ca2+]o may couple to signaling pathways important in skeletal metabolism.

PMID- 10579355
TI  - Differential expression of c-kit in mouse undifferentiated and differentiating
      type A spermatogonia.
AB  - The proto-oncogene c-kit is encoded at the white-spotting locus and in the mouse
      mutations at this locus affect the precursor cells of melanocytes, hematopoietic
      cells, and germ cells. c-kit is expressed in type A spermatogonia, but whether or
      not c-kit is present both in undifferentiated and differentiating type A
      spermatogonia or only in the latter cell type is still a matter of debate. Using
      the vitamin A-deficient mouse model, we studied messenger RNA (mRNA) and protein
      expression in undifferentiated and differentiating type A spermatogonia.
      Furthermore, we quantified the immuno-positive type A spermatogonia in the
      epithelial stages VI, VII, IX/X, and XII in normal mice to correlate c-kit
      expression in type A spermatogonia with the differentiation of these cells. Our
      results show that in the VAD situation undifferentiated type A spermatogonia
      express little c-kit mRNA. The A spermatogonia with a larger nucleus expressed c
      Kit protein, whereas the A spermatogonia with a smaller one did not. After
      induction of differentiation of these cells into type A1 spermatogonia, c-kit
      mRNA was enhanced. The percentage of A spermatogonia expressing c-Kit protein did
      not change during this process, suggesting that A spermatogonia, which are
      committed to differentiate express c-kit. Under normal circumstances in
      epithelial stage VI 16%+/-2% (mean +/- SD), in VII 45%+/-15%, in IX/X 78%+/-14%
      and in XII 90%+/-1.9% of the type A spermatogonia were c-kit positive, suggesting
      that Aaligned spermatogonia gradually change from c-Kit negative to c-Kit
      positive cells before their differentiation into A1 spermatogonia. It is
      concluded that c-kit can be used as a marker for differentiation of
      undifferentiated into differentiating type A spermatogonia.

PMID- 10579356
TI  - Three novel mutations at serine 314 in the thyroid hormone beta receptor
      differentially impair ligand binding in the syndrome of resistance to thyroid
      hormone.
AB  - The syndrome of resistance to thyroid hormone is associated with diverse
      mutations in the ligand-binding domain of the thyroid hormone beta receptor,
      localizing to three clusters around the hormone binding cavity. Here, we report
      three novel resistance to thyroid hormone mutations (S314C, S314F, and S314Y),
      due to different nucleotide substitutions in the same codon, occurring in six
      separate families. Functional characterization of these mutant receptors showed
      marked differences in their properties. S314F and S314Y receptor mutants
      exhibited significant transcriptional impairment in keeping with negligible
      ligand binding and were potent dominant negative inhibitors of wild-type receptor
      action. In contrast, the S314C mutant bound ligand with reduced affinity, such
      that its functional impairment and dominant negative activity manifest at low
      concentrations of thyroid hormone, but are more reversible at higher T3
      concentrations. The degree of functional impairment of mutant receptors in vitro
      may correlate with the magnitude of thyroid dysfunction in vivo. Modelling these
      mutations using the crystal structure of thyroid hormone receptor beta shows why
      ligand binding is perturbed and why the phenylalanine/tyrosine mutations are more
      deleterious than cysteine.

PMID- 10579357
TI  - Expression and molecular characterization of the growth hormone receptor in
      canine mammary tissue and mammary tumors.
AB  - GH synthesis has been documented in canine mammary tissue and mammary tumors. In
      the present report, the characteristics of the GH receptor (GHR) are studied in
      these tissues. First, using immunohistochemistry, GHR was found to be present
      throughout normal and tumorous mammary tissues, being localized in epithelial and
      myoepithelial/spindle cell components and in the activated fibroblasts of
      desmoplastic tumor stroma. GHR expression seemed to be down-regulated only in
      terminally differentiated alveoli in normal tissue. GHR immunoreactivity in
      particular mammary (adeno)carcinomas was heterogenous. Second, the canine GHR was
      characterized at the molecular level. Northern blot analysis revealed a major GHR
      transcript of approximately 4.2 kb. The coding sequence of the canine GHR shows
      extensive homology with the GHR of several species. Seminested RT-PCR (using
      primers annealing in exons 4-5, exon 6, and exon 9) generated, next to the
      primary product, four different products in mammary tissues and the canine
      mammary tumor cell line CMT-U335, which seemed to be alternative GHR transcripts.
      These alternative GHR transcripts were characterized by exon 8 skipping, exon 7
      skipping, and use of alternative splice donor and acceptor sites. Especially, the
      transcript that is missing exon 8 may encode a GH binding protein. In most
      malignant mammary samples, only the primary transcript was present; and
      alternative transcripts could not be detected. The absence of alternative GHR
      transcripts in mammary carcinomas, and thus putative inhibitors of GH-induced
      signal transduction, may contribute to enhanced sensitivity of malignant tumors
      to GH.

PMID- 10579358
TI  - Selective expression of neuropeptides in the rat mammary gland: somatostatin gene
      is expressed during lactation.
AB  - The existence of numerous neuropeptides in milk, in concentrations that exceed
      those in maternal plasma, is well established. It is still unclear whether these
      neuropeptides are produced by the mammary gland or that the gland concentrates
      them from the general circulation. In this study, we have examined the
      possibility that the genes of these neuropeptides are expressed in the rat
      mammary gland. RNA was extracted from the mammary glands of female rats during
      different stages of reproduction as well as from other tissues such as
      hypothalami, pancreas, pineal glands, small intestine, and ovaries. Following RT
      reaction, the resulting cDNA were amplified by radioactive PCR using specific
      oligonucleotide primers. We have used specific primers for the following
      neuropeptides: galanin, somatostatin, vasoactive intestinal peptide, TRH, GH
      releasing hormone, cholecystokinin, neurotensin, oxytocin, and relaxin. We have
      also used primers for serotonin N-acetyl-transferase, the enzyme that is involved
      in melatonin biosynthesis. The ribosomal protein S-16 served as an internal
      control. Among all the neuropeptides that have been examined, somatostatin was
      the only one that was found to be expressed in the mammary gland. Somatostatin
      was expressed in the mammary gland of lactating rats, but not of virgin rats.
      Expression of the somatostatin gene was confirmed by Southern blot analysis and
      by sequencing of the PCR products. Immunohistochemical studies demonstrated
      somatostatin immunoreactivity in the epithelial cells that compose the secretory
      alveoli and in the secretory material. In addition, we have found that the
      mammary glands of the lactating rat express the PC-1 proteinase gene that process
      prosomatostatin to generate somatostatin-14, but do not express furin, the enzyme
      that is responsible for somatostatin-28 production. This finding substantiates
      previous studies that demonstrated that only somatostatin-14 is present in milk.
      The finding that most of the neuropeptides, examined by RT-PCR, are not expressed
      by the mammary gland suggest that these neuropeptides are actively concentrated
      by the mammary glands from the general circulation. The GnRH gene has been
      previously demonstrated to be expressed in the mammary gland, and in this study
      somatostatin was the only neuropeptide that was found to be produced by the
      mammary gland. The observation that only a small portion of the neuropeptides
      that are present in milk are being produced by the lactating mammary gland
      suggest that these neuropeptides have important functions in the biology of the
      suckling neonate and probably also in the development and function of the breast.

PMID- 10579359
TI  - Effects of N-methyl-D-aspartate on luteinizing hormone release and Fos-like
      immunoreactivity in the male White-crowned sparrow (Zonotrichia leucophrys
      gambelii).
AB  - Seasonal breeding is terminated in the White-crowned sparrow by the onset of
      absolute photorefractoriness, a condition in which the reproductive system is
      switched off indefinitely until it is dissipated by short day lengths. Absolute
      photorefractoriness is controlled by the central nervous system; however, the
      mechanisms underlying GnRH quiescence in photorefractory birds have yet to be
      elucidated. Using the excitatory amino acid glutamate agonist N-methyl-D
      aspartate (NMDA), plasma LH levels in White-crowned sparrows were significantly
      elevated regardless of the reproductive or photoperiodic condition. NMDA also
      significantly induced Fos-like immunoreactivity (FLI) within the infundibular
      nucleus and median eminence, regions previously shown to express FLI after a
      photoperiodically driven LH rise. NMDA did not induce FLI within GnRH I neurons;
      instead, it significantly activated cells within the organum vasculosum of the
      lamina terminalis in close proximity to GnRH I perikarya. These findings provide
      the first evidence that photorefractoriness is not due to depletion of GnRH
      stores, as LH and presumably GnRH were secreted in response to excitatory amino
      acid stimulation. NMDA activation of FLI in the region of the organum vasculosum
      of the lamina terminalis and the basal tuberal hypothalamus suggests that
      seasonal reproductive neuroendocrine control may be mediated via cells in the
      region of the GnRH I perikarya and terminals.

PMID- 10579360
TI  - A subset of gonadotropin-releasing hormone neurons in the ovine medial basal
      hypothalamus is activated during increased pulsatile luteinizing hormone
      secretion.
AB  - GnRH neurons active in the preovulatory LH surge have been identified in several
      species using the early intermediate gene product, Fos, but the GnRH neurons
      active during episodic LH secretion remain unknown. In this study, we have used
      Fos and Fos-related antigens (FRA) to determine whether a subset of GnRH neurons
      is active when pulsatile LH secretion is acutely stimulated in sheep. In
      experiment 1, episodic LH secretion was stimulated in five of six ewes by
      injection of an opioid antagonist to luteal phase ewes. These five ewes had a 6
      fold increase in the percentage of GnRH neurons in the medial basal hypothalamus
      (MBH) expressing Fos/FRA, compared with control ewes that had no LH pulses before
      death. Fos/FRA expression was not increased in GnRH neurons found in any other
      area. In experiment 2, episodic LH secretion was induced in rams by introduction
      of estrous ewes. This treatment increased Fos/FRA expression in MBH GnRH neurons
      approximately 10-fold compared with control rams. Again, this increase in Fos/FRA
      expression in GnRH neurons was limited to the MBH. This selective activation of
      MBH GnRH neurons could reflect the preferential inhibition of these perikarya by
      endogenous opioid peptides. It also raises the possibility that a subset of GnRH
      neurons in the MBH may be responsible for episodic GnRH secretion in sheep.

PMID- 10579361
TI  - Activation of growth hormone receptor delivers an antiapoptotic signal: evidence
      for a role of Akt in this pathway.
AB  - A signaling pathway was delineated by which GH promotes cell survival.
      Experiments were performed in human leukemic cells (HL-60) and Chinese hamster
      ovary (CHO) cells. In HL-60 cells, GH treatment reduced starvation-induced cell
      death. In contrast, when HL-60 cells were treated with an anti-GH antibody, cell
      survival was sharply reduced. In CHO cells stably expressing either the wild-type
      (wtGHR) or a truncated form (delta454GHR) of the GH receptor in which GH induces
      a sustained activation of the receptor-associated tyrosine kinase JAK2, we found
      that GH stimulation inhibited programmed cell death induced by withdrawal of
      survival factors. This effect was enhanced in cells expressing the truncated
      form. In contrast, GH did not affect cell survival in CHO cells transfected with
      either the empty vector or a mutated GHR unable to transduce the signal
      (4P/AGHR). We also showed that the inhibitory action of GH on apoptosis is
      probably mediated via stimulation of the serine-threonine kinase Akt, as 1) GH
      treatment induces a prompt phosphorylation of Akt; and 2) GH effects on cell
      survival are abolished by transfection of an Akt mutant that exhibits dominant
      negative function. Experiments with pharmacological inhibitors demonstrated that
      GH-induced Akt phosphorylation is dependent on phosphoinositide 3-kinase
      activation. In contrast, we found no changes in Bcl-2 levels secondary to GHR
      activation.

PMID- 10579362
TI  - Generation of antisera to mouse insulin-like growth factor binding proteins
      (IGFBP)-1 to -6: comparison of IGFBP protein and messenger ribonucleic acid
      localization in the mouse embryo.
AB  - The insulin-like growth factor (IGF) system is an important regulator of fetal
      growth and differentiation. IGF bioavailability is modulated by IGF binding
      proteins (IGFBPs). We have generated six different antisera, directed to
      synthetic peptide fragments of mouse IGFBP-1 through -6. The specificity of the
      produced antisera was demonstrated by enzyme-linked immunosorbent assay, Western
      blotting, and by immunohistochemistry on sections of mouse embryos of 13.5 days
      post coitum. Specificity for the IGFBP-2 through -6 antisera also was confirmed
      immunohistochemically in liver and lung of corresponding gene deletion (knock
      out) mutant mice and wild-type litter mates. Immunohistochemistry and messenger
      RNA (mRNA) in situ hybridization on sections of mouse embryos of 13.5 days post
      coitum revealed tissue-specific expression patterns for the six IGFBPs. The only
      site of IGFBP-1 protein and mRNA production was the liver. IGFBP-2, -4, and -5
      protein and mRNA were detected in various organs and tissues. IGFBP-3 and -6
      protein and mRNA levels were low. In several tissues, such as lung, liver,
      kidney, and tongue, more than one IGFBP (protein and mRNA) could be detected.
      Differences between mRNA and protein localization were extensive for IGFBP-3, -5,
      and -6, suggesting that these IGFBPs are secreted and transported. These results
      confirm the different spatial localization of the IGFBPs, on the mRNA and protein
      level. The overlapping mRNA and protein localization for IGFBP-2 and -4, on the
      other hand, may indicate that these IGFBPs also function in an auto- or paracrine
      manner.

PMID- 10579363
TI  - Identification and developmental expression of the estrogen receptor alpha and
      beta in the baboon fetal adrenal gland.
AB  - We have previously shown that estrogen regulates the development and function of
      the fetal and definitive/transitional zones of the primate fetal adrenal gland.
      Thus, during baboon pregnancy estrogen acts directly on the fetal zone to
      suppress ACTH-stimulated dehydroepiandrosterone (DHA) formation, potentially to
      modulate C19-steroid production and consequently placental estrogen synthesis. It
      is proposed that this action of estrogen is mediated by the estrogen receptor.
      Therefore, in the present study a developmental approach was used to determine
      whether the messenger RNA (mRNA) and protein for the estrogen receptor were
      expressed in the fetal and definitive/transitional zones ofthe baboon fetal
      adrenal gland at mid (day 100) and late (day 170) gestation (term = 184 days).
      Estrogen receptor alpha mRNA levels, determined by competitive RT-PCR, were
      approximately 7-fold greater (P < 0.02) in the fetal adrenal of late (187.8+/
      40.3 attomoles/microg RNA) compared with mid (27.4+/-5.4 attomoles/microg RNA)
      gestation. Moreover, estrogen receptor alpha mRNA expression, determined by
      quantitative in situ hybridization, was approximately 2.5-fold greater (P < 0.05)
      in the definitive/transitional zones (21.6+/-0.5 silver grains/0.025 mm2) than in
      the fetal zone (8.3+/-1.5 grains/0.025 mm2) late in gestation. The mRNA for the
      beta-isoform of the estrogen receptor was also expressed in the baboon fetal
      adrenal cortex. There was a gradient of immunocytochemical staining for the
      estrogen receptor alpha and beta proteins, with extensive immunoreactivity for
      both isoforms in the definitive zone and lower staining in the transitional zone
      and the fetal zone. In summary, the results of the present study show that
      estrogen receptor alpha and beta were expressed in the fetal and
      definitive/transitional zones of the baboon fetal adrenal cortex at mid and late
      gestation. The presence of the estrogen receptor provides a mechanism for
      mediating the action of estrogen in modulating ACTH-dependent and cortical zone
      specific development and function of the primate fetal adrenal gland.

PMID- 10579364
TI  - Thyrotropin prevents apoptosis by promoting cell adhesion and cell cycle
      progression in FRTL-5 cells.
AB  - Apoptosis has been shown to be involved in endocrine tissue homeostasis as well
      as regression due to hormone deprivation. The goal of this study was to induce
      apoptosis and to investigate a potential role of TSH as a survival factor in
      thyroid follicular cells (FRTL-5) in vitro. Our results indicated that FRTL-5
      cells underwent anchorage-dependent apoptosis when plated in the absence of serum
      and hormones, but when the cells became attached to the substrate by addition of
      TSH in the medium, apoptosis was prevented. The apoptosis was evaluated by
      positive terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end
      labeling staining, typical apoptotic bodies by electron microscopy, DNA ladder by
      gel electrophoresis, and subdiploidy by propidium iodide-stained flow cytometry.
      TSH was shown to prevent apoptosis and maintain cell viability. cAMP partly
      mimicked this effect, which was inhibited by a specific inhibitor of protein
      kinase A, H-89. While investigating the mechanisms of apoptosis, we observed that
      the phosphorylated focal adhesion kinase was strengthened by TSH. Furthermore,
      FRTL-5 cells were found to undergo growth arrest in the G1 phase in the absence
      of TSH, accompanied by an elevated level of cyclin-dependent kinase inhibitor,
      p27, and a decreased level of cyclin D. In contrast, TSH promoted transition from
      G1 to S phase by decreasing P27 protein and increasing cyclin D expression. We
      concluded that in addition to regulating growth and differentiation, TSH may
      function as a survival factor in thyroid cells by preventing anchorage-dependent
      apoptosis in FRTL-5 cells partly via the cAMP pathway.

PMID- 10579366
TI  - Tyrosine phosphorylation and subcellular localization of focal adhesion proteins
      during in vitro decidualization of human endometrial stromal cells.
AB  - Human endometrial stromal cells undergo in vitro decidualization when treated
      with progesterone and estrogen. Using this model, we previously reported specific
      changes in the c-Src kinase activity and tyrosine phosphorylation of several
      proteins during in vitro decidualization. Focal adhesion kinase (FAK) and
      paxillin are known to form a complex with c-Src at the focal contacts and to
      participate in the integrin-mediated signal transduction as c-Src substrates. We
      here examined the tyrosine phosphorylation and subcellular localization of the
      focal adhesion proteins in stromal cells isolated from human endometrium. We
      found, however, that the total levels of FAK and paxillin tyrosine
      phosphorylation were not markedly changed during decidualization or after steroid
      withdrawal. In our culture system numerous multicellular nodules were developed
      in cultures of decidualized stromal cells, within whose nodules the focal
      contacts were found to disappear. Moreover, disruption of the focal contacts was
      accompanied by disorganization of the actin-based cytoskeleton. These findings
      suggest that tyrosine phosphorylation of the endometrial paxillin and FAK is not
      tightly regulated by the kinase activity of c-Src during in vitro
      decidualization. The escape from regulation by c-Src may be in part due to the
      dissociation of the focal adhesion proteins/c-Src complex caused by the breakdown
      of the focal adhesion plaques as well as the loss of the actin-based cytoskeletal
      architecture.

PMID- 10579365
TI  - Endotoxin stimulates nitric oxide production in the paraventricular nucleus of
      the hypothalamus through nitric oxide synthase I: correlation with hypothalamic
      pituitary-adrenal axis activation.
AB  - Nitric oxide (NO) is an unstable gas that is produced in brain tissues involved
      in the control of the activity of the hypothalamus-pituitary-adrenal (HPA) axis.
      Transcripts for constitutive neuronal NO synthase (NOS I), one of the enzymes
      responsible for NO formation in the brain, is up-regulated by systemic endotoxin
      [lipopolysaccharide (LPS)] injection. However, this change is delayed compared
      with LPS induced-ACTH release, which makes it difficult to determine whether it
      is functionally important for the hormonal response. To obtain a more resolutive
      time course of the NO response, we first measured NO in microdialysates of the
      paraventricular (PVN) nucleus of the hypothalamus. The iv injection of 100
      microg/kg LPS induced a rapid and short-lived increase in concentrations of this
      gas, which corresponded to the initiation of the ACTH response. LPS-induced Ca2+
      dependent NOS activity in the PVN as well as the number of PVN cells expressing
      citrulline (a compound produced stoichiometrically with NO) also increased
      significantly over a time course that corresponded to ACTH and corticosterone
      release. Finally, blockade of NO production with the arginine derivative Nomega
      nitro-L-argininemethylester (L-NAME; 50 mg/kg, sc), which attenuated the ACTH
      response to LPS, virtually abolished basal NOS activity in the PVN, as well as
      anterior and neurointermediate lobes of the pituitary, and prevented the
      appearance of citrulline in the PVN of rats injected with LPS. Collectively,
      these results show that LPS-induced activation of the HPA axis correlates with
      the activation of the PVN NOergic system, and supports a stimulatory role for NO
      in the modulation of the HPA axis in response to immune challenges.

PMID- 10579367
TI  - Orexin receptors are expressed in the adrenal medulla of the rat.
AB  - Two recently discovered hypothalamic peptides, orexin-A and orexin-B, play a role
      as mediators in the central mechanisms that regulate feeding behavior and sleep
      control. These peptides bind and activate two orexins receptors that belong to
      the G-protein coupled receptor superfamily. Morphological studies have detected
      mRNA expression of orexin receptors exclusively in the rat central nervous
      system. In this paper we demonstrate a strong level of expression of orexin
      receptor 1 and 2 in the adrenal medulla of the rat by RT-PCR and
      immunohistochemistry. The results of the present study provide the first evidence
      showing that the adrenal medulla expresses orexin receptors, and thus appears to
      be a target tissue for orexins. This could open a new loop in which the central
      and autonomous nervous system may be involved in body weight homeostasis and
      sleep control.

PMID- 10579368
TI  - Leptin gene expression in the brain and pituitary gland.
AB  - The adipocyte-derived hormone, leptin, and its receptor, are now known to be
      integral components of a physiological signalling system that regulates fuel
      stores and energy balance. Constitutive leptin expression has been demonstrated
      only in adipose tissue, placenta and stomach. We have used RT-PCR to show that
      leptin mRNA is selectively transcribed in specific areas of rat brain and
      pituitary, and in a rat glioblastoma cell line. Using immunocytochemistry we have
      also shown leptin protein immunoreactivity in the corresponding tissues and
      cells, and confirmed this by Western blot using two epitope-specific antisera.
      Leptin mRNA expression in the hypothalamus is suppressed by fasting (48hr),
      suggesting a role for brain leptin in the central regulation of appetite. These
      data support the hypothesis that central nervous system derived leptin is a
      likely ligand for central leptin receptors.

PMID- 10579369
TI  - Specific progesterone binding to a membrane protein and related nongenomic
      effects on Ca2+-fluxes in sperm.
AB  - Rapid, nongenomic effects of steroids are supposed to be transmitted by membrane
      receptors unrelated to the classic intracellular steroid receptors. In this
      context, a putative progesterone membrane binding protein (mPR) has been
      identified, recently. Here we show that expression of mPR-cDNA in CHO cells leads
      to increased microsomal progesterone binding. This result is mirrored by effects
      of an antibody raised against the recombinant E. coli mPR which suppressed the
      rapid progesterone-initiated Ca2+ increase in sperm. Our results support the
      assumption that mPR represents the first steroid membrane receptor or a part of
      it involved in rapid, nongenomic steroid signalling.

PMID- 10579370
TI  - A history of antipsychotic drug development.
AB  - The history of antipsychotic drug development has had a long and torturous
      course, often based on chance findings that bear little relationship to the
      intellectual background driving observations. In 1891, Paul Ehrlich observed the
      antimalarial effects of methylene blue, a phenothiazine derivative. Later, the
      phenothiazines were developed for their antihistaminergic properties. In 1951,
      Laborit and Huguenard administered the aliphatic phenothiazine, chlorpromazine,
      to patients for its potential anesthetic effects during surgery. Shortly
      thereafter, Hamon et al. and Delay et al. extended the use of this treatment in
      psychiatric patients and serendipitously uncovered its antipsychotic activity.
      Between 1954 and 1975, about 15 antipsychotic drugs were introduced in the United
      States and about 40 throughout the world. Thereafter, there was a hiatus in the
      development of antipsychotics until the introduction of clozapine treatment in
      the United States in 1990 opened the era of "atypical" antipsychotic drugs, which
      show a reduced potential to induce extrapyramidal symptoms (EPS), an increased
      efficacy for the negative symptoms of schizophrenia, no elevation of prolactin
      after chronic use (except risperidone), and, at least for clozapine,
      effectiveness in some patients previously regarded as treatment-refractory. This
      review describes the available atypical antipsychotic drugs and their
      characteristics, and concludes by highlighting those in the pharmaceutical
      "pipeline."

PMID- 10579371
TI  - Seasonal mood change and neuroticism: the same construct?
AB  - The personality trait of neuroticism has been found to be associated with a
      polymorphism in the regulatory region of the serotonin (5-HT) transporter gene (5
      HTTLPR). This same genetic polymorphism has also been associated with seasonal
      changes in mood and behavior, or seasonality. The purpose of the current study
      was to determine whether seasonality and neuroticism are actually the same
      construct given that they are both associated with the same genetic polymorphism.
      We administered the Seasonal Pattern Assessment Questionnaire (SPAQ), which
      measures the severity of seasonality, and the Revised NEO Personality Inventory
      (NEO-PI-R), which measures the severity of neuroticism, to 45 subjects diagnosed
      with seasonal affective disorder (SAD). SAD is a clinical expression of
      seasonality in which patients develop a major depressive disorder in the winter
      that remits in the summer and can be treated with light therapy. No significant
      correlation was found between neuroticism and seasonality. We conclude that
      seasonality and neuroticism are not the same construct, even though the 5-HTTLPR
      polymorphism is a genetic risk factor for each.

PMID- 10579372
TI  - Bipolar II versus unipolar chronic depression: a 312-case study.
AB  - Differences between bipolar II depression and unipolar depression have been
      reported, such as a lower age at onset and more atypical features in bipolar II
      depression. The aim of the present study was to compare chronic/nonchronic
      bipolar II depression with chronic/nonchronic unipolar depression to determine
      whether the reported differences are present when chronicity is taken into
      account. Three hundred twelve outpatients in a bipolar II/unipolar major
      depressive episode were assessed with the Structured Clinical Interview for DSM
      IV-Clinician Version (SCID-CV), the Montgomery and Asberg Depression Rating Scale
      (MADRS), and the Global Assessment of Functioning (GAF) Scale. No significant
      difference was found between chronic bipolar II and chronic unipolar depression
      (age at intake and onset, gender, duration of illness, recurrences, psychosis,
      atypical features, axis I comorbidity, and severity). A significantly lower age
      at onset and more atypical features were observed when comparing
      chronic/nonchronic bipolar II with nonchronic unipolar depression. These findings
      suggest that differences reported between bipolar II and unipolar depression are
      mainly due to nonchronic unipolar depression. Chronic unipolar depression may be
      a subtype intermediate between bipolar II depression and nonchronic unipolar
      depression.

PMID- 10579374
TI  - A behavioral comparison of female adolescent inpatients with and without
      borderline personality disorder.
AB  - Patients with borderline personality disorder (BPD) are thought to have
      problematic hospitalizations. This study seeks to examine this phenomenon in
      adolescence by documenting the specific problem behaviors exhibited by patients,
      and the staff interventions in response to these behaviors in patients with and
      without BPD. Data were collected from the charts of 81 hospitalized adolescent
      girls regarding restraints, seclusions, incidents of self-abuse and aggression,
      incidents of signing the intent-to-leave form, nonroutine drug and/or alcohol
      screens, and discharges against medical advice. The two groups were compared
      using the analysis of variance (ANOVA) statistic for continuous variables and the
      chi-square statistic for the categorical variable. A follow-up multivariate ANOVA
      (MANOVA) was performed using the length of stay as a covariate. The BPD group
      displayed significantly higher rates of certain behaviors per day, but not of
      others. The length of stay was significantly higher in the BPD group. Further
      analysis indicated that some of the behavioral differences between the two groups
      may be due to the effect of the difference in length of stay. The data also
      suggest that while most BPD patients behave similarly to other patients, there
      may be a subset of BPD patients who behave in an extreme manner while
      hospitalized. BPD patients may display more of certain problematic behaviors than
      non-BPD patients in the hospital. However, it is hypothesized that these
      differences in hospital behavior may be largely due to the different lengths of
      stay between the two groups or to an acting-out subgroup of BPD patients.

PMID- 10579373
TI  - Correlates of suicide risk in adolescent inpatients who report a history of
      childhood abuse.
AB  - The study objective was to examine correlates of suicide risk in psychiatrically
      hospitalized adolescents with a reported history of childhood abuse. Predictors
      of suicide risk were examined in 74 subjects who reported a history of childhood
      abuse and 53 depressed subjects who did not report a history of childhood abuse.
      Subjects completed a battery of psychometrically well-established self-report
      instruments to assess childhood abuse, suicide risk, and internalizing and
      externalizing psychopathology. Correlational analyses showed that higher levels
      of depression, self-criticism, and hopelessness were significantly associated
      with suicide risk in both study groups and violence was significantly associated
      with suicide risk in the childhood abuse group. For the childhood abuse group,
      multiple regression analyses with seven predictor variables accounted for 54% of
      the variance in suicide risk; depression and alcohol problems made significant
      independent contributions, while violence and self-criticism were independent
      predictors at the trend level. For the depressed/nonabused group, multiple
      regression analyses with the seven predictor variables accounted for 60% of the
      variance in suicide risk; depression, hopelessness, and self-criticism were
      independent predictors. Our findings suggest that both internalizing (i.e.,
      depression or self-criticism) and externalizing (i.e., violence or alcohol)
      factors predict suicide risk in adolescent inpatients who report childhood abuse.
      This profile appears different from the more internalizing pattern (i.e.,
      depression, self-criticism, and hopelessness) observed for the depressed
      adolescent inpatients who reported no history of childhood abuse.

PMID- 10579375
TI  - Perception of family functioning and depressive symptomatology in individuals
      with anorexia nervosa or bulimia nervosa.
AB  - This study investigated the relationship between the perception of family
      functioning and depressive symptomatology in individuals with eating disorders
      (EDs). Subjects were evaluated by diagnostic clinical interview using DSM-III-R
      criteria for EDs, the Schedule for Affective Disorders and Schizophrenia-Lifetime
      Version (SADS-L), and two self-report measures, the Beck Depression Inventory
      (BDI) and the Family Assessment Device (FAD). A significant association was found
      between self-reported depressive symptomatology and perceived poor family
      functioning. Subjects with bulimia nervosa (BN) reported a significantly more
      dysfunctional family background than subjects with anorexia nervosa (AN). In our
      sample, the presence of self-reported depressive symptomatology was a more
      powerful predictive variable for perceived family dysfunction than the diagnosis
      of affective disorder. Also, the diagnosis of BN was a more consistent predictor
      of dysfunctional family interaction than the diagnosis of affective disorder.
      Depressive symptoms and EDs seem to play different roles in the way in which they
      contribute to dysfunctional family patterns.

PMID- 10579376
TI  - Bright light therapy decreases winter binge frequency in women with bulimia
      nervosa: a double-blind, placebo-controlled study.
AB  - The study objective was to determine the effect of winter bright light therapy on
      binge and purge frequencies and depressive symptoms in subjects with bulimia
      nervosa. Thirty-four female bulimic outpatients were treated with either 10,000
      lux bright white light or 50 lux dim red light (placebo control) during the
      winter months. In this double-blind study, the placebo group (n = 18) and the
      bright light group (n = 16) were matched for age, degree of seasonality (measured
      by the Seasonal Patterns Assessment Questionnaire [SPAQ]), and concurrent
      depression (measured by Structured Clinical Interview for DSM-IV [SCID]). Three
      weeks of baseline data collection were followed by 3 weeks of half-hour daily
      morning light treatment and 2 weeks of follow-up evaluation. There was a
      significant light-treatment by time interaction (Wilks' lambda = .81, F(2,28) =
      3.31, P = .05). The mean binge frequency decreased significantly more from
      baseline to the end of treatment for the bright light group (F(1,29) = 6.41, P =
      .017) than for the placebo group. The level of depression (measured by daily Beck
      Depression Inventory [BDI] scores) did not significantly differ between the
      groups during any phase, and neither depression nor seasonality affected the
      response to light treatment. In this double-blind study, bulimic women who
      received 3 weeks of winter bright light treatment reported a reduced binge
      frequency between baseline and the active treatment period in comparison to
      subjects receiving dim red light.

PMID- 10579377
TI  - Three dimensions of depression in patients with acute psychotic disorders: a
      replication study.
AB  - Depressive symptoms in psychotic disorders are of high relevance but seem to be
      heterogeneous when assessed with a standard rating scale. The present analysis is
      a replication study on the dimensionality of the Bech-Rafaelsen Melancholia Scale
      (BRMES) in acutely psychotic patients with substantial depression defined
      according to a functional approach across the nosological borders of
      schizophrenia with major affective symptoms, schizoaffective disorder, depressed
      subtype, and major depression with psychotic features. The baseline data of 123
      patients participating in a multicenter pharmacological trial were evaluated with
      structural equation models. A previously reported three-dimensional model of the
      BRMES comprising the facets retardation, depressive core symptoms, and accessory
      depressive symptoms was cross-validated by confirmatory factor analysis (CFA).
      The three-dimensional model proved to be superior to one-, two-, or four-factor
      models with respect to goodness-of-fit (goodness-of-fit index [GFI] = 0.91 and
      comparative fit index [CFI] = 0.89) and parsimony (adjusted GFI [AGFI] = 0.85).
      When comparing the present model with the previously reported model, a highly
      satisfactory correspondence emerged (CFI = 0.87). The results corroborate our
      previous findings that depression-like symptoms in acutely psychotic patients
      assessed by the BRMES can best be represented by a three-dimensional model and
      should not be treated as a homogeneous syndrome.

PMID- 10579378
TI  - Symptom correlates of global measures of severity in schizophrenia.
AB  - There is an increasing need for practical instruments that can rapidly and
      accurately assess the effectiveness of treatments for mental illness in clinical
      settings. Symptom rating scales used in clinical research are too complex and
      time-consuming to be useful in these settings. In contrast, single-item global
      measures of severity such as the Clinical Global Impression-severity scale (CGI)
      and the Global Assessment of Function scale (GAF) are brief and easy to complete,
      but little is known about their relationship with the specific symptoms of severe
      mental illnesses. In this study, we examine the extent to which CGI and GAF
      scores reflect the severity and the change in severity of positive, negative,
      depressive, and agitation symptoms in a sample of 102 schizophrenia inpatients at
      the University of Michigan Medical Center. At admission, positive symptoms were
      the strongest correlates of both CGI and GAF scores, followed by negative
      symptoms, and agitation. Depressive symptoms did not correlate significantly with
      either global measure. The three symptom scores together explained 58% of the
      variation in CGI and 39% of the variation in GAF. A similar pattern of
      association was found for the scores measured at discharge and for the
      relationships between the change in global measures and change in specific
      symptom clusters. Thus, by demonstrating that single-item global measures,
      particularly the CGI, can be reasonably good indicators of psychopathology, this
      study suggests that these measures may be practical tools for routine monitoring
      of the effectiveness of treatments for severe mental illness in community
      settings.

PMID- 10579379
TI  - Increased occurrence of depression in psychosis-prone subjects: a follow-up study
      in primary care settings.
AB  - A follow-up survey was performed with a network of general practitioners (GPs) to
      examine whether a higher proneness for psychosis predicts a greater incidence of
      depression in subjects with no history of mood disorder. At the first stage of
      the survey (T1), a self-report questionnaire exploring delusional ideation
      (Peters et al. Delusional Inventory [PDI-21]) was administered to the patients of
      the GPs. Information on psychiatric status at the baseline and conclusion of the
      12-month follow-up period was provided by the GPs. The present study was
      restricted to 425 subjects with no lifetime history of depression. An incident
      depression was diagnosed in 18 subjects. Most items exploring delusional beliefs
      and hallucinations were more frequently endorsed by subjects with incident
      depression. Subjects with a PDI-21 score above the 90th percentile at T1 were
      nine times more likely to present with an incident depression during the follow
      up period than those with PDI-21 scores below the 10th percentile. Psychosis
      proneness is associated with a greater risk for depression, suggesting that a
      continuum of vulnerability may exist between affective disorder and nonaffective
      psychosis.

PMID- 10579380
TI  - Types of panic attacks and their association with psychiatric disorder and
      physical illness.
AB  - The differentiation of three types of panic attacks is proposed to be significant
      for understanding the course and etiology of panic and other psychiatric
      disorders and physical illnesses. The present investigation is based on
      longitudinal data from the Epidemiologic Catchment Area (ECA) Study of 1980 to
      1981 and its 1994 to 1996 follow-up. Multidimensional scaling (MDS) of panic
      symptoms identified three types of panic which were consistent over time and for
      which reliable scales were constructed to measure derealization, cardiac panic,
      and respiratory panic. Unlike panic disorder, none of the three types of panic
      attacks predicted the incidence of depression. Derealization was associated with
      a broader variety of psychiatric disorders than the other two types of panic,
      including simple phobias, but was not associated with physical diseases. Cardiac
      panic attacks were associated with a history of heart disease and predicted the
      incidence of agoraphobia but were not comorbid with depression, unlike the other
      two forms of panic. Respiratory panic attacks were consistently symptomatic of
      dysthymia and predicted a higher risk of hospitalization for breast cancer and
      myocardial infarction (MI).

PMID- 10579381
TI  - The cognitive failures questionnaire in psychiatry.
AB  - As a self-report questionnaire, the Cognitive Failures Questionnaire (CFQ) was
      originally devised to measure perception, memory, and motor lapses in daily life.
      CFQ scores have been found to correlate with some psychiatric symptoms associated
      with stress; hence, high scores on the CFQ are considered by some as an indicator
      of increased vulnerability to stress. Attempts to identify a stable factor
      structure for the CFQ have produced disparate results. However, there is a
      measure of agreement with regard to the presence of a "general cognitive" factor
      that includes loadings from most items and accounts for the lion's share of the
      variance. Not enough is known about the performance of the CFQ in clinical
      populations to use it as a measure of change. The current study sought to explore
      the performance of the CFQ in three groups of patients, organic (n = 209), mixed
      (n = 115), and functional (n = 322), and to identify correlations with measures
      of psychiatric morbidity (General Health Questionnaire [GHQ]), depression (Beck
      Depression Inventory [BDI]), and recognition memory (Signal Detection Memory
      Test). In the organic and functional samples, the CFQ score significantly
      correlated with the BDI and GHQ but not with the recognition memory measure.
      Three factors were found to be common to the organic and functional samples:
      cognitive, dissociation, and clumsiness. No characteristic pattern of CFQ item
      endorsement to differentiate between the organic and functional samples was
      found. Seven items of the CFQ performed badly because of ceiling or floor
      effects. The "negative" results reported herein are of relevance to researchers
      who may be planning to use the CFQ in clinical research. The CFQ remains a
      promising instrument, particularly on account of its "ecological" features, but
      far more investigation is needed before it is used as a standard measure in
      clinical practice.

PMID- 10579382
TI  - Deleterious effect of null phenoloxidase mutation on the survival rate in
      Drosophila melanogaster.
AB  - The effect of null activity of phenoloxidase on the survival rate was
      investigated in mutants of Drosophila melanogaster. MoxGM95 and Dox-3KD95,
      structural genes for prophenoloxidase A1 and A3, were found in natural
      populations in the former Soviet Union, and affected the phenoloxidase activity
      in active A1 or A3, respectively. After linking the visible markers located on
      the second chromosome together with the variants, cross experiments were
      performed to make homozygote, rdo Dox-3KD95 pr C MoxGM95 wt. No double mutant had
      emerged. In the mutant, c MoxGM95 wt Pu2, the viability was greatly reduced.
      These results suggested that phenoloxidase and tyrosine-3-hydroxylase act as
      indispensable proteins to maintain life in Drosophila.

PMID- 10579383
TI  - Maternal transmission of immunity to white spot syndrome associated virus (WSSV)
      in shrimp (Penaeus monodon).
AB  - Beta-1,3-1,6-glucan, derived from bakers' yeast Saccharomyces cerevisiae, was
      used in the present study to investigate the extent to which glucan is able to
      protect spawners from white spot syndrome associated virus (WSSV), and whether
      this protection (if any) can be passed on to hatchlings via maternal transmission
      of immunity. Results showed that fewer spawners in the glucan-injected groups
      showed the clinical symptoms of red body coloration and white spots on the shell
      during the 15 days between eyestalk ablation and the end of repeated spawning.
      This suggests that the application of glucan might lead to a slight enhancement
      of disease resistance in spawners, although the differences were not
      statistically significant within the confidence limit chosen. Challenge results
      showed a significant increase in relative percent survival for larvae derived
      from groups of glucan-injected spawners compared to those derived from groups of
      untreated spawners. It therefore seems that a maternally transmitted disease
      resistance induced by glucan, protected the larvae against a WSSV infection.
      Glucan immersion was not only shown to be effective for nauplii derived from
      spawners that were not injected with glucan, it also provided additional,
      cumulative protection for nauplii which already had a maternally transmitted
      resistance to WSSV. This is the first documented demonstration of a maternal
      transmission of immunity in invertebrates.

PMID- 10579384
TI  - Induction of mosquito hemolymph proteins in response to immune challenge and
      wounding.
AB  - The rapid induction of proteins in the hemolymph of the mosquito, Anopheles
      gambiae, was examined after wounding or injection of immune elicitors
      (Escherichia coli, lipopolysaccharide, laminarin, zymosan). One-dimensional gel
      electrophoresis revealed at least six hemolymph polypeptides >25 kDa that
      consistently appeared after any breech of the cuticle. All of these polypeptides
      appeared in the hemolymph within 30 min and reached a maximum concentration after
      approx. 6 h. No proteins were specifically induced by bacteria or bacterial or
      fungal cell wall products, however two constitutively expressed proteins were
      repressed by these injections. Patterns of hemolymph proteins were further
      analyzed by two-dimensional electrophoresis. Seven spots were enhanced or induced
      2 h after injection in four replicate experiments. An additional two spots
      demonstrated some variability between replicates, but were generally responsive
      to injection. These rapidly induced polypeptides are candidates for regulating
      and initiating the mosquito's responses to pathogens and wounding.

PMID- 10579385
TI  - Apolipophorin-III in Galleria mellonella potentiates hemolymph lytic activity.
AB  - Heat-inactivated serum of non-immune Galleria mellonella larvae enhanced the
      lytic activity of larval cell-free hemolymph against Micrococcus lysodeikticus.
      The increase in bacterial lysis was due to a 17.2 kDa protein known previously to
      bind to bacterial lipopolysaccharides. The protein enhanced the lytic activity of
      insect cell-free hemolymph and hen lysozyme in vitro and insect hemolymph in
      vivo. The hydrophobic protein, which adhered to M. lysodeikticus, was identified
      by its amino acid sequence homology as apolipophorin-III. The titer of
      apolipophorin-III in 200-250 mg last instar larvae was 8.7 mg/ml of hemolymph.
      Apolipophorin-III did not bind to lysozyme. A possible mode of action of
      apolipophorin-III with lysozyme in the insect is proposed.

PMID- 10579387
TI  - Inhibition of macrophage activity by mitogen-induced goldfish leukocyte
      deactivating factor.
AB  - Macrophage activating and deactivating cytokines have been characterized in
      mammalian systems but little is known about these immunoregulatory molecules in
      fish. Using gel permeation and chromatofocusing fast performance liquid
      chromatography (GP-FPLC and C-FPLC) we partially purified a macrophage
      deactivating factor (MDF) from mitogen-induced goldfish kidney leukocytes.
      Inhibition of the macrophage-derived nitric oxide (NO) response induced by this
      MDF was time-, dose- and temperature-dependent. Macrophages pre-treated for 6 or
      24 h with MDF before activation with macrophage activating factors (MAF) and/or
      bacterial lipopolysaccharide (LPS) exhibited a down-regulation in their NO
      response, while those treated with MDF 24 h after activation with MAF and LPS did
      not. MDF treatment also impaired the NO response of goldfish macrophages infected
      with the mammalian protozoan parasite Leishmania major. These results suggest
      that MDF exhibits its inhibitory effect downstream of the converging
      intracellular pathways induced by LPS and/or L. major. The novel teleost MDF has
      an approximate Mr of 15 kD and a pI < 4, and is the first endogenous molecule of
      teleosts known to down regulate macrophage antimicrobial responses.

PMID- 10579386
TI  - Identification of a beta 2 (CD18) molecule in a teleost species, Ictalurus
      punctatus Rafinesque.
AB  - Beta 2, in combination with the alpha subunit, is responsible for tight adhesion
      of leukocytes, especially neutrophils and macrophages, in areas of inflammation.
      Although identified in mammalian and avian species; the beta 2 or CD18 molecule
      has yet to be identified in fish. The present investigation has identified a full
      length channel catfish, Ictalurus punctatus, cDNA beta 2 molecule composed of 2.8
      kb and a deduced amino acid sequence of 772 amino acids. The catfish molecule has
      an amino acid homology ranging from 54 to 63% with mouse, bovine, rabbit, human
      and chicken. The channel catfish molecule retains several characteristics of
      mammalian beta 2 molecules, such as cysteine-rich repeat regions, N-linked
      glycosylation sites, and several proposed signal sequences. Expression of the
      beta 2 molecule on the catfish neutrophil cytoplasmic membranes is increased upon
      phorbol dibutyrate stimulation of the cells. Based on Western blotting and the
      immunoprecipitation test, the channel catfish beta 2 molecule has a molecular
      mass of approximately 95 kD, essentially the same as that for mammalian species.
      However, two additional molecules, perhaps alpha chains, of unexpected molecular
      mass appear to co-precipitate in the SPIT with the 95 kD CD18 molecule. These
      results confirm the existence and expression of a beta 2 gene in channel catfish,
      a species phylogenetically distant from mammalian species.

PMID- 10579388
TI  - Cloning and structural analysis of IgM (mu chain) and the heavy chain V region
      repertoire in the marsupial Monodelphis domestica.
AB  - To address the question of the Ig isotype repertoire of non placental mammals, we
      have examined the Ig expression in the marsupial Monodelphis domestica (grey
      short tailed opossum). Screening of an opossum spleen cDNA library has previously
      led to the isolation of full length clones for opossum IgG (gamma chain), IgE
      (epsilon chain) and IgA (alpha chain). We now present the isolation of several
      cDNA clones encoding the entire constant regions of the opossum IgM (mu chain). A
      comparative analysis of the amino acid sequences for IgM from various animal
      species showed that opossum IgM, within the various animals studied, is the most
      divergent member of its Ig class. However, it still conforms to the general
      structure of IgM in other vertebrates. Four Ig classes have now been identified
      in opossum and only one isotype is apparently present within each Ig class, IgM,
      IgG, IgA and IgE. Opossum has previously been shown to have a limited VH region
      diversity, with only two V gene families. Both of these belong to the group III
      of mammalian VH sequences. This limitation in variability is to some extent
      compensated for by a large variation in D, P and N regions, both in size and in
      sequence. However, evidence for the expression of only two functional J segments
      has so far been detected, which indicates a rather limited diversity also of the
      J segments in the opossum.

PMID- 10579390
TI  - Developmental expression of alloantigen systems in the chicken.
AB  - The different allelic forms of nine non-Mhc alloantigen systems of the chicken
      were examined for developmental expression on erythrocytes isolated from embryos
      and young chicks. Polyclonal alloantisera raised against the different antigens
      were used to detect these antigens on the cell surface by hemagglutination as
      well as by indirect immunofluorescence. The developmental stage of initial
      expression on erythrocytes for each of the genetic systems investigated (i.e., A,
      E, C, D, H, I, K, L and P) varied from day 4 to day 14 of incubation. The
      different antigens of each system appeared simultaneously at a particular stage
      of development except for those of the I system, where the I8 allelic form
      appeared earlier than I2.

PMID- 10579389
TI  - Variability of the immunoglobulin light chain in the Siberian sturgeon, Acipenser
      baeri.
AB  - All sturgeon VL segments isolated in this study belong to a single family, VLI,
      which can be divided into two subfamilies. Of the 79 cDNA clones isolated, 76
      belong to the larger subfamily, VLIa, and only 3 clones constitute the smaller
      subfamily, VLIb. To evaluate variability, the Shannon entropy was estimated for
      each individual amino acid position, and to facilitate comparisons of variability
      between species the mean entropy of the CDR regions was calculated. In such a
      comparison, the sturgeon was found to have CDR1 and CDR3 variability approaching
      those found in mouse and clawed frog, but showed very low variability for CDR2.
      Amino acid position 50 does however display variability in the range of mouse and
      clawed frog. It is further confirmed that the sturgeon has numerous J segments,
      but that the junctional diversity does not contribute greatly to the diversity of
      the light chain. Comparisons of cDNA clones and a genomic VL segment indicate
      that the VL undergoes changes, particularly in the CDR regions, in a manner that
      can be explained by somatic hypermutation and/or gene conversion.

PMID- 10579391
TI  - Bioactivities of a tumour necrosis-like factor released by chicken macrophages.
AB  - To test for tumour necrosis-like factor (TNF) of chickens, supernatants of a
      lipopolysaccharide (LPS)-stimulated chicken macrophage cell line MQ-NCSU were
      analysed. A sequence of ion-exchange and gel-permeation chromatography was
      utilised to isolate TNF-like activity from the culture supernatant. The peak of
      TNF-like cytotoxic activity corresponded to the fractions with a molecular weight
      of 81 kDa or higher. Polyclonal anti-human TNF-alpha antiserum cross-reacted by
      Western blotting with a 17 kDa protein in the TNF-containing fraction under
      denaturing conditions. This result indicated that chicken TNF-like factor in the
      biologically active form may be a protein multimer of monomers of about 17 kDa.
      The molecular weight of these monomers is similar to the molecular weight of
      mammalian TNF-alpha. Chicken TNF-like factor stimulated macrophages by inducing
      morphological changes, enhancing Ia-expression, nitric oxide (NO) production and
      by synergising with interferon (IFN)-gamma in the induction of NO release from
      macrophages. The biological activities were not neutralised by anti-human TNF
      antiserum. These data suggest that LPS-stimulated chicken macrophages produced a
      functional homologue to mammalian TNF-alpha. This may be structurally quite
      different from the mammalian TNF molecule. Other factors may have been co
      purified with the chicken TNF-like factor having overlapping functions and
      molecular weight. However, co-purification of chemokines and interleukin-1, major
      macrophage derived factors, with the chicken TNF-like factor can be excluded
      based on the purification strategies.

PMID- 10579392
TI  - Chemotactic activities of avian lymphocytes.
AB  - Chicken lymphocytes, enriched chicken T and B lymphocytes, and a turkey B
      lymphoblastoid cell line, the RP-9 cells, are used in the studies of chemotaxis
      in a Boyden-type chamber assay. The chemoattractants used are lipopolysaccharide,
      fMLP, interleukin-8, MIP1-beta, rabbit anti-chicken IgG and IgM. The results
      indicate that all these cells can migrate into the polycarbonate membranes in the
      absence of chemoattractants. When the chemoattractants are present, the numbers
      of migrating cells are greatly increased. It is, therefore, concluded that avian
      lymphocytes have the ability to migrate, and can respond to chemical signals
      which result in chemotaxis and accumulation of lymphocytes at the sites where the
      signals originate.

PMID- 10579393
TI  - Isolation and comparison of the IgM heavy chain constant regions from Australian
      (Trichosurus vulpecula) and American (Monodelphis domestica) marsupials.
AB  - cDNAs encoding IgM heavy chain constant region (Cmu) were isolated from two
      metatherians (marsupials)--the Australian common brushtail possum (Trichosurus
      vulpecula) and the South American grey short-tailed opossum (Monodelphis
      domestica). Analysis of the sequences suggested that they correspond to the
      secreted form of Cmu in both species. The domain size and structure of the
      marsupial Cmu sequences were compared with other Cmu sequences and a high degree
      of conservation throughout vertebrate evolution was observed. Amino acid sequence
      comparisons revealed a marked level of sequence similarity between the two
      marsupial sequences (79%), relatively high similarity between the marsupials and
      eutherians (63%), and lower similarities between marsupials and birds (45%),
      marsupials and amphibians (47%), marsupials and reptiles (45%) and marsupials and
      fish (37%). These data allow the incorporation of metatherians into the study of
      mammalian IgM evolution.

PMID- 10579394
TI  - Type I interferons and the Th1/Th2 paradigm.
AB  - During the past year significant advances have been made in our understanding of
      the factors contributing to the differentiation of CD4+ T helper cell subsets.
      These have been driven, in part, by the realization that cytokines from the
      innate immune response, such as interleukin-12 (IL-12) and interferons (IFNs),
      play a critical role in T cell subset differentiation. This review covers some of
      the most recent data concerning the divergent role that IFNs have in the
      differentiation of human versus mouse T helper cell subsets. In this review we
      discuss the molecular basis for the specie-specific effect of type I IFN on the
      selective induction of Th1 type immune responses. Furthermore, since IFN-beta is
      used in the treatment of multiple sclerosis (MS) we discuss the potential effects
      of such treatment and the value of the Th1/Th2 paradigm in MS.

PMID- 10579395
TI  - Increased gammadelta T-cell populations in draining lymph nodes of lambs during
      the elicitation phase of dinitrochlorobenzene-induced contact hypersensitivity.
AB  - Ten lambs were sensitised with the hapten DNCB in an acetone/olive oil vehicle.
      The hapten/vehicle solution was applied onto the skin on the shaved ventral
      surface of the right ear. Two weeks later these lambs were rechallenged with the
      DNCB/vehicle solution. Simultaneously, ten non-sensitised lambs were treated with
      vehicle only, serving as vehicle controls. The 20 lambs were slaughtered 48 h
      after challenge/vehicle treatment, along with ten untreated animals serving as
      normal controls. Specimens of draining lymph nodes were collected from the 30
      animals. All lambs were between 149 and 187 days old. Lymph node cryosections
      were stained for several leukocyte markers using monoclonal antibodies with the
      ABC immunohistochemical method. The stained sections were subsequently assessed
      in three different cortical compartments in each section, using an image analysis
      system. The resulting measurements from the three groups were compared. A marked
      increase of gammadelta T cells was detected in the DNCB group. The number of CD4+
      T helper cells was decreased in the DNCB group compared with the normal control
      group, but not with the vehicle control group. No differences were revealed for
      CD8+ T cytotoxic cells or B cells. These findings were interpreted to be the
      consequences of possible downregulatory mechanisms protecting the lymphoid tissue
      from hypersensitivity. The prominence of gammadelta T-cells could indicate that
      these cells are involved in downregulation.

PMID- 10579397
TI  - Preliminary investigations of ultraviolet-induced markings on domestic turkey
      chicks and a possible role in injurious pecking.
AB  - Several gallinaceous species including domestic turkeys have the capacity for
      ultraviolet (UV) vision. This might function in signalling between birds, for
      example in individual recognition, which would suggest the presence of plumage
      markings visible under UV radiation. Between 1 and 22 d of age, the plumage of 17
      male turkey poults (BIG6) was examined. When viewed under a conventional
      fluorescent white luminaire (which emits minimal UV) the birds were a uniform
      yellow or white according to the stage of feather emergence. However, when viewed
      under a lamp emitting radiation with peaks in the UV spectrum, distinct
      fluorescent and non-fluorescent patches were observable on several parts of the
      body including the wings, tail, shoulders, thighs, neck, breast and dorsal
      surface. This paper describes the changes in incidence, size, location and
      qualitative aspects of these UV-visible markings. The age at which UV-visible
      markings were first observed on the wings and tail corresponded closely with the
      age at which injuries to these sites were first caused by pecking, as reported
      previously. It is suggested that the 'unnatural' appearance of these markings
      under conventional lighting, which emits minimal UV radiation, might attract or
      protract injurious pecking from conspecifics.

PMID- 10579396
TI  - 'Self' tolerance in a parent-->F1 radiation chimera.
AB  - The extent to which T cell immune tolerance to self tissue antigens is acquired
      during intrathymic development, or also may occur elsewhere in the animal,
      remains unclear. Experiments have been designed to explore this using allogeneic
      hematopoietic radiation chimeras in which thymectomized CB6F1 (H-2(b/d)) host
      mice were engrafted with day 16 C57BL/6 (H-2b) fetal thymus tissues, irradiated
      with 950 rad 3 weeks later, and reconstituted with day 14 C57BL/6 fetal liver
      cells. Chimeras constructed in this manner had thymus grafts which developed with
      normal structure and cellularity as determined from histological sections, and
      had normal proportions of CD4+ 8- and CD4- 8+ peripheral T cells of donor H-2b
      origin. Mice showed no signs of acute or chronic GVHD when followed for six
      months and, although T cells from chimeras were non-reactive to donor (H-2b) or
      host (H-2d) MHC, they responded to third party (H-2k) alloantigens in primary
      mixed-lymphocyte reactions. To determine whether tolerance might have been
      induced by radioresistant host hematopoietic cells, mice were treated with anti-I
      Ad monoclonal antibody after irradiation and fetal liver cell transfer. The
      pattern of alloreactivity of T cells from those animals closely resembled that of
      non-antibody treated mice, suggesting that tolerance to MHC expressed within the
      host probably was not due to radioresistant class-II-bearing cells in chimeras.
      These findings imply that immune tolerance to self antigens can be controlled at
      sites outside the thymus, and they provide further evidence that allogeneic
      chimeras can be constructed when elimination of mature T cells from the donor
      hematopoietic pool has been effectively achieved.

PMID- 10579398
TI  - Early T-maze behaviour and subsequent growth in commercial broiler flocks.
AB  - Two batches of 2000 mixed-sex broiler chicks were obtained, one in summer and one
      in winter. Each flock was housed on the floor at a commercial farm. At 2 or 3 d
      of age, the latencies to escape from a T-maze were measured in 1044 and 1180
      chicks in the summer and winter flocks, respectively. Chicks were assigned to
      high (HP), moderate (MP) or low (LP) performance categories if their escape
      latencies were below 40 s, between 40 to 90 s, or above 90 s, respectively.
      Ninety male and 90 female chicks from each of the 3 categories were weighed when
      they were 3 d old. The birds then remained undisturbed, apart from routine
      maintenance, until similar numbers were weighed at 49 d of age. Some birds may
      have been weighed at both ages. Body weights were higher in males than females
      and higher in the winter than summer flock at 3 d of age. Significant main
      effects of chick category as well as gender and season were found at 49 d of age.
      There were no significant interactions. As expected, 49-d body weights were
      higher in males than females and in the flock reared in winter than in summer. 5.
      HP chicks (those that showed rapid escape from the T-maze at 3 d) were also
      significantly heavier at 49 d than their LP counterparts, with MP chicks
      occupying an intermediate position. This suggests that early performance in a T
      maze test is positively associated with subsequent growth. Furthermore, this
      relationship was apparent in each of the 2 flocks. Given this positive
      association, we suggest that this simple, rapid and non-invasive behavioural test
      could be a useful selection criterion for future breeding programmes.

PMID- 10579399
TI  - Prevalence of gastrointestinal helminths in different poultry production systems.
AB  - A cross-sectional prevalence study of gastrointestinal helminths in Danish
      poultry production systems was conducted on 268 adult chickens selected at random
      from 16 farms in Denmark from October 1994 to October 1995. The trachea and the
      gastrointestinal tract of each bird was examined for the presence of helminths.
      In the free-range/organic systems the following helminths were found: Ascaridia
      galli (63.8%), Heterakis gallinarum (72.5%), Capillaria obsignata (53.6%),
      Capillaria anatis (31.9%) and Capillaria caudinflata (1.5%). In the deep-litter
      systems: A. galli (41.9%), H. gallinarum (19.4%) and C. obsignata (51.6%). In the
      battery cages: A. galli (5%) and Raillietina cesticillus or Choanotaenia
      infundibulum (3.3%). Exact identification of the cestodes was not possible
      because of missing scolexices. In the broiler/parent system: C. obsignata (1.6%),
      and finally for the backyard system: A. galli (37.5%) H. gallinarum (68.8%), C.
      obsignata (50.0%), C. anatis (56.3%) and C. caudinflata (6.3%). The results
      confirm the higher risk of helminth infections in free-range and backyard systems
      but prevalence may also be high in deep litter systems.

PMID- 10579400
TI  - Changes in feather condition in relation to feather pecking and aggressive
      behaviour in laying hens.
AB  - The aim of this experiment was to describe and examine the relationship between
      pecks received by individual birds and the feather and skin damage of those birds
      at different ages. The effect of group size was also studied. Laying hens were
      raised in floor pens in group sizes of 15, 30, 60 and 120 birds, each with 4
      replicates. Behavioural observations were performed at the ages of 22, 27, 32 and
      37 weeks. Detailed feather scoring was carried out at the ages of 18, 23, 28 and
      33 weeks. Behavioural observations focused on the number of feather pecks (gentle
      and severe) and aggressive pecks received, and on the part of the body that was
      pecked. Scoring of feather and skin damage focused on the same 11 parts of the
      body. Increasing numbers of aggressive pecks received were associated with
      decreased body weight and increased feather damage at the ages of 27 and 32
      weeks. The number of severe feather pecks received was significantly related with
      feather damage at all ages; however, no relation with gentle feather pecks
      received was found. Group size had a significant effect on feather condition,
      with large group sizes having most feather damage.

PMID- 10579401
TI  - Effect of light source and regimen on growing broilers.
AB  - The aim of this study was to determine the effect of different light sources and
      light schedules on the growth and quality of commercial broilers. In each
      experiment 810 broiler chicks were divided into 3 groups, 3 replicates per group.
      All were reared at 20 lux. Body weight and food consumption were recorded weekly.
      Experiment 1. Birds were reared under 3 light sources: incandescent light bulb,
      warm-white fluorescent light tube or warm-white mini-fluorescent light bulb.
      Experiment 2. Birds were reared on 3 light schedules. 23 h light and 1 h dark
      (23L: 1D) throughout; an increasing light schedule with initial 23L:1D then 8L:
      16D increasing daylight gradually to 16L:8D or an intermittently increasing
      daylight schedule (16:8P) where light and dark periods were shorter but portioned
      to achieve the same total hours per day up to 16L:8D. Broilers reared under mini
      fluorescent light bulb were heavier than those under fluorescent tubes or
      incandescent bulbs by 49 d. Until 42 d of age, photoperiod had no effect on
      growth. However, at 49 d broilers reared under 16:8P and 16L:8D regimens were
      heavier than those or 23L:1D. At 42 d, female broilers on 23L:1D, were heavier
      than those on 16L:8D and 16:8P. Mortality was higher in groups on 23L:1D than on
      16L:8D on 16:8P. At 49 d incidence of leg condemnation was higher in the 16:8P
      group. However, skin damage was lower in this group than in those on 23L: 1D and
      16L:8D.

PMID- 10579402
TI  - Antioxidant systems of the avian embryo: tissue-specific accumulation and
      distribution of vitamin E in the turkey embryo during development.
AB  - Tissue-specific accumulation of tocopherols and tocotrienols in turkey tissues
      during embryonic development and their susceptibility to lipid peroxidation were
      investigated. Fertile turkey eggs were incubated using standard commercial
      conditions. Embryonic tissues were collected at 16, 22, 25 d of incubation and
      from day-old poults (referred to as day 29) and alpha-; beta- + gamma- and delta
      tocopherols and respective tocotrienols were analysed by HPLC. A turkey diet
      provided to the parent hens contained the complete range of tocopherols and
      tocotrienols. Between days 16 and 22 of embryo development, the alpha-tocopherol
      concentration in the liver remained constant and then increased significantly
      (P<0.01) reaching a maximum just after hatching. Similar changes were observed
      for the other tocopherols and tocotrienols. The accumulation of alpha-tocopherol
      in the yolk sac membrane (YSM) started after day 20 of development and at
      hatching the alpha-tocopherol concentration in the YSM was twice that of beta- +
      gamma-tocopherols and 15 times greater than that of alpha-tocotrienol. In the
      kidney, heart, lung, muscle and adipose tissues a gradual increase in tocopherol
      and tocotrienol concentrations took place between days 20 and 25 of development
      with a sharp increase in particular of alpha-tocopherol between days 25 and 29.
      There was a discrimination between tocopherols and tocotrienols during their
      assimilation from the diet by the parent hen and during metabolism by the
      developing turkey embryo. Tissue-specific features in the susceptibility to lipid
      peroxidation were found with the brain being the most susceptible to lipid
      peroxidation at day 25 and in day-old poults.

PMID- 10579403
TI  - Genetic study of embryonic mortality in White Leghorn lines selected for egg
      production traits.
AB  - The present study compares embryonic mortality between lines selected for
      different production traits, assesses the effects of inbreeding of the hen and
      embryo on embryonic mortality, and estimates genetic parameters of embryonic
      mortality. The experiment covered 10 generations of selection for increased egg
      number (EN), egg weight (EW), egg mass (EM) and a control line (C). The data
      included age at 1st egg, egg number and egg weight. Percent fertile eggs (PF),
      percent hatched of fertile eggs (PHF) and percent dead chick at hatch (PDH) were
      also recorded for the selected parents. PDH was higher in the selected lines than
      in the control line. Among the selected lines, the EW line had the highest
      embryonic mortality. Inbreeding of the hen and embryo had no significant effect
      on PDH in any of the lines. Estimates of heritability for PDH were 0.10+/-0.05,
      0.02+/-0.02, 0.03+/-0.02 and 0.02+/-0.02 for lines EN, EW, EM and C,
      respectively. There was a positive genetic correlation between egg weight and PDH
      in line EW indicating that selection for increased egg weight was associated with
      high embryonic mortality. A negative genetic correlation between PDH and
      reproductive traits in line EN was observed, which is favourable.

PMID- 10579404
TI  - Effects of drilling holes into the air cell of incubated goose eggs on
      distribution of oxygen partial pressures under the shell.
AB  - The purpose of this work was to measure changes in oxygen pressure in the air
      cell and under the eggshell (P(A)O2) of pre-pipping goose eggs before and after
      drilling holes into the air cell. Drilling a 0.6 mm (diameter of 0.9 mm) hole
      into the air cell caused an increase in air cell P(A)O2 of about 10 Torr. The
      rate of increase attenuated as hole area increased and reached about 21 Torr when
      the drilled area was 8.5 mm2. The P(A)O2 of intact eggs was not equally
      distributed under the shell. It was high in the air cell area (108 Torr) and
      decreased towards the pointed end (86 Torr). The increase in P(A)O2 after
      drilling a 4.9 mm2 hole was high in the air cell (18 Torr) and decreased with
      distance, becoming non-significant at the pointed end. The significant increase
      in P(A)O2 after drilling was limited to a distance of up to 38 mm along the shell
      from the edge of the air cell. This indicates that lateral diffusion in the shell
      membranes under the shell is limited. Drilling a hole of 3.5 to 4.9 mm2 was
      enough to increase air cell P(A)O2 in most of the eggs above the critical value
      of 100 Torr for hatching success. The increase in P(A)O2 was limited to about
      half the area of the shell and the average increase in P(A)O2 was 6.3 Torr
      (equivalent to a 0.9% increase in ambient O2). However, the blood perfusing
      chorioallantoic areas further away from the air cell edge may not be fully
      saturated with O2 and may not be sufficient to compensate fully for the low O2
      availability caused by low eggshell conductance.

PMID- 10579405
TI  - Effectiveness of different electrical stunning regimens for turkeys and
      consequences for carcase quality.
AB  - This study examined the effectiveness of electrical stunning of turkeys applied
      at 150 mA per bird utilising a range of waveform-frequency combinations. In
      addition, the effect of stunning treatment on subsequent carcase quality was
      examined. The effectiveness of stunning, as judged by time to recovery, was
      similar regardless of bird weight or applied stunning treatment. Increasing
      waveform frequency was associated with a decrease in the prevalence of
      ventricular fibrillation, although turkeys appeared more susceptible than
      broilers. Use of the higher frequency waveforms (500 and 1500 Hz) was associated
      with a marked improvement in carcase quality, particularly with regard to breast
      muscle haemorrhaging and their use may result in considerable commercial
      advantage.

PMID- 10579406
TI  - Comparative responses of genetically lean and fat broiler chickens to dietary
      threonine concentration.
AB  - Genetically lean (LL) or fat (FL) male broiler chicken's were fed on 5 diets
      containing either 3.80, 4.27, 4.75, 5.22 or 5.70 g true digestible threonine per
      kg. Threonine deficiency induced a more pronounced reduction in growth in the LL
      than in the FL but did not influence abdominal fat and breast muscle proportions
      in either line. Plotting weight gain or protein gain against threonine intake
      suggests that the requirement of both lines is very similar in terms of mg per g
      of gain. Thus food intake or appetite should account for differences between
      genotypes. Requirement for true digestible threonine was estimated as 10.70 mg
      per g of weight gain or 63.8 mg per g of protein gain, using a linear regression
      approach. The quadratic polynomial equations suggest that the requirements are
      13.9 and 12.4 mg digestible threonine per g of gain for LL and FL respectively.

PMID- 10579407
TI  - Comparison of metabolisable energy values of different foodstuffs determined in
      ostriches and poultry.
AB  - Apparent (AMEn) and true (TMEn) metabolisable energy values, corrected for
      nitrogen retention, of wheat bran, saltbush (Atriplex nummularia), common reed
      (Phragmites australis), lupins, soyabean oil cake meal (SBOCM), sunflower oil
      cake meal (SFOCM) and fishmeal were compared in 7 successive trials using 12
      mature South African Black ostriches and 10 adult Australorp cockerels per
      ingredient. TMEn values of 11.91, 7.09, 8.67, 14.61, 13.44, 10.79 and 15.13 MJ/kg
      for wheat bran, saltbush, common reed, lupins, SBOCM, SFOCM and fishmeal,
      respectively, were found for ostriches in comparison to lower (P<0.05) values of
      8.55, 4.50, 2.79, 9.40, 9.04, 8.89 and 13.95 MJ/kg for cockerels. The higher
      (P<0.05) ME values for ostriches confirm that the ostrich is capable of digesting
      foodstuffs, especially those with high fibre concentrations such as drought
      resistant fodders, more effectively than poultry. Plant protein sources could
      make a considerable energy contribution to diets for ostriches. It is concluded
      that it is essential to use energy values of foodstuffs determined using
      ostriches and not extrapolated values derived from poultry in diet formulation
      for ostriches.

PMID- 10579408
TI  - Effect of clinoptilolite on performance of Japanese quail (Coturnix coturnix
      japonica) during experimental aflatoxicosis.
AB  - Clinoptilolite (CLI, a natural zeolite), incorporated into the diet at 50 g/kg,
      was evaluated for its ability to reduce the deleterious effects of 2.0 mg total
      aflatoxin (AF;83.06% AFB1, 12.98% AFB2, 2.84% AFG1 and 1.12% AFG2)/kg diet on
      growing Japanese quail chicks from 10 to 45 d of age. A total of 40 Japanese
      quail chicks were divided into 4 treatment groups (control, AF, CLI, AF plus CLI)
      each consisting of 10 chicks. The performance of the birds was evaluated. The AF
      treatment significantly decreased food consumption and body weight gain from the
      3rd week onwards. The adverse effect of AF on food conversion ratio was also
      significant from week 4 of the experiment. The addition of CLI to an AF
      containing diet significantly reduced the deleterious effects of AF on food
      consumption, body weight gain and food conversion ratio. Food consumption was
      reduced by 14% in quail chicks consuming the AF diet without CLI, but by only 6%
      for quail chicks consuming the AF plus CLI diet. Similarly, overall body weight
      gain was reduced by 27% in birds consuming the AF diet without CLI, but by only
      8% for birds consuming the AF plus CLI diet. The addition of CLI to the AF-free
      diet significantly decreased food consumption and body weight gain during week 4,
      but these parameters were similar to the controls in week 5. No mortality was
      observed in any of the groups. These results suggest that CLI effectively
      diminished the detrimental effects of AF on the variables investigated in this
      study.

PMID- 10579409
TI  - Stunting syndrome in broilers: effect of electrolytes in drinking water on
      performance and intestinal glucose transport.
AB  - Posthatched naive or inoculated male broiler chicks were kept in separate rooms.
      An inoculum was prepared from intestines of stunting-syndrome affected broiler
      chicks. Tap water was supplied from 2 L cups, 1 cup per pen. In the Ist
      experiment, the naive chicks were provided with tap water only and the inoculated
      ones had free access to tap water or to an electrolyte solution. In the 2nd
      experiment, the naive and inoculated birds had free access to water in addition
      to an electrolyte solution. Supplementation was provided up to 3 weeks of age;
      thereafter all chicks had access to tap water only. Water or electrolyte
      consumption and body weight (BW) were determined. Total water intake of
      inoculated chicks was higher than that of naive counterparts (P<0.001).
      Electrolyte supplementation increased drinking (P<0.001) in inoculated birds more
      than in naive ones. At 1 week old the weight of the inoculated birds was about
      64% of the weight of naive ones; at the age of 4 and 6 weeks it was about 74% and
      86% respectively. Compensatory growth was most apparent in the inoculated chicks
      provided with electrolyte solution. At the age of 6 weeks, the latter exceeded
      the BW of the exclusively water supplied counterparts by 327 g. Electrolyte
      supplementation up to the age of 3 weeks had no effect on the naive counterparts.
      Osmolality was reduced slightly, but very significantly by inoculation;
      electrolyte supply had no effect on this variable. Sodium concentration in the
      plasma was higher in the inoculated birds. Plasma albumin was markedly reduced by
      inoculation on weeks 1 and 2. Whereas the inoculated chicks supplied with
      electrolytes resumed the level plasma albumin level of the naive chicks on week
      3, an over-compensation occurred in the inoculated-water-supplied (IW) group, and
      they surpassed the naive chicks significantly. Blood hematocrit increased
      significantly with age; inoculation, age and/or electrolyte supplementation had
      no effect on this variable. Sodium-dependent glucose transport rates were
      enhanced in vesicles obtained from inoculated chicks as compared to naive ones.
      While electrolyte supplementation had no effect on glucose active transport in
      naive chicks, electrolyte supplementation decreased rates of glucose active
      transport in inoculated ones. These data demonstrate that electrolyte
      supplementation during the early age may be used to enhance the tolerance of
      broiler chicks to stunting-syndrome by improving food and water consumption, and
      subsequently growth rate during and after cessation of electrolyte supply.

PMID- 10579410
TI  - Effects of ambient temperature on heat increment of feeding and energy retention
      in growing broilers maintained at different food intakes.
AB  - Zero-activity heat production (HP), body temperature (Tb) and energy retention
      were measured in growing broilers maintained at 5 ambient temperatures (Ta) (14
      degrees , 17 degrees , 22 degrees , 27 degrees and 32 degrees C) and at 5 feeding
      rates (ad libitum intake and 75%, 50%, 25% and 0% (fasting) of ad libitum). Zero
      activity HP increased with decreasing Ta and increasing food intake. However, at
      14 degrees C, zero-activity HP in birds fed ad libitum and 75% did not show
      further increase, but those in birds fed less than 75% of ad libitum increased
      rapidly. Results of the regression of zero-activity HP on Ta ranging from 32
      degrees to 17 degrees C indicated that the slope was affected little by food
      intake, but the intercept decreased with decreasing food intake. Tb increased
      significantly with increasing food intake. There was little variation with Ta
      but, at and above 27 degrees C, a slightly increased Tb was observed only in
      birds fed ad libitum. Overall effects of Ta and food intake on HIF (% TME intake)
      were not found, but HIF tended to increase with decreasing food intake at 14
      degrees C. Total energy retention and energy retention as fat decreased with
      decreasing Ta and food intake, although energy retention as protein decreased
      only with decreasing food intake. Results obtained here suggest that availability
      of TME is affected little by Ta ranging from 32 degrees to 17 degrees C and that
      HIF is utilised, in part, to maintain Tb at any Ta.

PMID- 10579411
TI  - Involvement of corticosterone in food intake, food passage time and in vivo
      uptake of nutrients in the chicken (Gallus domesticus).
AB  - To evaluate the effect of corticosterone on nutrient transport, 10-week-old male
      chickens were grouped in 4 categories and treated as follows: sham-operated,
      adrenalectomised, corticosterone (4 mg/kg injected subcutaneously for 5 d) in
      both sham-operated and adrenalectomised. The food intake, food passage time and
      uptake of calcium, phosphorus and glucose were determined by standard procedures.
      Corticosterone administration to both sham-operated and adrenalectomised groups
      stimulated significantly higher food intake, delayed food passage time and
      increased uptake of calcium, phosphorus and glucose, as compared to sham-operated
      control and adrenalectomised groups. Corticosterone administration increased
      absorption of these nutrients significantly more in the adrenalectomised group
      than in the sham-operated controls. Corticosterone also significantly elevated
      the plasma concentrations of these nutrients. The responses to the hormone were
      significantly greater in adrenalectomised birds. It is concluded that
      corticosterone increases food intake and retention and the absorption of calcium,
      phosphorus and glucose in the alimentary tract.

PMID- 10579412
TI  - Effect of different daily doses of gizzerosine on the serum 1,25
      dihydroxycholecalciferol concentration in laying hens.
AB  - Five groups of laying hens were treated with different gizzerosine doses (0, 2.5;
      5.0; 7.5; 10.0 mg/kg/body weight of gizzerosine) daily over a 21-day period to
      determine the serum concentrations of 1.25-dihydroxycholecalciferol (1,25(OH)2D),
      total calcium, inorganic phosphorus and magnesium. Blood samples were taken on
      days 7, 14, and 21 of the experiment. The concentration of 1,25(OH)2D remained
      unchanged after day 7 in the gizzerosine-treated birds compared to the control
      group. After 14 days, it was significantly lower in the birds receiving.
      gizzerosine, compared with the control group. On day 21, 1,25(OH2)D
      concentrations were also significantly decreased in all 4 gizzerosine-treated
      groups compared with the control hens. The serum total calcium, inorganic
      phosphorus and total magnesium concentrations varied significantly, but
      irregularly, during the period of the study.

PMID- 10579413
TI  - Development of body temperature regulation in ostrich chicks.
AB  - Information in the literature indicates that young ostrich chicks, despite being
      precocial, are poor thermoregulators and may take between 8 and 12 weeks to
      develop efficient homeothermy. We measured the body temperatures (Tb) of young
      ostrich chicks (1 to 10 d) at ambient temperatures between 13 degrees and 28
      degrees C under controlled conditions in the laboratory and under typical farm
      rearing conditions to assess their ability to thermoregulate. Even 1-d-old
      ostriches could maintain a Tb above 36 degrees C at temperatures of 20 degrees C
      and older chicks maintained typical adult Tb at ambient temperatures of 13
      degrees C in a constant temperature room. Chicks from 2-d-old could maintain
      adult T(b)s outdoors under a wide range of ambient temperatures and weather
      conditions. We conclude that ostrich chicks have well developed homeothermy soon
      after hatching and that some of the higher rearing temperatures recommended in
      the literature are unnecessary. In appropriate climates, chicks can be allowed
      outdoors soon after hatching provided they are not exposed to unfavourable
      weather conditions. Thermoregulation is, however, energetically expensive and
      thermoregulatory behaviour such as huddling may compete with other important
      activities like feeding.

PMID- 10579414
TI  - Effects of oestradiol-17beta and testosterone on progesterone production in the
      cultured granulosa cells of Japanese quail.
AB  - In order to study the effects of steroid hormones on steroidogenesis in the avian
      ovary, quail granulosa cells were cultured with follicle stimulating hormone
      (FSH), oestradiol-17beta or testosterone. The progesterone content of the medium
      during the culture period of 66 h and the following 3 h of incubation with
      luteinising hormone (LH), was measured by radioimmunoassay. When FSH, oestradiol
      17beta or testosterone were added during the 66 h culture, subsequent
      progesterone production by the cells during 3 h of incubation with LH was
      significantly increased. However, testosterone also stimulated progesterone
      production in the medium during the 66 h culture period, whereas FSH oroestradiol
      17beta did not. Addition of staurosporine during culture inhibited both LH
      stimulated progesterone production and testosterone-stimulated progesterone
      production. These results indicate that the processes during which granulosa
      cells acquired responsiveness to LH, and testosterone stimulates progesterone
      production might both be mediated by a staurosporine-sensitive protein kinase C
      dependent pathway in quail granulosa cells.

PMID- 10579415
TI  - Effects of ammonium chloride-induced acidosis on oxidative metabolism in liver
      mitochondria of chicks.
AB  - The present studies were undertaken to characterise oxidative metabolism with
      diverse substrates in hepatic mitochondria of acidotic chicks. Metabolic acidosis
      was experimentally induced by replacement of drinking water with ammonium
      chloride solution (15 g/l) for 5 d. State 3 oxidation rates in liver mitochondria
      were significantly reduced in acidotic chicks only for pyruvate and glutamate as
      substrates requiring complex I, III and IV of the electron transport chain, while
      they were not changed for either succinate-requiring complexes II, III and IV,
      ascorbate+TMPD-requiring complex IV, or alpha-ketoglutarate requiring complexes
      I, III and IV. It can be concluded that the impairment of oxidation rate was
      substrate-specific in liver mitochondria of acidotic animals and not associated
      with functional damage of the respiratory chain in mitochondria. Possible reasons
      for the reductions in oxidation rate with pyruvate and glutamate are discussed.

PMID- 10579416
TI  - Ovarian follicular growth and maturity and follicular production of progesterone
      and oestradiol in response to porcine luteinising hormone and porcine follicle
      stimulating hormone in albino (S*AS) hens in vivo and in vitro.
AB  - The effects of the SAS gene on follicular growth were studied by feeding Sudan IV
      and Sudan Black B, on follicular maturity by measuring P4 and E2 output of the 5
      largest follicles (F1 to F5) in vitro, and on ovarian response (plasma
      progesterone, P4, and oestradiol, E2) to administration of porcine follicle
      stimulating hormone (pFSH) and porcine luteinising hormone (pLH) in old laying
      hens. Albino hens had fewer dye rings in the yolks of their eggs than non-albinos
      (8.32 compared to 8.59) and the yolks from albinos weighed less. The numbers of
      normal and atretic follicles larger than 3 mm in diameter did not differ between
      the two genotypes. The P4 outputs from the F1 and F2 follicles were significantly
      greater for albino hens, but P4 production of other follicles was not different
      for the two genotypes. The P4 output of the F1 follicle in response to pLH was
      dose-dependent and greater for albino hens than for non-albinos. Porcine LH did
      not increase the follicular E2 output in either genotype. Administration of pLH,
      but not pFSH, increased plasma P4 and E2 concentrations, with no difference
      between genotypes. These data suggest that the F1 follicles for albino hens are
      precocious, resulting in a reduced growth period and a smaller weight at
      ovulation.

PMID- 10579417
TI  - Effect of dietary xylitol on growth and inflammatory responses in immune
      stimulated chickens.
AB  - It has been argued that stimulation of the immune system depresses performance.
      Accordingly, an experiment was conducted to determine the effect of dietary
      xylitol (150 g/kg diet) on growth and selected inflammatory responses in male
      broiler chickens. During the final 6 d of the experimental periods, chicks were
      injected with antigens: Escherichia coli lipopolysaccharide (LPS) on days 1, 3
      and 5 and with Sephadex-G50 superfine on days 2 and 4 to stimulate macrophage
      functions. The immune stimulation reduced body weight gain and food intake, but
      enhanced alpha 1 acid glycoprotein (AGP) concentration and interleukin (IL-1)
      like activity in plasma. Feeding the xylitol diet partially, but significantly,
      prevented the reductions in body weight gain and food intake, without affecting
      the early stage of inflammatory responses triggered by LPS and Sephadex
      injections.

PMID- 10579418
TI  - The influence of peripheral precues on the tendency to react towards a lateral
      relevant stimulus with multiple-item arrays.
AB  - Responses are faster when the side of the stimulus and response correspond than
      when they do not correspond. This has been ascribed to the influence of a spatial
      code on response selection. Regarding the origin of this code, three hypotheses
      were proposed that all assume that spatial codes decay as a function of time: the
      attention shift hypothesis, the static reference hypothesis, and the dynamic
      reference hypothesis. Arrays (a target among five distractors) requiring left or
      right responses, were preceded by peripheral cues indicating either the target
      position, the side of the target, or all array positions. Reaction times (RT),
      proportions correct, the response-locked lateralized readiness potential (LRP),
      and RT distributions were examined. A correspondence effect was present on RTs
      when all positions or the relevant side were cued, independently of response
      speed. No correspondence effect was found when the cue indicated the target
      position. The LRP results indicate that the correspondence effect is at least
      partially due to an effect at the level of motor preparation. The results favor
      the attention shift hypothesis which assumes that spatial codes are generated
      whenever there is a shift of attention.

PMID- 10579419
TI  - EEG differences and cognitive style.
AB  - Individuals differences in information processing related to cognitive style were
      investigated by EEG recording during cognitive tasks. Fifteen adults received the
      Cognitive Styles Analysis which assessed their positions on two dimensions: the
      wholist-analytic and the verbal-imagery. The EEG from midline, paramedial and
      lateral electrode clusters was recorded, while subjects viewed words presented at
      different rates. A button was pressed when a word was in a target conceptual
      category. Off-line analysis produced spectral powers for delta, theta, alpha,
      beta 1, beta 2 and gamma bands. For the midline, the wholists had higher output
      than analytics in theta and alpha, but lower in gamma. In the paramedial cluster,
      verbalisers had greater right power than imagers for all bands except alpha.
      Further, the overall power was greater on the right for imagers than verbalisers
      frontally, and the converse occipitally. In the lateral grouping, the wholist
      verbalisers had greater overall power left antero-temporally than other sub
      groups.

PMID- 10579420
TI  - Intraocular pressure changes: the influence of psychological stress and the
      Valsalva maneuver.
AB  - The effects of psychological stress and the Valsalva maneuver on short-term
      variations of intraocular pressure (IOP) were studied in 49 healthy adults.
      Psychological stress consisted of mental arithmetic tasks presented in
      counterbalanced order by computer and by the experimenter. Additionally, a
      standardized Valsalva maneuver was performed (in counterbalanced order with the
      psychological stressors). IOP was measured with a Goldmann tonometer before and
      after performance of each stressor. All three stressors transiently and highly
      significantly increased IOP, although the Valsalva maneuver produced changes of a
      greater magnitude (10.2 mmHg) than the psychological stressors (1.3 mmHg).
      Subjective stress ratings and heart rate increased in response to all stressors.
      There were no effects of task sequence, eye muscle tension, sex, smoking status
      (some smokers misreported their smoking status), or regular marijuana use, but
      regular physical exercise was associated with less IOP increase during
      psychological stress.

PMID- 10579421
TI  - On P300 measurement stability: habituation, intra-trial block variation, and
      ultradian rhythms.
AB  - P300 event-related brain potentials (ERPs) were elicited using a simple
      discrimination task in which participants discriminated two different
      equiprobable visual stimuli with button-press responses (n = 20). A total of ten
      trial blocks were presented at 10-min intervals. P300 amplitude declined
      significantly, but peak latency did not change reliably across trial blocks. P300
      amplitude demonstrated a reliable cyclical fluctuation across trial blocks,
      although P300 latency did not. Intra-trial block ERP variability was assessed by
      computing the correlation coefficients between the target and standard stimuli
      for amplitude and latency measures across participants within each trial block.
      P300 amplitude correlations were weakest at the Fz electrode, more strongly
      associated at Cz, and were most strongly correlated at Pz across trial blocks.
      P300 latency correlations were somewhat weaker and similar in strength across
      electrodes sites. The correlational patterns for both P300 amplitude and latency
      demonstrated reliable cyclical variation. The N100 component produced strong and
      consistent correlations for both amplitude and latency, whereas the P200 and N200
      component measures evinced cyclical correlational patterns similar to the P300
      across trial blocks. These results suggest that the stability of P300 and other
      component measures can vary appreciably within and across trial blocks in a
      manner that reflects ultradian variation in arousal level.

PMID- 10579422
TI  - Harm avoidance and serotonin.
AB  - The relationships between the Tridimensional Personality Questionnaire (TPQ) and
      serotonergic activity has been described in some studies with controversial
      results. These studies have focused on specific patient populations rather than
      normal controls. Therefore, the aim of the present study is to examine the
      relationships between the TPQ and serotonergic activity in a group of non-patient
      subjects. Twenty-three normal subjects answered the TPQ, and the serotonergic
      activity was assessed by the prolactin response to a highly potent and selective
      5-HT1a agonist (flesinoxan). A positive relationship between harm avoidance and
      PRL response to flesinoxan was found. This study is consistent with the
      hypothesized link between serotonergic activity and the harm avoidance dimension
      of the biosocial model of Cloninger.

PMID- 10579423
TI  - HLA-class II genes modify outcome of Toxoplasma gondii infection.
AB  - Associations between Human Leukocyte Antigen (HLA) (i.e. human major
      histocompatibility complex [MHC]) genes and susceptibility to infections and
      inflammatory processes have been described, but causal relationships have not
      been proven. We characterized effects of HLA-DQ alleles on outcome of congenital
      toxoplasma infection and found that among Caucasians, the DQ3 gene frequency was
      significantly higher in infected infants with hydrocephalus (0.783) than infected
      infants without hydrocephalus (0.444) or published normal controls (0.487). We
      then developed a novel animal model to definitively determine the effect of these
      HLA DQ molecules on the severity of toxoplasmosis. Human MHC-Class II transgenes
      reduced parasite burden and necrosis in brains of mice infected with Toxoplasma
      gondii. Consistent with the observed association between DQ3 and hydrocephalus in
      human infants, in the murine model the DQ3(DQ8; DQB1*0302) gene protected less
      than DQ1 (DQ6; DQB1*0601). Our findings definitively prove a cause and effect
      relationship between human MHC genes and resistance to infection, provide novel
      means to characterise human immune responses that are protective or pathogenic in
      infections, and are important for vaccine development.

PMID- 10579424
TI  - Increased mortality of black-browed albatross chicks at a colony heavily-infested
      with the tick Ixodes uriae.
AB  - At Bird Island, South Georgia, we studied the effects of the tick Ixodes uriae on
      survival of chicks at two colonies of the black-browed albatross Diomedea
      melanophrys, one where most chicks were infested with ticks, the other where most
      chicks were tick-free. When the two colonies were compared, it was found that the
      colony heavily-infested with ticks had significantly greater chick mortality than
      the colony lightly-infested with ticks. However, within each of the two colonies,
      there was no significant difference in survival between chicks with ticks and
      those without ticks.

PMID- 10579425
TI  - Peritrophins of adult dipteran ectoparasites and their evaluation as vaccine
      antigens.
AB  - Several peritrophins of larvae of Lucilia cuprina (sheep blowfly) have
      demonstrated potential as vaccine antigens, and some have been characterised and
      cloned. These proteins are tightly associated with the peritrophic matrix, a
      chitinous tube or sac lining the lumen of the gut of most insects. The
      peritrophins require strong denaturants for their removal from peritrophic
      matrix. We now report the preliminary characterisation of peritrophins of the
      adult stage of L. cuprina and Haematobia irritans exigua (buffalo fly). Similar
      SDS-PAGE profiles were obtained for proteins extracted in SDS or urea from
      isolated adult peritrophic matrices of both species. Radioiodination of urea
      extracted peritrophins improved sensitivity, indicating numerous proteins of 15
      75 kDa. Direct radioiodination of L. cuprina peritrophic matrix preferentially
      labelled high molecular weight complexes and proteins of 80-90 kDa. Two
      dimensional gel analyses of a urea extract of adult L. cuprina peritrophic matrix
      revealed that most proteins were moderately acidic. Antibodies produced against
      SDS-extracted peritrophins, or against sonicated peritrophic matrices of these
      two flies were crossreactive. The sera also appeared to recognise SDS-extracted
      components of Triton X-100 treated and washed adult peritrophic matrix of the
      mosquito, Aedes vigilax (Skause). This profile altered as the peritrophic matrix
      matured. In concordance with extracts from the adult L. cuprina and H.i. exigua
      peritrophic matrices, proteins in the 50-75 kDa region were immunodominant. The
      vaccine potential of the peritrophins of these Diptera were examined following
      vaccination of cattle and rabbits with adult H.i. exigua or L. cuprina
      peritrophins. When the adult life stages of H.i. exigua or two mosquitoes, A.
      vigilax and A. aegypti (Linnaeus), were fed on the sera or blood of vaccinated
      hosts, there were no detrimental effects to any life cycle stages of these
      Diptera.

PMID- 10579426
TI  - Isolation, propagation and characterisation of Cryptosporidium.
AB  - This review consists of 11 papers presented at the Consensus Conference on
      Cryptosporidium in Water (Parasitology Stream), held in Melbourne, Australia,
      from 5 to 6th October 1998. The conference was sponsored by the Water Services
      Association of Australia, the Australian Water and Wastewater Association, and
      the Collaborative Research Centre for Water Quality and Treatment. The papers
      summarise the advantages and disadvantages of various contemporary technologies
      applicable to parasite propagation and biochemical/molecular characterisation.
      Studies have detected distinct genetic differences between clinical isolates from
      humans and animals, and it is hoped that comprehensive documentation studies will
      facilitate the identification of environmental isolates in the not too distant
      future.

PMID- 10579427
TI  - Chemoattraction of Ichthyophthirius multifiliis (Ciliophora) theronts to host
      molecules.
AB  - Mechanisms in the host-finding process of Ichthyophthirius multifiliis were
      studied in vitro by a novel bioassay using 24-well multidishes supplied with
      bottom layers of agar with chemoattractants. It was shown that low molecular
      weight molecules (carbohydrates, amino acids, fatty acids, urea) did not attract
      theronts. In contrast, sera and mucus from a range of teleosts (including marine
      fish) were effective attractants. Fractionation by gel filtration of fish serum
      allowed determination of the molecular size of the attracting proteins. Further
      biochemical studies suggested the chemoattractants to be present in fractions
      with host immunoglobulin and some still undetermined proteins. No clear
      association between enzyme activity and chemotactic potential was seen. The high
      chemoattractive effect of serum from various unrelated teleosts corresponds to
      the low host specificity of I. multifiliis and suggests that serum factors in
      mucus could be involved in host finding of the parasite. Society for Parasitology
      Inc.

PMID- 10579428
TI  - Chemical communication and mate attraction in echinostomes.
AB  - Mate attraction is widespread among animals and appears to facilitate mating and
      to prevent hybridisation between closely related species. In this study we
      investigated mate preference between two geographical isolates of Echinostoma
      caproni (Trematoda, Platyhelminth) and another species of the genus Echinostoma
      E. sp. Because previous experiments showed a partial reproductive isolation
      between echinostome isolates, we examined the possibility that such isolation
      resulted from differential mate attraction. We compared intra-isolate, inter
      isolate and interspecific pairings using two in vitro experimental designs. In
      the first experiment we compared mate attraction of two individuals belonging to
      or not belonging to the same isolate, while in the second experiment we examined
      mate choice when individuals were in the presence of individuals from both the
      same isolate and from a different isolate or a different species. Distances
      between worms were measured over a period of 90 min. Results from both
      experiments suggested that mate attraction was similar for intra-isolate, inter
      isolate or interspecific combinations. This lack of mate preference in vitro
      would therefore support an alternative hypothesis of a reproductive isolation
      through sperm selection.

PMID- 10579429
TI  - Increased susceptibility to Toxoplasma gondii infection in SAG-1 transgenic mice.
AB  - SAG-1, one of the major surface proteins of Toxoplasma gondii, has been reported
      to play an important role in immune and pathogenic mechanisms of the parasites
      but its exact function is still unclear. We investigated the time courses of T.
      gondii infection in B6C3F1 transgenic mice carrying the SAG-1 gene. SAG-1
      transgenic mice were infected intraperitoneally with a high virulent RH strain or
      a low virulent Beverley strain of T. gondii. When infected with RH strain
      tachyzoites, no significant differences in time courses of survivals between SAG
      1 transgenic and wild-type mice were observed. Both groups succumbed to an acute
      infection within 8 days after infection. However, a lower survival rate (20%) was
      observed in SAG-1 transgenic mice than in wild-type (80%), when infected with
      Beverley strain cysts. This result indicates that SAG-1 transgenic mice are more
      susceptible to T. gondii infection as compared with their wild-type counterpart.
      ELISA using recombinant SAG-1 protein indicates that SAG-1 transgenic mice do not
      produce antibodies to the SAG-1 molecule. These findings may provide a critical
      tool for analysing the molecular mechanisms of pathogenesis and host immune
      responses during toxoplasmosis.

PMID- 10579430
TI  - Up-regulation of extracellular copper/zinc superoxide dismutase mRNA after
      transmission of the filarial parasite Acanthocheilonema viteae in the vertebrate
      host Meriones unguiculatus.
AB  - The gene encoding the cytoplasmic copper/zinc superoxide dismutase (AVSOD1) from
      the filarial parasite Acanthocheilonema viteae was isolated from a genomic DNA
      library using a degenerate oligonucleotide probe. Additionally, cDNAs of the
      AVSOD1 and the secreted extracellular SOD (AVSOD2) were both cloned by RT-PCR,
      and the AVSOD2 was expressed at high levels in E. coli. The amino acid sequence
      of the AVSOD1 is 89.5 and 87.5% identical to that of the corresponding enzymes of
      Brugia pahangi and Onchocerca volvulus, respectively. In contrast, the AVSOD2
      shows a lower degree of identity to the other filarial SODs and is extensively
      glycosylated. RT-PCR studies demonstrate the expression of both SOD subtypes in
      all developmental stages of A. viteae and indicate up-regulation of the AVSOD2
      expression after transmission from the vector to the definitive host. This
      suggests an enhanced requirement for SOD activity in post-infective larval stages
      and adults of A. viteae. ELISAs performed with purified recombinant AVSOD2 show
      that the AVSOD2 is not a major target for the immune system in naturally infected
      jirds.

PMID- 10579431
TI  - Differential transcription of histone genes in asexual and sexual stages of
      Plasmodium falciparum.
AB  - Molecular mechanisms of cell-cycle control in Plasmodium falciparum remain poorly
      understood. We have traced transcription of histones H2A, H2B and H3 as the
      parasite progresses through different developmental stages--rings, trophozoites,
      schizonts and gametocytes. Our results show that the ring stage parasites do not
      appear to synthesise any of the three histones. We also found a markedly elevated
      level of H3 transcript in the schizont stage parasite, while H2A and H2B were
      made in approximately equivalent amounts (in trophozoites, schizonts and
      garnetocytes). Further study might lead to a better understanding of the control
      elements involved in the regulation of histone levels in Plasmodium as it
      develops in the erythrocyte.

PMID- 10579432
TI  - Identification of an asparagine amidohydrolase from the filarial parasite
      Dirofilaria immitis.
AB  - The nematode cuticle is a complex extracellular structure which is secreted by an
      underlying syncytium of hypodermal cells. Recent studies have demonstrated that
      the cuticle of parasitic nematodes is a dynamic structure with important
      absorptive, secretory, and enzymatic activities. In addition, the cuticle serves
      as a protective barrier against the host. A 48-h third stage larval Dirofilaria
      immitis cDNA library was immunoscreened with sera raised against larval cuticles.
      One clone, L3MC4 that reacted strongly with the anti-cuticle antisera was
      sequenced. The composite cDNA sequence comprises 2073 bp coding for a full-length
      protein of 590 amino acids. GenBank analysis showed that DiAsp had significant
      similarity to a Caenorhabditis elegans gene-product (54% identity) and to other
      asparaginases at the amino acid level. Escherichia coli-expressed recombinant
      DiAsp (rDiAsp) catalysed the hydrolysis of asparagine to aspartate and ammonia.
      Antibodies raised against D. immitis larval cuticles reacted with rDiAsp in
      immunoblots. This is the first report of identification of a cDNA clone encoding
      an asparaginase enzyme from a parasitic nematode.

PMID- 10579433
TI  - In vitro stress response to elevated temperature, hydrogen peroxide and
      mebendazole in Trichinella spiralis muscle larvae.
AB  - Three stimuli, elevated temperature, hydrogen peroxide and mebendazole, were
      compared for their ability to induce heat-shock responses in Trichinella spiralis
      muscle larvae (L1). In vitro effectiveness of each 'stressor' was evaluated by
      viability score, protein content and levels of hsp90, hsp70 and hsp60. Detection
      of the respective heat-shock proteins was done by Western blotting and the heat
      shock proteins and quantitation of the immunoblots by image analysis. Exposure of
      L1 to elevated temperature (e.g. 45 degrees C, 2 h) had no measurable effect.
      However, exposure to hydrogen peroxide resulted in the induction of constitutive
      and higher mol. wt heat-shock proteins. In these experiments, heat-shock protein
      induction correlated strongly with other damage parameters, including loss of
      viability and increased mortality. Larvae stored in the presence of mebendazole
      showed no signs of damage. These data indicate that when L1 suffer damage through
      the action of stimuli, enhancement of heat-shock protein production and damage
      suffered are causally related.

PMID- 10579435
TI  - Genetic diversity in parthenogenetic triploid Paragonimus westermani.
AB  - Paragonimus westermani is a medically important foodborne trematode occurring
      throughout southeast Asia. We have used molecular techniques to test the
      hypothesis that the parthenogenetic triploid form of P. westermani has arisen
      only once. Sources of data for comparison were: (a) restriction fragment length
      polymorphisms (RFLPs) of ribosomal internal transcribed spacers (ITS); and (b)
      'fingerprint' patterns observed when genomic digests were probed with simple
      sequence repeats (ATT)10 and (ATGT)7. In all cases there were distinct
      differences among triploid isolates from southwest Japan, northeast China and
      Korea. These findings are considered in the context of previous cytogenetic,
      allozyme, mitochondrial-RFLP and partial cytochrome c-oxidase subunit I (COI)
      sequence studies and indicate that triploid lineages may have arisen
      independently on more than one occasion. We favour this view. An alternative
      explanation is that the triploids did have a single origin, but that different
      clonal lineages have undergone subsequent mutations.

PMID- 10579434
TI  - Evidence for host-specific clades of tetraphyllidean tapeworms (Platyhelminthes:
      Eucestoda) revealed by analysis of 18S ssrDNA.
AB  - Sequence data from the V4 and V7-V9 variable regions of the 18S small subunit
      ribosomal DNA (ssrDNA) gene were used to examine relationships among 26
      tetraphyllidean and two lecanicephalidean taxa. Newly collected specimens of 21
      of the tetraphyllidean species were used to generate ssrDNA sequences that were
      combined with sequences previously available, including those of two diphyllidean
      taxa used for outgroup rooting. The sequences were aligned by eye according to
      secondary structural motifs of the conserved core of the molecule. Of the 1520
      sites in the alignment, 874 (58%) were excluded from analysis due to alignment
      gaps and lack of positional homology as inferred by manual inspection. Genetic
      variability of the ssrDNA gene regions compared was greater than would be
      expected, based on the present taxonomy of the ingroup species, and the genetic
      divergences among tetraphyllidean 'families' and genera were comparable to that
      among tapeworm orders. Phylogenetic hypotheses were generated by the methods of
      maximum parsimony and maximum likelihood (GTR + I + Gamma nucleotide substitution
      model). Four most parsimonious trees resulted from analysis by maximum parsimony.
      Strict consensus of the four trees supported the monophyly of the Tetraphyllidea,
      with the lecanicephalidean taxa forming a sister lineage. Among the
      tetraphyllidean taxa included in the analysis were three major clades: a basal
      clade including species of the phyllobothriid genera Anthocephalum,
      Echeneibothrium, Rhinebothrium, Rhodobothrium and Spongiobothrium; a clade
      uniting the phyllobothriids of the genus Duplicibothrium with the dioecotaeniid
      genus Dioecotaenia; and a larger sister clade to the Duplicibothrium +
      Dioecotaenia clade that included the phyllobothriid genera Caulohothrium,
      Ceratobothrium, Clistobothrium, Paraoryigmatobothrium and Prosobothrium, the
      litobothriid genus Litobothrium and the onchobothriid genera Acanthobothrium,
      Calliobothrium, Phoreiobothrium and Platybothrium. Maximum likelihood analysis
      resulted in a topology that was congruent where nodes were strongly supported by
      parsimony analysis, but differed in the relative positions of the well-supported
      clades. In addition,maximum likelihood analysis grouped the lecanicephalidean
      taxa among the tetraphyllidean taxa, indicating paraphyly of the order
      Tetraphyllidea as currently defined. Relationships suggested by both methods of
      analysis reflected common host associations of the taxa better than their current
      classification, suggesting that coevolution has had a significant role in the
      evolution of the group.

PMID- 10579436
TI  - Meningococcal disease at the University of Southampton: outbreak investigation.
AB  - In October 1997, an outbreak of meningococcal disease occurred at the University
      of Southampton. All six cases were first year students living in halls of
      residence. Microbiological characterization of case and carrier strains, case
      interviews, and a meningococcal carriage prevalence survey were used to
      investigate the outbreak. Five cases were due to serogroup C strains, one case
      was unconfirmed. Serotyping did not distinguish between the strains but gene
      sequencing permitted identification of two distinct strains in the outbreak.
      Although none of the cases was known to each other, three had attended the same
      nightclub one evening 3-4 days before illness. Meningococcal carriage rates in
      undergraduates were within the range expected (147/587, 25%), but no carriers of
      outbreak strains were identified in this sample. The findings suggest that in
      communities with a high degree of social interaction, the introduction of highly
      virulent meningococcal strains may result in enhanced transmission with
      clustering of cases.

PMID- 10579437
TI  - Antimeningococcal herd immunity in the Czech Republic--influence of an emerging
      clone, Neisseria meningitidis ET-15/37.
AB  - For many years, invasive meningococcal disease in the Czech Republic occurred
      sporadically and was caused mainly by meningococci of serogroup B. In 1993, when
      a new clone (ET-15/37) emerged, the only phenotype found was C:2a:P1.2,5. In
      1995, an antigenic variation of the ET-15/37 clone, B:2a:P1.2,5, occurred. The
      results of immunological surveys conducted in 1989 and 1996 were compared. A
      significantly higher proportion of 1996 sera than those collected in 1989 showed
      bactericidal antibodies against N. meningitidis B:2a:P1.2,5 (19.7 vs. 5.1%) and
      N. meningitidis C:2a:P1.2,5 (15.9 vs. 7.4%), consistent with increased herd
      immunity due to the spread of the new clone in the Czech Republic. There were
      differences in the age distribution of the positive sera.

PMID- 10579438
TI  - Salivary antibodies following parenteral immunization of infants with a
      meningococcal serogroup A and C conjugated vaccine.
AB  - Bacterial and viral salivary antibody testing is proving sensitive and specific,
      useful for epidemiological studies, and is simple and non-invasive. Salivary
      serogroup C polysaccharide-specific (SC PS-S) IgA and IgG were determined as a
      proportion of total salivary IgA and IgG in a group of UK infants who were
      recipients of a conjugated A/C meningococcal PS vaccine. Geometric mean
      concentrations (GMCs) of salivary SC PS-S IgG per mg of total IgG (microg/mg)
      were 0.1 pre-vaccination, rising to 8.2 post first, 16.1 post second and 29.3
      post third dose of vaccine. For IgA, the corresponding GMCs in ng/mg were 0.1,
      82.8, 69.6 and 91.2. Significant correlations (P < 0.0001) were found between
      serum Ig and salivary IgG SC PS-S antibody for pre-vaccine and 1 month post each
      dose of vaccine suggesting that SC PS-S IgG in saliva was largely derived from
      serum. Of the five infants whose sera were analysed for isotype-specific
      responses, only traces of IgM and IgA were measurable suggesting that the SC PS-S
      IgA was locally produced. These findings suggests that the widespread use of
      meningococcal conjugate vaccines is likely to reduce nasopharyngeal carriage and
      may thereby induce herd immunity in the vaccinated population.

PMID- 10579439
TI  - Diphtheria is declining but continues to kill many children: analysis of data
      from a sentinel centre in Delhi, 1997.
AB  - Although diphtheria is declining in Delhi, case fatality rates (CFRs) are rising.
      In 1997, of 143 clinically suspected cases admitted to the Infectious Diseases
      Hospital 45 (32%) died. We examined their records to understand the epidemiology
      and reasons for high CFRs. About 53% of cases were from Delhi; they were not
      limited to any particular area. All the deaths and 92% (131/143) of cases
      occurred in children below 10 years of age. Only 12% of cases had received one or
      more doses of DPT. Muslims contributed significantly more cases than Hindus. CFRs
      were significantly higher in young (P = 0.03) and unvaccinated (P = 0.01)
      children and in those who received antitoxin on the third day of illness or later
      (P = 0.03). The study highlights the importance of improved vaccine coverage and
      early diagnosis and prompt administration of antitoxin in reducing CFRs for
      diphtheria in Delhi.

PMID- 10579440
TI  - An international outbreak of Vero cytotoxin-producing Escherichia coli O157
      infection amongst tourists; a challenge for the European infectious disease
      surveillance network.
AB  - In March 1997, an outbreak of Vero cytotoxin-producing Escherichia coli O157
      (VTEC) infection occurred amongst holidaymakers returning from Fuerteventura,
      Canary Islands. For the investigation, a confirmed case was an individual staying
      in Fuerteventura during March 1997, with either E. coli O157 VTEC isolated in
      stool, HUS or serological evidence of recent infection; a probable case was an
      individual with bloody diarrhoea without laboratory confirmation. Local and
      Europe-wide active case finding was undertaken through national centres, Salm-Net
      and the European Programme of Intervention Epidemiology, followed by a case
      control study. Fourteen confirmed and one probable case were identified from
      England (7), Finland (5), Wales (1), Sweden (1) and Denmark (1) staying in four
      hotels. Three of the four hotels were supplied with water from a private well
      which appeared to be the probable vehicle of transmission. The case-control study
      showed illness was associated with consumption of raw vegetables (OR 8.4, 95% CI
      1-5-48.2) which may have been washed in well water. This investigation shows the
      importance of international collaboration in the detection and investigation of
      clusters of enteric infection.

PMID- 10579441
TI  - Molecular characterization of Vibrio cholerae O1 and non-O1 from human and
      environmental sources in Malaysia.
AB  - A total of 31 strains of Vibrio cholerae O1 (10 from outbreak cases and 7 from
      surface water) and non-O1 (4 from clinical and 10 from surface water sources)
      isolated between 1993 and 1997 were examined with respect to presence of cholera
      enterotoxin (CT) gene by PCR-based assays, resistance to antibiotics, plasmid
      profiles and random amplified polymorphic DNA (RAPD) analysis. All were resistant
      to 9 or more of the 17 antibiotics tested. Identical antibiotic resistance
      patterns of the isolates may indicate that they share a common mode of developing
      antibiotic resistance. Furthermore, the multiple antibiotic resistance indexing
      showed that all strains tested originated from high risk contamination. Plasmid
      profile analysis by agarose gel electrophoresis showed the presence of small
      plasmids in 12 (7 non-O1 and 5 O1 serotypes) with sizes ranging 1.3-4.6 MDa. The
      CT gene was detected in all clinical isolates but was present in only 14 (6 O1
      serotype and 8 non-O1 serotype) isolates from environmental waters. The genetic
      relatedness of the clinical and environmental Vibrio cholerae O1 and non-O1
      strains was investigated by RAPD fingerprinting with four primers. The four
      primers generated polymorphisms in all 31 strains of Vibrio cholerae tested,
      producing bands ranging from < 250 to 4500 bp. The RAPD profiles revealed a wide
      variability and no correlation with the source of isolation. This study provides
      evidence that Vibrio cholerae O1 and non-O1 have significant public health
      implications.

PMID- 10579442
TI  - Serological evidence of Bartonella spp. infection in the UK.
AB  - We reviewed serological and epidemiological data relating to 1000 consecutive
      patients from whom specimens were submitted for estimation of bartonella
      antibodies, using MRL Diagnostics Bartonella IFA IgM and IgG kits. Using 289
      control sera, we estimated the specificity of the kits as > or = 99.0%. Evidence
      of bartonella infection was found in 16.3% of patients examined. Rates varied by
      patient group: 20% of patients for whom a diagnosis of cat scratch disease (CSD)
      was considered probable had evidence of infection, as did 10.4% of patients with
      'possible CSD', 8.1% of patients with possible bacillary angiomatosis, 18.2% of
      patients with 'culture negative' endocarditis and 17.6% of patients with possible
      bartonellosis with ophthalmic involvement. An IgM response was seen in 6.6% of
      patients and IgG in 15.1%. Cases were more frequent among males than females
      (18.5% vs. 13.9%). Analysis by age showed that although rates of infection were
      highest in the decades 0-9 years (19.4%) and 10-19 years (20.7%), they fell only
      slightly in the next three decades. MRL bartonella kits appears to provide a
      useful and specific approach to the diagnosis of these infections.

PMID- 10579443
TI  - Microbial quality of oysters sold in Western Trinidad and potential health risk
      to consumers.
AB  - The prevalence and characteristics of Escherichia coli and Salmonella spp. as
      well as counts of E. coli in raw oysters, condiments/spices, and raw oyster
      cocktails sampled from 72 vendors across Western Trinidad were determined. The
      microbial quality of the water used in the preparation of raw oysters was also
      investigated. Of 200 samples each of raw oysters, condiments/spices and oyster
      cocktails tested, 154 (77.0%), 89 (44.5%) and 154 (77.0%) respectively yielded E.
      coli. The differences were statistically significant (P = < 0.001; chi square =
      62.91). The mean E. coli count per g in the ready-to-eat oyster cocktail ranged
      from 1.5 x 10(3) +/- 2.7 x 10(3) in Couva to 8.7x10(6) +/- 4.9x10(7) in San
      Fernando. One hundred and forty-six (73.0%) oyster cocktails contaminated with E.
      coli had counts that exceeded the recommended standard of 16 per g. Of a total of
      590 E. coli isolates from various sources tested, 24 (4.1%), 20 (3.4%) and 69
      (11.7%) were mucoid, haemolytic and non-sorbitol fermenters respectively. Twelve
      (2.0%) isolates of E. coli were O157 strains, while 92 (46.0%) of 200 E. coli
      isolates tested belonged to enteropathogenic serogroups. Ninety (45.0%) and 73
      (36.5%) of 200 water samples contained total coliforms and faecal coliforms
      respectively, with counts that exceeded 2.2 coliforms per 100 ml. Salmonella spp.
      were isolated from 7 (3.5%), 1 (0.5%) and 2 (1.0%) of 200 samples each, of raw
      oysters, condiments/spices and oyster cocktails respectively. Oysters pose a
      health risk to consumers in Trinidad, particularly from colibacillosis and
      salmonellosis, and the need for increased public awareness of this hazard cannot
      be over-emphasized.

PMID- 10579445
TI  - Epidemiology of respiratory syncytial virus infection among paediatric patients
      in Hong Kong: seasonality and disease impact.
AB  - In a 5-year retrospective survey of respiratory syncytial virus (RSV) infections
      among hospitalized children, 1340 cases were identified of which, 98.4% were
      children < 5 years old with a male:female ratio of 1.5: 1. Most cases occurred
      from April to September showing a significant positive correlation with
      temperature and relative humidity. Community-acquired infections accounted for
      92.5% of the cases with a mean hospital stay of 5 days. The estimated annual
      incidence of RSV infection requiring hospitalization was 2.5/1000 children < 5
      years old with a mortality of 0.15% among hospitalized cases. On average, 248
      children were admitted each year to the 1400-bed acute regional hospital
      accounting for an expenditure of HK S1.94 ((approximately US +/-0.25) million for
      hospitalization costs which equates to an annual cost in excess of HK $6.67
      (approximately US $0.86) million for the whole of Hong Kong. An RSV vaccine
      should be a priority.

PMID- 10579444
TI  - Infection with wild-type mumps virus in army recruits temporally associated with
      MMR vaccine.
AB  - Four cases of mumps were reported among 180 army recruits who had received MMR
      vaccine 16 days earlier. Mumps serology, salivary mumps IgM and PCR tests for the
      SH gene were performed on the 4 cases and on 5 control recruits who remained
      well. PCR products were sequenced and the sequences compared to those of wild
      type and vaccine strains of mumps. Further salivary mumps IgM tests were
      performed on the remaining 171 recruits. Mumps infection was confirmed in the 4
      cases but not in the 5 controls. The controls had serological evidence of prior
      immunity. The SH gene sequence found in the 4 cases was wild type. Saliva tests
      identified 2 additional recruits with mumps IgM, one of whom had presented with
      suspected mumps 2 days before the MMR vaccine was given. Thus 6 (5 symptomatic
      and 1 asymptomatic) cases of mumps in army recruits recently receiving MMR
      vaccine were not due to the vaccine but to coincidental infection with wild-type
      mumps virus. The probable index case was revealed by salivary mumps IgM tests.
      This study highlights the importance of appropriate investigation of illness
      associated with MMR vaccination.

PMID- 10579447
TI  - Method used to identify previously undiagnosed infections in the HIV outbreak at
      Glenochil prison.
AB  - Four years after the occurrence of an outbreak of hepatitis B and HIV infection
      among injecting drug user inmates at Her Majesty's Prison Glenochil in Scotland,
      a study design was developed to complete the epidemiological account of the HIV
      outbreak. Our aim was to identify potential cases of (1) HIV transmission not
      diagnosed during the original outbreak investigation and (2) the source(s) of the
      outbreak. Scotland's HIV positive case register was searched for matches to a
      soundexed list of 636 Glenochil inmates imprisoned during January-June 1993.
      Eight HIV infections that may have been acquired in Glenochil and four possible
      sources of the outbreak were identified. The second stage of follow-up molecular
      epidemiological techniques used on stored sera samples from identified
      individuals is described in the companion paper. Without breach of medical or
      prisoner confidentiality, indirect and anonymous follow-up has proved possible
      for the Glenochil inmates.

PMID- 10579446
TI  - Prevalence of antibodies against rubella virus in The Netherlands 9 years after
      changing from selective to mass vaccination.
AB  - A two-dose mass vaccination programme with a combined vaccine against measles,
      mumps and rubella (MMR) was adopted in the Netherlands in 1987, replacing the
      selective schoolgirl vaccination strategy introduced in 1974. To obtain insight
      into the effect of mass vaccination and the population's immunity, the antibody
      levels against rubella were studied in the general Dutch population and in
      religious groups refusing vaccination. In the national sample, we observed a high
      prevalence (96.5%) for rubella antibodies in vaccinated cohorts as well as in the
      older unvaccinated cohorts. No indications of rapidly waning immunity after
      vaccination were found. There are indications of low virus circulation in the
      last few years. The very high seroprevalence in women at childbearing age is
      consistent with the few reported cases of congenital rubella syndrome (CRS) at
      present. However, individuals in the age group of 1-9 years who are not
      vaccinated for religious or other reasons have a considerably lower
      seroprevalence and thus there is a potential risk of a CRS outbreak in the
      future.

PMID- 10579448
TI  - Completing the molecular investigation into the HIV outbreak at Glenochil prison.
AB  - In a molecular investigation into the outbreak of HIV in Glenochil during the
      first 6 months of 1993, we previously demonstrated that 13 out of the 14 HIV
      positive inmates were infected with a virtually identical strain, and discounted
      2 others as potential sources. Here we investigate a further 8 potential contacts
      and 4 potential sources which were identified in the companion paper. We were
      able to examine viral sequence from all but one of these 12 and results have
      revealed them to be distinct both from each other and the original 14. Thus,
      despite an intensive follow-up investigation, we have been unable to identify any
      further HIV infections that might have been part of the 1993 outbreak. It is
      possible that persons who were infected at that time remain undetected; however
      this and the companion report strongly suggest that if this were the case the
      likely numbers would be few.

PMID- 10579449
TI  - Incidence of symptomatic toxoplasma eye disease: aetiology and public health
      implications.
AB  - Ocular disease is the commonest disabling consequence of toxoplasma infection.
      Incidence and lifetime risk of ocular symptoms were determined by ascertaining
      affected patients in a population-based, active reporting study involving
      ophthalmologists serving a population of 7.4 million. Eighty-seven symptomatic
      episodes were attributed to toxoplasma infection. Bilateral visual acuity of 6/12
      or less was found in seven episodes (8%) and was likely to have been transient in
      most cases. Black people born in West Africa had a 100-fold higher incidence of
      symptoms than white people born in Britain. Only two patients reported symptoms
      before 10 years of age. The estimated lifetime risk of symptoms in British born
      individuals (52% of all episodes) was 18/100000 (95% confidence interval: 10.8
      25.2). The low risk and mild symptoms in an unscreened British population
      indicate limited potential benefits of prenatal or postnatal screening. The late
      age at presentation suggests a mixed aetiology of postnatally acquired and
      congenital infection for which primary prevention may be appropriate,
      particularly among West Africans.

PMID- 10579450
TI  - Prevalence of Escherichia coli O157:H7 in range beef calves at weaning.
AB  - This study was designed to determine the prevalence of Escherichia coli O157:H7
      infection of beef calves at weaning, prior to arrival at the feedlot or mixing
      with cattle from other sources. Fifteen range cow-calf herds, which weaned calves
      in October and November, were sampled in Kansas, Missouri, Montana, Nebraska and
      South Dakota. Faecal culture for E. coli O157:H7 was performed and anti-O157
      serum antibody titres were determined by blocking ELISA. Thirteen of the 15 herds
      (87%) were found to have at least one positive isolation of E. coli O157:H7 in
      faecal samples. Within positive herds, prevalence ranged from 1.7-20.0%, with an
      average of 7.4+/-6.2% S.D. of individual animals shedding E. coli O157:H7 in
      faeces. All herds had high prevalence of anti-O157 antibodies, ranging 63-100% of
      individuals within herds seropositive. This study indicates that E. coli O157:H7
      infection before weaning, prior to entry into feedlots, is widespread.
      Furthermore, serologic evidence suggests that most calves (83%) and all herds
      (100%) have been exposed to E. coli O157.

PMID- 10579451
TI  - Genetic diversity of atypical Aeromonas salmonicida studied by pulsed-field gel
      electrophoresis.
AB  - Pulsed-field gel electrophoresis (PFGE) pattern analysis with XbaI restriction
      enzyme was used to study the genetic heterogeneity of 88 atypical Aeromonas
      salmonicida strains which were earlier or during this study characterized
      phenotypically, by ribotyping (ClaI/PstI) and by plasmid profile analysis. The
      strains of certain'ribotypes were also analysed by digestion with SpeI. The
      strains represented different geographic locations: Finland (72 strains), Iceland
      (5 strains), Norway (5 strains), Sweden (4 strains) and Denmark (2 strains), and
      they were from 17 fish species during 1981 97. Thirty-one PFGE genotypes found
      among these strains correlated well with the ribotypes, and in most cases PFGE
      pattern analysis subdivided ribotypes into several PFGE genotypes, and further
      within a PFGE genotype into subtypes. XbaI and SpeeI digests produced concordant
      results. In most cases, PFGE patterns of strains with the same ribotype shared
      many fragments, suggesting genetic relatedness. PFGE patterns of most Norwegian
      and Icelandic strains isolated during an approximately 10-year period had the
      same ribotype and their PFGE patterns shared most fragments, suggesting close
      genetic relatedness. Moreover, atypical strains of ribotypes B/B and H/H isolated
      from the same Finnish fish farms had closely related patterns suggesting genetic
      stability and persistence of these genotypes. Genotype 29 of Achromogenic strains
      was strongly associated with disease of Finnish arctic char and grayling. PFGE
      was shown to be a distinguishing method to study the genetic heterogeneity of
      atypical A. salmonicida. epidemiology of these infections.

PMID- 10579453
TI  - Epidemiological typing of bovine streptococci by pulsed-field gel
      electrophoresis.
AB  - Pulsed-field gel electrophoresis (PFGE) was used to investigate the epidemiology
      of streptococcal mastitis in dairy cattle. The most prevalent streptococcal
      species, Streptococcus uberis (60-80% of streptococcal isolates), was highly
      heterogeneous, with different cows only rarely sharing the same pulsotype. S.
      agalactiae was rarely encountered, however all eight isolates from one farm
      generated identical PFGE profiles, which differed from those of all other
      isolates examined, confirming cow-to-cow transmission. Fifty-two isolates of S.
      dysgalactiae from 27 cows on 5 farms generated 6 different profiles. However, on
      individual farms, only one or two pulsotypes usually predominated. This species
      is generally regarded as an environmental pathogen but our data suggest that cow
      to-cow transmission of S. dysgalactiae may occur. In spite of the variation in
      PFGE profiles of isolates from different cows, persistent infections in
      individual cows were usually caused by the same pulsotype of S. uberis or S.
      dysgalactiae.

PMID- 10579452
TI  - Prevalence of Cowdria ruminantium infection in Amblyomma hebraeum ticks from
      heartwater-endemic areas of Zimbabwe.
AB  - Analysis of the transmission dynamics of Cowdria ruminantium, the tick-borne
      rickettsial agent of heartwater in ruminants, requires accurate measures of
      infection in vector populations. To obtain these, Amblomnia hebraeum ticks were
      collected at two heartwater-endemic locations in the lowveld and highveld regions
      of Zimbabwe and assessed for C. ruminantium infection with specific polymerase
      chain reaction (PCR) and DNA probe detection assays. At the lowveld site, 11.2%
      (50/446) of adult ticks and 8.5% (23/271) of nymphs carried C. ruminantium, as
      detected by PCR. At the highveld site, the prevalence of infection in adult ticks
      was 10.2% (40/392). DNA probe analysis revealed that most infections at both
      sites were of low intensity; only 9% and 23% of all nymph and adult tick
      infections, respectively, were greater than 70000 organisms, the detection limit
      of the DNA probe. However, the majority (70%) of probe-detectable adult tick
      infections were high, between 10(7) and 10(9) organisms/tick, while those within
      nymphs were lower, between 10(5) and 10(6) organisms/tick.

PMID- 10579454
TI  - Phylogeographic patterns exhibited by Ontario rabies virus variants.
AB  - A previous study on N gene variation of rabies viruses circulating in Ontario red
      foxes identified four viral variants. This study confirms the geographical
      localization of these variants and extends the analysis to the less conserved G
      gene of these viruses. A greater number of regionally localized variants was
      revealed and their phylogenetic relationships have been examined. Ongoing
      surveillance on recent disease outbreaks revealed that variants do not always
      persist in specific areas. The distribution of these variants did however appear
      to be influenced by topographical features of the study area likely to affect
      host animal movements and contacts. The majority of G gene base changes were
      synonymous and limited glycoprotein sequence variation predominantly to the C
      terminal transmembrane and endo-domains. These data are most readily explained by
      random appearance of genetic viral variants followed by their spread throughout
      sub-populations of the fox host according to the easiest routes of transmission.

PMID- 10579455
TI  - African horse sickness in Portugal: a successful eradication programme.
AB  - African horse sickness (AHS) was diagnosed for the first time in southern
      Portugal in autumn 1989, following outbreaks in Spain. AHS virus presence was
      confirmed by virus isolation and serotyping. An eradication campaign with four
      sanitary zones was set up by Central Veterinary Services in close collaboration
      with private organizations. Vaccination began on 6 October. In February 1990,
      vaccination was extended to all Portuguese equines (170000 animals). There were
      137 outbreaks on 104 farms: 206 of the equidae present died (16%) or were
      slaughtered (14%); 81.5% were horses, 10.7% were donkeys and 7.8% were mules.
      Clinical AHS occurred more frequently in horses than donkeys and mules. In the
      vaccinated population, 82 animals (62.2% horses and 37.8% mules and donkeys),
      died or were slaughtered due to suspected or confirmed AHS. One year after ending
      vaccination, December 1991, Portugal was declared free of AHS. Cost of
      eradication was US$1955513 (US$11.5/Portuguese equine).

PMID- 10579456
TI  - Oncostatin M: signal transduction and biological activity.
AB  - Oncostatin M (OSM) is a multifunctional cytokine produced by activated T
      lymphocytes and monocytes that is structurally and functionally related to the
      subfamily of cytokines known as the IL-6-type cytokine family. OSM shares
      properties with all members of this family of cytokines, but is most closely
      related structurally and functionally to LIE OSM acts on a wide variety of cells
      and elicits diversified biological responses in vivo and in vitro which suggest
      potential roles in the regulation of gene activation, cell survival,
      proliferation and differentiation. OSM and LIF can bind to the same functional
      receptor complex (LIF-receptor beta and gp130 heteromultidimers) and thus mediate
      overlapping spectra of biological activities. There is a second specific beta
      receptor that binds OSM with high affinity and also involves the subunit gp130.
      The two receptors for OSM can be functionally different and be coupled to
      different signal transduction pathways. OSM-specific receptors are expressed in a
      wide variety of cell types and do not possess an intrinsic tyrosine kinase
      domain, but the JAK/STAT tyrosine kinase pathway mediates signal transduction.

PMID- 10579457
TI  - Inhibition of eosinophil activation in bronchoalveolar lavage fluid from atopic
      asthmatics by Y-24180, an antagonist to platelet-activating factor.
AB  - We examined the effects of Y-24180, a potent and long-acting antagonist to
      platelet-activating factor (PAF) receptor, on the expression of adhesion
      molecules in peripheral blood and bronchoalveolar lavage fluid (BALF) eosinophils
      from atopic asthmatics. Y-24180 (20 mg/day) was administered to 4 atopic
      asthmatics for 8 weeks. The number of eosinophils, the level of eosinophil
      cationic protein (ECP), the bindings of soluble intercellular adhesion molecule-1
      (sICAM-1) and fibronectin (FN), and the expressions of CD11b (alpha chain of Mac
      1) and CD49d (alpha chain of VLA-4) on eosinophils were evaluated in peripheral
      blood (n=4) and BALF (n=3) before and after the administration of Y-24180. The
      infiltration of eosinophils into the bronchial wall was also examined by taking
      biopsies. Eosinophil count, sICAM-1 and FN binding to eosinophils in BALF
      significantly decreased after the administration of Y-24180 (p<0.05). The level
      of CD11b expression also decreased remarkably after the administration (n=2). In
      peripheral blood, eosinophil count and ECP level did not change. The binding of
      sICAM-1 and FN, and expression of CD11b on eosinophils in peripheral blood showed
      a tendency to decrease after the administration. The level of CD49d expression on
      eosinophils changed neither in BALF nor in blood. Eosinophil infiltration into
      the bronchial wall markedly decreased in one out of 3 cases after the
      administration. These results suggest that Y-24180 inhibits the activation of
      eosinophils by antagonizing the actions of PAF in atopic asthmatics.

PMID- 10579458
TI  - Stable transfection of rat preporinsulin II gene into rat hematopoietic stem
      cells via recombinant adeno-associated virus.
AB  - We investigated the ability of recombinant adeno-associated virus (rAAV), to
      mediate the transfer of rat preproinsulin II (rI2) gene into rat hematopoietic
      stem cells in vitro and expression of rI2 following intra-venous (i.v.) injection
      of infected stem cells into syngeneic rats. The pLP-1 recombinant plasmid
      containing rI2 was engineered as follows: rI2 with RSV-promoter was released from
      pBC 12BI (ATCC), purified, and inserted into BamH1 site of rAAV vector plasmid
      pWP-19. Plasmid pLP-1, together with pAAV?AD (Somatix Corp.), was used to co
      transfect cell line 293 (ATCC). The rAAV genome was rescued using helper
      adenovirus and packaged into mature rAAV virions (vLP-1). Bone-marrow from female
      Wistar-Furth rats was enriched for stem cells by using plastic adherence and
      negative selection with monoclonal anti-rat CD3 and CD45RA to deplete T and B
      cells. The remaining cells were exposed to vLP-1 (moi=50:1) for 2 hours.
      Transfection was confirmed by PCR of neomycin resistance gene (neoR) after 8 days
      in culture. For in vivo studies, ten million exposed stem cells were injected
      i.v. into syngeneic rats (n=3). The results represent 3 identical experiments.
      Expression of neoR and rI2 was analyzed by RT-PCR. At week 1, neoR and rI2 were
      expressed in liver, spleen, thymus, peripheral blood lymphocytes and bone marrow.
      At week 2, neoR was expressed in spleen and brain, while at week 6, thymus, lymph
      nodes, bone-marrow, liver, spleen, and brain expressed neoR. rI2 was not detected
      after week 1. In summary, we showed that rAAV was efficient for transferring neoR
      and rI2 into rat hematopoietic stem cells.

PMID- 10579459
TI  - Chronic inflammation inhibits GH secretion and alters the serum insulin-like
      growth factor system in rats.
AB  - Adjuvant-induced arthritis in rats is associated with growth failure,
      hypermetabolism and accelerated protein breakdown. The aim of this work was to
      study the effects of adjuvant-induced arthritis on GH and insulin-like growth
      factor-I (IGF-I). Arthritis was induced by an intradermal injection of complete
      Freund's adjuvant and rats were killed 18 and 22 days later. IGF-I and GH levels
      were measured by radioimmunoassay. Pituitary GH mRNA was analyzed by northern
      blot and IGF binding proteins (IGFBPs) by western blot. Arthritic rats showed a
      decrease in both serum and hepatic concentrations of IGF-I. On the contrary,
      arthritis increased the circulating IGFBPs. The serum concentration of IGF-I in
      the arthritic rats was negatively correlated with the body weight loss observed
      in these animals. Arthritis decreased the serum concentration of GH and this
      decrease seems to be due to an inhibition of GH synthesis, since pituitary GH
      mRNA content was decreased in arthritic rats (p<0.01). These data suggest that
      the decrease in body weight gain in arthritic rats may be, at least in part,
      secondary to the decrease in GH and IGF-I secretion. Furthermore, the increased
      serum IGFBPs may also be involved in the disease process.

PMID- 10579460
TI  - Z-4 allele upstream of the aldose reductase gene is associated with proliferative
      retinopathy in Japanese patients with NIDDM, and elevated luciferase gene
      transcription in vitro.
AB  - We determined by PCR the number of (A-C)n repeats in the 2. 1 kb upstream of the
      aldose reductase (AR2) gene in healthy control subjects and in patients with
      NIDDM in Japanese. Sixty-one patients were recruited based on the severity of
      retinopathy and subdivided into two groups with proliferative retinopathy and
      without retinopathy. Japanese exhibited 10 different alleles in this region. The
      most prevalent allele was designated Z ((A-C)24 repeats) allele. The Z-4 allele
      was significantly associated with patients with proliferative retinopathy,
      whereas the Z+2 allele was significantly associated with patients without
      retinopathy. Erythrocyte AR2 protein levels were significantly elevated in
      patients exhibiting the Z-4 allele compared to those exhibiting other alleles.
      When Z-4 allele was ligated in transfection experiments to luciferase vector
      containing the promoter region of the AR2 gene, the construct showed
      significantly higher transcription of the reporter gene compared to constructs
      without (A-C) repeat or with Z-2, Z or Z+2 alleles. Our results suggest that the
      Z-4 allele in the 2. 1 kb upstream of the AR2 gene may enhance gene transcription
      and may be a genetic risk factor, which determines the predisposition to
      retinopathy in Japanese patients with NIDDM.

PMID- 10579461
TI  - Anticonvulsive and free radical scavenging actions of two herbs, Uncaria
      rhynchophylla (MIQ) Jack and Gastrodia elata Bl., in kainic acid-treated rats.
AB  - Uncaria rhynchophylla (Miq.) Jack (UR) and Gastrodia elata BI. (GE) are
      traditional Chinese herbs that are usually used in combination to treat
      convulsive disorders, such as epilepsy, in China. The aim of this study was to
      compare the anticonvulsive and free radical scavenging activities of UR alone and
      UR in combination with GE in rats. For the in vitro studies, brain tissues from 6
      male Sprague-Dawley (SD) rats were treated with 120 microg/ml kainic acid (KA),
      with or without varied concentrations of UR or UR plus GE. For the in vivo
      studies, male SD rats (6 per group) received intraperitoneal (i.p.) injection of
      KA 12 mg/kg to induce epileptic seizures and generation of free radicals, with or
      without oral administration of UR 1 g/kg alone or UR 1 g/kg plus GE 1 g/kg.
      Epileptic seizures were verified by behavioral observations, and
      electroencephalography (EEG) and electromyography (EMG) recordings. These results
      showed that UR alone decreased KA-induced lipid peroxide levels in vitro, whereas
      UR plus GE did not produce a greater effect than UR alone. UR significantly
      reduced counts of wet dog shakes (WDS), paw tremor (PT) and facial myoclonia (FM)
      in KA-treated rats and significantly delayed the onset time of WDS, from 27 min
      in the control group to 40 min in the UR group. UR plus GE did not inhibit
      seizures more effectively than UR alone, but did further prolong the onset time
      of WDS to 63 min (P < 0.05 vs. UR alone). UR alone reduced the levels of free
      radicals in vivo, as measured by lipid peroxidation in the brain and luminol
      chemiluminescence (CL) counts and lucigenin-CL counts in the peripheral whole
      blood, but the combination of GE and UR did not reduce free radical levels more
      markedly than UR alone. In conclusion, our results indicate that UR has
      anticonvulsive and free radical scavenging activities, and UR combined with GE
      exhibit greater inhibition on the onset time of WDS than UR alone. These findings
      suggest that the anticonvulsive effects of UR and GE may be synergistic. However,
      the mechanism of interaction between UR and GE remains unknown.

PMID- 10579462
TI  - Immortalized hippocampal cells contain functional luteinizing hormone/human
      chorionic gonadotropin receptors.
AB  - We used immortalized HN33p cells as surrogates for hippocampal neurons to
      investigate the functional importance of luteinizing hormone (LH)/human chorionic
      gonadotropin (hCG) receptors. The use of various detection techniques
      demonstrated that HN33p cells contain LH/hCG receptor transcripts and receptor
      protein that can bind 125I-hCG. Culturing them with highly purified hCG resulted
      in a significant, although modest, dose-and time-dependent and hormone specific
      increase in steady state 5-lipoxygenase (5-LO) mRNA and protein levels. The
      studies on signaling revealed that treatment of HN33p cells with hCG resulted in
      a robust dose- and a time-dependent significant increase in media cyclic AMP
      levels. In addition, treatment with a protein kinase (PK)A inhibitor,
      isoquinolinesulfonamide (H-89), but not with a PKC inhibitor, bisindolylmaleimide
      (Bis), prevented hCG from increasing the 5-LO protein levels. Pretreatment of
      HN33p cells for 48 hrs with 2 microM antisense, but not sense, phosphorothioate
      oligodeoxy-nucleotides (ODN) synthesized from mouse LH/hCG receptor sequence
      resulted in a dramatic decrease in LH/hCG receptor protein levels. In the
      antisense, but not in sense, ODN-treated cells, hCG was unable to increase cyclic
      AMP and 5-LO protein levels, suggesting that receptors are required for hCG to
      work in HN33p cells.

PMID- 10579463
TI  - Specific binding of benzodiazepines to human breast cancer cell lines.
AB  - Binding of [3H]Ro5-4864, a peripheral benzodiazepine receptor (PBR) agonist, to
      BT-20 human, estrogen- (ER) and progesterone- (PR) receptor negative breast
      cancer cells was characterized. It was found to be specific, dose-dependent and
      saturable with a single population of binding sites. Dissociation constant (K(D))
      was 8.5 nM, maximal binding capacity (Bmax) 339 fM/10(6) cells. Ro5-4864 (IC50
      17.3 nM) and PK 11195 (IC50 12.3 nM) were able to compete with [3H]Ro5-4864 for
      binding, indicating specificity of interaction with PBR. Diazepam was able to
      displace [3H]Ro5-4864 from binding only at high concentrations (>1 microM), while
      ODN did not compete for PBR binding. Thymidine-uptake assay showed a biphasic
      response of cell proliferation. While low concentrations (100 nM) of Ro5-4864, PK
      11195 and diazepam increased cell growth by 10 to 20%, higher concentrations (10
      100 microM) significantly inhibited cell proliferation. PK 11195, a potent PBR
      ligand, was able to attenuate growth of BT-20 cells stimulated by 100 nM Ro5-4864
      and to reverse growth reduction caused by 1 and 10 microM Ro5-4864, but not by 50
      microM and 100 microM. This indicates that the antimitotic activity of higher
      concentrations of Ro5-4864 is independent of PBR binding. It is suggested, that
      PBR are involved in growth regulation of certain human breast cancer cell lines,
      possibly by supplying proliferating cells with energy, as their endogenous ligand
      is a polypeptide transporting Acyl-CoA.

PMID- 10579464
TI  - A selective dopamine D4 receptor antagonist, NRA0160: a preclinical
      neuropharmacological profile.
AB  - NRA0160, 5 - [2- ( 4- ( 3 - fluorobenzylidene) piperidin-1-yl) ethyl] - 4 -(4
      fluorophenyl) thiazole-2-carboxamide, has a high affinity for human cloned
      dopamine D4.2, D4.4 and D4.7 receptors, with Ki values of 0.5, 0.9 and 2.7 nM,
      respectively. NRA0160 is over 20,000fold more potent at the dopamine D4.2
      receptor compared with the human cloned dopamine D2L receptor. NRA0160 has
      negligible affinity for the human cloned dopamine D3 receptor (Ki=39 nM), rat
      serotonin (5-HT)2A receptors (Ki=180 nM) and rat alpha1 adrenoceptor (Ki=237 nM).
      NRA0160 and clozapine antagonized locomotor hyperactivity induced by
      methamphetamine (MAP) in mice. NRA0160 and clozapine antagonized MAP-induced
      stereotyped behavior in mice, although their effects did not exceed 50%
      inhibition, even at the highest dose given. NRA0160 and clozapine significantly
      induced catalepsy in rats, although their effects did not exceed 50% induction
      even at the highest dose given. NRA0160 and clozapine significantly reversed the
      disruption of prepulse inhibition (PPI) in rats produced by apomorphine. NRA0160
      and clozapine significantly shortened the phencyclidine (PCP)-induced prolonged
      swimming latency in rats in a water maze task. These findings suggest that
      NRA0160 may have unique antipsychotic activities without the liability of motor
      side effects typical of classical antipsychotics.

PMID- 10579465
TI  - Effect of cardiac arrest on brain weight and the permeability of the blood-brain
      and blood-spinal cord barrier to albumin and tumor necrosis factor-alpha.
AB  - Time-dependent changes in brain and spinal cord were studied in mice in a cardiac
      arrest model. A transient decrease in body weight and a prolonged decrease in
      brain weight occurred after arrest whereas spinal cord weight was unchanged. The
      permeability of the blood-brain barrier (BBB) to I131-albumin and I131 tumor
      necrosis factor-alpha (TNF) showed maximal, non-significant increases on day 5
      after cardiac arrest, but the permeability of the blood-spinal cord barrier
      (BSCB) to both materials was unchanged with time. We conclude that selective
      weight loss occurs in the brain after cardiac arrest with the integrity of the
      BBB and BSCB remaining intact to serum proteins and minimal alteration in the
      blood to CNS transport of TNF.

PMID- 10579466
TI  - Tyrosine and calcium/calmodulin kinases are common signaling components in the
      generation of reactive oxygen species in human lymphocytes.
AB  - This study examined the signaling mechanism involved in the generation of
      reactive oxygen species (ROS) in human lymphocytes activated by formyl-Met-Leu
      Phenylalanine (fMLP; 200 nmol/L) or phorbol-myristate-acetate (PMA; 100 nmol/L).
      ROS were monitored spectrophotometrically using dichlorofluorescin diacetate.
      fMLP and PMA significantly increased ROS above the control levels (p<0.05 and
      0.001, respectively). These increases were significantly inhibited by catalase,
      sodium azide, and dimethylsulfoxide but not by superoxide dismutase, suggesting
      that the ROS apparently included hydrogen peroxide, singlet oxygen and hydroxyl
      ion but not superoxide anion. PMA-induced responses were reduced by tyrphostin
      (p<0.01), ST-638 (p<0.05), KN-62 (p<0.001), bisindolylmaleimide (p<0.001), RO-31
      8220 (p<0.001), and by LY-83583 (p<0.001), suggesting significant involvement of
      tyrosine kinase, calcium/calmodulin kinase II, protein kinase C and guanylyl
      cyclase. fMLP-induced responses were significantly reduced by only tyrphostin
      (p<0.001), ST-638 (p<0.05), and KN-62 (p<0.01). The results show that tyrosine
      kinase and calcium/calmodulin kinase II are common signalling components in the
      production of reactive oxygen species in activated lymphocytes.

PMID- 10579467
TI  - Melatonin activates Th1 lymphocytes by increasing IL-12 production.
AB  - Melatonin could act on immune system by regulating cytokine production of
      immunocompetent cells. The hormone enhances IL-2, IFN-gamma and IL-6 production
      by cultured human mononuclear cells. As enhancement of IL-6 production is related
      to monocyte activation by melatonin, the hormone acts on human lymphoid cells
      causing a Th1-type response. This paper shows that melatonin seems to promote a
      Th1-response by increasing IL-12 production. The hormone enhances IL-12
      production by cultured monocytes under suboptimal stimulation in a dose-dependent
      way. The effect of the hormone increases when PBMCs are incubated with melatonin
      before monocyte isolation. Enhanced IL-12 production by melatonin can also be
      shown in cultured human mononuclear cells.

PMID- 10579468
TI  - Comparison of vasodilator potency of adrenomedulling and proadrenomedullin N
      terminal 20 peptide in human.
AB  - Adrenomedullin (ADM) and proadrenomedullin N-terminal peptide (PAMP), both of
      which are derived from preproadrenomedullin, are reported to have a potent
      hypotensive effect in animals. However, no data are available concerning the
      vasodilatory potency of PAMP or comparing this potency to that of ADM in human
      vasculature. We examined the effects of intra-arterial infusion of graded doses
      of ADM (1.25, 2.5, 5.0 and 7.5 pmol/min per 100 ml of tissue) and PAMP (125, 250,
      500, 750 and 1000 pmol/min per 100 ml of tissue) on total forearm blood flow and
      forearm skin blood flow in 11 healthy subjects. ADM increased total forearm blood
      flow from 2.9 +/- 0.4 to 8.6 +/- 1.1 ml/min per 100 ml (p < 0.01), and skin blood
      flow from 0.07 +/- 0.02 to 0.14 +/- 0.03 volts (p < 0.01). In contrast to this
      potent vasodilatory effect, a significant rise in forearm skeletal blood flow was
      seen only in response to the maximum dose of PAMP (from 2.7 +/- 0.5 to 5.3 +/-
      1.0 ml/min per 100 ml; p < 0.01). In addition, PAMP had no significant vasoactive
      effect on skin blood flow (from 0.06 +/- 0.02 to 0.09 +/- 0.03 volts; NS). In
      conclusion, the skeletal muscle vasodilator potency of PAMP is less than one
      hundredth of that of ADM in human forearm. Given its weak dilator potency, it
      seems unlikely that PAMP alone could significantly regulate resistance vessel
      tone as a circulating hormone in humans.

PMID- 10579469
TI  - Diazepam effects of peritoneal macrophage activity and corticosterone serum
      levels in Balb/C mice.
AB  - In the present experiment we investigate the effects of diazepam on macrophage
      activity and serum corticosterone levels in mice. Adult mice were treated with
      diazepam (1.5 mg/kg/day - group E) or with control solution (group C1) for 7
      days; some animals were only handled, receiving no treatment (group C2). Oral
      onco-BCG was used for peritoneal macrophage activation. Diazepam treatment: 1
      decreased macrophage spreading and phagocytosis; 2-decreased the concentrations
      of H2O2 spontaneously but not phorbol myristate-acetate-induced release. In
      relation to mice of group C1, diazepam treatment increased the serum levels of
      corticosterone. No differences were detected between data of groups C1 and C2
      both for macrophage activity and serum corticosterone levels. The present data
      were explained on the basis of a synergistically action for diazepam through
      peripheral type binding sites (PBR) present in both adrenals and macrophages,
      stimulating adrenal glucocorticoid production and altering the macrophage
      cytokine network.

PMID- 10579470
TI  - The science of pharmacological variability: an essay.

PMID- 10579471
TI  - Repeated consumption of grapefruit juice considerably increases plasma
      concentrations of cisapride.
AB  - BACKGROUND: Grapefruit juice increases the bioavailability of several drugs that
      are metabolized during first pass by CYP3A4. In this study, the effect of
      grapefruit juice on the pharmacokinetics of orally administered cisapride was
      investigated. METHODS: In a randomized, two-phase crossover study, 10 healthy
      volunteers took either 200 mL double-strength grapefruit juice or water three
      times a day for 2 days. On day 3, each subject ingested 10 mg cisapride with
      either 200 mL grapefruit juice or water, and an additional 200 mL was ingested
      1/2 hour and 1 1/2 hours after cisapride administration. Timed blood samples were
      collected for 32 hours after cisapride intake, and a standard 12-lead ECG was
      recorded before the administration of cisapride and 2, 5, 8, and 12 hours later.
      RESULTS: The mean peak plasma concentration of cisapride was increased by 81%
      (range, 38% to 138%; P < .01) and the total area under the plasma cisapride
      concentration-time curve by 144% (range, 65% to 244%; P < .01) by grapefruit
      juice. The time of the peak concentration of cisapride was prolonged from 1.5 to
      2.5 hours (P < .05) and the elimination half-life from 6.8 to 8.4 hours (P < .05)
      by grapefruit juice. ECG tracings did not show any significant differences in the
      QTc interval between the grapefruit juice and control phases. CONCLUSIONS:
      Grapefruit juice significantly increases plasma concentrations of cisapride,
      probably by inhibition of the CYP3A4-mediated first-pass metabolism of cisapride
      in the small intestine. Concomitant use of high amounts of grapefruit juice and
      cisapride should be avoided, at least in patients with risk factors for cardiac
      arrhythmia.

PMID- 10579472
TI  - The roles of cytochrome P450 3A4 and 1A2 in the 3-hydroxylation of quinine in
      vivo.
AB  - OBJECTIVE: To investigate the roles of CYP3A4 and CYP1A2 in the 3-hydroxylation
      of quinine in vivo. METHODS: In a randomized, three-way crossover study, nine
      healthy Swedish volunteers received single oral doses of quinine hydrochloride
      (500 mg), quinine hydrochloride (500 mg) plus ketoconazole (100 mg twice daily
      for 3 days), and quinine hydrochloride (500 mg) plus fluvoxamine (25 mg twice
      daily for 2 days) on three different occasions. Blood and urine samples were
      collected before quinine intake and up to 96 hours thereafter. Plasma and urine
      samples were analyzed for both quinine and its main metabolite 3-hydroxyquinine
      with HPLC methods. RESULTS: Coadministration with ketoconazole (which inhibits
      CYP3A4) decreased the mean apparent oral clearance of quinine significantly (P <
      .001) by 31% (from 8.7 to 6.0 L/h), whereas coadministration with fluvoxamine
      (which inhibits CYP1A2 and to some extent CYP2C19) had no significant effect (P >
      .05) on the mean apparent oral clearance of quinine. Coadministration with
      ketoconazole also decreased the mean area under the plasma concentration versus
      time curve (AUC) of 3-hydroxyquinine (from 28.4 to 19.7 micromol x h x L(-1); P <
      .001), whereas coadministration with fluvoxamine increased 3-hydroxyquinine AUC
      significantly (from 28.4 to 30.2 micromol x h x L(-1); P < .05). CONCLUSION:
      Cytochrome P450 3A4 is important for the 3-hydroxylation of quinine in vivo. On
      the other hand, CYP1A2 had no significant effect on this metabolic pathway.

PMID- 10579473
TI  - Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of
      midazolam as an in vivo probe: effect of ketoconazole.
AB  - BACKGROUND: The cytochrome P450 3A (CYP3A) isoforms are responsible for the
      metabolism of a majority of therapeutic compounds, and they are abundant in the
      intestine and liver. CYP3A activity is highly variable, causing difficulty in the
      therapeutic use of CYP3A substrates. A practical in vivo probe method that
      characterizes both intestinal and hepatic CYP3A activity would be useful.
      OBJECTIVES: To determine the intestinal and hepatic contribution to the
      bioavailability of midazolam with use of the CYP3A inhibitor ketoconazole.
      METHODS: The pharmacokinetics of midazolam was assessed in nine (six men and
      three women) healthy individuals after single doses of 2 mg intravenous and 6 mg
      oral midazolam (phase I). These pharmacokinetic values were compared with those
      obtained after single doses of 2 mg intravenous and 6 mg oral midazolam and three
      doses of 200 mg oral ketoconazole (phase II). RESULTS: After ketoconazole
      therapy, area under the concentration versus time curve of midazolam increased 5
      fold after intravenous midazolam administration (P < or = .001) and 16-fold after
      oral midazolam administration (P < or = .001). Intrinsic clearance decreased by
      84% (P = .003). Total bioavailability increased from 25% to 80% (P < .001). The
      intestinal component of midazolam bioavailability increased to a greater extent
      than the hepatic component (2.3-fold [P = .003] and 1.5-fold [P < or = .001],
      respectively). In the control phase, female subjects had greater midazolam
      clearance values than the male subjects. CONCLUSIONS: Ketoconazole caused marked
      inhibition of CYP3A activity that was greater in the intestine than the liver.
      Administration of single doses of oral and intravenous midazolam with and without
      oral ketoconazole exemplifies a practical method for differentiating intestinal
      and hepatic CYP3A activity.

PMID- 10579474
TI  - Population pharmacokinetics of mefloquine in patients with acute falciparum
      malaria.
AB  - OBJECTIVE: To construct a population pharmacokinetic model for mefloquine in the
      treatment of falciparum malaria. BACKGROUND: Mefloquine is the treatment of
      choice for multidrug-resistant falciparum malaria. The factors that influence the
      pharmacokinetic properties of mefloquine in acute malaria are not well
      characterized. METHODS: The pharmacokinetic properties of mefloquine were
      evaluated in 257 patients with acute falciparum malaria by use of nonlinear mixed
      effects modeling. Two different oral dose regimens were used: (1) a split dose of
      15 mg base/kg initially followed by 10 mg/kg 24 hours later (n = 159) and (2) a
      single dose of 25 mg/kg (n = 98). Mefloquine was combined with artesunate in 105
      (41%) patients (74 received a split dose and 31 received a single dose). RESULTS:
      Splitting the mefloquine dose increased the area under the concentration-time
      curve [AUC(0-infinity)] by 50% (95% confidence interval [CI], 36% to 65%) for
      monotherapy and by 20% (95% CI, 3% to 40%) for combined therapy. The apparent
      volume of distribution (V/F) was significantly lower in patients receiving split
      doses of mefloquine monotherapy (mean, 8.14 L/kg; 95% CI, 7.49 to 8.86 L/kg)
      compared with a single dose (mean, 20.37 L/kg; 95% CI, 16.26 to 25.51 L/kg).
      Patients who received mefloquine monotherapy and cleared parasitemia in less than
      48 hours had a significantly higher AUC(0-infinity) independent of any
      confounders, compared with patients with slower parasite clearance (geometric
      mean [95% CI], 50,373 ng/mL x day [46,121 to 55,017 ng/mL x day] versus 45,583
      ng/mL x day [42,306 to 49,125 ng/mL x day]). CONCLUSIONS: The pharmacokinetic
      properties of mefloquine in malaria were relatively unaffected by demographic
      variables (other than body weight) or disease severity. If it is assumed that
      apparent clearance and volume of distribution are unaffected by dose regimen,
      then splitting the 25 mg/kg mefloquine dose improves oral bioavailability and the
      therapeutic response in the treatment of acute falciparum malaria.

PMID- 10579475
TI  - Pharmacokinetics of the somatostatin analog lanreotide in patients with severe
      chronic renal insufficiency.
AB  - OBJECTIVE: To characterize the pharmacokinetic profile of the somatostatin analog
      lanreotide in patients with severe chronic renal insufficiency. METHODS:
      Lanreotide was administered by intravenous bolus (7 microg/kg) to 12 patients
      with severe chronic renal insufficiency and to 12 healthy subjects. Lanreotide
      serum levels were determined by a radioimmunoassay procedure from time 0 until 24
      hours after the administration. The main pharmacokinetic parameters were
      estimated by a noncompartmental treatment of data. RESULTS: The total serum
      clearance of lanreotide was found to be significantly lower in patients with
      severe chronic renal insufficiency than in healthy subjects (mean +/- SEM values
      of 0.138 +/- 0.017 L/hr/kg versus 0.244 +/- 0.027 L/hr/kg; P < .005). The initial
      lanreotide concentration, the elimination half-life, the area under the curve
      from time zero to 24 hours, and the area under the curve from time zero to
      infinity were significantly greater in patients with severe chronic renal
      insufficiency than in healthy subjects (307.45 +/- 79.19 ng/mL versus 127.18 +/-
      22.65 ng/mL [P < .05]; 2.39 +/- 0.33 hours versus 1.32 +/- 0.20 hours [P < .005];
      62.55 +/- 9.73 ng/mL x hr versus 32.09 +/- 3.23 ng/mL x hr [P < .005]; and 62.95
      +/- 9.78 ng/mL x hr versus 32.30 +/- 3.23 ng/mL x hr [P < .005], respectively).
      The initial volume of distribution, but not the volume of distribution at steady
      state, was significantly lower in patients with severe chronic renal
      insufficiency (0.040 +/- 0.008 L/kg versus 0.092 +/- 0.020 L/kg [P < .05] and
      0.110 +/- 0.018 L/kg versus 0.172 +/- 0.046 L/kg [difference not statistically
      significant], respectively). The mean residence time was similar in both groups
      (0.77 +/- 0.06 hours versus 0.65 +/- 0.14 hours [difference not statistically
      significant]). CONCLUSIONS: A reduction in the total serum clearance and a
      decrease in the initial volume of distribution of lanreotide were observed in
      patients with severe chronic renal insufficiency treated with one intravenous
      bolus dose of 7 microg/kg lanreotide.

PMID- 10579476
TI  - The kinetics of mycophenolic acid and its glucuronide metabolite in adult kidney
      transplant recipients.
AB  - BACKGROUND: Mycophenolic acid kinetics have been reported to vary after renal
      transplantation, and mycophenolic acid area under the concentration-time curve
      (AUC) is the best predictor of suppression of graft rejection. METHODS: To
      determine whether mycophenolic acid kinetics vary after renal transplantation and
      to examine the potential role of enterohepatic recirculation, we investigated the
      kinetics of mycophenolic acid and mycophenolic acid glucuronide on days 2, 5, and
      28 after transplantation in 10 kidney transplant recipients (male/female ratio,
      1.5; mean age, 41.7 +/- 5.0 years) given 1 g mycophenolate mofetil twice a day.
      To facilitate therapeutic drug monitoring, we examined a limited sampling
      strategy for estimating 12-hour mycophenolic acid [AUC(0-12)]. RESULTS: The mean
      +/- SE AUC(0-12) for mycophenolic acid on day 28 was 38.5 +/- 1.6 mg x h/L, with
      a secondary peak 4 to 8 hours after dosing that was attributable to enterohepatic
      recirculation. Marked variability was shown in the kinetic profile of
      mycophenolic acid among patients across the three sampling days. Mycophenolic
      acid AUC(0-12) was positively predicted by both serum creatinine (P = .01) and
      serum albumin (P = .03) but not by time after transplantation, body weight, or
      trough concentration. Limited sampling (at 0, 1, 3, and 6 hours) accounted for
      84.1% of the variability in the mycophenolic acid AUC(0-12) data and predicted
      the AUC(0-12) closely (r2 = 0.954) when evaluated in 10 different kidney
      transplant recipients. CONCLUSIONS: Mycophenolic acid AUC(0-12) is predicted by
      serum albumin and creatinine after kidney transplantation, and the AUC(0-12) may
      be determined during the early posttransplant period while the patient remains
      hospitalized with use of a limited sampling strategy to facilitate therapeutic
      drug monitoring.

PMID- 10579477
TI  - Smoking accelerates absorption of inhaled neutrophil elastase inhibitor FK706.
AB  - PURPOSE: We compared the pharmacokinetics of the inhaled novel neutrophil
      elastase inhibitor FK706 between healthy nonsmokers and smokers. METHODS: Six
      healthy nonsmokers and six smokers inhaled 50 to 400 mg FK706 in two different
      doses. Series of plasma concentrations of the SSS form of FK706
      (pharmacologically active epimer) were analyzed model dependently and
      independently. Pharmacokinetic parameters obtained from each group were compared
      after standardization by doses. RESULTS: The plasma concentration-time curve of
      inhaled FK706 was apparently different between smokers and nonsmokers. The
      maximum plasma concentrations (Cmax) were significantly higher in the smokers
      than in the nonsmokers (smokers, 1.47 +/- 0.62 ng/mL/mg; nonsmokers, 0.49 +/-
      0.14 ng/mL/mg [mean +/- SD; P < .01]). The time to reach Cmax (tmax) and
      elimination half-life (t1/2) were statistically smaller in the smokers compared
      with the tmax and elimination t1/2 in the nonsmokers (tmax in smokers, 0.44 +/-
      0.27 hours; tmax in nonsmokers, 1.17 +/- 0.39 hours [P < .01]; t1/2 in smokers,
      1.23 +/- 0.40 hours; t1/2 in nonsmokers, 2.73 +/- 0.57 hours [P < .01]). The area
      under the plasma concentration-time curve and plasma clearance were not
      significantly different between the two groups. Model-dependent pharmacokinetic
      analysis, assuming a flip-flop model, revealed that the absorption rate constant
      (ka) was about 10 times greater in smokers than the ka in nonsmokers. CONCLUSION:
      Significant increases of Cmax and ka and reductions of tmax and elimination t1/2
      of the inhaled FK706 were observed in the healthy smokers, suggesting that the
      smoking habit accelerates the drug absorption after inhalation. These results
      suggest that we should pay attention to the drug-related adverse events caused by
      smoking, especially when the drug has a narrow therapeutic range.

PMID- 10579478
TI  - Multiple-dose pharmacokinetics of rectally administered acetaminophen in term
      infants.
AB  - OBJECTIVE: To investigate pharmacokinetics and pharmacodynamics of rectally
      administered acetaminophen (INN, paracetamol) in term neonates directly after
      birth. METHODS: In this prospective clinical trial, term neonates wtih painful
      conditions or who were undergoing painful procedures received multiple-dose
      acetaminophen. Serum concentrations were determined serially with an HPLC method,
      and pharmacokinetic analysis was performed. Pain assessment was performed by
      means of a validated pain score. RESULTS: Ten consecutive term neonates received
      four rectal doses of acetaminophen, 20 mg/kg body weight, every 6 hours. Mean
      peak serum concentrations (+/-SD) during multiple-dose administration were 10.79
      +/- 6.39 mg/L, 15.34 +/- 5.21 mg/L, and 6.24 +/- 3.64 mg/L for the entire group,
      boys, and girls, respectively. There was a significant difference between the
      boys and the girls (P = .01). No serum concentrations associated with toxicity
      (>120 mg/L) were found. Median time to peak serum concentration was 1.5 hours
      after the first dose and 15 hours for multiple doses. Mean (+/-SD) half-life was
      2.7 +/- 1.4 hours in eight patients. There was no correlation between dose and
      serum concentration or between pain score and serum concentration. There was a
      significant inverse relationship between the preceding pain score and peak serum
      concentrations. CONCLUSIONS: In term neonates, multiple rectal doses of
      acetaminophen, 20 mg/kg body weight, led to widely varying serum concentrations
      but did not result in therapeutic concentrations in all infants. Boys had higher
      peak concentrations. Because accumulation was not found, a dose of 30 mg/kg
      followed by doses of 20 mg/kg at 6- to 8-hour administration intervals are
      appropriate to reach therapeutic concentrations. A concentration-effect
      relationship could not be determined.

PMID- 10579479
TI  - Fluoxetine impairs the CYP2D6-mediated metabolism of propafenone enantiomers in
      healthy Chinese volunteers.
AB  - OBJECTIVE: To determine the effect of 20 mg/day fluoxetine on the
      pharmacokinetics of propafenone enantiomers and CYP2D6 activity by phenotyping
      with dextromethorphan. METHODS: Nine healthy Chinese volunteers (seven men and
      two women) were included in a two-phase study. Dextromethorphan (20 mg) was given
      before and after subjects took 20 mg/day fluoxetine for 10 days, and the
      dextromethorphan metabolic ratio was calculated to determine CYP2D6 phenotype.
      Pharmacokinetic studies of propafenone enantiomers after a single oral 400 mg
      dose before and after pretreatment with 20 mg/day fluoxetine for 10 days were
      also conducted in these subjects. Reversed-phase HPLC with precolumn
      derivatization was used to determine enantiomeric concentrations of propafenone
      in plasma. RESULTS: Mean CYP2D6 dextromethorphan metabolic ratios before and
      after fluoxetine therapy were 0.028 +/- 0.031 and 0.080 +/- 0.058, respectively
      (P = .001), indicating that a strong inhibition of CYP2D6 by fluoxetine activity
      was observed in Chinese subjects. Propafenone metabolism was also impaired
      significantly after fluoxetine treatment. The elimination half-life, peak
      concentration, and area under the curve from 0 hours to infinity of two
      enantiomers after fluoxetine therapy were significantly increased compared with
      those at baseline (P < .01), whereas oral clearance decreased from 75.01 +/-
      17.69 L/h to 49.36 +/- 8.62 L/h for S-propafenone (P = .005) and from 107.62 +/-
      33.82 L/h to 70.60 +/- 12.42 L/h for R-propafenone (P = .027). In addition,
      fluoxetine increased the peak concentration of S-propafenone by 39% and that of R
      propafenone by 71% (P < .05). A significant increase of the time to reach peak
      concentration was observed only in the R-enantiomer and not in the S-enantiomer
      of propafenone after fluoxetine therapy. There were no differences in the
      percentage changes of PR and QRS intervals before or after fluoxetine
      pretreatment at the time observed (P > .05). CONCLUSION: We conclude that
      fluoxetine may cause significant inhibition of the CYP2D6 activity as determined
      by dextromethorphan phenotyping. This inhibition impairs the metabolism of
      propafenone enantiomers in Chinese subjects. Caution must be exercised when
      fluoxetine and propafenone are coadministered to avoid potential toxicity.

PMID- 10579480
TI  - Neurokinin-1 receptor antagonist R116301 inhibits substance P-induced
      venodilation.
AB  - OBJECTIVE: To test the effect of the neurokinin-1 receptor antagonist
      hydroxybutanedioate (R116301) in human hand veins in vivo. METHODS: In a
      randomized, double-blind, placebo-controlled crossover study we used the hand
      vein compliance method to evaluate the inhibition of the response to substance P
      by R116301. RESULTS: In hand veins preconstricted with phenylephrine to 21% +/-
      2.6% (mean +/- SEM, placebo) and 25% +/- 3.0% (R116301) of the initial diameter,
      substance P resulted in a mean venodilation of 84% +/- 7% and 87% +/- 13% (P =
      .8) before administration of placebo and R116301, respectively. Oral
      administration of 300 mg R116301 resulted in peak plasma concentrations of 1.16
      +/- 0.1 microg/mL within 128 +/- 14 minutes. With increasing R116301 plasma
      concentrations, substance P-induced venodilation decreased significantly (P <
      .001), whereas placebo had no effect. Mean substance P-induced venodilation was
      markedly reduced to 8% +/- 7%. CONCLUSION: This study confirms the presence of
      neurokinin-1 receptors in human veins and the effectiveness of the neurokinin-1
      receptor antagonist R116301 in human hand veins.

PMID- 10579481
TI  - CYP2C19 genotype-related efficacy of omeprazole for the treatment of infection
      caused by Helicobacter pylori.
AB  - OBJECTIVES: Omeprazole is used for the treatment of infection caused by
      Helicobacter pylori, and it is metabolized by the polymorphic cytochrome P4502C19
      (CYP2C19). We have found that the anti-H pylori efficacy by the combination of
      omeprazole and antibiotics is related to the CYP2C19 genotype. METHODS: One
      hundred eight patients with cultured H pylori-positive gastritis or peptic ulcer
      were treated with three regimens: quadruple treatment without proton pump
      inhibitors (n = 25), dual treatment with omeprazole and amoxicillin (INN,
      amoxicilline) (n = 26), and triple treatment with omeprazole, amoxicillin, and
      clarithromycin (n = 57). The CYP2C19 genotype was determined by the polymerase
      chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and the
      assessment of the eradication of H pylori was based on all negative examinations,
      including culture, histology, and 13C-urea breath test. RESULTS: The eradication
      rates for the extensive metabolizers were 50% and 86% for the dual and triple
      treatments, respectively. In contrast, all of the poor metabolizers treated with
      omeprazole and antibiotics (n = 15) showed an eradication of H pylori.
      CONCLUSION: The anti-H pylori effect of dual treatment is highly efficient for
      CYP2C19 poor metabolizers, which suggests that clarithromycin is not necessary as
      a first line of therapy for this type of patients. Genotyping can provide a
      choice for the optimal regimen based on individual CYP2C19 genotype.

PMID- 10579482
TI  - Dose dependency of dextromethorphan for cytochrome P450 2D6 (CYP2D6) phenotyping.
AB  - Most dextromethorphan CYP2D6 phenotyping studies use a 30-mg dose, but data that
      show superiority of any particular dose are lacking. We compared metabolic ratios
      from six different dextromethorphan phenotyping doses to ascertain whether
      linearity existed over a dosage range. Forty subjects were enrolled in the study.
      Each subject received 0.05 mg/kg, 0.15 mg/kg, 0.3 mg/kg, 30 mg, 0.8 mg/kg, and
      1.2 mg/kg dextromethorphan in a randomized crossover fashion. Urinary
      dextromethorphan to dextrorphan molar ratios were used to measure CYP2D6
      activity. Single blood samples were obtained for CYP2D6 genotyping, which
      revealed one poor metabolizer and 39 extensive metabolizers. A statistical
      difference was found for the molar ratio between the 0.8 mg/kg and the 1.2 mg/kg
      dose compared with the other four doses. None of the 39 genotypic extensive
      metabolizers were incorrectly phenotyped with any of these doses. These data
      support the use of moderate doses of dextromethorphan for phenotyping to avoid
      dose dependency.

PMID- 10579483
TI  - Structural organization and interactions of COP1, a light-regulated developmental
      switch.
AB  - Arabidopsis seedling development follows contrasting patterns depending on
      ambient light conditions, photomorphogenesis in the light and skotomorphogenesis
      or etiolation in darkness. COP1 is a limiting or regulatory component in
      mediating repression of photomorphogenesis in the absence of light. COP1 acts
      within the nucleus in the dark, directly interacts and regulates specific
      transcription factors that are required for promoting photomorphogenesis. Light
      abrogates COP1 action and results in progressive nuclear depletion of COP1 with
      increasing light stimuli. COP1 contains multiple structural modules, which are
      responsible for interacting with distinct cellular factors and play specific
      functional roles. We review the most recent progress in understanding the COP1
      action and propose specific models based on the recent studies.

PMID- 10579484
TI  - Molecular genetic analysis of the drought-inducible linker histone variant in
      Arabidopsis thaliana.
AB  - Linker histones are ubiquitous structural components of chromatin that have been
      shown to influence the expression of a subset of genes in diverse organisms.
      Plants contain a minor linker histone variant that is expressed in most tissues
      of all organs, and is induced during drought stress. Based on reporter gene
      analysis in roots, His1-3 is expressed almost exclusively in emerging secondary
      roots in unstressed plants, but is primarily expressed in the root meristem and
      elongation zone of stressed plants. In shoots, expression is higher in younger
      tissues than older tissues. In order to investigate the function of H1-3, we have
      generated lines with altered levels of H1-3. Plants expressing an antisense His1
      3 transcript exhibit a greatly impaired induction (5% of wild-type RNA levels
      during stress) of His1-3 transcripts in shoots during drought and contain
      decreased protein relative to wild-type control plants. In plants overexpressing
      His1-3, more H1-3 is bound to chromatin than in unstressed wild-type plants. None
      of the plants containing these transgenes display phenotypic aberrations or
      differences in water content during drought stress. Additionally, the expression
      of several drought-responsive genes is not significantly altered in lines
      misexpressing His1-3.

PMID- 10579485
TI  - Age-dependent wound induction of a myrosinase-associated protein from oilseed
      rape (Brassica napus).
AB  - In order to study the expression of the induced form of myrosinase-associated
      protein (iMyAP), a genomic clone encoding the protein was isolated from Brassica
      napus. The coding portion of the gene was found to consist of five exons
      separated by one long intron of 938 bp and three shorter introns of ca. 100 bp. A
      1.9 kb promoter fragment including the 5'-untranslated region was cloned in front
      of the coding portion of the Escherichia coli iudA gene and transformed into
      Arabidopsis thaliana. Expression was observed in hypocotyls of 4-day seedlings,
      but in 7-day seedlings the iMyAP promoter did not direct expression. In flowering
      plants, only the abscission zone of the young silique displayed promoter
      activity. In contrast, mechanical wounding of 7-day seedlings induced a systemic
      expression in all cells of the cotyledons. Wounding of 14-day seedlings gave rise
      to systemic induced expression mainly in the vascular tissue. However, mechanical
      wounding and wounding by flea beetles (Phyllotreta undulata) of 4-week old plants
      only gave rise to a local induction of the promoter, suggesting that the systemic
      signal system is age-dependent. Methyl jasmonate also induced iMyAP expression.
      In situ and northern analysis of iMyAP transcripts in young leaves of B. napus
      showed that the induction was high after 1 h and absent after 24 h. Comparison of
      the effect of different types of wounding on the iMyAP promoter induction in
      transgenic Arabidopsis showed that similar degrees of local induction were
      achieved regardless of the degree of macerated tissue left on the plant.

PMID- 10579486
TI  - Identification of a promoter region responsible for the senescence-specific
      expression of SAG12.
AB  - SAG12, an Arabidopsis gene encoding a cysteine protease, is expressed only in
      senescent tissues. Studies of the expression patterns of a variety of genes
      showing senescence-specific or senescence-preferential expression indicate that
      plant senescence involves multiple regulatory pathways. In this study it is shown
      that the expression of SAG12 is specifically activated by developmentally
      controlled senescence pathways but not by stress- or hormone-controlled pathways.
      Using SAG12 as a molecular marker for the study of developmental senescence, we
      show that cytokinin, auxin, and sugars can repress developmental senescence at
      the molecular level. Studies using promoter deletions and recombination of
      promoter fragments indicate that a highly conserved region of the SAG12 promoter
      is responsible for senescence-specific regulation, while at least two other
      regions of the SAG12 promoter are important for full promoter activity. Extracts
      from young and senescent Arabidopsis leaves contain factors that exhibit
      differential binding to the senescence-responsive promoter element.

PMID- 10579487
TI  - Regulation of developmental senescence is conserved between Arabidopsis and
      Brassica napus.
AB  - SAG12 is a developmentally controlled, senescence-specific gene from Arabidopsis
      which encodes a cysteine protease. Using SAG12 as a probe, we isolated two SAG12
      homologues (BnSAG12-1 and BnSAG12-2) from Brassica napus. Structural comparisons
      and expression studies indicate that these two genes are orthologues of SAG12.
      The expression patterns of BnSAG12-1 and BnSAG12-2 in Arabidopsis demonstrate
      that the senescence-specific regulation of this class of cysteine proteases is
      conserved across these species. Gel-shift assays using the essential promoter
      regions of SAG12, BnSAG12-1, and BnSAG12-2 show that the extent of binding of a
      senescence-specific, DNA-binding protein from Arabidopsis is proportional to the
      expression levels of these genes in Arabidopsis. Therefore, the expression levels
      of these genes may reflect the affinities of the senescence-specific DNA-binding
      protein for the promoter element.

PMID- 10579488
TI  - Nectarin I is a novel, soluble germin-like protein expressed in the nectar of
      Nicotiana sp.
AB  - We have identified a limited number of proteins secreted into the nectar of
      tobacco plants. Nectarin I is the most highly expressed nectar protein and has a
      monomer molecular mass of 29 kDa. The other major nectar proteins are expressed
      at lower levels and have monomer molecular masses of 41, 54, and 65 kDa
      respectively. Nectarin I was purified and antiserum was raised against the
      protein. Under nondenaturing conditions, Nectarin I has an apparent molecular
      mass of > 120 kDa. The expression of Nectarin I was restricted to nectary tissues
      and to a much lower level in the ovary. No Nectarin I was found in petals, stems,
      leaves, or roots or other floral tissues. The expression of Nectarin I was also
      developmentally regulated. It is expressed in nectary tissues only while nectar
      is being actively secreted. Subsequently, the N-terminus of purified Nectarin I
      was sequenced. Sequence identity showed Nectarin I is related to wheat germin.
      Although hydrogen peroxide is readily detectable in tobacco floral nectar, we
      were unable to demonstrate any oxalate oxidase activity for Nectarin I. A partial
      cDNA encoding the mature Nectarin I N-terminus was isolated and used to probe a
      Nicotiana plumbaginifolia genomic library. The Nectarin I gene was isolated and
      the translated sequence was consistent with both N-terminal and internal cyanogen
      bromide-derived amino acid sequence. The gene contains a single 386 nt intron and
      encodes a mature protein of 197 amino acids.

PMID- 10579489
TI  - A novel promoter from soybean that is active in a complex developmental pattern
      with and without its proximal 650 base pairs.
AB  - We report the isolation of a novel soybean gene, Msg, which is highly expressed
      in developing soybean pods. The gene shows significant homology to a family of
      fruit- and flower-specific genes, designated the major latex protein (MLP)
      homologues, so far reported in only a few species and whose functions are
      unknown. The MLPs are more distantly related to a group of pathogenesis-related
      proteins (IPR or PR-10) whose functions are likewise unknown. This is the first
      report of a MLP homologue in a plant for which there is already an IPR-protein
      reported. We performed an analysis of the Msg promoter with 14 different promoter
      fragments ranging from 0.65 kb to 2.26 kb, fused to the uidA (GUS) gene. High
      transient expression was obtained with all the constructs upon particle
      bombardment in soybean and green bean pods. Stable Arabidopsis transformants were
      obtained with the Agrobacterium vacuum infiltration method. The promoter is fully
      active in Arabidopsis only in plants transformed with the 2.26 kb fragment
      promoter, expressing GUS in nectaries, nodes, short style and in guard cells of
      the silique, pedicel and stem but not in mature leaves. Surprisingly, the
      proximal 650 bp TATA-containing region cannot function on its own in Arabidopsis
      and can be deleted without a change in expression pattern in both Arabidopsis and
      soybean. Thus, tissue-specific regions of the complex Msg promoter reside in the
      distal 5' regions upstream of a dispensable TATA box in contrast to many examples
      of tissue-specific elements that reside much closer to the TATA box.

PMID- 10579490
TI  - High expression level of a gene coding for a chloroplastic amino acid selective
      channel protein is correlated to cold acclimation in cereals.
AB  - A cold-regulated gene (cor tmc-ap3) coding for a putative chloroplastic amino
      acid selective channel protein was isolated from cold-treated barley leaves
      combining the differential display and the 5'-RACE techniques. Cor tmc-ap3 is
      expressed at low level under normal growing temperature, and its expression is
      strongly enhanced after cold treatment. A positive correlation between the
      expression of cor tmc-ap3 and frost tolerance was found both among barley
      cultivars and among cereal species. The COR TMC-AP3 protein was expressed in
      vitro, purified and used to raise a polyclonal antibody. Western analysis showed
      that the cor tmc-ap3 gene product is localized to the chloroplastic outer
      envelope fraction, supporting its putative function. The frost-resistant winter
      cultivar Onice accumulated COR TMC-AP3 more rapidly and at a higher level than
      the frost-susceptible spring cultivar Gitane. After 28 days of cold acclimation
      the winter cultivar had about 2-fold more protein than the spring genotype. All
      these results suggest that an increased amount of a chloroplastic amino acid
      selective channel protein could be required for cold acclimation in cereals.
      Hypotheses about the role of COR TMC-AP3 during the hardening process are
      discussed.

PMID- 10579491
TI  - Regulation of endoreduplication in maize (Zea mays L.) endosperm. Isolation of a
      novel B1-type cyclin and its quantitative analysis.
AB  - To investigate the involvement of cyclin in mitotic and endoreduplicative cell
      cycle control, we have isolated a mitotic cyclin clone from a maize endosperm
      cDNA library. The deduced amino acid sequence of this clone identifies a novel B1
      type cyclin with distinctly different sequence in regions with putative
      involvement in intracellular localization. This cyclin, designated Zeama;CycB 1;3
      (CycZme1), was shown by RNA gel blots and quantitative RT-PCR to be specific for
      tissues engaging in cell proliferation. It accumulated in metaphase-arrested
      cells and declined rapidly upon release into G1 phase. During the transition from
      mitosis to endoreduplication in maize endosperm, CycZme1 transcript declined
      precipitously while transcripts associated with S phase (histone-H3 and PCNA) and
      multiple phases of the cell cycle (Cdc2, alpha-tubulin) remained at moderate to
      high levels. We conclude that CycZme1 down-regulation is involved in the cellular
      transition to endoreduplication.

PMID- 10579492
TI  - Cloning and expression of amino acid transporters from broad bean.
AB  - This work describes the isolation of a full-length (VfAAP2) and three partial
      amino acid transporter genes (VfAAPa, VfAAPb, VfAAPc) from broad bean (Vicia faba
      L.). The function of VfAAP2 was tested by heterologous expression in a yeast
      mutant deficient in proline uptake. VfAAP2 mediates proton-dependent proline
      uptake with an apparent Km of about 1 mM. Analysis of substrate specificity by
      competition experiments showed that aromatic amino acids, neutral aliphatic acids
      and L-citrulline are the best competitors, whereas basic amino acids do not
      compete with proline. Northern analysis indicates that all VfAAPs exhibit
      different patterns of expression. VfAAP2 is most strongly expressed in the stem
      and at a lower level in sink leaves and pods. VfAAPa, VfAAPb and VfAAPc are most
      strongly expressed in the flowers, but their expression in the other organs
      varies.

PMID- 10579493
TI  - Multiple DNA methyltransferase genes in Arabidopsis thaliana.
AB  - Methylation of plant DNA occurs at cytosines in any sequence context, and as the
      Arabidopsis methyltransferase, METI, preferentially methylates cytosines in CG
      dinucleotides, it is likely that Arabidopsis has other methyltransferases with
      different target specificities. We have identified five additional genes encoding
      putative DNA methyltransferases. Three of these genes are very similar to METI
      throughout the coding region; these genes probably arose by a series of gene
      duplication events, the most recent giving rise to METIIa and METIIb. METIIa and
      b are expressed at low levels in vegetative and floral organs and the level of
      transcripts is not affected by the introduction of a METI antisense transgene,
      nor do the METII enzymes substitute for the reduced activity of METI in
      methylating CG dinucleotides. METIII is not essential as it encodes a truncated
      protein. Two other genes encode a second class of DNA methyltransferase with the
      conserved motifs characteristic of cytosine methyltransferases, but with little
      homology to the METI-like methyltransferases through the remainder of the
      protein. These two methyltransferases are characterized by the presence of a
      chromodomain inserted within the methyltransferase domain, suggesting that they
      may be associated with heterochromatin. Both these genes are transcribed at low
      levels in vegetative and reproductive tissues.

PMID- 10579494
TI  - Molecular characterisation and expression of a wound-inducible cDNA encoding a
      novel cinnamyl-alcohol dehydrogenase enzyme in lucerne (Medicago sativa L.)
AB  - A lucerne (alfalfa, Medicago sativa) stem cDNA library was screened with a
      cinnamyl-alcohol dehydrogenase (CAD) cDNA probe from tobacco (Nicotiana tabacum
      cv. Samsun). Two distinctly different cDNA clones (54% identical) were isolated
      and identified as putative CAD-encoding cDNAs by comparison of their nucleotide
      sequences with those of CAD-encoding DNA sequences from other plant species. One
      of the cDNAs, MsaCad2, was found to be 99.4% identical at the nucleotide level to
      the previously isolated lucerne cad cDNA which encodes a CAD isoform involved in
      lignin biosynthesis. The other cDNA, MsaCad1, has not been reported previously in
      lucerne, and encodes a protein related to the ELI3 class of elicitor-inducible
      defence-related plant proteins. The MsaCad1- and MsaCad2-encoded proteins were
      expressed in Escherichia coli and CAD1 was shown to be active with a range of
      cinnamyl, benzyl and aliphatic aldehyde substrates, while CAD2 was specific for
      the cinnamyl aldehydes only. Each of the respective genes is present as one or
      two copies. The MsaCad1 gene is expressed most actively in stem and floral
      tissue, whereas MsaCad2 is most actively expressed in stem, hypocotyl and root
      tissue. In stem tissue, expression of both genes occurs predominantly in
      internodes 4 and 5 (from the apex). MsaCad2, in contrast to MsaCad1, is not
      significantly expressed in the top three internodes of the stem. Both MsaCad1 and
      MsaCad2 are wound-inducible, and the wound-responsiveness of each gene is
      modulated by salicylic acid.

PMID- 10579495
TI  - Unraveling the association between chronic widespread pain and psychological
      distress: an epidemiological approach.

PMID- 10579496
TI  - Frequent consulters in general practice: a systematic review of studies of
      prevalence, associations and outcome.
AB  - We conducted a systematic review of the observational literature on frequent
      consulters in general practice. Electronic searching identified 34 studies which
      met our inclusion criteria. Frequent consulters were identified in a wide range
      of primary health care settings, confirming that a small proportion of patients
      is responsible for a disproportionate number of consultations. A cutoff of 9-14
      consultations per annum was used to define a frequent consulter in most studies.
      Studies have examined a variety of associated characteristics, and indicate that
      frequent consulters are highly heterogeneous, and have high rates of physical
      disease, psychiatric illness and social difficulties. Few are likely to conform
      to the "heartsink" stereotype. These patients are likely to have multiple,
      complex problems, often including chronic physical disease, with or without
      psychological and social problems. The natural history of frequent consulting
      behavior seems to be to persist in many cases. Implications for management are
      discussed.

PMID- 10579497
TI  - A systematic review of the treatment of depression with antidepressant drugs in
      patients who also have a physical illness.
AB  - To determine whether antidepressants are clinically effective and acceptable for
      the treatment of depression in people who also have a physical illness. The
      method used was a systematic review of all randomised controlled trials (found by
      computer and hand searches) comparing any antidepressant drug with placebo or no
      treatment, in depressed adults with a specified physical disorder. The main
      outcome measures are numbers of individuals who recover/improve at the end of the
      trial and, as a proxy for treatment acceptability, numbers who complete
      treatment. 18 studies were included, covering 838 patients with a range of
      physical diseases. 6 studies used SSRIs, 3 atypical antidepressants, and the
      remainder tricyclics. Patients treated with antidepressants were significantly
      more likely to improve than those given placebo: about 4 patients would need to
      be treated with antidepressants to produce one recovery from depression which
      would not have occurred had they been given placebo (NNT 4.2, 95% CI 3.2-6.4).
      Most antidepressants (tricyclics and SSRIs together, 15 trials) produced a small
      but significant increase in dropout (OR 1.66, 95% CI 1.14-2.40. NNH 9.8, 95% CI
      5.4-42.9). The "atypical" antidepressant mianserin produced significantly less
      dropout than placebo. Trends towards tricyclics being more effective than SSRIs,
      but also more likely to produce dropout were noted. The review provides evidence
      that antidepressants, significantly more frequently than either placebo or no
      treatment, cause improvement in depression in patients with a wide range of
      physical diseases.

PMID- 10579498
TI  - Relations between anxiety sensitivity and dimensions of alexithymia in a young
      adult sample.
AB  - This study was conducted to assess the relations between anxiety sensitivity (AS)
      and dimensions of alexithymia in a nonclinical sample. We also sought to
      determine whether these relations persist after controlling for trait anxiety
      levels and panic attack history, and after controlling for item redundancy
      between the Anxiety Sensitivity Index (ASI) and the 20-item Toronto Alexithymia
      Scale (TAS-20). A sample of 238 undergraduate students completed the ASI, the TAS
      20, and measures of trait anxiety and panic. A group of high AS participants
      (n=36) was found to have a significantly higher TAS-20 total score than a group
      of low AS participants (n=41), both before and after conceptually redundant TAS
      20 items were removed. ASI scores were found to be significantly positively
      correlated with scores on the two TAS-20 subscales suspected of sharing a
      functional relation with AS (i.e., difficulty identifying emotions; difficulty
      describing emotions), whereas ASI scores were not significantly correlated with
      scores on the TAS-20 subscale believed to be functionally unrelated to AS (i.e.,
      external-oriented thinking). This pattern of correlations between ASI scores and
      alexithymia dimensions persisted following the removal of conceptually redundant
      TAS-20 items, suggesting that the relation between AS and alexithymia is not
      merely an artifact of item redundancy. ASI scores remained significantly
      correlated with scores on the TAS-20's difficulty identifying emotions subscale,
      and marginally correlated with scores on the TAS-20's difficulty describing
      emotions subscale, after accounting for the influences of trait anxiety and panic
      history. The results also revealed that individuals who both experience frequent
      anxiety and who greatly fear their anxiety symptoms report the greatest
      difficulties identifying and describing emotional states. Implications for
      understanding the alexithymia construct, as well as potential clinical
      implications of the findings, are discussed.

PMID- 10579499
TI  - The relationship between stress and health care use: an investigation of the
      buffering roles of personality, social support and exercise.
AB  - The main and interactive effects of social support, physical exercise, and
      personal hardiness on objective measures of health were investigated using a
      longitudinal research design. Data were collected from 192 working adults.
      Results showed main effects for hardiness and exercise on the dependent variables
      of health care costs and the number of health insurance claims filed. Hardiness
      appeared to be associated with fewer health problems. Contrary to prediction,
      those who exercised more appeared to have greater health care use. Three-way
      interactions suggested that health care use was lowest for those high in all
      three resistance resources: exercise: hardiness: and social support. But, the
      converse of this reasoning, that absence of these resources is associated with
      higher levels of illness, was not entirely supported. The interactions suggested
      that hardiness in the absence of exercise and social support was associated with
      the highest health care costs. The highest number of claims was apparent for
      those exhibiting hardiness and exercise. Thus, the presence of exercise,
      hardiness, and social support seemed to decrease health care use, but the factors
      contributing to greater health costs and claims were more complicated to
      interpret.

PMID- 10579500
TI  - Coping with coronary heart disease: a longitudinal study.
AB  - This longitudinal study evaluated the effects of two types of coping strategies,
      approach and avoidance, on anxiety, depression, and well-being in patients with
      coronary heart disease. Measurements were made at three timepoints: 1 month, 3
      months, and 12 months after the cardiac event. Both cross-sectional and
      longitudinal relations were explored. At all three measurement points significant
      negative cross-sectional relations were found between approach and well-being,
      and significant positive cross-sectional relations were found between approach,
      on the one hand, and anxiety and depression, on the other. At the first
      measurement point, avoidance showed a positive association with well-being, and a
      negative association with anxiety. Longitudinal analyses, however, revealed a
      negative relationship between approach at the first measurement points and
      anxiety and depression at later measurement points. Likewise, there was a
      positive association between approach at the first two measurement points and
      well-being at later measurement points. The results of this study demonstrate the
      importance of facing and working through the trauma of the coronary event.
      Although unfavorable in the short term, working through the trauma can attenuate
      long-term emotional distress. These results suggest that assessment of the
      psychological consequences of coronary heart disease and development of
      interventions should not be based only on cross-sectional data, but should take
      into account longitudinal relations between coping and psychosocial outcome
      measures.

PMID- 10579501
TI  - Psychogenic chemical sensitivity: psychogenic pseudoseizures elicited by
      provocation challenges with fragrances.
AB  - A middle-aged woman with a 10-year history of disability attributed to chemical
      sensitivities complained that exposure to specific fragrances immediately
      elicited seizures. Video-EEG monitoring was performed in a hospital
      neurodiagnostic laboratory during provocative challenge studies employing
      fragrances identified by the patient as reliably inducing symptoms. The baseline
      clinical EEG was normal. Immediately after each provocation with air deodorant
      and perfume, she consistently showed both generalized tonic/clonic and multifocal
      myoclonic jerking, at times was nonresponsive, spoke with slurred speech, and
      complained of right-sided paralysis and lethargy. None of these events were
      associated with any EEG abnormalities. Psychological assessment (MMPI-2, MCMI-II)
      revealed personality traits that predisposed her to somatization and beliefs
      about environmental sensitivities. The convulsions were a manifestation of
      psychogenic pseudoseizures that had been iatrogenically reinforced.

PMID- 10579502
TI  - Comparison of different methods for the isolation and purification of total
      community DNA from soil.
AB  - The efficiency and reproducibility of DNA extraction from soil was tested for
      variations in lytic and purification treatments and their effect on yield and
      purity of DNA. The extraction yield was improved by increasing the concentration
      of EDTA or monovalent ions in isolation buffers, by the introduction of
      mechanical lysis treatments, and by the use of ethanol precipitation in place of
      PEG precipitation. Purity was improved using buffers with decreasing
      concentration of EDTA or by reducing the ionic strength of the buffer, and by all
      mechanical treatments. No lytic treatment was efficient on its own, the highest
      purity was achieved using Crombach buffer and a combination of bead-beating with
      lysozyme and SDS lysis followed by potassium acetate and PEG precipitation,
      phenol/chloroform purification, isopropanol precipitation, and spermine-HCl
      precipitation. Sonication sheared the DNA more than bead-beating. Lysozyme and
      SDS lysis without any mechanical treatments allowed isolation of larger fragments
      (40-90 kb). Denaturing gradient gel electrophoresis analysis of DNA isolated
      using a range of lytic treatments revealed alterations in band patterns which
      might reflect differences in the efficiency of lytic treatments.

PMID- 10579503
TI  - A novel staining method for detecting phytase activity.
AB  - Differential agar media for the detection of microbial phytase activity use the
      disappearance of precipitated calcium or sodium phytate as an indication of
      enzyme activity. When this technique was applied to the study of ruminal
      bacteria, it became apparent that the method was unable to differentiate between
      phytase activity and acid production. Strong positive reactions (zones of
      clearing around microbial colonies) observed for acid producing, anaerobic
      bacteria, such as Streptococcus bovis, were not corroborated by subsequent
      quantitative assays. Experimentation revealed that acidic solutions generated
      false positive results on the selected differential medium. Empirical studies
      undertaken to find a solution to this limitation determined the false positive
      results could be eliminated through a two step counterstaining treatment (cobalt
      chloride and ammonium molybdate/ammonium vanadate) which reprecipitates acid
      solubilized phytate. This report discusses the application of the developed two
      step counterstaining treatment for the screening of phytase producing ruminal
      bacteria as well as its use in phytase zymogram assays.

PMID- 10579504
TI  - An evaluated improvement of the extinction dilution method for isolation of
      ammonia-oxidizing bacteria.
AB  - An improved method for isolation of ammonia-oxidizing bacteria (AOB) by the
      extinction dilution technique is described. It is important to prevent the growth
      of heterotrophic organisms, which may easily outnumber the AOB in mixed cultures.
      This was achieved by careful elimination of C sources in the medium and by
      sealing the cultures from contact with the atmosphere, thus excluding air-borne,
      volatile compounds which support growth of heterotrophs. The sealing of the
      cultures reduced the number of heterotrophs by a factor of 10, thus grossly
      increasing the chances of obtaining pure AOB cultures. Another important factor
      is to use actively growing 'late log' cultures during the final isolation step.
      This was achieved by adjusting the buffer capacity to ensure a clearly visible pH
      indicator shift at a stage when one-third to one-half of the ammonia had been
      oxidized. By this improved isolation procedure, AOB were isolated from three
      different locations: an arable soil, a lead-contaminated soil and an animal
      house. For an unknown reason, several attempts to isolate pure cultures from a
      forest soil were unsuccessful, despite the presence of AOB in the primary
      extinction dilution cultures. The isolates from soils were all Nitrosospira spp.
      For isolation of AOB from the animal house, two growth media were used, one
      containing ammonium sulfate, and one containing urea. From the cultures with
      ammonium sulfate, Nitrosomonas spp. were isolated, whereas Nitrosospira spp. were
      isolated from the cultures with urea as the main ammonia source. The
      identifications of all isolates are based on morphology and 16S rDNA sequences.

PMID- 10579505
TI  - Isolation and detection of Listeria spp, Salmonella spp and Yersinia spp using a
      simultaneous enrichment step followed by a surface adhesion immunofluorescent
      technique.
AB  - The use of a rapid surface adhesion immunofluorescent (SAIF) technique for the
      isolation of three pathogens using a single enrichment step from broth and
      enriched meat cultures was investigated. Buffered peptone water (BPW, 225 ml) was
      inoculated with Listeria monocytogenes, Salmonella enteritidis and Yersinia
      enterocolitica to a level of 10 cfu ml(-1) and incubated overnight at 30 degrees
      C. Minced beef samples (25 g) were inoculated with the three pathogens to a level
      of 100 cfu g(-1) and incubated overnight at 30 degrees C in BPW (225 ml).
      Pathogens were isolated by surface adhesion to a polycarbonate membrane which was
      immersed in the enriched culture. The pathogens were detected using membrane
      counts (rinse and immunofluorescent) and standard plate counts. It was noted that
      the attachment of the three pathogens to the membrane was considerably enhanced
      when compared with single inoculum experiments and the reasons and implications
      of this for the rapid method are discussed. A small selection of naturally
      contaminated retail samples (n = 60) was tested for the presence of L.
      monocytogenes and S. enteritidis using a simultaneous enrichment step with SAIF
      detection and a standard cultural method of detection. A good correlation was
      found between both methods for L. monocytogenes (r2 = 0.91, RSD = 0.26) and S.
      enteritidis (r2 = 0.89, RSD = 0.28). This indicates that simultaneous analysis of
      these two pathogens could be carried out using the SAIF assay.

PMID- 10579506
TI  - A simple and rapid serum bactericidal assay and its evaluation in clinical
      isolates of Klebsiella pneumoniae.
AB  - A simple and rapid assay for the determination of serum bactericidal activity was
      developed and evaluated in 125 clinical isolates of Klebsiella pneumoniae. The
      serum reactivity against these isolates was concomitantly determined by the
      conventional viable count technique in order to compare the efficacy of the two
      techniques. The rapid assay could be completed within 5-8 h and the results were
      recorded in terms of visible change of colour of the culture medium. Of the 125
      strains tested, more than 50% were found to be resistant to 20% normal human
      serum. There was an excellent agreement between the two methods. The degree of
      discordance observed in the results obtained by the two methods was statistically
      not significant (P>0.05). The conventional technique is labor intensive,
      cumbersome and time-consuming. The assay described here, on the other hand, is
      simple, easy and rapid enough to allow testing of a large number of bacterial
      isolates or recombinant clones in a single day. Thus, the assay can serve as an
      excellent alternative to the conventional technique for determining the bacterial
      serum susceptibility.

PMID- 10579507
TI  - Acid phosphatase activity as a measure of Haemophilus influenzae adherence to
      mucin.
AB  - Haemophilus influenzae is an important respiratory tract pathogen. Toward
      understanding the progression of H. influenzae from commensal to pathogen, we
      need to understand the steps of colonization and infection, processes which must
      involve overcoming the normal host mucociliary clearance mechanism. A reliable
      method for the screening and quantitation of mucin-H. influenzae binding to allow
      for the assessment of the physiological variables significant to H. influenzae
      mucin interactions in the normal and diseased conditions, will provide insight on
      how to intervene to prevent, inhibit, or treat infection. The current methods for
      enumeration of mucin-bound H. influenzae are labor intensive and rely on viable
      organisms. In this report, we present a new detection method, which reduces the
      number of variables, processing steps, and time involved, providing an
      economical, rapid, and reliable means to screen for and quantitate mucin-bound H.
      influenzae. Organisms are applied to mucin-coated microtiter wells for a set
      time; nonadherent organisms are removed with gentle rinses; wells are incubated
      with the phosphomonoesterase substrate p-nitrophenyl phosphate; and the
      absorbance, reflecting phosphatase activity of the mucin-bound organisms, is read
      at 410 nm in a microtiter plate reader against enzymatic activity calibration
      curves. All nonencapsulated and encapsulated H. influenzae tested exhibited
      significant acid phosphate activity within 20 min, which provided linear
      relationships with the numbers of organisms present. H. influenzae mucin binding
      characteristics obtained by this method were generally comparable to published
      data, and ranged from 10(3) to 10(6) organisms per well, depending on both strain
      of organism and type of mucin employed. This convenient, rapid and economical
      mucin adherence assay, will enable more extensive and comprehensive studies of
      the interactions of H. influenzae adhesins and specific ligands on mucin
      macromolecules, as well as the nonspecific means by which mucins function in
      preventing bacterial infection.

PMID- 10579508
TI  - Species-specific detection of hydrocarbon-utilizing bacteria.
AB  - Rapid detection and quantitative assessment of specific microbial species in
      environmental samples is desirable for monitoring changes in ecosystems and for
      tracking natural or introduced microbial species during bioremediation of
      contaminated sites. In the interests of developing rapid tests for hydrocarbon
      degrading bacteria, species-specific PCR primer sets have been developed for
      Pseudomonas aeruginosa, Stentrophomonas (Xanthomonas) maltophilia, and Serratia
      marsescens. Highly variable regions of the 16S rRNA gene were used to design
      these primer sets. The amplification products of these primer sets have been
      verified and validated with hemi-nested PCR and with ligase chain reaction (LCR)
      techniques, and have been applied to the analyses of environmental water samples.
      These species-specific primer sets were also chosen to amplify in conjunction
      with a universal set of PCR primers chosen from highly conserved neighboring
      sequences in the same gene. These multiplex or competitive PCR procedures enable
      testing with an internal marker and/or the quantitative estimation of the
      relative proportion of the microbial community that any one of these species
      occupies. In addition, this universal PCR primer set amplified the same size
      amplicon from a wide spectrum of procaryotic and eucaryotic organisms and may
      have potential in earth biota analyses.

PMID- 10579509
TI  - Comparison of differential plating media and two chromatography techniques for
      the detection of histamine production in bacteria.
AB  - The bacterial enzyme histidine decarboxylase (Hdc) catalyses the conversion of
      histidine into histamine. This amine is essential for the biosynthesis of iron
      chelators (siderophores) and is an important cause of food poisoning after
      consumption of fish contaminated with histamine-producing bacteria. In this work
      we compared different methods for detecting histamine secreted by different
      bacterial strains. The presence of histamine in the culture supernatant of Vibrio
      anguillarum, which produces Hdc and secretes the histamine-containing siderophore
      anguibactin, was detected by thin-layer chromatography. Similar results were
      obtained using the culture supernatant of the Acinetobacter baumannii 19606
      prototype strain that secretes the histamine-containing siderophore
      acinetobactin. Conversely, histamine was not detected in the culture supernatant
      of an isogenic V. anguillarum Hdc mutant and the A. baumannii 8399 strain that
      secretes a catechol siderophore different from anguibactin and acinetobactin.
      These results were confirmed by capillary gas chromatography/mass spectrometry.
      However, all these strains tested positive for histamine secretion when cultured
      on differential plating media containing histidine and a pH indicator, which were
      specifically designed for the detection of histamine-producing bacteria. The pH
      increase of the medium surrounding the bacterial colonies was however drastically
      reduced when the histidine-containing medium was supplemented with peptone, beef
      extract, and glucose. The histidine-containing culture supernatants of the A.
      baumannii and V. anguillarum strains showed an increase of about two units of pH,
      turned purple upon the addition of cresol red, and contained high amounts of
      ammonia. Escherichia coli strains, which are Hdc negative and do not use
      histidine as a carbon, nitrogen, and energy source, gave negative results with
      the differential solid medium and produced only moderate amounts of ammonia when
      cultured in the presence of excess histidine. This study demonstrates that,
      although more laborious and requiring some expensive equipment, thin-layer and
      gas chromatography/mass spectrometry are more accurate than differential media
      for detecting bacterial histamine secretion. The results obtained with these
      analytical methods are not affected by byproducts such as ammonia, which are
      generated during the degradation of histidine and produce false positive results
      with the differential plating media.

PMID- 10579510
TI  - A method for the determination of pyruvate carboxylase activity during the
      glutamic acid fermentation with Corynebacterium glutamicum.
AB  - A discontinuous lactate dehydrogenase coupled assay is described for the
      evaluation of the pyruvate carboxylase activity (Pc, EC 6.4.1.1) in a glutamate
      overproducing strain of Corynebacterium glutamicum. After an initial
      permeabilisation period of the cells, the method consisted of the fluorometric
      determination of the remaining pyruvate level after transformation into
      oxaloacetate by the endogenous Pc. The assay was demonstrated to be powerful and
      enabled the determination of the C. glutamicum Pc activity grown on different
      carbon sources. Besides, this method was used to assay Pc activity in C.
      glutamicum 2262 during a temperature triggered glutamate producing process with
      biotin excess or limitation.

PMID- 10579511
TI  - Object-oriented biomedical system modelling--the language.
AB  - The paper describes a new object-oriented biomedical continuous system modelling
      language (OOBSML). It is fully object-oriented and supports model inheritance,
      encapsulation, and model component instantiation and behaviour polymorphism.
      Besides the traditional differential and algebraic equation expressions the
      language includes also formal expressions for documenting models and defining
      model quantity types and quantity units. It supports explicit definition of model
      input-, output- and state quantities, model components and component connections.
      The OOBSML model compiler produces self-contained, independent, executable model
      components that can be instantiated and used within other OOBSML models and/or
      stored within model and model component libraries. In this way complex models can
      be structured as multilevel, multi-component model hierarchies. Technically the
      model components produced by the OOBSML compiler are executable computer code
      objects based on distributed object and object request broker technology. This
      paper includes both the language tutorial and the formal language syntax and
      semantic description.

PMID- 10579512
TI  - Context related artefact detection in prolonged EEG recordings.
AB  - The need for reliable detection of artefacts in raw and processed EEG is widely
      acknowledged. Although different EEG analysis systems have been described, only
      few general applicable artefact recognition techniques have emerged. This paper
      tackles the problem of artefact detection in seven 24 h EEG recordings in the
      intensive care unit. ICU recordings have received less attention than, e.g.
      epilepsy monitoring, although recordings in this environment present an
      interesting application area. The EEG data used here was recorded during the
      difficult circumstances of an explorative ICU study. The data set includes a
      diverse set of EEG patterns, as well as EEG artefacts. The study investigates
      objective artefact detection methods based on statistical differences between
      signal parameters, using time-varying autoregressive modelling (AR) and Slope
      detection. In addition to matching the performance of artefact detection against
      two human observers, the study focuses on the optimal settings for context
      incorporation by testing the algorithms for different time windows and epoch
      lengths. Results indicate that a relatively short period (20-40 s) provides
      sufficient context information for the methods used. The combined AR and Slope
      detection parameters yielded good performance, detecting approximately 90% of the
      artefacts as indicated by the consensus score of the human observers.

PMID- 10579513
TI  - The analysis of heart rate variability in unrestrained rats. Validation of method
      and results.
AB  - An experimental setting and software were developed to evaluate cardiac autonomic
      function in unrestrained rats. Subcutaneously implanted ECG electrodes and an
      indwelling venous catheter were tunneled to a tail cuff in five rats. The ECG was
      A/D converted at 1000 Hz. After peak detection, a time series of RR intervals was
      obtained. Programs for the analysis of heart rate variability (HRV) were
      implemented in LabVIEW. Statistical properties were determined in the time
      domain. After cubic spline function curve fitting, resampling at 0.1 s and test
      for stationarity, power spectral analysis was performed on sampled records of 30
      min duration after applying a sliding Hanning window (Welch method: 256 points
      (duration 25.6 s), 50% overlap and 0.039 Hz resolution). Algorithms were tested
      with simulated signals consisting of isolated frequency components, which were
      retrieved at their exact locations. Physiological validation of the system was
      performed by, beta-adrenergic and cholinergic blockade and by forced breathing at
      a fixed rate. Measurements were performed on five unrestrained rats under basal
      conditions. Mean RR was 174.2 +/- 3.6 ms; S.D., 13.3 +/- 4.6 ms; rMSSD, 5.2 + /-
      1.2 ms; pNN10, 3.5 +/- 1.9% and pNN5, 18.7 +/- 6.4%. Low (0.19-0.74 Hz) and high
      frequency (0.78-2.5 Hz) power were determined (and also percent of low to total
      and high to total): 18.42 +/- 10.74 ms2 (22.9 +/- 6.5%) and 15.66 +/- 5.56 ms2
      (19.9 +/- 2.7%), and the ratio low/high: 1.16 +/- 0.39. In conclusion, HRV
      analysis programs were developed and thoroughly tested through simulations and in
      vivo, under basal conditions and after pharmacological blockades. Using this
      software, HRV data from unrestrained rats were obtained.

PMID- 10579514
TI  - Telecommunication technology for the management of large scale clinical trials:
      the Gissi experience.
AB  - The Coordinating Centre (CC) of the Gruppo Italiano per lo Studio della
      Sopravvivenza nell'Infarto miocardico (GISSI) used telecommunication technology
      to develop a computerized network system for the data management of the GISSI
      studies. Through a personal computer (PC), a communication program, a modem and a
      telephone line, the investigator in each participating centre can connect with a
      micro-computer at the CC, to recruit/randomize patients and download reports on
      the progress of the trial. In the first case, the investigator is required to
      answer a set of predefined questions, and thereby the system automatically checks
      eligibility criteria and randomly assigns the patient to a treatment arm. In the
      second case, once the investigator has made a choice from a list of standard
      reports and the relative query on CC central database, the generation, the
      formatting and the transfer of the selected report to the PC are executed
      automatically on line. The main advantages of this system are a reduction in
      number of mistakes in data completion and in the human and economic resources
      required, as well as the real time updating of participating centres. The system
      was successfully adopted in the GISSI-3 trial (200 Coronary Care Units and 19,394
      patients enrolled), in the European arm of the CORE trial and it is currently
      being used in the GISSI-Prevenzione trial.

PMID- 10579515
TI  - PHMPL: a computer program for hazard estimation using a penalized likelihood
      method with interval-censored and left-truncated data.
AB  - The Cox model is the model of choice when analyzing right-censored and possibly
      left-truncated survival data. The present paper proposes a program to estimate
      the hazard function in a proportional hazards model and also to treat more
      complex observation schemes involving general censored and left-truncated data.
      The hazard function estimator is defined non-parametrically as the function which
      maximizes a penalized likelihood, and the solution is approximated using splines.
      The smoothing parameter is chosen using approximate cross-validation. Confidence
      bands for the estimator are given. As an illustration, the age-specific incidence
      of dementia is estimated and one of its risk factors is studied.

PMID- 10579516
TI  - Recombinant microbial lipases for biotechnological applications.
AB  - Lipases, mainly of microbial origin, represent the most widely used class of
      enzymes in biotechnological applications and organic chemistry. Modern methods of
      genetic engineering combined with an increasing knowledge of structure and
      function will allow further adaptation to industrial needs and exploration of
      novel applications. Production of such tailored lipases requires their functional
      overexpression in a suitable host. Hence, this article describes the functional
      heterologous production of commercially important microbial lipases. Based on the
      knowledge of different lipases' substrate binding sites, the most suitable lipase
      for a particular application may be selected.

PMID- 10579517
TI  - Purification and characterization of extracellular lipases from Ophiostoma
      piliferum.
AB  - Interest in lipases from microorganisms, animals, and plants has greatly
      increased in the past decade due to their applications in biotransformations and
      organic syntheses. We are reporting the purification and characterization of two
      lipases from the fungus, Ophiostoma piliferum, a saprophytic organism commonly
      found on wood. A major and a minor lipase have been co-purified by hydrophobic
      interaction chromatography on octyl sepharose FF, followed by ion exchange
      chromatography on Q sepharose FF. The lipases bound very tightly to octyl
      sepharose resulting in greater than 100-fold purification in this one step. The
      major lipase has a molecular weight of approximately 60 kDa, a pI of 3.79, and is
      glycosylated as determined by PAS staining. The minor lipase, which composes 10%
      of the total protein, has a pI of 3.6, and molecular weight of approximately 52
      kDa and did not stain with the PAS reagent. Deglycosylation of the major lipase
      produced two proteins of lower molecular weight, a 55 kDa protein and a 52 kDa
      protein. The deglycosylated protein at 52 kDa co-migrates with the minor lipase
      on SDS-PAGE gels. N-terminal amino acid sequencing of the major and minor lipases
      indicated both lipases have the same N-termini and MALDI-TOF mass spectral
      analysis showed similar peptide patterns. Available data indicate that the
      lipases are derived from the same protein and appear to differ in their post
      translational modification as evidenced by their pIs and molecular weight
      difference. The pH rate profile and thermal stability were determined for the
      purified O. piliferum lipase and were consistent with a mesophilic lipase. In
      aqueous solution, the lipases exhibited a higher rate of hydrolysis for p
      nitrophenylbutyrate (C4) than for p-nitrophenylstearate (C18), which is an
      unexpected result.

PMID- 10579518
TI  - Incremental truncation as a strategy in the engineering of novel biocatalysts.
AB  - The application and success of combinatorial approaches to protein engineering
      problems have increased dramatically. However, current directed evolution
      strategies lack a combinatorial methodology for creating libraries of hybrid
      enzymes which lack high homology or for creating libraries of highly homologous
      genes with fusions at regions of non-identity. To create such hybrid enzyme
      libraries, we have developed a series of combinatorial approaches that utilize
      the incremental truncation of genes, gene fragments or gene libraries. For
      incremental truncation, Exonuclease III is used to create a library of all
      possible single base-pair deletions of a given piece of DNA. Incremental
      truncation libraries (ITLs) have applications in protein engineering as well as
      protein folding, enzyme evolution, and the chemical synthesis of proteins. In
      addition, we are developing a methodology of DNA shuffling which is independent
      of DNA sequence homology.

PMID- 10579519
TI  - Polyamino acids as catalysts in asymmetric synthesis.
AB  - The use of polyamino acids in asymmetric organic synthesis is reviewed.
      Particular emphasis is placed on the asymmetric epoxidation of alpha,beta
      unsaturated ketones with hydrogen peroxide in the presence of polyalanine or
      polyleucine, and further transformations of the epoxide products.

PMID- 10579520
TI  - Biocatalytic combinatorial synthesis.
AB  - Combinatorial biocatalysis, based on a principle of the combinatorial use of
      biosynthetic steps rather than the combinatorial use of reagents, offers a
      complementary approach to combinatorial chemistry, which, used individually or in
      connection with synthetic organic transformations, provides access to analogues
      not readily accessible by chemical synthetic means alone. The issues and
      strategies particular to this approach are discussed. Examples are given
      demonstrating these principles as well as the unique advantages of achieving
      chemo-, regio- and stereoselectivity under mild reaction conditions that
      biocatalytic methods offer.

PMID- 10579521
TI  - Novel screening methods--the key to cloning commercially successful biocatalysts.
AB  - Providing sufficient biocatalyst to support the demands of multi tonne product
      supply can be problematical. Here we describe how screening for and cloning a
      gamma-lactamase overcame biocatalyst supply issues, and greatly improved the
      actual biocatalytic process. The isolation of an expressing gamma-lactamase clone
      from a gene library necessitated a combination of classical molecular biology
      techniques together with innovative screening methods to identify a functional
      clone. Once isolated the enzyme was characterised with regard to its process
      performance and proved to be active at 500 g L(-1) substrate. Further development
      of the recombinant fermentation and downstream processing has resulted in the
      ability to produce sufficient biocatalyst from one 5001 fermentation to resolve 5
      metric tonnes of (+/-)-lactam, whilst simplifying the process chemistry greatly.

PMID- 10579522
TI  - Directed evolution of an esterase: screening of enzyme libraries based on pH
      indicators and a growth assay.
AB  - In order to resolve a sterically hindered 3-hydroxy ethyl ester, which was not
      accepted as substrate by 20 wild-type hydrolases, a directed evolution of an
      esterase from Pseudomonas fluorescens (PFE) was performed. Mutations were
      introduced using the mutator strain Epicurian coli XL1-Red. Enzyme libraries
      derived from seven mutation cycles were assayed on minimal media agar plates
      supplemented with pH indicators (neutral red and crystal violet), thus allowing
      the identification of active esterase variants by the formation of a red color
      caused by a pH decrease due to the released acid. A further selection criteria
      was introduced by using the corresponding glycerol estar, because release of the
      carbon source glycerol facilitates growth on minimal media. By this strategy, one
      double mutant (A209D and L181V) of PFE was identified, which hydrolyzed the 3
      hydroxy ethyl ester in a stereoselective manner (25% ee for the remaining ester,
      E approximate to 5).

PMID- 10579523
TI  - In vivo screening of haloalkane dehalogenase mutants.
AB  - Haloalkane dehalogenase (Dh1A) from Xanthobacter autotrophicus GJ10 catalyzes the
      dehalogenation of short chain primary alkyl halides. Due to the high Km and low
      turnover, wild type Dh1A is not optimal for applications in bioremediation. We
      have developed an in vivo screen, based on a colorimetric pH indicator, to
      identify Dh1A mutant with improved catalytic activity. After screening 50,000
      colonies, we identified a Dh1A mutant with a lower pH optimum. Sequence analysis
      of the mutant revealed a single substitution, alanine 149 to threonine, which is
      located close to the active site of Dh1A. Replacement of alanine 149 via site
      directed mutagenesis with threonine, serine or cysteine retained the mutant
      phenotype. Other substitutions at position 149 show little or no activity.

PMID- 10579524
TI  - Visualization of enzyme-catalyzed reactions using pH indicators: rapid screening
      of hydrolase libraries and estimation of the enantioselectivity.
AB  - The use of pH indicators to monitor hydrolase-catalyzed reactions is described.
      The formation of acid following an enzyme-mediated hydrolysis causes a drop in
      the pH that can be visualized by a change in the color of the indicator
      containing solution. The best indicators are those showing a color transition
      within the operational pH range of the hydrolases, like bromothymol blue and
      phenol red. The enantioselectivity of lipases and esterases can be estimated
      using single isomers under the same conditions and comparing the color turnover
      for each one. The method has been tested to quickly evaluate the
      enantioselectivity of a lipase towards a set of ester substrates and applied to
      the hierarchical screening of a library of thermophilic esterases.

PMID- 10579525
TI  - Non-conventional hydrolase chemistry: amide and carbamate bond formation
      catalyzed by lipases.
AB  - Biocatalysis in nonaqueous media is becoming increasingly important in organic
      synthesis. Lipases are the most used enzymes, especially in transesterification
      reactions. However, in the last years the amidation reaction catalyzed by lipases
      has also been shown to be a useful tool for the organic chemists. In this review,
      we discuss the possibilities of the enzymatic aminolysis and ammonolysis
      reactions for the preparation of different amides and for the resolution of
      esters, amines and aminoalcohols. The enzymatic alkoxycarbonylation of amines
      opens a new way for the synthesis of chiral carbamates.

PMID- 10579526
TI  - An enzymatic synthesis of glucuronides of azetidinone-based cholesterol
      absorption inhibitors.
AB  - Two derivatives, 1 and 3, of a novel cholesterol absorption inhibitor, Sch 58235,
      were glucuronidated with the help of glucuronyl transferases derived from bovine
      and dog liver microsomes. An efficient procedure for the iodination of 4 was
      developed on an analytical scale to be used for the preparation of a 125I-labeled
      radioactive glucuronide 5.

PMID- 10579527
TI  - Continuous indirect electrochemical regeneration of galactose oxidase.
AB  - The development of an indirect anaerobic electrochemical regeneration of
      galactose oxidase (GOase) allows the prevention of the undesired production of
      the enzyme inhibitor hydrogen peroxide, which is generated under aerobic
      regeneration conditions during synthetic applications of GOase. The pH optimum
      for the electrochemical regeneration of GOase with polyethyleneglycol-modified
      ferrocene mediators in carbonate buffer is 10.8. Total turnover numbers achieved
      by either electrochemical or aerobic regeneration of GOase are almost the same.
      The electrochemical regeneration is half as fast as the aerobic regeneration. It
      is not necessary to work under anaerobic conditions, because at pH 10.8 the
      aerobic regeneration of GOase is prevented. The enzyme can be stabilized most
      effectively by immobilization on an aminopropylated polysiloxane (DELOXAN) via
      the glutaric dialdehyde procedure with good activity yields up to 37%. Buffers
      containing amino groups proved to be fatal for long-term GOase stability.

PMID- 10579528
TI  - Engineering of a novel biochemical pathway for the biosynthesis of L-2
      aminobutyric acid in Escherichia coli K12.
AB  - L-2-Aminobutyric acid was synthesised in a transamination reaction from L
      threonine and L-aspartic acid as substrates in a whole cell biotransformation
      using recombinant Escherichia coli K12. The cells contained the cloned genes
      tyrB, ilvA and alsS which respectively encode tyrosine aminotransferase of E.
      coli, threonine deaminase of E. coli and alpha-acetolactate synthase of B.
      subtilis 168. The 2-aminobutyric acid was produced by the action of the
      aminotransferase on 2-ketobutyrate and L-aspartate. The 2-ketobutyrate is
      generated in situ from L-threonine by the action of the deaminase, and the
      pyruvate by-product is eliminated by the acetolactate synthase. The concerted
      action of the three enzymes offers significant yield and purity advantages over
      the process using the transaminase alone with an eight to tenfold increase in the
      ratio of product to the major impurity.

PMID- 10579529
TI  - Genetic engineering of Escherichia coli for the production of precorrin-3 in vivo
      and in vitro.
AB  - The construction of a new recombinant strain of Escherichia coli in which two
      vitamin B12 biosynthetic genes, cobA and cobI, from Pseudomonas denitrificans are
      simultaneously overexpressed has resulted in the in vivo synthesis and
      accumulation of Factor III, an isobacteriochlorin not normally synthesized in E.
      coli. A lysate of the new strain can take the place of two lysates normally
      required to provide uroporphyrinogen III methyltransferase (cobA) and precorrin-2
      methyltransferase (cobI) in an anaerobic five-enzyme synthesis of the early B12
      intermediate, precorrin-3 (the reduced form of Factor III) from delta
      aminolevulinic acid.

PMID- 10579530
TI  - Use of enzyme penicillin acylase in selective amidation/amide hydrolysis to
      resolve ethyl 3-amino-4-pentynoate isomers.
AB  - The beta-amino acid, (S)-ethyl-3-amino-4-pentynoate, is a chiral synthon used in
      the synthesis of xemilofiban hydrochloride, an anti-platelet agent. A
      biocatalytic approach was developed to resolve (R)- and (S)-enantiomers of ethyl
      3-amino-4-pentynoate in enantiomerically pure form employing the enzyme
      Penicillin acylase. In the acylation, phenylacetic acid was used as an acylating
      agent. We have shown that both the acylation and deacylation can be employed and
      that the activity of the enzyme Penicillin acylase can be controlled by
      maintaining an appropriate pH of the reaction medium.

PMID- 10579532
TI  - 5-Cyanovaleramide production using immobilized Pseudomonas chlororaphis B23.
AB  - A biocatalytic process for the hydration of adiponitrile to 5-cyanovaleramide has
      been developed which can be run to higher conversion, produces more product per
      weight of catalyst, and generates significantly less waste products than
      alternate chemical processes. The biocatalyst consists of Pseudomonas
      chlororaphis B23 microbial cells immobilized in calcium alginate beads. The cells
      contain a nitrile hydratase (EC 4.2.1.84) which catalyzes the hydration of
      adiponitrile to 5-cyanovaleramide with high regioselectivity, and with less than
      5% selectivity to byproduct adipamide. Fifty-eight consecutive batch reactions
      with biocatalyst recycle were run to convert a total of 12.7 metric tons of
      adiponitrile to 5-cyanovaleramide. At 97% adiponitrile conversion, the yield of 5
      cyanovaleramide was 13.6 metric tons (93% yield, 96% selectivity), and the total
      weight of 5-cyanovaleramide produced per weight of catalyst was 3150 kg/kg (dry
      cell weight).

PMID- 10579531
TI  - Crosslinking of imprinted proteases to maintain a tailor-made substrate
      selectivity in aqueous solutions.
AB  - A covalent method to keep imprinted properties of proteins stable in aqueous as
      well as in organic environment is described. To stabilize the ligand induced
      acceptance for D-configured substrates by alpha-chymotrypsin or subtilisin
      Carlsberg, each protein was first vinylated by acylation with itaconic anhydride.
      Then, the tailoring of the derivatized proteins by precipitation in the presence
      of N-acetyl-D-tryptophan from an aqueous medium with 1-propanol, and the
      subsequent crosslinking of the enzyme preparations with ethylene glycol
      dimethacrylate in cyclohexane was carried out. The crosslinked imprinted proteins
      (CLIPs) obtained catalyzed the hydrolysis of N-acetyl-D-tryptophan ethyl ester in
      phosphate buffer and the corresponding back reaction in cyclohexane,
      respectively. The repeated use of CLIP-alpha-chymotrypsin in D-ester hydrolysis
      was demonstrated. Furthermore, this particular CLIP-alpha-chymotrypsin showed no
      loss in activity when it subsequently was used in the synthesis of N-acetyl-D
      tryptophan ethyl ester in cyclohexane again. In the case of D-ester hydrolysis
      the reaction rate acceleration (k(enz)/k(nonenz)) was in the same order of
      magnitude of about 10(4)-10(5) mM(-1) for the two CLIP-proteases. The results
      suggest that enzymes tailored by imprinting technique do not lose their induced
      "new" property in the presence of water when they are prepared according to the
      described vinylation/crosslinking method (CLIP technique).

PMID- 10579533
TI  - Enzymatic synthesis of L-6-hydroxynorleucine.
AB  - L-6-Hydroxynorleucine, a key chiral intermediate used for synthesis of a
      vasopeptidase inhibitor, was prepared in 89% yield and > 99% optical purity by
      reductive amination of 2-keto-6-hydroxyhexanoic acid using glutamate
      dehydrogenase from beef liver. In an alternate process, racemic 6
      hydroxynorleucine produced by hydrolysis of 5-(4-hydroxybutyl)hydantoin was
      treated with D-amino acid oxidase to prepare a mixture containing 2-keto-6
      hydroxyhexanoic acid and L-6-hydroxynorleucine followed by the reductive
      amination procedure to convert the mixture entirely to L-6-hydroxynorleucine,
      with yields of 91 to 97% and optical purities of > 99%.

PMID- 10579534
TI  - Commercial scale biocatalysis: myths and realities.
AB  - The unique ways in which enzymes are differentiated from other catalysts
      translate into special advantages. Understanding these advantages is the key
      toward better matching of biocatalysts needs in industrial chemistry. Specific
      cases where enzymes and biotransformations have been used successfully at the
      production scale are examined, permitting the realities of using biocatalysts to
      be separated from the misconceptions and myths. Five such misconceptions will be
      examined in the context of examples of some commercially-successful biocatalytic
      processes.

PMID- 10579535
TI  - Government advisory committee calls for a reduction in antibiotic use.

PMID- 10579536
TI  - Detection of Mycoplasma mycoides subspecies mycoides in tissues from an outbreak
      of contagious bovine pleuropneumonia by culture, immunohistochemistry and
      polymerase chain reaction.
AB  - Postmortem observations of 37 cattle from an outbreak of contagious bovine
      pleuropneumonia (CBPP) in north Italy in 1993 were made at the abattoir, where
      samples of lung and tracheobronchial lymph node tissues were taken for culture
      and identification of Mycoplasma mycoides subspecies mycoides (MmmSC),
      immunohistochemistry with the peroxidase anti-peroxidase (PAP) system, and
      molecular detection by the polymerase chain reaction (PCR) amplification of
      specific DNA from MmmSC. Nasal swabs were also taken for testing by PCR Lung
      pathology typical of CBPP was observed in 38 per cent of the animals, and MmmSC
      was isolated from 19 per cent DNA of MmmSC was detected by PCR in 64 per cent of
      lung samples and 35 per cent of the nasal swabs. Staining of lung tissue and
      lymph node tissue by PAP was positive in 27 per cent and 30 per cent of cases,
      respectively, and was a useful back-up test. These results suggest that PCR
      amplification from lung tissue may be used as a rapid and accurate confirmatory
      test for cases with pathology resembling CBPP.

PMID- 10579537
TI  - Rinderpest epidemic in wild ruminants in Kenya 1993-97.
AB  - A severe epidemic of rinderpest, affecting mainly wild ruminants, occurred
      between 1993 and 1997 in East Africa. Buffalo (Syncerus caffer), eland
      (Taurotragus oryx) and lesser kudu (Tragelaphus imberbis) were highly
      susceptible. The histopathological changes, notably individual epithelial cell
      necrosis with syncytia formation, were consistent with an infection with an
      epitheliotrophic virus. Serology, the polymerase chain reaction, and virus
      isolation confirmed the diagnosis and provided epidemiological information. The
      virus was related to a strain which was prevalent in Kenya in the 1960s, of a
      second lineage (II), and distinct from isolations of rinderpest virus in the
      region since 1986. The source of the virus was presumed to be infected cattle
      from the Eastern region of Kenya and Somalia. The pathogenicity of the virus
      varied during the epidemic. The mortality in buffalo populations was estimated to
      be up to 80 per cent, and population data suggested that the virus had an adverse
      effect on a wide range of species. The virus caused only a mild disease in
      cattle, with minimal mortality. The results confirmed the importance of wildlife
      as sentinels of the disease, but although wildlife were important in the spread
      of the virus, they did not appear to act as reservoirs of infection.

PMID- 10579538
TI  - Comparison of two combinations of sedatives before anaesthetising pigs with
      halothane and nitrous oxide.
AB  - Two groups of 21 three-month-old Landrace x Large White pigs were sedated with
      either azaperone (2 mg/kg), butorphanol (0.2 mg/kg) and ketamine (5 mg/kg) (group
      A), or detomidine (100 microg/kg), butorphanol (0.2 mg/kg) and ketamine (5 mg/kg)
      (group D) administered intramuscularly, before being anaesthetised with
      halothane, oxygen and nitrous oxide for a bilateral stifle arthrotomy. The pigs'
      heart rate, respiratory rate, mean arterial blood pressure, electrocardiogram,
      arterial oxygen saturation, arterial blood gases, and oesophageal and rectal
      temperature were measured while they were anaesthetised and five minutes after
      they were disconnected, and their recovery times and any complications were
      recorded. Both groups were well sedated. Their heart rate was unchanged during
      the period of anaesthesia but increased when they recovered. The respiratory
      rate, mean arterial blood pressure and rectal temperature were lower in group A
      than in group D (P<0.05). Mild respiratory acidosis developed during anaesthesia
      in both groups. Both groups recovered equally rapidly and complications were
      generally minor, though two pigs in group D appeared to develop malignant
      hyperthermia.

PMID- 10579539
TI  - A new species of Aegyptianella from south-east Asia.

PMID- 10579541
TI  - Society of veterinary assistants?

PMID- 10579540
TI  - Drug-induced euthanasia of stranded cetaceans.

PMID- 10579542
TI  - Uterine torsion in a cow.

PMID- 10579543
TI  - Effects of selegiline pretreatment on response to experimental cocaine
      administration
AB  - Several medications have been reported to alter the subjective effects of
      experimentally administered cocaine. We studied the effects of selegiline, a
      monoamine oxidase B inhibitor, on the subjective effects of experimentally
      administered cocaine in chronically cocaine-dependent subjects. Eight subjects
      completed a protocol that involved repeated administrations of cocaine before and
      after treatment with selegiline, given in extended release form, 10 mg per day.
      Four days of treatment with selegiline was associated with decreased self
      reported 'high' and 'stimulated' feelings after cocaine administration, measured
      as the area under the curve. Changes in other subjective effects were less
      pronounced. Selegiline pretreatment had minimal effects on the cardiovascular
      responses to cocaine administration.

PMID- 10579544
TI  - Serotonergic dysfunction in women with pure premenstrual dysphoric disorder: is
      the fenfluramine challenge test still relevant?
AB  - The fenfluramine (FEN) neuroendocrine challenge paradigm, which involves
      measuring the response of prolactin (PRL) release to an oral challenge dose of
      FEN, provides a means of assessing serotonin (5-HT) function. The purpose of this
      study was to ascertain the role of 5-HT in premenstrual dysphoric disorder (PMDD)
      by measuring: (1) PRL and cortisol (CORT) responses to FEN; and (2) platelet 3H
      imipramine binding levels, in females with pure PMDD (without a past or present
      comorbid mood disorder) in comparison to healthy controls. FEN challenge tests
      were administered to nine female patients with pure PMDD and nine healthy female
      controls during the follicular and late luteal phases of a menstrual cycle. There
      were no differences in the PRL response to FEN for women with PMDD compared to
      healthy controls. However, the trend toward a delayed response to FEN and a
      significant negative correlation between delta(max) PRL and basal CORT in
      patients but not in controls during both phases of the menstrual cycle suggest an
      underlying 5-HT dysfunction in patients as compared to controls. This is further
      supported by the finding of significantly lower Bmax 3H-imipramine binding levels
      in the patients during the late luteal phase.

PMID- 10579545
TI  - Effects of pregnancy and delivery on serum concentrations of Clara Cell Protein
      (CC16), an endogenous anticytokine: lower serum CC16 is related to postpartum
      depression
AB  - There is now some evidence that lower serum concentrations of Clara Cell Protein
      (CC16) are related to stress-induced anxiety, psychoses and major depression.
      This study was developed to determine whether serum CC16 is lowered in the early
      puerperium and whether Postnatal Depression and Postnatal Blues are associated
      with lower levels of serum CC16. Serum concentrations of CC16 were assayed in 17
      non-pregnant women and in 98 pregnant women before delivery and 1 and 3 days
      after delivery. On each occasion the parturients completed the State version of
      the Spielberger State-Trait Anxiety Inventory (STAI) and the Zung Depression
      Rating Scale (ZDS). Serum CC16 was significantly lower in pregnant women, at the
      end of pregnancy as well as 1 and 3 days after delivery, than in the non-pregnant
      women. Serum CC16 was somewhat, although significantly, higher 1 and 3 days after
      delivery than before delivery. Parturients who developed a postpartum depression
      had significantly lower serum CC16 concentrations than women who did not. There
      were no significant differences in serum CC16 between the puerperal women whose
      STAI or ZDS scores increased in the puerperium and those whose scores did not. It
      is concluded that in puerperal women there is a decreased anti-inflammatory
      capacity in the serum, in part caused by lowered serum CC16, and that the latter
      may be related to the development of postpartum depression.

PMID- 10579546
TI  - Elevated interleukin-6 in schizophrenia
AB  - Interleukin 6 (IL-6) levels have been shown to be increased in a number of
      autoimmune disorders and have recently been shown to be elevated in the serum of
      schizophrenic patients. Given the involvement of the CNS in schizophrenia, levels
      of interleukin-6 in the CSF are also of interest. Thus, we examined levels of
      both CSF and serum IL-6 concomitantly to determine if these levels were different
      from control values. In addition, we examined these measures in patients both on
      and off antipsychotic drugs to determine if any medication or exacerbation
      effects may account for the difference from controls. CSF IL-6 was measured by
      ELISA in 61 drug-free male schizophrenic (DSM-IIIR) patients and 25 well-screened
      healthy male control subjects. Serum IL-6 was measured in 43 of the 61 patients,
      and in 16 control subjects. Serum IL-6 was significantly higher in the
      schizophrenic patients compared to control subjects. CSF IL-6 was also higher in
      the patients, but the difference was not statistically significant. Paired data
      showed no medication or exacerbation effects on CSF IL-6, but plasma IL-6
      significantly decreased in patients that experienced an exacerbation after
      medication withdrawal. The results indicate that IL-6 levels may be altered in
      schizophrenia. The relative decrease in exacerbated patients following
      haloperidol withdrawal may be indicative of a compensatory response of plasma IL
      6 levels to relapse.

PMID- 10579547
TI  - The factor structure of schizophrenia spectrum personality disorders: signs and
      symptoms in relatives of psychotic patients from the UCLA family members study
AB  - The dimensions and limits of the concept of schizotypy are examined using an
      exploratory factor analysis of the 36 signs and symptoms in the Cluster A DSM-III
      R personality disorders as well as those in Borderline Personality Disorder and
      Avoidant Personality Disorder in the 307 first-degree relatives and half-siblings
      of 123 probands with schizophrenia/schizoaffective disorder. The personality
      disorders examined were assessed using sections of the Structured Clinical
      Interview for DSM-III-R Personality Disorders (SCID-II) and hospital and clinic
      records. Interviewers were blind to the proband diagnosis. The resulting six
      factor solution accounted for 40% of the variance. The results of the six-factor
      solution accounted for the greatest variance and gave the most easily
      interpretable simple structure of all the solutions examined. The six factors are
      labeled as (1) Borderline Symptoms, (2) Schizoid Symptoms, (3) Paranoid Symptoms,
      (4) Avoidant Symptoms, (5) Positive Schizotypy Symptoms, and (6) Disorganized
      Symptoms. The Schizotypal Personality items are spread across all but the
      'Borderline Symptoms' factor. We conclude schizotypy is a multidimensional
      construct that is not adequately characterized by any one DSM-III-R personality
      disorder. It appears to consist of six distinct dimensions, which, interestingly,
      parallel current thinking on dimensions in schizophrenia.

PMID- 10579548
TI  - Neuropsychological functioning among non-psychotic siblings and parents of
      schizophrenic patients
AB  - Several studies have shown subtle neuropsychological deficits in healthy
      relatives of schizophrenic patients. However, older relatives and parents have
      been less frequently assessed than younger adult relatives and siblings.
      Furthermore, some areas of neuropsychological functioning such as memory and
      learning have been little studied. Thirty-seven 22-70-year-old non-psychotic
      parents and siblings of schizophrenic patients were compared to 37 healthy
      control subjects on a battery of neuropsychological tests (Trail Making, parts A
      and B, verbal fluency, Wisconsin Card Sorting Test, and four subtests of the
      Wechsler Memory Scale-Revised: logical memory, design reproduction, verbal paired
      associates and digit span). Relatives did not differ from control subjects on
      Wisconsin Card Sorting Test performance and on visual memory, but were
      significantly impaired on verbal fluency; more subtle deficits were found on
      Trail Making, part B, digit span and paired associates. A higher proportion of
      relatives than control subjects showed impairment on verbal fluency and verbal
      memory. These neuropsychological weaknesseswere present as much in siblings as in
      parents of schizophrenic patients, and age did not cancel differences between
      relatives and control subjects. Thus, these subtle deficits seem to be potential
      phenotypic markers of schizophrenia.

PMID- 10579549
TI  - Flat affect and social skills in schizophrenia: evidence for their independence
AB  - Although flat affect and social skills deficits are generally considered to be
      distinct impairments in schizophrenia, flat affect is typically assessed via an
      interview - an inherently social context. To the extent that emotional
      expressivity is an important component of socially appropriate interaction, it is
      possible that schizophrenic patients' diminished expressiveness in a social
      situation is largely a function of their concurrent social skills deficit. In the
      present study, we examined the relation between social skills and flat affect by
      measuring flat affect in two contexts: during an interview (high social demand)
      and while participants watched emotional film clips alone (low social demand).
      Results showed that social skills were not significantly correlated with flat
      affect in either context, suggesting that the two constructs represent
      independent domains of functioning in schizophrenic patients.

PMID- 10579550
TI  - A breakdown of event schemas in patients with schizophrenia: an examination of
      their script for dining at restaurants
AB  - Event schemas, the conceptualization of past experience, in schizophrenic
      patients were examined based upon script theory. Forty schizophrenic patients and
      40 age- and education-matched normal control subjects participated in this study.
      This experiment consisted of three tasks. In the recall task, subjects recalled a
      typical scenario of going to a formal restaurant. In the frequency judgment task,
      subjects determined whether the given events happen frequently, occasionally or
      rarely in a restaurant. In the sequencing task, the subjects put the randomly
      presented events in the correct order. The responses of the schizophrenic
      patients in the recall task, when compared with those of the normal control
      subjects, had significantly fewer concepts and a greater proportion of highest
      frequency concepts. In addition, the sequence of their responses was less
      accurate than that of normal individuals. This abnormality is unlikely due
      primarily to a retrieval deficit (i.e. generating fewer concepts in the recall
      task) given that their performances on the frequency judgment and sequencing
      tasks, tasks that require less retrieval effort, were consistent with those of
      the recall task. These results suggest that event schemas in schizophrenic
      patients contain little detailed information and are incoherent in organization.

PMID- 10579551
TI  - Diagnostic efficiency of the Rorschach schizophrenia and depression indices in
      identifying first-episode schizophrenia and severe depression
AB  - We studied the diagnostic efficiency of the Rorschach schizophrenia (SCZI) and
      depression (DEPI) indices for detecting first-episode schizophrenia and severe
      depression with and without psychotic features using DSM-IV as a gold standard
      measure. Twenty-seven patients with first-episode schizophrenia, 13 with bipolar
      I disorder, 28 with psychotic depression, 29 with non-psychotic depression, and
      60 healthy controls were recruited for the study. The SCZI was highly specific
      with a very low false positive rate. The lowest positive value of 4, however, may
      yield false positives, especially among manic patients. The DEPI identified
      severe non-psychotic depression but not psychotic depression, suggesting that
      these patient groups invoke different perceptual-cognitive processes in
      formulating and articulating their Rorschach responses. Anyway, both the SCZI and
      the DEPI based on the psychological organization and functioning that are known
      to play a clearly formulated role in schizophrenia and depression, respectively,
      provide a valuable addition for diagnostics characterized by overt symptoms.

PMID- 10579552
TI  - Analysis of the symptoms of depression--a neural network approach
AB  - The purpose of this study is to determine the individual contribution, or
      importance number, of the symptoms to an analysis of depression, utilizing a
      neural network model. In addition, the presence of hopelessness and somatic
      complaints was examined, to determine their relevance to depression. Using Wave 1
      data from Duke University's contribution in the Epidemiological Catchment Area
      (ECA) study, we created a mathematical model, a neural network, to map the
      relationship of nine symptoms of major depression, hopelessness and somatic
      complaints to the presence or absence of the formal diagnosis of depression, and
      performed a contribution analysis. The contribution analysis using the neural
      network revealed that the symptoms with the greatest impact on the occurrence of
      depression, or with the largest importance number for depression, were sadness,
      loss of interest, tiredness and sleeping trouble, in that order. The most
      frequently reported symptoms, though, were sadness, sleeping trouble, suicidal
      ideation, tiredness and poor concentration, in that order. Hopelessness and
      somatic symptoms were the lowest in their contribution to the diagnosis of
      depression. The study thus provides the hierarchy of the symptoms of depression
      and supports the DSM classification of major depression.

PMID- 10579553
TI  - Artificial neural networks: a study in clinical psychopharmacology
AB  - Controlled trials in clinical psychopharmacology may fail to provide reliable
      information about the benefit of treatment when the patient is viewed in a real
      life setting rather than as part of a well-defined sampling procedure. A
      viewpoint, rooted in systems theory, is proposed based on the identification of
      complex relationships among such dimensions as clinician's reasoning, drug
      properties, and patient's condition. Artificial Neural Network (ANN) technology
      provides efficient tools for data analysis within a systems-oriented approach.
      This study proposes a way to predict the outcome of psychopharmacological
      treatment. Analysis was conducted on retrospective data from clinical records of
      psychiatric patients treated with moclobemide. Twelve pharmacological,
      diagnostic, and topological variables were identified as the decisional items
      considered by six clinicians: age at onset, sex, previous treatment, duration and
      dose of moclobemide treatment, other drugs, psychiatric diagnosis and other
      clinical features. Data were binarily coded and transformed into observed
      frequencies in the sampling space; treatment outcome was binarily scored as the
      model's target. A Back-Propagation ANN based on the Delta rule with logistic
      transfer function was used. ANN correctly classified all cases of successful
      treatment (n = 51, 100%) but only half of the unsuccessful cases (n = 14, 52%).
      Patterns of response and areas of uncertainty were analyzed in a topological
      approach.

PMID- 10579554
TI  - Computerized administration of the Symptom Checklist (SCL-90-R) and the Inventory
      of Interpersonal Problems (IIP-C) in psychosomatic outpatients
AB  - This study investigated whether the method of administration (computer vs. paper
      and-pencil) influenced mean scores on the Symptom-Checklist (SCL-90-R) and the
      Inventory of Interpersonal Problems (IIP-C). The performance of 32 psychosomatic
      outpatients on the computerized version was compared with the performance of a
      matched control group on the paper-and-pencil version. No systematic differences
      were observed in group means.

PMID- 10579555
TI  - Neuropsychological profiles of FMR-1 premutation and full-mutation carrier
      females
AB  - The present French-German investigation of fragile-X syndrome (fra-X) was
      undertaken to disentangle genetic from environmental effects on cognitive
      performance as assessed with the following measures: Wechsler Adult Intelligence
      Scale-Revised (WAIS-R), Wisconsin Card Sorting Test, Trail-Making Test, Tower of
      Hanai, Verbal Fluency Test, Stroop Test, short-term and consolidation memory, and
      the d2 task. Groups with different genotypes (n = 11 mothers with a full mutation
      in the FMR-1 gene of fra-X children; n = 65 mothers with a premutation in the FMR
      1 gene of fra-X children; n = 18 siblings of these mothers with normal CGG
      repeats) and with different psychosocial stressors from fra-X families (n = 14
      siblings with a premutation but without affected children of their own) were
      examined. A group of mothers of non-fra-X autistic children (n = 39) formed an
      external control group. Previous findings were replicated concerning cognitive
      performance of FMR-1 full-mutation carrier mothers, who were characterized by
      lower overall IQ and poorer performance than the group of mothers with the FMR-1
      premutation in verbal and performance subtests of the WAIS-R, tests of executive
      frontal lobe functioning, and tests of sustained attention. Carriers of the FMR-1
      premutation, whether they were mothers of affected children or not,performed in a
      similar way on all neuropsychological tasks to the intrafamilial control group
      without CGG amplification. On the basis of these results, it is concluded that
      there is no neuropsychological evidence of reduced cognitive performance of FMR-1
      premutation carriers compared with performance of two control groups with normal
      CGG repeats. Furthermore, the psychosocial burden of raising fra-X children does
      not exert an environmental effect on neuropsychological test performance.

PMID- 10579556
TI  - Serotonin-2A receptor polymorphism (102T/C) in mood disorders
AB  - Serotonergic dysfunction has been implicated in mood disorders and suicidal
      behaviors. This study examined the association between a serotonin-2A (5HT2A)
      receptor gene polymorphism (102T/C) and mood disorders. The genotype and allele
      frequencies did not differ between patients with mood disorders and control
      subjects. Furthermore, the 102T/C polymorphism was not found to be associated
      with suicidal history in mood disorder patients. Our results suggest that this
      polymorphism is unlikely to play a role in the genetic susceptibility to mood
      disorders.

PMID- 10579557
TI  - Genetic association analysis between CYP2D6*2 allele and tardive dyskinesia in
      schizophrenic patients
AB  - Previous studies have shown a possible association between tardive dyskinesia
      (TD) and debrisoquine 4-hydroxylase (CYP2D6) polymorphisms, which result in
      absent enzyme activity. We have recently found a positive association between TD
      and the CYP2D6*10 allele, which codes for the intermediate metabolizer (IM)
      phenotype and is characterized by decreased but not absent CYP2D6 activity in
      Japanese schizophrenic patients. In addition, the CYP2D6* 2 allele with the HhaI
      site mutation in exon 6 has also been reported to be an IM allele and a risk
      factor for Parkinson's disease (PD) in the Japanese population. In the present
      study, we investigated potential contributions of the CYP2D6*2 allele to TD using
      case-control and regression analysis in 99 schizophrenic patients. No significant
      differences in genotypic and allelic frequencies were found between patients with
      and without TD. Even after using regression analysis to adjust for the
      confounding variables, there was no significant association of the CYP2D6*2
      genotype with either outcome variable, the occurrence of TD or the total AIMS
      score. These results suggest that the CYP2D6*2 allele may not contribute to the
      pathogenesis of TD.

PMID- 10579558
TI  - No association between an intronic presenilin-1 gene polymorphism and
      schizophrenia in a Chinese population
AB  - We investigated the association between schizophrenic psychosis and an intronic
      polymorphism of the presenilin-1 (PS1) gene in a Chinese population.
      Schizophrenic and control groups had similar PS1 genotype distributions and
      allele frequencies, indicating that this polymorphism may not be involved in the
      development of schizophrenia.

PMID- 10579559
TI  - Somatostatin receptor subtype 2A expression in the rat retina.
AB  - Somatostatin is mainly expressed by sparsely occurring amacrine and
      interplexiform cells in the retina. In this study, we characterized the
      expression and cellular localization of one of the somatostatin subtype (sst)
      receptors, sst2A, in the rat retina. The presence of sst2A receptor messenger RNA
      in retinal extracts was demonstrated by reverse transcription-polymerase chain
      reaction using specific primers to detect the sst2 receptor and its isoforms,
      sst2A and sst2B. Specific sst2A receptor immunoreactivity was mainly localized to
      the plasma membrane of several neuronal cell types. In the outer retina,
      immunoreactivity was localized to cone photoreceptors, horizontal cells, and rod
      and cone bipolar cells. Double-label experiments showed the co-localization of
      sst2A receptor and protein kinase C (alpha and beta), a rod bipolar cell marker,
      and of sst2A receptor and Calbindin-D28k, a horizontal cell marker. In the inner
      retina, sst2A receptor immunoreactivity occurred in tyrosine hydroxylase-positive
      amacrine cells; most were of medium to large size. These findings indicate that
      somatostatin may act at a distance, in a paracrine manner, on several cell types
      that express the sst2A receptor, and therefore exert a broad modulatory influence
      on both scotopic and photopic visual pathways.

PMID- 10579560
TI  - Autoradiographic comparison of [3H](-)nicotine, [3H]cytisine and [3H]epibatidine
      binding in relation to vesicular acetylcholine transport sites in the temporal
      cortex in Alzheimer's disease.
AB  - The laminar binding distribution of three nicotinic receptor agonists, [3H](
      )nicotine, [3H]cytisine, and [3H]epibatidine, and their relation to the
      [3H]vesamicol binding, which is known to represent the vesicular acetylcholine
      transport sites, was performed employing in vitro autoradiography on the medial
      temporal cortex (Brodmann area 21). Autopsied brain tissue from nine Alzheimer
      patients and seven age-matched controls were used. The binding pattern of the
      three nicotinic ligands in the normal cortex was in general similar, showing
      binding maxima in the cortical layers I, III and V. The binding of [3H](
      )nicotine, [3H]cytisine, and [3H]epibatidine was lower in the older controls and
      more uniform throughout the layers as compared with younger controls. There was a
      significant age-related decrease in the binding of the three nicotinic ligands
      within the controls (age range: 58 to 89 years; P[3H](-)nicotine = 0.002,
      P[3H]epibatidine = 0.010, P[3H]cytisine = 0.037). In the older controls, the
      [3H]epibatidine binding was much decreased as compared with that of [3H](
      )nicotine and [3H]cytisine. This may indicate a higher selectivity of
      [3H]epibatidine for a nicotinic receptor subtype that is particularly affected by
      aging. The laminar binding pattern of [3H]vesamicol showed one maximum in the
      outer cortical layers II/III. The [3H]vesamicol binding did not change with
      aging. The binding of all ligands was significantly decreased in all layers of
      the temporal cortex in Alzheimer's disease, but the [3H]vesamicol binding
      decreased only half as much as the nicotinic receptors. Also, choline
      acetyltransferase activity was percentually more reduced than [3H]vesamicol
      binding in Alzheimer's disease. The cortical laminar binding pattern of all 3H
      ligands was largely absent in the Alzheimer's disease cases. The less severe loss
      of vesicular acetylcholine transport sites as compared with the loss of the
      nicotinic receptors and choline acetyltransferase activity may suggest that
      vesamicol binding sites might be more preserved in presynaptic terminals still
      existing and thereby expressing compensatory capacity to maintain cholinergic
      activity.

PMID- 10579561
TI  - Effects of blocking non-N-methyl-D-aspartate receptors on visual responses of
      neurons in the cat visual cortex.
AB  - To elucidate the function of non-N-methyl-D-aspartate types of glutamate
      receptors in the primary visual cortex of the adult cat, we studied the effects
      of the iontophoretically applied glutamate receptor antagonists 6-cyano-7
      nitroquinoxaline-2,3-dione and D-amino-5-phosphonovalerate. Antagonists were
      applied with ejecting currents that selectively blocked non-N-methyl-D-aspartate
      receptors. Among 93 cells in which stable recordings were obtained, 6-cyano-7
      nitroquinoxaline-2,3-dione reduced the visual response in all cells. The average
      response magnitude during 6-cyano-7-nitroquinoxaline-2,3-dione administration was
      reduced to 11.7% of the control (average ejecting current: 41.2 nA). The effect
      of 6-cyano-7-nitroquinoxaline-2,3-dione was obvious throughout all cortical
      layers. The effect of D-amino-5-phosphonovalerate on the visual response was
      tested in 14 cells and it was also effective in blocking the visual response: the
      average response magnitude during D-amino-5-phosphonovalerate administration was
      45.0% of the control (average ejecting current: 41.4 nA). The effect of 6-cyano-7
      nitroquinoxaline-2,3-dione on the response was compared in individual cells at
      both high and low firing rates in order to determine whether a differential
      effect exists on the level of firing activity of cells due to secondary
      inactivation of voltage-dependent N-methyl-D-aspartate receptors. However, no
      indication of response dependency on firing rate was seen with 6-cyano-7
      nitroquinoxaline-2,3-dione. We suggest that excitatory transmission at the
      geniculocortical and corticocortical synapses seems to be strongly dependent on
      non-N-methyl-D-aspartate receptors throughout the primary visual cortex of the
      adult cat, and that both non-N-methyl-D-aspartate and N-methyl-D-aspartate type
      glutamate receptors function additively.

PMID- 10579562
TI  - D-amphetamine-induced behavioral sensitization: implication of a glutamatergic
      medial prefrontal cortex-ventral tegmental area innervation.
AB  - Behavioral sensitization to amphetamine is expressed as a progressive enhancement
      of the behavioral activating effects of the drug when repeated injections are
      performed as well as a long-lasting hypersensitivity to later environmental or
      pharmacological challenges. The mesoaccumbens dopamine system has been proposed
      to be the major candidate so far responsible for the induction and expression of
      this process, which are dependent on the action of amphetamine in the ventral
      tegmental area and nucleus accumbens, respectively. The development of this
      process has been proposed to be the result of an interaction between
      somatodendritically released dopamine and dopaminergic D1 receptors localized on
      different inputs to the ventral tegmental area, including glutamate afferents
      arising in part from mesocorticolimbic areas such as the medial prefrontal cortex
      and the amygdala. Three groups of experiments were designed to test the role of
      each of these components in the behavioral sensitization to amphetamine. First,
      the intervention of the glutamatergic transmission of the ventral tegmental area
      in the induction of sensitization to amphetamine was tested. The effects of an N
      methyl-D-aspartate antagonist, 3-(R-2-carboxypiperazin-4-yl)-propyl-1-phosphonic
      acid. on the behavioral sensitization induced by amphetamine administered
      repeatedly in the ventral tegmental area was tested. It was found that the
      blockade of N-methyl-D-aspartate receptors with 3-(R-2-carboxypiperazin-4-yl)
      propyl-1-phosphonic acid coadministered with amphetamine in the ventral tegmental
      area dose-dependently prevented the induction of sensitization. In a second step,
      the role of the structures which send glutamatergic inputs to the ventral
      tegmental area in the process of behavioral sensitization was tested. We
      evaluated the effects of ibotenic acid lesion of the medial prefrontal cortex and
      the amygdala on behavioral sensitization induced by peripheral or intra-ventral
      tegmental area administration of amphetamine. We found that ibotenic acid lesion
      of the medial prefrontal cortex blocked the behavioral sensitization induced by
      both intra-ventral tegmental area and peripheral treatment with amphetamine. In
      contrast, ibotenic acid lesion of the amygdala produced no effect on behavioral
      sensitization induced peripherally or centrally. These experiments confirmed (i)
      that the ventral tegmental area, where dopaminergic cell bodies are located, is a
      critical site for the induction of behavioral sensitization, (ii) that this
      process implicates the glutamatergic transmission in the ventral tegmental area,
      and (iii) that the medial prefrontal cortex is crucially implicated merely
      because of its direct glutamatergic inputs on to ventral tegmental area neurons.
      Together, these results reinforce the view that the behavioral sensitization to
      amphetamine implicates not only the mesoaccumbens dopaminergic neurons, but also
      other structures of the mesocorticolimbic system, such as the medial prefrontal
      cortex and more specifically its glutamatergic component.

PMID- 10579563
TI  - Defensive conditioning-related functional heterogeneity among nuclei of the rat
      amygdala revealed by c-Fos mapping.
AB  - The amygdala is a complex forebrain structure proposed to play a pivotal role in
      fear conditioning circuitry. In this study, c-Fos immunomapping was applied to
      investigate the functional activation of particular amygdalar nuclei following a
      50-trial training session of two-way active avoidance reaction. To dissect
      distinctive responses displayed by the animals and to cluster them into groups of
      correlated behaviors, factor analysis was employed. The training procedure
      resulted in an increase of c-Fos expression within the cortical, medial, lateral
      and basolateral, but not central, nuclei. The expression in the cortical nucleus
      correlated negatively with grooming behavior, whereas c-Fos immunolabeling of the
      other three subdivisions of the amygdala could be associated with the number of
      intertrial responses. No correlation was observed between c-Fos expression and
      avoidance reactions performed or the amount of shock received by the animal. The
      results obtained with c-Fos mapping of various regions of rat amygdala, combined
      with a fine dissection of behavioral repertoire, imply that there are specific
      functional links between particular parts of the structure and distinctive
      behaviors that reflect various emotional states of the animal.

PMID- 10579564
TI  - Ultra-slow oscillation (0.025 Hz) triggers hippocampal afterdischarges in Wistar
      rats.
AB  - Oscillations in neuronal networks are assumed to serve various physiological
      functions, from coordination of motor patterns to perceptual binding of sensory
      information. Here, we describe an ultra-slow oscillation (0.025 Hz) in the
      hippocampus. Extracellular and intracellular activity was recorded from the CA1
      and subicular regions in rats of the Wistar and Sprague-Dawley strains,
      anesthetized with urethane. In a subgroup of Wistar rats (23%), spontaneous
      afterdischarges (4.7+/-1.6 s) occurred regularly at 40.8+/-15.7 s. The
      afterdischarge was initiated by a fast increase of population synchrony (100-250
      Hz oscillation; "tonic" phase), followed by large-amplitude rhythmic waves and
      associated action potentials at gamma and beta frequency (15-50 Hz; "clonic"
      phase). The afterdischarges were bilaterally synchronous and terminated
      relatively abruptly without post-ictal depression. Single-pulse stimulation of
      the commissural input could trigger afterdischarges, but only at times when they
      were about to occur. Commissural stimulation evoked inhibitory postsynaptic
      potentials in pyramidal cells. However, when the stimulus triggered an
      afterdischarge, the inhibitory postsynaptic potential was absent and the cells
      remained depolarized during most of the afterdischarge. Afterdischarges were not
      observed in the Sprague-Dawley rats. Long-term analysis of interneuronal activity
      in intact, drug-free rats also revealed periodic excitability changes in the
      hippocampal network at 0.025 Hz. These findings indicate the presence of an ultra
      slow oscillation in the hippocampal formation. The ultra-slow clock induced
      afterdischarges in susceptible animals. We hypothesize that a transient failure
      of GABAergic inhibition in a subset of Wistar rats is responsible for the
      emergence of epileptiform patterns.

PMID- 10579565
TI  - Spontaneous activity and sensory responses of hippocampal neurons during
      persistent theta-rhythm evoked by median raphe nucleus blockade in rabbit.
AB  - Spontaneous activity and responses to sensory stimuli were analysed in the
      hippocampal CA1 neurons of chronic unanesthetized rabbits before and after
      reversible functional blockade of the median raphe nucleus and medial septal area
      by local microinjections of anesthetic lidocaine. This evoked, correspondingly,
      persistent theta rhythm and its complete blockade for about 30 min. The results
      were compared to the neuronal data obtained earlier in the experiments with
      cholinergic drugs modulating expression of theta rhythm. Intra-median raphe
      nucleus injection of lidocaine evoked uniform increase of discharge rate in the
      hippocampal neurons with low and high spontaneous activity. Theta modulation of
      neuronal activity had increased regularity and frequency (by 0.5-2.0 Hz) and
      appeared in additional group of the neurons simultaneously with expression of
      persistent theta in the hippocampal electroencephalogram. Sensory responsiveness
      of the hippocampal neurons was drastically decreased (45% of the responses
      preserved). Reactions of all types were blocked, diminished, or inverted, but
      inhibitory responses were the most severely affected. Injection of lidocaine into
      medial septal area also blocked all brain stem afferents ascending to the
      hippocampus via medial septal area, thus, totally depriving hippocampus of
      brainstem-septal input. However, besides the total absence of theta modulation,
      spontaneous activity in majority of neurons was not significantly changed.
      Responsiveness to sensory stimuli also remained relatively high (77% of the
      responses preserved); on-effects were especially resistant to medial septal area
      blockade. Comparison of spontaneous and evoked activity in two theta states
      (physostigmine and median raphe nucleus blockade) revealed striking similarity of
      all characteristics, which suggested that theta-suppressing influences of median
      raphe nucleus (presumably serotonergic) are realized primarily through the
      control of cholinergic septo-hippocampal theta-generating mechanism. However, as
      the frequency of theta rhythm does not depend on it, an additional effect of
      disinhibition of activating reticular formation by the median raphe nucleus
      suppression is suggested. The data confirm that theta rhythm may be regarded as
      active filter in the information processing by the hippocampal neurons.

PMID- 10579566
TI  - Seizures, cell death, and mossy fiber sprouting in kainic acid-treated
      organotypic hippocampal cultures.
AB  - Sprouting of the mossy fiber axons of the dentate granule cells is a structural
      neuronal plasticity found in the mature brain of epileptic humans and
      experimental animals. Mossy fiber sprouting typically arises in experimental
      animals after repeated seizures and may contribute to the hyperexcitability of
      the epileptic brain. Investigation of the molecular triggers and spatial cues
      involved in mossy fiber sprouting has been hampered by the lack of an optimal in
      vitro model for studying this rearrangement. For an in vitro model to be
      feasible, the circuitry and receptors involved in convulsant-induced mossy fiber
      sprouting would have to be localized near the granule cells, rather than being
      dependent on long-range brain interconnections. However, it is not known whether
      this is the case. We report here that that application of the convulsant, kainic
      acid, to organotypic hippocampal explant cultures induces seizures, neuronal cell
      death, and subsequent dramatic mossy fiber sprouting with a similar laminar
      preference and time-course to that seen in intact animals. Prolonged (48 h) but
      not transient (4 h) kainic acid treatment caused regionally selective neuronal
      cell death. Cultures treated with kainic acid for a prolonged period displayed a
      time- and dose-dependent increase in supragranular Timm staining reflective of
      increased mossy fiber innervation to this area. Direct visualization of mossy
      fiber axons with neurobiotin-labeling revealed that mossy fibers in kainic acid
      treated cultures exhibited a dramatic increase in supragranular axonal branch
      points and synaptic boutons. The cellular and molecular determinants required for
      kainic acid-induced cell death and subsequent mossy fiber reorganization thus
      appear to be intrinsic to the hippocampal slice preparation, and are preserved in
      culture. Given the ease with which functional inhibitors or pharmacological
      agents may be utilized in this system, slice cultures may provide a powerful
      model in which to study the molecular components involved in triggering mossy
      fiber outgrowth and underlying its laminar specificity. Elucidation of these
      molecular pathways will likely have both specific utility in clarifying the
      functional consequences of mossy fiber sprouting, as well as general utility in
      understanding of synaptic reorganization in the mature central nervous system.

PMID- 10579567
TI  - Blockade of neuronal activity alters spine maturation of dentate granule cells
      but not their dendritic arborization.
AB  - Organotypic co-cultures of the entorhinal cortex and hippocampus were examined to
      determine the role of the entorhinal fibers in the dendritic development and
      formation of spines of dentate granule cells. Quantitative analysis of Golgi
      impregnated granule cells in single hippocampal cultures and co-cultures with the
      entorhinal cortex revealed that the presence of entorhinal fibers promoted the
      elongation and differentiation of the target granule cell dendrites. This was
      accompanied by an increase in the total number of spines. The contribution of
      neuronal activity to this afferent-mediated dendritic development was tested by
      chronic application of the sodium channel blocker tetrodotoxin for 20 days in
      vitro. Tracing with biocytin showed that the formation of the
      entorhinohippocampal pathway was unaffected by the blockade of neuronal activity.
      The dendritic arbor of cultured granule cells and the number of dendritic spines
      did not differ between tetrodotoxin-treated slices and untreated controls.
      However, there was a significant increase in the relative number of filiform
      spines on granule cell dendrites in tetrodotoxin-treated co-cultures. Such
      filiform spines are a characteristic feature of immature neurons. These results
      suggest the cooperation of two mechanisms in the dendritic development of dentate
      granule cells: the specific afferent-mediated dendritic arborization and the
      activity-dependent maturation of spines.

PMID- 10579568
TI  - Neurotensin depolarizes cholinergic and a subset of non-cholinergic
      septal/diagonal band neurons by stimulating neurotensin-1 receptors.
AB  - Identified cholinergic and a subtype of non-cholinergic, fast-firing neurons were
      recorded intracellularly in vitro from slices of guinea-pig brain. Recorded
      neurons were within the boundaries of the medial septum and vertical limb of the
      diagonal band of the forebrain. The effects of superfused neurotensin and
      neurotensin receptor antagonists were measured under single-electrode current
      clamp. Neurotensin consistently caused a dose-dependent, slow depolarization of
      cholinergic neurons that was accompanied by an increase in membrane resistance
      and a block of the long-duration (1-10 s) post-spike afterhyperpolarization when
      present. Neurotensin also blocked a shorter duration, slow
      afterhyperpolarization, but only in a minority of cholinergic neurons. When
      present, inhibition of the slow afterhyperpolarization changed the spike pattern
      from single spikes to short bursts. Inhibition of post-spike
      afterhyperpolarizations by neurotensin reversed more slowly than did other
      effects of neurotensin. Tetrodotoxin did not prevent the depolarizing effect of
      neurotensin. The non-selective neurotensin receptor antagonist, SR142948A,
      blocked the depolarizing effect of neurotensin but the low-affinity receptor
      antagonist, levocabastine, did not. A subgroup of noncholinergic, fast-firing
      neurons (23%) was also depolarized by neurotensin, an effect antagonized by
      SR142948A but not levocabastine. Neurotensin did not effect post-spike voltage
      transients or change the firing pattern of non-cholinergic neurons. These data
      suggest that neurotensin causes a slow depolarization and increased excitability
      of cholinergic and some noncholinergic neurons in an area of the brain that
      projects to the hippocampus. Neurotensin type 1 receptors appear to mediate these
      effects. Neurotensin may modulate hippocampal-dependent learning and memory
      processes through its effects on septohippocampal neurons.

PMID- 10579569
TI  - Zinc modulation of ionic currents in the horizontal limb of the diagonal band of
      Broca.
AB  - We examined modulation of ionic currents by Zn2+ in acutely dissociated neurons
      from the rat's horizontal limb of the diagonal band of Broca using the whole-cell
      patch-clamp technique. Application of 50 microM Zn2+ increased the peak amplitude
      of the transiently activated potassium current, I(A) (at + 30 mV), from 2.20+/
      0.08 to 2.57+/-0.11 nA (n = 27). This response was reversible and could be
      repeated in 0 Ca2+/1 microM tetrodotoxin (n = 15). Zn2+ shifted the inactivation
      curve to the right, resulting in a shift in the half-inactivation voltage from
      76.4+/-2.2 to -53.4+/-2.0 mV (n = 11), with no effect on the voltage dependence
      of activation gating (n = 15). There was no significant difference in the time to
      peak under control conditions (7.43+/-0.35 ms, n = 14) and in the presence of
      Zn2+ (8.20+/-0.57 ms, n = 14). Similarly, the time constant of decay of I(A)
      (tau(d)) at + 30 mV showed no difference (control: 38.68+/-3.68 ms, n = 15; Zn2+:
      38.48+/-2.85 ms, n = 15). I(A) was blocked by 0.5-1 mM 4-aminopyridine. In
      contrast to its effects on I(A), Zn2+ reduced the amplitude of the delayed
      rectifier potassium current (I(K)). The reduction of outward K+ currents was
      reproducible when cells were perfused with 1 microM tetrodotoxin in a 0 Ca2+
      external solution. The amplitude of the steady-state outward currents at +30 mV
      under these conditions was reduced from 6.40+/-0.23 (control) to 5.76+/-0.18 nA
      in the presence of Zn2+ (n = 16). The amplitudes of peak sodium currents (INa)
      were not significantly influenced (n = 10), whereas barium currents (I(Ba))
      passing through calcium channels were potently modulated. Zn2+ reversibly reduced
      I(Ba) at -10 mV by approximately 85% from -2.06+/-0.14 nA under control
      conditions to -0.30+/-0.10 nA in the presence of Zn2+ (n = 14). Further analyses
      of Zn2+ effects on specific calcium channels reveals that it suppresses all types
      of high-voltage-activated Ca2+ currents. Under current-clamp conditions,
      application of Zn2+ resulted in an increase in excitability and loss of
      accommodation (n = 13), which appears to be mediated through its effects on Ca2+
      dependent conductances.

PMID- 10579570
TI  - Central corticotropin-releasing hormone receptors modulate hypothalamic-pituitary
      adrenocortical and sympathoadrenal activity during stress.
AB  - The role of brain corticotropin-releasing hormone receptors in modulating
      hypothalamic-pituitary-adrenal and sympathoadrenal responses to acute
      immobilization stress was studied in conscious rats under central corticotropin
      releasing hormone receptor blockade by intracerebroventricular injection of a
      peptide corticotropin-releasing hormone receptor antagonist. Blood for
      catecholamines, adrenocorticotropic hormone and corticosterone levels was
      collected through vascular catheters, and brains were removed at 3 h for in situ
      hybridization for tyrosine hydroxylase messenger RNA in the locus coeruleus, and
      corticotropin-releasing hormone and corticotropin-releasing hormone receptor
      messenger RNA in the hypothalamic paraventricular nucleus. Central corticotropin
      releasing hormone receptor blockade reduced the early increases in plasma
      epinephrine and dopamine, but not norepinephrine, during stress. Immobilization
      stress increased tyrosine hydroxylase messenger RNA levels in the locus coeruleus
      by 36% in controls, but not in corticotropin-releasing hormone antagonist
      injected rats. In control rats, corticotropin-releasing hormone messenger RNA and
      type 1 corticotropin-releasing hormone receptor messenger RNA in the
      paraventricular nucleus increased after stress (P<0.01), and these responses were
      attenuated by central corticotropin-releasing hormone receptor blockade. In
      contrast, central corticotropin-releasing hormone antagonist potentiated plasma
      adrenocorticotropic hormone responses, but slightly attenuated plasma
      corticosterone responses to stress. The inhibition of plasma catecholamine and
      locus coeruleus tyrosine hydroxylase messenger RNA responses to stress by central
      corticotropin-releasing hormone receptor blockade supports the notion that
      central corticotropin-releasing hormone regulates sympathoadrenal responses
      during stress. The attenuation of stress-induced corticotropin-releasing hormone
      and corticotropin-releasing hormone receptor messenger RNA responses by central
      corticotropin-releasing hormone receptor blockade suggests direct or indirect
      positive feedback effects of corticotropin-releasing hormone receptor ligands on
      corticotropin-releasing hormone expression, whereas additional mechanisms
      potentiate adrenocorticotropic hormone responses at the pituitary level. In
      addition, changes in neural activity by central corticotropin-releasing hormone
      are likely to modulate adrenocortical responsiveness during stress.

PMID- 10579571
TI  - Transient or sustained transcriptional activation of the genes encoding rat
      adrenomedullary catecholamine biosynthetic enzymes by different durations of
      immobilization stress.
AB  - The impact of stress on the transcription of rat adrenal tyrosine hydroxylase and
      dopamine beta-hydroxylase genes was examined. Nuclear run-on assays revealed that
      repeated immobilization stress elicited marked (about threefold) increases in the
      relative rates of transcription, being sustained for at least one day. Parallel
      changes in the steady-state messenger RNA levels for tyrosine hydroxylase and
      dopamine beta-hydroxylase were also observed. A single episode of stress
      triggered similar enhancements in their relative transcription rates. Depending
      on the duration of the stress signal, the effect on gene transcription varied in
      its persistence. After very short (5 min) immobilization, there was a marked
      transient rise in the transcription of both genes, without an accumulation of the
      corresponding mRNAs. Longer episodes of stress (30 min) increased the relative
      rate of tyrosine hydroxylase transcription for hours, causing elevations in the
      steady-state messenger RNA levels. In contrast, although dopamine beta
      hydroxylase transcription was elevated to a similar extent by 30-min
      immobilization stress, the effect was transient and not reflected in significant
      accumulation of its messenger RNA. The results of our studies emphasize that the
      stress-evoked increases in the expression of the genes encoding adrenomedullary
      catecholamine biosynthetic enzymes involve transcriptional activation. Depending
      on the duration and reiteration of the stress signal, different transcriptional
      mechanisms may be employed.

PMID- 10579572
TI  - Definitive evidence for the existence of morphological plasticity in the external
      zone of the median eminence during the rat estrous cycle: implication of neuro
      glio-endothelial interactions in gonadotropin-releasing hormone release.
AB  - Despite intense investigation, the demonstration of morphological plasticity in
      the external zone of the median eminence concerning the gonadotropin-releasing
      hormone system has never been reported. In this study, we investigate whether
      dynamic transformations of the gonadotropin-releasing hormone nerve terminals
      and/or tanycytes in the external zone of the median eminence of the hypothalamus
      occurred during the rat estrous cycle, by following individual gonadotropin
      releasing hormone-immunoreactive nerve terminals on serial ultrathin sections
      observed by electron microscopy. Female rats were killed at 16.00 diestrus II (n
      = 3), i.e. when estrogen levels are basal and gonadotropin-releasing hormone
      release is low, and at 16.00 proestrus (n = 4), i.e. when estrogen levels peak
      and the preovulatory gonadotropin-releasing hormone surge occurs. Our results
      show that, in the median eminence obtained from proestrus rats, 12+/-2% of the
      gonadotropin-releasing hormone nerve terminals were observed to make physical
      contact with the parenchymatous basal lamina, i.e. the pericapillary space. In
      the median eminence obtained from diestrus II rats, no contacts were observed. On
      proestrus, numerous physical contacts between gonadotropin-releasing hormone
      nerve terminals and the basal lamina occurred by evagination of the basal lamina
      and/or by emerging processes from gonadotropin-releasing hormone nerve terminals.
      The quantification of the evagination of the basal lamina revealed that the basal
      lamina was at least twofold more tortuous in appearance during proestrus. These
      results demonstrate for the first time the existence of dynamic plastic changes
      in the external zone of the median eminence, allowing gonadotropin-releasing
      hormone nerve terminals to contact the pericapillary space on the day of
      proestrus, thus facilitating the release of the neurohormone into the pituitary
      portal blood.

PMID- 10579573
TI  - Differential polarization of serotonin transporters in axons versus soma
      dendrites: an immunogold electron microscopy study.
AB  - In spite of the conventional belief that neurotransmitter uptake occurs at the
      synapses, we demonstrated previously that serotonin transporters and the high
      affinity uptake of serotonin were not confined to the terminals but rather
      occurred throughout the axons [Zhou F. C. et al. (1998) Brain Res. 805, 241-254].
      In the present study, the detailed distribution of serotonin transporters over
      various parts of the neuron was illustrated and analysed morphometrically using a
      pre-embedding immunogold method with a characterized serotonin transporter
      antibody at the electron microscopic level. Our findings reveal a highly
      polarized distribution of serotonin transporters between axons and soma-dendrites
      in two aspects. (1) On the plasma membrane, serotonin transporter-immunogold is
      extremely low on soma-dendrites and synaptic junctions, but consistently dense
      along the axons and perisynaptic area. (2) In contrast, serotonin transporter
      labeling in the cytoplasm is concentrated in soma and dendrites, particularly on
      the membranes of rough endoplasmic reticulum, Golgi complexes and tubulovesicular
      structures, but low in the axoplasm. The extensive distribution of serotonin
      transporter along the axolemma suggests a broad range of uptake sites beyond
      synaptic junctions, and is consistent with the notion that the major mode of
      transmission for serotonin neurons is through volume (extrasynaptic)
      transmission. The highly polarized distribution also indicates that the major
      serotonin uptake sites are on axons and not on soma-dendrites.

PMID- 10579574
TI  - Neuronal response sensitivity to bidirectional off-vertical axis rotations: a
      dimension of imbalance in the bilateral vestibular nuclei of cats after
      unilateral labyrinthectomy.
AB  - In decerebrate cats after acute hemilabyrinthectomy, the response sensitivity of
      extracellularly recorded vestibular nuclear neurons on the lesioned and labyrinth
      intact sides were examined quantitatively during constant velocity off-vertical
      axis rotations with an aim to elucidate the functional contribution of otolithic
      inputs to the ipsilateral and contralateral vestibular nuclei. The bidirectional
      response sensitivity, delta, was determined as the ratio of the gain during
      clockwise to that during counterclockwise rotations. A continuum of response
      sensitivity was identified: one-dimensional neurons showed symmetrically
      bidirectional response patterns, while two-dimensional neurons showed
      asymmetrically bidirectional patterns that in some cases approached
      unidirectional patterns with change in velocity. The proportion of two
      dimensional neurons was significantly increased after acute hemilabyrinthectomy.
      Two-dimensional neurons that responded only to one direction of rotation in at
      least one of the velocities tested were described as unidirectional neurons. This
      unidirectional response pattern was observed in one-third of the entire neuronal
      population studied, but not in cats with both labyrinths intact, thus suggesting
      that such prominent broadly tuned responses are normally masked by converging
      otolithic inputs from the contralateral side. These neurons were found in higher
      proportion on the lesioned side than on the labyrinth-intact side. Among the 70%
      of unidirectional neurons that exhibited bidirectional response at some
      velocities and unidirectional response at others, prominent shifts in delta
      values (i.e. between 0/infinity and finite values) with velocity can be computed
      for each neuron. The shifts in delta values correlated with large shifts in the
      response dynamics and spatial orientation as the response pattern changed with
      velocity. The response orientations of the unidirectional neurons pointed in all
      directions on the horizontal plane. When all the two-dimensional neurons (i.e.
      both the unidirectionally and bidirectionally responsive ones) were pooled,
      imbalances in the distribution of the response orientations and in response gain
      were found between the ipsilateral-side-down/head-down half-circle and the
      contralateral-side-down/head-up half-circle on the labyrinth-intact side, but not
      on the lesioned side. These results, derived from spatiotemporal processing of
      gravitational signals, reveal a novel dimension of imbalance between neuronal
      populations in the two vestibular nuclear complexes after acute lesion of one
      labyrinth. This feature would provide, on the one hand, deranged cues of spatial
      orientation and direction during slow head excursions and, on the other, a
      framework for the dynamic behavioral deficits associated with
      hemilabyrinthectomy.

PMID- 10579575
TI  - Electrophysiological properties of the somatotopic organization of the
      vestibulospinal system in the frog.
AB  - In experiments on the preparation of a frog perfused brain (Rana ridibunda),
      field and intracellular potentials were recorded from neurons of the vestibular
      nuclear complex following stimulation of the ipsilateral vestibular nerve and
      different levels of the spinal cord. Stimulation of the vestibular nerve evoked
      mono- and polysynaptic excitatory postsynaptic potentials and orthodromic action
      potentials. In parallel, an antidromic activation of vestibular neurons sending
      their axons to the labyrinth was recorded. Vestibulospinal neurons sending their
      axons to the cervical (C neurons) and lumbar (L neurons) enlargements of the
      spinal cord were identified by their antidromic activation. A rather high
      conduction velocity along vestibulospinal fibres (mean 15.47 m/s) was observed. A
      somatotopic arrangement of the vestibulospinal system was established in spite of
      extremely large overlapping zones for the fore- and hindlimb representations in
      the vestibular nuclear complex. The hindlimbs were represented more poorly than
      the forelimbs. Antidromic potentials of C and L neurons were recorded in the
      medial, descending and with the highest density in the lateral vestibular nuclei
      (Deiters' nucleus). C neurons were evenly distributed in the other vestibular
      nuclei studied, while L neurons were located predominantly in the caudal parts of
      the vestibular nuclear complex. The multiplicity of the origin of the
      vestibulospinal axons was established. Peculiarities of the functional
      correlation between the vestibular input and vestibulospinal system are
      discussed.

PMID- 10579576
TI  - Optical measurements of synchronized activity in isolated mammalian cerebellum.
AB  - An experimental system that combines optical imaging of voltage-sensitive dyes
      with an in vitro isolated cerebellum preparation is described. The optical
      imaging system is based on a photodiode array and two rather simple amplification
      stages. The isolated cerebellum preparation preserves the integrity of the
      neuronal circuitry, thus allowing the exploration of the path of information
      flow. In this study, we characterize the nature and sources of the optical signal
      evoked in the cerebellar cortex by surface stimulation. We show that this signal
      reflects inhibitory and excitatory synaptic potentials generated by cell bodies
      and dendrites of cortical neurons, whereas action potentials of the parallel
      fibers are not detected by the system. The spatial distribution of the optical
      signals agrees with the classical view of cerebellar activity following surface
      stimulation. Hence, this experimental system provides a powerful means to explore
      the functional organization, in time and space, of the cerebellar cortex.

PMID- 10579577
TI  - Characterization of P2 receptors modulating neural activity in rat rostral
      ventrolateral medulla.
AB  - This study investigated the effects of ATP, and related compounds, on the
      activity of neurons within the rostral ventrolateral medulla, an area of
      fundamental importance in reflex control of the cardiovascular system.
      Extracellular recordings were made from single neurons in anaesthetized,
      paralysed and artificially ventilated rats. Ionophoretic application of
      alpha,beta-methylene-ATP, adenosine 5'-O-(2-thiodiphosphate), UTP, 2-methylthio
      ATP and ATP altered the ongoing activity in the majority of neurons (>74% of
      neurons), generally causing increases in the firing rate. Nine of 11 cells with
      presumed spinal projection were excited by ATP and/or the P2X-selective agonist
      alpha,beta-methylene-ATP. Desensitization of the excitatory responses to
      alpha,beta-methylene-ATP was observed in four of 20 rostral ventrolateral medulla
      neurons. For the remainder of the rostral ventrolateral medulla neurons, the
      increase in firing rate evoked by alpha,beta-methylene-ATP, and by the other
      purine compounds tested, did not undergo desensitization. Suramin, a P2 receptor
      antagonist, blocked excitatory responses to adenosine 5'-O-(2-thiodiphosphate) or
      alpha,beta-methylene-ATP in five of 16 neurons. These results indicate that ATP
      can modulate the activity of neurons in the rostral ventrolateral medulla via
      actions at P2 purine receptors. The data suggest that both P2X and P2Y receptors
      are involved, and that the functional expression of these receptors within the
      rostral ventrolateral medulla is not uniform.

PMID- 10579578
TI  - Different discharge properties of rat facial nucleus motoneurons.
AB  - In this paper, we describe two types of putative facial motoneuron based on their
      electrophysiological properties and on their firing frequency adaptation as
      recorded in rat brainstem slices. Type I motoneurons (n = 33, 61%) were
      characterized by a sustained spike firing during depolarizing current injections
      and a marked depolarizing sag (inward rectification) during hyperpolarizing
      pulses. The time-course and voltage-dependence of the inward rectification
      together with the finding that it was blocked by Cs+ are consistent with the
      involvement of a Na+ -and K+ -mediated Q current. Type II motoneurons (n = 21,
      39%) were identified by a fast spike firing adaptation. Type II cells showed a
      less pronounced inward rectification with hyperpolarizing current pulses and a
      higher discharge rate than type I cells during depolarizing current pulses. These
      distinct discharge properties imply the activation of a Ca2+ -dependent K+
      current, because when carbachol was added to the bath, or the slice was exposed
      to a Ca2+ -free solution, a decrease was noticed in the firing frequency
      adaptation. The two types of motoneuron were further differentiated by the
      initial delay of the first spike, observed only in type I cells, which was
      blocked by bath application of 4-aminopyridine, indicating the presence of a K+ 
      mediated A current. The addition of 4-aminopyridine to the bath also increased
      the firing rate due to a decrease of the post-spike afterhyperpolarization.
      However, the two types of motoneuron were not morphologically differentiated.
      Facial motoneurons exhibited rhythmic membrane potential oscillations (8-20 Hz)
      at depolarized membrane potentials or during the silence following spike
      frequency adaptation. It is suggested that the intrinsic properties of these two
      types of facial motoneuron may be relevant in the government of distinct facial
      muscle activities. The fact that their discharge rate and the level of spike
      frequency adaptation were modified by altering some K+ currents suggests a
      potential plasticity in the modulation of motoneuron firing activities depending
      upon functional motor needs.

PMID- 10579579
TI  - Changes in calcium signalling in dorsal horn neurons in rats with streptozotocin
      induced diabetes.
AB  - Intracellular calcium signalling was studied in the dorsal horn from neurons of
      rats with streptozotocin-induced diabetes versus control animals. The cytoplasmic
      Ca2+ concentration ([Ca2+]i) was measured in Fura-2 acetoxymethyl ester-loaded
      dorsal horn neurons from acutely isolated spinal cord slices using a fluorescence
      technique. The recovery of depolarization-induced [Ca2+]i increase was delayed in
      diabetic neurons compared with normal animals. In normal neurons, [Ca2+]i after
      the end of KCl depolarization recovered to the basal level monoexponentially with
      a time constant of 8.0+/-0.5 s (n = 23), while diabetic neurons showed two
      exponentials in the [Ca2+]i recovery. The time constants of these exponentials
      were 7.2+/-0.5 and 23.0+/-0.6 s (n = 19), respectively. The amplitude of calcium
      release from caffeine-sensitive endoplasmic reticulum calcium stores became
      significantly smaller in diabetic neurons. The amplitudes of [Ca2+]i transients
      evoked by 30 mM caffeine were 268+/-29 nM (n = 13) and 31+/-9 nM (n = 17) in
      control and diabetic neurons, respectively. We conclude that streptozotocin
      induced diabetes is associated with prominent changes in the mechanisms
      responsible for [Ca2+]i regulation, which presumably include a slowdown of Ca2+
      elimination from the cytoplasm by the endoplasmic reticulum.

PMID- 10579580
TI  - Calcium channels controlling acetylcholine release in the guinea-pig isolated
      anterior pelvic ganglion: an electropharmacological study.
AB  - An electropharmacological analysis of the type(s) of calcium channel controlling
      neurotransmitter release in preganglionic sympathetic nerve terminals in the
      guinea-pig anterior pelvic ganglion has been carried out. Conventional
      intracellular recording techniques were used to record excitatory postsynaptic
      potentials as a measure of neurotransmitter release. Excitatory postsynaptic
      potentials were abolished by hexamethonium (30-100 microM) and are therefore
      mediated by acetylcholine acting at nicotinic receptors. In studies of more than
      150 cells, the N-type calcium channel blocker omega-conotoxin GVIA (100-300 nM)
      failed to block the initiation of the nerve impulse by the excitatory
      postsynaptic potential. In single-cell studies, omega-conotoxin GVIA (1 microM)
      sometimes altered the configuration of the excitatory postsynaptic potential/cell
      body nerve action potential complex, but on only one occasion was the excitatory
      postsynaptic potential reduced below the threshold required to initiate the
      action potential. Nifedipine (10 microM), omega-agatoxin IVA (100 nM) and omega
      conotoxin MVIIC (300 nM), applied alone or in combination with omega-conotoxin
      GVIA (300 nM), were also ineffective. However, excitatory postsynaptic potentials
      evoked by trains of stimuli (0.1-0.5 Hz) were markedly reduced or abolished by
      the non-specific calcium channel blocker omega-grammotoxin SIA (300 nM). When
      trains of stimuli were delivered at higher frequencies (4 Hz), the block induced
      by omega-grammotoxin SIA could be overcome, and excitatory postsynaptic
      potentials were able to initiate action potentials even when omega-conotoxin
      GVIA, omega-agatoxin IVA and omega-conotoxin MVIIC were also present. The calcium
      channel(s) controlling acetylcholine release was (were) blocked by low
      concentrations of cadmium ions (30 microM) at all stimulation frequencies studied
      (0.1-50 Hz). Thus, the dominant calcium channels controlling acetylcholine
      release in sympathetic ganglia are not the L, N, P or Q types. At low frequencies
      of stimulation, omega-grammotoxin SIA-sensitive calcium channels play a dominant
      role in acetylcholine release, but at higher stimulation frequencies yet another
      pharmacologically distinct calcium channel (or subtype) supports neurotransmitter
      release.

PMID- 10579581
TI  - Nitric oxide is required for the maintenance but not initiation of ganglionic
      long-term potentiation.
AB  - The role of nitric oxide in long-term potentiation of the nicotinic pathway of
      synaptic transmission in the isolated superior cervical ganglia of rat was
      studied. Long-term potentiation was induced by a brief tetanizing pulse (tetanus,
      20 Hz/20 s) to the preganglionic nerve. The amplitude of the extracellularly
      recorded postganglionic compound action potential was used as an index of
      synaptic transmission. Pretreatment with the nitric oxide synthase inhibitor N(G)
      nitro-L-arginine methyl ester (10 microM) or L-N(G)-nitro-arginine (10 microM) 30
      min before tetanus, inhibited long-term potentiation. The inactive enantiomer of
      the nitric oxide synthase inhibitor, N(G)-nitro-D-arginine methyl ester (10
      microM), failed to inhibit the long-term potentiation when given 30 min before
      the tetanus. Washout of L-N(G)-nitro-arginine, but not N(G)-nitro-L-arginine
      methyl ester, resulted in complete recovery of long-term potentiation. The nitric
      oxide synthase inhibitor had no significant effect on the basal ganglionic
      neurotransmission or post-tetanic potentiation. Furthermore, established long
      term potentiation was blocked by superfusion of ganglia with N(G)-nitro-L
      arginine methyl ester 1 h after a tetanus. Pretreatment of ganglia with the
      nitric oxide donor, sodium nitroprusside (100 microM), or the nitric oxide
      synthase substrate, L-arginine (1 mM), completely prevented the inhibitory
      effects of N(G)-nitro-L-arginine methyl ester on the tetanus-induced long-term
      potentiation. These findings present evidence for a requirement of nitric oxide
      for the maintenance but not induction of long-term potentiation in rat isolated
      superior cervical ganglia.

PMID- 10579582
TI  - Neurons in laminae III and IV of the rat spinal cord with the neurokinin-1
      receptor receive few contacts from unmyelinated primary afferents which do not
      contain substance P.
AB  - We have previously demonstrated that neurons in laminae III and IV of the spinal
      dorsal horn which possess the neurokinin-1 receptor and have long dorsal
      dendrites receive a major synaptic input from substance P-containing primary
      afferents and a more limited input from myelinated afferents. In the present
      study we have carried out a quantitative analysis of the contacts which cells of
      this type receive from two other classes of unmyelinated primary afferent: those
      which contain somatostatin and those without neuropeptides. We found that
      although boutons belonging to both of these types of afferent do form contacts
      with neurons of this type, the contacts are far less numerous than those formed
      by substance P-containing afferents. In laminae I and II, the density of contacts
      which dendrites of these cells received from somatostatin-containing afferents
      was 1.2/100 microm and that from non-peptidergic C afferents was 2.0/100 microm,
      which is far lower than our previous estimate of 18.8/100 microm from substance P
      containing fibres in these laminae. These results indicate that although the
      dendrites of large neurons in laminae III and IV which possess the neurokinin-1
      receptor pass through regions of the dorsal horn in which many types of primary
      afferent terminate, their synaptic input from primary afferents is organized in a
      highly selective manner.

PMID- 10579583
TI  - Protein carbonyl formation and tyrosine nitration as markers of oxidative damage
      during ischaemia-reperfusion injury to rat sciatic nerve.
AB  - We have investigated the role of oxidative damage in peripheral nerve ischaemia
      reperfusion injury using a rat sciatic nerve model. After 5 h ischaemia blood
      flow to the sciatic nerve was restarted and markers of oxidative damage measured
      after various times of reperfusion. As a marker of protein oxidative damage,
      protein carbonyl formation was measured using a sensitive enzyme-linked
      immunosorbent assay. Protein carbonyl content was unaffected by ischaemia alone,
      but increased by 55% after 12-18 h reperfusion, correlating with the onset of
      nerve pathology. Pretreatment with the xanthine oxidase inhibitor allopurinol
      prevented these abnormalities, suggesting that xanthine oxidase activity is
      proximal to oxidative damage during reperfusion injury. To determine whether
      formation of the potent oxidant peroxynitrite from nitric oxide and superoxide
      contributed to ischaemia-reperfusion injury, we measured the accumulation of 3
      nitrotyrosine residues in proteins. Only one protein of 49,000 mol. wt contained
      significant amounts of 3-nitrotyrosine residues which was shown to be glial
      fibrillary acidic protein, an abundant cytoskeletal protein in Schwann cells.
      However glial fibrillary acidic protein contained 3-nitrotyrosine residues prior
      to ischaemia-reperfusion, and the amount of nitrated tyrosine residues in total
      glial fibrillary acidic protein did not increase significantly during
      reperfusion, therefore it was not possible to draw conclusions about the role of
      peroxynitrite in nerve reperfusion injury.

PMID- 10579584
TI  - Prevention of neuronal apoptosis by phorbol ester-induced activation of protein
      kinase C: blockade of p38 mitogen-activated protein kinase.
AB  - Consistent with previous studies on cell lines and non-neuronal cells, specific
      inhibitors of protein kinase C induced mouse primary cultured neocortical neurons
      to undergo apoptosis. To examine the complementary hypothesis that activating
      protein kinase C would attenuate neuronal apoptosis, the cultures were exposed
      for 1 h to phorbol-12-myristate-13-acetate, which activated protein kinase C as
      evidenced by downstream enhancement of the mitogen-activated protein kinase
      pathway. Exposure to phorbol-12-myristate-13-acetate, or another active phorbol
      ester, phorbol-12,13-didecanoate, but not to the inactive ester, 4alpha-phorbol
      12,13-didecanoate, markedly attenuated neuronal apoptosis induced by serum
      deprivation. Phorbol-12-myristate-13-acetate also attenuated neuronal apoptosis
      induced by exposure to beta-amyloid peptide 1-42, or oxygen-glucose deprivation
      in the presence of glutamate receptor antagonists. The neuroprotective effects of
      phorbol-12-myristate-13-acetate were blocked by brief (non-toxic) concurrent
      exposure to the specific protein kinase C inhibitors, but not by a specific
      mitogen-activated protein kinase 1 inhibitor. Phorbol-12-myristate-13-acetate
      blocked the induction of p38 mitogen-activated protein kinase activity and
      specific inhibition of this kinase by SB 203580 attenuated serum deprivation
      induced apoptosis. c-Jun N-terminal kinase 1 activity was high at rest and not
      modified by phorbol-12-myristate-13-acetate treatment. These data strengthen the
      idea that protein kinase C is a key modulator of several forms of central
      neuronal apoptosis, in part acting through inhibition of p38 mitogen-activated
      protein kinase regulated pathways.

PMID- 10579585
TI  - Survival of chronically-injured neurons can be prolonged by treatment with
      neurotrophic factors.
AB  - Axonal regeneration by chronically-injured supraspinal neurons can be enhanced by
      neurotrophic factor treatment at the site of injury, although the number of
      regenerating neurons decreases as the interval between spinal cord injury and
      treatment increases. This study investigated whether this decline in regenerative
      response could be due to continued loss of neurons during the post-injury period.
      Adult rats received a cervical hemisection lesion and axotomized neurons were
      labeled by retrograde transport of True Blue from the lesion site. Animals were
      killed one, four or eight weeks after injury and surviving neurons (True Blue
      labeled) were counted in the red nucleus and lateral vestibular nucleus. The
      neuron number in the lateral vestibular nucleus was stable for eight weeks after
      spinal cord injury, while survival in the red nucleus decreased by 25% between
      four and eight weeks. To test how neurons respond to a second injury with or
      without trophic factor treatment, at four, eight, 14 or 22 weeks after injury the
      lesion cavity was enlarged by 0.5 mm in a rostral direction. Gel foam saturated
      with ciliary neurotrophic factor, brain-derived neurotrophic factor or basic
      fibroblast growth factor was placed into the cavity. Animals were killed four
      weeks later. Re-injury of the spinal cord caused a significant decrease in neuron
      survival in both the red nucleus and lateral vestibular nucleus, the effects of
      which were lessened by treatment with ciliary neurotrophic factor or brain
      derived neurotrophic factor for the red nucleus and with ciliary neurotrophic
      factor for the lateral vestibular nucleus, when re-injured at four or eight
      weeks. Basic fibroblast growth factor did not affect neuron survival at any time
      post-injury. Ciliary neurotrophic factor was not effective with longer delays (14
      or 22 weeks) between the initial injury and re-injury. These results indicate a
      delayed pattern of secondary neuronal cell loss after spinal cord injury that is
      exaggerated by re-injury, but which can be ameliorated by treatment with
      neurotrophic factors.

PMID- 10579586
TI  - Localization of a glutathione-dependent dehydroascorbate reductase within the
      central nervous system of the rat.
AB  - In this study, we describe for the first time the occurrence, within the central
      nervous system of the rat, of a dehydroascorbate reductase analogous to the one
      we recently described in the liver. Dehydroascorbate reductase plays a pivotal
      role in regenerating ascorbic acid from its oxidation product, dehydroascorbate.
      In a first set of experiments, we showed that a dehydroascorbate reductase
      activity is present in brain cytosol; immunoblotting analysis confirmed the
      presence of an immunoreactive cytosolic protein in selected brain areas.
      Immunotitration showed that approximately 65% of dehydroascorbate reductase
      activity of brain cytosol which was recovered in the ammonium sulphate fraction
      can be attributed to this enzyme. Using immunohistochemistry, we found that a
      variety of brain areas expresses the enzyme. Immunoreactivity was confined to the
      gray matter. Amongst the several brain regions, the cerebellum appears to be the
      most densely stained. The enzyme was also abundant in the hippocampus and the
      olfactory cortex. The lesion of norepinephrine terminals following systemic
      administration of DSP-4 markedly decreased immunoreactivity in the cerebellum.
      Apart from the possible co-localization of the enzyme with norepinephrine, the
      relative content of dehydroascorbate reductase in different brain regions might
      be crucial in conditioning regional sensitivity to free radical-induced brain
      damage. Given the scarcity of protective mechanisms demonstrated in the brain,
      the discovery of a new enzyme with antioxidant properties might represent a
      starting-point to increase our knowledge about the antioxidant mechanisms
      operating in several central nervous system disorders.

PMID- 10579587
TI  - Characteristics of ischemia-induced taurine release in the developing mouse
      hippocampus.
AB  - Taurine release in the developing hippocampus is markedly potentiated in
      ischemia. The mechanisms of the ischemia-induced release were studied in
      hippocampal slices from seven-day-old mice using a superfusion system. The basal
      release of [3H]taurine was significantly increased in media under normal
      conditions, but the ischemia-evoked release decreased in Na+ -free media,
      indicating the participation of Na+ -dependent transport processes. The
      involvement of taurine transporters in the release was confirmed with the
      structural analogs, hypotaurine and beta-alanine. These amino acids potentiated
      the release by trans-stimulation, but not in Na+ -free media. In the absence of
      Ca2+, the basal taurine release was markedly increased in normoxia but diminished
      in ischemia, indicating that a part of basal taurine release in ischemia is Ca2+
      dependent. On the other hand, the K+ stimulation of taurine release was preserved
      in Ca2+ -free medium. The phospholipase and protein kinase inhibitors had no
      effect on ischemia-induced taurine release, nor did the chloride channel blockers
      4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonate (2 mM) and
      diisothiocyanostilbene-2,2'-disulfonate (0.1 mM) affect the release in ischemia.
      The increase in extracellular levels of taurine in the immature hippocampus in
      ischemia may serve as an important protective mechanism against excitotoxicity,
      to which the developing brain is particularly vulnerable, and contribute to the
      resistance of the immature brain to hypoxia.

PMID- 10579588
TI  - Comparison of munc-18 and cdk5 expression in the nervous system during mouse
      embryogenesis.
AB  - Cyclin-dependent kinase-5 (Cdk5) and its neuron-specific activator, p35, are
      essential for the proper migration of neurons. While the defects in p35 null mice
      are largely confined to the cerebral cortex, the anomalies in cdk5 nullizygous
      mice are also evident in the hippocampus and cerebellum. This suggested that
      additional cyclin-like activators, such as Munc-18, must be coexpressed with Cdk5
      in some migrating neurons. Therefore, the expression patterns of munc-18 and cdk5
      were determined in the developing mouse nervous system by in situ hybridization.
      In the embryonic day 11.5-13.5 developing neocortex, cdk5 was expressed in the
      proliferative zone and also in migratory and postmitotic neurons. In contrast,
      munc-18 messenger RNA was only detected in postmigratory, differentiated neurons.
      In the cerebellum and the hippocampus, cdk5 was expressed in proliferative,
      migrating and postmigratory neurons, while munc-18 was expressed in migrating and
      postmigratory neurons. This supports the hypothesis that Munc-18 could compensate
      for the loss of p35 in migrating neurons in the hippocampus and cerebellum, but
      not the cerebral cortex. Munc-18 levels increased substantially during late
      embryogenesis and into adulthood. Therefore, the function of Munc-18 is most
      likely relevant to mature neurons and any redundancy with p35 in migration is
      probably fortuitous.

PMID- 10579589
TI  - Influence of cutaneous nerves on keratinocyte proliferation and epidermal
      thickness in mice.
AB  - We evaluated the influence of skin innervation on the epidermis in mice. The rich
      innervation of skin was demonstrated by immunocytochemistry with protein gene
      product 9.5, a ubiquitin carboxy hydrolase. Protein gene product-immunoreactive
      nerve fibers were in the epidermis, subepidermal plexus, dermal nerve trunks, and
      nerve terminals around sweat glands. Effects of denervation on the plantar
      surface of the hind foot was assessed by comparing the thickness of the
      epidermis, which was innervated by the sciatic nerve. Within 48 h after
      sectioning of the sciatic nerve, protein gene product (+)-nerves in the territory
      of the sciatic nerve were completely degenerated. There was a significant
      thinning of the denervated epidermis 72 h post-transection (30.5+/-1.1 vs 41.4+/
      2.9 microm, 74+/-4% of the control side). The reduction in epidermal thickness
      persisted when skin remained denervated (69-75% of the control side).
      Incorporation of bromodeoxyuridine was reduced 24 h after denervation (71+/-6% of
      the control side). Reduction in bromodeoxyuridine-incorporation was most
      pronounced within 48 h after denervation (19+/-6% of the control side).
      Therefore, the reduction in bromodeoxyuridine-labeling followed a similar
      temporal course as the thinning of the epidermis (25-50%). Both epidermal
      thinning and reduced bromodeoxyuridine-labeling were reversed by epidermal
      reinnervation three months after denervation. Patterns of keratinocyte
      differentiation and programmed cell death were unaffected by skin denervation.
      These findings are consistent with the notion that skin innervation exerts
      influence on the proliferation of keratinocytes and the thickness of the
      epidermis, and offers a new look at the interaction between nociceptive nerves
      and their innervated targets.

PMID- 10579590
TI  - High-voltage-activated calcium channel messenger RNA expression in the 140-3
      neuroblastoma-glioma cell line.
AB  - Expression of calcium channel alpha1 subunits in oocytes or cell lines has proven
      to be a powerful method in the analysis of structure-function relations, but
      these experimental systems are of limited value in the examination of neuron
      specific functions such as transmitter release. Cell lines derived from neurons
      are often capable of these functions, but their intrinsic calcium channel alpha1
      subunits are complicating factors in experimental design. We have examined the
      biophysical and molecular properties of calcium channels in a little studied
      neuroblastoma-glioma hybrid cell line, 140-3, a close relative of the NG108-15
      cell line, to test whether this cell line might serve a role as an expression
      system for neural mechanisms. This cell was selected as it contains an intact
      transmitter release mechanism yet secretes little in response to depolarization.
      Patch-clamp recording revealed only a prominent low-threshold, rapidly
      inactivating calcium current with a single-channel conductance of approximately 7
      pS that was identified as T type. A search for calcium channel alpha1 subunit
      messenger RNA in the 140-3 cells with three different tests only revealed
      alpha1C, whereas alpha1A-alpha1C were present in the parent NG108-15 line. We
      made a particular effort to search for alpha1E, since this subunit has been
      associated with a low-voltage-activated current. Our findings suggest that, since
      the principal nerve terminal-associated calcium channels (alpha1A, alpha1B,
      alpha1E) are absent in the 140-3 cell, this cell line may prove a particularly
      useful model for the analysis of the role of high-voltage-activated calcium
      channels in complex functions of neuronal cells.

PMID- 10579591
TI  - Endocytic vacuoles formed following a short pulse of K+ -stimulation contain a
      plethora of presynaptic membrane proteins.
AB  - It is now well established that the membrane of synaptic vesicles is recycled
      following exocytosis. However, little is known concerning the identity of the
      primary or secondary endocytic structures and their molecular composition. Using
      cultured rat cerebellar granule cells we combined uptake of horseradish
      peroxidase as a fluid phase marker and immunogold labeling for a variety of
      presynaptic proteins to assess the molecular identity of the stimulation-induced
      endocytic compartments. Short periods (5 or 30 s) of stimulation with 50 mM KCl
      were followed by periods of recovery for up to 30 min. Stimulation resulted in
      the formation of horseradish-peroxidase-filled vacuoles in the axonal
      varicosities as the apparent primary endocytic compartment. Horseradish
      peroxidase-filled synaptic vesicles were formed when stimulated cells were
      allowed to recover in horseradish peroxidase-free culture medium. Horseradish
      peroxidase-filled vacuoles as wells as vesicles contained the synaptic vesicle
      membrane proteins VAMP II, synaptotagmin, SV2, and synaptophysin, the vesicle
      associated proteins rab 3A and synapsin I, and in addition SNAP-25. No
      incorporation of vesicle proteins into the plasma membrane was observed.
      Horseradish peroxidase-filled vesicles and vacuoles generated on incubation of
      unstimulated granule cells with horseradish peroxidase for prolonged periods of
      time were equally immunolabeled. Renewed stimulation of prestimulated granule
      cells with either 100 mM KCl or 30 microM Ca2+ ionophore A23187 resulted in a
      reduction of horseradish peroxidase-filled vacuoles suggesting that the vacuolar
      membrane compartment was exocytosis-competent. Our results suggest that
      varicosities of cultured cerebellar granule cells possess a fast stimulation
      induced pathway for recycling the entire synaptic vesicle membrane compartment.
      The primary endocytic compartment represents not a synaptic vesicle but a
      somewhat larger vesicle protein-containing vacuolar entity from which smaller
      vesicles of identical protein composition may be regenerated. Endocytic vacuoles
      and synaptic vesicles share membrane and membrane-associated proteins and
      presumably also major functional properties.

PMID- 10579592
TI  - Neuronal-specific and nerve growth factor-inducible expression directed by the
      preprotachykinin-A promoter delivered by an adeno-associated virus vector.
AB  - The ability to manipulate the expression of genes within neurons provides unique
      opportunities to study the role of individual gene products in nervous system
      function. Virus vectors are a potentially rapid tool for the experimental
      manipulation of gene expression in the mammalian nervous system. However, a block
      to the use of virus vector systems in neurobiology is often the lack of cell
      specific expression of the gene within the nervous system, and the immune and
      inflammatory responses to both the virus vector and the delivered gene. We have
      generated an adeno-associated virus vector that exploits the restricted
      expression pattern of the rat preprotachykinin-A promoter to support reporter
      gene expression. We demonstrate that this virus has a neuronal-specific
      expression pattern. Moreover, it is shown for the first time that the proximal
      rat preprotachykinin-A promoter is nerve growth factor inducible. This virus will
      be a useful tool to (i) modify neuronal phenotype by expressing therapeutic
      molecules or antisense nucleic acid and (ii) dissect the signal transduction
      pathways that regulate promoter function in vivo.

PMID- 10579593
TI  - Defense styles explain psychiatric symptoms: an empirical study.
AB  - To examine the relation between psychiatric symptoms and defense mechanisms, we
      administered two questionnaires, the Symptom Check-list 90 (SCL-90) and the
      Defense Style Questionnaire (DSQ) to 122 psychiatric out-patients and to a
      community sample of 337 subjects. Using regression analysis, we found that 51.8%
      of the variation in subject's Global Severity Index value could be explained by
      his defense style. Of the three defense styles, the immature style explained most
      of the variation in the symptoms. We found little overall evidence for specific
      connections between particular defenses and symptoms. Projection and dissociation
      were central in most of the symptom dimensions. We compared patients and controls
      with the same level of general symptom severity and found that patients used
      significantly more devaluation and splitting, and controls used significantly
      more altruism and idealization. Whether defenses predispose to certain
      symptomatology or are one of its aspects is discussed.

PMID- 10579594
TI  - Initial results, reliability, and validity of a mental health survey of Mount
      Pinatubo disaster victims.
AB  - This report presents the initial results of a mental health survey of 351 tribal
      and non-tribal Mount Pinatubo disaster victims 6 years after they were displaced
      following the volcanic eruption in the Philippines on June 12, 1991. Mental
      illness prevalence rates in both Filipino ethnic groups were comparable to those
      found in a U.S. study using the same assessment instrument. Post-traumatic stress
      disorder (PTSD; 27.6%) and major depression (14.0%) were the two most frequent
      diagnoses. Diagnostic test-retest interviewer agreement was good for probable
      alcohol abuse (kappa = .65, agreement = 97%) and any mood disorder (kappa = .53,
      agreement = 91%) but was reduced for any anxiety disorder (kappa = .15, agreement
      = 81%) and separately evaluated PTSD (kappa = .18, agreement = 69%). Diagnostic
      test-retest agreement was good among typical Filipinos (mean kappa = .66, mean
      agreement = 93%) but was reduced among tribal aborigines (mean = .30, mean
      agreement = 86%). Internal consistency of the PTSD rating scale was high within
      and across both ethnic groups, including total scale (alpha = .91) and DSM-IV
      Criteria B, C, and D sub-scales (alpha = .80, 81, and .78, respectively). With
      the exception of probable alcohol abuse, construct and criterion validity was
      demonstrated among both tribal and non-tribal Filipinos for all classes of
      psychiatric disorders by comparing diagnostic results with respondents' views of
      their physical and mental health and level of functional impairment. Overall, DSM
      IV mood, anxiety, alcohol use, and PTSDs with adequate reliability and construct
      and criterion validity were made in this culturally diverse, non-Western,
      disaster victim population. However, test-retest diagnostic agreement was reduced
      for anxiety disorders and among aboriginal respondents, and validity was not
      demonstrated for probable alcohol abuse.

PMID- 10579595
TI  - Image control and symptom expression in posttraumatic stress disorder.
AB  - Despite the devastating impact of affective dysregulation in posttraumatic stress
      disorder (PTSD), there has been little research on how trauma relates to affect
      regulation. This study examines the relationship between the cognitive capacity
      to control mental images and symptoms of individuals with (N = 23) and without (N
      = 23) PTSD after exposure to SCUD missile attacks during the Gulf War. The
      capacity to control mental images, symptoms of posttrauma, anxiety, and anger
      were assessed. PTSD subjects with a high image control reported a higher capacity
      to control anger, lower levels of anger state and expression, and lower levels of
      intrusive symptoms compared with PTSD subjects with low image control. In
      individuals without PTSD, results show that the better the image control, the
      lower the control of anger and the higher the expression of anger. Image control
      seems to play different functions in the emotional regulation of normal subjects
      (facilitatory) and PTSD patients (protective).

PMID- 10579596
TI  - Compensation-seeking and extreme exaggeration of psychopathology among combat
      veterans evaluated for posttraumatic stress disorder.
AB  - We extended the work of Smith and Frueh (1996) by evaluating whether combat
      veterans classified as "extreme exaggerators" were more likely to be compensation
      seeking, and to report greater levels of psychopathology across self-report
      instruments than "nonexaggerators." Of 119 veterans who completed the Minnesota
      Multiphasic Personality Inventory-2 (MMPI-2) at an outpatient posttraumatic
      stress disorder (PTSD) clinic, 26 (22%) and 17 (14%) were identified as extreme
      exaggerators using two MMPI-2 validity indicators with stringent cutoffs (F-K >
      or = 22; F(p) > or = 8). These veterans were much more likely to be compensation
      seeking and scored much higher on self-report measures of various psychological
      symptoms than nonexaggerators, despite having lower rates of PTSD diagnoses and
      similar rates of other comorbid diagnoses. Findings suggest that the validity
      indices of the MMPI-2 can play a critical role, as a screening instrument, in
      identifying veterans who may be exaggerating their psychopathology to gain
      disability compensation.

PMID- 10579597
TI  - Mood and the menopausal transition.
AB  - This study determined which variables affect women's mood state during the
      menopausal transition by using six prospective annual assessments of a community
      based sample of 354 Australian mid-aged women. Repeated measures multivariate
      analysis of covariance found that negative mood scores decreased significantly
      over time and were not related to natural menopausal transition, follicle
      stimulating hormone, estradiol, inhibin, age, or education. The magnitude of
      negative mood was significantly predicted by baseline reporting of premenstrual
      complaints, negative attitudes to ageing and menopause, and parity of one. During
      follow-up, the magnitude of negative mood was significantly adversely affected
      by: prior experience of negative mood, experience of bothersome symptoms, poor
      self-rated health, negative feelings for partner, no partner, current smoking,
      low exercise, daily hassles, and high stress. Negative mood was reduced by
      decreasing symptoms, improving health, positive feelings for partner, gaining a
      partner, and reducing stress. The menopausal transition had an indirect effect in
      amplifying the effect of reducing paid work, poor health, and daily hassles.

PMID- 10579598
TI  - Alternative therapy use by psychiatric outpatients.

PMID- 10579599
TI  - Wandering and associated factors in psychiatric inpatients with dementia of
      Alzheimer's type in Taiwan: clinical implications for management.

PMID- 10579600
TI  - Compulsive behavior in generalized anxiety disorder and obsessive-compulsive
      disorder.

PMID- 10579601
TI  - Multicenter patient records research: security policies and tools.
AB  - The expanding health information infrastructure offers the promise of new medical
      knowledge drawn from patient records. Such promise will never be fulfilled,
      however, unless researchers first address policy issues regarding the rights and
      interests of both the patients and the institutions who hold their records. In
      this article, the authors analyze the interests of patients and institutions in
      light of public policy and institutional needs. They conclude that the
      multicenter study, with Institutional Review Board approval of each study at each
      site, protects the interests of both. "Anonymity" is no panacea, since patient
      records are so rich in information that they can never be truly anonymous.
      Researchers must earn and respect the trust of the public, as responsible
      stewards of facts about patients' lives. The authors find that computer security
      tools are needed to administer multicenter patient records studies and describe
      simple approaches that can be implemented using commercial database products.

PMID- 10579602
TI  - The decline and fall of Esperanto: lessons for standards committees.
AB  - In 1887, Polish physician Ludovic Zamenhof introduced Esperanto, a simple, easy
      to-learn planned language. His goal was to erase communication barriers between
      ethnic groups by providing them with a politically neutral, culturally free
      standard language. His ideas received both praise and condemnation from the
      leaders of his time. Interest in Esperanto peaked in the 1970s but has since
      faded somewhat. Despite the logical concept and intellectual appeal of a standard
      language, Esperanto has not evolved into a dominant worldwide language. Instead,
      English, with all its idiosyncrasies, is closest to an international lingua
      franca. Like Zamenhof, standards committees in medical informatics have
      recognized communication chaos and have tried to establish working models, with
      mixed results. In some cases, previously shunned proprietary systems have become
      the standard. A proposed standard, no matter how simple, logical, and well
      designed, may have difficulty displacing an imperfect but functional "real life"
      system.

PMID- 10579603
TI  - IAIMS: an interview with Dick West. Integrated Advanced Information Management
      Systems. Interview by Joan S Ash and Frances E Johnson.
AB  - Richard T. West, IAIMS (Integrated Advanced Information Management Systems)
      Program Officer at the National Library of Medicine for 13 years, reflects on the
      origin, development, effectiveness, and future of IAIMS efforts. He dwells on the
      changes that have taken place as the concept of IAIMS has evolved from a
      technology-based to an organization-based level of integration. The role of IAIMS
      in patient care, education, and research is discussed, along with the role of the
      librarian in the implementation of IAIMS programs. He sees a need for training
      for librarians, informaticians, and others in preparation for these efforts and
      for the development of academic reward systems that encourage them. He expresses
      a desire for those working in information technology in hospitals to gain a
      clearer understanding of IAIMS, because the concept fits hospitals as well as
      academic health science centers. He exhorts informaticians to bring to reality
      the futuristic fantasies of a new information world.

PMID- 10579604
TI  - Medical informatics education: the University of Utah experience.
AB  - The University of Utah has been educating health professionals in medical
      informatics since 1964. Over the 35 years since the program's inception, 272
      graduate students have studied in the department. Most students have been male
      (80 percent) and have come from the United States (75 percent). Students entering
      the program have had diverse educational backgrounds, most commonly in medicine,
      engineering, computer science, or biology (59 percent of all informatics
      students). A total of 209 graduate degrees have been awarded, with an overall
      graduation rate of 87 percent since the program's start. Alumni are located in
      the United States (91 percent) and abroad (9 percent); half (51 percent) have
      remained in Utah. Former students are employed in a wide variety of jobs,
      primarily concerned with the application of medical informatics in sizable health
      care delivery organizations. Trends toward increasing managerial responsibility
      for medical informatics graduates and the emergence of the chief information
      officer role are noted.

PMID- 10579605
TI  - Pilot study of a point-of-use decision support tool for cancer clinical trials
      eligibility.
AB  - Many adults with cancer are not enrolled in clinical trials because caregivers do
      not have the time to match the patient's clinical findings with varying
      eligibility criteria associated with multiple trials for which the patient might
      be eligible. The authors developed a point-of-use portable decision support tool
      (DS-TRIEL) to automate this matching process. The support tool consists of a hand
      held computer with a programmable relational database. A two-level hierarchic
      decision framework was used for the identification of eligible subjects for two
      open breast cancer clinical trials. The hand-held computer also provides protocol
      consent forms and schemas to further help the busy oncologist. This decision
      support tool and the decision framework on which it is based could be used for
      multiple trials and different cancer sites.

PMID- 10579606
TI  - Organization of heterogeneous scientific data using the EAV/CR representation.
AB  - Entity-attribute-value (EAV) representation is a means of organizing highly
      heterogeneous data using a relatively simple physical database schema. EAV
      representation is widely used in the medical domain, most notably in the storage
      of data related to clinical patient records. Its potential strengths suggest its
      use in other biomedical areas, in particular research databases whose schemas are
      complex as well as constantly changing to reflect evolving knowledge in rapidly
      advancing scientific domains. When deployed for such purposes, the basic EAV
      representation needs to be augmented significantly to handle the modeling of
      complex objects (classes) as well as to manage interobject relationships. The
      authors refer to their modification of the basic EAV paradigm as EAV/CR (EAV with
      classes and relationships). They describe EAV/CR representation with examples
      from two biomedical databases that use it.

PMID- 10579607
TI  - Semi-automated entry of clinical temporal-abstraction knowledge.
AB  - OBJECTIVES: The authors discuss the usability of an automated tool that supports
      entry, by clinical experts, of the knowledge necessary for forming high-level
      concepts and patterns from raw time-oriented clinical data. DESIGN: Based on
      their previous work on the RESUME system for forming high-level concepts from raw
      time-oriented clinical data, the authors designed a graphical knowledge
      acquisition (KA) tool that acquires the knowledge required by RESUME. This tool
      was designed using Protege, a general framework and set of tools for the
      construction of knowledge-based systems. The usability of the KA tool was
      evaluated by three expert physicians and three knowledge engineers in three
      domains-the monitoring of children's growth, the care of patients with diabetes,
      and protocol-based care in oncology and in experimental therapy for AIDS. The
      study evaluated the usability of the KA tool for the entry of previously elicited
      knowledge. MEASUREMENTS: The authors recorded the time required to understand the
      methodology and the KA tool and to enter the knowledge; they examined the
      subjects' qualitative comments; and they compared the output abstractions with
      benchmark abstractions computed from the same data and a version of the same
      knowledge entered manually by RESUME experts. RESULTS: Understanding RESUME
      required 6 to 20 hours (median, 15 to 20 hours); learning to use the KA tool
      required 2 to 6 hours (median, 3 to 4 hours). Entry times for physicians varied
      by domain-2 to 20 hours for growth monitoring (median, 3 hours), 6 and 12 hours
      for diabetes care, and 5 to 60 hours for protocol-based care (median, 10 hours).
      An increase in speed of up to 25 times (median, 3 times) was demonstrated for all
      participants when the KA process was repeated. On their first attempt at using
      the tool to enter the knowledge, the knowledge engineers recorded entry times
      similar to those of the expert physicians' second attempt at entering the same
      knowledge. In all cases RESUME, using knowledge entered by means of the KA tool,
      generated abstractions that were almost identical to those generated using the
      same knowledge entered manually. CONCLUSION: The authors demonstrate that the KA
      tool is usable and effective for expert physicians and knowledge engineers to
      enter clinical temporal-abstraction knowledge and that the resulting knowledge
      bases are as valid as those produced by manual entry.

PMID- 10579608
TI  - Improving response to critical laboratory results with automation: results of a
      randomized controlled trial.
AB  - OBJECTIVE: To evaluate the effect of an automatic alerting system on the time
      until treatment is ordered for patients with critical laboratory results. DESIGN:
      Prospective randomized controlled trial. INTERVENTION: A computer system to
      detect critical conditions and automatically notify the responsible physician via
      the hospital's paging system. PATIENTS: Medical and surgical inpatients at a
      large academic medical center. One two-month study period for each service. MAIN
      OUTCOMES: Interval from when a critical result was available for review until an
      appropriate treatment was ordered. Secondary outcomes were the time until the
      critical condition resolved and the frequency of adverse events. METHODS: The
      alerting system looked for 12 conditions involving laboratory results and
      medications. For intervention patients, the covering physician was automatically
      notified about the presence of the results. For control patients, no automatic
      notification was made. Chart review was performed to determine the outcomes.
      RESULTS: After exclusions, 192 alerting situations (94 interventions, 98
      controls) were analyzed. The intervention group had a 38 percent shorter median
      time interval (1.0 hours vs. 1.6 hours, P = 0.003; mean, 4.1 vs. 4.6 hours, P =
      0.003) until an appropriate treatment was ordered. The time until the alerting
      condition resolved was less in the intervention group (median, 8.4 hours vs. 8.9
      hours, P = 0.11; mean, 14.4 hours vs. 20.2 hours, P = 0.11), although these
      results did not achieve statistical significance. The impact of the intervention
      was more pronounced for alerts that did not meet the laboratory's critical
      reporting criteria. There was no significant difference between the two groups in
      the number of adverse events. CONCLUSION: An automatic alerting system reduced
      the time until an appropriate treatment was ordered for patients who had critical
      laboratory results. Information technologies that facilitate the transmission of
      important patient data can potentially improve the quality of care.

PMID- 10579609
TI  - Development of fetal heart rate and behavior: indirect measures to assess the
      fetal nervous system.

PMID- 10579610
TI  - No transfer in a planned ICSI cycle: we cannot overcome some basic rules of human
      reproduction.
AB  - Since intracytoplasmic sperm injection (ICSI) has been introduced in the
      techniques for the non-causal treatment of severe male factor infertility failure
      of conventional in-vitro fertilisation and subsequent embryo transfer due to
      failed oocyte-fertilisation has become rare in these cases. Nonetheless, even in
      ICSI cycles cases occur where no transfer can be performed for several reasons.
      The contribution of sperm-, oocyte- and other factors are reviewed in this
      article. 78 (5.4%) out of 1433 ICSI cycles, performed from 1.1.1995 up to
      31.5.1997, in which no transfer could be done, despite a performed follicular
      puncture, were used as an example. 30 cycles with no fertilisation, 17 with no
      oocytes, 8 with only degenerated oocytes retrieved, 17 with no injectable sperms,
      4 with no normal fertilisation, and 2 with no cleavage after normal fertilisation
      were identified. In more than two thirds of the cases an oocyte factor,
      identified by a high FSH, low response to the hormonal stimulation or no
      fertilization despite the presence of motile sperms, was present. The other cases
      were attributed to a sperm factor or other causes. After one failed ICSI cycle -
      i.e. a cycle with no embryo transfer - the chance to conceive is very low in a
      subsequent cycle. Only 1 out of 24 cycles was successful in terms of an
      established and ongoing pregnancy.

PMID- 10579611
TI  - Gastric cancer in pregnancy: do pregnancy, age or female sex alter the prognosis?
      Case reports and review.
AB  - The coincidence of gastric cancer and pregnancy is a rare event. By literature
      research of the last three decades only 31 cases from outside Japan were
      identified including two own patients. The analysis of these and another 61 cases
      from Japan revealed the same predominance of poorly differentiated diffuse
      carcinomas with peritoneal and lymphatic metastases as in other young patients
      (<40 years). The survival rate is not obviously affected by pregnancy, young age
      or female sex. Experimental and epidemiological data suggest a protective effect
      of oestrogen against the induction of (intestinal) gastric cancer, while the
      cancer growth itself seems to be enhanced. Oestrogen receptors (ER) are found in
      about 22% of gastric cancer cells, especially in the poorly differentiated type.
      In contrast to target organs like the breast, ER in gastric cancer seem to be a
      sign of tumour adaptation involving e.g. the pathway of the epidermal growth
      factor. The results of treatment with anti-oestrogen are controversial in
      experimental and clinical settings. Due to the very common epigastric complaints
      early diagnosis of gastric cancer is even more difficult in pregnancy, so that
      early gastroscopy is advisable in patients on risk. Main effort should be given,
      however, to primary prevention.

PMID- 10579612
TI  - Tolerance of synthetic tissues in touch with vaginal scars: review to the point
      of 287 cases.
AB  - With an experience of 287 vaginal way operations using synthetic material, the
      authors make a review about the tolerance of the tissues. Three tissues were used
      (polytetrafluoroethylene, Dacron and Lyodura). The procedures are: Mouchel, big
      and small slings, Stamey and para vaginal refect procedures. At 30 months, the
      tolerance is 70% for Mouchel and 90% for sling procedures. The rejection rate
      with Dacron is globally 19.3% vs. 30.3% for Gore Tex . The authors describe
      materials' history, clinical symptoms and histopathologic signs of the
      intolerance. They think that the synthetic tissue tolerance is proportional to
      the exhibit surface and to the distance which separates it from the scar. The
      substratum of the intolerance process answers with two explanations: infection
      and foreign body reaction. Different theories are explained. Infection can be an
      ethiologic factor in early rejection. With rigid material, a small ulcer is
      formed and serves as a nidus for an ascending infection. Foreign material acts as
      an adjuvant by decreasing the number of bacteria necessary to produce an
      infection. The tissue reaction may be an immune response to Dacron, a delayed
      hypersensitivity reaction, or a graft vs. host antigen-antibody reaction. The
      ideal synthetic mesh material for pelvic surgery has yet to be developed.

PMID- 10579613
TI  - Goserelin acetate to avoid hysterectomy in pre-menopausal women with fibroids
      requiring surgery.
AB  - OBJECTIVE: To obtain information on the efficacy of repeated short cycles of GNRH
      agonist treatment in order to avoid hysterectomy in near-menopausal women with
      symptomatic fibroids. STUDY DESIGN: 72 pre-menopausal women (mean age 50 years)
      with one or more uterine fibroids >10 cm in diameter, symptomatic menorrhagia
      lasting three months or more and haemoglobin=9 g/dl entered the study. The
      patients were randomized with ratio of approximately 1:4 to: (a) immediate
      surgery; or (b) treatment with goserelin acetate. Patients randomized to
      goserelin acetate received a first cycle of 3.6 mg depot once every 28 days for
      four months. They were followed-up for three years. If menorrhagia was observed
      during the follow-up the woman was given goserelin acetate 3.6 mg depot for
      another three months. In case of further menorrhagia, a third cycle of goserelin
      acetate 3.6 mg depot for three months was given. After the third cycle of therapy
      if there was still menorrhagia, the patient underwent hysterectomy plus bilateral
      oophorectomy. RESULTS: A total of 13 women were assigned to the immediate surgery
      group and 59 to goserelin. Three years after trial entry a total of 23 women
      allocated to goserelin acetate treatment had undergone hysterectomy. CONCLUSION:
      This study suggests that GNRH agonists are efficacious for avoiding hysterectomy
      in women near menopause with uterine fibroids.

PMID- 10579614
TI  - Vaginectomy and laparoscopically assisted vaginal hysterectomy as adjunctive
      surgery for female-to-male transsexual reassignment: preliminary report.
AB  - OBJECTIVE: Reassignment surgery of the female-to-male transsexual is a rarely
      performed surgical procedure that should involve a gynecologist's consultation
      and expertise. This study examines the experience with this type of surgery at
      Baskent University Hospital, Ankara, Turkey, from the gynecologists' point of
      view. STUDY DESIGN: Eight patients underwent laparoscopically assisted vaginal
      hysterectomy, bilateral salpingo-oophorectomy and total vaginectomy, followed by
      phallic construction. Patients were followed up for 9 to 30 months post-surgery.
      RESULTS: The average operative time for total vaginectomy and laparoscopically
      assisted vaginal hysterectomy and bilateral salpingo-oophorectomy was 2 h and 20
      min. The estimated average blood loss was 250 ml. Other than one bladder
      perforation, which was repaired immediately and healed uneventfully, we
      encountered no operative or postoperative complications linked to the gynecologic
      surgery. CONCLUSION: Laparoscopy seems to be useful in female-to-male transsexual
      surgery in allowing the preservation of structures vital for phallic
      construction, such as inferior epigastric vessels and the rectus abdominis
      muscle. The application of vaginectomy awaits justification through long-term
      follow-up studies of transsexuals who have undergone colpocleisis.

PMID- 10579615
TI  - Thickness of the lower uterine segment: its influence in the management of
      patients with previous cesarean sections.
AB  - OBJECTIVE: To determine how ultrasound measurement of the lower uterine segment
      affects the decision about delivery for patients with previous cesarean sections
      (CS) and what are the consequences on cesarean section rates and uterine rupture
      or dehiscence. DESIGN: Prospective open study. PATIENTS: 198 patients: all women
      with a previous CS who gave birth in our department during 1995 and 1996 to an
      infant with a gestational age of at least 36 weeks and who underwent ultrasound
      measurement of their lower uterine segment (95-96 study group), compared with a
      similar population from 1989 to 1994 whose measurements were not provided to the
      treating obstetrician. RESULTS: Among the patients with one previous CS, the
      vaginal delivery rate did not differ significantly during the two periods (70.3%
      for the 89-94 study period vs. 67.9% for the 95-96 study period, P=0.53), but the
      95-96 study group experienced a significant increase in the rate of elective CS,
      compensated by a reduction in the rate of emergency CS (6.3% and 23.4%,
      respectively, for the 89-94 study period vs. 11.9% and 20.1% for the 95-96 study
      period, P=0.01). There was a very significant increase in the rate of vaginal
      delivery for the 95-96 study period among patients with two previous CS (26.7%
      vs. 8.0% for the 89-95 study period, P=0.01). The lower uterine segment was
      significantly thicker among women with a trial of labor than among those with an
      elective CS (4.5+/-1.4 mm compared with 3.8 +/- 1.5 mm; P=0.006); and the trial
      of labor group contained significantly fewer women with a lower uterine segment
      measurement less than 3.5 mm than did the elective CS group (24.0% compared with
      56.6%; P<0.001). Two patients (0.8%) were found to have a defect of the uterine
      scar, a rate significantly lower than that observed in the early group (3.9%,
      P=0.03). CONCLUSIONS: Ultrasound measurement of the lower uterine segment can
      increase the safe use of trial of labor, because it provides an additional
      element for assessing the risk of uterine rupture.

PMID- 10579616
TI  - Omphalocele and gastroschisis: prenatal diagnosis and peripartal management. A
      case analysis of the years 1989-1997 at the Department of Obstetrics and
      Gynecology, University of Homburg/Saar.
AB  - OBJECTIVE: The article presents a retrospective analysis (1989-1997) of the
      prenatal diagnosis, the course and completion of pregnancy of 26 fetuses with
      omphalocele and 18 fetuses with gastroschisis. SUBJECTS: 44 pregnancies with
      anterior fetal wall defect diagnosed by prenatal ultrasound, clinical or patho
      anatomic examination between 1989 and 1997 at the Department of Obstetrics and
      Gynecology, University of Homburg/Saar. RESULTS: In 40 of 44 pregnancies (91%)
      the fetal ventral abdominal wall defect could be detected antenatally with
      ultrasound. Associated malformations in fetuses with omphalocele were seen in 18
      cases (69%), whereas only five fetuses with gastroschisis (28%) had an associated
      malformation. Nineteen of 26 fetuses (73%) with omphalocele had a normal
      karyotype. Seven of 26 fetuses (27%) with omphalocele had an abnormal karyotype.
      Eleven fetuses with omphalocele were live born, three of them with minor
      anomalies. Ten babies with omphalocele survived. No chromosomal anomalies were
      detected in fetuses with gastroschisis. There were four gastrointestinal
      malformations and one lethal associated malformation in fetuses with
      gastroschisis. There were 15 live born babies with gastroschisis, all of whom
      have survived. In 20 of 44 cases (45%) with ventral abdominal wall defect
      oligohydramnios could be detected by ultrasound. In 28 of 44 cases (64%) we found
      fetal growth retardation <10th percentile for gestational age. CONCLUSION: In
      case of a fetal ventral abdominal wall defect, the detection and appropriate
      classification of associated fetal anomalies is of great importance for the
      further course of pregnancy. Fetal karyotyping should be offered in case of a
      fetal abdominal wall defect. Early and close prenatal consultation of the
      neonatologist and the pediatric surgeon will favorably influence the perinatal
      outcome.

PMID- 10579618
TI  - Intrapartum fetal invasive procedures and perinatal transmission of HIV.
AB  - OBJECTIVE: To study the effect of intrapartum use of fetal invasive procedures
      (scalp electrodes or scalp pH sampling) on perinatal transmission rate of HIV.
      STUDY DESIGN: We compared the perinatal transmission of 57 HIV pregnancies in
      which invasive procedures (IP) were performed with a control group of 214
      pregnancies without IP. We controlled for potentially risk factors (maternal CD4
      level, gestational age, antiretroviral therapy use, duration of rupture of
      membranes (ROM), length of labor and mode of delivery) by stratification and
      logistic regression. RESULTS: Transmission rate in the group with IP was 26.3%
      (15/57) versus 13.6% (29/214) in the control group, relative risk (RR) 1.9, 95%
      CI (1.1-3.4). By logistic regression we observed three significant factors
      involved in transmission of HIV: low maternal CD4 level (odds ratio (OR)=3.3, 95%
      CI=1.2-9.4), duration of ROM (OR=2.9, 95% CI=1.1-7.9) and IP use (OR=3.5, CI
      95%=1.2-9.6). Interaction between duration of ROM and IP are also significant
      (OR=5.1, CI 95%=1.5-17.5). CONCLUSIONS: Intrapartum use of fetal scalp electrodes
      or fetal scalp pH sampling increases the perinatal transmission of HIV and should
      therefore be avoided in HIV patients.

PMID- 10579617
TI  - Perinatal outcome and peripartum complications in preterm singleton and twins
      deliveries: a comparative study.
AB  - OBJECTIVE: Multiple pregnancy is one of the major risk factors for preterm
      births. The aim of the present study was to compare perinatal outcome and
      peripartum complications between twins and singletons, born preterm. STUDY
      DESIGN: The study population consisted of preterm deliveries of 435 pairs of
      twins (870 neonates) and the comparison group included 4754 preterm deliveries of
      singletons, born in the same period (January 1, 1989-December 31, 1996).
      Exclusion criteria were lack of prenatal care and births following infertility
      treatments. The three steps in statistical analysis consisted of (1) degree of
      concordance between the twins; (2) comparison between each twin (I and II) to
      their singleton comparison groups using SPSS computer program; (3) stratified
      analysis to examine perinatal mortality rates at different gestational age
      groups. RESULTS: The prevalence of preterm deliveries was 7.9% (6192/77610).
      Perinatal mortality was lower in twins of both birth orders, however, it was
      statistically significant only when APD is considered. Mortality rates in all
      gestational age groups and for both twin groups were lower than that of singleton
      [OR=0.45 (0.26-0.75; 95% CI) for twin-I; OR=0.36 (0.21-0.59; 95% CI) for twin
      II]. Compared to singletons, twin gestations had less congenital malformations.
      Twin gestation had statistically lower rates of preterm premature rupture of
      membranes, severe pregnancy induced hypertension, oligohydramnios, placenta
      previa, placental abruption and clinical chorioamnionitis [12.2 vs.17.3%, 2.5 vs.
      6.3%, 2.3 vs. 4.7%, 0.9 vs. 2.9%, 1.8 vs. 5%, 1.8 vs. 5.2%, respectively
      (P<0.01)]. Mothers of twins had less diabetes mellitus class B-R, hydramnios and
      chronic hypertension than that of singleton (1.8 vs. 2.6%, 5.5 vs. 7.4%, 3.7 vs.
      4.8%, respectively). Cesarean section rates were significantly higher in twin's
      gestation. Mothers of twins tended to be older and of higher birth and gravidity
      order. CONCLUSIONS: Perinatal mortality rates and peripartum complications were
      lower in twin compared to singleton gestations.

PMID- 10579619
TI  - A multivariate analysis of prognostic indicators in complete hydatidiform moles
      (CHM).
AB  - OBJECTIVE: To analyse prognostic factors in complete hydatidiform moles using
      multiple logistic regression analysis. METHODS: Evaluation of host and tumour
      related parameters including (a) gestational age, patient age, parity, molar
      phenotype, grade of proliferation of the tumour and cytological atypia, (b)
      expression of beta-HCG, EGF, EGFR, TGF-alpha, TGF-beta, IL1-alpha, IL1-beta by
      immunohistochemistry, (c) serial monitoring of serum beta-HCG levels by ELISA,
      and (d) lectin binding using jack fruit lectin histochemistry as indices for
      persisting trophoblastic disease (PTD). RESULTS: Serum beta-HCG levels at 4
      weeks, cellular atypia, lectin binding, expression of TGF-alpha and IL1-beta
      showed highly significant correlation with persistence of the tumour (P<0.001).
      The sensitivity and specificity at 4 weeks in combination with cytological atypia
      to identify spontaneously regressing lesions was 100% and those requiring
      chemotherapeutic intervention was 80%. CONCLUSION: The concentration of serum
      beta-HCG 4 weeks post evacuation(<300 mIU/ml) combined with cytological
      abnormalities could identify nearly 100% of the spontaneously regressing lesions
      (low risk) and 80% of those needing chemotherapeutic intervention (high risk),
      thereby suggesting that patients who have a serum beta-HCG at 4 weeks of
      evacuation <300 mIU/ml with no cytological atypia of the trophoblasts need only
      be followed up at long intervals, while those having a serum beta-HCG at 4 weeks
      of evacuation >300 mIU/ml accompanied with cytological atypia of the trophoblasts
      should be closely followed up.

PMID- 10579620
TI  - Serum oxytocin concentration during embryo transfer procedure.
AB  - OBJECTIVE: To determine the effect of the embryo transfer (ET) procedure on serum
      concentration of oxytocin. STUDY DESIGN: Prospective clinical study of 10 women
      undergoing in vitro fertilization (IVF) treatment with ET in the Section of
      Reproductive Medicine and Endocrinology at the Department of Obstetrics and
      Gynecology, University of Bonn, Germany. Serial blood samples were collected in
      time intervals of 20 s during embryo transfer procedure and serum oxytocin
      concentration was measured. RESULTS: In the absence of tenaculum placement, none
      of the procedures associated with ET led to an increase in serum oxytocin
      concentration. When tenaculum placement was used, it was temporally (four out of
      five patients) associated with an elevation in oxytocin level, which remained
      elevated until of the end of ET procedure. CONCLUSION: Application of a cervical
      tenaculum during ET or possibly also during intra uterine insemination (IUI)
      procedure can stimulate the release of oxytocin in some patients.

PMID- 10579621
TI  - Elevated levels of interleukin-2, soluble interleukin-2 receptor alpha,
      interleukin-6, soluble interleukin-6 receptor and vascular endothelial growth
      factor in serum and ascitic fluid of patients with severe ovarian
      hyperstimulation syndrome.
AB  - OBJECTIVE: To investigate the possible role of vascular endothelial growth
      factor, interleukin-2, soluble interleukin-2 receptor alpha, interleukin-6 and
      soluble interleukin-6 receptor in the pathogenesis of ovarian hyperstimulation
      syndrome. STUDY DESIGN: The study group consisted of 10 healthy women who
      developed severe ovarian hyperstimulation syndrome, group A (n=10), following
      ovarian stimulation by long GnRHa/hMG protocol for IVF. A control group B=10
      patients underwent stimulation with the same protocol and did not develop OHSS.
      Blood and ascitic fluid samples were assayed for VEGF, IL-2, sIL-2Ralpha, IL-6
      and sIL-6R by ELISA. RESULTS: The mean serum levels of IL-2, sIL-2Ralpha, IL-6,
      sIL-6R and VEGF in OHSS group were 297.5+/-190, 6588+/-5566, 40.6+/-16.6, 5280+/
      3326 and 492+/-165 pg/ml as compared to 50.8+/-17.4, 1100+/-391.6, 8.5+/-3.5,
      516+/-342 and 167+/-31.3 pg/ml in the control group, respectively, P<0.001. The
      mean ascitic fluid IL-2, sIL-2Ralpha, IL-6, sIL-6R and VEGF in the OHSS group
      were 282.5+/-191.5 pg/ml, 26020+/-13 995, 90.5+/-36, 14900+/-2789 and 660+/-359
      pg/ml as compared to 32+/-14.8, 1206+/-429.4, 12.6+/-1.7, 614+/-240 and 151+/
      20.5 pg/ml, respectively, P<0.001. CONCLUSIONS: The significantly high levels of
      VEGF in patients with severe OHSS suggest that VEGF is a major capillary
      permeability agent in OHSS. Elevated levels of IL-6 in serum and peritoneal fluid
      support the hypothesis that IL-6 may serve as a marker of OHSS. Although serum
      and ascitic fluid levels of IL-2 were elevated, accumulating evidence does not
      support a pivotal role for IL-2 in the pathogenesis of OHSS. However, it may have
      a peripheral role in mediating an increase in vascular permeability. Soluble IL
      2Ralpha and sIL-6R may be considered to be involved in OHSS. However, the patho
      physiologic mechanism is the subject of further investigations. Clinical
      application of VEGF-receptors in the management of OHSS is awaited with interest.

PMID- 10579622
TI  - Intracytoplasmic sperm injection is not associated with poor outcome in couples
      with normal semen parameters and previous idiopathic fertilization failure in
      conventional in vitro fertilization.
AB  - In this study, we compared the results of intracytoplasmic sperm injection (ICSI)
      in patients with normal semen parameters and a history of failed fertilization
      with conventional IVF (study group) and in patients with male factor infertility
      (control group). Patient and cycle characteristics were similar in both groups.
      The mean number of retrieved and metaphase II oocytes, fertilized oocytes,
      embryos developed, embryos transferred and the number of cycles with
      fertilization failure also did not differ between groups. Although differences
      were not statistically significant, pregnancy rate (56.3% vs. 31.5%),
      implantation rate (14.2% vs. 12%) and ongoing pregnancy rate (37.5% vs. 17.7%)
      per embryo transfer were higher in the study group than the ones in the control
      group. We concluded that previous idiopathic fertilization failure with
      conventional IVF is not associated with poor outcome in subsequent ICSI
      treatment.

PMID- 10579623
TI  - Heterotopic pregnancy in a spontaneous cycle: do not forget about it!
AB  - Heterotopic pregnancies are estimated to be less frequent than 1:30000 if no
      assisted reproduction technologies (ART) are performed. After ART this entity is
      more frequent and in the range of 1:100. In the case reported here an ectopic
      pregnancy was detected in the right fallopian tube at 7+ 1 weeks of gestation. It
      was misdiagnosed as an ectopic singleton, and treated by laparoscopic
      salpingectomy, because of a previous ectopic in the same tube. Rising hCG after
      laparoscopy during the subsequent days followed by ultrasound evaluation revealed
      a viable intrauterine pregnancy. The pregnancy continued uneventfully and a
      healthy child was delivered at term. The problems, which lead to the misdiagnosis
      are discussed. The problem of rare cases in medicine, and the problems of a
      'modern' medicine are discussed.

PMID- 10579624
TI  - Ovarian actinomycosis complicated by diabetes mellitus simulating an advanced
      ovarian carcinoma.
AB  - A patient presented with a pelvic tumor which mimicked an advanced ovarian
      carcinoma with invasion into urinary bladder, rectum and uterus, as detected by
      MR imaging. After surgery, however, actinomycosis of the left ovary was diagnosed
      by pathological examination. Ovarian actinomycosis in this patient was
      complicated by diabetes mellitus.

PMID- 10579625
TI  - Meconium toxicity on the umbilical cord.

PMID- 10579626
TI  - Sequential distribution of keratan sulphate and chondroitin sulphate epitopes
      during ameloblast differentiation.
AB  - Proteoglycans are complex macromolecules containing one or more glycosaminoglycan
      chains and exhibiting a variety of biological functions in connective tissues.
      The aim of the present study was to immunolocalize the distribution of keratan
      sulphate and chondroitin sulphate epitopes during initial enamel formation in
      order to study temporo-spatial expression patterns of these macromolecules. Third
      molars of four-months-old pigs were used for immunolocalization of keratan
      sulphate and chondroitin sulphate epitopes in the developing enamel layer. Tooth
      organs were prepared for paraffin sections in order to perform indirect
      immunohistochemistry. The results demonstrated a mutually exclusive positioning
      between these two epitopes. Keratan sulphate epitopes were observed in pre
      secretory pre-ameloblasts and adjacent stratum intermedium while chondroitin
      sulphate epitopes were demonstrated in secretory ameloblasts and adjacent stratum
      intermedium. Our findings suggest that proteoglycans containing glycosaminoglycan
      chains may play a regulatory role during enamel mineralization.

PMID- 10579627
TI  - Hyaluronan distribution in the human and canine intervertebral disc and cartilage
      endplate.
AB  - A biotinylated complex of aggrecan G1-domain and link protein was used to
      characterize the distribution of hyaluronan in paraffin-embedded sections of
      adult human and canine intervertebral disc and cartilage endplate. Limited
      chondroitinase ABC and trypsin digestions of the sections before staining was
      utilized to expose hyaluronan potentially masked by aggrecan. Hyaluronan
      concentration and hyaluronan to uronic acid ratio in different parts of the discs
      were measured as a background for the histological analysis. Hyaluronan staining
      was strong in the nucleus pulposus and inner parts of annulus fibrosus of both
      species, corroborated by biochemical assays of the same compartments.
      Particularly in human samples, hyaluronan in the interterritorial matrix of
      nucleus pulposus and annulus fibrosus was readily accessible to the probe without
      enzyme treatments. In contrast, the cell-associated hyaluronan signal was
      enhanced after trypsin or limited chondroitinase ABC-treatment of the sections,
      suggesting that pericellular hyaluronan was more masked by aggrecan than in the
      distant matrix. A puzzling feature of canine cartilage endplate cells was their
      intensive cell-associated hyaluronan signal, part of which appeared
      intracellular. Hyaluronan was abundant between the collagenous lamellae in
      annulus fibrosus, perhaps important in the plasticity of this tissue.

PMID- 10579628
TI  - Regulation of the p75 neurotrophin receptor in a rat myogenic cell line (L6).
AB  - Neurotrophins are expressed in muscle cells both during development and
      postnatally. Furthermore, during development muscle cells express high levels of
      the common p75 neurotrophin receptor, which binds all neurotrophins. Only
      fragmentary and controversial data are available regarding the responsiveness of
      muscle cells to neurotrophins and the importance of low-affinity p75 receptor in
      muscle development. The present study investigates in vitro the
      immunocytochemical expression of p75 in a rat myogenic cell line (L6) at various
      time points and in response to different coating substrates as a first step in
      elucidating the regulation of p75 in muscle. We found that in L6 myoblasts, p75
      is expressed only at very early stages of maturation and its levels of expression
      are regulated by the nature of the coating substrates. p75 expression decreases
      in cells growing on substrates more suitable for myoblast fusion into myotubes.
      Time course analysis indicates a reverse correlation between myoblast fusion into
      myotubes and the levels of p75 expression. Myotubes were always p75 negative.
      Substrates not suitable for the fusion process induced a prolonged presence of
      p75 in myoblasts with an increase of their apoptosis. We conclude that expression
      of p75, at least in this in vitro condition, is regulated by the stages of
      myoblast differentiation and the nature of the coating substrates. According to
      the observed time- and substrate-related evidences, future studies should
      investigate in vivo both the regulation of p75 in the myoblast fusion and the
      effects and the importance of neurotrophins binding during myoblast
      differentiation.

PMID- 10579629
TI  - Presence of invertebrate dystrophin-like products in obliquely striated muscle of
      the leech, Pontobdella muricata (Annelida, Hirudinea).
AB  - Dystrophin is a 427-kDa cytoskeletal protein, which occurs in scant amounts in
      vertebrate muscle and nerve cells. No previous references to dystrophin or
      associated proteins in invertebrates at the protein level have been found, while
      two recent studies investigated the presence of genes encoding proteins
      homologous to dystrophin in sea urchin and other invertebrates such as Drosophila
      melanogaster. In this study, the possible presence and distribution of dystrophin
      like proteins were studied in different invertebrate muscle cell types and
      species through Western blot analysis and light and electron microscope
      immunohistochemistry using a panel of antibodies whose specificities have been
      determined in vertebrates. Crude protein extracts of leech Pontobdella muricata
      were analysed by Western blotting. The revealed protein band, with 140 kDa
      molecular weight, was related to dystrophin, utrophin or dystrophin-related
      protein-2 (DRP2) according to the specificities of the antibodies used to detect
      them. The immunofluorescence study showed positive immunoreactions in obliquely
      striated muscle of this hyrudinean. The immunoelectron microscopy study confirmed
      specific immunogold labelling beneath the sarcolemma of muscle cells. We thus
      assume that this protein is an invertebrate dystrophin-like product that is
      referred to as IDLp140. The potential functions of this invertebrate dystrophin
      like protein in invertebrate muscles are discussed relative to previous data in
      vertebrate tissues.

PMID- 10579630
TI  - Effects of ischaemia and reperfusion on NADH coenzyme Q reductase activity in rat
      liver.
AB  - NADH coenzyme Q reductase (EC 1.6.5.3) has been suggested in the literature to be
      inactivated by ischaemia. In the present study, NADH coenzyme Q reductase
      activity was localized in unfixed cryostat sections of ischaemic rat livers and
      quantified using image analysis. In vitro ischaemia was induced by storage of rat
      liver fragments for 30, 60, and 120 min at 37 degrees C. In vivo ischaemia was
      provoked by clamping the afferent vessels of median and left lateral liver lobes
      for 60 min followed by 30, 60 and 180 min of reperfusion. NADH coenzyme Q
      reductase activity was demonstrated with the tetrazolium salt method in the
      presence of polyvinyl alcohol. Final reaction product was found in liver
      parenchymal cells and its distribution was homogeneous within liver lobules. Only
      low amounts of final reaction product were formed when the incubation was
      performed in the absence of the substrate NADH. A non-linear relation was found
      between the absorbance and incubation time when the reaction was performed in the
      presence of NADH. Therefore, the initial velocity was taken as the true rate of
      enzyme activity. A linear relationship was found for the initial velocity and
      section thickness up to 6 microm followed by a levelling off. Electron
      microscopically, NADH coenzyme Q reductase activity was localized at the outer
      and inner membranes of mitochondria. In vitro ischaemia up to 120 min did not
      affect NADH coenzyme Q reductase activity. At 30 min reperfusion after in vivo
      ischaemia for 60 min enzyme activity was slightly decreased in certain foci which
      also showed diminished lactate dehydrogenase activity. A further decrease of
      enzyme activities in foci was observed at 180 min reperfusion after ischaemia. It
      is concluded that NADH coenzyme Q reductase activity is not sensitive to
      ischaemia. Furthermore, it is likely that the enzyme leaks from liver parenchymal
      cells into the circulation during reperfusion after ischaemia.

PMID- 10579631
TI  - Calcitonin gene-related peptide, neuropeptide Y and atrial natriuretic peptide
      distribution in guinea pig heart from paraffin wax-embedded and formalin
      cryoprotected tissues.
AB  - In this study, the distributions of calcitonin gene-related peptide, neuropeptide
      Y, and alpha-atrial natriuretic peptide 1-28 immunoreactivity, were investigated
      within different regions of the guinea pig heart by utilising two different
      methods of tissue fixation for the immunocytochemistry. The results were compared
      with data obtained through radioimmunoassays. We observed similar concentrations
      and distributions of alpha-atrial natriuretic peptide in the right atrium, with
      results of radioimmunoassay and immunocytochemistry, but there were no myocytes
      containing alpha-atrial natriuretic peptide in the left atrium or ventricles with
      immunocytochemistry as opposed to radioimmunoassay. The immunoreaction obtained
      for neuropeptide Y was more intense in the right ventricle than left. Calcitonin
      gene-related peptide nerve fibres were about twice as abundant in the left atrium
      than in the right.

PMID- 10579632
TI  - The distribution of type VI collagen in the developing tissues of the bovine
      femoral head.
AB  - Type VI collagen appears central to the maintenance of tissue integrity. In adult
      articular cartilage, type VI collagen is preferentially localised in the chondron
      where it may be involved in cell attachment. In actively remodelling developing
      cartilage, the distribution is less certain. We have used confocal
      immunohistochemistry and in situ hybridisation to investigate type VI collagen
      distribution in third trimester bovine proximal femoral epiphyses. In general,
      type VI collagen immunofluorescence was concentrated in the chondrocyte
      pericellular matrix, with staining intensity strongest in regions which persist
      to maturity and weakest in regions that remodel during development. Type VI
      collagen was also present in cartilage canals. In the growth plate and around the
      secondary centre of ossification, the intensity of type VI collagen stain rapidly
      decreased with chondrocyte maturation and was absent at hypertrophy, except where
      canal branches penetrated the growth plate and stain was retained around the
      adjacent chondrocytes. In situ hybridisation confirmed the presence of type VI
      collagen mRNA in cartilage canal mesenchymal cells but the signal was low in
      chondrocytes, suggesting minimal levels of synthesis and turnover. The results
      are consistent with a role for type VI collagen in stabilising the extracellular
      matrix during development.

PMID- 10579633
TI  - Glucocorticoids, stress, and their adverse neurological effects: relevance to
      aging.
AB  - Glucocorticoids, the adrenal steroids secreted during stress, while critical for
      successful adaptation to acute physical stressors, can have a variety of
      deleterious effects if secreted in excess. It has come to be recognized that
      glucocorticoid excess can have adverse effects in the nervous system,
      particularly the hippocampus. These effects include disruption of synaptic
      plasticity, atrophy of dendritic processes, compromising the ability of neurons
      to survive a variety of coincident insults and, at an extreme, overt neuron
      death. This review considers the current cellular and molecular bases underlying
      these adverse glucocorticoid actions, and their relevance to brain aging.

PMID- 10579634
TI  - Body temperature and locomotor activity as marker rhythms of aging of the
      circadian system in rodents.
AB  - Most biological functions present rhythmic variations. These rhythms are
      distinguished by their period and concern all the levels of biological life.
      Circadian rhythms follow a periodicity close to 24-h, they allow individuals to
      survive via adaptation to the periodic variations of environment. Throughout the
      aging process, modifications in circadian rhythms of endocrinological,
      metabolical and behavioural fields have been found in many animal species. This
      review updates the body of knowledge on aging-related alterations of the
      circadian rhythms of body temperature and locomotor activity: modifications in
      circadian profiles, modifications in the period of free-running rhythms, internal
      desynchronisations and modifications in entrainment ability of these rhythms.

PMID- 10579635
TI  - Histone variants of H2A and H3 families are regulated during in vitro aging in
      the same manner as during differentiation.
AB  - In a previous communication, we showed that the H2A.1/H2A.2 histone variant ratio
      decreases in a linear manner during the in vitro aging of human diploid
      fibroblasts. This ratio is known to decrease in the same manner in progressive
      stages of development and in the process of differentiation, and is thus
      considered to be a biochemical marker for differentiation. A detailed analysis of
      the synthesis of H2A and H3 histone variants as a function of cumulative
      population doublings in the same in vitro cell system is presented in this study.
      Quantitative analysis of these variants in the G0 phase, synchronized fibroblasts
      has shown that their relative amount in chromatin, as well as their biosynthesis
      rate, change during in vitro aging of human diploid fibroblasts, revealing both
      up-and down-regulation of certain variants as a function of cumulative population
      doublings. Furthermore, we show by morphometric studies employing the seven
      distinct fibroblast morphotypes, as described by the Bayreuther classification,
      that this regulation is attributable to the replicative sub-populations. These
      results reveal that histone variants of the H2A and H3 families are regulated
      during in vitro aging in the same manner as that during differentiation.

PMID- 10579636
TI  - Ceroid/lipofuscin-loaded human fibroblasts show increased susceptibility to
      oxidative stress.
AB  - To test whether the possibly enhanced sensitivity of aged cells to oxidative
      stress may depend on their content of ceroid/lipofuscin, AG-1518 human
      fibroblasts with various amounts of the pigment accumulated due to prolonged
      cultivation under normobaric hyperoxia were exposed to acute oxidative stress
      (2.5 microM naphthazarin, 15 min) and then returned to standard culture
      conditions. Twenty-four hours after the naphthazarin treatment, 37% of the cells
      were still vital, whereas others had undergone oxidative stress-induced apoptosis
      with ensuing postapoptotic necrosis. The average amount of ceroid/lipofuscin
      within the surviving cells was only about half of that of the initial population
      of cells, as measured before the naphthazarin exposure. This finding suggests
      that ceroid/lipofuscin-rich cells have an increased sensitivity to oxidative
      stress. The ceroid/lipofuscin quantity strongly positively correlated with the
      size of the acidic compartment (as evaluated by uptake of the weakly basic
      lysosomotropic fluorochrome acridine orange) and with its content of the
      lysosomal protease cathepsin D, as assayed by immunocytochemistry. We hypothesize
      that the enhanced sensitivity of ceroid/lipofuscin-loaded cells to oxidative
      stress may be caused by the increased amounts of lysosomal enzymes, known as
      mediators of oxidative damage, and/or by catalysis of intralysosomal oxidative
      reactions by lipofuscin-associated iron.

PMID- 10579637
TI  - Unbiased estimation of the total number of nervous cells and volume of medial
      mammillary nucleus in humans.
AB  - In this study, we demonstrate that aging does not provoke any changes in neuronal
      number or in the glial cells of the medial mammillary nucleus (MMN) in humans.
      Three age groups were used: young (age 17-35), adult (age 50-57), and aged (age
      70-88). Furthermore, no age-dependent volumetric changes were observed in the
      MMN. All the estimations were performed with stereological methods: an optical
      fractionator and Cavalier's principle. The total number of neurons cells was
      estimated using an optical fractionator and amounted to 32x10(3) in the young
      group, 24x103 in the adult group, and 29x103 in the aged group. The number of
      glial cells was 164x10(3), 187x103, 185x103, respectively. Thus, all three age
      groups had a neuron/glial ratio of about 1:5, 1:8, and 1:6, respectively. The MMN
      volume was estimated using the Cavalier's principle. The total volume was 6.98
      mm3 in the young group, 6.66 mm3 in the adult group, and 6.80 mm3 in the aged
      group. We have demonstrated that neither the total number of neurons and glial
      cells nor the volume of MMN are affected by age.

PMID- 10579638
TI  - Transfected human B cells: a new model to study the functional and
      immunostimulatory consequences of APP production.
AB  - The ubiquitously expressed Alzheimer amyloid precursor protein (APP) has raised
      wide interest in view of its connection with Alzheimer's disease. We now provide
      a novel extraneuronal cell model in which human Epstein-Barr virus transformed B
      cells that constitutively hardly produce APP are transfected with wild-type or
      mutated APP695, harboring the Swedish mutation APPsw, or a dilysine endoplasmic
      reticulum retrieval motif--APP(ER). This leads to the generation of three types
      of cells, one with a high secretion of soluble APPs but low levels of
      intracellular APP, another with a high intracellular APP retention but a low APP
      secretion, and a third in which APP maturation and secretion are strongly
      impaired. The suitability of our cell model for various purposes is proven by its
      usage in different systems. We demonstrate that it is a useful tool for studies
      on the physiology of APPs and represents a good model system to analyze the
      cellular mechanisms of Abeta-directed autoimmune reactivity.

PMID- 10579639
TI  - The effects of dietary antioxidants on psychomotor performance in aged mice.
AB  - Male C57BL/6NIA mice were provided one of six different antioxidant diets:
      vitamin E, glutathione, vitamin E plus glutathione, melatonin, strawberry
      extract, or control, beginning at 18 months of age. A battery of motor tests--rod
      walk, wire hang, plank walk, and inclined screen-was administered either: 1)
      before dietary treatment and then 6 months later at 24 months of age: or 2) only
      after 6 months of dietary treatment at age 24 months. An untreated group of 4
      month-old mice served as young controls. Psychomotor performance was lower in 18
      month-old mice compared with 4-month-old mice in the rod walk, wire hang, and
      inclined screen tests; however, no further decline was seen from 18 to 24 months
      on any measure. Chronic dietary antioxidant treatments were not effective in
      reversing age-related deficits in psychomotor behavior, except for the
      glutathione diet on inclined screen performance. It seems that motor performance
      deteriorates profoundly with age, because deficits at 18 months of age were as
      severe as they were at 24 months, and these age-associated motor deficits may be
      difficult to reverse, even with antioxidant treatment.

PMID- 10579640
TI  - Effects of estrogen replacement therapy on the circadian rhythms of serum
      cortisol and body temperature in postmenopausal women.
AB  - Estrogen replacement therapy (ERT) seems to enhance longevity in women. Both
      gender and aging have been shown to influence the regulation of circadian
      rhythms, yet little is known about the effect of ERT on circadian regulation. The
      aim of this study was to determine the effects of ERT (oral conjugated estrogen:
      Premarin, 0.625 mg) for 6-8 weeks on circadian serum cortisol by continuous blood
      sampling every 15 min for 24 h with simultaneous measurements of body temperature
      in six healthy postmenopausal women (range, 54-61 years). The results are
      presented as median values (range in quartiles). The circadian amplitude of
      cortisol increased during ERT from 20.20 (18.35, 23.61) to 25.97 (24.94, 27.74)
      microg/dL (p = 0.016), whereas the timing of nocturnal nadir and morning
      acrophase did not differ significantly. ERT lowered the 24-h body temperature
      from 37.03 degrees C (36.95 degrees C, 37.07 degrees C) to 36.90 degrees C (36.77
      degrees C, 36.97 degrees C) (p = 0.038), but did not alter the peak and trough
      body temperatures significantly. These findings are noteworthy because the
      increased circadian amplitude of serum cortisol during ERT contrasts with the
      reduction in circadian amplitude seen with normal aging. The reduction in body
      temperature confirms the regulatory effect of ERT in thermoregulation and has
      implications regarding the correlation between basal metabolic rate and life
      span.

PMID- 10579641
TI  - A simple procedure for isolation of Bufo arenarum C3 complement fraction and
      preparation of antiserum.
AB  - Because of the need for antibodies in our studies involving the third component
      of complement in Bufo arenarum, we performed a simple procedure to purify C3 from
      B. arenarum serum to use as antigen in the preparation of the antiserum. The
      strategy was based on the well-known ability of C3 to bind to zymosan (Zy), a
      yeast cell wall extract comprised of polysaccharides. The Zy-bound fraction
      showed cross reactivity with a commercial antibody to human C3 as well as a
      similar electrophoretic profile (SDS-PAGE) to C3 from other species. The Zy-C3
      complex resulting from binding Zy to B. arenarum serum was injected into rabbits
      and the antiserum against this C3-like fraction was purified by protein A
      Sepharose chromatography. The purified C3 antibody was found to be suitable for
      immunochemical studies.

PMID- 10579642
TI  - Treatment of the growing pedicle with retinoic acid increased the size of the
      first antlers in fallow deer (Dama dama L.).
AB  - Unilateral injection of 10 mg of all-trans retinoic acid (RA) into the lateral
      portion of the growing pedicle of fallow bucks (n = 20) led to a significant (P =
      0.033, Wilcoxon matched-pairs test) increase in first antler volume (median, 25.5
      ml) as compared to the contralateral (control) side, injected with vehicle only
      (median, 21.5 ml). It is hypothesized that the RA treatment of the developing
      pedicle exercised a direct or indirect effect on the periosteal/perichondrial
      cells covering the growing cranial appendage, resulting in an increased
      proliferation rate of the cells of the antler perichondrium.

PMID- 10579643
TI  - Species differences in expression of angiotensin II receptors and angiotensin
      converting enzyme in human, canine and rat mitral valve leaflets.
AB  - In normal valvular collagen turnover in the rat, angiotensin (Ang) II and
      angiotensin-converting enzyme (ACE) seem to be involved. In common human and
      canine valvular diseases, changes in valvular collagen play a pathogenetic role
      and the valvular renin-angiotensin system is therefore of particular interest in
      these species. Healthy mitral valve leaflets and adjacent left ventricular
      myocardium were taken from five rats and five dogs immediately after euthanasia,
      and from five humans at autopsy. The valvular and myocardial Ang II receptors and
      ACE were detected and measured by quantitative autoradiography. In rat valves,
      high levels of Ang II receptors and ACE were found. In human and canine valves,
      insignificant levels were found. Significant myocardial levels of Ang II
      receptors and ACE were found only in the rat. The study demonstrated major
      species differences regarding the level of valvular and myocardial Ang II
      receptors and ACE in man, dog and rat. The lack of valvular Ang II receptors and
      ACE in man and dog, suggest that the renin-angiotensin system plays a minor, if
      any, role in the physiological valvular collagen formation in these two species.
      The findings in humans, however, need to be confirmed using fresh material.

PMID- 10579644
TI  - Involvement of mitogen-activated protein kinase in transforming growth factor
      alpha-stimulated cell proliferation in the cultured granulosa cells of the
      Japanese quail.
AB  - The avian granulosa cells proliferate during follicular growth phase and
      differentiate to produce progesterone in response to luteinizing hormone (LH)
      when the follicle becomes the largest. In order to study the involvement of
      mitogen-activated protein (MAP) kinase in proliferation of the granulosa cells in
      avian species, quail granulosa cells were cultured for 66 h with various hormones
      (follicle stimulating hormone (FSH), LH, progesterone, estradiol-17beta,
      testosterone), or growth factors (transforming growth factor alpha (TGF alpha),
      epidermal growth factor (EGF), insulin-like growth factor I (IGF-I), IGF-II), and
      the presence of immunodetectable MAP kinase was examined in the cell lysates.
      When the granulosa cells were cultured with TGF alpha, the cell number as well as
      the incorporation of [3H]thymidine was increased. Other hormones or growth
      factors caused no significant increase in cell numbers. Stimulation of the cells
      with TGF alpha for 10 min caused a retarded mobility of MAP kinase in the gel of
      SDS-PAGE. Both the increases in [3H]thymidine incorporation and the retarded
      mobility were inhibited by the presence of a tyrosine kinase inhibitor,
      genistein, indicating the importance of phosphorylation of protein during the TGF
      alpha-stimulation.

PMID- 10579645
TI  - Adaptation and validation of a radioimmunoassay kit for measuring plasma cortisol
      in turbot.
AB  - Levels of cortisol in fish blood provide quantitative information on the degree
      of stress induced by a variety of stressors. It is also useful in describing the
      social status of individual fish within groups. The commercial production of
      radioimmunoassay (RIA) kits, such as the DPC Coat-A-Count radioimmunoassay kit,
      has considerably reduced the effort required for cortisol measurement. These kits
      employ human plasma based cortisol standards which are not compatible for use
      with non mammalian species such as fish e.g. turbot, Scophthalmus maximus
      (Rafinesque), blood due to the interference effect of lipids and steroid binding
      proteins present in the plasma. In this study the DPC kit was used following the
      removal of these lipids and steroid binding proteins from the plasma using an
      ethanol-hexane extraction. Excessive variability in the cortisol values obtained
      using this method deemed it unsatisfactory in overcoming the problem of
      incompatibility. A second modification of this technique that was tested involved
      the preparation of turbot specific standards for use in the preparation of
      modified standard curves. Using this method, an accuracy of 93.4% was achieved,
      as opposed to 79.6% using the kit human plasma based standards, and 47.1% using
      samples following lipid removal using an ethanol-hexane extraction. Based on
      analysis of accuracy, precision and reproducibility it is concluded that
      commercially available cortisol kits are suitable for use with turbot plasma, but
      a number of minor modifications are necessary.

PMID- 10579646
TI  - Regulation of plasma insulin-like growth factor-I levels in brown trout (Salmo
      trutta).
AB  - In this study we report that the use of a heterologous radioimmunoassay (RIA) is
      valid for the detection of insulin-like growth factor-I (IGF-I) levels in plasma
      of a variety of fish species. Parallelism between standard curves and plasma
      dilutions were observed and the standard curve obtained with mammalian IGF-I
      presented the same characteristics as that obtained with coho salmon recombinant
      IGF-I. The RIA was biologically validated since total plasma IGF-I values were
      significantly modified by different experimental conditions. Hyperinsulinemia
      induced either by arginine or insulin injection was accompanied by increases in
      IGF-I plasma levels in brown trout (Salmo trutta). In contrast, parallel
      decreases in insulin and IGF-I circulating levels were observed after 45 days of
      fasting and 20 days after a single streptozotocin injection. Administration of
      arginine in fasted fish led to a relative increase in insulin and IGF-I plasma
      concentrations, while arginine injection in fish previously treated with
      streptozotocin increased IGF-I levels only. The above data suggest that insulin,
      together with other factors, may act to increase the levels of IGF-I in plasma.

PMID- 10579647
TI  - Cadmium content of the marine sponge Microciona prolifera, other sponges, water
      and sediment from the eastern Florida panhandle: possible effects on Microciona
      cell aggregation and potential roles of low pH and low salinity.
AB  - Marine sponges from shallow bays and estuaries along the Florida panhandle
      contained cadmium (Cd), 1.78-27.9 microg g(-1) (dry weight). Levels > 7 microg g(
      1) were never found in a variety of other benthic invertebrates. Water levels of
      Cd were of the order 0.22-0.43 microg ml(-1) and did not differ significantly
      between the two study areas (Panacea and St. Joseph Bay). Cd in organic sediment
      however, was significantly (P = 0.033) higher around Panacea (0.343 +/- 0.063
      S.E.M.) than in St. Joseph Bay (0.18 +/-0.223 S.E.M.). Salinity of 10 and pH 6.5
      were recorded following heavy rains, and can constitute a hostile environment for
      these organisms. Temporal variations of Cd and Cu but not Zn were observed in
      Microciona prolifera over a period of 2 years in St. Joseph Bay, and a negative
      correlation was observed between Cd content and the Ca(2+)-induced aggregation of
      Microciona cells suspended in Ca2+/Mg(2+)-free artificial seawater. Cells
      unresponsive to Ca2+ aggregated in response to releasers of Ca2+ from internal
      stores (thapsigargin, A23187 and tetredecylamine), suggesting that they were
      viable but dormant. In vitro studies showed that Cd2+ is about equipotent with
      Ca2+ in inducing aggregation of Microciona cells, whereas lower concentrations (1
      2 x 10(-3) M), added 10 min before inducing aggregation with CaCl2, inhibited
      aggregation, possibly by blocking Ca2+ uptake. Microciona contained a
      metallothionein (MT)-like protein. Taken together these results suggest that
      naturally-acquired Cd may interfere with cell regulatory processes in Microciona.
      Possible effects of low pH and salinity on Cd uptake and detrimental effects on
      cell function are discussed.

PMID- 10579648
TI  - Opioid-dopamine interaction in planaria: a behavioral study.
AB  - The behavioral response of planaria to the exposure to selective opioid agonists
      was studied. The mu agonist [d-ala2, N-methyl-Phe4,Gly5-ol]enkephalin (DAMGO) and
      the 6 agonist [D-Pen2, D-Pen5]enkephalin (DPDPE) failed to alter motor activity
      at all doses tested. Low doses of the selective kappa agonist (+/-)-trans-U-50
      trans-3,4-dichloro-N-methyl-N[2-(1-pyrrodinyl)-cyclohexyl]benzene acetamide
      methasulphonate (U50, 488) and bremazocine-HCl increased motor activity leading
      to C-like position (CLP) and screw-like hyperkinesia (SLH). These changes were
      identical to those seen previously with the exposure to D2 or D1 dopamine
      receptor agonists, respectively. Higher doses of kappa agonists produced the
      enhancement of CLP and SLH together with robust snake-like movements (SLM). This
      latter response, that was typical of stimulation of kappa opioid receptors, was
      blocked by co-exposure to naloxone or the selective kappa antagonist Nor
      binaltorphimine (Nor-BNI). Finally, co-exposure to sulpiride or SH-23390
      respectively blocked the CLP or SLH response produced by U50,488 or bremazocine.
      Our data indicate the presence of kappa opioid receptors in planaria and suggest
      the functional interaction between the opioid and dopamine system in this simple
      animal model.

PMID- 10579649
TI  - Responses to potential vasoactive substances of isolated mammary blood vessels
      from lactating sows.
AB  - The purpose of the investigation was to examine the response of the milk vein and
      the mammary artery to potential vasoactive substances in lactating sows. The
      response on artery and vein segments from the same sow was measured for the
      following substances: noradrenaline (NA), serotonin (5-HT), prostaglandin F2alpha
      (PGF2alpha), prostacyclin (PGI2), histamine (Hi) and potassium (K+).
      Interestingly, the contractile force in the mammary vein segments expressed per
      weight unit (mN/mg) was 1.5-2.5 fold larger than in the artery segments when NA,
      5-HT and PGF2alpha were used, but similar for K+, Hi and PGI2. In vein segments,
      the order of sensitivity to the substances expressed by their pD2 values was 5-HT
      > NA = PGF2alpha > Hi > K+. The present findings suggest that NA, 5-HT,
      PGF2alpha, PGI2, and Hi are involved in mammary blood flow regulation in the sow,
      and the mammary venous system may be as important as the mammary arterial system
      in this regulation.

PMID- 10579650
TI  - Seasonal variations in hepatic and ovarian zinc concentrations during the annual
      reproductive cycle in female channel catfish (Ictalurus punctatus).
AB  - Seasonal variations in hepatic and ovarian zinc concentrations were studied
      during the reproductive cycle in female channel catfish (Ictalurus punctatus).
      The gonadal somatic index (GSI) increased dramatically in April and peaked in
      June prior to spawning. Exogenous vitellogenesis was initiated in the fall as
      noted by increases in serum estradiol and testosterone and liver somatic index
      (LSI). Total hepatic zinc and zinc in the cytosolic high-molecular weight (HMW)
      and metallothionein-like (MT) fractions were elevated in March but decreased
      during rapid vitellogenic oocyte growth in April and May. Following spawning in
      July, total hepatic zinc and zinc in the HMW and MT-like fractions were again
      elevated. Total ovarian zinc and zinc associated with HMW and MT-like fractions
      increased with GSI, then decreased to a low after spawning. However, on a per g
      tissue basis, ovarian zinc concentrations in both cytosolic pools declined during
      rapid oocyte growth, indicating a different intracellular localization of the
      zinc binding proteins. Hepatic MT-like proteins exhibit UV absorption profiles
      similar to mammalian MT while the ovarian proteins appear to be different.
      Results give evidence for the homeostatic regulation of hepatic zinc by MT during
      exogenous vitellogenesis and a similar function for the ovarian MT-like protein
      during oocyte development.

PMID- 10579651
TI  - Characterization of superoxide dismutase activity in Chironomus riparius Mg.
      (Diptera, Chironomidae) larvae--a potential biomarker.
AB  - The activities of superoxide dismutase (SOD) isoenzymes were measured in fourth
      instar larvae of Chironomus riparius Mg. Three types of superoxide dismutase were
      identified: Cu,Zn-SOD in hemolymph and postmitochondrial fraction; Mn-SOD in
      mitochondrial fraction and presumably Fe-SOD in postmitochondrial fraction. The
      latter could have an endosymbiotic or a parasitic origin. Extracellular and
      cytosolic SOD activities, especially Cu,Zn-SOD, tended to increase in the last
      phase of larval development, independently of protein or hemoglobin contents.
      This supposes that SOD activity in Ch. riparius larvae is probably activated at
      the end of fourth instar stage. Cu,Zn-SOD and Mn-SOD activities showed a
      significant increase under severe hypoxia and slight hyperoxia. Oxygen radical
      scavengers such as SOD may play a role in the increased tolerance of Ch. riparius
      to oxidative stress. These results suggest that the specific induction of some
      SOD isoenzymes could be used as a biomarker of environmental disturbance such as
      oxidative stress initiated by xenobiotics.

PMID- 10579652
TI  - Ethanol has differential effects on rat neuron and thymocyte reactive oxygen
      species levels and cell viability.
AB  - In rat thymocytes and cerebellar granule cells, reactive oxygen species (ROS)
      levels were increased and cell viability was decreased as a result of exposure to
      ethanol (up to 0.4%). Thymocytes showed larger increases in ROS levels, but
      neurons showed more pronounced decreases in cell viability. These parameters in
      neurons were relatively unaffected when the cells were incubated with ethanol in
      the presence of inhibitors of alcohol-oxidizing enzymes, but in thymocytes, the
      presence of diallyl sulfide (an inhibitor of alcohol-inducible cytochrome P450,
      CYP2E1) or 4-methylpyrazole (an inhibitor of CYP2E1 and alcohol dehydrogenase)
      caused decreases in ROS production from ethanol. In both cell types, the presence
      of 3-aminotriazole (an inhibitor of catalase) did not decrease ROS production
      from ethanol. These studies show that the cytotoxic effects of ethanol in neurons
      may not be the result of oxidative metabolism of ethanol, whereas in thymocytes,
      the cytotoxic effect of ethanol is principally a result of its oxidative
      metabolism.

PMID- 10579653
TI  - Screening for fibrinolytic activity in eight Viperid venoms.
AB  - Snake venoms contain direct-acting fibrinolytic metalloproteinases (MMP) that
      could have important applications in medicine. Fibrinolytic enzymes isolated from
      venom can induce in vitro clot lysis by directly acting on a fibrin clot. The
      most ideal fibrinolytic enzyme would have high affinity for clots, dissolve clots
      directly without causing hemorrhage, and would not be neutralized in vivo by
      endogenous metalloproteinase inhibitors. The purpose of this study was to compare
      DEAE/HPLC venom profiles from Viperid snakes and identify fractions that contain
      fibrinolytic activity with no hemorrhagic activity and are not neutralized by
      animal sera. The sera selected were from four (Virginia opossum, Gray woodrat,
      Mexican ground squirrel, and Hispid cottonrat) animals known to neutralize
      hemorrhagic activity in snake venoms. Nineteen fractions from the Viperid venoms
      had fibrinolytic activity. Agkistrodon venom fractions contained the highest
      specific fibrinolytic activities. A. piscivorus leucostoma fraction 4 contained a
      high specific fibrinolytic activity, no hemorrhagic activity, and the
      fibrinolytic activity was not neutralized by the proteinase inhibitors of the
      four animal sera. A. contortrix laticinctus fraction 1 also had a high specific
      fibrinolytic activity and no hemorrhagic activity. However, the fibrinolytic
      activity was neutralized by Didelphis virginiana (Virginia opossum) serum.

PMID- 10579654
TI  - Synaptic neurone activity under applied 50 Hz alternating magnetic fields.
AB  - The effect of 50 Hz alternating magnetic fields of 10-150 Gauss (1-15 mT)
      intensity on neurone synaptic activity for glutamate and acetylcholine has been
      studied. The applied 50 Hz alternating magnetic field does not modify the
      synaptic activity induced by glutamate or acetylcholine on neurones. It has been
      observed that both caffeine and glutamate induce similar effects, either
      stimulation or inhibition, on different neurone types. It is shown that applied
      50 Hz alternating magnetic fields mimic the synaptic effect of glutamate. A mimic
      effect has also been observed between the induced effect by applying 50 Hz
      alternating magnetic field on neurones and the one induced by caffeine and
      glutamate on the same neurone. The application of Ringer solutions with different
      concentrations of Ca2+/K+ ions suggest that Ca2+ ions are involved in the
      elicited responses to either caffeine, glutamate or 50 Hz magnetic fields. Our
      conclusion is that the observed mimic induced effects for 50 Hz alternating
      magnetic fields, caffeine and glutamate on neurones corroborate that Ca2+ ions
      are the cytosolic effectors of the applied 50 Hz alternating magnetic fields
      interaction with neurone plasma membrane.

PMID- 10579655
TI  - Hormonal profiles correlated with season, cold, and starvation in Rana
      catesbeiana (bullfrog) tadpoles.
AB  - Bullfrog (Rana catesbeiana) tadpoles are of value to amphibian researchers
      because of their large size, and year-round availability due to overwintering in
      many latitudes. Concern over a possible difference in hormonal parameters in
      tadpoles obtained at different times of the year prompted us to investigate
      thyroid gland secretion in vitro, plasma and ocular melatonin, and plasma
      corticosteroids in late pre- to early prometamorphic larvae on 12L:12D. Winter
      tadpoles exposed to 22 degrees C for 3 weeks of acclimation (winter group) were
      compared to summer tadpoles kept at 22 degrees C (summer group), as well as to
      summer tadpoles exposed to cold (12 degrees C) for the 3 weeks (cold group), or
      kept at 22 degrees C and starved for the last week of acclimation (starved
      group). Thyroids from the summer group had a significantly higher response to 0.2
      microg/ml ovine thyrotropin (TSH) than the other groups, indicating that cold and
      starvation inhibited subsequent in vitro thyroid sensitivity to TSH. The thyroids
      of the starved tadpoles had significantly higher baseline (unstimulated)
      thyroxine (T4) secretion into the culture media, a finding that might be related
      to starvation-induced acceleration of metamorphosis. Plasma melatonin was lower,
      and ocular melatonin significantly higher in both summer and starved groups,
      while the reverse occurred in the winter and cold groups. Thus, seasonal or
      induced cold brought on a shift in the relationship of plasma to ocular melatonin
      but starvation had no effect. There were no significant differences among the
      treatment groups in plasma hydrocortisone (HC) and aldosterone (ALDO) levels,
      except that HC was lower than ALDO only in the plasma of winter tadpoles. We
      conclude that seasonal variation needs to be taken into account in endocrine
      experiments utilizing tadpoles obtained at different times of the year.

PMID- 10579656
TI  - Traumatic brain injury: a view from the inside.
AB  - Information about the outcomes after traumatic brain injury comes from
      observational studies and, increasingly, subjective sources. Narrative analysis
      provides an avenue to explore life after the trauma, and a perspective that may
      illuminate critical aspects of the relationship between the health professional
      and health consumer. Language use by health professionals in their interactions
      with health consumers may profoundly bias expectations and outcomes. Terms such
      as 'recovery', for example, may be inappropriate, as severe traumatic brain
      injury may not be an injury that one is able to 'recover' from. If the brain is
      seen as the basis of the personality and is altered by the trauma, then,
      philosophically, it is difficult to argue that the person is the same as before.
      Concepts of rehabilitation after severe traumatic brain injury should, therefore,
      take into account the expectation of the health consumer in shaping the outcomes
      and the possibility that new and adaptive patterns of behaviour need to be
      developed rather than focusing on returning to the pre-injured person. This
      introduces the notion of rehabilitation as assisting the injured person to re
      orientate or rebuild their life using a new set of 'maps' with which to navigate
      through life. The paradigm of 'new maps' is positive, challenging, and honest as
      far as expectations are concerned, and encompasses the idea of actively exploring
      new and unknown territory.

PMID- 10579657
TI  - Coping with community reintegration after severe brain injury: a description of
      stresses and coping strategies.
AB  - A basic qualitative approach was used to describe the stresses and coping
      strategies of 11 adults with severe brain injury during a critical period of
      reintegrating into a new community. Subjects identified nine problems as
      stressful. The stresses conform to a theoretical model of community integration,
      consisting of four factors: social support, independent living, occupation, and a
      general integration factor. These stresses identified by subjects may be used in
      the development of a new measure of stress for persons with brain injury.
      Subjects used eight coping strategies to deal with these stresses. The coping
      strategies represent a sampling of three major types of coping: problem-focused,
      perception-focused, and emotion-focused. The findings show that subjects made
      more use of problem-focused coping strategies than any other type of coping,
      suggesting that persons with brain injury have awareness of the problems they
      face and the ability to assert some control over eliminating or managing these
      problems. The stresses and coping strategies are consistent with existing studies
      involving persons with brain injury. However, significant differences in some
      coping strategies reported in this study change how some forms of coping are
      thought about. The findings delineate the need for professionals to assist
      persons with brain injury develop more positive, adaptive coping strategies.

PMID- 10579658
TI  - Cognitive and behavioural efficacy of amantadine in acute traumatic brain injury:
      an initial double-blind placebo-controlled study.
AB  - The objective of the current study was to determine the efficacy of amantadine in
      improving cognitive and behavioural performance in a traumatic brain injury (TBI)
      rehabilitation sample. The design was a prospective, randomized, double-blind,
      placebo-controlled, crossover design. Subjects were 10 adult traumatic brain
      injury patients in an acute brain injury rehabilitation unit. Subjects received a
      2-week trail of amantadine or placebo, followed by a 2-week washout, then a 2
      week trail of the alternative (placebo or amantadine). Neuropsychological outcome
      measures included orientation, attention, executive function, memory,
      orientation, behaviour, and a composite variable. Results of repeated measures
      ANOVA and regression analysis of slope/change showed a main effect of time, but
      no significant difference for amantadine versus placebo. In conclusion, although
      patients generally improved, this initial exploratory study found no differences
      in rate of cognitive improvement between subjects given amantadine versus those
      given placebo. However, the small sample size, heterogeneous population, acute
      time course, and large number of dependent variables limit power and
      generalizability. Implications are discussed for further research to better
      answer questions regarding efficacy of amantadine post-TBI.

PMID- 10579659
TI  - Effects of acute injury characteristics on neuropsychological status and
      vocational outcome following mild traumatic brain injury.
AB  - Despite recent attempts to define acute injury characteristics of mild traumatic
      brain injury (MTBI), neuropsychological outcome is often unpredictable. One
      hundred MTBI cases were prospectively collected, which were consecutive referrals
      to a concussion clinic, and the roles of various acute neurologic variables were
      examined in relation to neuropsychological status and vocational outcome.
      Significant differences were found between subgroups of patients classified by
      (1) mechanism of injury (i.e. acceleration/deceleration trauma in which the head
      strikes an object (HSO) versus acceleration/deceleration trauma in which the head
      does not strike an object (HNSO) versus trauma in which an object strikes the
      head (OSH), and (2) type of injury (i.e. motor vehicle collision, fall, assault,
      motor vehicle-pedestrian collision, falling object, sports/recreation). There was
      no difference, with respect to neuropsychological status or vocational outcome,
      between patients who had positive findings on computerized tomography (CT) versus
      those who were CT negative. Additionally, there was no difference between
      patients who had suffered brief loss of consciousness (LOC) and those without
      LOC. These findings suggest that selective acute injury characteristics may be
      used to classify subtypes of MTBI patients.

PMID- 10579660
TI  - Relations between traumatic brain injury and the environment: feedback reduces
      maladaptive behaviour exhibited by three persons with traumatic brain injury.
AB  - Feedback is a commonly used technique in neurorehabilitation. It functions to
      strengthen or weaken select relations between individuals' behaviour and their
      environment. The study of behaviour-environment relations is a focus of operant
      psychology, commonly referred to as behaviour analysis. Central to behaviour
      analysis is the analysis of interrelations among stimuli, behaviour, and
      consequences. The focus on behaviour-environment relations may have considerable
      benefits for designing clinical treatments and accounting for successful and
      unsuccessful treatments, especially psychological interventions for maladaptive
      behaviour. In the present investigation, three persons with traumatic brain
      injuries, diagnosed with depression and presenting mild cognitive impairments,
      received feedback about their maladaptive behaviour. Weekly feedback resulted in
      general reductions in the variability and frequency of maladaptive behaviour. The
      results support the utility of giving equal consideration to relations between
      persons with traumatic brain injury and their environment, despite existing
      psychological or cognitive impairments. Future research on variables that
      influence the development and maintenance of behaviour-environment relations, and
      more generally operant behaviour, may provide a unique perspective on the effects
      of traumatic brain injury.

PMID- 10579661
TI  - Bladder tone in patients in post-traumatic vegetative state.
AB  - The aim of the present study was to examine the bladder tone in vegetative
      patients using urodynamic tests. The study population consisted of 17 patients,
      13 men and four women, in a post-traumatic vegetative state under treatment at
      the Loewenstein Rehabilitation Centre. Time since injury ranged from 1 to 6
      months. Cystometry results indicated that 100% of the patients had neurogenic
      bladder, hypertonic type, two (12%) with mild spasticity and 15 (88%) with severe
      spasticity. None showed detrusor-sphincter dyssynergia or unstable bladder. Based
      on these unequivocal findings, it is suggested that all patients in trauma
      induced vegetative state be treated prophylactically from the 2nd week with
      anticholinergic agents.

PMID- 10579662
TI  - Olfactory function in patients with nasopharyngeal carcinoma following
      radiotherapy.
AB  - The aim of this study was to examine the impact of radiation treatment on
      olfactory function in patients with nasopharyngeal carcinoma (NPC). An olfactory
      function test battery was administered to 25 adult NPC patients having received
      radiotherapy, 24 adult nasopharyngeal carcinoma patients awaiting to receive
      radiation treatment, and 36 adult normal control subjects. Members of the three
      groups were matched in terms of age, educational level, and full-scaled IQ score.
      Comparing the test results revealed that the NPC patients with radiotherapy had
      olfactory information processing impairments including absolute threshold, odour
      tactile cross-modality matching, verbal identification of odours, and recall and
      recognition of identity of odours. The deficits of suprathreshold olfactory
      functioning in these patients did not seem to arise from impaired absolute
      threshold sensitivity. Provided that the results are reproducible, an evaluation
      of olfactory functioning in NPC patients during the period of radiotherapy may be
      useful for detecting or even avoiding side effects of radiation.

PMID- 10579663
TI  - Variability of neuropsychological deficits associated with carbon monoxide
      poisoning: four case reports.
AB  - Carbon monoxide (CO) poisoning is associated with variable neuropsychological
      deficits, depending on levels of CO exposure and individual differences. Studies
      to date have reported variable findings, as their subjects have been exposed to
      different levels of CO from different poisoning sources. Four unique case studies
      are presented, all of whom experienced the same level of CO poisoning (17-29%) in
      the same accident. Two of the individuals were brothers with an identical genetic
      disorder (i.e. syndactylism) and the other two were brother/sister. The results
      indicated: (1) variable neuropsychological deficits despite similar levels of CO
      poisoning; (2) consistent estimated decline in intelligence; (3) similar memory
      decline for the two brothers, but not for the brother and sister; and (4)
      consistent late-onset emotional-behavioural difficulties. The results also
      suggested that the neuropsychological and emotional-behavioural deficits had an
      impact on the individual's ability to work.

PMID- 10579664
TI  - Transcortical sensory aphasia due to a left frontal subcortical haemorrhage.
AB  - A case of transcortical sensory aphasia caused by a cerebral haemorrhage in the
      left frontal lobe is presented. A 72-year-old right-handed woman was admitted to
      the hospital, with a history of acute onset of speech disturbance and headache.
      On initial assessment, her spontaneous speech was fluent. She had no difficulty
      initiating speech, articulated normally, and did not exhibit logorrhea. Her
      ability to repeat phonemes and short sentences (5-6 words) was fully preserved,
      however she had severe difficulty with visual recognition of words, and with
      aural comprehension at the word level, although she was able to read words aloud.
      Computed tomography and magnetic resonance imaging showed cerebral haemorrhage in
      the left frontal lobe, involving the superior and middle frontal gyrus. Single
      photon emission CT revealed a wider area of low perfusion over the entire left
      frontal lobe, including the superior, middle and inferior frontal gyrus. The
      aphasia symptoms, mainly poor comprehension, disappeared quickly several weeks
      after the event. This may have been due to a reduction in the size of the
      haematoma and a resolution of the oedema around the haematoma. Clinically, the
      transcortical sensory aphasia in this case was indistinguishable from that caused
      by damage to the posterior language areas. Further case reports of transcortical
      sensory aphasia associated with frontal lobe lesions would help to confirm
      whether a relatively rapid recovery is characteristic in cases such as this.

PMID- 10579666
TI  - The research base of community-based rehabilitation.
AB  - This paper provides an overview of the current research on community-based
      rehabilitation (CBR) which can be found in the public domain. A brief background
      to the concept of CBR is given, and it is shown how much of this published
      research reflects the fundamental principles of CBR service delivery, technology
      transfer, community involvement, and organization and management. Specific
      research is discussed under these headings. Additional topics reviewed include
      the target populations of, and disabilities addressed in, CBR research, and the
      epidemiology of disability. A summary of locations where the research has taken
      place is also presented. It is concluded that, while there is still a need for
      additional research and evaluation in the extensive field of CBR, there has been
      some reluctance to either undertake or permit such activities. However, CBR and
      ultimately the disabled can only benefit from placing research and evaluation of
      CBR into the public domain.

PMID- 10579665
TI  - Cognitive outcome after emergent treatment of acute herpes simplex encephalitis
      with acyclovir.
AB  - Longitudinally designed case studies, reporting cognitive and psychosocial
      outcome of herpes simplex virus encephalitis (HSVE), were conducted prior to
      current antiviral medication usage and primarily in persons with either left
      hemispheric or bilateral temporal lobe involvement. The current study
      demonstrated relatively better outcome (cognitive recovery and functional
      independence for activities of daily life) in an individual treated with IV
      Acyclovir within hours of initial symptoms and whose CT scans showed right
      hemispheric involvement. In contrast with earlier case reports, no semantic
      specific categories of memory impairment were noted on serial assessment. The
      time from first symptoms to antiviral medical treatment appears to be the best
      predictor of outcome from HSVE. Historical case studies with relatively poorer
      outcome and differing deficits suggest survivors of HSVE are a heterogenous
      group. Variability in anatomic lesions and time to treatment contribute to
      outcome.

PMID- 10579667
TI  - Community-based rehabilitation in the Lao People's Democratic Republic.
AB  - An overview of the demography of the Lao People's Democratic Republic along with
      estimates of disability prevalence are given. The legislative response of the
      central government to disability and handicap is also described. The
      implementation, organization and manpower of the community-based rehabilitation
      (CBR) programme is discussed and illustrated using a case study from the Luang
      Prabang Province.

PMID- 10579668
TI  - Vietnam and activities of community-based rehabilitation.
AB  - This paper describes the development of, and current situation regarding,
      community-based rehabilitation (CBR) in Vietnam. Vietnam is one of the few
      countries to universally adopt CBR as a means of delivering effective
      rehabilitation to its citizens. Some information regarding the demography of the
      country is presented. The administrative structure associated with rehabilitation
      delivery and the prevalence of disability in the country are also discussed.
      Finally, the strengths, weaknesses and constraints of CBR are discussed.

PMID- 10579669
TI  - Primary health care and community-based rehabilitation in the People's Republic
      of China.
AB  - This paper provides the background to the introduction of community-based
      rehabilitation (CBR) into a rural area of Guandong Province in the People's
      Republic of China (PRC). CBR, in this pilot project, is implemented using the
      existing primary health-care network. Two examples, one from a township and the
      other from a rural village, are presented. It is concluded that, given the
      estimated 51840000 disabled persons in the PRC, CBR is the ideal means whereby
      'rehabilitation for all' can be achieved in China.

PMID- 10579670
TI  - Community-based rehabilitation in South Korea.
AB  - This paper gives a brief introduction to the geography and demography of the
      Republic of South Korea. Since 1988 South Korea has been actively legislating and
      implementing welfare policy for the disabled of the Republic. An overview of
      these policy changes is presented. The extent to which the policy has been
      implemented using community-based rehabilitation (CBR) is illustrated using an
      example from the North Wanju Project. Finally, there is a discussion of the
      future of CBR in South Korea and the means whereby there can be more social
      integration of the disabled.

PMID- 10579671
TI  - Community-based rehabilitation in the People's Republic of China.
AB  - This paper describes the implementation of a pilot community-based rehabilitation
      (CBR) programme in a densely populated urban centre of Guangzhou (Canton) City.
      The structure of the programme utilizing the existing administrative and
      government structures of the province (Guandong), the city and the urban centre
      (Jin Hua Street) and administration of the project are described. Finally, the
      paper addresses some issues related to research on CBR in the People's Republic
      of China (PRC).

PMID- 10579672
TI  - Community-based rehabilitation: a development programme in Negros Occidental.
AB  - This paper describes the establishment of a community-base rehabilitation (CBR)
      programme from its initiation to the current situation in the Philippine
      Republic. The impetus for the CBR project arose from an initiative of a non
      government organization in the state of Negros Occidental. The administrative
      structure, manpower recruitment and training, and the close working relationship
      between government and non-government organizations are also described.

PMID- 10579673
TI  - The Australia Commonwealth Rehabilitation Service.
AB  - This paper describes the background of the Australian Government's Rehabilitation
      Service and its role in disability and injury management. The health and other
      professionals who are employed in the Service and their clients are described.
      Priority and target groups are also described, as are some of the more recent
      achievements of the Service. There has been a shift in service delivery from a
      centralized focus to a community-based focus.

PMID- 10579674
TI  - Rehabilitation of the disabled in Hong Kong.
AB  - This paper examines the early history of the Hong Kong government's approach to
      rehabilitation services. The fundamental purpose of the programme was prevention
      founded on the premise that, by reducing the incidence of disability, the need
      for rehabilitation services would be reduced.

PMID- 10579675
TI  - Community-based rehabilitation in Lao--comparison of needs and services.
AB  - Efforts to address all disabilities are still very limited in the Lao People's
      Democratic Republic (PDR). Nevertheless, certain categories of disability have
      achieved a higher level of institution-centred attention. This attention is
      limited to the field of medical rehabilitation (amputees and movement-impaired
      persons). Further assistance such as education, vocational training and income
      generation, or attention to other large groups of disabled (deaf/mute and
      visually impaired persons) is largely non-existent. This article describes
      several attempts to implement community-based rehabilitation (CBR) strategies. A
      range of government, non-government, and foreign agencies are attempting to meet
      the needs of disabled persons in the Lao PDR. It is concluded, based on the
      evidence available in Lao: that it is easier to integrate the disabled person
      through education programmes; that there is a need to educate health
      professionals in the non-medical expectations of any rehabilitation programme;
      that occupational therapists may be the preferred health professionals to be
      involved in CBR programmes; and that new CBR programmes are more likely to
      receive support if they are modelled on existing and successful programmes.

PMID- 10579676
TI  - Community-based rehabilitation in Moshupa village, Botswana.
AB  - This article presents a summary of findings from the 'Moshupa Community Based
      Rehabilitation (CBR) project', which to date have been the subject of three
      studies: one initial survey of disabled people and two follow-up studies. Of the
      132 disabled people who were identified in the survey, all but three could be
      accounted for in the first follow-up. Seventy-seven were interviewed about
      independence of activities of daily living, school/jobs and quality of life. A
      high percentage of elderly (17% were 65 and over) were alive, and most had
      maintained high levels of ADL skills. Twenty per cent of the adult disabled were
      working, 10 out of 14 school-aged children were enrolled in schools, and life
      satisfaction was high. The second follow-up study indicated that personnel,
      although acknowledging the benefits of the programme, pointed to several
      remaining problems such as lack of rehabilitation education for the personnel.
      The results are discussed with reference to the CBR programme's aims, and
      implications drawn for industrialized countries.

PMID- 10579677
TI  - Community-based rehabilitation: the generalized model.
AB  - This article presents an overview of a generalized approach to rehabilitation
      services which have come to be known as community-based rehabilitation (CBR). The
      various administrative and government organizations that may be involved in the
      delivery of rehabilitation services are identified. Specific attention is given
      to the various forms of medical referral systems that might exist. In general,
      rehabilitation services are provided at the community level but more difficult
      cases, which require more sophisticated approaches, are referred to institutions
      more closely allied to a central government. This referral system also gives the
      disabled person access to more specialized personnel and services. The sources of
      information in this article consist of fundamental and formative primary
      references from documentation provided by the World Health Organization (WHO).
      These sources provide a valuable set of historical documents detailing the
      idealized concept of CBR.

PMID- 10579679
TI  - Insulin delivery governed by covalently modified lectin-glycogen gels sensitive
      to glucose.
AB  - A glucose-sensitive gel formulation containing concanavalin A and glycogen has
      been reported previously. Precipitation resulting from the addition of
      concanavalin A to glycogen has been documented, but the formation of glucose
      sensitive gels based on lectin-glycogen interactions is novel and used here in
      our studies. An improved in-vitro self-regulating drug-delivery system, using
      covalently modified glucose-sensitive gels based on concanavalin A and a
      polysaccharide displacement mechanism, is described. The successful use of the
      covalently modified gels addresses a problem identified previously where
      significant leaching of the mitogenic lectin from the gel membranes of non
      coupled gels was encountered. Concanavalin A was covalently coupled to glycogen
      by use of derivatives of Schiff's bases. The resulting gels, like the non-coupled
      gels, were shown to undergo a gel-sol transformation in response to glucose.
      Insulin delivery was demonstrated using this covalently modified system in
      conditions of repeated glucose triggering at 20 degrees C and 37 degrees C. The
      magnitude of the response was less variable than for the dextran-based gels
      studied previously. The performance of this system has been improved in terms of
      concanavalin A leaching. This could, therefore, be used as the basis of the
      design of a self-regulating drug-delivery device for therapeutic agents used to
      treat diabetes mellitus.

PMID- 10579678
TI  - An investigation into the erosion behaviour of a high drug-load (85%) particulate
      system designed for an extended-release matrix tablet. Analysis of erosion
      kinetics in conjunction with variations in lubrication, porosity and compaction
      rate.
AB  - The effects of the amounts of lubricants (magnesium stearate 0-5% and talc 0-3%)
      and changes in compaction rate and tablet porosity on the mechanism of drug
      release from high drug-load controlled-release theophylline tablets have been
      examined. Drug release was satisfactorily described by a surface-erosion model
      that takes into account the geometry of the tablet, differential radial and axial
      erosion rates, and the initial burst effect (r2 > 0.99 for all formulations). The
      axial and radial erosion rate constants were inversely proportional to the amount
      of magnesium stearate in the formulation (P < 0.0001). The most dramatic
      reductions in erosion rate occurred between 0 and 1% magnesium stearate content.
      For magnesium stearate concentrations > or =2.5% the ratio of radial to axial
      erosion rate constants was essentially constant at 3 (approx.); however, for
      formulations with magnesium stearate < or =1% the ratio tended toward unity.
      Reducing matrix porosity over the range 26 to 14% resulted in reduced erosion
      rates. However, a threshold of 17% (approx.) porosity was identified below which
      further reductions in porosity resulted in only incremental changes in release
      rates. The rate of erosion and drug release was insensitive to changes in machine
      speed over the range 20 to 100 rev min(-1). For highly loaded matrix tablets
      containing sparingly soluble drugs, such as theophylline, magnesium stearate at
      appropriate levels can modulate the erosion rate constants and act as an
      effective release-controlling excipient. Drug-release profiles are predictable
      and relatively robust in terms of changes in compaction rate and applied force
      routinely encountered in large-scale tablet manufacturing.

PMID- 10579680
TI  - Conjugation of an anti-B-cell lymphoma monoclonal antibody, LL2, to long
      circulating drug-carrier lipid emulsions.
AB  - Long-circulating submicron lipid emulsions, stabilized with poly(ethylene glycol)
      modified phosphatidylethanolamine (PEG-PE), are promising drug carriers with
      substantial capacity for solubilization of lipophilic anticancer agents. This
      study describes the conjugation of the anti-B-cell lymphoma monoclonal antibody
      LL2 to the surface of lipid-emulsion globules by use of a novel poly(ethylene
      glycol)-based heterobifunctional coupling agent. The efficiency of coupling of
      LL2 to the lipid emulsion was 85% (approx.) and essentially independent of the
      LL2/emulsion particle ratio and amount of surface-bound PEG-PE. Results from
      sucrose-gradient centrifugation and Sepharose CL-4B gel filtration indicated
      stable binding of the antibody to the emulsion. The immunoreactivity of the
      emulsion-LL2 conjugates was tested with alkaline phosphatase-conjugated LL2
      against a monoclonal anti-idiotype antibody, WN. The binding of the conjugates to
      WN increased with increasing surface density of LL2 up to 40 monoclonal
      antibodies/emulsion particle, and exceeded that for the free monoclonal antibody
      (approx. 20 molecules/particle). Results from competitive-binding ELISA were
      indicative of similar displacement curves for free LL2 and emulsion-LL2
      conjugates. Direct cellular ELISA revealed similar binding of emulsion-LL2
      complexes to three types of Burkitt's lymphoma cell lines, Raji, Ramos and Daudi.
      The results from this study indicate that emulsion-LL2 complexes might be a
      useful drug-carrier system for more specific delivery of anticancer drugs to B
      cell malignancy.

PMID- 10579681
TI  - Validation of a pharmacokinetic model of colon-specific drug delivery and the
      therapeutic effects of chitosan capsules containing 5-aminosalicylic acid on
      2,4,6-trinitrobenzenesulphonic acid-induced colitis in rats.
AB  - A pharmacokinetic model of colon-specific drug delivery developed in a previous
      study has been validated by use of 5-aminosalicylic acid (5-ASA) as a model anti
      inflammatory drug. The simulation curves obtained from the pharmacokinetic model
      were in good agreement with experimental data obtained after oral administration
      of 5-ASA-containing chitosan capsules. The concentrations of 5-ASA in the large
      intestinal mucosa after drug administration were higher than after administration
      of the drug in carmellose suspension. We then attempted colon-specific delivery
      of an anti-ulcerative colitis drug, in chitosan capsules, to accelerate healing
      of 2,4,6-trinitrobenzenesulphonic acid sodium salt (TNBS)-induced colitis in
      rats. To confirm this therapeutic model, salazosulphapyridine (SASP), a
      commercially available 5-ASA prodrug, was used as positive control. Colonic
      injury and inflammation were assessed by measuring myeloperoxidase activity and
      visual assessment (damage score), respectively. Because SASP is effective against
      TNBS-induced colitis in rats, use of the SASP-sensitive TNBS-induced colitis
      model validated the therapeutic effects of 5-ASA-containing chitosan capsules,
      which were significantly better than those of a suspension of the drug in
      carmellose. These findings suggest that our pharmacokinetic model of colon
      specific drug delivery can accurately evaluate this colon-specific delivery
      system and that 5-ASA-containing chitosan capsules are more effective than other
      5-ASA formulations for treatment of TNBS-induced colitis in rats.

PMID- 10579682
TI  - Immunohistochemical and functional characterization of pH-dependent intestinal
      absorption of weak organic acids by the monocarboxylic acid transporter MCT1.
AB  - The participation of the monocarboxylic acid transporter MCT1 in the intestinal
      absorption of weak organic acids has been clarified by functional
      characterization, by use of stably transfected cells, and by immunohistochemical
      location of the transporter in intestinal tissues. Immunohistochemical analysis
      by use of the anti-MCT1 antibody showed that MCT1 is distributed throughout the
      upper and lower intestines, especially in the basolateral membrane and, to a
      lesser extent, in the brush-border membrane. When the transporter gene rat MCT1
      was transfected into MDA-MB231 cells, transport of benzoic acid, a model weak
      organic acid that has been generally believed to be transported across the cell
      membranes by passive diffusion, and lactic acid in rat MCT1-transfected cells was
      significantly increased compared with transport in cells transfected with the
      expression vector pRc-CMV alone (mock cells). The observed transport was pH
      dependent and activity increased between pH 7.5 and pH 5.5, whereas pH-dependence
      in mock cells was moderate. Rat MCT1-mediated benzoic acid uptake was saturable,
      with an apparent Km value of 3.05 mM. In addition, MCT1 increased the efflux of
      [14C]benzoic acid from the cells. Several weak organic acids were also
      transported by rat MCT1. These results show that pH-dependent intestinal
      absorption of weak organic acids, previously explained in terms of passive
      diffusion according to the pH-partition hypothesis, is at least partially
      accounted for by MCT1-mediated transport energized at acidic pH by utilization of
      the proton gradient as a driving force.

PMID- 10579683
TI  - Skin delivery of oestradiol from deformable and traditional liposomes:
      mechanistic studies.
AB  - Deformable vesicles and traditional liposomes were compared as delivery systems
      for oestradiol to elucidate possible mechanisms of drug delivery through human
      skin. Accordingly, epidermal permeation of oestradiol from optimized deformable
      vesicles and traditional liposome formulations was studied under low dose non
      occluded conditions. Five mechanisms were investigated. A free drug mechanism
      compared low-dose permeation through skin with drug release determined after
      separation of the free drug. Penetration enhancement was researched by studying
      skin pretreatment with empty vesicles. Improved drug uptake by skin was monitored
      by dipping stratum corneum into different formulations for 10 min and determining
      drug uptake. The possibility that intact vesicles permeate through the epidermis
      was tested by comparing permeation from 136-nm vesicles with that from >500-nm
      vesicles, assuming that penetration depends on vesicle size. The possibility that
      different entrapment efficiencies in alternative formulations could be
      responsible for the difference in delivery was also evaluated. Lipid vesicles
      improved the skin delivery of oestradiol compared with delivery from an aqueous
      control. Maximum flux (Jmax) was increased 14- to 17-fold by use of deformable
      vesicles and 8.2- to 9.8-fold by use of traditional liposomes. Deformable
      vesicles were thus superior to traditional liposomes. Drug release was negligible
      over the period during which skin flux was maximum. Pretreatment with empty
      vesicles resulted in an enhancement ratio of 4.3 for pure phosphatidylcholine
      (PC) vesicles but the enhancement ratio ranged from only 0.8 to 2.4 for other
      formulations. Vesicles increased drug uptake into the stratum corneum 23- to 29
      fold. Relative flux values obtained from small and large vesicles were similar.
      No correlation was found between entrapment efficiency and skin delivery. The
      results showed no evidence of a free drug mechanism, but revealed a possible
      penetration-enhancing effect for pure PC vesicles, although this was not the only
      mechanism operating. The positive uptake suggested that lipid vesicles increased
      drug partitioning into the skin. The data provided no evidence for in-vitro
      liposome penetration through skin as distinct from vesicle penetration into the
      stratum corneum.

PMID- 10579684
TI  - Delivery of erythromycin to subcutaneous tissues in rats by means of a trans
      phase delivery system.
AB  - Topical administration of antibiotics is associated with reduced risk of systemic
      side-effects and alteration of gut microflora, and results in higher
      concentrations of antibiotics at the site of application (and so a lower dose of
      the drug is required). In conditions such as acne vulgaris, infiltration of the
      antibiotics into the infected subcutaneous layers is highly desirable. A trans
      phase delivery system (TPDS), a mixture of benzyl alcohol, acetone and
      isopropanol, has been shown to enhance the effective transport of the antibiotic
      erythromycin across the epidermal barrier and enhance accumulation in the dermis.
      Two formulations containing N-methyl[14C]erythromycin were compared, a TPDS
      solution and a propylene glycol solution. They were applied to the dorsal areas
      of 4-6 week old Fischer rats and tissues were removed for analysis of
      radioactivity after 2, 4, 8, 12 or 24 h and skin was biopsied and sectioned for
      autoradiography. The erythromycin dissolved in the TPDS solvent mixture
      penetrated the stratum corneum and a relatively high concentration was maintained
      in adjacent tissues for up to 24 h. Penetration was very effective and the
      erythromycin was detected in significant amounts in the underlying muscle,
      various organs and later in the urine. In contrast the propylene glycol carrier,
      probably because of its primarily hydrophilic character, caused the erythromycin
      to traverse tissue barriers rapidly and appear in the urine. Microautoradiographs
      qualitatively revealed progressive disappearance of radioactivity from the
      surface; this correlated with results obtained by direct isotope counting. The
      route of penetration, in addition to following the interkeratinocyte spaces,
      seemed to include the perimeter of the pilosebaceous glands and their appendages
      before diffusion into the capillaries. The propylene glycol solution seemed to
      traverse the epidermis and the papillary and reticular dermis more rapidly, which
      might explain its rapid appearance in the urine. These data suggest that the
      different solutions penetrate the skin by different mechanisms.

PMID- 10579685
TI  - Enterohepatic circulation model for population pharmacokinetic analysis.
AB  - An enterohepatic circulation model based on physiological aspects of biliary
      excretion has been developed for population pharmacokinetic analysis.
      Mycophenolate mofetil was selected as a model drug for validation of the model.
      As a secondary objective, the model was used for pharmacokinetic comparison among
      different races. The post-hoc plasma concentration-time course was well described
      by the newly developed enterohepatic model and a secondary peak arising from
      enterohepatic circulation was also well defined. The covariates predicted by the
      model agreed well with literature results. The model is useful for evaluation of
      the covariates of an enterohepatically circulated drug. The population
      pharmacokinetic approach is of benefit for evaluating racial differences for a
      pharmacokinetic bridging package.

PMID- 10579686
TI  - Effects of cyclosporin on the pharmacokinetics of propranolol after intravenous
      and oral administration to control rats and to rats with uranyl nitrate-induced
      acute renal failure.
AB  - The effects of cyclosporin on the pharmacokinetics of propranolol have been
      investigated after intravenous and oral administration of the drugs to control
      rats and to rats with uranyl nitrate-induced acute renal failure. The effects of
      intravenous cyclosporin, 30 mg kg(-1), on the pharmacokinetics of intravenous
      propranolol, 3 mg kg(-1), were significant both in control rats and in rats with
      uranyl nitrate-induced acute renal failure; after intravenous administration of
      cyclosporin plasma concentrations of propranolol were significantly lower, the
      area under the plasma concentration-time curve (AUC) for propranolol from time
      zero to time infinity was significantly smaller, and the time-averaged total body
      clearance of propranolol was significantly faster. The effects of oral
      cyclosporin, 100 mg kg(-1), on the pharmacokinetics of oral propranolol, 10 mg
      kg(-1), were also significant, both in control rats and in rats with uranyl
      nitrate-induced acute renal failure; after administration of oral cyclosporin
      plasma concentrations of propranolol were significantly higher and the AUC of
      propranolol was significantly greater. These data suggest that cyclosporin
      increases the elimination of propranolol, and that the first-pass effects of
      propranolol are reduced, or gastrointestinal absorption of propranolol is
      increased, or both, by cyclosporin.

PMID- 10579687
TI  - High-performance liquid-chromatographic-atmospheric-pressure chemical-ionization
      ion-trap mass-spectrometric identification of isomeric C6-hydroxy and C20-hydroxy
      metabolites of methylprednisolone in the urine of patients receiving high-dose
      pulse therapy.
AB  - Fourteen metabolites of methylprednisolone have been analysed by gradient-elution
      high-performance liquid chromatography coupled with tandem mass spectrometry (LC
      MS-MS). The compounds were separated on a Cp Spherisorb 5 microm ODS column
      connected to a guard column packed with pellicular reversed phase. The mobile
      phase was an acetonitrile- 1.0% aqueous acetic acid gradient at a flow rate of
      1.5 mL min(-1) The analysis gave a complete picture of parent drug, prodrugs and
      metabolites, and the alpha/beta stereochemistry was resolved. The short (1-2 h)
      elimination half-life of methylprednisolone is explained by extensive metabolism.
      The overall picture of the metabolic pathways of methylprednisolone is apparently
      simple-reduction of the C20 carbonyl group and further oxidation of the C20,C21
      side chain (into C21COOH and C20COOH), in competition with or in addition to
      oxidation at the C6 position.

PMID- 10579688
TI  - An in-vitro study on the metabolism of rokitamycin and possible interactions of
      the drug with rat liver microsomes.
AB  - This in-vitro study was designed to identify the enzyme(s) involved in the major
      metabolic pathway of rokitamycin, i.e. the formation of leucomycin A7, and to
      assess possible interactions of the drug with rat liver microsomes. Formation of
      leucomycin A7 was NADPH-independent and was not appreciably inhibited by anti-rat
      NADPH cytochrome P-450 reductase serum or cimetidine, a nonspecific inhibitor of
      cytochrome P-450 isoforms. Eadie-Hofstee plots for the formation of leucomycin A7
      were indicative of apparently monophasic behaviour for six rat liver microsomes
      tested. The mean (+/- s.d.) kinetic parameters, Km, Vmax and Vmax/Km, for the
      formation of leucomycin A7 from rokitamycin were 47+/-13 microM, 390+/-56 nmol
      min(-1) (mg protein)(-1) and 8.6+/-1.6 mL min(-1) (mg protein)(-1), respectively.
      Three esterase inhibitors (100 microM), bis-nitrophenylphosphate, physostigmine
      and metrifonate inhibited the formation of leucomycin A7 by more than 60%.
      Metabolism of rokitamycin was inhibited by terfenadine, but not by mequitazine,
      whereas chlorpheniramine and theophylline activated the formation of leucomycin
      A7. Rokitamycin, leucomycin A7, leucomycin V, erythromycin and clarithromycin
      were weak inhibitors of CYP3A-catalysed 3-hydroxylation of quinine with mean IC50
      values ranging from 71 to >100 microM. It is concluded that in rat liver
      microsomes the formation of leucomycin A7 from rokitamycin is catalysed mainly by
      an esterase (possibly cholinesterase, EC3.1.1.8), but not by cytochrome P-450
      enzyme(s). Although in this in-vitro animal study CYP3A activity was barely
      inhibited by rokitamycin, the possibility cannot be totally discounted in man
      when rokitamycin is co-administered with drugs metabolized by CYP3A.

PMID- 10579689
TI  - Diadenosine polyphosphates in cultured vascular smooth-muscle cells and
      endothelium cells--their interaction with specific receptors and their
      degradation.
AB  - The role of diadenosine polyphosphates (ApnA, where "A" denotes "adenosine" and
      "n" denotes the number of phosphate groups "p") as vasoconstrictors of smooth
      muscle cells and as blood-pressure regulating and insulin-releasing compounds has
      been described. It was the aim of this study to investigate whether specific
      receptors for these compounds, mediating the above mentioned effects, occur in
      cultured vascular smooth-muscle cells (VSMC) and in endothelium cells, and
      whether these compounds are degraded during incubation. Saturable binding sites
      for diadenosine polyphosphate [3H]Ap4A with an extremely quick saturation
      equilibrium, even at low temperature (4 degrees C), are present in vascular
      smooth-muscle cells. Diadenosine polyphosphates at micromolar concentrations
      displaced [3H]Ap4A from binding sites; the ranking order was Ap4A > Ap3A > Ap5A
      approximately Ap6A. Compounds interacting with purinergic P2X receptors such as
      suramin, alpha,beta-methylene ATP and pyridoxalphosphate-6-azophenyl-2',4'
      disulphonic acid (PPADS), albeit at high concentrations, displaced [3H]Ap4A from
      its binding sites. Surprisingly, at low concentrations the compounds tested
      increased the binding of [3H]Ap4A, which might imply the occurrence of positive
      receptor cooperativity or inhibition of [3H]Ap4A degradation. By use of thin
      layer chromatography it was observed that [3H]Ap4A was quickly degraded (half
      life approx. 12 min) in the extracellular medium to (mainly) adenosine and
      inosine. [3H]Ap4A and its degradation products were quickly taken up by the
      cells. Degradation can be inhibited by Ap6A, alpha,beta-methylene ATP or PPADS.
      Rather similar degradation and uptake results were also obtained when endothelium
      cells were used. These data indicate that specific binding sites for [3H]Ap4A are
      present in vascular smooth-muscle cells and that diadenosine polyphosphates at
      physiological concentrations displace binding. The receptors involved might be
      distinct diadenosine polyphosphate receptors, although the involvement of others,
      such as P2X receptors, is also possible. Ap4A is quickly degraded in the
      extracellular space and compounds that inhibit degradation result in an increase
      in [3H]Ap4A binding. It should be remembered that when diadenosine polyphos
      phates are being investigated in physiological and pathophysiological studies of
      their impact on smooth-muscle cell proliferation and on vasoconstriction (blood
      pressure regulation), results obtained from long-term incubations might be
      critical.

PMID- 10579690
TI  - Differences between the vasorelaxant activity of adenosine-receptor agonists on
      guinea-pig isolated aorta precontracted with noradrenaline or phenylephrine.
AB  - The relaxant effect of adenosine and 5'-(N-ethylcarboxamido)adenosine (NECA)
      against alpha-adrenoceptor-mediated contractile tone in guinea-pig isolated
      aortic rings has been examined to determine if this A2B-receptor-mediated
      relaxation was dependent upon the contracting agent, and whether the contractions
      were dependent upon intracellular or extracellular calcium. Relaxation responses
      were consistently greater for aortic rings pre-contracted with phenylephrine
      (3x10(-6) M) than for rings pre-contracted with noradrenaline (3x10(-6) M).
      Maximum inhibition by NECA was significantly greater for phenylephrine-contracted
      aortae than for noradrenaline-contracted (81.9+/-2.8% compared with 25.0+/-1.5%).
      These differences persisted in the presence of beta- and alpha2-adrenoceptor
      blockade and could not, therefore, be attributed to stimulation of these
      receptors by noradrenaline. The ratio of the contractions obtained before and in
      the presence of adenosine or NECA was compared with the control ratio obtained
      before and after vehicle. Experiments were performed both in the presence of
      normal calcium levels and under calcium-free conditions. In normal-calcium
      medium, NECA inhibited phenylephrine-induced contractions (test ratio, 76.7+/
      3.9%; control ratio, 133.1+/-9.8%) to a greater extent than noradrenaline-induced
      contractions (108.4+/-4.1 and 123.4+/-4.9%); adenosine similarly inhibited
      phenylephrine-induced contractions more than those induced by noradrenaline.
      Under calcium-free conditions, adenosine (36.7+/-11.9 and 110.7+/-26.6%) and NECA
      (55.2+/-9.1 and 87.1+/-14.9%) were only effective against phenylephrine-induced
      contractions. This suggests that activation of the A2B-receptor by these agonists
      inhibited intracellular mobilization of calcium for phenylephrine-induced
      contractions only. The effects on extracellular calcium influx were examined for
      phenylephrine- and noradrenaline-induced contractions in normal-calcium medium
      but in the presence of ryanodine to prevent intracellular calcium mobilization.
      NECA inhibited phenylephrine-induced contractions (77.3+/-12.4 and 111.4+/-9.3%),
      presumably by interfering with influx of calcium through receptor-operated
      calcium channels. In contrast, NECA failed to reduce noradrenaline-induced
      contractions (121.5+/-10.7 and 122.4+/-11.6%), suggesting that the effect on
      noradrenaline is predominantly via interaction with intracellular calcium.
      Adenosine was consistently a more effective relaxant than NECA, possibly because
      of an additional intracellular component of the response. We conclude that
      adenosine receptor agonists inhibit phenylephrine-induced contractions of guinea
      pig aorta more selectively than noradrenaline-induced contractions. A2B-receptor
      stimulation might reveal a fundamental difference between the modes of
      contraction elicited by these two alpha-adrenoceptor agonists.

PMID- 10579691
TI  - Pharmacological characterization of KR-30988, a novel non-peptide AT1 receptor
      antagonist, in rat, rabbit and dog.
AB  - The pharmacological profile of KR-30988, a non-peptide AT1-selective angiotensin
      receptor antagonist, has been investigated by use of a variety of experimental
      models in-vitro and in-vivo. KR-30988 inhibited the specific binding of
      [125I][Sar1, Ile8]-angiotensin II to the recombinant AT1 receptor from man with a
      potency similar to that of losartan (IC50 values, the concentrations of drugs
      displacing 50% of specific binding, 13.6 and 12.3 nM, respectively), but did not
      inhibit the binding of [125I]CGP 42112A to recombinant AT2 receptor from man
      (IC50 >10 microM for both drugs). Scatchard analysis showed that KR-30988
      interacted competitively with recombinant AT1 receptor from man in the same
      manner as losartan. In functional studies with rat and rabbit aorta, KR-30988
      noncompetitively inhibited the contractile response to angiotensin II (pD2, = 
      log EC50 (where EC50 is the dose resulting in 50% of a reference contraction),
      8.64 and 7.73, respectively) with a 20-85% decrease in the maximum contractile
      responses, unlike losartan. In pithed rats intravenous KR-30988 resulted in a non
      parallel shift to the right of the dose-pressor response curve to angiotensin II
      (ID50 value, the dose inhibiting the pressor response to angiotensin II by 50%,
      0.09 mg kg(-1)) with a dose-dependent reduction in the maximum responses; in this
      antagonistic effect KR-30988 was 20 times (approx.) more potent than losartan
      (ID50 1-74 mg kg(-1)). In conscious renal hypertensive rats oral administration
      of KR-30988 produced a dose-dependent and long-lasting (>24 h) anti-hypertensive
      effect; the potency was six times that of losartan (ED30 values, the dose
      reducing mean arterial blood pressure by 30 mmHg, 0.48 and 2.97 mg kg(-1),
      respectively). In conscious furosemide-treated dogs oral administration of KR
      30988 produced a dose-dependent and long-lasting (>8 h) hypotensive effect with a
      rapid onset of action (time to Emax, the maximum effect, 1-2 h); KR-30988 was
      eight times more potent than losartan (ED20, the dose reducing mean arterial
      blood pressure by 20 mm Hg, 1.04 and 7.96 mg kg(-1), respectively). These results
      suggest that KR-30988 is a potent, orally active selective AT1 receptor
      antagonist with a mode of insurmountable antagonism.

PMID- 10579692
TI  - Chromatographic resolution, chiroptical characterization and preliminary
      pharmacological evaluation of the enantiomers of butibufen: a comparison with
      ibuprofen.
AB  - Enantiomeric resolution of butibufen has been achieved on a cellulose tris(3,5
      dimethylphenylcarbamate) chiral stationary phase with hexane-isopropanol
      trifluoroacetic acid, 100:1.2:0.02 (v/v/v) as mobile phase at a flow rate of 1.0
      mL min(-1). Semi-preparative isolation of the enantiomers then chiroptical
      characterization indicated that the order of elution was (-)-R- before (+)-S
      butibufen. When tested for their effects on the cyclooxygenase and 5-lipoxygenase
      pathways of eicosanoid metabolism in calcium ionophore-activated rat peritoneal
      leukocytes it was found that (+)-S-butibufen inhibited generation of thromboxane
      B2 (TXB2) and prostaglandin E2 (PGE2) (cyclooxygenase pathway), with an IC50 of
      1.5 microM (approx.), whereas the (-)-R enantiomer was essentially inactive.
      Neither enantiomer inhibited the 5-lipoxygenase pathway. In this regard, (+)-S
      butibufen was approximately five times less potent as a cyclooxygenase inhibitor
      than (+)-S-ibuprofen. These results show the enantiomeric specificity and pathway
      selectivity of this novel non-steroidal anti-inflammatory drug.

PMID- 10579693
TI  - Himehabu lectin, a novel inducer of Ca2+-release from the venom of the snake
      Trimeresurus okinavensis, in sarcoplasmic reticulum.
AB  - The lectin himehabu lectin (HHL) has recently been isolated from crude venom of
      the snake Trimeresurus okinavensis. Ca2+ -electrode and fluorescent Ca2+ 
      indicator experiments showed that HHL induced release of Ca2+ from the heavy
      fraction of skeletal muscle sarcoplasmic reticulum (HSR). The release of Ca2+
      induced by caffeine from HSR was abolished by ryanodine, Mg2+ and ruthenium red,
      typical inhibitors of Ca2+ -release channels, whereas that induced by HHL was
      only partially reduced by these inhibitors. HHL, unlike caffeine, had no effect
      on [3H]ryanodine binding to HSR. These results suggest that HHL induces release
      of Ca2+ which is at least partially mediated through Ca2+ -release channels with
      novel pharmacological properties.

PMID- 10579694
TI  - Structural definition of arabinomannans from Mycobacterium bovis BCG.
AB  - The structures of the hydrophilic parietal and cellular arabinomannans isolated
      from Mycobacterium bovis BCG cell wall [Nigou et al. (1997) J Biol Chem 272:
      23094-103] were investigated. Their molecular mass as determined by MALDI-TOF
      mass spectrometry was around 16 kDa. Concerning cap structure, capillary
      electrophoresis analysis demonstrated that dimannoside (Manpalpha1-->2Manp) was
      the most abundant motif (65-75%). Using two-dimensional 1H-13C NMR spectroscopy,
      the mannan core was unambiguously demonstrated to be composed of -->6Manpalpha1-
      > backbone substituted at some O-2 by a single Manp unit. The branching degree
      was determined as 84%. Finally, arabinomannans were found to be devoid of the
      phosphatidyl-myo-inositol anchor and, by aminonaphthalene disulfonate tagging,
      the mannan core was shown to contain a reducing end. This constitutes the main
      difference between arabinomannans and lipoarabinomannans from Mycobacterium bovis
      BCG.

PMID- 10579695
TI  - New insights on the specificity of heparin and heparan sulfate lyases from
      Flavobacterium heparinum revealed by the use of synthetic derivatives of K5
      polysaccharide from E. coli and 2-O-desulfated heparin.
AB  - The capsular polysaccharide from E. Coli, strain K5 composed of ...-->4)beta-D
      GlcA(1-->4)alpha-D-GlcNAc(1-->4)beta-D-GlcA (1-->..., chemically modified K5
      polysaccharides, bearing sulfates at C-2 and C-6 of the hexosamine moiety and at
      the C-2 of the glucuronic acid residues as well as 2-O desulfated heparin were
      used as substrates to study the specificity of heparitinases I and II and
      heparinase from Flavobacterium heparinum. The natural K5 polysaccharide was
      susceptible only to heparitinase I forming deltaU-GlcNAc. N-deacetylated, N
      sulfated K5 became susceptible to both heparitinases I and II producing deltaU
      GlcNS. The K5 polysaccharides containing sulfate at the C-2 and C-6 positions of
      the hexosamine moiety and C-2 position of the glucuronic acid residues were
      susceptible only to heparitinase II producing deltaU-GlcNS,6S and deltaU,2S
      GlcNS,6S respectively. These combined results led to the conclusion that the
      sulfate at C-6 position of the glucosamine is impeditive for the action of
      heparitinase I and that heparitinase II requires at least a C-2 or a C-6 sulfate
      in the glucosamine residues of the substrate for its activity. Iduronic acid-2-O
      desulfated heparin was susceptible only to heparitinase II producing deltaU
      GlcNS,6S. All the modified K5 polysaccharides as well as the desulfated heparin
      were not substrates for heparinase. This led to the conclusion that heparitinase
      II acts upon linkages containing non-sulfated iduronic acid residues and that
      heparinase requires C-2 sulfated iduronic acid residues for its activity.

PMID- 10579696
TI  - Preparation and isolation of neoglycoconjugates using biotin-streptavidin
      complexes.
AB  - Glycoproteins commercially available in multi-gram quantities, were used to
      prepare milligram amounts of neoglycoproteins. The glycoproteins bromelain and
      bovine gamma-globulin were proteolyzed to obtain glycopeptides or converted to a
      mixture of glycans through hydrazinolysis. The glycan mixture was structurally
      simplified by carbohydrate remodeling using exoglycosidases. Glycopeptides were
      biotinylated using N-hydroxysuccinimide activated-long chain biotin while
      glycoprotein-derived glycans were first reductively aminated with ammonium
      bicarbonate and then biotinylated. The resulting biotinylated carbohydrates were
      structurally characterized and then bound to streptavidin to afford
      neoglycoproteins. The peptidoglycan component of raw, unbleached heparin (an
      intermediate in the manufacture of heparin) was similarly biotinylated and bound
      to streptavidin to obtain milligram amounts of a heparin neoproteoglycan. The
      neoglycoconjugates prepared contain well defined glycan chains at specific
      locations on the streptavidin core and should be useful for the study of protein
      carbohydrate interactions and affinity separations.

PMID- 10579697
TI  - Screening neutral and acidic IgG N-glycans by high density electrophoresis.
AB  - IgG carries bi-antennary N-linked glycans which differ in degrees of
      galactosylation, core fucosylation and bisecting N-acetyl glucosamine. The
      majority of these are non-sialyated closely related neutral structures which can
      be resolved by HPLC analysis, but which are difficult to separate in techniques
      such as fluorophore-coupled carbohydrate electrophoresis. Derivatisation with the
      singly charged fluorophore, 2-amino benzoic acid and separation in gels with a
      30% monomer content in tris/glycine buffer enabled separation of neutral glycans.
      In particular, agalactosyl glycans with either a core fucose substitution or
      bisecting N-acetyl galactosamine could be resolved. Good separation of mono- and
      di-galactosylated glycans was also achieved with this system. It was shown that
      IgG can be separated from serum by size-exclusion and anion exchange
      chromatography with minimal contamination, with complete glycan release
      accomplished by the enzyme peptide-N-glycosidase F (F. meningosepticum). This
      method of resolving IgG glycans could be used to monitor patients in which
      glycosylation changes may have a diagnostic value, as in rheumatoid arthritis. It
      could also be used to monitor recombinant IgG glycosylation where routine
      screening is required in the biotechnology industry.

PMID- 10579700
TI  - Methodological limitations of cost-effectiveness analysis in health care:
      implications for decision making and service provision.
AB  - This article reviews the methodological limitations identified in a recent
      authoritative US report by the Public Health Service, which provides the
      theoretical background to several other guidelines on cost effectiveness, such as
      those of the British Medical Journal. It places each limitation in context and
      discusses the implications of each individually and collectively. It concludes
      that while the report's interim solution by consensus agreement offers a way
      forward in the short term, the complexities identified reveal a range of
      limitations to the more heroic uses of cost effectiveness analysis in healthcare.
      More modest approaches, it is suggested, may have greater practical relevance.

PMID- 10579698
TI  - Structural determination of novel tetra- and hexasaccharide sequences isolated
      from chondroitin sulfate H (oversulfated dermatan sulfate) of hagfish notochord.
AB  - Oversulfated chondroitin sulfate H (CS-H) isolated from hagfish notochord is a
      unique dermatan sulfate consisting mainly of IdoAalpha1-3GalNAc(4S,6S), where
      IdoA, GalNAc, 4S and 6S represent L-iduronic acid, Nacetyl-D-galactosamine, 4-O
      sulfate and 6-O-sulfate, respectively. Several tetra- and hexasccharide fractions
      were isolated from CS-H after partial digestion with bacterial chondroitinase B
      to investigate the sequential arrangement of the IdoAalpha1-3GalNAc(4S,6S) unit
      in the CS-H polysaccharide. A structural analysis of the isolated
      oligosaccharides by enzymatic digestions, mass spectrometry and 1H NMR
      spectroscopy demonstrated that the major tetrasaccharides shared the common
      disulfated core structure delta4,5HexAalpha1-3GalNAc(4S)beta1-4IdoAalpha1-3
      GalNAc (4S) with 0 approximately 3 additional O-sulfate groups, where
      delta4,5HexA represents 4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid. The
      major hexasaccharides shared the common trisulfated core structure
      delta4,5HexAalpha1-3 GalNAc(4S)beta1-4 IdoAalpha1-3 GalNAc(4S)beta1-4IdoAalpha1-3
      GalNAc(4S) with 1 approximately 4 additional O-sulfate groups. Some extra sulfate
      groups in both tetra- and hexasaccharides were located at the C-2 position of a
      delta4,5HexA or an internal IdoA residue, or C-6 position of 4-O-sulfated GalNAc
      residues, forming the unique disulfated or trisulfated disaccharide units, IdoA
      (2S)-GalNAc(4S), IdoA-GalNAc(4S,6S) and IdoA (2S)-GalNAc(4S,6S), where 2S
      represents 2-O-sulfate. Of the demonstrated sequences, five tetra- and four
      hexasaccharide sequences containing these units were novel.

PMID- 10579699
TI  - Reduction of sialic acid O-acetylation in human colonic mucins in the adenoma
      carcinoma sequence.
AB  - The oligo-O-acetylation of sialic acids found in normal colonic mucins is greatly
      reduced in colorectal cancer. Mucins prepared from cancer tissue in
      adenocarcinoma showed this reduction, while normal O-acetylation was detected in
      resection margin and control cases and total mucin sialic acid content was
      significantly decreased in cancer vs. control samples. A reduction of the O
      acetyl transferase activity catalysing the O-acetylation reaction was also found.
      A series of cultured human colorectal cell lines derived from the same
      premalignant adenomatous line, and representative of the adenoma-carcinoma
      sequence were examined and revealed a depletion of oligo-O-acetylation in the
      original diploid premalignant line, re-expression in a further premalignant line
      and reduction in malignant mucinous and adenocarcinoma cell lines. Reduction of
      sialic acid O-acetylation appears as an early event in the process of malignant
      transformation in human colorectal cancer.

PMID- 10579701
TI  - Economic evaluations of community-based care: lessons from twelve studies in
      Ontario.
AB  - A series of 12 studies (five historic cohort and seven randomized trials)
      examined clients in community settings in Southern Ontario suffering from a
      variety of chronic physical and mental health conditions. These studies are
      appraised using a framework for evaluating possible outcomes of economic
      evaluation. In the 12 studies, sample composition and size varied. Each study was
      designed to quantify the well-being outcomes and expenditures associated with
      different community-based approaches to care provided in the context of a system
      of national health insurance. As a collective, these studies represent increasing
      methodological rigour. Multiple-perspective client well-being outcome measures
      were used. In two studies, caregiver burden also was analysed. A common approach
      to quantification and evaluation of expenditures for service consumption was used
      in all 12 studies. The nature of community-based health services (health vs.
      disease care orientation) was found to have direct and measurable impact on total
      expenditures for health service utilization and client well-being outcomes. In
      most cases, a recurring pattern of equal or better client outcomes, yet lower
      expenditures for use of community based health services, was associated with well
      integrated health oriented services. Integrated services aimed at factors which
      determine health are superior when compared to individual, fragmented, disease
      oriented, and focused approaches to care. The main lessons from the 12 studies
      are that it is as or more effective and as or less expensive to offer complete,
      proactive, community health services to persons living with chronic circumstance
      than to provide focused, on-demand, piecemeal services. Complete services would
      have a psychosocial and mental health focus included with the physical care
      approach. Furthermore, people with coexisting risk factors (age, living
      arrangements, mental distress and problem-solving ability) are the ones who most
      benefit at lower expense from health oriented, proactive interventions.

PMID- 10579702
TI  - Assessing low volume, high cost, potentially life saving surgical interventions:
      how and when? Left ventricular assist devices (LVADs) as a case study.

PMID- 10579703
TI  - Performance: a multi-disciplinary and conceptual model.
AB  - We contend that the scientific study of performance requires a model or paradigm.
      We propose a performance model with an underlying mathematical basis that is well
      defined, has explicit assumptions and has the potential to be both heuristic and
      scientifically testable. The model is based on an integration of concepts from
      health sciences and psychology that have been adapted to performance measurement
      in health care. The proposed performance model consists of a combination of four
      primary elements: quality of care, cost of care, access to care and satisfaction.
      Satisfaction is defined as a function of perceived and expected outcomes of care
      and perceived and expected input. This performance model can serve as both a tool
      for understanding and as a vehicle for comparing performance within and between
      health care organizations. We believe that this model can be used to develop a
      performance profile report and the future report card.

PMID- 10579704
TI  - The effectiveness of the use of patient-based measures of health in routine
      practice in improving the process and outcomes of patient care: a literature
      review.
AB  - Despite a number of potential benefits to both the clinician and the patient,
      patient-based measures of health have not been routinely or systematically used
      within routine practice by clinicians in the care of individual patients. There
      are a number of practical, methodological and attitudinal barriers which have so
      far limited the use of patient-based measures of health within routine practice.
      The extent to which these barriers are overcome is likely to influence the
      effectiveness of such instruments in improving the process and outcomes of
      patient care. This study reviewed the evidence for the effectiveness of this
      intervention and identified some of the factors that may influence its
      effectiveness. Thirteen relevant studies were located using search strategies on
      three computerized databases for 1987-97. The study found that clinicians see
      information from patient-based measures of health as valuable in the overall
      assessment of the patient and that its feedback to clinicians increases the
      detection of psychological and, to a lesser extent, functional problems. However,
      there was little evidence to suggest their use substantially changed patient
      management or improved patient outcomes. Our findings suggest that the ways in
      which patient based measures of health are implemented in routine practice may
      have an impact on their effectiveness. It is recommended that implementation
      strategies that are guided by theories of individual and organizational change
      might allow the barriers to using patient-based measures of health in routine
      practice to be identified and overcome more effectively.

PMID- 10579705
TI  - From the life-cycles of clinical evidence to the learning curve of clinical
      experience.
AB  - Treatments on offer to an individual with suspected disease are based on concepts
      which, like products, go through life-cycles (introduction, growth, maturity,
      decline). We argue that randomized controlled trials, meta-analyses, and
      guidelines have reached maturity and/or are already on the decline and note
      renewed interest in case reports and qualitative medicine. The latter emphasize
      individual rather than 'average' patients. Moreover, we point out that scientific
      evidence relates not only to variables that can be measured but also to
      categorical variables that are often neglected. An appropriate treatment strategy
      is probably one which is indicated by several methods based on different concepts
      rather than by a single standard method. The doctor's role is to use his critical
      judgement and experience to appraise evidence from formal trials and from
      analyses of observational data and to share his views with the patient.

PMID- 10579706
TI  - Evidence-based medicine and clinical experience.

PMID- 10579707
TI  - A consultant looks at the NHS today.

PMID- 10579708
TI  - Physiotherapy and the randomized controlled trial: an evaluation of research and
      development workshops in musculoskeletal physiotherapy.

PMID- 10579710
TI  - A first glimpse at the structure of the TOM translocase from the mitochondrial
      outer membrane.

PMID- 10579711
TI  - Life without perlecan has its problems.

PMID- 10579712
TI  - Loss of A-type lamin expression compromises nuclear envelope integrity leading to
      muscular dystrophy.
AB  - The nuclear lamina is a protein meshwork lining the nucleoplasmic face of the
      inner nuclear membrane and represents an important determinant of interphase
      nuclear architecture. Its major components are the A- and B-type lamins. Whereas
      B-type lamins are found in all mammalian cells, A-type lamin expression is
      developmentally regulated. In the mouse, A-type lamins do not appear until midway
      through embryonic development, suggesting that these proteins may be involved in
      the regulation of terminal differentiation. Here we show that mice lacking A-type
      lamins develop to term with no overt abnormalities. However, their postnatal
      growth is severely retarded and is characterized by the appearance of muscular
      dystrophy. This phenotype is associated with ultrastructural perturbations to the
      nuclear envelope. These include the mislocalization of emerin, an inner nuclear
      membrane protein, defects in which are implicated in Emery-Dreifuss muscular
      dystrophy (EDMD), one of the three major X-linked dystrophies. Mice lacking the A
      type lamins exhibit tissue-specific alterations to their nuclear envelope
      integrity and emerin distribution. In skeletal and cardiac muscles, this is
      manifest as a dystrophic condition related to EDMD.

PMID- 10579713
TI  - Human ECT2 is an exchange factor for Rho GTPases, phosphorylated in G2/M phases,
      and involved in cytokinesis.
AB  - Animal cells divide into two daughter cells by the formation of an actomyosin
      based contractile ring through a process called cytokinesis. Although many of the
      structural elements of cytokinesis have been identified, little is known about
      the signaling pathways and molecular mechanisms underlying this process. Here we
      show that the human ECT2 is involved in the regulation of cytokinesis. ECT2
      catalyzes guanine nucleotide exchange on the small GTPases, RhoA, Rac1, and
      Cdc42. ECT2 is phosphorylated during G2 and M phases, and phosphorylation is
      required for its exchange activity. Unlike other known guanine nucleotide
      exchange factors for Rho GTPases, ECT2 exhibits nuclear localization in
      interphase, spreads throughout the cytoplasm in prometaphase, and is condensed in
      the midbody during cytokinesis. Expression of an ECT2 derivative, containing the
      NH(2)-terminal domain required for the midbody localization but lacking the COOH
      terminal catalytic domain, strongly inhibits cytokinesis. Moreover,
      microinjection of affinity-purified anti-ECT2 antibody into interphase cells also
      inhibits cytokinesis. These results suggest that ECT2 is an important link
      between the cell cycle machinery and Rho signaling pathways involved in the
      regulation of cell division.

PMID- 10579714
TI  - Morphological control of inositol-1,4,5-trisphosphate-dependent signals.
AB  - Inositol-1,4,5-trisphosphate (InsP(3))-mediated calcium signals represent an
      important mechanism for transmitting external stimuli to the cell. However,
      information about intracellular spatial patterns of InsP(3) itself is not
      generally available. In particular, it has not been determined how the interplay
      of InsP(3) generation, diffusion, and degradation within complex cellular
      geometries can control the patterns of InsP(3) signaling. Here, we explore the
      spatial and temporal characteristics of [InsP(3)](cyt) during a bradykinin
      induced calcium wave in a neuroblastoma cell. This is achieved by using a unique
      image-based computer modeling system, Virtual Cell, to integrate experimental
      data on the rates and spatial distributions of the key molecular components of
      the process. We conclude that the characteristic calcium dynamics requires rapid,
      high-amplitude production of [InsP(3)](cyt) in the neurite. This requisite
      InsP(3) spatiotemporal profile is provided, in turn, as an intrinsic consequence
      of the cell's morphology, demonstrating how geometry can locally and dramatically
      intensify cytosolic signals that originate at the plasma membrane. In addition,
      the model predicts, and experiments confirm, that stimulation of just the
      neurite, but not the soma or growth cone, is sufficient to generate a calcium
      response throughout the cell.

PMID- 10579715
TI  - Conservation of a gliding motility and cell invasion machinery in Apicomplexan
      parasites.
AB  - Most Apicomplexan parasites, including the human pathogens Plasmodium,
      Toxoplasma, and Cryptosporidium, actively invade host cells and display gliding
      motility, both actions powered by parasite microfilaments. In Plasmodium
      sporozoites, thrombospondin-related anonymous protein (TRAP), a member of a group
      of Apicomplexan transmembrane proteins that have common adhesion domains, is
      necessary for gliding motility and infection of the vertebrate host. Here, we
      provide genetic evidence that TRAP is directly involved in a capping process that
      drives both sporozoite gliding and cell invasion. We also demonstrate that TRAP
      related proteins in other Apicomplexa fulfill the same function and that their
      cytoplasmic tails interact with homologous partners in the respective parasite.
      Therefore, a mechanism of surface redistribution of TRAP-related proteins driving
      gliding locomotion and cell invasion is conserved among Apicomplexan parasites.

PMID- 10579716
TI  - Replication of tobacco mosaic virus on endoplasmic reticulum and role of the
      cytoskeleton and virus movement protein in intracellular distribution of viral
      RNA.
AB  - Little is known about the mechanisms of intracellular targeting of viral nucleic
      acids within infected cells. We used in situ hybridization to visualize the
      distribution of tobacco mosaic virus (TMV) viral RNA (vRNA) in infected tobacco
      protoplasts. Immunostaining of the ER lumenal binding protein (BiP) concurrent
      with in situ hybridization revealed that vRNA colocalized with the ER, including
      perinuclear ER. At midstages of infection, vRNA accumulated in large irregular
      bodies associated with cytoplasmic filaments while at late stages, vRNA was
      dispersed throughout the cytoplasm and was associated with hair-like protrusions
      from the plasma membrane containing ER. TMV movement protein (MP) and replicase
      colocalized with vRNA, suggesting that viral replication and translation occur in
      the same subcellular sites. Immunostaining with tubulin provided evidence of
      colocalization of vRNA with microtubules, while disruption of the cytoskeleton
      with pharmacological agents produced severe changes in vRNA localization. Mutants
      of TMV lacking functional MP accumulated vRNA, but the distribution of vRNA was
      different from that observed in wild-type infection. MP was not required for
      association of vRNA with perinuclear ER, but was required for the formation of
      the large irregular bodies and association of vRNA with the hair-like
      protrusions.

PMID- 10579717
TI  - The TOM core complex: the general protein import pore of the outer membrane of
      mitochondria.
AB  - Translocation of nuclear-encoded preproteins across the outer membrane of
      mitochondria is mediated by the multicomponent transmembrane TOM complex. We have
      isolated the TOM core complex of Neurospora crassa by removing the receptors
      Tom70 and Tom20 from the isolated TOM holo complex by treatment with the
      detergent dodecyl maltoside. It consists of Tom40, Tom22, and the small Tom
      components, Tom6 and Tom7. This core complex was also purified directly from
      mitochondria after solubilization with dodecyl maltoside. The TOM core complex
      has the characteristics of the general insertion pore; it contains high
      conductance channels and binds preprotein in a targeting sequence-dependent
      manner. It forms a double ring structure that, in contrast to the holo complex,
      lacks the third density seen in the latter particles. Three-dimensional
      reconstruction by electron tomography exhibits two open pores traversing the
      complex with a diameter of approximately 2.1 nm and a height of approximately 7
      nm. Tom40 is the key structural element of the TOM core complex.

PMID- 10579718
TI  - Centriolar satellites: molecular characterization, ATP-dependent movement toward
      centrioles and possible involvement in ciliogenesis.
AB  - We identified Xenopus pericentriolar material-1 (PCM-1), which had been reported
      to constitute pericentriolar material, cloned its cDNA, and generated a specific
      pAb against this molecule. Immunolabeling revealed that PCM-1 was not a
      pericentriolar material protein, but a specific component of centriolar
      satellites, morphologically characterized as electron-dense granules,
      approximately 70-100 nm in diameter, scattered around centrosomes. Using a GFP
      fusion protein with PCM-1, we found that PCM-1-containing centriolar satellites
      moved along microtubules toward their minus ends, i.e., toward centrosomes, in
      live cells, as well as in vitro reconstituted asters. These findings defined
      centriolar satellites at the molecular level, and explained their pericentriolar
      localization. Next, to understand the relationship between centriolar satellites
      and centriolar replication, we examined the expression and subcellular
      localization of PCM-1 in ciliated epithelial cells during ciliogenesis. When
      ciliogenesis was induced in mouse nasal respiratory epithelial cells, PCM-1
      immunofluorescence was markedly elevated at the apical cytoplasm. At the electron
      microscopic level, anti-PCM-1 pAb exclusively labeled fibrous granules, but not
      deuterosomes, both of which have been suggested to play central roles in
      centriolar replication in ciliogenesis. These findings suggested that centriolar
      satellites and fibrous granules are identical novel nonmembranous organelles
      containing PCM-1, which may play some important role(s) in centriolar
      replication.

PMID- 10579719
TI  - Cell cycle-regulated attachment of the ubiquitin-related protein SUMO to the
      yeast septins.
AB  - SUMO is a ubiquitin-related protein that functions as a posttranslational
      modification on other proteins. SUMO conjugation is essential for viability in
      Saccharomyces cerevisiae and is required for entry into mitosis. We have found
      that SUMO is attached to the septins Cdc3, Cdc11, and Shs1/Sep7 specifically
      during mitosis, with conjugates appearing shortly before anaphase onset and
      disappearing abruptly at cytokinesis. Septins are components of a belt of 10-nm
      filaments encircling the yeast bud neck. Intriguingly, only septins on the mother
      cell side of the bud neck are sumoylated. We have identified four major SUMO
      attachment-site lysine residues in Cdc3, one in Cdc11, and two in Shs1, all
      within the consensus sequence (IVL)KX(ED). Mutating these sites eliminated the
      vast majority of bud neck-associated SUMO, as well as the bulk of total SUMO
      conjugates in G(2)/M-arrested cells, indicating that sumoylated septins are the
      most abundant SUMO conjugates at this point in the cell cycle. This mutant has a
      striking defect in disassembly of septin rings, resulting in accumulation of
      septin rings marking previous division sites. Thus, SUMO conjugation plays a role
      in regulating septin ring dynamics during the cell cycle.

PMID- 10579720
TI  - Ankyrin-B is required for intracellular sorting of structurally diverse Ca2+
      homeostasis proteins.
AB  - This report describes a congenital myopathy and major loss of thymic lymphocytes
      in ankyrin-B (-/-) mice as well as dramatic alterations in intracellular
      localization of key components of the Ca(2+) homeostasis machinery in ankyrin-B (
      /-) striated muscle and thymus. The sarcoplasmic reticulum (SR) and SR/T-tubule
      junctions are apparently preserved in a normal distribution in ankyrin-B (-/-)
      skeletal muscle based on electron microscopy and the presence of a normal pattern
      of triadin and dihydropyridine receptor. Therefore, the abnormal localization of
      SR/ER Ca ATPase (SERCA) and ryanodine receptors represents a defect in
      intracellular sorting of these proteins in skeletal muscle. Extrapolation of
      these observations suggests defective targeting as the basis for abnormal
      localization of ryanodine receptors, IP3 receptors and SERCA in heart, and of IP3
      receptors in the thymus of ankyrin-B (-/-) mice. Mis-sorting of SERCA 2 and
      ryanodine receptor 2 in ankyrin-B (-/-) cardiomyocytes is rescued by expression
      of 220-kD ankyrin-B, demonstrating that lack of the 220-kD ankyrin-B polypeptide
      is the primary defect in these cells. Ankyrin-B is associated with intracellular
      vesicles, but is not colocalized with the bulk of SERCA 1 or ryanodine receptor
      type 1 in skeletal muscle. These data provide the first evidence of a
      physiological requirement for ankyrin-B in intracellular targeting of the calcium
      homeostasis machinery of striated muscle and immune system, and moreover, support
      a catalytic role that does not involve permanent stoichiometric complexes between
      ankyrin-B and targeted proteins. Ankyrin-B is a member of a family of adapter
      proteins implicated in restriction of diverse proteins to specialized plasma
      membrane domains. Similar mechanisms involving ankyrins may be essential for
      segregation of functionally defined proteins within specialized regions of the
      plasma membrane and within the Ca(2+) homeostasis compartment of the ER.

PMID- 10579721
TI  - Rac downregulates Rho activity: reciprocal balance between both GTPases
      determines cellular morphology and migratory behavior.
AB  - Using biochemical assays to determine the activation state of Rho-like GTPases,
      we show that the guanine nucleotide exchange factor Tiam1 functions as a specific
      activator of Rac but not Cdc42 or Rho in NIH3T3 fibroblasts. Activation of Rac by
      Tiam1 induces an epithelial-like morphology with functional cadherin-based
      adhesions and inhibits migration of fibroblasts. This epithelial phenotype is
      characterized by Rac-mediated effects on Rho activity. Transient PDGF-induced as
      well as sustained Rac activation by Tiam1 or V12Rac downregulate Rho activity. We
      found that Cdc42 also downregulates Rho activity. Neither V14Rho or N19Rho
      affects Rac activity, suggesting unidirectional signaling from Rac towards Rho.
      Downregulation of Rho activity occurs independently of Rac- induced cytoskeletal
      changes and cell spreading. Moreover, Rac effector mutants that are defective in
      mediating cytoskeleton changes or Jun kinase activation both downregulate Rho
      activity, suggesting that neither of these Rac signaling pathways are involved in
      the regulation of Rho. Restoration of Rho activity in Tiam1-expressing cells by
      expression of V14Rho results in reversion of the epithelioid phenotype towards a
      migratory, fibroblastoid morphology. We conclude that Rac signaling is able to
      antagonize Rho activity directly at the GTPase level, and that the reciprocal
      balance between Rac and Rho activity determines cellular morphology and migratory
      behavior in NIH3T3 fibroblasts.

PMID- 10579722
TI  - Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho
      kinase in vivo.
AB  - Rho-associated kinase (Rho-kinase), which is activated by the small GTPase Rho,
      phosphorylates myosin-binding subunit (MBS) of myosin phosphatase and thereby
      inactivates the phosphatase activity in vitro. Rho-kinase is thought to regulate
      the phosphorylation state of the substrates including myosin light chain (MLC),
      ERM (ezrin/radixin/moesin) family proteins and adducin by their direct
      phosphorylation and by the inactivation of myosin phosphatase. Here we identified
      the sites of phosphorylation of MBS by Rho-kinase as Thr-697, Ser-854 and several
      residues, and prepared antibody that specifically recognized MBS phosphorylated
      at Ser-854. We found by use of this antibody that the stimulation of MDCK
      epithelial cells with tetradecanoylphorbol-13-acetate (TPA) or hepatocyte growth
      factor (HGF) induced the phosphorylation of MBS at Ser-854 under the conditions
      in which membrane ruffling and cell migration were induced. Pretreatment of the
      cells with Botulinum C3 ADP-ribosyltransferase (C3), which is thought to
      interfere with Rho functions, or Rho-kinase inhibitors inhibited the TPA- or HGF
      induced MBS phosphorylation. The TPA stimulation enhanced the immunoreactivity of
      phosphorylated MBS in the cytoplasm and membrane ruffling area of MDCK cells. In
      migrating MDCK cells, phosphorylated MBS as well as phosphorylated MLC at Ser-19
      were localized in the leading edge and posterior region. Phosphorylated MBS was
      localized on actin stress fibers in REF52 fibroblasts. The microinjection of C3
      or dominant negative Rho-kinase disrupted stress fibers and weakened the
      accumulation of phosphorylated MBS in REF52 cells. During cytokinesis,
      phosphorylated MBS, MLC and ERM family proteins accumulated at the cleavage
      furrow, and the phosphorylation level of MBS at Ser-854 was increased. Taken
      together, these results indicate that MBS is phosphorylated by Rho-kinase
      downstream of Rho in vivo, and suggest that myosin phosphatase and Rho-kinase
      spatiotemporally regulate the phosphorylation state of Rho-kinase substrates
      including MLC and ERM family proteins in vivo in a cooperative manner.

PMID- 10579723
TI  - A structural model for phosphorylation control of Dictyostelium myosin II thick
      filament assembly.
AB  - Myosin II thick filament assembly in Dictyostelium is regulated by
      phosphorylation at three threonines in the tail region of the molecule.
      Converting these three threonines to aspartates (3 x Asp myosin II), which mimics
      the phosphorylated state, inhibits filament assembly in vitro, and 3 x Asp myosin
      II fails to rescue myosin II-null phenotypes. Here we report a suppressor screen
      of Dictyostelium myosin II-null cells containing 3 x Asp myosin II, which reveals
      a 21-kD region in the tail that is critical for the phosphorylation control.
      These data, combined with new structural evidence from electron microscopy and
      sequence analyses, provide evidence that thick filament assembly control involves
      the folding of myosin II into a bent monomer, which is unable to incorporate into
      thick filaments. The data are consistent with a structural model for the bent
      monomer in which two specific regions of the tail interact to form an
      antiparallel tetrameric coiled-coil structure.

PMID- 10579725
TI  - p53 inhibits alpha 6 beta 4 integrin survival signaling by promoting the caspase
      3-dependent cleavage of AKT/PKB.
AB  - Although the interaction of matrix proteins with integrins is known to initiate
      signaling pathways that are essential for cell survival, a role for tumor
      suppressors in the regulation of these pathways has not been established. We
      demonstrate here that p53 can inhibit the survival function of integrins by
      inducing the caspase-dependent cleavage and inactivation of the serine/threonine
      kinase AKT/PKB. Specifically, we show that the alpha6beta4 integrin promotes the
      survival of p53-deficient carcinoma cells by activating AKT/PKB. In contrast,
      this integrin does not activate AKT/PKB in carcinoma cells that express wild-type
      p53 and it actually stimulates their apoptosis, in agreement with our previous
      findings (Bachelder, R.E., A. Marchetti, R. Falcioni, S. Soddu, and A.M.
      Mercurio. 1999. J. Biol. Chem. 274:20733-20737). Interestingly, we observed
      reduced levels of AKT/PKB protein after antibody clustering of alpha6beta4 in
      carcinoma cells that express wild-type p53. In contrast, alpha6beta4 clustering
      did not reduce the level of AKT/PKB in carcinoma cells that lack functional p53.
      The involvement of caspase 3 in AKT/PKB regulation was indicated by the ability
      of Z-DEVD-FMK, a caspase 3 inhibitor, to block the alpha6beta4-associated
      reduction in AKT/PKB levels in vivo, and by the ability of recombinant caspase 3
      to promote the cleavage of AKT/PKB in vitro. In addition, the ability of
      alpha6beta4 to activate AKT/PKB could be restored in p53 wild-type carcinoma
      cells by inhibiting caspase 3 activity. These studies demonstrate that the p53
      tumor suppressor can inhibit integrin-associated survival signaling pathways.

PMID- 10579724
TI  - Programmed cell death of embryonic motoneurons triggered through the Fas death
      receptor.
AB  - About 50% of spinal motoneurons undergo programmed cell death (PCD) after target
      contact, but little is known about how this process is initiated. Embryonic
      motoneurons coexpress the death receptor Fas and its ligand FasL at the stage at
      which PCD is about to begin. In the absence of trophic factors, many motoneurons
      die in culture within 2 d. Most (75%) of these were saved by Fas-Fc receptor
      body, which blocks interactions between Fas and FasL, or by the caspase-8
      inhibitor tetrapeptide IETD. Therefore, activation of Fas by endogenous FasL
      underlies cell death induced by trophic deprivation. In the presence of
      neurotrophic factors, exogenous Fas activators such as soluble FasL or anti-Fas
      antibodies triggered PCD of 40-50% of purified motoneurons over the following 3-5
      d; this treatment led to activation of caspase-3, and was blocked by IETD.
      Sensitivity to Fas activation is regulated: motoneurons cultured for 3 d with
      neurotrophic factors became completely resistant. Levels of Fas expressed by
      motoneurons varied little, but FasL was upregulated in the absence of
      neurotrophic factors. Motoneurons resistant to Fas activation expressed high
      levels of FLICE-inhibitory protein (FLIP), an endogenous inhibitor of caspase-8
      activation. Our results suggest that Fas can act as a driving force for
      motoneuron PCD, and raise the possibility that active triggering of PCD may
      contribute to motoneuron loss during normal development and/or in pathological
      situations.

PMID- 10579726
TI  - Enhancement of endothelial cell migration and in vitro tube formation by TAP20, a
      novel beta 5 integrin-modulating, PKC theta-dependent protein.
AB  - Migration, proliferation, and tube formation of endothelial cells are regulated
      by a protein kinase C isoenzyme PKCtheta. A full-length cDNA encoding a novel 20
      kD protein, whose expression was PKCtheta-dependent, was identified in
      endothelial cells, cloned, characterized, and designated as theta-associated
      protein (TAP) 20. Overexpression of TAP20 decreased cell adhesion and enhanced
      migration on vitronectin and tube formation in three-dimensional culture. An
      antiintegrin alphavbeta5 antibody prevented these TAP20 effects. Overexpression
      of TAP20 also decreased focal adhesion formation in alphavbeta3-deficient cells.
      The interaction between TAP20 and beta5 integrin cytoplasmic domain was
      demonstrated by protein coprecipitation and immunoblotting. Thus, the discovery
      of TAP20, which interacts with integrin beta5 and modulates cell adhesion,
      migration, and tube formation, further defines a possible pathway to angiogenesis
      dependent on PKCtheta.

PMID- 10579727
TI  - Analysis of the roles of 14-3-3 in the platelet glycoprotein Ib-IX-mediated
      activation of integrin alpha(IIb)beta(3) using a reconstituted mammalian cell
      expression model.
AB  - We have reconstituted the platelet glycoprotein (GP) Ib-IX-mediated activation of
      the integrin alpha(IIb)beta(3) in a recombinant DNA expression model, and show
      that 14-3-3 is important in GPIb-IX signaling. CHO cells expressing
      alpha(IIb)beta(3) adhere poorly to vWF. Cells expressing GPIb-IX adhere to vWF in
      the presence of botrocetin but spread poorly. Cells coexpressing integrin
      alpha(IIb)beta(3) and GPIb-IX adhere and spread on vWF, which is inhibited by
      RGDS peptides and antibodies against alpha(IIb)beta(3). vWF binding to GPIb-IX
      also activates soluble fibrinogen binding to alpha(IIb)beta(3) indicating that
      GPIb-IX mediates a cellular signal leading to alpha(IIb)beta(3) activation.
      Deletion of the 14-3-3-binding site in GPIbalpha inhibited GPIb-IX-mediated
      fibrinogen binding to alpha(IIb)beta(3) and cell spreading on vWF. Thus, 14-3-3
      binding to GPIb-IX is important in GPIb-IX signaling. Expression of a dominant
      negative 14-3-3 mutant inhibited cell spreading on vWF, suggesting an important
      role for 14-3-3. Deleting both the 14-3-3 and filamin-binding sites of GPIbalpha
      induced an endogenous integrin-dependent cell spreading on vWF without requiring
      alpha(IIb)beta(3), but inhibited vWF-induced fibrinogen binding to
      alpha(IIb)beta(3). Thus, while different activation mechanisms may be responsible
      for vWF interaction with different integrins, GPIb-IX-mediated activation of
      alpha(IIb)beta(3) requires 14-3-3 interaction with GPIbalpha.

PMID- 10579730
TI  - Thumbs up for Quebec!

PMID- 10579729
TI  - Perlecan maintains the integrity of cartilage and some basement membranes.
AB  - Perlecan is a heparan sulfate proteoglycan that is expressed in all basement
      membranes (BMs), in cartilage, and several other mesenchymal tissues during
      development. Perlecan binds growth factors and interacts with various
      extracellular matrix proteins and cell adhesion molecules. Homozygous mice with a
      null mutation in the perlecan gene exhibit normal formation of BMs. However, BMs
      deteriorate in regions with increased mechanical stress such as the contracting
      myocardium and the expanding brain vesicles showing that perlecan is crucial for
      maintaining BM integrity. As a consequence, small clefts are formed in the
      cardiac muscle leading to blood leakage into the pericardial cavity and an arrest
      of heart function. The defects in the BM separating the brain from the adjacent
      mesenchyme caused invasion of brain tissue into the overlaying ectoderm leading
      to abnormal expansion of neuroepithelium, neuronal ectopias, and exencephaly.
      Finally, homozygotes developed a severe defect in cartilage, a tissue that lacks
      BMs. The chondrodysplasia is characterized by a reduction of the fibrillar
      collagen network, shortened collagen fibers, and elevated expression of cartilage
      extracellular matrix genes, suggesting that perlecan protects cartilage
      extracellular matrix from degradation.

PMID- 10579731
TI  - Moving the goalposts on CVD research: seizing the CIHR opportunity.

PMID- 10579732
TI  - What's so funny?

PMID- 10579728
TI  - Matrix GLA protein is a developmental regulator of chondrocyte mineralization
      and, when constitutively expressed, blocks endochondral and intramembranous
      ossification in the limb.
AB  - Matrix GLA protein (MGP), a gamma-carboxyglutamic acid (GLA)-rich, vitamin K
      dependent and apatite-binding protein, is a regulator of hypertrophic cartilage
      mineralization during development. However, MGP is produced by both hypertrophic
      and immature chondrocytes, suggesting that MGP's role in mineralization is cell
      stage-dependent, and that MGP may have other roles in immature cells. It is also
      unclear whether MGP regulates the quantity of mineral or mineral nature and
      quality as well. To address these issues, we determined the effects of
      manipulations of MGP synthesis and expression in (a) immature and hypertrophic
      chondrocyte cultures and (b) the chick limb bud in vivo. The two chondrocyte
      cultures displayed comparable levels of MGP gene expression. Yet, treatment with
      warfarin, a gamma-carboxylase inhibitor and vitamin K antagonist, triggered
      mineralization in hypertrophic but not immature cultures. Warfarin effects on
      mineralization were highly selective, were accompanied by no appreciable changes
      in MGP expression, alkaline phosphatase activity, or cell number, and were
      counteracted by vitamin K cotreatment. Scanning electron microscopy, x-ray
      microanalysis, and Fourier-transform infrared spectroscopy revealed that mineral
      forming in control and warfarin-treated hypertrophic cell cultures was similar
      and represented stoichiometric apatite. Virally driven MGP overexpression in
      cultured chondrocytes greatly decreased mineralization. Surprisingly, MGP
      overexpression in the developing limb not only inhibited cartilage
      mineralization, but also delayed chondrocyte maturation and blocked endochondral
      ossification and formation of a diaphyseal intramembranous bone collar. The
      results show that MGP is a powerful but developmentally regulated inhibitor of
      cartilage mineralization, controls mineral quantity but not type, and appears to
      have a previously unsuspected role in regulating chondrocyte maturation and
      ossification processes.

PMID- 10579733
TI  - Determinants of hospital survival following reoperative single valve replacement.
AB  - OBJECTIVE: To determine the indicators of risk for hospital death, patients
      undergoing reoperative valve replacement were analyzed METHODS: Four hundred and
      eighteen consecutive patients undergoing reoperative valve replacement from 1977
      to 1994 were reviewed using univariate and multivariate analysis. RESULTS:
      Overall hospital mortality was 11.2% with 9.4% mortality with aortic valve
      replacement and 14.2% with mitral valve replacement (P=0.52). Mortality was 9.7%
      for patients less than 70 years of age compared with 19.4% for older patients
      (P=0.03), and was 8.5% for those with anoxia times less than 90 mins versus 21.9%
      for those with longer anoxia times (P=0.001). For first reoperations, 9.5% of
      patients died, while for patients undergoing second or more reoperation,
      mortality was 23.2% (P=0.01). While mortality increased from 8.9% to 19.0% with
      the addition of a concomitant procedure (P=0.008), it was not affected if the
      additional procedure was a coronary bypass (P=0. 96). The indication for surgery
      influenced outcome. Mortality was zero for thromboembolism, 9% for structural
      failure, 23% for nonstructural failure and 22% for endocarditis (P=0.006). For
      New York Heart Association (NYHA) functional class I patients, mortality was 1.6%
      compared with 22.3% for those in NYHA class IV (P=0.006). By multivariate
      analysis, however, only the indication for surgery and the NYHA functional class
      influenced survival. CONCLUSIONS: Reoperative valve surgery can be performed with
      a survival (88.8%) that is similar to the initial procedure (91.2%). The
      indication for surgery and NYHA functional class alone influenced outcome;
      therefore, possible early reoperation is indicated before clinical deterioration
      occurs.

PMID- 10579734
TI  - Ten-year heart transplantation experience at the MARITIME HEART CENTER: does
      volume affect results?
AB  - OBJECTIVE: To evaluate the experience of a small volume Canadian heart
      transplantation centre. DESIGN: Ninety-four consecutive primary heart transplants
      were performed from 1988 to 1998 at the Maritime Heart Center, Halifax, Nova
      Scotia, with 100% follow-up. Kaplan-Meier survival analysis was used. RESULTS:
      The mean recipient age was 48.5+/-12.3 years and donor age 33+/-13.2 years.
      Eighty per cent of recipients were men. The prevalence of elevated pulmonary
      vascular resistance (4 or more Wood units) was 20.2%. Etiology of heart failure
      was ischemic cardiomyopathy (50%), dilated cardiomyopathy (40.9%) and congenital
      heart disease (9.1%). Survival was 85.9% at one year (n=71), 75.3% at five years
      (n=33) and 60.5% at eight years (n=8). There was a trend toward survival benefit
      with human leukocyte antigen (HLA) -DR matching, body mass index ratio of donor
      to recipient greater than 0.8, ischemic time less than 90 mins and male donors.
      There was no effect on survival with donor or recipient age, recipient sex,
      diabetes, hypertension, hypercholesterolemia, elevated pulmonary vascular
      resistance and HLA-A/B mismatch. CONCLUSIONS: Excellent survival at one and five
      years following heart transplantation is reported that compares favourably with
      results published by the International Society for Heart and Lung
      Transplantation.

PMID- 10579735
TI  - A prospective transesophageal echocardiographic study to assess a new type of
      left atrial spontaneous contrast at rest and during respiratory manoeuvres.
AB  - BACKGROUND: Recent observations suggest that a spontaneous echocardiographic
      contrast with fast motion (FEC) mimicking intravenous contrast can be seen in the
      left atrium in the absence of intravenous contrast injection. OBJECTIVE: To
      assess the incidence of FEC and to evaluate the differentiating features between
      FEC and injected saline contrast. STUDY DESIGN: Prospective cohort study.
      SETTING: Tertiary referral centre. PATIENTS AND METHODS: Transesophageal
      echocardiography was performed in 91 consecutive patients with a mean age of 58+/
      15 years. Patients with mechanical valves and congenital heart disease were
      excluded. Images of the right atrium, left atrium and pulmonary veins were
      obtained in the absence of an intravenous catheter during quiet respiration,
      cough and the Valsalva manoeuvre. The same procedure was repeated during
      injection with agitated saline after venous cannulation. RESULTS: In the absence
      of intravenous cannulation, FEC was detected in eight patients (9%) during quiet
      respiration, 36 patients (40%) during cough and 55 patients (60%) during the
      Valsalva manoeuvre. During the Valsalva manoeuvre, FEC was detected in the right
      atrium in 41 patients (45%) and in the left atrium in 33 patients (36%) (P=0.15).
      FEC was not related to a history of embolic event, left atrial smoke or patent
      foramen ovale. Intra- and interobserver agreements in the detection of FEC were
      96% and 90%, respectively. CONCLUSIONS: FEC can be observed frequently in the
      left atrium during cough or the Valsalva manoeuvre, and awareness of FEC is
      important to avoid the erroneous diagnosis of patent foramen ovale.

PMID- 10579736
TI  - Characterization of ventricular tachycardias based on time and frequency domain
      analyses of cycle length variability in patients with implantable cardioverter
      defibrillator.
AB  - OBJECTIVE: To discriminate between monomorphic (MVT) and polymorphic (PVT)
      ventricular tachycardias in humans using cycle length variability (CLV), and to
      characterize the onset of MVT and PVT using power spectral analysis of the CLV
      during sinus rhythm and the number of ventricular extrasystoles before onset of
      arrhythmia. PATIENTS AND METHODS: Medtronic, Inc's Spontaneous Ventricular Tachy-
      arrhythmia Database was analyzed. This data base contains sets of 1000 RR
      intervals (n=135) that preceded spontaneous onset of ventricular tachycardia or
      fibrillation and sets of controls (n=135) without spontaneous ventricular
      tachycardia or fibrillation from 78 patients with the Medtronic Model 7218
      implantable cardioverter defibrillator. CLV was measured as the standard
      deviation of RR intervals normalized by the mean RR value. Power spectral
      analysis based on the fast Fourier transform analysis was performed on 128 RR
      samples, and the normalized power spectrum of the low frequency band (0.04 to
      0.15 Hz) and of the high (NHF) frequency band (0.15 to 0.4 Hz) were estimated.
      RESULTS: During PVT the CLV was much greater (0. 133+/-0.095) than during MVT
      (0.04+/-0.035) (P<0.0001). Also, 64% of patients who developed PVT had more than
      27 extrasystoles compared with 40% of patients during control conditions
      (P=0.03). This parameter was not significantly different in patients with MVT.
      Due to the high incidence of extrasystoles in this population, only 36% of PVT
      and 43% of MVT recordings could be analyzed for CLV during sinus rhythm. NHF
      characterizing parasympathetic activity decreased from 50.6% (PVT control) to
      34.4% (PVT onset) (P=0.06) and from 47. 4% (MVT control) to 43.7% (MVT onset)
      (P=0.18). CONCLUSIONS: Discrimination between MVT and PVT episodes was possible
      based on CLV analysis. The onset of PVT was characterized by a greater number of
      preceding extrasystoles compared with the control. During sinus rhythm, the NHF
      spectral power activity decreased at the onset of both types of arrhythmic
      episodes compared with control, although statistical significance was marginal.

PMID- 10579737
TI  - Conversion of cyclosporine A to tacrolimus following heart transplantation.
AB  - BACKGROUND: Cyclosporine A (CyA) is ususally the immunosuppressive drug of choice
      in organ transplantation; however, some side effects have limited its use.
      Tacrolimus is a novel immunosuppressive drug that is more potent than CyA, and
      has been used as a rescue agent following heart transplantation when the use of
      CyA is undesirable or inefficient. PATIENTS AND METHODS: Since 1996, 14 heart
      transplant recipients under CyA were switched to tacrolimus therapy, for
      refractory rejection or intolerance, to conventional immunosuppression. RESULTS:
      After a mean of 35+/-7 months of treatment, tacrolimus was substituted for CyA
      therapy. The reason for substitution was refractory rejection in six patients,
      gingival hypertrophy in five patients, hypertrichosis in one patient, severe
      arterial hypertension in one patient and hepatotoxicity in one patient. Five
      patients underwent a successful rescue therapy and one patient died of refractory
      rejection despite the use of tacrolimus. All patients with CyA side effects
      recovered with tacrolimus. After conversion from CyA to tacrolimus, the number of
      episodes of acute rejection decreased from a mean of 0.42+/-0.17 to 0.14+/-0.09
      episodes/patient/month under CyA and tacrolimus therapy (P=0.11), respectively.
      The mean dose of prednisone was 0.18+/-0.06 mg/kg/day before compared with 0.06+/
      0.01 mg/kg/day after conversion from CyA to tacrolimus (P=0.09). Creatinine serum
      levels averaged 124+/-7 mmol/L under CyA treatment compared with 113+/-7 mmol/L
      with tacrolimus therapy (P=0.002). CONCLUSION: In patients with refractory
      rejections or intolerance to CyA after heart transplantation, conversion to
      tacrolimus-based immunosuppression is safe and effective.

PMID- 10579738
TI  - Aortic medial changes associated with bicuspid aortic valve: myth or reality?
AB  - OBJECTIVE: To determine whether aortic medial changes are more severe in patients
      who require aortic valve replacement of congenitally bicuspid aortic valves (BAV)
      than in patients who require replacement of tricuspid aortic valves and acquired
      valvular disease (AVD). DESIGN: Aortas from autopsies of 14 patients with BAV and
      25 with AVD were histologically assessed by two 'blinded' cardiovascular
      pathologists and analyzed independently with computer-aided morphometry. The
      aortic valves were examined for valvular fibrosis and calcification. SETTING: The
      patient population was from a tertiary-care facility. PATIENTS: Patients were
      selected by retrospective review of autopsy records for patient deaths after
      aortic valve replacement, over the period 1984 to 1995. RESULTS: There were no
      significant differences in age (P=0.89), sex (P=0.94), prevalence of systemic
      arterial hypertension (P=0.37), valvular degenerative changes (P=0.10 and P=1.0)
      or heart weights (P=0.60) between the two groups. Histological scores for aortic
      medial degenerative changes including elastic fragmentation, fibrosis and
      medionecrosis were not statistically different between the groups. However,
      morphometry demonstrated less elastic tissue in patients with BAV (P=0.003).
      CONCLUSION: Routine microscopy shows no significant difference in the degree of
      aortic medial degenerative changes between patients with BAV and AVD. However,
      morphometry shows less elastic tissue in the aortas of BAV patients. This may
      explain the anecdotal increase in aortic fragility and propensity for aortic
      dissection in these patients.

PMID- 10579739
TI  - Left ventricular involvement in right ventricular dysplasia/cardiomyopathy.
AB  - OBJECTIVE: To characterize pathological features of left ventricular (LV)
      involvement in right ventricular dysplasia/cardiomyopathy (RVD/C). DESIGN:
      Retrospective morphological case study. SETTING: Two referral-based university
      medical centres. MATERIALS: Seventeen hearts were studied: 15 from sudden cardiac
      deaths outside hospital and two explanted hearts, one removed for intractable
      arrhythmias and the other for right-sided heart failure. The subjects (three
      female) were aged 16 to 60 years. MAIN RESULTS: All had typical right ventricular
      features of RVD/C and morphological evidence of LV wall involvement, seven with
      microscopic changes only. Of 10 hearts with gross and microscopic lesions, nine
      had large or laminar segments involved. The LV free wall was affected in all
      cases and the ventricular septum (VS) in 15. Sixteen hearts were hypertrophied.
      In involved areas, the LV or VS walls were of 'normal' thickness or slightly
      thinned. Five histological patterns of involvement were recognized, of which four
      were found in the LV. More severe LV involvement was seen in the hearts of older
      patients. Complete transmural fatty replacement of the myocardium was not
      observed, nor were the LVs aneurysmal. Minimal or mild focal aggregates of
      inflammatory cells were seen in nine hearts and moderate inflammatory changes in
      two. Inflammation was usually associated with myocyte atrophy and only rarely
      with myonecrosis. CONCLUSIONS: This study suggests that patients with RVD/C who
      live long enough will likely have LV free wall involvement with frequent VS
      involvement. Pathologists may miss LV involvement on gross examination. It should
      be sought diligently in patients dying of the condition or receiving transplants
      for heart failure. Appropriate histological sections from both free wall and
      septum must be examined.

PMID- 10579740
TI  - Echocardiographically guided pericardiocentesis - the gold standard for the
      management of pericardial effusion and cardiac tamponade.
AB  - BACKGROUND: The conventional surgical pericardiotomy and blind needle-puncture
      pericardiocentesis using a subxiphoid approach have been reported to have only
      moderate success rates and to be associated with unacceptably high rates of
      morbidity and mortality. More recently, echocardiographically guided
      pericardiocentesis was reported to improve considerably the likelihood of success
      and the safety of this procedure. OBJECTIVE: To evaluate the efficacy and safety
      of echocardiographically guided pericardiocentesis in the authors' institution.
      PATIENTS AND METHODS: A series of consecutive patients who underwent percutaneous
      pericardiocentesis at the Hamilton General Hospital, Hamilton, Ontario, from June
      1994 to December 1998. RESULTS: Forty-one patients underwent a total of 46
      echocardiographically guided pericardiocentesis procedures. The procedure was
      successful in 100% of attempts. Clinical complications occurred in two (5%)
      patients: one patient with known coagulopathy developed hemothorax and one
      patient developed purulent pericarditis several days after the procedure. There
      were no deaths, and no patient required urgent referral for surgical management.
      CONCLUSIONS: Echocardiographically guided pericardiocentesis is safe and
      effective, and is the method of choice for therapeutic and diagnostic drainage of
      pericardial effusions. While echocardiographically guided pericardiocentesis was
      described originally at centres with large volumes of patients with clinically
      significant pericardial effusions and with extensive experience in using this
      technique, similar high success and low complication rates were attained at an
      institution with relatively low numbers of patients requiring pericardial
      drainage.

PMID- 10579741
TI  - Low rates of preventive practices in patients with peripheral vascular disease.
AB  - BACKGROUND: Patients with peripheral vascular disease (PVD) have a three-fold
      increased risk of myocardial infarction, stroke and death. Recently, a number of
      therapies have been demonstrated to prevent morbidity or mortality in patients
      with PVD or other arterial disease. Given the scarcity of data on the preventive
      practice patterns of this high risk patient group, the in-hospital management of
      patients admitted to hospital for a peripheral vascular intervention was
      reviewed. PATIENTS AND METHODS: Charts of 195 patients with a diagnosis of
      peripheral arteriosclerotic disease (International Classification of Diseases,
      9th revision, code 440.2) who were hospitalized at a tertiary care hospital in
      Ontario between June 1996 and June 1998 were reviewed. RESULTS: The average age
      of patients admitted was 70.6 years, and 39% of patients were women. The main
      reason for admission was peripheral artery bypass graft surgery in 88% (172 of
      195). Fifty-four per cent (106 of 195) of patients had clinically apparent
      coronary or cerebrovascular disease, and 92% (180 of 195) of patients had at
      least one cardiovascular disease risk factor. Fewer than half of all patients
      (49%) were discharged on any antithrombotic therapy (antiplatelet agent or
      anticoagulant), and a small proportion of patients were treated with a beta
      blocker (20%) and cholesterol-lowering medications (16%). CONCLUSIONS: The
      leading cause of morbidity and mortality in PVD patients is coronary and
      cerebrovascular disease. Despite this, the use of proven antithrombotic agents
      and other cardiac medications is suboptimal. Health professionals need to be
      aware of the high risk nature of the PVD population and to develop strategies to
      ensure that patient care is optimized.

PMID- 10579742
TI  - Oxytocin receptor binding in rat and human heart.
AB  - OBJECTIVE: To determine whether cardiac oxytocin receptors are detectable by
      radioligand binding assay. Results from in vitro and in vivo animal studies
      suggest a possible direct effect of oxytocin on the cardiovascular system.
      DESIGN: A radioligand binding assay was used to characterize and quantify
      specific binding of [3H] oxytocin to standardized micropunches (thickness 400
      microm; diameter 2 mm) obtained from rat left ventricle and human right atrium.
      Tissues from fetal and newborn rat heart were also studied. MAIN RESULTS:
      Saturable, high affinity binding of [3H] oxytocin to rat left ventricle was
      observed, consisting of a high affinity site (affinity [KD] approximately 1 nM;
      receptor density [Bmax] approximately 1480 fmol/mg protein) and a higher
      capacity, lower affinity site (KD approximately 75 nM; Bmax 3730 fmol/mg
      protein). Binding was displaceable by oxytocin, vasopressin and the agonist
      [Thr4, Gly7] oxytocin but not by the antagonist atosiban. Cardiac binding was
      reduced in ovariectomized (ie, estrogen-free) rats and increased in late
      gestation rats, when blood levels of ovarian steroids are maximal. Cardiac
      oxytocin receptors were undetectable in fetal and newborn rat heart. High
      concentrations of specific [3H] oxytocin binding were also found in samples of
      human right atrial appendage. CONCLUSIONS: These data confirm the presence of a
      specific oxytocin binding site in rat left ventricle and in human atrium. Binding
      density is regulated by ovarian steroids and is especially marked in the late
      stage of pregnancy. These observations provide an explanation for the putative
      direct effect of oxytocin on cardiac function.

PMID- 10579743
TI  - Coding accuracy of hospital discharge data for elderly survivors of myocardial
      infarction.
AB  - OBJECTIVE: To assess the coding accuracy of primary and secondary discharge
      diagnoses in the Quebec hospital discharge database for elderly persons with
      myocardial infarction (MI). DESIGN: Retrospective chart review in a convenience
      sample of six Montreal hospitals. The diagnoses listed in the medical chart were
      compared with those listed in the hospital discharge database. For each subject,
      the Charlson comorbidity index was calculated twice, once based on the medical
      chart and again based on the hospital discharge database. PATIENTS: Subjects aged
      65 years and over who had an MI coded as the primary discharge diagnosis in the
      hospital discharge database and who were discharged alive. MAIN RESULTS: For 234
      MI survivors, the positive predictive value (ie, probability that a patient with
      MI reported in the hospital discharge database had an MI diagnosed by the
      discharging physician) for coding MI was 0.96 (95% CI 0.94, 0.98). Comorbid
      medical conditions and complications of the MI were under-reported in the
      hospital discharge database, which meant that the Charlson index based on the
      hospital discharge database was an average of 0.71 units lower than the Charlson
      index based on the medical chart. CONCLUSIONS: When studying survivors of MI by
      using hospital discharge databases, the advantages must be weighed against
      potential drawbacks in the quality of the information. Hospital discharge
      databases are almost as reliable as medical charts for identifying MI patients,
      but there is substantial under-reporting of comorbid medical conditions.

PMID- 10579744
TI  - Doppler echocardiographic evaluation of the hemodynamics in absent aortic valve.
AB  - Hemodynamics were estimated by Doppler echocardiography in a neonate with an
      absent aortic valve and absent or extremely hypoplastic mitral valve. The
      coronary blood flow depended on the increased end-diastolic pressure of the left
      ventricle. Pulmonary venous congestion, which was also due to the increased end
      diastolic pressure of the left ventricle, may induce decreased oxygen saturation
      and, subsequently, further myocardial hypoxia, poor contraction and increased end
      diastolic pressure of the left ventricle. Finally, hypoxic blood was supplied to
      each organ from the pulmonary artery through the ductus arteriosus, which induced
      severe acidosis and differential cyanosis after birth.

PMID- 10579745
TI  - Dr William Ford, winner of the second annual Dr Robert E Beamish Award.

PMID- 10579746
TI  - Angiotensin II receptor antagonists: enlarging therapeutic possibilities in
      arterial hypertension.

PMID- 10579747
TI  - Cardioprotective effect of angiotensin II receptor antagonists.
AB  - Angiotensin II plays a significant role in cell growth and proliferation in model
      systems and in humans. In addition, angiotensin II appears to facilitate
      sympathetic activation and the release of endothelin-1, and also to promote
      apoptosis. The use of angiotensin-converting enzyme (ACE) inhibitors has provided
      beneficial effects on left ventricular hypertrophy (LVH) regression and on
      cardiac remodelling in the presence of heart failure. Data from experimental
      models as well as studies in humans suggest that the increase of bradykinin
      mediated by ACE inhibitors provides most of the beneficial effects of ACE
      inhibitors. The new class of angiotensin receptor blocker appears to provide
      cardioprotective effects that are similar to those of the ACE inhibitors. Most of
      the beneficial effects provided by these agents appear to be related to a more
      complete blockade of angiotensin II type 1 (AT1) receptor. However, costimulation
      of the angiotensin II type 2 (AT2) receptor appears to increase nitric oxide and
      thus to cause some bradykinin-like effects. Evidence for the role of angiotensin
      II in promoting LVH and cardiac failure as well as for abnormal regulations of
      the angiotensin signal transduction pathways in model systems and in humans are
      reviewed. Second, the mechanisms for the beneficial effects of angiotensin II
      modulation by ACE inhibitors versus angiotensin II antagonists studied in model
      systems are presented. Finally, results from pivotal phase II studies such as
      Evaluation of Losartan In The Elderly (ELITE), as well as an overview of the
      ongoing phase III trials involving the use of ARB in high risk patients are
      presented.

PMID- 10579748
TI  - Uric acid in hypertension and cardiovascular disease.
AB  - Cardiovascular disease, and particularly coronary artery disease, remains the
      leading cause of mortality worldwide, despite recent substantial declines.
      Hypertension, long recognized as a risk factor for both stroke and myocardial
      infarction, is an important target for preventive intervention. However,
      effective hypotensive therapy produces incomplete cardioprotection, and most
      events that would have occurred in the natural state continue to occur among
      controlled hypertensive patients. Further progress in reducing the burden of
      cardiac disease will depend on early identification of risk in successfully
      treated hypertensive subjects and the development of preventive interventions
      that go beyond simple reduction of blood pressure. Recently, elevation of uric
      acid has been found to be associated with subsequent morbidity and mortality in
      the general population among patients with congestive heart failure, diabetes and
      hypertension. A prospective study in a large cohort of well controlled
      hypertensive subjects has revealed a strong, specific, stepwise, independent
      association of increasing serum uric acid and cardiac morbidity and mortality.
      Unanswered, however, is the question of whether uric acid is simply an associated
      phenomenon, or actually contributes to the occurrence of cardiac events.

PMID- 10579749
TI  - Pharmacological properties of angiotensin II receptor antagonists.
AB  - The availability of selective, potent, orally active and long acting nonpeptide
      angiotensin II type 1 (AT1) receptor antagonists has provided the opportunity to
      obtain the benefits of selectively blocking the renin-angiotensin-aldosterone
      system at the level of the AT1 receptor that mediates most, if not all, of the
      important actions of angiotensin II, and avoid the nonspecificity of the
      angiotensin I converting enzyme inhibitors. Losartan was the first, but by no
      means remained the only, AT1 receptor antagonist. Numerous other 'sartans' have
      emerged in the past several years and successfully completed clinical
      development. With the exception of eprosartan, all others, ie, candesartan,
      irbesartan, saprisartan, tasosartan, telmisartan, valsartan and zolasartan, are
      based on medications of losartan's prototypical chemical structure. Among the
      current AT1 receptor antagonists, the rank order of the relative binding
      affinities (highest affinity = 1) is: candesartan 1, telmisartan 10, E3174 (the
      active metabolite of losartan) 10, tasosartan 20, losartan 50, eprosartan 100 and
      the prodrug candesartan cilexetil 280. The mode of (functional) AT1 receptor
      antagonism has been characterized as surmountable/noncompetitive (losartan,
      tasosartan, eprosartan) or insurmountable/noncompetitive (candesartan,
      saprisartan, zolasartan, irbesartan, valsartan, telmisartan, E3174). It is very
      likely that slow dissociation kinetics from the AT1 receptor underlie
      insurmountable antagonism. However, competitive or noncompetitive antagonism does
      not determine the antihypertensive efficacy, but the slow off-rate may extend the
      occupancy of the AT1 receptor and thereby lengthen the duration of the
      antihypertensive effect.

PMID- 10579750
TI  - Efficacy of angiotensin II antagonists in hypertension.
AB  - Advertising claims of superior antihypertensive efficacy of one angiotensin
      antagonist over another are not substantiated by a review of available evidence
      from 43 randomized, controlled clinical trials, in which 11,281 patients were
      included. There were no clinically important differences among the drugs. At
      initial doses, the mean reduction of diastolic pressure was 8.5 mmHg and of
      systolic pressure was 10.7 mmHg; 50% were responders. Doubling the dose of these
      agents produced only small additional blood pressure reduction. Diastolic blood
      pressure fell by an additional 1.5 mmHg, and systolic blood pressure by 2.5 mmHg;
      there were only 7% more responders. In contrast, the addition of
      hydrochlorothiazide 12.5 mg daily to the initial doses provided 40% to 60% more
      reduction of blood pressure and 40% more responders. The author concludes that
      adding hydrochlorothiazide to any angiotensin II antagonist results in much
      greater efficacy than switching or increasing doses of the angiotensin II
      antagonist.

PMID- 10579751
TI  - Choice of initial antihypertensive medication and continuation of use.
AB  - Three recent studies that have focused on the discontinuation of initial
      antihypertensive medications are reviewed. The studies reviewed indicate that
      newly prescribed antihypertensive medications are associated with high levels of
      discontinuation in the months following the initiation of treatment. After six
      months, less than 50% of patients are on initial treatment regardless of which of
      the following classes of medication has been prescribed: diuretics, beta
      blockers, calcium antagonists or angiotensin-converting enzyme inhibitors. A
      higher proportion of patients on losartan than on angiotensin-converting enzyme
      inhibitors continue their initial treatment after 12 months. More research
      designed to assess the effectiveness of treatments in real life situations is
      needed. In particular, there is a need to clarify the role of side effects on
      continuation of initial treatment.

PMID- 10579752
TI  - Looking forward and back at health care: An Internet survey.

PMID- 10579753
TI  - Culture crash: trauma in 1994 Cambodia.

PMID- 10579754
TI  - President's message. Chaos and complexity: preparing for the future of emergency
      nursing.

PMID- 10579755
TI  - Looking back.

PMID- 10579756
TI  - Looking forward: A glimpse into the future.

PMID- 10579757
TI  - New Zealand's hutt hospital addresses ED noise proactively

PMID- 10579759
TI  - Holding admitted patients: one emergency department's experience

PMID- 10579758
TI  - Decent wages are the best reward for ED nurses with seniority

PMID- 10579760
TI  - Article by ED nurse in spain applauded

PMID- 10579761
TI  - Plastic cable ties are a hazard to children

PMID- 10579762
TI  - Lidocaine jelly always used with male urinary catheterizations in the united
      kingdom

PMID- 10579763
TI  - Research poster summaries from the ENA 1999 annual meeting

PMID- 10579764
TI  - Clinical poster summaries from the ENA 1999 annual meeting

PMID- 10579765
TI  - A 59-year-old man who had undergone cervical laminectomy with sharp neck and
      chest pain.

PMID- 10579766
TI  - Re-evaluating triage in the new millennium: A comprehensive look at the need for
      standardization and quality.

PMID- 10579767
TI  - Emergency care in space: An interview with two astronauts. Interview by Susan
      Budassi Sheehy.

PMID- 10579768
TI  - Cyberdocs.com: A virtual encounter.

PMID- 10579769
TI  - The emergency department of the future-The challenge is in changing how we
      operate!

PMID- 10579770
TI  - A global perspective on emergency nursing and the new millennium.

PMID- 10579771
TI  - Understanding the legal process: your best defense.

PMID- 10579772
TI  - Florida's bicycle helmet law and a bicycle safety educational program: did they
      help?
AB  - INTRODUCTION: This research studied the effectiveness of Florida's mandatory
      helmet law for children and a community bicycle safety campaign promoting helmet
      use. Children's use of helmets before and after the law's enactment and the type
      and extent of head injuries sustained in bicycle crashes were evaluated. METHODS:
      The trauma and medical records from Broward General Medical Center's Pediatric
      Referral Trauma Center provided demographic data, injury severity scores, and
      information on the type and extent of head injuries sustained. Data were compared
      using independent sample t tests and Pearson chi(2) statistics with.05 as the
      significance level. RESULTS: Each group consisted of 72 children, predominantly 7
      to 12-year-old boys. Known helmet use rose from 5.6% to 20.8%, with children
      aged 10 to 12 years having the greatest increase in helmet use (27%). Helmet use
      rose in urban and suburban areas. Changes in the type and extent of head injuries
      were mixed. Injury severity scores were higher for nonhelmeted children in the
      after-law group. DISCUSSION: Although helmet use increased, especially among the
      7- to 12-year-olds targeted during the bicycle safety campaigns, bicycle helmet
      use remains too low, and nonhelmeted children continue to have a higher risk for
      serious injuries. Community bicycle safety programs that promote helmet use
      remain an important adjunct to mandatory helmet use laws.

PMID- 10579773
TI  - One urban hospital's experience with false anthrax exposure disaster response.

PMID- 10579774
TI  - Occupational exposure: organizing ED care to determine rapid postexposure
      prophylaxis within hours instead of days.

PMID- 10579775
TI  - Addressing the emergency nursing staffing shortage: implementing an internship
      using a nursing school instructor model.

PMID- 10579776
TI  - Management of diabetic ketoacidosis.

PMID- 10579777
TI  - Using internal ED resources to develop a team-building program: St Luke's 6-year
      experience.

PMID- 10579778
TI  - CEN review questions

PMID- 10579779
TI  - The Columbine High School tragedy: one emergency department's experience.

PMID- 10579780
TI  - Clinical nurses forum

PMID- 10579781
TI  - So you want to be a flight nurse.

PMID- 10579782
TI  - From the feds

PMID- 10579784
TI  - Managers forum

PMID- 10579783
TI  - Bookmarks for trauma Web resources.

PMID- 10579785
TI  - Evaluating an emergency nurse practitioner educational program for its relevance
      to the role.

PMID- 10579786
TI  - A MedicAlert primer and new educational packet.

PMID- 10579787
TI  - Confessions of a former nurse manager.

PMID- 10579788
TI  - Preparing your application for a nursing scholarship: practical tips from the
      "other side".

PMID- 10579789
TI  - Staff nurses: using research in everyday practice.

PMID- 10579790
TI  - After the examination: tracking sexual assault cases through the legal system.

PMID- 10579791
TI  - Air bags and eye injuries: assessment and treatment for ED patients.

PMID- 10579792
TI  - A 30-year-old woman with a generalized rash.

PMID- 10579793
TI  - Interleukin-6 activates phosphatidylinositol-3 kinase, which inhibits apoptosis
      in human prostate cancer cell lines.
AB  - BACKGROUND: A number of recent studies have identified interleukin (IL)-6 as an
      important regulator of prostate cancer growth. Here, we investigate the potential
      interaction of IL-6 with phosphatidylinositol (PI)-3 kinase, a key growth
      regulatory enzyme, in prostate cancer cell lines. METHODS: Tyrosine
      phosphorylation of p85, the regulatory subunit of PI-3 kinase, in the human
      prostate cancer cell lines LNCaP and PC-3 was assessed by sequential
      immunoprecipitation with anti-p85 antibody and immunoblotting with anti
      phosphotyrosine. The effects of wortmannin, an inhibitor of PI-3 kinase, and/or
      IL-6 on cell growth were assessed by MTT assays. DNA laddering experiments were
      performed to assay for programmed cell death. RESULTS: Tyrosine phosphorylation
      of p85 is upregulated by IL-6 in both LNCaP and PC-3. IL-6 promotes
      coprecipitation of p85 with gp130, the signal-transducing component of the IL-6
      receptor. Inhibition of PI-3 kinase with wortmannin induces programmed cell death
      in PC-3 cells. In contrast, wortmannin has no effect on LNCaP growth when used
      alone; however, combined with IL-6, wortmannin promotes apoptosis in these cells.
      CONCLUSIONS: PI-3 kinase is involved in IL-6 signal transduction and delivers an
      antiapoptotic signal in human prostate cancer cell lines.

PMID- 10579794
TI  - Expression of a kallikrein-like protein in prostatic intraepithelial neoplasia in
      ventral prostate of the noble rat.
AB  - BACKGROUND: In an effort to identify biomarker(s) for prostatic cancer (PCa), we
      analyzed the changes of secretory proteins in the ventral prostate (VP) of Noble
      rats at early stages of carcinogenesis. METHODS: Ventral prostates were removed
      from both control (n = 36) and experimental (n = 88) rats implanted with a known
      ratio of testosterone (T) and 17beta-estradiol (E(2)). Tissue sections were
      stained by hematoxylin and eosin (H&E) for pathological screening, and secretions
      were collected for SDS-PAGE analysis followed by N-terminal microsequencing,
      antiserum production, Western blot, and immunohistochemical study. RESULTS:
      Pathologically, low-grade prostatic intraepithelial neoplasia (LGPIN) and high
      grade PIN (HGPIN) were observed in ducts or alveoli after 3 and 5 months of T +
      E(2) treatment, respectively. The results of SDS-PAGE showed an elevated
      expression of 18-kDa protein (p18) in secretions of VP with HGPIN or cancerous
      lesions. Analysis of p18 by N-terminal sequencing showed a high score of homology
      to rat glandular kallikrein. To characterize the expression pattern of the
      protein in tissue samples, an antiserum was raised against the N-terminus of the
      p18. The monospecificity of the antiserum against p18 was confirmed by Western
      blot analysis. Immunohistochemical study showed that in ducts or alveoli of
      normal and LGPIN samples, a mild positive staining for p18 was observed in
      secretions. However, the reactivity was intense not only in luminal secretions
      but also in some luminal secretory cells in HGPIN and cancer cells as well.
      CONCLUSIONS: The high expression of p18 in connection with neoplastic
      transformation of cells strongly suggests that the potential application of this
      protein as a marker for early detection of PCa should be further investigated.

PMID- 10579795
TI  - Localization and quantification of mRNA for matrix metalloproteinase-2 (MMP-2)
      and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) in human benign and
      malignant prostatic tissue.
AB  - BACKGROUND: The family of matrix metalloproteinases (MMPs) has been shown to be
      involved in proteolytic degradation of the extracellular matrix, which is an
      essential step in tumor invasion and metastasis. MMPs are tightly regulated by
      the levels of active enzymes and their inhibitors, the tissue inhibitors of
      metalloproteinases (TIMPs). MMP-2 and its ratio to TIMP-2 have been associated
      with tumor recurrence and progression in a number of human malignancies. METHODS:
      We examined the relationship between MMP-2 and TIMP-2 mRNA expression in 42 men
      with malignant (n = 32) and benign (n = 10) prostates using nonisotopic in situ
      hybridization and Northern blot analysis. RESULTS: mRNA for MMP-2 and TIMP-2 was
      localized to the malignant epithelial cells of both high- and low-grade tumors in
      the periphery of the glands and in areas of extracapsular involvement, and to the
      glandular epithelium in the benign prostates. Using Northern blot analysis, the
      mean MMP-2 to TIMP-2 ratio was approximately one in the benign prostates and low
      grade and -stage cancers. The MMP-2 to TIMP-2 ratio increased to 3.3 in the high
      grade and 2.8 in the high-stage tumors. CONCLUSIONS: The results suggest a close
      association between MMP-2/TIMP-2 expression and local tumor invasion, with a
      disruption in expression of the two genes leading to disease progression. Future
      studies should focus on the activity of these enzymes and on the ratio of
      enzyme/inhibitor expression, which may become a useful prognostic marker in
      prostate cancer.

PMID- 10579796
TI  - Tumor angiogenesis is associated with progression after radical prostatectomy in
      pT2/pT3 prostate cancer.
AB  - BACKGROUND: The clinical relevance of tumor angiogenesis has been investigated in
      several human tumor types. Angiogenesis (measured as microvessel density; MVD)
      was recently correlated with tumor stage, grade, and clinical course in prostate
      cancer (PC). However, considerable controversy remains concerning the prognostic
      value of angiogenesis in PC. METHODS: We examined MVD in primary PCs to further
      establish the prognostic relevance of angiogenesis in this tumor entity. In 98
      paraffin-embedded PCs of various stages, 5 prostate adenomas, and 20 normal
      prostate tissues, MVD was determined immunohistochemically using a polyclonal
      antibody against factor VIII. The findings were correlated with the clinical data
      of the patients. RESULTS: Normal prostate tissue and prostate adenomas had a low
      MVD. In PC, MVD increased significantly with tumor stage and grade (P < 0.001).
      The Wilcoxon rank statistics showed significant differences for MVD (P < 0.0001),
      tumor stage (P < 0. 0027), and grade (P < 0.0001), but not for preoperative
      prostate-specific antigen values in PC patients with and without tumor
      progression subsequent to treatment, respectively. Importantly, multivariate
      survival analysis revealed that MVD and tumor grade were the only independent
      markers for progression in prostate carcinoma. CONCLUSIONS: In this study, tumor
      angiogenesis measured by MVD was associated with a dismal pathologic appearance
      and a negative clinical prognosis in PC after radical prostatectomy.

PMID- 10579797
TI  - Androgen-independent growth is induced by neuropeptides in human prostate cancer
      cell lines.
AB  - BACKGROUND: Androgen-independent growth leads to progressive prostate cancer
      after androgen-ablation therapy. This may be caused by altered specificity of the
      androgen receptor (AR), by ligand-independent stimulation of the AR, or by
      paracrine growth modulation by neuropeptides secreted by neuroendocrine (NE)
      cells. METHODS: We established and characterized the androgen-independent FGC-DCC
      from the androgen-dependent LNCaP fast growing colony (FGC) cell line. The
      androgen-independent DU-145, FGC-DCC, and PC-3, and the androgen-dependent LNCaP
      and PC-346C cell lines were used to study growth modulation of gastrin-releasing
      peptide (GRP), calcitonin (CT), serotonin (5-HT), and vasoactive intestinal
      peptide (VIP) by (3)H-thymidine incorporation. Specificity of the growth
      modulating effects was tested with the anti-GRP monoclonal antibody 2A11 and
      induction of cAMP by neuropeptides. RESULTS: Androgen-independent growth
      stimulation by neuropeptides was shown in DU-145 and PC-346C. 2A11 inhibited GRP
      induced (3)H-thymidine incorporation in DU-145 and PC-346C and inhibited
      proliferation of the FGC-DCC and PC-3 cell lines. With some exceptions, cAMP
      induction paralleled growth stimulation. Dideoxyadenosine (DDA) inhibited the GRP
      induced growth effect in DU-145 and PC-346C, whereas oxadiazoloquinoxaline-1-one
      (ODQ) had no effect on (3)H-thymidine incorporation. None of the neuropeptides
      stimulated growth of LNCaP, FGC-DCC, or PC-3. CONCLUSIONS: GRP-induced growth of
      DU-145 and PC-346C was specific and cAMP-mediated. Androgen-independent growth of
      FGC-DCC cells was mainly due to an induction of Bcl-2 expression and possibly
      through the activation of an autocrine and NE-like pathway, as has been shown
      also for the PC-3 cell line. Growth induction of non-NE cells by neuropeptides
      could be a possible role for NE cells in clinical prostate cancer.

PMID- 10579798
TI  - Changes in the endocrine environment of the human prostate transition zone with
      aging: simultaneous quantitative analysis of prostatic sex steroids and
      comparison with human prostatic histological composition.
AB  - BACKGROUND: It is well-known that the incidence of benign prostatic hyperplasia
      (BPH) increases with aging. The age-dependent changes in the ratio of serum sex
      steroid concentrations may play a role in BPH development. To clarify the
      relationship between the prostatic tissue concentrations of these steroids and
      age, we established a precise method of simultaneous quantitative analysis for
      prostatic sex steroids and used this method to investigate the tissue
      concentrations of three major sex steroids (testosterone, dihydrotestosterone,
      and estradiol) in the human prostate. METHODS: The methodology for the
      simultaneous quantitative analysis of prostatic sex steroids was established
      using castrated rat prostatic tissue, coupled with internal standards, for
      androgen-deprived medium, and the validation of the method was examined. Human
      prostatic tissues were collected during surgery and immediately frozen at -70
      degrees C. Using our method, the steroidal fractions were extracted, purified,
      and quantified. The proportions of stroma, epithelium, and glandular lumen were
      measured on each histological specimen, using an image analyzer. RESULTS: The
      validation tests showed that our method of quantitative analysis was precise and
      sensitive enough for the quantification of testosterone, dihydrotestosterone, and
      estradiol in the prostate. In humans, the prostatic dihydrotestosterone
      concentration decreased with age, but the concentrations of testosterone and
      estradiol showed no relation with age. Therefore, the ratio of estradiol to
      dihydrotestosterone concentration (E2/DHT) in prostate increased with age. The
      E2/DHT ratio showed a significant positive correlation with the proportion of
      stroma. CONCLUSIONS: The age-dependent decrease in prostatic dihydrotestosterone
      and constant estradiol concentration lead to a relatively estrogen-dominant
      environment compared to that at younger ages. We assume that this relatively
      estrogen-dominant status induces stromal proliferation by some mechanism and
      leads to the development of BPH.

PMID- 10579799
TI  - Meta-analysis for combining relative risks of alcohol consumption and prostate
      cancer.
AB  - BACKGROUND: Prostate cancer has become the most common cancer among men in the
      United States, but little is known about factors associated with prostate cancer
      incidence. METHODS: A meta-analysis of studies published prior to July 1998 was
      conducted to pool relative risk (RR) estimates from the existing literature on
      the association between prostate cancer and alcohol consumption, in an attempt to
      determine whether there is an association, and if so, what its magnitude is.
      RESULTS: The overall pooled RR estimate was 1. 05 for both fixed and random
      effects models, based on six cohort studies and 27 case-control studies. The RR
      estimate varied little by study design. Among types of consumption, the highest
      risk was found for beer (RR = 1.27), but this was based on only eight studies
      that reported type of alcohol consumed. A linear dose-response was fit to the 15
      studies reporting amount of alcohol consumed, finding a RR of 1.05 (95%
      confidence interval (CI), 0.91-1.20) for each additional drink of alcohol per day
      or a RR of 1.21 for 4 drinks per day. When the average drinks per day consumed in
      the 15 studies were used to estimate the overall risk for all 33 studies, a RR of
      1.02 was found for each additional drink of alcohol per day. CONCLUSIONS:
      Overall, no association between prostate cancer and alcohol consumption was seen.
      While some categories of consumption showed an increased risk, the studies
      reporting such categories appeared to be biased towards reporting a positive
      association among the categories.

PMID- 10579800
TI  - Use of artificial neural networks in evaluating prognostic factors determining
      the response to dendritic cells pulsed with PSMA peptides in prostate cancer
      patients.
AB  - BACKGROUND: Our purpose was to compare the importance of over 22 measurements
      used in evaluating the clinical responses of patients with metastatic or locally
      recurrent prostate cancer, treated by dendritic cell (DC) infusions with prostate
      specific membrane antigen (PSMA) peptides. METHODS: Artificial neural networks
      (ANNs) were employed for assessment, as well as the traditional methods of
      logistic regression. RESULTS: Twenty-six patients with metastatic disease and 37
      patients with local recurrence were available for evaluation and comparison. ANN
      evaluation ranked the collective effects of DC infusion, immune responses (CD3+
      cells, CD16+ cells, zeta chain+ cells), and cytokines, e.g., IL-6 and PSMA
      levels, very highly. Logistic regression identified all of these parameters to
      some degree, but in a different rank order. Patients with metastases showed a
      sharp rate of response secondary to the level of DC infusion, in contrast to
      those patients with local recurrence, in which it was more gradual. CONCLUSIONS:
      ANN analysis emphasizes the importance of level of DC infusion, immune
      parameters, cytokines, and markers such as PSMA in determining the response to
      PSMA peptide immunotherapy. The criteria of response were judged to be correct in
      86% of metastatic patients and 83% of locally recurrent patients evaluated in
      this study.

PMID- 10579801
TI  - Over-expression of cyclooxygenase-2 in human prostate adenocarcinoma.
AB  - Aberrant or increased expression of cyclooxygenase (COX)-2 has been implicated in
      the pathogenesis of many diseases including carcinogenesis. COX-2 has been shown
      to be over-expressed in some human cancers. Employing semi-quantitative reverse
      transcription-PCR, immunoblotting, and immunohistochemistry we assessed COX-2
      expression in samples of pair-matched benign and cancer tissue obtained from the
      same prostate cancer patient. Mean levels of COX-2 mRNA were 3.4-fold higher in
      prostate cancer tissue (n = 12) compared with the paired benign tissue. The
      immunoblot analysis demonstrated that as compared to benign tissue COX-2 protein
      was over-expressed in 10 of 12 samples examined. Immunohistochemical analysis
      also verified COX-2 over-expression in cancer than in benign tissue. To our
      knowledge, this is the first in vivo study showing an over-expression of COX-2 in
      prostate cancer. These data suggest that COX-2 inhibitors may be useful for
      prevention or therapy of prostate cancer in humans.

PMID- 10579802
TI  - Selective enhancement of non-NMDA receptor-mediated responses following induction
      of long-term potentiation in entorhinal cortex.
AB  - The contribution of NMDA receptors to the expression of long-term potentiation
      (LTP) is controversial. In entorhinal cortex (EC) previous studies reported
      either that LTP was exclusively expressed through NMDA receptors or that both
      NMDA and non-NMDA receptors were involved in LTP expression. To reexamine this
      issue, horizontal entorhinal cortical slices were prepared from adult rats and
      electrical stimulation was delivered in layer II/III, while field potential
      recordings were made in layer III. In the standard condition (2.5 mM Mg(++)), LTP
      was reliably induced by theta burst stimulation, but was blocked by 100 microM D
      AP5, an NMDA receptor antagonist. This corroborates previous reports that NMDA
      receptor activation is required for induction of EC LTP. The field potential
      response was not affected by D-AP5, but completely blocked by 10 microM CNQX, a
      non-NMDA receptor antagonist. This indicates that the expression of LTP is
      mediated by non-NMDA receptors in the standard condition. LTP of NMDA receptor
      mediated responses was tested by comparing NMDA responses before and after
      applying theta burst stimulation in medium containing low magnesium (0.4-1 mM).
      Theta burst stimulation induced 43.2+/-9.7% increase of non-NMDA responses (i.e.,
      AP5-insensitive fast component) but 5.6+/-9.0% decrease of the NMDA receptor
      component (AP5-sensitive slow component). These results indicate that activation
      of NMDA receptors is critical for induction of LTP, but LTP expression is
      mediated by non-NMDA receptors in EC under these experimental conditions.

PMID- 10579803
TI  - In vivo characterization of the specific cannabinoid receptor antagonist,
      SR141716A: behavioral and cellular responses after acute and chronic treatments.
AB  - To characterize the behavioral and biochemical effects of the cannabinoid CB1
      antagonist SR141716A, we injected the compound intraperitoneally (ip) at doses
      from 0.625 mg/kg to 5 mg/kg in rats. SR141716A per se induced a dose-dependent
      increase of some behavioral signs such as wet dog and head shakes, forepaw
      fluttering, grooming, and facial rubbing. When the highest dose of SR141716A (5
      mg/kg ip) was injected once a day for four days, tolerance developed to most of
      the behavioral signs, although with different time courses, except for grooming
      behavior, which was still significantly different from controls after the fourth
      injection although reduced by 38% from the first. To characterize the biochemical
      mechanism underlying these effects, we designed a series of biochemical studies
      on specific cerebral areas from rats treated with the highest dose of SR141716A
      (5 mg/kg ip). Thirty minutes after SR141716A injection, cAMP accumulation in the
      cortex, striatum, hippocampus, mesencephalon, and cerebellum was the same as in
      controls, whereas protein kinase A (PKA) activity was significantly increased in
      the hippocampus (65%) and striatum (87%). To explain this difference, we
      performed a cAMP assay at an early time (10 min) and found a significant increase
      in the striatum and hippocampus, suggesting that the change in cAMP level is the
      earliest event in the G protein-coupled receptor transduction pathway ending in a
      pharmacological effect after 30 min. When the same assays were done in tolerant
      animals, no change was seen in either cAMP levels or PKA activity in the brain
      areas considered. To conclude, we found in vivo that SR141716A acts through
      activation of the cAMP cascade and our results represent an important point for
      developing potential therapeutic application for SR141716A.

PMID- 10579804
TI  - Selective c-fos induction and decreased dopamine release in the central nucleus
      of amygdala in rats displaying a mecamylamine-precipitated nicotine withdrawal
      syndrome.
AB  - In the present study the neuronal expression of Fos, the protein product of c
      fos, was used to study changes in neuronal activity in nerve terminal regions of
      the ascending dopaminergic system during nicotine withdrawal. Rats were infused
      for 14 days with nicotine (9 mg/kg/day nicotine hydrogen tartrate) via minipumps,
      whereas control animals carried empty pumps. Withdrawal was induced by the
      nicotinic receptor (nAChR) antagonist mecamylamine (1 mg/kg, s.c.). The behavior
      of each animal was observed after mecamylamine injection and subsequently its
      brain was processed for Fos-like immunoreactivity. Following mecamylamine, the
      score of abstinence signs increased in the nicotine-treated rats as compared to
      controls. The number of Fos-positive nuclei was substantially increased in the
      central nucleus of amygdala (CNA) in animals undergoing mecamylamine-precipitated
      withdrawal, whereas no significant changes in c-fos expression were observed in
      the basolateral amygdaloid nucleus, the core and the shell of the nucleus
      accumbens, the dorsolateral striatum, or the medial prefrontal cortex. Since
      there are indications of involvement of amygdaloid dopaminergic neurotransmission
      in anxiety-a core symptom of withdrawal from dependence-producing drugs-in a
      second experiment utilizing microdialysis we examined whether nicotine withdrawal
      affects dopaminergic neurotransmission in the CNA. Following mecamylamine
      injection, dopamine (DA) significantly decreased in nicotine-treated animals
      compared with controls. These results indicate that the mecamylamine-precipitated
      nicotine withdrawal reaction is accompanied by a selective induction of c-fos and
      a concurrent decrease in DA release in the CNA, which may have a bearing on
      symptoms such as anxiety and distress, which frequently are associated with the
      nicotine abstinence reaction in humans.

PMID- 10579805
TI  - Electrodiffusion of synaptic receptors: a mechanism to modify synaptic efficacy?
AB  - We analysed physical forces that act on synaptic receptor-channels following the
      release of neurotransmitter. These forces are: 1) electrostatic interaction
      between receptors, 2) stochastic Brownian diffusion in the membrane, 3) transient
      electric field force generated by currents through open channels, 4) viscous drag
      force elicited by the flowing molecules and 5) strong in-membrane friction. By
      considering alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type
      receptors, we show that, depending on the size and electrophoretic charge of the
      extracellular receptor domain, release of an excitatory neurotransmitter
      (glutamate) can induce receptor clustering towards the release site on a fast
      time scale (8-100 ms). This clustering progresses whenever repetitive synaptic
      activation exceeds a critical frequency (20-100 s(-1), depending on the currents
      through individual channels). As a result, a higher proportion of the receptors
      is exposed to higher glutamate levels. This should increase by 50-100% the peak
      synaptic current induced by the same amount of released neurotransmitter. In
      order for this mechanism to contribute to long-term changes of synaptic efficacy,
      we consider the possibility that the in-membrane motility of the AMPA receptors
      is transiently increased during synaptic activity, e. g., through the breakage of
      receptor anchors in the postsynaptic membrane due to activation of N-methyl-d
      aspartic acid receptors.

PMID- 10579806
TI  - Effects of chronic 17beta-estradiol treatment on the serotonin 5-HT(1A) receptor
      mRNA and binding levels in the rat brain.
AB  - Acute 17beta-estradiol treatment had been shown to downregulate the 5-HT(1A)
      receptor mRNA expression in limbic areas of the female rat brain. The aim of the
      present study was to determine the effects of chronic 17beta-estradiol treatment
      on 5-HT(1A) receptor mRNA expression and 5-HT(1A) receptor binding in
      ovariectomized female rats. Using in situ hybridization histochemistry, no
      alterations were found on the 5-HT(1A) receptor mRNA levels after the estradiol
      treatment (2 weeks). Radioligand autoradiographic studies using the selective 5
      HT(1A) receptor antagonist [(3)H]WAY-100635 revealed reduced receptor binding in
      the amygdala, hippocampus, perirhinal cortex, and motor cortex after estradiol
      treatment, whereas no changes were observed in the piriform or retrosplenial
      cortex. Thus, the previous findings together with the present results indicate
      that estradiol-induced alterations in 5-HT(1A) receptor mRNA expression appears
      within hours, but diminishes with chronic treatment when significant changes on
      the receptor-protein level are apparent. The effects of estradiol treatment on
      the 5-HT(1A) receptor binding in the limbic areas suggest that estrogen can
      modulate functions such as learning, memory, cognition, emotional processing, and
      social behavior. Consequently, estradiol modulation of 5-HT(1A) receptor circuits
      might be a possible pathway for the estrogen influence in the expression of
      psychiatric and neurological disorders such as Alzheimer's disease, affective
      disorders, and schizophrenia.

PMID- 10579807
TI  - Dual localization of neuropeptide FF receptors in the rat dorsal horn.
AB  - Although neuropeptide FF (NPFF) is generally considered an anti-opioid, its
      intrathecal administration produces analgesia. In the present study, the stable
      analog 1DMe ([D.Tyr(1), (NMe)Phe(3)]neuropeptide FF) was used in quantitative
      autoradiographic experiments in combination with surgical and chemical lesions to
      precisely localize NPFF receptors in the rat spinal cord. Ligation of lumbar
      dorsal spinal roots revealed the presence of NPFF receptors in dorsal root fibers
      and it induced a significant accumulation of [(125)I]1DMe-specific binding on the
      side peripheral to the ligature, demonstrating that a population of NPFF
      receptors is synthesized in dorsal root ganglia and migrates anterogradely
      towards primary afferent nerve endings. Complete mid-thoracic spinal cord
      transection failed to modify the [(125)I]1DMe labeling density in the dorsal
      horn, indicating that NPFF receptors are not located on the descending fiber
      terminals. In contrast, unilateral microinjections of kainic acid into the dorsal
      horn dramatically reduced [(125)I]1DMe-specific binding in the superficial
      layers, revealing localization of a population of NPFF receptors on the spinal
      intrinsic neurons. NPFF receptor binding was not modified during the development
      of spinal opioid tolerance. The pre- and postsynaptic localization of spinal NPFF
      receptors provide further support for heterogeneity in the pain modulation by
      NPFF and related agonists.

PMID- 10579809
TI  - Preclinical testing of N-[(11)c]-methyl-piperidin-4-yl 2-cyclohexyl-2-hydroxy-2
      phenylacetate, a novel radioligand for detection of cerebral muscarinic receptors
      using PET.
AB  - The muscarinic antagonist N-[(11)C]methyl-piperidin-4-yl 2-cyclohexyl-2-hydroxy-2
      phenylacetate (VC-004) 1 was tested for visualization of muscarinic receptors in
      the brain. The active (R)-isomer (pKb = 10.92) was labeled by reacting [(11)C]
      CH(3)I with the secondary amine precursor (40-60% decay-corrected radiochemical
      yield, specific activity 13.0-34.3 TBq/mmol, 45 min after end of bombardment).
      Biodistribution studies were performed in male Wistar rats. Brain uptake of (R)
      [(11)C]-VC-004 was high, standard uptake values (SUVs) ranging from 1.6 in
      cerebellum to 3.3 in frontal cortex. In all brain regions, the nonsubtype
      selective muscarinic antagonist scopolamine (2.5 mg/kg) blocked (R)-[(11)C]-VC
      004 binding to the same extent (84.6 +/- 3.3%) as nonlabeled (R)-VC-004 (2.0
      mg/kg, 83.2 +/- 4.6%). In contrast, the fraction of [(11)C]VC-004 binding which
      was blocked by atropine (2.5 mg/kg) was significantly smaller (54 +/- 17%). The
      reduction of (R)-[(11)C]-VC-004 binding by low-dose atropine (0.5 mg/kg) was not
      significantly different from that caused by (R)-(-)-QNB (20 microg/kg). The
      decrease in specific binding of (R)-[(11)C]VC-004 after (R)-(-)-QNB block
      correlated well with literature values for the percentages of M(2) receptors in
      the brain regions studied. (R)-[(11)C]VC-004 was rapidly cleared from plasma (92%
      with a half-life of 0.27 min) and the fraction of total plasma radioactivity
      representing parent compound decreased from 99% to 42% at 10 min postinjection.
      Although (R)-[(11)C]VC-004 can visualize muscarinic receptors in the brain, it
      does not show selectivity for the M(2)-subtype. A low dose (0.5 mg/kg) of
      atropine seems to preferentially block M(2)-receptors in vivo, as has been
      reported for (R)-(-)-QNB.

PMID- 10579808
TI  - Preferential modulation of mesolimbic vs. nigrostriatal dopaminergic function by
      serotonin(2C/2B) receptor agonists: a combined in vivo electrophysiological and
      microdialysis study.
AB  - Electrophysiological and in vivo microdialysis were used to investigate and
      compare the effect of tonic activation of serotonin(2C/2B) (5-HT(2C/2B))
      receptors on nigrostriatal and mesolimbic dopaminergic (DA) function. Thus,
      extracellular single unit recordings of neurochemically-identified DA neurons in
      the SNc and the VTA, as well as simultaneous monitoring of striatal and accumbal
      DA release were performed following the administration of the unselective 5
      HT(2C/2B) agonists, mCPP (m-chlorophenylpiperazine) and MK 212 [6-chloro-2-(1
      piperazinyl)piperazine]. Both mCPP (5-320 microg/kg i. v.) and MK 212 (5-320
      microg/kg i.v.) dose-dependently decreased the firing rate of VTA DA neurons. The
      maximal effect was reached at the cumulative dose of 320 microg/kg mCPP and MK
      212, which caused a decrease of 42.6 +/- 12.8% and 56.4 +/- 12.6%, respectively.
      In addition, the total number of events in bursts and the number of bursts of VTA
      DA cells were significantly reduced by both mCPP and MK 212. On the other hand,
      mCPP (5-320 microg/kg i.v.) and MK 212 (5-320 microg/kg i.v.) induced a slight
      decrease in the basal firing rate, but not in bursting activity of SNc DA
      neurons. Consistent with electrophysiological data, dialysate DA levels in the
      nucleus accumbens decreased significantly, reaching the maximum of 26.6 +/- 9.6%
      below baseline levels 120 min after mCPP (1 mg/kg i.p.) administration, and of
      25.2 +/- 5.5% 140 min after MK 212 (1 mg/kg i. p.) injection. DA outflow in the
      striatum was unaffected by both drugs. The inhibitory effect of both mCPP and MK
      212 on VTA DA cell activity was blocked completely by pretreatment with the
      selective 5-HT(2C) antagonist SB 242084 ?6-chloro-5-methyl-1-[2-(2-methylpyridyl
      3-oxy)-pyrid-5-yl carbamoyl] indoline? (200 microg/kg), given intravenously 10
      min before the first injection of the 5-HT(2C/2B) agonists. SB 242084 (2. 5 mg/kg
      i.p.) antagonized also the decrease in DA release induced by mCPP and MK 212 in
      the nucleus accumbens. Taken together, these data indicate that mCPP and MK 212
      selectively inhibit mesolimbic dopaminergic function by acting on 5-HT(2C)
      receptors. Therefore, selective 5-HT(2C) receptor agonists might be useful in
      clinical conditions where it is necessary to reduce the mesolimbic dopaminergic
      activity without affecting the nigrostriatal function.

PMID- 10579810
TI  - Kinetic modeling of benzodiazepine receptor binding with PET and high specific
      activity [(11)C]Iomazenil in healthy human subjects.
AB  - Quantitation of the PET benzodiazepine receptor antagonist, [(11)C]Iomazenil,
      using low specific activity radioligand was recently described. The purpose of
      this study was to quantitate benzodiazepine receptor binding in human subjects
      using PET and high specific activity [(11)C]Iomazenil. Six healthy human subjects
      underwent PET imaging following a bolus injection of high specific activity (>100
      Ci/mmol) [(11)C]iomazenil. Arterial samples were collected at multiple time
      points after injection for measurement of unmetabolized total and nonprotein
      bound parent compound in plasma. Time activity curves of radioligand
      concentration in brain and plasma were analyzed using two and three compartment
      model. Kinetic rate constants of transfer of radioligand between plasma,
      nonspecifically bound brain tissue, and specifically bound brain tissue
      compartments were fitted to the model. Values for fitted kinetic rate constants
      were used in the calculation of measures of benzodiazepine receptor binding,
      including binding potential (the ratio of receptor density to affinity), and
      product of BP and the fraction of free nonprotein-bound parent compound (V(3)').
      Use of the three compartment model improved the goodness of fit in comparison to
      the two compartment model. Values for kinetic rate constants and measures of
      benzodiazepine receptor binding, including BP and V(3)', were similar to results
      obtained with the SPECT radioligand [(123)I]iomazenil, and a prior report with
      low specific activity [(11)C]Iomazenil. Kinetic modeling using the three
      compartment model with PET and high specific activity [(11)C]Iomazenil provides a
      reliable measure of benzodiazepine receptor binding. Synapse 35:68-77, 2000.
      Published 2000 Wiley-Liss, Inc.

PMID- 10579811
TI  - Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as highly potent and
      selective human A(3) adenosine receptor antagonists.

PMID- 10579812
TI  - Potent and selective inhibition of varicella-zoster virus (VZV) by nucleoside
      analogues with an unusual bicyclic base.
AB  - We herein report the discovery of an entirely new category of potent antiviral
      agents based on novel deoxynucleoside analogues with unusual bicyclic base
      moieties. Target structures, previously known as byproducts in Pd-catalyzed
      coupling of terminal alkynes with 5-iodo-nucleosides, are recognized herein for
      the first time to be potent and selective inhibitors of varicella-zoster virus
      (VZV) in vitro. As an unusual structure-activity relationship we noted the
      absolute requirement of a long alkyl side chain, with an optimum length of C(8)
      C(10), for antiviral activity. We thus report the synthesis and characterization
      of a series of chain-modified analogues and their extensive in vitro evaluation.
      The lead compounds have a ca. 300-fold enhancement in anti-VZV activity over the
      reference compound acyclovir, with no detectable in vitro cytotoxicity. The novel
      structure of these compounds, coupled with their ease of synthesis, excellent
      antiviral profile, and promising physical properties, makes them of great
      interest for possible antiviral drug development.

PMID- 10579813
TI  - Endothelin antagonists: substituted mesitylcarboxamides with high potency and
      selectivity for ET(A) receptors.
AB  - We have previously disclosed the discovery of 2,4-disubstituted
      anilinothiophenesulfonamides with potent ET(A)-selective endothelin receptor
      antagonism and the subsequent identification of sitaxsentan (TBC11251, 1) as a
      clinical development compound (Wu et al. J. Med. Chem. 1997, 40, 1682 and 1690).
      The orally active 1 has demonstrated efficacy in a phase II clinical trial of
      congestive heart failure (Givertz et al. Circulation 1998, 98, Abstr. #3044) and
      was active in rat models of myocardial infarction (Podesser et al. Circulation
      1998, 98, Abstr. #2896) and acute hypoxia-induced pulmonary hypertension (Chen et
      al. FASEB J. 1996, 10 (3), A104). We now report that an additional substituent at
      the 6-position of the anilino ring further increases the potency of this series
      of compounds. It was also found that a wide range of functionalities at the 3
      position of the 2,4,6-trisubstituted ring increased ET(A) selectivity by
      approximately 10-fold while maintaining in vitro potency, therefore rendering the
      compounds amenable to fine-tuning of pharmacological and toxicological profiles
      with enhanced selectivity. The optimal compound in this series was found to be
      TBC2576 (7u), which has approximately 10-fold higher ET(A) binding affinity than
      1, high ET(A)/ET(B) selectivity, and a serum half-life of 7.3 h in rats, as well
      as in vivo activity.

PMID- 10579814
TI  - Design of MKC-442 (emivirine) analogues with improved activity against drug
      resistant HIV mutants.
AB  - Two analogues of the nonnucleoside inhibitor of HIV-1 RT, MKC-442 (emivirine),
      containing different C6 substituents have been designed to be less susceptible to
      the commonly found drug-resistance mutation of Tyr181Cys. Compound TNK-6123 had a
      C6 thiocyclohexyl group designed to have more flexibility in adapting to the
      mutated drug-binding site. GCA-186 had additional 3',5'-dimethyl substituents
      aimed at forming close contacts with the conserved residue Trp229. Both compounds
      showed approximately 30-fold greater inhibitory effect than MKC-442 to the
      Tyr181Cys mutant virus as well as to the clinically important Lys103Asn virus. X
      ray crystallographic structure determination of complexes with HIV-1 RT confirmed
      the predicted binding modes. These strategies might be used to improve the
      resilience of other NNRTI series against common drug-resistance mutations.

PMID- 10579815
TI  - Affinity and selectivity of matrix metalloproteinase inhibitors: a chemometrical
      study from the perspective of ligands and proteins.
AB  - A novel strategy to understand affinity and selectivity for enzyme inhibitors
      using information from ligands and target protein 3D structures is described. It
      was applied to 2-arylsulfonyl-1,2,3, 4-tetrahydro-isoquinoline-3-carboxylates and
      -hydroxamates as inhibitors of the matrix metalloproteinases MMP-3 (stromelysin
      1) and MMP-8 (human neutrophil collagenase). As the first step, consistent and
      predictive 3D-QSAR models were derived using CoMFA, CoMSIA, and GRID/Golpe
      approaches, leading to the identification of binding regions where steric,
      electronic, or hydrophobic effects are important for affinity. These models were
      validated using multiple analyses using two or five randomly chosen cross
      validation groups and randomizations of biological activities. Second, 3D-QSAR
      models were derived based on the affinity ratio IC(50)(MMP-8)/IC(50)(MMP-3),
      allowing the identification of key ligand determinants for selectivity toward one
      of both enzymes. In addition to this ligands' view, the third step encompasses a
      chemometrical approach based on principal component analysis (PCA) of
      multivariate GRID descriptors to uncover the major differences between both
      protein binding sites with respect to their GRID probe interaction pattern. The
      resulting information, based on the accurate knowledge of the target protein 3D
      structures, led to a consistent picture in good agreement with experimentally
      observed differences in selectivity toward MMP-8 or MMP-3. The interpretation of
      all three classes of statistical models leads to detailed SAR information for MMP
      inhibitors, which is in agreement with available data for binding site
      topologies, ligand affinities, and selectivities. Thus the combined chemical
      analyses provide guidelines and accurate activity predictions for designing
      novel, selective MMP inhibitors.

PMID- 10579817
TI  - Molecular modeling studies on G-quadruplex complexes of telomerase inhibitors:
      structure-activity relationships.
AB  - Inhibition of the ability of the enzyme telomerase to add telomeric repeats to
      the end of chromosomes is a novel target for potential anticancer therapy. This
      paper examines the hypothesis that compounds possessing a planar aromatic
      chromophore inhibit telomerase via stabilization of, and binding to, a folded
      guanine quadruplex structure. Two series of telomerase inhibitors have been
      designed based on the 2,6-disubstituted amidoanthracene-9,10-dione and 3,6
      disubstituted acridine chromophores in order to investigate structure-activity
      relationships between biological activity and substituent group size. The
      relative binding energies between these compounds and the folded human telomere
      DNA quadruplex were determined using molecular simulation methods, involving
      explicitly solvated structures. The results obtained are in excellent agreement
      with the biological activity as measured in vitro using a modified TRAP assay and
      in general agreement with the ranking order of binding enthalpies found in
      isothermal titration calorimetry studies. This broad agreement provides strong
      support for the hypothesis that guanine quadruplexes are the primary target for
      telomerase inhibitors with extended planar chromophores.

PMID- 10579816
TI  - Angiotensin II analogues encompassing 5,9- and 5,10-fused thiazabicycloalkane
      tripeptide mimetics.
AB  - A simple experimental procedure on solid phase for the construction of new
      tripeptidic 5,9- and 5,10-fused thiazabicycloalkane scaffolds that adopt beta
      turns has been developed. This N-terminal-directed bicyclization, relying on
      masked aldehyde precursors derived from glutamic acid as key building blocks,
      provides a complement to the related bicyclization previously reported, where an
      aspartic acid-derived precursor was employed to induce cyclization toward the C
      terminal end of the peptide. Thus, the regioselectivity of the bicyclization can
      be altered simply by varying the chain length of the incorporated aldehyde
      precursor. Four analogues of the hypertensive octapeptide angiotensin II,
      comprising the new scaffolds in the 3-5- and 5-7-positions, were synthesized. One
      of these conformationally constrained angiotensin II analogues exhibited AT(1)
      receptor affinity (K(i) = 750 nM). Results from theoretical conformational
      analysis of model compounds of the bicyclic tripeptide mimetics are presented,
      and they demonstrate that subtle differences in geometry have a strong impact on
      the affinity to the AT(1) receptor.

PMID- 10579818
TI  - Design, synthesis, and biological evaluation of potent thiazine- and thiazepine
      based matrix metalloproteinase inhibitors.
AB  - The synthesis and enzyme inhibition data for a series of thiazine- and thiazepine
      based matrix metalloproteinase (MMP) inhibitors are described. The thiazine- and
      thiazepine-based inhibitors were discovered by optimization of hetererocyclic
      sulfonamide-based inhibitors. The most potent series of inhibitors was obtained
      by modification of the amino acid D-penicillamine. This amino acid provides a gem
      dimethyl group on the thiazine or thiazepine ring which has a dramatic effect on
      the in vitro potency of this series. In particular, the sulfide 4a and the
      sulfone 5a were potent, broad-spectrum inhibitors of the MMPs with IC(50)'s
      against MMP-1 of 0.8 and 1.9 nM, respectively. The binding mode of this novel
      thiazepine-based series of MMP inhibitors was established based on X-ray
      crystallography of the complex of stromelysin and 4a.

PMID- 10579819
TI  - Metabolism-based brain-targeting system for a thyrotropin-releasing hormone
      analogue.
AB  - Gln-Leu-Pro-Gly, a progenitor sequence for the thyrotropin-releasing hormone
      (TRH) analogue [Leu(2)]TRH (pGlu-Leu-Pro-NH(2)), was covalently and bioreversibly
      modified on its N- and C-termini (by a 1,4-dihydrotrigonellyl and a cholesteryl
      group, respectively) to create lipoidal brain-targeting systems for the TRH
      analogue. The mechanism of targeting and the recovery of the parent peptide at
      the target site involve several enzymatic steps, including the oxidation of the
      1,4-dihydropyridine moiety. Due to the lipid insolublity of the peptide
      pyridinium conjugate obtained after this reaction, one of the rudimentary steps
      of brain targeting (i.e., trapping in the central nervous system) can be
      accomplished. Our design also included spacer amino acid(s) inserted between the
      N-terminal residue of the progenitor sequence and the dihydrotrigonellyl group to
      facilitate the posttargeting removal of the attached modification. The release of
      the TRH analogue in the brain is orchestrated by a sequential metabolism
      utilizing esterase/lipase, peptidyl glycine alpha-amidating monooxygenase (PAM),
      peptidase cleavage, and glutaminyl cyclase. In addition to in vitro experiments
      to prove the designed mechanism of action, the efficacy of brain targeting for
      [Leu(2)]TRH administered in the form of chemical-targeting systems containing the
      embedded progenitor sequence was monitored by the antagonistic effect of the
      peptide on the barbiturate-induced anesthesia (measure of the activational effect
      on cholinergic neurons) in mice, and considerable improvement was achieved over
      the efficacy of the parent peptide upon using this paradigm.

PMID- 10579820
TI  - Specific nonpeptide photoprobes as tools for the structural study of the
      angiotensin II AT(1) receptor.
AB  - The aim of this work was to obtain photoactivatable nonpeptide antagonists of the
      angiotensin II AT(1) receptor. Based on structure-function relationships, two
      chemical structures as well as appropriate synthetic schemes were chosen as a
      frame for the design of radiolabeled azido probes. The feasibility of the
      strategy was first assessed by the synthesis of two tritiated ligands 21 and 22
      possessing a high affinity for the AT(1) receptor and a low nonspecific binding
      to membrane or cell preparations. We then prepared two unlabeled azido
      derivatives 7 and 14 which retained a fairly high affinity for the AT(1)
      receptor. The latter compound proved to be suitable for receptor irreversible
      labeling and was prepared in its tritiated form 28. This tritiated azido
      nonpeptide probe displayed a K(d) value of 11.8 nM and a low nonspecific binding.
      It was suitable for specific and efficient covalent labeling of the recombinant
      AT(1A) receptor stably expressed in CHO cells. The electrophoretic pattern of the
      specifically labeled entity was strictly identical to that of purified receptor
      photolabeled with a biotinylated peptidic photoactivatable probe. This new tool
      should be useful for the mapping of the nonpeptide receptor binding site. These
      potential applications are discussed in light of the current knowledge of
      molecular mechanisms of G-protein coupled receptor activation and inactivation.

PMID- 10579822
TI  - Solution structure of polymyxins B and E and effect of binding to
      lipopolysaccharide: an NMR and molecular modeling study.
AB  - The cyclic decapeptides polymyxin B (PmB) and E (PmE) (mo-K'TK'-cyclo
      [K'K'XLK'K'T]; mo, methyl octanoate; K', diaminobutyric acid; X, D-Phe (PmB) or D
      Leu (PmE)) display antimicrobial and lipopolysaccharide (LPS) antagonistic
      activities. We have investigated the conformational behavior of PmB and PmE in
      water solution, free and bound to LPS, by homonuclear NMR and molecular modeling
      methods. The free peptides exist in equilibria of fast exchanging conformations
      with local preferences for a distorted type II' beta-turn from residues 5-8,
      and/or a gamma-turn in residue 10. These two motifs are not present in the bound
      conformation of the peptides. The latter is amphiphilic separating the two
      hydrophobic residues in the cycle from the positively charged diaminobutyric acid
      side chains by an envelope-like fold of the cycle. The bound conformation is used
      for the derivation of a model of the PmB-lipid A complex based on electrostatic
      interactions and reduction of hydrophobic area. The proposed mode of binding
      breaks up the supramolecular structure of LPS connected with its toxicity. The
      model should contribute to the understanding of entropy-driven PmB-lipid A
      binding at the molecular level and assist the design of inhibitors of endotoxic
      activity.

PMID- 10579821
TI  - Design and synthesis of thrombin inhibitors: analogues of MD-805 with reduced
      stereogenicity and improved potency.
AB  - Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains
      four stereogenic centers, has been the starting point for an optimization
      program. A systematic synthetic study resulted in thrombin inhibitors achiral at
      P2 and P3 but with a 10-fold increase in potency over the original lead. A number
      of 4-substituted piperidines were synthesized and examined as replacements for 2
      carboxy-4-methylpiperidine at P2; 4-fluoroethylpiperidine (FEP) among others
      provided inhibitors (e.g. 45g) of increased potency. An enantioselective route
      was developed to 3(R)-methyl-1,2,3,4-tetrahydroquinolinesulfonyl chloride.
      Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to
      the racemic material and provided support, with modeling studies, for the
      preparation of the gem 3,3-disubstituted compounds. A series of inhibitors
      containing the novel 3, 3-dimethyl-1,2,3,4-tetrahydroquinolinesulfonyl (DMTHQS)
      P3 (Table 5) were synthesized and showed a similar activity profile as the
      monomethyl series. The combination of P3-DMTHQS, P2-FEP, and P1-arginine (45g)
      had a K(i) of 6 nM (MD-805 K(i) = 85 nM). In animal models of both venous and
      arterial thrombosis, one inhibitor (42e) was shown to produce a dose-dependent
      inhibition of thrombus formation that in some situations was superior to that of
      MD-805.

PMID- 10579823
TI  - C(60) and water-soluble fullerene derivatives as antioxidants against radical
      initiated lipid peroxidation.
AB  - C(60), vitamin E, and three C(60) derivatives (polar 1 and water-soluble
      C(3)/D(3)C(60)s) were examined for their antioxidant effects on prevention of
      lipid peroxidation induced by superoxide and hydroxyl radicals. The protection
      effect on lipid peroxidation was found to be in the sequence: C(60) >/= vitamin E
      > 1 > none, for liposoluble antioxidants, and C(3)C(60) >> D(3)C(60) > none, for
      water-soluble ones. Fluorescence quenching of PyCH(2)COOH (Py = pyrene) by both
      C(3)- and D(3)C(60)s shows that the Stern-Volmer constant, K(SV), is about the
      same for both quenchers in aqueous solution. Upon addition of liposomes, the
      fluorescence quenching becomes more efficient: 5-fold higher in K(SV) for
      C(3)C(60) than for D(3)C(60). When Py(CH(2))(n)()COOH (n = 1, 3, 5, 9, or 15) was
      incorporated in lipid membranes, the K(SV)s all were small and nearly equal for
      D(3)C(60) but were quite large and different for C(3)C(60) with the sequence: n =
      1 < 3 < 5 < 9 < 15. The better protection effect of C(3)C(60) on lipid
      peroxidation than that of D(3)C(60) is attributed to its stronger interaction
      with membranes. Overall, the antioxidation abilities of the compounds examined
      were rationalized in terms of the number of reactive sites, the location of
      antioxidant in lipid membranes, and the strength of interactions between
      antioxidants and membranes.

PMID- 10579824
TI  - Asymmetric synthesis of 9-alkyl-2-benzyl-6,7-benzomorphans: characterization as
      novel sigma receptor ligands.
AB  - A convenient enantioselective synthesis of (1R,5R,9R)- and (1S,5S, 9S)-9-alkyl-2
      benzyl-6,7-benzomorphans (2a-c) which starts with naphthaldehyde is described.
      These compounds were designed to gain additional information on the structure
      sigma binding relationship of the 6,7-benzomorphan class of sigma ligands. In
      contrast to pentazocine and most 6,7-benzomorphans, the (1R,5R,9R)-isomers of 2a
      c showed greater affinity for the sigma(1) receptor than the (1S, 5S,9S)-isomers.
      Despite reversal of enantioselectivity at the sigma(1) sites, moderate affinity
      and enantioselectivity at the sigma(2) sites [greater affinity for (1R,5R,9R)
      isomers than (1S,5S, 9S)-isomers] were maintained. A comparison of the binding
      affinities of 2a-c to the more conformationally flexible trans-2-alkyl-1
      benzaminoethyl-1,2-dihydronaphthalenes (10a-c) suggested that the relatively
      rigid structure of 2a-c played an important part in their sigma(1) binding
      properties. These compounds, particularly (1R,5R,9R)-2-benzyl-9-methyl-6,7
      benzomorphan [(-)-2a], which has a K(i) value of 0.96 nM, will be useful in
      further characterization of the sigma(1) receptor.

PMID- 10579825
TI  - Structural specificity of chloroquine-hematin binding related to inhibition of
      hematin polymerization and parasite growth.
AB  - Considerable data now support the hypothesis that chloroquine (CQ)-hematin
      binding in the parasite food vacuole leads to inhibition of hematin
      polymerization and parasite death by hematin poisoning. To better understand the
      structural specificity of CQ-hematin binding, 13 CQ analogues were chosen and
      their hematin binding affinity, inhibition of hematin polymerization, and
      inhibition of parasite growth were measured. As determined by isothermal
      titration calorimetry (ITC), the stoichiometry data and exothermic binding
      enthalpies indicated that, like CQ, these analogues bind to two or more hematin
      mu-oxo dimers in a cofacial pi-pi sandwich-type complex. Association constants
      (K(a)'s) ranged from 0.46 to 2.9 x 10(5) M(-1) compared to 4.0 x 10(5) M(-1) for
      CQ. Remarkably, we were not able to measure any significant interaction between
      hematin mu-oxo dimer and 11, the 6-chloro analogue of CQ. This result indicates
      that the 7-chloro substituent in CQ is a critical structural determinant in its
      binding affinity to hematin mu-oxo dimer. Molecular modeling experiments
      reinforce the view that the enthalpically favorable pi-pi interaction observed in
      the CQ-hematin mu-oxo dimer complex derives from a favorable alignment of the out
      of-plane pi-electron density in CQ and hematin mu-oxo dimer at the points of
      intermolecular contact. For 4-aminoquinolines related to CQ, our data suggest
      that electron-withdrawing functional groups at the 7-position of the quinoline
      ring are required for activity against both hematin polymerization and parasite
      growth and that chlorine substitution at position 7 is optimal. Our results also
      confirm that the CQ diaminoalkyl side chain, especially the aliphatic tertiary
      nitrogen atom, is an important structural determinant in CQ drug resistance. For
      CQ analogues 1-13, the lack of correlation between K(a) and hematin
      polymerization IC(50) values suggests that other properties of the CQ-hematin mu
      oxo dimer complex, rather than its association constant alone, play a role in the
      inhibition of hematin polymerization. However, there was a modest correlation
      between inhibition of hematin polymerization and inhibition of parasite growth
      when hematin polymerization IC(50) values were normalized for hematin mu-oxo
      dimer binding affinities, adding further evidence that antimalarial 4
      aminoquinolines act by this mechanism.

PMID- 10579826
TI  - 3-O-Desacyl monophosphoryl lipid A derivatives: synthesis and immunostimulant
      activities.
AB  - The synthesis of a series of novel analogues of lipid A, the active principle of
      lipopolysaccharide, is reported. In these compounds, the 1-O-phosphono and (R)-3
      hydroxytetradecanoyl moieties of native Salmonella minnesota R595 lipid A have
      been replaced with hydrogen and the length of the normal fatty acyl residues has
      been systematically varied. Normal fatty acid chain length in the 3-O-desacyl
      monophosphoryl lipid A (MLA) series is shown to be a critical determinant of iNOS
      gene expression in activated mouse macrophages and the induction of
      proinflammatory cytokines in human peripheral monocytes. Examination of
      pyrogenicity in rabbits and lethal toxicity in D-galactosamine-treated mice shows
      that toxic effects in the MLA series can be ameliorated by modifying fatty acid
      chain length. When used as an adjuvant for tetanus toxoid vaccines, certain MLA
      derivatives enhance the production of tetanus toxoid-specific antibodies in mice.

PMID- 10579827
TI  - Predicting binding affinities of protein ligands from three-dimensional models:
      application to peptide binding to class I major histocompatibility proteins.
AB  - A simple and fast free energy scoring function (Fresno) has been developed to
      predict the binding free energy of peptides to class I major histocompatibility
      (MHC) proteins. It differs from existing scoring functions mainly by the explicit
      treatment of ligand desolvation and of unfavorable protein-ligand contacts. Thus,
      it may be particularly useful in predicting binding affinities from three
      dimensional models of protein-ligand complexes. The Fresno function was
      independently calibrated for two different training sets: (a) five HLA-A0201
      peptide structures, which had been determined by X-ray crystallography, and (b)
      three-dimensional models of 37 H-2K(k)-peptide structures, which had been
      obtained by knowledge-based homology modeling. For both training sets, a good
      cross-validated fit to experimental binding free energies was obtained with
      predictive errors of 3-3.5 kJ/mol. As expected, lipophilic interactions were
      found to contribute the most to HLA-A0201-peptide interactions, whereas H-bonding
      predominates in H-2K(k) recognition. Both cross-validated models were afterward
      used to predict the binding affinity of a test set of 26 peptides to HLA-A0204
      (an HLA allele closely related to HLA-A0201) and of a series of 16 peptides to H
      2K(k). Predictions were more accurate for HLA-A2-binding peptides as the training
      set had been built from experimentally determined structures. The average error
      in predicting the binding free energy of the test peptides was 3.1 kJ/mol. For
      the homology model-derived equation, the average error in predicting the binding
      free energy of peptides to K(k) was significantly higher (5.4 kJ/mol) but still
      very acceptable. The present scoring function is thus able to predict with a good
      accuracy binding free energies from three-dimensional models, at the condition
      that the backbone coordinates of the MHC-bound peptide have first been determined
      with an accuracy of about 1-1.5 A. Furthermore, it may be easily recalibrated for
      any protein-ligand complex.

PMID- 10579828
TI  - 5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based potent and
      selective CCK(1) receptor antagonists: structural modifications at the tryptophan
      domain.
AB  - Analogues of the previously reported potent and highly selective CCK(1) receptor
      antagonist (4aS, 5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhydropyrido
      [1, 2-c]pyrimidine (2a) were prepared to explore the structural requirements at
      the Boc-tryptophan domain for CCK(1) receptor affinity. Structural modifications
      of 2a involved the Trp side chain, its conformational freedom, the Boc group, and
      the carboxamide bond. Results of the CCK binding and in vitro functional activity
      evaluation showed three highly strict structural requirements: the type and
      orientation of the Trp side chain, the H-bonding acceptor carbonyl group of the
      carboxamide bond, and the presence of the Trp amino protection Boc. Replacement
      of this acid-labile group with 3, 3-dimethylbutyryl or tert-butylaminocarbonyl
      conferred acid stability to analogues 14a and 15a, which retained a high potency
      and selectivity in binding to CCK(1) receptors, as well as an in vivo antagonist
      activity against the acute pancreatitis induced by caerulein in rats. Oral
      administration of compounds 14a and 15a also produced a lasting antagonism to the
      hypomotility induced by CCK-8 in mice, suggesting a good bioavailability and
      metabolic stability.

PMID- 10579829
TI  - Amide analogues of trichostatin A as inhibitors of histone deacetylase and
      inducers of terminal cell differentiation.
AB  - Inhibitors of histone deacetylase (HD) bear great potential as new drugs due to
      their ability to modulate transcription and to induce apoptosis or
      differentiation in cancer cells. We have described previously analogues of the
      complex natural HD inhibitors trapoxin B and trichostatin A with activities in
      the submicromolar range. Here we report structure-activity relationship analyses
      of further analogues of trichostatin A with respect to in vitro inhibition of
      maize HD-2 and their ability to induce terminal cell differentiation in Friend
      leukemic cells. This is the first report that shows the correlation between HD
      inhibitory activity and action on cancer cells on a larger series of similar
      compounds. Only the compounds that inhibit HD induce differentiation and/or exert
      antiproliferative activities in cell culture. Our studies support the use of in
      vitro systems as screening tools and provide structure-activity relationships
      that merit further investigation of this interesting target.

PMID- 10579830
TI  - Discovery of novel non-peptide CCR1 receptor antagonists.
AB  - Ligands for the CCR1 receptor (MIP-1alpha and RANTES) have been implicated in a
      number of chronic inflammatory diseases, most notably multiple sclerosis and
      rheumatoid arthritis. Because these ligands share a common receptor, CCR1, we
      sought to discover antagonists for this receptor as an approach to treating these
      disorders. A novel series of 4-hydroxypiperidines has been discovered by high
      throughput screening (HTS) which potently inhibits the binding of MIP-1alpha and
      RANTES to the recombinant human CCR1 chemokine receptor. The structure-activity
      relationships of various segments of this template are described as the initial
      HTS lead 1 was optimized synthetically to the highly potent receptor antagonist
      6s. This compound has been shown to have at least 200-fold selectivity for
      inhibition of CCR1 over other human 7-TM receptors, including other chemokine
      receptors. In addition, data obtained from in vitro functional assays demonstrate
      the functional antagonism of compound 6s and structurally related analogues
      against the CCR1 receptor in a concentration dependent manner. The discovery and
      optimization of potent and selective CCR1 receptor antagonists represented by
      compound 6s potentially represent a novel approach to the treatment of chronic
      inflammatory diseases.

PMID- 10579831
TI  - LASSOO: a generalized directed diversity approach to the design and enrichment of
      chemical libraries.
AB  - Pharmaceutical discovery relies on the screening of chemical libraries that are
      as diverse as possible yet constrained in favor of compounds possessing
      attributes that are normally associated with successful drug candidates. We
      describe a new algorithm for simultaneously addressing both objectives, providing
      an effective means to increase structural diversity in a chemical library while
      maintaining a bias toward compounds that retain the desirable properties of
      drugs. The LASSOO algorithm exploits differences in descriptor distributions to
      identify novel compounds that are most dissimilar to the members of an existing
      screening library and most similar to members of a target library with desirable
      characteristics. We illustrate the LASSOO technique using publicly available
      compound databases and bit string descriptors. The architecture of the algorithm
      is general enough to allow any set of descriptors or similarity measures to be
      employed, and it is easily adaptable to other means of directing diversity, such
      as the avoidance of toxicity and/or poor pharmacokinetic properties.

PMID- 10579832
TI  - Structure-activity relationships of novel 2-substituted quinazoline antibacterial
      agents.
AB  - High-throughput screening of in-house compound libraries led to the discovery of
      a novel antibacterial agent, compound 1 (MIC: 12-25 microM against S. pyogenes).
      In an effort to improve the activity of this active compound, a series of 2
      substituted quinazolines was synthesized and evaluated in several antibacterial
      assays. One such compound (22) displayed improved broad-spectrum antibacterial
      activity against a variety of bacterial strains. This molecule also inhibited
      transcription/translation of bacterial RNA, suggesting a mechanism for its
      antibiotic effects. Structure-activity relationship studies of 22 led to the
      synthesis of another 24 compounds. Although some of these molecules were found to
      be active in bacterial growth assays, none were as potent as 22. Compound 22 was
      tested for its ability to cure a systemic K. pneumonia infection in the mouse and
      displayed moderate effects compared with a control antibiotic, gentamycin.

PMID- 10579833
TI  - Vancomycin binding to low-affinity ligands: delineating a minimum set of
      interactions necessary for high-affinity binding.
AB  - Bacterial resistance to vancomycin has been attributed to the loss of an
      intermolecular hydrogen bond between vancomycin and its peptidoglycan target when
      cell wall biosynthesis proceeds via depsipeptide intermediates rather than the
      usual polypeptide intermediates. To investigate the relative importance of this
      hydrogen bond to vancomycin binding, we have determined crystal structures at 1.0
      A resolution for the vancomycin complexes with three ligands that mimic peptides
      and depsipeptides found in vancomycin-sensitive and vancomycin-resistant
      bacteria: N-acetylglycine, D-lactic acid, and 2-acetoxy-D-propanoic acid. These,
      in conjunction with structures that have been reported previously, indicate
      higher-affinity ligands elicit a structural change in the drug not seen with
      these low-affinity ligands. They also enable us to define a minimal set of drug
      ligand interactions necessary to confer higher-affinity binding on a ligand. Most
      importantly, these structures point to factors in addition to the loss of an
      intermolecular hydrogen bond that must be invoked to explain the weaker affinity
      of vancomycin for depsipeptide ligands. These factors are important
      considerations for the design of vancomycin analogues to overcome vancomycin
      resistance.

PMID- 10579834
TI  - Synthesis and pharmacological evaluation of some 8-cyanopyrido[3',
      2':4,5]thieno[3,2-d]triazine derivatives as inhibitors of nitric oxide and
      eicosanoid biosynthesis.
AB  - A series of 8-cyanopyrido[3',2':4,5]thieno[3,2-d]-1,2,3-triazines, substituted at
      C-4 and C-7, were synthesized and evaluated as nitric oxide and prostaglandin
      E(2) inhibitors in murine peritoneal macrophages stimulated with bacterial
      endotoxin. Several compounds exhibited considerable activity, compounds 10 and 13
      being the most interesting ones with IC(50) values of 11.2 and 3.4 microM on
      nitrites and 0.9 and 0.6 microM on prostaglandin E(2) production, respectively.
      None of the examples of pyridothienotriazines that were active at 10 microM
      showed any effect on inducible nitric oxide synthase, cyclooxygenase-2, and
      cyclooxygenase-1 enzymes, suggesting that they act by modifiying the level of
      expression of these inducible enzymes.

PMID- 10579835
TI  - Inhibition and substrate activity of conformationally rigid vigabatrin analogues
      with gamma-aminobutyric acid aminotransferase.
AB  - Several cyclopentene GABA analogues were synthesized as conformationally rigid
      analogues of the epilepsy drug vigabatrin and tested as inhibitors and substrates
      of gamma-aminobutyric acid aminotransferase (GABA-AT). None of these compounds
      produced time-dependent inhibition. (1R, 4S)-(+)-4-Amino-2-cyclopentene-1
      carboxylic acid ((+)-3), (4R)-(-)-4-amino-1-cyclopentene-1-carboxylic acid ((-)
      4), and d, l-3-amino-1-cyclopentene-1-carboxylic acid (6) are good substrates.
      The K(m) and k(cat) values for the latter two compounds are very similar to those
      of GABA, suggesting that they bind in an orientation similar to that of GABA. The
      K(m) value for (+)-3 is 24 times lower than that for GABA, although its k(cat)
      value is only one-fourth that for GABA; nonetheless, it is a better substrate for
      GABA-AT than is GABA. All of these compounds, as well as the enantiomers of 3 and
      4 and d, l-trans-4-amino-2-cyclopentene-1-carboxylic acid (5), are competitive
      inhibitors of GABA-AT. These results demonstrate the effects of the carboxylate
      group orientation and the stereochemistry of the amino and carboxylate groups on
      the substrate activity and inhibitor activity, and this should be important to
      the future design of inhibitors of GABA-AT.

PMID- 10579836
TI  - Synthesis and biological evaluation of the first N-alkyl cage dimeric 4-aryl-1,4
      dihydropyridines as novel nonpeptidic HIV-1 protease inhibitors.
AB  - A first series of novel NH and N-alkyl-substituted cage dimeric 4-aryl-1,4
      dihydropyridines 3a-f has been synthesized and evaluated as HIV-1 protease
      inhibitors in in vitro assays. While the NH and N-methyl derivatives 3a,b,e,f
      were almost inactive with IC(50) values of about 200 microM, the N-Benzyl
      compounds exhibited stronger activity with an IC(50) value of 16.2 microM for the
      presently best compound 3c. The type of HIV-1 protease inhibition of these novel
      inhibitors was characterized as competitive. With the increase of observed
      activity from NH and N-methyl derivatives to N-benzyl compounds, respectively,
      the binding mode may correspond to that of cyclic and azacyclic ureas showing
      hydrophobic interactions of the four aromatic residues to the S1/S1' and S2/S2'
      regions of HIV-1 protease.

PMID- 10579837
TI  - Synthesis and in vitro anti-HIV activity in human monocyte-derived macrophages of
      2-oxothiazolidine-4(R)-carboxylic acid derivatives.
AB  - Oxidative stress and glutathione (GSH) deficit may play an important role in HIV
      infection pathogenesis, and oral administration of GSH-replenishing drugs such as
      N-acetylcysteine (NAC) and 2-oxothiazolidine-4(R)-carboxylic acid (OTC) may be
      associated with an increased survival rate of HIV-infected patients.
      Nevertheless, beneficial effects of these molecules are restricted in vivo by the
      high concentrations that are necessary to obtain biological effects, rapid
      extracellular metabolization, and low availability and plasma concentrations. We
      synthesized OTC derivatives that are more lipophilic than OTC and theoretically
      able to overcome these limitations and to generate, in addition to cysteine,
      other substrates of the gamma-glutamyl cycle. Their antiviral effects were
      investigated in human HIV-1/Ba-L-infected monocyte-derived macrophages. In our
      experimental conditions, OTC exhibited anti-HIV-1 effects and little cytotoxicity
      at high doses. None of the nine tested derivatives showed higher cytotoxicity
      than OTC, nor anti-HIV-1/Ba-L activity.

PMID- 10579838
TI  - Synthesis and structure-activity relationships of potential anticancer agents:
      alkylcarbamates of 3-(9-acridinylamino)-5-hydroxymethylaniline.
AB  - A series of potential 9-anilinoacridine antitumor agents, 3-(9-acridinylamino)-5
      hydroxymethylaniline (AHMA) derivatives with monosubstituent at C4' and
      disubstituents at C4' and C5' of the acridine ring and their alkylcarbamates,
      were synthesized for evaluation of their antitumor activity. A structure-activity
      relationship (SAR) study showed that the AHMA-alkylcarbamates were more potent
      than their corresponding parent AHMA compounds. In addition, the cytotoxicity of
      the AHMA-alkylcarbamate decreased with increasing length and size of the alkyl
      function. Among these compounds, AHMA-ethylcarbamate (18) and 4'-methyl-5'
      dimethylaminoethylcarboxamido-AHMA-ethylcarb amate (34) possess potent
      cytotoxicity on the inhibition of human leukemic HL-60 cell growth in culture.
      Further in vivo studies of these compounds displayed significant anticancer
      therapeutic effects in mice bearing sarcoma 180, Lewis lung carcinoma, and P388
      leukemia.

PMID- 10579839
TI  - Structure-immunosuppressive activity relationships of new analogues of 15
      deoxyspergualin. 2. Structural modifications of the spermidine moiety.
AB  - A series of new analogues of 15-deoxyspergualin (DSG), an immunosuppressive agent
      commercialized in Japan, was synthesized and tested in a graft-versus-host
      disease (GVHD) model in mice. Various substitutions of the spermidine "D" region
      were made in order to determine its optimum structure in terms of in vivo
      immunosuppressive activity. Various positions of methylation were first
      investigated leading to the discovery of the monomethylated malonic derivative
      56h in which the pro-R hydrogen of the methylene alpha to the primary amine of
      the spermidine moiety has been replaced by a methyl group. Synthesis of the
      similarly methylated analogue of the previously reported glycolic derivative LF
      08-0299 afforded 60e which demonstrated a powerful activity at a dose as low as
      0.3 mg/kg in the GVHD model and was much more potent than DSG in the demanding
      heart allotransplantation model in rats. The improvement of in vivo activity was
      supposed to be related to an increase of the metabolic stability of the
      methylated analogues compared to the parent molecules. Due to its very low active
      dose, compatible with a subcutaneous administration in humans, and its favorable
      pharmacological and toxicological profile, 60e was selected as a candidate for
      clinical evaluation.

PMID- 10579840
TI  - Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 1.
      Structure-activity relationship in dihydropyrimidinones.
AB  - Dihydropyrimidinones such as compound 12 exhibited high binding affinity and
      subtype selectivity for the cloned human alpha(1a) receptor. Systematic
      modifications of 12 led to identification of highly potent and subtype-selective
      compounds such as (+)-30 and (+)-103, with high binding affinity (K(i) = 0.2 nM)
      for alpha(1a) receptor and greater than 1500-fold selectivity over alpha(1b) and
      alpha(1d) adrenoceptors. The compounds were found to be functional antagonists in
      human, rat, and dog prostate tissues. Compound (+)-103 exhibited excellent
      selectively to inhibit intraurethral pressure (IUP) as compared to lowering
      diastolic blood pressure (DBP) in mongrel dogs (K(b)(DBP)/K(b)(IUP) = 40)
      suggesting uroselectivity for alpha(1a)-selective compounds.

PMID- 10579841
TI  - Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 2.
      Approaches to eliminate opioid agonist metabolites via modification of linker and
      4-methoxycarbonyl-4-phenylpiperidine moiety.
AB  - We have previously described compound 1a as a high-affinity subtype selective
      alpha(1a) antagonist. In vitro and in vivo evaluation of compound 1a showed its
      major metabolite to be a mu-opioid agonist, 4-methoxycarbonyl-4-phenylpiperidine
      (3). Several dihydropyrimidinone analogues were synthesized with the goal of
      either minimizing the formation of 3 by modification of the linker or finding
      alternative piperidine moieties which when cleaved as a consequence of metabolism
      would not give rise to mu-opioid activity. Modification of the linker gave
      several compounds with good alpha(1a) binding affinity (K(i) = < 1 nM) and
      selectivity (>300-fold over alpha(1b) and alpha(1d)). In vitro analysis in the
      microsomal assay revealed these modifications did not significantly affect N
      dealkylation and the formation of the piperidine 3. The second approach, however,
      yielded several piperidine replacements for 3, which did not show significant mu
      opioid activity. Several of these compounds maintained good affinity at the
      alpha(1a) adrenoceptor and selectivity over alpha(1b) and alpha(1d). For example,
      the piperidine fragments of (+)-73 and (+)-83, viz. 4-cyano-4-phenylpiperidine
      and 4-methyl-4-phenylpiperidine, were essentially inactive at the mu-opioid
      receptor (IC(50) > 30 microM vs 3 microM for 3). Compounds (+)-73 and (+)-83 were
      subjected to detailed in vitro and in vivo characterization. Both these
      compounds, in addition to their excellent selectivity (>880-fold) over alpha(1b)
      and alpha(1d), also showed good selectivity over several other recombinant human
      G-protein coupled receptors. Compounds (+)-73 and (+)-83 showed good functional
      potency in isolated human prostate tissues, with K(b)s comparable to their in
      vitro alpha(1a) binding data. In addition, compound (+)-73 also exhibited good
      uroselectivity (DBP K(b)/IUP K(b) > 20-fold) in the in vivo experiments in dogs,
      similar to 1a.

PMID- 10579842
TI  - Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 3.
      Approaches to eliminate opioid agonist metabolites by using substituted
      phenylpiperazine side chains.
AB  - Dihydropyrimidinones, such as 1, represent a novel class of alpha(1a)
      adrenoceptor antagonists with potential for the treatment of benign prostatic
      hyperplasia (BPH) (see part 1 of this series). Analysis of the metabolites of 1
      revealed that 4-methoxycarbonyl-4-phenylpiperidine is formed as the major
      metabolite and is an agonist at the mu-opioid receptor. To circumvent any
      potential liability resulting from the metabolite, we decided to identify
      alternate templates devoid of agonist activity at the mu-opioid receptor to
      replace the 4-methoxycarbonyl-4-phenylpiperidine moiety. The present study
      describes the synthesis and SAR of dihydropyrimidinones linked to substituted 4
      phenylpiperazine containing side chains. Compound (+)-38 was identified as a lead
      compound with a binding and functional profile comparable to that of 1. The
      putative metabolite 2-carboxamidophenylpiperazine has negligible affinity for the
      mu-opioid receptor.

PMID- 10579843
TI  - Design and synthesis of novel alpha(1)(a) adrenoceptor-selective antagonists. 4.
      Structure-activity relationship in the dihydropyrimidine series.
AB  - We have previously disclosed dihydropyridines such as 1a,b as selective alpha(1a)
      antagonists as a potential treatment for benign prostatic hyperplasia (BPH). The
      propensity of dihydropyridines toward an oxidation led us to find suitable
      replacements of the core unit. The accompanying papers describe the structure
      activity relationship (SAR) of dihydropyrimidinones 2a,b as selective alpha(1a)
      antagonists. We report herein the SAR of dihydropyrimidines such as 4 and
      highlight the similarities and differences between the dihydropyrimidine and
      dihydropyrimidinone series of compounds.

PMID- 10579844
TI  - Synthesis, physicochemical characterization, and biological evaluation of 2-(1'
      hydroxyalkyl)-3-hydroxypyridin-4-ones: novel iron chelators with enhanced pFe(3+)
      values.
AB  - The synthesis of a range of 2-(1'-hydroxyalkyl)-3-hydroxypyridin-4-ones as
      bidentate iron(III) chelators with potential for oral administration is
      described. The pK(a) values of the ligands and the stability constants of their
      iron(III) complexes have been determined. Results indicate that the introduction
      of a 1'-hydroxyalkyl group at the 2-position leads to a significant improvement
      in the pFe(3+) values. Such an effect was found to be greater with the
      hydroxyethyl substituent than with the hydroxymethyl substituent, particularly in
      the cases of 1-ethyl-2-(1'-hydroxyethyl)-3-hydroxypyridin-4-one (pFe(3+) = 21.4)
      and 1,6-dimethyl-2-(1'-hydroxyethyl)-3-hydroxypyridin-4-one (pFe(3+) = 21.5)
      where an enhancement on pFe(3+) values in the region of two orders of magnitude
      is observed, as compared with Deferiprone (1, 2-dimethyl-3-hydroxypyridin-4-one)
      (pFe(3+) = 19.4). The ability of these novel 3-hydroxypyridin-4-ones to
      facilitate the iron excretion in bile was investigated using a [(59)Fe]ferritin
      loaded rat model. Chelators and prodrug chelators possessing high pFe(3+) values
      show great promise in their ability to remove iron under in vivo conditions.

PMID- 10579845
TI  - Synthesis, acid-base behavior, and binding properties of 6-modified myo-inositol
      1,4,5-tris(phosphate)s.
AB  - myo-Inositol 1,4,5-tris(phosphate) was modified at position 6. The analogues
      synthesized are reported in this publication are 6-deoxy-myo-inositol 1,4,5
      tris(phosphate), 6-fluoro-6-deoxy-myo-inositol 1,4,5-tris(phosphate), epi
      inositol 1, 4,5-tris(phosphate), and 6-amino-6-deoxy-myo-inositol 1,4, 5
      tris(phosphate). These derivatives showed poor affinity for the Ins(1,4,5)P(3)
      receptors. The inframolecular acid-base behavior and the cooperative effects
      between the phosphate groups could help explain the loss of affinity of these 6
      modified analogues.

PMID- 10579846
TI  - Synthesis and pharmacology of site-specific cocaine abuse treatment agents: 2
      substituted-6-amino-5-phenylbicyclo[2.2.2]octanes.
AB  - A series of 2-substituted-6-amino-5-phenylbicyclo[2.2.2]octanes was synthesized
      and tested for inhibitor potency in [(3)H]WIN 35,428 (WIN) binding at the
      dopamine (DA) transporter and [(3)H]DA uptake assays. To demonstrate transporter
      selectivity for the compounds, inhibitor potency was also tested using
      [(3)H]nisoxetine and [(3)H]paroxetine binding assays for the norepinephrine (NE)
      and serotonin (5-HT) transporters, respectively. Synthesis was accomplished by
      bisannulation of the enamine derived from phenylacetaldehyde and dimethylamine
      with 2-cyclohexenone to give a mixture of endo- and exo-trans-6-amino-5
      phenylbicyclo[2.2. 2]octan-2-ones. The separated ketones were reduced to the four
      diastereomeric alcohols which were converted to acetyl and benzoyl esters. The
      ketones, alcohols, and acetyl esters generally have low affinity for the three
      transporters and do not effectively inhibit the uptake of [(3)H]DA. In all cases,
      the benzoates show significantly greater inhibition of WIN binding compared to
      the corresponding ketones, alcohols, or acetate esters. One compound, (1R/S,4R/S)
      6R/S-(N,N-dimethylamino)-5R/S-phenylbicyclo[2.2. 2]oct-2S/R-yl benzoate, is
      almost as potent as cocaine in binding to the DA transporter (IC(50) = 270 nM
      versus 159 nM for cocaine). The C-2 epimer, (1R/S,4R/S)-6R/S-(N, N-dimethylamino)
      5R/S-phenylbicyclo[2.2.2]oct-2R/S-yl benzoate, was selective and potent in
      binding to the 5-HT transporter (IC(50) = 53 nM versus 1050 nM for cocaine) as
      compared to the DA transporter (IC(50) = 358 nM). A preliminary molecular
      modeling study of the benzoyl esters indicates that their relative potencies in
      the WIN binding assay are not correlated to the nitrogen to benzoate phenyl
      (centroid) distance or to the deviation of the nitrogen from the plane defined by
      the benzoate ring.

PMID- 10579847
TI  - Discovery of a series of cyclohexylethylamine-containing protein
      farnesyltransferase inhibitors exhibiting potent cellular activity.
AB  - Synthesis of a library of secondary benzylic amines based on the Sebti-Hamilton
      type peptidomimetic farnesyltransferase (FTase) inhibitor FTI-276 (1) led to the
      identification of 6 as a potent enzyme inhibitor (IC(50) of 8 nM) which lacked
      the problematic thiol residue which had been a common theme in many of the more
      important FTase inhibitors reported to date. It has previously been disclosed
      that addition of o-tolyl substitution to FTase inhibitors of the general
      description 2 had a salutary effect on both FTase inhibition and inhibition of
      Ras prenylation in whole cells. Combination of these two observations led us to
      synthesize 7, a potent FTase inhibitor which displayed an IC(50) of 0.16 nM for
      in vitro inhibition of FTase and an EC(50) of 190 nM for inhibition of whole cell
      Ras prenylation. Modification of 7 by classical medicinal chemistry led to the
      discovery of a series of potent FTase inhibitors, culminating in the
      identification of 25 which exhibited an IC(50) of 0.20 nM and an EC(50) of 4.4
      nM. In vivo tests in a nude mouse xenograft model of human pancreatic cancer
      (MiaPaCa cells) showed that oral dosing of 25 gave rise to impressive attenuation
      of the growth of this aggressive tumor cell line.

PMID- 10579848
TI  - Structure-based design of selective inhibitors of dihydrofolate reductase:
      synthesis and antiparasitic activity of 2, 4-diaminopteridine analogues with a
      bridged diarylamine side chain.
AB  - As part of a larger search for potent as well as selective inhibitors of
      dihydrofolate reductase (DHFR) enzymes from opportunistic pathogens found in
      patients with AIDS and other immune disorders, N-[(2,4-diaminopteridin-6
      yl)methyl]dibenz[b,f]azepine (4a) and the corresponding
      dihydrodibenz[b,f]azepine, dihydroacridine, phenoxazine, phenothiazine,
      carbazole, and diphenylamine analogues were synthesized from 2, 4-diamino-6
      (bromomethyl)pteridine in 50-75% yield by reaction with the sodium salts of the
      amines in dry tetrahydrofuran at room temperature. The products were tested for
      the ability to inhibit DHFR from Pneumocystis carinii (pcDHFR), Toxoplasma gondii
      (tgDHFR), Mycobacterium avium (maDHFR), and rat liver (rlDHFR). The member of the
      series with the best combination of potency and species selectivity was 4a, with
      IC(50) values against the four enzymes of 0. 21, 0.043, 0.012, and 4.4 microM,
      respectively. The dihydroacridine, phenothiazine, and carbazole analogues were
      also potent, but nonselective. Of the compounds tested, 4a was the only one to
      successfully combine the potency of trimetrexate with the selectivity of
      trimethoprim. Molecular docking simulations using published 3D structural
      coordinates for the crystalline ternary complexes of pcDHFR and hDHFR suggested a
      possible structural interpretation for the binding selectivity of 4a and the lack
      of selectivity of the other compounds. According to this model, 4a is selective
      because of a unique propensity of the seven-membered ring in the
      dibenz[b,f]azepine moiety to adopt a puckered orientation that allows it to fit
      more comfortably into the active site of the P. carinii enzyme than into the
      active site of the human enzyme. Compound 4a was also evaluated for the ability
      to be taken up into, and retard the growth of, P. carinii and T. gondii in
      culture. The IC(50) of 4a against P. carinii trophozoites after 7 days of
      continuous drug treatment was 1.9 microM as compared with previously observed
      IC(50) values of >340 microM for trimethoprim and 0.27 microM for trimetrexate.
      In an assay involving [(3)H]uracil incorporation into the nuclear DNA of T.
      gondii tachyzoites as the surrogate endpoint for growth, the IC(50) of 4a after 5
      h of drug exposure was 0.077 microM. The favorable combination of potency and
      enzyme selectivity shown by 4a suggests that this novel structure may be an
      interesting lead for structure-activity optimization.

PMID- 10579849
TI  - Novel modifications in the alkenyldiarylmethane (ADAM) series of non-nucleoside
      reverse transcriptase inhibitors.
AB  - In an effort to obtain more insight into the interaction between HIV-1 reverse
      transcriptase and the alkenyldiarylmethanes (ADAMs), a new series of compounds
      has been synthesized and evaluated for inhibition of HIV-1 replication. The
      modifications reported in this new series include primarily changes to the
      alkenyl chain. The most potent compound proved to be methyl 3',3' '-dibromo-4',4'
      '-dimethoxy-5',5' '-bis(methoxycarbonyl)-6,6-diphenyl-5-hexenoate (28), which
      displayed an EC(50) of 1.3 nM for inhibition of the cytopathic effect of HIV
      1(RF) in CEM-SS cells. ADAM 28 inhibited HIV-1 reverse transcriptase with an
      IC(50) of 0.3 microM. Mutations that conferred greater than 10-fold resistance to
      ADAM 28 clustered at residues Val 106, Val 179, Tyr 181, and Tyr 188. Results
      derived from this series indicate that ADAMs containing chlorines in the aromatic
      rings might bind to HIV-1 reverse transcriptase in a slightly different mode when
      compared with those analogues incorporating bromine in the aromatic rings.

PMID- 10579850
TI  - Fused bicyclic Gly-Asp beta-turn mimics with specific affinity for GPIIb-IIIa.
AB  - Disubstituted isoquinolones 2 and 3 have affinity for GPIIb-IIIa and represent
      leads for further structural evaluation. Structure-activity studies centered on
      the bicyclic beta-turn mimic contained in these molecules indicated that this
      moiety could accommodate a variety of modifications. Specifically, monocyclic, 6,
      5-bicyclic, and 6,7-bicyclic structures provide compounds with affinity for GPIIb
      IIIa. Within the 6,6-series, isoquinoline, tetralin, tetralone, and benzopyran
      nuclei yield potent antagonists that are specific for GPIIb-IIIa. Attachment of
      the arginine isostere (benzamidine) to the supporting nucleus can be accomplished
      with an ether or amide linkage, although the latter enhances activity. Several
      compounds in this series provided measurable blood levels after oral dosing.
      Conversion of the acid moiety in these molecules to an ester generally provided
      compounds which gave greater systemic exposure after oral administration.
      Absolute bioavailabilities in the rat for the ethyl ester prodrug derivatives of
      the tetralin, tetralone, and benzopyran analogues of 3 were 28%, 23%, and 24%,
      respectively.

PMID- 10579851
TI  - New alpha-substituted succinate-based hydroxamic acids as TNFalpha convertase
      inhibitors.
AB  - Tumor necrosis factor alpha convertase (TACE), the enzyme responsible for the
      processing of pro-TNFalpha to TNFalpha, has been reported to be a
      metalloproteinase closely related to matrix metalloproteinases (MMPs). Current
      inhibitors of TACE such as succinate-based hydroxamic acids exemplified by
      Marimastat (TACE IC(50): 3.8 nM; blood IC(50): 7 microM) and BB1101 (TACE IC(50):
      0.2 nM; blood IC(50): 2.3 microM) suffer from modest potency in blood and poor in
      vivo properties. The introduction of new bulky alpha-substituents into these
      succinate-based hydroxamic acids was studied. Substituents such as thioethers,
      sulfonamides, and ethers showed improved potency against TACE when compared with
      Marimastat. Although this improvement did not translate into better blood potency
      for thioether or ether substituents, the sulfonamide series exhibited improved
      potency both against TACE and in blood when compared with Marimastat.
      Optimization of this sulfonamide series has culminated in the identification of
      heterocyclic bicyclic sulfonamides such as 3t (TACE IC(50): 0.57 nM; blood
      IC(50): 0.28 microM).

PMID- 10579852
TI  - Synthesis and biological evaluation of a potent E-selectin antagonist.
AB  - An early step of the inflammatory response-the rolling of leukocytes on activated
      endothelial cells-is mediated by selectin/carbohydrate interactions. The
      tetrasaccharide sialyl Lewis(x) (sLe(x)) 1 is a ligand for E-, P-, and L-selectin
      and, therefore, serves as a lead structure to develop analogues which allow the
      control of acute and chronic inflammation. Here we describe the efficient
      synthesis (10 linear steps) of the potent sLe(x) mimetic 2. Compared to sLe(x),
      compound 2 showed a 30-fold improved affinity in a static, cell-free E-selectin
      ligand binding assay (IC(50) = 36 microM). These data were confirmed by a marked
      inhibition in an in vitro cell-cell rolling assay which simulates in vivo
      conditions (IC(50) approximately 40 microM). The assays are predictive for the in
      vivo efficacy of test compounds as indicated by a marked inhibitory effect of 2
      in a thioglycollate induced peritonitis model of acute inflammation in mice
      (ED(50) approximately 15 mg/kg).

PMID- 10579853
TI  - Synthesis and human neurotensin receptor binding activities of neurotensin(8-13)
      analogues containing position 8 alpha-azido-N-alkylated derivatives of ornithine,
      lysine, and homolysine.
AB  - A series of neurotensin(8-13) (NT) analogues were synthesized through
      intermediates in which the N-terminal Arg(8) was replaced by various omega-bromo
      2(S)-azido residues spanning 3-5 methylene units in side-chain length. Subsequent
      nucleophilic substitution of the omega-bromo groups with ammonia, methylamine,
      dimethylamine, or trimethylamine provided peptides containing N-terminal 2(S)
      azido residues containing primary through quaternary N-alkylated side chains
      corresponding in length to ornithine, Lys, and homolysine. The synthetic
      procedure appears applicable for incorporation of a wide variety of amine
      containing nonnatural amino acids into peptides. The particular modifications
      were intended to enhance physiochemical properties of NT(8-13) responsible for
      human NT 1 receptor (hNTR) binding, overall lipophilicity, and stability that may
      influence the potency of the peptides in vivo. When the peptides were tested for
      hNTR binding, the affinities in each series followed the order primary >
      secondary > tertiary > quaternary amine with the homolysine side-chain length
      being favored. All analogues possess binding affinities between acetyl-NT(8-13)
      and NT(8-13) indicating that the sterically less bulky alpha-azido may be
      inherently preferable to the acetyl group for N-terminal protection. This study
      extends the strategy of modifying amine-containing drugs through alkylations to
      peptide modification. The set of alkylated side chains also offers a new method
      of steric selection between receptor subtypes and could be used to modify the
      properties and biological effects of any peptide that contains cationic residues.

PMID- 10579854
TI  - Paclitaxel derivatives for targeted therapy of cancer: toward the development of
      smart taxanes.
AB  - The pharmacologic efficacy of the promising antitumor agent paclitaxel (Taxol)
      may be potentially enhanced through derivatization of the drug to a water-soluble
      tumor-recognizing conjugate. This work reports the design and synthesis of the
      first tumor-directed derivative of paclitaxel. A 7-amino acid synthetic peptide,
      BBN[7-13], which binds to the cell surface bombesin/gastrin-releasing peptide
      (BBN/GRP) receptor, was conjugated to the paclitaxel-2'-hydroxy function by a
      heterobifunctional poly(ethylene glycol) linker. The resulting conjugate,
      designated PTXPEGBBN[7-13], was soluble to the upper limit of tested
      concentrations (250 mg/mL). The conjugate completely retained the receptor
      binding properties of the attached peptide as compared with those of the
      unconjugated BBN[7-13]. In experiments with NCI-H1299 human nonsmall cell lung
      cancer cells, the cytotoxicity of the PTXPEGBBN[7-13] conjugate at a 15 nM dose
      was enhanced by a factor of 17.3 for 24 h and 10 for 96 h exposure times,
      relative to paclitaxel. The IC(50) of the conjugate, tested against the same cell
      line, was lower than the free drug by a factor of 2.5 for both 24 h and 96 h
      exposures. These results describe, for the first time, the design and synthesis
      of a soluble tumor-directed paclitaxel prodrug which may establish a new mode for
      the utilization of this drug in cancer therapy.

PMID- 10579855
TI  - Dihydrochalcones and flavonolignans from Iryanthera lancifolia.
AB  - An extract from the pericarps of I. lancifolia afforded two dihydrochalcones (1
      and 2) and two flavonolignans (3 and 4), with compounds 2-4 being of novel
      structure. The antioxidant activities of compounds 1-4 were evaluated through the
      measurement of malondialdehyde production, and Q(1/2) (concentration necessary
      for 50% inhibition of autoxidation) data were calculated. The Q(1/2) values
      obtained for 1-4 and the standard compounds alpha-tocopherol and quercetin were
      6.9, 4.7, 5.5, 4.8, 12.1, and 7.6 microg/mL, respectively.

PMID- 10579856
TI  - Novel highly oxygenated bisabolane sesquiterpenes from Cremanthodium discoideum.
AB  - Five new highly oxygenated bisabolane sesquiterpenes (1-5) were isolated from
      Cremanthodium discoideum. Their structures were elucidated on the basis of
      spectroscopic analysis and chemical transformations. The structure and relative
      stereochemistry of 1 were determined by single-crystal X-ray crystallography on
      the acetate derivative, 1a. Compound 1 showed antibacterial activity against
      Bacillus acidilatici and Bacillus subtilis.

PMID- 10579857
TI  - New biphenyl compounds with DNA strand-scission activity from Clusia paralicola.
AB  - Three new biphenyl derivatives, clusiparalicolines A (1), B (2), and C (3), were
      isolated from the roots of Clusia paralicola by bioassay-directed fractionation
      using the DNA strand-scission and the KB human cancer cell line cytotoxicity
      assays. Compounds 1 and 2 were found to be active in the DNA strand-scission
      assay, whereas all three compounds exhibited modest cytotoxicity against the KB
      cell line. The structures of 1-3 were elucidated by spectroscopic methods
      including 1D and 2D NMR techniques.

PMID- 10579858
TI  - Synthesis of 11,12-epoxydrim-8,12-en-11-ol, 11,12-diacetoxydrimane, and
      warburganal from (-)-sclareol.
AB  - The first syntheses are reported for recently isolated drimanes 11, 12-epoxydrim
      8,12-en-11-ol (2) and 11,12-diacetoxydrimane (3), from (-)-sclareol (1).
      Furthermore, two efficient new routes to the potent bioactive warburganal (4)
      starting also from 1 are described.

PMID- 10579859
TI  - Configurative correlation and conformational analysis of strictosidine and
      vincoside derivatives
AB  - On the basis of the configuration of C-15 of the secologanin unit, using detailed
      NMR analysis, the configuration of C-3, the solution conformation around C-14,
      and the glucosidic bridge, as well as those of the dihydropyran and
      tetrahydropyridine rings, were determined in the vincosamide and strictosamide
      derivatives 4b and 5b. The stereochemical analysis was extended by chemical
      correlation to the 4-benzylated strictosidine and vincoside derivatives 3c and
      3d. Experimental proof was presented for the interpretation of the "anomalous"
      chemical shift of acetylated strictosamide derivatives.

PMID- 10579860
TI  - Phenolic compounds from tournefortia sarmentosa
AB  - Three new isoprenylbenzenes, tournefolins A (1), B (2), and C (3), and two new 2
      ethoxy-4,5-dihydroxybenzoyl compounds, 4 and 5, together with the known
      compounds, salicylic acid and allantoin, were isolated from the stems of
      Tournefortia sarmentosa. The structures of new compounds were elucidated as 2
      (4beta-methyltetrahydrofuran-2alpha-yl)-5-(4beta-methyltetrahydrofu ran-2beta-yl)
      1,4-dihydroxybenzene (1), methyl 5-(5-hydroxy-2-methoxyphenyl)-3-furoate (2),
      methyl 5-(2, 5-dihydroxyphenyl)-3-furoate (3), 2-ethoxy-4,5-dihydroxybenzaldehyde
      (4), and 2-ethoxy-4,5-dihydroxybenzoic acid (5), on the basis of spectral and
      chemical methods. The relative configuration of 1 was determined by single
      crystal X-ray crystallography.

PMID- 10579861
TI  - Sesterterpenoids and diterpenoids of the wax excreted by a scale insect,
      Ceroplastes pseudoceriferus.
AB  - A new sesterterpene, (2Z,6Z,10E)-cericerene-15,24-diol (1), and its 30
      hydroxytriacontanoate (2) were isolated from the wax exuded by the scale insect
      Ceroplastes pseudoceriferus, together with the acetates and 30
      hydroxytriacontanoates of 3,15-dihydroxy- and 15, 20-dihydroxylabda-7,13-diene (3
      6). The absolute configurations of the labdadiene alcohols were antipodal to the
      ordinary labdanes isolated from terrestrial plants.

PMID- 10579862
TI  - Anti-HIV-1 protease triterpenoid saponins from the seeds of Aesculus chinensis.
AB  - Eight bioactive triterpenoid saponins (1-8) were isolated from the seeds of
      Aesculus chinensis, four of which are novel compounds. The major saponins were
      identified as escin Ia (1), Ib (2), isoescin Ia (3) and Ib (4), while the new
      compounds were identified as 22alpha-tigloyl-28-acetylprotoaescigenin-3beta-O
      ?beta -D-glucopyranos yl (1-2) ?beta-D-glucopyranosyl (1-4)-beta-D
      glucopyranosiduronic acid (escin IVc, 5), 22alpha-angeloyl-28
      acetylprotoaescigenin-3beta-O-?bet a-D-glucopyrano syl (1-2) ?beta-D
      glucopyranosyl (1-4)-beta-D-glucopyranosiduronic acid (escin IVd, 6), 28
      tigloylprotoaescigenin-3beta-O-?beta-D-glucopyranosyl (1-2) ?beta-D
      glucopyranosyl (1-4)-beta-D-glucopyranosiduronic acid (escin IVe, 7), and 28
      angeloylprotoaescigenin-3beta-O-?beta-D-glucopyranosyl (1-2) ?beta-D
      glucopyranosyl (1-4)-beta-D-glucopyranosiduronic acid (escin IVf, 8). The
      structures were determined by chemical and spectroscopic methods. All the above
      compounds were evaluated for their inhibitory activity against HIV-1 protease.

PMID- 10579863
TI  - Limonoids from Swietenia macrophylla and S. aubrevilleana.
AB  - An investigation of the seeds of Swietenia macrophylla and S. aubrevilleana
      (Meliaceae) is reported. Three new compounds, augustineolide (1) and 3beta,6
      dihydroxydihydrocarapin (2) from S. macrophylla and 6-acetoxyhumilinolide C (3)
      from S. aubrevilleana were isolated and characterized along with fifteen known
      compounds. Four of the compounds were subjected to an antifeedant bioassay on the
      final instar larvae of Spodoptera frugiperda. The antifeedant activity was
      comparable to that of bicyclononanolides previously tested.

PMID- 10579864
TI  - Cytotoxic terpenoids from the Formosan soft coral Nephthea brassica.
AB  - Two new cytotoxic cembranoid diterpenes, brassicolide (1) and brassicolide
      acetate (2); a new cytotoxic sesquiterpene, (-)-4alpha-O-acetyl-selin-11-en (3);
      and six cytotoxic terpenoids, (-)-selin-11-en-4alpha-ol (4), 2-hydroxynephthenol
      (5), nephthenol (6), cembrene A (7), epoxycembrene A (8), and (-)-beta-elemene
      (9), have been isolated from the Formosan soft coral Nephthea brassica. The
      structures of compounds 1-9 were determined by spectral, chemical, and X-ray
      crystallographic analysis.

PMID- 10579865
TI  - Immunosuppressive diterpenoids from Tripterygium wilfordii.
AB  - A clinically used extract of Tripterygium wilfordii afforded three new
      diterpenoids-3beta,19-dihydroxyabieta-8,11,13-triene (triptobenzene L) (1); 12,19
      dihydroxy-3-oxoabieta-8,11,13-triene (triptobenzene M) (2); and 19-hydroxy-3,7
      dioxo-abieta-8,11, 13-triene (triptobenzene N) (3)-along with 14 known
      diterpenoids. The structures of 1-3 were established on the basis of
      spectroscopic studies. Of the known compounds, the stereochemistry at C-4 of
      triptonediol (4) was reassigned. Tripterifordin (8) and 13-epi-manoyl oxide-18
      oic acid (9) showed significant inhibitory effects on cytokine production.

PMID- 10579866
TI  - Polyphenolic glycosides from african proteaceae
AB  - The phytochemical investigation of members of the genus Protea afforded a series
      of polyphenolic compounds (1-5) that were identified by 1D and 2D NMR
      experiments. Of these, 2-5 are new compounds. Chemical syntheses of 1-3 were
      performed in order to confirm the structures and to prepare additional material
      for biological evaluation.

PMID- 10579867
TI  - Diterpenes from the fruits of Vitex rotundifolia.
AB  - Eight new labdane-type diterpenes (1-8) were isolated from the fruit of Vitex
      rotundifolia along with two known abietane-type diterpenoids (9, 10), and their
      structures were characterized on the basis of spectroscopic data and X-ray
      crystallographic analysis. Among them, the abietane-type diterpenoid ferruginol
      (9) exhibited a stronger antioxidative activity than the standard antioxidant, 3
      tert-butyl-4-hydroxyanisole (BHA), using a ferric thiocyanate method.

PMID- 10579868
TI  - Four new steroids from two octocorals
AB  - In search of analogues of isogosterones A-D (1-4), a group of antifouling 13,17
      seco-steroids found in octocorals of the order Alcyonacea, we have isolated four
      new steroids possessing aromatic, enone, or dienone A-rings from two octocorals,
      Alcyonium gracillimum and Dendronephthya sp. These compounds, 3-methoxy-19
      norpregna-1,3, 5(10),20-tetraene (5), 3-(4-O-acetyl-6-deoxy-beta
      galactopyranosyloxy)-19-norpregna-1,3, 5(10),20-tetraene (6), 22,23
      dihydroxycholesta-1,24-dien-3-one (7), and methyl 3-oxochola-4,22-dien-24-oate
      (8), showed no antifouling activity against barnacle (Balanus amphitrite) larvae,
      but lethality to barnacle larvae at a concentration of 100 &mgr;g/mL (LD(100)).

PMID- 10579869
TI  - Characterization of new illudanes, illudins F, G, and H from the basidiomycete
      omphalotus nidiformis
AB  - This investigation reports the isolation and characterization of three new
      illudane-type sesquiterpenes (1-3) from Omphalotus nidiformis, a Basidiomycete
      native to Australia and usually found in eucalypt forests in the eastern region
      of the country. These compounds are closely related to metabolites of North
      American and European Omphalotus species.

PMID- 10579871
TI  - O- and N-methylation in the biosynthesis of staurosporine.
AB  - The feeding of (13)C- and (2)H-enriched methionine to Streptomyces staurosporeus
      established that the methyl carbon and proton source of both the 3'-O- and 4'-N
      methyl groups of staurosporine (1) was methionine and that all three methyl
      protons from methionine were retained on 1. In the presence of the
      methyltransferase inhibitor, sinefungin, the biosynthesis of staurosporine was
      blocked at the last step, O-methylation. An intermediate, 3'-demethoxy-3'
      hydroxystaurosporine (2), was efficiently accumulated in the medium. Other
      general methyltransferase inhibitors failed to produce any other staurosporine
      intermediates or analogues.

PMID- 10579870
TI  - Cytotoxic sesquiterpenoids from Ratibida columnifera.
AB  - Bioassay-directed fractionation of the flowers and leaves of Ratibida columnifera
      using a hormone-dependent human prostate (LNCaP) cancer cell line led to the
      isolation of 10 cytotoxic substances, composed of five novel xanthanolide
      derivatives (2-4, 7, and 8), a novel nerolidol derivative (9), and three known
      sesquiterpene lactones, 9alpha-hydroxy-seco-ratiferolide-5alpha-O-angelate+ ++
      (1), 9alpha-hydroxy-seco-ratiferolide-5alpha-O-(2-methylbut yrate) (5), 9-oxo
      seco-ratiferolide-5alpha-O-(2-methylbutyrate) (6), as well as a known flavonoid,
      hispidulin (10). On the basis of its cytotoxicity profile, compound 5 was
      selected for further biological evaluation, and was found to induce G1 arrest and
      slow S traverse time in parental wild type p53 A2780S cells, but only G2/M arrest
      in p53 mutant A2780R cells, with strong apoptosis shown for both cell lines. The
      activity of 5 was not mediated by the multidrug resistance (MDR) pump, and it was
      not active against several anticancer molecular targets (i.e., tubulin
      polymerization/depolymerization, topoisomerases, and DNA intercalation). While
      these results indicate that compound 5 acts as a cytotoxic agent via a novel
      mechanism, this substance was inactive in in vivo evaluations using the murine
      lung carcinoma (M109) and human colon carcinoma (HCT116) models.

PMID- 10579872
TI  - Lyso-PAF analogues and lysophosphatidylcholines from the marine sponge
      Spirastrella abata as inhibitors of cholesterol biosynthesis.
AB  - A series of phospholipids, including previously undescribed compounds 4-7, were
      isolated by a bioactivity-guided fractionation from the marine sponge
      Spirastrella abata as inhibitors of cholesterol biosynthesis in human liver
      cells. These compounds were identified as lyso-PAF analogues (1-5) and
      lysophosphatidylcholines (6, 7) based on NMR and MS analyses. Compounds 1-7
      specifically blocked the conversion of lanosterol into cholesterol in the Chang
      liver cell.

PMID- 10579874
TI  - Methylsulfomycin I, a new cyclic peptide antibiotic from a Streptomyces sp. HIL Y
      9420704.
AB  - Methylsulfomycin I (1) is a new cyclic peptide antibiotic isolated from the
      fermentation broth of a Streptomyces sp. HIL Y-9420704. Its structure was
      elucidated by NMR and GC-MS. The in vitro activity (MIC) against a wide range of
      Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus
      (MRSA) and vancomycin-, and teicoplanin-resistant strains, is described.

PMID- 10579873
TI  - Phenolic glycosides from Dirca palustris.
AB  - Five novel phenolic glycosides (1-5) were isolated from the MeOH extract of the
      dried twigs of Dirca palustris, as confirmed by their (1)H NMR, (13)C NMR, and MS
      data. Compounds 1-3 were not active against cyclooxygenase I (COX-I), but
      compound 4 (200 microg/mL) and compound 5 (125 microg/mL) showed 12.5 and 9.2%
      inhibition of the COX-I enzyme, respectively. Compounds 1-5 did not exhibit
      cyclooxygenase II (COX-II) enzyme inhibition. Compound 5 did not show any
      antioxidant activity using the liposome assay; however, compounds 1-4 displayed
      antioxidant activity at 60 microg/mL, with compound 2 being the most efficacious.

PMID- 10579875
TI  - A revised structure for (-)-dihydropertusaric acid, a gamma-butyrolactone acid
      from the lichen punctelia microsticta
AB  - The gamma-butyrolactone acid (1) and two known compounds, (-)-isomuronic acid and
      the tridepside gyrophoric acid, have been isolated from the lichen Punctelia
      microsticta. The structure and stereochemistry of compound 1 were determined on
      the basis of spectroscopic evidence and molecular modeling. Spectroscopic and
      physical data of 1 and (-)-dihydropertusaric acid, previously isolated from the
      lichen Pertusaria albescens, showed that both are the same compound, although for
      the latter the epimeric structure 2 has been proposed.

PMID- 10579876
TI  - Novel radicinol derivatives from long-term cultures of alternaria chrysanthemi
AB  - Cultures of Alternaria chrysanthemi normally produce radicinin (1) and radicinol
      (2) when cultured on Czapek-Dox medium or on potato dextrose broth. We have
      observed that long-term cultures of A. chrysanthemi grown on malt-extract broth
      produce 3-epiradicinol (3), the novel metabolites 3-methoxy-3-epiradicinol (4)
      and 9, 10-epoxy-3-methoxy-3-epiradicinol (5), and (2).

PMID- 10579877
TI  - African elephant sesquiterpenes.
AB  - GC-MS analysis of extracts from temporal gland secretions of an African elephant
      has revealed the presence of several farnesol-related sesquiterpenes. Among these
      are (E)-2, 3-dihydrofarnesol (3), a bumblebee pheromone not seen before in
      mammals, and a rare component of a Greek tobacco, drimane-8alpha, 11-diol (4),
      never observed before in an animal.

PMID- 10579878
TI  - 6-Methoxy-7-methyl-8-oxoguanine, an unusual purine from the ascidian Symplegma
      rubra.
AB  - A new purine derivative, 6-methoxy-7-methyl-8-oxoguanine (1), along with 8
      oxoadenine (2) and the human metabolite 3-methylxanthine (3), has been isolated
      from the ascidian Symplegma rubra collected on the southeastern coastline of
      Brazil. The structures of the three purines were established by analysis of
      spectroscopic data.

PMID- 10579879
TI  - Sesquiterpene polyol esters from the leaves of maytenus macrocarpa
AB  - The aerial parts of Maytenus macrocarpa yielded three new beta-dihydroagarofuran
      sesquiterpene polyol esters. Their structures were elucidated by spectroscopic
      analyses including 2D NMR techniques as 6beta,8beta,15-triacetoxy-1alpha, 9alpha
      dibenzoyloxy-4beta-hydroxy-beta-dihydroagarofuran (1); 1alpha, 6beta,8beta, 15
      tetraacetoxy-9alpha-benzoyloxy-4beta-hydroxy-beta-dihydroagarofura n (2) and
      (1S,4S,6R,7R,8R,9R)-1,6,15-triacetoxy-8, 9-dibenzoyloxy-4-hydroxy-beta
      dihydroagarofuran (3). Compounds 1 and 2 showed marginal antitumor activity
      against four cell lines.

PMID- 10579880
TI  - UV-Guided isolation of verrucines A and B, novel quinazolines from penicillium
      verrucosum structurally related to anacine from penicilliumaurantiogriseum
AB  - Two novel quinazolines, verrucines A (1) and B (2), have been isolated as a major
      and a minor metabolite, respectively, of Penicillium verrucosum. Both are
      condensates of one mole each of anthranilic acid, phenylalanine, and glutamine.
      The structures were elucidated by spectroscopic methods, and the two compounds
      were found to be epimers. The spectroscopic data for the ostensible
      benzodiazepine anacine reported from Penicillium aurantiogriseum, composed of one
      mole each of anthranilic acid, leucine, and glutamine, appeared very similar to
      those of 1. Therefore, a revised quinazoline structure for anacine is proposed.

PMID- 10579881
TI  - Mukanadins A-C, new bromopyrrole alkaloids from marine sponge agelasnakamurai
AB  - Three new bromopyrrole alkaloids, mukanadins A-C (1-3), have been isolated from
      the Okinawan marine sponge Agelas nakamurai, and the structures were elucidated
      from spectroscopic data.

PMID- 10579882
TI  - Two new 19-oxygenated polyhydroxy steroids from the soft coral nephthea
      chabroli(1)
AB  - Two new 19-oxygenated polyhydroxy steroids, 24-methylene cholest-5-en
      1alpha,3beta,19-triol (1) and 24-methylene cholest-5-en-3beta,7beta,9alpha,19
      tetrol (2), and three known steroids, ergost-5,24(28)-dien-3beta,19-diol
      (litosterol), cholest-5-en-3beta,7beta,19-triol, and ergost-5,24 (28)-dien-3beta,
      7beta,19-triol, have been isolated from the soft coral Nephthea chabroli and
      characterized through interpretation of spectral data.

PMID- 10579884
TI  - Phytomedicines: back to the future.

PMID- 10579883
TI  - Squarroside C, a new cycloartene bisdesmoside from Thalictrum squarrosum.
AB  - Squarroside C (1), a new cycloartane 3,21-bisdesmoside, was isolated from the
      above-ground parts of Thalictrum squarrosum. The structure of 1 was established
      as 3-O-[O-alpha-L-rhamnopyranosyl-(1-->6)-beta-D-glucopyranosyl]-21-O-be ta-D
      glucopyranosyl-21(S),22(S),23(R),3beta,21alpha,22beta, 30-tetrahydroxy-21,23
      epoxycycloart-24-ene by 2D NMR spectroscopy and FABMS.

PMID- 10579885
TI  - Family relations in adolescence.

PMID- 10579886
TI  - Supportive parenting and adolescent adjustment across time in former East and
      West Germany.
AB  - Using a 3-year longitudinal data set, we examined the effects of consistently
      versus inconsistently supportive parenting on several aspects of adolescent
      adjustment. Supportive parenting was a multidimensional construct which included
      parental sensitivity, predictability and involvement. The sample consisted of 283
      German early adolescents (mean age=11.4 years, S.D.=1.2 at time 1) from former
      East (n=97) and West (n=186) Germany. As hypothesized, adolescents who reported
      their parents to be consistently supportive (e.g. supportive for at least two
      points in time) had lower levels of depression and delinquency, higher levels of
      self-efficacy and did better in school over the 3-year period than adolescents
      who reported their parents to be inconsistently supportive (e.g. supportive at
      only one time point or less). The results showed that there were no significant
      interactions between region and supportive parenting, indicating that the effects
      of consistently supportive parenting "worked" in a similar manner in both
      contexts of former East and West Germany. Results also reveal that supportive
      parenting is not necessarily a stable phenomenon, but may fluctuate from year to
      year.

PMID- 10579887
TI  - To know you is to trust you: parents' trust is rooted in child disclosure of
      information.
AB  - As adolescents spend increasing amounts of time away from home, parental trust
      should become important. Little is known about how trust develops, however. We
      propose that parental trust is primarily based on knowledge. In this study, we
      pitted three types of knowledge of the child against each other in the prediction
      of parental trust: knowledge of feelings and concerns; of past delinquency; and
      of daily activities. Results showed that knowledge of daily activities was more
      important than knowledge of past delinquency. In further analyses, knowledge of
      daily activities that came from the child's spontaneous disclosure was most
      closely linked to parental trust. These findings add support to a recent re
      interpretation of parental "monitoring" as parental knowledge that mainly comes
      from spontaneous child disclosure. Additionally, the role of parental trust for
      dysfunctional family relations was examined and it was found that the relations
      between the child's delinquency and family dysfunction were mediated by parental
      trust. Finally, even though there was substantial agreement between parents and
      children about parental trust in the child, the individual's unique perspectives
      were important. Family dysfunction from the child's perspective was based on
      whether they believed that their parents trusted them, and parental perceptions
      of family dysfunction were based on their own trust in the child.

PMID- 10579888
TI  - Emotional autonomy, psychosocial adjustment and parenting: interactions,
      moderating and mediating effects.
AB  - Following inconsistent results on the developmental outcomes of emotional
      autonomy, this study examined the consequences of emotional and behavioural
      autonomy for different aspects of psychosocial adjustment in the context of the
      parenting process as perceived by the adolescent. Measures of emotional autonomy,
      behavioural autonomy, perceived parenting and various aspects of psychosocial
      adjustment were completed by a sample of 558 adolescent boys and girls (aged 12
      17 years) from the Dutch-speaking part of Belgium. A continuous measure of
      authoritativeness was constructed for this study. Correlations revealed that
      authoritativeness was associated with a positive pattern of adjustment, while
      autonomy was associated with a negative pattern of adjustment, except for self
      reliance. Analyses indicated that authoritativeness and autonomy did not interact
      to produce mean differences in adjustment. Further, hierarchical multiple
      regression analyses showed that it was only for self-reliance that the
      interaction between emotional autonomy and authoritativeness explained
      significantly more variance than a model that comprised only the main effects.
      Finally, path analysis clarified the difference between emotional and behavioural
      autonomy, in that emotional autonomy predicted only higher levels of internal
      distress, while behavioural autonomy predicted only lower school grades and
      higher levels of deviant behaviour, at least when authoritativeness was
      partialled out. These results reveal that it is useful to study autonomy and its
      developmental outcomes in the broader family context, but they also reveal the
      limitations of such an approach.

PMID- 10579889
TI  - Autonomy, attachment and psychosocial adjustment during adolescence: a double
      edged sword?
AB  - Both autonomy and attachment are positively related to psychosocial adjustment
      during adolescence. The aim of the present study was to examine the assumption
      that a high level of autonomy within a context of attachment provides the best
      constellation for psychosocial adjustment. Subjects were 400 adolescents.
      Attitudinal, emotional and functional autonomy were connected with attachment to
      father, mother and peers to predict indices of psychosocial adjustment: social
      competence, academic competence, self-esteem, problem behaviour and depressive
      mood. Only main effects of autonomy and attachment were found. There was no
      evidence for an extra positive effect of being both autonomous and strongly
      attached.

PMID- 10579890
TI  - Parent-child communication and adolescent self-esteem in separated, intercountry
      adoptive and intact non-adoptive families.
AB  - The purpose of the present study was to verify whether there are some differences
      in parent-child communication and in adolescent self-esteem among adoptive,
      separated and intact non-adoptive families and to investigate the extent to which
      parent-child communication is related to adolescent self-esteem in the three
      types of families. The study sample was composed of 450 adolescents aged between
      11 and 17 years (160 from intact non-adoptive families, 140 from separated or
      divorced families and 150 from intercountry adoptive families). Subjects
      completed the Parent-Adolescent Communication Scale by Barnes and Olson, the
      Rosenberg Self-esteem Scale and some socio-demographic items. The results show
      that adolescents from separated families have more difficulties in their
      relationships with both the mother and the father than their peers, and that
      adoptive children perceive a more positive communication with their parents than
      biological children. Moreover, adoptees showed lower self-esteem than the other
      two groups of adolescents. Lastly, it emerged that male and female adolescents'
      self-esteem is related to positive communication with both parents in intact non
      adoptive families, while no link was significant for male and female children of
      divorced parents or for adoptees.

PMID- 10579891
TI  - Differential trajectories of parent-child relationships and psychosocial
      adjustment in adolescents.
AB  - In this 2-year longitudinal study, trajectories of family development during the
      second half of adolescence were examined. Cluster analyses of 208 adolescents'
      reports of family connectedness and individuality yielded three groups: families
      who were constantly high on connectedness and individuality, families who were
      high on connectedness and showed an increase in individuality over time and
      families who were higher on individuality than connectedness at every point in
      time. Adolescents in the latter group had higher levels of aggressiveness and
      depressive mood than those in the other two types of families. Findings are
      discussed with reference to theories of family individuation in adolescence.

PMID- 10579892
TI  - Parental attachment and identity in Portuguese late adolescents.
AB  - Based on a life-span attachment perspective and on identity status paradigm, this
      study investigated the relationship between attachment and identity in a sample
      of 361 Portuguese late adolescents as a function of parental and adolescent
      gender. The results indicated gender differences in the association between
      attachment variables and identity foreclosure. Although adolescents tended to
      report close emotional bonds with both parents, relationships with mothers seemed
      to play an important role in the tendency for foreclosure identity in boys.
      Adolescents who were in diffusion reported the least secure parental attachment
      and experienced the least separation anxiety. Parental inhibition of exploration
      and individuality, as perceived by adolescents, did not correlate with the
      identity dimensions.

PMID- 10579893
TI  - Relational support and person characteristics in adolescence.
AB  - In this paper, an heuristic model of the personality characteristics of
      adolescents and the supportive dimensions of interactions, relationships and
      groups is presented. The model takes the concept of developmental tasks as its
      starting point and it is assumed that developmental tasks can be characterized in
      terms of four modalities: intentions, behaviour, cognitions and affect. The same
      four modalities can also be used to characterize dimensions of personality and
      aspects of interactional and relational support. The results of several empirical
      studies are presented to illustrate the model. Together, these studies present a
      transactional picture of the personality of adolescents and their relationships
      in which personality and relationships influence each other and jointly determine
      psychosocial functioning.

PMID- 10579894
TI  - The importance of importance: adolescents' perceptions of parental communication
      about sexuality.
AB  - High-schoolers (n=298) completed surveys describing the frequency and importance
      of mother and father communication about 20 different sex-related topics. There
      were four domains of sex-related topics: Development and Societal Concerns,
      Sexual Safety, Experiencing Sex, and Solitary Sexual Activity. Adolescents
      reported infrequent communication which varied by domain and gender of parent and
      teen. When communication occurred, it was most frequently about the first two
      domains. Mothers were reported as more frequent communicators about sexuality
      than fathers and girls received more communication than boys. Young people rated
      parental communication about sexuality as unimportant, with findings that
      paralleled those for frequency. Examination of the match between frequency and
      perceived importance of parental communication revealed more matches than
      mismatches. Almost all matches resulted from responses indicating low frequency
      and little importance. Most mismatches reflected a perception of insufficient
      rather than excessive parental communication about sexuality. It is argued that
      we need to consider the relative importance given to parental communication, as
      well as its frequency, if parents are to be effective communicators.

PMID- 10579895
TI  - Conflict management of mothers and daughters belonging to individualistic and
      collectivistic cultural backgrounds: a comparative study.
AB  - Research on the mother-daughter relationship during adolescence is mostly
      conducted in Western and European cultures where individualism is stressed. To
      examine ethnic/cultural differences and similarities in this relationship, 80
      dyads of British (white) and Pakistani mothers and their adolescent daughters
      were studied. On the basis of the theories of cultural variability dimension and
      conflict face negotiation, it was hypothesized that mothers and daughters from
      the two cultures would use different styles of handling disagreements/conflicts.
      That is, Pakistani mothers and daughters would use an avoiding style, whereas
      British mothers and daughters would use either a dominating or compromising
      style, to a greater degree. It was also argued that Pakistani daughters and
      mothers will express more intimacy and relational harmony, will exhibit greater
      connectedness and mutuality and demonstrate lesser individuality and self
      assertion compared to their British counterparts. However, it appeared that both
      the groups used an avoiding style equally, although the British group used a
      dominating style more than Pakistani group. As hypothesized, Pakistani mothers
      and daughters expressed more intimacy, relational harmony, connectedness and
      mutuality and lesser individuality than British mothers and daughters.

PMID- 10579896
TI  - Ethnic identity and its relationship to self-esteem, perceived efficacy and
      prosocial attitudes in early adolescence.
AB  - This study examined the relationship of ethnic identity to self-esteem, perceived
      self-efficacy and prosocial attitudes. The sample included 100 male and female
      early adolescents, ranging from 11 to 13 years old, from different racial/ethnic
      backgrounds. Structural equations modeling was used to examine the latent
      structure of the multi-dimensional constructs and their interrelationships. Self
      esteem and ethnic identity factors emerged which were related and which evidenced
      efficacy-mediated effects upon prosocial attitudes. The findings suggested that
      ethnic identity and self-esteem are distinct but related contributors to young
      people's perceptions of their ability to achieve academically, to find meaningful
      careers and to value prosocial means of goal attainment.

PMID- 10579897
TI  - Contents and index

PMID- 10579898
TI  - p53 does not control the spindle assembly cell cycle checkpoint but mediates G1
      arrest in response to disruption of microtubule system.
AB  - p53 plays a critical role as a tumour-suppressor in restricting the proliferation
      of damaged cells, thus preventing formation of genetically altered cell clones.
      Its inactivation leads, in particular, to accumulation of polyploid and aneuploid
      cells. To elucidate the role of p53 in control of chromosome number, we analysed
      its participation in the cell cycle checkpoints controlling: (1) spindle
      assembly; and (2) G1-to-S transitions in cells with disintegrated microtubule
      cytoskeleton. Treatment with 8-10 ng/ml of colcemid causing no visible
      destruction of the spindle leads to arrest of metaphase-to-anaphase transition in
      both p53-positive and p53-negative murine fibroblasts, as well as in p53-positive
      REF52 cells and their counterparts (where the p53 function was inactivated by
      transduction of dominant-negative p53 fragment). Furthermore, p53-positive and
      p53-defective rodent and human cells showed no significant difference in kinetics
      of metaphase-to-interphase transitions in cultures treated with high colcemid
      doses preventing spindle formation. These data argue against the hypothesis that
      p53 is a key component of the spindle-assembly checkpoint. However, p53 mediates
      activation of the G1 checkpoint in response to depolymerization of microtubules
      in interphase cells. Treatment of synchronized G0/G1 cells with colcemid causes
      arrest of G1-to-S transition. Inactivation of the p53 function by transduction of
      dominant-negative p53 fragment abolishes the G1 checkpoint that prevents entry
      into S phase of cells with disrupted microtubules. Transduction of kinase
      defective dominant-negative c- raf mutant or application of PD 098059, a specific
      inhibitor of MEK1, also abrogates the G1 cell cycle arrest in cells with
      disintegrated microtubule system. It seems that Raf-MAP-kinase signalling
      pathways are responsible for p53 activation induced by depolymerization of
      microtubules.

PMID- 10579899
TI  - Spectrin-like proteins in green algae (Desmidiaceae).
AB  - Immunochemical detection of actin as well as spectrin-like proteins have been
      carried out in the green algae Micrasterias denticulata, Closterium lunula, and
      Euastrum oblongum. In these algae, actin is detected on Western blots at 43 kDa
      with antibodies to actin from higher plant and animal origin. By use of
      antibodies to human and chicken erythrocyte spectrin a cross-reactivity with
      desmid proteins is found at about the molecular mass of 220 kDa, where also human
      erythrocyte spectrin is detected. Additional bands are present at 120 kDa and 70
      kDa, which are probably breakdown products. An antibody against chicken alpha
      actinin, a small protein of the spectrin superfamily, recognizes bands at 90 kDa,
      where it is expected, and 70 kDa, probably the same breakdown product as
      mentioned for spectrin. Isoelectric focusing provides staining at pI 4.6 with
      antibodies against spectrin. Immunogold labelling of spectrin and alpha-actinin
      antigens on high-pressure frozen, freeze-substituted Micrasterias denticulata
      cells with the same antibodies exhibits staining, especially at membranes of
      different populations of secretory vesicles, at dictyosomes, and the plasma
      membrane. However, no clear correlation to the growth pattern of the cell could
      be observed. Taken together, our results demonstrate the presence of spectrin
      like proteins in desmid cells which are probably functional in exocytosis.

PMID- 10579900
TI  - The effect of oxidative stress induced by t-butyl hydroperoxide on the structural
      dynamics of membrane proteins of Chinese hamster fibroblasts.
AB  - A method based on the measurement at room temperature of tryptophan
      phosphorescence (RTTP) gives the unique possibility to investigate the dynamic
      structure of membrane proteins without their isolation from cells. This method
      was used to study the influence of tert- butyl hydroperoxide (t -BHP) on Chinese
      hamster fibroblasts. The treatment of fibroblasts with t -BHP in a concentration
      range of 0. 5-2 m m for 60 min caused an increase of frequency and amplitude of
      membrane protein motions with lifetimes of hundreds miliseconds (a decrease of
      RTTP tau(2)). In parallel, cell viability was studied by trypan blue exclusion
      test and the content of thiobarbituric acid reactive substances was measured in
      cells. The dependences of the RTTP tau(2)and cell viability on t -BHP
      concentration were similar. Contrary to this, t -BHP did not induce the
      activation of lipid peroxidation processes in cells. This indicates that cell
      death is connected with the excessive increase of intramolecular dynamics of
      membrane proteins during t -BHP action.

PMID- 10579901
TI  - Elevated level of gas3 gene expression is correlated with G0 growth arrest in
      human fibroblasts.
AB  - The gas3/PMP22 gene product is a dual function protein, involved in both
      peripheral nerve myelination and cell proliferation. gas 3/PMP22 is highly
      expressed in myelinating Schwann cells and is required for normal PNS
      development. In addition, a more general function for gas3 is suggested by its
      expression in non-neural tissues and upregulation by growth arrest in cultured
      rodent fibroblasts. In the present work, the expression of the gas3 gene has been
      studied in human fibroblasts. We have confirmed that gas3 mRNA is upregulated
      when cells are serum starved or grown to high cell density (G0 arrest). When
      quiescent cells were stimulated by serum or platelet-derived growth factor-BB
      (PDGF-BB), gas3 mRNA was down regulated. In contrast, we found that the
      expression of gas3 mRNA was neither upregulated in senescent cells nor in cells
      arrested in G1 using Lovastatin. Thus, high expression of gas3 is not related to
      growth inhibition in general, but more probably to the G0 growth arrest state.
      Furthermore, we found that in two malignant fibrous histiocytoma cell lines, gas3
      expression was lower than in normal fibroblasts, suggesting an altered regulation
      of the gas3 gene in transformed cells.

PMID- 10579902
TI  - Adhesion of L1210 cells to sulfonated styrene copolymer surfaces: imaging of F
      actin AND alpha-actinin.
AB  - The static adhesion of living L1210 cells to sulfonated copolymer surfaces of
      different sulfonic group content and the actin cytoskeleton organization in the
      adhering cells were studied. The strength of the cell-substratum interaction was
      estimated by determining the relative number of cells remaining adherent despite
      experiencing a shearing force equal to 1.25 x 10(-11) N caused by the laminar
      flow of the medium. The cell-substratum interaction took place in a medium with
      or without serum. The distribution of F-actin and alpha-actinin in the adhering
      cells was determined in sequences of fluorescent images of cell optical slices
      with the use of a computer method of cell image analysis. It was shown that the
      surface sulfonic groups affect not only the rate and strength of cell-substratum
      adhesion but also the F-actin and alpha-actinin distribution (in the cell regions
      near the substratum surface) in cells adhering in the medium containing serum.
      These proteins, concentrated in the tips of microvilli, were observed as dots.
      The distinctness (discernibleness) and sizes of these dots depend on the surface
      content of sulfonic groups. F-actin is located at the periphery of the cells in
      cells adhering in the medium without serum and alpha-actinin is concentrated in
      small dots at the periphery and in the central part of the cells.

PMID- 10579903
TI  - Hepatocyte growth factor supports androgen stimulation of growth of mouse ventral
      prostate epithelial cells in collagen gel matrix culture.
AB  - To assess the role of hepatocyte growth factor (HGF) and androgen in growth of
      prostate epithelial cells, we isolated mouse ventral prostate epithelial cells
      and cultured them in a three-dimensional type I collagen gel matrix under serum
      free conditions. Although the prostate epithelial cells tended to die in the
      insulin-supplemented basal medium, 5alpha-dihydrotestosterone (DHT) prevented the
      cell death, and HGF slightly stimulated the growth. By contrast, coexistence of
      DHT and HGF greatly augmented the growth and branching morphogenesis of the
      epithelial cells. Some of the outgrowths formed under these conditions showed
      enlarged structures resembling the prostate ducts or alveoli. Examination of the
      stromal cell-conditioned medium revealed that a growth-stimulating activity is
      present in the conditioned medium. A major portion of this activity was abolished
      by anti-HGF IgG. These observations suggest that HGF is produced by the stromal
      cells of the prostate gland and supports the androgen stimulation of growth of
      the epithelial cells.

PMID- 10579904
TI  - Comparison of the growth patterns and morphological characteristics of
      mechanically and enzymatically isolated fallopian tube epithelial cells.
AB  - This study set out to compare the growth patterns and morphological
      characteristics of human fallopian tube epithelial cells isolated: (1)
      mechanically; and (2) enzymatically. Cells were cultured in medium supplemented
      with fetal bovine serum and antibiotics and their epithelial nature was
      established by immunocytochemistry for cytokeratins. Primary cultures were
      polygonal in shape with centrally located nuclei, irrespective of the isolation
      method. Cells isolated enzymatically exhibited a higher growth rate, but the
      survival rate was poor after more than 2-3 passages. Mechanical isolation gave a
      lower yield of cells, but had a higher survival rate when sub-cultured, even
      beyond 8 passages. Thus, mechanically isolated cells might be useful for longer
      term cultures, whereas enzymatically isolated cells are best only for short-term
      work.

PMID- 10579905
TI  - The IGF-I receptor in cancer research.
AB  - The type 1 insulin-like growth factor receptor (IGF-IR) plays an important role
      in both normal and abnormal growth. It is particularly important in anchorage
      independent growth. Impairment of its function causes apoptosis of tumor cells
      and inhibition of tumor growth in experimental animals. However, the IGF-IR can
      also induce differentiation, and eventually cell death, of certain types of
      cells. Its major substrates, IRS-1 and Shc, determine whether the IGF-IR will
      transform cells or will cause their differentiation.

PMID- 10579906
TI  - Cytokines and JAK-STAT signaling.
AB  - Characterization of the ability of IFNs to induce immediate early genes led to
      the identification of the STAT (signal transducers and activators of
      transcription) signaling paradigm. STATs are activated at the receptor and then
      directly transduce signals to the nucleus. Subsequent studies have determined
      that all cytokines transduce critical signals through this pathway.

PMID- 10579907
TI  - Phospholipase C-gamma as a signal-transducing element.
AB  - A ubiquitous signaling event in hormonal responses is the phospholipase C (PLC)
      catalyzed hydrolysis of phosphatidylinositol 4, 5-bisphosphate to produce the
      metabolite second messenger molecules inositol 1,4,5-trisphosphate and
      diacylglycerol. The former provokes a transient increase in intracellular free
      Ca(2+), while the latter serves as a direct activator of protein kinase C. In
      tyrosine kinase-dependent signaling pathways this reaction is mediated by the PLC
      gamma isozymes. These are direct substrates of many tyrosine kinases in a wide
      variety of cell types. The mechanism of PLC-gamma activation involves its
      association with and phosphorylation by receptor and non-receptor tyrosine
      kinases, as well as interaction with specialized adaptor molecules and, perhaps,
      other second messenger molecules. However, the biochemistry of PLC-gamma is at a
      more advanced state than a clear understanding of exactly how this signaling
      element functions in the generation of a mitogenic response.

PMID- 10579908
TI  - Hedgehog signal transduction: from flies to vertebrates.
AB  - The patterning and morphogenesis of multicellular organisms require a complex
      interplay of inductive signals which control proliferation, growth arrest, and
      differentiation of different cell types. A number of such signaling molecules
      have been identified in vertebrates and invertebrates. The molecular dissection
      of these pathways demonstrated that in vertebrates, mutations or abnormals
      function of these signaling pathways were often associated with developmental
      disorders and cancer formation. The Hedgehog (Hh) family of secreted proteins
      provides a perfect example of such signaling proteins. In the following review,
      we will not discuss in detail the role of Hh as a morphogen, but rather focus on
      its signal transduction pathway and its role in various human disorders.

PMID- 10579909
TI  - Isotype-specific functions of Raf kinases.
AB  - The family of Raf-protein kinases consisting of A-Raf, B-Raf, and c-Raf-1 is
      involved in cellular processes which regulate proliferation, differentiation, and
      apoptosis. Cell-culture experiments and the knockout of individual Raf genes
      suggested that the three Raf isoforms have overlapping and unique regulatory
      functions. However, it is not known how these isotype-specific functions of Raf
      kinases occur in the cell. Published data suggest that Raf proteins might differ
      in the regulation of their activation as well as in their ability to connect to
      downstream signaling pathways. Since Raf is part of a multiprotein complex and
      protein-protein interactions are important for Raf signaling, we propose that
      isotype-specific functions can be achieved by isotype-restricted protein binding.
      Recently we were able to identify candidates for such Raf-isoform-specific
      interaction partners.

PMID- 10579910
TI  - Shp-2 tyrosine phosphatase: signaling one cell or many.
AB  - Shp-2, a widely expressed cytoplasmic tyrosine phosphatase with two src-homology
      2 (SH2) domains, has received much attention in the signal transduction field
      recently. Significant progress has been made in understanding the structure and
      function of this phosphatase, together with its Drosophila homologue, Corkscrew,
      as well as the close relative Shp-1 tyrosine phosphatase. The crystal structure
      of Shp-2 revealed an autoinhibitory mechanism of the catalytic activity by the N
      terminal SH2 domain. Shp-2 apparently participates in signaling events downstream
      of receptors for growth factors, cytokines, hormones, antigens, and extracellular
      matrixes in the control of cell growth, differentiation, migration, and death.
      Shp-2 is an important molecule that integrates signals among various cytoplasmic
      pathways and may also couple intracellular and intercellular information flow.

PMID- 10579911
TI  - Insulin signaling regulating the trafficking and plasma membrane fusion of GLUT4
      containing intracellular vesicles.

PMID- 10579912
TI  - Function of the c-Myc oncogenic transcription factor.
AB  - The c-myc gene and the expression of the c-Myc protein are frequently altered in
      human cancers. The c-myc gene encodes the transcription factor c-Myc, which
      heterodimerizes with a partner protein, termed Max, to regulate gene expression.
      Max also heterodimerizes with the Mad family of proteins to repress
      transcription, antagonize c-Myc, and promote cellular differentiation. The
      constitutive activation of c-myc expression is key to the genesis of many
      cancers, and hence the understanding of c-Myc function depends on our
      understanding of its target genes. In this review, we attempt to place the
      putative target genes of c-Myc in the context of c-Myc-mediated phenotypes. From
      this perspective, c-Myc emerges as an oncogenic transcription factor that
      integrates the cell cycle machinery with cell adhesion, cellular metabolism, and
      the apoptotic pathways.

PMID- 10579913
TI  - The role of the epidermal growth factor receptor family in mammary tumorigenesis
      and metastasis.
AB  - A number of receptor systems have been implicated to play an important role in
      the development and progression of many human cancers. The epidermal growth
      factor (EGF) receptor tyrosine kinase family has been found to consistently play
      a leading role in tumor progression. Indeed, in human breast cancer cases the
      prognosis of a patient is inversely correlated with the overexpression and/or
      amplification of this receptor family. Furthermore, downstream signaling
      components such as the Src kinases, PI3'K, and the Ras pathway display evidence
      of deregulation that can accelerate tumor progression. The transgenic mouse
      system has been ideal in elucidating the biological significance of this receptor
      family in mammary tumorigenesis. Molecular events involved in mammary
      tumorigenesis such as ligand binding, receptor dimerization, and the activation
      of downstream pathways have been addressed using this system. Although there are
      many molecular steps that appear to drive each stage of tumor development, the
      EGF receptor family appears to play a causal role in the progression to a
      transformed phenotype.

PMID- 10579914
TI  - Plasminogen-related growth factor and semaphorin receptors: a gene superfamily
      controlling invasive growth.
AB  - Plasminogen-related growth factors (PRGFs), also known as "scatter factors,"
      trigger a unique biological program leading to "invasive growth." This is a
      result of the integration of apparently independent biological responses
      including cell proliferation, cell survival, cell motility, invasion of
      extracellular matrices, and induction of cell polarity. Under physiological
      conditions, the coordinated execution of the underlying genetic programs leads to
      the formation of tubular structures by epithelial organs (the so-called branching
      morphogenesis). PRGF receptors are tyrosine kinases, encoded by a family of
      oncogenes: MET and RON. They feature unique signal transduction properties as
      their cytoplasmic tails contain a two-tyrosine multifunctional docking site that
      binds multiple SH2-containing intracellular signal transducers. Invasive growth
      results from the concomitant activation of Ras (growth), phosphatidylinositol 3
      kinase ("scattering"), and signal transducer and activator of transcription (cell
      polarity and morphogenesis). We recently identified a new human gene family,
      encoding large transmembrane proteins, sex/plexins, sharing homologies with Met.
      These molecules are receptors for semaphorins, involved in axon guidance and cell
      cell repulsion, a process reminiscent of scattering and invasive growth.
      Deregulated activation of PRGF or semaphorin ligands or receptors, by mutation or
      overexpression, confers to cancer cells invasive and metastatic properties.

PMID- 10579915
TI  - Ribosomal S6 kinase signaling and the control of translation.
AB  - The highly homologous 40S ribosomal protein S6 kinases (S6K1 and S6K2) play a key
      role in the regulation of cell growth by controlling the biosynthesis of
      translational components which make up the protein synthetic apparatus, most
      notably ribosomal proteins. In the case of S6K1, at least eight phosphorylation
      sites are believed to mediate kinase activation in a hierarchical fashion.
      Activation is initiated by phosphatidylinositide-3OH kinase (PI3K)-mediated
      phosphorylation of key residues in the carboxy-terminus of the kinase, allowing
      phosphorylation of a critical residue residing in the activation loop of the
      catalytic domain by phosphoinositide-dependent kinase 1 (PDK1). The kinases
      responsible for phosphorylating the carboxy-terminal sites have yet to be
      identified. Additionally, S6 kinases are under the control of the PI3K relative,
      mammalian Target Of Rapamycin (mTOR), which may serve an additional function as a
      checkpoint for amino acid availability. In this review we set out to discuss the
      present state of knowledge regarding upstream signaling components which have
      been implicated in the control of S6K1 activation and the role of the kinase in
      controlling cell growth through regulating ribosome biogenesis at the
      translational level.

PMID- 10579916
TI  - Insight into regulatory factor targeting to transcriptionally active subnuclear
      sites.
AB  - Mechanisms that coordinate the spatial organization of genes and regulatory
      proteins within the three-dimensional context of nuclear architecture contribute
      to the sorting of regulatory information as well as the assembly and activity of
      sites within the nucleus that support gene expression. In this article we will
      present an overview of experimental approaches that provide insight into the
      trafficking of the hematopoietic and bone-specific AML/CBF family of regulatory
      factors to transcriptionally active subnuclear sites.

PMID- 10579917
TI  - Signaling via vascular endothelial growth factor receptors.
AB  - Angiogenesis, or development of blood vessels from preexisting vasculature, has
      important functions under both normal and pathophysiological conditions. Vascular
      endothelial growth factor receptors 1-3, also known as flt-1, KDR, and flt-4, are
      endothelial cell-specific receptor tyrosine kinases which serve as key mediators
      of the angiogenic responses. The review focuses on the signaling pathways that
      are initiated from these receptors and the recently identified VEGF coreceptor
      neuroplilin-1.

PMID- 10579918
TI  - Neurotrophin signaling via Trks and p75.
AB  - This review focuses on recent advances in our understanding of receptor-mediated
      signaling by the neurotrophins NGF, BDNF, NT3, and NT4/5. Two distinct receptor
      types have been distinguished, Trks and p75. The Trks are receptor tyrosine
      kinases that utilize a complex set of substrates and adapter proteins to activate
      defined secondary signaling cascades required for neurotrophin-promoted neuronal
      differentiation, plasticity, and survival. A specialized aspect of
      Trk/neurotrophin action in neurons is the requirement for retrograde signaling
      from the distal periphery to the cell body. p75 is a universal receptor for
      neurotrophins that is a member of the TNF receptor/Fas/CD40 superfamily. p75
      appears to modify Trk signaling when the two receptor types are coexpressed. When
      expressed in the absence of Trks, p75 mediates responses to neurotrophins
      including promotion of apoptotic death. The mechanisms of p75 receptor signaling
      remain to be fully understood.

PMID- 10579919
TI  - Signal transduction in the erythropoietin receptor system.
AB  - Events relayed via the single transmembrane receptor for erythropoietin (Epo) are
      essential for the development of committed erythroid progenitor cells beyond the
      colony-forming unit-erythroid stage, and this clearly involves Epo's inhibition
      of programmed cell death (PCD). Less well resolved, however, are issues regarding
      the precise nature of Epo-dependent antiapoptotic mechanisms, the extent to which
      Epo might also promote mitogenesis and/or terminal erythroid differentiation, and
      the essential vs modulatory nature of certain Epo receptor cytoplasmic
      subdomains, signal transducing factors, and downstream pathways. Accordingly,
      this review focuses on the following aspects of Epo signal transduction: (1) Epo
      receptor/Jak2 activation mechanisms; (2) the critical vs dispensable nature of
      (P)Y sites and SH2 domain-encoding effectors in survival, growth, and
      differentiation responses; (3) primary mechanisms by which Epo inhibits PCD; (4)
      the integration of signals relayed by coexpressed and possibly directly
      interacting cytokine receptors; and (5) predictions regarding effector function
      which are provided by the association of certain primary and familial
      polycythemias with mutated human Epo receptor forms.

PMID- 10579920
TI  - Ras and Rap1: two highly related small GTPases with distinct function.
AB  - The Ras-like family of small GTPases includes, among others, Ras, Rap1, R-ras,
      and Ral. The family is characterized by similarities in the effector domain.
      While the function of Ras is, at least in part, elucidated, little is known about
      other members of the family. Currently, much attention is focused on the small
      GTPase Rap1. Initially, this member was identified as a transformation suppressor
      protein able to revert the morphological phenotype of Ras-transformed
      fibroblasts. This has led to the hypothesis that Rap1 antagonizes Ras by
      interfering in Ras effector function. Recent analysis revealed that Rap1 is
      activated rapidly in response to activation of a variety of receptors. Rap1
      activation is mediated by several second messengers, including calcium,
      diacylglycerol, and cAMP. Guanine nucleotide exchange factors (GEFs) have been
      identified that mediate these effects. The most interesting GEF is Epac, an
      exchange protein directly activated by cAMP, thus representing a novel cAMP
      induced, protein kinase A-independent pathway. Furthermore, Rap1 is inactivated
      by specific GTPase-activating proteins (GAPs), one of which is regulated through
      an interaction with Galphai. While Ras and Rap1 may share some effector pathways,
      evidence is accumulating that Ras and Rap1 each regulate unique cellular
      processes in response to various extracellular ligands. For Rap1 these functions
      may include the control of cell morphology.

PMID- 10579921
TI  - Signaling to Rho GTPases.
AB  - Rho GTPases regulate many important processes in all eukaryotic cells, including
      the organization of the actin cytoskeleton, gene transcription, cell cycle
      progression, and membrane trafficking. Their activity is regulated by signals
      originating from different classes of surface receptors including G-protein
      coupled receptors, tyrosine kinase receptors, cytokine receptors, and adhesion
      receptors. Recent work has identified multiple mechanisms by which receptors can
      signal to Rho GTPases and this will be the major focus of this review. In
      addition, there is growing evidence for cross-talk within the Rho GTPase family
      as well as between the Rho and Ras GTPase families. These signaling networks are
      thought to provide the cooperative and coordinated interactions that are crucial
      for regulating complex biological processes such as cell migration.

PMID- 10579922
TI  - AP-1: one switch for many signals.
AB  - The transcription factor AP-1 is activated in response to an incredible array of
      stimuli, including mitogenic growth factors, inflammatory cytokines, growth
      factors of the TGF-beta family, UV and ionizing irradiation, cellular stress,
      antigen binding, and neoplastic transformation. In this review, I discuss genetic
      evidence that supports a role for AP-1 in the cellular response to some of these
      stimuli and describe biochemical properties that might explain the ability of
      this transcription factor to activate different sets of genes in response to
      different stimuli.

PMID- 10579923
TI  - The EH network.
AB  - The EH domain is an evolutionary conserved protein-protein interaction domain
      present in a growing number of proteins from yeast to mammals. Even though the
      domain was discovered just 5 years ago, a great deal has been learned regarding
      its three-dimensional structure and binding specificities. Moreover, a number of
      cellular ligands of the domain have been identified and demonstrated to define a
      complex network of protein-protein interactions in the eukaryotic cell.
      Interestingly, many of the EH-containing and EH-binding proteins display
      characteristics of endocytic "accessory" proteins, suggesting that the principal
      function of the EH network is to regulate various steps in endocytosis. In
      addition, recent evidence suggests that the EH network might work as an
      "integrator" of signals controlling cellular pathways as diverse as endocytosis,
      nucleocytosolic export, and ultimately cell proliferation.

PMID- 10579924
TI  - The regulation and activities of the multifunctional serine/threonine kinase
      Akt/PKB.
AB  - The serine/threonine kinase Akt, or protein kinase B (PKB), has recently been a
      focus of intense research. It appears that Akt/PKB lies in the crossroads of
      multiple cellular signaling pathways and acts as a transducer of many functions
      initiated by growth factor receptors that activate phosphatidylinositol 3-kinase
      (PI 3-kinase). Akt/PKB is particularly important in mediating several metabolic
      actions of insulin. Another major activity of Akt/PKB is to mediate cell
      survival. In addition, the recent discovery of the tumor suppressor PTEN as an
      antagonist of PI 3-kinase and Akt/PKB kinase activity suggests that Akt/PKB is a
      critical factor in the genesis of cancer. Thus, elucidation of the mechanisms of
      Akt/PKB regulation and its physiological functions should be important for the
      understanding of cellular metabolism, apoptosis, and cancer.

PMID- 10579925
TI  - Bioactive lysophospholipids and their G protein-coupled receptors.
AB  - Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are serum-borne
      lysophospholipids that signal through their cognate G protein-coupled receptors
      to evoke a great variety of responses in numerous cell types. In addition to
      stimulating cell proliferation and survival, LPA and S1P induce profound
      cytoskeletal changes through Rho-mediated signaling pathways, leading to such
      diverse responses as cell rounding, neurite retraction, and modulation of tumor
      cell invasiveness (transcellular migration). A major recent advance is the
      identification of a subfamily of heptahelical receptors for LPA and S1P.

PMID- 10579926
TI  - Signaling by distinct classes of phosphoinositide 3-kinases.
AB  - Many signaling pathways converge on and regulate phosphoinositide 3-kinase (PI3K)
      enzymes whose inositol lipid products are key mediators of intracellular
      signaling. Different PI3K isoforms generate specific lipids that bind to FYVE and
      pleckstrin homology (PH) domains in a variety of proteins, affecting their
      localization, conformation, and activities. Here we review the activation
      mechanisms of the different types of PI3Ks and their downstream actions, with
      focus on the PI3Ks that are acutely triggered by extracellular stimulation.

PMID- 10579927
TI  - New insights into the control of MAP kinase pathways.

PMID- 10579928
TI  - Multiple roles for Src in a PDGF-stimulated cell.
AB  - The observation that platelet-derived growth factor (PDGF) increases the
      catalytic activity of Src family members (Src) suggests that they contribute to
      PDGF-dependent responses. The role of Src in PDGF-dependent cell cycle
      progression, phosphorylation of proteins, and chemotaxis has been tested by
      investigators using a variety of cell types and approaches, and it appears that
      the contribution of Src is highly variable. This idea is perhaps best illustrated
      by the finding that Src plays radically different roles downstream of the PDGF
      alpha- and beta-receptor subunits. Hence, Src is a versatile signal relay enzyme,
      whose contribution to a signaling cascade depends on variables such as the nature
      of the receptor via which the cell is activated, as well as the cell type itself.

PMID- 10579929
TI  - Methods issue on nuclear structure and chromatin.

PMID- 10579930
TI  - Tracking components of the transcription apparatus in living cells.
AB  - Transcription regulatory proteins are an integral component of the cell nucleus
      and a great deal of work has been done to characterize the subnuclear
      distribution of these proteins. Much of the early work on this subject was done
      with immunofluorescence. The development of the green fluorescent protein (GFP)
      as a marker for intracellular protein localization has allowed for the real time
      study of protein localization and dynamics in living cells. In this review, an
      overview of the way in which GFP can be utilized to study protein localization is
      presented.

PMID- 10579931
TI  - Dynamics and mobility of nuclear envelope proteins in interphase and mitotic
      cells revealed by green fluorescent protein chimeras.
AB  - Understanding how membrane proteins are targeted to and retained within the
      nuclear envelope (NE) and the fate of these proteins during NE
      disassembly/reassembly in mitosis is central for insight into the function of the
      NE in nuclear organization and dynamics. To address these issues we have attached
      green fluorescent protein (GFP) to a well-characterized protein of the inner
      nuclear membrane, lamin B receptor, believed to be one of the major chromatin
      docking protein in the NE. We have used this construct in a variety of
      applications, including dual-color GFP time-lapse imaging, to investigate the
      mechanisms underlying protein targeting to the NE and NE breakdown and reassembly
      during mitosis. In this review, we present a summary of the results from such
      studies and discuss the photobleaching and imaging methodology on which they were
      derived.

PMID- 10579932
TI  - Three-dimensional imaging by deconvolution microscopy.
AB  - Deconvolution is a computational method used to reduce out-of-focus fluorescence
      in three-dimensional (3D) microscope images. It can be applied in principle to
      any type of microscope image but has most often been used to improve images from
      conventional fluorescence microscopes. Compared to other forms of 3D light
      microscopy, like confocal microscopy, the advantage of deconvolution microscopy
      is that it can be accomplished at very low light levels, thus enabling multiple
      focal-plane imaging of light-sensitive living specimens over long time periods.
      Here we discuss the principles of deconvolution microscopy, describe different
      computational approaches for deconvolution, and discuss interpretation of
      deconvolved images with a particular emphasis on what artifacts may arise.

PMID- 10579933
TI  - Using inducible vectors to study intracellular trafficking of GFP-tagged
      steroid/nuclear receptors in living cells.
AB  - Intracellular trafficking and localization of proteins can now be efficiently
      visualized by fusion of a polypeptide to the green fluorescent protein (GFP).
      Many spectral variants of this reagent are now available, providing powerful
      tools for studies in living cells. This approach is particularly useful for
      members of the steroid/nuclear receptor superfamily, since these molecules
      frequently undergo rapid subcellular redistribution on ligand activation. A major
      roadblock in the application of this technology concerns problems associated with
      transient transfections. This technique produces cell populations that are highly
      heterogeneous with respect to the newly introduced protein and usually contain
      the protein in a highly overexpressed state. In addition, long-term studies
      related to cell cycle and cellular differentiation are essentially impossible
      with this approach. These problems can be overcome by introduction of the GFP
      fusion into cells under appropriate induction control. We describe application of
      the tetracycline regulatory system to inducible control of a glucocorticoid
      receptor (GR)/GFP chimera. Intracellular concentrations of GFP-GR can be very
      effectively controlled in this system, providing an ideal environment in which to
      study subcellular trafficking of the receptor and interactions with a variety of
      intracellular targets.

PMID- 10579934
TI  - Intranuclear relocalization of matrix binding sites during T cell activation
      detected by amplified fluorescence in situ hybridization.
AB  - We describe a method for analyzing the nuclear localization of specific DNA
      sequences, with special emphasis on their binding status to the nuclear matrix,
      depending on the developmental stage of the cells. This method employs high
      resolution fluorescence in situ hybridization procedures. For our studies, it was
      important to examine the nuclear localization of a particular gene locus.
      Previously, however, it was not possible to detect a single-copy genomic sequence
      using a DNA probe less than several kilobases in size. We describe here a signal
      amplification technique based on tyramide which makes such a task possible. Using
      this method, we monitored single-copy loci using a short, 509-bp DNA sequence
      that binds in vivo to the T cell factor SATB1 within T cell nuclei, high-salt
      extracted nuclei (histone-depleted nuclei generating "halos" with distended
      chromatin loops), and the nuclear matrix, before and after T cell activation. We
      found that these loci were anchored onto the nuclear matrix, creating new bases
      of chromatin loops, only after T cell activation. This experimental strategy,
      therefore, enabled us to detect the changes in higher order chromatin structure
      upon activation and study gene regulation at a new dimension: the loop domain
      structure. The methods shown here can be widely applied to explore other
      functions involving chromatin, including recombination and replication.

PMID- 10579935
TI  - Use of digitonin-permeabilized cells in studies of steroid receptor subnuclear
      trafficking.
AB  - The application of a cell permeabilization technique to the analysis of nuclear
      import has led to many major breakthroughs in our understanding of this
      trafficking pathway. Digitonin permeabilization maintains the nucleus in a state
      competent for faithful, signal-dependent translocation through the nuclear pore
      complex. This system has also been used to probe the mechanism of hormone
      regulated nuclear import through the use of glucocorticoid receptors (GR) as a
      model substrate. In this report we provide detailed descriptions of the digitonin
      permeabilized cell system for use in studies of GR nuclear import. In addition,
      we present several novel applications that expand the utility of this system to
      probe for mechanisms of nuclear protein export and subnuclear trafficking.

PMID- 10579936
TI  - Transcriptional analysis of purified histone acetyltransferase complexes.
AB  - Acetylation of lysine residues within the amino-terminal tails of the core
      histone proteins is strongly correlated to the regulation of gene transcription
      in vivo. To directly study the effects of histone acetylation on transcription,
      we have developed a biochemical system examining the regulation of RNA polymerase
      II-directed transcription by native histone acetyltransferases (HATs). For the
      promoter sequences investigated, it has been demonstrated that HATs facilitate
      transcription from nucleosomal DNA templates in an acetyl-CoA-dependent fashion
      but do not affect transcription from histone-free templates. Here, protocols are
      presented describing the in vitro assembly of evenly spaced nucleosomal arrays on
      DNA fragments harboring gene regulatory sequences and the use of these templates
      with purified HAT complexes in transcription assays.

PMID- 10579937
TI  - Preparation of site-specific antibodies to acetylated histones.
AB  - Synthetic peptides corresponding to regions within the amino-terminal domains of
      the core histones H2A, H2B, H3, and H4, in which epsilon-acetyllysine has been
      substituted for selected lysines, have been used to raise polyclonal antisera in
      rabbits. Such antisera can be specific not only for individual acetylated
      histones but also for histone isoforms acetylated at particular lysine residues.
      In this article, we describe procedures for the preparation, affinity
      purification, and initial characterization of site-specific antisera to
      acetylated histones.

PMID- 10579939
TI  - Use of DNA photoaffinity labeling to study nucleosome remodeling by SWI/SNF.
AB  - The ability of large protein assemblies to reorganize chromatin in an ATP
      dependent manner is an important process for regulation of gene expression and
      potentially for DNA replication and recombination. The manner in which these
      proteins remodel chromatin to make the DNA accessible to DNA binding proteins
      such as transcription factors is not well understood. Site-directed DNA-protein
      cross-linking has been used to understand the architecture of the SWI/SNF
      nucleosomal complex and the mechanistic details of how the nucleosome is
      remodeled. A detailed protocol for such a study is presented along with examples
      of the extent of this approach.

PMID- 10579938
TI  - In vivo cross-linking and immunoprecipitation for studying dynamic Protein:DNA
      associations in a chromatin environment.
AB  - Chromatin structure plays important roles in regulating many DNA-templated
      processes, such as transcription, replication, and recombination. Considerable
      progress has recently been made in the identification of large, multisubunit
      complexes dedicated to these nuclear processes, all of which occur on nucleosomal
      templates. Mapping specific genomic loci relative to the position of selectively
      modified or unique histone variants or nonhistone components provides valuable
      insights into how these proteins (and their modifications) function in their
      normal chromatin context. Here we describe a versatile and high-resolution method
      which involves two basic steps: (1) in vivo formaldehyde cross-linking of intact
      cells followed by (2) selective immunoprecipitation of protein-DNA complexes with
      specific antibodies. This method allows for detailed analyses of protein-DNA
      interactions in a native chromatin environment. Recently, this technique has been
      successfully employed to map the boundaries of specifically modified (e.g.,
      acetylated) histones along target genes, to define the cell cycle-regulated
      assembly of origin-dependent replication and centromere-specific complexes with
      remarkable precision, and to map the in vivo position of reasonably rare
      transcription factors on cognate DNA sites. Thus, the basic chromatin
      immunoprecipitation technique is remarkably versatile and has now been used in a
      wide range of cell types, including budding yeast, fly, and human cells. As such,
      it seems likely that many more studies, centered around chromatin structure and
      protein-DNA interactions in its native setting, will benefit from this technique.
      In this article, a brief review of the history of this powerful approach and a
      discussion of the basic method are provided. Procedures for protein recovery as
      well as limitations and extensions of the method are also presented.

PMID- 10579940
TI  - Pyrimidine dimer formation as a probe of nucleosome core and linker structure in
      situ.
AB  - The photoinduced dimerization of adjacent pyrimidines in DNA is influenced in
      predictable ways by DNA conformation. A method is described for determining
      patterns of pyrimidine dimer formation under conditions in which the chromatin is
      minimally perturbed. The relation of such patterns to the conformation of
      nucleosomal core DNA and linker DNA, as well as the interaction of histone H1
      with nucleosomal DNA, is presented. Such data indicate that sharp bends in the
      path of DNA seen in crystals of isolated nucleosome core particles are also
      present in intact chromatin. They also indicate that most of the linker has very
      little curvature except for a small bend at its junction with the nucleosome
      core. The linker path inferred from such experiments supports models in which the
      chromatin fiber consists of a zigzag chain of nucleosomes.

PMID- 10579941
TI  - Characterization of specific nucleosomal states by use of selective substitution
      reagents in model octamer and tetramer structures.
AB  - Packaging of the DNA in nucleosomes restricts its access to regulatory factors
      and enzymatic complexes, making a local remodeling of the nucleosome structure a
      prerequisite to the establishment of protein-DNA interactions. The use of an
      experimental system in which one nucleosome is reconstituted on a topologically
      constrained DNA minicircle allows the visualization of different conformations of
      the nucleoprotein particle. The single cysteine located at position 110 of
      histone H3 can be titrated with thiol reagents, such as iodoacetamide (IAM), N
      ethylmaleimide (NEM), and dithiobisnitrobenzoic acid (DTNB), in both histone
      octamers and histone (H3-H4)(2) tetramers. Treatment of histone H3 with IAM, NEM,
      and DTNB allows the trapping of different conformations of the (H3-H4)(2)
      tetramer within the nucleoprotein particle. When H3 cysteines are titrated within
      the histone octamer, IAM, NEM, and DTNB block the tetramer in the left-handed
      conformation, the conformation it adopts within the nucleosome. The left-handed
      conformation is initially dictated by H2A-H2B dimers and then frozen by the thiol
      reagents. When cysteines are titrated within the histone tetramer, the
      flexibility of the particle becomes apparent. NEM and IAM behave differently from
      DTNB. The first two reagents block the particle in its left-handed conformation
      while DTNB treatment favors the right-handed conformation. These thiol reagents
      that block the nucleoprotein particles in a given conformation should allow their
      structural analysis. They may also help the investigation of the role of the (H3
      H4)(2) nucleoprotein particle structural transition in biological processes
      involving nucleosome dynamics, such as DNA transcription, replication, and
      repair.

PMID- 10579942
TI  - Identification of 5-methylcytosine in complex genomes.
AB  - Cytosine methylation is attracting new attention for regulatory roles in gene
      expression and there is an increasing interest in detecting, at a single-base
      resolution, any 5-methylcytosine in genes from complex genomes. Differential base
      modification by chemicals followed by PCR-based genomic sequencing procedures can
      provide the resolution, sensitivity, and specificity required for such a goal.
      The various methods available are not devoid of artifacts but if used carefully
      and in combination, very reliable information can be obtained. We compare the
      methods using bisulfite and conventional PCR with those using either hydrazine or
      potassium permanganate and ligation-mediated PCR and provide a step-by-step
      description of the corresponding procedures.

PMID- 10579943
TI  - Beyond k-space: spectral localization using higher order gradients.
AB  - Chemical shift imaging (CSI) often suffers from the inconvenient shape of its
      spatial response function (SRF), which affects both localization and signal-to
      noise ratio. Replacing the magnetic field gradients for phase encoding by higher
      order magnetic fields allows a better adjustment of the SRF to the structures in
      the sample. We combined this principle with the SLOOP (spectral localization with
      optimal pointspread function) technique to simultaneously obtain spectra from
      several arbitrarily shaped compartments within a sample. Linear combinations of
      the fields of the shim coils are used to generate the pulsed fields for phase
      encoding. Their shapes are matched to the given sample geometry by numerical
      optimization. Using this method, spectra from a phantom were obtained that show a
      higher signal-to-noise ratio and a strongly reduced contamination compared to an
      equivalent CSI experiment.

PMID- 10579944
TI  - Quantification of regional intrapulmonary oxygen partial pressure evolution
      during apnea by (3)He MRI.
AB  - We present a new method to determine in vivo the temporal evolution of
      intrapulmonary oxygen concentrations by functional lung imaging with
      hyperpolarized (3)Helium ((3)He-->). Single-breath, single-bolus visualization of
      (3)He--> administered to the airspaces is used to analyze nuclear spin relaxation
      caused by the local oxygen partial pressure p(O(2))(t). We model the dynamics of
      hyperpolarization in the lung by rate equations. Based hereupon, a double
      acquisition technique is presented to separate depolarization by RF pulses and
      oxygen induced relaxation. It permits the determination of p(O(2)) with a high
      accuracy of up to 3% with simultaneous flip angle calibration using no additional
      input parameters. The time course of p(O(2)) during short periods of
      breathholding is found to be linear in a pig as well as in a human volunteer. We
      also measured the wall relaxation time in the lung and deduced a lower limit of
      4.3 min.

PMID- 10579945
TI  - A system for low field imaging of laser-polarized noble gas.
AB  - We describe a device for performing MRI with laser-polarized noble gas at low
      magnetic fields (<50 G). The system is robust, portable, inexpensive, and
      provides gas-phase imaging resolution comparable to that of high field clinical
      instruments. At 20.6 G, we have imaged laser-polarized (3)He (Larmor frequency of
      67 kHz) in both sealed glass cells and excised rat lungs, using approximately 0.1
      G/cm gradients to achieve approximately 1 mm(2) resolution. In addition, we
      measured (3)He T(2)(*) times greater than 100 ms in excised rat lungs, which is
      roughly 20 times longer than typical values observed at high ( approximately 2 T)
      fields. We include a discussion of the practical considerations for working at
      low magnetic fields and conclude with evidence of radiation damping in this
      system.

PMID- 10579946
TI  - Detection and characterization of boric acid and borate ion binding to cytochrome
      c using multiple quantum filtered NMR.
AB  - The application of multiple quantum filtered (MQF) NMR to the identification and
      characterization of the binding of ligands containing quadrupolar nuclei to
      proteins is demonstrated. Using relaxation times measured by MQF NMR multiple
      binding of boric acid and borate ion to ferri and ferrocytochrome c was detected.
      Borate ion was found to have two different binding sites. One of them was in slow
      exchange, k(diss) = 20 +/- 3 s(-1) at 5 degrees C and D(2)O solution, in
      agreement with previous findings by (1)H NMR (G. Taler et al., 1998, Inorg. Chim.
      Acta 273, 388-392). The triple quantum relaxation of the borate in this site was
      found to be governed by dipolar interaction corresponding to an average B-H
      distance of 2.06 +/- 0.07 A. Other, fast exchanging sites for borate and boric
      acid could be detected only by MQF NMR. The binding equilibrium constants at
      these sites at pH 9.7 were found to be 1800 +/- 200 M(-1) and 2.6 +/- 1.5 M(-1)
      for the borate ion and boric acid, respectively. Thus, detection of binding by
      MQF NMR proved to be sensitive to fast exchanging ligands as well as to very weak
      binding that could not be detected using conventional methods.

PMID- 10579947
TI  - Calculations of multipulse sequence in NQR of spins 32.
AB  - The general formalism of the interaction representation with respect to an
      operator which is its own inverse is developed and applied to pure NQR of spins I
      = 32. Under the assumption of no relaxation and no dipolar coupling, it is shown
      that the calculation of the response to pure NQR multipulse sequences can be
      performed with the same concepts used in high field NMR, such as coherence
      pathways. All the tools and mathematical expressions to predict the time
      evolution of the signal created by a pure NQR multipulse sequence are presented
      explicitly. It takes into account the off-resonance irradiation as well as the
      angular dependence of the excitation and detection for every value of the
      electric field gradient asymmetry parameter. Particular attention is devoted to
      the powder average, which is performed via a probability function derived
      analytically for the first time, leading to a drastic reduction of simulation
      times. The theory is illustrated by the study of the optimization and excitation
      bandwidths of one- to three-pulse sequences and compared to experimental results
      on Chloranil. We show that the three-pulse "stimulated echo" sequence gives a
      more uniform excitation profile than the traditional two-pulse echo sequence for
      powder samples. Thus, the "stimulated echo" sequence could be useful to cover a
      large spectrum when the experiment duration, or the signal to noise ratio, are
      not critical parameters. Analytical expressions for the nutation spectra obtained
      by one or two-pulse sequences are also derived for the first time.

PMID- 10579948
TI  - Lanthanide chelates as bilayer alignment tools in NMR studies of membrane
      associated peptides.
AB  - Theequimolar complex, consisting of the lipid-like, amphiphilic chelating agent
      1,11-bis[distearylamino]-diethylenetriamine pentaacetic acid (DTPA-18) and
      Tm(3+), is shown by deuterium ((2)H) NMR to be useful in aligning bicelle-like
      model membranes, consisting of dimyristoylphosphatidylcholine (DMPC) and
      dihexanoylphosphatidylcholine (DHPC). As shown previously (1996, R. S. Prosser et
      al., J. Am. Chem. Soc. 118, 269-270), in the absence of chelate, the lanthanide
      ions bind loosely with the lipid phosphate groups and confer the membrane with a
      sufficient positive magnetic anisotropy to result in parallel alignment (i.e.,
      average bilayer normal along the field). Apparently, DTPA-18 sequesters the
      lanthanide ions and inserts into the phospholipid bilayer in such a manner that
      bilayer morphology is preserved over a wide temperature range (35-70 degrees C).
      The inherent paramagnetic shifts and line broadening effects are illustrated by
      (2)H NMR spectra of the membrane binding peptide, Leu-enkephalin (Lenk-d(2), Tyr
      (Gly-d(2))-Gly-Phe-Leu-OH), in the presence of varying concentrations of Tm(3+),
      and upon addition of DTPA-18. Two conclusions could be drawn from this study: (1)
      The addition of Tm(3+) to the bicelle system is consistent with a conformational
      change in the surface associated peptide, and this effect is shown to be reversed
      by addition of the chelate, and (2) The paramagnetic shifts are shown to be
      significantly reduced by addition of chelate.

PMID- 10579949
TI  - J pulses for multiplet-selective NMR.
AB  - Exact product operator solutions have been obtained for the evolution of weakly
      coupled spin-(1/2) I(m)S(n) systems during arbitrary RF irradiation of one spin.
      These solutions, which completely characterize the nature of J-coupling
      modulation during RF pulses, show that significant exchange occurs between single
      spin magnetization and two-spin product operator states when the RF field
      strength is comparable to the coupling. In particular, a long (t(p) = [2J](-1)
      s), low-power (B(1) = J/2 Hz), constant amplitude pulse applied on resonance to
      one spin in an IS system completely interconverts the spinstates S(z) <-->
      2S(x)I(z) and S(x) <--> 2S(z)I(z) when the RF is applied to the S spins, and
      interconverts S(x) <--> 2S(y)I(y) in 100% yield when the RF is applied to the I
      spins. Thus, these "J pulses," which select a bandwidth approximately equal to J
      Hz, may replace any combination of a (2J)(-1) delay period and a consecutive hard
      90 degrees pulse in any polarization transfer or multiple quantum sequence.
      Although these rectangular pulses are highly frequency selective, in general they
      increase the replaced (2J)(-1) period by only a modest 40%, a time saving of a
      factor of 5 compared to existing pulses exhibiting the same selectivity. In
      favorable cases, there is no increase in duration of a pulse sequence using a
      particular type of J pulse, the 90(J) variety, which accomplishes the third spin
      state transformation listed above. J pulses will be advantageous for systems
      subject to rapid signal loss from relaxation and more generally for the enhanced
      operation of pulse sequences via the use of J modulation during RF irradiation.

PMID- 10579950
TI  - Exact product operator evolution of weakly coupled spin-12 I(m)S(n) systems
      during arbitrary RF irradiation of the I spins.
AB  - In this article, we consider the evolution of weakly coupled I(m)S(n) systems of
      spin-12 nuclei during arbitrary RF irradiation of the I spins. Exact solutions
      are presented for the time dependence of the density operator in terms of its
      constituent product operator components for a complete set of initial states
      derived from polarization of either the I or the S spin. The solutions extend the
      range of applications that are accessible to the product operator formalism and
      its associated vector picture of nuclear spin evolution. This marriage of quantum
      mechanics and a literal vector description of spin dynamics during RF irradiation
      supports physical intuition and has led to simple pulses for selective coherence
      transfer, among other new applications. The evolution of initial states that are
      free of transverse S-spin components can be described by classical precession of
      the I-spin components about effective fields defined by the interaction between
      the coupling and RF fields. Although there is no analogue involving classical
      rotations for the evolution of initial states composed of S(x) or S(y), a vector
      description is still possible, and the solutions completely characterize the
      nature of J-coupling modulation during RF pulses. We emphasize the Cartesian
      product operator basis in the present treatment, but the solutions are readily
      obtained in any other basis that might prove suitable in analyzing an experiment.
      For a system of N coupled spins, standard exact methods involving diagonalization
      and multiplication of the 2(N) x 2(N) matrices that represent the system require
      on the order of (2(N))(3) operations to calculate the system response to a
      general RF waveform at each point in the time domain. By contrast, the efficiency
      of the present method scales linearly with the number of spins. Since the
      formalism presented also accommodates the absence of either RF irradiation or the
      coupling, the solutions provide an efficient means of general pulse sequence
      simulation, encompassing any combination of arbitrary RF waveforms, delays, and
      coherence gradients.

PMID- 10579951
TI  - In vivo triple quantum filtered twisted projection sodium MRI of human articular
      cartilage.
AB  - In this work, we present the first triple quantum filtered (TQF) sodium MR images
      of the human knee joint in vivo. A 3D TQF data set of 16 slices was obtained in
      20 min using a TQF pulse sequence preencoded to a twisted projection imaging
      readout. Images clearly demarcate patellar cartilage and also demonstrate fluid
      signal suppressed by the triple quantum filter. Biexponential transverse
      relaxation times were calculated by fitting the TQF free induction decay to a
      theoretical signal expression. The average values from three healthy volunteers
      were T(2fall)(*) = 9.59 +/- 0.35 ms and T(2rise)(*) = 0.84 +/- 0.06 ms.
      Application of TQF imaging in biological tissues is discussed.

PMID- 10579952
TI  - Non-kramers ENDOR and ESEEM of the S = 2 ferrous ion of [Fe(II)EDTA](2-).
AB  - We report here the first non-Kramers (NK) ESEEM and ENDOR study of a mononuclear
      NK center, presenting extensive parallel-mode ESEEM and ENDOR measurements on the
      S(t) = 2 ferrous center of [Fe(II)ethylenediamine-N,N,N',N'-tetraacetato](2-);
      [Fe(II)EDTA)](2-). The results disclose an anomalous equivalence of the
      experimental patterns produced by the two techniques. A simple theoretical
      treatment of the frequency-domain patterns expected for NK-ESEEM and NK-ENDOR
      rationalizes this correspondence and further suggests that the very observation
      of NK-ENDOR is the result of an unprecedentedly large hyperfine enhancement
      effect. The mixed nitrogen-carboxylato oxygen coordination of [Fe(II)EDTA](2-)
      models that of the protein-bound diiron centers, although with a higher
      coordination number. Analysis of the NK-ESEEM measurements yields the quadrupole
      parameters for the (14)N ligands of [Fe(II)EDTA](2-), K = 1.16(1) MHz, 0 </= eta
      </= 0.05, and the analysis indicates that the electronic zero-field splitting
      tetragonal axis lies along the N-N direction.

PMID- 10579953
TI  - Theoretical analysis of the inter-ligand overhauser effect: a new approach for
      mapping structural relationships of macromolecular ligands.
AB  - A theoretical framework has been developed for the evaluation of inter-ligand
      Overhauser effects (ILOE), predicted when pairs of ligands are observed in the
      presence of a macromolecular receptor which can form a ternary complex such that
      some of the protons on the two ligands are in close proximity with each other
      (generally less than approximately 5 A). Simulations for a pair of ligands with
      three spins each have been performed for a variety of geometric and rate
      parameters. Analogous to previously described calculations of TRNOE behavior,
      theoretical behavior of each of the nine cross peaks, A(ij), in a NOESY
      experiment involving ligands which can exist in the free, binary, or ternary
      complex states can be calculated. However, for exchange which is sufficiently
      rapid on the relaxation and chemical shift time scales, use of a collapsed
      matrix, C, corresponding to sums of sets of nine elements, will often be
      appropriate and generally simplifies the analysis. In order to generate inter
      ligand Overhauser effects, it is optimal for the fraction of receptor involved in
      the ternary complex to be reasonably large; i.e., concentrations of both ligands
      should be near saturation. Based on a model assuming random binding order of the
      ligands, the dependence of ILOE resonance intensities on kinetic rate constants
      roughly parallels the dependence of transferred NOE (TRNOE) intensities. For
      diffusion controlled binding, i.e., k(on) approximately 10(8) M(-1) s(-1), the
      method is best suited for equilibrium dissociation constants in the micromolar
      millimolar range (k(off) approximately 10(2)-10(5) s(-1)). Toward the slower
      dissociation rate constant end of this range, TRNOE and ILOE effects are still
      predicted, but the initial build-up curves become markedly nonlinear. For a
      kinetic binding scheme which assumes ordered binding of the ligands, the inherent
      asymmetry of the ligand binding process leads to more complex kinetics and alters
      the dependence of the ILOE on the kinetic parameters. In this case, the binding
      of the second ligand effectively reduces the exchange rate of the first ligand,
      reducing the transfer of NOE and ILOE information. The reduction in TRNOE and
      ILOE information which is prediced for the ordered ligand binding model is
      overcome at larger dissociation rate constants for either ligand 1 or ligand 2.
      In addition to the structural information available from ILOE data, the strong
      dependence of TRNOE and ILOE curves on ordered ligand binding suggests that such
      measurements could be useful for the characterization of ligand binding kinetics.

PMID- 10579954
TI  - A procedure for obtaining pure absorption 2D J-spectra: application to
      quantitative fully J-decoupled homonuclear NMR spectra.
AB  - The phase-twisted lines, resulting from a double complex Fourier transform, can
      greatly alter the quality of two-dimensional spectra. This problem, which is
      generally overcome by experimental procedures (requiring twice as much time as a
      standard measurement), is inevitable in the two-dimensional J-resolved
      experiment. This experiment is revisited theoretically and a postprocessing
      treatment, leading to pure 2D J-spectra, is deduced. Quantitative fully J
      decoupled homonuclear spectra are accordingly obtained by means of a projection
      onto the F2 axis after a 45 degrees tilt.

PMID- 10579955
TI  - Efficient refocusing of one-spin and two-spin interactions for NMR quantum
      computation.
AB  - The use of spin echoes to refocus one-spin interactions (chemical shifts) and two
      spin interactions (spin-spin couplings) plays a central role in both conventional
      NMR experiments and NMR quantum computation. Here we describe schemes for
      efficient refocusing of such interactions in both fully and partially coupled
      spin systems.

PMID- 10579956
TI  - NMR relaxation in multipolar AX systems under spin locking conditions.
AB  - A relaxation matrix has been calculated for a multipolar AX spin system under the
      on-resonance spin-locking condition. Auto- and cross-correlation terms between
      dipolar, quadrupolar, and CSA interactions are considered. It is shown that the
      spin-lock leads to many relaxation pathways being blocked, resulting in a
      considerably simplified relaxation network. The presence of spectral densities at
      zero frequency, associated with locked nuclei, allows efficient relaxation also
      in the absence of fast molecular motions.

PMID- 10579957
TI  - Probing membrane surfaces and the location of membrane-embedded peptides by (13)C
      MAS NMR using lanthanide ions.
AB  - A simple but efficient (13)C MAS NMR method is presented for the determination of
      the location of embedded molecules such as peptides relative to biological
      membrane surfaces by exploiting the interaction with paramagnetic lanthanide
      ions. Using various aqueous Dy(3+) concentrations a distance-dependent
      differential paramagnetic quenching of NMR lipid resonance intensities for
      specific carbon sites was observed, with residues at the bilayer surface quenched
      effectively and hydrophobic sites unaffected by Dy(3+). Tested on the membrane
      embedded 50 residue long M13 coat protein, (13)C labeled at its Val-29 and Val-31
      residues, no paramagnetic quenching was observed for the peptide resonances by
      Dy(3+), suggesting that Val-29 and Val-31 are not in close proximity to the
      bilayer interface, but buried deeply inside the hydrophobic region of the lipid
      bilayer.

PMID- 10579958
TI  - Asymmetric MRI magnet design using a hybrid numerical method.
AB  - This paper describes a hybrid numerical method for the design of asymmetric
      magnetic resonance imaging magnet systems. The problem is formulated as a field
      synthesis and the desired current density on the surface of a cylinder is first
      calculated by solving a Fredholm equation of the first kind. Nonlinear
      optimization methods are then invoked to fit practical magnet coils to the
      desired current density. The field calculations are performed using a semi
      analytical method. A new type of asymmetric magnet is proposed in this work. The
      asymmetric MRI magnet allows the diameter spherical imaging volume to be
      positioned close to one end of the magnet. The main advantages of making the
      magnet asymmetric include the potential to reduce the perception of
      claustrophobia for the patient, better access to the patient by attending
      physicians, and the potential for reduced peripheral nerve stimulation due to the
      gradient coil configuration. The results highlight that the method can be used to
      obtain an asymmetric MRI magnet structure and a very homogeneous magnetic field
      over the central imaging volume in clinical systems of approximately 1.2 m in
      length. Unshielded designs are the focus of this work. This method is flexible
      and may be applied to magnets of other geometries.

PMID- 10579959
TI  - 1H DNP at 1.4 T of water doped with a triarylmethyl-based radical.
AB  - Recently a triarylmethyl-based (TAM) radical has been developed for research in
      biological and other aqueous systems, and in low magnetic fields, 10 mT or less,
      large (1)H dynamic nuclear polarization (DNP) enhancements have been reported. In
      this paper the DNP properties of this radical have been investigated in a
      considerably larger field of 1.4 T, corresponding to proton and electron Larmor
      frequencies of 60 MHz and 40 GHz, respectively. To avoid excessive microwave
      heating of the sample, an existing DNP NMR probe was modified with a screening
      coil, wound around the sample capillary and with its axis perpendicular to the
      electric component of the microwave field. It was found that with this probe the
      temperature increase in the sample after 4 s of microwave irradiation with an
      incident power of 10 W was only 16 degrees C. For the investigations, 10 mM of
      the TAM radical was dissolved in deionized, but not degassed, water and put into
      a 1-mm i.d. and 6-mm long capillary tube. At 26 degrees C the following results
      were obtained: (I) The relaxivity of the radical is 0.07 (mMs)(-1), in accordance
      with the value extrapolated from low-field results; (II) The leakage factor is
      0.63, the saturation factor at maximum power is 0.85, and the coupling factor is 
      0.0187. It is shown that these results agree very well with an analysis where the
      electron-dipolar interactions are the dominant DNP mechanism, and where the
      relaxation transitions resulting from these interactions are governed by
      translational diffusion of the water molecules. Finally, the possibilities of
      combining DNP with magnetic resonance microscopy (MRM) are discussed. It is shown
      that at 26 degrees C the overall DNP-enhanced proton polarization should become
      maximal in an external field of 0.3 T and become comparable to the thermal
      equilibrium polarization in a field of 30 T, considerably larger than the largest
      high-resolution magnet available to date. It is concluded that DNP MRM in this
      field, which corresponds to a standard microwave frequency of 9 GHz, has the
      potential to significantly increase the sensitivity in NMR and MRI experiments of
      small aqueous samples doped with the TAM radical.

PMID- 10579961
TI  - Bimonthly Publication, Same Number of Pages.

PMID- 10579960
TI  - Capillary array electrophoretic NMR of proteins in biological buffer solutions.
AB  - The capillary array electrophoretic NMR (CA-ENMR) was developed to study protein
      mixtures in biological buffer solutions of high ionic strength. By enhancing the
      strength of the effective electric field across the sample, the technique permits
      the detection of the electrophoretic motion of 1 mM lysozyme in 50 mM NaH(2)PO(4)
      aqueous solution, which was previously not achievable using conventional ENMR.
      Heat-induced convection was dramatically reduced by blocking convective current
      loops and by improving the efficiency of heat exchange. Thus, the capability of
      ENMR study of electrolyte solutions was extended from low to high ionic strength.
      In addition, capillary walls reduced rf-induced electrical eddy current, thereby
      maintaining good probe Q factors. Because of its parallel configuration to the
      static magnetic field, the capillary array chamber produced no susceptibility
      distortions of the ENMR signal. The technique offers great potential in
      characterizing multiple protein conformations and protein interactions in
      solution.

PMID- 10579962
TI  - Playing Follow the Leader: Status-Determining Traits in Relation to Collective
      Efficacy across Cultures.
AB  - Increasing pressure on managing international teams has created a need for
      further understanding culturally relevant group processes. In this study, the
      cultural context of power distance is examined in relation to the status
      characteristics possessed by group members and their influence on group efficacy
      estimations and performance. Data obtained from 288 senior managers coming from
      England, France, Thailand, and the United States were used to test the hypothesis
      that power distance would moderate the influence of member status on collective
      decisions made by a group. Results demonstrate that in high power distance
      cultures, collective judgments of group capability are more strongly tied to
      higher rather than to lower status group members' personal judgments. In low
      power distance cultures, members appear to contribute comparably to collective
      efficacy judgments. The implications of the study are discussed in terms of
      status differentials and group decision making across cultures. Copyright 1999
      Academic Press.

PMID- 10579963
TI  - Value-Focused Thinking versus Alternative-Focused Thinking: Effects on Generation
      of Objectives.
AB  - Within the context of decision analysis, the aim of this work is to discover
      whether the structure of objectives generated with value-focused thinking (VFT)
      is different from the structure generated with alternative-focused thinking
      (AFT). In the first of two studies, two different groups of subjects created a
      structure of objectives for the same decision problem. Fourteen independent
      assessments were made for each group. After the terms used by the two groups,
      were standardized, it was found that the group using VFT generated a more
      extensive and hierarchical structure than the AFT group. With regard to the
      content of the objectives, it can be stated that the VFT structure covered
      aspects of the problem not covered by AFT. In the second study, structures
      representative of the two approaches were judged by a group of decision-makers
      actually involved in the problem-with respect to several qualities. It was found
      that the structure generated by VFT was equal or superior to that generated by
      AFT in all qualities judged. Copyright 1999 Academic Press.

PMID- 10579964
TI  - Comparison Opportunity and Judgment Revision.
AB  - Prior evaluations are frequently challenged and need to be revised. We propose
      that an important determinant of such revisions is the degree to which the
      challenge provides an opportunity to compare the target against a competitor.
      Whenever a challenge offers an opportunity, the information contained in the
      challene will carry a disproportionate weight in the revised judgments. We call
      this proposition the comparison-revision hypothesis. In Experiments 1-3, we
      manipulated comparison opportunity by varying the format of the challenge and
      examined the weights assigned to different inputs in the revised judgments. The
      results indicate that prior information about the target receives a greater
      weight under a noncomparative challenge (which provides information only about
      the target) than under a comparative challenge (which compares the target with a
      competitor). In contrast, information presented in the challenge receives a
      greater weight under a comparative challenge than under a noncomparative
      challenge. Interestingly, when presented in a comparative format, the information
      contained in the challenge received a relatively disproportionate weight even
      when the attributes presented in the challenge were less important than those on
      which the prior target evaluations were based. Results from Experiment 4 suggest
      that, under certain conditions, even a noncomparative challenge from a superior
      competitor can provide strong comparison opportunity and thus cause greater
      revisions in the prior evaluations of the target. Specifically, a greater
      elaboration of the initial target information and a high degree of
      commensurability between the target and competitor information jointly promote
      comparison opportunity and thus cause greater revisions of the prior target
      judgments. Our findings offer important extensions to previous research on the
      effects of amount and elaboration of prior target information on subsequent
      judgment revision. Copyright 1999 Academic Press.

PMID- 10579965
TI  - The Negotiation Matching Process: Relationships and Partner Selection.
AB  - We present 3 studies that examine the process of partner selection in
      negotiations and the influence that relationships may have on the partner
      selection decision. In Study 1, we present a simulated matching market experiment
      in which we compare the matching process when relationships can influence the
      partner-selection decision with the matching process when relationships cannot
      influence this decision. We find that when relationships are not allowed to
      influence the matching process, there are more economically optimal agreements, a
      larger market surplus, and more search activity. In Study 2, a simulation of a
      naturally occurring market selection process provides additional quantitative
      support for the findings from Study 1 and offers qualitative data on the
      reasoning process behind partner selection, including the social factors that are
      influential in this decision. Study 3 utilizes a repeated trial experimental
      simulation to offer further support for the negative relationship between
      relationships and economic outcomes and to suggest that the relative power of the
      negotiators influences the extent to which relationships help versus hurt
      individual profitability. Implications of these findings are discussed. Copyright
      1999 Academic Press.

PMID- 10579966
TI  - More attention to functional disorders.

PMID- 10579967
TI  - Thalidomide therapy for patients with refractory Crohn's disease: an open-label
      trial.
AB  - BACKGROUND & AIMS: Inhibition of tumor necrosis factor is a proposed mechanism
      for the anti-inflammatory properties of thalidomide. We performed an open-label
      trial of thalidomide in refractory Crohn's disease. METHODS: Twenty-two patients
      with refractory Crohn's disease (Crohn's Disease Activity Index [CDAI] > 200
      and/or draining perianal disease) initiated therapy with thalidomide, 200 mg at
      bedtime (18 patients), or 300 mg at bedtime (4 patients). CDAI and goal interval
      scores (GIS) were assessed at weeks 0, 4, and 12. Clinical response for patients
      with luminal disease was defined as reduction in CDAI score of >150 points and
      for fistula patients was 2 scores of >/=1+ in 3 parameters of the GIS. Clinical
      remission was defined as a total CDAI < 150 (luminal patients) or >/=2+ for all
      parameters of the GIS (fistula patients). RESULTS: Nine patients with luminal
      disease and 13 with fistulas (16 male, 6 female) were enrolled. The median CDAI
      score at entry was 371 (95-468). Sixteen patients completed 4 weeks of treatment
      (12 clinical responses, 4 clinical remissions). All 14 patients completing 12
      weeks met criteria for clinical response. Nine achieved clinical remission (3
      luminal, 6 fistula patients). The median CDAI score was 175 (30-468; P < 0.001
      vs. baseline). CONCLUSIONS: Thalidomide is efficacious in some patients with
      refractory Crohn's disease.

PMID- 10579968
TI  - An open-label pilot study of low-dose thalidomide in chronically active, steroid
      dependent Crohn's disease.
AB  - BACKGROUND & AIMS: Thalidomide decreases production of tumor necrosis factor
      alpha, a proinflammatory cytokine associated with Crohn's disease (CD). In this
      study the safety, tolerance, and efficacy of low-dose thalidomide were evaluated
      for treatment of moderate-to-severe, steroid-dependent CD. METHODS: Twelve adult
      male patients with Crohn's Disease Activity Index (CDAI) scores of > or = 250 and
      < or = 500 despite > or = 20 mg prednisone/day were enrolled. The first 6
      patients received 50 mg thalidomide every night, the next 6 received 100 mg every
      night. Steroid doses were stable during the first 4 weeks of treatment, then
      tapered during weeks 5-12. CDAI was used to assess response. RESULTS: (1) Disease
      activity improved consistently in all patients during weeks 1-4: 58% response,
      17% remission. (2) Clinical improvement was generally maintained despite steroid
      taper during weeks 5-12. All patients were able to reduce steroids by >/=50%.
      Forty-four percent discontinued steroids entirely. In weeks 5-12, 70% of patients
      responded and 20% achieved remission. (3) Side effects were mild and mostly
      transient, with the most common being drowsiness, peripheral neuropathy, edema,
      and dermatitis. CONCLUSIONS: Low-dose thalidomide appears to be well tolerated
      and effective over a 12-week period. Results of this pilot study support the need
      for controlled multicenter trials of thalidomide for treatment of CD.

PMID- 10579969
TI  - Polypectomy may be adequate treatment for adenoma-like dysplastic lesions in
      chronic ulcerative colitis.
AB  - BACKGROUND & AIMS: Chronic ulcerative colitis (CUC)-associated adenoma-like DALMs
      (dysplasia-associated lesions or masses) pose a difficult clinical problem to
      both gastroenterologists and pathologists because they are difficult to
      distinguish endoscopically and pathologically from sporadic adenomas that develop
      coincidentally in patients with CUC. The aim of this study was to evaluate the
      outcome of CUC patients with an adenoma-like DALM treated conservatively and to
      compare the findings with CUC patients with a coincidental sporadic adenoma.
      METHODS: Clinical, endoscopic, and pathological features and outcome of 24 CUC
      patients with an adenoma-like DALM were compared with those of 10 CUC patients
      with a coincidental sporadic adenoma and 49 non-CUC (control) patients with a
      sporadic adenoma. Patients were followed up for a mean of 42.4 and 41.2 months
      for the 2 CUC groups, respectively, and 37.0 months for the non-CUC controls by
      endoscopic surveillance. RESULTS: Of the 24 CUC patients with adenoma-like DALMs
      (male/female ratio, 14/10; mean age, 61.5 years; mean duration of colitis, 10.4
      years), 14 (58%) developed further adenoma-like DALMs within the follow-up
      interval. Only 1 patient (4%) developed an isolated focus of low-grade dysplasia,
      and none developed adenocarcinoma. Five of 10 (50%) CUC patients with sporadic
      adenomas developed further adenomas, and none of the patients in this group
      developed either dysplasia or adenocarcinoma. Of the 49 non-CUC control patients,
      39% developed further adenomas. CONCLUSIONS: CUC patients who develop an adenoma
      like DALM that endoscopically and histologically resembles a sporadic adenoma,
      regardless of its location (either within or outside areas of documented
      colitis), may be treated with polypectomy and endoscopic surveillance because of
      its relatively benign course.

PMID- 10579970
TI  - Colonoscopic polypectomy in chronic colitis: conservative management after
      endoscopic resection of dysplastic polyps.
AB  - BACKGROUND & AIMS: Adenomatous polyps are by definition dysplastic and
      pathologically indistinguishable from the dysplasia-associated lesion or mass
      (DALM) described in 1981. Yet, adenomatous polyps in noncolitic colons are
      usually removed definitively endoscopically, whereas DALMs are regarded as
      harbingers of colon cancer, mandating colectomy. METHODS: Since 1988, all of our
      patients with chronic ulcerative or Crohn's colitis and dysplastic polyps and no
      coexistent dysplasia in flat mucosa underwent colonoscopic polypectomy. Biopsy
      specimens were obtained also adjacent to polypectomy sites, from strictures, and
      throughout the colon at 10-cm intervals. Follow-up colonoscopies and biopsies
      were performed within 6 months after polypectomy and yearly thereafter. RESULTS:
      Colonoscopy in 48 patients with chronic colitis (mean duration, 25.4 years)
      resected 70 polyps (60 in colitic and 10 in noncolitic mucosa). Polyps were
      detected on screening colonoscopies (29%) and on surveillance (71%). Pathology
      was tubular adenoma in all polyps from noncolitic mucosa and low-grade dysplasia
      (57), high-grade dysplasia (2), or carcinoma (1) in polyps from colitic mucosa.
      Subsequent colonoscopies (mean follow-up, 4.1 years) revealed additional polyps
      in 48% but no carcinomas. Surgical resection (6 patients) for recurrent polyps
      confirmed colonoscopic findings. No dysplasia or cancers in flat mucosa were
      found at surgery or on follow-up colonoscopies. CONCLUSIONS: In patients with
      chronic colitis who have no dysplasia in flat mucosa, colonoscopic resection of
      dysplastic polyps can be performed effectively, just as in noncolitic colons.

PMID- 10579971
TI  - Unsedated small-caliber esophagogastroduodenoscopy (EGD) versus conventional EGD:
      a comparative study.
AB  - BACKGROUND & AIMS: Significant portions of the cost and complications of
      esophagogastroduodenoscopy (EGD) are related to sedation. This study aimed to
      assess the feasibility, acceptability, and accuracy of unsedated small-caliber
      transoral EGD (sc-EGD). METHODS: A 4-phase study was performed in healthy
      volunteers and patients. Phases 1 and 2 involved assessment of the technical
      feasibility of sedated sc-EGD and the tolerability of unsedated sc-EGD,
      respectively, in volunteers. Subsequently, the technical feasibility,
      tolerability, and diagnostic accuracy of sedated and unsedated sc-EGD were
      determined by having each patient undergo sc-EGD (Pentax EG-1840) with (phase 3)
      and without (phase 4) sedation, followed by sedated conventional EGD (c-EGD)
      (Olympus GIF-100 or GIF-Q140) by a staff endoscopist blinded to the findings of
      the sc-EGD. The t test for paired samples was used for statistical analysis. A P
      value of <0.05 was considered significant. RESULTS: Sedated and unsedated sc-EGD
      were technically feasible and tolerable in all volunteers. In patients, compared
      with sedated c-EGD, sedated and unsedated sc-EGD were 96% and 97% accurate,
      respectively. The overall acceptability of unsedated sc-EGD was only slightly
      worse than that of sedated c-EGD (median, 2 vs. 1 on a scale of 1-10). After
      unsedated sc-EGD, 98% of patients expressed willingness to undergo the procedure
      again. No complications were observed during any phase of the study. CONCLUSIONS:
      Unsedated sc-EGD is technically feasible, tolerable, and accurate. It can
      potentially decrease the costs and complications of sedated conventional EGD.

PMID- 10579972
TI  - Conservation of the cag pathogenicity island of Helicobacter pylori: associations
      with vacuolating cytotoxin allele and IS605 diversity.
AB  - BACKGROUND & AIMS: Specific regions of the cag pathogenicity island (PAI)
      believed to enhance the virulence of Helicobacter pylori, as well as vacuolating
      cytotoxin gene alleles and IS605 inserts, were investigated to define diversity
      within infecting strain populations from patients with peptic ulcer disease and
      from healthy individuals. METHODS: The H. pylori studied comprised 67 isolates
      from 26 subjects and 14 reference strains. Specific polymerase chain reaction
      assays were used to test for cagA and picB in the cagI region, the virD4
      homologue in the cagII region, IS605 in the genome and in the cag PAI, the "empty
      site" indicating absence of the cag PAI, and different vacA gene alleles.
      RESULTS: Most (89%) subjects were infected by H. pylori with a contiguous cag
      PAI. No intermediate forms were found. IS605 was not detected within the cag PAI
      of any strain but was present elsewhere in the genomes of strains from 62% of
      subjects. Twenty individuals were infected with genotypically conserved
      populations of H. pylori. Six subjects had mixed infections, and in 3 of these
      cag(+)/cag(-) variants were present. CONCLUSIONS: The cag PAI-positive H. pylori
      was a feature of most infected individuals, irrespective of severity of
      associated disease. Combined genotyping showed that 8 individuals (31%) had mixed
      infections, which suggests that strain population structure may be an additional
      contributing factor in disease development.

PMID- 10579973
TI  - Treatment of Helicobacter pylori infection in rhesus monkeys using a novel
      antiadhesion compound.
AB  - BACKGROUND & AIMS: Helicobacter pylori can be eradicated by administration of
      antimicrobials, but resistant strains have emerged, and there is a need for novel
      therapeutic approaches against this infection. This study aimed to determine the
      safety and efficacy of 3'-sialyllactose sodium salt (3'SL), an oligosaccharide
      that occurs naturally in human and bovine milk and that can inhibit the adhesion
      of H. pylori to human epithelial cells in vitro. METHODS: Twelve H. pylori
      positive rhesus monkeys were given 3'SL, either alone (regimens 1 and 2; n = 6)
      or in combination with omeprazole (regimen 3; n = 4), or bismuth subsalicylate
      (regimen 4; n = 6). Videogastroscopies were performed before, during, and after
      treatment, and gastric biopsy specimens were obtained for quantitative cultures
      and histology. The H. pylori strains colonizing the animals were genotyped.
      RESULTS: After regimen 1 or 2, 2 of 6 animals were cured permanently, and a third
      animal was transiently cleared. The 3 other animals remained persistently
      colonized and did not respond to regimen 3. Regimen 4 resulted in transient
      decreases in colony counts in 3 of 6 other animals. Gastritis was suppressed only
      in the 2 animals who became persistently H. pylori negative. There was no
      apparent relation between 3'SL efficacy and any of the H. pylori tested
      genotypes. No side effects were observed in any of the animals receiving 3'SL.
      CONCLUSIONS: Antiadhesive therapy is safe; it can cure or decrease H. pylori
      colonization in some rhesus monkeys, but the addition of a proton pump inhibitor
      or bismuth subsalicylate does not increase cure rate.

PMID- 10579974
TI  - Cdx1 promotes differentiation in a rat intestinal epithelial cell line.
AB  - BACKGROUND & AIMS: Homeobox genes are involved in establishing and maintaining
      differentiated patterns in adult tissues. Cdx1 might carry out that function in
      the intestinal epithelium because its expression is specific to that tissue and
      increases during development. METHODS: Cdx1 expression was induced in IEC-6
      intestinal epithelial cells by stable transfection, and subsequent changes in
      cell growth, resistance to apoptosis, migration, and differentiation were
      monitored. RESULTS: Compared with control, IEC-6/Cdx1 cells proliferated more
      rapidly, were more resistant to apoptosis, and migrated 3-4 times faster, as
      shown by an in vitro wound assay. IEC-6/Cdx1 cells in culture formed multilayers.
      Morphology of the top layer was similar to that of columnar epithelium, with
      cells showing typical features of differentiated enterocytes, including complex
      junctions and well-developed microvilli with glycocalix. Expression of 2 markers
      of enterocyte differentiation, aminopeptidase N and villin, was induced in IEC
      6/Cdx1 cells. Aminopeptidase N was targeted to the basolateral membrane, and
      villin was localized to the cytoplasm. Actin filaments, which were mostly present
      in transcytoplasmic stress fibers in control cells, were redistributed to the
      cortex in Cdx1-transfected cells. CONCLUSIONS: Cdx1 expression in IEC-6 cells
      induces phenotypic changes characteristic of differentiating enterocytes,
      suggesting an important role for Cdx1 in the transition from stem cells to
      proliferating/transit cells.

PMID- 10579975
TI  - Coordinated expression of 3' hox genes during murine embryonal gut development:
      an enteric Hox code.
AB  - BACKGROUND & AIMS: Hox genes are highly conserved developmental control genes
      that may be organized and expressed in the form of a code required for correct
      morphogenesis. Little is known about their control of the embryonal gut. However,
      Hox paralogues 4 and 5, which are expressed at the sites of origin of vagal
      neural crest cells and splanchnic mesoderm, are likely to be important. We have
      studied the expression domains of these genes in the gut both spatially and
      temporally. METHODS: CD1 mice embryos of embryonic days E8.5-E17.5 were studied.
      The spatial and temporal expression patterns of messenger RNA of Hoxa4, b4, c4,
      d4, a5, c5, and b5 homeoprotein were determined by in situ hybridization and
      immunohistochemistry in whole embryos, whole gastrointestinal tracts, and
      vibratome sections. RESULTS: There were different spatial, temporal, and
      combinatorial expression patterns in different morphological regions: foregut,
      prececal gut, cecum, and postcecal gut. Two dynamic gradients, rostral and
      caudal, were coordinated with nested expression domains along the gut primordium.
      Region-specific domains were present in the stomach and cecum. CONCLUSIONS: The
      expression patterns of genes in paralogous groups 4 and 5 suggest that they are
      organized to form a specific enteric Hox code required for correct enteric
      development.

PMID- 10579976
TI  - Prostaglandin E(2) stimulates rat and human colonic mucin exocytosis via the
      EP(4) receptor.
AB  - BACKGROUND & AIMS: Mucins form an integral part of innate host defenses against
      intestinal pathogens and irritants. However, the mechanisms whereby mucin
      secretion is regulated during inflammation are poorly understood. Because
      prostaglandin E(2) (PGE(2)) is prominent during intestinal inflammation, we
      investigated its receptor-signaling pathway coupled to mucin exocytosis in the
      colonic epithelial cell line LS174T and rat colon. METHODS: Reverse-transcription
      polymerase chain reaction (RT-PCR) and [(3)H]PGE(2) binding assays were used to
      identify the PGE(2) receptors (EP). Intracellular cyclic adenosine monophosphate
      ([cAMP](i)) was quantified by enzyme immunoassay. Mucins were metabolically
      labeled with [(3)H]glucosamine, and mucin secretion was quantified by Sepharose
      4B column chromatography, immunoblot analysis, and cesium chloride density
      gradient centrifugation. RESULTS: RT-PCR and DNA sequence analysis identified
      EP(2), EP(3), and EP(4) receptors. Mucin secretion and [cAMP](i) production by
      LS174T cells were stimulated dose-dependently by PGE(2), the EP(4)-receptor
      agonist 1-OH-PGE(1), and the EP(3)/EP(4) agonist M&B28767 and were inhibited with
      the adenylate cyclase inhibitor SQ22536. The EP(1), EP(2), and EP(3)/EP(1)
      receptor agonists iloprost, butaprost, and sulprostone, respectively, had no
      effect. Similar results were obtained in rat colonic loop studies confirming that
      the EP(4) receptor is linked to mucin exocytosis in vivo. [(3)H]PGE(2) binding to
      cell membranes identified a high-affinity binding site that was competitively
      inhibited by M&B28767 (EP(3)/EP(4)) > 1-OH-PGE(1) (EP(4)) > sulprostone
      (EP(3)/EP(1)) > butaprost (EP(2)). CONCLUSIONS: PGE(2) coupling to the EP(4)
      receptor stimulates [cAMP](i)-dependent mucin exocytosis.

PMID- 10579977
TI  - L-Type calcium channels in enterochromaffin cells from guinea pig and human
      duodenal crypts: an in situ study.
AB  - BACKGROUND & AIMS: This study has investigated stimulus-secretion coupling of
      enterochromaffin cells by studying the cellular location and function of voltage
      gated Ca(2+) channels within small intestinal crypts. METHODS: Digital
      fluorescence imaging and electrochemical detection were used to measure
      intracellular Ca(2+) responses and serotonin (5-hydroxytryptamine [5-HT])
      secretion in intact crypts isolated from guinea pig and human duodenum. RESULTS:
      In fluo-3-loaded crypts, electrical depolarization with high K(+) solution
      increased cytosolic free [Ca(2+)] only in single cells subsequently identified by
      immunocytochemistry as enterochromaffin cells. In guinea pig enterochromaffin
      cells, the L-type Ca(2+) channel agonist FPL 64176 (3 micromol/L) did not change
      resting intracellular [Ca(2+)] but potentiated the depolarization-evoked increase
      in [Ca(2+)] (298 +/- 72 nmol/L) by 19 +/- 3-fold. In the majority of human
      enterochromaffin cells, FPL 64176 alone increased resting [Ca(2+)] by 423 +/- 171
      nmol/L. Secretion studies in guinea pig crypts showed that high K(+) and FPL
      64176 caused a 12-fold increase in 5-HT release. Noradrenaline caused increases
      in both enterochromaffin cell [Ca(2+)] and 5-HT release. CONCLUSIONS: Using this
      approach, we have found that in duodenal crypts, enterochromaffin cells, but not
      other epithelial cells, contain L-type voltage-gated Ca(2+) channels involved in
      regulating 5-HT secretion. These data have implications for the pharmacological
      control of intestinal disorders involving enterochromaffin cell dysfunction.

PMID- 10579978
TI  - Hepatocanalicular bile salt export pump deficiency in patients with progressive
      familial intrahepatic cholestasis.
AB  - BACKGROUND & AIMS: Progressive familial intrahepatic cholestasis (PFIC), an
      inherited liver disease of childhood, is characterized by cholestasis and either
      normal or increased serum gamma-glutamyltransferase activity. Patients with
      normal gamma-glutamyltransferase activity have mutations of the FIC1 locus on
      chromosome 18q21 or mutations of the BSEP gene on chromosome 2q24. Also, patients
      with bile acid synthesis defects have low gamma-glutamyltransferase activity. We
      investigated expression of the bile salt export pump (BSEP) in liver samples from
      patients with a PFIC phenotype and correlated this with BSEP gene mutations.
      METHODS: BSEP and multidrug resistance protein 2 (MRP2) expressions were studied
      by immunohistochemistry in liver specimens of 28 patients and BSEP gene mutation
      analysis in 19 patients. Bile salt kinetics were studied in 1 patient. RESULTS:
      Sixteen of 28 liver samples showed no canalicular BSEP staining. Staining for
      MRP2 showed a normal canalicular pattern in all but 1 of these samples. Ten of 19
      patients showed BSEP gene mutations; BSEP protein expression was lacking in all
      10 patients. No mutations were found in 9 of 19 patients, and in all except 1,
      BSEP protein expression was normal. Bile salt concentration in bile of BSEP
      negative/MRP2-positive PFIC patients was 0.2 +/- 0.2 mmol/L (n = 9; <1% of
      normal) and in BSEP-positive PFIC patients 18.1 +/- 9.9 mmol/L (n = 3; 40% of
      normal). The kinetic study confirmed the dramatic decrease of bile salt secretion
      in BSEP-negative patients. CONCLUSIONS: The findings show a close correlation
      between BSEP gene mutations and canalicular BSEP expression. Biliary secretion of
      bile salts is greatly reduced in BSEP-negative patients.

PMID- 10579979
TI  - Localization of the Wilson's disease protein in human liver.
AB  - BACKGROUND & AIMS: Wilson's disease is an autosomal-recessive disorder of copper
      metabolism that results from the absence or dysfunction of a copper-transporting
      P-type adenosine triphosphatase that leads to impaired biliary copper excretion
      and disturbed holoceruloplasmin synthesis. To gain further insight into the role
      of the Wilson's disease protein in hepatic copper handling, its localization in
      human liver was investigated. METHODS: By use of a specific antibody,
      localization of the Wilson's disease protein was studied in liver membrane
      fractions and liver sections by immunoblotting, immunohistochemistry, and double
      label confocal scanning laser microscopy. RESULTS: The 165-kilodalton protein,
      found by immunoblotting, was most abundant mainly in isolated plasma membrane
      fractions enriched in canalicular domains. Immunohistochemistry revealed
      intracellular punctuate staining of hepatocytes in certain regions of the liver,
      whereas a canalicular membrane staining pattern was observed in other regions.
      Double-labeling studies showed that in the latter regions the transporter is
      present mainly in vesicular structures just underneath the canalicular membrane
      that are positive for markers of the trans-Golgi network. A weak staining of the
      canalicular membrane, identified by staining for P-glycoprotein, was observed.
      CONCLUSIONS: These results show that in human liver the Wilson's disease protein
      is predominantly present in trans-Golgi vesicles in the pericanalicular area,
      whereas relatively small amounts of the protein appear to localize to the
      canalicular membrane, consistent with a dual function of the protein in
      holoceruloplasmin synthesis and biliary copper excretion.

PMID- 10579980
TI  - Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated
      with the control of infection.
AB  - BACKGROUND & AIMS: Cytotoxic T cells have been suggested to be responsible for
      lysis of hepatitis B virus (HBV)-infected hepatocytes and control of virus
      infection. The frequency, kinetics, phenotype, and capacity for clonal expansion
      of circulating HBV-specific CD8 cells were analyzed directly in patients with
      acute HBV infection to clarify their pathogenetic role. METHODS: Three HLA-A2
      peptide tetramers able to visualize HBV core, envelope, and polymerase epitope
      specific cytotoxic T lymphocytes were synthesized and used for flow cytometric
      analysis of antigen-specific populations. RESULTS: Tetramer-positive cells
      specific for the core 18-27 epitope were found at a higher frequency than those
      specific for polymerase 575-583 and envelope 335-343 epitopes in most patients
      with acute HBV. The number of HBV-specific CD8 cells was highest during the
      clinically acute stage of infection and decreased after recovery. These cells
      expressed an activated phenotype and had an impaired capacity to expand in vitro
      and to display cytolytic activity in response to peptide stimulation. Recovery of
      these functions was observed when the frequency of specific CD8 cells decreased,
      coincident with a progressive decrease in their expression of activation markers.
      CONCLUSIONS: This study provides the first ex vivo evidence that the highest
      frequency of circulating HBV-specific CD8 cells coincides with the clinically
      acute phase of hepatitis B. These cells exhibit an activated phenotype with
      limited further proliferative capacity that is restored during recovery.

PMID- 10579981
TI  - Hepatitis C virus-like particles synthesized in insect cells as a potential
      vaccine candidate.
AB  - BACKGROUND & AIMS: Hepatitis C virus (HCV) is a leading cause of chronic
      hepatitis in the world. Successful vaccine development is crucial in controlling
      global HCV infection. We have previously described the generation of HCV-like
      particles (HCV-LPs) in insect cells using a recombinant baculovirus containing
      the complementary DNA of the HCV structural proteins. These HCV-LPs had similar
      morphological and biophysical properties as the putative virions. In this study,
      we analyzed the structural features, antigenic composition, seroreactivity, and
      immunogenicity of purified HCV-LPs. METHODS: HCV-LPs were analyzed by electron
      microscopy and antibody immunolabeling and precipitation. An enzyme-linked
      immunosorbent assay (ELISA) using HCV-LPs was developed. The humoral response to
      HCV-LPs in mice was studies by core and envelope ELISAs, Western immunoblotting,
      and immunofluorescence. RESULTS: Structural and antigenic compositions of HCV-LPs
      were shown to be similar to those of putative HCV virions. Using the HCV-LP
      ELISA, high-titer anti-HCV antibodies were detected in individuals infected with
      various HCV genotypes. In vivo, HCV-LPs elicited a humoral response broadly
      directed against HCV structural proteins. CONCLUSIONS: HCV-LPs resemble HCV
      virions and are capable of inducing a humoral response targeted against various
      regions of HCV structural proteins, suggesting that HCV-LPs may be promising as a
      potential vaccine candidate.

PMID- 10579982
TI  - Differential expression of basolateral and canalicular organic anion transporters
      during regeneration of rat liver.
AB  - BACKGROUND & AIMS: Liver regeneration in response to various forms of injury or
      surgical resection is a complex process resulting in restoration of the original
      liver mass and maintenance of liver-specific functions such as bile formation.
      However, liver regeneration is frequently associated with cholestasis, whose
      molecular pathogenesis remains unknown. METHODS: To study the molecular
      mechanisms leading to cholestasis, expression of all major hepatic organic anion
      transporters contributing to bile formation was determined for up to 2 weeks in
      rats after 70% partial hepatectomy. RESULTS: Inversely related to serum bile acid
      levels, basolateral transporters including the sodium-taurocholate cotransporter
      (Ntcp) and the organic anion transporting polypeptides Oatp1 and Oatp2 were
      markedly down-regulated at both protein and steady-state mRNA levels by 50%-60%
      of controls (P < 0.05) during early replicative stages of regeneration (12 hours
      to 2 days) with a slightly delayed time course for Oatp2. Expression of all
      basolateral transporters returned to control values between 4 and 4 days after
      partial hepatectomy. In contrast, protein and mRNA expression of both the
      canalicular ATP-dependent bile salt export pump (Bsep) and the multiorganic anion
      transporter Mrp2 remained unchanged or were slightly increased during liver
      regeneration, but also returned to control values 7-14 days after partial
      hepatectomy. CONCLUSIONS: The data suggest a differential regulation of
      basolateral and canalicular organic anion transporters in the regenerating liver.
      Unaltered expression of Bsep and Mrp2 provides a potential molecular mechanism
      for regenerating liver cells to maintain or even increase bile secretion
      expressed per weight of remaining liver. However, down-regulation of basolateral
      organic anion transporters might protect replicating liver cells by diminishing
      uptake of potentially hepatotoxic bile salts, because the remaining liver
      initially cannot cope with the original bile acid pool size.

PMID- 10579983
TI  - Expansion of Pdx1-expressing pancreatic epithelium and islet neogenesis in
      transgenic mice overexpressing transforming growth factor alpha.
AB  - BACKGROUND & AIMS: The progenitor cells responsible for transforming growth
      factor (TGF)-alpha-induced pancreatic ductal metaplasia and neoplasia remain
      uncharacterized. During pancreatic development, differentiated cell types arise
      from ductal progenitor cells expressing the Pdx1 homeodomain transcription
      factor. The aims of this study were, first, to evaluate the role of Pdx1
      expressing stem cells in MT-TGFalpha transgenic mice, and second, to further
      characterize cell proliferation and differentiation in this model. METHODS: To
      assess Pdx1 gene expression in normal and metaplastic epithelium, we performed in
      vivo reporter gene analysis using heterozygous Pdx1(lacZ/+) and bigenic
      Pdx1(lacZ/+)/MT-TGFalpha mice. RESULTS: Pdx1(lacZ/+)/MT-TGFalpha bigenics showed
      up-regulated Pdx1 expression in premalignant metaplastic ductal epithelium. In
      addition to Pdx1 gene activation, TGF-alpha-induced metaplastic epithelium
      demonstrated a pluripotent differentiation capacity, as evidenced by focal
      expression of Pax6 and initiation of islet cell neogenesis. The majority of Pdx1
      positive epithelial cells showed no expression of insulin, similar to the pattern
      observed during embryonic development. CONCLUSIONS: Overexpression of TGF-alpha
      induces expansion of a Pdx1-expressing epithelium characterized by focal
      expression of Pax6 and initiation of islet neogenesis. These findings suggest
      that premalignant events induced by TGF-alpha in mouse pancreas may recapitulate
      a developmental program active during embryogenesis.

PMID- 10579984
TI  - Decreased food intake and body weight in pancreatic polypeptide-overexpressing
      mice.
AB  - BACKGROUND & AIMS: Pancreatic polypeptide (PP) is a 36-amino acid hormone
      produced by F cells within the pancreatic islets and the exocrine pancreas. The
      definitive function of PP in mammalian physiology remains to be determined. This
      study examined the effects of chronic overexpression of PP through the
      development of PP transgenic mice. METHODS: PP transgenic mice were created by
      using mouse PP complementary DNA under the control of the cytomegalovirus
      immediate early enhancer-chicken beta-actin hybrid promoter (pCAGGS expression
      vector). RESULTS: A unique line of transgenic mice was created that overexpresses
      PP in the pancreatic islets with low levels of expression in other tissues
      including the brain. Plasma PP concentrations were more than 20 times higher than
      those of control littermates. However, PP overproduction led to postnatal
      lethality in half of the pups because of markedly decreased milk intake. The
      remaining PP transgenic mice gained less weight with specifically reduced food
      intake and fat mass compared with controls, a result that was more evident in
      male than in female mice. The transgenic mice exhibited a reduced rate of gastric
      emptying of a solid meal but had normal oxygen consumption and fasting leptin
      levels. Immunoneutralization with anti-PP antiserum reversed the phenotypic
      changes of transgenic animals. CONCLUSIONS: PP could be involved in feeding and
      body weight regulation partly through regulation of gastric emptying.

PMID- 10579985
TI  - The relationship between infliximab treatment and lymphoma in Crohn's disease.
AB  - The relationship between chronic inflammatory conditions and malignancy is
      complex. We describe the clinical course of 2 patients with Crohn's disease (CD)
      in whom lymphoma was diagnosed after treatment with infliximab. The first patient
      was a 61-year-old man with a 30-year history of fistulizing CD in whom B-cell non
      Hodgkin's lymphoma was diagnosed 9 months after treatment with infliximab. The
      second is a 29-year-old man with CD in whom nodular sclerosing Hodgkin's lymphoma
      was diagnosed 3 weeks after infusion with infliximab. The lymphoma presented with
      pleural effusions, mediastinal and cervical adenopathy, and no gastrointestinal
      lesion. We describe the implications of these cases for the use of
      immunomodulatory therapy in CD and the questionable association between CD and
      lymphoma.

PMID- 10579986
TI  - Plasticity in the enteric nervous system.
AB  - Enteric ganglia can maintain integrated functions, such as the peristaltic
      reflex, in the absence of input from the central nervous system, which has a
      modulatory role. Several clinical and experimental observations suggest that
      homeostatic control of gut function in a changing environment may be achieved
      through adaptive changes occurring in the enteric ganglia. A distinctive feature
      of enteric ganglia, which may be crucial during the development of adaptive
      responses, is the vicinity of the final effector cells, which are an important
      source of mediators regulating cell growth. The aim of this review is to focus on
      the possible mechanisms underlying neuronal plasticity in the enteric nervous
      system and to consider approaches to the study of plasticity in this model. These
      include investigations of neuronal connectivity during development, adaptive
      mechanisms that maintain function after suppression of a specific neural input,
      and the possible occurrence of activity-dependent modifications of synaptic
      efficacy, which are thought to be important in storage of information in the
      brain. One of the applied aspects of the study of plasticity in the enteric
      nervous system is that knowledge of the underlying mechanisms may eventually
      enable us to develop strategies to correct neuronal alterations described in
      several diseases.

PMID- 10579987
TI  - Gastroenterology: a career for a lifetime.
AB  - Following is an edited reprint of the Presidential Address delivered by Donald O.
      Castell, M.D., during the AGA Plenary Session at Digestive Disease Week 1999.

PMID- 10579988
TI  - American gastroenterological association medical position statement:
      epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma.
AB  - This document presents the official recommendations of the American
      Gastroenterological Association (AGA) on the Epidemiology, Diagnosis, and
      Treatment of Pancreatic Ductal Adenocarcinoma. It was approved by the Clinical
      Practice and Practice Economics Committee in March 1999 and by the AGA Governing
      Board in May 1999.

PMID- 10579989
TI  - AGA technical review on the epidemiology, diagnosis, and treatment of pancreatic
      ductal adenocarcinoma. American Gastroenterological Association.
AB  - This literature review and the recommendations therein were prepared for the
      American Gastroenterological Association Clinical Practice and Practice Economics
      Committee. The paper was approved by the Committee in March 1999 and by the AGA
      Governing Board in May 1999.

PMID- 10579990
TI  - New life in a sleeper: thalidomide and Crohn's disease.

PMID- 10579991
TI  - ALMs versus DALMs in ulcerative colitis: polypectomy or colectomy?

PMID- 10579992
TI  - A wake-up call? Unsedated versus conventional esophagogastroduodenoscopy.

PMID- 10579993
TI  - Intrahepatic cholestasis: order out of chaos.

PMID- 10579994
TI  - SIGNALING TO COLON CANCER.

PMID- 10579996
TI  - IDENTIFYING THE MOTILIN RECEPTOR: SCIENCE, SERENDIPITY, OR SIMPLY BUSINESS?

PMID- 10579995
TI  - Nutrition in the ICU: are all systematics go?

PMID- 10579997
TI  - An Acknowledgment.

PMID- 10579998
TI  - Cellular survival: a play in three Akts.

PMID- 10579999
TI  - The Rbx1 subunit of SCF and VHL E3 ubiquitin ligase activates Rub1 modification
      of cullins Cdc53 and Cul2.
AB  - The RING-H2 finger protein Rbx1 is a subunit of the related SCF (Skp1-Cdc53/Cul1
      F-box protein) and von Hippel-Lindau (VHL) tumor suppressor (elongin BC-Cul2-VHL)
      E3 ubiquitin ligase complexes, where it functions as a component of Cdc53/Rbx1
      and Cul2/Rbx1 modules that activate ubiquitination of target proteins by the E2
      ubiquitin-conjugating enzymes Cdc34 and Ubc5. Here we demonstrate that the
      Cdc53/Rbx1 and Cul2/Rbx1 modules also activate conjugation of the ubiquitin-like
      protein Rub1 to Cdc53 and Cul2 by the dedicated E2 Rub1 conjugating enzyme Ubc12.
      Our findings identify Rbx1 as a common component of enzyme systems responsible
      for ubiquitin and Rub1 modification of target proteins.

PMID- 10580000
TI  - Different upstream transcriptional activators have distinct coactivator
      requirements.
AB  - Activated transcription by RNA polymerase II (Pol II) requires coactivators, one
      of which is the SRB/mediator. Whereas Srb4, an essential subunit of the
      SRB/mediator, is broadly required for Pol II transcription in yeast, we have
      shown that it is dispensable for the transcriptional activation of some genes.
      Here, we show that transcriptional activation by different natural activators,
      and by artificial recruitment of various transcription factors, have very
      different degrees of Srb4 independence. These data, and the analysis of an rgr1
      mutant, point to an Rgr1 subcomplex of the SRB/mediator as the mechanistic route
      of activation by Srb4-independent activators in vivo.

PMID- 10580001
TI  - The Spt components of SAGA facilitate TBP binding to a promoter at a post
      activator-binding step in vivo.
AB  - The SAGA complex of Saccharomyces cerevisiae is required for the transcription of
      many RNA polymerase II-dependent genes. Previous studies have demonstrated that
      SAGA possesses histone acetyltransferase activity, catalyzed by the SAGA
      component Gcn5. However, the transcription of many genes, although SAGA
      dependent, is Gcn5 independent, suggesting the existence of distinct SAGA
      activities. We have studied the in vivo role of two other SAGA components, Spt3
      and Spt20, at the well-characterized GAL1 promoter. Our results demonstrate that
      both Spt3 and Spt20 are required for the binding of TATA-binding protein but not
      of the activator Gal4 and that this role is Gcn5 independent. These results
      suggest a coactivator role for Spt3 and Spt20 in the recruitment of TBP.

PMID- 10580002
TI  - Dephosphorylation of cyclin-dependent kinases by type 2C protein phosphatases.
AB  - Activating phosphorylation of cyclin-dependent protein kinases (CDKs) is
      necessary for their kinase activity and cell cycle progression. This
      phosphorylation is carried out by the Cdk-activating kinase (CAK); in contrast,
      little is known about the corresponding protein phosphatase. We show that type 2C
      protein phosphatases (PP2Cs) are responsible for this dephosphorylation of
      Cdc28p, the major budding yeast CDK. Two yeast PP2Cs, Ptc2p and Ptc3p, display
      Cdc28p phosphatase activity in vitro and in vivo, and account for approximately
      90% of Cdc28p phosphatase activity in yeast extracts. Overexpression of PTC2 or
      PTC3 results in synthetic lethality in strains temperature-sensitive for yeast
      CAK1, and disruptions of PTC2 and PTC3 suppress the growth defect of a cak1
      mutant. Furthermore, PP2C-like enzymes are the predominant phosphatases toward
      human Cdk2 in HeLa cell extracts, indicating that the substrate specificity of
      PP2Cs toward CDKs is evolutionarily conserved.

PMID- 10580003
TI  - The RING finger/B-box factor TAM-1 and a retinoblastoma-like protein LIN-35
      modulate context-dependent gene silencing in Caenorhabditis elegans.
AB  - Context-dependent gene silencing is used by many organisms to stably modulate
      gene activity for large chromosomal regions. We have used tandem array transgenes
      as a model substrate in a screen for Caenorhabditis elegans mutants that affect
      context-dependent gene silencing in somatic tissues. This screen yielded multiple
      alleles of a previously uncharacterized gene, designated tam-1 (for tandem-array
      modifier). Loss-of-function mutations in tam-1 led to a dramatic reduction in the
      activity of numerous highly repeated transgenes. These effects were apparently
      context dependent, as nonrepetitive transgenes retained activity in a tam-1
      mutant background. In addition to the dramatic alterations in transgene activity,
      tam-1 mutants showed modest alterations in expression of a subset of endogenous
      cellular genes. These effects include genetic interactions that place tam-1 into
      a group called the class B synMuv genes (for a Synthetic Multivulva phenotype);
      this family plays a negative role in the regulation of RAS pathway activity in C.
      elegans. Loss-of-function mutants in other members of the class-B synMuv family,
      including lin-35, which encodes a protein similar to the tumor suppressor Rb,
      exhibit a hypersilencing in somatic transgenes similar to that of tam-1 mutants.
      Molecular analysis reveals that tam-1 encodes a broadly expressed nuclear protein
      with RING finger and B-box motifs.

PMID- 10580004
TI  - Maintenance of genomic imprinting at the Arabidopsis medea locus requires zygotic
      DDM1 activity.
AB  - In higher plants, seed development requires maternal gene activity in the haploid
      (gametophytic) as well as diploid (sporophytic) tissues of the developing ovule.
      The Arabidopsis thaliana gene MEDEA (MEA) encodes a SET-domain protein of the
      Polycomb group that regulates cell proliferation by exerting a gametophytic
      maternal control during seed development. Seeds derived from female gametocytes
      (embryo sacs) carrying a mutant mea allele abort and exhibit cell proliferation
      defects in both the embryo and the endosperm. In this study we show that the mea
      mutation affects an imprinted gene expressed maternally in cells of the female
      gametophyte and after fertilization only from maternally inherited MEA alleles.
      Paternally inherited MEA alleles are transcriptionally silent in both the young
      embryo and endosperm. Mutations at the decrease in DNA methylation1 (ddm1) locus
      are able to rescue mea seeds by functionally reactivating paternally inherited
      MEA alleles during seed development. Rescued seeds are larger than the wild type
      and exhibit some of the abnormalities found in aborting mea seeds. Our results
      indicate that the maintenance of the genomic imprint at the mea locus requires
      zygotic DDM1 activity. Because DDM1 encodes a putative chromatin remodeling
      factor, chromatin structure is likely to be interrelated with genomic imprinting
      in Arabidopsis.

PMID- 10580005
TI  - Gata5 is required for the development of the heart and endoderm in zebrafish.
AB  - The mechanisms regulating vertebrate heart and endoderm development have recently
      become the focus of intense study. Here we present evidence from both loss- and
      gain-of-function experiments that the zinc finger transcription factor Gata5 is
      an essential regulator of multiple aspects of heart and endoderm development. We
      demonstrate that zebrafish Gata5 is encoded by the faust locus. Analysis of faust
      mutants indicates that early in embryogenesis Gata5 is required for the
      production of normal numbers of developing myocardial precursors and the
      expression of normal levels of several myocardial genes including nkx2.5. Later,
      Gata5 is necessary for the elaboration of ventricular tissue. We further
      demonstrate that Gata5 is required for the migration of the cardiac primordia to
      the embryonic midline and for endodermal morphogenesis. Significantly,
      overexpression of gata5 induces the ectopic expression of several myocardial
      genes including nkx2.5 and can produce ectopic foci of beating myocardial tissue.
      Together, these results implicate zebrafish Gata5 in controlling the growth,
      morphogenesis, and differentiation of the heart and endoderm and indicate that
      Gata5 regulates the expression of the early myocardial gene nkx2.5.

PMID- 10580006
TI  - The glucocorticoid receptor is required for stress erythropoiesis.
AB  - The glucocorticoid receptor (GR) coordinates a multitude of physiological
      responses in vivo. In vitro, glucocorticoids are required for sustained
      proliferation of erythroid progenitors (ebls). Here, we analyze the impact of the
      GR on erythropoiesis in vivo, using GR-deficient mice or mice expressing a GR
      defective for transactivation. In vitro, sustained proliferation of primary ebls
      requires an intact GR. In vivo, the GR is required for rapid expansion of ebls
      under stress situations like erythrolysis or hypoxia. A particular, GR-sensitive
      progenitor could be identified as being responsible for the stress response.
      Thus, GR-mediated regulation of ebl proliferation is essential for stress
      erythropoiesis in vivo.

PMID- 10580007
TI  - Nuclear matrix attachment regions antagonize methylation-dependent repression of
      long-range enhancer-promoter interactions.
AB  - The immunoglobulin intragenic mu enhancer region acts as a locus control region
      that mediates transcriptional activation over large distances in germ line
      transformation assays. In transgenic mice, but not in transfected tissue culture
      cells, the activation of a variable region (V(H)) promoter by the mu enhancer is
      dependent on flanking nuclear matrix attachment regions (MARs). Here, we examine
      the effects of DNA methylation, which occurs in early mouse development, on the
      function of the mu enhancer and the MARs. We find that methylation of rearranged
      mu genes in vitro, before transfection, represses the ability of the mu enhancer
      to activate the V(H) promoter over the distance of 1.2 kb. However, methylation
      does not affect enhancer-mediated promoter activation over a distance of 150 bp.
      In methylated DNA templates, the mu enhancer alone induces only local chromatin
      remodeling, whereas in combination with MARs, the mu enhancer generates an
      extended domain of histone acetylation. These observations provide evidence that
      DNA methylation impairs the distance independence of enhancer function and
      thereby imposes a requirement for additional regulatory elements, such as MARs,
      which facilitate long-range chromatin remodeling.

PMID- 10580009
TI  - Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1).
AB  - The p16(INK4a) tumor suppressor inhibits cyclin-dependent kinases (CDK4 and
      CDK6). Here we report the isolation of a novel gene, SEI-1, whose product
      (p34(SEI-1)) appears to antagonize the function of p16(INK4a). Addition of
      p34(SEI-1) to cyclin D1-CDK4 renders the complex resistant to inhibition by
      p16(INK4a). Expression of SEI-1 is rapidly induced on addition of serum to
      quiescent fibroblasts, and ectopic expression of p34(SEI-1) enables fibroblasts
      to proliferate even in low serum concentrations. p34(SEI-1) seems to act as a
      growth factor sensor and may facilitate the formation and activation of cyclin D
      CDK complexes in the face of inhibitory levels of INK4 proteins.

PMID- 10580011
TI  - MEMORANDUM FOR: Science Writers and Editors on the Journal Press List :
      Vaccination Fights Spread of Colon Cancer to the Liver in Animals.

PMID- 10580008
TI  - The interface of sigma with core RNA polymerase is extensive, conserved, and
      functionally specialized.
AB  - The sigma subunit of eubacterial RNA polymerase is required throughout
      initiation, but how it communicates with core polymerase (alpha(2)betabeta') is
      poorly understood. The present work addresses the location and function of the
      interface of sigma with core. Our studies suggest that this interface is
      extensive as mutations in six conserved regions of sigma(70) hinder the ability
      of sigma to bind core. Direct binding of one of these regions to core can be
      demonstrated using a peptide-based approach. The same regions, and even
      equivalent residues, in sigma(32) and sigma(70) alter core interaction,
      suggesting that sigma(70) family members use homologous residues, at least in
      part, to interact with core. Finally, the regions of sigma that we identify
      perform specialized functions, suggesting that different portions of the
      interface perform discrete roles during transcription initiation.

PMID- 10580010
TI  - MEMORANDUM FOR: Science Writers and Editors on the Journal Press List : Some
      Women May Be Genetically Susceptible to Cancer From Environmental Tobacco Smoke.

PMID- 10580013
TI  - Gene-by-environment interaction for passive smoking and glutathione S-transferase
      M1?

PMID- 10580012
TI  - Application of pharmacogenetics to optimization of mercaptopurine dosing.

PMID- 10580014
TI  - Enzyme/prodrug-based tumor vaccination: all politics (and immunity) are local.

PMID- 10580015
TI  - Genetic profiling for cancer surfaces slowly in the clinic.

PMID- 10580016
TI  - Do autoimmune diseases raise the risk of cancer?

PMID- 10580017
TI  - Some Examples of Autoimmune Diseases.

PMID- 10580018
TI  - Hope lodges: "Safe Havens" for adult cancer patients, spouses, and other
      companions.

PMID- 10580019
TI  - Stat bite: Distribution of U.S. childhood cancers.

PMID- 10580020
TI  - Informing confident decisions when weighing uncertain risks.

PMID- 10580023
TI  - Middle East Cancer Registries Develop.

PMID- 10580022
TI  - Britain Upgrades Its Cancer Program.

PMID- 10580021
TI  - First responses seen in cancer patients to a recombinant immunotoxin.

PMID- 10580025
TI  - Environmental tobacco smoke, genetic susceptibility, and risk of lung cancer in
      never-smoking women.
AB  - BACKGROUND: Exposure to environmental tobacco smoke (ETS) is considered to be a
      major lung cancer risk factor for never smokers. We investigated the hypothesis
      that never-smoking women who are exposed to ETS and develop lung cancer are a
      genetically susceptible population. METHODS: Archival tumor tissues were analyzed
      from 106 never-smoking women enrolled in a case-control study of ETS (and other
      personal and environmental factors) and lung cancer risk. We analyzed germline
      polymorphisms in genes that have been associated with cancer susceptibility and
      whose products activate (cytochrome P450 1A1 [CYP1A1]) and detoxify (glutathione
      S-transferases M1 [GSTM1] and T1 [GSTT1]) chemical carcinogens found in tobacco
      smoke. RESULTS: When compared with never smokers who had no ETS exposure and
      developed lung cancer (n = 55), never smokers with exposure to ETS who developed
      lung cancer (n = 51) were more likely to be deficient in GSTM1 activity (i.e.,
      were GSTM1 null) because of a genetic polymorphism in the GSTM1 gene (odds ratio
      = 2.6; 95% confidence interval = 1.1-6.1). A statistically significant rising
      trend in risk occurred with increasing ETS exposure (two-sided P =. 02), reaching
      a more than sixfold excess risk in those exposed to 55 pack-years of ETS (ETS
      pack-year = ETS produced by an active smoker, within a confined space such as a
      room, who smokes one pack of cigarettes a day for a year). No evidence was found
      of associations between GSTT1 deficiency or the CYP1A1 valine variant and lung
      cancer risk due to ETS exposure. CONCLUSIONS: A common genetic polymorphism
      divides the population of never smokers into two groups of approximately equal
      size, one (homozygous carriers of the GSTM1 null allele) that has a statistically
      significant greater risk of lung cancer from ETS than the other (heterozygous or
      homozygous carriers of the wild-type GSTM1 allele).

PMID- 10580024
TI  - Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S
      methyltransferase gene locus.
AB  - BACKGROUND: Patients with acute lymphoblastic leukemia are often treated with 6
      mercaptopurine, and those with homozygous deficiency in thiopurine S
      methyltransferase (TPMT) enzyme activity have an extreme sensitivity to this drug
      as a result of the accumulation of higher cellular concentrations of thioguanine
      nucleotides. We studied the metabolism, dose requirements, and tolerance of 6
      mercaptopurine among patients with different TPMT phenotypes. METHODS: We
      compared, by use of statistical modeling, 6-mercaptopurine pharmacology and
      tolerance in 180 patients who achieved remission on St. Jude Children's Research
      Hospital Protocol Total XII composed of weekly methotrexate (40 mg/m(2)) and
      daily oral 6-mercaptopurine (75 mg/m(2)) given for 2.5 years, interrupted every 6
      weeks during the first year for treatment with either high-dose methotrexate or
      teniposide plus cytarabine. Statistical tests were two-sided. RESULTS:
      Erythrocyte concentrations of thioguanine nucleotides (pmol/8 x 10(8)
      erythrocytes) were inversely related to TPMT enzyme activity (P<.01), with
      averages (+/- standard deviations) of 417 (+/-179), 963 (+/-752), and 3565 (+/
      1282) in TPMT homozygous wild-type (n = 161), heterozygous (n = 17), and
      homozygous-deficient (n = 2) patients, respectively. There was complete
      concordance between TPMT genotype and phenotype in a subset of 28 patients for
      whom TPMT genotype was determined. There were no sex differences in thioguanine
      nucleotide concentrations (P =.24), TPMT enzyme activity (P =.22), or average
      weekly prescribed dose of 6-mercaptopurine (P=.49). The cumulative incidence of 6
      mercaptopurine dose reductions due to toxicity was highest among patients
      homozygous for mutant TPMT (100%), intermediate among heterozygous patients
      (35%), and lowest among wild-type patients (7%) (P<.001), with average (+/-
      standard deviation) final weekly 6-mercaptopurine doses of 72 (+/-60), 449 (+/
      160), and 528 (+/-90) mg/m(2), respectively. Lowering doses of 6-mercaptopurine
      in TPMT heterozygotes and in deficient patients allowed administration of full
      protocol doses of other chemotherapy while maintaining high thioguanine
      nucleotide concentrations. CONCLUSION: We conclude that genetic polymorphism in
      TPMT is an important determinant of mercaptopurine toxicity, even among patients
      who are heterozygous for this trait.

PMID- 10580026
TI  - Cytosine deaminase/5-fluorocytosine-based vaccination against liver tumors:
      evidence of distant bystander effect.
AB  - BACKGROUND: The cytosine deaminase gene of Escherichia coli converts the nontoxic
      compound 5-fluorocytosine into 5-fluorouracil (5-FU), thereby acting as a suicide
      gene when introduced into cancer cells, killing the cells when they are exposed
      to 5-fluorocytosine. We analyzed the efficacy of using cytosine deaminase-bearing
      cancer cells as an autologous tumor vaccine in a rat model that mimics liver
      metastasis from colon carcinoma. METHODS: We introduced a plasmid vector
      containing the E. coli cytosine deaminase gene into a BDIX rat colon carcinoma
      cell line. Intrahepatic injection of the modified cells in syngeneic animals
      generates a single experimental liver "suicide tumor." We then analyzed the
      effect of 5-fluorocytosine treatment in terms of regression of cytosine deaminase
      expressing cells in vivo as well as protection against wild-type cancer cells.
      RESULTS: Treatment with 5-fluorocytosine induced regression of cytosine deaminase
      expressing (CD+) tumors, with seven of 11 treated animals being tumor free at the
      end of 30 days and a statistically significant difference in tumor volumes
      between treated and control animals (two-sided P<.0001). Intrahepatic injection
      of CD+ cells followed by 5-fluorocytosine treatment rendered the treated animals
      resistant to challenge with wild-type tumor cells, with no (zero of seven)
      treated animals developing wild-type tumors in contrast to all (four of four)
      control animals. Moreover, in animals with established wild-type liver tumors,
      injection of CD+ tumor cells followed by 5-fluorocytosine treatment produced a
      statistically significant increase in survival time (two-sided P<.0001). In vivo
      immunodepletion and immunohistologic analysis of experimental tumors indicate
      that natural killer cells are the major immune component involved in this
      antitumor effect. CONCLUSIONS AND IMPLICATIONS: Taken together, these results
      suggest the potential use of suicide gene-modified tumor cells as therapeutic
      vaccines against liver metastasis from colon carcinoma.

PMID- 10580027
TI  - Breast tumor characteristics as predictors of mammographic detection: comparison
      of interval- and screen-detected cancers.
AB  - BACKGROUND: Although mammographic screening is useful for detecting early breast
      cancer, some tumors are detected in the interval between screening examinations.
      This study attempted to characterize fully the tumors detected in the two
      different manners. METHODS: Our study utilized a case-control design and involved
      a cohort of women undergoing mammographic screening within the defined population
      of a health maintenance organization (the Group Health Cooperative of Puget
      Sound). Women were classified as having "interval" or "interval-detected" cancers
      (n = 150) if their diagnosis was made within 24 months after a negative-screening
      mammogram or one that indicated a benign condition. Cancers were classified as
      "screen detected" (n = 279) if the diagnosis occurred after a positive assessment
      by screening mammography. Tumors from women in each group were evaluated for
      clinical presentation, histology, proliferative characteristics, and expression
      of hormone receptors, p53 tumor suppressor protein, and c-erbB-2 protein.
      RESULTS: Interval-detected cancers occurred more in younger women and were of
      larger tumor size than screen-detected cancers. In unconditional logistic
      regression models adjusted for age and tumor size, tumors with lobular (odds
      ratio [OR] = 1.9; 95% confidence interval [CI] = 0.9-4.2) or mucinous (OR = 5.5;
      95% CI = 1.5-19.4) histology, high proliferation (by either mitotic count [OR =
      2.9; 95% CI = 1.5-5.7] or Ki-67 antigen expression [OR = 2.3; 95% CI = 1.3-4.1]),
      high histologic grade (OR = 2.1; 95% CI = 1.2-4.0), high nuclear grade (OR = 2.0;
      95% CI = 1.0-3.7), or negative estrogen receptor status (OR = 1.8; 95% CI = 1.0
      3.1) were more likely to surface in the interval between screening examinations.
      Tumors with tubular histology (OR = 0.2; 95% CI = 0.0-0.8) or with a high
      percentage of in situ components (50%) (OR = 0.5; 95% CI = 0.2-1.2) were
      associated with an increased likelihood of screen detection. CONCLUSIONS: Our
      data from a large group of women in a defined population indicate that screening
      mammography may miss tumors of lobular or mucinous histology and some rapidly
      proliferating, high-grade tumors.

PMID- 10580028
TI  - Diagnosis of renal cancer by molecular urinalysis.
AB  - BACKGROUND: Organ-confined renal malignancies can be cured in the majority of
      patients, whereas more extensive lesions have a poor prognosis. We sought to
      develop a noninvasive test for renal cancer detection based on a novel molecular
      approach. METHODS: Matched urine and serum DNA samples were obtained before
      surgery from 30 patients with clinically organ-confined solid renal masses (25
      with malignant tumors and five with tumors of low malignant potential) and were
      subjected to microsatellite analysis. Serum samples and urine samples obtained
      from 16 individuals without clinical evidence of genitourinary malignancy served
      as controls. RESULTS: Nineteen (76%) of the 25 patients with malignant tumors
      were found to have one or more microsatellite DNA alterations in their urine
      specimen, and 15 (60%) were found to have alterations in their serum DNA by
      microsatellite analysis. In every case, the microsatellite changes in urine or
      serum were identical to those found in the primary tumor. Three of five patients
      with tumors of low malignant potential were found to have DNA alterations in
      their urine, but none displayed alterations in their serum. Moreover,
      microsatellite alterations were not identified in either the urine or the serum
      samples from normal control subjects and patients with hematuria due to
      nephrolithiasis (renal stones). CONCLUSION: These data suggest that
      microsatellite DNA analysis of urine specimens provides a potentially valuable
      tool for the early detection of resectable kidney cancer. Furthermore,
      microsatellite analysis of serum samples reveals evidence of circulating tumor
      specific DNA in approximately half of these patients and may reflect the
      propensity of these tumors to spread to distant sites at an early stage.

PMID- 10580029
TI  - Implications and prognostic value of K-ras mutation for early-stage lung cancer
      in women.
AB  - BACKGROUND: Because there is no clear consensus as to the predictive value of K
      ras gene mutation for survival in patients with lung cancer, we examined the
      occurrence of K-ras mutations in a large, prospective case series of non-small
      cell lung cancer (NSCLC). Our goals were to define the patient characteristics
      associated with K-ras mutation and to determine whether mutation of this gene
      might be a biomarker of patient prognosis. METHODS: Consecutive, newly diagnosed
      patients with lung cancer treated with potentially curative resection over a 4
      year period were recruited for study. The mutation status of K-ras codon 12 in
      each patient's tumor DNA was determined by means of polymerase chain reaction
      restriction fragment length polymorphism analysis of archived pathology
      specimens. Analyses were restricted to adenocarcinoma. RESULTS: There was a
      statistically significant association between female sex and K-ras mutation after
      adjustment for carcinogen exposures (odds ratio = 3.3; 95% confidence interval
      [CI] = 1.3-7.9); mutations were found only in smokers. Comparison of Kaplan-Meier
      curves indicated a strong association between K-ras mutation and decreased
      patient survival (two-sided P =.009); analysis stratified by pathologic staging
      groups revealed that this association was statistically significant only for
      stage I tumors (two-sided P =.002). Cox proportional hazards modeling indicated
      that K-ras codon 12 mutation was a statistically significant predictor of patient
      survival, after adjustment for the effects of age, sex, and stage (risk ratio =
      1.8; 95% CI = 1.1-3.1). CONCLUSIONS: After adjustment for environmental
      exposures, non-small-cell lung tumors in women appear to be more likely than
      those in men to harbor K-ras mutations, suggesting a possible role of estrogen
      exposure in either the initiation or the selection of K-ras mutant clones in
      adenocarcinoma. In addition, our data suggest that K-ras codon 12 mutation is a
      marker of aggressive NSCLC, as evidenced by its association with decreased
      patient survival, particularly for early-stage disease.

PMID- 10580030
TI  - Heterocyclic amine content of cooked meat and risk of prostate cancer.
AB  - BACKGROUND: Some epidemiologic studies have described positive associations
      between prostate cancer risk and meat consumption, but underlying mechanisms have
      not been identified. Heterocyclic amines are mutagens formed during the cooking
      of meat. Well-done meat has been associated with increased risks of colorectal
      and breast cancers in humans. This study examined associations between prostate
      cancer risk and 1) estimated daily intake of heterocyclic amines from cooked meat
      and 2) level of cooked-meat doneness. METHODS: A population-based, case-control
      study involving 317 case patients with prostate cancer and 480 age-matched
      control subjects was carried out in Auckland, New Zealand. Levels of meat
      doneness and daily intake of heterocyclic amines were determined from self
      reported dietary data and experimentally measured heterocyclic amine levels in
      locally sourced meat samples cooked under controlled conditions to varying
      degrees of doneness. RESULTS: The heterocyclic amines found in the highest
      concentrations in meat samples were 2-amino-1,6-dimethylfuro[3,2-e]imidazo[4,5
      b]pyridine (IFP) and 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) from
      well-done chicken and pork and very well-done beefsteak. Meat doneness was weakly
      and inconsistently associated with prostate cancer risk for individual types of
      meat, but increased risk was observed for well-done beefsteak (relative risk =
      1.68; 95% confidence interval = 1.02-2.77; two-sided P for trend =.03). A weak
      positive gradient of increased risk was associated with estimated daily exposure
      to IFP but not with the other major heterocyclic amines. CONCLUSIONS: Meat
      doneness and estimated intake of heterocyclic amines from cooked meat were not
      clearly associated with prostate cancer risk.

PMID- 10580031
TI  - Re: Sunscreen use and duration of sun exposure: a double-blind, randomized trial.

PMID- 10580032
TI  - RESPONSE: Re: Sunscreen Use and Duration of Sun Exposure: a Double-Blind,
      Randomized Trial.

PMID- 10580033
TI  - Re: Folylpolyglutamyl synthetase gene transfer and glioma antifolate sensitivity
      in culture and in vivo.

PMID- 10580034
TI  - RESPONSE: Re: Folylpolyglutamyl Synthetase Gene Transfer and Glioma Antifolate
      Sensitivity in Culture and In Vivo.

PMID- 10580035
TI  - RESPONSE: Re: Folylpolyglutamyl Synthetase Gene Transfer and Glioma Antifolate
      Sensitivity in Culture and In Vivo.

PMID- 10580036
TI  - Re: Brain and other central nervous system cancers: recent trends in incidence
      and mortality.

PMID- 10580037
TI  - RESPONSE: Re: Brain and Other Central Nervous System Cancers: Recent Trends in
      Incidence and Mortality.

PMID- 10580038
TI  - Re: Prospective study of colorectal cancer risk in men and plasma levels of
      insulin-like growth factor (IGF)-I and IGF-binding protein-3.

PMID- 10580039
TI  - RESPONSE: Re: Prospective Study of Colorectal Cancer Risk in Men and Plasma
      Levels of Insulin-Like Growth Factor (IGF)-I and IGF-Binding Protein-3.

PMID- 10580040
TI  - Molecular biology of the tobraviruses.

PMID- 10580041
TI  - Effect of mutations within the cys-rich region of potyvirus helper component
      proteinase on self-interaction.
AB  - The first approximately 60 amino acids of the N-terminal part of the potyvirus
      helper component-proteinase (HC-Pro) include highly conserved residues comprising
      a Cys-rich region. In the present study, the domain in Potato virus Y sufficient
      for self-interaction was mapped using the yeast two-hybrid system to the 83 N
      terminal amino acids of HC-Pro. Mutations in the conserved His and two Cys
      residues within the Cys-rich region have a strong debilitating effect on self
      interaction when introduced in the full-length HC-Pro, but not when introduced in
      the N-terminal fragment.

PMID- 10580042
TI  - Transformation of tobacco and potato with cDNA encoding the full-length genome of
      potato leafroll virus: evidence for a novel virus distribution and host effects
      on virus multiplication.
AB  - A full-length cDNA copy of the genome of Potato leafroll virus (PLRV) was
      introduced into the genome of tobacco and potato plants by Agrobacterium
      tumefaciens-mediated transformation. Transgenic lines were obtained in which the
      transgene was readily detected by PCR with DNA extracted from T(1) tobacco
      seedlings and clonally multiplied potato plants. PLRV-specific genomic and sub-
      genomic RNAs, coat protein antigen and virus particles were detected in
      transgenic plants. Aphids fed on the transgenic tobacco plants readily
      transmitted PLRV to test plants. Infected transgenic tobacco plants, like non
      transgenic (WT) PLRV-infected plants, displayed no symptoms of the infection but
      transgenic plants of potato were severely stunted. In parallel tests, the mean
      PLRV titres in WT tobacco plants and transgenic tobacco plants were 600 and 630
      ng virus/g leaf, respectively, although differences in PLRV titres among
      transgenic plants were much greater than those among infected WT plants. In
      similar tests with potato, the mean PLRV titre of WT plants was 50 ng virus/g
      leaf whereas higher concentrations (up to 3400 ng virus/g leaf) accumulated in
      transgenic potato plants. In tissue prints of stems, PLRV was detected in similar
      proportions of phloem cells in transgenic and infected WT plants. In transgenic
      tobacco and potato plants, but not in infected WT plants, a few stem epidermal
      cells also contained virus. From tissue prints of transgenic tobacco leaves, it
      was estimated that about one in 40000 mesophyll cells contained virus, but in
      transgenic potato, a greater proportion of mesophyll cells was infected.

PMID- 10580043
TI  - Tomato chlorotic dwarf viroid: an evolutionary link in the origin of
      pospiviroids.
AB  - Over 40 isolates of potato spindle tuber viroid (PSTVd) have been reported from
      potato, other Solanum species and greenhouse tomato. These isolates have sequence
      similarities in the range 95-99%. A viroid which caused chlorotic leaves and
      severe dwarfing of plants in greenhouse tomato crops was detected. The viroid was
      found to hybridize readily with PSTVd probes. It migrated faster than PSTVd in
      return-polyacrylamide gel electrophoresis and was not amplified in RT-PCR by a
      primer pair based on the lower strand of the central conserved region of PSTVd.
      Nucleotide sequencing of the viroid indicated that it is a circular RNA of 360
      nt, with less than 90% sequence similarities with PSTVd isolates. The Variable
      domain (V) has less than 60% and the Terminal Right domain less than 90% sequence
      similarity, while the remainder of the molecule has greater than 97% similarity
      with PSTVd. Because of its less-than 90% sequence similarities, unique V domain,
      lack of seed-transmission and lack of cross-protection by PSTVd, the viroid from
      tomato is proposed to be a distinct viroid species (tomato chlorotic dwarf
      viroid; TCDVd) which also differs from two viroids infecting tomato in nature.
      TCDVd may be an evolutionary link in the development of crop viroids, with
      Mexican papita viroid as the ancestral viroid.

PMID- 10580044
TI  - Induction of immune responses to bovine herpesvirus type 1 gD in passively immune
      mice after immunization with a DNA-based vaccine.
AB  - The potential for plasmids encoding a secreted form of bovine herpesvirus type 1
      (BHV-1) glycoprotein D (gD) to elicit immune responses in passively immune mice
      following intramuscular immunization was investigated. In these experiments, 6-
      to 8-week-old female C3H/HeN or C57BL/6 mice were passively immunized with
      hyperimmune antisera raised against BHV-1 recombinant, truncated (secreted) gD
      immediately prior to immunization with plasmids. A single immunization of
      passively immune mice with plasmid encoding the secreted form of BHV-1 gD
      resulted in rapid development of both cell-mediated immunity and antibody
      responses. Furthermore, 50% of mice immunized with a suboptimal dose of
      recombinant gD formulated into an adjuvant developed significant levels of serum
      antibodies if mice were pre-treated with hyperimmune antisera. The apparent
      failure of passive polyclonal antisera to suppress the induction of immune
      responses to pSLRSV may be related to the immunoglobulin subtypes present in the
      hyperimmune sera.

PMID- 10580045
TI  - Expression of bovine viral diarrhoea virus glycoprotein E2 by bovine herpesvirus
      1 from a synthetic ORF and incorporation of E2 into recombinant virions.
AB  - Expression cassettes containing the codons for the pestivirus E (rns) signal
      peptide (Sig) followed by a chemically synthesized ORF that encoded the bovine
      viral diarrhoea virus (BVDV) strain C86 glycoprotein E2, a class I membrane
      glycoprotein, were constructed with and without a chimeric intron sequence
      immediately upstream of the translation start codon, and incorporated into the
      genome of bovine herpesvirus-1 (BHV-1). The resulting recombinants, BHV-
      1/SigE2(syn) and BHV-1/SigE2(syn)-intron, expressed comparable quantities of
      glycoprotein E2, and Northern blot hybridizations indicated that the presence of
      the intron did not increase significantly the steady-state levels of transcripts
      encompassing the SigE2(syn) ORF. In BHV-1/SigE2(syn)- infected cells, the 54 kDa
      E2 glycoprotein formed a dimer with an apparent molecular mass of 94 kDa, which
      was further modified to a 101 kDa form found in the envelope of recombinant virus
      particles. Penetration kinetics and single-step growth curves indicated that the
      incorporation of the BVDV E2 glycoprotein in the BHV-1 envelope, which apparently
      did not require BHV-1-specific signals, interfered with entry into target cells
      and egress of progeny virions. These results demonstrate that a pestivirus
      glycoprotein can be expressed efficiently by BHV-1 and incorporated into the
      viral envelope. BHV-1 thus represents a promising tool for the development of
      efficacious live and inactivated BHV-1-based vector vaccines.

PMID- 10580046
TI  - Identification and characterization of bovine herpesvirus type 5 glycoprotein H
      gene and gene products.
AB  - Bovine herpesvirus type 5 (BHV-5) is the causative agent of a fatal meningo
      encephalitis in calves and is closely related to BHV-1 which causes infectious
      bovine rhinotracheitis. The gene encoding BHV-5 glycoprotein gH was sequenced. A
      high degree of conservation was found between BHV-1 and BHV-5 deduced gH amino
      acid sequences (86. 4%), which is also observed for all alphaherpesvirus gH
      sequences. Transcriptional analysis revealed a 3.1 kb mRNA as the specific gH
      transcript which was detected 2 h post-infection (p.i.). Twelve out of twenty-one
      MAbs directed against BHV-1 gH immunoprecipitated a 108-110 kDa glycoprotein,
      which was then designated BHV-5 gH. Synthesis and intracellular processing of BHV
      5 gH was analysed in infected MDBK cells using gH cross-reacting MAbs.
      Glycoprotein gH was expressed as a beta-gamma protein, detected by
      radioimmunoprecipitation as early as 3 h p.i. Glycosylation studies indicated
      that BHV-5 gH contains N-linked carbohydrates which are essential for the
      recognition of the protein by the MAbs. This suggests that N-linked glycans are
      involved in protein folding or are targets for the gH cross-reacting MAbs. Plaque
      reduction neutralization assays showed that at least one BHV-1 gH antigenic
      domain is lacking in BHV-5 which may possibly relate to in vivo differences in
      virus tropism.

PMID- 10580047
TI  - Free thiol groups are essential for infectivity of human cytomegalovirus.
AB  - The membrane-impermeable thiol blocker 5'5-dithiobis 2- nitrobenzoic acid (DTNB)
      blocked infectivity of human cytomegalovirus (CMV) although the virus still bound
      to cells. DTNB-treated CMV regained 65% of its infectivity after incubation with
      the disulfide bond-reducing agent dithiothreitol. These observations suggest that
      free thiol groups on CMV are required for infectivity and may participate in
      disulfide bond formation during virus entry.

PMID- 10580048
TI  - Modification of human cytomegalovirus tropism through propagation in vitro is
      associated with changes in the viral genome.
AB  - Following extensive propagation in fibroblasts, human cytomegalovirus (HCMV)
      loses tropism for a number of otherwise natural host cells, in particular,
      endothelial cells. In this study, the hypothesis was tested that loss of
      endothelial tropism is associated with the appearance of genomic variants.
      Initial quantitative focus expansion assays on endothelial monolayers
      demonstrated that, while the laboratory strains AD169 and Towne failed to form
      detectable foci, 29 out of 30 recent clinical HCMV isolates had the potential to
      expand in endothelial cell culture. By long-term adaptation in fibroblast
      cultures, nonendotheliotropic strains could be selected from clinical HCMV
      isolates, while long-term endothelial-adapted strains of the same isolates
      retained both fibroblast tropism and endothelial tropism. Such differentially
      adapted isolate pairs always displayed genomic differences in restriction
      fragment length analyses. Coinfection of endothelial cells by two
      nonendotheliotropic HCMV strains yielded an endotheliotropic recombinant HCMV
      variant combining portions of the genomes of both parental viruses. When DNA
      purified from various isolates was transfected into fibroblasts, progeny virus
      retained the specific tropism of parental virus from which the DNA was isolated.
      These findings demonstrate that endothelial tropism is an inherent property of
      most clinical HCMV isolates and is determined by the viral genome. Although the
      specific determinants of HCMV cell tropism are still unknown, this study provides
      the first evidence for a genetic contribution.

PMID- 10580049
TI  - Assembly of the epstein-barr virus BBLF4, BSLF1 and BBLF2/3 proteins and their
      interactive properties.
AB  - Epstein-Barr virus (EBV) encodes putative helicase-primase proteins BBLF4, BSLF1
      and BBLF2/3, which are essential for the lytic phase of viral DNA replication.
      The BSLF1, BBLF4 and BBLF2/3 proteins were expressed in B95-8 cells after
      induction of a virus productive cycle, possessing apparent molecular masses of 89
      kDa, 90 kDa and 80 kDa, respectively. The anti-BSLF1 or anti-BBLF2/3 protein
      specific antibody, which recognizes its target protein in both Western blotting
      and immunoprecipitation analyses, immunoprecipitated all of the BSLF1, BBLF4 and
      BBLF2/3 proteins from the extract of the cells with a virus productive cycle,
      indicating that these viral proteins are assembled together in vivo. To
      characterize their protein-protein interactions in detail, recombinant
      baculoviruses capable of expressing each of these viral gene products in insect
      cells were constructed. The assembly of the three virus replication proteins was
      reproduced in insect cells co- infected with the three recombinant baculoviruses,
      indicating that complex formation does not require other EBV replication
      proteins. Furthermore, experiments performed by using the extracts from insect
      cells co-infected with each pair of the recombinant viruses demonstrated that the
      BSLF1 protein could interact separately with both the BBLF4 and BBLF2/3 proteins
      and that the BBLF2/3 protein also interacted with the BBLF4 protein. These
      observations strongly suggest that within the BBLF4-BSLF1-BBLF2/3 complex each
      component interacts directly with the other two, resulting in helicase-primase
      enzyme activity.

PMID- 10580050
TI  - Human herpesvirus-8-encoded LNA-1 accumulates in heterochromatin- associated
      nuclear bodies.
AB  - Subnuclear distribution of the human herpesvirus-8 (HHV-8)- encoded nuclear
      protein LNA-1 was analysed at high resolution in body cavity (BC) lymphoma
      derived cell lines, in cell hybrids between BC cells and various human and mouse
      cells and in freshly infected K562 and ECV cell lines. Three-dimensional
      reconstruction of nuclei from optical sections and quantitative analysis of the
      distribution of LNA-1 fluorescence in relation to chromatin showed that LNA-1
      associates preferentially with the border of heterochromatin in the interphase
      nuclei. This was further confirmed in the following systems: in endo- and
      exonuclease-digested nuclei, in human-mouse (BC-1-Sp2- 0) hybrids and on
      chromatin spreads. LNA-1 was found to bind to mitotic chromosomes at random.
      Epstein-Barr virus (EBV), but not HHV-8, was rapidly lost from mouse-human hybrid
      cells in parallel with the loss of human chromosomes. HHV-8 could persist on the
      residual mouse background for more than 8 months. In early human-mouse hybrids
      that contain a single fused nucleus, LNA-1 preferentially associates with human
      chromatin. After the gradual loss of the human chromosomes, LNA-1 becomes
      associated with the murine pericentromeric heterochromatin. In human-human
      hybrids derived from the fusion of the HHV-8-carrying BCBL-1 cells and the EBV
      immortalized lymphoblastoid cell line IB4, LNA-1 did not co-localize with EBNA-1,
      EBNA-2, EBNA-5 or EBNA-6. LNA-1 was not associated with PML containing ND10
      bodies either. DNase but not RNase or detergent treatment of isolated nuclei
      destroys LNA-1 bodies. In advanced apoptotic cells LNA- 1 bodies remain intact
      but are not included in the apoptotic bodies themselves.

PMID- 10580051
TI  - Effect of virulence on immunogenicity of single and double vaccinia virus
      recombinants expressing differently immunogenic antigens: antibody-response
      inhibition induced by immunization with a mixture of recombinants differing in
      virulence.
AB  - It has been shown recently that the residual virulence of vaccinia virus (VV) is
      an important factor that influences the outcome of immunization with VV
      recombinants. This study focused on the correlation of the residual virulence of
      several VV recombinants with antibody responses against the strongly immunogenic
      extrinsic glycoprotein E of varicella-zoster virus and the weakly immunogenic
      extrinsic protein preS2-S of hepatitis B virus and against VV proteins, with mice
      used as a model organism. Furthermore, the effects of mixing different
      recombinants on the antibody response were studied. The results obtained
      indicated that: (i) the antibody response depended on the residual virulence of
      the recombinants, more so in the case of the weakly immunogenic protein; (ii) the
      residual virulence, the growth rate of the VV recombinants in extraneural tissues
      and the immunogenicity were associated features; (iii) immunization with mixtures
      of two differently virulent recombinants or with unequal amounts of two similarly
      virulent recombinants sometimes led to the suppression of antibody response. The
      appearance of this suppression was dependent on three factors: the residual
      virulence of the recombinants, the immunogenicity of the extrinsic proteins and
      the ratio of the recombinants in the mixtures. Thus, the data obtained
      demonstrate that there are various limitations to the use of replicating VV
      recombinants for immunization purposes.

PMID- 10580052
TI  - Porcine adenovirus-3 as a helper-dependent expression vector.
AB  - Porcine adenovirus has been proposed as a potential vector for generating novel
      and effective vaccines for pigs. As a prerequisite for the generation of helper
      dependent porcine adenovirus-3 (PAV-3) vectors, two E1-complementing porcine cell
      lines expressing E1 proteins of human adenovirus-5 (HAV-5) were made. These cell
      lines could be efficiently transfected with DNA and allowed the rescue and
      propagation of a PAV-3 recombinant, PAV201, containing a 0.597 kb E3 deletion and
      a 0.803 kb E1A deletion. Our data demonstrate that E1A proteins of HAV-5 have the
      capacity to transform foetal porcine retina cells and complement for the E1A
      proteins of PAV-3. The green fluorescent protein (GFP) gene placed under the
      control of a cytomegalovirus immediate early promoter was inserted into the E1A
      region of the PAV201 genome. Using these cell lines, a helper-dependent PAV-3
      recombinant expressing GFP, PAV202, was constructed and characterized. The wild
      type PAV-3 and the recombinant PAV202 expressing GFP were used to determine the
      ability of the virus to enter and replicate in cells of human and animal origin
      under cell culture conditions. Our results suggest that PAV-3 enters but does not
      replicate in dog, sheep, bovine and human cells.

PMID- 10580053
TI  - Polyomavirus large- and small-T relieve middle-T-induced cell cycle arrest in
      normal fibroblasts.
AB  - Papovavirus tumour antigens have been widely used to study cell growth regulation
      in cultured cells. We investigated the role of mouse polyomavirus T antigens,
      small-, middle- and large-T, in stimulating growth-arrested REF52 fibroblasts to
      enter the S phase. Microinjecting cells with cDNAs encoding the various T
      antigens showed: first, that middle-T expression blocked cell cycle stimulation
      by serum; second, that middle-T-arrested cells were released into the S phase
      upon coexpression of small-T; third, that expression of middle-T together with
      large-T committed resting cells to enter the cell cycle even in the absence of
      serum. Our data indicate that extensive cooperation among polyomavirus T antigens
      is essential for T antigen-mediated cell cycle stimulation in growth-arrested
      cells. In addition, the data suggest a new role for small-T in signalling to
      mitogenic pathways.

PMID- 10580054
TI  - Complete nucleotide sequence, genomic organization and phylogenetic analysis of a
      novel genital human papillomavirus type, HLT7474-S.
AB  - A novel human papillomavirus (HPV) type, HLT7474-S, was isolated from a cervical
      scraping of a female sex worker with a wart virus infection. The complete DNA
      sequence of 7812 bp was derived from four overlapping PCR products and
      authenticated by RFLP analysis. The L1 gene exhibited 78% identity to those of
      its most closely related known HPV types in group A7, comprising HPV types 18,
      39, 45, 59, 68 and 70. The genomic organization and phylogenetic analysis of
      HLT7474-S and group A7 HPVs reiterated their relatedness. Of significance were
      the strong sequence similarity, phylogenetic relationship and conservation of
      critical motifs between the transforming E6 and E7 of HLT7474-S and E6 of HPV-18
      and E7 of HPV-59, respectively. These features clearly suggest that HLT7474-S is
      a high-risk genital HPV isolate, closely related to HPV-18 and other members of
      the A7 group of genital HPVs.

PMID- 10580055
TI  - Human immunodeficiency virus infection in vitro activates naturally integrated
      human papillomavirus type 18 and induces synthesis of the L1 capsid protein.
AB  - Human papillomavirus (HPV) infections are prevalent in human immunodeficiency
      virus (HIV)-positive individuals. To highlight the effect of HIV on HPV
      expression, HPV-18-positive HIV-permissive HeLa-T4 cells were either infected
      with HIV-1 or treated with Tat or with the cytokines IL-1alpha, IL-1beta, IL-6
      and TNF-alpha. The presence of HPV-18 E1 (early) and L1 (late) transcripts was
      then determined by dot-blot or Northern blot hybridization with E1 and L1 or with
      genomic HPV-18 DNA probes, respectively. Protein extracts from parallel cultures
      were challenged by Western blotting with an antiserum raised against an L1-beta
      galactosidase hybrid protein. Results indicated that HeLa-T4 cells constitutively
      express E1 and L1 transcripts. When cells were infected with HIV, the amounts of
      E1 and L1 RNAs increased with time, followed by the de novo appearance of L1
      protein. E1 and L1 transcripts were also increased, in a dose-dependent manner,
      by treatment of uninfected cultures with Tat or with IL-6, but were not affected
      by IL-1alpha, IL-1beta and TNF- alpha. Neither Tat nor IL-6 could induce L1
      translation. These findings raise the hypothesis that the increase of HPV
      shedding and of HPV-associated diseases in HIV-infected individuals could be due
      in part to a direct or cytokine-mediated action of HIV, in addition to the HIV
      induced immunodeficiency.

PMID- 10580056
TI  - Pseudotyping human immunodeficiency virus type 1 by vesicular stomatitis virus G
      protein does not reduce the cell-dependent requirement of vif for optimal
      infectivity: functional difference between Vif and Nef.
AB  - The functions of Vif and Nef in human immunodeficiency virus type 1 (HIV-1)
      infection have some similarities: Vif- and Nef-dependent enhancement of HIV-1
      replication is cell type-specific, and defective mutations in these genes result
      in restricted proviral DNA synthesis in infected cells. It has recently been
      shown that pseudotyping HIV-1 by the envelope glycoprotein of vesicular
      stomatitis virus (VSV-G) targets HIV-1 entry to an endocytic pathway and
      suppresses the requirement of Nef for virus infectivity. In this study, we
      examined whether VSV-G pseudotyping suppresses the requirement of Vif for HIV-1
      infectivity. It was found that pseudotyping HIV-1 by VSV-G did not compensate for
      the Vif function. Together with the findings that Vif does not influence virus
      binding/entry and virion incorporation of Env, it is concluded that Vif enhances
      HIV-1 infectivity at the post-entry step(s) independently of the Env function by
      a different mechanism to that of Nef.

PMID- 10580057
TI  - Lack of negative influence on the cellular transcription factors NF-kappaB and AP
      1 by the nef protein of human immunodeficiency virus type 1.
AB  - In order to investigate the molecular mechanism of the reported negative effect
      of the Nef protein of human immunodeficiency virus type 1 (HIV-1) on the cellular
      transcription factors NF-kappaB and AP-1, human T cell lines (both populations
      and subclones) expressing the nef gene from HIV-1 clone pNL432 were constructed.
      Functional expression of the nef gene was confirmed by downregulation of CD4 and
      MHC class I proteins on the cell surface as measured by fluorescence-activated
      cell sorter analysis. However, contrary to previous reports, no significant
      difference was found in the induced level of NF-kappaB and AP-1 activity between
      nef(+) and nef(-) cell lines upon stimulation by phorbol 12-myristate 13-acetate
      and phytohaemagglutinin, as measured by transient transfection and
      electromobility shift assays. These data indicate that the Nef protein does not
      have a negative effect on the induction of NF-kappaB and AP-1.

PMID- 10580058
TI  - Forced recombination of psi-modified murine leukaemia virus-based vectors with
      murine leukaemia-like and VL30 murine endogenous retroviruses.
AB  - Co-encapsidation of retroviral RNAs into virus particles allows for the
      generation of recombinant proviruses through events of template switching during
      reverse transcription. By use of a forced recombination system based on
      recombinational rescue of replication- defective primer binding site-impaired Akv
      MLV-derived vectors, we here examine putative genetic interactions between vector
      RNAs and copackaged endogenous retroviral RNAs of the murine leukaemia virus
      (MLV) and VL30 retroelement families. We show (i) that MLV recombination is not
      blocked by nonhomology within the 5' untranslated region harbouring the supposed
      RNA dimer-forming cis -elements and (ii) that copackaged retroviral RNAs can
      recombine despite pronounced sequence dissimilarity at the cross-over site(s) and
      within parts of the genome involved in RNA dimerization, encapsidation and strand
      transferring during reverse transcription. We note that recombination-based
      rescue of primer binding site knock-out retroviral vectors may constitute a
      sensitive assay to register putative genetic interactions involving endogenous
      retroviral RNAs present in cells of various species.

PMID- 10580059
TI  - An analysis of the role of neuraminidase in the receptor-binding activity of
      influenza B virus: the inhibitory effect of Zanamivir on haemadsorption.
AB  - We analysed the role of neuraminidase (NA) on haemadsorption by the
      haemagglutinin (HA) protein of influenza B virus. The influenza B virus mutant ts
      7 has a temperature-sensitive mutation in the NA protein. At high temperature,
      cells infected with this virus did not exhibit haemadsorption activity, but the
      addition of bacterial neuraminidase (bNA) restored haemadsorption activity. COS
      cells transfected with HA cDNAs of B/Kanagawa/73 or B/Lee/40 virus showed no
      evidence of haemadsorption. However, with the addition of bNA or co- transfection
      with NA cDNA of the B/Lee/40 virus, haemadsorption was observed. Experiments with
      point-mutated HA cDNAs of B/Lee/40 virus showed that two N-acetyl glycosylation
      sites at amino acid residues 160 and 217 were responsible for the inability of
      the HA protein to adsorb to erythrocytes. These results indicated that
      haemadsorption by the HA protein of influenza B virus required the involvement of
      NA. Because the NA inhibitor Zanamivir was reported not to penetrate cells, we
      investigated the action of this inhibitor and found that Zanamivir inhibited
      haemadsorption on MDCK cells infected with B/Kanagawa/73 or B/Lee/40 virus. After
      removing Zanamivir by washing, the addition of bNA restored the haemadsorption
      activity on the infected cells. Scanning electron microscopy indicated that at
      0.4 microM Zanamivir, HA protein did not adsorb to erythrocytes but retained the
      ability to aggregate virions. However, at 4 microM Zanamivir, distinct virion
      formation could not be observed.

PMID- 10580060
TI  - Characterization of Sendai virus M protein mutants that can partially interfere
      with virus particle production.
AB  - Substitution of Val(113) in Sendai virus (SeV) M protein generates non-functional
      polypeptides, characterized by their exclusion from virus particles and by their
      ability to interfere with virus particle production. These phenotypic traits
      correlate with a single-band PAGE migration profile, in contrast to wild-type M
      (M(wt )), which separates into two species, one of which is a phosphorylated
      form. The single-band migration is likely to result from a conformational change,
      as evidenced by the lack of maturation of a native epitope and by a particular
      tryptic digestion profile, and not from the phosphorylation of all M molecules,
      an assumption consistent with the PAGE migration feature. One of the M mutants
      (HA-M(30 ), an M protein carrying Thr(112)Met and Val(113) Glu substitutions
      tagged with an influenza virus haemagglutinin epitope) was characterized further
      in the context of SeV infection, i.e. under conditions of co-expression with
      M(wt). HA-M (30) is shown (i) to bind mainly to membrane fractions, (ii) not to
      co-precipitate M(wt), as HA-M(wt) does, (iii) to interfere with the binding of
      nucleocapsids to membranes and (iv) to accumulate in perinuclear regions, in
      contrast to HA-M(wt ), which is also found at the cell periphery. Such mutants
      constitute potential tools for the identification of critical steps in
      paramyxovirus assembly and budding.

PMID- 10580061
TI  - Generation of recombinant lentogenic Newcastle disease virus from cDNA.
AB  - Recombinant lentogenic Newcastle disease virus (NDV) of the vaccine strain Clone
      30 was reproducibly generated after simultaneous expression of antigenome-sense
      NDV RNA and NDV nucleoprotein, phosphoprotein and RNA-dependent RNA polymerase
      from plasmids transfected into cells stably expressing T7 RNA polymerase. For
      this purpose, the genome of Clone-30, comprising 15186 nt, was cloned and
      sequenced prior to assembly into a full-length cDNA clone under control of a T7
      RNA polymerase promoter. Recombinant virus was amplified by inoculation of
      transfection supernatant into the allantoic cavity of embryonated specific
      pathogen-free (SPF) chicken eggs. Two marker restriction sites comprising a total
      of five nucleotide changes artificially introduced into noncoding regions were
      present in the progeny virus. The recombinant NDV was indistinguishable from the
      parental wild-type virus with respect to its growth characteristics in cell
      culture and in embryonated eggs. Moreover, an intracerebral pathogenicity index
      of 0.29 was obtained for both viruses as determined by intracerebral inoculation
      of day-old SPF chickens, proving that the recombinant NDV is a faithful copy of
      the parental vaccine strain of NDV.

PMID- 10580062
TI  - Inducible nitric-oxide synthase plays a minimal role in lymphocytic
      choriomeningitis virus-induced, T cell-mediated protective immunity and
      immunopathology.
AB  - By using mice with a targetted disruption in the gene encoding inducible nitric
      oxide synthase (iNOS), we have studied the role of nitric oxide (NO) in
      lymphocytic choriomeningitis virus (LCMV)-induced, T cell-mediated protective
      immunity and immunopathology. The afferent phase of the T cell-mediated immune
      response was found to be unaltered in iNOS-deficient mice compared with wild-type
      C57BL/6 mice, and LCMV- induced general immunosuppression was equally pronounced
      in both strains. In vivo analysis revealed identical kinetics of virus clearance,
      as well as unaltered clinical severity of systemic LCMV infection in both
      strains. Concerning the outcome of intracerebral infection, no significant
      differences were found between iNOS-deficient and wild-type mice in the number or
      composition of mononuclear cells found in the cerebrospinal fluid on day 6 post
      infection. Likewise, NO did not influence the up-regulation of proinflammatory
      cytokine/chemokine genes significantly, nor did it influence the development of
      fatal meningitis. However, a reduced virus-specific delayed-type hypersensitivity
      reaction was observed in iNOS-deficient mice compared with both IFN-gamma
      deficient and wild-type mice. This might suggest a role of NO in regulating
      vascular reactivity in the context of T cell-mediated inflammation. In
      conclusion, these findings indicate a minimal role for iNOS/NO in the host
      response to LCMV. Except for a reduced local oedema in the knockout mice, iNOS/NO
      seems to be redundant in controlling both the afferent and efferent phases of the
      T cell-mediated immune response to LCMV infection.

PMID- 10580063
TI  - Dynamic analysis of hepatitis C virus replication and quasispecies selection in
      long-term cultures of adult human hepatocytes infected in vitro.
AB  - Primary human hepatocytes were used to develop a culture model for in vitro
      propagation of hepatitis C virus (HCV). Production of positive- strand full
      length viral RNA in cells and culture supernatants was monitored by PCR methods
      targeting three regions of the viral genome: the 5' NCR, the 3' X-tail and the
      envelope glycoprotein E2. De novo synthesis of negative-strand RNA was also
      demonstrated. Evidence for a gradual increase in viral components over a 3 month
      period was obtained by two quantitative assays: one for evaluation of genomic
      titre (quantitative PCR) and one for detection of the core antigen. Production of
      infectious viral particles was indicated by passage of infection to naive
      hepatocyte cultures. Reproducibility of the experiments was assessed using
      cultures from three liver donors and eleven sera. Neither the genotype, nor the
      genomic titre, nor the anti-HCV antibody content, were reliable predictive
      factors of serum infectivity, while the liver donor appeared to play a role in
      the establishment of HCV replication. Quasispecies present in hepatocyte cultures
      established from three different liver donors were analysed by sequencing
      hypervariable region 1 of the E2 protein. In all three cases, the complexity of
      viral quasispecies decreased after in vitro infection, but the major sequences
      recovered were different. These data strongly suggest that human primary
      hepatocytes are a valuable model for study of persistent and complete HCV
      replication in vitro and for identification of the factors (viral and/or
      cellular) associated with successful infection.

PMID- 10580064
TI  - Sequence of the non-structural protein gene encoded by RNA1 of striped jack
      nervous necrosis virus.
AB  - Striped jack nervous necrosis virus (SJNNV), the causative agent of viral nervous
      necrosis in marine fish, is a member of the family Nodaviridae whose genome
      consists of two positive-sense RNA molecules encapsidated in a single virion. In
      this study, the nucleotide sequence of SJNNV RNA1 was determined. The SJNNV RNA1
      was 3081 bases long and contained a single ORF encoding 983 aa of approximately
      110 kDa. The sequence identities between RNA1 of SJNNV and RNA1 of insect
      nodaviruses were 28% at the nucleotide and amino acid levels, although the
      conserved motifs for the RNA-dependent RNA polymerase were located at almost the
      same positions in the amino acid sequences. The present study, together with our
      previous work on SJNNV RNA2, suggests that a new genus, Piscinodavirus, should be
      created in the family Nodaviridae.

PMID- 10580065
TI  - Mapping a neutralizing epitope on the coat protein of striped jack nervous
      necrosis virus.
AB  - Striped jack nervous necrosis virus (SJNNV), a fish nodavirus, is the causative
      agent of viral nervous necrosis in marine fishes. The fish nodaviruses are
      divided into four different genotypes based on the nucleotide sequence of the
      coat protein gene. In the present study, partial coat protein genes of fish
      nodaviruses were expressed. This allowed the serological relationship among the
      different virus genotypes to be analysed and neutralizing epitopes on the coat
      protein to be mapped. Western blot analysis revealed that SJNNV and other fish
      nodavirus genotypes shared a significant number of common antigenic determinants,
      although SJNNV was serologically distinguishable. The results suggested that the
      SJNNV determinant for neutralizing MAbs was a linear epitope, which consisted of
      a repeated amino acid sequence within the coat protein. One of the neutralizing
      epitopes of SJNNV was deduced to be PAN at aa 254-256 in the coat protein.

PMID- 10580066
TI  - Comparative studies of human rotavirus serotype G8 strains recovered in South
      Africa and the United Kingdom.
AB  - Epidemiological studies on the VP7 serotype prevalence of human rotaviruses in
      South Africa and the United Kingdom identified several strains which could not be
      serotyped as G1-G4 by monoclonal antibodies. Further analysis of these strains
      with a G8-specific monoclonal antibody and with probes for human rotaviruses
      confirmed them as G8 rotaviruses. These G8 strains exhibited a high degree of
      sequence identity when compared with each other and with other rotavirus G8
      strains. Five South African strains were further characterized as VP6 subgroup I,
      but with a long RNA electropherotype, which is similar to the G8 strains
      previously isolated in Finland. In the UK strains, one was VP6 subgroup II with a
      long RNA electropherotype (similar to the Italian G8 strain). The other two were
      subgroup I with a short RNA electropherotype. None of these strains exhibited the
      super-short RNA electropherotype described in the prototype G8 strains recovered
      from Indonesia (69M).

PMID- 10580067
TI  - Pathogenesis of the oral route of infection of mice with scrapie and bovine
      spongiform encephalopathy agents.
AB  - Transmissible spongiform encephalopathies can be transmitted via the oral route.
      The understanding of this mode of contamination has become a major issue since it
      is responsible for the appearance of bovine spongiform encephalopathy (BSE) and
      is probably implicated in new variant Creutzfeldt-Jakob disease. In this study,
      we addressed the questions of the propagation pathway and the strain specificity
      of the pathogenesis of oral contamination of mice with the C506M3 scrapie strain
      and the 6PB1 BSE strain. PrPres was used as a marker of infectivity and was
      searched for sequentially in 22 organs during the whole incubation period and
      clinical stage. PrPres was first detectable in the Peyer's patches and mesenteric
      lymph nodes at 45 days post-inoculation. It became detectable 1 to 3 months later
      in the other tissues of the lymphoreticular system (LRS) such as the spleen and
      the lymph nodes not related to the digestive tract. These data indicate that
      after an oral route of entry, the infectious agent is propagated from the Peyer's
      patches to the mesenteric lymph nodes by the lymphatic route, then enters the
      bloodstream and is distributed to the secondary replication site, the LRS. The
      major difference between the two agents is that PrPres could be detected in the
      digestive tract (from the stomach to the colon) with the scrapie agent only. This
      observation may have implications for the horizontal transmission of scrapie in
      endemically affected sheep flocks.

PMID- 10580068
TI  - Transmission of the 263K scrapie strain by the dental route.
AB  - Apart from a few cases of iatrogenic and familial human transmissible spongiform
      encephalopathies (TSEs) or prion diseases, the cause of Creutzfeldt-Jakob disease
      (CJD) remains unknown. In this paper we investigated the possibility that dental
      procedures may represent a potential route of infection. This was assessed by
      using the experimental model of scrapie in hamster. In the first part of this
      study we found that after intraperitoneal inoculation, oral tissues commonly
      involved in dental procedures (gingival and pulp tissues) bore a substantial
      level of infectivity. We also found high scrapie infectivity in the trigeminal
      ganglia, suggesting that the scrapie agent had reached the oral tissues through
      the sensitive terminal endings of the trigeminal nerves. In the second part of
      the study we inoculated a group of hamsters in the tooth pulp and showed that all
      of them developed scrapie disease. In these animals, we detected both infectivity
      and the pathological prion protein (PrPsc) in the trigeminal ganglion homolateral
      to the site of injection but not in the controlateral one. This finding suggests
      that the scrapie agent, and likely other TSE agents as well, spreads from the
      buccal tissues to the central nervous system through trigeminal nerves. Although
      these findings may not apply to humans affected by TSEs, they do raise concerns
      about the possible risk of transmitting these disorders through dental
      procedures. Particular consideration should be taken in regard to new variant CJD
      patients because they may harbour more infectivity in peripheral tissues than
      sporadic CJD patients.

PMID- 10580069
TI  - Effect of mode of delivery in nulliparous women on neonatal intracranial injury.
AB  - BACKGROUND: Infants delivered by vacuum extraction or other operative techniques
      may be more likely to sustain major injuries than those delivered spontaneously,
      but the extent of the risk is unknown. METHODS: From a California data base, we
      identified 583,340 live-born singleton infants born to nulliparous women between
      1992 and 1994 and weighing between 2500 and 4000 g. One third of the infants were
      delivered by operative techniques. We evaluated the relation between the mode of
      delivery and morbidity in the infants. RESULTS: Intracranial hemorrhage occurred
      in 1 of 860 infants delivered by vacuum extraction, 1 of 664 delivered with the
      use of forceps, 1 of 907 delivered by cesarean section during labor, 1 of 2750
      delivered by cesarean section with no labor, and 1 of 1900 delivered
      spontaneously. As compared with the infants delivered spontaneously, those
      delivered by vacuum extraction had a significantly higher rate of subdural or
      cerebral hemorrhage (odds ratio, 2.7; 95 percent confidence interval, 1.9 to
      3.9), as did the infants delivered with the use of forceps (odds ratio, 3.4; 95
      percent confidence interval, 1.9 to 5.9) or cesarean section during labor (odds
      ratio, 2.5; 95 percent confidence interval, 1.8 to 3.4), but the rate of subdural
      or cerebral hemorrhage associated with vacuum extraction did not differ
      significantly from that associated with forceps use (odds ratio for the
      comparison with vacuum extraction, 1.2; 95 percent confidence interval, 0.7 to
      2.2) or cesarean section during labor (odds ratio, 0.9; 95 percent confidence
      interval, 0.6 to 1.4). CONCLUSIONS: The rate of intracranial hemorrhage is higher
      among infants delivered by vacuum extraction, forceps, or cesarean section during
      labor than among infants delivered spontaneously, but the rate among infants
      delivered by cesarean section before labor is not higher, suggesting that the
      common risk factor for hemorrhage is abnormal labor.

PMID- 10580070
TI  - Missense mutations in the rod domain of the lamin A/C gene as causes of dilated
      cardiomyopathy and conduction-system disease.
AB  - BACKGROUND: Inherited mutations cause approximately 35 percent of cases of
      dilated cardiomyopathy; however, few genes associated with this disease have been
      identified. Previously, we located a gene defect that was responsible for
      autosomal dominant dilated cardiomyopathy and conduction-system disease on
      chromosome 1p1-q21, where nuclear-envelope proteins lamin A and lamin C are
      encoded by the LMNA (lamin A/C) gene. Mutations in the head or tail domain of
      this gene cause Emery-Dreifuss muscular dystrophy, a childhood-onset disease
      characterized by joint contractures and in some cases by abnormalities of cardiac
      conduction during adulthood. METHODS: We evaluated 11 families with autosomal
      dominant dilated cardiomyopathy and conduction-system disease. Sequences of the
      lamin A/C exons were determined in probands from each family, and variants were
      confirmed by restriction-enzyme digestion. The genotypes of the family members
      were ascertained. RESULTS: Five novel missense mutations were identified: four in
      the alpha-helical-rod domain of the lamin A/C gene, and one in the lamin C tail
      domain. Each mutation caused heritable, progressive conduction-system disease
      (sinus bradycardia, atrioventricular conduction block, or atrial arrhythmias) and
      dilated cardiomyopathy. Heart failure and sudden death occurred frequently within
      these families. No family members with mutations had either joint contractures or
      skeletal myopathy. Serum creatine kinase levels were normal in family members
      with mutations of the lamin rod but mildly elevated in some family members with a
      defect in the tail domain of lamin C. CONCLUSIONS: Genetic defects in distinct
      domains of the nuclear-envelope proteins lamin A and lamin C selectively cause
      dilated cardiomyopathy with conduction-system disease or autosomal dominant Emery
      Dreifuss muscular dystrophy. Missense mutations in the rod domain of the lamin
      A/C gene provide a genetic cause for dilated cardiomyopathy and indicate that
      this intermediate filament protein has an important role in cardiac conduction
      and contractility.

PMID- 10580071
TI  - Comparison of mortality in all patients on dialysis, patients on dialysis
      awaiting transplantation, and recipients of a first cadaveric transplant.
AB  - BACKGROUND AND METHODS: The extent to which renal allotransplantation - as
      compared with long-term dialysis - improves survival among patients with end
      stage renal disease is controversial, because those selected for transplantation
      may have a lower base-line risk of death. In an attempt to distinguish the
      effects of patient selection from those of transplantation itself, we conducted a
      longitudinal study of mortality in 228,552 patients who were receiving long-term
      dialysis for end-stage renal disease. Of these patients, 46,164 were placed on a
      waiting list for transplantation, 23,275 of whom received a first cadaveric
      transplant between 1991 and 1997. The relative risk of death and survival were
      assessed with time-dependent nonproportional-hazards analysis, with adjustment
      for age, race, sex, cause of end-stage renal disease, geographic region, time
      from first treatment for end-stage renal disease to placement on the waiting
      list, and year of initial placement on the list. RESULTS: Among the various
      subgroups, the standardized mortality ratio for the patients on dialysis who were
      awaiting transplantation (annual death rate, 6.3 per 100 patient-years) was 38 to
      58 percent lower than that for all patients on dialysis (annual death rate, 16.1
      per 100 patient-years). The relative risk of death during the first 2 weeks after
      transplantation was 2.8 times as high as that for patients on dialysis who had
      equal lengths of follow-up since placement on the waiting list, but at 18 months
      the risk was much lower (relative risk, 0.32; 95 percent confidence interval,
      0.30 to 0.35; P<0.001). The likelihood of survival became equal in the two groups
      within 5 to 673 days after transplantation in all the subgroups of patients we
      examined. The long-term mortality rate was 48 to 82 percent lower among
      transplant recipients (annual death rate, 3.8 per 100 patient-years) than
      patients on the waiting list, with relatively larger benefits among patients who
      were 20 to 39 years old, white patients, and younger patients with diabetes.
      CONCLUSIONS: Among patients with end-stage renal disease, healthier patients are
      placed on the waiting list for transplantation, and long-term survival is better
      among those on the waiting list who eventually undergo transplantation.

PMID- 10580072
TI  - Leydig-cell tumors caused by an activating mutation of the gene encoding the
      luteinizing hormone receptor.

PMID- 10580073
TI  - Images in clinical medicine. Taenia saginata.

PMID- 10580074
TI  - Endoscopy of the upper gastrointestinal tract.

PMID- 10580075
TI  - Gestational diabetes mellitus.

PMID- 10580076
TI  - Birth injury and method of delivery.

PMID- 10580077
TI  - Pathogenesis of inherited forms of dilated cardiomyopathy.

PMID- 10580078
TI  - A survival advantage for renal transplantation.

PMID- 10580079
TI  - Precocious puberty in boys.

PMID- 10580080
TI  - Active compression-decompression cardiopulmonary resuscitation.

PMID- 10580081
TI  - Lipoprotein lipase, a key role in atherosclerosis?
AB  - Lipoprotein lipase (LPL) plays a central role in lipid metabolism and transport
      by catalysing the hydrolysis of triacylglycerol-rich lipoproteins. The importance
      of LPL expressed by the adipose tissue and muscles in the provision of non
      esterified fatty acids and 2-monoacylglycerol for tissue utilisation is well
      established. However, recent studies on LPL expressed by cells of the vascular
      wall, particularly macrophages, have identified additional actions of the enzyme
      that contribute to the promotion of foam cell formation and atherosclerosis. This
      review deals with the role of LPL in atherosclerosis, and its regulation by
      mediators that are known to be present in the lesion.

PMID- 10580082
TI  - The mechanism of the alkaline phosphatase reaction: insights from NMR,
      crystallography and site-specific mutagenesis.
AB  - The proposed double in-line displacement mechanism of Escherichia coli alkaline
      phosphatase (AP) involving two-metal ion catalysis is based on NMR spectroscopic
      and X-ray crystallographic studies. This mechanism is further supported by the X
      ray crystal structures of the covalent phospho-enzyme intermediate of the H331Q
      mutant AP and of the transition state complex between the wild-type enzyme and
      vanadate, a transition state analog. Kinetic and structural studies on several
      genetically engineered versions of AP illustrate the overall importance of the
      active site's metal geometry, hydrogen bonding network and electrostatic
      potential in the catalytic mechanism.

PMID- 10580083
TI  - Origin of the interferon-inducible (2'-5')oligoadenylate synthetases: cloning of
      the (2'-5')oligoadenylate synthetase from the marine sponge Geodia cydonium.
AB  - In vertebrates cytokines mediate innate (natural) immunity and protect them
      against viral infections. The cytokine interferon causes the induction of the (2'
      5')oligoadenylate synthetase [(2-5)A synthetase], whose product, (2'
      5')oligoadenylate, activates the endoribonuclease L which in turn degrades
      (viral) RNA. Three isoforms of (2-5)A synthetases exist, form I (40-46 kDa), form
      II (69 kDa), and form III (100 kDa). Until now (2-5)A synthetases have only been
      cloned from birds and mammals. Here we describe the cloning of the first putative
      invertebrate (2-5)A synthetase from the marine sponge Geodia cydonium. The
      deduced amino acid sequence shows signatures characteristic for (2-5)A
      synthetases of form I. Phylogenetic analysis of the putative sponge (2-5)A
      synthetase indicates that it diverged first from a common ancestor of the
      hitherto known members of (vertebrate) (2-5)A synthetases I, (2-5)A synthetases
      II and III. Moreover, it is suggested that the (2-5)A synthetases II and III
      evolved from this common ancestor (very likely) by gene duplication. Together
      with earlier results on the existence of the (2'-5')oligoadenylates in G.
      cydonium, the data presented here demonstrate that also invertebrates, here
      sponges, are provided with the (2-5)A system. At present, it is assumed that this
      system might be involved in growth control, including control of apoptosis, and
      acquired its additional function in innate immune response in evolutionarily
      younger animals, in vertebrates.

PMID- 10580084
TI  - Cloning and expression pattern of EPAS1 in the chicken embryo. Colocalization
      with tyrosine hydroxylase.
AB  - EPAS1 is a hypoxia-inducible transcription factor, highly expressed in
      vasculature and recently shown to be necessary for catecholamine production
      during embryogenesis. We report here the cloning and detailed expression pattern
      of this factor in the chicken embryo. We show that chicken EPAS1 presents an
      overall identity of 76% with the human sequence and that it is strongly expressed
      in the blood vessel wall, mostly in endothelial cells, but also in vascular
      smooth muscle cells. Moreover, we report non-vascular expression sites: liver,
      kidney, and, quite interestingly, cells of the sympathetic nervous system where
      EPAS1 is coexpressed with one of its putative target genes, the tyrosine
      hydroxylase. EPAS1 could therefore represent the link between the vascular system
      and the sympathetic nervous system, both sensitive to hypoxia.

PMID- 10580085
TI  - Insulin and insulin antagonists evoke phosphorylation of P20 at serine 157 and
      serine 16 respectively in rat skeletal muscle.
AB  - We show here that insulin and insulin antagonists differentially modify
      phosphorylation of three phospho-isoforms of P20 (termed S1, S2 and S3) in rat
      skeletal muscle. Precise phosphorylation sites of S1 and S2 were mapped to serine
      157 and serine 16 respectively. Insulin evoked phosphorylation of P20 at serine
      157 through the phosphatidylinositol (PI) 3-kinase pathway. Epinephrine and
      calcitonin gene-related peptide decreased phosphorylation at serine 157 and
      increased phosphorylation at serine 16 and other unidentified sites. These
      results demonstrate that the PI-3-kinase pathway of anabolic insulin and the cAMP
      pathway of catabolic hormones converge on P20 and suggest a potential role of
      this protein in regulating energy metabolism of skeletal muscle.

PMID- 10580086
TI  - Two types of arrestins expressed in medaka rod photoreceptors.
AB  - Similar to visual arrestins of other vertebrates, two subtypes of medaka visual
      arrestins, KfhArr-R1 and KfhArr-C, are selectively expressed in rods and cones,
      respectively [Hisatomi et al. (1997) FEBS Lett. 411, 12-18]. We isolated a cDNA
      encoding the third arrestin, KfhArr-R2, from a medaka retinal cDNA library.
      Phylogenetic analysis of arrestin sequences suggests that KfhArr-R2 is classified
      into the rod arrestin subtype. In situ hybridization indicated that KfhArr-R2
      mRNA is localized in most of the rod photoreceptors, suggesting that both KfhArr
      R1 and -R2 are co-expressed in rods. Antisera against KfhArr-R2 recognized outer
      segments, but anti-KfhArr-R1 antisera reacted with cell bodies and synaptic
      termini in light-adapted rods. It seems likely that KfhArr-R1 and -R2 play
      different roles in rod photoreceptors.

PMID- 10580087
TI  - Intracellular localization of an active green fluorescent protein-tagged Pho84
      phosphate permease in Saccharomyces cerevisiae.
AB  - Green fluorescent protein (GFP) from Aequorea victoria was used as an in vivo
      reporter protein when fused to the carboxy-terminus of the Pho84 phosphate
      permease of Saccharomyces cerevisiae. Both components of the fusion protein
      displayed their native functions and revealed a cellular localization and
      degradation of the Pho84-GFP chimera consistent with the behavior of the wild
      type Pho84 protein. The GFP-tagged chimera allowed for a detection of conditions
      under which the Pho84 transporter is localized to its functional environment,
      i.e. the plasma membrane, and conditions linked to relocation of the protein to
      the vacuole for degradation. By use of the methodology described, GFP should be
      useful in studies of localization and degradation also of other membrane proteins
      in vivo.

PMID- 10580088
TI  - Fluorescence labeling of the C-terminus of proteins with a puromycin analogue in
      cell-free translation systems.
AB  - We have developed a new method for the C-terminus-specific fluorescence labeling
      of proteins. This method is based on the experimental finding that a fluorescent
      puromycin analogue at lower concentrations bonds efficiently to the C-terminus of
      mature proteins in cell-free translation systems using mRNA without a stop codon.
      This labeling is performed under moderate conditions and its labeling efficiency
      is in the range of 50-95%. Here we demonstrate a protein-protein interaction
      assay using fluorescence polarization measurement. This labeling method should
      also be useful for other rapid molecular interaction assays without purification
      of the labeled proteins, such as fluorescence correlation spectroscopy.

PMID- 10580089
TI  - Acyl and alkyl chain length of GPI-anchors is critical for raft association in
      vitro.
AB  - We determined the acyl and alkyl chain composition of GPI-anchors isolated from
      MDCK and Fischer rat thyroid (FRT) cells. Both cell lines synthesize GPI-anchors
      containing C16/C18 or C18/C18 saturated acyl and alkyl chains. The GPI-anchored
      placental alkaline phosphatase (PLAP) expressed in both cells is raft-associated
      and PLAP purified from FRT cells is raft-associated in vitro when reconstituted
      into liposomes containing raft lipids. In contrast, the GPI-anchored variant
      surface glycoprotein from Trypanosoma brucei which contains C14 acyl and alkyl
      chains shows no significant raft association after reconstitution in vitro. These
      data indicate that the acyl and alkyl chain composition of GPI-anchors determines
      raft association.

PMID- 10580090
TI  - Specific binding of protein kinase CK2 catalytic subunits to tubulin.
AB  - Protein kinase CK2 is composed of two regulatory beta-subunits and two catalytic
      alpha- or alpha'-subunits. To analyse these subunits individually we generated
      antibodies against unique peptides derived from the alpha-, alpha'- and beta
      subunit. Immunofluorescence studies with these antibodies revealed the presence
      of all three CK2 subunits in the cytoplasm and weakly in the nucleus with strong
      signals around the nuclear membrane. Double staining experiments revealed a co
      localisation of all three subunits with tubulin. A direct association between the
      CK2 alpha- and the alpha'-subunit and tubulin was confirmed by co
      immunoprecipitation experiments as well as by Far Western analysis. There was no
      binding of the CK2 beta-subunit to tubulin. Thus, with tubulin we have identified
      a new binding partner specific for the catalytic subunits of CK2.

PMID- 10580091
TI  - Apoptosis induced by denied adhesion to extracellular matrix (anoikis) in thyroid
      epithelial cells is p53 dependent but fails to correlate with modulation of p53
      expression.
AB  - In normal epithelial cells, impaired cell-matrix contact leads to induction of
      programmed cell death, a process that has been termed 'anoikis'. We investigated
      the role of p53 and other apoptotic proteins in anoikis in thyroid epithelial
      cells. Western blot analysis demonstrated that neither p53 nor Bcl-2, Bcl-XL and
      Bax protein expression changed during anoikis. However, loss of endogenous p53
      activity in cells transfected with a dominant-negative mutated p53 inhibited
      anoikis demonstrating the involvement of p53-dependent processes. The phosphatase
      inhibitor sodium orthovanadate opposed anoikis when added to the cells within 6
      h, suggesting a role for phosphorylated proteins.

PMID- 10580092
TI  - Functional analysis of a human A(1) adenosine receptor/green fluorescent
      protein/G(i1)alpha fusion protein following stable expression in CHO cells.
AB  - Fusion proteins between the human A(1) adenosine receptor and the pertussis toxin
      resistant (Cys351Gly) mutant of the G-protein alpha subunit G(i1)alpha (A1/Gi),
      and between the human A(1) adenosine receptor, the Aequorea victoria green
      fluorescent protein (GFP) and Cys351Gly G(i1)alpha (A1/GFP/Gi), were expressed in
      CHO cells. The agonist NECA caused a stimulation of [(35)S]GTPgammaS binding at
      both fusion proteins with similar concentration dependence as at the native
      receptor. However in the presence of pertussis toxin NECA stimulation of
      [(35)S]GTPgammaS binding was only seen at the A1/GFP/Gi fusion protein. The
      regulation of the adenylyl cyclase and MAP kinase effector systems by both fusion
      proteins was attenuated following pertussis toxin treatment. These studies
      demonstrate for the first time the characterisation of a fusion protein between a
      G-protein coupled receptor, GFP and a G-protein alpha subunit.

PMID- 10580093
TI  - Pyrococcus furiosus glyceraldehyde 3-phosphate oxidoreductase has comparable
      W(6+/5+) and W(5+/4+) reduction potentials and unusual [4Fe-4S] EPR properties.
AB  - Pyrococcus furiosus glyceraldehyde 3-phosphate oxidoreductase has been
      characterized using EPR-monitored redox titrations. Two different W signals were
      found. W(1)(5+) is an intermediate species in the catalytic cycle, with the
      midpoint potentials E(m)(W(6+/5+))=-507 mV and E(m)(W(5+/4+))=-491 mV. W(2)(5+)
      represents an inactivated species with E(m)(W(6+/5+))=-329 mV. The cubane cluster
      exhibits both S=3/2 and S=1/2 signals with the same midpoint potential: E(m)([4Fe
      4S](2+/1+))=-335 mV. The S=1/2 EPR signal is unusual with all g values below 2.0.
      The titration results combined with catalytic voltammetry data are consistent
      with electron transfer from glyceraldehyde 3-phosphate first to the tungsten
      center, then to the cubane cluster and finally to the ferredoxin.

PMID- 10580094
TI  - Inhibitory effect of phosphate on in vitro development of 2-cell rat embryos is
      overcome by a factor(s) in oviductal extracts.
AB  - It has been found that inorganic phosphate (P) at concentrations as low as 10
      microM markedly inhibits in vitro development of early rat embryos at the 1-cell
      or 2-cell stage to the blastocyst stage, although P is present at concentrations
      of 0.37-1.19 mM in oviductal fluid, in which the development of early embryos
      occurs. We show here that fractions (PTF, 50-250 microg/ml) of rat oviductal
      extracts (OVEs) passed through a Blue CL6B affinity column have the ability to
      overcome the inhibitory effects of P on the development of 2-cell rat embryos in
      a dose-dependent manner, whereas 250 microg/ml OVE or 250 microg/ml of the bound
      fractions (BF) induced degenerative changes in the embryos at the 2-cell stage.
      Moreover, PTF at concentrations of >/=100 microg/ml stimulated the hatching of
      blastocysts both in medium with and without P, although none of the blastocysts
      in medium without PTF hatched from their zona pellucida.

PMID- 10580095
TI  - Activation volumes for intramolecular electron transfer in bovine heart
      cytochrome c oxidase.
AB  - The present work examines the activation volumes associated with intramolecular
      electron transfer (ET) within the CO-mixed-valence form of bovine heart
      cytochrome c oxidase (CcO). Activation volumes for intramolecular ET between
      cytochrome a(3) and cytochrome a (k=(6. 7+/-0.9)x10(5) s(-1) at ambient pressure)
      and between cytochrome a and Cu(A) (k=(5.9+/-1.7)x10(4) s(-1)) are found to be
      +41+/-5 ml/mol and +28+/-4 ml/mol, respectively. Examination of the crystal
      structures of both the fully oxidized and fully reduced forms of bovine heart CcO
      suggest that the activation volume for the ET between cytochrome a(3) and
      cytochrome a arises from structural changes localized at cytochrome a(3) upon
      heme reduction. Similarly, the activation volume for the ET between cytochrome a
      and Cu(A) is primarily due to structural changes localized at Cu(A) upon
      reduction of this site. Reduction/oxidation of cytochrome a does not appear to
      make any significant contribution to the activation volume. Overall, these
      results suggest conformational regulation of ET by both Cu(A) and cytochrome a(3)
      but not cytochrome a.

PMID- 10580096
TI  - Secondary structure in the 5'-leader or 3'-untranslated region reduces protein
      yield but does not affect the functional interaction between the 5'-cap and the
      poly(A) tail.
AB  - The 5'-cap structure and poly(A) tail of eukaryotic mRNAs cooperate to promote
      translation initiation but whether this functional interaction benefits certain
      classes of mRNAs has not been investigated. In this study, we investigate whether
      a structured 5'-leader or 3'-untranslated region (UTR) affects the cap/poly(A)
      tail interaction. A structured leader reduced the degree to which the 5'-cap
      promoted translation in plant cells and inhibited translation from capped and
      uncapped mRNAs equally in yeast. Secondary structure within the 3'-UTR reduced
      translational efficiency when adjacent to the stop codon but had little effect on
      the cap/poly(A) tail synergy. The functional interaction between the cap and
      poly(A) tail was as important for an mRNA with a structured leader or 3'-UTR as
      it was for an unstructured mRNA in either species, suggesting that these
      structures can reduce translation without affecting the functional interaction
      between the cap and poly(A) tail. However, the loss of Xrn1p, the major 5'-->3'
      exoribonuclease in yeast, abolished cap-dependent translation and the functional
      interaction between the cap and poly(A) tail, suggesting that the cap/poly(A)
      tail synergy is of particular importance under conditions of active RNA turnover.

PMID- 10580097
TI  - Point mutations within 663-666 bp of intron 6 of the human TDO2 gene, associated
      with a number of psychiatric disorders, damage the YY-1 transcription factor
      binding site.
AB  - Single base mutations G-->A at position 663 and G-->T at position 666 of intron 6
      of the human tryptophan oxygenase gene (TDO2) are associated with a variety of
      psychiatric disorders [Comings, D.E. et al. (1996) Pharmacogenetics 6, 307-318].
      Binding of rat liver nuclear extract proteins to synthetic double-strand
      oligonucleotides corresponding to three allelic states of the region between 651
      bp and 680 bp of human TDO2 intron 6 has been studied by gel shift assay. It has
      been demonstrated that to each allelic state of the region there corresponds a
      specific set of proteins that interacts with it. With the aid of computer
      analysis and using specific anti-YY-1 antibodies it has been shown that both
      mutations damage the YY-1 transcription factor binding site.

PMID- 10580098
TI  - Mannan-binding lectin (MBL)-associated plasma protein present in human urine
      inhibits calcium oxalate crystal growth.
AB  - Mannan-binding lectin (MBL)-associated plasma protein (MAp19) is an alternatively
      spliced form of MBL-associated serine protease-2, a component of a complement
      activation cascade. We observed that MAp19 is excreted in human urine.
      Interestingly, the amount of MAp19 was higher in urine of renal cell carcinoma
      patients than healthy people. Pretreatment of urine dialysate with 50 mM EDTA
      increased the recovery of MAp19, suggesting that MAp19 is a calcium-binding
      protein. The recombinant MAp19 showed a strong inhibition of calcium oxalate
      crystal growth in vitro in a concentration-dependent manner. Thus, we conclude
      that MAp19 plays a role in the inhibition of calcium oxalate renal stone
      formation.

PMID- 10580099
TI  - The first determination of pseudouridine residues in 23S ribosomal RNA from
      hyperthermophilic Archaea Sulfolobus acidocaldarius.
AB  - We describe the first identification of pseudouridine (Psi) residues in ribosomal
      RNA (23S rRNA) of an hyperthermophilic Archaea Sulfolobus acidocaldarius. In
      contrast to Eucarya rRNA, only six Psi residues were detected, which is rather
      close to the situation in Bacteria. However, three modified positions (Psi(2479),
      Psi(2535) and Psi(2550)) are unique for S. acidocaldarius. Two Psi residues at
      positions 2060 and 2594 are universally conserved, while one other Psi (position
      2066) is also common to Eucarya. Taken together the results argue against the
      conservation of Psi-synthases between Archaea and Bacteria and provide a basis
      for the search of snoRNA-like guides for Psi formation in Archaea.

PMID- 10580100
TI  - Distribution of Mahogany/Attractin mRNA in the rat central nervous system.
AB  - The Mahogany/Attractin gene (Atrn) has been proposed as a downstream mediator of
      Agouti signaling because yellow hair color and obesity in lethal yellow (A(y))
      mice are suppressed by the mahogany (Atrn(mg)) mutation. The present study
      examined the distribution of Atrn mRNA in the brain and spinal cord by in situ
      hybridization. Atrn mRNA was found widely distributed throughout the central
      nervous system, with high levels in regions of the olfactory system, some limbic
      structures, regions of the brainstem, cerebellum and spinal cord. In the
      hypothalamus, Atrn mRNA was found in specific nuclei including the
      suprachiasmatic nucleus, the supraoptic nucleus, the medial preoptic nucleus, the
      paraventricular hypothalamic nucleus, the ventromedial hypothalamic nucleus, and
      the arcuate nucleus. These results suggest a broad spectrum of physiological
      functions for the Atrn gene product.

PMID- 10580101
TI  - Farnesol-induced generation of reactive oxygen species dependent on mitochondrial
      transmembrane potential hyperpolarization mediated by F(0)F(1)-ATPase in yeast.
AB  - An isoprenoid farnesol (FOH) inhibited cellular oxygen consumption and induced
      mitochondrial generation of reactive oxygen species (ROS) in cells of
      Saccharomyces cerevisiae in correlation with hyperpolarization of the
      mitochondrial transmembrane potential (mtDeltaPsi). The FOH-induced events were
      coordinately abolished with the F(1)-ATPase inhibitor sodium azide as well as the
      F(0)F(1)-ATPase inhibitor oligomycin, suggesting the dependence of ROS generation
      on mtDeltaPsi hyperpolarization mediated by the proton pumping function of
      F(0)F(1)-ATPase as a result of ATP hydrolysis. The role of F(1)-ATPase activity
      in mtDeltaPsi hyperpolarization was supported by the intracellular depletion of
      ATP in FOH-treated cells and its protection with sodium azide. An indirect
      mechanism was suggested to exist in the regulation of F(0)F(1)-ATPase by FOH to
      accelerate its ATP-hydrolyzing activity.

PMID- 10580102
TI  - Oxysterols from oxidized LDL are cytotoxic but fail to induce hsp70 expression in
      endothelial cells.
AB  - Oxidized low density lipoprotein (OxLDL) possesses several proatherogenic
      characteristics, among which a marked cytotoxicity. In vitro, cytotoxicity of
      OxLDL to endothelial cells is associated with an increase in the expression of
      the inducible form of heat shock protein 70 (hsp70), generally regarded as a
      cytoprotective protein. Oxidized derivatives of cholesterol which form upon LDL
      oxidation are cytotoxic. Moreover, most of the OxLDL cytotoxicity is due to its
      lipid moiety, in particular to oxysterols. In this report we demonstrate that
      although oxysterols identified in OxLDL are cytotoxic, they cannot trigger the
      increase in hsp70 expression observed with intact oxidized lipoproteins. We
      speculate therefore that oxysterols may represent the most toxic form of oxidized
      lipids in LDL because they cannot activate a rescue mechanism (i.e. the hsp
      response) and may contribute significantly to cell death within atherosclerotic
      plaques.

PMID- 10580103
TI  - Two tetrodotoxin-resistant sodium channels in human dorsal root ganglion neurons.
AB  - Two tetrodotoxin-resistant (TTX-R) voltage-gated sodium channels, SNS and NaN,
      are preferentially expressed in small dorsal root ganglia (DRG) and trigeminal
      ganglia neurons, most of which are nociceptive, of rat and mouse. We report here
      the sequence of NaN from human DRG, and demonstrate the presence of two TTX-R
      currents in human DRG neurons. One current has physiological properties similar
      to those reported for SNS, while the other displays hyperpolarized voltage
      dependence and persistent kinetics; a similar TTX-R current was recently
      identified in DRG neurons of sns-null mouse. Thus SNS and NaN channels appear to
      produce different currents in human DRG neurons.

PMID- 10580104
TI  - Loss of heterozygosity in tumor cells requires re-evaluation: the data are biased
      by the size-dependent differential sensitivity of allele detection.
AB  - Normal tissue contamination of tumors may eclipse the detection of loss of
      heterozygosity (LOH) by microsatellite analysis and may also hamper isolation of
      tumor suppressor genes. To test the potential impact of this problem, we prepared
      artificial mixtures of mouse-human microcell hybrid lines that carried different
      alleles of the same chromosome 3 marker. After performing an allele titration
      assay, we found a consistent difference between the LOH of a high molecular
      weight (H) allele and the LOH of a low molecular weight (L) allele of the same CA
      repeat marker. It follows that normal tissue admixtures will be less of a problem
      when LOH affects a H allele than with a L allele. Random screening of 100 papers
      published between 1994 and 1999 revealed that the loss of a L allele was recorded
      at about half the frequency (52%) of loss of a H allele. To avoid this bias, we
      have developed rules for the evaluation of LOH data. We suggest that the loss of
      a L allele should be given more weight than the loss of a H allele in LOH studies
      using microsatellite markers.

PMID- 10580105
TI  - Napsin A, a member of the aspartic protease family, is abundantly expressed in
      normal lung and kidney tissue and is expressed in lung adenocarcinomas.
AB  - A pair of 35 kDa polypeptides (TAO1/TAO2) are expressed in more than 90% of all
      primary lung adenocarcinomas but not in other major malignancies. Mass
      spectrometry of tryptic peptides showed that TAO1/TAO2 is identical to napsin A,
      a recently described member of the aspartic proteinase family. The site of
      processing of pronapsin A to the mature form was located. Napsin expression was
      detected in human lung adenocarcinoma tumors, compatible with the marker nature
      of TAO1/TAO2 in the diagnosis of primary lung adenocarcinoma. This is important
      since identification of markers which can distinguish primary lung
      adenocarcinomas from distant metastases is desirable. Northern blot analysis
      showed expression of napsin also in normal lung and kidney tissue, and in situ
      hybridization showed expression in type II alveolar cells of the lung. This
      protease is concluded to have a specific functional role in the normal alveolar
      epithelium and is a candidate protease for the proteolytic processing of
      surfactant precursors.

PMID- 10580106
TI  - Human napsin A: expression, immunochemical detection, and tissue localization.
AB  - A novel aspartic proteinase, called napsin, has recently been found in human and
      mouse. Due to high similarity with cathepsin D a structural model of human napsin
      A could be built. Based on this model a potential epitope SFYLNRDPEEPDGGE has
      been identified, which was used to immunize rabbits. The resulting antibody was
      employed in monitoring the expression of recombinant human napsin A in HEK293
      cell line. Western blot analysis confirmed the specificity of the antibody and
      showed that human napsin A is expressed as a single chain protein with the
      molecular weight of approximately 38 kDa. Immunohistochemical studies revealed
      high expression levels of napsin A in human kidney and lung but low expression in
      spleen.

PMID- 10580107
TI  - Human immunodeficiency virus-1-tat induces matrix metalloproteinase-9 in
      monocytes through protein tyrosine phosphatase-mediated activation of nuclear
      transcription factor NF-kappaB.
AB  - We have previously shown that human immunodeficiency virus (HIV)-1-tat induces
      the production of matrix metalloproteinase-9 (MMP-9) in human monocytes by a
      mechanism that is not understood. In the present report, we demonstrate that HIV
      tat-induced expression of MMP-9 is blocked by inhibitors of protein tyrosine
      phosphatases (PTPases). PTPase inhibitors also blocked HIV-tat-induced nuclear
      transcription factor NF-kappaB activation and IkappaBalpha degradation required
      for MMP-9 induction. These results suggest that HIV-tat induces MMP-9 in human
      monocytes through activation of PTPase and NF-kappaB.

PMID- 10580108
TI  - Induced expression of adipophilin mRNA in human macrophages stimulated with
      oxidized low-density lipoprotein and in atherosclerotic lesions.
AB  - Oxidized low-density lipoprotein (OxLDL) plays a critical role in foam cell
      formation and atherosclerogenesis. A cDNA encoding adipophilin was identified in
      cultured human macrophages stimulated with OxLDL using mRNA differential display.
      Adipophilin is a 50 kDa protein known to be a specific marker for adipocyte cell
      differentiation and lipid accumulation in a variety of cells. The time-dependent
      induction of adipophilin mRNA in macrophages was specific to OxLDL but not native
      LDL, and not to various cytokines and serum. In human atherosclerotic lesions,
      adipophilin mRNA expression was localized in a subset of lipid-rich macrophages.
      These data suggest that adipophilin-expressing macrophages may represent foam
      cells and this gene expression is likely to be associated with the lipid
      accumulation in foam cells of the atherosclerotic lesions.

PMID- 10580109
TI  - Biosynthetic origin of syringomycin and syringopeptin 22, toxic secondary
      metabolites of the phytopathogenic bacterium Pseudomonas syringae pv. syringae.
AB  - The biosynthesis of syringomycin (SR) and syringopeptin 22 (SP22), bioactive
      lipodepsipeptides of the phytopathogenic bacterium Pseudomonas syringae pv.
      syringae, was studied by feeding (14)C-labeled precursors to chloramphenicol
      containing bacterial suspensions. The preferential sites of incorporation were
      determined by comparing the specific activities of the intact radiolabeled
      metabolites and their single structural elements, obtained by hydrolytic
      degradation followed by derivatization and isolation by high performance liquid
      chromatography. The results show that, upon feeding L-[(14)C(U)]-Thr, 35.0 and
      31.0% of the SR radioactivity is retained in 2,3-dehydro-2-aminobutyric acid
      (Dhb) and 4-chlorothreonine (Thr(4-Cl)), respectively. L-[(14)C(U)]-Asp labels
      the same sites, though less efficiently, and is also incorporated in 2,4
      diaminobutyric acid (Dab) and 3-hydroxyaspartic acid (Asp(3-OH)). Dhb is also
      labeled by Thr and Asp in SP22. These are the first data on the biosynthetic
      origin of the modified residues in P. syringae lipopeptides.

PMID- 10580110
TI  - Molecular electroporation: a unifying concept for the description of membrane
      pore formation by antibacterial peptides, exemplified with NK-lysin.
AB  - The antibacterial activity of many small, positively charged peptides and
      proteins is based on pore formation in lipid bilayers. It is here proposed to
      arise from an electroporation effect. This hypothesis is supported by
      calculations of the electrostatic potential of NK-lysin associated to a membrane.
      For a significant area of the protein-membrane interface, the electrostatic
      potential is found to be above the minimum threshold for electroporation. A
      single highly charged alpha-helical segment of NK-lysin is mainly responsible for
      this effect. It is experimentally demonstrated that a peptide comprising this
      helix has antibacterial activity. We propose that superficial association to
      membranes suffices to trigger electroporation, provided the peptide is
      sufficiently charged. The effect is referred to as molecular electroporation.

PMID- 10580111
TI  - Non-invasive transgenic mouse genotyping using stool analysis.
AB  - Commonly applied genotyping of transgenic mice involves using tail or ear
      biopsies which may cause discomfort to the animal. We tested the possibility of
      polymerase chain reaction (PCR)-based mouse genotyping using stool specimens from
      three transgenic mouse lines that overexpress 10-18 transgene copies of human
      keratin polypeptide 18, as compared to genotyping using tail biopsies. Stool
      specimens were obtained with ease and provided easy detection of the human
      transgene product. The method was also able to detect endogenous mouse actin and
      keratin genes which presumably are present at two copies each. Nested PCR was not
      necessary for genotyping using stool-derived genomic material but did increase
      the relative magnitude of the signal obtained. The non-invasive genotyping method
      described herein offers a reproducible, sensitive and effective modality that
      could replace invasive tissue sampling procedures currently used to test
      thousands of genetically altered mice.

PMID- 10580112
TI  - A single-stranded loop in the 5' untranslated region of cucumber mosaic virus RNA
      4 contributes to competitive translational activity.
AB  - The 5' untranslated region (UTR) of cucumber mosaic virus (CMV) RNA 4 confers a
      highly competitive translational advantage on a heterologous luciferase open
      reading frame. Here we investigated whether secondary structure in the 5' UTR
      contributes to this translational advantage. Stabilization of the 5' UTR RNA
      secondary structure inhibited competitive translational activity. Alteration of a
      potential single-stranded loop to a stem by substitution mutations greatly
      inhibited the competitive translational activity. Tobacco plants infected with
      wild type virus showed a 2.5-fold higher accumulation of maximal coat protein
      than did plants infected with a loop-mutant virus. Amplification of viral RNA in
      these plants could not explain the difference in accumulation of coat protein.
      Phylogenetic comparison showed that potential single-stranded loops of 12-23
      nucleotides in length exist widely in subgroups of CMV.

PMID- 10580113
TI  - Protection against peroxynitrite by cocoa polyphenol oligomers.
AB  - Flavonoids, natural plant constituents, protect against peroxynitrite and can
      thereby play a role in defense against this mediator of inflammation. Procyanidin
      oligomers of different size (monomer through nonamer), isolated from the seeds of
      Theobroma cacao, were examined for their ability to protect against peroxynitrite
      dependent oxidation of dihydrorhodamine 123 and nitration of tyrosine. By
      molarity, oligomers were more effective than the monomeric epicatechin; the
      tetramer was particularly efficient at protecting against oxidation and nitration
      reactions. These results suggest that epicatechin oligomers found in cocoa powder
      and chocolate may be a potent dietary source for defense against peroxynitrite.

PMID- 10580114
TI  - Voltage-dependent Ca(2+) channel subunit expression and immunolocalization in
      mouse spermatogenic cells and sperm.
AB  - Though voltage-dependent Ca(2+) channels contribute to the orchestration of sperm
      differentiation and function, many questions remain concerning their molecular
      architecture. This study shows that alpha(1A) and alpha(1C) Ca(2+) channel pore
      forming subunits are expressed in spermatogenic cells. In addition, it provides
      what is to our knowledge the first evidence for the presence of the Ca(2+)
      channel beta auxiliary subunits in spermatogenic cells and sperm. Using RT-PCR we
      demonstrated the expression of all four known genes encoding the beta subunits in
      spermatogenic cells. Specific antibodies detected three of these proteins in
      spermatogenic cells and sperm. In spermatogenic cells both alpha(1) and beta
      subunits are diffusely distributed throughout the cytoplasm while in sperm they
      appear to be regionally localized.

PMID- 10580116
TI  - Serial analysis of gene expression in HIV-1-infected T cell lines.
AB  - The gene expression profile of the HIV-1 infection state was analyzed in the
      human T cell line MOLT-4. Using the serial analysis of gene expression (SAGE)
      method, a total of 142? omitted?603 SAGE tags were sequenced and identified,
      representing 43? omitted?581 unique mRNA species. Comparison of expression
      patterns revealed that 53 cellular genes were differentially expressed upon HIV-1
      infection. Northern blot and RT-PCR analyses confirmed the altered expression of
      the genes in both MOLT-4 and MT-4 cells. Up-regulated genes were mainly composed
      of transcription factors and genes related to T cell activation, whereas down
      regulated genes were comprised of mitochondrial proteins, actin-related factors
      and translational factors. These findings indicate that persistent T cell
      activation, which may accelerate HIV-1 replication, and the disruption of
      cellular housekeeping genes including those involved in anti-apoptotic systems,
      may play an important role in HIV-1-induced pathogenesis.

PMID- 10580115
TI  - The mammalian homologues of frog Bv8 are mainly expressed in spermatocytes.
AB  - Bv8, a protein from skin secretions of Bombina variegata, reacts with receptors
      present in mammalian brain and intestine (Mollay et al. (1999) Eur. J. Pharmacol.
      374, 189-196). As deduced from cloned cDNAs, the murine and human Bv8 homologues
      have identical amino-terminal sequences and also contain 10 cysteines. From mouse
      testes, two forms of Bv8 mRNA have been characterized, of which one contains an
      additional exon which codes for 21 mostly basic amino acids. The mouse Bv8 gene
      is most active in mid-late pachytene spermatocytes. In mouse testes, Bv8 mRNA can
      first be detected at the end of the second week post partum.

PMID- 10580117
TI  - AATF, a novel transcription factor that interacts with Dlk/ZIP kinase and
      interferes with apoptosis.
AB  - Dlk, also known as ZIP kinase, is a serine/threonine kinase that is tightly
      associated with nuclear structures. Under certain conditions, which require
      cytoplasmic localization, Dlk can induce apoptosis. In search for interaction
      partners that might serve as regulators or targets of this kinase we identified
      apoptosis antagonizing transcription factor (AATF), a nuclear phosphoprotein of
      523 amino acids. The 1.8 kb mRNA seems to be ubiquitously expressed. AATF
      contains an extremely acidic domain and a putative leucine zipper characteristic
      of transcription factors. Indeed, a Gal4-BD-AATF fusion protein exhibited strong
      transactivation activity. Interestingly, AATF interfered with Dlk-induced
      apoptosis.

PMID- 10580118
TI  - The antioxidant functions of cytochrome c.
AB  - Low (C(1/2) = 1.5 x 10(-7) M) concentrations of horse cytochrome c strongly
      inhibit H(2)O(2) production by rat heart mitochondria under conditions of reverse
      electron transfer from succinate to NAD(+). The effect is abolished by binding of
      cytochrome c with liposomes and is not prevented by SOD. Yeast cytochrome c is
      much less effective than the horse protein whereas acetylated horse cytochrome c
      is without effect. H(2)O(2) formation stimulated by antimycin A is resistant to
      added cytochrome c. In inside-out submitochondrial vesicles, H(2)O(2) production
      is suppressed by all three cytochrome c samples tested, but at higher
      concentrations (C(1/2) is about 5 x 10(-7) M). In vesicles, SOD abolishes the
      cytochrome c inhibition. We conclude that extramitochondrial cytochrome c is
      competent in down-regulation of the Complex I H(2)O(2) production linked to the
      reverse electron transfer. Such an effect is absent in the inside-out
      submitochondrial vesicles where another antioxidant cytochrome c function can be
      observed, i.e. the oxidation of O(2-*) to O(2). A possible role of cytochrome c
      in the antioxidant defence is discussed.

PMID- 10580119
TI  - Anthrax lethal factor cleaves MKK3 in macrophages and inhibits the LPS/IFNgamma
      induced release of NO and TNFalpha.
AB  - The lethal toxin of Bacillus anthracis consists of two proteins, PA and LF, which
      together induce lethal effects in animals and cause macrophage lysis. LF is a
      zinc-endopeptidase which cleaves two mitogen-activated protein kinase kinases
      (MAPKKs), Mek1 and Mek2, within the cytosol. Here, we show that also MKK3,
      another dual-specificity kinase that phosphorylates and activates p38 MAP kinase,
      is cleaved by LF in macrophages. No direct correlation between LF-induced cell
      death and cleavage of these MAPKKs was found in macrophage cell lines and primary
      peritoneal cells exhibiting different sensitivity to LF. However, we present the
      first evidence that sublytic doses of LF cleave Meks and cause a substantial
      reduction in the production of NO and tumour necrosis factor-alpha induced by
      lipopolysaccharide/interferon gamma. We suggest that this effect of LF is
      relevant during the first stages of B. anthracis infection, when a reduction of
      the inflammatory response would permit growth and diffusion of the bacterium.

PMID- 10580120
TI  - Factors important for fusogenic activity of peptides: molecular modeling study of
      analogs of fusion peptide of influenza virus hemagglutinin.
AB  - Nine analogs of fusion peptide of influenza virus hemagglutinin whose membrane
      perturbation activity has been thoroughly tested [Murata et al. (1992)
      Biochemistry 31, 1986-1992; Murata et al. (1993) Biophys. J. 64, 724-734] were
      characterized by molecular modeling techniques with the aim of delineating any
      specific structural and/or hydrophobic properties inherent in peptides with
      fusogenic activity. It was shown that, regardless of characteristics common to
      all analogs (peripheral disposition at the water-lipid interface, amphiphilic
      nature, alpha-helical structure, etc.), only fusion active peptides reveal a
      specific 'tilted oblique-oriented' pattern of hydrophobicity on their surfaces
      and a certain depth of penetration to the non-polar membrane core. The conclusion
      was reached that these factors are among the most important for the specific
      destabilization of a bilayer, which is followed by membrane fusion.

PMID- 10580121
TI  - Cloning and expression analysis of a Petunia hybrida flower specific mitotic-like
      cyclin.
AB  - A cyclin cDNA clone (Pethy;CycB1;1) was isolated from a Petunia hybrida ovary
      specific cDNA library. Sequence comparison revealed that Pethy;CYCB1;1 protein is
      highly homologous to mitotic B1 cyclins. Northern analysis and in situ
      hybridisation experiments showed that its expression is developmentally regulated
      and restricted to flower organs. We have attempted to define some of the cell
      division patterns which contribute to shaping each floral organ by analysing
      Pethy;CycB1;1 expression on Petunia flower sections. While in sepals, epidermis
      and parenchyma cell division patterns were comparable, there were two distinct
      cell division patterns in petals. In the epidermis, Pethy;CYCB1;1 expression was
      found both at the petal tip and along epidermis, whereas in the parenchyma only
      at the petal tips. In reproductive organs cell divisions were detected only in
      sporophytic tissues. No signals were detected inside meiotic cells.

PMID- 10580122
TI  - Stabilization of iron regulatory protein 2, IRP2, by aluminum.
AB  - Iron regulatory protein 2 (IRP2) is one of the central regulators of iron
      homeostasis. IRP2 regulates expression of molecules involved in iron metabolism
      by binding to iron responsive elements (IREs) in the transcripts of those
      molecules in iron depletion. IRP2 is regulated by the accelerated degradation
      initiated by the iron-catalyzed oxidation. Here we report that aluminum
      antagonizes the iron-induced decrease in IRE binding activity of IRP2. Aluminum
      also inhibits iron-induced oxidation of IRP2 in vitro. These results suggest that
      aluminum stabilizes IRP2 by interfering with the iron-catalyzed oxidation, which
      results in perturbation of iron metabolism.

PMID- 10580123
TI  - Synergy of importin alpha recognition and DNA binding by the yeast
      transcriptional activator GAL4.
AB  - The N-terminus of the yeast transcriptional activator GAL4 contains partially
      overlapping nuclear targeting and DNA binding functions. We have previously shown
      that GAL4 is recognised with high affinity by importin beta and not by the
      conventional nuclear localisation sequence binding importin alpha subunit of the
      importin alpha/beta heterodimer. The present study uses ELISA-based binding and
      electrophoretic mobility shift assays to show that recognition of GAL4 by
      importin alpha can occur, but only when GAL4 is bound to its specific DNA
      recognition sequence. Intriguingly, binding by importin alpha enhances DNA
      binding on the part of GAL4, implying a synergistic co-operation between these
      two functions. The results implicate a possible role for importin alpha in the
      nucleus additional to its established role in nuclear transport, as well as
      having implications for the use of GAL4 as a DNA carrier in gene therapy
      applications.

PMID- 10580124
TI  - A new matrix protein family related to the nacreous layer formation of Pinctada
      fucata.
AB  - We have isolated a new matrix protein family (N16) which is specific to the
      nacreous layer of the Japanese pearl oyster, Pinctada fucata, and have cloned and
      characterized the cDNAs coding for the components. Analysis of the deduced amino
      acid sequence revealed that N16 showed no definitive homology with other
      proteins. The in vitro studies of the crystallization clarified that N16 induced
      aragonite crystals when fixed on the substrate but inhibited crystal formation
      without it. The aragonite crystals showed platy morphology different from those
      formed inorganically, and long intervals of incubation resulted in crystalline
      layers highly similar to the nacreous layer.

PMID- 10580125
TI  - On the frequency of protein glycosylation, as deduced from analysis of the SWISS
      PROT database.
AB  - The SWISS-PROT protein sequence data bank contains at present nearly 75,000
      entries, almost two thirds of which include the potential N-glycosylation
      consensus sequence, or sequon, NXS/T (where X can be any amino acid but proline)
      and thus may be glycoproteins. The number of proteins filed as glycoproteins is
      however considerably smaller, 7942, of which 749 have been characterized with
      respect to the total number of their carbohydrate units and sites of attachment
      of the latter to the protein, as well as the nature of the carbohydrate-peptide
      linking group. Of these well characterized glycoproteins, about 90% carry either
      N-linked carbohydrate units alone or both N- and O-linked ones, attached at 1297
      N-glycosylation sites (1.9 per glycoprotein molecule) and the rest are O
      glycosylated only. Since the total number of sequons in the well characterized
      glycoproteins is 1968, their rate of occupancy is 2/3. Assuming that the same
      number of N-linked units and rate of sequon occupancy occur in all sequon
      containing proteins and that the proportion of solely O-glycosylated proteins
      (ca. 10%) will also be the same as among the well characterized ones, we conclude
      that the majority of sequon containing proteins will be found to be glycosylated
      and that more than half of all proteins are glycoproteins.

PMID- 10580126
TI  - The alpha1-6-fucosyltransferase gene and its biological significance.
AB  - GDP-L-Fuc:N-acetyl-beta-D-glucosaminide alpha1-6-fucosyltransferase (alpha1
      6FucT) catalyzes the transfer of fucose from GDP-Fuc to N-linked type complex
      glycoproteins. This enzyme was purified from a human fibroblast cell line,
      porcine brain, a human gastric cancer cell line and human blood platelets. cDNA
      cloning of porcine and human alpha1-6FucT was performed from a porcine brain and
      gastric cancer cell cDNA libraries, respectively. Their homology is 92.2% at the
      nucleotide level and 95.7% at the amino acid level. No putative N-glycosylation
      sites were found in the predicted amino acid sequence. No homology to other
      fucosyltransferases such as alpha1-2FucT, alpha1-3FucT and alpha1-4FucT was found
      except for a region consisting of nine amino acids. The alpha1-6FucT gene is
      located at chromosome 14q24.3, which is also a different location from other
      fucosyltransferases reported to date. The alpha1-6FucT gene is the oldest gene
      family in the phylogenic trees among the nine cloned fucosyltransferase genes.
      alpha1-6FucT is widely expressed in various rat tissues and the expression of
      alpha1-6FucT in the liver is enhanced during hepatocarcinogenesis of LEC rats
      which develop hereditary hepatitis and hepatomas. In cases of human liver
      diseases, alpha1-6FucT is expressed in both hepatoma tissues and their
      surrounding tissues with chronic liver disease, but not in the case of normal
      liver. Serum alpha1-6-fucosylated alpha-fetoprotein (AFP) has been employed for
      an early diagnosis of patients with hepatoma. The mechanisms by which alpha1-6
      fucosylation of AFP occurs in the hepatoma is not due to the up-regulation of
      alpha1-6FucT alone. Interestingly, when the alpha1-6FucT gene is transfected into
      Hep3B, a human hepatoma cell line, tumor formation in the liver of nude mice
      after splenic injection is dramatically suppressed. In this review, we focus on
      alpha1-6FucT and summarize its properties, gene expression and biological
      significance.

PMID- 10580127
TI  - Glycoprotein glycosylation and cancer progression.
AB  - Glycosylation of glycoproteins and glycolipids is one of many molecular changes
      that accompany malignant transformation. GlcNAc-branched N-glycans and terminal
      Lewis antigen sequences have been observed to increase in some cancers, and to
      correlate with poor prognosis. Herein, we review evidence that beta1, 6GlcNAc
      branching of N-glycans contributes directly to cancer progression, and we
      consider possible functions for the glycans. Mgat5 encodes N
      acetylglucosaminyltransferase V (GlcNAc-TV), the Golgi enzyme required in the
      biosynthesis of beta1,6GlcNAc-branched N-glycans. Mgat5 expression is regulated
      by RAS-RAF-MAPK, a signaling pathway commonly activated in tumor cells. Ectopic
      expression of GlcNAc-TV in epithelial cells results in morphological
      transformation and tumor growth in mice, and over expression in carcinoma cells
      has been shown to induce metastatic spread. Ectopic expression of GlcNAc-TIII, an
      enzyme that competes with GlcNAc-TV for acceptor, suppresses metastasis in B16
      melanoma cells. Furthermore, breast cancer progression and metastasis induced by
      a viral oncogene expressed in transgenic mice is markedly suppressed in a GlcNAc
      TV-deficient background. Mgat5 gene expression and beta1, 6GlcNAc-branching of N
      glycans are associated with cell motility, a required phenotype of malignant
      cells.

PMID- 10580128
TI  - Identification and characterization of large galactosyltransferase gene families:
      galactosyltransferases for all functions.
AB  - Enzymatic glycosylation of proteins and lipids is an abundant and important
      biological process. A great diversity of oligosaccharide structures and types of
      glycoconjugates is found in nature, and these are synthesized by a large number
      of glycosyltransferases. Glycosyltransferases have high donor and acceptor
      substrate specificities and are in general limited to catalysis of one unique
      glycosidic linkage. Emerging evidence indicates that formation of many glycosidic
      linkages is covered by large homologous glycosyltransferase gene families, and
      that the existence of multiple enzyme isoforms provides a degree of redundancy as
      well as a higher level of regulation of the glycoforms synthesized. Here, we
      discuss recent cloning strategies enabling the identification of these large
      glycosyltransferase gene families and exemplify the implication this has for our
      understanding of regulation of glycosylation by discussing two
      galactosyltransferase gene families.

PMID- 10580129
TI  - Beta-1,4-galactosylation of N-glycans is a complex process.
AB  - Most beta-1,4-galactosyltransferase (beta-1,4-GalT)-knockout mice die after
      birth. Although several defects were found transiently in these animals, the
      primary cause of death is obscure. Not only beta-1,4-linked galactose residues on
      N-glycans, but also beta-1, 4-GalT activities were found in some of the tissues.
      Recently, five human genes which encode beta-1,4-GalTs have been cloned, and the
      possible presence of such novel beta-1,4-GalTs in mice is considered to bring
      about survival of the mutant animal beyond birth. In order to understand the semi
      lethal nature of this animal, it is inevitable to clarify how individual novel
      beta-1,4-GalTs are involved in the biosynthesis of glycoconjugates based on their
      acceptor-substrate specificities.

PMID- 10580130
TI  - Pathways of O-glycan biosynthesis in cancer cells.
AB  - Glycoproteins with O-glycosidically linked carbohydrate chains of complex
      structures and functions are found in secretions and on the cell surfaces of
      cancer cells. The structures of O-glycans are often unusual or abnormal in
      cancer, and greatly contribute to the phenotype and biology of cancer cells. Some
      of the mechanisms of changes in O-glycosylation pathways have been determined in
      cancer model systems. However, O-glycan biosynthesis is a complex process that is
      still poorly understood. The glycosyltransferases and sulfotransferases that
      synthesize O-glycans appear to exist as families of related enzymes of which
      individual members are expressed in a tissue- and growth-specific fashion.
      Studies of their regulation in cancer may reveal the connection between cancerous
      transformation and glycosylation which may help to understand and control the
      abnormal biology of tumor cells. Cancer diagnosis may be based on the appearance
      of certain glycosylated epitopes, and therapeutic avenues have been designed to
      attack cancer cells via their glycans.

PMID- 10580131
TI  - Importance of glycosidases in mammalian glycoprotein biosynthesis.
AB  - Processing glycosidases play an important role in N-glycan biosynthesis in
      mammalian cells by trimming Glc(3)Man(9)GlcNAc(2) and thus providing the
      substrates for the formation of complex and hybrid structures by Golgi
      glycosyltransferases. Processing glycosidases also play a role in the folding of
      newly formed glycoproteins and in endoplasmic reticulum quality control. The
      properties and molecular nature of mammalian processing glycosidases are
      described in this review. Membrane-bound alpha-glucosidase I and soluble alpha
      glucosidase II of the endoplasmic reticulum remove the alpha1,2-glucose and
      alpha1,3-glucose residues, respectively, beginning immediately following transfer
      of Glc(3)Man(9)GlcNAc(2) to nascent polypeptides. The alpha-glucosidases
      participate in glycoprotein folding mediated by calnexin and calreticulin by
      forming the monoglucosylated high mannose oligosaccharides required for the
      interaction with the chaperones. In some mammalian cells, Golgi endo alpha
      mannosidase provides an alternative pathway for removal of glucose residues.
      Removal of alpha1,2-linked mannose residues begins in the endoplasmic reticulum
      where trimming of mannose residues in the endoplasmic reticulum has been
      implicated in the targeting of malfolded glycoproteins for degradation. Removal
      of mannose residues continues in the Golgi with the action of alpha1, 2
      mannosidases IA and IB that can form Man(5)GlcNAc(2) and of alpha-mannosidase II
      that removes the alpha1,3- and alpha1,6-linked mannose from GlcNAcMan(5)GlcNAc(2)
      to form GlcNAcMan(3)GlcNAc(2). These membrane-bound Golgi enzymes have been
      cloned and shown to have very distinct patterns of tissue-specific expression.
      There are also broad specificity alpha-mannosidases that can trim Man(4
      9)GlcNAc(2) to Man(3)GlcNAc(2), and provide an alternative pathway toward complex
      oligosaccharide formation. Cloning of the remaining alpha-mannosidases will be
      required to evaluate their specific functions in glycoprotein maturation.

PMID- 10580132
TI  - Physiological aspects of chitin catabolism in marine bacteria.
AB  - Chitin, a carbohydrate polymer composed of alternating beta-1, 4-linked N
      acetylglucosamine residues is the second most abundant organic compound in
      nature. In the aquatic biosphere alone, it is estimated that more than 10(11)
      metric tons of chitin are produced annually. If this enormous quantity of
      insoluble carbon and nitrogen was not converted to biologically useful material,
      the oceans would be depleted of these elements in a matter of decades. In fact,
      marine sediments contain only traces of chitin, and the turnover of the
      polysaccharide is attributed primarily to marine bacteria, but the overall
      process involves many steps, most of which remain to be elucidated. Marine
      bacteria possess complex signal transduction systems for: (1) finding chitin, (2)
      adhering to chitinaceous substrata, (3) degrading the chitin to oligosaccharides,
      (4) transporting the oligosaccharides to the cytoplasm, and (5) catabolizing the
      transport products to fructose-6-P, acetate and NH(3). The proteins and enzymes
      are located extracellularly, in the cell envelope, the periplasmic space, the
      inner membrane and the cytoplasm. In addition to these levels of complexity, the
      various components of these systems appear to be carefully coordinated by
      intricate regulatory mechanisms.

PMID- 10580133
TI  - The remodeling of glycoconjugates in mice.
AB  - A role for glycoconjugates in mediating cellular interactions is well
      established. To further understand the formation, function and regulation of
      various glycoconjugates in vivo, gene targeting approaches have been applied to
      glycosyltransferase and glycosidase enzymes involved in different biosynthetic
      pathways. The growing number of gene targeted mice generated have brought
      confirmations of the importance of both core and terminal glycosylation enzymes
      in normal development and physiology. Of particular interest has been the degree
      of cell and tissue specificity of phenotypes generated by systemic null mutations
      as well as the number of enzymes belonging to multigene families having
      overlapping activities.

PMID- 10580134
TI  - Trafficking of oligomannosides released during N-glycosylation: a clearing
      mechanism of the rough endoplasmic reticulum.
AB  - The main reaction of N-glycosylation of proteins is the transfer 'en bloc' of the
      oligosaccharide moieties of lipid intermediates to an asparagine residue of the
      nascent protein. For the past 15 years, a few laboratories including ours have
      shown that the process was accompanied by the release of oligosaccharide
      phosphates and of neutral oligosaccharides possessing one GlcNAc (OS-Gn(1)) or
      two GlcNAc (OS-Gn(2)) at the reducing end. The aim of this review is to gather
      the evidence for the different origins of these soluble oligomannosides, to
      examine their subcellular location and intracellular trafficking. Furthermore,
      using Brefeldin A we demonstrated that this released oligomannoside material
      could be the substrate for the Golgi glycosidases and glycosyltransferases.
      Indeed, released oligomannoside never reach the Golgi vesicles either because
      they are directly produced in the cytosol as has been demonstrated for
      oligosaccharide-phosphates and for neutral oligosaccharides possessing one GlcNAc
      at the reducing end or because they are actively transported out of the rough
      endoplasmic reticulum to the cytosol. One of the functions of oligomannoside
      trafficking between rough endoplasmic reticulum, cytosol and lysosomes could be
      to prevent these oligosaccharides for competing with glycosylation in the Golgi.

PMID- 10580135
TI  - Intracellular lectins associated with N-linked glycoprotein traffic.
AB  - The vectorial intracellular transport of N-glycan-linked glycoproteins is
      indispensable for biological functions. In order to sort these glycoproteins to
      the correct destination, animal intracellular lectins play important roles as
      sorting receptors. The roles of such lectins in the biosynthetic pathway from the
      endoplasmic reticulum (ER) to the cell surface are addressed in this review.
      Calnexin and calreticulin function via specific carbohydrates in quality control
      of newly synthesized glycoproteins in the ER, and ERGIC-53 seems to function in
      the transport of glycoproteins from ER to the Golgi complex. In addition to the
      well-understood role of mannose 6-phosphate receptor in lysosomal protein
      sorting, the vesicular integral protein of 36 kDa (VIP36) functions as a sorting
      receptor by recognizing high-mannose type glycans containing alpha1-->2Man
      residues for transport from Golgi to the cell surface in polarized epithelial
      cells.

PMID- 10580136
TI  - O-GlcNAc and the control of gene expression.
AB  - Many eukaryotic proteins contain O-linked N-acetylglucosamine (O-GlcNAc) on their
      serine and threonine side chain hydroxyls. In contrast to classical cell surface
      glycosylation, O-GlcNAc occurs on resident nuclear and cytoplasmic proteins. O
      GlcNAc exists as a single monosaccharide residue, showing no evidence of further
      elongation. Like phosphorylation, O-GlcNAc is highly dynamic, transiently
      modifying proteins. These post-translational modifications give rise to
      functionally distinct subsets of a given protein. Furthermore, all known O-GlcNAc
      proteins are also phosphoproteins that reversibly form multimeric complexes that
      are sensitive to the state of phosphorylation. This observation implies that O
      GlcNAc may work in concert with phosphorylation to mediate regulated protein
      interactions. The proteins that bear the O-GlcNAc modification are very diverse,
      including RNA polymerase II and many of its transcription factors, numerous
      chromatin-associated proteins, nuclear pore proteins, proto-oncogenes, tumor
      suppressors and proteins involved in translation. Here, we discuss the functional
      implications of O-GlcNAc-modifications of proteins involved in various aspects of
      gene expression, beginning with proteins involved in transcription and ending
      with proteins involved in regulating protein translation.

PMID- 10580137
TI  - Secretion of the galectin family of mammalian carbohydrate-binding proteins.
AB  - Galectins are cytosolic proteins that lack any signal sequence for transport into
      the endoplasmic reticulum and are not glycosylated, although several galectins
      contain consensus sites for N-glycosylation, indicating that these proteins do
      not traverse the ER-Golgi network. However, there is abundant evidence for the
      extracellular localisation of some galectins at cell surfaces, in the
      extracellular matrix and in cell secretions consistent with other evidence for
      extracellular roles of galectins as modulators of cell adhesion and signalling.
      How then are galectins secreted if not through the classical secretory pathway?
      Do all galectins share the same secretory pathway? Can a particular galectin
      utilise more than one secretory pathway? If galectins play important
      extracellular roles how is their secretion regulated in relation to function?
      These are still largely unanswered questions but recent studies are beginning to
      give glimpses into some novel aspects of the secretion of these intriguing
      proteins.

PMID- 10580138
TI  - Structure and biology of mannan-binding protein, MBP, an important component of
      innate immunity.

PMID- 10580139
TI  - The glycobiology of gametes and fertilization.

PMID- 10580140
TI  - Structures of sugar chains included in mammalian zona pellucida glycoproteins and
      their potential roles in sperm-egg interaction.

PMID- 10580141
TI  - Fucose in N-glycans: from plant to man.
AB  - Fucosylated oligosaccharides occur throughout nature and many of them play a
      variety of roles in biology, especially in a number of recognition processes. As
      reviewed here, much of the recent emphasis in the study of the oligosaccharides
      in mammals has been on their potential medical importance, particularly in
      inflammation and cancer. Indeed, changes in fucosylation patterns due to
      different levels of expression of various fucosyltransferases can be used for
      diagnoses of some diseases and monitoring the success of therapies. In contrast,
      there are generally at present only limited data on fucosylation in non-mammalian
      organisms. Here, the state of current knowledge on the fucosylation abilities of
      plants, insects, snails, lower eukaryotes and prokaryotes will be summarised.

PMID- 10580142
TI  - O-mannosyl glycans in mammals.
AB  - Most proteins within living organisms contain glycans. Glycan structures can
      modulate the biological properties and functions of glycoproteins. The major
      glycans of glycoproteins can be classified into two groups, N-glycans and O
      glycans, according to their glycan-peptide linkage regions. Developments in
      glycobiology have revealed a new type of glycosidic linkage to the peptide
      portion, the O-mannosyl linkage, in mammals, while so far it had been thought to
      be specific to yeast. This review will give an outline of the O-mannosyl glycans
      of mammalian glycoproteins. Since one of the most well known O-mannosyl-modified
      mammalian glycoproteins is dystroglycan, the functional aspects of the O-mannosyl
      glycan of dystroglycan will be described to help understand this new
      glycobiological field.

PMID- 10580143
TI  - Antigen structure and genetic basis of histo-blood groups A, B and O: their
      changes associated with human cancer.
AB  - Three areas of research involved in blood group (or histo-blood group) ABO
      antigens and their genes, developed by our research group, are reviewed: (1)
      Antigen structures. The structural basis of A and H, A(1) and A(2), i and I
      antigens expressed in erythrocyte membranes. Major carriers of A and H
      determinants in erythrocytes are type 2 chain poly-LacNAc, short vs. long and
      unbranched vs. branched structures termed A(a), A(b), A(c), A(d) and H(1), H(2),
      H(3), H(4). Regular A (A(1)) and weak A (A(2)) were identified respectively as
      repetitive A (type 3 chain A) and A-associated H. A(1)- and A(2)-specific type 3
      chain A and H, type 1 chain (representing Lewis blood group antigens), and type 4
      chain (globo-series antigen; an extremely minor component in erythrocytes) are
      all glycosphingolipids. A and H determinants in fetal and newborn erythrocytes
      are carried by unbranched poly-LacNAc, whereas these determinants in adult
      erythrocytes are carried by branched poly-LacNAc. (2) ABO genes. A few cDNAs
      encoding A enzyme (UDP-GalNAc: H-a-GalNAc transferase) were cloned based on the
      amino acid sequence of purified A enzyme and their structures were compared with
      those of homologous cDNA from blood cells of B and O individuals (genotype BB,
      OO). Four nucleotide substitutions and four corresponding amino acid sequences
      essential for expression of A(1) allele and B allele, and differences between A
      and B enzymes, were identified. Amino acids 266 and 268, i.e. Leu and Gly for A
      enzyme vs. Met and Ala for B enzyme, were dominant in determining A vs. B
      activity (presumably recognizing UDP-GalNAc vs. UDP-Gal). The A(2) allele was
      characterized by deletion of the termination codon, extending nucleotides up to
      1128 and thus encoding 21 extra amino acids at the C terminus, which may affect
      (diminish) the dominant function of amino acids 266 and 268. Typical O allele
      (O(1)) is characterized by deletion of nucleotide 261 G, causing frame shift and
      encoding of an entirely different, short polypeptide, due to appearance of early
      termination codon at nucleotide 354. Structures of other O alleles (O(1 v), O(2))
      and other weak A alleles (A(3), A(el)) are also described. The genomic structure
      of ABO genes consists of seven exons which span approximately 19 kb of genomic
      DNA on chromosome 9, band q34. Most of the coding sequence is located in exon 7.
      Analysis of the 5' upstream region revealed the presence of the binding site for
      transcription factors and enhancer element. (3) Antigens and genes in cancer. A
      and B phenotypes aberrantly expressed in various types of human cancer, and their
      genetic basis, have been studied. One widely-occurring change observed in a large
      variety of human cancers is deletion of A or B epitope, associated with
      accumulation of their precursor H (Le(y), Le(b)), which causes enhanced
      malignancy. A less-commonly observed change is expression of incompatible A,
      identified as real type 1 chain A, in tumors of O or B individuals. A possible
      molecular genetic mechanism leading to such phenotypic changes is discussed.

PMID- 10580144
TI  - Uridine insertion/deletion RNA editing in trypanosome mitochondria--a review.
AB  - The uridine insertion/deletion RNA editing in trypanosome mitochondria is a
      unique posttranscriptional RNA maturation process that involves the addition or
      removal of uridine residues at precise sites usually within the coding regions of
      mitochondrial transcripts. This process creates initiation and termination
      codons, corrects frameshifts and even builds entire open-reading frames from
      nonsense sequences. The development of several in-vitro editing assays has
      provided much insight into the molecular mechanism of RNA editing, which appears
      to involve cleavage, U addition, exonuclease trimming and ligation, essentially
      as proposed in the original 'enzyme cascade' model (Blum, B., Bakalara, N.,
      Simpson, L., 1990. A model for RNA editing in kinetoplastid mitochondria: 'Guide'
      RNA molecules transcribed from maxicircle DNA provide the edited information.
      Cell 60, 189-198). However, little is known about the biochemical properties of
      the proteins involved and the significance and role of this process. This article
      is a review of recent findings on uridine-insertion/deletion editing in
      trypanosome mitochondria, with an emphasis on the proteins isolated and
      characterized that may have a role in this process.

PMID- 10580145
TI  - An Sp1 binding site is essential for basal activity of the human prostate
      specific transglutaminase gene (TGM4) promoter.
AB  - Human prostate-specific transglutaminase (hTG(P)) is a cross-linking enzyme
      encoded by the TGM4 gene. The TGM4 gene promoter was characterized by deletion
      mapping and mutational analysis. Promoter constructs, containing the minimal
      promoter requirements, could efficiently drive transcription in the prostate
      cancer cell lines PC346C and LNCaP and the hepatic cancer cell line Hep3B. The
      region between positions -113 and -61 was demonstrated to be essential for core
      promoter activity. Further analysis revealed the functional importance of an Sp1
      binding motif, 5'-ACCCCGCCCC-3', at positions -96 to -87. This sequence is a
      binding site of the ubiquitous transcription factors Sp1 and Sp3.

PMID- 10580146
TI  - Densely methylated sequences that are preferentially localized at telomere
      proximal regions of human chromosomes.
AB  - We have constructed a library of densely methylated DNA sequences from human
      blood DNA by selecting fragments with a high affinity for a methyl-CpG binding
      domain (MBD) column. PCR analysis of the library confirmed the presence of known
      densely methylated CpG island sequences. Analysis of random clones, however,
      showed that the library was dominated by sequences whose G+C content and CpG
      frequency were intermediate between those of bulk genomic DNA and bona fide CpG
      islands. When human chromosomes were probed with the library by fluorescent in
      situ hybridisation (FISH), the predominant sites of labelling were at terminal
      regions of many chromosomes, approximately corresponding to T-bands. Analysis of
      the methylation status of random clones indicated that all were heavily
      methylated at CpGs in blood DNA, but many were under-methylated in sperm DNA.
      Lack of methylation in germ cells may reduce CpG depletion at some sub-terminal
      sequences and result in a high density of methyl-CpG when these regions become
      methylated in somatic cells.

PMID- 10580147
TI  - Cloning and characterization of the rat Crisp-1 gene.
AB  - Rat androgen-regulated acidic epididymal glycoprotein (AEG), also known as
      Protein DE, is a product of the Crisp-1 gene. Protein DE is secreted into the
      epididymal lumen and binds to sperm heads during their transit through the
      epididymis. In experiments reported here, the rat Crisp-1 gene has been cloned
      and its structure determined. The rat Crisp-1 gene spans 38kb and contains nine
      exons encoding an 1120bp epididymal Protein DE mRNA. The boundaries of the
      protein-coding exons are structurally organized similar to the mouse Crisp-1
      gene, except for the 5' untranslated sequence, which is encoded by one exon in
      the mouse Crisp-1 gene and two exons in the rat gene. All the introns are flanked
      by AG/GT consensus splice sequences. Crisp-1 is a single-copy gene as shown by
      the presence of single bands by Southern blot analysis and PCR using rat genomic
      DNA as template. Recognition sites for steroid hormone receptors are present in
      the 5' flanking region and in intron 1, consistent with the known regulation of
      Protein DE expression by androgens. RT-PCR experiments demonstrate three splice
      variant mRNAs involving the non-coding exon 2. The Crisp-1 gene also produces an
      mRNA without an exon 1 sequence by utilizing a transcription start site in intron
      1, 5' of the start of exon 2. All forms of the Crisp-1 mRNA are predicted to
      encode Protein DE.

PMID- 10580148
TI  - Isolation of the novel cDNA of a gene of which expression is induced by a
      demethylating stimulus.
AB  - We have isolated a novel cDNA clone, named AZ2, from a cDNA library of mRNA
      prepared from C3H10T1/2 cells that had been transiently exposed to 5-azacytidine,
      a potent inhibitor of DNA methyltransferase. The elucidated nucleotide sequence
      revealed that the 5' region of the cDNA was rich in the CpG sequence. The AZ2
      cDNA contained a 1215-nucleotide open reading frame, and the expected amino acid
      sequence had a molecular mass of 46090. The amount of the transcript increased on
      5-azacytidine treatment of C3H10T1/2 cells, and the transcript was significantly
      expressed in mouse testis, brain, lung, kidney, heart and ovary. Specific
      antibodies raised against a fusion protein including glutathione S-transferase
      revealed a band of an approximately 48kDa translation product for testis, brain,
      lung, and cultured cells that ectopically expressed the AZ2 protein. The AZ2
      protein was mainly localized in the cytoplasm. The amino-terminal part of the AZ2
      protein was homologous to the previously reported TANK (Cheng and Baltimore,
      1996. Genes Dev. 10, 963-973) and I-TRAF (Rothe, 1996. Proc. Natl. Acad. Sci. USA
      93, 8241-8246), which participate in the signal transduction cascade from the
      tumor necrosis factor-receptor to the transcription factor, NFkappaB.
      Overexpression of AZ2 inhibited TNF alpha mediated NFkappaB activation. AZ2 could
      be a component of a regulator of the NFkappaB activation cascade.

PMID- 10580150
TI  - The Arabidopsis thaliana genome encodes at least four thioredoxins m and a new
      prokaryotic-like thioredoxin.
AB  - Screening of cDNA libraries at low stringency and complete sequencing of EST
      clones with homology to thioredoxins allowed us to characterize five new
      prokaryotic type Arabidopsis thaliana thioredoxins. All present N-terminal
      extensions with characteristics of transit peptides. Four are clustered in a
      phylogenetic tree with the chloroplastic thioredoxin m from red and green algae
      and higher plants, and their transit peptides have typical characteristics of
      chloroplastic transit peptides. One is clearly divergent and defines a new
      prokaryotic thioredoxin type that we have named thioredoxin x. Its transit
      peptide sequence presents characteristics of both chloroplastic and mitochondrial
      transit peptides. The five corresponding genes are expressed at different levels,
      but mostly in green tissues and in in-vitro cultivated cells.

PMID- 10580149
TI  - Fine physical and transcript mapping of a 1.8 Mb region spanning the locus for
      childhood acute lymphoblastic leukemia on chromosome 12p12. 3.
AB  - Rearrangements of the short arm of chromosome 12 are frequently observed in
      hematological disorders. Previous studies of loss of heterozygosity identified a
      small genetic interval on chromosome 12p12.3 that is frequently deleted in
      childhood acute lymphoblastic leukemia (ALL). Two genes, ETV6/TEL and p27/KIP1,
      are located in this interval. Evidence has accumulated that an as-yet
      unidentified tumor suppressor gene is closely linked to these. To facilitate the
      identification of candidate genes, a long-range high-resolution restriction map
      of the ALL locus was constructed using a contig of YAC clones. Several marker
      loci, including 11 STS, three newly developed YAC end-based STS, six EST, and
      seven genes were unambiguously positioned in the new map. The map covers 1.8Mb
      and extends from the distal salivary proline-rich protein gene cluster to the
      proximal p27/KIP1 gene. The data confirmed the order tel-D12S358-p27/KIP1-cen and
      excluded p27/KIP1 as a candidate tumor suppressor gene. The critical region
      delimited by D12S89 and D12S358 is a 750kb CpG-island rich region that includes
      the 240kb TEL/ETV6 gene as well as CLAPS3 (clathrin-adaptor small chain 3). The
      new map provides a molecular framework for the identification of novel genes and
      transcriptional units in the ALL interval.

PMID- 10580151
TI  - Molecular cloning, genomic organization, and identification of the promoter for
      the human pituitary tumor transforming gene (PTTG).
AB  - Recently, we cloned and sequenced cDNA of a potent pituitary tumor transforming
      gene (PTTG) from human testis and showed that this gene is expressed highly in
      various human tumors, including tumors of the pituitary and adrenal glands, and
      the liver, kidney, endometrium, uterus, and ovary. To determine the genomic
      organization of the PTTG and its transcriptional regulation in tumors, we
      isolated the gene. The PTTG spans more than 10kb and contains five exons and four
      introns. Primer extension and RNA protection assays indicated a transcription
      start site at an adenine residue at 37 bases upstream of the translation start
      site (ATG). Analysis of the 5' flanking region of the gene revealed the existence
      of three SP1/GC boxes, three AP1 and one AP2 binding sequences, a cyclic AMP
      response element sequence, and an insulin response element sequence. The promoter
      activity of the PTTG was evaluated by transfecting a human ovarian tumor cell
      line (SKOV3) and a mouse fibroblast cell line (NIH 3T3) with a chimeric fusion
      construct containing the 5' flanking sequence (nucleotide from -1336 to +34) and
      luciferase reporter gene (pluc 1370). The promoter activity of this construct was
      210-fold higher in SKOV3 and 20-fold higher in NIH 3T3 cells than the
      promoterless vector. Deletion of sequences at the 5' end of the pluc 1370
      construct from nucleotide -1336 to -1157 (pluc 1190), from nucleotide -1336 to 
      977 (pluc 1010) and from nucleotide -1336 to -707 (pluc 740) further increased
      luciferase activity. Further deletion of the 5' sequence from nucleotide -1336 to
      -407 (pluc 440), and from nucleotide -1336 to -127 (pluc 160) decreased activity
      by 95%. These results suggest that the sequence from nucleotide -126 to +34 is
      sufficient for PTTG promoter activity and that the sequence between nucleotide 
      706 and -407 contains an enhancer element. PTTG promoter activity was eight- to
      ten-fold higher in SKOV3 cells than NIH 3T3 cells, suggesting a basis for the
      tumor-specific expression of the PTTG. Knowledge of the genomic organization and
      the promoter region of the human tumor transforming gene will allow further
      studies of possible disorders of the PTTG as well as facilitate elucidation of
      the transcriptional control of PTTG expression in human tumors.

PMID- 10580152
TI  - Genomic organization and promoter activity of embigin, a member of the
      immunoglobulin superfamily.
AB  - Embigin is a transmembrane glycoprotein belonging to the immunoglobulin
      superfamily, which is preferentially expressed in early stages of mouse
      embryogenesis and enhances integrin-mediated cell-substratum adhesion. The mouse
      embigin gene, which we cloned, spanned more than 50kb, in which nine exons were
      present. All exons contained protein-coding sequences. Each of the two
      immunoglobulin domains was encoded by two exons, and the C-proximal half of the
      second immunoglobulin domain and the transmembrane domain were in the same exon.
      These features are shared by the basigin gene; together with protein sequence
      homology, our results defined a family in the immunoglobulin superfamily, to
      which embigin and basigin both belong. The major transcriptional initiation site
      of embigin gene was 103 bases upstream from the translation initiation site, as
      determined by 5' rapid amplification of cDNA ends. A 3kb DNA fragment upstream
      from the transcriptional initiation site contained three Sp1 binding sites and
      had a promoter sequence capable of expressing the downstream gene not only in F9
      embryonal carcinoma cells which express the gene, but also in L and G401 cells
      which do not, indicating the presence of a regulatory region outside the 3kb DNA
      region. Deletion analysis of the 3.5kb DNA fragment revealed that the region
      between -125 to +1, containing a single Sp1 binding site, is essential for
      transcription of the embigin gene.

PMID- 10580153
TI  - Protein isoaspartyl methyltransferase protects from Bax-induced apoptosis.
AB  - Protein L-isoaspartyl methyltransferase (Pimt) is a highly conserved enzyme
      utilising S-adenosylmethionine (AdoMet) to methylate aspartate residues of
      proteins damaged by age-related isomerisation and deamidation. We have been
      particularly interested in this enzyme since addition of the compound CGP3466 to
      primary rat astroglia cell cultures resulted in an upregulation of Pimt at the
      mRNA level, as shown here by semi-quantitative RT-PCR. CGP3466 is a compound
      related to the anti-Parkinson's drug R-(-)-deprenyl, which has been shown to
      protect from neural apoptosis induced by trophic factor withdrawal [Tatton et
      al., 1994. J. Neurochem. 63, 1572]. The pro-apoptotic gene Bax is required in the
      cascade of events following withdrawal [Deckwerth et al., 1996. Neuron 17, 401].
      We therefore investigated whether Pimt overexpression was able to affect Bax
      induced apoptosis in primary mouse cortical neurons. Our results show that Pimt
      is indeed able to protect from Bax-induced apoptosis. Furthermore, this activity
      is not restricted to brain-specific cell types, since the same effect is also
      demonstrated in COS1 cells. In addition, mutational analysis suggests that the
      protective effect is dependent on the adenosine methionine-binding motif, which
      is well conserved in protein methyltransferases, and that a mutation destroying
      this motif crucially affects cytoskeletal structures of the cell.

PMID- 10580154
TI  - Identification of a Manduca sexta NSF ortholog, a member of the AAA family of
      ATPases.
AB  - Transport between intracellular compartments requires the activity of an N
      ethylmaleimide-sensitive fusion protein (NSF). NSF is a member of a growing
      family of ATPases regulating several membrane fusion reactions. We have cloned
      the NSF ortholog from the moth, Manduca sexta (MsNSF). MsNSF is highly conserved
      in domains critical for NSF function in vertebrates. MsNSF codes for a protein of
      745 amino acids, translating to a M(r) of 83kDa in vitro. MsNSF is 72% and 61%
      similar in amino acid sequence to Drosophila and vertebrate NSFs, respectively.
      We expressed the D1 ATP domain of MsNSF toward which antibodies selective to
      MsNSF were generated. Affinity purified alpha-MsNSF antibodies detect a 83kDa
      protein which is highly enriched in nervous tissues. Levels of MsNSF expression
      are substantially lower in other tissues examined. Anti-MsNSF antibodies are
      capable of inhibiting vertebrate intra-Golgi transport of a cargo protein in
      vitro. The identification of NSF ortholog from Manduca, whose neuroendocrine
      system is well studied, should facilitate isolation of complexes involved in
      protein trafficking from insect models. Phylogenetic analysis of NSF and related
      proteins suggests that the members of the AAA family arose from different
      ancestors, since the ingroup was not monophyletic. Proteasomal subunits and p97
      homologs form two distinct subfamilies, while NSF homologs branch in to the
      third.

PMID- 10580155
TI  - Structure, organization and expression of the eukaryotic translation initiation
      factor 5, eIF-5, gene in Zea mays.
AB  - The maize genomic DNA sequence encoding the eukaryotic translation initiation
      factor 5 (eIF-5) has been isolated from genomic library of maize seedlings and
      the exon-intron structure determined (accession number AJ132240). The length of
      genomic DNA sequenced was about 7kb and contained two exons with the translation
      start site in exon 2. The only intron is located in the non-coding 5' region and
      it is 1298bp long with the splice acceptor and donor sites conforming to the
      AG/GT rules. Repetitive sequence fragments are located in the 5' and 3'
      intergenic region. The accumulation of eIF-5 mRNA was studied by RNA blot and in
      situ hybridization. The observed distribution of mRNA may correlate with the
      function of the protein, as it appears to be highly abundant in tissues where the
      proportion of cells actively dividing is very high, such as meristematic regions.

PMID- 10580156
TI  - The Mycobacterium tuberculosis mysB gene product is a functional equivalent of
      the Escherichia coli sigma factor, KatF.
AB  - Mycobacterium tuberculosis, the causative agent of tuberculosis, may remain
      dormant within its host for many years. The nature of this dormant or latent
      state is not known, but it may be a specialized form of the stationary growth
      phase. In Escherichia coli, KatF (or RpoS) is the major stationary phase sigma
      factor regulating an array of genes expressed in this phase of growth. A
      potential M. tuberculosis katF homologue was cloned using a fragment of the E.
      coli katF gene as a probe. DNA sequence analysis of a resultant clone showed 100%
      identity to a fragment of DNA encoding the M. tuberculosis mysA and mysB genes.
      Overexpression of mysB in M. bovis BCG resulted in an increase in katG mRNA and
      catalase and peroxidase activity, and an increase in sensitivity of the cells to
      isoniazid. An increase in katG promoter activity from a reporter vector was
      demonstrated when mysB was overexpressed from the same plasmid, indicating a
      direct relationship between MysB and katG expression.

PMID- 10580157
TI  - Gene organization and sequence of the region containing the ribosomal protein
      genes RPL13A and RPS11 in the human genome and conserved features in the mouse
      genome.
AB  - We have determined the organization and sequence of the region containing two
      ribosomal protein (rp) genes in the human and mouse genomes. The two genes, human
      RPL13A and RPS11, and mouse Rpl13a and Rps11, are tandemly located in both
      genomes with an interval of only 4.6kb in the case of the human genes and 1.6kb
      in the case of the mouse genes. The human RPL13A and RPS11 are 4236bp and 3254bp
      in length and comprise eight and five exons respectively, whereas the mouse Rps11
      is 1951bp long and has five exons. Structural comparison of these genes,
      including previously reported mouse Rpl13a, revealed a significant conservation
      of sequences in the promoter regions. Although most rp genes are dispersed
      throughout the human genome, the conserved features and adjacent localization
      indicate possible coordinate transcription of the two genes. Furthermore, we have
      found that four small nucleolar RNA (snoRNA) genes are located in the introns of
      the two rp genes, both human and mouse. U32, U33, and U34 snoRNAs are encoded in
      introns 2, 4, and 5 of RPL13A respectively, and U35 in the sixth intron of RPL13A
      and the third intron of RPS11. The same organization of these snoRNA genes was
      also observed in the case of the mouse genes.

PMID- 10580158
TI  - Isolation and characterization of a cDNA clone encoding a putative white spruce
      glycine-rich RNA binding protein.
AB  - A presumably full-length cDNA encoding a putative glycine-rich RNA binding
      protein was isolated from a lambdaZAP cDNA library prepared from mRNAs extracted
      from needles of 2year old white spruce seedlings, which had been either wounded
      or jasmonate-treated. The cDNA, designated PgRNP (Picea glauca RNP protein),
      presents a 468bp open reading frame encoding a 155 amino acid protein. This
      polypeptide possesses an RNA binding domain (RNP-CS) and a glycine-rich domain.
      Comparative alignment reveals extensive homologies to glycine-rich RNA binding
      proteins containing an RNP-CS found in other angiosperm species. Genomic
      hybridization experiments suggest that the PgRNP gene is part of a small
      multigene family with at least four members. RNA blot analysis revealed that the
      PgRNP transcript is expressed in all tissues from non-stressed plants.
      Constitutive mRNA level was found in needle tissue from control as well as methyl
      jasmonate treated plants. Wounding had no clear induction effect. Jasmonic acid
      treatment and systemic wound response had a positive effect on transcript
      accumulation. Transcript accumulation was slightly induced by cold in needles,
      and repressed by drought stress in both needle and root tissues of 2year old
      plants. Finally, the level of PgRNP accumulation was induced by wounding and
      repressed in 2week old dark-grown seedlings upon jasmonate treatments.

PMID- 10580159
TI  - Cloning of the murine unconventional myosin gene Myo9b and identification of
      alternative splicing.
AB  - We report the cloning of a cDNA for the mouse unconventional myosin Myo9b, the
      orthologue of the rat myr5 and human MYOIXb genes. A full-length spleen cDNA of
      7087bp encoding a protein of 1961 amino acids was isolated. By RT-PCR, we show
      that Myo9b is expressed in a wide range of tissues, including heart, brain,
      muscle and inner ear. In addition, we have identified two alternatively spliced
      exons. Equivalent exons have not been previously reported for either the human or
      rat homologues. These exons are located in the Myo9b specific actin-binding site
      insert of the head domain and in the tail region. A third splice form utilizing
      an alternative reading frame within the 3'UTR is also described. Several
      polymorphisms within the coding region were identified; of interest is an in
      frame 33bp imperfect duplication within the tail region that was observed only in
      the C57Bl/6 strain. Myo9b has been previously mapped to mouse chromosome 8 and is
      a candidate for the mouse mutations myodystrophy and quinky.

PMID- 10580160
TI  - The kindergarten-path effect: studying on-line sentence processing in young
      children.
AB  - A great deal of psycholinguistic research has focused on the question of how
      adults interpret language in real time. This work has revealed a complex and
      interactive language processing system capable of rapidly coordinating linguistic
      properties of the message with information from the context or situation (e.g.
      Altmann & Steedman, 1988; Britt, 1994; Tanenhaus, Spivey-Knowlton, Eberhard &
      Sedivy, 1995; Trueswell & Tanenhaus, 1991). In the study of language acquisition,
      however, surprisingly little is known about how children process language in real
      time and whether they coordinate multiple sources of information during
      interpretation. The lack of child research is due in part to the fact that most
      existing techniques for studying language processing have relied upon the skill
      of reading, an ability that young children do not have or are only beginning to
      acquire. We present here results from a new method for studying children's moment
      by-moment language processing abilities, in which a head-mounted eye-tracking
      system was used to monitor eye movements as participants responded to spoken
      instructions. The results revealed systematic differences in how children and
      adults process spoken language: Five Year Olds did not take into account relevant
      discourse/pragmatic principles when resolving temporary syntactic ambiguities,
      and showed little or no ability to revise initial parsing commitments. Adults
      showed sensitivity to these discourse constraints at the earliest possible stages
      of processing, and were capable of revising incorrect parsing commitments.
      Implications for current models of sentence processing are discussed.

PMID- 10580161
TI  - Human simulations of vocabulary learning.
AB  - The work reported here experimentally investigates a striking generalization
      about vocabulary acquisition: Noun learning is superior to verb learning in the
      earliest moments of child language development. The dominant explanation of this
      phenomenon in the literature invokes differing conceptual requirements for items
      in these lexical categories: Verbs are cognitively more complex than nouns and so
      their acquisition must await certain mental developments in the infant. In the
      present work, we investigate an alternative hypothesis; namely, that it is the
      information requirements of verb learning, not the conceptual requirements, that
      crucially determine the acquisition order. Efficient verb learning requires
      access to structural features of the exposure language and thus cannot take place
      until a scaffolding of noun knowledge enables the acquisition of clause-level
      syntax. More generally, we experimentally investigate the hypothesis that
      vocabulary acquisition takes place via an incremental constraint-satisfaction
      procedure that bootstraps itself into successively more sophisticated linguistic
      representations which, in turn, enable new kinds of vocabulary learning. If the
      experimental subjects were young children, it would be difficult to distinguish
      between this information-centered hypothesis and the conceptual change
      hypothesis. Therefore the experimental "learners" are adults. The items to be
      "acquired" in the experiments were the 24 most frequent nouns and 24 most
      frequent verbs from a sample of maternal speech to 18-24-month-old infants. The
      various experiments ask about the kinds of information that will support
      identification of these words as they occur in mother-to-child discourse. Both
      the proportion correctly identified and the type of word that is identifiable
      changes significantly as a function of information type. We discuss these results
      as consistent with the incremental construction of a highly lexicalized grammar
      by cognitively and pragmatically sophisticated human infants, but inconsistent
      with a procedure in which lexical acquisition is independent of and antecedent to
      syntax acquisition.

PMID- 10580162
TI  - Evolution and devolution of folkbiological knowledge.
AB  - In this paper we present evidence in support of the hypothesis that the average
      person's knowledge about trees, and about the natural world in general, has
      declined during the 20th century. Our investigations are based on examination of
      a large sample of written material from the 16th through 20th centuries contained
      in the Oxford English Dictionary. In Analysis 1, we show a precipitous decline in
      the use of tree terms after, but not before, the 19th century. In Analysis 2, we
      analyze tree terms at different levels of organization and show that the decline
      observed in Analysis 1 occurs for all levels of organization. This second
      analysis also reveals that during the 16th to 19th centuries tree terms became
      progressively more specific, suggesting that during these periods knowledge about
      trees increased. In Analysis 3, we show similar rates of decline in other
      folkbiological categories, indicating that the change in tree terms reflects a
      general decline in knowledge about living kinds. Also in Analysis 3, we show that
      several non-biological categories have experienced evolution during the 20th
      century, indicating that the declines in the 20th century for folkbiological
      categories are not an inevitable outcome of the corpus. Finally, Analysis 4 also
      shows declines in the frequency of quotations for which the tree term was not the
      topic of the sentence, and thus incidental to the purposes of the writer. The
      results from Analysis 4 reassure us that the results from Analyses 1-3 were not
      solely due to change in the aims and purposes of writers over the centuries. In
      sum, the analyses indicate that in the domain of trees, there has been a long and
      sustained period of conceptual evolution followed by a recent pronounced period
      of devolution.

PMID- 10580163
TI  - Affordance, proper function, and the physical basis of perceived heaviness.
AB  - The physical basis of perceived heaviness requires consideration of the haptic
      perceptual system's role in controlling actions (the system's proper function)
      and the relation of an object's inertial properties to properties of the human
      movement system (the object's affordance). We show that the mass of a wielded
      object and particular scalar variables calculated from the object's inertia
      tensor combine linearly in determining perceived heaviness. The tensor-derived
      scalars reflect the symmetry and volume of the corresponding inertia ellipsoid.
      These measures bear directly on the object's wieldability, that is, on the
      patterning and level of muscular forces required to move the object in a
      controlled fashion.

PMID- 10580164
TI  - Age-of-acquisition and frequency effects in speeded word naming.
AB  - An experiment was conducted to assess the importance of age-of-acquisition and
      frequency in a speeded word naming task, where participants were instructed to
      read aloud words before they disappeared from the computer screen. Under such
      speeded naming instructions, reading latencies were over 100ms (or 20%) faster
      than in "standard" (or immediate) word naming. There were clear effects of word
      frequency and age-of-acquisition under speeded naming. Compared to standard
      immediate naming, the age-of-acquisition effect was larger, with early-acquired
      words being speeded up more than late-acquired words, which is interpreted in
      terms of speeded naming reducing the contribution of sublexical processing to
      word naming times.

PMID- 10580165
TI  - A proposed model for the assembly of chylomicrons.
AB  - The intestine synthesizes very low density lipoproteins (VLDL) and chylomicrons
      (CM) to transport fat and fat-soluble vitamins into the blood. VLDL assembly
      occurs constitutively whereas CM assembly is a characteristic property of the
      enterocytes during the postprandial state. The secretion of CM is specifically
      inhibited by Pluronic L81. CM are very heterogeneously-sized particles that
      consist of a core of triglycerides (TG) and cholesterol esters and a monolayer of
      phospholipids (PL), cholesterol and proteins. The fatty acid composition of TG,
      but not PL, in CM mirrors the fatty acid composition of fat in the diet. CM
      assembly is deficient in abetalipoproteinemia and CM retention disease.
      Abetalipoproteinemia results due to mutation in the mttp gene and is
      characterized by the virtual absence of apoB-containing lipoproteins in the
      plasma. Patients suffer from neurologic disorders, visual impairment, and exhibit
      acanthocytosis. CM retention disease, an inherited recessive disorder, is
      characterized by chronic diarrhea with steatorrhea in infancy, abdominal
      distention and failure to thrive. It is caused by a specific defect in the
      secretion of intestinal lipoproteins; secretion of lipoproteins by the liver is
      not affected. Besides human disorders, mice that do not assemble intestinal
      lipoproteins have been developed. These mice are normal at birth, but defective
      in fat and fat-soluble vitamin absorption, and fail to thrive. Thus, fat and fat
      soluble vitamin transport by the intestinal lipoproteins is essential for proper
      growth and development of neonates. Recently, differentiated Caco-2 cells and
      rabbit primary enterocytes have been described that synthesize and secrete CM.
      These cells can be valuable in distinguishing between the two different models
      proposed for the assembly of CM. In the first model, the assembly of VLDL and CM
      is proposed to occur by two 'independent' pathways. Second, CM assembly is
      proposed to be a product of 'core expansion' that results in the synthesis of
      lipoproteins of different sizes. According to this model, intestinal lipoprotein
      assembly begins with the synthesis of 'primordial' lipoprotein particles and
      involves release of the nascent apoB with PL derived from the endoplasmic
      reticulum (ER) membrane. In addition, TG-rich 'lipid droplets' of different sizes
      are formed independent of apoB synthesis. The fusion of lipid droplets and
      primordial lipoproteins results in the formation of different size lipoproteins
      due to the 'core expansion' of the primordial lipoproteins.

PMID- 10580166
TI  - Cytosolic triglycerides and oxidative stress in central obesity: the missing link
      between excessive atherosclerosis, endothelial dysfunction, and beta-cell
      failure?
AB  - Central obesity is increasingly recognized as a risk factor for atherosclerosis
      and type 2 diabetes mellitus. Here we present a hypothesis that may explain the
      excess atherosclerosis, endothelial dysfunction and progressive beta-cell
      failure. Central obesity is associated with increased cytosolic triglyceride
      stores in non-adipose tissues such as muscles, liver and pancreatic beta-cells. A
      high cytosolic triglyceride content is accompanied by elevated concentrations of
      cytosolic long-chain acyl-CoA esters, the metabolically active form of fatty
      acids. These esters inhibit mitochondrial adenine nucleotide translocators,
      resulting in an intramitochondrial ADP deficiency. In vitro, such ADP deficiency
      is a potent stimulator of mitochondrial oxygen free radical production, and we
      assume that this mechanism is also active in vivo. The decline of organ function
      with normal ageing is thought to be due, at least partly, to a continuous low
      grade mitochondrial oxygen free radical production. In tissues containing
      increased cytosolic triglyceride stores this process will be accelerated. Tissues
      with a high-energy demand or poor free radical scavenging capacity, such as
      pancreatic beta-cells, are likely to be more susceptible to this process. This is
      how we explain their gradual dysfunctioning in central obesity. Likewise we
      propose that the enhanced production of oxygen free radicals in endothelial
      cells, or vascular smooth muscle cells, leads to the increased subendothelial
      oxidation of LDL and atherosclerosis, as well as to the endothelial dysfunction
      and microalbuminuria.

PMID- 10580167
TI  - Activated nuclear factor-kappaB is present in the coronary vasculature in
      experimental hypercholesterolemia.
AB  - BACKGROUND: Experimental hypercholesterolemia (HC) is characterized by a decrease
      in nitric oxide (NO) bioavailability and cellular proliferation. Nuclear factor
      kappaB (NF-kappaB) is a transcriptional factor which plays a coordinating role in
      inflammation and cellular proliferation and may be involved in early
      atherosclerosis. We examined whether activated NF-kappaB was present in
      experimental hypercholesterolemia in the coronary vasculature in association with
      a decrease in NO bioavailability. METHODS: A total of 14 juvenile domestic
      crossbred pigs were placed on a HC diet and six pigs on a normal diet for 10-12
      weeks. A monoclonal antibody to the activated form of the p65 subunit of NF
      kappaB was used to detect immunoreactivity in coronary artery sections. Coronary
      tissue homogenates were analyzed for activated NF-kappaB and endothelial nitric
      oxide synthase (eNOS) using Western blotting. In vitro coronary endothelium
      dependent relaxation was performed in response to bradykinin, as a measure of NO
      bioavailability. RESULTS: Intimal staining for activated NF-kappaB was present in
      12/14 HC pigs as compared with 0/6 controls (P<0.001). Confocal microscopy
      confirmed the presence of NF-kappaB in the nucleus of intimal cells although the
      majority of the staining was cytoplasmic. In the HC group, Western blotting
      revealed an increase in activated NF-kappaB in the vessel wall compared to the
      normal group, in association with a decrease in the presence of eNOS protein and
      an attenuated vasorelaxation response to bradykinin. CONCLUSION: This study
      suggests a potential role for activation of NF-kappaB, in association with a
      decrease in NO bioavailability, in the initial stages of atherosclerosis in the
      coronary vasculature.

PMID- 10580168
TI  - Estradiol 17beta inhibition of LDL oxidation and endothelial cell cytotoxicity is
      opposed by progestins to different degrees.
AB  - Progestins oppose the effects of estrogens in many biological systems, but it is
      not known if progestins oppose the antioxidant effects of estrogen and to
      differing degrees. To test these questions, the effects of various sex steroids
      on LDL oxidation and cytotoxicity were studied in the absence or presence of
      endothelial cells. Freshly isolated LDL was incubated in the presence of Cu(++)
      in the absence or presence of cultured bovine aortic endothelial cells in phenol
      red-free medium and without or with hormones in 0.5% ethanol. The hormones
      included 17beta-estradiol (E(2)), progesterone (Pg), norgestimate (NGM),
      levonorgestrel (LNG), and medroxyprogesterone acetate (MPA). LDL oxidation was
      measured as formation of conjugated dienes, lipid peroxides, and TBARS, and
      cyotoxicity by tetrazolium salt reduction (MTT reduction). Progestins diminished
      conjugated diene lag phase, accelerated lipid peroxide and TBARS production in
      the absence and presence of cells and accelerated cytotoxicity. When E(2) and
      progestin were incubated with cells at a molar ratio of 1:5, lipid peroxides were
      reduced from baseline by E(2) alone 31%, E(2)/Pg 29%, E(2)/NGM 16%, E(2)/LNG 9%
      (all P<0.05 or more) and E(2)/MPA 8% (ns) (E(2) or E(2)E(2)/NGM, E(2)/LNG and
      E(2)/MPA [P<0.001]; E(2)E(2)/LNG or E(2)/MPA [P<0.05]). MTT reduction followed a
      similar gradient, greatest with E(2) alone, least with E(2)/MPA. CONCLUSIONS:
      Progestins promote LDL oxidation and, conjointly, endothelial cell cytotoxicity.
      Progestins oppose the antioxidant and cytoprotective effects of estrogen when
      given in combination. MPA and LNG have the strongest prooxidant and cytotoxic
      effects, which may limit the cardiovascular benefit of estrogen during combined
      administration in vivo.

PMID- 10580169
TI  - Partial inhibition of nitric oxide synthase primes the stimulated pathway of vWF
      secretion in man.
AB  - Increased release of von Willebrand factor (vWF) has been linked to the
      pathogenesis of atherosclerosis. For this complex disease, impairment of
      endothelium-derived, nitric oxide production and impaired vascular relaxation has
      also been reported. Since endothelially produced nitric oxide (NO) is known to
      inhibit secretion of the Weibel-Palade bodies in animals, we hypothesized that NO
      could mitigate vWF secretion. In a randomized, placebo controlled cross-over
      trial, eight male volunteers received N-monomethyl-L-arginine (LNMMA) to block
      endothelial NO production or placebo, and vWF release was stimulated by infusing
      desmopressin in three cumulative doses (0.05, 0.15, 0.4 microg/kg) in both
      periods. At a threshold dose of 0.l5 microg/kg desmopressin, concomitant partial
      blockade of NO production resulted in 20% higher levels of vWF (P<0.04). However,
      maximal vWF release after 0.4 microg/kg desmopressin was unaffected by L-NMMA
      (Delta7% between periods, P=0.88). These data show the dampening effect of NO
      production on vWF release in response to threshold concentrations of
      secretagogues. This may in part explain the higher vWF levels in cardiovascular
      diseases associated with impaired endothelial NO generation.

PMID- 10580170
TI  - Serum carotenoids and atherosclerosis. The Rotterdam Study.
AB  - High circulating levels of carotenoids have been thought to exhibit a protective
      function in the development of atherosclerosis. We investigated whether aortic
      atherosclerosis was associated with lower levels of the major serum carotenoids
      in alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, lycopene, and
      zeaxanthin-in a subsample of the elderly population of the Rotterdam Study.
      Aortic atherosclerosis was assessed by presence of calcified plaques of the
      abdominal aorta. The case-control analysis comprised 108 subjects with aortic
      atherosclerosis and controls. In an age- and sex-adjusted logistic regression
      model, serum lycopene was inversely associated with the risk of atherosclerosis.
      The odds ratio for the highest compared to the lowest quartile of serum lycopene
      was 0.55 (95% CI 0.25-1.22; p(trend)=0.13). Multivariate adjustment did not
      appreciably alter these results. Stratification by smoking status indicated that
      the inverse association between lycopene and aortic calcification was most
      evident in current and former smokers (OR=0.35; 95% CI 0.13-0.94; p(trend)=0.04).
      No association with atherosclerosis was observed for quartiles of serum
      concentrations of alpha-carotene, beta-carotene, lutein, and zeaxanthin. In
      conclusion, this study provides evidence for a modest inverse association between
      levels of serum lycopene and presence of atherosclerosis, the association being
      most pronounced in current and former smokers. Our findings suggest that lycopene
      may play a protective role in the development of atherosclerosis.

PMID- 10580171
TI  - Race and gender differences in cord blood lipoproteins.
AB  - Race and gender differences in lipoproteins and apolipoproteins have repeatedly
      been demonstrated in adults. The same disparities have been observed in children
      of different race and gender, implying that these differences may be influenced
      by genetic factors. To further explore this hypothesis, cord blood concentrations
      of both lipoproteins and apolipoproteins were examined in black and white
      neonates of both sexes. Results were controlled for the observed effects of
      gestational age and growth parameters. Similar patterns of lipoprotein
      differences to those observed in adults and children were also detected between
      black and white, and between male and female neonates. These findings support the
      concept that the aetiology of the difference in lipoprotein concentration
      observed between race and gender groups includes a significant genetic component.

PMID- 10580172
TI  - Inhibitory effect of Chinese green tea on endothelial cell-induced LDL oxidation.
AB  - Green tea has been shown to inhibit Cu(2+)-induced LDL oxidation and suppress
      lipoxygenase activity. Since LDL oxidation is a characteristic feature of
      atherogenesis and lipoxygenase is involved in the disease process, the effect of
      Lung Chen Tea, a non-fermented Chinese green tea, on LDL oxidation induced by
      human umbilical cord vascular endothelial cell was investigated in the present
      study. Lung Chen Tea was extracted with methanol and the dried powder was
      redissolved in water before extraction with chloroform and then ethyl acetate.
      Lung Chen Tea, chloroform and ethyl acetate fractions dose-dependently reduced
      LDL oxidation and decreased its relative electrophoretic mobility (P<0.001) when
      compared to the oxidized LDL. The lipid peroxidation products, thiobarbituric
      acid reactive substances, and cellular cholesterol were also significantly
      lowered by 5 and 10 microg/ml Lung Chen Tea (P<0.001) in a dose-dependent manner.
      The remaining aqueous layer, which was devoid of catechins after chloroform and
      ethyl acetate extractions, did not prevent LDL oxidation. The results of this
      study demonstrated that Lung Chen Tea and catechin-rich fractions significantly
      prevented endothelial cell induced LDL oxidation. The consumption of Lung Chen
      Tea may therefore lower the risk of coronary heart diseases.

PMID- 10580173
TI  - Platelets induce alterations of chemotactic and adhesive properties of
      endothelial cells mediated through an interleukin-1-dependent mechanism.
      Implications for atherogenesis.
AB  - Platelets and alterations of chemotactic and adhesive properties of endothelium
      play an important role in the pathophysiology of atherosclerosis. We investigated
      the effect of platelets on secretion of monocyte chemotactic protein-1 (MCP-1)
      and on surface expression of intercellular adhesion molecule-1 (ICAM-1) of
      cultured endothelium. Pretreatment of cultured monolayers of endothelial cells
      with alpha-thrombin-activated platelets significantly enhanced secretion of MCP-1
      and ICAM-1 surface expression (P<0.01) that could be inhibited by interleukin-1
      (IL-1) antagonists by approximately 40%. Activation of transcription factor
      nuclear factor-kappaB (NF-kappaB) which regulates transcription of early
      inflammatory response genes such as MCP-1, was significantly increased in
      endothelial cells treated with activated platelets via an IL-1 mediated mechanism
      as determined by electrophoretic mobility shift assay (EMSA) and kappaB-dependent
      transcriptional activity. In trans-well experiments, alpha-thrombin-activated
      platelets enhanced IL-1-dependent surface expression of vitronectin receptor
      (alpha(v)beta(3)) on the luminal aspect of endothelial monolayers and promoted
      alpha(v)beta(3)-mediated platelet/endothelium adhesion that could be inhibited by
      the antiadhesive peptides GRGDSP and c(RGDfV). We conclude that activated
      platelets induce significant changes in chemotactic (secretion of MCP-1) and
      adhesive (surface expression of ICAM-1 and alpha(v)beta(3)) properties of
      cultured endothelium. These findings imply a potential pathophysiological
      mechanism of platelets in an early stage of atherogenesis.

PMID- 10580174
TI  - Alpha- and beta-carotenes in low density lipoprotein are the preferred target for
      nitric oxide-induced oxidation.
AB  - Whereas low plasma levels of carotenes are strongly associated with the elevated
      risk of atherosclerosis, the reason for this is still unknown. We hypothesized
      that lipoprotein oxidation in the arterial wall might selectively deplete
      carotenes, thus explaining the observed effects. In order to assess this
      hypothesis, we incubated plasma low density lipoprotein (LDL) with different
      oxidants and measured the consumption of carotenes and tocopherols. We found that
      when LDL oxidation was induced by nitric oxide, both alpha- and beta-carotene
      were consumed at a significantly higher relative rate than alpha- or gamma
      tocopherol. In contrast, superoxide, peroxynitrite, hypochlorite or transition
      metal ions were unable to induce selective consumption of carotenes in LDL. These
      data suggest that the decreased plasma levels of alpha- and beta-carotene
      frequently measured in atherosclerosis may be related to their preferred
      consumption by reactive nitrogen species in the arterial wall.

PMID- 10580175
TI  - Is lipoprotein(a)-cholesterol a better predictor of vascular disease events than
      total lipoprotein(a) mass? A nested case control study from the West of Scotland
      Coronary Prevention Study.
AB  - The clinical utility of a new assay for plasma lipoprotein(a)-cholesterol (Lp(a)
      C) was assessed in parallel with our routine Lp(a) mass measurements in a nested
      case control study of subjects within the placebo arm of the West of Scotland
      Coronary Prevention Study (WOSCOPS). A total of 238 control patients and 108
      patients who had suffered a serious vascular event during the course of the
      WOSCOPS were examined. Lp(a) mass was assessed within 2 years of sampling by an
      ELISA method on baseline EDTA plasma samples which had been stored at -70 degrees
      C. Subsequently, the Lp(a) mass was re-measured by an immunoturbidimetric assay
      approximately 8 years after sampling. On the same stored aliquot the Lp(a)-C was
      measured. These analyses allowed us to assess whether the Lp(a)-C assay could
      provide any additional information over and above that which would be obtained
      from our Lp(a) mass assays. In addition the apo(a) isoform sizes of these
      subjects were measured using a high resolution immunoblotting system. The Lp(a)-C
      and Lp(a) mass measurements provided exactly the same information in the study,
      as they were equally non-discriminatory between cases and controls. The only
      difference between the two patient groups was the percentage of 'null' apo(a)
      alleles (control: 25.6% versus cases: 19.4%). We conclude that these results
      reinforce the concordance of the two assay systems and confirm that the Lp(a)-C
      assay provides no added information over and above that gained from traditional
      Lp(a) mass assays, which may be faster and less expensive.

PMID- 10580176
TI  - Vegetable oil based versus wood based stanol ester mixtures: effects on serum
      lipids and hemostatic factors in non-hypercholesterolemic subjects.
AB  - A pine wood based stanol ester mixture-composed of sitostanol (92%) and
      campestanol (8%) effectively lowers cholesterol absorption and consequently LDL
      cholesterol concentrations. It has been postulated that the less absorbable plant
      sterols reduce cholesterol absorption more effectively. As sitostanol is absorbed
      less than campestanol, we decided to examine if a vegetable oil based stanol
      ester mixture with 68% sitostanol and 32% campestanol is less effective than the
      wood based stanol ester mixture. For this, 112 non-hypercholesterolemic men and
      women consumed for 4 weeks a rapeseed oil (LEAR) based margarine and shortening.
      For the next 8 weeks, 42 subjects continued with these products, while the other
      subjects received products with a vegetable oil (n=36) or a pine wood based
      stanol ester mixture (n=34). Consumption of 3.8 g vegetable oil based stanols
      (2.6 g sitostanol plus 1.2 g campestanol) lowered LDL cholesterol 14.6+/-8.0% (
      0.37 mmol/l; vs. the control group; P<0.001; 95% CI for the difference, -0.22 to 
      0. 51 mmol/l). Four grams pine wood based stanols (3.7 g sitostanol plus 0.3 g
      campestanol) showed a comparable decrease of 12.8+/-11.2% (-0.34 mmol/l; P<0.001;
      95% CI-0.18 to-0.51 mmol/l). Decreases in LDL cholesterol were not different
      between the two experimental groups (P=0.793), while apoE genotype did not have a
      major impact on this hypocholesterolemic response. Serum HDL cholesterol and
      triacylglycerol concentrations were not changed. The decreases in apo B in both
      experimental groups differed significantly (P<0.001) from changes in the control
      group. Coagulation and fibrinolytic parameters were not affected. We therefore
      conclude that vegetable oil and wood based stanol ester mixtures, with a
      different sitostanol/campestanol ratio, have similar LDL cholesterol lowering
      effects in a non-hypercholesterolemic population.

PMID- 10580177
TI  - Coexisting dysbetalipoproteinemia and familial hypercholesterolemia. Clinical and
      laboratory observations.
AB  - Type III dysbetalipoproteinemia and familial hypercholesterolemia (FH) are two
      metabolic disorders giving rise to severe disturbances of lipid homeostasis and
      premature atherosclerosis. Both metabolic abnormalities have a genetic basis and
      co-occurrence in the same patient has seldom been described. Because of the
      unique structure of the French Canadian population, there was an opportunity to
      observe patients with both dysbetalipoproteinemia (E2/2 homozygotes) and FH
      (N=14) and to compare their clinical data with that of patients with type III
      (N=75), patients with FH (N0.7 and the presence of beta-VLDL on electrophoresis.
      Presence of a low density lipoprotein receptor, LDL-R, mutation should be
      suspected in a type III patient with a LDL-C level above 3.0 mmol/l and a family
      history of premature CAD. In the group of patients studied, the coexistence of
      dysbetalipoproteinemia and heterozygous FH does not appear to increase the
      prevalence of cardiovascular complications above that observed among control type
      III or control E3/3-FH patients. Thus, the presence of two epsilon2 alleles in
      these patients affects the expression of the abnormal LDL-R allele and the
      resulting phenotype substantiates the non additive effects of alleles at these
      two loci (epistasis).

PMID- 10580178
TI  - Genetic polymorphism of heparan sulfate proteoglycan (perlecan, HSPG2), lipid
      profiles and coronary artery disease in the Australian population.
AB  - Perlecan is one of the three major classes of heparan sulfate proteoglycans
      (HSPGs) within the cardiovascular system; it interacts with lipid metabolism by
      binding to lipoprotein lipase (LpL) and apolipoprotein B (apo B) and may be
      related to vascular disease. We explored interactions between an HSPG2
      polymorphism (BamHI marker), and apo B and coronary artery disease (CAD) in
      patients undergoing coronary angiography. The frequencies of the HSPG2 BamHI +/+,
      +/-, and -/- genotypes were 4.7, 31.7 and 63.6%, respectively, with a '+' allele
      frequency of 20.6%. The genotype distribution was in Hardy-Weinberg equilibrium
      (chi(2)=0.669, P0.05). The +/+homozygotes had the lowest apo B levels (0.74+/
      0.06 g/l, n=36) compared to +/- (0.89+/-0.03 g/l, n=241) and -/- (0.93+/-0.02
      g/l, n=480) genotypes. Although plasma apo B concentration was the strongest
      lipid risk factor for significant CAD, the HSPG2 genotypes were not independently
      associated with the presence of CAD (P=0.640 in males; P=0.224 in females), with
      significant CAD (P=0.764; P=0.110) or with the number of significantly stenosed
      coronary arteries (P=0.945; P=0. 335). In Australian Caucasians undergoing
      coronary angiography the HSPG2 BamHI polymorphism is associated with lower
      circulating apo B but not with the occurrence or severity of CAD. This may be due
      to HSPG2-mediated alterations in the HSPG2-apo B-LpL system and requires further
      exploration.

PMID- 10580180
TI  - Low density lipoprotein particle size and risk factors of insulin resistance
      syndrome.
AB  - The present study aimed to examine the association between low density
      lipoprotein (LDL) particle size and glucose and insulin variables and with other
      risk factors that have been related to insulin resistance syndrome. LDL particle
      size was determined in two groups of subjects who participated in the first
      examination of the Jerusalem Diabetes Study and who were invited to be re
      examined after 8-10 years. The first group were non-diabetic subjects who were
      found to have at the first examination high insulin levels (above the sex and age
      specific 90th percentile of the 2 h post-glucose load insulin distribution). The
      second group was a random sample of individuals who had normal insulin and
      glucose levels at baseline. Sex-, Age- and body mass index (BMI) mean adjusted
      LDL-cholesterol (C), triglyceride (TG) and high density lipoprotein cholesterol
      (HDL-C) levels were significantly different among the LDL subclass groups.
      Fasting glucose levels and hemoglobin A(1c) did not differ statistically by LDL
      subclasses. Fasting and 2-h post load insulin levels were significantly higher in
      persons with LDL subclasses III and IV (small LDL), intermediate in those with
      LDL subclass II, and lowest in those with LDL subclass I (large LDL). Insulin
      resistance had an effect on the association between lipids, lipoproteins and LDL
      particle size. Multivariate analyses indicated that LDL-C, HDL-C and TG were
      independently associated with LDL particle size variability. The addition of
      'insulin resistance' or insulin and glucose levels had no independent effects on
      LDL particle size. In conclusion, an association of LDL particle size with the
      cluster of risk factors that characterize the insulin resistance syndrome has
      been demonstrated. The association of 'insulin resistance' and LDL particle
      diameter, however, is not mediated directly through the level of insulinemia but
      via alterations in lipid metabolism.

PMID- 10580179
TI  - Uric acid and serum antioxidant capacity: a reaction to atherosclerosis?
AB  - BACKGROUND: the evidence of a potential beneficial role of antioxidants in
      preventing atherosclerotic disease is not entirely consistent. OBJECTIVE: to
      assess the longitudinal association of serum total antioxidant capacity and serum
      antioxidants with the presence of subclinical carotid atherosclerosis. METHODS:
      Prospective case-control study nested within an historical cohort. Cases were 150
      individuals with elevated carotid intimal-medial thickness measured by B-mode
      ultrasound at the first two examinations of the Atherosclerosis Risk in
      Communities Study (1987-92). Controls were 150 age-gender-matched individuals
      with low carotid intimal-medial thickness. Serum antioxidant vitamins, uric acid,
      and serum total antioxidant capacity were measured in frozen serum samples
      collected from the same individuals in 1974 (13-15 years prior to the
      determination of case-control status). RESULTS: Compared to controls,
      atherosclerosis cases had significantly higher levels of serum total antioxidant
      capacity in 1974 than controls. This difference was almost entirely explained by
      increased serum concentration of uric acid in cases. In contrast with cross
      sectional results, uric acid serum concentration in 1974, was significantly
      higher in cases than in controls, even after adjusting for the main
      cardiovascular risk factors. Cases had significantly lower levels of alpha
      carotene in the 1974 sera than controls, but no other differences in serum
      antioxidant vitamin concentrations were observed. CONCLUSIONS: The higher serum
      uric acid concentration seemed associated with elevated total serum antioxidant
      capacity among individuals with atherosclerosis. This finding is consistent with
      experimental evidence suggesting that hyperuricemia may be a compensatory
      mechanism to counteract oxidative damage related to atherosclerosis and aging in
      humans.

PMID- 10580181
TI  - Lipoprotein correlates of LDL particle size.
AB  - Correlations of low-density lipoprotein (LDL) predominant particle diameters
      (PPD) were investigated in samples taken from the San Antonio Family Heart Study.
      A frequency histogram showed LDL PPD occurs in at least two distinct modes, at
      about 25.5 and 26.9 nm, with the nadir at about 26.2 nm. Triglyceride (TG)
      concentrations were strongly correlated with LDL PPD, accounting for nearly 50%
      of the variation. However, examination of the relationship between TG
      concentrations and LDL PPD showed considerable overlap of the two LDL size
      categories for samples having intermediate levels of TG (1-3 mmol/l). In order to
      examine the factors associated with particle size variation within this region of
      overlap, 163 pairs of samples, which contrasted peak particle diameters, were
      matched for TG concentrations and for sex and age. In this matched set, LDL
      related measures (i.e. LDL-C, apoB, apoE, and TG concentrations) did not differ.
      However, several high-density lipoprotein (HDL) measures were significantly
      related to the LDL particle size category. This category predicted a substantial
      proportion of variation in HDL-C (9.7%) and apoAI (7.5%) concentrations, and in
      HDL size distributions of cholesterol (13.6%) and apoAI (10.3%). Other traits
      related to insulin resistance syndrome (IRS) (glucose and insulin concentrations,
      blood pressure, and adiposity measures) were tested for association with the LDL
      size category. None of these traits were related to LDL size after adjusting for
      TG, except fasting and postchallenge glucose concentrations which showed modest
      correlations (P-values were 0.02 and 0.05, respectively). The data suggest that
      in addition to the strong effects of TG, there is also an aspect of LDL particle
      size variation that is strongly associated with variation in HDL concentration
      and particle size distribution, perhaps reflecting common metabolic determinants
      of lipoprotein size.

PMID- 10580182
TI  - Are predictors of coronary heart disease and lower-extremity arterial disease in
      type 1 diabetes the same? A prospective study.
AB  - In the Type 1 diabetes population, coronary heart disease (CHD) and lower
      extremity arterial disease (LEAD) are the two common macrovascular complications
      leading to early mortality and morbidity. However, it is not clear if these two
      complications share the same risk factors. The Pittsburgh Epidemiology of
      Diabetes Complications (EDC) Study prospectively examined and compared the risk
      factors for LEAD and CHD (including CHD morbidity and mortality). EDC subjects
      (332 men and 325 women), all diagnosed at Children's Hospital of Pittsburgh
      between 1950 and 1980, were first examined at baseline (1986-1988), and then
      biennially, for diabetes complications and their risk factors. Data used in the
      current analysis were from the first 6 years of follow-up, 98% provided at least
      some follow-up data for these analyses. CHD was defined as the presence of angina
      (diagnosed by the EDC examining physician) or a history of confirmed myocardial
      infarction or CHD death. An ankle-to-arm ratio of less than 0.9 at rest was
      considered to be evidence of LEAD. Among 635 subjects without CHD at baseline, 57
      developed CHD (1.69/100 person-years), and among 579 without LEAD at baseline, 70
      developed LEAD (2.31/100 person-years). CHD incidence rate was slightly higher in
      males, while LEAD incidence rate was slightly higher in females. Compared to non
      incident cases, subjects who developed either complication were older, had a
      longer diabetes duration, higher LDL and total cholesterol, and were more likely
      to be hypertensive. In multivariate analyses, hypertension, low HDL cholesterol
      level, high white cell count, depression, and nephropathy were the independent
      risk factors for CHD (including morbidity and mortality). For LEAD, higher HbA1
      level, higher LDL cholesterol level and smoking were the important contributing
      factors. In conclusion, the risk factor patterns differ between the two vascular
      complications. Glycemic control does not predict CHD overall but does predict
      LEAD, while hypertension and inflammatory markers are more closely related to CHD
      than to LEAD.

PMID- 10580183
TI  - Inverse relationship between circulating oxidized low density lipoprotein (oxLDL)
      and anti-oxLDL antibody levels in healthy subjects.
AB  - Oxidized low density lipoprotein (oxLDL) has been implicated in the pathogenesis
      of atherosclerosis. Recent studies have shown that immunization of animals with
      oxLDL results in suppression of atherogenesis. Antibody against oxLDL (oxLDL Ab)
      is detectable in human sera, although its biological significance is not well
      established. We examined the relationship between oxLDL Ab titer and circulating
      oxLDL level in 130 healthy Japanese subjects. OxLDL was measured as
      apolipoprotein (apo) B-containing lipoproteins carrying oxidized
      phosphatidylcholines by a sensitive ELISA. IgG class oxLDL Ab titer was measured
      by ELISA. Plasma oxLDL concentration was very low and it corresponded on average
      to one to two out of 1000 apoB-containing lipoproteins in plasma. Plasma oxLDL
      correlated positively with LDL cholesterol and inversely with oxLDL Ab titer.
      These associations remained significant and independent in multiple regression
      analysis including age, gender, smoking, and high-density lipoprotein
      cholesterol. These data indicate that healthy subjects have a very low
      concentration of oxLDL in the circulation, and that oxLDL Ab titer is in an
      inverse relationship with plasma oxLDL concentration in this population. Although
      these results suggest that oxLDL Ab may play a role in maintaining the low level
      of plasma oxLDL, its role in atherogenesis awaits further studies.

PMID- 10580184
TI  - Inflammatory and hemostatic markers in relation to cardiovascular prognosis in
      patients with stable angina pectoris. Results from the APSIS study. The Angina
      Prognosis Study in Stockholm.
AB  - Increased inflammatory activity and platelet activation have been associated with
      an increased risk of cardiovascular (CV) events in epidemiological studies, but
      their prognostic importance in patients with stable angina pectoris is less well
      established. The Angina Prognosis Study in Stockholm (APSIS), comprised 809
      patients (2766 patient years) with stable angina pectoris on double-blind
      treatment with verapamil or metoprolol. Plasma levels of fibrinogen and
      orosomucoid (an acute phase reactant), white blood cell counts (WBC), platelet
      counts and the urinary excretion of beta-thromboglobulin (reflecting platelet
      secretion), were related to the risk of CV death (n=36), non-fatal myocardial
      infarction (MI) (n=30) or revascularization (n=99) in a subgroup of 782 patients.
      Verapamil and metoprolol had only minor effects on the inflammatory variables. In
      multivariate Cox regression analyses (adjusted for previous MI, hypertension,
      diabetes mellitus and smoking), fibrinogen and WBC were independent predictors of
      CV death or non-fatal MI, as well as the risk of revascularization. Orosomucoid
      did not carry any independent information. Platelet counts and urinary beta
      thromboglobulin were not significantly related to CV prognosis. The treatment
      given did not significantly influence the prognostic impact of either fibrinogen
      or WBC. Fibrinogen and WBC were independent predictors of CV death or non-fatal
      MI as well as disease progression leading to revascularization in patients with
      stable angina pectoris. As fibrinogen is also an acute-phase reactant, the
      present findings indicate that inflammatory activity is involved in disease
      progression in stable angina pectoris.

PMID- 10580185
TI  - Serum level of vascular endothelial growth factor is decreased by hormone
      replacement therapy in postmenopausal women without hypercholesterolemia.
AB  - The administration of hormone replacement therapy (HRT) to postmenopausal women
      (PMW) reportedly has beneficial effects on their levels of lipid and
      lipoproteins. Estrogen retards the development of atherosclerosis induced by a
      high-fat diet in animals. Although vascular endothelial growth factor (VEGF) may
      be involved in the development of atherosclerosis in humans, there is no
      information on effect of estrogen administration on VEGF level and lipid
      metabolism. We evaluated 64 healthy normotensive or hypertensive PMW before and
      during the administration of HRT (0.625 mg conjugated equine estrogen combined
      with 2.5 mg medroxyprogesterone acetate orally) daily for 6 months. All
      hypertensive PMW were well-controlled on antihypertensive drug therapy. According
      to their total cholesterol level at baseline, we divided the PMW with HRT (n=54)
      into a normocholesterolemic group (NC, total cholesterol <220 mg/dl, n=35) and a
      hypercholesterolemic group (HC, total cholesterol >/=220 mg/dl, n=19). We
      evaluated the serum levels of VEGF at baseline, and again at 3 and 6 months after
      starting HRT. HRT significantly (P<0.01) reduced the mean VEGF level from 31.5+/
      4.3 pg/ml at baseline to 18.2+/-2.3 pg/ml after 6 months in the NC group.
      However, the VEGF levels in the HC group and the control group exhibited no
      significant change at either 3 or 6 months after starting HRT. In summary, HRT,
      using a combination of conjugated equine estrogen and medroxyprogesterone
      acetate, reduced the level of VEGF in normocholesterolemic PMW more effectively
      than in those with hypercholesterolemia.

PMID- 10580186
TI  - Dicarboxylic acids as markers of fatty acid peroxidation in diabetes.
AB  - Increased urinary excretion of dicarboxylic acids (DAs) has been well known in
      patients with diabetic ketoacidosis (DKA). It was known that small amounts of
      such DAs were also detected in urine from healthy humans. Upon chemical,
      radiation-induced or enzymatic oxidation, cis-polyunsaturated fatty acids (PUFA)
      have previously been shown to generate saturated short- and medium-chain length
      DAs. In diabetes, it was confirmed that the imbalance between the generation of
      free radicals and antioxidant defense systems increases oxidative stress and
      leads to the damage of lipid, which contains PUFA. Some peroxidation products of
      PUFA, such as malondialdehyde and conjugated diene, are generally known to be
      elevated in patients with diabetes. The present study was undertaken to determine
      if urinary excretion of DAs is elevated in diabetic patients without DKA. Urine
      samples from ten non-ketoacidotic patients with type 2 diabetes and ten healthy
      subjects were examined for DAs by combined gas chromatography and mass
      spectrometry with selected ion monitoring. The diabetic subjects had
      significantly (Psebacic acid. Being stable and easily detectable compounds, DAs
      may be considered potential markers of oxidative attack on PUFA in diabetes.

PMID- 10580188
TI  - The control of influenza: antivirals as an adjunct to vaccines.
AB  - The advent of neuraminidase inhibitors as a new and promising generation of
      antivirals against influenza, has necessitated the identification of their future
      role as an adjunct to the currently used vaccines. Their additional role in the
      treatment and prevention of influenza is indicated.

PMID- 10580189
TI  - Ending polio immunisation: stars and gutters.
AB  - Although we are moving towards eradication, risks remain. The number of people at
      risk of polio paralysis has been seriously underestimated, as has the danger of
      escape of polioviruses from laboratories. Virulent strains, still used in the US,
      should be destroyed. Surveillance of acute flaccid paralysis (AFP) and tracing
      suspected cases is difficult and still uncertain in many countries. The crucial
      definition by WHO of polio paralysis as asymmetric is ambiguous and misleading:
      in the Indian sub-continent and elsewhere, 75% have received unnecessary
      injections for fever 48 h before paralysis. These injections alter the severity
      and pattern of paralysis: 50% of Indian cases have symmetrical paralysis by limb
      and 25% by muscle. Eradication of polio promises a New Deal for Health, it must
      succeed.

PMID- 10580187
TI  - DNA and RNA-based vaccines: principles, progress and prospects.
AB  - DNA vaccines were introduced less than a decade ago but have already been applied
      to a wide range of infectious and malignant diseases. Here we review the current
      understanding of the mechanisms underlying the activities of these new vaccines.
      We focus on recent strategies designed to enhance their function including the
      use of immunostimulatory (CpG) sequences, dendritic cells (DC), co-stimulatory
      molecules and cytokine- and chemokine-adjuvants. Although genetic vaccines have
      been significantly improved, they may not be sufficiently immunogenic for the
      therapeutic vaccination of patients with infectious diseases or cancer in
      clinical trials. One promising approach aimed at dramatically increasing the
      immunogenicity of genetic vaccines involves making them 'self-replicating'. This
      can be accomplished by using a gene encoding RNA replicase, a polyprotein derived
      from alphaviruses, such as Sindbis virus. Replicase-containing RNA vectors are
      significantly more immunogenic than conventional plasmids, immunizing mice at
      doses as low as 0.1 microg of nucleic acid injected once intramuscularly. Cells
      transfected with 'self-replicating' vectors briefly produce large amounts of
      antigen before undergoing apoptotic death. This death is a likely result of
      requisite double-stranded (ds) RNA intermediates, which also have been shown to
      super-activate DC. Thus, the enhanced immunogenicity of 'self-replicating'
      genetic vaccines may be a result of the production of pro-inflammatory dsRNA,
      which mimics an RNA-virus infection of host cells.

PMID- 10580190
TI  - Synthetic peptides induce antibody against a host-protective antigen of
      Echinococcus granulosus.
AB  - The immunogenicity of four synthetic peptides was investigated in sheep. The
      sequences of the peptides (6, 12/13, 21/22 and 24) were derived from linear,
      antibody-binding epitopes of the EG95 recombinant protein, a host-protective
      antigen of the parasite Echinococcus granulosus. Sheep were immunised with either
      free peptide or peptide conjugated to diphtheria toxoid. All sheep responded to
      both conjugated and unconjugated forms of the peptides. For two of the four
      peptides (6 and 21/22), the amount of antibody elicited was significantly greater
      for the conjugated form of the peptides than for the corresponding unconjugated
      forms. For the other two peptides (12/13 and 24), peak antibody levels to both
      forms of the peptide were equivalent. Maximal antibody titres against peptides 6,
      12/13 and 21/22 were established after only one immunisation and were not boosted
      by a second dose. Antisera to all four peptides reacted with the recombinant
      antigen, and three of the four peptides generated antibodies, which bound to the
      native parasite oncosphere antigen. Antisera raised against the peptides were
      unable to kill the parasite in in vitro culture, although each of the peptides
      could be used to affinity purify lethal antibody from antisera raised against the
      recombinant protein. These results indicate that peptides 6, 12/13, 21/22 and 24
      of the EG95 recombinant vaccine are immunogenic and suggest that they are
      associated with host-protective epitopes.

PMID- 10580191
TI  - The antigen 85 complex vaccine against experimental Mycobacterium leprae
      infection in mice.
AB  - The proteins in culture filtrate derived from Bacillus Calmette-Guerin (BCG) were
      examined for protection against infection by Mycobacterium leprae. Immunization
      with the major secreted proteins, antigen 85 complex (Ag 85) A, B and C, induced
      effective protective immunity against multiplication of M. leprae in the foot
      pads of mice. The most effective protection was observed when mice were immunized
      with Ag 85A. A single immunization with Ag 85 could induce antigen-specific
      interferon gamma (IFNgamma) synthesis and more effective protection than live BCG
      vaccine. This study demonstrates that Ag 85 is an important immunoprotective
      molecule against leprosy infection.

PMID- 10580192
TI  - An aerosol challenge mouse model for Moraxella catarrhalis.
AB  - A simple, reproducible, and non-invasive mouse pulmonary clearance model for
      Moraxella catarrhalis via aerosol challenge was established. All of eight tested
      strains could be inoculated into mice at more than 10(5) colony-forming units
      (CFU)/lung with a challenge concentration of 1x10(9)-6x10(9) CFU/ml in a
      nebulizer. The number of bacteria retained at 6 h postchallenge was more than
      10(4) CFU/lung while at 24 h postchallenge, approximate 10(3) CFU/ml or less
      remained in the lungs. A maximum of 100 mice could be challenged per aerosol
      exposure. The number of bacteria inoculated in the lungs could be adjusted by the
      bacterial challenge concentration, the exposure time, and the negative pressure.
      Lung tissue sections revealed that bacteria were evenly distributed in the lungs.
      Passive immunization significantly enhanced pulmonary clearance of the homologous
      strain in this model. These data indicate that this model will be useful for
      evaluating M. catarrhalis vaccine candidates and studying roles of immunity
      against M. catarrhalis.

PMID- 10580193
TI  - DNA immunization: effect of secretion of DNA-expressed hemagglutinins on antibody
      responses.
AB  - DNA vaccines expressing plasma membrane and secreted forms of the influenza and
      measles virus hemagglutinins (HAs) have been used to evaluate the effect of
      secretion on DNA-raised antibody responses. At low doses of DNA, the plasma
      membrane form of the influenza virus HA raised higher titers of antibody than the
      secreted form. The isotype of the DNA-raised antibodies depended on both the
      method of DNA delivery and the form of the expressed antigen. Following
      intramuscular injections, DNAs expressing membrane bound forms of the influenza
      and measles HAs raised predominantly IgG2a. By contrast, DNAs expressing the
      secreted from of the two HAs as well as another secreted protein, human growth
      hormone, raised predominantly IgG1. Gene gun delivery resulted in predominantly
      IgG1 antibody responses for both secreted and membrane bound forms of the
      hemagglutinins. The raising of predominantly IgG1 by i.m. delivery of the
      secreted form of the influenza hemagglutinin was IL-4 dependent suggesting that a
      T-helper 2-biased immune response had been raised.

PMID- 10580195
TI  - Vaccination and HIV: a review of the literature.
AB  - People with HIV are at risk for a variety of infections both at home and abroad.
      Recent studies have reported conflicting data concerning potential harmful
      effects following several inactivated vaccines. Antigenic stimulation by vaccines
      designed to prevent secondary infections may promote HIV-1 replication in certain
      patients. In HIV-positive subjects, immune response worsens with progression of
      the HIV infection. When vaccination is considered, administration of the vaccine
      must be performed as early as possible in the course of HIV infection because an
      HIV-infected patient's response to inactivated vaccines is closely related to HIV
      infection stage. A minority of subjects have a protective antibody response to
      vaccination. Consequently, specific antibody titers should be measured after
      vaccination to ensure immune protection. Immune response is improved by highly
      active antiretroviral therapy. Some live attenuated vaccines are considered as
      beneficial in some specific indications and if administered in the early stages
      of AIDS. However, viral load variations following administration of live
      attenuated vaccines have not been studied yet.

PMID- 10580194
TI  - Improvement of the immune response against plasmid DNA encoding OspC of Borrelia
      by an ER-targeting leader sequence.
AB  - The present study outlines the characterization of a DNA-based immune response
      against the OspC antigen, one of the most promising candidates for a Borrelia
      vaccine. Balb/c mice were injected intradermally with plasmid DNA encoding the
      OspC gene (lacking the natural leader sequence) under transcriptional control of
      the cytomegalovirus (CMV) promotor. Immunization with this construct elicited
      only a marginal response, which was drastically improved by a fusion construct
      containing the human tissue plasminogen activator (hTPA) signal sequence. The
      results indicate that for DNA-based immunization against OspC an ER-targeting
      signal may be necessary for both antibody production as well as cellular immune
      responses.

PMID- 10580196
TI  - Long-lasting protective immunity against rodent malaria parasite infection at the
      blood stage by recombinant BCG secreting merozoite surface protein-1.
AB  - Previously, we constructed a recombinant live BCG (rBCG) secreting a 15 kDa C
      terminal region of MSP-1 from Plasmodium yoelii (MSP-1(15)) and succeeded in the
      induction of more efficient protective immunity against parasite infection than
      observed with artificial adjuvants (Matsumoto S, Yukitake H, Kanbara H, Yamada T.
      Recombinant Mycobacterium bovis bacillus Calmette-Guerin secreting merozoite
      surface protein 1 (MSP-1) induces protection against rodent malaria parasite
      infection depending on MSP-1-stimulated interferon gamma and parasite-specific
      antibodies. J Exp Med 1998;188:845-54 [1]). In this study, we examined the
      endurance of the protective effects. The protective effect generated by rBCGMSP
      1(15) was observed even 9 months after final immunization, whereas the effects of
      immunization by MSP-1(15) together with incomplete Freund adjuvant (IFA) were
      found to last only 4 months.

PMID- 10580198
TI  - The protective capacities of histone H1 against experimental murine cutaneous
      leishmaniasis.
AB  - In a murine model of experimental cutaneous leishmaniasis, we investigated the
      protection elicited by injection of histone H1 isolated from parasites by
      perchloric extraction, of a H1 recombinant protein produced in E. coli, and of H1
      long and short synthetic peptides, against infection by L. major. Partial
      protection was achieved in most of the animals as shown by reduction in lesion
      size, upon immunization with histone H1 or its peptides, provided that the region
      1-60 was present in the molecule. These observations argue in favor of a thorough
      examination of the possibility of including histone H1 described here in a
      cocktail vaccine against human leishmaniasis.

PMID- 10580197
TI  - Vaccine-induced cytotoxic T lymphocytes against human immunodeficiency virus type
      1 using two complementary in vitro stimulation strategies.
AB  - CD8+ cytotoxic T lymphocytes (CTL) against human immunodeficiency virus type 1
      (HIV-1) induced by candidate HIV-1 vaccines may be a mechanism of immune
      protection against HIV-1 infection. We measured in vitro inducible CD8+ and CD4+
      CTL using two in vitro effector cell stimulation strategies. Peripheral blood
      mononuclear cells (PBMC) for CTL assay were obtained after the third and/or
      fourth immunization timepoints from 23 healthy, uninfected adult volunteers, of
      whom 19 received a canarypox virus vaccine expressing HIV-1 env, gag, pol, nef
      and protease gene products (vCP300) with or without injections of HIV-1(SF-2)
      rgp120 subunit vaccine and four subjects received only control injections. CD8+
      CTL activity was detected employing the two in vitro stimulation strategies
      against one or more HIV-1 antigens in 15 (79%) of 19 HIV-1 vaccine recipients on
      at least one occasion and repeatedly against the same antigen in 8 (42%).
      Canarypox virus-based HIV-1 vaccines represent a step forward in HIV-1 vaccine
      development.

PMID- 10580199
TI  - Cloning and immunologic characterization of a truncated Bordetella bronchiseptica
      filamentous hemagglutinin fusion protein.
AB  - Filamentous hemagglutinin (FHA) is an outer-membrane associated adhesin conserved
      within the genus Bordetella. FHA provides protection against B. pertussis
      infections in humans and is a component of acellular whooping cough vaccines.
      Furthermore, FHA serves as a protective antigen in several animal models of
      infection with B. bronchiseptica and may serve as a protective antigen of canine
      bordetellosis. In this study, polyclonal anti-B. pertussis FHA antiserum was used
      to identify an immunoreactive clone from the genomic DNA library of a canine B.
      bronchiseptica field isolate. The nucleotide and predicted amino acid sequences
      of the immunoreactive clone were compared to fhaB and FhaB from B. pertussis
      revealing 94% identity at the nucleic acid level, and 86% identity at the protein
      level. A truncated fusion protein (FHAt) was prepared which included a conserved
      domain homologous to the immunodominant region in the FHA of B. pertussis
      [Leininger E, Bowen S, Renauld-Mongen G, Rouse JH, Menozzi FD, Locht C, Heron I,
      Brennan MJ. Immunodominant domain present on the Bordetella pertussis vaccine
      component filamentous hemagglutinin. J. Infect. Dis. 1997;175:1423-1431; Wilson
      DR, Siebers A, Finlay BB. Antigenic analysis of Bordetella pertussis filamentous
      hemagglutinin with phage display libraries and rabbit anti-filamentous
      hemagglutinin polyclonal antibodies. Infect. Immun. 1998;66:4884-4894]. FHAt was
      shown to be safe and antigenic in rabbits. FHAt induced the formation of
      antibodies that inhibit the hemagglutination associated with full length B.
      pertussis FHA, and inhibit adherence of B. bronchisepitca to canine fibroblasts
      by as much as 65%. This information may have implications for the development of
      safe and efficacious subunit vaccines for the prevention of canine bordetellosis
      and may contribute to future acellular whooping cough vaccines.

PMID- 10580200
TI  - DNA vaccination with the serine rich Entamoeba histolytica protein (SREHP)
      prevents amebic liver abscess in rodent models of disease.
AB  - Amebiasis remains one of the leading parasitic causes of death worldwide. A
      vaccine that prevented amebic liver abscess would significantly reduce mortality
      from this disease. To test the feasibility of a DNA vaccine to prevent amebic
      liver abscess, we immunized both mice and gerbils with plasmid DNA encoding the
      serine rich Entamoeba histolytica protein (SREHP). Animals receiving the SREHP
      DNA vaccine developed both antibody and cell mediated immune responses that
      recognized amebic trophozoites. A single dose of the SREHP DNA vaccine protected
      80% of vaccinated mice and 60% of vaccinated gerbils from developing amebic liver
      abscess after direct hepatic inoculation of amebic trophozoites. Our study
      indicates that DNA vaccination with SREHP can provide high levels of protection
      against amebic liver abscess in animal models of disease.

PMID- 10580201
TI  - Immunity induced by DNA immunization with herpes simplex virus type 2
      glycoproteins B and C.
AB  - The complete sequence of herpes simplex virus type 2 (HSV-2) glycoproteins B and
      C (gB & gC) were cloned into plasmid expression vectors and evaluated in murine
      and guinea pig genital HSV-2 models. Balb/c mice were immunized with either pgB-2
      or pgC-2 plasmids intramuscularly (IM) or intradermally (ID). The vaccines
      induced HSV-2-specific neutralizing and ELISA IgG antibody, but little or no
      enhancement of viral clearance from the vagina was detected following
      intravaginal challenge. Immunization of guinea pigs with pgB-2 or pgC-2 induced
      ELISA IgG antibody; however, antibody titers were approximately one log(10) unit
      lower than that seen in HSV-2 convalescent sera. IM immunization of guinea pigs
      with either plasmid also did not decrease vaginal viral shedding following
      vaginal challenge, but the severity of the acute disease and the subsequent
      number of recurrent lesion days were reduced in animals immunized with pgB-2.
      Lastly, IM immunization of latently infected guinea pigs with a combined gB-2 and
      gC-2 plasmid vaccine significantly reduced the number of subsequent HSV-2
      recurrences. DNA vectors expressing gB-2 or gC-2 were both immunogenic, although
      the gB-2 plasmid induced higher titers of antibody and significantly reduced
      primary and recurrent herpetic disease in the guinea pig model. These results
      also suggest that immunotherapy with plasmid expression vectors may be effective
      against recurrent genital HSV-2 disease.

PMID- 10580202
TI  - Vaccination of infants with a four-dose and a three-dose vaccination schedule.
AB  - Swedish infants were vaccinated with diphtheria, tetanus and pertussis toxoids,
      inactivated poliovirus vaccine and a Haemophilus influenzae type b - tetanus
      toxoid conjugate vaccine at 2, 4, 6 and 15 months (US vaccination program, 'US
      arm', n=118) or at 3, 5 and 12 months of age (Swedish vaccination program,
      'Swedish arm', n=103). The antigen amounts in the diphtheria and tetanus vaccines
      were higher in the Swedish than in the US arm while the amounts in the other
      vaccines were the same in both arms. There were no serious side effects. Local
      reactions increased with the numbers of doses but did not differ significantly
      between the groups. Serum was obtained at 2, 7, 15 and 16 months in the US arm
      and at 3, 6, 12 and 13 months of age in the Swedish arm. A fifth serum was
      obtained in both groups at 4 yr of age. For vaccines with the same antigen amount
      the following was observed: a. three doses at 2, 4 and 6 months were more
      immunogenic than two doses at 3 and 5 months; b. the third dose in the Swedish
      arm was more immunogenic than the third dose in the US arm; c. the fourth dose in
      the US arm induced higher antibodies than the third dose in the Swedish arm
      (except for pertussis toxin antibodies that were similar in both groups) and the
      differences tended to remain at the age of 4 yr. Children in the Swedish arm
      received a higher diphtheria toxoid dose (25 Lf) than in the US arm (15 Lf) which
      led to higher diphtheria toxin antibodies in the Swedish arm at comparable ages.
      Children in the Swedish arm received a higher tetanus toxoid dose (7 Lf) than in
      the US arm (6 Lf). Tetanus antibodies were similar at comparable ages. In
      conclusion, the immunogenicity of vaccines in infancy can be improved by
      increasing the number of doses, by prolonging the intervals between doses and by
      increasing the antigen amount in the vaccine.

PMID- 10580203
TI  - Hepatitis A virus-specific humoral and cellular immune responses following
      immunization with a formalin-inactivated hepatitis A vaccine.
AB  - To evaluate proliferative T cell responses elicited by a formalin-inactivated HAV
      vaccine, we immunized 10 subjects with an inactivated HAV vaccine, and measured
      HAV antibody titers and HAV-specific T cell proliferation. gamma-Interferon
      production by PBMC's was evaluated in selected subjects. By week 30,
      seroconversion (geometric mean titer=2299 mIU/ml), and HAV-specific proliferation
      was detected in all subjects. HAV also induced gamma-interferon in the three
      subjects studied. These data indicate that the inactivated HAV vaccine induces
      proliferative T cell responses in addition to HAV antibody. This may be important
      for protection against hepatitis A, and suggests that recall memory for HAV
      antigen is elicited by the vaccine.

PMID- 10580204
TI  - Evaluation of trivalent, live, cold-adapted (CAIV-T) and inactivated (TIV)
      influenza vaccines in prevention of virus infection and illness following
      challenge of adults with wild-type influenza A (H1N1), A (H3N2), and B viruses.
AB  - Trivalent, live, cold-adapted influenza vaccine (CAIV-T) is highly effective in
      the prevention of influenza in children, and a variety of monovalent and bivalent
      cold-adapted influenza vaccines have been efficacious in adults. In order to
      determine the efficacy of CAIV-T in healthy adults, we administered CAIV-T,
      trivalent inactivated influenza vaccine (TIV) or placebo to 103 adults in
      randomized double-blind fashion, and then challenged those subjects who had pre
      screening serum hemagglutination-inhibition antibody titers of 1:8 or less with
      wild-type influenza viruses corresponding to the strains contained in the
      vaccine. CAIV-T was well tolerated. Upon challenge with wild-type influenza
      virus, laboratory documented influenza illness (respiratory symptoms with either
      isolation of wild-type influenza virus from nasal secretions or 4-fold and/or
      greater HAI antibody response to challenge) occurred in 14/31 (45%) placebo
      recipients, 4/32 (13%) TIV recipients, and 2/29 (7%) CAIV-T recipients. The
      estimated protective efficacy of CAIV-T was therefore 85% and of TIV was 71%.
      These results are consistent with those of previous studies using monovalent
      preparations of cold-adapted influenza vaccine in this model, and indicate that
      CAIV-T will be an effective means to prevent influenza illness in adults.

PMID- 10580206
TI  - Mice immunised with synthetic peptide from N-terminal conserved region of
      merozoite surface antigen-2 of human malaria parasite Plasmodium falciparum can
      control infection induced by Plasmodium yoelii yoelii 265BY strain.
AB  - Synthetic peptides representing conserved MSA-2 sequences are being considered as
      a possible component of a blood stage malaria vaccine. Antibody response towards
      the entire N-terminal conserved region of MSA-2 and its constituent B-epitope
      SNTFINNA following immunisation of BALB/c and C57BL/6 mice with different peptide
      constructs was assessed by ELISA and immunofluorescence antibody test (IFAT). Co
      linear synthesis of SNTFINNA-epitope in tandem with the entire N-terminal
      conserved region peptide (P23) made this construct, namely P8.P23, to be highly
      immunogenic in both mouse strains, with the antibody response to the SNTFINNA
      epitope comparable to that following tetanus toxoid protein conjugate
      immunisation. The antibodies raised specifically recognised the schizont stages
      of Plasmodium falciparum and Plasmodium yoelii. There was no protection observed
      upon challenge of immunised BALB/c and C57BL/6 mice with the highly lethal
      Plasmodium yoelii nigeriensis strain. On the contrary, BALB/c mice immunised with
      P8.P23 construct were able to resist blood stage infection induced by Plasmodium
      yoelii yoelii 265BY parasites, while animals inoculated with P23 did not control
      infection. Affinity purified rabbit anti-SNTFINNA IgG showed more than 60%
      inhibition of merozoite invasion of fresh erythrocytes in in vitro P. falciparum
      culture. The low prevalence of antibody response to SNTFINNA-epitope, tested in a
      dot-blot assay, was observed in sera of 80 individuals living in malaria endemic
      area in a India; the phenomenon may point out the cryptic character of epitopes
      residing at the N-terminal conserved region of MSA-2.

PMID- 10580205
TI  - The efficacy of modified-live bovine respiratory syncytial virus vaccines in
      experimentally infected calves.
AB  - The efficacy of modified-live (MLV) bovine respiratory syncytial virus (BRSV)
      vaccines and the correlates of vaccine-induced immunity were investigated in
      calves using a virulent experimental infection. Clinical disease and pulmonary
      pathology were significantly reduced, relative to unvaccinated controls, in
      calves vaccinated according to label directions with commercial multivalent MLV
      BRSV vaccines. In vitro assays of cellular immunity were more consistent
      correlates of vaccine associated protection than presence of post vaccination
      serum antibody. Most vaccinated calves shed virus, but peak virus titre was
      suppressed compared to unvaccinated controls, with clearance coincident with the
      simultaneous appearance of mucosal antibody, cytotoxic cells in the lung and
      anamnestic or primary serum antibody responses. Virus clearance in unvaccinated
      calves was coincident with the appearance of BRSV specific cytotoxic cells,
      before mucosal antibody was detected.

PMID- 10580207
TI  - Sero-epidemiology of measles antibodies in the Netherlands, a cross-sectional
      study in a national sample and in communities with low vaccine coverage.
AB  - Serum antibodies against measles were measured in the Dutch general population
      and in municipalities with low vaccine coverage, where religious groups that
      refuse vaccination are clustered sociogeographically. The results suggest that
      wild measles virus may still circulate in municipalities with low vaccine
      coverage; the circulation in the general population seems to have decreased
      significantly right after the introduction of mass vaccination. The overall
      prevalence in the general population was high (95.7%, 95% confidence limits 95.3
      96.2%); the seroprevalence in the age groups offered two vaccinations (91.7%, 95%
      confidence limits 89.4-94.0%) was lower than the level believed to be necessary
      for the elimination of measles. Protective levels of maternal antibodies in
      newborns have waned several months before the first vaccination is scheduled.

PMID- 10580208
TI  - Should adolescents be vaccinated against hepatitis A: the Hong Kong experience.
AB  - Hong Kong is a well developed city in the center of an endemic region for
      hepatitis A. The age at which hepatitis A occurs has shifted from childhood and
      adolescence to adults like many western countries. There is a high chance of
      outbreaks with the introduction of infection from neighbouring countries.
      Reducing the susceptibility of a population by vaccination can eliminate the
      diseases but updated sero-epidemiological data is needed to analyse the level of
      natural immunity, and identify those susceptible to infection for preventive
      measures. This study conducted amongst secondary school children seeks to
      identify those who are at risk and to obtain data on the present sero-prevalence
      of anti-HAV. Overall prevalence of anti-HAV in this age group was 7% increasing
      with age. Analysed by multiple regression model, those students living in
      mainland China over 3 years had odds ratio of 31.6 (95% c. i. 17.4-57.3) compared
      with those born in Hong Kong. Students with a father in a skilled occupation and
      an education level of secondary school or above, and both parents with secondary
      education or above, had an odds ratio of 0.22 (95% c.i. 0.07-0.7) and 0.35 (95%
      c.i. 0. 17-0.72) associated with presence of anti-HAV, respectively. Improved
      socio-economic state exposes higher proportion of the population at risk.
      Immunisation is worthwhile to be considered for the adolescents in Hong Kong.
      Prevaccination screening is cost effective only for those adolescents who are
      most likely to have natural immunity.

PMID- 10580209
TI  - Immunogenicity study of a combined diphtheria, tetanus, acellular pertussis,
      inactivated poliomyelitis vaccine used to reconstitute a freeze-dried Haemophilus
      influenzae type b vaccine (DTaP-IPV//PRP-T) administered simultaneously with a
      hepatitis B vaccine at two, three and four months of life.
AB  - This study was designed to assess the immunogenicity of a vaccine combining
      diphtheria and tetanus toxoids, acellular pertussis vaccine, and inactivated
      poliovirus vaccine reconstituting Haemophilus influenzae type b polysaccharide
      conjugated to tetanus protein (DTaP-IPV//PRP-T; Pasteur Merieux Connaught, Lyon,
      France) administered simultaneously in association with hepatitis B vaccine
      (RECOMBIVAX (?trade mark omitted?) Merck, Sharp & Dohme, West Point, PA, USA) for
      the primary immunization of infants. The vaccines were administered at two, three
      and four months of age. One hundred and sixty-two healthy infants, aged 8-10
      weeks, were enrolled in the study. Blood samples were taken before the first dose
      and 4 weeks after the third dose. The infants were observed for 15 minutes after
      vaccination for any immediate reaction. Adverse events requiring a medical
      consultation were recorded by the parents in a diary over the 7 days following
      vaccination. Four weeks after the third immunization, the percentages of infants
      fulfilling seroconversion criteria were 98.9% for pertussis toxin, 95.9% for
      filamentous haemagglutinin, 100.0% for tetanus, 100.0% for diphtheria, 99.3% for
      poliovirus type 1, 100.0% for both poliovirus types 2 and 3, 98.0% for
      Haemophilus influenzae type b, and 100% for hepatitis B surface antigen. No
      vaccine-related serious adverse event was reported. The simultaneous
      administration of DTaP-IPV//PRP-T and hepatitis B vaccines at two, three and four
      months of age yielded clinically satisfactory immune responses to all antigens
      compared with historical controls and gave a good safety profile.

PMID- 10580211
TI  - Y2K: need for health care professionals to be responsible and prepared.

PMID- 10580212
TI  - Y2K: effects on pacemaker and implantable defibrillator programmers.
AB  - All permanent pacemakers and implantable defibrillators (PPM/ICDs) will continue
      to function as programmed without regard to the date in the year 2000 (Y2K). All
      manufacturers contacted reassured us that some of these devices incorporate a
      day/year clock in the circuitry; however, these are not involved in sensing or
      delivering programmed therapy. Some manufacturers' device programmers will roll
      over to the year 2000 without any problems at all, whereas others may have
      difficulty with date and time stamping on printed reports. We tested 14 different
      types of PPM/ICD programmers for Y2K compliance using 8 tests. Five of the 14
      models passed each test and were labeled at our institution with a green "Y2K"
      sticker to identify them as Y2K compatible and needing no special attention after
      December 31, 1999. The most common test failed was the ability to roll the date
      forward from December 31, 1999, with the programmer power off. Organizations
      should consider testing and replacing noncompliant device programmers or placing
      a red sticker with "Y2K" crossed out on noncompliant pieces. The red sticker
      alerts the advanced practice nurse or physician to the need to confirm the
      appropriate date and time in the programmer after startup in the year 2000 and
      before interrogating or programming any PPM/ICD, to avoid inappropriate date and
      time stamping on printed reports from that programmer.

PMID- 10580213
TI  - Anorexia in response to acute illness.
AB  - Anorexia associated with acute illness remains one of the most common,
      challenging, and difficult symptoms to treat. Surprisingly, little attention has
      been devoted to development of interventions to reverse this form of anorexia.
      Although incomplete, current understanding of the mechanisms responsible for
      illness-induced anorexia is sufficient to suggest therapeutic approaches. In this
      article, the major physiologic mechanisms underlying illness-induced anorexia are
      described. In addition, potential moderating effects of social, psychologic, and
      environmental factors are discussed. This information was used to develop
      recommendations for the treatment of anorexia. A majority of these interventions,
      however, are not research based. Further advances in the treatment of illness
      induced anorexia will require greater understanding of the complex, interactive
      effects of psychologic, environmental, and biologic factors on eating behavior
      during illness. Therefore, areas requiring continued investigation are also
      outlined.

PMID- 10580214
TI  - A community hospital's effort to expedite treatment for patients with chest pain.
AB  - OBJECTIVE: The purpose of this study was to determine treatment times at a
      community hospital that does not receive prehospital electrocardiogram (ECG)
      transmission and to determine the effect of time to first hospital ECG on overall
      door-to-drug time. DESIGN: Descriptive. SETTING: 238-bed Regional Medical Center
      in Burlington, North Carolina. SAMPLE: One hundred four patients with a final
      diagnosis of acute myocardial infarction were included in this 16-month study.
      RESULTS: A median door-to-ECG time of 5 minutes was within the American College
      of Cardiology/American Heart Association recommendation of 10 minutes. Shorter
      treatment times to obtain the first ECG and initiate thrombolytic therapy were
      associated with younger patients and those arriving by ambulance. CONCLUSIONS:
      While efficiency in obtaining a first hospital ECG on patients with suspected
      acute myocardial infarctions was achieved, this did not result in low door-to
      drug times. Further streamlining of protocol and the exploration of prehospital
      initiatives may result in a significant reduction in door-to-drug times.

PMID- 10580215
TI  - Quality of life comparisons after coronary angioplasty and coronary artery bypass
      graft surgery.
AB  - OBJECTIVE: To examine the differences in realization of expected benefits,
      complications, and quality of life (QOL) 3 months after percutaneous transluminal
      coronary angioplasty (PTCA) and coronary artery bypass graft (CABG) surgery.
      DESIGN: Nonexperimental, prospective, and comparative. Before discharge,
      participants listed benefits expected from the procedure, as well as comorbid
      health problems (Charlson Comorbidity Index) and complications. At 3 months, they
      quantified their realization of expected benefits, reported postdischarge
      complications, and completed Ferrans and Powers' Quality of Life Index-Cardiac
      Version III. SAMPLE: 36 patients who had PTCA; 38 patients who had CABG. RESULTS:
      There were no differences between groups in realization of expected benefits or
      QOL. Patients who had CABG reported a greater number of complications after
      discharge, and a greater proportion of patients who had PTCA reported angina.
      Patients who had PTCA and then recurrent angina had significantly lower health
      QOL and psychologic and spiritual QOL. CONCLUSIONS: Patients who undergo CABG
      need guidance regarding what complications to expect, and patients who undergo
      PTCA need to know that recurrent angina is possible and how to manage it.

PMID- 10580216
TI  - Allergy to protamine sulfate.
AB  - Adverse responses to protamine sulfate have been identified for many years. The
      antigen-antibody response to protamine sulfate results in a type I anaphylactic
      reaction. Manifestations of allergic reactions include hypotension, bronchospasm,
      and skin and mucous membrane reactions. The severity of the adverse responses may
      vary from mild to causing death. Several potential risk factors for adverse
      reactions to protamine have been identified, including insulin-dependent diabetes
      mellitus, vasectomy, allergy to fish, prior exposure to protamine sulfate, and
      the rate of infusion. A case study is presented, and strategies for improving
      patient outcomes are discussed.

PMID- 10580217
TI  - Symptom experiences of lung transplant recipients: comparisons across gender,
      pretransplantation diagnosis, and type of transplantation.
AB  - PURPOSES: To investigate symptom experiences of patients who have single and
      bilateral-sequential lung transplantation and to determine whether differences
      exist according to gender, pretransplantation diagnosis, and type of
      transplantation procedure. DESIGN AND METHODS: In the context of a descriptive,
      comparative survey design, surviving recipients of single and bilateral
      sequential lung transplants (n = 56) were mailed a symptom frequency and distress
      questionnaire. The response rate was 85.7% (n = 48). The average time since the
      recipients' lung transplantations was 1.5 +/- 0.7 years. RESULTS: Recipients of
      lung transplants reported that several symptoms (eg, muscle weakness, shortness
      of breath with activity, and changed appearance) were both frequently occurring
      and quite distressing. Other symptoms were identified as being distressing, but
      not frequently occurring, or vice versa. Significant (P <.05) differences were
      found for symptom experiences among pretransplant diagnostic groups and between
      genders and types of transplant procedures. CONCLUSIONS: These findings elucidate
      the symptom experiences of recipients of lung transplants and suggest that
      subgroup differences exist. The data provide a basis for strengthening patient
      and family education and for developing symptom management strategies. Further
      investigation of the symptom experiences of the recipients of lung transplants is
      needed, especially in relation to subgroups.

PMID- 10580218
TI  - Nursing intervention and smoking cessation: A meta-analysis.
AB  - OBJECTIVE: To determine with meta-analysis the effects of nursing-delivered
      smoking cessation interventions. RESULTS: Fifteen studies comparing nursing
      intervention with a control or usual care found intervention to significantly
      increase the odds of smoking cessation. There was heterogeneity among the study
      results, but pooling by using a random effects model did not alter the estimate
      of effect. There was no evidence from indirect comparison that interventions
      classified as intensive had a larger effect than less intensive ones. There was
      evidence that interventions were more effective for hospital inpatients with
      cardiovascular disease than for inpatients with other conditions. Interventions
      in nonhospitalized patients also showed evidence of efficacy. Nurse counseling on
      smoking cessation during a screening health check was likely to have less effect.
      The results indicate the potential benefits of smoking cessation advice and
      counseling given by nurses to their patients, with reasonable evidence that
      intervention can be effective.

PMID- 10580219
TI  - New hope for patients with emphysema: lung volume reduction surgery.

PMID- 10580220
TI  - Parents cannot detect mild hearing loss in children. First place--Resident
      Clinical Science Award 1998.
AB  - Otitis media with effusion is among the most common illnesses of childhood and is
      often associated with chronic or persistent middle ear effusion (MEE). Our goal
      was to develop and validate a self-administered parent survey that would identify
      children at high risk for mild hearing loss caused by MEE. We evaluated 115
      children. Parents rated their child's hearing using the HL-7, a 7-item self
      administered survey, and a global visual-analog scale. Static admittance and
      gradient were recorded. Test-retest reliability, internal consistency, and
      validity of the HL-7 were compared with the 4-frequency pure-tone average (PTA)
      hearing level (HL) for the better hearing ear. The HL-7 had good test-retest
      reliability and internal consistency. Survey scores correlated well with the
      global hearing rating (R = 0.67, P < 0.001) but did not correlate with PTA (R =
      0.10, P = 0.29). Tympanometric gradient was unrelated to ear-specific PTA, but
      not abnormal static admittance (<0.2 cc), which produced a mean 7-dB HL decrease
      in hearing (ANOVA, P = 0.02). The HL-7 is a reliable and internally consistent
      measure of parent perception of child hearing, but unfortunately these
      perceptions are inaccurate for mild hearing loss. Abnormal static admittance is a
      risk factor for hearing loss.

PMID- 10580221
TI  - Allergy increases susceptibility to otitis media with effusion in a rat model.
      Second place--Resident Clinical Science Award 1998.
AB  - To investigate the possible relationship between allergy and otitis media with
      effusion (OME), we investigated the hypothesis that allergen presentation to the
      middle ear causes functional disruption of the eustachian tube predisposing to
      the development of OME. Thirteen of 19 Brown-Norway rats were sensitized to
      ovalbumin, and the remaining 6 served as nonallergic controls. To mimic
      subclinical exposure to allergen, we transtympanically injected ovalbumin at a
      dose (0.01 mg) that produced no changes detectable by otologic examination. Next,
      both allergic and nonallergic rats were exposed to transtympanic injection of
      either low-dose (10 microg/mL) or high-dose (100 microg/mL) lipopolysaccharide to
      simulate bacterial exposure. The allergic rats were found to have larger middle
      ear effusions when exposed to high-dose lipopolysaccharide as compared with the
      nonallergic controls. This response could be inhibited by diphenhydramine. We
      conclude that allergen presentation to the middle ear of allergic rats causes
      eustachian tube dysfunction predisposing to OME.

PMID- 10580222
TI  - Effects of cis-platinum chemotherapy on otoacoustic emissions: the development of
      an objective screening protocol. Third place--Resident Clinical Science Award
      1998.
AB  - To develop an objective, fast, and simply performed screening protocol for cis 
      platinum (CP) ototoxicity, we compared the efficacy of screening with distortion
      product otoacoustic emissions (DPOAEs) with the outcome of both conventional and
      ultra-high-frequency (UHF) audiometry. Baseline audiometric and DPOAE testing was
      performed in 66 patients, 33 of whom met criteria for inclusion in the final
      database. Comparisons were made between baseline measurements and those recorded
      before subsequent CP infusions. Outcomes were analyzed clinically and with paired
      repeated-measures analysis of variance. Results indicated that DPOAEs and UHF
      were better measures than conventional audiometry. Further, DPOAEs may be better
      suited for screening older patients receiving CP chemotherapy because DPOAEs are
      as sensitive as UHF and are present in a greater number of these patients.
      Screening with DPOAEs may be enhanced by testing only in the 3- to 5.2-kHz range,
      thus decreasing testing time. Higher time averages to increase the signal-to
      noise ratio and use of this narrower bandwidth might also allow for accurate
      bedside testing.

PMID- 10580223
TI  - Clinimetric evaluation of the Sinonasal Outcome Test-16. Student Research Award
      1998.
AB  - This study describes the reliability, validity, and responsiveness of the
      Sinonasal Outcome Test-16 (SNOT-16), a rhinosinusitis-specific health-related
      quality-of-life instrument, in the University of Washington Department of
      Otolaryngology-Head and Neck Surgery patient population. The SNOT-16 was
      completed by 47, 24, and 22 patients at weeks 0, 6, and 12, respectively. In
      addition, all 47 patients completed the Short-form 36-item Health Survey (SF-36)
      at week 0. Furthermore, an additional cohort of patients from the otology clinic
      who denied symptoms of rhinosinusitis or previous physician diagnoses of
      rhinosinusitis were asked to complete the SNOT-16. These scores were subsequently
      used to determine discriminant validity of the instrument. Cronbach's alpha was
      0.89, indicating a high degree of homogeneity of the test items. The SNOT-16
      demonstrated excellent discriminant validity, and mean total SNOT-16 scores were
      significantly correlated with patient-reported overall health, overall bother,
      and 7 of the 8 SF-36 subscales. The standardized response mean calculated between
      weeks 0 and 6 was 0.69, indicating moderate sensitivity to change. We conclude
      that the SNOT-16 is a reliable, valid, and responsive instrument for measuring
      rhinosinusitis-specific health-related quality of life.

PMID- 10580225
TI  - Relating speech and swallow function to dropout in a longitudinal study of head
      and neck cancer.
AB  - The relation between functional outcome and dropout from a 12-month follow-up
      period was examined in a longitudinal study whose objective was to define and
      quantify the functional effects of oral surgical resection and reconstruction on
      speech and swallowing in patients with head and neck cancer. In a group of 150
      patients recruited to a surgical study in the Cancer Control Science Program in
      Head and Neck Cancer Rehabilitation, dropout from all causes and dropout from
      specific causes (medical, patient, and administrative specific) were assessed in
      relation to longitudinal speech and swallow function. In univariate analysis,
      better speech articulation was associated with decreased risk of dropout from all
      causes and from medical-specific causes. Better swallow performance was
      associated with decreased risk of medical-specific dropout. Multivariate analysis
      revealed the following: (1) only articulation function was associated with
      dropout from all causes; (2) the association of speech articulation function with
      medical dropout was diminished after adjusting for advanced age and surgical
      resection variables; (3) the association of speech articulation function became
      significant for patient-specific dropout after adjusting for advanced age and
      surgical resection variables and indicated that better function decreased the
      risk of this type of dropout; and (4) swallowing function was not related to
      dropout. Patients treated for oral or oropharyngeal cancer who have poorer speech
      outcomes are more likely to drop out from a longitudinal study. Basing study
      results on only patients who complete a longitudinal study will understate the
      level of dysfunction experienced.

PMID- 10580224
TI  - Cytokine-mediated bone resorption is cytochrome P-450 dependent. Student Research
      Award 1998.
AB  - Localized bone loss leads to much of the morbidity of chronic otitis media.
      Although the cellular events of bone remodeling have been well established, their
      regulation remains poorly understood. Various cytokines, including tumor necrosis
      factor-alpha, interleukin-1beta, and interferon-gamma, used alone and in
      combination, are powerful inducers of bone resorption. One of the modulators of
      cytokine-induced bone resorption is nitric oxide (NO), a product of the action of
      NO synthase (NOS) on L -arginine to form NO. Cytochrome P-450, an enzyme that is
      similar to NOS both structurally and functionally, may also have a role in NO
      production in various cellular systems. The goal of this study was to elucidate a
      possible role of cytochrome P-450 in bone. In this study cytokine-induced bone
      resorption was blocked with cimetidine and clotrimazole, which are selective
      inhibitors of the cytochrome P-450 IIIA family and 7-ethoxyresorufin, a
      nonspecific cytochrome P-450 inhibitor. A concomitant reduction of NO was also
      observed. This effect may be explained by cytochrome P-450 being a preferred
      alternative pathway or providing an essential cofactor to NOS in bone.

PMID- 10580226
TI  - Airway abnormalities in patients with Arnold-Chiari malformation.
AB  - OBJECTIVES: The goal was to determine the incidence and types of airway
      abnormalities in patients with Arnold-Chiari malformation (ACM). METHODS: The
      study was a retrospective chart review of 24 patients with ACM who were evaluated
      and treated between November 1991 and August 1997. RESULTS: Eighteen (75%) and 6
      (25%) of the 24 patients had types I and II ACM, respectively. Three (12.5% of 24
      patients) of the type II ACM patients had vocal cord impairment: 1 bilateral
      paralysis, 1 bilateral paresis, and 1 unilateral paralysis. None of the type I
      ACM patients had vocal cord impairment. Tracheotomy was necessary in 3 of the 24
      patients and all in patients with type II ACM. Central sleep apnea was found in 5
      of 6 type II ACM patients, but not in any of the type I ACM patients.
      CONCLUSIONS: Vocal cord impairment and sleep apnea were found in 12. 5% and 21%,
      respectively, of this ACM population. When type II ACM patients were considered
      separately, the incidences of vocal cord impairment and sleep apnea were 50% and
      83%, respectively. Type II ACM patients tend to have a higher incidence of airway
      abnormalities and other neurologic dysfunctions. Flexible fiberoptic laryngoscopy
      is recommended in the airway evaluation of ACM patients. Early recognition,
      diagnosis, and management of these abnormalities may be lifesaving.

PMID- 10580227
TI  - Pharyngeal acid reflux in patients with single and multiple otolaryngologic
      disorders.
AB  - OBJECTIVE: This study was designed to determine the prevalence and
      characteristics of pharyngeal acid reflux (PAR) events in single and multiple
      otolaryngologic disorders. METHODS: Sixty-seven patients with otolaryngologic
      symptoms and objective findings and 34 healthy control subjects were studied with
      an ambulatory 24-hour, 3-site pharyngoesophageal pH monitoring technique.
      Otolaryngologic diagnosis included isolated posterior laryngitis (PL) in 28
      patients, isolated chronic rhinosinusitis (SIN) in 12, combined PL and SIN
      (PL+SIN) in 6, PL plus laryngotracheal stenosis (PL+LTS) in 12, and PL plus vocal
      cord nodules (PL+VCN) in 9. RESULTS: PAR events were documented in 68% of
      patients with PL, 34% of patients with SIN, 67% of patients with PL+SIN, 67% of
      patients with PL+LTS, 78% of patients with PL+VCN, and 21% of controls. The
      prevalence of PAR events in patients with isolated PL as well as those with PL
      combined with other disorders was significantly higher than that in patients
      without PL and that in controls. As a group, patients with PL had a greater
      number of PAR events and acid exposure time than other patients and controls.
      Distal and proximal esophageal reflux parameters were not significantly different
      among groups. CONCLUSIONS: The prevalence of PAR is significantly higher in
      patients with isolated PL compared to patients with other isolated
      otolaryngologic disorders and in controls. The prevalence of PAR in isolated
      otolaryngologic disorders other than PL is similar to that in healthy controls.
      The prevalence of PAR is significantly higher in patients with both PL and other
      otolaryngologic disorders than in controls and in patients with isolated
      otolaryngologic disorders.

PMID- 10580228
TI  - Osteoplastic flap for obliteration of the frontal sinus: five years' experience.
AB  - The objective of this retrospective study was to evaluate the osteoplastic flap
      (OPF) for the obliteration of the frontal sinus in this current era of endoscopic
      management of frontal sinus disease. A review of consecutive OPF procedures (n =
      43) performed by the senior author (J.A.D.) from 1992 to 1997 was carried out.
      Data were gathered regarding chief symptom, medical history, previous sinus
      surgery, endoscopic findings in the office and at surgery, CT scan findings, and
      follow-up results (mean 19.4 months). Previous endoscopic management of frontal
      sinus disease had failed in 24% of patients; 97% had eventual resolution of
      frontal sinusitis with OPF. After OPF, 63% also had improvement or resolution of
      disease in other paranasal sinuses. Statistically significant, positive
      correlations (P < 0.05) were noted between the resolution of frontal sinusitis
      and improved or resolved pain, as well as the resolution of frontal sinusitis and
      improved or resolved infections in other paranasal sinuses. In 1998 OPF remains
      the standard for treating frontal sinus disease refractory to other methods. OPF
      can decrease the pain associated with frontal sinus infections and has a positive
      impact on inflammatory disease in other paranasal sinuses.

PMID- 10580229
TI  - Maxillofacial injuries caused by all-terrain vehicle accidents.
AB  - With the rise in popularity of all-terrain vehicles (ATVs), especially in rural
      America, injuries associated with their use are becoming more commonplace. A
      retrospective review was conducted of 153 patients with ATV-related injuries seen
      at West Virginia University Hospitals between January 1990 and June 1996. Of
      these patients, 33 had maxillofacial injuries. Only 2 of 21 (9.5%) patients noted
      to be wearing helmets had facial injuries, whereas 17 of 19 (89.5%) patients who
      had facial injuries were not wearing helmets. Most patients with maxillofacial
      injuries occurring at night had been drinking alcohol. Injury Severity Scores
      were worse for those patients with maxillofacial injuries, as well as for those
      patients who had been drinking alcohol. Patients with maxillofacial injuries were
      more likely to require a stay in the intensive care unit. Furthermore, children
      with facial injuries had higher Injury Severity Scores and longer hospital stays
      than the adults. To reduce these accidents and related injuries, the industry,
      local and federal governments, and ultimately individuals must change their
      attitudes regarding these potentially dangerous vehicles.

PMID- 10580230
TI  - Endoscopic-assisted adenoidectomy.
AB  - Adenoidectomy is a commonly performed procedure. The advent of endoscopic sinus
      surgery has popularized the use of endoscopes. Endoscopic-assisted adenoidectomy
      (EAA) is a natural progression of this technology to allow a more complete
      adenoidectomy. Two hundred thirty-six patients undergoing adenoidectomy were
      evaluated with an endoscopic technique. A routine transoral adenoidectomy was
      performed first. Then a 4-mm 0 degrees telescope was used transnasally, and
      residual adenoid tissue was removed from the anterior superior nasopharynx.
      Invariably, residual adenoid tissue was found after transoral adenoidectomy. The
      EAA technique is minimally invasive, adds less than 5 minutes to the procedure,
      and is not associated with excessive bleeding. Readily available telescope and
      endoscopic equipment is used. The EAA technique is advocated for use as an
      adjunct to a more complete adenoidectomy.

PMID- 10580231
TI  - Endoscopic cerebrospinal fluid rhinorrhea repair: is a lumbar drain necessary?
AB  - OBJECTIVES: To determine the necessity for lumbar drains during endoscopic
      cerebrospinal fluid (CSF) rhinorrhea repair. METHODS: Thirty-three patients
      underwent endoscopic repair of CSF rhinorrhea without a lumbar drain during a 7
      year period. The size of the dural defect ranged from a microleak (less than 1 mm
      dural defect) to a 3-cm dural defect of the anterior skull base. RESULTS: All of
      the procedures in patients with smaller defects (<5 mm) were performed on an
      outpatient basis. Thirty-two patients (97%) had complete resolution of their CSF
      leak after 1 procedure without any recurrence (average follow-up 29 months).
      CONCLUSION: A lumbar drain is not routinely necessary for successful closure of
      CSF rhinorrhea of any size. Smaller dural defects may be safely performed on an
      outpatient basis without complications.

PMID- 10580232
TI  - Secondary intention healing of exposed scalp and forehead bone after Mohs
      surgery.
AB  - For Mohs surgical wounds that show exposed bone (ie, bone denuded of periosteum),
      healing by secondary intention may be preferable to surgical reconstruction. To
      determine the appropriateness of secondary intention healing, we reviewed
      surgical outcome in 205 patients with Mohs wounds of the scalp and forehead that
      had healed by secondary intention. Of these patients, 38 had Mohs wounds showing
      exposed bone. The mean area of exposed bone was 1074 mm(2); the mean area of
      exposed soft tissue was 1575 mm(2). The mean time for wounds with intact
      periosteum to epithelialize was 7 weeks; the mean time for bare bone to
      epithelialize was 13 weeks. All wounds healed without infection or tissue
      breakdown. We conclude that secondary intention healing of scalp and forehead
      wounds showing exposed bone is a safe and effective method of wound management
      after Mohs surgery.

PMID- 10580233
TI  - Clinical care pathways: decreasing resource utilization in head and neck surgical
      patients.
AB  - In this era of decreasing reimbursement, health systems have been forced to
      become more efficient and decrease resource utilization to remain financially
      viable. One of the methods of internal cost control has been the use of clinical
      pathways. Given the complexity of treatment of head and neck cancer patients,
      clinical pathways can help to standardize decision making and introduce
      uniformity in resource utilization. The objective of this study is to compare
      resource utilization and outcomes before and after implementation of a clinical
      pathway for head and neck surgical patients. We observed significant decreases in
      hospital costs as well as shorter lengths of stay after pathway implementation.
      It is our belief that a uniform management tool is beneficial in this complex
      disease.

PMID- 10580234
TI  - Evaluation and management of bilateral vocal cord immobility.
AB  - Bilateral vocal cord immobility can be life threatening for some patients.
      Others, who have an open glottic chink, may have a breathy dysphonia,
      intermittent dyspnea, and stridor. These signs and symptoms may also be found in
      a number of other conditions that cause weakness or paradoxical motion of the
      vocal cords that mimics paralysis. These other conditions include central nervous
      system diseases, neuromuscular disorders, laryngospasm, and psychogenic
      disorders. In addition, patients with cricoarytenoid joint immobility or
      interarytenoid scar can also have similar symptoms at presentation. It is
      critical to consider the differential diagnosis of an assumed bilateral vocal
      cord paralysis and understand the management of paradoxical movement, weakness,
      joint fixation, interarytenoid scar, laryngospasm, and psychogenic disorders. The
      treatment for bilateral immobility should proceed only after a thorough
      evaluation, which might include electromyography and/or examination during
      general anesthesia under dense anesthetic paralysis. Reconstructive procedures
      are the treatments of choice, and destructive procedures should be chosen only as
      a last resort.

PMID- 10580236
TI  - Adam Politzer as an art collector. Vienna: Neues Wiener Abendblatt 1920 Nov 17;
      Kunst und Kunstmarkt sect: no. 316. Translation.

PMID- 10580235
TI  - Unique characteristics of malignant schneiderian papilloma.
AB  - PURPOSE: To ascertain the characteristics unique to malignant schneiderian
      papilloma (MSP). METHODS: A case-control study of all schneiderian papilloma (SP)
      patients treated between 1978 and 1997 was conducted. Comparison was made between
      patients with MSP and patients with benign SP (BSP). RESULTS: A diagnosis of SP
      was made in 72 patients. Malignant changes, all of them the inverted papilloma
      subtype, were found in 8 of these patients. Three were diagnosed carcinoma in
      situ, and 5 were defined as invasive squamous cell carcinoma. At presentation,
      the MSP patients had significantly larger tumor spread into the ethmoid and
      sphenoid sinuses. The recurrence rate was significantly lower in SP patients
      treated with extensive surgical procedures. An association was found between the
      presence of malignant lesions and positive smoking history, subjective awareness
      of a nasal mass, and ethmoid and sphenoid sinus involvement. Also, histologic
      multicentricity was a feature more often seen in MSP than BSP and was a
      significant correlate with malignancy. CONCLUSION: The physician evaluating a
      patient with SP should be aware of the features described and of their possible
      association with a malignant lesion.

PMID- 10580237
TI  - Intraoperative portable computed tomography scanning: An adjunct to sinus and
      skull base surgery.

PMID- 10580238
TI  - Hearing preservation in solitary vestibular schwannoma surgery using the
      retrosigmoid approach.
AB  - The results of 50 cases of vestibular schwannoma surgery with hearing
      preservation performed by the retrosigmoid approach at Addenbrooke's Hospital,
      Cambridge, during a 10-year period are presented. The hearing-preservation rate,
      using audiometric criteria set by others as "serviceable hearing" (Wade PJ, House
      W. Otolaryngol Head Neck Surg 1984;92:1184-93; Silverstein H, et al. Otolaryngol
      Head Neck Surg 1986;95:285-91; Cohen NL, et al. Am J Otol 1993;14:423-33) was 8%
      (4 of 50 cases). When the more stringent selection criteria of near-normal
      hearing and reporting criteria of socially useful hearing preservation (pure-tone
      average < 30 dB/speech discrimination score > 70%) is used, the hearing
      preservation rate is 4.8% (1 of 21 cases). The only preoperative factor that may
      predict a favorable hearing-preservation outcome is normal auditory brain stem
      response morphology (Fisher's exact 2-tailed test, P < 0.001). The number of
      suitable candidates for hearing-preservation surgery are few. Reasonable
      indications for attempted vestibular schwannoma surgery with hearing preservation
      are discussed.

PMID- 10580239
TI  - Rise of oxygenation in cervical lymph node metastasis during the initial course
      of radiochemotherapy.
AB  - It has been hypothesized that during radiation treatment a reoxygenation of
      hypoxic tumor tissue takes place. To test this hypothesis, we have investigated
      whether reoxygenation in lymph node metastases could be determined by invasive PO
      (2) measurements. Through a hypodermic needle inserted transcutaneously into
      tumor-positive lymph nodes, polarographic oxygen determinations were made in 18
      patients with advanced squamous cell carcinomas of the oropharynx and
      hypopharynx. These measurements were performed before therapy and a week after
      the onset of radiotherapy or radiochemotherapy, respectively. Low PO (2) values
      before treatment (mean value of the patient's median was 12.6 mm Hg PO (2)) and a
      mean hypoxic fraction (PO (2) < 5 mm Hg) of 39.6% indicated manifest tumor
      hypoxia. After 1 week of treatment, a significant increase in the median PO (2)
      (mean value of shift: 7.3 mm Hg) and a reduction in the hypoxic fraction (mean
      value of shift: 13.4% PO (2) < 5 mm Hg, P < 0.03) were observed after both
      radiotherapy and radiochemotherapy. Thus invasive PO (2) histography fulfills the
      requirements for a method to confirm tumor hypoxia in head and neck tumors. The
      results obtained indicate that reoxygenation occurs during the initial phases of
      radiotherapy and radiochemotherapy, and they will form the basis for future
      comparative investigations on the possible influence of hypoxic parameters on
      tumor responsiveness toward radiation and radiochemotherapy.

PMID- 10580241
TI  - Hearing ability by telephone of patients with cochlear implants.
AB  - We investigated the telephone communication ability of patients with cochlear
      implants who could understand conversations in natural voice without difficulty.
      The hearing ability of those patients with telephone adapters, which usually are
      used to reduce noise level in the telephone and to record into a tape recorder,
      was also investigated. Vowel-confusion, consonant-confusion, and speech-tracking
      test results of patients listening to voices by telephone and by telephone
      adapter were compared with those of patients listening to natural, nontelephone
      voices. The average score of the speech-tracking test with natural voice was
      111.5 phrases per 5 minutes. This score dropped to 62.4 by telephone. However,
      with a telephone adapter, the score of the speech-tracking test was 109.3 phrases
      per 5 minutes. This was almost the same score as that of the natural voice. So,
      generally speaking, the telephone communication ability of cochlear implant
      patients was not good enough. However, hearing ability with a telephone adapter
      came close to hearing ability during natural speech.

PMID- 10580240
TI  - Multiple-frequency tympanometry in children with acute otitis media.
AB  - Multiple-frequency tympanometry (MFT) is a sweep-frequency method of acoustic
      immittance measurement, recently introduced in clinical practice. It provides
      values for the resonant frequency of the middle ear system. The purpose of this
      study was to use MFT to collect information about the mechanoacoustical changes
      occurring to the middle ear system after acute otitis media and to compare it
      with the results of conventional, low probe-tone tympanometry. Children with
      acute otitis media were followed up with both methods for 1 month after an
      episode of acute infection. Also, children with normal hearing were studied to
      establish normative data. Resonant frequency of the middle ear was found to be
      lower than normal even 1 month past the initial episode, for all types of 226-Hz
      tympanograms. MFT seemed to record changes in the middle ear after acute otitis
      media that 226-Hz tympanometry was unable to detect, implying persistence of
      pathology. More extended research will illuminate the clinical value of this
      method in the follow-up of acute otitis media.

PMID- 10580242
TI  - Passive smoking and nonrecurrent acute otitis media in children.
AB  - INTRODUCTION: It remains uncertain whether passive smoking is a risk factor (RF)
      for nonrecurrent acute otitis media (AOM). The aim of this study was to evaluate
      whether exposure to second-hand smoke at home increased the prevalence of an
      isolated single episode of nonrecurrent AOM in children. METHODS AND MATERIAL: We
      performed a cross-sectional study with 192 children younger than 3 years who were
      seen at a general pediatric clinic. A questionnaire was used to quantify the
      exposure to cigarette smoke at home and to assess other RFs for AOM. The
      diagnosis of AOM was made by pediatricians using otoscopy. The results of the
      associations were reported by prevalence ratios with 95% confidence intervals.
      Multiple logistic regression was used to investigate the role of confounding
      variables among other potential RFs and passive smoking. RESULTS: The prevalence
      ratio of an isolated single episode of nonrecurrent AOM between patients exposed
      and those not exposed to passive smoking was 0.82 (0.67 to 1.02). In logistic
      regression, any RF changed the main association significantly. CONCLUSION:
      Exposure to passive smoking did not change the prevalence of an isolated single
      episode of nonrecurrent AOM in children.

PMID- 10580243
TI  - Management of Zenker's diverticulum and postlaryngectomy pseudodiverticulum with
      the CO2 laser.
AB  - Dysphagia is a common symptom and can be caused by anterior pharyngeal
      (pseudodiverticulum after laryngectomy) and posterior pharyngeal (Zenker's)
      diverticula. The only treatment is surgical. The experience with an endoscopic
      treatment, especially with the CO(2) laser, is limited. Between 1984 and 1996, 81
      patients with dysphagia were treated endoscopically with the CO(2) laser at the
      Department of Otorhinolaryngology-Head and Neck Surgery, University of Kiel. In
      70 patients the swallowing disorder was caused by a hypopharyngeal diverticulum,
      and in 11 patients it was caused by a pseudodiverticulum after laryngectomy. In
      the Zenker's group, more than 90% of the patients were treated successfully.
      Eight of 11 patients with pseudodiverticula were without symptoms, and in the
      remaining 3 patients dysphagia was improved after laser therapy. The excision
      technique was superior to the incision procedures. The rate of postoperative
      complications was generally low. The microendoscopic approach with the CO(2)
      laser is a recommendable method for the treatment of Zenker's diverticulum and
      pseudodiverticulum in the postlaryngectomy patient. The surgical technique with
      the CO(2) laser at low power settings is a less invasive, quick, relatively safe,
      and effective procedure requiring only short hospitalization.

PMID- 10580244
TI  - Diplophonia in unilateral vocal fold paralysis and intracordal cyst.
AB  - Diplophonia is the production by the voice of 2 separate tones through
      quasiperiodic variations in the vocal fold vibration (Ward PH, Moore GP. Ann Otol
      Rhinol Laryngol 1969;78:771-7). Clinically, diplophonia can be observed in
      patients with unilateral vocal fold paralysis with incomplete glottal closure and
      a mass lesion of the vocal fold, intracordal cyst, and granuloma (Kiritani S, et
      al. Ann Bull RILP 1991;25:55-62; Hirano M, et al. Ann Otol Rhinol Laryngol
      1989;98:791-5). In this study we report 16 subjects with unilateral vocal cord
      paralysis or an intracordal cyst characterized perceptually by diplophonia.
      Diplophonia during tension imbalance may occur after surgery and is characterized
      by an improved perceptual score, a reduced number of vibratory cycles in each
      quasiperiodic waveform, and a reduced occurrence rate of the diplophonic
      waveform. During mass imbalance, no diplophonia occurred after surgery. Regarding
      the relationship of diplophonia with glottal condition at production of stops, in
      our study diplophonia varied significantly according to the different phonologic
      environments of stops during tension imbalance. We presume that there is a close
      relationship between the occurrence of diplophonia and the glottal conditions in
      tension imbalance, but not in mass imbalance.

PMID- 10580245
TI  - Proposed classification scheme for quantitative olfactory function alterations.
AB  - Given the need for a clinical classification for daily patient examinations to
      refer to each type of quantitative alteration in the sense of smell, we have
      created a topographic classification of such alterations, establishing groups to
      distinguish among patients with decreased or total loss of olfaction. Because the
      classification is based on the diagnosis of the different causes of anosmia, it
      implicitly includes etiologic and topographic considerations. We have established
      3 main groups on the basis of the site of the causal lesion: conduction,
      sensorineural, and mixed anosmias. In addition, within the sensorineural
      anosmias, we distinguish between the epithelial, retroepithelial, and central
      anosmias.

PMID- 10580246
TI  - Solitary fibrous tumor of the nasal cavity.

PMID- 10580247
TI  - Mandibular sclerosing osteomyelitis of Garre.

PMID- 10580248
TI  - Use of rotation flap in the treatment of cutaneous ulceration after cochlear
      implantation.

PMID- 10580249
TI  - Skin: An unusual site of metastases in nasopharyngeal carcinoma.

PMID- 10580250
TI  - Solitary plasmacytoma of the hyoid bone.

PMID- 10580252
TI  - Schwannoma of the true vocal cord.

PMID- 10580251
TI  - Septic arthritis of the temporomandibular joint.

PMID- 10580253
TI  - Use of upper lip flap for correction of nostril stenosis.

PMID- 10580254
TI  - Interferon in the treatment of base of the skull hemangioendothelioma.

PMID- 10580255
TI  - Erosive form of lichen planus.

PMID- 10580256
TI  - Larsen's syndrome.

PMID- 10580258
TI  - Cost-effective screening for acoustic neuroma

PMID- 10580257
TI  - Cost-effective screening for acoustic neuroma.

PMID- 10580260
TI  - Light and electron microscopic study of the hindgut of the ant (Formica
      nigricans, hymenoptera): I. Structure of the ileum.
AB  - The study of the ileum of the ant Formica nigricans by light and electron
      microscopy revealed the existence of three differentiated regions: proximal,
      middle, and distal ileum. The middle region constitutes most of the length of the
      organ. Its wall is made up by a folded simple epithelium lined by a cuticle,
      which is surrounded by an inner circular muscle layer and various external
      longitudinal muscle fibers adjacent to the hemolymph. A subepithelial space is
      present between the epithelium and the circular muscle layer. Epithelial cells
      show extensive infoldings of the apical, and to a lesser extent the basolateral
      plasma membrane. Apical infoldings are characterized by the presence of 10-nm
      particles (portasomes) covering the cytoplasmic side of the membrane.
      Mitochondria are abundant throughout the cytoplasm, although they mainly are
      present underneath the apical infoldings. Lateral borders of epithelial cells
      display an apical junctional complex, mainly constituted by a long and convoluted
      pleated septate junction. These features support the view that epithelial cells
      in the middle ileum are specialized in ion solutes and water transport. The
      proximal ileum connects with the ampulla into which the Malpighian tubules drain.
      As opposed to the middle ileum, epithelial cells of the proximal ileum show less
      developed basolateral infoldings, and the apical plasma membrane is devoid of
      portasomes and only occasionally invaginates. These features suggest that the
      proximal ileum plays no relevant role in ion and water transport. The distal
      ileum penetrates into the rectal sac, forming a valve-like structure; this region
      presumably controls the amount of urine reaching the rectum.

PMID- 10580259
TI  - Standard of care?

PMID- 10580261
TI  - Light and electron microscopic study of the hindgut of the ant (Formica
      nigricans, hymenoptera): II. Structure of the rectum.
AB  - The rectum of the ant Formica nigricans is composed of six ovoid rectal papillae
      inserted into a rectal pouch. The wall of the rectal pouch is made up of a flat
      epithelium of simple rectal cells lined by cuticle, and surrounded by a circular
      muscle layer. Each rectal papilla is comprised by a simple columnar epithelium of
      principal cells facing the lumen, and a simple cuboid epithelium of secondary
      cells towards the hemolymph; a group of 20-25 slender junctional cells lies
      laterally between both epithelia enclosing an intrapapillar sinus. The muscle
      layer of the rectal wall also surrounds the base of the papillae. Principal cells
      do not exhibit extensive infoldings at the apical and basal plasma membranes.
      Lateral membranes, in contrast, develop highly folded mitochondria-scalariform
      junction complexes enclosing very narrow intercellular canaliculi between
      adjacent cells. These canaliculi open to wider intercellular sinuses that
      ultimately drain into the intrapapillar sinus at the sites of entry of tracheal
      cells. The lateral plasma membranes do not link to the apical or basal plasma
      membrane, thus originating a syncytium throughout the principal cells. The apical
      plasma membrane of secondary cells shows invaginations in relation with an apical
      tubulovacuolar system, bearing portasomes to the cytoplasmic side of the
      membrane. Secondary cells unite by convoluted septate junctions, and basolateral
      infoldings are also developed. These ultrastructural traits, some of them
      different from those found in other insects, are discussed and examined in
      relation to their role in water and solute absorption. A route for rectal
      transport in F. nigricans is proposed.

PMID- 10580262
TI  - Description of the chondrocranium and osteogenesis of the Chacoan burrowing frog,
      Chacophrys pierotti (Anura: Leptodactylidae).
AB  - The larval chondrocranium of the large-headed leptodactylid frog, Chacophrys
      pierotti (Ceratophryinae), is described in detail. Descriptions include the
      ontogeny of the chondrocranium and osteogenesis of the cranial skeleton. The
      chondrocranium of C. pierotti is profoundly different from the chondrocrania
      previously described for the other genera of the Ceratophryinae (Ceratophrys and
      Lepidobatrachus). The chondrocranium of Chacophrys is longer than wide and not
      particularly robust or laterally expanded; that of Ceratophrys is very robust,
      whereas the chondrocranium of Lepidobatrachus is widely expanded laterally. These
      differences are particularly apparent in the elements associated with the jaw
      (i.e., suprarostral, infrarostral, Meckel's cartilage, palatoquadrate, cornua
      trabeculae), which are robust in Ceratophrys and thin and elongate in
      Lepidobatrachus. Unlike Ceratophrys and Lepidobatrachus, which possess highly
      specialized carnivorous larva, the chondrocranium of Chacophrys more closely
      resembles the typical microphagous herbivore morphology characteristic of other
      leptodactylid frogs for which the chondrocrania are known. These data suggest
      that Chacophrys is the basal taxon within the monophyletic Ceratophryinae. The
      ontogeny of the chondrocranium of Chacophrys, as well as the cranial ossification
      sequence, do not differ greatly from those described for Ceratophrys. Detailed
      descriptions of the ontogeny of the chondrocranium and the bony skeleton are
      needed for additional taxa within the Ceratophryinae (especially
      Lepidobatrachus). Such descriptive ontogenetic studies promise new insight into
      the phylogeny and morphological evolution of this remarkable group of large
      headed frogs.

PMID- 10580263
TI  - Morphologic study of the efferent ductules of the pigeon (Columba livia).
AB  - The efferent ductules of the pigeon are localized in the epididymal region and
      are topographically divided into proximal and distal, both portions being lined
      with stereociliated pseudostratified epithelium. Transmission electron microscopy
      shows five distinct cell types: light, dark, and angular non-ciliated cells with
      possible apocrine secretory role cells and halo cells, possibly intraepithelial
      leucocytes. The proximal efferent ductules have the widest diameter among all
      ductules in the epididymal region.

PMID- 10580264
TI  - Description of the postcloacal glands of Plethodon cinereus, the red-backed
      salamander, during bouts of scent marking.
AB  - Plethodon cinereus, the red-backed salamander, is a small territorial vertebrate
      that defends refugia located on the forest floor. As a component of territorial
      defense, these animals use scent marks to advertise their refugia. Behavioral
      evidence indicates that scent marks are produced by the postcloacal glands
      located on the ventral surface of the tail just posterior to the cloaca. We
      placed animals on unmarked substrates and recorded changes in serous acini from
      the postcloacal and shoulder region over a 48-h period. Within the first hour
      there was an increase in the number of acini filled with secretory product in the
      postcloacal region. At 12 h the number of full acini decreased and the number of
      empty acini increased. By 24 h the number of empty acini had decreased and the
      number of renewing acini containing secretory cells producing product had
      increased. By 48 h the ratio of full to empty to renewing acini was similar to
      those observed at the start of the study. In the shoulder region, no significant
      changes in the ratio of full to empty to renewing acini were observed.
      Observations of the serous acini within the postcloacal region and the shoulder
      region indicate that the mode of secretory production is holocrine. These
      findings are additional evidence that the postcloacal glands are the site of
      scent mark production.

PMID- 10580265
TI  - Cell death in ovarioles causes permanent sterility in Frieseomelitta varia worker
      bees.
AB  - Frieseomelitta varia worker bees do not lay eggs even when living in queenless
      colonies, a condition that favors ovary development and oviposition in the
      majority of highly social bees. The permanent sterility of these worker bees was
      initially attributed to a failure in ovary morphogenesis and differentiation.
      Using transmission electron microscopy we found that at the beginning of the
      pupal phase the ovaries of F. varia workers are formed by four ovarioles, each of
      them composed of 1) a terminal filament at the apex of the ovarioles, containing
      juxtaposed and irregularly shaped cells, 2) a germarium with clusters of
      cystocytes and prefollicular cells showing long cytoplasmic projections that
      envelop the cystocyte clusters, 3) fusiform interfollicular and basal stalk
      precursor cells, and 4) globular, irregularly contoured basal cells with large
      nuclei. However, during the pupal phase an accentuated and progressive process of
      cell death takes place in the ovarioles. The dying cells are characterized by
      large membrane bodies, electron-dense apoptotic bodies, vacuoles, vesiculation,
      secondary lysosomes, enlarged rough endoplasmic reticulum cisternae, swollen
      mitochondria, pycnotic nuclei, masses of chromatin adjacent to the convoluted
      nuclear envelope, and nucleoli showing signs of fragmentation. Cell death
      continues in ovarioles even after the emergence of the workers. Once they become
      nurse bees, the ovaries have become transformed into a cell mass in which
      structurally organized ovarioles can no longer be identified. In F. varia
      workers, ovariole cell death most certainly is part of the program of caste
      differentiation.

PMID- 10580266
TI  - Reexamination of hemocytes in brine shrimp (Crustacea, branchiopoda).
AB  - In 1941, a single type of hemocyte was described in the blood of the brine shrimp
      Artemia salina using light microscopy. This condition is unusual because most
      crustaceans examined using morphological, cytochemical, and functional methods
      have at least two types of hemoctyes. Upon examining A. franciscana, we found a
      single type of disk-shaped hemocyte, with a centrally located nucleus and about
      15 large (6 microm diameter) granules. The granules stain for the presence of
      acid phosphatase and react with L-DOPA suggesting, respectively, that they are
      involved in degrading ingested material and possess the phenoloxidase system.
      Hemocytes require calcium for adhesion, bind together to mend small wounds in the
      body wall, and are able to phagocytose bacteria. Blood cells of A. franciscana
      are morphologically and functionally similar to those of the primitive
      chelicerate, Limulus polyphemus, and both forms have apparently given rise to
      more advanced taxa with multiple types of hemocytes. The major difference between
      the two species is the presence of the phenoloxidase system in the Crustacea and
      its apparent absence in the chelicerates.

PMID- 10580268
TI  - Meeting announcements

PMID- 10580267
TI  - Microscopic and histochemical study of odontoclasts in physiologic resorption of
      teeth of the polyphyodont lizard, Liolaemus gravenhorsti.
AB  - Using tartrate-resistant acid phosphatase (TRAP), we examined the
      cytodifferentiation of odontoclast cells in resorbing areas of dental tissues
      during the replacement of teeth in a polyphyodont lizard, Liolaemus gravenhorsti.
      We also report, by means of Lectin-HRP histochemistry, the distribution pattern
      of some specific sugar residues of TRAPase-positive cells. For detection of
      TRAPase activity, the azo dye-coupling technique was used. Lectin binding sites
      were demonstrated by means of specific HRP-lectins. The process of tooth
      resorption was divided into four stages: 1) preresorption-the wall of the dental
      pulp is covered with an odontoblast layer, and no TRAP-positive cells are in the
      dental pulp; 2) early resorption-TRAP-positive multinucleate odontoclasts are
      present on the dental wall, but the rest of the pulp surface is still covered
      with an odontoblast layer; 3) later resorption-the entire surface of the pulp
      chamber is lined with multinucleate odontoclasts; and 4) final resorption-the
      tooth has been totally resorbed. Odontoclasts are usually detached from the
      resorbed surface, and show signs of degeneration. Of the six lectins used, PNA,
      ECA, and UEA-1 bind to multinucleated but not mononuclear cells. All the
      remaining lectins, BS-1, RCA(120), and LTA showed no binding to any cells of the
      teeth. The significance of saccharidic moieties such as acetyl-galactosamine,
      acetyl-glucosamine, and fucose sugar residues is difficult to ascertain. Perhaps
      these oligosaccharides might be borne on molecules associated with odontoclastic
      resorption or associated with multinucleation of odontoclasts after attachment to
      the dentine surface.

PMID- 10580269
TI  - Participation of group 2 CD1 molecules in the control of murine tuberculosis.
AB  - Besides the classical major histocompatibility complex (MHC) class I and MHC
      class II molecules, human CD1 molecules have been shown to present mycobacterial
      antigens in vitro. In this study, in vivo treatment of mice with anti-CD1
      monoclonal antibodies resulted in exacerbated tuberculosis at very early time
      points. In CD1-modulated mice, Mycobacterium tuberculosis-specific production of
      the type 1 cytokines, IL-12, TNF, and IFN-gamma as well as of TGF beta was
      reduced. These findings suggest an antigen-presenting role of CD1 molecules in
      tuberculosis.

PMID- 10580270
TI  - CD14 expression by human mononuclear phagocytes is modulated by Clostridium
      difficile toxin B.
AB  - Toxin B, an exotoxin produced by the anaerobic Gram-positive bacteria Clostridium
      difficile, is responsible for pseudomembranous colitis in humans. It deeply
      modifies morphology of cultured cells and enhances their membrane surface area,
      which suggests a possible alteration of membrane receptor distribution. Since
      toxin B and bacterial lipopolysaccharide can act synergistically on TNF-alpha
      production by mononuclear phagocytes, the effect of toxin B on CD14 expression
      was investigated using flow cytometric analysis. It was shown that monocytes
      overexpressed CD14 after 5 h of treatment with toxin B. In contrast, after 24 h
      of treatment, the percentage of CD14 monocytes decreased, although, most
      frequently, the remaining positive cells expressed high levels of CD14 compared
      with untreated cells. Macrophages treated for 5 h with toxin B overexpressed
      CD14, but this effect persisted for at least 24 h. Both the percentage of
      positive macrophages and the mean level of CD14 per cell were increased. Thus
      toxin B can modulate expression of CD14 and its modulation depends on the
      differentiation status and maybe on the activation state, since some individual
      variations were observed in monocyte response to toxin.

PMID- 10580271
TI  - Caspase-dependent apoptosis during infection with Cryptosporidium parvum.
AB  - The protozoan parasite Cryptosporidium parvum causes persistent diarrhea and
      malnutrition in children and the diarrhea-wasting syndrome in AIDS. No therapy
      exists for eliminating the parasite in the absence of a healthy immune response.
      Although it had been reported that infection of intestinal cell lines with C.
      parvum leads to host cell death, the mechanisms of cytolysis have not been
      characterized. We show here that infection with C. parvum leads to typical
      apoptotic nuclear condensation and DNA fragmentation in host cells. Both nuclear
      condensation and DNA fragmentation are inhibited by a caspase inhibitor, showing
      that caspases are involved in this type of apoptosis. Finally, blocking apoptosis
      with the caspase inhibitor increases the percentage of infected cells, suggesting
      that parasites may use apoptosis to exit from the infected cell or that the
      infected cells may eliminate the parasite through apoptosis. These results
      suggest that apoptosis could be involved in the pathogenesis of C. parvum
      infections in vivo, and raise the possibility that therapeutic interference with
      host cell death could alter the course of the pathology in vivo.

PMID- 10580272
TI  - Antifungal type 1 responses are upregulated in IL-10-deficient mice.
AB  - C57BL/6 mice are highly resistant to infections caused by Candida albicans and
      Aspergillus fumigatus. To elucidate the role of IL-10 produced by C57BL/6 mice
      during these infections, parameters of infection and immunity to it were
      evaluated in IL-10-deficient and wild-type mice with disseminated or
      gastrointestinal candidiasis or invasive pulmonary aspergillosis. Unlike
      parasitic protozoan infection, C. albicans or A. fumigatus infection did not
      induce significant acute toxicity in IL-10-deficient mice, who, instead, showed
      reduced fungal burden and fungal-associated inflammatory responses. The increased
      resistance to infections as compared to wild-type mice was associated with
      upregulation of innate and acquired antifungal Th1 responses, such as a
      dramatically higher production of IL-12, nitric oxide (NO) and TNF-alpha as well
      as IFN-gamma by CD4+ T cells. Pharmacological inhibition of NO production greatly
      reduced resistance to gastrointestinal candidiasis, thus pointing to the
      importance of IL-10-dependent NO regulation at mucosal sites in fungal
      infections. These results are reminiscent of those obtained in genetically
      susceptible mice, in which IL-10 administration increased, and IL-10
      neutralization decreased, susceptibility to C. albicans and A. fumigatus
      infections. Collectively, these observations indicate that the absence of IL-10
      augments innate and acquired antifungal immunity by upregulating type 1 cytokine
      responses. The resulting protective Th1 responses lead to a prompt reduction of
      fungal growth, thus preventing tissue destruction and lethal levels of
      proinflammatory cytokines.

PMID- 10580273
TI  - The use of nocodazole in cell cycle analysis and parasite purification from
      Theileria parva-infected B cells.
AB  - Theileria parasites transform bovine leukocytes and induce uncontrolled
      lymphoproliferation only in the macroschizont stage of their life cycle. The
      isolation of highly purified stage-specific parasite RNA and proteins is an
      essential prerequisite when studying the Theileria-host relationship. We
      therefore improved a protocol based on the cytolytic bacterial toxin aerolysin by
      taking advantage of the microtubule inhibitor nocodazole. In this report we
      describe that nocodazole-mediated separation of the parasite from the host cell
      microtubule network was used with success to improve quantity and quality of
      purified parasites. We furthermore show that nocodazole is a useful tool to study
      cell cycle checkpoints due to its capacity to induce reversible cell cycle arrest
      in Theileria-infected B cells.

PMID- 10580274
TI  - Characterization of M. tuberculosis strains from west African patients by
      spoligotyping.
AB  - Analysis of Mycobacterium tuberculosis strains was carried out using isolates
      collected from 69 Senegalese and 20 Ivory Coast tuberculosis patients. These 89
      isolates were typed by means of the spoligotyping technique, showing clusterized
      populations of bacterial strains. In the Senegalese patients, 35 genetic profiles
      were observed with 10 clusters of spoligotypes from 44 isolates. Among Ivory
      Coast patients, 11 spoligotypes were found for 20 isolates. A particular cluster
      of isolates was evident both in Senegalese (10) and Ivory Coast (11) patients.
      These results show the existence of polymorphism of the direct repeat region for
      African M. tuberculosis strains. However they suggest that additionnal markers
      are needed for accurate epidemiological studies in areas that are highly endemic
      for tuberculosis.

PMID- 10580275
TI  - Identification of Ebola virus sequences present as RNA or DNA in organs of
      terrestrial small mammals of the Central African Republic.
AB  - The life cycle of the Ebola (EBO) virus remains enigmatic. We tested for EBO
      virus in the organs of 242 small mammals captured during ecological studies in
      the Central African Republic. EBO virus glycoprotein or polymerase gene sequences
      were detected by reverse transcription PCR in RNA extracts of the organs of seven
      animals and by PCR in DNA extract of one animal. Neither live virus nor virus
      antigen was detected in any organ sample. Direct sequencing of amplicons
      identified the virus as being of the Zaire/Gabon subtype. Virus-like
      nucleocapsids were observed by electron microscopy in the cytoplasm of the spleen
      cells of one animal. The animals belonged to two genera of rodents (Muridae; Mus
      setulosus, Praomys sp1 and P. sp2) and one species of shrew (Soricidae;
      Sylvisorex ollula). These preliminary results provide evidence that common
      terrestrial small mammals living in peripheral forest areas have been in contact
      with the EBO virus and demonstrate the persistence of EBO virus RNA and DNA in
      the organs of the animals. Our findings should lead to better targeting of
      research into the life cycle of the EBO virus.

PMID- 10580276
TI  - Gene transfer in Legionella pneumophila.
AB  - This review describes the mechanisms of gene transfer in Legionella pneumophila.
      To date, conjugation and transformation have been reported for this organism.
      Recent reports indicate that an endogenous system of plasmid transfer appears to
      be required for the intracellular survival and multiplication of L. pneumophila
      in host cells.

PMID- 10580277
TI  - Intracellular lifestyle of Brucella spp. Common genes with other animal
      pathogens, plant pathogens, and endosymbionts.
AB  - Brucella spp. are intracellular pathogens that belong, like Agrobacterium,
      Rhizobium and Rickettsia, to the alpha-2-subgroup of proteobacteria. The genome
      organization of most Brucella spp. is characterized by the presence of two
      chromosomes. The intracellular lifestyle of Brucella, as well as the possible
      genes involved in pathogenesis and host cell signaling, are discussed, including
      the presence of genes with high similarity to those from other animal pathogens,
      plant pathogens and endosymbionts.

PMID- 10580278
TI  - DsbA: a protein-folding catalyst contributing to bacterial virulence.
AB  - DsbA, a periplasmic thiol:disulphide oxidoreductase, catalyses the folding of
      various factors, among which are virulence determinants or the components of type
      III secretory machinery. It is also necessary for intracellular survival and cell
      to-cell spread of the intracellular pathogen Shigella flexneri.

PMID- 10580280
TI  - 1,2-sn-Diacylglycerol in plant cells: Product, substrate and regulator.
AB  - 1,2-sn-Diacylglycerol (DAG) is a family of lipidic molecular species varying in
      the lengths and desaturation levels of acyl groups esterified at positions sn-1
      and sn-2 of the glycerol backbone. In plant cells, DAG originating from plastid
      and from extraplastidial membranes have distinct molecular signatures, C18/C16
      and C18/C18 structures, respectively. Under normal conditions, DAG is consumed
      nearly as fast as it is produced and is therefore a transient compound in the
      cell. In plants, DAG proved to be the most basic ingredient for cell membrane
      biogenesis and fat storage, but we still lack formal evidence to assert that DAG
      is also an intracellular messenger, as demonstrated for animals. From the
      biochemical and molecular comparisons of the best known DAG-manipulating proteins
      of prokaryotic and eukaryotic cells (phosphatidate phosphatases, diacylglycerol
      kinases, MGDG synthase, protein kinase C, etc.) this review aims to identify
      general rules driving DAG metabolism, and emphasizes its unique features in plant
      cells. DAG metabolism is an intricate network of local productions and
      utilizations: many isoenzymes can catalyse similar DAG modifications in distinct
      cell compartments or physiological processes. The enzymatic- or binding
      specificity for DAG molecular species demonstrates that discrete DAG molecular
      subspecies fluxes are finely controlled (particularly for C18/C16 and C18/C18
      structures in plastid membrane biogenesis). Eventually, this review stresses the
      diversity of structures and functioning of DAG-manipulating proteins. As a
      consequence, because DAG metabolism in plants is unique, the deciphering of
      genomic information cannot rely on homology searches using known prokaryotic,
      animal or yeast sequences, but requires sustained efforts in biochemical and
      molecular characterizations of plant DAG-manipulating proteins.

PMID- 10580279
TI  - Hantavirus infections: epidemiology and pathogenesis.
AB  - Hantaviruses are enveloped RNA viruses that persistently infect rodent hosts
      without ill-effect. The host persistently excretes virus in urine and saliva. Man
      becomes infected from the rodents when one enters the ecological niche of the
      other. There are two major clinical presentations--haemorrhagic fever with renal
      syndrome, found worldwide in various forms and hantavirus pulmonary syndrome,
      found only in the Americas. This review examines the virology, epidemiology and
      pathogenesis of these emerging pathogens.

PMID- 10580281
TI  - Molecular cloning and characterization of the enzyme UDP-glucose: protein
      transglucosylase from potatodaggerdaggerThis paper is specially dedicated to the
      memory of Dr Juana S. Tandecarz, deceased on December 10, 1996.
AB  - UDP-Glc:protein transglucosylase (UPTG) (EC 2.4.1.112) is an autocatalytic
      glycosyl-transferase previously postulated as a protein that primes starch
      biosynthesis. Polyclonal antibodies raised against UPTG purified from potato
      (Solanum tuberosum L.) tubers were used to screen a potato swelling stolon tip
      cDNA expression library. The isolation, cloning and sequencing of two cDNAs
      corresponding to UPTG are described. Recombinant UPTG was labelled after
      incubation with UDP-[(14)C]-Glc and Mn(2+), indicating that it was enzymatically
      active. It was determined that purified as well as recombinant UPTG can be
      reversibly glycosylated by UDP-Glc, UDP-Xyl or UDP-Gal. RNA hybridization studies
      and western blot analysis indicate that UPTG mRNA and protein are expressed in
      all potato tissues. Databank searches revealed a high degree of identity between
      UPTG and several plant sequences that encode for proteins with apparent
      localization at the cytoplasmic face of the Golgi apparatus and at plasmodesmata.
      The biochemical properties of UPTG and the apparent lack of a signal peptide that
      could allow its entrance into plastids argue against the postulated role of UPTG
      in starch synthesis and point towards a possible role of the protein in the
      synthesis of cell wall polysaccharides.

PMID- 10580282
TI  - Transcriptional activation of the parsley chalcone synthase promoter in
      heterologous pea and yeast systems.
AB  - Introduction by electroporation of different parsley (Petroselinum crispum) CHS
      promoter/beta-glucuronidase(GUS)-reporter constructs into pea (Pisum sativum L.)
      protoplasts leads to a high constitutive GUS-expression and to the loss of the
      light-inducibility seen in the homologous parsley protoplast system. These
      results indicate that Unit 1 of the parsley CHS-promoter is only partly
      responsible for the GUS-expression detected. Instead, additional cis-elements,
      which are located downstream within 100 bp from the transcriptional start site,
      mediate the de-repression in pea protoplasts. In contrast, in yeast
      (Saccharomyces cerevisiae) cells, the GUS expression from the heterologous
      CHS/GUS construct is controlled by elements between Unit 1 and -100 bp. In both
      pea and yeast cells, transcription factors different from those regulating UV
      responsiveness in parsley, are probably mediating the constitutive expression
      from the heterologous construct. The results with pea protoplasts imply that
      protoplastation of pea leaf cells itself induces de-repression as a result of
      stress to the protoplasts. This notion was strengthened by the finding that mRNA
      levels of the endogenous chalcone synthase were drastically increased as the
      result of the protoplastation procedure.

PMID- 10580283
TI  - The TAG1 locus of Arabidopsis encodes for a diacylglycerol acyltransferase.
AB  - Diacylglycerol acyltransferase (DGAT, EC 2.3.1.20) is a membrane enzyme that
      drives the final step in the formation of oils using diacylglycerol (DAG) and
      acyl-CoA to yield triacylglycerol (TAG). We identified a putative plant DGAT gene
      (TRIACYLGLYCEROL1: TAG1) and demonstrated its function by the cloning of two
      mutated alleles, designated AS11 (tag1-1) and ABX45 (tag1-2). One allele, AS11,
      has been previously characterised at the biochemical level. Mutant seeds
      contained less oil with a modified fatty acid profile and have reduced
      germination rates compared to wild-type controls. The TAG1 cDNA encodes for a 520
      aa protein that possesses multiple putative transmembrane domains and shows 70 %
      similarity to a human DGAT cDNA.

PMID- 10580284
TI  - Characterization of polyphenol oxidase from aerial roots of an orchid, Aranda
      'Christine 130'
AB  - Four isoforms of polyphenol oxidase (PPO) were demonstrated in the aerial roots
      of a tropical orchid, Aranda 'Christine 130'. They were extracted at neutral pH
      and purified to homogeneity as judged by SDS-gel electrophoresis. Purification
      was achieved by a combination of Triton X-114 treatment, temperature phase
      partitioning, gel filtration chromatography, ion-exchange separation and
      chromatofocusing. Two of the isoforms, designated PPO(a) and PPO(d), differed in
      their N-terminal sequence, tryptic peptide map and substrate affinity for (+)
      catechin, but exhibited similarity in their molecular mass under denaturing
      conditions, pH optimum and kinetic behaviour toward 4-methyl catechol. The other
      two isoforms, PPO(b) and PPO(c), were identical to PPO(a) and PPO(d),
      respectively, in terms of their N-terminal sequence, substrate preference and pH
      maximum, but were different with regard to their molecular mass under denaturing
      conditions. These four isoforms differed in their isoelectric point.

PMID- 10580285
TI  - Post-translational maturation of natural and drug-induced missorted
      phytohemagglutinin.
AB  - The bean lectin phytohemagglutinin (PHA) was expressed in transgenic suspension
      cultured BY-2 tobacco cells simultaneously with another recombinant vacuolar
      protein, the sweet potato sporamin. In contrast to previous observations in
      different transgenic plant systems when expressed in BY-2 tobacco cells,
      phytohemagglutinin is mostly but not exclusively targeted to the vacuole. Indeed,
      a small amount of recombinant phytohemagglutinin is secreted into the culture
      medium of tobacco cells. Furthermore part of this extracellular
      phytohemagglutinin has no lectin activity and presents an abnormal glycosylation
      consistent with higher accessibility of glycans N-linked to these extracellular
      phytohemagglutinin forms. Phytohemagglutinin secretion occurs regardless of
      recombinant protein expression level. Consequently, missorting in this case is
      due to an abnormal phytohemagglutinin conformation or oligomerization rather than
      to receptor saturation. The treatment of BY-2 cells with drugs, such as monensin
      and wortmannin, increases even more the transport of phytohemagglutinin to the
      cell surface through a general inhibition of the sorting mechanisms of vacuolar
      proteins. The sensitivity to wortmannin is similar for the sorting of
      phytohemagglutinin and endogenous tobacco chitinase and beta-1,3-glucanase,
      suggesting that phytohemagglutinin and COOH-terminal propeptide mediated vacuolar
      sorting share similar mechanisms. A characterization of glycans N-linked to
      extracellular phytohemagglutinin secreted by monensin- or wortmannin-treated
      transgenic tobacco cells illustrates that in contrast with monensin, wortmannin
      completely inhibits the sorting of vacuolar proteins without having any effect on
      the efficiency of Golgi processing enzymes.

PMID- 10580286
TI  - Stress induction of a nuclear gene encoding for a plastid protein is mediated by
      photo-oxidative events.
AB  - Fibrillin was originally identified as a chromoplast protein involved in the
      assembly of carotenoid-containing fibrils and was also found to accumulate in
      chloroplasts of wounded or water-stressed leaves. We now show that the promoter
      from the pepper fibrillin (nuclear) gene can be induced in leaves of stable
      tomato transformants by various stresses, namely wounding, drought, cold and salt
      stress, in light but not in darkness, as well as by high light intensities.
      Various herbicides causing reactive oxygen (superoxide, singlet oxygen)
      production in chloroplasts also induce the promoter. Higher expression levels are
      observed in transgenic tobacco plants which are apparently more sensitive to
      photo-oxidative stress than tomato. Similarly, wounding which causes strong
      induction of the promoter in tobacco, produces only weak induction in tomato.
      Hydrogen peroxide produced in plastids or added exogenously causes the induction
      of this nuclear gene. Our data suggest that the ascorbate/glutathione pathway
      (which eliminates hydrogen peroxide) can influence indirectly the induction of
      the fibrillin promoter. We propose a generalized model which links stresses of
      external origin to nuclear gene induction, via the plastid compartment which is
      subjected to photo-oxidative stress.

PMID- 10580287
TI  - Chlorogenic acid in a Nicotiana plumbaginifolia cell suspension.
AB  - A phenylpropanoid compound has been characterized in a Nicotiana plumbaginifolia
      cell suspension. This compound has been isolated and purified by semi-preparative
      reverse phase-high performance liquid chromatography. Its structure has been
      identified by NMR spectroscopy as 5-O-caffeoylquinic acid, which is chlorogenic
      acid (CA). The influence of culture conditions on the accumulation of this
      metabolite by N. plumbaginifolia cell suspensions has been studied. Darkness
      strongly inhibits the CA accumulation. Moreover, it has been shown that feeding
      experiments with caffeic acid had a deleterious effect upon the CA content. This
      one was not influenced by a supplementation with quinic acid.

PMID- 10580288
TI  - Differential responses to different light spectral ranges of violaxanthin de
      epoxidation and accumulation of Cbr, an algal homologue of plant early light
      inducible proteins, in two strains of Dunaliella.
AB  - Unicellular green algae of the genus Dunaliella, similar to higher plants,
      respond to light stress by enhanced de-epoxidation of violaxanthin and
      accumulation of Cbr, a protein homologous to early light inducible proteins
      (Elips) in plants. These proteins belong to the superfamily of chlorophyll a/b
      binding proteins. Two Dunaliella strains, D. bardawil and D. salina, were
      compared for these two responses under light in the UVA, blue, green and red
      spectral ranges. In D. bardawil, the two stress responses were similarly induced
      under UVA, blue or red light and to a lesser extent under green light. In D.
      salina, a similar spectral range dependence was exhibited for violaxanthin de
      epoxidation. However, Cbr accumulated only under UVA or blue light but not under
      green or red light. A strong synergistic effect of a low dose of blue light
      superimposed on red light resulted in Cbr accumulation. These results reveal
      strain-specific differences in spectral range requirements of the two light
      stress responses. In the two strains, violaxanthin de-epoxidation is triggered
      under photosynthetically-active spectral ranges but at least in D. salina, Cbr
      accumulation appears to require a specific light signal additionally to a
      signal(s) generated by light stress.

PMID- 10580289
TI  - Identification of neural projections from the forebrain to the kidney, using the
      virus pseudorabies.
AB  - These data demonstrate a chain of synaptically connected neurons extending to the
      rat kidney through several levels of the neuraxis from the forebrain, and the
      lamina terminalis -- an area known to be involved in the regulation of body fluid
      homeostasis. The Bartha strain of pseudorabies virus was injected into the kidney
      of male Sprague-Dawley rats, resulting in retrograde infections in spinal cord
      segments (T1-T8), and successive infection in five autonomic 'premotor' areas of
      the brain, the rostroventrolateral medulla, rostroventromedial medulla, raphe
      nuclei, A5 region of the pons, and the paraventricular nucleus of the
      hypothalamus, as well as the nucleus of the solitary tract, locus coeruleus, and
      subcoeruleus nuclei. Higher order labelling was found in regions of the
      forebrain, including the organum vasculosum of the lamina terminalis, median
      preoptic nucleus, subfornical organ, medial preoptic area, bed nucleus of the
      stria terminalis, anteroventral periventricular nucleus, lateral preoptic area,
      suprachiasmatic nucleus, retrochiasmatic nucleus, primary motor cortex, and
      visceral cortex. This polysynaptic pathway to the kidney may form the substrate
      underlying the impact of forebrain structures on renal function.

PMID- 10580290
TI  - Excitation of dorsal motor vagal neurons evokes non-nicotinic receptor-mediated
      gastric relaxation.
AB  - Vagal stimulation results in both gastric motor excitatory and non-adrenergic non
      cholinergic (NANC) inhibitory responses. The NANC pathway involves preganglionic
      cholinergic neurons, which act through nicotinic receptors to ultimately evoke
      gastric smooth muscle relaxation via release of nitric oxide (NO) and other
      neurotransmitters. Within the dorsal motor nucleus of the vagus (DMN), some
      preganglionic neurons also contain NO synthase. The NO synthase-containing
      neurons innervate the gastric fundus where adaptive relaxation occurs. This study
      tests the hypothesis that chemical stimulation of vagal motor neurons in animals,
      in which nicotinic receptors are blocked, evokes an NO-dependent gastric
      relaxation. A cell body excitant, N-methyl-D-aspartate (NMDA, 0.03-3 nmol), was
      microinjected into the DMN in anesthetized rats while recording intragastric
      pressure (IgP). The first group received NMDA before and after administration of
      a ganglionic blocker, hexamethonium bromide (15 mg/kg, i.v.) and atropine (1.0
      mg/kg). Significant dose-dependent increases in IgP and gastric motility occurred
      before hexamethonium after the 0.3 and 3 nmol doses of NMDA. After hexamethonium,
      0.3 and 3 nmol NMDA evoked significant decreases in IgP. A second group of rats
      was hexamethonium-pretreated and received NMDA microinjection into the DMN before
      and after an NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (10 mg/kg,
      i.v.). The NMDA-evoked decrease in IgP was completely abolished by the NO
      synthase inhibitor. These data support the novel idea that NO synthase-containing
      preganglionic neurons mediate gastric relaxation that is independent of nicotinic
      receptors.

PMID- 10580291
TI  - Differential effects of apamin on neuronal excitability in the nucleus tractus
      solitarii of rats studied in vitro.
AB  - We demonstrated previously that microinjection of the calcium-dependent potassium
      channel antagonist, apamin, into the nucleus tractus solitarius (NTS) in vivo
      potentiated the baroreceptor reflex mediated bradycardia but attenuated the
      cardiopulmonary reflex. The latter result was surprising since, intuitively,
      potassium channel blockade would be expected to increase neuronal excitability
      leading to reflex potentiation. The aim of this in vitro study was to investigate
      possible neuronal mechanisms to explain our in vivo observations. Transverse
      brainstem slices of rat were cut at the level of area postrema and recordings
      were made from 36 NTS neurones in whole-cell mode. The neurones were classified
      into three groups, based on their response to apamin (10 nM). Each group had a
      similar resting membrane potential (RMP; -55 +/- 1 mV; n = 36) and input
      resistance (404 +/- 20 M omega; n = 36). (1) In 15/36 neurones, apamin decreased
      the number of spikes evoked during injection of positive current by 37 +/- 6%;
      this was associated with a concomitant fall in input resistance of 12 +/- 2% (P <
      0.05). Stimulation of the ipsilateral tractus solitarius evoked EPSP-IPSP
      complexes in nine of the 12 neurones tested; the inhibitory components were
      increased in amplitude, at a holding potential of -46 mV, from -1.7 +/- 0.4 to 
      3.2 +/- 0.6 mV (P < 0.01) in the presence of apamin, while the EPSPs were
      unaffected. All three of these effects were bicuculline (10 microM) sensitive.
      (2) In 8/36 neurones, apamin increased the number of spikes evoked during
      injection of positive current by 27 +/- 8%, but affected neither RMP nor input
      resistance. Only one of five neurones tested demonstrated a synaptically evoked
      EPSP-IPSP complex. The remaining four neurones displayed a single evoked EPSP,
      the amplitudes of which were unaffected by apamin. (3) In the remaining neurones
      (13/36), apamin affected neither responsiveness to positive current injection,
      RMP, nor input resistance. Six of 12 neurones demonstrated synaptically evoked
      EPSP-IPSP complexes; at a holding potential of -46 mV, apamin increased the IPSP
      component from -2.6 +/- 1 to -3.6 +/- 0.8 mV (P < 0.05), while the EPSPs were
      unaffected. In conclusion, apamin can both increase and decrease NTS neuronal
      excitability: the former reflecting blockade of channels on the recorded neurone;
      the latter may possibly result from an increase in GABA release by interneurones
      impinging onto the recorded neurone. The possibility of a differential
      distribution of apamin-sensitive channels in sub-populations of NTS neurones
      subserving different reflexes is discussed.

PMID- 10580292
TI  - Distribution of NADPH-d and nNOS-IR in the thoracolumbar and sacrococcygeal
      spinal cord of the guinea pig.
AB  - The distribution of NADPH-d staining and neuronal nitric oxide synthase (nNOS)
      immunoreactivity in the spinal cord of the guinea pig was studied to evaluate the
      potential role of nitric oxide in lumbosacral afferent and spinal autonomic
      pathways and to compare the distribution of these two markers to that observed in
      other species. NADPH-d staining and nNOS-immunoreactivity were present in neurons
      and fibers in the superficial dorsal horn, dorsal commissure and in neurons
      around the central canal in all levels of the spinal cord examined. Sympathetic
      preganglionic neurons in the thoracic and rostral lumbar segments identified by
      choline acetyl transferase (ChAT) immunoreactivity exhibited prominent NADPH-d
      staining and nNOS-immunoreactivity; whereas the ChAT-immunoreactive
      parasympathetic preganglionic neurons in the sacral segments were not stained.
      The most prominent NADPH-d staining in the sacral segments occurred in fibers
      extending from Lissauer's tract through laminae I along the lateral edge of the
      dorsal horn to the region of the sacral parasympathetic nucleus (lateral
      collateral pathway of Lissauer). These fibers were prominent in the S1-S3
      segments but not in adjacent (L5-L7 and Cx1) or thoracolumbar segments. These
      NADPH-d fibers were, for the most part, not nNOS-immunoreactive, but did overlap
      with a prominent fiber bundle containing vasoactive intestinal polypeptide
      immunoreactivity in the sacral spinal cord. These results indicate that nitric
      oxide may function as a transmitter in thoracolumbar sympathetic preganglionic
      neurons, but not in sacral parasympathetic preganglionic neurons. Although the
      functional significance of the NADPH-d positive, nNOS-negative fiber bundle on
      the lateral edge of the sacral dorsal horn remains to be determined, this fiber
      tract may represent, in part, visceral afferent projections to the sacral
      parasympathetic nucleus.

PMID- 10580293
TI  - Extended angiotensin converting enzyme inhibition changes the innervation of
      renal glomerular afferent arterioles.
AB  - Chronic inhibition of the angiotensin I converting enzyme (ACE) with enalapril,
      results in a phenotypic change of the medial cells of renal afferent arterioles
      from contractile smooth muscle cells to renin containing epithelioid cells. In
      normal animals, the density of the innervation of the juxtaglomerular renin
      containing epithelioid cells is much lower compared to the contractile cells. The
      effector tissues are known to play an important role in determining the pattern
      and density of their innervation. In this study, we tested the hypothesis that
      the density of the innervation of the afferent arteriole smooth muscle cells
      decreases when they change their phenotype from contractile to renin containing
      epithelioid cells. The results show that the density of the innervation had
      significantly increased and the association of the terminals with the smooth
      muscle cells had changed. There were significantly more varicosities around renal
      afferent arterioles from rabbits treated with enalapril (10 microg/kg/h) for 6
      weeks (mean +/- SEM = 634 +/- 175 x 10(3)/mm2 vessel surface, cf. 329 +/- 69 x
      10(3)/mm2 vessel surface in untreated rabbits, P = 0.05), with the number of
      neuroeffector junctions remaining the same (124 +/- 14 and 164 +/- 32 x 10(3)/mm2
      vessel surface) and significantly more non-contacting varicosities (i.e. lying >
      100 nm from the medial cells) (74 +/- 5% and 25 +/- 7%, respectively; P = 0.003).
      Thus, there was no reduction in the innervation of afferent arterioles in which
      the smooth muscle cells had changed phenotype in response to enalapril treatment
      as hypothesised. Instead, it would appear that proliferation of the innervation
      had occurred, with the formation of additional varicosities but these
      varicosities failed to form neuromuscular junctions. This study has identified a
      form of neural plasticity in the kidney that has not previously been described.

PMID- 10580294
TI  - Modulation of sympathetic nerve activity by perivascular sensory nerves in the
      arterioles of the guinea-pig small intestine.
AB  - OBJECTIVE: The aim of this study was to assess the role of perivascular sensory
      nerves in modulating constrictions of intestinal submucosal arterioles. METHODS:
      Arteriole constrictions were induced either by nerve released adenosine 5'
      triphosphate (ATP) or exogenous ATP or phenylephrine (PE). Individual nerve
      shocks were used to elicit excitatory junction potentials (EJPs) in the arteriole
      smooth muscle whereas trains of stimuli were used to evoke transient
      constrictions of the arteriole. Effects of the sensory neurotoxin, capsaicin,
      were examined on constrictions and EJPs. RESULTS: Pre-treatment of the arteriole
      preparation with capsaicin did not cause any significant change in the amplitude
      of arteriole constrictions to exogenously applied ATP or PE. However, there was a
      significant increase in the amplitude of neurally evoked arteriole constrictions
      and EJPs, without a significant change in the decay time constant (tau(decay)) of
      the EJPs. Exogenous application of calcitonin gene related peptide (CGRP)
      significantly decreased tau(decay) of the EJPs without affecting their amplitude,
      whereas substance P (SP) significantly decreased the amplitude of EJPs without
      affecting tau(decay). Both, CGRP and SP, decreased the amplitude of neurally
      evoked and ATP induced constrictions. Whilst the inhibitory effects of CGRP on
      evoked and ATP induced constrictions were not significantly different, the
      reduction in evoked constrictions obtained with SP was significantly greater than
      the reduction in ATP induced constrictions. SP antagonist significantly increased
      the amplitude of neurally evoked constrictions. CONCLUSIONS: It is concluded that
      capsaicin-sensitive afferents inhibit the release of transmitter from
      perivascular sympathetic nerves via the prejunctional modulatory action of SP.
      The other putative sensory neurotransmitter, CGRP, appears to act
      postjunctionally on the arteriole smooth muscle.

PMID- 10580295
TI  - Morphology of aortic depressor nerve myelinated fibers in normotensive Wistar
      Kyoto and spontaneously hypertensive rats.
AB  - Reports on the morphology of the baroreceptor terminal of spontaneously
      hypertensive rats (SHR) did not demonstrate any difference when compared to the
      axonal terminal of normotensive rats. Although several studies reporting
      baroreceptor terminal and blood vessel wall morphology have been carried out to
      better understand the baroreceptor function and resetting to hypertensive levels,
      there are no reports examining the morphology of the fibers of the aortic
      depressor nerve (ADN) in hypertensive models. Therefore, the objective of the
      present study was to investigate the morphological aspects of SHR ADN compared to
      Wistar-Kyoto (WKY) rats. Before the morphologic study, the nerves were isolated
      and the pressure-nerve activity curve was determined for each ADN. SHR exhibited
      an increase in the threshold pressure for baroreceptor activation, a rightward
      shift in the pressure-nerve activity curve with decreases in slope and maximum
      activity. Semithin (0.3 to 0.5 microm thick) sections of the proximal (close to
      the nodose ganglion) and distal (close to the aortic arch) segments of the ADN
      were analyzed by light microscopy. A morphometric study of the nerve fascicles
      and myelinated fibers was performed. Comparison between proximal and distal
      segments of the two strains revealed that the ADN of WKY rats were consistently
      larger. All morphometric parameters studied in myelinated fibers and their
      respective axons were smaller in SHR. The area of the myelin sheath was
      comparatively larger in WKY rats. These data show morphologic differences between
      the ADN of SHR and WKY rats, which may explain, at least in part, the decreased
      slope and maximum activity of the pressure-nerve activity curve observed with the
      baroreceptor resetting in SHR.

PMID- 10580297
TI  - Physiological and anatomical studies of the development of the sympathetic
      innervation to rat iris arterioles.
AB  - The development of the sympathetic innervation to rat irideal arterioles has been
      investigated using histochemical and in vitro pharmacological and
      electrophysiological methods. A plexus of fibres and varicosities appeared over
      the surface of the vessels after the first postnatal week and increased to reach
      a maximum density during the fourth postnatal week. Transmural nerve stimulation
      produced small, consistent contractions that were first recorded in arterioles of
      7-day old rats. Contractions became larger and faster, reaching the adult form
      during the fourth postnatal week. Contractions became more sensitive to the
      alpha1-adrenoceptor antagonists, prazosin and naftopidil, and less sensitive to
      the alpha1A/D antagonist, WB4101 and alpha2 antagonist, yohimbine, during
      development. At both 10 and 21 days, contractile responses resulted from the
      release of intracellular calcium as they were abolished by caffeine (10(-3) M),
      thapsigargin (2 x 10(-6) M) and cyclopiazonic acid (3 x 10(-6) M), but not by
      nifedipine (10(-6) M). Intracellular recordings showed that nerve stimulation
      produced large, slow depolarizations at all ages tested. Time to peak potential
      decreased during development, while the amplitude of the depolarizations did not
      vary significantly. Results suggest that, throughout development, sympathetic
      nerves cause constriction of iris arterioles due to the release of noradrenaline
      and activation of alpha-adrenoceptors on the smooth muscle cells. Early responses
      involved both alpha1- and alpha2-adrenoceptors, while later responses were due to
      alpha1-adrenoceptors only. Irrespective of these changes in adrenoceptor
      subtypes, smooth muscle contraction resulted from the mobilization of
      intracellular calcium suggesting that both alpha1- and alpha2-adrenoceptors were
      coupled to pathways which accessed this source of calcium.

PMID- 10580296
TI  - c-Fos expression in the myenteric plexus, spinal cord and brainstem following
      injection of formalin in the rat colonic wall.
AB  - Fos expression induced by injection of dilute formalin (50 microl, 5% in
      physiological saline) into the colonic wall was examined in the myenteric plexus,
      lumbosacral spinal cord and brainstem of the rat. The aims of this study were (i)
      to determine whether neurons in these regions express Fos in response to the
      injection of formalin into the colon and (ii) to examine whether administration
      of an alpha 2 adrenoceptor agonist modulates Fos expression. Tissues were removed
      2 h after the injection of saline or formalin. Saline injected in the colon
      induced Fos in enteric glia in the myenteric plexus. The number of Fos
      immunoreactive nuclei significantly increased in both myenteric neurons and
      enteric glia after the injection of formalin. Similarly, Fos immunoreactive
      neuronal nuclei were significantly increased in the spinal cord, area postrema
      and nucleus of the solitary tract after the injection of formalin. Pretreatment
      of rats with the alpha 2 adrenoceptor agonist xylazine (2, 4 and 8 mg/kg) 15 min
      before the injection of formalin, dose-dependently reduced the number of Fos
      immunoreactive neuronal and glial nuclei in the myenteric plexus, and neuronal
      nuclei in the spinal cord and brainstem. Simultaneous administration of xylazine
      (8 mg/kg) and the alpha 2 adrenoceptor antagonist yohimbine (1 mg/kg) reversed
      the effects of xylazine in the spinal cord and brainstem, but not in the
      myenteric plexus. These data show that injection of formalin in the colonic wall
      results in Fos expression in myenteric neurons and enteric glia, and neurons in
      the spinal cord and brainstem. This may be due to the direct chemical stimulation
      of the innervation of the colon and/or the subsequent acute colitis. The observed
      neuronal Fos expression can be modulated by an alpha 2 adrenoceptor agonist
      through noradrenergic pathways and/or reduction of the excitability of the
      enteric neural circuitry.

PMID- 10580298
TI  - Vagal control of heart rate is modulated by extracellular potassium.
AB  - Heart rate (HR) recovery from heavy exercise is associated with a shift in
      cardiac sympatho-vagal balance and a transient hypokalaemia. Since changes in
      extracellular potassium ([K+]0) affect membrane currents in the sino-atrial node,
      in particular the acetylcholine-activated potassium current (I(K,ACh)), the
      hyperpolarization-activated current (I(f)) and the L-type calcium current
      (I(Ca,L)), we investigated whether mimicking [K+]0 concentrations seen during and
      immediately after exercise could directly modulate the HR response to vagal nerve
      stimulation (VNS) in the isolated guinea-pig atria preparation pre-stimulated
      with noradrenaline (NA, 1 microM). Lowering [K+]0 from 4 to 3 mM significantly
      enhanced the HR response to VNS (5 Hz, 5 V, 30 s, deltaHR 84.5 +/- 14.1 bpm and
      119.3 +/- 18.2 bpm, respectively). Increasing [K+]0 to 8 or 10 mM significantly
      decreased the drop in HR with VNS in comparison to the response to 3 mM K+ Tyrode
      (deltaHR 56.4 +/- 9.1 bpm and 52.1 +/- 8.7 bpm, respectively). These results
      could be simulated using the OXSOFT heart sino-atrial node computer model by
      activating I(K,ACh) during changes in [K+]0. However, changing [K+]0 in the model
      had no significant effect on the decrease in beating frequency brought about by
      decreasing I(f) or I(Ca,L). We conclude that the magnitude of the decrease in HR
      with VNS is enhanced in low [K +]0 and reduced in high [K+]0. The increased
      efficacy of cardiac vagal activation in low [K+]0 might therefore facilitate the
      drop in HR after heavy exercise where there is a transient hypokalaemia.
      Modelling suggests this result may be explained by the effects of changes in
      [K+]0 on the current-voltage relationship for I(K,ACh).

PMID- 10580299
TI  - Quantitative studies on myelinated and unmyelinated nerve fibres in the
      interatrial septal region of aged rat hearts.
AB  - Intracardiac nerve fibres from the interatrial septum were studied quantitatively
      and qualitatively by electron microscopy of transversely sectioned nerve bundles
      in male Wistar rats of 4 and 24 months. No significant changes were found in the
      myelinated fibre diameters, myelinated axon diameters, myelin sheath thicknesses,
      g ratios, myelinated fibre areas, unmyelinated axon diameters and unmyelinated
      axon areas. However, there was evidence of structural changes to the nerve fibres
      and Schwann cells at 4 and 24 months, increasing in prevalence with age: some
      myelinated fibres showed infolds, disruptions and clefts of the myelin sheath and
      accumulation of electron dense myelin-like fragments in the axoplasm.
      Unmyelinated axons showed fewer changes in structure but also contained similar
      fragments in the axoplasm. The numbers of neurotubules and neurofilaments per
      microm2 in unmyelinated intracardiac axons was significantly greater than in
      those in samples of the cervical vagal trunk. This may be an adaptation to the
      continuous mechanical stress experienced by these intracardiac nerves. It is
      concluded that there is little structural evidence to suggest that the conductive
      properties of intracardiac nerve fibres are adversely affected in aged rats.

PMID- 10580300
TI  - Effects of treatment of obstructive sleep apnea on circadian hemodynamics.
AB  - INTRODUCTION: The role of obstructive sleep apnea syndrome (OSAS) in the etiology
      of daytime hypertension is still an issue of debate, which is fed by the high
      prevalence of the syndrome in hypertensive patients. In this study the anti
      hypertensive effect of short-term treatment of obstructive sleep apnea with nasal
      continuous positive airway pressure (nCPAP) was assessed. PATIENTS AND METHODS:
      In eight patients with documented OSAS (mean apnea index 62 apneas/h), two 24-h
      continuous finger blood pressure registrations (Portapres) were performed. At
      baseline and after 3 weeks of treatment with nCPAP. Ten hypertensive control
      subjects were studied. Stroke volume (SV), cardiac output (CO) and total
      peripheral resistance (TPR) were assessed by pulse contour analysis. RESULTS:
      Hemodynamics were highly reproducible in the controls. nCPAP therapy improved
      apnea-activity in all OSAS patients. This was associated with a reduction of
      nighttime systolic (SBP), mean arterial (MAP) and diastolic blood pressure (DBP).
      Treatment also reduced daytime MAP by -11 mm Hg (ranging from -27 to 1; P <
      0.05), and DBP by -7 mm Hg (-24 to 3; P < 0.05). CO was significantly increased
      in daytime by 9% (-4 to 25; P < 0.05), whereas TPR was reduced by -15% (-34 to 3;
      P < 0.05). CONCLUSIONS: Treatment of OSAS caused a reduction in daytime MAP and
      DBP, associated with a reduction of vascular resistance. These findings are
      consistent with the hypothesis of a reduced sympathetic outflow at night after
      therapy of obstructive sleep apnea, carrying over to the day.

PMID- 10580301
TI  - Auditory brainstem responses in patients with autonomic failure with Parkinson's
      disease and multiple system atrophy.
AB  - Auditory brainstem responses (ABRs) were examined in six patients with autonomic
      failure with Parkinson's disease (AF with PD) and 10 patients with autonomic
      failure with multiple system atrophy (AF with MSA), all of which showed marked
      parkinsonian features as a principal sign. We designated the central
      abnormalities of ABRs as prolongation of latencies (wave III or V) and interpeak
      latencies (IPLs; I-III, I-V, and III-V IPL) or decreased amplitude ratios of wave
      III or V to those of wave I (less than 1.0). None of the patients with AF with PD
      showed abnormalities in ABRs. In contrast, in those with AF with MSA, the peak
      latencies or IPLs were prolonged in two of the 10 patients, and the amplitude
      ratios of wave III or V to those of wave I were decreased in other two of these
      patients. Moreover, both prolongation of latencies and a decreased ratio were
      observed in other one. Overall, five of the 10 patients with AF with MSA showed
      central abnormalities in ABRs. It is clinically difficult to differentiate AF
      with PD from AF with MSA, particularly when no cerebellar signs are apparent in
      AF with MSA patients. When central abnormalities of ABRs are observed in AF
      patients, AF with MSA should be suspected rather than AF with PD. In conclusion,
      ABRs provide useful information for the differential diagnosis of AF with PD and
      AF with MSA.

PMID- 10580302
TI  - Assessment of autonomic nervous system function in patients with Behcet' s
      disease by spectral analysis of heart rate variability.
AB  - The purpose of this study was to evaluate the autonomic nervous system (ANS)
      function in patients with Behcet's disease by using power spectral analysis of
      heart rate variability (HRV). The study population consisted of 71 patients with
      Behcet's disease, and 26 normal volunteers. HRV was measured by power spectral
      analysis in supine and standing position. In supine position, Behcet's patients
      had increased low frequency component in absolute (LF) and normalized units (LF
      nU) but had lower values of high frequency component in absolute (HF) and
      normalized units (HF nU) than the controls (P < 0.05). In standing position,
      higher values were obtained in LF and LF nU but lower values of HF and HF nU in
      Behcet's patients than controls (P < 0.05). LF/HF was significantly higher in
      patients both in supine (2.5 +/- 1.0 vs. 1.2 +/- 0.8, P = 0.001) and standing
      (21.9 +/- 7 vs. 1.8 +/- 0.3, P < 0.001) positions. Our data suggest that patients
      with Behcet's disease may have asymptomatic ANS dysfunction, which is in the form
      of increased sympathetic and decreased parasympathetic modulation, and power
      spectral analysis of HRV is beneficial in assessing the ANS function.

PMID- 10580303
TI  - Time-frequency mapping of R-R interval during complex partial seizures of
      temporal lobe origin.
AB  - BACKGROUND: Activation of autonomic nervous system is common with seizures. No
      reliable biological markers of impending seizures have been found. Evaluation of
      autonomic changes might help elucidate the transition from interictal to ictal
      states. METHODS: We studied twelve patients (eight females, four males), from 19
      to 62 years old with temporal lobe complex partial seizures (CPS). Dynamics of
      autonomic functions from oscillations in R-R interval (RRI) using time-frequency
      mapping based upon a Wigner distribution during pre-ictal, ictal and post-ictal
      periods. Oscillations in RRI at respiratory frequencies (RF) (> 0.1 Hz) are
      parasympathetically mediated and at nonrespiratory frequencies (NONRF) (0.01-0.09
      Hz) are under combined sympathetic and parasympathetic influence. RESULTS: CPS
      evoked marked autonomic imbalance and tachycardia. Spectral powers at both RF_RRI
      and NONRF_RRI increased over the pre-ictal period. RF_RRI power then fell rapidly
      over the 30 s before seizure onset and remained markedly reduced during seizure
      (P < 0.004). NONRF_RRI power reached a maximum at seizure onset and declined to a
      minimum before the seizure cessation (P < 0.05). CONCLUSION: Time-frequency
      analysis revealed that autonomic activation hallmarks clinical seizure onset for
      several minutes. After combined parasympathetic and sympathetic activation, rapid
      parasympathetic withdrawal occurred approximately 30 s before the seizure, and
      sympathetic activation peaks at seizure onset. Therefore, the transition from
      interictal to ictal states is relatively long and associated with subclinical
      autonomic changes.

PMID- 10580304
TI  - Proximate and evolutionary studies of anxiety, stress and depression: synergy at
      the interface.
AB  - While enormous progress has been made in unraveling the proximate physiological
      mechanisms that account for anxiety, stress, and low mood, these states continue
      to give rise to considerable conceptual confusion. This is, in part, because
      proximate studies have neither been adequately distinguished from, nor integrated
      with, evolutionary explanations for the adaptive functions of anxiety, stress,
      and mood. A complete biological explanation that incorporates both proximate and
      evolutionary explanations will be of great value to better define the border
      between normal and pathological, to help to explain why pathological anxiety and
      depression are so common, and to provide a much-needed basis for sensible
      decisions about when different pharmacological manipulations are likely to be
      helpful or harmful. Ideally, evolutionary considerations should provide a
      conceptual framework within which the biological significance of the proximate
      mechanisms can be better understood, and the proximate findings should provide
      tests of evolutionary hypotheses. Studies at the interface between evolutionary
      and proximate explanations will be difficult, but important to better understand
      individual differences in vulnerability and the etiology of diseases that result
      from dysregulation of anxiety and mood.

PMID- 10580305
TI  - Ethological research in clinical psychiatry: the study of nonverbal behavior
      during interviews.
AB  - Ethology is relevant to clinical psychiatry for two different reasons. First,
      ethology may contribute significantly to the development of more accurate and
      valid methods for measuring the behavior of persons with mental disorders.
      Second, ethology, as the evolutionary study of behavior, may provide psychiatry
      with a theoretical framework for integrating a functional perspective into the
      definition and clinical assessment of mental disorders. This article describes an
      ethological method for studying the nonverbal behavior of persons with mental
      disorders during clinical interviews and reviews the results derived from the
      application of this method in studies of patients who had a diagnosis of
      schizophrenia or depression. These findings and others that are emerging from
      current ethological research in psychiatry indicate that the ethological approach
      is not limited simply to a mere translation into quantitative and objective data
      of what clinicians already know on the basis of their judgment or the use of
      rating scales. Rather, it produces new insights on controversial aspects of
      psychiatric disorders. Although the impact of ethology on clinical psychiatry is
      still limited, recent developments in the fields of ethological and Darwinian
      psychiatry can revitalize the interest of clinical psychiatrists for ethology.

PMID- 10580306
TI  - Social stress, autonomic neural activation, and cardiac activity in rats.
AB  - Animal models of social stress represent a useful experimental tool to
      investigate the relationship between psychological stress, autonomic neural
      activity and cardiovascular disease. This paper summarizes the results obtained
      in a series of experiments performed on rats and aimed at verifying whether
      social challenges produce specific modifications in the autonomic neural control
      of heart rate and whether these changes can be detrimental for cardiac electrical
      stability. Short-term electrocardiographic recordings were performed via
      radiotelemetry and the autonomic input to the heart evaluated by means of time
      domain heart rate variability measures. Compared to other stress contexts, a
      social defeat experience produces a strong shift of autonomic balance toward
      sympathetic dominance, poorly antagonized by vagal rebound, and associated with
      the occurrence of cardiac tachyarrhythmias. These effects were particularly
      severe when a wild-type strain of rats was studied. The data also suggest that
      the cardiac autonomic responses produced by different types of social contexts
      (dominant-subordinate interaction, dominant-dominant confrontation, social
      defeat) are related to different degrees of emotional activation, which in turn
      are likely modulated by the social rank of the experimental animal and the
      opponent, the prior experience with the stressor, and the level of
      controllability over the stimulus.

PMID- 10580307
TI  - Coping styles in animals: current status in behavior and stress-physiology.
AB  - This paper summarizes the current views on coping styles as a useful concept in
      understanding individual adaptive capacity and vulnerability to stress-related
      disease. Studies in feral populations indicate the existence of a proactive and a
      reactive coping style. These coping styles seem to play a role in the population
      ecology of the species. Despite domestication, genetic selection and inbreeding,
      the same coping styles can, to some extent, also be observed in laboratory and
      farm animals. Coping styles are characterized by consistent behavioral and
      neuroendocrine characteristics, some of which seem to be causally linked to each
      other. Evidence is accumulating that the two coping styles might explain a
      differential vulnerability to stress mediated disease due to the differential
      adaptive value of the two coping styles and the accompanying neuroendocrine
      differentiation.

PMID- 10580308
TI  - Chronic psychosocial stress and antidepressant treatment in tree shrews: time
      dependent behavioral and endocrine effects.
AB  - Social defeat has been shown to cause a number of behavioral, physiological, and
      central nervous changes in male tree shrews. The present study was designed to
      assess: (i) a potential time lag in the occurrence of behavioral alterations
      (locomotor activity, self-grooming, marking behavior, food and water intake, and
      avoidance behavior) after stress and long-term antidepressant treatment; and (ii)
      to investigate potential interactions between behavioral and endocrine variables
      (urinary cortisol and norepinephrine). Male tree shrews were submitted to chronic
      psychosocial stress for 39 days. In this paradigm, the stress-induced behavioral
      and endocrine alterations in subordinate animals are based exclusively on the
      central nervous interpretation of the continuous visual presence of the dominant
      conspecific. During the last 29 days of stress exposure, the tricyclic
      antidepressant clomipramine was administered daily to the subordinate animals (50
      mg/kg, p.o). Results from this group were compared with three other experimental
      groups: one group was just stressed, one group received only clomipramine, and
      one group only vehicle. To determine the time-dependent effects of psychosocial
      stress and clomipramine treatment, behavior was recorded immediately after and 9
      h after daily social encounters. Depending on the observation time, significant
      differences between the effects of psychosocial stress and antidepressant
      treatment were found. Generally, the effect of stress on behavioral parameters
      tended to be less distinct immediately after the social encounter compared to the
      later observation time. Furthermore the drug had a time-dependent restorative
      influence on marking and grooming behavior, locomotor activity, avoidance
      behavior, as well as on urinary cortisol, and norepinephrine excretion.
      Correlation analysis revealed significant interdependencies between locomotor
      activity, marking behavior, and avoidance behavior on 1 day with cortisol and
      norepinephrine quantified in the morning urine of the following day. These
      findings indicate that experimental manipulations, stress, and psychotropic drug
      application have a time lag on bio-behavioral parameters which should be
      considered when studying animal behavior in response to stressors and/or to drug
      treatment.

PMID- 10580310
TI  - Selection, evolution of behavior and animal models in behavioral neuroscience.
AB  - We investigated whether genetic differences in various forms of intraspecific
      aggression and anxiety in four different genetic lines of mice (i.e. wild,
      outbred Swiss-CD1, inbred DBA/2 and inbred C57/BL6N) may reflect modifications in
      behavioral strategy. Experiments 1 and 2 used ethologically based paradigms to
      analyze aggressive and anxiety responses both in social (i.e. aggression) and non
      social (i.e. novel environment exploration) contexts. In Experiment 3, an
      anxiolytic drug (chlordiazepoxide (CDP)) was used to examine possible differences
      in proximal mechanisms underlying anxiety-related behaviors. The data show that
      intrasexual aggression, infanticide and maternal aggressions are related and
      covarying. Genetic lines with the highest levels of intermale attack (i.e. Wild
      and Swiss-CD1) also have highest levels of infanticide, interfemale attack and
      maternal aggression but, interestingly, the lowest levels of anxiety. In fact,
      exploratory behavior is lower and risk assessment behavior markedly higher in
      DBA/2 and C57/BL6N mice (i.e. the less aggressive strains) compared to Swiss and
      Wild genetic lines. Although reproductive status influences anxiety levels in
      female mice, our findings show that (contrary to previous studies) lactating mice
      are more anxious than virgin females in terms of risk assessment activities.
      These data demonstrate the importance of studying behavior in a more ecologically
      relevant context which emphasizes the function of behavior in a specific
      situation. Moreover, differential strain sensitivity to the behavioral effects of
      CDP suggests that genetic lines of mice may differ in the underlying mechanisms
      mediating behavior. It is therefore possible that artificial selection of
      different genotypes has resulted in differences in proximate mechanisms
      modulating the levels of aggression and anxiety, thereby leading to modification
      of social behavior. Overall, the results presented here suggest that subtle
      genetic alterations in specific underlying neural mechanisms are likely to cause
      profound effects on behavioral responses and their adaptive significance.
      Implications for behavioral neuroscience research that seeks to understand both
      the proximal and ultimate mechanisms of behavior are discussed.

PMID- 10580309
TI  - Effects of cortisol on brain alpha2-adrenoceptors: potential role in stress.
AB  - It has been proposed that behavioural changes induced by chronic psychosocial
      stress in male tree shrews might be related to alterations in the central nervous
      alpha2-adrenoceptor system. In the noradrenergic centres of the brain, alpha2
      adrenoceptors function as autoreceptors regulating noradrenaline release. Chronic
      stress downregulates these receptors in several brain regions. Since during
      stress, the activity of the hypothalamus-pituitary-adrenal axis is increased
      leading to high concentrations of plasma glucocorticoids, we investigated whether
      the effects of chronic stress can be mimicked by cortisol treatments. Two
      experiments were performed: a short-term treatment (males were injected i.v. with
      1.5 mg cortisol and brains were dissected 2 h later) and a long-term treatment
      (animals received the hormone in their drinking water for 5 days; daily uptake 3
      7 mg). The short-term treatment (injection), similar to the stress effects,
      downregulated alpha2-adrenoceptors in several brain regions. In contrast, the
      long-term oral treatment induced regional receptor upregulation. These data show:
      (i) that glucocorticoids regulate alpha2-adrenoceptors in the brain; (ii) that
      the duration and/or the route of cortisol application determines the results: and
      (iii) that chronic stress effects are not only due to the long-term
      glucocorticoid exposure, but also to other elements of the stress response.

PMID- 10580311
TI  - Influence of spatial and temporal manipulations on the anxiolytic efficacy of
      chlordiazepoxide in mice previously exposed to the elevated plus-maze.
AB  - It has been widely reported that the anxiolytic efficacy of benzodiazepines in
      the elevated plus-maze test is abolished in subjects (rats or mice) that have
      been given a single prior undrugged experience of the test apparatus. The present
      series of experiments was designed to further characterise the key experiential
      determinants of this intriguing phenomenon in Swiss Webster mice. Using a
      standard 5 min test duration for both trials, Experiment 1 confirmed the
      anxiolytic efficacy of chlordiazepoxide (CDP; 5-20 mg/kg) in mice naive to the
      plus-maze, but a virtual elimination of drug effects in animals that had been pre
      exposed to the maze 24 h earlier. Experiments 2 and 3 demonstrated that, while
      extending the duration of initial exposure to 10 min did not prevent the loss of
      CDP (10 mg/kg) efficacy in a standard-duration second trial, increasing the
      duration of both trials reinstated an anxiolytic profile for the compound.
      Finally, although trial 1 confinement to an open arm did not compromise CDP
      efficacy when animals were subsequently allowed to freely explore the maze
      (Experiment 4), closed arm confinement during initial exposure abolished the
      drug's anxiolytic action upon retest (Experiment 5). In contrast to previous
      findings in rats, these data suggest that the experientially induced loss of
      benzodiazepine efficacy in the mouse plus-maze depends rather critically upon
      prior discovery and exploration of relatively safe areas of the maze (i.e. closed
      arms). Results are discussed in relation to the hypothesis that the absence of an
      anxiolytic response to benzodiazepines in plus-maze-experienced subjects reflects
      the acquisition of an open arm phobia during trial 1.

PMID- 10580312
TI  - Cocaine potentiates defensive behaviors related to fear and anxiety.
AB  - Cocaine use has been associated with a number of psychiatric disturbances, and an
      emerging literature attests to its ability to enhance anxiety-like behaviors in
      animal models. Ethoexperimental analyses of defensive behaviors, and tests
      designed specifically to provide individual measures of these behaviors, have
      been shown to respond very selectively and appropriately to anxiolytic and
      panicogenic or panicolytic drugs, suggesting that these tests, and this approach,
      might provide a more detailed and comprehensive description of the emotionality
      effects of cocaine than is currently available. In a Mouse Defense Test Battery
      (MDTB) using mouse subjects and an anesthetized rat as the threat stimulus,
      cocaine consistently enhanced flight and escape, with effects seen at 10-30 mg/kg
      (i.p.) dose levels. The effect was so potent that a lack of cocaine effect on
      other behaviors may have been due to response competition, or to early distancing
      of cocaine-dosed subjects from the threat stimulus. In a Rat Runway Test (RRT)
      similar to the MDTB but with rat subjects, 4 mg/kg cocaine, i.v. produced an
      explosive, but well directed, flight response. Flight was still elevated,
      although of lesser magnitude than originally, 30 min. after the i.v. cocaine, and
      defensive threat/attack to the oncoming threat stimulus were also reliably
      increased. Cocaine enhancement of defense was also seen in tests of sniffing
      "stereotypy" in rats. Sniffing after 30 mg/kg cocaine, i.p. was found to be
      appropriately oriented toward the direction of incoming air flow, suggesting that
      it may be part of a defensive risk assessment pattern. In undosed rats, risk
      assessment is suppressed by the presence of high-magnitude threat stimuli such as
      a cat, and the same, durable, phenomenon was obtained after 30 mg/kg (i.p.)
      cocaine. Toy cat exposure initially suppressed sniffing in cocaine-dosed rats,
      but this suppression was removed and sniffing increased, over repeated dose/toy
      cat exposures. Crouching in the same animals over these testing regimes supported
      a "sniffing-suppression" interpretation of these changes and also provided data
      suggesting that cocaine may enhance crouching. These data, indicating that
      cocaine enhances a number of defensive behaviors--some more strikingly than
      others--have implications for the involvement of cocaine in defense-linked
      psychopathologies; and for the involvement of defense in both conditioning and
      "sensitization" phenomena associated with cocaine. These effects raise the issue
      of the relationship between the defense-enhancing and the reinforcing
      consequences of cocaine.

PMID- 10580313
TI  - Psychobiological risk factors for vulnerability to psychostimulants in human
      adolescents and animal models.
AB  - Adolescence is associated with an increased risk of developing drug
      abuse/dependence. During this ontogenetic phase, brain and hormonal systems are
      still undergoing crucial maturational rearrangements, which take place together
      with significant modifications in psychosocial development. However, the
      neurohormonal and behavioral facets of adolescence have been poorly investigated
      in relation to the vulnerability to psychostimulants such as MDMA ("Ecstasy") and
      amphetamine (AMPH). Novelty-seeking, a temperamental/behavioral trait that is
      typical of this age period, might substantially contribute to both psychological
      and psychobiological vulnerability. In humans, an elevated score of novelty
      sensation seeking and a derangement of monoaminergic function were both
      associated with late adolescence MDMA users compared to controls. In animal
      models of periadolescence, the search for novel stimuli and sensations actually
      shares a common neurobiological substrate (the reward-related brain mesolimbic
      pathways) with psychostimulants. The present review summarises recent work in
      mice, which indicates that periadolescent subjects are characterized by an
      unbalanced and "extremes-oriented" behavior and by elevated novelty-seeking
      compared to adults. Repeated and intermittent administration of cocaine or AMPH
      was associated with the development of a prominent locomotor sensitization in
      periadolescents, which failed to exhibit the marked sensitization of the
      stereotyped behavioral syndrome--possibly associated with poor welfare--that was
      typical of adults. A unique profile of integrated behavioral and physiological
      hyporesponsivity to both forced novelty and acute AMPH administration during
      periadolescence was also found. As a whole, these results, together with previous
      work on this topic, suggest that periadolescents may be more "protected" from
      AMPH-related aversive properties, and perhaps more vulnerable to the experience
      of internal states of reward, than older animals. Thus, the present animal model
      of adolescence seems to represent a reliable and useful method for the
      investigation of vulnerability to a variety of habit-forming agents or emotional
      experiences whose positive reinforcing properties may rely on common
      neurobiological substrates. A deeper understanding of psychostimulant effects
      during adolescence on the complex interaction between genetic, neurobiologic,
      psychosocial, and environmental factors will lead to earlier and more effective
      prevention and treatment.

PMID- 10580314
TI  - Prenatal exposure to endocrine disrupting chemicals: effects on behavioral
      development.
AB  - Numerous chemicals released into the environment by man are able to disrupt the
      functioning of the endocrine system by binding to hormonal receptors. Exposure to
      estrogenic endocrine disruptors during critical periods in fetal life can alter
      the development of reproductive organs, the neuroendocrine system and subsequent
      behavior. We present a series of studies on the effects of exposure during fetal
      life to low, environmentally relevant doses of two pesticides, o,p'DDT and
      methoxychlor, and of low doses of the synthetic estrogen, diethylstilbestrol on
      subsequent neuro-behavioral development in house mice. The main findings can be
      summarized as follows: (1) Mice prenatally exposed to methoxychlor showed changes
      in reflex development. Exposure to a very low dose of methoxychlor appeared to
      produce an increased reactivity during early postnatal life. (2) Methoxychlor
      exposed periadolescent mice showed a decreased reaction time exploring both a
      novel environment and a novel object. (3) The onset of male intrasex aggression
      appeared to be delayed in males prenatally exposed to low doses of methoxychlor,
      since exposed males showed low levels of aggressive interactions during early
      adolescence but not after they reached adulthood. (4) The rate of depositing
      urine marks in a novel environment was increased in males prenatally exposed to
      DES, and also to o,p'DDT and methoxychlor. (5) The proportion of both males and
      females attacking a same-sex conspecific was increased in mice prenatally exposed
      to low doses of DES and, marginally, to o,p'DDT. This effect appeared to be
      related to a decreased latency to attack. However, males prenatally exposed to
      o,p'DDT displayed a decreased intensity of aggression. The possible implications
      of perturbing the hormonal milieu during fetal development on the modulation of
      developmental turnpoints and future behavioral responses are discussed.

PMID- 10580315
TI  - Sickness and behaviour in animals: a motivational perspective.
AB  - Proinflammatory cytokines, produced by the activated immune system, induce a
      whole set of non-specific symptoms in the infected individual (i.e. hypophagia,
      adipsia, reduced social interest). However, evidence summarised in this review
      shows that behavioural changes induced by cytokines are not merely the
      consequence of a degraded state but reflect motivational reorganisation. If the
      set-up of these new priorities is expressed by a general decrease in behavioural
      activities (e.g. immobility, sleepiness), the sick individual remains
      nevertheless an open system still able to respond to environmental stimuli. If
      these cues are evaluated as relevant to the new priorities (e.g. cues from
      scattered pups or cues from nest material when ambient temperature is low), the
      sick individual interrupts sickness behaviour in order to respond specifically to
      the cues (e.g. retrieving of the pups or nest building). Once this is done, there
      is a return to recuperative behaviour. These findings represent a primary
      characterisation of biobehavioural action of immune stimuli, and they open new
      perspectives to facilitate further progress in our understanding of cytokine
      effects on behaviour.

PMID- 10580316
TI  - Parasites and behavior: an ethopharmacological analysis and biomedical
      implications.
AB  - Parasites and disease are increasingly recognized as agents of behavioral,
      ecological and evolutionary importance having a variety of influences on their
      hosts other than the more obvious pathological and immunological changes.
      Parasites can have significant behavioral effects even when parasitism is sub
      clinical with these effects proposed to either benefit the parasite (parasite
      'manipulation'), benefit the host, or to simply arise as side-effects of the
      infection (parasitic 'constraints'). However, until relatively recently little
      attention has been paid to the neuromodulatory substrates that mediate these
      behavioral changes. Ethopharmacology incorporates an evolutionary approach to the
      study of behavior with pharmacological analysis of neuromodulatory mechanisms. As
      such, this approach is appropriate for, and has been applied to, the analysis of
      the effects of ectoparasites (e.g. biting and blood-feeding flies) and
      endoparasites (e.g. protozoa, nematodes) on a number of behaviors (e.g. pain
      inhibition, learning and memory, responses to predators and anxiety, mate
      selection) in selected host-parasite systems. Ethopharmacology suggests a
      promising direction by which neuromodulatory mechanisms that underlie the effects
      of parasites on behavior, including that of humans, can be addressed.

PMID- 10580317
TI  - Advantages of bias and prejudice: an exploration of their neurocognitive
      templates.
AB  - Bias is common in mental-processing tasks as diverse as target recognition,
      heuristic estimation and social judgment. This paper holds that cognitive biases
      stem from the covert operation of neural modules, which evolved to subserve
      adaptive behavior. Such modules can be innate or forged early in development.
      Research shows links between (i) biases in cognitive tasks and (ii) neural
      devices, which may mediate them. Evidence is included from biases that arise
      spontaneously in artificial neural networks during recognition/decision tasks.
      Two linked propositions follow. First, there are continuities in biasing
      strategies across different levels of cognitive processing. Second, a proclivity
      for stereotyping and prejudice depends on the biased functions of lower-level
      neural modules that promote adaptations to social environments. The propositions
      rest on evidence of biological preparedness for stereotyping and of deficits in
      social judgment in patients with neurological lesions. To test such claims,
      research studies are suggested at the boundary of cognitive neuroscience and
      social psychology. Advantages of bias and prejudice as evolved tools may include
      their: (1) speeding of scrutiny and improving of target detection in changing or
      uncertain situations; (2) aiding of a rapid choice of practical short-term rather
      than optimal longer term plans; (3) allowing appraisal of a workable world by
      creating fairly stable categories; (4) motivating of exploration and completion
      of problem-solving which might otherwise be abandoned too early. The biological
      priming of social biases need not mean that they are immutable; understanding
      them could lead to better ways of controlling them.

PMID- 10580318
TI  - MR imaging of the liver: techniques and clinical applications.
AB  - With a recent advance of fast MR imaging techniques including fast gradient-echo
      (GRE), fast spin-echo (FSE), single shot FSE (SSFSE) and echo-planar imaging
      (EPI), and availability of a phased-array torso coil, there can be many possible
      pulse sequences for liver MR imaging. In clinical practice, optimization of pulse
      sequences is important for improving diagnostic performance of liver diseases. In
      this article, we review the current status of liver MR imaging, focusing on the
      description of standard pulse sequences, and the utility of fast scanning
      technique and contrast-enhancement studies.

PMID- 10580319
TI  - Computed tomography scan of the liver.
AB  - Computed tomography (CT) examination of the liver has continually been improving
      our understanding and assessment of liver disease since its introduction into
      clinical practice. The hallmark of the advances in CT imaging has undoubtably
      been helical CT, which made a great impact on body imaging with its many
      advantages, the most important being optimization of multiphasic enhanced
      studies, CT hepatic angiography (CTHA), and CT arterial portography (CTAP).
      Various applications and protocols of CT imaging rendering advantages and
      drawbacks to the technique are highlighted in this review article.

PMID- 10580320
TI  - Doppler sonography of the native liver.
AB  - Doppler sonography is being used routinely in evaluating the vascular structures
      of the native liver because of its ease of use, lower cost, easier availability,
      lack of need for X-ray and accuracy. Doppler sonography can well demonstrate the
      vascularization of liver tumors, portal vein thrombosis, portal vein
      abnormalities in patients with portal hypertension and hepatic venous findings in
      patients with Budd Chiari syndrome. The purpose of this article is to present
      information about Doppler sonography of the native liver and to show its
      usefulness in the evaluation of hepatic vascular diseases.

PMID- 10580321
TI  - The changing role of radiology in imaging liver tumors: an overview.
AB  - The surgical and the radiological advances in liver tumors in last two decades
      have made some malignant tumors operable which were considered inoperable and
      have completely changed the expectations from radiology. However, accurate
      staging, that is performed by imaging modalities, has critical importance in the
      selection of patients who can benefit from resection. Radiologists and referring
      physicians, therefore, should be aware of the current concepts in imaging liver
      tumors. This report updates both the changing role of radiology in hepatic
      neoplasms and the appropriate use of radiological modalities in liver tumors.

PMID- 10580322
TI  - Benign liver lesions: differentiation by magnetic resonance.
AB  - Optimal hepatic imaging involves both detection and characterization of focal
      lesions. Detection involves both determination of the presence of lesions and of
      their segmental extent of liver involvement. In the evaluation of hypervascular
      lesions, magnetic resonance imaging (MRI) has a greater impact on patient
      management than ultrasound (US) and computed tomography (CT). Most benign tumors
      are incidental findings and do not produce clinical symptoms. They must be
      accurately diagnosed without using aggressive procedures. Knowledge of their
      imaging features is essential to avoid unnecessary work-up and to minimize
      patient anxiety. In this article, the MR appearance, vascular and functional
      behavior of the most common benign liver tumors will be discussed.

PMID- 10580323
TI  - Focal inflammatory diseases of the liver.
AB  - Inflammatory lesions constitute an important subgroup of focal liver lesions.
      They may mimic primary or metastatic neoplastic lesions and their differentiation
      from neoplasia is clinically very important since management of the patient
      significantly changes. Radiologists should have an important role in both the
      diagnosis and therapy of these lesions by performing percutaneous aspirations and
      drainages. In this review we discussed the radiological findings of pyogenic
      abscesses, amebic abscesses, candidiasis, tuberculosis, hydatic cysts,
      fascioliasis, ascariasis, schistosomiasis, and sarcoidosis with a special
      emphasis on US, CT and MR characteristics.

PMID- 10580324
TI  - Percutaneous treatment of liver hydatid cysts.
AB  - Hydatic disease caused by Echinococcus granulosus is an endemic disease and an
      important public health problem in some countries of the world. The results of
      surgical treatment are associated with a high rate of mortality, morbidity,
      postoperative recurrence and a long period of hospital stay and the medical
      treatment results are still controversial. Although the percutaneous aspiration
      and treatment of liver hydatid cysts were considered to be contraindicated due to
      risks of anaphylactic shock and dissemination of clear-crystal fluid into the
      abdomen, several reports of successful percutaneous treatment of liver hydatid
      cysts have been published in the literature. Today, percutaneous treatment of
      liver hydatid cysts is the most effective and reliable treatment procedure in the
      selected cases. In this review, indications, contraindications, method and
      techniques, healing criteria, complications, results and importance of the
      percutaneous treatment of liver hydatid cysts are discussed.

PMID- 10580325
TI  - Hepatocellular carcinoma: treatment with transcatheter arterial
      chemoembolization.
AB  - This article presents a review of the literature regarding the use of
      transcatheter arterial chemoembolization (TACE) in the treatment of
      hepatocellular carcinoma (HCC). There have been two different approaches to the
      treatment: (a) percutaneous tumor ablation methods which can be divided into
      injectable and thermal methods; percutaneous ethanol injection (PEI) is the most
      widely used method, and (b) TACE. PEI is the treatment of choice for single HCCs
      smaller or equal to 3 cm in size. For patients with large HCCs combined TACE and
      PEI is probably the most effective nonsurgical treatment. In the presence of
      multiple HCC nodules, TACE remains the treatment of choice.

PMID- 10580326
TI  - Quiz-case 12. Intrabiliary rupture of the hydatid cyst.

PMID- 10580327
TI  - On the specificity of allene oxide cyclase.
AB  - Jasmonic acid is a carbocyclic fatty acid that is biosynthesized from alpha
      linolenic acid in several steps. The formation of the ring structure of jasmonic
      acid is catalyzed by the enzyme allene oxide cyclase (EC 5.3.99.6) and involves
      the cyclization of an unstable allene oxide into the cyclopentenone 12-oxo
      10,15(Z)-phytodienoic acid. In this study, a number of allene oxides were
      generated, and their enzymatic and nonenzymatic cyclization into cyclopentenones
      was investigated. Nonenzymatic cyclization was observed with allene oxides having
      one pair of conjugated double bonds and an additional isolated double bond in the
      beta,gamma position relative to the epoxide group, i.e., the partial structure
      4,5-epoxy-1,3,7-octatriene. Enzymatic cyclization took place provided that this
      structural element was inserted in the fatty acid chain with its epoxide group in
      the n-6,7 position and the isolated double bond in the n-3 position. A number of
      oxygenated fatty acids having structural features in common with the natural
      allene oxides were tested as inhibitors of allene oxide cyclase. Fatty acids
      having an allene oxide structure in the n-6,7 position but lacking the double
      bond in the n-3 position, as well as fatty acids having a saturated epoxide group
      in the n-6,7 position, served as competitive inhibitors of the enzyme. Data on
      the substrate specificity of allene oxide synthase (EC 4.2.1.92) from corn seeds
      indicated that fatty acid hydroperoxides with a double bond at n-3 and with the
      hydroperoxide function at n-6 exhibit the highest affinity but the slowest
      reaction velocity.

PMID- 10580328
TI  - Effects of conjugated linoleic acid on oxygen diffusion-concentration product and
      depletion in membranes by using electron spin resonance spin-label oximetry.
AB  - The effect of conjugated linoleic acid (CLA) on the relation between structure
      and function of membranes is described in this paper. Electron spin resonance
      (ESR) spin-label oximetry was used in the present study to evaluate if oxygen
      transport and oxygen depletion were affected by incorporation of CLA instead of
      linoleic acid into membrane phospholipids. Specifically, 1-stearoyl-2-(9cis, 11
      trans-octadecadienoyl)-phosphorylcholine (SCLAPC) was incorporated into soy plant
      phosphatidylcholine (soy PC) or egg yolk PC (EYPC) bilayers. The use of spin
      labels attached to different carbons along the fatty acid chain makes it possible
      to carry out structural and oximetric determinations with the same test sample.
      For example, the incorporation of 5 mol% SCLAPC increased the oxygen diffusion
      concentration product in soy PC or EYPC liposomes at 37 degrees C, slightly
      decreased the ordering of the hydrocarbon chains at the C10 and C12 positions (in
      the region of the conjugated double bonds), and increased the rate of oxygen
      depletion from the aqueous medium. Similar results were not obtained by
      incorporating 5 mol% of 1-stearoyl-2-linoleoyl-PC (SLPC). In our model system,
      free-radical generation was initiated by extended incubation of the liposomes, by
      induction by 2,2'-azobis(2-amidinopropane)hydrochloride, or by ultraviolet
      irradiation of H2O2. The rate of consumption of molecular oxygen was studied by
      monitoring the oxygen concentration in the aqueous phases of the liposomes. The
      effect of 5 mol% SCLAPC in soy PC was significantly larger than 5 mol% SLPC in
      soy PC; the response patterns with soy PC and EYPC were similar. Furthermore, 5
      mol% SCLAPC in 1-palmitoyl-2-linoleoyl-PC showed similar oxygen consumption to
      that observed with 5 mol% SCLAPC in EYPC. On the other hand, 5 mol% SCLAPC in
      synthetic PC membranes containing saturated or monounsaturated fatty acids showed
      low oxygen depletion rates. The perturbation of membrane structure and the
      increase of the relative oxygen diffusion-concentration products provided a
      potential mechanism by which CLA incorporated into membrane lipids could affect
      oxidative stress.

PMID- 10580329
TI  - Interaction of curcumin with human serum albumin--a spectroscopic study.
AB  - Curcumin (diferuloyl methane) has a wide range of physiological and
      pharmacological actions. Curcumin interaction with human serum albumin (HSA) has
      been followed by fluorescence quenching and circular dichroism (CD) measurements.
      Based on fluorescence measurements, the equilibrium constant for the interaction
      is 2.0+/-0.2x10(5) M(-1). Binding of curcumin to HSA induces an extrinsic CD band
      in the visible region. From the induced CD band measurements, the equilibrium
      constant has a value of 2.1+/-0.3x10(4) M(-1). Thus, HSA has two kinds of
      affinity sites for curcumin, one with high affinity and the other with lower
      affinity. Job's plot indicated a binding stoichiometry of 1:1 for the high
      affinity site. The equilibrium constant was invariant with temperature in the
      range of 15 to 45 degrees C, suggesting the role of hydrophobic interactions in
      the binding of curcumin to HSA. Curcumin does not change the conformation of the
      HSA molecule. These measurements have implications in the understanding of the
      curcumin transport under physiological conditions.

PMID- 10580330
TI  - Solubilization and stabilization of carotenoids using micelles: delivery of
      lycopene to cells in culture.
AB  - The use of the organic cosolvents tetrahydrofuran and dimethylsulfoxide was found
      to be unsuitable for prostate tumor cell cultures because of solvent cytotoxicity
      and the poor solubility and instability of lycopene. For example, the half-life
      of lycopene in organic/aqueous solution was found to be less than 2 h. Therefore,
      a micellar preparation of lycopene was developed for the solubilization and
      stabilization of lycopene in cell culture media. Neither the micelles themselves
      nor lycopene solubilized in micelles at concentrations up to 10 microg/mL in the
      cell culture media produced cytotoxicity or inhibition of cell proliferation in
      either LNCaP human prostate cells or Hs888Lu human lung cells. Lycopene
      solubilized in micelles was stable for at least 96 h under standard cell culture
      conditions so that a constant lycopene supply could be provided to the cells.
      During the culture process, lycopene was taken up by LNCaP cells and reached a
      plateau at approximately 12 h. Micelles provide a convenient, inexpensive, and
      nontoxic vehicle for dissolving and stabilizing carotenes such as lycopene in
      tissue culture media and then delivering them to cells growing in culture.

PMID- 10580331
TI  - Regulation of mevalonate synthesis in low density lipoprotein receptor knockout
      mice fed n-3 or n-6 polyunsaturated fatty acids.
AB  - 3-Hydroxy-3-methylglutaryl (HMG)-CoA reductase, the rate-limiting enzyme in
      cholesterol biosynthesis, catalyzes the formation of mevalonate which is also
      required for cell proliferation. Changes in HMG-CoA reductase may mediate the
      differential effects of n-3 and n-6 polyunsaturated fatty acids (PUFA) on
      experimental mammary tumorigenesis, but the mechanisms by which these fatty acids
      regulate HMG-CoA reductase are unclear. To determine whether the low density
      lipoprotein receptor (LDL-R) is required for this regulation, groups of female
      LDL-R knockout (-/-) and wild-type (+/+) mice were fed 7% fat diets rich in
      either n-3 (menhaden oil) or n-6 (safflower oil) PUFA for 1 wk. Dietary PUFA and
      deletion of the LDL-R had independent effects on HMG-CoA reductase and serum
      lipids, and a significant diet-gene interaction was observed. The effects of PUFA
      on HMG-CoA reductase in the mammary gland, but not the liver, were mediated by
      the LDL-R. We also observed that differences in HMG-CoA reductase and serum LDL
      cholesterol, high density lipoprotein cholesterol, and triglycerides between -/-
      and +/+ mice were dependent on whether the mice were fed n-3 or n-6 PUFA.
      Differences between -/- and +/+ mice were much greater when animals were fed n-6
      PUFA rather than n-3 PUFA. These results show that the LDL-R mediates the effects
      of PUFA on HMG-CoA reductase in the mammary gland but not the liver. Furthermore,
      the composition of dietary PUFA profoundly influences the effects of deleting the
      LDL-R on HMG-CoA reductase and serum lipids and suggests that diet may influence
      the phenotype of other knock-out or transgenic animals.

PMID- 10580332
TI  - Synthesis and estimation of calorific value of a structured lipid-potential
      reduced calorie fat.
AB  - The majority of reduced calorie fats and fat substitutes available today, though
      similar in texture and flavor to natural fats, contain fatty acids that are not
      usually present in edible oils and fats and thus do not fully match the chemistry
      and functions of natural fats. For example, such products do not provide
      nutritionally important essential fatty acids (EFA). In this investigation, we
      prepared and evaluated a reduced calorie fat, prepared entirely from natural
      fats, taking advantage of the fact that long-chain saturated fatty acids (LCSFA),
      such as behenic acid (22:0), are poorly absorbed. Mustard oil (MO) and sunflower
      oil (SO) were used as substrates to yield a structured lipid (SL). The product,
      being derived from a natural vegetable oil, would thus provide EFA, as would a
      native fat, a feature not provided by the low-calorie fats available in the
      market. Erucic acid (22:1) was isolated from MO by a lipase (EC 3.1.1.3)
      catalyzed reaction. It was then hydrogenated to behenic acid, the ethyl ester of
      which was subsequently enzymatically transesterified with SO to yield a plastic
      fat containing about 30-35% behenic acid. Absorption of this fat was studied in
      Wistar rats. In a preliminary single oral dose experiment, rats were fed equal
      amounts (2 mL) of SO and the SL. Plasma triacylglycerol (TAG) levels were
      estimated after 1, 2, and 3 h of feeding. The significantly lower concentration
      of plasma TAG in the 2-h sample, observed in the SL-fed group compared to the SO
      fed group (P<0.001), indicated poor absorption of the SL. In order to estimate
      the calorific value of the SL, we conducted a restricted diet growth experiment
      over 21 d on weanling Wistar male rats with SO as caloric control. Diets for the
      test groups were modified by adding 5, 10, and 15% SO for the control groups, and
      5 and 10% SL for the experimental groups. Food consumption of the test groups was
      restricted to 50% of the feed containing 5% SO that had been consumed by the ad
      libitum group the previous day. Body weights were recorded during the experiment.
      Calorific value of the SL was estimated by comparing the 21 st-d mean body weight
      gain of the control group with that of the experimental group. Estimated
      calorific value of the SL was 5.36 kcal/g. Most of the behenic acid fed was
      excreted, as indicated by the analysis of the fatty acids of plasma and fecal
      total lipid. A second growth experiment on ad libitum diet was conducted over 21
      d on weanling Wistar male rats to compare the absorption behavior of the SL with
      that of natural oil. SO (10%) was added to the diet of the control group, and SL
      (10%) was added to the diet of the experimental group. Feed consumption, as well
      as body weights, was recorded during the experiment. The growth pattern of the
      experimental group was identical to that of the control group during the period
      of study. The mean feed intake (9.8 g/d/rat for the control group vs. 9.9 g/d/rat
      for the experimental group) indicated good palatability of the product. In
      conclusion, the enzymatically synthesized SL containing EFA and natural
      antioxidants has nutritional properties almost identical to those of natural
      fats, and can be used as a reduced calorie fat.

PMID- 10580333
TI  - Effects of gamma-linolenic acid and docosahexaenoic acid in formulae on brain
      fatty acid composition in artificially reared rats.
AB  - This study evaluated the effects of dietary supplementation with gamma-linolenic
      acid (GLA, 18:3n-6) and docosahexaenoic acid (DHA, 22:6n-3) on the fatty acid
      composition of the neonatal brain in gastrostomized rat pups reared artificially
      from days 5-18. These pups were fed rat milk substitutes containing fats that
      provided 10% linoleic acid and 1% alpha-linolenic acid (% fatty acids) and, using
      a 2x3 factorial design, one of two levels of DHA (0.5 and 2.5%), and one of three
      levels of GLA (0.5, 1.0, and 3.0%). A seventh artificially reared group served as
      a reference group and was fed 0.5% DHA and 0.5% arachidonic acid (AA, 20:4n-6);
      these levels are within the range of those found in rat milk. The eighth group,
      the suckled control group, was reared by nursing dams fed a standard American
      Institute of Nutrition 93M chow. The fatty acid composition of the
      phosphatidylethanolamine, phosphatidylcholine, and
      phosphatidylserine/phosphatidylinositol membrane fractions of the forebrain on
      day 18 reflected the dietary composition in that high levels of dietary DHA
      resulted in increases in DHA but decreases in 22:4n-6 and 22:5n-6 in brain. High
      levels of GLA increased 22:4n-6 but, in contrast to previous findings with high
      levels of AA, did not decrease levels of DHA. These results suggest that dietary
      GLA, during development, differs from high dietary levels of AA in that it does
      not lead to reductions in brain DHA.

PMID- 10580334
TI  - Infant cerebellar gray and white matter fatty acids in relation to age and diet.
AB  - There is little evidence as to the fatty acid composition of the cerebellum in
      infancy and it remains uncertain whether milk diet can influence its composition.
      We therefore examined cerebellar gray and white matter of infants less than 6
      month old who had died unexpectedly. The fatty acid content of 33 gray and 21
      white matter specimens from infants born at term and 6 gray and 5 white matter
      specimens from preterm infants was assessed by gas chromatographic/mass
      spectrometric analysis. Infants were grouped according to whether they had
      received human or manufactured formula milk. Whereas cerebellar cortex
      docosahexaenoic acid (DHA, 22:6n-3) concentrations were significantly lower
      (P<0.01) in the formula-fed than breast-fed infants, no differences existed
      between the term (n = 10) and preterm (n = 5) Synthetic Milk Adapted [corrected]
      (SMA) formula-fed infants. Cerebellar white matter DHA concentrations were
      similarly lower (P<0.01) in the SMA formula-fed infants (n = 8) than in an age
      matched breast-fed group. Low concentrations of cerebellar white matter
      lignoceric (24:0) and nervonic acid (24:1n-9) in two 7-wk-old preterm infants
      appeared to correlate with postgestational rather than chronological age. Dietary
      long-chain polyunsaturated fatty acids, particularly DHA, are probably essential
      for normal development of the infant cerebellum.

PMID- 10580335
TI  - Influence of diet on fatty acids of three subtropical fish, subfamily Caesioninae
      (Caesio diagramma and C. tile) and family Siganidae (Siganus canaliculatus).
AB  - The total lipid and fatty acid compositions of tissues and the stomach contents
      of three subtropical marine fish species, subfamily Caesioninae, Caesio diagramma
      and C. tile, and family Siganidae Siganus canaliculatus, were investigated to
      clarify the differences between these species. Triacylglycerols (TAG) were the
      dominant depot lipids of the three species, whereas wax esters were found as a
      minor component. In particular, muscle lipids were found to contain mainly
      glycerol derivatives such as TAG and phospholipids. The major fatty acids
      identified in the three species were 16:0, 18:0, 18:1 n-9, and 22:6n-3
      (docosahexaenoic acid, DHA). In addition, noticeable levels of 16:1 n-7, 18:1 n
      7, 20:4n-6 (arachidonic acid, AA), and 20:5n-3 (eicosapentaenoic acid) were
      found. DHA was the most abundant polyunsaturated fatty acid (PUFA) in the muscle
      and viscera lipids of the three species. The high DHA levels in the lipids of all
      the organs were found to be higher than those of the lipid extracted from the
      stomach contents of the three fishes. In addition, the specimens of S.
      canaliculatus contained significantly higher levels of AA in its tissues than did
      the other two species. A high AA content is unusual since such high levels of n-6
      PUFA are rarely found in higher marine organisms. These levels may be due to its
      characteristic feeding pattern, because S. canaliculatus prefer and mainly feed
      on seaweed, which often contains high amounts of n-6 PUFA, such as linoleic acid
      (18:2n-6) and AA.

PMID- 10580337
TI  - Lipids of the pawpaw fruit: Asimina triloba.
AB  - The fatty acid composition and structure of pawpaw fruit (Asimina triloba)
      triglycerides were examined and found to contain fatty acids ranging from C6 to
      C20. Octanoate represented 20% of the fatty acids while other medium-chain fatty
      acids were present in low amounts. Analysis of the intact triglycerides by high
      temperature gas-liquid chromatography gave an unusual three-cycle carbon number
      distribution. Analysis of triglyceride fractions separated according to degree of
      unsaturation suggested that one octanoate was paired with diglyceride species
      containing long-chain fatty acids. Determination of the double-bond positions of
      monoene fatty acids revealed cis delta9 and cis delta11 hexadecenoate and cis
      delta9, cis delta11, and cis delta13 octadecenoate isomers were present in
      significant quantities. Octanoate and positional monoene fatty acid isomers were
      found only in the fruit lipids and not in the seed lipids. Phenacyl esters of
      fatty acids were found to be useful derivatives for structure determination using
      multiple types of analyses.

PMID- 10580336
TI  - Arachidonic, eicosapentaenoic, and biosynthetically related fatty acids in the
      seed lipids from a primitive gymnosperm, Agathis robusta.
AB  - The fatty acid composition of the seeds from Agathis robusta, an Australian
      gymnosperm (Araucariaceae), was determined by a combination of chromatographic
      and spectrometric techniques. These enabled the identification of small amounts
      of arachidonic (5,8,11,14-20:4) and eicosapentaenoic (5,8,11,14,17-20:5) acids
      for the first time in the seed oil of a higher plant. They were apparently
      derived from gamma-linolenic (6,9,12-18:3) and stearidonic (6,9,12,15-18:4)
      acids, which were also present, via chain elongation and desaturation, together
      with other expected biosynthetic intermediates [bis-homo-gamma-linolenic (8,11,14
      20:3) and bishomo-stearidonic (8,11,14,17-20:4) acids]. Also present were a
      number of C20 fatty acids, known to occur in most gymnosperm families, i.e., 5,11
      20:2, 11,14-20:2 (bishomo-linoleic), 5,11,14-20:3 (sciadonic), 11,14,17-20:3
      (bishomo-alpha-linolenic), and 5,11,14,17-20:4 (juniperonic) acids. In contrast
      to most other gymnosperm seed lipids analyzed so far, A. robusta seed lipids did
      not contain C18 delta5-desaturated acids [i.e., 5,9-18:2 (taxoleic), 5,9,12-18:3
      (pinolenic), or 5,9,12,15-18:4 (coniferonic)]. These structures support the
      simultaneous existence of delta6- and delta5-desaturase activities in A. robusta
      seeds. The delta6-ethylenic bond is apparently introduced into C18
      polyunsaturated acids, whereas the delta5-ethylenic bond is introduced into C20
      polyunsaturated acids. A general metabolic pathway for the biosynthesis of
      unsaturated fatty acids in gymnosperm seeds is proposed. When compared to
      Bryophytes, Pteridophytes (known to contain arachidonic and eicosapentaenoic
      acids), and species from other gymnosperm families (without such acids), A.
      robusta appears as an "intermediate," with the C18 delta6-desaturase/C18-->C20
      elongase/C20 delta5-desaturase system in common with the former subphyla, and the
      unsaturated C18-->C20 elongase/C20 delta5-desaturase system specific to
      gymnosperms. The following hypothetical evolutionary sequence for the C18
      delta6/delta5-desaturase class in gymnosperm seeds is suggested: delta6 (initial)
      ->delta6/delta5 (intermediate)-->delta5 (final).

PMID- 10580338
TI  - Stability of cyclopropane and conjugated linoleic acids during fatty acid
      quantification in lactic acid bacteria.
AB  - Seven methods commonly used for fatty acid analysis of microorganisms and foods
      were compared to establish the best for the analysis of lyophilized lactic acid
      bacteria. One of these methods involves fat extraction followed by methylation of
      fatty acids, while the other methods use a direct methylation of the samples,
      under different operating conditions (e.g., reaction temperature and time,
      reagents, and pH). Fatty acid methyl esters were identified by gas chromatography
      mass spectrometry and quantified by on-column capillary gas chromatography. Two
      reliable methods for the analysis of fatty acids in bacteria were selected and
      further improved. They guarantee high recovery of classes of fragile fatty acids,
      such as cyclopropane and conjugated acids, and a high degree of methylation for
      all types of fatty acid esters. These two direct methylation methods have already
      been successfully applied to the analysis of fatty acids in foods. They represent
      a rapid and highly reliable alternative to classical time- and solvent-consuming
      methods and they give the fatty acid profile and the amount of each fatty acid.
      Using these methods, conjugated linoleic acids were identified and quantified in
      lactic acid bacteria.

PMID- 10580339
TI  - Synthesis of trans-4,5-epoxy-(E)-2-decenal and its deuterated analog used for the
      development of a sensitive and selective quantification method based on isotope
      dilution assay with negative chemical ionization.
AB  - The volatile compound trans-4,5-epoxy-(E)-2-decenal (1) was synthesized in two
      steps with good overall yields. The newly developed method is based on trans
      epoxidation of (E)-2-octenal with alkaline hydrogen peroxide followed by a Wittig
      type chain elongation with the ylide formylmethylene triphenylphosphorane. For
      the synthesis of [4,5-2H2]-trans-4,5-epoxy-(E)-2-decenal (d-1), [2,3-2H2]-(E)-2
      octenal was prepared by reduction of 2-octyn-1-ol with lithium aluminum deuteride
      and subsequent oxidation of [2,3-2H2]-(E)-2-octen-1-ol with manganese oxide.
      Compound d1 was used as internal standard for the quantification of 1 by isotope
      dilution assay. Among various mass spectrometry (MS) ionization techniques
      tested, negative chemical ionization with ammonia as reagent gas gave best
      results with respect to both sensitivity and selectivity. The detection limit was
      found to be at about 1 pg of the analyte introduced into the gas chromatography
      MS system.

PMID- 10580340
TI  - Islet transplantation.

PMID- 10580341
TI  - Increased myogenic potential and fusion of matrilysin-expressing myoblasts
      transplanted in mice.
AB  - The success of myoblast transplantation in clinical trials has been limited in
      part by the low dispersion of grafted cells outside the injection site. Our
      research group previously reported that the culture of myoblasts with
      concanavalin A, a stimulator of metalloproteinase production, increased their
      migration. Several lines of evidence also suggested that muscle cell fusion
      involves metalloproteinase-sensitive mechanisms. To determine whether the
      increased expression of metalloproteinases had an influence on myoblast fusion
      and dispersion through the muscle following transplantation, we generated a
      myoblast cell line expressing human matrilysin (MMP-7). The MMP-7-expressing
      myoblasts were obtained by the stable transfection of a matrilysin expression
      vector in a TnILacZ immortomouse myoblast clone. Matrilysin-expressing myoblasts
      showed a highly increased in vitro fusion index, forming seven times (p < 0.001)
      more myotubes than the control cell line and three times (p < 0.001) more
      myotubes than the Immortomyoblast parental clone. Single-site transplantation of
      matrilysin-expressing myoblasts generated more fibers (p < 0.001), over a greater
      surface (p < 0.001) than the control cell line. The cotransplantation of
      matrilysin-expressing myoblasts and of normal human myoblasts in SCID mice
      increased the number of human dystrophin-positive fibers and myotubes by sixfold.
      Although no significant increased migration of myoblasts outside the injection
      sites was observed, our results show that the metalloproteinase activity can
      improve the myogenic potential of myoblasts in vitro and the fusion of myoblasts
      with host fibers in vivo. MMP-7 expression may be useful in increasing myoblast
      transplantation success.

PMID- 10580342
TI  - Fabrication of compliant hybrid grafts supported with elastomeric meshes.
AB  - We devised tubular hybrid medial tissues with mechanical properties similar to
      those of native arteries, which were composed of bovine smooth muscle cells
      (SMCs) and type I collagen with minimal reinforcement with knitted fabric meshes
      made of synthetic elastomers. Three hybrid medial tissue models that incorporated
      segmented polyester (mesh A) or polyurethane-nylon (mesh B) meshes were designed:
      the inner, sandwich, and wrapping models. Hybrid medial tissues were prepared by
      pouring a cold mixed solution of SMCs and collagen into a tubular glass mold
      consisting of an inner mandrel and an outer sheath and subsequent thermal
      gelation, followed by further culture for 7 days. For the inner model, the
      mandrel was wrapped with a mesh. For the sandwich model, a cylindrically shaped
      mesh was incorporated into a space between the mandrel and the sheath. The
      wrapping model was prepared by wrapping a 7-day-incubated nonmesh gel with a
      mesh. The inner diameter was 3 mm, irrespective of the model, and the length was
      2.5-4.0 cm, depending on the model. The intraluminal pressure-external diameter
      relationship showed that nonmesh and inner models had a very low burst strength
      below 50 mmHg, while the sandwich model ruptured at around 110-120 mmHg; no
      rupturing below 240 mmHg was observed for the wrapping model, regardless of the
      type of mesh used. Compliance values of wrapping and sandwich models were close
      to those of native arteries. Pressure-dependent distensibility characteristics
      similar to native arteries were observed for a mesh A wrapping model, whereas a
      mesh B wrapping model expanded almost linearly as intraluminal pressure
      increased, which appeared to be due to elasticity of the incorporated mesh. Thus,
      design criteria for hybrid vascular grafts with appropriate biomechanical
      matching with host arteries were established. Such hybrid grafts may be
      mechanically adapted in an arterial system.

PMID- 10580343
TI  - Lack of effect of short-term depletion of plasma complement C3 on the survival of
      syngeneic dopaminergic neurons following grafting into the intact rat striatum.
AB  - Metabolically compromised cells may be subject to complement-mediated
      cytotoxicity. The aim of this study was to clarify to what extent plasma
      complement C3 might contribute to the low survival (5-20%) of grafted
      dopaminergic neurons. The survival of intrastriatal cell suspension grafts of
      syngeneic dopaminergic, tyrosine hydroxylase (TH)-containing neurons was compared
      in rats subjected to short-term i.v. treatment with 1) cobra venom factor (CVF),
      or 2) placebo treatment. Depletion of plasma complement C3 by CVF was confirmed
      by crossed immunoelectrophoresis. With 159 +/- 37 (mean +/- SEM) TH
      immunoreactive and 154 + /- 40 TH mRNA-expressing neurons in the CVF-treated rats
      (n = 9), and 117 +/- 34 TH-immunoreactive and 160 +/- 49 TH mRNA-expressing
      neurons in placebo rats (n = 6), the CVF treatment did not increase the survival
      of the grafted dopaminergic neurons. Similarly, CVF had no apparent effect on the
      astroglial, microglial, or oligodendroglial cell response within and around the
      graft. The data indicate that depletion of plasma complement C3 at the time of
      grafting has no effect on the long-term survival of syngeneic ventral
      mesencephalic dopaminergic neuronal grafts.

PMID- 10580344
TI  - Characterization of iris pigment epithelial cell for auto cell transplantation.
AB  - To establish auto iris pigment epithelial (IPE) transplantation, we characterized
      the properties of IPE cells and the method of culture using auto serum. Monkey
      and human IPE cells were obtained and cultured in several conditions, using auto,
      mouse, rabbit, bovine, or human serum. Immunocytochemical study was performed to
      confirm that the cells were epithelial in origin. The proliferation rate of the
      IPE was also calculated from fresh human IPE cells, which were obtained during
      filtering glaucoma surgery. Proliferation rate was also compared to that of
      retinal pigment epithelial (RPE) cells. Reverse-transcriptase and polymerase
      chain reaction for melanogenesis was performed, and the amount of pigment in the
      IPE cells was also calculated. Mouse and rabbit sera were not effective for the
      monkey IPE cell culture. Conversely, the cells grew well in the medium with auto,
      bovine, or human serum. Human IPE cells grew exponentially by the described
      methods and reached to 60,000 cells after about 4-5 weeks. When we compared them
      by proliferation rate, IPE cells were less proliferative than RPE cells. The gene
      expression for melanogenesis and the amount of pigment in the IPE gradually
      decreased through successive passages. Transplantation has been tried for the
      treatment of age-related macular degeneration using RPE from fetus or from eye
      bank eyes. However, focal rejection may play an important role in the clinical
      results. The establishment of auto IPE cell transplantation may improve the
      problem of rejection. In the present study, we established auto IPE cell culture
      using auto serum. The cultured IPE cell showed pigment epithelial cell properties
      until around five passages in both human and monkey.

PMID- 10580345
TI  - High variability in rabbit bone marrow-derived mesenchymal cell preparations.
AB  - The rabbit has been extensively used for preclinical models, especially in
      orthopedic applications. One of the more troubling features of this model is the
      high interindividual variability that is encountered and that requires a careful
      experimental design with sufficient sample size to make judgments valid. We have
      processed 241 individual preparations of rabbit bone marrow-derived mesenchymal
      progenitor cells (MPCs) over the last 3 years and have kept detailed records of
      the performance of these cells in various assays. This communication details the
      lack of correlation between the analyzed parameters. Bone marrow was harvested
      from 4-month-old rabbits; the cells were centrifuged, resuspended, and cultured.
      When cells reached 80% of confluence, they were removed from the plates with
      trypsin and assayed for their osteo- and chondrogenic potential. The average
      yield of the 241 individual MPC preparations exhibited a coefficient of variation
      of 77. An in vivo implantation assay with porous calcium phosphate ceramic cubes
      exhibited scores with a coefficient of variation of 65. Lastly, an in vitro assay
      of alkaline phosphatase enzyme activity exhibited the most variability with a
      coefficient of variation of 132. All of the cell preparations tested in an in
      vitro aggregate culture assay underwent chondrogenic differentiation. No
      relationships between any of these parameters were found. The variability of the
      results within the different assays is interpreted to be the result of the
      heterogeneity of the preparations. The lack of correlation between the parameters
      studied shows the importance of the conditions intrinsic to the different assays.
      These results serve to emphasize that any experimental design involving rabbit
      progenitor cells must include a sufficiently large sample size to allow
      statistically significant and rigorous conclusions.

PMID- 10580346
TI  - Freezing characteristics of genetically modified lymphocytes for the treatment of
      MPS II.
AB  - The freezing characteristics of genetically modified lymphocytes obtained from a
      donor with mucopolysaccharidosis type II (MPS II) were determined using
      cryomicroscopy and controlled rate freezing studies to determine postthaw
      viability. The cells from a donor with MPS II used in this investigation were
      cultured and transduced with a retroviral vector for the iduronate-2-sulfatase
      (IDS) enzyme for clinical studies for human gene therapy. The water transport and
      intracellular ice formation (IIF) characteristics of the cells were determined
      after completion of the culture and transduction protocol. The water transport
      parameters, I(pg) and E(lp), for the cultured and transduced cells were
      determined to be 4.4 +/- 1.3 x 10(-14) m3/Ns and 173 +/- 25 kJ/mol, respectively.
      The IIF nucleation parameters, kappa and omega, were 5.5 x 10(10) K5 and 3.5 x
      10(11) (l/m2 s), respectively. The postthaw viability of the genetically modified
      cells was less than the viability of the freshly isolated cells from the same
      donor. The postthaw viability of the cultured and transduced cells from a donor
      with MPS II was also less than that observed with cells from a normal donor that
      were frozen and thawed under the same conditions. These studies are essential in
      understanding the biophysical changes resulting from the ex vivo culture of cells
      and the manner in which these changes influence the ability of the cells to be
      cryopreserved.

PMID- 10580347
TI  - A new bioartificial liver using porcine hepatocyte spheroids in high-cell-density
      suspension perfusion culture: in vitro performance in synthesized culture medium
      and in 100% human plasma.
AB  - A prototype of a bioartificial liver (BAL) based on suspension perfusion culture
      of porcine hepatocyte spheroids was developed at 150 ml scale. About 2% (4 x
      10(9) cells) of whole human liver cells was immobilized. The cell density in the
      bioreactor was 2.7 x 10(7) cells/ml, which was almost comparable to that of
      presently developed packed-bed-type BALs. The bioreactor was perfused with
      culture medium while retaining spheroids. This was done using a rotating
      stainless filter (pore size 50 microm). In vitro 8-h perfusion experiments
      utilizing both synthesized culture medium and 100% human plasma demonstrated the
      spheroids in the bioreactor had almost the same functions on a unit/cell basis as
      those in small-scale rotational culture. This indicated that the functional
      deterioration often associated with scaling up had been minimized. Rapid spheroid
      aggregation and dysfunction in specific human plasma pool must be eliminated
      before clinical application, although this phenomenon seemed to be inherent to
      porcine hepatocyte-based BALs. This prototype shows promise in meeting present
      clinical demands by achieving maximal metabolic activities even in the short
      term.

PMID- 10580348
TI  - 15AU81, a prostacyclin analog, enhances donor-specific hepatocytes to prolong the
      survival of rat heart but not small bowel allografts.
AB  - Prostacyclin analogs have previously been shown to have not only cytoprotective
      but also independent immunosuppressive effects. The effect of one such analog,
      15AU81, to enhance the immunosuppressive effects of liver was investigated. We
      have previously demonstrated that cyclosporine (CsA) in conjunction with
      rapamycin (RAPA) potentiates class I+, class II- donor-specific hepatocytes to
      prolong rat cardiac and small bowel allograft survival. Brown Norway (BN; RT1n)
      hepatocytes alone (5 x 10(7)/kg, administered intrasplenically) failed to prolong
      the survival of BN heart allografts in Wistar Furth (WFu; RT1u) recipients,
      beyond that of untreated controls (MST = 7.2 +/- 0.8 days). Survival of BN hearts
      was increased to 11.4 +/- 1.7 days in WFu recipients treated with BN hepatocytes
      and 50 microg/kg/day 15AU81 administered by continuous s.c. infusion for 14 days
      using osmotic pumps (p < 0.05). The further addition of RAPA 0.0075 mg/kg/day and
      CsA 0.375 mg/kg/day delivered for 14 days by continuous i.v. infusion (CIVI)
      using osmotic pumps (a combination that alone prolonged BN heart allografts in
      WFu hosts to 18.4 +/- 1.3 days and in conjunction with BN hepatocytes prolonged
      survival to 27.2 +/- 1.9 days) prolonged allograft survival to 35.2 +/- 5.2 days.
      In contrast, the survival of small bowel allografts was not enhanced by 15AU81
      administration. Survival of BN small bowel transplants in LEW recipients treated
      with hepatocytes alone (MST = 11.6 +/- 1.5 days) or hepatocytes plus 15AU81 (MST
      = 10.0 +/- 1.0 days) was similar to controls (MST = 10.2 +/- 1.9 days). Treatment
      with hepatocytes and RAPA/CsA increased survival to 21.2 +/- 1.5 days. The
      further addition of 15AU81 failed to augment this (MST = 17.0 +/- 1.9 days). In
      vitro WFu lymphocyte proliferative responses from animals pretreated with BN
      hepatocytes, 15AU81, or both treatments, for 2 weeks prior to harvesting,
      exhibited a reduction of at least 50%, compared to untreated controls upon
      allostimulation with irradiated BN or ACI spleen cells. These findings
      demonstrate that 15AU81 interacts favorably with hepatocytes either alone or in
      conjunction with RAPA and CsA to enhance their immunosuppressive effects on rat
      heart allograft survival. The failure to enhance small bowel allograft survival
      may be explained by the inability at this low dosage of 15AU81 to influence the
      intense graft versus host reaction elicited by small bowel transplants.

PMID- 10580349
TI  - Water and cryoprotectant permeability characteristics of isolated human and
      canine pancreatic islets.
AB  - Cryopreservation allows accumulation of the necessary islet transplantable mass
      as well as adequate time for tissue typing and infectious disease screening.
      Cryopreservation protocols may be optimized by modeling the osmotically induced
      volume excursions that occur during the addition and removal of cryoprotective
      agents (CPAs). To that end, three transport parameters were measured at 22
      degrees C in canine and human islets isolated by collagenase digestion and
      euroficoll purification: (i) the apparent hydraulic conductivity (Lp), (ii) the
      permeability coefficient of the CPA (Ps), and (iii) the associated reflection
      coefficient (sigma). The parameters were determined by volumetric analysis of
      islets upon abrupt exposure to 1, 2, and 3 M dimethyl sulfoxide (DMSO), ethylene
      glycol (EG), glycerol (GLY), and propylene glycol (PG). The parameters were
      calculated using the Kedem-Katchalsky theory to describe islet volume excursion
      kinetics (assuming islets to be single equivalent osmotic units with the same
      volume and surface area of the actual islet) and a three-parameter curve fit was
      performed using the Marquardt-Levenberg method. It was determined that the
      permeability characteristics of pancreatic islets are species specific, and based
      upon the measured parameters, the highest Ps values for canine islets were
      observed following exposure to 2 M EG, and the highest Ps values for human islets
      were observed following exposure to 2 M PG. The permeability parameters were
      analyzed adjusting for islet radius using ANCOVA procedures to acquire least
      square means. For canine islets exposed to 2 M EG these values were determined to
      be 0.936 microm/min/atm, 2.47 microm/s, and 0.90 (for Lp, Ps, and phi,
      respectively) and for human islets exposed to 2 M PG the values were determined
      to be 1.56 microm/min/atm, 3.48 microm/s, and 0.85 (for Lp, Ps, and sigma,
      respectively). These parameters were used in a model to calculate osmotically
      induced islet volumetric response upon addition/dilution of the optimum CPAs,
      taking into consideration critical volume excursion limits at which irreversible
      damage occurs.

PMID- 10580350
TI  - Long-term treatment of streptozotocin-induced diabetes by continuous insulin
      minipump in the Syrian hamster.
AB  - It is difficult to normalize plasma glucose for a prolonged period of time by
      s.c. injection in experimental animals. The goal of this study was to determine
      the feasibility and the dosage of insulin needed to maintain 24-h normoglycemia
      in streptozotocin-diabetic Syrian hamsters with a s.c.-implanted osmotic
      minipump. The pumps, which release insulin at a constant rate, were replaced
      every 14 days with fresh pumps for as long as 52 days. A high insulin dose (1
      U/kg/h) was required to normalize plasma glucose and fatty acid concentrations,
      water and food consumption, urine output, and body weight.

PMID- 10580351
TI  - Ruling out acute deep vein thrombosis by ELISA plasma D-dimer assay versus
      ultrasound in inpatients more than 70 years old.
AB  - In geriatric care, deep-vein thrombosis (DVT) is mostly diagnosed by noninvasive
      techniques. The objectives of this prospective study were: (1) to evaluate the
      power of ELISA plasma D-dimer assay versus ultrasound (US) in ruling out acute
      DVT of the lower limbs in symptomatic geriatric inpatients, and (2) to determine
      the most effective D-dimer cutoff value over the age of 70 years. Over a 10-month
      period, inpatients with suspected lower limb DVT simultaneously underwent US
      examination and ELISA plasma D-dimer assay. Noninclusion criteria were comorbid
      conditions able to modify the D-dimer level. Data were processed by receiver
      operating characteristic (ROC) curve analysis. In total, 150 patients (125 women,
      25 men), average age 86.3 years (range 70-101) were included. A diagnosis of
      lower limb DVT was established in 53 patients (35.3%). With a 500 ng/mL D-dimer
      cutoff conventional value, DVT was ruled out in only five patients (3.3%),
      whereas a 750 ng/mL value ruled out DVT in 19 patients (12.7%) with a sensitivity
      of 98.1%, and a negative predictive value of 95.0%. The only false negative
      corresponded to a patient with a 15-mm thrombus in the distal calf. In inpatients
      above 70, an ELISA plasma D-dimer value smaller than 750 ng/mL is a rapid
      reliable noninvasive means to rule out lower limb DVT, if color flow Doppler
      ultrasound is not available on site.

PMID- 10580352
TI  - Treatment of venous leg ulcers with sulodexide.
AB  - Venous ulcers are still today one of the main socioeconomic problems of medical
      interest in terms of prevalence, morbidity, and costs to the health service. In
      the past, various studies have been carried out to identify a systemic
      pharmacologic treatment able to accelerate venous ulcer healing times, but
      frequently the results have not been satisfactory. The aim of this study was to
      evaluate the efficacy of sulodexide, a drug with profibrinolytic and
      antithrombotic activity, in accelerating venous ulcer's healing time. Ninety-four
      patients (32 men and 62 women), aged 72 years old on average, were randomly
      distributed between two groups. In the first group ("control group") a standard
      treatment was applied, which consisted of cleansing by washing with physiological
      solution and the application of elastic compression with short-extensibility,
      removable bandages. The second group ("sulodexide group") received the standard
      treatment plus sulodexide (600 lipoprotein lipase releasing units [LRU] by im
      route per day for 30 consecutive days, followed by 500 LRU by oral route per day
      for a further 30 days). After 2 months the venous ulcers were found healed in 15
      patients (36%) in the control group and in 30 patients (58%) in the sulodexide
      group (p = 0.03). The life table showed that the healing times were shorter in
      the sulodexide group in the first 2 months of treatment. Total healing times
      amounted to 110 days in the control group and 72 days in the sulodexide group (p
      = 0.08) and the results were in proportion to the initial severity of the lesion.
      A significant correlation was noted between ulcer healing times and severity of
      the initial ulcerous lesion, the duration of the ulcer, and the group the patient
      belonged to. No correlation was found between age, gender of the patient and the
      etiology of the ulcer. In conclusion sulodexide was shown effective in the
      treatment of venous leg ulcers, yielding healing more quickly than the standard
      treatment.

PMID- 10580353
TI  - Results of saphenous vein graft stent implantation: single center results from
      use of oversized balloon catheters.
AB  - The results and complications of a single-center experience of stent implantation
      in old saphenous vein grafts (SVGs) need to be defined. The authors studied their
      initial consecutive 92 patients (125 stents, 1.4 stents/per patient) with a mean
      age of 67+/-9 years. The patients' mean saphenous vein graft (SVG) age was 10+/-4
      years, and the mean left ventricular ejection fraction was 46%+/-15. Patient
      population included unstable angina (65%), stable angina (10%), myocardial
      infarction (21%), and silent ischemia (4%). The authors implanted 122 Palmaz
      Schatz/biliary and three Gianturco-Roubin stents. They aimed at a balloon-artery
      ratio of 1.1/1.0. Procedural success, defined as stent deployment with <50%
      stenosis without death/Q-wave myocardial infarction/coronary artery bypass
      grafting (MI/CABG) was 95%. The mean luminal diameter (MLD) increased from 0.6+/
      0.5 to 3.3+/-0.8 mm (p<0.001) and mean SVG stenosis diameter was decreased from
      80%+/-14 to -10%+/-11 (p<0.001). Angiographic SVG lesions exhibited thrombus
      (17%), ulceration (38%), and plaque rupture (28%). Sixty-two patients were
      treated with warfarin and aspirin and 30 with ticlid and aspirin. Complications
      included death in three patients (3.3%) who sustained subacute stent thrombosis,
      and two of three had Q-wave MI. Distal embolization occurred in seven patients
      (8%); six of seven sustained a non Q-wave acute myocardial infarction (AMI); and
      one of seven a Q-wave MI. Eight (9%) patients had major groin hematoma, two had
      pseudoaneurysm (2.2%), one had arteriovenous (A-V) fistula (1.1%), two had
      vascular surgery (2.2%), nine had blood transfusion (9.8%), and three had stent
      migration (3.3%). Single-center experience with stents in SVGs indicates a highly
      successful procedural and angiographic immediate result. However, it was
      complicated by significant risk of non Q-wave MI due to distal coronary
      embolization which may affect prognosis.

PMID- 10580354
TI  - Coronary stent deployment without predilation in acute myocardial infarction: a
      feasible, safe, and effective technique.
AB  - Direct percutaneous transcatheter revascularization (PTCR) is becoming an
      acceptable therapy for acute myocardial infarction (AMI). Stenting in the setting
      of AMI, once considered contraindicated, is emerging as a suitable option in this
      situation. Coronary stenting without predilation (SWOP) may potentially shorten
      the procedure and radiation time, reduce costs, and decrease procedural
      complications such as coronary dissection and distal embolization. It is expected
      to cause less vascular injury, with a reduction in the rate of in-stent
      restenosis. In this preliminary study the authors evaluated the feasibility of
      the SWOP procedure in 22 selected patients with AMI. Indications for catheter
      based myocardial reperfusion were the following: extensive anterior wall MI
      (68%), inferior wall and right ventricular MI (23%), and inferior wall MI with
      contraindication for thrombolytic therapy (9%). Patients with cardiogenic shock
      or with contraindications for aspirin or ticlopidine were excluded. SWOP was
      successful in 21 attempts (95%), and final procedural success was achieved in
      all. Proximal or distal dissections were seen in three cases and were treated by
      additional three stents. Thrombolysis in myocardial infarction (TIMI) flow 3 was
      restored in all patients. There were no distal embolizations, side branch
      occlusions, coronary perforations, procedure-related emergency bypass operations,
      or deaths. It is concluded that in selected patients with AMI, coronary artery
      stenting without predilation is feasible and safe and does not introduce
      additional risk to the patients.

PMID- 10580355
TI  - Ultrasonic evaluation of congestive liver after tricuspid annuloplasty.
AB  - To assess the effect of tricuspid annuloplasty (TAP), the authors measured the
      size of the liver by using echography in the patients undergoing tricuspid
      annuloplasty. From April 1989 to August 1996, 18 patients underwent TAP. The
      authors measured preoperatively and postoperatively the hepatic index (HI) by
      echography, defined as follows: HI=L x D/BSA (L: the top-to-bottom length of the
      left hepatic lobe; D: the front-to-back length of the left hepatic lobe; BSA:
      body surface area). They also calculated the reducing rate (RR) of HI. The mean
      HI decreased after TAP; preoperative HI: 39.7+/-11.8 vs postoperative HI: 33.8+/
      10.5 (p=0.0069). The RR of the patients with postoperatively residual tricuspid
      regurgitation (TR) over 2 degrees (n=4) was significantly lower than that of the
      other patients (n=14): -11.0+/-6.0% vs 20.2+/-3.2% (p=0.0003). They conclude that
      the use of echography to measure the HI is a good method of assessing congestion
      after TAP.

PMID- 10580356
TI  - Changes in QT dispersion magnitude during respiratory phases: role of maximum
      inspiration and expiration.
AB  - There is still controversy about the reliability and prognostic value of QT
      interval dispersion because of interobserver and intraobserver variability. The
      authors aimed to study the effect of respiratory phases on QT dispersion. Sixty
      healthy volunteers (38 men, 22 women, mean age 25+/-3 years) from the medical
      staff comprised the study group. Electrocardiograms were recorded by the same
      technician with a rate of 50 mm/s during normal breathing, maximum inspiration
      and expiration. QT dispersion was defined as the difference between the maximal
      and minimal QT interval measurement occurring among any of the 12 leads.
      Corrected QT (QTc) interval was calculated according to Bazzet's formula. There
      were no significant differences between QTc max interval during maximum
      inspiration and expiration compared with those in normal breathing (409+/-20 ms
      vs 417+/-26 ms, p>0.05 and 412+/-18 vs 417+/-26 ms, p>0.05 respectively). QTc
      dispersion during maximum inspiration and expiration was significantly lower than
      that of normal breathing (36+/-8 ms vs 44+/-9 ms, p<0.003 and 32+/-7 vs 44+/-9
      ms, p< 0.003, respectively). And the QTc dispersion during maximum expiration was
      also lower than that during maximum inspiration (p<0.01). QT dispersion magnitude
      is affected by the respiratory phases in healthy subjects and decreases during
      both maximum inspiration and expiration as compared with normal respiration.

PMID- 10580357
TI  - Coronary flow velocity immediately after reperfusion reflects myocardial
      microcirculation in canine models of acute myocardial infarction.
AB  - Recent reports indicate that the coronary microcirculation is sometimes injured,
      despite successful reperfusion in acute myocardial infarction (AMI). However, it
      is difficult to evaluate the coronary microcirculation immediately after
      reperfusion by using only angiography. The purpose of this study was to examine
      the relationship between the pattern of coronary blood flow velocity and
      myocardial microcirculatory injury immediately after reperfusion in AMI. The
      authors recorded the left circumflex coronary flow velocity by using the Doppler
      guide wire method 10 minutes after reperfusion in a canine model of AMI. In
      addition, myocardial contrast echocardiography was performed with the injection
      of contrast medium into the left circumflex coronary artery before clamping of
      the coronary artery and 15 minutes after release of the clamp. From these images,
      the ratio of the normalized gray-level postreperfusion to preclamping in the
      contrast-enhanced area was determined. It was compared with coronary flow
      velocity variables. In the 10 dogs with a diastolic-to-systolic velocity ratio
      (DSVR) < 4.0, this velocity ratio 10 minutes after reperfusion correlated
      positively (r = 0.75, p < 0.01) with the normalized gray-level ratio. However,
      the remaining three dogs with a DSVR > or = 4.0 markedly deviated from this
      pattern. Coronary flow velocities in the three dogs were characterized by a
      greater decrease in systolic flow velocity and occurrence of early systolic
      retrograde flow. Myocardial contrast echocardiographic images in these three dogs
      demonstrated a lower normalized gray-level ratio. In conclusion, the coronary
      flow velocity pattern immediately after reperfusion may reflect myocardial
      microcirculatory injury.

PMID- 10580358
TI  - Experimental inhibition of protamine cardiotoxicity by prostacyclin.
AB  - Twelve animals (26+/-5 kg) were subjected to the study. In this experimental
      study, the authors used prostacyclin to inhibit the toxic metabolite release
      during protamine administration. Animals were divided into two equal groups. Six
      animals received prostacyclin (the prostacyclin group), and the other six animals
      did not receive any additional treatment (the control group). All cardiac output
      and biochemical measurements were evaluated at baseline; before cardiopulmonary
      bypass; and at 5, 30, and 60 minutes after protamine administration. The measured
      cardiac index showed that the hearts treated with prostacyclin had satisfactory
      preservation of left ventricular function. Metabolic and biochemical data showed
      that the tumor necrosis factor level was raised significantly in the control
      group (20.75+/-2.2 in the control group and 13.75+/-2.5 pg/mL in the prostacyclin
      group). Also, E and P selectin levels were elevated in the control group, but
      this change was less marked in the prostacyclin group. In addition, the
      intracellular adhesion molecule-1 (ICAM-1) level was significantly higher in the
      control group than in the prostacyclin group (9.26+/-2.13 in the control group
      and 5.13+/-1.66 ng/mL in the prostacyclin group). The authors observed that
      prostacyclin inhibited the toxic mediator release during heparin reversal with
      protamine. This inhibition is one way of protecting the myocardium reserves from
      protamine cardiotoxicity.

PMID- 10580359
TI  - Chronic/subacute total occlusion of the left main coronary artery--a case report
      and review of literature.
AB  - Total occlusion of the left main coronary artery is rare. Acute occlusion is
      invariably fatal; however, survival is possible if the patient reaches the
      hospital in time. Patients usually present with acute myocardial infarction,
      cardiogenic shock, and sudden cardiac death. Chronic total occlusion presents
      with angina, myocardial infarction, or congestive heart failure. The authors
      describe complete occlusion of the left main coronary artery in a patient who
      presented with recent-onset angina. They review the clinical and angiographic
      features of 60 cases described in the literature.

PMID- 10580360
TI  - Accelerated transplant coronary artery disease and massive silent acute
      myocardial infarction in a heart transplant patient--a case report and brief
      review of literature.
AB  - This case report describes an aggressive form of accelerated atherosclerosis
      predicted early after transplant by dobutamine stress echocardiography in a
      patient who died of massive myocardial infarction 32 months after
      transplantation. The main objective finding of this event was markedly increased
      cardiac filling pressures during an elective cardiac catheterization and coronary
      angiography. The literature is briefly reviewed.

PMID- 10580361
TI  - Peripheral arterial involvement in neurofibromatosis type 1--a case report.
AB  - Neurofibromatosis is a dominantly inherited, progressive, generalized dysplasia
      of mesodermal and neuroectodermal tissues. Vascular lesions associated with
      neurofibromatosis type 1 (NF-1) are mainly characterized by stenosis, occlusion,
      aneurysm, pseudoaneurysm, and rupture or fistula formation of small, medium, and
      large-sized arteries. The authors hereby present a rare case of NF-1 with
      bilateral aneurysms and large pseudoaneurysms of the femoral and popliteal
      arteries and occlusion of the left superficial femoral artery.

PMID- 10580362
TI  - Regarding "smoking is associated with dose-related increase of intima-media
      thickness and endothelial dysfunction".

PMID- 10580363
TI  - Contribution of glutamate receptors to benzodiazepine withdrawal signs.
AB  - Recent research has demonstrated that the receptor for glutamate, a major
      excitatory neurotransmitter, may play an important role in the expression of
      benzodiazepine withdrawal signs. This proposal is based on various observations.
      For example, antagonists for N-methyl-D-aspartate (NMDA), non-NMDA and
      metabotropic glutamate (mGlu) receptors can suppress the behavioral signs of
      benzodiazepine withdrawal in mice and rats. Furthermore, the NMDA receptor in the
      cerebrocortical area of diazepam-withdrawn rats is upregulated. Finally, the
      stimulation of phosphoinositide hydrolysis mediated by mGluR is enhanced in
      cerebrocortical slices from lorazepam-withdrawn mice. These findings show that
      the upregulation of signal transduction mediated by glutamate receptors during
      diazepam withdrawal plays a role in the neuroadaptive response responsible for
      the expression of diazepam withdrawal signs. Furthermore, ligands for glutamate
      receptors may be suitable targets for treating benzodiazepine withdrawal signs.

PMID- 10580364
TI  - Antioxidant action of the antiarrhythmic drug mexiletine in brain membranes.
AB  - Mexiletine is a class Ib antiarrhythmic drug used in the treatment of ventricular
      arrhythmias. The Na+ channel blocker mexiletine inhibits calcium influx in cells
      via decreasing reverse operation of the Na+-Ca2+ exchanger. Thus this drug is
      shown to protect the CNS white matter against anoxic/ischemic injury. The aim of
      our study was to investigate if this drug could act as an antioxidant drug as
      well. The antioxidant action of this drug was studied under different oxidant
      conditions in vitro, and thiobarbituric acid-reactive substances were measured to
      follow lipid peroxidation. Mexiletine inhibited iron-ascorbate-H2O2-induced lipid
      peroxidation in brain membranes, liver microsomes and phospholipid liposomes,
      being most effective in brain membranes. The inhibition was dose- and time
      dependent. Mexiletine also inhibited copper-ascorbate-H2O2-induced lipid
      peroxidation but to a lesser extent. It is concluded that mexiletine has a dual
      effect toward oxidative injury in brain, both by inhibiting Na+-Ca2+ exchanger
      dependent Ca2+ influx and by acting as an inhibitor of lipid peroxidation.
      However, as this drug is effective at millimolar concentrations, it should be
      considered less active than natural antioxidants that are effective at micromolar
      concentrations.

PMID- 10580365
TI  - Analysis of domain responsible for desensitization of beta1-adrenergic receptor.
AB  - When the wild type beta1-adrenergic receptor (WT-beta1AR) was expressed in Sf9
      cells, the beta1AR-stimulated adenylyl cyclase activities were desensitized by
      prior treatment with isoproterenol. The extent of beta1AR desensitization was not
      modified, and the onset was not promoted by the overexpression of G protein
      coupled receptor kinase 2 (GRK2), GRK5 or GRK6. However, overexpression of the
      dominant negative mutant of GRK2 appeared to inhibit desensitization of the
      beta1AR. The change of the potential protein kinase A phosphorylation site
      located at the intracellular third loop did not affect beta1AR desensitization.
      Desensitization of the truncated mutant, in which nearly all of the serine and
      threonine residues from the carboxyl terminus were eliminated, was the same as
      that of the WT-beta1AR. A deletion mutant that lacked serine and threonine
      residues of the intracellular third loop was also desensitized by isoproterenol
      stimulation. Furthermore, the deletion of serine and threonine residues from both
      the intracellular third loop and carboxyl terminus did not affect desensitization
      of the beta1AR. These results suggested that phosphorylation by endogenous GRKs
      in Sf9 cells contributed to desensitization of the beta1AR and that the regions
      other than third intracellular loop and carboxyl terminus may be responsible for
      beta1AR desensitization.

PMID- 10580366
TI  - ATZ1993, an orally active and novel nonpeptide antagonist for endothelin
      receptors and inhibition of intimal hyperplasia after balloon denudation of the
      rabbit carotid artery.
AB  - The present experiments were designed to investigate the effect of ATZ1993 [3
      carboxy-4,5-dihydro-1-[1-(3-ethoxyphenyl)propyl]-7-(5-pyrimidinyl)met hoxy-[1H]
      benz[g]indazole] on the intimal hyperplasia after balloon endothelial denudation
      of the rabbit carotid artery. ATZ1993 inhibited the specific [125I]endothelin
      (ET)-1 binding not only to ET-receptor subtype A (ET(A)) with a pKi value of
      8.69+/-0.02, but also to ET-receptor subtype B (ET(B)) with a pKi value of 7.20+/
      0.03. Counterscreening in the binding assay (30 different receptors) confirmed
      that ATZ1993 had a high selectivity for ET receptors. Increases in intima:media
      ratio and DNA content in the vessel wall were significantly (P < 0.005) inhibited
      by ATZ1993 in a daily dose of 30 mg x 200 ml(-1) x kg(-1) for 1 week before and 6
      weeks after balloon denudation. Inhibition of the intimal hyperplasia with
      ATZ1993 was determined as approximately 77% for increases in intima:media ratio
      and DNA content. Plasma concentrations of ATZ1993 ranged between 121.6+/-26.6 and
      131.7+/-20.9 nM throughout experimental periods. Mean arterial blood pressure,
      heart rate and body weight gain remained unaffected by administering ATZ1993.
      These results demonstrate that ATZ1993 is a novel nonpeptide and nonselective
      ET(A)/ET(B)-receptor antagonist, and the agent when administered orally inhibits
      effectively intimal hyperplasia after balloon denudation of the rabbit carotid
      artery.

PMID- 10580367
TI  - Melatonin inhibits the central sympatho-adrenomedullary outflow in rats.
AB  - Central effects of melatonin on the sympatho-adrenomedullary outflow were
      investigated in urethane-anesthetized rats. In the intact animals,
      intracerebroventricularly (i.c.v.) administered interleukin-1beta (IL-1beta) (100
      ng/animal) slightly, but significantly, elevated the plasma level of
      noradrenaline (NA), but not the level of adrenaline (Ad). Melatonin (100
      microg/animal, i.c.v.) did not modulate the effects of IL-1beta on plasma levels
      of catecholamines. In the pinealectomized animals, however, the same dose of IL
      1beta markedly elevated plasma levels of both Ad and NA, and the elevation of Ad
      was more potent than that of NA. In these pinealectomized animals, the serum
      level of melatonin was significantly lower than that in the sham-operated control
      animals. Furthermore, the IL-1beta-induced elevations of plasma catecholamines in
      these pinealectomized animals were attenuated by i.c.v. administered melatonin.
      These results suggest that melatonin plays an inhibitory role in the central
      regulation of sympatho-adrenomedullary outflow in rats.

PMID- 10580368
TI  - Antinociceptive effect of R-(+)-hyoscyamine on the conjunctival reflex test in
      rabbits.
AB  - R-(+)-Hyoscyamine (1-10 microg/kg, s.c.) dose-dependently increased the local
      anesthetic effect of procaine (50 microg/ml) and lidocaine (50 microg/ml) in the
      conjunctival reflex test in the rabbit. This potentiating effect is completely
      prevented by the M1 antagonist dicyclomine (10 mg/kg, s.c.). The intensity of R
      (+)-hyoscyamine antinociception was comparable to that induced by morphine (2
      mg/kg, s.c.) and minaprine (15 mg/kg, s.c.), used as analgesic reference drugs.
      In the same experimental conditions, the S-(-)-enantiomer of atropine (0.1-10
      microg/kg, s.c.), was completely ineffective. The present results confirm the
      ability of R-(+)-hyoscyamine to produce a paradoxical antinociceptive effect
      mediated by a cholinergic mechanism not only in rodents but also in the rabbit.

PMID- 10580369
TI  - 6-Hydroxydopamine induced cardiac malformations and alterations of the autonomic
      nervous system in the developing chicken embryo.
AB  - 6-Hydroxydopamine (6-OHDA) was injected into the air sac of developing chicken
      embryos on day E3 in order to study its effects on cardiac development both
      morphologically and biochemically. A dose-dependent teratogenic effect and
      fetotoxicity were observed in the 6-OHDA-treated embryos. Cardiac malformations,
      including ventricular septal lesions, detachment of the apical portions of the
      ventricles, cardiac hypertrophy, areas of coagulative necrosis with pyknotic
      nuclei and broken nuclear membranes, and swollen mitochondria were evident from
      gross histologic and ultrastructural examinations. A LD50 of 0.3 mg/egg on day
      E11 was obtained. Biochemically, 6-OHDA induced a significant dose-dependent
      reduction in the total cardiac choline acetyltransferase (ChAT) activities on
      days E8 and E11, followed by a recovery on days E15 and E20. The effects on
      muscarinic acetylcholine receptors (mAChRs) were less marked than on ChAT,
      indicating the effects on the cholinergic nervous system development are
      primarily presynaptic. There was a significant decrease in the level of
      norepinephrine (NE) and a delay in the appearance of detectable cardiac NE. It is
      suggested that 6-OHDA-induced cardiac malformation can be a useful model to study
      the mechanisms of cardiovascular development.

PMID- 10580370
TI  - Repeated antigen inhalations alter chemical mediators that cause asthmatic
      obstruction in guinea pigs.
AB  - The contributions of histamine, cysteinyl leukotrienes (CysLTs) and thromboxane
      A2 (TXA2) to the asthmatic responses and the magnitudes of blood and lung
      eosinophilia at acute and chronic stages of our asthmatic model were
      comparatively determined. Guinea pigs were alternately sensitized/challenged by
      inhalation with ovalbumin+Al(OH)3 and ovalbumin, once every 2 weeks. Effects of
      mepyramine, pranlukast (a CysLT antagonist) and seratrodast (a TXA2 antagonist)
      on the early (EAR) and/or the late asthmatic response (LAR) were assessed at the
      second and fourth antigen challenges. The second challenge caused EAR but not
      LAR. Although the EAR was decreased at the fourth challenge, a substantial LAR
      was seen. Both mepyramine and seratrodast inhibited the EAR at the second
      challenge by approximately 50%. However, at the fourth challenge, these drugs did
      not inhibit the EAR. The LAR at the fourth challenge was attenuated by pranlukast
      and seratrodast by 45% and 40%, respectively. Both the blood and lung
      eosinophilia were modestly and markedly induced 5 h after the second and fourth
      challenges, respectively. These results strongly suggest that repetition of
      antigen challenge induces quantitative alterations of chemical mediators
      participating in the asthmatic responses and a change of the body state under
      which eosinophils exhibit enhanced migratory activities.

PMID- 10580371
TI  - Metabolites of isopropyl unoprostone as potential ophthalmic solutions to reduce
      intraocular pressure in pigmented rabbits.
AB  - The intraocular metabolism of isopropyl unoprostone, a novel prostaglandin
      related anti-glaucoma compound, was investigated using pigmented rabbits to
      clarify which metabolites are involved in actions in the eye. Tritium-labeled
      isopropyl unoprostone eyedrops were administered. The cornea, aqueous humor,
      iris, ciliary body and retina were then collected at 5, 15 or 30 min or at 2, 6
      or 12 h after instillation. Isopropyl unoprostone and its metabolites were
      fractionated using high-performance liquid chromatography, and the radioactivity
      of each fraction was measured. Unmetabolized isopropyl unoprostone was never
      detected in any sample at any time point. In the cornea, only the de
      esterificated metabolite, M1, and the further metabolized compound, M2, were
      detected; and the concentrations of these metabolites decreased with time. In the
      aqueous humor, M1, M2 and another metabolite, M3, were detected, with peak
      concentrations of M1 at 30 min and M2 at 2 h. The iris and ciliary body showed a
      similar metabolism with peak concentrations of M1 and M2 at 30 min. In the
      aqueous humor, iris and ciliary body, M2 was the dominant metabolite from 30 min.
      In the retina, only total radioactivity was detected. These results indicate that
      the main metabolites involved in actions in the eye are M1 and M2.

PMID- 10580372
TI  - Comparative study of TA-606, a novel angiotensin II receptor antagonist, with
      losartan in terms of species difference and orthostatic hypotension.
AB  - Losartan is a prodrug type Angiotensin II (Ang II) AT1-receptor antagonist whose
      efficacy depends on the oxidase activity of individuals. In addition, losartan
      affects the normal blood pressure and can potentially cause orthostatic
      hypotension. In this report, we examined effects of TA-606 [(3
      pentyloxy)carbonyloxymethyl-5-acetyl-2-n-propyl-3-[2'(1H -tetrazole-5-yl)biphenyl
      4-yl]methyl-4,5,6,7-tetrahydro imidazo[4,5-c]pyridine-4-carboxylate
      hydrochloride], a prodrug type AT1-receptor antagonist, on the Ang II-induced
      pressor response and hypertension in a dog model, which is known to have lower
      oxidase activity than other species, and orthostatic hypotension in the rat
      tilting model. The results indicated that TA-606 was immediately converted to its
      active form, 606A, after oral administration, and it demonstrated potent
      inhibition of the Ang II-induced pressor response in conscious normotensive dogs
      (0.3-3 mg/kg, p.o.). It also had a potent hypotensive effect in conscious 2K,1C
      renal hypertensive dogs (0.3-10 mg/kg, p.o.). These effects of TA-606 were 32 and
      30 times more potent than those of losartan, respectively. In addition, EXP3174
      (1, 10 mg/kg, i.v.), an active metabolite of losartan, but not 606A (1-30 mg/kg,
      i.v.) showed an orthostatic hypotensive effect in the rat tilting model. These
      results suggest that TA-606 is an effective Ang II receptor antagonist without
      the drawbacks of losartan.

PMID- 10580373
TI  - Recombinant E1-deleted adenoviral vectors induce apoptosis in a rat airway
      epithelial mucous goblet cell line.
AB  - Replication-defective adenoviruses (Ad) are used as vectors for delivering
      therapeutic genes to human airway cells. We examined whether E1-deleted Ad
      vectors (Ad5-CMV-LacZ) had effects on cell kinetics in SPOC1 cells, which is a
      rat airway epithelial mucous goblet cell line. There was a vector multiplicity of
      infection (moi)-dependent increase of the transduction efficiency of the LacZ
      reporter gene in SPOC cells. Cell proliferation was inhibited in the vector
      infected cells compared with that in vehicle-exposed cells. However, increased
      cell death was observed in the vector-infected cells with a higher moi. The
      morphology of vector-exposed cells revealed apoptotic features including nuclear
      condensation and a fragmented nucleus. These results indicate that higher moi of
      vectors allows the cells to achieve higher gene transfer, but also induce
      apoptosis of infected cells. Minimizing the induction of apoptosis of vector
      infected cells may be an important strategy for the prolongation of transduction
      efficiency of Ad vectors in airway epithelial mucous goblet cells.

PMID- 10580374
TI  - Effects of a class III antiarrhythmic drug, dofetilide, on the in situ canine
      heart assessed by the simultaneous monitoring of hemodynamic and
      electrophysiological parameters.
AB  - The cardiovascular profile of dofetilide was examined using halothane
      anesthetized, closed-chest in vivo canine model (n=6). Dofetilide was
      administered at the dose of 1, 10 or 100 microg/kg, i.v. over 10 min with a pause
      of 20 min. After the lowest infusion rate, no significant change was detected in
      any of the cardiovascular parameters. Infusion of 10 microg/kg dofetilide, which
      was close to the submaximal clinically effective antiarrhythmic dose, decreased
      the heart rate and prolonged the ventricular repolarization phase and refractory
      period. After the highest dose of dofetilide, the cardiac output and left
      ventricular contraction decreased during sinus rhythm, the latter of which was
      not changed during the constant heart rate of 150 beats/min, while the dose
      related effects were observed on the heart rate, repolarization phase and
      refractory period. The afterload and preload to the left ventricle and AV nodal
      as well as intraventricular conductions were hardly affected even at 100
      microg/kg, i.v. These results obtained in the in vivo canine model support the
      previous reports describing that dofetilide possesses a highly selective blocking
      property for I(Kr). Moreover, the absence of effects on the afterload and preload
      to the left ventricle and the cardiac conduction makes dofetilide favorable as an
      antiarrhythmic drug because it is often used for patients with moderate to severe
      left ventricular dysfunction.

PMID- 10580375
TI  - Rat gastric mucous gel layer contains sialomucin not produced by the stomach.
AB  - The sialylated mucus components of the normal gastric mucosa and mucous gel layer
      of rats were studied by using various histochemical staining methods including
      Maackia amurensis II (MAL-II) and Sambucus nigra (SNA) lectins, alcian blue (AB)
      pH 2.5 -- periodic acid Schiff (PAS) and high iron diamine (HID) -- AB pH 2.5.
      The acidic and neutral mucins characterized by the AB-PAS staining were
      abundantly present in the mucous gel layer as well as in the gastric mucosa. The
      sialomucin characterized by HID-AB was barely found in either the mucous gel
      layer or the mucosa. The sialomucin positive to MAL-II and SNA, which react with
      the N-acetyl neuraminic acid residue linked to galactose via an alpha-linkage,
      was moderately detected only in the mucous gel layer, but not in the entire
      mucosal layer. Furthermore, in animals given surgery to form an esophageal
      fistula through which saliva was excluded or in animals subjected to salivectomy,
      the mucous gel layer stained with MAL-II and SNA lectins was markedly decreased.
      These results indicate that a part of the sialomucin containing-mucous gel layer
      covering normal rat gastric mucosa originates from the saliva and that MAL-II and
      SNA lectins are useful for detecting this specific sialomucin.

PMID- 10580376
TI  - The profile of FR140423, a novel anti-inflammatory compound, in yeast-induced rat
      hyperalgesia.
AB  - The mechanism of action of FR140423 (3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4
      (methylsulfinyl)phenyl]pyra zole), a novel anti-inflammatory compound, in a rat
      yeast-induced hyperalgesic model was investigated and compared with those of
      indomethacin and morphine. We tested the inhibitory effects of FR140423 on the
      formation of arachidonic acid metabolites, prostaglandin (PG) E2, thromboxane
      (TX) B2 and leukotriene (LT) B4, in yeast-injected inflamed paws and the effect
      of the opioid receptor antagonist naloxone on FR140423-induced anti-hyperalgesic
      effect and inhibition of the formation of arachidonic acid metabolites. Oral
      administration of FR140423 showed a dose-dependent anti-hyperalgesic effect. This
      effect was fourfold more potent than that of indomethacin but less potent than
      that of morphine. Unlike morphine, FR140423 suppressed the levels of PGE2 and
      TXB2 but not LTB4 in inflamed paws. FR140423 did not inhibit yeast-induced paw
      edema. The anti-hyperalgesic effect of FR140423 in yeast-injected rat paws was
      partially blocked by naloxone. However, the inhibitory effects of FR140423 on the
      formation of PGE2 and TXB2 in yeast-injected rat paws were not antagonized by
      naloxone. These results suggest that FR140423 shows a potent anti-hyperalgesic
      effect mediated by inhibition of PGs in inflamed tissue and by activation of
      opioid receptors.

PMID- 10580377
TI  - Mechanism of structural remodelling of the rat aorta during long-term NG-nitro-L
      arginine methyl ester treatment.
AB  - The aim of the present study was to determine whether decreased nitric oxide (NO)
      synthase production or rather N(G)-nitro-L-arginine methyl ester (L-NAME)-induced
      hypertension was responsible for metabolic and structural remodelling of the rat
      aorta during four-week L-NAME treatment. Three groups of male Wistar rats were
      investigated: control, treated with 20 mg/kg per day L-NAME (L-NAME20), and
      treated with 40 mg/kg per day L-NAME (L-NAME40). Systolic blood pressure
      significantly increased in L-NAME20 to 146% and in L-NAME40 to 149% of the
      control value. NO synthase activity in the aorta significantly decreased in L
      NAME20 and L-NAME40 to 86% and 65% of the control values, respectively.
      Proteosynthesis was significantly elevated in both L-NAME groups, while nuclear
      DNA concentration was significantly elevated only in the L-NAME40 group. Cyclic
      GMP concentration significantly decreased in L-NAME20 to 73% and in L-NAME40 to
      46% of the control. Cyclic AMP concentration significantly increased in L-NAME20
      and L-NAME40 to 128% and 145% of the control value, respectively. The diameter
      and wall thickness-to-diameter ratio were significantly elevated only in the L
      NAME40 group. We conclude that remodelling of the aorta in L-NAME-treated rats
      was rather associated with NO deficiency than L-NAME-induced hypertension.

PMID- 10580378
TI  - Vasodilating effect and tissue accumulation of prostaglandin E1 incorporated in
      lipid microspheres on the rat ductus arteriosus.
AB  - Prostaglandin E1 incorporated in lipid microspheres (lipo PGE1) was administered
      to the umbilical vein of neonatal rats. Morphological measurement and
      quantitative autoradioluminography assessed the relationship between the
      vasodilating effect and tissue accumulation of lipo PGE1 in the ductus
      arteriosus. In the morphological measurement under microscopy, the inner diameter
      ratio of the ductus arteriosus to the main pulmonary artery after infusion of 3H
      labeled lipo PGE1 (3H-lipo PGE1) continued to remain significantly higher than
      that of free 3H-PGE1. Autoradioluminography of the frozen frontal section of
      neonates after intravenous infusion of 3H-lipo PGE1 for 2 h revealed that the
      ductus levels of radioactivity were higher than those of free 3H-PGE1 in saline
      solution, although the blood levels were almost equal. Localization of lipo PGE1
      labeled with a lipophilic fluorescent probe, 1,1'-dioctadecyl-3,3,3',3
      tetramethyl-indocarbocyanine perchlorate (diI), in the endothelial cells of the
      ductus arteriosus was confirmed by confocal laser scanning microscopy. These
      findings suggest that the incorporation of lipid microspheres by the endothelial
      cells is one of the mechanisms that enables lipo PGE1 to accumulate to higher
      levels in the ductus tissue and to act more efficiently than free PGE1 in
      neonatal rats.

PMID- 10580379
TI  - The inhibition of monoamine oxidase activity by various antidepressants:
      differences found in various mammalian species.
AB  - The effects of the antidepressant drugs zimeldine, imipramine, maprotiline or
      nomifensine on mitochondrial monoamine oxidase (MAO) activity in mouse, rat, dog
      and monkey brains were compared in vitro. Mouse, rat, dog and monkey brain MAO-B
      activities were inhibited by zimeldine more potently than MAO-A activity.
      Imipramine inhibited MAO-B more potently than MAO-A activity in mouse and rat
      brains. When dog and monkey brains were investigated, MAO-A activity was
      inhibited more potently than MAO-B activity at high concentrations of imipramine,
      while at low concentrations, MAO-B activity was more potently inhibited.
      Maprotiline and nomifensine inhibited mouse and rat brain MAO-B activity more
      potently than MAO-A activity, while the inverse was true for dog and monkey
      brains. All four drugs are competitive inhibitors of MAO-A, but noncompetitive
      inhibitors of MAO-B in all animal brains. The respective Ki values of these
      reagents for monkey brain MAO-A and MAO-B were low compared to those of mouse,
      rat and dog. These results indicate that monkey brain MAOs are more sensitive to
      antidepressant drugs than those in rodent brain.

PMID- 10580380
TI  - Diazepam increases calcium sensitivity of the skinned cardiac muscle fiber in
      guinea pig.
AB  - Influences of diazepam, a benzodiazepine derivative, on the contractile response
      to calcium in skinned trabecular fibers of guinea pig heart were examined.
      Diazepam (100 microM) enhanced the contractile response of the skinned fiber to
      calcium and shifted the concentration-response curve to the left. The pCa50
      values were 6.07+/-0.03 and 6.28+/-0.03 (P<0.05) in the absence and presence of
      diazepam, respectively. This result suggests that diazepam increases calcium
      sensitivity of contractile proteins in heart muscles.

PMID- 10580381
TI  - Roselipins, inhibitors of diacylglycerol acyltransferase, produced by Gliocladium
      roseum KF-1040.
AB  - Gliocladium roseum KF-1040, a marine isolate, was found to produce a series of
      new inhibitors of diacylglycerol acyltransferase (DGAT). Four active compounds,
      designated roselipins 1A, 1B, 2A and 2B, were isolated from the fermentation
      broth of the producing strain by solvent extraction, ODS column chromatography
      and preparative HPLC. The highest production of roselipins was observed when
      cultured in the medium containing natural sea water. Roselipins inhibit DGAT
      activity with IC50 values of 15 approximately 22 microM in an enzyme assay system
      using rat liver microsomes.

PMID- 10580382
TI  - Rhodopeptins (Mer-N1033), novel cyclic tetrapeptides with antifungal activity
      from Rhodococcus sp. I. Taxonomy, fermentation, isolation, physico-chemical
      properties and biological activities.
AB  - Five novel cyclic tetrapeptides, named rhodopeptin C1, C2, C3, C4 and B5, were
      isolated from a strain named Rhodococcus sp. Mer-N1033. They are a novel type of
      cyclic tetrapeptide composed of a beta-amino acid and three usual alpha-amino
      acids. Rhodopeptins show high in vitro antifungal activity against Candida
      albicans and Cryptococcus neoformans, whereas they show no activity against
      bacteria.

PMID- 10580383
TI  - Rhodopeptins, novel cyclic tetrapeptides with antifungal activities from
      Rhodococcus sp. II. Structure elucidation.
AB  - The structures of rhodopeptins, novel antifungal peptides, were determined on the
      basis of physico-chemical analyses of the intact molecules and their acid
      hydrolysates. The structures of rhodopeptins C1, C2, C3, C4 and B5 were
      determined to be cyclo (-Gly-L-Orn-L-Val-3-amino-10-methyldodecanoyl-), cyclo (
      Gly-L-Orn-L-Ile-3-amino-10-methyldodecanoyl-), cyclo (-Gly-L-Orn-L-Val-3-amino-12
      methyltridecanoyl-), cyclo (-Gly-L-Orn-L-Val-3-amino- 12-methyltetradecanoyl-)
      and cyclo (-Gly-L-Lys-L-Val-3-amino-13-methyltetradecanoyl-), respectively. They
      are novel cyclic tetrapeptides containing a lipophilic beta-amino acid.

PMID- 10580384
TI  - Rhodopeptins, novel cyclic tetrapeptides with antifungal activities from
      Rhodococcus sp. III. Synthetic study of rhodopeptins.
AB  - Total syntheses of cyclo (-Gly-L-Lys-L-Val-(R)-3-aminododecanoyl-); LV9nA and its
      diastereomer cyclo (-Gly-L-Lys-L-Val-(S)-3-aminododecanoyl-); LV9nB, congeners of
      rhodopeptin B5 on beta-amino acid moiety, were achieved. The beta-amino acid
      moiety was prepared as a racemate by the thermal Michael addition of an amine to
      alpha,beta-unsaturated ester. The racemic beta-amino acids were converted to
      their L-Valylamide derivatives and the obtained diastereomers were separated.
      Coupling of both diastereomers, L-Val-beta-amino acids with Gly-L-Lys gave linear
      tetrapeptides, and tetrapeptides were cyclized by diphenylphosphoryl azide (DPPA)
      method between C-terminus of beta-amino acid and N-terminus of Gly to give cyclic
      tetrapeptides. The deprotected cyclic tetrapeptides, LV9nA and LV9nB, both
      exhibited almost the same antifungal activity as the naturally obtained
      rhodopeptins. Furthermore, comparison of the 1H NMR spectra of two congeners and
      rhodopeptin B5 suggested that the stereochemistry of beta-amino acid moiety in
      natural rhodopeptin B5 has (R)-configuration.

PMID- 10580385
TI  - Melithiazols, new beta-methoxyacrylate inhibitors of the respiratory chain
      isolated from myxobacteria. Production, isolation, physico-chemical and
      biological properties.
AB  - New antibiotic compounds, melithiazols, were isolated from the culture broth of
      strains of the myxobacteria Melittangium lichenicola, Archangium gephyra, and
      Myxococcus stipitatus. The compounds belong to the group of beta-methoxyacrylate
      (MOA) inhibitors and are related to the myxothiazols. The melithiazols show high
      antifungal activity, but are less toxic than myxothiazol A and its methyl ester
      in a growth inhibition assay with mouse cell cultures. The melithiazols inhibit
      NADH oxidation by submitochondrial particles from beef heart. Melithiazol A
      blocks the electron transport within the bc1-segment (complex III) and causes a
      red shift in the reduced spectrum of cytochrome b.

PMID- 10580387
TI  - Production of 6-deoxy-13-cyclopropyl-erythromycin B by Saccharopolyspora
      erythraea NRRL 18643.
AB  - Cyclopropane carboxylic acid was fed to Saccharopolyspora erythraea NRRL 18643 (6
      deoxyerythromycin producer), resulting in the production of 6-deoxy-13
      cyclopropyl-erythromycin B. These studies provide further evidence that
      deoxyerythronolide B synthase has a relaxed specificity for the starter unit.

PMID- 10580386
TI  - Ala(0)-actagardine, a new lantibiotic from cultures of Actinoplanes liguriae ATCC
      31048.
AB  - The actagardine-producing strain Actinoplanes liguriae ATCC 31048, forms an
      additional lantibiotic when it is cultured on mannitol and soya meal. The new
      compound, Ala(0)-actagardine (1), has been isolated by solid-phase extraction
      followed by a two-step chromatographic separation. The molecular formula of 1 is
      C84H129N21O25S4. Its chemical structure was determined by 2D-NMR analysis and was
      further confirmed by an amino acid analysis, Edman degradation, and partial
      synthesis from actagardine. 1 exhibits a slightly higher biological activity than
      the parent compound actagardine. The synthetic analogs Lys(0)-actagardine (2) and
      Ile(0)-actagardine (3) demonstrate also antibacterial activities and emphasize
      the importance of the N-terminus for further derivatization.

PMID- 10580388
TI  - UK-2A,B,C and D, novel antifungal antibiotics from Streptomyces sp.517.02. V.
      Inhibition mechanism of bovine heart mitochondrial cytochrome bc1 by the novel
      antibiotic UK-2A.
AB  - UK-2A is a potent antifungal antibiotic isolated from Streptomyces sp. 517-02 and
      its structure is highly similar to that of antimycin A. We investigated the
      inhibition mechanism of bovine heart mitochondrial cytochrome bc1 complex by the
      UK-2A using antimycin A and myxothiazol as the reference inhibitors of ubiquinol
      oxidation (Qo) and ubiquinone reduction (Qi) sites, respectively. The inhibitory
      potency of UK-2A was about 3-fold less than antimycin A. On the basis of the
      effects of UK-2A on the reduction kinetics of b and c1 hemes, this compound
      appeared to be an inhibitor of the Qi site. However, since spectral changes of
      dithionite-reduced cytochrome b induced by UK-2A binding differed from that of
      antimycin A, the precise binding manner of UK-2A to the enzyme is not identical
      to that of antimycin A. It could be concluded that antimycin A binding to
      cytochrome b is primarily decided by structural specificity of the salicylic acid
      moiety.

PMID- 10580389
TI  - Novel cyclopentanone derivatives pentenocins A and B with interleukin-1beta
      converting enzyme inhibitory activity, produced by Trichoderma hamatum FO-6903.

PMID- 10580390
TI  - Phenazostatin C, a new diphenazine with neuronal cell protecting activity from
      Streptomyces sp.

PMID- 10580391
TI  - Guidelines for hypertension in the elderly--1999 revised version. Ministry of
      Health and Welfare of Japan.

PMID- 10580392
TI  - Relationships among blood pressures obtained using different measurement methods
      in the general population of Ohasama, Japan.
AB  - To examine the relationships between casual, ambulatory and home blood pressure
      measurements in the general population, these measurements were obtained in 1,695
      of 3,744 subjects aged 20 yr or older in Ohasama, Japan. Of these 1,695 subjects,
      1,207 measured their home blood pressure more than 14 times in each of the
      morning and evening (881 untreated subjects including normotensives and untreated
      hypertensives, 56.4 +/- 11.5 yr of age; 326 treated subjects, 66.0 +/- 9.2 yr of
      age). We analyzed data in these 1,207 subjects, examining the distribution of
      each measurement, the relationships among measurements, and the factors affecting
      the blood pressure differences among the measurements. For systolic pressure, the
      casual measurement was the highest among the methods examined. The daytime
      ambulatory measurement was significantly higher than morning and evening home
      measurements. Morning home measurements were significantly higher than those in
      the evening. For diastolic pressure, however, the morning home measurement was
      the highest among the methods examined. Short-term pressure variability (standard
      deviation and variation coefficient of ambulatory measurements) was greater than
      long-term pressure variability (standard deviation and variation coefficient of
      home measurements). The pressure variability in treated subjects was greater than
      that in untreated subjects. The correlation between casual pressure and the other
      pressures was not as strong (r<0.567). Among the relationships between ambulatory
      and home measurements, the strongest correlation was observed between the 24-h
      ambulatory measurement and the morning home measurement (r=0.738) in untreated
      subjects. The morning home measurement was highly correlated with the evening
      home measurement (r>0.814). The differences among the methods examined were
      affected by blood pressure level and age. It should be noted that in elderly and
      treated subjects, blood pressure measurement using one method does not
      necessarily correlate with that obtained using the other methods. This
      information is useful for the estimation of the value of one type of blood
      pressure measurement from values obtained with other methods.

PMID- 10580393
TI  - Plasma concentrations of angiotensin metabolites in young male normotensive and
      mild hypertensive subjects.
AB  - The plasma concentrations of angiotensin (Ang) I, Ang II, and their metabolites
      (Ang (3-8), (4-8), (5-8), and (3-4)) following in vitro ACE inhibitory activity
      were examined in young male normotensive (NT) (n = 7), and mild hypertensive (HT)
      volunteers (n = 6). There were no differences in supine plasma levels of Ang I,
      Ang II, and Ang (5-8) between the NT and HT groups: Ang I, 304 +/- 43 fmol/ml vs.
      293 +/- 15 fmol/ml; Ang II, 32 +/- 6 fmol/ml vs. 43 +/- 10 fmol/ml; Ang (5-8),
      176 +/- 22 fmol/ml vs. 133 +/- 32 fmol/ml. In addition, there were no significant
      differences between groups in any of these Ang levels when measured after
      standing for 60 min. However, the HT group showed significantly reduced supine
      and upright plasma Ang (3-8) and Ang (3-4) levels as compared to the NT group. In
      particular, the supine plasma level of Ang (3-4) (71 +/- 13 fmol/ml-plasma) in
      the HT group was significantly (1/3-fold) lower than that in the NT group (197 +/
      35 fmol/ml-plasma). An inverse correlation between the plasma level of Ang (3-4)
      and the upright systolic blood pressure (r = -0.627, p < 0.02, n = 13) was
      observed, indicating that the metabolism of Ang (3-4) might have been associated
      with the change in blood pressure.

PMID- 10580394
TI  - Creatinine clearance as a substitute for the glomerular filtration rate in the
      assessment of glomerular hemodynamics.
AB  - A method for the clinical assessment of glomerular hemodynamics has been
      published previously. We here examined whether, when using this method, renal
      creatinine clearance (Ccr) can be substituted for the glomerular filtration rate
      (GFR). The study subjects comprised 57 inpatients from Osaka City General
      Hospital: 30 with type 2 diabetes mellitus and 27 with chronic
      glomerulonephritis. During the 2-wk study, patients received a high-salt diet for
      1 wk and a low-salt diet for 1 wk. Urinary sodium excretion and systemic blood
      pressure were measured daily. The renal plasma flow, Ccr, and plasma total
      protein concentration were also evaluated simultaneously on the last day of the
      high-salt diet. The GFR was also calculated from the fractional renal
      accumulation of 99mTc-diethylenetriaminepentaacetic acid (DTPA). Glomerular
      hemodynamics, represented by the glomerular capillary hydraulic pressure and the
      resistance of afferent and efferent arterioles, were calculated using the renal
      clearance, the plasma total protein concentration, and the pressure-natriuresis
      relationship. Values for renal hemodynamics with the Ccr-derived GFR were
      compared with those from the 99mTc-DTPA-derived GFR. Ccr values of 53 to 169
      ml/min correlated with the 99mTc-DTPA-derived clearance of 39 to 179 ml/min
      (n=57, r=.71, p<.001). Values for the glomerular pressure and the resistances of
      afferent and efferent arterioles calculated using the Ccr-derived GFR correlated
      significantly with those calculated using the 99mTc-DTPA-derived GFR (r=.99,
      p<.001 and r=.99, p<.001, respectively). These results indicate that the Ccr is
      an accurate representation of the GFR for use in glomerular hemodynamic analysis
      of the pressure-natriuresis relationship.

PMID- 10580395
TI  - Renin gene MboI dimorphism is a discriminator for hypertension in hyperlipidaemic
      subjects.
AB  - As renin is the key enzyme of the renin-angiotensin-aldosterone system, the renin
      gene (REN) represents a good candidate quantitative trait locus for
      investigations aimed at uncovering the molecular and genetic influences
      implicated in the molecular etiology of essential hypertension. Among the various
      polymorphic markers that are available at the REN gene locus, an MboI dimorphic
      site located in the ninth intron of the REN gene has previously been shown to be
      significantly associated with a family history of hypertension in a Japanese
      population and with direct clinical diagnosis of essential hypertension in a Gulf
      population. We determined MboI allele and genotype distributions in a sample
      population of 349 (178 men, 171 women) hyperlipidaemic US Caucasians (mean age
      55.4+/-13.1 yr), comprising 122 hypertensive and 227 normotensive subjects. A
      statistically significant association was found between alleles on which the MboI
      site was present [MboI(+)] and clinical diagnosis of hypertension. REN MboI(+)
      alleles are thus in linkage disequilibrium with genetic influences that
      contribute to increased individual susceptibility to hypertension of
      hyperlipidaemic patients (with an associated odds ratio of 2.15, 95% CI: 1.34
      3.45). This positive association does not seem to occur through the effect of
      classical risks factors represented by lipid, lipoprotein and apolipoprotein
      levels.

PMID- 10580396
TI  - Characteristics of cardiovascular morphology and function in the high-normal
      subset of hypertension defined by JNC-VI recommendations.
AB  - A cross-sectional study was conducted to compare the morphological and functional
      characteristics of the cardiovascular system among subgroups of hypertension
      defined by the JNC-VI recommendations. One hundred and sixteen subjects
      (normotensives and unmedicated hypertensives: 49+/-10 yr) were classified into 4
      groups based on the criteria of JNC-VI: normotensive (NOR: n = 38), high-normal
      blood pressure (HN: n = 16), stage 1 hypertensive (SI: n = 28), and stage 2 to 3
      hypertensive (SII-III: n = 34). Ultrasonographic examinations of the heart and
      carotid artery were performed in all subjects, and the following parameters were
      obtained: left ventricular mass index (LVMI), relative wall thickness at end
      diastole (RWTd), cardiac diastolic function (A/E), common carotid artery diameter
      (CAD), intimal media thickness of the common carotid artery (IMT), and
      distensibility of the common carotid artery (Distens). RWTd, A/E, and IMT in SI
      (RWTd, 0.41+/-0.07; A/E, 1.21+/-0.41; IMT, 0.69+/-0.17 mm) and SII-III patients
      (0.40+/-0.08, 1.38+/-0.33, 0.80+/-0.21 mm) were larger than those in NOR patients
      (0.33+/-0.03, 0.86+/-0.21, 0.56+/-0.10 mm) (p < .01). Furthermore, LVMI in SII
      III (135.5+/-35.5 g/m2) patients was larger than that in NOR patients (99.4+/
      17.5 g/m2) (p < .05). RWTd in HN patients (0.37+/-0.06) was significantly higher
      than that in NOR patients (p < .05). A/E tended to be larger in HN than in NOR
      patients (p < 0.1). In the normotensives, no significant difference in any of the
      parameters was detected between those with optimal (n = 19) and normal (n = 19)
      blood pressure. Thus, both morphological and functional changes were associated
      with elevation of blood pressure. Cardiac morphological adaptation and functional
      impairment were present even in subjects with high-normal blood pressure level,
      while there were no significant differences between the normal and optimal
      subsets.

PMID- 10580397
TI  - Serum creatinine level underestimates hypertensive renal involvement in elderly
      patients with essential hypertension.
AB  - It is well recognized that serum creatinine level provides a quick general
      assessment of renal function. However, we frequently encounter elderly
      hypertensive patients with renal involvement whose serum creatinine levels are
      within normal limits. The aim of this study was thus to determine whether serum
      creatinine level is a sensitive indicator of renal function in elderly
      hypertensive patients. Study groups were classified according to age: 82 elderly
      patients (aged 65 yr or older) and 98 middle-aged patients (aged 40-65 yr) with
      essential hypertension. To assess hypertensive renal involvement, serum
      creatinine and serum uric acid levels were measured. We also measured the left
      ventricular mass (LVM) index by using echocardiography as a marker of
      hypertensive target organ damage. There was no age-related difference in the LVM
      index, but the serum creatinine level in elderly hypertensive patients was
      significantly lower than that in middle-aged hypertensive patients. There was no
      significant difference in serum uric acid level between the two groups. In
      addition, the LVM index was correlated with the serum uric acid level (r = 0.46,
      p = 0.0001) but not with the serum creatinine level in elderly hypertensive
      patients. In middle-aged hypertensive patients, the LVM index was related to both
      serum uric acid level (r = 0.41, p = 0.007) and serum creatinine level (r = 0.43,
      p = 0.003). In conclusion, serum creatinine level may underestimate hypertensive
      renal involvement in elderly hypertensive patients. In contrast, serum uric acid
      level may be a sensitive indicator of hypertensive target organ damage
      irrespective of age.

PMID- 10580398
TI  - Effects of angiotensin inhibitors on renal injury and angiotensin receptor
      expression in early hypertensive nephrosclerosis.
AB  - Angiotensin converting enzyme inhibitors (ACEI) are known to inhibit the
      progression of established renal failure. The aim of this study was to compare
      the efficacy of an ACEI and an AT1 receptor antagonist (AT1R-Ant) in preventing
      the development of renal disease, at an early stage of hypertensive
      nephrosclerosis. SHRSP/Izm rats (n = 61) were treated from 10 wk until 22 wk with
      the ACEI delapril (40 mg/kg/d) or the AT1R-Ant candesartan cilexetil (1 mg/kg/d).
      Proteinuria, and structural/ultrastructural changes were assessed at 14 and 22
      wk. Treatment with either agent resulted in reductions in blood pressure and
      cardiovascular hypertrophy. Neither proteinuria nor major renal histological
      changes were evident at 14 wk. At 22 wk, however, proteinuria accompanied by
      nephrosclerotic changes was seen in the untreated SHRSP/Izm. Treatment with
      either ACEI or AT1R-Ant resulted in similar reductions in proteinuria (untreated,
      32.2 +/- 7.4; delapril-treated, 5.5 +/- 1.2; candesartan-treated, 3.9 +/- 0.3
      mg/100 g/d). Prominent sclerosis of small-to-medium sized renal arteries was seen
      in the untreated SHRSP/Izm at 22 wk, but was similarly attenuated by the ACEI and
      AT1R-Ant. The glomerular ultrastructure was comparable between the two groups. No
      significant changes in renal AT1a or AT1b receptor subtype mRNA expression were
      seen throughout the course of the study. In contrast, a decrease in AT2 receptor
      mRNA was seen in the drug-treated groups at 14 wk but not at 22 wk. These results
      suggest that both ACEI and AT1R-Ant have similar efficacy in attenuating the
      onset of renal injury in early hypertensive nephrosclerosis, and that treatment
      with either agent is associated with a transient decrease in AT2 receptor mRNA
      expression.

PMID- 10580399
TI  - Anti-HIV effect of saquinavir combined with ritonavir is limited by previous long
      term therapy with protease inhibitors.
AB  - Combination therapy of saquinavir (SQV) and ritonavir (RTV) seems to have a
      strong antiretroviral effect pharmacokinetically. The purpose of this study was
      to examine the effectiveness of combined therapy using SQV and RTV in patients
      previously treated with protease inhibitors (PIs) and to identify the factors
      compromising the response to such combination therapy. Nineteen HIV-infected
      Japanese patients participated in this trial between June 1997 and July 1998, and
      were monitored until November 1998. Patients were treated with SQV (400 mg twice
      daily) and RTV (300 or 400 mg twice daily). Among the 17 patients who continued
      such therapy for longer than 3 months, 6 were responders. Among nonresponders,
      the duration of PI therapy was longer and a higher frequency of preexisting PI
      resistance viral mutations was detected than in responders. No significant
      differences were found in previous use of reverse transcriptase inhibitor
      therapy, CD4+ and CD8+ T cell counts, viral load at baseline, and plasma
      concentrations of SQV and RTV between responders and nonresponders. Our results
      suggest that the response to SQV combined with RTV therapy is complicated by
      previous long-term treatment with PIs, probably owing to multiple PI resistance
      mutations. Even in patients with a PI-sensitive HIV genotype, however, resistance
      mutations can develop during therapy and abrogate the effect of high plasma SQV
      concentrations.

PMID- 10580400
TI  - Assessment of type 1 and type 2 cytokines in HIV type 1-infected individuals:
      impact of highly active antiretroviral therapy.
AB  - Although the effect of highly active antiretroviral therapy (HAART) on HIV-1
      replication has been established, the mechanisms involved in restoration of
      immune responses and reconstitution remain unknown. This study provides evidence
      of changes in expression of type 1 and type 2 cytokine-specific mRNA occurring
      during HIV-1 infection, before and after initiation of HAART. Unstimulated PBMCs
      from nine HIV-1-infected individuals obtained at different time intervals before
      and after the initiation of HAART were assessed for specific IFN-gamma, IL-2, IL
      4, and IL-10 mRNA expression, using RT-PCR. Correlation with CD4+ T cell counts
      and viral load was also carried out. Before initiation of HAART, in all patients,
      little expression of specific IFN-gamma and IL-2 (type 1 cytokine) mRNA was
      noted. In contrast, expression of specific IL-4 and/or IL-10 (type 2) mRNA was
      readily detectable in the majority of patients. After initiation of HAART there
      was a continuous increase in IFN-gamma and IL-2 mRNA expression, although the
      latter occurred in lower amounts. This paralleled a dramatic reduction in viral
      load and increase in CD4+ T cell counts. Type 2 cytokine-specific mRNA expression
      fell to undetectable levels and in some cases reappeared later in the course of
      HAART. Predominant expression of type 2 cytokine mRNA, before initiation of
      HAART, concurs with previous findings of a dominant antiproliferative, type 2
      cytokine profile during HIV-1 infection. Reversion of the cytokine profile, after
      HAART, to a strong type 1 profile suggests that in addition to suppressing virus
      replication directly the immune system may be given a chance to recover.

PMID- 10580401
TI  - Activation-induced CD4+ T cell death in HIV-positive individuals correlates with
      Fas susceptibility, CD4+ T cell count, and HIV plasma viral copy number.
AB  - The relevance of activation-induced cell death (AICD) of CD4+ T cells to AIDS
      pathogenesis is unknown. The present study investigates the relationship of AICD
      to a defined molecular mechanism regulating peripheral T cell homeostasis, Fas
      mediated apoptosis, and clinical correlates of the pathogenesis of AIDS.
      Increased pokeweed mitogen (PWM)-induced AICD (22.8 versus 4.4%, p = 0.006) and
      Fas-mediated apoptosis (27.7 versus 12.0%, p = 0.002) of CD4+ T cells were
      observed in HIV+ versus HIV- individuals. Similarly, increased PWM-mediated AICD
      (16.2 versus 2.2%, p < 0.001) and Fas-mediated apoptosis (25.8 versus 7.6%, p =
      0.005) were noted in CD8+ T cells from HIV+ versus HIV- individuals. PWM-induced
      AICD of CD4+ T cells was blocked (83% median specific inhibition) by Fas-blocking
      antibodies, whereas PWM-induced AICD of CD8+ T cells was Fas independent.
      Comparison between PWM- and anti-CD3-mediated AICD of CD4+ T cells indicated that
      PWM- and not CD3-induced AICD is Fas dependent. HIV+ individuals with an HIV RNA
      copy number of <30,000 copies/ml had lower PWM-induced AICD of CD4+ T cells than
      did those with an HIV RNA copy number of >30,000 copies/ml (5.7 versus 22.1%, p =
      0.034), and PWM-induced AICD inversely correlated with CD4+ T cell count (R = 
      0.567, p = 0.043). Initiation of HAART decreased PWM-induced CD4+ T cell AICD
      from 24.4 to 9.4% posttreatment (p = 0.035). These results demonstrate that PWM
      induced AICD of CD4+ T cells from HIV+ individuals is mediated by Fas/FasL,
      parallels the in vivo susceptibility of the CD4+ T cell to Fas-mediated
      apoptosis, and correlates with clinical markers of AIDS pathogenesis and response
      to HAART.

PMID- 10580402
TI  - Effect of long-term infection with nef-defective attenuated HIV type 1 on CD4+
      and CD8+ T lymphocytes: increased CD45RO+CD4+ T lymphocytes and limited
      activation of CD8+ T lymphocytes.
AB  - Members of the Sydney Blood Bank Cohort (SBBC) have been infected with an
      attenuated strain of HIV-1 with a natural nef/LTR mutation and have maintained
      relatively stable CD4+ T lymphocyte counts for 14-18 years. Flow cytometric
      analysis was used to examine the phenotype of CD4+ and CD8+ T lymphocytes in
      these subjects, including the immunologically important naive (CD45RA+CD62L+),
      primed (CD45RO+), and activated (CD38+HLA-DR+ and CD28-) subsets. The median
      values were compared between the SBBC and control groups, comprising age-, sex-,
      and transfusion-matched HIV-1-uninfected subjects; transfusion-acquired HIV-1
      positive LTNPs; and sexually acquired HIV-1-positive LTNPs. Members of the SBBC
      not only had normal levels of naive CD4+ and CD8+ T lymphocytes, but had primed
      CD45RO+ CD4+ T lymphocytes at or above normal levels. Furthermore, these primed
      cells expressed markers suggesting recent exposure to specific antigen. SBBC
      members exhibited variable activation of CD8+ T lymphocytes. In particular, SBBC
      members with undetectable plasma HIV-1 RNA had normal levels of activated CD8+ T
      lymphocytes. Therefore, the result of long-term infection with natural nef/LTR
      mutant HIV-1 in these subjects suggests a decreased cytopathic effect of
      attenuated HIV-1 on susceptible activated CD4+ T lymphocyte subsets in vivo, and
      minimal activation of CD8+ T lymphocytes.

PMID- 10580403
TI  - Phylogeny of a novel family of human endogenous retrovirus sequences, HERV-W, in
      humans and other primates.
AB  - A novel human endogenous retrovirus, HERV-W, has been characterized on the basis
      of multiple sclerosis-associated retrovirus (MSRV) probes. We have analyzed the
      phylogenetic distribution of HERV-W in humans and other primate species. As HERV
      W presents a C/D chimeric nature and is largely composed of deleted elements,
      Southern blots were performed using gag, pol, env, and LTR probes. The relative
      complexities observed for gag, pol, env, and LTR regions were similar in humans,
      apes, and Old World monkeys, the minimal number of bands observed after Southern
      blot analysis being 25, 50, 10, and at least 100, respectively. The HERV-W family
      entered the genome of catarrhines more than 25 million years ago.

PMID- 10580404
TI  - Resistance of the human immunodeficiency virus to the inhibitory action of
      negatively charged albumins on virus binding to CD4.
AB  - Negatively charged albumins (NCAs) have been identified as potent inhibitors of
      HIV-1 replication in vitro. Time of addition studies suggest that succinylated
      and aconitylated human serum albumin (Suc-HSA and Aco-HSA) act at an early stage
      of the virus life cycle, and surface plasmon resonance (BIAcore) experiments have
      confirmed a direct interaction of NCAs with HIV-1 gp120. Resistance to Suc-HSA
      and Aco-HSA was analyzed by characterizing HIV-1 variants that were selected in
      cell culture after serial passage of the NL4-3 strain in the presence of the
      compounds. After 24 passages (126 days) we isolated variants that were resistant
      to Suc-HSA (>27-fold) and Aco-HSA (37-fold), as compared with the wild-type NL4-3
      virus. The binding of the NCA-resistant HIV strains to CD4+ MT-4 cells could no
      longer be inhibited by either Suc- or Aco-HSA. The emergence of mutations in the
      envelope gp120 of the resistant virus paralleled the emergence of the resistant
      phenotype. The Suc-HSA-resistant strain was 100-fold cross-resistant to the G
      quartet-containing oligonucleotide AR177 (Zintevir, an HIV-binding inhibitor),
      and partially cross-resistant to dextran sulfate, but remained sensitive to the
      bicyclam AMD3100 and the chemokine SDF-1alpha, which block HIV replication by
      interaction with the chemokine receptor CXCR4. Furthermore, neither Suc-HSA nor
      Aco-HSA inhibited the binding of monoclonal antibodies 12G5 and 2D7 (directed to
      CXCR4 and CCR5, respectively) in SUPT-1 cells or THP-1 cells. These results
      confirm that NCAs bind primarily to gp120 and do not interact directly with the
      HIV chemokine receptor but block the binding of the virus particles (through
      gp120) with CD4+ cells.

PMID- 10580405
TI  - Human immunodeficiency virus infection of human placental cord blood CD34+AC133+
      stem cells and their progeny.
AB  - The AC133 is a novel antigen selectively expressed on primitive CD34bright stem
      cells and is a valuable marker for the selection of long-term culture-initiating
      cells (LTC-ICs) and severe combined immunodeficiency (SCID)-repopulating cells.
      Human placental cord blood (HPCB) is a rich source of CD34+AC133+ cells. Since
      AC133 antibody is likely to be used as an alternative to CD34 for the selection
      of stem cells in transplant and gene therapy situations, we examined the
      susceptibility of HPCB-isolated CD34+AC133+ stem cells to infection with free and
      cell-associated HIV-1 in vitro. Freshly isolated HPCB CD34+AC133+ stem cells were
      not susceptible to HIV-1 infection as determined by PCR and reverse transcriptase
      assays. Inoculation with HIV-1 did not affect the viability and clonogenic
      ability of HPCB CD34+AC133+ cells. Although the highly purified HPCB CD34+AC133+
      stem cells contained mRNA for CD4 and CXCR4 receptors, CD4 and CXCR4 proteins
      were not expressed on these cells. Similarly, CCR5 protein, the major macrophage
      tropic HIV-1 coreceptor, was not expressed in freshly isolated HPCB CD34+AC133+
      stem cells, although the transcript for CCR5 was identified in these cells.
      Expression of CD4, CXCR4, and CCR5 receptor proteins on the progeny derived from
      HPCB CD34+AC133+ stem cells was detected and correlated with susceptibility to
      HIV-1 infection in vitro. These findings suggest that freshly isolated HPCB
      CD34+AC133+ stem cells are not susceptible to HIV-1 infection and may not be a
      viral reservoir. These data have important implications for the use of AC133
      antibody as a means of enriching for primitive hematopoietic stem cells from
      placental cord blood and in the design of stem cell or progenitor cell-based gene
      therapeutic strategies for perinatal HIV-1 infection.

PMID- 10580406
TI  - T cell-derived suppressive activity: evidence of autocrine noncytolytic control
      of HIV type 1 transcription and replication.
AB  - The ability of CD8+ T lymphocytes to suppress the transcription and replication
      of HIV-1 is well documented. We have demonstrated that the factor(s) responsible
      for the suppression of HIV-1 LTR-mediated gene expression are not the CC
      chemokines RANTES, MIP-1alpha, and MIP-1beta. Interestingly, these and other
      chemokines and cytokines are produced by both CD8+ and CD4+ T lymphocytes. On the
      presumption that CD4+ T lymphocytes may also be able to modulate HIV-1 expression
      in vitro we assessed the LTR-modulatory effects of a panel of culture
      supernatants derived from stimulated CD4+ T lymphocytes from HIV-positive
      patients and uninfected controls. Supernatants of both CD4+ and CD8+ T cells
      mediated a suppression of LTR-driven gene expression in Jurkat T cells and an
      enhancement of gene expression in U38 monocytic cells. On the basis of these
      results, and using a herpesvirus saimiri (HVS)-transformed CD4+ T lymphocyte
      clone (HVSCD4), we demonstrate that both suppressive and enhancing effects are
      dose dependent. Furthermore, we have shown that supernatants of both HVSCD4 and
      HVSCD8 cells suppress LTR-mediated gene expression and HIV-1 replication in
      transfected/infected T cells. In U1 monocytic cells, supernatants of both CD4+
      and CD8+ lymphocytes from an HIV-1-infected individual enhanced LTR-mediated gene
      expression, HIV-1 replication, and TNF-alpha production. However, only these
      effects as induced by CD8+ T cells were sensitive to the G protein inhibitor
      pertussis toxin. These results indicate that factors produced by both CD4+ and
      CD8+ T cells exert dichotomous effects on HIV-1 gene expression and replication
      in T cells and monocytes.

PMID- 10580408
TI  - Lack of differences in nef alleles among HIV-infected asymptomatic long-term
      survivors and those who progressed to disease.
AB  - Sequences of the human immunodeficiency virus (HIV) nef gene in virus isolates
      from 12 long-term survivors (LTSs) and 7 progressors were compared to determine
      if any association existed between the sequences and the corresponding clinical
      status. The sequences of at least five clones were determined for each subject.
      Conceptual translations of the open reading frames (ORFs) were examined with
      respect to a consensus with a prototypic nef sequence (HIV-1SF2) and for
      conservation of functionally described motifs. Premature stops were observed at
      equivalent, yet low, frequencies among the different clinical groups: 2 of 60
      (3.33%) and 1 of 45 (2.22%) respectively. No remarkable differences in protein
      motifs implicated in several activities ascribed to Nef were noted. An
      association between nef sequence characteristics and the clinical state was not
      found.

PMID- 10580407
TI  - Primary isolate neutralization by HIV type 1-infected patient sera in the era of
      highly active antiretroviral therapy.
AB  - Sera from highly selected HIV-1-positive patients are known to have the ability
      to neutralize a diverse array of primary isolates of HIV-1. The human
      osteosarcoma cell line that expresses CD4 and chemokine receptors (GHOST cells)
      was adapted to study HIV-1 neutralization in 37 HIV-1-infected individuals who
      were selected because of slow disease progression or nonprogression. Many of
      these individuals were receiving combination drug therapy. Molecularly cloned HIV
      1 JR-FL and NL4-3 viruses were used as prototypes to define assay conditions.
      Sera were then tested at a 1:40 dilution against six additional primary isolates,
      three of which utilized CCR5 and three of which used both CCR5 and CXCR4. The
      assay was highly reproducible and independent of viral input titer, with a
      readout at 48 hr equivalent to that at later time points. As previously reported,
      neutralization sensitivity was entirely independent of coreceptor usage. Only a
      few sera from slow progressors were able to neutralize a broad array of primary
      isolates at a 1:40 dilution, and the best clinical predictor of broadly
      neutralizing antibody for primary isolates was the present use of antiretroviral
      agents. In further studies it was found that purified antibody accounted for the
      majority of the measured neutralization. However, experiments with exogenous
      addition of antiviral agents showed that the use of nucleosides also greatly
      contributed to the measured neutralization in some patients. Measurement of
      neutralization of HIV-1 primary isolates by sera from patients receiving
      antiretroviral therapy must be carried out with some caution.

PMID- 10580409
TI  - Circulation of subtype A and gagA/envB recombinant HIV type 1 strains among
      injecting drug users in St. Petersburg, Russia, correlates with geographical
      origin of infections.
AB  - Countries of the former Soviet Union are experiencing an emerging HIV-1 epidemic
      due to a rapid expansion of HIV-1 among injecting drug users (IDUs). To study the
      molecular epidemiology of HIV-1 among IDUs in St. Petersburg, Russia, virus
      sequences were obtained from 22 individuals. Phylogenetic analysis of the env and
      gag regions revealed circulation of two major HIV-1 populations, one belonging to
      HIV-1 subtype A, and another being a recombinant of subtype A and B viruses
      (gagA/envB). Both virus populations were highly homogeneous, with a mean pairwise
      genetic distance of <2%, and similar to viruses obtained earlier from IDUs in
      other regions of the former Soviet Union. Distribution of the two major HIV-1
      genotypes in St. Petersburg correlated with geographical origin of infections. In
      one individual, a virus type previously unseen among IDUs was found, which
      demonstrates the possibility that new viruses are entering this risk group.

PMID- 10580410
TI  - An unusual HIV type 1 env sequence embedded in a mosaic virus from Cameroon:
      identification of a new env clade. European Network on the study of in utero
      transmission of HIV-1.
AB  - An atypical HIV-1 strain (CAM001) was identified in a pregnant Cameroonian woman
      in 1995. HMA subtyping of the env region was unsuccessful, and sequence analyses
      were performed. Unique sequence motifs were found at the V3 tip (GAGRALHA and
      GAGRAWIHA), and phylogenetic studies showed that the env C2-V5 sequence branched
      within group M but remained distinct from all known HIV-1 subtypes, while p17 gag
      branched with the subtype F sequences. Four other HIV group M viruses,
      undetermined by HMA, of African origin were found to cluster with CAM001 in the
      C2-V5 sequences. With the BLAST method, we found in databases three strains whose
      V3 sequences also clustered with CAM001. These unusual env sequences from eight
      HIV-1 strains derived from Cameroon formed a separate cluster in HIV-1 group M,
      which we designated k.

PMID- 10580411
TI  - Differential stability of the mRNA secondary structures in the frameshift site of
      various HIV type 1 viruses.
AB  - For many retroviruses, one or more ribosomal frameshift events are required for
      translation of the Gag-Pol precursor protein, which is subsequently processed
      into the structural and enzymatic proteins found in mature virions. A specific
      nucleotide motif, the slippery sequence, as well as a downstream mRNA secondary
      structure are generally believed to have roles in the frameshift event. In HIV-1,
      a particular stem-loop mRNA secondary structure has been proposed for subtype B.
      On the basis of this model, HIV-1 subtypes A, E, and F were found in this study
      to share a similar stem-loop structure predicted to have a lower thermodynamic
      stability as compared with HIV-1 subtypes B, C, and D. The potential impact of
      this differential thermodynamic stability on HIV-1 replication remains to be
      determined.

PMID- 10580412
TI  - How are free fatty acids transported in membranes? Is it by proteins or by free
      diffusion through the lipids?
AB  - Although transport of long-chain free fatty acids (FFAs) into cells is often
      analyzed in the same way as glucose transport, we argue that the transport of the
      lipid-soluble amphipathic FFA molecule must be viewed differently. The
      partitioning of FFAs into phospholipid bilayers and their interfacial ionization
      are particularly relevant to transport. We summarize new data supporting the
      diffusion hypothesis in simple lipid bilayers and in plasma membranes of cells.
      Along with previous supporting data, the new data indicate that transport of FFAs
      through membranes could occur rapidly by flip-flop of the un-ionized form of the
      FFA. It appears that, at least for the adipocyte, passive diffusion guarantees
      fast entry and exit of FFAs at both low and high concentrations. Although there
      are several candidate proteins for the membrane transport of FFAs, most of these
      proteins have other established functions. Thus, unlike the glucose transporters,
      these proteins would not be single-function proteins. Definitive proof of their
      function as FFA transporters awaits their reconstitution into simple model
      systems.

PMID- 10580413
TI  - Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in
      increased beta-cell mass and improved glucose tolerance in diabetic rats.
AB  - Diabetes is a disease of increasing prevalence in the general population and of
      unknown cause. Diabetes is manifested as hyperglycemia due to a relative
      deficiency of the production of insulin by the pancreatic beta-cells. One
      determinant in the development of diabetes is an inadequate mass of beta-cells,
      either absolute (type 1, juvenile diabetes) or relative (type 2, maturity-onset
      diabetes). Earlier, we reported that the intestinal hormone glucagon-like peptide
      I (GLP-I) effectively augments glucose-stimulated insulin secretion. Here we
      report that exendin-4, a long-acting GLP-I agonist, stimulates both the
      differentiation of beta-cells from ductal progenitor cells (neogenesis) and
      proliferation of beta-cells when administered to rats. In a partial
      pancreatectomy rat model of type 2 diabetes, the daily administration of exendin
      4 for 10 days post-pancreatectomy attenuates the development of diabetes. We show
      that exendin-4 stimulates the regeneration of the pancreas and expansion of beta
      cell mass by processes of both neogenesis and proliferation of beta-cells. Thus,
      GLP-I and analogs thereof hold promise as a novel therapy to stimulate beta-cell
      growth and differentiation when administered to diabetic individuals with reduced
      beta-cell mass.

PMID- 10580414
TI  - Evidence for glucose/hexosamine in vivo regulation of insulin/IGF-I hybrid
      receptor assembly.
AB  - Hybrid receptors composed of an insulin alphabeta-hemireceptor and a type 1 IGF
      alphabeta-hemireceptor are formed in tissues expressing both molecules. We
      recently reported an increased hybrid receptor expression in skeletal muscle of
      type 2 diabetic patients that is inversely correlated with in vivo insulin
      sensitivity. It is unclear whether these changes were due to primary
      abnormalities or to secondary derangements acting in vivo, such as hyperglycemia.
      To address this, we determined abundance of hybrids in skeletal muscle from three
      groups of rats: controls, diabetic (90% pancreatectomy), and diabetic treated
      with phlorizin to normalize plasma glucose levels. We found that the abundance of
      hybrid receptors was higher in diabetic rats compared with control and phlorizin
      treated diabetic rats (percentage of 125I-insulin bound versus total added
      radioactivity [B/T] = 1.8+/-0.11, 0.4+/-0.01, and 0.32+/-0.04, respectively; P <
      0.0001). Fasting plasma glucose levels were positively correlated with hybrids
      abundance (r = 0.77, P < 0.002). Hybrid receptor protein content, assessed by
      immunoblotting, was 2.4-fold higher in diabetic rats as compared with control and
      phlorizin-treated diabetic rats. Because it has been shown that some of the
      regulatory effects of glucose may be mediated by the glucosamine pathway, we
      subsequently determined the effect of an in vivo glucosamine infusion on hybrid
      receptor formation. We found that abundance of hybrids was significantly higher
      in muscle from glucosamine-treated rats compared with control rats (B/T = 0.17+/
      0.02 and 0.11+/-0.01, respectively; P < 0.009). Quantitation of hybrid content by
      immunoblotting revealed that their abundance was 1.9-fold higher in glucosamine
      treated rats. The results demonstrate that 1) elevated glucose levels in diabetic
      rats are associated with increased expression of hybrid receptors in muscle, 2)
      correction of hyperglycemia with phlorizin completely reverses increased
      expression of hybrids, and 3) glucosamine infused into control rats mimics the
      effects of hyperglycemia on hybrid receptor formation. Thus, the results support
      the hypothesis that glucose acting, at least in part, through the glucosamine
      pathway may play an important role in regulating hybrid receptor assembly in
      vivo.

PMID- 10580415
TI  - Hypothalamic neuronal histamine as a target of leptin in feeding behavior.
AB  - Leptin, an ob gene product, has been shown to suppress food intake by regulating
      hypothalamic neuromodulators. The present study was designed to examine the
      involvement of brain histamine in leptin-induced feeding suppression. A bolus
      infusion of 1.0 microg leptin into the rat third cerebroventricle (i3vt) elevated
      the turnover rate of hypothalamic neuronal histamine (P < 0.05) as assessed by
      pargyline-induced accumulation of tele-methylhistamine (t-MH), a major metabolite
      of histamine. No remarkable change in the mRNA expression of histidine
      decarboxylase (HDC), a histamine-synthesizing enzyme, was observed in the
      hypothalamus after i3vt infusion of leptin. These results indicate that leptin
      increases histamine turnover by affecting the posttranscriptional process of HDC
      formation or histamine release per se. As expected, concomitant suppression in 24
      h cumulative food intake was also observed after infusion of leptin. Systemic
      depletion of brain histamine levels by pretreatment with an intraperitoneal
      injection of 224 micromol/kg alpha-fluoromethylhistidine (FMH), a suicide
      inhibitor of HDC, attenuated the leptin-induced feeding suppression by 50.7% (P <
      0.05). This attenuation of feeding suppression was mimicked by the i3vt infusion
      of 2.24 micromol/kg FMH before leptin treatment (P < 0.05). In addition,
      concentrations of hypothalamic histamine and t-MH were lowered in diabetic
      (db/db) mice, which are known to be deficient in leptin receptors (P < 0.05 vs.
      lean littermates for each amine), although the amine levels were higher in diet
      induced obese rats (P < 0.05 for each amine). Leptin-deficient obese mice (ob/ob)
      showed lower histamine turnover (P < 0.05 vs. lean littermates), which recovered
      after leptin infusion. Thus, a growing body of results points to an important
      role for the hypothalamic histamine neurons in the central regulation of feeding
      behavior controlled by leptin.

PMID- 10580416
TI  - Effects of graft-versus-host reaction on intrahepatic islet transplants.
AB  - The use of donor-specific bone marrow transplantation might represent a valuable
      approach for the induction of hyporesponsiveness to concurrent allogeneic organ
      and tissue grafts. In this setting, the occurrence of subclinical forms of graft
      versus-host reaction (GVHR) can seldom be formally ruled out. When systemic
      administration of donor-specific bone marrow is performed together with
      intraportal transplantation of islets of Langerhans, GVHR might damage the
      implanted islets through an innocent bystander mechanism. The liver is, in fact,
      a prominent target of GVHR, and islets are sensitive to the noxious effects of
      proinflammatory mediators, including selected cytokines produced during GVHR. A
      parent (Lewis) to F1 (Lewis x Brown Norway) splenocyte transfer model was used to
      induce GVHR in rats. Islets were also obtained from Lewis donors and implanted
      into F1 recipients to examine the effects of GVHR on islet function in the
      absence of rejection. Selected doses of splenocytes were infused in F1 recipients
      to induce GVHR. When 150 x 10(6) cells were administered, all recipients
      developed clinical lethal GVHR. When 100 x 10(6) or 80 x 10(6) cells were given,
      lethal GVHR was observed in 40 and 20% of the F1 animals, respectively. A
      transient clinical syndrome occurred in the remaining animals and spontaneously
      subsided; histological findings consistent with persistent low-grade GVHR were
      observed in these animals at the time of death several months after splenocyte
      inoculation. When simultaneous splenocyte infusions and islet grafts were
      performed in chemically diabetic animals, no adverse effect of either clinical or
      subclinical GVHR was observed on islet function. Blood glucose profiles were
      normal, as were intravenous glucose tolerance test profiles. In conclusion, GVHR
      does not seem to adversely influence function of islets of Langerhans implanted
      intrahepatically in this parent to F1 experimental model.

PMID- 10580417
TI  - Immunotherapy of NOD mice with bone marrow-derived dendritic cells.
AB  - We evaluated two bone marrow-derived dendritic cell (DC) populations from NOD
      mice, the murine model for type 1 human diabetes. DCs derived from GM-CSF
      [granulocyte/macrophage colony-stimulating factor] + interleukin (IL)-4 cultures
      expressed high levels of major histocompatibility complex (MHC) class II, CD40,
      CD80, and CD86 molecules and were efficient stimulators of naive allogeneic T
      cells. In contrast, DCs derived from GM-CSF cultures had low levels of MHC class
      II costimulation/activation molecules, were able to take up mannosylated bovine
      serum albumin more efficiently than GM + IL-4 DCs, and were poor T-cell
      stimulators. The two DC populations migrated to the spleen and pancreas after
      intravenous injection. To determine the ability of the two DC populations to
      modulate diabetes development, DCs were pulsed with a mixture of three islet
      antigen-derived peptides or with medium before injection into prediabetic NOD
      mice. Despite phenotypic and functional differences in vitro, both populations
      prevented in vivo diabetes development. Pulsing of the DCs with peptide in vitro
      did not significantly improve the ability of DCs to prevent disease, which
      suggests that DCs may process and present antigen to T-cells in vivo. In
      addition, we detected GAD65 peptide-specific IgG1 antibody responses in DC
      treated mice. Overall, these results suggest that a Th2 response was generated in
      DC-treated mice. This response was optimal when using GM + IL-4 DCs, which
      suggests that the balance between regulatory Th2 and effector Th1 cells may have
      been altered in these mice.

PMID- 10580418
TI  - Autoantibodies to CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) in
      Caucasian patients with diabetes: effects on insulin release from human islets.
AB  - The type II transmembrane glycoprotein CD38 (ADP-ribosyl cyclase/cyclic ADP
      ribose hydrolase) has been proposed as a mediator of insulin secretion from
      pancreatic beta-cells and as a candidate for autoimmune reactions in type 2
      diabetes. We evaluated the presence of anti-CD38 autoantibodies in Caucasian
      patients with diabetes and investigated the effect of these antibodies on insulin
      secretion from isolated human pancreatic islets. The presence of anti-CD38
      autoantibodies was evaluated by using Western blot analysis in 236 patients with
      type 2 diabetes (mean age 63 years), in 160 patients with type 1 diabetes (mean
      age 38 years), and in 159 nondiabetic subjects. Anti-CD38 autoantibody titers at
      least 3 SD above the mean value of the control group were found in 9.7% of type 2
      diabetic patients and in 13.1% of type 1 diabetic patients (chi2 = 15.9, P =
      0.0003 vs. 1.3% of control subjects). No significant differences were observed in
      sex distribution, current age, age at diabetes onset, BMI, fasting serum glucose,
      or glycemic control between anti-CD38+ and anti-CD38-diabetic patients in either
      the type 2 or type 1 diabetic groups. The effect of 23 anti-CD38- and 13 anti
      CD38+ sera on insulin secretion at low (3.3 mmol/l) or high (16.7 mmol/l) medium
      glucose concentrations was evaluated in isolated human pancreatic islets. Data
      are medians (interquartile range). The anti-CD38+ sera potentiated insulin
      release both at low [95 (64) vs. 23 (12) microU/ml of control incubations,
      respectively, P < 0.0001] and high [271 (336) vs. a control of 55 (37) microU/ml,
      respectively, P = 0.001] medium glucose concentrations, whereas the anti-CD38-
      sera did not. Furthermore, in the pooled data from all 36 tested sera, insulin
      levels in the islet incubation medium were directly related to the anti-CD38
      antibody titer. We conclude that autoantibodies to CD38 are associated with both
      type 1 and type 2 diabetes in Caucasian subjects. These autoantibodies exert a
      stimulatory effect on insulin secretion by cultured human islets. The role of
      this autoimmune reaction in the pathogenesis of diabetes remains to be
      elucidated.

PMID- 10580419
TI  - Circulating antibodies against an exocrine pancreatic enzyme in type 1 diabetes.
AB  - In this article, we report the identification of a new autoantigen in type 1
      diabetes originating from the exocrine pancreas. This antigen is a pancreatic
      enzyme termed bile salt-dependent lipase (BSDL). We show that antibodies present
      in the sera of newly diagnosed type 1 diabetic patients recognize BSDL and more
      specifically the COOH-terminal mucin-like region of the protein. Therefore, we
      engineered the COOH-terminal peptide of BSDL and demonstrated that autoreactivity
      was linked to specific glycosylation sites by at least two glycosyltransferases:
      the Core 2 beta(1-6)N-acetylglucosaminyltransferase and the alpha(1-3)
      fucosyltransferase FUT7. We next examined the prevalence of circulating anti-BSDL
      antibodies in type 1 diabetic patients and found 73.5% positivity (25 sera among
      34 patients tested) at onset, whereas only 8.4% of normal individuals (7 of 83)
      were positive. Within a cohort of first-degree relatives of diabetic patients
      followed prospectively until development of diabetes, 6 of 19 (31.6%) were also
      positive. Interestingly, two prediabetic individuals were already positive for
      anti-BSDL antibodies (Abs), while islet cell cytoplasmic Abs and antibodies to
      GAD65, IA-2, and insulin were not detected. Anti-BSDL autoantibodies were weakly
      or not detected in patients suffering from pancreatitis or pancreatic
      adenocarcinoma or in patients with Graves' disease. Although autoreactivity to
      BSDL in prediabetic and newly diagnosed diabetic patients might reflect cross
      reactivity, our results strongly suggest that in addition to pancreatic beta
      cells, acinar cells may be also affected in type 1 diabetes.

PMID- 10580420
TI  - Beta-cell maturation leads to in vitro sensitivity to cytotoxins.
AB  - Pancreatic beta-cells are more sensitive to several toxins (e.g., streptozotocin,
      alloxan, cytokines) than the other three endocrine cell types in the islets of
      Langerhans. Cytokine-induced free radicals in beta-cells may be involved in beta
      cell-specific destruction in type 1 diabetes. To investigate if this sensitivity
      represents an acquired trait during beta-cell maturation, we used two in vitro
      cultured cell systems: 1) a pluripotent glucagon-positive pre-beta-cell phenotype
      (NHI-glu) that, after in vivo passage, matures into an insulin-producing beta
      cell phenotype (NHI-ins) and 2) a glucagonoma cell-type (AN-glu) that, after
      stable transfection with pancreatic duodenal homeobox factor-1 (PDX-1), acquires
      the ability to produce insulin (AN-ins). After exposure to interleukin (IL)
      1beta, both of the insulin-producing phenotypes were significantly more
      susceptible to toxic effects than their glucagon-producing counterparts. Nitric
      oxide (NO) production was induced in both NHI phenotypes, and inhibition with 0.5
      mmol/l N(G)-monomethyl-L-arginine (NMMA) fully protected the cells. In addition,
      maturation into the NHI-ins phenotype was associated with an acquired dose
      dependent sensitivity to the toxic effect of streptozotocin. Our results support
      the hypothesis that the exquisite sensitivity of beta-cells to IL-1beta and
      streptozotocin is an acquired trait during beta-cell maturation. These two cell
      systems will be useful tools for identification of molecular mechanisms involved
      in beta-cell maturation and sensitivity to toxins in relation to type 1 diabetes.

PMID- 10580421
TI  - Early prophylaxis with recombinant human interleukin-11 prevents spontaneous
      diabetes in NOD mice.
AB  - We evaluated the effects of recombinant human (rh) interleukin (IL)-11 on the
      development of spontaneous and cyclophosphamide-induced diabetes in female NOD
      mice. Prolonged treatment with rhIL-11 10 microg i.p. five consecutive times a
      week between the 4th and 22nd weeks of age significantly suppressed both
      development and cumulative incidence of type 1 diabetes. Disease protection was
      transient because most of the animals developed type 1 diabetes within 3 months
      of treatment withdrawal. In contrast, rhIL-11 failed to prevent type 1 diabetes
      when administered for the first time to euglycemic 18-week-old NOD mice. Most
      likely, this discrepancy was not due to age-dependent differences in the
      immunological responses of NOD mice to rhIL-11 because staphylococcus aureus
      enterotoxin B-induced tumor necrosis factor (TNF) and IL-12 production were
      equally suppressed by rhIL-11 in 12- and 25-week-old NOD mice. Relative to
      controls, NOD mice pretreated with rhIL-11 also showed significantly diminished
      blood levels of TNF, interferon-gamma, and IL-12 induced by anti-CD3 antibody
      and/or lipopolysaccharide. The results demonstrate that rhIL-11 has powerful anti
      inflammatory effects that are capable of down-regulating early immunodiabetogenic
      pathways in NOD mice.

PMID- 10580422
TI  - A critical role for human CD4+ T-cells in rejection of porcine islet cell
      xenografts.
AB  - T-cell-mediated rejection is likely to present a significant barrier to porcine
      islet xenotransplantation. Little is known, however, about human anti-porcine
      islet rejection because no suitable model exists to study this process. To
      address this problem, we have developed an immunodeficient mouse model to study
      rejection of fetal porcine islet cell clusters (ICCs) by human lymphocytes.
      Transplantation of porcine ICCs into hyperglycemic recombinase activating gene
      deficient (R-) mice restores normal blood glucose levels within 5 weeks. Adoptive
      transfer of in vitro-stimulated human peripheral blood mononuclear cells into R-
      mice before islet cell transplantation leads to acute cellular rejection of
      porcine ICCs. The first human cells observed to infiltrate rejecting grafts are
      CD4+ T-cells. Although CD8+ T-cells are observed within the grafts at later time
      points, CD4+ T-cells predominate until the graft is destroyed. Adoptive transfer
      of purified human CD4+ T-cells before ICC transplantation is sufficient to cause
      acute cellular rejection. These data demonstrate that human CD4+ T-cells play a
      critical role in porcine ICC xenograft rejection.

PMID- 10580423
TI  - ATP-sensitive potassium channels and efaroxan-induced insulin release in the
      electrofusion-derived BRIN-BD11 beta-cell line.
AB  - The properties of ATP-sensitive K+ (K(ATP)) channels were explored in the
      electrofusion-derived, glucose-responsive, insulin-secreting cell line BRIN-BD11
      using patch-clamp techniques. In intact cells, K(ATP) channels were inhibited by
      glucose, the sulfonylurea tolbutamide, and the imidazoline compounds efaroxan and
      phentolamine. Each of these agents initiated insulin secretion and potentiated
      the actions of glucose. K(ATP) channels were blocked by ATP in a concentration
      dependent manner and activated by ADP in the presence of ATP. In both intact
      cells and excised inside-out patches, the K(ATP) channel agonists diazoxide and
      pinacidil activated channels, and both compounds inhibited insulin secretion
      evoked by glucose, tolbutamide, and imidazolines. The mechanisms of action of
      imidazolines were examined in more detail. Pre-exposure of BRIN-BD11 cells to
      either efaroxan or phentolamine selectively inhibited imidazoline-induced insulin
      secretion but not the secretory responses of cells to glucose, tolbutamide, or a
      depolarizing concentration of KCl. These conditions did not result in the loss of
      depolarization-dependent rises in intracellular Ca2+ ([Ca2+]i), K(ATP) channel
      operation, or the actions of either ATP or efaroxan on K(ATP) channels.
      Desensitization of the imidazoline receptor following exposure to high
      concentrations of efaroxan, however, was found to result in an increase in SUR1
      protein expression and, as a consequence, an upregulation of K(ATP) channel
      density. Our data provide 1) the first characterization of K(ATP) channels in
      BRIN-BD11 cells, a novel insulin-secreting cell line produced by electrofusion
      techniques, and 2) a further analysis of the role of imidazolines in the control
      of insulin release.

PMID- 10580424
TI  - Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into
      glucagon- and insulin-producing cells.
AB  - In this article, we show that glucagon-like peptide 1 (GLP-1) can induce AR42J
      cells to differentiate into insulin, pancreatic polypeptide, and glucagon
      positive cells. In their natural state, these cells, which are derived from a
      chemically induced pancreatic tumor, possess exocrine and neuroendocrine
      properties but are negative for islet hormones and their mRNAs. We found that
      when these cells were exposed to GLP-1 (1 or 10 nmol), a peptide normally
      released from the gut in response to food and a modulator of insulin release,
      intracellular cAMP levels were increased, and proliferation of cells was
      increased for the first 24 h, followed by inhibition. Up to 50% of the cells
      became positive for islet hormones. The mRNAs for glucose transporter 2 and
      glucokinase were detected in the GLP-1-treated cells. Insulin was detected by
      radioimmunoassay (RIA) in the medium of GLP-1-treated cells, and the cells were
      capable of releasing insulin in a glucose-mediated fashion. Exendin-4, an analog
      of GLP-1, in some critical experiments performed in a similar manner to GLP-1,
      with the exception of it being 10-fold more potent. We therefore propose that GLP
      1 and exendin-4 are capable of causing pancreatic precursor cells to
      differentiate into islet cells.

PMID- 10580425
TI  - Decreased expression of t-SNARE, syntaxin 1, and SNAP-25 in pancreatic beta-cells
      is involved in impaired insulin secretion from diabetic GK rat islets:
      restoration of decreased t-SNARE proteins improves impaired insulin secretion.
AB  - The physiological role of soluble N-ethylmaleimide-sensitive factor attachment
      protein (SNAP) receptor (SNARE) proteins in insulin exocytosis has been reported
      in pancreatic beta-cells. To determine whether the beta-cells of GK rats, a
      nonobese rodent model of type 2 diabetes, exhibit abnormalities in their SNARE
      proteins, we studied the expression and function of target (t)-SNAREs, syntaxin
      1A, and synaptosomal-associated protein of 25 kDa (SNAP-25) in GK rat islets.
      Although insulin release and insulin content of islets isolated from 12-week-old
      GK rats were reduced, the proinsulin biosynthetic rate was about twofold higher
      than that in control rat islets, and no change in the preproinsulin mRNA level
      was observed. Pulse-chase experiments suggested the increased degradation of
      insulin in GK rat islets. Immunoblot analysis revealed that protein levels of
      syntaxin 1A and SNAP-25 in GK rat islets decreased to approximately 60% of the
      levels in control rat islets. We then examined whether the restoration of the
      decreased expression of t-SNAREs to the normal level in GK rat islets affected
      insulin secretion. Restoration was achieved by the overexpression of syntaxin 1A
      and SNAP-25 via the recombinant adenovirus-mediated gene transduction system,
      which recovered levels of these proteins to almost control levels. Glucose
      stimulated insulin release from AdexlCA syntaxin 1A and Adex1CA SNAP-25-infected
      GK rat islets increased up to approximately 135 and 200%, respectively, of those
      from uninfected GK rat islets, although no difference in basal (2.2 mmol/l
      glucose) insulin release was evident between them. We conclude that decreased
      expression of t-SNAREs in GK rat islets is in part the defect responsible for
      impaired insulin secretion.

PMID- 10580426
TI  - Oscillations of insulin secretion can be triggered by imposed oscillations of
      cytoplasmic Ca2+ or metabolism in normal mouse islets.
AB  - Glucose-induced insulin secretion depends on an acceleration of glucose
      metabolism, requires a rise in the cytoplasmic free Ca2+ concentration ([Ca2+]i),
      and is modulated by activation of protein kinases in beta-cells. Normal mouse
      islets were used to determine whether oscillations of these three signals are
      able and necessary to trigger oscillations of insulin secretion. The approach was
      to minimize or abolish spontaneous oscillations and to compare the impact of
      forced oscillations of each signal on insulin secretion. In a control medium,
      repetitive increases in the glucose concentration triggered oscillations in
      metabolism [NAD(P)H fluorescence], [Ca2+]i (fura-PE3 method), and insulin
      secretion. In the presence of diazoxide, metabolic oscillations persisted, but
      [Ca2+]i and insulin oscillations were abolished. When the islets were depolarized
      with high K+ with or without diazoxide, [Ca2+]i was elevated, and insulin
      secretion was stimulated. Forced metabolic oscillations transiently decreased or
      did not affect [Ca2+]i and potentiated insulin secretion with oscillations of
      small amplitude. These oscillations of secretion followed metabolic oscillations
      only when [Ca2+]i did not change. When [Ca2+]i fluctuated, these changes
      prevailed over those of metabolism for timing secretion. Repetitive
      depolarizations with high K+ in the presence of stable glucose (10 mmol/l)
      induced synchronous pulses of [Ca2+]i and insulin secretion with only small
      oscillations of metabolism. Continuous stimulation of protein kinase A (PKA) and
      protein kinase C (PKC) did not dissociate the [Ca2+]i and insulin pulses from the
      high K+ pulses. However, the amplitude of the insulin pulses was consistently
      increased, whereas that of the [Ca2+]i pulses was either increased (PKA) or
      decreased (PKC). In conclusion, metabolic oscillations can induce oscillations of
      insulin secretion independently of but with a lesser effectiveness than [Ca2+]i
      oscillations. Although oscillations in metabolism may cyclically influence
      secretion through an ATP-sensitive K+ channel (K+-ATP channel)-independent
      pathway, their regulatory effects are characterized by a hysteresis that makes
      them unlikely drivers of fast oscillations, unless they also involve [Ca2+]i
      changes through the K+-ATP channel-dependent pathway.

PMID- 10580427
TI  - Increases in phosphorylation of the myosin II heavy chain, but not regulatory
      light chains, correlate with insulin secretion in rat pancreatic islets and
      RINm5F cells.
AB  - Although cytoskeletal proteins such as myosin II are implicated in the control of
      insulin secretion, their precise role is poorly understood. In other secretory
      cells, myosin II is predominantly regulated via the phosphorylation of the
      regulatory light chains (RLC). The current study was aimed at investigating RLC
      phosphorylation in beta-cells. In both the insulin-secreting cell line RINm5F and
      rat pancreatic islets, the RLC was basally phosphorylated on the myosin light
      chain kinase sites (Ser19/Thr18). Phosphorylation at these sites was not
      consistently increased by either metabolic stimuli (glyceraldehyde/glucose) or
      the depolarizing agent KCl. The RLC sites phosphorylated by protein kinase C
      (PKC) (Ser1/Ser2) were unphosphorylated in the basal state, not affected by
      nutrients or KCl, and only slightly increased by the PKC activator phorbol 12
      myristate 13-acetate (PMA). Like the other insulin secretagogues, however, PMA
      did promote serine phosphorylation of the myosin heavy chain (MHC) in RINm5F
      cells. Phosphopeptide mapping suggested that the same peptide was phosphorylated
      under both PMA and glyceraldehyde stimulation, which further extends our previous
      study of the Ca2+-dependent phosphorylation of this protein (Wilson JR, Ludowyke
      RI, Biden TJ: Nutrient stimulation results in a rapid Ca2+-dependent threonine
      phosphorylation of myosin heavy chain in rat pancreatic islets and RINm5F cells.
      J Biol Chem 273:22729-22737, 1998). Overall, our results demonstrate that in
      RINm5F cells and rat pancreatic islets, MHC phosphorylation correlates better
      with insulin secretion than phosphorylation of the RLC. We therefore propose that
      in beta-cells, in contrast to other secretory cells, phosphorylation of the MHC
      is more important than that of the RLC for regulation of the myosin II protein
      complex during insulin secretion.

PMID- 10580428
TI  - Different effects of tolbutamide and diazoxide in alpha, beta-, and delta-cells
      within intact islets of Langerhans.
AB  - Interaction between the different types of cells within the islet of Langerhans
      is vital for adequate control of insulin release. Once insulin secretion becomes
      defective, as in type 2 diabetes, the most useful drugs to increase insulin
      release are sulfonylureas. It is well-known that sulfonylureas block K(ATP)
      channels, which results in depolarization of the membrane that provokes calcium
      influx and increases intracellular calcium concentration ([Ca2+]i), which thereby
      triggers insulin secretion. The sulfonamide diazoxide produces the opposite
      effect: it activates K(ATP) channels, resulting in a decreased insulin secretion.
      Despite such evidence, little is known about the effect of sulfonylureas and
      sulfonamides in non-beta-cells of the islet of Langerhans. In this article, we
      describe the effects of tolbutamide and diazoxide on [Ca2+]i in alpha-, beta-,
      and delta-cells within intact islets of Langerhans. Tolbutamide elicits an
      increase in [Ca2+li in beta- and delta-cells, regardless of glucose
      concentrations. Remarkably, tolbutamide is without effect in alpha-cells. When
      diazoxide is applied, glucose-induced [Ca2+]i oscillations in beta- and delta
      cells are abolished, whereas [Ca2+]i oscillations in alpha-cells remain
      unaltered. Furthermore, the existence of sulfonylurea receptors is demonstrated
      in beta-cells but not in alpha-cells by using binding of glybenclamide-4,4
      difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) combined with immunostaining for
      insulin and glucagon.

PMID- 10580429
TI  - Beneficial effects of antioxidants in diabetes: possible protection of pancreatic
      beta-cells against glucose toxicity.
AB  - Oxidative stress is produced under diabetic conditions and possibly causes
      various forms of tissue damage in patients with diabetes. The aim of this study
      was to examine the involvement of oxidative stress in the progression of
      pancreatic beta-cell dysfunction in type 2 diabetes and to evaluate the potential
      usefulness of antioxidants in the treatment of type 2 diabetes. We used diabetic
      C57BL/KsJ-db/db mice, in whom antioxidant treatment (N-acetyl-L-cysteine [NAC],
      vitamins C plus E, or both) was started at 6 weeks of age; its effects were
      evaluated at 10 and 16 weeks of age. According to an intraperitoneal glucose
      tolerance test, the treatment with NAC retained glucose-stimulated insulin
      secretion and moderately decreased blood glucose levels. Vitamins C and E were
      not effective when used alone but slightly effective when used in combination
      with NAC. No effect on insulin secretion was observed when the same set of
      antioxidants was given to nondiabetic control mice. Histologic analyses of the
      pancreases revealed that the beta-cell mass was significantly larger in the
      diabetic mice treated with the antioxidants than in the untreated mice. As a
      possible cause, the antioxidant treatment suppressed apoptosis in beta-cells
      without changing the rate of beta-cell proliferation, supporting the hypothesis
      that in chronic hyperglycemia, apoptosis induced by oxidative stress causes
      reduction of beta-cell mass. The antioxidant treatment also preserved the amounts
      of insulin content and insulin mRNA, making the extent of insulin degranulation
      less evident. Furthermore, expression of pancreatic and duodenal homeobox factor
      1 (PDX-1), a beta-cell-specific transcription factor, was more clearly visible in
      the nuclei of islet cells after the antioxidant treatment. In conclusion, our
      observations indicate that antioxidant treatment can exert beneficial effects in
      diabetes, with preservation of in vivo beta-cell function. This finding suggests
      a potential usefulness of antioxidants for treating diabetes and provides further
      support for the implication of oxidative stress in beta-cell dysfunction in
      diabetes.

PMID- 10580430
TI  - Localization of the O-linked N-acetylglucosamine transferase in rat pancreas.
AB  - O-linked N-acetylglucosamine transferase (OGT) catalyzes the attachment ofN
      acetylglucosamine (GlcNAc) monosaccharides to the hydroxyl group of serine or
      threonine residues of intracellular proteins and may play an important role in
      the hexosamine pathway. Glucose-induced insulin resistance is mediated by
      increased activity of the hexosamine pathway. In the present study, we examined
      the localization of OGT mRNA and OGT protein in the rat pancreas. The sites of
      OGT mRNA expression were determined by in situ hybridization histochemistry with
      a digoxigenin (DIG)-labeled antisense cRNA probe. Intense hybridization signals
      were present in the exocrine acinar cells, while weaker ones were detected in the
      islets of Langerhans. This distribution was confirmed using additional antisense
      cRNA or oligo-cDNA probes complementary to different regions of OGT mRNA. In
      addition, immunofluorescence staining with antibody raised against OGT stained
      both the exocrine acinar cells and endocrine islet cells. In the acinar cell
      nucleus, the zymogen granule region and contour of the cell were intensely
      stained. In the islets of Langerhans, especially in the alpha-cells, intense
      staining with anti-OGT antibody was observed. These staining patterns were almost
      identical to those seen when staining for the O-linked GlcNAc (O-GlcNAc)
      modification. Immuno-electron microscopy showed that OGT is localized to the
      euchromatin of the nucleus and around the secretory granules of exocrine acinar
      cells and endocrine islet cells. These results suggest that OGT is involved in
      the regulation of transcription and of granular secretion. Thus, one or more O
      GlcNAcylated proteins may be important components of the glucose-sensing
      mechanism in the pancreas.

PMID- 10580431
TI  - A comparison of troglitazone and metformin on insulin requirements in euglycemic
      intensively insulin-treated type 2 diabetic patients.
AB  - Troglitazone and metformin lower glucose levels in diabetic patients without
      increasing plasma insulin levels. We compared the insulin sparing actions of
      these two agents and their effects on insulin sensitivity and insulin secretion
      in 20 type 2 diabetic patients. To avoid the confounding effect of improved
      glycemic control on insulin action and secretion, patients were first rendered
      euglycemic with 4 weeks of continuous subcutaneous insulin infusion (CSII) before
      randomization to CSII plus troglitazone (n = 10) or CSII plus metformin (n = 10);
      euglycemia was maintained for another 6-7 weeks. Insulin sensitivity was assessed
      by a hyperinsulinemic-euglycemic clamp 1) at baseline, 2) after 4 weeks of CSII,
      and 3) after CSII plus either troglitazone or metformin. The 24-h glucose,
      insulin, and C-peptide profiles were performed on the day before the second and
      third glucose clamps. Good glycemic control was achieved with CSII alone and was
      maintained with CSII plus an oral agent (mean 24-h glucose: troglitazone, 6.2+/
      0.6 mmol/l; metformin, 6.2 +/-0.3 mmol/l). Insulin requirements decreased 53%
      with troglitazone compared with CSII alone (48+/-4 vs. 102+/-13 U/day, P <
      0.001), but only 31% with metformin (76+/-13 vs. 110+/-18 U/day, P < 0.005). The
      24-h C-peptide profiles were similar. Normal fasting hepatic glucose output was
      maintained with both agents despite lower insulin levels than on CSII alone.
      Insulin sensitivity did not change significantly with CSII alone or with CSII
      plus metformin, but improved 29% with CSII plus troglitazone (P < 0.005 vs. CSII
      alone) and was then 45% higher than in the CSII plus metformin patients (P <
      0.005). In conclusion, metformin has no effect on insulin-stimulated glucose
      disposal independent of glycemic control in type 2 diabetes. Troglitazone (600
      mg/day) has greater insulin-sparing effects than metformin (1,700 mg/day) in CSII
      treated euglycemic patients. This is probably explained by the peripheral tissue
      insulin-sensitizing effects of troglitazone.

PMID- 10580432
TI  - Insulin resistance syndrome in 8-year-old Indian children: small at birth, big at
      8 years, or both?
AB  - We have studied 477 8-year-old Indian children to define the relationship between
      birth weight and cardiovascular risk factors, including insulin resistance
      syndrome (IRS) variables and plasma total and LDL cholesterol concentrations. All
      risk factors were strongly related to current weight. After adjustment for
      current weight, age, and sex, lower birth weight was associated with higher
      systolic blood pressure (P = 0.008), fasting plasma insulin and 32-33 split
      proinsulin concentrations (P = 0.08 and 0.02), glucose and insulin concentrations
      30 min postglucose (P = 0.06 and 0.04), subscapular/triceps skinfold ratio (P =
      0.003), and plasma total and LDL cholesterol concentrations (P = 0.002 and
      0.001). Lower birth weight was associated with increased calculated insulin
      resistance (homeostasis model assessment [HOMA], P = 0.03), but was not related
      to the HOMA index of beta-cell function. The highest levels of IRS variables and
      total and LDL cholesterol were in children of low birth weight but high fat mass
      at 8 years. Taller height at 8 years predicted higher fasting plasma insulin
      concentrations, insulin resistance, and plasma total and LDL cholesterol
      concentrations. The most insulin-resistant children were those who had short
      parents but had themselves grown tall. Although the implications of our findings
      in relation to height are unclear, interventions to improve fetal growth and to
      control obesity in childhood are likely to be important factors in the prevention
      of cardiovascular disease and IRS in India.

PMID- 10580433
TI  - Antepartum predictors of the development of type 2 diabetes in Latino women 11-26
      months after pregnancies complicated by gestational diabetes.
AB  - In this study, we sought to identify antepartum characteristics that predict the
      de novo development of diabetes 11-26 months after the index pregnancy in a
      carefully characterized cohort of women with gestational diabetes mellitus (GDM).
      Oral and frequently sampled intravenous glucose tolerance tests (OGTTs and
      FSIGTs), hyperinsulinemic-euglycemic clamps with labeled glucose, and body
      composition studies were performed on 91 islet cell antibody-negative Latino
      women with GDM during the third trimester of pregnancy. The women were documented
      to be diabetes-free within 6 months postpartum. Their diabetes status was
      ascertained again between 11 and 26 months postpartum. Logistic regression
      analysis was used to identify independent predictors of the development of
      diabetes within that interval. Fourteen of the women developed diabetes by World
      Health Organization criteria 11-26 months after delivery of the index pregnancy.
      Three antepartum variables were independent predictors of diabetes: the 1-h
      postchallenge plasma glucose concentration from the 100-g OGTT at which GDM was
      diagnosed (higher = increased risk; P = 0.003); an index of pancreatic beta-cell
      compensation for insulin resistance, defined as the product of the 30-min
      incremental plasma insulin:glucose ratio on a 75-g OGTT and the insulin
      sensitivity index from a hyperinsulinemic-euglycemic clamp (lower = increased
      risk, P = 0.009); and the basal glucose production rate after an overnight fast
      (higher = increased risk; P = 0.04). We conclude that postchallenge
      hyperglycemia, poor pancreatic beta-cell compensation for insulin resistance, and
      elevated endogenous glucose production during pregnancy precede the development
      of type 2 diabetes in young Latino women by at least 1-2 years.

PMID- 10580434
TI  - Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent
      relaxation through nitric oxide/O2- imbalance in insulin-resistant rat aorta.
AB  - To investigate underlying mechanisms responsible for the impaired nitric oxide
      (NO)-dependent vascular relaxation in the insulin-resistant state, we examined
      production of both NO and superoxide anion radical (O2-) and those modulating
      factors in aortas obtained from normal (CTR), insulin-treated (INS), or high
      fructose-fed (FR) rats. FR rats showed insulin resistance with endogenous
      hyperinsulinemia, whereas INS rats showed normal insulin sensitivity. Only FR
      aortic strips with endothelium elicited impaired relaxation in response to either
      acetylcholine or calcium ionophore A23187. Endothelial NO synthase (eNOS)
      activity and its mRNA levels were increased only in vessels from INS rats (P <
      0.001), whereas eNOS activity in FR rats was decreased by 58% (P < 0.05) when
      compared with CTR rats. NO production from aortic strips stimulated with A23187
      was significantly lower in FR than CTR rats. In contrast, A23187-stimulated O2-
      production was higher (P < 0.01) in FR than CTR rats. These differences were
      abolished when aortic strips were preincubated in the media including (6R)
      5,6,7,8-tetrahydrobiopterin (BH4), an active cofactor for eNOS. Furthermore, as
      compared with CTR rats, aortic BH4 contents in FR rats were decreased (P <
      0.001), whereas the levels of 7,8-dihydrobiopterin, the oxidized form of BH4,
      were increased, with opposite results in INS rats. These results indicate that
      insulin resistance rather than hyperinsulinemia itself may be a pathogenic factor
      for decreased vascular relaxation through impaired eNOS activity and increased
      oxidative breakdown of NO due to enhanced formation of O2- (NO/O2- imbalance),
      which are caused by relative deficiency of BH4 in vascular endothelial cells.

PMID- 10580435
TI  - Amadori albumin in type 1 diabetic patients: correlation with markers of
      endothelial function, association with diabetic nephropathy, and localization in
      retinal capillaries.
AB  - Nonenzymatic glycation is increased in diabetes. Most studies so far have focused
      on the role of advanced glycation end products (AGEs) in vascular complications,
      whereas the role of early glycation Amadori-modified proteins, which is the
      predominant form of glycated proteins, has not been systemically investigated in
      humans. We developed an antiserum against glycated human serum albumin (HSA) and
      used this to study the role of early glycation products in vascular complications
      in type 1 diabetic patients. Amadori albumin was determined to be the recognition
      epitope of the antiserum. The antibody recognized a specific glucose adduct and a
      conformational component specific for human albumin in Amadori albumin, with no
      recognition of AGEs. Plasma Amadori albumin levels were significantly higher in
      type 1 diabetic patients (n = 55) than in healthy control subjects (n = 60)
      (39.2+/-9.9 vs. 20.9+/-4.0 U/ml, P < 0.0005). Amadori albumin correlated with
      levels of plasma markers of endothelial function von Willebrand factor (r = 0.29,
      P < 0.05) and vascular cell adhesion molecule-1 (r = 0.41, P < 0.005), but not
      soluble E-selectin. In addition, Amadori albumin immunoreactivity was detected in
      the capillaries of retinas of diabetic patients. Plasma levels of Amadori albumin
      were determined in a second group of type 1 diabetic patients with long-standing
      diabetes with (n = 199) or without (n = 192) diabetic nephropathy. Patients with
      nephropathy had higher Amadori albumin levels than did those without it (50.9+/
      9.5 vs. 45.1+/-6.3 U/ml, P < 0.0005). Age-, sex-, and diabetes duration-adjusted
      analyses showed that nephropathy was significantly associated with Amadori
      albumin with an odds ratio (OR [95% CI]) of 1.11 [1.08-1.15] per U/ml increase.
      After additional adjustment for levels of creatinine, glycated hemoglobin,
      cholesterol, triglycerides, blood pressure, preexistent retinopathy, and
      cardiovascular disease, Amadori albumin continued to be significantly associated
      with nephropathy (OR 1.06 [1.01-1.11]) per U/ml increase. Our results are
      consistent with a proposed pathophysiological role of Amadori albumin in
      microvascular complications of type 1 diabetic patients.

PMID- 10580436
TI  - Evidence that elevated glucose causes altered gene expression, apoptosis, and
      neural tube defects in a mouse model of diabetic pregnancy.
AB  - Congenital malformations, including neural tube defects (NTDs), are significantly
      increased in the offspring of diabetic mothers. We previously reported that in
      the embryos of a mouse model of diabetic pregnancy, NTDs are associated with
      reduced expression of the gene Pax-3, which encodes a transcription factor that
      regulates neural tube development, and that reduced expression of Pax-3 leads to
      neuroepithelial apoptosis. In this study, we used three approaches to test
      whether glucose alone could be responsible for these adverse effects of diabetes
      on embryonic development. First, primary culture of embryo tissue in medium
      containing 15 mmol/l glucose inhibited Pax-3 expression compared with culture in
      medium containing 5 mmol/l glucose. Second, inducing hyperglycemia in pregnant
      mice by subcutaneous glucose administration significantly inhibited Pax-3
      expression (P < 0.05), as demonstrated by quantitative reverse transcription
      polymerase chain reaction assay of Pax-3 mRNA, and also increased neural tube
      apoptosis (P < 0.05). NTDs were significantly increased in glucose-injected
      pregnancies when blood glucose levels were >250 mg/dl (P < 0.002) but not in
      moderately hyperglycemic pregnancies (150-250 mg/dl, P = 0.37). Third, phlorizin
      administration to pregnant diabetic mice reduced blood glucose levels and the
      rate of NTDs. As seen with glucose-injected pregnancies, the rate of NTDs in
      phlorizin-treated diabetic pregnancies was related to the severity of
      hyperglycemia, since NTDs were significantly increased in severely hyperglycemic
      (>250 mg/dl) diabetic pregnancies (P < 0.001) but not in moderately hyperglycemic
      pregnancies (150-250 mg/dl, P = 0.35). These two findings, that elevated glucose
      alone can cause the changes in Pax-3 expression observed during diabetic
      pregnancy and that the NTD rate rises with significant increases in blood glucose
      levels, suggest that congenital malformations associated with diabetic pregnancy
      are caused by disruption of regulatory gene expression in the embryo in response
      to elevated glucose.

PMID- 10580437
TI  - Pathophysiological and genetic characterization of the major diabetes locus in GK
      rats.
AB  - Genetic studies of the type 2 diabetes-like GK rat have revealed several
      susceptibility loci for the compound diabetes phenotype. Congenic strains were
      established for Niddm1, the major quantitative trait locus (QTL) for postprandial
      glucose levels, by transfer of GK alleles onto the genome of the normoglycemic
      F344 rat. Despite the polygenic nature of diabetes in GK, the locus-specific
      diabetes phenotype was retained in the congenic strain Niddmla, containing a GK
      derived genomic fragment of 52 cM from the Niddm1 locus. Furthermore, Niddm1 was
      divided into two non-overlapping loci, physically separated in the two congenic
      strains Niddmlb and Niddm1i with distinct metabolic phenotypes. Both strains
      displayed postprandial hyperglycemia and reduced insulin action in isolated
      adipose cells. Furthermore, Niddm1i already exhibits a pronounced in vivo insulin
      secretion defect at 65 days, while Niddm1b develops a relative insulin secretory
      defect at 95 days. This suggests that Niddm1i impairs mechanisms common to
      insulin secretion in pancreatic B-cells and insulin action in adipocytes. Niddm1b
      rats show signs of increasing insulin resistance with age associated with
      obesity, hyperinsulinemia, and dyslipidemia. Moreover, the data indicated
      nonallelic interaction (epistasis) between Niddm1b and Niddm1i on the
      postprandial glucose levels. These data emphasize the pathophysiological
      complexity of diabetes, even within an apparently single QTL, and demonstrate the
      potential of the GK model in transforming the multifactorial diabetes phenotype
      into single traits, suitable for positional cloning.

PMID- 10580438
TI  - A transcriptional repressor regulates mouse GLUT4 gene expression during the
      differentiation of 3T3-L1 cells.
AB  - GLUT4, the major glucose transporter in adipose tissue, is expressed during the
      differentiation of 3T3-L1 cells from preadipocytes to adipocytes. We previously
      examined the mouse GLUT4 promoter activity up to -590 bp, and demonstrated that
      the 5'-flanking region of the GLUT4 gene between -200 and -100 bp contains
      sequences that act as a repressor in preadipocytes, but not in adipocytes. Here
      we examine in detail the activity of this repressor in 3T3-L1 cells. Transient
      transfections indicated that the region extending from -125 to -112 bp functions
      as a repressor element only in preadipocytes. In electrophoretic mobility shift
      assay (EMSA), this GLUT4 repressor element (G4RE) generated specific bands with
      nuclear extracts from preadipocytes, but not from adipocytes. Southwestern blot
      analysis identified a protein of approximately 96 kDa from preadipocytes that
      bound to the G4RE site. Mutation of the G4RE site, which abolished the
      protein/DNA complex formation by EMSA, increased GLUT4 promoter activity only in
      preadipocytes. These results suggest that the G4RE site and its binding protein
      may regulate GLUT4 gene transcription during adipocyte differentiation.

PMID- 10580439
TI  - Parent-offspring trios: a resource to facilitate the identification of type 2
      diabetes genes.
AB  - The transmission disequilibrium test with use of trios (an affected proband with
      both parents) is a robust method for assessing the role of gene variants in
      disease that avoids the problem of population stratification that may confound
      conventional case/control studies and allows the detection of parent-of-origin
      effects. Trios have played a major role in defining genes in a number of
      polygenic conditions, including type 1 diabetes. We assessed the prevalence,
      clinical characteristics, and suitability for defining type 2 susceptibility
      genes of European type 2 diabetes trios. In a Caucasian population in the U.K.,
      only 2.5% of type 2 patients had both parents alive. Using a nationwide strategy,
      we collected 182 trios defined by strict clinical criteria. Immunological and
      genetic testing resulted in the exclusion of 25 trios as a result of latent
      autoimmune diabetes (n = 13), inconsistent family relationships (n = 7), and
      maternally inherited diabetes and deafness (n = 5). The 157 remaining probands
      had similar treatment requirements to familial type 2 diabetic subjects but
      presented at a younger age, were more obese, and more frequently had affected
      parents. Using this resource, we have not found any evidence for linkage
      disequilibrium between type 2 diabetes and the glucokinase gene markers GCK1 and
      GCK2 and the chromosome 20 marker D20S197. We conclude that European type 2
      diabetes trios are difficult to collect but provide an important additional
      approach to dissecting the genetics of type 2 diabetes.

PMID- 10580440
TI  - A piece of my mind. Ward 55.

PMID- 10580441
TI  - Gauging the impact of statins using number needed to treat.

PMID- 10580442
TI  - Report documents causes of child death.

PMID- 10580443
TI  - New vaccine targets childhood pneumonia.

PMID- 10580444
TI  - Child psychiatrists address problem of youth violence.

PMID- 10580445
TI  - From the Centers for Disease Control and Prevention. Safer and healthier foods-
      1900-1999.

PMID- 10580446
TI  - The crisis in clinical research.

PMID- 10580448
TI  - The crisis in clinical research.

PMID- 10580447
TI  - The crisis in clinical research.

PMID- 10580449
TI  - The crisis in clinical research.

PMID- 10580450
TI  - Attitudes toward and definitions of having sex.

PMID- 10580451
TI  - Attitudes toward and definitions of having sex.

PMID- 10580452
TI  - Attitudes toward and definitions of having sex.

PMID- 10580453
TI  - Attitudes toward and definitions of having sex.

PMID- 10580454
TI  - Attitudes toward and definitions of having sex.

PMID- 10580455
TI  - Attitudes toward and definitions of having sex.

PMID- 10580456
TI  - Misadministration of topical bovine thrombin.

PMID- 10580457
TI  - Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid
      arthritis: a randomized controlled trial.
AB  - CONTEXT: In vitro studies have shown that celecoxib inhibits cyclooxygenase 2
      (COX-2) but not COX-1, suggesting that this drug may have anti-inflammatory and
      analgesic activity without adverse upper gastrointestinal (GI) tract effects that
      result from COX-1 inhibition. OBJECTIVE: To test whether celecoxib has efficacy
      as an anti-inflammatory and analgesic with reduced GI tract mucosal damage
      compared with conventional nonsteroidal anti-inflammatory drugs in patients with
      rheumatoid arthritis. DESIGN: Randomized, multicenter, placebo-controlled, double
      blind trial lasting 12 weeks, with follow-up at weeks 2, 6, and 12, from
      September 1996 thorugh February 1998. SETTING: Seventy-nine clinical sites in the
      United States and Canada. PATIENTS: A total of 1149 patients aged 18 years or
      older with symptomatic rheumatoid arthritis who met inclusion criteria were
      randomized; 688 (60%) of these completed the study. INTERVENTIONS: Patients were
      randomized to receive celecoxib, 100 mg, 200 mg, or 400 mg twice per day (n =
      240, 235, and 218, respectively); naproxen, 500 mg twice per day (n = 225); or
      placebo (n = 231). MAIN OUTCOME MEASURES: Improvement in signs and symptoms of
      rheumatoid arthritis as assessed using standard measures of efficacy and GI tract
      safety as assessed by upper GI tract endoscopy before and after treatment,
      compared among treatment groups. RESULTS: All dosages of celecoxib and naproxen
      significantly improved the signs and symptoms of arthritis compared with placebo.
      Maximal anti-inflammatory and analgesic activity was evident within 2 weeks of
      initiating treatment and was sustained throughout the 12 weeks. The incidence of
      endoscopically determined gastroduodenal ulcers in placebo-treated patients was 4
      (4%) of 99, and the incidences across all dosages of celecoxib were not
      significantly different (P>.40): 9 (6%) of 148 with 100 mg twice per day, 6 (4%)
      of 145 with 200 mg twice per day, and 8 (6%) of 130 with 400 mg twice per day. In
      contrast, the incidence with naproxen was 36 (26%) of 137, significantly greater
      than either placebo or celecoxib (P<.001). The overall incidences of GI tract
      adverse effects were 19% for placebo; 28%, 25%, and 26% for celecoxib 100 mg, 200
      mg, and 400 mg twice per day, respectively; and 31 % for naproxen. CONCLUSION: In
      this study, all dosages of celecoxib were efficacious in the treatment of
      rheumatoid arthritis and did not affect COX-1 activity in the GI tract mucosa as
      evidenced by less frequent incidence of endoscopic ulcers compared with naproxen.

PMID- 10580458
TI  - Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs.
AB  - CONTEXT: Nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal
      (GI) toxic effects, such as upper GI tract perforations, symptomatic
      gastroduodenal ulcers, and upper GI tract bleeding (PUBs), are thought to be
      attributable to cyclooxygenase 1 (COX-1) inhibition. Rofecoxib specifically
      inhibits COX-2 and has demonstrated a low potential for causing upper GI injury.
      OBJECTIVE: To compare the incidence of PUBs in patients with osteoarthritis
      treated with rofecoxib vs NSAIDs. DESIGN: Prespecified analysis of all 8 double
      blind, randomized phase 2b/3 rofecoxib osteoarthritis trials conducted from
      December 1996 through March 1998, including one 6-week dose-ranging study, two 6
      week efficacy studies vs ibuprofen and placebo, two 1-year efficacy studies vs
      diclofenac, two 6-month endoscopy studies vs ibuprofen and placebo, and one 6
      week efficacy study vs nabumetone and placebo. SETTING: Multinational sites.
      Participants Osteoarthritis patients (N = 5435; mean age, 63 years [range, 38-94
      years]; 72.9% women). INTERVENTIONS: Rofecoxib, 12.5, 25, or 50 mg/d (n = 1209,
      1603, and 545, respectively, combined) vs ibuprofen, 800 mg 3 times per day (n =
      847), diclofenac, 50 mg 3 times per day (n = 590); or nabumetone, 1500 mg/d (n =
      127) (combined). MAIN OUTCOME MEASURE: Cumulative incidence of PUBs for rofecoxib
      vs NSAIDs, based on survival analysis of time to first PUB diagnosis, using PUBs
      that met pre-specified criteria judged by a blinded, external adjudication
      committee. RESULTS: The incidence of PUBs over 12 months was significantly lower
      with rofecoxib vs NSAIDs (12-month cumulative incidence, 1.3% vs 1.8%; P = .046;
      rate per 100 patient-years, 1.33 vs 2.60; relative risk, 0.51; 95% confidence
      interval, 0.26-1.00). The cumulative incidence of dyspeptic GI adverse
      experiences was also lower with rofecoxib vs NSAIDS over 6 months (23.5% vs
      25.5%; P = .02), after which the incidence rates converged. CONCLUSION: In a
      combined analysis of 8 trials of patients with osteoarthritis, treatment with
      rofecoxib was associated with a significantly lower incidence of PUBs than
      treatment with NSAIDs.

PMID- 10580459
TI  - Hysterectomy and sexual functioning.
AB  - CONTEXT: Women considering hysterectomy often are concerned about its potential
      effects on their sexual functioning but the effects of hysterectomy on sexual
      functioning remain unclear. OBJECTIVE: To examine changes in sexual functioning
      after hysterectomy. DESIGN AND SETTING: A 2-year prospective study (Maryland
      Women's Health Study) of hysterectomy, which included measures of sexual
      functioning prior to hysterectomy and at 6, 12, 18, and 24 months after
      hysterectomy, performed during 1992 and 1993. PATIENTS: Of 1299 women interviewed
      prior to hysterectomy, 1101 (84.8%) completed the study and provided information
      about their sexual functioning. Most were between the ages of 35 and 49 years,
      white, married or living with a partner, and high school graduates. MAIN OUTCOME
      MEASURES: Frequency of sexual relations, dyspareunia, orgasm, vaginal dryness,
      and sexual desire. RESULTS: The percentage of women who engaged in sexual
      relations increased significantly from 70.5% before hysterectomy to 77.6% and
      76.7% at 12 and 24 months after hysterectomy. The rate of frequent dyspareunia
      dropped significantly from 18.6% before hysterectomy to 4.3 % and 3.6% at 12 and
      24 months after hysterectomy. The rates of not experiencing orgasms dropped
      significantly from 7.6% before hysterectomy to 5.2% and 4.9% at 12 and 24 months
      after hysterectomy. Low libido rates also decreased significantly from 10.4%
      before hysterectomy to 6.3% and 6.2% at 12 and 24 months after hysterectomy. The
      distribution of women not reporting vaginal dryness in the past month improved
      significantly from 37.3% before hysterectomy to 46.8% and 46.7% at 12 and 24
      months after hysterectomy. Prehysterectomy depression was associated with
      experiencing dyspareunia, vaginal dryness, low libido, and not experiencing
      orgasms after hysterectomy. CONCLUSIONS: Sexual functioning improved overall
      after hysterectomy. The frequency of sexual activity increased and problems with
      sexual functioning decreased.

PMID- 10580460
TI  - Borrelia burgdorferi-specific immune complexes in acute Lyme disease.
AB  - CONTEXT: Diagnosis of infection with Borrelia burgdorferi, the cause of Lyme
      disease (LD), has been impeded by the lack of effective assays to detect active
      infection. OBJECTIVE: To determine whether B. burgdorferi-specific immune
      complexes are detectable during active infection in LD. DESIGN, SETTING, AND
      PATIENTS: Cross-sectional analysis of serum samples from 168 patients fulfilling
      Centers for Disease Control and Prevention surveillance criteria for LD and 145
      healthy and other disease controls conducted over 8 years. Tests were performed
      blinded. MAIN OUTCOME MEASURE: Detection of B. burgdorferi immune complexes by
      enzyme-linked immunosorbent assay and Western blot. RESULTS: The B. burgdorferi
      immune complexes were found in 25 of 26 patients with early seronegative erythema
      migrans (EM) LD; 105 of 107 patients with seropositive EM LD; 6 of 10 samples
      that were seronegative [corrected] with culture-positive EM; 0 of 12 patients who
      were treated and recovered from LD; and 13 of 13 patients with neurologic LD
      without EM. Among 147 controls, B. burgdorferi immune complex was found in 0 of
      50 healthy individuals; 0 of 40 patients with persistent fatigue; 0 of 7
      individuals with frequent tick exposure; and 2 of 50 patients with other
      diseases. CONCLUSION: These data suggest that B. burgdorferi immune complex
      formation is a common process in active LD. Analysis of the B. burgdorferi immune
      complexes by a simple technique has the potential to support or exclude a
      diagnosis of early as well as active LD infection.

PMID- 10580461
TI  - Challenges to human subject protections in US medical research.
AB  - United States regulations governing federally supported research with human
      subjects derive in part from 2 international codes, the Nuremberg Code and the
      Declaration of Helsinki. The Declaration of Helsinki states that "concern for the
      interests of the subject must always prevail over the interests of science and
      society." The concept of minimal risk and the principle of informed consent are
      the key means by which US federal regulations seek to protect the rights and
      welfare of the individual in the research setting. Current trends in medical
      research-including increased funding, ever-greater capabilities of computers,
      development of new clinical tools that can also be used in research, and new
      research tools developed through research itself are creating greater demand for
      human subjects, for easier recruitment and conscription of these subjects, and
      for unimpeded access to patient medical records and human biological materials.
      Nationally and internationally, there are new pressures to subordinate the
      interests of the subject to those of science and society. The National Bioethics
      Advisory Commission, which is about to undertake a comprehensive review of the US
      system of human subject protections, faces a daunting task.

PMID- 10580462
TI  - A 40-year-old woman with a strong family history of breast cancer.

PMID- 10580463
TI  - An 87-year-old woman taking a benzodiazepine, 1 year later.

PMID- 10580464
TI  - COX-1-sparing NSAIDs--is the enthusiasm justified?

PMID- 10580465
TI  - Keeping research subjects out of harm's way.

PMID- 10580467
TI  - JAMA Patient Page: arthritis.

PMID- 10580466
TI  - Sexual behaviors and reproductive health outcomes: associations with wife abuse
      in India.
AB  - CONTEXT: Wife abuse has been associated with a variety of health concerns.
      Associations between abuse and reproductive health in India are not well known.
      OBJECTIVE: To examine relationships between men's reports of wife abuse and
      reproductive health issues in northern India. DESIGN: Structured face-to-face
      interviews were conducted as part of the male reproductive health supplement of
      the PERFORM System of Indicators Survey, a systematic multistage survey conducted
      in 1995-1996. SETTING: The northern state of Uttar Pradesh, one of the least
      developed states in India. PARTICIPANTS: A total of 6632 married men aged 15 to
      65 years who lived with their wives and completed all survey questions for the
      study variables reported here. MAIN MEASURES: Physically and sexually abusive
      behaviors toward wives, sexual activities outside marriage, sexually transmitted
      disease (STD) symptoms, contraception use, unplanned pregnancies, and
      sociodemographic characteristics. RESULTS: Fifty-four percent of men reported not
      abusing their wives, while 17% reported physically but not sexually abusing their
      wives, 22% reported sexual abuse without physical force, and 7% reported sexual
      abuse with physical force. Abuse was more common among men who had extramarital
      sex (for sexual abuse using force: odds ratio [OR], 6.22; 95% confidence interval
      [CI], 3.98-9.72). Similarly, men who had STD symptoms were more likely to abuse
      their wives (with current symptoms: OR, 2.43; 95% CI, 1.73-3.42). Unplanned
      pregnancies were significantly more common among wives of abusive men, especially
      sexually abusive men who used force (OR, 2.62; 95% CI, 1.91-3.60). CONCLUSIONS:
      Wife abuse appears to be fairly common in northern India. Our findings that
      abusive men were more likely to engage in extramarital sex and have STD symptoms
      suggest that these men may be acquiring STDs from their extramarital
      relationships, thereby placing their wives at risk for STD acquisition, sometimes
      via sexual abuse. These abusive sexual behaviors also may result in an elevated
      rate of unplanned pregnancies.

PMID- 10580468
TI  - Thiophilic metal ion rescue of phosphorothioate interference within the
      Tetrahymena ribozyme P4-P6 domain.
AB  - Divalent metal ions are essential for the folding and catalytic activities of
      many RNAs. A commonly employed biochemical technique to identify metal-binding
      sites in RNA is the rescue of Rp alpha-phosphorothioate (PS) interference by the
      addition of soft divalent metal ions. To access the ability of such experiments
      to accurately identify metal-ion coordinations within a complex RNA fold, we
      report metal-rescue results from the Tetrahymena group I intron P4-P6 domain,
      where the location and coordination of five divalent metal ions have been
      determined by X-ray crystallography [J.H. Cate et al., Nat Struct Biol, 1997,
      4:553]. We used a native gel mobility-shift to assay for P4-P6 folding in the
      presence of various divalent metal ions, and found that even moderate
      concentrations of Mn2+ (> or =0.5 mM) can rescue PS interference at sites that do
      not coordinate metal ions within the P4-P6 crystal structure. To control for such
      effects, 2'-deoxynucleotide interference was used to titrate the Mn2+
      concentration to a level that produces metal-ion-specific rescue (0.3 mM). This
      concentration of Mn2+ specifically rescued four of the six metal-dependent
      phosphorothioate effects within the RNA domain, including PS interference
      resulting from outer-sphere coordination to the metals. Both sites that were not
      specifically rescued make inner-sphere metal-ion coordinations. Cd2+ and Zn2+
      afforded rescue at a smaller subset of the six metal-specific PS sites, though
      again phosphates making outer-sphere coordinations to metal ions were rescued
      preferentially. These data on P4-P6 domain folding reinforce the need for caution
      when interpreting metal-rescue experiments.

PMID- 10580469
TI  - Metastable structures and refolding kinetics in hok mRNA of plasmid R1.
AB  - Programmed cell death by hok/sok of plasmid R1 and pnd/pndB of R483 mediates
      plasmid maintenance by killing of plasmid-free cells. It has been previously
      suggested that premature translation of the plasmid-mediated toxin is prevented
      during transcription of the hok and pnd mRNAs by the formation of metastable
      hairpins in the mRNA at the 5' end. Here, experimental evidence is presented for
      the existence of metastable structures in the 5' leader of the hok and pnd mRNAs
      in vitro. The kinetics of refolding from the metastable to the stable structure
      in the isolated fragments of the 5' ends of both the hok and pnd mRNAs could be
      estimated, in agreement with the structural rearrangement in this region, as
      predicted to occur during transcription and mRNA activation. The refolding rates
      of hok and pnd structures are slow enough to allow for the formation of
      downstream hairpin structures during elongation of the mRNAs, which thereby helps
      to stabilize the metastable structures. Thus, the kinetic refolding parameters of
      the hok and pnd mRNAs are consistent with the proposal that the metastable
      structures prevent premature translation and/or antisense RNA binding during
      transcription.

PMID- 10580470
TI  - Structure of the phylogenetically most conserved domain of SRP RNA.
AB  - The signal recognition particle (SRP) is a phylogenetically conserved
      ribonucleoprotein required for cotranslational targeting of proteins to the
      membrane of the endoplasmic reticulum of the bacterial plasma membrane. Domain IV
      of SRP RNA consists of a short stem-loop structure with two internal loops that
      contain the most conserved nucleotides of the molecule. All known essential
      interactions of SRP occur in that moiety containing domain IV. The solution
      structure of a 43-nt RNA comprising the complete Escherichia coli domain IV was
      determined by multidimensional NMR and restrained molecular dynamics refinement.
      Our data confirm the previously determined rigid structure of a smaller
      subfragment containing the most conserved, symmetric internal loop A (Schmitz et
      al., Nat Struct Biol, 1999, 6:634-638), where all conserved nucleotides are
      involved in nucleotide-specific structural interactions. Asymmetric internal loop
      B provides a hinge in the RNA molecule; it is partially flexible, yet also
      uniquely structured. The longer strand of internal loop B extends the major
      groove by creating a ledge-like arrangement; for loop B however, there is no
      obvious structural role for the conserved nucleotides. The structure of domain IV
      suggests that loop A is the initial site for the RNA/protein interaction creating
      specificity, whereas loop B provides a secondary interaction site.

PMID- 10580471
TI  - Identity and geometry of a base triple in 16S rRNA determined by comparative
      sequence analysis and molecular modeling.
AB  - Comparative sequence analysis complements experimental methods for the
      determination of RNA three-dimensional structure. This approach is based on the
      concept that different sequences within the same gene family form similar higher
      order structures. The large number of rRNA sequences with sufficient variation,
      along with improved covariation algorithms, are providing us with the opportunity
      to identify new base triples in 16S rRNA. The three-dimensional conformations for
      one of our strongest candidates involving U121 (C124:G237) and/or U121
      (U125:A236) (Escherichia coli sequence and numbering) are analyzed here with
      different molecular modeling tools. Molecular modeling shows that U121 interacts
      with C124 in the U121 (C124:G237) base triple. This arrangement maintains
      isomorphic structures for the three most frequent sequence motifs (approximately
      93% of known bacterial and archaeal sequences), is consistent with chemical
      reactivity of U121 in E. coli ribosomes, and is geometrically favorable. Further,
      the restricted set of observed canonical (GU, AU, GC) base-pair types at
      positions 124:237 and 125:236 is consistent with the fact that the canonical base
      pair sets (for both base pairs) that are not observed in nature prevent the
      formation of the 121 (124:237) base triple. The analysis described here serves as
      a general scheme for the prediction of specific secondary and tertiary structure
      base pairing where there is a network of correlated base changes.

PMID- 10580472
TI  - Functional analysis of SNF, the Drosophila U1A/U2B" homolog: identification of
      dispensable and indispensable motifs for both snRNP assembly and function in
      vivo.
AB  - In Drosophila, the spliceosomal protein SNF fulfills the functions of two
      vertebrate proteins, U1 snRNP-UlA and U2 snRNP-U2B". The structure and sequence
      of SNF, U1A, and U2B" are nearly identical with two RNA recognition motifs (RRM)
      separated by a short linker region, yet they have different RNA-binding
      properties: U1A binds U1 snRNA, U2B" binds U2 snRNA, and SNF binds both snRNAs.
      Structure/function studies on the human proteins have identified motifs in the N
      terminal RRM that are critical for RNA-binding specificity but have failed to
      identify a function for the C-terminal RRM. Interestingly, SNF is chimeric in
      these motifs, suggesting a basis for its dual specificity. Here, we test the
      importance of these motifs by introducing site-directed mutations in the snf
      coding region and examining the effects of these mutations on assembly into the
      snRNP and on snf function in vivo. We found that an N-terminal RRM mutant protein
      predicted to eliminate RNA binding still assembles into snRNPs and is capable of
      rescuing snf's lethal phenotype only if the normally dispensable C-terminal RRM
      is present. We also found that the mixed motif in the "RNA-specificity" domain is
      necessary for SNF's dual function whereas the mixed motif in the U2A'-protein
      binding region is not. Finally, we demonstrate that animals carrying a snf
      mutation that converts SNF from a bifunctional protein to a U1 snRNP-specific
      protein are viable. This unexpected result suggests that SNF's presence within
      the U2 snRNP is not essential for splicing.

PMID- 10580473
TI  - Translational suppressors and antisuppressors alter the efficiency of the Ty1
      programmed translational frameshift.
AB  - Certain viruses, transposons, and cellular genes have evolved specific sequences
      that induce high levels of specific translational errors. Such "programmed
      misreading" can result in levels of frameshifting or nonsense codon readthrough
      that are up to 1,000-fold higher than normal. Here we determine how a number of
      mutations in yeast affect the programmed misreading used by the yeast Ty
      retrotransposons. These mutations have previously been shown to affect the
      general accuracy of translational termination. We find that among four nonsense
      suppressor ribosomal mutations tested, one (a ribosomal protein mutation)
      enhanced the efficiency of the Tyl frameshifting, another (an rRNA mutation)
      reduced frameshifting, and two others (another ribosomal protein mutation and
      another rRNA mutation) had no effect. Three antisuppressor rRNA mutations all
      reduced Tyl frameshifting; however the antisuppressor mutation in the ribosomal
      protein did not show any effect. Among nonribosomal mutations, the allosuppressor
      protein phosphatase mutation enhanced Tyl frameshifting, whereas the partially
      inactive prion form of the release factor eRF3 caused a slight decrease, if any
      effect. A mutant form of the other release factor, eRF1, also had no effect on
      frameshifting. Our data suggest that Ty frameshifting is under the control of the
      cellular translational machinery. Surprisingly we find that translational
      suppressors can affect Ty frameshifting in either direction, whereas
      antisuppressors have either no effect or cause a decrease.

PMID- 10580474
TI  - Predicting oligonucleotide affinity to nucleic acid targets.
AB  - A computer program, OligoWalk, is reported that predicts the equilibrium affinity
      of complementary DNA or RNA oligonucleotides to an RNA target. This program
      considers the predicted stability of the oligonucleotide-target helix and the
      competition with predicted secondary structure of both the target and the
      oligonucleotide. Both unimolecular and bimolecular oligonucleotide self structure
      are considered with a user-defined concentration. The application of OligoWalk is
      illustrated with three comparisons to experimental results drawn from the
      literature.

PMID- 10580475
TI  - Characterization of U6 snRNA-protein interactions.
AB  - Through a combination of in vitro snRNP reconstitution, photocross-linking and
      immunoprecipitation techniques, we have investigated the interaction of proteins
      with the spliceosomal U6 snRNA in U6 snRNPs, U4/U6 di-snRNPs and U4/U6.U5 tri
      snRNPs. Of the seven Lsm (Sm-like) proteins that associate specifically with this
      spliceosomal snRNA, three were shown to contact the RNA directly, and to maintain
      contact as the U6 RNA is incorporated into tri-snRNPs. In tri-snRNPs, the U5
      snRNP protein Prp8 contacts position 54 of U6, which is in the conserved region
      that contributes to the formation of the catalytic core of the spliceosome. Other
      tri-snRNP-specific contacts were also detected, indicating the dynamic nature of
      protein interactions with this important snRNA. The uridine-rich extreme 3' end
      of U6 RNA was shown to be essential but not sufficient for the association of the
      Lsm proteins. Interestingly, the Lsm proteins associate efficiently with the 3'
      half of U6, which contains the 3' stem-loop and uridine-rich 3' end, suggesting
      that the Lsm and Sm proteins may recognize similar features in RNAs.

PMID- 10580476
TI  - A tiny RNA that catalyzes both aminoacyl-RNA and peptidyl-RNA synthesis.
AB  - A 29-nt RNA catalyst successively forms the aminoacyl ester phe-RNA, and then
      peptidyl-RNA (phe-phe-RNA), given phenylalanine adenylate (phe-AMP) as substrate.
      Catalysis of two related reactions at similar rates supports the argument that
      RNA catalysts would evolve as groups with similar mechanisms. In particular,
      successive aminoacyl- and peptidyl-RNA synthesis by one RNA suggests that uncoded
      but RNA-catalyzed peptide synthesis would evolve before the synthesis of coded
      peptides.

PMID- 10580477
TI  - The relationship of thermodynamic stability at a G x U recognition site to tRNA
      aminoacylation specificity.
AB  - The G x U pair at the third position in the acceptor helix of Escherichia coli
      tRNA(Ala) is critical for aminoacylation. The features that allow G x U
      recognition are likely to include direct interaction of alanyl-tRNA synthetase
      with distinctive atomic groups and indirect recognition of the structural and
      stability information encoded in the sequence of G x U and its immediate context.
      The present work investigates the thermodynamic stability and acceptor activity
      for a comprehensive set of variant RNAs with substitutions of the G x U pair of
      E. coli tRNA(Ala). The four RNAs with Watson-Crick substitutions had a lower
      acceptor activity and a higher stability relative to the G x U RNA. On the other
      hand, the RNAs with mispair substitutions had a lower stability, but either a
      higher or a lower acceptor activity. Thus, the entire set of variant RNAs does
      not exhibit a correlation between thermodynamic stability of the free, unbound
      tRNA and its acceptor activity. The substantial acceptor activity of tRNAs with
      particular mispair substitutions may be explained by their ability to assume the
      conformational preferences of alanyl-tRNA synthetase. Moreover, the G x U pair
      may provide a point of deformability for the substrate tRNA to adapt to the
      enzyme's active site.

PMID- 10580478
TI  - A limited number of pseudouridine residues in the human atac spliceosomal UsnRNAs
      as compared to human major spliceosomal UsnRNAs.
AB  - Two forms of spliceosomes were found in higher eukaryotes. The major form
      contains the U1, U2, U4, U5, and U6 snRNAs; the minor form contains the U11, U12,
      U4atac, U5, and U6atac snRNAs. Assembly and function of the major form are based
      on a complex dynamic of UsnRNA-UsnRNA and UsnRNA-pre-mRNA interactions, and the
      involved UsnRNA segments are highly posttranscriptionally modified in plants and
      vertebrates. To further characterize the minor form of spliceosomes, we looked
      for the psi residues in HeLa cells' U11, U12, U4atac, and U6atac snRNAs, using
      chemical approaches. Four psi residues were detected in total for these four atac
      UsnRNAs, compared to 20 in their counterparts of the major spliceosomes. The two
      psi residues detected in U12 are also found in U2 snRNA. One of them belongs to
      the branch-site-recognition sequence. It forms one of the base pairs that bulge
      out the A residue, responsible for the nucleophilic attack. Conservation of this
      strategic psi residue probably reflects a functional role. Another psi residue
      was detected in a U4atac snRNA segment involved in formation of helix II with
      U6atac. The fourth one was detected in the additional stem-loop structure present
      at the 3' end of U6atac snRNA. Differences in psi content of the atac and major
      UsnRNAs of human cells may participate in the differentiation of the two splicing
      systems. Based on secondary structure similarity, U2 and U12 snRNAs on the one
      hand and U4 and U4atac snRNAs on the other hand may share common psi synthases.

PMID- 10580479
TI  - Resolution of the mammalian E complex and the ATP-dependent spliceosomal
      complexes on native agarose mini-gels.
AB  - A great deal of progress in elucidating the mechanisms of spliceosome assembly
      has been achieved by analyzing the A, B, and C spliceosomal complexes on native
      polyacrylamide gels. In contrast, progress in understanding the earliest
      spliceosomal complex E has been hampered because this complex dissociates on
      native gels and is difficult to detect by other methods. Here we report
      conditions for resolving the spliceosomal complex E using a native horizontal
      agarose mini-gel system. This system also provides a simple alternative to
      polyacrylamide gels for resolving the ATP-dependent spliceosomal complexes.

PMID- 10580481
TI  - Keeping the record straight on AIDS.

PMID- 10580480
TI  - StreptoTag: a novel method for the isolation of RNA-binding proteins.
AB  - We describe a fast and simple one-step affinity-purification method for the
      isolation of specific RNA-binding proteins. An in vitro-transcribed hybrid RNA
      consisting of an aptamer sequence with high binding specificity to the antibiotic
      streptomycin and a putative protein-binding RNA sequence is incubated with crude
      extract. After complex formation, the sample is applied to an affinity column
      containing streptomycin immobilized to Sepharose. The binding of the in vitro
      assembled RNA-protein complex to streptomycin-Sepharose is mediated by the
      aptamer RNA and the specifically bound proteins are recovered from the affinity
      matrix by elution with the antibiotic. Employing two well-characterized RNA
      protein interactions, we tested the performance of this new method. The
      spliceosomal U1A protein and the bacteriophage MS2 coat protein could be isolated
      via their appropriate RNA motif containing hybrid RNA from crude yeast extracts
      in high yield and purity after only one round of affinity purification. As the
      purification principle is independent of the extract source, this new affinity
      chromatography strategy that makes use of an in vitro-selected antibiotic-binding
      RNA as a tag, "StreptoTag," should be applicable to extracts from other organisms
      as well. Therefore, we propose StreptoTag to be a versatile tool for the
      isolation of unknown RNA-binding proteins.

PMID- 10580482
TI  - Alliance of US labs plans to build map of cell signalling pathways.

PMID- 10580483
TI  - Professors use web to catch students who plagiarize...and author gets similar
      paper retracted.

PMID- 10580484
TI  - AZT critics 'swayed South African president'.

PMID- 10580485
TI  - Genetically modified foods face rigorous safety evaluation.

PMID- 10580486
TI  - Challenge for global e-journal project.

PMID- 10580487
TI  - Much food, many problems.

PMID- 10580488
TI  - Achilles and the maggots.

PMID- 10580489
TI  - Fishing for function in noise.

PMID- 10580490
TI  - Mutant mice live longer.

PMID- 10580491
TI  - What makes ATP synthase spin?

PMID- 10580493
TI  - Why 'false' colours are seen by butterflies

PMID- 10580492
TI  - Guido Pontecorvo (1907-99)

PMID- 10580494
TI  - Variable cell number in nematodes.

PMID- 10580495
TI  - Selecting and maintaining a diverse T-cell repertoire.
AB  - To provide a T-cell population that will respond promptly to foreign antigen, the
      immune system looks inward, using the variety of self-antigens to select and
      maintain a diverse repertoire of receptors. A protective immune system must
      include a T-lymphocyte population that is poised to respond to foreign antigenic
      peptides presented by self-major histocompatibility complex molecules. As the
      organism cannot predict the precise pathogen-derived antigens that will be
      encountered, the system uses the diverse array of self-peptides bound to self
      major histocompatibility complex molecules, not only to select a receptor
      repertoire in the thymus, but also to keep naive T cells alive and 'ready for
      action' in the periphery.

PMID- 10580496
TI  - Structural changes linked to proton translocation by subunit c of the ATP
      synthase.
AB  - F1F0 ATP synthases use a transmembrane proton gradient to drive the synthesis of
      cellular ATP. The structure of the cytosolic F1 portion of the enzyme and the
      basic mechanism of ATP hydrolysis by F1 are now well established, but how proton
      translocation through the transmembrane F0 portion drives these catalytic changes
      is less clear. Here we describe the structural changes in the proton
      translocating F0 subunit c that are induced by deprotonating the specific
      aspartic acid involved in proton transport. Conformational changes between the
      protonated and deprotonated forms of subunit c provide the structural basis for
      an explicit mechanism to explain coupling of proton translocation by F0 to the
      rotation of subunits within the core of F1. Rotation of these subunits within F1
      causes the catalytic conformational changes in the active sites of F1 that result
      in ATP synthesis.

PMID- 10580497
TI  - A low-temperature origin for the planetesimals that formed Jupiter.
AB  - The four giant planets in the Solar System have abundances of 'metals' (elements
      heavier than helium), relative to hydrogen, that are much higher than observed in
      the Sun. In order to explain this, all models for the formation of these planets
      rely on an influx of solid planetesimals. It is generally assumed that these
      planetesimals were similar, if not identical, to the comets from the Oort cloud
      that we see today. Comets that formed in the region of the giant planets should
      not have contained much neon, argon and nitrogen, because the temperatures were
      too high for these volatile gases to be trapped effectively in ice. This means
      that the abundances of those elements on the giant planets should be
      approximately solar. Here we show that argon, krypton and xenon in Jupiter's
      atmosphere are enriched to the same extent as the other heavy elements, which
      suggests that the planetesimals carrying these elements must have formed at
      temperatures lower than predicted by present models of giant-planet formation.

PMID- 10580498
TI  - Energetic constraints on the diet of terrestrial carnivores.
AB  - Species in the mammalian order Carnivora exhibit a huge diversity of life
      histories with body sizes spanning more than three orders of magnitude. Despite
      this diversity, most terrestrial carnivores can be classified as either feeding
      on invertebrates and small vertebrates or on large vertebrates. Small carnivores
      feed predominantly on invertebrates probably because they are a superabundant
      resource (sometimes 90% of animal biomass); however, intake rates of invertebrate
      feeders are low, about one tenth of those of vertebrate feeders. Although small
      carnivores can subsist on this diet because of low absolute energy requirements,
      invertebrate feeding appears to be unsustainable for larger carnivores. Here we
      show, by reviewing the most common live prey in carnivore diets, that there is a
      striking transition from feeding on small prey (less than half of predator mass)
      to large prey (near predator mass), occurring at predator masses of 21.5-25 kg.
      We test the hypothesis that this dichotomy is the consequence of mass-related
      energetic requirements and we determine the predicted maximum mass that an
      invertebrate diet can sustain. Using a simple energetic model and known
      invertebrate intake rates, we predict a maximum sustainable mass of 21.5 kg,
      which matches the point where predators shift from small to large prey.

PMID- 10580499
TI  - Use of behavioural stochastic resonance by paddle fish for feeding.
AB  - Stochastic resonance is the phenomenon whereby the addition of an optimal level
      of noise to a weak information-carrying input to certain nonlinear systems can
      enhance the information content at their outputs. Computer analysis of spike
      trains has been needed to reveal stochastic resonance in the responses of sensory
      receptors except for one study on human psychophysics. But is an animal aware of,
      and can it make use of, the enhanced sensory information from stochastic
      resonance? Here, we show that stochastic resonance enhances the normal feeding
      behaviour of paddlefish (Polyodon spathula), which use passive electroreceptors
      to detect electrical signals from planktonic prey. We demonstrate significant
      broadening of the spatial range for the detection of plankton when a noisy
      electric field of optimal amplitude is applied in the water. We also show that
      swarms of Daphnia plankton are a natural source of electrical noise. Our
      demonstration of stochastic resonance at the level of a vital animal behaviour,
      feeding, which has probably evolved for functional success, provides evidence
      that stochastic resonance in sensory nervous systems is an evolutionary
      adaptation.

PMID- 10580500
TI  - The amygdala modulates prefrontal cortex activity relative to conditioned fear.
AB  - Animals learn that a tone can predict the occurrence of an electric shock through
      classical conditioning. Mice or rats trained in this manner display fear
      responses, such as freezing behaviour, when they hear the conditioned tone.
      Studies using amygdalectomized rats have shown that the amygdala is required for
      both the acquisition and expression of learned fear responses. Freezing to a
      conditioned tone is enhanced following damage to the dorsal part of the medial
      prefrontal cortex, indicating that this area may be involved in fear reduction.
      Here we show that prefrontal neurons reduce their spontaneous activity in the
      presence of a conditioned aversive tone as a function of the degree of fear. The
      depression in prefrontal spontaneous activity is related to amygdala activity but
      not to the freezing response itself. These data indicate that, in the presence of
      threatening stimuli, the amygdala controls both fear expression and prefrontal
      neuronal activity. They suggest that abnormal amygdala-induced modulation of
      prefrontal neuronal activity may be involved in the pathophysiology of certain
      forms of anxiety disorder.

PMID- 10580501
TI  - Kainate receptors are involved in synaptic plasticity.
AB  - The ability of synapses to modify their synaptic strength in response to activity
      is a fundamental property of the nervous system and may be an essential component
      of learning and memory. There are three classes of ionotropic glutamate receptor,
      namely NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4
      isoxazole-4-propionic acid) and kainate receptors; critical roles in synaptic
      plasticity have been identified for two of these. Thus, at many synapses in the
      brain, transient activation of NMDA receptors leads to a persistent modification
      in the strength of synaptic transmission mediated by AMPA receptors. Here, to
      determine whether kainate receptors are involved in synaptic plasticity, we have
      used a new antagonist, LY382884 ((3S, 4aR, 6S, 8aR)-6-((4-carboxyphenyl)methyl
      1,2,3,4,4a,5,6,7,8,8a-decahydro isoquinoline-3-carboxylic acid), which
      antagonizes kainate receptors at concentrations that do not affect AMPA or NMDA
      receptors. We find that LY382884 is a selective antagonist at neuronal kainate
      receptors containing the GluR5 subunit. It has no effect on long-term
      potentiation (LTP) that is dependent on NMDA receptors but prevents the induction
      of mossy fibre LTP, which is independent of NMDA receptors. Thus, kainate
      receptors can act as the induction trigger for long-term changes in synaptic
      transmission.

PMID- 10580502
TI  - Activation of the epithelial Na+ channel (ENaC) requires CFTR Cl- channel
      function.
AB  - It is increasingly being recognized that cells coordinate the activity of
      separate ion channels that allow electrolytes into the cell. However, a
      perplexing problem in channel regulation has arisen in the fatal genetic disease
      cystic fibrosis, which results from the loss of a specific Cl- channel (the CFTR
      channel) in epithelial cell membranes. Although this defect clearly inhibits the
      absorption of Na+ in sweat glands, it is widely accepted that Na+ absorption is
      abnormally elevated in defective airways in cystic fibrosis. The only frequently
      cited explanation for this hypertransport is that the activity of an epithelial
      Na+ channel (ENaC) is inversely related to the activity of the CFTR Cl- channel.
      However, we report here that, in freshly isolated normal sweat ducts, ENaC
      activity is dependent on, and increases with, CFTR activity. Surprisingly, we
      also find that the primary defect in Cl- permeability in cystic fibrosis is
      accompanied secondarily by a Na+ conductance in this tissue that cannot be
      activated. Thus, reduced salt absorption in cystic fibrosis is due not only to
      poor Cl- conductance but also to poor Na+ conductance.

PMID- 10580503
TI  - Activated T cells regulate bone loss and joint destruction in adjuvant arthritis
      through osteoprotegerin ligand.
AB  - Bone remodelling and bone loss are controlled by a balance between the tumour
      necrosis factor family molecule osteoprotegerin ligand (OPGL) and its decoy
      receptor osteoprotegerin (OPG). In addition, OPGL regulates lymph node
      organogenesis, lymphocyte development and interactions between T cells and
      dendritic cells in the immune system. The OPGL receptor, RANK, is expressed on
      chondrocytes, osteoclast precursors and mature osteoclasts. OPGL expression in T
      cells is induced by antigen receptor engagement, which suggests that activated T
      cells may influence bone metabolism through OPGL and RANK. Here we report that
      activated T cells can directly trigger osteoclastogenesis through OPGL. Systemic
      activation of T cells in vivo leads to an OPGL-mediated increase in
      osteoclastogenesis and bone loss. In a T-cell-dependent model of rat adjuvant
      arthritis characterized by severe joint inflammation, bone and cartilage
      destruction and crippling, blocking of OPGL through osteoprotegerin treatment at
      the onset of disease prevents bone and cartilage destruction but not
      inflammation. These results show that both systemic and local T-cell activation
      can lead to OPGL production and subsequent bone loss, and they provide a novel
      paradigm for T cells as regulators of bone physiology.

PMID- 10580504
TI  - The p66shc adaptor protein controls oxidative stress response and life span in
      mammals.
AB  - Gene mutations in invertebrates have been identified that extend life span and
      enhance resistance to environmental stresses such as ultraviolet light or
      reactive oxygen species. In mammals, the mechanisms that regulate stress response
      are poorly understood and no genes are known to increase individual life span.
      Here we report that targeted mutation of the mouse p66shc gene induces stress
      resistance and prolongs life span. p66shc is a splice variant of p52shc/p46shc
      (ref. 2), a cytoplasmic signal transducer involved in the transmission of
      mitogenic signals from activated receptors to Ras. We show that: (1) p66shc is
      serine phosphorylated upon treatment with hydrogen peroxide (H2O2) or irradiation
      with ultraviolet light; (2) ablation of p66shc enhances cellular resistance to
      apoptosis induced by H2O2 or ultraviolet light; (3) a serine-phosphorylation
      defective mutant of p66shc cannot restore the normal stress response in p66shc-/-
      cells; (4) the p53 and p21 stress response is impaired in p66shc-/- cells; (5)
      p66shc-/- mice have increased resistance to paraquat and a 30% increase in life
      span. We propose that p66shc is part of a signal transduction pathway that
      regulates stress apoptotic responses and life span in mammals.

PMID- 10580505
TI  - Structural insights into phosphoinositide 3-kinase catalysis and signalling.
AB  - Phosphoinositide 3-kinases (PI3Ks) are ubiquitous lipid kinases that function
      both as signal transducers downstream of cell-surface receptors and in
      constitutive intracellular membrane and protein trafficking pathways. All PI3Ks
      are dual-specificity enzymes with a lipid kinase activity which phosphorylates
      phosphoinositides at the 3-hydroxyl, and a protein kinase activity. The products
      of PI3K-catalysed reactions, phosphatidylinositol 3,4,5-trisphosphate
      (PtdIns(3,4,5)P3), PtdIns(3,4)P2 and PtdIns(3)P, are second messengers in a
      variety of signal transduction pathways, including those essential to cell
      proliferation, adhesion, survival, cytoskeletal rearrangement and vesicle
      trafficking. Here we report the 2.2 A X-ray crystallographic structure of the
      catalytic subunit of PI3Kgamma, the class I enzyme that is activated by
      heterotrimeric G-protein betagamma subunits and Ras. PI3Kgamma has a modular
      organization centred around a helical-domain spine, with C2 and catalytic domains
      positioned to interact with phospholipid membranes, and a Ras-binding domain
      placed against the catalytic domain where it could drive allosteric activation of
      the enzyme.

PMID- 10580506
TI  - Sustained oscillations in living cells.
AB  - Glycolytic oscillations in yeast have been studied for many years simply by
      adding a glucose pulse to a suspension of cells and measuring the resulting
      transient oscillations of NADH. Here we show, using a suspension of yeast cells,
      that living cells can be kept in a well defined oscillating state indefinitely
      when starved cells, glucose and cyanide are pumped into a cuvette with outflow of
      surplus liquid. Our results show that the transitions between stationary and
      oscillatory behaviour are uniquely described mathematically by the Hopf
      bifurcation. This result characterizes the dynamical properties close to the
      transition point. Our perturbation experiments show that the cells remain
      strongly coupled very close to the transition. Therefore, the transition takes
      place in each of the cells and is not a desynchronization phenomenon. With these
      two observations, a study of the kinetic details of glycolysis, as it actually
      takes place in a living cell, is possible using experiments designed in the
      framework of nonlinear dynamics. Acetaldehyde is known to synchronize the
      oscillations. Our results show that glucose is another messenger substance, as
      long as the glucose transporter is not saturated.

PMID- 10580507
TI  - A ribozyme that lacks cytidine.
AB  - The RNA-world hypothesis proposes that, before the advent of DNA and protein,
      life was based on RNA, with RNA serving as both the repository of genetic
      information and the chief agent of catalytic function. An argument against an RNA
      world is that the components of RNA lack the chemical diversity necessary to
      sustain life. Unlike proteins, which contain 20 different amino-acid subunits,
      nucleic acids are composed of only four subunits which have very similar chemical
      properties. Yet RNA is capable of a broad range of catalytic functions. Here we
      show that even three nucleic-acid subunits are sufficient to provide a
      substantial increase in the catalytic rate. Starting from a molecule that
      contained roughly equal proportions of all four nucleosides, we used in vitro
      evolution to obtain an RNA ligase ribozyme that lacks cytidine. This ribozyme
      folds into a defined structure and has a catalytic rate that is about 10(5)-fold
      faster than the uncatalysed rate of template-directed RNA ligation.

PMID- 10580508
TI  - Furosemide action on cerebellar GABA(A) receptors in alcohol-sensitive ANT rats.
AB  - Furosemide increases the basal tert-[35S]butylbicyclophosphorothionate
      ([35S]TBPS) binding and reverses the inhibition of the binding by gamma
      aminobutyric acid (GABA) in the cerebellar GABA(A) receptors containing the
      alpha6 and beta2/beta3 subunits. These effects are less pronounced in the alcohol
      sensitive (ANT) than in the alcohol-insensitive (AT) rat line. The difference
      between the rat lines in the increase of basal [35S]TBPS binding was removed
      after a longer preincubation with ethylendiaminetetraacetic acid (EDTA)
      containing buffer, but long preincubation did not reduce the GABA content of the
      incubation fluid or remove the difference in GABA antagonism by furosemide. The
      GABA sensitivity of the [35S]TBPS binding did not differ between the rat lines.
      There was no nucleotide sequence difference in the beta2 or beta3 subunits
      between the rat lines and similar beta2/3 subunit-dependent agonistic actions by
      methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in the rat lines
      were detected. The data suggest that there are still unknown structural
      alterations in the cerebellar GABA(A) receptors between the AT and ANT rat lines,
      possibly associated with differential alcohol sensitivity.

PMID- 10580509
TI  - Effects of NMDA antagonists on ethanol-withdrawal induced "anxiety" in the
      elevated plus maze.
AB  - The anxiolytic effects of NMDA antagonists during ethanol withdrawal were
      assessed in Long-Evans rats. Anxiety was measured by the elevated plus maze. Male
      rats were exposed to ethanol (6.5%) in a liquid diet for 10 days. Behavioral
      testing took place 12 h after withdrawal of ethanol. The competitive NMDA
      antagonists, AP-7 (0.02-0.32 mg/kg) and CGP-37849 (0.64-10 mg/kg), at least
      partially reversed the anxiety-like effects induced by withdrawal from ethanol.
      Both drugs produced a small increase in total arm entries, and a much larger
      increase in the percentage of open arm entries. AP-7, but not CGP-37849, also
      increased the percentage of open arm time. In contrast, the NMDA channel blocker,
      dizocilpine (MK-801; 0.08-0.32 mg/kg), produced only a small increase in the
      percentage of open arm entries and of open arm time. HA-966, a glycine-site
      antagonist, also failed to produce changes in ethanol withdrawal induced changes
      in anxiety at the doses tested. These results suggest that competitive NMDA
      antagonists may be useful for reduction of signs of anxiety during ethanol
      withdrawal.

PMID- 10580510
TI  - Effects of acute and chronic ethanol exposure on the hepatic gamma-aminobutyric
      acid transport system in rats.
AB  - Ethanol-induced increases in gamma-aminobutyric (GABA)ergic activity contribute
      to the impairment in hepatic regeneration associated with alcohol-induced liver
      disease. To determine the mechanism(s) whereby ethanol increases GABAergic
      activity in the liver, we documented the effects of acute (5 g/kg x 1) and
      chronic (36% of total calories over 6 weeks) ethanol exposure as well as
      exogenous GABA (500 microg/g body weight) administration on GABA transport
      protein (GABA-TP) mRNA expression in the livers of adult male Sprague-Dawley rats
      at various times (0-72 h) post 70% partial hepatectomy (PHx). We also documented
      the in vitro effects of ethanol (30-90 microM) on [3H]-GABA uptake in isolated
      rat hepatocytes. The results of the study revealed that compared to saline
      exposed controls, acute but not chronic ethanol exposure resulted in significant
      decreases in GABA-TP mRNA expression at 12, 24, and 48 h post PHx (saline
      exposed, 1.04 +/- 0.06, 1.19 +/- 0.21, and 1.15 +/- 0.05. vs. acute ethanol
      exposed, 0.80 +/- 0.16, 0.88 +/- 0.09, and 0.86 +/- 0.16 optical density units, p
      < 0.01, 0.05, and 0.05, respectively). An inhibitory effect was also observed
      following exogenous GABA administration (GABA-TP mRNA expression at 3 h was
      approximately 40% that of baseline, p < 0.05). [3H]-GABA uptake in isolated rat
      hepatocytes in vitro was unaffected by the presence of ethanol. In conclusion,
      the results of this study indicate that acute but not chronic ethanol exposure
      and exogenously administrated GABA inhibit hepatic GABA-TP mRNA expression
      following partial hepatectomy in the rat. These findings suggest that the
      increased GABAergic activity that occurs in the liver following acute ethanol
      exposure results from alterations in the hepatic GABA transport system at a
      transcriptional level.

PMID- 10580511
TI  - Effects of acute ethanol exposure on polyamine and gamma-aminobutyric acid
      metabolism in the regenerating liver.
AB  - Recently, it has been suggested that ethanol-induced inhibition of liver
      regeneration results from decreases in hepatic putrescine levels and/or increases
      in hepatic gamma-aminobutyric acid (GABA)ergic activity. Because putrescine can
      be metabolized by diamine (DAO) and monoamine (MAO) oxidases to GABA, we
      documented the effects of acute ethanol exposure on hepatic MAO or DAO activity
      following partial hepatectomy (PHx) in rats. We also documented the effects of
      ethanol on GABA transaminase (GABA-T), the enzyme responsible for GABA metabolism
      in the liver, and tissue putrescine and GABA levels. Adult, male Sprague-Dawley
      rats (200-250 g) were treated with either ethanol (3 g/kg) or equal volumes of
      saline by gastric gavage 1 h prior to a 70% PHx or sham surgery. Rats were then
      sacrificed (n = 5-7/group) at various times (0-72 h) post-PHx. Enzymatic activity
      and putrescine/GABA levels were determined by standard isotopic techniques and
      high-performance liquid chromatography respectively. Hepatic DAO activities in
      ethanol-treated rats were transiently higher than in saline-treated controls (30%
      increases at 6 h, p < 0.05). Hepatic MAO and GABA-T activities in acute ethanol
      treated rats were essentially identical to saline-treated controls. Although
      hepatic putrescine levels were similar in ethanol- and saline-treated rats,
      hepatic GABA levels were approximately three times higher in ethanol-treated rats
      at 12 and 24 h post-PHx (p < 0.0001). In conclusion, the results of this study
      indicate that acute ethanol exposure has a limited effect on the enzymatic
      conversion of putrescine to GABA following partial hepatectomy in the liver. The
      results also indicate that increased GABAergic inhibition rather than decreased
      putrescine stimulation is more likely to play a role in ethanol-induced
      inhibition of hepatic regeneration.

PMID- 10580512
TI  - Effect of chronic ethanol dosing on hepatic triglyceride and phospholipid profile
      and fatty acids in the guinea pig.
AB  - An alcohol feeding study was conducted with guinea pigs to evaluate the influence
      of alcohol upon hepatic triglyceride and total phospholipid profile as well as
      phospholipid fatty acids. Twenty-seven guinea pigs were randomly assigned into
      four groups consisting of a control and alcohol-treated group and each group
      carried over a 105- or 135-day period . Alcohol was administered via the drinking
      water starting with a 2.5% solution (v/v) and gradually increased to 12.5% (v/v)
      over a 30-day period and thereafter maintained continuously for either 75 or 105
      days, respectively. Control guinea pigs received glucose via the drinking water
      to match isocalorically the alcohol given to the test animals. At the end of the
      105- and 135-day periods, animals were sacrificed and livers collected. Hepatic
      triglycerides were significantly elevated by alcohol dosing, whereas total
      phospholipid fraction remained essentially unaltered. No significant time effect
      was observed on hepatic triglyceride and phospholipid profiles. In ethanol-fed
      guinea pigs, significant increases in percentages of 18:1 n-9 and 18:2 n-6 and
      decreases in 16:0, 20:3 n-6 and 20:4 n-6 were observed in hepatic total
      phospholipid fatty acid profile compared to controls. In addition, other
      polyenoic acids including 22:4 n-6, 22:5 n-6, 22:5 n-3, and 22:6 n-3 were found
      to be highly significantly depressed in alcohol-treated animals in comparison to
      the controls. This study provides important baseline lipid data on guinea pig
      responses to ethanol and provides a starting point for the use of the guinea pig
      as an experimental model.

PMID- 10580513
TI  - Symposium at the ISBRA meeting in Copenhagen, 1998. "Alcohol biomarkers, protein
      glycosylation, and trafficking": introduction.

PMID- 10580514
TI  - Alcohol and molecular regulation of protein glycosylation and function.
AB  - Chronic alcohol exposure leads to the appearance of carbohydrate-deficient
      transferrin (CDT), a N-glycosylated protein and sialic acid-deficient
      apolipoprotein E (apoE), an O-glycosylated protein. We show that chronic ethanol
      treatment destabilizes sialyltransferase (ST) mRNA resulting in a concomitant
      decreased steady-state level of ST mRNA. As a result, alcohol markedly decreases
      the hepatic synthetic rate of ST. This leads to impaired sialylation of
      transferrin and apoE. Consequently, apoE content in plasma high-density
      lipoproteins (HDL) is decreased. ApoE plays a significant role in the delivery of
      HDL cholesterol to the liver via apo B/E receptor, a process called reverse
      cholesterol transport (RCT). Desialylation of apoE results in its decreased
      association with HDL. Thus, the dissociation constant of HDL for binding to sialo
      apoE is 90 +/- 35 nM, whereas that for desialo-apoE is 1010 +/- 250 nM. More
      importantly, the uptake of labeled cholesterol by human HepG2 cells is decreased
      by 30-40% from reconstituted HDL particles (rHDL)-containing desialo-apoE
      compared to rHDL with sialo-apoE. We conclude that chronic alcohol exposure down
      regulates the expression of sialyltransferase genes resulting in impaired
      sialylation of apoE. This leads to its decreased binding to plasma HDL and
      thereby, impairs the RCT function of HDL.

PMID- 10580515
TI  - Carbohydrate deficient transferrin in alcoholic liver disease: mechanisms and
      clinical implications.
AB  - Carbohydrate-deficient transferrin (CDT) is now considered to be the most
      sensitive and specific biological marker of alcohol abuse. The mechanism by which
      chronic alcohol consumption causes an elevation of CDT levels in serum is
      discussed. The sensitivity and specificity of various test procedures are
      compared, with special emphasis on the impact of liver disease. Clinical
      applications are reviewed, including the utility of CDT as a marker of relapse in
      alcoholic patients, and the use of CDT for the systematic screening of drinking
      in vulnerable populations as part of a public health approach to alcoholism.

PMID- 10580516
TI  - Effects of ethanol on receptor-mediated endocytosis in the liver.
AB  - Ethanol administration impairs multiple aspects in the process of receptor
      mediated endocytosis (RME) in the liver. Studies from our laboratory over the
      last 10 years have carefully examined RME by the hepatocyte-specific
      asialoglycoprotein receptor (ASGP-R). We have identified a time course for
      ethanol-induced defects in RME and established that many of the impairments occur
      initially in the centrilobular region of the liver and as early as one week after
      ethanol administration. Impaired intravesicular acidification in ethanol-fed
      animals has been identified, and these defects in acidification could alter
      multiple protein trafficking pathways including RME. In addition to altered
      acidification, altered receptor function (including receptor inactivation) could
      also contribute to impaired trafficking. Current studies in our laboratory are
      aimed at an examination of posttranslational modifications in the receptor
      (acylation and phosphorylation) that are known to affect its function. A role for
      the ASGP-R in the process of alcoholic apoptosis is also being examined because
      proper functioning of the ASGP-R is thought to be important in clearance of
      apoptotic cells.

PMID- 10580517
TI  - Carbohydrate-deficient transferrin as compared to other markers of alcoholism: a
      systematic review.
AB  - This is a systematic review of the studies in which carbohydrate-deficient
      transferrin (CDT) has been compared to other laboratory markers in different
      experimental conditions, clinical settings, and populations. Only the studies (n
      = 54) in which CDT was compared either to the conventional or new biological
      markers of alcoholism, heavy drinking, or alcohol use were selected for further
      evaluation. Two prospective studies indicate that in men CDT is slightly more
      sensitive than gamma-GT in reflecting changes in these markers caused by drinking
      of a moderate and fixed amount of alcohol during three to four weeks. In one
      prospective study, in which the drinking history of male heavy drinking
      volunteers was as close the golden standard as possible; that is, obtained by a
      prospective anonymous drinking diary, CDT was slightly but not significantly
      better marker than conventional laboratory markers (ASAT, ALAT, gamma-GT and beta
      Hex) in the identification of men drinking more than 400 g of alcohol daily.
      Similar prospective studies concerning women have not been done. Six prospective
      treatment outcome studies indicate that CDT may be a significantly more sensitive
      marker than gamma-glutamyltransferase (gamma-GT) in the detection of relapses in
      male alcoholics. However, these two tests can also be considered to be
      complementary markers. Furthermore, in the detection of relapses the baseline
      values of CDT and gamma-GT should be measured and compared on individual basis to
      the pretreatment values. Comparable data are not available from female
      alcoholics. In selective materials comprising male alcoholics and heavy drinkers,
      CDT was found to be a slightly more sensitive marker than gamma-GT in seven
      retrospective studies. In five studies, gamma-GT was slightly better. However,
      the differences between CDT and gamma-GT in general were not statistically
      significant. In three studies, the combined use of CDT and gamma-GT improved the
      sensitivity but with the expense of specificity. Only four studies included women
      and in three of these the sensitivity of gamma-GT was better than that of CDT,
      whereas in one study CDT was better than gamma-GT in the detection of female
      heavy drinkers. Seven studies performed in primary health care settings and among
      young populations demonstrate that the performance of CDT in the identification
      of heavy and problem drinkers in this type of populations is very low, although
      comparable to the poor performance of the conventional laboratory markers, too.
      According to seven studies, the sensitivity of gamma-GT is slightly better than
      that of CDT in the identification of excessive alcohol consumption among
      hospitalized male and female patients. However, in this type of hospital setting,
      the specificity of CDT is markedly higher than that of gamma-GT. There is some
      evidence indicating that the performance of the tests can be improved with the
      combined use of both tests. Eight studies indicate that both in men and women CDT
      is a better marker than gamma-GT in the identification of alcohol abuse among
      patients with alcoholic and nonalcoholic liver diseases. This is mostly due to
      the higher specificity of CDT as compared to that of gamma-GT.

PMID- 10580518
TI  - Intermittent oxygen deficiency as the cause of dementia.
AB  - It is well known that peroxidic materials can be expected to accumulate in simple
      molecules such as ethers or complex organic systems. Most such peroxides are
      stable at body temperature for long periods of time. However, when the supply of
      oxygen is depleted, certain metallic substances, e.g. iron, initiate a rapid
      chain reaction. This process, the rapid chain reaction of peroxide decomposition
      catalyzed by ferrous iron, is to be expected in any part of living tissue as an
      immediate result of oxygen deprivation. Dementia, it is postulated, is the result
      of limited, but repeated, oxygen deprivation in parts of the brain. The
      particular form of dementia will depend upon the specific part of the brain
      affected. Since tiny clots are the most likely source of blood and hence oxygen
      deficiency, it should not be surprising that various parts of the brain may be
      are affected. Dementia prevention would then require action to avoid even the
      smallest clots in the bloodstream. In general, actions which prevent coronary
      disease are indicated.

PMID- 10580519
TI  - Causal models in conventional and non-conventional medicines.
AB  - The author describes the possible causal models in both conventional and non
      conventional therapies. Ontological determinism is used as a metaphysical
      assumption and linear causalism as a reference model. The linear causalism is
      here based on the following properties: sufficient condition, necessary
      condition, specificity, dose-response relationship, unidirectionality and
      externality. A subdivision of the therapy into two categories is then proposed:
      strong activity therapies, with strict causation, are close to linear causalism,
      and correspond to the therapeutic model of conventional medicine; weak activity
      therapies, with a much weaker type of causation, apparently tending towards
      indeterminacy, correspond to non-conventional medicines. Considering the internal
      state of a human being as a causal factor of therapeutic response, the difficulty
      in interpreting weak activity therapies is in part resolved and the differences
      with the strong activity therapies are also less pronounced.

PMID- 10580520
TI  - Schematic illustration of the mechanisms for maintenance of electrolyte and
      glucose homeostasis.
AB  - The aim of the present paper is to give a schematic illustration of the basic
      humoral mechanisms of sodium, calcium and glucose homeostasis regulation. These
      can be compared to a lever system that maintains a dynamic equilibrium.

PMID- 10580521
TI  - Small for gestational age: a new insight?
AB  - Acidosis reduces the ability of nitric oxide synthase to generate nitric oxide
      (NO) from L-arginine (L-arg), even if dietary intake or circulating plasma levels
      of L-arg are normal. During systemic acidemia, therefore, vascular perfusion in
      one or more organs may be compromised. Arginine is also a powerful anabolic amino
      acid. If dietary sources of L-arg are lower than normal, or if the production of
      NO is reduced even without frank acidemia, then vascular perfusion, and growth,
      and tissue repair are likely to be compromised. Two conditions in which acidemia
      is reported to occur, namely slow fetal growth in utero (acidemia is severe) and
      loss of bone and muscle in microgravity (acidemia is modest), are compared with
      respect to the accompanying alteration in the balance between acidemia and NO
      production.

PMID- 10580522
TI  - Frontal lobe dysfunction in patients with non-frontal malignant gliomas: a
      monoaminergic dysregulation?
AB  - Previous investigations concerned with the neuropsychological function of
      patients with intracerebral supratentorial malignant gliomas has revealed the
      frequent occurrence of signs suggestive of an inhibitory frontal lobe dysfunction
      regardless of the intracerebral localization of the tumor and before the
      diagnosis was known to either the investigator or the patient. Upon closer
      analysis, the frontal lobe dysfunction has been verified by the demonstration of
      reduced blood flow in frontal areas in these patients. Since many of the findings
      can be related to a dysfunction of dopaminergic neurotransmission, we hypothesize
      that abnormal astrocytes interfere with the metabolism, transport and release of
      various neurotransmitters of which dopamine may be the one responsible for the
      most striking neuropsychological abnormalities in patients with malignant
      gliomas.

PMID- 10580523
TI  - The altered homeostatic theory: a holistic approach to multiple diseases,
      including atherosclerosis, ischemic diseases, and hypertension.
AB  - The altered homeostatic theory proposes that multiple acquired and genetic
      factors (risk factors) move the basic homeostatic balance in an 'action'
      direction which 'inappropriately' activates defense mechanisms and thus favors
      multiple diseases; factors which improve these disorders move the homeostatic
      balance in the opposite 'rest' direction. Diseases include hypertension,
      atherosclerosis, and ischemic disorders as ischemic heart disease (IHD), stroke,
      migraine, and Raynaud's disease. The theory has its origins in the premises of
      the spasm-of-resistance-vessel (S-RV) concept of ischemic diseases (which
      attributes symptoms in ischemic diseases to S-RV), and in a study designed to
      provide more evidence for this concept. The study showed that multiple risk
      factors for IHD express the combination of S-RV and a tendency toward thrombosis,
      and are risk factors for hypertension, migraine, Raynaud's disease, and stroke;
      factors which ameliorate IHD express vasodilation of resistance vessels and are
      anti-thrombotic, and ameliorate the other disorders.

PMID- 10580524
TI  - New evidence for the spasm-of-resistance-vessel concept of ischemic diseases.
AB  - The spasm of resistance vessel (S-RV) concept of ischemic diseases avers that S
      RV representing vascular autoregulatory dysfunction directly induces symptoms in
      ischemic diseases. The most important ischemic diseases, ischemic heart disease
      (IHD) and stroke, generally are not attributed to S-RV, and new evidence will be
      provided in this communication that S-RV induces IHD and stroke. Hypertension and
      the ischemic disorders of migraine and Raynaud's disease have been attributed to
      S-RV and to vascular dysregulation, and this information was used to help
      structure the study. It was found that these disorders are closely associated
      with IHD and stroke, and this is consistent with S-RV and vascular dysregulation
      as the mechanism for IHD and stroke. Also, it was found that multiple risk
      factors for IHD foster S-RV and are risk factors for hypertension, migraine,
      Raynaud's disease, and stroke, and this supports S-RV as the mechanism for IHD
      and stroke.

PMID- 10580525
TI  - Depressive symptoms and disorders, levels of functioning and psychosocial stress:
      an integrative hypothesis.
AB  - The objective of this manuscript is to propose an integrative conceptual model
      linking depressive disorders and depressive symptoms. Existing conceptual models
      of depression etiology tend to make this distinction in an arbitrary way. For
      example, in the current edition of the Diagnostic and Statistical Manual of
      Mental Disorders (DSM-IV), there is a requirement that severe and persistent
      depressive symptoms be present for a period of two weeks or more before the
      depressive syndrome qualifies as a major depressive disorder. The concept of
      psychosocial stress is a potentially unifying concept relating depressive
      symptoms to disorders, as stress is a risk factor for both depressive symptoms
      and depressive disorders. Furthermore, a key feature of the depressive disorders
      is that they are associated with psychosocial dysfunction, which may be
      conceptualized as an inability to adapt to environmental stress. The hypothesis
      presented here is that subclinical depressive symptoms represent an adaptive
      biological response pattern to psychosocial stress, fostering adaptation in the
      face of a changing (stressful) environment. However, when a threshold of symptom
      severity is exceeded, the depressive syndrome becomes maladaptive, impairing
      adaptation to environmental stress and leading to an accumulation of stressful
      circumstances and experiences. As such, a vicious cycle may be created, leading,
      perhaps, to the occurrence of a depressive disorder.

PMID- 10580526
TI  - Epidemics of violence.
AB  - The concept of behavioral contagion implies that certain behaviors may spread
      through populations in a way analogous to the spread of microbial diseases. If
      so, mathematical models that are helpful in understanding the spread of
      infectious diseases may also help to understand the spread of certain behaviors.
      The objective of this paper was to explore the possibility that the Kermack
      McKendrick model of epidemic spread may help to explain the outbreak of riots in
      crowds. Predictions made by the mathematical model were compared to descriptions
      of crowd behavior and of police methods for preventing and controlling the
      outbreak of riots. Many of the predictions made by the model are consistent with
      published observations about circumstances where riots may occur, and methods
      useful for controlling them.

PMID- 10580527
TI  - New phylism theory and the homosexualization of the visualization of lust.
AB  - Nature needs nurture is the paradigm that replaces nature versus nurture.
      Nature's determinants are phylismic, i.e. they belong to the person
      phylogenetically as a member of the species and are not individually fortuitous.
      Phylismically, in the human species, vision and contrectation supplant pheromones
      as procreative attractants. The primary visual attractant, the sexual body
      morphology of a potential partner, is in all likelihood hormonally encoded into
      the sexual brain in fetal and/or neonatal life. Should the prenatal or neonatal
      encoding of the visual attractant become transposed from the visual image of the
      body morphology of the other sex to that of the same sex, then the brain would be
      biased in subsequent development toward some degree or variation of homosexual or
      bisexual attraction.

PMID- 10580528
TI  - Diarrhoea and nitrogen oxides.
AB  - It is hypothesized that higher indoor nitrogen dioxide levels cause diarrhoea in
      infants and that this is the result of a direct action of oxides of nitrogen on
      the gut. This hypothesis is tested by reviewing the reported association between
      methaemoglobin and diarrhoea in children and two recent reports on indoor air and
      diarrhoea in infants. The collection of further empirical data is now needed.
      Studies which measure indoor levels of nitrogen dioxide could usefully collect
      data on infants symptoms that are not exclusively respiratory. Similarly, studies
      which are collecting diary information on children's health symptoms should
      consider collecting data on indoor air quality with respect to the oxides of
      nitrogen.

PMID- 10580529
TI  - Growing alliums and brassicas in selenium-enriched soils increases their
      anticarcinogenic potentials.
AB  - The concentrating of essential minerals, vitamins, and bioactive phytochemicals
      into human foodstuffs is of vital importance in our rapidly expanding world.
      Selenium is an essential micronutrient which is currently receiving much
      publicity for its anticarcinogenic potentials. Unfortunately, this mineral is
      deficient in most soils worldwide, and as a result most geographical food chains
      contain highly inadequate amounts of selenium. Scientific evidence in now
      available which shows that common vegetable members of the allium genus,
      especially garlic, are seleniferous in that they readily uptake inorganic
      selenium from the soil and incorporate it into bioactive organic chemicals. The
      brassicas have also been found to be highly seleniferous in nature and to produce
      various seleno amino acids and potentially bioactive organic selenium-containing
      phytochemicals. Upon consumption by humans, these selenium phytochemicals,
      derived from both plant genus, show anticarcinogenic potentials. Due to the high
      concentrations of natural phytochemicals, and the additional assimilation of
      selenium, the commercial or small scale production of selenium-enriched brassicas
      and garlic is an excellent way of introducing anticarcinogenic phytochemicals
      into the human diet.

PMID- 10580530
TI  - Possible physiological roles of acetone metabolism in humans.
AB  - Recently, the metabolic routes for acetone metabolism have been described.
      Therefore, acetone cannot further be regarded as a waste product of metabolism.
      However, its physiological role in biochemical machinery is not clear. Here, an
      integrative model for the role of acetone metabolism is presented that orders the
      events occurring in acetonemia in sequence: (i) acetone participates in pH
      regulation; and (ii) acetone degradation in the liver both contributes to
      glucostatic function of the liver and provides C3 fragments to peripheral tissues
      as additional fuel. The model raises a novel approach to the study of the
      physiological role of acetone metabolism.

PMID- 10580531
TI  - Differentiation, histogenesis and morphogenesis: their implications for tumor
      diagnosis.
AB  - Differentiation, as employed in tumor classification for histopathology, refers
      to the resemblance of neoplastic cells to their presumed cell/tissue of origin.
      Since differentiation for diagnosis is obtained by analysing histological images,
      this histogenetic concept creates practical limitations. Morphogenesis, a variant
      of differentiation, is a wider concept since it takes into consideration the
      nature of the tumor cells, their organization and their synthetic products.
      Consequently, morphogenesis, rather than differentiation, seems to be a better
      predictor of histogenesis in tumor diagnosis.

PMID- 10580532
TI  - Fractures of the lumbar vertebral endplate in the etiology of low back pain: a
      hypothesis on the causative role of spinal compression in aspecific low back
      pain.
AB  - It is hypothesized that, in a large number of cases of aspecific low back pain,
      the primary cause of the pain is a fracture of the vertebral endplate caused by
      compression forces. Clinical studies have shown that, in many low back pain
      patients, damage of the vertebral bodies and or the intervertebral disc is
      present. In vitro studies reveal that the most likely type of failure of this
      anterior part of the spine is a fracture of the endplate as a result of
      compression. The high incidence of aspecific low back pain concurs with the
      likeliness of compression fractures of the endplate to occur in everyday life.
      Furthermore, epidemiological findings and the natural history of low back pain
      appear to be in line with the proposed hypothesis.

PMID- 10580533
TI  - Acceptable regret in medical decision making.
AB  - When faced with medical decisions involving uncertain outcomes, the principles of
      decision theory hold that we should select the option with the highest expected
      utility to maximize health over time. Whether a decision proves right or wrong
      can be learned only in retrospect, when it may become apparent that another
      course of action would have been preferable. This realization may bring a sense
      of loss, or regret. When anticipated regret is compelling, a decision maker may
      choose to violate expected utility theory to avoid regret. We formulate a concept
      of acceptable regret in medical decision making that explicitly introduces the
      patient's attitude toward loss of health due to a mistaken decision into decision
      making. In most cases, minimizing expected regret results in the same decision as
      maximizing expected utility. However, when acceptable regret is taken into
      consideration, the threshold probability below which we can comfortably withhold
      treatment is a function only of the net benefit of the treatment, and the
      threshold probability above which we can comfortably administer the treatment
      depends only on the magnitude of the risks associated with the therapy. By
      considering acceptable regret, we develop new conceptual relations that can help
      decide whether treatment should be withheld or administered, especially when the
      diagnosis is uncertain. This may be particularly beneficial in deciding what
      constitutes futile medical care.

PMID- 10580534
TI  - Idiopathic dilated cardiomyopathy. Elastic parallel element dysfunction as a
      physiopathological hypothesis for ventricular failure.
AB  - BACKGROUND: Idiopathic dilated cardiomyopathy is a disease of unknown etiology,
      although the viral-immunologic pathogenesis has recently emerged as an important
      hypothesis. Its distinctive anatomopathologic features are: macroscopically, a
      great ventricular dilation with little hypertrophy, and microscopically marked
      diffuse interstitial fibrosis not observed in other pathologic entities with
      dilation. Hemodynamically, its main characteristic is a progressive loss of the
      systolic function, although the diastolic function is also impaired. To date it
      is accepted that in dilated states ventricular remodeling occurs due to sliding
      of fiber with a maximal sarcomere distention; it is also assumed that the
      ventricular dysfunction is due to a primary deficit in contractility caused by
      the injury and loss of myocites. HYPOTHESIS: The aggressive agent mainly attacks
      the interstitial tissue, thus damaging the elastic parallel element structures.
      This results in a loss of absorbing power during diastole, starting a progressive
      dilation which results in maximum sarcomere distention, and compromises the
      ventricular function. The organ response is to create a new parallel element,
      which results in an increased fibrosis which also compromises this function.

PMID- 10580535
TI  - A topological hypothesis for the functional connections of the cortex. A
      principle of the cortical graphs' based on the neuroimaging.
AB  - Combined EEG and PET techniques show three activation levels of the cortex: deep
      sleep, relaxed state and alert. We propose, correspondingly, that a cortical
      module can be in one of three equivalent states: inactivated, pre-activated, and
      activated. Neuroimaging techniques can show activated cortical regions in detail.
      However, the functional connections (FCs) among them are not shown in the image.
      They can be found by EEG-coherence functions. This can be seen as a 'three-level-
      cortical graph'. A cortical graph is a mathematical representation where the
      cortical units (modules or regions) are represented by points (nodes) and the FCs
      are represented by lines between these points. At the upper level, activated
      modules can establish FCs implying high electrical coherence (they are the
      winners of a competitive process between preactivated modules at the middle
      level). We propose that, during alert state, the activated nodes and the dynamic
      switching among them always form connected graphs. It means that, for any
      possible configuration, there always exists a path (direct or indirect) between
      any couple of nodes. We base our view on (1) analysis of simple tasks by PET; (2)
      the existence of coordinated behavior in normal subjects; (3) cortical topologies
      previously proposed; and (4) computer simulations of cortico-cortical
      connections. We also suggest that disengaged (nonconnected) cortical graphs,
      produce 'functional disconnection syndromes' which cause some symptoms in
      schizophrenia, and Alzheimer disease.

PMID- 10580536
TI  - Difficulties in estimating age using root dentine translucency in human teeth of
      varying antiquity.
AB  - Estimation of age at death is an essential part of reconstructing information
      from skeletal material. This becomes more difficult after development has ceased
      and following taphonomic alteration in archaeological material. Most biological
      markers of age do not record the chronological age (calendar age), but the
      biological or physiological age of the individual. Of the age-related changes in
      the mature dentition of modern samples, the extent of root dentine translucency
      (RDT) has been shown to correlate closely with chronological age. A protocol for
      measurement of RDT was established and applied to modern and archaeological teeth
      of known age (Spitalfields sample). Percentage length of RDT in sectioned teeth
      was found to correlate well with chronological age in the modern sample but not
      in the archaeological sample. The majority of the archaeological sample was
      affected by a morphological change creating a "chalky" appearance to the dentine.
      Removal of the obviously affected teeth did not improve the correlation
      coefficients to any useful degree. "Chalky" dentine appeared, under the light
      microscope, to be composed of large fenestrations, islands of mineralized tissue
      and masses of filiform structures that appeared to be following the path of the
      dentinal tubules in their invasion of the peripheral dentine. The filiform
      structures are consistent in their appearance with a previously reported
      tunnelling mycelium and impart such an effect on RDT that it cannot readily be
      used for age estimation in affected teeth.

PMID- 10580537
TI  - Effects of topical application of free and liposome-encapsulated lactoferrin and
      lactoperoxidase on oral microbiota and dental caries in rats.
AB  - Four groups of rats were inoculated with Streptococcus sobrinus ATCC 33478 and
      fed a cariogenic diet for 42 days. Topical treatment with either distilled water,
      sodium fluoride (0.2%), a solution containing lactoferrin and lactoperoxidase, or
      a solution containing liposome-encapsulated lactoferrin and liposome-encapsulated
      lactoperoxidase was applied at intervals for 35 days. Caries incidence in groups
      treated with liposome-encapsulated lactoferrin and lactoperoxidase was
      significantly lower than in control groups. The number of viable Strep. sobrinus
      and the proportion of Strep. sobrinus in the total counts were significantly
      higher in liposome-treated groups. Free lactoferrin and lactoperoxidase did not
      cause a significant reduction in caries incidence.

PMID- 10580538
TI  - In situ hybridization for matrix metalloproteinase-1 and cathepsin K in rat root
      resorbing tissue induced by tooth movement.
AB  - The movement of teeth during orthodontic treatment occasionally induces
      undesirable root resorption. Although high collagenolytic activity has been
      detected in resorbing tissue of deciduous teeth, the cellular origin of
      collagenolytic enzymes in root-resorbing tissue caused by tooth movement has not
      been identified. Here, rats were subject to 7 days of experimental tooth movement
      to induce root resorption. In situ hybridization with digoxigenin-labelled RNA
      probes was performed on sections of the maxillary bone to detect the mRNAs that
      encode matrix metalloproteinase-1 (MMP-1) and cathepsin K in root-resorbing
      tissue. MMP-1 mRNA was detected in fibroblastic cells, cementoblasts and
      osteoblasts, but not in odontoclasts nor osteoclasts. Moreover, MMP-1 mRNA was
      highly expressed in some cementocytes located near odontoclasts and in many
      osteocytes. In contrast, cathepsin K mRNA was expressed only in odontoclasts and
      osteoclasts. These results suggest that MMP-1 and cathepsin K are important in
      root resorption during tooth movement in a mode similar to bone resorption.

PMID- 10580539
TI  - Mapping of a gene causing mouse gutter-shaped tooth root to chromosome 5.
AB  - A study was conducted to identify the major candidate chromosome and to detect
      the region which included the candidate gene causing gutter-shaped root (GSR) in
      an inbred strain of mice. The candidate chromosomal analysis was performed on
      genetic crosses of C57L/J strain mice, which have GSR, and C57BL/6J strain mice,
      which have normal roots. Linkage analysis suggested that mouse chromosome 5 was
      one of the major candidates and therefore this chromosome was investigated in
      detail by individual genotyping of all backcross mice. The highest linkage was
      found at D5Mit161, and other high linkages were evident at D5Mit29, 321 and 427.
      Based on these findings, it is suggested that the gene causing GSR formation in
      mice maps close to these microsatellite loci.

PMID- 10580540
TI  - The effects of dental wear on third molar eruption and on the curve of Spee in
      human archaeological dentitions.
AB  - The abrasiveness of food is a key determinant in the rate of physiological
      attrition (dental wear) in humans. With increasing food processing through time,
      the rate of physiological dental wear in human teeth has decreased markedly. Many
      consider such wear to be beneficial to oral health and that insufficient wear may
      result in impaction of the third molars. If enhanced extraoral food processing
      provides an evolutionary advantage, then it is possible that agenesis of the
      redundant third molar may follow. One of the aims here was to examine impaction
      and agenesis of the third molars in four populations of varying antiquity and
      hence varying dental-wear rates. Paradoxically, whilst there is a decrease in the
      rate of dental wear with modernity, there is also an increasing prevalence of
      advanced dental wear due to prolongation of the lifespan of the human dentition.
      As the effect of dental wear on the curve of Spee was unknown, a second aim was
      to examine it in an archaeological population with a high rate of dental wear.
      The results showed an increase in non-eruption and impaction of the third molars
      with modernity, but did not demonstrate a significant increase in the rate of
      agenesis. The time period over which impaction and agenesis could be discerned
      was of the order of 600 years and this may not be sufficient to observe adaptive
      changes at the genetic level in humans. In molar teeth there was no clear
      indication of maintenance of the curve of Spee with dental wear. This has
      potential implications on the design of prostheses for the worn dentition.

PMID- 10580541
TI  - Enhancement by hepatocyte growth factor of bone and cartilage formation during
      embryonic mouse mandibular development in vitro.
AB  - To elucidate the possible roles of hepatocyte growth factor (HGF) in the early
      development of mouse mandible, HGF was applied to an organ-culture system with
      chemically defined media. Mandibular arches microdissected from mouse embryos at
      the 10th day of gestation were cultured for 10 days with or without HGF, HGF plus
      HGF-receptor (c-met) antisense oligodeoxyribonucleotide, or HGF plus c-met sense
      oligodeoxyribonucleotide in the media. The cultured mandibles were then analysed,
      histologically in serial paraffin sections. In the absence of HGF, the tooth
      organs of bud stage, Meckel's cartilage and the tongue were formed, whereas only
      a slight amount of bone tissue was formed in the cultured mandible. The
      expression of intrinsic HGF and c-met in the cultured mandibles was confirmed by
      reverse transcriptase-polymerase chain reaction. Furthermore,
      immunohistochemistry demonstrated that both HGF and c-met were localized in areas
      of the mesenchymal tissue forming bone and cartilage. With HGF in the medium, the
      volume of both bone and cartilage increased significantly and dose-dependently.
      HGF also increased the rate of proliferation of osteogenic cells and
      chondrocytes. Addition of c-met antisense oligodeoxyribonucleotide partially
      inhibited the HGF-induced enhancement of bone and cartilage formation, whereas
      addition of c-met sense oligodeoxyribonucleotide had no effect. These results
      revealed that exogenous HGF enhances bone and cartilage morphogenesis in the
      cultured mandibles, suggesting physiological roles for intrinsic HGF in the early
      development of mouse mandible.

PMID- 10580542
TI  - The human mandibular intercondylar angle measured by computed tomography.
AB  - In axial computed tomography it is possible to measure the intercondylar angle at
      the intersection of the longitudinal axes of the condyles. Published values range
      from 131 to 165 degrees. This angle was determined here in two groups of patients
      with (n = 22) and without (n = 12) temporomandibular joint dysfunction. A third
      group of children (n = 12) aged 4-9 years was included to investigate any age
      related change in the angle. In the group of healthy individuals, a range of 105
      to 165 degrees was found, with a mean intercondylar angle of 139 degrees. In the
      group with temporomandibular joint dysfunction the mean angle was 143 degrees
      with a range from 85 to 170 degrees. No statistically significant relation could
      be shown between intercondylar angle and joint dysfunction. In the group of
      children the mean angle was 138 degrees with values ranging from 90 to 180
      degrees. No significant differences could be demonstrated among the groups. The
      absolute value of the intercondylar angle seems to be independent of factors such
      as sex, age and functional disorders of the joint.

PMID- 10580543
TI  - Effect of 24 hours light on circadian rhythms of secretory enzymes and morphology
      of rat von Ebner's glands.
AB  - Von Ebner's glands of the rat are minor salivary serous glands in the posterior
      portion of the tongue. They secrete two digestive enzymes, lingual lipase and
      amylase. In this investigation, circadian rhythm in feeding was established under
      a normal 12 h light/12 h dark cycle, with the rats eating primarily during the
      dark period. At lights on, the size of the acinar cells and the area of the
      inclusive secretory granules, and the amount of digestive enzyme activity
      (lingual lipase and amylase) remaining in the gland was significantly less than
      in the mid-afternoon, after very little daylight food consumption. However, after
      7 days of continuous light the circadian rhythm was altered: the food consumption
      during the normal night-time hours (5 p.m. to 8 a.m.) went from 88% of total 24 h
      food consumption to 45%, and during normal daylight hours (8 a.m. to 5 p.m.) from
      12% to 55%. These changes were correlated with histometric findings of a near
      reversal of the areas of acinar cells and secretory granules of a.m. and p.m.
      samples under continuous light. Lingual lipase activity in the glands went from
      35% under 12 h light to 61% under continuous light in the a.m. and from 65% to
      39% in the p.m. Amylase activity also showed nearly a reversal in activity
      remaining in the gland, from 36% at 12 h light to 58% at 24 h light in the a.m.
      and 64% to 41% for the p.m. samples. These results indicate that the von Ebner's
      glands of the rat have a circadian rhythm of secretion and storage of secretory
      proteins that is subject to light entrainment similar to that seen in other
      exocrine glands such as the parotid and pancreas.

PMID- 10580544
TI  - Implications for tooth eruption of the effect of interleukin-1alpha on nuclear
      factor-kappaB gene expression in the rat dental follicle.
AB  - Tooth eruption is a localized event and a cascade of molecular signals generated
      in the dental follicle and stellate reticulum appears to initiate its onset.
      Consequently, mononuclear cells are recruited into the follicle and, in turn,
      fuse to become osteoclasts needed to resorb the alveolar bone to form an eruption
      pathway. One of the transcription factors involved in the sequence of molecular
      signalling may be nuclear factor (NF)kappaB. This study shows that NFkappaB is
      expressed and synthesized by cultured dental follicle cells. Moreover, its
      transcription, activation and translocation were enhanced by interleukin (IL)
      1alpha, a potential eruption molecule. The enhancement of transcription of the
      NFkappaB gene by IL-1alpha was blocked by a tyrosine-specific kinase inhibitor,
      suggesting that the enhancement may require the phosphorylation of the NFkappaB
      complex. In vivo, NFkappaB is maximally expressed in the dental follicle of the
      rat first mandibular molar at day 3 postnatally, the age at which there is a peak
      influx of mononuclear cells into the follicle. Thus, a transcription factor
      apparently required for eruption (NFkappaB) is present in the tissue required for
      eruption, the dental follicle, and its gene expression is maximal at a critical
      time in eruption.

PMID- 10580545
TI  - Effect of cold pressor stimulation (4 degrees C) on human masseter muscle
      haemodynamics during and after sustained isometric contraction.
AB  - The effect of cold pressor (CP) stimulation and sustained isometric contraction
      on the blood volume of the right masseter muscle was examined in seven healthy
      males, who performed 1 min of isometric jaw clenching at 50% of their maximum
      voluntary contraction without, with and again without a 4 degrees C CP
      stimulation. Total haemoglobin was measured in the masseter before, during and
      after the contraction task using near-infrared spectroscopy. CP stimulation
      during the isometric contraction diminished the magnitude of the contraction
      induced decrease of blood volume when compared to the trials without CP
      stimulation. However, in the immediate post-contraction period (while the CP
      stimulation was still in place), no increase in blood volume above the usual post
      contraction hyperaemia was evident. Once the CP stimulation had been removed,
      there was a clear decrease (faster return to baseline) in the vasodilation
      occurring in the post-contraction period. This diminished period of vasodilation
      occurred in spite of the fact that the vascular resistance (blood pressure) and
      heart rate were still substantially elevated by the CP effect during this same
      period. These data suggest that the strong CP stimulation produced a biphasic
      response. First, there was an early-onset strong vasodilation (during CP), which
      was followed by a period of diminished vasodilation, suggesting that an active,
      but delayed, vasoconstrictive drive may be induced by the CP stimulus.

PMID- 10580546
TI  - The neurotoxic effects of methylenedioxymethamphetamine (MDMA) and its
      metabolites on rat brain spheroids in culture.
AB  - Rat whole-brain spheroids were used to assess the intrinsic neurotoxicity of
      methylenedioxy-methamphetamine (MDMA, Ecstasy) and two of its metabolites,
      dihydroxymethamphetamine (DHMA) and 6-hydroxy-MDMA (6-OH MDMA). Exposure of brain
      spheroids to MDMA or the metabolite 6-OH MDMA (up to 500 micromol/L) for 5 days
      in culture did not alter intracellular levels of glutathione (GSH), glial
      fibrillary acidic protein (GFAP) or serotonin (5-HT). In contrast, exposure to
      the metabolite DHMA, which can deplete intracellular thiols, significantly
      increased GSH levels (up to 170% of control) following exposure to 50 and 100
      micromol/L DHMA. There was also a significant reduction in the levels of glial
      fibrillary acidic protein (GFAP) and GSH by DHMA at the highest concentration
      tested (500 micromol/L) but there was no effect on 5HT. This may constitute a
      sublethal neurotoxic compensatory response to DHMA in an attempt to replenish
      depleted intraneural GSH levels following metabolite exposure. Rat whole-brain
      spheroids may thus be a useful in vitro model to delineate mechanisms and effects
      of this class of neurotoxin.

PMID- 10580547
TI  - Development of a new in vitro system for continuous in vitro exposure of lung
      tissue to complex atmospheres: application to diesel exhaust toxicology.
AB  - The purpose of this study was the development of a new incubation system that can
      allow continuous exposure of lung tissue to complex atmospheres as a tool for the
      assessment of aerial environmental lung toxicology. To assess the pertinence of
      this new exposure system, we studied the impact of diesel engine exhausts as a
      complex atmosphere containing both gaseous and particulate fractions and have
      been able to discriminate between the toxicological impacts of the gaseous phase
      and particulate matter from diesel exhausts. Continuous flow-through rotating
      chambers with controlled PO2, pCO2, and hygrometry have been designed in which
      lung slices are positioned in rolling inserts that allow free access of
      atmosphere to the exposed lung tissue. Under control conditions, cell viability
      was preserved for at least 48 h as assessed by intracellular ATP, GSH, and K+
      levels and slice O2 consumption levels. Short-term exposure (1 h) to diesel whole
      exhausts did not affect intracellular potassium or slice O2 consumption, while
      intracellular ATP and GSH levels were markedly decreased. Exposure to filtered
      exhausts showed less marked effects on both ATP and GSH levels. Superoxide
      dismutase activity was decreased in a similar way by both total and filtered
      exhausts while Se(+)-dependent glutathione peroxidase activity was induced by
      filtered exhausts to a larger extent than after total exhaust exposure, showing
      different response patterns of lung tissue after exposure to whole or filtered
      exhausts. In conclusion, this newly designed model opens a promising area in in
      vitro environmental lung toxicology testing.

PMID- 10580549
TI  - Glutathione depletion in lung cells by low-molecular-weight aldehydes.
AB  - Use of oxygenates in gasoline in the United States may increase atmospheric
      levels of aldehydes. To assist in health assessments of inhalation exposure to
      aldehydes, we studied glutathione (GSH) depletion by low-molecular-weight n
      alkanals and 2-alkenals, ubiquitous air pollutants, in adult rat lung (ARL) cells
      by laser cytometry. For each homologous series, the effective aldehyde
      concentration that depleted GSH by 50% (EC50) in ARL cells correlates with
      published values for the median lethal dose of the chemicals and with
      Hammett/Taft electronic parameters, sigma* for n-alkanals and sigma(+)p for 2
      alkenals. n-Alkanals (EC50, 110-400 mmol/L) were 1000 times less effective in
      depleting GSH than were 2-alkenals (EC50, 2-180 micromol/L), of which acrolein
      was the most potent. Ability of the 2-alkenals to deplete GSH follows the second
      order rate constant for adduct formation. Ability of n-alkanals to deplete GSH
      follows chain length. Within a homologous series of low-molecular-weight
      aldehydes, structure-activity relationships are useful for predicting the
      toxicity of the aldehydes in vitro and in vivo.

PMID- 10580548
TI  - Immortalized human endothelial cells have a decreased response to IL-1 secondary
      to an IL-1 receptor defective expression restored by corticosteroids.
AB  - A human endothelial cell line is a convenient tool for exploring cell physiology
      and testing drugs and toxics. Several attempts have been made using SV40 to
      immortalize endothelial cells. We used human umbilical vein endothelial cells
      (HUVEC) transformed with a construct made of promoter of the vimentin gene and
      SV40 Tag. The proliferation of immortalized vascular endothelial cells (IVEC), as
      measured by [methyl-3H]thymidine incorporation, was compared to that of HUVEC in
      the presence of endothelial cell growth factor and cytokines: tumor necrosis
      factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interferon-gamma (IFN
      gamma). Inhibition of [methyl-3H]thymidine incorporation by IL-1beta was lower
      than that observed with HUVEC, while TNF-alpha reduced the proliferation of IVEC
      and HUVEC to similar extents. Induction of intercellular adhesion molecule (ICAM
      1), vascular cell adhesion molecule (VCAM-1) and E-selectin by TNF-alpha,
      measured by a radiometric technique, was similar in IVEC and HUVEC, while the
      induction of E-selectin by IL-1beta on IVEC was limited and significantly
      different from that observed on HUVEC (p<0.001). The number of 125I-IL-1beta
      binding sites on IVEC is 3-fold less than on HUVEC and the IL-1beta receptor
      number was reduced. Dexamethasone treatment of IVEC restored their reactivity to
      IL-1beta and corrected the IL-1beta binding and the receptor number. These
      results showed that the introduction of SV40 gene not only immortalized the cell
      but also altered IL-1 receptor expression. This alteration may be improved by
      addition of corticosteroids to the cell culture, which extends the possibility of
      using IVEC as a model of endothelial cells.

PMID- 10580550
TI  - The effect of acrylonitrile on gap junctional intercellular communication in rat
      astrocytes.
AB  - Rats chronically exposed to acrylonitrile (ACN) have shown a dose-dependent
      increase in the incidence of astrocytomas in the brain. The mechanism(s) by which
      ACN induces cancer in rodents has not been established. ACN does not appear to be
      directly genotoxic in the brain and thus a nongenotoxic mode of action has been
      proposed. Inhibition of gap junctional intercellular communication (GJIC) has
      been shown to be a property of many nongenotoxic carcinogens. The present study
      examined the effects of ACN on GJIC in a rat astrocyte transformed cell line, DI
      TNC1 cells (a target cell for ACN carcinogenicity) and primary cultured
      hepatocytes (a nontarget cell for ACN carcinogenicity). ACN inhibited GJIC in rat
      astrocytes in a dose-dependent manner. Inhibition of GJIC was observed following
      2 h treatment with 0.10 mmol/L and 1.00 mmol/L ACN. However, in primary cultured
      hepatocytes, ACN exposed did not result in inhibition of GJIC even after 48 h of
      continued treatment. In the astrocytes, GJIC inhibition plateaued after 4 h of
      treatment and remained blocked throughout the entire experimental period
      examined. Inhibition of GJIC in DI TNC1 cells was reversed by removal of ACN from
      the culture medium after 4 or 24 h of treatment. Cotreatment of astrocytes with
      vitamin E reduced the effect of ACN-induced inhibition of GJIC. Similarly,
      inhibition of GJIC was prevented by treatment with 2-oxothiazolidine-4-carboxylic
      acid (OTC), a precursor of glutathione synthesis. Decreasing cellular glutathione
      by treatment with buthionine sulfoxamine alone (without ACN) did not affect GJIC
      in astrocytes. Collectively, these results demonstrate that treatment with ACN
      caused a selective inhibition of GJIC in rat DI TNC1 astrocytes (the target cell
      type), but not in rat hepatocytes (a nontarget tissue). Inhibition of GJIC in
      astrocytes was reversed by treatment with antioxidants and suggests a potential
      role for oxidative stress in ACN-induced carcinogenesis.

PMID- 10580551
TI  - Detection by the comet assay of apoptosis induced in lymphoid cell lines after
      growth factor deprivation.
AB  - Dysregulation of apoptosis contributes to various diseases such as
      neurodegenerative or aging disorders, autoimmune syndromes or cancers. Numerous
      experimental paradigms have been explored to characterize molecular and cellular
      modulators of apoptosis. Similarly, numerous techniques have been described for
      detecting and/or quantifying accurately cells committed to apoptosis. Besides the
      conventional techniques, we describe in this report that the comet assay, which
      detects DNA single- and double-strand breaks in situ, at the cellular level, is
      relevant for the characterization of apoptotic cells. The comet assay is very
      sensitive and detects DNA fragmentation occurring in the apoptotic process as
      early as exposure of phosphatidylserine residues on the outer leaflet. Thus the
      comet assay can be used for the recognition of apoptosis that follows the death
      signal caused, for example, by genotoxic stress as well as lack of survival
      signal as in growth factor deprivation.

PMID- 10580552
TI  - Intracellular fate and nuclear targeting of plasmid DNA.
AB  - One of the major steps limiting nonviral gene transfer efficiency is the entry of
      plasmid DNA from the cytoplasm into the nucleus of the transfected cells. The
      nuclear localization signal (NLS) of the SV40 large T antigen is known to
      efficiently induce nuclear targeting of proteins. We have developed two chemical
      strategies for covalent coupling of NLS peptides to plasmid DNA. One method
      involves a site-specific labeling of plasmid DNA by formation of a triple helix
      with an oligonucleotide NLS peptide conjugate. After such modification with one
      NLS peptide per plasmid molecule, plasmid DNA remained fully active in cationic
      lipid-mediated transfection. In the other method, we randomly coupled 5-115 p
      azidotetrafluorobenzyllissamine-NLS peptide molecules per plasmid DNA by
      photoactivation. Oligonucleotide-NLS and plasmid lissamine-NLS conjugates
      interacted specifically with the NLS-receptor importin alpha. Plasmid-lissamine
      NLS conjugates were not detected in the nucleus, after cytoplasmic
      microinjection. Plasmids did not diffuse from the site of injection and plasmid
      lissamine-NLS conjugates appeared to be progressively degraded in the cytoplasm.
      The process of plasmid DNA sequestration/degradation stressed in this study might
      be as important in limiting the efficiency of nonviral gene transfer as the
      generally recognized entry step of plasmid DNA from the cytoplasm into the
      nucleus.

PMID- 10580553
TI  - Gerstmann-Straussler-Scheinker disease- the dilemma of molecular and clinical
      correlations.
AB  - Gerstmann-Straussler-Scheinker disease (GSSD) is a hereditary as well as
      transmissible human prion disease, restricted to families carrying point
      mutations of the PRPN gene on chromosome 20. To date 7 different causative
      mutations have been found. In this review the results of molecular biology with
      regard to the clinical course are discussed. As the findings of the disorder are
      very variable, the clinical picture and the neuropathology are extensively
      reported. An attempt has been made to define the disease, and filter out atypical
      non-GSSD cases. Finally, a comprehensive bibliography and tabulation of cases
      reported in the Western and Japanese literature are provided.

PMID- 10580554
TI  - Immunohistochemical analysis in a case of idiopathic Lennox-Gastaut syndrome.
AB  - We herein report a neuropathological and immunohistochemical analysis of a brain
      from a 25-year-old male with idiopathic type of Lennox-Gastaut syndrome (LGS).
      The clinical pictures, such as seizure type and progressive mental deterioration
      with an initial normal psychomotor and mental development in a man were typical
      of LGS. A routine neuropathological examination showed no pronounced changes,
      such as neuronal loss, morphologically abnormal neurons, inflammation, vascular
      changes, Lafora bodies and tumor cells, except that mild gliosis was seen only in
      CA4 of the hippocampus. Numerous corpora amylacea were observed throughout the
      cerebral cortices subjacent to the pia mater. An immunohistochemical analysis
      showed no marked findings for such proteins as glutamate transporters, glutamate
      decarboxylase, glutamine synthetase, neuronal cytoskeleton proteins and heat
      shock proteins. However, intense ubiquitin-immunostained neurons were only found
      in CA4 of the hippocampus, whereas numerous astrocytes showed a strong
      immunoreaction for glial fibrillary acidic protein, but showed an exclusively
      reduced immunoreactivity for metallothionein-I/II, zinc-chelating protein. Our
      findings thus suggest that the pathology in the hippocampus is either causally or
      consequentially associated with the seizures occurring in LGS.

PMID- 10580556
TI  - Microscopic appearance of iatrogenic foreign bodies in neurosurgery.
AB  - Increased frequency of reoperation in neurosurgery has made the microscopic
      examination of tissue from previously operated sites more common. Various
      synthetic materials are in common use in neurosurgery, and these can cause
      clinical complications as well as presenting a diagnostic dilemma for the
      pathologist. The microscopic appearance of synthetic materials used by
      neurosurgeons to aid hemostasis, prevent aneurysm rupture, serve as dural
      prosthesis and suture wounds is reviewed. The importance of the polarizing
      microscope in differentiating synthetic materials is emphasized.

PMID- 10580555
TI  - Nigral degeneration in a case of amyotrophic lateral sclerosis: evidence of Lewy
      body-like and skein-like inclusions in the pigmented neurons.
AB  - This report describes a 58-year-old man who exhibited the clinical features of
      amyotrophic lateral sclerosis (ALS) at autopsy, 1 year after clinical onset of
      the disease. Neuropathologically, in addition to degeneration of the upper and
      lower motor neurons, marked degeneration of the substantia nigra with the
      appearance of Lewy body-like inclusions (LBI) and skein-like inclusions (SLI)
      were observed in the remaining pigmented neurons. An immunohistochemical study
      revealed that both LBI and SLI were immunopositive for ubiquitin.
      Ultrastructurally, LBI in the substantia nigra were composed of randomly arranged
      15 nm thick tubular structures associated with ribosome-like granules, similar to
      those of LBI in the lower motor neurons. SLI in the substantia nigra were
      composed of curved bundles of 5 nm thick filaments (thinner than those comprising
      the SLI in the lower motor neurons). We believe that degeneration of the
      substantia nigra could be one of the degenerative processes involved in ALS.

PMID- 10580557
TI  - Traumatic induced total myelomalacia of the cervical spinal cord associated with
      a space-occupying subdural hematoma.
AB  - We report the case of a 20-year-old male driver who suffered from a trauma to the
      cervical vertebral column in a head-on collision with a tree. The injuries
      included subluxation of the 2nd and 3rd cervical vertebrae and fracture of the
      odontoid process of the axis with ventrally directed displacement of the proximal
      fragment and dorsally directed displacement of the distal fragment. Already at
      admission to hospital a space-occupying spinal subdural hematoma was diagnosed.
      Clinically, paraplegia was diagnosed with progressive loss of consciousness.
      Pneumonia led to death 40 days after the accident. Autopsy disclosed a total
      myelomalacia of the cervical spinal cord obviously resulting from an ischemia
      caused by a traumatic lesion of the dorsal truncus arteriosus spinalis as well as
      a compression by the spinal subdural hematoma.

PMID- 10580558
TI  - Myelin staining of archival brain tissue.
AB  - To evaluate the feasibility of staining for myelin in archival materials,
      paraffin blocks were prepared from brain tissue that had been in formalin for
      intervals ranging from 7 months to over 53 years. Verhoeff and Luxol fast blue
      stains of the resulting sections yielded staining whose quality was unaffected by
      duration of fixation. Myelinated and unmyelinated areas were clearly
      distinguished, and the morphology of individual myelin sheaths was well
      preserved. No changes to conventional protocols were required, but it was
      necessary carefully to monitor the progress of differentiation. With antigen
      retrieval, it was possible to display immunoreactivity for myelin basic protein.
      While this persisted even after prolonged fixation, fine detail was lost from the
      myelin sheaths, and there was staining of oligodendroglial cytoplasm and nuclei,
      which was not seen in recently fixed tissue. In contrast to this loss of detail
      in myelin sheaths, immunohistochemistry for glial fibrillary acidic protein
      displayed astrocytic morphology clearly, even in the oldest tissue. We conclude
      that archival, formalin-fixed material can be adequately examined for myelin loss
      and astrocytosis.

PMID- 10580559
TI  - Arterial elastorrhexis: manifestation of a generalized elastic tissue disorder in
      beta-thalassaemia major.
AB  - Pseudoxanthoma elasticum-like lesions of the eye and skin are frequently observed
      in beta-thalassaemia, and there has been speculation about associated vascular
      lesions. This led to our study of histopathological material from thalassaemic
      patients. Histological re-examination was made of a series of 45 spleens and 45
      surgical liver biopsies from 45 patients with beta-thalassaemia major, aged 6-25
      yr and treated over the 20-yr period 1975-95. Correlations between clinical,
      laboratory and histological findings were demonstrated by statistical analysis.
      Arteriopathy characterized by fragmentation and multiple defects of the internal
      elastic lamina ('arterial elastorrhexis'), with deposits of iron and calcium
      salts, was found in the hilar arteries of the spleen with a frequency of 96%.
      Similar lesions were observed in the parenchymal arteries and the stromal elastic
      tissue ('stromal elastorrhexis') of the spleen, liver and lymph nodes. Arterial
      and elastic tissue alterations appear in the first decade of life and become
      generalized over the course of the disease, independent of the time of onset of
      transfusion and iron chelation therapy. Arterial elastorrhexis is the earliest
      and most frequent manifestation of a systemic elastic tissue disorder in beta
      thalassaemia major. It appears to be an acquired pseudoxanthoma elasticum-like
      syndrome, related primarily to tissue hypoxia and disturbance of elastin
      metabolism.

PMID- 10580560
TI  - Pathophysiological significance of simultaneous measurement of reticulated
      platelets, large platelets and serum thrombopoietin in non-neoplastic
      thrombocytopenic disorders.
AB  - An automated reticulocyte counter using flowcytometric analysis, the R-3000
      (Sysmex Inc. Kobe, Japan), has recently been modified to determine reticulated
      platelets (RPs) and large platelets (LPs). We measured frequencies of RPs, LPs in
      total platelet count and serum thrombopoietin concentration comprehensively in
      non-neoplastic thrombocytopenic patients with immune thrombocytopenic purpura
      (ITP, n = 23), aplastic anemia (AA, n = 21), liver cirrhosis (LC, n= 17), and
      hematologically normal subjects (control, n = 151). ITP was characterized as high
      frequencies of both RP and LP, AA as high RP frequency and elevated
      thrombopoietin concentration, and LC as no difference compared with control.
      Interestingly, the frequency of RP appeared to depend on total platelet count
      rather than the cause of thrombocytopenia, while the frequency of LP appeared to
      depend much less on total platelet count. Furthermore, significant positive
      correlations were observed between frequencies of RP and LP in control, ITP and
      LC subjects, in whom bone marrow stem cells are intrinsically normal. However,
      there was no such correlation in AA patients with stem cell deficiency,
      suggesting that this correlation might be a useful new parameter for detecting
      qualitatively abnormal platelets. Measurement of RP and LP is thus useful for
      elucidating the pathophysiology of thrombocytopenic disorders.

PMID- 10580561
TI  - Membrane protein pattern in hereditary spherocytosis in five subjects from north
      east Italy obtained by SDS-PAGE using N,N'-diallyltartardiamide.
AB  - In the present study we examined five subjects affected by hereditary
      spherocytosis (three unsplenectomized and two splenectomized), coming from an
      area in the north-east of Italy where hereditary spherocytosis is an anaemic
      disease with very low incidence. All patients showed a low degree of spectrin
      deficiency (14%), detected with sodium dodecyl sulfate polyacrylamide gel
      electrophoresis. Moreover, when this analysis was performed with N,N'
      diallyltartardiamide as cross-linking agent instead of N,N'
      methylenbisacrylamide, some unusual bands appeared in the region between proteins
      4.2 and 5, the three unsplenectomized and two splenectomized patients showing
      different patterns. We hypothesise that some alterations of proteins in this
      region (e.g. the 4.5 or 4.9 bands), possibly due to proteolysis, must have
      occurred in relation to the disease.

PMID- 10580563
TI  - Ectopic haematopoiesis in the mouse: roles of stroma and cytokines in
      granulocytopoiesis in in vivo diffusion chamber cultures.
AB  - We have examined a possible role of two different types of irradiated stromal
      cells, i.e. murine bone marrow (BM) stromal cells and stromal cell line MS-5R,
      when cocultured with murine blood-borne progenitors or sorted Lin- Sca-1+ bone
      marrow cells in vivo in peritoneal diffusion chambers (DC). Retrieval and
      quantification of the cultured cells were performed after 4, 7, and 14 d.
      Granulocyte and/or macrophage colony-forming cells (G/M-CFC) were enumerated in
      subcultures from the DC. G/M-CFC production was not enhanced in the stroma
      contact cultures, in comparison with the standard stroma-non-contact cultures,
      but early granulocytopoiesis was stimulated. Perturbation of the humoral
      environment of DC was investigated in a number of ways, for example with
      continuous infusion of rhG-CSF from a subcutaneous implanted minipump to DC host
      mice, with DC host mice carrying a transplantable leukaemia, secreting
      interleukin 3 (IL-3), and with injections of various cytokines. None of these
      interventions sustained the expansion of the G/M-CFC population. In conclusion,
      for ectopic haematopoiesis to take place, several requirements must be met.
      Relevant stromal cells apparently affect haematopoiesis both via direct cell-cell
      interactions and via humoral mediators (viz. cytokines) which they secrete.

PMID- 10580562
TI  - Erythropoietin induces the expansion of c-kit+ progenitors for myeloid and
      erythroid cells, but not for lymphoid cells, in the bone marrow and liver.
AB  - In humans, the numbers of erythrocytes and granulocytes, but not that of
      lymphocytes, tend to increase in parallel. To determine the mechanism, we
      investigated how the administration of erythropoietin induces the expansion of
      erythroid cells and other lineage cells in the bone marrow, liver, and other
      organs of mice. When mice were injected twice (days 1 and 2) with erythropoietin
      at a dose of 20 or 200 IU/day/ mouse, a prominent expansion of TER 19+ (erythroid
      cells) and Gr-1high cells (granulocytes) occurred in the liver, spleen, and bone
      marrow day 3 after the initial injection. On the other hand, lymphoid cells,
      including NK cells, extrathymic T cells, and conventional T cells, did not
      expand. In parallel with the expansion of erythroid cells and granulocytes, the
      levels of c-kit(+)Lin- cells increased in the liver and bone marrow. Despite the
      increase in the proportion of c-kit(+) Lin(-) cells, the generation of
      lymphocytes (e.g., T cells) decreased when such bone marrow cells were injected
      to scid mice. These results suggest that erythropoietin has the ability to induce
      the expansion of not only erythroid cells but also granulocytes in the liver,
      spleen, and bone marrow. Furthermore, c-kit+ progenitors which may commit
      themselves to erythroid and myeloid cells, but not to lymphoid cells, were also
      activated in the liver and bone marrow of mice treated with erythropoietin.

PMID- 10580564
TI  - Combination of granulocyte-macrophage colony-stimulating factor (GM-CSF) anf
      erythropoietin (EPO) for the treatment of advanced non-responsive chronic
      lymphocytic leukemia.
AB  - We report the use of a colony-stimulating granulocyte-macrophage factor (GM/CSF)
      and erythropoietin (EPO) combination as salvage treatment in four heavily
      pretreated patients with refractory/ recurrent B-CLL. Induction therapy was
      subcutaneous GM-CSF 2.5 microg/ kg, and EPO, 150 units/kg both daily for the
      first 14 d. Maintenance therapy was GM-CSF on days 1, 3 and 5 and Epo on days 2,
      4 and 6 at the same doses with weekly recycling. All the patients responded
      favourably. A significant reduction of lymphocytosis, lymphoadenomegaly, and
      organomegaly was obtained within one month of therapy. The number of infections
      and transfusional requirement decreased dramatically. The hemoglobin increased to
      over 11 g/dl in 3 out of 4 patients. With a median follow-up of 11 months (range
      5-13) we observed 4 partial responses (NCI/IWCLL) and only one progression after
      a 10-month partial response. This combination regimen seems very active, safe and
      easy to administer. It may represent a promising therapeutical option in heavily
      pretreated patients. Further clinical and biological studies on a larger cohort
      of patients are needed to confirm these preliminary data, to clarify the
      hypothetical interactions between these cytokines and B-CLL cell proliferation
      pathways, and to establish if this therapy may have an impact on survival.

PMID- 10580565
TI  - Incidence of nucleoli in erythroblasts in patients suffering from refractory
      anemia of myelodysplastic syndrome.
AB  - Nucleoli of erythroblasts have been studied in patients suffering from refractory
      anemia (RA) of myelodysplastic syndrome (MDS) and in control patients without a
      disturbed erythropoiesis in order to provide information on the incidence of
      nucleoli and micronucleoli in these cells. Nucleoli in erythroblasts were
      visualized by a simple cytochemical procedure for the demonstration of RNA which
      facilitated the visualization not only large nucleoli but also micronucleoli in
      advanced stages of the erythroblastic maturation. In control patients nucleoli
      were detected in all stages of erythroblastic development. In patients suffering
      from RA of MDS, a relatively large population of polychromatic and orthochromatic
      erythroblasts was characterized by a loss of nucleoli accompanied by the
      decreased incidence of micronucleoli characteristic of these cells. In contrast
      to control patients, in patients suffering from RA of MDS the number of nucleoli
      expressed by the values of the nucleolar coefficient of erythroblasts was
      smaller, particularly in both the early and terminal stages of erythroblastic
      development. Thus in patients with RA of MDS both the abnormal loss of nucleoli
      and decreased number of nucleoli in erythroblasts apparently represent and
      reflect a further abnormality of disturbed erythropoiesis.

PMID- 10580566
TI  - Response and adverse drug reactions to combination chemotherapy in elderly
      patients with aggressive non-Hodgkin's lymphoma: comparison of CHOP, COP-BLAM,
      COP-BLAM III, and THP-COPBLM.
AB  - We retrospectively compared therapeutic results and adverse events in 198 elderly
      patients (> or = 70 yr old) with aggressive non-Hodgkin's lymphoma diagnosed
      between 1981 and 1995 who underwent CHOP, COP-BLAM, COP-BLAM III, or THP-COPBLM
      chemotherapy. Complete remission (CR) was achieved in 138 patients (69.7%). The
      CR rate was 47.0% for CHOP, 76.3% for COP-BLAM, 67.9% for COP-BLAM III, and 74.4%
      for THP-COPBLM therapy (p = 0.013). The 5-yr survival rate was 37.0% for CHOP,
      49.0% for COP-BLAM, and 53.5% for COP-BLAM III. The event-free survival rate
      showed no significant differences between the four treatments. Adverse events of
      Grade 3 or worse were commonly anemia or granulocytopenia in patients receiving
      THP-COPBLM therapy. Cardiac sympathetic dysfunction and cardiac mitochondrial
      damage were less common with pirarubicin than with doxorubicin. For elderly
      patients, it is better to select therapy with as few adverse events as possible
      based on the complications and medical history of the individual patients.

PMID- 10580567
TI  - Apoptosis, proliferation and NF-kappaB activation induced by agonistic Fas
      antibodies in the human myeloma cell line OH-2: amplification of Fas-mediated
      apoptosis by tumor necrosis factor.
AB  - Tumor necrosis factor (TNF) is known to be a growth factor for several myeloma
      cell lines. However, in the presence of the agonistic Fas antibody CH 11, TNF
      enhanced the level of apoptosis in cultures of the human myeloma cell line OH-2.
      This pro-apoptotic effect of TNF was explained at least in part by a TNF-mediated
      enhancement of Fas expression. TNF induces proliferation of OH-2 by activating
      nuclear transcription factor kappa-B (NF-kappaB). The proliferative effect of TNF
      on OH-2 cells was abrogated by CH11, but this was not caused by an inhibition of
      the translocation of NF-kappaB. On the contrary, CH11 could by itself activate NF
      kappaB in OH-2 cells, and in the presence of an inhibitor of caspase-1 induce
      proliferation of the cells. The relationship between stimulation of TNF receptors
      and Fas and the level of NF-kappaB activation was also examined in three other
      myeloma cell lines. RPMI-8226 cells showed NF-kappaB activation by TNF, but
      contrary to OH-2, not by CH11. Unstimulated U-266 and JJN-3 cells had high levels
      of activated NF-kappaB. This shows that NFkappa-B is either constitutively
      activated or inducible in myeloma cells. Modulation of Fas expression and
      inhibition of NF-kappaB activation can potentially be of therapeutic importance
      in multiple myeloma.

PMID- 10580568
TI  - Sezary syndrome in a patient with multiple myeloma: demonstration of a clonally
      distinct second malignancy.

PMID- 10580569
TI  - Guillain-Barre syndrome after autologous peripheral blood stem cell
      transplantation for CML.

PMID- 10580570
TI  - Arginine 490 is a hot spot for mutation in the band 3 gene in hereditary
      spherocytosis.

PMID- 10580571
TI  - Acute haemolytic anaemia after cephalosporin therapy in a young child.

PMID- 10580572
TI  - Light chain myeloma presenting as severe obstructive jaundice due to hepatic
      amyloidosis.

PMID- 10580573
TI  - IgM myeloma: different features from multiple myeloma and macroglobulinaemia.

PMID- 10580574
TI  - Involvement of phosphatidylserine and non-phospholipid components of the
      hepatitis B virus envelope in human Annexin V binding and in HBV infection in
      vitro.
AB  - BACKGROUND/AIMS: We have previously demonstrated that human liver Annexin V
      (hAV), a Ca2+-dependent phospholipid binding protein, binds specifically to small
      HBsAg (SHBsAg). Because of the propensity of AV to bind phospholipids, we here
      examine the role of phospholipids, as component of the HBV envelope, in binding
      to hAV and in HBV infection. METHODS: The influence of phospholipids
      (phosphatidylserine and phosphatidylcholine) on the binding of hAV to SHBsAg or
      to anti-hAV monoclonals was determined by ELISA. Their influence on HBV infection
      was investigated using an in vitro HBV infection assay. RESULTS: Two monoclonals,
      specific against hAV, were able to block the binding of hAV to SHBsAg and
      recognized different epitopes of hAV. The binding of one of these monoclonals to
      hAV could be inhibited by phosphatidylserine, but not by phosphatidylcholine.
      Further experiments revealed that phosphatidylserine could also inhibit the
      binding of hAV to SHBsAg and could even prevent HBV infection in vitro.
      Phosphatidylcholine had no effect on the binding of hAV to SHBsAg and could not
      prevent HBV infection in vitro. However, since phosphatidylserine was not able to
      abolish the binding of the other blocking monoclonal to hAV, a non-phospholipid
      component of the HBV envelope must also be involved in hAV binding. CONCLUSIONS:
      These results indicate that phosphatidylserine and a non-phospholipid component
      of the HBV envelope are involved in hAV binding and in HBV infection.

PMID- 10580575
TI  - Effect of interferon alpha on hepatitis B virus replication and gene expression
      in transiently transfected human hepatoma cells.
AB  - BACKGROUND/AIMS: Chronic hepatitis B virus (HBV) infection is predominantly
      treated with interferon alpha (IFNalpha), which results in efficient reduction of
      the viral load only in 10-20% of treated patients. The mechanisms induced by
      IFNalpha resulting in reduction of viremia in responding patients are unknown.
      The aim of this study was to characterize HBV-specific IFNalpha-induced
      intracellular inhibitory mechanisms and IFNalpha-sensitive HBV targets. METHODS:
      To determine the antiviral activity, cells transiently transfected with HBV DNA
      were treated with IFNalpha and thereafter, viral products were quantified at
      different time points. RESULTS: Time-dependent reduction of RNA, replicative DNA
      intermediates, core protein and secreted HBsAg/HBeAg levels was observed in
      IFNalpha-treated cells. Viral RNA levels were reduced most effectively early post
      treatment whereas those of core protein and replicative intermediates decreased
      later. By expression of subgenomic HBV sequences, an RNA target region mediating
      IFNalpha-induced RNA degradation was mapped. CONCLUSIONS: These data indicate
      that HuH7 cells transiently transfected with HBV-DNA represent a system well
      suited for detailed analysis of IFNa-induced antiviral mechanisms and HBV
      targets. At least two IFNalpha-induced HBV-specific antiviral activities are
      active in this system: one reduces the levels of core protein and replicative
      intermediates, the other leads to posttranscriptional degradation of HBV-RNA.
      Based on the established in vitro system a detailed characterization of the
      IFNalpha-sensitive RNA-region and of factors mediating this intracellular
      antiviral effect is feasible. This may lead to the development of novel
      strategies for therapy of chronic hepatitis.

PMID- 10580576
TI  - Natural history and etiology of liver disease in patients with previous community
      acquired acute non-A, non-B hepatitis. A follow-up study of 178 Danish patients
      consecutively enrolled in The Copenhagen Hepatitis Acuta Programme in the period
      1969-1987.
AB  - BACKGROUND/AIMS: Consecutive patients originally diagnosed with acute non-A, non
      B hepatitis were followed up to assess the long-term morbidity and mortality and
      to re-evaluate the etiology in surviving patients. METHODS: Follow-up was
      performed in 178 patients with acute non-A, non-B hepatitis enrolled in the
      Copenhagen Hepatitis Acuta Programme in the period 1969-1987. Mortality and
      morbidity were assessed using: i) death certificates and ii) diagnoses at
      discharge following all somatic admissions. All patients who were alive were
      offered a re-examination encompassing clinical, biochemical and virological
      evaluation. RESULTS: After a median of 23 years, 71 (40%) had died and seven (4%)
      were untraceable. Overall mortality and mortality due to cirrhosis and accidents,
      mainly intoxication with drugs, were significantly higher compared to those of an
      age- and sex-matched Danish population. Chronic hepatitis had been diagnosed in
      19 (11%) and cirrhosis in 16 (9%). Of 100 patients who were alive, 57 accepted a
      re-examination. Anti-HCV was detected in 24 (42%) and 19 (33%) were HCV-RNA
      positive. Of the viremic patients, 11 (58%) had elevated P-ALT, but only three
      (16%) had already been diagnosed with HCV infection. A history of intravenous
      drug use was tantamount to anti-HCV positivity. CONCLUSIONS: Danish patients with
      community-acquired acute non-A, non-B hepatitis had an increased mortality due to
      liver cirrhosis during the first years after the acute infection. Alcohol was the
      etiological agent in several cases, but HCV infection may also have been present.
      However, the long-term HCV-related morbidity and mortality were low.

PMID- 10580577
TI  - Antioxidant status and glutathione metabolism in peripheral blood mononuclear
      cells from patients with chronic hepatitis C.
AB  - BACKGROUND/AIMS: Oxidative stress could play a role in the pathogenesis of
      hepatitis C virus infection. We investigated the oxidant/antioxidant status in
      peripheral blood mononuclear cells from patients with chronic hepatitis C and
      controls. METHODS/RESULTS: Lipid peroxidation products and superoxide dismutase
      activity in peripheral blood mononuclear cells were higher in chronic hepatitis C
      patients than in healthy subjects while glutathione S-transferase activity was
      reduced in patients as compared to controls. Catalase, glutathione peroxidase and
      glutathione reductase were similar in chronic hepatitis C and normal individuals.
      No statistically significant differences were found between patients and controls
      with regard to glutathione levels in peripheral blood mononuclear cells, but 35%
      of patients with chronic hepatitis C showed values of glutathione and oxidized
      glutathione which were below and above, respectively, the limits of normal
      controls. Finally, the glutathione synthetic capacity of the cytosol of
      peripheral blood mononuclear cells was significantly higher in patients than in
      controls, indicating increased glutathione turnover in lymphocytes from patients
      with chronic hepatitis C. CONCLUSIONS: Oxidative stress is observed in peripheral
      blood mononuclear cells from chronic hepatitis C patients. This process might
      alter lymphocyte function and facilitate the chronicity of the infection.

PMID- 10580578
TI  - Interleukin-10 inhibits hepatic injury and tumor necrosis factor-alpha and
      interferon-gamma mRNA expression induced by staphylococcal enterotoxin B or
      lipopolysaccharide in galactosamine-sensitized mice.
AB  - BACKGROUND/AIMS: Proinflammatory cytokines including tumor necrosis factor alpha
      (TNF-alpha) and interferon gamma (IFN-gamma) play a critical role in the
      pathogenesis of liver injury induced by lipopolysaccharide (LPS) or
      staphylococcal enterotoxin B (SEB) in D-galactosamine (GalN)-sensitized mice. The
      aim of this study was to examine the ability of interleukin-10 (IL-10), a
      recently characterized, highly potent anti-inflammatory mediator, to protect
      sensitized mice against hepatotoxicity induced by SEB or LPS. METHODS: IL-10 was
      injected at various concentrations into BALB/c mice treated by GalN/SEB or
      GalN/LPS. Liver injury was assessed biochemically and histologically. Serum
      levels of TNF-alpha and IFN-gamma were measured and the expressions of TNF-alpha
      and IFN-gamma mRNA in the liver and spleen were determined by reverse
      transcription polymerase chain reaction. RESULTS: Treatment with IL-10 markedly
      reduced serum transaminase activities in a dose-dependent manner and reduced
      hemorrhagic liver damage in sensitized mice exposed to either toxin. IL-10 also
      inhibited increases in serum TNF-alpha and IFN-gamma concentrations with either
      toxin. Treatment with IL-10 significantly reduced TNF-alpha mRNA and IFN-gamma
      mRNA expression in the liver and spleen after administration of either toxin to
      sensitized mice. CONCLUSIONS: These findings suggest that IL-10 is capable of
      regulating both T cell- and macrophage-mediated hepatic injury in vivo and that
      this cytokine might be useful in the treatment of acute liver failure.

PMID- 10580579
TI  - Biphasic effect of colchicine on acute liver injury induced by carbon
      tetrachloride or by dimethylnitrosamine in mice.
AB  - BACKGROUND/AIMS: The effects of colchicine on acute liver injury induced by
      carbon tetrachloride or by dimethylnitrosamine in mice were examined. METHODS:
      Nonlethal acute liver injury was induced in male BALB/c mice by a single
      intraperitoneal injection of 0.8 ml/kg carbon tetrachloride or 15 mg/kg
      dimethylnitrosamine. 0.6 mg/kg colchicine was administered 18 h or 2 h
      intraperitoneally before hepatotoxin treatment. RESULTS: Reversible centrilobular
      to mid-zone necrosis and apoptosis occupying half the liver lobular area was
      evoked by carbon tetrachloride, and dimethylnitrosamine, respectively.
      Administration of colchicine 18 h before hepatotoxins markedly suppressed liver
      injury, whereas colchicine administration 2 h before the hepatotoxins accelerated
      it. The hepatoprotective effect evoked by colchicine was due to reduction in
      liver cytochrome P450 content and P450 2E1 activity. In contrast, the
      hepatodestructive effect seen in the carbon tetrachloride model was related to
      the extent of lipid peroxidation promoting plasma membrane destruction, while the
      hepatodestructive effect in the dimethylnitrosamine model was due to suppression
      of Bcl-X(L) expression, leading to acceleration of apoptosis. CONCLUSIONS: A
      biphasic effect of colchicine on carbon tetrachloride- and dimethylnitrosamine
      induced acute liver injury was seen. The time interval between colchicine
      administration and the hepatotoxin treatment is crucial to the subsequent
      development of liver lesions.

PMID- 10580580
TI  - Treatment of concanavalin A-induced hepatitis in mice with low molecular weight
      heparin.
AB  - BACKGROUND/AIMS: Heparin has been noted to inhibit inflammation independent of
      its known anti-coagulant activity. In the present study, we examined the ability
      of heparin and low molecular weight heparin to prevent immune-mediated,
      concanavalin A-induced liver damage. METHODS: Mice were pretreated with either
      heparin or low molecular weight heparin (Fragmin) prior to their inoculation with
      concanavalin A (10 mg/kg). Liver enzymes, liver histology, and the serum levels
      of tumor necrosis factor-a, interleukin-6, and interleukin-10 were examined in
      the control and treated mice. RESULTS: The histopathologic damage in the liver,
      and the concanavalin A-induced release of aminotransferases, tumor necrosis
      factor-a, and interleukin-6 were significantly inhibited in mice pretreated with
      low molecular weight heparin, whereas the serum levels of the anti-inflammatory
      cytokine interleukin-10 were increased (p<0.01). Interestingly, maximal
      inhibition was obtained with low low molecular weight heparin doses (5 and 1
      microg/mouse, p<0.001), while higher doses were less effective. Concanavalin A
      induced liver injury was not prevented by pretreatment of the mice with heparan
      sulphate (p<0.001), which although it is structurally similar to heparin
      possesses neither anti-inflammatory nor anti-coagulant properties. CONCLUSIONS:
      This study demonstrates the efficacy of low molecular weight heparin in
      preventing immune-mediated liver damage in mice.

PMID- 10580581
TI  - Resistance of three immortalized human hepatocyte cell lines to acetaminophen and
      N-acetyl-p-benzoquinoneimine toxicity.
AB  - BACKGROUND/AIMS: Acetaminophen toxicity in hepatocytes is attributed to
      generation of the toxic metabolite N-acetyl-p-benzoquinoneimine, leading to
      depletion of intracellular glutathione, alteration of redox potential and
      ultimately, cellular necrosis. We aimed to determine the effect of acetaminophen
      and N-acetyl-p-benzoquinoneimine on three human hepatocyte cell lines HH25, HH29
      and HHY41, and for comparison, on primary rat hepatocytes, a cell type that is
      relatively resistant to acetaminophen-induced toxicity. METHODS: We investigated
      the effect of incubation of rat hepatocytes and 3 hepatocyte cell lines with
      acetaminophen or N-acetyl-p-benzoquinoneimine on LDH release, glutathione status,
      mitochondrial function, CYP1A activity, albumin synthesis and DNA content.
      RESULTS: We demonstrated that HH25, HH29 and HHY41 are resistant to the toxic
      effects of acetaminophen under conditions that induce cytotoxicity in rat primary
      hepatocytes, as indicated by maintenance of glutathione levels and basal LDH
      release. Incubation with N-acetyl-p-benzoquinoneimine caused a dose-dependent
      cytotoxicity in rat hepatocytes. Under comparable conditions N-acetyl-p
      benzoquinoneimine had no effect on any of the hepatocyte cell lines.
      Nevertheless, when culturing the cells for a further 48 h, a decrease in
      glutathione levels, albumin synthesis, CYP1A activity, DNA content and
      mitochondrial function was apparent. CONCLUSION: HH25, HH29 and HHY41 cells are
      highly resistant to acetaminophen and N-acetyl-p-benzoquinoneimine-induced
      toxicity. They tolerate a much higher concentration of both toxins for a longer
      period of time compared to rat primary hepatocytes. These results are of
      relevance in the use of these cell lines to investigate acetaminophen
      hepatotoxicity, and may be of importance in the choice of cells for use in
      bioartificial liver support systems.

PMID- 10580582
TI  - Demonstration and partial characterisation of phospholipid methyltransferase
      activity in bile canalicular membrane from hamster liver.
AB  - BACKGROUND/AIMS: Methylation of phosphatidylethanolamine to phosphatidylcholine
      predominantly takes place in mitochondrial-associated membrane and the
      endoplasmic reticulum of the liver. The transport of the phospholipids from
      endoplasmic reticulum to the bile canalicular membrane is via vesicular and
      protein transporters. In the bile canalicular membrane a flippase enzyme helps to
      transport phosphatidylcholine specifically to the biliary leaflet. The
      phosphatidylcholine then enters the bile where it accounts for about 95% of the
      phospholipids. We postulated that the increased proportion of phosphatidylcholine
      in the bile canalicular membrane and the bile compared to the transport vesicles
      may be due to a methyltransferase activity in the bile canalicular membrane
      which, using s-adenosyl methionine as the substrate, converts
      phosphatidylethanolamine on the cytoplasmic leaflet to phosphatidylcholine, which
      is transported to the biliary leaflet. The aim of our study was to demonstrate
      and partially characterise methyltransferase activity in the bile canalicular
      membrane. METHODS: Organelles were obtained from hamster liver by homogenisation
      and separation by sucrose gradient ultracentrifugation. These, along with
      phosphatidylethanolamine, were incubated with radiolabelled s-adenosyl
      methionine. Phospholipids were separated by thin-layer chromatography and
      radioactivity was counted by scintigraphy. RESULTS: We demonstrated
      methyltransferase activity (nmol of SAMe converted/mg of protein/h at 37 degrees
      C) in the bile canalicular membrane of 0.442 (SEM 0.077, n=8), which is more than
      twice that found in the microsomes at 0.195 (SEM 0.013, n=8). The Km and pH
      optimum for the methyltransferase in the bile canalicular membrane and the
      microsomes were similar (Km 25 and 28 microM, respectively, pH 9.9 for both). The
      Vmax was different at 0.358 and 0.168 nmol of SAMe converted/mg of protein/h for
      the bile canalicular membrane and the microsomes, respectively. CONCLUSION: The
      presence of the methyltransferase activity in the bile canalicular membrane may
      be amenable to therapeutic manipulation.

PMID- 10580583
TI  - Chronic liver disease in the extremely elderly of 80 years or more: clinical
      characteristics, prognosis and patient survival analysis.
AB  - BACKGROUND/AIMS: This study aimed to elucidate the clinical characteristics of
      patients with chronic liver disease aged 80 years or more, especially the factors
      affecting prognosis and carcinogenesis. METHODS: A total of 135 patients aged 80
      years or above were divided into chronic liver disease without cirrhosis (non-LC)
      and cirrhosis (LC) groups according to the severity of fibrosis, and the clinical
      characteristics and prognoses were evaluated. RESULTS: Seventy-three (54.1%) of
      135 patients were in the LC group and 79 patients (58.5%) had hepatitis C virus.
      Various concomitant diseases were seen in 122 patients (90.4%). Liver-related
      deaths occurred in only 19 (36.5%) of 52 patients who died during observation,
      although 28 patients (53.8%) had liver cancer at the time of death. Cumulative
      survival rates in the non-LC and the LC groups were 85.7% and 58.8% at the 5th
      year, and 69.4% and 19.4% at the 9th year, respectively. Cumulative liver cancer
      appearance rates in the non-LC and the LC groups were 1.6% and 6.1% at the 1st
      year, 12.4% and 19.9% at the 5th year, and 12.4% and 32.0% at the 7th year,
      respectively. A multivariate Cox regression analysis revealed that the presence
      of liver cancer (p=0.0001), platelet count (p=0.0242), and fibrotic stage
      (p=0.0118) were independently associated with survival period, and alfa
      fetoprotein (p=0.0194) and bilirubin (p=0.0282) were independently associated
      with carcinogenesis. CONCLUSIONS: Cirrhosis is the major risk factor affecting
      the prognosis. On the other hand, we must pay more attention to concomitant
      diseases specific to advanced age.

PMID- 10580584
TI  - Non-invasive diagnosis of esophageal varices in chronic liver diseases.
AB  - BACKGROUND/AIMS: The primary prevention of bleeding from esophageal varices is a
      major therapeutic issue requiring early screening of esophageal varices. Our aim
      was to study the diagnostic accuracy of non-endoscopic means for the diagnosis of
      esophageal varices. METHODS: Sixty-three clinical, biochemical, endoscopic and
      Doppler ultrasound variables were prospectively recorded in 207 consecutive
      patients with chronic liver disease. Diagnostic accuracy was evaluated by
      discriminant analysis, first globally using all variables with diagnostic
      accuracy > or = 65% in univariate analysis, then by stepwise regression. RESULTS:
      A) whole group (n=207), 1) diagnosis of esophageal varices: diagnostic accuracy
      was globally 81%, and 81% with 1 variable: irregular liver surface at ultrasound,
      2) Diagnosis of large esophageal varices (grades 2+3): diagnostic accuracy was
      globally 80%, and 79% with 2 variables: prothrombin index, gamma-globulins. B)
      patients with cirrhosis (n=116), 1) diagnosis of esophageal varices: diagnostic
      accuracy was globally 71%, and 72% with 2 variables: platelet count, prothrombin
      index, 2) diagnosis of large esophageal varices (grades 2+3): diagnostic accuracy
      was globally 71%, and 72% with 3 variables: platelet count, prothrombin index,
      spider naevi. The ROC curve showed that the best threshold for the diagnostic
      accuracy of platelet count was 160 G/l providing a sensitivity of 80% and a
      specificity of 58%. Platelet count > or = 260 G/l has a negative predictive value
      > or = 91%. CONCLUSIONS: Using a few non-endoscopic criteria, esophageal varices
      can be correctly diagnosed in 81% of patients with chronic liver disease and in
      71% of patients with cirrhosis. These results show that the non-invasive
      screening of patients who are candidates for the primary prevention of variceal
      bleeding is possible, but should be improved before being used in a clinical
      setting.

PMID- 10580585
TI  - Acute hemodynamic changes following hemorrhage and volume restitution, using a
      low viscosity plasma expander, in anesthetized portal hypertensive rats.
AB  - BACKGROUND/AIM: The aim of this study was to examine, in a portal hypertensive
      rat model, the hemodynamic changes following hemorrhage and volume restitution
      with blood and Haemaccel (a low viscosity, volume expander). METHODS: Portal
      hypertension was induced by portal vein constriction. Under ketamine anesthesia,
      blood was withdrawn at a constant rate of 0.3 ml/min, for 15 min followed by 15
      min of stabilization. The shed blood or Haemaccel was infused at the same rate
      and volume used for withdrawal. Hemodynamic measurements were performed using
      radioactive microspheres. Blood viscosity was measured with an Ostwald
      viscometer. Vascular hindrance was calculated as the resistance/viscosity ratio.
      RESULTS: Twelve rats were studied in each group. During blood withdrawal,
      significant reductions in arterial pressure and portal pressure were observed.
      Volume replacement with blood was accompanied by increased mean arterial pressure
      and portal pressure to baseline. Arterial pressure following volume replacement
      with Haemaccel was lower and portal pressure was higher than baseline (128+/-16
      and 17.1+/-3.9 vs 146+/-13 and 15.9+/-3.0 mmHg, respectively; p<0.05). Volume
      replacement with Haemaccel, compared to blood, was followed by increased cardiac
      output and portal venous inflow (39.3+/-11.6 and 4.4+/-1.5 vs 28.9+/-3 and 2.9+/
      0.8 ml x min(-1) x 100 g bw(-1), respectively; p<0.05), decreased hematocrit and
      viscosity (29.3+/-3.8% and 2.8+/-1.3 vs 35.7+/-3.4% and 4.0+/-1.3, respectively;
      p<0.01) and decreased peripheral and splanchnic arteriolar resistance (3.6+/-1.4
      and 29.2+/-14.0 vs 5.0+/-1.4 and 43.9+/-12.7 mmHg x ml(-1) x min x 100 g bw,
      respectively; p<0.05). There were no significant changes in vascular hindrance in
      any vascular beds between the two groups. CONCLUSION: In this model, volume
      replacement with Haemaccel induced an increase in cardiac output and portal
      venous inflow, thus preventing the reduction in portal pressure which might be
      expected when viscosity is reduced.

PMID- 10580586
TI  - Combination treatment of hepatic encephalopathy due to thioacetamide-induced
      fulminant hepatic failure in the rat with benzodiazepine and opioid receptor
      antagonists.
AB  - BACKGROUND/AIMS: Treatment of hepatic encephalopathy with drugs acting on the
      target organ of this syndrome, the brain, is unsatisfactory. Combination
      treatment with different neurotransmitter receptor antagonists may be a rational
      option to optimize treatment. METHODS: The effects of various doses of the
      benzodiazepine receptor antagonist Ro 15-3505 and the opioid receptor antagonist
      naloxone, alone or in combination, were tested on hepatic encephalopathy in rats
      with thioacetamide-induced hepatic failure in an open-field activity meter.
      Comparison of single and combination treatment was also done using a neurological
      test battery. In addition, we compared survival of treatment-responder rats with
      treatment non-responders. RESULTS: Naloxone dose dependently increased ambulatory
      activity and improved neurological score. Ro 15-3505 also improved ambulatory
      activity and neurological score; however, the improvement was less evident at
      higher doses. Combination treatment was not superior to single treatment.
      Survival was increased in treatment-responder rats. CONCLUSIONS: The failure of
      combination treatment with Ro 15-3505 and naloxone to further improve hepatic
      encephalopathy may suggest that the two neurotransmitter systems are interrelated
      or that hepatic encephalopathy may not be further improved by drugs acting on the
      brain.

PMID- 10580587
TI  - In vivo regulation by glutathione of methionine adenosyltransferase S
      nitrosylation in rat liver.
AB  - BACKGROUND/AIMS: Ethanol consumption and pathological conditions such as
      cirrhosis lead to a reduction of hepatic glutathione. Hepatic methionine
      adenosyltransferase, the enzyme that synthesizes S-adenosylmethionine, the major
      methylating agent, is regulated in vivo by glutathione levels. We have previously
      shown that nitric oxide inactivates methionine adenosyltransferase in vivo by S
      nitrosylation. In this study, we aimed to investigate the regulation by
      glutathione of methionine adenosyltransferase S-nitrosylation in rat liver.
      METHODS: Rat hepatocytes and whole animals were treated with buthionine
      sulfoximine, an inhibitor of glutathione synthesis, and methionine
      adenosyltransferase S-nitrosylation and activity were determined. RESULTS: In
      hepatocytes, buthionine sulfoximine led to the S-nitrosylation and inactivation
      of methionine adenosyltransferase. Restoring glutathione levels in hepatocytes
      treated with buthionine sulfoximine, by the addition of glutathione monoethyl
      ester, a permeable derivative of glutathione, led to the denitrosylation and
      reactivation of methionine adenosyltransferase. In whole animals, buthionine
      sulfoximine led also to methionine adenosyltransferase S-nitrosylation and
      inactivation. S-Nitrosylation and inactivation of methionine adenosyltransferase
      induced by buthionine sulfoximine in whole animals was prevented by glutathione
      monoethyl ester. CONCLUSIONS: These results indicate that in vivo hepatic
      methionine adenosyltransferase exists in two forms in equilibrium, nitrosylated
      (inactive) and denitrosylated (active), which are regulated by both the cellular
      levels of nitric oxide and glutathione.

PMID- 10580588
TI  - Effects of growth and differentiation factors on the epithelial-mesenchymal
      transition in cultured neonatal rat hepatocytes.
AB  - BACKGROUND/AIMS: Loss of specific differentiation markers, adoption of a
      migrating morphology and progressive replacement of the cytokeratin network by
      vimentin intermediate filaments characterize the epithelial-mesenchymal
      transition of cultured neonatal rat hepatocytes. In a previous study (Hepatology
      1997; 25: 598-606), we reported that this process can be differentially regulated
      by EGF and DMSO, two agents that affect hepatocyte growth and differentiation.
      The aim of the present study was to determine if growth activation or
      differential gene expression could explain the differences in EMT observed
      between these two factors. METHODS: We compared the effects of EGF, HGF, TGF
      beta1 and DMSO on growth, proto-oncogene expression, epithelial-mesenchymal
      transition markers and expression of liver transcription factors in cultured
      neonatal rat hepatocytes using thymidine incorporation, Northern blotting and
      Western blotting analysis. RESULTS: When TGF-beta1 or DMSO was added to the
      cultures supplemented with EGF and HGF, the mitogenic activity induced by these
      factors was inhibited. DMSO down-regulated c-myc and c-fos expression. mRNA
      levels of some liver-specific genes such as albumin, or liver-enriched
      transcription factors such as C/EBPdelta, HNF-4 and HNF-1beta were slightly
      different in cultures supplemented with DMSO or TGF-beta1. However, no
      differences were found when DMSO or TGF-beta1 was added to the cultures
      supplemented with EGF. Western blotting analysis showed that TGF-beta1 decreased
      cytokeratin and increased vimentin levels, while DMSO decreased both cytokeratin
      and vimentin. When DMSO or TGF-beta1 was added in combination with EGF or HGF,
      both factors maintained the increase in albumin and cytokeratin induced by the
      growth factors although DMSO, but not TGF-beta1, inhibited vimentin expression.
      CONCLUSIONS: Activation of vimentin expression produced in cultures supplemented
      with the mitogenic factors (EGF and HGF) is independent of the activation of cell
      growth, because DMSO but not TGF-beta1 can abolish vimentin synthesis, although
      both inhibited growth. Moreover, the vimentin expression in these cultures seems
      to be independent of the mRNA levels of transcription factors associated with the
      differentiated liver phenotype.

PMID- 10580589
TI  - Organ blood flow after partial hepatectomy in rats: modification by endotoxin
      neutralizing bactericidal/permeability-increasing protein (rBPI23).
AB  - BACKGROUND/AIM: Both maintenance of adequate perfusion and regeneration of the
      remnant liver are important in the recovery of liver function after partial
      hepatectomy. In previous experiments, we have shown that profound hypotension and
      liver injury can be attenuated by neutralizing endotoxins. The relative
      contribution of endotoxemia to changes in liver blood flow and blood flow to
      other major organs after partial hepatectomy is not known. The aim of this study
      was to examine the effect of endotoxin neutralization on individual organ blood
      flows including hepatic artery and splanchnic blood flow after experimental
      partial hepatectomy and its relation to liver cell proliferation. METHODS: Male
      Wistar rats underwent either two-thirds partial hepatectomy or sham operation.
      Treatment consisted of continuous infusion of recombinant N-terminal
      bactericidal/permeability-increasing protein (rBPI23) or control protein. At 4 h
      after surgery, organ blood flows were measured using the radiolabeled microsphere
      technique, and at 24 h, proliferation index in liver tissue was calculated.
      RESULTS: After partial hepatectomy, blood flows to virtually all organs were
      significantly lower as compared to values obtained in sham-operated rats. rBPI23
      greatly improved hepatic artery flow (p<0.001) but not portal venous flow. These
      effects of rBPI23 on liver flow preceded an equally enhanced liver cell
      proliferation (p<0.01). Endotoxin neutralization led to significantly higher
      flows to some but not all splanchnic organs. Lung perfusion was significantly
      improved by rBPI23. CONCLUSIONS: Neutralization of endogenous endotoxins improves
      liver blood flow after partial hepatectomy and also periportal and pericentral
      liver cell proliferation. This proliferation effect may result from an increased
      hepatic artery flow. Lung, colon, spleen and pancreas flow but not kidney flow
      was greatly enhanced by rBPI23.

PMID- 10580590
TI  - Cytomegalovirus infection of bile duct epithelial cells, hepatic artery and
      portal venous endothelium in relation to chronic rejection of liver grafts.
AB  - BACKGROUND/AIM: Chronic rejection is an important cause of graft loss following
      liver transplantation. A number of risk factors for chronic rejection have been
      identified previously, albeit inconsistently. These include cytomegalovirus
      infection detected by a number of different techniques, including
      immunohistochemical staining and in situ hybridisation of liver grafts. However,
      tissue-based techniques for the detection of CMV have not been applied to grafts
      lost to conditions other than chronic rejection. The purpose of this study was to
      investigate the relationship between the presence of cytomegalovirus infection
      detected by in situ hybridisation and immunohistochemistry with respect to graft
      outcome, the presence of cytomegalovirus infection detected by other techniques
      and in addition, the type of infected cell. METHODS: The 29 patients studied
      included 15 patients who lost their primary liver graft to chronic rejection in 8
      cases, to hepatic artery thrombosis in 4 cases and to causes other than chronic
      rejection or hepatic artery thrombosis in 3 further cases. In each case, sections
      containing septal or large ducts and vessels were selected (usually blocks) since
      these may be more representative. Needle biopsies from 14 further patients who
      ultimately achieved satisfactory graft function served as control tissue. Of
      these, ten had evidence of cytomegalovirus infection at the time of study by
      serum/urine PCR, DEAFF testing or seroconversion, while 4 patients had no
      evidence of cytomegalovirus infection according to these techniques. RESULTS:
      Cytomegalovirus infection was detected in the liver of 12 of the 29 patients.
      These included 8/15 grafts lost, which comprised 3/8 with chronic rejection, 2/3
      with hepatic artery thrombosis and 3/4 with grafts lost to other causes, as well
      as 4/14 who retained grafts. CMV was detected most commonly in association with
      symptomatic infection and notably was detected only by in situ hybridisation in
      two cases. Predominant cell types that contained cytomegalovirus were hepatocytes
      and mononuclear cells. However, bile duct epithelial cells, hepatic artery
      endothelial cells and portal venous endothelial cells also contained
      cytomegalovirus in some cases. CONCLUSIONS: These data support previous studies
      that cytomegalovirus infection is detectable in patients with chronic rejection
      and are consistent with the theory that CMV is involved in chronic rejection.
      However, cytomegalovirus infection was detected in explanted grafts lost to
      conditions other than chronic rejection, and the association may not be causal
      but a consequence of graft injury.

PMID- 10580591
TI  - Hepatocellular oxidative stress and initial graft injury in human liver
      transplantation.
AB  - BACKGROUND/AIMS: The mechanisms underlying the initial graft dysfunction in liver
      transplantation are not completely understood, although much of the liver graft
      injury derives from the ischemia/reperfusion-induced oxidative stress. Thus, the
      purpose of our study was to determine the involvement of oxidative stress in the
      initial graft dysfunction in human liver transplantation. METHODS: Liver biopsies
      were taken at different times of the transplantation procedure, at the organ
      donor laparatomy (T1), before graft reperfusion (T2), and 5-60 min after graft
      reperfusion (T3), determining the levels of GSH, GSSG, as well as peroxides and
      malondialdehyde in liver homogenates. RESULTS: Patients were graded into two
      groups depending on whether the peak serum alanine aminotransferases within the
      first 3 postoperative days were lower (group A, mild to moderate injury: 32
      patients) or higher (group B, severe injury: 5 patients) than 2500 U/l. The
      levels of GSH at time intervals T1-T3 were similar for groups A and B, with a
      trend to lower GSSG levels in group B at T2 and T3 samples. This outcome was
      accompanied by unchanged levels of malondialdehyde and hydrogen peroxide in the
      same samples in both groups of patients. No patient developed primary graft
      nonfunction. One-year cumulative survival was 81% and 60% in groups A and B,
      respectively (p>0.05). CONCLUSIONS: These findings indicate a lack of significant
      generation of reactive oxygen species and consequent oxidative stress as a major
      factor involved in the pathogenesis of the initial graft dysfunction in human
      liver transplantation.

PMID- 10580592
TI  - Images in hepatology. Pseudotumoral hepatic actinomycosis.

PMID- 10580593
TI  - International Autoimmune Hepatitis Group Report: review of criteria for diagnosis
      of autoimmune hepatitis.

PMID- 10580594
TI  - Telomeres, telomerase and HCC: the long and the short of it.

PMID- 10580595
TI  - Liver involvement in cystic fibrosis.

PMID- 10580596
TI  - Nutrition and liver transplantation.

PMID- 10580597
TI  - Hyperinsulinemia and insulin resistance in non-alcoholic steatohepatitis.

PMID- 10580598
TI  - Anti-pyruvate dehydrogenase autoantibodies in extrahepatic disorders.

PMID- 10580599
TI  - Hepatocellular carcinoma expressing both hepatocellular and biliary markers also
      expresses cytokeratin 14, a marker of bipotential progenitor cells.

PMID- 10580600
TI  - Squirrel monkey retrovirus (SMRV) sequence from an SMRV-negative cell line?

PMID- 10580601
TI  - Regulation of T-cell activities at the feto-placental interface--by placenta?

PMID- 10580602
TI  - A placenta-derived suppressor factor with a T-cell bias.
AB  - PROBLEM: Functional and mechanistic aspects of immunosuppression by murine
      placental supernatants (MPS) were investigated. METHOD OF STUDY: MPS and a low
      molecular weight fraction of the supernatant (MPSf) were tested for suppressive
      action on T-cell reactivity in vitro and in vivo, on B-cell responses and on T
      cell activation events. RESULTS: MPS and MPSf suppress mitogen-induced
      proliferation and mixed lymphocyte reactions of human and murine lymphocytes,
      antigen-induced proliferation of T cells in vitro and in vivo, proliferation of
      CD8+ lymphocytes, proliferation induced by cross-linking of surface CD3 and the
      in vivo response of mice to allogeneic stimuli. MPSf affects cell cycling of
      activated T cells and blocks interleukin (IL)-2 production. MPSf does not affect
      antibody production or the induction of MHC class II expression on B cells.
      CONCLUSIONS: MPSf is a potent inhibitor of T-cell responses in vitro and in vivo,
      with no demonstrable effect on B-cell function.

PMID- 10580603
TI  - Immunoglobulins of the human amniotic fluid.
AB  - PROBLEM: Except for the description of a secretory immunoglobulin (S-Ig) of a low
      size, no recent study has investigated the molecular status of antibodies in the
      human amniotic fluid. METHOD: After separation with a high performance
      chromatography, we analyzed the different isotypes of amniotic Igs by
      immunoblotting and ELISA. RESULTS: IgG is found to be the major isotype and to
      contain mother-derived tetanus antitoxins. IgA is much less abundant, whereas no
      IgM can be detected. IgA is monomeric, with a low level of secretory IgA and with
      various amounts of free secretory component (SC). The presence of a low level of
      SC-containing immunoglobulin of a low size is confirmed during the last trimester
      of pregnancy. This molecule contains no alpha chain but includes a Fabgamma
      fragment noncovalently associated with SC. IgG, IgA, and SC are detected in the
      fetal urine and, therefore, can reach the amniotic fluid by this route.
      CONCLUSION: In addition to the predominant maternal IgG, the amniotic fluid
      contains different molecular forms of fetal immunoglobulins. Their function as an
      immune barrier against infection and against mother-derived autoantibodies is
      discussed.

PMID- 10580604
TI  - Fetal treatment of congenital heart block ascribed to anti-SSA antibody: case
      reports with observation of cardiohemodynamics and review of the literature.
AB  - PROBLEM: Maternal anti-SSA(B) antibody crosses the placenta and causes fetal
      myocarditis, congenital heart block (CHB), hydrops fetalis, and intrauterine
      fetal death. The aim of this study was to evaluate corticosteroids' efficacy as a
      treatment for CHB. METHOD OF STUDY: One fetus with complete CHB and one fetus
      with incomplete CHB due to anti-SSA(B) antibody received maternal prednisolone
      (PSL) and dexamethasone (DEXA) treatments. Heart rate, cardiothoracic ratio
      (CTR), left ventricular fractional shortening (FS), and preload index (PLI) were
      longitudinally measured by serial fetal echocardiograms. RESULTS: In the former
      case, after maternal PSL/DEXA administration, improvement of cardiohemodynamics,
      i.e., the reduction of PLI from 1.7 to 0.4, CTR from 70 to 52%, and FS from 63 to
      54% were observed. In the latter case, second degree 2:1 block was converted to
      3:2 block/sinus rhythm, resulting in the increase of the fetal heart rate from 65
      to 116 beats per minute (bpm). CONCLUSIONS: We disclosed for the first time the
      beneficial effects of corticosteroids in the fetal cardiohemodynamics and
      conduction system of affected fetuses with the presence of maternal anti-SSA(B)
      antibodies.

PMID- 10580605
TI  - Possible susceptibility of the HLA-DPB1*0402 and HLA-DPB1*04 alleles to
      unexplained recurrent abortion: analysis by means of polymerase chain reaction
      restricted fragment length polymorphism method.
AB  - PROBLEM: To clarify whether HLA-DP antigens are associated with patient
      population of unexplained recurrent abortion. METHOD OF STUDY: The frequency of
      HLA-DPB1 alleles in patients with unexplained recurrent abortion, and the
      compatibility of HLA-DPB1 alleles between patient couples, were studied using a
      polymerase chain reaction (PCR)-restricted fragment length polymorphism (RFLP)
      method. Thirty patients who had a history of unexplained primary recurrent
      abortion, and their husbands, were typed for HLA-DPB1 genotype. Two hundred and
      ninety-nine base pair fragments from the second exon of HLA-DPB1 genes were
      selectively amplified using the PCR-primers. After amplification, the DNAs were
      digested with restriction endonucleases, and subjected to electrophoresis in a
      12% polyacrilamide gel to determine HLA-DPB1 genotype. RESULTS: The frequency of
      HLA-DPB1*0402 and DPB1*04 alleles in the patient group (n = 30) was significantly
      increased, as compared to that in the normal fertile women (n = 30). The
      frequency of HLA-DPB1*04 allele in the patient group was significantly increased,
      as compared to that in the general population (n = 112). No significant
      compatibility of HLA-DPB1 alleles could be observed between patient couples and
      normal fertile couples. CONCLUSION: These findings suggest a possible new class
      II association with patient population of unexplained recurrent abortion.

PMID- 10580606
TI  - Distribution of Th1, Th2, and Th0 and the Th1/Th2 cell ratios in human peripheral
      and endometrial T cells.
AB  - PROBLEM: To examine whether normal pregnancy involves type 2 T-helper (Th2)
      immune condition or not. METHOD OF STUDY: We measured the percentage of Th0, Th1,
      and Th2 and the Th1/Th2 cell ratios of human peripheral blood and endometrial T
      cells using flow cytometry, which can analyze both the surface marker CD3, and
      intracellular cytokines, interleukin 4 (IL-4) and interferon gamma (IFNgamma).
      RESULTS: No significant differences were found in the percentages of Th1, Th2,
      and Th0 and the Th1/Th2 cell ratios in the peripheral blood T cells of
      nonpregnant women and women in early pregnancy. On the other hand, the percentage
      of Th1 cells was highest during the proliferative phase of the endometrium,
      followed by the secretory phase and early pregnancy decidua. The percentage of
      Th2 cells was highest in early pregnancy decidua and lowest during the
      proliferative phase of the endometrium. The Th1/Th2 ratio was 147.48+/-96.68
      during the proliferative phase of the endometrium, 37.74+/-21.33 during the
      secretory phase, and 1.31+/-0.48 in the early pregnancy decidua. CONCLUSIONS:
      These data indicate that Th1 cells predominate in the nonpregnant endometrium,
      especially during the proliferative phase, while Th2 cells predominate in early
      pregnancy decidua.

PMID- 10580607
TI  - Spontaneous accumulation of eosinophils and macrophages throughout the stroma of
      the epididymis and vas deferens in alymphoplasia (aly) mutant mice: I. A
      histological study.
AB  - PROBLEM: The alymphoplasia (aly) mutation of mice causes the systemic absence of
      lymph nodes and Peyer's patches. Histopathological analysis has revealed that
      lymphocytes accumulate in some organs such as the salivary glands, lungs,
      kidneys, liver, and pancreas of homozygotes (aly/aly) but not heterozygotes (aly/
      + ). However, the presence of lymphocytic accumulation in male reproductive
      tissues of aly/aly mice has not been reported. METHOD OF STUDY: The male
      reproductive organs of homozygous aly/aly, heterozygous aly/ +, and other
      immunodeficient mice bred in a specific pathogen-free state were histologically
      investigated. RESULTS: Testes, ductuli efferentes, prostates, coagulating glands,
      and seminal vesicles of homozygous aly/aly mice were free from any pathological
      accumulation of leukocytes. However, their epididymides and vasa deferentia
      exhibited massive infiltration by leukocytes, which were composed of eosinophils
      and macrophages. In all homozygotes examined, both eosinophils and macrophages
      were extensively observed throughout the stroma of the epididymis and vas
      deferens, but never within the epithelium or lumen of the ducts, with no
      parenchymal tissue damage. The accumulation of eosinophils was never found in
      nonreproductive organs. In aly/ + heterozygous mice and other immunodeficient
      mice, no pathological accumulation of leukocytes were noted. CONCLUSIONS: The
      accumulation of eosinophils and macrophages is specific to the epididymides and
      vasa deferentia of immunodeficient aly/aly homozygotes, although the pathogenesis
      remains unknown.

PMID- 10580608
TI  - Isolation and biological characterization of boar sperm capacitation-related
      antigen.
AB  - PROBLEM: Monoclonal anti-capacitated sperm antibody has been used as a probe to
      identify, isolate, and characterize specific, fertilization-related antigen with
      some characteristic features that point to its possible significance in
      immunocontraception. METHOD OF STUDY: Fast protein liquid chromatography (FPLC),
      enzyme-linked immunosorbent assay (ELISA), sodium dodecyl sulfate polyacrylamide
      gel electrophoresis (SDS-PAGE), and isoelectrofocusing were used for isolation,
      immunochemical and physicochemical characterization of a monoclonal antibody
      (mAb) 1F10 cognate antigen. Sperm-zona pellucida binding and hemizona assay were
      used for testing the biological roles of mAb 1F10 and Ag 1F10 in boar and human
      fertilization processes. RESULTS: The Ag 1F10 was found to be eluted in the
      eighth protein peak of FPLC-fractionated Nonidet P40 (NP40) extracts of
      capacitated boar spermatozoa. The SDS-PAGE and immunoelectrofocusing experiments
      showed that Ag 1F10 is a protein composed of a single peptide chain with a
      relative molecular mass of 68/70 kDa and an isoelectric point of 3.5. It was
      demonstrated that the zona binding activity of spermatozoa preincubated in the
      presence of mAb 1F10 was significantly inhibited both in porcine and human in
      vitro fertilization (IVF) systems. A dose-dependent manner of inhibition of the
      sperm/ligand activities of porcine and human zona pellucida was observed when the
      effect of purified Ag 1F10 was investigated by its preincubation with zona
      pellucida. CONCLUSIONS: It is assumed that the protein bearing the epitope
      recognized by mAb 1F10 may be accepted as one of the molecules with receptor
      function in sperm-zona pellucida interaction during fertilization.

PMID- 10580610
TI  - Glycation of plasma low density lipoproteins increases interaction with arterial
      proteoglycans.
AB  - The increased susceptibility to atherosclerosis of diabetic individuals, may
      result from diabetes-associated modification in plasma low density lipoproteins
      (LDL) which enhance their interaction with arterial extracellular matrix
      proteoglycans. Using a nonhuman primate model for human diabetes, studies were
      conducted to examine diabetes-induced changes in LDL. Plasma LDL were isolated
      from control (n = 4) and streptozotocin-induced diabetic (n = 3) cynomolgus
      macaques by differential ultracentrifugation. An in vitro binding assay was used
      to measure LDL interaction with arterial proteoglycans. Significantly more
      diabetic LDL bound to proteoglycans than control LDL (12.9+/-0.7 microg LDL
      cholesterol/microg proteoglycan versus 8.9+/-0.5 microg LDL cholesterol/microg
      proteoglycan (mean +/- S.E.M.), P < 0.005). Glycation of LDL, determined by
      fructosamine content, was significantly enhanced in diabetic versus control
      animals (37+/-3.1 versus 20+/-1.5 micromol/l (mean +/- S.E.M.) P < 0.005). The
      correlation coefficient between fructosamine content of LDL and its binding to
      arterial proteoglycans was 0.95. No LDL compositional variables other than
      glycation correlated with proteoglycan binding. Removal of the glycated portion
      of LDL from diabetic animals returned LDL proteoglycan binding to normal. These
      data demonstrate that the diabetes induced glycation of LDL increases its
      proteoglycan binding properties: thus, a critical mechanism in atherosclerosis,
      enhanced LDL interaction with arterial proteoglycans, may be accelerated by the
      diabetic state.

PMID- 10580609
TI  - Change in the lipid profile, lipogenic and related enzymes in the livers of
      experimental diabetic rats: effect of insulin and vanadate.
AB  - Administration of sodium orthovanadate to diabetic animals exhibits insulin-like
      effects and has been effective in the reversal of biochemical complications. This
      study evaluates the effect of sodium orthovanadate (0.6 mg/ml) treatment for 21
      days on the hepatic glucose homeostasis and lipid metabolism in alloxan diabetic
      rats. The activities of two lipogenic enzymes, glucose-6-phosphate dehydrogenase
      and malic enzyme; and related enzymes, hexokinase and glucose-6-phosphatase were
      measured in the liver cytosolic fractions of diabetic rats and diabetic rats
      treated separately with insulin and sodium orthovanadate. The total lipids,
      triglycerides and cholesterol levels were estimated in the livers of the diabetic
      and the treated rats. The activities of both the lipogenic enzymes and hexokinase
      isozymes were significantly decreased, whereas the activity of glucose-6
      phosphatase was significantly increased in the diabetic liver. During diabetes,
      the levels of total lipids and triglycerides increased significantly with a
      decrease in the cholesterol levels in the liver. Insulin and vanadate were able
      to restore the altered enzyme activities to almost control levels. Both insulin
      and vanadate were found to partially restore the altered levels of total lipids,
      triglycerides and cholesterol in the livers of diabetic rats. The results
      indicate that vanadate administration to diabetic animals normalizes blood
      glucose and causes marked improvement of altered lipid metabolism during
      diabetes. The present study and earlier reports suggest the possible use of
      vanadate as insulin replacement in the therapy of diabetes when administered at
      pharmacological doses.

PMID- 10580611
TI  - Does instantaneous blood glucose affect vibration perception threshold
      measurement using biothesiometer?
AB  - Diabetic neuropathy is a common and troublesome complication of diabetes
      mellitus. Vibration sensation is a measure of large fiber nerve conduction, which
      is very commonly affected in diabetes. The present study addresses the question
      of whether vibration perception threshold (VPT) measurement using a
      biothesiometer is reproducible under different levels of blood glucose at
      different hours of the day. Seventy-five diabetic patients, 31 insulin-dependent
      diabetes mellitus and 44 non-insulin-dependent diabetes mellitus, with mean age
      50.33+/-14.22 years (21-70 years) and diabetes duration of 14.3+/-10.6 years (1
      60 years) were included in the study. Forty-one patients were male and 34 were
      female. In conclusion, VPT was found to be reproducible under different blood
      glucose levels at different hours of the day, which is affected only by the
      height of the patient.

PMID- 10580612
TI  - Postprandial plasma glucose: a good index of glycemic control in type 2 diabetic
      patients having near-normal fasting glucose levels.
AB  - To investigate the effect of postprandial plasma glucose (PG) concentrations on
      HbA1c levels in type 2 diabetic patients, we evaluated the relationship between
      HbA1c levels and postprandial PG concentrations after a meal tolerance test in 35
      type 2 diabetic patients who had fasting PG concentrations persistently < 7.8
      mmol/l and stable HbA1c levels. Two-hour postprandial PG concentrations were
      found to be more strongly correlated (r = 0.51) with HbA1c levels than 1-h
      postprandial PG (r = 0.35) and fasting PG (r = 0.46) concentrations. Patients
      whose HbA1c levels were high (HbA1c > or = 7%) had significantly higher 2-h
      postprandial PG concentrations and areas under the glucose curve than those whose
      HbA1c levels were lower (8.12+/-1.10 (SD) vs 6.70+/-2.22 mmol l(-1), P = 0.004
      and 17.43+/-1.92 vs 15.58+/-3.26 mmol h(-1) l(-1), P = 0.02, respectively).
      Although fasting PG concentrations of patients with higher HbA1c levels were
      slightly higher, they did not differ significantly from those with lower HbA1c
      levels (6.21+/-0.89 vs 5.73+/-0.68 mmol l(-1)). Age, duration of diabetes, body
      mass index, serum C-peptide, both fasting and postprandial, did not differ
      between these two groups. This study suggests that postprandial hyperglycemia,
      particularly 2-h postprandial PG concentrations, is associated with high HbA1c
      levels in type 2 diabetic patients whose fasting PG levels were within normal or
      near-normal levels.

PMID- 10580613
TI  - Impact of body mass on autonomic function in persons with type 2 diabetes.
AB  - The aim of this study was to investigate the influence of body mass on autonomic
      nerve function in persons with type 2 diabetes. Towards this aim we studied two
      groups of diabetic persons. Group 1: n = 30 lean (mean age 57.2+/-12.5 years,
      body mass index (BMI) 22.5+/-1.8 kg/m2]. Group 2: n = 35 overweight and obese
      (age 52.3+/-10.3 years, BMI 28.8 + 3.2 kg/m2). Autonomic neuropathy (DAN) was
      assessed using the battery of the five classical tests. DAN was diagnosed when at
      least two of the five tests were abnormal. Abnormalities of the heart rate based
      tests were considered as indication of parasympathetic and of blood pressure
      changes as indication of sympathetic dysfunction. The prevalence rates of DAN
      were not different between group 2 and group 1 (54.2 and 53.3%, respectively, P =
      0.54). The same was valid for the rates of parasympathetic and sympathetic
      dysfunction in the studied groups (51.4 and 53.3% (P = 0.87) in group 2 and 34.2
      and 33.3% (P = 0.93) in group 1, respectively). When the values of the arithmetic
      expression of each single autonomic function test were compared, no significant
      difference could be shown between the studied groups. In addition, no significant
      correlation was found between BMI and indices of DAN. These data indicate that
      moderate increase of body mass does not affect autonomic function in persons with
      type 2 diabetes.

PMID- 10580615
TI  - The relationship between glycated hemoglobin and polymorphonuclear leukocyte
      leukotriene B4 release in people with diabetes mellitus.
AB  - In order to evaluate polymorphonuclear leukocyte (PMN) activity in diabetes
      mellitus, leukotriene B4 (LTB4) levels were measured in sixty patients, 31
      affected with Type 1 diabetes mellitus and 29 affected with Type 2 diabetes
      mellitus. The LTB4 levels (12.1+/-0.2 pg/100 microl) in diabetic patients were
      higher compared to those of the control group (7.9+/-0.1 pg/100 microl) (P <
      0.001), and remained significantly higher (P < 0.001) (12.8+/-0.2 pg/100 microl)
      than in the control group (11.0+/-0.2 pg/100 microl) after stimulation with
      calcium ionophore. A significant and positive correlation between glycated
      hemoglobin and LTB4 was demonstrated (P < 0.001, r = 0.80). This study
      demonstrates that in diabetic patients there is a PMN activation and that this
      activation is correlated to glycated hemoglobin level.

PMID- 10580614
TI  - The effect of insulin sensitizer, troglitazone, on lipoprotein lipase mass in
      preheparin serum.
AB  - Lipoprotein lipase mass exists in preheparin serum, even though the activity is
      scarcely found. The implication of this is unclear. We studied the effect of an
      insulin sensitizer, troglitazone, on this preheparin serum lipoprotein lipase
      mass (preheparin LPL mass) in non-insulin-dependent diabetes mellitus (NIDDM)
      patients as well as on serum lipid levels and low density lipoproteins (LDL)
      particle size. Thirty-one NIDDM patients with poor control were administered
      troglitazone 400 mg/day. Hemoglobin A1c had significantly decreased (13%, P <
      0.001) 2 months later. Preheparin LPL mass had gradually increased and a 69%
      increase (P<0.01) was observed 4 months later. Triglyceride significantly
      decreased (23%, P < 0.01) and high density lipoprotein-cholesterol increased
      (10%, P < 0.01), whereas total cholesterol and LDL levels did not change 4 months
      later. The size of LDL increased significantly (P < 0.01). These results were
      consistent with the idea that preheparin LPL mass might be relating to the
      insulin sensitivity enhanced by troglitazone, as well as LDL particle size.

PMID- 10580616
TI  - Risk factors for the progression of microalbuminuria in Japanese type 2 diabetic
      patients--a 10 year follow-up study.
AB  - To clarify risk factors for the progression of microalbuminuria in Japanese type
      2 diabetic patients, the longitudinal study for 10 years was conducted on 67
      outpatients with type 2 diabetes, who had shown no overt proteinuria at baseline.
      The urinary albumin index (UAI) has been determined based on the mean of at least
      two random urine samples each year. Categories were defined as normoalbuminuria
      (UAI < 30.0 mg/g x Cr.), microalbuminuria (30.0 < or = UAI < 300.0), and
      macroalbuminuria (UAI > or = 300.0). Progression was defined as worsening of the
      category and/or more than doubling of the baseline UAI value. Multiple logistic
      regression analysis was performed using age, duration of diabetes, HbA1c, blood
      pressure, BMI, serum lipids, smoking habits, and alcohol consumption as
      independent variables and the progression of microalbuminuria as a dependent
      variable. Age and HbA1c were estimated as significant and independent variables.
      Furthermore, genetic polymorphisms of angiotensin I-converting enzyme (ACE) and
      angiotensinogen were analyzed to evaluate the genetic contribution. The D/D
      genotype of ACE was significantly more common in progressors than in non
      progressors. These results suggest that glycemic control and age are important
      risk factors and the D/D genotype of ACE acts as a risk factor for the
      progression of microalbuminuria in Japanese type 2 diabetic patients.

PMID- 10580617
TI  - Serum levels of leptin and changes during the course of recovery from diabetic
      ketoacidosis.
AB  - Secretion of leptin, the obese gene product, is stimulated by insulin and
      glucocorticoids and reduced by fasting. In subjects with diabetic ketoacidosis
      (DKA), severe insulinopenia and prolonged fasting might cause a decrease in serum
      leptin levels, and subsequent insulin therapy would reverse the decrease.
      Otherwise, some other confounding factors, neither insulin nor fasting, might
      affect serum leptin levels in patients with DKA. The present study was undertaken
      to address these issues. Eleven patients with type 1 diabetes mellitus (seven
      males and four females, aged 44+/-6 years, mean +/- SEM), admitted to Jichi
      Medical School Hospital presenting DKA, were studied during the therapeutic
      period. Thirty-five sex-, age- and body mass index-matched healthy subjects
      served as controls. Serum leptin levels at the hospitalization were significantly
      greater than those of the matched control subjects (5.5+/-1.0 vs. 3.2+/-0.3
      microg/l, P < 0.01). After the start of therapy with a small dose of short-acting
      insulin and a large volume of fluid infusion, serum leptin concentrations further
      increased to 10.6+/-3.6 microg/l at 24 h, and thereafter the concentrations
      gradually decreased and normalized at the discharge (3.3+/-0.7 microg/l, day 24+/
      4). The peak levels at 24 h were significantly higher than the levels at the
      discharge (P < 0.05), and also +77+/-34% higher than those at the hospitalization
      (P < 0.005). Serum cortisol levels (1830+/-200 nmol/l) were markedly elevated at
      hospitalization. These results indicate that serum leptin levels are increased
      even under insulinopenia and fasting in the patients with DKA. Such a finding may
      be associated with marked hyperglycemia or enhanced secretion of glucocorticoid
      hormone, although the exact mechanisms remain to be elucidated. We speculate that
      leptin may serve as a stress peptide in DKA, but further analysis is necessary to
      explore a physiological role of leptin in DKA.

PMID- 10580618
TI  - Health-related quality of life in insulin-treated diabetic patients in the Sudan.
AB  - To determine health-related quality of life (HRQL) in people with insulin-treated
      diabetes mellitus in Sudan, a total of 89 patients aged 25-55 years and with > or
      = 5 years diabetes duration was studied. HRQL was measured with a 68-item
      questionnaire from the Medical Outcomes Study. Late diabetic complications were
      assessed, and haemoglobin A1c (HbA1c) was measured to assess the metabolic
      control. Of the patients (m = 36; f = 53), only 13.5%, had good metabolic control
      ((HbA1c) < 7.5%). These patients rated their HRQL as worse than patients with
      poor metabolic control ((HbA1c) > 10%). However, the latter were significantly
      younger, had shorter diabetes duration, and were free from late complications.
      Overall, 49.4% of the patients had one or more of the late diabetic
      complications. These patients rated their HRQL significantly lower when compared
      with patients without complications. Older age and the presence of late diabetic
      complications were the most important predictors for HRQL. It is concluded that
      self-rated HRQL in this group of patients is generally low. Improving diabetes
      knowledge and the metabolic control since early in the course of the disease,
      will not only retard the development of late complications, but will certainly
      improve the HRQL of these patients.

PMID- 10580619
TI  - Impact of the American Diabetes Association diagnosis criteria on high-risk
      Spanish population. IGT Research Group. Impaired glucose tolerance.
AB  - To research into the impact of the new American Diabetes Association (ADA)
      diagnostic criteria on high risk Spanish population, two cross-sectional studies
      involving seven primary health care centers in Catalonia (Spain) were revised.
      Individuals aged > 40 years with any major risk factor for diabetes were screened
      according to the World Health Organization (WHO) rules using a 75 g oral glucose
      tolerance test to measure fasting plasma glucose (FPG) and 2 h plasma glucose.
      The changes on diabetes prevalence and on epidemiological characteristics were
      evaluated applying the ADA criteria on the basis of FPG alone. A total of 970
      individuals, 453 males (46.7%), mean age 59 years and mean body mass index (BMI)
      30.6 kg/m2 were screened. Among the 459 diabetic subjects according to either the
      WHO or the ADA criteria, 314 (68.4%) were classified as having diabetes with
      respect to both sets of criteria (WHO and ADA). The overlap between impaired
      glucose tolerance (WHO) and impaired fasting glucose (ADA) diagnoses was 20.7%.
      Using the ADA criteria results in a decrease of the prevalence of diabetes by
      1.5% (95% confidence interval (CI) = -2.2 to -0.8%). No changes in the diabetic
      phenotype (age, sex and BMI) were found. Impaired fasting glucose prevalence was
      18.4% (95% CI = 16-21%). Overall concordance in terms of crude and weighted kappa
      value was only acceptable (kappa = 0.51 and kappa = 0.61, respectively). To apply
      the new ADA diagnostic criteria on high risk Spanish population evidenced a
      decrease on diabetes prevalence. Nevertheless, the change of criteria undervalued
      the risk of postprandial hyperglycaemia related to impaired glucose tolerance.

PMID- 10580620
TI  - The price of a surgical-site infection: more than just excess length of stay.

PMID- 10580621
TI  - The impact of surgical-site infections in the 1990s: attributable mortality,
      excess length of hospitalization, and extra costs.
AB  - OBJECTIVE: To determine mortality, morbidity, and costs attributable to surgical
      site infections (SSIs) in the 1990s. DESIGN: A matched follow-up study of a
      cohort of patients with SSI, matched one-to-one with patients without SSI.
      SETTING: A 415-bed community hospital. STUDY POPULATION: 255 pairs of patients
      with and without SSI were matched on age, procedure, National Nosocomial
      Infection Surveillance System risk index, date of surgery, and surgeon. OUTCOME
      MEASURES: Mortality, excess length of hospitalization, and extra direct costs
      attributable to SSI; relative risk for intensive care unit (ICU) admission and
      for readmission to the hospital. RESULTS: Of the 255 pairs, 20 infected patients
      (7.8%) and 9 uninfected patients (3.5%) died during the postoperative
      hospitalization (relative risk [RR], 2.2; 95% confidence interval [CI95], 1.1
      4.5). Seventy-four infected patients (29%) and 46 uninfected patients (18%)
      required ICU admission (RR, 1.6; CI95, 1.3-2.0). The median length of
      hospitalization was 11 days for infected patients and 6 days for uninfected
      patients. The extra hospital stay attributable to SSI was 6.5 days (CI95, 5-8
      days). The median direct costs of hospitalization were $7,531 for infected
      patients and $3,844 for uninfected patients. The excess direct costs attributable
      to SSI were $3,089 (CI95, $2,139-$4,163). Among the 229 pairs who survived the
      initial hospitalization, 94 infected patients (41%) and 17 uninfected patients
      (7%) required readmission to the hospital within 30 days of discharge (RR, 5.5;
      CI95, 4.0-7.7). When the second hospitalization was included, the total excess
      hospitalization and direct costs attributable to SSI were 12 days and $5,038,
      respectively. CONCLUSIONS: In the 1990s, patients who develop SSI have longer and
      costlier hospitalizations than patients who do not develop such infections. They
      are twice as likely to die, 60% more likely to spend time in an ICU, and more
      than five times more likely to be readmitted to the hospital. Programs that
      reduce the incidence of SSI can substantially decrease morbidity and mortality
      and reduce the economic burden for patients and hospitals.

PMID- 10580622
TI  - An outbreak of hospital-acquired hepatitis B virus infection among patients
      receiving chronic hemodialysis.
AB  - OBJECTIVE: To investigate a cluster of hepatitis B virus (HBV) infections between
      December 1995 and May 1996 among chronic hemodialysis patients in one county.
      SETTING: Two dialysis centers (A and B) and a hospital (C) in one county.
      PATIENTS: Six case-patients who were dialyzed in one of two centers, A and B, and
      had all been hospitalized between January and February 1996 at hospital C.
      METHODS: Patient 1, usually dialyzed in center A, sero-converted to hepatitis B
      surface antigen (HBsAg) in December 1995 and could have been the source of
      infection for the others, who seroconverted between March and April 1996. Two
      cohort studies were conducted: one among patients dialyzed in center A, to
      determine where transmission had occurred, and one among patients dialyzed at
      hospital C at the time patient 1 was hospitalized, to identify factors associated
      with infection. RESULTS: Four (15%) of the 26 susceptible patients dialyzed at
      center A became infected with HBV. Hospitalization at hospital C when patient 1
      was hospitalized was associated with infection (P = .002). A cohort study of the
      10 susceptible patients dialyzed at hospital C during the time patient 1 was
      hospitalized did not identify specific risk factors for infection. However,
      supplies and multidose vials were shared routinely among patients, providing
      opportunities for transmission. CONCLUSION: When chronic hemodialysis patients
      require dialysis while hospitalized, their HBsAg status should be reviewed, and
      no instrument, supplies, or medications should be shared among them.

PMID- 10580623
TI  - Safety of peripheral intravenous catheters in children.
AB  - OBJECTIVES: To determine the overall and per-day risk of complications of short
      peripheral intravenous (PIV) catheters placed for indefinite periods. DESIGN:
      During 5 months, general pediatric patients receiving intravenous therapy through
      short PIV catheters were monitored. Patient and catheter characteristics were
      recorded, complications were noted, and rolled semiquantitative cultures of
      removed catheters were performed. Major endpoints were infection and phlebitis.
      Per-day risk of complications and catheter colonization (>15 colony-forming
      units) were calculated. SETTING: University children's hospital. PATIENTS:
      General pediatric ward inpatients with PIV. RESULTS: We studied 642 Teflon
      catheters in place >24 hours (mean, 3.7 days) in 525 patients. There were no
      cases of catheter sepsis (0%; 95% confidence interval [CI95], 0%-0.6%), one
      possible insertion-site infection (0.2%; CI95, 0.004%-0.9%), and seven cases of
      phlebitis (1.1%; CI95, 0.4%-2.3%). Catheter colonization occurred in 92 (26%) of
      348 catheters cultured. Neither the per-day risk of phlebitis nor of catheter
      colonization increased significantly with placement >3 days. CONCLUSION: Current
      guidelines recommend replacement of PIV catheters in adults within 2 to 3 days;
      no recommendations are made for children. Our findings and those of others
      indicate that the overall risk of PIV catheter complications in children is
      extremely low and would not be reduced substantially by routine catheter
      replacement.

PMID- 10580624
TI  - "Pulse" nasal mupirocin maintenance regimen in patients undergoing continuous
      ambulatory peritoneal dialysis.
AB  - OBJECTIVE: To determine, among patients undergoing continuous ambulatory
      peritoneal dialysis (CAPD) who were Staphylococcus aureus nasal carriers, if
      periodic brief "pulses" of nasal mupirocin calcium ointment 2% after completion
      of a mupirocin eradication protocol would maintain these patients free of
      carriage. DESIGN: Noncomparative, nonblinded study with historical controls.
      SETTING: A county medical center. PATIENTS: Patients in a CAPD program during the
      period April 1996 to May 1998. METHODS: All patients in the CAPD program had
      monthly nasal cultures for S. aureus. After informed consent, S. aureus nasal
      carriers were administered mupirocin to the nares twice a day for 5 days followed
      by nasal mupirocin twice monthly. Peritonitis and exit-site infection rates were
      monitored independently by CAPD nursing staff. Patients were monitored monthly
      for adverse effects of mupirocin and compliance with the maintenance regimen.
      RESULTS: Twenty-four patients in the CAPD program were enrolled in the study and
      had a median duration of follow-up of 8.5 months. Fifteen (63%) of the 24
      patients remained free of nasal carriage on follow-up cultures. Of the 9 patients
      with positive nasal cultures during the study, 8 had only one positive culture.
      There was no significant difference in the mean yearly peritonitis rate or S.
      aureus peritonitis rate (January 1995-May 1998). However, there was a significant
      decrease in the mean yearly exit-site infection rates both overall (from 8.8
      episodes per 100 patients dialyzed per month in 1995 to 4.0 in 1998; P = .008)
      and due to S. aureus (from 5.6 in 1995 to 0.9 in 1998; P = .03). Adverse effects
      of nasal mupirocin were mild overall; 1 patient was removed from the study due to
      an allergic reaction to mupirocin. CONCLUSIONS: Among CAPD patients who were S.
      aureus nasal carriers, periodic brief treatment with nasal mupirocin after an
      initial eradication regimen kept them free of carriage, for the most part, with
      few adverse effects. The pulse mupirocin regimen offers simplicity and possibly
      better compliance, as well as minimizing exposure to this agent, thereby possibly
      reducing the risk of resistance. Further studies are warranted to compare this
      regimen to other commonly used mupirocin maintenance regimens in dialysis
      patients.

PMID- 10580625
TI  - An outbreak of gram-negative bacteremia in hemodialysis patients traced to
      hemodialysis machine waste drain ports.
AB  - OBJECTIVE: To investigate an outbreak of gram-negative bacteremias at a
      hemodialysis center (December 1, 1996-January 31, 1997). DESIGN: Retrospective
      cohort study. Reviewed infection control practices and maintenance and
      disinfection procedures for the water system and dialysis machines. Performed
      cultures of the water and dialysis machines, including the waste-handling option
      (WHO), a drain port designed to dispose of saline used to flush the dialyzer
      before patient use. Compared isolates by pulsed-field gel electrophoresis.
      SETTING: A hemodialysis center in Maryland. RESULTS: 94 patients received
      dialysis on 27 machines; 10 (11%) of the patients had gram-negative bacteremias.
      Pathogens causing these infections were Enterobacter cloacae (n = 6), Pseudomonas
      aeruginosa (n = 4), and Escherichia coli (n = 2); two patients had polymicrobial
      bacteremia. Factors associated with development of gram-negative bacteremias were
      receiving dialysis via a central venous catheter (CVC) rather than via an arterio
      venous shunt (all 10 infected patients had CVCs compared to 31 of 84 uninfected
      patients, relative risk [RR] undefined; P<.001) or dialysis on any of three
      particular dialysis machines (7 of 10 infected patients were exposed to the three
      machines compared to 20 of 84 uninfected patients, RR = 5.8; P = .005). E
      cloacae, P aeruginosa, or both organisms were grown from cultures obtained from
      several dialysis machines. WHO valves, which prevent backflow from the drain to
      dialysis bloodlines, were faulty in 8 (31%) of 26 machines, including 2 of 3
      machines epidemiologically linked to case-patients. Pulsed-field gel
      electrophoresis patterns of available dialysis machine and patient E cloacae
      isolates were identical. CONCLUSIONS: Our study suggests that WHO ports with
      incompetent valves and resultant backflow were a source of cross-contamination of
      dialysis bloodlines and patients' CVCs. Replacement of faulty WHO valves and
      enhanced disinfection of dialysis machines terminated the outbreak.

PMID- 10580626
TI  - A Canadian survey of prophylactic antibiotic use among hip-fracture patients.
AB  - OBJECTIVE: To study how surgical prophylactic antibiotics (SPAs) were utilized in
      the perioperative management of surgery for hip fractures. DESIGN: Retrospective
      chart review of randomly selected medical records. SETTING: Twenty-two hospitals
      (teaching, nonteaching, community, and large urban referral centers) from across
      Canada. PATIENTS: Patients admitted in 1990 with a diagnosis of hip fracture.
      METHODS: Complete medical records of 438 patients were examined; 352 cases who
      underwent surgical repair of a fractured hip with insertion of prosthetic
      material were included in analysis. Perioperative SPA use was assessed by
      abstracting the agent(s) chosen, dosages, time given with respect to the
      incision, and duration of postoperative use. Fourteen patient and process-of-care
      variables related to SPA were examined. RESULTS: 247 (70%) of 352 cases did not
      receive a dose of SPA 2 hours preoperatively. Ten percent of preoperative SPA was
      administered either too early or during the procedure. In 91 (39%) of 231 cases
      receiving SPA, the first dose was not administered until the end of the
      procedure. Preoperative SPA consisted of a parenteral first-generation
      cephalosporin for 94% of cases. SPAs were continued more than 24 hours
      postoperatively in 78% of cases. Lack of a written order for SPA, being a
      nonteaching hospital, and shorter duration of surgical procedure were predictive
      of failure to receive SPA in an effective manner. CONCLUSIONS: Most hip-fracture
      surgery patients did not receive effective antibiotic prophylaxis as required to
      prevent serious wound infections. This important variable can be included for
      surveillance, so that corrective measures can be taken to assure effective
      prophylactic antibiotic administration.

PMID- 10580627
TI  - Outbreak of Stenotrophomonas maltophilia bacteremia among patients undergoing
      bone marrow transplantation: association with faulty replacement of handwashing
      soap.
AB  - Using molecular typing methods, we confirmed an outbreak of Stenotrophomonas
      maltophilia among bone marrow transplant patients. The likely source was a
      healthcare worker who may have washed with moisturizer instead of soap between
      patients. Hospital epidemiologists need to go beyond antibiograms when evaluating
      outbreaks and be vigilant about all aspects of hand washing.

PMID- 10580628
TI  - Usefulness of pulsed-field gel electrophoresis in assessing nosocomial
      transmission of pertussis.
AB  - During a 2-week period, three infants with a cough lasting at least 8 days with
      whoops, were admitted to the pediatric unit; Bordetella pertussis was isolated
      from nasopharyngeal aspirates collected from the three infants. Approximately 1
      week later, a nurse working on the same unit developed influenza-like symptoms
      followed by whooping cough; B pertussis was isolated. Isolates from the nurse and
      from one of the infants were shown to be indistinguishable by pulsed-field gel
      electrophoresis. These data demonstrate that B pertussis transmission to
      healthcare workers is possible and emphasize the need to use respiratory
      protection devices (Droplet Precautions) for healthcare workers having close
      contact with infected children.

PMID- 10580629
TI  - A case-control study to detect modifiable risk factors for colonization with
      vancomycin-resistant enterococci.
AB  - A case-control study was conducted to determine the modifiable risk factors
      associated with vancomycin-resistant Enterococcus (VRE) colonization during a
      hospital outbreak. Cephalosporin use was identified as the only independent risk
      factor (odds ratio, 13.8; 95% confidence interval, 2.5-76.3; P = .01). Nursing
      work-load intensity was not associated with VRE colonization in this study.

PMID- 10580631
TI  - staffTRAK-TB: software for surveillance of tuberculosis infection in healthcare
      workers.
AB  - The Centers for Disease Control and Prevention (CDC) recommends periodic
      tuberculin skin testing of healthcare workers with potential exposure to
      Mycobacterium tuberculosis. However, many healthcare facilities have neither a
      system to identify workers due for their skin test nor a means of analyzing
      aggregate data. To illustrate some of the complexities involved in tuberculin
      skin test (TST) tracking and analysis, and how these might be addressed, this
      report describes a software package called staffTRAK-TB, developed by the CDC to
      facilitate surveillance of tuberculosis infection in healthcare workers.
      staffTRAK-TB records data for each healthcare worker, including demographic
      information, occupation, work location, multiple TST results, and results of
      evaluations to determine if clinically active tuberculosis is present. Programmed
      reports include lists of workers due and overdue for skin tests, and skin test
      conversion rates by occupation or worksite. Standardization of types of
      occupations and locations allows data from multiple facilities to be aggregated
      and compared. Data transfer to the CDC can be performed via floppy diskettes.
      staffTRAK-TB illustrates important issues in software structure, standardization
      of occupation and work-location information, relevant data items, and reports and
      analyses that would be useful in practice. Developing software that adequately
      addresses the epidemiological issues is complex, and the lessons learned may
      serve as a model for hospital epidemiologists, infection control personnel,
      occupational health personnel, and computer programmers considering software
      development in this area or trying to optimize their facility's TST surveillance.

PMID- 10580630
TI  - Infection control programs in long-term-care facilities: structure and process.
AB  - Due to the rapid transfer of patients from the acute-care setting, the intensity
      of nursing care among residents in long-term-care facilities (LTCFs) has
      increased, transforming today's LTCFs into subacute healthcare facilities. Given
      the increased risk of infection among residents in LTCFs and the associated
      morbidity and mortality, evaluation of infection control programs in skilled
      nursing LTCFs is warranted. This article addresses the current structure and
      process of infection control programs in skilled nursing LTCFs.

PMID- 10580632
TI  - Satellite videoconferencing for healthcare workers: audience characteristics and
      the importance of continuing education credits.
AB  - To assess the opinions of healthcare workers (HCWs) about a satellite
      videoconference as a means of earning continuing education credit, a telephone
      survey was conducted in September 1998, 1 month after a live interactive
      satellite videoconference on antimicrobial use and resistance. There were 180
      registered sites in 45 states surveyed, representing 1,589 viewers: 764 nurses
      (48.1%), 201 physicians (12.6%), and 624 other HCWs (39.3%). Continuing education
      credit was requested by 51% of nurses, 31% of physicians, and 27% of all other
      HCWs. Although preferred learning formats varied, 70% of respondents said it was
      important to offer continuing education credit. Furthermore, 31% of the
      respondents stated that the videoconference influenced institutional strategies.
      We concluded that satellite videoconferences are a method to reach audiences
      around the world efficiently and effectively, provide the latest information,
      facilitate interaction, and meet some of the demand for continuing education
      credit for HCWs.

PMID- 10580633
TI  - The role of tapasin in MHC class I antigen assembly.
AB  - The discovery of tapasin has shed new light on the mechanisms of major
      histocompatibility complex (MHC) class I assembly in the endoplasmic reticulum
      (ER). Tapasin appears to play an important role in the stable assembly of class I
      molecules with peptide, however, the precise function of tapasin remains elusive.
      The pursuit of tapasin function is complicated by the observation that tapasin is
      not required for successful antigen presentation by all class I molecules. In
      addition, current data suggest that the putative role of tapasin as a bridging
      molecule between transporter associated with antigen presentation (TAP) and class
      I is only of minor importance in tapasin action, and tapasin' s major role
      appears to be as an active cofactor in the assembly of class I. Furthermore, it
      is clear that class I molecules can follow multiple pathways for successful
      assembly in the ER. These pathways may or may not include the interaction of
      class I molecules with the accessory proteins tapasin, calreticulin, ERp57, or
      TAP. I would like to suggest that the particular pathway utilized by a given
      class I molecule depends more upon the availability of appropriate peptides
      rather than on an intrinsic property of the class I molecule, and that tapasin
      may serve a peptide editing function.

PMID- 10580635
TI  - The immune system in the elderly: I. Specific humoral immunity.
AB  - Profound and complex changes in the immune response occur during the aging
      process. Immunosenescence is reflected by a sum of disregulations of the immune
      system and its interaction with other systems. Many of the changes would appear
      to implicate age-related deficiencies of the immune responses. The term
      immunosenescence designates therefore a sort of deterioration of the immune
      function which is believed to manifest itself in the increased susceptibility to
      cancer, autoimmune disease, and infectious disease. Evidence has been
      accumulating from several studies which suggest an association between immune
      function and individual longevity. However, there are observations, especially in
      very old healthy people, that several immune functions are unexpectedly well
      preserved and substantially comparable to those observed in young subjects. These
      findings raise the question of whether the alterations that can be observed in
      the immune parameters of the elderly are a cause or a result of underlying
      disease processes. Moreover, studies on centenarians revealed a remodeling of the
      immune system rather than a deterioration, suggesting that the changes observed
      during immunosenescence do not correspond to immunodeficiency. The underlying
      mechanisms of these events are however still unclear. The purpose of the present
      review is to assess the status of research on the immunobiology of aging. In this
      first section, we focus attention on the B cell biology of aging. In clinical
      practice, the changes in humoral immune responsiveness and antibody-mediated
      defense mechanisms could greatly influence the incidence and outcome of bacterial
      infections and autoimmune diseases as well as the response to vaccines.

PMID- 10580634
TI  - CD43, a molecule with multiple functions.
AB  - To initiate a specific immune response, lymphoid cells integrate a variety of
      signals generated through the orchestrated interaction of multiple cell surface
      molecules with their counter-receptors. As a result of the specific recognition
      of the antigen through antigen-specific receptors, and of the monitoring of their
      particular environment through the so-called coreceptor molecules, lymphoid cells
      go through elaborate processes of maturation and activation, contributing to the
      plasticity and sensitivity of immune response. CD43 is the major sialic acid rich
      protein on the surface of lymphocytes. However, the specific roles of this
      protein in different lymphoid cells under normal physiological conditions remain
      largely unknown. In this review we will mainly focus on the recent advances
      concerning the functions of this molecule as a coreceptor of different lymphoid
      cells as well as on the participation of this molecule in different pathologies.

PMID- 10580636
TI  - The immune system in the elderly: II. Specific cellular immunity.
AB  - Numerous changes occur in the immune system with advancing age, probably
      contributing to the decreased immunoresponsiveness in the elderly. These changes
      are often associated with important clinical manifestations such as increased
      susceptibility to infection and cancer frequently observed in the elderly
      population. Although both cellular and humoral immune responses are modified with
      advancing age, much of the decrease in immunoresponsiveness seen in elderly
      populations is associated with changes in T cell responses. The loss of effective
      immune activity is largely due to alterations within the T cell compartment which
      occur, in part, as a result of thymic involution. Substantial changes in both the
      functional and phenotypic profiles of T cells have been reported with advancing
      age. In fact, two prominent features of immunosenescence are altered T cell
      phenotype and reduced T cell response. One of the most consistent changes noted
      in T cells with advancing age is the decrease in the proportion of naive T cells
      with a concomitant increase in T cells with an activated/memory phenotype. In
      addition, there is evidence that the T cell population from aged individuals is
      hyporesponsive. The observed functional changes include decreased responsiveness
      to T cell receptor stimulation, impaired T cell proliferative capacity, a decline
      in the frequency of CD4+ T cells producing IL-2 and a decreased expression in IL
      2 receptors. These latter findings probably explain the loss of proliferative
      capability of T cells from aged individuals. There is also evidence of a decrease
      in the early events of signal transduction, decreased activation-induced
      intracellular phosphorylation, and decreased cellular proliferative response to T
      cell receptor stimulation. The present review analyzes the main changes of the T
      cell compartment characterizing immunosenescence and discusses the possible
      mechanisms underlying these disregulations and their clinical implications.

PMID- 10580637
TI  - The immune system in the elderly: III. Innate immunity.
AB  - The capability to cope with infectious agents and cancer cells resides not only
      in adaptive immune responses against specific antigens, mediated by T and B
      lymphocytes clonally distributed, but also in natural immune reactions. These
      innate defence mechanisms include chemotaxis, phagocytosis, natural cytotoxicity,
      cell interactions, and soluble mediators or cytokines. However, specific and
      natural immune mechanisms are always closely linked and interconnected, providing
      the primary defense against pathogens. The Authors discuss the main changes
      observed with advancing age in granulocytes and natural killer (NK) cell
      activity, in the expression and function of adhesion molecules, and in the
      pattern of cytokine production. Since phagocytic function is the primary
      mechanism through which the immune system eliminates most extracellular
      pathogenic microorganisms, analysis of this function is of clinical importance.
      Neutrophils from aged subjects often exhibit a diminished phagocytic capacity, as
      well as a depressed respiratory burst, notwithstanding an activated state. The
      activity of NK cells during aging has been studied extensively and different
      results have been reported. The most consistent data indicate an increase in
      cells with high NK activity with advancing age. Cells from healthy centenarians
      can efficiently kill target cells. This finding seems to suggest that innate
      immunity and in particular NK cell activity, is not heavily deteriorated with
      age. Conversely, a low NK activity is a predictor of impending morbidity.
      Immunosenescence is associated with increased expression of several cell adhesion
      molecules (CAM) resulting in an augmented capacity to adhere. Finally, also the
      cytokine network, responsible for differentiation, proliferation, and survival of
      lymphoid cells, undergoes complex changes with age. The main findings are a Th1
      to Th2 cytokine production shift and an increased production of proinflammatory
      cytokines, which could explain many aspects of age-associated pathological
      events, such as atherosclerosis and osteoporosis.

PMID- 10580639
TI  - The paradigm of Th1 and Th2 cytokines: its relevance to autoimmunity and allergy.
AB  - In the past few years, considerable evidence has accumulated to suggest the
      existence of functionally polarized responses by the CD4+ T helper (Th)--and the
      CD8+ T cytotoxic (Tc)-cell subsets that depend on the cytokines they produce. The
      Th1 and Th2 cellular immune response provide a useful model for explaining not
      only the different types of protection, but also the pathogenic mechanisms of
      several immunopathological disorders. The factors responsible for the
      polarization of specific immune response into a predominant Th1 or Th2 profile
      have been extensively investigated in mice and humans. Evidence has accumulated
      from animal models to suggest that Th1-type lymphokines are involved in the
      genesis of organ-specific autoimmune diseases, such as experimental autoimmune
      uveitis, experimental allergic encephalomyelitis, or insulin-dependent diabetes
      mellitus. Accordingly, data so far available in human diseases favor a prevalent
      Th1 lymphokine profile in target organs of patients with organ-specific
      autoimmunity. By contrast, Th2-cell predominance was found in the skin of
      patients with chronic graft-versus host disease, progressive systemic sclerosis,
      systemic lupus erythematosus, and allergic diseases. The Th1/Th2 concept suggests
      that modulation of relative contribution of Th1- or Th2-type cytokines regulate
      the balance between protection and immunopathology, as well as the development
      and/or the severity of some immunologic disorders. In this review, we have
      discussed the paradigm of Th1 and Th2 cytokines in relation to autoimmunity and
      allergy.

PMID- 10580638
TI  - Regulation of integrin function by T cell activation: points of convergence and
      divergence.
AB  - Lymphocyte adhesiveness is dynamically regulated in response to conditions in the
      extracellular environment. One mechanism of regulation of integrin adhesion
      receptors involves a rapid, but transient, increase in integrin function upon T
      lymphocyte activation. These integrin activating signals can be initiated either
      via ligation of Ig superfamily members that are coupled to tyrosine kinase
      cascades, such as the CD3/T cell receptor, CD2, and CD28, or by G protein-coupled
      receptors for chemokines. Analysis of integrin activation induced by CD3/TCR, CD2
      and CD28 suggests a critical role for phosphoinositide 3-OH kinase (PI 3-K). This
      review summarizes recent insights into PI 3-K-dependent regulation of integrin
      function in leukocytes, including the mechanisms by which these receptors are
      coupled to PI 3-K, and potential downstream effectors of PI 3-K that regulate
      integrin-mediated adhesion in leukocytes.

PMID- 10580641
TI  - The hereditary hemochromatosis gene (HFE): a MHC class I-like gene that functions
      in the regulation of iron homeostasis.
AB  - The iron overload disorder, hereditary hemochromatosis, is one of the most common
      genetic diseases of individuals of Northern European descent. The disorder is
      characterized by the progressive accumulation of dietary iron in the major organs
      of the body, which if not diagnosed, leads to numerous medical maladies and
      eventually death. The locus for this disorder was mapped by genetic linkage to
      the short arm of chromosome over twenty years ago, but it was not until 1996 that
      the gene for this disorder was cloned by an identity-by-descent positional
      cloning approach. The gene, called HFE, encodes a major histocompatibility
      complex (MHC) class I-like protein that is mutated in approx 85% of all
      individuals known to have hereditary hemochromatosis (HH). Since the cloning of
      the HFE gene, considerable work has been carried out which has furthered our
      understanding of the genetics of this prevalent disorder. In addition, with the
      identification of the transferrin receptor as a protein capable of interacting
      with HFE we are now beginning to understand how a protein with the structural
      characteristics of an MHC class I molecule can influence cellular iron
      homeostasis.

PMID- 10580642
TI  - Designing secondary structures: 5-azidomethyl tetrahydrofuran-2-carboxylates as
      carbohydrate-derived dipeptide isosteres.
AB  - The potential of carbohydrate-like tetrahydrofuran frameworks as building blocks
      with predictable conformational propensities useful in the design and synthesis
      of novel peptidomimetic materials which adopt well-defined secondary structures
      is discussed.

PMID- 10580640
TI  - Immune response to staphylococcal superantigens.
AB  - Staphylococcal exotoxins, staphylococcal enterotoxins A-E (SEA-SEE), and toxic
      shock syndrome toxin- (TSST-1) are potent activators of the immune system and
      cause a variety of diseases in humans, ranging from food poisoning to shock.
      These toxins are called superantigens because of their ability to polyclonally
      activate T cells at picromolar concentrations. Superantigens bind to both MHC
      class II molecules and specific Vbeta regions of the T cell receptor, leading to
      the activation of both antigen-presenting cells and T lymphocytes. These
      interactions lead to excessive production of proinflammatory cytokines and T cell
      proliferation, causing clinical symptoms that include fever, hypotension, and
      shock. Recent studies suggest that staphylococcal superantigens may also be
      involved in the pathogenesis of arthritis and other autoimmune disorders. This
      review summarizes the in vitro and in vivo effects of staphylococcal enterotoxins
      and TSST-1, recent progress with the use of transgenic knockout mice to identify
      key mediators and receptors involved in superantigen-induced shock, and
      therapeutic agents to mitigate the toxic effects of staphylococcal superantigens.

PMID- 10580643
TI  - High level of aspartic acid-bond isomerization during the synthesis of an N
      linked tau glycopeptide.
AB  - An increased degree of utilization of the potential N-glycosylation site in the
      fourth repeat unit of the human tau protein may be involved in the inability of
      tau to bind to the corresponding tubulin sequence(s) and in the subsequent
      development of the paired helical filaments of Alzheimer's disease. To model
      these processes, we synthesized the octadecapeptide spanning this region without
      sugar, and with the addition of an N-acetyl-glucosamine moiety. The carbohydrate
      protected, glycosylated asparagine was incorporated as a building block during
      conventional Fmoc-solid phase peptide synthesis. While the crude non-glycosylated
      analog was obtained as a single peptide, two peptides with the identical,
      expected masses, in approximately equal amounts, were detected after the cleavage
      of the peracetylated glycopeptide. Surprisingly, the two glycopeptides switched
      positions on the reversed-phase high performance liquid chromatogram after
      removal of the sugar-protecting acetyl groups. Nuclear magnetic resonance
      spectroscopy and peptide sequencing identified the more hydrophobic deprotected
      peak as the target peptide, and the more hydrophilic deprotected peak as a
      peptide analog in which the aspartic acid-bond just preceding the glycosylated
      asparagine residue was isomerized resulting in the formation of a beta-peptide.
      The anomalous chromatographic behavior of the acetylated beta-isomer could be
      explained on the basis of the generation of an extended hydrophobic surface which
      is not present in any of the other three glycopeptide variants. Repetition of the
      syntheses, with altered conditions and reagents, revealed reproducibly high
      levels of aspartic acid-bond isomerization of the glycopeptide as well as lack of
      isomerization for the non-glycosylated parent analog. If similar increased
      aspartic acid-bond isomerization occurs in vivo, a protein modification well
      known to take place for both the amyloid deposits and the neurofibrillary tangles
      in Alzheimer's disease, this process may explain the aggregation of glycosylated
      tau into the paired helical filaments in the affected brains.

PMID- 10580644
TI  - A side-reaction in the SPPS of Trp-containing peptides.
AB  - Syntheses of several Trp-containing peptides on a Wang solid support afforded
      significant amounts of a side-product. 1H-NMR and MS data showed that an
      unexpected alkylation by the linker has occurred on the indole nucleus. This was
      observed whatever the scavenger used, and whatever the position of the Trp
      residue in the sequence, unless it was in the C-terminal position.

PMID- 10580646
TI  - How pure is your thiosialoside? A reinvestigation into the HPLC purification of
      thioglycosides of N-acetylneuraminic acid.
AB  - The synthesis of thiosialosides as potential biological probes for investigations
      involving the use of sialic acid-recognising proteins has been reinvestigated. It
      has been found that the most efficient method for the preparation of
      thiosialosides free from any 2,3-didehydro sialic acid contaminants involves an
      intermediate HPLC purification of thiosialosides as their methyl esters.
      Subsequent methyl ester hydrolysis provides thiosialosides (eg. 6 and 14) which
      are suitable for studies involving the use of sialic acid-recognising proteins.

PMID- 10580645
TI  - CFTR antisense phosphorothioate oligodeoxynucleotides (S-ODns) induce tracheo
      bronchial mucin (TBM) mRNA expression in human airway mucosa.
AB  - Mucus hypersecretion is a critical component of cystic fibrosis (CF)
      pathogenesis. The effects of dysfunction of the cystic fibrosis transmembrane
      regulator (CFTR) on mucin expression were examined using the tracheo-bronchial
      mucin (TBM) gene as an indicator. TBM mRNA expression was assessed in a human
      bronchial epithelial cell line (HBE1) and human nasal mucosal explants in vitro.
      Antisense phosphorothioate oligodeoxynucleotides (S-ODN) to TBM suppressed
      baseline expression of TBM mRNA in both systems, but had no effect on
      glyceraldehyde phosphate dehydrogenase mRNA (GAPDH) expression. Sense and
      missense (multiple scrambled control oligonucleotides) S-ODNs had no effect. 8Br
      cAMP and PGE1 significantly elevated TBM mRNA expression. These increases were
      also specifically inhibited by the antisense S-ODNs. In order to induce a CF-like
      state, S-ODN to CFTR were added to explants. Antisense CFTR S-ODNs were
      anticipated to reduce the expression of cellular CFTR protein, and the level of
      CFTR function. Antisense, but not sense or missense, CFTR S-ODN significantly
      increased TBM mRNA expression. These data suggest that mucin hypersecretion in CF
      may be a direct consequence of CFTR dysfunction; the specific mechanism through
      which this effect is mediated is not known.

PMID- 10580647
TI  - Structural study of fucoidan from Cladosiphon okamuranus TOKIDA.
AB  - A structural study was carried out on a fucoidan isolated from the brown seaweed
      Cladosiphon okamuranus. The polysaccharide contained fucose, glucuronic acid and
      sulfate in a molar ratio of about 6.1 : 1.0 : 2.9. The results of Smith
      degradation showed that this polysaccharide has a linear backbone of 1-->3-linked
      alpha-fucopyranose with a half sulfate substitution at the 4-positions, and a
      portion of the fucose residues was O-acetylated. The data obtained from partial
      acid hydrolysis, a methylation analysis and NMR spectra indicated that the alpha
      glucuronic acid residue is linked to the 2-positions of the fucose residues,
      which were not substituted by a sulfate group. These results indicated that the
      average structure of this fucoidan is as follows: -[(-->3Fuc-4(+/-OSO3-)alpha1-)5
      ->3[GlcA alpha1-->2]Fuc alpha1-]n-. (Half of each fucose residue was sulfated.
      One O-acetyl ester was present in every 6 fucose residues.)

PMID- 10580648
TI  - Cloning and expression of a beta-glycosidase gene from Thermus thermophilus.
      Sequence and biochemical characterization of the encoded enzyme.
AB  - A 3.2 kilobase pair DNA fragment from Thermus thermophilus HB27 coding for a beta
      galactosidase activity was cloned and sequenced. A gene and a truncated open
      reading frame orf1 encoding respectively a beta-glycosidase (ttbeta-gly) and
      probably a sugar permease were located directly adjacent to each other. The
      deduced aminoacid sequence of the enzyme Ttbeta-gly showed strong identity with
      those of beta-glycosidases belonging to the glycosyl hydrolase family 1. The
      enzyme was overexpressed in Escherichia coli and was purified by a two-step
      purification procedure. The recombinant enzyme is monomeric with a molecular mass
      of 49-kDa. It catalyzes the hydrolysis of beta-D-galactoside, beta-D-glucoside
      and beta-D-fucoside derivatives. However, the kcat/Km ratio is much higher for p
      nitrophenyl-beta-D-glucoside and p-nitrophenyl-beta-D-fucoside than for p
      nitrophenyl-beta-D-galactoside. The specificity towards linkage positions of the
      disaccharides tested decreased in the following order: beta1-3 (100%) > beta1-2
      (71%) > beta1-4 (40%) > beta1-6 (10%). Ttbeta-gly is a thermostable enzyme
      displaying an optimum temperature of 88 degrees C and a half life of 10 min at 90
      degrees C. It performs transglycosylation reactions at high temperature with a
      yield exceeding 63% for transfucosylation reactions. On the basis of this work,
      the enzyme appears to be an attractive tool in the synthesis of fucosyl adducts
      and fucosyl sugars.

PMID- 10580649
TI  - Antigenicity of the carbohydrate moiety of ganglioside GM3 having 3-O-acetyl
      ceramide.
AB  - To elucidate the effect of a modification of ceramide on antigenicity of the
      carbohydrate of ganglioside, the reactivity of O-acetyl GM3 having 3-O-acetyl
      ceramide, which has been characterized as a glioma-related ganglioside, with
      monoclonal antibody M2590 was examined in comparison to that of non-acetylated
      GM3, by means of quantitative enzyme-linked immunosorbent assay, TLC
      immunostaining and liposome immune lysis assay. In all these assay systems, O
      acetyl GM3 showed less activity than GM3 as follows: GM3 was detected till 0.1
      nmol in TLC-immunostaining, whereas O-acetyl GM3 could not be detected even at
      0.25 nmol; the GM3 reaction was approximately twofold that of O-acetyl GM3 at
      each diluted point in the enzyme-linked immunosorbent assay; and 20% of the
      liposomes containing GM3 were lysed at 6 mol%, while liposomes containing O
      acetyl GM3 did not lyse at that concentration. The lesser antigenicity of the
      sugar moiety of O-acetyl GM3 could be ascribed to the presence of an acetyl group
      in the ceramide at the 3-position of sphingosine.

PMID- 10580650
TI  - Liquid chromatography "on-flow" 1H nuclear magnetic resonance on native
      glycosphingolipid mixtures together with gas chromatography/mass spectrometry on
      the released oligosaccharides for screening and characterisation of carbohydrate
      based antigens from pig lungs.
AB  - Glycosphingolipids were prepared from pig lung and pooled into two fractions with
      (i) < or = 3 sugar residues, and (ii) > or = 3 sugar residues. Oligosaccharides
      were prepared and used for gas chromatography, gas chromatography/mass
      spectrometry and matrix-assisted laser desorption/ionization mass spectrometry.
      The glycolipid fractions i and ii were further characterised and purified using a
      novel method based on high performance liquid chromatography "on-flow" proton
      nuclear magnetic resonance. The LC "on-flow" NMR technique showed good
      chromatographic separation and gave NMR spectral information which could be used
      as guidance for pooling of the separated mixture glycolipids. Conventional 1H
      NMR, thin layer immunostaining, gas chromatography, gas chromatography/mass
      spectrometry and matrix-assisted laser desorption/ionization mass spectrometry
      were used to characterise the glycolipids and to validate LC-NMR spectral data.

PMID- 10580651
TI  - Activation of human T lymphocytes by ganglioside-containing liposomes.
AB  - We investigated the in vitro stimulatory effect of ganglioside (GM3, GD1a, GD1b,
      GT1b, or GQ1b)-containing liposomes on human immune cells. The effect of
      ganglioside-containing liposomes on the concentration of cytoplasmic free calcium
      ions ([Ca2+]i) in human immunocytes was examined using the confocal laser
      fluorescence microscopic method. The GD1a- and GT1b-containing liposomes
      significantly increased [Ca2+]i of human T lymphocytes compared with the GM3-,
      GD1b- and GQ1b-containing ones. The response of CD8+ and CD4+ cells was
      significantly higher than that of CD20+ cells. Our results show that the increase
      in [Ca2+]i may be caused by not the number of sialic acids contained in the
      gangliosides but the conformation of the sialic acid moiety to protrude
      exteriorly from the liposomal membrane surface, and that a sort of receptor
      recognizing the sialic acid moiety exists on human T lymphocytes (both CD8+ and
      CD4+ cells), which may be involved in the activation of the cells. The present
      results are almost the same as those obtained for the rat T lymphocyte system
      previously reported. This clearly confirms that a sort of ganglioside surely
      stimulates T lymphocytes directly, which is not species-specific but conserved in
      humans and rats among animal species.

PMID- 10580652
TI  - Determination of the cell adhesion specificity of Streptococcus suis with the
      complete set of monodeoxy analogues of globotriose.
AB  - Streptococcus suis causes meningitis and other serious infections in pigs and
      humans, and binds to host cell globotriosylceramide. In order to determine the
      essential hydroxyls involved in binding, the complete set of monodeoxy
      derivatives of the receptor trisaccharide Gal alpha1-Gal beta1-4Glc were tested
      as inhibitors of bacterial hemagglutination. Removal of the 4''-, 6'', 2' or 3'
      hydroxyls abolished inhibitory activity, which indicated that they were
      critically involved in binding. The same results were obtained using synthetic
      lipid-linked monodeoxy derivatives of the trisaccharides in a thin-layer overlay
      assay. The P(N) and P(O) subtypes of the S. suis adhesin showed similar binding
      patterns. The hydroxyls of the glucose moiety were not critical for binding,
      although the adhesin binds better to the trisaccharide Gal alpha1-4Gal beta1-4Glc
      than the disaccharide Gal alpha1-4Gal.

PMID- 10580653
TI  - Differences in N-acetyllactosamine synthesis between beta-1,4
      galactosyltransferases I and V.
AB  - Unlike classical beta-1,4-galactosyltransferase (beta-1,4-GalT I), beta-1,4-GalT
      V (formerly IV**) has little activity towards 1 mM N-acetylglucosamine [Sato et
      al. (1998) Proc Natl Acad Sci USA 95:472-477]. The human beta-1,4-GalTs I and V
      were expressed individually in Sf-9 cells by transfection of the full coding
      sequences, and their N-acetyllactosamine synthetase activities were determined
      towards different N-acetylglucosamine concentrations. Kinetic studies using the
      cell homogenates as an enzyme source revealed that beta-1,4-GalTs I and V possess
      Km values of 0.6 mM and 33 mM towards N-acetylglucosamine, and of 48 microM and
      41 microM towards UDP-Gal, respectively. No significant inhibition of N
      acetyllactosamine synthesis with alpha-lactalbumin was observed for beta-1,4-GalT
      V but the significant inhibition with alpha-lactalbumin was observed for beta-1,4
      GalT I.

PMID- 10580654
TI  - Abnormal deposition of laminin and type IV collagen at corneal epithelial
      basement membrane during wound healing in diabetic rats.
AB  - PURPOSE: To understand the pathophysiology of the corneal basement membrane in
      diabetes, we compared the localization of laminin and type IV collagen in the
      epithelial basement membrane during corneal epithelial wound healing in diabetic
      and nondiabetic rats. METHODS: Streptozotocin was used to induce diabetes in half
      the rats. Two weeks later, the whole corneal epithelium was debrided. Diabetic
      and healthy rats (3-5 per group) were sacrificed before debridement and 1, 3, and
      7 days and 1 month afterwards. The localization of laminin and type IV collagen
      was observed in cryosections by epifluorescence microscopy. RESULTS: In unwounded
      corneas of both diabetic and normal rats, laminin and type IV collagen were
      localized in the corneal epithelial basement. The intensity of fluorescence,
      however, was clearly stronger in the diabetic rats. In normal rats, wounding
      initially removed laminin and type IV collagen, but during healing these two
      proteins reappeared beneath the resurfacing corneal epithelium. Although similar
      results were observed in diabetic rats, the expression of laminin and type IV
      collagen was delayed, and their deposition was fragmented and irregular.
      CONCLUSIONS: These results suggest that delayed corneal epithelial wound healing
      in diabetes might involve delayed reappearance and abnormal reformation of
      epithelial basement membrane proteins.

PMID- 10580655
TI  - Changes in extracellular matrix components after excimer laser photoablation in
      rat cornea.
AB  - PURPOSE: To learn more about corneal wound healing after excimer laser
      photoablation. METHODS: Observations were made on the chronological changes in
      type I collagen, fibronectin, laminin, and type IV collagen after excimer
      ablation of rat cornea. Immunohistochemical techniques were used. RESULTS: There
      was no obvious change in the localization of type I collagen in the ablated area,
      but the localization of fibronectin, laminin, and type IV collagen changed
      remarkably. One day after ablation, immunofluorescent staining for fibronectin
      increased on the ablated surface. Subsequently, the fluorescence of fibronectin,
      laminin, and type IV collagen increased remarkably; in particular, the
      localization of these extracellular matrix proteins was sustained in the shallow
      layer of the stroma until about 24 weeks after ablation. Hematoxylin-eosin
      staining indicated that keratocytes temporarily disappeared 1 day after ablation,
      and activated keratocytes then migrated to the ablated areas. CONCLUSIONS: These
      results suggest that activated keratocytes might be synthesizing the
      extracellular matrix components. Therefore sustained responses of keratocytes may
      be induced by excimer laser photoablation.

PMID- 10580656
TI  - Effects of tranilast on cultured rabbit corneal keratocytes and corneal haze
      after photorefractive keratectomy.
AB  - PURPOSE: In vitro and in vivo studies were performed to elucidate the effects of
      tranilast on cellular proliferation and collagen synthesis. METHODS: Subculturing
      was carried out using keratocytes from rabbits that underwent photorefractive
      keratectomy (PRK) and developed corneal haze, and keratocytes from normal rabbit
      cornea. RESULTS: Tranilast suppressed proliferation in cultured keratocytes from
      the corneal haze region at doses of 30 and 300 micromol/L and collagen synthesis
      at doses of 3, 30, and 300 micromol/L. Normal corneal cultures showed suppression
      of keratocyte proliferation and collagen synthesis only at a high dose of
      tranilast (300 micromol/L). Betamethasone suppressed proliferation of keratocytes
      in both haze and normal cornea at a dose of 10 micromol/L, as well as collagen
      synthesis at respective doses of 1 and 10 micromol/L. Diclofenac sodium
      suppressed collagen synthesis of keratocytes in haze cornea at a high dose of 100
      micromol/L, and in keratocytes in normal cornea, at doses of 10 and 100
      micromol/L. In an in vivo study, either 0.5% tranilast, 0.1% betamethasone
      phosphate eye drops, or a tranilast base solution (control) was instilled four
      times daily to rabbits that had undergone PRK. Weekly evaluation of the
      inhibitory effect of these drugs on the development of haze was performed 2 weeks
      after surgery. Tranilast suppressed haze 6-13 weeks after PRK, but betamethasone
      phosphate showed no effect. CONCLUSION: These results indicate that tranilast is
      potentially effective for inhibiting the corneal haze that occurs after PRK.

PMID- 10580657
TI  - Lens reconstruction after mature cataract in SCR rat.
AB  - PURPOSE: To conduct a long-term observation study of SCR rats that had developed
      a mature cataract at 11 weeks of age at 3-month intervals until the rats were 12
      months old. METHODS: Lenses of 15 rats were examined with both light and electron
      microscopes. RESULTS: At 12 weeks, opacity was observed in the perinuclear zone
      and the cortical intermediate layer. Liquefaction of the posterior subcapsular
      area and regression of cortical superficial fibers were also observed at this
      stage. Epithelial cells at the anterior polar area were multilayered. At 12
      months, the lens recovered as a result of the regenerated lens fibers in the
      intermediate layer and the cortical superficial layer, although the opacity
      remained in the perinuclear zone. The multilayered cellular structure in the
      center of the epithelium returned to its original monolayer form. However, the
      equatorial epithelial cells became vacuolated and swollen with age, showing
      regression from the bow region. CONCLUSIONS: These results suggest that the
      decrease of opacity in SCR rats is merely a temporary phenomenon that reflects
      the differentiating and metabolizing functions of the epithelial cells. With
      initiation of epithelial regression, the regeneration of the lens fibers ceased,
      suggesting that further decrease in opacity was no longer possible.

PMID- 10580658
TI  - Experimental uveitis induced by intravitreal or intravenous lipoteichoic acid in
      rabbits.
AB  - PURPOSE: To investigate the role of lipoteichoic acid (LTA), one of the cell wall
      components in gram-positive bacteria in uveitis. METHODS: Intraocular
      inflammation in rabbit eyes was induced by intravitreal or intravenous injections
      of LTA from Staphylococcus aureus or Streptococcus sanguis. The inflammation was
      monitored progressively with the laser flare-cell photometer, and examined by
      periodic clinical observations. Histological examinations were performed 24 hours
      after administration, and aqueous protein concentrations and cell counts were
      also determined. RESULTS: Intraocular inflammation appeared within 6-9 hours of
      LTA intravitreal injection. became maximal at about 24-48 hours postinjection,
      and lasted for nearly 6 days. Intraocular inflammation was also induced by
      intravenous injection of LTA at a higher dose. Inflammation reached a peak 4-5
      hours after injection, and rapidly disappeared in 24 hours. No cellular response
      was observed in intravenous LTA-treated eyes. CONCLUSIONS: This study
      demonstrates that LTAs from gram-positive bacteria have the biological activity
      to induce intraocular inflammation in rabbits by intravitreal or intravenous
      injection. Therefore, we suggest that LTA may play a role in the pathogenesis of
      uveitis as one of the etiological factors.

PMID- 10580659
TI  - Confocal scanning laser microscopic findings of excised choroidal neovascular
      membranes of age-related macular degeneration and their comparison with the
      clinical features.
AB  - PURPOSE: To evaluate the histopathological characteristics of choroidal
      neovascular membranes excised from eyes of patients with age-related macular
      degeneration (AMD) and to correlate their characteristics with the clinical
      features of AMD. METHODS: Choroidal neovascular tissues were excised from 3
      patients with AMD and examined by light and confocal scanning laser microscopy.
      The clinical features were obtained by fundus photography, fluorescein
      angiography (FA), and indocyanine green angiography (IA) and compared with the
      histopathological findings. RESULTS: Light microscopy showed the presence around
      the vascular structures of cells containing pigment. Confocal scanning laser
      microscopy revealed lipofuscin signals of the retinal pigment epithelium cells
      around the vascular tissue that was also confirmed by three-dimensional
      reconstructed views from serial optical sections. Clinical observations of the
      fundus by IA showed that all 3 cases had areas with hyperfluorescence in early
      phase on IA. A dark rim was observed around the area of hyperfluorescence in 2
      cases, and the dark rim was located within the neovascular membrane. The patterns
      of fluorescence were heterogeneous in some phases on IA, which reflected the
      histological heterogeneity of the neovascular membrane. CONCLUSIONS: The retinal
      pigment epithelium cells appear to play a special role in the induction and
      regression of the choroidal neovascular membrane associated with age-related
      macular degeneration.

PMID- 10580660
TI  - Effect of topical dorzolamide on tissue circulation in the rabbit optic nerve
      head.
AB  - PURPOSE: To examine the effect of 1% topical dorzolamide on tissue circulation in
      the optic nerve head (ONH) of Dutch rabbits. METHODS: A laser speckle tissue
      circulation analyzer was used. One eye of each rabbit received 1% topical
      dorzolamide twice daily for 20 days, and the fellow eye received the vehicle in a
      masked, randomized manner. Intraocular pressure (IOP) was measured every 5 days.
      The normalized blur (NB) value, a quantitative index of tissue blood flow
      velocity in the ONH, was measured before treatment and 2 hours after the last
      instillation on the 20th day. RESULTS: The IOP was lowered by about 2 mm Hg only
      in the dorzolamide-treated eyes (P < .01). The NB value showed no significant
      change in either dorzolamide-treated or vehicle-treated eyes. CONCLUSIONS: Long
      term topical dorzolamide does not affect the ONH tissue circulation in
      dorzolamide- and vehicle-treated eyes of Dutch rabbits.

PMID- 10580661
TI  - Influence of myopic disc shape on the diagnostic precision of the Heidelberg
      Retina Tomograph.
AB  - PURPOSE: To investigate the diagnostic capability of a glaucoma diagnostic
      classification program for the Heidelberg Retina Tomograph (HRT) in eyes with
      myopic disc shapes. METHODS: Sixty-six normal subjects (66 eyes) and 78 open
      angle glaucoma patients (78 eyes) were enrolled. The eyes were divided into two
      groups; those eyes with myopic and those with nonmyopic disc shapes. The
      classification was based on clinical judgment made after the examination of
      stereophotographs of the discs without considering the refractive errors. The
      agreement between the classification program and the clinical diagnosis was
      evaluated for sensitivity, specificity, and diagnostic precision. The influence
      of the disc shape on the HRT topographic parameters was evaluated. RESULTS: The
      sensitivity, specificity, and diagnostic precision of the HRT were 83%, 95%, and
      89% in eyes with nonmyopic disc shapes, but 71%, 96%, and 83% in those with
      myopic disc shapes. Rim volume, height variation contour, mean retinal fiber
      nerve layer (RNFL) thickness, and RNFL cross-section area were significantly
      larger in eyes with myopic disc shapes than in eyes with nonmyopic discs,
      regardless of the clinical diagnosis. CONCLUSIONS: The classification program
      should be modified to take into account the myopic disc shape in order to improve
      its capability to make more accurate diagnosis of glaucoma possible.

PMID- 10580662
TI  - Changes in refraction caused by induction of acute hyperglycemia in healthy
      volunteers.
AB  - PURPOSE: To determine whether the myopic changes and ocular hypotension after a
      glucose load are caused by hyperglycemia. METHODS: Oral glucose tolerance tests
      were conducted on seven healthy young subjects with normal vision. The changes in
      the hematologic parameters and the refractive system were measured periodically
      for 150 minutes after the glucose load. RESULTS: After the glucose load, there
      was an increase in plasma glucose level and the level of plasma osmosis, ocular
      hypotension, a myopic change in refractive power, shallowing of the anterior
      chamber, and a thickening of the lens. The degree of the myopic change exceeded
      the power of the residual accommodation. Normalization of the plasma glucose
      level led to a normalization of the intraocular pressure and a reversal of the
      myopic changes. CONCLUSIONS: These findings suggest that the myopic changes that
      accompanied hyperglycemia were caused by a thickening of the lens resulting from
      a decrease in the tension of the zonule fibers of Zinn, and were secondary to
      ocular hypotension. Hyperopia appeared to be caused by the reversal of the myopia
      after normalization of plasma glucose levels.

PMID- 10580664
TI  - Scanning laser tomography to evaluate optic discs of normal eyes.
AB  - PURPOSE: To investigate the effects of age, eye refraction, and disc area on
      topographic parameters of the optic nerve head in normal volunteers, using the
      Heidelberg Retina Tomograph. METHODS: Seventy-seven eyes of 77 normal volunteers
      were examined by scanning laser tomography. The topographic parameters analyzed
      were disc area, cup area, cup/disc area ratio, rim area, cup volume, rim volume,
      mean cup depth, maximum cup depth, cup shape measure, height variation contour,
      mean retinal nerve fiber layer thickness (MnRNFLT), and retinal nerve fiber layer
      (RNFL) cross-section area. The effect of age, refraction, and disc area on each
      parameter was analyzed by the multiple linear regression model. RESULTS:
      Significant declines in MnRNFLT and RNFL cross-section area were found with
      increasing age (P < .05). The mean cup depth and maximum cup depth were
      significantly deeper in myopic subjects (P < .05). Large discs had large cup
      area, cup/disc area ratio, rim area, cup volume, mean cup depth, cup shape
      measure (P < .01), and maximum cup depth (P < .05). The MnRNFLT was smaller in
      large discs (P < .01). Rim volume was unaffected by age, refraction, or disc
      area. CONCLUSIONS: The age, refraction, and disc area were related to several
      optic disc parameters obtained by the Heidelberg Retina Tomograph. Because of
      these relationships, care should be taken to analyze the appearance of the optic
      disc on the basis of these parameters in patients with glaucoma or other
      diseases. Rim volume appears to be a good parameter for evaluating the optic disc
      without considering age, refraction, or disc area.

PMID- 10580663
TI  - Clinical course of HTLV-I-associated uveitis.
AB  - PURPOSE: To define the long-term clinical course and visual outcome of human T
      cell lymphotrophic virus type I (HTLV-I)-associated uveitis (HAU). METHODS: We
      reviewed the clinical data on 96 eyes of 70 patients, 26 men and 44 women, with
      HAU, with specific reference to recurrence of the disease and long-term visual
      outcome. The mean follow-up period was 83 months (range, 12-276 months). RESULTS:
      The mean age of onset was 42.8 years (range, 7-78 years of age), with men
      presenting at a significantly younger age. Forty-seven patients had isolated HAU;
      in 10 patients, HTLV-I-associated myelopathy occurred before or after the onset
      of HAU; in 14 patients, hyperthyroidism had preceded HAU. A single episode of
      mild to moderate acute uveal inflammation with resolution in a few weeks or more
      occurred in 44 (62.9%) patients, and multiple episodes in 26 (37.1%), with a mean
      interval of 16 months (range, 1-250 months), which affected the same eye, fellow
      eye, or both. The majority of patients had favorable visual outcome at the last
      examination, whereas only a few patients suffered poor vision resulting from
      steroid cataract and retinochoroidal degeneration. CONCLUSIONS: The clinical
      course of HAU is virtually benign and its visual outcome is favorable, although
      its recurrence is common. The uveitis is usually isolated and affects a portion
      of otherwise unremarkable HTLV-I carriers, but it may sometimes be manifest as a
      symptom of syndromic diseases such as HTLV-I-associated myelopathy or
      hyperthyroidism. This study describes for the first time cases of HAU that
      occurred many years before manifestation of HTLV-I-associated myelopathy.

PMID- 10580665
TI  - Morphometric features of laminar pores in lamina cribrosa observed by scanning
      laser ophthalmoscopy.
AB  - PURPOSE: To describe a method for making morphometric analysis of the pores in
      the lamina cribrosa with a confocal scanning laser ophthalmoscope (SLO). METHODS:
      Sixteen consecutive images were acquired with an SLO from the retinal surface to
      the bottom of the optic disc in +0.25-diopter increments. An He-Ne laser (633 nm)
      with a 20 degrees field of view was used. The images from each section were
      processed and combined with the aid of Macintosh software. RESULTS: Eyes with
      physiological cupping showed uniformly round or nearly round pores, whereas eyes
      with primary open-angle glaucoma frequently had compressed pores. CONCLUSIONS: In
      vivo morphometry of the surface of the internal lamina cribrosa can be performed
      by this technique, which should be useful for evaluating the progression of
      glaucomatous changes of the optic nerve head.

PMID- 10580666
TI  - Bilateral large peripapillary venous and arterial loops.
AB  - BACKGROUND: Peripapillary loops of venous origin are extremely rare. CASE: A 55
      year-old woman was referred to us for further examination of peripapillary
      vascular abnormalities. OBSERVATIONS: Fundus examination and fluorescein
      angiography clearly showed a venous and an arterial peripapillary loop in both
      her right and left fundi. The venous loop in the right eye was in a large hairpin
      configuration, extending into the retina about 1 disc diameter from the optic
      disc. Fluorescein angiography in the left eye revealed slow and irregular filling
      of dye into a venous loop that showed stasis of the bloodstream through the loop.
      Various retinal vascular abnormalities, including cilioretinal artery and triple
      branching of the retinal vein were also observed. CONCLUSION: The findings in
      this case of bilateral peripapillary venous and arterial loops and unilateral
      trifurcation of retinal vein suggest that there could be an association in the
      other retinal abnormalities. Periodic follow-up examinations seem necessary.

PMID- 10580667
TI  - Results of transmedial-canthal ethmoidal decompression for severe dysthyroid
      optic neuropathy.
AB  - PURPOSE: To study the effects of ethmoidal wall (one-wall) decompression using a
      transmedial-canthal approach (transmedial-canthal ethmoidectomy) for the
      treatment of dysthyroid optic neuropathy. METHODS: The ethmoidal wall and air
      cells were completely removed using a transmedial-canthal approach in 6 eyes of 4
      patients (mean age = 55 years; age range, 46-69 years) with dysthyroid optic
      neuropathy. Similar surgery was performed on 2 contralateral eyes in 2 of the
      patients for cosmetic reasons. The preoperative corrected visual acuity in the 6
      eyes ranged from hand motion to 20/100. Centrocecal scotomas were detected using
      automatic static threshold perimetry in the 6 eyes. RESULTS: After transmedial
      canthal ethmoidectomy, the corrected visual acuity improved to better than 20/20
      in the 6 eyes, and the centrocecal scotomas had almost completely resolved. There
      were no major complications, such as cerebrospinal fluid leakage or diplopia
      associated with the surgery. There were no relapses during an average follow-up
      period of 29 months. CONCLUSIONS: These findings suggest that transmedial-canthal
      ethmoidectomy is an effective and safe therapy for dysthyroid optic neuropathy.

PMID- 10580668
TI  - Electroretinograms and visual evoked potentials elicited by spectral stimuli in a
      patient with enhanced S-cone syndrome.
AB  - PURPOSE: To evaluate the properties of the retina of a Japanese patient with
      enhanced S-cone syndrome by analyzing electroretinograms (ERGs) and visual evoked
      potentials (VEPs) elicited by different spectral stimuli. METHODS: Ganzfeld
      spectral flashes in the presence of strong white adapting background illumination
      were used to elicit cone ERGs and VEPs. RESULTS: The cone ERG elicited in the
      patient by short wavelength stimuli was distinctly different from the normal S
      cone ERG. The action spectrum of the cone ERG confirmed its relative
      hypersensitivity to short wavelengths. The action spectrum of the VEP for the
      patient showed a similar relative hypersensitivity to short wavelengths. The
      response of the VEPs to short wavelength stimuli was different in waveform from
      the VEP response to longer wavelength stimuli observed in a normal subject.
      CONCLUSIONS: These results indicate that the hypersensitivity to short
      wavelengths is transmitted to the central nervous system and that there is a
      short wavelength transducing photopigment in many of the photoreceptors, either
      abnormal S-cones or photopic rods.

PMID- 10580669
TI  - Pattern visual evoked cortical potentials in patients with toxic optic neuropathy
      caused by toluene abuse.
AB  - PURPOSE: Electrophysiological evaluation of the visual function of patients with
      toxic neuropathy caused by toluene abuse. METHODS: Fifteen patients (mean age
      25.6 years, eight men and seven women) were diagnosed with bilateral optic
      neuropathy. Pattern visual evoked cortical potentials (PVECPs) and clinical
      symptoms were investigated. RESULTS: Visual acuities at the initial visit were
      less than 0.1 in 5 cases and 0.1-1.0 in 10 cases. PVECPs were followed up in the
      15 cases. At the first recording, PVECPs were nonrecordable in both eyes of 11
      cases, the P100 peak latency was prolonged in both eyes of 3 cases, and only 1
      case showed a normal P100 peak latency. After treatment, visual acuities improved
      more than 2 lines in 6 cases, 3 of whom showed normal P100 peak latency in the
      PVECPs. Visual prognosis and PVECP changes were identical in both eyes of all
      patients. CONCLUSIONS: In patients with toluene optic neuropathy, the P100 peak
      latency of PVECP shortened as visual acuity improved. The VECP abnormalities in
      these patients suggest that there is a severe effect on the optic nerve after
      prolonged exposure to toluene.

PMID- 10580670
TI  - Predictive markers of pre-eclampsia in hypertensive disorders of pregnancy.
AB  - OBJECTIVE: The aim of this work is to assess the most widespread methods
      currently proposed and two new markers for predicting the development of pre
      eclampsia in pregnant women with hypertension. METHODS: The study involved 212
      pregnant Caucasian women: 104 normotensive, 68 pregnancy-induced hypertensive and
      40 chronic hypertensive. Blood and urine were sampled between 28 and 30 weeks
      gestation. All 108 hypertensive pregnant women, at the time of sampling,
      demonstrated proteinuria below 0.3 g/24 h. The following laboratory tests were
      performed: fibronectin, antithrombin-III, alpha-1-microglobulin, U-N-acetyl-beta
      glucosaminidase, uric acid and albumin excretion rate. Student's t-test,
      discriminant analysis and chi2 (chi-square) test were used as statistical
      methods. A P value less than 0.05 was considered significant. RESULTS: After
      discriminating analysis, only three of the six variables analyzed were able to
      discriminate patients who would develop pre-eclampsia from the remaining
      hypertensive pregnant women: microalbuminuria, uric acid and fibronectin (chi2 =
      29.122, P < 0.01). CONCLUSIONS: In agreement with previous studies, albumin
      excretion rate appeared to be the best predictive test for pre-eclampsia in
      hypertensive pregnant women, giving a higher positive predictive value and
      specificity (87.5 and 98.9%, respectively).

PMID- 10580671
TI  - Calcium metabolism in pre-eclampsia.
AB  - OBJECTIVES: To study calcium metabolism in pre-eclampsia and normotensive gravid
      women. METHOD: Ten milliliters of heparinized blood samples and 24-h urine
      samples were collected from 50 pre-eclamptic and 50 normotensive primigravidae.
      Blood samples were studied for calcium uptake, intracellular calcium level and
      calcium-dependent adenosine triphosphatase activity of red blood cell ghost.
      Urinary calcium excretion was estimated from the 24-h urine samples. These values
      were compared in the two groups. RESULTS: The mean gestational age at recruitment
      was similar in both the groups. The mean maternal age was 24.28 +/- 2.41 years in
      pre-eclamptic and 23.48 +/- 4.16 years in normotensive women. In pre-eclampsia 24
      h urinary calcium excretion (71.20 +/- 22.95 mg/day) and calcium-dependent ATPase
      activity (10.78 +/- 2.40 nmol/Pi/mg protein/min) was significantly lower compared
      to normotensive primigravidae (calcium excretion = 189.24 +/- 57.06 mg/day; Ca2+
      dependent ATPase = 12.64 +/- 2.42 nmolPi/mg /protein per min; P < 0.001).
      Intracellular calcium levels and calcium uptake at 10 min by red blood cells were
      significantly higher in pre-eclampsia (P < 0.05). Calcium uptake by red blood
      cells at 20 and 30 min was similar in both groups. CONCLUSION: Pre-eclampsia is
      associated with increased levels of intracellular calcium, decreased calcium
      dependent ATPase activity of erythrocytes and hypocalciuria.

PMID- 10580672
TI  - Helicobacter pylori seropositivity in patients with hyperemesis gravidarum.
AB  - OBJECTIVE: The aim of this study was to analyze the hypothesis that there was an
      association between hyperemesis gravidarum (HG) and Helicobacter pylori (HP)
      infection. METHODS: The study group consisted of 95 pregnant women with HG and
      116 asymptomatic pregnant women who were admitted to our hospital between January
      1997 and October 1998. Specific serum immunoglobulin G for HP was assayed in the
      sera of the study group after informed consent was obtained. Chi-square and
      Student's t-test were used accordingly for statistical analysis of the data.
      RESULTS: Serologically positive HP infection was detected in 87 of the 95
      patients with HG (91.5%) whereas 52 of the 116 asymptomatic gravidas (44.8%)
      serving as the control group had positive antibody concentrations against HP. The
      ratio of HP positivity in pregnant women with HG was significantly higher than
      asymptomatic pregnant women (P < 0.001). The mean index percentages of IgG titers
      were 73.8 +/- 9.7% in the hyperemesis gravidarum and 25.8 +/- 5.6% control group
      (P < 0.01). CONCLUSION: HP infection seemed to be significantly associated with
      hyperemesis gravidarum in our pregnant patient population with hyperemesis
      gravidarum.

PMID- 10580673
TI  - Transvaginal color Doppler ultrasonography and CA-125 in suspicious adnexal
      masses.
AB  - OBJECTIVE: To compare diagnostic performance of color Doppler ultrasound and CA
      125 in suspicious adnexal masses on B-mode sonography. MATERIALS AND METHODS:
      Data on 94 patients (mean age: 47.4 years, range: 17-79 years. Fifty-two (55.3%)
      premenopausal and 42 (44.7%) postmenopausal women) managed in our institution
      because of a suspicious adnexal mass were reviewed. All patients were evaluated
      by transvaginal color Doppler ultrasonography (CD) and serum CA-125 level
      determination prior to surgery. Definitive histopathological diagnosis was
      obtained in each case. Sonographic morphology evaluation was suspicious in all
      cases. CD was considered as suspicious when flow was detected and the lowest RI
      found was < or = 0.45. CA-125 cut-off was > or = 35 UI/ml. Sensitivity,
      specificity, positive predictive value (PPV) and negative predictive value (NPV)
      were calculated for each method and compared. ROC analysis was performed for RI
      and CA-125. Areas under curve (AUC) were calculated and compared. RESULTS: Fifty
      six (59.6%) tumors were found to be malignant and 38 (40.4%) benign. Sensitivity,
      specificity, PPV and NPV for CD were 87.5% (95% CIs: 75.3-94.4), 84.2% (95% CIs:
      68.7-94), 89.1% (95% CIs: 77.7-95.9) and 82.1% (95% CIs: 66.5-92.5),
      respectively. Sensitivity, specificity, PPV and NPV for CA-125 were 83.9% (95%
      CIs: 71.7-92.4), 68.4% (95% CIs: 51.3-82.5), 79.7% (95% CIs: 66.2-89) and 74.3%
      (95% CIs: 56.7-87.5), respectively. Sensitivity, PPV and NPV were not
      statistically different. CD had higher specificity (P = 0.01). AUC curve for
      Doppler (0.75) was significantly higher than for CA-125 (0.61) (P = 0.0002).
      CONCLUSIONS: Our results indicate that color Doppler ultrasound has a better
      diagnostic performance as compared with CA-125, being significantly more
      specific.

PMID- 10580674
TI  - Epidemiologic aspects of endometrial cancer in Thrace, Greece.
AB  - To describe the epidemiologic characteristics of endometrial cancer in relation
      with certain risk factors affecting the two major ethnic groups (Christian
      Orthodox and Muslims) in the area of Thrace, Greece. We performed a cross
      sectional study of 166 consecutive patients, aged between 29 and 87 years, with
      documented endometrial cancer who were referred to our clinic for treatment from
      January 1986 to June 1998. Epidemiologic characteristics of the patients were
      abstracted from medical charts. To evaluate our results we used the direct
      standardization method (1995 Eur. Population) and chi2 test. The endometrial
      cancer incidence for the two study populations (Christian Orthodox and Muslims)
      was 16.96 and 3.16/100,000, respectively. We observed statistically significant
      differences in most epidemiologic characteristics between the two major ethnic
      groups in Thrace (Christian Orthodox and Muslims) regarding endometrial cancer.
      Our results confirm the increasing trend of endometrial cancer incidence as
      established in previous investigations.

PMID- 10580675
TI  - Hysteroscopic evaluation of the endometrium of post-menopausal patients with
      breast cancer before and after tamoxifen use.
AB  - OBJECTIVE: To evaluate by hysteroscopy and histopathology the influence of
      tamoxifen in the endometrium of post-menopausal women with previous breast
      cancer. METHOD: Out of 46 patients studied, 20 of them had been using tamoxifen
      for an average length of 12 months, and are still being followed-up. Hysteroscopy
      with endometrial biopsy was performed before and after the use of the drug.
      RESULTS: The prevalence of endometrial activity before and after this
      hormoniotherapy was the same, i.e. 10.0%, showing a non-significant variation.
      CONCLUSION: The hormoniotherapy with tamoxifen has not increased the endometrial
      proliferactive activity of postmenopausal patients with breast cancer. The most
      common hysteroscopical finding was numerous vesicles disseminated throughout the
      uterine cavity probably due to atrophy of the endometrium.

PMID- 10580676
TI  - Ultrasound guided embryo transfer significantly improves pregnancy rates in women
      undergoing oocyte donation.
AB  - OBJECTIVES: Recent reports suggest ultrasound (US) guided embryo transfer (ET)
      improves pregnancy rates. Using the ovum donation model to eliminate confounding
      variables, we assessed the impact of US guided ET on pregnancy rates,
      implantation rates, and multiple gestation rates. METHODS: All women who
      underwent IVF-ET cycles using donated oocytes from November 1997 to September
      1998 (n = 137) were evaluated retrospectively. ET from November 1997 to April
      1998 were performed without US, while all ET from May 1998 to September 1998 were
      performed using transvaginal or transabdominal US. ET was further categorized as
      easy or difficult. Difficult ET was defined as requiring at least two attempts
      and/or the presence of blood on the catheter and/or > 5 min. RESULTS: Pregnant
      patients (n = 73) were similar with respect to the number and morphology of the
      embryos transferred compared to non-pregnant patients (n = 65). US guidance
      significantly improved implantation and pregnancy rates in cycles with easy
      transfers [28.8 vs. 18.4% and 63.1 vs. 36.1%, respectively (P < 0.05)] without
      impacting multiple pregnancy rates. CONCLUSION: US guided ET is simple and
      reassuring and appears to significantly improve pregnancy outcomes in ovum
      donation cycles by optimizing the placement of embryos.

PMID- 10580677
TI  - Clinical presentation and management of menopause in Lagos, Nigeria.

PMID- 10580678
TI  - Postpartum urinary retention.

PMID- 10580679
TI  - HIV seroprevalence and rapid testing in unbooked pregnant African women.

PMID- 10580680
TI  - Endometrial carcinoma in a 22-year-old virgin.

PMID- 10580681
TI  - Pseudo-Meigs' syndrome secondary to bilateral ovarian endometrioid carcinomas.

PMID- 10580682
TI  - Prevention of preterm delivery: nifedipine or magnesium sulfate.
AB  - OBJECTIVE: to establish the efficacy and safety of nifedipine and magnesium
      sulfate in arresting preterm labor. METHOD: seventy-four patients with singleton
      pregnancies at 23-36 weeks in preterm labor, were selected randomly to receive
      either oral nifedipine or intravenous magnesium sulfate. RESULTS: both drugs had
      similar tocolytic efficacy and side effects while nifedipine was faster than
      magnesium sulfate in arresting uterine contractions (4.8 +/- 4.23 vs. 2.98 +/-
      3.03 h) P = 0.04. CONCLUSION: this data suggests that oral nifedipine with the
      same efficacy, side effects and faster action could be a suitable and more
      convenient alternative to intravenous magnesium sulfate in arresting preterm
      labor.

PMID- 10580683
TI  - Recto-vaginal fistula following coitus: an aftermath of vaginal douching with
      aluminium potassium sulphate dodecahydrate (potassium alum).

PMID- 10580684
TI  - FIGO Committee for the Ethical Aspects of Human Reproduction and Women's Health.
      International Federation of Gynecology and Obstetrics.

PMID- 10580685
TI  - ACOG committee opinion. Scheduled cesarean delivery and the prevention of
      vertical transmission of HIV infection. Number 219, August 1999. Committee on
      Obstetric Practice. American College of Obstetricians and Gynecologists.

PMID- 10580686
TI  - ACOG committee opinion. Breastfeeding and the risk of hepatitis C virus
      transmission. Number 220, August 1999. Committee on Obstetric Practice. American
      College of Obstetricians and Gynecologists.

PMID- 10580688
TI  - The comet assay: a tool to study alteration of DNA integrity in developing plant
      leaves.
AB  - DNA integrity of Nicotiana tabacum L. and Vicia faba L. leaves in different
      stages of growth was analysed with the single cell gel electrophoresis (comet)
      assay. With this test DNA of individual cells is stretched by electrophoresis and
      the migration is measured, which gives an image of the nuclear DNA organisation.
      Nuclei were sampled when the plants had developed an apical bud, five true leaves
      and cotyledons. To get an idea of the kind of lesions observed, three different
      comet protocols were used. The neutral protocol with electrophoresis in a neutral
      buffer and the semi-alkaline or alkaline assay with alkaline unwinding followed
      by electrophoresis in neutral alkaline buffer, respectively. For V. faba there
      was a successive increased cellular DNA mobility with age of the leaves. The
      percentage DNA migration in control cells of fully developed leaves from N.
      tabacum almost reached the same level than after irradiation of not fully
      developed leaves with 50 Gy X-rays. The increased stretching of DNA with leaf age
      was most obvious if the DNA duplex was converted to single strands by alkali
      treatment before electrophoresis. Therefore, it could be concluded that with the
      ageing of leaves there is a decrease in DNA integrity, which could be the result
      of rising amounts of DNA single-strand breaks and 'alkali-vulnerable sites'.

PMID- 10580687
TI  - Age-related alteration of intracellular ATP maintenance in the cell suspensions
      of mice cerebral cortex.
AB  - Neurological alteration in the aging brain has been suggested to be due to, in
      part, a declined cellular energy metabolism. In order to understand age-related
      alteration of intracellular ATP maintenance, the present in vitro study measured
      change of intracellular adenosine triphosphate (ATP) content in cell suspensions
      of cerebral cortex isolated from male ICR mice aged 2 days (infant), 8 weeks
      (young adult) and 12 months (aged) under several different conditions, using the
      chemiluminescence technique. Among the three different ages, significant decrease
      of intracellular ATP content by oxygen deprivation for 15 min was observed in the
      cell suspensions of cerebral cortex from 12-month-old mice (P < 0.05). When cell
      suspensions of 8-week cerebral cortex were incubated with or without glucose (0
      60 min), intracellular ATP content decreased in a time-dependent manner under
      both conditions, but depletion rate was significantly high in the glucose-free
      condition. This decrease was maximally restored by adding 1 mM glucose as tested.
      In addition, the ability for intracellular ATP maintenance in the presence or
      absence of glucose was age-dependently different. The rank order of difference of
      intracellular ATP content between with and without glucose was 3 months > 12
      months > 2 days. The highest decrease of intracellular ATP content by incubation
      without glucose was observed in the 12-month samples. Sodium cyanide (100 microM)
      produced a gradual ATP depletion in cerebral cortex suspended from 2-day-old
      mice, but rapid change in both 8-week and 12-month samples. Combination of
      cyanide and iodoacetate (3.5 mM) rapidly depleted the intracellular ATP content
      in all age groups tested. These results suggest that the aging process in the
      cerebral cortex of mice is accompanied by alteration of maintenance of
      intracellular ATP homeostasis under a given condition, and this may be associated
      with pathological change of overall mechanisms involved in the development of
      neuronal disease in the senescent brain.

PMID- 10580689
TI  - Accumulation of DNA damage in pre- and posthepatectomized liver of aged rats.
AB  - Although the majority of the literature supports the concept that an accumulation
      of DNA damage or a modification in the DNA structure of postmitotic cells occurs
      with increasing age, there are also several reports that show no DNA changes in
      these cells with increasing age. In the study reported here, two components of
      the DNA damage hypothesis of aging were tested. Young (4-6 months) and old (18-20
      month) unirradiated or irradiated, pre- and posthepatectomized male Fisher 344
      rats were killed, and the posterior lateral lobe of the liver removed. Single
      cell/nuclei suspensions were made, and the DNA damage accumulated with age or
      remaining at various times after irradiation was measured using the alkaline
      elution technique. The results demonstrate that, 1) DNA damage accumulates in rat
      liver cells with age, and 2) liver cells repair their radiation-induced DNA
      damage slower in posthepatectomized, but not prehepatectomized aged rats.

PMID- 10580690
TI  - Age-dependent alterations in mRNA level and promoter methylation of collagen
      alpha1(I) gene in human periodontal ligament.
AB  - In an attempt to understand the molecular mechanisms of age-dependent
      degenerative alteration in human periodontal tissues, we examined mRNA level and
      DNA methylation of collagen alpha1(I) gene. Using healthy periodontal ligament
      tissues from humans aged 9-76 years, we found that the collagen alpha1(I) mRNA
      level decreased almost linearly with age. It was observed in both Northern blot
      and dot blot hybridization. Examination of DNA methylation in the collagen
      alpha1(I) gene promoter region by its susceptibility to methylation-sensitive
      restriction enzyme followed by Southern blot analysis showed age-dependent
      increase of DNA methylation at -1705 and -80 positions located upstream of the
      gene. The data suggest the possible importance of alterations in collagen
      alpha1(I) gene expression and its DNA methylation in promoter region in age
      dependent degeneration of periodontal ligament.

PMID- 10580691
TI  - Age-related loss of proliferative activity of human vascular smooth muscle cells
      in culture.
AB  - This work studied the proliferation activity in cultures of vascular smooth
      muscle cells (SMC) from individuals of different ages. The cells derived from
      arteries of 12 donors of both sexes from 45 to 91 years of age. The main
      parameter considered was the 'proliferation rate' (cells grown per day in the
      different culture passages) taking into account the age of the donor. No
      significant relationship between age of the donor and the cell life in
      proliferation was found. On the contrary, the mean time of passage duration for
      reaching the maximum of proliferation as well as its 'efficiency' (maximum of
      proliferation rate registered/mean time of passage duration) show a statistically
      significant dependence on the age of the donor. Furthermore, the proliferation
      rate measured in each passage is statistically significant related to donor age.
      The regressions obtained show a similar negative slope (VC 4%). Considering the
      first five culture passages, the regression crosses the x-axis at the age of
      105.6+/-11.7 years. This age in which no proliferative activity of human SMC
      would be expected lies near the limit of maximum life potential for human beings.
      Our results suggest that with advancing donor age there is an increasing number
      of senescent SMC either primarily transferred or appeared in the culture.
      Vascular SMC of individuals whose life is near the end would almost be all
      senescent and therefore show extremely low proliferation rates in the culture. If
      the proliferative activity of arterial SMC is a condition for atherogenesis, the
      proportion of senescent cells would be inversely related to the propensity of
      developing the atheroma because of the inability of these cells to divide.

PMID- 10580693
TI  - Age-associated changes in the stimulatory effect of transforming growth factor
      beta on human osteogenic colony formation.
AB  - Previous studies have indicated that the mitogenic responsiveness of human bone
      cells may change with age. In the present study, we examined whether aging
      affects the capacity of transforming growth factor beta (TGF-beta) to stimulate
      the colony formation of human osteoprogenitor cells. Outgrowths of bone cells
      from 98 iliac crest biopsies were plated at a density of 25 cells/cm2 and
      cultured for 3 weeks in the presence of 10% fetal calf serum. Approximately 5% of
      the plated cells gave rise to clonal colonies. TGF-beta (10(-11) M) significantly
      increased the estimated number of cells per colony. However, the stimulatory
      effect of TGF-beta significantly declined with donor age (r = -0.26, P = 0.01).
      Whereas TGF-beta raised the average number of cells per colony in cultures from
      donors below the age of 50 years by 136+/-50%, the average increase was only 43+/
      16% in donors older than 60 years. These data raise the possibility that aging
      may be associated with a declining capacity of TGF-beta to enlarge the pool of
      bone cells that can be generated from a single human osteoblast progenitor cell.

PMID- 10580692
TI  - Cysteine sulfinate decarboxylase and cysteine dioxygenase activities do not
      correlate with strain-specific changes in hepatic and cerebellar taurine content
      in aged rats.
AB  - Taurine is a free sulfur-containing amino acid that is found in abundance in
      mammalian tissues and fluids. Many biological roles have been proposed for this
      amino acid, including reducing oxidative stress and cytotoxicity. Taurine has
      previously been reported to decline in tissues during aging which could
      exacerbate an age-related increase in oxidative stress. The aim of the present
      study was to elucidate the mechanism responsible for the observed decline in
      tissue taurine content. We measured the activity of the major taurine
      biosynthetic enzymes, cysteine sulfinate decarboxylase and cysteine dioxygenase,
      in liver and cerebellar tissues of rats. Tissues from male adult and aged Fischer
      344 (F344; 10 and 28 months), Sprague-Dawley (SD; 5, 20 and 25 months), and
      F344/Brown-Norway hybrid (FBNF1; 14 and 33.5 months) rats were used. We observed
      a significant decline in hepatic taurine content of the F344 animals but the
      decline in the liver of SD and FBNF1 animals was non-significant. Hepatic
      cysteine sulfinate decarboxylase and cysteine dioxygenase activities were
      significantly lower in aged F344 rats but not in the other strains. Cerebellar
      taurine content was significantly lower in aged F344 and SD rats without a
      concomitant decline in cysteine sulfinate decarboxylase activity. These results
      suggest that a decline in hepatic de novo taurine biosynthesis might be partially
      responsible for a reduction in tissue taurine content in F344 rats.

PMID- 10580695
TI  - Theoretical Gompertzian implications on life span variability among genotypically
      identical animals.
AB  - Aging is a highly polygenic trait (Kirkwood, T.B.L., Franceschi, C., 1992. Is
      aging as complex as it would appear? Annals of the New York Academy of Sciences
      663, 412-417) who's underlying mechanisms are still unresolved. Animal models are
      an important help for understanding this process and a recent report drew
      attention to a putative gene which causes variability in the life span among
      genotypically identical mice (de Haan, G., Gelman, R., Watson, A., Yunis, E., van
      Zant, G., 1998. A putative gene causes variability in life span among
      genotypically identical mice. Nature Genetics 19, 114-116). De Haan et al.
      observed that the time between the death of the first and last member of a group
      of inbred mice (the death range) is controlled by a locus, which they mapped to
      chromosome 11. The authors conclude that well-known effects like modifiers,
      suppressors or epistatic genes might not be able to explain how this variability
      in genetically identical organisms is generated and that such a trait has broad
      implications for genetic studies of the aging process. Here we give a possible
      answer to the question of what mechanism could cause such a phenotype. We show
      that all genes which affect the Gompertz parameters are possible candidates.

PMID- 10580694
TI  - The effect of dietary fat on malondialdehyde concentrations in Fischer 344 rats.
AB  - The effects of dietary fat and age on the level of malondialdehyde (MDA), a
      product of lipid peroxidation, were investigated in cerebellum, kidney, and liver
      tissues of female Fischer 344 rats. Groups of rats were fed diets containing
      various levels of corn oil (3, 5, 10, 15, or 20%), starting at 57 days of age,
      for a duration of 2, 10, or 20 weeks. High fat diets are thought to promote tumor
      formation, diabetes, and cardiovascular diseases via induction of oxidation
      stress, and this can begin early in the lifespan. However, it was observed that
      rats chronically consuming 3 and 5% corn oil diets yielded significantly higher
      levels of MDA, as analyzed by high-performance liquid chromatography, compared
      with those fed higher fat diets. After 20 weeks of feeding, the concentration of
      MDA in each of the three organs studied showed no significant differences among
      rats consuming diets containing 10, 15, or 20% corn oil. The levels of MDA were
      highest in the cerebellum, followed by kidney, and lowest in liver. Over the 20
      week feeding period, a decrease in MDA level in both cerebellum and liver was
      observed.

PMID- 10580696
TI  - Resistance of the aged myocardium to exercise-induced chronic changes in glucose
      transport related protein content.
AB  - The effects of acute exercise on myocardial content of glut-1 and glut-4
      transporters, insulin and IGF-1 receptors were assessed in control and
      chronically exercised 24-month-old C57B1/6 mice. Myocardial glut-1, glut-4,
      insulin receptor (Ins R) and insulin like growth factor-1 receptor (IGF-1 R)
      protein levels were unaffected by 36 weeks of chronic exercise. However,
      myocardial protein content of glut-1, but not glut-4, was increased 12 h
      following an acute exercise bout in control (46%) and chronically exercised (83%)
      aged animals. This increased glut-1 response following acute exercise occurred
      despite the finding that the chronic exercise failed to increase cardiac or
      skeletal muscle oxidative capacity as indicated by no change in citrate synthase
      activity. Myocardial IGF-1 R content was unaffected by acute exercise whereas Ins
      R protein content was decreased 12 h following the acute exercise bout in the
      chronically exercised (-52%) and control (-28%) animals. The effect of acute
      exercise on the protein content of glut-1 and Ins R was 80 and 84% greater
      respectively, in the chronically exercised animals. This suggests that the
      amplitude of the expression of these two proteins may be increased by chronic
      exercise, thus constituting a form of adaptation.

PMID- 10580697
TI  - The DLP1 mutant of the yeast Saccharomyces cerevisiae with an increased copy
      number of the 2micron plasmid shows a shortened lifespan.
AB  - We isolated and characterized a recessive mutant, named dlp1, which shows the Dlp
      phenotype (delayed loss of proliferation activity) during the autophagic death of
      cdc28. The dip1 mutant was found to consist of two subtypes of cells based on
      colony morphology. One subtype with the Dlp phenotype, named dlp1-1, became
      large, red, and nibbled during the incubation, suggesting that the cells on the
      surface of the colonies were dying. The other without the Dlp phenotype, named
      dlp1-s, retained small, white colonies even after a prolonged incubation and was
      found to be a petite mutant. The change from dlp1-1 to dlp1-s (petite) occurred
      much more frequently (about 15%) than that from the wild-type to petite mutant
      (less than 1%). The lifespan of both subtypes of cells was severely shortened.
      The copy number of the endogenous 2micron plasmid of dlp1-1 was 68-fold that of
      the original cdc28, and decreased by half after the conversion to dlp1-s
      (petite). A 4.0-kbp fragment of the 2micron plasmid containing REP2 decreased the
      copy number of the endogenous 2micron plasmid to 8-fold that of the original
      cdc28 cells and partially rescued the shortened lifespan, in addition to
      resulting in the complete complementation of the Dlp and nibbled-colony
      phenotypes. These results suggest that DLP1 is a chromosomal gene that regulates
      the copy number of the 2micron plasmid, and that the shortening of the lifespan
      and other effects of the dlp1 mutation are likely caused by the increased copy
      number of the endogenous 2micron plasmid.

PMID- 10580698
TI  - Protein kinase C inhibition has only a transient growth arresting effect on in
      vitro regenerating mouse sensory neurons.
AB  - Adult mice sensory ganglia were cultured in an extracellular matrix gel. Analyses
      of extending axons were made 48 h (long-term) or immediately (short-term) after
      addition of protein kinase inhibitors. Long- and short-term growth was
      insensitive to protein kinase A/G inhibition by HA-1004. Long-term protein kinase
      C inhibition by chelerythrine affected only certain, long axons. In the short
      term virtually all axon growth was arrested, but largely recovered on the
      following day. When combined, the drugs inhibited all long- and short-term growth
      and largely prevented the recovery of the latter. The transient effect by
      chelerythrine, and the permanent inhibition after combination with HA-1004,
      suggests compensatory mechanisms, perhaps via other kinases.

PMID- 10580699
TI  - Increased levels of tau-like protein in patients with Down syndrome.
AB  - Tau-like protein levels from 40 Down syndrome (DS) persons (31-70 years old), 40
      non-DS age-matched normal controls, 18 non-DS mentally retarded (MR) persons (26
      91 years old), 25 probable Alzheimer disease (AD) patients (55-99 years old) and
      24 non-demented elderly controls (54-79 years old) were measured using a sandwich
      enzyme linked immunosorbent assay. The levels were detected in 22 of 40 DS
      persons and were significantly higher in DS than any other group (P < 0.0001).
      There was no relationship between tau-like protein levels and age, gender or
      apolipoprotein E phenotypes in any of the five groups.

PMID- 10580700
TI  - Sr2+ induce a release of divalent cation from internal Ca2+ store by nerve
      stimulation at frog neuromuscular junction.
AB  - The effects of Sr2+ on the transmitter release at the frog neuromuscular junction
      were examined electrophysiologically. The nerve trunk was stimulated by paired
      pulses at various time intervals after replacing extracellular Ca2+ by Sr2+, the
      paired-pulse facilitation at the 10 ms interval was smaller than that at 20-30 ms
      intervals. Administration of several intracellular Ca2+ mobilizers decreased the
      paired-pulse facilitation. These results suggest that the transmitter release in
      Sr2+ solution is caused, at least partly, by the release of divalent cations from
      the intracellular stores.

PMID- 10580701
TI  - Pre-ischemic depletion of brain norepinephrine decreases infarct size in
      normothermic rats exposed to transient focal cerebral ischemia.
AB  - This study examined the importance of brain norepinephrine concentration on
      outcome from a focal ischemic insult. Fasted temperature-controlled male Wistar
      rats pretreated with DSP-4, (N-(chloroethyl)-N-ethyl-2-bromobenzylamine), to
      selectively deplete brain norepinephrine, were subjected to reversible filament
      occlusion of the middle cerebral artery for 75 min in the awake state. After 3
      days recovery, total infarct volume in DSP-4 treated rats (185 +/- 107 mm3) was
      reduced vs. untreated control animals (242 +/- 71 mm3, P = 0.04). Subcortical
      infarct volume was also smaller in the DSP-4 group (93 +/- 44 vs. 121 +/- 28 mm3,
      P = 0.02). Cortical infarct volume was not statistically different between
      groups. Neurologic function correlated with infarct-size. These findings suggest
      that brain norepinephrine affects stroke development either by direct neuronal
      toxicity and/or through influences on the penumbral circulation. Dampening of the
      central stress response induced by the onset of stroke may thus be advantageous.

PMID- 10580702
TI  - The regulation of externally paced human locomotion in virtual reality.
AB  - The goal of the present experiment was to study regulation of human locomotion
      under externally paced temporal constraints. On a screen placed in front of a
      treadmill a virtual hallway was projected (Silicon Graphics systems) in which a
      pair of doors were presented that continuously opened and closed at a rate of 1
      Hz. Subjects were attached to a locometer and instructed to regulate walking pace
      such that the doors were passed correctly. Performance outcome, movement
      kinematics (stride duration, stride length and synchronization of stride and door
      cycles) and flow patterns (change in visual angle of door aperture) were used to
      examine the data. The analysis of the synchronization patterns indicates that
      stride cycles were not linked to the period of door oscillation. Moreover,
      results for stride duration reveal that subjects walked at their preferred speed
      up to the final phase of the approach. This observation is supported by the
      inspection of the flow patterns, revealing a final increase in variability as a
      result of regulation. In sum, regulation of locomotion under externally paced
      temporal constraints seems to generate a specific functional behavior. It appears
      that regulations are postponed until the final stage of the approach during which
      adaptations are made according to the requirements of the current situation.

PMID- 10580703
TI  - Diabetes alters neurite regeneration from mouse retinal explants in culture.
AB  - We examined the effect of experimental diabetes on neurite regeneration from
      adult mouse retinal explants cultured in the presence of different concentrations
      of glucose. The numbers of regenerating neurites at 3, 6 and 10 days in culture
      at normal glucose concentration (7 mM) were significantly smaller in
      streptozotocin-induced diabetic C57BL/6 mice than in normal control mice. In
      contrast, treatment of retinal explants with high glucose concentration (57 mM)
      significantly diminished the number of regenerating neurites in the control mice,
      but not in the diabetic mice. These results suggest that retina in diabetic mice
      has impaired capability of neurite regeneration in a normal glucose environment,
      but is adaptable to a high glucose environment in vitro.

PMID- 10580704
TI  - Increase in bombesin-like peptides in the spinal cord after dexamethasone
      treatment of adrenalectomized rats.
AB  - The potential influence of corticosteroids on the bombesin (BN)-like peptide
      family is unknown. Therefore, the effects of adrenalectomy (ADX) on the nervous
      system of Sprague-Dawley rats, some of them being treated with high doses of the
      synthetic glucocorticoid dexamethasone (DEX), were investigated. After 8-10 days
      of treatment, the rats were sacrificed and tissues were prepared for
      radioimmunoassay (RIA) and immunohistochemical examination. We found an increase
      in BN-like immunoreactivity in the superficial layers of the dorsal horn of the
      lumbar spinal cord in the ADX + DEX animals. This increase was confirmed by RIA
      (P < 0.05). The observations show that the expression of BN-like peptides is
      influenced by glucocorticoids. The altered levels of BN-like peptides may be
      related to the trophic and antinociceptive effects previously reported for these
      peptides.

PMID- 10580705
TI  - Identification of a novel polymorphism in the promoter region of the tau gene
      highly associated to progressive supranuclear palsy in humans.
AB  - An intronic polymorphism and other changes in the transcribed region of the tau
      gene forming a haplotype have been previously described associated to progressive
      supranuclear palsy (PSP). These results raised the possibility that a change at
      or near the tau gene could be responsible for an increased risk to develop PSP.
      We initiated the present work in research for potential changes in the promoter
      region of the tau gene that could further extend the previously described
      haplotype. The tau promoter region was analyzed through single strand
      conformation polymorphism followed by direct sequencing in PSP patients (n = 35),
      in controls (n = 195) and in Alzheimer's disease (AD; n = 74) patients. We have
      been able to identify a G to C change at position -221 of the tau gene promoter
      region. The CC genotype has been detected to be present with a significantly
      higher frequency in PSP patients (91.4%; P < 0.00001; OR = 11.8), but not in AD
      patients, as compared with controls (49.74%). Subsequently we have detected that
      the CC -221 tau promoter genotype is significantly associated to the tau intronic
      A0/A0 genotype (P < 0.00001). The detected -221 tau G to C change occurs within a
      potential c-myb proto-oncogene element present in the promoter region. Thus, in
      addition to extending the previously described haplotype associated to PSP, this 
      221 G to C change is an interesting candidate that could provide a potential
      explanation for the association of the haplotype to increased risk for developing
      PSP.

PMID- 10580706
TI  - Suppressive action produced by beta-amyloid peptide fragment 31-35 on long-term
      potentiation in rat hippocampus is N-methyl-D-aspartate receptor-independent:
      it's offset by (-)huperzine A.
AB  - Extracellular recordings of field potential from CA1 region of rat hippocampal
      slices were used to observe the effects of a shorter synthetic fragment of beta
      amyloid peptide (A beta31-35) on the induction of long-term potentiation (LTP)
      and the action of (-)huperzine A, a potent acetylcholinesterase (AChE) inhibitor
      on these processes was also observed. The results showed that: (1) 0.1 microM A
      beta31-35 suppressed the induction of LTP in a similar mode as the longer
      fragment A beta25-35, did, while they did not change the amplitude of the
      baseline population spike (PS); (2) when PSs were recorded separately in Mg2+
      free medium, which unveils the N-methyl-D-aspartate (NMDA)-mediated responses,
      both A beta31-35 and A beta25-35 showed little effect on the components of
      multiple PSs; (3) two concentrations of 0.1 microM or 1.0 microM (-)huperzine A
      showed no effects on the PS amplitude while the latter could enhance the LTP and
      (4) co-administration of (-)huperzine A with 0.1 microM concentration could block
      most of the suppressive action induced by A beta31-35 or A beta25-35 upon the
      LTP. The results suggest that the shorter fragment A beta31-35, is long enough to
      suppress the induction of LTP and these two fragments might suppress the
      induction of LTP through a NMDA receptor-independent pathway that involves
      cholinergic terminals in hippocampus.

PMID- 10580707
TI  - Immunoglobulins induce increased myelin debris clearance by mouse macrophages.
AB  - The present study investigated the effect of human immunoglobulins on migration
      and myelin phagocytosis by macrophages. Mouse sciatic nerves and macrophages were
      cocultured and treated with 1, 10 and 20 mg/ml immunoglobulins for 10 days in
      vitro. Numbers of invading macrophages, myelin density within the nerves and
      macrophage myelin load were determined in semithin sections. Human
      immunoglobulins lead to an increased myelin removal by macrophages as proven by a
      statistically significant higher myelin load of the macrophage cytoplasm when
      compared with untreated control macrophages. The results suggest that one
      possible action of immunoglobulins in demyelinating diseases is an improved
      clearance of lesional debris with the removal of myelin-associated inhibitory
      molecules.

PMID- 10580708
TI  - Lesions of the rat piriform cortex prevent long-lasting sensorimotor gating
      deficits induced by stimulation of the ventral hippocampus.
AB  - Prepulse inhibition (PPI) is a cross-species operational measure of sensorimotor
      gating. Reduced PPI is found in schizophrenics and can be induced experimentally
      in rats. Stimulation of the rat ventral hippocampus (VH) with N-methyl-D
      aspartate (NMDA) results in long-lasting PPI deficits (carry-over effect). Since
      we have previously shown that this carry-over effect was accompanied by increased
      expression of c-Fos in the piriform cortex (PIR), we here tested the effects of
      lesions of the PIR on PPI after stimulation of the VH. PIR lesioned rats still
      showed disruption of PPI after injection of NMDA into the VH. However, the carry
      over effect observed in controls was prevented by PIR lesions. These data suggest
      that the PIR is important for long-lasting alterations in brain functioning
      leading to impaired sensorimotor gating.

PMID- 10580709
TI  - Nitric oxide release from substantia gelatinosa of the rat spinal cord in vitro.
AB  - To study characteristics of nitric oxide (NO) release from substantia gelatinosa
      (SG) in the spinal cord, we measured NO concentration in transverse spinal cord
      slices of rats using electrochemical NO probes. Electrical stimulation of the
      dorsomedial white matter adjacent to SG elicited transient current changes in NO
      probes placed on SG and the amplitude corresponded to a NO concentration of 200
      300 pM. This NO release was not affected by the application of antagonists of
      glutamate or substance P receptors. The NO release in the rats, which were
      neonatally treated with capsaicin for denervating C-fibers, was significantly
      smaller than that in control rats. These data suggest that NO is mainly derived
      from the unmyelinated afferent nerves in the SG of the spinal cord.

PMID- 10580710
TI  - Rat primary cultured microglia express glial cell line-derived neurotrophic
      factor receptors.
AB  - The neurotrophic effect of glial cell line-derived neurotrophic factor (GDNF) has
      been well documented in both the central and peripheral nervous systems. From the
      histological findings, target cells of GDNF have been considered to be neurons.
      In the present study, the expression of GDNF receptors, ret and GFRalpha-1, was
      demonstrated in rat primary cultured microglia by reverse transcription
      polymerase chain reaction and the protein-level expression of Ret was also
      confirmed by Western-blotting analyses. Moreover, GDNF stimulated the
      phosphorylation of MAP kinase (ERK1/2) in the cells. These results suggest that
      GDNF regulates not only neuronal survival and maturation but also certain
      functions of microglia in the brain.

PMID- 10580711
TI  - Pulsed high-frequency electromagnetic field affects human sleep and sleep
      electroencephalogram.
AB  - To investigate whether the electromagnetic field (EMF) emitted by digital
      radiotelephone handsets affects the brain, healthy, young subjects were exposed
      during an entire night-time sleep episode to an intermittent radiation schedule
      (900 MHz; maximum specific absorption rate 1 W/kg) consisting of alternating 15
      min on-15-min off intervals. Compared with a control night with sham exposure,
      the amount of waking after sleep onset was reduced from 18 to 12 min. Spectral
      power of the electroencephalogram in non-rapid eye movement sleep was increased.
      The maximum rise occurred in the 10-11 Hz and 13.5-14 Hz bands during the initial
      part of sleep and then subsided. The results demonstrate that pulsed high
      frequency EMF in the range of radiotelephones may promote sleep and modify the
      sleep EEG.

PMID- 10580712
TI  - Sigmoidal admission rate-dependence of toluene narcotic potency in rats:
      comparison with nitrous oxide.
AB  - Aromatic solvents, such as toluene, can cause depression of the central nervous
      system functions in both solvent-exposed workers and abusers. The mechanism by
      which toluene produces its effects is generally thought to be similar to that
      produced by general anaesthetics, including inert gases and alcohols. However,
      whether lipophilic compounds indirectly influence activity by perturbing membrane
      lipids or bind directly to proteins remains a major question. In a recent study,
      the sigmoidal admission rate-dependence of inert gas anaesthetic potency has been
      suggested to possibly reflect a direct narcotic-protein interaction. Therefore,
      experiments have been carried out using seven input toluene flows of 0.5, 1, 2,
      3, 4, 5 and 6 l/min. Our results indicate that as the rate of toluene delivery
      increased, the concentration of toluene required to produce anaesthetic effects
      increased. Although this was fitted relatively well with linear regression, this
      fitted better when using a sigmoidal model (r = 0.998 vs. r = 0.971, P < 0.01).
      In addition, comparison with previous data on nitrous oxide shows a striking
      similarity between plots (r = 0.991) which appears consistent with a similar site
      of action for both agents. We suggest that all classes of lipophilic agents could
      produce their inhibitory effects at similar 'non-specific' sites of action of
      finite size and limited occupancy.

PMID- 10580713
TI  - A stereological study on the neuroprotective actions of acute modafinil treatment
      on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced nigral lesions of the
      male black mouse.
AB  - The effect of an acute administration of the vigilance-promoting drug modafinil
      ((+/-)(diphenyl-methyl)-sulfinyl-2 acetamide; Modiodal) on the nigrostriatal
      dopamine system was studied after damage induced by MPTP (1-methyl-4-phenyl
      1,2,3,6-tetrahydropyridine) by means of immunohistochemistry for tyrosine
      hydroxylase (TH) and a stereological method. MPTP (40 mg/kg) reduced from 24,380
      +/- 902 to 13,501 +/- 522 and from 37,868 +/- 3300 to 20,568 +/- 1270,
      respectively, the number of TH immunoreactive (IR) and non-TH IR nigral neurons.
      Co-administration of Modafinil restored to normal the number of these neuronal
      populations. MPTP treatment induced also a reduction in the volume of TH IR
      neurons, which was counteracted by Modafinil administration. The data provide
      morphological evidence, based on unbiased stereological analysis, for a potential
      neuroprotective role of Modafinil, not only in dopaminergic neurons, but also
      with a similar magnitude in the non-DA nerve cell population of the substantia
      nigra after MPTP lesion. These results suggest that Modafinil has a
      neuroprotective role in the substantia nigra via a still undefined mechanism in
      which a crucial role of DA uptake blockade should be excluded. Modafinil may
      therefore have a therapeutic potential in neurodegenerative processes such as
      those occurring in Parkinson's disease.

PMID- 10580714
TI  - The organization of rapid eye movement activity during rapid eye movement sleep
      is impaired in the elderly.
AB  - Rapid eye movement activity (REMA) during rapid eye movement activity (REM) sleep
      was studied in eight elderly subjects and six young adults as a control group.
      Beyond global quantitative features (REMA density), we evaluated the
      organizational aspects of REMA, that is its occurrence in burst mode, still
      largely unknown in the aged. REMA density in the elderly is not significantly
      different than that of young adults. By contrast, the duration of REMA bursts is
      reduced in the elderly, as well as the 'burst state-to-burst-state' probability,
      i.e. the probability for successive inter-REMA time intervals to be part of the
      same REMA burst. These results show that global aspects of the quantitative
      features of REMA are preserved in the elderly, whereas their organizational
      aspects are impaired. These data are consistent with the hypothesis that aging is
      associated with a difficulty in maintaining physiological processes over time.

PMID- 10580715
TI  - Analysis of music-brain interaction with simultaneous measurement of regional
      cerebral blood flow and electroencephalogram beta rhythm in human subjects.
AB  - To elucidate the neural substrates of the receptive aspect of music, we measured
      regional cerebral blood flow (rCBF) with positron emission tomography (PET) and
      simultaneously recorded the electroencephalogram (EEG) in eight normal
      volunteers. Compared with the rest condition, listening to music caused a
      significant increase in EEG beta power spectrum (13-30 Hz) averaged over the
      posterior two third of the scalp. The averaged beta power spectrum was positively
      correlated with rCBF in the premotor cortex and adjacent prefrontal cortices
      bilaterally, the anterior portion of the precuneus and the anterior cingulate
      cortex in both the rest and the music conditions. Listening to music newly
      recruited the posterior portion of the precuneus bilaterally. This may reflect
      the interaction of the music with the cognitive processes, such as music-evoked
      memory recall or visual imagery.

PMID- 10580716
TI  - Different types of synapses with different spectral types of cones underlie color
      opponency in a bipolar cell of the turtle retina.
AB  - Electrophysiologically, color-opponent retinal bipolar cells respond with
      opposite polarities to stimulation with different wavelengths of light. The
      origin of these different polarities in the same bipolar cell has always been a
      mystery. Here we show that an intracellularly recorded and HRP-injected, red-ON,
      blue/green-OFF bipolar cell of the turtle retina made invaginating (ribbon
      associated) synapses exclusively with L-cones. Non-invaginating synapses
      resembling wide-cleft basal junctions were made exclusively with M-cones. Input
      from S-cones was not seen. From these results we suggest sign-inverting
      transmission from L-cones at invaginating synapses via metabotropic glutamate
      receptors, and sign-conserving transmission from M-cones at wide-cleft basal
      junctions via ionotropic receptors. To explain the pronounced blue sensitivity of
      the bipolar cell, computer simulations were performed using a sign-conserving
      input from a yellow/blue chromaticity-type (H3) horizontal cell. The response
      properties of the red-ON, blue/green-OFF bipolar cell could be quantitatively
      reproduced by this means. The simulation also explained the asymmetry in L- and M
      cone inputs to the bipolar cell as found in the ultrastructural analysis and
      assigned a putative role to H3 horizontal cells in color processing in the turtle
      retina.

PMID- 10580717
TI  - Electrical coupling of retinal horizontal cells mediated by distinct voltage
      independent junctions.
AB  - Electrical coupling between H2 horizontal cell pairs isolated from the hybrid
      bass retina was studied using dual whole-cell, voltage-clamp technique. Voltage
      dependent inactivation of junctional currents in response to steps in
      transjunctional voltage (Vj) over a range of +/-100 mV was characterized for 89
      cell pairs. Approximately one-quarter of the pairs exhibited strongly voltage
      dependent junctions (>50% reduction in junctional current at +/-100 mV), another
      quarter of the pairs exhibited voltage-independent junctional current (<5%
      reduction at +/-100 mV), and the remainder of the pairs exhibited intermediate
      values for voltage inactivation. We focused on further characterizing the Vj
      independent junctions of horizontal cells, which have not been described
      previously in detail. When Lucifer Yellow dye was included in one recording
      pipette, pairs exhibiting Vj-independent coupling showed no (9/12), or limited
      (3/12), passage of dye. Vj-independent coupling was markedly less sensitive to
      the modulators SNP (100-300 microM, -9% reduction in coupling) and dopamine (100
      300 microM, -6%) than were Vj-dependent junctions (-45% and -44%). However,
      simultaneous application of both SNP and dopamine significantly reduced Vj
      independent coupling (-56%). Both Vj-independent and Vj-dependent junctions were
      blocked by DMSO (1-2%), but Vj-independent junctions were not blocked by
      heptanol. Single-channel junctional conductances of Vj-independent junctions
      range from 112-180 pS, versus 50-60 pS for Vj-dependent junctions. The results
      reveal that Vj-independent coupling in a subpopulation of horizontal cells from
      the hybrid bass retina is mediated by cellular junctions with physiological and
      pharmacological characteristics distinct from those previously described in fish
      horizontal cells.

PMID- 10580718
TI  - Preganglionic endings from nucleus of Edinger-Westphal in pigeon ciliary ganglion
      contain neuronal nitric oxide synthase.
AB  - The avian ciliary ganglion (CG) controls choroidal blood flow by its choroidal
      neurons, and pupil constriction and accommodation by its ciliary neurons. It was
      previously reported that both choroidal and ciliary neurons label positively for
      NADPH diaphorase (NADPHd), a marker for nitric oxide synthase (NOS). To assess if
      this labeling is preganglionic or postganglionic and to determine if it is
      attributable to neuronal NOS (nNOS), we studied pigeon CG using NADPHd
      histochemistry and nNOS immunohistochemistry (IHC). Short-duration staining times
      by NADPHd histochemistry yielded intense labeling of structures that appeared to
      be the cap-like endings on ciliary neurons and the boutonal endings on choroidal
      neurons that arise from the nucleus of Edinger-Westphal (EW), and light or no
      postganglionic perikaryal staining. The light postganglionic staining that was
      observed tended to be localized to ciliary neurons. Consistent with this, NADPHd+
      nerve fibers were observed in the postganglionic ciliary nerves but rarely in the
      postganglionic choroidal nerves. These same staining times yielded robust
      staining of neurons in the orbital pterygopalatine microganglia network, which
      are known to be nNOS+. Diffuse staining of CG perikarya was observed with longer
      staining durations, and this staining tended to mask the preganglionic labeling.
      Preganglionic NADPHd+ staining in CG with short staining times was blocked by the
      NOS inhibitors iodonium diphenyl (IDP) and dichlorophenol-indophenol (DPIP), but
      the diffuse postganglionic staining observed with the longer staining times was
      not completely blocked. Labeling of CG sections for substance P (SP) by IHC
      (which labels EW-originating preganglionic endings in CG) and subsequently for
      NADPHd confirmed that NADPHd was localized to preganglionic endings on CG
      neurons. Immunohistochemical double labeling for nNOS and SP or enkephalin
      further confirmed that nNOS is found in boutonal and cap-like endings in the CG.
      Two studies were then carried out to demonstrate that the nNOS+ preganglionic
      endings in CG arise from EW. First, NADPHd+ and nNOS+ neurons were observed in EW
      in pigeons treated with colchicine to enhance perikaryal labeling. Second,
      NADPHd+ and nNOS+ preganglionic endings were eliminated from CG ipsilateral to an
      EW lesion. These various results indicate that NOS is present in EW-arising
      preganglionic endings on choroidal and ciliary neurons in avian CG. NOS also
      appears to be found in some ciliary neurons, but its presence in choroidal
      neurons is currently uncertain.

PMID- 10580719
TI  - AMPA receptor kinetics limit retinal amacrine cell excitatory synaptic responses.
AB  - Amacrine cells that respond transiently to maintained illumination are thought to
      mediate transient inhibitory input to ganglion cells. The excitation of these
      transient amacrine cells is thought to be limited by inhibitory feedback to
      bipolar cells. We investigated the possibility that desensitizing AMPA and/or
      kainate (KA) receptors on amacrine cells might also limit the duration of
      amacrine cell excitation. To determine how these receptors might affect amacrine
      cell input and output, we made whole-cell recordings from amacrine and ganglion
      cells in the salamander retinal slice. The specific AMPA receptor antagonist GYKI
      53655 blocked non-NMDA receptor-mediated amacrine cell excitatory postsynaptic
      currents (EPSCs) and kainate puff-elicited currents, indicating that AMPA, and
      not KA, receptors mediated the responses. Cyclothiazide, an agent that reduces
      AMPA receptor desensitization, increased the amplitude and duration of amacrine
      cell EPSCs. To measure the output of transient amacrine cells, we recorded
      glycinergic inhibitory postsynaptic currents (IPSCs) from ganglion cells, and
      found that these were also enhanced by cyclothiazide. Thus, prolongation of
      amacrine cell AMPA receptor activation enhanced amacrine cell output. Current
      responses elicited by puffing glycine onto ganglion cell dendrites were not
      affected by cyclothiazide, indicating that the enhancement of glycinergic IPSCs
      was not due to a direct effect on glycine receptors. These data suggest that
      rapid AMPA receptor desensitization and/or deactivation limits glycinergic
      amacrine cell excitation and the resulting inhibitory synaptic output.

PMID- 10580720
TI  - Circadian organization in quail retina: differential regulation of melatonin
      synthesis and iodopsin gene expression in vitro.
AB  - Adult Japanese quail have an endogenous circadian clock located in their eyes
      that has been shown to regulate melatonin biosynthesis. We investigated if a
      circadian oscillator is present in cultures of dispersed embryonic quail retina.
      Melatonin release in retinal cell culture is modulated by the light cycle,
      indicating that there are functional photoreceptors in culture. However, when
      cultures were placed in constant darkness no rhythm of melatonin was observed,
      indicating that at this period of development the circadian oscillator does not
      influence melatonin release. To explore further the question of whether a
      circadian oscillator is present in embryonic cell culture, we examined expression
      of iodopsin, the red visual pigment. Iodopsin mRNA is expressed in a circadian
      rhythm with peak levels occurring late in the afternoon (ZT 9). Analysis
      indicates that the clock influence is at the level of gene transcription. These
      results suggest that a clock is not "hooked up" to melatonin release
      embryonically or that a different oscillator regulates photopigment expression
      versus melatonin release.

PMID- 10580721
TI  - Projections from V1 to lateral suprasylvian cortex: an efferent pathway in the
      cat's visual cortex that originates preferentially from CO blob columns.
AB  - The patchy pattern of retrograde labeling produced by injections of anatomical
      tracers into the lateral suprasylvian (LS) visual area was compared to the
      cytochrome oxidase (CO) blobs in cat visual cortex. Following large injections of
      anatomical tracers in LS, retrograde labeling formed an irregular lattice of
      patches with a spacing of slightly less than 1 mm in area 17, and slightly
      greater than 1 mm in area 18. By comparing labeling in alternate serial sections,
      patches of LS-projecting cells in both areas were found to align with CO blobs.
      The conclusion of alignment between CO blob columns and patches of LS-projecting
      cells was confirmed by a quantitative analysis which showed a significant
      correlation between the local density of LS-projecting cells in reconstructions
      of charted cells and the intensity of CO staining in the CO-reacted sections. As
      for areas 17 and 18, labeling in other afferent areas of LS was also patchy with
      a spacing on the order of 1 mm except for area 19 where we found patches of LS
      projecting cells with a larger spacing, roughly 2 mm. No matching fluctuations in
      CO density could be discerned in area 19, however. In conjunction with recent
      evidence that CO blob columns in cats receive strong input from Y-cells of the
      lateral geniculate nucleus (Boyd & Matsubara, 1996; Shoham, et al., 1996), these
      data support the hypothesis (Shipp & Grant, 1991) that the patches of LS
      projecting cells correspond to Y-cell input columns. As a relationship between
      the CO architecture and certain classes of efferent cells has previously been
      shown in primates, these findings show new similarities between CO blobs in
      different mammalian species.

PMID- 10580722
TI  - Large retinal ganglion cells that form independent, regular mosaics in the
      bufonoid frogs Bufo marinus and Litoria moorei.
AB  - Population-based methods were used to study labeled retinal ganglion cells from
      the cane toad Bufo marinus and the treefrog Litoria moorei, two visually
      competent bufonoid neobatrachians with contrasting habitats. In both, cells with
      large somata and thick dendrites formed distinct types with independent mosaics.
      The alpha(a), alpha(ab), and alpha(c) mosaics of Bufo in all major respects
      resembled those of ranids, studied previously, and could be provisionally matched
      to the same functional classes. As in other frogs, some alpha(a) cells were
      displaced and many alpha-cells of all types were asymmetric, but within each type
      all variants belonged to one mosaic. Nearest-neighbor analyses and spatial
      correlograms confirmed that all three mosaics were regular and independent. In
      Litoria, monostratified alpha(a) cells were not found. Instead, two bistratified
      types were present, distinguished individually by soma size and dendritic caliber
      and collectively by membership of independent mosaics: the larger (approximately
      0.8% of all ganglion cells) was termed alpha1(ab) and the smaller (approximately
      2.2%) alpha2ab. An alpha(c) cell type was also present, although too inconstantly
      labeled for mosaic analysis. Nearest-neighbor analyses and spatial correlograms
      confirmed that the two alpha(ab) mosaics were regular and independent. Densities,
      proportions, soma sizes, and mosaic statistics are tabulated for each species.
      The emergence of a consensus pattern of alpha-cell types in fishes and frogs,
      from which this treefrog partly diverges, offers new possibilities for studying
      correlations between function, phylogeny, ecology, and neuronal form.

PMID- 10580723
TI  - ERG assessment of zebrafish retinal development.
AB  - Research has shown that adult zebrafish have a complex visual system, with two
      possible opponent mechanisms. Anatomically, zebrafish retina develops in a
      sequential manner and is immature at hatching. The purpose of the present study
      was to assess zebrafish retinal development using the electroretinogram (ERG).
      ERG responses to visual stimuli were obtained from 4-5, 6-8, 13-15, and 21-24
      days postfertilization (dpf) zebrafish. Individual waveforms were assessed and
      compared across the four age groups. Spectral-sensitivity functions were
      calculated for the a- and b-wave components of the ERG response. Results showed
      that the ERG waveforms and spectral-sensitivity functions varied with age. While
      the 21-24 dpf subjects had an ERG waveform that was similar to that of adults,
      the younger subjects did not. Although there were modest differences in the a
      wave spectral sensitivity, substantial differences were found in the b-wave
      spectral sensitivities across the ages. There was a consistent strong response to
      ultraviolet wavelengths, while across the remaining parts of the spectrum, there
      was a gradual increase in sensitivity with age. Also, the 21-24 dpf subjects
      appear to have adult-like U- and S-cone functions, but were missing the L-M and
      the M-S opponent mechanisms found in the adult. These results support the
      findings of the anatomical studies and demonstrate that the zebrafish is a useful
      model for examining the development of retinal function.

PMID- 10580724
TI  - Dual actions of isthmic input to tectal neurons in a reptile, Gekko gekko.
AB  - We analyzed postsynaptic potentials and dye-labeled morphology of tectal neurons
      responding to electrical stimulation of the optic nerve and of the nucleus isthmi
      in a reptile, Gekko gekko, in order to compare with previously reported
      interactions between the optic tectum and the nucleus isthmi in amphibians and
      birds. The results indicate that isthmic stimulation exerts inhibitory and
      excitatory actions on tectal cells, similar to dual isthmotectal actions in
      amphibians. It appears that dual actions of the isthmotectal pathway in
      amphibians and reptiles are shared by two subdivisions of the nucleus isthmi in
      birds. The morphology of tectal cells responding to isthmic stimulation is
      generally similar to that of tectoisthmic projecting neurons, but they differ
      particularly in that some tectoisthmic cells bear numerous varicosities whereas
      cells receiving isthmic afferents do not. Thus, it is likely that at least some
      tectoisthmic cells may not be in the population of tectal cells that can be
      affected by isthmic stimulation. Forty-four percent of injections resulted in dye
      coupled labeling, suggesting extensive electrical connections between tectal
      cells in reptiles.

PMID- 10580725
TI  - Electroretinogram of the parietal eye of lizards: photoreceptor, glial, and lens
      cell contributions.
AB  - Local electroretinograms (ERGs) were recorded in the parietal eye of Xantusia
      vigilis. The responses to monochromatic light under dark- and light-adapted
      conditions were studied. We found that two antagonistic chromatic mechanisms
      dominate the overall response. With the electrode tip in the lumen of the eye,
      light stimulation under dark-adapted conditions evoked responses of negative
      polarity with maximum sensitivity to green light. Intense green background
      illumination saturated the green-sensitive mechanism, and superposition of a blue
      stimulus then elicited responses of opposite polarity, driving the potentials
      back toward the dark resting level. The spectral sensitivities of the two
      chromatic mechanisms were determined using chromatic adaptation. The lower
      threshold, green-sensitive mechanism has a maximum sensitivity at 495 nm while
      the antagonistic mechanism, with its maximal spectral sensitivity at 430 nm, is
      at least 2 log units less sensitive. The polarity of the ERG recording inverts as
      the electrode traverses the photoreceptor layer, suggesting that the
      photoreceptors are the major source of the ERG. This result was confirmed with
      intracellular recordings from photoreceptors, glial, and lens cells. The glial
      and lens cells of the parietal eye respond to local changes in [K+]o.
      Intracellular recordings of the responses of these cells to light stimuli follow
      time courses similar to changes in extracellular potassium concentrations
      measured with K+ -specific electrodes. These results suggest that the glial and
      lens cell membranes are highly permeable to potassium and, therefore, the
      electrical responses of these cells are evoked by changes in [K+]o elicited by
      light stimulation of the photoreceptors. Nevertheless, the major component of the
      parietal eye ERG is the photoreceptor signal. A circuit model of the ERG sources
      is presented.

PMID- 10580726
TI  - Circadian control of photoreceptor outer segment membrane turnover in mice
      genetically incapable of melatonin synthesis.
AB  - Vertebrate retinal photoreceptors periodically shed membrane from their outer
      segment distal tips; this material is phagocytosed and degraded by the retinal
      pigmented epithelium. Both a circadian oscillator and the daily light-dark cycle
      affect disk shedding, and the effects of both may be mediated by melatonin. To
      clarify melatonin's role in this process, we asked whether endogenous melatonin
      is required for rhythmic disk shedding in mouse retina. We analyzed disk shedding
      in two mouse strains: C3H, which produce melatonin in retina and pineal under the
      control of circadian oscillators, and C57BL/6, which do not produce melatonin. In
      cyclic light, both strains exhibited a robust cycle of disk phagosome content in
      the pigmented epithelium. Peak shedding occurred just after dawn, and trough
      levels occurred during the middle of the dark phase. In constant darkness, mice
      exhibited circadian rhythms of locomotor activity, the characteristics of which
      were similar between strains. Both strains also exhibited rhythmic disk shedding
      in constant darkness, although amplitudes of the rhythms were damped. Exogenous
      melatonin delivered once per day failed to reestablish high-amplitude cyclic
      shedding in mice held in constant darkness. Our results show that, while disk
      shedding in cyclic light is robustly rhythmic, neither rhythmic production of
      melatonin nor the circadian oscillator responsible for rhythmic locomotor
      activity is sufficient to drive high-amplitude rhythmic shedding in constant
      darkness. More importantly, melatonin is required neither for cyclic changes in
      the rate of disk shedding in cyclic light, nor for the circadian rhythm of disk
      shedding in constant darkness.

PMID- 10580727
TI  - Human symmetry detection exhibits reverse eccentricity scaling.
AB  - Human symmetry detection in dense patterns exhibits a spatial integration range
      that becomes narrower with distance of the symmetry axis from the fovea. This
      narrowing violates the general properties of eccentricity that have been found
      for all previous visual cortical areas, tasks, and assessment techniques. This
      reverse eccentricity scaling may, in conjunction with the long-range matching
      properties for symmetry described in Tyler and Hardage (1996), imply that
      symmetry is processed by a specialized cortical area with non-retinotopic neural
      architecture.

PMID- 10580728
TI  - Modulation of voltage-dependent K+ currents (IK(V)) in retinal bipolar cells by
      ascorbate is mediated by dopamine D1 receptors.
AB  - Ascorbic acid (AA), a neuromodulator in the vertebrate CNS, is released from
      glutamatergic neurons in exchange with glutamate uptake and, in turn, modulates
      the release of both glutamate and dopamine. We have reported that voltage-gated
      K+ currents (IK(V)) in ON-mixed rod/cone bipolar cells (Mb) were suppressed 60%
      by 100-200 microM AA when added to an ascorbate-free solution. However, as the in
      vivo [AA]o in retina is about 200 microM, we studied the effects of changes in
      [AA]o on IK(V) when [AA]o was varied around a baseline concentration of 200
      microM. Whole-cell currents were recorded with patch-clamp methods from goldfish
      Mb cells in retinal slices, bathed in a solution containing 200 microM AA. We
      found that (1) IK(V) was enhanced (180+/-36%, n = 9) by increases of [AA]o less
      than 40 microM with an average latency of 8 min. (2) However, IK(V) was
      suppressed without an appreciable latent period by two conditions: increases more
      than 40 microM [AA]o and decreases by any amount greater than 10 microM. (3)
      Effects of delta[AA]o on IK(V) were blocked by a D1 dopamine receptor antagonist,
      SCH 23390, but not by a D2 receptor antagonist, spiperone. Increased
      concentrations of a D1 agonist (SKF 38390) and dopamine had similar concentration
      dependent effects on IK(V) as did AA, even in the presence of 200 microM
      ascorbate. Ascorbate has complicated concentration-dependent effects on IK(V) of
      Mb cells in vitro that were mediated by D1 dopamine receptors, suggesting that
      dopamine and ascorbate may be involved reciprocally in modulating IK(V), with
      consequences on the transmission of rod signals to the inner retina.

PMID- 10580729
TI  - A stereological analysis of the lateral geniculate nucleus in adult Macaca
      nemestrina monkeys.
AB  - The Cavalieri method and the optical fractionator were employed to estimate the
      volume and neuron numbers, respectively, of the dorsal lateral geniculate nucleus
      (dLGN) in seven adult male pigtail monkeys (Macaca nemestrina). Unbiased
      estimates were selectively obtained for the parvocellular (P), magnocellular (M),
      and interlaminar plus superficial (I + S) layers of the nucleus. The dLGN had a
      mean volume of 56.5 mm3, and contained on average 1.79 million neurons. The P
      layers contributed 64% of the volume and 83% of the neurons in the dLGN; the
      corresponding proportions for the other layers were 13% and 9% (M), and 23% and
      8% (I + S). Interindividual variability was large for neuron counts, which varied
      within a two-fold range, and lower for volume estimates. Since no published data
      are available for the pigtail dLGN, the present results are compared with
      quantitative studies of the dLGN in other macaque species, placing special
      emphasis in the discussion of the methodologies used.

PMID- 10580730
TI  - Long-range interactions modulate the contrast gain in the lateral geniculate
      nucleus of cats.
AB  - In previous work, we have shown that sudden image displacements well outside the
      classical receptive field modulate the visual sensitivity of LGN relay cells.
      Here we report the effect of image displacements on the response versus contrast
      function. The stimuli consisted of a central spot of optimal size and polarity
      (contrast range: 3-98%), flashed alone or in the presence of a peripheral annulus
      (radii: 5-15 deg) containing a low spatial-frequency grating displaced at saccade
      like velocities (shift). The most consistent effect of the shift on the response
      to a central spot was to reduce the responsiveness of Y relay cells and, to a
      lesser extent, of X relay cells. The reduction in responsiveness was primarily a
      divisive rather than a subtractive effect and could be modelled by assuming that
      a greater contrast was required to produce a given excitatory response. In the
      absence of a central spot, remote motion had inhibitory effects on the firing
      rates of the majority of relay cells, but its effect on retinal ganglion cells
      was mainly excitatory. When the shifting grating covered the classical receptive
      field and its periphery, facilitatory effects or suppressive effects, depending
      on the spatial phase of the pattern, were observed in both retinal and geniculate
      cells. Remote motion strongly suppresses the responsiveness of relay cells to
      stimuli within the classical receptive field. This suppressive effect involves
      intrageniculate processing and is primarily associated with a reduction in
      contrast gain. It is likely that shift suppression contributes to the loss of
      visual sensitivity observed in saccadic suppression.

PMID- 10580731
TI  - Midget and parasol ganglion cells of the primate retina express the alpha1
      subunit of the glycine receptor.
AB  - Glycine is a major inhibitory neurotransmitter in the mammalian retina and has
      been shown to influence the responses of ganglion cells. Midget and parasol
      ganglion cells serve distinct physiological roles in the primate retina and show
      differences in their response characteristics to light stimuli. In the present
      study, we addressed the question of whether the expression of glycine receptors
      differs in midget and parasol ganglion cells. Ganglion cells in the retinae of
      marmoset and macaque monkeys were injected with Neurobiotin in a live in vitro
      retinal whole-mount preparation. Retinal pieces were then processed with an
      antibody against the alpha1 subunit of the glycine receptor. Strong punctate
      immunoreactivity indicative of synaptic localization is present in the ON and OFF
      sublamina of the inner plexiform layer. Many of the immunoreactive puncta
      coincide with the dendrites of both midget and parasol ganglion cells.
      Immunoreactive puncta are present on distal and proximal dendrites of ON and OFF
      cells. These results suggest that ON and OFF midget and parasol cells do not
      differ with respect to the distribution of the alpha1 subunit of the glycine
      receptor.

PMID- 10580732
TI  - Modulation of horizontal cell function by GABA(A) and GABA(C) receptors in dark-
      and light-adapted tiger salamander retina.
AB  - The physiological function of GABA transporters and GABA receptors in retinal
      horizontal cells (HCs) under dark-and light-adapted conditions were studied by
      whole-cell voltage clamp and intracellular recording techniques in retinal slices
      and whole-mounted isolated retinas of the larval tiger salamander. Puff
      application of GABA in picrotoxin elicited a NO-711 (a potent GABA transporter
      blocker)-sensitive inward current that did not exhibit a reversal potential in
      the physiological range, consistent with the idea that these HCs contain
      electrogenic GABA transporters. Application of GABA in NO-711 elicited a chloride
      current in HCs; about half of the current was suppressed by bicuculline or I4AA
      (a GABA(C) receptor antagonist), and the remaining half was suppressed by
      bicuculline + I4AA or picrotoxin. In whole-mount retinas, NO-711, bicuculline,
      I4AA, or picrotoxin hyperpolarized the HCs and enhanced the light responses under
      dark-adapted conditions, and blocked the time-dependent recovery of HC membrane
      potential and light responses during background illumination. Based on the
      parallel conductance model, GABA released in darkness mediates a chloride
      conductance about three times greater than the leak conductance or the glutamate
      gated cation conductance. About half of this chloride conductance is mediated by
      GABA(A) receptors, and the other half is mediated by GABA(C) receptors. These
      results suggest that GABA released from HCs through the NO-711-sensitive GABA
      transporters activates GABA(A) and GABA(C) receptors, resulting in chloride
      conductance increase which leads to a HC depolarization and reduction of the
      light response. Additionally, GABA transporters also mediate GABA release in
      background light that is responsible for the recovery of HC membrane potential
      and light responses.

PMID- 10580733
TI  - Optimizing antimicrobial therapy in respiratory-tract infections: new agents, new
      strategies. Introduction.

PMID- 10580734
TI  - The impact of antimicrobial resistance: changing epidemiology of community
      acquired respiratory-tract infections.
AB  - Current surveillance data and mechanisms of resistance for the three most common
      bacteria infecting the respiratory tract are reviewed. Many pathogens, once
      susceptible to available antimicrobials, are now demonstrating high levels of
      resistance to commonly prescribed antimicrobial agents for the treatment of
      respiratory-tract infections. The three most common respiratory-tract pathogens,
      Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, all
      exhibit high-level resistance to one or a number of agents, including penicillin,
      ampicillin, erythromycin, tetracycline, and first-generation cephalosporins. To
      determine the prevalence of resistance in these organisms, surveillance programs
      have begun tracking the emergence of antimicrobial resistance in the United
      States and worldwide. Data recovered from several national surveillance studies
      should help guide decisions about empirical therapeutic treatment.

PMID- 10580735
TI  - In vitro dynamic model for determining the comparative pharmacology of
      fluoroquinolones.
AB  - An in vitro model for determining the comparative pharmacology of
      fluoroquinolones is presented. The true therapeutic potential of fluoroquinolones
      against bacterial pathogens may be best understood before clinical testing with
      the use of in vitro dynamic models. These models simulate pharmacokinetics in
      humans and can be used to compare different drugs in the same class over a wide
      range of dosages with respect to the antimicrobial effect (AME). Two models for
      evaluating AME are described. In one (a two-compartment model), a simple
      bacterial killing curve is generated after exposure to simulated clinical doses
      of antimicrobial. In the other (a one-compartment model), AME is defined as the
      area between the control bacterial growth curve in the absence of drug and the
      curve that represents bacterial killing and regrowth. This area can be readily
      measured and is referred to as the intensity of the effect (I(e)). In general,
      AME is correlated with drug exposure, as simulated in the model at different
      ratios of the area under the concentration-time curve (AUC) to the minimum
      inhibitory concentration (MIC) for the organism under study. With this in vitro
      dynamic model, several fluoroquinolones were tested over a range of AUC/MIC
      ratios for their AMEs against Staphylococcus aureus, Escherichia coli, and
      Klebsiella pneumoniae. The data generated illustrate the usefulness of in vitro
      dynamic models for comparing AMEs of different fluoroquinolones. Because the
      model incorporates pharmacokinetic variables, it provides a method for comparing
      various dosage regimens or schedules of administration and is useful in
      preclinical drug development.

PMID- 10580736
TI  - Using pharmacodynamic and pharmacokinetic surrogate markers in clinical practice:
      optimizing antimicrobial therapy in respiratory-tract infections.
AB  - Pharmacodynamic and pharmacokinetic surrogate markers and their relationship to
      outcomes in respiratory-tract infections are reviewed. While several limitations
      affect the universal application of antimicrobial pharmacodynamic principles in
      clinical practice, recent studies have suggested that these principles may allow
      optimization of selected therapies. For the fluoroquinolones, the pharmacodynamic
      variable that has been correlated with antimicrobial efficacy is the ratio of the
      area under the serum concentration-time curve to the minimum inhibitory
      concentration. On the basis of their pharmacodynamic profiles, the newer
      fluoroquinolones, including such investigational agents as gatifloxacin, should
      produce satisfactory clinical and microbiological outcomes against pathogens
      commonly associated with community-acquired respiratory-tract infections. An
      assessment of the individual agent's pharmacodynamic profile will assist in
      choosing the best fluoroquinolone regimen; however, consideration should also be
      given to the agent's adverse-event potential.

PMID- 10580737
TI  - Pharmacokinetic and pharmacodynamic surrogate markers: studies with
      fluoroquinolones in patients.
AB  - Several relevant studies of fluoroquinolones are reviewed, and the pneumonia
      model is used to predict clinical efficacy. In vitro pharmacokinetic and
      pharmacodynamic relationships help the clinician understand the pharmacologic
      effects of an antimicrobial agent. The clinical translation of in vitro
      determinants has proved challenging, however. Surrogate markers that define
      specific relationships between pharmacokinetic and pharmacodynamic
      characteristics of antimicrobials have been used to predict positive patient
      outcomes. Studies have shown that the ratio of the area under the serum
      concentration-time curve from 0 to 24 hours to the minimum inhibitory
      concentration, also known as the area under the inhibitory curve, is uniquely
      suited as a surrogate for identifying fluoroquinolone concentrations that
      correlate with clinical efficacy. In patients, appropriate dosage levels can be
      readily examined with the nosocomial pneumonia model. Modeling patient responses
      to infection has become a useful way of interpreting the clinical effects of
      fluoroquinolone therapy.

PMID- 10580738
TI  - Pharmacoeconomics of antimicrobial therapy.
AB  - Switch therapy, sequential therapy, and step-down therapy are discussed in terms
      of their contribution to reducing antimicrobial expenditures. Pharmacoeconomics
      is the science used to identify and compare the costs and consequences of drug
      therapy in terms of efficacy, safety, and overall health care. Pharmacoeconomic
      studies of antimicrobials for respiratory-tract infections have identified
      significant cost savings associated with regimens that are optimized for a
      particular patient on the basis of a drug's pharmacokinetic profile. For
      fluoroquinolones, optimal therapy has been associated with targeting the specific
      pharmacodynamic variable known as the ratio of the area under the serum
      concentration-time curve from 0 to 24 hours (AUC) to the minimum inhibitory
      concentration, also referred to as the area under the inhibitory curve (AUIC).
      Several studies have shown that regimens that achieve targeted AUIC values of 125
      to 250 against gram-negative aerobic bacteria are cost-effective; cost savings
      are linked to decreased time to bacterial eradication and higher AUICs.
      Additional cost-effective measures for hospitals and health care institutions
      include the implementation of formalized i.v.-to-oral conversions and
      streamlining programs. Pharmacoeconomic analysis of therapies for respiratory
      tract and other infections demonstrates that reducing health care costs may best
      be achieved by curing the infection in the shortest possible time through dosage
      optimization individualized to the patient.

PMID- 10580739
TI  - The effect of cytokines on parathyroid hormone-related protein (PTH-rP)
      production in human amnion cells.
AB  - In the present study, the effects of various cytokines on parathyroid hormone
      related protein (PTH-rP) production and PTH-rP mRNA expression in human amnion
      cells were studied. Immunoreactive (ir) PTH-rP was measured by immunoradiometric
      assay and the expression of PTH-rP mRNA was determined by Northern blot analysis.
      The addition of interleukin-1beta (IL-1beta, 10 ng/ml) and IL-6 (10 ng/ml) in
      culture medium for 24 hours resulted in a significant increase in ir-PTH-rP
      levels by 1.5 and 1.6 fold, respectively. The effects of these agents were dose
      dependent. In contrast, IL-2 (10 ng/ml) and IL-8 (10 ng/ml) showed no effect on
      the production of ir-PTH-rP from amnion cells. Treatment with IL-1beta or IL-6
      for 6 hours increased the expression of PTH-rP mRNA in amnion cells. The
      stimulatory effect of IL-1beta was reduced by IL-1 receptor antagonist (IL-1Ra)
      in a dose dependent manner. Both tetradecanoyl phorbol acetate (TPA), and
      forskolin increased PTH-rP mRNA levels and the PTH-rP production in amnion cells,
      and the effect of TPA was much greater than that of forskolin. The findings of
      the present study suggest of the participation of inflammatory cytokines for the
      regulation of PTH-rP production in human amnion cells.

PMID- 10580740
TI  - Temporal profiles of interleukin-1beta, interleukin-6, and tumor necrosis factor
      alpha in the plasma and hypothalamic paraventricular nucleus after intravenous or
      intraperitoneal administration of lipopolysaccharide in the rat: estimation by
      push-pull perfusion.
AB  - Lipopolysaccharide (LPS) is known to stimulate the synthesis and secretion of
      various proinflammatory cytokines in both the peripheral immune cells and the
      brain. Yet, the relative contribution of peripheral and central cytokines to the
      LPS-induced activation of the hypothalamo-pituitary-adrenal axis is still poorly
      understood. In this study, utilizing the push-pull perfusion technique of the rat
      brain, we attempted to characterize in detail the temporal profiles of
      interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha after
      intravenous (i.v.) or intraperitoneal (i.p.) administration of LPS in both the
      general circulation and the hypothalamic paraventricular nucleus (PVN), which is
      the primary source of corticotropin releasing hormone (CRH). Temporal changes in
      plasma adrenocorticotropic hormone (ACTH) and CRH levels in the PVN were also
      monitored. We collected blood and perfusates every 30 min from 11:00 to 17:00 h.
      At 12:00 h, 1.0 or 2.5 mg/kg body weight of LPS was given via an i.v. or i.p.
      route, respectively. Peak ACTH response occurred 30 min after i.v. LPS and 1.5 h
      after ip LPS. Of the three cytokines measured in the plasma, TNF-alpha showed the
      fastest rise in synchrony with peak ACTH secretion after both i.v. and i.p. LPS.
      Although plasma IL-6 also showed a robust rise, its peak level occurred later
      than the ACTH peak. Elevation of plasma IL-1beta was the smallest among the three
      cytokines. CRH levels in the PVN reached their peaks 1 and 2.5 h after the ACTH
      peak following i.p. and i.v. LPS, respectively. Irrespective of the route of LPS
      administration, IL-6 and TNF-alpha levels in the PVN showed significant rises 1-2
      h after the ACTH peak, but IL-1beta in the PVN did not significantly change
      during the entire period of observation. The results of the present study suggest
      that circulating TNF-alpha may play the most important role in triggering the
      early, peak phase of ACTH secretion after both i.v. and i.p. LPS. Although it is
      possible that brain TNF-alpha, IL-6, and circulating IL-6, may be involved in the
      later, protracted phase of ACTH secretion induced by LPS, IL-1beta in both the
      brain and peripheral circulation seems to play the smallest role in ACTH
      secretion. This is the first study to characterize the LPS-induced temporal
      changes in IL-1beta, IL-6, and TNF-alpha in both plasma and PVN simultaneously in
      conscious, freely moving rats.

PMID- 10580741
TI  - Effect of streptozotocin-induced diabetes mellitus on type 1 deiodinase (D1) in
      inherited D1-deficient mice.
AB  - We investigated the effects of streptozotocin (STZ)-induced diabetes on thyroid
      hormone levels, type 1 deiodinase (D1) activity and messenger RNA (mRNA) levels
      in inherited D1 deficient C3H mice in a comparative manner with control C57 mice.
      The apparent maximum velocity (Vmax) D1 values in C3H mice were 3% (liver) and
      26% (kidney) of those in C57 mice. In C3H mice, similar serum T3, slightly higher
      T4, and 2.6-fold higher rT3 levels were observed compared with C57 mice. In STZ
      induced diabetes, serum T4 level markedly decreased in both C3H and C57 mice.
      Serum T3 levels in STZ-C3H mice similarly decreased as in STZ-C57 mice. On the
      other hand, serum rT3 levels increased to 3.3-fold higher in STZ-C3H than in STZ
      C57 mice. The Vmax values were decreased to 12% (STZ-C3H) and to 30% (STZ-C57) in
      liver, and decreased to 33% (both STZ-C3H and STZ-C57) in kidney. The changes in
      D1 mRNA levels in diabetes versus control were comparable to those of D1
      activities in both strains. In summary, similar mechanism(s) to those which
      decrease the D1 expression and the serum T3 level in diabetes, function in D1
      deficient C3H mice as in C57 mice. It appears that hepatic and renal D1 activity
      alone can not explain the similar reduction in T3 level in STZ-C3H mice and STZ
      C57 mice.

PMID- 10580742
TI  - Lymphocytic hypophysitis and infundibuloneurohypophysitis; clinical and
      pathological evaluations.
AB  - This report describes the clinical and pathological characteristics of two
      patients with lymphocytic hypophysitis (LHy) and two with
      infundibuloneurohypophysitis (INHy). Two of the patients were women and two were
      men, and their ages were between 27 and 38 years old. This disease was not
      associated with either pregnancy or the postpartum period in the female patients.
      Two of the patients presented with diabetes insipidus, one with
      panhypopituitarism and right abducens paralysis and one with headache and
      galactorrhea. At presentation three of the patients had mild to moderate
      hyperprolactinemia and one had low prolactin levels. All four had abnormal
      magnetic resonance imaging (MRI): focal nodular enlarging of the infundibulum and
      normal hypophysis in one, expanding sellar masses in two, and diffusely thickened
      stalk with slightly enlarged pituitary gland in one. Three cases showed no sign
      of adenohypophysial deficiency with stimulation tests. One patient had associated
      chronic lymphocytic thyroiditis. Of the first three patients, one patient
      underwent transcranial and two underwent transnasal transsphenoidal (TNTS)
      surgery for mass excisions since they were thought to have pituitary tumors.
      Endoscopic endonasal transsphenoidal biopsy was performed in the last one with a
      suspicion of LHy. The pathological and immunohistochemical examinations revealed
      lymphocytic infiltration. Hyperprolactinemia resolved with surgery in two
      patients and one developed diabetes insipidus as a complication. We conclude that
      LHy and infundibuloneurohypophysitis should be considered in the differential
      diagnosis of the mass lesions of the sellar region and also should be kept in the
      mind for the etiopathogenesis of cases of hyperprolactinemia, galactorrhea and
      diabetes insipidus. In suspected cases endoscopic endonasal biopsy for the
      histopathological diagnosis can be a safe approach.

PMID- 10580743
TI  - Growth stimulation of a rat pituitary cell line MtT/E-2 by environmental
      estrogens in vitro and in vivo.
AB  - Endocrine disruptors are a diverse group of chemicals that alter the functions of
      the endocrine system. A large proportion of endocrine disruptors have estrogenic
      effects, thus are called environmental estrogens. In the present study, an
      estrogen (E2) responsive rat pituitary cell line, MtT/E-2, was employed to
      examine 1) the potency of several endocrine disruptors including bisphenol A
      (BPA), o,p'-DDD, methoxychlor, 1,2,3,4,5,6-hexachlorocyclohexane (HCH) and
      dibromoacetic acid (DBAA) in terms of E2 responsive pituitary cell growth; 2)
      whether BPA has estrogenic action in vivo causing the growth of MtT/E-2 cells
      grafted in rats. Binding assays showed the test chemicals were able to compete
      with 3H-E2 binding to the estrogen receptor (ER). The compounds also stimulated
      growth of MtT/E-2 cells at rates corresponding to their ER binding affinity.
      Their transcription activation of an (ERE)3-SV40-luciferase reporter in MtT/E-2
      cells was comparable to their stimulation of cell growth, with the exception of
      HCH which showed little induction of cell growth but strong stimulation in ERE
      dependent transcription activation. MtT/E-2 cells were inoculated into
      ovariectomized female F344 rats treated with E2 or BPA. The first tumors were
      noted at day 22 in the E2 treated group, at day 25 in the highest dose of BPA
      group and at day 41 in the control group. These results suggest 1) that the
      growth assay with MtT/E-2 cells provides simple and sensitive test for detection
      of estrogenic activity of environmental chemicals; 2) that BPA has estrogenic
      potency to stimulate E2 responsive cell growth in vivo as well as in vitro.

PMID- 10580744
TI  - A close association between insulin resistance and dehydroepiandrosterone sulfate
      in subjects with essential hypertension.
AB  - To examine the serum levels of dehydroepiandrosterone sulfate (DHEAS) and its
      relation with insulin resistance and the other risk factors in essential
      hypertension, serum DHEAS and insulin sensitivity were assessed in 35 male
      hypertensive and 17 male healthy control subjects aged 50-59 years. Fasting
      plasma insulin and the area under curve of plasma insulin were determined during
      a 75 g oral glucose tolerance test. Insulin sensitivity was measured by the
      steady state plasma glucose method. Fasting plasma insulin and the area under
      curve of plasma insulin were significantly higher in the hypertensive group than
      in control group. Steady state plasma glucose was significantly higher in
      hypertensive subjects indicating insulin resistance compared with control
      subjects. On the other hand, fasting serum DHEAS levels were significantly lower
      in the hypertensive group than in the control group. Fasting serum DHEAS levels
      were inversely correlated with steady state plasma glucose significantly
      (p=0.0008), indicating a close association between DHEAS levels and insulin
      resistance. Fasting serum DHEAS was inversely correlated with systolic blood
      pressure and fasting plasma insulin. In multiple regression analysis of
      hypertensive subjects, steady state plasma glucose was the strongest determinant
      of the fasting serum level of DHEAS, followed by systolic blood pressure and
      fasting plasma insulin. These 3 factors accounted for 51.6% of the variation in
      DHEAS. In nonobese and nondiabetic essential hypertension, serum DHEAS was lower
      and insulin resistance was the most significant independent determinant of
      reduced serum DHEAS, followed by systolic blood pressure and fasting plasma
      insulin.

PMID- 10580745
TI  - Changes in nitric oxide synthase activity in the ovary of gonadotropin treated
      rats: the role of nitric oxide during ovulation.
AB  - Immature rats receiving equine chorionic gonadotropin (eCG) and human CG (hCG)
      were used to study the time course changes in nitric oxide synthase (NOS)
      activity in the ovary during ovulation. To study the role of NO in ovulation, the
      effects of intrabursal injection of L-N(G)-monomethylarginine (L-NMMA, 125
      microg/20 microl/bursa), a NOS inhibitor, on the number of ova shed were also
      examined. Rats were sacrificed at -48, 0, 3, 6, 9, 12, and 24 h after hCG
      injection, and the ovaries were collected for the NOS activity assay, Western
      blotting, NADPH-diaphorase histochemistry and immunohistochemistry. Total NOS and
      constitutive NOS activities in the ovary increased significantly at 9 h after hCG
      injection and the values remained high thereafter. Inducible NOS (iNOS) activity
      was detectable as a small peak at 3 and 6 h after hCG injection. Endothelial NOS
      (eNOS) protein production increased after hCG injection with a peak at 12 h,
      whereas iNOS protein production decreased at 12 and 24 h after hCG injection.
      NADPH-diaphorase positive cells increased at the thecae of growing follicles
      after hCG injection, appeared at mural granulosa cells before ovulation, and were
      detected in newly formed corpora lutea, which coincided with the results in eNOS
      positive cells by immunohistochemistry. L-NMMA given to rats at 5 or 7 h after
      hCG was most effective in reducing the number of ova shed. These results indicate
      that the NOS activity and NOS positive cells increased after hCG injection, and
      that eNOS was likely the main NOS increasing in the ovary during ovulation. It is
      concluded that NO produced between 5 and 9 h after hCG might play a supportive
      role in ovulation.

PMID- 10580746
TI  - Loss of wild-type MEN1 gene expression in multiple endocrine neoplasia type 1
      associated parathyroid adenoma.
AB  - Multiple endocrine neoplasia type 1 (MEN1) is a human hereditary tumor syndrome
      characterized by the development of endocrine adenomas of the parathyroid,
      anterior pituitary, and enteropancreatic tissue. Several lines of evidence have
      implicated the recently identified MEN1 gene located on chromosome 11q13 as a
      recessive tumor suppressor gene. Here, we analyzed MEN1 wild-type gene expression
      in tumors from a large MEN1 kindred. A deletion of codons 227-228 (678del6)
      located in exon 4 was found in tumor and peripheral blood complementary DNA using
      a simplified single-strand conformational polymorphism (SSCP) approach well
      suited for clinical MEN1 mutation screening. The identified 678del6 cDNA mutation
      deletes a potential phosphorylation site (Tyr227) and corresponds to a germ line
      mutation co-segregating with disease phenotype in this MEN1 family. Loss of
      heterozygosity analysis by fluorescent microsatellite PCR showed an exclusive
      loss of the MEN1 wild-type (and retention of the mutated) allele detectable in
      DNA from microdissected parathyroid and pancreatic, but not in adrenal, adenomas.
      Our findings confirm the synergism between MEN1 gene mutations and subsequent
      MEN1 allelic losses in the tumorigenesis of MEN1-associated adenomas.

PMID- 10580747
TI  - Transforming growth factor-beta stimulates articular chondrocyte cell growth
      through p44/42 MAP kinase (ERK) activation.
AB  - Transforming growth factor-beta1 (TGF-beta1) stimulates articular chondrocyte
      cell proliferation and extracellular matrix formation. We reported previously
      that immediate and transient expression of c-fos mRNA through protein kinase C
      activation is required for the mitogenic effect of TGF-beta1 on cultured rat
      articular chondrocytes (CRAC). In gel kinase assays using myelin basic protein
      (MBP) showed that total cell lysates from cells treated with TGF-beta1 caused
      rapid phosphorylation of MBP, which suggests the involvement of mitogen-activated
      protein kinase (MAPK) activation. To identify specific MAPK pathways activated by
      TGF-beta1, we performed in vitro kinase assays using specific substrates. TGF
      beta1 induced a rapid activation of extracellular signal regulated kinase (ERK)
      with a peak at 5 min, which decreased to basal levels within 240 min after TGF
      beta1 stimulation. In contrast, the c-jun N-terminal kinase activity increased
      only about 2.5-fold after 240 min of stimulation and p38 MAPK activity did not
      change significantly. ERK activation by TGF-beta1 was also confirmed by in vivo
      phosphorylation assays of Elk1. However, a specific MEK1 inhibitor, PD98059,
      significantly decreased TGF-beta1 induced Elk1 phosphorylation in a dose
      dependent manner. Furthermore, PD98059 reduced the TGF-beta1-induced cell growth
      by 40%. These results indicate that TGF-beta1 specifically activates MEK1 and
      subsequent ERK pathways in CRAC, and that the activation of this MAPK pathway
      plays a role in the mitogenic response to TGF-beta1.

PMID- 10580748
TI  - Growth hormone advances spermatogenesis in premature rats treated with
      gonadotropin-releasing hormone agonist.
AB  - To clarify the effect of GH on the development of seminiferous tubules in
      premature male rats, we investigated whether GH accelerates spermatogenesis under
      the condition of gonadotropin deprivation. Male Wistar rats aged three weeks were
      divided into three groups and subjected to administration of either long-acting
      GnRH agonist (GnRHa) or a combination of GnRHa and rat GH, with normal saline
      solution as control. After the 4-week treatment, sperm density and motility in
      the right epididymis were measured and seminiferous tubules of right testes were
      histologically examined. Sperm density and motility were significantly higher in
      GnRHa+GH-treated rats than in GnRHa-treated rats. In histological examination,
      the numbers of germ cells in various stages were increased in GnRHa+GH-treated
      rats compared with GnRHa-treated rats, with the number of mature spermatid being
      noticeably higher in GnRHa+GH-treated rats. These results suggest that
      administration of GH decreases loss of germ cells at various stages of
      spermatogenesis under the condition of gonadotropin withdrawal.

PMID- 10580749
TI  - High molecular weight corticotropin measured with immunoradiometric assay in a
      patient with asymptomatic pituitary corticotropinoma.
AB  - A 57-yr-old female with corticotropinoma showing no Cushingoid stigmata is
      reported. Basal plasma levels of ACTH measured with immunoradiometric assay and
      beta-endorphin were high, 12.6-15.9 pmol/l and 3.5 pmol/l, respectively. Plasma
      cortisol level and urinary free cortisol excretion were normal, 303-359 nmol/l
      and 171-226 nmol/day, respectively. Plasma ACTH markedly increased to 70.5 pmol/l
      with intravenous administration of 100 microg CRH. Diurnal rhythm of plasma ACTH
      was seen, but its level in the night was still high. Plasma ACTH suppression with
      dexamethasone was insufficient. CRH stimulation after dexamethasone suppression
      increased plasma ACTH level from 4.4 to 13.7 pmol/l. Intravenous administration
      of 4 microg desmopressin increased plasma ACTH from 15.6 to 19.6 pmol/l. Oral
      administration of 16 mg lepramide insufficiently decreased plasma ACTH from 7.3
      to 5.3 pmol/l. However, plasma cortisol responses in these conditions were
      normal. Postoperative pathological study revealed subtype 1 corticotropinoma
      immunohistochemically and electron-microscopically. Postoperative basal plasma
      ACTH decreased to 3.9 pmol/l, although plasma cortisol did not change. Diurnal
      rhythm and dexamethasone suppressibility of plasma ACTH became normal. Plasma
      sample was chromatographed on a Sephadex G-75 column. The elution profile showed
      two peaks of ACTH, one of which was compatible with 1-39 ACTH and another with
      higher molecular weight ACTH which was probably secreted from corticotropinoma.
      Anomaly in processing of proopiomelanocortin was suspected.

PMID- 10580750
TI  - Effect of octreotide treatment on Graves' ophthalmopathy.
AB  - In this study, nine patients with Graves' ophthalmopathy with positive clinical
      activity score (CAS), who were either unresponsive or not suitable for
      glucocorticoid treatment, were given 100 microg of octreotide three times daily,
      subcutaneously, for three months. The mean age was 49+/-13 years. All patients
      were under either propylthiouracil or methimazole therapy and were euthyroid for
      at least one month prior to the start of the octreotide treatment. The mean
      degree of proptosis as measured with the Hertel exophthalmometer decreased
      slightly after the treatment (22.0+/-3.0 vs 19.6+/-2.4 for the right eye and
      22.2+/-1.9 vs 20.2+/-2.2 for the left eye; p<0.05). The mean activity score
      decreased from 3.2+/-0.8 to 1.7+/-1.1 (p<0.005) and the mean score of eye signs
      according to the NOSPECS classification showed improvement with octreotide
      therapy (3.2+/-0.7 vs. 2.2+/-1.4; p<0.05). Seven patients responded favorably to
      octreotide treatment. In the remaining two no improvement was observed. Four of
      the responders could be followed up for 20 months after the treatment and all
      maintained the favorable state of eye findings obtained with octreotide. We
      conclude that octreotide seems to be a safe and effective drug in Graves'
      ophthalmopathy, especially in improving soft tissue involvement, and can be used
      in patients who are unresponsive to glucocorticoid treatment or who cannot use
      these drugs for some reason.

PMID- 10580751
TI  - Levothyroxine-induced liver dysfunction in a primary hypothyroid patient.
AB  - Here we report a case of levothyroxine-induced liver dysfunction. T4
      (levothyroxine) has been more commonly used for the treatment of hypothyroidism
      than T3 active hormone (triiodothyronine), because with the former drug a stabler
      plasma concentration is obtained after oral administration. Although there are
      few reports on levothyroxine-induced liver dysfunction, we treated a primary
      hypothyroid patient with high serum aminotransferase after administration of
      levothyroxine. Liver dysfunction was improved after cessation of the drug
      administration. Antibody to T4 was found in the serum of the patient after this
      event. From clinical course and laboratory data of the patient, the episode of
      liver damage was considered to be induced by levothyroxine. We then administrated
      triiodothyronine, and it did not induce liver dysfunction. Changing levothyroxine
      to triiodothyronine resulted in a successful clinical course in this case, as re
      administration of the doubtful drug is strictly limited.

PMID- 10580752
TI  - Sleep-disordered breathing in acromegalics--relation of hormonal levels and
      quantitative sleep study by means of bedside oximeter.
AB  - Sleep-disordered breathing (SDB) is common in patients with growth hormone (GH)
      secreting pituitary adenomas. Since long-term untreated SDB aggravates systemic
      conditions (hypertension and arrhythmia etc.), the therapeutic outcome of SDB is
      important in reducing morbidity and mortality rates. But the results of a
      quantitative analysis of the lowered GH and IGF-1 levels in SDB in a relatively
      large number of patients are not detailed. Ten consecutive acromegalic patients
      were studied with a bedside oximeter. Preoperatively they were divided into two
      groups based on the presence (SDB group = 6 patients) or absence (non-SDB group =
      4 patients) of clinical symptoms of SDB such as habitual snoring, excessive
      daytime somnolence and nocturnal apneic episodes. The serum IGF-1 averaged 931.7
      ng/ml in SDB group and 898.3 ng/ml in non-SDB group. The oxygen desaturation
      index (ODI) (the number of oxygen desaturations exceeding 4% from the base line)
      was 29.1+/-15.4 in the SDB group and 2.5+/-1.8 in the non-SDB group (P=0.01).
      Other oximeter parameters such as the percent of the time spent at O2 saturation
      < 90% and the mean and the lowest O2 saturations closely correlated with the
      degree of the clinical symptoms. A postoperative sleep study was conducted in 5
      patients in the preoperative SDB group, 4 months or more after the surgery. The
      serum GH and IGF-1 levels normalized in 3 patients but remained slightly high in
      2. ODI became 9.1+/-5.6, which was significantly lower than the preoperative
      value (P=0.026). One patient had a complete clinical resolution. The other 4
      obtained slight to moderate improvement clinically and oximetrically despite
      normalized or decreased hormonal levels. This study clarified that the response
      of SDB to lowering of the GH level varies from one patient to another and
      persisting SDB despite the normalization of the hormonal levels suggests the
      involvement of other factors in the production of SDB.

PMID- 10580753
TI  - Adrenal insufficiency due to metastatic hepatocellular carcinoma.
AB  - A 73-year-old man with general malaise and nausea following a common cold
      diagnosed by a local physician was found to have multiple hepatocellular
      carcinomas with enlarged bilateral adrenal glands, combined with adrenal
      insufficiency. Hydrocortisone replacement improved the symptoms and laboratory
      findings. Autopsy findings revealed that each adrenal gland was completely
      replaced by the tumor measuring 11 cm in diameter, and no adrenal tissue was
      recognized. Histologically, the adrenal tumors, as well as the liver tumors, were
      moderately differentiated Edmondson type II hepatocellular carcinomas. This is a
      second report of adrenal insufficiency due to hepatocellular carcinoma as a
      primary site of metastatic adrenal tumor.

PMID- 10580754
TI  - Reconstituted basement membrane reduces proliferation and increases prolactin
      expression of GH3 cells.
AB  - This study investigated the effects of reconstituted basement membrane Matrigel
      on the proliferation and prolactin expression of GH3 cells in culture for 6 days.
      When cells were cultured on Matrigel, the initial attachment was increased but
      the cell number was not changed with time whereas rapid increase in cell number
      was observed in cultures on plastic. Bromodeoxyuridine (BrdU)-labeling showed
      that BrdU incorporation ratio of GH3 cells cultured on Matrigel was about one
      half of that observed with cells cultured on plastic (9.7+/-0.7% vs. 18.7+/
      1.2%). Immunocytochemistry revealed that the ratio of the prolactin
      immunoreactive GH3 cells was about 3.6 times (58.4+/-2.9% on Matrigel vs. 16.2+/
      1.4% on plastic), which was compatible with the results of Western blot analysis.
      In situ hybridization demonstrated that prolactin mRNA-positive cells were
      identified more frequently when cells were cultured on Matrigel compared to
      cultures on plastic. These findings indicate that Matrigel is a proper culture
      substrate for the long-term culture of GH3 pituitary cells due to the inhibition
      of overgrowth and promotion of prolactin expression.

PMID- 10580755
TI  - Pharmacokinetics and metabolic effects of high-dose growth hormone administration
      in healthy adult men.
AB  - To evaluate pharmacokinetics of growth hormone (GH) and its effects on IGF-I,
      glucose, insulin, nonesterified fatty acid (NEFA) and triglyceride (TG), fifteen
      Japanese healthy adult male volunteers (20-27 years old) were studied. The
      subjects were divided into three groups, and received with a single s.c.
      injection of 0.075, 0.15 and 0.30 IU/kg of GH, respectively. The subjects
      assigned to receive 0.30 IU/kg were administered for additional 6 days. After a
      single administration of GH, Cmax and AUC of GH were increased in a dose
      dependent manner. There was a significant positive correlation between the AUC
      and the T1/2 (r=0.516, P<0.05). Total body clearance was significantly greater in
      0.075 IU/kg group than the other groups and showed a significant negative
      correlation with Cmax (r=-0.694, P<0.005) and AUC (r=-0.723, P<0.005). After a
      single administration of each dose, serum IGF-I concentrations were increased
      gradually. In the repeated administered group (0.30 IU/kg), IGF-I concentrations
      almost reached a plateau at a significantly high level four days after the start
      of administration and remained at a high level (786-405.4 ng/ml) until day 8.
      There was no significant difference in diurnal change of blood glucose and serum
      insulin after a single administration of GH among three groups. In the 0.3 U/kg
      group, there was no significant difference in diurnal change of blood glucose
      between day 1 and day 7, but serum insulin level was significantly higher in day
      7 than in day 1 (P<0.01). Serum concentrations of NEFA were increased over time
      after administration in all subjects administered once or repeatedly. TG
      concentrations showed no changes after single administration of each dose level,
      but were significantly increased on day 7 in the subjects repeatedly treated with
      0.30 IU/kg/day. This effect is speculated to be caused by high dose GH treatment.
      The above findings demonstrated that higher GH dose significantly influences on
      carbohydrate and lipid metabolism. It remains necessary to elucidate what kinds
      of effects of the long-lasting increased levels of insulin and triglyceride, even
      if reversible, would have on glucose and lipid metabolism.

PMID- 10580756
TI  - Gene amplification as a common cause of inherited thyroxine-binding globulin
      excess: analysis of one familial and two sporadic cases.
AB  - T4-binding globulin (TBG) is the major thyroid hormone transport protein in
      humans. Inherited abnormalities in the level of serum TBG have been classified as
      partial deficiency, complete deficiency and excess. A single nucleotide deletion
      or substitution in the TBG gene, located on Xq22, has been detected in partial
      and complete deficiencies. As for inherited TBG excess, the gene amplification
      has been recognized in two Japanese families recently. In this study, an
      additional three Japanese families, one familial (F-I) and two sporadic TBG
      excess (F-II, F-III), were analyzed. Serum TBG levels in hemizygous males were
      73, 47 and 42 microg/ml, three- to two-fold the normal value. The molecule had
      normal properties in terms of heat stability and isoelectric focussing pattern.
      The gene dosage of TBG was evaluated by coamplification with autosomal betaGlobin
      or X-chromosomal Duchenne Muscular Dystrophy (DMD) and subsequent quantitation by
      HPLC. The TBG/betaGlobin ratios of the affected male and female of F-I were 3.09-
      and 3.86-times, respectively, compared to that of the normal males. The TBG/DMD
      ratios were 2.93- and 2.09-times, respectively. These results are compatible with
      three copies of the TBG gene on the affected X-chromosome. Similarly, a twofold
      increase in gene dosage was demonstrated in the affected males of sporadic cases.
      Their mothers with normal TBG values had the same TBG gene dosage as normal
      females, suggesting that de novo gene duplication arose in gametes probably
      during meiosis. Amplification of the TBG gene was not recognized in these three
      families by in situ hybridization of prometaphase chromosomes. Though the
      mechanism remains unproved, gene amplification of TBG was considered to be a
      common cause for inherited TBG excess.

PMID- 10580757
TI  - Analysis of polybrominated diphenyl ethers in Swedish human milk. A time-related
      trend study, 1972-1997.
AB  - A previously described method for analysis of organochlorine compounds in human
      milk was adopted for analysis of brominated diphenyl ethers (BDEs) substituted
      with three to six bromine atoms. Analytes were extracted from human milk with the
      lipophilic gel Lipidex 5000. Further purifications were performed on partly
      deactivated aluminum oxide and silica gel columns, followed by gel permeation
      chromatography. The concentrations of BDEs were determined by gas
      chromatography/mass spectrometry (GC/MS). The average recoveries of 2,2',4-triBDE
      (BDE-17), 2,4,4'-triBDE (BDE-28), 2,2',4,4'-tetraBDE (BDE-47), 2,3',4,4'-tetraBDE
      (BDE-66), 2,2,3,4,4'-pentaBDE (BDE-85), 2,2',4,4',5-pentaBDE (BDE-99),
      2,2',4,4',6-pentaBDE (BDE-100), 2,2',4,4',5,5'-hexaBDE (BDE-153), and
      2,2',4,4',5,6'-hexaBDE (BDE-154) added to the samples before extraction ranged
      from 86% to 102%. Pooled samples of breast milk, collected at eight time periods
      between 1972 and 1997, were analyzed for PBDEs. BDE-47 was the most abundant PBDE
      congener in all samples. In total, eight PBDE congeners were identified in the
      milk. The sum of the concentrations of BDE congeners in human milk increased from
      0.07 to 4.02 ng/g lipids during the 25-yr period studied.

PMID- 10580758
TI  - Effect of welding fume solubility on lung macrophage viability and function in
      vitro.
AB  - It was shown previously that fumes generated from stainless steel (SS) welding
      induced more pneumotoxicity and were cleared from the lungs at a slower rate than
      fumes collected from mild steel (MS) welding. These differences in response may
      be attributed to the metal composition of SS and MS welding fumes. In this study,
      fumes with vastly different metal profiles were collected during gas metal arc
      (GMA) or flux-covered manual metal arc (MMA) welding using two different
      consumable electrodes, SS or MS. The collected samples were suspended in saline,
      incubated for 24 h at 37 degrees C, and centrifuged. The supernatant (soluble
      components) and pellets (insoluble particulates) were separated, and their
      effects on lung macrophage viability and the release of reactive oxygen species
      (ROS) by macrophages were examined in vitro. The soluble MMA-SS sample was shown
      to be the most cytotoxic to macrophages and to have the greatest effect on their
      function as compared to the GMA-SS and GMA-MS fumes. Neither the soluble nor
      insoluble forms of the GMA-MS sample had any marked effect on macrophage
      viability. The flux-covered MMA-SS fume was found to be much more water soluble
      as compared to either the GMA-SS or the GMA-MS fumes. The soluble fraction of the
      MMA-SS samples was comprised almost entirely of Cr. The small fraction of the GMA
      MS sample that was soluble contained Mn with little Fe, while a more complex
      mixture was observed in the soluble portion of the GMA-SS sample, which contained
      Mn, Ni, Fe, Cr, and Cu. Data show that differences in the solubility of welding
      fumes influence the viability and ROS production of macrophages. The presence of
      soluble metals, such as Fe, Cr, Ni, Cu, and Mn, and the complexes formed by these
      different metals are likely important in the pulmonary responses observed after
      welding fume exposure.

PMID- 10580759
TI  - Toxicity evaluation of petroleum blending streams: reproductive and developmental
      effects of light catalytic cracked naphtha distillate in rats.
AB  - A distillate of light catalytic cracked naphtha (CAS number 64741-55-5, LCCN-D),
      administered by inhalation, was tested for reproductive and developmental
      toxicity in Sprague-Dawley rats, following a modified OECD Guideline 421,
      Reproductive/Developmental Toxicity Screening Protocol. LCCN-D was administered
      as a vapor, 6 h/d, 7 d/wk at target concentrations of 0, 750, 2500 or 7500 ppm to
      female rats for approximately 7 wk from 2 wk prior to mating, during mating
      through gestational d 19, and to males beginning 2 wk prior to mating for 8
      consecutive weeks. Dams and litters were sacrificed on postnatal d 4, and males
      were sacrificed within the following week. Parental systemic effects observed at
      the 7500 ppm exposure level were increased kidney weights and relative liver
      weights in males and increased spleen weights in high-dose females. Livers and
      spleens from rats in the high-dose group were normal in appearance at necropsy.
      IncreaSed kidney weights in high-dose males were indicative of male-rat-specific
      light hydrocarbon nephropathy. No test-related microscopic changes were observed
      in the reproductive organs or nasal turbinate tissues of either sex. Reproductive
      performance was unaffected by treatment with LCCN-D. Fertility index was > or
      =90% in all dose groups. There were no exposure-related differences in
      implantation sites and live pups per litter, and no gross abnormalities were
      observed. Pups born from treated dams showed comparable body weights and weight
      gains to controls. The viability index on postpartum d 4 was > or =97%; the high
      dose group had more male than female pups at birth and at d 4 postpartum. Under
      the conditions of this study, the no-observable-adverse-effect level (NOAEL) for
      exposure to light catalytic cracked naphtha distillate for parental toxicity was
      2500 ppm and the NOAEL for reproductive performance and developmental toxicity
      was 7500 ppm.

PMID- 10580760
TI  - Absorption and disposition of cobalt naphthenate in rats after a single oral
      dose.
AB  - The absorption and disposition of inorganic cobalt salts after oral
      administration have not been completely characterized. The objective of this
      project was to investigate the absorption and disposition of cobalt naphthenate
      in Fischer 344 rats following a single oral dose. Cobalt naphthenate was given
      orally at 3 doses: 0.333, 3.33, or 33.3 mg Co(II)/kg. Tissues, urine, and feces
      were collected over a 36-h period from the low- and high-dose groups; blood was
      collected from all 3 dose groups. The majority of the dose in both the low- and
      high-dose groups was excreted in the feces (42% and 73.1%, respectively),
      indicating that cobalt was incompletely absorbed from the gastrointestinal tract
      following oral dosing. The percent of the dose excreted in the urine was similar
      for low and high doses (31.8% and 26.3%, respectively). Cobalt concentrations
      were found to be highest in the liver and kidneys. The blood versus time cobalt
      concentration curves for the low-dose, intermediate-dose, and high-dose groups
      were elevated 4- to 5-fold, 14- to 25-fold, and 25- to 60-fold over control blood
      levels, respectively. The peak plasma concentrations of 0.6 and 1.7 microg
      Co(II)/ml occurred at approximately 4.3 h for the intermediate-dose group, and
      3.3 h for the high-dose group. The terminal elimination half-lives were 24.7 and
      24 h for the intermediate- and high-dose groups, respectively. Thus, although the
      extent of cobalt absorption as indicated by the blood concentrations and areas
      under the blood-time curves was not proportional to dose, the calculated
      pharmacokinetic values for the time to peak blood concentration and the apparent
      elimination rate constants were independent of dose. The amount excreted in the
      urine was also proportional to the dose. These apparent anomalies were not
      related to protein binding in blood.

PMID- 10580761
TI  - MRI of the lumbar intervertebral disc.
AB  - The lumbar spine is one of the commonest regions of the body imaged with MRI.
      Various pathological processes can involve the lumbar intervertebral disc,
      including degeneration, infection and trauma and these may present with a variety
      of signal intensity and morphological changes as depicted by MRI. The aim of this
      pictorial review is to illustrate these abnormalities and discuss their clinical
      relevance where appropriate.

PMID- 10580763
TI  - Ultrasound detection of pneumothorax.
AB  - OBJECTIVE: To determine the accuracy of ultrasound in the detection of
      pneumothorax. METHODS: Prospective blinded study comparing ultrasound, CT and
      radiographic findings in 29 patients following 41 CT-guided lung biopsies.
      Ultrasound examination of the chest was limited to the biopsy needle entry site.
      RESULTS: Thirteen patients developed a post-biopsy pneumothorax demonstrated by
      CT. Seven of these were detected by ultrasound and six were visible on erect
      chest radiographs. Six of the 13 pneumothoraces were not detected by ultrasound,
      but five of these were loculated away from the biopsy needle entry site and were
      therefore in areas not examined during the limited ultrasound examination. There
      were no false-positive diagnoses of pneumothorax using ultrasound. The positive
      predictive value for ultrasound was 100% and the negative predictive value was
      82%. CONCLUSION: In this patient group, ultrasound was more sensitive than erect
      chest radiography in the detection of pneumothorax. Both have a specificity of
      100%. This study suggests that ultrasound may prove valuable in pneumothorax
      detection when rapid conventional radiography is not possible or practical, and
      in circumstances where ultrasound is readily available, such as during ultrasound
      guided interventional procedures.

PMID- 10580762
TI  - Incident screening cancers detected with a second mammographic view: pathological
      and radiological features.
AB  - Previous studies and epidemiological data from the UK National Health Service
      Breast Screening Programme (NHSBSP) have indicated significantly increased
      sensitivity for cancer detection with two-view rather than one-view mammographic
      screening. The radiological and pathological features of these extra cancers have
      not been previously reported in detail. We have studied all screen-detected
      cancers found as incident cases in the South West London Breast Screening Service
      between 1994-1997 on the second round of screening. To assess the effect of two
      view versus one-view mammography on cancer detection, these cases were mixed with
      controls in a 1:2 ratio in nine test sets and each set read independently by
      three film readers. They initially read the oblique view, then the craniocaudal
      views, and recorded abnormalities on the films and likelihood of recall.
      Radiological and histological data were recorded for each case. Using two views,
      8.9% (P < 0.05) more invasive cancers were detected. The sensitivity increase was
      highest for invasive cancers less than 10 mm (11%) and cancers of low grade
      (11.9%). These sensitivity increases may underestimate the increase in 'real
      life' because of over-recalling of normal mammograms, particularly with one view,
      under study conditions. The most significant radiological feature of invasive
      cancers was an irregular mass, which, seen on one view had a positive predictive
      value of 82.2% and 89.9% with two views. The craniocaudal view was helpful,
      firstly, because some cancers were not visible on the oblique view only.
      Secondly, benign appearing round masses and asymmetric densities seen with the
      oblique view only were resolved as more suspicious irregular masses with both
      views, leading to recall. In conclusion, there are cancers that cannot be
      adequately visualized on the oblique view alone. These are most commonly the
      small invasive cancers, which are of the greatest prognostic significance in
      breast cancer screening.

PMID- 10580764
TI  - Transorbital optic nerve sheath ultrasonography in normal children.
AB  - AIM: Early diagnosis of acute intracranial hypertension is essential to enable
      prompt, optimal treatment. The optic nerve sheath diameter (ONSD) is increased in
      raised ICP and there has been recent interest in the use of ultrasound to
      diagnose and indirectly monitor raised ICP by ONSD measurement. The advantages of
      the technique include its non-invasiveness, wide availability, portability, low
      cost and the absence of ionizing radiation. This prospective study was designed
      to establish the range of normal values for ONSD in infants and children up to 15
      years of age. PATIENTS AND METHODS: One hundred and two children attending the
      hospital for other reasons were recruited to the study. Three measurements of the
      ONSD were taken for each eye, 3 mm behind the optic nerve head using a 7 MHz
      sector probe. RESULTS: The range for ONSD was 2.1-4.3 mm, mean 3.08 (SD 0.36).
      There were no significant differences on ONSD measurement between boys and girls
      (P = 0.59) or between right and left eyes (P=0.66). When the data were grouped
      and analysed, a correlation between increasing age and increasing ONSD was seen
      (r2=0.48), with the greatest increase occurring in the first 2 months of life.
      CONCLUSION: Using the technique described here, our results suggest that an ONSD
      of greater than 4 mm in infants less than 1 year, and 45 mm or greater in older
      children, should be regarded as abnormal.

PMID- 10580765
TI  - MRI appearances of the infrapatellar fat pad in occult traumatic patellar
      dislocation.
AB  - AIM: A study was undertaken to determine the status of Hoffa's infrapatellar fat
      pad in instances of acutely dislocated patellae. MATERIALS AND METHODS: The study
      consisted of MR examinations performed on 18 consecutive patients with acutely
      dislocated and relocated patellae with a mean interval between injury and MR
      examination date of 14.8 days (range 1-60 days). An analysis of the attachments
      and intrinsic signal characteristics of the fat pad was performed for each
      individual case. RESULTS: Hoffa's fat pad was abnormal in all cases. Shear injury
      from the inferior pole of the patella was present in 16 cases. Intrasubstance
      disruption with fluid filled clefts were noted in 12 cases. In 17 cases diffuse
      oedema of Hoffa's fat pad had occurred. In nine cases the damaged fat pad
      mimicked a loose body, while in five cases an intra-articular post-traumatic
      loose body was identified. CONCLUSION: Post-traumatic change in Hoffa's fat pad
      is a constant secondary MR feature not previously reported, that can be added to
      the spectrum of indirect findings in cases of occult patellar dislocation. In
      addition, the MRI distinction between post-traumatic changes in Hoffa's
      infrapatellar fat pad from loose osteo-chondral bodies can be difficult,
      requiring further correlative imaging.

PMID- 10580766
TI  - Supradiaphragmatic manifestations of papillary serous adenocarcinoma of the
      ovary.
AB  - AIM: To illustrate unusual patterns of isolated supradiaphragmatic presentation
      and relapse of papillary serous adenocarcinoma of the ovary. METHODS:
      Retrospective study of five women (26-57 years) managed by a specialist
      gynaecological oncology unit. RESULTS: Three women relapsed in the neck,
      mediastinal or axillary nodes 3 to 5 years after complete abdomino-pelvic
      remission. Two women presented with pleural or cervical lymph node metastases
      respectively 2 and 13 years before the primary pelvic tumour was discovered.
      Clinical presentations in these five women mimicked metastatic thyroid and breast
      cancer and mesothelioma. In four of the five woman supradiaphragmatic nodal
      disease was heavily calcified. CONCLUSION: Women with papillary serous ovarian
      cancer may develop supradiaphragmatic disease without evidence of peritoneal
      metastasis or primary pelvic tumours. Isolated supradiaphragmatic relapse may
      occur many years after complete remission of abdomino-pelvic disease.
      Calcification in supradiaphragmatic lymph nodes should not be assumed to be due
      to old granulomatous disease as this may be the only clue to relapsing disease.
      Review of prior histology and use of immunohistochemical stains were valuable in
      diagnosis of these cases.

PMID- 10580767
TI  - Extra-renal pseudoaneurysm: an uncommon complication following renal
      transplantation.
AB  - Vascular complications are reported in a significant proportion of patients
      following renal transplantation and are a contributory cause of graft
      dysfunction. Of these, pseudoaneurysm formation is one of the least common. We
      present three patients in whom extra-renal transplant artery pseduoaneurysms
      arising from the surgical anastomosis between the external iliac and renal
      transplant artery were initially diagnosed with colour Doppler ultrasound, and
      outline their subsequent management.

PMID- 10580768
TI  - Long-term follow-up of the Bird's Nest IVC Filter.
AB  - AIM: This study is a long-term clinical follow-up of the Bird's Nest Filter which
      addresses issues such as caval patency, filter integrity, morbidity and
      mortality. MATERIALS AND METHODS: 78 consecutive patients with Bird's Nest
      Filters inserted between 1989 and 1994 were recalled for clinical assessment and
      imaging follow-up. Pre- and post-filter medical histories were obtained from the
      patients and their medical records. They were examined for clinical signs of
      inferior vena cava occlusion. Imaging follow-up was by plain abdominal
      radiography, colour duplex ultrasound and computed tomography. RESULTS: 52
      patients were alive and well at 4-6 years. Thirty-day mortality was 5.1%. Three
      year mortality was 19.2%. Recurrent pulmonary embolus occurred in 1.3%. IVC
      occlusion was demonstrated in 4.7%. No evidence of filter migration was seen.
      Wire prolapse occurred in 70% on abdominal X-ray and asymptomatic performation of
      the caval wall in 85.3% on CT. Morbidity and mortality were the same whether the
      patient was anticoagulated or not. CONCLUSION: The Bird's Nest Filter is safe and
      effective in both the short and long term.

PMID- 10580770
TI  - Synchronous multicentric extraadrenal phaeochromocytoma: implications for
      management.

PMID- 10580769
TI  - Imaging features of leptomeningeal metastases.
AB  - AIMS: To assess the range of appearances, and accuracy of various methods of
      diagnosing leptomeningeal metastases. MATERIALS AND METHODS: In a retrospective
      study, the notes and imaging of all patients with a radiological and/or CSF
      cytological diagnosis of leptomeningeal metastasis (LM) were identified, and
      assessed for the following: age and sex, primary tumour type, presenting
      symptoms, initial radiological and cytological diagnosis, radiological
      appearances and length of survival following diagnosis. Discordance between the
      CSF cytology and radiological diagnosis of LM was also noted. RESULTS: 41
      positive cases (36 female) of LM were identified over a 2.7 year period
      (diagnosis based on: imaging only--19 cases, cytology only--6, both--16 cases).
      The average age was 48 years, and the most frequent primary tumour was breast
      carcinoma (27/41). Two thirds of patients presented with at least one cranial or
      spinal nerve palsy. Where performed, contrast-enhanced CT was normal in 40%
      (10/25), with LM mistaken for parenchymal disease in a further 24% (6/25). CSF
      cytology was positive in 85% (22/26). Gadolinium-enhanced MRI was positive in all
      cases where it was performed (25/25). Pial enhancement and nodularity was the
      commonest finding (67%), but other manifestations included nodular disease,
      neural enhancement and white matter changes. Prognosis was uniformly poor.
      CONCLUSION: Leptomeningeal metastatic disease has a poor prognosis, and treatment
      regimen may differ from those of parenchymal CNS metastases. CT is normal or
      misleading in two thirds of patients, and CSF cytology may also be negative.
      Gadolinium-enhanced T1-weighted MRI complements CSF cytology, and is the
      investigation of choice in patients with a non-haematological primary tumour and
      suspected LM.

PMID- 10580771
TI  - MRI of double hypophysis.

PMID- 10580772
TI  - CT diagnosis of reversible liver transplant ischemia.

PMID- 10580773
TI  - Multiple Symmetric Lipomatosis--MR appearances.
AB  - Multiple Symmetric Lipomatosis (MSL) is a rare disorder of lipid metabolism which
      is mainly seen in Mediterranean and eastern European populations, which results
      in massive fat accumulation mainly around the neck and back. The main
      differential diagnosis lies between MSL and the fat accumulation of Cushing's
      disease, and liposarcoma. This case demonstrates that MR imaging is a valuable
      aid to the diagnosis and treatment of this disease by giving excellent definition
      of soft tissue and vascular structures, allowing accurate assessment and
      preoperative planning of the disease.

PMID- 10580774
TI  - Reflections on reaching a quadricentennial.

PMID- 10580775
TI  - Serious co-morbidity among unselected cancer patients newly diagnosed in the
      southeastern part of The Netherlands in 1993-1996.
AB  - The purpose of this study was to determine the prevalence of serious concomitant
      conditions at diagnosis among unselected patients with cancer, increasingly older
      in industrialized countries. About 34,000 newly diagnosed cancer patients were
      recorded in the Eindhoven Cancer Registry between 1993 and 1996; subsequently
      data on serious co-morbidity, classified according to the Charlson scheme (J
      Chron Dis 1987; 40: 373-383), were collected from the clinical records by
      registry personnel. Co-morbid conditions were present in 12% of adult patients
      below 45 years of age, 28% of those 45-59 years, 53% of those 60-74 years, and
      63% of patients over 75 years of age, the prevalence being highest for patients
      with lung (58%), kidney (54%), stomach (53%), bladder (53%), and prostate cancer
      (51%). Males exhibited a 10% higher prevalence than females with similar tumors.
      Among patients over 60 years the most frequent conditions were heart and vascular
      diseases (ranging across the various tumors from 10% to 30%), hypertension (11
      25%), another cancer (10-20%), COPD (chronic obstructive pulmonary disease) (3
      25%), and diabetes mellitus (5-25%). Inclusion of frequent co-morbid conditions
      in prognostic research as well as the development of specific guidelines for
      patient care seems warranted.

PMID- 10580776
TI  - A comparison of two comorbidity instruments in arthritis.
AB  - Comorbidity (CM) is a powerful predictor of health outcome and cost, as well as
      an important confounder in many epidemiologic studies. However, choosing the most
      appropriate CM measurement instrument is difficult because comparative data on
      how the available instruments perform in various disease settings are limited. We
      collected CM data (from the complete medical records) for two population-based
      prevalence cohorts with rheumatoid arthritis (RA) and osteoarthritis (OA) and a
      comparison cohort without arthritis (NA), using two different CM instruments: the
      Charlson CM index (Charl), which is based on 17 diagnoses each weighted by
      mortality risk, and the Index of Coexistent Diseases (ICED), which estimates the
      severity and frequency of 14 comorbid conditions and provides an assessment of
      the impairment or disability caused by each. Cox proportional hazards modeling
      was used to assess the impact of the two types of comorbidity scores (Charl and
      ICED) on survival after prevalence (index) date, adjusting for the age, sex, and
      disease status. There were 450, 441, and 889 individuals in the RA, OA, and NA
      groups, respectively, with a mean follow-up period of 10.6 years. During the
      follow-up, 293, 307, and 546 deaths occurred in the RA, OA, and NA groups,
      respectively. The mean age and percent females were: 63.3 years, 74%; 70.7 years,
      74%; and 67.5 years, 75% for the RA, OA, and NA groups, respectively. Comorbidity
      was highest in RA, intermediate in OA, and lowest in NA by both Charl and ICED.
      Cox proportional hazards modeling demonstrated that both Charl and ICED were
      highly statistically significant predictors of mortality (P<0.0001) after
      adjusting for age, sex, and disease state (RA, OA, or NA) and that ICED remained
      highly significant as a predictor of mortality, even after adjusting for Charl.
      We conclude that estimating CM from medical records using ICED, an instrument
      that incorporates an assessment of impairment and disability, is feasible and
      that such as assessment provides information that independently predicts
      mortality, even after adjusting for the results of traditional diagnosis-based CM
      measures, such as Charl.

PMID- 10580777
TI  - Barriers to participation in randomised controlled trials: a systematic review.
AB  - METHOD: A systematic review of three bibliographic databases from 1986 to 1996
      identified 78 papers reporting barriers to recruitment of clinicians and patients
      to randomised controlled trials. RESULTS: Clinician barriers included: time
      constraints, lack of staff and training, worry about the impact on the doctor
      patient relationship, concern for patients, loss of professional autonomy,
      difficulty with the consent procedure, lack of rewards and recognition, and an
      insufficiently interesting question. Patient barriers included: additional
      demands of the trial, patient preferences, worry caused by uncertainty, and
      concerns about information and consent. CONCLUSIONS: To overcome barriers to
      clinician recruitment, the trial should address an important research question
      and the protocol and data collection should be as straightforward as possible.
      The demands on clinicians and patients should be kept to a minimum. Dedicated
      research staff may be required to support clinical staff and patients. The
      recruitment aspects of a randomised controlled trial should be carefully planned
      and piloted. Further work is needed to quantify the extent of problems associated
      with clinician and patient participation, and proper evaluation is required of
      strategies to overcome barriers.

PMID- 10580778
TI  - Validation of a predictive model for asthma admission in children: how accurate
      is it for predicting admissions?
AB  - We studied 364 index presentations to the Emergency Department of a children's
      hospital with a diagnosis of asthma. The admission rate for this group of
      children was about 31%. We developed a parsimonious multiple logistic regression
      model to predict asthma hospital admission based on asthma severity indicators.
      We then evaluated the model's predictive ability using two methods of cross
      validation, using the same sample that was used for the predictive model, and
      using data from a split sample. The logistic regression model had a predictive
      accuracy of 90% (95% confidence interval 85-95%). The sensitivity and specificity
      were 86% and 88%, respectively. Cross-validation models confirmed that the
      predictive ability of the model was stable. In studies with limited sample sizes,
      it is possible to validate a model without setting aside a split sample for cross
      validation.

PMID- 10580779
TI  - Analysis of case-cohort designs.
AB  - The case-cohort design is most useful in analyzing time to failure in a large
      cohort in which failure is rare. Covariate information is collected from all
      failures and a representative sample of censored observations. Sampling is done
      without respect to time or disease status, and, therefore, the design is more
      flexible than a nested case-control design. Despite the efficiency of the
      methods, case-cohort designs are not often used because of perceived analytic
      complexity. In this article, we illustrate computation of a simple variance
      estimator and discuss model fitting techniques in SAS. Three different weighting
      methods are considered. Model fitting is demonstrated in an occupational exposure
      study of nickel refinery workers. The design is compared to a nested case-control
      design with respect to analysis and efficiency in a small simulation. In this
      example, case-cohort sampling from the full cohort was more efficient than using
      a comparable nested case-control design.

PMID- 10580780
TI  - Design of a case control etiologic study of sarcoidosis (ACCESS). ACCESS Research
      Group.
AB  - Sarcoidosis is a chronic granulomatous disorder of unknown cause, characterized
      by activation of T-lymphocytes and macrophages. A Case Control Etiologic Study of
      Sarcoidosis (ACCESS) is a multicenter study designed to determine the etiology of
      sarcoidosis. The study organization includes 10 Clinical Centers, a Clinical
      Coordinating Center, specialized Core Laboratories, a Central Specimen
      Repository, and a Project Office at the National Heart, Lung, and Blood
      Institute. In addition to etiology, ACCESS will examine the socioeconomic status
      and clinical course of patients with sarcoidosis. We propose to enroll 720 newly
      diagnosed cases of sarcoidosis and compare them to 720 age, sex, and race matched
      controls and follow the first 240 cases for two years. Leads to the etiology of
      sarcoidosis have come from diverse sources: in clinical laboratory
      investigations, alveolitis has been found to precede granulomatous inflammation;
      in case control studies, familial aggregation has been identified; and in case
      reports, recurrence of granulomatous inflammation has been observed after lung
      transplantation. We describe the rationale for the study design based on genetic,
      environmental, infectious, and immune dysregulation hypotheses and the methods
      used for selecting controls. The cause may not prove to be a single, known
      exposure. Interactions of exposures with genetic predispositions would have
      important implications for our understanding of immune responses as well as the
      pathogenesis of sarcoidosis.

PMID- 10580781
TI  - Effect of hormone replacement therapy on the validity of the Friedewald equation
      in postmenopausal women: the postmenopausal estrogen/progestins interventions
      (PEPI) trial.
AB  - The Friedewald equation is often used to estimate low-density lipoprotein
      cholesterol (LDL-C). Hormone therapy is known to raise triglyceride (TG) and high
      density lipoprotein cholesterol (HDL-C) and alter lipid contents of lipoproteins.
      We compared Friedewald estimated LDL-C to measured LDL-C in PEPI participants on
      placebo or four different hormone treatment groups. At baseline, the 0.2
      coefficient for triglyceride (TG) was accurate for all five treatment groups.
      Among women who took >80% of their pills and whose TG was <4.5 mmol/l (400
      mg/dl), LDL-C was underestimated for 69-82% of the participants in the active
      treatment groups, compared to 50% in the placebo group. After 3 years of therapy,
      the TG coefficient that offered a better fit of the Friedewald equation in the
      active treatment groups was 0.39 for the equation in mmol/l (0.17 for the
      equation in mg/dl). Using this coefficient is clearly warranted for greater
      accuracy in research studies.

PMID- 10580783
TI  - Plasma fibrinogen and its correlates in elderly Japanese men living in Japan and
      Hawaii.
AB  - Plasma fibrinogen levels were determined using comparable methods for 329
      Japanese men in Hiroshima Japan, and 3571 Japanese-American men in Honolulu
      Hawaii, aged 71-93 years. The age-adjusted mean fibrinogen level in Japanese
      American men (307 mg/dl) was significantly higher (p<0.0001) than in native
      Japanese men (270 mg/dl). In multiple linear regression models, the fibrinogen
      level was associated significantly and positively with white blood cell count
      (WBC) and total cholesterol, and inversely with HDL cholesterol and hematocrit in
      both study samples. The strongest association with fibrinogen was shown for WBC,
      and this association was not mediated through cigarette smoking. The observed
      difference in fibrinogen levels could not be fully explained by WBC, total and
      HDL cholesterol, triglyceride, hematocrit, body mass index, and diabetes. Some
      unmeasured environmental or lifestyle variables such as diet and physical
      activity may be partly responsible for the observed difference in fibrinogen
      levels between native Japanese men and Japanese-American men in Hawaii.

PMID- 10580782
TI  - Lipid-lowering medication and risk of injury.
AB  - Meta-analyses of early primary prevention trials of lipid-lowering therapies
      suggested increased risk of injury deaths among treated persons. Our population
      based case-control study examined the association of lipid-lowering medication
      use with fatal and nonfatal injuries in 298 cases and 332 controls. No increased
      injury risk was observed among current (OR = 0.46, 95% CI 0.18-1.21) or past
      users (OR = .92, 95% CI 0.44-1.95), after adjustment for behavioral disorders,
      medical conditions, and health status. Stratified analyses did not reveal sub
      groups at significantly increased risk. These results, consistent with recent
      clinical trials and meta-analyses, suggest no increased injury risk associated
      with lipid-lowering medications.

PMID- 10580784
TI  - Serum ascorbic acid and other correlates of self-reported cataract among older
      Americans.
AB  - The purpose of this study was to examine the correlates of self-reported cataract
      among older Americans, and specifically, to determine whether serum ascorbic acid
      levels are associated with a decreased prevalence of cataract. A national
      probability survey of Americans, the Second National Health and Nutrition
      Examination Survey (NHANES II), was conducted between 1976 and 1980. A total of
      4001 participants were included between the ages of 60 and 74 years with data on
      serum ascorbic acid level and other variables of interest. A total of 252 women
      (12%) and 164 men (9%) reported a history of cataract. Serum ascorbic acid level
      was inversely associated with prevalence of cataract in multiple logistic
      regression analyses; each 1 mg/dl increase was independently associated with a
      26% decrease in cataract (P = 0.03). Other independent correlates of cataract
      included increasing age, female sex, smoking, and diabetes mellitus (all P<0.01).
      We identified four correlates of cataract among older Americans: serum ascorbic
      acid level, increasing age, smoking, and diabetes mellitus. Ascorbic acid, a
      water-soluble antioxidant found in high concentrations in the lens, may be of
      importance for the prevention of cataract among older Americans.

PMID- 10580785
TI  - Varying sensitivity of waist action levels to identify subjects with overweight
      or obesity in 19 populations of the WHO MONICA Project.
AB  - It has been suggested in the literature that cut-off points based on waist
      circumference (waist action levels) should replace cut-off points based on body
      mass index (BMI) and waist-to-hip ratio in identifying subjects with overweight
      or obesity. In this article, we examine the sensitivity and specificity of the
      cut-off points when applied to 19 populations with widely different prevalences
      of overweight. Our design was a cross-sectional study based on random population
      samples. A total of 32,978 subjects aged 25-64 years from 19 male and 18 female
      populations participating in the second MONICA survey from 1987 to 1992 were
      included in this study. We found that at waist action level 1 (waist
      circumference > or =94 cm in men and > or =80 cm in women), sensitivity varied
      between 40% and 80% in men and between 51% and 86% in women between populations
      when compared with the cut-off points based on BMI (> or =25 kg/m2) and waist-to
      hip ratio (> or =0.95 for men, > or =0.80 for women). Specificity was high (> or
      =90%) in all populations. At waist action level 2 (waist circumference > or =102
      cm and > or =88 cm in men and women, respectively, BMI > or =30 kg/m2),
      sensitivity varied from 22% to 64% in men and from 26% to 67% in women, whereas
      specificity was >95% in all populations. Sensitivity was in general lowest in
      populations in which overweight was relatively uncommon, whereas it was highest
      in populations with relatively high prevalence of overweight. We propose that cut
      off points based on waist circumference as a replacement for cut-off points based
      on BMI and waist-to-hip ratio should be viewed with caution. Based on the
      proposed waist action levels, very few people would unnecessarily be advised to
      have weight management, but a varying proportion of those who would need it might
      be missed. The optimal screening cut-off points for waist circumference may be
      population specific.

PMID- 10580786
TI  - Assessing smallest detectable change over time in continuous structural outcome
      measures: application to radiological change in knee osteoarthritis.
AB  - Interpreting changes in continuous structural outcome measures is a common
      problem in clinical research and in daily practice. We propose a method for
      estimating whether difference observed between two successive measures in an
      individual constitutes a statistically relevant change or a change induced by
      variability. This statistically relevant change is based on an analysis of
      reproducibility. The continuous structural outcome measure investigated as an
      example was joint space width (JSW) measurement on standard X-rays, which is
      known to be the primary end-point for assessing structural osteoarthritis
      progression. The results of the present study demonstrate that cutoffs are
      closely dependent on all sources of variabilities in JSW measurement such as
      joint positioning, radiographic procedure, and the measurement process itself.
      Therefore, we suggest to determine cutoffs for each study using a representative
      sample of the population studied and using the procedures and methods of
      measurement of the specific study. This approach may easily be extended to other
      continuous structural outcome measures.

PMID- 10580787
TI  - Discrepant analysis: a biased and an unscientific method for estimating test
      sensitivity and specificity.
AB  - Discrepant analysis is a widely used technique for estimating test performance
      indices (sensitivity, specificity, etc.) of DNA-amplification tests for detecting
      infectious diseases. It has recently been claimed that the discrepant analysis
      based estimates of specificity are typically less biased than those based on
      culture and that the discrepant analysis-based specificity shows little
      appreciable bias. In this article, I show that those conclusions are incorrect.
      Using a typical example from the published literature, I show that the discrepant
      analysis-based estimates of sensitivity and specificity can generate a
      significant and clinically important overestimation of the true sensitivity and
      specificity values. Moreover, I demonstrate that the concept of discrepant
      analysis is profoundly flawed and unscientific. It violates a fundamental
      principle of diagnostic testing-the principle that the new test should not be
      used to determine the true disease status. Thus, the major problem with
      discrepant analysis is not only that it is biased but that it is unscientific.
      Therefore, discrepant analysis should not be adopted for the evaluation of any
      diagnostic or screening test.

PMID- 10580788
TI  - A comparison of model-building strategies for lower respiratory tract infection
      in long-term care.
AB  - Five strategies for creating predictive models of lower respiratory tract
      infection in residents of long-term care facilities were compared. A linear
      judgment model was derived by administering clinical vignettes to physicians who
      indicated the risk of infection based on the presence or absence of five
      predictor variables. A model based on physician consensus was created using the
      same variables. Three models based on empirical data (logistic regression,
      proportional hazards, and recursive partitioning) were created from a
      "derivation" sample of data from a cohort study of lower respiratory tract
      infections in nursing homes using the five predictor variables. All models were
      applied to a validation set and compared using receiver operating characteristic
      (ROC) curves. The data-derived and consensus models showed the highest
      discriminative ability while the linear judgment model showed inferior
      performance.

PMID- 10580789
TI  - Quantifying excess length of postoperative stay attributable to infections: a
      comparison of methods.
AB  - To quantify the net effect of deep surgical site infection (DSSI) on
      postoperative stay (POS) among patients who had undergone open heart surgery, and
      to assess the comparability of two methods, two observational studies were
      conducted: one on a retrospective cohort of 701 operated patients, and the other
      on a cohort of 31 infected patients versus a cohort of uninfected patients, with
      1:1 matching. In addition to DSSI, a further three factors were identified by
      multivariate analysis as independent POS-related predictor variables. After
      internal validation of the multivariate model, excess POS attributable to DSSI
      amounted to 20.7 days (95% confidence interval [CI] 16.7-24.9). In contrast,
      excess length of stay attributable to DSSI among the matched pairs who survived
      infection (22) totaled 14.3 days (95% CI 3.2-25.4) and 26.5 days (mean and median
      differences). Multivariate techniques may prove a more appropriate and reliable
      analysis than matched-pair comparisons for the purpose of evaluating the extra
      stay and cost attributable to the nosocomial infections.

PMID- 10580790
TI  - Screening for coronary heart disease in elderly men based on current and past
      cholesterol levels.
AB  - Efficient use of cholesterol measurements to screen for coronary heart disease in
      the elderly is not well defined. The purpose of this report is to examine such
      screening based on national guidelines in a sample of older men. Since relations
      between cholesterol and coronary heart disease are better established in those
      who are younger, screening in the elderly will also consider levels of
      cholesterol that existed earlier in life. Data are from a prospective study of
      1,170 men enrolled in the Honolulu Heart Program who were followed over a 12-year
      period for coronary heart disease. Follow-up began from 1980 to 1982, when
      cholesterol levels were determined in men who were aged 61 to 81 years. Past
      cholesterol levels were measured 10 years earlier (1970-1972). During the course
      of follow-up, coronary heart disease developed in 117 of the men. Risk of disease
      rose significantly (P = 0.003) with increases in past cholesterol levels (1970
      1972) but not with more recent levels (1980-1982). For men with current
      cholesterol levels that were desirable (<5.2 mmol/L [200 mg/dl], as defined by
      guidelines from the National Cholesterol Education Program), disease incidence
      continued to rise with increasing past cholesterol levels (P<0.001). Accounting
      for high-density lipoprotein cholesterol and other screening factors did little
      to alter these findings. We conclude that desirable cholesterol levels in the
      elderly may not be a marker of a healthy risk profile if past cholesterol levels
      were high. Screening for coronary heart disease in the elderly could be improved
      by considering past cholesterol levels, rather than just a single measurement in
      later life.

PMID- 10580791
TI  - Risk factors for mental disorder hospitalization after the Persian Gulf War: U.S.
      Armed Forces, June 1, 1991-September 30, 1993.
AB  - Effects of Persian Gulf War (August 2, 1990-July 31, 1991) and Gulf War
      occupation on post-War hospitalization risk were evaluated through Cox
      proportional hazards modeling. Active-duty men (n = 1,775,236) and women (n =
      209,760) in the Army, Air Force, Navy, and Marine Corps had 30,539 initial
      postwar hospitalizations for mental disorders between June 1, 1991 and September
      30, 1993. Principal diagnoses in the Defense Manpower Data Center hospitalization
      database were grouped into 10 categories of ICD-9-CM codes. Gulf War service was
      associated with significantly greater risk for acute reactions to stress and
      lower risk for personality disorders and adjustment reactions among men.
      Personnel who served in ground war support occupations (men and women) were at
      greater risk for postwar drug-related disorders. Men who served in ground war
      combat occupations were at higher risk for alcohol-related disorders.
      Longitudinal studies of health, hospitalization, and exposure beginning at
      recruitment, are needed to better understand how exposure to combat affects the
      mental health of military personnel.

PMID- 10580793
TI  - On the alleged protective effect of stratification against "type I" error.

PMID- 10580792
TI  - Determining exposure underreporting in pharmacoepidemiologic case-control
      studies: methods and example.
AB  - Many pharmacoepidemiologic case-control studies have to rely on what their
      subjects relate about the drugs to which they have been exposed and the durations
      of exposure. There is often good reason to suppose that not all exposures are
      actually reported and to suspect reporting rates may differ between cases and
      controls. We introduce two procedures designed to determine the extent of
      underreporting of exposures. These procedures make use of data from the case
      control study itself, as well as sales, demographic and market research data for
      a reference population to which study subjects belong. We apply these procedures
      to data from the International Primary Pulmonary Hypertension Study (IPPHS)
      linking anorexigens with PPH. We show that exposures to the anorectic agent
      dexfenfluramine beginning in or before 1989 were highly significantly
      underrepresented in the data for IPPHS controls, relative to exposures beginning
      after 1989 (P<0.01); there is no corresponding evidence for relative
      underrepresentation of early exposure for IPPHS cases. However, data on control
      exposures from 1990 to 1992 are consistent with the hypothesis that these
      exposures were not underreported to the IPPHS. Subject to certain key modeling
      assumptions and the availability of some supplemental data, it is possible to
      investigate the extent of underreporting of exposure in a pharmacoepidemiologic
      case-control study and in particular to determine if study results are likely to
      have been affected by recall bias.

PMID- 10580794
TI  - Onset of natural menopause.

PMID- 10580795
TI  - Role of the cervical lymphatics in the Th2-type hierarchy of CNS immune
      regulation.
AB  - CNS immune regulation is intimately dependent on the dynamics of cerebral
      extracellular fluid circulation. Animal models indicate that following the
      introduction of antigen into the CNS, normal circulation of interstitial and
      cerebrospinal fluids provides the opportunity for (a) delivery of CNS-derived
      antigen to lymphoid organs, as well as, (b) retention of immunologically
      significant amounts of antigen within the CNS. Thus, even in the absence of
      disease, CNS-derived antigen can induce antigen-specific activation of naive
      lymphocytes in lymphoid organs and specific reactivation of lymphoblasts that
      have migrated into the CNS. The initial peripheral immune response to CNS-derived
      antigen is induced in cervical lymph nodes and is characterized by a strong
      antibody response, no delayed-type hypersensitivity, and only priming for
      cytotoxic T-cell responses. This Th-2 type hierarchy of immune regulation is
      reinforced within the antigen-stimulated CNS where specific B lymphoblasts are
      permitted to develop their effector function but cell-mediated immunity is
      inhibited. Developing a paradigm for CNS immune regulation is important in
      understanding how CNS disorders in humans are induced, perpetuated, and may be
      manipulated.

PMID- 10580796
TI  - Mast cell production of TNF-alpha induced by substance P evidence for a
      modulatory role of substance P-antagonists.
AB  - Unregulated increasing of Tumor necrosis factor-alpha (TNF-alpha) could be
      pathogenic in inflammatory diseases. The aim of this study was to investigate the
      anti-inflammatory role of the Substance P-antagonists (SPAs) through the
      inhibition of histamine release (HR) and TNF-alpha production from mast cell. Rat
      peritoneal mast cells (PMC) stimulated with Substance P (SP), in the presence of
      SPAs or not, were analyzed for HR and TNF-alpha protein production. Competitive
      Polymerase Chain Reaction, with an internal standard competing with target cDNA
      for the same primers, was used to determine the TNF-alpha mRNA expression. We
      show that the increase of either HR and TNF-alpha levels in peritoneal (PMC)
      after induction with SP was inhibited by pre-incubation with SPA or with the
      Peptide 101 (P101), while the [D-Pro2, D-Phe7, D-Trp9]-SP (dSP) had no effect.
      Neuraminidase treatment suggests that dSP, as well as SP, interacts with sialic
      acid residues on the cell surface. Moreover, SPA and P101 also inhibit the
      release of histamine and TNF-alpha induced by dSP suggesting that a receptor
      independent mechanism is involved. These data could be useful to better
      understand the mechanisms involved in the mast cell activation and TNF-alpha
      production in the inflammatory diseases where SP is involved.

PMID- 10580797
TI  - Lymphocytic responses and the gradual hippocampal neuron loss following infection
      with lymphocytic choriomeningitis virus (LCMV).
AB  - Infection of rats with LCMV is known to cause a bi-phasic neurodegeneration
      characterized by acute T lymphocyte-mediated cerebellar damage, followed by
      gradual hippocampal neuron loss that occurs by an undefined mechanism. We found
      infiltration of CD8 + T-cells (but not CD4 + or NK cells) in the hippocampus
      which correlated with the acute phase, but not the chronic hippocampal
      degenerative phase. While immunosuppression of T lymphocytes protected the
      cerebellum and revealed the infection of corticohippocampal glia, the
      degeneration in the hippocampus was unabated. These data suggest that T
      lymphocytes control glial infection and mediate degeneration in the cerebellum
      but not the hippocampus.

PMID- 10580798
TI  - Increased expression of bioactive chemokines in human cerebromicrovascular
      endothelial cells and astrocytes subjected to simulated ischemia in vitro.
AB  - Leukocyte infiltration into the brain has been implicated in the development of
      ischemic brain damage. In this study, simulated in vitro ischemia/reperfusion and
      IL-1beta were found to up-regulate both the expression of intercellular adhesion
      molecule- (ICAM-1) in cultured human cerebromicrovascular endothelial cells
      (HCEC) and the adhesion of allogenic neutrophils to HCEC. Both HCEC and human
      fetal astrocytes (FHAS) also responded to IL-1beta and to in vitro
      ischemia/reperfusion by a pronounced up-regulation of IL-8 and MCP-1 mRNA and by
      increased release of IL-8 and MCP-1 in cell culture media. FHAS were found to
      release 30-times higher levels of MCP-1 than HCEC under both basal and ischemic
      conditions. However, 100 u/ml IL-1beta induced greater stimulation of both IL-8
      and MCP-1 secretion in HCEC (50 and 20 times above controls, respectively) than
      in FHAS (three and two times above controls, respectively). IL-8 was the
      principal neutrophil chemoattractant released from IL-1beta-treated HCEC, since
      IL-8 antibody completely inhibited neutrophil chemotaxis enticed by HCEC media.
      However, the IL-8 antibody neutralized only 50% of IL-1beta-stimulated neutrophil
      chemoattractants released from FHAS, and 40%-60% of ischemia-stimulated
      chemotactic activity released by either HCEC or FHAS. These results suggest that
      simulated in vitro ischemia, in addition to IL-8 and MCP-1, stimulates secretion
      of other bioactive chemokines from HCEC and FHAS.

PMID- 10580799
TI  - Cerebrospinal fluid levels of soluble CD14 in inflammatory and non-inflammatory
      diseases of the CNS: upregulation during bacterial infections and viral
      meningitis.
AB  - The CD14 antigen, an important cell surface molecule of monocytic cells, is
      involved in cellular activation: it binds lipopolysaccharide and other cellular
      lipid structures. Brain macrophages play a pivotal role during inflammatory
      reactions of the CNS parenchyma, ventricles and meninges. A soluble form of CD14
      (sCD14) was measured in paired cerebrospinal fluid (CSF) and serum samples from
      91 patients with different neurological diseases. Mean levels of circulating
      sCD14 in CSF in a control group of 22 patients with neurologic complaints but no
      neurological deficit on clinical examination were 0.19 +/- 0.06 (mean +/- SD)
      mg/l. The CSF/blood ratios of sCD14 was 49 +/- 16 x 10(-3), while those of
      albumin were 4.4 +/- 1.4 x 10(-3). These extremely high CSF/blood ratios of the
      sCD14 molecule compared to albumin indicate a local cerebral production. No
      significant changes in CSF sCD14 levels were found in patients with non
      inflammatory neurological diseases (NID). In contrast, CSF sCD14 levels were
      markedly elevated during acute meningitis, but there was no direct correlation
      between sCD14 and monocyte count in the CSF. Thus, sCD14 could not originate in
      the CSF compartment from monocytes alone. The highest values for sCD14 were found
      in CSF during infections with various pathogens such as Staphylococcus aureus or
      Listeria monocytogenes. While sCD14 serum levels dramatically increased during
      acute bacterial meningitis, sCD14 ratios did not correlate with albumin ratios
      during the course of disease. Therefore, increased CSF sCD14 may originate from
      cerebral production by activated or infiltrated macrophages rather than passive
      diffusion from the blood, while elevated sCD14 serum levels resulted from
      enhanced local production. Increased CSF and serum sCD14 values were also
      observed in meningitis caused by viral infection. As in bacterial meningitis,
      sCD14 in CSF specimens did not correlate with the function of the blood/CSF
      barrier. Repeated lumbar punctures revealed a normalization of CSF sCD14 levels
      during clinical recovery. These results provide the first evidence for local
      production of sCD14 within the CNS. Our findings further indicate that sCD14 in
      CSF is a reliable marker for activation of macrophages within the CNS during
      inflammatory processes.

PMID- 10580800
TI  - Immunoblot and immunohistochemical comparison of murine monoclonal antibodies
      specific for the rat D1a and D1b dopamine receptor subtypes.
AB  - The two D1-like dopamine receptor subtypes, D1a and D1b, are structurally similar
      and pharmacologically indistinguishable using currently available ligands. To
      differentiate between the D1-like dopamine receptor subtypes, murine monoclonal
      antibodies to the rat Dla and the rat D1b dopamine receptor have been prepared.
      Rat D1-like and D2-like dopamine receptors expressed in Sf9 cells were used to
      verify the immunospecificity of the monoclonal anti-(D1a dopamine receptor) and
      anti-(D1b dopamine receptor) antibodies using immunoblot and immunohistochemical
      techniques. These two antibodies were used to compare the temporal dynamics of D1
      like dopamine receptors expressed in Sf9 cells following infection with
      recombinant baculovirus and to monitor the partial purification of detergent
      solubilized receptors following ion exchange chromatography. Immunoreactivity of
      the anti-(D1a receptor) antibody was observed in the striatum and cortical
      regions of the rat brain using immunoblot techniques. No reactivity on
      immunoblots was observed for the anti-(D1b receptor) antibody using rat brain
      tissue, probably due to the low levels of receptor expression. For
      immunohistochemical studies using rat brain slices, the anti-(D1a receptor)
      antibody heterogeneously labeled cells and punctate processes within the striatal
      neuropil while labeling in the adjacent cerebral cortex was weak. Anti-(D1b
      receptor) antibody immunoreactivity was weak in the .striatum and generally
      limited to sparse perikarya in the dorsal region. However, immunoreactivity was
      observed in numerous cells within the vertical and horizontal limbs of the
      diagonal band and in the ventral pallidum. Immunoreactivity of the anti-(D1b
      receptor) antibody was also observed in layer V pyramidal neurons of the frontal
      sensorimotor cortex.

PMID- 10580801
TI  - IL-6 plays a crucial role in the induction phase of myelin oligodendrocyte
      glucoprotein 35-55 induced experimental autoimmune encephalomyelitis.
AB  - We investigated the role of IL-6 in myelin oligodendrocyte glycoprotein (MOG)
      peptide induced experimental autoimmune encephalomyelitis (EAE) using IL-6
      deficient mice and found that IL-6-deficient mice were resistant to active
      induction of EAE, but that the treatment of those mice with IL-6 during the
      preclinical phase caused typical EAE. We also found that both wild-type and IL-6
      deficient mice were resistant to passive transfer of EAE by lymphocytes from IL-6
      deficient mice, but that passive transfer of lymphocytes from wild-type mice
      induced typical EAE in IL-6-deficient mice. Histological abnormalities of the
      central nervous system (CNS) in those IL-6-deficient mice with EAE were similar
      to those in wild-type mice with EAE. Reverse transcriptase-polymerase chain
      reaction (RT-PCR) analysis revealed no difference in the production of
      inflammatory cytokines such as IL-1beta, IL-2, TNF-alpha, and IFN-gamma in the
      CNS of IL-6-deficient mice with EAE as compared to the CNS of wild-type mice with
      EAE. These results indicated that IL-6 might be an important factor in the
      induction phase, but might have little influence on the effector phase of EAE. We
      further estimated the production of cytokines in MOG-stimulated lymph node (LN)
      cells by enzyme-linked immunosorbent assay. Increased IL-4 and IL-10 production
      and reduced IL-2 and IFN-gamma production were observed in LN cells from IL-6
      deficient mice as compared to LN cells from wild-type mice. These results
      suggested that a shift of T cell responses from Thl to Th2 might explain the
      resistance of IL-6-deficient mice to EAE. Taken together, IL-6 may play a crucial
      role in the induction phase of EAE by modulating Th1/Th2 balance.

PMID- 10580802
TI  - Polymorphisms at - 174 and in the 3' flanking region of interleukin-6 (IL-6) gene
      in patients with myasthenia gravis.
AB  - We examined the bi-allelic polymorphism at - 174 in the promoter region and the
      polymorphism in the 3' flanking AT rich region of the interleukin-6 (IL-6) gene
      in Swedish patients with myasthenia gravis (MG) and ethnically matched healthy
      individuals. There was no association between the polymorphisms and the disease.
      There was no relation of the polymorphisms to the clinical variables, the thymic
      histopathologies, the level of serum acetylcholine receptor antibodies or the
      concentrations of IgG and its subclasses. Our data yield no evidence for the IL-6
      gene contributing to the disease susceptibility.

PMID- 10580803
TI  - Comparison of the effects of dopaminergic and serotonergic activity in the CNS on
      the activity of the immune system.
AB  - This work demonstrates that the natural killing function of the innate immune
      system is affected in psychiatric disorders related primarily to serotonergic
      pathways in the CNS rather than to psychiatric disorders which involve mainly
      dopaminergic pathways. Only depressive patients demonstrated low natural killer
      (NK) cell activity, which is inversely correlated to the intensity of depression
      and could be reversed by serotonin selective re-uptake inhibitors concomitant
      with clinical improvement. This phenomenon is absent in Parkinson's and
      schizophrenic patients, in whom no reduction in NK activity was observed. Also,
      no effect on NK activity could be demonstrated following the specific respective
      treatments by dopamine (D2) blockers or agonists.

PMID- 10580804
TI  - Oligoclonal IgG bands in Japanese multiple sclerosis patients.

PMID- 10580805
TI  - Interleukin-10 (IL10) promoter polymorphisms and multiple sclerosis.
AB  - Interleukin-10 (IL10) is an anti-inflammatory cytokine which may modulate disease
      expression in multiple sclerosis (MS). Three dimorphic polymorphisms within the
      IL10 promoter region at positions - 1082, -819 and -519 have previously been
      identified. The - 1082*A allele has been associated with low and the - 1082*G
      allele with high in vitro IL10 production. We have genotyped 185 Caucasian MS
      patients and 211 ethnically matched controls for each of these three dimorphisms.
      MS patients were stratified for severity of disease outcome. No associations were
      found for any IL10 promoter polymorphisms when the MS cases were compared with
      controls or with disease outcome with regards to disability. IL10 polymorphism
      does not appear to be associated with MS or to influence disease progression.

PMID- 10580806
TI  - IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic
      brain injury: relationship to IL-6, TNF-alpha, TGF-beta1 and blood-brain barrier
      function.
AB  - Controlling the extent of inflammatory responses following brain injury may be
      beneficial since posttraumatic intracranial inflammation has been associated with
      adverse outcome. In order to elucidate the potential role of anti-inflammatory
      mediators, the production of interleukin-10 (IL-10) was monitored in paired
      cerebrospinal fluid (CSF) and serum of 28 patients with severe traumatic brain
      injury (TBI) and compared to control samples. The pattern of IL-10 was analyzed
      with respect to the patterns of IL-6, tumor necrosis factor-alpha (TNF-alpha) and
      transforming growth factor-beta1 (TGF-beta1) in both fluids during a time period
      of up to 22 days. In parallel, the function/dysfunction of the blood-brain
      barrier (BBB) was monitored using the CSF-/serum-albumin quotient (Q(A)) and
      compared to intrathecal cytokine levels. Mean IL-10 concentration in CSF was
      elevated in 26 out of 28 TBI patients (range: 1.3-41.7 pg/ml) compared to
      controls (cut-off: 1.06 pg/ml), whereas only seven patients had elevated mean IL
      10 concentration in serum (range: 5.4-23 pg/ml; cut-off: 5.14 pg/ml). The time
      course of IL-10 was similar in both fluids, showing a peak during the first days
      and a second, lower rise in the second week. Intrathecal IL-10 synthesis is
      hypothesized since CSF-IL-10 levels exceeded serum-IL-10 levels in most of the
      patients, IL-10-index (CSF/serum-IL-10/QA) was elevated in 23 individuals, and
      elevation of CSF-IL-10 showed to be independent from severe BBB dysfunction.
      Neither CSF nor serum IL-10 values correlated with the dysfunction of the BBB. IL
      10, IL-6 and TGF-beta1 showed similar patterns in CSF over time, whereas rises of
      TNF-alpha corresponded to declines of IL-10 levels. Our results suggest that IL
      10 is predominantly induced intrathecally after severe TBI where it may
      downregulate inflammatory events following traumatic brain damage.

PMID- 10580807
TI  - Interleukin-17 stimulates the expression of IkappaB alpha mRNA and the secretion
      of IL-6 and IL-8 in glioblastoma cell lines.
AB  - Interleukin-17 (IL-17) has been characterized as a proinflammatory cytokine
      produced by CD4+ activated memory T cells. In an effort to elucidate the
      biological effects of IL-17 in glial cells, we investigated the ability of this
      cytokine in order to activate nuclear factor (NF)-kappaB, which is being
      discussed as one of the most important transcription factors in the regulation of
      neuronal and glial cell function. Activation of NF-kappaB involves the
      degradation of its cytoplasmatic inhibitor IkappaB-alpha, which allows the
      nuclear translocation of NF-kappaB, and ensures transcriptional activation of
      genes including IkappaB-alpha itself. Using a competitive RT-PCR, we examined the
      IL-17-induced IkappaB-alpha mRNA expression in glioblastoma cells, and we
      examined IL-17 up-regulated IkappaB-alpha mRNA expression in a dose- and time
      dependent fashion with a maximum time between 1 and 3 h. This induction could be
      inhibited by Calphostin C (protein kinase C inhibitor) and genistein (tyrosine
      kinase inhibitor). After 60 min of IL-17 stimulation, a degradation of the
      IkappaB-alpha protein was detectable. Furthermore, IL-17 stimulated the secretion
      of IL-6 and IL-8 in glial cells, and IL-17 and IL-1beta in combination showed a
      superadditive effect. We suggest IL-17 to play a role as an immune factor,
      possibly involved in complex pathophysiological interactions of neurodegenerative
      diseases.

PMID- 10580808
TI  - Cytokine regulation of CD40 expression in fetal human astrocyte cultures.
AB  - CD40 can participate in inflammatory processes after binding its cognate ligand
      (CD40L). We found that fetal human astrocytes constitutively express CD40 mRNA
      and protein. Upon incubating cultures with proinflammatory cytokines (TNF-alpha,
      IL-1beta and IFN-gamma) or with lipopolysaccharide (LPS), CD40 expression was
      increased. No change in CD40 expression was noted in astrocyte cultures incubated
      with IL-6, HIV or gp41. Astrocytes also showed increased release of
      proinflammatory cytokines TNF-alpha, IL-1beta and IL-6 after incubation with
      CD40L peptide. These observations suggest a role for CD40 in central nervous
      system (CNS) inflammation and that CD40/CD40L autocrine or paracrine pathways may
      mediate this role.

PMID- 10580810
TI  - Differential effector and secretory functions of microglial cell lines derived
      from BCG-resistant and -susceptible congenic mouse strains.
AB  - Using congenic strains of mice susceptible (bcg(s)) or resistant (bcg(r)) to BCG,
      murine microglial cell lines, RR4.R (BCG-resistant) and RR8.S (BCG-susceptible),
      were established in vitro. Comparative studies revealed that, although phagocytic
      to a similar extent, RR4.R cells were more active than RR8.S cells in terms of
      antimycobacterial activity. Interestingly, cells of resistant genotype secreted
      more nitric oxide, TNF-alpha and IL-12, but less IL-6, than susceptible cells,
      when stimulated with IFN-gamma alone or in combination with lipopolysaccharide.
      Nevertheless, no significant differences were observed between the two cell lines
      in terms of IL-1 beta or IL-10 secretion, or on assessment of cytokine production
      following exposure to a massive dose of lipopolysaccharide. Overall, these data
      provide the first evidence that resistant/susceptible genotype influences
      antimycobacterial activity, NO and cytokine production in microglial cells, the
      prototype of cerebral macrophages.

PMID- 10580809
TI  - Microglial proliferation in cortical neural cultures exposed to feline
      immunodeficiency virus.
AB  - Microglia are thought to play an important role in neurodegenerative changes due
      to infection with human or animal immunodeficiency viruses. Using feline
      immunodeficiency virus and cat neural cultures, we observed a dramatic increase
      in the accumulation of microglia from a basal rate of 5-7% day(-1) to 25-126%
      day(-1). Both live virus and heat-inactivated virus induced proliferation.
      Negligible proliferation was seen in purified microglial cultures. Conditioned
      medium from astrocytes or mixed neural cultures treated with feline
      immunodeficiency virus stimulated the proliferation of purified microglia.
      Disease progression may be facilitated by early non-infectious interactions of
      lentiviruses with neural tissue that promote the activation and proliferation of
      microglia.

PMID- 10580811
TI  - Depletion of Vbeta4 TCR does not induce resistance to EAN--further evidence for
      diversity of TCR usage.
AB  - In EAN, TCR variable (V) gene usage is still controversial. A dominant usage of a
      TCR Vbeta4-associated idiotype has been reported. To assess the role of TCR
      Vbeta4 positive T-cells in susceptibility to induction of EAN, we suppressed the
      selection of this idiotype by neonatal treatment of Lewis rats with anti-TCR
      Vbeta4 monoclonal antibody (mAb). Anti-Vbeta4 treatment had no effect on
      development of clinical disease after immunization with the neuritogenic P2
      peptide amino acids (aa) 53-78. Furthermore, lymph node cells from anti-Vbeta4
      treated animals isolated after immunization with P2-peptide did not exhibit a
      reduced proliferative response towards whole P2-protein or P2-peptide. Our
      results indicate that T-cells utilizing other TCR V chains can functionally
      replace the neuritogenic cell population, which is dominant in stable T-cell
      lines.

PMID- 10580812
TI  - Role of S-100beta as potential autoantigen in an autoimmune disease of the inner
      ear.
AB  - In Lewis rats, adoptive transfer of T cells specific for the calcium-binding
      protein S-100beta mediates experimental autoimmune encephalomyelitis, but
      surprisingly also induced a marked labyrinthitis associated with impairment of
      hearing. This suggests that transfer of S-100beta-specific T cells into
      susceptible animals could be a novel model to study autoimmunity of inner ear
      diseases. The investigation demonstrated in detail an inner ear involving,
      central nervous system (CNS)-specific autoimmune disease in order to identify a
      putatively shared autoantigen(s) in these pathologies. In fact, the model will be
      a useful tool to investigate in detail, the pathological mechanisms of the human
      inner ear disease associated with Vogt-Koyanagi-Harada disease.

PMID- 10580813
TI  - Signals for proinflammatory cytokine secretion by human Schwann cells.
AB  - Wallerian degeneration is a post-traumatic process of the peripheral nervous
      system whereby damaged axons and their surrounding myelin sheaths are
      phagocytosed by infiltrating leukocytes. Our studies indicate that Schwann cells
      could initiate the process of Wallerian degeneration by releasing proinflammatory
      cytokines involved in leukocyte recruitment and differentiation including IL
      1beta, MCP-1, IL-8 and IL-6. A comparison of the secretory pattern between nerve
      explants and cultured Schwann cells showed that each cytokine was differentially
      regulated by growth factor deprivation or axonal membrane fragments. Since
      Wallerian-like degeneration occurs in a wide variety of peripheral neuropathies,
      Schwann cell-mediated cytokine production may play an important role in many
      disease processes.

PMID- 10580814
TI  - The role of anti-myelin (auto)-antibodies in the phagocytosis of myelin by
      macrophages.
AB  - Plasma cells secreting antibodies directed to myelin components are present in
      CNS of MS patients and although the pathogenic role of such antibodies has yet to
      be established it is apparent from animal studies that anti-myelin antibodies are
      involved in myelin damage. In this study, we have investigated the effect of
      disease-promoting anti-myelin mAb on the phagocytosis of myelin by macrophages.
      Monoclonal antibodies directed to myelin basic protein (MBP)--clones 1, 12, 17,
      22, 26, proteolipid protein (PLP), galactocerebroside (GalC) and myelin
      oligodendrocyte glycoprotein (MOG)--clones Y1, Y4, Y6, Y7, Y9, Y10, Y11 and Z12
      were incubated with purified murine myelin labeled with DiI. The degree of
      phagocytosis of antibody-treated myelin by murine macrophages in vitro was
      determined using a quantitative flow cytometric assay. In comparison to untreated
      myelin pretreatment with myelin-specific mAb modified the degree of phagocytosis.
      The degree of opsonization of myelin was dependent on the isotype of antibody and
      the epitope recognized in addition to the ability of the mAb to fix complement.
      The greatest degree of opsonization of myelin was observed with the monoclonal
      antibody MOG Z12 that has previously been shown to enhance EAE and augment
      demyelination. These findings suggest a major role for anti-myelin antibodies, in
      particular antibodies directed to MOG, for the phagocytosis of myelin by
      macrophages in vitro. This may have relevance to the pathogenesis of myelin
      damage in vivo and provide a helpful tool for the classification of heterogeneous
      diseases such as MS.

PMID- 10580815
TI  - Beta2-adrenergic receptor stimulation inhibits nitric oxide generation by
      Mycobacterium avium infected macrophages.
AB  - Catecholamine regulation of nitric oxide (NO) production by IFNgamma-primed
      macrophages infected with Mycobacterium avium was investigated. Epinephrine
      treatment of IFNgamma-primed macrophages at the time of M. avium infection
      inhibited the anti-mycobacterial activity of the cells. The anti-mycobacterial
      activity of macrophages correlated with NO production. Using specific adrenergic
      receptor agonists, the abrogation of mycobacterial killing and decreased NO
      production by catecholamines was shown to be mediated via the beta2-adrenergic
      receptor. Elevation of intracellular cAMP levels mimicked the catecholamine
      mediated inhibition of NO in both M. avium infected and LPS stimulated
      macrophages. Specific inhibitors of both adenylate cyclase and protein kinase A
      prevented the beta2-adrenoceptor-mediated inhibition of nitric oxide production.
      Beta2-adrenoreceptor stimulation at the time of M. avium infection of IFNgamma
      primed macrophages also inhibited expression of iNOS mRNA. These observations
      show that catecholamine hormones can affect the outcome of macrophage-pathogen
      interactions and suggest that one result of sympathetic nervous system activation
      is the suppression of the capacity of macrophages to produce anti-microbial
      effector molecules.

PMID- 10580816
TI  - Expression of MHC class I heavy chain and beta2-microglobulin in rat brainstem
      motoneurons and nigral dopaminergic neurons.
AB  - We demonstrate here that motoneurons and nigral dopaminergic neurons in the
      brainstem of the adult rat, with the exception of motoneurons innervating ocular
      muscles, display high levels of both MHC class I heavy chain and beta2
      microglobulin mRNAs. These neurons also display interferon-gamma receptor mRNA.
      We find it striking that these particular neurons are those which are vulnerable
      to neurodegeneration in diseases such as Parkinson's disease (PD) and amyotrophic
      lateral sclerosis (ALS).

PMID- 10580817
TI  - Non-MHC gene regulation of nerve root injury induced spinal cord inflammation and
      neuron death.
AB  - Spinal ventral root avulsion leads to an inflammatory response around lesioned
      motoneurons and the subsequent degeneration of a large proportion of the neurons.
      We demonstrate here differences in the regulation of cytokine mRNAs,
      microglia/macrophage activation, MHC expression and nerve cell survival in the
      two inbred rat strains DA and ACI. These strains have similar major MHC
      haplotypes, but differ in their non-MHC background genes. T cells were rare in
      the lesioned segments and depletion of T cells did not affect the response. Thus,
      non-MHC gene(s) regulate the inflammation and neuron death after nerve trauma by
      mechanisms not involving antigen-specific immune responses.

PMID- 10580818
TI  - Changes in plasma cytokines induced by interferon-beta1a treatment in patients
      with multiple sclerosis.
AB  - It has been postulated that the efficacy of interferon-beta1a in multiple
      sclerosis may be due to the induction of type 2 cytokines. In this report we
      demonstrate that after 3 months of therapy, there is no sustained alteration in
      the plasma levels of type 1 (IL-12, IL-1beta and TNF-alpha) or type 2 (IL-6, IL
      10) cytokines, but rather repeated induction of both with each injection. Little
      alteration is seen in the profile of cytokines induced with time, despite a
      decline in side effects. This suggests that IFN-beta1a causes repeated transient
      modulation of cytokine expression, but no sustained deviation in the type 1/type
      2 balance.

PMID- 10580819
TI  - Physician surplus and its remedies.

PMID- 10580820
TI  - Combined limited internal fixation with circular frame external fixation of intra
      articular tibial fractures.
AB  - High-energy intra-articular fractures of the tibial plateau and plafond cause
      ongoing management problems for the orthopedic surgeon. This study
      retrospectively evaluated 37 such fractures treated with limited internal
      fixation and circular frame external fixators. Seventeen plateau fractures (5
      open) and 20 plafond fractures (9 open) were treated. Time to union, number of
      procedures, complications, and functional outcomes were evaluated. All tibial
      plateau fractures healed within an average of 3.8 months. Eighteen of 20 plafond
      fractures healed at an average of 4.8 months. There was a high complication rate
      as is common with these injuries, but most of the complications were minor and
      easily treated.

PMID- 10580821
TI  - The use of three-dimensional computed tomography in evaluating snapping scapula
      syndrome.
AB  - This article evaluates imaging of the scapula and scapulothoracic joint in
      patients with snapping scapula syndrome. Between 1990 and 1996, a total of 20
      patients (10 men and 10 women) with snapping scapula syndrome were evaluated.
      Diagnosis was based on patient complaints and physical examination findings.
      There were 26 affected scapulae (6 patients had bilateral presentation). Imaging
      of the scapula included plain radiography, computed tomography (CT), and 3
      dimensional computed tomography (3-D CT) reconstruction. Plain radiography
      revealed bony incongruity between the anterior aspect of the scapula and the
      chest wall in 7 scapulae, CT revealed such incongruity in 19 scapulae, and 3-D CT
      revealed incongruity in all 26 scapulae. Treatment was conservative, consisting
      of nonsteroidal anti-inflammatory drugs, a physiotherapy program, and subscapular
      injection of a local anesthetic and steroids. In 5 patients who responded poorly
      to conservative treatment, the region responsible for the snapping was resected.
      Pain relief and resolution of the snapping were complete following surgery in 4
      patients, while pain and crepitation persisted in the fifth. Three-dimensional CT
      is recommended as the main imaging modality in the evaluation of any patient with
      snapping scapula syndrome who is a candidate for surgical intervention.

PMID- 10580822
TI  - Clinical, radiographic, and scintigraphic comparison of the mechanical stability
      of Mueller and Zweymueller total hip prostheses.
AB  - Twenty-two cemented Mueller and 25 uncemented Zweymueller total hip
      arthroplasties (THAs) were performed in the same period in 47 consecutive
      randomly selected patients with unilateral primary osteoarthritis. Patients were
      evaluated using the same clinical and radiographic protocol preoperatively; 3, 6,
      and 12 months postoperatively; and annually thereafter as well as with Tc 99m MDP
      three-phase bone scintigraphy 3, 6, 12, and 24 months postoperatively. At 11
      periprosthetic regions of interest (ROIs) around the stem and socket of each
      prosthesis, several radiographic parameters and bone scintigram uptake grade were
      recorded and correlated to determine the significance of early scintigraphic
      uptake for prediction of the stability of cemented and uncemented THA components
      over time. Around stable Zweymueller and Mueller sockets, the radionuclide uptake
      was similar during all periods of observation. Radionuclide uptake around stable
      Zweymueller stems was significantly more than around stable Mueller stems at the
      medial femoral cortex 3 and 6 months postoperatively, at the lateral femoral
      cortex 3-24 months postoperatively, and near the tip of the stem 3 months
      postoperatively. Radionuclide uptake around stable Mueller stems was
      significantly more than around Zweymueller stems at the greater trochanter 6 and
      12 months postoperatively and at the lesser trochanter 12 months postoperatively.
      Any significant deviation of radionuclide uptake at any ROI, time, and THA
      component during the first 2 years postoperatively in combination with
      radiographic findings of loosening should be considered a serious predictive sign
      for loosening of a Mueller or Zweymueller THA component.

PMID- 10580823
TI  - Behavior of the femoral stem in the Bihapro hip prosthesis.
AB  - This study evaluated the hydroxyapatite-coated femoral stem of the Bihapro hip
      prosthesis (Biomet Ltd, Bridgend, United Kingdom) using radiography, TC-99
      scintigraphy, and bone densitometry. Thirty stems with >2 years of follow-up
      (mean: 31 months) were evaluated. No loosening or changes in the position of the
      implant were seen, and the mean subsidence was 2.2 mm. Radiography revealed a
      densification in the metaphyseal zone with reconstruction of the trabecular lines
      in 21 cases, while in 22 patients, radiolucent lines in the distal area of the
      femoral component were observed. Scintigraphy showed a diaphyseal normo-captation
      in 19 cases and a hypercaptation <1.4 with a mean index of 1.1 in 10 patients.
      Metaphyseal hypercaptation >1.4 was seen in 24 patients. Bone densitometry
      revealed increased density in the metaphyseal zones in 29 patients with a
      periprosthetic/normal bone quotient of 1.4.

PMID- 10580824
TI  - Excision and radiotherapy for heterotopic ossification of the elbow.
AB  - Radiotherapy has a well-defined role in prophylaxis of recurrent heterotopic
      ossification of the hip, but has been described infrequently in other situations.
      This article reports the use of excision and low-dose external beam radiotherapy
      in three patients with heterotopic ossification of the elbow treated between
      February 1995 and September 1996. Radiotherapy was delivered in a single fraction
      of 7-8 Gy within 48 hours postoperatively using opposed anteroposterior portals.
      After a median follow-up of 10.5 months, all three patients demonstrated a
      significant increase in range of motion without any evidence of recurrence. These
      results indicate adjuvant postexcision radiotherapy may be used for prophylaxis
      of recurrent heterotopic ossification of the elbow.

PMID- 10580825
TI  - Tarsal coalition.

PMID- 10580826
TI  - The vertebral artery: surgical anatomy.
AB  - Anterior cervical decompressive surgery is widely performed for spondylosis,
      herniated intervertebral disk, tumor, infection, and trauma in the subaxial
      cervical spine region. Laceration of the vertebral artery is the most challenging
      of surgical dilemmas during anterior cervical spine surgery, as gaining control
      of the massive hemorrhage from a ruptured vertebral artery is difficult and could
      possibly result in an uncertain neurologic morbidity. As such, the understanding
      the surgical anatomy of the vertebral artery is essential to prevent iatrogenic
      injuries.

PMID- 10580827
TI  - Intraosseous ganglion of the greater trochanter.

PMID- 10580828
TI  - Lymphoma presenting as a disk prolapse.

PMID- 10580829
TI  - Osteoid osteoma of the distal phalanx.

PMID- 10580830
TI  - Synovial cutaneous fistula of the shoulder after failed rotator cuff repair.

PMID- 10580831
TI  - Radiologic case study. Osteochondritis dissecans of the talus.

PMID- 10580832
TI  - Synthetic DNA minor groove-binding drugs.
AB  - In this review, both cationic and neutral synthetic ligands that bind in the
      minor groove of DNA are discussed. Certain bis-distamycins and related
      lexitropsins show activities against human immunodeficiency virus (HIV)-1 and HIV
      2 at low nanomolar concentrations. DAPI binds strongly to AT-containing polymers
      and is located in the minor groove of DNA. DAPI intercalates in DNA sequences
      that do not contain at least three consecutive AT bp. Berenil can also exhibit
      intercalative, as well as minor groove binding, properties depending on sequence.
      Furan-containing analogues of berenil play an important role in their activities
      against Pneumocystis carinii and Cryptosporidium parvuam infections in vivo.
      Pt(II)-berenil conjugates show a good activity profile against HL60 and U-937
      human leukemic cells. Pt-pentamidine shows higher antiproliferative activity
      against small cell lung, non-small cell lung, and melanoma cancer cell lines
      compared with many other tumor cell lines. trans-Butenamidine shows good anti-P.
      carinii activity in rats. Pentamidine is used against P. carinii pneumonia in
      individuals infected with HIV who are at high risk from this infection. A
      comparison of the cytotoxic potencies of adozelesin, bizelesin, carzelesin,
      cisplatin, and doxorubicin indicates that adozelesin is a potent analog of CC
      1065. Naturally occurring pyrrolo[2,1-c][l,4]benzodiazepines such as anthramycin
      have a 2- to 3-bp sequence specificity, but a synthetic PBD dimer spans 6 bp,
      actively recognizing a central 5'-GATC sequence. The crosslinking efficiency of
      PBD dimers is much greater than that of other major groove crosslinkers, such as
      cisplatin, melphalan, etc. Neothramycin is used clinically for the treatment of
      superficial carcinoma of the bladder.

PMID- 10580833
TI  - Composite action of three GC/GT boxes in the proximal promoter region is
      important for gastrin gene transcription.
AB  - The proximal region of the human gastrin gene promoter contains three GC/GT boxes
      at positions -140 to -134 bp, -108 to -102 bp and -67 to -61 bp. In this study we
      have examined the significance of the three elements, and their role in Sp1 and
      Sp3 mediated gastrin transcription. In AGS cells, mutation of each of the boxes
      caused a moderate decrease in promoter activity from 33 to 63%, whereas double or
      triple mutations reduced activity to 3-12%. In Drosophila cells Sp1 activated the
      promoter, mainly through the distal GC box. Similarly, co-transfection of
      heterologous promoter constructs revealed that only the distal GC box increased
      activation by Sp1. The effect of Sp3 was cell-line dependent, since Sp3 inhibited
      the gastrin promoter activity in AGS cells and caused a synergistic activation of
      the Sp1 stimulated gastrin promoter in Drosophila cells. Both effects were
      dependent on the C-terminal DNA binding domain of Sp3. The results indicates that
      the combined effect of the GC/GT boxes and the ratio between Sp1 and Sp3 are
      important for gastrin gene expression.

PMID- 10580835
TI  - Corticotropin-releasing hormone stimulates steroidogenesis in cultured human
      adrenal cells.
AB  - The effects of corticotropin releasing hormone (CRH) on steroid production by
      cultures of human fetal adrenal cells was investigated. We found that CRH, at
      concentrations that have been reported to exist in human fetal serum, stimulated
      dehydroepiandrosterone sulfate (DS) and cortisol production by cultured fetal
      zone and neocortical zone cells. A dose-dependent increase in secretion of both
      steroids was noted, with the cortisol pathway being preferentially enhanced by
      CRH at high concentrations. Pretreatment of adrenal cells for 3 days made them
      more responsive to ACTH stimulation and such effects were dose-dependent also.
      Inclusion of the antagonist, alpha-helical CRH (9-41) blocked CRH-induced
      stimulation of DS and cortisol over a broad dose range and also interfered with
      the augmentation of cortisol secretion noted after ACTH in CRH treated cells. CRH
      had no effects on adrenal cell proliferation or total cell protein. These studies
      are suggestive that CRH, either of systemic origin or else produced within the
      adrenal itself, has the potential to be a modulator of adrenal steroid production
      in the human.

PMID- 10580834
TI  - Androgens decrease and retinoids increase the expression of insulin-like growth
      factor-binding protein-3 in LNcaP prostatic adenocarcinoma cells.
AB  - Changes in circulating levels of insulin-like growth factors (IGF) and IGF
      binding proteins (IGFBP) have been related to prostate cancer, but the nature and
      the significance of this relationship remains elusive. Recent reports suggest
      that modulation of the production of IGFBP-3 by retinoids may affect growth of
      breast and prostate tumor cells. In the present study we explored whether
      androgens (R1881), retinoids (all-trans- and 9-cis-retinoic acid: atRA and 9cRA),
      deltanoids (1alpha,25-dihydroxycholecalciferol: VD3) and thyroid hormone
      (triiodothyronine: T3) influence the production of IGFBPs by LNCaP prostatic
      adenocarcinoma cells and whether the observed changes affect tumor cell growth.
      Northern blot experiments demonstrated that LNCaP cells express IGFBP-2, -3, -4
      and (to a small extent) -5. IGFBP-4 and -5 were not measurably affected by the
      mentioned agonists. At a growth promoting concentration (10(-10) M), R1881
      increased IGFBP-2 transcript levels two- to three-fold and this effect was
      neutralized by atRA and VD3. Similar effects could not be demonstrated, however,
      at the protein level using Western ligand blotting. R1881 decreased and atRA
      increased the mRNA levels of IGFBP-3 and these effects were confirmed by Western
      ligand blotting and by radioimmunoassay. The effects of atRA were mimicked by
      9cRA and by a specific RAR agonist but not by a RXR agonist. VD3 and T3 had no
      significant effect on IGFBP-3 secretion but respectively enhanced or decreased
      the effect of 9cRA. The effects of retinoids required high concentrations (10(-6)
      10(-5) M) that also induced growth inhibition. R1881, however, decreased IGFBP-3
      at growth promoting (10(-10) M) as well as at growth inhibitory (10(-8) M)
      concentrations. Moreover, under serum-free conditions, we were unable to
      demonstrate any growth modulating effect of IGFBP-3. It is concluded that several
      agonists acting by nuclear receptors affect IGFBP-3 secretion by LNCaP cells but
      that the functional significance of these changes warrants further investigation.

PMID- 10580836
TI  - Developmental expression of proprotein convertase 1/3 in the rat.
AB  - We have isolated a clone that has 3' end sequence identity with prohormone
      convertase 1/3 (PC1/3) from a rat islet cDNA library. Northern blot analysis and
      immunocytochemical studies have confirmed its presence in the endocrine pancreas.
      Analysis of poly A mRNA from various adult tissues demonstrated that it was
      relatively abundant in whole brain, lung and spleen, but not detectable in
      kidney, testis and heart. Using probes consisting of either the coding region or
      the 3' end sequences, the mRNA transcripts identified were 5.0, 3.0 and 8.5 kb.
      The 8.5 kb transcript detected has not been described previously. RT-PCR of RNA
      isolated from rat embryonic tissues using a primer set corresponding to the 3'
      end of the PC1/3 sequence showed a steady increase of expression in fetal
      pancreas and intestine during the course of development. In contrast,
      comparatively high and constant levels of PC1/3 expression were detected in fetal
      lung, whereas low and constant expression was detected in fetal liver. Double
      immuno-staining showed that PC1/3 was co-localised with insulin throughout
      development, and at mid-gestation, PC1/3 immunoreactivity could also be detected
      within glucagon-producing cells in the developing pancreas. Thus, we have
      identified a novel PC1/3 mRNA transcript in the rat by using sequence-specific
      probes and have demonstrated that the developmental expression of prohormone
      convertase PC1/3 is confined primarily to pancreas and intestine, suggesting that
      it may play a possible role in regulating growth and differentiation of these
      tissues.

PMID- 10580837
TI  - Prolactin and insulin synergize to regulate the translation modulator PHAS-I via
      mitogen-activated protein kinase-independent but wortmannin- and rapamycin
      sensitive pathway.
AB  - The synergism between insulin and prolactin (PRL) in their effect on protein
      synthesis in the mammary gland was studied in differentiating mammary epithelial
      CID-9 cells. Both hormones were needed to induce phosphorylation of PHAS-I which
      resulted in its dissociation from the eIF-4E translation initiation factor. This
      step is crucial for the initiation of translation. The induction of PHAS-I
      phosphorylation was rapid and its rate matched that demonstrated for the
      JAK2/STAT5a and the binding of STAT5a to its DNA binding motif. However, 120 min
      was needed for complete phosphorylation of the PHAS-I protein. In the presence of
      insulin, PRL induced MAP kinase activity, initiated at a comparable rate to that
      of PHAS-I phosphorylation. However, a line of evidence suggested that although
      this kinase phosphorylates PHAS-I in vitro, it does not actively participate in
      its phosphorylation in vivo: (a) the level of insulin needed to enable PRL
      induced ERK-1/ERK-2 activation was one order of magnitude higher than that needed
      for PHAS-I phosphorylation; and (b) PD 098059, a MEK-1 inhibitor, completely
      inhibited insulin-dependent, PRL-induced ERK-1/ERK-2 activation but had no effect
      on the PRL-induced PHAS-I phosphorylation. In contrast, wortmannin, a
      phosphatidylinositol 3-kinase (PI 3'-kinase) inhibitor and the immunosuppressant
      rapamycin abrogated PHAS-I phosphorylation and caused a reciprocal shift between
      the fully phosphorylated PHAS-I gamma form and its non-phosphorylated alpha form.
      Since the partly phosphorylated PHAS-I beta form was not significantly affected
      by these inhibitors, it is possible that more than a single kinase mediates the
      synergistic effect of prolactin and insulin on PHAS-I phosphorylation.

PMID- 10580839
TI  - Pseudosubstrate peptide inhibitors of beta-cell protein kinases: altered
      selectivity after myristoylation.
AB  - Inhibitors of protein kinases are widely used to study stimulus-response pathways
      in pancreatic beta-cells. Synthetic peptides modelled on the pseudosubstrate
      sites of protein kinases, or of their endogenous inhibitor proteins, offer
      potentially specific inhibitors of individual protein kinases or kinase isoforms.
      However, the use of these inhibitors in studies of beta-cell physiology has been
      limited, since such peptide sequences are usually poorly membrane permeant.
      Myristoylation of these peptides enhances their ability to cross intact plasma
      membranes and thus inhibit intracellular protein kinases, and this approach is
      becoming increasingly common in identifying the cellular role(s) of particular
      protein kinases. In this study, using insulin-secreting beta-cells, we
      demonstrate that myristoylation alters the specificity of pseudosubstrate
      peptides such that all myristoylated peptides tested, even those lacking
      pseudosubstrate domains, acted as protein kinase C (PKC) inhibitors. This effect
      of myristoylation was limited to the inhibition of PKC, since the specificity of
      peptide inhibitors towards beta-cell protein kinase A activity was not affected
      by myristoylation. These results demonstrate that myristoylated pseudosubstrate
      peptides have value as protein kinase inhibitors in intact beta-cells, but
      emphasise that studies using them to ascribe role(s) for protein kinases in beta
      cells must be interpreted with caution.

PMID- 10580838
TI  - Transcription control and neuronal differentiation by agents that activate the
      LXR nuclear receptor family.
AB  - LXR and PPAR receptors belong to the nuclear receptor superfamily of
      transcriptional activating factors. Using ligand-dependent transcription assays,
      we found that 5-tetradecyloxy-2-furancarboxylic acid (TOFA) transactivates
      chimeric receptors composed of the glucocorticoid receptor DNA binding domain and
      the ligand binding regions of PPARalpha, PPARbeta (NUC-1) and LXRbeta (NER)
      receptors. In the same assays, ligands for PPARs (oleic acid, WY-14643 and L
      631,033) and LXRs (hydroxycholesterols) maintain their respective receptor
      selectivity. TOFA and hydroxycholesterols also stimulate transcription from a
      minimal fibrinogen promoter that is under the control of AP-1 or NF-kappaB
      transcription factor binding sites. In addition to their effects on
      transcription, these LXRbeta activators induce neuronal differentiation in rat
      pheochromocytoma cells. TOFA and the natural LXR agonist, 22 (R)
      hydroxycholesterol, stimulate neurite outgrowth in 55 and 28% of cells,
      respectively. No neurite outgrowth was induced by the related 22(S)
      hydroxycholesterol, which does not activate the LXR family. These results suggest
      that the hydroxycholesterol signaling pathway has a complex effect on
      transcription that mediates the activity of TOFA and hydroxycholesterol on
      neuronal differentiation in pheochromocytoma cells.

PMID- 10580840
TI  - Androgens down-regulate the expression of the human homologue of paternally
      expressed gene-3 in the prostatic adenocarcinoma cell line LNCaP.
AB  - mRNA differential display polymerase chain reaction analysis was used to screen
      systematically for novel androgen-regulated genes in the human prostatic
      adenocarcinoma cell line LNCaP. A 232 bp PCR fragment was found to be
      consistently down-regulated by the synthetic androgen R1881. Sequencing revealed
      complete identity with the human homologue of mouse Paternally expressed gene 3
      (Peg3), an imprinted gene that plays an important role as a downstream mediator
      of the effects of tumor necrosis factor (TNF). The down-regulation of Peg3 mRNA
      by androgens was confirmed by Northern blot hybridization. The effect proved time
      and dose dependent with maximal repression (3.5-fold) after 24 h of treatment
      with 10(-8) M R1881. The steroid specificity of Peg3 mRNA regulation reflected
      the aberrant ligand specificity of the mutated androgen receptor in LNCaP cells,
      supporting the involvement of the androgen receptor in the repression process.
      Basal expression of Peg3 mRNA was almost completely abolished by the protein
      synthesis inhibitor cycloheximide. Experiments with Actinomycin D suggested that
      androgens act at a transcriptional level rather than by changing the stability of
      Peg3 mRNA. Comparison of the expression of Peg3 mRNA in 50 different human
      tissues revealed ubiquitous expression, but low levels in the prostate. The
      highest levels were observed in endocrine tissues such as ovary, placenta,
      adrenal and pituitary. High levels were also noted in various parts of the brain.
      No detectable levels of Peg3 mRNA were observed in two other androgen receptor
      positive prostate tumor cell lines (MDA PCa-2a and -2b), and in the poorly
      differentiated and androgen receptor-negative prostate tumor lines PC-3 and DU
      145. It is concluded that both androgens and loss of differentiation may affect
      the expression of Peg3, a mediator of the effects of TNF. Further experiments
      will be required to explore whether these changes affect the responsiveness of
      prostate tumor cells to TNF.

PMID- 10580841
TI  - Intracellular free calcium in response to oxytocin in pig endometrial cells.
AB  - Intracellular free calcium concentration ([Ca2+]i) in response to oxytocin (OT)
      was studied in stromal, glandular epithelial and luminal epithelial cells
      obtained from the endometrium of gilts 16 days post-estrus. The amplitude of
      increased [Ca2+]i in response to 100 nM OT was greatest in stromal cells,
      intermediate in glandular epithelial cells and not evident in luminal epithelial
      cells. During continuous OT administration, stromal cells responded initially
      with a synchronous spike of [Ca2+]i that did not require extracellular Ca2+ and
      then displayed spontaneous asynchronous [Ca2+]i spikes that required
      extracellular Ca2+. Each cell possessed its own characteristic response.
      Increasing concentrations of OT induced an increasing percentage of stromal cells
      responding, with some cells having nearly equal [Ca2+]i responses at all
      concentrations and others having graded [Ca2+]i responses as the concentration of
      OT increased. These results are consistent with the proposed mechanism of OT
      action in pig endometrium involving activation of phosphoinositide-Ca2+ signaling
      pathway.

PMID- 10580842
TI  - Steroid-induced conformational changes of rat glucocorticoid receptor cause
      altered trypsin cleavage of the putative helix 6 in the ligand binding domain.
AB  - Steroid-induced changes in receptor protein conformation constitute a logical
      means of translating the variations in steroid structures into the observed array
      of whole cell biological activities. One conformational change in the rat
      glucocorticoid receptor (GR) can be readily discerned by following the ability of
      trypsin digestion to afford a 16-kDa fragment. This fragment is seen after
      proteolysis of steroid-free receptors but disappears in digests of either
      glucocorticoid- or antiglucocorticoid-bound receptors. The location of this
      cleavage site has now been located unambiguously as R651, in helix 6 of the
      ligand binding domain, by a combination of point mutagenesis, arginine specific
      protease digestion, and radiochemical sequencing. This 16-kDa species,
      corresponding to amino acids 652-795, was non-covalently associated with another,
      approximately 17-kDa species that was determined to be amino acids 518-651 after
      a comparison of co-immunoprecipitated fragments from wild type and two chimeric
      receptors. These assignments revise our earlier report of amino acids 537-673
      being the 16-kDa fragment and suggest that sequences of the entire ligand binding
      domain are required for high affinity and specificity binding. This was supported
      by the observation that trypsin digestion of the steroid-free R651A mutant GR
      gave rise to the 30-kDa meroreceptor (amino acids 518-795), which displayed wild
      type affinity. This 30-kDa species is thus the smallest non-associated fragment
      of GR possessing wild type steroid binding affinity. This suggests that other GR
      regions do not influence steroid binding affinity. The above results are
      reminiscent of those observed for the estrogen receptor. However, unlike the
      estrogen receptor or the more closely related progesterone receptor, the precise
      proteolytic cleavage points of both the steroid-free and -bound GR fall within
      regions that are predicted, on the basis of X-ray crystal structures of related
      receptors, to be alpha-helical and resistant to proteolysis. Thus, the tertiary
      structure of the GR ligand binding domain may be distinctly different from that
      of estrogen and progesterone receptors.

PMID- 10580843
TI  - The inducible cyclic adenosine monophosphate early repressor (ICER) in the
      pituitary intermediate lobe: role in the stress response.
AB  - The cAMP signalling pathway plays a key role in the regulation of the
      hypothalamic-pituitary-adrenal axis. Transcription factor CREM (cAMP response
      element modulator) is implicated in the modulation of a number of neuroendocrine
      functions. By virtue of an alternative, intronic promoter CREM generates the
      powerful transcriptional repressor ICER (inducible cAMP early repressor), which
      displays a pronounced neuroendocrine-specific expression. Here we document a
      remarkable induction of ICER in response to acute stress in the intermediate lobe
      (IL) of the pituitary gland. The induction is transient and is preceded by CREB
      phosphorylation. Adrenergic stimulation directs ICER induction in the IL through
      the activation of both beta2-adrenergic and corticotrophin-releasing hormone
      receptors. These receptors are positively coupled to the adenylate cyclase
      signalling pathway, which regulates hormone release from the IL, implicating ICER
      in the modulation of peptide secretion. We show that targeted ablation of the
      CREM gene in the mouse causes a chronic increase of beta-endorphin levels.
      Altered hormonal production occurs both in basal conditions and after stress.
      Thus, early ICER induction in the IL may be involved in the modulation of gene
      expression in response to stress.

PMID- 10580844
TI  - Angiotensinogen expression by rat epididymis: evidence for an intrinsic,
      angiotensin-generating system.
AB  - Previous studies have suggested the presence of an intrinsic renin-angiotensin
      system (RAS) in the rat epididymis with functions in epididymal activity and
      sperm maturation. In the present study, the localization and expression of
      angiotensinogen, the component of the RAS which is indispensable for
      intracellular angiotensin generation, were investigated by immunochemistry,
      hybridization histochemistry and by reverse-transcriptase polymerase chain
      reaction (RT-PCR). Western blot analysis of protein from the epididymis confirmed
      the presence of angiotensinogen with the expected molecular mass of about 60 kDa,
      in agreement with results from other tissues. Immunocytochemistry showed the
      regional localization of immunoreactivity for angiotensinogen in the rat
      epididymis. In situ hybridization histochemistry further demonstrated the
      expression of angiotensinogen mRNA by the epididymal epithelium in a region
      specific manner along the length of the rat epididymis. RT-PCR confirmed that the
      rat epididymis expresses angiotensinogen mRNA. On the other hand, mRNA of renin
      was not detected in the rat epididymis using Northern blot and RT-PCR analyses.
      The present study strongly supports the existence of an intrinsic, angiotensin
      generating system based on locally formed angiotensinogen as a precursor for
      angiotensin production. This epididymal RAS may have paracrine or autocrine roles
      in mediating the epididymal and sperm functions.

PMID- 10580845
TI  - Progesterone mediates decreases in uterine smooth muscle cell interleukin-1alpha
      by a mechanism involving decreased stability of IL-1alpha mRNA.
AB  - The regulation, by progesterone, of serotonin-induced interleukin-1alpha
      production was studied in primary cultures of rat uterine smooth muscle cells.
      Prior reports from this laboratory have demonstrated that these cells produce IL
      1alpha and IL-1beta mRNAs in response to the hormonal action of serotonin.
      Results of the present study indicate that treatment of myometrial smooth muscle
      cells with medroxyprogesterone acetate (MPA) results in a marked decrease in IL
      1alpha protein as measured by western blot analysis. These decreases occur even
      in the presence of maximally-inducing concentrations of serotonin. MPA-mediated
      changes in IL-1alpha protein are characterized by a rapid decline in IL-1alpha
      mRNA levels. This inhibition by medroxyprogesterone also occurs when cells are
      stimulated to produce IL-1alpha by PMA rather than serotonin. Thus, when cells
      are cultured in the presence of both inducer and inhibitor, the inhibitor,
      progesterone, clearly dominates in the control of IL-1alpha expression. This
      effect is concentration-dependent, can be mimicked by native progesterone or
      glucocorticoids, but is unaffected by estradiol. The ability of progestins to
      decrease IL-1alpha mRNA is blocked by both inhibitors of transcription and
      translation and by treatment with RU-486. Progesterone had no effect on
      chloramphenicol acetyl transferase (CAT) transcription from two different IL
      1alpha promoter constructs, indicating that progesterone's action appears to be
      dependent on post-transcriptional rather than transcriptional regulation.
      Conversely, progesterone accelerated the normal rate of decay of IL-1alpha mRNA
      that occurs following the removal of serotonin from the cultures. These results
      suggest that progesterone decreases IL-1alpha levels by stimulating the
      production of an intracellular intermediate that decreases the stability of IL
      1alpha mRNA.

PMID- 10580846
TI  - TOR kinase homologs function in a signal transduction pathway that is conserved
      from yeast to mammals.
AB  - Rapamycin is a natural product with potent antifungal and immunosuppressive
      activities. Rapamycin binds to the FKBP12 prolyl isomerase, and the resulting
      protein-drug complex inhibits the TOR kinase homologs. Both the FKBP12 and the
      TOR proteins are highly conserved from yeast to man, and genetic and biochemical
      studies reveal that these proteins are the targets of rapamycin in vivo.
      Treatment of yeast or mammalian cells with rapamycin inhibits translational
      initiation of a subset of mRNAs and dramatically represses ribosomal mRNA and
      tRNA transcription. Furthermore, rapamycin exposure blocks cell cycle progression
      in the early G1 phase of the cell cycle, driving cells into a G0 state and,
      ultimately, triggering autophagy. Recent findings reveal that the upstream
      factors regulating the TOR signaling cascade are involved in detecting amino
      acids, nutrients, or growth factors. These findings indicate that the TOR
      proteins function in a signal transduction pathway that coordinates nutritional
      and mitogenic signals to control protein biosynthesis and degradation.

PMID- 10580847
TI  - Is TP53 dysfunction required for BRCA1-associated carcinogenesis?
AB  - The identification of the breast/ovarian susceptibility genes, BRCA1 and BRCA2
      was an important advancement in the field of breast and ovarian cancer research.
      About 40-50% of site specific hereditary breast cancers and up to 80% of
      hereditary breast-ovarian cancers result from mutations in the BRCA1 gene.
      Although BRCA1 mediates multiple functions in the cell, including a role in DNA
      damage repair and gene transcription, the role of BRCA1 has not completely been
      elucidated yet. It has been suggested that mutational inactivation of TP53 may be
      required for BRCA1-associated tumorigenesis. Several studies have shown that TP53
      is more frequently inactivated in BRCA1-associated tumors than in sporadic breast
      or ovarian cancer. Up to 90% of BRCA1-associated tumors harbor either a TP53
      mutation and/or TP53 protein accumulation. The remaining tumors may well have
      other alterations affecting the cell cycle checkpoint. Loss of this checkpoint
      may be obligatory for BRCA1-tumorigenesis. In this review, we discuss recent
      advances in BRCA1-research and stress the pivotal role TP53 may play in BRCA1
      associated carcinogenesis.

PMID- 10580848
TI  - In situ hybridisation study of type I, II, X collagens and aggrecan mRNas in the
      developing condylar cartilage of fetal mouse mandible.
AB  - The aim of this study was to investigate the developmental characteristics of the
      mandibular condyle in sequential phases at the gene level using in situ
      hybridisation. At d 14.5 of gestation, although no expression of type II collagen
      mRNA was observed, aggrecan mRNA was detected with type I collagen mRNA in the
      posterior region of the mesenchymal cell aggregation continuous with the
      ossifying mandibular bone anlage prior to chondrogenesis. At d 15.0 of gestation,
      the first cartilaginous tissue appeared at the posterior edge of the ossifying
      mandibular bone anlage. The primarily formed chondrocytes in the cartilage matrix
      had already shown the appearance of hypertrophy and expressed types I, II and X
      collagens and aggrecan mRNAs simultaneously. At d 16.0 of gestation, the condylar
      cartilage increased in size due to accumulation of hypertrophic chondrocytes
      characterised by the expression of type X collagen mRNA, whereas the expression
      of type I collagen mRNA had been reduced in the hypertrophic chondrocytes and was
      confined to the periosteal osteogenic cells surrounding the cartilaginous tissue.
      At d 18.0 of gestation before birth, cartilage-characteristic gene expression had
      been reduced in the chondrocytes of the lower half of the hypertrophic cell
      layer. The present findings demonstrate that the initial chondrogenesis for the
      mandibular condyle starts continuous with the posterior edge of the mandibular
      periosteum and that chondroprogenitor cells for the condylar cartilage rapidly
      differentiate into hypertrophic chondrocytes. Further, it is indicated that
      sequential rapid changes and reductions of each mRNA might be closely related to
      the construction of the temporal mandibular ramus in the fetal stage.

PMID- 10580849
TI  - Development of early postnatal peripheral nerve abnormalities in Trembler-J and
      PMP22 transgenic mice.
AB  - Mutations in the gene for peripheral myelin protein 22 (PMP22) are associated
      with peripheral neuropathy in mice and humans. Although PMP22 is strongly
      expressed in peripheral nerves and is localised largely to the myelin sheath, a
      dual role has been suggested as 2 differentially expressed promoters have been
      found. In this study we compared the initial stages of postnatal development in
      transgenic mouse models which have, in addition to the murine pmp22 gene, 7 (C22)
      and 4 (C61) copies of the human PMP22 gene and in homozygous and heterozygous
      Trembler-J (TrJ) mice, which have a point mutation in the pmp22 gene. The number
      of axons that were singly ensheathed by Schwann cells was the same in all groups
      indicating that PMP22 does not function in the initial ensheathment and
      separation of axons. At both P4 and P12 all mutants had an increased proportion
      of fibres that were incompletely surrounded by Schwann cell cytoplasm indicating
      that this step is disrupted in PMP22 mutants. C22 and homozygous TrJ animals
      could be distinguished by differences in the Schwann cell morphology at the
      initiation of myelination. In homozygous TrJ animals the Schwann cell cytoplasm
      had failed to make a full turn around the axon whereas in the C22 strain most
      fibres had formed a mesaxon. It is concluded that PMP22 functions in the
      initiation of myelination and probably involves the ensheathment of the axon by
      the Schwann cell, and the extension of this cell along the axon. Abnormalities
      may result from a failure of differentiation but more probably from defective
      interactions between the axon and the Schwann cell.

PMID- 10580850
TI  - Localisation and quantitation of autonomic innervation in the porcine heart I:
      conduction system.
AB  - This study was prompted by the prospect of transgenic pigs providing donor hearts
      for transplantation in human recipients. Autonomic innervation is important for
      the control of cardiac dynamics, especially in the conduction system. Our
      objective was to assess the relative distribution of autonomic nerves in the pig
      heart, focusing initially on the conduction system but addressing also the
      myocardium, endocardium and epicardium (see Crick et al. 1999). Quantitative
      immunohistochemical and histochemical techniques were adopted. All regions of the
      conduction system possessed a significantly higher relative density of the total
      neural population immunoreactive for the general neuronal marker protein gene
      product 9.5 (PGP 9.5) than did the adjacent myocardium. A similar density of PGP
      9.5-immunoreactive innervation was observed between the sinus node, the
      transitional region of the atrioventricular node, and the penetrating
      atrioventricular bundle. A differential pattern of PGP 9.5-immunoreactive
      innervation was present within the atrioventricular node and between the
      components of the ventricular conduction tissues, the latter being formed by an
      intricate network of Purkinje fibres. Numerous ganglion cell bodies were present
      in the peripheral regions of the sinus node, in the tissues of the
      atrioventricular groove, and even in the interstices of the compact
      atrioventricular node. Acetylcholinesterase (AChE)-containing nerves were the
      dominant subpopulation observed, representing 60-70% of the total pattern of
      innervation in the nodal tissues and penetrating atrioventricular bundle.
      Tyrosine hydroxylase (TH)-immunoreactive nerves were the next most abundant
      neural subpopulation, representing 37% of the total pattern of innervation in the
      compact atrioventricular node compared with 25% in the transitional nodal region.
      A minor population of ganglion cell bodies within the atrioventricular nodal
      region displayed TH immunoreactivity. The dominant peptidergic nerve supply
      possessed immunoreactivity for neuropeptide Y (NPY), which displayed a similar
      pattern of distribution to that of TH-immunoreactive nerve fibres. Calcitonin
      gene-related peptide (CGRP)-immunoreactive nerves represented 8-9% of the total
      innervation of the nodal tissues and penetrating atrioventricular bundle,
      increasing to 14-19% in the bundle branches. Somatostatin-immunoreactive nerve
      fibres were relatively sparse (4-13% of total innervation) and were most abundant
      in the nodes, especially the compact atrioventricular node. The total pattern of
      innervation of the porcine conduction system was relatively homogeneous. A
      substantial proportion of nerve fibres innervating the nodal tissues could be
      traced to intracardiac ganglia indicative of an extensive intrinsic supply. The
      innervation of the atrioventricular node and ventricular conduction tissues was
      similar to that observed in the bovine heart, but markedly different to that of
      the human heart. It is important that we are aware of these findings in view of
      the future use of transgenic pig hearts in human xenotransplantation.

PMID- 10580851
TI  - Localisation and quantitation of autonomic innervation in the porcine heart II:
      endocardium, myocardium and epicardium.
AB  - The immunological problems of pig hearts supporting life in human recipients have
      potentially been solved by transgenic technology. Nevertheless, other problems
      still remain. Autonomic innervation is important for the control of cardiac
      dynamics and there is evidence suggesting that some neurons remain intact after
      transplantation. Previous studies in the human heart have established regional
      differences in both general autonomic innervation and in its component neural
      subpopulations. Such studies are lacking in the pig heart. Quantitative
      immunohistochemical and histochemical techniques were used to demonstrate the
      pattern of innervation in pig hearts (Sus scrofa). Gradients of immunoreactivity
      for the general neural marker protein gene product 9.5 were observed both within
      and between the endocardial, myocardial and epicardial plexuses throughout the 4
      cardiac chambers. An extensive ganglionated plexus was observed in the epicardial
      tissues and, to a lesser extent, in the myocardial tissues. The predominant
      neural subpopulation displayed acetylcholinesterase activity, throughout the
      endocardium, myocardium and epicardium. These nerves showed a right to left
      gradient in density in the endocardial plexus, which was not observed in either
      the myocardial or epicardial plexuses. A large proportion of nerves in the
      ganglionated plexus of the atrial epicardial tissues displayed AChE activity,
      together with their cell bodies. Tyrosine hydroxylase (TH)-immunoreactive nerves
      were the next most prominent subpopulation throughout the heart. TH
      immunoreactive cell bodies were observed in the atrial ganglionated plexuses.
      Endocardial TH- and NPY-immunoreactive nerves also displayed a right to left
      gradient in density, whereas in the epicardial tissues they showed a ventricular
      to atrial gradient. Calcitonin gene-related peptide (CGRP)-immunoreactive nerves
      were the most abundant peptide-containing subpopulation after those possessing
      NPY immunoreactivity. They were most abundant in the epicardial tissues of the
      ventricles. Several important differences were observed between the innervation
      of the pig heart compared with the human heart. These differences may have
      implications for the function of donor transgenic pig hearts within human
      recipients.

PMID- 10580852
TI  - Sequential changes in trace metal, metallothionein and calmodulin concentrations
      in healing skin wounds.
AB  - Metalloenzymes have an important role in repair and regenerative processes in
      skin wounds. Demands for different enzymes vary according to the phase in the
      healing cascade and constituent events. Sequential changes in the concentrations
      of calcium, copper, magnesium and zinc were studied in the incisional wound model
      in the rat over a 10 d period. Copper levels remained low (< 10 microg/g dry
      weight) throughout, but calcium, magnesium and zinc increased from wounding and
      peaked at about 5 d at a time of high inflammation, granulation tissue formation
      and epidermal cell proliferation. Metal concentrations declined to normal by 7 d
      when inflammation had regressed, re-epithelialisation of the wound site was
      complete and the 'normalisation' phase had commenced. Although the wound was
      overtly healed by 10 d, the epidermis was still moderately hyperplastic. In view
      of competitive binding of trace metals at membrane receptors and carrier
      proteins, the ratios or balance between these trace metals was examined and the
      significance is discussed. Using immunocytochemistry, we demonstrated increases
      in metallothionein immunoreactivity as an indication of zinc and copper activity
      in the papillary dermis and in basal epidermal cells near the wound margin 1-5 d
      after wounding. This is consistent with metalloenzyme requirements in
      inflammation and fibrogenesis. Calmodulin, a major cytosolic calcium binding
      protein was highest in maturing keratinocytes and in sebaceous gland cells of
      normal skin; it was notably more abundant in the epidermis near the wound margin
      and in re-epithelialising areas at a time when local calcium levels were highest.

PMID- 10580853
TI  - Kinetics of neovascularisation of splenic autotransplants in mice.
AB  - The aim of this study was to examine the kinetics of neovascularisation of
      splenic autoimplants into the abdominal cavity after splenectomy in mice. Sixty
      eight female Swiss mice were submitted to splenectomy. The spleen from each
      animal was sliced and the slices were implanted into the abdominal cavity. Groups
      of animals were killed after 1, 2, 3, 5, 7, 15, 21, 28, 42, 56, 70 and 84 d.
      Fluorescent polystyrene microspheres were injected via the orbital venous plexus
      before killing and the splenules were removed 5 min later for light and electron
      microscopy. Mesenteric blood vessels were injected with coloured latex to study
      the origin of the nutrient vessels. Three days after the implant the microspheres
      were observed at the periphery and then migrating to the internal parts of the
      implant in the subsequent days. The blood supply to the implants originated from
      branches of the splenic, short gastric, mesenteric and gastroepiploic arteries.
      It is concluded that revascularisation of splenic autografts proceeds
      centripetally, starting as early as 3 d after implantation.

PMID- 10580854
TI  - Morphometric study of the regeneration of individual rays in teleost tail fins.
AB  - The results obtained using morphometric variables which describe fin ray
      regeneration patterns are reported for individual fin ray amputations in the
      goldfish (Carassius auratus) and zebrafish (Brachydanio rerio). Classical and
      updated experiments are compared to verify previous morphogenetic models of cell
      tractions (Oster et al. 1983) or epidermis-mesenchyme induction (Saunders et al.
      1959) applied to the limb of other vertebrates. Position-dependent patterns
      within the fin of Carassius auratus are analysed under a comparative protocol
      using morphometric methods. Conditions in which the apical epidermis is separated
      from blastema may differentiate small fin rays, thus suggesting this epidermis is
      involved in blastemal formation. Blastemal cells differentiating as lepidotrichia
      forming cells (LFCs) may also be related to morphological changes in covering
      epidermis. Long-range interactions from neighbouring fin ray blastemas or short
      range interactions within the blastema, may be postulated through the analysis of
      segmentation.

PMID- 10580855
TI  - Autogenous artery grafts in hypertensive (SHR) rats do not have increased smooth
      muscle cell hyperplasia in the graft neointima, compared with grafts in
      normotensive rats.
AB  - Vein-to-artery graft surgery is used widely to by-pass arterial stenoses, but
      such grafts can fail over a prolonged period as a result of excessive neointimal
      hyperplasia causing thrombosis and graft occlusion. It has been suggested that
      neointimal hyperplasia, in vein grafts, is a result of the vessel wall adapting
      to the higher intraluminal pressure of the arterial circulation, compared with
      the venous circulation. Autologous artery grafts have been used to bypass
      arterial stenoses. Initially it was assumed that donor artery segments would not
      develop neointimal hyperplasia as they are already adapted to the arterial
      circulation but this is not so. In this study we postulated that surgical or
      postsurgical trauma was the cause of neointimal hyperplasia in autologous artery
      to-artery grafts. In addition, as artery grafts are pre-adapted to the arterial
      circulation, autologous artery-to-artery grafts in hypertensive rats should
      develop similar levels of neointimal hyperplasia as seen in normotensive rats.
      Artery-to-artery grafts were placed in a series of 20 spontaneously hypertensive
      rats (SHR). In a separate series of sham grafting experiments the effects of
      anoxia and clamp trauma were assessed in SHR and WKy normotensive control rats.
      Finally, clamping, anoxia and anastomosis trauma were assessed in a similar
      series of rats. In the artery-to-artery graft series there was no difference in
      neointimal thickness between the SHR and that previously reported for
      normotensive rats. Minimal neointimal hyperplasia was demonstrated in the sham
      grafted series of rats and only slightly more in the single anastomosis series.
      It was only in the full grafting procedure that considerable neointimal
      hyperplasia developed. These data demonstrate that neointimal hyperplasia in
      artery-to-artery grafts is not exacerbated by the hypertension. In addition,
      trauma appears to be the initiator of neointimal hyperplasia and the extent of
      trauma correlates with the degree of neointimal hyperplasia.

PMID- 10580856
TI  - The vomeronasal organ in the human embryo, studied by means of three-dimensional
      computer reconstruction.
AB  - The human vomeronasal organ is of interest because of its potential role in sex
      pheromone detection. Due to the scarcity of early human material, studies of its
      development have concentrated on fetal rather than embryonic stages. The
      availability of embryonic specimens in the Walmsley Collection has enabled us to
      study the development of the vomeronasal organ (VNO) in human embryos between
      Carnegie Stages 17 and 23. Embryos at Carnegie Stage 17 or below showed no
      evidence of a VNO. One embryo with characteristics intermediate between Carnegie
      stages 17 and 18 was the earliest to show evidence of a VNO, in the form of a
      shallow indentation. All embryos at Carnegie Stages 18 or later had VNOs. Three
      dimensional computer reconstructions were made of the VNO in each specimen where
      this was possible. This in part depended on the plane of section. The total
      volume and lumen volume were measured from these reconstructions and the volume
      of the vomeronasal epithelium was calculated by subtraction. A generally
      consistent increase in total volume and epithelial volume was observed with
      increasing developmental stage. The lumen contributed rather little to the total
      volume at these stages.

PMID- 10580857
TI  - Structural abnormalities do not explain the early functional abnormalities in the
      peripheral nerves of the streptozotocin diabetic rat.
AB  - The streptozotocin (STZ)-diabetic rat, the most commonly employed model of
      experimental diabetic neuropathy, is characterised by a reduction in nerve
      conduction velocity, pain threshold and blood flow. Whether or not structural
      abnormalities underlie these functional abnormalities is unclear. 10 adult male
      Sprague-Dawley STZ-diabetic rats (diabetes duration 27 d) and 10 age-matched (23
      wk) control animals were studied. Motor nerve conduction velocity (m s(-1)) was
      significantly reduced in diabetic (41.31 +/- 0.8) compared with control (46.15 +/
      1.5) animals (P < 0.001). The concentration of sciatic nerve glucose (P <
      0.001), fructose (P < 0.001) and sorbitol (P < 0.001) was elevated, and
      myoinositol (P < 0.001) was reduced in diabetic compared with control animals.
      Detailed morphometric studies demonstrated no significant difference in
      fascicular area, myelinated fibre density, fibre and axon areas as well as
      unmyelinated fibre density and diameter. Endoneurial capillary density, basement
      membrane area and endothelial cell profile number did not differ between diabetic
      and control animals. However, luminal area (P < 0.03) was increased and
      endothelial cell area (P < 0.08) was decreased in the diabetic rats. We conclude
      there is no detectable structural basis for the reduction in nerve conduction
      velocity, pain threshold or blood flow, observed in the streptozotocin diabetic
      rat.

PMID- 10580858
TI  - Application of the fractionator and vertical slices to estimate total capillary
      length in skeletal muscle.
AB  - A new stereological method is proposed which combines vertical slice projections
      with the fractionator to estimate the total capillary length in a skeletal
      muscle. The method was demonstrated on the soleus muscle of a Wistar rat. The
      implementation required capillary highlighting, tissue sampling, and data
      acquisition in the form of intersection counts between capillary projections and
      cycloid test lines. The capillaries were demonstrated using vascular perfusion
      (with gelatine) of the hind leg of the rat. The sampling procedure followed the
      fractionator design, namely a multistage systematic sampling design with a known
      sampling fraction at each stage. To make the design unbiased, vertical slices
      were used; for efficiency, the vertical axis was chosen parallel to the main axis
      of the muscle. As prescribed to avoid bias, the cycloid test lines were
      superimposed on the slice projections, viewed under the light microscope, with
      their minor axes normal to the vertical axis. The estimation precision was
      compared for different sampling and subsampling fractions. The proposed method
      was globally highly efficient, unbiased, and easy to implement.

PMID- 10580859
TI  - Postnatal development of intestinal endocrine cell populations in the water
      buffalo.
AB  - The frequency and distribution of 11 endocrine cell populations were studied in
      the intestine of differently aged buffalo, grouped on the basis of diet: 2-d-olds
      (suckling), 5-mo-olds (weaning) and 5-y-olds (ruminant adult diet). The endocrine
      cell populations were identified immunocytochemically using antisera against 5
      hydroxytryptamine (5-HT), somatostatin, gastrin, cholecystokinin (CCK), COOH
      terminal octapeptide of gastrin/CCK, neurotensin, motilin, gastric inhibitory
      polypeptide (GIP), secretin, glucagon/glicentin (GLU/GLI) and polypeptide YY
      (PYY). In adult buffalos the regional distribution of endocrine cells is similar
      to that of other adult ruminants. During postnatal development, these cell types
      showed the following changes in their frequency and distribution: (1) 5-HT,
      neurotensin and gastrin/CCK immunoreactive cells (i.c.) showed a decrease in
      frequency with age; (2) somatostatin i.c. frequency remained stable with age; (3)
      motilin, GIP, secretin and CCK i.c. showed a slight increase in frequency with
      age; (4) GLU/GLI and PYY i.c. decreased in frequency with age in the small
      intestine, caecum and proximal colon and an increase in frequency in the rectum.
      It was hypothesised that the endocrine cell types, whose presence and
      localisation is substantially stable in all examined ages, probably contain
      substances that are strictly necessary for intestinal function. In contrast the
      hormones contained in the cell populations that decreased with age, are probably
      involved in physiological needs during the milk and weaning diet or play a role
      in intestinal growth.

PMID- 10580860
TI  - Elastic fibres in the vesicourethral junction and urethra of the guinea pig:
      quantification with computerised image analysis.
AB  - Elastic fibres, which are intimately associated with collagen, a major component
      of the urethra, have been assumed to contribute to the resting urethral closure
      pressure. The Miller stain for elastin was used to demonstrate elastic fibres in
      cryostat sections of guinea pig bladder base, vesicourethral junction (VUJ) and
      urethra. Computerised image analysis was employed to objectively quantify these
      fibres. Both male and female guinea pigs showed significantly greater amounts of
      circularly disposed elastic fibres in the VUJ than in the other 2 regions
      examined. This particular disposition of fibres may be responsible for imparting
      resiliency and plasticity to the VUJ, allowing it to distend and recoil
      repeatedly in response to urine outflow. Furthermore, the elastic fibres may be
      partly responsible for the passive occlusive force in this region. Elastic fibres
      in the distal urethra were not quantified because of their relative paucity.
      Sagittal sections of the urethra revealed a mass of longitudinally arranged
      elastic fibres localised almost exclusively within the mucosa, submucosa and
      longitudinal smooth muscle layer. Functionally, this arrangement may exist to
      facilitate urethral length changes that occur in micturition.

PMID- 10580862
TI  - Immunolocalisation of NHE3-like immunoreactivity in the gills of the rainbow
      trout (Oncorhynchus mykiss) and the blue-throated wrasse (Pseudolabrus tetrious).
AB  - Na+/H+ exchange has been implicated in models of ion transport across the
      branchial epithelium of marine and freshwater fishes. In this preliminary study,
      we present immunohistochemical data using a polyclonal antibody raised against
      NHE3 which show NHE3-like immunoreactivity (IR) in the gills from a freshwater
      and a marine teleost species. In both species, branchial epithelial cells
      demonstrating NHE3-like IR were localised predominantly to the junction between
      the filament and the secondary lamellae. However, there was a marked difference
      in the morphology of the NHE3-like immunoreactive epithelial cells between the
      species. This morphological difference between the species suggests functional
      differences in the exchanger, which may be related to marine versus freshwater
      environments.

PMID- 10580863
TI  - An unusual branching pattern of the superficial brachial artery accompanied by an
      ulnar nerve with two roots.

PMID- 10580861
TI  - Immunohistochemical localisation of amelogenin-like proteins and type I collagen
      and histochemical demonstration of sulphated glycoconjugates in developing
      enameloid and enamel matrices of the larval urodele (Triturus pyrrhogaster)
      teeth.
AB  - The presence of collagen in enameloid distinguishes it clearly from true enamel,
      but little is known about the phylogenetic relationship between these 2 tissues.
      It has previously been reported that amelogenins are the principal proteins of
      the enamel matrix, that type I collagen and chondroitin sulphates are the
      predominant matrices in dentine, and that amphibian and reptilian aprismatic
      enamels, contain no sulphated glycoconjugates, although certain sulphated
      substances are secreted into mammalian prismatic enamel during matrix formation.
      The larval urodele (Triturus pyrrhogaster) teeth are known to be composed of
      enameloid, dentine, and enamel-like tissue. To characterise the tooth matrices,
      the localisation of amelogenin-like proteins, type I collagen, and sulphated
      glycoconjugates was investigated. Chondroitin sulphates and fine fibrils
      immunoreactive for type I collagen were elaborated as the enameloid matrix inside
      the dental basement membrane. After the matrix had been deposited in full
      thickness, coarse collagen fibrils also immunoreactive for type I collagen and
      chondroitin sulphates were deposited below as the first dentine matrix. Further,
      enamel-like matrix with no collagen fibrils or sulphated glycoconjugates but
      strongly immunoreactive for amelogenins was deposited on the dentine. Although no
      immunolabelling for amelogenins was found over the enameloid matrix, at least at
      the formation stage, the zone of coarse collagen fibrils of dentine was partially
      immunoreactive as observed in mammalian mantle dentine. From the ontogeny and
      matrix constituents of larval urodele teeth, it is suggested that enameloid is
      originally a dentine-like tissue.

PMID- 10580864
TI  - Large breast cancer tumors and radiotherapy: biology vs. chronology.

PMID- 10580865
TI  - Caution on the use of altered fractionation for nasopharyngeal carcinoma.
AB  - Randomized trials and overviews on the value of altered fractionation for head
      and neck cancers are reviewed. Attention is drawn to the unexpectedly high
      incidence of temporal lobe necrosis incurred in patients with nasopharyngeal
      carcinoma. Preliminary analyses suggest that incomplete repair is likely to be
      the major factor, even a 6-h interfraction interval may be inadequate if
      substantial volumes of nervous tissues are included within the target volume.

PMID- 10580866
TI  - Post-mastectomy radiotherapy in pT3N0M0 breast cancer: is it needed?
AB  - BACKGROUND AND PURPOSE: It is not been established whether breast cancer patients
      who have a primary tumor 5 cm or larger but no axillary nodal or distant
      metastases at the time of the diagnosis (pT3N0M0) benefit from post-operative
      radiation therapy after mastectomy. MATERIAL AND METHODS: We identified 81
      patients with T3N0M0 breast cancer out of the total of 4190 breast cancer
      patients treated in one university radiotherapy department from 1987 to 1994 from
      the department patient registry, and examined the clinical records and
      histopathological slides. RESULTS: Only 38 of the 81 patients had true pT3N0M0
      breast cancer after the review (0.9% of the 4190 new breast cancer patients
      registered in the department from 1987 to 1994). Three (60%) of the five patients
      who were not treated with post-operative radiation therapy developed locoregional
      recurrence of breast cancer as compared with only three (9%) of the 33 patients
      who were given post-operative radiotherapy during a median follow-up of 58 months
      (P = 0.0003). Patients who were given post-operative radiotherapy had a better
      distant disease-free survival rate (P = 0.04) and overall survival rate (P =
      0.03) than the ones who were not treated with radiation therapy after surgery. Of
      the 29 patients who had chest wall irradiation only, one had in-field recurrence
      at the surgical scar, one both at the scar and the unirradiated axilla, and only
      one (3%) solely in the axilla. CONCLUSIONS: Patients with true pT3N0M0 breast
      cancer are rare. The results suggest that women with pT3N0M0 breast cancer
      benefit from post-operative radiotherapy, but the value of irradiating the
      dissected ipsilateral axilla remains unsettled.

PMID- 10580867
TI  - Selective avoidance of lymphatic radiotherapy in the conservative management of
      women with early breast cancer.
AB  - BACKGROUND AND PURPOSE: Until recently, elective treatment of the lymphatic
      pathways in women with early invasive breast cancer was assumed to impact on
      quality of life rather than on overall survival. In a multidisciplinary breast
      clinic these considerations underpinned a policy of observation of the lymphatic
      pathways if axillary lymph nodes were not palpably enlarged and if
      recommendations for adjuvant systemic therapy did not depend on knowledge of
      pathological node status. This paper evaluates the long-term outcome of the
      observation policy in terms of lymphatic morbidity due to cancer recurrence.
      MATERIAL AND METHODS: Seven hundred and fifty-nine patients with operable breast
      cancer and suitable for breast conserving surgery were seen between January 1984
      and December 1994. Of these, 291 (38.3%) were recommended a policy of observation
      to the lymphatic pathways. The case records of these patients were reviewed to
      record regional relapse patterns and morbidity. RESULTS: At a median follow up of
      60 months, 32/291 (11%) patients suffered ipsilateral lymphatic relapse at some
      stage prior to death or last follow up, representing a 22% actuarial 10-year risk
      of lymphatic relapse. Metastases coincided with, or preceded, lymphatic relapse
      in 8/32 (25%) patients. Eighteen out of 32 (56%) patients suffered symptoms of
      lymphatic relapse prior to death or last follow up, despite subsequent surgery,
      radiotherapy and/or systemic therapies. The absolute risk of symptomatic
      ipsilateral lymphatic relapse in the observation group was 18/291 (6.2%),
      representing an actuarial 10-year risk of 17%. CONCLUSION: A policy of
      observation on the axilla with deferred treatment of lymphatic relapse has
      benefited 273/291 (94%) patients, but at the expense of cancer-related regional
      morbidity in 18 (6%) patients. We conclude that the cancer-related morbidity
      suffered by a minority of patients and the strengthening evidence of an overall
      survival benefit conferred by elective local-regional therapy favours a policy of
      elective treatment of the lymphatic pathways in the routine setting.

PMID- 10580868
TI  - Evaluation of early response to radiotherapy in head and neck cancer measured
      with [11C]methionine-positron emission tomography.
AB  - PURPOSE: To evaluate whether positron emission tomography (PET) with carbon-11
      methionine (MET) can be used for detection of early response to external beam
      radiotherapy (RT) in untreated head and neck cancer using locoregional control
      and survival as study endpoints. MATERIALS: Fifteen patients with head and neck
      cancer underwent a MET PET study before RT and after a median dose of 24 Gy.
      Fractionation was standard (n = 6) or hyperfractionated (n = 9), and 13 out of 15
      patients had planned surgery after RT. SUV was calculated for primary tumor (n =
      13) or largest lymph node metastasis in two patients of whom one had his primary
      excised before study enrollment and one presented with unknown primary tumor
      syndrome. METHODS: Attenuation corrected PET scans acquired 20-40 min from tracer
      injection were used for evaluation of MET uptake in tumors. A quantitative MET
      uptake index was expressed as standardized uptake value (SUV) or SUV(lean)
      (corrected for lean body mass). The PET results were correlated with clinical
      follow-up data. The median follow-up time is currently 28 months (range 22-34).
      RESULTS: A total of 13 primary tumors and 12 metastatic lymph nodes were visually
      identified in MET PET. In the first PET study the median SUV in tumor was 8.6
      (range, 5.5-14.0). In the second PET study performed during RT the median SUV
      decreased to 5.7 (range, 3.1-8.2, P = 0.001). Two out of 15 patients showed no
      radiation-induced decrease in SUV. The median tumor SUV ratio of patients
      remaining in local control (CR) after RT was 0.7 (range 0.6-0.8, n = 6), and that
      of relapsing patients similarly 0.7 (range 0.5-1.0, n = 9, NS). The SUV ratio was
      not associated with survival time. The MET uptake of submandibular salivary
      glands decreased in all patients during the first two or three weeks of RT (P =
      0.03). CONCLUSIONS: MET uptake in tumor shows a significant decrease during the
      first two to three weeks of RT of head and neck cancer. It appears that the rate
      of decrease in tracer uptake is comparable in relapsing patients and those who
      remain locally controlled and thus the use of MET PET for prediction of response
      to RT is limited.

PMID- 10580869
TI  - Radiotherapy in the management of giant pituitary adenomas.
AB  - BACKGROUND AND PURPOSE: The description of giant pituitary adenoma is not clear
      yet. In this study we tried to identify which adenomas can be defined as giant
      pituitary adenomas when tumor control and progression free survival (PFS) are
      taken as end points and we also tried to evaluate prognostic factors other than
      tumor size. MATERIALS AND METHODS: Between January 1981 and December 1997, 74
      patients with pituitary macroadenomas more than 2 cm in size were treated. Of
      these 30 had tumors of more than 4 cm, while 44 patients were with tumors of 2-4
      cm. Two patients received primary radiotherapy, while 72 were treated
      postoperatively. In the postoperative group, 52 patients underwent immediate
      radiotherapy after surgery and 20 were treated with irradiation after regrowth or
      progression of the tumor after initial surgery. The mean and median tumor doses
      were 5518 and 5425 cGy, respectively. RESULTS: Overall primary tumor control rate
      was 84%. The local control rates among patients with tumors more than 4 cm and
      among patients with tumors 2-4 cm after radiotherapy were 73 and 91%,
      respectively. PFS was 65% for patients who had a tumor size of more than 4 cm and
      87% for the patients with tumor size of 2-4 cm (P = 0.09). Young age (<20) and
      tumors of unclassified histology were the bad prognostic factors. Six months
      after radiotherapy normalisation or improvement in hormonal hypersecretion and
      visual field and acuity deficits were 82 and 63%, respectively. CONCLUSION:
      Tumors more than 4 cm in size may be more convenient for the definition of 'giant
      pituitary adenoma' when tumor control and PFS are taken as the end points.

PMID- 10580870
TI  - Curative-intent radiation therapy in anal carcinoma: quality of life and
      sphincter function.
AB  - In 22 colostomy-free survivors of curative-intent radiation therapy or
      chemoradiation for anal carcinoma, measurement of the Gastrointestinal Quality of
      Life Index (GIQLI) revealed a mean 114 of a maximum 144 points, as compared to
      121 in healthy volunteers (n = 150) and 113 in patients with benign anorectal
      diseases (n = 325). Sixteen patients underwent anorectal manometry to determine
      anal sphincter length (SL), resting pressure (RP), maximum squeeze pressure
      (MSP), rectal compliance (RC) and relaxation of the internal anal sphincter
      (RIAS). SL, RP and MSP were significantly lower in anal carcinoma patients than
      in healthy volunteers. Complete continence was detected in 56% of patients.

PMID- 10580871
TI  - Clinical course of solitary extramedullary plasmacytoma.
AB  - BACKGROUND AND PURPOSE: Solitary extramedullary plasmacytoma (EMP) represents a
      rare category of malignant disease on which there are limited data in regard to
      diagnosis, staging and natural history. This study attempted to clarify the
      clinical course of solitary extramedullary plasmacytoma after radiation or
      surgical therapy given with curative intent. MATERIALS AND METHODS: The diagnosis
      was based on a mass of clonal plasma cells separate from bone or bone marrow
      without evidence of occult disease elsewhere. Between 1963 and 1996, 22
      previously untreated patients with an EMP were diagnosed. Disease presented in
      the head or neck in 86%, usually in the nasal cavity (NC) or maxillary sinus
      (MS), and in these areas local bone destruction was found in 10 of 11 patients.
      Among all patients, serum myeloma protein was present in three patients (14%) and
      Bence Jones protein alone was found in two patients (9%). Radiation therapy was
      the sole treatment for 18 of 22 patients, and the median radiotherapy dose was 50
      Gy (range, 40-60 Gy); five of seven patients with an EMP of oral cavity (OC),
      oropharynx (OP), nasopharynx (NP), parotid or larynx also received elective neck
      irradiation. Two patients underwent surgery plus postoperative irradiation of a
      plasmacytoma of the sigmoid colon or pleura, and two patients had resection alone
      of a plasmacytoma of the colon or cervical lymph node. RESULTS: Local control was
      achieved in 21 of 22 patients (95%), and disease never recurred in regional
      nodes. Disappearance of myeloma protein occurred in three of five patients with
      an evaluable abnormality. Multiple myeloma developed in seven patients (32%), all
      within 5 years. The 5-year rate of freedom from progression to multiple myeloma
      was 56% and the median survival was 9.5 years. CONCLUSION: Radiation therapy
      achieved excellent locoregional control of EMP with an approximate cure fraction
      of 50%.

PMID- 10580872
TI  - HDR-brachytherapy boost for residual tumour after external beam radiotherapy in
      patients with tracheal malignancies.
AB  - Seven inoperable patients with tracheal neoplasms received a high dose rate (HDR)
      brachytherapy boost (median 15 Gy, single dose 3-5 Gy) for residual tumour after
      external beam radiotherapy (median 50 Gy, 5 x 2 Gy/week). The median actuarial
      survival was 34.3 months. The 1-, 2- and 3-year actuarial survival rates were
      85.7%, 85.7% and 32%. Local control was obtained in 5/7 patients. Late toxicity
      occurred in three patients (stenosis n = 2, hemorrhage n = 1). Our data indicate,
      that a HDR brachytherapy boost is effective and feasible.

PMID- 10580873
TI  - New interstitial HDR brachytherapy technique for prostate cancer: CT based 3D
      planning after transrectal implantation.
AB  - We have developed a new interstitial HDR brachytherapy technique for the
      treatment of prostate cancer using CT based 3D planning after transrectal
      implantation of four non-parallel needles. CT based needle reconstruction, target
      definition, evaluation and documentation, including DVHs and 3D imaging, is a
      feasible, safe and well tolerated treatment concept.

PMID- 10580874
TI  - Monitoring of tumor reoxygenation following irradiation by 31P magnetic resonance
      spectroscopy: an experimental study of human melanoma xenografts.
AB  - BACKGROUND AND PURPOSE: Inadequate tumor reoxygenation during radiation therapy
      may cause local treatment failure. This study was aimed at investigating the
      potential usefulness of 31P-MRS in monitoring tumor reoxygenation following
      radiation treatment. MATERIALS AND METHODS: Tumors of two human melanoma
      xenograft lines (BEX-t and HUX-t) were exposed to 15.0 Gy, and then the fraction
      of radiobiologically hypoxic cells, measured by using the paired survival curve
      method, or tumor bioenergetic status, measured by 31P-MRS as the (PCr +
      NTPbeta)/Pi resonance ratio, was determined versus time after the radiation
      exposure. RESULTS: Untreated BEX-t and HUX-t tumors showed similar fractions of
      radiobiologically hypoxic cells and similar bioenergetic status, whereas both
      parameters differed substantially between the lines in irradiated tumors. A close
      association was found between radiation-induced changes in tumor bioenergetic
      status and radiation-induced changes in the fraction of radiobiologically hypoxic
      cells. CONCLUSION: 31P-MRS is a potentially useful method for monitoring tumor
      reoxygenation following radiation treatment.

PMID- 10580876
TI  - An adaptable mechanical multileaf delineator.
AB  - A mechanical device for a multileaf delineator, designed and built in our
      department, is described. Its scope is used as an accessory mounted on the head
      of the radiation therapy simulator to obtain reliable images of the treatment
      field, shaped for multileaf collimation, on the patient's skin and to record them
      on the reference X-ray films normally acquired during the simulation phases.

PMID- 10580875
TI  - In-vivo dosimetry by diode semiconductors in combination with portal films during
      TBI: reporting a 5-year clinical experience.
AB  - BACKGROUND AND PURPOSE: In-vivo dosimetry is vital to assure an accurate delivery
      of total body irradiation (TBI). In-vivo lung dosimetry is strongly recommended
      because of the risk of radiation-induced interstitial pneumonia (IP). Here we
      report on our 5-year experience with in-vivo dosimetry using diodes in
      combination with portal films and assessing the effectiveness of in-vivo
      dosimetry in improving the accuracy of the treatment. Moreover, we wished to
      investigate in detail the possibility of in-vivo portal dosimetry to yield
      individual information on the lung dose and to evaluate the impact of CT planning
      on the correspondence between stated and in-vivo measured doses. MATERIALS AND
      METHODS: From March 1994 to March 1999, 229 supine-positioned patients were
      treated at our Institute with TBI, using a 6 MV X-rays opposed lateral beam
      technique. 146 patients received 10 Gy given in three fractions, once a day
      (FTBI), shielding the lungs by the arms; 70 received 12-13.2 Gy, given in 6-11
      fractions, 2-3 fractions per day (HFTBI): in this case about 2/3 of the lungs
      were shielded by moulded blocks (mean shielded lung dose equal to 9 or 9.5 Gy).
      Thirteen patients received 8 Gy given in a single fraction (SFTBI, lung dose: 7
      Gy). For all HFTBI and FTBI patients, midline in-vivo dosimetry was performed at
      the first fraction by positioning two diodes pairs (one at entrance and one at
      the exit side) at the waist (umbilicus) and at the pelvis (ankles). If at least
      one of the two diodes doses (waist-pelvis) was outside +/-5% from the prescribed
      dose, actions could be initiated, together with possible checks on the following
      fractions. Transit dosimetry by portal films was performed for most patients; for
      165 of them (117 and 48, respectively for FTBI and HFTBI) the midline in-vivo
      dose distribution of the chest region was derived and mean lung dose assessed. As
      a CT plan was performed for all HFTBI patients, for these patients, the lung dose
      measured by portal in-vivo dosimetry was compared with the expected value.
      RESULTS: Concerning all diodes data, 528 measurements were available: when
      excluding the data of the first fraction(s) of the patients undergoing
      corrections (n = 392), mean and SD were respectively 0.0% and 4.5% (FTBI: -0.3 +/
      4.8%; HFTBI: 0.4 +/- 3.9%). In total 105/229 patients had a change after the
      first fraction and 66/229 were controlled by in-vivo dosimetry for more than one
      fraction. Since January 1998 a CT plan is performed for FTBI patients too: when
      comparing the diodes data before and after this date, a significant improvement
      was found (i.e. rate of deviations larger than 5% respectively equal to 30.7% and
      13.1%, P = 0.007). When considering only the patients with a CT plan, the global
      SD reduced to 3.5%. Concerning transit dosimetry data, for FTBI, the mean
      (midline) lung dose was found to vary significantly from patient to patient
      (Average 9.13 +/- 0.81 Gy; range 7.4-11.4 Gy); for the HFTBI patients the mean
      deviation between measured and expected lung dose was 0.0% (1 SD = 3.8%).
      CONCLUSIONS: In vivo dosimetry is an effective tool to improve the accuracy of
      TBI. The impact of CT planning for FTBI significantly improved the accuracy of
      the treatment delivery. Transit dosimetry data revealed a significant inter
      patient variation of the mean lung dose among patients undergoing the same
      irradiation technique. For patients with partial lung shielding (HFTBI), an
      excellent agreement between measured and expected lung dose was verified.

PMID- 10580877
TI  - The cutaneous vasoconstrictor response to venous stasis is normal in subjects
      with primary Raynaud's disease.
AB  - In control subjects and in subjects with primary Raynaud's disease, sudden sound
      or a mild cool stimulus evokes the pattern of alerting response that includes
      cutaneous vasoconstriction but vasodilatation in forearm muscle. In control
      subjects, response habituates on repetition of these stimuli both within
      experimental sessions and over successive days. However, in subjects with primary
      Raynaud's disease, the cutaneous vasoconstriction and the muscle vasodilatation
      persist. We have now tested whether a similar disparity exists for the cutaneous
      vasoconstriction evoked by venous stasis, a response considered to be a veno
      arteriolar reflex mediated by sympathetic fibers, but not requiring transmission
      through the spinal cord. In 10 subjects with primary Raynaud's disease and in 10
      matched controls, a sphygmomanometer cuff on the left arm was inflated to 40 mm
      Hg for 2 minutes, five times on each of three experimental sessions on days 1, 3,
      and 5. Cutaneous red cell flux (RCF) was recorded from the pulp and dorsum of the
      left index finger by using a laser Doppler meter; digital vascular conductance
      (DCVC) was computed as RCF divided by arterial pressure. The first venous stasis,
      in session 1, evoked a decrease in pulp and dorsum DCVC in the control and
      primary Raynaud's subjects. There were no differences between the groups in the
      magnitudes or durations of these responses. Within session 1, the magnitude of
      the decrease in DCVC diminished on repetition of venous stasis in the dorsum in
      controls and in the pulp in primary Raynaud's subjects. We propose these effects
      reflected the similar reductions in baseline DCVC over time; there was no change
      in the duration of the responses. Repetition of venous stasis had similar effects
      in both groups of subjects within sessions 2 and 3. Further, judging from the
      mean of the responses evoked in each Session the decreases evoked in pulp and
      dorsum DCVC by venous stasis were fully consistent in magnitude and duration over
      the three sessions in both groups. These results indicate that the direct
      constrictor influence of sympathetic fibers upon cutaneous blood vessels is
      similar in magnitude and similarly reproducible in controls and subjects with
      primary Raynaud's disease. This reinforces our view that the lack of habituation
      of the cutaneous vasoconstrictor component of the alerting response in subjects
      with primary Raynaud's disease reflects impairment of the central neural process
      of habituation, rather than a peripheral phenomenon, and that this lack of
      habituation predisposes these subjects to vasospasm.

PMID- 10580878
TI  - Contribution of nitric oxide to exercise-induced hypotension in human sympathetic
      denervation.
AB  - The cardiovascular, catecholamine, and nitrate/nitrite (NO) responses to bicycle
      exercise were measured in 14 normal subjects (controls) and two groups with
      sympathetic denervation; 14 with peripheral autonomic failure (pure autonomic
      failure [PAF]); and 13 with central autonomic failure (multiple system atrophy
      [MSA]). With exercise, blood pressure increased in control subjects by 40 +/-
      7/24 +/- 5 mm Hg (p < 0.001) and fell in PAF by 24 +/- 8/24 +/- 5 mm Hg (p < 0.02
      and p < 0.007) and MSA by 31 +/- 7/11 +/- 3 mm Hg (p < 0.005 and p < 0.04). With
      exercise, the increase in heart rate was greater in control subjects (60 +/- 3 to
      111 +/- 4/min; p < 0.0001) than in PAF (69 +/- 3 to 86 +/- 4/min; p < 0.0001) and
      MSA (70 +/- 4 to 90 +/- 4; p < 0.001). Resting plasma noradrenaline levels were
      similar in controls (291 +/- 51 pg ml(-1)) and MSA (257 +/- 49 pg ml(-1)), but
      lower in PAF (82 +/- 14 pg ml(-1)). With exercise, plasma noradrenaline increased
      in controls but was unchanged in PAF and MSA. Resting NOx was similar in controls
      (50 +/- 5 nmol/L; range, 23.3-87.6 nmol/L) and PAF patients (59+/-8 nmol/l;
      range, 19.3-116.4 nmol/L), but was higher in MSA patients (87 +/-14 nmol/L; p
      <0.025, range 15.4-157.2 nmol/L). With exercise, NOx was unchanged in control
      subjects and increased by 10% and 17% in PAF and MSA, respectively; these changes
      were not statistically significant. This study suggests that circulating changes
      in NOx levels do not exert a major role in exercise-induced hypotension in
      subjects with sympathetic denervation.

PMID- 10580880
TI  - MRI signal changes in the white matter after corpus callosotomy.
AB  - Magnetic resonance imaging (MRI) changes reported after corpus callosotomy
      include hyperintensity in the corpus callosum, perifalcine hyperintensity caused
      by surgical retraction, and acute changes associated with surgical complications.
      The authors have observed MRI signal changes in the cerebral white matter of
      corpus callosotomy patients that are separate from the sectioned callosum and not
      clearly related to surgical manipulation or injury. Brain MRI scans were
      retrospectively reviewed in 25 of 38 patients who underwent anterior, posterior,
      or total callosotomy for refractory seizures between 1988 and 1995. Nine patients
      had signal changes in the cerebral white matter on postoperative MRI. Six of
      these patients had preoperative MRI studies available for comparison, and none of
      the white matter signal abnormalities were evident preoperatively. T2
      prolongation or hyperintensity on proton-density images was observed in areas
      including the centrum semiovale, forceps major, and forceps minor. Three patients
      had signal changes that had distinct borders extending only to the posterior
      limit of the callosotomy. MRI signal changes in the cerebral white matter after
      corpus callosotomy have not been previously reported and may represent distant
      effects of callosal section. Wallerian degeneration occurring in the neuronal
      processes cut during surgery could account for the signal changes.

PMID- 10580881
TI  - Human herpesviruses types 6 and 7 and febrile seizures.
AB  - The frequency was studied with which human herpesviruses types 6 and 7 (HHV-6 and
      HHV-7) occur in the cerebrospinal fluid (CSF) of patients with febrile seizures
      and matched control patients. CSF samples were prospectively collected from a
      case series of patients with febrile seizures and from age-, sex-, and race
      matched control patients without febrile seizures, all of whom were evaluated in
      the emergency department of an urban, tertiary care, pediatric medical center.
      Using polymerase chain reaction, the samples were examined for the presence of
      viral DNA from HHV-6, HHV-7, herpes simplex viruses types 1 and 2 (HSV-1 and HSV
      2), and cytomegalovirus (CMV). CSF from a subset of both groups was also examined
      for RNA from enteroviruses. During the 7-month, 2-week collection period, a total
      of 174 patients were evaluated for fever and seizures. Of these, 23 (13.2%) met
      the study criteria. Their mean age was 1.4 +/- 0.7 years. Sixteen (70%) of the 23
      were male. The 23 patients were matched to 21 control subjects. None of the
      samples from the patients or control subjects had polymerase chain reaction
      evidence of HHV-6, HHV-7, HSV-1, or HSV-2. All samples from the patients were
      negative for CMV. One control subject was positive for CMV. The 10 patients and
      seven control subjects tested for enteroviral RNA were negative. Neither HHV-6
      nor HHV-7 appears to be present in the CSF of patients with febrile seizures.
      What role, if any, they have in the pathogenesis of febrile seizures merits
      further study.

PMID- 10580879
TI  - Abnormal suppression of arginine-vasopressin by clonidine in multiple system
      atrophy.
AB  - In normal man, the centrally active alpha2-adrenoceptor agonist clonidine reduces
      arginine-vasopressin (AVP) secretion, probably by presynaptic inhibition of
      noradrenergic neuron terminals in the supraoptic nucleus. A lesion of
      noradrenergic pathways in animals abolishes this response to clonidine. At
      postmortem in multiple system atrophy (MSA) there is marked loss of hypothalamic
      noradrenergic innervation. We hypothesized that the AVP response to clonidine in
      MSA may be abnormal and therefore studied the AVP response to clonidine (2
      microg/ kg iv) in 10 subjects with MSA and compared them to six healthy age
      matched control subjects. Basal levels of AVP were similar in controls and MSA.
      Following clonidine there was a significantly greater fall in controls than MSA (
      47 +/- 4% vs -25 +/- 6%; p < 0.05). There was a similar fall in mean arterial
      pressure (MAP) and plasma catecholamines in both groups, with no change in plasma
      osmolarity, excluding these as a contributary factor. In conclusion, there is an
      abnormal AVP response to clonidine in MSA, which probably represents loss of
      functional noradrenergic innervation of the supraoptic nucleus.

PMID- 10580882
TI  - Clinical assessment, MRI, and EMG in congenital brachial plexus palsy.
AB  - Thirteen infants with congenital brachial plexus palsy (eight with upper, five
      with upper and lower) were monitored by magnetic resonance imaging (the first
      performed between 7 and 41 days of age and the second at 3 months of age),
      electromyography (the first performed between 27 and 50 days and the second at 3
      months), and the muscle scoring system of the Hospital for Sick Children (at 3,
      6, and 9 months of age). The findings were evaluated with respect to the clinical
      status of the patients at 12 months of age. Magnetic resonance imaging, which
      could be performed readily even in the neonatal period, revealed
      pseudomeningoceles in two of the five patients with a poor prognosis (in all
      planes even in the early days after birth) and in two of the eight patients with
      a good prognosis (more easily visible at 3 months of age). Electromyography
      implied root avulsion in three of five patients with a poor prognosis.
      Electromyography can be of great value for patients with a poor prognosis and
      root avulsion but may underestimate the severity. The muscle scoring system
      (Hospital for Sick Children) was determined to be the most predictive method for
      prognosis.

PMID- 10580883
TI  - Development of spinal motoneurons in rats after a neonatal hypoxic insult.
AB  - To determine the developmental changes of cervical and lumbar motoneurons (MNs)
      during normal development and after a neonatal hypoxic insult, cervical and
      lumbar MNs were studied in rats of various postnatal ages using a retrograde
      neurotracing technique combined with immunohistochemistry. The results regarding
      normal development could be summarized as follows: (1) the dendrites elongated
      mainly during the first 5 postnatal days (PNDs), being longer and more extensive
      in cervical MNs than in lumbar MNs; (2) the average cell body area increased from
      PND 5 to 14; and (3) the distribution of cell body areas changed from a unimodal
      to a bimodal pattern between PND 5 and 14. The temporal differences in
      morphologic development between cervical and lumbar MNs may influence the motor
      development in a rostrocaudal manner. The dendrites of lumbar MNs were shorter
      and less extensive in rats with a neonatal hypoxic insult than in rats without
      one; no significant difference was observed in cervical MNs between the two
      groups. The developmental difference between cervical and lumbar MNs after a
      neonatal hypoxic insult may contribute to motor deficits, with greater effect on
      the lower than the upper limbs.

PMID- 10580884
TI  - Risk factors for developing brain herniation during diabetic ketoacidosis.
AB  - The charts were reviewed of children admitted in diabetic ketoacidosis (DKA) to
      one hospital within 12 years. The frequency of brain herniation after admission
      was nine of 153 children admitted for one or more episodes of DKA. The severity
      of acidosis and hypercapnea were the most reliable risk factors. None of the
      children who maintained a blood pH greater than 7.1 and a capillary blood partial
      pressure of carbon dioxide (PCO2) greater than 20 mm Hg manifested brain
      herniation. The rate of initial fluid administration in severe DKA was also a
      risk factor. Of 119 patients having a blood pH less than 7.1 or PCO2 less than 20
      mm Hg, none of 32 receiving less than 25 mL/kg, one of 42 receiving 25-50 mL/kg,
      and eight of 40 receiving more than 50 mL/kg of intravenous fluid during the
      first (in Patient 9, the second) 4 hours of therapy sustained brain herniation.
      Equally dehydrated unaffected patients initially receiving 25-50 mL/kg/4 hours of
      intravenous fluid did not develop signs of hypovolemia or worsening DKA. In this
      series, hydrating at a rate greater than 50 mL/kg during the first 4 hours
      offered no advantage and was associated with an increased risk of brain
      herniation.

PMID- 10580885
TI  - The effect of tiagabine on spasticity in children with intractable epilepsy: a
      pilot study.
AB  - Preliminary pharmacologic evidence suggests that tiagabine, a new presynaptic
      gamma-aminobutyric acid-uptake inhibitor developed as an antiepileptic drug, may
      also relieve spasticity. This pilot study assessed the drug's efficacy in 14
      children with congenital or acquired spastic quadriplegia and concomitant
      intractable epilepsy refractory to treatment with multiple antiepileptic drugs.
      The primary outcome variable was change in motor function; the secondary outcome
      was change in seizure frequency. Tiagabine was initiated at 0.1-0.2 mg/kg/day and
      then gradually titrated upward until seizures ceased, adverse effects supervened,
      or the maximum dose of 1.1 mg/kg/day was reached. When a modified Ashworth scale
      was used to assess motor function, a mean improvement of approximately 50% was
      observed. Common findings included improved tone, strength, coordination, range
      of motion, and relaxation of extremities, with less ataxia and wobbling. Mean
      reduction in seizure frequency was 50-74%. Randomized, double-blind controlled
      studies are needed to confirm the suggested efficacy of tiagabine in relieving
      chronic spasticity in children with neurodevelopmental disorders.

PMID- 10580886
TI  - Tuberous sclerosis associated with MDR1 gene expression and drug-resistant
      epilepsy.
AB  - Intractable seizures are the most common manifestation in severe cases of
      tuberous sclerosis. Multidrug resistance type 1 (MDR1) gene expression is
      directly linked to the resistance of tumor cells to chemotherapy as the major
      cause of treatment failure, but it has not been reported in tuberous sclerosis
      cells nor has the relationship between the MDR1 gene and antiepileptic drugs been
      described. A 4-month-old female is described with poorly controlled seizures
      secondary to tuberous sclerosis. The patient was treated with antiepileptic
      drugs, including phenytoin, phenobarbital, and lorazepam, without improvement of
      symptoms. Phenytoin blood levels were invariably subtherapeutic and ranged from
      0.45 to 3.55 microg/mL, despite several consecutive intravenous loading doses.
      Surgical treatment with total resection of the brain lesions was performed as a
      last resort. Immunohistochemical analysis of the resected tissues revealed high
      levels of P-glycoprotein 170 expression, the product of the MDR1 gene. Both MDR1
      gene expression and persistently low phenytoin levels likely share a common
      pathway liable to induce drug-resistant epilepsy.

PMID- 10580887
TI  - Extensive late-onset primary subarachnoid hemorrhage in a preterm infant.
AB  - Primary subarachnoid hemorrhage is a rare event in the preterm infant and is most
      often diagnosed at the postmortem examination. An extremely preterm infant who
      developed septicemia from Staphylococcus aureus infection in the second postnatal
      week and presented with hypotension, metabolic acidosis, anemia,
      thrombocytopenia, and seizures is reported. Cranial ultrasound revealed a large
      extra-axial fluid collection involving the left parietal cortex that at
      postmortem examination was observed to be a large left-sided primary subarachnoid
      hemorrhage. The subarachnoid hemorrhage is most likely secondary to events
      associated with septic shock and probable disseminated vascular coagulopathy.

PMID- 10580888
TI  - Cerebral blood flow velocities in an infant with moyamoya disease.
AB  - Moyamoya disease is a progressive cerebrovascular disorder with bilateral
      occlusion of the basal circulation and development of collateral blood supply. In
      a 6-month-old female with multifocal ischemic infarctions, transcranial pulsed
      Doppler sonography revealed extremely high and low cerebral blood flow
      velocities, dampened waveforms, reversed flow, and musical murmurs. Magnetic
      resonance angiography revealed different degrees of vascular stenosis and an
      abnormal collateral network. Moyamoya disease was confirmed by conventional
      angiography at the age of 10.5 months. Pulsed-wave transcranial Doppler
      sonography is a noninvasive screening method in infants at risk of moyamoya
      disease.

PMID- 10580889
TI  - Sympathetic storms in a child with a midbrain glioma: a variant of diencephalic
      seizures.
AB  - The authors report the unusual case of a 7-year-old child, one of the youngest
      reported to date, who developed repeated episodes of sympathetic hyperactivity
      after surgical resection of a midbrain glioma. These paroxysmal events were
      similar to previously described diencephalic seizures. However, there was no
      evidence of epileptogenic activity on electroencephalography, and radiologic
      imaging did not reveal hydrocephalus or intraparenchymal hemorrhage. In this
      report, clinical features are described of this patient, along with the novel use
      of clonidine--a sympathetic blocking agent--in his treatment, published reports
      are reviewed on diencephalic seizures, and steps are recommended in the treatment
      of a patient who presents in this manner. The authors believe that diencephalic
      seizures can present with a spectrum of autonomic features, and treatment should
      be tailored with the appropriate pharmacologic blockade.

PMID- 10580890
TI  - Cerebellar hypoperfusion and developmental dysphasia in a male.
AB  - A male with developmental dysphasia is documented with fine motor dysfunction
      whose improvement in expressive language was associated with increased cerebellar
      perfusion, as detected by serial N-isopropyl-p-[iodine-123] iodoamphetamine
      single photon emission computed tomography (SPECT). His expressive language has
      been improving since 6 years, 8 months of age, and his verbal intelligence
      quotient improved from less than 45 at 5 years of age to 80 at 8 years of age.
      Compared with the SPECT findings at 4 years of age, the ratio of the average
      pixel values of the cerebellum to the frontal cortices increased at 9 years of
      age (from 0.81 to 1.03-1.09 in the hemisphere and from 0.66 to 0.98 in the
      vermis). However, he was not able to understand stories presented orally even at
      9 years, 4 months of age. These results suggest that developmental dysphasia,
      which mostly involves expressive impairment, in this patient could have been the
      result of delayed maturation of cerebellar function, mainly that of the vermis.

PMID- 10580891
TI  - Critical illness neuropathy in pediatric intensive care patients.
AB  - Critical illness neuropathy is an axonal polyneuropathy recognized more
      frequently in adult intensive care patients with sepsis and multiple organ
      dysfunction. In children the diagnosis is rarely made. Within 1 year the authors
      observed two children with critical illness neuropathy. Both patients, a male 6
      years, 6 months of age with a brain contusion and a male 2 years, 6 months of age
      who underwent craniectomy for Crouzon's disease, required prolonged mechanical
      ventilation and developed sepsis with multiple organ dysfunction. Three to 4
      weeks after successful treatment of the sepsis, a flaccid tetraparesis was
      noticed in both patients. Laboratory investigations of blood and cerebrospinal
      fluid and spinal magnetic resonance imaging revealed normal results.
      Electrophysiologic examinations were indicative of an axonal polyneuropathy.
      Spontaneous improvement occurred within several months. It is likely that
      critical illness neuropathy occurs more often in critically ill children than
      previously thought. Careful neurologic examination and early electrophysiologic
      investigations are necessary to establish the diagnosis. Important differential
      diagnoses of acquired lower motor neuron weakness in pediatric intensive care
      medicine are discussed.

PMID- 10580892
TI  - Hemifacial spasm caused by a pilocytic astrocytoma of the fourth ventricle.
AB  - An 11-year-old male in whom hemifacial spasm was the presenting sign of a
      pilocytic astrocytoma within the fourth ventricle is reported. The child's
      hemifacial spasm decreased substantially after resection of the tumor. Hemifacial
      spasm is largely a disease of adults and only rarely is attributed to brain
      tumors. In contrast, this marks the fifth case of hemifacial spasm reported in a
      child, three of which have been attributed to tumors of the fourth ventricle.

PMID- 10580893
TI  - A case in the spectrum of the oculo-encephalo-hepato-renal syndrome.
AB  - An 18-year-old male is presented with unprecedented central nervous system
      findings (cerebral dysplasia and sacral meningocele) possibly in the spectrum of
      the oculo-encephalo-hepato-renal syndrome. He had severe mental retardation,
      triplegia, epilepsy, retinitis pigmentosa, and chronic renal failure. Magnetic
      resonance imaging demonstrated cerebral dysplasia (left dominant abnormal gyri,
      hypoplastic white matter, basal ganglia, and thalamus, and absence of the septum
      pellucidum) and the hypoplastic cerebellum and brainstem. A sacral meningocele
      was observed first at 16 years of age. His renal function gradually worsened
      after 11 years of age. His liver function was normal. The previously reported 72
      cases with the oculo-encephalo-hepato-renal syndrome are reviewed.

PMID- 10580894
TI  - Alternating hemiplegia of childhood.

PMID- 10580895
TI  - Strategies for enhancing viral-based gene therapy using ionizing radiation.
AB  - Many gene-therapy strategies under investigation aim to increase the efficacy of
      current cancer-treatment regimens. Promising results have been obtained in the
      laboratory and early clinical trials using viral-based motifs specifically
      designed to enhance the efficacy of ionizing radiation or chemotherapy. These
      strategies fall into two general categories: replication-incompetent viral
      shuttle vectors for the delivery of specific genes encoding a chemo/radiation
      modulator and attenuated replication-competent viruses with proposed replicative
      advantages in tumor cells. In this review, we discuss the rational, molecular
      mechanisms, and clinical application of these strategies with particular focus on
      recent research applying these viral-based strategies to improve the therapeutic
      index of ionizing radiation.

PMID- 10580896
TI  - Effects of azetidine-2-carboxylic acid on treatments of hepatoma cells with
      single or fractionated X-ray irradiations and on thermal radiosensitization in
      normal and thermotolerant cells.
AB  - The amino acid analog azetidine-2-carboxylic acid (azetidine) is a potent
      sensitizer to both hyperthermia and ionizing radiation. Incubation of H35
      hepatoma cells with 2.5 mM azetidine before or after treatments with X-rays
      causes a time- and sequence-dependent enhancement of cell killing. Exposure of
      cells to 1-1.5 mM azetidine for 96 h in combination with repeated doses of 3 Gy X
      rays at 24 h intervals causes an enhanced reduction of the surviving cell
      population due to both radiosensitization and an additional growth inhibition.
      Azetidine does not prevent the induction of thermotolerance after a heat shock.
      This thermotolerance proportionally reduces thermal radiosensitization but does
      not seem to affect azetidine radiosensitization. It is suggested that thermal
      radiosensitization and azetidine radiosensitization operate by different
      mechanisms.

PMID- 10580897
TI  - Long-term complications with prostate implants: iodine-125 vs. palladium-103.
AB  - The linear quadratic model predicts that the normal tissue biologically effective
      dose (BED) will be lower with palladium-103 (Pd-103) vs. iodine-125 (I-125) for
      the currently prescribed minimum tumor doses (MTD) used for I-125 (160 Gy) and Pd
      103 (115 Gy) prostate cancer brachytherapy. The predicted BEDs for I-125 and Pd
      103 suggest that the long-term complication rates should be lower with Pd-103 vs.
      I-125 in clinical practice. A review of 123 early stage T1c and T2 prostate
      cancer patients implanted at Yale University with I-125 (82 patients) or Pd-103
      (41 patients) reveals a significantly lower overall complication rate with Pd-103
      (0%) vs. I-125 (13%). Most important, the grade III-IV complication rate for Pd
      103 was 0% vs. 6% for I-125. The 3-year actuarial probability of remaining free
      of a long-term complication was 100% for Pd-103 vs. 82% for I-125 (P<0.01). A
      review of the literature for 992 patients implanted with I-125 vs. 540 patients
      implanted with Pd-103 shows a consistently higher complication rate for I-125 vs.
      Pd-103. Assuming that the MTD for Pd-103 may be increased to produce an
      equivalent late-reacting normal tissue BED to that for I-125, then the
      radiobiology model predicts the log10 cell kill for Pd-103 implant will be
      greater than that of an I-125 implant for all tumor doubling times (high-grade
      tumors and low-grade tumors). The implications of these findings are discussed in
      terms of future research directions for prostate implants.

PMID- 10580898
TI  - Combined low-dose-rate brachytherapy and external beam radiation for cervical
      cancer: experience over ten years.
AB  - Cervical cancer was treated with a combination of external beam and intracavitary
      radiation during a 10-year period at Wayne State University. Data were collected
      for 216 patients treated radically with external beam radiation (EBRT) and low
      dose-rate brachytherapy for cervical cancer between 1980 and 1991 at Wayne State
      University. Patient distribution by stage was IB, 20.8%; IIA, 7.4%; IIB, 26.9%;
      IIIA, 1.8%; IIIB, 40.7%; and IVA, 2.3 %. Survival curves were constructed using
      Kaplan-Meier methods and differences between groups were tested for significance
      using the log-rank test. Multivariate analysis was done using the Cox
      proportional hazards model. With a median follow-up of 114 months, actuarial
      disease-free survival for all patients was 60% at 5 years and 55% at 10 years.
      Actuarial 5-year survival for Stage IB was 79%; for Stage II, 59%; and for Stage
      III, 53%. There were 14/216 (6%) of patients with severe late complications. On
      univariate analysis, race was found to be statistically significant, with
      Caucasian patients having better survival than African American (P = 0.03). The
      survival for patients treated in shorter overall times was significantly higher
      (P<0.001), especially with treatment completion in under 58 days. The stepwise
      Cox multivariate analysis provided the following significant results: race
      (African American vs. Caucasian; P = 0.04, RR = 1.6), Stage (II vs. I, P = 0.004,
      RR = 2.6), Stage (III vs. I; P = 0.004, RR = 2.5), and overall treatment time (P
      = 0.006, RR = 1.62). Rates of local control, survival, and complications among
      women treated with combined external beam and intracavitary radiation for cervix
      cancer were similar to those of prior retrospective studies.

PMID- 10580900
TI  - Radiation therapy for neurosarcoidosis: report of three cases from a single
      institution.
AB  - Sarcoidosis is a chronic, multisystemic disorder of unknown etiology. The
      incidence of central nervous system involvement is as high as 5%. Although
      steroids have been the cardinal treatment for sarcoidosis, many patients become
      symptomatically unresponsive to them. Other patients may suffer from glucose
      intolerance, cataracts, and obesity, which are adverse effects of high-dose
      steroids. Various reports in the literature suggest that some chemotherapeutic
      agents and/or radiation may be useful in these situations. We present three
      patients with neurosarcoidosis who were treated with radiation at a single
      institution. We also review previous reports on radiation-treated neurosarcoid
      patients. While the results vary, some patients clearly derive symptomatic
      benefits from low-dose radiation. Since the side effects of low-dose cranial
      irradiation are minimal, it may be prudent to use radiation therapy for patients
      who are refractory to steroids or who suffer adversely from high-dose steroids.

PMID- 10580899
TI  - Results of multifield conformal radiation therapy of nonsmall-cell lung carcinoma
      using multileaf collimation beams.
AB  - A five-field conformal technique with three-dimensional radiation therapy
      treatment planning (3-DRTP) has been shown to permit better definition of the
      target volume for lung cancer, while minimizing the normal tissue volume
      receiving greater than 50% of the target dose. In an initial study to confirm the
      safety of conventional doses, we used the five-field conformal 3-DRTP technique.
      We then used the technique in a second study, enhancing the therapeutic index in
      a series of 42 patients, as well as to evaluate feasibility, survival outcome,
      and treatment toxicity. Forty-two consecutive patients with nonsmall-cell lung
      carcinoma (NSCLC) were evaluated during the years 1993-1997. The median age was
      60 years (range 34-80). The median radiation therapy (RT) dose to the gross tumor
      volume was 6,300 cGy (range 5,000-6,840 cGy) delivered over 6 to 6.5 weeks in 180
      275 cGy daily fractions, 5 days per week. There were three patients who received
      a split course treatment of 5,500 cGy in 20 fractions, delivering 275 cGy daily
      with a 2-week break built into the treatment course after 10 fractions. The
      stages of disease were II in 2%, IIIA in 40%, IIIB in 42.9%, and recurrent
      disease in 14.3% of the patients. The mean tumor volume was 324.14 cc (range 88.3
      773.7 cc); 57.1% of the patients received combined chemoradiotherapy, while the
      others were treated with radiation therapy alone. Of the 42 patients, 7 were
      excluded from the final analysis because of diagnosis of distant metastasis
      during treatment. Two of the patients had their histology reinterpreted as being
      other than NSCLC, 2 patients did not complete RT at the time of analysis, and 1
      patient voluntarily discontinued treatment because of progressive deterioration.
      Median follow-up was 11.2 months (range 3-32.5 months). Survival for patients
      with Stage III disease was 70.2% at 1 year and 51.5% at 2 years, with median
      survival not yet reached. Local control for the entire series was 23.3+/-11.4% at
      2 years. However, for Stage III patients, local control was 50% at 1 year and 30%
      at 2 years. Patients who received concurrent chemotherapy had significantly
      improved survival (P = 0.002) and local control (P = 0.004), compared with RT
      alone. Late esophageal toxicity of > or =Grade 3 occurred in 14.1+/-9.3% of
      patients (3 of 20) receiving combined chemoradiotherapy, but in none of the 15
      patients treated with RT alone. Pulmonary toxicity limited to Grades 1-2 occurred
      in 6.8% of the patients, and none developed > or =Grade 3 pulmonary toxicity.
      Patients with locally advanced NSCLC, who commonly have tumor volumes in excess
      of 200 cc, presenta challenge for adequate dose delivery without significant
      toxicity. Our five-field conformal 3-DRTP technique, which incorporates treatment
      planning by dose/volume histogram (DVH) was associated with minimal toxicity and
      may facilitate dose escalation to the gross tumor.

PMID- 10580901
TI  - Treatment outcome for patients with primary nonsmall-cell lung cancer and
      synchronous brain metastasis.
AB  - The purpose of this study was to evaluate the outcome of treatment for patients
      with newly diagnosed nonsmall-cell lung cancer (NSCLC) with an isolated, single,
      synchronous brain metastasis. A retrospective review was performed evaluating any
      patient diagnosed between 1982 and 1996 at the Cleveland Clinic Foundation with
      NSCLC metastatic only to the brain. Patients with multiple brain metastases or
      with systemic metastases to any other organ were excluded. Survival was measured
      from the date of the first treatment for malignancy. All hospital records were
      thoroughly reviewed in a retrospective manner. Thirty-three patients were
      identified who met the study criteria. Twelve patients had primary disease
      limited to the lung and hilar nodes, and 21 had more advanced primary disease
      with involvement of the mediastinum. Treatment of the chest was considered
      aggressive in 13 patients and palliative in 15. The primary tumor was observed in
      5 patients. The management of the brain metastasis was as follows: 21 patients
      underwent surgical resection and postoperative whole brain radiotherapy (WBRT), 5
      underwent stereotactic radiosurgery (SRS) and WBRT, 3 had resection alone, 2 had
      SRS alone, and 2 underwent WBRT alone. The median overall and disease-free
      survival for all patients was 6.9 months and 3.3 months, respectively. Overall
      survival was markedly improved with the addition of WBRT (P = 0.002) and with the
      aggressive management of the primary tumor (P = 0.005). A total of 9 patients
      experienced CNS failure, including both patients receiving WBRT alone. CNS
      failures were divided as follows: 3 local, 5 distant, and 1 local and distant.
      Two of the 4 patients with a local failure were salvaged, and ultimate local
      control of the original brain metastasis was achieved in 93.6% of cases. Survival
      remains poor for patients with Stage IV NSCLC even when metastatic disease is
      limited to a single site within the brain; however, aggressive therapy of both
      the lung primary and the brain metastasis may provide a survival advantage.
      Excellent local control of single brain metastases was achieved with a
      combination of WBRT with either surgical resection or SRS.

PMID- 10580902
TI  - In-house canine and feline blood typing.

PMID- 10580904
TI  - Idiopathic thrombocytopenic purpura in a cat.
AB  - An 11-year-old, castrated, male domestic shorthair cat was presented for
      hematuria and pollakiuria. The cat had a marked thrombocytopenia, and a bone
      marrow core biopsy demonstrated megakaryocytic hyperplasia with many
      megakaryocyte-associated neutrophils (i.e., emperipolesis). On peripheral blood,
      collected at initial presentation, what appeared to be platelets were noted to be
      within or adherent to occasional neutrophils. The thrombocytopenia was idiopathic
      in that no definitive cause could be found. However, platelet concentrations
      appeared to increase and decrease in response to changes in prednisone and
      cyclosporine therapy, suggesting a possible immune-mediated pathogenesis. As
      tests to detect increased feline platelet-associated antibodies are unavailable,
      immune-mediated thrombocytopenia can only be tentatively diagnosed in cats by
      exclusion and response to therapy.

PMID- 10580903
TI  - Nasopharyngeal diseases in cats: a retrospective study of 53 cases (1991-1998).
AB  - The records of 53 cats with nasopharyngeal disease were examined. Of the cats
      with nasopharyngeal disease, 49% had lymphosarcoma and 28% had polyps. Clinical
      signs in these cats were compared to 24 cats with nasal disease alone. Cats with
      only nasal disease more commonly had historical nasal discharge and sneeze,
      whereas cats with nasopharyngeal disease more often had stertorous respiration,
      phonation change, and typically reported less nasal discharge or sneeze. It is
      important to include nasopharyngeal disease in the differential diagnosis for
      cats with nasal discharge, sneeze, stertor, or phonation change.

PMID- 10580905
TI  - Leukoerythroblastosis and normoblastemia in the cat.
AB  - Over a six-month period, 6% of 313 cats evaluated hematologically had either
      leukoerythroblastosis or normoblastemia. Diseases associated with these
      hematological conditions included haemobartonellosis, hepatic lipidosis, trauma,
      viral and bacterial infections, myeloproliferative disorders, and
      hemangiosarcoma. The finding of leukoerythroblastosis or normoblastemia may aid
      in diagnosing cats presenting with nonspecific signs.

PMID- 10580906
TI  - Long-term case study of myelodysplastic syndrome in a dog.
AB  - A 10-year-old, female shih tzu was diagnosed as having myelodysplastic syndrome
      (MDS) based on the presence of a nonregenerative anemia, dysplastic changes in
      the three hematopoietic cell lines, a normal to hypercellular bone marrow, and
      less than 30% blast cells of all nucleated cells in the bone marrow. Low-dose
      aclarubicin, a differentiation-induction therapy for MDS and atypical leukemias
      in humans, was administered. Hematological improvement was observed, and the dog
      lived for 809 days after the first presentation.

PMID- 10580907
TI  - Paraneoplastic thrombocytosis-induced systemic thromboembolism in a cat.
AB  - A six-year-old cat presented with clinical signs consistent with distal aortic
      thromboembolism while clinical signs of cardiovascular disease were absent.
      Diagnostics, including thoracic radiographs, electrocardiography, and
      echocardiography revealed no cardiovascular anomalies. Thoracic radiographs
      revealed multifocal pulmonary lesions consistent with neoplasia. Complete blood
      cell count demonstrated a marked thrombocytosis, leukopenia, and neutropenia.
      Histopathology of the pulmonary lesions confirmed multiple bronchoalveolar
      carcinomas. Myelodysplasia with megakaryocytic hyperplasia and ineffective
      myelopoiesis was noted on bone-marrow histopathology from multiple sites. The
      absence of other causes suggested a paraneoplastic thrombocytosis. The diagnosis
      of paraneoplastic thrombocytosis-induced thromboembolism was made due to the lack
      of underlying cardiac disease and the presence of a marked thrombocytosis. The
      presence of thrombocytosis and thromboembolism associated with neoplasia is
      discussed.

PMID- 10580908
TI  - Primary hypothyroidism associated with leishmaniasis in a dog.
AB  - A case of primary hypothyroidism associated with leishmaniasis is described in a
      four-year-old, male Yorkshire terrier. Clinical diagnosis of hypothyroidism was
      confirmed by a low baseline serum tetraiodothyronine (T4), a reduced response to
      thyroid-stimulating hormone (TSH) stimulation, an increased serum TSH
      concentration, and scintigraphic thyroid gland examination. Examination of a
      thyroid biopsy showed many Leishmania amastigotes, both inside and outside of
      macrophages, together with signs of follicular atrophy.

PMID- 10580909
TI  - Suspected myelinolysis following rapid correction of hyponatremia in a dog.
AB  - A dog developed signs of neurological dysfunction five days after rapid
      correction of severe electrolyte derangements, including hyponatremia, caused by
      gastrointestinal parasitism (i.e., trichuriasis). History, laboratory findings,
      and onset of neurological signs following correction of hyponatremia led to a
      diagnosis of myelinolysis. Myelinolysis is a noninflammatory, demyelinating brain
      disease caused by sudden, upward osmotic shifts in central nervous system plasma,
      often a result of rapid correction of chronic hyponatremia. The pathogenesis is
      complex, but recovery is possible. Iatrogenic damage due to myelinolysis can be
      avoided by adherence to therapeutic guidelines for correction of chronic
      hyponatremia.

PMID- 10580910
TI  - Regression of hypertrophic osteopathy in a cat after surgical excision of an
      adrenocortical carcinoma.
AB  - A 12-year-old, spayed, female domestic shorthair cat was diagnosed with severe
      and extensive hypertrophic osteopathy of the appendicular skeleton. Diagnostic
      ultrasound detected a mass lesion in the right adrenal gland. A right
      adrenalectomy was performed, and histopathological examination confirmed an
      adrenocortical carcinoma. No radiographic evidence of pulmonary metastasis was
      found on initial presentation or recheck thoracic radiographs taken 15 weeks
      later. Almost complete regression of periosteal new bone formation occurred 15
      weeks following the successful surgical removal of the adrenal tumor.

PMID- 10580911
TI  - Invasive multiple lymphangiomas in a young dog.
AB  - An unusual case of multiple lymphangiomas with lymph node involvement is
      described. A seven-month-old, spayed female golden retriever was presented with a
      myriad of cystic masses in the inguinal and caudal mammary regions. She was
      diagnosed with congenital lymphangiomas (i.e., lymphatic hamartomas). As in human
      lymphangiomas, lymphatic endothelial cells expressing factor VIII-related antigen
      and smooth muscle were present in this case. A literature search did not identify
      similar characteristics in other reported canine lymphangiomas. The dog was
      treated surgically and had a recurrence. Following a second surgical
      intervention, she is now disease-free.

PMID- 10580912
TI  - Feline retinal degeneration: clinical experience and new findings (1994-1997).
AB  - A retrospective case series of 26 cats with diffuse retinal degeneration is
      presented. The most common presenting complaints included bumping into objects,
      dilated pupils, and reluctance to jump. Ophthalmic examination findings were
      consistent with those reported in dogs with progressive retinal atrophy. Breed
      predilection of the Siamese cat was observed. Cats with primary retinal
      degeneration presented late in the clinical course of their disease, when vision
      loss was severe. Early symptoms such as night blindness and secondary ocular
      complications (i.e., cataract and retinal detachment), reported in dogs with
      progressive retinal degeneration, were not observed in this study. All cats
      showed excellent adaptive capabilities to blindness.

PMID- 10580913
TI  - A two-dimensional analysis of limb symmetry in the trot of Labrador retrievers.
AB  - Sixteen sound Labrador retriever and Labrador retriever cross-breed adult dogs
      were evaluated for symmetry while in a trot gait using a two-dimensional motion
      analysis system. Reflective markers were placed at selected joint centers. Each
      dog had the right side and then the left side videotaped while in the trot gait.
      The markers on the videotape were then digitized for analysis. There was no
      significant difference (p less than 0.05) between the movements of the two sides.
      It was concluded that the trot gait is symmetrical and that a two-dimensional
      system can be used to analyze gait in the dog.

PMID- 10580914
TI  - Surgical treatment of idiopathic pericardial effusion in the dog: 25 cases (1978
      1993).
AB  - Twenty-five cases of canine idiopathic pericardial effusion are described. All
      were treated surgically and underwent thoracotomy and pericardectomy, with
      histopathological evaluation of the resected pericardial sac. No tumor,
      infection, granulation tissue, or foreign body was found. Thirteen of the 25 dogs
      were golden retrievers, and all were large or giant breeds. Three (12%) died in
      the immediate postoperative period, and four (16%) died within one year of signs
      possibly related to the original condition. Eighteen (72%) survived at least 18
      months; seven died or were euthanized for reasons unrelated to pericardial
      effusion (median, 44 months); and 11 were still alive at last contact (median, 61
      months).

PMID- 10580915
TI  - Irritable bowel syndrome: definition, diagnosis and epidemiology.
AB  - Based on clinical studies, the Rome Criteria for the irritable bowel syndrome
      (IBS) were developed by consensus. The criteria emphasize the presence of
      abdominal pain and the link between pain and changes in bowel habit. The reliance
      on a clinical gold standard rather than a biological marker remains one of the
      major limitations in refining diagnostic criteria. A convincing argument can be
      mounted that IBS is a disease (a cause of unease). Approximately 10-15% of the
      general population have IBS, and it affects females more often than males, for
      unexplained reasons. The annual incidence is probably 1-2%. The onset of symptoms
      is balanced by symptom loss, so the prevalence remains stable from year to year.
      Up to one half have symptom improvement over time. Only a minority present for
      medical care; pain severity as well as psychological distress in part explain
      health-care seeking. IBS significantly impacts on quality of life. The economic
      impact is enormous, representing a multi-billion dollar problem in the United
      States. The development of acceptable, symptom-based diagnostic criteria has
      advanced the field, stimulating interest in the pathophysiology and targeted
      pharmacological therapy, which are essential steps if the disease burden is to be
      reduced.

PMID- 10580916
TI  - Disturbances in small bowel motility.
AB  - Recently, the small intestine has become the focus of investigation as a
      potential site of dysmotility in the irritable bowel syndrome (IBS). A number of
      motor abnormalities have been defined in some studies, and include 'clustered'
      contractions, exaggerated post-prandial motor response and disturbances in
      intestinal transit. The significance of these findings remains unclear. The
      interpretation of available studies is complicated by differences in subject
      selection, the direct influence of certain symptoms, such as diarrhoea and
      constipation, and the interference of compounding factors, such as stress and
      psychopathology. Dysmotility could also reflect autonomic dysfunction, disturbed
      CNS control and the response to heightened visceral sensation or central
      perception. While motor abnormalities may not explain all symptoms in IBS,
      sensorimotor interactions may be important in symptom pathogenesis and deserve
      further study.

PMID- 10580917
TI  - Disturbances in large bowel motility.
AB  - Although there is a wide variability in symptoms, disorders of colonic motility
      are the most prominent features in irritable bowel syndrome (IBS). Stool weight
      is within the normal range but many patients appear to have abnormal rectal
      sensations. Straining even with soft stool is common. Dietary fibre stimulates
      ileocolonic flow and may induce more symptoms in IBS than normal. There is
      evidence of increased responsiveness of the IBS colon, both to the effect of
      eating and to stress. Defaecatory disorders are common and may reflect both
      increased or decreased rectal sensitivity. The normal colon is quiescent during
      sleep, but in IBS coma sleep is often abnormal, with more periods of arousal and
      the colon consequently more active. There is evidence of increased responsiveness
      to corticotrophin releasing factor, which mediates much of the effect of stress
      on the gut. Many patients show a sympathetic/vagal imbalance with relative excess
      of sympathetic influence in keeping with increased levels of psychological stress
      and anxiety. There is undoubtedly more than one cause of IBS and around 25%
      appear to develop symptoms after an infectious enteritis. This has effects on the
      entero-endocrine system which may take many years to subside.

PMID- 10580918
TI  - Sensory dysfunction and the irritable bowel syndrome.
AB  - Dysfunction of the sensory system of the gut is now generally believed to be
      important in the pathophysiology of irritable bowel syndrome (IBS). This
      disturbance may well account for some of the symptoms of the disorder, such as
      abdominal pain, by virtue of the fact that intra-lumenal events (e.g.
      contractions) may be 'sensed' more easily. It can be assessed in the laboratory
      by a variety of techniques, but usually involves measuring the patient's response
      to distension of any site of the gut, most commonly the rectum. Hypersensitivity
      is the most frequent finding, but hyposensitivity can also occur-
      hypersensitivity does not appear to be specific to any particular pattern of
      bowel habit, but hyposensitivity does tend to be generally only seen in patients
      with constipation, especially those with the 'no urge' type. Although there is
      some evidence to support hypersensitivity being related to enhanced vigilance in
      some patients, other data suggest that there may be a true alteration in sensory
      processing. The mechanisms underlying this sensory dysfunction remain to be
      elucidated, but could involve changes in either the enteric, spinal and/or
      central nervous systems. Finally, factors such as gender, stress, emotion and
      infection can all influence the sensitivity of the gut and may therefore play a
      role in IBS.

PMID- 10580919
TI  - Putative inflammatory and immunological mechanisms in functional bowel disorders.
AB  - The observations that irritable bowel syndrome (IBS) may be precipitated by an
      acute enteric infection, or occurs commonly in patients in remission from
      inflammatory bowel disease (IBD) has prompted consideration of inflammation as a
      putative basis for symptom generation in IBS. In this regard, IBS may follow a
      pattern of pathogenesis that is similar to asthma--which was once considered a
      psychosomatic disease. This review examines the basic scientific evidence of a
      functional interface between the immune and sensory-motor systems of the gut and
      discusses how this may be relevant to a subgroup of IBS patients. In addition,
      review will examine the implications of this for the diagnosis and treatment of
      IBS.

PMID- 10580920
TI  - The role of psychosocial factors in irritable bowel syndrome.
AB  - Psychosocial factors, as appreciated within the context of the biopsychosocial
      model, are necessary for understanding the clinical expression of irritable bowel
      syndrome (IBS) by virtue of their key roles in the development, precipitation and
      perpetuation of IBS. Addressing psychosocial factors in assessment and management
      leads to improvement in the clinical outcome for IBS patients. Pertinent
      management components include adopting a 'care' approach within an ongoing
      collaborative treatment relationship; offering any psychological or psychiatric
      intervention as part of a multi-disciplinary treatment approach; providing
      education and reassurance; and using mental health professionals when indicated.

PMID- 10580921
TI  - Irritable bowel syndrome: a management strategy.
AB  - In the development of a management strategy for irritable bowel syndrome (IBS)
      patients we must consider the great number of people with the condition, most of
      whom do not consult doctors for it. Furthermore, we must be aware of the hidden
      agenda of those that do. The cause of IBS is unknown, and consequently cure of
      this chronic recurrent condition is not likely. Moreover, the disorder is very
      costly, drawing precious resources from the care of more serious diseases. In
      this chapter I propose a management strategy based on a firm diagnosis of IBS
      using a minimum of tests, consideration of the patient's agenda, the use of
      dietary advice, the strategic use of drugs only in resistant cases, a graded
      therapeutic response and continuing care. There is no specific treatment. The
      doctor-patient interaction is most important to allay patients' fears and
      concerns, assist them with psychosocial difficulties, and provide the caring
      support known to maximize the 'placebo' effect of any treatment.

PMID- 10580922
TI  - Irritable bowel syndrome: new pharmaceutical approaches to treatment.
AB  - The irritable bowel syndrome (IBS) is a consortium of symptoms including
      abdominal pain and alterations in the pattern of defaecation. There is no single
      pathophysiological marker of IBS although it is generally accepted that some
      patients do have abnormalities of intestinal motility and/or enhanced visceral
      sensitivity. There is also an increasing acceptance that the central nervous
      system, an important component of the brain-gut axis, also plays an important
      role in symptom production both in the response to stress and when there is an
      underlying affective disorder. During the past decade new therapeutic targets
      have been identified that have permitted the development of new drugs with
      therapeutic potential for IBS. Identification and characterization of 5
      hydroxytryptamine (5-HT) receptors in the gastrointestinal tract particularly 5
      HT3 and 5-HT4 receptors, which are involved not only in modulating gut motility
      but in visceral sensory pathways, has led to a number of studies of 5-HT3
      (Alosetron, Granisetron and Ondansetron) and 5-HT4 (SB-207266A) antagonists. Both
      classes of drug appear to reduce visceral sensitivity and have inhibitory effects
      on motor activity in the distal intestine. Early clinical studies suggest that
      these agents may have a role in painful, diarrhoea-predominant IBS. 5-HT4
      agonists (HTF919, Zelmac) may improve constipation-predominant IBS by normalizing
      bowel habit and thereby reducing abdominal pain. Alternative approaches to
      reducing visceral sensation include the use of the opioid kappa agonists, which
      have no central opioid effects although clinical trials have suggested that these
      agents are not highly effective in relieving IBS pain. There are in addition, new
      approaches to modify intestinal motility including the development of gut
      selective muscarinic M3 receptor antagonists such as zamifenacin and the 5-HT4
      partial agonist, HTF919. Preliminary studies suggest that these agents may have
      therapeutic potential in IBS. Anti-depressants are increasingly used to treat
      affective disorder in IBS but in addition appear to have added value because of
      their ability to reduce visceral hypersensitivity and alter gut transit.
      Therapeutic effects are often obtained at doses below those normally used to
      treat depression. IBS continues to be a therapeutic challenge because of its
      diverse symptomatology and lack of a single pathophysiological target for drug
      intervention.

PMID- 10580923
TI  - Harnessing the patient's powers of recovery: the role of the psychotherapies in
      the irritable bowel syndrome.
AB  - The aim of this chapter is to provide a clear and balanced account of the role of
      the various forms of psychotherapy in the irritable bowel syndrome (IBS). It
      commences with an account of the philosophical basis for psychotherapy,
      attempting to integrate the concepts of autonomic arousal, repression, conversion
      and a developmental disorder of thinking and emotional expression. These concepts
      are used to explain why separation and loss can lead to the development of IBS
      and how the gut is such an important vehicle for emotional expression. Against
      this background the role and philosophy of relaxation therapy, hypnotherapy,
      biofeedback, cognitive behavioural therapy and analytical psychotherapy are
      discussed. These therapies describe a philosophical approach that is quite
      different from biomedical treatments in that it attempts to harness the patient's
      own powers for recovery. For that reason the efficacy of psychotherapies cannot
      be evaluated by randomized controlled trials. Psychotherapies rely on the
      relationship between therapist and patient and vary according to whether the
      locus of responsibility lies mainly with the therapist or mainly with the
      patient. Different patients may well require different therapies.

PMID- 10580925
TI  - Cytotoxic activities of hypocretenolides from leontodon hispidus

PMID- 10580924
TI  - Irritable bowel syndrome: making sense of it all.
AB  - Though the basic science of the irritable bowel syndrome is far from certain, and
      the clinical science is often confusing, it is still possible to make some sense
      of the syndrome in a clinical context. These common complaints of altered bowel
      patterns, pain and bloating are extremely common and vary greatly in the impact
      they have on person's lives. From 'non-patients' who do not present for medical
      care to those who seek referral to multiple specialists, the spectrum is well
      known. If sense is to be made, the physician must understand the patient's major
      symptoms, how and to what degree they disturb their lifestyle, what is the
      patient's knowledge about and understanding of the syndrome, what has been done
      before, and why the patient is now presenting. What are the expectations and
      potential frustrations anticipated with this present consultation? A positive
      diagnostic approach can be taken but care is necessary to assuage lingering fears
      of organic disease, to correct misconceptions of the syndrome, to settle existing
      frustrations of the patient, and to educate. With these approaches, managing
      irritable bowel syndrome can be rewarding, though demanding.

PMID- 10580926
TI  - Serological evidence for protection by human papillomavirus (HPV) type 6
      infection against HPV type 16 cervical carcinogenesis.
AB  - Human papillomavirus (HPV) exists as more than 100 genotypes. It is not well
      established whether the different HPV types interfere with infection or
      pathogenesis by each other. Possible interactions in cervical carcinogenesis
      between infection with the most common HPV types (6, 11, 16, 18 and 33) were
      studied in a seroepidemiological case- control study of 218 women with primary
      untreated cervical cancer and 219 healthy age-matched control women. As
      previously shown, HPV-16 seropositivity was associated with cervical cancer risk
      [odds ratio (OR), 2.39], but HPV-16 was not associated with cervical cancer risk
      among HPV-6 seropositive women (OR, 1.0). The relative excess risk due to
      interaction between HPV-6 and -16 was -2. 35 (95% confidence interval, -0.04 to 
      4.65), indicating significant antagonism. The results suggest that infection with
      HPV-6 may interfere with HPV-16-associated cervical carcinogenesis.

PMID- 10580927
TI  - Manuscript Reviewers - A Note of Thanks.

PMID- 10580928
TI  - Book Reviewers - A Note of Thanks.

PMID- 10580929
TI  - Abstractors of Current Literature -A Note of Thanks.

PMID- 10580930
TI  - Research Trainee Prizes from the 1999 RSNA Scientific Assembly and Annual
      Meeting.

PMID- 10580932
TI  - Award-winning Papers and Honored Lectures.

PMID- 10580931
TI  - What's the evidence?

PMID- 10580933
TI  - Epitaph for the urogram.

PMID- 10580934
TI  - American College of Radiology Imaging Network: new national cooperative group for
      conducting clinical trials of medical imaging technologies.

PMID- 10580935
TI  - MR imaging abbreviations, definitions, and descriptions: a review.

PMID- 10580936
TI  - Acute ureterolithiasis: nonenhanced helical CT findings of perinephric edema for
      prediction of degree of ureteral obstruction.
AB  - PURPOSE: To determine whether the extent of perinephric edema on helical computed
      tomographic (CT) images without contrast material enhancement can be used to
      predict the degree of ureteral obstruction in patients with acute
      ureterolithiasis. MATERIALS AND METHODS: Nonenhanced helical CT and excretory
      urographic images in 82 patients with flank pain were retrospectively reviewed.
      For each patient, a radiologic diagnosis was established, and the degree of
      ureteral obstruction determined on urograms was compared with the extent of
      perinephric edema assessed on CT images. RESULTS: None of 29 patients with no
      abnormalities seen at urography had evidence of perinephric edema at CT. Of six
      patients with noncalculous disease, two with acute pyelonephritis had perinephric
      edema at CT. Of 47 patients with acute ureterolithiasis, eight had no perinephric
      edema at CT and a nonobstructing calculus at urography, 21 had limited edema at
      CT and low-grade obstruction at urography, and 15 had extensive edema at CT and
      high-grade obstruction at urography. Three patients had extensive perinephric
      edema at CT but low-grade obstruction at urography. The extent of edema allowed
      accurate prediction of the degree of ureteral obstruction in 44 (94%) of 47
      patients with acute ureterolithiasis. CONCLUSION: The extent of perinephric edema
      on nonenhanced helical CT images can be used to predict the degree of ureteral
      obstruction in acute ureterolithiasis.

PMID- 10580937
TI  - Ureteropelvic junction obstruction: use of helical CT for preoperative assessment
      -comparison with intraarterial angiography.
AB  - PURPOSE: To evaluate helical computed tomography (CT) in the preoperative
      assessment of crossing arteries in kidneys with ureteropelvic junction (UPJ)
      obstruction and to compare the results with those obtained by means of
      angiography. MATERIALS AND METHODS: Forty-one consecutive patients with
      symptomatic UPJ obstruction in 42 obstructed kidneys underwent renal helical CT
      and renal intraarterial digital subtraction angiography (DSA; flush aortography
      and bilateral selective renal injections). The helical CT and DSA images were
      interpreted in a blinded manner by two readers, and the results were compared.
      RESULTS: DSA showed 126 renal arteries in the 41 patients; 56% of patients had
      supernumerary renal arteries. Helical CT depicted 121 (96%) of these 126 renal
      arteries prospectively. Retrospectively, 124 (98%) renal arteries were visible on
      CT images. Twelve (29%) of the 42 kidneys with UPJ obstruction had identifiable
      arteries crossing the UPJ on DSA images. If DSA is used as the standard of
      reference, CT angiography was 100% sensitive and 96.6% specific for depicting
      these crossing arteries. CONCLUSION: Renal helical CT seems suitable to replace
      intraarterial DSA in the preoperative assessment of crossing arteries in kidneys
      with UPJ obstruction.

PMID- 10580938
TI  - Delayed CT to evaluate renal masses incidentally discovered at contrast-enhanced
      CT: demonstration of vascularity with deenhancement.
AB  - PURPOSE: To determine whether delayed computed tomography (CT) can help confirm
      vascularity in a neoplasm and differentiate it from a high-density cyst when a
      well-demarcated homogeneous high-attenuating (> 30-HU) renal mass is incidentally
      discovered during contrast material-enhanced CT. MATERIALS AND METHODS: In 25
      patients, 26 well-demarcated, homogeneous high-attenuating renal masses (mean
      diameter, 2.5 cm; range, 1-4 cm) detected at initial postcontrast CT were further
      evaluated with delayed CT (mean, 38 minutes; range, 15-240 minutes) performed
      with identical parameters. On both the initial postcontrast and delayed CT scans,
      region-of-interest measurements were obtained in renal masses and in the
      gallbladder or low-density renal cysts as controls. Correlation with surgical or
      additional imaging findings was used to determine proof of diagnosis. RESULTS:
      Nine of the masses demonstrated no change in attenuation between initial
      postcontrast and delayed CT, indicating that they represented avascular lesions
      consistent with high-density cysts. These cases were confirmed with prior or
      follow-up imaging studies that demonstrated stability. Seventeen masses (nine
      surgically proved neoplasms and eight neoplasms that demonstrated interval growth
      at follow-up or previous CT) demonstrated decreased attenuation at delayed CT
      compared with initial postcontrast CT, which indicates vascularity. CONCLUSION:
      Delayed CT of incidentally discovered well-demarcated homogeneous high
      attenuating (> 30-HU) renal masses detected at postcontrast CT enables
      differentiation of high-density cysts from renal neoplasms by demonstrating
      deenhancement as a proof of vascularity and, hence, neoplasm.

PMID- 10580939
TI  - Prediction of perinatal outcome in fetuses suspected to have intrauterine growth
      restriction: Doppler US study of fetal cerebral, renal, and umbilical arteries.
AB  - PURPOSE: To determine and compare the diagnostic performance of fetal middle
      cerebral (MCA), renal (RA), and umbilical (UA) arterial Doppler ultrasonography
      (US) for prediction of adverse perinatal outcome in suspected intrauterine growth
      restriction (IUGR). MATERIALS AND METHODS: Two hundred ninety-three small-for
      gestational age fetuses (24-39 weeks at recruitment and US-estimated weight or
      abdominal circumference below 10th percentile) were prospectively examined with
      Doppler US of the UA, MCA, and RA. Clinicians were blinded to MCA and RA Doppler
      measurements. RESULTS: Seventy-six fetuses (25.9%) had at least one major or
      minor adverse perinatal outcome. Major outcomes included stillbirth, neonatal
      death, neurologic complication, and necrotizing enterocolitis. The MCA
      pulsatility index (PI), compared with the UA PI and RA PI, was more sensitive
      (72.4% vs 44.7% and 8.3%) but less specific (58.1% vs 86.6% and 92.6%) in
      predicting adverse outcome. The UA PI had the highest positive likelihood ratio
      (ratio, 3.3); the MCA PI had the lowest negative likelihood ratio (ratio, 0.48).
      When gestational age at the first Doppler US examination was less than 32 weeks,
      the MCA PI had a sensitivity of 95.5% and negative predictive value of 97.7% for
      major adverse outcome (negative likelihood ratio, 0.10). CONCLUSION: In suspected
      IUGR, while an abnormal UA PI is a better predictor of adverse perinatal outcome
      than an abnormal MCA or RA PI, a normal MCA PI may help to identify fetuses
      without major adverse perinatal outcome, especially before 32 weeks gestational
      age.

PMID- 10580940
TI  - Complex fetal disorders: effect of MR imaging on management--preliminary clinical
      experience.
AB  - PURPOSE: To determine the effect of magnetic resonance (MR) imaging findings on
      management of complex fetal disorders. MATERIALS AND METHODS: MR imaging of the
      fetus was performed in 25 consecutive pregnant patients referred because of
      possible complex fetal disorders suspected on the basis of ultrasonographic (US)
      findings. Spoiled gradient-echo and single-shot rapid acquisition with relaxation
      enhancement MR imaging were performed in multiple planes anatomic to the fetus
      during maternal breath holding. RESULTS: In the fetuses in 24 of 25 women, MR
      studies were technically satisfactory. MR imaging directly influenced fetal care
      in four (17%) of 24 cases by demonstrating congenital high airway obstruction
      syndrome, congenital hemochromatosis, unilateral cerebellar deficiency in
      association with congenital diaphragmatic hernia, and severe facial disfigurement
      due to a giant anterior neck mass. In eight (33%) cases, MR imaging provided
      supplementary findings, but did not affect fetal care. In 12 (50%) cases, MR
      imaging results confirmed US findings. CONCLUSION: In cases of complex fetal
      disorders, MR imaging results can be used to supplement or confirm US findings
      and may directly affect management.

PMID- 10580941
TI  - Anterior cruciate ligament tears: MR imaging-based diagnosis in a pediatric
      population.
AB  - PURPOSE: To evaluate the diagnostic accuracy of primary and secondary magnetic
      resonance (MR) imaging findings of anterior cruciate ligament (ACL) tears in
      young patients with immature skeletal systems. MATERIALS AND METHODS: MR images
      obtained in 43 patients aged 5-16 years who underwent arthroscopy were
      retrospectively reviewed. Two reviewers evaluated primary findings (abnormal
      signal intensity, abnormal course as defined by Blumensaat angle, and
      discontinuity), secondary findings (bone bruise in lateral compartment, anterior
      tibial displacement, uncovering of posterior horn of lateral meniscus, posterior
      cruciate ligament line, and posterior cruciate angle), and meniscal and other
      ligamentous injuries. RESULTS: There were 19 ACL tears and 24 intact ACLs.
      Overall sensitivity and specificity of MR imaging in detecting ACL tears were 95%
      and 88%, respectively. Sensitivities of the primary findings were 94% for
      abnormal Blumensaat angle; 79%, abnormal signal intensity; and 21% discontinuity.
      The specificity of all primary findings was 88% or greater. The sensitivity and
      specificity of the secondary findings, respectively, were 68% and 88% for bone
      bruise; 63% and 92%, anterior tibial displacement; 42% and 96%, uncovered
      posterior horn of lateral meniscus; 68% and 92%, positive posterior cruciate
      line; and 74% and 71%, abnormal posterior cruciate angle. Fifteen (79%) patients
      had meniscal tears, and five (26%) had collateral ligament injuries. CONCLUSION:
      Primary and secondary findings of ACL tears in young patients have high
      specificity and are useful for diagnosis.

PMID- 10580942
TI  - Shoulder after rotator cuff repair: MR imaging findings in asymptomatic
      individuals--initial experience.
AB  - PURPOSE: To assess the magnetic resonance (MR) imaging appearance of the
      successfully repaired rotator cuff in an asymptomatic population. MATERIALS AND
      METHODS: Fifteen subjects who had undergone clinically successful rotator cuff
      repair were included in the study. All underwent functional testing of the
      affected shoulder and had good to excellent scores on the Constant scale.
      Standard MR imaging sequences were performed at 1.5 T, including oblique coronal
      fast spin-echo T2-weighted MR imaging with fat saturation. RESULTS: Three (10%)
      of 30 supraspinatus and infraspinatus tendons had normal signal intensity, and 16
      (53%) had mildly increased signal intensity on fast spin-echo T2-weighted fat
      saturated images, compatible with tendonitis or tendinosis. Three partial and
      four complete tears of the supraspinatus tendon and two partial and two complete
      tears of the infraspinatus tendon were seen. Other findings included subacromial
      subdeltoid effusion (10 subjects), joint effusions (five subjects), and bone
      marrow edema (six subjects). CONCLUSION: Postoperative signal intensity changes
      consistent with tendonitis or tendinosis were common, and clinically "silent"
      partial and complete rotator cuff tears were seen. Such postoperative MR imaging
      findings should be interpreted with caution, and meticulous correlation with
      symptoms and clinical results is recommended.

PMID- 10580943
TI  - Subscapularis tendon tears: detection and grading at MR arthrography.
AB  - PURPOSE: To assess diagnostic accuracy in the detection and grading of
      subscapularis tendon lesions at magnetic resonance (MR) arthrography. MATERIALS
      AND METHODS: MR arthrograms in 50 consecutive patients (29 with normal
      subscapularis tendons, 11 with a lesion in the cranial quarter, seven with a
      major tear but not complete detachment, three with complete detachment) with
      arthroscopic or surgical confirmation were evaluated independently by two
      radiologists. Diagnosis was established on findings from transverse and/or
      parasagittal images. RESULTS: With transverse images alone, sensitivity was
      95%/100% (reader 1/reader 2); specificity was 55%/62%. With parasagittal images
      alone, sensitivity was 91%/91%; specificity was 76%/90%. With combined images,
      sensitivity was 91%/91%; specificity was 86%/79%. Interobserver agreement was
      substantial (kappa = 0.67). Forty-one of 50 (82%) grades for subscapularis
      abnormalities matched at MR imaging and surgery; nine mismatches differed by only
      one degree. Several signs were specific (90%-100%) but insensitive (29%-62%);
      these included leakage of contrast material onto the lesser tuberosity, fatty
      degeneration of the subscapularis muscle, and abnormality in the course of the
      long biceps tendon (luxation, subluxation). CONCLUSION: MR arthrography is
      accurate in the detection and grading of subscapularis tendon lesions.
      Specificity of findings on transverse images for this diagnosis can be improved
      by including indirect signs and findings on parasagittal images.

PMID- 10580944
TI  - Bone marrow edema and associated pain in early stage osteonecrosis of the femoral
      head: prospective study with serial MR images.
AB  - PURPOSE: To determine whether the marrow edema around focal osteonecrosis on
      magnetic resonance (MR) images is associated with clinical symptoms. MATERIALS
      AND METHODS: Thirty-three patients with 37 hips showing early stage osteonecrosis
      of the femoral head were followed up at 3-month intervals with clinical
      evaluation, conventional radiography, and serial MR imaging. RESULTS: Seven (50%)
      of 14 symptomatic hips showed marrow edema around focal osteonecrosis on initial
      MR images, whereas only one (4%) of 23 asymptomatic hips showed edema (P < .01).
      Six (86%) of seven hips that were moderately to severely painful were associated
      with surrounding marrow edema. All eight hips showing osteonecrosis with marrow
      edema at the initial MR examination had joint effusion and exhibited intense
      radionuclide uptake in the proximal femur, which corresponded to the extent of
      edema on MR images. In all eight hips, the marrow edema resolved on follow-up MR
      images, and the pain subsided with the resolution of edema. CONCLUSION: The
      results of this study suggest that the combination of marrow edema of the
      proximal femur and focal osteonecrosis of the femoral head are strongly
      associated with hip pain in early stage osteonecrosis, even prior to collapse.
      Pain improvement usually parallels the resolution of edema.

PMID- 10580945
TI  - Computer-aided diagnosis of pulmonary nodules: results of a large-scale observer
      test.
AB  - PURPOSE: To determine the effect of computer-aided diagnosis (CAD) on the
      accuracy of pulmonary nodule detection. MATERIALS AND METHODS: Twenty abnormal
      chest radiographs, each with a single nodule, and 20 normal radiographs were
      digitized with a laser scanner. These images were analyzed by using a computer
      program that indicates areas that may represent pulmonary nodules. The
      radiographs were displayed on computer workstations in randomized order, and an
      observer test was performed. One hundred forty-six observers participated,
      including 23 chest radiologists, 54 other radiologists, 27 radiology residents,
      and 42 nonradiologists. Cases were interpreted first without and then with the
      use of CAD. The observers' responses were recorded on a continuous confidence
      rating scale. Detection accuracy both with and without CAD was evaluated with
      receiver operating characteristic analysis. RESULTS: The detection accuracy was
      significantly higher for all categories of observers when CAD was used (chest
      radiologists, P = 8 x 10(-6); other radiologists, P = 2 x 10(-16); radiology
      residents, P = 6 x 10(-7); and nonradiologists, P = 8 x 10(-9)). CONCLUSION: CAD
      has the potential to improve diagnostic accuracy in the detection of lung nodules
      on digital radiographs.

PMID- 10580946
TI  - Detection of subtle lung nodules: relative influence of quantum and anatomic
      noise on chest radiographs.
AB  - PURPOSE: To assess the relative influence of quantum mottle and structured lung
      patterns (anatomic noise) on the detection of subtle lung nodules on chest
      radiographs. MATERIALS AND METHODS: Sixty 8 x 8-cm lung pattern images were
      extracted from digital chest radiographs in healthy individuals. Sixty quantum
      mottle images of the same size and quantum noise level were extracted from
      uniformly exposed digital radiographs. Simulated nodules with various peak
      contrast-diameter products (CD) that emulated subtle tissue-equivalent lung
      nodules were numerically superimposed at the center on three-fourths of the
      images. Printouts were independently viewed and scored by five experienced
      radiologists. The area under the receiver operating characteristic curve (Az) was
      estimated as a measure of the detectability of the nodules. RESULTS: At a fixed
      observer performance level (e.g., Az = 0.8), much smaller and lower-contrast
      nodules were detected on quantum mottle images (1-mm diameter, CD = 0.01 mm),
      compared with those on anatomic images (4.5-mm diameter, CD = 0.20 mm). The
      findings generally agreed with the signal-to-noise ratio calculations based on
      statistical observer models. CONCLUSION: The detection of subtle lung nodules on
      chest radiographs is limited by anatomic noise.

PMID- 10580947
TI  - Respiratory viral infections in lung transplant recipients: radiologic findings
      with clinical correlation.
AB  - PURPOSE: To evaluate radiologic finding of respiratory viral infection in lung
      transplant recipients with clinical correlation. MATERIALS AND METHODS: Over 5
      years, 21 episodes of respiratory viral infection (parainfluenza [n = 9],
      respiratory syncytial virus [n = 8], adenovirus [n = 5], influenza [n = 2]) were
      diagnosed 6-727 days (mean, 270 days) after lung transplantation in 20
      recipients. Chest radiographs, computed tomographic (CT) images, and clinical
      records were reviewed. RESULTS: Sixteen episodes of respiratory viral infection
      were diagnosed in patients with symptoms of lower respiratory tract infection or
      acute allograft dysfunction; five were diagnosed in asymptomatic patients. Chest
      radiographs were abnormal in 11 (52%) episodes; findings included heterogeneous
      or homogeneous opacities and masslike consolidation. All patients with
      radiographic abnormalities were symptomatic. Chest radiographs were unchanged
      from baseline in 10 (48%) episodes; in one, CT revealed findings not depicted at
      radiography. Adenoviral infection (n = 5) was typically symptomatic, was
      associated with new radiographic abnormalities, and was rapidly lethal (n = 4).
      Infection with parainfluenza and/or respiratory syncytial virus was commonly
      asymptomatic and was not associated with radiographic abnormalities; affected
      patients had good outcomes. CONCLUSION: Respiratory viral infections are
      important causes of morbidity and mortality in lung transplant recipients.
      Radiographic abnormalities in patients with respiratory viral infections were
      usually accompanied by symptoms of lower respiratory tract infection. Adenoviral
      infection was frequently accompanied by progressive pulmonary opacity and fatal
      outcome.

PMID- 10580948
TI  - Identifying the cause of unilateral hypoperfusion in patients suspected to have
      chronic pulmonary thromboembolism: diagnostic accuracy of helical CT and
      conventional angiography.
AB  - PURPOSE: To determine the prevalence of unilateral hypoperfusion in patients
      suspected to have chronic thromboembolism (CTE), to identify the most common
      cause of hypoperfusion, and to compare the accuracy of helical computed
      tomographic (CT) angiography with that of conventional angiography in helping to
      determine the cause. MATERIALS AND METHODS: Radionuclide lung scan reports showed
      asymmetric hypoperfusion in 47 of 410 consecutive patients referred because of
      suspected CTE. Twenty-seven patients had unilateral or predominantly unilateral
      perfusion abnormalities. Each pulmonary angiogram and CT angiogram in these
      patients was interpreted independently by two readers blinded to clinical
      information and surgical outcome. Surgical confirmation of the diagnosis was
      available in 39 of the 47 patients with asymmetric hypoperfusion. RESULTS:
      Unilateral (n = 11) or predominantly unilateral hypoperfusion (n = 16) was found
      in 6.6% (27 of 410 patients) of patients referred, and CTE was the most common
      cause. The accuracies of CT angiogram readers (reader 1, 83%; reader 2, 89%) were
      greater than those of conventional angiogram readers (reader 1, 73%; reader 2,
      65%) for distinguishing CTE from other causes. CONCLUSION: Unilateral
      hypoperfusion occurred in 6.6% of our study population, most frequently because
      of CTE. CT angiography is an excellent diagnostic alternative to conventional
      angiography for distinguishing patients with CTE from those with other causes.

PMID- 10580949
TI  - Cardiac motion of coronary arteries: variability in the rest period and
      implications for coronary MR angiography.
AB  - PURPOSE: To measure the duration of the rest period in the cardiac cycle, a
      parameter vital to data acquisition in coronary magnetic resonance (MR)
      angiography. MATERIALS AND METHODS: Motion of coronary arteries was measured in
      13 patients by using breath-hold, biplane, conventional angiography, with frontal
      and lateral projections of the left and right coronary arteries acquired at 30
      frames per second. The time courses of the coordinates of bifurcations of
      proximal parts of the coronary arteries were measured, from which the rest period
      (motion < 1 mm in orthogonal axes), velocity, displacement range, motion
      correlation, and reproducibility from heartbeat to heartbeat were estimated.
      RESULTS: Both the motion pattern and the amplitude varied substantially from
      patient to patient. The rest period varied from 66 to 333 msec (mean, 161 msec)
      for the left coronary artery and from 66 to 200 msec (mean, 120 msec) for the
      right coronary artery. CONCLUSION: The rest period for coronary arteries in the
      cardiac cycle varies substantially from patient to patient, which may cause
      quality to be inconsistent in current coronary MR angiography. A cardiac motion
      image prior to coronary data acquisition (preimage) may be used to estimate the
      optimal duration and timing in the cardiac cycle for coronary MR angiography.

PMID- 10580950
TI  - Improved patency of transjugular intrahepatic portosystemic shunts in humans:
      creation and revision with PTFE stent-grafts.
AB  - PURPOSE: To determine whether polytetrafluoroethylene (PTFE) stent-grafts yield
      longer patency for creation or revision of transjugular intrahepatic
      portosystemic shunts (TIPS). MATERIALS AND METHODS: Fourteen PTFE-covered
      Wallstents were placed in 13 patients with TIPS: seven at shunt creation and
      seven during revision of TIPS with one to five prior thromboses at 1 day to 1
      year after initial TIPS formation. In six cases, prior to stent-graft placement
      persistent biliary-TIPS fistulas were demonstrated despite repeated shunt
      revisions with additional metallic stents. RESULTS: All but one graft-lined TIPS
      were widely patent at a mean duration of venographic follow-up of 19 months
      (median, 17 months; range, 5-32 months). The limiting percentage of stenosis
      within the grafted shunts was 0%-10%. One patient developed stent-graft
      thrombosis; the prior biliary-TIPS fistula was seen despite the graft. A second,
      parallel PTFE-lined transcaval shunt was created in this patient; it was widely
      patent at 11-month follow-up. In two asymptomatic patients, stenoses developed in
      the short, nongrafted portions of the outflow hepatic veins. CONCLUSION: PTFE
      stent-grafts can markedly prolong TIPS patency, potentially reducing the need for
      shunt follow-up and revision and the risk of recurrent symptoms associated with
      shunt stenosis or occlusion.

PMID- 10580951
TI  - Leakages after endovascular repair of aortic aneurysms: classification based on
      findings at CT, angiography, and radiography.
AB  - PURPOSE: To ascertain whether the configuration and location of leakages
      identified at computed tomography (CT) could provide evidence of their
      angiographically and fluoroscopically confirmed causes. MATERIALS AND METHODS:
      Fifty patients aged 26-79 years underwent endovascular repair of traumatic (n =
      4) or arteriosclerotic (n = 46) aortic aneurysms (four thoracic, 46 infrarenal).
      Radiographic examinations in three planes and helical CT were performed 1 week
      after implantation and every 3 months thereafter. Angiography was performed when
      there was evidence of a leakage at CT. RESULTS: CT demonstrated evidence of
      leakages in 13 patients. Broad-based leakages immediately adjacent to the
      prosthesis were termed "perigraft leakages." If the area most affected by the
      leakage lay along the border of the aneurysm, then retrograde leakages were
      apparent at angiography. If the leakage was ventral to the prosthesis, then its
      source was the inferior mesenteric artery; if it was dorsolateral, then it was
      supplied by either the lumbar arteries or the median sacral artery through the
      hypogastric artery. One circumferential leakage could not be evaluated adequately
      at CT or angiography. Radiography depicted a rupture of the stent mesh in the
      middle of the prosthesis. Selective angiography demonstrated all types of
      leakages and permitted CT classification. CONCLUSION: The cause of a leakage can
      be determined with CT on the basis of its configuration and location in the
      majority of cases.

PMID- 10580952
TI  - Severe skin reactions from interventional fluoroscopy: case report and review of
      the literature.
AB  - Some patients with certain preexisting health conditions may be at elevated risk
      for unusually intense radiation-induced skin reactions and late tissue damage
      from high-dose interventional procedures. The authors present a case report of a
      patient with mixed connective tissue disease and non-insulin-dependent diabetes
      mellitus who developed an unusual complication after placement of a transjugular
      intrahepatic portosystemic shunt. On the basis of a review of the literature, the
      following experiences may help identify patients at increased risk: previous high
      dose procedures, connective tissue disease, diabetes mellitus, and homozygosity
      for ataxia telangiectasia.

PMID- 10580953
TI  - Maximum internal carotid arterial stenosis: assessment with rotational
      angiography versus conventional intraarterial digital subtraction angiography.
AB  - PURPOSE: To assess how often rotational angiography depicts more severe internal
      carotid arterial stenosis compared with conventional intraarterial digital
      subtraction angiography (DSA) in two or three projections and how frequently this
      factor may affect patient treatment. MATERIALS AND METHODS: Rotational
      angiography (16 or 32 projections) was performed in addition to DSA in 47
      stenotic internal carotid arteries (ICAs) in 38 symptomatic patients. ICA
      stenosis was measured independently at DSA and at rotational angiography with
      North American Symptomatic Carotid Endarterectomy Trial criteria. The degree of
      stenosis was categorized as 0%-29%, 30%-49%, 50%-69%, or 70%-99%. RESULTS: In
      three ICAs, rotational angiography was nondiagnostic. In 28 of the remaining 44
      ICAs, the degree of stenosis was categorized similarly with DSA and rotational
      angiography, whereas with rotational angiography, 15 ICAs were classified one
      category higher and one ICA was classified two categories higher, owing to the
      increased number of projections available. Seventy percent to 99% stenosis was
      demonstrated in 18 ICAs with DSA and in 25 ICAs with rotational angiography.
      Thus, rotational angiography could have facilitated a change in the optimal
      treatment (from nonsurgical treatment to carotid arterial endarterectomy) in
      seven ICAs. CONCLUSION: Compared with DSA in two or three projections, rotational
      angiography frequently depicts more severe ICA stenosis. This indicates a
      limitation of DSA in depicting the maximum ICA stenosis.

PMID- 10580954
TI  - Necrotic tumor versus brain abscess: importance of amino acids detected at 1H MR
      spectroscopy--initial results.
AB  - PURPOSE: To assess the usefulness of the 0.9-ppm peak from amino acids (-CH3
      moieties from valine, leucine, and isoleucine) for the differentiation of brain
      abscesses and tumors at in vivo hydrogen 1 magnetic resonance (MR) spectroscopy.
      MATERIALS AND METHODS: Amino acid concentrations were determined in vitro in 13
      purulent samples from brain and nonbrain tissues and in nine aseptic fluids from
      necrotic brain tumors at two-dimensional (2D) 1H MR spectroscopy and liquid
      chromatography. Thirty-four patients with cystic intracerebral mass lesions (28
      tumors, six abscesses) were examined at 1H MR spectroscopy in vivo. RESULTS:
      Amino acids were identified in vitro in both purulent and aseptic samples. Amino
      acid concentrations measured in the aseptic fluids at both liquid chromatography
      and 2D MR spectroscopy were far below the detection threshold of in vivo 1H MR
      spectroscopy. Quantitative results obtained at 2D MR spectroscopy showed no
      overlap in the ranges of amino acid concentrations in purulent and aseptic
      samples. In vivo, the proton spectra obtained with a 136-msec echo time (TE)
      revealed amino acids (inverted peak at 0.9 ppm) in only the abscesses.
      CONCLUSION: The detection of amino acid resonance at 0.9 ppm at in vivo 1H MR
      spectroscopy (136-msec TE) is a promising tool for distinguishing bacterial
      abscesses and cystic brain tumors.

PMID- 10580956
TI  - Late radiation injury to the temporal lobes: morphologic evaluation at MR
      imaging.
AB  - PURPOSE: To study the morphologic characteristics of late radiation injury to the
      temporal lobes of the brain on magnetic resonance (MR) images. MATERIALS AND
      METHODS: This was a prospective study involving 34 patients (age range, 37-72
      years) with known radiation injury to the temporal lobes from radiation therapy
      administered 2-10 years previously for nasopharyngeal carcinoma MR imaging was
      performed with T2-weighted gradient- and spin-echo, gradient-recalled echo, T1
      weighted spin-echo, fluid-attenuated inversion-recovery, and T1-weighted
      postcontrast spin-echo sequences. RESULTS: Radiation injury was present in 57 of
      the 68 temporal lobes. The white matter lesions in radiation-induced injury were
      predominantly hyperintense on T2-weighted images, but in 37 (65%) of the 57
      lobes, foci with heterogeneous signal intensity consistent with necrosis were
      detected. In the 57 involved lobes, gray matter lesions were detected in 50
      (88%); blood-brain barrier disruption based on parenchymal contrast enhancement,
      in 51 (89%); and hemosiderin deposits, in 30 (53%). There was a significant
      correlation between white matter necrosis, gray matter lesions, and blood-brain
      barrier disruption, all of which were located mainly in the inferior temporal
      lobes that received the highest radiation dose. CONCLUSION: The lesion components
      of radiation-induced injury to the temporal lobes at MR imaging were more varied
      than have been previously described. In addition to the classic white matter
      lesions, gray matter lesions, blood-brain barrier disruption, and hemosiderin
      deposition also were frequently seen.

PMID- 10580955
TI  - Wegener granulomatosis: MR imaging findings in brain and meninges.
AB  - PURPOSE: To determine the spectrum of intracranial magnetic resonance (MR)
      imaging appearances of Wegener granulomatosis. MATERIALS AND METHODS: MR imaging
      studies in 19 patients with Wegener granulomatosis and possible central nervous
      system involvement were reviewed by two neuroradiologists. Intermediate-weighted
      and T2-weighted fast spin-echo MR images of the brain had been acquired in all
      patients, and spin-echo T1-weighted nonenhanced and gadolinium-enhanced images
      had been acquired in 18 patients. RESULTS: MR imaging findings included diffuse
      linear dural thickening and enhancement (n = 6); focal dural thickening and
      enhancement contiguous with orbital, nasal, or paranasal disease (n = 5);
      infarcts (n = 4); nonspecific white matter areas of high signal intensity on
      intermediate-weighted and T2-weighted images (n = 10); enlarged pituitary gland
      with infundibular thickening and enhancement (n = 2); a discrete cerebellar
      lesion that was probably granulomatous in origin (n = 1); and cerebral (n = 8)
      and cerebellar atrophy (n = 2). CONCLUSION: MR imaging demonstrated the wide
      spectrum of findings of central nervous system involvement in patients with
      Wegener granulomatosis and was particularly useful for the evaluation of direct
      intracranial spread from orbital, nasal, or paranasal disease.

PMID- 10580957
TI  - Sinus histiocytosis (Rosai-Dorfman disease) of the suprasellar region: MR imaging
      findings--a case report.
AB  - Sinus histiocytosis with massive lymphadenopathy (SHML) is an uncommon disorder
      that typically manifests as systemic symptoms and lymphadenopathy. Extranodal,
      intracranial disease is uncommon. The authors report on a 15-year-old adolescent
      girl who had a suprasellar mass at magnetic resonance imaging. Biopsy results
      demonstrated lymphophagocytosis consistent with a diagnosis of SHML. The
      clinical, radiologic, and histologic aspects of the disease are discussed.

PMID- 10580958
TI  - Case 21.

PMID- 10580959
TI  - Diagnosis please. Case 17: hypertrophic olivary degeneration secondary to pontine
      hemorrhage.

PMID- 10580960
TI  - MR imaging of the cochlear modiolus: area measurement in healthy subjects and in
      patients with a large endolymphatic duct and sac.
AB  - PURPOSE: To evaluate the cochlear modiolus with thin-section magnetic resonance
      (MR) imaging in healthy subjects and patients with a large endolymphatic duct and
      sac, and to assess whether the cochlea is normal or abnormal in patients with a
      large endolymphatic duct and sac. MATERIALS AND METHODS: MR images were obtained
      in 10 ears in five volunteers (group 1), 40 ears in 20 patients with bilateral
      sensory hearing loss (group 2), three ears in two patients with Mondini
      malformation (group 3), and 12 ears in seven patients with a large endolymphatic
      duct and sac (group 4). RESULTS: In groups 1 and 2, all modiolar areas were
      larger than 4.0 mm2. In group 3, each modiolus was smaller than 2.0 mm2. In group
      4, modiolar areas were smaller than 2.0 mm2 in eight ears and were larger than
      4.0 mm2 in four ears. CONCLUSION: Findings in this study confirm that a large
      endolymphatic duct and sac is frequently associated with modiolar deficiency, but
      the modiolar area is normal in some cases. This result does not support the
      recently proposed hypothesis that hearing loss with a large endolymphatic duct
      and sac is caused by the transmission of subarachnoid pressure forces into the
      labyrinth through a deficient modiolus.

PMID- 10580961
TI  - Size of colorectal liver metastases at abdominal CT: comparison of precontrast
      and postcontrast studies.
AB  - PURPOSE: To investigate whether measurements of hepatic metastases from
      colorectal carcinoma before contrast material administration are significantly
      different statistically from measurements after contrast material administration.
      MATERIALS AND METHODS: Twenty-four patients with hepatic metastases from
      colorectal carcinoma underwent spiral computed tomography (CT) with 7-mm
      collimation. The liver was imaged before and in the portal-dominant phase after
      intravenous contrast material administration. For each scan, one to three
      discrete liver lesions were selected for measurement (n = 49). Three experienced
      radiologists performed independent measurements of the selected lesions on both
      pre- and postcontrast images at a computer workstation. A three-way analysis of
      variance (ANOVA) was performed: subjects by raters (the three independent
      radiologists) by pre- or postcontrast status. The dependent variable was the
      product of bidimensional measurements. RESULTS: Sixty-seven percent (33 of 49) of
      the lesions were measured as larger on precontrast images; 33% (16 of 49), as
      smaller. There was high interrater reliability, with an intraclass correlation
      coefficient greater than 0.9 ANOVA showed significant subject, rater, and
      contrast material effects (P < .001) for the largest lesions in each liver.
      Contrast material status was a significant factor for all lesion sizes (P <
      .003). CONCLUSION: On average, hepatic metastases from colorectal carcinoma are
      significantly smaller after contrast material administration.

PMID- 10580962
TI  - Acute biliary disease: initial CT and follow-up US versus initial US and follow
      up CT.
AB  - PURPOSE: To evaluate the utility of ultrasonography (US) versus that of computed
      tomography (CT) for assessment of acute biliary disease. MATERIALS AND METHODS:
      Radiologic reports and clinical charts were reviewed in all patients who
      underwent US and CT within 48 hours of each other for evaluation of acute right
      upper quadrant pain. Radiologic findings and clinical outcome were correlated.
      RESULTS: CT was the initial imaging study in 57 patients, and CT findings
      resulted in underdiagnosis or misdiagnosis of acute biliary disease in eight of
      11 patients. Follow-up US results were suggestive of the correct diagnosis and
      provided additional clinical information in seven of these eight patients. US
      findings resulted in altered clinical treatment in six of 11 patients with acute
      biliary disease. US was the initial study in 66 patients, and US findings were
      suggestive of biliary disease or the correct diagnosis in seven of seven patients
      with acute biliary disease. Follow-up CT did not result in changes in clinical
      treatment in any patient with acute biliary disease. CONCLUSION: Initial US is
      better than initial CT in patients suspected of having acute biliary disease.
      Follow-up CT provides no additional information regarding the biliary system, and
      its use should be limited to those patients with a wider differential diagnosis
      or with confusing clinical symptoms and signs.

PMID- 10580963
TI  - The "hide-bound" bowel sign.

PMID- 10580964
TI  - Permanent implantation of 125I sources in the prostate: radical limits of
      simplicity.
AB  - PURPOSE: To determine the effect of reducing the number of sources per
      implantation on the dose coverage of the prostate volume. MATERIALS AND METHODS:
      Idealized source distributions were planned for four, eight, 16, 24, 32, and 48
      sources. The peripheral loading technique was used to plan a uniform, conformal
      dose distribution to the target volume, which was the prostate volume as
      visualized at ultrasonography. Source-placement error was estimated by using
      measured error magnitudes and was expressed with systematic and random
      components. The relative sensitivities of the plans to the source-placement error
      were studied. RESULTS: Idealized planned target coverage can be adequately
      achieved with comparable dose distributions with eight or more sources. The
      sensitivity to source-placement error is comparable for plans with 16 or more
      sources. CONCLUSION: It is theoretically possible to radically simplify
      implantation without compromising target coverage or error tolerance.

PMID- 10580965
TI  - Non-small cell lung cancer: prognostic factors in patients treated with surgery
      and postoperative radiation therapy.
AB  - PURPOSE: To determine survival outcomes, to identify adverse prognostic factors
      for relapse, and to compare American Joint Commission on Cancer (AJCC) staging
      systems in patients with non-small cell lung cancer (NSCLC) treated with surgery
      and postoperative radiation therapy. MATERIALS AND METHODS: Between 1980 and
      1995, 211 patients with NSCLC underwent surgery and postoperative radiation
      therapy. Surgery consisted of wedge resection (12.5%), lobectomy (67.8%), or
      pneumonectomy (19.7%). Pathologic stages (1992 AJCC) included I (n = 22), II (n =
      70), IIIA (n = 104), and IIIB (n = 12). Indications for radiation therapy
      included compromised margins (n = 81) and/or positive mediastinal nodes (n = 55).
      Prognostic factors were identified by using univariate and multivariate models.
      RESULTS: Overall 3-year survival for patients with stage I, II, and IIIA cancer
      was 58.9%, 44.1%, and 43.2%, respectively. Older age (P = .008), male sex (P =
      .021), large primary tumor (P = .004), and multiple positive mediastinal nodes (P
      = .046) were associated with worse rates of survival. Actuarial risk of local
      regional relapse (36 patients) was 21.4% at 3 years. In a multivariate model, use
      of wedge resection (P = .001), positive margins (P = .010), and larger pathologic
      tumor (P = .059) were risk factors for local-regional recurrence. Actuarial rate
      of distant failure was 55.2% at 3 years. CONCLUSION: Local-regional control can
      be achieved with surgery and radiation therapy in approximately 80% of patients;
      however, the rate of distant metastasis remains unacceptably high. Other
      variables, such as multiple positive nodes, may serve to identify patients at
      higher risk for relapse and poorer survival. Methods for improving treatment
      outcomes in these patients should be pursued.

PMID- 10580966
TI  - Transjugular intrahepatic portosystemic shunts formed with polyethylene
      terephthalate-covered stents: experimental evaluation in pigs.
AB  - PURPOSE: To evaluate the safety, efficacy, and tissue response associated with
      Wallstents covered with polyethylene terephthalate (PETP) compared with those
      associated with uncovered Wallstents for creation of transjugular intrahepatic
      portosystemic shunts (TIPS) in a porcine model. MATERIALS AND METHODS: Thirteen
      TIPS were created in 13 minipigs: eight with PETP-covered Wallstents, five with
      standard Wallstents. Shunt venography was performed at 5-8 weeks, and necropsy
      was performed at 7-8 weeks. Histopathologic, immunohistochemical, and scanning
      electron microscopic examinations were performed. RESULTS: Mean shunt stenoses of
      the control and graft groups were 45% and 53%, respectively. Graft stenoses
      involved the entire graft-bearing segment, whereas bare stent stenoses were
      localized within the liver tract. Myofibroblast and extracellular collagen matrix
      proliferation encompassed both control and graft-covered stents. There was one
      graft TIPS occlusion. One control TIPS stenosis was due to transstent
      proliferation of normal porcine hepatic tissue. A small focus of bile staining
      was seen on the abluminal surface of one TIPS, which was a patent PETP-lined
      shunt. CONCLUSION: PETP graft TIPS provided equal, but not superior, patency to
      that of bare stent TIPS. The pattern of PETP TIPS graft healing differed from
      that of bare stents but was similar to that reported with other polyester graft
      vascular implants and consisted of diffuse transmural penetration and paving of
      the graft surface by extracellular collagen matrix and myofibroblasts.

PMID- 10580967
TI  - Survival of mammalian cells exposed to ultrahigh dose rates from a laser-produced
      plasma x-ray source.
AB  - PURPOSE: To determine whether intense laser-produced x rays have an increased
      radiation hazard. MATERIALS AND METHODS: Mammalian cells were exposed to x rays
      from a laser-produced plasma that produced ultrahigh peak absorbed dose rates, up
      to a factor of 10(10) higher than those produced by conventional x rays used in
      imaging. The cell survival was studied as a function of the absorbed dose. The
      survival of mammalian cells exposed to high peak absorbed dose rates with laser
      produced x rays was compared with the survival of cells exposed to standard
      absorbed dose rates with conventional x-ray sources. Comparative survival studies
      were performed by using a conventional x-ray tube and a cobalt 60 source. The
      absorbed doses in the irradiation field were measured with thermoluminescent
      dosimeters. RESULTS: Cell survival following irradiation by filtered, laser
      produced x rays with a high dose rate was not markedly different from the
      survival following irradiation by conventional sources. There was, however, a
      notable difference between the survival after exposure to filtered, laser
      produced x rays and the survival after exposure to unfiltered laser-produced x
      rays. CONCLUSION: Exposure to filtered, laser-produced x rays with a high dose
      rate does not lead to increased harm to mammalian cells exposed in vitro compared
      with the harm from exposure to x rays from conventional sources, which indicates
      that the use of high-power laser facilities for medical imaging is justified.

PMID- 10580968
TI  - Near-infrared optical imaging of protease activity for tumor detection.
AB  - PURPOSE: To build and test an optical imaging system that is sensitive to near
      infrared fluorescent molecular probes activated by specific enzymes in tumor
      tissues in mice. MATERIALS AND METHODS: The imaging system consisted of a source
      that delivered 610-650-nm excitation light within a lighttight chamber, a 700-nm
      longpass filter for selecting near-infrared fluorescence emission photons from
      tissues, and a charge-coupled device (CCD) for recording images. The molecular
      probe was a biocompatible autoquenched near-infrared fluorescent compound that
      was activated by tumor-associated proteases for cathepsins B and H. Imaging
      experiments were performed 0-72 hours after intravenous injection of the probe in
      nude mice that bore human breast carcinoma (BT-20). RESULTS: The imaging system
      had a maximal spatial resolution of 60 microns, with a field of view of 14 cm2.
      The detection threshold of the nonquenched near-infrared fluorescent dye was
      subpicomolar in the imaging phantom experiments. In tissue, 250 pmol of
      fluorochrome was easily detected during the 10-second image acquisition. After
      intravenous injection of the probe into the tumor-bearing animals, tumors as
      small as 1 mm became detectable because of tumor-associated enzymatic activation
      of the quenched compound. CONCLUSION: Tumor proteases can be used as molecular
      targets, allowing visualization of millimeter-sized tumors. The development of
      this technology, probe design, and optical imaging systems hold promise for
      molecular imaging, cancer detection, and evaluation of treatment.

PMID- 10580969
TI  - Pulmonary disorders: ventilation-perfusion MR imaging with animal models.
AB  - PURPOSE: To demonstrate the capability of magnetic resonance (MR) imaging to
      assess alteration in regional pulmonary ventilation and perfusion with animal
      models of airway obstruction and pulmonary embolism. MATERIALS AND METHODS:
      Airway obstruction was created by inflating a 5-F balloon catheter into a
      secondary bronchus. Pulmonary emboli were created by injecting thrombi into the
      inferior vena cava. Regional pulmonary ventilation was assessed with 100% oxygen
      as a T1 contrast agent. Regional pulmonary perfusion was assessed with a two
      dimensional fast low-angle shot, or FLASH, sequence with short repetition and
      echo times after intravenous administration of gadopentetate dimeglumine.
      RESULTS: Matched ventilation and perfusion abnormalities were identified in all
      animals with airway obstruction. MR perfusion defects without ventilation
      abnormalities were seen in all animals with pulmonary emboli. CONCLUSION:
      Ventilation and perfusion MR imaging are able to provide regional pulmonary
      functional information with high spatial and temporal resolution. The ability of
      MR imaging to assess both the magnitude and regional distribution of pulmonary
      functional impairment could have an important effect on the evaluation of lung
      disease.

PMID- 10580970
TI  - Breast carcinoma: effect of preoperative contrast-enhanced MR imaging on the
      therapeutic approach.
AB  - PURPOSE: To determine if magnetic resonance (MR) imaging can help determine the
      therapeutic approach in women with breast cancer. MATERIALS AND METHODS:
      Preoperative contrast-enhanced MR imaging of the breast was performed in 463
      patients with probably benign lesions (n = 63), suspicious lesions (n = 230), or
      lesions highly suggestive of malignancy (n = 170) per established clinical,
      mammographic, and/or ultrasonographic (US) criteria. T1-weighted fast low-angle
      shot MR imaging was performed before and after administration of gadopenetetate
      dimeglumine. MR imaging findings were correlated with other imaging results and
      histopathologic findings. Special attention was paid to multifocality and
      multicentricity. RESULTS: Histopathologic analysis revealed 143 benign and 405
      malignant lesions. The sensitivity, specificity, and accuracy were 58%, 76%, and
      62% for clinical examination; 86%, 32%, and 72% for conventional mammography;
      75%, 80%, and 76% for US; and 93%, 65%, and 85% for contrast-enhanced MR imaging.
      Multifocality in 30 of 42 patients, multicentricity in 24 of 50 patients, and
      additional contralateral carcinomas in 15 of 19 patients were depicted with MR
      imaging alone. Due to the MR imaging findings, therapy was changed correctly in
      66 patients (14.3%); unnecessary open biopsy was performed in 16 patients (3.5%).
      CONCLUSION: Contrast-enhanced MR imaging of the breast is highly sensitive for
      invasive breast cancer. MR imaging may reveal unsuspected multifocal,
      multicentric, or contralateral breast carcinoma and result in therapy changes.

PMID- 10580971
TI  - Benign versus malignant solid breast masses: US differentiation.
AB  - PURPOSE: To investigate the general applicability and interobserver variability
      of ultrasonographic (US) features in differentiating benign from malignant solid
      breast masses. MATERIALS AND METHODS: One hundred sixty-two consecutive solid
      masses with a tissue diagnosis were reviewed. Three radiologists reviewed the
      masses without knowledge of clinical history or histologic examination results.
      RESULTS: US features that most reliably characterize masses as benign were a
      round or oval shape (67 of 71 [94%] were benign), circumscribed margins (95 of
      104 [91%] were benign), and a width-to-anteroposterior (AP) dimension ratio
      greater than 1.4 (82 of 92 [89%] were benign). Features that characterize masses
      as malignant included irregular shape (19 of 31 [61%] were malignant),
      microlobulated (four of six [67%] were malignant) or spiculated (two of three
      [67%] were malignant) margins, and width-to-AP dimension ratio of 1.4 or less (28
      of 70 [40%] were malignant). If the three most reliable criteria had been
      strictly applied by each radiologist, the overall cancer biopsy yield would have
      increased (from 23% to 39%) by 16%. When US images and mammograms were available,
      the increase in biopsy yield contributed by US was not statistically significant
      (2%, P = .73). However, in independent reviews, one to three reviewers
      interpreted four carcinomas as benign at US. CONCLUSION: The data confirm that
      certain US features can help differentiate benign from malignant masses. However,
      practice and interpreter variability should be further explored before these
      criteria are generally applied to defer biopsy of solid masses.

PMID- 10580972
TI  - US-guided implantation of metallic markers for permanent localization of the
      tumor bed in patients with breast cancer who undergo preoperative chemotherapy.
AB  - Metallic markers were implanted with ultrasonographic guidance in 51 malignant
      breast tumors in 49 patients to tag the tumor bed in anticipation of complete or
      almost complete response to preoperative neoadjuvant induction chemotherapy
      before breast-conservation surgery. The markers were the only remaining evidence
      of the original tumor site in 47% (23 of 49) of the patients preoperatively. This
      technique effectively addresses the problem of preoperative localization of the
      tumor bed in complete or nearly complete response of breast cancer to neoadjuvant
      chemotherapy.

PMID- 10580973
TI  - Percutaneous interventions in the presacral space: CT-guided precoccygeal
      approach--early experience.
AB  - A computed tomography (CT)-guided, precoccygeal approach was used for
      interventions in the presacral space in four patients (three biopsies, one
      abscess drainage). Localization comprised palpation of the coccyx and measurement
      of the distance from the coccyx to the lesion on a prone CT scan. This approach
      provided an easy, straight vector to all points in the presacral space and
      involved no radiation exposure to the physician.

PMID- 10580974
TI  - Tracheobronchial strictures: treatment with a polyurethane-covered retrievable
      expandable nitinol stent--initial experience.
AB  - A polyurethane-covered retrievable expandable stent was placed in 13 patients
      with tracheobronchial strictures. In four patients with benign strictures, the
      stent was removed with use of a retrieval hook 2-6 months after placement. After
      stent removal, three of the four patients did not need further treatment. The
      retrievable stent warrants further investigation in the treatment of
      tracheobronchial strictures.

PMID- 10580975
TI  - Optimal protocol for injection of contrast material at MR angiography: study of
      healthy volunteers.
AB  - Forty healthy volunteers, matched for age and body weight, underwent abdominal
      magnetic resonance angiography with gadopentetate dimeglumine administered by
      using a power injector. Injection rates were 0.3, 1.0, 2.0, or 3.0 mL/sec.
      Contrast material doses were 0.1 (single dose) or 0.2 (double dose) mmol/kg.
      Increased contrast enhancement in the aorta and minimum arteriovenous overlap can
      be achieved with high flow rate and double-dose injection.

PMID- 10580976
TI  - Human prostate: multisection proton MR spectroscopic imaging with a single spin
      echo sequence--preliminary experience.
AB  - The authors investigated the feasibility of a multisection proton magnetic
      resonance (MR) spectroscopic imaging technique for the acquisition of metabolic
      information in the human prostate. Multisection MR spectroscopic imaging was
      performed of a citrate phantom and of the prostates of eight adult volunteers.
      High-quality proton MR spectra and citrate metabolite maps of the prostate were
      obtained with this method.

PMID- 10580977
TI  - Assessing the effect of hormone replacement therapy on the performance of
      screening mammography.

PMID- 10580978
TI  - Hepatic vascular malformations in hereditary hemorrhagic telangiectasia:
      treatment with embolization.

PMID- 10580979
TI  - Caution with use of hepatic embolization in the treatment of hereditary
      hemorrhagic telangiectasia.

PMID- 10580981
TI  - Abstracts of Current Literature.

PMID- 10580982
TI  - Consilience, complexity, and communication: three challenges at the start of the
      new century.

PMID- 10580983
TI  - Dr. Dolittle and the making of the mitotic spindle.
AB  - The intrinsic polarity of microtubules within cells is exploited each time cells
      divide. Kinesins, microtubule-associated motor proteins, are required to execute
      the dramatic events of mitosis: bipolar spindle assembly, metaphase chromosome
      alignment, anaphase chromosome segregation, and separation of spindle poles prior
      to cytokinesis. Surprisingly, kinesin-related proteins have been found to move in
      either "plus-ward" or "minus-ward" directions along microtubules. Evidence from
      genetic analyses of simple eukaryotes and in vitro activity assays supports the
      notion that certain subfamilies of kinesin-related proteins provide antagonistic
      activities necessary to balance mitotic forces. A recent study by Sharp et
      al.((1)) sheds further light on the subject by exploiting the genetics and
      cytology of the fruit fly embryo.

PMID- 10580984
TI  - Surviving Drosophila eye development: integrating cell death with differentiation
      during formation of a neural structure.
AB  - Normal differentiation requires an appropriately orchestrated sequence of
      developmental events. Regulation of cell survival and cell death is integrated
      with these events to achieve proper cell number, cell type, and tissue structure.
      Here we review regulation of cell survival in the context of a precisely
      patterned neural structure: the Drosophila compound eye. Numerous mutations lead
      to altered differentiation and are frequently accompanied by altered patterns of
      cell death. We discuss various critical times of normal eye development,
      highlighting how inappropriate regulation of cell death contributes to different
      mutant phenotypes associated with genes that specify the entire eye primordia,
      others that pattern the retina, and those that eliminate extraneous cells to
      refine the precise pigment cell lattice. Finally, we address how the Drosophila
      eye may allow identification of additional mechanisms that contribute to the
      normal integration of cell survival with appropriate events of cellular
      differentiation.

PMID- 10580985
TI  - Brave little yeast, please guide us to thebes: sphingolipid function in S.
      cerevisiae.
AB  - Sphingolipids typically cover the exoplasmic leaflet of the plasma membrane of
      eukaryotic cells. They differ from the more abundant glycerophospholipids in that
      they contain ceramide instead of diacylglycerol as a hydrophobic anchor. Why did
      nature choose to invent this complex class of lipids, and why do eukaryotic cells
      follow elaborate remodelling pathways in order to generate dozens to hundreds of
      different molecular species of sphingolipid, depending on cell type? Yeast may,
      once again, serve as a model to dissect sphingolipid function at various levels.
      Almost the complete pathway for sphingolipid synthesis in yeast has been
      uncovered during the past two decades. More recently, key enzymes in sphingolipid
      degradation and signalling have been identified. Together with a wealth of
      genetic data obtained from the characterization of various suppressor mutants,
      this information now allows for an unprecedented analysis of sphingolipid
      function in this organism. This overview summarizes recent data on sphingolipid
      function in cell signalling, their role in the heat-stress response and Ca(2+)
      homeostasis, and addresses their function in transport of
      glycosylphosphatidylinositol-anchored proteins.

PMID- 10580986
TI  - Chemosensory signaling in C. elegans.
AB  - The nematode Caenorhabditis elegans can sense and respond to hundreds of
      different chemicals with a simple nervous system, making it an excellent model
      for studies of chemosensation. The chemosensory neurons that mediate responses to
      different chemicals have been identified through laser ablation studies,
      providing a cellular context for chemosensory signaling. Genetic and molecular
      analyses indicate that chemosensation in nematodes involves G protein signaling
      pathways, as it does in vertebrates, but the receptors and G proteins involved
      belong to nematode-specific gene families. It is likely that about 500 different
      chemosensory receptors are used to detect the large spectrum of chemicals to
      which C. elegans responds, and one of these receptors has been matched with its
      odorant ligand. C. elegans olfactory responses are also subject to regulation
      based on experience, allowing the nematode to respond to a complex and changing
      chemical environment.

PMID- 10580987
TI  - beta-catenin signaling and cancer.
AB  - Since its discovery as a protein associated with the cytoplasmic region of E
      cadherin, beta-catenin has been shown to perform two apparently unrelated
      functions: it has a crucial role in cell-cell adhesion in addition to a signaling
      role as a component of the Wnt/wg pathway. Wnt/wg signaling results in beta
      catenin accumulation and transcriptional activation of specific target genes
      during development. It is now apparent that deregulation of beta-catenin
      signaling is an important event in the genesis of a number of malignancies, such
      as colon cancer, melanoma, hepatocellular carcinoma, ovarian cancer, endometrial
      cancer, medulloblastoma pilomatricomas, and prostate cancer. beta-catenin
      mutations appear to be a crucial step in the progression of a subset of these
      cancers, suggesting an important role in the control of cellular proliferation or
      cell death. The APC/beta-catenin pathway is highly regulated and includes players
      such as GSK3-beta, CBP, Groucho, Axin, Conductin, and TCF. c-MYC and cyclin D1
      were recently identified as a key transcriptional targets of this pathway and
      additional targets are likely to emerge. Published 1999 John Wiley & Sons, Inc.

PMID- 10580988
TI  - Carboxyl/cholinesterases: a case study of the evolution of a successful multigene
      family.
AB  - The evolution of organismal diversity among the Metazoa is dependent on the
      proliferation of genes and diversification of functions in multigene families.
      Here we analyse these processes for one highly successful family, the
      carboxyl/cholinesterases. One key to the expansion of the functional niche of
      this group of enzymes is associated with versatile substrate binding and
      catalytic machinery. Qualitatively new functions can be obtained by substitution
      of one or a very few amino acids. This crudely adapted new functionality is then
      refined rapidly by a pulse of change elsewhere in the molecule; in one case about
      13% amino acid divergence occurred in 5-10 million years. Furthermore, we
      postulate that the versatility of the substrate binding motifs underpins the
      recruitment of several family members to additional noncatalytic signal
      transduction functions.

PMID- 10580989
TI  - Early origins of modern birds and mammals: molecules vs. morphology.
AB  - Recent claims from molecular evidence that modern orders of birds and mammals
      arose in the Early Cretaceous, over 100 million years (Myr) ago, are contrary to
      palaeontological evidence. The oldest fossils generally fall in the time range
      from 70-50 Myr ago, with no earlier finds. If the molecular results are correct,
      then the first half of the fossil record of modern birds and mammals is missing.
      Suggestions that this early history was played out in unexplored parts of the
      world, or that the early progenitors were obscure forms, are unlikely. Intense
      collecting over hundreds of years has failed to identify these missing fossils.
      Control experiments, in the form of numerous Cretaceous-age fossil localities
      which yield excellently preserved lizards, salamanders, birds, and mammals, fail
      to show the modern forms. The most likely explanation is that they simply did not
      exist, and that the molecular clock runs fast during major radiations.

PMID- 10580990
TI  - Molecular evidence for the early divergence of placental mammals.
AB  - Paleontological and molecular data suggest quite different patterns for the early
      evolution of placental mammals. Paleontological evidence indicates a radiation,
      with most of the extant orders diverging at approximately the same time, close to
      the Cretaceous-Tertiary boundary, 65 Myr ago. Molecular evidence suggests a
      branching pattern of evolution that started much earlier. Resolving this
      discrepancy requires a consideration of the assumptions that underlie both
      approaches. It is argued here that the pattern indicated by the molecular
      approach is the most likely to be correct. If it is correct then either: 1) A
      diversity of placental mammals remains to be sampled from the Cretaceous, or 2)
      The placental orders diverged phylogenetically long before they diversified
      morphologically, implying a decoupling of the evolutionary processes associated
      with speciation and adaptation. The adaptive diversification of placental mammals
      may have required the demise of the dinosaurs at the end of the Cretaceous, but
      it occurred in lineages that had a long prior history of independent existence.
      1999.

PMID- 10580991
TI  - Reply to easteal

PMID- 10580992
TI  - Reply to benton

PMID- 10580993
TI  - How I learned to love carrots: the role of the cytoskeleton in shaping plant
      cells.
AB  - The carrot cell suspension was originally used because it provided a model system
      for studying directional cell expansion - a key process in plant morphogenesis.
      Early immunofluorescence studies of plant microtubules, using these cells,
      provided hints that the cortical array of microtubules was dynamic and this was
      later confirmed by microinjection studies on plant epidermal cells. A nonfixation
      approach for detecting F-actin was then developed on these cells and showed that,
      unlike animal cells, actin filaments remained associated with the nucleus
      throughout division and could have a role in aligning the plane of cell division.
      Currently, we are using detergent-extracted carrot cytoskeletons for isolating
      microtubule-associated proteins (MAPs). I discuss how MAPs may be involved in the
      oriented deposition of cellulose in the cell wall.

PMID- 10580994
TI  - Why do so many stimuli induce tyrosine phosphorylation of FAK?
AB  - Engagement of integrins and other adhesion receptors can induce tyrosine
      phosphorylation of focal adhesion kinase (FAK), a tyrosine kinase present in
      focal adhesions. Furthermore, in addition to adhesion receptors, a surprising
      variety of stimuli, acting either on specific surface receptors or on
      intracellular molecules, such as PKC or Rho, can induce also tyrosine
      phosphorylation of FAK. I suggest that a potential mechanism by which such
      distinct factors may modulate the tyrosine phosphorylation of FAK is the
      promotion of integrin or other adhesion receptor clustering at focal adhesions.

PMID- 10580995
TI  - Autoregulation of actin synthesis requires the 3'-UTR of actin mRNA and protects
      cells from actin overproduction.
AB  - Monomeric (G) actin was shown to be involved in inhibiting its own synthesis by
      an autoregulatory mechanism that includes enhanced degradation of the actin mRNA
      [Bershadsky et al., 1995; Lyubimova et al., 1997]. We show that the 3'
      untranslated region (3'-UTR) of beta-actin mRNA, but not its 5'-untranslated
      region, is important for this regulation. The level of full-length beta-actin
      mRNA in cells was reduced when actin filaments were depolymerized by treatment
      with latrunculin A and elevated when actin polymerization was induced by
      jasplakinolide. By contrast, the level of actin mRNA lacking the 3'-UTR remained
      unchanged when these drugs modulated the dynamics of actin assembly in the cell.
      Moreover, the transfection of cells with a construct encoding the autoregulation
      deficient form of beta-actin mRNA led to very high levels of actin expression
      compared with transfection with the control actin construct and was accompanied
      by characteristic changes in cell morphology and the structure of the actin
      cytoskeleton. These results suggest that the autoregulatory mechanism working via
      the 3'-UTR of actin mRNA is involved in controlling the maintenance of a defined
      pool of actin monomers that could be necessary for the proper organization of the
      microfilament system and the cytoskeleton-mediated signaling.

PMID- 10580996
TI  - Glucocorticoid can reduce the transcriptional activation of HIV-1 promoter
      through the reduction of active NF-kappaB.
AB  - It is well documented that glucocorticoid (GC) can induce the transcription of
      the IkappaBalpha gene in several cell lines. GC treatment then increases
      IkappaBalpha protein levels and markedly reduces the amount of active NF-kappaB.
      NF-kappaB is a strong activator of HIV-1 promoter, but the mechanism by which GC
      influence the HIV-1 activities is not well documented. In the present study,
      MOLT4 and Jurkat cells were transfected with HIV-1-LTR-CAT DNA and treated with
      0.2 mM H(2)O(2) or 10 ng/ml of TPA. CAT activities of the transformed MOLT4 and
      Jurkat cells were greatly enhanced by these treatments, but the CAT activities
      were markedly reduced when cells were pretreated with GC. This reduction in
      activity correlated well with the reduction in active NF-kappaB and the
      accumulation of IkappaBalpha. These findings suggest that GC can reduce the
      transcription of HIV-1 promoter through the reduction of active NF-kappaB.

PMID- 10580997
TI  - In vitro poly(ADP-ribosyl)ated histones H1a and H1t modulate rat testis chromatin
      condensation differently.
AB  - Rat testis H1 proteins were poly(ADP-ribosyl)ated in vitro. The modifying
      product, poly(ADP-ribose), was found covalently bound to each histone variant at
      various extents and exhibited distinct structural features (linear and short,
      rather than branched and long chains). Interest was focused on the somatic H1a,
      particularly abundant in the testis, as compared with other tissues, and the
      testis-specific H1t, which appears only at the pachytene spermatocyte stage of
      germ cell development. These H1s were modified with poly(ADP-ribose) by means of
      two in vitro experimental approaches. In the first system, each variant was
      incubated with purified rat testis poly(ADP-ribose)polymerase in the presence of
      [(32)P] NAD. In parallel, poly(ADP-ribosyl)ated H1s were also prepared following
      incubation of intact rat testis nuclei with [(32)P] NAD. In both experiments, the
      poly(ADP-ribosyl)ated proteins were purified from the native forms by means of
      phenyl boronic agarose chromatography. The results from both analyses were in
      agreement and showed qualitative differences with regard to the poly(ADP-ribose)
      covalently associated with H1a and H1t. Comparison of the bound polymers clearly
      indicated that the oligomers associated with H1a were within 10-12 units long,
      whereas longer chains (</=20 ADP-R units) were linked to H1t. Individual poly(ADP
      ribosyl)ated H1s were complexed with homologous H1-depleted oligonucleosomes (0.5
      2.5 kbp) in order to measure their ability to condensate chromatin, in comparison
      with the native ones. Circular dichroism showed that the negative charges of the
      oligomeric polyanion, although present in limited numbers, highly influenced the
      DNA-binding properties of the analyzed H1s. In particular, the poly(ADP
      ribosyl)ated H1a and H1t had opposite effects on the condensation of H1-depleted
      oligonucleosomes.

PMID- 10580998
TI  - Effect of lactoferrin on the production of tumor necrosis factor-alpha and nitric
      oxide.
AB  - One of the biological functions of lactoferrin is the modulation of the host
      defense systems, including cytokine production and immune responses. We have
      tested the effect of lactoferrin on the productions of tumor necrosis factor
      alpha and nitric oxide in some cells. Lactoferrin itself did not induce either
      tumor necrosis factor-alpha production or nitric oxide production, but
      lipopolysaccharide-stimulated tumor necrosis factor-alpha production of
      macrophages and monocytes were inhibited by lactoferrin treatment combined with
      stimulant. The induction of nitric oxide synthesis in stimulated macrophages and
      vascular smooth muscle cells was not affected by the lactoferrin.

PMID- 10580999
TI  - Relative roles of T-cell receptor ligands and interleukin-2 in driving T-cell
      proliferation.
AB  - Stimulation of T cells by the T-cell receptor (TCR)/CD3 complex results in
      interleukin-2 (IL-2) synthesis and surface expression of the IL-2 receptor (IL
      2R), which in turn drive T-cell proliferation. However, the significance of the
      requirement of IL-2 in driving T-cell proliferation, when TCR stimulation itself
      delivers potential mitogenic signals, is unclear. We show that blocking of IL-2
      synthesis by Cyclosporin A (CsA) suppressed both the Concanavalin A (Con A)- and
      phorbol myristate acetate (PMA)/ionomycin-induced proliferation of T cells. The
      latter is also inhibited by anti-IL-2R. Kinetic studies showed that T-cell
      proliferation begins to become resistant to CsA inhibition by about 12 h and
      became largely resistant by 18 h of stimulation. PMA, the protein kinase C
      activator, enhanced Con A-induced T-cell proliferation if added only within first
      12 h of stimulation, and not after that. Given the fact that, in the present
      study, TCR is downregulated within 2 h of Con A stimulation and T cells entered
      the S phase of cell cycle by about 18 h of stimulation, the above results suggest
      that TCR stimulation provides the initial trigger to the resting T cells, which
      allows the cells to traverse the first two third portions of G1 phase of cell
      cycle and become proliferation competent. IL-2 action begins afterward,
      delivering the actual proliferation signal(s), allowing the cells to traverse the
      rest of G1 phase and enter the S phase of the cell cycle.

PMID- 10581000
TI  - Role of a serine/threonine kinase, Mst1, in megakaryocyte differentiation.
AB  - Platelets, which play a central role in thrombosis and hemostasis, develop from
      megakaryocytes. Signal transduction originated from the megakaryocyte growth and
      development factor, the Mpl ligand, which leads to megakaryocyte differentiation,
      polyploidization, and maturation, has been gradually characterized. In this
      study, we report the inducibility of Mst1, a recently described serine/threonine
      kinase, by Mpl ligand and the effect of its induced expression on megakaryocyte
      differentiation. The steady-state level of mst1 message and Mst1-associated
      kinase activity increased in response to Mpl ligand. Ectopic expression of human
      mst1 in a mouse megakaryocytic cell line resulted in a drastic increase in DNA
      content per cell. Elevated expression of megakaryocyte differentiation markers,
      such as acetylcholine esterase, PF4, and GPIIb was also observed in hmst1
      expressing cells. Activation of p38 MAPK, a known downstream effector of Mst1,
      was shown to be required for polyploidization, but not for enhanced expression of
      differentiation markers. Our study thus designates Mst1 as a Mpl ligand
      responsive signaling molecule that promotes induction of lineage-specific
      cellular programming.

PMID- 10581001
TI  - HIV-1 gp120 envelope protein modulates proliferation of human glomerular
      epithelial cells.
AB  - Glomerular epithelial cells (GEC) have been demonstrated to undergo morphological
      alterations in human immunodeficiency virus (HIV)-associated focal
      glomerulosclerosis. In the present study, we evaluated the effect of HIV-1 gp120
      envelope protein on the growth of cultured human (H) GEC. gp120 protein enhanced
      (P < 0.001) the proliferation of HGEC at lower concentrations. The mitogenic
      effect of gp120 protein on HGEC was further confirmed by enhanced accumulation of
      proliferating nuclear cell antigen (PCNA) by gp120 protein-treated cells, as
      compared with control cells. On the contrary, gp120 protein at higher
      concentrations suppressed (P < 0. 001) the growth of HGEC. To evaluate the
      mechanism of gp120 protein-induced HGEC growth suppression, we examined the
      effect of gp120 protein on HGEC apoptosis. gp120 protein at higher concentrations
      promoted the apoptosis of HGEC. At higher concentrations, gp120 protein also
      enhanced DNA fragmentation of HGEC. Anti-gp120 antibody attenuated the
      proliferative as well as the apoptotic effects of gp120 protein on HGEC. Because
      protein kinase C as well as tyrosine kinase inhibitors partially inhibited gp120
      induced proliferation, gp120 appears to be activating both the protein kinase C
      and tyrosine kinase pathways. In addition, gp120 protein at lower concentrations
      enhanced mRNA expression of c-fos and at higher concentrations promoted mRNA
      expression of c-jun. We conclude that gp120 has a bimodal effect on proliferation
      of HGEC. This effect may be mediated through the activation of early growth
      genes.

PMID- 10581002
TI  - Serum bound forms of PSP94 (prostate secretory protein of 94 amino acids) in
      prostate cancer patients.
AB  - PSP94 (prostate secretory protein of 94 amino acids) was regarded as a possible
      prostate cancer marker, however, it has been controversial. All prior studies
      were designed to test the free form in serum using antibodies to PSP94. Results
      presented here demonstrate that PSP94 exists in prostate cancer patients in two
      forms, free and bound, and that the majority is present as serum bound complexes.
      This result was demonstrated by using both native and SDS-PAGE analyses of serum
      proteins from prostate cancer patients. Chromatographic separation of serum total
      proteins by a molecular sieve column generated two peaks (peak I and II), which
      were reactive with rabbit antiserum to human PSP94 in Western blot experiments.
      Peak I was eluted before the IgG fraction at a molecular weight larger than 150
      kDa, and peak II appeared after serum albumin ( approximately 67 kDa) was eluted.
      By using a biotinylated PSP94 as an indicator of the free form of PSP94, we
      demonstrate that peak I contains serum PSP94-bound complexes and peak II is
      likely the free form of serum PSP94. Since the molecular weight of serum PSP94
      bound complexes is close to IgG during molecular sieve separation, serum PSP94
      complexes were further purified through two rounds of protein A column
      separation, followed by DEAE-ion exchange column chromatography. In vitro
      dissociation tests of the purified PSP94-bound complexes showed that the binding
      of serum PSP94-complexes is probably via disulfide bonds and is chemically
      stable. The results presented here indicate that serum PSP94-bound complexes must
      be considered in evaluating the clinical utility of PSP94 as a prostate cancer
      marker.

PMID- 10581003
TI  - Regulation of growth, protein synthesis, and maturation of fetal bovine
      epiphyseal chondrocytes grown in high-density culture in the presence of ascorbic
      acid, retinoic acid, and dihydrocytochalasin B.
AB  - Phenotypic expression of chondrocytes can be modulated in vitro by changing the
      culture technique and by agents such vitamins and growth factors. We studied the
      effects of ascorbic acid, retinoic acid (0.5 and 10 microM), and
      dihydrocytochalasin B (3, 10, 20 microM DHCB), separately or in combination
      (ascorbic acid + retinoic acid or ascorbic acid + DHCB), on the induction of
      maturation of fetal bovine epiphyseal chondrocytes grown for up to 4 weeks at
      high density in medium containing 10% fetal calf serum and the various agents. In
      the absence of any agent or with retinoic acid or DHCB alone, the metabolic
      activity of the cells remained very low after day 6, with no induction of type I
      or X collagen synthesis nor increase in alkaline phosphatase activity.
      Chondrocytes treated with fresh ascorbic acid showed active protein synthesis
      associated with expression of types I and X after 6 and 13 days, respectively.
      This maturation was not accompanied by obvious hypertrophy of the cells or high
      alkaline phosphatase activity. Addition of retinoic acid to the ascorbic acid
      treated cultures decreased the level of type II collagen synthesis and delayed
      the induction of types I and X collagen, which were present only after 30 days. A
      striking increase in alkaline phosphatase activity (15-20-fold) was observed in
      the presence of both ascorbic acid and the highest dose of retinoic acid (10
      microM). DHCB was also a potent inhibitor of the maturation induced by treatment
      with ascorbic acid, as the chondrocytes maintained their rounded shape and
      synthesized type II collagen without induction of type I or X collagen. The
      pattern of protein secretion was compared under all culture conditions by two
      dimensional gel electrophoresis. The different regulations of chondrocyte
      differentiation by ascorbic acid, retinoic acid, and DHCB were confirmed by the
      important qualitative and quantitative changes in the pattern of secreted
      proteins observed by two-dimensional gel electrophoresis along the study.

PMID- 10581004
TI  - Characterization of paxillin LIM domain-associated serine threonine kinases:
      activation by angiotensin II in vascular smooth muscle cells.
AB  - Recently we reported a novel means of regulating LIM domain protein function.
      Paxillin LIM zinc-finger phosphorylation in response to cell adhesion regulates
      the subcellular localization of this cytoskeletal adaptor protein to focal
      adhesions, and also modulates cell adhesion to fibronectin (Brown et al. [1998]
      Mol. Biol. Cell 9:1803-1816). In the present study, we characterize further the
      protein kinases that phosphorylate paxillin LIM2 on threonine and LIM3 on serine.
      Analysis of the subcellular distribution of the LIM kinases demonstrated that the
      LIM3 protein kinase, but not the LIM2 kinase, resides within a detergent
      insoluble fraction. The activities of the paxillin LIM domain kinases are
      differentially regulated during embryogenesis, and analysis of tissue
      distribution indicated a specificity in expression patterns between the LIM2 and
      LIM3 kinases. In addition, these protein kinases were refractory to inhibition by
      a panel of broad-spectrum serine/threonine kinase inhibitors, suggesting a novel
      derivation. The paxillin protein kinase activities were stimulated in serum
      starved CHO.K1 cells by the mitogen phorbol myristate acetate (PMA), and by PMA
      and angiotensin II in rat aortic smooth muscle cells. In vivo labeling,
      phosphoamino acid analysis, and phosphopeptide mapping of paxillin
      immunoprecipitated from angiotensin II-stimulated smooth muscle cells confirmed
      an induction of paxillin serine/threonine phosphorylation and supports the
      contention that these newly identified paxillin kinases are dynamic components of
      growth factor signaling through the cytoskeleton.

PMID- 10581005
TI  - New role for tRNA and its fragment purified from human urinary bladder carcinoma
      conditioned medium: inhibition of endothelial cell growth.
AB  - The growth of endothelial cells is necessary for angiogenesis, which in turn is
      required for later steps of tumor progression. In an attempt to purify new
      modulators of endothelial cell growth from the conditioned medium of human
      urinary bladder carcinoma cells, we isolated a small and stable oligonucleotide
      containing 10 to 16 bases. This oligonucleotide inhibited the growth of
      endothelial cells in vitro and was identified as a fragment of transfer RNA
      (tRNA). When unfractionated bovine tRNA was added to the cell culture, it
      specifically inhibited growth of endothelial cells, but not smooth muscle cells,
      bovine kidney cells, 3T3 fibroblasts, and several cancer cell lines. In contrast,
      ribosomal RNA, total yeast RNA, and single nucleosides from tRNA hydrolysate had
      no effect. These results demonstrate a new role for tRNA and its fragment as a
      selective endothelial cell inhibitor in vitro.

PMID- 10581006
TI  - Defective growth in vitro of Duchenne Muscular Dystrophy myoblasts: the molecular
      and biochemical basis.
AB  - As the molecular basis of Duchenne Muscular Dystrophy (DMD) was being discovered,
      increasing focus was placed on the mechanisms of progressive failure of
      myoregeneration. In this study, we propose a pathogenesis model for DMD, where an
      autocrine growth factor release of TGF-beta1-from necrotic myofibers-could
      contribute to the increasing loss of muscle regeneration. In fact, we report
      evidence that DMD myoblasts reduce their proliferation rate, in time and later
      cultures; in connection with this, we observed TGF-beta1 increase in conditioned
      media of DMD myoblasts, able to control the myoblast growth by reducing fusion
      and differentiation of DMD satellite cells.

PMID- 10581007
TI  - Comparison of the intracellular trafficking of two alternatively spliced isoforms
      of pp120, a substrate of the insulin receptor tyrosine kinase.
AB  - pp120, a substrate of the insulin receptor tyrosine kinase, is a plasma membrane
      glycoprotein in the hepatocyte. It is expressed as two spliced isoforms differing
      by the presence (full length) or absence (truncated) of most of the intracellular
      domain including all phosphorylation sites. Because the two isoforms differ by
      their ability to regulate receptor-mediated insulin endocytosis and degradation,
      we aimed to investigate the cellular basis for this functional difference by
      comparing their intracellular trafficking. During its intracellular assembly,
      pp120 is transported from the trans-Golgi network to the sinusoidal domain of the
      plasma membrane before its final transcytosis to the bile canalicular domain.
      Because both isoforms are expressed in hepatocytes, we examined their
      intracellular trafficking in NIH 3T3 fibroblasts individually transfected with
      each isoform. Pulse-chase experiments demonstrated that most of the newly
      synthesized full-length isoform reached complete maturation at about 60 min of
      chase. By contrast, only about 40% of the newly synthesized truncated isoform
      underwent complete maturation, even at more prolonged chase. Moreover, a
      significant portion of the truncated isoform appeared to be targeted to
      lysosomes. Abolishing basal phosphorylation on Ser(503) by cAMP-dependent serine
      kinase by mutating this residue to alanine was correlated with incomplete
      maturation of full length pp120 in NIH 3T3 cells and hepatocytes. This finding
      suggests that the intracellular domain of pp120 contains information that
      regulates its vectorial sorting from the trans-Golgi network to the plasma
      membrane.

PMID- 10581008
TI  - Polyamine depletion up-regulates c-Myc expression, yet induces G(1) arrest and
      terminal differentiation of F9 teratocarcinoma stem cells.
AB  - The ornithine decarboxylase (ODC) gene is a transcriptional target of c-Myc.
      Exponentially growing cells usually exhibit high c-Myc levels and high ODC
      levels, whereas stationary phase cells and terminally differentiated cells have
      low levels of both proteins. Therefore, we were surprised to find that when F9
      teratocarcinoma stem cells were blocked in the G(1) phase of their cell cycle and
      induced to differentiate by irreversible inhibition of the ODC activity, the
      expression of c-Myc was up-regulated instead of being down-regulated. During the
      course of differentiation, the c-myc gene was constitutively expressed, and c-Myc
      protein accumulated. In transfection experiments, using ODC promoter-reporter
      gene fusion constructs, the accumulation of c-Myc protein, resulting from
      polyamine depletion, led to increased reporter gene expression. This finding is
      consistent with the view that depletion of polyamines relieves the suppression
      that they exert on c-myc mRNA translation, causing an accumulation of c-Myc
      protein, which in turn transactivates its target gene, the bona fide ODC gene.
      Thus, the accumulation of an active c-Myc protein does not preclude
      differentiative events, nor does it override the growth arrest caused by
      polyamine depletion. These results suggest a new role for polyamines-as negative
      regulators of c-Myc expression.

PMID- 10581009
TI  - Polyplex-mediated gene transfer into human retinal pigment epithelial cells in
      vitro.
AB  - The human retinal pigment epithelium (RPE) is a potential target tissue for
      directed transfer of candidate genes to treat age-related macular degeneration
      (AMD). The RPE is uniquely suited to gene therapy protocols that use liposome
      mediated DNA transfer because of its high intrinsic phagocytic function in vivo.
      In these studies, we examined the efficacy of human RPE cell uptake and
      expression of the green fluorescent protein (GFP) and neomycin resistance marker
      genes by polyplex-mediated gene transfer in vitro. The effects of varying DNA and
      polyplex concentration and ratios on GFP transgene expression were examined. A
      narrow range of experimental conditions were found to maximize transgene
      expression; most important were the DNA concentration and the DNA:polyplex ratio.
      The transfection efficiency for human RPE cells was reproducibly 20% in vitro by
      this method and reached a maximum level of expression after 48 h. There was a
      rapid decline in gene expression over 2 weeks following polyplex-mediated gene
      transfer, but stable integration does occur at low frequencies with and without
      selection.

PMID- 10581010
TI  - E-, P-, and N-cadherin are co-expressed in the nasopharyngeal carcinoma cell line
      TW-039.
AB  - The cadherin/catenin complex plays a key role in the initiation of cell-cell
      recognition, and adhesion, and the elaboration of structural and functional
      organization in multicellular tissues and organs. It is associated with tumor
      metastasis and also acts as an "invasion suppressor" of cancer cells.
      Nasopharyngeal carcinoma (NPC) is notorious for its highly metastatic nature. The
      expression of the E-cadherin/catenin complex is down-regulated in NPC tumor
      specimens. To obtain better insight into the intercellular adhesive property of
      NPC cells, we used immunofluorescence microscopy, immunoprecipitation, and
      immunoblot analysis to examine the expression of the classical cadherins and beta
      catenin in a NPC cell line, TW-039. The results demonstrate a change in the
      distribution of E-cadherin from cytosolic flakes to cell-cell contacts with
      increasing time in culture. Between days 1 and 5 after plating, the detergent
      insoluble fraction of E-cadherin increased from 20% to 37% of total E-cadherin,
      and that for P-cadherin increased from 33% to 40%. By contrast, the values for
      beta-catenin remained unchanged (26% and 25%). Both immunofluorescence and
      immunoblot studies suggested that P-cadherin may be involved in pioneer contact
      adhesion of TW-039 cells. Interestingly, E-, P-, and N-cadherin are co-expressed
      in this cell line. Immunoprecipitation studies also showed that other members of
      the cadherin family may be involved in the contact adhesion of TW-039 cells.

PMID- 10581011
TI  - Thinking postgenomics.

PMID- 10581012
TI  - Blast ahead.

PMID- 10581013
TI  - Paths of glorious proteases.

PMID- 10581014
TI  - Skeletal development in the zebrafish.

PMID- 10581015
TI  - Dissecting de novo methylation.

PMID- 10581016
TI  - At the end of the millennium, a view of the end.

PMID- 10581017
TI  - TOUCHINGbase.

PMID- 10581019
TI  - Incorrect use of the term synteny.

PMID- 10581018
TI  - Analysis of human transcriptomes.

PMID- 10581020
TI  - Vestiges of a DNA methylation system in Drosophila melanogaster?

PMID- 10581021
TI  - Expansion of a novel CAG trinucleotide repeat in the 5' region of PPP2R2B is
      associated with SCA12.

PMID- 10581023
TI  - Even the musical was better than this.

PMID- 10581022
TI  - Mutations in RGR, encoding a light-sensitive opsin homologue, in patients with
      retinitis pigmentosa.

PMID- 10581024
TI  - Population choice in mapping genes for complex diseases.
AB  - The difficulty of identifying susceptibility genes for common diseases has
      polarized geneticists' views on what disease models are appropriate and how best
      to proceed once high-density genome maps become available. Different disease
      models have different implications for using linkage or linkage-disequilibrium
      based approaches for mapping complex disease genes. We argue that the choice of
      study population is a critical factor when designing a study, and that
      genetically simplified isolates are more useful than diverse continental
      populations under most assumptions.

PMID- 10581026
TI  - Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13).
AB  - We report that mutation of COL11A2 causes deafness previously mapped to the
      DFNA13 locus on chromosome 6p. We found two families (one American and one Dutch)
      with autosomal dominant, non-syndromic hearing loss to have mutations in COL11A2
      that are predicted to affect the triple-helix domain of the collagen protein. In
      both families, deafness is non-progressive and predominantly affects middle
      frequencies. Mice with a targeted disruption of Col11a2 also were shown to have
      hearing loss. Electron microscopy of the tectorial membrane of these mice
      revealed loss of organization of the collagen fibrils. Our findings revealed a
      unique ultrastructural malformation of inner-ear architecture associated with non
      syndromic hearing loss, and suggest that tectorial membrane abnormalities may be
      one aetiology of sensorineural hearing loss primarily affecting the mid
      frequencies.

PMID- 10581025
TI  - TIN2, a new regulator of telomere length in human cells.
AB  - Telomeres are DNA-protein structures that cap linear chromosomes and are
      essential for maintaining genomic stability and cell phenotype. We identified a
      novel human telomere-associated protein, TIN2, by interaction cloning using the
      telomeric DNA-binding-protein TRF1 as a bait. TIN2 interacted with TRF1 in vitro
      and in cells, and co-localized with TRF1 in nuclei and metaphase chromosomes. A
      mutant TIN2 that lacks amino-terminal sequences effects elongated human telomeres
      in a telomerase-dependent manner. Our findings suggest that TRF1 is insufficient
      for control of telomere length in human cells, and that TIN2 is an essential
      mediator of TRF1 function.

PMID- 10581027
TI  - Loss-of-function mutations in the cathepsin C gene result in periodontal disease
      and palmoplantar keratosis.
AB  - Papillon-Lefevre syndrome, or keratosis palmoplantaris with periodontopathia
      (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained
      by dentists because of the severe periodontitis that afflicts patients. Both the
      deciduous and permanent dentitions are affected, resulting in premature tooth
      loss. Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt
      hyperkeratosis, typically develops within the first three years of life.
      Keratosis also affects other sites such as elbows and knees. Most PLS patients
      display both periodontitis and hyperkeratosis. Some patients have only
      palmoplantar keratosis or periodontitis, and in rare individuals the
      periodontitis is mild and of late onset. The PLS locus has been mapped to
      chromosome 11q14-q21 (refs 7, 8, 9). Using homozygosity mapping in eight small
      consanguineous families, we have narrowed the candidate region to a 1.2-cM
      interval between D11S4082 and D11S931. The gene (CTSC) encoding the lysosomal
      protease cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval.
      We defined the genomic structure of CTSC and found mutations in all eight
      families. In two of these families we used a functional assay to demonstrate an
      almost total loss of cathepsin C activity in PLS patients and reduced activity in
      obligate carriers.

PMID- 10581028
TI  - Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the
      molecular chaperone HSP70.
AB  - At least eight inherited human neurodegenerative diseases are caused by expansion
      of a polyglutamine domain within the respective proteins. This confers dominant
      toxicity on the proteins, leading to dysfunction and loss of neurons. Expanded
      polyglutamine proteins form aggregates, including nuclear inclusions (NI), within
      neurons, possibly due to misfolding of the proteins. NI are ubiquitinated and
      sequester molecular chaperone proteins and proteasome components, suggesting that
      disease pathogenesis includes activation of cellular stress pathways to help
      refold, disaggregate or degrade the mutant disease proteins. Overexpression of
      specific chaperone proteins reduces polyglutamine aggregation in transfected
      cells, but whether this alters toxicity is unknown. Using a Drosophila
      melanogaster model of polyglutamine disease, we show that directed expression of
      the molecular chaperone HSP70 suppresses polyglutamine-induced neurodegeneration
      in vivo. Suppression by HSP70 occurred without a visible effect on NI formation,
      indicating that polyglutamine toxicity can be dissociated from formation of large
      aggregates. Our studies indicate that HSP70 or related molecular chaperones may
      provide a means of treating these and other neurodegenerative diseases associated
      with abnormal protein conformation and toxicity.

PMID- 10581029
TI  - An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y.
AB  - In humans, deletion of any one of three Y-chromosomal regions- AZFa, AZFb or AZFc
      disrupts spermatogenesis, causing infertility in otherwise healthy men. Although
      candidate genes have been identified in all three regions, no case of
      spermatogenic failure has been traced to a point mutation in a Y-linked gene, or
      to a deletion of a single Y-linked gene. We sequenced the AZFa region of the Y
      chromosome and identified two functional genes previously described: USP9Y (also
      known as DFFRY) and DBY (refs 7,8). Screening of the two genes in 576 infertile
      and 96 fertile men revealed several sequence variants, most of which appear to be
      heritable and of little functional consequence. We found one de novo mutation in
      USP9Y: a 4-bp deletion in a splice-donor site, causing an exon to be skipped and
      protein truncation. This mutation was present in a man with nonobstructive
      azoospermia (that is, no sperm was detected in semen), but absent in his fertile
      brother, suggesting that the USP9Y mutation caused spermatogenic failure. We also
      identified a single-gene deletion associated with spermatogenic failure, again
      involving USP9Y, by re-analysing a published study.

PMID- 10581030
TI  - Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock
      in cyclic haematopoiesis.
AB  - Human cyclic haematopoiesis (cyclic neutropenia, MIM 162800) is an autosomal
      dominant disease in which blood-cell production from the bone marrow oscillates
      with 21-day periodicity. Circulating neutrophils vary between almost normal
      numbers and zero. During intervals of neutropenia, affected individuals are at
      risk for opportunistic infection. Monocytes, platelets, lymphocytes and
      reticulocytes also cycle with the same frequency. Here we use a genome-wide
      screen and positional cloning to map the locus to chromosome 19p13.3. We
      identified 7 different single-base substitutions in the gene (ELA2) encoding
      neutrophil elastase (EC 3. 4.21.37, also known as leukocyte elastase, elastase 2
      and medullasin), a serine protease of neutrophil and monocyte granules, on unique
      haplotypes in 13 of 13 families as well as a new mutation in a sporadic case.
      Neutrophil elastase (a 240-aa mature protein predominantly found in neutrophil
      granules) is the target for protease inhibition by alpha1-antitrypsin, and its
      unopposed release destroys tissue at sites of inflammation. We hypothesize that a
      perturbed interaction between neutrophil elastase and serpins or other substrates
      may regulate mechanisms governing the clock-like timing of haematopoiesis.

PMID- 10581031
TI  - Genetic evidence of an early exit of Homo sapiens sapiens from Africa through
      eastern Africa.
AB  - The out-of-Africa scenario has hitherto provided little evidence for the precise
      route by which modern humans left Africa. Two major routes of dispersal have been
      hypothesized: one through North Africa into the Levant, documented by fossil
      remains, and one through Ethiopia along South Asia, for which little, if any,
      evidence exists. Mitochondrial DNA (mtDNA) can be used to trace maternal
      ancestry. The geographic distribution and variation of mtDNAs can be highly
      informative in defining potential range expansions and migration routes in the
      distant past. The mitochondrial haplogroup M, first regarded as an ancient marker
      of East-Asian origin, has been found at high frequency in India and Ethiopia,
      raising the question of its origin. (A haplogroup is a group of haplotypes that
      share some sequence variations.) Its variation and geographical distribution
      suggest that Asian haplogroup M separated from eastern-African haplogroup M more
      than 50,000 years ago. Two other variants (489C and 10873C) also support a single
      origin of haplogroup M in Africa. These findings, together with the virtual
      absence of haplogroup M in the Levant and its high frequency in the South-Arabian
      peninsula, render M the first genetic indicator for the hypothesized exit route
      from Africa through eastern Africa/western India. This was possibly the only
      successful early dispersal event of modern humans out of Africa.

PMID- 10581032
TI  - Patterning the zebrafish axial skeleton requires early chordin function.
AB  - Members of the bone morphogenetic protein (BMP) family actively promote ventral
      cell fates, such as epidermis and blood, in the vertebrate gastrula. More
      dorsally, the organizer region counteracts BMP signalling through secretion of
      BMP-binding antagonists chordin and noggin, allowing dorsally derived tissues
      such as neurectoderm and somitic muscle to develop. BMPs also function in
      skeletal development and regeneration of bone following injury. Noggin antagonism
      is thought to prevent osteogenesis at sites of joint formation, whereas chordin
      has not yet been implicated in skeletogenesis. Analyses of zebrafish mutants have
      confirmed the action of chordin (chd) in opposing ventralizing signals at
      gastrulation. Some ventralized mutants recover and develop into fertile adults,
      thereby revealing a requirement for chd function for the later processes of fin
      and caudal skeletal patterning. We observe in mutants the misexpression of genes
      encoding BMPs and putative downstream genes, and ectopic sclerotomal cells.
      Through injections of chd mRNA into the early embryo, we restored wild-type gene
      expression patterns, and the resultant fish, although genotypically mutant,
      developed normal axial skeletons and fins. Our results demonstrate that chordin
      function during gastrulation is important for the correct morphogenesis of the
      adult zebrafish skeleton.

PMID- 10581033
TI  - Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast
      mediated extracellular acidification.
AB  - Solubilization of bone mineral by osteoclasts depends on the formation of an
      acidic extracellular compartment through the action of a V-proton pump that has
      not yet been characterized at the molecular level. We previously cloned a gene
      (Atp6i, for V-proton pump, H+ transporting (vacuolar proton pump) member I)
      encoding a putative osteoclast-specific proton pump subunit, termed OC-116kD
      (ref. 4). Here we show that targeted disruption of Atp6i in mice results in
      severe osteopetrosis. Atp6i-/- osteoclast-like cells (OCLs) lose the function of
      extracellular acidification, but retain intracellular lysosomal proton pump
      activity. The pH in Atp6i-/- liver lysosomes and proton transport in microsomes
      of Atp6i-/- kidney are identical to that in wild-type mice. Atp6i-/- mice exhibit
      a normal acid-base balance in blood and urine. Our results demonstrate that Atp6i
      is unique and necessary for osteoclast-mediated extracellular acidification.

PMID- 10581034
TI  - A general approach to single-nucleotide polymorphism discovery.
AB  - Single-nucleotide polymorphisms (SNPs) are the most abundant form of human
      genetic variation and a resource for mapping complex genetic traits. The large
      volume of data produced by high-throughput sequencing projects is a rich and
      largely untapped source of SNPs (refs 2, 3, 4, 5). We present here a unified
      approach to the discovery of variations in genetic sequence data of arbitrary DNA
      sources. We propose to use the rapidly emerging genomic sequence as a template on
      which to layer often unmapped, fragmentary sequence data and to use base quality
      values to discern true allelic variations from sequencing errors. By taking
      advantage of the genomic sequence we are able to use simpler yet more accurate
      methods for sequence organization: fragment clustering, paralogue identification
      and multiple alignment. We analyse these sequences with a novel, Bayesian
      inference engine, POLYBAYES, to calculate the probability that a given site is
      polymorphic. Rigorous treatment of base quality permits completely automated
      evaluation of the full length of all sequences, without limitations on alignment
      depth. We demonstrate this approach by accurate SNP predictions in human ESTs
      aligned to finished and working-draft quality genomic sequences, a data set
      representative of the typical challenges of sequence-based SNP discovery.

PMID- 10581035
TI  - Heterochromatin protein 1 modifies mammalian PEV in a dose- and chromosomal
      context-dependent manner.
AB  - Locus control regions (LCRs) are gene regulatory elements in mammals that can
      overcome the highly repressive effects normally associated with heterochromatic
      transgene locations (for example the centromere) in mice. Deletion of essential
      LCR sequences renders the cognate gene susceptible to this form of repression, so
      a proportion of the cells from transgenic mice that would normally express the
      transgene are silenced-a phenomenon known as position effect variegation (PEV).
      We show here that PEV can also occur when the transgene is non-centromeric and
      that the extent of variegation can be developmentally regulated. Furthermore, by
      overexpressing a mammalian homologue (M31) of Drosophila melanogaster
      heterochromatin protein 1 (HP1; refs 7,8) in transgenic mouse lines that exhibit
      PEV, it is possible to modify the proportion of cells that silence the transgene
      in a dose-dependent manner. Thus, we show M31 overexpression to have two
      contrasting effects which are dependent on chromosomal context: (i) it enhanced
      PEV in those lines with centromeric or pericentromeric transgene locations; and
      (ii) it suppressed PEV when the transgene was non-centromeric. Our results
      indicate that components or modifiers of heterochromatin may have a chromosomal
      context-dependent role in gene silencing and activation decisions in mammals.

PMID- 10581036
TI  - A new gene, encoding an anion transporter, is mutated in sialic acid storage
      diseases.
AB  - Sialic acid storage diseases (SASD, MIM 269920) are autosomal recessive
      neurodegenerative disorders that may present as a severe infantile form (ISSD) or
      a slowly progressive adult form, which is prevalent in Finland (Salla disease).
      The main symptoms are hypotonia, cerebellar ataxia and mental retardation;
      visceromegaly and coarse features are also present in infantile cases.
      Progressive cerebellar atrophy and dysmyelination have been documented by
      magnetic resonance imaging (ref. 4). Enlarged lysosomes are seen on electron
      microscopic studies and patients excrete large amounts of free sialic acid in
      urine. A H+/anionic sugar symporter mechanism for sialic acid and glucuronic acid
      is impaired in lysosomal membranes from Salla and ISSD patients. The locus for
      Salla disease was assigned to a region of approximately 200 kb on chromosome 6q14
      q15 in a linkage study using Finnish families. Salla disease and ISSD were
      further shown to be allelic disorders. A physical map with P1 and PAC clones was
      constructed to cover the 200-kb area flanked by the loci D6S280 and D6S1622,
      providing the basis for precise physical positioning of the gene. Here we
      describe a new gene, SLC17A5 (also known as AST), encoding a protein (sialin)
      with a predicted transport function that belongs to a family of anion/cation
      symporters (ACS). We found a homozygous SLC17A5 mutation (R39C) in five Finnish
      patients with Salla disease and six different SLC17A5 mutations in six ISSD
      patients of different ethnic origins. Our observations suggest that mutations in
      SLC17A5 are the primary cause of lysosomal sialic acid storage diseases.

PMID- 10581037
TI  - Retinopathy and attenuated circadian entrainment in Crx-deficient mice.
AB  - Crx, an Otx-like homeobox gene, is expressed specifically in the photoreceptors
      of the retina and the pinealocytes of the pineal gland. Crx has been proposed to
      have a role in the regulation of photoreceptor-specific genes in the eye and of
      pineal-specific genes in the pineal gland. Mutations in human CRX are associated
      with the retinal diseases, cone-rod dystrophy-2 (adCRD2; refs 3, 4, 5), retinitis
      pigmentosa (RP) and Leber congenital amaurosis (LCA), which all lead to loss of
      vision. We generated mice carrying a targeted disruption of Crx. Crx-/- mice do
      not elaborate photoreceptor outer segments and lacked rod and cone activity as
      assayed by electroretinogram (ERG). Expression of several photoreceptor- and
      pineal-specific genes was reduced in Crx mutants. Circadian entrainment was also
      affected in Crx-/- mice.

PMID- 10581038
TI  - Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in
      Huntington disease transgenic mice.
AB  - Huntington disease (HD), an autosomal dominant, progressive neurodegenerative
      disorder, is caused by an expanded CAG repeat sequence leading to an increase in
      the number of glutamine residues in the encoded protein. The normal CAG repeat
      range is 5-36, whereas 38 or more repeats are found in the diseased state; the
      severity of disease is roughly proportional to the number of CAG repeats. HD
      shows anticipation, in which subsequent generations display earlier disease
      onsets due to intergenerational repeat expansion. For longer repeat lengths,
      somatic instability of the repeat size has been observed both in human cases at
      autopsy and in transgenic mouse models containing either a genomic fragment of
      human HD exon 1 (ref. 9) or an expanded repeat inserted into the endogenous mouse
      gene Hdh (ref. 10). With increasing repeat number, the protein changes
      conformation and becomes increasingly prone to aggregation, suggesting important
      functional correlations between repeat length and pathology. Because dinucleotide
      repeat instability is known to increase when the mismatch repair enzyme MSH2 is
      missing, we examined instability of the HD CAG repeat by crossing transgenic mice
      carrying exon 1 of human HD (ref. 16) with Msh2-/- mice. Our results show that
      Msh2 is required for somatic instability of the CAG repeat.

PMID- 10581039
TI  - Transcriptional repression mediated by the human polycomb-group protein EED
      involves histone deacetylation.
AB  - Polycomb-group (PcG) proteins form multimeric protein complexes, which are
      involved in maintaining the transcriptional repressive state of genes over
      successive cell generations. Components of PcG complexes and their mutual
      interactions have been identified and analysed through extensive genetic and
      biochemical analyses. Molecular mechanisms underlying PcG-mediated repression of
      gene activity, however, have remained largely unknown. Previously we reported the
      existence of two distinct human PcG protein complexes. The EED/EZH protein
      complex contains the embryonic ectoderm development (EED) and enhancer of zeste 2
      (EZH2; refs 9,10) PcG proteins. The HPC/HPH PcG complex contains the human
      polycomb 2 (HPC2; ref. 11), human polyhomeotic (HPH), BMI1 (ref. 13 ) and RING1
      (refs 14, 15) proteins. Here we show that EED (refs 4, 5, 6, 7, 8) interacts,
      both in vitro and in vivo, with histone deacetylase (HDAC) proteins. This
      interaction is highly specific because the HDAC proteins do not interact with
      other vertebrate PcG proteins. We further find that histone deacetylation
      activity co-immunoprecipitates with the EED protein. Finally, the histone
      deacetylase inhibitor trichostatin A (ref. 17) relieves transcriptional
      repression mediated by EED, but not by HPC2, a human homologue of polycomb. Our
      data indicate that PcG-mediated repression of gene activity involves histone
      deacetylation. This mechanistic link between two distinct, global gene repression
      systems is accomplished through the interaction of HDAC proteins with a
      particular PcG protein, EED.

PMID- 10581040
TI  - Stocking stuffers.

PMID- 10581041
TI  - Delayed early embryonic lethality following disruption of the murine cyclin A2
      gene.

PMID- 10581044
TI  - 1999 Subject index * Volumes 21 - 23.

PMID- 10581042
TI  - Repression of the gene encoding the TGF-beta type II receptor is a major target
      of the EWS-FLI1 oncoprotein.

PMID- 10581045
TI  - Replacing competition with cooperation.

PMID- 10581046
TI  - Cell membrane estrogen receptors resurface.

PMID- 10581047
TI  - Cell membrane estrogen receptors resurface.

PMID- 10581048
TI  - Viral phenotype and CCR5 genotype.

PMID- 10581049
TI  - E1A and the Ewing tumor translocation.

PMID- 10581050
TI  - E1A and the Ewing tumor translocation.

PMID- 10581051
TI  - EC panel decisions surprise malaria community.

PMID- 10581052
TI  - Wellcome reports on malaria research in Africa.

PMID- 10581053
TI  - Critics rain on MMV parade.

PMID- 10581054
TI  - Japan hosts its first xenotransplantation conference.

PMID- 10581056
TI  - Spending spree to end Canadian 'brain drain'.

PMID- 10581055
TI  - Ethicists bemoan shortened clinical trial approval time.

PMID- 10581057
TI  - Medical records ruling should not hamper research.

PMID- 10581058
TI  - Women gain ground on men in PhD passes.

PMID- 10581059
TI  - Novartis expands academic research funding.

PMID- 10581060
TI  - Stanford donation funds transdisciplinary center.

PMID- 10581061
TI  - First independent aging research center opens.

PMID- 10581062
TI  - Poor attendance bankrupts conference.

PMID- 10581064
TI  - The Devil's Workshop.

PMID- 10581063
TI  - Stem cell politics, ethics and medical progress.
AB  - Tremendous controversy has surrounded efforts to undertake research on totipotent
      human stem cells. To date public policy in the United States has attempted to
      skirt the ethical and social questions raised by this research. Annas et al.
      argue that research using human embryos as a source of totipotent stem cells can
      secure broad public support if there is an open and public discussion about the
      ethical justification for undertaking such research and the assurance of adequate
      federal regulation and oversight.

PMID- 10581065
TI  - Memory: From Mind to Molecules.

PMID- 10581066
TI  - T-cell stimulation: an abundance of B7s.

PMID- 10581067
TI  - Is it thee or me?--autoimmunity in Lyme disease.

PMID- 10581069
TI  - Are thalamocortical rhythms the Rosetta Stone of a subset of neurological
      disorders?

PMID- 10581068
TI  - Aspirin for cancer.

PMID- 10581070
TI  - Who's that lady?

PMID- 10581071
TI  - Is calcium the 'cure' for dilated cardiomyopathy?

PMID- 10581073
TI  - Runt domains take the lead in hematopoiesis and osteogenesis.

PMID- 10581072
TI  - NOS knockouts and neuroprotection.

PMID- 10581074
TI  - Ancient HTLV-1.

PMID- 10581075
TI  - A new HIV hideout.

PMID- 10581076
TI  - Clinical applications of angiogenic growth factors and their inhibitors.
AB  - Promoting the formation of new collateral vessels in ischemic tissues using
      angiogenic growth factors (therapeutic angiogenesis) is a an exciting frontier of
      cardiovascular medicine. Conversely, inhibition of the action of key regulators
      of angiogenesis, such as VEGF, constitutes a promising approach for the treatment
      of solid tumors and intraocular neovascular syndromes. These concepts are being
      tested now in clinical trials.

PMID- 10581077
TI  - B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and
      interleukin-10 secretion.
AB  - The B7 family members B7-1 and B7-2 interact with CD28 and constitute an
      essential T-cell co-stimulatory pathway in the initiation of antigen-specific
      humoral and cell-mediated immune response. Here, we describe a third member of
      the B7 family, called B7-H1 that does not bind CD28, cytotoxic T-lymphocyte A4 or
      ICOS (inducible co-stimulator). Ligation of B7-H1 co-stimulated T-cell responses
      to polyclonal stimuli and allogeneic antigens, and preferentially stimulated the
      production of interleukin-10. Interleukin-2, although produced in small amounts,
      was required for the effect of B7-H1 co-stimulation. Our studies thus define a
      previously unknown co-stimulatory molecule that may be involved in the negative
      regulation of cell-mediated immune responses.

PMID- 10581078
TI  - Reversal of virus-induced systemic shock and respiratory failure by blockade of
      the lymphotoxin pathway.
AB  - At present, little is known about the pathogenesis of acute virus-induced shock
      and pulmonary failure. A chief impediment in understanding the underlying disease
      mechanisms and developing treatment strategies has been the lack of a suitable
      animal model. This study describes a mouse model of virus-induced systemic shock
      and respiratory distress, and shows that blockade of the lymphotoxin beta
      receptor pathway reverses the disease.

PMID- 10581079
TI  - Identification of candidate T-cell epitopes and molecular mimics in chronic Lyme
      disease.
AB  - Elucidating the cellular immune response to infectious agents is a prerequisite
      for understanding disease pathogenesis and designing effective vaccines. In the
      identification of microbial T-cell epitopes, the availability of purified or
      recombinant bacterial proteins has been a chief limiting factor. In chronic
      infectious diseases such as Lyme disease, immune-mediated damage may add to the
      effects of direct infection by means of molecular mimicry to tissue autoantigens.
      Here, we describe a new method to effectively identify both microbial epitopes
      and candidate autoantigens. The approach combines data acquisition by positional
      scanning peptide combinatorial libraries and biometric data analysis by
      generation of scoring matrices. In a patient with chronic neuroborreliosis, we
      show that this strategy leads to the identification of potentially relevant T
      cell targets derived from both Borrelia burgdorferi and the host. We also found
      that the antigen specificity of a single T-cell clone can be degenerate and yet
      the clone can preferentially recognize different peptides derived from the same
      organism, thus demonstrating that flexibility in T-cell recognition does not
      preclude specificity. This approach has potential applications in the
      identification of ligands in infectious diseases, tumors and autoimmune diseases.

PMID- 10581080
TI  - Spontaneous combined hyperlipidemia, coronary heart disease and decreased
      survival in Dahl salt-sensitive hypertensive rats transgenic for human
      cholesteryl ester transfer protein.
AB  - The acceleration of atherosclerosis by polygenic (essential) hypertension is well
      characterized in humans; however, the lack of an animal model that simulates
      human disease hinders the elucidation of pathogenic mechanisms. We report here a
      transgenic atherosclerosis-polygenic hypertension model in Dahl salt-sensitive
      hypertensive rats that overexpress the human cholesteryl ester transfer protein
      (Tg[hCETP]DS). Male Tg[hCETP]DS rats fed regular rat chow showed age-dependent
      severe combined hyperlipidemia, atherosclerotic lesions, myocardial infarctions
      and decreased survival. These findings differ from various mouse atherosclerosis
      models, demonstrating the necessity of complex disease modeling in different
      species. The data demonstrate that cholesteryl ester transfer protein can be
      proatherogenic. The interaction of polygenic hypertension and hyperlipidemia in
      the pathogenesis of atherosclerosis in Tg[hCETP]DS rats substantiates
      epidemiological observations in humans.

PMID- 10581081
TI  - Regulation of vascular endothelial growth factor-dependent retinal
      neovascularization by insulin-like growth factor-1 receptor.
AB  - Although insulin-like growth factor 1 (IGF-1) has been associated with
      retinopathy, proof of a direct relationship has been lacking. Here we show that
      an IGF-1 receptor antagonist suppresses retinal neovascularization in vivo, and
      infer that interactions between IGF-1 and the IGF-1 receptor are necessary for
      induction of maximal neovascularization by vascular endothelial growth factor
      (VEGF). IGF-1 receptor regulation of VEGF action is mediated at least in part
      through control of VEGF activation of p44/42 mitogen-activated protein kinase,
      establishing a hierarchical relationship between IGF-1 and VEGF receptors. These
      findings establish an essential role for IGF-1 in angiogenesis and demonstrate a
      new target for control of retinopathy. They also explain why diabetic retinopathy
      initially increases with the onset of insulin treatment. IGF-1 levels, low in
      untreated diabetes, rise with insulin therapy, permitting VEGF-induced
      retinopathy.

PMID- 10581082
TI  - Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces
      ischemic brain injury.
AB  - We describe here a new strategy for the treatment of stroke, through the
      inhibition of NAALADase (N-acetylated-alpha-linked-acidic dipeptidase), an enzyme
      responsible for the hydrolysis of the neuropeptide NAAG (N-acetyl-aspartyl
      glutamate) to N-acetyl-aspartate and glutamate. We demonstrate that the newly
      described NAALADase inhibitor 2-PMPA (2-(phosphonomethyl)pentanedioic acid)
      robustly protects against ischemic injury in a neuronal culture model of stroke
      and in rats after transient middle cerebral artery occlusion. Consistent with
      inhibition of NAALADase, we show that 2-PMPA increases NAAG and attenuates the
      ischemia-induced rise in glutamate. Both effects could contribute to
      neuroprotection. These data indicate that NAALADase inhibition may have use in
      neurological disorders in which excessive excitatory amino acid transmission is
      pathogenic.

PMID- 10581083
TI  - Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the
      MPTP model of Parkinson disease.
AB  - MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) damages dopaminergic neurons
      as seen in Parkinson disease. Here we show that after administration of MPTP to
      mice, there was a robust gliosis in the substantia nigra pars compacta associated
      with significant upregulation of inducible nitric oxide synthase (iNOS). These
      changes preceded or paralleled MPTP-induced dopaminergic neurodegeneration. We
      also show that mutant mice lacking the iNOS gene were significantly more
      resistant to MPTP than their wild-type littermates. This study demonstrates that
      iNOS is important in the MPTP neurotoxic process and indicates that inhibitors of
      iNOS may provide protective benefit in the treatment of Parkinson disease.

PMID- 10581084
TI  - Transplanted embryonic stem cells survive, differentiate and promote recovery in
      injured rat spinal cord.
AB  - Transplantation approaches using cellular bridges, fetal central nervous system
      cells, fibroblasts expressing neurotrophin-3 (ref. 6), hybridoma cells expressing
      inhibitory protein-blocking antibodies, or olfactory nerves ensheathing glial
      cells transplanted into the acutely injured spinal cord have produced axonal
      regrowth or functional benefits. Transplants of rat or cat fetal spinal cord
      tissue into the chronically injured cord survive and integrate with the host
      cord, and may be associated with some functional improvements. In addition, rats
      transplanted with fetal spinal cord cells have shown improvements in some gait
      parameters, and the delayed transplantation of fetal raphe cells can enhance
      reflexes. We transplanted neural differentiated mouse embryonic stem cells into a
      rat spinal cord 9 days after traumatic injury. Histological analysis 2-5 weeks
      later showed that transplant-derived cells survived and differentiated into
      astrocytes, oligodendrocytes and neurons, and migrated as far as 8 mm away from
      the lesion edge. Furthermore, gait analysis demonstrated that transplanted rats
      showed hindlimb weight support and partial hindlimb coordination not found in
      'sham-operated' controls or control rats transplanted with adult mouse
      neocortical cells.

PMID- 10581085
TI  - Direct, convergent hypersensitivity of calcium-activated force generation
      produced by hypertrophic cardiomyopathy mutant alpha-tropomyosins in adult
      cardiac myocytes.
AB  - Familial hypertrophic cardiomyopathy is a clinically and genetically diverse
      autosomal dominant disorder characterized by ventricular hypertrophy and myocyte
      disarray in the absence of known hypertrophic stimuli. It has been linked to many
      cardiac contractile proteins, including four point mutations in alpha-tropomyosin
      (Tm). Here we use adenoviral-mediated gene transfer into adult cardiac myocytes
      in vitro to show that all four hypertrophic cardiomyopathy alpha-Tm proteins can
      be expressed and incorporated into normal sarcomeric structures in cardiac
      myocytes at similar levels as normal alpha-Tm proteins after 5-6 days in culture.
      Isometric force recordings of single cardiac myocytes demonstrated inappropriate
      increased force output at submaximal calcium concentration with a specific mutant
      allele hierarchy. These data indicate that the severity of direct calcium
      sensitizing effect of mutations in alpha-Tm may predict the clinical severity of
      mutant alpha-Tm-associated hypertrophic cardiomyopathy.

PMID- 10581086
TI  - Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into
      mechanisms and implications for cancer growth and ulcer healing.
AB  - Angiogenesis, the formation of new capillary blood vessels, is essential not only
      for the growth and metastasis of solid tumors, but also for wound and ulcer
      healing, because without the restoration of blood flow, oxygen and nutrients
      cannot be delivered to the healing site. Nonsteroidal anti-inflammatory drugs
      (NSAIDs) such as aspirin, indomethacin and ibuprofen are the most widely used
      drugs for pain, arthritis, cardiovascular diseases and, more recently, the
      prevention of colon cancer and Alzheimer disease. However, NSAIDs produce
      gastroduodenal ulcers in about 25% of users (often with bleeding and/or
      perforations) and delay ulcer healing, presumably by blocking prostaglandin
      synthesis from cyclooxygenase (COX)-1 and COX-2 (ref. 10). The hypothesis that
      the gastrointestinal side effects of NSAIDs result from inhibition of COX-1, but
      not COX-2 (ref. 11), prompted the development of NSAIDs that selectively inhibit
      only COX-2 (such as celecoxib and rofecoxib). Our study demonstrates that both
      selective and nonselective NSAIDs inhibit angiogenesis through direct effects on
      endothelial cells. We also show that this action involves inhibition of mitogen
      activated protein (MAP) kinase (ERK2) activity, interference with ERK nuclear
      translocation, is independent of protein kinase C and has prostaglandin-dependent
      and prostaglandin-independent components. Finally, we show that both COX-1 and
      COX-2 are important for the regulation of angiogenesis. These findings challenge
      the premise that selective COX-2 inhibitors will not affect the gastrointestinal
      tract and ulcer/wound healing.

PMID- 10581087
TI  - Thymosin beta 4 sulfoxide is an anti-inflammatory agent generated by monocytes in
      the presence of glucocorticoids.
AB  - The possibility that glucocorticoids upregulate the expression of anti
      inflammatory mediators is an exciting prospect for therapy in inflammatory
      diseases, because these molecules could give the therapeutic benefits of steroids
      without toxic side effects. Supernatants from monocytes and macrophages cultured
      in the presence of glucocorticoids increase the dispersion of neutrophils from a
      cell pellet in the capillary tube migration assay. This supernatant factor,
      unlike other neutrophil agonists, promotes dispersive locomotion of neutrophils
      at uniform concentration, lowers their adhesion to endothelial cells, inhibits
      their chemotactic response to fMLP and induces distinctive morphological changes.
      Here we show that thymosin beta4 sulfoxide is generated by monocytes in the
      presence of glucocorticoids and acts as a signal to inhibit an inflammatory
      response. In vitro, thymosin beta4 sulfoxide inhibited neutrophil chemotaxis, and
      in vivo, the oxidized peptide, but not the native form, was a potent inhibitor of
      carrageenin-induced edema in the mouse paw. Thymosin beta4 is unique, because
      oxidation attenuates its intracellular G-actin sequestering activity, but greatly
      enhances its extracellular signaling properties. This description of methionine
      oxidation conferring extracellular function on a cytosolic protein may have far
      reaching implications for future strategies of anti-inflammatory therapy.

PMID- 10581088
TI  - The presence of ancient human T-cell lymphotropic virus type I provirus DNA in an
      Andean mummy.
AB  - The worldwide geographic and ethnic clustering of patients with diseases related
      to human T-cell lymphotropic virus type I (HTLV-I) may be explained by the
      natural history of HTLV-I infection. The genetic characteristics of indigenous
      people in the Andes are similar to those of the Japanese, and HTLV-I is generally
      detected in both groups. To clarify the common origin of HTLV-I in Asia and the
      Andes, we analyzed HTLV-I provirus DNA from Andean mummies about 1,500 years old.
      Two of 104 mummy bone marrow specimens yielded a band of human beta-globin gene
      DNA 110 base pairs in length, and one of these two produced bands of HTLV-I-pX
      (open reading frame encoding p40x, p27x) and HTLV-I-LTR (long terminal repeat)
      gene DNA 159 base pairs and 157 base pairs in length, respectively. The
      nucleotide sequences of ancient HTLV-I-pX and HTLV-I-LTR clones isolated from
      mummy bone marrow were similar to those in contemporary Andeans and Japanese,
      although there was microheterogeneity in the sequences of some mummy DNA clones.
      This result provides evidence that HTLV-I was carried with ancient Mongoloids to
      the Andes before the Colonial era. Analysis of ancient HTLV-I sequences could be
      a useful tool for studying the history of human retroviral infection as well as
      human prehistoric migration.

PMID- 10581090
TI  - ON THE MARKET.

PMID- 10581091
TI  - Genetic capsid modifications allow efficient re-targeting of adeno-associated
      virus type 2.

PMID- 10581089
TI  - Neural control of mechanical ventilation in respiratory failure.

PMID- 10581092
TI  - New DNA enzyme targeting Egr-1 mRNA inhibits vascular smooth muscle proliferation
      and regrowth after injury.

PMID- 10581094
TI  - 1999 Subject index * Volume 5.

PMID- 10581105
TI  - Aquatic plants for toxicity assessment.

PMID- 10581106
TI  - Short-term effects of air pollution on childhood respiratory illness in Piraeus,
      Greece, 1987-1992: nonparametric stochastic dynamic analysis.
AB  - The short-term effects of air pollution on childhood respiratory illness are
      analyzed for the city of Piraeus, Greece during the 1987-1992 period using a
      distinct, nonparametric, stochastic dynamical system approach. This approach
      accounts for the time continuity of the phenomenon, including contemporaneous,
      lagged, and unstructured cumulative effects. It also accounts for the presence of
      autocorrelation and nonstationary structures in the series and aims at revealing
      the potentially subtle relationships among the examined pollutants (smoke, CO,
      SO(2), NO(2), O(3)), meteorological factors (temperature, humidity), and hospital
      admissions. The approach is also capable of assessing the individual effects of
      any isolated pollutant, as well as the total effects of all measured pollutants.
      The study is based upon 4042 hospital admissions, and its results indicate
      statistically significant effects of each individual pollutant, as well as
      meteorological factor, on hospital admissions. It is interesting that these
      effects appear stronger for the second half of the examined period, despite
      declines in the observed mean concentrations for most pollutants. The total
      effects of the four pollutants (excluding O(3)) are characterized by multiple
      coherence measures of 18.37 and 21.66% in the first and second halves of the
      examined period, respectively, and are confirmed as statistically significant.

PMID- 10581107
TI  - Intrauterine lead exposure and preterm birth.
AB  - The objective of this study was to determine the risk of preterm birth in
      relation to umbilical cord blood lead levels (UCL) among primiparous and
      multiparous women. A case-cohort study was performed in Mexico City during 1995.
      A total of 459 full-term births was compared with 161 preterm births (before 37
      gestational weeks). Mothers were interviewed before the delivery about their
      reproductive histories and other related factors of preterm birth. Lead was
      determined by atomic absorption spectrophotometry. Lead levels were higher in
      primiparous women who had a preterm birth than in primiparous women with a full
      term birth (9.77+/-2.0 microgram/dl vs 8.24+/-2.15 microgram/dl); this difference
      was marginally significant. After adjusting for other known preterm birth risk
      factors, the frequency of preterm birth was almost three times higher among women
      who had UCL levels greater or equal to 5.1 microgram/dl compared to those who had
      UCL levels lower than 5.1 microgram/dl. This difference was not observed among
      multiparous women. Our results suggest that intrauterine lead exposure may be
      associated with preterm birth in first deliveries but not in subsequent ones.

PMID- 10581108
TI  - Esophageal cancer mortality and total hardness levels in Taiwan's drinking water.
AB  - The possible association between the risk of esophageal cancer and hardness
      levels in drinking water from municipal supplies was investigated in a matched
      case-control study in Taiwan. All eligible esophageal cancer deaths (2084 cases)
      of Taiwan residents from 1987 through 1996 were compared with deaths from other
      causes (2084 controls), and the hardness levels of the drinking water used by
      these residents were determined. Data on water hardness throughout Taiwan have
      been collected from the Taiwan Water Supply Corporation (TWSC). The control group
      consisted of people who died from other causes and the controls were pair-matched
      to the cases by sex, year of birth, and year of death. The results show that
      there is a 42% excess risk of mortality from esophageal cancer in relation to the
      use of soft water (adjusted odds ratio and 95% confidence intervals was 1.42
      (1.22-1.66). This is an important finding for the Taiwan water industry and human
      health.

PMID- 10581109
TI  - Ingested aggregates of ultrafine carbon particles and interferon-gamma impair rat
      alveolar macrophage function.
AB  - Alveolar macrophages (AM), obtained by lavage from the rat lung, were allowed to
      ingest aggregated ultrafine carbon particles, about 1 microgram/10(6) AM, which
      is a realistic result of long-term exposure to ambient air. The effects of the
      ingested carbon on the phagocytosis of test particles and oxidative metabolism of
      the AM were studied. In addition, the effects of short-term (40 min or 2 h) and
      long-term (28 or 44 h) incubation with interferon gamma (IFN-gamma) on AM loaded
      and unloaded with carbon were investigated. Phagocytic activity was studied using
      fluorescein-labeled 3.2-microgram silica particles. The attachment and ingestion
      processes were evaluated separately. The ingested carbon markedly impaired the
      phagocytosis of silica particles; the accumulated attachment (sum of attached and
      ingested particles per AM) decreased from 5.0 to 4.2 particles/AM and the
      ingested fraction (number of ingested particles per AM divided with accumulated
      attachment) from 0.42 to 0.27. The short-term incubation with IFN-gamma tended to
      increase the accumulated attachment (from 5.0 to 5.7 particles/AM) and decreased
      the ingested fraction (from 0.42 to 0.34) in unloaded AM. Long-term incubation
      with IFN-gamma markedly impaired both the accumulated attachment (to 3.8
      particles/AM) and the ingested fraction (to 0.24) in unloaded AM and the carbon
      load further decreased the accumulated attachment to 2.8 particles/AM, and the
      ingested fraction to 0.21. The oxidative metabolism was not effected by the
      ingested carbon or the short-term incubation with IFN-gamma, but the long-term
      incubation with IFN-gamma increased it with a factor of almost 3. Our results
      suggest that ingested environmental particles in AM may markedly impair their
      phagocytic capacity, especially during long-term exposure to IFN-gamma as after
      infections, and there might be an increased risk for additional infections.
      Moreover, during an episode of high ambient particle concentration the inhaled
      particles will not be efficiently phagocytized and may thereby damage the Lung
      tissue.

PMID- 10581110
TI  - Estimation and evaluation of exposures from a large sulfur fire in South Africa.
AB  - A massive fire at a sulfur stockpile in the Western Cape Province of South Africa
      in December 1995 is estimated to have released over 14,000 t of sulfur dioxide
      (SO(2)) over a 20-h period. High and persistent winds greatly reduced the
      effectiveness of fire-fighting activities and increased the severity of impacts.
      Nearby urban and agricultural areas were seriously affected. Thousands of people
      were evacuated from the nearby town of Macassar located 2.5-4 km downwind, and at
      least several deaths occurred. Agricultural impacts ranged over a broad area
      extending to 30 km from the fire site and included severe damage to plants and
      some animal deaths. This paper describes the chronology of the fire, the
      emergency responses, and the immediate impacts. SO(2) concentrations are
      estimated using dispersion modeling, and predictions are evaluated using
      available monitoring information. Sensitivity analyses are used to test unknown
      or uncertain model parameters. The SO(2) concentrations estimated in Macassar
      reached extremely dangerous levels, at times over the IDLH level (100 ppm).
      Predictions agree with the available but very limited monitoring data, as well as
      with the symptomology of Macassar residents and plant damage patterns. Procedures
      to deal with the limited information and variability in this fire and similar
      incidents are suggested. The fire is a tragic demonstration of shortcomings in
      hazardous material management and emergency response.

PMID- 10581111
TI  - Low-cost household paint abatement to reduce children's blood lead levels.
AB  - The purpose was to examine the effectiveness of low-cost abatement on children's
      blood lead levels. Blood lead was analyzed before and after abatement in 37 homes
      of children under 7 years old with initial blood lead levels of 25-44
      microgram/dL. Ninety-five percent of homes were built before 1950. Abatement
      methods used were wet-scraping and repainting deteriorated surfaces and wrapping
      window wells with aluminum or vinyl. A control group was retrospectively
      selected. Control children were under 7 years old, had initial blood lead levels
      of 25-44 microgram/dL and a follow-up level at least 28 days afterward, and did
      not have abatements performed in their homes between blood lead levels. After
      abatement, statistically significant declines occurred in the intervention
      children's blood lead levels. The mean decline was 22%, 1 to 6 months after
      treatment. After adjustment for seasonality and child's age, the mean decline was
      6.0 microgram/dL, or 18%. The control children's blood levels did not decline
      significantly. There was a mean decline of 0.25 microgram/dL, or 0.39%. After
      adjustment for seasonality and age, the mean decline for control children was 1.6
      microgram/dL, or 1.8%. Low-cost abatement and education are effective short-term
      interim controls.

PMID- 10581112
TI  - Use of personal passive samplers for measurement of NO(2), NO, and O(3) levels in
      panel studies.
AB  - We measured personal exposure to nitrogen dioxide (NO(2)), nitrogen monoxide
      (NO), and ozone (O(3)), using personal passive samplers during three 4-day
      periods, in a panel study of asthmatics continuing the normal activities of
      everyday life. Fifty-five adults, mean age 42 years, 53% men, and 39 children,
      mean age 11 years, 67% boys, wore two Ogawa passive samplers simultaneously: one
      for O(3), the other for NO(2) and NO. Mean outdoor pollution was measured at a
      regional monitoring network. Personal exposure levels were scattered; they were
      (on average) higher than stationary-site levels for NO and lower for NO(2) and
      O(3). In adults, 41% of the variance of personal exposure to NO(2) was explained
      by mean stationary-site measurement levels (P<0.0001). Twenty-one percent
      additional variance was explained by living near a main road, not having an
      extractor fan over the cooker, older age, and male sex. NO and O(3) personal
      exposures correlated poorly with stationary-site measurements. In panel studies
      of the health effects of air pollution, personal exposure to NO(2) and NO can be
      measured satisfactorily by passive samplers: such measurements are necessary for
      NO but not for NO(2). For O(3), accurate personal exposure measurement remains a
      challenge and further technical development is required.

PMID- 10581114
TI  - Ecotoxicology and Environmental Safety Environmental Research, Section B.

PMID- 10581113
TI  - Evidence of endocrine disruption in the imposex-affected gastropod Bolinus
      brandaris.
AB  - Testosterone/estradiol tissue levels and cytochrome P450-dependent aromatase
      activity have been evaluated in the gastropod Bolinus brandaris. Samples were
      collected from two locations on the Mediterranean coast (St. Carles and
      Barcelona) according to their different degrees of imposex development and
      organotin residues. St. Carles was chosen as a relatively clean site, as only 37%
      of the females were imposex affected compared to 100% of the females from
      Barcelona. A strong reduction of estradiol levels was seen in both males and
      females from the organotin-polluted site in comparison to those of the reference
      site, whereas weaker differences between the sites in testosterone levels were
      revealed. Despite the observed alterations in sex hormone levels, no changes in
      aromatase activity were recorded. These results suggest that mechanisms other
      than inhibition of aromatase activity might be involved in the development of
      imposex in B. brandaris.

PMID- 10581115
TI  - Environmental Research Section A.

PMID- 10581116
TI  - Water-sediment controversy in setting environmental standards for selenium.
AB  - A substantial amount of laboratory and field research on selenium effects to
      biota has been accomplished since the national water quality criterion was
      published for selenium in 1987. Many articles have documented adverse effects on
      biota at concentrations below the current chronic criterion of 5 microg/L. This
      commentary will present information to support a national water quality criterion
      for selenium of 2 microg/L, based on a wide array of support from federal, state,
      university, and international sources. Recently, two articles have argued for a
      sediment-based criterion and presented a model for deriving site-specific
      criteria. In one example, they calculate a criterion of 31 microg/L for a stream
      with a low sediment selenium toxicity threshold and low site-specific sediment
      total organic carbon content, which is substantially higher than the national
      criterion of 5 microg/L. Their basic premise for proposing a sediment-based
      method has been critically reviewed and problems in their approach are discussed.

PMID- 10581117
TI  - Effects of low levels of lead on growth and reproduction of the Asian earthworm
      Perionyx excavatus (Oligochaeta).
AB  - The effects of sublethal concentrations of lead nitrate on growth and
      reproduction of the Asian composting earthworm species Perionyx excavatus was
      studied experimentally by exposing worms in an organic substrate to lead nitrate
      contaminated food over a period of 76 days. The results revealed that growth was
      affected negatively by the presence of lead while maturation rate and cocoon
      production was not affected. In agreement with other studies on Eisenia fetida,
      cocoon viability was affected negatively by lead, making this a sensitive
      toxicity endpoint. Lead accumulation was of the same order of magnitude as for
      other previously studied species.

PMID- 10581118
TI  - Use of crayfish in biomonitoring studies of environmental pollution of the river
      Meuse.
AB  - The river Meuse, located in western Europe, is contaminated by different
      pollutants, of both organic and inorganic nature. The predominant sources of
      Meuse contamination in The Netherlands are agricultural activities and pollution
      derived from urban areas. Crayfish, water, and sediment samples were collected at
      four different locations of the river Meuse, in order to cover a large part of
      the catchment area of this river in The Netherlands. Crayfish may be very useful
      in biomonitoring studies, since they can integrate body load by pollutants over
      time in an area-bound manner. In these crayfish, levels of aromatic DNA adducts,
      heavy metal residues, polychlorinated biphenyls (PCBs), and organochlorine
      pesticides were determined in hepatopancreatic tissue. Also analyzed were water
      and sediment samples derived from the same locations, for polycyclic aromatic
      hydrocarbons (PAHs), heavy metals, and organochlorine compounds. In sediments
      from the four different sampling sites, no clear differences were observed in PCB
      levels. Organochlorine pesticide concentrations were highest at location A, the
      most upstream sampling site, whereas a general decrease was observed following
      the river Meuse downstream. A similar pattern was observed for the metal
      compounds. For PAH sediment levels no consistent tendency could be observed.
      Highest values were detected at site B, followed by, respectively, locations A,
      D, and C. In water samples, a different pattern was observed. The highest metal
      concentration was observed at location D, whereas the total organochlorine level
      was higher at sites B and D, compared to the two other sampling sites.
      Differences in pollution levels in crayfish between sampling sites were evident.
      Site D, the most downstream-situated site examined, appeared to be the most
      polluted site with respect to PCBs, DDT, DDE, and Cu in crayfish. Moreover, DNA
      adduct levels, which may serve as a dosimeter for the internal dose of aromatic
      compounds such as PAHs and PCBs, were also significantly higher in
      hepatopancreatic tissue of crayfish captured at site D, compared to the three
      other sampling sites. Moreover, significant correlations were observed between
      DNA adduct levels and the lower chlorinated PCB congeners (PCB 28-PCB 101). By
      correlating the different pollutants in water and/or sediment with xenobiotic
      levels in crayfish, no consistency could be observed, indicating that monitoring
      aquatic species may provide specific information on the presence of surface water
      pollutants. These results indicate that crayfish can be used as biological
      indicators of exposure to both organic and inorganic pollution in aquatic
      systems.

PMID- 10581119
TI  - Assessment of the bioactivity of creosote-contaminated sediment by liver
      biotransformation system of rainbow trout.
AB  - A sediment site in the Lake Jamsanvesi (municipality of Petajavesi, Finland)
      contaminated by creosote was investigated to assess the possible ecotoxicological
      risks it may cause to benthic animals, including ones which may arise due to
      physical measures in remediating the site. It is suggested that polycyclic
      aromatic hydrocarbons (PAHs) are bioavailable to fish and other aquatic animals
      during exposure to contaminated water, sediment, and food. In order to assess
      toxicological risks of sediment contents to fish, juvenile rainbow trout
      (Onchorhynchus mykiss) were intraperitoneally dosed with extracts of the creosote
      contaminated sediments and their elutriates. This was compared to pristine lake
      sediment spiked with creosote. Activity of CYP1A1 in trout liver was measured as
      ethoxyresorufin O-deethylase (EROD). When compared to vehicle controls and the
      pristine reference sediment (0.9-1.3 pmol/min/mg PMS protein), the extract of
      creosote-contaminated sediment of Lake Jamsanvesi induced EROD activity up 20-30
      times with a dose of 100 mg/kg [total PAHs (mg)/(kg) in fish]. The rise of EROD
      was associated with increasing levels of PAH metabolites in bile, analyzed as 1
      OH pyrene equivalents.

PMID- 10581120
TI  - Variation in the deoxynucleotide composition between organic and nonorganic
      strawberries.
AB  - The differences in xenobiotic chemical content between organic and nonorganic
      products can be chemically measured. In this study, the deoxynucleotide
      composition of strawberry samples is used to demonstrate chromatographic methods
      of quantifying the differences between pesticide- and toxic-exposed strawberries.
      The samples were analyzed by (32)P labeling and two-dimensional thin-layer
      chromatography. This technique is sensitive for detecting rare (1/10(10))
      deoxynucleotide adducts and analogues (minor bases) in DNA. The results indicate
      differences in the amount and type of adduct formation between organic and
      nonorganic strawberry samples and within different parts of the same type of
      sample. The elucidation of the content and effects of pesticides and toxics in
      foods is critical in differentiating organic from common produce. It can also aid
      the agricultural industry in improving the application of chemicals in pest
      management. Furthermore, it helps to enhance the understanding of long-term
      epidemiology in nutrition research, especially in susceptible populations. These
      findings are of particular application in the pediatric population, where dietary
      habits are restricted to specific food groups.

PMID- 10581121
TI  - UV-B-Induced acute toxicity of pyrene to the waterflea Daphnia magna in natural
      freshwaters.
AB  - The effects of various water characteristics in natural freshwaters on the acute
      toxicity of one polycyclic aromatic hydrocarbon (PAH), pyrene, to a pelagic
      invertebrate Daphnia magna was studied under ultraviolet B (UV-B) radiation and
      in the dark. Pyrene was photoactivated and was more toxic to D. magna in the
      presence of UV-B radiation. Dissolved organic material (DOM), measured as
      dissolved organic carbon (DOC), significantly reduced the photoenhanced toxicity
      of pyrene. Under UV-B radiation the EC(50) values were lower and in relation to
      the amount of DOM, ranging from 3.0 to 30.0 microg/L pyrene, whereas in the dark
      they were between 29.2 and 54.8 microg/L and not related to the amount of DOM in
      the waters. Although the condition and mortality of the daphnids in the control
      groups were not affected by UV-B irradiation, the increased toxicity was
      considered to be either an additive or a synergistic effect of both the
      photomodified pyrene and the stressing light conditions of UV-B. The measured
      binding of pyrene to DOM was low, although it was related to the amount of DOC.
      Despite the relatively high intensity of UV-B used, humic substances in the
      waters remained undegraded. It was thus concluded that with their brownish
      yellowish color, waters rich in humic substances decreased the photomodification
      of the freely dissolved parent compound simply by diminishing the light
      penetration in these waters and, by implication, contact with the intact
      compound. These results suggest that DOM in surface waters plays an important
      role in protecting against the photoinduced toxicity of PAHs.

PMID- 10581122
TI  - Environmental conditions and pesticide pollution of two coastal ecosystems in the
      Gulf of California, Mexico.
AB  - In December 1997 and April and September 1998, water temperature, salinity,
      dissolved oxygen, nutrients, chlorophyll, and pesticide residues were determined
      in two coastal ecosystems of Sinaloa, NW Mexico: Ensenada del Pabellon and Bahia
      de Santa Maria. These two are considered to be among the greatest shrimp
      producers in the region. Temperature, salinity, and dissolved oxygen were similar
      to those of other ecosystems of this region: high temperatures and salinity in
      spring and summer (dry season) and lower in winter and the rainy season. Levels
      of nitrites and phosphates and chlorophyll concentration were relatively higher
      than those of other ecosystems nearby, probably due to fertilizers used in the
      agricultural lands surrounding the water bodies studied. The pesticides more
      frequently detected were BHCalpha, aldrin, endosulfan and parathion. In some
      cases, pesticides forbidden by Mexican regulations were detected. These results
      indicate that the ecosystems studied are in a warning condition, because severe
      biochemical and physiological alterations have been reported in crustaceans
      exposed to pesticides. Therefore these pesticides could be one cause of the slow
      growth, diverse pathologies, and mortality in shrimp that have been reported in
      recent years.

PMID- 10581123
TI  - Novel bioassay based on acetylcholinesterase and lactate dehydrogenase activities
      to evaluate the toxicity of chemicals to soil isopods.
AB  - This study developed a bioassay with the isopod Porcellio dilatatus based on the
      activity of the enzymes acetylcholinesterase (AChE) and lactate dehydrogenase
      (LDH). The in vivo effects of the insecticides parathion-ethyl and endosulfan
      sulfate on AChE and LDH activities of P. dilatatus under laboratory conditions
      were investigated. The route of uptake of the pesticides was through the food
      (alder leaves). Isopods were exposed to a wide range of concentrations of
      parathion or endosulfan (0.1, 1, 10, 25, 50, 100, 250, and 500 microg/g of food)
      for 21 days. After this period, the activity of AChE and LDH was determined.
      Parathion induced significant depression of both AChE and LDH activities. Animals
      fed with endosulfan-contaminated food exhibited lower LDH activities than control
      animals, while AChE activity was similar in all treatments. The results of the
      present investigation suggest that the isopod. P. dilatatus is a suitable species
      for use in toxicity tests and indicate that the enzymes AChE and LDH could be
      used as effect criteria both in laboratory and in field studies with this
      species.

PMID- 10581124
TI  - Relating environmental availability to bioavailability: soil-type-dependent metal
      accumulation in the oligochaete Eisenia andrei.
AB  - Body residues are often better estimates of the amount of a chemical at the sites
      of toxic action in an organism than ambient soil concentrations, because
      bioavailability differences among soils are explicitly taken into account in
      considerations of body residues. Often, however, insufficient attention is paid
      to the rate and extent at which tissue concentrations respond to soil
      concentrations and soil characteristics. In this contribution the impact of soil
      characteristics on the environmental bioavailability of heavy metals for the
      oligochaete worm Eisenia andrei is reported. Uptake of As, Cd, Cr, Cu, Ni, Pb,
      and Zn in 20 Dutch field soils and in OECD artificial soil was quantified as a
      function of time. Internal metal concentrations varied less than the
      corresponding external levels. Metal uptake and elimination were both metal- and
      species-dependent. Worms typically attained steady-state concentrations rapidly
      for Cr, Cu, Ni, and Zn. Internal concentrations similar to those in the
      cultivation medium, linearly increasing body concentrations, or steady-state
      internal concentrations well above those in the cultivation medium were found for
      As, Cd, and Pb. Multivariate expressions were derived to describe uptake rate
      constants, steady-state concentrations, and bioaccumulation factors as a function
      of soil characteristics. Soil acidity is the most important solid-phase
      characteristic modulating the availability of As, Cd, and Pb. Although additional
      semimechanistic calculations yielded evidence of pore-water-related uptake of Cd
      and Pb modulated by competition between H(+) and metal ions at the active sites
      of the membranes, the findings for Cr, Cu, Ni, and Zn point to additional
      influences, among which is probably regulation.

PMID- 10581125
TI  - Acute toxicity of 2,4,6-trinitrotoluene in earthworm (Eisenia andrei).
AB  - 2,4,6-Trinitrotoluene (TNT) is an worldwide recalcitrant environmental
      contaminant and is toxic to a number of organisms including humans. This study
      examines the acute effects (lethal and biomass changes) of TNT on the
      oligochaetes species Eisenia andrei, using the 3-day filter paper, and the 7- and
      14-day direct contact spiked soil (OECD artificial and forest soil) toxicity
      tests. Studies using the filter paper test indicated that the lethality of TNT
      could be detected in the range 1.5 to 14.2 microg/cm(2), with significant biomass
      (body weight) changes occurring at the lowest concentration. Acute effects
      (lethality) could not be measured when earthworms were placed on filter paper
      containing a saturated aqueous solution of TNT. This may indicate that with these
      exposure conditions, TNT may have been adsorbed to the filter paper, and that
      this matrix should be saturated with TNT before becoming available to the
      earthworms. Spiked soil toxicity tests indicated that the E. andrei lethality by
      TNT was >1.5 times higher when earthworms were exposed to TNT-spiked forest soil
      (LOEC:260 mg/kg; LC(50) 14 days 222.4 mg/kg) than to spiked OECD artificial soil
      (LOEC:420 mg/kg; LC(50) 14 days: 364.9 mg/kg). The sublethal effect on biomass
      change at the selected TNT concentrations in soil was not significant compared to
      controls. Results indicate that the bioanalytical methods described in this
      article could be used as TNT toxicity assessment tools. This soil quality test
      method gives valuable information for the screening of soil toxicity.

PMID- 10581127
TI  - Papers to appear in environmental research section A

PMID- 10581128
TI  - Cumulative chemical index for volumes 42-44

PMID- 10581126
TI  - Intact and photomodified polycyclic aromatic hydrocarbons inhibit photosynthesis
      in natural assemblages of Lake Erie phytoplankton exposed to solar radiation.
AB  - Recently, there has been a trend toward less turbid water and greater light
      penetration in parts of western Lake Erie. This could lead to greater
      phototoxicity from sediment-bound polycyclic aromatic hydrocarbons. To test
      photosynthesis as a bioindicator of contaminant impacts on algae, water samples
      containing natural assemblages of phytoplankton were collected from the western
      and central basins of Lake Erie. These samples were incubated with 0.2 to 2 mg L(
      1) anthracene or its photomodified product 1, 2-dihydroxyanthraquinone for 60 min
      in darkness or in 50% sunlight, to mimic exposure of phytoplankton in the photic
      zone of a mixed water column. Photosynthetic efficiency was determined from
      filtered phytoplankton immediately after exposure using a pulse-amplitude
      modulated chlorophyll fluorometer. Phytoplankton incubated with chemicals in the
      dark demonstrated chlorophyll fluorescence values similar to those of controls.
      However, exposure to anthracene or 1, 2-dihydroxyanthraquinone in sunlight
      diminished photosystem II photosynthetic efficiency and photosynthetic quantum
      yield in a concentration-dependent manner. Anthracene inhibited photosynthesis at
      lower concentrations than 1,2-dihydroxyanthraquinone, which is consistent with
      the different modes of action and toxic strengths of these two contaminants.
      These results demonstrate that phytoplankton in Lake Erie can be subject to
      phototoxicity from intact and photomodified polycyclic aromatic hydrocarbons
      after very short exposures. Further, chlorophyll fluorescence was found to be an
      effective bioindicator in the field for this form of chemical stress.

PMID- 10581129
TI  - The merit of beta(1)-blockade in heart failure.

PMID- 10581130
TI  - Passive cigarette smoking increases risk of coronary heart disease.

PMID- 10581131
TI  - What is concealed in concealed accessory pathways?

PMID- 10581132
TI  - The effectiveness and timing of elective pharmacological cardioversion for
      paroxysmal atrial fibrillation.

PMID- 10581133
TI  - A plea for provisional stenting.

PMID- 10581134
TI  - Coronary angioplasty after the age of 80--why not dust where the dust is?

PMID- 10581135
TI  - Impact of smoking cessation and smoking interventions in patients with coronary
      heart disease.

PMID- 10581136
TI  - Stent implantation reduces restenosis in patients with suboptimal results
      following coronary angioplasty.
AB  - BACKGROUND: Primary intracoronary stenting reduces the rate of restenosis when
      compared with balloon angioplasty (PTCA) in selected patients. The strategy of
      PTCA followed by provisional stent placement for suboptimal PTCA results may be
      preferable to universal stenting but has not yet been tested in a randomized
      trial. METHODS: An attempt was made to obtain an optimal result with PTCA alone
      in 143 patients. Stenting was required in 50 patients (35%) for significant
      coronary dissection or PTCA failure. In the remaining 93 patients, the
      angiographic result was assessed immediately using on-line quantitative coronary
      angiography and classified as either optimal (<15% residual stenosis) or
      suboptimal (>/=15% residual stenosis). Sixteen patients (11%) had an optimal
      result from PTCA. The remaining 77 (54%) patients had a suboptimal result and
      were immediately randomized either to no further treatment or to the placement of
      a stent. The primary end-point was the rate of restenosis (>50% stenosis),
      assessed by quantitative coronary angiography, at 6 months. RESULTS: Angiographic
      follow-up was completed in 132 patients. Restenosis occurred in 53 (36,69)% of
      patients with a suboptimal result randomized to PTCA alone compared with 24
      (12,41)% of patients randomized to stent (P=0.023). There was no significant
      difference in minimal luminal diameter at follow-up between the randomized
      groups. The rate of restenosis was 14 (2,43)% in patients with an optimal PTCA
      result and 14 (5,28)% in those that required stenting. CONCLUSIONS: Optimal
      angiographic results following conventional PTCA are rare and the restenosis rate
      following suboptimal results is high. The strategy of stenting suboptimal results
      is associated with a significant reduction in the rate of stenosis.

PMID- 10581137
TI  - Coronary angioplasty in octogenarians. Quality of life and costs.
AB  - BACKGROUND: Improvement in quality of life is the major motivation for
      angioplasty in very elderly patients. The alleviation of symptoms with this
      method is therefore of particular interest. However, little is known about the
      impact of angioplasty in terms of quality of life in octogenarian patients and
      what the treatment costs are. METHODS AND RESULTS: We prospectively compared
      patients aged 80 years or above (n=34, 83+/-3 years) with younger patients (n=34,
      62+/-8 years) regarding their quality of life following coronary angioplasty.
      Patients were interviewed immediately following angioplasty and 6 months later
      using the SF-36 health survey. Key determinants of costs and follow-up for 6
      months were documented. The number of diseased vessels, interventions performed
      and number of lesions treated were comparable in both groups. Success rates were
      lower in the octogenarian than in the control group (88 vs 97%). In both groups
      angioplasty significantly improved the ability to fulfil physical role
      expectations and decreased bodily pain. Both the effects on Role Physical and on
      Bodily Pain were more pronounced in the octogenarian patients. Determinants of
      costs did not differ significantly between the two groups. CONCLUSIONS: Our data
      demonstrate that in octogenarians with symptomatic coronary heart disease,
      coronary angioplasty significantly increases physical abilities and decreases
      pain. Further, these effects were more pronounced in octogenarian patients than
      in younger patients.

PMID- 10581138
TI  - Plasma brain natriuretic peptide level as a biochemical marker of morbidity and
      mortality in patients with asymptomatic or minimally symptomatic left ventricular
      dysfunction. Comparison with plasma angiotensin II and endothelin-1.
AB  - AIMS: To evaluate the level of plasma brain natriuretic peptide as a predictor of
      morbidity and mortality in patients with asymptomatic or minimally symptomatic
      left ventricular dysfunction. METHODS: We measured plasma levels of atrial
      natriuretic peptide, brain natriuretic peptide, norepinephrine, angiotensin II,
      and endothelin-1 and monitored haemodynamic parameters in 290 consecutive
      patients with asymptomatic or minimally and newly symptomatic left ventricular
      dysfunction (functional classes I-II, mean left ventricular ejection
      fraction=37%). All patients were followed up for a median period of 812 days. The
      Cox proportional hazards model was used to assess the association of variables
      with mortality and morbidity. RESULTS: At the end of the follow-up, 24 patients
      had suffered cardiac death and 25 had been hospitalized for worsening heart
      failure during the follow-up period. Among 21 variables such as clinical
      characteristics, treatment, haemodynamics, and neurohumoral factors, high levels
      of plasma brain natriuretic peptide (P<0.0001), norepinephrine (P=0.042), left
      ventricular end-diastolic volume index (P=0.0035), and left ventricular end
      diastolic pressure (P=0.033) were shown to be independent predictors of mortality
      and morbidity by stepwise multivariate analysis. Moreover, only a high level of
      plasma brain natriuretic peptide (P<0.0001) was shown to be an independent
      predictor of mortality in these patients. CONCLUSIONS: These results indicate
      that a high plasma brain natriuretic peptide level provides information about
      mortality and morbidity in patients with asymptomatic or minimally symptomatic
      left ventricular dysfunction.

PMID- 10581139
TI  - Changes in the left ventricular outflow tract after transcoronary ablation of
      septal hypertrophy (TASH) for hypertrophic obstructive cardiomyopathy as assessed
      by transoesophageal echocardiography and by measuring myocardial glucose
      utilization and perfusion.
AB  - AIMS AND METHODS: Transcoronary ablation of septal hypertrophy (TASH) leads to
      marked clinical and haemodynamic improvement in patients with hypertrophic
      obstructive cardiomyopathy. In order to obtain more detailed information about
      changes in the outflow tract after TASH, transoesophageal echocardiography and a
      repeat invasive investigation were conducted before as well as 2 weeks and 6
      months after TASH (n=62). In a subset of patients (n=11), metabolism and
      perfusion of the myocardium ((18)F-FDG-PET and(99m)Tc-MIBI-SPET) were
      investigated. RESULTS: After TASH there was a typical regional subaortic
      contraction disorder. It was quantified by a significant decrease in the
      fractional shortening of the left ventricular end-diastolic diameter, which
      declined from an average of 40.6% to 18.0%. The end-diastolic diameter increased
      from an average of 39.1 to 40.6 mm. There was also a significant reduction in
      septal thickness, which continued for up to 6 months after TASH, from an average
      of 20.0 mm to 11.1 mm in the region of ablation and from 23. 2 to 21.7 mm outside
      this region. The decrease in the gradient post TASH corresponded with a
      concomitant significant increase in the outflow tract area from a mean value of
      1.04 cm(2)before the process to a value of 3.0 cm(2)after. In contrast to
      coronary heart disease, these changes were accompanied by non-diffuse, well
      demarcated subaortic-septal necrosis verified by(18)F-FDG-PET and(99m)Tc-MIBI
      SPET. On average the TASH induced necrotic area comprised 6.6% of the left
      ventricle and correlated significantly with echocardiographic changes in the
      outflow tract. CONCLUSIONS: Alterations post TASH indicated that this catheter
      interventional treatment for hypertrophic obstructive cardiomyopathy affects the
      specific region of obstruction. The changes reflect a 'therapeutic remodelling'
      of the outflow tract of the left ventricle. They were demonstrable over the
      entire 6 months investigation period and obviously constituted the basis of post
      TASH clinical and haemodynamic improvement. Progressive alterations post TASH
      (post TASH reduction of subaortic septal thickness and an increase in the end
      diastolic diameter) need special consideration during long-term follow up.

PMID- 10581140
TI  - Local slow potential preceding the surface QRS complex detected at the
      subvalvular mitral annulus in patients with a left-sided concealed accessory
      pathway. Incidence, electrophysiological characteristics and the possible
      mechanism, with demonstration of anterograde concealed conduction through the
      pathway.
AB  - AIM: We sought to evaluate the incidence and electrophysiological features of the
      local slow potential preceding the surface QRS complex (pre-QRS potential) which
      was detected more frequently at successful sites of catheter ablation of left
      parietal concealed accessory pathways, than at unsuccessful sites. METHODS AND
      RESULTS: Thirty eight consecutive patients with a single left sided concealed
      accessory pathway underwent radiofrequency catheter ablation exclusively from the
      subvalvular mitral annulus. The local bipolar electrograms during sinus rhythm
      from the target sites were carefully analysed and the incidence of pre-QRS
      potentials was compared between successful and unsuccessful ablation sites. All
      ablation sessions attained a successful outcome with a total of 84 radiofrequency
      current applications (38 at successful sites, 46 at unsuccessful sites). The
      incidence of pre-QRS potentials (preceding by 10 ms or more) was 12/38 at
      successful sites (32%) and 1/46 at unsuccessful sites (2%) (P<0.001). The QV
      interval, defined as the interval between the upstroke of the QRS complex and the
      ventricular electrogram, including the pre-QRS potential, was -5.6+/-9.1 ms at
      successful sites, while it was 1.2+/-6.1 ms at unsuccessful sites (P<0.001). The
      pre-QRS potential disappeared during atrioventricular reciprocating tachycardia
      and right ventricular pacing, and was eliminated by successful ablation.
      CONCLUSIONS: Detection of the pre-QRS potential was clinically relevant and could
      be distinguished from artifact. This potential may be caused by anterograde
      concealed conduction through the accessory pathways.

PMID- 10581141
TI  - Radiofrequency catheter ablation of accessory pathways. Outcome and use of
      antiarrhythmic drugs during follow-up.
AB  - AIMS: The purpose of this study was to assess the acute and long-term success of
      accessory pathway ablation in a single large-volume centre, concentrating on long
      term recurrences and the clinical use of antiarrhythmic drugs. METHODS AND
      RESULTS: A total of 519 consecutive patients (mean age 40+/-14 years) underwent
      radiofrequency ablation of manifest or concealed accessory pathways. The patients
      were seen in the hospital or by the referring physician at 6 and 12 months. Long
      term follow-up information was obtained by questionnaire. Pathway conduction was
      abolished in 476 cases (91.7%). 'Redo' procedures, due to recurrence, were
      performed in 38 patients (7.3%) and were successful in 30 (78.9%). Follow-up data
      were obtained from 454 patients (87.5%) with a follow-up duration of 22. 6+/-12.4
      months. Among the 398 patients with successful ablations who responded to the
      questionnaire, 340 (85.4%) were asymptomatic with only 10.6% taking
      antiarrhythmic drugs. An additional 20 patients (5.0%) had symptoms suspicious of
      recurrence. In total, 66 out of 398 successfully treated patients (16.6%) were
      taking antiarrhythmic drugs. Twenty-three out of 56 (41.1%) patients with failed
      ablations were asymptomatic, 12 of whom (21.4% of patients with failed ablations)
      had not been administered antiarrhythmic drugs. In the total group of 454
      patients with ablation attempts and available follow-up data, 99 (21.8%) were
      still taking antiarrhythmic drugs during follow-up. CONCLUSIONS: Patients with
      successful ablation of accessory pathways show excellent long-term results.
      However, 17% of successfully treated patients were still taking antiarrhythmic
      drugs during the period of long-term follow-up. On the other hand, 21% of
      patients with failed ablations were symptom-free without antiarrhythmic drugs. On
      an intention-to-treat basis, 22% of the patients with ablation attempts were
      still taking antiarrhythmic drugs during follow-up.

PMID- 10581142
TI  - Conversion of recent onset paroxysmal atrial fibrillation to normal sinus rhythm:
      the effect of no treatment and high-dose amiodarone. A randomized, placebo
      controlled study.
AB  - BACKGROUND: Spontaneous conversion of recent onset paroxysmal atrial fibrillation
      to normal sinus rhythm occurs commonly and is not affected by low-dose amiodarone
      treatment. METHODS: In a randomized, placebo-controlled trial of 100 patients
      with paroxysmal atrial fibrillation of recent onset (<48 h) we compared the
      effects of treatment with continuous intravenous amiodarone 125 mg per hour
      (total 3 g) and intravenous placebo. Patients in the placebo group who did not
      convert to normal sinus rhythm within 24 h were started on amiodarone therapy.
      RESULTS: Conversion to normal sinus rhythm occurred within 24 h in 32 of 50
      patients (64%) in the placebo group, most of whom converted within 8 h. Lower
      conversion rates were observed in patients with hypertension, ischaemic heart
      disease or congestive heart failure and in patients with echocardiographic
      findings of left atrial diameter above 45 mm, ejection fraction below 45% or
      significant mitral regurgitation. However, in most patients these clinical or
      echocardiographic risk factors of decreases in conversion rate were not present.
      In such patients the spontaneous conversion rate was approximately 90%. The
      conversion rate during 24 h of treatment in the amiodarone group was 92%
      (P=0.0017, compared to the placebo group). In this group, the conversion rate was
      largely unaffected by baseline characteristics. Of the 18 patients who did not
      convert with placebo, 15 (85%) converted after being crossed over to amiodarone.
      All patients not responding to high-dose amiodarone were in chronic atrial
      fibrillation within 1 month. In patients still in atrial fibrillation after 8 h
      of treatment, the pulse rate decreased significantly more in the amiodarone as
      compared to the placebo group (83+/-15 vs 114+/-20 beats. min(-1), P=0.0014).
      CONCLUSION: The spontaneous conversion of recent onset paroxysmal atrial
      fibrillation is high and approaches 90% in specific clinical and
      echocardiographically defined subgroups. Intravenous high-dose amiodarone safely
      facilitates conversion of paroxysmal atrial fibrillation. However, such treatment
      should be reserved for patients with unfavourable risk factor profiles, not
      converting during 8 h of observation or requiring rate control.

PMID- 10581143
TI  - Sporadic cases of dilated cardiomyopathies associated with atrioventricular
      conduction defects are not linked to mutation within the connexins 40 and 43
      genes.

PMID- 10581144
TI  - Cardiac rehabilitation.

PMID- 10581145
TI  - Lipoprotein (a) concentrations in Greek hyperlipidaemic patients: relationship to
      serum lipid parameters.

PMID- 10581146
TI  - Inadequate blood pressure control in 'low risk' Mediterranean population.

PMID- 10581147
TI  - The guanylyl cyclase receptors.

PMID- 10581148
TI  - Studying the structure and regulation of soluble guanylyl cyclase.
AB  - Soluble guanylyl cyclase acts as the receptor for the signaling molecule nitric
      oxide. The enzyme consists of two different subunits. Each subunit shows the
      cyclase catalytic domain, which is also conserved in the membrane-bound guanylyl
      cyclases and the adenylyl cyclases. The N-terminal regions of the subunits are
      responsible for binding of the prosthetic heme group of the enzyme, which is
      required for the stimulatory effect of nitric oxide (NO). The five-coordinated
      ferrous heme displays a histidine as the axial ligand; activation of soluble
      guanylyl cyclase by NO is initiated by binding of NO to the heme iron and
      proceeds via breaking of the histidine-to-iron bond. Recently, a novel
      pharmacological and possibly physiological principle of guanylyl cyclase
      sensitization was demonstrated. The substance YC-1 has been shown to activate the
      enzyme independent of NO, to potentiate the effect of submaximally effective NO
      concentrations, and to turn carbon monoxide into an effective activator of
      soluble guanylyl cyclase.

PMID- 10581149
TI  - Activation of soluble guanylate cyclase by carbon monoxide and nitric oxide: a
      mechanistic model.
AB  - Soluble guanylate cyclase (GC) from bovine lung is activated 4-fold by carbon
      monoxide (CO) and 400-fold by nitric oxide (NO). Spectroscopic and kinetic data
      for ligation of CO and NO with GC are summarized and compared with similar data
      for myoglobin (Mb), hemoglobin (Hb), and heme model compounds. Kinetic,
      thermodynamic, and structural data form a basis on which to construct a model for
      the manner in which the two ligands affect protein structure near the heme for
      heme proteins in general and for GC in particular. The most significant datum is
      that although association rates of ligands with GC are similar to those with Mb
      and Hb, their dissociation rates are dramatically faster. This suggests a
      delicate balance between five- and six-coordinate heme iron in both NO and CO
      complexes. Based on these and other data, a model for GC activation is proposed:
      The first step is formation of a six-coordinate species concomitant with tertiary
      and quaternary structural changes in protein structure and about a 4-fold
      increase in enzyme activity. In the second step, applicable to NO, the bond from
      iron to the proximal histidine ruptures, leading to additional relaxation in the
      quaternary and tertiary structure and a further 100-fold increase in activity.
      This is the main event in activation, available to NO and possibly other
      activators or combinations of activators. It is proposed, finally, that the
      proximal base freed in step 2, or some other protein base suitably positioned as
      a result of structural changes following ligation, may provide a center for
      nucleophilic substitution catalyzing the reaction GTP --> cGMP. An example is
      provided for a similar reaction in a derivatized protoheme model compound. The
      reaction mechanism attempts to rationalize the relative enzymatic activities of
      GC, heme-deficient GC, GC-CO, and GC-NO on a common basis and makes predictions
      for new activators that may be discovered in the future.

PMID- 10581150
TI  - Identification and characterization of the phosphorylation sites of the guanylyl
      cyclase-linked natriuretic peptide receptors A and B.
AB  - The binding of atrial natriuretic peptide and C-type natriuretic peptide to the
      guanylyl cyclase-linked natriuretic peptide receptors A and B (NPR-A and NPR-B),
      respectively, results in decreases in extracellular volume, vascular tension and
      cell proliferation. Both NPR-A and NPR-B are extensively phosphorylated in
      resting cells and receptor dephosphorylation is correlated with ligand-induced
      homologous desensitization. To understand the role of phosphorylation in the
      regulation of these receptors, we identified the in vivo phosphorylation sites of
      NPR-A and NPR-B and found that the phosphorylation of multiple sites within their
      kinase homology domains is absolutely required for their activation. In this
      review, we give a detailed description of the phosphopeptide mapping techniques
      that were used to identify and characterize these sites and discuss the potential
      pitfalls that are associated with them.

PMID- 10581151
TI  - Regulation of photoreceptor membrane guanylyl cyclases by guanylyl cyclase
      activator proteins.
AB  - Guanylyl cyclase (GC) plays a central role in the responses of vertebrate rod and
      cone photoreceptors to light. cGMP is an internal messenger molecule of
      vertebrate phototransduction. Light stimulates hydrolysis of cGMP, causing the
      closure of cGMP-dependent cation channels in the plasma membranes of
      photoreceptor outer segments. Light also lowers the concentration of
      intracellular free Ca(2+) and by doing so it stimulates resynthesis of cGMP by
      guanylyl cyclase. The guanylyl cyclases that couple Ca(2+) to cGMP synthesis in
      photoreceptors are members of a family of transmembrane guanylyl cyclases that
      includes atrial natriuretic peptide receptors and the heat-stable enterotoxin
      receptor. The photoreceptor membrane guanylyl cyclases, RetGC-1 and RetGC-2 (also
      referred to as GC-E and GC-F), are regulated intracellularly by two Ca(2+)
      binding proteins, GCAP-1 and GCAP-2. GCAPs bind Ca(2+) at three functional EF
      hand structures. Several lines of biochemical evidence suggest that guanylyl
      cyclase activator proteins (GCAPs) bind constitutively to an intracellular domain
      of RetGCs. In the absence of Ca(2+) GCAP stimulates and in the presence of Ca(2+)
      it inhibits cyclase activity. Proper functioning of RetGC and GCAP is necessary
      not only for normal photoresponses but also for photoreceptor viability since
      mutations in RetGC and in GCAP cause photoreceptor degeneration.

PMID- 10581152
TI  - Dominant negative mutants of guanylyl cyclase: probes for global functions and
      intramolecular mechanisms.
AB  - Dominant negative mutants are unique tools to define functions of a protein, not
      only within complex cellular and organismal contexts, but also mechanistically
      within a protein. Guanylyl cyclases are amenable to studies with dominant
      negative mutants, with their own sets of opportunities for insight and pitfalls
      to overcome. Membrane and soluble forms of guanylyl cyclase represent self
      contained signal transduction modules that recognize, transduce, and amplify an
      external signal to give a carefully controlled response. Beginning with
      recognition of peptide hormones versus nitric oxide, membrane and soluble
      guanylyl cyclases are considerably different, except that their catalytic domains
      are closely related. Studies on these catalytic domains and their counterparts in
      adenylyl cyclases have raised an integral question of whether one or two domains
      form a catalytic site, which remains unresolved. Regardless of which model is
      correct, guanylyl cyclases appear to require an oligomeric state to function
      properly. The inferred relationship between protein-protein interaction and
      function is the basis for developing dominant negative mutants, which can be
      designed without prior structural information. Soluble guanylyl cyclases exist in
      a heterodimeric state, whereas membrane guanylyl cyclases are homodimeric, or
      possibly higher-order oligomers. These properties dictate that dominant negative
      mutants of membrane and soluble guanylyl cyclases be approached in fundamentally
      different ways, with regard to their design, their functional consequences, and
      their limitations. Using dominant negative mutants as specific inhibitors in
      complex systems, such as transgenic animals, represents a significant advance,
      and continuing improvements are just an inkling of the extraordinary potential of
      this approach. For example, the function of a protein can be obscured because it
      is expressed in multiple cell types; by restricting its pattern of expression, a
      cell-specific promoter, coupled to a dominant negative mutant, can pinpoint this
      function. As more sophisticated methods are developed, dominant negative mutants
      will provide additional opportunities to unveil new regulatory mechanisms, new
      signaling pathways, or even new therapeutic approaches.

PMID- 10581153
TI  - Conversion of a guanylyl cyclase to an adenylyl cyclase.
AB  - Guanylyl cyclases catalyze the formation of cGMP from GTP, but display extensive
      identity at the catalytic domain primary amino acid level with the adenylyl
      cyclases. The recent solving of the crystal structures of soluble forms of
      adenylyl cyclase has resulted in predictions of those amino acids important for
      substrate specificity. Modeling of a membrane-bound homodimeric guanylyl cyclase
      predicted the comparable amino acids that would interact with the guanine ring.
      Based on these structural data, the replacement of three key residues in the
      heterodimeric form of soluble guanylyl cyclase has led to a complete conversion
      in substrate specificity. Furthermore, the mutant enzyme remained fully sensitive
      to sodium nitroprusside, a nitric oxide donor.

PMID- 10581154
TI  - Targeted gene disruption in the development of mouse models to elucidate the role
      of receptor guanylyl cyclase signaling pathways in physiological function.
AB  - The physiological role of receptor guanylyl cyclases (GCs), which transduce a
      signal via the generation of intracellular cyclic GMP, has been somewhat
      speculative since there are few specific inhibitors that discriminate among
      various receptor isoforms. Although the natriuretic peptide receptors have been
      thought to regulate cardiovascular and renal function, the exact contribution of
      the receptor subtypes has not been clarified. The normal role of the heat-stable
      enterotoxin receptor guanylyl cyclase remains undefined, and several orphan
      members of the family await the identification of ligands as well as function.
      Targeted gene disruption, familiarly known as gene knockout, has emerged during
      the past decade as a powerful technique for probing the function of gene
      products, and has been used to develop animal models of inherited human diseases.
      We are just beginning to apply gene targeting technology to the guanylyl cyclase
      receptor family. Reviewed here is the information gained to date from the
      targeted disruption of several members of the guanylyl cyclase receptor family,
      their ligands, or effector molecules.

PMID- 10581155
TI  - Regulation of stearoyl-CoA desaturase genes: role in cellular metabolism and
      preadipocyte differentiation.
AB  - The degree of fatty acid unsaturation in cell membrane lipids determines membrane
      fluidity, whose alteration has been implicated in a variety of disease states
      including diabetes, obesity, hypertension, cancer, and neurological and heart
      diseases. Stearoyl-CoA desaturase (SCD) is a key rate-limiting enzyme in the
      synthesis of unsaturated fatty acids by insertion of a cis-double bond in the
      Delta9 position of fatty acid substrates. Palmitate and stearate are the
      preferred substrates, which are converted to palmitoleate and oleate,
      respectively. These monounsaturated fatty acids are the major constituents of
      cellular membrane phospholipids and triacylglycerol stores found in adipose
      tissue. Two mouse and rat SCD genes (SCD1 and SCD2) have been cloned and
      characterized. During the differentiation of 3T3-L1 preadipocytes into
      adipocytes, SCD1 and SCD2 mRNAs are induced concomitant with increased de novo
      synthesis of palmitoleate and oleate. The physiological significance of
      expressing the two isoforms in the adipocytes is currently unknown. In this
      review we discuss the role of the SCD isoforms in metabolism and the recent
      findings on the differential regulation of mouse SCD genes by the antidiabetic
      thiazolidinediones (TZDs), during preadipocyte differentiation.

PMID- 10581156
TI  - Identification of a mineralocorticoid/glucocorticoid response element in the
      human Na/K ATPase alpha1 gene promoter.
AB  - Sodium-potassium ATPase (Na/K ATPase) is a major target of mineralocorticoids.
      Both aldosterone and glucocorticoids activate the human Na/K ATPase alpha1 and
      beta1 genes transcriptionally. The mineralocorticoid receptor (MR) and the
      glucocorticoid receptor (GR) have been shown to bind the glucocorticoid response
      element (GRE); however, a specific element responsible for the activation of the
      MR is not known. Sequence analysis of the putative regulatory region of the Na/K
      ATPase alpha1 gene revealed the presence of a hormone response element that
      allows the MR to interact with it, at least as well as if not better than the GR.
      This response element is designated MRE/GRE. In this investigation, we
      demonstrated the MR and GR induced gene expression in COS-1 cells by
      cotransfecting with respective expression plasmids (RshMR and RshGR) along with a
      luciferase reporter. The synthetic MRE/GRE linked to a neutral promoter was
      activated by MR (6-fold); however, the GR induced a lower level of expression
      (3.8-fold), suggesting that the element may be preferably MR responsive.
      Mutations in the synthetic MRE/GRE could not induce the expression with MR,
      whereas GR had a small effect. Electrophoretic mobility shift analyses
      demonstrated a direct interaction of MR and GR with the MRE/GRE that was
      supershifted by an antiMR antibody and the complex was partially cleared by an
      antiGR antibody, respectively, whereas nonimmune serum had no effect.
      Footprinting analyses of the promoter region showed that a portion of the DNA
      containing this element is protected by recombinant MR and GR. Thus these data
      confirm that this MRE/GRE interacts with both MR and GR but interaction with
      receptors may be more MR-responsive than response elements previously described.

PMID- 10581157
TI  - TSH control of PKA catalytic subunit activity in thyroid cell cultures.
AB  - The protein expression and the enzyme activity of the catalytic subunit (C) of
      the cAMP-dependent protein kinases were studied in porcine thyroid cell primary
      cultures stimulated with two doses of TSH (0.1 mU/ml and 1 mU/ml) for 1 to 3
      days. In TSH-stimulated cells the desensitization of the catalytic subunit
      activity was accompanied by a simultaneous and parallel decrease of its
      immunoreactivity. The loss of catalytic subunit was rapid and reached its maximum
      after 1 day of culture. It is similar in the two subcellular compartments:
      cytosol and particulate extracts. Contrary to the observed loss of the C subunit
      protein molecules in TSH-stimulated cells, the expression of the Cbeta subunit
      mRNA in these cells was increased fivefold compared to controls, while no
      significant change was observed on the Calpha subunit mRNA. These results suggest
      that TSH controls the Cbeta subunits of PKA at two levels: at the transcriptional
      level it increases Cbeta mRNA expression, and at the translational or
      posttranslational level TSH decreases the amount and the activity of the Cbeta
      protein molecules.

PMID- 10581158
TI  - Recombinant soluble human CD69 dimer produced in Escherichia coli: reevaluation
      of saccharide binding.
AB  - We reevaluate here an earlier report of monosaccharide binding by the C-type
      lectin-like, leukocyte surface protein CD69 in the form of a recombinant soluble
      dimer, and we examine polysaccharide binding by the protein. We have expressed in
      Escherichia coli a new construct of the extracellular part (Q(65)-K(199)) of
      human CD69. We describe the folding in vitro to produce, in good yield, the
      protein in a soluble, disulphide-linked, dimeric form, and the results of binding
      experiments with monosaccharides: glucose, galactose, mannose, fucose, N
      acetylglucosamine, and N-acetylgalactosamine, linked to bovine serum albumin.
      Monosaccharide-binding signals are not detectable. Among the polysaccharides,
      heparin, chondroitin sulphates A, B, and C, fucoidan, and dextran sulphate, CD69
      dimer gives a weak binding signal with fucoidan.

PMID- 10581159
TI  - Interaction between GPIbalpha and FcgammaIIA receptor in human platelets.
AB  - Glycoprotein (GP) Ib (alpha and beta) in platelets forms a noncovalent hetero
      oligomeric complex with GPIX and GPV and serves as a receptor for von Willebrand
      factor (vWF), which mediates the initial adhesion of platelets to the
      subendothelium after vascular damage and also plays a role in thrombin-induced
      platelet activation. We investigated the interaction between GPIbalpha and
      FcgammaIIA receptor using a yeast two-hybrid system and mutagenesis, and we
      identified residues R542G543R544 in GPIbalpha and D298D299D300 in FcgammaIIA
      receptor as the primary interaction sites. These results further confirmed the
      interaction between GPIbalpha and FcgammaIIA receptor and support the hypothesis
      that the signal transduction of GPIb-IX-V that leads to platelet activation may
      be partially mediated through FcgammaIIA receptor.

PMID- 10581160
TI  - A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin
      and Tcf-mediated gene expression.
AB  - Upon binding of a Wnt to its receptor, GSK3beta is inhibited through an unknown
      mechanism involving Dishevelled (Dsh), resulting in the dephosphorylation and
      stabilization of beta-catenin, which translocates to the nucleus and interacts
      with Lef/Tcf transcription factors to activate target gene expression. Axin is a
      scaffold protein which binds beta-catenin and GSK3beta (as well as several other
      proteins) and thus promotes the phosphorylation of beta-catenin. Here we report
      that Axin is phosphorylated on Ser and Thr residues in several regions in vivo,
      while only one region (amino acids 600-672) is efficiently phosphorylated by
      GSK3beta in vitro. Site-directed mutagenesis, together with in vitro and in vivo
      phosphorylation assays, demonstrates that Axin residues T609 and S614 are
      physiological GSK3beta targets. Substitutions for one or more of these residues,
      which lie within a beta-catenin binding site, reduce the ability of Axin to
      modulate Wnt-induced signaling in a Lef/Tcf reporter assay. These amino acid
      substitutions also reduce the binding between Axin and beta-catenin. We propose a
      model in which inhibition of GSK3beta activity upon Wnt signaling leads to the
      dephosphorylation of GSK3beta sites in Axin, resulting in the release of beta
      catenin from the phosphorylation complex.

PMID- 10581161
TI  - Platelet-activating factor induction of secreted phosphatase activity in
      Trypanosoma cruzi.
AB  - The effects of platelet-activating factor (PAF) on the ecto-phosphatase activity
      of Trypanosoma cruzi were investigated. Living parasites hydrolyzed p-nitrophenyl
      phosphate (p-NPP) at a rate of 5.71 +/- 0.37 nmol P(i) mg(-1) min(-1). This ecto
      phosphatase activity increased to 8.70 +/- 1.12 nmol P(i) mg(-1) min(-1) when the
      cells were grown in the presence of 10(-9) M PAF. This effect was probably due to
      stimulation of the release of the ecto-phosphatase and/or the secretion of an
      intracellular phosphatase to the extracellular medium, as suggested by
      cytochemical analysis. Modulation of the ecto-phosphatase activity was also
      observed when PAF was added during the time course of the reaction. WEB 2086, a
      competitive PAF antagonist, was able to revert PAF effects when both were used at
      the same concentration. When PAF was added to a membrane enriched fraction
      preparation of T. cruzi, no alteration on the phosphatase activity was observed.
      This result suggests an involvement of intracellular signaling, as PAF was only
      effective on intact cells. Sphingosine and phorbol-12-myristate-13-acetate (PMA)
      were then used to investigate a possible involvement of protein kinase C (PKC)
      with PAF-induced phosphatase secretion. Sphingosine by itself stimulated the
      secretion of a phosphatase but did not significantly interfere with PAF effects
      on this enzyme. On the other hand, PMA was able to abrogate PAF-induced release
      of this phosphatase. These data are highly suggestive of a putative involvement
      of signal transduction mediated by a ligand of mammalian origin (PAF), through
      PKC and a specific receptor located on the cell surface of the human parasite
      Trypanosoma cruzi.

PMID- 10581162
TI  - An important von Hippel-Lindau tumor suppressor domain mediates Sp1-binding and
      self-association.
AB  - VHL is the causative gene for both von Hippel-Lindau (VHL) disease and sporadic
      clear-cell renal cancer. We showed earlier that VHL downregulates vascular
      endothelial growth factor transcription by directly binding and inhibiting the
      transcriptional activator Sp1. We have now mapped the VHL Sp1-binding domain to
      amino acids 96-122. The 96-122 domain is disproportionately affected by
      substitution mutations, which interfere with the VHL-Sp1 interaction. Deletion of
      the 96-122 domain prevents VHL effects on Sp1 DNA binding and on VHL target gene
      expression, indicating the domain contributes importantly to VHL tumor suppressor
      activity. Nevertheless, prevention of the VHL-Sp1 interaction only partially
      abrogates VHL's transcriptional repressor activity, supporting the existence of
      VHL transcriptional effectors in addition to Sp1. VHL also directly interacts
      with the Sp1 zinc fingers and self-associates via the 96-122 domain, which
      furthermore suggest the domain may bind other metalloproteins and contribute to
      VHL dominant-negative effects.

PMID- 10581163
TI  - Internalization of factor J and cellular signalization after factor J-cell
      interaction.
AB  - Factor J (FJ) is a cationic glycoprotein with inhibitory activity in vitro
      against both classical and alternative pathways of complement activation.
      Recently FJ has been implicated in adhesion to several cell lines, through a
      membrane receptor identified as nucleolin. In the present work we study the
      events that follow the binding of FJ to cells. After incubation of K562 with FJ,
      this protein was internalized actively and localized in the cytoplasm and
      nucleus. Adhesion to immobilized FJ induced tyrosine phosphorylation of several
      intracellular proteins in Jurkat cell line with a similar pattern to that induced
      by fibronectin (FN), an extracellular matrix protein. This effect was maximal at
      5 min and decreased after 10 min, and inhibited by anti-FJ monoclonal antibody
      (mAb). These results suggest that the binding of FJ to cells may play an
      important role in transduction of biochemical signals across the plasma membrane
      to the cell interior.

PMID- 10581164
TI  - Nucleotide binding drives conformational changes in the isolated alpha and beta
      subunits of the F(1)-ATPase from Escherichia coli.
AB  - The modeling of the rotatory mechanism performed by the F(1)-ATPase complex
      during ATP synthesis shows that the beta, but not the alpha subunit, undergoes
      large conformational changes that depend on the occupancy of the catalytic site.
      Here we determined by fluorescence spectroscopy the changes in tertiary structure
      and hydrophobic exposed area of the isolated alpha and beta subunits of the F(1)
      ATPase complex from Escherichia coli upon adenine nucleotide binding. The results
      show that in the absence of intersubunit contacts, the two subunits exhibit
      markedly similar conformational movements.

PMID- 10581165
TI  - Efficient discovery of inhibitory ligands for diverse targets from a small
      combinatorial chemical library of chimeric molecules.
AB  - Living systems are mainly composed and regulated by compounds in four biochemical
      classes and their polymers-nucleotides, carbohydrates, lipids, and amino acids.
      Early combinatorial chemistry libraries consisted of peptides. The present report
      describes the general bioactivity and biophysical properties of a combinatorial
      chemical library that used glyco, nucleotidyl, and lipid building blocks. The
      resulting chimeric combinatorial library of 361 compounds had a confirmed
      cumulative hit rate of 0.16%, which is 8-fold higher than a commonly claimed
      industrial benchmark of 0. 02%. It produced 7 structurally confirmed hits for a
      third of 12 proprietary drug discovery projects, and these comprised a variety of
      molecular targets. Diversity analyses demonstrated that despite the small number
      of compounds, a wider range of diversity space was covered by this library of
      biochemical chimeras than by a branched tripeptide library of the same size and
      similar generic formula.

PMID- 10581166
TI  - Compositional correlation studies among the three different codon positions in 12
      bacterial genomes.
AB  - Compositional distributions in the three codon positions of the coding sequences
      of 12 fully sequenced prokaryotic genomes, which are publicly available, were
      investigated. A universal compositional correlation was observed in most of the
      genomes under investigation irrespective of their overall genomic GC contents. In
      all the genomes, the GC contents at the first codon positions are always greater
      than the overall GC contents of the genomes whereas the reverse is true in the
      case of second codon positions. GC contents at the third codon positions are
      higher than the overall genomic GC contents in high GC containing genomes, and
      the opposite situation was found in case of low GC genomes except for
      Helicobacter pylori. In high-GC rich genomes, the GC contents at the first +
      second codon positions are less than the GC contents at the third codon
      positions, and they are low in low-GC genomes except for Helicobacter pylori. The
      distributions of four bases at the three different positions were also
      investigated for all 12 organisms. It was observed that in high-GC genomes G is
      the most dominant base and in low-GC genomes A is the most dominant base in the
      first codon positions. But purine bases, i.e., (A + G), predominantly occur in
      the first codon position. In the second codon position, A is the most dominant
      base in most of the organisms and G is the least dominant base in all the
      organisms. There is no unique regular pattern of individual bases at the third
      codon positions; however, there are significant differences in the occurrences of
      (G + C) contents in the third codon positions among the different organisms.
      Calculations of dinucleotide frequencies in 12 different organisms indicate that
      in GC-rich genomes GG, GC, CC, and CG dinucleotides are the most dominant whereas
      the reverse is true in case of low-GC genomes. Biological implications of these
      results are discussed in this paper.

PMID- 10581167
TI  - Oxalate-induced and cell-cycle-dependent expression of nuclear pore complex
      oxalate binding protein gp210.
AB  - The effect of oxalate, a constituent of renal stone, on the expression of nuclear
      pore complex oxalate binding protein (gp210) in Vero monkey kidney cells was
      examined. The expression of this protein was found to increase more in mitotic
      phase than in S phase, suggesting cell cycle dependency. Exposure of cells to
      oxalate-containing growth medium resulted in a relative increase in nuclear pore
      complex oxalate binding protein in each stage of cell cycle. The concentration of
      this protein was found to increase six times in the telophase stage of the cells
      exposed to high concentrations of oxalate in the growth medium, though slight
      reduction in cell density was observed. Structural analogues of oxalate did not
      show any stimulatory effect on expression of this oxalate binding protein. Hence,
      the expression of the nuclear pore complex oxalate binding protein gp210 was
      specific to oxalate and is cell cycle dependent.

PMID- 10581168
TI  - Modulation of cIAP-1 by novel antitubulin agents when combined with bryostatin 1
      results in increased apoptosis in the human early pre-B acute lymphoblastic
      leukemia cell line Reh.
AB  - Previous studies have shown that bryostatin 1 induces a decrease in the
      expression of the antiapoptotic protooncogene Bcl-2 in the human acute
      lymphoblastic leukemia (ALL) cell line Reh. This down-regulation has been shown
      to reduce drug resistance of the Reh cells to anti-tubulin polymerization agents.
      In the present study we investigated the effect of bryostatin 1 alone and in
      combination with novel anti-tubulin agents (dolastatin 10 and auristatin PE) and
      the chemotherapeutic vincristine on the inhibitor of apoptosis protein cIAP-1.
      Cells were cultured with bryostatin 1 (1 nM), dolastatin 10 (0.1 ng/ml),
      auristatin PE (0.1 ng/ml), or vincristine (0.5 ng/ml) alone or the combination of
      these anti-tubulins with bryostatin 1. Western blots were conducted to assess the
      effects of the above agents on cIAP-1 protein level. Flow-cytometric analysis [7
      amino-actinomycin D (7AAD)] was conducted to assess apoptosis as well as staining
      for morphology using tetrachrome stain. Our results show that cIAP-1 is induced
      in a time-dependent fashion after bryostatin 1 exposure up to 72 h. However, upon
      treatment of cells with a combination of bryostatin 1 and dolastatin 10 or
      auristatin PE, the induction of cIAP-1 was abolished, leading to a significant
      increase in apoptosis. The initial 24- and 48-h reduction in cIAP-1 protein level
      recorded in the bryostatin 1 and vincristine combination recovered to control
      levels by 72 h. We believe that this phenomenon is responsible for the reduced
      apoptosis recorded in this combination. Results of this study should prove useful
      in guiding the clinical application of these novel agents in the treatment of
      ALL.

PMID- 10581169
TI  - A new member of a hepatoma-derived growth factor gene family can translocate to
      the nucleus.
AB  - Hepatoma-derived growth factor (HDGF) and HDGF-related proteins (HRP) belong to a
      gene family with a well-conserved amino acid sequence at the N-terminus (the hath
      region). A new member of the HDGF family in humans and mice was identified and
      cloned; we call it HRP-3. The deduced amino acid sequence from HRP-3 cDNA
      contained 203 amino acids without a signal peptide for secretion. HRP-3 has its
      97-amino-acid sequence at the N-terminus, which is highly conserved with the hath
      region of the HDGF family proteins. It also has a putative bipartite nuclear
      localizing signal (NLS) sequence in a similar location in its self-specific
      region of HDGF and HRP-1. Northern blot analysis shows that HRP-3 is expressed
      predominantly in the testis and brain, to an intermediate extent in the heart,
      and to a slight extent in the ovaries, kidneys, spleen, and liver in humans.
      Transfection of green fluorescent protein (GFP)-tagged HRP-3 cDNA showed that HRP
      3 translocated to the nucleus of 293 cells. GFP-HRP-3 transfectants significantly
      increased their DNA synthesis more than cells transfected with vector only. The
      HRP-3 gene was mapped to chromosome 15, region q25 by FISH analysis. These
      findings suggest that a new member of the HDGF gene family, HRP-3, may function
      mainly in the nucleus of the brain, testis, and heart, probably for cell
      proliferation.

PMID- 10581170
TI  - The novel neuropeptide Y Y(1) receptor antagonist J-104870: a potent feeding
      suppressant with oral bioavailability.
AB  - Neuropeptide Y (NPY) is known to induce robust feeding through the action of NPY
      receptors in the hypothalamus. Among the subtypes of NPY receptors, Y(1)
      receptors may play a key role in feeding regulation. In the present study, we
      demonstrated that a novel Y(1) antagonist, J-104870, shows high selectivity and
      potency for the Y(1) receptor with an anorexigenic effect on NPY-mediated
      feeding. J-104870 displaced [(125)I]peptide YY (PYY) binding to cloned human and
      rat Y(1) receptors with K(i) values of 0.29 and 0.54 nM, respectively, and
      inhibited the NPY (10 nM)-induced increase in intracellular calcium levels
      (IC(50) = 3.2 nM) in cells expressing human Y(1) receptors. In contrast, J-104870
      showed low affinities for human Y(2) (K(i) > 10 microM), Y(4) (K(i) > 10 microM),
      and Y(5) receptors (K(i) = 6 microM). In rat hypothalamic membranes, J-104870
      also completely displaced the binding of [(125)I]1229U91, which is known to bind
      to the typical Y(1) receptor, with a high affinity (K(i) = 2.0 nM).
      Intracerebroventricular (ICV) injection of J-104870 (200 microg) significantly
      suppressed NPY (5 microg)-induced feeding in satiated Sprague-Dawley rats by 74%.
      Furthermore, ICV and oral administration of J-104870 (200 microg and 100 mg/kg,
      respectively) significantly suppressed spontaneous food intake in Zucker fatty
      rats. These findings suggested that J-104870 is a selective and potent nonpeptide
      Y(1) antagonist with oral bioavailability and brain penetrability. In addition,
      the anorexigenic effect of J-104870 clearly revealed the participation of the
      Y(1) receptor in NPY-mediated feeding regulation. The potent and orally active
      Y(1) antagonist J-104970 is a useful tool for elucidating the physiological roles
      of NPY in obesity.

PMID- 10581171
TI  - A switching system regulating subcellular localization of nuclear proteins using
      a viral protease.
AB  - We explored a novel approach to the functional regulation of nuclear proteins;
      altering their subcellular localization. To anchor a nuclear protein, beta
      galactosidase with the nuclear localization signal of SV40 (nbeta-gal), within
      the cytoplasm, nbeta-gal was fused to the transmembrane domain of granulocyte
      colony-stimulating factor receptor (G-CSFR), a membrane protein. To liberate the
      nbeta-gal portion from the fusion protein, we used a protease derived from a
      plant virus, whose recognition sequence was inserted between the G-CSFR and nbeta
      gal. Western analysis showed that the chimeric protein was cleaved in the
      presence of the protease in 293 cells and that the fusion protein without the
      recognition sequence remained intact. This chimeric protein was localized
      exclusively in the cytoplasm as visualized by X-gal staining and
      immunofluorescence microscopy. In contrast, when expressed together with the
      protease, beta-gal was predominantly detected in the nuclei. Moreover, we
      isolated 293-cell clones constitutively expressing the protease, indicating that
      this protease is not cytotoxic. These results suggest that the viral protease
      mediated alteration of subcellular localization can potentially regulate the
      function of nuclear proteins.

PMID- 10581172
TI  - Identification and characterization of a new phospholipase C-like protein, PLC
      L(2).
AB  - We have isolated a cDNA encoding a novel protein, PLC-L(2), with homology to the
      phospholipase C-like protein PLC-L and delta-type phospholipase C. PLC-L(2)
      contains a relatively well-conserved PH domain, PLC catalytic region, and X and Y
      domains. However, it did not have PLC activity. This inactivation was thought to
      be caused by the replacement of two amino acids that are essential for PLC
      activity, His356 and Tyr552, with Thr and Phe in the X and Y domain. PLC-L(2) has
      a wide distribution with strong expression in skeletal muscle and mapped to
      chromosome 3p24-25. The PH domain of PLC-L(2) bound strongly to PI(4,5)P(2) and
      Ins(1,4,5)P(3), and moderately to PI(4)P and PI(3,4,5)P(3). PLC-L(2)
      predominantly localized to perinuclear areas in both myoblast and myotube C2C12
      cells. Ectopically expressed GFP-PLC-L(2) also mainly localized in perinuclear
      areas, including endoplasmic reticulum in COS 7 cells. Furthermore, the
      expression of GFP-PH showed the same intracellular distribution as the full
      length PLC-L(2). All these results suggest that PLC-L(2) plays an important role
      in the regulation of Ins(1,4, 5)P(3) around the endoplasmic reticulum on which
      the Ins(1,4,5)P(3) receptor exists.

PMID- 10581173
TI  - Up-regulated uridine kinase gene identified by RLCS in the ventral horn after
      crush injury to rat sciatic nerves.
AB  - Rat sciatic nerve crush injury is one of the models commonly employed for
      studying the mechanisms of nerve regeneration. In this study, we analyzed the
      temporal change of gene expression after injury in this model, to elucidate the
      molecular mechanisms involved in nerve regeneration. First, a cDNA analysis
      method, Restriction Landmark cDNA Scanning (RLCS), was applied to cells in the
      ventral horn of the spinal cord during a 7-day period after the crush injury. A
      total of 1991 cDNA species were detected as spots on gels, and 37 of these were
      shown to change after the injury. Temporally changed patterns were classified
      into three categories: the continuously up-regulated type (10 species), the
      transiently up-regulated type (22 species), and the down-regulated type (5
      species). These complex patterns of gene expression demonstrated after the injury
      suggest that precise regulation in molecular pathways is required for
      accomplishing nerve regeneration. Secondly, the rat homologue of uridine kinase
      gene was identified as one of the up-regulated genes. Northern blot analysis on
      rat ventral horn tissue and brain revealed that the UK gene had three transcripts
      with different sizes (4.3, 1. 4, and 1.35 kb, respectively). All of the
      transcripts, especially the 4.3 kb one, were up-regulated mainly in a bimodal
      fashion during the 28-day period after the injury. The RLCS method that we
      employed in the present study shows promise as a means to fully analyze molecular
      changes in nerve regeneration in detail.

PMID- 10581174
TI  - Genomic organization of the human gamma adducin gene.
AB  - We report the genomic structure of the human gamma adducin gene (ADD3). Adducin
      is a protein involved in cytoskeletal assembly and composed of alpha-beta or
      alpha-gamma subunits which share a high degree of homology between human and rat.
      Mutations in alpha subunit have been shown associated to both human and rat
      hypertension. The human ADD3 gene spans over 20 kb and is composed of at least 13
      introns and 14 exons covering the entire coding region. The exon size ranges from
      81 bp to greater than 293 bp and the intron size from 111 bp to longer than 3.2
      kb. We also demonstrate the presence of an alternative splicing event around exon
      13, whose sequence, position, and expression is analogous in rat Add3 gene.
      Moreover, human ADD3 amino acid sequence presents 91.9% of identity compared to
      rat sequence. Characterization of human ADD3 gene provides an important tool for
      mutation analysis.

PMID- 10581175
TI  - A novel human gene encoding HECT domain and RCC1-like repeats interacts with
      cyclins and is potentially regulated by the tumor suppressor proteins.
AB  - Cyclin E-Cdk2 is an evolutionary conserved cyclin-dependent kinase (CDK) complex
      that drives the G1 to S phase transition of the cell cycle. A novel cDNA encoding
      a HECT family protein also containing RCC1-like repeats was isolated by a yeast
      two-hybrid screening using both cyclin E and its inhibitor p21. The protein
      product of this cDNA, Ceb1, interacts with various cyclin subunits of CDKs in
      mammalian cells. Expression of Ceb1 is specifically detected in testis and ovary
      and is highly elevated when the functions of the tumor suppressor proteins, p53
      and RB, are compromised by mutations or viral oncoproteins. The present results
      suggest that Ceb1 may play a critical role when its expression and the CDK
      activity are upregulated by inactivation of p53 and RB.

PMID- 10581176
TI  - Induced expression, localization, and chromosome mapping of a gene for the TBP
      interacting protein 120A.
AB  - TBP-interacting protein 120A (TIP120A) is a novel eukaryotic transcriptional
      regulator and has been suggested to be involved in the general regulation of
      transcription because of its ability to potentiate transcription of all classes
      of genes and to interact with common transcriptional machineries. In the present
      study, we investigated the expression of the tip120a gene. TIP120A transcripts
      were expressed abundantly in the heart and liver, moderately in the brain and
      skeletal muscle, and only slightly in the spleen and lung. This ubiquitous
      expression pattern was similar to that of TBP. Gene expression of TIP120A in the
      rat liver was not stimulated by hepatocarcinogenesis or liver regeneration.
      TIP120A was thus suggested not to be a growth-related protein. On the other hand,
      in P19 mouse embryonal carcinoma cells, TIP120A expression was elevated upon
      retinoic acid treatment, which induces differentiation. Notably, the foci-like
      nuclear localization pattern of TIP120A was transformed into a speckle-like
      pattern. The level of TIP120A was also elevated in such stem-like cells as F9 and
      HL60 after each differentiation procedure, retinoic acid and DMSO, respectively.
      In HEp-2 cells, TIP120A was observed as a limited number of nuclear foci, and the
      localization coincided with that of the PML oncogenic domain. FISH detection
      revealed that the human tip120a gene was located at 12q14, the position to which
      a myopathic type scapuloperoneal syndrome locus also mapped. Our study suggests
      that, contrary to an early assumption, TIP120A is involved in tissue-specific
      and/or differentiation-related gene expression.

PMID- 10581177
TI  - Cyclic AMP inhibits the activity of c-Jun N-terminal kinase (JNKp46) but not
      JNKp55 and ERK2 in human helper T lymphocytes.
AB  - The cyclic AMP (cAMP) elevating agent PGE(2) and dibutyryl cyclic AMP (dBcAMP)
      affect T cell functions. Using human helper T cell clones, we examined effects of
      cAMP on c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase
      (ERK), which are assumed to play a role in T cell regulation. When we analyzed
      the effects of dBcAMP on activities of mitogen-activated protein kinase (MAPK)
      family members ERK2, JNKp55 and JNKp46, dBcAMP did not inhibit the activities of
      ERK2 and JNKp55 induced by PMA/A23187 stimulation. JNKp46 activity was, however,
      inhibited by dBcAMP. JNK phosphorylates c-Jun on Ser-63 and Ser-73, the result
      being induction of its transcriptional activity. We found that dBcAMP inhibited
      the phosphorylation of c-Jun Ser-63 induced by PMA/A23187 stimulation. We suggest
      a different mechanism of regulation of JNKp55 and JNKp46 activities and that
      JNKp46 is a specific c-Jun kinase by which the activity of c-Jun is regulated in
      T lymphocytes.

PMID- 10581178
TI  - Functional genomic analysis reveals the utility of the I/LWEQ module as a
      predictor of protein:actin interaction.
AB  - The I/LWEQ module is a conserved sequence that we have identified as an actin
      binding motif in the metazoan focal adhesion protein talin and the yeast protein
      Sla2p. Both of these proteins are associated with the actin cytoskeleton in
      cells. To better establish the value of the I/LWEQ module for prediction of actin
      binding function, we have applied a functional genomics approach. Analysis of the
      23 available I/LWEQ module sequences supports the division of I/LWEQ protein
      superfamily into four groups: (1) metazoan talin, (2) Dictyostelium discoideum
      talin homologs TalA/B, (3) metazoan Hip1p, and (4) yeast Sla2p. We show here that
      I/LWEQ modules from each major group bind to F-actin in vitro and that GFP-fusion
      proteins of the I/LWEQ modules of talin and Sla2p bind to F-actin in vivo.
      Therefore, the presence of an I/LWEQ module is strongly predictive of protein
      actin interactions. The structural and functional conservation of the I/LWEQ
      module across the phylogenetic distance between cellular slime molds and mammals
      implies that the role of the I/LWEQ module is to connect diverse proteins
      involved in distinct cellular processes, including cell adhesion, cytoskeletal
      organization, and cell differentiation, to the actin cytoskeleton.

PMID- 10581179
TI  - Identification of a mammalian mitochondrial homolog of ribosomal protein S7.
AB  - Bovine mitochondrial small subunit ribosomal proteins were separated by two
      dimensional electrophoresis. The region containing the most basic protein(s) was
      excised and the protein(s) present subjected to in-gel digestion with trypsin.
      Electrospray tandem mass spectrometry was used to provide sequence information on
      some of the peptide products. Searches of the human EST database using the
      sequence of the longest peptide analyzed indicated that this peptide was from the
      mammalian mitochondrial homolog of prokaryotic ribosomal protein S7 (MRP
      S7(human)). MRP S7(human) is a 28-kDa protein with a pI of 10. Significant
      homology to bacterial S7 is observed especially in the C-terminal half of the
      protein. Surprisingly, MRP S7(human) shows less homology to the corresponding
      mitochondrial proteins from plants and fungi than to bacterial S7.

PMID- 10581180
TI  - MIDA1, an Id-associating protein, has two distinct DNA binding activities that
      are converted by the association with Id1: a novel function of Id protein.
AB  - Id proteins not only regulate cell differentiation negatively, but they also
      promote growth, immortalization, and apoptosis. To know the mechanism of how Id
      regulates cell fate, we previously isolated an Id-associating protein, MIDA1,
      which positively regulates cell growth (1). Its predicted amino acid sequence
      consists of a Zuotin (a Z-DNA binding protein in yeast) homology region and
      tryptophan-mediated repeats (Tryp-med repeats). MIDA1 exhibits a sequence
      specific DNA binding activity through the Tryp-med repeats (manuscript in
      preparation). In this study, we revealed that, like Zuotin, MIDA1 can
      specifically bind to Z-DNA. This suggested that MIDA is a novel DNA binding
      protein that has two different DNA binding activities. Furthermore, association
      of Id1 with MIDA1 stimulated the sequence-specific DNA binding activity, while it
      inhibited the Z-DNA binding activity. Therefore, we concluded that MIDA1 may act
      as a mediator of the growth-promoting function of Id, by switching the two DNA
      binding activities of MIDA1.

PMID- 10581181
TI  - Mechanisms involved in desensitization of particulate guanylyl cyclase in human
      airway smooth muscle: the role of protein kinase C.
AB  - We recently showed that cultured human airway smooth muscle cells (HASMC) express
      both soluble and particulate guanylyl cyclases (GC) and that long term treatment
      with atrial natriuretic peptide (ANP) causes homologous desensitization of
      particulate GC. Here we determine if protein kinase C (PKC) activation would
      desensitize particulate GC and probe the role of PKC in particulate GC
      desensitization. Pretreatment of HASMC with phorbol 12-myristate 13-acetate
      (PMA), a PKC activator led to time and concentration-dependent desensitization of
      ANP-stimulated cGMP accumulation. GF109203X, a selective PKC inhibitor, blocked
      the PMA-induced desensitization, but did not block ANP-induced desensitization.
      In addition, desensitization by PMA and ANP showed an additive effect. These
      results suggest that PKC activation can desensitize particulate GC but that the
      desensitization induced by ANP is PKC-independent.

PMID- 10581182
TI  - Hypoxia increases glyceraldehyde-3-phosphate dehydrogenase transcription in rat
      alveolar epithelial cells.
AB  - Alveolar epithelial type II (ATII) cells are particularly hypoxia-tolerant in
      vitro. As one of the mechanisms of hypoxia tolerance is the induction of certain
      proteins, one of which is glyceraldehyde-3-phosphate dehydrogenase (GAPDH), we
      investigated whether hypoxia modified GAPDH expression in ATII cells. Hypoxia
      induced a time- and O(2) concentration-dependent accumulation of GAPDH mRNA in
      cultured rat ATII cells (2- to 3-fold the normoxic value after 18 h in 0% O(2)),
      an effect completely reversed by reoxygenation. GAPDH mRNA induction was
      accounted for by an increase in GAPDH gene transcription during hypoxia with no
      change in mRNA stability. GAPDH protein synthesis increased 3- to 4-fold after 18
      h of 0% O(2), while the GAPDH protein steady-state level rose by 75%. GAPDH
      enzymatic activity in hypoxic cell homogenates increased by 45%. These results
      indicate that hypoxia induces GAPDH expression in ATII cells through an increase
      in transcription.

PMID- 10581183
TI  - Mutations in two distinct regions of acetolactate synthase regulatory subunit
      from Streptomyces cinnamonensis result in the lack of sensitivity to end-product
      inhibition.
AB  - Acetolactate synthase small subunit encoding ilvN genes from the parental
      Streptomyces cinnamonensis strain and mutants resistant either to valine
      analogues or to 2-ketobutyrate were cloned and sequenced. The wild-type IlvN from
      S. cinnamonensis is composed of 175 amino acid residues and shows a high degree
      of similarity with the small subunits of other valine-sensitive bacterial
      acetolactate synthases. Changes in the sequence of ilvN conferring the
      insensitivity to valine in mutant strains were found in two distinct regions.
      Certain point mutations were located in the conserved domain near the N terminus,
      while others resulting in the same phenotype shortened the protein at V(104) or
      V(107). To confirm whether the described mutations were responsible for the
      changed biochemical properties of the native enzyme, the wild-type large subunit
      and the wild-type and mutant forms of the small one were expressed separately in
      E. coli and combined in vitro to reconstitute the active enzyme.

PMID- 10581184
TI  - Treatment of multidrug resistant (MDR1) murine leukemia with P-glycoprotein
      substrates accelerates the course of the disease.
AB  - The prognosis of patients with tumors expressing P-glycoprotein (P-gp), the MDR1
      gene product, is generally poor. It is assumed that this is due to decreased
      tumor responsiveness that results from decreased drug accumulation. We observed
      that treatment of animals bearing MDR1-transfected leukemic cells with P-gp
      substrates (i.e., drugs that are transported by P-gp) significantly worsened host
      survival compared to treatment with vehicle or non-P-gp substrates. This effect
      was seen with cancer chemotherapeutic agents (paclitaxel and vincristine) and
      with the MDR modulator, trans-flupenthixol. To determine the mechanism(s)
      underlying this observation, we studied alterations in pharmacokinetics,
      pharmacodynamics, and metastasis. We found that the drug-induced acceleration of
      disease was associated with increased metastases. P-gp(+) cells treated with P-gp
      substrates demonstrated several pro-metastatic features, including membrane
      ruffling and invasion through a hepatocyte monolayer. These results suggest that
      the treatment of MDR tumors with P-gp substrates may produce changes in malignant
      behavior that could adversely affect therapeutic outcomes.

PMID- 10581185
TI  - Identification of urotensin II as the endogenous ligand for the orphan G-protein
      coupled receptor GPR14.
AB  - Urotensin II (UII) is a neuropeptide with potent cardiovascular effects. Its
      sequence is strongly conserved among different species and has structural
      similarity to somatostatin. No receptor for UII has been molecularly identified
      from any species so far. GPR14 was cloned as an orphan G protein-coupled receptor
      with similarity to members of the somatostatin/opioid receptor family. We have
      now demonstrated that GPR14 is a high affinity receptor for UII and designate it
      UII-R1a. HEK293 cells and COS-7 cells transfected with rat GPR14 showed strong,
      dose-dependent calcium mobilization in response to fish, frog, and human UII.
      Radioligand binding analysis showed high affinity binding of UII to membrane
      preparations isolated from HEK293 cells stably expressing rat GPR14. In situ
      hybridization analysis showed that GPR14 was expressed in motor neurons of the
      spinal cord, smooth muscle cells of the bladder, and muscle cells of the heart.
      The identification of the first receptor for UII will allow better understanding
      of the physiological and pharmacological roles of UII.

PMID- 10581186
TI  - Long-term analysis of differentiation in human myoblasts repopulated with
      mitochondria harboring mtDNA mutations.
AB  - Short-term analysis of myogenesis in respiration-deficient myoblasts demonstrated
      that respiratory chain dysfunction impairs muscle differentiation. To investigate
      long-term consequences of a deficiency in oxidative phosphorylation on
      myogenesis, we quantitated myoblast fusion and expression of sarcomeric myosin in
      respiration-deficient myogenic cybrids. We produced viable myoblasts harboring
      exclusively mtDNA with large-scale deletions by treating wild-type myoblasts with
      rhodamine 6G and fusing them with cytoplasts homoplasmic for two different
      mutated mtDNAs. Recovery of growth in transmitochondrial myoblasts demonstrated
      that respiratory chain function is not required for recovery of rhodamine 6G
      treated cells. Both transmitochondrial respiration-deficient cultures exhibited
      impaired myoblast fusion. Expression of sarcomeric myosin was also delayed in
      deficient myoblasts. However, 4 weeks after induction of differentiation, one
      cell line was able to quantitatively recover its capacity to form postmitotic
      muscle cells. This indicates that while oxidative phosphorylation is an important
      source of ATP for muscle development, myoblast differentiation can be supported
      entirely by glycolysis.

PMID- 10581187
TI  - Spectral properties of the oxyferrous complex of the heme domain of cytochrome
      P450 BM-3 (CYP102).
AB  - Here we describe for the first time the formation of a complex of reduced CYP102
      (cytochrome P450 BM-3) heme domain with molecular oxygen. To stabilize the
      oxycomplex, the experiments had to be done under argon atmosphere at cryogenic
      temperatures (-25 degrees C) in the presence of 50% glycerol. The spectral
      properties of this species were different from those of another P450-type
      autosuffisant enzyme, i.e., the neuronal nitric oxide synthase. On the contrary,
      the oxyferrous complex of CYP102 possesses spectral properties similar to those
      of complexes of microsomal cytochromes P450, e.g., CYP2B4.

PMID- 10581188
TI  - Difference in strength of autonomously replicating sequences among repeats in the
      rDNA region of Saccharomyces cerevisiae.
AB  - The rDNA region of Saccharomyces cerevisiae contains 100-200 tandemly repeated
      copies of a 9 kb unit, each with a potential replication origin. In the present
      studies of cloned fragments from the region involved in the regulation of
      replication of rDNA, we detected differences in autonomously replicating sequence
      (ARS) activity for clones from the same yeast strain. One clone, which showed
      very low ARS activity, carried a point mutation, a C instead of T, in position 9
      of the essential 11 bp consensus ARS as compared to clones carrying the normal 10
      of-11-bp match to the consensus. The mutation could be traced back to genomic
      rDNA where it represents about one-third of the rDNA units in that strain.
      Differences in ARS activity have implications for understanding the regulation of
      replication of rDNA, and the ratio of active to inactive ARS in the rDNA region
      may be important for potential generation of extrachromosomal copies.

PMID- 10581189
TI  - Structure/function studies of hepatocyte nuclear factor-1alpha, a diabetes
      associated transcription factor.
AB  - Mutations in the transcription factor hepatocyte nuclear factor-1alpha (HNF
      1alpha) cause maturity-onset diabetes of the young type 3 (MODY3), a form of
      diabetes mellitus characterized by autosomal dominant inheritance, early onset,
      and pancreatic beta-cell dysfunction. We have examined the effects of five
      diabetes-associated mutations (L12H, G191D, R263C, P379fsdelCT, and
      L584S585fsinsTC) on HNF-1alpha function including DNA binding ability,
      intracellular localization, and transactivation activity. L12H, P379fsdelCT, and
      L584S585fsinsTC mutations were found in patients with a clinical diagnosis of
      MODY, while G191D and R263C mutations were identified in patients diagnosed with
      type 2 diabetes. These mutations had diverse effects on the functional properties
      of HNF-1alpha. Comparison of the functional data with clinical information
      suggested that transactivation activity of mutant HNF-1alpha in beta cells like
      MIN6 may be the primary determinants of the phenotypic differences observed among
      diabetic patients with HNF-1alpha mutations.

PMID- 10581190
TI  - Inhibition of cell death in human mammary epithelial cells by the cooked meat
      derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine.
AB  - 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mammary gland
      carcinogen present in the human diet in cooked meat. To examine if PhIP and its
      reactive metabolite N-hydroxy-PhIP inhibit apoptosis in human mammary epithelial
      MCF-10A cells, confluent cultures deprived of serum and growth factors were
      incubated for 24 h with either compound. The percentages of dead cells (mean +/-
      SEM, n = 3) as measured by trypan blue exclusion were 5.7 +/- 0.6, 3.4 +/- 0.3,
      2.7 +/- 0.3, and 0.2 +/- 0.003%, in control, 1 microM N-hydroxy-PhIP-, 5 microM N
      hydroxy-PhIP-, and 100 microM PhIP-treated dishes, respectively. The expression
      of Bcl-2 and Bcl-x(L) as quantitated by Western blotting was 1.2- to 1.9-fold
      higher in the treated groups. PhIP-DNA adducts induced by N-hydroxy-PhIP in MCF
      10A cells measured by the (32)P-postlabeling assay were low (<1 x 10(7), relative
      adduct labeling). No adducts were detected after incubation with PhIP. Western
      blot analysis indicated that PhIP increased ERK2 phosphorylation concomitant with
      Bcl-2. The results suggest that the inhibition of cell death in mammary
      epithelial cells by PhIP occurs independently of PhIP-DNA adducts and may involve
      enhanced signaling through the MAP kinase pathways.

PMID- 10581191
TI  - Identification of new genes ndr2 and ndr3 which are related to Ndr1/RTP/Drg1 but
      show distinct tissue specificity and response to N-myc.
AB  - Ndr1 was isolated as a gene upregulated in N-myc mutant mouse embryos and is
      repressed by N-myc and c-myc. Consistent with Myc regulation, the same gene was
      also isolated as one sensitive to transformation (Drg1), and in addition as one
      induced under a few stress conditions (RTP). Two new genes, Ndr2 and Ndr3, were
      identified which encode proteins highly related to Ndr1/RTP/Drg1 and constitute
      the Ndr gene family. Ndr2 and Ndr3 are under spatio-temporal regulations distinct
      from Ndr1, and are not activated in N-myc mutants. When whole embryo RNA was
      analyzed, Ndr3 expression was already high at 9.5 days postcoitus (dpc), while
      expression of Ndr2 and Ndr1 became significant after 12.5 dpc and 13. 5 dpc,
      respectively. At 14.5 dpc, expression of these genes partially overlaps, but many
      tissues are unique to one of them. For instance, Ndr1 is strongly expressed in
      the liver and gut epithelium, Ndr2 in the ventricular zone throughout the CNS,
      and Ndr3 in the spinal cord and the thymus rudiment. Genes of the Ndr family
      probably have tissue-dependent allotments of the possibly related functions.

PMID- 10581192
TI  - Identification of EPS8 as a Dvl1-associated molecule.
AB  - Dishevelled (Dsh) is involved in both Wingless (Wg) and Frizzled (Fz) signaling
      pathways. To further determine the function of Dsh, we have performed yeast two
      hybrid screening and isolated several genes encoding the molecules associated
      with the PDZ domain of Dvl1, one of the murine Dsh homologs. During the
      screening, we found that EPS8, which is a substrate for activated EGF receptor
      (EGFR), specifically interacted with Dvl1. This interaction was also confirmed in
      vitro. Through transfection studies, we observed the mutual action between Dvl1
      and EPS8. Dvl1 was hyperphosphorylated in the presence of EPS8, whereas the
      tyrosine phosphorylation of EPS8 by activated EGFR was inhibited in the presence
      of Dvl1. Immunohistochemistry showed that Dvl1 and EPS8 expression overlap in
      particular tissues during organogenesis. These results indicate that interaction
      between Dvl1 and receptor tyrosine kinase signal plays certain roles in
      developmental events.

PMID- 10581193
TI  - Induction of tight junctions in human connexin 32 (hCx32)-transfected mouse
      hepatocytes: connexin 32 interacts with occludin.
AB  - Small gap junction plaques are associated with tight junction strands in some
      cell types including hepatocytes and it is thought that they may be closely
      related to tight junctions and the establishment of cell polarity. In order to
      examine roles of gap junctions in regulating expression and structure of tight
      junctions, we transfected human Cx32 cDNA into immortalized mouse hepatocytes
      (CHST8 cells) which lack endogenous Cx32 and Cx26. Immunocytochemistry revealed
      that endogenous integral tight junction protein occludin was strongly localized
      and was colocalized with Cx32 at cell borders in transfectants, whereas neither
      was detected in parental cells. In Northern blots, mRNAs encoding occludin and
      the other integral tight junction proteins, claudin-1 and -2, were induced in the
      transfectants compared to parental cells. In Western blots, occludin protein was
      increased in the transfectants compared to parental cells, and binding of
      occludin to Cx32 protein was demonstrated by immunoprecipitation. In freeze
      fracture of the transfectants, tight junction strands were more numerous and
      complex compared to parental cells, and small gap junction plaques appeared
      within induced tight junction strands. Nevertheless, no change in barrier
      function of tight junctions was observed. These results indicate that in
      hepatocytes, gap junction, and tight junction expression are closely coordinated,
      and that Cx32 may play a role in regulating occludin expression.

PMID- 10581194
TI  - A mutant streptokinase lacking the C-terminal 42 amino acids is less reactive
      with preexisting antibodies in patient sera.
AB  - Streptokinase (SK) is an efficacious thrombolytic drug for the treatment of
      myocardial infarction. Because of its immunogenicity, patients receiving SK
      therapy develop high anti-SK antibody (Ab) titers, which might provoke severe
      allergic reactions and neutralize SK activity. In this report we studied the
      reactivity of a synthetic 42-residue peptide resembling SKC-2 C-terminus with
      patient sera. SKC-2(373-414) peptide was recognized by 39 and 64% of patients,
      before and after SKC-2 therapy, respectively. An SKC-2 deletion mutant (mut-C42),
      lacking the same 42 C-terminal residues, was constructed and expressed in
      Escherichia coli. Recognition of mut-C42 by preexisting Abs from patient sera was
      51 and 68% of reactivity to SKC-2, as assessed by direct binding and competition
      assays, respectively. For most of the patients, mut-C42-neutralizing activity
      titer (NAT) significantly decreased with respect to SKC-2-NAT. This study opens
      the possibility of producing a less immunogenic variant of SK, which could
      constitute a preferred alternative for thrombolytic therapy.

PMID- 10581195
TI  - Identification of a new tachykinin from the midgut of the desert locust,
      Schistocerca gregaria, by ESI-Qq-oa-TOF mass spectrometry.
AB  - This paper reports the purification of a tachykinin isoform from the midgut of
      the desert locust, Schistocerca gregaria. One hundred locust midguts were
      extracted in an acidified methanolic solvent, after which three HPLC column
      systems were used to obtain a pure peptide. A tachykinin immunoassay was used to
      monitor all collected fractions. After each purification step the purity of the
      sample was monitored by MALDI-TOF mass spectrometry. The pure peptide was
      sequenced by ESI-Qq-oa-TOF mass spectrometry. Edman degradation-based automated
      microsequencing and chemical synthesis confirmed the sequences. The midgut
      peptide, GNTKKAVPGFYGTRamide (Scg-midgut-TK), belongs to the tachykinin family
      with identified members in all vertebrate phyla and some invertebrate phyla:
      arthropods, annelids and molluscs. Scg-midgut-TK is the first tachykinin purified
      from midguts of the desert locust Schistocerca gregaria. In comparison to locust
      brain tachykinins, the midgut tachykinin is N-terminally extended. Similar to
      neuropeptide gamma, an N-terminally extended mammalian tachykinin, first isolated
      from rabbit intestine, the present identified locust intestinal tachykinin
      contains a putative dibasic cleavage site.

PMID- 10581196
TI  - A genetic screen to identify sequences that mediate protein oligomerization in
      Escherichia coli.
AB  - Many proteins assemble as oligomeric complexes and in several cases a distinct
      domain mediates the interaction between the subunits. The identification of new
      oligomerization modules is relevant to comprehend both the architecture and the
      evolution of protein sequences and also for protein engineering applications.
      Using the bacteriophage lambda repressor dimerization assay, we searched
      Escherichia coli genomic libraries for sequences able to mediate protein
      oligomerization in vivo. We identified short peptides that can substitute very
      effectively the dimerizing domain of the repressor. Most of these peptides belong
      to open reading frames that are normally not expressed in the bacterial cell.

PMID- 10581197
TI  - In vivo modification of porin activity conferring antibiotic resistance to
      Enterobacter aerogenes.
AB  - Cephalosporins are widely used in chemotherapy of bacterial infections and
      resistance mechanisms seriously impair their antibacterial activity. Several
      resistant strains of Enterobacter aerogenes, a frequently isolated nosocomial
      pathogen, were analyzed. One isolate exhibited a strong modification of the porin
      antigenic pattern, especially with an immunological probe directed against an
      epitope located inside the pore lumen. A strong decrease of cefepime uptake was
      evidenced for this isolate, similarly to ones observed for porin-deficient
      strains: these kinetics show a serious alteration of the channel properties which
      may support cephalosporin resistance. This is the first E. aerogenes isolate
      using such adaptive response which defines an original enterobacterial answer to
      cephalosporin.

PMID- 10581199
TI  - Rapid nongenomic effects of aldosterone in mineralocorticoid-receptor-knockout
      mice.
AB  - In addition to genomic effects of aldosterone, rapid nongenomic effects of
      steroids have been reported in various tissues that were clearly incompatible
      with a genomic action of aldosterone. Rapid effects of aldosterone involve second
      messengers such as calcium and cAMP. Specific high affinity binding sites for
      aldosterone have been characterized in membranes for different cells, which
      probably transmit those rapid steroid effects. To date, it is unclear if these
      binding sites are modified classical mineralocorticoid receptors (MR) or if they
      represent an unrelated receptor protein. The aim of the present study was to
      investigate whether rapid aldosterone action still occurs in the absence of the
      classical MR. For this purpose we used the model of MR knockout mice. Rapid
      effects were analyzed in skin cells, measuring intracellular calcium and cAMP
      levels after stimulation with aldosterone. We found that rapid effects are not
      only present in MR knockout mice, but that the effects are even larger than in
      wild-type mice cells. The results of the present study demonstrate that the
      classic MR is dispensable for rapid aldosterone action. The study, thus, proves
      that a receptor different from the classic intracellular receptor is involved in
      rapid aldosterone signaling.

PMID- 10581198
TI  - Hyperglycemia impairs the insulin signaling step between PI 3-kinase and Akt/PKB
      activations in ZDF rat liver.
AB  - Akt/PKB activation is reportedly essential for insulin-induced glucose metabolism
      in the liver. During the hypoinsulinemic and hyperglycemic phase in the Zucker
      diabetic fatty (ZDF) rat liver, insulin-induced phosphorylations of the insulin
      receptor (IR) and insulin receptor substrate (IRS)-1/2 were significantly
      enhanced. Similarly, phosphatidylinositol (PI) 3-kinase activities associated
      with IRS-1/2 were markedly increased in ZDF rat liver compared with those in the
      control lean rat liver. However, interestingly, insulin-induced phosphorylation
      and kinase activation of Akt/PKB were severely suppressed. The restoration of
      normoglycemia by sodium-dependent glucose transporter (SGLT) inhibitor to ZDF
      rats normalized elevated PI 3-kinase activation and phosphorylation of IR and IRS
      1/2 to lean control rat levels. In addition, impaired insulin-induced Akt/PKB
      activation was also normalized. These results suggest that chronic hyperglycemia
      reduces the efficiency of the activation step from PI 3-kinase to Akt/PKB kinase
      and that this impairment is the molecular mechanism underlying hyperglycemia
      induced insulin resistance in the liver.

PMID- 10581200
TI  - Cytochrome P450 and steroid hydroxylase activity in mouse olfactory and
      vomeronasal mucosa.
AB  - The aims of this study are to identify the sex steroid-metabolizing cytochrome
      P450 enzymes of the vomeronasal organ (VNO) and to determine the activities of
      VNO microsomes to metabolize estradiol, progesterone, and testosterone. Several
      P450 isoforms, including CYP1A2, CYP2A, CYP2B, CYP2C, CYP2G1, and CYP3A, NADPH
      P450-reductase, and microsomal epoxide hydrolase were detected in mouse VNO,
      although their expression levels were much lower than those in the main olfactory
      epithelium. VNO microsomes were active toward the three steroid hormones,
      producing metabolite profiles similar to those seen with olfactory mucosal
      microsomes. Thus, the mammalian VNO, a steroid hormone target tissue, contains
      multiple steroid-metabolizing P450 isoforms and is capable of metabolic
      disposition of the three major sex steroid hormones. These findings support the
      proposed roles of olfactory mucosal and VNO microsomal P450 enzymes in
      maintaining cellular hormonal homeostasis and other perireceptor processes
      associated with olfactory chemosensory function.

PMID- 10581201
TI  - Hyaluronidase expression in human skin fibroblasts.
AB  - Hyaluronidase activity has been detected for the first time in normal human
      dermal fibroblasts (HS27), as well as in fetal fibroblasts (FF24) and
      fibrosarcoma cells (HT1080). Enzymatic activity was secreted predominantly into
      the culture media, with minor amounts of activity associated with the cell layer.
      In both classes of fibroblasts, hyaluronidase expression was confluence
      dependent, with highest levels of activity occurring in quiescent, post-confluent
      cells. However, in the fibrosarcoma cell cultures, expression was independent of
      cell density. The enzyme had a pH optimum of 3.7 and on hyaluronan substrate gel
      zymography, activity occurred as a single band corresponding to an approximate
      molecular size of 57 kDa. The enzyme could be immunoprecipitated in its entirety
      using monoclonal antibodies raised against Hyal-1, human plasma hyaluronidase.
      PCR confirmed that fibroblast hyaluronidase was identical to Hyal-1. The
      conclusion by previous investigators using earlier technologies that fibroblasts
      do not contain hyaluronidase activity should be reevaluated.

PMID- 10581202
TI  - Structural and functional analysis of the N-terminal extracellular region of beta
      dystroglycan.
AB  - A protein fragment corresponding to the mouse beta-dystroglycan N-terminal
      extracellular region from position 654 to 750, beta-DG(654-750) was recombinantly
      expressed in BL21(DE3) Escherichia coli cells. Secondary structure prediction of
      the protein fragment reveals about 70% of random coil, as confirmed by circular
      dichroism analysis. Moreover, fluorescence analysis shows that the tryptophan
      residue in position 659 lays in a solvent-exposed fashion. These data suggest
      that the beta-DG(654-750) is likely to have a quite flexible structure and to be
      only partially folded. Interestingly, the protein still retains its biological
      function since using solid-phase assays we have detected binding of biotinylated
      beta-DG(654-750) both to native alpha-dystroglycan and to a recombinant fragment
      which spans the C-terminal region of alpha-dystroglycan.

PMID- 10581203
TI  - Protein phosphatase-1 activation and association with the retinoblastoma protein
      in colcemid-induced apoptosis.
AB  - Protein phosphatase-1 (PP1) is cell cycle regulated and potentially related to
      apoptosis. We studied PP1 in HeLa cells exposed to colcemid, which leads first to
      mitotic block, then to cell death within 72 h. The soluble PP1 activity, which
      was low at 14 h (mitosis), was then reversibly activated (maximally around 48 h),
      with parallel changes in the protein levels of the alpha, gamma1 and delta PP1
      isoforms. PP1 activation suggested its involvement in dephosphorylating proteins
      relevant to apoptosis. Among these, we examined the retinoblastoma protein (pRb).
      This was found hyperphosphorylated at 14 h. Hypophosphorylated pRb appeared at 24
      h, increased at 48 h, and was the only form left at 72 h. PP1 was found to
      associate with immunoprecipitated pRb, as indicated by PP1 activity assays on the
      pRb-immunocomplexes. The pRb-associated PP1 activity was low at 14 h, maximal at
      24 h, low again by 72 h and was due to PP1delta. The presence of active PP1
      suggests its involvement in pRb dephosphorylation.

PMID- 10581204
TI  - Identification of two distinct regions of p38 MAPK required for substrate binding
      and phosphorylation.
AB  - The mechanism by which different mitogen activated protein kinases (MAPKs)
      distinguish between different substrates is poorly understood. For example, p38
      and SAPK4 are two closely related p38 MAPKs that both phosphorylate ATF2 and MBP.
      However, p38 phosphorylates MAPKAPK-2 and -3, whereas SAPK4 does not. In this
      study, we have used mutagenesis to determine the regions of p38 required for
      substrate selection. Alanine scanning mutagenesis identified one region of p38
      that was required for its ability to phosphorylate MAPKAPK-2 and -3, but that did
      not significantly affect its binding to these substrates. Chimeras of p38 and
      SAPK4 identified a second region of p38 that affected the ability of p38 to both
      bind and phosphorylate MAPKAPK-2 and -3. Hence, we show for the first time that
      MAPKs contain two distinct regions for recognizing and phosphorylating protein
      substrates.

PMID- 10581205
TI  - Silica binds serum proteins resulting in a shift of the dose-response for silica
      induced chemokine expression in an alveolar type II cell line.
AB  - There is a growing concern about whether the myriad of culture conditions, cell
      lines, and doses of nonfibrous and fibrous particles used in vitro are truly
      representative of the complex environment of the in vivo particle exposure
      situation. The use of serum as a supplement to the growth medium of cultured
      cells is a widely accepted practice. However, little is known about whether the
      various serum proteins may interact with the surfaces of particles, consequently
      altering their toxicity, inflammatory properties, or fibrogenicity, etc. observed
      in vivo. Using a murine alveolar type II cell line, MLE-15, we measured the early
      changes in various chemokine mRNA species following exposure of the cells to
      silica (cristobalite) in the presence or absence of serum. Total mRNA was
      isolated and assayed using an RNase protection assay after 6 h of particle
      exposure. We observed that the addition of serum to the culture media reduced the
      in vitro silica-induced chemokine response (i.e., shift in the dose-response
      curve) in MLE-15 cells. Further, using Western blot analysis and protein
      sequencing techniques, we have identified a specific serum component,
      apolipoprotein-A1 (apo-A1), as a protein in serum that binds selectively to
      silica, thus leading to the altered chemokine response. We also found that apo-A1
      not only binds to silica but also binds to other nonfibrous and fibrous particles
      such as titanium dioxide and asbestos. These results demonstrate the importance
      of culture conditions for modifying the outcome of an experiment when performing
      in vitro particle exposure studies.

PMID- 10581206
TI  - Metabolism-based polycyclic aromatic acetylene inhibition of CYP1B1 in 10T1/2
      cells potentiates aryl hydrocarbon receptor activity.
AB  - We have used polycyclic aromatic hydrocarbon (PAH) alkyne metabolism-based
      inhibitors to test whether CYP1B1 metabolism is linked to aryl hydrocarbon
      receptor (AhR) activation in mouse embryo fibroblasts (MEF). 1-ethynylpyrene
      (1EP) selectively inactivated CYP1B1 dimethylbenzanthracene (DMBA) metabolism in
      C3H10T1/2 MEFs; whereas 1-(1-propynyl)pyrene (1PP) preferentially inhibited
      CYP1A1 activity in Hepa-1c1c7 mouse hepatoma cells (Hepa). In each cell type >90%
      inhibition of DMBA metabolism after 1 h treatment with each inhibitor (0.1
      microM) was progressively reversed and then increased to levels seen with 2,3,7,8
      tetrachlorodibenzo-p-dioxin (TCDD) induction (fourfold stimulation). It was found
      that 0.1 microM 1EP and 1PP maximally induce CYP1B1 and CYP1A1 mRNA levels
      in10T1/2 and Hepa cells, respectively, after 6 h. 1-Ethylpyrene (EtP), which
      lacks the activatable acetylene moiety, was far less effective as an inhibitor
      and as an inducer. AhR activation is essential for 1EP induction as evidenced by
      the use of AhR antagonists and AhR-deficient MEFs and absence of induction
      following inhibition of DMBA metabolism with carbon monoxide (CO). Inhibition of
      CYP1B1 was linked to enhanced AhR activation even at early stages prior to
      significant ligand depletion. 1EP and EtP were similarly effective in stimulating
      AhR nuclear translocation, though 5-10 times slower compared with TCDD, and
      produced no significant down-regulation of the AhR. TCDD activated AhR/Arnt
      complex formation with an oligonucleotide xenobiotic response element far more
      extensively than 1EP or EtP, even at concentrations of 1EP that increased CYP1B1
      mRNA to similar levels. CO did not influence these responses to EtP, event hough
      CO treatment potentiated EtP induction of CYP1B1 mRNA. These differences suggest
      a fundamental difference between PAH/AhR and TCDD/AhR complexes where CYP1B1
      metabolic activity regulates the potency, rather than the formation of the
      AhR/Arnt complex.

PMID- 10581207
TI  - Menadione-induced vascular endothelial dysfunction and its possible significance.
AB  - Although several studies have shown that treatment with menadione leads to
      endothelial cell cytotoxicity, investigations of menadione's effects on blood
      vessels are limited. Our previous studies have shown that menadione can
      indirectly induce alterations in vasomotor tone through platelet cytotoxicity. To
      determine if menadione affects vascular function, we investigated the effect of
      menadione on blood vessels using the isolated rat aortic rings in vitro organ
      bath system. Treatment with menadione directly resulted in contraction of aortic
      rings with endothelium but did not cause any effect on aortic rings without
      endothelium. Menadione irreversibly inhibited the acetylcholine- and histamine
      induced relaxation of aortic rings with endothelium in a time- and concentration
      dependent manner. Menadione treatment potentiated phenylephrine- and serotonin
      induced vasoconstriction in aortic rings with endothelium. These in vitro results
      were observed at concentrations of menadione that are highly relevant to human
      therapeutics with menadione. When menadione was administrated intravenously to
      rats, blood pressure increased significantly in a concentration-dependent manner.
      Furthermore, menadione infusion suppressed the blood pressure reduction induced
      by acetylcholine. By demonstrating that menadione caused in vitro endothelial
      dysfunction (i.e., decreased relaxation and increased vasoconstriction in the
      organ bath experiments) and confirming that these results were consistent with in
      vivo observations, we have provided evidence suggesting that a quinone such as
      menadione can alter vasomotor tone through endothelial dysfunction. Such
      dysfunction could possibly contribute to vascular diseases.

PMID- 10581208
TI  - Cadmium inhibits albumin endocytosis in opossum kidney epithelial cells.
AB  - Chronic exposure to cadmium results in proteinuria. To gain insights into the
      mechanism by which cadmium inhibits the protein transport in the renal proximal
      tubule, we investigated the effects of cadmium on the receptor-mediated
      endocytosis of albumin, using fluorescein isothiocyanate-labeled bovine serum
      albumin (FITC-albumin) as a model substrate and opossum kidney cell line (OK
      cell) as a proximal tubular cell model. Cell monolayers grown to confluence were
      treated with 100 microM CdCl(2) for 60 min at 37 degrees C, washed, and tested
      for FITC-albumin uptake (37 degrees C) and surface binding (4 degrees C). The
      amounts of FITC-albumin uptake and binding were quantified by fluorimetrically
      determining the cell-adherent fluorescence. Both the binding and uptake of FITC
      albumin by OK cells appeared to be saturable and inhibitable by unlabeled albumin
      in the medium, indicating that specific receptor sites were involved. The uptake
      of FITC-albumin was inhibited by agents that interfere with the formation of
      endocytotic vesicle (hypertonic mannitol), endosomal acidification (NH(4)Cl), and
      vesicular trafficking (cytochalasin D and nocodazole), confirming that the uptake
      occurred via the process of receptor-mediated endocytosis. In cells treated with
      cadmium, the specific FITC-albumin uptake was significantly attenuated, and this
      was due to a reduction in V(max) and a rise in K(m). These changes in kinetic
      parameters were similar to those induced by NH(4)Cl. The binding of FITC-albumin
      to the apical surface of OK cells was inhibited by cadmium treatment, and this
      was attributed to a reduction in B(max). The values of K(d) and its pH dependency
      were not altered by cadmium treatment. The formation of endocytotic vesicles, as
      judged by fluid phase endocytosis of FITC-inulin, was not changed by cadmium
      treatment. These results indicate that the receptor-mediated endocytosis of
      albumin is impaired in cadmium-treated OK cells most likely due to a defect in
      endosomal acidification and the attendant fall in ligand-receptor dissociation,
      which impairs receptor recycling and the overall efficiency of endocytosis.

PMID- 10581209
TI  - Correlation between induction of DNA fragmentation and micronuclei formation in
      kidney cells from rats and humans and tissue-specific carcinogenic activity.
AB  - Five chemicals, known to induce kidney tumors in rats, were assayed for their
      ability to induce DNA damage and formation of micronuclei in primary cultures of
      rat and human kidney cells and in the kidney of intact rats. Significant dose
      dependent increases of DNA fragmentation, as measured by the Comet assay, and of
      micronuclei frequency were obtained in primary kidney cells from both rats and
      humans with the following concentrations of the five test compounds: lead acetate
      (not tested for micronuclei induction) and potassium bromate from 0.56 to 1.8 mM,
      phenacetin from 1 to 3.2 mM, and 1, 4-dichlorobenzene and nitrilotriacetic acid
      from 1.8 to 5.6 mM. In terms of DNA-damaging potency all the five chemicals were
      more active in rat than in human kidney cells, whereas the potencies in inducing
      micronuclei formation were similar in the two species with the exception of 1,4
      dichlorobenzene, which was slightly more potent in human than in rat cells.
      Consistently with the results observed in vitro, statistically significant
      increases in the average frequency of both DNA breaks and micronucleated cells
      were detected in the kidney of rats given po a single (12 LD50) or three
      successive daily doses (13 LD50) of the five test compounds. 4, 4'
      Methylenedianiline, a carcinogen which does not induce kidney tumors in rats,
      gave negative responses in both in vitro and in vivo assays. These findings give
      evidence that kidney carcinogens may be identified by short-term genotoxicity
      assays using as target kidney cells and show that the five chemicals tested
      produce in primary cultures of kidney cells from human donors effects similar to
      those observed in rats.

PMID- 10581210
TI  - Induction of hepatic CYP2B is a more sensitive indicator of exposure to aroclor
      1260 than CYP1A in male rats.
AB  - To evaluate the effect of exposure to an environmentally relevant polychlorinated
      biphenyl mixture, adult male rats were treated with Aroclor 1260 for 7 days and
      levels of several cytochrome P450 (CYP) enzymes were measured in liver microsomes
      prepared 3 days after the last dose. Treatment with Aroclor 1260 at dosages
      ranging from 0.5 to 50 mg/kg/day had no effect on body weight, but liver weight
      was increased significantly in rats treated with the two highest dosages. Of the
      monooxygenase activities examined, benzyloxyresorufin O-dealkylase and
      testosterone 16beta-hydroxylase activities were increased to the greatest extent
      with maximal induction of both activities reached at 5 mg/kg/day. Densitometric
      quantitation of blots probed with antibody against CYP2B revealed that CYP2B1 and
      CYP2B2 protein levels were increased approximately 55-fold and 16-fold,
      respectively, after treatment with Aroclor 1260 at 5 mg/kg/day. Ethoxyresorufin O
      deethylase activity and CYP1A1 protein levels displayed linear dose-dependent
      increases, but the hepatic CYP1A1 content did not exceed 10% that of CYP2B1 at
      all dosages of Aroclor 1260. Microsomal CYP3A- and CYP2A1-mediated enzyme
      activities and protein levels were also increased by treatment with Aroclor 1260
      but to a lesser extent, whereas CYP2C11-mediated enzyme activities and protein
      levels were reduced. A separate time-course study showed that induction of CYP2B,
      but not of CYP1A, enzymes persisted for at least 48 days after treatment with
      Aroclor 1260 at 10 mg/kg/day. In summary, the results indicate that induction of
      CYP2B enzymes is a more sensitive biomarker of exposure to Aroclor 1260 than
      CYP1A.

PMID- 10581211
TI  - Enhanced pulmonary epithelial replication and axial airway mucosubstance changes
      in F344 rats exposed short-term to mainstream cigarette smoke.
AB  - Cigarette smoking is associated with respiratory diseases that may be caused by
      injury to specific pulmonary cells. The injury may manifest itself as site
      specific enhanced cellular replication. In this study, rats were exposed either
      to mainstream cigarette smoke (CS; 250 mg total particulate matter/m(3)) or to
      filtered air (FA) for 6 h/day, 5 days/week, for 2 weeks. In one group, cells in S
      phase were labeled over 7 days by bromodeoxyuridine (BrdU) released from
      implanted osmotic pumps (pump labeled), while another group received BrdU by
      injection 2 h prior to necropsy (pulse labeled). Morphometry showed that the type
      II epithelial BrdU labeling index (LI) was significantly elevated in the CS
      exposed animals of both labeling groups. The axial airway and terminal
      bronchiolar LIs were enhanced by CS only in the pump-labeled group. In a third
      group (pulse labeled), 2 weeks of recovery following exposure to CS allowed a
      normalization in the type II LI. In the pump-labeled rats, the CS-induced
      elevation of the type II LI was greater than the LI elevation in conducting
      airways, suggesting that the parenchyma may have been injured more than the
      conducting airways. The terminal bronchiolar LI in the pump-labeled group,
      regardless of exposure, was significantly greater than the axial airway LI. Pump
      labeling, in contrast to pulse labeling, could therefore discern differences
      among replication rates of conducting airway epithelium in different regions of
      the lung. Mucosubstance (MS) within the axial airway epithelium was quantified by
      morphometry. The CS exposure did not increase the total number of MS-containing
      cells or the total number of axial airway epithelial cells, but there was a
      phenotype change in the MS cells. Neutral MS cells (periodic acid-Schiff
      positive) were significantly decreased, while acid MS cells (alcian blue
      positive) were slightly increased by CS exposure. Either cell replication and
      differentiation or differentiation alone may have changed the phenotype in the MS
      cell population.

PMID- 10581212
TI  - The role of thymus-dependent T cells in hexachlorobenzene-induced inflammatory
      skin and lung lesions.
AB  - The involvement of thymus-dependent T cells in the inflammatory skin and lung
      lesions and spleen effects induced by hexachlorobenzene (HCB) was investigated by
      using genetically athymic and euthymic WAG/Rij rats and Brown Norway (BN) rats
      with or without depletion of T cells by adult thymectomy, lethal irradiation, and
      bone marrow reconstitution. Rats were exposed to diets with no supplementation or
      diets supplemented with 150 or 450 mg HCB per kg diet for 4 (BN) or 6 (WAG/Rij)
      weeks. Skin lesion development and body weight gains were assessed during
      exposure and spleen and liver weights as well as histopathologic changes in skin,
      lung, and spleen were assessed after exposure. Oral HCB exposure of athymic and
      euthymic rats of both rat strains resulted in a dose-dependent increase of
      relative liver weight at doses of 150 and 450 mg/kg HCB and increased relative
      spleen weights at a dose of 450 mg/kg. HCB exposure of both strains further
      resulted in inflammatory changes in skin, lungs, and splenic red pulp independent
      of the T cell status except for skin lesions in the BN strain. HCB-exposed T cell
      competent BN rats showed faster skin lesion development than the T cell-depleted
      rats, although qualitatively and quantitatively similar skin pathology was
      observed at the end of the 4-week exposure in both groups. In the WAG/Rij strain
      skin lesions could not be comparatively assessed due to preexistent inflammatory
      skin pathology in the nude rats. This study showed that thymus-derived T cells
      are not required for the induction of skin and lung pathology and splenic changes
      by HCB and therefore it is suggested that HCB acts differently from many
      allergenic and autoimmunogenic low molecular weight compounds that trigger
      pathology via thymus-dependent mechanisms. A role for mononuclear phagocytes and,
      in BN rats, eosinophilic granulocytes, in the HCB-induced pathology is suggested
      since these cells were prominently present in the HCB-induced lesions.

PMID- 10581213
TI  - The protein kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methyl-piperzine (H-7)
      prevents and reverses Ca(2+)-mediated injury in isolated rat hepatocyte couplets.
AB  - We have recently shown that protein kinase C (PKC) activation induces similar
      morphological and functional alterations in couplets to that caused by increments
      of intracellular Ca(2+). Since certain PKC isoforms are activated by Ca(2+), we
      tested whether the PKC inhibitor H-7 can counteract the alterations induced by
      this ion in couplets. The Ca(2+) ionophore A23187, which can mobilize Ca(2+) from
      extracellular and intracellular sources, decreased, in a dose-dependent manner,
      the percentage of couplets accumulating the fluorescent bile acid analogue cholyl
      lysyl-fluorescein (CLF) in their canalicular vacuoles, i.e., in the canalicular
      vacuolar accumulation test (cVA of CLF), a measure of the overall capability of
      the couplets to secrete and retain CLF. To a similar extent, A23187 also
      decreased the percentage of couplets retaining CLF once secreted, i.e., in the
      canalicular vacuole retention test (cVR of CLF), a measure of tight junctional
      integrity. ATP (50 microM), another Ca(2+)-elevating compound, altered
      canalicular function in a similar extent to A23187. All these functional changes
      were prevented by H-7 in a dose-dependent manner. Canalicular dysfunction was
      accompanied by bleb formation and extensive redistribution of F-actin from the
      pericanalicular area to the cell body, which was also fully prevented by H-7; the
      intracellular Ca(2+) chelator, 1, 2-bis(o-aminophenoxy)-ethene-N,N,N',N'
      tetraacetate tetrakis-(acetomethylester), (BAPTA/AM) (20 microM) had virtually
      the same preventive effects as H-7. Both H-7 and BAPTA/AM not only prevented but
      also reversed the decrease in cVA of CLF and blebbing induced by A23187. Thus, H
      7 can both prevent and reverse Ca(2+)-mediated hepatocellular injury.

PMID- 10581214
TI  - AA-861-induced Ca(2+) mobilization in Madin Darby canine kidney cells.
AB  - The effect of 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1, 4-benzoquinone
      (AA-861), a 5-lipoxygenase inhibitor, on Ca(2+) mobilization in Madin Darby
      canine kidney (MDCK) cells has been examined by fluorimetry using fura-2 as a
      Ca(2+) indicator. AA-861 at 10-200 microM increased [Ca(2+)](i) concentration
      dependently. The signal comprised an initial rise and a sustained phase. Ca(2+)
      removal inhibited the Ca(2+) signals by reducing both the initial rise and the
      sustained phase. In Ca(2+)-free medium, pretreatment with 50 microM AA-861
      abolished the Ca(2+) release induced by thapsigargin (1 microM), an endoplasmic
      reticulum Ca(2+) pump inhibitor, and carbonylcyanide m-chlorophenylhydrazone
      (CCCP; 2 microM), a mitochondrial uncoupler. Pretreatment with CCCP, thapsigargin
      and gly-phe-beta-naphthylamide to deplete the Ca(2+) stores in mitochondria, the
      endoplasmic reticulum, and lysosomes, respectively, only partly inhibited AA-861
      induced Ca(2+) release. This suggests AA-861 released Ca(2+) from multiple
      internal pools. Addition of 3 mM Ca(2+) induced a [Ca(2+)](i) rise after
      pretreatment with 50 microM AA-861 in Ca(2+)-free medium. AA-861 (50 microM)
      induced internal Ca(2+) release was not altered by inhibition of phospholipase C
      with U73122 (2 microM) but was inhibited by 40% by inhibition of phospholipase
      A(2) with aristolochic acid (40 microM). Collectively, we found that AA-861
      increased [Ca(2+)](i) in MDCK cells by releasing Ca(2+) from multiple internal
      stores in a manner independent of the formation of inositol-1,4,5-trisphosphate,
      followed by Ca(2+) entry from external medium.

PMID- 10581216
TI  - Fitting two languages into one brain.

PMID- 10581215
TI  - trans-Activation of PPARalpha and PPARgamma by structurally diverse environmental
      chemicals.
AB  - A large number of industrial chemicals and environmental pollutants, including
      trichloroethylene (TCE), di(2-ethylhexyl)phthalate (DEHP), perfluorooctanoic acid
      (PFOA), and various phenoxyacetic acid herbicides, are nongenotoxic rodent
      hepatocarcinogens whose human health risk is uncertain. Rodent model studies have
      identified the receptor involved in the hepatotoxic and hepatocarcinogenic
      actions of these chemicals as peroxisome proliferator-activated receptor alpha
      (PPARalpha), a nuclear receptor that is highly expressed in liver. Humans exhibit
      a weak response to these peroxisome proliferator chemicals, which in part results
      from the relatively low level of PPARalpha expression in human liver. Cell
      transfection studies were carried out to investigate the interactions of
      peroxisome proliferator chemicals with PPARalpha, cloned from human and mouse,
      and with PPARgamma, a PPAR isoform that is highly expressed in multiple human
      tissues and is an important regulator of physiological processes such as
      adipogenesis and hematopoiesis. With three environmental chemicals, TCE,
      perchloroethylene, and DEHP, PPARalpha was found to be activated by metabolites,
      but not by the parent chemical. A decreased sensitivity of human PPARalpha
      compared to mouse PPARalpha to trans-activation was observed with some (Wy-14,
      643, PFOA), but not other, peroxisome proliferators (TCE metabolites,
      trichloroacetate and dichloroacetate; and DEHP metabolites, mono[2
      ethylhexyl]phthalate and 2-ethylhexanoic acid). Investigation of human and mouse
      PPARgamma revealed the transcriptional activity of this receptor to be stimulated
      by mono(2-ethylhexyl)phthalate, a DEHP metabolite that induces developmental and
      reproductive organ toxicities in rodents. This finding suggests that PPARgamma,
      which is highly expressed in human adipose tissue, where many lipophilic foreign
      chemicals tend to accumulate, as well as in colon, heart, liver, testis, spleen,
      and hematopoietic cells, may be a heretofore unrecognized target in human cells
      for a subset of industrial and environmental chemicals of the peroxisome
      proliferator class.

PMID- 10581217
TI  - Neuropsychological outcome following unilateral pallidotomy.
AB  - Despite the findings of significantly improved motor functioning following
      pallidotomy for the treatment of Parkinson's disease, the cognitive sequelae
      following surgery have yet to be clearly defined. With increasing knowledge of
      the surgery's effect on frontostriatal circuits, the cognitive processes
      potentially affected by the procedure require further exploration to evaluate
      fully the efficacy of the treatment. We reviewed 10 studies on the
      neuropsychological outcome after pallidotomy that were published in peer-reviewed
      journals. A general agreement exists that pallidotomy is a relatively safe and
      effective treatment for ameliorating the motor symptoms of Parkinson's disease,
      with relatively few cognitive changes reported following surgery. However, a
      number of conceptual and methodological concerns, including diverse selection
      criteria, small sample sizes and short follow-up periods, limit the
      interpretation and generalizability of these findings. These concerns are
      discussed in detail, along with a summary of the current neuropsychological
      literature, suggested guidelines for the conduct of research and future research
      directions. The neuropsychological findings are critically reviewed and tabulated
      by study, cognitive domain and follow-up period, with particular emphasis on
      hemisphere-specific cognitive changes.

PMID- 10581218
TI  - A functional imaging study of translation and language switching.
AB  - The neural systems underlying translation and language switching were
      investigated using PET. Proficient German-English adult bilinguals were scanned
      whilst either translating or reading visually presented words in German (L1),
      English (L2) or alternating L1/L2. We refer to alternating L1/L2 as 'switching'.
      The results revealed contrasting patterns of activation for translation and
      switching, suggesting at least partially independent mechanisms. Translation, but
      not switching, increased activity in the anterior cingulate and subcortical
      structures whilst decreasing activation in several other temporal and parietal
      language areas associated with the meaning of words. Translation also increased
      activation in regions associated with articulation (the anterior insula,
      cerebellum and supplementary motor area) arguably because the reading response to
      the stimulus must be inhibited whilst a response in a different language is
      activated. In contrast, switching the input language resulted in activation of
      Broca's area and the supramarginal gyri, areas associated with phonological
      recoding. The results are discussed in terms of the cognitive control of language
      processes.

PMID- 10581219
TI  - Does sympathetic nerve discharge affect the firing of polymodal C-fibre afferents
      in humans?
AB  - Experimental and clinical studies in animals and humans have indicated that
      nociceptive nerve fibres can acquire sensitivity to norepinephrine after injury
      or chemical sensitization. To evaluate the functional relevance of such
      sensitization, we recorded the activity of single polymodal C-fibre afferents in
      healthy human volunteers and investigated whether intense physiological sympatho
      excitation could affect their firing properties. This was studied before and
      after chemical sensitization of receptive fields by topical application of
      mustard oil. All afferent C fibres investigated (11 units in 10 subjects) were
      mechano-heat-sensitive, and four of seven fibres subjected to mustard oil were
      also chemosensitive. Putative sensitivity to sympathetic stimulation was
      investigated during low-frequency (0.25 Hz) electrical stimulation of the unit
      receptive field at a threshold intensity sufficient to evoke an action potential
      in the afferent fibre after every second to third stimulus. Following a prolonged
      period of silent rest, sympathoexcitation was elicited by forced mental
      arithmetic for 60 s, again followed by a long silent rest period. During stress,
      sympathetic nerve traffic increased to 625 +/- 146% of the control level, while
      firing of the afferent units remained unchanged. There was no sign of
      sympathetically mediated direct activation of afferent units and no change in the
      relative amounts of afferent activations caused by the background electrical
      stimulation. Results were similar for all units, both before (seven units in six
      subjects) and after (seven units in seven subjects) chemical sensitization of
      their cutaneous receptive field. The results suggest that if chemical
      sensitization of nociceptive C afferent neurons with mustard oil does induce
      sensitivity to noradrenaline in humans, it is not sufficient to make C
      nociceptive fibres respond to short-lasting physiological variations in
      sympathetic outflow.

PMID- 10581220
TI  - Secondary hyperalgesia to punctate mechanical stimuli. Central sensitization to A
      fibre nociceptor input.
AB  - Tissue injury induces enhanced pain sensation to light touch and punctate stimuli
      in adjacent, uninjured skin (secondary hyperalgesia). Whereas hyperalgesia to
      light touch (allodynia) is mediated by A-fibre low-threshold mechanoreceptors,
      hyperalgesia to punctate stimuli may be mediated by A- or C-fibre nociceptors. To
      disclose the relative contributions of A- and C-fibres to the hyperalgesia to
      punctate stimuli, the superficial radial nerve was blocked by pressure at the
      wrist in nine healthy subjects. Secondary hyperalgesia was induced by intradermal
      injection of 40 microg capsaicin, and pain sensitivity in adjacent skin was
      tested with 200 micron diameter probes (35-407 mN). The progress of conduction
      blockade was monitored by touch, cold, warm and first pain detection and by
      compound sensory nerve action potential. When A-fibre conduction was blocked
      completely but C-fibre conduction was fully intact, pricking pain to punctate
      stimuli was reduced by 75%, but burning pain to capsaicin injection remained
      unchanged. In normal skin without A-fibre blockade, pain ratings to the punctate
      probes increased significantly by a factor of two after adjacent capsaicin
      injection. In contrast, pain ratings to the punctate probes were not increased
      after capsaicin injection when A-fibre conduction was selectively blocked.
      However, hyperalgesia to punctate stimuli was detectable immediately after block
      release, when A-fibre conduction returned to normal. In conclusion, the pricking
      pain to punctate stimuli is predominantly mediated by A-fibre nociceptors. In
      secondary hyperalgesia, this pathway is heterosynaptically facilitated by
      conditioning C-fibre input. Thus, secondary hyperalgesia to punctate stimuli is
      induced by nociceptive C-fibre discharge but mediated by nociceptive A-fibres.

PMID- 10581221
TI  - Air-puff-induced facilitation of motor cortical excitability studied in patients
      with discrete brain lesions.
AB  - Air-puff stimulation applied to a fingertip is known to exert a location-specific
      facilitatory effect on the size of the motor evoked potentials elicited in hand
      muscles by transcranial magnetic stimulation. In order to clarify its nature and
      the pathway responsible for its generation, we studied 27 patients with discrete
      lesions in the brain (16, 9 and 2 patients with lesions in the cerebral cortex,
      thalamus and brainstem, respectively). Facilitation was absent in patients with
      lesions affecting the primary sensorimotor area, whereas it was preserved in
      patients with cortical lesions that spared this area. Facilitation was abolished
      with thalamic lesions that totally destroyed the nucleus ventralis
      posterolateralis (VPL), but was preserved with lesions that at least partly
      spared it. Lesions of the spinothalamic tract did not impair facilitation. The
      size of the N20-P25 component of the somatosensory evoked potential showed a mild
      correlation with the amount of facilitation. The facilitation is mainly mediated
      by sensory inputs that ascend the dorsal column and reach the cortex through VPL.
      These are fed into the primary motor area via the primary sensory area,
      especially its anterior portion, corresponding to Brodmann areas 3 and 1
      (possibly also area 2), without involving other cortical regions. The
      spinothalamic tract and direct thalamic inputs into the motor cortex do not
      contribute much to this effect. Some patients could generate voluntary movements
      despite the absence of the facilitatory effect. The present method will enable us
      to investigate in humans the function of one of the somatotopically organized
      sensory feedback input pathways into the motor cortex, and will be useful in
      monitoring ongoing finger movements during object manipulation.

PMID- 10581222
TI  - A quantitative analysis of oligodendrocytes in multiple sclerosis lesions. A
      study of 113 cases.
AB  - We studied quantitatively the fate of oligodendrocytes (OGs) during lesion
      formation in 395 lesion areas from biopsy and autopsy tissue of 113 multiple
      sclerosis cases. The density of OGs in multiple sclerosis lesions was variable at
      all stages of demyelinating activity, ranging from nearly complete loss to values
      exceeding those in the periplaque white matter (range 0-970 OGs/mm2) determine
      whether there were distinct patterns of OG pathology in different patients, we
      restricted our analysis to the 56 cases in which the longitudinal extent of the
      lesion extended from periplaque white matter into the active demyelinating edge
      and inactive plaque centre. Two major groups of OG pathology were defined by the
      presence or absence of increased OGs within the lesion. In 70% (39 out of 56) of
      the cases, OGs were variably reduced during active stages of myelin destruction,
      but reappeared within inactive or remyelinating areas. In inactive areas, an
      increased number of OGs expressing proteolipid protein (PLP) mRNA compared with
      those expressing myelin oligodendrocyte glycoprotein (MOG) suggested these cells
      may have been derived from the progenitor pool. In the remaining 30% (17 out of
      56) of the cases, extensive destruction of myelinating cells at active sites of
      demyelination was observed, but OGs were absent in inactive plaque areas without
      remyelination. In all lesions from a given patient the pattern of OG pathology
      remained consistent. A highly significant negative correlation was observed
      between number of macrophages in lesions and number of MOG- and PLP mRNA-labelled
      OGs (MOG: r = -0.32, P < 0.0000118; PLP mRNA: r = -0.23, P < 0.00238). OG density
      did not correlate with T-cell and plasma cell inflammation, or axonal loss. The
      profound heterogeneity in extent and topography of OG destruction in active
      demyelinating lesions suggests that in subsets of multiple sclerosis patients,
      myelin, mature OGs and possibly OG progenitors are differentially affected.

PMID- 10581224
TI  - An autopsy-verified study of the effect of education on degenerative dementia.
AB  - A longitudinal study of the relationship between education and age of onset, rate
      of progression and cerebral lesion burden in a series of autopsy-confirmed
      demented patients with clinical and 6-monthly psychometric follow-up and autopsy
      was carried out. The study was conducted at the London Health Sciences Centre
      University Campus of the University of Western Ontario on 87 patients with
      pathologically confirmed Alzheimer's disease (60), dementia with Lewy bodies (11)
      or dementia with Lewy bodies plus Alzheimer's disease (16). Their educational
      attainment was classified as below high school, high school or above high school,
      and was similar to that of the age-adjusted general Ontario population. The age
      of onset of dementia, age at death, progression of cognitive decline, amount of
      neurodegenerative changes (senile plaques, neurofibrillary tangles and Lewy
      bodies) and cerebrovascular lesions (infarcts, lacunar state and white matter
      rarefaction) were assessed. Less educated patients became demented later and died
      later, but cognitive function declined at the same rate in all educational groups
      and there was no difference in the burden of neurodegenerative lesions between
      them. However, the less educated patients had more cerebrovascular lesions. It
      can be concluded that higher education does not modify the course of Alzheimer's
      disease, but lower education relates to the occurrence of cerebral infarcts. Our
      results suggest that a 'brain battering' model related to the higher prevalence
      of small vascular lesions in less educated individuals may explain their
      increased risk of dementia described by epidemiological studies better than the
      prevalent 'brain reserve' hypothesis.

PMID- 10581223
TI  - Immunological profile of patients with primary progressive multiple sclerosis.
      Expression of adhesion molecules.
AB  - Adhesion molecules are important in the trafficking of peripheral leucocytes into
      the central nervous system, a major event in the pathogenesis of multiple
      sclerosis, which is an inflammatory and demyelinating disease. The latest MRI
      evidence supports clinical divergence between forms of multiple sclerosis with
      relapses and the primary progressive form without relapses, which shows fewer and
      smaller inflammatory lesions. With the aim of elucidating whether different
      pathogenic mechanisms are involved in primary progressive multiple sclerosis, we
      compared membrane expression of the adhesion molecules ICAM-1 (CD54), LFA-1alpha
      (CD11a), VLA-4 [alpha(4)/beta(1) integrin (CD49d/CD29)], L-selectin (CD62L) and
      ICAM-3 (CD50) in peripheral blood and the serum-soluble forms ICAM-1, L-selectin,
      VCAM-1 and ICAM-3 in 89 patients (39 with the primary progressive form, 25 with
      the secondary progressive form and 25 with the relapsing-remitting form) and 38
      healthy controls. We found a significant decrease in leucocyte surface expression
      of most of the adhesion molecules tested and an increase in soluble ICAM-1 and L
      selectin levels in secondary progressive and relapsing-remitting multiple
      sclerosis compared with primary progressive multiple sclerosis, which gave
      results similar to those in controls. These results, which are supported by MRI
      evidence, show that trafficking of autoreactive leucocytes through the blood
      brain barrier is crucial to the pathogenesis of secondary progressive and
      relapsing-remitting forms of multiple sclerosis, whereas other mechanisms leading
      to progressive axonal damage would account for primary progressive forms of the
      disease.

PMID- 10581225
TI  - Primary CA1 and conditionally immortal MHP36 cell grafts restore conditional
      discrimination learning and recall in marmosets after excitotoxic lesions of the
      hippocampal CA1 field.
AB  - Common marmosets (Callithrix jacchus, n = 18) were trained to discriminate
      between rewarded and non-rewarded objects (simple discriminations, SDs) and to
      make conditional discriminations (CDs) when presented sequentially with two
      different pairs of identical objects signifying reward either in the right or
      left food well of the Wisconsin General Test Apparatus. After bilateral N-methyl
      D-aspartate (0.12 M) lesions through the cornu ammonis-1 (CA1) field (7 microl in
      five sites), marmosets showed profound impairment in recall of CDs but not SDs,
      and were assigned to lesion only, lesion plus CA1 grafts and lesion plus Maudsley
      hippocampal cell line, clone 36 (MHP36) grafts groups matched for lesion-induced
      impairment. Cell suspension grafts (4 microl, 15-25 000 cells/microl) of cells
      dissected from the CA1 region of foetal brain at embryonic day 94-96, or of
      conditionally immortalized MHP36 cells, derived from the H-2Kb-tsA58 transgenic
      mouse neuroepithelium and labelled with [3H]thymidine, were infused at the lesion
      sites. The lesion plus MHP36 grafts group was injected five times per week with
      cyclosporin A (10 mg/kg) throughout testing. Lesion, grafted and intact control
      marmosets (n = 4-5/group) were tested on recall of SDs and CDs learned before
      lesioning and on acquisition of four new CDs over a 6-month period. Lesioned
      animals were highly impaired in recall and acquisition of CD tasks, but recall of
      SDs was not significantly disrupted. Both grafted groups of marmosets showed
      improvement to control level in recall of CDs. They were significantly slower in
      learning the first new CD task, but mastered the remaining tasks as efficiently
      as controls and were substantially superior to the lesion-only group. Visualized
      by Nissl staining, foetal grafts formed clumps of pyramidal-like cells within the
      denervated CA1 field, or jutted into the lateral ventricles. MHP36 cells,
      identified by beta-galactosidase staining and autoradiography, showed neuronal
      and astrocytic morphology, and were distributed evenly throughout the CA1 region.
      The results indicate that MHP36 cell grafts are as functionally effective as
      foetal grafts and appear to integrate into the host brain in a structurally
      appropriate manner, showing the capacity to differentiate into both mature
      neurons and glia, and to develop morphologies appropriate to the site of
      migration. These findings, which parallel the facilitative effects of foetal and
      MHP36 grafts in rats with ischaemic CA1 damage, offer encouragement for the
      development of conditionally immortal neuroepithelial stem cell lines for
      grafting in conditions of severe amnesia and hippocampal damage following
      recovery from cardiac arrest or other global ischaemic episodes.

PMID- 10581226
TI  - The neural correlates of verb and noun processing. A PET study.
AB  - The hypothesis that categorical information, distinguishing among word classes,
      such as nouns, verbs, etc., is an organizational principle of lexical knowledge
      in the brain, is supported by the observation of aphasic subjects who are
      selectively impaired in the processing of nouns and verbs. The study of lesion
      location in these patients has suggested that the left temporal lobe plays a
      crucial role in processing nouns, while the left frontal lobe is necessary for
      verbs. To delineate the brain areas involved in the processing of different word
      classes, we used PET to measure regional cerebral activity during tasks requiring
      reading of concrete and abstract nouns and verbs for lexical decision. These
      tasks activated an extensive network of brain areas, mostly in the left frontal
      and temporal cortex, which represents the neural correlate of single word
      processing. Some left hemispheric areas, including the dorsolateral frontal and
      lateral temporal cortex, were activated only by verbs, while there were no brain
      areas more active in response to nouns. Furthermore, the comparison of abstract
      and concrete words indicated that abstract word processing was associated with
      selective activations (right temporal pole and amygdala, bilateral inferior
      frontal cortex), while no brain areas were more active in response to concrete
      words. There were no significant interaction effects between word class and
      concreteness. Taken together, these findings are compatible with the view that
      lexical-semantic processing of words is mediated by an extensive, predominantly
      left hemispheric network of brain structures. Additional brain activations appear
      to be related to specific semantic content, or, in the case of verbs, may be
      associated with the automatic access of syntactic information.

PMID- 10581227
TI  - How to improve the clinical diagnosis of Creutzfeldt-Jakob disease.
AB  - This paper describes a prospective follow-up of 364 patients initially notified
      as suspected Creutzfeldt-Jakob disease to a Surveillance Unit in Gottingen,
      Germany. Six patients were diagnosed as having genetic prion disease by blood
      analysis and were excluded from the study. After examination and review of the
      remaining 358, 193 were classified as probable Creutzfeldt-Jakob disease.
      However, autopsy revealed that five of the 193 did not have Creutzfeldt-Jakob
      disease (four cases, Alzheimer's disease; one case, cerebral lymphoma). Of the 54
      patients classified as possible Creutzfeldt-Jakob disease, 10 had another
      diagnosis made at autopsy. Two of the 111 cases originally classified as having
      other diseases were found to have Creutzfeldt-Jakob disease on autopsy. Autopsy
      evidence, together with follow-up of the patients still living and those who died
      without autopsy, revealed a broad range of other diagnoses. In the younger age
      groups, the commonest were chronic inflammatory diseases including Hashimoto
      encephalitis, whilst rapidly progressive Alzheimer's disease was most common in
      the older age groups. The presence of 14-3-3 protein in the CSF discriminated
      better between Creutzfeldt-Jakob disease and other rapidly progressive dementias
      than did the EEG pattern or the MRI. The inclusion of this CSF protein in the
      criteria of Masters and colleagues (Ann Neurol 1979; 5: 177-88) improves the
      accuracy and confidence in the clinical diagnosis of Creutzfeldt-Jakob disease.

PMID- 10581228
TI  - Huntington's disease progression. PET and clinical observations.
AB  - Using serial [(11)C]SCH 23390- and [11C]raclopride-PET, we have measured the rate
      of loss of striatal dopamine D1 and D2 receptor binding over a mean of 40 months
      in nine asymptomatic adult Huntington's disease mutation carriers, four patients
      with symptomatic disease, seven mutation-negative controls and three subjects at
      risk for the disease. Eight of the nine asymptomatic Huntington's disease
      mutation carriers had serial [11C]raclopride-PET and showed a mean annual loss of
      striatal D2 binding of 4.0%. Only five of these eight, however, showed active
      progression, and they had a mean annual loss of D2 binding of 6.5%. All nine
      asymptomatic mutation carriers had serial [11C]SCH 23390-PET and showed a mean
      annual loss of striatal D1 binding of 2. 0%. Four of these subjects demonstrated
      active progression and they had a mean annual loss of 4.5%. Our four symptomatic
      Huntington's disease patients showed a mean annual loss of D2 binding of 3.0% and
      of D1 binding of 5.0%. Loss of striatal D1 and D2 binding was significantly
      greater in the known mutation carriers than in the combined at-risk and gene
      negative groups (P < 0.05). At follow-up PET all subjects were clinically
      assessed using the Unified Huntington's Disease Rating Scale. Scores for motor
      function and total functional capacity correlated with PET measures of striatal
      dopamine receptor binding both in the asymptomatic mutation carriers (D1, P <
      0.01) and across the combined asymptomatic and clinically affected Huntington's
      disease mutation carrier group (D1 and D2, P < 0.001). We conclude that PET
      measures of striatal D1 and D2 dopamine binding can be used to identify
      asymptomatic Huntington's disease mutation carriers who are actively progressing
      and who would thus be suitable for putative neuroprotective therapies. Measures
      of disease progression rates in Huntington's disease patients and asymptomatic
      mutation carriers will be of critical importance in future trials of experimental
      restorative treatments.

PMID- 10581229
TI  - Bilateral subthalamic nucleus stimulation improves frontal cortex function in
      Parkinson's disease. An electrophysiological study of the contingent negative
      variation.
AB  - Parkinson's disease involves impaired activation of frontal cortical areas,
      including the supplementary motor area and prefrontal cortex, resulting from
      impaired thalamocortical output of the basal ganglia. Electrophysiologically,
      such impaired cortical activation may be seen as a reduced amplitude of the
      contingent negative variation (CNV), a slow negative potential shift reflecting
      cognitive processes associated with the preparation and/or anticipation of a
      response. Surgical interventions aimed at increasing basal ganglia-thalamic
      outflow to the cortex, such as electrical stimulation of the subthalamic nucleus
      with chronically implanted electrodes, have been shown to be effective in
      improving the clinical symptoms of Parkinson's disease. This study examined
      changes in cortical activity, as reflected in the CNV, associated with bilateral
      subthalamic nucleus stimulation in Parkinson's disease. The CNV was recorded from
      10 patients with Parkinson's disease when on and off bilateral subthalamic
      nucleus stimulation, and was compared with the CNV of 10 healthy control
      subjects. Without subthalamic nucleus stimulation, Parkinson's disease patients
      showed reduced CNV amplitudes over the frontal and frontocentral regions compared
      with control subjects. With bilateral subthalamic nucleus stimulation, however,
      CNV amplitudes over the frontal and frontocentral regions were significantly
      increased. Results therefore suggest that impaired cortical functioning in
      Parkinson's disease, particularly within the frontal and premotor areas, is
      improved by subthalamic nucleus stimulation.

PMID- 10581230
TI  - Prominent psychiatric features and early onset in an inherited prion disease with
      a new insertional mutation in the prion protein gene.
AB  - In five generations of the French M-E kindred, 11 members are now known to be or
      have been affected by a form of spongiform encephalopathy previously recorded as
      Gerstmann-Straussler-Scheinker disease. Mean age at onset was 28 years (range 21
      34 years). In six instances, these patients were hospitalized in psychiatric
      institutions with various diagnoses, the most frequent being mania or mania-like
      symptoms. Dementia occurred progressively after a lengthy course. Histological
      studies showed atrophy of the cerebellar molecular layer, which contained kuru
      and multicentric plaques labelled with anti-prion protein antibodies. Spongiosis
      was not prominent and remained largely limited to the periphery of plaques; it
      was more marked in the thalamus, where plaques were scarce. A 192 base pair (bp)
      insert (eight extra repeats of 24 bp) in the octapeptide coding region of the
      prion protein gene (PRNP) within a codon-129 methionine allele was found in four
      symptomatic subjects. Early age at onset, the prominence of psychiatric symptoms
      and the long course of the disease are noticeable clinical features in this
      family with an inherited prion disease due to a new insertional mutation in PRNP.

PMID- 10581231
TI  - Voxel-based mapping of irreversible ischaemic damage with PET in acute stroke.
AB  - Objective mapping of irreversible tissue damage in the acute stage of ischaemic
      stroke would be useful for prognosis and in assessing the efficacy of therapeutic
      manoeuvres in impeding extension of infarction. From our database of 30 patients
      studied with 15O-PET within 5-18 h after onset of first-ever middle cerebral
      artery territory stroke, we extracted a subgroup of 19 survivors (age 74.6 +/-
      8.5 years) in whom late CT coregistered with PET was available to determine final
      infarct topography. By means of a voxel-based analysis of the PET data, we
      determined putative thresholds for irreversible tissue damage as the lower limit
      of the 95% confidence interval calculated from all voxels within the ultimately
      non-infarcted brain parenchyma ipsilateral to the insult. The following values
      were found: 8.43 ml/100 ml/min, 0.87 ml/100 ml/min, 1.64 ml/100 ml, 0.27 and
      2.21/min, for cerebral blood flow (CBF), oxygen consumption (CMRO2), blood volume
      (CBV), oxygen extraction fraction and the ratio CBF : CBV, respectively. Voxels
      below these thresholds occurred significantly more frequently in the final
      infarct region than in the non-infarcted parenchyma for CBF and CMRO2 (P = 0.016
      and P = 0.0045, respectively, Wilcoxon test), but not for the other PET
      variables. Furthermore, with both CBF and CMRO2, the percentage of irreversible
      tissue damage voxels in the affected hemisphere relative to the opposite
      hemisphere was significantly positively correlated to both the volume of final
      infarct and the neurological outcome at 2 months (all P < 0.005, Spearman ranked
      test). These findings validate our voxel-based CBF and CMRO2 thresholds for
      probabilistic mapping of irreversible tissue damage within the 5-18 h interval
      after stroke onset; however, whether they would be applicable to earlier
      intervals remains to be determined. Transfer of our procedure for determination
      of irreversible tissue damage thresholds to other imaging modalities such as
      single proton emission computed tomography and diffusion-weighted MRI should be
      straightforward.

PMID- 10581233
TI  - Light and dark in chromatin repair: repair of UV-induced DNA lesions by
      photolyase and nucleotide excision repair.
AB  - Nucleotide excision repair (NER) and DNA repair by photolyase in the presence of
      light (photoreactivation) are the major pathways to remove UV-induced DNA lesions
      from the genome, thereby preventing mutagenesis and cell death. Photoreactivation
      was found in many prokaryotic and eukaryotic organisms, but not in mammals, while
      NER seems to be universally distributed. Since packaging of eukaryotic DNA in
      nucleosomes and higher order chromatin structures affects DNA structure and
      accessibility, damage formation and repair are coupled intimately to structural
      and dynamic properties of chromatin. Here, I review recent progress in the study
      of repair of chromatin and transcribed genes. Photoreactivation and NER are
      discussed as examples of how an individual enzyme and a complex repair pathway,
      respectively, access DNA lesions in chromatin and how these two repair processes
      fulfil complementary roles in removal of UV lesions. These repair pathways
      provide insight into the structural and dynamic properties of chromatin and
      suggest how other DNA repair processes could work in chromatin.

PMID- 10581232
TI  - Riboflavin therapy. Biochemical heterogeneity in two adult lipid storage
      myopathies.
AB  - Two unrelated adult males, aged 36 (patient 1) and 25 (patient 2) years,
      presented with subacute carnitine-deficient lipid storage myopathy that was
      totally and partly responsive to riboflavin supplementation in the two patients,
      respectively. Plasma acyl-carnitine and urinary organic acid profiles indicated
      multiple acyl coenzyme A dehydrogenase deficiency, which was mild in patient 1
      and severe in patient 2. The activities of short-chain and medium-chain acyl
      coenzyme A dehydrogenases in mitochondrial fractions were decreased, especially
      in patient 2. This was in agreement with Western blotting results. Flavin
      dependent complexes I and II were studied by immunoblotting and densitometric
      quantification of two-dimensional electrophoresis with comparable results.
      Complex I was present in normal amounts in both patients, whereas complex II was
      decreased only in the pretherapy muscle of patient 2. Flavin adenine dinucleotide
      (FAD) and flavin mononucleotide (FMN) concentrations in muscle and isolated
      mitochondria, and the activity of mitochondrial FAD pyrophosphatase, showed that
      patient 1 had low levels of FAD (46%) and FMN (49%) in mitochondria, with a
      significant increase (P < 0.01) in mitochondrial FAD pyrophosphatase (273%)
      compared with controls. Patient 2 had similar low levels of FAD and FMN in both
      total muscle (FAD and FMN 22% of controls) and mitochondria (FAD 26%; FMN 16%)
      and normal activity of mitochondrial FAD pyrophosphatase. All of these
      biochemical parameters were either totally or partly corrected after riboflavin
      therapy.

PMID- 10581234
TI  - Crystal structure of a thwarted mismatch glycosylase DNA repair complex.
AB  - The bacterial mismatch-specific uracil-DNA glycosylase (MUG) and eukaryotic
      thymine-DNA glycosylase (TDG) enzymes form a homologous family of DNA
      glycosylases that initiate base-excision repair of G:U/T mismatches. Despite low
      sequence homology, the MUG/TDG enzymes are structurally related to the uracil-DNA
      glycosylase enzymes, but have a very different mechanism for substrate
      recognition. We have now determined the crystal structure of the Escherichia coli
      MUG enzyme complexed with an oligonucleotide containing a non-hydrolysable
      deoxyuridine analogue mismatched with guanine, providing the first structure of
      an intact substrate-nucleotide productively bound to a hydrolytic DNA
      glycosylase. The structure of this complex explains the preference for G:U over
      G:T mispairs, and reveals an essentially non-specific pyrimidine-binding pocket
      that allows MUG/TDG enzymes to excise the alkylated base, 3, N(4)-ethenocytosine.
      Together with structures for the free enzyme and for an abasic-DNA product
      complex, the MUG-substrate analogue complex reveals the conformational changes
      accompanying the catalytic cycle of substrate binding, base excision and product
      release.

PMID- 10581235
TI  - The structure of a chromosomal high mobility group protein-DNA complex reveals
      sequence-neutral mechanisms important for non-sequence-specific DNA recognition.
AB  - The high mobility group (HMG) chromosomal proteins, which are common to all
      eukaryotes, bind DNA in a non-sequence-specific fashion to promote chromatin
      function and gene regulation. They interact directly with nucleosomes and are
      believed to be modulators of chromatin structure. They are also important in
      V(D)J recombination and in activating a number of regulators of gene expression,
      including p53, Hox transcription factors and steroid hormone receptors, by
      increasing their affinity for DNA. The X-ray crystal structure, at 2.2 A
      resolution, of the HMG domain of the Drosophila melanogaster protein, HMG-D,
      bound to DNA provides the first detailed view of a chromosomal HMG domain
      interacting with linear DNA and reveals the molecular basis of non-sequence
      specific DNA recognition. Ser10 forms water-mediated hydrogen bonds to DNA bases,
      and Val32 with Thr33 partially intercalates the DNA. These two 'sequence-neutral'
      mechanisms of DNA binding substitute for base-specific hydrogen bonds made by
      equivalent residues of the sequence-specific HMG domain protein, lymphoid
      enhancer factor-1. The use of multiple intercalations and water-mediated DNA
      contacts may prove to be generally important mechanisms by which chromosomal
      proteins bind to DNA in the minor groove.

PMID- 10581236
TI  - Mre11 is essential for the maintenance of chromosomal DNA in vertebrate cells.
AB  - Yeast Mre11 functions with Rad50 and Xrs2 in a complex that has pivotal roles in
      homologous recombination (HR) and non-homologous end-joining (NHEJ) DNA double
      strand break (DSB) repair pathways. Vertebrate Mre11 is essential. Conditionally,
      MRE11 null chicken DT40 cells accumulate chromosome breaks and die upon Mre11
      repression, showing frequent centrosome amplification. Mre11 deficiency also
      causes increased radiosensitivity and strongly reduced targeted integration
      frequencies. Mre11 is, therefore, crucial for HR and essential in mitosis through
      its role in chromosome maintenance by recombinational repair. Surprisingly
      perhaps, given the role of Mre11 in yeast NHEJ, disruption of NHEJ by deletion of
      KU70 greatly exacerbates the effects of MRE11 deficiency, revealing a significant
      Mre11-independent component of metazoan NHEJ.

PMID- 10581237
TI  - Quantitative comparison of DNA looping in vitro and in vivo: chromatin increases
      effective DNA flexibility at short distances.
AB  - The probability that two sites on a linear DNA molecule will contact each other
      by looping depends on DNA flexibility. Although the flexibility of naked DNA in
      vitro is well characterized, looping in chromatin is poorly understood. By
      extending existing theory, we present a single equation that describes DNA
      looping over all distances. We also show that DNA looping in vitro can be
      measured accurately by FLP recombination between sites from 74 bp to 15 kb apart.
      In agreement with previous work, a persistence length of 50 nm was determined.
      FLP recombination of the same substrates in mammalian cells showed that chromatin
      increases the flexibility of DNA at short distances, giving an apparent
      persistence length of 27 nm.

PMID- 10581238
TI  - Replication cycle-coordinated change of the adenine nucleotide-bound forms of
      DnaA protein in Escherichia coli.
AB  - The ATP-bound but not the ADP-bound form of DnaA protein is active for
      replication initiation at the Escherichia coli chromosomal origin. The hydrolysis
      of ATP bound to DnaA is accelerated by the sliding clamp of DNA polymerase III
      loaded on DNA. Using a culture of randomly dividing cells, we now have evidence
      that the cellular level of ATP-DnaA is repressed to only approximately 20% of the
      total DnaA molecules, in a manner depending on DNA replication. In a synchronized
      culture, the ATP-DnaA level showed oscillation that has a temporal increase
      around the time of initiation, and decreases rapidly after initiation. Production
      of ATP-DnaA depended on concomitant protein synthesis, but not on SOS response,
      Dam or SeqA. Regeneration of ATP-DnaA from ADP-DnaA was also observed. These
      results indicate that the nucleotide form shifts of DnaA are tightly linked with
      an epistatic cell cycle event and with the chromosomal replication system.

PMID- 10581239
TI  - Solution structure of the methyl-CpG-binding domain of the methylation-dependent
      transcriptional repressor MBD1.
AB  - CpG methylation in vertebrates is important for gene silencing, alterations in
      chromatin structure and genomic stability, and differences in the DNA-methylation
      status are correlated with imprinting phenomena, carcinogenesis and embryonic
      development. Methylation signals are interpreted by protein factors that contain
      shared methyl-CpG-binding domains (MBDs). We have determined the solution
      structure of the MBD of the human methylation-dependent transcriptional repressor
      MBD1 by multi-dimensional heteronuclear NMR spectroscopy. It folds into an
      alpha/beta-sandwich structure with characteristic loops. Basic residues conserved
      in the MBD family are largely confined to one face of this fold and a flexible
      loop, which together form a large positively charged surface. Site-directed
      mutagenesis and chemical shift changes upon complexing with a methylated DNA
      facilitated identification of this surface as the DNA interaction site. In
      addition to three basic residues, conserved Tyr34 and Asp32 were shown to be
      important for the DNA binding.

PMID- 10581240
TI  - A new regulatory domain on the TATA-binding protein.
AB  - Recognition of the TATA box by the TATA-binding protein (TBP) is a highly
      regulated step in RNA polymerase II-dependent transcription. Several proteins
      have been proposed to regulate TBP activity, yet the TBP domains responsive to
      all these regulators have not been defined. Here we describe a new class of TBP
      mutants that increase transcription from core promoters in vivo. The majority of
      these mutations alter amino acids that cluster tightly on the TBP surface,
      defining a new TBP regulatory domain. The mutant TBP proteins are defective for
      binding the transcriptional regulator yNC2, are resistant to inhibition by yNC2
      in vitro and exhibit allele-specific genetic interactions with yNC2. These
      results provide strong biochemical and genetic evidence that TBP is directly
      repressed in vivo, and define a new TBP domain important for transcriptional
      regulation.

PMID- 10581241
TI  - Gal83 mediates the interaction of the Snf1 kinase complex with the transcription
      activator Sip4.
AB  - The Snf1/AMPK protein kinase family is widely conserved in eukaryotes. In
      Saccharomyces cerevisiae, the Snf1 kinase is an essential element of the glucose
      response pathway and has diverse regulatory roles. The Snf1 complex contains one
      of the related proteins Sip1, Sip2 and Gal83, which are also conserved in higher
      eukaryotes. Previous studies showed that the Sip1/Sip2/Gal83 component plays a
      structural role in the complex. We present evidence that this component also
      mediates the interaction of the Snf1 kinase complex with specific targets. We
      show that Gal83 mediates the association of the kinase with Sip4, a Snf1
      regulated transcription activator of gluconeogenic genes. Gal83 interacts with
      Sip4 in two-hybrid assays in vivo, and bacterially expressed proteins bind in
      vitro. Moreover, Gal83 is required for the two-hybrid interaction of Sip4 with
      the Snf1 kinase. Gal83 also facilitates the rapid Snf1-dependent phosphorylation
      and activation of Sip4 in response to glucose limitation, indicating that Gal83
      mediates the functional interaction of Snf1 with Sip4. Evidence indicates that
      Sip1 and Sip2 do not interact with Sip4. We propose that members of the
      Sip1/Sip2/Gal83 family confer specificity to the kinase complex in its
      interactions with target proteins.

PMID- 10581242
TI  - An N-terminal nuclear export signal is required for the nucleocytoplasmic
      shuttling of IkappaBalpha.
AB  - The potent transcriptional activities of Rel/NF-kappaB proteins are regulated in
      the cytoplasm and nucleus by the inhibitor, IkappaBalpha. The mechanism, by which
      IkappaBalpha can either sequester NF-kappaB in the cytoplasm or act as a nuclear
      post-induction repressor of NF-kappaB, is uncertain. We find that IkappaBalpha
      shuttles continuously between the nucleus and cytoplasm. This shuttling requires
      a previously unidentified CRM1-dependent nuclear export signal (NES) located
      within the N-terminal domain of IkappaBalpha at amino acids 45-55. Deletion or
      mutation of the N-terminal NES results in nuclear localization of IkappaBalpha.
      NF-kappaB (p65) association with IkappaBalpha affects steady-state localization
      but does not inhibit its shuttling. Endogenous complexes of IkappaBalpha-NF
      kappaB shuttle and will accumulate in the nucleus when CRM1 export is blocked. We
      find TNFalpha can activate the nuclear IkappaBalpha-NF-kappaB complexes by the
      classical mechanism of proteasome-mediated degradation of IkappaBalpha. These
      studies reveal a more dynamic nucleocytoplasmic distribution for IkappaBalpha and
      NF-kappaB suggesting previously unknown strategies for regulating this ubiquitous
      family of transcription activators.

PMID- 10581243
TI  - NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a
      novel IKK-related kinase.
AB  - The activation of NF-kappaB by receptors in the tumor necrosis factor (TNF)
      receptor and Toll/interleukin-1 (IL-1) receptor families requires the TRAF family
      of adaptor proteins. Receptor oligomerization causes the recruitment of TRAFs to
      the receptor complex, followed by the activation of a kinase cascade that results
      in the phosphorylation of IkappaB. TANK is a TRAF-binding protein that can
      inhibit the binding of TRAFs to receptor tails and can also inhibit NF-kappaB
      activation by these receptors. However, TANK also displays the ability to
      stimulate TRAF-mediated NF-kappaB activation. In this report, we investigate the
      mechanism of the stimulatory activity of TANK. We find that TANK interacts with
      TBK1 (TANK-binding kinase 1), a novel IKK-related kinase that can activate NF
      kappaB in a kinase-dependent manner. TBK1, TANK and TRAF2 can form a ternary
      complex, and complex formation appears to be required for TBK1 activity. Kinase
      inactive TBK1 inhibits TANK-mediated NF-kappaB activation but does not block the
      activation mediated by TNF-alpha, IL-1 or CD40. The TBK1-TANK-TRAF2 signaling
      complex functions upstream of NIK and the IKK complex and represents an
      alternative to the receptor signaling complex for TRAF-mediated activation of NF
      kappaB.

PMID- 10581244
TI  - Kinetic dissection of fundamental processes of eukaryotic translation initiation
      in vitro.
AB  - Approaches have been developed for the kinetic dissection of eukaryotic
      translation initiation in vitro using rabbit reticulocyte ribosomes and a crude
      preparation of initiation factors. These new approaches have allowed the kinetics
      of formation of the 43S and 80S ribosomal complexes to be followed and have
      substantially improved the ability to follow formation of the first peptide bond.
      The results suggest the existence of a new step on the initiation pathway that
      appears to require at least one additional factor and the hydrolysis of GTP and
      may prepare the 80S complex for the formation of the first peptide bond. The
      initial kinetic framework and methods developed herein will allow the properties
      of individual species along the initiation pathway to be probed further and will
      facilitate dissection of the mechanistic roles of individual translation factors
      and their interplay with RNA structural elements.

PMID- 10581245
TI  - Calreticulin functions in vitro as a molecular chaperone for both glycosylated
      and non-glycosylated proteins.
AB  - Calreticulin (CRT) is thought to be a molecular chaperone that interacts with
      glycoproteins exclusively through a lectin site specific for monoglucosylated
      oligosaccharides. However, this chaperone function has never been directly
      demonstrated nor is it clear how lectin-oligosaccharide interactions facilitate
      glycoprotein folding. Using purified components, we show that CRT suppresses the
      aggregation not only of a glycoprotein bearing monoglucosylated oligosaccharides
      but also that of non-glycosylated proteins. Furthermore, CRT forms stable
      complexes with unfolded, non-glycosylated substrates but does not associate with
      native proteins. ATP and Zn(2+) enhance CRT's ability to suppress aggregation of
      non- glycoproteins, whereas engagement of its lectin site with purified
      oligosaccharide attenuates this function. CRT also confers protection against
      thermal inactivation and maintains substrates in a folding-competent state. We
      conclude that in addition to being a lectin CRT possesses a polypeptide binding
      capacity capable of discriminating between protein conformational states and that
      it functions in vitro as a classical molecular chaperone.

PMID- 10581246
TI  - MtGimC, a novel archaeal chaperone related to the eukaryotic chaperonin cofactor
      GimC/prefoldin.
AB  - Group II chaperonins in the eukaryotic and archaeal cytosol assist in protein
      folding independently of the GroES-like cofactors of eubacterial group I
      chaperonins. Recently, the eukaryotic chaperonin was shown to cooperate with the
      hetero-oligomeric protein complex GimC (prefoldin) in folding actin and tubulins.
      Here we report the characterization of the first archaeal homologue of GimC, from
      Methanobacterium thermoautotrophicum. MtGimC is a hexamer of 87 kDa, consisting
      of two alpha and four beta subunits of high alpha-helical content that are
      predicted to contain extended coiled coils and represent two evolutionarily
      conserved classes of Gim subunits. Reconstitution experiments with MtGimC suggest
      that two subunits of the alpha class (archaeal Gimalpha and eukaryotic Gim2 and
      5) form a dimer onto which four subunits of the beta class (archaeal Gimbeta and
      eukaryotic Gim1, 3, 4 and 6) assemble. MtGimalpha and beta can form hetero
      complexes with yeast Gim subunits and MtGimbeta partially complements yeast
      strains lacking Gim1 and 4. MtGimC is a molecular chaperone capable of
      stabilizing a range of non-native proteins and releasing them for subsequent
      chaperonin-assisted folding. In light of the absence of Hsp70 chaperones in many
      archaea, GimC may fulfil an ATP-independent, Hsp70-like function in archaeal de
      novo protein folding.

PMID- 10581247
TI  - Hsp26: a temperature-regulated chaperone.
AB  - Small heat shock proteins (sHsps) are a conserved protein family, with members
      found in all organisms analysed so far. Several sHsps have been shown to exhibit
      chaperone activity and protect proteins from irreversible aggregation in vitro.
      Here we show that Hsp26, an sHsp from Saccharomyces cerevisiae, is a temperature
      regulated molecular chaperone. Like other sHsps, Hsp26 forms large oligomeric
      complexes. At heat shock temperatures, however, the 24mer chaperone complex
      dissociates. Interestingly, chaperone assays performed at different temperatures
      show that the dissociation of the Hsp26 complex at heat shock temperatures is a
      prerequisite for efficient chaperone activity. Binding of non-native proteins to
      dissociated Hsp26 produces large globular assemblies with a structure that
      appears to be completely reorganized relative to the original Hsp26 oligomers. In
      this complex one monomer of substrate is bound per Hsp26 dimer. The temperature
      dependent dissociation of the large storage form of Hsp26 into a smaller, active
      species and the subsequent re-association to a defined large chaperone-substrate
      complex represents a novel mechanism for the functional activation of a molecular
      chaperone.

PMID- 10581248
TI  - Two activities of cofilin, severing and accelerating directional depolymerization
      of actin filaments, are affected differentially by mutations around the actin
      binding helix.
AB  - The biochemical activities of cofilin are controversial. We demonstrated that
      porcine cofilin severs actin filaments and accelerates monomer release at the
      pointed ends. At pH 7.1, 0.8 microM cofilin cut filaments (2.2 microM actin)
      about every 290 subunits and increased the depolymerization rate 6.4-fold. A kink
      in the major alpha-helix of cofilin is thought to constitute a contact site for
      actin. Side chain hydroxyl groups of Ser119, Ser120 and Tyr82 in cofilin form
      hydrogen bonds with main chain carbonyl moieties from the helix, causing the
      kink. We eliminated side chain hydroxyls by Ser-->Ala and/or Tyr-->Phe
      mutagenesis. Severing and depolymerization-enhancing activities were reduced
      dramatically in an Ala120 mutant, whereas the latter was decreased in a Phe82
      mutant with a relatively small effect on severing, suggesting different
      structural bases for the two activities of cofilin. The Ala120-equivalent
      mutation in yeast cofilin affected cell growth, whereas that of the Phe82
      equivalent had no effect in yeast. These results indicate the physiological
      significance of the severing activity of cofilin that is brought about by the
      kink in the helix.

PMID- 10581249
TI  - Interaction of agrin with laminin requires a coiled-coil conformation of the
      agrin-binding site within the laminin gamma1 chain.
AB  - Coiled-coil domains are found in a wide variety of proteins, where they typically
      specify subunit oligomerization. Recently, we have demonstrated that agrin, a
      multidomain heparan sulfate proteoglycan with a crucial role in the development
      of the nerve-muscle synapse, binds to the three-stranded coiled-coil domain of
      laminin-1. The interaction with laminin mediates the integration of agrin into
      basement membranes. Here we characterize the binding site within the laminin-1
      coiled coil in detail. Binding assays with individual laminin-1 full-length
      chains and fragments revealed that agrin specifically interacts with the gamma1
      subunit of laminin-1, whereas no binding to alpha1 and beta1 chains was detected.
      By using recombinant gamma1 chain fragments, we mapped the binding site to a
      sequence of 20 residues. Furthermore, we demonstrate that a coiled-coil
      conformation of this binding site is required for its interaction with agrin. The
      finding that recombinant gamma1 fragments bound at least 10-fold less than native
      laminin-1 indicates that the structure of the three-stranded coiled-coil domain
      of laminin is required for high-affinity agrin binding. Interestingly, no binding
      to a chimeric gamma2 fragment was observed, indicating that the interaction of
      agrin with laminin is isoform specific.

PMID- 10581250
TI  - Host cyclophilin A mediates HIV-1 attachment to target cells via heparans.
AB  - The present study proposes a novel mode of action for cyclophilin A (CypA) in the
      HIV-1 life cycle. We demonstrate that CypA-deficient viruses do not replicate
      because they fail to attach to target cells. We show that CypA is exposed at the
      viral membrane and mediates HIV-1 attachment. We identify heparan as the
      exclusive cellular binding partner for CypA. Furthermore, CypA binds directly to
      heparan via a domain rich in basic residues similar to known heparin-binding
      motifs. This interaction between exposed CypA and cell surface heparans
      represents the initial step of HIV-1 attachment and is a necessary precursor to
      gp120-binding to CD4. In conclusion, HIV-1 attachment to target cells is a multi
      step process that requires an initial CypA-heparan interaction followed by the
      gp120-CD4 interaction.

PMID- 10581251
TI  - Dynein motor regulation stabilizes interphase microtubule arrays and determines
      centrosome position.
AB  - Cytoplasmic dynein is a microtubule-based motor protein responsible for vesicle
      movement and spindle orientation in eukaryotic cells. We show here that dynein
      also supports microtubule architecture and determines centrosome position in
      interphase cells. Overexpression of the motor domain in Dictyostelium leads to a
      collapse of the interphase microtubule array, forming loose bundles that often
      enwrap the nucleus. Using green fluorescent protein (GFP)-alpha-tubulin to
      visualize microtubules in live cells, we show that the collapsed arrays remain
      associated with centrosomes and are highly motile, often circulating along the
      inner surface of the cell cortex. This is strikingly different from wild-type
      cells where centrosome movement is constrained by a balance of tension on the
      microtubule array. Centrosome motility involves force-generating microtubule
      interactions at the cortex, with the rate and direction consistent with a dynein
      mediated mechanism. Mapping the overexpression effect to a C-terminal region of
      the heavy chain highlights a functional domain within the massive sequence
      important for regulating motor activity.

PMID- 10581252
TI  - Yersinia enterocolitica type III secretion-translocation system: channel
      formation by secreted Yops.
AB  - 'Type III secretion' allows extracellular adherent bacteria to inject bacterial
      effector proteins into the cytosol of their animal or plant host cells. In the
      archetypal Yersinia system the secreted proteins are called Yops. Some of them
      are intracellular effectors, while YopB and YopD have been shown by genetic
      analyses to be dedicated to the translocation of these effectors. Here, the
      secretion of Yops by Y.enterocolitica was induced in the presence of liposomes,
      and some Yops, including YopB and YopD, were found to be inserted into liposomes.
      The proteoliposomes were fused to a planar lipid membrane to characterize the
      putative pore-forming properties of the lipid-bound Yops. Electrophysiological
      experiments revealed the presence of channels with a 105 pS conductance and no
      ionic selectivity. Channels with those properties were generated by mutants
      devoid of the effectors and by lcrG mutants, as well as by wild-type bacteria. In
      contrast, mutants devoid of YopB did not generate channels and mutants devoid of
      YopD led to current fluctuations that were different from those observed with
      wild-type bacteria. The observed channel could be responsible for the
      translocation of Yop effectors.

PMID- 10581253
TI  - Cysteine-scanning mutagenesis provides no evidence for the extracellular
      accessibility of the nucleotide-binding domains of the multidrug resistance
      transporter P-glycoprotein.
AB  - Multidrug resistance of cancer cells is, at least in part, conferred by
      overexpression of P-glycoprotein (P-gp), a member of the ATP-binding cassette
      (ABC) superfamily of active transporters. P-gp actively extrudes chemotherapeutic
      drugs from cells, thus reducing their efficacy. As a typical ABC transporter, P
      gp has four domains: two transmembrane domains, which form a pathway through the
      membrane through which substrates are transported, and two hydrophilic nucleotide
      binding domains (NBDs), located on the cytoplasmic side of the membrane, which
      couple the energy of ATP hydrolysis to substrate translocation. It has been
      proposed that the NBDs of ABC transporters, including the histidine permease of
      Salmonella typhimurium and the cystic fibrosis transmembrane conductance
      regulator, are accessible from the extracellular surface of the cell, spanning
      the membrane directly or potentially contributing to the transmembrane pore. Such
      organization would have significant implications for the transport mechanism. We
      determined to establish whether the NBDs of P-gp are exposed extracellularly and
      which amino acids are accessible, using cysteine-scanning mutagenesis and limited
      proteolysis. In contrast to other transporters, the data provided no evidence
      that the P-gp NBDs are exposed to the cell surface. The implications for the
      structure and mechanism of P-gp and other ABC transporters are discussed.

PMID- 10581254
TI  - Redox signalling in the chloroplast: structure of oxidized pea fructose-1,6
      bisphosphate phosphatase.
AB  - Sunlight provides the energy source for the assimilation of carbon dioxide by
      photosynthesis, but it also provides regulatory signals that switch on specific
      sets of enzymes involved in the alternation of light and dark metabolisms in
      chloroplasts. Capture of photons by chlorophyll pigments triggers redox cascades
      that ultimately activate target enzymes via the reduction of regulatory disulfide
      bridges by thioredoxins. Here we report the structure of the oxidized, low
      activity form of chloroplastic fructose-1, 6-bisphosphate phosphatase (FBPase),
      one of the four enzymes of the Calvin cycle whose activity is redox-regulated by
      light. The regulation is of allosteric nature, with a disulfide bridge promoting
      the disruption of the catalytic site across a distance of 20 A. Unexpectedly,
      regulation of plant FBPases by thiol-disulfide interchange differs in every
      respect from the regulation of mammalian gluconeogenic FBPases by AMP. We also
      report a second crystal form of oxidized FBPase whose tetrameric structure
      departs markedly from D(2) symmetry, a rare event in oligomeric structures, and
      the structure of a constitutively active mutant that is unable to form the
      regulatory disulfide bridge. Altogether, these structures provide a structural
      basis for redox regulation in the chloroplast.

PMID- 10581255
TI  - Carbohydrate deficient glycoprotein syndrome type IV: deficiency of dolichyl-P
      Man:Man(5)GlcNAc(2)-PP-dolichyl mannosyltransferase.
AB  - Type IV of the carbohydrate deficient glycoprotein syndromes (CDGS) is
      characterized by microcephaly, severe epilepsy, minimal psychomotor development
      and partial deficiency of sialic acids in serum glycoproteins. Here we show that
      the molecular defect in the index patient is a missense mutation in the gene
      encoding the mannosyltransferase that transfers mannose from dolichyl-phosphate
      mannose on to the lipid-linked oligosaccharide (LLO) intermediate Man(5)GlcNAc(2)
      PP-dolichol. The defect results in the accumulation of the LLO intermediate and,
      due to its leaky nature, a residual formation of full-length LLOs. N
      glycosylation is abnormal because of the transfer of truncated oligosaccharides
      in addition to that of full-length oligosaccharides and because of the incomplete
      utilization of N-glycosylation sites. The mannosyltransferase is the structural
      and functional orthologue of the Saccharomyces cerevisiae ALG3 gene.

PMID- 10581256
TI  - Crystal structure of the surfactin synthetase-activating enzyme sfp: a prototype
      of the 4'-phosphopantetheinyl transferase superfamily.
AB  - The Bacillus subtilis Sfp protein activates the peptidyl carrier protein (PCP)
      domains of surfactin synthetase by transferring the 4'-phosphopantetheinyl moiety
      of coenzyme A (CoA) to a serine residue conserved in all PCPs. Its wide PCP
      substrate spectrum renders Sfp a biotechnologically valuable enzyme for use in
      combinatorial non-ribosomal peptide synthesis. The structure of the Sfp-CoA
      complex determined at 1.8 A resolution reveals a novel alpha/beta-fold exhibiting
      an unexpected intramolecular 2-fold pseudosymmetry. This suggests a similar fold
      and dimerization mode for the homodimeric phosphopantetheinyl transferases such
      as acyl carrier protein synthase. The active site of Sfp accommodates a magnesium
      ion, which is complexed by the CoA pyrophosphate, the side chains of three acidic
      amino acids and one water molecule. CoA is bound in a fashion that differs in
      many aspects from all known CoA-protein complex structures. The structure reveals
      regions likely to be involved in the interaction with the PCP substrate.

PMID- 10581257
TI  - The E2-E3 interaction in the N-end rule pathway: the RING-H2 finger of E3 is
      required for the synthesis of multiubiquitin chain.
AB  - We dissected physical and functional interactions between the ubiquitin
      conjugating (E2) enzyme Ubc2p and Ubr1p, the E3 component of the N-end rule
      pathway in Saccharomyces cerevisiae. The binding of the 20 kDa Ubc2p by the 225
      kDa Ubr1p is shown to be mediated largely by the basic residue-rich (BRR) region
      of Ubr1p. However, mutations of the BRR domain that strongly decrease the
      interaction between Ubr1p and Ubc2p do not prevent the degradation of N-end rule
      substrates. In contrast, this degradation is completely dependent on the RING-H2
      finger of Ubr1p adjacent to the BRR domain. Specifically, the first cysteine of
      RING-H2 is required for the ubiquitylation activity of the Ubr1p-Ubc2p complex,
      although this cysteine plays no detectable role in either the binding of N-end
      rule substrates by Ubr1p or the physical affinity between Ubr1p and Ubc2p. These
      results defined the topography of the Ubc2p-Ubr1p interaction and revealed the
      essential function of the RING-H2 finger, a domain that is present in many
      otherwise dissimilar E3 proteins of the ubiquitin system.

PMID- 10581258
TI  - Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation
      and apoptosis in response to UV radiation.
AB  - Components of the ras signaling pathway contribute to activation of cellular p53.
      In MCF-7 cells, p38 kinase activated p53 more effectively than other members of
      the ras pathway. p53 and p38 kinase exist in the same physical complex, and co
      expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53
      at Ser33 and Ser46, a newly identified site. Mutation of these sites decreased
      p53-mediated and UV-induced apoptosis, and the reduction correlated with total
      abrogation of UV-induced phosphorylation on Ser37 and a significant decrease in
      Ser15 phosphorylation in mutant p53 containing alanine at Ser33 and Ser46.
      Inhibition of p38 activation after UV irradiation decreased phosphorylation of
      Ser33, Ser37 and Ser15, and also markedly reduced UV-induced apoptosis in a p53
      dependent manner. These results suggest that p38 kinase plays a prominent role in
      an integrated regulation of N-terminal phosphorylation that regulates p53
      mediated apoptosis after UV radiation.

PMID- 10581259
TI  - A single amino acid alteration (101L) introduced into murine PrP dramatically
      alters incubation time of transmissible spongiform encephalopathy.
AB  - A mutation equivalent to P102L in the human PrP gene, associated with Gerstmann
      Straussler syndrome (GSS), has been introduced into the murine PrP gene by gene
      targeting. Mice homozygous for this mutation (101LL) showed no spontaneous
      transmissible spongiform encephalopathy (TSE) disease, but had incubation times
      dramatically different from wild-type mice following inoculation with different
      TSE sources. Inoculation with GSS produced disease in 101LL mice in 288 days.
      Disease was transmitted from these mice to both wild-type (226 days) and 101LL
      mice (148 days). In contrast, 101LL mice infected with ME7 had prolonged
      incubation times (338 days) compared with wild-type mice (161 days). The 101L
      mutation does not, therefore, produce any spontaneous genetic disease in mice but
      significantly alters the incubation time of TSE infection. Additionally, a rapid
      TSE transmission was demonstrated despite extremely low levels of disease
      associated PrP.

PMID- 10581260
TI  - Meiotic mutants in potato. Valuable variants.

PMID- 10581261
TI  - Role of exonucleolytic degradation in group I intron homing in phage T4.
AB  - Homing of the phage T4 td intron is initiated by the intron-encoded endonuclease
      I-TevI, which cleaves the intronless allele 23 and 25 nucleotides upstream of the
      intron insertion site (IS). The distance between the I-TevI cleavage site (CS)
      and IS implicates endo- and/or exonuclease activities to resect the DNA segment
      between the IS and CS. Furthermore, 3' tails must presumably be generated for
      strand invasion by 5'-3' exonuclease activity. Three experimental approaches were
      used to probe for phage nucleases involved in homing: a comparative analysis of
      in vivo homing levels of nuclease-deficient phage, an in vitro assay of nuclease
      activity and specificity, and a coconversion analysis of flanking exon markers.
      It was thereby demonstrated that T4 RNase H, a 5'-3' exonuclease, T4 DNA
      exonuclease A (DexA) and the exonuclease activity of T4 DNA polymerase (43Exo),
      3'-5' exonucleases, play a role in intron homing. The absence of these functions
      impacts not only homing efficiency but also the extent of degradation and
      flanking marker coconversion. These results underscore the critical importance of
      the 3' tail in intron homing, and they provide the first direct evidence of a
      role for 3' single-stranded DNA ends as intermediates in T4 recombination. Also,
      the involvement of RNase H, DexA, and 43Exo in homing provides a clear example of
      the harnessing of functions variously involved in phage nucleic acid metabolism
      for intron propagation.

PMID- 10581262
TI  - Intron homing with limited exon homology. Illegitimate double-strand-break repair
      in intron acquisition by phage t4.
AB  - The td intron of bacteriophage T4 encodes a DNA endonuclease that initiates
      intron homing to cognate intronless alleles by a double-strand-break (DSB) repair
      process. A genetic assay was developed to analyze the relationship between exon
      homology and homing efficiency. Because models predict exonucleolytic processing
      of the cleaved recipient leading to homologous strand invasion of the donor
      allele, the assay was performed in wild-type and exonuclease-deficient (rnh or
      dexA) phage. Efficient homing was supported by exon lengths of 50 bp or greater,
      whereas more limited exon lengths led to a precipitous decline in homing levels.
      However, extensive homology in one exon still supported elevated homing levels
      when the other exon was completely absent. Analysis of these "one-sided" events
      revealed recombination junctions at ectopic sites of microhomology and implicated
      nucleolytic degradation in illegitimate DSB repair in T4. Interestingly, homing
      efficiency with extremely limiting exon homology was greatly elevated in phage
      deficient in the 3'-5' exonuclease, DexA, suggesting that the length of 3' tails
      is a major determinant of the efficiency of DSB repair. Together, these results
      suggest that illegitimate DSB repair may provide a means by which introns can
      invade ectopic sites.

PMID- 10581263
TI  - DNA sequence similarity requirements for interspecific recombination in Bacillus.
AB  - Gene transfer in bacteria is notoriously promiscuous. Genetic material is known
      to be transferred between groups as distantly related as the Gram positives and
      Gram negatives. However, the frequency of homologous recombination decreases
      sharply with the level of relatedness between the donor and recipient. Several
      studies show that this sexual isolation is an exponential function of DNA
      sequence divergence between recombining substrates. The two major factors
      implicated in producing the recombinational barrier are the mismatch repair
      system and the requirement for a short region of sequence identity to initiate
      strand exchange. Here we demonstrate that sexual isolation in Bacillus
      transformation results almost exclusively from the need for regions of identity
      at both the 5' and 3' ends of the donor DNA strand. We show that, by providing
      the essential identity, we can effectively eliminate sexual isolation between
      highly divergent sequences. We also present evidence that the potential of a
      donor sequence to act as a recombinogenic, invasive end is determined by the
      stability (melting point) of the donor-recipient complex. These results explain
      the exponential relationship between sexual isolation and sequence divergence
      observed in bacteria. They also suggest a model for rapid spread of novel
      adaptations, such as antibiotic resistance genes, among related species.

PMID- 10581264
TI  - Saccharomyces cerevisiae G1 cyclins are differentially involved in invasive and
      pseudohyphal growth independent of the filamentation mitogen-activated protein
      kinase pathway.
AB  - Several lines of evidence suggest that the morphogenetic transition from the
      yeast form to pseudohyphae in Saccharomyces cerevisiae may be regulated by the
      cyclin-dependent kinase (Cdk). To examine this hypothesis, we mutated all of the
      G1 cyclin genes in strains competent to form pseudohyphae. Interestingly,
      mutation of each G1 cyclin results in a different filamentation phenotype,
      varying from a significant defect in cln1/cln1 strains to enhancement of filament
      production in cln3/cln3 strains. cln1 cln2 double mutants are more defective in
      pseudohyphal development and haploid invasive growth than cln1 strains. FLO11
      transcription, which correlates with the level of invasive growth, is low in cln1
      cln2 mutants and high in grr1 cells (defective in proteolysis of Cln1,2),
      suggesting that Cln1,2/Cdks regulate the pseudohyphal transcriptional program.
      Epistasis analysis reveals that Cln1,2/Cdk and the filamentation MAP kinase
      pathway function in parallel in regulating filamentous and invasive growth. Cln1
      and Cln2, but not Ste20 or Ste12, are responsible for most of the elevated FLO11
      transcription in grr1 strains. Furthermore, phenotypic comparison of various
      filamentation mutants illustrates that cell elongation and invasion/cell-cell
      adhesion during filamentation are separable processes controlled by the
      pseudohyphal transcriptional program. Potential targets for G1 cyclin/Cdks during
      filamentous growth are discussed.

PMID- 10581265
TI  - The role of centromere alignment in meiosis I segregation of homologous
      chromosomes in Saccharomyces cerevisiae.
AB  - During meiosis, homologous chromosomes pair and then segregate from each other at
      the first meiotic division. Homologous centromeres appear to be aligned when
      chromosomes are paired. The role of centromere alignment in meiotic chromosome
      segregation was investigated in Saccharomyces cerevisiae diploids that contained
      one intact copy of chromosome I and one copy bisected into two functional
      centromere-containing fragments. The centromere on one fragment was aligned with
      the centromere on the intact chromosome while the centromere on the other
      fragment was either aligned or misaligned. Fragments containing aligned
      centromeres segregated efficiently from the intact chromosome, while fragments
      containing misaligned centromeres segregated much less efficiently from the
      intact chromosome. Less efficient segregation was correlated with crossing over
      in the region between the misaligned centromeres. Models that suggest that these
      crossovers impede proper segregation by preventing either a segregation-promoting
      chromosome alignment on the meiotic spindle or some physical interaction between
      homologous centromeres are proposed.

PMID- 10581266
TI  - The identification of Wos2, a p23 homologue that interacts with Wee1 and Cdc2 in
      the mitotic control of fission yeasts.
AB  - The Wee1 kinase inhibits entry into mitosis by phosphorylation of the Cdc2
      kinase. Searching for multicopy suppressors that abolish this inhibition in the
      fission yeast, we have identified a novel gene, here named wos2, encoding a
      protein with significant homology to human p23, an Hsp90-associated cochaperone.
      The deletion mutant has a modest phenotype, being heat-shock sensitive. Using
      antibodies raised against bacterially produced protein, we determined that Wos2
      is very abundant, ubiquitously distributed in the yeast cell, and its expression
      dropped drastically as cells entered into early stationary phase, indicating that
      its function is associated with cell proliferation. In proliferating cells, the
      amount of Wos2 protein was not subjected to cell cycle regulation. However, in
      vitro assays demonstrated that this Hsp90 cochaperone is potentially regulated by
      phosphorylation. In addition to suppressing Wee1 activity, overproduction of Wos2
      displayed synthetic lethality with Cdc2 mutant proteins, indicating that this
      Hsp90 cochaperone functionally interacts with Cdc2. The level of Cdc2 protein and
      its associated H1 kinase activity under synthetic lethal conditions suggested a
      regulatory role for this Wos2-Cdc2 interaction. Hsp90 complexes are required for
      CDK regulation; the synergy found between the excess of Wos2 and a deficiency in
      Hsp90 activity suggests that Wos2 could specifically interfere with the Hsp90
      dependent regulation of Cdc2. In vitro analysis indicated that the above genetic
      interactions could take place by physical association of Wos2 with the single CDK
      complex of the fission yeast. Expression of the budding yeast p23 protein
      (encoded by the SBA1 gene) in the fission yeast indicated that Wos2 and Sba1 are
      functionally exchangeable and therefore that properties described here for Wos2
      could be of wide significance in understanding the biological function of
      cochaperone p23 in eukaryotic cells.

PMID- 10581267
TI  - Transcriptional activation in yeast cells lacking transcription factor IIA.
AB  - The general transcription factor IIA (TFIIA) forms a complex with TFIID at the
      TATA promoter element, and it inhibits the function of several negative
      regulators of the TATA-binding protein (TBP) subunit of TFIID. Biochemical
      experiments suggest that TFIIA is important in the response to transcriptional
      activators because activation domains can interact with TFIIA, increase
      recruitment of TFIID and TFIIA to the promoter, and promote isomerization of the
      TFIID-TFIIA-TATA complex. Here, we describe a double-shut-off approach to deplete
      yeast cells of Toa1, the large subunit of TFIIA, to <1% of the wild-type level.
      Interestingly, such TFIIA-depleted cells are essentially unaffected for
      activation by heat shock factor, Ace1, and Gal4-VP16. However, depletion of TFIIA
      causes a general two- to threefold decrease of transcription from most yeast
      promoters and a specific cell-cycle arrest at the G2-M boundary. These results
      indicate that transcriptional activation in vivo can occur in the absence of
      TFIIA.

PMID- 10581268
TI  - Frequent meiotic recombination between the ends of truncated chromosome fragments
      of Saccharomyces cerevisiae.
AB  - A single truncated chromosome fragment (TCF) in diploid cells undergoes frequent
      ectopic recombination during meiosis between markers located near the ends of the
      fragment. Tetrads produced by diploids with a single TCF show frequent loss of
      one of the two markers. This marker loss could result either from recombination
      of the TCF with one of the two copies of the chromosome from which it was derived
      or from ectopic recombination between the ends of the TCF. The former would
      result in shortening of a normal chromosome and lethality in one of the four
      spores. The high frequency of marker loss in tetrads with four viable spores
      supports recombination between the TCF ends as the main source of marker loss.
      Most of the spore colonies that display TCF marker loss contained a TCF with the
      same marker on both ends. Deletion of most of the pBR322 sequences distal to the
      marker at one of the subtelomeric regions of the TCF did not reduce the overall
      frequency of recombination between the ends, but affected the loss of one marker
      significantly more than the other. We suggest that the mechanism by which the
      duplication of one end marker and loss of the other occurs is based on
      association and recombination between the ends of the TCF.

PMID- 10581269
TI  - Analysis of the seven-member AAD gene set demonstrates that genetic redundancy in
      yeast may be more apparent than real.
AB  - Saccharomyces cerevisiae has seven genes encoding proteins with a high degree
      (>85%) of amino-acid sequence identity to the aryl-alcohol dehydrogenase of the
      lignin-degrading, filamentous fungus, Phanerochaete chrysosporium. All but one
      member of this gene set are telomere associated. Moreover, all contain a sequence
      similar to the DNA-binding site of the Yap1p transcriptional activator either
      upstream of or within their coding sequences. The expression of the AAD genes was
      found to be induced by chemicals, such as diamide and diethyl maleic acid ester
      (DEME), that cause an oxidative shock by inactivating the glutathione (GSH)
      reservoir of the cells. In contrast, the oxidizing agent hydrogen peroxide has no
      effect on the expression of these genes. We found that the response to anti-GSH
      agents was Yap1p dependent. The very high level of nucleotide sequence similarity
      between the AAD genes makes it difficult to determine if they are all involved in
      the oxidative-stress response. The use of single and multiple aad deletants
      demonstrated that only AAD4 (YDL243c) and AAD6 (YFL056/57c) respond to the
      oxidative stress. Of these two genes, only AAD4 is likely to be functional since
      the YFL056/57c open reading frame is interrupted by a stop codon. Thus, in terms
      of the function in response to oxidative stress, the sevenfold redundancy of the
      AAD gene set is more apparent than real.

PMID- 10581270
TI  - The STE12alpha homolog is required for haploid filamentation but largely
      dispensable for mating and virulence in Cryptococcus neoformans.
AB  - Cryptococcus neoformans is a fungal pathogen that causes meningitis in
      immunocompromised hosts. The organism has a known sexual cycle, and strains of
      the MATalpha mating type are more virulent than isogenic MATa strains in mice,
      and they are more common in the environment and infected hosts. A C. neoformans
      homolog of the STE12 transcription factor that regulates mating, filamentation,
      and virulence in Saccharomyces cerevisiae and Candida albicans was identified
      previously, found to be encoded by a novel region of the MATalpha mating type
      locus, and shown to enhance filamentous growth when overexpressed. We have
      disrupted the C. neoformans STE12 gene in a pathogenic serotype A isolate. ste12
      mutant strains exhibit a severe defect in filamentation and sporulation (haploid
      fruiting) in response to nitrogen starvation. In contrast, ste12 mutant strains
      have only modest mating defects and are fully virulent in two animal models
      compared to the STE12 wild-type strain. In genetic epistasis experiments, STE12
      functions in a MAP kinase cascade to regulate fruiting, but not mating. Thus, the
      C. neoformans STE12alpha transcription factor homolog plays a specialized
      function in haploid fruiting, but it is dispensable or redundant for mating and
      virulence. The association of the MATalpha locus with virulence may involve
      additional genes, and other transcription factors that regulate mating and
      virulence remain to be identified.

PMID- 10581271
TI  - Dominant mutations in three different subunits of replication factor C suppress
      replication defects in yeast PCNA mutants.
AB  - To identify proteins that interact with the yeast proliferating cell nuclear
      antigen (PCNA), we used a genetic approach to isolate mutations that compensate
      for the defects in cold-sensitive (Cs(-)) mutants of yeast PCNA (POL30). Because
      the cocrystal structure of human PCNA and a p21(WAF1/CIP1) peptide shows that the
      interdomain region of PCNA is a site of p21 interaction, we specifically looked
      for new mutations that suppress mutations in the equivalent region of yeast PCNA.
      In independent screens using three different Cs(-) mutants, we identified
      spontaneously arising dominant suppressor mutations in the RFC3 gene. In
      addition, dominant suppressor mutations were identified in the RFC1 and RFC2
      genes using a single pol30 mutant. An intimate association between PCNA and
      RFC1p, RFC2p, and RFC3p is suggested by the allele-restricted suppression of 10
      different pol30 alleles by the RFC suppressors. RFC1, RFC2, and RFC3 encode three
      of the five subunits of the replication factor C complex, which is required to
      load PCNA onto DNA in reconstituted DNA replication reactions. Genomic sequencing
      reveals a common region in RFC1p, RFC2p, and RFC3p that is important for the
      functional interaction with PCNA. Biochemical analysis of the wild type and
      mutant PCNA and RFC3 proteins shows that mutant RFC3p enhances the production of
      long DNA products in pol delta-dependent DNA synthesis, which is consistent with
      an increase in processivity.

PMID- 10581272
TI  - Mutational analysis of the [Het-s] prion analog of Podospora anserina. A short N
      terminal peptide allows prion propagation.
AB  - The het-s locus is one of nine known het (heterokaryon incompatibility) loci of
      the fungus Podospora anserina. This locus exists as two wild-type alleles, het-s
      and het-S, which encode 289 amino acid proteins differing at 13 amino acid
      positions. The het-s and het-S alleles are incompatible as their coexpression in
      the same cytoplasm causes a characteristic cell death reaction. We have proposed
      that the HET-s protein is a prion analog. Strains of the het-s genotype exist in
      two phenotypic states, the neutral [Het-s*] and the active [Het-s] phenotype. The
      [Het-s] phenotype is infectious and is transmitted to [Het-s*] strains through
      cytoplasmic contact. het-s and het-S were associated in a single haploid nucleus
      to generate a self-incompatible strain that displays a restricted and abnormal
      growth. In the present article we report the molecular characterization of a
      collection of mutants that restore the ability of this self-incompatible strain
      to grow. We also describe the functional analysis of a series of deletion
      constructs and site-directed mutants. Together, these analyses define positions
      critical for reactivity and allele specificity. We show that a 112-amino-acid
      long N-terminal peptide of HET-s retains [Het-s] activity. Moreover, expression
      of a mutant het-s allele truncated at position 26 is sufficient to allow
      propagation of the [Het-s] prion analog.

PMID- 10581273
TI  - SEL-5, a serine/threonine kinase that facilitates lin-12 activity in
      Caenorhabditis elegans.
AB  - Ligands present on neighboring cells activate receptors of the LIN-12/Notch
      family by inducing a proteolytic cleavage event that releases the intracellular
      domain. Mutations that appear to eliminate sel-5 activity are able to suppress
      constitutive activity of lin-12(d) mutations that are point mutations in the
      extracellular domain of LIN-12, but cannot suppress lin-12(intra), the untethered
      intracellular domain. These results suggest that sel-5 acts prior to or during
      ligand-dependent release of the intracellular domain. In addition, sel-5
      suppression of lin-12(d) mutations is tissue specific: loss of sel-5 activity can
      suppress defects in the anchor cell/ventral uterine precursor cell fate decision
      and a sex myoblast/coelomocyte decision, but cannot suppress defects in two
      different ventral hypodermal cell fate decisions in hermaphrodites and males. sel
      5 encodes at least two proteins, from alternatively spliced mRNAs, that share an
      amino-terminal region and differ in the carboxy-terminal region. The amino
      terminal region contains the hallmarks of a serine/threonine kinase domain, which
      is most similar to mammalian GAK1 and yeast Pak1p.

PMID- 10581274
TI  - Mutational analysis of the Caenorhabditis elegans cell-death gene ced-3.
AB  - Mutations in the gene ced-3, which encodes a protease similar to interleukin
      1beta converting enzyme and related proteins termed caspases, prevent programmed
      cell death in the nematode Caenorhabditis elegans. We used site-directed
      mutagenesis to demonstrate that both the presumptive active-site cysteine of the
      CED-3 protease and the aspartate residues at sites of processing of the CED-3
      proprotein are required for programmed cell death in vivo. We characterized the
      phenotypes caused by and the molecular lesions of 52 ced-3 alleles. These alleles
      can be ordered in a graded phenotypic series. Of the 30 amino acid sites altered
      by ced-3 missense mutations, 29 are conserved with at least one other caspase,
      suggesting that these residues define sites important for the functions of all
      caspases. Animals homozygous for the ced-3(n2452) allele, which is deleted for
      the region of the ced-3 gene that encodes the protease domain, seemed to be
      incompletely blocked in programmed cell death, suggesting that some programmed
      cell death can occur independently of CED-3 protease activity.

PMID- 10581275
TI  - A stomatin and a degenerin interact to control anesthetic sensitivity in
      Caenorhabditis elegans.
AB  - The mechanism of action of volatile anesthetics is unknown. In Caenorhabditis
      elegans, mutations in the gene unc-1 alter anesthetic sensitivity. The protein
      UNC-1 is a close homologue of the mammalian protein stomatin. Mammalian stomatin
      is thought to interact with an as-yet-unknown ion channel to control sodium flux.
      Using both reporter constructs and translational fusion constructs for UNC-1 and
      green fluorescent protein (GFP), we have shown that UNC-1 is expressed primarily
      within the nervous system. The expression pattern of UNC-1 is similar to that of
      UNC-8, a sodium channel homologue. We examined the interaction of multiple
      alleles of unc-1 and unc-8 with each other and with other genes affecting
      anesthetic sensitivity. The data indicate that the protein products of these
      genes interact, and that an UNC-1/UNC-8 complex is a possible anesthetic target.
      We propose that membrane-associated protein complexes may represent a general
      target for volatile anesthetics.

PMID- 10581276
TI  - A quantitative genetic analysis of male sexual traits distinguishing the sibling
      species Drosophila simulans and D. sechellia.
AB  - A quantitative trait locus (QTL) genetic analysis of morphological and
      reproductive traits distinguishing the sibling species Drosophila simulans and D.
      sechellia was carried out in a backcross design, using 38 markers with an average
      spacing of 8.4 cM. The direction of QTL effects for the size of the posterior
      lobe was consistent across the identified QTL, indicating directional selection
      for this trait. Directional selection also appears to have acted on testis
      length, indicating that sexual selection may have influenced many reproductive
      traits, although other forms of directional selection cannot be ruled out. Sex
      comb tooth number exhibited high levels of variation both within and among
      isofemale lines and showed no evidence for directional selection and, therefore,
      may not have been involved in the early speciation process. A database search for
      genes associated with significant QTL revealed a set of candidate loci for
      posterior lobe shape and size, sex comb tooth number, testis length, tibia
      length, and hybrid male fertility. In particular, decapentaplegic (dpp), a gene
      known to influence the genital arch, was found to be associated with the largest
      LOD peak for posterior lobe shape and size.

PMID- 10581277
TI  - Unusually high recombination rate detected in the sex locus region of the honey
      bee (Apis mellifera).
AB  - Sex determination in Hymenoptera is controlled by haplo-diploidy in which
      unfertilized eggs develop into fertile haploid males. A single sex determination
      locus with several complementary alleles was proposed for Hymenoptera [so-called
      complementary sex determination (CSD)]. Heterozygotes at the sex determination
      locus are normal, fertile females, whereas diploid zygotes that are homozygous
      develop into sterile males. This results in a strong heterozygote advantage, and
      the sex locus exhibits extreme polymorphism maintained by overdominant selection.
      We characterized the sex-determining region by genetic linkage and physical
      mapping analyses. Detailed linkage and physical mapping studies showed that the
      recombination rate is <44 kb/cM in the sex-determining region. Comparing genetic
      map distance along the linkage group III in three crosses revealed a large marker
      gap in the sex-determining region, suggesting that the recombination rate is
      high. We suggest that a "hotspot" for recombination has resulted here because of
      selection for combining favorable genotypes, and perhaps as a result of selection
      against deleterious mutations. The mapping data, based on long-range restriction
      mapping, suggest that the Q DNA-marker is within 20,000 bp of the sex locus,
      which should accelerate molecular analyses.

PMID- 10581278
TI  - Lack of nucleotide polymorphism in the Y-linked sperm flagellar dynein gene Dhc
      Yh3 of Drosophila melanogaster and D. simulans.
AB  - We studied levels of intra- and interspecific nucleotide variation associated
      with a Y-linked gene in five members of the Drosophila melanogaster subgroup.
      Using published sequence for 348 bp of the Dhc-Yh3 gene, and degenerate PCR
      primers designed from comparisons of the sea urchin and Chlamydomonas flagellar
      dynein genes, we recovered a 1738-bp region in D. melanogaster. Analyses of
      sequence variation in a worldwide collection of 11 lines of D. melanogaster and
      10 lines of D. simulans found only a single silent polymorphism in the latter
      species. The synonymous site divergence per site for Dhc-Yh3 is comparable to
      values for X and autosomal genes. Assuming a Wright-Fisher population model, the
      lack of variation is statistically less than expected using appropriately reduced
      estimates of theta from the X and autosomes. Because the Y chromosome encodes
      only six known genes, genetic hitchhiking associated with background selection is
      unlikely to explain this low variation. Conversely, adaptive hitchhiking, as
      associated with sex-ratio chromosomes, or a large variance in male fertility may
      reduce the polymorphism on the Y chromosome. Codon bias is very low, as seen for
      other genes in regions of low recombination.

PMID- 10581279
TI  - Large number of replacement polymorphisms in rapidly evolving genes of
      Drosophila. Implications for genome-wide surveys of DNA polymorphism.
AB  - We present a survey of nucleotide polymorphism of three novel, rapidly evolving
      genes in populations of Drosophila melanogaster and D. simulans. Levels of silent
      polymorphism are comparable to other loci, but the number of replacement
      polymorphisms is higher than that in most other genes surveyed in D. melanogaster
      and D. simulans. Tests of neutrality fail to reject neutral evolution with one
      exception. This concerns a gene located in a region of high recombination rate in
      D. simulans and in a region of low recombination rate in D. melanogaster, due to
      an inversion. In the latter case it shows a very low number of polymorphisms,
      presumably due to selective sweeps in the region. Patterns of nucleotide
      polymorphism suggest that most substitutions are neutral or nearly neutral and
      that weak (positive and purifying) selection plays a significant role in the
      evolution of these genes. At all three loci, purifying selection of slightly
      deleterious replacement mutations appears to be more efficient in D. simulans
      than in D. melanogaster, presumably due to different effective population sizes.
      Our analysis suggests that current knowledge about genome-wide patterns of
      nucleotide polymorphism is far from complete with respect to the types and range
      of nucleotide substitutions and that further analysis of differences between
      local populations will be required to understand the forces more completely. We
      note that rapidly diverging and nearly neutrally evolving genes cannot be
      expected only in the genome of Drosophila, but are likely to occur in large
      numbers also in other organisms and that their function and evolution are little
      understood so far.

PMID- 10581280
TI  - Mapping of hybrid incompatibility loci in Nasonia.
AB  - According to theory, F(2) hybrid breakdown (lethality or sterility) is due to
      incompatibilities between interacting genes of the different species (i.e., the
      breaking up of coadapted gene complexes). Detection of such incompatibilities is
      particularly straightforward in haplodiploid species, because virgin F(1) hybrid
      females will produce haploid recombinant F(2) males. This feature allows for
      screening of the complete genome for recessive genetic incompatibilities. Crosses
      were performed between Nasonia vitripennis (v) and its sibling species N.
      giraulti (g). First, a linkage map was produced using RAPD markers. RAPD markers
      showed an overall bias toward vitripennis alleles, a pattern not predicted by the
      basic two-interactor Dobzhansky-Muller model. Recovery patterns of visible
      markers were consistent with those of linked RAPD markers. If particular genetic
      interactions between two loci are causing hybrid lethality, then those genotypes
      should be underrepresented or absent among adult F(2) males. Four sets of
      significant incompatibilities were detected by performing pairwise comparisons of
      markers on different chromosomes. Likely explanations for the observed patterns
      are maternal effect-zygotic gene incompatibilities or clustering of
      incompatibility loci. Due to the short generation time, advantages of
      haplodiploidy, and availability of markers, Nasonia promises to be a productive
      system for investigating the genetics of hybrid inviability.

PMID- 10581281
TI  - Insights into genome differentiation: pheromone-binding protein variation and
      population history in the European corn borer (Ostrinia nubilalis).
AB  - Examination of sequence variation at nuclear loci can give insights into
      population history and gene flow that cannot be derived from other commonly used
      molecular markers, such as allozymes. Here, we report on sequence variation at a
      single nuclear locus, the pheromone-binding protein (PBP) locus, in the European
      corn borer (Ostrinia nubilalis). The European corn borer has been divided into
      three races in New York State on the basis of differences in pheromone
      communication and life history. Previous allozyme data have suggested that there
      is a small but significant amount of genetic differentiation between these races.
      The PBP does not appear to be involved in the pheromone differences between these
      races. Examination of variation at the PBP locus in the three races reveals no
      fixed differences between races despite high levels of polymorphism. There also
      appears to have been considerable recombination in the history of the pheromone
      binding protein alleles. Observation of both recombination between alleles and
      lack of significant nucleotide or insertion/deletion divergence between races
      leads us to suggest that these populations are either recently diverged or have
      continued to exchange genetic material subsequent to divergence in pheromone
      communication and life history.

PMID- 10581282
TI  - A screen for identifying genes interacting with armadillo, the Drosophila homolog
      of beta-catenin.
AB  - Drosophila Armadillo is a multifunctional protein implicated in both cell
      adhesion, as a catenin, and cell signaling, as part of the Wingless signal
      transduction pathway. We have generated viable fly stocks with alterations in the
      level of Armadillo available for signaling. Flies from one stock overexpress
      Armadillo and, as a result, have increased vein material and bristles in the
      wings. Flies from the other stock have reduced cytoplasmic Armadillo following
      overexpression of the intracellular domain of DE-cadherin. These flies display a
      wing-notching phenotype typical of wingless mutations. Both misexpression
      phenotypes can be dominantly modified by removing one copy of genes known to
      encode members of the wingless pathway. Here we describe the identification of
      further mutations that dominantly modify the Armadillo misexpression phenotypes.
      These mutations are in genes encoding three different functions: establishment
      and maintenance of adherens junctions, cell cycle control, and Egfr signaling.

PMID- 10581283
TI  - Cosuppression of I transposon activity in Drosophila by I-containing sense and
      antisense transgenes.
AB  - We have previously shown that the activity of functional I elements introduced
      into Drosophila devoid of such elements can be repressed by transgenes containing
      an internal nontranslatable part of the I element itself and that this repressing
      effect presents features characteristic of homology-dependent gene silencing or
      cosuppression. Here we show that transgenes containing a fragment of the I
      element in antisense orientation induce I-element silencing with the same
      characteristic features as the corresponding sense construct: namely, repression
      takes several generations to be fully established, with similar rates for sense
      and antisense constructs, and it is only maternally transmitted, with reversal of
      the effect through paternal transmission. We also show that transcription of the
      transgenes is necessary to produce the silencing effect and that repression can
      be maintained for at least one generation following elimination of the
      transgenes, thus strongly suggesting that a transgene product and not the
      transgene per se is the essential intermediate in the silencing effect. The data
      presented strongly support models in which the repressing effect of antisense
      transcripts involves the same mechanisms as cosuppression by sense constructs and
      emphasize the role of symmetrically acting nucleic acid structures in mediating
      repression.

PMID- 10581284
TI  - A comparison of the genetic basis of wing size divergence in three parallel body
      size clines of Drosophila melanogaster.
AB  - Body size clines in Drosophila melanogaster have been documented in both
      Australia and South America, and may exist in Southern Africa. We crossed flies
      from the northern and southern ends of each of these clines to produce F(1),
      F(2), and first backcross generations. Our analysis of generation means for wing
      area and wing length produced estimates of the additive, dominance, epistatic,
      and maternal effects underlying divergence within each cline. For both females
      and males of all three clines, the generation means were adequately described by
      these parameters, indicating that linkage and higher order interactions did not
      contribute significantly to wing size divergence. Marked differences were
      apparent between the clines in the occurrence and magnitude of the significant
      genetic parameters. No cline was adequately described by a simple additive
      dominance model, and significant epistatic and maternal effects occurred in most,
      but not all, of the clines. Generation variances were also analyzed. Only one
      cline was described sufficiently by a simple additive variance model, indicating
      significant epistatic, maternal, or linkage effects in the remaining two clines.
      The diversity in genetic architecture of the clines suggests that natural
      selection has produced similar phenotypic divergence by different combinations of
      gene action and interaction.

PMID- 10581285
TI  - Genetic characterization of cytological region 77A-D harboring the presenilin
      gene of Drosophila melanogaster.
AB  - We performed a systematic lethal mutagenesis of the genomic region uncovered by
      Df(3L)rdgC-co2 (cytological interval 77A-D) to isolate mutations in the single
      known Presenilin (Psn) gene of Drosophila melanogaster. Because this segment of
      chromosome III has not been systematically characterized before, inter se
      complementation testing of newly recovered mutants was carried out. A total of 79
      lethal mutations were isolated, representing at least 17 lethal complementation
      groups, including one corresponding to the Psn gene. Fine structure mapping of
      the genomic region surrounding the Psn transcription unit by transgenic rescue
      experiments allowed us to localize two of the essential loci together with Psn
      within an approximately 12-kb genomic DNA region. One of these loci, located 3'
      to Psn, encodes a Drosophila protein related to the yeast 60S ribosomal protein
      L10 precursor. We also determined which of the newly recovered lethal mutant
      groups correspond to previously isolated lethal P-element insertions, lethal
      inversion breakpoints, and lethal polo gene mutants. Point mutations were
      identified in all five recovered Psn alleles, one of which results in a single
      amino acid substitution G-E at a conserved residue in the C-terminal cytoplasmic
      tail of the protein, suggesting an important functional role for this C-terminal
      domain of Presenilin. In addition, some viable mutations were recovered in the
      screen, including new alleles of the clipped and inturned loci.

PMID- 10581286
TI  - Evolution of the proportions of two sigma viral types in experimental populations
      of Drosophila melanogaster in the absence of the allele that is restrictive of
      viral multiplication.
AB  - A minority of flies in natural populations of Drosophila melanogaster are
      endemically infected by a rhabdovirus, sigma. The virus is vertically transmitted
      through male and female gametes. Two alleles of a fly locus, the ref(2)P locus,
      are present as a polymorphism in all populations: O permissive, and P restrictive
      for viral multiplication and transmission. Two viral types are known, Type I,
      which is very sensitive to the P allele, and Type II, which is more resistant.
      Previous observations have shown that, in presence of the P allele, viral Type II
      is selected for, in both natural and experimental populations. The aim of the
      present study was to determine whether, in the absence of P, Type I is selected
      for, or whether the two types are equivalent. For this purpose, experimental
      populations deprived of the P allele and differing in the initial proportions of
      the two viral types were established. After several generations, and despite a
      possible bias toward Type I, the frequencies of Type I and Type II clones
      differed in the various populations, depending on their initial values. These
      findings do not rule out selective advantage of viral Type I in the absence of P,
      but suggest that, if any, this advantage is in no way comparable to that
      displayed by viral Type II in the presence of P.

PMID- 10581287
TI  - The tamas gene, identified as a mutation that disrupts larval behavior in
      Drosophila melanogaster, codes for the mitochondrial DNA polymerase catalytic
      subunit (DNApol-gamma125).
AB  - From a screen of pupal lethal lines of Drosophila melanogaster we identified a
      mutant strain that displayed a reproducible reduction in the larval response to
      light. Moreover, this mutant strain showed defects in the development of the
      adult visual system and failure to undergo behavioral changes characteristic of
      the wandering stage. The foraging third instar larvae remained in the food
      substrate for a prolonged period and died at or just before pupariation. Using a
      new assay for individual larval photobehavior we determined that the lack of
      response to light in these mutants was due to a primary deficit in locomotion.
      The mutation responsible for these phenotypes was mapped to the lethal
      complementation group l(2)34Dc, which we renamed tamas (translated from Sanskrit
      as "dark inertia"). Sequencing of mutant alleles demonstrated that tamas codes
      for the mitochondrial DNA polymerase catalytic subunit (DNApol-gamma125).

PMID- 10581288
TI  - A selective screen reveals discrete functional domains in Drosophila Nanos.
AB  - The Drosophila protein Nanos encodes an evolutionarily conserved protein with two
      zinc finger motifs. In the embryo, Nanos protein function is required for
      establishment of the anterior-posterior body pattern and for the migration of
      primordial germ cells. During oogenesis, Nanos protein is involved in the
      establishment and maintenance of germ-line stem cells and the differentiation of
      oocyte precursor cells. To establish proper embryonic patterning, Nanos acts as a
      translational regulator of hunchback RNA. Nanos' targets for germ cell migration
      and development are not known. Here, we describe a selective genetic screen aimed
      at isolating new nanos alleles. The molecular and genetic analysis of 68 new
      alleles has allowed us to identify amino acids critical for nanos function. This
      analysis shows that the CCHC motifs, which coordinate two metal ions, are
      essential for all known functions of Nanos protein. Furthermore, a region C
      terminal to the zinc fingers seems to constitute a novel functional domain within
      the Nanos protein. This "tail region" of Nanos is required for abdomen formation
      and germ cell migration, but not for oogenesis.

PMID- 10581289
TI  - Genetic analyses of visual pigments of the pigeon (Columba livia).
AB  - We isolated five classes of retinal opsin genes rh1(Cl), rh2(Cl), sws1(Cl),
      sws2(Cl), and lws(Cl) from the pigeon; these encode RH1(Cl), RH2(Cl), SWS1(Cl),
      SWS2(Cl), and LWS(Cl) opsins, respectively. Upon binding to 11-cis-retinal, these
      opsins regenerate the corresponding photosensitive molecules, visual pigments.
      The absorbance spectra of visual pigments have a broad bell shape with the peak,
      being called lambdamax. Previously, the SWS1(Cl) opsin cDNA was isolated from the
      pigeon retinal RNA, expressed in cultured COS1 cells, reconstituted with 11-cis
      retinal, and the lambdamax of the resulting SWS1(Cl) pigment was shown to be 393
      nm. In this article, using the same methods, the lambdamax values of RH1(Cl),
      RH2(Cl), SWS2(Cl), and LWS(Cl) pigments were determined to be 502, 503, 448, and
      559 nm, respectively. The pigeon is also known for its UV vision, detecting light
      at 320-380 nm. Being the only pigments that absorb light below 400 nm, the
      SWS1(Cl) pigments must mediate its UV vision. We also determined that a
      nonretinal P(Cl) pigment in the pineal gland of the pigeon has a lambdamax value
      at 481 nm.

PMID- 10581290
TI  - Complete DNA sequence of the mitochondrial genome of the ascidian Halocynthia
      roretzi (Chordata, Urochordata).
AB  - The complete nucleotide sequence of the 14,771-bp-long mitochondrial (mt) DNA of
      a urochordate (Chordata)-the ascidian Halocynthia roretzi-was determined. All the
      Halocynthia mt-genes were found to be located on a single strand, which is rich
      in T and G rather than in A and C. Like nematode and Mytilus edulis mtDNAs, that
      of Halocynthia encodes no ATP synthetase subunit 8 gene. However, it does encode
      an additional tRNA gene for glycine (anticodon TCT) that enables Halocynthia
      mitochondria to use AGA and AGG codons for glycine. The mtDNA carries an unusual
      tRNA(Met) gene with a TAT anticodon instead of the usual tRNA(Met)(CAT) gene. As
      in other metazoan mtDNAs, there is not any long noncoding region. The gene order
      of Halocynthia mtDNA is completely different from that of vertebrate mtDNAs
      except for tRNA(His)-tRNA(Ser)(GCU), suggesting that evolutionary change in the
      mt-gene structure is much accelerated in the urochordate line compared with that
      in vertebrates. The amino acid sequences of Halocynthia mt-proteins deduced from
      their gene sequences are quite different from those in other metazoans,
      indicating that the substitution rate in Halocynthia mt-protein genes is also
      accelerated.

PMID- 10581291
TI  - Nonequilibrium migration in human history.
AB  - A nonequilibrium migration model is proposed and applied to genetic data from
      humans. The model assumes symmetric migration among all possible pairs of demes
      and that the number of demes is large. With these assumptions it is
      straightforward to allow for changes in demography, and here a single abrupt
      change is considered. Under the model this change is identical to a change in the
      ancestral effective population size and might be caused by changes in deme size,
      in the number of demes, or in the migration rate. Expressions for the expected
      numbers of sites segregating at particular frequencies in a multideme sample are
      derived. A maximum-likelihood analysis of independent polymorphic restriction
      sites in humans reveals a decrease in effective size. This is consistent with a
      change in the rates of migration among human subpopulations from ancient low
      levels to present high ones.

PMID- 10581292
TI  - Long inverted repeats are an at-risk motif for recombination in mammalian cells.
AB  - Certain DNA sequence motifs and structures can promote genomic instability. We
      have explored instability induced in mouse cells by long inverted repeats (LIRs).
      A cassette was constructed containing a herpes simplex virus thymidine kinase
      (tk) gene into which was inserted an LIR composed of two inverted copies of a 1.1
      kb yeast URA3 gene sequence separated by a 200-bp spacer sequence. The tk gene
      was introduced into the genome of mouse Ltk(-) fibroblasts either by itself or in
      conjunction with a closely linked tk gene that was disrupted by an 8-bp XhoI
      linker insertion; rates of intrachromosomal homologous recombination between the
      markers were determined. Recombination between the two tk alleles was stimulated
      5-fold by the LIR, as compared to a long direct repeat (LDR) insert, resulting in
      nearly 10(-5) events per cell per generation. Of the tk(+) segregants recovered
      from LIR-containing cell lines, 14% arose from gene conversions that eliminated
      the LIR, as compared to 3% of the tk(+) segregants from LDR cell lines,
      corresponding to a >20-fold increase in deletions at the LIR hotspot. Thus, an
      LIR, which is a common motif in mammalian genomes, is at risk for the stimulation
      of homologous recombination and possibly other genetic rearrangements.

PMID- 10581293
TI  - Inbreeding load, average dominance and the mutation rate for mildly deleterious
      alleles in Mimulus guttatus.
AB  - The goal of this study is to provide information on the genetics of inbreeding
      depression in a primarily outcrossing population of Mimulus guttatus. Previous
      studies of this population indicate that there is tremendous inbreeding
      depression for nearly every fitness component and that almost all of this
      inbreeding depression is due to mildly deleterious alleles rather than recessive
      lethals or steriles. In this article I assayed the homozygous and heterozygous
      fitnesses of 184 highly inbred lines extracted from a natural population. Natural
      selection during the five generations of selfing involved in line formation
      essentially eliminated major deleterious alleles but was ineffective in purging
      alleles with minor fitness effects and did not appreciably diminish overall
      levels of inbreeding depression. Estimates of the average degree of dominance of
      these mildly deleterious alleles, obtained from the regression of heterozygous
      fitness on the sum of parental homozygous fitness, indicate that the detrimental
      alleles are partially recessive for most fitness traits, with h approximately
      0.15 for cumulative measures of fitness. The inbreeding load, B, for total
      fitness is approximately 1.0 in this experiment. These results are consistent
      with the hypothesis that spontaneous mildly deleterious mutations occur at a rate
      >0.1 mutation per genome per generation.

PMID- 10581294
TI  - Resistance to gap repair of the transposon Tam3 in Antirrhinum majus: a role of
      the end regions.
AB  - The extremely homogeneous organization of the transposon family Tam3 in
      Antirrhinum majus is in sharp contrast to the heterogeneity of the copies
      constituting many other transposon families. To address the issue of the Tam3
      structural uniformity, we examined two possibilities: (1) recent invasion of Tam3
      and (2) failure of gap repair, which is involved in conversion from autonomous
      forms to defective forms. The phylogenetic analysis of 17 Tam3 copies suggested
      that the invasion of Tam3 into the Antirrhinum genome occurred at least 5 mya,
      which is sufficiently long ago to have produced many aberrant copies by gap
      repair. Thus, we investigated gap repair events at the nivea(recurrens:Tam3)
      (niv(rec)::Tam3) allele, where Tam3 is actively excised. We show here that the
      gap repair of de novo somatic Tam3 excision was arrested immediately after
      initiation of the process. All of the identified gap repair products were short
      stretches, no longer than 150 bp from the ends. The Tam3 ends have hairpin
      structures with low free energies. We observed that the gap repair halted within
      the hairpin structure regions. Such small gap repair products appear to be
      distributed in the Antirrhinum genome, but are unlikely to be active. Our data
      strongly suggest that the structural homogeneity of Tam3 was caused by immunity
      to gap repair at the hairpins in both of the end regions. The frequency of
      extensive gap repair of de novo excision products in eukaryotic transposons was
      found to be correlated with the free energies of the secondary structures in the
      end regions. This fact suggests that the fates of transposon families might
      depend on the structures of their ends.

PMID- 10581295
TI  - Induction and characterization of Ph1 wheat mutants.
AB  - The cloning of genes for complex traits in polyploid plants that possess large
      genomes, such as hexaploid wheat, requires an efficient strategy. We present here
      one such strategy focusing on the homologous pairing suppressor (Ph1) locus of
      wheat. This locus has been shown to affect both premeiotic and meiotic processes,
      possibly suggesting a complex control. The strategy combined the identification
      of lines carrying specific deletions using multiplex PCR screening of fast
      neutron irradiated wheat populations with the approach of physically mapping the
      region in the rice genome equivalent to the deletion to reveal its gene content.
      As a result, we have located the Ph1 factor controlling the euploid-like level of
      homologous chromosome pairing to the region between two loci (Xrgc846 and
      Xpsr150A). These loci are located within 400 kb of each other in the rice genome.
      By sequencing this region of the rice genome, it should now be possible to define
      the nature of this factor.

PMID- 10581296
TI  - Transposon tagging of the sulfur gene of tobacco using engineered maize Ac/Ds
      elements.
AB  - The Sulfur gene of tobacco is nuclearly encoded. A Su allele at this locus acts
      as a dominant semilethal mutation and causes reduced accumulation of chlorophyll,
      resulting in a yellow color in the plant. An engineered transposon tagging
      system, based upon the maize element Ac/Ds, was used to mutate the gene. High
      frequency of transposon excision from the Su locus produced variegated sectors.
      Plants regenerated from the variegated sector exhibited a similar variegated
      phenotype. Genetic analyses showed that the variegation was always associated
      with the transposase construct and the transposon was linked to the Su locus.
      Sequences surrounding the transposon were isolated, and five revertant sectors
      possessed typical direct repeats following Ds excisions. These genetic and
      molecular data are consistent with the tagging of the Su allele by the
      transposon.

PMID- 10581297
TI  - The Mla (powdery mildew) resistance cluster is associated with three NBS-LRR gene
      families and suppressed recombination within a 240-kb DNA interval on chromosome
      5S (1HS) of barley.
AB  - Powdery mildew of barley, caused by Erysiphe graminis f. sp. hordei, is a model
      system for investigating the mechanism of gene-for-gene interaction between large
      genome cereals and obligate-fungal pathogens. A large number of loci that confer
      resistance to this disease are located on the short arm of chromosome 5(1H). The
      Mla resistance-gene cluster is positioned near the telomeric end of this
      chromosome arm. AFLP-, RAPD-, and RFLP-derived markers were used to saturate the
      Mla region in a high-resolution recombinant population segregating for the (Mla6
      + Mla14) and (Mla13 + Ml-Ru3) resistance specificities. These tightly linked
      genetic markers were used to identify and develop a physical contig of YAC and
      BAC clones spanning the Mla cluster. Three distinct NBS-LRR resistance-gene
      homologue (RGH) families were revealed via computational analysis of low-pass and
      BAC-end sequence data derived from Mla-spanning clones. Genetic and physical
      mapping delimited the Mla-associated, NBS-LRR gene families to a 240-kb interval.
      Recombination within the RGH families was at least 10-fold less frequent than
      between markers directly adjacent to the Mla cluster.

PMID- 10581298
TI  - Population models of genomic imprinting. I. Differential viability in the sexes
      and the analogy with genetic dominance.
AB  - Many single-locus, two-allele selection models of genomic imprinting have been
      shown to reduce formally to one-locus Mendelian models with a modified parameter
      for genetic dominance. One exception is the model where selection at the
      imprinted locus affects the sexes differently. We present two models of maternal
      inactivation with differential viability in the sexes, one with complete
      inactivation, and the other with a partial penetrance for inactivation. We show
      that, provided dominance relations at the imprintable locus are the same in both
      sexes, a globally stable polymorphism exists for a range of viabilities that is
      independent of the penetrance of imprinting. The conditions for a polymorphism
      are the same as in previous models with differential viability in the sexes but
      without imprinting and in a model of the paternal X-inactivation system in
      marsupials. The model with incomplete inactivation is used to illustrate the
      analogy between imprinting and dominance by comparing equilibrium bifurcation
      plots for fixed values of dominance and penetrance. We also derive a single
      expression for the dominance parameter that leaves the frequency and stability of
      equilibria unchanged for all levels of inactivation. Although an imprinting model
      with sex differences does not formally reduce to a nonimprinting scheme, close
      theoretical parallels clearly exist.

PMID- 10581299
TI  - A comparison of multilocus clines maintained by environmental adaptation or by
      selection against hybrids.
AB  - There has recently been considerable debate over the relative importance of
      selection against hybrids ("endogenous" selection) vs. adaptation to different
      environments ("exogenous") in maintaining stable hybrid zones and hence in
      speciation. Single-locus models of endogenous and exogenous viability selection
      generate clines of similar shape, but the comparison has not been extended to
      multilocus systems, which are both quantitatively and qualitatively very
      different from the single-locus case. Here we develop an analytical multilocus
      model of differential adaptation across an environmental transition and compare
      it to previous heterozygote disadvantage models. We show that the shape of clines
      generated by exogenous selection is indistinguishable from that generated by
      endogenous selection. A stochastic simulation model is used to test the
      robustness of the analytical description to the effects of drift and strong
      selection, and confirms the prediction that pairwise linkage disequilibria are
      predominantly generated by migration. However, although analytical predictions
      for the width of clines maintained by heterozygote disadvantage fit well with the
      simulation results, those for environmental adaptation are consistently too
      narrow; reasons for the discrepancy are discussed. There is a smooth transition
      between a system in which a set of loci effectively act independently of each
      other and one in which they act as a single nonrecombining unit.

PMID- 10581300
TI  - Effect of DNA sequence divergence on homologous recombination as analyzed by a
      random-walk model.
AB  - A point connecting a pair of homologous regions of DNA duplexes moves along the
      homology in a reaction intermediate of the homologous recombination. Formulating
      this movement as a random walk, we were previously successful at explaining the
      dependence of the recombination frequency on the homology length. Recently, the
      dependence of the recombination frequency on the DNA sequence divergence in the
      homologous region was investigated experimentally; if the methyl-directed
      mismatch repair (MMR) system is active, the logarithm of the recombination
      frequency decreases very rapidly with an increase of the divergence in a low
      divergence regime. Beyond this regime, the logarithm decreases slowly and
      linearly with the divergence. This "very rapid drop-off" is not observed when the
      MMR system is defective. In this article, we show that our random-walk model can
      explain these data in a straightforward way. When a connecting point encounters a
      diverged base pair, it is assumed to be destroyed with a probability that depends
      on the level of MMR activity.

PMID- 10581301
TI  - New methods employing multilocus genotypes to select or exclude populations as
      origins of individuals.
AB  - A new method for assigning individuals of unknown origin to populations, based on
      the genetic distance between individuals and populations, was compared to two
      existing methods based on the likelihood of multilocus genotypes. The
      distribution of the assignment criterion (genetic distance or genotype
      likelihood) for individuals of a given population was used to define the
      probability that an individual belongs to the population. Using this definition,
      it becomes possible to exclude a population as the origin of an individual, a
      useful extension of the currently available assignment methods. Using simulated
      data based on the coalescent process, the different methods were evaluated,
      varying the time of divergence of populations, the mutation model, the sample
      size, and the number of loci. Likelihood-based methods (especially the Bayesian
      method) always performed better than distance methods. Other things being equal,
      genetic markers were always more efficient when evolving under the infinite
      allele model than under the stepwise mutation model, even for equal values of the
      differentiation parameter F(st). Using the Bayesian method, a 100% correct
      assignment rate can be achieved by scoring ca. 10 microsatellite loci (H
      approximately 0.6) on 30-50 individuals from each of 10 populations when the
      F(st) is near 0.1.

PMID- 10581302
TI  - Fluxes and metabolic pools as model traits for quantitative genetics. I. The L
      shaped distribution of gene effects.
AB  - The fluxes through metabolic pathways can be considered as model quantitative
      traits, whose QTL are the polymorphic loci controlling the activity or quantity
      of the enzymes. Relying on metabolic control theory, we investigated the
      relationships between the variations of enzyme activity along metabolic pathways
      and the variations of the flux in a population with biallelic QTL. Two kinds of
      variations were taken into account, the variation of the average enzyme activity
      across the loci, and the variation of the activity of each enzyme of the pathway
      among the individuals of the population. We proposed analytical approximations
      for the flux mean and variance in the population as well as for the additive and
      dominance variances of the individual QTL. Monte Carlo simulations based on these
      approximations showed that an L-shaped distribution of the contributions of
      individual QTL to the flux variance (R(2)) is consistently expected in an F(2)
      progeny. This result could partly account for the classically observed L-shaped
      distribution of QTL effects for quantitative traits. The high correlation we
      found between R(2) value and flux control coefficients variance suggests that
      such a distribution is an intrinsic property of metabolic pathways due to the
      summation property of control coefficients.

PMID- 10581303
TI  - Detecting population expansion and decline using microsatellites.
AB  - This article considers a demographic model where a population varies in size
      either linearly or exponentially. The genealogical history of microsatellite data
      sampled from this population can be described using coalescent theory. A method
      is presented whereby the posterior probability distribution of the genealogical
      and demographic parameters can be estimated using Markov chain Monte Carlo
      simulations. The likelihood surface for the demographic parameters is complicated
      and its general features are described. The method is then applied to published
      microsatellite data from two populations. Data from the northern hairy-nosed
      wombat show strong evidence of decline. Data from European humans show weak
      evidence of expansion.

PMID- 10581304
TI  - Effect of cysteine substitutions on the topology of the S4 segment of the Shaker
      potassium channel: implications for molecular models of gating.
AB  - 1. The gating properties of voltage-gated potassium channels are largely
      determined by the amino acid sequence of their S4 segments. To investigate the
      nature of S4 movement during gating, we introduced single cysteines into the S4
      segment of the Shaker potassium channel and expressed the mutants in Xenopus
      oocytes. We then measured the conductance-voltage (g-V) relationships and the
      rate and the voltage dependence of movement of the engineered cysteines, using p
      chloromercuribenzene sulphonate (pCMBS) as a probe. 2. Mutation of charged
      residues at positions 362, 365 and 368, but not the uncharged residues (positions
      360, 361, 363, 364 and 366), to cysteines shifted the g-V relationships to more
      positive potentials. Mutant channels in which cysteines replaced the charged
      residues at positions 362 and 365 (R362C and R365C) reacted faster with pCMBS
      than those in which cysteines were introduced in place of uncharged residues at
      positions 360 and 361 (I360C and L361C). Furthermore, the R365C mutant channel
      reacted with pCMBS even at hyperpolarised (-120 mV) potentials. Currents
      expressed by the doubly mutated R365S/V367C and R368S/V367C channels, but not the
      singly mutated V367C channel, were inhibited by pCMBS. Moreover, the R368C mutant
      channel was also affected by pCMBS. 3. Voltage dependence of block by pCMBS (2
      min exposure) was steeper for L366C than for L361C and V363C mutant channels
      (effective charge 2.19, 1. 41 and 1.45, respectively). The voltage dependence of
      the pCMBS effect was also shifted to more depolarising potentials the deeper in
      the membrane the position of the residue mutated to cysteine (voltages for half
      maximal effect -107, -94 and -73 mV for positions 361, 363 and 366,
      respectively). 4. Our data show firstly that charge-neutralising mutations in S4
      alter the topology of this region such that the membrane-spanning portion of S4
      is reduced. Secondly, our data for the other mutant channels suggest that S4
      might move in at least two sequential steps, and can move up to its maximal limit
      even at the resting potential of the cell.

PMID- 10581305
TI  - Permeability and single channel conductance of human homomeric rho1 GABAC
      receptors.
AB  - 1. Homomeric human rho1 GABAC receptors were expressed in Xenopus oocytes and in
      human embryonic kidney cells (HEK293) in order to examine their conductance and
      permeability. 2. Reversal potentials of currents elicited by gamma-aminobutyric
      acid (GABA) were measured in extracellular solutions of various ionic composition
      to determine relative permeability of homomeric rho1 receptors. The rank order of
      anionic permeability was: SCN- > I- > NO3- > Br- > Cl- > formate (For-) > HCO3- >
      acetate (Ac-) approximately proprionate (Prop-) approximately isethionate (Ise-)
      approximately F- approximately PO4-. 3. In the oocyte expression system, relative
      permeabilities to SCN-, I-, NO3-, Br- and HCO3- were higher for rho1 GABAC
      receptors than alpha1beta2gamma2L GABAA receptors. 4. Expression of rho1 GABAC
      receptors in Xenopus oocytes and in HEK293 cells gave similar relative
      permeabilities for selected anions, suggesting that the expression system does
      not significantly alter permeation properties. 5. The pore diameter of the
      homomeric rho1 GABAC receptor expressed in oocytes was estimated to be 0.61 nm,
      which is somewhat larger than the 0.56 nm pore diameter estimated for
      alpha1beta2gamma2L GABAA receptors. 6. Homomeric rho1 GABA receptors expressed in
      oocytes had a single channel chord conductance of 0.65 +/- 0.04 pS (mean +/-
      s.e.m.) when the internal chloride concentration ([Cl-]i) was 20 mM. With a [Cl
      ]i of 100 mM, the single channel chord conductance was 1.59 +/- 0.24 pS. 7. The
      mean open time directly measured from 43 GABA-induced channel openings in six
      patches was 3. 2 +/- 0.8 s. The mean open time in the presence of 100 microM
      picrotoxin was 0.07 +/- 0.01 s (77 openings from 3 patches). 8. The differences
      observed in ionic permeabilities, pore size, single channel conductance and mean
      open time suggest that the rho1 homomeric receptor may not be the native retinal
      GABAC receptor reported previously.

PMID- 10581306
TI  - Altered functional properties of KATP channel conferred by a novel splice variant
      of SUR1.
AB  - 1. ATP-sensitive potassium (KATP) channels are composed of pore-forming (Kir6.x)
      and regulatory sulphonylurea receptor (SURx) subunits. We have isolated a novel
      SUR variant (SUR1bDelta33) from a hypothalamic cDNA library. This variant lacked
      exon 33 and introduced a frameshift that produced a truncated protein lacking the
      second nucleotide binding domain (NBD2). It was expressed at low levels in
      hypothalamus, midbrain, heart and the insulin-secreting beta-cell line MIN6. 2.
      We examined the properties of KATP channels composed of Kir6.2 and SUR1bDelta33
      by recording macroscopic currents in membrane patches excised from Xenopus
      oocytes expressing these subunits. We also investigated the effect of truncating
      SUR1 at either the start (SUR1bT1) or end (SUR1bT2) of exon 33 on KATP channel
      properties. 3. Kir6.2/SUR1bDelta33 showed an enhanced open probability (Po = 0.6
      at -60 mV) and a reduced ATP sensitivity (Ki, 86 microM), when compared with wild
      type channels (Po = 0.3; Ki, 22 microM). However, Kir6.2/SUR1bT1 and
      Kir6.2/SUR1bT2 resembled the wild-type channel in their Po and ATP sensitivity.
      4. Neither MgADP, nor the K+ channel opener diazoxide, enhanced
      Kir6.2/SUR1bDelta33, Kir6.2/SUR1bT1 or Kir6.2/SUR1bT2 currents, consistent with
      the idea that these agents require an intact NBD2 for their action.
      Sulphonylureas blocked KATP channels containing any of the three SUR variants,
      but in excised patches the extent of block was less than that for the wild-type
      channel. In intact cells, the extent of sulphonylurea block of
      Kir6.2/SUR1bDelta33 was greater than that in excised patches and was comparable
      to that found for wild-type channels. 5. Our results demonstrate that NBD2 is not
      essential for functional expression or sulphonylurea block, but is required for
      KATP channel activation by K+ channel openers and nucleotides. Some of the
      unusual properties of Kir6.2/SUR1bDelta33 resemble those reported for the KATP
      channel of ventromedial hypothalamic (VMH) neurones, but the fact that this mRNA
      is expressed at low levels in many other tissues makes it less likely that
      SUR1bDelta33 serves as the SUR subunit for the VMH KATP channel.

PMID- 10581307
TI  - Constitutive beta2-adrenergic signalling enhances sarcoplasmic reticulum Ca2+
      cycling to augment contraction in mouse heart.
AB  - 1. Transgenic overexpression of the beta2-adrenergic receptor (beta2AR) in mouse
      heart augments baseline cardiac function in a ligand-independent manner, due to
      the presence of spontaneously active beta2AR (beta2AR*). This study aims to
      elucidate the mechanism of beta2AR*-mediated modulation of cardiac excitation
      contraction (EC) coupling. 2. Confocal imaging was used to analyse Ca2+ sparks
      and spatially resolve Ca2+ transients in single ventricular myocytes from
      transgenic (TG4) and non-transgenic (NTG) littermates. Whole-cell voltage- and
      current-clamp techniques were used to record L-type Ca2+ currents (ICa) and
      action potentials, respectively. 3. In the absence of any beta2AR ligand, TG4
      myocytes had greater contraction amplitudes, larger Ca2+ transients and faster
      relaxation times than did NTG cells. 4. The action potentials of TG4 and NTG
      myocytes were similar, except for a prolonged end-stage repolarization in TG4
      cells; the ICa density and kinetics were nearly identical. The relationship
      between peak Ca2+ and contraction, which reflects myofilament Ca2+ sensitivity,
      was similar. 5. In TG4 cells, the frequency of Ca2+ sparks (spontaneous or evoked
      at -40 mV) was 2-7 times greater, despite the absence of change in the resting
      Ca2+, sarcoplasmic reticulum (SR) Ca2+ content, and ICa. Individual sparks were
      brighter, broader and lasted longer, leading to a 2.3-fold greater signal mass.
      Thus, changes in both spark frequency and size underlie the greater Ca2+
      transient in TG4 cells. 6. The inverse agonist ICI 118,551 (ICI, 5 x 10-7 M),
      which blocks spontaneous beta2AR activation, reversed the aforementioned beta2AR*
      effects on cardiac EC coupling without affecting the sarcolemmal ICa. However,
      ICI failed to detect significant constitutive beta2AR activity in NTG cells. 7.
      We conclude that beta2AR*-mediated signalling enhances SR release channel
      activity and Ca2+-induced Ca2+ release in TG4 cardiac myocytes, and that beta2AR*
      enhances EC coupling by reinforcing SR Ca2+ cycling (release and reuptake), but
      bypassing the sarcolemmal ICa.

PMID- 10581308
TI  - Co-regulation of synaptic efficacy at stable polyneuronally innervated
      neuromuscular junctions in reinnervated rat muscle.
AB  - 1. Intracellular recordings and quantal analysis of synaptic transmission were
      made at neuromuscular junctions receiving stable convergent innervation in
      reinnervated rat lumbrical muscles, following recovery from chronic nerve
      conduction block. The polyneuronally innervated motor endplates (pi-junctions)
      were identified by vital staining of lateral plantar nerve (LPN) and sural nerve
      (SN) motor terminals, using the activity-dependent staining properties of the
      aminostyryl dyes RH414 and FM1-43, respectively. 2. Endplate depolarisation and
      quantal content per unit area varied by more than a factor of ten ( approximately
      0.1-1. 4 quanta microm-2) between fibres. However, the stable pi-junctions
      produced nearly equivalent endplate depolarisations and quantal content per unit
      area, suggesting that synaptic strengths were co-regulated at these motor
      endplates. Quantal content per unit area was also independent of the size of
      individual synaptic inputs, or whether one, both or neither input was judged
      sufficient to produce suprathreshold or subthreshold endplate depolarisations. 3.
      Simultaneous excitation of convergent LPN and SN inputs from some pi-junctions
      resulted in profound non-linear summation, and in some cases complete occlusion
      of the response of the smaller input. The amplitude of the smaller, test
      responses recovered with a time constant of 2.1 +/- 0.5 ms (mean +/- s.e.m.) on
      varying the interval between paired stimuli, of similar order to the time
      constant of repolarisation of the conditioning endplate potential. 4. The data
      show that it is not necessary for a motor nerve terminal to occupy most of an
      endplate, or to produce a suprathreshold response in order to become stable. The
      occlusion of linear summation, similar to that described previously at
      polyneuronal junctions in neonates, suggests that convergent inputs comprising
      interdigitated synaptic boutons evoke self-contained synaptic responses at
      endplates, and that these are non-co-operative with respect to overall endplate
      depolarisation or safety margin for synaptic transmission.

PMID- 10581309
TI  - Peroxynitrite is a positive inotropic agent in atrial and ventricular fibres of
      the frog heart.
AB  - 1. We report opposite inotropic effects of NO donors in frog cardiac fibres. The
      negative effect, elicited by either 3-morpholino-sydnonimine (SIN-1) or S-nitroso
      N-acetyl-penicillamine (SNAP), involved cyclic GMP (cGMP) production. However,
      SIN-1, unlike SNAP, could elicit a positive effect, in a superoxide dismutase
      (SOD)-sensitive manner. SIN-1, unlike SNAP, can release both NO and superoxide
      anion, the precursors of peroxynitrite (OONO-). The role of these messengers was
      examined. 2. Catalase did not reduce the positive inotropic effect of SIN-1.
      Thus, a conversion of superoxide anion into hydrogen peroxide was not involved in
      this effect. In addition, catalase did not modify the negative effects of SIN-1
      plus SOD, or SNAP plus SOD. 3. LY 83583, a superoxide anion generator, elicited a
      positive inotropic effect, like SIN-1. The effect of LY 83583 was additive to the
      negative effects of SIN-1 or SNAP, and to the positive effect of SIN-1. Thus,
      superoxide anion generation, per se, did not account for the positive effect of
      SIN-1. 4. Authentic peroxynitrite (OONO-), but not mock-OONO- (negative control
      plus decomposed OONO-), exerted a dramatic positive inotropic effect in cardiac
      fibres. The effect of OONO- was larger in atrial fibres, as compared with
      ventricular fibres. 5. The positive effect of OONO- was not additive with that of
      SIN-1, suggesting a common mechanism of action. In contrast, the effects of
      either OONO- or SIN-1 were additive with the negative inotropic effect of SNAP.
      Furthermore, the effect of OONO-, like that of SIN-1, was not antagonized by 1H
      [1,2,4]xidiazolo[4, 3-a]quinoxaline-1-one (ODQ; 10 microM), the guanylyl cyclase
      inhibitor. 6. The positive inotropic effects of SIN-1 and OONO- were not modified
      by hydroxyl radical scavengers, such as dimethyl-thio-urea (DMTU; 10 mM). 7. The
      positive inotropic effect of SIN-1 (100 microM) was abolished in sodium-free
      solutions, a treatment that eliminates the activity of the sodium-calcium
      exchanger. In contrast, the effect of SIN-1 was unchanged by a potassium channel
      inhibitor (tetraethyl-ammonium, 20 mM), or a sodium-potassium pump inhibitor
      (ouabain 10 microM). 8. We conclude that OONO- is a positive inotropic agent in
      frog cardiac fibres. The generation of OONO- accounts for the positive inotropic
      effect of SIN-1. OONO- itself was responsible for the positive inotropic effect,
      and appeared to modulate the activity of the sodium-calcium exchanger.

PMID- 10581310
TI  - Actin cytoskeleton depolymerization with clostridium spiroforme toxin enhances
      the secretory activity of rat melanotrophs.
AB  - 1. We measured membrane capacitance (Cm) in cultured rat melanotrophs pretreated
      with Clostridium spiroforme toxin (CST), which specifically depolymerizes
      cortical filamentous actin (F-actin). Phalloidin staining confirmed that CST
      treatment depolymerised the F-actin. 2. In control cells, cytosol dialysis with 1
      microM Ca2+i increased Cm by 23 +/- 4 % (n = 11) relative to the resting Cm 400 s
      after the start of patch rupture. In CST-treated cells the increase in Cm was 32
      +/- 5 % (n = 15), not significantly different from controls. The rate of Cm
      increase was affected transiently by CST treatment, peaking at 1 min after patch
      rupture. The maximal rate of Cm increase was 4.27 +/- 0.85 fF s-1 (n = 12;
      measured 200 s after the start of patch rupture) in controls and 8.0 +/- 1.35 fF
      s-1 (n = 23; measured 75 s after the start of patch rupture) in CST-treated cells
      (P < 0.01). 3. In control cells cytosol dialysis with 0 microM Ca2+i decreased Cm
      by 9 +/- 3 % (n = 7), in CST-treated cells Cm increased by 11 +/- 3 % (n = 7)
      relative to resting Cm 400 s after the start of cytosol dialysis. The rate of
      change in Cm remained constant (controls: -1 to -2 fF s-1; CST treatment: 1-2 fF
      s-1). 4. Transient and sustained effects of CST treatment on changes in Cm at
      high or low [Ca2+]i, respectively, suggest a distinct role of cytoskeleton in
      Ca2+-dependent and Ca2+-independent changes in Cm. Transient enhancement of the
      rate of Cm by CST is consistent with a barrier role of cytoskeleton in regulated
      exocytosis. The sustained effect of CST on Ca2+-independent changes in Cm
      suggests cytoskeletal involvement in endocytosis.

PMID- 10581311
TI  - Non-genomic actions of 17beta-oestradiol in mouse pancreatic beta-cells are
      mediated by a cGMP-dependent protein kinase.
AB  - 1. Intracellular calcium concentration ([Ca2+]i) was measured in mouse whole
      islets of Langerhans using the calcium-sensitive fluorescent dye Indo-1. 2.
      Application of physiological concentrations of 17beta-oestradiol in the presence
      of a stimulatory glucose concentration (8 mM) potentiated the [Ca2+]i signal in
      83 % of islets tested. Potentiation was manifested as either an increase in the
      frequency or duration of [Ca2+]i oscillations. 3. The effects caused by 17beta
      oestradiol were mimicked by the cyclic nucleotide analogues 8-bromoguanosine
      3',5'-cyclic monophosphate (8-Br-cGMP) and 8-bromoadenosine-3',5'-cyclic
      monophosphate (8-Br-cAMP). 4. Direct measurements of both cyclic nucleotides
      demonstrated that nanomolar concentrations of 17beta-oestradiol in the presence
      of 8 mM glucose increased cGMP levels, yet cAMP levels were unchanged. The
      increment in cGMP was similar to that induced by 11 mM glucose. 5. Patch-clamp
      recording in intact cells showed that 8-Br-cGMP reproduced the inhibitory action
      of 17beta-oestradiol on ATP-sensitive K+ (KATP) channel activity. This was not a
      membrane-bound effect since it could not be observed in excised patches. 6. The
      action of 17beta-oestradiol on KATP channel activity was not modified by the
      specific inhibitor of soluble guanylate cyclase (sGC) LY 83583. This result
      indicates a likely involvement of a membrane guanylate cyclase (mGC). 7. The
      rapid decrease in KATP channel activity elicited by 17beta-oestradiol was greatly
      reduced using Rp-8-pCPT-cGMPS, a specific blocker of cGMP-dependent protein
      kinase (PKG). Conversely, Rp-cAMPS, which inhibits cAMP-dependent protein kinase
      (PKA), had little effect. 8. The results presented here indicate that rapid, non
      genomic effects of 17beta-oestradiol after interaction with its binding site at
      the plasma membrane of pancreatic beta-cells is a cGMP-dependent phosphorylation
      process.

PMID- 10581312
TI  - Muscarinic receptor heterogeneity in follicle-enclosed Xenopus oocytes.
AB  - 1. Ionic current responses elicited by acetylcholine (ACh) in follicle-enclosed
      Xenopus oocytes (follicles) were studied using the two-electrode voltage-clamp
      technique. ACh generated a fast chloride current (Fin) and inhibited K+ currents
      gated by cAMP (IK,cAMP) following receptor activation by adenosine, follicle
      stimulating hormone or noradrenaline. These previously described cholinergic
      responses were confirmed to be of the muscarinic type, and were independently
      generated among follicles from different frogs. 2. Inhibition of IK,cAMP was
      about 100 times more sensitive to ACh than Fin activation; the half-maximal
      effective concentrations (EC50) were 6.6 +/- 0.4 and 784 +/- 4 nM, respectively.
      3. Both responses were blocked by several muscarinic receptor antagonists. Using
      the respective EC50 concentrations of ACh as standard, the antagonist 4
      diphenylacetoxy-N-methylpiperidine methiodide blocked the two effects with very
      different potencies. Fin was blocked with a half-maximal inhibitory concentration
      (IC50) of 2.4 +/- 0.07 nM, whilst the IC50 for IK,cAMP inhibition was 5.9 +/- 0.2
      microM. 4. Oxotremorine, a muscarinic agonist, preferentially stimulated IK, cAMP
      inhibition (EC50 = 15.8 +/- 1.4 microM), whilst Fin was only weakly activated. In
      contrast, oxotremorine inhibited Fin generated by ACh with an IC50 of 2.3 +/- 0.7
      microM. 5. Fin elicited via purinergic receptor stimulation was not affected by
      oxotremorine, indicating that the inhibition produced was specific to the
      muscarinic receptor, and suggesting that muscarinic actions do not exert a strong
      effect on follicular cell-oocyte coupling. 6. Using reverse transcription-PCR,
      transcripts of a previously cloned muscarinic receptor from Xenopus (XlmR) were
      amplified from the RNA of both the isolated follicular cells and the oocyte. The
      pharmacological and molecular characteristics suggest that XlmR is involved in
      IK,cAMP inhibition. 7. In conclusion, follicular cells possess two different
      muscarinic receptors, one resembling the M2 (or M4) subtype and the other the M3
      subtype. These receptors are coupled to distinct membrane mechanisms leading to
      independent regulation of two membrane conductances.

PMID- 10581313
TI  - Differential regulation of synaptic GABAA receptors by cAMP-dependent protein
      kinase in mouse cerebellar and olfactory bulb neurones.
AB  - 1. It has been demonstrated that the regulation of recombinant GABAA receptors by
      phosphorylation depends on the subunit composition. Here we studied the
      regulation of synaptic GABAA receptor function by cAMP-dependent protein kinase
      (PKA) in neurones expressing distinct receptor subtypes. 2. Light microscopic
      immunocytochemistry revealed that granule cells of the olfactory bulb express
      only the beta3 as the beta subunit variant, whereas cerebellar stellate and
      basket cells express only the beta2 as the beta subunit. 3. In cerebellar
      interneurones, intracellular application of 20 microM microcystin, a protein
      phosphatase 1/2A inhibitor, prolonged (63 +/- 14 %; mean +/- s.e.m.) the decay
      time course of miniature IPSCs (mIPSCs) without significantly affecting their
      amplitude, rise time and frequency. The effect of microcystin could be blocked by
      co-applying PKA inhibitory peptide (PKA-I, 1 microM). 4. No significant changes
      in any of the mIPSC parameters could be detected after intracellular application
      of PKA-I alone or following the inhibition of calcineurin with FK506 (50 nM). 5.
      In granule cells of the olfactory bulb expressing the beta3 subunit fast and
      slowly rising mIPSCs were detected, resulting in a bimodal distribution of the 10
      90 % rise times, suggesting two distinct populations of events. Fast rising
      mIPSCs (mIPSCFR) had a 10-90 % rise time of 410 +/- 50 micros, an amplitude of 68
      +/- 6 pA, and a weighted decay time constant (tauw) of 15.8 +/- 2.9 ms. In
      contrast, slowly rising mIPSCs (mIPSCSR) displayed an approximately threefold
      slower rise time (1.15 +/- 0.12 ms), 57 % smaller amplitude (29 +/- 1.7 pA), but
      had a tauw (16.8 +/- 3.0 ms) similar to that of the fast events. 6. mIPSCs in
      olfactory granule cells were not affected by the intracellular perfusion of
      microcystin. In spite of this, intracellular administration of constitutively
      active PKA caused a small, gradual, but significant increase (18 +/- 5 %) in the
      amplitude of the events without changing their time course. 7. These findings
      demonstrate a cell-type-dependent regulation of synaptic inhibition by protein
      phosphorylation. Furthermore, our results show that the effect of PKA-mediated
      phosphorylation on synaptic inhibition depends upon the subunit composition of
      postsynaptic GABAA receptors.

PMID- 10581314
TI  - Effects of a naturally occurring neurosteroid on GABAA IPSCs during development
      in rat hippocampal or cerebellar slices.
AB  - 1. The effects of the naturally occurring neurosteroid
      tetrahydrodeoxycorticosterone (THDOC) on GABAA receptor-mediated miniature,
      spontaneous and evoked IPSCs was tested using patch-clamp techniques in slices of
      hippocampus and cerebellum from rats at two developmental stages ( approximately
      10 and approximately 20 days postnatal). The cells studied were hippocampal
      granule cells and cerebellar Purkinje and granule cells. 2. Most miniature
      GABAergic currents (mIPSCs) decayed with two exponentials and neurosteroids
      caused a approximately 4-fold increase in the decay time constant of the second
      exponential at the highest concentration used (2 microM). Similar effects were
      seen at high concentrations of THDOC (1-2 microM) in all cell groups tested. No
      effects were seen on amplitude or rise time of mIPSCs. 3. The effects of THDOC (1
      microM) were shown to be stereoselective and rapidly reversible, indicating that
      the neurosteroid binds to the GABAA receptor, rather than acting genomically. 4.
      At concentrations of THDOC likely to occur physiologically (50-100 nM), the decay
      time of IPSCs was also enhanced (25-50 %) in all cerebellar cell groups tested.
      In contrast, at 100 nM THDOC, seven of 11 hippocampal granule cells were
      sensitive from the 10 day group but the 20 day hippocampal granule cells showed
      no significant enhancement in the presence of these lower concentrations of
      THDOC. 5. The differences in sensitivity of hippocampal and cerebellar cells to
      THDOC are compared to data reported in the literature on regional development of
      expression of different receptor subunits in the brain and it is suggested that
      the progressive relative insensitivity of the 20 day hippocampal cells may depend
      on increasing expression of the delta subunit of the GABAA receptor and possibly
      an increase in the alpha4 subunit.

PMID- 10581315
TI  - Effects of adenosine receptors on the synaptic and EPSP-spike components of long
      term potentiation and depotentiation in the guinea-pig hippocampus.
AB  - 1. Long-term potentiation (LTP) of synaptic efficacy comprises two components: a
      synaptic component consisting of increased field excitatory postsynaptic
      potentials (EPSPs), and a component consisting of a larger population spike
      amplitude for a given EPSP size (E-S potentiation). In hippocampal CA1 neurons,
      delivery of three weak bursts (5 pulses at 100 Hz, 20 min intervals) induced LTP
      in both the EPSP and E-S components. In the same cells, reversal of LTP
      (depotentiation, DP) in the field EPSP and the E-S component was achieved by
      delivering three trains of low-frequency stimuli (LFS; 200 pulses at 1 Hz, 20 min
      intervals). 2. The effects of adenosine A1 and A2 receptor antagonists on the
      synaptic and E-S components of LTP and DP in CA1 neurons were studied by
      perfusing guinea-pig hippocampal slices with either 8-cyclopentyltheophylline (8
      CPT) or CP-66713. 3. When bursts or LFS were applied to CA1 inputs in the
      presence of the A1 receptor antagonist 8-CPT, the field EPSP was enhanced in LTP
      and attenuated in DP, while the E-S relationship was not significantly affected
      in either LTP or DP. 4. When similar experiments were performed using the A2
      receptor antagonist CP-66713, the field EPSP was blocked in LTP, but facilitated
      in DP, while E-S potentiation was enhanced during both LTP and DP. 5. The results
      show that A1 and A2 adenosine receptors modulate both the synaptic and E-S
      components of the induction and reversal of LTP. Based on these results, we
      discuss the key issue of the contribution of these receptors to the dynamics of
      neuronal plasticity modification in hippocampal CA1 neurons.

PMID- 10581316
TI  - Mechanisms and consequences of action potential burst firing in rat neocortical
      pyramidal neurons.
AB  - 1. Electrophysiological recordings and pharmacological manipulations were used to
      investigate the mechanisms underlying the generation of action potential burst
      firing and its postsynaptic consequences in visually identified rat layer 5
      pyramidal neurons in vitro. 2. Based upon repetitive firing properties and
      subthreshold membrane characteristics, layer 5 pyramidal neurons were separated
      into three classes: regular firing and weak and strong intrinsically burst
      firing. 3. High frequency (330 +/- 10 Hz) action potential burst firing was
      abolished or greatly weakened by the removal of Ca2+ (n = 5) from, or by the
      addition of the Ca2+ channel antagonist Ni2+ (250-500 microm; n = 8) to, the
      perfusion medium. 4. The blockade of apical dendritic sodium channels by the
      local dendritic application of TTX (100 nM; n = 5) abolished or greatly weakened
      action potential burst firing, as did the local apical dendritic application of
      Ni2+ (1 mM; n = 5). 5. Apical dendritic depolarisation resulted in low frequency
      (157 +/- 26 Hz; n = 6) action potential burst firing in regular firing neurons,
      as classified by somatic current injection. The intensity of action potential
      burst discharges in intrinsically burst firing neurons was facilitated by
      dendritic depolarisation (n = 11). 6. Action potential amplitude decreased
      throughout a burst when recorded somatically, suggesting that later action
      potentials may fail to propagate axonally. Axonal recordings demonstrated that
      each action potential in a burst is axonally initiated and that no decrement in
      action potential amplitude is apparent in the axon > 30 microm from the soma. 7.
      Paired recordings (n = 16) from synaptically coupled neurons indicated that each
      action potential in a burst could cause transmitter release. EPSPs or EPSCs
      evoked by a presynaptic burst of action potentials showed use-dependent synaptic
      depression. 8. A postsynaptic, TTX-sensitive voltage-dependent amplification
      process ensured that later EPSPs in a burst were amplified when generated from
      membrane potentials positive to -60 mV, providing a postsynaptic mechanism that
      counteracts use-dependent depression at synapses between layer 5 pyramidal
      neurons.

PMID- 10581317
TI  - Spatially segregated control of Ca2+ release in developing skeletal muscle of
      mice.
AB  - 1. Confocal laser scanning microscopy was used to monitor Ca2+ signals in primary
      cultured myotubes, prepared from forelimbs of wild-type or ryanodine receptor
      type 3 (RyR3) knockout mice. Myotubes loaded with the acetoxymethyl ester (AM)
      form of fluo-3 were imaged at rest or under whole-cell patch clamp. 2. Discrete
      Ca2+ release events were detected in intact wild-type and RyR3-knockout myotubes.
      They showed almost no difference in amplitude and width, but were substantially
      different in duration. In wild-type myotubes (660 events, 57 cells) the amplitude
      was 1.27 (0.85, 1.97) (median (25 %, 75 %)) units of resting fluorescence, the
      full width at half-magnitude (FWHM) was 1.4 (0.9, 2.3) microm, and the full
      duration at half-magnitude (FDHM) was 25.3 (9.6, 51.7) ms. In RyR3-knockout
      myotubes (655 events, 83 cells) the amplitude was 1.30 (0.84, 2.08), FWHM was
      1.63 (1.02, 2.66) microm, and FDHM was 43.6 (23.6, 76.9) ms. 3. Depolarization
      under voltage clamp of both wild-type and RyR3-knockout myotubes produced
      substantial Ca2+ release devoid of discrete Ca2+ events. Discrete events were
      still present but occurred without correlation with the applied pulse, largely at
      locations where the pulse did not elicit release. 4. The local correspondence
      between voltage control and absence of discrete events implies that the
      functional interaction with voltage sensors suppresses the mechanism that
      activates discrete events. Because it applies whether RyR3 is present or not, it
      is this exclusion by voltage of other control mechanisms, rather than isoform
      composition, that primarily determines the absence of discrete Ca2+ events in
      adult mammalian muscle.

PMID- 10581318
TI  - Dynamic Ca2+ signalling in rat arterial smooth muscle cells under the control of
      local renin-angiotensin system.
AB  - 1. We visualized the changes in intracellular Ca2+ concentration ([Ca2+]i), using
      fluo-3 as an indicator, in individual smooth muscle cells within intact rat tail
      artery preparations. 2. On average in about 45 % of the vascular smooth muscle
      cells we found spontaneous Ca2+ waves and oscillations ( approximately 0.13 Hz),
      which we refer to here as Ca2+ ripples because the peak amplitude of [Ca2+]i was
      about one-seventh of that of Ca2+ oscillations evoked by noradrenaline. 3. We
      also found another pattern of spontaneous Ca2+ transients often in groups of two
      to three cells. They were rarely observed and are referred to as Ca2+ flashes
      because their peak amplitude was nearly twice as large as that in noradrenaline
      evoked responses. 4. Sympathetic nerve activity was not considered responsible
      for the Ca2+ ripples, and they were abolished by inhibitors of either the Ca2+
      pump in the sarcoplasmic reticulum (cyclopiazonic acid) or phospholipase C (U
      73122). 5. Both angiotensin antagonists ([Sar1,Ile8]-angiotensin II and losartan)
      and an angiotensin converting enzyme inhibitor (captopril) inhibited the Ca2+
      ripples. 6. The extracellular Ca2+-dependent tension borne by unstimulated
      arterial rings was reduced by the angiotensin antagonist by approximately 50 %.
      7. These results indicate that the Ca2+ ripples are generated via inositol 1,4, 5
      trisphosphate-induced Ca2+ release from the intracellular Ca2+ stores in response
      to locally produced angiotensin II, which contributes to the maintenance of
      vascular tone.

PMID- 10581319
TI  - Mechanisms underlying spontaneous rhythmical contractions in irideal arterioles
      of the rat.
AB  - 1. Mechanisms underlying spontaneous rhythmical contractions have been studied in
      irideal arterioles of the rat using video microscopy and electrophysiology. 2.
      Rhythmical contractions (4 min-1) were more common during the second and third
      postnatal weeks and were always preceded by large, slow depolarizations (5-40
      mV). 3. Spontaneous contractions were unaffected by tetrodotoxin (1 microM),
      neurotransmitter receptor antagonists, the sympathetic neurone blocker,
      guanethidine (5 microM) or sensory neurotoxin, capsaicin (1 microM). 4.
      Stimulation of sensory nerves inhibited spontaneous activity and this was not
      prevented by L-NAME (10 microm). 5. L-NAME (10 microm) caused an increase in
      frequency of spontaneous contractions, while forskolin (30 nM), in the presence
      of L-NAME, abolished spontaneous, but not nerve-mediated, contractions. 6.
      Spontaneous activity was not affected by felodipine (1 nM) or nifedipine (1
      microM), but was abolished by cadmium chloride (1 microM) or superfusion with
      calcium-free solution. 7. Caffeine (1 mM), thapsigargin (2 microM) and
      cyclopiazonic acid (3 microM), but not ryanodine (3 microM), abolished
      spontaneous and nerve-mediated contractions. After preincubation in L-NAME (10
      microM), cyclopiazonic acid abolished spontaneous contractions only. 8.
      Spontaneous depolarizations and contractions were abolished by 18alpha
      glycyrrhetinic acid (20 microM). 9. Results suggest that spontaneous rhythmical
      contractions are myogenic and result from the cyclical release of calcium from
      intracellular stores, without a contribution from voltage-dependent calcium
      channels. Intercellular coupling through gap junctions appears to be essential
      for co-ordination of these events which could be modulated by nitric oxide and
      increases in cAMP. The possibility that different intracellular stores underly
      spontaneous and nerve-mediated contractions is discussed.

PMID- 10581320
TI  - Sensitization of visceral afferents to bradykinin in rat jejunum in vitro.
AB  - 1. We have investigated the effects of inflammatory mediators on visceral
      afferent discharge and afferent responses to bradykinin (BK) in rat jejunum using
      a novel in vitro technique. 2. Prostaglandin E2 (1 microM) augmented responses to
      BK without affecting basal firing, while histamine (100 microM) and adenosine
      (100 microM) activated basal discharge and enhanced BK responses. In contrast, 5
      HT (100 microM) increased basal discharge without influencing responses to BK. 3.
      Afferent discharge induced by histamine was inhibited by both H1 (pyrilamine) and
      H3 (thioperamide) but not H2 (ranitidine) receptor antagonists at 10 microM. In
      contrast, sensitization to BK induced by histamine was inhibited by ranitidine
      (10 microM). 4. Afferent discharge induced by adenosine was blocked by the A1
      receptor antagonist DPCPX (10 microM) but remained unaffected by A2A receptor
      blockade with ZM241385 (10 microM). In contrast, sensitization of BK responses by
      adenosine was unaffected by both antagonists. Basal discharge and BK-induced
      responses were unaffected by the A3 receptor agonist IB-MECA (1 microM). While
      involvement of A2B receptors is not excluded, adenosine may activate afferent
      discharge through A1 receptors, while sensitization to BK could involve a
      receptor other than A1, A2A or A3, possibly the A2B receptor. 5. Inhibition of
      cyclo-oxygenase with naproxen (10 microM) prevented sensitization after histamine
      but not adenosine. 6. Sensitization was mimicked by dibutyryl cAMP. This occurred
      without changes in basal firing and was unaffected by naproxen. 7. In conclusion,
      afferent discharge induced by BK is augmented by histamine, adenosine and PGE2,
      but not by 5-HT. Evidence suggests that sensitization involves separate
      mechanisms from afferent activation. Sensitization may be mediated by increases
      in cAMP following direct activation by mediators at the nerve terminal or through
      indirect pathways such as the release of prostaglandins.

PMID- 10581321
TI  - Responsiveness of rat substantia gelatinosa neurones to mechanical but not
      thermal stimuli revealed by in vivo patch-clamp recording.
AB  - 1. Synaptic responses of 46 substantia gelatinosa (SG) neurones in the spinal
      dorsal horn to cutaneous mechanical and/or thermal stimuli were investigated in
      an in vivo rat preparation with whole-cell patch-clamp recordings. The clamped
      neurones were identified as being in the SG based on either their morphological
      features by intrasomatic injection of biocytin or the depth of the neurones from
      the surface of the spinal cord. 2. In all SG neurones examined where spontaneous
      EPSCs occurred, pinch (noxious) and air (innocuous) stimuli applied to the
      ipsilateral hindlimb elicited a barrage of EPSCs (some of which initiated an
      action potential under current-clamp conditions), which subsided just after
      cessation of the stimuli without any residual slow current (or after-discharge).
      The spontaneous and evoked EPSCs were reversibly abolished by a non-N-methyl-D
      aspartate (non-NMDA) receptor antagonist, CNQX (20 microM). 3. Noxious (>= 45 C)
      or innocuous (<= 40 C) thermal stimuli did not elicit any synaptic responses in
      all 18 SG neurones tested which were sensitive to mechanical stimuli. Noxious
      cold stimulation (<= 10 C) also failed to produce any responses (n = 6). 4. It is
      concluded that both noxious and innocuous mechanical information to SG neurones
      are transmitted primarily by activation of non-NMDA receptors, probably without
      any involvement of slow synaptic transmission, and that thermal information is
      conveyed to areas of the dorsal horn other than SG.

PMID- 10581322
TI  - Pulmonary oedema produced by scorpion venom augments a phenyldiguanide-induced
      reflex response in anaesthetized rats.
AB  - 1. The involvement of pulmonary oedema produced by scorpion venom in augmenting a
      phenyldiguanide (PDG)-induced reflex response was evaluated in urethane
      anaesthetized rats. 2. PDG-induced bradycardiac, hypotensive and apnoeic
      responses, expressed as time-response area, exhibited similarities before or
      after venom treatment. Hence, the time-response area of bradycardia was taken as
      a reflex parameter. Pulmonary oedema was determined by physical evaporation and
      histological methods. 3. Exposure to Indian red scorpion (Buthus tamulus, BT;
      i.v.) venom for 30 min increased the pulmonary water content (P < 0.05; Student's
      t test) and augmented the PDG-induced bradycardiac reflex response by more than 2
      times (P < 0.001). The increase of pulmonary water content was maximal with 100
      microg kg-1 of venom and the augmentation was maximal with 10 microg kg-1. In a
      separate series of experiments, the venom (100 microg kg-1)-induced pulmonary
      oedema was confirmed by histological and physical methods. In this group also,
      the venom augmented the reflex to the same magnitude. 4. Pulmonary oedema
      (physical and histological) and augmentation of the bradycardiac reflex response
      after BT venom (100 microg kg-1; i.v.) were absent in animals pretreated with
      aprotinin, a kallikrein-kinin inhibitor (6000 KIU; i. v.). 5. Ondansetron (10
      microg kg-1; i.v.), a 5-HT3 receptor antagonist, failed to block the venom
      induced pulmonary oedema (physical and histological) but blocked the venom
      induced augmentation of the reflex. 6. The results of this study indicate that
      the venom-induced augmentation of the PDG reflex is associated with pulmonary
      oedema involving kinins utilizing 5-HT3 receptors.

PMID- 10581323
TI  - Intraneural stimulation elicits an increase in subcutaneous interstitial glycerol
      levels in humans.
AB  - 1. The effect of intraneural electrical stimulation of the lateral femoral
      cutaneous nerve on lipolysis in the innervation territory of the stimulated nerve
      fascicle was studied in seven healthy women. Lipolysis was evaluated by
      microdialytic measurement of the interstitial glycerol concentration in
      subcutaneous adipose tissue. 2. Ten minutes of unilateral intraneural stimulation
      elicited a 22 +/- 8 % (mean +/- s.e.m.) increase in glycerol levels in the
      stimulated region (P < 0.05), whereas no change was registered in the
      corresponding area of the contralateral unstimulated leg. 3. Significantly higher
      glycerol levels in the stimulated vs. contralateral unstimulated region (47 +/-
      13 %, P < 0.05) were already observed at baseline (30 min resting period
      preceding the 10 min stimulation), in all probability as a consequence of the
      nerve searching procedure and trial stimulations. After the 10 min stimulation,
      the overall glycerol increase was 72 +/- 17 % compared with the contralateral
      leg, illustrating the degree of lipolysis induced by the whole experimental
      procedure. 4. The sympathetic discharge in the lateral femoral nerve (6
      recordings) showed typical characteristics of skin sympathetic activity, and the
      firing pattern was strikingly similar to simultaneously recorded sympathetic
      discharge in cutaneous nerve fascicles innervating regions without prominent
      subcutaneous fat stores (2 double nerve recordings). Thus, no component of
      cutaneous sympathetic outflow specific for the nerve innervating prominent
      subcutaneous fat stores could be identified. 5. Our findings suggest that
      sympathetic nerve fibres travelling in cutaneous nerve fascicles exert a
      regulatory influence on subcutaneous fat tissue in humans. The combination of
      intraneural recording/stimulation and subcutaneous microdialysis provides a model
      for evaluating neural control of human fat metabolism.

PMID- 10581324
TI  - The unilateral and bilateral control of motor unit pairs in the first dorsal
      interosseous and paraspinal muscles in man.
AB  - 1. The discharges of two motor units were identified in an intrinsic hand muscle
      (first dorsal interosseous, FDI) or an axial muscle (lumbar paraspinals, PSP) in
      ten healthy subjects. Each motor unit was situated in the homologous muscle on
      either side of the body (bilateral condition) or in the same muscle (ipsilateral
      condition). The relationship between the times of discharge of the two units was
      determined using coherence analysis. 2. Motor unit pairs in the ipsilateral FDI
      showed significant coherence over the frequency bands 1-10 Hz and 12-40 Hz. Motor
      units in the ipsilateral PSP were significantly coherent below 5 Hz. In contrast
      there was no significant coherence at any frequency up to 100 Hz in the bilateral
      FDI condition and only a small but significant band of coherence below 2 Hz in
      the bilateral PSP condition. 3. Common drive to motor units at frequencies of < 4
      Hz was assessed by cross-correlation of the instantaneous frequencies of the
      motor units. A significantly higher coefficient was found in the ipsilateral FDI,
      ipsi- and bilateral PSP compared with shifted, unrelated data sets. This was not
      the case for the bilateral FDI condition. 4. The presence of higher frequency
      coherence ( > 10 Hz) in the ipsilateral FDI condition and its absence in
      ipsilateral PSP is consistent with a more direct and influential cortical supply
      to the intrinsic hand muscles compared with the axial musculature. The presence
      of low frequency drives (< 4 Hz) in the bilateral PSP condition and its absence
      in the bilateral FDI condition is consistent with a bilateral drive to axial, but
      not distal, musculature by the motor pathways responsible for this oscillatory
      input.

PMID- 10581325
TI  - Catechol-O-methyltransferase (COMT): biochemistry, molecular biology,
      pharmacology, and clinical efficacy of the new selective COMT inhibitors.

PMID- 10581326
TI  - Enigma of the peripheral benzodiazepine receptor.

PMID- 10581327
TI  - Adrenergic and muscarinic receptors in the human heart.

PMID- 10581328
TI  - Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors.

PMID- 10581329
TI  - International Union of Pharmacology. XXI. Structure, distribution, and functions
      of cholecystokinin receptors.

PMID- 10581330
TI  - Risk of importation of diseases exotic to Great Britain following the relaxation
      of quarantine regulations.

PMID- 10581331
TI  - Seasonal variations in coronary heart disease.
AB  - Coronary heart disease exhibits a winter peak and summer trough in incidence and
      mortality, in countries both north and south of the equator. In England and
      Wales, the winter peak accounts for an additional 20,000 deaths per annum. It is
      likely that this reflects seasonal variations in risk factors. Seasonal
      variations have been demonstrated in a number of lifestyle risk factors such a
      physical activity and diet. However, a number of studies have also suggested a
      direct effect of environmental temperature on physiological and rheological
      factors. We review the available evidence on seasonal variations in coronary
      heart disease and possible explanations for them.

PMID- 10581332
TI  - The management of vasovagal syncope.

PMID- 10581333
TI  - Capture-recapture-adjusted prevalence rates of type 2 diabetes are related to
      social deprivation.
AB  - We examined the prevalence of type 2 diabetes and social deprivation in one urban
      district in Liverpool from October 1995 to September 1996 inclusive. This area
      has a stable Caucasian population of 176, 682. Lists were made of all known
      diabetics attending six different medical points of contact during the year, and
      were condensed and aggregated to eliminate duplicates. From postcode data, each
      patient was assigned to residence in one of the 14 electoral wards in the
      district, for which demographic structure and standardized measures of social
      deprivation were known (Townsend index). The crude period prevalences of type 1
      and type 2 diabetes were estimated for each ward. Crude prevalence data were then
      corrected by applying capture-recapture (CR) techniques to the different patient
      datasets to allow for undercount. The crude period prevalence (95%CI) of diabetes
      was 1.5% (1.4-1.5%), or 2585/176, 682. The mean age of people with diabetes was
      not significantly different between electoral wards. The crude period prevalence
      of type 2 diabetes within individual wards ranged from 0.4% (0.3-0.6%) in the
      least deprived area to 4.1% (3.6-4.6%) in the most deprived area. The
      corresponding range of CR-adjusted period prevalence rates of type 2 diabetes was
      from 3.2% (2.8-3.6%) to 6.7% (6.1-7.4%), and there was strong correlation between
      both crude and CR-adjusted prevalence and social deprivation in each ward
      (r=0.76, p<0.001 for crude; and r=0. 49, p<0.005 for CR-adjusted prevalence).
      There was no correlation between the crude or CR-adjusted period prevalence rates
      of type 1 diabetes and Townsend index (r=0.14, p=NS). This strong correlation
      between the prevalence of type 2 diabetes and social deprivation has important
      implications for the planning of health-care delivery.

PMID- 10581334
TI  - Troponin-I, myoglobin, and mass concentration of creatine kinase-MB in acute
      myocardial infarction.
AB  - Myoglobin, creatine kinase-MB (CKMB) mass concentration and troponin-I are newer
      biochemical markers for the diagnosis of acute myocardial infarction (AMI). We
      conducted a prospective study to formulate a model for the collective
      interpretation of these three markers in the diagnosis of AMI. Eighty-seven
      patients with AMI had serial serum samples taken to establish the time-frame
      sensitivity of individual markers. None of the markers had a good sensitivity
      within the first 4 h of infarction. Myoglobin and CKMB (mass) had sensitivities
      of 92.3% and 96.2%, respectively, at 4-8 h post infarct. CKMB (mass) and troponin
      I had sensitivities >92% at 8-24 h. Troponin-I maintained sensitivity >93% until
      72 h. A guideline was formulated based on the results. Our data suggest that
      troponin-I, myoglobin and CKMB (mass) yield satisfactory diagnostic sensitivity
      when used with reference to specific time frames. The combined use of these
      markers can provide valuable information for clinicians in managing AMI patients.

PMID- 10581335
TI  - Acute bacterial meningitis in adults: a hospital-based epidemiological study.
AB  - Bacterial meningitis, a world-wide disease, has to be reviewed periodically
      because the specific micro-organisms responsible for the infection vary with
      time, geography and patient age. To determine its incidence and clinical features
      in Taiwan, we reviewed the microbiological records for cerebrospinal fluid (CSF)
      and blood cultures, and the medical records of patients with bacterial meningitis
      admitted between 1981 and mid-1998. Bacterial micro-organisms were demonstrated
      in the CSF and/or blood in 395 patients with 418 episodes of bacterial
      meningitis. Streptococcus species were the most common causative micro-organism
      group, at 23. 21% of all episodes. Its prevalence rate significantly decreased
      from the first 7 years of study (41.9%) to the last 10.5 years (19. 2%). However,
      Klebsiella meningitis and Staphylococcal meningitis were more frequently noted
      after 1987. More than 70% of patients had at least one underlying disease or
      condition. Poor prognostic factors indicated by univariable analysis were: age
      >60 years; diabetes mellitus; severe neurological deficits on the first day of
      treatment; infection with Gram-negative bacilli; CSF WBC count >5000x10(6)/l;
      malignancy; seizure; and bacteraemia. The overall mortality rate was 29.4%, 29.7%
      in the first 7 years of study and 29. 4% in the last 10.5 years. The use of new
      antibiotics has not reduced the mortality rate in our patients with bacterial
      meningitis.

PMID- 10581336
TI  - Behcet's syndrome: a multidisciplinary approach to clinical care.
AB  - Behcet's syndrome is a multisystem disorder characterized by recurrent orogenital
      ulceration and an occlusive vasculitis. Histologically, there is a combination of
      a perivascular lymphocytic infiltration with endothelial cell damage coupled with
      a pro-thrombotic tendency. We present a multidisciplinary approach to the
      management of Behcet's syndrome, and compare our findings with other published
      studies. Over a nine-year period, 50 patients with Behcet's syndrome were
      followed in a multidisciplinary combined clinic. Patients were assessed by an
      ophthalmologist, a rheumatologist and a specialist in oral medicine. Data on
      disease activity and damage were collected using a standardized proforma for each
      specialty. Mean age of onset was 30 years; 56% were male. Recurrent oral
      ulceration was the commonest manifestation and the presenting feature in 76%. The
      commonest second systems involved were genital mucosae and eyes. We found a
      larger proportion of patients with ophthalmic (80%) and central nervous system
      (14%) manifestations compared with many other studies. There was an association
      between central nervous system and thrombotic events (p<0.001). Our
      multidisciplinary approach allowed us to keep each system involved in Behcet's
      syndrome under careful review. The development of recurrent sight-threatening eye
      disease was unpredictable and occurred despite aggressive immunosuppression.

PMID- 10581337
TI  - Outcome of surgery for acromegaly--the experience of a dedicated pituitary
      surgeon.
AB  - Previous large series of outcome following pituitary surgery for acromegaly,
      including our own, have demonstrated poor results, with cure, defined as GH <5
      mU/l, achieved in only 33-42% of patients. In our previous series, surgery was
      performed by one of eight different surgeons. Largely based on the disappointing
      results of this previous audit of outcome, our practice since 1990 has been,
      whenever possible, to refer all patients with acromegaly to a dedicated pituitary
      surgeon (APJ). The objective of the current study was to re-analyse the outcome
      of surgical treatment for acromegaly since instituting this change. Tumour size
      and extension was determined on CT/MRI scanning. Biochemical cure was defined as
      a basal GH <5 mU/l or a nadir GH of <2 mU/l across an OGTT following initial
      pituitary surgery. Surgery was performed on 66 patients and 42 (64%) were cured,
      compared with 26/78 (33%) in our previous study (p<0.0005, chi (2) test). The
      cure rate for microadenomas (n=22) was 86%, and for macroadenomas 52%, compared
      with 54% (p<0.05, chi (2) test) and 30% (p<0.05, chi (2) test) respectively, in
      our previous study. We conclude that surgical outcome for acromegaly is enhanced
      if patients are operated on by a single experienced surgeon.

PMID- 10581338
TI  - Cold adaptation and the seasonal distribution of acute myocardial infarction.

PMID- 10581339
TI  - Ninety-third annual general meeting of the association of physicians of great
      britain and ireland 1999

PMID- 10581340
TI  - [A study on mutation of exon 5 of presenilin-1 in Alzheimer's disease].
AB  - OBJECTIVE: To explore the role of the mutation of presenilin-1 in pathogenesis of
      sporadic Alzheimer's disease. METHODS: The exon 5 of presenilin-1 was analysed by
      using polymerase chain reaction- single strand conformation polymorphism (PCR
      SSCP) and ABI 310 genetic analyzer technique in 68 patients with Alzheimer's
      disease and 65 normal controls. RESULTS: A mobility shift of SSCP in exon 5 of
      presenilin-1 was detected in 4 patients with Alzheimer's disease;two missense
      mutations were found. One mutation was at Leu 130 Met and the other at Val157
      Leu. Another mobility shift of SSCP in exon 5 of presenilin-1 was detected in 11
      patients with Alzheimer's disease. One missense mutation was at Leu 130 Met and
      one same sense mutation C462-->T. But no mobility shift of SSCP was found in
      patients with vascular dementia and in normal controls. CONCLUSION: The authors
      found that mutations in exon 5 of presenilin-1 also existed in patients with
      sporadic Alzheimer's disease, which might be one of the points of mutations in
      sporadic Alzheimer's disease in Chinese.

PMID- 10581341
TI  - [Comparative genomic hybridization analysis of primary gastric carcinomas].
AB  - OBJECTIVE: To investigate whether unknown genes are involved in the tumorigenesis
      of gastric cancer. METHODS: Fourty-three primary gastric carcinomas were analyzed
      by comparative genomic hybridization(CGH). RESULTS: A gain in chromosome
      3p(8/43), 8q(8/43), 20[20(9/43), 20p(7/43), 20q(4/43)], 12q (16/43), and
      13q(12/43) was observed while a loss of 19[19(15/43), 19p (13/43)], 17[17(8/43),
      17p(10/43)], 16(10/43) and 1p(11/43) was discovered. CONCLUSION: There were
      characteristic changes in 3p, 8q, 20, 12q, 13q, 19, 17, 16, and 1p in gastric
      carcinoma, and some unknown genes located in the above regions might be of
      importance to gastric carcinoma pathogenesis.

PMID- 10581342
TI  - [Vector construction for embryonic stem cell gene targeting of site specific
      point mutation mouse coagulation factor IX gene].
AB  - OBJECTIVE: To construct the recombinant vectors for embryonic stem(ES) cell gene
      targeting which contain the mouse coagulation factor IX (F IX) gene modified by
      PCR site-directed mutagenesis. METHODS: Three site specific point mutations were
      introduced into exon 8 of mouse F IX gene respectively. The replacement targeting
      vectors were constructed and transfected into ES cells. The drug-resistant cell
      clones were picked after drug selection. RESULTS: The construction of targeting
      vectors was successful and several drug-resistant ES cell clones were gained.
      CONCLUSION: The site specific point mutation system can modify human gene in
      vitro more accurately. It is useful in the setting up of animal models.

PMID- 10581343
TI  - [Construction and expression of HLA-DRalpha, DRB1*0401 transgenic mice model].
AB  - OBJECTIVE: To construct transgenic mice model on DR alpha and DRB1*0401 of human
      MHC-II molecules. METHODS: By microinjection techniques on germ nucleus of
      zygotes, DRalpha and DRB1*0401 genes were injected into zygotes of C57BL/6 x
      DBA/1 hybrid mice and transplanted into the oviducts of pseudopregnancy female
      mice. The integration and expression of exogenous genes in offspring were
      detected by PCR, Southern blot and Northern blot, RT-PCR analysis. RESULTS: There
      were 5 founders of all injected mice, which had steadily inherited to the fifth
      generation. It was found that 95 mice were positive by PCR and 68 mice were
      integrated exogenous gene by Southern blot analysis. DRalpha and DRB1*0401 genes
      were expressed on spleen and kidney of transgenic mice. CONCLUSION: This
      experiment on the construction of DRalpha and DRB1*0401 transgenic mice model is
      a success.

PMID- 10581344
TI  - [Cloning of mouse polycystic kidney disease 1 gene].
AB  - OBJECTIVE: To obtain mouse Polycystic kidney disease 1(PKD1) gene by plagues in
      situ hybridization from a genomic library. METHODS: With the use of partial mouse
      PKD1 genomic DNA fragments amplified by PCR as probes, a genomic library of
      129SvTer mouse in bacteriophage vector was screened by plagues in situ
      hybridization. The inserts of genomic DNA fragments were analyzed by Southern
      blot, subclone and verified by sequencing. RESULTS: A positive phage clone was
      obtained after four-round screening. The sequence of the genomic DNA fragments
      inserted in the positive clone was in accordance with that of the Genebank.
      CONCLUSION: The authors found that the length and structure of mouse PKD1 genomic
      DNA fragments obtained from a genomic library were available to construct a
      replacement targeting vector.

PMID- 10581345
TI  - [Study on the inhibition of nude mice transplantation tumor growth by telomerase
      ribozyme].
AB  - OBJECTIVE: To explore whether telomerase ribozyme could inhibit the growth of
      nude mice transplantation tumor. METHODS: A xenograft human-nude mouse model was
      constructed. A total of 24 mice were divided into 4 groups, namely, the saline
      control(Group 1), the blank plasmid control(Group 2), the 20 microg/mouse/day
      p(XJ-neo-teloRZ)(Group 3) and the 30 microg/mouse/day p(XJ-neo-teloRZ)(Group 4).
      All plasmids were packaged by lipofectamine and used for subcutaneous, continuous
      infusions over 14 days. Tumor measurements and observations of animal behavior
      were recorded daily. On completion of the study, the mice were killed by cervical
      dislocation and their organs were removed, weighed, and stored in formaldehyde
      for histological examination. The telomerase activities of tumor tissues of each
      group were also detected. RESULTS: The telomerase ribozyme effectively inhibited
      the telomerase activities of tumor tissues and promoted the apoptosis of tumor
      cells. The in vivo studies showed a significant decrease in tumor size in mice
      treated with p(XJ-neo-teloRZ) when compared to the mice treated with controls.
      Furthermore, the in vivo effect of p(XJ-neo-teloRZ) was dose dependent.
      CONCLUSION: Telomerase ribozyme is a powerful telomerase inhibition agent;
      probably it could be effective in tumor gene therapy.

PMID- 10581346
TI  - [Comparative study of HLA-DRB1 allele in patients with chronic bronchitis and
      bronchial asthma].
AB  - OBJECTIVE: To make a comparative study of HLA-DRB1 allele frequencies in the
      cases of chronic bronchitis and bronchial asthma. METHODS: The authors
      investigated 74 patients with chronic bronchitis and 64 patients with bronchial
      asthma from among the Han people in Shanxi province. PCR/SSP technique was used
      for HLA-DRB1 typing, and the patients' data were compared with the normal
      controls'. RESULTS: The frequency of HLA-DRB1*1201/1202(24.32%) was significantly
      increased in the chronic bronchitis group(P<0.01),and the frequency of HLA
      DRB1*1501/1502(23.44%) was significantly increased in the bronchial asthma
      group(P<0.05). The frequencies of other DRB1 alleles were not significantly
      increased in these groups. CONCLUSION: The results indicate that HLA
      DRB1*1201/1202 allele is associated with chronic bronchitis and HLA
      DRB1*1501/1502 allele is associated with bronchial asthma in the patients among
      the Hans in Shanxi province.

PMID- 10581347
TI  - [The influences of genetic and environmental factors on plasma plasminogen
      activator inhibitor-1 levels in patients with essential hypertension].
AB  - OBJECTIVE: To investigate the influence of a 4G/5G polymorphism in the PAI-1 gene
      promoter and environmental factors on plasma plasminogen activator inhibitor
      1(PAI-1) levels in subjects with essential hypertension. METHODS: A total of 240
      patients with essential hypertension(males 120, females 120, aged 33-89 years,
      mean 65 years) were randomly enrolled in this study. Plasma PAI-1 antigen was
      measured by ELISA. The 4G/5G polymorphism was analyzed by the allele specific
      oligonucleotide hybridization method. RESULTS: Plasma PAI-1 levels were
      significantly associated with 4G/5G polymorphism with the highest levels
      occurring in subjects with 4G/4G genotype, the intermediate levels in 4G/5G
      subjects and the lowest levels in 5G/5G subjects. 4G/5G polymorphism, diabetes
      mellitus and triglyceride(TG) were three independent predictors of plasma PAI-1
      levels in a stepwise multiple regression model. Furthermore, the relationship
      between plasma PAI-1 levels and TG was genotype dependent. CONCLUSION: Plasma PAI
      1 levels are not only under genetic control, but also influenced by several
      environmental factors. There is an interaction between genetic and environmental
      factors.

PMID- 10581348
TI  - [Observation on the development of stomach innervation in trisomy 16 mouse, an
      animal model for Down syndrome].
AB  - OBJECTIVE: To study the nervous development in the stomach of trisomy 16 mouse
      embryos and their normal littermates from embryonic days 13-18 (ED 13-ED 18) by
      using primary antibody against protein gene product (PGP) 9.5. METHODS: (A)
      trisomy 16 mouse breeding; (B) trisomy 16 mouse embryos were confirmed by
      examining their chromosomes; (C) PGP 9.5 immunohistochemical method. RESULTS: In
      normal littermates, the precursor cells from the neural crest migrated into
      stomach at ED13. Numerous nervous processes connected each other and formed early
      nervous networks at ED14. Original ganglia appeared in the muscular plexus with
      very simple arrangement at ED15. The developed myenteric and submucosal plexuses
      were found at ED16 and ED17 respectively. The myenteric plexus and the internal
      and external submucosal plexuses were differentiated at ED18. In comparison with
      the normal littermates, the trisomy 16 mice's stomach nervous development was
      much slower. Their immature neurons did not appear in the stomach until ED14; the
      development and differentiation of stomach nervous plexuses were delayed. A clear
      link was noted between the development of stomach plexuses and the density of PGP
      9.5 immunostaining. A semiquantitative analysis and rank sum test of the data
      showed that the trisomy 16 mouse embryos were markedly retarded in nervous
      development of stomach, compared with their normal littermates (P<0.05).
      CONCLUSION: Trisomy 16 mouse, as an animal model for Down syndrome, has
      abnormality not only in several systems and organs but also in stomach
      innervation. This is the first report on delayed nervous development in the
      stomach of trisomy 16 mice.

PMID- 10581349
TI  - [Investigation of Y chromosome and polymorphism of 5 Chinese ethnic groups in
      Yunnan Province, China].
AB  - OBJECTIVE: To investigate the polymorphism of DYS287 in the Han, Dai, Lahu, Wa
      and Tibetan groups living in Yunnan Province, China. METHODS: YAP element was
      detected by PCR amplification and agarose gel electrophoresis. RESULTS: With
      150bp product in all Han,Dai, Lahu and Wa individuals, YAP element is absent. In
      11 Tibetan individuals out of 30, YAP element is present and the PCR product is
      455bp. CONCLUSION: As an important and stable genetic marker, DYS287 can provide
      reliable evidence in evolution study.

PMID- 10581350
TI  - [Determination of trisomy 9p by molecular cytogenetic technology].
AB  - OBJECTIVE: To use molecular cytogenetic techniques for the determination of
      complex chromosomal aberrations that could not be distinguished by conventional
      cytogenetic method. METHODS: Chromosome painting, comparative genomic
      hybridization (CGH) and color banding chromosome analysis (RxFISH) were used to
      identify a case with chromosome 9 aberration by G-banding. RESULTS: The patient
      has a karyotype of 46,XX,9p+ by G-banding. Both chromosomes 9 were uniformly
      painted, including the extra segment on one of the 9p alleles. CGH revealed a
      duplication of the entire 9p short arm. After analysis with RxFISH the patient's
      karyotype could be accurately described as 46,XX,dup9p (p11-->p24::p24-->qter).
      CONCLUSION: The present report shows that some late technological developments in
      the field of cytogenetics can facilitate the study of the diseases linked to
      complex chromosomal aberrations and may find significant application in basic and
      clinical medical studies.

PMID- 10581351
TI  - [Detection of RB1 mutations by using quantitative fluorescent mutiplex PCR].
AB  - OBJECTIVE: To develop a half-automatic, simple, non-radioactive technique for
      rapid detection of mutation in the RB gene. METHODS: Quantitative fluorescent
      multiplex PCR (QFM-PCR) involves amplification of the promoter region and all 27
      exons of the RB1 gene with fluorescein labeled primers in multiplex sets. Primers
      were divided into multiplex sets of three to seven pairs of primers, also
      contained were internal control primers C4. Four external controls were also
      tested by using nullisomic, monosomic, diploid, and trisomic for RB1. The number
      of copies of a fragment in a test sample was calculated by comparing fluorescence
      intensity of the fragment with these standards. Fragment value detection and
      subsequent calculations were performed automatically by Fragment Manager 2.1
      Software. RESULTS: Small deletions, insertions and whole exon deletion in the RB1
      gene were detected from genomic DNA. Sequencing analysis and RB tumor homozygous
      mutation comfirmed the defects detected by QFM-PCR. CONCLUSION: The approach is a
      rapid, cost-effective initial method for screening patient samples. It has been
      used to identify approximately 50% positives of tested samples. The mutations
      shown were not only small deletion and insertion, but also the single copy exons
      heterozygous mutation in the RB1 gene which the previously used methods were
      unable to detect. These features make the technique an attractive approach to
      clinical diagnosis of gene defects.

PMID- 10581352
TI  - [Detection of R277Q mutation of SRD5alpha2 gene by amplification refractory
      mutation system].
AB  - OBJECTIVE: To set up a simple method for identifying the mutation of R227Q of
      SRD5alpha2 gene which is one of the most common mutations in congenital
      hypospadias in China. METHODS: The amplification refractory mutation system(ARMS)
      was employed in detecting the SRD5alpha2 gene R227Q mutation in congenital
      hypospadias confirmed by PCR-SSCP and DNA sequencing. RESULTS: The ARMS was
      successfully applied to the detection of the R227Q mutation of SRD5alpha2 gene.
      Three out of 23 congenital hypospadias were positive for R227Q mutation. The
      mutations determined by ARMS were in full agreement with those obtained by the
      DNA sequencing. CONCLUSION: This is a simple, rapid and accurate method. It can
      be used for detecting the SRD5alpha2 gene R227Q mutation in congenital
      hypospadias and male pseudohermaphroditism.

PMID- 10581353
TI  - [An investigation of small marker chromosome in eight Turner syndrome patients by
      fluorescence in situ hybridization and DNA analysis].
AB  - OBJECTIVE: To direct genetic counseling and identify the origin of small marker
      chromosome in patients with Turner syndrome stigmata. METHODS: The specific
      primer on the sex determining region on Y (SRY) and biotin labeled X- and Y
      chromosome DNA probes were utilized in the analysis of sex chromosome-derived
      markers. The PCR product from the amplification was detected on agarose gel, and
      fluorescence in situ hybridization (FISH) was conducted to metaphase chromosome.
      RESULTS: In 8 patients who had a small marker chromosome, five markers were
      derived from the X chromosome and three from the Y chromosome. Two patients with
      a Y-derived marker were determined by Y-chromosome probe as well as by SRY
      sequences amplification. One patient with a Y-derived marker was only
      demonstrated by FISH. CONCLUSION: The findings of this study demonstrate
      successfully the value and necessity of FISH utilizing DNA probes combined with
      specific amplification on SRY gene in the identification of sex chromosome
      marker. Such identification is important not only for clinical care, but also for
      understanding phenotype-karyotype correlations.

PMID- 10581354
TI  - [The establishment and application of genomic DNA extraction from peripheral
      blood].
AB  - OBJECTIVE: To establish the method of genomic DNA extraction. METHODS: Genomic
      DNA was directly extracted from peripheral blood with the use of potassium
      iodide. RESULTS: The genomic DNA extracted with potassium iodide was of large
      molecular weight. A(260)/A(280) and A(260)/ A(230) were 1.85 and 2.2
      respectively. The extraction efficiency was greater than 90%. The result of PCR
      for the DNA was good. CONCLUSION: The method is simple, quick, economical and
      could be used for studying numbers of clinical samples.

PMID- 10581355
TI  - ABC transporters: bacterial exporters-revisited five years on.

PMID- 10581356
TI  - Structure-function analysis of multidrug transporters in Lactococcus lactis.
AB  - The active extrusion of cytotoxic compounds from the cell by multidrug
      transporters is one of the major causes of failure of chemotherapeutic treatment
      of tumor cells and of infections by pathogenic microorganisms. A multidrug
      transporter in Lactococcus lactis, LmrA, is a member of the ATP-binding cassette
      (ABC) superfamily and a bacterial homolog of the human multidrug resistance P
      glycoprotein. Another multidrug transporter in L. lactis, LmrP, belongs to the
      major facilitator superfamily, and is one example of a rapidly expanding group of
      secondary multidrug transporters in microorganisms. Thus, LmrA and LmrP are
      transport proteins with very different protein structures, which use different
      mechanisms of energy coupling to transport drugs out of the cell. Surprisingly,
      both proteins have overlapping specificities for drugs, are inhibited by the same
      set of modulators, and transport drugs via a similar transport mechanism. The
      structure-function relationships that dictate drug recognition and transport by
      LmrP and LmrA represent an intriguing area of research.

PMID- 10581357
TI  - Mechanism of the ArsA ATPase.
AB  - The ArsAB ATPase confers metalloid resistance in Escherichia coli by pumping
      toxic anions out of the cells. This transport ATPase shares structural and
      perhaps mechanism features with ABC transporters. The ArsAB pump is composed of a
      membrane subunit that has two groups of six transmembrane segments, and the
      catalytic subunit, the ArsA ATPase. As is the case with many ABC transporters,
      ArsA has an internal repeat, each with an ATP binding domain, and is
      allosterically activated by substrates of the pump. The mechanism of allosteric
      activation of the ArsA ATPase has been elucidated at the molecular level. Binding
      of the activator produces a conformational change that forms a tight interface of
      the nucleotide binding domains. In the rate-limiting step in the overall
      reaction, the enzyme undergoes a slow conformational change. The allosteric
      activator accelerates catalysis by increasing the velocity of this rate-limiting
      step. We postulate that similar conformational changes may be rate-limiting in
      the mechanism of ABC transporters.

PMID- 10581358
TI  - Inventory and function of yeast ABC proteins: about sex, stress, pleiotropic drug
      and heavy metal resistance.
AB  - Saccharomyces cerevisiae was the first eukaryotic organism whose complete genome
      sequence has been determined, uncovering the existence of numerous genes encoding
      proteins of the ATP-binding cassette (ABC) family. Fungal ABC proteins are
      implicated in a variety of cellular functions, ranging from clinical drug
      resistance development, pheromone secretion, mitochondrial function, peroxisome
      biogenesis, translation elongation, stress response to cellular detoxification.
      Moreover, some yeast ABC proteins are orthologues of human disease genes, which
      makes yeast an excellent model system to study the molecular mechanisms of ABC
      protein-mediated disease. This review provides a comprehensive discussion and
      update on the function and transcriptional regulation of all known ABC genes from
      yeasts, including those discovered in fungal pathogens.

PMID- 10581359
TI  - An inventory of the human ABC proteins.
AB  - Currently 30 human ABC proteins are represented by full sequences in various
      databases, and this paper provides a brief overview of these proteins. ABC
      proteins are composed of transmembrane domains (TMDs), and nucleotide binding
      domains (NBDs, or ATP-binding cassettes, ABSs). The arrangement of these domains,
      together with available membrane topology models of the family members, are
      presented. Based on their sequence similarity scores, the members of the human
      ABC protein family can be grouped into eight subfamilies. At present the MDR/TAP,
      the ALD, the MRP/CFTR, the ABC1, the White, the RNAseL inhibitor, the ANSA, and
      the GCN20 subfamilies are identified. Mutations of many human ABC proteins are
      known to be causative in inherited diseases, and a short description of the
      molecular pathology of these ABC gene-related genetic diseases is also provided.

PMID- 10581360
TI  - Differential function of the two nucleotide binding domains on cystic fibrosis
      transmembrane conductance regulator.
AB  - The genetic disease cystic fibrosis is caused by defects in the chloride channel
      cystic fibrosis transmembrane conductance regulator (CFTR). CFTR belongs to the
      family of ABC transporters. In contrast to most other members of this family
      which transport substrates actively across a membrane, the main function of CFTR
      is to regulate passive flux of substrates across the plasma membrane. Chloride
      channel activity of CFTR is dependent on protein phosphorylation and presence of
      nucleoside triphosphates. From electrophysiological studies of CFTR detailed
      models of its regulation by phosphorylation and nucleotide interaction have
      evolved. These investigations provide ample evidence that ATP hydrolysis is
      crucial for CFTR gating. It becomes apparent that the two nucleotide binding
      domains on CFTR not only diverge strongly in sequence, but also in function.
      Based on previous models and taking into account new data from pre-steady-state
      experiments, a refined model for the action of nucleotides at two nucleotide
      binding domains was recently proposed.

PMID- 10581361
TI  - Influence of phosphorylation by protein kinase A on CFTR at the cell surface and
      endoplasmic reticulum.
AB  - CFTR possesses a large cluster of strict dibasic consensus sites for
      phosphorylation by protein kinase A (PKA) in the R-domain and an obligatory
      dependence on phosphorylation is a hallmark of CFTR Cl(-) channel function.
      Removal of as many as 11 of these sites reduces the conformational change in the
      R-domain and the degree of channel activation in response to PKA. However, until
      recently a completely PKA-unresponsive CFTR variant has not been reported,
      leaving open the possibility that the residual response may be mediated by
      associating ancillary phosphoproteins. We traced the residual PKA-catalyzed (32)P
      labelling of the variant with 11 sites mutagenized (11SA) to distinct CNBr
      phosphopeptides within the R-domain. Mutagenesis of 4 additional monobasic sites
      in these segments produced a 15SA variant in which Cl(-) channel response to PKA
      was abolished. Therefore, it can be concluded that ancillary phosphoproteins do
      not contribute to CFTR activation by PKA. Notably, however, the 15SA protein did
      exhibit a low level of constitutive channel activity not dependent on PKA, which
      might have reflected a down-regulating effect of phosphorylation of one or two of
      the 15 sites as suggested by others. However, this did not prove to be the
      case.Since immature CFTR has been claimed to be active in the endoplasmic
      reticulum (ER), we also examined whether it can be phosphorylated in cells and
      what influence if any this might have on its susceptibility to degradation.
      Teleologically, activation by phosphorylation of CFTR Cl(-) channels in the ER
      might be undesirable to the cell. Using various phosphorylation site mutants and
      kinase and phosphatase inhibitors in pulse-chase experiments, we have found that
      although nascent CFTR can be phosphorylated at the ER, this is without effect on
      its ability to mature and avoid proteolysis. Furthermore, we found that
      microsomes from cells expressing CFTR processing mutants such as DeltaF508 do not
      generate Cl(-) active channels when fused with planar bilayers unless maturation
      is promoted, e.g. by growth of cells at reduced temperature or other means. We
      conclude that the ER-retained mutant nascent chains which are incapable of
      maturation may be phosphorylated but do not form active channels. Stimulation by
      PKA of the insertion of CFTR containing vesicles into the plasma membrane as part
      of the mechanism of stimulation of chloride secretion has been reported, as has
      an influence of CFTR on the balance between endocytosis and exocytosis but these
      findings have not been universally confirmed.

PMID- 10581362
TI  - Sulfonylurea receptors: ABC transporters that regulate ATP-sensitive K(+)
      channels.
AB  - The association of sulfonylurea receptors (SURs) with K(IR)6.x subunits to form
      ATP-sensitive K(+) channels presents perhaps the most unusual function known for
      members of the transport ATPase family. The integration of these two protein
      subunits extends well beyond conferring sensitivity to sulfonylureas. Recent
      studies indicate SUR-K(IR)6.x interactions are critical for all of the properties
      associated with native K(ATP) channels including quality control over surface
      expression, channel kinetics, inhibition and stimulation by Mg-nucleotides and
      response both to channel blockers like sulfonylureas and to potassium channel
      openers. K(ATP) channels are a unique example of the physiologic and medical
      importance of a transport ATPase and provide a paradigm for how other members of
      the family may interact with other ion channels.

PMID- 10581363
TI  - Comparative aspects of the function and mechanism of SUR1 and MDR1 proteins.
AB  - ATP-binding cassette (ABC) superfamily proteins have divergent functions and can
      be classified as transporters, channels, and receptors, although their predicted
      secondary structures are very much alike. Prominent members include the
      sulfonylurea receptor (SUR1) and the multidrug transporter (MDR1). SUR1 is a
      subunit of the pancreatic beta-cell K(ATP) channel and plays a key role in the
      regulation of glucose-induced insulin secretion. SUR1 binds ATP at NBF1, and ADP
      at NBF2 and the two NBFs work cooperatively. The pore-forming subunit of the
      pancreatic beta-cell K(ATP) channel, Kir6.2, is a member of the inwardly
      rectifying K(+) channel family, and also binds ATP. In this article, we present a
      model in which the activity of the K(ATP) channel is determined by the balance of
      the action of ADP, which activates the channel through SUR1, and the action of
      ATP, which stabilizes the long closed state by binding to Kir6.2. The
      concentration of ATP could also affect the channel activity through binding to
      NBF1 of SUR1. MDR1, on the other hand, is an ATP-dependent efflux pump which
      extrudes cytotoxic drugs from cells before they can reach their intracellular
      targets, and in this way confers multidrug resistance to cancer cells. Both NBFs
      of MDR1 can hydrolyze nucleotides, and their ATPase activity is necessary for
      drug transport. The interaction of SUR1 with nucleotides is quite different from
      that of MDR1. Variations in the interactions with nucleotides of ABC proteins may
      account for the differences in their functions.

PMID- 10581364
TI  - Determining the structure and mechanism of the human multidrug resistance P
      glycoprotein using cysteine-scanning mutagenesis and thiol-modification
      techniques.
AB  - The multidrug resistance P-glycoprotein is an ATP-dependent drug pump that
      extrudes a broad range of hydrophobic compounds out of cells. Its physiological
      role is likely to protect us from exogenous and endogenous toxins. The protein is
      important because it contributes to the phenomenon of multidrug resistance during
      AIDS and cancer chemotherapy. We have used cysteine-scanning mutagenesis and
      thiol-modification techniques to map the topology of the protein, show that both
      nucleotide-binding domains are essential for activity, examine packing of the
      transmembrane segments, map the drug-binding site, and show that there is cross
      talk between the ATP-binding sites and the transmembrane segments.

PMID- 10581365
TI  - Insights into the structure and substrate interactions of the P-glycoprotein
      multidrug transporter from spectroscopic studies.
AB  - The P-glycoprotein multidrug transporter is a 170-kDa efflux pump which exports a
      diverse group of natural products, chemotherapeutic drugs, and hydrophobic
      peptides across the plasma membrane, driven by ATP hydrolysis. The transporter
      has been proposed to interact with its drug substrates within the membrane
      environment; however, much remains to be learned about the nature and number of
      the drug binding site(s). The two nucleotide binding domains are responsible for
      ATP binding and hydrolysis, which is coupled to drug movement across the
      membrane. In recent years, P-glycoprotein has been purified and functionally
      reconstituted in amounts large enough to allow biophysical studies. The use of
      spectroscopic techniques has led to insights into both its secondary and tertiary
      structure, and its interaction with nucleotides and drugs. In this review, we
      will summarise what has been learned by application to purified P-glycoprotein of
      fluorescence spectroscopy, circular dichroism spectroscopy and infra-red
      spectroscopy.

PMID- 10581366
TI  - The multidrug resistance protein family.
AB  - The human multidrug resistance protein (MRP) family contains at least six
      members: MRP1, the godfather of the family and well known as the multidrug
      resistance protein, and five homologs, called MRP2-6. In this review, we
      summarize what is known about the protein structure, the expression in tissues,
      the routing in cells, the physiological functions, the substrate specificity, and
      the role in multidrug resistance of the individual members of the MRP family.

PMID- 10581367
TI  - Structural, mechanistic and clinical aspects of MRP1.
AB  - The cDNA encoding ATP-binding cassette (ABC) multidrug resistance protein MRP1
      was originally cloned from a drug-selected lung cancer cell line resistant to
      multiple natural product chemotherapeutic agents. MRP1 is the founder of a branch
      of the ABC superfamily whose members (from species as diverse as plants and yeast
      to mammals) share several distinguishing structural features that may contribute
      to functional and mechanistic similarities among this subgroup of transport
      proteins. In addition to its role in resistance to natural product drugs, MRP1
      (and related proteins) functions as a primary active transporter of structurally
      diverse organic anions, many of which are formed by the biotransformation of
      various endo- and xenobiotics by Phase II conjugating enzymes, such as the
      glutathione S-transferases. MRP1 is involved in a number of glutathione-related
      cellular processes. Glutathione also appears to play a key role in MRP1-mediated
      drug resistance. This article reviews the discovery of MRP1 and its relationships
      with other ABC superfamily members, and summarizes current knowledge of the
      structure, transport functions and relevance of this protein to in vitro and
      clinical multidrug resistance.

PMID- 10581368
TI  - Conjugate export pumps of the multidrug resistance protein (MRP) family:
      localization, substrate specificity, and MRP2-mediated drug resistance.
AB  - The membrane proteins mediating the ATP-dependent transport of lipophilic
      substances conjugated to glutathione, glucuronate, or sulfate have been
      identified as members of the multidrug resistance protein (MRP) family. Several
      isoforms of these conjugate export pumps with different kinetic properties and
      domain-specific localization in polarized human cells have been cloned and
      characterized. Orthologs of the human MRP isoforms have been detected in many
      different organisms. Studies in mutant rats lacking the apical isoform MRP2
      (symbol ABCC2) indicate that anionic conjugates of endogenous and exogenous
      substances cannot exit from cells at a sufficient rate unless an export pump of
      the MRP family is present in the plasma membrane. Several mutations in the human
      MRP2 gene have been identified which lead to the absence of the MRP2 protein from
      the hepatocyte canalicular membrane and to the conjugated hyperbilirubinemia of
      Dubin-Johnson syndrome. Overexpression of recombinant MRP2 confers resistance to
      multiple chemotherapeutic agents. Because of its function in the terminal
      excretion of cytotoxic and carcinogenic substances, MRP2 as well as other members
      of the MRP family, play an important role in detoxification and chemoprevention.

PMID- 10581369
TI  - The ABCA subclass of mammalian transporters.
AB  - We describe here a subclass of mammalian ABC transporters, the ABCA subfamily.
      This is a unique group that, in contrast to any other human ABC transporters,
      lacks a structural counterpart in yeast. The structural hallmark of the ABCA
      subfamily is the presence of a stretch of hydrophobic amino acids thought to span
      the membrane within the putative regulatory (R) domain. As for today, four ABCA
      transporters have been fully characterised but 11 ABCA-encoding genes have been
      identified. ABCA-specific motifs in the nucleotide binding folds can be detected
      when analysing the conserved sequences among the different members. These motifs
      may reveal functional constraints exclusive to this group of ABC transporters.

PMID- 10581370
TI  - Function of the transport complex TAP in cellular immune recognition.
AB  - The transporter associated with antigen processing (TAP) is essential for peptide
      loading onto major histocompatibility complex (MHC) class I molecules by
      translocating peptides into the endoplasmic reticulum. The MHC-encoded ABC
      transporter works in concert with the proteasome and MHC class I molecules for
      the antigen presentation on the cell surface for T cell recognition. TAP forms a
      heterodimer where each subunit consists of a hydrophilic nucleotide binding
      domain and a hydrophobic transmembrane domain. The transport mechanism is a
      multistep process composed of an ATP-independent peptide association step which
      induces a structural reorganization of the transport complex that may trigger the
      ATP-driven transport of the peptide into the endoplasmic reticulum lumen. By
      using combinatorial peptide libraries, the substrate selectivity and the
      recognition principle of TAP have been elucidated. TAP maximizes the degree of
      substrate diversity in combination with high substrate affinity. This ABC
      transporter is also unique as it is closely associated with chaperone-like
      proteins involved in bonding of the substrate onto MHC molecules. Most
      interestingly, virus-infected and malignant cells have developed strategies to
      escape immune surveillance by affecting TAP expression or function.

PMID- 10581371
TI  - Serial evoked potential studies and MRI imaging in chronic progressive multiple
      sclerosis.
AB  - Measurements of serial evoked potential latencies and plaque burden on MRI scans
      are often obtained during clinical studies of multiple sclerosis patients to
      provide additional information to the disability-based primary endpoints. The
      ideal laboratory-based marker of progression would be expected to significantly
      change over the time period of study. Serial visual (VEP) and brainstem auditory
      evoked potentials (BAEP) and MRI scans of 11 chronic progressive MS patients were
      obtained over a 1.5 year period in a clinical study. Over this period, there was
      no significant change in disability as measured by the Kurtzke EDSS, Ambulation
      Index or Neurological Rating Score. The VEP P100 significantly progressed over
      the period of study. However, the MRI T(2) plaque burden and BAEP I-V intrapeak
      latency did not significantly progress over the 1.5 years. We conclude that, in
      chronic progressive MS, serial visual evoked potential tests may complement
      standard disability-based endpoints to assess disease progression.

PMID- 10581372
TI  - Glutamate enhances phosphorylation of neurofilaments in cerebellar granule cell
      culture.
AB  - In amyotrophic lateral sclerosis (ALS), an abnormal increase of glutamate in the
      central nervous system indicates that it may play a key role in motor neuron
      death. The neuronal accumulation of phosphorylated neurofilaments (NFs) suggests
      an alteration of phosphorylation of NFs is also involved. Rat cerebellar granule
      cells (CGCs) are sensitive to glutamate neurotoxicity and provide a suitable
      model system for clarifying its mechanisms. Using cultured CGCs, we investigated
      the relationship between glutamate neurotoxicity and the phosphorylation of NFs.
      Because glutamate showed a dose-dependent neurotoxicity for CGCs, we adopted a 10
      microM glutamate treatment, which produced no acute neurotoxicity during the
      experiments. The number of phosphorylated heavy subunits of neurofilaments (NF
      Hs) increased to approximately twice that of the control after 72 h, although the
      total number of NF-Hs remained constant throughout the experiment. The
      phosphorylation of NF-Hs was significantly suppressed by the AMPA-receptor
      antagonist CNQX, but not by the NMDA-receptor antagonist MK-801. Our findings
      therefore suggest that exposure to a low concentration of glutamate enhances the
      phosphorylation of NF-Hs, mainly via the AMPA receptor.

PMID- 10581373
TI  - Polymorphisms in the presenilin 1 and presenilin 2 genes and risk for sporadic
      Alzheimer's disease.
AB  - We examined the possible involvement of polymorphisms of the presenilin 1 (PS1)
      and presenilin 2 (PS2) genes in the risk for sporadic Alzheimer's disease (AD),
      either through an independent effect or through interaction with the existing
      apolipoprotein E (ApoE) risk, in 211 AD cases and 188 age-matched control
      subjects. No significant differences were obtained in any of the comparisons
      relating the effect of the PS1 and PS2 polymorphisms; thus, these polymorphisms
      do not appear to be sufficient risk factors by themselves for sporadic AD.
      Although the ApoE varepsilon4 genotype is the only definite predictor of risk,
      homozygosity for either the 1 allele of the PS1 or the C allele of the PS2 genes
      may increase the risk conferred by the presence of an ApoE epsilon4 allele.
      Additionally, combination of PS1/11 and PS2/CC genotypes might have a small
      synergistic effect on the risk for AD.

PMID- 10581374
TI  - Increased cerebrospinal fluid protein tau concentration in neuro-AIDS.
AB  - OBJECTIVES: Assessment of cerebrospinal fluid (CSF) levels of protein tau in
      human immunodeficiency virus type 1 (HIV-1) infection. MATERIAL AND METHODS: CSF
      tau levels were analyzed in 52 HIV-1-infected patients, 37 of whom had no
      neurological symptoms, eight had aquired immunodeficiency syndrome (AIDS)
      dementia complex (ADC), and seven had AIDS with other neurological complications.
      RESULTS: A significantly higher mean CSF tau concentration was found in patients
      with ADC (380 pg/ml) compared with patients with neuroasymptomatic HIV-1
      infection (120 pg/ml, P<0.01) and HIV-negative controls (150 pg/ml, P<0.05). No
      difference in CSF tau levels was found between patients with ADC and patients
      with AIDS with other neurological complications. CONCLUSION: CSF tau might be
      used as a biochemical marker for axonal degeneration and might be of use to
      identify HIV-1-infected patients with ADC and other neurological complications,
      but it cannot discriminate between ADC and other neurological complications in
      HIV-1-infection.

PMID- 10581375
TI  - Myelinated fibers in Charcot-Marie-Tooth disease type 1B with Arg98His mutation
      of Po protein.
AB  - This study was undertaken to characterize the clinical, electrophysiologic, and
      histopathologic features of five presumably unrelated Japanese patients with
      Charcot-Marie-Tooth (CMT) disease type 1B and Arg98His substitution of Po protein
      and, in particular, to correlate Arg98His substitution to the ultrastructural
      abnormalities of the myelin sheath. Systematic morphometric studies of the sural
      nerve, where the CMT type 1B gene abnormality is expressed, have not been
      performed, especially on the basis of the type of mutation causing CMT type 1B.
      Electrophysiologic evaluation of limb nerves and morphometric analysis of sural
      nerves obtained at biopsy were performed. Ultrastructural myelin abnormalities
      were precisely examined. Clinical symptoms appeared from the second to the fifth
      decade. All probands presented with gait disturbance. Motor and sensory
      conduction velocities in the median and ulnar nerves ranged from 10 to 30 m/s.
      Segmental demyelination and remyelination and marked loss of myelinated fibers
      were the main findings. On electron microscopy, widening between major dense
      lines was found between the paired intraperiod lines, where the extramembranous
      portion of the Po protein resides. This widening is probably directly related to
      Arg98His substitution. Focal uncompaction of major dense lines coexisted with
      this widening. This uncompaction, which directly decreases the number of myelin
      lamellae, may be a secondary effect of Arg98His substitution on the
      intramembranous domain of Po protein. In conclusion, myelin changes at both
      extracellular and cytoplasmic appositions of Schwann cell membranes were found in
      association with Arg98His substitution of Po protein. This study contributes to a
      better understanding of myelin abnormalities in patients with CMT type 1B and
      Arg98His or other similar extramembranous amino acid substitutions of Po protein.

PMID- 10581376
TI  - Ex vivo response to aspirin differs in stroke patients with single or recurrent
      events: a pilot study.
AB  - The dose of aspirin for secondary stroke prevention and the clinical meaning of
      ex vivo platelet abnormalities are debated. We assessed prospectively 39
      noncardioembolic stroke patients in which 300 mg/day aspirin had proved effective
      (n=24) or ineffective (n=15) to prevent recurrent ischemic events. We evaluated
      platelet aggregation induced by arachidonic acid, adenosine diphosphate and
      epinephrine, and the sensitivity of platelets to increasing concentrations of the
      synthetic thromboxane mimetic U46619. Aggregation studies were repeated while
      subjects received 300 (study phase 1), and 600 (study phase 2) mg/day aspirin,
      respectively. Overall, arachidonic acid-induced platelet aggregation was less
      effectively inhibited during study phase 1 compared to phase 2. Arachidonic acid
      and epinephrine promoted a stronger platelet aggregation in aspirin nonresponders
      than in aspirin responders while taking 300 mg/day aspirin. On the other hand,
      600 mg/day effectively inhibited platelet function in both clinical groups. A
      lower sensitivity to thromboxane receptors was also found during phase 1 of the
      study, although the response was similar between aspirin responders and
      nonresponders. This pilot study suggests that 300 mg/day aspirin is less
      effective than 600 mg/day to block the cyclooxygenase pathway in noncardioembolic
      stroke and, incomplete cyclooxygenase inhibition is associated with recurrent
      thromboembolic events despite adequate aspirin compliance. It is likely that
      patients could receive a more efficacious stroke prevention if the dose of
      aspirin is tailored to individual needs as reflected by laboratory findings.

PMID- 10581377
TI  - Fever and infection early after ischemic stroke.
AB  - Previous studies showed that elevated body temperature early after ischemic
      stroke is associated with severe neurological deficit and a poor outcome. The aim
      of this study was to analyse the prevalence and putative etiology of febrile body
      temperature (>/=38.0 degrees C) early after stroke and to investigate the
      association between body temperature, stroke severity and outcome. We
      investigated 119 consecutive patients who were admitted within 24 h after
      ischemic stroke. Patients were examined for infection before ischemia using a
      standardized questionnaire and received daily clinical examination after stroke.
      In case of fever, standardized radiological and microbiological examinations were
      performed. Fever within 48 h after stroke was observed in 30 (25.2%) patients.
      The probable cause of fever was infective or chemical aspiration pneumonia
      (n=12), other respiratory tract infection (n=7), urinary tract infection (n=4),
      viral infections (n=3) or insufficiently defined (n=5). (One patient had two
      potential causes of fever.) In thirteen of these patients, infection was most
      probably acquired before stroke. Fever newly developed more often during day 1 to
      2 than day 3 to 7 after stroke (P=0.016). Fever was associated with a more severe
      deficit on admission independent from age, vascular diseases and risk factors
      (odds ratio 9.6; 95% confidence interval 3.1-29). Fever is a frequent
      complication early after stroke and in the majority of cases, it can be explained
      by infection or chemical aspiration pneumonia. In about half of the infected
      patients, infection was most probably acquired before stroke. Fever was
      associated with a more severe neurological deficit on admission.

PMID- 10581378
TI  - Correlations between clinical and MRI involvement in multiple sclerosis:
      assessment using T(1), T(2) and MT histograms.
AB  - The degree of disability and cerebellar and brainstem impairments in multiple
      sclerosis (MS) patients were correlated with several magnetic resonance imaging
      (MRI) measures of tissue damage in the whole brain, cerebellum and brainstem to
      determine the relative contributions of the factors underlying the development of
      disability in MS. Dual-echo conventional spin-echo, T(1)-weighted and
      magnetization transfer (MT) scans were obtained from 72 patients with MS and 20
      age- and sex-matched controls. The following MRI-derived quantities were
      considered for the brain as a whole, for the cerebellum and for the brainstem:
      (a) the number and volume of lesions seen on T(2)-weighted images; (b) the number
      and volume of lesions seen on T(1)-weighted images; (c) the size of these
      structures measured on T(1)-weighted scans; (d) the average MT ratio (MTR), peak
      height and peak position for the MT histogram. With univariate analysis, many MRI
      measures were significantly different in patients with different levels of
      disability or cerebellar and brainstem functional system impairments. However,
      with multivariate analysis, only whole-brain average MTR was significantly
      related to physical disability, while cerebellar and brainstem T(1) lesion volume
      and average MTR were related to cerebellar and brainstem impairment. This study
      shows that increased pathological damage in clinically eloquent sites is the
      major cause of disability in patients with MS. It also suggests that measures
      derived from MT histogram analysis and T(1) hypointense lesion load should be
      considered when evaluating long-term MS evolution.

PMID- 10581379
TI  - Cumulative effect of a weekly low dose of interferon beta 1a on standard and
      triple dose contrast-enhanced MRI from multiple sclerosis patients.
AB  - In patients with multiple sclerosis (MS), we assessed the short- and long-term
      effects of a weekly low dose of recombinant human interferon beta 1a (rh-IFN beta
      1a) on the development of new magnetic resonance imaging (MRI) lesions enhancing
      at different gadolinium-DTPA (Gd) doses. Every 4 weeks, standard dose (SD) (0.1
      mmol/kg of Gd) and triple dose (TD) (0.3 mmol/kg of Gd) Gd-enhanced brain MRI
      scans were obtained from 18 patients with relapsing-remitting MS for 3 months
      before treatment, 4 months after treatment initiation (treatment period [TP] I)
      and 4 months after 1 year of treatment (TP II) with 44 microg of rh-IFN beta 1a
      subcutaneously, once a week. The mean numbers of new enhancing
      lesions/patient/month were 1.4 (baseline), 1.1 (TP I) and 0.7 (TP II) on SD scans
      and 2.4 (baseline), 1.3 (TP I) and 0.8 (TP II) on TD scans. On average, treatment
      decreased the rate of new enhancing lesion appearance by 24% (SD scans) and 45%
      (TD scans) during TP I and by 52% (SD scans) and 66% (TD scans) during TP II.
      This study indicates that the effect of 44 microg of rh-IFN beta 1a given once a
      week on MRI-monitored MS activity increases over time. It also suggests that TD
      MRI is useful in detecting early treatment effect, that would otherwise be
      missed.

PMID- 10581380
TI  - A multiparametric MRI study of frontal lobe dementia in multiple sclerosis.
AB  - Previous studies achieved conflicting results when correlating magnetic resonance
      imaging (MRI) abnormalities and cognitive impairment in multiple sclerosis (MS)
      patients. Recently, the estimation of MS lesion load on T1-weighted images and
      the analysis of magnetization transfer ratio (MTR) histograms, increased the
      degree of the correlation between physical disability and MRI findings in MS. We
      assessed the relationship of conventional and non-conventional MRI-derived
      measures with frontal lobe dementia in MS. Dual echo, T1-weighted and MT MRI
      scans of the brain were obtained in 11 MS patients with and in 11 without frontal
      lobe dementia, matched for age, sex, education and disability. Total (TLL) and
      frontal (FLL) lesion loads were assessed from T2- and T1-weighted scans. MTR
      histogram analysis was performed for the whole brain, the frontal lobe and the
      cerebellum. Median TLL and FLL were significantly higher in cognitively impaired
      patients on both T2- and T1-weighted scans. The MRI measure that better
      discriminated the two groups of patients was T1-weighted TLL (median values were
      19.1 ml for demented and 1.9 ml for non-demented patients, P=0.006). Average MTR,
      peak height and location of overall brain and frontal lobe histograms were
      significantly lower for cognitively impaired than for cognitively intact patients
      (P values ranged from 0.0001 to 0.001). Cerebellar MTR histogram metrics did not
      significantly differ in patients with and without cognitive decline. The presence
      of cognitive decline in MS is associated with the extent and pathological
      severity of brain MRI abnormalities.

PMID- 10581381
TI  - Treatment of cerebral Langerhans cell histiocytosis.
AB  - Cerebral Langerhans cell histiocytosis (LCH) is a rare granulomatous disorder
      which may be primary or secondary or solitary or multiple. Brain structures
      outside the hypothalamic-pituitary axis are only scarcely involved, even in
      multisystem varieties. Since there are neither controlled therapeutic trials nor
      systematic analyses of hitherto reported cases, optimal treatment strategies are
      not known. To evaluate the effect of different treatment modalities, we analyzed
      previous reports of extrahypothalamic LCH back to 1980 in which the diagnosis was
      made on the basis of examination of cerebral tissues. Thirty-five histologically
      examined cases were identified, including 10 patients presenting with multiple
      cerebral lesions. Adding one own case followed up for 10 years, 16 patients had
      cerebral involvement secondary to multisystem LCH, while another 20 patients had
      primary cerebral LCH. The peak incidence was far beyond the pediatric range for
      both primary and secondary cerebral LCH. Localized lesions can be treated
      successfully by surgery or radiation following biopsy. Chemotherapy may be an
      additional option. Multiple lesions can tentatively be controlled by chemotherapy
      and, possibly, radiation. The ultimate outcome is determined by whether or not
      recurrencies or de-novo lesions will appear and the course of the systemic
      disease. Studies addressing the effects of therapy in cerebral LCH are urgently
      needed.

PMID- 10581382
TI  - Perforin pathway is essential for protection of mice against lethal ocular HSV-1
      challenge but not corneal scarring.
AB  - Perforin (cytolysin; pore-forming protein) is expressed in both CD8(+) cytotoxic
      T lymphocytes (CTLs) and natural killer (NK) cells, and is a major factor
      responsible for the cytolytic activities of these cells. Both CD8(+) T-cells and
      NK cells are important in eliminating cells infected with certain viruses. We
      examined the role of perforin in a mouse model of HSV-1 infection using perforin
      deficient mice. Naive perforin knockout (perforin(0/0)) mice were more
      susceptible to lethal HSV-1 ocular challenge (60% survival), than naive parental
      C57BL/6 (100% survival). In contrast, both C57BL/6 and perforin(0/0) mice had
      similar levels of HSV-1 induced corneal scarring. Vaccination of perforin(0/0)
      mice induced a significantly higher HSV-1 neutralizing antibody titer than
      vaccination of C57BL/6 mice, and the mice were completely protected against
      lethal ocular challenge. These results suggest that in naive mice ocularly
      challenged with HSV-1, the perforin pathway was involved in protection against
      death, but not in protection against corneal scarring.

PMID- 10581383
TI  - Identification of a novel surface mutant of hepatitis B virus in a seronegative
      chronic liver disease patient.
AB  - Hepatitis B virus (HBV) with mutations in the envelope proteins can emerge during
      natural infections, vaccinations or interferon therapy and appears occasionally
      to escape virus elimination or detection. The implications of such mutations at
      the molecular level are often obscure. We report the identification of a new
      surface mutant of HBV. This mutant was identified, and isolated from a chronic
      liver disease patient, negative for HBsAg as well as other serological markers
      but positive for HBV DNA. Several mutations were observed in the surface antigen
      gene out of which a Thr118-Ala118 change was predicted to have a destabilizing
      effect on the structural integrity of the 'a' determinant and also alter the
      antigenicity profile of the mutant HBsAg. Besides a RNA hairpin loop was
      predicted for the transcript generated by the small surface protein of this
      mutant, which could have an inhibitory effect at the translational level. These
      observations thus indicate that mutations in the surface gene could lead to a
      considerable decrease or complete absence of properly folded surface antigen
      which in turn could explain the absence of reactive HBsAg in the serum of the
      patient.

PMID- 10581384
TI  - Reevaluation of nucleotide sequences of wild-type and attenuated polioviruses of
      type 3.
AB  - Published sequences of wild-type and attenuated Sabin strains of type 3
      poliovirus (Leon/37 and Leon 12a(1)b) were derived from cDNA clones. Recent
      direct sequencing of Sabin 3 RNA showed that it differed from the published
      sequence in at least two sites. Here results of direct sequencing of genomes of
      three independently re-derived sub-strains of attenuated Sabin 3 poliovirus used
      for oral poliovirus vaccine (OPV) production in addition to the most widely used
      Pfizer sub-strain are reported. The results showed that all four sub-strains of
      attenuated type 3 poliovirus contain unique patterns of mutations. Two stocks of
      the wild-type progenitor Leon/37 strain were also sequenced. Analysis of the two
      samples of Leon/37 virus showed that one of them is much closer to the Sabin 3
      strain, and is an intermediate product of the attenuation process. In addition,
      we created genetically engineered constructs which contained some of the
      mutations suspected for their possible role in neurovirulence, and tested them in
      monkeys and in transgenic mice sensitive to poliovirus. The results suggested
      that none of them increased neurovirulence of the virus, but some may improve
      virus replication. Therefore the only mutation occurring in Sabin 3 under vaccine
      production conditions that appears to affect neurovirulence of the virus is the
      well known U-->C reversion at nucleotide 472.

PMID- 10581385
TI  - Genetic diversity of GBV-C/HGV strains among HIV infected-IVDU and blood donors
      from Buenos Aires, Argentina.
AB  - GBV-C/HGV RNA was investigated in serum samples from 70 HIV(+) intravenous drug
      users (IVDU), as well as from 200 blood donors from Buenos Aires, Argentina.
      Viral RNA was demonstrated in 21 IVDU by reverse transcription-nested PCR of the
      5' UTR. c-DNA amplified products were analyzed and their sequences compared with
      those downloaded from GenBank. A phylogenetic tree based on 171 sequences
      demonstrated the presence of three major genogroups, including two subgroups,
      within local samples, i.e. group 1 (n=1), 2a (n=11), 2b (n=4) and 3 (n=5). These
      results agreed entirely with those obtained by a novel RFLP (J. Clin. Microbiol.
      37, 1340-1347, 1999) of the same 5' UTR amplicons. As expected, GBV-C/HGV RNA
      prevalence was significantly higher among IVDU than among blood donors
      (P<0.0001), although within the latter group an unexpectedly high rate was also
      detected, since 11 of 200 sera (5.5%) proved positive. These viral isolates were
      ascribed either to subgroup 2a (n=5), subgroup 2b (n=5) or genogroup 3 (n=1).
      Briefly, this partial view of GBV-C/HGV molecular epidemiology in Argentina
      shows: (i) different rates of GBV-C/HGV infection within both IVDU and blood
      donors; (ii) a high prevalence of viral RNA among blood donors; and (iii) a
      predominant circulation of genogroup 2, with minor contribution of groups 3 and
      1.

PMID- 10581386
TI  - Characterization of the transactivation domain of the equine herpesvirus type 1
      immediate-early protein.
AB  - Equine herpesvirus type 1 (EHV-1) possesses a sole diploid immediate early gene
      (IE) that encodes a major regulatory protein of 1487 amino acids capable of
      modulating gene expression from both early and late promoters and also of trans
      repressing its own promoter. Using a series of GAL-4-IE fusion constructs, we
      previously demonstrated that the minimal transactivation domain (TAD) of the IE
      protein maps within amino acids 3-89. Additional studies revealed that that the
      carboxyl terminus of the IE protein may be required for full transactivation
      activity in vitro. Analyses of the minimal TAD revealed the presence of 13 acidic
      amino acids and six basic residues giving the TAD region a net negative charge of
      -7. In addition, there are conserved hydrophobic residues (Leu(12) and Phe(15))
      that may be critical for transactivation function. To identify residues essential
      for IE transactivation and to ascertain if the overall net negative charge of the
      TAD or the position of specific hydrophobic residues within the IE TAD are
      critical for the transactivation function, plasmids expressing mutant forms of
      the TAD were generated using specifically designed mutagenic oligonucleotides and
      PCR mutagenesis. Mutagenized TADs in which the acidic and hydrophobic amino acid
      residues were replaced, singly and in combination, with polar, uncharged amino
      acids were cloned into a GAL-4/CAT reporter expression system and assayed in
      transient transfection assays. To determine if the carboxyl terminus is necessary
      for full transactivation activity, a series of constructs that express forms of
      the IE protein-containing deletions within this region were generated and assayed
      for transactivation function in transient transfection assays. These assays
      demonstrated that mutation of any acidic residue, either singly or in
      combination, or deletion of the carboxyl terminus of the IE protein resulted in a
      severe impairment of transactivation activity. These results show that both
      acidic and hydrophobic residues within the IE TAD are critical for
      transactivation function and that the carboxyl terminus of the IE protein is
      required for full transactivation activity.

PMID- 10581387
TI  - Two distinct regions of the BPV1 E1 replication protein interact with the
      activation domain of E2.
AB  - Papillomavirus E1 and E2 proteins co-operation in viral DNA replication is
      mediated by protein-protein interactions that lead to formation of an E1-E2
      complex. To identify the domains involved, portions of the two proteins were
      expressed as fusions to the DNA-binding protein LexA or the transactivation
      domain of VP16 and analyzed by the yeast two-hybrid system. The C-terminal 266
      amino acids of BPV1 E1 (E1C266) interacted strongly with E2 in the yeast system
      and in a mammalian two-hybrid assay. VP16-E1C266 interacted with a region
      encompassing amino acids 1-200 of the transactivation domain of E2 that was fused
      to LexA. The interaction between E1 full length and E2 was clearly observed only
      when E1 was expressed as LexA-E1 chimera. In addition, we found that in the LexA
      context also the N-terminal region encompassing the first 340 amino acids of E1
      (E1N340) interacted with E2 full length. The interactions of E1N340 and E1C266
      with E2 were confirmed also by in vitro binding studies. These observations
      demonstrate that two distinct regions of E1 mediate the interaction with E2 in
      vivo.

PMID- 10581388
TI  - Echovirus 9 strain barty non-structural protein 2C has NTPase activity.
AB  - Non-structural protein 2C is known to play a fundamental role in the replication
      of picornaviruses. Sequence analyses revealed that 2C belongs to a rapidly
      expanding group of proteins containing a consensus sequence for nucleotide
      binding (NTB). We report that echovirus 9 polypeptide 2C displays NTPase activity
      in vitro. In our experiments, several P2 genes were expressed in Escherichia coli
      as fusion proteins linked to glutathione S-transferase (GST) prior to
      purification close to homogeneity. In contrast to GST-2B, both GST-2C and GST-2BC
      showed ATPase as well as GTPase activity indicating that the site for NTB binding
      and splitting is located in 2C.

PMID- 10581389
TI  - Parvovirus H-1-induced cell death: influence of intracellular NAD consumption on
      the regulation of necrosis and apoptosis.
AB  - The autonomous parvovirus H-1 exerts tumor-suppressive effects in living
      organisms and has been shown to specifically interfere with the survival of
      transformed cells in culture. The mechanism(s) by which H-1 virus induces death
      of transformed cells is not yet well understood. It has recently been reported
      that H-1 virus induces apoptotic cell death in the human monocytic U937 cell
      line, as assessed by biochemical and morphological changes of infected cells
      (Rayet, B., Lopez-Guerrero, J.-A., Rommelaere, J., Dinsart, C., 1998. Induction
      of programmed cell death by parvovirus H-1 in U937 cells: connection with the
      TNFalpha signalling pathway. J. Virol. 72, 8893-8903). Here we show that
      parvovirus H-1 infection induced early biochemical changes pointing to apoptotic
      events also in the transformed human keratinocyte cell line, HeLa, and the
      transformed rat fibroblast cell line, P1. Morphologic changes, however, and in
      particular the early breakdown of plasma membrane integrity, suggested that
      apoptosis did not go to completion, leading to necrotic cell death as the major
      result of parvovirus infection of HeLa and P1 cells. Parvovirus infection of
      these, and to a significantly lesser extent of U937 cells, was accompanied by
      rapid depletion of intracellular NAD stores. Inhibition of NAD-consuming enzymes
      interfered with parvovirus-induced NAD depletion and increased the proportion of
      H-1 virus-infected cells displaying apoptotic features of cell death. In
      contrast, a similar prevention of NAD depletion through stimulation of NAD
      production had little influence on the cell death pathway, suggesting that NAD
      consuming enzymes may promote necrosis in a direct way rather than through
      inducing the overall drop of intracellular NAD.

PMID- 10581390
TI  - Suppression of interferon response gene expression in cells persistently infected
      with mumps virus, and restoration from its suppression by treatment with
      ribavirin.
AB  - Persistent infections with mumps virus were established in human B-lymphoid cell
      line Akata and in the human chronic myelogenous leukaemia cell line K562. Even
      after IFN treatment a drastic decrease in STAT-1alpha (signal transducers and
      activators of transcription-1alpha), STAT-2 and p48 (ISGF-3gamma: IFN-stimulated
      gene factor-3gamma), which are closely correlated with the IFN-signaling pathway,
      was found in these persistently infected cells (Akata-MP1 and K-MTP). Therefore,
      the IFN-signaling pathway is thought to be defective in these persistently
      infected cells. In other words, most of the IFN-inducible genes in these cells
      persistently infected with mumps virus may not be able to respond to IFN
      treatment. Indeed, poor induction of 2',5'-oligoadenylate synthetase (2-5AS),
      dsRNA activated protein kinase (PKR), and MxA protein mRNAs were demonstrated in
      these cell lines after IFN treatment. Expression of MHC class-I antigen was also
      significantly reduced in the persistently infected cell lines as compared with
      that of uninfected control cells. HLA antigen was augmented by IFN-alpha in Akata
      and K562 cells, but not in persistently infected cells. Furthermore, suppression
      of IFN-induced 2-5AS induction and MHC class-I expression was restored by
      treatment of persistently infected cells with ribavirin through inhibition of
      virus replication. The result of restoration was also confirmed by IFN-induced
      STAT-1 induction in persistently infected cells treated with ribavirin.

PMID- 10581391
TI  - Sequence analysis of the turkey coronavirus nucleocapsid protein gene and 3'
      untranslated region identifies the virus as a close relative of infectious
      bronchitis virus.
AB  - The 3' end of the turkey coronavirus (TCV) genome (1740 bases) including the
      nucleocapsid (N) gene and 3' untranslated region (UTR) were sequenced and
      compared with published sequences of other avian and mammalian coronaviruses. The
      deduced sequence of the TCV N protein was determined to be 409 amino acids with a
      molecular mass of approximately 45 kDa. The TCV N protein was identical in size
      and had greater than 90% amino acid identity with published N protein sequences
      of infectious bronchitis virus (IBV); less than 21% identity was observed with N
      proteins of bovine coronavirus and transmissible gastroenteritis virus. The 3'
      UTR showed some variation among the three TCV strains examined, with two TCV
      strains, Minnesota and Indiana, containing 153 base segments which are not
      present in the NC95 strain. Nucleotide sequence identity between the 3' UTRs of
      TCV and IBV was greater than 78%. Similarities in both size and sequence of TCV
      and IBV N proteins and 3' UTRs provide additional evidence that these avian
      coronaviruses are closely related.

PMID- 10581392
TI  - Adenosine and behavioral state control: adenosine increases c-Fos protein and AP1
      binding in basal forebrain of rats.
AB  - In several brain areas, extracellular adenosine (AD) levels are higher during
      waking than sleep and during prolonged wakefulness AD levels in the basal
      forebrain increase progressively. Similarly, c-Fos levels in several brain areas
      are higher during waking than sleep and remain elevated during prolonged
      wakefulness. In the present study, we investigated the effect of extracellular AD
      levels on c-Fos protein and activator protein-1 (AP1) binding in the basal
      forebrain of rats. Increased levels of extracellular AD were induced either by
      keeping the animals awake, or by local perfusion of AD into the basal forebrain.
      During prolonged wakefulness extracellular AD concentration was monitored using
      in vivo microdialysis. The effect of AD perfusion on the behavioral states was
      recorded using polysomnography. At the end of the perfusion period the basal
      forebrain tissue was analyzed for the levels of c-Fos protein and AP1 binding. In
      vivo microdialysis measurements showed an increase in AD levels with prolonged
      wakefulness. Unilateral perfusion of AD (300 microM) increased non-REM sleep and
      delta power (0.5 to 4 Hz) when compared to rats perfused with artificial CSF. The
      levels of c-Fos protein and the AP1 DNA binding were high in the basal forebrain
      of both sleep-deprived animals and in animals perfused with AD. The results
      suggest that AD might mediate, at least in part, the long term effects of sleep
      deprivation by inducing c-Fos protein and subsequent AP1 binding.

PMID- 10581393
TI  - Isolation and characterization of the hypoxia-inducible factor 1beta in
      Drosophila melanogaster.
AB  - The hypoxia-inducible factor 1 (HIF-1), a heterodimer composed of alpha and beta
      subunits, plays an important role in the cellular response to O(2) deprivation.
      In this paper, Drosophila HIF-1beta (dHIF-1beta) homolog is cloned and
      characterized. Further, Northern analyses showed that dHIF-1alpha and dHIF-1beta
      expressed their highest level at an embryonic stage. From the pupal stage on,
      their expression was sharply reduced and maintained at a steady level. Anoxia
      treatment up-regulated the expression of the both alpha and beta subunits. Over
      expression of dHIF-1alpha in transgenic embryos resulted in embryonic lethality,
      while over-expression of dHIF-1beta significantly prolonged fly recovery time
      from a 5-min anoxic stupor. The cloning and characterization dHIF-1beta reported
      in this paper provide a framework for further genetic dissection of the HIF-1
      complex in its role in the cellular or tissue response to O(2) deprivation.

PMID- 10581394
TI  - Expression of cytokine genes and increased nuclear factor-kappa B activity in the
      brains of scrapie-infected mice.
AB  - A number of aspects of the pathogenesis of scrapie remain to be elucidated. The
      cellular and molecular aspects of the neuropathology in scrapie suggest the
      possibility that the proinflammatory cytokines could act as pathogenic mediators
      in this neurodegenerative disease. To understand this possibility, we examined
      the expression of proinflammatory cytokine genes in brains of IM mice-infected
      with 87V scrapie agent. Additionally, we also analyzed the activity of nuclear
      factor-kappa B (NF-kappaB), which is the major transcriptional activator for
      inflammatory cytokines, and formation of reactive oxygen species (ROS) as a
      common upstream messenger for its activation. The induction of mRNAs of the
      inflammatory cytokines, IL-1alpha, IL-1beta and TNF-alpha, was detected only in
      the brains of scrapie-infected mice. The activity of NF-kappaB was significantly
      increased in the nuclear extracts from brains of the scrapie-infected group and
      the immunoreactivity of NF-kappaB was increased in the hippocampus and thalamus
      in the brains of scrapie-infected mice. The NF-kappaB immunoreactivity was
      observed mainly in GFAP-positive astrocytes and also detected in the PrP-amyloid
      plaques in the brains of 87V scrapie-infected mice. Gene expression of IL-6 and
      iNOS, the representative target genes for NF-kappaB activation, were activated
      only in the infected group. The production of ROS was significantly increased in
      the brain mitochondrial fractions of scrapie-infected mice. These results suggest
      that prion accumulation in astrocytes might activate NF-kappaB through the
      increase of ROS generation, and thus alterations in NF-kappaB-directed gene
      expression may contribute to both the neurodegeneration and proinflammatory
      responses which occur in scrapie.

PMID- 10581395
TI  - Channel properties determine the transient activation kinetics of recombinant
      GABA(A) receptors.
AB  - To understand the mechanisms underlying activation and deactivation of GABA(A)
      receptor (GABAR) channels, we studied the properties of an identified GABAR
      isoform under conditions similar to those present at central GABAergic synapses.
      Recombinant alpha5beta3gamma2L GABARs were expressed in L929 fibroblasts and
      studied using patch-clamp recording techniques. Brief application of a high GABA
      concentration to outside-out membrane patches elicited transient currents that
      resembled those reported for miniature inhibitory postsynaptic currents (mIPSCs),
      as well as native GABAR currents recorded under similar conditions.
      Characteristic of these currents was a rapid activation phase followed by a
      prolonged biphasic deactivation phase that far outlasted GABA application. Single
      channel recordings revealed unique patterns of channel activity with two channel
      conductance states of 22 and 16 pS. The prolonged deactivation phase appeared to
      be sustained by entry into and reopening from long-lasting closures or
      desensitized states. Agonist affinity determined the time course of deactivation,
      indicating that occupied receptors drove the channel activity underlying the
      decay of current. The time course of deactivation was also longer at depolarized
      membrane potentials. The similarities between transient activation kinetics of
      recombinant alpha5beta3gamma2L GABARs to activation of synaptic GABARs (rapid
      activation and prolonged, voltage-dependent deactivation) suggest that intrinsic
      channel properties determine much of the response patterns of native GABARs.

PMID- 10581396
TI  - Cocaine reward and MPTP toxicity: alteration by regional variant dopamine
      transporter overexpression.
AB  - Polygenic factors play important roles in animal models of substance abuse and
      susceptibility to dopaminergic neurodegeneration. Genetic factors are also likely
      to contribute to the etiology of human drug abuse disorders, and may alter human
      vulnerabilities to Parkinsonian neurodegeneration. The dopamine transporter (DAT;
      SLC6A3) is densely expressed by the dopaminergic midbrain neurons that play
      central roles in drug reward and is believed to be a primary site of action for
      cocaine reward. This transporter is necessary for the action of selective
      dopaminergic neurotoxins, and is uniquely expressed on neurons that are the
      primary targets of Parkinsonian neurodegeneration. To study possible influences
      of variant DAT expression on these processes, we have constructed transgenic mice
      (THDAT) in which tyrosine hydroxylase (TH) promoter sequences drive expression of
      a rat DAT cDNA variant, increase striatal DAT expression by 20-30%, and provide
      modest alterations in striatal levels of dopamine and its metabolites. THDAT mice
      habituate more rapidly to a novel environment than wildtype littermates. These
      animals display enhanced reward conferred by cocaine, as measured by conditioned
      place preference. However, locomotor responses to cocaine administration are
      similar to those of wildtype mice, except at high cocaine doses. THDAT mice
      display more than 50% greater losses of dopaminergic neurons following a course
      of MPTP treatment than do wildtype control mice. These results document a model
      for allelic variation at a gene locus that can exert significant effects in
      murine models of human substance abuse vulnerability and dopaminergic
      neurodegeneration.

PMID- 10581398
TI  - Dimorphic expression of medial basal hypothalamic-preoptic area calbindin-D(28K)
      mRNA during perinatal development and adult distribution of calbindin-D(28K) mRNA
      in Sprague-Dawley rats.
AB  - The calcium-binding protein, calbindin (CALB) is: (a) distributed throughout the
      central nervous system (CNS), (b) abundant in neurons and, (c) thought to act as
      a buffer by binding intracellular calcium, mediating neurogenesis (cell
      profileration) and neuronal programmed cell death. Using Northern analysis, CALB
      mRNA distribution was characterized in 12 different adult brain regions.
      Additionally, CALB mRNA levels were characterized in the medial basal
      hypothalamus (MBH) and preoptic area (POA) in perinatal male and female rats, in
      order to compare this mRNA pattern to the dimorphic MBH-POA CALB protein profile
      our laboratory previously reported. Three CALB mRNA species were detected (at
      1.9, 2.8 and 3.2 kilobase pairs) in all CNS regions. The smallest mRNA transcript
      (at 1.9 kilobase pairs) was the most abundant of the three CALB mRNAs. To
      quantify these mRNA signals, CALB mRNA levels were normalized to 18s ribosomal
      RNA bands. Among the various adult brain sites assayed, the cerebellum expressed
      the highest CALB mRNA signals. High CALB mRNAs were observed in the MBH-POA,
      olfactory bulb and hippocampal regions. Moderate CALB mRNA levels were seen in
      the striatum and frontal cortex while moderate to low CALB mRNA levels were
      observed in the posterior cortex, entorhinal cortex, midbrain, pons, thalamus and
      medulla. During perinatal development, MBH-POA CALB mRNA levels were lowest at
      gestation day (GD) 18, increased four-fold in newborns and remained at moderate
      levels during early postnatal development. Male CALB mRNA levels were notably
      greater than female values at GD 18 and in newborns. Whereas, at PND 2, the CALB
      mRNA levels were approximately equivalent in males and females. These findings
      suggest that in the adult CNS CALB mRNAs vary among different brain regions. The
      present male vs. female MBH-POA CALB mRNA levels confirm previously reported
      dimorphic protein patterns of MBH-POA CALB during perinatal development. Thus,
      the genesis of sexually dimorphic structures may be influenced by the dimorphic
      CALB expression in the MBH-POA region.

PMID- 10581397
TI  - Regulation of heme oxygenase-1 expression by dopamine in cultured C6 glioma and
      primary astrocytes.
AB  - Heme oxygenase-1 (HO-1) is an inducible enzyme involved in heme catabolism,
      tissue iron homeostasis and the cellular response to oxidative stress. Elevated
      HO-1 expression in astrocytes has been observed in association with abnormal iron
      deposition and increased oxidative stress in Parkinson's disease (PD). Since HO-1
      could contribute to these aspects of PD pathobiology we have investigated its
      regulation in cultured astrocytes and C6 glioma cells. Here we report that
      dopamine is a potent inducer of HO-1. This induction is not mediated by a
      classical dopamine receptor and is not mimicked by a range of catecholamines and
      dopamine metabolites. When the time-course of HO-1 expression was compared
      between dopamine and hemin, the latter induced the gene immediately while the
      former did so with a lag. This suggested two distinct signal transduction
      pathways. However, cycloheximide blocked both hemin- and dopamine-induced HO-1
      expression, suggesting that both pathways may involve proteins with short half
      lives. Ascorbic acid blocked dopamine induction of HO-1 but had no effect on
      hemin-induced expression. This suggested that dopamine may signal upstream of the
      unstable protein by producing pro-oxidant metabolites or byproducts. Inhibition
      of monoamine oxidases A or B or catechol-O-methyl transferase did not block HO-1
      induction by dopamine, indicating that these enzymes were not converting dopamine
      to an active metabolite. These results suggest that dopamine, released or
      secreted from affected neurons, may trigger HO-1 expression in neighboring
      astrocytes. HO-1 and its metabolites could then contribute to the oxidative
      stress and iron deposition associated with PD.

PMID- 10581399
TI  - An anchoring factor targets protein phosphatase 2A to brain microtubules.
AB  - Protein phosphatase 2A (PP2A) is a ubiquitously expressed serine/threonine
      phosphatase composed of a heterodimeric core enzyme that associates with a
      variety of regulatory subunits. A fraction of brain PP2A associates with
      microtubules and may play a role in regulating phosphorylation of microtubule
      associated proteins. We examined the isoform specificity and the mechanism
      involved in the association of PP2A with brain microtubules. Only the R2alpha
      (B/PR55alpha) and R2beta (B/PR55beta) regulatory subunits associated with
      endogenous neural microtubules. Neither the R2gamma (B/PR55gamma) nor members of
      the R5 (B'/PR56) family of regulatory subunits co-sedimented with microtubules,
      although abundant amounts of these proteins were detected in brain. The efficient
      association of PP2A with microtubules in vitro was dependent on an anchoring
      activity present in a brain protein fraction containing microtubule-associated
      and microtubule-interacting proteins. Anchoring factor-dependent association of
      PP2A with microtubules was specific for the heterotrimeric form of PP2A. The core
      dimer and the isolated subunits of PP2A had very little affinity for
      microtubules. Characterization of a fraction enriched in the anchoring factor
      showed that the activity was a heat labile protein that does not correspond to
      classical microtubule-associated proteins. The anchoring factor associated with
      microtubules independently of PP2A. These results indicate the association of
      PP2A with microtubules can be mediated by an anchoring factor that interacts in
      an isoform-specific manner with heterotrimeric forms of the phosphatase.

PMID- 10581400
TI  - L-DOPA-quinone inactivates tryptophan hydroxylase and converts the enzyme to a
      redox-cycling quinoprotein.
AB  - Tryptophan hydroxylase, the initial and rate limiting enzyme in the biosynthesis
      of serotonin (5-HT), is inactivated by the quinone of L-DOPA. L-DOPA itself has
      no effect on enzyme activity. The inactivation of tryptophan hydroxylase could be
      prevented by glutathione (GSH), dithiothreitol, cysteine, and ascorbic acid but
      not by scavengers of hydrogen peroxide (catalase), hydroxyl radical (DMSO), or
      superoxide (superoxide dismutase). All cysteinyl residues within tryptophan
      hydroxylase are modified after treatment with L-DOPA-quinone as revealed by loss
      of DTNB-reactivity and formation of cysteinyl-DOPA residues. L-DOPA-quinone also
      converts tryptophan hydroxylase to a redox-cycling quinoprotein. These results
      suggest a possible mechanism of 5-HT neuronal damage in Parkinson's Disease by a
      redox-cycling quinoprotein.

PMID- 10581401
TI  - Evidence for alternative splicing of ecto-ATPase associated with termination of
      purinergic transmission.
AB  - Ectonucleotidases provide the signal termination mechanism for purinergic
      transmission, including fast excitatory neurotransmission by ATP in the CNS. This
      study provides evidence for ectonucleotidase expression in the rat cochlea, brain
      and other tissues. In addition to detection of rat ecto-ATPase and ecto-ATPDase
      in these tissues, we identify a novel ecto-ATPase splice variant arising from the
      loss of a putative exon (193 bp) in the C-terminal coding region. This is the
      first evidence of alternative splicing in the ecto-ATPase gene family. Splicing
      of the 193-bp putative exon containing a stop codon extends the open reading
      frame and provides translation of an additional 50 amino acids compared with the
      isoform isolated earlier from the rat brain (rEATPase(A); GenBank accession
      #Y11835). The splice variant (rEATPase(B); GenBank accession #AF129103) encodes
      545 amino acids with a predicted protein molecular mass of 60 kDa. rEATPase(B)
      contains a long cytoplasmic tail (62 amino acids) with three potential protein
      kinase CK2 phosphorylation sites not present in rEATPase(A). Co-expression of two
      ecto-ATPase isoforms with different regulatory sites suggests that the
      extracellular ATP signal levels may be differently influenced by intracellular
      feedback pathways.

PMID- 10581402
TI  - Cloning of novel splice variants of mouse mGluR1.
AB  - Three splice variants of the mouse metabotropic glutamate receptor 1, mGluR1E55,
      mGluR1a and mGluR1b, have been isolated from mouse brain cDNA libraries. The
      sequences of mGluR1a and mGluR1b are similar to those from rat and human.
      mGluR1E55 is a novel splice variant. mGluR1E55 has two additional exons. One is
      80-bp long at the 5' untranslational region. The other (E55) is 110-bp long at
      the cysteine-rich region after the ligand-binding domain and before the seven
      transmembrane domain. Insertion of the E55 exon results in an inframe stop codon.
      The predicted protein product contains only the extracellular domain of the
      receptor and may be secreted.

PMID- 10581403
TI  - Reduced editing of low-affinity kainate receptor subunits in optic nerve glial
      cells.
AB  - We have analyzed the degree of editing of adult optic nerve mRNAs encoding the
      low-affinity kainate receptor subunits, GluR5 and GluR6, the two major
      constituents of native receptors in this family. To this end, we used reverse
      transcription (RT) followed by polymerase chain reaction (PCR), and subsequent
      cloning and sequencing of the amplified fragments. Our results revealed that the
      GluR5 subunit is unedited at the Q/R site of cismembrane domain 2 (M2), whereas
      the GluR6 subunit is edited to a low extent at this site. These findings are in
      contrast to those reported by others using mRNAs from the adult brain in which
      GluR5 and GluR6 are edited at the Q/R site of M2 to a larger extent. In addition,
      we found that the adenosine deaminases, DRADA, RED1 and RED2, which edit
      ionotropic glutamate receptors in the brain, are expressed in the adult optic
      nerve and in oligodendrocytes, the major cell type in this structure. It thus
      appears that editing of kainate receptors in optic nerve cells is not limited by
      the availability of editing enzymes but rather by other, as yet unidentified
      factors. Overall, reduced editing of kainate receptor subunits in glial cells may
      result in different functional responses of the native receptors present in these
      cells with respect to those in neurons.

PMID- 10581404
TI  - Exo-rhodopsin: a novel rhodopsin expressed in the zebrafish pineal gland.
AB  - The zebrafish, a useful animal model for genetic studies, has a photosensitive
      pineal gland, which has an endogenous circadian pacemaker entrained to
      environmental light-dark cycles [G.M. Cahill, Brain Res. 708 (1996) 177-181].
      Although pinopsin has been found in the pineal glands of birds and reptiles, the
      molecular identity responsible for fish pineal photosensitivity remains unclear.
      This study reports identification of a novel opsin gene expressed in the
      zebrafish pineal gland. The deduced amino acid sequence is similar to, but not
      identical (74% identity) with that of canonical rhodopsin in the zebrafish
      retina. This novel rhodopsin is expressed in the majority of pineal cells but not
      in retinal cells, and hence named exo-rhodopsin after extra-ocular rhodopsin.
      This study first shows that two different rhodopsin genes are expressed in an
      individual animal each within a unique location. A phylogenetic analysis
      indicated that the exo-rhodopsin gene was produced by a duplication of the
      rhodopsin gene at an early stage in the ray-finned fish lineage. As expected, the
      exo-rhodopsin gene was found in the medakafish and European eel genomes,
      suggesting strongly that exo-rhodopsin is a pineal opsin common to teleosts.
      Identification of exo-rhodopsin in the zebrafish provides an opportunity for
      studying the role of pineal photoreceptive molecules by using genetic approaches.

PMID- 10581405
TI  - Effects of tamoxifen on serotonin transporter and 5-hydroxytryptamine(2A)
      receptor binding sites and mRNA levels in the brain of ovariectomized rats with
      or without acute estradiol replacement.
AB  - Estradiol-17beta (E(2)), in its positive feedback mode for gonadotropin release
      in the female rat, induces expression of the genes for the 5
      hydroxytryptamine(2A) receptor (5-HT(2A)R) and the serotonin transporter (SERT)
      in the dorsal raphe nucleus (DRN) with a concomitant increase in the densities of
      5-HT(2A)R and the SERT in rat forebrain. The forebrain regions affected are those
      which, in humans, are concerned with the control of mood, mental state, cognition
      and emotion. Here we have used the mixed estradiol agonist/antagonist, tamoxifen,
      to determine whether this action of estradiol is mediated by cytoplasmic
      estradiol receptors. Acute treatment ( approximately 32 h) of ovariectomized rats
      with estradiol benzoate (EB) increased significantly the amount of 5-HT(2A)R mRNA
      and SERT mRNA in the DRN and the densities of 5-HT(2A)R and SERT binding sites in
      the forebrain. These effects of EB were completely blocked by tamoxifen.
      Treatment with tamoxifen alone had no effect on either gene expression or the
      density of binding sites. Together, these data show that tamoxifen acts as a pure
      estradiol antagonist with respect to serotonergic mechanisms in brain. Detailed
      analysis of the effects of estradiol and tamoxifen on the DRN showed that SERT
      gene expression is constitutive only in the posterior DRN; in the anterior DRN,
      SERT gene expression appears to depend upon estrogen induction which is blocked
      by tamoxifen. Our findings strongly suggest that estradiol receptors are involved
      in mediating estradiol action on central serotonergic mechanisms and are relevant
      for our understanding of the effects of antiestrogens as well as estradiol on
      mood, mental state and cognition.

PMID- 10581406
TI  - The bovine mu-opioid receptor: cloning of cDNA and pharmacological
      characterization of the receptor expressed in mammalian cells.
AB  - The cDNA coding for the bovine mu-opioid receptor has been cloned and sequenced.
      Conserved sequences from murine delta-receptor cDNA were used as primers in
      polymerase chain reaction (PCR) to amplify cDNA, prepared by reverse
      transcription of bovine brain mRNA. This cDNA was used to probe a bovine brain
      library. The partial sequence obtained was extended to provide the full length
      clone by PCR. The cDNA has an open reading frame of 1203 base pairs (bp) with a
      3'-untranslated region of 1900 bp and a 5'-untranslated region of 265 bp. The
      protein contains 401 amino acids and has 94% amino acid identity with the human
      and 91% with the rat mu-opioid receptor. It has the putative seven transmembrane
      domains, characteristic of G protein-coupled receptors and contains 5 potential N
      linked glycosylation sites near the N-terminus. Several potential phosphorylation
      sites and a putative palmitoylation site are also present. The receptor was
      stably expressed in HEK293 cells. The binding profile was found to be that of a
      typical mu receptor, i. e., mu agonists and antagonists, but not delta and kappa
      ligands, bound with high affinity. Functional assays, namely, opioid stimulation
      of [35S]GTPgammaS binding and inhibition of forskolin-activated adenylyl cyclase,
      were also found to be highly specific for mu-opioid agonists. The receptor was
      downregulated by chronic exposure to mu agonists but not delta or kappa agonists.
      Evidence is presented indicating that the cloned receptor is the same as the
      bovine mu receptor previously purified to homogeneity in our laboratory. No
      evidence was found for genes for multiple mu-type opioid receptors.

PMID- 10581407
TI  - Expression of cell death-associated phospho-c-Jun and p53-activated gene 608 in
      hippocampal CA1 neurons following global ischemia.
AB  - Persistent activation of c-Jun N-terminal kinases (JNKs) and phosphorylation of c
      Jun has been shown in various cell death paradigms. Inhibition of the JNK signal
      transduction pathway prevented neuronal cell death both in vitro and in vivo. In
      the present study, nuclear phospho-c-Jun immunoreactivity became apparent
      selectively in vulnerable hippocampal CA1 neurons at 24 h after transient global
      cerebral ischemia. A high constitutive expression of phospho-JNK1 was detected by
      immunoblot analysis of hippocampal extracts. Expression of JNK interacting
      protein-1 (JIP-1), which facilitates JNK signaling, remained unchanged in post
      ischemic hippocampal neurons. By contrast, p53-activated gene 608 (PAG608), which
      promotes cell death in vitro, was strongly induced in post-ischemic CA1 neurons.
      Our data suggest that transcription factors p53 and phospho-c-Jun may contribute
      to programmed CA1 cell death following ischemia.

PMID- 10581408
TI  - Activator protein-1 DNA binding activation by hydrogen peroxide in neuronal and
      astrocytic primary cultures of trisomy-16 and diploid mice.
AB  - The effect of H(2)O(2) on DNA binding activity of activator protein-1 (AP-1) was
      studied by electrophoretic mobility shift assay (EMSA) in cortical primary
      cultures of trisomy-16 mice and their diploid littermates. Exposure to 10 microM
      H(2)O(2) for 15 min elicited a greater and earlier occurring increase of AP-1 DNA
      binding in neuronal primary cultures of trisomy-16 mice than of diploid mice.
      When astrocyte-rich primary cultures were exposed to 10 microM H(2)O(2) a two
      fold increase of AP-1 DNA binding activity was found in trisomy-16 and diploid
      mice. Supershift EMSA analysis revealed that c-jun was a component of AP-1 in
      neuronal and glial cultures of diploid and trisomic mice. A 15-min exposure to 10
      microM H(2)O(2) increased c-jun mRNA in cortical neuronal cultures by six-fold,
      compared with a two-fold increase in cultured astrocytes. The results documented
      that H(2)O(2)-elicited activation of AP-1 DNA binding in trisomy-16 primary
      cultures is transcriptionally regulated. Since oxidative stress also activates
      various stress-inducible protein kinases that may phosphorylate AP-1 dimers, the
      increase of AP-1 DNA binding may, in part, be triggered by phosphorylation.

PMID- 10581409
TI  - Localization of GDNF/neurturin receptor (c-ret, GFRalpha-1 and alpha-2) mRNAs in
      postnatal rat brain: differential regional and temporal expression in
      hippocampus, cortex and cerebellum.
AB  - Recent studies have identified a multi-component receptor system for the
      neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF) and its
      homolog, neurturin (NTN), comprising the signaling tyrosine kinase, Ret and
      multiple GPI-linked binding proteins, GDNF family receptor alpha-1 and alpha-2
      (GFRalpha-1 and GFRalpha-2). In the present study the localization of c-ret and
      GFRalpha-1 and GFRalpha-2 mRNAs was assessed in the developing rat brain from
      postnatal day 4 to 70 by in situ hybridization histochemistry, using specific
      [35S]-labeled oligonucleotides. GFRalpha-1 and GFRalpha-2 mRNAs were
      differentially distributed throughout the brain at all ages studied, particularly
      in cerebral cortex, hippocampus, substantia nigra and regions of the thalamus and
      hypothalamus - both distributions overlapping but different to that of c-ret
      mRNA. C-ret mRNA was abundant in areas such as the lateral habenula, reticular
      thalamic nucleus, substantia nigra pars compacta, cranial motor nuclei, and the
      Purkinje cell layer of the cerebellum. GFRalpha-1 mRNA was abundant in dorsal
      endopiriform nucleus, medial habenula, reticular thalamic nucleus, pyramidal and
      granule cell layers of the hippocampus, substantia nigra pars compacta and in
      cranial motor nuclei. GFRalpha-2 mRNA was highly expressed in many regions
      including olfactory bulb, lateral olfactory tract nucleus, neocortical layers IV
      and VI, septum, zona incerta, and arcuate and interpeduncular nuclei. GFRalpha-2
      mRNA was detected in the pyramidal cell layers (CA3) of hippocampus at P4 and P7,
      but was no longer detectable at P14 and beyond, including P70 (adult). GFRalpha-2
      mRNA was also detected in Purkinje cells throughout the cerebellum in young
      postnatal rats, but was enriched in the posterior lobes at P28 and P70. These
      localization studies support evidence of GDNF/NTN as target-derived and
      autocrine/paracrine trophic factors in developing brain pathways and earlier
      suggestions of unique and complex signaling mechanisms for these factors via a
      family of receptors. Strong expression of GFRalpha-1 and GFRalpha-2 mRNAs in
      adult brain suggests possible non-trophic functions of GDNF/NTN, as described for
      other neurotrophins, such as brain-derived neurotrophic factor.

PMID- 10581410
TI  - The mouse GABA(A) receptor alpha3 subunit gene and promoter.
AB  - Gamma-aminobutyric acid (GABA) type A receptors are multisubunit ligand-gated ion
      channels which mediate inhibition in the brain. The GABA(A) receptor alpha3
      subunit gene exhibits extensive variation in its developmental and regional
      expression, but the detailed mechanisms governing the expression patterns of this
      gene remain unknown. We have cloned and begun to characterize the murine alpha3
      subunit gene Gabra3. All but one of the 10 exons and the intron-exon boundaries
      have been sequenced; the first intron is in the 5' untranslated region (5'UTR) of
      the alpha3 mRNA. Rapid amplification of the cDNA 5'-end (5'-RACE) and RNase
      protection indicated many transcription start sites, with the major site (=+1)
      corresponding to a 5'UTR of 178 bases. Most sites were in or just downstream of a
      region of 55 (mouse) and 25 (human) GA repeats in the proximal promoter, as
      revealed by genome walking of Gabra3 and the human gene GABRA3. No canonical TATA
      or CAAT boxes or initiator (Inr) sites were found in either promoter, but both
      contained conserved consensus sites for several transcription factors.
      Progressive deletion of the mouse promoter produced positive or negative effects
      on expression of reporter (luciferase) constructs, with the highest observed
      activity in several types of transiently transfected cells for a construct
      containing bases -320 to +35. The GA repeats and a much shorter nearby series of
      four GC repeats, the first three of which are part of a consensus E2F site,
      appear to contribute significantly to mouse promoter activity. Upstream GA
      repeats enhanced activity of the SV40 promoter, and the GA repeat sequence bound
      nuclear proteins from several tissues.

PMID- 10581411
TI  - Dopamine transporter mRNA in autopsy studies of chronic cocaine users.
AB  - The effects of chronic cocaine abuse on transcriptional regulation of human
      dopamine transporter (DAT) mRNA in midbrain dopaminergic neurons was assessed by
      reverse transcription-polymerase chain reaction (RT-PCR). DAT/cyclophilin mRNA
      ratios in the substantia nigra (SN) were unchanged in cocaine overdose (CO)
      victims as compared to age-matched and drug-free control (CTRL) subjects. In
      contrast, DAT mRNA levels were decreased significantly in agitated cocaine
      delirium victims (67%, p<0.05). These findings demonstrate the lack of a
      regulatory influence by cocaine on the steady state content of DAT mRNA in
      cocaine abusers. In contrast, DAT gene expression was altered significantly in
      cocaine abusers at risk for agitated delirium.

PMID- 10581412
TI  - Increased expression of mitochondrial respiratory enzymes in the brain of
      activated epilepsy-prone El mice.
AB  - The El mouse is an internationally registered animal model for hereditary
      temporal lobe epilepsy. When the mice receive weekly vestibular stimulation,
      e.g., 30 "tosses" 10-15 cm vertically, they start to convulse after 6-7 weeks on
      application of appropriate vestibular stimulation. The aim of this study was to
      explore the pathogenesis of the disease. By means of differential mRNA display we
      have screened five cDNAs which were upregulated in the brain of activated El mice
      given repeated vestibular stimulation. The differential expression of two (DD7/8
      and DD8/24) cDNAs could be confirmed by Northern analyses. Sequence of the clones
      revealed that they were associated with mitochondrial respiratory enzymes, i.e.,
      type 1 subunit of cytochrome c oxidase and a precursor of type 1 subunit of NADH
      dehydrogenase. The expression of these two genes was significantly increased in
      the El mice, which were activated by periodically repeated vestibular
      stimulation. The increased expression of these two genes may reflect increased
      demand for energy due to neuronal activation caused by repeated vestibular
      stimulation.

PMID- 10581413
TI  - A mutation in the glycine binding pocket of the N-methyl-D-aspartate receptor NR1
      subunit alters agonist efficacy.
AB  - Alanine 714 of the NMDA receptor NR1 subunit resides in the glycine binding
      pocket. The Ala714Leu mutation substantially shifts glycine affinity, but here no
      effect on antagonism by DCK is detected. Ala714Leu is also found to limit the
      efficacy of a partial agonist without altering its apparent affinity. The
      differential sensitivity of Ala714Leu to glycine agonists suggests that alanine
      714 may be an intermediary in transducing the ligand binding signal.

PMID- 10581414
TI  - Effects of atypical antipsychotic drugs vs. haloperidol on expression of heat
      shock protein in the discrete brain regions of phencyclidine-treated rats.
AB  - Haloperidol augmented a trend of an increase in the heat shock protein (hsp70)
      mRNA levels induced by phencyclidine (PCP) in rat medial prefrontal cortex,
      nucleus accumbens and striatum, while the atypical antipsychotic drugs such as
      clozapine, olanzapine and risperidone decreased it. When administered alone,
      clozapine, but not haloperidol, decreased hsp70 mRNA levels. Haloperidol and the
      atypical antipsychotic drugs may thus have differential effects on hsp70
      expression in some brain regions of PCP-treated rats.

PMID- 10581415
TI  - Regulation of PTEN expression in neuronal apoptosis.
AB  - PTEN phosphatase is a tumor suppressor gene that dephosphorylates
      phosphatidylinositol phosphates. PTEN restrains the function of a major
      antiapoptotic and survival pathway involving phosphoinositide 3-kinase and Akt
      kinase. Our purpose was to find out whether apoptotic inducers affect the
      expression of PTEN in cerebellar granule neurons and neuroblastoma 2a cells
      (Neuro-2a). PTEN mRNA expression showed a major 5.5-kb and a lower abundance 2.5
      kb transcripts. In Neuro-2a cells, serum withdrawal induced a prominent,
      continuous decrease both in 5.5- and 2.5-kb transcripts of PTEN mRNA.
      Simultaneously, the expression level of 56-kDa PTEN protein decreased in Neuro-2a
      cells. The decrease in PTEN expression precedes apoptotic changes observed after
      serum withdrawal. On the contrary, okadaic acid and etoposide only slightly
      affected the expression of PTEN although they induce a prominent apoptosis in
      Neuro-2a cells. In cerebellar granule neurons, okadaic acid treatment induced a
      prominent increase in PTEN mRNA expression after 6-h treatment, both at the 5.5-
      and 2.5-kb transcripts. The early response in PTEN mRNA expression disappeared in
      5.5-kb transcripts already at 12 h and in the case of 2.5-kb transcripts it
      lasted up to 24 h. Potassium deprivation, known to induce apoptosis in cerebellar
      granule cells, did not affect PTEN mRNA expression but together with serum
      deprivation induced a clear decrease in the 5. 5-kb PTEN transcripts. It seems
      that the changes in PTEN expression level and neuronal apoptosis are not related
      to each other in general but the expression of PTEN phosphatase seems to regulate
      certain apoptotic signals affecting phosphoinositide 3-kinase function.

PMID- 10581416
TI  - Formulation and evaluation of release and swelling mechanism of a water-in-oil
      emulsion using factorial design.
AB  - Water-in-oil emulsions have a potential as a parenteral prolonged release system
      for hydrophilic drugs. A consistent challenge when developing an emulsion drug
      delivery system is to obtain a proper release characteristic of the entrapped
      drug. The aim of the present study was to study the release mechanism from water
      in-oil emulsions. Secondly, to study the effects of droplet size, phase ratio and
      osmotic pressure on the release rate of glucose from water-in-oil emulsions in a
      factorial experimental design. The release mechanism of glucose was deduced from
      the release kinetics of two coentrapped marker molecules, glucose and inulin,
      with a molecule weight of 180 and 5000 g/mol, respectively. The results indicate
      that release of glucose was dominated by diffusion through the oily barrier as
      opposed to membrane rupture. Using statistical methodology, the release rate of
      glucose could be varied 8 fold in a controlled manner with osmotic pressure as
      the most important parameter. The osmotic behaviour of the emulsions was further
      studied in a dynamic swelling study. These results show that the release of
      entrapped hydrophilic drug can be controlled within certain limits using
      pharmaceutical formulation principles.

PMID- 10581418
TI  - Determination of unbound ceftriaxone in rat blood by on-line microdialysis and
      microbore liquid chromatography.
AB  - In vivo microdialysis was used to determine unbound ceftriaxone in rat blood. A
      microdialysis probe was inserted into the jugular vein/right atrium of Sprague
      Dawley rats, and dose of 10 mg/kg ceftriaxone was then administered via the
      femoral vein. Dialysates were automatically collected and injected into a liquid
      chromatographic system via an on-line injector. Isocratic elution of ceftriaxone
      within 10 min was achieved using a microbore liquid chromatographic system. The
      chromatographic mobile phase consisted of methanol-100 mM monosodium phosphoric
      acid (15:85, v/v, pH 7.0). The wavelength of the UV detector was set at 280 nm.
      Intra- and inter-assay accuracy and precision of the assay were less than 15%.
      The detection limit of ceftriaxone was 20 ng/ml. The results suggest that unbound
      ceftriaxone in rat blood is best fit to a biexponential decay model.

PMID- 10581417
TI  - Isothermal microcalorimetry and inverse phase gas chromatography to study small
      changes in powder surface properties.
AB  - It is known that processing can alter the surface energetics of powders. In this
      study a sample of drug has been processed by use of different drying techniques.
      The samples were then assessed using inverse phase gas chromatography. It was
      seen that the original material had a highest surface energy and the tray-dried
      sample had the lowest energy surface, other samples were intermediate. The use of
      isothermal microcalorimetry to study water sorption to the powders revealed that
      the surface of the original material was unstable, as the water sorption response
      changed on repeat cycling. The tray-dried sample did have a stable surface which
      gave the same sorption response on repeat exposure to water vapour. It was
      concluded that the drug had minor variations in surface energy, with the as
      received material being in a high energy unstable state, which could be due to it
      being partially amorphous. The tray-dried sample had a lower energy stable
      surface. In certain applications differences in surface energetics could be
      expected to lead to changes in processing nature of the powder, so these vapour
      sorption techniques offer a good way of providing an assurance of the same
      surface energy between batches of nay material which may be at risk.

PMID- 10581419
TI  - The back diffusion of glucose across human skin in vitro.
AB  - For diabetic patients, blood glucose monitoring is an important part in the
      management of their disease, however the acquisition of blood requires the use of
      invasive and often painful methods, and the development of a technique that
      removes these problems would represent a major advance. The uppermost membrane of
      the skin, the stratum corneum, has been shown to be the main barrier to
      percutaneous absorption, but there have been claims that polar water-soluble
      compounds diffuse across it via aqueous pathways. In this study, skin diffusion
      cells were used to investigate the back diffusion of tritiated water and the
      convective transport of 3H-glucose across full thickness human skin after the
      application of a number of different materials to the stratum corneum.
      Significant amounts of 3H-glucose back diffused only after complete removal of
      the stratum corneum by tape stripping, and it is likely that any future attempts
      to monitor blood glucose levels using non-physical techniques will require a
      certain degree of damage to the stratum corneum. The extraction through the skin
      of tritiated water and 3H-glucose after the application of solutions with
      different osmotic pressures were consistent with the theory that solutions with
      high osmotic pressures dehydrate the stratum corneum which suggests that passive
      transport of these radiolabelled molecules through porous pathways was
      insignificant.

PMID- 10581420
TI  - Response surface methodology as a predictive tool for determining the effects of
      preparation conditions on the physicochemical properties of
      poly(isobutylcyanoacrylate) nanoparticles.
AB  - Preparation conditions of nanoparticles greatly influence their physicochemical
      characteristics. A factorial design was used to evaluate the influence of these
      conditions on the particle diameter, zeta potential, polydispersity, percentage
      recovery, and molecular weight of poly(isobutylcyanoacrylate) nanoparticles. The
      relationship between these responses and the effects of simultaneously varying
      three preparation factors (monomer concentration, surfactant concentration, pH of
      the polymerization medium) were modelled by response-surface methodology. Three
      levels were chosen for each factor, giving 27 trials. The responses obtained in
      the experimental design were found to be modelled by either a reduced quadratic
      or second-order model. Particle diameter was found to be a function of the pH,
      whereas zeta potential depended on pH and to a lesser extent of the monomer
      concentration. Polydispersity depended on the pH and an interaction term between
      pH and the surfactant concentration. The particle recovery was significantly
      influenced by all three factors, whereas the pH was the primary influence on the
      molecular weight. Thus, response surface methodology gave detailed information on
      the predicted physicochemical characteristics found on
      poly(isobutylcyanoacrylate) nanoparticles prepared using a wide range of
      experimental conditions.

PMID- 10581421
TI  - Influence of lecithin on some physical chemical properties of poloxamer gels:
      rheological, microscopic and in vitro permeation studies.
AB  - Thermoreversible gels may be used in delivery systems which require a sol-gel
      transition at body temperature. The influence of the addition of lecithin, a
      permeation enhancer, on the rheological and in vitro permeation properties of
      poloxamer 407 gels was investigated. Light microscopy and rheological parameters
      were used to characterize the microscopic structure of the formulations which
      showed non Newtonian behaviour, pseudoplastic flow with a yield value. Increased
      concentrations of lecithin increased the thixotropy, yield value, apparent
      viscosity, and the gelation temperature of the gels. Light microscopy showed the
      formation of micellar structures by the addition of lecithin, which may account
      for changes in rheological properties. In vitro permeation of a model drug,
      triamcinolone acetonide, was decreased when the lecithin concentration was
      increased. The presence of lecithin in the poloxamer gel improved the
      characteristics for topical drug delivery.

PMID- 10581422
TI  - Pulsed release of nitroglycerin from transdermal drug delivery systems.
AB  - To achieve a discontinuous drug delivery to the skin a new actively controlled
      transdermal system has been developed. The system consists of a tube shaped drug
      reservoir in combination with an electronic circuit and a gas producing cell. A
      magnetic switch was used to control the onset of the production of hydrogen gas.
      The gas was generated with a constant rate. The tube reservoir was filled with a
      solution of nitroglycerin in propylene glycol. A discontinuous distribution of
      nitroglycerin in the reservoir is responsible for the pulsed release. 2, 3, 4, or
      6 fractions of nitroglycerin solution, which were separated from each other by
      sections with air, were filled into the tube reservoir. The release studies show
      that the release patterns directly reflect the number of doses, which were filled
      into the tube. A lag time of about 60 min was obtained, if the gas production is
      regulated by a 2.7 kOmega resistor. The drug is released during the pre
      programmed time intervals within 6-7 h. Between the time intervals no drug
      release occurs.

PMID- 10581423
TI  - A critical evaluation of the Heckel equation.
AB  - Great differences between published Heckel parameters, obtained from 'at
      pressure' data or the 'in-die' method, are outlined. The general validity of the
      concept of yield pressures derived from slopes of such Heckel plots is
      questioned. When the ability of the Heckel and the Walker equations is compared
      to fit density/pressure data from tabletting different pharmaceutical powders, a
      generally better fit is obtained with the Walker equation in the region of 5-100
      MPa. The ability to discriminate between materials by data from the compression
      phase is improved by using the Walker model. For Emcompress(R), apparent yield
      pressures derived from Heckel plots are dependent strongly on the maximum
      pressure of the compression process.

PMID- 10581424
TI  - Development and evaluation of a multiple-unit oral sustained release dosage form
      for S(+)-ibuprofen: preparation and release kinetics.
AB  - Mini-matrix tablets containing S(+)-ibuprofen have been prepared by the wet
      granulation method. The hydrophilic matrix was formed with either xanthan gum,
      karaya gum or hydroxymethylcellulose (HPMC) together with a choice of additives
      from lactose, Encompress(R), Avicel(R) PH101, talc and Lubritab(R). Multiple unit
      dosage forms (MUDFs) were subsequently obtained by encapsulating the mini-matrix
      tablets into hard gelatin capsules. Preparation, in vitro release profiles and
      release kinetics are presented.

PMID- 10581425
TI  - Influence of the preparation method on the physicochemical properties of binary
      systems of econazole with cyclodextrins.
AB  - Equimolar combinations of econazole, a very poorly water soluble antifungal
      agent, with beta-cyclodextrin and statistically substituted methyl-beta
      cyclodextrin were investigated for both solid state characterization
      (differential scanning calorimetry, hot-stage microscopy, infrared spectroscopy,
      scanning electron microscopy) and dissolution properties (dispersed amount
      method). The influence of the preparation method (physical mixing, ball-milling,
      kneading, sealed-heating) on the physicochemical properties of the products was
      evaluated. Kneading and sealed-heating techniques led to amorphous products in
      the case of systems with methyl-beta-cyclodextrin, whereas crystalline drug was
      still clearly detectable in all products with beta-cyclodextrin. Independently of
      the preparation technique, all combinations with methyl-beta-cyclodextrin yielded
      better performance than the corresponding ones with beta-cyclodextrin. However,
      the influence of the preparation method was clearly more marked for products with
      methyl-beta-cyclodextrin and made to be possible to better display the different
      performance of the examined carriers. In fact, the sealed-heated with the beta
      derivative showed an increase of drug dissolution efficiency of 130% with respect
      to the corresponding physical mixture, in comparison to the 70% increase obtained
      from that with beta-cyclodextrin. Moreover, whereas the difference in dissolution
      efficiency values between coground products was only about 8% in favor of the
      beta-derivative, it reached 80 and 90% between sealed-heated and kneaded
      products, respectively.

PMID- 10581426
TI  - Molecular localization and state of amphotericin B in PEG liposomes.
AB  - We investigated the molecular localization and state of amphotericin B (AmB)
      encapsulated in polyethylene glycol (PEG)-coated liposomes. AmB-encapsulating PEG
      liposomes composed of dipalmitoylphosphatidylcholine (DPPC), cholesterol (CH) and
      distearoyl-N-(monomethoxy poly(ethylene glycol)succinyl) phosphatidylethanolamine
      (DSPE-PEG, average MW of the PEG chain 2000) were prepared by hydration with 9%
      sucrose solution and extrusion. The amount of AmB encapsulated in the liposomes
      increased with incorporation of DSPE-PEG and decreased with that of CH. The
      molecular localization and state of AmB were investigated by PEG/dextran two
      phase partition, potassium permeability measurement, fluorescence quenching
      measurement and circular dichroism (CD) spectroscopy. The results suggest that
      there are two types of AmB localization in PEG-liposomes, one of which
      corresponds to the complex of AmB with DSPE-PEG on the membrane surface, while
      the other corresponds to the pore form of AmB in the hydrophobic core of the
      liposomal membrane. AmB in PEG liposomes was present in both aggregated and
      monomeric states.

PMID- 10581427
TI  - Primidone-loaded poly-epsilon-caprolactone nanocapsules: incorporation efficiency
      and in vitro release profiles.
AB  - This paper describes the preparation of primidone-loaded poly-epsilon
      caprolactone nanocapsules according to the interfacial deposition technique. The
      colloidal suspension obtained showed a monomodal size distribution with a mean
      diameter ranging from 308 to 352 nm. By adjusting the process parameters, the
      encapsulation efficiency was about 74% with good reproducibility. Primidone
      release from the nanocapsules was found to be slower as compared to the oily
      control solution despite an important burst-effect. The release profile was not
      influenced by the pH of the release medium.

PMID- 10581428
TI  - Kinetics of in vitro release of a model nucleoside deoxyuridine from crosslinked
      insoluble collagen and collagen-gelatin microspheres.
AB  - The objective of this research is to investigate the effect of highly crosslinked
      insoluble collagen and collagen-gelatin hybrid matrices as platforms for
      controlled release of a highly water soluble model nucleoside, deoxyuridine as
      well as a high molecular weight model compound fluoroscienisothoicyanate (FITC)
      dextran. Collagen and gelatin can be considered as biodegradable proteinous
      materials. Microspheres of deoxyuridine and FITC-dextran were prepared by
      emulsification solvent evaporation technique using collagen alone and collagen
      gelatin combination. The microencapsulation efficiency, particle size and in
      vitro release profiles were compared. Microencapsulation efficiency of
      approximately 10% was obtained with collagen while 20% encapsulation efficiency
      was obtained when collagen was used in combination with gelatin. Particle size
      range became wider when only collagen was used as compared to collagen-gelatin
      combination. A slower release profile was observed for crosslinked as compared to
      noncrosslinked microspheres. This study demonstrated diffusion controlled release
      of both compounds from the two polymers used. A good correlation was obtained
      between theoretically predicted and experimentally obtained in vitro release
      rates for both deoxyuridine and FITC-dextran using Higuchi's square root model.

PMID- 10581429
TI  - Enhanced inhibition of platelet aggregation in-vitro by niosome-encapsulated
      indomethacin.
AB  - In order to achieve sustained antiplatelet effect from indomethacin, it was
      incorporated in a non-ionic surfactant vesicle (niosome). The objective was to
      study the effect of niosomal-encapsulated indomethacin on platelet function such
      as inhibition of aggregation and ATP release induced by a variety of agonists
      (adenosine 5'-diphosphate (ADP), epinephrine, arachidonic acid, ristocetine) and
      to explore the feasibility of carrier-mediated drug delivery to the platelets.
      Multilamellar vesicles (niosomes) were prepared from Tween-60 by the lipid
      hydration method. Freshly prepared human platelet rich plasma (PRP) was used for
      aggregation/inhibition studies, the extent of which was observed as a change in
      light transmission measured by the Chronolog Aggregometer. The percent inhibition
      of aggregation induced by the agonist ADP ranged from 28. 21+/-0.28 at the 2.0
      micromol level to 92.6+/-1.20 at 12.7 micromol of the encapsulated drug while the
      same concentrations of the drug inhibited aggregation only to the extent of
      13.75+/-0.13 and 36. 82+/-0.57%, respectively. A 100% inhibition of aggregation
      induced by arachidonic acid was achieved by niosomal indomethacin while
      inhibition by the free drug was 41.9% at equimolar concentrations. ATP release
      study showed that 100% inhibition was achieved by 8 micromol of the encapsulated
      drug while inhibition by the free drug was 40.00+/-1.82%. Therefore, at equimolar
      doses, the niosomal drug proved to be more efficient in inhibiting platelet
      aggregation than the free drug, probably due to greater quantity of the drug
      reaching the specific site of inhibition in the interior of the platelets and
      acting directly on the cyclo-oxygenase system to prevent thromboxane formation.

PMID- 10581430
TI  - Characterization of recombinant strains of the Clostridium acetobutylicum
      butyrate kinase inactivation mutant: need for new phenomenological models for
      solventogenesis and butanol inhibition?
AB  - Two metabolic engineering tools, namely gene inactivation and gene
      overexpression, were employed to examine the effects of two genetic modifications
      on the fermentation characteristics of Clostridium acetobutylicum. Inactivation
      of the butyrate kinase gene (buk) was examined using strain PJC4BK, while the
      combined effect of buk inactivation and overexpression of the aad gene-encoding
      the alcohol aldehyde dehydrogense (AAD) used in butanol formation-was examined
      using strain PJC4BK(pTAAD). The two strains were characterized in controlled pH >
      or = 5.0 fermentations, and by a recently enhanced method of metabolic flux
      analysis. Strain PJC4BK was previously genetically characterized, and
      fermentation experiments at pH > or = 5.5 demonstrated good, but not exceptional,
      solvent-production capabilities. Here, we show that this strain is a solvent
      superproducer in pH > or = 5.0 fermentations producing 225 mM (16.7 g/L) of
      butanol, 76 mM of acetone (4.4 g/L), and 57 mM (2.6 g/L) of ethanol. Strain
      PJC4BK(pTAAD) produced similar amounts of butanol and acetone but 98 mM (4.5 g/L)
      of ethanol. Both strains overcame the 180 mM (13 g/L) butanol toxicity limit,
      without any selection for butanol tolerance. Work with strain PJC4BK(pTAAD) is
      the first reported use of dual antibiotic selection in C. acetobutylicum. One
      antibiotic was used for selection of strain PJC4BK while the second antibiotic
      selected for the pTAAD presence. Overexpression of aad from pTAAD resulted in
      increased ethanol production but did not increase butanol titers, thus indicating
      that AAD did not limit butanol production under these fermentation conditions.
      Metabolic flux analysis showed a decrease in butyrate formation fluxes by up to
      75% and an increase in acetate formation fluxes of up to 100% during early
      growth. The mean specific butanol and ethanol formation fluxes increased
      significantly in these recombinant strains, up to 300% and 400%, respectively.
      Onset of solvent production occurred during the exponential-growth phase when the
      culture optical density was very low and when total and undissociated butyric
      acid levels were <1 mM. Butyrate levels were low throughout all fermentations,
      never exceeding 20 mM. Thus, threshold butyrate concentrations are not necessary
      for solvent production in these stains, suggesting the need for a new
      phenomenological model to explain solvent formation.

PMID- 10581431
TI  - Adsorption of thermomonospora fusca E(5) cellulase on silanized silica.
AB  - The adsorption kinetics and dodeceyltrimethylammonium-bromide-mediated elution of
      Thermomonospora fusca E(5) cellulase were recorded in situ, at hydrophobic,
      silanized silica. Experiments were performed at different solution
      concentrations, ranging from 0.001 to 0.70 mg/mL. Plateau values of adsorbed mass
      generally increased with increasing solution concentration, with the adsorbed
      layer being only partially eluted by buffer. Treatment with surfactant removed
      more of the adsorbed enzyme in each case, with the remaining adsorbed mass
      varying little among experiments. Adsorption of E(5) into this nonremovable state
      was suggested to occur early in the adsorption process and continue until some
      critical surface concentration was reached. Beyond this critical value of
      adsorbed mass, adsorption progressed with the protein adopting more loosely bound
      states. Adsorption kinetic data were interpreted with reference to an adsorption
      mechanism allowing for irreversible adsorption into two dissimilar states. These
      states were distinguished by differences in occupied interfacial area, and
      binding strength, presumably a result of differences in structure. Comparison of
      the data to the kinetic model based on this mechanism showed that the fraction of
      adsorbed molecules present in the more tightly bound state decreased as
      adsorption occurred from solutions of increasing concentration. However, the
      absolute values of more tightly bound molecules were less dependent on adsorption
      conditions.

PMID- 10581432
TI  - Modeling of biological processes using self-cycling fermentation and genetic
      algorithms.
AB  - Self-cycling fermentation (SCF) was coupled with a genetic algorithm (GA) to
      provide a simple system for evaluating biological models. The SCF provided the
      necessary system excitation and data "richness" required to completely define the
      fitted biological models. The solution scheme based on the GA avoided the
      computational difficulties often associated with calculus-based nonlinear
      regression techniques, resulting in rapid and accurate convergence. After
      validating the mathematical approach, data from the SCF obtained under
      denitrifying conditions were fitted successfully to an established model using
      the GA. Finally, data obtained in the SCF for the removal of phenol were used to
      compare multiple models. This work suggests that the SCF, in conjunction with the
      GA, provides a coherent system that can facilitate the characterization of
      biological systems.

PMID- 10581433
TI  - Multiple steady states with distinct cellular metabolism in continuous culture of
      mammalian cells.
AB  - Mammalian cells have the ability to proliferate under different nutrient
      environments by utilizing different combinations of the nutrients, especially
      glucose and the amino acids. Under the conditions often used in in vitro
      cultivation, the cells consume glucose and amino acids in great excess of what is
      needed for making up biomass and products. They also produce large amounts of
      metabolites with lactate, ammonia, and some non-essential amino acids such as
      alanine as the most dominant ones. By controlling glucose and glutamine at low
      levels, cellular metabolism can be altered and can result in reduced glucose and
      glutamine consumption as well as in reduced metabolite formation. Using a fed
      batch reactor to manipulate glucose at a low level (as compared to a typical
      batch culture), cell metabolism was altered to a state with substantially reduced
      lactate production. The culture was then switched to a continuous mode and
      allowed to reach a steady-state. At this steady-state, the concentrations of
      cells and antibody were substantially higher than a control culture that was
      initiated from a batch culture without first altering cellular metabolism. The
      lactate and other metabolite concentrations were also substantially reduced as
      compared to the control culture. This newly observed steady-state was achieved at
      the same dilution rate and feed medium as the control culture. The paths leading
      to the two steady-states, however, were different. These results demonstrate
      steady-state multiplicity. At this new steady-state, not only was glucose
      metabolism altered, but the metabolism of amino acids was altered as well. The
      amino acid metabolism in the new steady-state was more balanced, and the
      excretion of non-essential amino acids and ammonia was substantially lower. This
      approach of reaching a more desirable steady-state with higher concentrations of
      cells and product opens a new avenue for high-density- and high-productivity-cell
      culture.

PMID- 10581434
TI  - Mathematical description of microbiological reactions involving intermediates.
AB  - Stoichiometric relationships for biological reactions involving intermediate
      formation are developed from microbial reaction fundamentals and thermodynamic
      principles. Biological reactions proceed through intermediates, which sequester
      carbon and electrons whenever their degradation is relatively slow. Modeling
      intermediate formation and subsequent utilization requires evaluation of the
      distribution of electrons, energy, and macronutrients (C and N) between energy
      generating pathways and cell-synthesis pathways for each step in the
      mineralization of the primary electron-donor substrate. We describe how energy
      and electron balances are utilized to predict the stoichiometry for each step of
      a multi-step degradation process. Each stoichiometric relationship developed
      predicts substrate utilization, cell growth, and the formation of other products
      (e.g., H(2)CO(3) or H(+)) for one step in the pathway to full mineralization. A
      modeling example demonstrates how different kinetics for each step in the
      degradation of nitrilotriacetic acid (NTA) leads to observed patterns in
      experimental results, such as a delay in the release of H(2)CO(3) after NTA is
      removed from solution.

PMID- 10581435
TI  - Diffusion coefficients of metabolites in active biofilms.
AB  - Diffusion coefficients of actual metabolites in completely active biofilms can be
      determined by applying a new concept that is based on a constant local activity
      in the entire biofilm. In that case, a concentration step will be transmitted
      unattenuated. Subsequently, the diffusion coefficient can be calculated from the
      response monitored with a microelectrode positioned in the biofilm without
      quantitative knowledge of the local microbial kinetics. The conditions required
      for such a constant microbial biofilm activity were formulated in terms of the
      Thiele modulus and the substrate concentration in the bulk liquid. This proposed
      method was successfully applied to determine diffusion coefficients of oxygen and
      glucose in agar gels containing various fractions of active immobilized
      microorganisms. The values obtained were compared to experimental results from
      well-defined inert systems. The transient response of oxygen was far more
      affected by the presence of the immobilized cells than glucose. This can be
      explained by partition of the diffusing solute between the microbial cells and
      the aqueous phase.

PMID- 10581436
TI  - The effect of inoculum density and conditioned medium on the production of
      ajmalicine and catharanthine from immobilized Catharanthus roseus cells.
AB  - The effect of the cell-inoculum size and the addition of conditioned medium on
      ajmalicine and catharanthine production were studied using immobilized
      Catharanthus roseus cells. Higher specific-uptake rates of ammonium, nitrate, and
      sugars were observed in the low-inoculum-density cultures (50 g FW/L) compared to
      the high-inoculum-density cultures (100 g FW/L). Alkaloid production was not
      correlated with the exhaustion of a particular nutrient from the medium. The high
      inoculum-density cultures produced higher ajmalicine concentrations throughout
      the experiment. Catharanthine production was similar between the two inoculum
      density cultures. The addition of conditioned medium to MS-production medium
      dramatically improved the production of ajmalicine and catharanthine. The
      addition of conditioned medium enhanced ajmalicine production from immobilized
      Catharanthus roseus cultures on day 15 by at least two- to fourfold compared to
      media without the conditioning factors. Catharanthine production was increased by
      nearly fivefold in cultures with conditioned medium compared to those without
      conditioned medium. The enhancing effects of conditioned medium on alkaloid
      production were attributed to an unidentified factor produced and secreted by
      suspension cultures of C. roseus. The presence of conditioned medium also
      decreased the sucrose hydrolysis rate. The ajmalicine concentration in these
      immobilized cell cultures was found to be a function of the fresh-weight
      concentration, irrespective of the inoculum density or the culture medium. The
      medium choice and the inoculum density determined how rapidly fresh weight was
      accumulated and thus, how quickly ajmalicine was produced. Ajmalicine production
      correlated positively with fresh-weight concentration, but catharanthine
      production was not correlated with fresh-weight concentration.

PMID- 10581437
TI  - Biodesulfurization of dibenzothiophene in Escherichia coli is enhanced by
      expression of a Vibrio harveyi oxidoreductase gene.
AB  - One possible alternative to current fuel hydrodesulfurization methods is the use
      of microorganisms to remove sulfur compounds. Biodesulfurization requires much
      milder processing conditions, gives higher specificity, and does not require
      molecular hydrogen. In the present work we have produced two compatible plasmids:
      pDSR3, which allows Escherichia coli to convert dibenzothiophene (DBT) to
      hydroxybiphenyl (HBP), and pDSR2, which produces a Vibrio harveyi flavin
      oxidoreductase. We show that the flavin oxidoreductase enhances the rate of DBT
      removal when co-expressed in vivo with the desulfurization enzymes. The plasmids
      pDSR2 and pDSR3 were co-expressed in growing cultures. The expression of
      oxidoreductase caused an increase in the rate of DBT removal but a decrease in
      the rate of HBP production. The maximum rate of DBT removal was 8 mg/h. g dry
      cell weight. Experiments were also conducted using resting cells with the
      addition of various carbon sources. It was found that the addition of glucose or
      glycerol to cultures with oxidoreductase expression produced the highest DBT
      removal rate (51 mg/h. g dry cell weight). The culture with acetate and no
      oxidoreductase expression had the highest level of HBP production. For all carbon
      sources, the DBT removal rate was faster and the HBP generation rate slower with
      the expression of the oxidoreductase. Analysis of desulfurization intermediates
      indicates that the last enzyme in the pathway may be limiting.

PMID- 10581438
TI  - Nitrogen removal reactor using packed gel envelopes containing Nitrosomonas
      europaea and Paracoccus denitrificans.
AB  - Packed gel envelopes were constructed as simple, compact reactors for removing
      nitrogen from wastewater. Each packed gel envelope consisted of two plate gels
      with a spacer in between. Nitrosomonas europaea and Paracoccus denitrificans were
      co-immobilized in the plate gels, and ethanol, serving as an electron donor for
      denitrification, was injected into the internal spaces of the envelopes. The
      external surfaces of the envelopes were in contact with ammonia-containing
      wastewater; the N. europaea present in the gels oxidized the ammonia to nitrite
      aerobically. On the other hand, the internal surfaces of the envelopes were in
      contact with the ethanol solution, which P. denitrificans used to reduce the
      nitrite to nitrogen gas anaerobically. In this way, the reactor using the packed
      gel envelopes removed ammonia from wastewater in a single step. When artificial
      wastewater containing 200 mg-N/L was treated using the reactor using eight
      envelopes, the ammonia was removed by the reactor without accumulating nitrite or
      ethanol. This simple system exhibited high rates of nitrification (ammonia to
      nitrite; 1.9 kg-N/day for 1m(3) of reactor volume) and nitrogen removal (ammonia
      to nitrogen gas; 1.6 kg-N/day). It is presumed that these high rates were
      achieved as a consequence of cooperation between the N. europaea and P.
      denitrificans present in the gels and the efficient uptake and exhaust of gases
      leading to the smooth conversion of ammonia to nitrogen gas.

PMID- 10581439
TI  - The rational design of semisynthetic peroxidases.
AB  - A semisynthetic peroxidase was designed by exploiting the structural similarity
      of the active sites of vanadium dependent haloperoxidases and acid phosphatases.
      Incorporation of vanadate ion into the active site of phytase (E.C. 3.1.3.8),
      which mediates in vivo the hydrolysis of phosphate esters, leads to the formation
      of a semisynthetic peroxidase, which catalyzes the enantioselective oxidation of
      prochiral sulfides with H(2)O(2) affording the S-sulfoxide, e.g. in 66% ee at
      100% conversion for thioanisole. Under reaction conditions the semi-synthetic
      vanadium peroxidase is stable for over 3 days with only a slight decrease in
      turnover frequency. Polar water-miscible cosolvents, such as methanol, dioxane,
      and dimethoxyethane, can be used in concentrations of 30% (v/v) at a small
      penalty in activity and enantioselectivity. Among the transition metal oxoanions
      that are known to be potent inhibitors, only vanadate resulted in a semisynthetic
      peroxidase when incorporated into phytase. A number of other acid phosphatases
      and hydrolases were tested for peroxidase activity, when incorporated with
      vanadate ion. Phytases from Aspergillus ficuum, A. fumigatus, and A. nidulans,
      sulfatase from Helix pomatia, and phospholipase D from cabbage catalyzed
      enantioselective oxygen transfer reactions when incorporated with vanadium.
      However, phytase from A. ficuum was unique in also catalyzing the
      enantioselective sulfoxidation, albeit at a lower rate, in the absence of
      vanadate ion.

PMID- 10581440
TI  - Stable recombinant expression of the anti HIV-1 monoclonal antibody 2F5 after
      IgG3/IgG1 subclass switch in CHO cells.
AB  - The human monoclonal antibody (humAb) 2F5 is a potent candidate for immunotherapy
      of HIV-1. The xenohybridoma derived humAb 2F5 is of IgG3 kappa isotype.
      Generally, IgG1 isotype has a longer half-life (beta-clearance) in humans than
      IgG3. Therefore the isotype was switched to an IgG1 by ligation of the 2F5 heavy
      chain variable region to an IgG1 constant region and expressed as IgG1 kappa in
      CHO cells. CHO clones have been established, which stably express humAb 2F5 at
      high levels. The specificity, affinity and in vitro function of both isotypes
      were identical.

PMID- 10581441
TI  - Self-assembly of the infectious bursal disease virus capsid protein, rVP2,
      expressed in insect cells and purification of immunogenic chimeric rVP2H
      particles by immobilized metal-ion affinity chromatography.
AB  - A gene encoding a structural protein (VP2) of a local strain (P3009) of
      infectious bursal disease virus (IBDV) was cloned and expressed using the
      baculovirus expression system to develop a subunit vaccine against IBDV infection
      in Taiwan. The expressed rVP2 proteins formed particles of approximately 20-30 nm
      in diameter. Those particles were partially purified employing sucrose density
      gradient ultracentrifugation, and the purified particles were recognized by a
      monoclonal antibody against the VP2 protein of IBDV P3009. To facilitate the
      purification of the particles, the VP2 protein was engineered to incorporate a
      metal ion binding site (His)(6 )at its C-terminus. The chimeric rVP2H proteins
      also formed particles, which could be affinity-purified in one step with
      immobilized metal ions (Ni(2+)). Particle formation was confirmed by direct
      observation under the electron microscope. The production level of rVP2H protein
      was determined to be 20 mg/L in a batch culture of Hi-5 cells by quantifying the
      concentration of the purified proteins. The chicken protection assay was
      performed to evaluate the immunogenicity of the rVP2H protein. When susceptible
      chickens were inoculated with the recombinant rVP2H proteins (40 microg/bird),
      virus-neutralizing antibodies were induced, thereby conferring a high level of
      protection against the challenge of a very virulent strain of IBDV. In
      conclusion, the most significant finding in this work is that both of the
      expressed rVP2 and rVP2H proteins can form a particulate structure capable of
      inducing a strong immunological response in a vaccinated chicken.

PMID- 10581442
TI  - Intrinsic effects of solvent polarity on enzymic activation energies.
AB  - The effect of organic solvents on subtilisin Carlsberg catalysis has been
      investigated with the aid of a thermodynamic analysis. Saturation solubility
      experiments were performed to provide a quantitative measure of substrate
      desolvation from the reaction medium. This enabled calculation of the intrinsic
      enzymic activation energy and resulted in a linear free energy relationship with
      respect to solvent polarity. The results indicate that the intrinsic activation
      energy of subtilisin catalysis is lowest in polar organic solvents, which may be
      due to transition state stabilization of the enzyme's polar transition state for
      transesterification.

PMID- 10581443
TI  - Controlled electrophoretic deposition of bacteria to surfaces for the design of
      biofilms.
AB  - In this report, the formation of ordered clusters of both spherical and rod
      shaped bacteria on an electrode during electrophoretic deposition is described.
      Inside clusters, adhering bacteria are regularly spaced with an interbacterial
      distance that can be controlled by adjusting the ionic strength of the suspending
      solution and the DC density used. Formed clusters can be immobilized on the
      surface by applying a sufficiently high current density. This method enables the
      design of bacterial biofilms for biotechnological and biomedical applications.
      When AC fields were used, rod-shaped bacteria adhering on the electrode were seen
      to align parallel to the applied field.

PMID- 10581444
TI  - Genetic improvement of Aspergillus carbonarius for pectinase overproduction
      during solid state growth.
AB  - Low pectinase production by Aspergillus carbonarius growing on wheat bran solid
      substrate was found to be due to reduced colonizational ability of the fungus.
      Since A. niger showed higher growth rates on wheat bran, strain improvement to
      obtain higher pectinase production in solid state was carried out by inter
      specific fusion of protoplasts of A. carbonarius and A. niger. One of the mutants
      selected for higher activities of alpha-glucosidase showed improved growth rates
      on wheat bran solid substrate together with increased pectinase production. Size
      similarities of amplified polymorphic DNA of the mutant with the two parents and
      identification of a 66 kDa polygalacturonase specific to A. niger suggested
      genetic recombination in the mutant.

PMID- 10581461
TI  - Neurogenesis and identification of developing layers in the visual cortex of the
      wallaby (Macropus eugenii).
AB  - Birthdates of the neurons that comprise the layers of the mature visual cortex in
      the wallaby (Macropus eugenii) have been determined with the aid of tritiated
      thymidine autoradiography. The laminar positions of cells, identified by their
      birthdates, have then been followed at early stages during development and
      compared with previously published data on the distribution of thalamocortical
      afferents and corticothalamic projecting cells (Sheng et al. [1991] J. Comp.
      Neurol. 307:17-38). Neurons are born in a deep to superficial sequence typical of
      other mammals. The loosely packed zone of cells, which develops at the base of
      the thin compact zone of cells at the superficial margin of the cortical plate
      early in development, was identified as being part of the cortical plate.
      Afferents did not wait below this zone but grew into the developing cortical
      layers immediately after the cells that form these layers began accumulating in
      the loosely packed zone, starting with layer 6 on postnatal day 22 (P22). The
      genesis of layer 4 did not begin until P32, and these cells reached the
      superficial cortical plate at P54 and entered the loosely packed zone by P65.
      Cells of layers 5 and 6 formed the initial projection to the thalamus. Despite
      the protracted development of the wallaby and the large discrepancy between the
      time of thalamic ingrowth and genesis of layer 4, there was no extended waiting
      period for afferents in the subplate.

PMID- 10581462
TI  - Structural changes at cut ends of earthworm giant axons in the interval between
      dye barrier formation and neuritic outgrowth.
AB  - We describe structural changes at the cut ends of invertebrate myelinated
      earthworm giant axons beginning with the formation of a dye barrier (15 minutes
      posttransection or postcalcium addition) and ending with the formation of a
      neuritic outgrowth (2-10 days posttransection). The morphology of the cut end,
      and the location and morphological configuration of the dye barrier, were
      assessed by time-lapse confocal, fluorescence microscopy and by electron
      microscopy. During the interval from 15 to 35 minutes postcalcium addition, the
      dye barrier continuously migrated away from a cut axonal end; the dye barrier
      then remained stable for up to 5 hours. The size, packing density, and
      arrangement of membranous structures were correlated with changes in the dye
      barrier from 15 to 35 minutes postcalcium addition. During this interval, uptake
      of an externally placed hydrophilic dye by these membranous structures was also
      variable. After 35 minutes postcalcium addition, the membranous structures
      remained stable until they completely disappeared between 1 and 2 days
      posttransection. The disappearance of membranous structures always preceded
      neuritic outgrowth, which only arose from cut axonal ends. These results
      demonstrate that the dye barrier and associated membranous structures, which form
      after transection of earthworm giant axons, are very dynamic in the short term
      (35 minutes) with respect to their location and morphological configuration and
      suggest that axolemmal repair must be completed before neuritic outgrowth can
      occur.

PMID- 10581463
TI  - Synaptic localization of GABA(A) receptor subunits in the striatum of the rat.
AB  - The inhibitory amino acid gamma-aminobutyric acid (GABA) is widely distributed in
      the basal ganglia. It plays a critical role in the functioning of the striatum as
      it is the transmitter of projection neurons and sub-populations of interneurons,
      as well as afferents from the globus pallidus. Some of the factors controlling
      GABA transmission are the type(s) of GABA receptor expressed at the site of
      transmission, their subunit composition, and their location in relation to GABA
      release sites. To address these issues, we examined the sub-cellular localization
      of subunits of the GABA(A) receptor in the striatum of the rat. Sections of
      freeze-substituted, Lowicryl-embedded striatum were immunolabelled by the post
      embedding immunogold technique with antibodies specific for subunits of the
      GABA(A) receptor. Immunolabelling for alpha1, beta2/3, and gamma2 GABA(A)
      receptor subunits was primarily located at symmetrical synapses on perikarya,
      dendrites, and spines. Quantitative analysis of the distribution of
      immunolabelling for the beta2/3 subunits revealed that the majority of membrane
      associated immunogold particles were at synapses and that, on average for the
      whole population, they were evenly distributed across the synapse. Double
      labelling for the beta2/3 subunits and for GABA itself revealed that receptor
      positive synapses were formed by at least two populations of terminals. One
      population (59.3%) of terminals forming receptor-positive synapses was positive
      for GABA, whereas the other (40.7%) had low or undetectable levels of GABA.
      Furthermore, the post-synaptic neurons were characterised on neurochemical and
      morphological grounds as both medium spiny neurons and GABA interneurons. Triple
      immunolabelling revealed the co-localization of alpha1, beta2/3, and gamma2
      subunits at some symmetrical axodendritic synapse. It is concluded that fast
      GABA(A)-mediated transmission occurs primarily at symmetrical synapses within the
      striatum, that the populations of boutons giving rise to receptor-positive
      synapses are heterogeneous, and that previously reported co-existence of
      different subunits of the GABA(A) receptor at the cellular level also occurs at
      the level of individual synapses.

PMID- 10581464
TI  - Plasticity of the auditory brainstem: cochleotomy-induced changes of calbindin
      D28k expression in the rat.
AB  - Calbindin is a calcium binding protein that is characteristically expressed in
      several auditory brainstem nuclei during ontogeny and is thought to serve as a
      buffer, protecting cells against toxic levels of calcium. Upon maturation,
      calbindin is drastically reduced or entirely lost in many auditory nuclei. We
      made cochleotomies in mature rats to study effects of deafening and
      deafferentation on the expression of calbindin in the auditory brainstem.
      Following unilateral cochleotomy, we observed a substantial increase in the
      number of calbindin-immunoreactive fibers and boutons in the ventral subdivisions
      of the ipsilateral cochlear nucleus. At the same time, calbindin-positive
      astrocytes emerged in the dorsal and ventral cochlear nucleus. Beyond the
      immediately affected ipsilateral cochlear nucleus, we found calbindin-positive
      neurons in the lateral superior olive and in the central inferior colliculus,
      both contralateral to the operation. The loss of one cochlea reduces auditory
      input and puts the flow of neuronal activity originating in the two ears out of
      balance. Our findings indicate that the need for the neuronal networks in the
      auditory brainstem to adjust to this drastically changed pattern of sensory
      signals invokes the expression of calbindin in glial cells as well as in directly
      and indirectly affected neuronal cell populations.

PMID- 10581465
TI  - Retinal projections throughout optic nerve regeneration in the ornate dragon
      lizard, Ctenophorus ornatus.
AB  - In goldfish and frog, optic nerve regeneration is successful, with restoration of
      retinotopic projections in visual brain centres and the return of functional
      vision within 1-2 months. By contrast, at 1 year after unilateral optic nerve
      crush in the ornate dragon lizard (Ctenophorus ornatus), the regenerated
      retinotectal projections lack topographic order, presumably explaining why the
      lizards are blind via the experimental eye (Beazley et al. [1997] J. Comp.
      Neurol. 377:105-120). To determine whether other abnormalities are associated
      with the inability to restore topographic projections in the lizard, we charted
      anatomically the time course, accuracy, and stability of optic nerve regeneration
      by examining visual projections with the lipophillic dye 1,1'-dioctadecyl-3,3,3',
      3'-tetramethylindocarbocyanine perchlorate (DiI) applied to the optic disk at
      intervals up to 1 year after optic nerve crush; in addition, DiI tracing of small
      groups of axons was used to examine the topicity of axons projecting to the
      tectum. Axons re-innervated visual centres from between 1 and 2 months, a time
      frame comparable with that in goldfish and frog. However, the projections in
      lizard were found to differ from those in goldfish and frog in three major ways.
      First, there was considerable variability within the projection patterns both
      between individual lizards at any one stage and with time. Second, the
      projections were inaccurate. As in normal lizards, the major projection was to
      the contralateral optic tectum, although it lacked detectable retinotopic axon
      order throughout. Furthermore, misrouting occurred such that regenerating axons
      formed a persistent projection to the ipsilateral side of the brain that was
      considerably stronger and more widespread than normal. Minor visual centres also
      became re-innervated but, in addition, regenerating axons formed persistent
      projections into the opposite optic nerve and to non-retino-recipient regions
      such as the nucleus rotundus, hypothalamus, and olfactory nerve, as well as the
      posterior and tectal commissures. Third, the projections appeared unstable.
      Projections to both tecta were strongest between 3 and 5 months, but they
      diminished thereafter. The results suggest that, compared with goldfish and frog,
      in lizards both pathway and target cues are degraded and/or cannot be read
      adequately; as a consequence, regenerating axons are unable to navigate
      exclusively to visual centres and cannot re-form stable connections.

PMID- 10581466
TI  - Expression of the netrin-1 receptor, deleted in colorectal cancer (DCC), is
      largely confined to projecting neurons in the developing forebrain.
AB  - Axon guidance mechanisms are crucial to the development of an integrated nervous
      system. One family of molecules that may be important in establishing axonal
      connectivity in mammals is the Netrins, and their putative receptors DCC (deleted
      in colorectal cancer), Neogenin, and Unc-5. Knockout and mutational analyses of
      some of these genes have shown that they are critically involved in the
      development of several specific pathways in the developing brain. However,
      previous expression analyses of these genes have largely been confined to the
      developing spinal cord. In the present study, we analyzed the expression of DCC
      in the developing mouse forebrain. We found that DCC protein is expressed in
      specific axonal populations projecting from the developing olfactory bulb,
      neocortex, hippocampus, and epithalamus/habenular complex. In the developing
      olfactory bulb and neocortex, DCC expression is particularly evident during the
      targeting phase of axon outgrowth and is then rapidly downregulated. As predicted
      from the knockout and mutational analyses of this gene, DCC is expressed in
      axonal commissures, in particular the corpus callosum, hippocampal commissure,
      and the anterior commissure. In addition, we found that DCC is expressed in the
      habenular commissure, the fasciculus retroflexus, and the stria medularis.
      Therefore, this analysis implicates a function for DCC in additional axonal
      guidance systems not predicted from the knockout and mutational analyses.

PMID- 10581467
TI  - Unequal representation of the temporal and nasal retina in an anomalous
      projection to the lateral thalamus.
AB  - Study of an anomalously regenerated, nontopographically organized retinal
      projection in the frog olfactory cortex revealed that the temporal retina is the
      main source of this projection, suggesting the existence of specific temporal
      fiber-directed attractant or trophic influences. In the present study, we
      examined the organization of an anomalous retinal projection that forms in the
      frog thalamus after ablation of the optic tectum. The projections from different
      sectors of the retina were studied by means of the anterograde transport of
      biotinylated dextran-amine (BDA) delivered to incisions made across the nerve
      fiber layer in frogs surviving ablation of the contralateral tectal hemisphere
      for 13-46 weeks. The projections from nasal retinal sectors were always lightly
      constructed in the aberrant terminal field, whereas their projections to the
      lateral geniculate complex remained reasonably strong. In contrast, the
      projections from temporal retinal sectors, though also weak initially, in time
      became robust and filled the aberrant field over most of its extent. The specific
      amplification of the temporal fiber projection now observed in two foreign
      targets provides further evidence for the existence of target-based,
      attractant/trophic molecules with functional specificity for temporal retinal
      fibers. That such agents can exist or be inducible in a foreign area would
      suggest that they belong to a family of molecules having natural biological
      activity in normal development or regeneration. However, the possibility that the
      augmented role of the temporal retina in these projections is a result of
      experience-based plasticity is also discussed.

PMID- 10581468
TI  - Patterns of corticocortical, corticotectal, and commissural connections in the
      opossum visual cortex.
AB  - Patterns of connections of the visual cortex of the South American opossum,
      Didelphis aurita, were revealed by using neuronal tracers to identify and
      characterize visual specializations of the peristriate cortex (PS). The visuotopy
      of corticotectal connections of the anterolateral portion of PS (PSal) is
      symmetrical to that of the striate cortex (ST or primary visual area [V1]). Three
      consecutive bands of commissural connections coincide, respectively, with the ST
      PS border, the limit between the caudal and rostral PSal halves (PSc and PSr),
      and the border of PS with the parietal and temporal cortices. PSc and PSr contain
      regular commissural rings similar to those present in the peristriate cortex of
      eutherian mammals. ST projections define in PSc two strings of periodical foci
      consecutively concentric to V1 and a single focus in PSr. Although they were
      organized topographically, ascending, descending, and commissural connections
      between ST and PSal showed a high degree of convergence and divergence. These
      results conform to the model of a single area homologous to the second visual
      area (V2) bordering V1. Moreover, they suggest the possibility that PSal includes
      either one or two additional belt-like areas successively anterior to V2. Along
      with the finding of alternating bands of high and low cytochrome oxidase activity
      in PSal, the data further suggest that this region contains modular
      specializations similar to those of the peristriate cortex of primates and other
      eutherian mammals. The posterolateral peristriate cortex (PSpl) constitutes
      another visual area, since it consists of a distinct focus of reciprocal
      corticocortical and interhemispheric connections and a separate source of
      corticotectal projections. Finally, a visuomotor function for the orbital cortex
      is proposed based on its direct projections to optical tectal layers. The close
      cladistic relationship of opossums to mammalian ancestral forms suggests that the
      PSal parcelation into belt-like areas that contain modules reflects the primitive
      organization of the visual cortex. Moreover, a highly diffuse pattern of
      corticocortical connections may represent a requirement for a brain with few
      visual areas to perform global processing.

PMID- 10581469
TI  - Central complex in the brain of crayfish and its possible homology with that of
      insects.
AB  - A small, medial heterolateral neuropil in the brain of crustaceans has long been
      regarded as the central body of the crustacean brain. Its simplicity and the
      absence of clear layers within its neuropil have led to the question of its
      homology with the more complex central body that occupies an approximately
      equivalent position in the brain of insects. We have labelled neurons in the
      central body of the Australian freshwater crayfish Cherax destructor by the
      extracellular application of dextrans and by treating the brain with antibodies
      to anti-CCAP, anti-locustatachykinin, anti-perisulfakinin, anti-proctolin, anti
      dip-allatostatin AI, anti-PEA-head-peptide, anti-serotonin, and anti-rabbit anti
      substance P, all of which label neurons in the insect brain. The dextran and
      immunocytochemical labelling have revealed a neural complex associated with the
      crayfish central body that is very similar in overall anatomical architecture to
      the subset of neuropils that are incorporated in the central complex of the
      insects, and in particular to that of the locust. Similarities between the
      crayfish and locust central complexes extend to the number and position of the
      neuropils, the location of the cell body clusters of the neurons that belong to
      the central complex, the numbers of tracts that link some of the constituent
      neuropils together, and the form and immunoreactivity of many of the individual
      neuron classes. These similarities are taken as evidence to support a possible
      homology between the crustacean central complex and that of the insects.

PMID- 10581470
TI  - Aberrant dendrite growth in central nervous system white matter induced by a
      mutant proteolipid protein transgene.
AB  - Transgenic mice were produced that carry a construct encoding a mutant form of
      the DM20 isoform of myelin proteolipid protein. The transgene is under the
      direction of the human Plp gene promoter, which has previously been shown to
      direct tissue-specific expression of transgenes. Two lines of mice were generated
      with this construct, both of which express the transgene at extremely low levels.
      Central nervous system myelination proceeds normally in the transgenic mice.
      However, in aged transgenic mice, areas of dendrite processes synapsed with
      axonal termini were observed within the white matter of the spinal cord. This
      phenotype was accompanied by focal areas of astrocytic hypertrophy and an
      increase in apoptotic cell death in white matter but not gray matter. One
      interpretation of these findings is that expression of the mutant DM20 alters
      signaling between oligodendrocytes and neurons, producing abnormal neurite
      outgrowth.

PMID- 10581471
TI  - Cellular localization of neuronal nitric oxide synthase (NOS-1) in the human and
      rat retina.
AB  - The neuronal form of nitric oxide synthase (NOS-1) has been localized to several
      cell types in the retinas of experimental animals; however, localization in the
      human retina has not been definitive. By using in situ hybridization and
      immunohistochemistry, we have compared the cellular expression and localization
      of NOS-1 in the rat and human retinas. In both rat and human retinas, NOS-1 is
      expressed in the inner segments of photoreceptors, cells in the inner nuclear
      layer, particularly amacrine cells, and retinal ganglion cells. In human cones,
      NOS-1 is abundantly present in the outer segments. In the rat, optic nerve
      transection caused a loss of cells that were positive for NOS-1 in the ganglion
      cell layer. Although a retinal ganglion cell localization has not been reported
      consistently in the literature, our data clearly localize NOS-1 to the retinal
      ganglion cells of the rat and human retinas.

PMID- 10581472
TI  - Mental function in males and females.

PMID- 10581473
TI  - No evidence for involvement of polymorphisms of the dopamine D4 receptor gene in
      anorexia nervosa, underweight, and obesity.
AB  - Family and twin studies suggest a genetic contribution to the etiology of
      anorexia nervosa (AN) and obesity. Genes involved in weight regulation can be
      considered as candidate genes for AN. The dopaminergic system has been implicated
      in weight regulation; previous results had suggested a possible involvement of
      the dopamine D4 receptor gene (DRD4). We screened for alleles of two different
      polymorphisms (13-bp deletion, 48-bp repeat) in the DRD4. For association tests,
      allele frequencies were compared between 109 inpatients with AN, 82 underweight
      students, and 327 extremely obese children and adolescents. For application of
      transmission disequlibrium tests (TDT) we additionally genotyped 57 and 137 trios
      comprising a patient with AN or an extremely obese child or adolescent,
      respectively, and both parents. All genotyping was performed with polymerase
      chain reaction fragment length polymorphism analyses. None of the association
      tests or TDT rendered nominal P values below 0.1. An influence of alleles of the
      DRD4 on the development of AN, underweight, or extreme early onset obesity was
      not detected. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:594-597, 1999.

PMID- 10581474
TI  - Studies of the DXS7 polymorphism at the MAO loci in unipolar depression.
AB  - From the fact that DXS7 polymorphism is closely related to monoamine oxidase
      (MAO) genes and MAO inhibitors are widely used in the treatment of unipolar
      depression, it is of particular interest to study the relationship between the
      DXS7 polymorphism and unipolar depression. Thus, this study examined the possible
      association between DXS7 polymorphism and unipolar depression in 66 cases versus
      85 controls from Shanghai. Polymerase chain reaction and amplification fragment
      length polymorphism techniques were used for genotyping of the DXS7 locus in this
      study. Four alleles at the DXS7 locus were detected with length generated by
      polymerase chain reaction amplification ranging from 157 to 167 bp. Comparison of
      allele frequency in the DXS7 locus showed no difference between unipolar
      depression cases and normal controls in the total population set. When
      subclassified by age, a significant difference of allele frequency distribution
      was observed between early onset (before age 40) and late onset (after age 40)
      patients. The frequency of the 157-bp allele was decreased, whereas the frequency
      of the 165 allele was increased in late onset patients (0.3810 for the 157-bp
      allele and 0.5238 for the 165-bp allele) compared with that of early onset
      patients (0.6304 for the 157-bp allele and 0. 3261 for the 165-bp allele). There
      was also a difference of allele frequency between patients and normal controls
      with age over 40 years. The frequency of 165-bp allele increased significantly in
      late onset patients (0.5238) compared with that of controls within the same age
      range (0.3454). Association studies suggested that in the population with age
      over 40 years, presence of the 165-bp allele of DXS7 locus was significantly
      associated with unipolar depression (relative risk = 2.08, P < 0.05), whereas in
      the total population set, this association did not exist. Am. J. Med. Genet.
      (Neuropsychiatr. Genet.) 88:598-600, 1999.

PMID- 10581475
TI  - Association analysis of the 5-HT(6) receptor polymorphism (C267T) in mood
      disorders.
AB  - The serotonergic system is implicated in the etiology of mood disorders. Among
      those most recently discovered serotonin receptors, the relative abundance of
      serotonin type 6 receptor (5-HT(6)) in the limbic area and the high affinity of
      some antidepressants to 5-HT(6) receptors suggest that this receptor might be
      involved in the pathogenesis of mood disorders. In a population-based association
      study, we tested the hypothesis that the allelic variant (C267T) of the human 5
      HT(6) gene confers susceptibility to mood disorders. We genotyped the 5-HT(6)
      receptor in 139 patients with mood disorders and 147 controls. The results
      demonstrated that there were no significant differences in genotype or allele
      frequencies between controls and all patients, or between controls and patients
      with bipolar disorders or major depression, separately. Am. J. Med. Genet.
      (Neuropsychiatr. Genet.) 88:601-602, 1999.

PMID- 10581476
TI  - Testing for linkage of eye tracking dysfunction and schizophrenia to markers on
      chromosomes 6, 8, 9, 20, and 22 in families multiply affected with schizophrenia.

PMID- 10581477
TI  - Suggestive linkage of chromosome 10p to schizophrenia is not due to transmission
      ratio distortion.
AB  - The genome scan of the European-American schizophrenia families from the Human
      Genetics Initiative of the National Institute of Mental Health (NIMH) reported a
      suggestive linkage to chromosome 10p. Subsequently, Paterson and Petronis [1999]
      reported evidence for transmission ratio distortion on 10p to females. They
      suggested that transmission ratio distortion to females might have created
      spurious evidence for linkage to 10p. To address this issue, we reanalyzed our
      10p data using only male-male affected sibling pairs. The two chromosome 10p
      markers that gave the most evidence for linkage in our prior report continued to
      show evidence for linkage: D10S1423 (NPL Z = 3.0, P = 0.001) and its neighbor
      D10S582 (NPL Z = 2.9, P = 0.002). These data suggest that our prior report of
      suggestive linkage of schizophrenia to markers on 10p cannot be attributed to the
      transmission ratio distortion to females reported by Paterson and Petronis. Am.
      J. Med. Genet. (Neuropsychiatr. Genet.) 88:607-608, 1999.

PMID- 10581478
TI  - An autosomal genomic screen for autism. Collaborative linkage study of autism.
AB  - Autism is a severe neurodevelopmental disorder defined by social and
      communication deficits and ritualistic-repetitive behaviors that are detectable
      in early childhood. The etiology of idiopathic autism is strongly genetic, and
      oligogenic transmission is likely. The first stage of a two-stage genomic screen
      for autism was carried out by the Collaborative Linkage Study of Autism on
      individuals affected with autism from 75 families ascertained through an affected
      sib-pair. The strongest multipoint results were for regions on chromosomes 13 and
      7. The highest maximum multipoint heterogeneity LOD (MMLS/het) score is 3.0 at
      D13S800 (approximately 55 cM from the telomere) under the recessive model, with
      an estimated 35% of families linked to this locus. The next highest peak is an
      MMLS/het score of 2.3 at 19 cM, between D13S217 and D13S1229. Our third highest
      MMLS/het score of 2.2 is on chromosome 7 and is consistent with the International
      Molecular Genetic Study of Autism Consortium report of a possible susceptibility
      locus somewhere within 7q31-33. These regions and others will be followed up in
      the second stage of our study by typing additional markers in both the original
      and a second set of identically ascertained autism families, which are currently
      being collected. By comparing results across a number of studies, we expect to be
      able to narrow our search for autism susceptibility genes to a small number of
      genomic regions. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:609-615, 1999.

PMID- 10581479
TI  - Presenilin 1 and alpha-1-antichymotrypsin polymorphisms in Down syndrome: no
      effect on the presence of dementia.
AB  - As people with Down syndrome (DS) age, they are at greater risk for Alzheimer
      disease (AD) than the general population. It has been suggested that
      polymorphisms at the genes for presenilin-1 (PS-1) and alpha-1-antichymotrypsin
      (ACT) confer an increased risk for AD in the general population, and therefore
      potentially to AD in people with DS. We obtained DNA from 231 individuals with DS
      and 233 population controls. People with DS were evaluated for dementia. Allele
      frequencies at PS-1 and ACT polymorphisms in people with DS were compared to
      those in age-matched controls. There were no frequency differences between the
      control sample and DS sample for PS-1 or ACT alleles or genotypes. Similarly,
      there were no differences in allele frequencies between the demented and age
      matched non-demented DS samples. However a higher frequency of PS-1 heterozygotes
      in the demented DS group was noted. We conclude that unlike the general
      population, neither PS-1 nor ACT polymorphisms appear to have a similar
      detrimental effect on dementia in DS. Am. J. Med. Genet. (Neuropsychiatr. Genet.)
      88:616-620, 1999.

PMID- 10581480
TI  - Unified approach to the analysis of genetic variation in serotonergic pathways.
AB  - Serotonin is a key neurotransmitter in the central nervous system, and
      dysregulation of serotonergic pathways has been implicated in the pathogenesis of
      many complex psychiatric diseases. Polymorphisms of many of the genes involved in
      serotonin biosynthesis, catabolism, and response have been reported, suggesting
      that genetic variability may underlie the development of diseases such as
      schizophrenia, obsessive compulsive disorder, and suicide. A number of single
      gene polymorphisms in serotonergic pathways have been examined in these and other
      diseases, but to date results from this candidate gene approach have been
      disappointing. Although this may be because the detection of a small effect may
      require the analysis of large numbers of patients and controls, an alternative
      explanation is that the clinical importance of a single subtle genetic variant
      may be overlooked unless other functionally related genes are studied in tandem.
      To facilitate an integrated analysis, we have developed a PCR-SSP-based assay
      that permits the simultaneous genotyping of 13 single nucleotide polymorphisms in
      9 serotonergic genes under identical conditions. These genes include tryptophan
      hydroxylase, tryptophan dioxygenase, monoamine oxidase A, and the serotonin
      receptors 5HT1A, 5HT1D-alpha, 5HT1D-beta, 5HT2A, 5HT2C, and 5HT5A. Using this
      technology, we have genotyped 100 Caucasoid control individuals and demonstrate
      that this approach is reliable, quick, cheap, and easy to interpret. We
      anticipate that this will facilitate the analysis of the genetic basis of
      susceptibility and phenotypic variability of a number of complex psychiatric
      diseases. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:621-627, 1999.

PMID- 10581481
TI  - Homicidal behavior in schizophrenia associated with a genetic polymorphism
      determining low catechol O-methyltransferase (COMT) activity.
AB  - Although aggressive, violent, and dangerous behavior in man has multifactorial
      causes, genetic factors are estimated by twin and adoption studies to
      substantially contribute to the development of such conduct. Recently,
      homozygosity of a low enzyme activity variant of the catechol O-methyltransferase
      (COMT) gene was reported to be associated with aggressive behavior in a group of
      schizophrenic patients. We observe a similar tendency in a group of 30
      schizophrenic patients who were confined to a maximum-security psychiatric
      facility for homicide. Significant excess (46.7% versus 21.0%) homozygosity of
      the low activity COMTmet/met genotype was observed in 30 mostly male (28 of 30)
      homicidal schizophrenic patients compared with 415 control subjects (Pearson
      chi(2) = 10.53, P = 0.005, df = 2). No difference in COMT genotype was found
      between 62 nonviolent schizophrenic patients and the 415 control subjects (chi(2)
      = 0.963, P > 0.1, df = 2). A trend for excess (46.7% versus 25.8%) homozygosity
      of the low activity COMTmet/met genotype was also observed when the homicidal
      schizophrenic subjects were compared directly with the nonviolent schizophrenic
      patients (chi(2) = 4.03, P = 0.1, df = 2). Similarly, an excess of the low
      activity COMTmet allele was observed in homicidal versus nonviolent schizophrenic
      patients (chi(2) = 2.92, P = 0.087, df = 2). Similar results were obtained if
      only male subjects were examined. No significant difference was found between
      control (257 Ashkenazi and 152 non-Ashkenazi Jews) COMT genotypes in the two
      principal ethnic groups examined (chi(2) = 3.79, P > 0.1, df = 2). Finally, no
      association was observed between homicidal behavior in schizophrenic patients and
      the dopamine D4 exon III repeat length polymorphism (D4DR) and the serotonin
      transporter promoter-region polymorphism (5-HTTLPR). Am. J. Med. Genet.
      (Neuropsychiatr. Genet.) 88:628-633, 1999.

PMID- 10581483
TI  - Cognitive deficits in normally intelligent patients with tuberous sclerosis.
AB  - Webb, Thomson, and Osborne [1991: Arch Dis Child 66:1375-1377] reported on the
      pattern of cerebral lesions found in an epidemiological sample of patients with
      tuberous sclerosis (TS) and clinically judged to be of normal intellect. Varying
      numbers of tubers and subependymal nodules were found, but clinically there
      appeared to be few associated neuropsychological impairments. Our objectives in
      this study were to conduct a detailed neuropsychological assessment to determine
      whether these patients were indeed free of cognitive deficits. We report the
      results of a detailed neuropsychological assessment in this sample and a matched
      comparison group. Although of average intelligence, most TS individuals had a
      significant cognitive deficit of one sort or another, and in a number of cases
      the pattern of cognitive impairments matched that seen in other neurological
      disorders. Additionally, the overall rate of cognitive deficits was significantly
      greater than in the controls. We conclude that normally intelligent individuals
      with TS are prone to specific cognitive difficulties. Further research will be
      required to clarify the nature of the links between the brain abnormalities and
      type of neuropsychological dysfunction. Am. J. Med. Genet. (Neuropsychiatr.
      Genet.) 88:642-646, 1999.

PMID- 10581482
TI  - Personality traits and dopamine receptors (D2 and D4): linkage studies in
      families of alcoholics.
AB  - Activation of the mesolimbic dopamine pathway appears to promote drug- and
      alcohol-seeking behavior in laboratory animals. Results for association and
      linkage analysis between various alcohol dependence phenotypes and the dopamine
      receptors have been quite mixed. Similarly, both positive and negative results
      have been presented concerning dopamine receptor genes and temperament. Cloninger
      has postulated that the novelty seeking factor from the Tridimensional
      Personality Questionnaire (TPQ) may be related to the dopamine neurotransmitter
      system. As novelty seeking is a trait of some importance for substance-dependent
      individuals, our goal was to test this relationship within a sample of families
      of alcoholics. No evidence favoring linkage between D2, D4, or DAT1 was found for
      TPQ novelty seeking. However, the harm-avoidance trait from the TPQ showed
      evidence for linkage to both the D4 and one of the D2 loci (TaqI A). The
      Multidimensional Personality Questionnaire (MPQ) was used to provide converging
      evidence for these results. The TPQ harm-avoidance scale loads heavily on
      introversion (worry, pessimism, shyness), characteristics that may be especially
      salient in alcoholic families. Thus, planned comparisons were made between
      selected MPQ traits measuring the affective dimension (negative affectivity,
      stress reaction, alienation, and well-being). We find evidence favoring linkage
      between the D2 and D4 receptor loci and these MPQ traits, with stronger evidence
      being seen for the D2 polymorphisms. Am. J. Med. Genet. (Neuropsychiatr. Genet.)
      88:634-641, 1999.

PMID- 10581484
TI  - Sex-exclusive quantitative trait loci influences in alcohol-related phenotypes.
AB  - During the past half century, researchers have identified and examined sex
      differences in alcohol-related phenotypes, focusing more recently on
      understanding of the mechanisms underlying these differences. In general, the
      genetic contributions influencing these differences are not consistent with an
      interpretation of sex linkage and must, therefore, reflect some form of sex
      limitation in which allelic differences at particular autosomal loci have
      different consequences in males and females. Significant sex differences in
      measures of alcohol consumption in mice have been demonstrated in previous work
      in our laboratory. To investigate these differences further, we explore the
      limiting case of sex-exclusive effects using data from (BXD) recombinant inbred
      (RI) strains of mice and from an intercross derived from the same progenitors,
      C57BL/6J (B) and DBA/2J (D). By the use of two statistical approaches
      (examination of residual scores as a sex-exclusive phenotypic value for the RI
      strains and multivariate regression on sex and genotype in the F(2)) we have
      identified and confirmed female-exclusive markers for alcohol acceptance on
      chromosomes 9 and 12 and one marker for alcohol preference on chromosome 2. Am.
      J. Med. Genet. (Neuropsychiatr. Genet.) 88:647-652, 1999.

PMID- 10581485
TI  - Novel PRNP sequence variant associated with familial encephalopathy.
AB  - Human transmissible spongiform encephalopathies (TSEs) are a group of chronic
      progressive neurodegenerative disorders that may be hereditary, infectious, or
      sporadic. Hereditary TSEs are associated with mutations in the PRNP gene on
      chromosome 20p12-pter. We report on a family in which seven patients developed
      limb and truncal ataxia, dysarthria, myoclonic jerks, and cognitive decline. The
      age of onset in the 30s, 40s, or 50s, prolonged disease duration, cerebellar
      atrophy on imaging, and the presence of synchronic periodic discharges on
      electroencephalogram suggested a familial encephalopathy resembling Gerstmann
      Straussler-Scheinker disease. A novel H187R mutation has been identified in
      affected, but not in unaffected, family members or unrelated controls suggesting
      a pathogenic role for this mutation. Am. J. Med. Genet. (Neuropsychiatr. Genet.)
      88:653-656, 1999. Published 1999 Wiley-Liss, Inc.

PMID- 10581486
TI  - Transmission ratio distortion in females on chromosome 10p11-p15.
AB  - A number of recent reports of linkage of markers on chromosome 10p to
      schizophrenia, and evidence for linkage in one study to bipolar affective
      disorder, provide encouragement for psychiatric genetics, after nonreplication of
      linkage findings at other chromosomal regions. The same region on chromosome 10
      also demonstrates evidence for linkage to obesity, female alcoholism, and female
      type 1 diabetes. However, evidence for linkage can be confounded by the
      biological phenomenon of transmission ratio distortion. Transmission ratio
      distortion (also termed segregation distortion or meiotic drive) results in non
      Mendelian segregation of alleles to live born offspring, and has not been
      investigated at the majority of loci for complex traits. We examined evidence for
      transmission ratio distortion using 40 Centre d'Etude du Polymorphisme Humain
      (CEPH) pedigrees across chromosome 10 using CEPH genotype data. Evidence for
      linkage of females to D10S211 was found (multipoint non-parametric linkage Z
      score [NPL] = 1.84, P = 0.040), while there was no linkage of this marker to male
      sex. The observation of possible transmission ratio distortion in females on
      chromosome 10p requires additional study, and may impact on the interpretation of
      positive linkage findings in this region. Am. J. Med. Genet. (Neuropsychiatr.
      Genet.) 88:657-661, 1999.

PMID- 10581487
TI  - Predictive testing of 25 percent at-risk individuals for Huntington disease (1987
      1997).
AB  - Before the mutation causing Huntington disease was identified, predictive testing
      of 25% at-risk persons with a 50% at-risk parent who did not wish to know his/her
      genetic status, was only possible by exclusion testing. The exclusion test, using
      linked markers, ensures the parent's wish not to know because the parent's risk
      is not changed. When mutation analysis became available in 1993, new testing
      options for 25% at-risk persons emerged: viz., the exclusion-definitive test and
      direct mutation analysis. These new tests not only disclose the risk of the test
      candidate, but may also change the risk of the at-risk parent and siblings. The
      testing options for 25% at-risk test applicants and their consequences are
      discussed and the testing procedures and results of testing 64 25% at-risk
      persons in the period 1987 to 1997 are described. Relatives received unsought
      information in 56% of the test procedures before and 34% after the mutation was
      identified. A decision tree and guidelines for predictive testing of 25% at-risk
      test applicants are proposed. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:662
      668, 1999.

PMID- 10581488
TI  - Segregation analysis of obsessive-compulsive disorder using symptom-based factor
      scores.
AB  - Obsessive-compulsive disorder (OCD) is a complex psychiatric disorder
      characterized by recurring obsessions or compulsions that cause significant
      distress to the patient or significantly interfere with the patient's normal
      home, work, or social activities [Diagnostic and Statistical Manual of Mental
      Disorders, 4th Edition. Washington, DC: American Psychiatric Association, 1994].
      Twin and family studies have suggested that OCD has a significant genetic
      component. We performed complex segregation analyses using POINTER with families
      ascertained through an OCD-affected proband. In an attempt to resolve the
      phenotypic heterogeneity observed among individuals with OCD these segregation
      analyses used four factor-analytic symptom dimensions to subset the family sample
      based upon probands' symptom factor scores. Analysis of the entire sample allowed
      rejection of only the no transmission model; that model was also rejected in all
      subsequent analyses. Limiting the analyses to families with at least one OCD
      affected member in addition to the proband (the demonstrably familial form of
      OCD) allowed rejection of all models except the mixed model. Analyses limited to
      families of high-factor-3 (symmetry and ordering symptoms) probands led to
      rejection of the polygenic model, indicating the involvement of a major locus.
      Additionally, the relative risk of OCD or subclinical OCD was 1.7 for relatives
      of probands with a factor 3 score greater than zero compared with relatives of
      probands with a low factor score. The symptoms attributed to high factor 3 scores
      (symmetry and ordering) may constitute a genetically significant symptomatic
      subtype of OCD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:669-675, 1999.

PMID- 10581489
TI  - Linkage studies of D2 and D4 receptor genes and alcoholism.
AB  - The purpose of the present study was to evaluate two polymorphisms near the D2
      receptor gene (TaqI A RFLP and C microsatellite) and a VNTR for D4. A
      nonparametric linkage (NPL) technique, SIBPAL, was used to test for the presence
      or absence of linkage in 54 multiplex alcoholic families. These families had been
      ascertained through two alcoholic proband siblings in order to increase the
      density of alcoholic cases within these pedigrees. Phenotypic definitions of
      alcoholism were manipulated in an effort to determine the impact of severity
      (signs of physical dependence, early age of onset, presence of antisocial
      personality disorder) on the likelihood of finding positive evidence for linkage.
      A regression analysis that simultaneously evaluated the allele sharing identical
      by descent for Feighner criteria alcoholism in affected, unaffected, and
      discordant sib pairs (SIBPAL) for two D2 polymorphisms and the D4 polymorphism
      gave no evidence for linkage. Phenotypes associated with greater alcoholism
      severity (presence of physical dependence symptoms, earlier onset, or comorbid
      antisocial personality disorder) revealed some evidence for linkage. The presence
      of one or more physical dependence symptoms in combination with Feighner criteria
      alcoholism provided some evidence favoring linkage (TaqI A and D4). Alcoholics
      with an earlier onset of alcoholism showed some evidence for linkage especially
      when the presence of physical dependence was required (e. g., morning drinking,
      wanted to stop drinking but could not, binges or benders, and evidence of
      withdrawal symptoms). Finally, alcoholics with antisocial personality disorder
      differed significantly in their allele sharing from nonalcoholics for both D2
      polymorphisms. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:676-685, 1999.

PMID- 10581490
TI  - Anticipation in schizophrenia: a review and reconsideration.
AB  - There have been several reports on anticipation and schizophrenia, and the
      purpose of the present article is to review the literature and present data from
      an ongoing family study of schizophrenia. The published data find on average a 10
      year difference in the age of onset between the parental and offspring generation
      in family sets that have been ascertained for a genetic linkage study. The biases
      inherent in such studies include the biases of ascertainment that were described
      by Penrose [1948]. Several investigators have searched for evidence of enlarged
      triplet repeats, and some find evidence consistent with expanded triplet repeats,
      whereas others do not. In any event the phenomenon of anticipation in
      schizophrenia appears to be consistently found and an explanation is needed. Data
      are presented from pairwise analyses using intergenerational pairs from 61
      pedigrees with schizophrenia showing evidence of anticipation as well as the
      fertility bias. Anticipation was found in aunt:niece/nephew pairs (14.5 years)
      but not in uncle:niece/nephew pairs (0.5 years). The sex difference in age of
      onset was accentuated in uncles versus aunts (8.5 years), present in parents (4.5
      years), but absent in the proband generation. Therefore, there appears to be an
      interaction within families between age of onset and sex that deserves further
      investigation. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:686-693, 1999.

PMID- 10581491
TI  - Analysis of 14 CAG repeat-containing genes in schizophrenia.
AB  - Recently, it has been suggested that trinucleotide repeat-containing genes may be
      involved in the etiology of schizophrenia. This study was aimed at investigating
      putative associations between allelic variants or expansions of CAG repeat
      containing genes (CAGrCG) and schizophrenia or its variability with respect to
      responsiveness to conventional neuroleptics. CAG repeat allelic variants of 14
      expressed sequences were compared among three groups of subjects: neuroleptic
      responder (R; n = 43) and neuroleptic-nonresponder (NR; n = 63) schizophrenic
      patients, and a control group (C; n = 122). No CAG expansions, in the range of
      those observed in neurodegenerative diseases, were identified in these 14
      expressed sequences. The sizes of CAG repeat for the hGT1 gene were marginally
      different among the three groups of subjects (Kruskal-Wallis H (2, 456) = 10.48,
      Bonferroni corrected P = 0.047). Comparisons among the different groups indicated
      that neuroleptic responders have shorter alleles compared to controls (Mann
      Whitney adjusted Z = -3.23, P = 0.0012). NR patients were not different from
      controls. These preliminary results suggest that the hGT1 gene, or a gene in its
      vicinity, may be involved in the etiology of schizophrenia or in modifying the
      disease phenotype with regard to outcome and/or neuroleptic responsiveness. Am.
      J. Med. Genet. (Neuropsychiatr. Genet.) 88:694-699, 1999.

PMID- 10581492
TI  - Novel polymorphism in the promoter and coding regions of the human
      cholecystokinin B receptor gene: an association analysis with schizophrenia.
AB  - Genetic variations in the 5'-untranslated region and the coding region of the CCK
      B receptor (CCK-BR) gene were investigated in healthy controls. Novel variants (
      215 C-->A, Leu37Phe, Arg319Glu) were found in addition to the mutations
      (Val125Iso, His207His, Arg215His, 2491 C-->A) reported previously. In the present
      study, association analysis was carried out for these variants between 80
      unrelated schizophrenic patients and 100 healthy controls. The genotype frequency
      of the -215 C-->A nucleotide substitution in the 5'-untranslated region of CCK-BR
      gene was significantly higher in the schizophrenic patients than in the controls
      (6.25%, P = 0.037). However, the difference was not significant after Bonferroni
      correction for multiple comparisons. Moreover, no association was found between
      the clinical characteristics of the patients and the genotype frequencies of the
      variants. These results suggest that the CCK-BR gene polymorphisms have no
      association with schizophrenia nor its clinical heterogeneity. Am. J. Med. Genet.
      (Neuropsychiatr. Genet.) 88:700-704, 1999.

PMID- 10581493
TI  - Tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4).
AB  - The dopamine D4 receptor (DRD4) is a member of the D2-like dopamine receptor
      family. Polymorphisms at the DRD4 gene have been examined for association with a
      wide range of neuropsychiatric disorders and normal behavioral variation. The
      DRD4 gene is unusual in its high amount of expressed polymorphism in humans. Here
      we study the identification of a polymorphic tandem duplication of 120 bp located
      1.2 kb upstream of the initiation codon. The duplicated region contains consensus
      sequences of binding sites for several known transcription factors, suggesting
      that different alleles may differ in their transcriptional activity. Because
      chimpanzees, gorillas, and orangutans lack the duplication, the duplicated allele
      is inferred to be derived. The frequency of this derived duplication allele
      ranges from 0.40-0.81 in the 11 populations from around the world typed for this
      polymorphism. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:705-709, 1999.

PMID- 10581494
TI  - Linkage study of catechol-O-methyltransferase and attention-deficit hyperactivity
      disorder.
AB  - Attention-deficit hyperactivity disorder is the most common child psychiatric
      disorder with a prevalence rate in an Ontario study of 9% in boys and 3% in girls
      [Szatmari et al., 1989]. This disorder is characterized by problems in the areas
      of attention, overactivity, impulse control, and distractibility. Strong evidence
      for a genetic component has been provided from twin, family, and adoption studies
      [for review see Levy et al., 1998] and molecular genetic studies are in progress
      by several groups worldwide. The Catechol-O-Methyltransferase (COMT) gene is an
      interesting candidate for ADHD as it is involved in the breakdown of dopamine and
      norepinephrine, neurotransmitters strongly implicated in the etiology of ADHD. In
      addition, children with velo-cardio-facial syndrome, a deletion syndrome of the
      chromosomal region 22q11 where the COMT gene has been localized, often have
      symptoms of ADHD suggesting this gene may have an etiological role in ADHD. In
      this study, we have tested for linkage in ADHD families using the functional
      polymorphism at codon 158 that determines COMT activity [Lachman et al., 1996]
      and analyzed the data with the transmission disequilibrium test (TDT). A total of
      77 nuclear families collected from Toronto were genotyped. We find no evidence
      for linkage of this polymorphism and ADHD in our sample. Am. J. Med. Genet.
      (Neuropsychiatr. Genet.) 88:710-713, 1999.

PMID- 10581495
TI  - Early speech and language development in children with velocardiofacial syndrome.
AB  - Speech-language impairment is one of the most common clinical features in
      velocardiofacial syndrome (VCFS). This report describes the speech and language
      development of four children with VCFS studied longitudinally from 6 to 30 months
      of age and compares their performance with three groups of children: (1) normally
      developing children, (2) children with cleft lip and palate, and (3) children
      with isolated cleft palate. The data show that young children with VCFS show a
      receptive-expressive language impairment from the onset of language. Further,
      speech and expressive language development were severely delayed beyond a level
      predicted by their other developmental or receptive language performance. The
      children with VCFS showed severe limitations in speech sound inventories and
      early vocabulary development that far exceeded those shown by the children with
      cleft lip and palate and children with isolated cleft palate. This study
      indicates that young children with VCFS emerge from a critical speech and
      language learning period with severe limitations in their communicative
      abilities. Further studies are required to describe the later course of these
      early speech and language impairments and to explore the relationship to learning
      disabilities described for older children with VCFS. Am. J. Med. Genet.
      (Neuropsychiatr. Genet.) 88:714-723, 1999.

PMID- 10581497
TI  - Association study of the NF1 gene and autistic disorder.
AB  - Neurofibromatosis type 1 (NF1) is increased about 150-fold in autistic patients.
      The aim of this study was to test for an association between the NF1 locus and
      autistic disorder. The allele distributions of three markers of the NF1 gene were
      studied in 85 autistic patients and 90 controls. No differences in allele
      distributions were observed. However, we found a new allele (allele 5) of the
      GXAlu marker in four autistic patients. Allele 5 was absent in a larger control
      population (213 individuals). The patients with allele 5 had a more severe
      clinical picture, mainly in the fields of motility and tonus. Our preliminary
      results suggest that the NF1 region is not a major susceptibility locus for
      autism. However, the GXAlu marker of the NF1 gene appears as a possible candidate
      for a susceptibility locus in a small subgroup of severely affected autistic
      patients. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:729-732, 1999.

PMID- 10581496
TI  - Heritability of BDNF alleles and their effect on brain morphology in
      schizophrenia.
AB  - Accumulating evidence suggests that disturbed brain development may play a role
      in the etiology of schizophrenia, and that the illness is, to a significant
      degree, heritable. We therefore investigated brain derived neurotrophic factor
      (BDNF), a neurotrophin expressed in fetal brain, as a candidate disease gene for
      schizophrenia. We also investigated the effect of BDNF on adult brain morphology.
      All subjects were diagnosed by DSM-IIIR or DSM-IV criteria with schizophrenia
      spectrum disorders. Association of a BDNF polymorphism was examined in 48 proband
      parent trios using the haplotype based haplotype relative risk method of case
      control. In a related group of 63 subjects, relationships between the presence or
      absence of allele 1 and the volumes of the major cerebral lobes, the ventricles,
      and the cerebellum were assessed using logistic regression. No association was
      found between this polymorphism and schizophrenia. Subjects who had at least one
      copy of allele 1, however, had larger parietal lobes than those who did not when
      controlling for overall cortical volume and age at the time of magnetic
      resonance. We did not find support for BDNF as a disease gene for schizophrenia.
      Allelic variability of the gene may, however, influence brain morphology in these
      same subjects. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:724-728, 1999.

PMID- 10581498
TI  - Mutational analysis of the anion exchanger 3 gene in familial paroxysmal dystonic
      choreoathetosis linked to chromosome 2q.
AB  - Familial paroxysmal dystonic choreoathetosis (PDC) is an autosomal dominant
      neurological disorder characterized by episodes of involuntary movement
      precipitated by caffeine, alcohol, or emotional stress. The locus for PDC has
      recently been mapped to chromosome 2q32-36, but its causative gene has not yet
      been identified. PDC is most likely a kind of channelopathy, as suggested by the
      fact that other paroxysmal neurological disorders are caused by various ion
      channel mutations. Although no ion channel is located in this candidate region,
      anion exchanger 3 (AE3) has been mapped to 2q36 and has also been reported to be
      the most promising candidate gene of PDC. In this study we performed sequencing
      of the coding region of the AE3 gene in patients with familial PDC linked to
      chromosome 2q and excluded the AE3 gene as the causative gene for PDC. Am. J.
      Med. Genet. (Neuropsychiatr. Genet.) 88:733-737, 1999.

PMID- 10581499
TI  - Analysis of ERDA1, CTG18.1, and uncloned CAG/CTG repeat sequences in familial
      Parkinson's disease with anticipation.
AB  - In several neurodegenerative diseases, anticipation or increase in disease
      severity in succeeding generations within families correlates with expansions of
      an intragenic CAG/CTG repeat sequence above the normal range through the
      generations of a pedigree. Some kindreds of familial Parkinson's disease (PD)
      exhibit genetic anticipation. We used the repeat expansion detection (RED) method
      to detect repeat expansions directly in DNA samples from the index cases of 34
      different PD families with anticipation. The mean age at onset of the younger
      probands was 48.8 +/- 10.8 years and the mean intergenerational difference was
      19.2 +/- 10 years. The distribution of the RED products greater than 40 repeats
      was not significantly different between patients and controls with the Mann
      Whitney U test (U = 510.5, p = 0.67). The samples were then screened for the two
      expanded-repeat loci, ERDA1 and CTG18.1. We found that in all cases the repeat
      expansion detected by the RED method may be accounted for by an expansion at
      these loci. Our results demonstrate that unstable CAG/CTG expansions
      corresponding to uncloned or cloned sequences (ERDA1, CTG18.1) are not involved
      in the etiology of rare familial case of PD with genetic anticipation. Am. J.
      Med. Genet. (Neuropsychiatr. Genet.) 88:738-741, 1999

PMID- 10581501
TI  - No evidence for segregation distortion in females in a sample of 72 families with
      schizophrenia with potential linkage to chromosome 10p14-p11.

PMID- 10581500
TI  - Environmental, medical, and family history risk factors for Parkinson's disease:
      a New England-based case control study.
AB  - Controversy persists about the etiology of Parkinson's disease (PD). Pesticides,
      herbicides, well-water consumption, head injury, and a family history of PD have
      been reported as risk factors for PD. The purpose of this study was to (1)
      investigate the impact of environmental factors on PD risk (2) estimate the
      chronology, frequency, and duration of those exposures associated with PD; and
      (3) investigate the effects of family history on PD risk. One-hundred and forty
      PD cases were recruited from Boston University Medical Center. The control group
      was composed of 147 friends and in-laws of PD patients. Environmental, medical,
      and family history data were obtained by structured interview from each
      participant for events recalled prior to PD onset for cases, or corresponding
      censoring age for controls (mean age = 56 years of age for each group). A
      traditional stratified analysis, adjusting for birth cohort and sex, was
      employed. Four factors were associated with increased risk for PD: (1) head
      injury (OR=6.23, confidence interval [CI]: 2.58-15.07); (2) family history of PD
      (OR=6.08, CI: 2.35-15. 58); (3) family history of tremor (OR=3.97, CI: 1.17
      13.50); and (4) history of depression (OR=3.01, CI: 1.32-6.88). A mean latency of
      36. 5 (SE=2.81) years passed between the age of first reported head injury and PD
      onset. A mean latency of 22 (SE=2.66) years passed between the onset of the first
      reported symptoms of depression and onset of PD. Years of education, smoking, and
      well-water intake were inversely associated with PD risk. PD was not associated
      with exposure to pesticides or herbicides. These findings support the role of
      both environmental and genetic factors in the etiology in PD. The results are
      consistent with a multifactorial model. Am. J. Med. Genet. (Neuropsychiatr.
      Genet.) 88:742-749, 1999.

PMID- 10581502
TI  - MR imaging of tumor microcirculation: promise for the new millennium.
AB  - Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) is a method of
      imaging the physiology of the microcirculation. A series of recent clinical
      studies have shown that DCE MRI can measure and predict tumor response to
      therapy. Recent advances in MR technology provide the enhanced spatial and
      temporal resolution that allow the application of this methodology in the
      management of cancer patients. The September issue of this journal provided a
      microcirculation section to update readers on this exciting and challenging
      topic. Evidence is mounting that DCE MRI-based measures correlate well with tumor
      angiogenesis. DCE MRI has already been shown in several types of tumors to
      correlate well with traditional outcome measures, such as histopathologic
      studies, and with survival. These new measures are sensitive to tumor physiology
      and to the pharmacokinetics of the contrast agent in individual tumors. Moreover,
      they can present anatomical images of tumor microcirculation at excellent spatial
      resolution. Several issues have emerged from recent international workshops that
      must be addressed to move this methodology into routine clinical practice. First,
      is complex modeling of DCE MRI really necessary to answer clinical questions
      reliably? Clinical research has shown that, for tumors such as bone sarcomas,
      reliable outcome measures of tumor response to chemotherapy can be extracted from
      DCE MRI by methods ranging from simple measures of enhancement to pharmacokinetic
      models. However, the use of similar methods to answer a different question-the
      differentiation of malignant from benign breast tumors-has yielded contradictory
      results. Thus, no simple, one-size-fits-all-tumors solution has yet been
      identified. Second, what is the most rational and reliable data collection
      procedure for the DCE MRI evaluation? Several groups have addressed population
      variations in some key variables, such as tumor T(1)0 (T(1) prior to contrast
      administration) and the arterial input function C(a)(t) for contrast agent, and
      how they influence the precision and accuracy of DCE MRI outcomes. However,
      despite these potential complications, clinical studies in this section show that
      some tumor types can be assessed by relatively simple dynamic measures and
      analyses. The clinical scenario and tumor type may well determine the required
      complexity of the DCE MRI exam procedure and its analysis. Finally, we suggest
      that a consensus on naming conventions (nomenclature) is needed to facilitate
      comparison and analysis of the results of studies conducted at different centers.
      J. Magn. Reson. Imaging 10:903-907, 1999.

PMID- 10581503
TI  - Right ventricular volumes and ejection fraction with fast cine MR imaging in
      breath-hold technique: applicability, normal values from 52 volunteers, and
      evaluation of 325 adult cardiac patients.
AB  - Our goal was to establish right ventricular (RV) volume and ejection fraction
      (EF) values in normal volunteers with fast magnetic resonance (MR) imaging using
      a breath-hold technique, to assess the frequency and severity of RVEF abnormality
      in cardiac patients and to compare RV with left ventricular (LV) data. We
      performed simultaneously derived RV and LV fast cine measurements in 52 normals
      and 325 patients with coronary artery disease (CAD), acquired valvular disease
      (VD), cardiomyopathy (CM), or congenital heart disease (CHD). RVEF was reduced in
      31% (102) of all patients, in 50% dilated CM, 39% CHD, 34% CAD, and 22% acquired
      VD patients. Solitary abnormally low RVEF was found in only 15/325 (5%) of all
      patients, whereas combined with LVEF deterioration in 87/172 (51%) patients. RVEF
      reduction was mild in 64%, moderate in 25%, and severe in 11%. Although RVEF
      correlated significantly (r = 0.55, P < 0.001) with LVEF, the predictive value of
      LVEF for RVEF was low. We conclude that RV volumes can be routinely assessed with
      fast MRI and should be performed in addition to LV evaluation in CHD, in right
      sided VD, and in all patients with an abnormal LVEF.J. Magn. Reson. Imaging 1999;
      10:908-918.

PMID- 10581504
TI  - Image artifacts due to a time-varying contrast medium concentration in 3D
      contrast-enhanced MRA.
AB  - The purpose of this work was to study image effects due to time-varying contrast
      medium concentration in contrast-enhanced three dimensional (3D) magnetic
      resonance angiography (MRA) images. Two different simulation models (1D and 3D)
      and two different contrast medium variation schemes were used. Phantom
      measurements were also performed. Experiments were performed for several
      different bolus timings. Similar sequence and image object parameters were used
      in both simulations and measurements (TE/TR 2. 1/7.8 mses, flip angle 30 degrees,
      T1/T2 1200-80/150-40 msec, flow velocity 100 cm/sec). A small variation in bolus
      timing yielded large variations in the appearance of the image effects,
      especially if the center of k-space was sampled in the vicinity of rapid contrast
      medium concentration variation. For a typical bolus injection in a patient, a
      severe signal loss but only minor ringing and edge artifacts appeared if the
      bolus injection was poorly timed. Effects of pulsatile flow were minor. The 3D
      model proved to be a useful tool in these studies. J. Magn. Reson. Imaging
      1999;10:919-928.

PMID- 10581505
TI  - Evaluation of radiofrequency pulses and contrast agent doses for use in 3D
      pulmonary magnetic resonance angiography.
AB  - Ten healthy volunteers were imaged with breath-hold, three-dimensional (3D) time
      of-flight (TOF) magnetic resonance angiography (MRA) using single-variable-angle
      uniform signal excitation (VUSE), double-VUSE, and flat radiofrequency (RF)
      pulses with various doses of contrast agent. The ability of each technique to
      display pulmonary vasculature was evaluated. Images were segmented to isolate
      lungs, and maximum intensity projections (MIPs) were computed. All MIPs were
      assigned an image quality (IQ) rating, and signal-to-noise ratios (SNRs) were
      measured in pulmonary vessels. Without contrast agent, subsegmental vessels were
      displayed in single- and double-VUSE images while no vessels were visible in flat
      images. With equal doses of contrast agent, SNRs and IQ ratings were comparable
      for images obtained with VUSE and flat pulses. In addition, single-VUSE pulses
      produced more uniform signal from vessels than flat pulses in contrast-enhanced
      images. The results indicate that non-contrast-enhanced 3D TOF pulmonary MRA with
      VUSE RF pulses may be a useful screening tool. In addition, contrast-enhanced 3D
      TOF MRA with VUSE pulses may be useful as a stand-alone technique for assessing
      the pulmonary vasculature or as an adjunct to contrast-enhanced 3D TOF MRA with
      flat pulses. J. Magn. Reson. Imaging 10:929-938, 1999.

PMID- 10581506
TI  - 3D TOF turbo MR angiography for intracranial arteries: phantom and clinical
      studies.
AB  - This work investigated whether turbo magnetic resonance angiography (MRA) can
      replace conventional MRA in screening examination of intracranial arteries. A
      phantom was used to evaluate the effect of the zero-filling interpolation (ZFI)
      technique on spatial resolution and partial volume effect. Thirty-one consecutive
      patients underwent both turbo MRA with a slice thickness of 0.7 mm (data were
      measured as 1.33 mm sections) and conventional MRA with 1.0 mm sections. In the
      phantom studies, ZFI did not improve the spatial resolution, but the partial
      volume effect was somewhat reduced. In the clinical evaluation, turbo MRA showed
      better signal-to-noise and contrast-to-noise ratios of the intracranial major
      vessels than conventional MRA. The lesions included cerebral aneurysms less than
      3 mm in diameter, occlusive vascular disease, arteriovenous malformations, and
      arteriovenous fistulas. These were all depicted on both turbo MRA and
      conventional MRA. Turbo MRA is a useful screening procedure because of its
      capability of delineating lesions in approximately half the usual imaging time.
      J. Magn. Reson. Imaging 1999;10:939-944.

PMID- 10581507
TI  - Dynamic contrast-enhanced MRI in the differentiation of breast tumors: user
      defined versus semi-automated region-of-interest analysis.
AB  - Dynamic contrast-enhanced MR mammography is an increasingly used method of
      evaluating breast pathology. The purpose of this study was to compare two semi
      automated methods of region of interest (ROI) analysis with a user-defined
      method, in the discrimination of breast tumors using dynamic contrast-enhanced
      MRI. Results are presented from the retrospective analysis of 81 malignant and 36
      benign breast lesions. The study demonstrates the importance of a consistent ROI
      strategy and also shows that semi-automated approaches offer a standardized
      method, which may improve the discrimination of primary breast tumors. J. Magn.
      Reson. Imaging 1999; 10:945-949.

PMID- 10581508
TI  - Stomach diseases: MR evaluation using combined t2-weighted single-shot echo train
      spin-echo and gadolinium-enhanced spoiled gradient-echo sequences.
AB  - The aim of this study was to describe the magnetic resonance (MR) appearances of
      diseases of the stomach using combined T1-weighted spoiled gradient-echo, T2
      weighted single-shot echo train spin-echo and gadolinium-enhanced spoiled
      gradient-echo sequences. All patients with gastric diseases who underwent
      combined T2-weighted single-shot echo train spin-echo and gadolinium-enhanced
      conventional and fat-suppressed spoiled gradient-echo imaging between October 1,
      1996 and March 1, 1999, and who had histological or other imaging proof of
      disease, were included in this study. This patient population was comprised of 40
      patients with subsequently proven gastric abnormalities, including malignant
      tumors (25) or benign disease (15). The MRI sequences included T1-weighted, T2
      weighted, and early and late gadolinium-enhanced spoiled gradient-echo (SGE)
      images. Evaluation was made of the following parameters: a) the ability to detect
      the disease process on MRI, by comparing the original prospective MR reports with
      the records of the pathology department; b) the MR appearance of a variety of
      gastric diseases; and c) the sequences that most clearly demonstrated
      abnormalities by retrospective review of the MR studies. MR images demonstrated
      22 of 25 malignant tumors. Evaluation of the extent of the tumor was correctly
      shown in 22 of 25 tumors. Small-volume tumor (one patient with gastric
      adenocarcinoma, and one patient with lymphoma) and coexistent infiltrative
      adenocarcinoma and gastritis (one patient) rendered demonstration of tumor poor
      on MR images in three patients. Tumors were mildly hypointense on T1-weighted
      images and mildly hyperintense on T2-weighted images. Tumors enhanced in a
      heterogeneous fashion compared with background stomach wall, but they ranged from
      hypointense to hyperintense on early and late post-gadolinium SGE images.
      Regarding benign diseases, the changes of gastritis were evident in three of four
      cases. Gastritis appeared as increased mucosal enhancement that ranged from
      moderate to intense on early and late post-gadolinium SGE images. Imaging
      findings of the various entities are described in greater detail in the text. MR
      findings in a variety of neoplastic and non-neoplastic diseases of the stomach
      are described. Neoplastic diseases were consistently observed in most cases;
      however, small tumors and tumors coexistent with inflammatory changes were poorly
      evaluated. The changes of gastritis were demonstrated as increased enhancement of
      the gastric wall. J. Magn. Reson. Imaging 10:950-960, 1999.

PMID- 10581509
TI  - Sodium and proton MR properties of cartilage during compression.
AB  - Proton and sodium MR relaxation times of bovine articular cartilage specimens
      were measured as a function of proteoglycan (PG) depletion and as a function of
      mechanical compression. Proton and sodium relaxation times of normal cartilage
      were compared with relaxation times of PG-depleted cartilage to evaluate the
      significance of PG depletion-induced changes in MR relaxation parameters. These
      comparisons were conducted for both uncompressed and mechanically compressed
      states. The mechanical compressions were performed with an MR-compatible pressure
      cell and evaluated dynamically via interleaved one-dimensional proton and sodium
      MR projection imaging. The comparisons indicate that sodium relaxation parameters
      are sensitive to PG depletion when cartilage is in a mechanically compressed
      state or an uncompressed state. In contrast, proton relaxation parameters do not
      change significantly with PG depletion when cartilage is in an uncompressed
      state. However, during mechanical compression, proton T2 becomes sensitive to PG
      depletion. These results support the potential of sodium magnetic resonance
      imaging (MRI) as a possible modality for obtaining imaging contrast related to PG
      depletion. The results also indicate the potential of proton MRI to provide such
      contrast if the image acquisition is conducted in conjunction with a mechanical
      compression via physical exercise.J. Magn. Reson Imaging 10:961-967, 1999.

PMID- 10581510
TI  - A simple and realistic tissue-equivalent breast phantom for MRI.
AB  - A simple and inexpensive breast phantom is described for use in magnetic
      resonance imaging. The work demonstrates the similarity of the phantom materials
      to in vivo breast tissue in terms of T(1) relaxation times. The phantom is also
      qualitatively compared with images acquired from a patient with a primary breast
      lesion.J. Magn. Reson. Imaging 10:968-971, 1999.

PMID- 10581512
TI  - Technical report of the international working group on breast MRI

PMID- 10581513
TI  - Technical report of the international working group on breast MRI

PMID- 10581511
TI  - Design and validation of a motion stage for in vitro MR experiments.
AB  - A computer-controlled motion stage was designed to facilitate motion studies and
      simulations of cardiac magnetic resonance (MR) experiments. The stage was
      constructed to move a phantom of up to 6 kg at velocities up to 15 cm/sec along a
      two-dimensional trajectory within an MR scanner. The operation of the motion
      stage was validated and found to be accurate to within 0.08 cm in displacement
      and 1.5 cm/sec in velocity (root-mean-square error). No image degradation was
      observed.J. Magn. Reson. Imaging 1999;10:972-977.

PMID- 10581515
TI  - Key personnel

PMID- 10581514
TI  - Technical report of the International Working Group on Breast MRI.

PMID- 10581516
TI  - Lesion Diagnosis Working Group report.

PMID- 10581517
TI  - Breast Cancer Staging Working Group report.

PMID- 10581518
TI  - High Risk Screening Working Group report.

PMID- 10581519
TI  - Dedicated Breast MRI Systems Working Group report.

PMID- 10581520
TI  - Biopsy and Intervention Working Group report.

PMID- 10581521
TI  - Predictive medicine: computational techniques in therapeutic decision-making.
AB  - The current paradigm for surgery planning for the treatment of cardiovascular
      disease relies exclusively on diagnostic imaging data to define the present state
      of the patient, empirical data to evaluate the efficacy of prior treatments for
      similar patients, and the judgement of the surgeon to decide on a preferred
      treatment. The individual variability and inherent complexity of human biological
      systems is such that diagnostic imaging and empirical data alone are insufficient
      to predict the outcome of a given treatment for an individual patient. We propose
      a new paradigm of predictive medicine in which the physician utilizes
      computational tools to construct and evaluate a combined anatomic/physiologic
      model to predict the outcome of alternative treatment plans for an individual
      patient. The predictive medicine paradigm is implemented in a software system
      developed for Simulation-Based Medical Planning. This system provides an
      integrated set of tools to test hypotheses regarding the effect of alternate
      treatment plans on blood flow in the cardiovascular system of an individual
      patient. It combines an Internet-based user interface developed using Java and
      VRML, image segmentation, geometric solid modeling, automatic finite element mesh
      generation, computational fluid dynamics, and scientific visualization
      techniques. This system is applied to the evaluation of alternate, patient
      specific treatments for a case of lower extremity occlusive cardiovascular
      disease.

PMID- 10581522
TI  - Stereotactic imaging quality assurance using an anthropomorphic phantom.
AB  - OBJECTIVE: A custom-designed anthropomorphic head phantom, containing computed
      tomography (CT) and magnetic resonance (MR) viewable targets, was used in the
      assessment of stereotactic localization accuracy. MATERIALS AND METHODS: The
      Brown-Roberts-Wells (BRW) or Leksell stereotactic ring was rigidly fixed to the
      phantom. CT and MR images were then obtained according to radiosurgery protocols
      with the corresponding localizer frame attached. Plastic spheres and rods
      appeared at various locations within the phantom, when filled with aqueous
      solution, and their images served as targets to compute stereotactic target
      coordinates using software compatible with each frame. Coordinates derived using
      CT and MR were compared with mechanical measurements obtained using the BRW or
      Leksell stereotactic arc systems. RESULTS: For the BRW stereotactic system, the
      average vector distance to agreement of image-derived coordinates with the
      mechanical measurements was 1.41 +/- 0.90 mm (CT) and 1.37 +/- 0.38 mm (MR).
      Similar results were obtained using the Leksell system: 0.78 +/- 0.33 mm (CT) and
      1.45 +/- 0.86 mm (MR). The vector distance to agreement between CT and MR was
      1.42 +/- 0.55 mm for the BRW and 1.31 +/- 0.60 mm for the Leksell systems.
      CONCLUSIONS: The data support the use of our anthropomorphic phantom, and present
      a methodology for assessing radiosurgery target localization and imaging
      accuracy.

PMID- 10581523
TI  - Remote-rendered 3D CT angiography (3DCTA) as an intraoperative aid in
      cerebrovascular neurosurgery.
AB  - OBJECTIVE: To assess the viability and utility of network-based rendering in the
      treatment of patients with cerebral aneurysms, we implemented an intraoperative
      rendering system and protocol using both three-dimensional CT angiography (3DCTA)
      and perspective volume rendering (PVR). MATERIALS AND METHODS: A Silicon Graphics
      InfiniteReality engine was connected via a Fast Ethernet network to a workstation
      in the neurosurgical operating room. A protocol was developed to isolate bone and
      vessels using an appropriate transfer function. Three-dimensional CT angiogram
      images were volume rendered and transmitted to the workstation using a bandwidth
      conserving remote rendering system, and were rotated, cut using clipping planes,
      and viewed using normal and perspective views. Twelve patients with intracranial
      aneurysms were examined at surgery using this system. RESULTS: Rendering
      performance at optimal operating bandwidths (50-60 Mb/s) was excellent, with
      regeneration of a high-resolution image in less than 1 s. Network performance
      varied in two cases, slowing image regeneration. Surgeons found the images to be
      useful as an adjunct to conventional imaging in understanding the morphology of
      complex aneurysms and their relationship to the skull base. CONCLUSIONS:
      Intraoperative volume rendering using 3DCTA is achievable over a network, can
      reduce hardware costs by amortizing hardware among multiple users, and provides
      useful imaging information during the surgical treatment of cerebral aneurysms.
      Future operating suites may incorporate network-transmitted three-dimensional
      images as additional sources of imaging information.

PMID- 10581524
TI  - A surgical planning and guidance system for high tibial osteotomy.
AB  - OBJECTIVE: To develop a three-dimensional pre-surgical planner and an
      intraoperative guidance system for high tibial osteotomy. The parameters that
      describe the placement and orientation of the osteotomy resection planes were to
      be transmitted to an accompanying guidance system that allowed the surgeon to
      reproducibly perform the planned procedure. MATERIALS AND METHODS: The planning
      system and guidance system were coded using OpenGL on UNIX workstations. In vitro
      tests were performed to compare the reproducibility of the computer-enhanced
      technique to that of the traditional technique, and an in vivo pilot study was
      initiated. RESULTS: In vitro, the computer-enhanced technique produced a
      significant reduction, by one half, in both the maximum error of correction and
      the standard deviation of the correction error. Preliminary in vivo results on
      six patients suggest that similar error diminution will occur during regular
      clinical application of the technique. CONCLUSIONS: Both studies showed that the
      computer system is simple to use. The work suggests that three-dimensional
      planning and performance of high tibial osteotomy is essential for accurate
      correction of the alignment of the lower limb.

PMID- 10581525
TI  - Contribution of low-dose CT-scan protocols to the total positioning error in
      computer-assisted surgery.
AB  - PURPOSE: To quantify the contribution of a computed tomography (CT) scan to
      navigation accuracy in computer-assisted surgery. METHODS: Eighty-eight patients
      undergoing computer-assisted facial or skull-base surgery were fitted
      preoperatively with 4 to 12 markers, either attached to the skin (n = 20) or
      fixed in the osseous skull (micro-screws; n = 68). Low-dose high-resolution
      spiral CT was achieved with 25-cm field of view (FoV), 1-mm slice thickness, 2-mm
      table increment, 1-mm reconstruction interval, 140 kV, 40 mA, bony reconstruction
      algorithm, and 180 degrees reconstruction profile (effective slice thickness =
      1.8 mm). During surgery, navigation accuracy was evaluated using two navigation
      systems. RESULTS: Mean error was 0.66 mm for osseous markers and 1.58 mm for
      cutaneous markers. Both values are markedly smaller than the effective slice
      thickness of the scan protocol used. Radiation exposure of the patient for the
      entire examination never exceeded that necessary for one single 10-mm slice in a
      standard brain examination. Despite the reduced dose, landmarks and fiducials
      were precisely identified in all cases. CONCLUSIONS: The CT-induced positioning
      error in the Z-axis is considerably reduced by overlapping raw data
      reconstruction. For 1-mm slices and a 25-cm FoV, the average scan-induced
      positioning error is about 0.3 mm. Spatial resolution is not affected by the low
      dose applied. For MRI-based navigation, a 1 mm3 voxel size is the best compromise
      between signal-to-noise ratio, spatial resolution and scan time.

PMID- 10581526
TI  - Real-time simulation of tissue deformation for the nasal endoscopy simulator
      (NES).
AB  - Endonasal sinus surgery requires a great amount of training before it can be
      adequately performed. The complicated anatomy involved, the proximity of relevant
      structures, and the variability of the anatomy due to inborn or iatrogenic
      variations make several complications possible. Today, cadaver dissections are
      the "gold standard" for surgical training. To overcome the drawbacks of
      traditional training methods, the Fraunhofer Institute for Computer Graphics is
      currently developing a highly interactive medical simulation system for nasal
      endoscopy and endonasal sinus surgery, in cooperation with the Mainz University
      Hospital. For the simulation of a rhinoscopic procedure, not only are the
      realization of the 3D interaction and the geometric representation of the
      anatomical structures necessary, but also a real-time simulation of the
      deformation behavior constrained by the instrument collisions. The challenge is
      to close the gap between a maximal degree of realism and the required real-time
      conditions.

PMID- 10581527
TI  - An overall perspective of X-ray damage to a DNA oligomer mediated by reactive
      oxygen species.
AB  - The products produced by X irradiation of an oxygenated aqueous solution
      containing d(CpApTpG) were analyzed by NMR spectroscopy and mass spectrometry.
      Thirteen different base modifications were detected, including a novel product
      formed by the addition of oxygen to guanine. Seven different strand break
      products were identified, including strands having 5'-phosphoryl groups, 3'
      phosphoryl groups and groups having 3'-phosphoglycolates as termini. The products
      produced in largest yield contained base modifications: Pyrimidine bases degraded
      to a formamido moiety, the 8-oxo-7,8-dihydroguanine (8-oxoguanine) lesion, and
      double base lesions in which both the 8-oxo-7,8-dihydroguanine lesion and a
      formamido remnant are present.

PMID- 10581528
TI  - Free radical yields in crystalline DNA X-irradiated at 4 K.
AB  - The objective of this work is to determine the extent to which various structural
      factors influence the yield of trapped free radicals, G(tfr), in DNA irradiated
      at 4 K. G(tfr) was measured in a series of 13 different oligodeoxynucleotides
      using electron paramagnetic resonance (EPR) spectroscopy. Each sample consisted
      of crystalline duplex DNA for which the crystal structure was verified to be that
      reported in the literature. We find that the G(tfr) of these samples is
      remarkably high, ranging from 0.55 to 0.75 micromol/J. The standard deviation in
      G(tfr) for a given crystal structure is generally small, typically less than +/
      10%. Furthermore, G(tfr) does not correlate with DNA base sequence, conformation,
      counterion or length of base stacking. Two observations point to the importance
      of DNA packing: (1) The radical yields in crystalline DNA are greater than those
      determined previously for DNA films (0.2 to 0.5 micromol/J); and (2) the
      variability in G(tfr) is less in DNA crystals than in DNA films. We conclude that
      closely packed DNA maximizes radical trapping by minimizing the interhelical
      solvent space. Furthermore, the high efficiency of electron and hole trapping at
      4 K is not consistent with DNA possessing properties of a metallic conductor.
      Indeed, it behaves as an insulator, whether it is in A-, B-, or Z-form and
      whether base stacking is short- (8 bp) or long-range (>1000 bp).

PMID- 10581529
TI  - Degradation of the nuclear matrix is a common element during radiation-induced
      apoptosis and necrosis.
AB  - Human promyelocytic leukemia (HL60) cells were irradiated with 10 or 50 Gy of X
      rays and studied for up to 72 h postirradiation to determine the mode of death
      and assess changes in the nuclear matrix. After 50 Gy irradiation, cells were
      found to die early, primarily by apoptosis, while cells irradiated with 10 Gy
      died predominantly by necrosis. Disassembly of the nuclear lamina and degradation
      of the nuclear matrix protein lamin B occurred in cells undergoing radiation
      induced apoptosis or necrosis. However, using Western blotting and a recently
      developed flow cytometry assay to detect changes in nuclear matrix protein
      content, we found that the kinetics and mechanisms of disassembly of the nuclear
      lamina are different for each mode of cell death. During radiation-induced
      apoptosis, cleavage and degradation of lamin B to a approximately 28-kDa fragment
      was detected in most cells within 4-12 h after irradiation. Measurements of dual
      labeled apoptotic cells revealed that nonrandom DNA fragmentation was evident
      prior to or concomitant with breakdown of the nuclear lamina. Disassembly of the
      nuclear lamina during radiation-induced necrosis occurred much later (between 30
      60 h after irradiation), and a different cleavage pattern of lamin B was
      observed. Degradation of the nuclear lamina was also inhibited in apoptosis
      resistant BCL2-overexpressing HL60 cells exposed to 50 Gy until approximately 48
      h after irradiation. These data indicate that breakdown of the nuclear matrix may
      be a common element in radiation-induced apoptosis and necrosis, but that the
      mechanisms and temporal patterns of breakdown of the nuclear lamina during
      apoptosis are distinct from those of necrosis.

PMID- 10581530
TI  - Modulation of tumor cell proliferation and apoptosis by polyamine depletion in
      cells of head and neck squamous cell carcinomas.
AB  - These studies were carried out to examine the capacity of alpha
      difluoromethylornithine (DFMO) to modulate cell proliferation and apoptosis in
      cells of squamous cell carcinomas (SCCs) of the head and neck. Exposure of cells
      to DFMO (5 mM for 48 h) depleted intracellular putrescine and spermidine levels
      (greater than 5-fold) and inhibited proliferation of the cells without
      manifestation of cytotoxicity as measured by a clonogenic assay. Exposure of the
      cells to DFMO did not influence the survival response after exposure to single
      dose radiation between 0 and 10 Gy. Treatment of polyamine-depleted cells with
      200 nM staurosporine amplified apoptosis 65% (1.65-fold) over that in controls,
      as determined by flow cytometry. The increased apoptosis after DFMO treatment was
      effectively inhibited by the addition of 1 mM putrescine or spermidine. Cleavage
      of poly(ADP-ribose) polymerase (PARP) illustrated that the staurosporine
      treatment induced apoptosis in the cells within 6 h. Analysis of PARP cleavage
      indicated that treatment with DFMO accelerated the kinetics of progression of
      apoptosis but did not influence the sensitivity of cells to 10 nM-1 microM
      staurosporine. These data suggest an involvement of endogenous polyamines in
      modulation of proliferation kinetics and apoptosis in human SCCs and suggest
      opportunities to explore new therapeutic strategies in head and neck cancer
      patients to be treated with radiation therapy.

PMID- 10581531
TI  - Inhibition of store-operated calcium entry in human lymphocytes by radiation:
      protection by glutathione.
AB  - The influence of gamma radiation on basal compared to activation-dependent Ca(2+)
      influx in human lymphocytes was investigated. A new quantitative fluorescence
      technique termed differential ratiometric fluorescence spectroscopy (DRFS) was
      employed. DRFS facilitated the real-time detection of changes in fluorescence in
      experimental and control cell samples simultaneously, enabling the resolution of
      acute moderate changes ( congruent with10-30%) in Ca(2+) (manganese) influx after
      exposure to ionizing radiation and other oxidant interventions. Exposure to
      radiation inhibited thapsigargin-stimulated store-operated Ca(2+) influx but not
      basal Ca(2+) influx in Jurkat T cells and human peripheral blood lymphocytes. The
      response of store-operated Ca(2+) influx to gamma radiation was dependent on dose
      between 5 and 40 Gy and was inhibited by preincubation with the Ca(2+) channel
      blocker Ni(2+), as determined with Jurkat T cells. Elevation of the intracellular
      concentration of glutathione significantly reduced the inhibition of Ca(2+)
      influx by gamma radiation. Similar to radiation, both the superoxide anion
      generating xanthine/xanthine oxidase system and hydrogen peroxide inhibited
      thapsigargin-stimulated Ca(2+) influx in Jurkat T cells, and this inhibition was
      reversed in the presence of the antioxidant N-acetyl-l-cysteine. In conclusion,
      (1) ionizing radiation inhibited store-operated Ca(2+) entry in human
      lymphocytes, (2) the sensitivity of Ca(2+) influx to radiation was strictly
      dependent on depletion of Ca(2+) stores, and (3) glutathione protected against
      the inhibition of store-operated Ca(2+) entry by gamma radiation.

PMID- 10581532
TI  - Radiation-induced alterations in rat mesangial cell Tgfb1 and Tgfb3 gene
      expression are not associated with altered secretion of active Tgfb isoforms.
AB  - Despite evidence of selective radiation-induced modulation of expression of rat
      mesangial cell Tgfb gene isoforms, it is unclear whether these changes in gene
      expression are accompanied by changes in protein secretion. To address this
      issue, primary cultures of rat mesangial cells (passage number 6- 11) were placed
      in serum-free medium 24 h prior to irradiation with single doses of 0.5-20 Gy of
      (137)Cs gamma rays. After irradiation, cells were maintained in serum-free medium
      for a further 24 h. Irradiation of quiescent mesangial cells resulted in a
      significant (P </= 0.05) dose-independent increase in steady-state levels of
      Tgfb1 mRNA 24 h postirradiation. In contrast, steady-state levels of Tgfb3 mRNA
      exhibited a dose-dependent reduction after irradiation; this reduction was
      statistically significant after doses of 5 and 10 Gy compared to control cells (P
      </= 0.05). These radiation-induced changes in Tgfb gene expression were
      associated with modest increases in Tgfb protein as determined using mink lung
      epithelial cells transfected with the Pai1 promoter-luciferase construct. Twenty
      four hours after a single dose of 5 Gy, the total Tgfb protein secreted by the
      mesangial cells was 181 +/- 2.0% of that secreted by unirradiated control cells
      (P </= 0.01). However, this increase was seen in terms of latent Tgfb protein;
      radiation failed to increase significantly the amount of active Tgfb protein
      secreted by mesangial cells. Both quiescent and irradiated rat mesangial cells
      secreted active Tgfb as primarily the Tgfb3 isoform. These data reinforce the
      need to interpret changes in Tgfb gene expression with caution.

PMID- 10581533
TI  - Interleukin 4 promotes survival of lethally irradiated mice in the absence of
      hematopoietic efficacy.
AB  - The therapeutic potential of Il4 in lethally irradiated mice was evaluated in
      C57BL6/J mice subjected to 7 to 10 Gy total-body irradiation (TBI) from a (60)Co
      gamma-ray source. Il4 was administered 2 h after TBI either in a single injection
      or for 5 consecutive days. Il4 treatment increased 30-day survival of mice
      irradiated with doses as high as 8.5 Gy, which caused 100% mortality in placebo
      treated animals. By convention, hematopoietic failure would induce death over a
      period of up to 30 days. However, in our study, the Il4-enhanced survival of mice
      within this period could not be attributed to significantly accelerated
      hematopoietic reconstitution as shown by blood cell counts and progenitor cell
      contents in the bone marrow and spleen. Our data strongly suggest that aplasia is
      not the only cause of death of animals irradiated with doses around the LD(50)
      and that Il4-treated animals can survive in spite of a very poor hematopoietic
      activity.

PMID- 10581535
TI  - A model for radiation-related cancer suggested by atomic bomb survivor data.
AB  - The age-time patterns of excess cancer risk among A-bomb survivors followed up by
      the Radiation Effects Research Foundation inevitably carry implications regarding
      the mechanisms of radiation-related cancer. It has recently been found, quite
      surprisingly and in contrast to impressions given by the relative risks, that for
      most solid cancers the excess incidence rates themselves depend very little on
      age at exposure or time since exposure, but mainly on attained age. This paper
      investigates a mechanistic model that conforms to these age-time patterns. The
      essence of the model, which is highly idealized, is that: (a) a cancer is caused
      by mutations that accumulate in a stem cell throughout life, essentially the
      Armitage-Doll multistage model, and (b) radiation is a general mutagen that can
      cause virtually any of these mutations. Although postulate (b) departs from
      previous modeling considerations, the extent to which it explains various aspects
      of the data in substantial detail is remarkable. A strength of the model is that,
      similarly to the Armitage-Doll multistage model but differently from many others,
      it predicts characteristic age-time patterns of excess rates rather independently
      of its parameter values. The consequence of (a) is that, in Armitage-Doll
      fashion, background rates increase throughout life as a power of age. The
      consequence of (b) is that excess absolute rates do not depend on age at exposure
      and increase with age to a power one less than that of the background rates. Thus
      the excess relative risk, which is the ratio of these rates, decreases throughout
      life as 1/age with no dependence on age at exposure. Although this age pattern of
      relative risks corresponds closely to the RERF data for solid cancer, the
      interpretation of such a description is quite different from the usual one in
      which age at exposure plays a primary role.

PMID- 10581536
TI  - Biological dosimetry of chernobyl cleanup workers: inclusion of data on age and
      smoking provides improved radiation dose estimates.
AB  - We report the results of a study of chromosome translocations in 126 Russian
      subjects who participated in the cleanup activities at Chernobyl and another 53
      subjects, from other places in Russia, who were not exposed at Chernobyl. In
      agreement with our earlier study, we find increased translocation frequencies
      among the exposed compared to Russian controls. We describe statistical methods
      for estimating the dose of ionizing radiation determined by scoring chromosome
      translocations found in circulating lymphocytes sampled several years after
      exposure. Two statistical models were fitted to the data. One model assumed that
      translocation frequencies followed an overdispersed Poisson distribution. The
      second model assumed that translocation frequencies followed a negative binomial
      distribution. In addition, the effects of radiation exposure were modeled as
      additive or as multiplicative to the effects of age and smoking history. We found
      that the negative binomial model fit the data better than the overdispersed
      Poisson model. We could not distinguish between the additive and the
      multiplicative model with our data. Individual dose estimates ranged from 0 (for
      43 subjects) to 0.56 Gy (mean 0.14 Gy) under the multiplicative model and from 0
      to 0.95 Gy (mean 0.15 Gy) under the additive model. Dose estimates were similar
      under the two models when the number of translocations was less than 4 per 100
      cells. The additive model tended to estimate larger doses when the number of
      translocations was greater than 4 per 100 cells. We also describe a method for
      estimating upper 95% tolerance bounds for numbers of translocations in unexposed
      individuals. We found that inclusion of data on age and smoking history was
      important for dose estimation. Ignoring these factors could result in gross
      overestimation of exposures, particularly in older subjects who smoke.

PMID- 10581534
TI  - Magnesium activation of GTP hydrolysis or incubation in S-adenosyl-l-methionine
      reverses iron-56-particle-induced decrements in oxotremorine enhancement of K+
      evoked striatal release of dopamine.
AB  - Previous research has determined that the deficits in motor behavior seen in aged
      animals irradiated with (56)Fe particles involved alterations in muscarinic
      receptor sensitivity. In the present experiments, we determined whether
      increasing either membrane fluidity by exposure of striatal slices from
      irradiated ((56)Fe particles) animals to S-adenosyl-l-methionine (SAM) or GTP
      hydrolysis with Mg(2+) would reverse this (56)Fe-particle-induced loss of
      muscarinic receptor sensitivity, as has been observed in aged animals. Results
      indicated that, while increasing Mg(2+) concentrations in the incubation medium
      was effective in reducing the radiation effects, SAM was able to effect some
      reversal of the radiation effects only at the lower concentration (200 microM).
      These results suggest that similar mechanisms may be involved in the deficits in
      signal transduction seen after (56)Fe-particle irradiation to those seen in
      aging, and that these may include changes in the membrane structure or
      composition that could alter subsequent responsiveness of transduction pathways.
      The results further suggest that, as has been reported previously, (56)Fe
      particle irradiation may accelerate brain aging, and that since these HZE
      particles contribute at least 1% of the dose that astronauts would receive from
      cosmic rays, long-term exposure on extended space flights (e.g. to Mars) may
      produce similar deficits that could have immediate or delayed effects on
      behavior.

PMID- 10581537
TI  - Radiofrequency electromagnetic fields have no effect on the in vivo proliferation
      of the 9L brain tumor.
AB  - The intracranial 9L tumor model was used to determine if exposure to a
      radiofrequency (RF) electromagnetic field similar to those used in cellular
      telephone has any effects on the growth of a central nervous system tumor.
      Fischer 344 rats implanted with different numbers of 9L gliosarcoma cells were
      exposed to 835.62 MHz frequency-modulated continuous wave (FMCW) or 847.74 MHz
      code division multiple access (CDMA) RF field with nominal slot-average specific
      absorption rates in the brain of 0.75 +/- 0.25 W/kg. The animals were exposed to
      the RF field for 4 h a day, 5 days a week starting 4 weeks prior to and up to 150
      days after the implantation of tumor cells. Among sham-exposed animals injected
      with 2 to 10 viable cells (group 1), the median survival was 70 days, with 27% of
      the animals surviving at 150 days. The median survival length and final survival
      fraction for animals injected with 11 to 36 viable cells (group 2) were 52 days
      and 14%, respectively, while the values for those injected with 37 to 100 cells
      (group 3) were 45 days and 0%. The animals exposed to CDMA or FMCW had similar
      survival parameters, and the statistical comparison of the survival curves for
      each of the groups 1, 2 and 3 showed no significant differences compared to sham
      exposed controls.

PMID- 10581538
TI  - Integrative approaches to protein folding.

PMID- 10581539
TI  - If the loop fits...
AB  - The structure of the yeast L30 ribosomal protein bound to its autoregulatory RNA
      site has been determined by NMR spectroscopy. The intricate architecture of the
      RNA internal loop and the structure of the binding region of the protein both are
      stabilized in the complex, highlighting the importance of mutually-induced fit in
      RNA-protein interactions.

PMID- 10581540
TI  - Protein unfolding: mitochondria offer a helping hand.
AB  - Post-translocational protein import into mitochondria requires that the protein
      be unfolded prior to import. Mapping the mitochondrial-assisted unfolding pathway
      of a cargo protein and demonstrating that it deviates from the spontaneous
      unfolding pathway have provided valuable insight into the energetics of the
      translocation process.

PMID- 10581542
TI  - Tales of science

PMID- 10581541
TI  - The 'dynamics' in the thermodynamics of binding.
AB  - Assumptions of restricted flexibility upon binding conflict with emerging data
      showing that motion can increase, decrease or stay the same within molecular
      complexes. Now, calculations of entropic contributions from dynamics at specific
      positions in a complex suggest that increases in motion can dominate the free
      energy of association in certain cases.

PMID- 10581543
TI  - A guide for the bioinformatics novice

PMID- 10581544
TI  - The discovery of chaperonins.

PMID- 10581545
TI  - Picture story. How proton pumps make ATP.

PMID- 10581546
TI  - Mg2+-dependent folding of a large ribozyme without kinetic traps.
AB  - The folding kinetics of the catalytic domain of Bacillus subtilis ribonuclease P
      is analyzed here by fluorescence and catalytic activity. The folding pathway is
      apparently free of kinetic traps, as indicated by a decrease in folding rates
      upon the addition of urea. We apply Mg2+ and urea chevron analysis to fully
      describe the folding and unfolding kinetics of this ribozyme. A folding scheme
      containing two kinetic intermediates completely accounts for the free energy, the
      Mg2+ Hill coefficient and the surface buried in the equilibrium transition. At
      saturating Mg 2+concentrations, folding is limited by a barrier that is
      independent of Mg2+ and urea. These results describe the first trap-free folding
      pathway of a large ribozyme and indicate that kinetic traps are not an obligate
      feature of RNA folding.

PMID- 10581547
TI  - A novel endonuclease mechanism directly visualized for I-PpoI.
AB  - A novel mechanism of DNA endonucleolytic cleavage has been visualized for the
      homing endonuclease I-PpoI by trapping the uncleaved enzyme-substrate complex and
      comparing it to the previously visualized product complex. This enzyme employs a
      unique single metal mechanism. A magnesium ion is coordinated by an asparagine
      residue and two DNA oxygen atoms and stabilizes the phosphoanion transition state
      and the 3'oxygen leaving group. A hydrolytic water molecule is activated by a
      histidine residue for an in-line attack on the scissile phosphate. A strained
      enzyme-substrate-metal complex is formed before cleavage, then relaxed during the
      reaction.

PMID- 10581548
TI  - GTP plus water mimic ATP in the active site of protein kinase CK2.
AB  - The structures of the catalytic subunit of protein kinase CK2 from Zea mays
      complexed with Mg2+ and with analogs of ATP or GTP were determined to 2.2 A
      resolution. Unlike most other protein kinases, CK2 from various sources shows
      'dual-cosubstrate specificity', that is, the ability to efficiently use either
      ATP or GTP as a cosubstrate. The structures of these complexes demonstrate that
      water molecules are critical to switch the active site of CK2 from an ATP- to a
      GTP-compatible state. An understanding of the structural basis of dual
      cosubstrate specificity may help in the design of drugs that target CK2 or other
      kinases with this property.

PMID- 10581549
TI  - Open conformation of a flavocytochrome c3 fumarate reductase.
AB  - Fumarate reductases and succinate dehydrogenases play central roles in the
      metabolism of eukaryotic and prokaryotic cells. A recent medium resolution
      structure of the Escherichia coli fumarate reductase (Frd) has revealed the
      overall organization of the membrane-bound complex. Here we present the first
      high resolution X-ray crystal structure of a water-soluble bacterial fumarate
      reductase in an open conformation. This structure reveals a mobile domain that
      modulates substrate access to the active site and provides new insights into the
      mechanism of this widespread and important family of FAD-containing respiratory
      proteins.

PMID- 10581550
TI  - Structural and mechanistic mapping of a unique fumarate reductase.
AB  - The 1.8 A resolution crystal structure of the tetraheme flavocytochrome c3, Fcc3,
      provides the first mechanistic insight into respiratory fumarate reductases or
      succinate dehydrogenases. The multi-redox center, three-domain protein shows a 40
      A long 'molecular wire' allowing rapid conduction of electrons through a new type
      of cytochrome domain onto the active site flavin, driving the reduction of
      fumarate to succinate. In this structure a malate-like molecule is trapped in the
      enzyme active site. The interactions between this molecule and the enzyme suggest
      a clear mechanism for fumarate reduction in which the substrate is polarized and
      twisted, facilitating hydride transfer from the reduced flavin and subsequent
      proton transfer. The enzyme active site in the oxidized form is completely buried
      at the interface between the flavin-binding and the clamp domains. Movement of
      the cytochrome and clamp domains is postulated to allow release of the product.

PMID- 10581551
TI  - Structure and mechanism of the flavocytochrome c fumarate reductase of Shewanella
      putrefaciens MR-1.
AB  - Fumarate respiration is one of the most widespread types of anaerobic
      respiration. The soluble fumarate reductase of Shewanella putrefaciens MR-1 is a
      periplasmic tetraheme flavocytochrome c. The crystal structures of the enzyme
      were solved to 2.9 A for the uncomplexed form and to 2.8 A and 2.5 A for the
      fumarate and the succinate-bound protein, respectively. The structures reveal a
      flexible capping domain linked to the FAD-binding domain. A catalytic mechanism
      for fumarate reduction based on the structure of the complexed protein is
      proposed. The mechanism for the reverse reaction is a model for the homologous
      succinate dehydrogenase (complex II) of the respiratory chain. In flavocytochrome
      c fumarate reductase, all redox centers are in van der Waals contact with one
      another, thus providing an efficient conduit of electrons from the hemes via the
      FAD to fumarate.

PMID- 10581552
TI  - Increased protein backbone conformational entropy upon hydrophobic ligand
      binding.
AB  - For complexes between proteins and very small hydrophobic ligands, hydrophobic
      effects alone may be insufficient to outweigh the unfavorable entropic terms
      resulting from bimolecular association. NMR relaxation experiments indicate that
      the backbone flexibility of mouse major urinary protein increases upon binding
      the hydrophobic mouse pheromone 2-sec-butyl-4,5-dihydrothiazole. The associated
      increase in backbone conformational entropy of the protein appears to make a
      substantial contribution toward stabilization of the protein-pheromone complex.
      This term is likely comparable in magnitude to other important free energy
      contributions to binding and may represent a general mechanism to promote binding
      of very small ligands to macromolecules.

PMID- 10581553
TI  - K+ channels lacking the 'tetramerization' domain: implications for pore
      structure.
AB  - The difficulty of obtaining high-resolution structures of integral membrane
      proteins has been a frustrating barrier to understanding the membrane-based
      functions of living cells. The mere handful of such structures stands out in
      dismal contrast to the cornucopia of water-soluble proteins comprehensible at the
      atomic level. Nevertheless, crystallographically tractable preparations of
      aqueous domains of membrane proteins have provided molecular insight into
      phenomena as varied as chemotaxis, immune cell responses to antigens, viral
      infectivity and cellular synthesis of ATP. Recently, the first structural glimpse
      of a neuronal ion channel was reported - the T1, or 'tetramerization,' domain of
      a Shaker-type voltage-gated K+ channel at 1.6 A resolution. The isolated domain
      associates into a water-soluble four-fold symmetric homotetramer. This structure
      prompted the novel, provocative proposal that the T1 domain is an essential
      component of the ion permeation pathway, forming a previously unsuspected ion
      coordinating constriction on the cytoplasmic side of the channel and acting as
      the receptor for the pore-blocking 'ball and chain' inactivation peptide. It has
      also been commonly conjectured that the T1 domain is required for tetramerization
      in the channel maturation process. By studying the detailed properties of Shaker
      K+ channels in which the T1 domain is deleted, we show all these proposals to be
      invalid. The structure of the T1 domain expressed in isolation is therefore
      unlikely to mirror in detail its structure when attached to the ion-conducting
      channel.

PMID- 10581554
TI  - Crystal structure of transhydrogenase domain III at 1.2 A resolution.
AB  - The nicotinamide nucleotide transhydrogenases (TH) of mitochondria and bacteria
      are membrane-intercalated proton pumps that transduce substrate binding energy
      and protonmotive force via protein conformational changes. In mitochondria, TH
      utilizes protonmotive force to promote direct hydride ion transfer from NADH to
      NADP, which are bound at the distinct extramembranous domains I and III,
      respectively. Domain II is the membrane-intercalated domain and contains the
      enzyme's proton channel. This paper describes the crystal structure of the
      NADP(H) binding domain III of bovine TH at 1.2 A resolution. The structure
      reveals that NADP is bound in a manner inverted from that previously observed for
      nucleotide binding folds. The non-classical binding mode exposes the NADP(H)
      nicotinamide ring for direct contact with NAD(H) in domain I, in accord with
      biochemical data. The surface of domain III surrounding the exposed nicotinamide
      is comprised of conserved residues presumed to form the interface with domain I
      during hydride ion transfer. Further, an adjacent region contains a number of
      acidic residues, forming a surface with negative electrostatic potential which
      may interact with extramembranous loops of domain II. Together, the distinctive
      surface features allow mechanistic considerations regarding the NADP(H)-promoted
      conformation changes that are involved in the interactions of domain III with
      domains I and II for hydride ion transfer and proton translocation.

PMID- 10581558
TI  - 1999 subject index - volume 6

PMID- 10581555
TI  - Mitochondria unfold precursor proteins by unraveling them from their N-termini.
AB  - Protein unfolding is a key step in the life cycle of many proteins, including
      certain proteins that are degraded by ATP-dependent proteases or translocated
      across membranes. The detailed mechanisms of these unfolding processes are not
      understood. Precursor proteins are unfolded and imported into mitochondria by a
      macromolecular machine that spans two membranes and contains at least nine
      different proteins. Here we examine import of a model precursor protein derived
      from the ribonuclease barnase and show that mitochondria unfold this protein by
      unraveling it from its N-terminus. Because barnase in free-solution unfolds by a
      different pathway, our results demonstrate that mitochondria catalyze unfolding
      in the way that enzymes catalyze reactions, namely by changing reaction pathways.
      The effectiveness of this mechanism depends on the structure of the N-terminal
      part of the precursor protein.

PMID- 10581559
TI  - [Microsurgical anatomy as the anatomical basis for microsurgery].
AB  - The article presents the notions, contents and methods of studying microsurgical
      anatomy, which comprises macromicroscopic construction of an organ, biomechanic
      and morphometric characteristics of its structures, extraorgan macromicroscopic
      topography, intraorgan histotopography, macromicroscopic angio- and
      neuroarchitecture. The peculiarities of microsurgical anatomy of different organs
      and its clinical applications have been described.

PMID- 10581556
TI  - A novel loop-loop recognition motif in the yeast ribosomal protein L30
      autoregulatory RNA complex.
AB  - The yeast Saccharomyces cerevisiae ribosomal protein L30 negatively autoregulates
      its production by binding to a helix-loop-helix structure formed in its pre-mRNA
      and its mRNA. A three-dimensional solution structure of the L30 protein in
      complex with its regulatory RNA has been solved using NMR spectroscopy. In the
      complex, the helix-loop-helix RNA adopts a sharply bent conformation at the
      internal loop region. Unusual RNA features include a purine stack, a reverse
      Hoogsteen base pair (G11anti-G56syn) and highly distorted backbones. The L30
      protein is folded in a three-layer alpha/beta/alpha sandwich topology, and three
      loops at one end of the sandwich make base-specific contacts with the RNA
      internal loop. The protein-RNA binding interface is divided into two clusters,
      including hydrophobic and aromatic stacking interactions centering around G56,
      and base-specific hydrogen-bonding contacts to A57, G58 and G10-U60 wobble base
      pair. Both the protein and the RNA exhibit a partially induced fit for binding,
      where loops in the protein and the internal loop in the RNA become more ordered
      upon complex formation. The specific interactions formed between loops on L30 and
      the internal loop on the mRNA constitute a novel loop-loop recognition motif
      where an intimate RNA-protein interface is formed between regions on both
      molecules that lack regular secondary structure.

PMID- 10581560
TI  - [Changes in the capillary bed of the brain in experimental venous stasis (a
      quantitative analysis)].
AB  - Using morphometry with the following variational-statistical analysis the study
      of the structural reorganization of brain capillary bed in different model
      disturbances of intracranial venous circulation was performed. It was shown that
      in acute stage of venous congestion, obtained by different ways, capillary bed
      displayed reaction of one type, in chronic stage it was dependent on the level of
      the venous block. Integrative index of degrees of capillary bed blood supply is a
      value of its volume in 1 cubic millimeter brain parenchyma.

PMID- 10581561
TI  - [Extracranial lymphatic pathways during the compensation of cerebral
      hemorrhages].
AB  - A process of brain haemorrhages compensation, manifested by migration of free
      erythrocytes from centres of haemorrhages into the cerebrum into the cervical
      lymph nodes was studied on 40 experimental and 37 sectional observations. Typical
      zones of forming of erythrocytes aggregations in nodes were revealed, dynamics of
      compensation process was shown. Experimental data were confirmed and groups of
      lymph nodes, participating in compensations of brain haemorrhages were shown on
      the sectional material.

PMID- 10581562
TI  - [The projection anatomy of the deep median brain structures to the cranial
      vault].
AB  - The image of deep median structures of cerebrum on magnetic resonance tomogrammes
      of 20 people with different form of skull aged 20-50 years has been showed on
      craniogrammes. Projection of these formations were created on the calvaria
      [correction of convalaria] with lines, perpendicular to horizontal plane of the
      skull and penetrating the deep median structures. The data obtained can be used
      in choosing the operative approach to the callous body and infracallous
      structures.

PMID- 10581563
TI  - [The macro-microscopic anatomy of the cerebral dura mater on the internal surface
      of the skull base].
AB  - The investigations of the inner base of the human skull have been carried out on
      18 preparations using macro-microscopic preparation and morphometry of the basal
      parts of dura mater and a plaster model of their inner surface. Thickness of dura
      mater, fibrous framework constructions, its relief and interrelation with bony
      base have been studied.

PMID- 10581564
TI  - [The macro-microscopic anatomy and topography of the area of the ciliary body in
      different segments of the eyeball].
AB  - Differences in parameters of ciliary body and Schlemm's canal in different
      meridians of the eyeball has been described using histotopographic methods on 20
      eyeballs of human corpses. Circular stripe of sclera with the width to 2.1 mm
      from limb was a point of projection of Schlemm's canal, iridocorneal and
      iridociliary angles on the sclera surface. The projection of denticulate line was
      variable in limits of 1.6 mm to 5.5 mm from limb.

PMID- 10581565
TI  - [The anatomical basis for autoscleral tunnel drainage as an antiglaucoma
      operation].
AB  - Anatomical peculiarities of anterior part of the sclera have been described in 26
      cadaver eyeballs. Autoscleral tunnel drainage as antiglaucomatous operation have
      been explained.

PMID- 10581566
TI  - [The histotopography of the eye rectus muscles as an anatomical basis for
      microsurgical operations in strabismus].
AB  - The forms of vessels and muscular bundles localization in the eye rectal muscles
      were investigated by methods of morphometry and quantitative analysis. The
      vessels and the muscular bands may be disposed loose or compact as it has been
      shown. Inferior and medical rectal muscles the compact variant of bands
      distribution prevail and they are rich in vessels.

PMID- 10581567
TI  - [The morphological changes in different grafts in scleroplasty].
AB  - In the paper experimental and morphological investigations of cadaveric aorta
      wall and dura mater grafting for scleroplasty are analysed. The experiments were
      performed of 20 chinchilla rabbit eyes. The investigations have shown the
      processes of aortic allotransplants replacement by recipient tissues.
      Histological peculiarities of the sclera structural regeneration in the
      conditions of the aorta and dura mater grafting have been established.

PMID- 10581568
TI  - [The effect of neuroendocrine factors on the reparative histogenesis of the
      parotid gland cultivated in diffusion chambers].
AB  - Morphofunctional changes of parotid gland were studied in adult male rats by the
      method of subcutaneous implantation of diffusion chambers (45 transplants). The
      transplants were examined in 1, 3, 6, 8, 10 days after the beginning of
      cultivation. The implantation of tissues of parotid gland was performed with
      hypothalamic nonapeptidergic nuclei (supraoptic) as well. The work was performed
      by means of light microscopy and histochemistry. Hypothalamic neurohormones
      influence the maintenance of secretory epithelium viability, fibrogenesis and
      vasculogenesis.

PMID- 10581569
TI  - [The topographic anatomical basis for a cervical approach to the styloid process
      of the temporal bone in the surgical treatment of the styloid-hypoglossal
      syndrome].
AB  - Surgical anatomy of the temporal bone styloid process has been studied on 20
      cadavers of adults and the cervical operative approach for process resection has
      been anatomically explained. The approach provides the radical excision of the
      process without damaging the surrounding anatomical formations.

PMID- 10581570
TI  - [The microsurgical anatomy of the coronary arteries and veins of the heart].
AB  - The study has been carried out in 80 corpses of adults by macro-microscopic
      preparation and histotopographic methods. Four neurovascular bundles: right and
      left coronary, anterior and posterior interventricular ones have been described.
      Three divisions: periadventitial, perivasal and paravasal were established in
      perivascular part of cardiac nervous plexus. Morphometry of the coronary arteries
      wall layers has been performed under normal conditions and in coronarosclerosis.

PMID- 10581571
TI  - [The histotopography of the main and lobar bronchi as an anatomical basis for
      microsurgical bronchial suture].
AB  - Histotopographical study of the main and lobar bronchus was performed from 15
      corpses of people aged from 23 to 62 who did not die from lung pathology. The
      peculiarities of histotopography and their possible application in microsurgical
      operations on bronchus were shown.

PMID- 10581572
TI  - [The histotopography of the gastroduodenal junction].
AB  - Morphometrical parameters of the anterior, posterior, superior and inferior walls
      of gastroduodenal passage have been investigated in 26 preparations. Three
      anatomical forms of the pyloric sphincter were distinguished. Histotopography of
      vessels and nerves in gastroduodenal passage and their distribution in the walls
      of the passage have been investigated.

PMID- 10581573
TI  - [The microsurgical anatomy of the major duodenal papilla and of the sphincter of
      the hepatopancreatic ampulla].
AB  - Morphometrical parameters of the anterior, posterior, superior and inferior walls
      of gastroduodenal passage have been investigated in 26 preparations. Three
      anatomical forms of the pyloric sphincter were distinguished. Histotopography of
      vessels and nerves in gastroduodenal passage and their distribution in the walls
      of the passage have been investigated.

PMID- 10581574
TI  - [The morphological characteristics of microsurgical biliodigestive anastomoses].
AB  - The morphological characteristics of 3 new types of microsurgical biliodigestive
      antireflux anastomosis created in 66 mongrel dogs has been presented.
      Histotopographic data in all series of experiment are indicative of the accretion
      of mucous coats of sutured organs not later than on d 4-6. The regeneration
      processes in wound channel finishes on d 14 without forming of a scar. Adaptation
      mechanisms, occurring in the area of biliodigestive junctions are manifested
      through dislocation of the intestinal mucosa into the biliary duct, the change of
      its surface and hypertrophy of the intestinal circular muscles, surrounding the
      anastomosis, which provides its antireflux characteristic.

PMID- 10581575
TI  - [The microsurgical anatomy of the pancreas].
AB  - 70 prepared human pancreas were studied by methods of the three dimension
      sections, macro-microscopic preparation and duct injections were studied.
      Regularities of the first order lobules structure and peculiarities of duct
      system architecture were revealed. The presence of paraduodenal, paracholedochal,
      perivasal loose connective tissue, lobular organ structure and the presence of
      interlobular connective tissue septae and peculiarities of spatial distribution
      of the ducts are the anatomical basis of microsurgical interventions to the
      pancreas.

PMID- 10581576
TI  - [The x-ray anatomical characteristics of skeletopic differences and the external
      structure of the colon].
AB  - On the basis of intravital radiogrammes of the colon in 100 persons aged from 20
      to 69 without colon pathology, the range of the individual colon differences has
      been determined as well as two extreme forms and 7 intermediate variants of its
      position and external structure. The range of differences in skeletotopy of the
      right and left colic flexurae [correction of flections], in the number and the
      width of colon haustra has been shown.

PMID- 10581577
TI  - [The surgical anatomy of the extraperitoneal portions of the colonic wall].
AB  - On the 100 unfixed corpses the differences in extraperitoneal segments of the
      wall of the ascending and descending colon were found. Three basic forms of
      individual differences of blood vessels topography of the posterior wall of
      ascending and descending colon were revealed.

PMID- 10581578
TI  - [Macro-microscopic changes in the uterine tube in uterine myoma].
AB  - Macro-microscopic investigation and morphometry of uterine tubes in normal
      conditions and in uterus myoma has been carried out n 100 uterine tubes of 50
      women at reproductive age. The data were obtained on peculiarities of the
      structure of different parts, thickness of the layers, changes of the blood
      supply and microarchitecture of the uterine tube wall in various phases of
      menstrual cycle in uterus myoma.

PMID- 10581579
TI  - [Differences in the arrangement and morphometric characteristics of the umbilical
      blood vessels].
AB  - On the cross histotopographic sections of 76 cords individual differences in the
      location of two arteries and veins of cord have been studied. The data are
      obtained on the changes of morphometric parameters of cord in normal and
      complicated pregnancy (obesity, neurocirculatory dystonia in hypertension type
      and miscarriages).

PMID- 10581580
TI  - [Computer modelling of the organs of the upper abdominal cavity].
AB  - Method of creation computer models of upper floor of abdomen organs: liver,
      gallbladder, duodenum, pancreas, stomach, blood vessels with using computer
      system "DUCT" was described. Details of modelled structures of the cylindric and
      complicated forms were noted.

PMID- 10581581
TI  - [A method for the intravital systems computer visualization of an organ's
      vascular bed].

PMID- 10581582
TI  - [Current problems in the surgical anatomy of the thyroid and parathyroid glands].

PMID- 10581583
TI  - [The organizational-methodological support for the academic process as a systems
      type of activity of a department].

PMID- 10581584
TI  - [A system of ongoing and final control over topographic anatomy and operative
      surgery].

PMID- 10581586
TI  - [In Process Citation]

PMID- 10581585
TI  - [The history of anatomy on postage stamps and covers (from the philately
      collection of Prof. I. I. Kagan)].

PMID- 10581587
TI  - Radiolabelled amines and the lung.

PMID- 10581588
TI  - Predictive value of 99Tcm-sestamibi gated SPET for long-term myocardial perfusion
      and functional recovery after an acute myocardial infarction.
AB  - We assessed the predictive value of 99Tcm-sestamibi gated single photon emission
      tomography (SPET) for changes in perfusion and functional outcome after an acute
      myocardial infarction and compared the findings on functional recovery with
      echocardiography using low-dose dobutamine. Gated 99Tcm-sestamibi SPET and
      radionuclide angiocardiography were performed in 17 patients 4-10 days after an
      acute myocardial infarction. Six months later, both isotopic studies and rest
      dobutamine echocardiography were performed to assess outcome. Perfusion improved
      in six of seven severely hypoperfused segments (positive predictive value =
      85.7%) that showed wall thickening but not in any of 28 segments (negative
      predictive value = 100%) without wall thickening. The mean ejection fraction
      improved from 47.7 to 52.3% (P = 0.018). Furthermore, there was a greater
      improvement in ejection fraction in the group of patients in whom wall thickening
      predicted a recovery in perfusion (9.0 vs 3.7%, P = 0.01). A comparison of the
      assessment of functional recovery between gated SPET and dobutamine
      echocardiography showed good agreement (81.4%). We conclude that the presence of
      wall thickening in severely hypoperfused segments on 99Tcm-sestamibi gated SPET
      is predictive of changes in perfusion and functional recovery after acute
      myocardial infarction, thus identifying the presence of viable myocardium. In
      contrast, segments showing hypoperfusion and dysfunction after an acute
      myocardial infarction probably contain scar tissue only.

PMID- 10581589
TI  - Quality assurance in myocardial perfusion tomography: a collaborative BNCS/BNMS
      audit programme. British Nuclear Cardiology Society/British nuclear Medicine
      Society.
AB  - The aim of this study was to assess the status of acquisition and reporting of
      myocardial perfusion tomography in the UK. Centres were asked to provide an
      expert panel with clinical and technical information, digital and hard copy of
      raw data and reconstructed tomograms, as well as their report (optional) for five
      randomly selected studies. Ninety studies were received from 18 centres; report
      text was provided for 66 studies. Six parameters (stress technique,
      radiopharmaceutical usage, image acquisition and processing, report images and
      text) were scored as good (2), adequate (1) or poor (0) by consensus. Centres
      received the quality scores for each study and a consensus clinical report from
      the panel. Stress technique was scored as inadequate in 10 (11%) studies,
      radiopharmaceutical usage and image acquisition as inadequate in 5 (6%) studies,
      image processing as inadequate in 8 (10%) studies and report images as inadequate
      in 2 (3%) studies. Report text was felt to be inadequate in 21 of 66 (32%)
      studies; in 11 of these (52%), the report text was judged to be incorrect and in
      10 (48%) it was essentially correct but misleading because of poor phraseology.
      The mean quality score per study was 1.3 (range 0.5-2.0). Seventeen of 88 (19%)
      studies scored less than 1.0 and were considered to be of poor quality. In
      conclusion, a large variation in standards of myocardial perfusion tomography was
      seen. Data acquisition was generally satisfactory, but 32% of reports were
      inadequate.

PMID- 10581591
TI  - Early diagnosis of cardiac involvement in systemic sclerosis by 123I-MIBG
      neurotransmitter scintigraphy.
AB  - Cardiac involvement of systemic sclerosis (SSc) is associated with a poor
      prognosis. Arrhythmias and conduction disturbances are a known feature of SSc.
      From histopathological examinations, it is known that the conducting system is
      secondarily involved as a result of focal fibrosis of the myocardium. Fibrotic
      changes are believed to be related to vasospasms, such as Raynaud's phenomenon.
      The sympathetic nervous system is very sensitive to ischaemia, impairing the
      energy-dependent uptake of intraneuronal norepinephrine. 123I
      metaiodobenzylguanidine (123I-MIBG) is a metabolic analogue of norepinephrine and
      can therefore be used as a marker of norepinephrine depletion. The aim of the
      study was to evaluate the incidence and extent of SSc-associated ischaemic damage
      due to primary cardiac involvement by assessing intraneuronal 123I-MIBG uptake
      and distribution. Supplementary myocardial stress and rest perfusion
      scintigraphy, together with cardiological examinations (including an exercise
      stress test, Holter ECG and echocardiography), were performed in 18 patients.
      None of the patients showed evidence of ischaemia upon myocardial perfusion
      stress SPET or exercise stress. ECG at rest detected pathological conductance
      disturbances in one patient (6%). Holter ECG evoked pathological arrhythmias in
      three patients (17%). The echocardiograms of four patients (22%) showed a slight
      impairment of left ventricular diastolic function. 123I-MIBG scintigraphy
      revealed an inhomogeneous reduction of norepinephrine content in 15 patients
      (83%). It would appear that 123I-MIBG scintigraphy is able to detect cardiac SSc
      involvement prior to cardiological investigations.

PMID- 10581590
TI  - Myocardial fatty acid imaging with 123I-labelled 9-methyl-branched pentadecanoic
      acid (9MPA) using SPET.
AB  - 123I-labelled 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA) is a
      modified long-chain fatty acid that shows some beta-oxidation. Some basic aspects
      of this fatty acid, including myocardial uptake, distribution, clearance and
      differences from 201Tl myocardial perfusion, have yet to be evaluated. An average
      of 150 MBq of 123I-9MPA was injected intravenously into 16 patients with coronary
      artery disease. Planar images were obtained 45, 120 and 240 min post-injection,
      and single photon emission tomography (SPET) was performed at the initial (5
      min), middle (45 min) and late (120 min) phases after injection. Myocardial
      uptake and clearance were evaluated by planar imaging, and a segmental comparison
      between 123I-9MPA and reinjection or resting 201Tl was performed on the SPET
      images. 123I-9MPA showed good uptake between 5 and 60 min, but a severe decrease
      was seen after 120 min in three (19%) patients. The heart-to-mediastinum ratio
      was 1.68 +/- 0.19, 1.55 +/- 0.19 and 1.40 +/- 1.40 at 45, 120 and 240 min,
      respectively. The washout rate after background subtraction was 28% for 45 min to
      2 h and 47% for 45 min to 4 h. The segmental comparison (n = 182) between 123I
      9MPA and 201Tl showed complete agreement of 72, 75 and 65% at 10, 45 and 120 min,
      respectively. The grading of the uptake of 123I-9MPA was less than that of 201Tl
      in 20-30% of the segments indicating myocardial fatty acid metabolic impairment
      relative to perfusion. The regional clearance from 5 to 120 min in the reduced
      count region was lower than that in the normal region (28 +/- 7% vs 36 +/- 8%, P
      < 0.01). All 123I-9MPA SPET images showed good contrast if the data were acquired
      within 60 min. Based on the clearance of 123I-9MPA from the myocardium, imaging
      within 120 min is desirable. A mismatch of fatty acids and perfusion was seen in
      one-quarter of patients, and differential regional clearance may be clinically
      significant and should be investigated.

PMID- 10581592
TI  - Assessment of 99Tcm-tetrofosmin lung uptake: a modified method to avoid the
      contribution from high chest wall activity.
AB  - Evaluation of lung uptake during routine 99Tcm-tetrofosmin myocardial SPET
      (single photon emission tomography) studies may be hindered by substantial chest
      muscle uptake, particularly post-exercise. This study investigated this proposal
      and analysed the various components of chest activity that may add to the real
      lung uptake. Exercise SPET studies were performed on normal subjects using 99Tcm
      tetrofosmin and compared with the results of 99Tcm-sestamibi and 201Tl studies.
      The chest to heart count ratio (CHR) was calculated from the anterior SPET
      projection and further subclassified into lung, anterior chest and posterior
      chest to heart ratios (LHR, AHR, PHR) from the left anterior oblique (LAO)
      projection. On post-exercise images, the 99Tcm-tetrofosmin CHR was significantly
      higher than that of 201Tl and 99Tcm-sestamibi. Both the 99Tcm-tetrofosmin AHR and
      PHR were higher than those of 201Tl and 99Tcm-sestamibi. However, the LHR was
      similar for all three radiopharmaceuticals. In contrast, the rest 99Tcm
      tetrofosmin images differed little from the 201Tl and 99Tcm-sestamibi ones. Thus,
      99Tcm-tetrofosmin lung uptake post-exercise should be interpreted with caution,
      as chest muscle uptake is higher than normal. A more accurate evaluation of 99Tcm
      tetrofosmin lung uptake is achieved from the LAO projection, where the
      contribution from chest muscle counts is much less than in the routinely used
      anterior projection.

PMID- 10581594
TI  - Application of iterative and non-stationary smoothing filters for statistical
      noise reduction in nuclear medicine.
AB  - A new method for the enhancement of smoothing filters has been developed. It is
      an iterative and non-stationary (INS) process by which averaging is limited only
      to pixels that are 'statistically consistent' with the central pixel of the
      filter window. Adjustment of filter performance is achieved by the iterative
      calculation of filtered data variance. INS versions of the 25-point weighted and
      Butterworth filters have been validated and compared with their classical
      stationary versions using a numerical phantom and clinical data. The iterative
      procedure converges well after two or three iterations and produces more
      smoothing without any loss of contrast or resolution. Qualitative and
      quantitative results show that, unlike the stationary versions, the INS versions
      of the filters do not impede the detection of small or low-contrast objects and
      do preserve the contours of anatomical structures. In 99Tcm myocardial single
      photon emission tomography, the INS version of the Butterworth filter can be used
      with the same order and critical frequency, whether data have been recorded at
      rest (data with a high level of noise) or at stress (data with a low level of
      noise). In conclusion, INS filters enable noise reduction while maintaining
      contrast and resolution in filtered images. The procedure can be easily applied
      to any smoothing filter.

PMID- 10581593
TI  - Combined hyperinsulinaemic glucose clamp and oral acipimox for optimizing
      metabolic conditions during 18F-fluorodeoxyglucose gated PET cardiac imaging:
      comparative results.
AB  - To obtain optimal image quality in myocardial viability studies, it is
      recommended that 18F-fluordeoxyglucose (18F-FDG) studies be performed with
      hyperinsulinaemic glucose clamping. 18F-FDG imaging after oral administration of
      acipimox, a nicotinic acid derivative, results in comparable image quality to
      clamping. Twenty consecutive patients (7 with diabetes mellitus) with
      angiographically confirmed coronary artery disease and similar
      demographic/clinical profiles were randomly allocated to gated cardiac 18F-FDG
      PET with a standard euglycaemic hyperinsulinaemic clamp protocol or using a
      combination of oral administration of acipimox and the insulin clamp technique.
      The image quality, expressed as the myocardial-to-blood pool activity ratio, was
      superior in the combined protocol compared with the insulin clamping technique
      alone (3.37 +/- 1.46 vs 2.27 +/- 0.62, P = 0.037). Although there were no
      significant differences in plasma insulin and free fatty acids concentrations
      between the two protocols, plasma glucose concentrations obtained with the
      standard protocol were elevated compared with the combined protocol (11.1 +/- 3.7
      vs 6.3 +/- 3.0 mM during clamping; 10.2 +/- 3.3 vs 5.5 +/- 3.0 mM during
      acquisition). We conclude that gated 18F-FDG-PET imaging after oral
      administration of acipimox plus insulin clamping yields image quality superior to
      that obtained with clamping alone.

PMID- 10581595
TI  - Gastrointestinal symptoms and delayed gastric emptying in Fabry's disease:
      response to metoclopramide.
AB  - The pathophysiology of gastrointestinal symptoms in patients with Fabry's disease
      is uncertain, despite the demonstration of histological and radiographic
      abnormalities of the gastrointestinal tract. The aims of this study were to
      determine if the gastrointestinal symptoms reported by patients with Fabry's
      disease are associated with abnormal gastric emptying and, if they are, whether
      prokinetic drug therapy would be beneficial. Ten patients with Fabry's disease
      had radionuclide gastric emptying studies performed to determine if
      gastrointestinal symptoms correlated with objective evidence of abnormal gastric
      emptying. A second study was performed in seven patients who received 5 days of
      therapy with oral metoclopramide. The mean percent solid gastric emptying for
      Fabry's patients was significantly less than that of a normal control group (40
      vs 67%, P < 0.005). Five of seven patients with symptoms had abnormal gastric
      emptying. Six of seven symptomatic patients reported clinical improvement with
      metoclopramide. Of four symptomatic patients who had a repeat study after
      treatment, two showed improved emptying. In conclusion, our results suggest that
      gastrointestinal symptoms in Fabry's disease are frequently associated with
      delayed gastric emptying and that treatment with metoclopramide produces
      symptomatic and sometimes functional improvement.

PMID- 10581596
TI  - Quantitative SPET 99Tcm-DMSA uptake by the kidneys: age-related decline in
      healthy males.
AB  - To evaluate if 99Tcm-dimercaptosuccinic acid (99Tcm-DMSA) uptake by the kidneys
      is related to age and creatinine clearance in males with normal renal function,
      quantitative single photon emission tomography (SPET) of DMSA uptake by the
      kidneys was performed in 18 volunteers aged 20-79 years. The quantitative uptake
      of DMSA in the right kidney was 13.9 +/- 2.9% and in the left kidney 14.2 +/-
      3.0%. There was no statistically significant difference between left and right
      kidney uptake (t = 1.2, N.S.). Global kidney uptake (right + left) was 28.1 +/-
      5.9%. There was a statistically significant age-related decline in global DMSA
      uptake. The estimated DMSA uptake (%) was given by -0.27 x age + 42 (r = -0.87, P
      < 0.001). A good correlation was found between creatinine clearance and global
      DMSA uptake (r = 0.87, y = 2.8x + 28.3, P < 0.001). The results suggest that
      normal values of DMSA uptake by the kidneys are age-dependent.

PMID- 10581597
TI  - Reproducibility of 99Tcm-MAG3 clearance in normal volunteers with the two-sample
      method: comparison with 131I-OIH.
AB  - The aim of this study was to evaluate the reproducibility of 99Tcm
      mercaptoacetyltriglycine (99Tcm-MAG3) clearance and to compare it with that of
      131I-orthoiodohippurate (131I-OIH), which is widely used in clinical practice.
      Twelve young healthy volunteers with a mean age of 23.4 years (range 19-28) were
      enrolled in the study. The investigations were repeated at an interval of 1 month
      under similar physiological conditions. Each volunteer received a simultaneous
      injection of 99Tcm-MAG3 and 131I-OIH that was commercially available in an
      already labelled form. Blood samples were obtained at 44 and 104 min post
      injection. Clearance values were calculated using the two-sample method. The mean
      (+/- S.D.) change from the first to the second measurement was -7.1 +/- 11.1% for
      99Tcm-MAG3 and 1.7 +/- 13.6% for 131I-OIH. There were no significant differences
      between the first and the second measurements of 99Tcm-MAG3 and 131I-OIH
      clearance, respectively. 99Tcm-MAG3 clearance was shown to be very similar to
      that of 131I-OIH in healthy volunteers.

PMID- 10581598
TI  - The interpretation of lung scans.

PMID- 10581599
TI  - Adjuvant therapy for gastric carcinoma: closing out the century.
AB  - Gastric cancer is often advanced and unresectable at diagnosis. Even when a
      curative resection is possible, the 5-year survival rate for patients with T2 or
      higher tumors is less than 50%. Survival rates are even lower if lymph node
      metastases are present at surgery. Many phase III trials of adjuvant therapy have
      been conducted around the world during the past 4 decades, but their
      interpretation varies in the East and West. In the West, postoperative treatment
      modalities have not proven to be superior to postsurgical observation alone.
      Thus, at present, the routine use of postoperative therapy should be discouraged.
      In the Orient, however, routine use of postoperative chemotherapy and/or
      immunotherapy is common after a surgical procedure. Further investigations that
      correlate treatment response with molecular markers are needed. Improved clinical
      trial designs, including better preoperative staging, standardized surgical
      techniques, inclusion of adequate numbers of patients, and the continued use of a
      surgery-alone control group, are essential. In addition, the incorporation of
      newer active agents, radiotherapy, and new strategies, such as preoperative
      therapy and selection of patients based on tumor biology, would result in much
      needed advances. Less toxic approaches with novel mechanisms of action, such as
      antiangiogenesis therapy, tumor vaccines, monoclonal antibodies, and matrix
      metalloproteinase inhibitors, also hold promise.

PMID- 10581600
TI  - Current management of unusual genitourinary cancers. Part 2: Urethral cancer.
AB  - Often overshadowed by more common genitourinary cancers, such as prostate,
      testicular, and kidney cancers, penile and urethral cancers nonetheless represent
      difficult treatment challenges for the clinician. The management of these cancers
      is slowly evolving. In the past, surgery, often extensive, was the treatment of
      choice. Recently, however, radiation and chemotherapy have begun to play larger
      roles as initial therapies, with surgery being reserved for salvage. With these
      modalities in their treatment armamentarium, oncologists may now be able to spare
      patients some of the physical and psychological sequelae that often follow
      surgical intervention without compromising local control and survival. Part 1 of
      this two-part article, published in last month's issue, dealt with cancer of the
      penis. This second part focuses on cancer of the urethra in both females and
      males.

PMID- 10581601
TI  - Clinical trials referral resource. Clinical trials with the farnesyl transferase
      inhibitor R115777.

PMID- 10581602
TI  - Pain management in patients with advanced prostate cancer.
AB  - Prostate cancer is the most commonly diagnosed cancer among American men. The
      majority of patients with advanced disease have metastatic bone lesions, which
      are frequently very painful. These lesions tend to respond well to treatment with
      both nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, although careful
      dose titration and individualized treatment plans may be needed to achieve
      maximal analgesia. Opioid side effects are often transient or well controlled
      with additional medication. Patients with intolerable side effects may experience
      fewer adverse reactions with a different opioid. Palliative radiation provides
      pain relief in up to 80% of prostate cancer patients with single or at most a few
      sites of localized bone pain. Bisphosphonates, powerful inhibitors of osteoclast
      mediated bone resorption, are promising new agents for the treatment of painful
      bone lesions in prostate cancer patients. Radioisotopes, which deliver high-dose
      radiation to bone lesions without significantly affecting normal bone, are highly
      effective in providing some degree of pain relief in up to 80% of patients with
      diffuse, painful bone metastases. Also, chemotherapy shows promise in alleviating
      pain and possibly extending survival in patients with advanced prostate cancer.

PMID- 10581603
TI  - Vaccine therapy for patients with melanoma.
AB  - Investigation into the therapeutic use of vaccines in patients with metastatic
      melanoma is critically important because of the lack of effective conventional
      modalities. The most extensively studied melanoma vaccines in clinical trials are
      whole-cell preparations or cell lysates that contain multiple antigens capable of
      stimulating an immune response. Unfortunately, in the majority of studies, immune
      responses to these vaccines have not translated into a survival advantage.
      Advances in tumor cell immunology have led to the identification of candidate
      tumor cell antigens that can stimulate an immune response; this, in turn, has
      allowed for refinements in vaccine design. However, the exact tumor antigens that
      should be targeted with a specific vaccine are unknown. The univalent antigen
      vaccines, which have greater purity, ease of manufacturing, and reproducibility
      compared with polyvalent vaccines, may suffer from poorer efficacy due to
      immunoselection and appearance of antigen-negative clones within the tumor. Novel
      approaches to vaccine design using gene transfection with cytokines and dendritic
      cells are all promising. However, the induction of immune responses does not
      necessarily confer a therapeutic benefit. Therefore, these elegant newer
      strategies need to be studied in carefully designed clinical trials so that
      outcomes can be compared objectively with standard therapy. If survival is
      improved with these vaccine approaches, their ease of administration and lack of
      toxicity will firmly entrench active specific vaccine immunotherapy as a standard
      modality in the treatment of the melanoma patient.

PMID- 10581604
TI  - Counseling cancer patients about changes in sexual function.
AB  - Cancer treatments often cause sexual dysfunctions that remain severe long after
      therapy is over. Nevertheless, sexual counseling is not routinely provided in
      most oncology treatment settings. Most patients and their partners can benefit
      from brief counseling that includes education on the impact of cancer treatment
      on sexual functioning; suggestions on resuming sex comfortably and improving
      sexual communication; advice on how to mitigate the effects of physical
      handicaps, such as having an ostomy, on sexuality; and self-help strategies to
      overcome specific sexual problems, such as pain with intercourse or loss of
      sexual desire. Brief counseling can be provided by one of the allied health
      professionals on the oncology treatment team. A minority of patients will need
      specialized, intensive medical or psychological treatment for a sexual
      dysfunction. In a large cancer center, such treatment could be provided as part
      of a reproductive health clinic serving the special needs of cancer patients. In
      smaller settings, the oncologist should build a referral network of specialists.
      Not all managed care organizations reimburse for these services, however.

PMID- 10581605
TI  - [Crystallins: recruiting proteins to perform new functions].
AB  - The main properties of major water-soluble proteins of the lens, i.e.,
      crystallins, include high ability to aggregation and stability. It is these
      properties of crystallins which are required for the formation of the transparent
      lens and maintenance of lens transparency over the whole lifespan of the animal.

PMID- 10581607
TI  - [The mutant gene "wal" is active in cells of mouse hair follicles].
AB  - In order to determine the place of action of the mutant gene waved alopecia
      (wal), we have obtained chimeric wal/wal c/c Gpi-1aa<-->+/+ C/C Gpi-1bb animals
      by aggregation of eight-cellular embryos of BALB/c-wal/wal mice and CBA (+/+)
      mice. The presence or absence of the chimeric structure was determined from the
      mosaic nature of fur color and hair structure, as well as on the basis of the
      presence of electrophoretically distinct variants of glucosephosphate isomerase
      in blood. Chimeras had alternating transverse patches of different lengths and
      widths consisting of curly (genotype wal/wal) or straight (genotype +/+) hairs.
      The percentage of cells with wal/wal mutant genotype in chimeras established on
      the basis of glucosephosphate isomerase isozymes varied from 10 to 80%. A higher
      percentage of the parental wal/wal component in chimeras correlated with the
      number of patches having wavy hairs. Analysis of the fur pattern represented by
      the alternation of transverse patches of wavy or straight hairs in chimeric
      wal/wal (+/+ mice has shown that mutant gene wal acts in ectodermal cells of hair
      follicles.

PMID- 10581606
TI  - [Role of chorionic gonadotropin in the differentiation of thymocytes].
AB  - The effects of chorionic gonadotropin, a basic hormone of pregnancy, on the
      differentiation of the human thymocytes were studied. The hormone does not affect
      the phenotype as determined by expression of the membrane molecules CD3, CD4, CD8
      and functional activity of intrathymic pre-T-lymphocytes, but stimulates
      production of autocrine growth factors by these cells. Cultivation of cortical
      thymocytes in the presence of chorionic gonadotropin induces their phenotypic
      maturation with predominant development of CD4+ CD8- cells. In addition, at a
      high physiological dose (100 MU/ml) the hormone induces functional maturation of
      the cortical thymocytes. Thus, the data obtained allow us to consider this
      hormone as a factor regulating antigen-independent differentiation of T
      lymphocytes during pregnancy and determining development of the immune system in
      embryogenesis.

PMID- 10581608
TI  - [Use of the copolymer ethylenevinylacetate for studying the effect of hemopoietic
      cytokines].
AB  - Copolymer ethylenevinylacetate is known as a polymeric carrier, which ensures a
      lasting release of biologically active substances. An attempt has been made to
      use it for testing the effects of hemopoietic cytokinins. It was shown that
      erythropoietin, embedded in this polymer, induces formation of erythropoietic
      foci on acetate-cellulose membranes in the peritoneal cavity of mice.

PMID- 10581609
TI  - Interaction of Plasmodium gallinaceum ookinetes and oocysts with extracellular
      matrix proteins.
AB  - Plasmodium ookinetes are elongate, motile and invasive while inside the mosquito
      gut but promptly metamorphose into spherical immobile oocysts upon coming in
      contact with the basement membrane surrounding the midgut. There they begin a
      prolonged growth period characterized by massive DNA synthesis for the production
      of sporozoites. Living Plasmodium gallinaceum ookinetes attached avidly to the
      murine extracellular matrix proteins, laminin and collagen type IV. In ELISA-type
      assays, the main ookinete surface protein, Pgs28 was implicated as a mediator of
      parasite attachment to these basement membrane constituents. Laminin and collagen
      IV adhered to ookinete and oocyst lysates spotted onto nitrocellulose membranes.
      Receptor-ligand blot assays demonstrated that Pgs28 and an oocyst-specific
      antigen recognized by the mAb 10D6 interact with murine collagen IV and laminin.
      10D6 antigen was also recognized by monospecific antiserum against the human
      epidermal growth factor receptor. Mosquito-derived laminin was incorporated into
      oocyst capsules of P. gallinaceum growing in Aedes aegypti. We hypothesize that
      contact with the mosquito basement membrane triggers the transformation of
      ookinetes into oocysts. Coalescence of basement membrane proteins onto the
      capsules masks developing oocysts from the mosquito's immune system and
      facilitates their prolonged extracellular development in the mosquito body
      cavity.

PMID- 10581610
TI  - IgG reactivities against recombinant Rhoptry-Associated Protein-1 (rRAP-1) are
      associated with mixed Plasmodium infections and protection against disease in
      Tanzanian children.
AB  - A cross-sectional sero-epidemiological study was performed in Magoda, Tanzania,
      an area where malaria is holoendemic. Blood samples were collected from children
      (1-4 years) and tested for IgG antibody reactivity against 2 recombinant protein
      fragments of Plasmodium falciparum Rhoptry-Associated Protein-1 (rRAP-1). The
      data were related to the prevalence of malarial disease and single P. falciparum
      or mixed Plasmodium infections. Fever (> or = 37.5 degrees C) in combination with
      parasite densities > 5000/microliter were used to distinguish between children
      with asymptomatic malaria infections and those with acute clinical disease.
      Furthermore, C-reactive protein (CRP) was applied as a surrogate marker of
      malaria morbidity. The prevalence of Plasmodium infections was 96.0%. Eleven
      children were defined as clinical malaria cases, all with single P. falciparum
      infections. The density of P. falciparum was significantly lower in children with
      mixed Plasmodium infections compared to those with single P. falciparum
      infections. Children with asymptomatic P. falciparum infections had higher IgG
      reactivities to rRAP-1, compared to IgG reactivities of children with malarial
      disease. Children with mixed Plasmodium infections generally showed elevated IgG
      reactivity to rRAP-1, when compared to children with single P. falciparum
      infections. The possible relationship between mixed species infections, clinical
      outcome of the disease and antibody responses to RAP-1 is discussed.

PMID- 10581611
TI  - Association of cg2 and pfmdr1 genotype with chloroquine resistance in field
      samples of Plasmodium falciparum from Nigeria.
AB  - This study examines polymorphisms in 2 genes (pfmdr1 and cg2), which have been
      associated with resistance to chloroquine in Plasmodium falciparum, to determine
      their value as predictors of resistance status. Among field samples from children
      in Zaria, northern Nigeria, the Tyr-86 polymorphism in pfmdr1 and Ala-281 and the
      Dd2 kappa repeat of cg2, were significantly associated. In 8 samples classified
      resistant by the micro-in vitro test, or, where this failed, by in vivo trial, 7
      showed the cg2 Dd2 type kappa repeat, and 6 of these had both the Ala-281 allele
      and the pfmdr1 Tyr-86 allele. In 26 chloroquine-sensitive samples, none had this
      combination of 3 polymorphisms (P = 0.00002). This indicates 75% sensitivity and
      100% specificity in detection of resistance and shows a positive predictive value
      for resistant infections of 100%. The negative predictive value, because of
      sensitivity less than 100%, would depend on the prevalence of resistance. Where
      prevalence of resistance is approx. 21% as in Zaria, the negative predictive
      value would be 94%, while in Gabon, with a prevalence of ca 73% it would be 60%.
      The use of (cg2: Ala-281, Dd2 kappa. pfmdr1: Tyr-86) genotype detection as a
      predictive epidemiological tool to examine the distribution of chloroquine
      resistance in parts of Africa is therefore possible. The sensitivity of detection
      of resistant strains still requires improvement.

PMID- 10581612
TI  - Taxonomy and systematics of some Eimeria species of murid rodents as determined
      by the ITS1 region of the ribosomal gene complex.
AB  - Eimeria arizonensis, E. albigulae and E. onychomysis, morphologically similar
      species from closely related murid rodents, were distinguished using nuclear rDNA
      ITS1 sequences obtained from multiple isolates of each taxon. ITS1 sequences were
      also obtained from 6 other species parasitizing murid rodents: E. falciformis, E.
      langebarteli, E. nieschulzi, E. papillata, E. separata and E. sevilletensis, and
      from E. reedi, a parasite of heteromyid rodents. Under parsimony and maximum
      likelihood analyses, the isolates of E. arizonensis, E. albigulae and E.
      onychomysis were differentiated as closely related, monophyletic lineages.
      Maximum likelihood pairwise distances between the latter species ranged from 7 to
      12%, and distances within each species ranged from < 1 to 5%; thus it is
      suggested that ITS1 genetic distances may be used to facilitate taxonomic
      differentiation of Eimeria spp. Against expectation, phylogenetic procedures
      placed E. reedi within the phylogeny of the Eimeria of murid rodents. ITS1
      sequencing appears to provide data that can be used for taxonomic and
      phylogenetic studies on the speciose genus Eimeria, and may be especially useful
      when samples contain insufficient numbers of oocysts for other molecular-based
      methods, e.g. RAPD-PCR.

PMID- 10581613
TI  - An improved method to distinguish Entamoeba histolytica and Entamoeba dispar.
AB  - A 482 base pair gene fragment from samples of amoebae E. histolytica and E.
      dispar was amplified by PCR. The amplification products of fragments from the 2
      species of amoebae presented differences in mobility in non-denaturing
      polyacrylamide gel, probably due to sequence-dependent conformational alterations
      in the DNA fragments. The method described here permits E. histolytica and E.
      dispar to be distinguished with greater sensitivity and rapidity.

PMID- 10581614
TI  - Discrimination between two Perkinsus spp. isolated from the softshell clam, Mya
      arenaria, by sequence analysis of two internal transcribed spacer regions and the
      5.8S ribosomal RNA gene.
AB  - The internal transcribed spacer (ITS-1 and ITS-2) regions and the 5.8S ribosomal
      RNA gene of 2 Perkinsus spp. (G117 and H49) originating from the softshell clam,
      Mya arenaria, of the Chesapeake Bay were cloned and sequenced to obtain evidence
      for their genetic divergence. A high level of heterogeneity in both regions,
      probably resulting from deletions, insertions, and base substitutions, was
      evident from alignments of the sequences of the 2 isolates with published
      sequences of other Perkinsus spp. The isolate G117 and other Perkinsus spp. were
      highly divergent (13-26% and 19-20% sequence divergence in ITS-1 and ITS-2,
      respectively). These regions in the isolate H49 and Perkinsus marinus were
      similar (99.07% and 99% for ITS-1 and ITS-2, respectively). Evidence obtained
      from a phylogenetic analysis using the aligned sequences suggests that G117 and
      H49 belong to 2 distinct species of Perkinsus. The isolate G117 possibly belongs
      to an as yet undescribed species of Perkinsus, and H49 belongs to the species P.
      marinus. The conclusions drawn from the genetic analysis of H49 and G117 are
      supported by previously reported morphological characteristics (McLaughlin &
      Faisal, 1998b). Isolates H49 and G117 originated from the same molluscan species
      demonstrating that at least 2 different species of Perkinsus can co-exist in 1
      host.

PMID- 10581615
TI  - Geographical distances and the similarity among parasite communities of
      conspecific host populations.
AB  - The geographical distance between conspecific host populations is no doubt a key
      determinant of the likelihood that exchanges of parasite species occur between
      these populations. This variable must therefore be taken into account in studies
      that compare parasite species richness or similarity among host populations. This
      paper presents a multivariate approach, based on the permutation of matrices,
      that allows all pairwise geographical distances between host populations to be
      included as independent variables. The method is illustrated with 3 separate data
      sets on parasite communities of conspecific fish from different lakes. In 2 of 3
      cases, geographical distances among lakes had a significant influence on the
      similarity of their parasite communities. The effect of geographical distance on
      species richness of parasite communities also proved important in 2 of the 3 case
      studies. These examples demonstrate the pervasive influence of distances among
      host populations on their parasite communities, and the need to properly control
      for them in statistical analyses.

PMID- 10581616
TI  - An electrophoretic comparison of Schistosoma japonicum (Trematoda) from different
      provinces in the People's Republic of China suggests the existence of cryptic
      species.
AB  - Schistosoma japonicum from the People's Republic of China is considered to
      represent a single species comprising either 1 or 4 'strains'. We conducted an
      allozyme electrophoretic study to examine the extent of genetic variation in S.
      japonicum from mainland China. The allelic profiles of S. japonicum from 7
      provinces were established at 16 enzyme loci. S. japonicum from Sichuan had 3-5
      (19-31%) fixed differences compared with those from Zhejiang, Anhui, Jiangxi,
      Hunan, Hubei and Yunnan, suggesting that S. japonicum in mainland China
      represents a species complex. In addition, genetic markers were also established
      for different laboratory-maintained populations of S. japonicum which has
      significant implications for studying the biology of these organisms in human and
      animal hosts, and for the control and surveillance of human schistosomiasis in
      China.

PMID- 10581617
TI  - Efficacy of ivermectin in the treatment of Wuchereria bancrofti infection: a
      model-based analysis of trial results.
AB  - Ivermectin is a promising drug for the treatment of lymphatic filariasis. A meta
      analysis of trials investigating the effects of a single treatment suggested a
      dose-dependent effect on the production of microfilariae (mf) by adult Wuchereria
      bancrofti parasites. A mathematical model that describes the parasite dynamics in
      the human host and the impact of ivermectin treatment is presented and its
      outputs compared with these trials. The calculated trend in mf density after
      treatment appears to be particularly sensitive to the assumption about the mean
      life-span of mf. Adopting 0.5-2 years as a range of plausible values for this mf
      life-span, the model is used to estimate the impact of treatment on the parasite.
      It is found that irrespective of dosage, ivermectin eliminates 100% of the blood
      mf from a patient. Furthermore, at a dosage level of 400 micrograms/kg a single
      treatment irreversibly reduces the mf production of the adult parasites by at
      least 65%. For a dosage of 200 micrograms/kg this reduction is at least 35%. No
      such effect can be concluded from the results of trials using lower dosages.

PMID- 10581618
TI  - Evidence from two planorbid snails of a complex and dedicated response to
      digenean (echinostome) infection.
AB  - The planorbid snail Biomphalaria glabrata responded to exposure to either the
      compatible digenetic trematode Echinostoma paraensei or the incompatible species
      Echinostoma trivolvis by producing increased amounts of several distinctive
      plasma polypeptides. These polypeptides characteristically precipitated from
      plasma when mixed with secreted-excreted products (SEP) of sporocysts or rediae
      from either digenean species. In contrast, control snails, or snails that had
      been wounded or infected with bacteria (Serratia marcesens or Staphylococcus
      epidermidis) showed no obvious plasma alterations and no precipitates formed when
      their plasma was mixed with SEP. Another planorbid species, Helisoma trivolvis,
      which displays reverse compatibility for the echinostome species used, also
      responded to exposure to both echinostomes by increased production of plasma
      polypeptides that precipitated in the presence of SEP. With some individual
      variation, these 2 snail species synthesized SEP-reactive plasma polypeptides
      forming diffuse bands centred at 53, 65, 80-120 and 200 kDa (the latter absent in
      Helisoma trivolvis). The 53 kDa polypeptides had not been observed before,
      whereas the others have been noted from B. glabrata. The diffuse 65 kDa band was
      strongly bound by anti-fibrinogen antibodies, supportive of earlier studies
      indicating it contains fibrinogen-related domains. The other specified
      polypeptides were also bound by these antibodies raising the possibility that
      they too contain fibrinogen domains. The results are suggestive of a general
      ability of these 2 planorbid snails to detect the presence of echinostomes even
      if the latter are subsequently incapable of development. The complex response
      they then mount, one not evoked by other challenges such as wounding or bacterial
      infection, may represent a dedicated response to a frequently encountered group
      of pathogenic parasites, the digeneans (echinostomes).

PMID- 10581619
TI  - Molecular cloning and characterization of gut-derived cysteine proteinases
      associated with a host protective extract from Haemonchus contortus.
AB  - Cysteine proteinases have been implicated in the protection conferred by
      vaccination with detergent-soluble extracts of Haemonchus contortus. In the
      present study, antisera from sheep refractory to Haemonchus challenge following
      vaccination with a 'proteinase-enriched' Haemonchus gut membrane extract, were
      employed to screen a cDNA expression library of the adult parasite. This resulted
      in the isolation of 3 cDNAs (designated hmcp1, 4 and 6) encoding cathepsin B-like
      cysteine proteinases. Immunocytochemical studies specifically localized the
      products of these genes to the microvillar surface of the parasite's gut and RT
      PCR experiments revealed that these were developmentally regulated, being
      expressed exclusively during the blood-feeding parasitic stages. In addition, a
      generic PCR approach was adopted in order to identify the predominant cysteine
      proteinases in a UK strain of Haemonchus. A panel of 5 cDNAs, including hmcp1 and
      4, was amplified in this way. Genomic Southern blot analysis indicated that some
      of these enzymes were encoded by single-copy genes, whereas others were encoded
      by multi-copy genes. Subsequent sequence analysis revealed that the proteases
      identified in this study were distinct from those previously reported in USA
      strains of the parasite.

PMID- 10581620
TI  - gamma delta T cells do not play a major role in controlling infection in
      experimental cysticercosis.
AB  - Protective immunity against larval Taenia crassiceps has been shown to rely on T
      cells; however, the roles of the specific subsets of T cells during infection are
      not known. To investigate a possible role for gamma delta T cells, this study
      investigated larval infection in delta-chain knock-out C57BL/6 (deltaKO) and wild
      type C57BL/6 mice. It was found that deltaKO mice and C57BL/6 mice were equally
      susceptible to infection suggesting gamma delta T cells do not play a major role
      in protective immunity. Cytokine production by concanavalin A (ConA)-stimulated
      spleen cells from infected deltaKO mice and C57BL/6 mice were determined. All
      infected mice demonstrated an increased IL-10 production suggesting a Th1
      inhibitory function. Cells from infected deltaKO mice and C57BL/6 mice did not
      show increases in IL-4 production. Heavily-infected C57BL/6 mice showed a
      decrease in IFN-gamma production compared to deltaKO mice. These observations
      suggest that an increase in IL-10 production best correlates with a non
      protective immune response. To make comparisons between in vitro cytokine
      production and systemic immune responses, cytokine levels in serum were
      determined. C57BL/6 mice and deltaKO mice showed increases in serum levels of IL
      4 and IFN-gamma at 52 days post-infection. The systemic immune response of these
      mice, therefore, is a mixed Th1/Th2-type response and gamma delta T cells are
      apparently not responsible for the systemic increases in these cytokines.

PMID- 10581622
TI  - Are student research projects good for research and practice?

PMID- 10581621
TI  - Single nucleotide variation in rDNA ITS-2 differentiates Psoroptes isolates from
      sheep and rabbits from the same geographical area.
AB  - Psoroptic sheep scab and psoroptic otoacariasis of domestic rabbits occur in the
      same geographical regions of Switzerland. To address the question as to whether
      Psoroptes mites are naturally transmitted between sheep and rabbits, we
      determined the sequences of the rDNA second internal transcribed spacer (ITS-2)
      from psoroptic mites from sheep (5 field isolates from Switzerland and 2
      laboratory isolates from Ireland and the UK) and from rabbits (8 field isolates
      from Switzerland). The ITS-2 sequences for all Psoroptes mites originating from
      sheep were identical and differed at 1 nucleotide position from all the sequences
      of the rabbit-derived isolates. A statistically significant difference between a
      rabbit-derived isolate and isolates originating from sheep was also obtained by
      morphometric analysis of the lengths of the outer opisthosomal setae. For
      comparative purposes, the ITS-2 sequences from Chorioptes and Sarcoptes collected
      in Switzerland were also determined. No intraspecies variation was found in 6
      sarcoptic isolates from red foxes, with a sequence identity of 41% as compared to
      Psoroptes. The ITS-2 sequences of 3 chorioptic isolates differed by 24-29% from
      the Psoroptes sequence. Identical sequences were found for the Chorioptes
      isolates from sheep and a camel, which differed by 18% from the sequence of an
      isolate from a cow. These genetic data of psoroptic mites originating from sheep
      and rabbits from the same geographical area suggest the existence of
      epidemiologically separated populations.

PMID- 10581623
TI  - Prevalence of back, neck and shoulder problems in the inner city: implications
      for the provision of physiotherapy services in primary healthcare.
AB  - BACKGROUND AND PURPOSE: More general practitioners are offering physiotherapy
      services within primary healthcare; however, this provision may result in
      increased demand. Resource allocation, based on previous patterns of consultation
      for musculoskeletal conditions, may be inadequate since the need for treatment in
      the community may not have been met in the past. Therefore the aim of this study
      was to determine the prevalence of back, neck and shoulder problems that had
      restricted normal activity for more than one week during the last year and which
      health professionals (if any) patients had consulted about their symptoms.
      METHOD: A postal survey of 2400 adult patients selected at random from four
      general practices in Newcastle upon Tyne (600 from each practice). RESULTS: A
      total of 1546 questionnaires were returned, a 64% response rate. Overall, 40% of
      respondants reported having at least one back, neck and/or shoulder problem. Back
      problems were most common (30%), followed by those with neck (21%) and shoulder
      (20%) problems. Approximately one-third of those with problems consulted no one,
      a further third consulted a general practitioner and only one in six consulted a
      physiotherapist. CONCLUSIONS: There is a high prevalence of substantial back,
      neck and shoulder problems in the community and thus a wider provision of
      physiotherapy services within primary healthcare may be required to manage the
      considerable levels of potentially unmet need.

PMID- 10581624
TI  - Motivation for change in patients with prolonged musculoskeletal disorders: a
      qualitative two-year follow-up study.
AB  - BACKGROUND AND PURPOSE: The purpose of this study was to obtain a deeper
      understanding of the process of motivation for change in patients with prolonged
      musculoskeletal disorders and to identify factors that might influence change
      resulting in increased independence. METHOD: A qualitative two-year follow-up
      study. Data collection and analysis were performed according to the qualitative
      case study design. An initial conceptual framework was developed to bound and
      guide the study. Twenty patients were selected using purposive sampling with
      respect to motivation level (highly motivated to less-motivated) to create a
      sample of maximum variation. Data were collected using repeated interviews and
      standardized scales. The study comprised three data collection periods. RESULTS:
      Motivation for change followed different processes depending on the level at
      entry to the study. The highly motivated patients improved in independence, the
      moderately motivated ones remained at an unchanged level and the less-motivated
      patients became more dependent. Central themes of importance to the process of
      motivation for change were: the utilization of professional networks (healthcare,
      regional social insurance office), emotional support (nuclear family, close
      relatives), use of personal coping resources (energy, positive beliefs, problem
      solving) and social support at work (employers, colleagues). CONCLUSIONS: The
      performance of a structured motivation analysis, including questions about
      emotional networks and social support at work in addition to the clinical
      examination of the patient, is recommended. This might guide healthcare
      professionals when it comes to motivation for change in the patient.

PMID- 10581625
TI  - Fall events described by people with Parkinson's disease: implications for
      clinical interviewing and the research agenda.
AB  - BACKGROUND AND PURPOSE: The aim of this study was to describe the terminology
      used by people with Parkinson's disease (PD) when recounting falls and near
      misses (fall events) and to identify the surrounding circumstances. METHOD: This
      cross-sectional study (part of an investigation identifying risk factors for
      falling in PD) utilized structured interviews about falling, conducted in
      participants' homes. Content analysis of participants' descriptions of events was
      performed. Fifty-five independently mobile, community-dwelling people with PD,
      identified via general practices in Southampton took part in the study. RESULTS:
      Mean participant age was 71.5 years (SD = 7.6 years); mean time since diagnosis
      was 3.6 years (SD = 2.3 years). Thirty-four participants (62%) reported having
      fallen and 41 (75%) reported having nearly fallen in the previous 12 months.
      Recounting events, participants mentioned the location, frequency, process and
      landing, their activity and fall-avoidance. Falls at home, tripping, events
      arising when turning, falling forward, frequent near-misses and unsuccessful
      restoration of balance were commonly described. CONCLUSIONS: Frequent recounting
      of processes, locations and landings suggest these details are memorable and
      easily recalled. Eliciting the activities during which events occurred, their
      frequency and avoidance-strategies, may necessitate probing by interviewers. An
      interview schedule is proposed. Aspects common to falls and near-misses,
      particularly turning, suggest a natural progression of activity-related falls.

PMID- 10581626
TI  - Back pain in women post-partum is not a unitary concept.
AB  - BACKGROUND AND PURPOSE: At least half of all pregnant women experience back pain
      at some time during pregnancy and some of them also have persisting back pain
      post-partum. The aim of the present study was to identify and classify back
      problems in women post-partum by use of different pain provocation tests and
      define their relationship to spinal sagittal configuration and mobility. METHOD:
      One hundred and nineteen women with back pain persisting two months after
      delivery were interviewed and examined, on average 7.2 months post-partum. Ten
      clinical pain provocation tests were performed. The first was performed to
      identify hip pain, the second to identify radiating pain and the other eight
      tests were performed to provoke pain in the areas of the posterior
      pelvic/sacroiliac joints, the symphysis pubis and the lumbar spine. The spinal
      sagittal configuration and mobility were measured in the thoracic and lumbar
      spine, respectively, with Debrunner's kyphometer (Protek AG, Berne, Switzerland).
      RESULTS: Twenty-seven per cent of women had pain in the area of the posterior
      pelvic/sacroiliac joints, 18% in the area of the lumbar spine, 39% both in the
      area of the posterior pelvic/sacroiliac joints and in the lumbar spine, and in
      16% no pain could be provoked. There were no statistically significant
      differences between the four groups with respect to the spinal sagittal
      configuration or the mobility in the thoracic or lumbar spine. CONCLUSIONS: Back
      pain post-partum is not a unitary concept. Based on the clinical tests, women
      with back pain post-partum can be separated into groups with different pain
      localizations. The measuring of the spinal sagittal configuration and mobility
      did not help to further identify or classify post-partum back pain.

PMID- 10581627
TI  - Intra- and inter-rater reliability of an 11-test package for assessing
      dysfunction due to back or neck pain.
AB  - BACKGROUND AND PURPOSE: The intra- and inter-rater reliability of 11 tests
      assembled by physiotherapists for clinical purposes was investigated. Forty-five
      patients and 23 healthy volunteers participated in the study. METHOD: Twenty-one
      patients were tested simultaneously and independently by two physiotherapists to
      determine inter-rater reliability for two raters. Twenty-four patients and 11
      healthy volunteers were tested by one physiotherapist three times in a week to
      determine intra-rater reliability over time. Twelve healthy volunteers were
      tested by three different physiotherapists in a week to determine inter-rater
      reliability for three raters. RESULTS: Inter-rater agreement for two simultaneous
      raters was clinically acceptable. Repeatability on three test occasions was
      clinically acceptable in six of the 11 tests. There were no systematic
      differences between occasions. CONCLUSIONS: Intra- and inter-rater reliability
      was acceptable for six of the 11 tests in the form described here: three gait
      tests, two functional lifting tests and a functional muscular endurance test in
      the right leg. If these tests are to be used as outcome measures, account must be
      taken of the size of the typical fluctuation in measurements shown. The
      repeatability figures given may be used as guidelines for interpreting the
      clinical value of possible changes in test values.

PMID- 10581628
TI  - A simplified measure of balance by functional reach.

PMID- 10581629
TI  - [Predicting the secondary structures of the ribonucleic acids (RNA)].

PMID- 10581630
TI  - [The secondary structural motifs of RNA].

PMID- 10581631
TI  - [Mechanism of gene expression of positive stranded RNA viruses].

PMID- 10581632
TI  - [Calcium oscillations participate in regulation of gene expression].

PMID- 10581633
TI  - [The Crabtree effect as a metabolic strategy of fast growing tumors and other
      rapidly proliferating cells].

PMID- 10581634
TI  - [Interaction of urokinase-type plasminogen activator receptor with integrins
      during cell adhesion and migration].

PMID- 10581635
TI  - [Proteins of Alzheimer's disease].

PMID- 10581636
TI  - [Bacterial resistance to vancomycin and other glycopeptide antibiotics: an
      emerging threat].

PMID- 10581637
TI  - [Baculoviruses--insect specific viruses. Structure, infectivity and heterologous
      gene expression].

PMID- 10581638
TI  - [Bio-insecticides and insect defense mechanisms].

PMID- 10581639
TI  - [RNA with polynucleotide kinase properties, isolated by in vitro selection].
AB  - Data on isolation from a large pool of RNAs of a fragment characterized by high
      affinity ATP binding are reviewed. This ATP-binding domain flanking the regions
      of randomly sequenced nucleotide residues was used for preparation of an RNA
      pool, from which ribozymes displaying a polynucleotide kinase activity were
      isolated. The isolated ribozymes catalyzed the transfer of gamma-thiophosphate
      from ATP-gamma S to the 5' hydroxyl or to internal 2'-hydroxyls of their own
      chains. ATP was also used as a donor of phosphate; however, in this case the
      reaction rate was 55-300 times lower. Similarly to a true enzyme, one of these
      ribozymes shortened by 40 nucleotide residues at the 5' end repeatedly catalyzed
      the transfer of thiophosphate or phosphate to the 5' hydroxyl of an exogenous
      oligonucleotide.

PMID- 10581640
TI  - [Features of the elemental composition of medicinal plants, synthesizing phenolic
      compounds].
AB  - A total of 52 species of medicinal plants capable of synthesizing phenolic
      compounds were subjected to mass-scale screening for 24 chemical elements. The
      screening was performed by atomic absorption spectrometry in combination with
      spectrophotometric detection. The plant species tested were found to accumulate
      groups of two to ten chemical elements (Fe, Cr, Cu, Co, Mn, etc.), which are
      known cofactors and activators of many enzymes of phenol metabolism. Some of the
      plant species tested are overconcentrators of Cr, Co, Mn, I, and other chemical
      elements. The possibility of the use of these plants in the treatment and
      prophylaxis of disorders of the microelement metabolism is discussed.

PMID- 10581641
TI  - [The insecto-fungicidal preparation, gaupsin, isolated from Pseudomonas
      aureofaciens strains].
AB  - The integrated insectofungicidal preparation Gaupsin was developed on the basis
      of the Pseudomonas aureofaciens strains UKM V-111, which is active against
      bacterial and fungal phytopathogens, and UKM V-306, active against codling moth
      larvae. Gaupsin is an effective means for protection of orchards against moths
      and fungi. A method for production of Gaupsin in the liquid form with a titer of
      not less than 1 x 10(10) cells/ml under aeration conditions was elaborated. After
      spraying, the preparation remained on apple leaves for seven days. The efficiency
      of Gaupsin against codling moth was 88-94%. The effect of a fungal attack
      decreased 10 to 25-fold.

PMID- 10581642
TI  - The role of opioid-dopamine interactions in the induction and maintenance of
      ethanol consumption.
AB  - 1. Alcohol is one of the most widely used recreational drugs, but also one of the
      most widely abused, causing vast economic, social and personal damage. 2. Several
      animal models are available to study the reinforcing mechanisms that are the
      basis of the abuse liability of ethanol. Innate differences in opioid or dopamine
      neurotransmission may enhance the abuse liability of ethanol, as indicated by
      animal and human studies. 3. Opioid antagonists have been shown to be effective,
      both experimentally and clinically, in decreasing ethanol consumption, presumably
      since ethanol induces the release of endogenous opioid peptides in vivo. However,
      ethanol may also stimulate the formation of opiate-like compounds, which could
      interact with opioid (or dopamine) receptors. Ethanol may cause changes in
      neurotransmission mediated via opioid receptors that determines whether alcohol
      abuse is more or less likely. 4. Ethanol appears to facilitate dopamine release
      by increasing opioidergic activity, disinhibiting dopaminergic neurons (by
      inhibition of GABAergic neurotransmission) via mu-opioid receptors in the ventral
      tegmental area (VTA) and delta-opioid receptors in the nucleus accumbens (NAcc).
      The effects of ethanol would be antagonised by presynaptic kappa-opioid receptors
      present on dopaminergic terminals in the NAcc. 5. Mesolimbic dopamine release
      induced by ethanol consumption seems to indicate ethanol-related stimuli are
      important, focussing attention on and enabling learning of the stimuli. However,
      studies indicate that there are redundant pathways, and neural pathways
      'downstream' of the mesolimbic dopamine system, which also enable the reinforcing
      properties of ethanol to be mediated.

PMID- 10581643
TI  - Prevention of muscimol-induced long-term depression by brain-derived neurotrophic
      factor.
AB  - 1. The authors have recently reported a new protocol for inducing long-term
      depression through activation of GABAA receptors in the hippocampal slices. This
      long-term depression is reversed by bicuculline and potentiated by neurosteroids
      such as alphaxalone. It was also shown that glutamate receptor activity is not
      involved in the induction of this novel type of long-term depression. Brain
      derived neurotrophic factor is a member of the neurotrophins family widely
      expressed in the central nervous system. There is increasing evidence that
      indicate an important role for brain-derived neurotrophic factor in synaptic
      plasticity. It has been reported that brain-derived neurotrophic factor level is
      downregulated by GABA system. The present study investigated a possible relation
      between muscimol-induced long-term depression and brain-derived neurotrophic
      factor level. 2. Extracellular recordings were made in the CA1 pyramidal cell
      layer of rat hippocampal slices following orthodromic stimulation of Schaffer
      collateral fibers in stratum radiatum. 3. It was observed that brain-derived
      neurotrophic factor at concentration that did not have any effect itself on the
      population spike, prevents the induction of long-term depression by muscimol. In
      addition to this, K-252a an inhibitor of Trk type kinase blocked the prevention
      of muscimol-induced LTD by brain-derived neurotrophic factor. 4. The results
      suggest that there is an interaction between muscimol-induced long-term
      depression and brain-derived neurotrophic factor and may explain the post
      receptor mechanism of muscimol-induced long-term depression through a bilateral
      relation between GABAA activity and brain-derived neurotrophic factor.

PMID- 10581644
TI  - Effects of isradipine, a dihydropyridine-class calcium channel antagonist, on d
      methamphetamine-induced reduction in hunger.
AB  - 1. The authors studied the effects of isradipine, a dihydropyridine-class calcium
      channel antagonist, on d-methamphetamine-induced changes in somatic and
      psychological perceptions of hunger state using a placebo-controlled, double
      blind, Latin Square, cross-over design in 18 healthy volunteers. 2. D
      methamphetamine significantly decreased these subjective ratings of hunger,
      presumably by increasing monoaminergic turnover. 3. Effects on hunger are
      hypothesized to be mediated by norepinephrine primarily, while dopamine plays
      only a modest role. Isradipine alone, an inhibitor of dopamine release, had no
      significant effect on the hunger measures. Additionally, isradipine pretreatment
      did not significantly alter d-methamphetamine's anorexic effects. 4. Isradipine
      may, therefore, not significantly modify the control of hunger in humans.

PMID- 10581645
TI  - Effect of the alpha 2 adrenoreceptor antagonist, idazoxan, on motor disabilities
      in MPTP-treated monkey.
AB  - 1. The motor effect of the alpha 2 adrenoreceptor antagonist, idazoxan, was
      compared to that of L-dopa in MPTP-treated monkeys. 2. Idazoxan 2.0 mg/kg
      improved parkinsonian motor abnormalities which was comparable to the effects of
      a minimal effective dose of L-dopa. 3. At 2.0 and 5.0 mg/kg, the parkinsonian
      rigidity was the item most frequently alleviated by idazoxan (respectively 63.6%
      and 68.2%). 4. These findings provide support for the therapeutic utility of
      alpha 2 antagonists in the treatment of Parkinson's disease.

PMID- 10581646
TI  - Effects of the benzodiazepine antagonist flumazenil on conditioned fear stress in
      rats.
AB  - 1. The authors investigated the effect of the benzodiazepine receptor antagonist
      flumazenil on freezing behavior induced by conditioned fear stress and used a
      time-sampling procedure. 2. Rats were individually subjected to 5 min of
      inescapable electric footshock in a shock chamber. Twenty-four hours after the
      footshock, the rats were again placed in the shock chamber and observed for 5 min
      without shocks: this procedure is termed conditioned fear stress. 3. Subcutaneous
      administration of flumazenil (10 mg/kg) 30 min before conditioned fear stress
      reduced conditioned freezing, while flumazenil (1-10 mg/kg) 30 min before
      footshock did not. This indicates that flumazenil reduced the expression of
      conditioned fear, suggesting an anxiolytic effect of flumazenil. 4. This effect
      may be attributable to antagonism by flumazenil to endogenous inverse agonist
      like ligands for benzodiazepine receptors. It is suggested that endogenous
      inverse agonist-like ligands for benzodiazepine receptors are involved in the
      expression of conditioned fear stress.

PMID- 10581647
TI  - Effects of the serotonin2A/2C receptor agonist and antagonist on phencyclidine
      induced dopamine release in rat medial prefrontal cortex.
AB  - 1. Systemic administration of PCP (7.5 mg/kg, i.p.) produced a greater increase
      in extracellular DA levels in the mPFC than in the STR and NAC, as determined by
      in vivo microdialysis of awake, freely moving rats. Preferential activation by
      PCP of prefrontal DA neurons may be, at least in part, the basis for the
      pathophysiology of PCP-induced psychosis as well as schizophrenia. 2. Recent
      studies suggest a possible involvement of 5-HT2A receptors in the pathophysiology
      and treatment of schizophrenia. This study was designed to examine whether and
      how 5-HT2A receptors modulate PCP-induced DA release in the mPFC. 3. The 5
      HT2A/2C receptor agonist (+/-)-DOI (2.5 mg/kg, but not 0.75 mg/kg, i.p.),
      administered 60 min prior to PCP, significantly attenuated the PCP-induced
      increase in extracellular DA levels. Pretreatment of the 5-HT2A/2C receptor
      antagonist ritanserin (1.0 and 5.0 mg/kg, i.p.), administered 60 min prior to
      PCP, did not influence the PCP-induced increase. When administered alone, neither
      DOI (2.5 mg/kg) nor ritanserin (1.0 mg/kg) affected basal extracellular DA levels
      in the mPFC. 4. The NMDA receptor antagonist MK-801 (1.0 mg/kg, i.p.) also
      increased extracellular DA levels in the mPFC, but this effect was unaffected by
      pretreatment with DOI (2.5 mg/kg). 5. These results suggest that the stimulation
      of 5-HT2A/2C receptors may inhibit DA release in the mPFC when it is facilitated
      by PCP. Other than the NMDA receptor-mediated mechanism may also be involved in
      the neurochemical interaction between 5-HT2A receptors and PCP in the mPFC.

PMID- 10581648
TI  - Effect of amphetamine, alpha-methyl-p-tyrosine (alpha-MPT) and antipsychotic
      agents on dopamine D2-type receptor occupancy in rats.
AB  - 1. EEDQ inactivates unoccupied receptors in vivo in brain tissue and is useful in
      determining which receptors are occupied by a drug treatment. 2. alpha-MPT,
      inhibits the synthesis of dopamine, reducing D2-type receptor occupancy by
      dopamine and enhances the amount of receptor inactivation by EEDQ. 3. Amphetamine
      releases dopamine resulting in increased occupancy of dopamine D2-type receptors
      and we have shown that it protects those receptors from EEDQ. 4. Clozapine and
      remoxipride, two antipsychotic agents, occupied the dopamine receptors in both
      the caudate and cortex. 5. These findings are important because they substantiate
      other results obtained with amphetamine and SPECT, which demonstrated an
      exaggerated dopamine neurotransmission in schizophrenic patients versus normal
      controls.

PMID- 10581649
TI  - Effects of glucose and fructose on recently reactivated and recently acquired
      memories.
AB  - 1. The effects of glucose and fructose on memory reactivation were investigated.
      2. Rats were trained originally on a brightness discrimination passive avoidance
      task. 3. Memory reactivation treatment consisted of re-exposing the rats 24 hr
      later to the footshock unconditioned stimulus in the experimental room. Glucose
      or fructose (32, 100, 320, 1000, or 2000 mg/kg) was administered immediately
      after reactivation. 4. Twenty-four hr after reactivation (48 hr after training)
      the rats were tested for their ability to acquire an active avoidance (reversal)
      task. 5. The dose-response functions for the effects of both glucose and fructose
      on the reactivated memory followed identical cubic trends. However, a combined
      dose of glucose and fructose was significantly less effective at modulating
      memory than was an equimolar dose of either sugar alone. 6. We compared
      analytically the effects of combined glucose and fructose treatment on new versus
      old memories. The dose-response functions for both types of memories follow cubic
      trends, suggesting that similar multiple interacting mechanisms operate when
      memories are originally stored and when they are later re-encoded.

PMID- 10581650
TI  - The relationship between central serotonergic activity and insulin sensitivity in
      healthy volunteers.
AB  - In order to determine whether central serotonin (5-HT) activity is related to
      sensitivity of insulin receptors, 19 healthy volunteers with normal basal
      glycemia and HbAlc were studied. The relationship between prolactin response to D
      fenfluramine (delta PRL) in a challenge test and metabolic clearance rates (MCR)
      of glucose during the hyperinsulinemic-euglycemic clamp technique was evaluated.
      delta PRL had been chosen as a correlate of central 5-HT activity. Two levels of
      insulin concentration of approximately 70 mU/l (MCRsubmax) and 2000 mU/l (MCRmax)
      were used in a clamp, each for a duration of 120 min. A negative correlation was
      found between delta PRL and MCRsubmax (r = -0.55, P < 0.02) and between delta PRL
      and MCRmax (r = -0.51, P < 0.03). We did not find any correlation between the
      prolactin response to D-fenfluramine and body weight, body mass index (BMI) or
      waist and hip circumference (WHR). The data support the hypothesis of a close
      connection between 5-HT activity in the brain and peripheral sensitivity to
      insulin. The possible physiological mechanisms of this connection are discussed.

PMID- 10581651
TI  - Peripheral steroid sulfatase inhibition potentiates improvement of memory
      retention for hippocampally administered dehydroepiandrosterone sulfate but not
      pregnenolone sulfate.
AB  - Dehydroepiandrosterone sulfate (DHEAS) improves memory retention when
      administered peripherally. Estrone-3-O-sulfamate (EMATE), a steroid sulfatase
      inhibitor, potentiates the effect of DHEAS on memory retention such that lower
      doses of DHEAS improve memory retention. It is not clear if this effect is
      mediated by both compounds entering the central nervous system. In the current
      studies, mice were trained to avoid footshock in a T-maze and memory retention
      was tested 1 week later. DHEAS, injected into the hippocampus after training,
      improved memory retention in a dose-dependent manner. In previous studies,
      pregnenolone sulfate (PREGS) improved memory retention when injected into the
      hippocampus. EMATE, administered peripherally, potentiated the effect of
      centrally administered DHEAS on memory retention. However, EMATE did not
      potentiate the effect of centrally administered PREGS. It was concluded that
      EMATE, acting peripherally, increased plasma levels of DHEAS which entered the
      brain and added to the effect of centrally administered DHEAS. The failure of
      EMATE to potentiate PREGS is discussed.

PMID- 10581652
TI  - Testosterone levels and spatial ability in men.
AB  - Testosterone (T) levels were measured by salivary assays in 59 males at times of
      the day when T was expected to be highest and lowest. Relationships were
      evaluated for mean hormone levels across the two sessions and hormone level
      changes between sessions with performance on three-dimensional mental rotations,
      a spatial test which customarily favours males. An anagrams task and the digit
      symbol test were used as controls. Mental rotations scores showed a significant
      positive relationship with mean T levels but not with changes in T. There were no
      significant relationships between control test scores and mean T levels. Findings
      are discussed in terms of their contributions to the resolution of ambiguities in
      prior reported data.

PMID- 10581653
TI  - Dipeptidyl peptidase IV and adenosine deaminase activity. Decrease in depression.
AB  - Dipeptidyl peptidase IV (DPPIV) and adenosine deaminase (ADA), two T cell
      associated enzymes, are known to have a possible interaction and play essential
      roles in immune system functioning. On the other hand, depression has been shown
      to be accompanied with some immune-inflammatory alterations. In this regard, in
      order to make a contribution to the understanding of the ongoing immune
      disturbances in depression, serum DPPIV and ADA activities were determined in
      minor and major depressives and compared with healthy controls. Both enzyme
      activities were found to be decreased in major depressives compared to controls
      while only DPPIV activity was significantly lower in major depressives than the
      minor depressives. There were significant inverse relationships between enzyme
      activities and the severity of depression. Moreover, a positive intracorrelation
      was found between decreased DPPIV and ADA levels. The correlated decrease in
      DPPIV and ADA, might be a further support for their possible association. Results
      also suggest that decreased enzyme activities might reflect the impaired immune
      state in depression while major depressed patients might have a greater tendency
      to immune dysfunction than the minor depressed ones.

PMID- 10581654
TI  - Increased plasma ACTH in rats exposed to the elevated plus-maze is independent of
      the pineal gland.
AB  - The involvement of the pineal gland in activation of the hypothalamic-pituitary
      adrenocortical (HPA) axis evoked by a stressful stimulus (exposure to the
      elevated plus-maze) was investigated. Plasma ACTH levels were measured in
      pinealectomized and pineal-intact rats (sham-operated and non-operated)
      immediately after a 5 min placement into a plus-maze. A statistically significant
      elevation in plasma ACTH was measured within all groups; however, no statistical
      differences between pinealectomized and pineal-intact rats were observed.
      Similarly, comparison of the plasma ACTH basal values obtained from animals only
      kept in their home cages did not reveal any statistical differences between
      pinealectomized and pineal-intact rats. From these results it can be concluded
      that the pineal gland is not involved in anxiety-related behavior and ACTH
      response.

PMID- 10581655
TI  - The problems of treating adolescent asthma: what are the alternatives to inhaled
      therapy?
AB  - The prevalence of asthma in children and adolescents continues to increase world
      wide, with asthma remaining the most common chronic illness of childhood.
      Morbidity is high in the latter age group, indicating that many adolescents with
      asthma symptoms are not receiving appropriate treatment for their condition.
      Inadequate symptomatic control should alert the physician to the possibility of
      non-compliance, which is not limited to those patients with a poor understanding
      of their condition. Psychosocial problems, such as isolation and low self-esteem,
      are inherent in adolescents with asthma due, in part, to the highly visible
      nature of symptoms and the method of delivery of current inhaled therapy.
      Compliance with therapy in adolescents in particularly low if the dosing regimen
      is more than twice daily, with poor inhaler technique contributing to ineffective
      control. Failure to take asthma medication can result in asthma exacerbations and
      increased disease severity, with the resultant need for powerful medication and
      hospitalization (incurring substantial patient and healthcare costs). Although
      better management techniques, such as tailoring medication and individualizing
      treatment regimens may improve compliance in this group, there is an obvious need
      for alternative treatment options. An effective and well tolerated oral tablet
      therapy, with a simple unobtrusive regimen, would provide a potential solution to
      the high level of non-compliance seen in this age group. The leukotriene receptor
      antagonists offer a practical alternative amongst existing oral therapies, and
      their efficacy and simple oral dosing regimen may prove valuable in increasing
      compliance in adolescents.

PMID- 10581656
TI  - Office spirometry: temperature conversion of volumes measured by the Vitalograph
      R bellows spirometer is not necessary.
AB  - The aim of the present study was to investigate the relevance of BTPS (gas at
      body temperature, atmospheric pressure and saturated with water vapour)
      conversion of volumes measured with the Vitalograph bellows spirometer. The
      Vitalograph bellows were tested against a MicroMedical turbine spirometer in
      extreme temperatures (0-37 degrees C) using a biological control to deliver
      expired gas at BTPS. Before testing, it was shown that the accuracy of the
      DairyCard turbine was stable in the relevant temperature range. In a clinical
      trial six patients with emphysema performed home spirometry b.i.d for 1 month
      using both the Vitalograph and the turbine. Both the DairyCard and the
      Vitalograph showed stable accuracy at extreme temperatures when results were
      reported without any BTPS conversion. These findings were supported by the
      clinical trial but the conclusions from the clinical setting were weakened by the
      surprising fact that domiciliary temperatures showed almost no variation. We
      conclude that the Vitalograph bellows, during dynamic spirometry, measures
      expired volume at conditions closer to BTPS (than to ATPS) gas at ambient
      temperature, atmospheric pressure and saturated with water vapour). The use of
      the BTPS correction based on ambient temperature seems unjustified at office
      temperatures close to 23 degrees C and at extreme temperatures the conversion of
      volume will introduce significant over or underestimation.

PMID- 10581657
TI  - Oral steroid-sparing effect of two doses of nebulized fluticasone propionate and
      placebo in patients with severe chronic asthma.
AB  - Inhaled steroids, delivered by metered dose aerosol and dry powder inhalers, have
      proved effective in reducing the need for oral steroids in patients with oral
      steroid-dependant asthma. This randomized, double-blind study, compared the
      efficacy and tolerability of nebulized fluticasone propionate (FP Nebules), 2 mg
      b.d. (FP 4 mg) and 0.5 mg b.d. (FP 1 mg) with placebo, on the reduction of oral
      steroid requirement in 301 adult patients with oral steroid-dependent asthma.
      Primary efficacy was assessed by the reduction in daily oral steroid dose.
      Secondary efficacy parameters included daily diary card peak expiratory flow
      (PEF), day and night-time symptoms and clinic lung function measurements. Safety
      was assessed by adverse event monitoring and serum cortisol levels. After 12
      weeks of treatment the adjusted mean +/- SEM reduction in oral prednisolone was
      significantly greater in the FP 4 mg group (4.44 +/- 0.98 mg day-1) compared with
      FP 1 mg (2.16 +/- 1.00 mg day-1, P = 0.039) and placebo (1.20 +/- 1.02 mg day-1,
      P = 0.004). A higher percentage of patients discontinued the use of oral steroids
      with FP 4 mg (37%) compared with FP 1 mg (26%, P = 0.038) and placebo (18%, P <
      0.001). Following treatment, the adjusted mean morning PEF showed a trend in
      favour of FP 4 mg (280 +/- 41 min-1) compared with placebo (270 +/- 51 min-1, P =
      0.053) and the evening PEF was significantly higher with FP 4 mg (305 +/- 41 min
      1) compared with FP 1 mg (292 +/- 41 min-1, P = 0.010). FP 4 mg resulted in a
      significantly higher percentage of days when the patients were free from daytime
      (P = 0.036) and night-time (P = 0.021) wheeze, compared with placebo.
      Significantly fewer patients withdrew from the FP 4 mg group compared with the
      other two groups (vs. FP 1 mg, P = 0.003; vs. placebo, P = 0.032). All three
      treatments were well tolerated and the incidence of adverse events was similar
      between the groups. FP Nebules at a daily dose of between 1 and 4 mg are a safe
      and effective means of reducing the oral steroid requirement of patients with
      chronic oral steroid dependent asthma.

PMID- 10581658
TI  - An investigation of factors limiting aerobic capacity in patients with ankylosing
      spondylitis.
AB  - Ankylosing spondylitis (AS) has been shown to produce exercise limitation and
      breathlessness. The purpose of this study was to investigate factors which may be
      responsible for limiting aerobic capacity in patients with AS. Twenty patients
      with no other cardio-respiratory disease performed integrative cardiopulmonary
      exercise testing (CPET). The results were compared to 20 age and gender matched
      healthy controls. Variables that might influence exercise tolerance, including
      pulmonary function tests (body plethysmography), respiratory muscle strength
      (MIP, MEP) and endurance (Tlim), AS severity assessment including chest expansion
      (CE), thoracolumber movement (TL), wall tragus distance and peripheral muscle
      strength assessed by maximum voluntary contraction of the knee extensors (Qds),
      hand grip strength and lean body mass (LBM), were measured in the patients with
      AS and used as explanatory variables against the peak VO2 achieved during CPET.
      As subjects achieved a lower peak VO2 than controls (25.2 +/- 1.4 vs. 33.1 +/-
      1.6 ml kg-1min-1, mean +/- SEM, P = 0.001). When compared with controls,
      ventilatory response (VE/VCO2) in AS was elevated (P = 0.01); however gas
      exchange indices, transcutaneous blood gases and breathing reserve were similar
      to controls. AS subjects developed a higher HR/VO2 response (P < 0.01) on
      exertion but without associated abnormalities in ECG, blood pressure response or
      anaerobic threshold. The AS group experienced a greater degree of leg fatigue (P
      < 0.01) than controls at peak exercise. Although the breathlessness scores (BS)
      were comparable to controls at peak exercise, the slopes of the relationship
      between BS and work rate (WR) [AS 0.054 (0.1), Controls 0.043 (0.06); P < 0.05]
      and BS and % predicted oxygen uptake [AS 0.084 (0.18), Controls 0.045 (0.06); P <
      0.01] were steeper in the AS subjects. There was weak association between peak
      VO2 and vital capacity (r2% 12.0), MIP (11.8) but no association between Tlim,
      CE, Wall tragus distance or TL movement. The strongest association with aerobic
      capacity was between measurements of peripheral muscle strength (Qds; r = 0.75;
      hand grip; r = 0.47) accounting for 53% (P < 0.001) and 23.5% (P < 0.01) of the
      total variance in peak VO2, respectively. The addition of LBM to Qds in the
      regression model significantly improved the explained variance to 78.3% (P <
      0.001). This study shows that peripheral muscle function is the most important
      determinant of exercise intolerance in AS patients suggesting that deconditioning
      is the main factor in the production of the reduced aerobic capacity.

PMID- 10581659
TI  - Characteristics of users of inhaled long-acting beta 2-agonists in a southern
      European population.
AB  - We characterized the population of users of inhaled long-acting beta 2-agonists
      in the region of Friuli-Venezia Giulia, in Italy, and assessed changes in asthma
      treatment and control after initiating long-acting beta 2-agonists. All residents
      using formoterol or salmeterol between 1992 and 1996 were identified in the
      regional Health Databases. Utilization rates of asthma medications and
      hospitalization rates for asthma were computed for the year before and after the
      date of the first long-acting beta 2-agonist prescription. There were 3803 users
      of formoterol and 20,054 users of salmeterol. Overall, 65% of users were older
      than 54 years of age. All formoterol users and 86% of salmeterol users received
      their first prescription for the respective drug during the study period (new
      users). Among these new users, 50% had not received any asthma drug during the 4
      months preceding the start of long-acting beta 2-agonist administration. Prior 1
      yr utilization rates of asthma medications and hospitalization rates for asthma
      were greater among new users of long-acting beta 2-agonists than among new users
      of salbutamol and xanthines. In addition, formoterol new users had higher prior
      use of asthma drugs than new users of salmeterol. One year prior hospitalization
      rates for asthma were also higher among formoterol than salmeterol new users with
      rate ratios of 1.7 (95% CI 1.3-2.2) for patients younger than 45 and 1.5 (1.2
      1.9) for older patients. Use of short-acting beta 2-agonists, oral steroids and
      xanthines significantly declined after starting formoterol, whereas the use of
      inhaled steroids increased after the start of either formoterol or salmeterol.
      Asthma hospitalizations decreased by 32% in patients under age 45, by 43% in
      older patients, during the year following the start of formoterol, and by 15% and
      24%, respectively, after the start of salmeterol. We conclude that long-acting
      beta 2-agonists were mainly prescribed to middle-aged and elderly patients and
      that formoterol appeared to be preferentially prescribed to patients with more
      severe asthma than salmeterol. Changes in asthma treatment and reduction in
      hospitalization rates for asthma after starting formoterol and salmeterol are
      compatible with an improvement in the control of asthma.

PMID- 10581660
TI  - Steroid reversibility test followed by inhaled budesonide or placebo in
      outpatients with stable chronic obstructive pulmonary disease. The Danish Society
      of Respiratory Medicine.
AB  - The aim of this study was evaluate the predictive value of a 2 week course of
      prednisolone on the effect of 6 months treatment with inhaled budesonide in
      patients with stable chronic obstructive pulmonary disease (COPD). Forty patients
      with stable COPD entered the study, and received prednisolone (37.5 mg o.d.) for
      2 weeks. They were subsequently divided into steroid-irreversible and steroid
      irreversible, using 15% of baseline as a dividing point. In each group patients
      were randomized to receive budesonide 400 micrograms b.i.d. or placebo for 6
      months. During treatment with prednisolone, three patients dropped out because of
      side effects. Of the remaining 37, only two patients (5%) were reversible with
      prednisolone forced expiratory volume in 1s [(FEV1) > 15% of baseline], and among
      the steroid-irreversible, 26 patients were evaluated after 6 months treatment
      with either placebo or budesonide. No significant differences in spirometry
      values, symptoms, or number of exacerbations were found between these two groups.
      Reversibility with prednisolone is rarely seen in COPD. In outpatients with
      stable COPD and no signs of asthma or atopy, 2 weeks treatment with prednisolone
      seems to be of no value in choosing subsequent long-term therapy.

PMID- 10581661
TI  - Non-invasive evaluation of lower airway inflammation in hyper-responsive elite
      cross-country skiers and asthmatics.
AB  - Asthma-like symptoms and bronchial hyper-responsiveness (BHR) to methacholine are
      prevalent in competitive cross-country skiers. Whether these symptoms (ski
      asthma) in these athletes are caused by asthma remains uncertain. Bronchial
      responsiveness to adenosine 5'-monophosphate (AMP) and nitric oxide (NO)
      concentration in exhaled air, both indirect markers of asthmatic airway
      inflammation, were investigated in two non-smoking study populations of skiers
      and asthmatics. Of 18 skiers with ski asthma, 15 non-steroid and 14 steroid
      treated asthmatics, BHR to AMP was present in five (28%), six (40%) and 10 (71%)
      subjects respectively. Although the groups were not significantly different in
      responsiveness to methacholine, responsiveness to AMP increased in order of
      magnitude from ski asthma < non-steroid-treated < steroid-treated asthma. Exhaled
      NO in 44 (nine with ski asthma) skiers was not significantly different from 82
      healthy non-atopic controls [median [interquartile range (IQR)] 6.5 (4.1-9.9) vs.
      5.2 (4.2-6.5) ppb]. Exhaled NO in 29 subjects with mild intermittent asthma was
      three-fold greater [median (IQR) 19.2 (5.1-25.6) ppb, P < 0.01] than in skiers.
      Exhaled NO was two- and four-fold greater in atopic than non-atopic subjects in
      the skier (P < 0.001) and asthmatic (P < 0.01) groups, respectively, and was
      correlated to methacholine responsiveness in atopic asthmatics (n = 22, rho =
      0.55, P < 0.01). Exhaled NO was not elevated in ski asthma and may be more useful
      as a marker of atopic status than inflammation in the lower airway in skiers. Few
      skiers were hyper-responsive to AMP, indicating that pre-activated mucosal mast
      cells are not a predominant feature in ski asthma.

PMID- 10581662
TI  - Chronic respiratory symptoms, von Willebrand factor and longitudinal decline in
      FEV1.
AB  - Although some risk factors for accelerated decline in forced expiratory volume in
      1 s (FEV1) such as cigarette smoking, are well defined, it is not possible to
      identify those individuals with the most rapid rates of decline. Von Willebrand
      factor (vWF) is a product of both the pulmonary and systemic endothelium, and
      serum levels are raised during episodes of acute bronchitis. We hypothesized that
      raised serum levels of vWF may indicate sub-clinical pulmonary injury and so may
      predict subsequent accelerated decline in FEV1. The aims of this study were 1. to
      define the prevalence of chronic respiratory symptoms and obstructive airway
      disease in an inner-city British population and 2. to determine whether elevated
      levels of von Willebrand factor (vWF) identify those individuals at risk for more
      rapid decline in FEV1 over time. In 1987, all 2013 individuals aged 45 to 74
      years at an inner-city general practice were mailed a respiratory symptom
      questionnaire. One in six of the responders were asked to attend for spirometry
      and for assessment of serum vWF. In 1996, those individuals who had spirometry
      and vWF assessed in 1987 were traced, and repeat spirometry was performed. In
      1987, 1527 of 2013 (75.8%) individuals completed the questionnaire. Forty-two
      point two percent of responders reported shortness of breath on hills, 34.7%
      reported wheeze and 31.6% reported mucus hypersecretion. Smokers were more likely
      to report these symptoms. Two hundred and ten of the 251 (84%) individuals
      approached had spirometry and vWF assessed. Eleven percent of these had both an
      FEV1 < 75% predicted and a forced expiratory ratio (FEV1 forced vital capacity
      (FVC)) < 70%. Sub-normal spirometry was associated with wheeze, mucus
      hypersecretion, cigarette smoking and increasing age. By 1996, 32 (15%) of the
      original group of 210 individuals had died, and 117 of the remaining 178 (66%)
      had spirometry repeated. FEV1 < 75% predicted was a strong predictor of interim
      mortality, independent of age, sex and smoking history. The average decline in
      FEV1 was 46.7 ml yr-1. There was no significant correlation between serum vWF
      levels and subsequent decline in FEV1. Chronic respiratory symptoms and
      spirometric evidence of airflow limitation are common in inner-city residents of
      the U.K., and are associated with smoking history. Much of this disease is
      unrecognised by health professionals. An FEV1 < 75% predicted is a strong
      independent predictor of subsequent mortality. The measurement of serum vWF
      levels is unhelpful in identifying those individuals at increased risk of
      accelerated decline in FEV1.

PMID- 10581663
TI  - Exercise-induced respiratory symptoms are not always asthma.
AB  - Eighty-eight patients with a history of exercise-induced respiratory symptoms
      performed a maximal exercise test in order to study the reasons for stopping the
      test. There was a wide range of percentage maximal fall in peak expiratory flow
      (PEF), from minus 3% to 63%, mean 11%, recorded 0-30 min, mean 12 min after the
      break. In the controls the maximal decrease was 0-16%, mean 6%. Diagnostic
      criteria for asthma were fulfilled by 48 patients (55%). Of these patients 42%
      had a fall in PEF > or = 15% (exercise-induced asthma). Of the non-asthma
      patients 10% had a fall > or = 15%. The most common reason for stopping the
      exercise in the asthma group was breathing troubles (46%), the most common reason
      in the non-asthma group was chest pain/discomfort (35%). In about 20% of the
      patients dizziness and/or pricking sensations in arms or legs indicated
      hyperventilation as an additional reason for stopping the exercise. It is
      concluded that other kinds of reaction, than bronchial obstruction such as
      breathing troubles not directly related to bronchial obstruction and chest pain,
      may be important factors that can restrict physical capacity in patients with
      exercise-induced respiratory symptoms.

PMID- 10581664
TI  - Lack of effects of moderate-high altitude upon lung function in healthy middle
      aged volunteers.
AB  - This study investigates the effects of moderate-high altitude on lung function
      and exercise performance in 46 volunteers (19 females, 27 males), with a mean age
      of 42.4 +/- 1.4 years (+/- SEM) and varying smoking and exercise habits, who were
      not previously acclimatized. Measures obtained in the base camp (1140 m) and at
      altitude (2630 m), in random order, included forced spirometry, maximal voluntary
      ventilation, maximal inspiratory and expiratory pressures, arterial oxygen
      saturation and capillary lactate concentration after a standardized exercise
      test. The smoking history, Fagerstrom test and degree of habitual physical
      activity were also recorded for each participant. The percentage of smokers was
      similar in males (19%) and females (21%) (P = n.s.). Mean habitual physical
      activity index was 8.2 +/- 0.2 (range, 5.88-11.63). At the base camp, all lung
      function variables were within the normal range. Lactate concentration after
      exercise averaged 3.7 +/- 0.3 mm l-1. No significant change was observed at
      altitude, except for a higher heart rate and a lower arterial oxygen saturation
      (SaO2) (both at rest and after inspiratory manoeuvres). The smoking history and
      the degree of physical activity did not influence lung function or exercise
      performance at altitude. The results of this study show that in middle-aged,
      healthy, not particularly well-trained individuals, lung function is not
      significantly altered by moderate-high altitude, despite the absence of any
      acclimatization period and independent of their smoking history and previous
      exercise habits.

PMID- 10581665
TI  - Inflammatory markers in acute exacerbations of obstructive pulmonary disease:
      predictive value in relation to smoking history.
AB  - The aim of this study was to investigate the relationship between the effect of
      emergency treatment and inflammatory markers in patients with acute exacerbations
      of obstructive pulmonary disease, especially with respect to smoking history. We
      investigated 50 unselected patients with acute bronchial obstruction. Blood,
      urine and sputum samples were taken and analysed for eosinophil and neutrophil
      markers. The patients were observed for at least 2 h and recordings of forced
      expiratory volume in 1 s (FEV1) were taken. They were re-examined after 1 and 4
      weeks. The absolute levels of inflammatory markers did not differ significantly
      between non- or short-term smokers (< or = 5 pack-years) and long-term smokers (>
      5 pack-years) with the exception of myeloperoxidase in serum (S-MPO), which was
      higher in long-term smokers. The patients with higher levels of eosinophil
      markers before emergency treatment experienced a greater improvement in lung
      function. In non- or short-term smokers this relationship was found in blood and
      urine, whereas in long-term smokers it was seen in sputum. No correlation was
      found between neutrophil markers and changes in lung function. We conclude that
      patients with obstructive pulmonary disease with acute exacerbations and high
      levels of eosinophil markers respond well to treatment.

PMID- 10581667
TI  - A case of non-specific interstitial pneumonia associated with primary lung
      cancer: possible role of antibodies to lung cancer cells in the pathogenesis of
      non-specific interstitial pneumonia.

PMID- 10581666
TI  - Promoter variation of tumour necrosis factor-alpha gene: possible high risk for
      chronic bronchitis but not diffuse panbronchiolitis.

PMID- 10581668
TI  - Cloning of the Dam methyltransferase gene from Haemophilus influenzae
      bacteriophage HP1.
AB  - The putative product of orf13 from the genome of Haemophilus influenzae HP1
      bacteriophage shows homology only to bacteriophage T1 Dam methyltransferase, and
      a weak similarity to the conserved amino acids sequence motifs characteristic of
      m6A-methyltransferases. Especially interesting is lack of characteristic motif I
      responsible for binding of S-adenosylmethionine. Despite this fact, a DNA
      sequence of HP1 bacteriophage of Haemophilus influenzae encoding
      methyltransferase activity was cloned and expressed in Escherichia coli using
      pMPMT4 omega expression vector. The cloned methyltransferase recognizes the
      sequence 5'-GATC-3' and methylates an adenine residue. The enzyme methylates both
      double- and single-stranded DNA substrates.

PMID- 10581669
TI  - Application of Salmonella strains with altered nitroreductase and O
      acetyltransferase activities to the evaluation of the mutagenicity of airborne
      particles.
AB  - The Ames test was applied to evaluation of the mutagenicity of month's samples of
      airborne particles from the center of Wroclaw (SW Poland) collected in August and
      December 1997. The strains used for the study were TA 98, TA 100 and their
      derivatives: TA 98 NR, YG 1021, YG 1024, YG 1026, YG 1029, YG 1041, YG 1042. Both
      studied samples were mutagenic for almost all tested strains, with the exception
      of the August sample which did not influence the strain TA 100 without the
      metabolic activation with the S9 fraction. The December sample exhibited higher
      genotoxic activity than the August sample. Mutagenicity ratios of the strains
      with reduced nitroreductase and O-acetyltransferase activities were higher, and
      of the strain without the nitroreductase--lower than those of the parent strains.
      This indicates that nitro and amino derivatives of PAHs are responsible for the
      significant proportion of total mutagenicity of the studied samples of
      particulates. Metabolic activation with the S9 fraction caused the increase of
      the mutagenic activity of the samples, which indicates the presence of
      promutagens. The GC-MS analysis revealed the presence of known indirect mutagens
      from the PAHs group.

PMID- 10581670
TI  - Autolysis of Listeria monocytogenes.
AB  - Physiological conditions that could provide maximal rates of autolysis of
      Listeria monocytogenes were examined. L. monocytogenes was found to be refractory
      to most treatments that promote rapid autolysis in other bacteria. Best rates of
      autolysis were obtained after resuspending the cells in Tris-hydrochloride buffer
      at 37 degrees C with the pH optimum at 8.0. Autolysis was also efficiently
      promoted by the surfactant Triton X-100. Antibiotics that interfere with the
      biosynthesis of the cell wall murein (peptidoglycan) caused death of the cells
      without autolysis after prolonged incubation in the presence of the drug. Only
      nisin, which has been shown to bind in vitro to the murein precursors lipid I and
      lipid II brings about autolysis of L. monocytogenes cells, although with slower
      kinetics than in the case of Tris-HCl and Triton.

PMID- 10581671
TI  - Antigenic properties of LPS extracted from Bacteroides fragilis enterotoxin
      producing strains.
AB  - Antigenic properties of enterotoxigenic Bacteroides fragilis (ETBF) strains
      isolated in Poland were compared with reference strains. The agglutination and
      passive hemagglutination, SDS-PAGE analysis and immunoblotting tests as well as
      analyses of sugars and fatty acids were performed with lipopolysaccharide (LPS)
      preparations obtained from water-phase of phenol-water extracts. Some differences
      in serological reactivity between ETBF antigens were observed. The antigen of the
      NTBF (nonenterotoxigenic) reference strain IPL E-323 expressed weak cross
      reactivity with sera against whole cells of ETBF strains in serological tests.
      There were some differences observed between ETBF and NTBF strains in fatty acids
      and sugar composition. The LPS preparations probably possess a common core
      structure and the O-specific polysaccharides of variable chain length.

PMID- 10581672
TI  - Biodegradation of engine oil in soil.
AB  - Laboratory experiments were conducted with the aim of bioremediation of sandy
      soil from engine oil in 5% concentration. Bacterial strains, active in degrading
      oil hydrocarbons as a sole source of carbon and energy were selected and
      identified. Optimal parameters, such as concentration of inorganic nutrients
      (expressed as C:N and C:P ratio) and the size of inoculum were established in
      experiments on 1% engine oil biodegradation. Process enhancing role of
      surfactants addition, the application of immobilized biomass and reinoculations
      was also evaluated.

PMID- 10581673
TI  - Effect of DnaK and DnaJ proteins deprivation on Escherichia coli response to
      starvation.
AB  - E. coli defects in response to nutritional starvation caused by DnaK and DnaJ
      proteins deprivation are examined. The ability of delta dnaKdnaJ mutant to
      survive carbon, nitrogen and phosphorus starvation is highly impaired while delta
      dnaJ mutant is characterized by the diminished survival of phosphorus starvation
      only. delta dnaKdnaJ mutant grows slowly utilizing maltose and glycerol and delta
      dnaJ mutant utilizes glycerol inefficiently. The growth on alternate nitrogen
      sources is comparable to wild-type strain.

PMID- 10581674
TI  - Resistant enterococci: prevalence and factors associated with colonization in a
      Turkish university hospital.
AB  - The prevalence of high level aminoglycoside-resistant (HLAR) and vancomycin
      resistant enterococci were investigated in this study. Enterococci were isolated
      from 264 of all specimens (70.9%). Thirty strains were identified as high level
      aminoglycoside-resistant enterococci (11.4%). Vancomycin resistant enterococcus
      has not been isolated in this study.

PMID- 10581675
TI  - Adsorption and activity of Trichoderma reesei cellobiohydrolase I, endoglucanase
      II, and the corresponding core proteins on steam pretreated willow.
AB  - The adsorption and the hydrolytic action of purified cellulases of Trichoderma
      reesei, namely, cellobiohydrolase I (CBH I), endoglucanase II (EG II), and their
      core proteins, on steam-pretreated willow were compared. The two enzymes differed
      clearly in their adsorption and hydrolytic behavior. CBH I required the cellulose
      binding domain (CBD) for efficient adsorption and hydrolysis, whereas EG II was
      able to adsorb to steam pretreated willow without its CBD. Absence of the CBD
      decreased the hydrolysis of cellulose by EG II, but the decrease was less
      pronounced than with CBH I. A linear relationship was observed between the amount
      of enzyme adsorbed and the degree of hydrolysis of cellulose only for CBH I. EG
      II and EG II core appeared to be able to hydrolyze only 1 to 2% of the substrate
      regardless of the amount of protein adsorbed.

PMID- 10581676
TI  - Anaerobic toxicity and biodegradability of hydrolysis products of chemical
      warfare agents.
AB  - The toxicity and biodegradability of the main hydrolysis products of chemical
      warfare agents were investigated under methanogenic conditions. Among the tested
      substances, only MPhA does not have any toxic effect with regard to the
      aceticlastic methanogenic activity. The toxicity of other compounds varied
      between moderate (TDG, mercaptoethanol) to strong (ethanolamine, diisobutyl ester
      of MPhA). Biodegradability tests showed that all the products of chemical
      detoxification of mustard gas (ethanolamine, ethylene glycol, TDG,
      mercaptoethanol) can be biomineralized under methanogenic conditions. On the
      contrary, phosphorus-containing compounds from the chemical detoxification of
      nerve warfare agents (Sarin, Soman, Vx-gases) are quite persistent under these
      conditions.

PMID- 10581677
TI  - Long-distance transport of radionuclides between PET cyclotron and PET
      radiochemistry.
AB  - At the Rossendorf PET Centre the PET cyclotron and the radiochemical laboratories
      are 500 m away from each other. The distance is bridged by a radionuclide
      transport system (RATS) whose details such as layout, technical parameters,
      control system and radiation protection are described along with our experience
      in long-distance transport of radionuclides.

PMID- 10581678
TI  - Separation of carrier free 151,152Tb produced in 16O irradiated lanthanum oxide
      matrix.
AB  - Charged particle activation of natural La2O3 with approximately 78.5 MeV 16O
      results in the formation of carrier free 151,152Tb isotopes in the matrix. The
      liquid cation exchanger, HDEHP, has effectively been utilised as an extractant in
      the quantitative separation of the activation products from the bulk target
      matrix of lanthanum oxide.

PMID- 10581680
TI  - A new technique for processing airborne gamma ray spectrometry data for mapping
      low level contaminations.
AB  - A new technique for processing airborne gamma ray spectrometry data has been
      developed. It is based on the noise adjusted singular value decomposition method
      introduced by Hovgaard in 1997. The new technique opens for mapping of very low
      contamination levels. It is tested with data from Latvia where the remaining
      contamination from the 1986 Chernobyl accident together with fallout from the
      atmospheric nuclear weapon tests includes 137Cs at levels often well below 1
      kBq/m2 equivalent surface contamination. The limiting factors for obtaining
      reliable results are radon in the air, spectrum stability and accurate altitude
      measurements.

PMID- 10581679
TI  - Synthesis of new hypoxia markers EF1 and [18F]-EF1.
AB  - We report on the preparation of a hypoxia marker 2-(2-nitroimidazol-1[H]-yl)-N-(3
      fluoropropyl)acetamide (EF1) and its 18F analog, 2-(2-nitroimidazol-1[H]-yl)-N-
      (3-[18F]fluoropropyl)acetamide ([18F]-EF1). Two methods for the preparation of 3
      fluoropropylamine, the EF1 side chain, are described. [18F]-EF1 was prepared with
      a radiochemical yield of 2% by nucleophilic substitution of bromine in 2-(2
      nitroimidazol-1[H]-yl)-N-(3-bromopropyl)acetamide (EBr1) by carrier-added 18F in
      DMSO at 120 degrees C. Our results demonstrate the preparation of clinically
      relevant amounts of [18F]-EF1 for use as a non-invasive hypoxia marker with
      detection using positron emission tomography (PET).

PMID- 10581681
TI  - Quantification aspects of patient studies with 52Fe in positron emission
      tomography.
AB  - Quantification accuracy in positron emission tomography (PET) using non-pure
      positron emitters, such as 52Fe, may be influenced by gamma radiation emitted in
      the decay of these isotopes. High-energy positrons, emitted in the decay of the
      52Fe-daughter 52mMn, also affect the quantification accuracy. A specific problem
      of the 52Fe/52mMn decay chain in vivo is that the kinetics of iron and manganese
      are different, and that PET cannot discriminate between the two nuclides. The
      effect of the decay properties of 52Fe/52mMn on the performance of PET was
      investigated using phantoms. Minor degradation in PET performance was found for
      52Fe/52mMn compared to the pure low-energy positron emitter 18F. A method is
      presented to obtain a correction factor for the 52mMn radioactivity in blood. A
      model for correction of 52mMn-radioactivity in organs, based on existing data on
      manganese kinetics, is given. The presented corrections are discussed and
      illustrated in a patient study.

PMID- 10581682
TI  - Iron and activated oxygen species in biology: the basic chemistry.
AB  - This paper briefly presents a critical review concerning the chemical reactions
      involved when superoxide or hydrogen peroxide meet iron complexes. The data
      commented on are required for a correct interpretation of the chemical processes
      which play a paramount role in the biological activation of dioxygen and arise in
      normal metabolism as well as in pathological processes.

PMID- 10581683
TI  - Molecular recognition of synthetic siderophore analogues: a study with receptor
      deficient and fhu(A-B) deletion mutants of Escherichia coli.
AB  - The biological activity of six synthetic siderophore analogues (two
      dihydroxamates, two trihydroxamates, one tetrahydroxamate and one 3-hydroxy
      4(1H)pyridinone) has been studied in Escherichia coli, Morganella morganii 13 and
      Proteus mirabilis 8993 strains by using growth promotion tests. Various transport
      deficient mutants of E. coli were used to study the route of entry into gram
      negative bacteria. The results indicated that the synthetic hydroxamate compounds
      are transported via Fhu-mediated transport systems, although receptor specificity
      was low. This could be proven by using a delta (fhuA-B) E. coli mutant as a
      control in which growth promotion by natural hydroxamates was completely
      abolished, suggesting that a periplasmic binding-protein-dependent transport
      system (FhuB, C, D) is required for the transport of all synthetic ferric
      hydroxamate complexes. Although utilization of the synthetic hydroxamates was
      generally lower than that of the natural siderophores, differences in growth
      promotion could be detected. Highest activity was observed with the dihydroxamate
      DOCYDHAMA ligand which supported growth at concentrations < 1 mM. In comparison
      with other polyamino-polyhydroxamate ligands studied, this dihydroxamate ligand
      has an extra diamide backbone that could be important for the interaction with
      the receptors or with FhuD. The synthetic trihydroxamate and tetrahydroxamate
      ligands showed a relatively low siderophore activity. Studies with Proteus and
      Morganella in the presence of increasing bipyridyl concentrations showed a
      decreased growth promotion with the synthetic ferric hydroxamates, suggesting the
      involvement of a reduction step during iron mobilization or an increased toxicity
      of bipyridyl. This was not observed in the case of the 3-hydroxy-4(1H)pyridinone
      where bipyridyl had no effect.

PMID- 10581684
TI  - Fluorescence and circular dichroism spectroscopic studies on bovine
      lactoperoxidase.
AB  - Intrinsic steady-state fluorescence of lactoperoxidase (LPO) and its ligand-bound
      complexes has been characterized as a structural probe of its structure in
      solution. On excitation at 295 nm, a broad emission maximum is observed around
      338 nm for LPO and for its ligand-bound complexes. The quantum yield is 0.0185 +/
      0.0005 for LPO and indicates tryptophan-->heme energy transfer. Tryptophan
      residues are located away from heme and are approximately equally distributed
      among hydrophobic and hydrophilic environments. From Forster resonance energy
      transfer equations, the "average" distance between tryptophans and heme within
      the enzyme is computed to be 25.1 +/- 0.2 A. These fluorescence properties are
      consistent with the recent theoretical three-dimensional model for LPO and reveal
      that Trp337 and Trp404 dominate the intrinsic fluorescence, and together
      contribute approximately 64% of the observed intensity. The effects of the
      denaturing agents guanidine hydrochloride and urea on the intrinsic fluorescence
      of LPO and CD of the backbone amide chromophores have been examined. The
      considerably red shifted emission maximum at 356 nm indicates that tryptophans,
      buried in the hydrophobic environment, are exposed to the solvent on
      denaturation. A simple two-state transition between the native and denatured
      forms of the protein has been used to explain the results. [Denaturant]1/2
      approximately 5.5 M, determined from both these experiments, indicates that LPO
      is relatively stable toward the denaturing agents. Quenching studies using. I-,
      Cs+ and polar neutral acrylamide are consistent with this picture. Acrylamide can
      penetrate the protein matrix. It is an efficient quencher and the quenching
      process is essentially homogeneous with all the tryptophans being accessible. Cs+
      ion is a very inefficient quencher but the iodide ion shows the quenching process
      to be predominantly heterogeneous with widely differing tryptophan accessibility.
      The Stern-Volmer constants deduced are Ksv = 8.4 +/- 1.4 M-1 and Ksv = 4.05 +/-
      0.65 M-1 for acrylamide and iodide quenching, respectively. The fractional
      accessibility, fa, deduced is fa = 0.52 +/- 0.03 for iodide quenching.

PMID- 10581685
TI  - Dental amalgam mercury exposure in rats.
AB  - The aim of this study was to measure the distribution of mercury, in tissues of
      rats exposed to amalgam over a two months period. Possible interaction of mercury
      with copper and zinc in organs was also evaluated. Rats were either exposed to
      mercury from 4 dental amalgams, or fed the diet containing powdered amalgam
      during two months. Mercury was measured in the kidney, liver and brain, copper in
      kidney and brain and zinc in kidney. The results showed significantly higher
      concentrations of mercury in the kidneys and the brains of rats in both exposed
      groups compared to control. Even after two months of exposure to mercury brain
      mercury concentration in rats with amalgam fillings was 8 times higher than in
      the control and 2 times higher than in rats exposed to amalgam supplemented diet.
      The highest mercury concentration in the latter group was found in the kidneys
      and it was 5 times higher than in the control group. We found no significant
      differences between mercury levels in exposed and control rat's liver. Exposure
      to mercury from dental amalgams did not alter the concentrations of copper and
      zinc in the tissues. Histopathological analyses of rats tissues did not show any
      pathological changes. These results support previously proposed nose-brain
      transport of mercury released from dental amalgam fillings.

PMID- 10581686
TI  - Interaction of p-phenylenediamine with the iron-bleomycin complex.
AB  - The iron-bleomycin complex has been shown to catalyze the oxidation of p
      phenylenediamine to a stable, purple coloured oxidation product, characterized by
      an absorption maximum around 520 nm. Molecular oxygen is used for reoxidizing
      Fe(II)-bleomycin after reduction by p-phenylenediamine. An apparent Michaelis
      constant of 5.2 mM and a catalytic constant of 17.2 min-1 were obtained from
      kinetic studies. ATP, ADP and orthophosphate inhibited the catalytic oxidation of
      p-phenylenediamine, while AMP was without effect. It is proposed that p
      phenylenediamine may be used as 'substrate' in kinetic studies involving the
      'oxidase' activity of iron-bleomycin.

PMID- 10581687
TI  - Prooxidant action of aluminum ion--stimulation of iron-mediated lipid
      peroxidation by aluminum.
AB  - Prooxidant nature of aluminum ion was analyzed in relation to iron coordination.
      Aluminum ion effectively enhanced the formation of thiobarbituric acid-reactive
      substances as a marker of lipid peroxidation of microsomes from rat liver under
      the acidic conditions, and this metal further attenuated the antioxidant action
      of flavonoids such as quercetin and baicalein under neutral conditions.
      Autooxidation of ferrous ion was markedly inhibited by aluminum ion. Aluminum can
      act as a prooxidant by stabilizing reduced iron the initiating species for lipid
      peroxidation, and by inhibiting the antioxidant action of flavonoid.

PMID- 10581688
TI  - New metal-binding ethyldiamino- and dicarboxy-products from Aspergillus niger
      industrial wastes.
AB  - The metal-binding ability of Aspergillus niger mycelial waste was improved by
      chemical modification. The latter was performed by introducing additional carboxy
      groups using oxidation methods or the introduction of the ethyldiamino group
      first by chlorination of A. niger using mesyl chloride and subsequent reaction of
      the product with ethylene diamine. Metal binding abilities of the products for
      Cd2+, Co2+, Ni2+ and Zn2+ were determined according to the Langmuir model,
      whereby pKD*-values of 3.88 up to 5.02 were revealed. Maximum capacities for the
      metals were found to be in the range 172 to 1064 mmol/kg.

PMID- 10581689
TI  - Uptake and intracellular distribution of labile and total Zn(II) in C6 rat glioma
      cells investigated with fluorescent probes and atomic absorption.
AB  - The uptake, intracellular distribution and cytotoxicity of high doses of
      extracellular zinc was investigated in C6 rat glioma cells. Net zinc uptake
      occurred only above certain thresholds in time and concentration, below them no
      alterations of the intracellular zinc level were observed. These results were
      obtained by measurements with the fluorescent dye Zinquin and by atomic
      absorption spectrometry, yielding similar results with both methods.
      Sequestration of zinc in intracellular vesicles was observed by fluorescence
      microscopy. A protective effect of vesicular sequestration is indicated, because
      increased levels of intracellular zinc located in vesicles did not necessarily
      lead to an increase in cytotoxicity. We were able to show that in C6 cells, in
      contrast to other cell lines, zinc that is released from proteins by the NO donor
      SNOC is also sequestered in vesicular structures. These zinc-carrying vesicles
      showed to be constitutive and are assumed to have a function in the maintainance
      of the cytosolic content of Zn2+ ions.

PMID- 10581690
TI  - Degradation of desferrioxamines by Azospirillum irakense: assignment of
      metabolites by HPLC/electrospray mass spectrometry.
AB  - Based on a recent finding that an Azospirillum isolate ASP-1 possessing high 16S
      rDNA similarity to Azospirillum irakense was able to degrade desferrioxamine type
      siderophores (Winkelmann et al. BioMetals 9, 78-83, 1996), various members of the
      genus Azospirillum were analyzed for their ability to degrade desferrioxamines.
      While the desferrioxamine-degrading activity was absent or scarcely detectable in
      strains of A. lipoferum, A. brasilense, A. amazonense, degradation activity
      seemed to be confined to the species A. irakense (KBC-1, KA3). Also the identity
      of strain ASP-1 as A. irakense could be confirmed by species-specific
      oligonucleotide hybridization, Inter-LINE PCR fingerprinting and carbon source
      utilization pattern (BIOLOG) analysis. Products of desferrioxamine B degradation
      were analyzed by analytical HPLC and HPLC/electrospray mass spectrometry. Using
      whole cells and purified enzyme it was shown that the trihydroxamate
      desferrioxamine B (561 amu) is split at the N-terminal amide bond yielding a
      monohydroxamate (MH1, 219 amu) and a dihydroxamate (DH1, 361 amu) metabolite. A
      second monohydroxamate (MH2, 319 amu) resulted from DH1 after splitting the
      acetylhydroxamate bond. Minor amounts of a further dihydroxamate (DH2, 419 amu)
      originated from splitting the second amide bond in desferrioxamine B. In addition
      to desferrioxamine B, several other linear and cyclic desferrioxamines and
      derivatives were degraded, whereas desferricoprogen and desferri-ferrichrome were
      not degraded, indicating high substrate specificity of the desferrioxamine
      hydrolase in A. irakense species. A simple microtiter plate assay was developed
      which can be used to phenotypically discriminate and identify species of A.
      irakense from other Azospirillum species by their characteristic feature of
      desferrioxamine degradation.

PMID- 10581691
TI  - Sequence heterogeneity of the ferripyoverdine uptake (fpvA), but not the ferric
      uptake regulator (fur), genes among strains of the fluorescent pseudomonads
      Pseudomonas aeruginosa, Pseudomonas aureofaciens, Pseudomonas fluorescens and
      Pseudomonas putida.
AB  - Pseudomonas aeruginosa, Pseudomonas aureofaciens, Pseudomonas fluorescens and
      Pseudomonas putida are of importance to medicine, agriculture and biocycling.
      These microbes acquire ferric ion via the use of the siderophores pyochelin and
      the family known as the pyoverdines or pseudobactins. The ferric uptake regulator
      (fur) gene is responsible, at least in part, for the regulation of siderophore
      synthesis and uptake in P. aeruginosa. To determine whether the organisms contain
      single or multiple homologues of the siderophore-related genes fpvA
      (ferripyoverdine uptake) and fur, and whether these homologues displayed sequence
      heterogeneity, their chromosomal DNAs were probed with fur and fpvA sequences. As
      a representative of a non-fluorescent pseudomonad, the bacterium Burkholderia
      (Pseudomonas) cepacia was also examined. The pseudomonads all contained fpvA- and
      fur-like homologues, and heterogeneity was observed among the different species.
      The presence of two or more fpvA-like genes is indicated in all of the
      fluorescent pseudomonads surveyed. In contrast, B. cepacia DNA either did not
      hybridize to these probes, or did so only very weakly, suggesting that fur- and
      fpvA-like homologues are either absent or significantly different in B. cepacia
      compared to the fluorescent pseudomonads examined.

PMID- 10581692
TI  - Individual study of chromium in the stainless steel implants degradation: an
      experimental study in mice.
AB  - To study the accumulation and the histological effects in mice organs caused by
      hexavalent chromium, one of the corrosion products released from AISI 316L
      stainless steel implants, mice groups were subcutaneously injected with a
      metallic solution of chromium during a certain period of time. Similar injections
      were made with HBSS (Hank's Balanced Salt Solution) in other groups to be used as
      controls. The levels of chromium found in the liver, kidney and spleen of the
      control and the treated animals were obtained by atomic absorption spectrometry
      (AAS) and were compared to those obtained by AdSV (adsorptive stripping
      voltammetry) to test the accuracy of the results. During the experimental period,
      the liver and spleen showed a progressive and significant accumulation of
      chromium whereas in the kidney the significant accumulation found after the first
      week practically remained unchanged during the four weeks. Apparently, the
      histological analysis of these tissues did not evidence any relevant
      morphological alteration induced by the chromium accumulations during the four
      weeks of treatment.

PMID- 10581693
TI  - Synthesis and characterization of sodium cis
      dichlorochenodeoxycholylglycinato(O,N) platinum(II)--cytostatic activity.
AB  - With a view to using bile acids as shuttles for delivering platinum-related
      cytostatic drugs to liver tumors, a chenodeoxycholylglycinato(CDCG)-derivative of
      platinum(II) has been synthesized. The complex--named Bamet-M2--was chemically
      characterized by elemental analysis, FT-IR, NMR, FAB-MS, and UV spectroscopy. The
      results indicate the following composition: C26H42N2O5Cl2NaPt(II), the metal
      Pt(II) being bound to two Cl- and one bidentate CDCG moiety, i.e., Na[Pt
      CDCG(N,O) Cl2]. The compound is highly soluble (up to 20 mM) in water and (up to
      35 mM) in ethanol, methanol and DMSO. Hydrolysis was investigated because this is
      assumed to be an important step in intracellular activation and interaction with
      DNA of this type of compounds. The reaction kinetics of this complex in aqueous
      solution show unusual behaviour; the substitution process with the displacement
      of two Cl- was almost instantaneous, and the resulting species were found to be
      very stable. Kinetic studies carried out in the presence of different NaCl
      concentrations (up to 500 mM) revealed similar fast and nonreversible aquations
      of Bamet-M2. This contrasts with the slow aquation of cisplatin in extracellular
      line solutions (i.e., at high NaCl concentrations) as compared with fast
      hydrolysis in cells. This difference may partly account for the low cytostatic
      activity observed here for Bamet-M2 against several tumor cell-lines.

PMID- 10581694
TI  - Occurrence of butyltin residues in sediment and mussel tissues from the lower
      most Tennessee River and Kentucky Lake, U.S.A.
AB  - Surface sediments and mussel samples were collected at six selected locations in
      the lower-most Tennessee River and Kentucky Lake, U.S.A. and analyzed for
      butyltin (BT) derivatives. In sediments, total BT concentrations ranged from 6.8
      to 356 ng g-1 dry wt. A wide range of concentrations in sediments suggested the
      presence of localized area of contamination. In mussel tissues, total BT
      concentrations varied between 26-107 ng g-1 dry wt. BT levels were comparable to
      the levels reported in mussels from some coastal sites as well as a few
      freshwater ecosystems. Leaching of tributyltin-containing anti-fouling paints in
      the ocean-going ships is a source of tributyltin, and discharge of municipal
      sewage and industrial waste waters in to this watershed may account for the
      presence of the monobutyltin and dibutyltin derivatives detected in the samples.
      To our knowledge, this is the first report on the butyltin concentrations in
      sediment and mussel tissues from the lower-most Tennessee River and Kentucky
      Lake.

PMID- 10581695
TI  - Singlet oxygen mediated degradation of Klason lignin.
AB  - After some results concerning photochemical generated singlet oxygen on lignins
      from steam explosion, the reactions of chemically generated singlet oxygen with
      Klason lignins from pine and beech are described. Singlet oxygen was produced
      through the reaction of hydrogen peroxide with sodium hypochlorite. The
      degradation of lignin was followed by uv spectroscopy and gel permeation
      chromatography. Extensive degradation of the lignins was observed when 20 mg of
      Klason lignin was treated with 1 ml of 30% hydrogen peroxide and 8.56 ml of 1.093
      M sodium hypochlorite. In the uv spectra registered after the treatment with
      singlet oxygen the absorptions typical of lignin (210-220 nm and 250-280 nm) were
      completely absent. The gpc analysis of lignin after a treatment with 0.1 ml of
      hydrogen peroxide and 0.86 ml of sodium hypochlorite showed a clear reduction of
      signals due to the lignin and a shift to lower molecular weight. The potential
      use of this procedure in the bleaching procedure was tested by using recycled
      paper. A maximum reduction of 51% in the amount of lignin in this paper was
      observed.

PMID- 10581696
TI  - The relation between levels of selected PCB congeners in human serum and
      follicular fluid.
AB  - Individual congener and total PCB concentrations were determined in serum and
      follicular fluid obtained from women undergoing assisted reproductive
      technologies (in-vitro fertilization and embryo replacement). Although the mean
      individual PCB levels revealed varying degrees of contamination, the results fall
      in the same range as that observed by other investigators. Except for PCB 118,
      correlations between levels in serum and follicular fluid were strong, and
      statistically significant at p < 0.05. Moreover PCB 153, a major and very stable
      PCB congener has been shown to correlate to the total amount of PCBs (r = 0.994,
      and r = 0.987, for serum and follicular fluid, respectively). The same
      accumulation patterns of PCBs for serum and follicular fluid have been observed.

PMID- 10581697
TI  - Bird blood as bioindicator for mercury in the environment.
AB  - Mercury concentrations were studied in blood, down and feathers of Common Gull
      (Larus canus L.) to investigate the suitability of bird blood as a matrix for
      biomonitoring of mercury in the marine environment. Chicks were collected in 1996
      on the Elbe river and the Jade Bay. Like the side feathers, blood indicated site
      differences in mercury contamination. Correlational analyses showed that mercury
      concentrations in blood are significantly related to levels in side feathers (p <
      0.001; Pearson), but not to those in down (p > 0.05; Pearson). Therefore, blood
      can be considered as a suitable matrix to indicate the current mercury burden in
      wild birds.

PMID- 10581698
TI  - Sorption of arsenate and arsenite anions by iron(III)-poly(hydroxamic acid)
      complex.
AB  - Iron(III)-poly(hydroxamic acid) resin complex has been studied for its sorption
      abilities with respect to arsenate and arsenite anions from an aqueous solution.
      The complex was found effective in removing the arsenate anion in the pH range of
      2.0 to 5.5. The maximum sorption capacity was found to be 1.15 mmol/g. The
      sorption selectivity showed that arsenate sorption was not affected by chloride,
      nitrate and sulphate. The resin was tested and found effective for removal of
      arsenic ions from industrial wastewater samples.

PMID- 10581699
TI  - Variation of toxaphene indicator compounds in fish from single fishing grounds:
      conclusions for sampling.
AB  - The levels of three toxaphene indicator compounds were determined in individual
      lots of herring, redfish, Greenland halibut and farmed salmon. Concentration
      levels of the three marine fish species were characterised by a right-skewed
      frequency distribution whereas residue concentrations in farmed salmon were
      normally distributed. The toxaphene concentrations in the edible part of redfish,
      herring and Greenland halibut were found to be positively correlated to the sizes
      and thus to age. As results show, for representative sampling of a landed catch,
      not more than 10 individual fishes from typical size classes of a lot are
      necessary for a pooled sample.

PMID- 10581700
TI  - Thermodynamic studies on oxygen binding by human red blood cells.
AB  - Oxygen equilibrium curves have been measured on human normal red blood cells, at
      the temperatures of 20, 25, 30, 37 and 41 degrees C, and at pHs ranging from 6.8
      to 8.2. The thermodynamical parameters have been determined for the four
      successive steps of oxygenation and for overall oxygenation, according to the
      Adair and MWC models [Monod J, Wyman J, Changeux JP. On the nature of allosteric
      transitions: a plausible model. J Mol Biol 1965;12:88-118]. The heat release
      appears to be nearly equal for the four steps. At the first three steps, the
      delta H change is counterbalanced by a nearly equivalent change of delta S,
      resulting in a rather small delta G value. delta G is greater at the fourth step,
      because of diminution of this enthalpy-entropy compensation phenomenon. The four
      steps are both enthalpy and entropy driven. According to the MWC model, the T to
      R transition is endothermic, and allosteric quaternary transition occurs at
      binding of the third oxygen. The average heat release increases by 2.8 kcal/mol
      when pH raises from 7.4 to 8.2, but flattens below pH 7.4. After correction for
      the heat of solution of oxygen and for the heat of proton release (referred to
      intracellular pH), an intrinsic heat for oxygenation of the heme of approximately
      -13 kcal/mol is obtained for the successive steps of oxygenation (at pH 7.4, 37
      degrees C). These results are compared with those previously obtained for pigeon
      and trout red blood cells.

PMID- 10581701
TI  - Ruminal transport and metabolism of short-chain fatty acids (SCFA) in vitro:
      effect of SCFA chain length and pH.
AB  - The unidirectional transport and metabolism of 14C-labeled acetate, propionate
      and butyrate across the isolated bovine rumen epithelium was measured in vitro by
      the Ussing chamber technique. There was a significant, but relatively small, net
      secretion of acetate and propionate, and a large and significant net absorption
      of butyrate. The results demonstrate that the mucosal-serosal (MS) pathway for
      short-chain fatty acids (SCFA) is different from the serosal-mucosal (SM)
      pathway, and that butyrate is treated differently from acetate and propionate by
      the epithelium. The results support that the main route for epithelial SCFA
      transport is transcellular. The correlation between SCFA lipophility and the flux
      rate was positive but weak at both pH 7.3 and 6.0. Decreasing pH increased all
      SCFA fluxes significantly, but not proportionally to the increase of protonized
      SCFA in the bathing solution. There was a significant and apparently non
      competitive interaction between the transport of acetate, propionate and
      butyrate. It seems that mediated transport mechanisms must be involved in
      epithelial SCFA transport in the bovine rumen, but the data do not exclude that
      passive diffusion could account for a significant part of the flux. The
      metabolism of SCFA in the Ussing chamber system was considerable, and there was a
      clear preference for excretion of CO2 from this metabolism to the mucosal side,
      while side preference for non-CO2 metabolite excretion was not studied. Of the
      propionate and butyrate transported in the MS direction, 78 and 95% was
      metabolised, while only 37 and 38% was metabolised in the SM direction (acetate
      metabolism could not be measured). There was, however, no simple relation between
      the degree of metabolism and the transport rate or the transport asymmetry of the
      SCFA.

PMID- 10581702
TI  - Distribution of gamma-aminobutyric acid in catfish (Heteropneustes fossilis)
      forebrain in relation to season, ovariectomy and E2 replacement, and effects of
      GABA administration on plasma gonadotropin-II level.
AB  - In the catfish Heteropneustes fossilis, the hypothalamus and telencephalon showed
      seasonal variations in gamma-aminobutyric acid (GABA) with high levels in
      prespawning and spawning phases and low levels in preparatory and postspawning
      phases. Ovariectomy for 4 and 5 weeks reduced significantly the GABA contents
      only in the hypothalamus. Replacement with E2 (1 microgram/g BW) restored the
      levels to that of sham ovariectomized or parallel control group. Treatment with
      GABA (i.p.; 10 or 50 micrograms/g body weight (BW) alone did not produce any
      significant effect on plasma gonadotropin-II (GTH-II) level in any of the
      seasons. Injection of GABA, but not baclofen (a GABAB agonist), stimulated GTH-II
      secretion in pimozide or GnRH analogue-pimozide pretreated fish at both 0.5 and 2
      h in early prespawning phase except at 0.5 h in the pimozide--GABA (10
      micrograms) group. This stimulatory effect was not evident in other seasons. The
      results of the present study suggest that Estradiol-17 beta (E2) seems to
      stimulate GABA which may account for its high level in the recrudescent phase.
      GABA seems to have a permissive role in GTH-II secretion when dopamine receptor
      function is inhibited.

PMID- 10581703
TI  - Bursal anti-steroidogenic peptide (BASP): modulation of mitogen-stimulated bursal
      lymphocyte DNA synthesis.
AB  - The present study examined the effects of bursal anti-steroidogenic peptide
      (BASP) on mitogen-induced DNA synthesis in bursa-derived B-lymphocytes in short
      term culture. Partially purified extracts of chicken bursa of Fabricius tissue,
      containing BASP, significantly (P < 0.05) reduced DNA synthesis in bursal
      lymphocytes exposed to increasing concentrations of phorbol 12,13-dibutyrate
      (PDB). Following these initial observations, BASP, further purified from bursal
      extracts using sequential rpHPLC fractionation, was observed to reduce (P < 0.05)
      both B-lymphocyte PDB-stimulated DNA synthesis and ovarian granulosa cell
      progesterone biosynthesis with bioactivity observed at similar retention times in
      each assay, suggesting that each bioactivity may be due to the same or similar
      molecules. A similar BASP-enriched fraction was not effective in altering basal
      levels of DNA synthesis in chick embryonic kidney cells. Subsequently, BASP was
      further purified by several sequential chromatographic methods including: C-18
      rpHPLC (preparative rpHPLC followed by a semi-preparative rpHPLC column), cation
      exchange chromatography, molecular sieve HPLC chromatography, and SDS-PAGE.
      Biologically active material was observed at approximately 29 or 34 kDa. Protein
      concentration was determined and bioactivity was evaluated. Anti-proliferative
      effects of this partially purified BASP on bursal-lymphocytes was observed at
      concentrations as low as 1.6 micrograms ml-1, with complete suppression of
      mitogen-stimulated DNA synthesis observed at approximately 25 micrograms ml-1.
      This partially purified BASP was also efficacious for attenuation of ovarian
      granulosa cell progesterone biosynthesis at concentrations as low as 0.4
      microgram ml-1, with complete suppression of gonadotrophin-stimulated
      progesterone biosynthesis observed at approximately 0.8 microgram ml-1. While
      BASP is efficacious for attenuation of both granulosa cell steroidogenesis and
      bursal-lymphocyte proliferation, these data suggest that BASP is much more potent
      with regard to anti-steroidogenic activity.

PMID- 10581704
TI  - Arousal from torpor in the Chilean mouse-opposum (Thylamys elegans): does non
      shivering thermogenesis play a role?
AB  - We examined the effect of norepinephrine injections on non-shivering
      thermogenesis (NST), rewarming rate, and metabolic cost during torpor arousal in
      warm- and cool-acclimated Chilean mouse-opposums, Thylamys elegans. Warm- and
      cool-acclimated animals did not display NST in response to NE injections. Values
      of VO2 (resting, after saline and NE injections) were not significantly different
      within treatments. Rewarming rates of warm-acclimated animals did not differ
      significantly from those in cool-acclimated animals. In contrast, the metabolic
      cost of torpor arousal was significantly affected by acclimation temperature.
      Warm-acclimated animals required more energy for arousal than cool-acclimated
      animals. Our study suggests that the main thermoregulatory mechanism during
      torpor arousal in this Chilean marsupial is shivering thermogenesis, and that its
      amount can be changed by thermal acclimation.

PMID- 10581705
TI  - Transport of butyrate across the isolated bovine rumen epithelium--interaction
      with sodium, chloride and bicarbonate.
AB  - The Ussing chamber technique was used for studying unidirectional fluxes of 14C
      butyrate across the bovine rumen epithelium in vitro. Significant amounts of
      butyrate were absorbed across the bovine rumen epithelium in vitro, without any
      external driving force. The paracellular pathway was quantitatively
      insignificant. The transcellular pathway was predominately voltage-insensitive.
      The serosal to mucosal (SM) pathway was regulated by mass action, whereas the
      mucosal to serosal (MS) pathway further includes a saturable process, which
      accounted for 30 to 55% of the MS flux. The studied transport process for 14C
      butyrate across the epithelium could include metabolic processes and transport of
      14C-labelled butyrate metabolites. The transport of butyrate interacted with Na+,
      Cl- and HCO3-, and there was a linear relationship between butyrate and sodium
      net transport. Lowering the sodium concentration from 140 to 10 mmol l-1
      decreased the butyrate MS flux significantly. Amiloride (1 mmol l-1) did,
      however, not reduce the butyrate flux significantly. Chloride concentration in
      itself did not seem to influence the transport of butyrate, but chloride-free
      conditions tended to increase the MS and SM flux of butyrate by a DIDS-sensitive
      pathway. DIDS (bilateral 0.5 mmol l-1) did further decrease the butyrate SM flux
      significantly at all chloride concentrations. Removing bicarbonate from the
      experimental solutions decreased the MS and increased the SM flux of butyrate
      significantly, and abolished net butyrate flux. There were no significant effects
      of the carbonic anhydrase inhibitor Acetazolamide (bilateral 1.0 mmol l-1). The
      results can be explained by a model where butyrate and butyrate metabolites are
      transported both by passive diffusion and by an electroneutral anion-exchange
      with bicarbonate. The model couples sodium and butyrate via CO2 from metabolism
      of butyrate, and intracellular pH.

PMID- 10581706
TI  - Two uncompetitive, activated, and transport sites of the Na+/H+ exchanger for pH
      regulation in perfused rat kidney.
AB  - The purpose of this study is to assess the effect of an apparent alteration in
      intracellular pH and the effect of amiloride on the activity of the Na+/H+
      antiporter in perfused rat kidney. Rat kidney-Na+ retention was determined using
      tracer 22Na in perfusate composed of HCl-glycine buffer (pH 3.80 to pH 5.92) or
      NH4OH-glycine buffer (pH 6.22-7.95) containing Na+ to match physiologic
      concentrations. Plotting renal Na+ retention for 10 min versus pH in absence of
      amiloride showed two classical uncompetitive activator curves for H+, one curve
      from pH 4.19 to 5.10 and another from pH 6.22 to 7.95. H+ acts as an
      uncompetitive reversible binding substrate with the receptor triggering
      activation of the exchanger already sequestered with Na+, thus yielding two Ka
      values for the exchanger suggesting non-first order kinetics. Using an equation
      derived for uncompetitive-activation binding of Nao+ and Hi+, plotting [mM Na+ mg
      protein-1 10 min-1]-1 versus [H+], two linear plots are observed on Cartesian
      coordinates with abscissa intersecting at 47 +/- 1 microM, pKa = 4.32 +/- 0.02
      (pH 4.19-5.10) and 4.21 +/- 0.02 microM, pKa = 5.38 +/- 0.01 (pH 6.22-7.95),
      respectively. Perfusing buffer containing 2 mM amiloride, completely inactivated
      the antiporter showing stronger inhibition between pH 3.80 and 5.92. Results
      suggest the presence of two uncompetitive binding sites for H+ with the Na+/H+
      exchanger. One is a high affinity binding site at physiological intracellular
      apparent pH, and another is a low affinity binding site at ischaemic apparent pH,
      implying the existence of two titration sites for intracellular pH regulation.

PMID- 10581707
TI  - Foetal calf serum and dexamethasone effects on Vero cell growth and
      differentiation.
AB  - Vero cells were cultured without foetal calf serum (FCS), with 10% FCS, 10% FCS
      plus dexamethasone (DEX) or 20% FCS for 48, 120 or 240 h. The cells were analysed
      by a growth curve, cytochemical and immunocytochemical (anti-cellular fibronectin
      or anti-collagen IV) methods. In 48 h Vero cells produced fibronectin and
      collagen IV. All samples showed basophilic cytoplasm indicating high protein
      synthesis. The growth of metachromatic multicellular masses was induced by DEX.
      The Vero cells produced collagen IV with 10 and 20% FCS, and also cells which did
      not have this activity (without FCS or with 10% FCS + DEX). The multicellular
      masses induced by DEX were rich in fibronectin. DEX induced differentiation and
      the expression of collagen IV and fibronectin in Vero cells. This work was
      carried out to evaluate the possible therapeutic effects of glucocorticoids as
      inducers of cell differentiation.

PMID- 10581708
TI  - Heat shock response during development of the malaria vector Anopheles stephensi
      (Culicidae: Diptera).
AB  - The pattern of synthesis of heat shock proteins (HSP) and thermotolerance to
      elevated temperatures during the development of the malaria vector Anopheles
      stephensi normally reared at 28 +/- 2 degrees C was studied using SDS-PAGE. In
      total twelve heat shock proteins (i.e. 31, 33, 38, 43, 44, 51, 57, 62, 69, 71,
      113 and 121 kD were induced by heat shock during various stages of development.
      Eight polypeptides (HSP during one or other of the instars) appeared during
      normal development of the adult, which showed very little response towards heat
      shock. Only two polypeptides (57 and 69 kD) were induced while the 22.5 kD
      protein disappeared during adult life. The HSP 62 and 71 kD induced during the
      larval stages showed a sharp decline in quantity in male and female adults upon
      heat shock. Three HSP (31, 43 and 44 kD) were induced in pupae due to heat shock.
      The synthesis of HSP in A. stephensi was correlated with the various
      morphological and physiological events occurring during development.

PMID- 10581709
TI  - Pseudomonas aeruginosa (GRC1) as a strong antagonist of Macrophomina phaseolina
      and Fusarium oxysporum.
AB  - A plant growth promotory bacterial strain, isolated from the potato rhizosphere,
      was characterized as Pseudomonas aeruginosa (GRC1). The isolate produced an
      hydroxamate type of siderophore after 48 h of incubation on tryptic soy medium
      under iron deficient conditions. The in vitro antifungal activity of P.
      aeruginosa was tested against two soil-borne plant pathogens, Macrophomina
      phaseolina and Fusarium oxysporum. The antagonistic behaviour of the isolate was
      tested by dual culture technique. The growth inhibition of M. phaseolina and F.
      oxysporum was 74.1% and 70.5%, respectively, after 5 days of incubation. The
      production of hydrocyanic acid and indole acetic acid was also recorded under
      normal growth conditions.

PMID- 10581711
TI  - Borrelia burgdorferi sensu lato in Ixodes ricinus ticks and rodents in a
      recreational park in south-western Ireland.
AB  - Ixodes ricinus ticks infected with Borrelia burgdorferi sensu lato were numerous
      on the edges of paths and roads in a recreational park in south-western Ireland.
      The abundance of ticks at different sites was related to the presence of deer,
      but a negative relationship was shown between tick abundance and tick infection
      rates. This is thought to be due to the deposition of large numbers of uninfected
      ticks by deer, which are apparently not good reservoir hosts of B. burgdorferi
      s.l. Blood meal analysis only detected deer DNA in uninfected nymphs. Reservoir
      competent rodents, Apodemus sylvaticus and Clethrionomys glareolus, were abundant
      at all sites and a high proportion of captured specimens were infested with
      larval ticks. However, very few rodents were infected with B. burgdorferi s.l.
      and none of the unfed infected nymphs analysed for the identity of their larval
      blood meal had fed on rodents. The spirochaetes detected in I. ricinus in the
      study area may be poorly adapted to rodents or are not transmitted readily
      because of the absence of nymphal infestation. The majority of spirochaetes in
      these ticks were apparently acquired from non-rodent hosts, such as birds.

PMID- 10581710
TI  - Ticks feeding on humans: a review of records on human-biting Ixodoidea with
      special reference to pathogen transmission.
AB  - In this article, literature records of argasid and ixodid ticks feeding on humans
      worldwide are provided in view of increased awareness of risks associated with
      tick bites. Ticks can cause paralyses, toxicoses, allergic reactions and are
      vectors of a broad range of viral, rickettsial, bacterial and protozoan
      pathogens. Approximately 12 argasid species (Argas and Ornithodos) are frequently
      found attached to humans who intrude into tick-infested caves and burrows. Over
      20 ixodid tick species are often found on humans exposed to infested vegetation:
      four of these are Amblyomma species, 7 Dermacentor spp., 3 Haemaphysalis spp., 2
      Hyalomma spp. and 6 Ixodes species. Personal protection methods, such as
      repellents and acaricide-impregnated clothing are advised to minimize contact
      with infected ticks. Acaricidal control of ixodid ticks is impractical because of
      their wide distribution in forested areas, but houses infested with soft ticks
      can be sprayed with acaricidal formulations. Attached ticks should be removed
      without delay. The best way is to grasp the tick as close to the skin as possible
      with fine tweezers and pull firmly and steadily without twisting. Finally,
      despite the fact that most people who are bitten destroy the offending tick in
      disgust, it is recommended that they preserve specimens in ethanol for taxonomic
      identification and detection of pathogens by molecular methods.

PMID- 10581712
TI  - Abundance of ticks (Acari: Ixodidae) infesting the western fence lizard,
      Sceloporus occidentalis, in relation to environmental factors.
AB  - We examined the impact of environmental characteristics, such as habitat type,
      topographic exposure and presence of leaf litter, on the abundance of Ixodes
      pacificus ticks infesting the western fence lizard (Sceloporus occidentalis) at
      the University of California Hopland Research and Extension Center (HREC),
      Mendocino County, California. A total of 383 adult lizards were slip-noosed and
      examined for tick infestation in April and May 1998. At least 94% of the lizards
      were infested by ticks and at least 20% of the females and 33% of the males
      carried > 15 ticks. This intensive utilization of western fence lizards (which do
      not serve as natural reservoirs for Lyme disease spirochetes) by subadult ticks,
      is probably the primary reason for the low prevalence of infection with Borrelia
      burgdorferi in I. pacificus nymphs and adults previously recorded at the HREC.
      Tick loads were higher on male than female lizards. Also, male lizards were
      generally more heavily infested in late April than in late May. The prevalence of
      tick infestation exceeded 88% in all habitat types but males collected in
      woodland and grass/woodland edges had higher tick loads than those collected in
      open grassland. Male lizards captured in open, exposed grassland tended to carry
      heavier tick loads in northern/eastern, as compared to southern/western,
      exposures, and when leaf litter was present.

PMID- 10581713
TI  - Mite population dynamics on different grape varieties with or without phytoseiids
      released (Acari: Phytoseiidae).
AB  - In a three-year study, mite populations were monitored in two vineyards, each
      having two grape varieties with different leaf hair density. In both vineyards
      native phytoseiids were present: Amblyseius andersoni in one vineyard, and
      Phytoseius finitimus in the other. The economically important predators
      Kampimodromus aberrans and Typhlodromus pyri were released in both vineyards in
      order to study their efficacy in controlling tetranychids and eriophyids and
      their persistence during periods of prey scarcity. In both vineyards, relative
      abundances of the mite species, especially phytoseiids, were found to differ on
      different varieties in the same vineyard. In the first experiment, A. andersoni
      reached higher densities and was more persistent on the variety with slightly
      pubescent leaf under-surface (Merlot). Typhlodromus pyri and K. aberrans releases
      were successful and the mites became more abundant on the variety with pubescent
      leaf under-surface (Verduzzo). In the second experiment, P. finitimus was more
      abundant on a variety with pubescent leaf under-surface (Prosecco) than with
      glabrous leaf under-surface (Riesling). The most interesting results of the
      present study concerned the interactions between native and released predators.
      In the first vineyard, different results were obtained when releasing T. pyri on
      the two varieties. On the variety with pubescent leaves, A. andersoni was rapidly
      displaced by T. pyri, whereas the former species persisted on the other variety
      throughout the three-year study, apparently becoming dominant during the last
      season. In contrast to T. pyri, interactions between K. aberrans and A. andersoni
      in this vineyard did not depend on variety. The results of the experiments
      carried out in the second vineyard stressed the importance of interspecific
      competition for phytoseiid releases. Typhlodromus pyri colonization failed on
      both varieties. Kampimodromus aberrans releases appeared to be more successful on
      Riesling than on Prosecco; where P. finitimus was more abundant. At the end of
      the experiments, K. aberrans displaced P. finitimus on both varieties.

PMID- 10581714
TI  - Integrated control of acaricide-resistant Boophilus microplus populations on
      grazing cattle in Mexico using vaccination with Gavac and amidine treatments.
AB  - Throughout most of the twentieth century, tick infestations on cattle have been
      controlled with chemical acaricides, typically administered by dipping or
      spraying. This approach can cause environmental and residue problems and has
      created a high incidence of acaricide resistance within tick populations in the
      field. Recently we developed a vaccine against Boophilus microplus employing a
      recombinant Bm86 antigen preparation (Gavac), (Heber Biotec S.A., Havana, Cuba)
      which has been shown to induce a protective response in vaccinated animals. Here
      we show for the first time under field conditions a near 100% control of B.
      microplus populations resistant to pyrethroids and organophosphates, by an
      integrated system employing vaccination with Gavac and amidine treatments. This
      method effectively controls tick infestations while reducing the number of
      chemical acaricide treatments and consequently the rise of B. microplus
      populations resistant to chemical acaricides.

PMID- 10581715
TI  - Potential definition of the time of death from autolytic myocardial cells: a
      morphometric study.
AB  - Morphometric methods and transmission electron microscopy were used to quantify
      modifications occurring in the mitochondria of dog myocardium during the first
      four hours of autolysis. Myocardial fragments were obtained from the outer free
      wall of the left ventricle, during anesthesia (control-zero) and at 15, 45, 120,
      and 240 min after cardiac arrest, maintaining the heart "in situ" at 22 degrees
      C. During the 240 min of autolysis, the main parameters evaluated showed: (a) a
      decrease in the number of mitochondria from 0.31 to 0.12 per micron 3 of
      cytoplasm. The decrease over the first 45 min reached 50% of the initial value;
      (b) an increase in mitochondrial volume, three times greater after the first 45
      min (from 0.92 to 2.68 micron 3) and four times greater after 240 min (from 0.92
      to 3.79 micron 3); (c) an increase in mitochondrial outer membrane surface area
      from 5.51 to 12.54 micron 2; (d) an increase in the surface area of individual
      mitochondria inner membrane and cristae from 27.60 to 56.96 micron 2. The
      progressive nature of the alterations and the difference in the numerically
      expressed values allow correlation with the time of somatic death. The authors
      emphasize the need for further studies in order to complement the present study.

PMID- 10581716
TI  - Significance of inflammatory changes in the brainstem in forensic autopsy cases.
AB  - Brain stem encephalitis is an uncommon disease. In order to assess the
      significance of inflammatory changes in the brain stem in a forensic autopsy
      material we reviewed the findings over a 12-year period. Between January 1st 1982
      December 31st 1993, neuropathological examination of the brain was carried out in
      29% of the autopsy cases from the Institute of Forensic Medicine, University of
      Oslo. Out of 4546 brains, 110 (2.2%) showed microglial nodules and perivascular
      lymphocytic cuffing in the lower brain stem. In 66 of the cases (60%), the
      abnormalities were limited to the nucleus and/or the spinal tract of the fifth
      cranial nerve. Only 16 of the 39 cases with more widespread changes, diagnosed as
      brain stem encephalitis, had a serious underlying or concomitant disease. Three
      particular cases of brain stem encephalitis are reported in more detail. In all
      three cases we suggest that the brain stem inflammatory changes may be either the
      direct or a contributory cause of death.

PMID- 10581717
TI  - Alcohol use among fatally injured drivers in Spain.
AB  - Blood from 285 fatally injured drivers in Northern Spain was collected and tested
      for the presence of alcohol and drugs. Alcohol was detected in 50.5% of all
      fatalities. Alcohol alone was detected in 44.2% of all samples and in the
      remaining 6.3% another substance was found together with alcohol. Blood alcohol
      concentration was classified in different levels. It has been observed that in
      35.4% of the cases the blood alcohol level was > or = 0.8 g/l, the legal limit in
      Spain for car drivers. Alcohol together with other substances was encountered in
      18 cases, with medication in 22.2% (4 out of 18), alcohol with illegal drugs in
      66.6% of the cases (12 out of 18), and alcohol with medicines and illegal drugs
      in 11.1% (2 out of 18). Cocaine was the most commonly detected drug. The study
      shows how widespread the incidence of a high level of alcohol concentration among
      drivers involved in fatal accidents in Spain.

PMID- 10581718
TI  - Injury analyses of fatal motorcycle collisions in south-east Scotland.
AB  - The timing of death and pathological findings in fatal motorcycle accidents in
      south-east Scotland between 1987 and 1997 were investigated. Of the 59
      motorcyclists who died, 38 were dead when found at the accident scene, six others
      were alive when found but died at the scene, two died in an ambulance in transit
      to hospital and 13 died after reaching hospital. Scoring of the injuries
      according to the Abbreviated Injury Scale revealed Injury Severity Scores (ISS)
      ranging from 25 to 75. Overall, injuries to the head, neck and chest were
      responsible for the most severe injuries. Twenty-five motorcyclists had injuries
      acknowledged to be unsurvivable (ISS = 75), most of which involved the thoracic
      aorta, brainstem and cervical spinal cord. The greatest potential to reduce the
      death rate amongst motorcyclists lies with accident prevention/injury reduction
      measures, rather than through improved treatment of injuries. Efforts to try to
      alter driving behaviour and to improve the design of vehicles and helmets need to
      continue.

PMID- 10581719
TI  - Age-related variation in the interstitial tissues of the cardiac conduction
      system; and autopsy study of 230 Han Chinese.
AB  - The amount of fatty and fibrous tissues in 230 Han Chinese who died of noncardio
      vascular diseases has been studied by a semi-quantitative method and analysed by
      chi-square test. The results have shown some consistency. Generally, in the sino
      atrial node (SAN), fibrosis and fatty influtratin appear only after 40 years of
      age and increase one grade with every 20 years. The atrio-ventricular node (AVN)
      showed fatty change after 30 years of age and fibrosis appeared after 60. In the
      His bundle (HB), fatty infiltration and fibrosis appear after 40 years. The left
      bundle branch (LBB) showed similar changes. The appearance of fibrosis in the AVN
      seems to be later than that reported by Lev.

PMID- 10581720
TI  - Typing of eight short tandem repeat (STR) loci in a Saudi Arabian population.
AB  - Allele frequency data for eight short tandem repeat (STR) loci, HUMF13A01,
      HUMFESFPS, HUMF13B, HUMLPL, HUMCSF1PO, HUMTPOX, HUMTHO1 and HUMvWA, were obtained
      for unrelated individuals in a Saudi Arabian population. All loci, except F13B (P
      = 0.037) and LPL (P = 0.035), meet Hardy-Weinberg expectations, based on the
      exact test. The most informative locus is HUMvWA (PD = 0.936) and the least
      discriminating is the HUMTPOX locus (PD = 0.820). There was only one observation
      of a departure from expectation from pairwise locus comparisons. These data can
      be used for estimating the frequency of STR profiles in a Saudi Arabian
      population.

PMID- 10581721
TI  - Knitted fractures of the laryngopharynx framework as a medico-legal matter.
AB  - The article presents the analysis of knitted trauma to the hyoid bone and
      laryngeal cartilages, revealed while searching for fresh fractures of the
      laryngopharynx skeleton for medico-legal purposes. Neck organocomplexes (n = 440)
      were completely prepared after fixation in formalin. Old injuries were found in
      17.3% of cases, and in 3.2% of cases two elements of the complex were formerly
      broken. More often there was consolidated trauma to the thyroid (11.4% of cases)
      and cricoid cartilages (7.3%) and, rarely, to the hyoid bone (1.6%) and cervical
      part of the trachea (0.2%). These injuries occurred twice as often in men (20.3%
      of cases) than in women (P < 0.01). Substantiated conclusions are: (1) people of
      working age are most prone to neck trauma; and (2) from the 1960s the percentage
      of such traumas in the St. Petersburg region has grown due to urbanization. This
      article presents data on the localization and morphology of the injuries, as well
      as a review of symptoms and the course of blunt neck trauma. Despite the
      difficulties associated with the complete regeneration of injured tissues,
      forensic pathologists can obtain certain information which police officials may
      be interested in.

PMID- 10581722
TI  - On the contamination of ambient air by preparations carried out with a band-saw.
AB  - The aim was to evaluate contamination by bone-dust and formaldehyde when using a
      band-saw for preparations of the base of the skull and the cervical vertebral
      spine (stationary band-saw, 1400 upm, saw blade with 160 saw teeth/m; distances
      19-26 cm, time intervals 55-90 s). The asservation of bone particles was done
      with adhesive microscopic slides and calcium-specific staining by alizarin-red.
      The quantification of air contamination was carried out with micrometry and a
      particle-counter. Drager-tubes 0.2/9 were utilized for estimation of
      formaldehyde. The band-saw did not produce high amounts of bone-dust with
      suspension power. Nevertheless, 75% of the particles ranged below 5 microns in
      size and were respirable. Contamination decreased with an increasing height above
      the floor. A massive flow of particles was observed during the first minutes of
      sawing. The bone-dust spread some metres away. The formaldehyde levels ranged
      throughout between 0.5 and also over 5 ppm (MAK = 0.5 ppm). This fact makes clear
      an intensive contamination of the air. Therefore, a ventilation directed to the
      floor is necessary when a band-saw is used, as well as breathing masks and safety
      goggles.

PMID- 10581723
TI  - Dynamics of stab wounds: force required for penetration of various cadaveric
      human tissues.
AB  - It is often said that once the skin has been penetrated no further force is
      required to produce penetration of underlying tissues. This experimental study
      has used technology which was not available to earlier investigators to examine
      this issue in detail. The results confirm the importance of skin penetration but
      indicate that the penetration of other tissues may also require significant
      force.

PMID- 10581724
TI  - Increase of pulmonary density of macrophages in sudden infant death syndrome.
AB  - A 1996 cytodensitometric study found increased cellular density in the pulmonary
      parenchyma of infants who died of sudden infant death syndrome (SIDS). The
      present study clarifies these results in quantifying the density of
      immunohistochemical subtyped inflammatory cells. Histomorphometry was used to
      compare the density of macrophages, granulocytes and T and B lymphocytes in the
      lungs of two groups of infants. From the post-mortem records of infant deaths
      between 1983 and 1995, 29 (mean age = 5 months) were randomly selected including
      16 cases of SIDS and 13 who died of other non-pulmonary causes. Densities of
      immunoreactive cells were measured under blind conditions in the parenchyma. The
      mean density of macrophages was significantly higher in cases of SIDS compared
      with the controls (P = 0.0318), but there were no differences for the lymphocytes
      and the granulocytes. These morphometrical results must be interpreted within the
      methodological limits of this study, especially the non-uniform level of lung
      inflation between selected subjects. However, the differences in level of
      inflation are not sufficient to explain the observed increase of macrophage
      density. Indeed, the mean values of alveolar surface area, which represent an
      indirect measure of lung inflation, are not significantly different between the
      two groups. Increase of pulmonary macrophage density in SIDS agrees with three
      non-exclusive hypotheses: (1) an abnormal inflammatory reaction by expression of
      Th1 helper cell phenotype activation; (2) consequence of passive smoking; and (3)
      post-agonal mechanisms. Bacterial superantigens produced by toxigenic bacteria in
      the respiratory tract could play a role as a trigger factor that initiates a
      fatal cascade with overproduction of cytokines leading to death. The significant
      increase of pulmonary macrophage density would be the morphological expression of
      this potential mechanism of death.

PMID- 10581725
TI  - Unexpected findings in the investigation of an airplane crash.
AB  - We report on the discovery at autopsy of an unexpected cause of a crash during
      landing of a small sports plane with four people on board. Surprisingly, an
      intact bullet and fragments of the casing were found in the body of the pilot. As
      expected, autopsy of the other passengers predominantly revealed signs of
      polytraumatization. In addition, one passenger had a tunnel wound to the left
      hand and another, a soft tissue tear between the thumb and forefinger of the
      right hand. These wounds were considered to be associated with a shooting
      incident in the cabin. The autopsy findings and additional gunpowder trace
      investigations suggested that the pilot had been incapacitated by a shot from
      behind, resulting in the plane crash. The present findings underscore the
      importance of conducting autopsies on all air crash victims.

PMID- 10581726
TI  - Antibacterial activities of anthozoan corals on some marine microfoulers.
AB  - The antibacterial activities of twelve species of anthozoans (4 gorgonians, 5
      soft corals and 3 antipatharians) collected off the east coast of India were
      assayed against four dominant marine fouling bacterial strains isolated from the
      biofilm of fouled aluminium panels. Of the 48 combinations (12 corals x 4
      bacteria) eighteen interactions showed antibacterial activity (37.5%). Such
      activity was most apparent in gorgonians, which inhibited bacterial growth in ten
      out of sixteen interactions (62.5%) compared with that of five out of twenty
      interactions (25%) among soft corals and three out of twelve interactions (25%)
      among antipatharians. The activity scores varied with different extracts and test
      organisms used, and was highest in antipatharians. Among the four bacterial
      strains Vibrio sp. was the least sensitive (2/12) when compared with
      Flavobacterium sp. (6/12). This is the first report of antibacterial activities
      of antipatharian colonies against marine microfoulers. The results imply that
      anthozoan corals harbour potent agents which could be exploited for the
      development of antifouling technology.

PMID- 10581727
TI  - Effect of nitrogen source on pullulan production by Aureobasidium pullulans grown
      in a batch bioreactor.
AB  - Pullulan production by Aureobasidium pullulans ATCC 201253 using selected
      nitrogen sources was studied in a medium using corn syrup as a carbon source.
      Independent of the corn syrup concentration present, the use of corn steep liquor
      or hydrolysed soy protein as a nitrogen source instead of ammonium sulphate did
      not elevate polysaccharide production by ATCC 201253 cells grown in an aerated,
      batch bioreactor containing 4 litres of medium. Pullulan production on corn steep
      liquor or hydrolysed soy protein as a nitrogen source became more comparable as
      the concentration of corn syrup was increased. Cell weights after 7 days of
      growth on any of the nitrogen sources were similar. The viscosity of the
      polysaccharide on day 7 was highest for cells grown on ammonium sulphate and
      12.5% corn syrup. The pullulan content of the polysaccharide elaborated by
      ammonium sulphate-grown cells on day 7 decreased as the corn syrup level rose in
      the medium while the pullulan content of polysaccharide produced by cells grown
      on corn steep liquor or soytone generally increased.

PMID- 10581728
TI  - Isolation and characterization of the K6 type yeast killer protein.
AB  - The optimum production of K6 type yeast killer protein by Kluyveromyces fragilis
      NCYC 587 occurred at pH 4.0-4.4 and at 22-24 degrees C in a killer-zone assay
      test. The K6 killer protein was concentrated by acetone precipitation of the
      culture supernatant and purified by native polyacrylamide rod gel
      electrophoresis. The protein migrated as a single band on discontinuous gradient
      SDS polyacrylamide gel electrophoresis and had a molecular weight of 42,313. The
      isoelectric point of the K6 type protein was determined at pH 5.97 by high
      voltage vertical polyacrylamide gel electrofocusing. Western blot analysis
      revealed that the K6 killer toxin was a nonglycosylated protein.

PMID- 10581730
TI  - The transfer of bacteria to, and survival on, dental records.
AB  - The purpose of this study was to ascertain whether viable bacteria could be
      transferred from gloves to laboratory cards in dental records and, if so, to
      determine whether bacteria could survive on the paper. The thumbs and forefingers
      of two types of glove (Biogel D and Microtouch) were inoculated with
      Streptococcus sanguis and left for various periods of time. A sterile dental
      laboratory card was then held with the gloves and the number of bacteria
      surviving on the card determined after various periods of incubation of the card
      at room temperature. Bacteria were transferred to the laboratory cards and
      remained viable for up to 72 h. More viable bacteria were transferred from the
      Microtouch gloves than from the Biogel D gloves, and this was attributable, in
      part, to the latter gloves exerting a bactericidal effect. The results
      demonstrated that bacteria can be transferred from gloves to laboratory cards and
      that these organisms can remain viable for long periods of time. Dental records
      may, therefore, represent a possible route of cross-infection.

PMID- 10581729
TI  - Characterization and analysis of antibiotic activity of some aquatic
      actinomycetes.
AB  - Nine different isolates of aquatic actinomycetes identified as Streptomyces spp.
      were studied for their morphological and cultural characteristics. One of these
      isolates (C4-S, Streptomyces violaceusniger) was extensively studied for its
      inhibitory effect against a wide range of Gram-positive, Gram-negative bacteria,
      Mycobacterium vaccae ATCC 29678, Candida albicans and several food associated
      filamentous fungi and yeasts. Most of these were characterized by flexous
      sporophore morphology and their inability to produce cultural pigments. Bioassay
      results indicated that S. violaceusniger of 10 days culture age was highly active
      against Gram-positive cocci and bacilli with an inhibition zone of 16-25 mm, and
      slightly active against M. vaccae ATCC 29678 with an inhibition zone of 5-10 mm.
      The inhibitory effect was slight against Escherichia coli, Aspergillus niger 1
      and C. albicans with an inhibition zone of 8-10 mm for each of them. There was no
      inhibitory effect of S. violaceusniger against other Gram-negative bacteria,
      filamentous fungi and yeast. The nature of the active molecule produced by S.
      violaceusniger showed a maximum absorption in the UV region at 210-260 nm.

PMID- 10581731
TI  - Effects of glucose and phenylalanine upon 2,4,6-trichlorophenol degradation by
      Pseudomonas paucimobilis S37 cells in a no-growth state.
AB  - Pseudomonas paucimobilis S37, a strain able to degrade 2,4,6-trichlorophenol (246
      TCP), was isolated from an aquatic environment polluted with this compound. The
      effect of two natural organic compounds on the degradation of 246-TCP by this
      strain, in a no-growth state, was studied. Bacterial cultures were exposed to 0.1
      mM and 0.5 mM of 246-TCP, alone, or in the presence of similar concentrations of
      glucose, a growth supporting substrate, or phenylalanine, a no-growth supporting
      compound. The effects on viable counts and 246-TCP degradation were measured. The
      bacterial culture died with 0.5 mM 246-TCP. This effect was overcome by the
      presence of glucose or phenylalanine, although no degradation of 246-TCP was
      detected. At 0.1 mM 246-TCP, the viability was not altered, and cells were able
      to degrade this compound. Glucose at 0.1 mM increased the degradative activity,
      but higher levels were inhibitory. Phenylalanine at 0.67 mM or higher
      concentration was also inhibitory of the 246-TCP degradation.

PMID- 10581732
TI  - Biosynthesis and localization of glutamylendopeptidase from Bacillus intermedius
      strain 3-19.
AB  - The biosynthesis of glutamylendopeptidase from Bacillus intermedius strain 3-19
      and localization of the enzyme in the bacterial cells was studied. The synthesis
      of the enzyme was suppressed by easily metabolizable carbon sources. Inorganic
      phosphate and NH4+ ions stimulated the production of glutamylendopeptidase.
      Complicated organic substrates such as casein, gelatine, and haemoglobin did not
      affect the biosynthesis of the enzyme. The divalent metallic ions Ca2+, Mg2+,
      Co2+ increased the production of glutamylendopeptidase while Zn2+, Cu2+, and Fe2+
      reduced the biosynthesis of proteinase. The rate of synthesis of the enzyme
      increased when the rate of the bacterial growth decreased. The maximum enzyme
      activity in the culture fluid was determined at the stationary phase of growth.
      In the cells glutamylendopeptidase was bound to the cytoplasmic membrane, and the
      maximal enzyme activity was detected in the stationary growth phase. The results
      facilitated the development of a medium which yielded the maximum
      glutamylendopeptidase production by B. intermedius strain 3-19.

PMID- 10581733
TI  - Effect of the raw extract of Arthrinium strains (Hyphomycetes, Dematiaceae) on
      the growth of pathogenic bacteria in poultry feed.
AB  - Poultry feed contains a significant reservoir of bacteria and is a possible
      source of Salmonella typhimurium, Staphylococcus aureus and Escherichia coli,
      which can potentially infect farm animals and humans. The objective of this study
      was to determine whether the extract obtained from the culture of some Arthrinium
      species was able to inhibit the growth of these bacteria. The results obtained
      showed that the raw extracts of Arthrinium aureum, Arthrinium serenensis and
      Arthrinium phaeospermum inhibited the growth of Escherichia coli in poultry feed.
      In some cases the percentage inhibition of the growth of Escherichia coli was >
      80%. With the raw extract of Arthrinium in poultry feed, the rate of growth of S.
      typhimurium fell to between 50% and 80%. The raw extract of A. serenensis had the
      lowest inhibitory activity. S. aureus counts were not affected by any Arthrinium
      raw extracts.

PMID- 10581734
TI  - Correlation of actinomycin X2 to the lipid profile in static and shaken cultures
      of Streptomyces nasri strain YG62.
AB  - Streptomyces nasri strain YG62 produces a broad-spectrum antibiotic designated
      actinomycin X2. The influence of static and shaken incubation on the production
      of actinomycin X2 and lipid profiles of S. nasri strain YG62 was investigated. It
      was found that shaken incubation was superior to the static process for both
      actinomycin X2 (2-fold) and total lipids (1.6-fold). Triglyceride and
      phospholipid levels paralleled the actinomycin X2 production with an increase in
      the triglyceride (2.8-fold) and phospholipid (1.2-fold) concentrations in the
      shaken culture over the static incubation. Analysis of fatty acid patterns
      revealed the occurrence of a wide range of fatty acids (C10-C22). The mean
      percentage of total saturated fatty acids in shaken culture was higher than those
      of the static culture. The mean percentage of mono-unsaturated fatty acids was
      almost the same in both cultures. The mean percentage of the total
      polyunsaturated fatty acids in the static culture was slightly higher than that
      of the shaken culture. The polyunsaturated/saturated fatty acid ratio (P/S) was
      higher in the static culture compared with the shaken culture. A positive
      correlation was recorded between triglycerides, phospholipids and actinomycin X2.
      A negative correlation on the other hand, was found between fatty acids and
      actinomycin X2.

PMID- 10581735
TI  - NMR study of pradimicin derivative BMY-28864 and its interaction with calcium
      ions in D2O.
AB  - The dynamic structure of the antifungal antibiotic pradimicin BMY-28864 in D2O
      and its interaction with calcium ions were analyzed using one- and two
      dimensional 1H nuclear magnetic resonance (NMR). Spectra indicate extensive self
      association of molecules in the solution. Two-component spectra were observed
      simultaneously in a very dilute solution, suggesting equilibrium of two
      aggregative states. The addition of CaCl2 caused a number of changes in NMR
      spectra. Therefore we concluded that pradimicin BMY-28864 could form a complex
      with the Ca2+ ion, causing a movement of the equilibrium. The position of the
      bound calcium ion is determined indirectly by observing how the NMR shift affects
      protons that are close to the binding site. The stoichiometry of Ca2+ ion to the
      Pradimicin molecule for the Ca(2+)-saturated complex is verified to be 1:2.
      Signal broadening and changes in chemical shift in the 1H NMR spectroscopy of BMY
      28864 are assumed to be related to changes in the molecular aggregate
      conformation.

PMID- 10581736
TI  - A novel Cu,Zn superoxide dismutase from the fungal strain Humicola lutea 110:
      isolation and physico-chemical characterization.
AB  - The fungal strain Humicola lutea 110 produces a mangan- and a copper zinc
      containing superoxide dismutases (SOD). In this study, the purification, N
      terminal sequence and spectroscopic properties of the new Cu,Zn SOD are
      described. The preparation of the pure metalloenzyme was achieved via treatment
      of the strain with acetone followed by gel and ion exchange chromatography. The
      protein consists of 302 amino acid residues and has a molecular mass of
      approximately 32 kDa, as determined by PAG electrophoresis and 3100 U mg-1
      protein-specific activity. It is a dimeric enzyme with two identical subunits of
      15,950 Da, as indicated by SDS-PAGE, mass spectroscopic and amino acid analysis.
      The N-terminal sequence analysis of the Cu,Zn SOD from the fungal strain revealed
      a high degree of structural homology with enzymes from other eukaryotic sources.
      Conformational stability and reversibility of unfolding of the dimeric enzyme
      were determined by fluorescence and circular dichroism (CD) spectroscopy. The
      critical temperature of deviation from linearity (Tc) of the Arrhenius plot ln (Q
      1(-1)) vs. 1/T was calculated to be 68 degrees C and the respective activation
      energy for the thermal deactivation of the excited indole chromophores is 42 kcal
      mol-1. The melting temperatures (Tm) were determined by CD measurements to be 69
      degrees C for the holo- and 61 degrees C for the apo-enzyme. The fluorescence
      emission of the Cu,Zn SOD is dominated by 'buried' tryptophyl chromophores.
      Removal of the copper-dioxygen system from the active site caused a 4-fold
      increase of the fluorescence quantum yield and a 10 nm shift of the emission
      maximum position towards higher wavelength.

PMID- 10581737
TI  - Vibrational spectroscopic studies of solid recombinant bovine growth hormone and
      related growth hormone analogs.
AB  - Infrared and Raman spectra have been obtained for lyophilized recombinant bovine
      growth hormone (r-bGH), partially reduced, and completely reduced r-bGH, plus a
      tryptic digest fragment of r-bGH. Amide I and II data indicate r-bGH to have
      substantial helical character. Partially reduced r-bGH, in which the carboxyl
      terminal disulfide bridge (residues 181, 189) has been cleaved, has slightly less
      helical content than r-bGH. The spectral data indicate that breaking the carboxyl
      terminal cystine link produces only localized structural alterations. The
      additional cleavage of the second disulfide bridge (residues 53,164) leads to a
      further decrease in helix content, accompanied by increases in beta-sheet and
      disordered structures. A tryptic digest r-bGH fragment (residues 96-133), which
      contains a small amount of biological activity (approximately 10%), has
      predominantly helical structure.

PMID- 10581738
TI  - Antigen-antibody interactions: binding studies with fluorescence and surface
      plasmon resonance exemplified by acid-traseolide as antigen.
AB  - The interaction between the musk fragrance acid-traseolide and monoclonal
      antibodies (mAB) generated against this odorant has been investigated with two
      different techniques. Fluorescence spectroscopy was used to study the quenching
      of tryptophan fluorescence of the antibody upon binding acid-traseolide. This
      spectroscopic approach is based on measurements under equilibrium conditions. The
      second technique exploited the surface plasmon resonance (SPR) phenomenon. The
      acid-traseolide was immobilized in the surface matrix and upon presenting mAB
      changes in SPR were recorded in real time during the association reaction. The
      SPR approach can be considered as a kinetic method. Although having a different
      origin, both methods lead to comparable equilibrium dissociation constants (Kd).
      However, the results obtained with fluorescence spectroscopy were more accurate
      and reproducible. Not only the association of acid-traseolide with antibody was
      evaluated, also Fab fragment and peptide (H3-peptide) mimicking the heavy chain
      CDR3 of this antibody were included in this study. The Kd-values, determined by
      both methods, increase in the order mAB < Fab < H3-peptide because of diminishing
      recognition.

PMID- 10581739
TI  - Natural history specimen analysis using micro FT-IR attenuated total reflectance
      spectroscopy and transmission electron microscopy.
AB  - A combination of micro Fourier transform infrared (FT-IR) attenuated total
      reflectance (ATR) spectroscopy and transmission electron microscopy (TEM)
      provided a complete analysis of the interaction between nematode cuticle
      structure and preservation fluids. Spectroscopic results were successfully
      correlated with TEM results. While fresh nematode cuticle yielded uniform
      spectra, damaged cuticles were characterised by large spectrum to spectrum
      variations in the 1000-1100 cm-1 region. An important outcome of this
      investigation was the demonstrated potential of micro FT-IR ATR as a technique
      for the analysis of challenging natural history samples.

PMID- 10581740
TI  - Circular dichroism study of the carbohydrate-modified opioid peptides.
AB  - The conformational preferences of enkephalins and the related glycoconjugates in
      which free or protected carbohydrate moieties were linked to the opioid peptides
      through an ether, ester or amide bond were investigated by circular dichroism
      spectroscopy in water, trifluoroethanol and water-trifluoroethanol mixtures. The
      analysis of the spectra revealed that the conformation of the enkephalin molecule
      is very sensitive to slight changes in the peptide structure around the C
      terminal region. It was found that the type II beta-turn structures are populated
      in N-terminal tetrapeptide enkephalin fragment, while leucine-enkephalin amide
      feature a type I (III) beta-turn structure in solution. Incorporation of the
      sugar moiety into opioid peptide compound did not significantly influence the
      overall conformation of the peptide backbone, although minor intensity changes
      may reflect shifts in the population of the different turn systems. These small
      structural alterations can be responsible for the receptor-subtype selectivity of
      the various carbohydrate-modified enkephalin analogs.

PMID- 10581741
TI  - [Application of basic biological study to clinical research--My research
      history].

PMID- 10581742
TI  - [Myocardial diseases].

PMID- 10581743
TI  - [Physiopathology and therapy of diabetes mellitus].

PMID- 10581744
TI  - [Rational therapy of HIV infections].

PMID- 10581745
TI  - [Blood coagulation disorders--special reference to thrombosis].

PMID- 10581746
TI  - [Pulmonary emphysema--the etiology and therapy].

PMID- 10581747
TI  - [Oxidative stress and aging].

PMID- 10581748
TI  - [Molecular genetic study of senescence-accelerated Klotho mice].

PMID- 10581749
TI  - [Human genes in premature aging].

PMID- 10581750
TI  - [Molecular mechanisms of arteriosclerosis].

PMID- 10581751
TI  - [Alzheimer's disease and neuronal death].

PMID- 10581752
TI  - [Coronary angiographic findings in acute coronary syndrome--disease progression,
      coronary plaque disruption and etiological mechanism].

PMID- 10581753
TI  - [Etiology of acute coronary syndrome-coronary plaque disruption].

PMID- 10581754
TI  - [Physiopathology and therapy of acute coronary syndrome-- molecular cell
      mechanisms in coronary thrombosis].

PMID- 10581755
TI  - [Physiopathology and therapy of acute coronary syndrome--molecular mechanism of
      formation and disruption of coronary atheroma].

PMID- 10581756
TI  - [Conservative therapy of acute coronary syndrome in its acute phase and
      preventive measures].

PMID- 10581757
TI  - [Intervention therapy of acute coronary syndrome].

PMID- 10581758
TI  - [Recent studies on therapy of peptic ulcers].

PMID- 10581760
TI  - [Recent progress in the treatment of interferon-resistant hepatitis C].

PMID- 10581759
TI  - [Recent progress in therapy of inflammatory bowel diseases].

PMID- 10581761
TI  - [Recent progress in the diagnosis and therapy of autoimmune hepatitis].

PMID- 10581762
TI  - [Clinical studies on hyperlipidemia].

PMID- 10581763
TI  - [Kidneys and hypertension].

PMID- 10581764
TI  - [Physiopathology and therapy of fulminant hepatitis].

PMID- 10581765
TI  - [Diffuse panbronchiolitis and erythromycin therapy].

PMID- 10581766
TI  - [Reliability and limitations of ECG diagnosis of ischemic heart diseases].

PMID- 10581767
TI  - [Antiplatelet therapy].

PMID- 10581768
TI  - [Molecular mechanism of collagen diseases].

PMID- 10581769
TI  - [Acute gastric mucosal lesion].

PMID- 10581770
TI  - [Characteristics of hereditary spherocytosis].

PMID- 10581771
TI  - [Present status and future prospects in Cardiac MRI].

PMID- 10581772
TI  - [Relationship between neuromuscular diseases and cancers].

PMID- 10581773
TI  - [Current status and future prospects in the treatment of acute-phase cerebral
      infarction].

PMID- 10581774
TI  - [Etiology and therapy of insulin resistance].

PMID- 10581775
TI  - [Pulmonary lesions in collagen diseases--special reference to interstitial
      pneumonia with polymyositis-dermatomyositis].

PMID- 10581776
TI  - [Collagen disease-related afflictions: development of a new disease concept].

PMID- 10581777
TI  - [Mixed collective tissue diseases].

PMID- 10581778
TI  - [Sjogren syndrome].

PMID- 10581779
TI  - [Behcet disease].

PMID- 10581780
TI  - [Angiitis syndrome].

PMID- 10581781
TI  - [Malignant rheumatoid arthritis].

PMID- 10581782
TI  - [Felty's syndrome].

PMID- 10581783
TI  - [Adult-onset Still's disease].

PMID- 10581784
TI  - [Fibromyalgia].

PMID- 10581785
TI  - [Polymyalgia rheumatica].

PMID- 10581786
TI  - [Antiphospholipid syndrome].

PMID- 10581787
TI  - [Seronegative spondyloarthropathies].

PMID- 10581788
TI  - [Eosinophilic fasciitis].

PMID- 10581789
TI  - [Adrenocorticosteroid preparations].

PMID- 10581790
TI  - [Nonsteroidal anti-inflammatory drugs].

PMID- 10581791
TI  - [Disease modifying anti-rheumatic drugs].

PMID- 10581792
TI  - [Immunosuppressive agents].

PMID- 10581793
TI  - [Comprehending pathophysiology in the management of collagen disease-related
      conditions and key points in their treatment: discussion].

PMID- 10581794
TI  - [Case of Wegener's granuloma complicated with chronic thyroiditis and myelopathy
      and developing epidural lipomatosis during treatment].

PMID- 10581795
TI  - [Case of infectious hepatic cyst caused by Aeromonas caviae].

PMID- 10581796
TI  - [Case of chronic myelocytic leukemia preceded by myelofibrosis].

PMID- 10581797
TI  - [Case of cranial sinus thrombosis discovered by the onset of slowly progressing
      cognition disorder].

PMID- 10581798
TI  - [Case of Klinefelter syndrome complicated with acute lymphocytic leukemia and
      treated with homologous bone marrow transplantation].

PMID- 10581799
TI  - [Relationship between autoimmune diseases and malignant cancer-- correlation of
      Sjogren's syndrome with lymphoma as a model].

PMID- 10581800
TI  - [Thyroid hormone receptors and thyroid hormone resistance].

PMID- 10581802
TI  - [New treatment of stroke].

PMID- 10581801
TI  - [Early treatment of diabetic nephropathy].

PMID- 10581803
TI  - [Blood cells and transcription factor].

PMID- 10581804
TI  - The travelling tooth.

PMID- 10581805
TI  - Anatomy a factor in complications.

PMID- 10581806
TI  - Safety measures for sucking cups.

PMID- 10581807
TI  - Transferral of guilt disheartening.

PMID- 10581808
TI  - The positive side of vocational training.

PMID- 10581809
TI  - Unusual asymmetry explained.

PMID- 10581810
TI  - Case report--hypersensitivity to denture materials.
AB  - Hypersensitivity reactions to the commonly used denture base resins are
      infrequently reported. When they have been reported, most acrylic
      hypersensitivity reactions have been described as local contact reactions with
      few reports identifying any significant systemic symptoms. This paper reports a
      case where the patient suffered extensive systemic symptoms which were strongly
      linked to denture wear. A variety of alternative dentures of different resin
      content were constructed over time with varying reactions. The patient was patch
      tested and responded with positive reactions to pure dye samples supplied by
      manufacturers of the resins. She also failed to react to dentures made in a clear
      acrylic with no dye components. These factors strongly support the hypothesis
      that the reactions experienced by this patient to some denture resins was the
      result of the incorporated colouring agents. It is therefore suggested that in
      cases where a hypersensitivity reaction with systemic manifestations to a denture
      base resin is suspected, questioning with regard to other reactions to colourants
      and patch testing for dyestuffs should be considered in addition to the use of a
      resin with no colouring agents in construction of replacement prostheses.

PMID- 10581811
TI  - The new MFGDP (UK) examination (formerly, the DGDP [UK])
AB  - The October 1998 diet of Part 1 of the Diploma in General Dental Practice (DGDP
      (UK)) of the Faculty of General Dental Practitioners (UK) was notable for two
      reasons. First, it was reciprocal with the first part (Part A) of the new
      Membership of the Faculties of Dental Surgery/Faculty of Dentistry (MFDS/MFD) and
      second, it was the final Part 1 diet of that examination. In November 1998 the
      General Dental Council approved its change of title to that of Membership of the
      Faculty of General Dental Practitioners (UK)--the new MFGDP (UK). This paper
      traces the origins of the MFGDP (UK) in particular and in the context of dental
      postgraduate qualifications in general, and it explains how its Part 1 differs
      from that of the DGDP (UK).

PMID- 10581812
TI  - Radiographic techniques.

PMID- 10581813
TI  - The use of pendulum appliance in the treatment of Class II malocclusion.
AB  - A case of correction of molar Class II using the pendulum appliance is described.
      Upper first molars were distalized into Class I, crowding was eliminated in the
      upper arch and space was provided to attain Class I relationship. Treatment
      lasted for 18 months. A two year follow up shows stability of the occlusion.

PMID- 10581814
TI  - The criteria used by editors of scientific dental journals in the assessment of
      manuscripts submitted for publication.
AB  - OBJECTIVE: To examine the factors that influence editors of scientific dental
      journals in deciding whether or not to publish submitted manuscripts and to
      determine if there is a consistent pattern for their decisions. DESIGN: The study
      was by a postal questionnaire. SETTING: The questionnaires were sent to editors
      of 50 major English language scientific dental journals in September 1996.
      MATERIALS AND METHODS: Respondents were asked to rank a number of frequently
      stated criteria for success in the production of papers. The editors were asked
      to suggest other factors which 'influenced their decision to accept or reject a
      manuscript'. Additionally they were asked to suggest factors that 'gave them most
      heartache', 'would make their life easier' and 'would expedite publication'.
      Information was sought on editorial policy regarding the use of referees.
      RESULTS: Forty two editors responded (84%). 6 replies were from journals regarded
      as 'generalist', and excluded from the final analysis. Factors which most
      frequently led to rejection included 'poor construction of the paper' (cited by
      49% of respondents) and 'poor research design' (37%). Factors which editors
      valued highly were 'scientific novelty and timeliness of the topic' (29%).
      Factors that caused most problems were 'poor use of English and careless
      preparation of the manuscript' (46%). 'Attention to guide lines to authors' was
      cited by 68% of editors as a means of expediting publication. CONCLUSIONS: The
      application of these results can help authors to prepare manuscripts that are
      more attractive to editors of dental journals. Editors valued papers that were
      appropriate to the stated aims of their journal and regarded the significance and
      validity of the research work as the most important aspects of manuscripts
      submitted for publication.

PMID- 10581815
TI  - The cost, effectiveness and cost effectiveness of removal and retention of
      asymptomatic, disease free third molars.
AB  - PURPOSE OF INVESTIGATION: The study was undertaken to identify the least costly,
      most effective and most cost-effective management strategy for asymptomatic,
      disease free mandibular third molars. METHODS AND PATIENTS: A decision tree model
      of the outcomes of mandibular third molar retention and removal was constructed.
      Probability data for possible outcomes were obtained from a comprehensive
      literature review and entered into the decision tree. The cost to the NHS in
      treating each outcome was calculated. 100 patients attending the oral surgery
      clinics, University of Wales Dental Hospital rated the effect of each outcome on
      their own life. The cost and effectiveness data for each outcome were entered
      into the decision tree and the analyses were conducted by 'folding back' the
      decision tree based on the probabilities. MAIN FINDINGS: Mandibular third molar
      retention was less costly (170 Pounds), more effective (69.5 effectiveness units
      on a 100 point scale) and more cost-effective (2.43 Pounds per unit of
      effectiveness) than removal (226 Pounds, 63.3 and 3.57 Pounds respectively).
      These findings were sensitive to changes in the probability of pericoronitis,
      periodontal disease and caries. PRINCIPAL CONCLUSIONS: Mandibular third molar
      retention is less costly to the NHS, more effective for the patient and more cost
      effective to both parties than removal. However, should the likelihood of
      developing pericoronitis, periodontal disease and caries increase substantially
      then removal becomes the more cost-effective strategy.

PMID- 10581816
TI  - An evaluation of a communication skills workshop for dentists: cultural and
      clinical relevance of the patient-centred interview.
AB  - The benefits for both doctors and patients of effective communication skills in
      medical care have been widely documented and are generally accepted. There has
      been less research on this topic with respect to dental care. However, based on
      available studies and the reported success of teaching communication skills at
      the undergraduate level in dental schools, a workshop was developed to improve
      the communication skills of dentists working in government clinics in Hong Kong.
      The patient-centred interview as used in medical care formed the basis for
      teaching communication skills in this workshop. Objective and subjective measures
      of dentists' knowledge, attitude and skills related to the patient-centred
      interview were obtained before, immediately and eight weeks after the workshops.
      Objective measures showed immediate gains in knowledge. However, attitudes
      declined during the period of study. Subjective evaluations revealed improved
      communication skills eight weeks after the workshop and that the patient-centred
      interview was considered relevant to the practices of these dentists.
      Participants made specific reference to the concept of empathy as a means of
      promoting more effective communication between dentists and patients.

PMID- 10581817
TI  - British Paediatric Surveillance Unit: annual report for 1998/99.

PMID- 10581819
TI  - Communicable diseases surveillance.

PMID- 10581820
TI  - Complementary medicine or antagonistic medicine?

PMID- 10581818
TI  - Unusual cluster of mild invasive serogroup C meningococcal infection in a
      university college.
AB  - The objective of this study was to describe the epidemiology and public health
      response to an apparent cluster of Neisseria meningitidis serogroup C infection
      in university students in a residential college. A conventional epidemiological
      approach was taken, supported by routine and novel diagnostic techniques. Over
      the two days of 21-22 August 1997, three cases of suspected meningococcal
      infection were notified from a residential college complex at a university campus
      in the Sydney metropolitan area. Neisseria meningitidis was grown from throat
      swabs of all three cases, and was isolated from the blood of one case only. All
      three isolates were typed as C:2a:P1.5,2. Seroconversion was demonstrated by a
      novel method in the three cases. Rifampicin was given to all identified contacts.
      Forty-seven days after the index case, a 19 year old female living in the same
      complex was diagnosed with bacterial meningitis, and identified contacts given
      rifampicin. When this isolate was found to be group C, it was decided to
      vaccinate residents of the college complex. Genotyping and serotyping (C:2a:P1.5)
      later revealed the fourth isolate to be distinct from isolates from Cases 1-3. In
      conclusion the authors note that Australia's increasing capacity to type
      meningococcal strains is essential to understanding the epidemiology of this
      disease. Furthermore, typing information is of critical importance when decisions
      are made regarding mass vaccination. As early antibiotic treatment may inhibit
      isolation of the organism, development of novel approaches to diagnosis and
      typing should be supported.

PMID- 10581821
TI  - Nettle sting of Urtica dioica for joint pain--an exploratory study of this
      complementary therapy.
AB  - This exploratory study aims to explore the present use of the common stinging
      nettle to treat joint pain. Eighteen self-selected patients using the nettle
      sting of Urtica dioica were interviewed. Information regarding patients' use of
      nettle therapy was elicited, in particular mode of application, dosage and
      effects. All except one respondent were sure that netles had been very helpful
      and several considered themselves cured. No observed side effects were reported,
      except a transient urticarial rash. This exploratory study suggests nettle sting
      is a useful, safe and cheap therapy which needs further study. A randomized
      controlled trial is planned in collaboration with a rheumatology specialist.

PMID- 10581822
TI  - A randomized comparison of homoeopathic and standard care for the treatment of
      glue ear in children.
AB  - OBJECTIVE: To pilot a model for determining whether homoeopathic treatment of
      children suffering from glue ear is more effective than standard GP care at
      producing a return to normal hearing (a hearing loss of less than 20 dB) within
      12 months. DESIGN: Non-blind, randomized controlled trial. SETTING: General
      practice in two locations in southern England. SUBJECTS: Thirty-three children
      aged 18 months to 8 years with otitis media with effusion, hearing loss > 20 dB
      and an abnormal tympanogram. OUTCOME MEASURES: Hearing loss, tympanogram,
      referrals to specialists and number of courses of antibiotics at 12 month follow
      up. RESULTS: A higher proportion of children receiving homoeopathic care had a
      hearing loss less then 20 dB at follow-up (64 vs 56%), though this difference did
      not reach statistical significance (95% confidence interval for the difference
      between means of -25 and 42%). More homoeopathy patients than controls had a
      normal tympanogram (75 vs 31%, P = 0.015). Referrals to specialists and
      antibiotic consumption was lower in the homoeopathy group, though differences
      between groups did not reach statistical significance. CONCLUSION: Further
      research comparing homoeopathy to standard care is warranted. Assuming recovery
      rates of 50 and 30% in homoeopathy and standard care groups respectively, 270
      patients would be needed for a definitive trial.

PMID- 10581823
TI  - Attitudes to evidence on complementary medicine: the perspective of British
      healthcare purchasers.
AB  - OBJECTIVES: To determine the attitude of those who make decisions on the
      allocation of health-care resources (health-care purchasers/commissioners)
      towards the relative importance of different types of evidence on complementary
      medicine. DESIGN: Questionnaire study of GPs and Directors of Public Health.
      SETTING: General practices in the UK and Directors of Public Health of Health
      Authorities in the Greater London region. SUBJECTS: 500 randomly selected general
      practices in 10 randomly selected UK regions, 100 randomly selected general
      practices who had previously referred to the Royal London Homoeopathic Hospital
      and all 28 directors of public health of health authorities in the Greater London
      region. MAIN OUTCOME MEASURE: Importance of the following on a four point scale
      ranging from 0 (not important) to 3 (very important): randomized clinical trials,
      audit outcome data from homoeopathic hospitals, uncontrolled outcome studies,
      patient satisfaction, patient demand, economic evaluation, colleagues' views,
      expert opinion, theoretical understanding, laboratory research, safety and
      availability of literature. RESULTS: 462 general practitioners and 19 Directors
      of Health Authorities responded. Safety data and randomised clinical trials were
      considered very important, colleagues' views and patient demand as slightly
      important, uncontrolled outcome studies as not important. The remaining aspects
      were considered to be important. Differences between the categories of
      respondents were small. CONCLUSIONS: While randomized clinical trials remain very
      important, more emphasis should be placed on further substantiating the safety
      and value for money of complementary medicine in 'real world' clinical settings.

PMID- 10581824
TI  - Systematic review of randomized clinical trials of complementary/alternative
      therapies in the treatment of tension-type and cervicogenic headache.
AB  - OBJECTIVES: To conduct a systematic review of the randomized controlled clinical
      trials (RCTs) of complementary/alternative (CAM) therapies in the treatment of
      non-migrainous headache (i.e. excluding migraine, cluster and organic headaches).
      DESIGN: Systematic review with quality scoring and evidence tables. MAIN OUTCOME
      MEASURES: Number of RCTs per therapy, quality scores, evidence tables. RESULTS:
      Twenty-four RCTs were identified in the categories of acupuncture, spinal
      manipulation, electrotherapy, physiotherapy, homeopathy and other therapies.
      Headache categories included tension-type (under various names pre-1988),
      cervicogenic and post-traumatic. Quality scores for the RCT reports ranged from
      approximately 30 to 80 on a 100 point scale. CONCLUSION: RCTs for CAM therapies
      of the treatment of non-migrainous headache exist in the literature and
      demonstrate that clinical experimental studies of these forms of headache can be
      conducted. Evidence from a sub-set of high quality studies indicates that some
      CAM therapies may be useful in the treatment of these common forms of headache.

PMID- 10581825
TI  - Efficacy of a potentized homoeopathic drug (Arsenicum Album-30) in reducing
      genotoxic effects produced by arsenic trioxide in mice: II. Comparative efficacy
      of an antibiotic, actinomycin D alone and in combination with either of two
      microdoses.
AB  - OBJECTIVE: To determine whether actinomycin-D (AMD), an antibiotic, alters the
      reported efficacy of a potentized homoeopathic drug, Arsenicum Album, in reducing
      genotoxic effects produced in arsenic-trioxide-injected mice. DESIGN: Mice were
      separately injected with AMD, As2O3, and conjointly with AMD plus As2O3, AMD plus
      homoeopathic drug, AMD plus As2O3 plus homoepathic drug, and As2O3 plus
      homoeopathic drug in separate sets. METHODS: Several standard cytogenetical
      endpoints were assessed at different fixation intervals by adopting conventional
      techniques. RESULTS: Both Ars Alb-30 and Ars Alb-200 showed protective ability
      against AMD and As2O3 when injected individually, but this ability was reduced
      considerably in mice injected with AMD and As2O3 together. AMD itself had
      genotoxic effects, but also apparently reduced genotoxic effects of arsenic to
      some extent. CONCLUSION: AMD reduced the protective efficacy of the homoeopathic
      drug against arsenic. This result suggests a mechanism of action for homoeopathy,
      as AMD is a known transcription-blocker.

PMID- 10581826
TI  - Postmodern attitudes about health: a population-based exploratory study.
AB  - OBJECTIVE: This paper presents a preliminary exploration of the prevalence of
      postmodern attitudes about health. DESIGN: In a region of southeastern Australia
      structured telephone interviews with a random sample of 209 participants.
      RESULTS: Responses suggesting postmodern attitudes to health were prevalent: the
      majority of respondents appear to hold a holistic view of health, believe in
      individual responsibility for achieving health, reject medical authority, hold
      consumerist values, prefer natural products over chemical drugs, think most
      prescription drugs have side effects, do not believe all illnesses require
      medication from doctors and hold anti-technology sentiments. However, results
      reveal that most people have much faith in science. CONCLUSION: Attitudes
      prevalent among the public in south eastern Australia are congruent with the
      philosophy of most complementary therapists. This may be one reason for the
      growth of complementary medicine.

PMID- 10581827
TI  - Will the GP commissioner role make a difference? Exploratory findings from a
      pilot project offering complementary therapy to people with musculo-skeletal
      problems.
AB  - The paper focuses on the interprofessional relationships which developed between
      general practitioners (GPs) and complementary practitioners (CPs) during a pilot
      project where GPs referred to acupuncturists, osteopaths and chiropractors. It is
      based on interviews with GPs and CPs, that took place at the beginning and end of
      an evaluative study on patients referred with musculoskelal conditions. Referrals
      to hospital orthopaedic outpatients departments and pain clinics were also
      examined. The most common relationship that developed was where the GP delegated
      responsibility for treatment to the CP. One CP and GP developed a more
      interactive relationship which included a shared diagnostic role. The NHS reforms
      offer opportunities for different types of working relationships to develop
      between health professionals. They also offer opportunities for professionals who
      have not traditionally worked in the NHS to do so. The findings discussed here
      are exploratory. Further research to identify the types of relationships
      developing between CPs and GPs and to establish whether the type of relationship
      has an impact on secondary referrals and treatment outcomes is recommended.

PMID- 10581828
TI  - The health beliefs, experiences and personality of Japanese patients seeking
      orthodox vs complementary medicine.
AB  - OBJECTIVE: This study compared the personality traits, health beliefs and
      'medical experiences' of Japanese patients of both orthodox (OM) and
      complementary medicine (CM). DESIGN AND OUTCOME MEASURE: Altogether, ninety-eight
      Japanese patients completed a questionnaire. This looked at the types of illness
      they had had, medical history, satisfaction with GP, general health beliefs and
      three personality dimensions. RESULTS: No differences were seen between the two
      medical groups on medical history and general health beliefs. However,
      significant differences on present illness, satisfaction with their GP and two
      personality traits (agreeableness, conscientiousness) were found between the
      groups. The CM patients appeared to be less satisfied with orthodox medicine,
      less agreeable and more conscientious compared to the GP group. CONCLUSION: The
      results imply that the combination of the type of illness, the level of patient's
      satisfaction and their personality tendency in part determines their choice of
      practitioner. This study based in Japan replicated many of the findings already
      established in the West. It also uniquely added an examination of personality
      differences.

PMID- 10581829
TI  - Social research that treats the whole therapy: a personal appeal.

PMID- 10581830
TI  - Counselling training for complementary therapists: how much can it help the
      healing encounter?

PMID- 10581831
TI  - Tuberculous chronic otitis media.

PMID- 10581832
TI  - The value of computer-aided (image-guided) systems for endoscopic sinus surgery.

PMID- 10581834
TI  - Congenital lesions of the internal acoustic canal (lipoma).

PMID- 10581833
TI  - Hemorrhagic vocal fold polyp and varicosities.

PMID- 10581835
TI  - Positional nystagmus in only one position.

PMID- 10581836
TI  - Overview of phase I surgery for obstructive sleep apnea syndrome.
AB  - It is well established that obstructive sleep apnea syndrome is associated with
      increased morbidity and mortality. Surgical therapy has been demonstrated to be a
      viable treatment option for cure. Thorough presurgical evaluation with the
      identification of the type of airway abnormality is mandatory to allow for the
      utilization of a surgical protocol that results in improved clinical outcomes.
      Phase I surgical protocol is designed to apply specific surgical procedures to
      alleviate the obstruction(s) present. Following a logical, stepwise surgical
      approach in airway reconstruction will minimize surgical interventions and avoid
      unnecessary operations. The incorporation of a risk-management protocol will
      minimize treatment complications while achieving cure.

PMID- 10581837
TI  - Operative techniques of uvulopalatopharyngoplasty.
AB  - Uvulopalatopharyngoplasty is, for the most part, both safe and effective as a
      surgical treatment for obstructive sleep apnea and severe snoring. Most
      complications can be avoided with proper surgical technique. Palatal dysfunction
      can be avoided if the shortening of the soft palate in the midline (uvula) area
      is minimized. Nasopharyngeal stenosis can be avoided with minimization of the
      posterior pillar resection and by avoidance of pharyngeal undermining. The
      effectiveness of surgery can be improved by placing emphasis 1) on opening the
      nasopharynx widely in the lateral port areas and 2) on tissue removal deep in the
      inferior tonsillar poles (and hypopharynx) with mucosal advancement and suturing.

PMID- 10581838
TI  - Overview of phase II surgery for obstructive sleep apnea syndrome.
AB  - Maxillomandibular advancement is an extremely effective surgical procedure for
      the treatment of obstructive sleep apnea syndrome. When properly executed, it is
      associated with minimal morbidity and is well accepted by patients. It is a
      treatment option that achieves long-term care.

PMID- 10581839
TI  - Insurance coding for the diagnosis and treatment of obstructive sleep disorders.
AB  - In order to assist the physician in obtaining reimbursement for the treatment of
      patients with sleep disordered breathing, this article presents a few simple
      guidelines on insurance coding for various procedures.

PMID- 10581840
TI  - Snoring surgery: which one is best for you?
AB  - Excessive snoring is a common problem that is frequently treated surgically. In
      the early 1980s, uvulopalatopharyngoplasty was introduced to the United States as
      the first surgical treatment for excessive snoring. It remains in common use, but
      its limitations created an incentive to develop a procedure that is as effective,
      but safer and more economical. Several other surgical procedures for snoring were
      developed, including laser-assisted uvulopalatoplasty, palatal stiffening
      operations, and radiofrequency ablation. Each of these procedures has its own
      advantages and limitations; which procedure is the best treatment for excessive
      snoring is controversial. We present our experience with each of these
      procedures, along with a thorough review of the literature, to help the
      otolaryngologist determine which is the best snoring surgery for the individual
      patient.

PMID- 10581841
TI  - The distinct morphological and biological features of primary brain tumors and
      their influence upon prognosis and treatment.
AB  - Primary tumors of the central nervous system apart from features common with
      tumors of other organs and tissues in man show some different and distinct
      features which give significant meaning for prognosis and treatment. One of the
      most important features which characterizes their distinctness is the relation of
      the tumor to its surroundings. Macroscopic and microscopic evaluation of this
      relation decides of possibilities of an early diagnosis and totality of removal.
      Basing on comparison with tumors of other organs e.g. lung, stomach and liver the
      difficult task of differentiation of the infiltration zone with the use of
      morphological criteria only in glial tumors is discussed. Notice has been taken
      of elements which determine the limitation of totality of removal and factors
      conditioning the recurrences. Attention was directed on discrepancy between
      morphological criteria and biological activity of the tumors, specially of those
      which in agreement with cytogenetic classification are included to the group of
      tumors of astrocytic origin. Additionally, the dependency of prognosis and
      treatment on age and localization of the primary brain tumors have been taken
      into consideration.

PMID- 10581842
TI  - Electron microscopy in diagnosis of tumors of the nervous system.
AB  - An abbreviated catalogue of major categories of brain tumors and ultrastructural
      findings regarding these neoplasms are presented in short review.

PMID- 10581843
TI  - Immunohistochemistry in diagnostic neuropathology--limitations and
      interpretations.
AB  - Immunohistochemistry is widely used for diagnostic neuropathology, but contrary
      to some anxieties--it is not method which may replace an experienced pathologist.
      On the contrary--only an experienced pathologist may use this method safely. If
      the differential diagnosis is wrong, the results may be misleading. Similarly,
      the specificity of used antibodies does not guarantee the clearcut
      differentiation.

PMID- 10581844
TI  - The methods of molecular genetic analysis applied for the diagnosis of brain
      tumors.
AB  - The basic knowledge of most commonly used molecular methods applied for the
      diagnosis of neoplasms of the central nervous system is shortly reported.

PMID- 10581845
TI  - Brain damage in children in course of neoplastic diseases.
AB  - The aim of our neuropathologic study was to evaluate the changes in the CNS of
      children occurring in course of neoplastic diseases. First of all we looked for
      those which correspond to paraneoplastic syndromes and others which could be
      considered as secondary toxic lesions after prolonged chemotherapy. Twenty seven
      brains of children aged 0-11 years, 20 without and 7 with metastatic or primary
      neoplastic changes within CNS were examined. In all cases cerebellopathy which
      morphologically corresponded to paraneoplastic changes was found. The generalized
      damage of cerebral cortex less severe of the brain stem, and in several cases
      white matter changes were seen. They seem to be dependent on the prolonged
      treatment using cytostatic drugs.

PMID- 10581846
TI  - Phenotype of mast cells in the brain tumor. Capillary hemangioblastoma.
AB  - Mast cells (MC) are heterogenous cell population. In normal human brain they are
      not numerous. Increases in number of mast cells within CNS occur in certain
      disease states including neoplasms. In capillary hemangioblastoma several authors
      reported mast cells as a fourth cell type of the tumor. The aim of the present
      study was to examine phenotype and distribution of MC in cerebellar capillary
      hemangioblastoma by means of specific immunological markers. Study was performed
      on the tumor of ten affected individuals. Tumor specimens of seven cases were
      fixed in formalin and embedded in paraffin wax. Additional three tumours were
      fresh-frozen samples. Mast cells were identified with two monoclonal antibodies
      generated against tryptase and chymase. In all capillary hemangioblastomas mast
      cells were numerous exclusively in the tumor mass and only occasionally found in
      adjacent or far from the tumor located areas of the cerebellum. The cells
      contained tryptase and chymase. At periphery of hemangioblastomas some mast cells
      underwent degeneration and calcification. Our results confirm previous
      observations that mast cells are numerous in the capillary hemangioblastoma and
      show that most of these cells are tryptase/chymase phenotype (MCTC).

PMID- 10581847
TI  - CT-guided stereotactic biopsy of brain. Three years of experience.
AB  - In our center from 1995 up to now (08.06.99) we have performed 78 CT-guided
      stereotactic biopsies (SB) of brain. In all cases the stereotactic biopsy was
      performed as the first surgical, diagnostic procedure. Indications for SB were as
      follows (in brackets, the number of SBs): diffuse, inoperable tumor (43), tumor
      of central region of brain (19), multiple tumors (7), a change of the obscure
      nature in CT/NMR scan (15), stereotactic assistance of the "classic: craniotomy
      and surgery of tumor (4). Among 78 SBs in 49 cases the primary and in 13 cases-
      secondary (metastatic) brain tumors were diagnosed. In the remaining 16 cases
      nonspecific changes like gliosis or necrosis were found. Of 49 primary tumors 40
      were gliomas. Different pathomorphological methods, including especially
      immunohistochemistry with GFAP, vimentin, p53, Ki-67, and topoisomerase II alpha
      if applied together, may at least partially help to overcome the problems of the
      differentiation of reactive and neoplastic gliosis. We found a grading system of
      gliomas according to Daumas-Duport very useful in interpretation of SB material.
      Our preliminary observations suggest that immunolabelling of the biopsy material
      by means of topoisomerase II alpha antibody may be very useful in SB since it
      gives technically very good results on smears and because on the grounds of what
      is known on this enzyme it is the "target" of many antineoplastic drugs and hence
      may indicate the potential sensitivity to drugs.

PMID- 10581848
TI  - Proton magnetic resonance spectroscopy of primary pediatric brain tumors:
      neuropathological correlation.
AB  - Forty-five children with primary brain tumors were evaluated by in vivo proton
      magnetic resonance spectroscopy (MRS) with the aim of detecting correlations
      between the obtained spectra and tumor malignancy and histology. All
      investigations were performed using a 1.5 T MR scanner (Picker) with point
      resolved spectroscopic (PRESS) sequence (TR 1600 ms, TE 270 ms, NEX 256). Spectra
      were analyzed for N-acetylaspartate (NAA), choline containing-compounds (Cho),
      creatine and phosphocreatine (Cr) and lactate (Lac). The Cho/NAA ratio was the
      most useful parameter for differentiating between normal brain, benign and
      malignant tumors as well as discriminating the three main groups of pediatric
      brain tumors namely pilocytic astrocytoma, ependymoma and medulloblastoma. Proton
      MRS appears to be an important noninvasive technique in the differential
      diagnosis of pediatric brain tumors.

PMID- 10581849
TI  - Clinicopathological analysis of pilocytic astrocytomas and gangliogliomas in
      children.
AB  - We present here a clinico-pathological analysis of 58 pilocytic astrocytomas (PA)
      and 11 gangliogliomas (GG) based on an analysis of neuronal markers (GFAP, SYN,
      NFP) in these two groups of neoplasms. During the retrospective review of 58
      cases recognized primarily as PA, 11 verified neoplasms demonstrated strong
      reaction for SYN or NFP or for both antibodies. These cases were reclassified as
      gangliogliomas. None of 11 tumors recognized as GG were further reclassified as
      PA. The overall 5-year survival was 88.89% in PA and 70.00% in GG group.

PMID- 10581850
TI  - The significance of immunocytochemical markers, synaptophysin and neurofilaments
      in diagnosis of ganglioglioma.
AB  - Ganglioglioma is a tumor composed of neoplastic neurons and neoplastic glial
      cells mixed in different proportions. Astrocytes are the essential glial
      component. The tumor proliferates mostly in the temporal lobe cortex, scarcely in
      other areas of the brain. In ganglioglioma the population of ganglionic neurons
      is very difficult to diagnose. In the last ten years, immunocytochemical reaction
      with synaptophysin and neurofilament protein (NFP) triad considered as neoplastic
      neuron markers seemed to differentiate neoplastic nerve cells from normal neurons
      occurring incidentally within neoplastic proliferation area. In our study, the
      reaction with synaptophysin and NFP was performed on fragments of normal frontal
      lobe, pons and cerebellum as well as on fragments of post-operation tumor
      diagnosed as ganglioglioma. A positive synaptophysin reaction was obtained on the
      surface of neoplastic neurons in gangliogliomas, as well as on the surface of
      normal neurons in the encephalon, cerebellum and pons. Both neoplastic and normal
      neurons and their processes showed the expression of neurofilaments protein
      triad. Thus, a positive reaction of neurons with synaptophysin and NFP seems to
      be nonpathognomic in the diagnosis of the neoplastic neuron population in
      gangliogliomas.

PMID- 10581851
TI  - Dysembryoplastic neuroepithelial tumor. A case report.
AB  - Dysembryoplastic neuroepithelial tumor (DNT) is a rare, benign tumor encountered
      in the cortex. It is characterized by the presence of cells of different
      histogenesis. Due to its mixed nature (glial-neuronal), WHO histological
      classification of brain tumors included it into the group of neuronal and glial
      neuronal mixed tumors. Case of tumor in a 19-year-old woman experiencing for
      three years seizure of temporal lobe epilepsy is presented. A cranial magnetic
      resonance imaging (MRI) showed "pseudocystic" tumor in temporal lobe.
      Histological and immunocytochemical examinations of the tumor fragment removed
      during surgery revealed large numbers of neuronalglial nodules occurring in the
      cerebral cortex. Columns of glial-neuronal structures crossing parallely to the
      cortex surface, surrounded by oligodendrocyte-like cells (OLC) were a
      characteristic feature of the tumor texture. In the tumor interstitium,
      "floating" maturated, dysplastic-free ganglionic cells were visible in numerous
      bright spaces. In addition, numerous lobuliform--structured areas consisted of
      oligodendrocyte-like cells. Oligodendrocyte-like cells were characterized by
      positive immunoreaction to the presence of S-100 protein and synaptophysin.
      Basing on clinical manifestation and histopathological findings dysembryoplastic
      neuroepithelial tumor was diagnosed.

PMID- 10581852
TI  - Dysembryoplastic neuroepithelial tumor (DNT): an ultrastructural study of six
      cases.
AB  - We report six cases od DNT with a detailed ultrastructural characteristics. The
      patient age ranged from 7 to 16 years (mean 12), the location was temporal in
      three cases and frontal, temporooccipital and parietooccipital in each of one
      remaining cases. The predominant clinical feature in each case was history of
      episodes of intractable seizures. Histopathologically, the neoplasms were
      multinodular, each nodule was well-circumscribed and was composed of glioneuronal
      elements embedded in the variable amount of myxoid matrix. The oligodendroglial
      like cells (OLC) predominated in the nodules with some accompanying mature
      neurons. The nodules were frequently surrounded by small calcifications which
      could be found also within the tumors. OLCs were immunoreactive for S-100 protein
      and neurons had the expression of synaptophysin and neurofilament proteins.
      Ultrastructurally, each tumor consisted of three major elements: neoplastic cells
      (OLC), elongated processes forming neuropil-like structure and expanded "mucoid"
      extracellular space: the latter gave an impression of cellular elements floating
      within it. Neoplastic cells had round, oval or elongated nuclei, no discernible
      nucleoli and a relatively narrow rim of the cytoplasm. Some nuclei were irregular
      and invaginated and pseudoinclusions were observed; a part of cytoplasm
      sequestered within pseudoinclusions often appeared degenerated with large blabs
      and electron-lucent vesicles, some of these contained in turn semicircular
      profiles of unknown significance. The second element consisted of innumerable
      cellular processes. Some of these were elongated and formed stacks connected by
      symmetrical symmetric or asymmetric adhesive plaque junctions. The others had
      shorter "neck" containing microtubules, these extended into bullous extensions.
      Dense-cored vesicles were occasionally observed, in both cytoplasm of neoplastic
      cells and within processes. In one cell, cross-sectioned annulate lamellae were
      found. In cytoplasm of a few cells, unusual inclusions reminiscent ribosome
      lamellae complexes were observed. These were cylindrical resembling "laboratory
      tubes" with a cone-like endings. At higher power, walls of the "tubes" resolved
      into layered structures composed of several laminae; between laminae, ribosome
      like structures were visible.

PMID- 10581853
TI  - The ultrastructural study of primary intracranial germ tumors.
AB  - We describe here ultrastructural and clinicopathological features of five primary
      intracranial germinomas. By electron microscopy, two major tumor components were
      defined as large, well differentiated tumor cells and non-neoplastic cells such
      as macrophages, astrocytes and lymphocytes. Nuclei of tumor cells were round to
      oval, often presented irregularly contoured nuclear membranes with oval
      indentations and, occasionally, cytoplasmic invagination. Some of them
      constituted unusual conformational changes of nuclear membranes rarely described
      as intranuclear pockets. Desmosome-like intercellular junctions were observed in
      several neoplastic cells. The nucleoli were composed of a loose, fragmented
      nucleolonema, whereas elongated, anastomosing and rope-like nucleolonemas,
      described previously as characteristic for germinomas were not seen. Most tumor
      cells had villous cytoplasmic projections sometimes intermingled with similar
      projections of macrophages. Cytoplasm contained a moderate number of
      mitochondria, a few lysosomes, annulate lamellae, centrioles and glycogen
      particles. The other distinct components of tumor were lymphocytes, macrophages
      and astrocytes. Scattered astrocytes typically contained abundant glial filaments
      adjacent to primary tumor cell. A filopodia-like processes of macrophages often
      interspersed between other cells, were very prominent features of germinomas.
      Small lymphocytes were found scattered between the tumor cells, single or in
      clusters.

PMID- 10581854
TI  - The occurrence of cerebellar hemangioblastoma in numerous first degree relatives
      with von Hippel-Lindau disease.
AB  - Von Hippel-Lindau disease is an autosomal dominant disorder caused by a mutation
      of VHL gene. The incidence of the disease is one in 36,000 and its clinical
      manifestation is a familial occurrence of hemangioblastoma of the central nervous
      system and retina, renal cell cancer and pheochromocytoma. Cerebellar
      hemangioblastoma is the most frequent or sometimes the only abnormality observed
      in this syndrome. We present a family with von Hippel-Lindau disease in which
      four first degree relatives had a cerebellar hemangioblastoma. This neoplasm
      caused the death of two brothers aged 27 and 24 years old, respectively and their
      mother aged 62. The third son of this family was affected ten years ago, at the
      age of 30. The healthy family members are counselled in Oncological Genetic
      Outpatient Unit in Gdansk.

PMID- 10581855
TI  - Recurrent meningiomas--the immunohistochemical analysis of angiogenesis and
      cellular proliferation. Preliminary study.
AB  - Meningiomas exhibit a tendency to the local regrowth after their surgical
      resection, and some of those recurrent tumors show histological malignancy
      progression. The present study was performed on 10 cases of recurrent meningiomas
      chosen out of total 122 meningiomas diagnosed in our Department of
      Pathomorphology in the period 1993-1998. The tissue material from both operations
      was examined. One patient was operated three times. In three cases at the second
      operation there was progression from benign to atypical meningioma. The other
      tumors did not change their histological grade (four benign, one atypical and two
      anaplastic). The tumor tissue section were stained immunohistochemically with
      monoclonal antibodies raised against epithelial membrane antigen (EMA), Ki-67 and
      von Willebrand factor (vWf). The percentage of EMA-positive cells and Ki-67
      immunoreactive cells (proliferation cell index--PCI) were counted. The vascular
      density (number of blood vessels/mm2) was assessed in the preparations stained
      with anti-vWf, as the measure of the intensity of angiogenesis. The values of the
      examined parameters were greatly differentiated within both the initial and the
      recurrent tumor groups. The values of vascular density ranged 12-96 vessels/mm2,
      the percentage of EMA-positive cells was 0.75%, PCI was from 0.3 to 9.3%. The
      values of the examined parameters did not differ significantly between initial
      and recurrent meningiomas groups. It is however worth to point out that PCI in
      the most recurrent tumors were higher than in their primary counterparts.

PMID- 10581856
TI  - Giant cervico-thoracic schwannoma with long clinical history. Case report.
AB  - An unusual case of a giant intraspinal schwannoma in a 45-year-old woman with 14
      year history of preoperative symptoms was presented. MRI of the spine revealed an
      intradural, extramedullary tumor extending from the intervertebral space C4/C5 to
      T4 vertebral body level (2 x 1.2 x 12 cm) and filling almost the entire spinal
      canal. Microscopical examination showed a typical neurinoma pattern with two
      distinct zones of Antoni A and Antoni B tissue. Some areas exhibited nuclear
      atypia and hyperchromasia reflecting the degenerative changes in this slowly
      growing nerve sheath tumor. A rich pericellular reticulin network was seen in the
      areas composed of Antoni A tissue. Immunohistochemically, the tumor cells were
      strongly positive for S-100 protein. The diagnostic difficulties in the presented
      case of longstanding schwannoma resulted in the late surgical treatment. The
      importance of the early diagnosis of spinal nerve sheath tumors for the patient's
      quick recovery is stressed.

PMID- 10581857
TI  - Computerized morphometric analysis of human leukemic and lymphomatous cells in
      various histological environments of central nervous system.
AB  - The leukemic and lymphomatous cells appear within the central nervous system
      (CNS) in 5 different environments: in CNS vessels, perivascular spaces, meninges,
      nervous tissue and in CNS hemorrhages. A computerized analysis of geometric and
      densitometric parameters of neoplastic cells in these compartments were done for
      better recognition of penetration and spreading of leukemia and lymphoma within
      the CNS. A post-mortem neuropathological investigations were carried out on 16
      patients deceased due to acute myeloblastic leukemias (M1, M2), blastic phase of
      chronic myelogenous leukemia, lymphoblastic lymphoma and acute lymphoblastic
      leukemia. Following nuclear parameters of neoplastic cells were analyzed: area,
      "form factor", mean, minimal and maximal density. An evident differentiation of
      nuclear parameters within the CNS environments was found. The nuclei within the
      perivascular spaces and especially in CNS hemorrhages were significantly shrunken
      and dense (p < 0.01), but not evidently deformed. The intracerebral infiltrates
      appeared to be most differentiated group (p < 0.01). Morphometric values of
      leukemic and lymphomatous cells show regressive changes of neoplastic cells
      within the CNS perivascular spaces, nervous tissue and in CNS hemorrhages. These
      changes depend on unfavorable factors in the mentioned CNS environments, and also
      on time of cell persistence in these regions. Meninges were found to be the only
      CNS structure facilitating the survival and proliferation of leukemic and
      lymphomatous cells.

PMID- 10581858
TI  - The metastases of lung cancer to the brain--the examination of angiogenesis and
      p53 expression.
AB  - The aim of the present study was to investigate the intensity of angiogenesis and
      p53 protein expression in metastases of lung cancer to the brain. There were
      eight cases of squamous cell type and nine adenocarcinomas among 17 examined
      cases of metastatic carcinomas. The antibodies against von Willebrand factor
      (vWF)--to highlight the microvessels and against p53 protein--for detection of
      immunopositive cells were used. The intensity of angiogenesis was represented by
      the mean number of the blood vessels in three tumor fields with the highest
      microvascular density ("hot spots"). The measurements were taken in three
      microscopic fields under 200x magnification (the examined area was 0.785 mm2).
      The mean number of p53-positive cells in three tumor areas under 200x
      magnification with the highest number of p53-positive cells was the measure of
      protein p53 expression. The values of vascular density and p53 expression
      differed a lot among the examined tumors. The values of vascular density were
      between 4.2-106 vessels/mm2 (mean value 49.3 vessel/mm2). The number of p53
      immunopositive cells was between 0-284 cells/mm2 (mean value 110.6 cells/mm2).
      There was no significant correlation between examined parameters (correlation
      coefficient 0.18).

PMID- 10581859
TI  - Immunofluorescent analysis of antibodies against neurons in the case of
      paraneoplastic syndrome.
AB  - The authors report clinical and neuropathological findings especially
      immunofluorescent detection of antineuronal antibodies in the case of
      paraneoplastic syndrome in course of the small-cell lung carcinoma. The clinical
      symptoms, observed in 48-year-old woman, covered bilateral pyramidal syndrome,
      cerebellar syndrome, myasthenic syndrome and impairment of the cranial nerves.
      Neuropathological investigation revealed paraneoplastic encephalopathy in the
      form of encephalitis. Immunofluorescent analysis showed brightly fluorescent
      neurons standing out against a dull background.

PMID- 10581860
TI  - Localization and a role of cyclooxygenases in the CNS.

PMID- 10581861
TI  - Behavioural research and nonconvulsive spontaneous electrocortical seizures in
      laboratory rats. A note of concern.
AB  - A proportion of subjects of rat strains and lines commonly used for behavioural
      research in neurotoxicology, neuropharmacology and related fields show
      spontaneous generalized nonconvulsive EEG seizures. The seizures have the form of
      bursts of spike and wave discharges (SWD) reminiscent of human petit-mal
      epilepsy. Behavioural manifestations of SWD seizures are poor and, therefore,
      their occurrence is not taken into account either during selection or during
      grouping of rats for the experiment. This paper comprises a short discussion of
      literature data which allow one to suspect that the rats with SWD seizures differ
      from normal nonepileptic ones with respect to behavioural performance in some
      test situations and behavioural effects of exposure to drugs or other chemicals.
      Thus, considering the fact that the proportion of subjects with SWD seizures may
      vary considerably in rat samples, it seems likely that the broad use of rat
      populations heterogenous with respect to this EEG pathology may be responsible,
      at least in part, for inconsistent results of similar experiments performed at
      different laboratories. Therefore, attempts should be made in order to reduce the
      use of such rat population in behavioural research, particularly those intended
      to supply data which may consist the basis of hygiene standards of exposure to
      xenobiotics.

PMID- 10581862
TI  - The disposition and metabolism of naphthalene in rats.
AB  - The aim of this study was to investigate the distribution, excretion and
      metabolism of naphthalene-[ring-U-3H] in rats. The experiments were performed on
      54 male outbred IMP: Wist rats with body weight of 200-220 g. The compound was
      administered intraperitoneally in olive oil in a single dose of 20 mg/kg (about
      540 kBq per animal). 3H radioactivity was traced in selected organs and tissues,
      blood, urine and faeces, 1-72 h following the administration. The main
      metabolites were isolated from urine and identified by the GC-MS method. Urine
      and faeces proved to be the main route of tritium elimination. Over 88% of the
      compound was excreted during the first 72 hours. Maximum level of tritium in
      plasma was observed at the 2nd h after administration following a biphasic
      decline. Half-lifes for phases I and II were 0.8 and 99 h, respectively. In
      erythrocytes 3H-decline was monophasic with the half-life of about 9 h. In organs
      and tissues, the highest concentrations during the first hours after
      administration were detected in the fat, liver and kidneys. Then, gradual decline
      of tritium was noticed in all examined tissues. In urine of rats the following
      substances were identified: (1) naphthalene, (2) 1-naphthol, (3) 2-naphthol, (4)
      1,2-naphthalenediol-1,2-dihydro, (5) methylthionaphthalenes (two isomers). In
      conclusion, naphthalene has a relatively rapid turnover rate in the rat organism
      and does not form considerable deposits in the tissue. The metabolism encompasses
      ring hydroxylation, hydration and glutathione conjugation.

PMID- 10581863
TI  - Measurement of 210Po atoms content in glass as an indicator of long-term exposure
      to radon.
AB  - Measurements of exposure to radon are performed using numerous research methods
      which register either temporary or periodic radon concentrations. The method
      presented below allows for the estimation of average radon concentration in the
      past. This is possible due to indirect measurement of the contents of 210Pb
      embedded in glass structure. The half-life of 210Pb is about 22 years. A number
      of exposures of window glass to radon have been carried out in laboratory
      conditions (radon chamber) and the obtained results were used to calculate the
      coefficient that renders it possible to define global indoor exposure to radon.
      The registration was made using a track detector CR-39, which records alpha
      particles resulting from the disintegration of 210Po, one of 222Rn decay
      products.

PMID- 10581864
TI  - Radium and radon in natural underground water supply in the region of Lodz,
      Poland.
AB  - The region of Lodz, located in the central part of Poland, is very specific with
      respect to water supply coverage. In this densly populated and extensively
      industrialised region there is a lack of natural reservoirs of surface water in
      the nearest vicinity of Lodz. Therefore, over 50% of water for public and
      domestic use is provided from underground water intakes. It is well known from
      the literature that in underground water may occur radionuclides in the uranium
      and thorium decay series. Underground water intakes in Lodz used for public water
      supplies have been surveyed for the presence of radium-226 and radon-222 since
      the earlier studies of quality standards of the gross alpha and gross beta
      activity pointed to their possible excessive values. The surveillance was based
      on the guidelines set by the World Health Organisation (WHO). The measurements of
      radium-226 activity showed its different concentrations depending on the age of
      the water-bearing level. These concentrations fell within the range of < 10
      divided by 50 Bqm-3. Measurements of radon yielded similar results and its
      highest concentrations were found in the Lower cretaceous and Jurassic
      formations. Radon concentrations ranged from 200 to 11,400 Bqm-3. A maximum
      annual dose taken into the body in the population drinking this water may account
      for 0.85 microSv which is lower than the limit recommended by WHO.

PMID- 10581865
TI  - Occupational exposure to high frequency electromagnetic fields and its effect on
      human immune parameters.
AB  - The present study recorded a considerable excess of recommended exposure limits
      in the vicinity of shortwave diathermy devices used for medical treatment of
      patients. Different kinds of field probes were used to measure electric and
      magnetic field strength and the whole body exposure of medical personnel
      operating shortwave, decimeter wave and microwave units was calculated. To
      investigate the influence of chronic exposure on the immune system of operators,
      blood was sampled from physiotherapists working at the above mentioned devices.
      Eighteen exposed and thirteen control persons, matched by sex and age, were
      examined. Total leucocyte and lymphocyte counts were performed and leucocytic
      subpopulations determined by flow cytometry and monoclonal antibodies against
      surface antigens. In addition, to quantify subpopulations of immunocompetent
      cells, the activity of lymphocytes was measured. Lymphocytes were stimulated by
      mitogen phytohemagglutinin and their proliferation measured by a flow cytometric
      method. No statistically significant differences between the control and exposed
      persons were found. In both study groups all immune parameters were within normal
      ranges.

PMID- 10581866
TI  - The effects of different materials of protective gloves on thermoregulatory
      responses.
AB  - The effects of two kinds of protecting gloves for pesticide spraying made of
      different materials on thermoregulatory responses during exercise were studied at
      ambient temperature of 28 degrees C and relative humidity of 60% in six healthy
      females, aged 19. One kind of gloves was made of polyurethane (A) and the other
      of Goretex (B) with cotton lining in each glove. Both kinds of gloves had almost
      the same volume. Main results of the experiment were summarised as follows: (1)
      during the exercise an increase of rectal temperature was inhibited more
      effectively in B than in A; (2) skin temperature of hand was significantly lower
      in B than in A; (3) absolute humidity and temperature inside the gloves were
      significantly lower during the period from the gripping bar exercise to the end
      of the experiment; (4) the number of contractions by the handgrip exercise
      performed immediately after the second turning of the screw was significantly
      smaller in A than in B. The findings presented suggest that the gloves made of
      Goretex material could reduce thermal strain during intermittent work in warm
      environmental conditions.

PMID- 10581867
TI  - Background on the system of integral evaluation of human exposure to toxic
      substances in the work and municipal environments.
AB  - Exposure to toxic chemicals in the work, natural and home environments is
      recognised as combined exposure. The system of integral evaluation of human
      exposure should take account of all toxic substances occurring in all
      environmental media (air, water, soil and food), and all routes through which
      they enter the human body. To provide the integral evaluation it is necessary to
      develop different exposure scenarios based on dose intake or derived values.
      Following the toxicological criteria, calculated exposure indicators, after their
      standardisation and aggregation, should be converted into combined exposure
      indices. The index value will reflect the level of combined exposure.

PMID- 10581868
TI  - The assessment of Big Five Personality Factors and Temperament Domains as
      modifiers of cardiovascular response to occupational stress.
AB  - The aim of the study was to explore the role of Big Five Personality Factors and
      Temperament Domains as the factors influencing cardiovascular response to work,
      and their moderating effect on the relationship between occupational stress and
      cardiovascular reactivity. The self-reported data on occupational stress and
      filled in NEO-Five Factor Inventory by Costa, and McCrae and Pavlovian
      Temperament Survey by Strelau et al. were collected from 97 bank clerks employed
      in large bank branches. The subjects also responded to the questionnaire on
      personal and professional background factors. A 24 hour monitoring of
      cardiovascular reactivity (heart rate and blood pressure) was also provided.
      Conscientiousness was found to be the only modifier of cardiovascular response to
      occupational stress reflected by systolic blood pressure. Several main,
      independent of stress effects of personality and temperament domains were also
      found. The ratio of heart rate at work to heart rate during sleep was associated
      with the strength of excitatory process, the percentage of maximum heart rate
      index with Conscientiousness, and systolic blood pressure at work was influenced
      by the strength of inhibitory process. However, generally speaking, physiological
      indicators of the cardiovascular system functioning were not very sensitive to
      changes in values of personality and temperament variables at the level of
      occupational stress reported by the bank clerks who participated in the study.

PMID- 10581869
TI  - Call for an international ban on asbestos.

PMID- 10581870
TI  - [Mechanism of the "acetylene effect" during interaction of organophosphorus
      compounds with cholinesterases].
AB  - Here we present data on the anticholinesterase activity of 58 synthesized ethers
      of phosphorus thioacids with an acetylene bond in the thioether group.
      Anticholinesterase activity of the compounds, with acetylene group in beta and
      especially alpha position, in the thioether radical is many times that of their
      saturated analogs. Reaction between the enzymes and acetylene organophosphorous
      inhibitors, as well as their saturated analogs, results in phosphorylated enzyme.
      The triple bond plays a significant role in the acceleration of cholinesterases
      phosphorylation. Antienzyme activity of acetylene organophosphorous inhibitors is
      discussed.

PMID- 10581871
TI  - [Analysis of various taxon specific parameters of the guard hair cuticles for
      development of the mammalian identification system by morphometric
      characteristics of their hair].
AB  - Mathematical indices of the structure of the external surface of guard hairs have
      been developed on the basis of a KS300 system of automatic image analysis
      (Kontrom Elektronik, Germany), which are capable of serving, in some cases, as
      diagnostic parameters of large taxa (order, family). The guard hair morphology is
      affected by various factors, such as body region where a given hair is located,
      season, diet, sex of individual, and state of its health, which is expressed in
      changes of some morphometric data. For a more complete analysis of the
      characteristics of the guard hair structure, it is necessary to use indices that
      describe the macro- and microstructure of the external surface of the stem and
      its internal structure.

PMID- 10581872
TI  - [Discovery of internal sources of the neural retinal regeneration after its
      detachment in Pleurodeles. II. The radioautography study].
AB  - We continued to study internal sources of neural retina regeneration in adult
      lower vertebrates. A radioautographic study carried out was aimed at the
      visualization of proliferating cells in different areas of the retina and at
      different times after its detachment in the newts Pleurodeles waltl. Analysis of
      serial standards and semithin sections has shown several types of cells capable
      of incorporating a labeled DNA synthesis precursor. The marker of proliferating
      cells was incorporated in the cells of Mullerian glia, pigment epithelium, and
      growth zone and in small neural cells of the vitreal part of the inner nuclear
      layer. A source of formation of neuroepithelial "insertions" responsible for
      restoration of the complete cell composition of the retina damaged as a result of
      detachment should be searched among these cell types. Neither bipolar cells with
      Landoldt's club in the inner nuclear layer, nor bipolar-like cells in the outer
      nuclear layer, which are a source of formation of additional photoreceptors, were
      found among the 3H-thymidine- labeled cells. A conclusion was drawn that the
      bipolar-like cells of P. waltl are postmitotic cells, that did not reach terminal
      differentiation.

PMID- 10581873
TI  - [Regulation of the mitotic activity in the rat cornea in response to protective
      and therapeutic effects of para-aminobenzoic acid in experiments with roentgen
      radiation].
AB  - The protective and therapeutic action of p-aminobenzoic acid (PABA), at doses
      effective in interferon induction (Akberova et al., 1999), was studied on the rat
      cornea in the experiments with X-irradiation (5 Gy). PABA at 10 mg/kg preserved
      the postradiation mitotic activity at the level of irradiated control, while at
      1.4 and 100 mg/kg it increased the mitotic activity above the control level. In
      all experiments, PABA at all three doses decreased the rate of pathological
      mitoses in equal proportions to the total number of mitoses.

PMID- 10581874
TI  - [Effects of stress and types of the animal behavior on the binding aldosterone
      with the brain corticosterone receptors].
AB  - Specific accumulation of 3H aldosterone by corticosteroid receptors of the brain
      structures was determined in in vitro and in vivo experiments on rats of
      different behavioral types under the normal conditions and within two weeks after
      stress. In both variants, stress decreased binding of 3H aldosterone to
      corticosteroid receptors of the rat brain. Differences were found in binding of
      3H aldosterone to corticosteroid receptors of the hippocampus, rather than the
      whole brain, in animals with different behavioral types both under normal
      conditions and after stress. The experimental results agree with the published
      data about involvement of the corticosteroid receptor system of the brain limbic
      structures in the formation of emotional reactivity in animals.

PMID- 10581875
TI  - Pacific Island suicide in comparative perspective.
AB  - All available data for thirteen Pacific Island nations are used in a comparative
      analysis of suicide levels and characteristics. Age, sex and method of suicide
      are examined in detail. Global comparison shows Pacific rates are amongst the
      highest reported. Female youth rates exceed male rates in Western Samoa and
      amongst Fiji Indians. Method of suicide (paraquat ingestion) is instrumental in
      determining high rates in Western Samoa, especially in females. The broad causal
      theme is societal transition. Commonality and diversity are discussed.

PMID- 10581877
TI  - Family-building patterns and childhood mortality: a family-level analysis.
AB  - It has been suggested that altering the pace of reproduction would improve the
      health of women and children. For formulating intervention policies, it is
      important to know whether on its own such a strategy is likely to lead to risk
      reduction. This paper analyses mortality risk in sibships to explore the
      relationship between family formation factors and other household characteristics
      that identify women whose families are at higher risk. The analysis allows for
      the fact that reproductive behaviour may be modified by the family's prior
      experience of child death, using simultaneous equations methods to purge the
      model of the 'feedback' effects of death on the endogenous variable, childbearing
      pace. The strong relationship between reproductive pace and average risk in a
      family appears to be due to the association of both with other differences
      between households. Other aspects of family formation patterns are good
      indicators of which families are likely to experience excess risks to their
      children. These factors are associated with maternal education, but measure
      characteristics of the family or mother that educational attainment does not
      fully capture. They indicate that high-risk mothers are likely to have less
      control over many aspects of their lives. The pace of family building does not
      lead to excess average family risk, but may result, at least in part, from the
      concentration of risk in families with other characteristic patterns of family
      formation and few resources. The paper argues for a broader conception of
      household influences on child health and the health-related behaviour of parents.

PMID- 10581876
TI  - Community perceptions of reasons for preference for consanguineous marriages in
      Pakistan.
AB  - Although the recent Pakistan Demographic and Health Survey (DHS) show that two
      thirds of marriages in Pakistan are consanguineous, the sociocultural
      determinants of such marriages remain largely unexplored. This paper examines the
      relative importance of the three commonly perceived reasons for such marriages:
      religious, economic and cultural. The analysis is based on qualitative data
      collected in 1995 from multi-ethnic and multi-religious communities in Karachi,
      the largest city of Pakistan. Results show that consanguineous marriages are
      preferred across all ethnic and religious groups to a varying degree, and that
      parents continue to be the prime decision-makers for marriages of both sons and
      daughters. The major reasons for a preference for consanguineous marriages are
      sociocultural rather than any perceived economic benefits, either in the form of
      consolidation of family property or smaller and less expensive dowries. Among
      Muslims, following religious traditions is the least commonly cited reason for
      such marriages. Despite the reported sociocultural advantages of consanguineous
      marriages, such unions are perceived to be exploitative as they perpetuate the
      existing power structures within the family.

PMID- 10581878
TI  - Chinese traditional medicine and abnormal sex ratio at birth in China.
AB  - A study of the abnormal sex ratio at birth in China reveals that it is not an
      entirely new phenomenon that emerged since the 1980s, but is simply more visible
      at present. Deliberate intervention to determine the sex of children has existed
      in the past few decades, at least in certain groups. Apart from modern medical
      methods, traditional Chinese medical practice is shown to be highly accurate in
      identifying the sex of a fetus. This may lead to sex-selective abortion and an
      abnormal sex ratio at birth. The possible causes of the abnormal sex ratio at
      birth include not only the real imbalance due to the disturbance of social
      factors, but also a spurious one attributable to the undercounting of female
      births. The real magnitude of the imbalance has been exaggerated by statistical
      error. The phenomenon is a complicated one reflecting the comprehensive
      socioeconomic setting. Among these factors, the stage of the fertility transition
      is one of the most decisive.

PMID- 10581879
TI  - Nutrition, fertility and steady-state population dynamics in a pre-industrial
      community in Penrith, northern England.
AB  - The effect of nutrition on fertility and its contribution thereby to population
      dynamics are assessed in three social groups (elite, tradesmen and subsistence)
      in a marginal, pre-industrial population in northern England. This community was
      particularly susceptible to fluctuations in the price of grains, which formed
      their basic foodstuff. The subsistence class, who formed the largest part of the
      population, had low levels of fertility and small family sizes, but women from
      all social groups had a characteristic and marked subfecundity in the early part
      of their reproductive lives. The health and nutrition of the mother during
      pregnancy was the most important factor in determining fertility and neonatal
      mortality. Inadequate nutrition had many subtle effects on reproduction which
      interacted to produce a complex web of events. A population boom occurred during
      the second half of the 18th century; fertility did not change but there was a
      marked improvement in infant mortality and it is suggested that the steadily
      improving nutritional standards of the population, particularly during crucial
      periods in pregnancy (i.e. the last trimester), probably made the biggest
      contribution to the improvement in infant mortality and so was probably the major
      factor in triggering the boom.

PMID- 10581880
TI  - The stratifying force of family size, urbanization and parental education in
      socialist-era Poland.
AB  - The strength of influence upon statural variation of: (1) the degree of
      urbanization of the locality of habitat, (2) family size, (3) paternal and (4)
      maternal educational status was analysed in three generations of 19-year-old
      Polish conscripts, examined in 1965, 1986 and 1995. Each of the above factors of
      an individual's social situation was described by a 4-level scale. Each factor
      was found to exert a highly significant residual effect on stature throughout the
      three decades considered, even after the effects of other correlated factors were
      partialed out by three-factor ANOVA. However, the stratifying force of each
      factor, as expressed by the dispersal of the level-specific main effects around
      the national mean, has been changing over time. For example, the growth-stunting
      effect of the condition of coming from a large sibship was dramatic in the 1965
      cohort and considerably attenuated in 1986 but ceased to diminish thereafter. The
      growth-enhancing effect of the condition of being a large-city dweller, initially
      marked, has almost disappeared; but the growth-stunting effect of the condition
      of being a rural dweller has remained equally strong across all cohorts. These
      and other shifts in the relative importance of the social factors, as presumed
      determinants of family living standards, are described and some explanations
      attempted.

PMID- 10581881
TI  - Contraceptive use dynamics of Asian women in Britain.
AB  - In-depth interviews were conducted with married Asian women from Indian,
      Pakistani and Bangladeshi backgrounds, to investigate patterns of contraceptive
      use and influences on contraceptive decision making. The results show two
      distinctively different contraceptive 'lifecycles'. Non-professional women
      typically have little knowledge about contraception until after their marriage or
      first birth. Their patterns of contraceptive behaviour show low levels of
      contraceptive use until after their first birth, when condom use is most
      prevalent. Non-professional women are influenced by their extended family,
      religion and cultural expectations on their fertility and family planning
      decisions. Professional women show an entirely different pattern of contraceptive
      behaviour. They are more likely to have knowledge about contraception before
      marriage, use some method of contraception throughout their childbearing years
      (typically the pill) and cite personal, practical or economic considerations in
      their fertility decisions rather than religious, cultural or extended family
      influences.

PMID- 10581882
TI  - Reliability of self-reported body height and weight of adult Japanese women.
AB  - The purpose of this study was to validate the self-reported body height and
      weight of adult Japanese women. The subjects were women, aged 20-42 years, who
      participated in a survey on eating disorders in women in 1995. Physically
      measured height and weight data were obtained for 368 (89.8%) of the 469 women
      who self-reported their height and weight. The report-based heights and weights
      were compared with the measured values. The correlation coefficients for height
      and weight were 0.990 and 0.963 (p < 0.0001), respectively. Mean reported height
      was 0.1 cm shorter and mean reported weight 0.2 kg lighter than the measured
      values. Shorter women tended to report a taller height than their actual height,
      and heavier women to report a lower weight than their actual weight. Despite
      these limitations, the self-reported heights and weights of adult Japanese women
      were precise and accurate, and their use in epidemiological surveys is considered
      acceptable.

PMID- 10581883
TI  - Mass transit strike effects on access to medical care.

PMID- 10581884
TI  - The public's health, its national identity, and the continuing dilemma of
      minority status.
AB  - Racial and ethnic disparities in health status are persistent phenomena well
      described in the arena of public health. Such disparities are perhaps best
      understood in their full social, political, and historical context. While
      recognizing the rich literature on social determinants of health, this paper
      provides a specific discussion of the status of "the minority" in the United
      States. The dynamic nature of the American identity is first presented, along
      with implications for differential health status. Next discussed are emerging
      paradigms in research and intervention that incorporate the dynamic nature of the
      American identity as both an explanation and an opportunity for remedy of health
      status disparities. Finally, a critical leadership role for the public health
      profession is proposed as urgently needed and as yet incompletely embraced.

PMID- 10581885
TI  - Tracking and follow-up of marginalized populations: a review.
AB  - Maintaining study cohorts is a key element of longitudinal research. Participant
      attrition introduces the possibility of bias and limits the generalizability of a
      study's findings, but with appropriate planning it is possible to sustain contact
      with even the most transient participants. This paper reviews the essential
      elements of tracking and follow-up of marginalized populations, which are (1)
      collection of contact information, (2) thorough organization of tracking efforts,
      (3) attention to staff training and support, (4) use of phone and mail follow-up,
      (5) use of incentives, (6) establishing rapport with participants, (7) assurance
      of confidentiality, (8) use of agency tracking, (9) use of field tracking, and
      (10) attention to safety concerns. Diligent application of these tracking
      strategies allows researchers to achieve follow-up rates of 75 percent to 97
      percent with vulnerable populations such as homeless, mentally ill adults,
      injection drug users, and runaway youth.

PMID- 10581886
TI  - Evaluation of a targeted HIV testing program for at-risk youth.
AB  - With the advent of new therapies for HIV, case identification through HIV
      counseling and testing (CTS) has become critically important. Young women, youth
      of color, and disenfranchised youth are at significant risk of acquiring HIV.
      This study describes clients who access CTS at a program of comprehensive care
      for high-risk youth (aged 12 to 24 years), and assessed, using logistic
      regression analyses, whether youth at highest risk utilized CTS. Most of the 531
      youth were female (72 percent) and nonwhite (60 percent). Sixty-eight percent
      received CTS. Logistic regression modeling revealed that white race and receiving
      care at the teaching hospital were the only independent predictors of testing.
      Data indicate that, despite targeted, youth-specific, developmentally appropriate
      and culturally sensitive outreach and intervention efforts, youth of color and
      high-risk youth are poorly accessing CTS. A greater understanding of the barriers
      to and cultural norms regarding CTS is needed.

PMID- 10581887
TI  - Health problems and service utilization in the homeless.
AB  - This study examined the health problems and utilization patterns of homeless
      individuals (n = 292) seeking medical services in a small, southern community.
      Results showed that the medical problems for which the homeless sought treatment
      were often (72.6 percent) a reoccurring problem for which treatment had been
      previously received. The most prevalent medical problem was upper respiratory
      infection (47 percent), likely exacerbated by the high rate (73 percent) of
      cigarette smoking found among the sample. More than half (51.4 percent) of the
      participants had used other medical services in the past month. Despite these
      high rates of utilization, the homeless may, in fact, be underutilizing
      appropriate preventive medical services, waiting until the medical problem
      becomes serious before seeking treatment, and overutilizing emergency rooms for
      nonemergency care. Community-based services sensitive to the needs of the
      homeless are likely to cost communities less money while providing better
      services to the homeless.

PMID- 10581888
TI  - Access to care for low-income women: the impact of Medicaid.
AB  - This study was undertaken to assess how low-income women with Medicaid, private
      insurance, or no insurance vary with regard to personal characteristics, health
      status, and health utilization. Data are from a telephone interview survey of a
      representative cross-sectional sample of 5,200 low-income women in Minnesota,
      Oregon, Tennessee, Florida, and Texas. On the whole, low-income women were found
      to experience considerable barriers to care; however, uninsured low-income women
      have significantly more trouble obtaining care, receive fewer recommended
      services, and are more dissatisfied with the care they receive than their insured
      counterparts. Women on Medicaid had access to care that was comparable with their
      low-income privately insured counterparts, but in general had significantly lower
      satisfaction with their providers and their plans. Future federal and state
      efforts should focus on expanding efforts to improve the scope and reach of
      health care coverage to low-income women through public or private means.

PMID- 10581889
TI  - [The physical and chemical changes in the eye structure after sulfurhexafluoride
      injection into the rabbit vitreous].
AB  - AIM: The aim of our paper was to observe the physical and chemical changes in the
      aqueous humor, lens, gelatous and fluid part of the vitreous body after the
      sulfurhexafluoride injection into the vitreous body. MATERIAL AND METHODS: The
      New Zealand rabbits were randomized into the control and experimental group which
      were injected the gas into the vitreous body. The interesting samples were
      investigated during the 2nd, 7th and 14th day of the experiment. We estimated the
      volume of the fluid part of the vitreous body, its electrical resistance, the
      whole protein concentration (in the aqueous humor, lens and vitreous), and
      electrolite concentration (in the aqueous humor and fluid part of the vitreous
      body). RESULTS: We observed the increase of the fluid fraction in the vitreous
      body with the increasing of the whole protein concentration, changes in the K+
      concentration and decrease of the electrical resistance in the vitreous fluid
      fraction. CONCLUSION: On the basis of our experimental results we can assume that
      expanding sulfurhexafluoride gas could mechanically disrupt the vitreous
      structure. Moreover, the rapid intrabulbar pressure increase after the injection
      can cause the cilliary body ischaemia and the eye barrier collapse.

PMID- 10581891
TI  - [Application of automated perimetry in diagnosis of macular diseases].
AB  - PURPOSE: Evaluation of automated perimetry application in diagnosis of macular
      diseases. MATERIAL AND METHODS: Examinations were performed in 27 patients with
      central chorioretinopathy (CSCR), 29 patients with diabetic maculopathy, 12
      patients with drusen, 13 patients with macular hole, 55 patients with age-related
      macular degeneration (AMD) and 23 healthy volunteers. Central visual fields were
      tested with automated threshold-measuring perimetry using the LED-PERS perimeter.
      Localisation, depth and spread of defect in central visual field were estimated.
      All threshold values, mean sensitivity, fixation, fluctuation and visual acuity
      were calculated. Statistical comparison of examined parameters and
      multidimensional analysis of variance (MANOVA) was performed using software.
      RESULTS: Significant differences were found when comparing all threshold values,
      mean sensitivity, fixation and fluctuation between the control and the other
      groups, and between patients with CSCR, with drusen and with AMD. Good results of
      MANOVA were obtained in 3 distinguishable classes between patients with CSCR,
      diabetic maculopathy and AMD. Positive correlation between threshold values of
      fields and visual acuity was noticed. CONCLUSIONS: Automated perimetry has been
      confirmed to be very useful in differential diagnosis of patients with macular
      diseases.

PMID- 10581890
TI  - [Oscillatory potentials in electroretinographic evaluation of retinal function in
      insulin-dependent diabetics without retinopathy].
AB  - PURPOSE: Can oscillatory potentials be a useful method for detection of retinal
      dysfunction in insulin-dependent diabetics without retinopathy? MATERIAL AND
      METHODS: In this study scotopic oscillatory potentials (OPs) were obtained in 35
      subjects (70 eyes) with insulin-dependent diabetes without retinopathy (mean
      disease duration--5 years) and in 15 healthy subjects (30 eyes). This examination
      was performed according to the recommendations of the International Society of
      Clinical Electrophysiology of Vision (ISCEV). The oscillatory potentials were
      extracted from the maximal combined response by high-pass filtering. We analysed
      amplitude and peak-latencies of the first three electroretinographic oscillatory
      potentials O1, O2, O3, index of wavelets [sum of amplitudes (O1 + O2 + O3)] and
      compared with the results of the control group. RESULTS: In group of patients
      with insulin-dependent diabetes without retinopathy, we received statistically
      significant reduction of amplitude O1 (p < 0.003) and index of wavelets (p <
      0.04). Reduced amplitude O1 was obtained in 10%, index of wavelets in 31.4% of
      analysed eyes. We didn't observe statistically significant changes in amplitudes
      O2, O3 and latencies O1, O2, O3. CONCLUSIONS: Our results suggest that retinal
      dysfunction is present in insulin-dependent diabetics without retinopathy 5 years
      after onset of the disease. The sum of amplitudes (O1 + O2 + O3) was the most
      sensitive parameter of retinal abnormalities. It seems reasonable to have more
      frequent ophthalmological examination of the diabetics with abnormal oscillatory
      potentials.

PMID- 10581892
TI  - [Deep sclerectomy ab externo with implant: description of surgery technique].
AB  - The authors present the modified associated technique of deep sclerectomy ab
      externo with implant. The indications, advantages and disadvantages are
      presented.

PMID- 10581893
TI  - [Trans-sclerally fixated PC-IOLs: six year of investigations].
AB  - PURPOSE: To present the results of PC IOLs transscleral fixation to the ciliary
      sulcus in six years follow-up. MATERIAL AND METHODS: 152 eyes in 3 groups: 15
      eyes with primary fixations of PC IOLs, 92 eyes with secondary fixations of PC
      IOLs and 45 eyes with secondary fixations of PC IOLs combined with penetrating
      keratoplasty. RESULTS: Postoperative corrected visual acuity was 0.5 or better in
      32.2% of cases, the most common complications in our material was CME (9.9%),
      lens tilt (4.6%) and increase of IOP (3.95%). CONCLUSION: Transscleral fixation
      of PC IOLs offers good visual outcome with relatively low rate of complications
      and is recommended in cases with inadequate posterior capsule support.

PMID- 10581894
TI  - [Secondary posterior chamber intraocular lens implantation without scleral
      fixation].
AB  - AIM: Retrospective evaluation of results of secondary PC IOL implantation without
      scleral fixation. MATERIAL AND METHODS: 29 eyes of 21 patients including 8
      children underwent secondary PC IOL implantation into the sulcus. In all these
      eyes there was partially or completely preserved posterior capsule. RESULTS:
      Final postoperative visual acuity of 20/40 or better was achieved in 82.7% of the
      eyes with PC IOL. CONCLUSION: Secondary PC IOL implants give good anatomical and
      functional results.

PMID- 10581895
TI  - [Glaucoma after penetrating keratoplasty in the material of the ocular department
      of the Mountain Hospital in Sosnowiec].
AB  - PURPOSE: To evaluate the necessity of antiglaucoma therapy in patients after
      penetrating keratoplasty (PK). MATERIAL AND METHODS: An analysis of 537
      penetrating keratoplasties performed in our department was undertaken. Incidence
      of glaucoma after penetrating keratoplasty procedure, necessity of
      pharmacological antiglaucoma treatment as well as the kind of surgical procedure
      and its influence on the graft transparency were estimated. RESULTS: The
      incidence of post keratoplasty glaucoma was 11.2% (60/537). 42 patients required
      pharmacological treatment (42/60) and the remaining 18 required surgery. 12
      trabeculectomies, 6 drainage devices procedures and 1 cyclokrytherapy were
      performed and stabilization of intraocular pressure was obtained. 14 of the
      grafts treated surgically lost their transparency. CONCLUSIONS: Multiple surgical
      treatment of post-penetrating keratoplasty glaucoma, despite the stabilisation of
      the intraocular pressure, may lead to loss of graft transparency in most cases.

PMID- 10581896
TI  - [Late manifestations of the optic nerve damage after closed head trauma].
AB  - PURPOSE: A follow-up assessment of the visual system in patients who had
      undergone close head injury and in whom simple atrophy of the optic nerve
      occurred several months after the trauma. PATIENTS: Among patients treated in
      Department of Ophthalmology in Bialystok in the years 1984-1995 there were 2
      women and 3 men, aged 19-61 years, who suffered from advancing simple atrophy of
      the optic nerve and who had undergone severe closed head trauma 3-5 months
      earlier. In one case the time interval between trauma and the visual sequelae
      amounted to 11 years. METHODS: The patients underwent a follow-up examination at
      3 to 11 years after their initial treatment in the Department of Ophthalmology.
      Besides a conventional ophthalmologic examination, a static perimetry was
      performed as well as ultrasonography in projection B and Colour-Coded Doppler
      sonography (TCCD) of the orbital vessels. RESULTS: When compared to the findings
      at discharge, in 2 patients visual acuity improved to 5/12, in the remaining 3 no
      improvement was noted. In all patients the optic discs were white, while other
      structures of the globe appeared within normal limits. Blood flow in the central
      retinal artery, ophthalmic artery and in the long posterior cilliary arteries
      remained undisturbed, as assessed with TCCD. CONCLUSIONS: 1. Lack of visual
      disturbances immediately after head injury does not preclude their development in
      the protracted period after the trauma. 2. The reason of the late development of
      visual sequelae after head trauma is not clear. Normal flow, found in the major
      vessels of the globe, might indirectly suggest disturbances of microcirculation
      within the optic nerve with a consequent optic atrophy.

PMID- 10581897
TI  - [Attempts of orbit irradiation after enucleation of the eye with malignant
      choroidal melanoma. Part I].
AB  - PURPOSE: The problem of orbit irradiation after enucleation of the eye with
      choroidal melanoma is controversial. We have decided to analyse our own material
      in order to estimate the effectiveness of this method. MATERIAL AND METHODS: The
      clinical material comprised 202 patients, 97 women and 105 men, in the age of 15
      84 years, whose eyeballs were enucleated because of choroidal melanoma. In 72
      patients the orbit was irradiated after enucleation with 60Co applicator (CKA4).
      The dose was about 50 Gy, 5 mm deep. The height of tumour, its location,
      histological type, infiltration of the sclera or beyond the eyeball and the
      treatment of tumour before enucleation were analysed. The follow-up time was 5-20
      years. RESULTS AND CONCLUSIONS: The survival time of patients in the age below 30
      years (p < 0.05) and of patients with choroidal melanoma of the height above 3 mm
      (p < 0.01) was significantly longer when the orbit was irradiated. Also the
      survival time of patients with scleral infiltration and with spindle-cell type of
      tumour was longer (but statistically not significantly) in those, whose orbits
      were irradiated after enucleation. Exenteration of the orbit was necessary in 4
      cases not irradiated after enucleation, only in 1 case after irradiation. The
      probability of survival after irradiation of the orbit was significantly higher
      than in cases not irradiated (0.6971 vs. 0.6219). The estimated mean survival
      time (in months) was longer, but not significantly, in patients after irradiation
      of the orbit (197.017 vs. 181.409). We conclude that irradiation of the orbit
      after enucleation of the eye with choroidal melanoma should be recommended.
      Further investigations will be continued with collaboration of Institute of
      Oncology in Cracow.

PMID- 10581898
TI  - [Amblyopia without strabismus in context of research on concomitant strabismus].
AB  - PURPOSE: To evaluate pathogenic factors for unilateral amblyopia in the group of
      amblyopic patients without strabismus. MATERIAL AND METHODS: In the study 141
      patients with unilateral amblyopia without strabismus were evaluated according to
      age, sex, visual acuity, refraction error, presence of anisometropia, age of
      mother on delivery, weight on birth, hereditary transmission of strabismus or
      refractive error, pregnancy and delivery complications, response to treatment.
      RESULTS: Serious birth and pregnancy complications were noted only in 14.2% of
      cases, hereditary transmission might be suspected in 41.2% of patients.
      Anisometropia was found in 72% of cases. No significant difference in prevalence
      of possible pathogenic or risk factors such as age, sex, birth-weight, age of
      mother on delivery, hereditary transmission, pregnancy or delivery complications
      were found between anisometropic and isometropic group. Anisometropic group had
      bigger refractive error and deeper amblyopia, but responded better to treatment.
      CONCLUSION: Etiology of amblyopia without strabismus, particularly in the group
      of patients with isometropia, should be associated with trauma to central nervous
      system either in pre-natal or early after birth period.

PMID- 10581899
TI  - [Coexistence of unilateral retinoblastoma and Leber-Coats's disease in
      contralateral eye-case report].
AB  - PURPOSE: A case report of retinoblastoma and Leber-Coats' disease coexistence-
      two diseases which are very dangerous to the organ of vision. MATERIAL AND
      METHODS: The paper presents a young patient who was sent to our Clinic at the age
      of 6 with very advanced unilateral retinoblastoma. He underwent enucleation of
      the eyeball as the initial treatment. Histopathological examination confirmed
      clinical diagnosis without infiltration of optic nerve or sclera. After 9 years
      of oncological observation there were characteristic changes for Leber's
      angiomatosis (temporo-inferior part of the retina) in another eye.
      Laserocoagulation of changes was performed twice. RESULTS: During 14 years of
      observation there was no retinoblastoma recurrence. In the peripheral part of the
      retina in the only eye there is constant progression of vessel changes which are
      the sources of periodical preretinal bleeding. In the macular region there were
      extensive exudative changes which lifted the retina and caused the total
      secondary retinal detachment. Laser photocoagulation, cryopexy and steroid
      therapy were ineffective. Ultimately the patient's visual acuity at distance
      deteriorated to light perception.

PMID- 10581900
TI  - [Hemangioma racemosum of retina: a case report].
AB  - PURPOSE: To report a case of haemangioma racemosum, a rare congenital disease.
      PATIENT: Female patient, aged 17, with unilateral decrease of visual acuity.
      Examination showed retinal arteriovenous malformations. Fluorescein angiography
      demonstrated variably sized arteriovenous communications, tortuosity and
      dilatation of the malformed vessels as well as normal vessels. CONCLUSION: The
      reported case shows the difficulties that may be encountered in differentiating
      haemangioma racemosum from hemangiomas associated with other disorders. A
      complete physical examination and angiography are essential in distinguishing
      difficult cases.

PMID- 10581901
TI  - [Intraocular refractive surgery].
AB  - The aim of this paper was presentation of current opinions about intraocular
      refractive surgery. The implantation of Baikoff and Worst-Fechner lenses to
      anterior chamber and usage of refractive PC IOL is described. The extraction of
      clear lens in high ametropia and implantation of PC IOLs of adequate power was
      also presented. The paper is illustrated by own material.

PMID- 10581902
TI  - [Amniotic membrane transplantation (AMT) for ocular surface reconstruction].
AB  - The authors present current opinions about the possibility of amniotic membrane
      transplantation for ocular surface treatment in patients with chemical and
      thermal burns, Stevens-Johnson syndrome, ocular cicatrical pemphigoid, persistent
      epithelial defects with ulceration and large conjunctival defects. Amniotic
      membrane facilitates migration of epithelial cells, promotes their
      differentiation, prevents epithelial apoptosis, does not provoke
      neovascularization and a typical host-versus-graft rejection. Amniotic membrane
      transplantation is an advance in techniques for managing ocular surface
      reconstruction revolutionizing corneal disease treatment.

PMID- 10581903
TI  - [The role of the NMDA receptors in the creating of amblyopia].
AB  - The present state of knowledge concerning the etiopathogenesis of amblyopia is
      discussed. The morphological and functional changes taking place in the neuronal
      system of the Brodmann's 17th area during the amblyopia creation are described.
      The factors affecting the primary and secondary visual cortex are characterized.
      Special attention was focused on the N-methyl-D-aspartate (NMDA) receptors. Their
      structure and function is described. The role of the NMDA receptors in the
      formation of the visual cortex plasticity is discussed. The necessity of
      amblyopia treatment before the critical period is over has been pointed out. The
      possibilities of using the newest experimental results in amblyopia treatment are
      indicated.

PMID- 10581904
TI  - Involuntary manslaughter in relation to patient care.

PMID- 10581905
TI  - The Bournewood judgment: a way forward?
AB  - In this article we provide a commentary on the various reasonings behind the Law
      Lords' unanimous judgements in their recent decision (25 June 1998) in Regina v.
      Bournewood Community and Mental Health NHS Trust, Ex parte L. After summarizing
      the judgment and commenting on its important implications, we suggest a way
      forward. The 1995 Law Commission incapacity proposals, on which the 1997
      consultation paper Who Decides? was based, do afford a mechanism which could
      resolve much of the practical difficulty which practitioners feared from the
      Appeal Court decision, whilst at the same time affording the sorts of rights
      which the House of Lords decision denies.

PMID- 10581906
TI  - Whose body is it anyway?

PMID- 10581907
TI  - Discrepancies between clinical and post-mortem diagnoses of causes of death.
AB  - Medical institutions unjustifiably 'walk in a fog of misplaced optimism',
      convinced of the accuracy of clinical diagnosis. They disregard the fact that the
      latest diagnostic research has not reduced the frequency of diagnostic
      inaccuracy. We reviewed the autopsy records from the archive of the Institute of
      Forensic Medicine of 921 decreased persons in 1997 and compared the clinical with
      the post-mortem diagnoses. Group 1 included cases of complete agreement between
      the clinical and post-mortem diagnoses, Group 2 cases of partial disagreement
      about the direct cause of death, Group 3 cases of disagreement about the basic
      illness, Group 4 cases of total disagreement between the clinical diagnosis and
      the post-mortem. Group 5 included cases of improper filling out of documentation
      according to the ABC international classification of diseases, injuries and
      causes of death, which has been accepted by the World Health Organisation in 10
      revisions to date (WHO, 1992). The diagnoses were in total agreement in 48.87% of
      the cases, in partial agreement (disagreement about the direct cause of death) in
      22.74%, and in disagreement about the basic illness in 13.5%. Of the cases, 9.68%
      were classified into Group 5.

PMID- 10581908
TI  - Retrospective analysis of the forensic autopsy cases of psychiatric patients.
AB  - This paper describes a retrospective analysis dealing with the sudden natural or
      unnatural death of psychiatric patients using actual autopsy findings, clinical
      information and demographic status. More than 70% of the 141 patients had
      schizophrenia, mood disorders or substance-related disorders. Accidental deaths
      were the most common (34.8%) and followed by natural deaths (28.4%), suicide
      (22.7%) and homicide (9.2%). Nearly half of mentally retarded patients died
      natural deaths, whereas two-thirds of patients with substance-related disorders
      died accidental deaths and about one-third of patients with schizophrenia and
      mood disorders committed suicide. Furthermore, patients with substance-related
      disorders were significantly more likely to live alone than were patients with
      schizophrenia or mood disorders. Twenty-five cases died in hospitals or other
      healthcare facilities; it is noteworthy that in the 12 patients who died natural
      deaths the reported symptoms had been less severe than might be expected and
      correct clinical diagnosis was not made before death. The present findings should
      be useful for both forensic pathologists and clinical psychologists.

PMID- 10581909
TI  - A cost analysis of untoward incidents in a medium secure unit.
AB  - All untoward incidents perpetrated by 36 patients--residents in a medium-secure
      hospital--over a period of six months were examined using a prospective design.
      Demographic and psychiatric details of patients involved in incidents were
      compared with those of patients not involved in incidents. Financial costs
      associated with incidents were calculated. A minority of patients were found to
      be responsible for the majority of incidents. Patients detained under criminal
      sections of the Mental Health Act 1983 were involved in disproportionately more
      incidents than their civil section counterparts. The female patients involved in
      untoward incidents all had a diagnosis of personality disorder and were over
      represented in the number of incidents. However, most of the financial burden of
      untoward incidents was incurred by those incidents perpetrated by male patients.
      Likewise, although patients detained under the legal category of psychopathic
      disorder were involved in a higher number of incidents, higher costs were
      associated with incidents perpetrated by patients detained under the category of
      mental illness.

PMID- 10581910
TI  - How informed are community psychiatric nurses (CPNs) of their role in the
      implementation of supervised discharge?
AB  - A questionnaire was delivered to community psychiatric nurses (CPNs) (n = 23) in
      order to determine whether they had received adequate training in relation to the
      1995 Mental Health (Patients in the Community) Act. Data collected were analyzed.
      The findings suggest that there is a lack of knowledge in relation to the
      documentation. The research suggests that more formal training in relation to
      policy documents should be provided by employers.

PMID- 10581911
TI  - A study of patients identified as unmanageable prior to admission to an
      independent medium-secure hospital.
AB  - A previous study of patient admissions to an independent medium-secure
      psychiatric hospital by Moss, Green and Naismith (1996) suggested an increased
      flexibility in the admission of patients identified as having 'exceptional
      management problems.' In particular this was found to relate to a cohort of 59
      patients admitted after having been identified as 'unmanageable' in their parent
      district. This appeared to provide the impetus, for a number of reasons, for
      their subsequent referral to the private sector. This study examines the
      characteristics of these patients, and discusses how the independent sector may
      be providing a service either unavailable within the National Health Service or
      for which the National Health Service is unsuitable, in terms of patients either
      requiring medium- to long-term hospital care in conditions of security, or those
      who cannot live independently and therefore require 'asylum' (which is no longer
      available within the National Health Service). In this sense the independent
      sector could be seen as meeting a national need by acting as a 'safety valve' for
      National Health Service psychiatric facilities.

PMID- 10581912
TI  - Application of the powers of compulsory admission to psychiatric hospital by
      general practitioners, social workers and psychiatrists.
AB  - Ways of extending or consolidating the powers of compulsory admission under the
      Mental Health Act 1983 have been discussed by the government and other
      organizations, including the Royal College of Psychiatrists. However there is
      little data on how existing legislation is applied. The authors examined the
      differential application of the Act between GPs, psychiatrists and social workers
      by means of an anonymous, confidential questionnaire. Fourteen case vignettes
      were interpreted by 20 social workers, 19 GPs and 28 Section 12 approved
      psychiatrists, who were asked to decide if they would detain the patient under
      the Act. Responses were analysed between and within the three groups. There was
      general agreement between groups on situations involving 'danger to self' and
      'danger to others', but social workers were less likely to detain on health
      grounds and GPs tended to use the Act unpredictably, in areas not covered by the
      Act. The authors conclude that the Act may not be used to its fullest extent due
      to differences in interpretation or in knowledge, which may arise from
      differential constructs of mental illness and training. A national study of
      knowledge of mental health law is suggested.

PMID- 10581913
TI  - Extraction of chloroform and methylene chloride in human whole blood and urine by
      headspace solid phase microextraction (SPME).
AB  - Chloroform and methylene chloride were extracted from human whole blood and urine
      by headspace solid phase microextraction (SPME) using a
      Carboxen/polydimethylsiloxane (Carboxen/PDMS) fibre before capillary gas
      chromatography (GC)/flame ionization detection (FID). Whole blood or urine was
      placed in a vial and mixed with distilled water. The vial was heated at 30
      degrees C, and the solvents were extracted from the headspace by SPME. The
      extraction efficiencies of chloroform and methylene chloride from whole blood
      were 40.3% and 35.8%, respectively; those for urine were 57.0% and 43.6%,
      respectively. The calibration curves for chloroform were linear in the range of 1
      8 micrograms/ml for blood and urine samples, and those for methylene chloride in
      the range of 0.5-8 micrograms/ml. The detection limits for both compounds were
      0.3 microgram/ml for whole blood and 0.2 microgram/ml for urine. The headspace
      SPME with Carboxen/PDMS fibre coupled with GC/FID seems useful for analyses of
      chloroform and methylene chloride in forensic toxicology and environmental
      chemistry.

PMID- 10581914
TI  - A study to investigate the ability of subjects with chronic lung diseases to
      activate the roadside Lion Alcolmeter SL-400.
AB  - The Lion Alcolmeter SL-2 is widely used for road-side breath-testing by police in
      the UK. However, some individuals with lung diseases have difficulty in
      activating the device. This study describes an investigation that we have carried
      out on a new device called the Lion Alcolmeter SL-400 which has recently been
      introduced into use by police forces in the UK. The manufacturers state that the
      machine requires a minimum continuous expiratory flow rate of 25 litres per
      minute and a minimum expired volume of 1.5 litres, after which a breath sample is
      automatically taken and analysed. Our study was designed to investigate the
      ability of subjects with a variety of lung diseases to activate this device. The
      40 adult subjects investigated consisted of 10 normal controls, 10 with asthma,
      10 with chronic obstructive pulmonary disease and 10 with restrictive lung
      disease. After baseline lung function tests were performed, the subjects were
      then given alcohol to drink, the amount of which was based upon their body
      weight. After a gap of at least 20 minutes, the subjects were then asked to
      attempt up to three blows into the Alcolmeter. Our results showed that three
      asthmatic subjects, four with chronic obstructive pulmonary disease and two with
      restrictive lung disease, failed to successfully activate the device even after
      three attempts. All of the subjects who failed to activate the device had an
      expired breath volume of more than 1.5 litres, but seven out of these nine
      subjects had a Forced Expiratory Volume (FEV1) of less than 1.1 litres. In
      conclusion, this study has shown that some subjects with lung diseases may have
      difficulty in activating the SL-400 roadside alcolmeter device.

PMID- 10581915
TI  - Accidental hanging with delayed death in a lift.
AB  - While hanging is a common method of committing suicide in India, accidental
      hanging is uncommon. However, it does occur when people are engaged in auto
      erotic practices. An adult male who was helping passengers trapped in the lift of
      an outpatient department at a teaching hospital was accidentally hanged. He
      survived for 39 days. This case highlights a rare but serious hazard in the use
      of lifts.

PMID- 10581916
TI  - Heart disease vis-a-vis trauma.
AB  - Virtually all forensic experts deal not only with criminal, suspicious,
      accidental and suicidal deaths, but are also confronted with a wide range of
      deaths where a significant natural element is revealed at autopsy. The assaulted
      victim that dies suddenly or unexpectedly from a stroke during or immediately
      succeeding the receipt of some non-fatal injuries, or otherwise suffers a
      clinically unexplained death, can pose far greater difficulties over causation
      than a gun-shot or a stabbing. This paper presents an analysis of the problem and
      an approach for determining the cause of death in cases of concurrent trauma with
      heart disease, and in cases with a substantial natural element of disease but
      exclusion of trauma. Relevant cases with history, autopsy findings,
      histopathological findings and toxicological findings are presented in order to
      illustrate the issue from a practical angle.

PMID- 10581917
TI  - Suicide by drowning in the bath.
AB  - A series of 14 cases of suicide by drowning in the bath in the Bristol area,
      England between 1974 and 1996 is presented. There were six males and eight
      females with a mean age of 66 years. The majority were married and lived with
      their spouse or another relative. Most drowned at home, face down, fully clothed.
      Six cases had evidence of concomitant alcohol or substance use. Seven cases had a
      past psychiatric history and a history of previous deliberate self-harm. Issues
      concerning prevention are discussed.

PMID- 10581918
TI  - Homicidal poisoning with glibenclamide.
AB  - Homicidal poisoning is rare in Sri Lanka although suicidal poisoning, especially
      with pesticides, is a grave health problem. Clinical and medicolegal findings and
      the subsequent court proceedings of two cases of homicide due to induced
      hypoglycaemia with an anti-diabetic drug are presented. The drug used was
      glibenclamide. Findings emphasize the importance of toxicological analysis and
      extensive police investigations when the clinical diagnosis and the cause of
      death are in doubt.

PMID- 10581919
TI  - Reply to letter from Margaret Stark and Guy Norfolk about the management of
      opiate addicts in police custody.

PMID- 10581920
TI  - Caring for adults with mental retardation: survey of family practice residency
      program directors.
AB  - In their core curriculum guidelines, the Society of Teachers of Family Medicine
      has recognized the importance of training family physicians in caring for persons
      with mental retardation. We mailed surveys to all family practice residency
      directors in the United States, questioning them about experiences and methods
      used to teach residents about health care needs of adults with mental retardation
      and the importance of this education. We found that 84% of programs provide
      residents with one or more experiences, and 60% instruct residents in this area.
      Most directors ranked this education as very important or important. There was no
      relationship between type or age of residency program and likelihood that
      residents were educated about mental retardation. The importance of this
      education is discussed.

PMID- 10581921
TI  - Self-determination across living and working environments: a matched-samples
      study of adults with mental retardation.
AB  - The environments in which people live, learn, work, and play influence many
      aspects of their lives, including their self-determination. These environments
      differ in the degree to which they enable people to receive personally designed
      and individualized supports. In the present study self-determination, autonomy,
      life choices, and lifestyle satisfaction for adults with mental retardation
      matched by level of intelligence, age, and gender but differing in type of
      residence or working environment were examined. Analyses indicated that
      respondent self-determination, autonomy, and satisfaction as well as
      opportunities for choice-making differed according to settings.

PMID- 10581923
TI  - Later-life planning for older adults with mental retardation: a field experiment.
AB  - A quasi-experimental design was used to assess the efficacy of a leisure
      education-based later-life planning model for 10 older adults with mental
      retardation. Prior to the initiation of the planning process, they were
      interviewed and completed three standardized scales designed to assess life and
      leisure satisfaction and leisure constraints. A comparison group completed these
      scales but did not participate in the planning process. At the completion of the
      study, both groups completed the same scales. Results demonstrated that the
      planning-process group had significantly higher life and leisure satisfaction at
      the end of the study. Many participants also made changes to their lifestyles
      consistent with plans made during the study. Results suggest that a later-life
      planning process may contribute to the quality of life of older adults with
      mental retardation.

PMID- 10581922
TI  - Assessment of orientation: relationship between informant report and direct
      measures.
AB  - Although informant reports of everyday functioning are often used in dementia
      assessments, the actual correspondence between such indirect reports of
      functioning and actual performance has not been examined. Orientation results on
      the Dementia Questionnaire for Mentally Retarded Persons were compared to those
      obtained in direct assessment of orientation of 138 adults with mental
      retardation. Fair to good agreement was found between informant report and direct
      assessment. However, for some orientation items, nonverbal IQ, cause of mental
      retardation, and age affected the level of agreement. Thus, both informant report
      and direct measures of orientation are necessary in dementia assessments, and
      further work is needed on informant scale validation.

PMID- 10581924
TI  - Impact of coworker involvement with supported employees on wage and integration
      outcomes.
AB  - This report is the fourth in a series on positive relations of typical employment
      features and coworker involvement with higher wage and integration outcomes for
      persons in supported employment. Imbedded in the discussion about natural
      supports in recent years has been the extent and value of coworker participation
      in the work life of employees with disabilities. Previous studies have
      illustrated the connection between natural supports and meaningful and satisfying
      employment outcomes. We investigated specific details associated with coworker
      training and support and their relation to social and economic outcomes that
      enable persons with disabilities to succeed economically and socially in
      inclusive employment.

PMID- 10581925
TI  - How adult beliefs shape the speech communities of a child who has multiple
      disabilities.
AB  - Ethnographic and micro-ethnographic techniques were used to investigate how the
      strategies employed by two adults (a mother and a physical therapist) to initiate
      and maintain interactions with a 2-year-old child with multiple disabilities were
      reflective of the adult partner's beliefs and values about communication in
      general and about this child in particular. Results indicate that the physical
      therapist believed in using the child's existing abilities as the primary
      reference point for establishing a speech community with the child. The mother
      used the demands of the larger, mostly nondisabled speech community as her
      primary reference point. How these differences affect the nature of the child's
      membership and level of independence in these speech communities is discussed.

PMID- 10581926
TI  - Presidential address 1999--working for justice: responsibilities for the next
      millennium.

PMID- 10581927
TI  - CT findings of idiopathic subchoroidal calcifications.

PMID- 10581928
TI  - All for one and one for all. Except if it's your HMO that's being sued.

PMID- 10581929
TI  - Oversight is lax.

PMID- 10581930
TI  - Peer review committee is learning laboratory.
AB  - The peer review process benefits dentists, their patients and the volunteers who
      conduct the process and learn its most valuable lessons. These lessons are to
      keep impeccable records, charge reasonable fees while maintaining high standards,
      make sure treatment plans are appropriate, refrain from disparaging the work of
      colleagues, and be an effective communicator.

PMID- 10581931
TI  - Warthin's tumor of the parotid salivary gland. A case report.
AB  - Neoplasms of the salivary glands are not uncommon. The dentist is in the unique
      position to make an early diagnosis and refer the patient for definitive
      treatment. This article will review the clinical appearance, pathology, treatment
      and potential complications of Warthin's tumor, a benign salivary gland tumor. It
      describes a case presented at the Salivary Gland Center. Columbia University
      School of Dental and Oral Surgery, New York Presbyterian Hospital-Columbia
      Campus.

PMID- 10581932
TI  - Periodontitis and systemic disease.
AB  - Recent evidence suggests that periodontal disease may play an etiologic role in
      the pathogenesis of several systemic illnesses, such as cardiovascular disease
      and preterm birth. This article reviews proposed mechanisms for such associations
      and outlines studies currently underway aimed at clarifying this issue. Results
      from this line of research may fundamentally change the way we approach our
      periodontitis patients.

PMID- 10581933
TI  - Orthodontic and periodontal considerations in treatment of adult patients.
AB  - The coordination of orthodontics with periodontics in treating adult patients
      with high esthetic expectations is essential. In this article, three broad
      categories of relationships between the two specialties are described. In
      addition, several simple clinical situations illustrate how the interactions can
      help to improve the outcome of dental treatments.

PMID- 10581934
TI  - More about prostate cancer--expectant management versus treatment.

PMID- 10581935
TI  - More about prostate cancer--expectant management versus treatment.

PMID- 10581936
TI  - A ruling on required exposure to pepper spray--et sequelae.

PMID- 10581937
TI  - Professionalism. The medical ethic versus the business ethic.

PMID- 10581938
TI  - The malaise of millennial medicine.

PMID- 10581939
TI  - If I had a retained common bile duct stone....

PMID- 10581940
TI  - Historic representations of medicine in art. North Carolina Medical Centers
      collaborate in a rare exhibition.

PMID- 10581941
TI  - A 47-year-old woman with Crohn's disease who bled and bled and bled.

PMID- 10581942
TI  - Should doctors give hormones to healthy elders?

PMID- 10581943
TI  - Diabetes-related leg amputations in elderly North Carolinians. A status report
      and a challenge.

PMID- 10581944
TI  - The influence of laser surgery on the assessment of "molecular margins" in
      carcinomas and mucous membranes of the upper aerodigestive tract.
AB  - BACKGROUND AND OBJECTIVE: A correlation has been shown between the occurrence of
      the p53 protein in margins of excised carcinomas and a higher incidence of
      recurrences. The presented study deals with thermic alterations in resection
      margins after laser surgery and their impact on p53 protein and LDH detection.
      STUDY DESIGN/MATERIAL AND METHODS: Healthy mucosa of the oropharynx and carcinoma
      samples were excised with scalpel, CO2 laser and Nd:YAG laser. Alterations of
      lactate dehydrogenase (LDH) and the p53 status of the samples were determined by
      immunohistochemistry and molecular biologic methods. RESULTS: Total activity of
      LDH was not altered by the different modes of excision. The expression of p53
      could be detected in all mucosa specimen by ELISA. In laser-surgically excised
      tissue regularly a small zone adjacent to the cutting edge could be demonstrated
      where p53 could not be detected by immunohistochemistry. CONCLUSION:
      Immunohistochemical and molecular assessment of laser surgical margins is
      possible despite thermic artefacts. Laser surgery therefore does not minimize the
      prognostic value of resection margins of carcinomas of the upper aerodigestive
      tract.

PMID- 10581945
TI  - [Vascular pedicle flap of the thyroid or submandibular gland in the
      reconstruction following partial laryngectomy].
AB  - The paper presents the merits and drawbacks of vascular pedicled flaps of thyroid
      and submandibular glands in the reconstructive surgery following partial
      laryngectomy (combined with the resection of tongue base if necessary), as well
      as the results of clinical, radiological, radionucleoloid++ and histological
      investigation carried out in 81 cases with various extend of neoplasm (T1-T4).
      The average observation period was 8.2 (min. 1, max. 14) years. The discussed
      flaps were satisfactorily elastic and rigid, allowed formation in monobloc even
      complex structures (for instance vocal cord, arytenoid eminence, lateral wall of
      the larynx) with the high healing rate (1 total and 2 partial losses only), with
      an insignificant degree of atrophy in the larynx and a considerably greater one
      in the tongue base (despite a very difficient cover with mucosa), as well as a
      small local recidive range (3/81 cases all coming from the tissue out of the
      flap). With the above data, the discussed flaps seem to be superior in many
      respects to the materials conventionally used in the reconstruction of the
      larynx. A subclinical form of hypothyreosis (reduced level of T3, T4 and TSH) was
      stated in 1 case only, whereas xerostomy was not observed in any. The detailed
      oncological and functional results obtained in the whole group of patients will
      be published in another paper.

PMID- 10581946
TI  - [Evaluation of severity and clinical course of acute mucosal reaction during
      postop radiotherapy of laryngeal cancer].
AB  - In the group of 110 epiglottic and glottic cancer patients treated with
      postoperative radiotherapy, relationships between the severity of acute mucosal
      reaction and time of treatment for different types of surgery and for different
      intervals between surgery and postoperative radiotherapy were analysed. The
      dependence between the total dose and the radiation reaction was assigned. The
      maximal radiation reaction appeared in the fourth week of irradiation
      independently of operation type. The highest grade of reaction in the last week
      of irradiation appeared in the group after limited operations and the lowest one
      in the group after total laryngectomy. There was a statistically significant
      difference between distribution of acute radiation injury grade in a group after
      limited operation and a group after hemilaryngectomy compared by Wilcoxon matched
      pairs test. For the interval between operation and radiotherapy shorter than 6
      weeks the highest reaction was in the fourth, for the interval 6 to 12 weeks in
      the third and for the interval longer than 22 weeks in the fifth week of
      irradiation. The highest reaction in the last irradiation week appeared in the
      first group, the lowest one in the second group. However, generally the time
      interval between surgery and radiotherapy does not influence the severity of
      acute mucosal reaction (there was no statistically significant difference between
      reaction grade distribution compared by Wilcoxon matched pairs test). There was
      also no correlation between the total dose and intensity of radiation injury in
      last irradiation week. The interrelationships and other factors which could
      influence the obtained results were considered. The main final conclusions were
      formed: maximal intensity of mucous membrane radiation injury and the intensity
      in the last week of treatment depend on the character of previous operation
      (smaller operation--bigger postradiation reaction) and do not depend on total
      dose or on the interval between operation and beginning of radiotherapy.

PMID- 10581947
TI  - [The level of diagnosis and treatment results in nasopharyngeal cancer patients].
AB  - A group of twenty patients with nasopharyngeal cancer treated in Lower Silesian
      Oncological Centre from year 1991 to 1995 have been presented. In seven of them
      the extent of the primary tumor was small (T1 or T2), but the rest of them
      (thirteen) had large extent of it (T3 or T4). In seven patients metastases to the
      cervical lymphonodes were not observed. The histopathology exam showed in eight
      cases well differentiated carcinoma, in another eight--lymphoepitelioma, in three
      -undifferentiated carcinoma and in one case adenocarcinoma. All of the patients
      were treated with radiotherapy using variable schedules of fractionaction, and
      three of them were given chemotherapy. Only seven (35%) are still alive without
      symptoms of disease. Such unsatisfactory results should be ascribed to a very
      high extent of illness in most patients, a result of coming to the doctor late
      and of big difficulties in diagnosis. Only several patients (20%) had CT of the
      head made before the treatment, which could be a reason for an incorrect location
      of the planning target volume (PTV).

PMID- 10581948
TI  - [Mechanisms of formation and liquidation of glosso-laryngeal recesses after
      classical and extended supraglottic laryngectomies. Computerized topokinetic
      analysis of rentgenocinematographic images].
AB  - As many as 42 examinations of the pharyngeal phase of deglutition act were
      studied in patients after supraglottic classical and extended laryngectiomies, in
      whom the above examinations were performed by means of computerized topokinetic
      analysis of the rentgenocinematographic images. A swallowing group with formed
      glosso+-laryngeal recesses was isolated. In three among the six patients in whom
      the examinations were carried out twice (i.e. half a year after the procedure and
      2 years after the operation) the formed recesses underwent liquidation. The
      parameters facilitating the liquidation of the above recesses between the first
      and the second examinations were analyzed. The liquidation of recesses
      corresponded with the restoration of good deglutition.

PMID- 10581949
TI  - [Inverted papilloma of the nose and paranasal sinuses].
AB  - The authors present 23 cases of inverted papilloma treated in the Department of
      Otolaryngology of S. Zeromski's Hospital in Krakow. The symptoms, methods of
      treatment and results are discussed.

PMID- 10581950
TI  - [Rhabdomyosarcoma of the middle ear in childhood].
AB  - The authors have described a case of a 2.5-year-old boy who suffered from
      rhabdomyosarcoma of the middle ear. The clinical course, differential
      histopathology diagnosis and dynamic growth of the tumor have also been
      presented. In spite of combined therapy--surgery and chemotherapy--prognosis in
      rhabdomyosarcoma of the middle ear in childhood is poor.

PMID- 10581951
TI  - [Nasal dermoid cysts and sinuses].
AB  - The authors discuss problems of the nasal dermoids treatment. They point at
      difficulties with settlement of right term of operation, and they stress that X
      ray diagnosis before operation should be taken into consideration to exclude the
      contact of the dermal cyst or sinuses with cranial cavity. They confirm
      necessities of radical removal of the cyst or/and the sinus to gain the recovery.
      They analyse the material of 6 patients with dermal cysts or sinuses who were
      operated since 1988 to 1997 in the ENT Department of Municipal Hospital, Gdynia.
      They were 4 boys and 2 girls. In each case a cyst with fistulas was observed. All
      children were treated surgically, and their ages were 2-14 years (mean 6 1/2). In
      2 cases there was self-existent destruction of the nasal bones, other 2 patients
      had median rhinotomy made, in 2 cases only simple excision of the cyst and
      sinuses was performed. In any case it was no recurrence of the disease (time of
      follow-up is 1-10 years). The analysis is illustrated with two case reports. The
      first case was a 2-year-old boy who had a dermal cyst with sinus penetrating into
      the cranial cavity. CT imaging did not reveal obvious evidences of that. During
      operation, a momentary CSF leak was observed but it was stopped using oxycel and
      tissucol. The second case, a 7-year-old boy, was treated by curettage of the
      dermoid, with recurrence after 6 months. This patient was cured after total
      resection of the cyst and sinuses. In conclusion, the authors present in detail
      signs that can attest that contact of the cyst with the cranial cavity exists.
      They stress the necessity of right surgical treatment in cases of dermal cysts of
      the nose to avoid recurrence or complications.

PMID- 10581953
TI  - [Pathology of the parotid gland in the parapharyngeal space].
AB  - In Otorhinolaryngology Department of Medical Academy in Warsaw 49 cases of tumors
      of the parapharyngeal space were recognized and treated in the period between
      1977 and 1996. 48 patients were operated on, one died in the terminal phase of
      cancer disease. General rules of qualification for operation are as follows: a)
      CT scans, b) arteriography, c) in changes suggesting neoplasms histological
      examination during operation is necessary. External approach was applied in all
      cases, which gave full control over vascular structures. In 49% of cases
      malignant neoplasms were recognized. Each operation of malignant neoplasms of the
      parapharyngeal space, as not radical, was supplemented with radiation.

PMID- 10581952
TI  - [Tumors of the parotid glands in the material of the Department of otolaryngology
      of the Medical Academy in Warsaw in 1986-1995].
AB  - In the Department of Otolaryngology, Medical Academy in Warsaw, 332 patients were
      surgically treated between 1986 and 1995 because of parotid gland tumors. In 275
      cases benign tumors, in 57 cases--malignant tumors were observed. The majority of
      benign tumors were pleomorphic adenoma (61.45%) and lymphadenoma (22.54%); the
      majority of malignant tumors were adenocarcinoma (28%), adenoid cystic carcinoma
      (21%), mucoepidermoid carcinoma (15.78%). All patients with benign tumors were
      surgically treated, patients with malignant tumors were operated on and
      irradiated. The surgical procedure used superficial parotidectomy and total
      parotidectomy with preservation of facial nerve where possible. Ten patients
      required total parotidectomy with facial nerve resection because of malignant
      tumors, six patients had neck dissection performed. Of the 57 patients treated on
      account of malignant tumors 43 survived; 14 patients died of a local recurrence
      or generalization neoplasm disease.

PMID- 10581954
TI  - [Nasal polyps. Definitions and development of pathogenesis theory].
AB  - This paper presents definitions and types of classifications of nasal polyps. The
      precise pathogenesis of nasal polyps is not known, although there are several
      important factors: chronic and recurrent infection of nasal mucose, abnormal
      vasomotor response, airflow blockade of the middle meatus and ostia of the
      paranasal sinuses. Since 1843 several pathogenic theories have been introduced.

PMID- 10581955
TI  - [On "Position of Brunings++" during caloric tests].
AB  - In common opinion one of the sitting position used during caloric tests is
      "position V of Brunings". The name of this position is incorrectly applied by a
      lot of authors (without knowledge of original paper of Brunings [1]. This
      designation could concern a modification of position V, presented by Barre in
      1927 [2].

PMID- 10581956
TI  - [Results of the surgical management of congenital malformations of the external
      auditory canal and of the middle ear in children with special reference to vein
      xenografts].
AB  - The paper deals with the possibility of surgical reconstruction of congenital
      malformations of the ear, the choice of a proper surgical method with the
      utilization of calf-vein xenografts, and with postoperative effects of the
      employed operative technique modified by the authors. The research material
      comprised 70 children between 3 and 17 years of age treated in years 1992-1995.
      Reconstructive surgery was performed in 24 children (29 ears). Calf-vein
      xenografts were used for myringoplasty and for the lining of the bony walls of
      the postoperative cavity (of the created external auditory canal and of the
      mastoid cavity). Hearing improvement was gained in 79% of cases, and in 55% of
      patients it was 24 dB or higher. Patent and epithelilized external auditory
      canals were obtained in 81% of the operated "atretic" ears. Failures referred to
      fibrodermal restenosis and lack of hearing improvement. Surgical treatment of
      bilateral congenital aural "atresia" can be performed in children at 4-6 years of
      age. Vein xenografts are a good reconstructive material recommended in congenital
      aural malformations for myringoplasty and canaloplasty.

PMID- 10581957
TI  - [Air conduction threshold values in expanded range of frequencies (250 Hz-18 kHz)
      in otologically normal persons as assessment of mobility hearing organ in
      presbycusis].
AB  - High-frequency hearing loss is most significant for the organ of hearing aging.
      Air conduction threshold measurements were taken in 4 groups (aged 31-40, 41-50,
      51-60, 61-70 years) of otologically normal persons in expanded range of
      frequencies (250-18,000 Hz). The threshold of air conduction increase parallel to
      age and to pure tone frequency was stated.

PMID- 10581958
TI  - [Hair cell regeneration in a chicken's inner ear after damage due to exposure to
      industrial noise].
AB  - In mammals, the damage to the hair cells of the inner ear due to exposure to
      noise or other ototoxic agents is irreversible. In fish, reptiles and birds,
      however, the hair cells may regenerate, probably from the supporting cells. This
      regeneration process in the inner ear is being intensively examined in animals in
      the hope of curing the sensorineural hearing loss in human subjects in future.
      The aim of the study was to assess hair cell regeneration in the inner ear of
      chicks after exposure to industrial noise, depending on the level of exposure.
      The birds were exposed either to the noise at the level of 110 dB (A), 4 hours a
      day, for 5 consecutive days, or at the level of 125 dB (A), 8 hours a day, for 5
      consecutive days. The results confirm that the regeneration starts immediately
      during the period of recovery from acoustic trauma, and the supporting cells are
      the main source for new, developing hair cells. Moreover, we found that the
      complete damage to hair cells is not necessary to the proliferation of supporting
      cells and that the intensity of proliferation of these cells depends on the level
      and time of exposure.

PMID- 10581959
TI  - [Vestibular findings in children's epilepsy].
AB  - 20 children between ages 6 and 15 who suffered from epilepsy classified according
      to suggestions of International League Against Epilepsy to partial seizures
      evolving to generalized seizures were tested otoneurologically. The aim of the
      study was to estimate the frequency and location of vestibular disturbances
      coexisting with the disease. Subjective and objective (using
      electronystagmography--ENG--and videonystagmography--VNG) otoneurological study
      was performed. Dizziness was noted in most cases. Nobody demonstrated normal
      ENG/VNG recordings and the character of the pathology suggested its central
      origin. Eye-tracking proof and optokinetic nystagmus (cortical and subcortical)
      revealed to be most helpful during diagnostic procedures. No correlation between
      the location of EEG pathological patterns and ENG pathological signs was proved.

PMID- 10581960
TI  - [Hormonal conditioning of vocal changes in male].
AB  - Porophonia pubertum is the change of voice following activation of gonads in
      puberty. The present paper shows disorders of porophonia pubertum in 3 boys. The
      objective of the paper was to explain the pathogenesis of these disorders. Basing
      on clinical and genetic tests, a non-physiological, high position of spoken voice
      typical for the prolonged porophonia pubertum was proved. The genetic test
      confirmed the male sex. However, hormonic tests proved a significantly increased
      level of estradiol. We suppose that excessively increased estradiol level in
      blood serum caused the porophonia pubertum disorders in our patients.

PMID- 10581961
TI  - [Preliminary results of nasality tests in patients wtih cleft palate after
      operations performed with different surgical methods].
AB  - The study analyses results of tests carried out in a group of 82 patients with
      cleft palate defect after operations performed with different surgical methods.
      In the primary plastic group--the minimal degree of nasality was observed among
      patients after vomer flaps aged 2-3 years. The next group of patients after
      secondary surgical operations of phoniatric indication--better results were
      observed where Orticochea method was applied. The author expects to obtain more
      credible effects based on wider prospective and retrospective clinical
      observation.

PMID- 10581962
TI  - [Metastasis of the cutis malignant melanoma of the parotid gland].
AB  - The authors presented a rare case of metastases of the cutis malignant melanoma
      to the parotid nodes. The attention was directed towards clinical aspects and
      diagnostic difficulties. Basing on data from the literature frequency and
      possibilities of cutis malignant melanoma metastases were analysed.

PMID- 10581963
TI  - [A rare case of foreign body in external auditory meatus].
AB  - The authors present a case of a foreign body in external auditory meatus--cement
      mordant. Particularly++ we have described frequency and kind of the foreign
      bodies which we have met for 6 years. The foreign bodies were removed in 117
      persons, 3 from these were hospitalized and foreign bodies were removed in
      general anesthesia.

PMID- 10581964
TI  - Integration of non-linear cellular mechanisms regulating microvascular perfusion.
AB  - It is becoming increasingly evident that interactions between the different cell
      types present in the vessel wall and the physical forces that result from blood
      flow are highly complex. This short article will review evidence that irregular
      fluctuations in vascular resistance are generated by non-linearity in the control
      mechanisms intrinsic to the smooth muscle cell and can be classified as chaotic.
      Non-linear systems theory has provided insights into the mechanisms involved at
      the cellular level by allowing the identification of dominant control variables
      and the construction of one-dimensional iterative maps to model vascular
      dynamics. Experiments with novel peptide inhibitors of gap junctions have shown
      that the coordination of aggregate responses depends on direct intercellular
      communication. The sensitivity of chaotic trajectories to perturbation may
      nevertheless generate a high degree of variability in the response to
      pharmacological interventions and altered perfusion conditions.

PMID- 10581965
TI  - Haemodynamics, wall mechanics and atheroma: a clinician's perspective.
AB  - Atherosclerosis, leading to myocardial infarction and stroke, is the major cause
      of death and morbidity in Western societies. Atheromatous lesions
      characteristically occur in regions of branching and marked curvature. Low shear
      stress and increased mural tensile stress may be major determinants underlying
      atheroma formation at these sites. Furthermore, the distribution of
      circumferential tensile stresses may play a critical role in where, why and when
      advanced atheromatous plaques rupture, leading to catastrophic ischaemic events.
      Recent advances in the application of computational modelling to in vivo vascular
      ultrasound and magnetic resonance imaging data should further elucidate the roles
      of haemodynamic factors and vessel wall mechanics in atherosclerosis. In future
      this is likely to lead to better use of currently available anti-atherosclerosis
      strategies. It may also facilitate the discovery, evaluation and development of
      novel treatments.

PMID- 10581966
TI  - A review of the measurement of blood velocity and related quantities using
      Doppler ultrasound.
AB  - Ultrasound systems can be used to investigate blood flow by use of the Doppler
      effect. The flow information may be displayed as either a real-time sonogram or a
      two-dimensional colour image. Estimates of maximum velocity using commercial
      systems are in error by typically 10-100 per cent; this is associated with the
      inability of the single-beam Doppler method to measure the true direction of
      flow, and with geometric spectral broadening. Vector Doppler systems acquire
      Doppler information along two beam directions and are able to measure accurately
      the velocity and direction of motion within the scan plane. The small beam width
      of modern Doppler systems means that the condition of uniform insonation,
      required for estimation of mean velocity from mean frequency shift, is not valid
      except for the very smallest vessels. Other quantities related to the velocity
      may also be estimated, such as the volumetric flow and wall shear stress. Flow
      visualization using colour flow imaging suffers from dependence of the displayed
      colour on the direction of blood motion. The vector Doppler technique may be
      extended to colour flow to give improved visualization of flow, in which there is
      no angle dependence within the scan plane.

PMID- 10581967
TI  - Local haemodynamics of arterial bypass graft anastomoses.
AB  - One of the main causes of failure of expanded polytetrafluoroethylene (PTFE)
      bypass grafts used in the lower limbs is the development of myointimal
      hyperplasia (MIH). Clinical studies show that higher patency rates can be
      obtained with the use of an autologous vein cuff (the Miller cuff) interposed
      between the graft and artery. The reasons for the improved performance are still
      unclear, but preliminary studies suggest that the change in local haemodynamics
      due to the cuff geometry may be the significant factor rather than the presence
      of autologous material. If this is the case, then PTFE grafts can be produced
      with an integral cuff, i.e. a precuffed graft, with similar haemodynamic patterns
      to that of the Miller cuff. In this paper, two different types of precuffed graft
      are presented and their flow patterns are compared with those recorded in the
      Miller cuff and the conventional end-to-side anastomosis. The haemodynamic
      studies were carried out using optically clear silicone rubber models under
      simulated in vivo pulsatile flow conditions. Flow structures similar to those
      observed in the Miller cuff were seen in the precuffed grafts.

PMID- 10581968
TI  - Reconstruction of blood flow patterns in human arteries.
AB  - Local haemodynamic factors in large arteries are associated with the
      pathophysiology of cardiovascular diseases such as atherosclerosis and strokes.
      In search of these factors and their correlation with atheroma formation,
      quantitative haemodynamic data in realistic arterial geometry become crucial. At
      present no in vivo non-invasive technique is available that can provide accurate
      measurement of three-dimensional blood velocities and shear stresses in curved
      and branching sites of vessels where atherosclerotic plaques are found
      frequently. This paper presents a computer modelling technique which combines
      state-of-the-art computational fluid dynamics (CFD) with new noninvasive magnetic
      resonance imaging techniques to provide the complete haemodynamic data in 'real'
      arterial geometries. Using magnetic resonance angiographic and velocity images
      acquired from the aortic bifurcation of a healthy human subject, CFD simulations
      have been carried out and the predicted flow patterns demonstrate the non-planar
      type flow characteristics found in experimental studies.

PMID- 10581969
TI  - Comparison of flow in numerical and physical models of a ventricular assist
      device using low- and high-viscosity fluids.
AB  - The flows in a model of a ventricular assist device (VAD) were investigated
      numerically and experimentally for two different Newtonian test fluids. These
      were a blood analogue fluid and a much higher viscosity fluid. A finite volume
      method was employed to solve the governing equations for a three-dimensional
      unsteady laminar flow on a transient grid. The numerical solutions were compared
      with experimental results from an identical physical model. The experimental
      flows were investigated by flow visualization and by laser Doppler velocity
      measurements at selected points in the flow field. The validation was based on
      comparisons of flow patterns and of non-component velocity-time histories. The
      maximum Reynolds numbers in the inflow tube of the model VAD were approximately
      460 and 3300 using the high- and low-viscosity fluids respectively. The
      investigation showed that the flow patterns were better predicted for the high
      viscosity fluid. However, the agreement between the velocity-time histories was
      found to be slightly better for the low-viscosity fluid. The discrepancies in the
      flow patterns may be due to intermittent turbulence with a further contribution
      from numerical diffusion.

PMID- 10581970
TI  - Density modification for macromolecular phase improvement.
AB  - Density modification provides a simple and largely automatic tool for improving
      phase estimates for observed structure factors. The phase information arises from
      a combination of the known structure factor magnitudes, the current phase
      estimates, and stereochemical information. The magnitudes, the current phase
      estimates, and stereochemical information. The addition of these phase
      information derived from theoretical sources renders new structures amenable to
      solution, and reduces the effort required to solve other structures. A diverse
      array of techniques which have been applied to the phase improvement problem are
      reviewed.

PMID- 10581971
TI  - The evolutionary transition from monomeric to oligomeric proteins: tools, the
      environment, hypotheses.
AB  - Recently, renewed interest in the evolution of oligomeric proteins has seen new
      approaches explored and new hypotheses proposed. The model systems chosen are
      generally made up of pairs of homologous proteins, each composed of a monomer and
      a dimeric counterpart, but the question has been also approached by comparing
      statistically significant structural patterns in sets of monomeric and oligomeric
      proteins. Here the tools of genetics and chemistry potentially available to the
      evolution of oligomeric proteins are discussed, as well as the possible effects
      of environments on the early attempts to oligomerization. Traces of an ancestral
      monomeric status of oligomers may be detected in the significant presence of
      polar and charged residues at intersubunit interfaces, and by the recognition
      that, besides the hydrophobic effect, a 'hydrophilic' effect has also had a role
      in the construction of these interfaces. The traditional 'mutation' model is
      described and found to be based on a hierarchy of mutations, crowned by a
      'primary' mutation, one that could prime oligomerization by irreversibly altering
      the structure of an ancestral monomer. The mechanism of oligomerization based on
      the exchange or 'swap' of structural elements between monomers is discussed. The
      possibility is also discussed that the main steps in the folding pathway of an
      oligomeric protein reiterate the main steps in its evolution.

PMID- 10581972
TI  - The F-box: a new motif for ubiquitin dependent proteolysis in cell cycle
      regulation and signal transduction.
AB  - The ubiquitin system of intracellular protein degradation controls the abundance
      of many critical regulatory proteins. Specificity in the ubiquitin system is
      determined largely at the level of substrate recognition, a step that is mediated
      by E3 ubiquitin ligases. Analysis of the mechanisms of phosphorylation directed
      proteolysis in cell cycle regulation has uncovered a new class of E3 ubiquitin
      ligases called SCF complexes, which are composed of the subunits Skp1, Rbx1,
      Cdc53 and any one of a large number of different F-box proteins. The substrate
      specificity of SCF complexes is determined by the interchangeable F-box protein
      subunit, which recruits a specific set of substrates for ubiquitination to the
      core complex composed of Skp1, Rbx1, Cdc53 and the E2 enzyme Cdc34. F-box
      proteins have a bipartite structure--the shared F-box motif links F-box proteins
      to Skp1 and the core complex, whereas divergent protein-protein interaction
      motifs selectively bind their cognate substrates. To date all known SCF
      substrates are recognised in a strictly phosphorylation dependent manner, thus
      linking intracellular signalling networks to the ubiquitin system. The plethora
      of different F-box proteins in databases suggests that many pathways will be
      governed by SCF-dependent proteolysis. Indeed, genetic analysis has uncovered
      roles for F-box proteins in a variety of signalling pathways, ranging from
      nutrient sensing in yeast to conserved developmental pathways in plants and
      animals. Moreover, structural analysis has revealed ancestral relationships
      between SCF complexes and two other E3 ubiquitin ligases, suggesting that the
      combinatorial use of substrate specific adaptor proteins has evolved to allow the
      regulation of many cellular processes. Here, we review the known signalling
      pathways that are regulated by SCF complexes and highlight current issues in
      phosphorylation dependent protein degradation.

PMID- 10581973
TI  - Correlates of hypochondriasis in a nonclinical population.
AB  - Because few community surveys of hypochondriasis have been completed, little is
      known about the epidemiology of this disorder outside of clinical populations. To
      address this deficiency, the authors obtained information about hypochondriasis
      and pertinent characteristics from a group of first-degree relatives of
      hypochondriacal and nonhypochondriacal probands who participated in a family
      study. In addition to psychiatric diagnoses, the authors elicited information on
      demographic variables, medical history, impairment in functioning, psychiatric
      comorbidity, psychiatric symptoms, personality traits, and childhood experiences.
      The authors identified hypochondriasis in 7.7% of the relatives. These relatives
      had a high rate of comorbid anxiety, depressive, and somatoform disorders. They
      also reported substantial physical and psychological impairment, including
      diminished work performance and disability. In addition, these relatives reported
      greater utilization of health care but less satisfaction with that care. These
      relatives showed most of the same characteristics found in earlier studies of
      hypochondriacal patients.

PMID- 10581974
TI  - Health Attitude Survey. A scale for assessing somatizing patients.
AB  - The authors designed an instrument, the Health Attitude Survey, to assess
      somatization, and administered it to over 1,000 patients attending a general
      medicine clinic. Within this population, a series of somatizing patients and
      control patients were identified for purposes of developing and testing the
      instrument. The 27-item scale was rapidly administered and acceptable to the
      patients. Based on comparisons with other measures of somatization, the
      instrument appeared to be a valid measure of the attitudes and perceptions of
      somatizing patients, and it distinguished these patients from the control
      subjects. The measure showed acceptable predictive value and may prove useful in
      clinical settings, where rapid screening is desired.

PMID- 10581975
TI  - A psychometric normative database for pre-liver transplantation evaluations. The
      Florida cohort 1991-1996.
AB  - In this study, the authors describe the psychological characteristics of a large
      sample (N = 407) of adult patients evaluated for liver transplantation, and
      provide normative data on commonly used measures of cognitive functioning,
      affective status, psychosocial adjustment, coping, quality of life, and life
      satisfaction. The normative data suggest that the study's liver transplant
      candidates have poorer cognitive functioning and health-related quality of life
      when compared with available normative comparison groups, yet the former group is
      more comparable to medically ill peers on measures of anxiety, depression,
      psychosocial adjustment, and coping. Data also suggest a high rate of affective
      disturbance in liver transplant candidates. Results indicate the utility of
      normative data, such as the authors', for providing an appropriate comparison
      group for liver pretransplant candidates.

PMID- 10581977
TI  - Economic consequences of comorbid depression, anxiety, and allergic rhinitis.
AB  - The present study extends prior work on the association between allergic rhinitis
      (AR) and common mental disorders by testing three related hypotheses: 1) that AR
      is associated with increased rates of depression and anxiety disorders in a large
      insured population, 2) comorbid AR, depression, and anxiety are associated with
      increased health and mental health expenditures, and 3) allergy treatment
      moderates the association between increased expenditures and comorbid AR,
      depression, and anxiety. Data are from MARKETSCAN, a large health care claims
      database of over 600,000 privately insured persons. Results indicate that AR is
      associated with higher rates of depression and anxiety disorder. Outpatient
      health care expenditures were increased by an average annual amount of $207 when
      AR and anxiety disorder were comorbid and $363 when AR and depression were
      comorbid. Finally, prescription treatment of AR moderated the increased
      expenditures associated with comorbidity.

PMID- 10581976
TI  - Psychiatric aspects of parathyroid disease.
AB  - Parathyroid diseases can present with psychiatric symptoms and can be recognized
      through determinations of serum electrolytes, especially the calcium level.
      Psychiatric evaluations should include a serum calcium concentration test, which
      is also essential in reassessment of patients poorly responsive to mental illness
      treatment. A magnesium and a phosphate assay may also be diagnostically helpful.
      Abnormality of divalent cation levels may provide evidence for consideration of,
      or ruling out, parathyroid disorders. Determinations of parathyroid hormone are
      performed if clinically indicated, and if abnormal divalent cation
      quantifications are confirmed. If parathyroid disease is identified, corrective
      endocrine therapies may diminish or even cure psychiatric aspects of parathyroid
      pathology. Failure to recognize a parathyroid disorder leaves an endocrine
      induced mental dysfunction without proper treatment.

PMID- 10581978
TI  - Psychosocial correlates of pain attributions in women with dyspareunia.
AB  - The relationship between patients' causal attributions for pain and
      biopsychosocial measures was investigated in a sample of 100 women with
      dyspareunia. Independently of findings from the gynecological examinations,
      causal attributions were related to adjustment. More specifically, the women who
      made psychosocial attributions reported higher pain scores, higher levels of
      psychological distress, lower levels of marital adjustment, more problems with
      sexual function, and more frequent reports of sexual assault. The relationship
      between psychosocial causal attributions for pain and psychosocial distress may
      be clinically useful in the multidisciplinary treatment of this and other pain
      disorders, regardless of actual physical pathology.

PMID- 10581980
TI  - Five cases of interferon-alpha-induced depression treated with antidepressant
      therapy.

PMID- 10581979
TI  - Psychological symptom levels and their correlates in lung and heart-lung
      transplant recipients.
AB  - This study examined depression, anxiety, and anger-hostility symptom levels, as
      well as overall quality of life, in a cohort of 50 lung and heart-lung transplant
      recipients. Only the subjects' mean anxiety symptoms were substantially elevated
      over normative levels. However, nearly half of the sample showed clinically
      significant distress in one or more of the three symptom areas. Pretransplant
      psychiatric history, educational level, posttransplant caregiver support, and
      health concerns were the most important independent correlates of the recipients'
      psychological outcome. Low sense of mastery and poorer physical functional status
      also showed some evidence of association with mental health.

PMID- 10581981
TI  - Long-term psychological and neurological complications of lindane poisoning.
AB  - A thin, healthy, partial-vegetarian, white female, who was exposed to three doses
      of lindane (through the application of Kwell), developed a severe case of long
      term lindane poisoning. Review of the literature suggests that her toxicity was
      so severe because of the repetitive nature of her exposure and the fact that she
      was partly protein restricted when first exposed. She developed profound central
      nervous system toxicity, as well as skin and gastrointestinal changes, that
      persisted for 20 months. She was treated with high doses of Valium. It was noted
      that every time her Valium was diminished below a critical level, her symptoms
      tended to recur until she had adequately cleared the lindane from her system. We
      believe this is the longest term of poisoning reported following exposure to an
      organochloride insecticide. Her symptoms are well explained by the physiology of
      these compounds as described in the literature. The case is important, for it
      represents the longest persistence of symptoms clearly associated with poisoning
      by the potent gamma isomer of BHC-lindane.

PMID- 10581982
TI  - Clozapine, neuroleptic malignant syndrome, and pancerebellar syndrome.

PMID- 10581984
TI  - Creutzfeldt-Jakob disease presenting as secondary mania.

PMID- 10581983
TI  - Acute intermittent porphyria.

PMID- 10581986
TI  - CD4 counts of HIV-positive patients with cognitive disorders in Japan.

PMID- 10581985
TI  - Childhood trichotillomania. Successful treatment with fluoxetine following an
      SSRI failure.

PMID- 10581987
TI  - Is "ergomania" a predisposing factor to chronic pain and fatigue?

PMID- 10581988
TI  - Musical hallucinations after living-donor liver transplantation.

PMID- 10581989
TI  - [Medical care to illegal immigrants: law and ethics].

PMID- 10581990
TI  - [The last breath: symbolism and uncertainties of death].

PMID- 10581991
TI  - [Thrombosis and its therapeutic targets].
AB  - Pathophysiological factors of thrombosis (flow, exposed surface and blood
      reactivity) explain when, how and why a thrombosis does develop. The same factors
      associated to the fibrinolytic capacity of the vessel wall explain the
      spontaneous evolution of the thrombosis. Among these factors, blood flow
      determines the relative participation of platelets and that of coagulation
      cascade. In arterial thrombosis, atherosclerotic plaque rupture is the triggering
      factor and platelets are the main actors in the thrombotic reaction: in
      consequence platelets are the main target and antiplatelet agents the main drugs
      to use for preventing atherothrombotic ischaemic events. In venous thrombosis,
      flow (stasis) is the main factor (with an additional role of blood coagulability
      and of venous wall lesion), and blood coagulation is the main contributor:
      anticoagulants are the logical option to prevent venous thromboembolic events.
      Thrombolytic agents can be used in arterial thrombosis only when a fibrin network
      completes and stabilizes the occluding platelet thrombosis (in myocardial
      infarction and not in unstable angina) and this has to be applied very early so
      that the physiological dethrombosis can still be possible.

PMID- 10581992
TI  - [Antiplatelet agents and their therapeutic use].
AB  - Antiplatelet agents have a well established effect against thrombosis
      complicating atherosclerosis. Drugs currently in use in France are: aspirin and
      flurbiprofen, inhibiting thromboxane synthesis; ticlopidine and clopidogrel,
      inhibiting platelet activation by adenosine diphosphate; dipyridamole, inhibiting
      platelet activation through adenosine; abciximab, acting on the mechanism of
      aggregation. Their molecular and cellular pharmacology is in agreement with the
      clinical effects and the guidelines for practical use. These drugs have in common
      that they carry a risk of hemorrhage, albeit low but difficult to cope with in
      case of invasive procedures. There is no antidote. They also have specific
      contraindications. No laboratory tests aimed at assessing their effect on primary
      haemostasis are proved of any clinical value.

PMID- 10581993
TI  - [Indications for antiplatelet medications].
AB  - Platelet active drugs are part of the antithrombotics. Their biological effect is
      not assessed in current practice. Their clinical efficacy has been firmly
      established in randomised controlled trials. Aspirin has been the most widely
      tested drug and is effective in various forms of coronary artery disease and in
      the secondary prevention after a first ischaemic stroke; in these settings,
      aspirin reduces the incidence of myocardial infarction, stroke and cardiac death;
      aspirin has been tested in various daily doses from 30 to 1300 mg: best evidence
      has been gathered for dosages between 75 and 300 mg; good clinical practice is to
      use the lowest effective dose. Ticlopidine and clopidogrel have been shown to be
      superior to aspirin in 2 trials where the incidence of myocardial infarction has
      been lowered by the new drugs; nevertheless the superiority is apparent only in
      patients with lower limb atherosclerosis and after stroke. The combination of
      dipyridamole and aspirin has been proven to be superior to aspirin in the
      secondary prevention of stroke in one trial contrasting with the other trials
      performed with other combinations of those two drugs. Glycoprotein GP IIb/IIIa
      antagonists have been tested in coronary angioplasty and in acute coronary
      syndromes and only in short intravenous administration; these drugs reduce the
      incidence of myocardial infarction without any effect on 6-month mortality.

PMID- 10581994
TI  - [Anticoagulants in clinical practice].
AB  - Four classes of anticoagulants are now available: vitamin K antagonists, heparin,
      Orgaran and hirudin. For each of these classes the mechanism of the anticoagulant
      effect, the usual doses and biological monitoring are described. Each low
      molecular weight heparin must be considered as an original product. Orgaran and
      hirudin are new antithrombotic agents allowing to solve the dramatic problems
      raised by heparin-induced thrombocytopenia.

PMID- 10581995
TI  - [Indications for anticoagulants].
AB  - Anticoagulant therapy includes heparin, either unfractionned or of low molecular
      weight, danaparoid, vitamin K antagonists and direct thrombin inhibitors. Low
      molecular weight heparins are now the cornerstone of venous thromboembolism
      prevention in surgery, and once daily regimen is available for the treatment of
      acute deep vein thrombosis. Vitamin K antagonists are mostly used for secondary
      prevention of venous thromboembolism and for primary prevention of arterial
      embolism in patients with permanent atrial fibrillation or with cardiac
      prosthetic valve. Thrombotic complications of heparin-induced thrombocytopenia
      are prevented and treated by direct thrombin inhibitors or danaparoid.

PMID- 10581996
TI  - [Thrombolytics and their use].
AB  - Thrombolytic agents directly or indirectly activate plasminogen into plasmin, the
      true thrombolytic being plasmin. Streptokinase is a non-enzyme protein which has
      occupied the reference position so far. Streptokinase is immunogenic and its
      activity is neutralised by pre-existing antistreptococcal antibodies. Its
      administration provokes a systemic activation of fibrinolysis. Urokinase and
      anisoylated streptokinase-plasminogen complex have no clear advantages when
      compared with streptokinase. More fibrin specific agents (tissue plasminogen
      activator, prourokinase) do not improve the risk of bleeding (0.75% in brain).
      Haemostasis survey does not allow bleeding prediction, but contributes to its
      control by quantifying the systemic fibrinolytic activity of the drug and
      checking the anticoagulation level induced by heparin (which is often associated
      to thrombolysis).

PMID- 10581997
TI  - [Indications for thrombolytics].
AB  - Thrombolytic drugs, streptokinase and urokinase, were initially used in pulmonary
      embolism. More recently, new drugs like alteplase, reteplase, lanoteplase and
      saruplase have been a breakthrough in the treatment of acute myocardial
      infarction. Their efficacy has been demonstrated when treatment is initiated
      before the 6th hour of infarction onset. A 50% reduction of death rate is
      expected, if treatment starts within the 1st hour. Alteplase and reteplase are
      the most efficient thrombolytics despite a higher risk of cerebral bleeding. In
      pulmonary embolism with clinical signs of severity, thrombolysis is clearly
      indicated. In deep vein thrombosis of the lower limbs, therapeutic thrombolysis
      is still controversial. Some acute ischemic strokes (before the 3rd hour) could
      be treated with alteplase if there is no absolute or relative contraindication
      for thrombolysis. In prosthetic heart valve thrombosis, thrombolysis may be used
      if surgical treatment is contraindicated but the risk of bleeding and embolism
      should be taken into account.

PMID- 10581998
TI  - [Where to look for progress in antithrombotic treatments?].
AB  - Thrombosis is the most frequent cause of venous and arterial vascular events.
      Anticoagulants and antiplatelet agents are able to prevent both types of
      thrombotic episodes. However, available agents have limitations which justify the
      search for new antithrombotic drugs or at least the clinical investigation of
      combined treatment with already available drugs. Progress in the knowledge of the
      mechanism of thrombosis guides the search for new antithrombotic agents. Novel
      strategies should take into account the intensity of the thrombogenic stimulus
      involved in the occurrence of the thrombotic episodes. Among antiplatelet agents,
      the logic combination of aspirin and ticlopidine or clopidogrel is already
      challenging the anti-GP IIb/IIIa orally active compounds. Among anticoagulant
      agents a long list of competitors for the replacement of oral anticoagulants and
      heparins is already available. They target factors Xa, IIa or VIIa. A promising
      alternative is to increase the thromboresistance of the vascular wall.

PMID- 10581999
TI  - [War against nicotinism: when good will goes up in smoke...].

PMID- 10582000
TI  - [Visual decline of recent onset. Diagnostic view].

PMID- 10582001
TI  - [Rickets. Physiopathology, diagnosis, preventive and curative treatment].

PMID- 10582002
TI  - [Suicidal ideation or behavior and their emergency management].

PMID- 10582003
TI  - [Renal colic and its emergency management].

PMID- 10582004
TI  - [Bedridden state. Etiology, prevention of complications].

PMID- 10582005
TI  - [Hand wounds. Diagnosis, treatment during the first 24 hours].

PMID- 10582006
TI  - [Persistent biological inflammatory syndrome. Diagnostic view].

PMID- 10582007
TI  - [The antioxidant activity of the lacrimal fluid in patients with primary open
      angle glaucoma].
AB  - Antioxidant activity (AOA) of lacrimal fluid and blood plasma was studied in 10
      normal subjects (20 eyes) and 35 patients with primary open-angle glaucoma (POAG)
      (67 eyes with glaucoma at different stages). The findings indicate that the
      progress of glaucoma is paralleled by a gradual decrease in the lacrimal fluid
      AOA, which becomes significant at the third stage of POAG. Plasma AOA also
      decreased significantly in the third far advanced stage. A course of total
      antioxidant therapy including oral aevit and vitamin complexes and intramuscular
      ascorbic acid normalized plasma AOA even in patients with far advanced glaucoma,
      while the lacrimal AOA did not normalize. Therefore, local antioxidants are
      preferable in glaucoma patients.

PMID- 10582008
TI  - [Crystallography of the lacrimal fluid as a method for predicting the risk of
      developing cataract in patients with primary glaucoma].
AB  - Results of crystallographic analysis of the lacrimal fluid in patients with
      glaucoma combined with cataract are analyzed. The characteristic features of
      lacrimal crystallograms of such patients consist in changed ratio of the
      crystallization zones with disappearance of the intermediate zone and appearance
      of stellate structures on crystallograms of patients with progressing cataracts.
      The method of lacrimal crystallography is suggested to be used in examinations of
      patients with glaucoma.

PMID- 10582009
TI  - [Vitrectomy in traumatic cataracts and in the complications of surgery in
      congenital cataract in children].
AB  - Vitrectomies were carried out in 35 children with traumatic cataracts and
      complications of surgery for cataracts, caused by injury to the posterior
      lenticular capsule and incorporation of its fragments to the vitreous. Complete
      removal of lenticular rudiments rapidly eliminated phacogenic iridocyclitis and
      improved visual acuity. Improvement of visual functions was attained in 66.6%
      cases; in 33.4% cases visual acuity did not change. Hemorrhages to the vitreous
      cavity occurred in 4 cases with pronounced iridocyclitis; therefore, a corneal
      approach is preferable for cases with pronounced iridocyclitis.

PMID- 10582011
TI  - [Anomalies of optic nerve excavation: the clinical manifestations and
      differential diagnosis].
AB  - Clinical features, electrophysiological characteristics, neuroradiological
      symptoms and associations with systemic malformations have been studied in 76
      children with abnormalities of the optic nerve excavation: the morning glory
      syndrome, optic nerve coloboma, and congenital peripapillary staphyloma. Based on
      the results, the criteria are determined for the differential diagnosis of these
      optic nerve abnormalities and the hypothesis on their different embryogenesis is
      confirmed.

PMID- 10582010
TI  - [Reinforcement of the sclera with new types of synthetic materials in progressive
      myopia].
AB  - The possibility of using a new synthetic material mersilene for scleroplastic
      operations has been evaluated in experiments and clinical trials were carried out
      in patients with progressive myopia subjected to sclera fortification.
      Morphological studies showed the formation of a connective tissue capsule round
      mersilene; new collagen fibers grow through its cellular structures, thus
      fortifying the strength of the sclera-graft complex. Clinical results indicate
      that sclera fortification by a mersilene graft arrested the progress of myopia in
      almost all (98%) patients by the end of the first year postoperation; by the end
      of the second year, myopic refraction stabilized in 92% patients. Hence,
      mersilene transplants are recommended for scleroplasty in progressive myopia.

PMID- 10582012
TI  - [The prevention and treatment of recurrences after dacryorhinostomies].
AB  - A total of 1206 dacryorhinostomies carried out from January, 1991 to December,
      1997 at Institute of Ocular Diseases of the Russian Academy of Medical Sciences
      are analyzed. The main causes of relapses were underevaluation of the data of
      examinations and improper choice of operative access and method of surgery,
      errors in the technique of operation, and wrong postoperative treatment. For
      improving the efficacy of surgery, the authors developed a comprehensive method
      for preventing and treating relapses. X-ray and rhinological data are decisive
      for the choice of the access and method of operation. Unfavorable rhinogenic
      factors are removed and measured aimed at suppression of the cicatricial process
      at the site of anastomosis are carried out in primary dacryorhinostomy. For this
      purpose the authors for the first time in Russia applied a cytostatic antibiotic
      mitomycin C to the site of dacryostoma (44 cases) and a polymeric film Diplen
      with hemostatic and wound-healing effects (87 cases) with good results. Thorough
      follow-up after surgery detected a threatened relapse sufficiently early to carry
      out adequate treatment promoting cure.

PMID- 10582013
TI  - [An analysis of the results in dopplerography of the normal central retinal
      artery and in various eye pathologies].
AB  - The blood flow velocity in the central retinal artery was evaluated by ultrasonic
      dopplerography in 577 patients (1154 eyes), 738 of these were normal eyes and 416
      eyes with various ocular diseases. The patients' ages were 10-75 years.
      Hemodynamic parameters of normal bloodflow in the central retinal artery were
      determined: 9-15 cm/sec, diastolic velocity 4-6 cm/sec, and resistive index <
      0.75. General tendencies in changes of the dopplerographic parameters in various
      ocular diseases were determined.

PMID- 10582015
TI  - [The characteristics of the clinical picture of lymphosarcoma and of a metastatic
      tumor of the orbit of another origin].
AB  - Clinical symptoms in patients with primary orbital lymphosarcoma, generalized
      lymphosarcoma involving the orbital tissues, and metastatic tumors of the orbit
      of another origin are analyzed. The orbital process has bee studied in 158
      patients. The most frequent symptoms were ptosis and exophthalmos. Decreased
      visual acuity, pain, sensation of swelling in the orbit caused by rapid tumor
      growth were characteristic of metastases to the tumor and orbital lymphosarcoma
      in total system's involvement. In case of an isolated involvement of the orbit,
      lymphosarcoma ran a more swift course than metastases to the orbit and orbital
      lymphomas in systemic involvement which ran an aggressive course. These data
      cannot serve as differential diagnostic signs. The decisive information is
      provided by morphological examination of a biopsy specimen.

PMID- 10582014
TI  - [The treatment of posttraumatic uveitis with low-intensity laser radiation].
AB  - Eighty-two patients with severe posttraumatic uveitis which could not be treated
      by traditional antiinflammatory therapy were exposed to low-intensity laser
      (LIL). The patients were divided into 3 groups: 1) infrared laser exposure using
      Ulei 2K semiconductor pulsed laser, 2) intravenous exposure of the blood to a He
      Ne laser LG-75, and 3) both treatments. The treatment efficacy was monitored by
      measuring lipid peroxides and superoxide dismutase in the lacrimal fluid. The
      treatment proved to be effective. The best results were attained by applying both
      methods of exposure, as was shown by sooner normalization of the content of lipid
      peroxidation products and activity of superoxide dismutase.

PMID- 10582016
TI  - [Cytomegalovirus infection in children with endogenous uveitis].
AB  - A total of 405 children aged 3 months to 15 years with uveitis of different
      origin and localization and 50 mothers of children with intrauterine uveitis were
      tested for cytomegaloviruses (CMV). Chronic CMV infection was detected in 79%
      children and 88% mothers. Active CMV infection was diagnosed in 7.1% children
      with various clinical forms of uveitis; it was somewhat more frequent in cases
      with grave posterior uveitis and panuveitis complicated by detachment of the
      retina and vitreous fibrosis. Anti-CMV IgG antibodies indicate an infection, but
      their detection is insufficient for identifying the etiology of uveitis. Active
      CMV infection can be a cause of uveitis or aggravate uveitis of another etiology
      and favor the development of postoperative complications. In many cases active
      CMV infection was detected in children during remission without clinical signs of
      uveitis activity. Individual analysis of clinical laboratory data is needed for
      each patient in order to evaluate the etiological and pathogenetic role of active
      CMV infection.

PMID- 10582017
TI  - [The pathomorphological characteristics of the corneal subepithelial haze after
      photorefractive keratectomy].
AB  - Morphological characteristics of the haze [correction of fleur] (subepithelial
      corneal opacity) observed after photorefraction interventions are described.
      Early haze [correction of fleur] (during the first 14 days) is caused by
      structural and spatial disorders and edema of the surface stromal layers under
      the hyperplastic epithelium. By its pattern and localization it can be classified
      as early subepithelial exudative. With differentiation of the epithelium and
      restructuring of the extracellular matrix, early haze [correction of fleur] as a
      rule gradually and spontaneously resolves within 10-14 days. Late haze
      [correction of fleur] is more stable and stubborn; it develops as a result of
      proliferation and migration of activated keratocytes into surface layers of the
      stroma at the site of photoablation usually 3 months and more after
      photorefraction keratectomy. Therefore, exposure of the cornea to an eximer laser
      is a source of its exogenous (physical) injury leading to an aseptic
      inflammation. The task of the refraction surgeon is timely drug correction,
      adequate to phases of inflammation, in order to create conditions for rapid
      complete regeneration of corneal tissue and restoration of its transparency.

PMID- 10582018
TI  - [Biological mineralization in melanoma of the vascular coat of the eye].
AB  - Strontium hydroxide Sr(OH)2 has been identified in tumor tissues of patients with
      melanoma of the vascular coat of the eye and in metastatic tumors to the vascular
      coat of the eye by x-ray structural analysis. Normal vascular coat of the eye is
      represented by a mineral natrolite, an adsorbent belonging to zeolites.
      Presumably, during an oncological process strontium modifies natrolite by
      changing its adsorption and adhesive properties.

PMID- 10582019
TI  - [The effect of neurohumoral factors of the sympathoadrenal system on the results
      of cataract extraction with intraocular lens implantation in diabetic patients].
AB  - Effect of the sympathoadrenal system (SAS) on the results of cataract extraction
      with IOL implantation was studied by analyzing the stress index in 64 patients
      with diabetes mellitus and 20 reference patients. SAS reaction to surgical stress
      was abnormal in 34 (53.1%) diabetics. The level of SAS activity, postoperative
      complications, and kinetics of regenerative repair processes in the cornea were
      related. In 15 (23.%) diabetics with a low stress index the postoperative period
      was characterized by frequent inflammations, longer repair of normal corneal
      homeostasis, and coarse cicatrization. In 19 (29.7%) diabetics with a high stress
      index after cataract extraction normalization of the corneal homeostatic
      parameters was delayed and macular edema developed 4.8 times more often.

PMID- 10582020
TI  - [The results of treating aphakic glaucoma with beta-blockers].
AB  - Treatment of patients with aphakia and increased intraocular pressure by beta
      blockers is sufficiently effective. Instillations of these agents decreases
      ophthalmic tone in patients with aphakia combined with primary glaucoma and in
      those with aphakic glaucoma. Intraocular pressure decreased in 70% patients and
      the effect persisted for at least 3 months in the majority of cases.

PMID- 10582021
TI  - [The classification, causes and clinical manifestations of the complications from
      specialized laser keratomileusis in the correction of myopia and hypermetropia].
AB  - Complications of specialized laser keratomileusis (LASIK) are analyzed in 1667
      patients with 1.0-19.5 diopter myopia and hypermetropia of +2.25-10.0 diopters.
      LASIK was carried out by the standard method using Hansatome TM 230 HT device and
      eximer laser Nidek EC-5000. Classification of LASIK complications depending on
      the mechanism of exposure and stage at which they manifest is offered. Such
      complications as inadequate adaptation of the corneal flap (0.7%), lensodonesis
      (0.1%), viral keratitis (0.05%), turned-under edge of a flap (0.4%), stromal
      "feedback" pouch are described for the first time. Causes of complications are
      enumerated and analyzed and methods for their correction are described. The
      authors claim that the type and incidence of LASIK complications are largely
      determined by the experience of the surgeon and quality of equipment. Use of new
      lasers and new keratomes will rule out many complications.

PMID- 10582022
TI  - [The efficacy of training the accommodation muscle using the AT-1
      Accomodotrainer].
AB  - A new modification of an AT-1 device for training of the ciliary muscle is
      described and the results of individual treatment by this device are analyzed.
      The device was used by 110 patients (220 eyes) aged 8-20 years with slight and
      medium myopia (group 1, 71 patients) and with slight hypermetropia with an
      accommodation spasm (group 2, 39 patients). After training visual acuity without
      correction improved in 71.5% cases in group 1 and in 95.6% in group 2. The
      relative accommodation reserves improved in 78.6 and 98.5% cases, respectively.
      The device is simple and reliable and easy to use, which recommends it as a
      trainer for maintenance therapy at home and as a component of multiple-modality
      treatment in an inpatient setting.

PMID- 10582023
TI  - [Clinical, pathogenetic, diagnostic and treatment problems in congenital glaucoma
      in children].

PMID- 10582024
TI  - [The use of peptide bioregulators in ophthalmology].

PMID- 10582025
TI  - [The morphological characteristics and immunohemostatic mechanisms of the
      development of diabetic retinopathy].

PMID- 10582026
TI  - Endocrine disrupting chemicals and human reproduction: fact or fiction?

PMID- 10582027
TI  - Chrysotile, tremolite and fibrogenicity.
AB  - Recently published analyses have shown that the risks of mesothelioma and lung
      cancer in Quebec chrysotile miners and millers were related to estimated level of
      fibrous tremolite in the mines where they had worked. An analysis has therefore
      been made of radiographic changes in men who in 1965 were employed by companies
      in Thetford Mines where the same question could be examined for fibrogenicity. Of
      294 men who met the necessary requirements, 129 had worked in six centrally
      located mines, where the tremolite content was thought to be high, 81 in 10
      peripheral mines where it was thought to be low and 84 in both. The median
      prevalence of small parenchymal opacities (> or = 1/0) in chest radiographs read
      by six readers was higher among men ever than never employed in the central mines
      (13.6% against 7.4%), despite the fact that the mean cumulative exposure was
      lower in the former (430 mpcf.y vs 520 mpcf.y). After accounting by logistic
      regression for cigarette smoking, age, smoking-age interaction and cumulative
      exposure, the adjusted odds ratio for central mine employment was 2.44 (95% lower
      bound: 1.06). Together with other surveys of asbestos miners and millers, this
      study suggests that amphibole fibres, including tremolite, are more fibrogenic
      than chrysotile, perhaps to the same extent that they are carcinogenic, though
      the data available were not sufficient to address the latter question.

PMID- 10582028
TI  - Measurements of the effectiveness of dust control on cut-off saws used in the
      construction industry.
AB  - Materials used in the construction industry frequently contain large quantities
      of silica. When they are cut or shaped with power tools considerable respirable
      dust can be produced. Three dust control systems for use with cut-off saws have
      been evaluated on site: wet dust suppression using mains water, the same system
      using water from a portable water tank, and local exhaust ventilation. The
      efficiency of water suppression on cut-off saws has been precisely quantified in
      controlled laboratory conditions by means of measurements with and without dust
      control. When dust control was used on-site, the mean concentrations of airborne
      silica were reduced by a factor of between three and seven, the accuracy being
      limited by the relatively high limit of detection for silica. All controls
      systems generally reduced respirable dust levels by at least 90%. Although the
      effectiveness of dust suppression did not depend on blade type, a diamond blade
      was more effective than a resin-bonded blade with the pressurised water system;
      cutting a slab with this type of blade could be completed before the water tank
      required repressurization. In laboratory tests, the application of water reduced
      the dust concentration to < 4% of its value without control. The method for
      monitoring the dust concentration was sufficiently sensitive to measure a
      difference in concentration produced during cutting in different directions. It
      is important, however, that the pressure in supply reservoirs is properly
      maintained, that the water is correctly applied and that it is used at the
      correct rate. If this is done effective dust control can be achieved.

PMID- 10582029
TI  - Application of mixed models to assess exposures monitored by construction workers
      during hot processes.
AB  - Particulate exposures were assessed among construction workers engaged in hot
      processes in four jobs (boilermakers, ironworkers, pipefitters and welder
      fitters) at nine sites in the U.S. After being trained by occupational
      hygienists, the workers obtained shift-long personal samples at each site for
      total particulates (TP). Selected samples were also assayed for manganese (Mn),
      nickel (Ni), and chromium (Cr). Workers provided information about process- and
      task-related covariates that were present on the days of monitoring. Data were
      investigated with mixed-model regression analyses that designated the jobs and
      covariates as fixed effects and the worker and error terms as random effects.
      Results indicated that the within-worker variance components, but not the between
      worker variance components, could be pooled among jobs. Mean air levels for a
      given agent varied by roughly six to 100 fold among the jobs, with boilermakers
      and ironworkers experiencing much higher levels of TP and Mn than pipefitters and
      welder-fitters. Limited data also suggested that welder-fitters were exposed to
      greater levels of Ni and Cr than pipefitters. Sufficient sample sizes were
      available to evaluate the effects of covariates upon exposures to TP and Mn. As
      expected, processes involving more than 50% hot work led to substantially higher
      levels of TP and Mn than those involving shorter durations of hot work. Local
      exhaust or mechanical ventilation reduced exposure to TP (but not Mn) by as much
      as 44%, and shielded or manual arc welding increased exposure to Mn (but not TP)
      by about 80%. Parameters estimated with these mixed models were used to calculate
      probabilities that workers were exposed at levels above U.S. occupational
      exposure limits (OELs). Regarding TP and Mn, these calculations suggested that 26
      95% of exposures to boilermakers and pipefitters and 2-13% of exposures to
      pipefitters and welder-fitters exceeded the current Threshold Limit Values. Among
      welder-fitters, limited data also pointed to probabilities of 2-50% for exceeding
      particular OELs for Ni and Cr. Using the significance of the estimated random
      worker effects as a gauge for the uniformity of exposure within a job,
      administrative or engineering changes appear appropriate for reducing exposures
      to boilermakers and ironworkers, while individual personal environments should be
      investigated for pipefitters and welder-fitters.

PMID- 10582030
TI  - Measuring the noise attenuation of shotblasting helmets.
AB  - Air-fed blasting helmets are used in abrasive blasting operations to provide
      essential face, eye and respiratory protection. BS EN 271: 1995 (equivalent to
      the European Standard EN 271: 1997), the standard that deals with the
      construction of blasting helmets, addresses the above matters and also the
      problem of noise generated by the breathing air supply. However it has no
      requirements for manufacturers to measure or report the helmet's ability to
      attenuate the very high levels of noise generated by the blasting process. The
      aim of the project was to develop a test method to measure the noise attenuation
      of shotblasting helmets. The method developed is an objective measurement, using
      a head and torso simulator (HATS), which provides a suitable means for helmet
      manufacturers to report their product's ability to attenuate blasting noise. The
      results from this project showed that the HATS currently prescribed by BS EN 271:
      1995 can be used for measuring the noise attenuation of helmets against typical
      shotblasting noise. Using such a HATS in the proposed test method will give
      attenuation values that correlate well with those measured using human subjects.
      Therefore the HATS already used by manufacturers to show compliance of their
      product with BS EN 271: 1995 could also be used to provide information on the
      helmet's noise attenuation. Results from this project also showed that the same
      HATS can be used, in place of human subjects, to measure the air supply noise
      according to the method defined in BS EN 271: 1995. BS EN 271: 1995 is due for
      revision in 2000. The results from this work should be used to influence future
      revisions of the standard so that requirements to measure and report noise
      attenuation of shotblasting helmets are considered, a major omission in the
      present standard.

PMID- 10582031
TI  - Refinements in magnetic field exposure assignment for a case-cohort study of
      electrical utility workers.
AB  - This study examined the effect of refinements in exposure assignment on annual
      and career exposure to 60 Hz magnetic fields, using all deaths from brain cancer
      (145) and leukemia (164) and a random sample of 800 workers from a cohort of
      138,905 men. Reassessment of 1060 job titles in the measurement database
      generated 20 subcategories in addition to 28 occupational categories used in the
      original cohort mortality study. Furthermore, previously misclassified jobs were
      corrected. The complete work history of each sub-cohort member was re-examined.
      Original and refined average annual exposures were 0.086 and 0.088 microT,
      respectively. The average career cumulative exposures were 1.40 and 1.44 microT
      years, respectively. Spearman correlation coefficients between the original and
      refined methods across the companies were 0.81 for annual exposure and 0.93 for
      career cumulative exposure. 23% of the workers were assigned to another exposure
      ranking after refinement, but 85% of these moved to an adjacent group, suggesting
      that the differences in exposure ranking are small. The results of this study
      indicate that refinements have modest influence on the average annual and career
      exposures. However, the refinements may only change a very rough exposure
      assessment into one that is slightly less crude. The proportion of workers
      assigned to another exposure ranking indicated that nondifferential exposure
      misclassification in the original cohort mortality study may have occurred.
      Implications of these changes for the risk estimates of brain cancer and leukemia
      cases will to be examined.

PMID- 10582032
TI  - Minimising health hazards associated with derogated products and in-situ
      materials containing chrysotile contaminated with amphibole asbestos fibres.

PMID- 10582033
TI  - Inventory of recent and ongoing occupational exposure research.

PMID- 10582034
TI  - Temporal awareness: pivotal in performance?
AB  - This paper describes an experiment where operators have to deal with various
      parallel asynchronous processes. The authors were interested in the level of
      'temporal awareness' developed by the operator. By temporal awareness, one means
      the ability of the operator to build a representation of the situation including
      the recent past and the near future. The hypothesis was that this ability is
      linked to other elements of performance. The authors also looked at the effects
      of an aid aimed at supporting the construction of temporal representation. The
      experiment showed that this support system was largely ineffective, but that the
      presence of temporal awareness proves to be a good indicator of performance, both
      in terms of errors committed and multiple-goal optimization.

PMID- 10582035
TI  - Error mode prediction.
AB  - The study of accidents ('human errors') has been dominated by efforts to develop
      'error' taxonomies and 'error' models that enable the retrospective
      identification of likely causes. In the field of Human Reliability Analysis (HRA)
      there is, however, a significant practical need for methods that can predict the
      occurrence of erroneous actions--qualitatively and quantitatively. The present
      experiment tested an approach for qualitative performance prediction based on the
      Cognitive Reliability and Error Analysis Method (CREAM). Predictions of possible
      erroneous actions were made for operators using different types of alarm systems.
      The data were collected as part of a large-scale experiment using professional
      nuclear power plant operators in a full scope simulator. The analysis showed that
      the predictions were correct in more than 70% of the cases, and also that the
      coverage of the predictions depended critically on the comprehensiveness of the
      preceding task analysis.

PMID- 10582036
TI  - The influence of aircraft proximity data on the subjective mental workload of
      controllers in the air traffic control task.
AB  - This paper outlines an investigation of the impact of aircraft proximity and
      relationship data on the subjective mental workload of air traffic controllers.
      Aircraft relationships were categorized into one of 81 different categories, and
      these relationships were then used to predict subjective mental workload values
      (as reported by the participants). The results indicated that this methodology
      could predict subjective mental workload to an accuracy of 73%, with post-hoc
      analysis improving this prediction rate to 93%. These results are discussed with
      respect to their contribution to an understanding of the drivers of mental
      workload in Air Traffic Control.

PMID- 10582037
TI  - Modelling cognitive processes of experienced air traffic controllers.
AB  - A model of the cognitive activities of experienced air traffic controllers is
      presented as an example of the challenging theoretical task to model mental
      processes in a dynamic task environment. Owing to the continuous changes in the
      task environment and the demand for the temporal co-ordination of activities in
      air traffic control, the model pays special attention to the mental
      representation of the situation. This unit of the model plays a salient role in
      maintaining situational awareness, in anticipating future states, and in co
      ordinating simultaneously ongoing events. The assumptions about the mental
      representation of the changing task environment are discussed within the mental
      model approach. Its realization within the proposed model is outlined. The model
      has been developed on the basis of experimental research with air traffic
      controllers. Brief outlines of the experiments on information intake, and the
      mental representation as examples of the empirical investigation are presented.
      In an experiment on information intake, controllers with different levels of
      experience had to control a traffic scenario while the information on the radar
      screen and on the flight-strips were masked. The frequencies of unmasking showed
      that the controller's picture is built up by means of a considerable reduction of
      information regardless of the level of experience. However, less experienced
      controllers used more planning data, especially information needed for short-term
      anticipation. A card-sorting task was used to investigate the underlying
      dimensions for situation assessment. A measure for correspondence between
      classifications and multidimensional scaling established that situation
      assessment is based not only on anticipation, but also on the evaluation of
      further information processing requirements. The influence of the empirical
      results on the model is discussed.

PMID- 10582038
TI  - Methodological considerations in analysing anaesthetists' habits of action in
      clinical situations.
AB  - Human activity can be seen as an intentional, context-dependent enterprise
      explained through meanings the actors attach to their activity and their directly
      observable interactions with the environment. The authors have demonstrated
      previously a new conceptual framework to describe the anaesthetist's activity.
      One of the central concepts besides orientation is habit of action referring to
      the way in which the actor has organized his actions when interacting with his
      environment, in this case a patient with unique physiological potentials,
      information monitors and anaesthetic drugs. The activity dependent on contingent,
      particular circumstances, needs to be studied as it appears in a natural
      situation. Using an idiographic study design the authors have examined the
      activity of eight expert anaesthetists in clinical settings to determine the
      characteristics of their habits of action. To capture the fleeting circumstances
      during the anaesthetic process, a wide observational basis was necessary. It
      consisted of videotapes, detailed expert observations, and interviews. The
      conceptual analysis of the subject, habit of action, is described step-by-step.
      Two distinct habits of action could be identified, confirming earlier results.
      The interpretative habit of action was characterized by extensive use of
      situational information in order to construct a cumulative conception of the
      patient's physiological potentials to control the process accurately. Moreover,
      rich dialogue between formal professional knowledge and patient-specific,
      particular knowledge was evident. The reactive habit of action was characterized
      by a tendency to regulate the process by means of predetermined conventional
      ranges of measured patient parameters shown by monitors. The authors discuss
      their methodological solutions and results, and explicate their differences to
      the earlier approaches.

PMID- 10582039
TI  - Conceptual design of industrial process displays.
AB  - Today, process displays used in industry are often designed on the basis of
      piping and instrumentation diagrams without any method of ensuring that the needs
      of the operators are fulfilled. Therefore, a method for a systematic approach to
      the design of process displays is needed. This paper discusses aspects of process
      display design taking into account both the designer's and the operator's points
      of view. Three aspects are emphasized: the operator tasks, the display content
      and the display form. The distinction between these three aspects is the basis
      for proposing an outline for a display design method that matches the industrial
      practice of modular plant design and satisfies the needs of reusability of
      display design solutions. The main considerations in display design in the
      industry are to specify the operator's activities in detail, to extract the
      information the operators need from the plant design specification and
      documentation, and finally to present this information. The form of the display
      is selected from existing standardized display elements such as trend curves,
      mimic diagrams, ecological interfaces, etc. Further knowledge is required to
      invent new display elements. That is, knowledge about basic visual means of
      presenting information and how humans perceive and interpret these means and
      combinations. This knowledge is required in the systematic selection of graphical
      items for a given display content. The industrial part of the method is first
      illustrated in the paper by a simple example from a plant with batch processes.
      Later the method is applied to develop a supervisory display for a condenser
      system in a nuclear power plant. The differences between the continuous plant
      domain of power production and the batch processes from the example are analysed
      and broad categories of display types are proposed. The problems involved in
      specification and invention of a supervisory display are analysed and conclusions
      from these problems are made. It is concluded that the design method proposed
      provides a framework for the progress of the display design and is useful in pin
      pointing the actual problems. The method was useful in reducing the number of
      existing displays that could fulfil the requirements of the supervision task. The
      method provided at the same time a framework for dealing with the problems
      involved in inventing new displays based on structured analysis. However the
      problems in a systematic approach to display invention still need consideration.

PMID- 10582040
TI  - An experimental study on estimating human error probability (HEP) parameters for
      PSA/HRA by using human model simulation.
AB  - A framework of Human Error Probability (HEP) parameters, which is needed for
      Human Reliability Analysis (HRA) within a practice of Probabilistic Safety
      Assessment (PSA) of Nuclear Power Plant is first proposed. Then a laboratory
      experiment was conducted in order to construct a computer simulation model (human
      model) that describes human cognitive behaviour on detecting and diagnosing plant
      anomaly causes. An inter-comparison between experimental data and human model
      simulation was performed to estimate Human Cognitive Reliability (HCR) curves, in
      order to confirm the applicability of a human model for estimating these HEP
      parameters for PSA/HRA practice.

PMID- 10582041
TI  - The multiple self: working with dissociation and trauma.
AB  - This paper describes a patient who appears to have a chronic dissociative
      personality disorder. Renewed clinical interest in dissociative disorders had
      arisen in North America in the 1980s, in part due to the influence of the Women's
      Movement which had highlighted the incidence of child sexual abuse. The early
      psychological observations of Janet, Freud and Jung on hysterical patients who
      displayed dissociative phenomena were similar to those displayed by the patient.
      consideration is given to theoretical understanding of the condition, taking into
      account the views of the earlier theorists and object-relations theory. The
      possibility of trauma, in particular childhood sexual abuse, as a causative
      factor in dissociative disorders is discussed.

PMID- 10582043
TI  - An appreciation of Jane Bunster 17 April 1930-16 June 1999

PMID- 10582042
TI  - Jane Bunster 1930-1999

PMID- 10582044
TI  - Toxicity of Bacillus thuringiensis beta-exotoxin to three species of fruit flies
      (Diptera: Tephritidae).
AB  - The current study describes toxic effects of the Bacillus thuringiensis beta
      exotoxin toward 3rd instars of 3 fruit fly species: Anastrepha ludens (Loew), A.
      obliqua (Macquart), and A. serpentina (Wiedemann). The beta-exotoxin was highly
      toxic to all 3 species tested, with LC50 values calculated as 0.641, 0.512, and
      0.408 microgram/cm2 of filter paper used to expose the larvae, for A. ludens, A.
      obliqua, and A. serpentina, respectively. Exposure to beta-exotoxin was
      associated with an increase in the incidence of deformed pupae. The adult
      survivors from beta-exotoxin treatments showed no negative effects in terms of
      their longevity, fecundity, or egg eclosion (fertility). We conclude that the
      beta-exotoxin may have potential as a control agent for fruit fly pests.

PMID- 10582045
TI  - Phytoseiid mites on peppermint and effectiveness of Neoseiulus fallacis to
      control Tetranychus urticae (Acari: Phytoseiidae, Tetranychidae) in arid growing
      regions.
AB  - The humid-adapted species Neoseiulus fallacis (German) was the most common
      phytoseiid mite collected in either humid (> 100 cm annual rainfall) or arid (20
      45 cm annual rainfall) mint growing regions of Washington, Oregon, Montana,
      Idaho, and California during 1991-1995. In experimental field plots, this
      predator gave excellent biological control of Tetranychus urticae Koch on mint
      grown under arid conditions in central Oregon when evaluated by an insecticide
      check method or by the caging of mites. N. fallacis is effective as a predator in
      arid areas probably because regular irrigation creates a humid environment in the
      canopy. The selective miticide propargite, when used in combination with
      predators, was effective at reducing high spider mite populations to below the
      treatment threshold faster than did N. fallacis alone.

PMID- 10582046
TI  - Selection of a nucleopolyhedrovirus for control of Spodoptera frugiperda
      (Lepidoptera: Noctuidae): structural, genetic, and biological comparison of four
      isolates from the Americas.
AB  - Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae) is the principal
      pest of maize in tropical and subtropical regions of the Americas. Larvae of this
      species are susceptible to a nucleopolyhedrovirus (NPV) which has attracted
      interest as a potential biocontrol agent. Four strains of NPV isolated from
      infected S. frugiperda larvae in the United States, Nicaragua, and Argentina were
      subjected to a structural, genetic, and biological comparison to select a
      candidate isolate for use in biocontrol experiments in Mexico and Honduras. All
      isolates had an occlusion body polyhedrin protein of 32 kDa, but the virions of
      each isolate differed subtly in the pattern and abundance of certain structural
      polypeptides revealed by SDS-PAGE analysis. Restriction endonuclease analysis of
      viral DNA confirmed that these isolates were strains of a single virus species
      but showed that they were not genetically homogeneous; each isolate could be
      differentiated from the others using common restriction enzymes. Droplet feeding
      bioassays indicated that an isolate from Nicaragua (Sf-NIC) and an isolate from
      the United States (Sf-US) had the highest infectivity when tested against 2nd
      instars originating from a Honduran S. frugiperda colony. No significant
      differences were detected in the speed of kill of Sf-NIC (102.7 h), Sf-US (102.3
      h) and Sf-AR (103.4 h), whereas that of Sf-2 (97.3 h) was significantly shorter.
      Additional bioassays of the Sf-NIC isolate against 2nd to 6th instars
      demonstrated that LC50 values increased with larval stage from 2.03 x 10(5)
      OBs/ml for 2nd instars to 1.84 x 10(8) OBs/ml for 5th instars. The concentration
      required to elicit a lethal infection of 6th instars was so high that a reliable
      estimate of LC50 could not be obtained. The mean time to death for each stage
      challenged with the Sf-NIC isolate increased with instar from an average of 102.7
      h in 2nd instars to 136.9 h in 5th instars.

PMID- 10582047
TI  - Infectivity studies of a new baculovirus isolate for the control of the
      diamondback moth (Plutellidae: Lepidoptera).
AB  - This study describes a new baculovirus isolate recovered from infected larvae of
      the diamondback moth, Plutella xylostella (L.), and identified as a multiple
      nucleopolyhedrovirus (MNPV). The plaque purified isolate designated as PxMNPVCL3
      was found to be pathogenic to P. xylostella, Heliothis virescens (F.),
      Trichoplusia ni (Hubner), H. subflexa (Guenee), Helicoverpa zea (Boddie),
      Spodoptera exigua (Hubner), and S. frugiperda (J. E. Smith) larvae in decreasing
      order of susceptibility. The LC50 for diamondback moth, the most susceptible, was
      6 occlusion bodies (OB)/cm2, whereas the most resistant species, namely S.
      frugiperda, was 577 OB/cm2. PxMNPVCL3 was more pathogenic to diamondback moth by
      3-4 log cycles as compared with 2 broad-spectrum baculoviruses, namely Autographa
      california (alfalfa looper) MNPV and Anagrapha falcifera (celery looper) MNPV.
      The 3 baculoviruses were compared with each other and characterized by
      restriction endonuclease (REN) analysis, hybridization, and neutralization tests.
      Fragmentation profiles generated by REN showed that the 3 baculoviruses shared
      some fragments in common. Hybridization studies employing digoxigenin labeled
      PxMNPVCL3 DNA as a probe revealed the close but distinct relationship of these 3
      viruses. Neutralization tests confirmed the hybridization studies, namely that
      the 3 viruses although genetically similar are distinguishable from each other.

PMID- 10582048
TI  - Effect of temperature and the synergist piperonyl butoxide on imidacloprid
      toxicity to the cat flea (Siphonaptera: Pulicidae).
AB  - The toxicity of imidacloprid to cat fleas on glass was investigated at 20, 26,
      30, and 35 degrees C. Imidacloprid was most toxic to adult cat fleas at 35
      degrees C and to larvae at 20 degrees C. Piperonyl butoxide (PBO), a synergist,
      increased the relative potency of imidacloprid (1:5 imidacloprid:PBO) 16-fold at
      26 degrees C against adults, but had no effect at 35 degrees C. No synergism
      occurred in larvae at 20 degrees C, but addition of PBO (1:5 imidacloprid:PBO)
      doubled toxicity at 26 degrees C. PBO (1:5 imidacloprid:PBO) could possibly be
      used to synergize imidacloprid premise treatments (20-30 degrees C), but it is
      not likely to be effective in pet treatments because no synergism occurred in
      adult fleas at 35 degrees C (average fur temperature of tested cats and dogs).

PMID- 10582050
TI  - Resistance in sunflower and interaction with Bacillus thuringiensis for control
      of banded sunflower moth (Lepidoptera: Tortricidae).
AB  - Four sunflower accessions were compared with a susceptible check, hybrid '894',
      in the greenhouse to determine their resistance to the banded sunflower moth,
      Cochylis hospes Walsingham, and their interaction with Bacillus thuringiensis
      Berliner variety kurstaki. Antibiosis, expressed as lower larval weight, was
      detected in all of the accessions. In addition to being antibiotic, sunflower
      accession Ames 3291 was antixenotic to banded sunflower moth oviposition and
      exhibited an additional impact on larval weight when B. thuringiensis was
      applied. By itself, B. thuringiensis provided better control of banded sunflower
      moth than the resistance tested. However, banded sunflower moth-resistant
      sunflower would be a good option when B. thuringiensis or another insecticide is
      not applied, and it may prevent the economic threshold from being reached.

PMID- 10582049
TI  - Control of Boophilus annulatus (Acari: Ixodidae) on cattle using injectable
      microspheres containing ivermectin.
AB  - The efficacy of an injectable microsphere formulation of ivermectin for control
      of the cattle tick, Boophilus annulatus (Say), was tested on 2 groups of 6
      Hereford heifers held on separate 7-ha, tick-infested, buffel grass pastures.
      Cattle in one pasture were injected subcutaneously in the neck with a controlled
      release microsphere formulation of ivermectin at the rate of 2.4 mg AI/kg body
      weight; the other group was injected with carrier only. Beginning 4 wk after
      injection and continuing throughout the remainder of the test (16 wk), no
      engorged ticks (> or = 5.5 mm) were found on any of the treated cattle, whereas
      large numbers of engorged ticks were found on the untreated controls. During this
      period, a few ticks were recovered from untreated sentinel animals placed in the
      treatment pasture during 7-8 wk after treatment, but none were recovered from
      animals exposed from 11-12 wk or 14-15 wk. Large numbers of B. annulatus ticks
      were found on untreated sentinel cattle placed in the control pasture during
      these same periods. Although the cattle, pastures, and tick habitat were
      approximately equal, the treated cattle gained an average of 77 kg compared with
      an average of 42 kg for the control group. This technology offers a possible
      alternative to the current official program of dipping and vacating pastures for
      eradication of Boophilus sp. infestations from the quarantine zone in southern
      Texas. Larger scale testing is needed to determine the potential of the
      injectable microsphere formulation and to optimize its use in eradication or
      control strategies.

PMID- 10582051
TI  - Health priorities in SA.

PMID- 10582052
TI  - Professionals unite to help abused children.

PMID- 10582053
TI  - Co-operation to improve health in southern Africa.

PMID- 10582054
TI  - Action plan for rural health care.

PMID- 10582055
TI  - Patients to get rights Charter.

PMID- 10582056
TI  - New thoughts in the understanding of female urinary incontinence.

PMID- 10582057
TI  - Challenged by the small screen--responding to HIV-positive people on video in
      KwaZulu-Natal.

PMID- 10582058
TI  - Ruptured abdominal aortic aneurysm.

PMID- 10582059
TI  - My hysterectomy.

PMID- 10582060
TI  - Ultrasound training in South Africa.

PMID- 10582061
TI  - Human group C rotavirus identified in South Africa.

PMID- 10582062
TI  - Should hepatitis A vaccination be routinely given to children?

PMID- 10582063
TI  - Methylphenidate (Ritalin) use and abuse.

PMID- 10582064
TI  - The epidemiology of respiratory syncytial virus (RSV) infections in South African
      children.
AB  - OBJECTIVES: To review the incidence, outcomes and risk factors associated with
      respiratory syncytial virus (RSV) infection in South African children. DESIGN:
      Review of published literature and laboratory records. METHODS: Review of the
      published literature. Articles listed on MEDLINE with 'South African' or
      'children' and 'respiratory syncytial virus' or 'acute respiratory tract
      infections' as text words were retrieved. We analysed the data on respiratory
      virus activity from January 1990 to June 1996. Data were obtained from the
      National Institute for Virology database, which includes information on viral
      respiratory infections from the seven academic virology departments in South
      Africa. RESULTS: Acute respiratory tract infections cause approximately 8% of all
      deaths in the under-5 age group in South Africa. The published hospital-based
      incidence of RSV infection varies from 3% to 18%. Mortality rates in these
      studies were between 12% and 43%. Risk factors identified for severe RSV
      infection requiring hospitalisation were malnutrition, prematurity, age < 6
      months, vitamin A deficiency, environmental pollution and congenital heart
      disease. There is a seasonal peak in RSV cases, with the majority occurring in
      winter. CONCLUSIONS: Acute respiratory tract infections and RSV infections are an
      important cause of mortality and morbidity in young children in South Africa.
      However, currently available information from laboratory records and published
      South African literature is not sufficient to assess the impact of this
      infection. Age-specific incidence data in the 0-5-year age group are essential
      for the rational planning and implementation of future vaccine strategies, public
      health interventions and treatment of RSV infections.

PMID- 10582065
TI  - Evaluation of the infant at risk for neurodevelopmental disability.
AB  - BACKGROUND: Infants with neurodevelopmental abnormality need to start therapy
      early, and because of this they should be detected as soon as possible.
      Currently, no widely accepted method of early evaluation exists. OBJECTIVES: To
      assess and compare, in terms of predicting neurodevelopmental outcome at 1 year
      of age: (i) a perinatal risk rating (PRR); (ii) the Dubowitz Neurological
      Assessment (DNA); and (iii) the Infant Neuromotor Assessment (INA). DESIGN AND
      SETTING: A prospective neurodevelopmental follow-up study on graduates from the
      Groote Schuur Hospital (GSH) neonatal intensive care unit (NICU). SUBJECTS: A
      cohort of 130 consecutive NICU graduates were selected according to high-risk
      criteria. OUTCOME MEASURES: Each infant was examined at term gestational age on
      the DNA before discharge, and a PRR was allocated. Study infants were seen again
      at 18 weeks of age when an INA was done, and at 1 year of age a Griffiths
      Developmental Assessment and full neurological examination was carried out.
      RESULTS: All of the 130 infants assessed at term were seen at 18 weeks.
      Thereafter 5 were lost to follow-up and 2 died. The outcome for the remaining 123
      is known. CONCLUSIONS: Prediction of a normal outcome at 1 year of age was 96% on
      the DNA and 98% for the PRR, but for an abnormal outcome they predicted only 56%
      and 42%, respectively. The INA done at 18 weeks predicted a normal outcome at 1
      year in 99% of cases if 3 or less abnormal signs were present and an abnormal
      outcome in 82% of cases with 4 or more abnormal signs. Based on these findings a
      protocol for follow-up of these high-risk infants is suggested.

PMID- 10582066
TI  - Nephrotic syndrome in Namibian children.
AB  - BACKGROUND AND OBJECTIVES: Patterns of nephrotic syndrome vary between regions
      and countries, and influence approaches to management. In the mid-1970s the
      University of Stellenbosch became involved in providing tertiary care to Namibia,
      including a paediatric nephrology service. The aim of this study was to document
      the clinical, pathological and outcome features of nephrotic syndrome in Namibian
      children. SUBJECTS: Seventy black Namibian children with nephrotic syndrome were
      managed from 1975 to 1988. Sixty-eight renal specimens (67 biopsies and 1 autopsy
      specimen) were evaluated. RESULTS: Twenty-nine of the 70 children (41.4%) were
      hepatitis B virus (HBV) carriers, of whom 25 (86.2%) were male. Of the 29, 26 had
      predominantly membranous glomerulonephritis (MGN), 1 mesangiocapillary
      glomerulonephritis (MCGN), and 1 focal segmental glomerulosclerosis (FSGS); 1
      child in advanced renal failure was not biopsied. Five children (7.4%) showed
      minimal change disease (MCD), 11 (16.2%) FSGS and 15 (22.1%) diffuse mesangial
      proliferative glomerulonephritis (DMP). The remaining 10 children showed diffuse
      glomerulosclerosis (6), MCGN (3) and endocapillary proliferative GN (1). Four of
      the 5 children with MCD went into remission on immunosuppressive treatment. Of
      the 15 with DMP, 4 improved spontaneously and only 1 of those treated did not
      improve. Only 2 of those with FSGS improved on treatment. The children with HBV
      associated MGN and MCGN were offered symptomatic rather than specific treatment.
      Thirteen children presented with degrees of chronic renal failure. Eight are
      known to have died, 3 of relentless nephrotic syndrome and 4 (of whom 3 were HBV
      carriers) of end-stage renal failure. One child died of penicillin anaphylaxis.
      CONCLUSIONS: The pattern of nephrotic syndrome in black Namibian children
      differed greatly from the non-African pattern elsewhere in that MCD was uncommon
      and HBV-associated GN was the most common single group. The most frequent pattern
      of HBV-associated GN was MGN with some mesangiocapillary features showing marked
      male predominance. MCD and DMP were potentially treatable and could only be
      identified by biopsy. HBV carrier rates exert a major influence on the
      proportions of morphological subgroups of nephrotic syndrome in children. As
      these HBV carrier rates alter in future due to the influence of vaccination and
      urbanisation, the relative size of nephrotic subgroups seems likely to alter.

PMID- 10582067
TI  - Practical management of therapeutic diphenylhydantoin concentrations in children.
AB  - OBJECTIVE: Development of easy, practical methods for the management and
      optimisation of therapeutic diphenylhydantoin (DPH) concentrations in children.
      DESIGN: Investigation of DPH concentration profiles and pharmacokinetic
      parameters in children with poorly controlled epilepsy. Subsequent determination
      of individual-specific DPH maintenance dosage and volume of distribution data
      suitable for use in routine therapeutic concentration management procedures.
      SETTING: Department of Paediatrics and Child Health and Department of
      Pharmacology, University of Stellenbosch, Tygerberg Hospital. SUBJECTS: Children
      of both sexes between the ages of 4 and 12 years with poorly controlled epilepsy
      receiving DPH as sole medication. RESULTS: In all subjects evaluated epilepsy was
      unsatisfactorily controlled because of inadequate DPH dosage regimens. Individual
      specific maintenance dosage and volume of distribution data could be calculated
      for all individuals participating in the trial. The calculated data were suitable
      for use in routine management procedures and in no instance was it necessary to
      recalculate parameters in a 12-month follow-up period subsequent to evaluation.
      CONCLUSIONS: Therapeutic DPH concentration profiles can be managed satisfactorily
      in children in individual-specific DPH pharmacokinetic parameters are derived and
      skillfully applied.

PMID- 10582069
TI  - Endovascular intervention: a new beginning for vascular surgery, or ... the
      beginning of the end?

PMID- 10582068
TI  - Compliance of the respiratory system as a predictor for successful extubation in
      very-low-birth-weight infants recovering from respiratory distress syndrome.
AB  - OBJECTIVE: To develop additional criteria to predict for successful extubation of
      very-low-birth-weight infants recovering from respiratory distress syndrome.
      DESIGN: Prospective study. SETTING: Neonatal intensive care unit at a university
      teaching hospital. INTERVENTIONS: Infants ready for extubation according to
      clinical, ventilatory and blood gas criteria were studied. Before extubation,
      tidal volume (Vt), minute ventilation, respiratory rate/Vt and mean inspiratory
      flow were measured during two different ventilatory settings: (i) during
      intermittent mandatory ventilation (IMV); and (ii) while breathing spontaneously
      with endotracheal continuous positive airway pressure (CPAP). Tidal volume was
      obtained through electronically integrated flow measured by a hot-wire
      anemometer. Total respiratory compliance (Crs) was determined during IMV and was
      derived from the formula Vt/PIP-PEEP, where the difference between peak
      inspiratory pressure (PIP) and positive end-expiratory pressure (PEEP)
      represented the ventilator inflation pressure. MEASUREMENTS AND MAIN RESULTS:
      Each of 49 infants was studied once before extubation. 33 infants (67%) were
      successfully extubated and 16 (32.6%) required reintubation. Infants in the
      success and failure groups were matched for gestation, post-conceptional age,
      study weight and methylxanthine therapy at the time of study. Successful
      extubation was associated with a higher mean absolute Crs value (ml/cm H2O)
      specific Crs value (standardised for body length; ml/cm H2O/cm) compared with
      infants in whom extubation failed (0.67 v. 0.46; P = 0.01 and 0.018 v. 0.014; P =
      0.03, respectively). Analysis of ROC curves detected thresholds for Crs (0.5
      ml/cm H2O) and Vt (7 ml) for predicting successful extubation. An absolute Crs
      value 0.5 ml/cm H2O or more improved the likelihood of successful extubation when
      compared with clinical/ventilator and blood gas criteria. The likelihood of
      successful extubation was 81% if the Crs value was > or = 0.5 ml/cm H2O. A tidal
      volume of 7 ml or more was less sensitive in contributing to successful
      extubation (sensitivity 69%). The major causes for extubation failure included
      atelectasis (diffuse and/or localised) and the presence of a patent ductus
      arteriosus. CONCLUSIONS: In addition to following very precise ventilatory
      criteria for extubation, we found that bedside measurement of total respiratory
      system compliance added to the likelihood of extubation success in infants
      recovering from respiratory distress syndrome. Prospective studies are needed to
      validate the findings of this study.

PMID- 10582070
TI  - Fissure-in-ano, to divide or not to divide?
AB  - Anal fissure is one of the most common and painful proctological pathologies
      affecting mainly young individuals. The physiopathology in the development of a
      chronic anal fissure seems to be a combination of internal anal sphincter
      hypertonia and poor vascularization at the posterior midline. Treatment of acute
      fissures is conservative with supportive therapy, leading to healing in the
      majority of the patients. Open or closed lateral internal sphincterotomy is the
      treatment of choice for chronic anal fissures. In low pressure chronic fissures,
      sphincterotomy should be avoided and a V-Y island advancement flap may be an
      alternative procedure. Sphincterotomy can induce anal incontinence, a feared
      complication of this technique. Recent interest has developed in chemical
      sphincterotomy with local botulin toxin injections or glyceryl trinitrate
      application. Long-term follow-up is needed to evaluate these new therapeutic
      options.

PMID- 10582071
TI  - Cranial nerve injury after carotid surgery.

PMID- 10582072
TI  - The effect of pneumoperitoneum on bacterial clearance and RES functions in a
      model of E. coli peritonitis.
AB  - The use of laparoscopic surgery in peritonitis has increased rapidly. The present
      study examined the effects of pneumoperitoneum on bacterial clearance. Spraque
      Dawley rats were divided into six groups of seven animals. In groups 1 and 4,
      laparotomy with a midline incision was performed and 10(9) E. coli in a volume of
      1 ml inserted into the peritoneal cavity. Groups 2, 3, 5, 6 received an identical
      quantity of E. coli by intraperitoneal injection. Groups 3 and 6 received carbon
      dioxide pneumoperitoneum at a constant pressure of 5 mmHg for 60 minutes after
      intraperitoneal injection of E. coli. In one hour groups; the mean bacterial
      counts per lung from the E. coli injection with laparotomy group was
      significantly higher than for the E. coli injection with pneumoperitoneum group
      (p < 0.05). The mean bacterial counts per kidney in the E. coli injection with
      laparotomy group was higher compared with the E. coli injection and E. coli
      injection with pneumoperitoneum groups (p < 0.0001). There was statistically
      significant difference in quantitative bacteraemia between the E. coli injection
      with laparotomy group and the E. coli injection or E. coli injection with
      pneumoperitoneum groups (p < 0.05). In four-hour groups; the mean bacterial
      counts of lungs and liver-spleen were significantly higher in the E. coli
      injection with laparotomy group than in the E. coli injection and E. coli
      injection with pneumoperitoneum groups (p < 0.05 and p < 0.001 respectively). The
      quantitative bacteria was significantly higher in the E. coli injection with
      laparotomy group than in the E. coli injection and E. coli injection with
      pneumoperitoneum groups (p < 0.05). This study demonstrates that pneumoperitoneum
      impairs the clearance of bacteria from the peritoneal cavity in an experimental
      model of peritonitis. However, we could not detect the deleterious effects of
      pneumoperitoneum compared with laparotomy.

PMID- 10582073
TI  - The importance of magnetic resonance imaging in the diagnosis and treatment of
      diffuse lymphangioma.
AB  - In this study, we will investigate the importance of MRI in the diagnosis and
      treatment of diffuse lymphangioma. Twenty-nine patients with lymphangiomas were
      treated at the U.Z. Leuven between March 1988 and September 1997. They all
      underwent a total surgical excision of the lesion. A global recurrence rate of
      34.45% corresponds with a recurrence rate of 30.76% found in literature. In our
      study, a remarkable difference in recurrence rates is noticed between cystic
      hygroma (5/19 patients or 26.39%) and the more diffuse types of lymphangioma
      (5/10 patients or 50%). On three patients, preoperative MRI was performed. All
      these illustrate the important role of MRI in the diagnosis of lymphangioma,
      namely the characteristic appearance of the lesions on T1- and T2-weighted images
      and the better visualization of the lymphangioma extent. In line with the high
      recurrence rates of diffuse lymphangiomas and the advantages of MRI of these
      lesions, the role of MRI in the treatment of diffuse lymphangiomas is discussed.

PMID- 10582074
TI  - Factors influencing patency of infrainguinal bypasses with
      polytetrafluoroethylene.
AB  - This retrospective study was undertaken to investigate the patency and limb
      salvage rates of 308 PTFE infrainguinal bypasses in 272 patients over a 5-year
      period. In addition a univariate analysis was performed to identify factors that
      could predict the outcome of these operations. Long-term survival was 83% and 50%
      at one and five years respectively. For the whole series the primary cumulative
      patency at one and five years was 70% and 41% respectively. Graft revision for
      failed or failing grafts resulted in secondary patency rates of 78% and 43% for
      the same periods. The limb salvage rates were 93% and 84% at one and five years.
      Patency rates showed no statistical significant difference for gender, age at
      operation or the use of a venous cuff at the distal anastomosis. Although there
      was a tendency towards better results for above the knee operations, this
      difference failed to achieve statistical significance. Only redo operations were
      associated with a significant worse outcome.

PMID- 10582075
TI  - Aorto-bi-femoral bypass for aorto-iliac occlusive disease using a videoscopic
      assisted retroperitoneal approach--a preliminary report.
AB  - In recent years laparoscopic techniques have been adapted for application in
      vascular surgery. Since 1993 several authors have published preliminary results
      of complete or videoscopic-assisted reconstructions of the abdominal aorta. The
      aim of this retrospective study was to report our initial results with the
      retroperitoneal videoscopic-assisted technique of aorto-bifemoral grafting (AFG)
      in ten patients (age 45-71). In one case, conversion into classic reconstruction
      was necessary because the aorta was to heavily calcified. The duration of the
      procedures varied between 230 and 390 minutes. The length of the incision ranged
      between 6 and 9 cm. The hospital stay varied between 5 and 13 days. One patient
      developed gout, and a left sided, temporary ureteral stent was necessary in
      another because of hydronephrosis. It is confirmed that video-assisted AFG is
      feasible. However, whether this technique is truely less invasive, will have to
      be demonstrated by randomized, prospective studies, once the equipment and
      instruments have sufficiently been developed and a technique of choice finalized.

PMID- 10582076
TI  - Incidence of invasive versus non-invasive carcinoma in comparing palpable and non
      palpable solid breast lesions.
AB  - A retrospective study was done of all patients with a suspicious mammographic
      breast lesion surgically biopsied in our institution within the last 5 years.
      Incidence of invasive versus non-invasive carcinoma and stage at presentation
      (according to TNM classification system) of palpable and non-palpable lesions
      were compared. We found a significant difference of non-invasive carcinoma in non
      palpable and palpable cancers: 42.2% versus 4.3% (p < 0.001). Patients with a non
      palpable invasive carcinoma presenting at stage I (i.e. pT1 with no axillary
      metastasis) rated significantly higher compared to those with palpable lesions
      51.8% versus 9.4% (p < 0.001). The true positive biopsy rate is 30%. As low as
      10% has been considered reasonable. We have a total of 56% carcinomas detected on
      all biopsies: 30% for non-palpable lesions and 66.8% for palpable lesions. A more
      aggressive approach towards screening and biopsy of breast lesions might increase
      early detection of carcinoma and so improve survival.

PMID- 10582077
TI  - Laparoscopic management of neuroendocrine tumours of the pancreas.
AB  - Neuroendocrine tumours of the pancreas are rare but can be fatal due to excessive
      secretion of regulatory peptides. The localization of these small tumours can be
      difficult while open surgical treatment is associated with a relatively high
      morbidity. Two cases are presented where endocrine tumours of the pancreas were
      successfully removed by laparoscopy. In the surgical treatment of endocrine
      pancreatic tumours, the use of laparoscopic techniques can provide a valuable
      means for localizing the tumour while improving the patient's comfort and
      decreasing operative morbidity.

PMID- 10582078
TI  - Perforation due to ileocaecal tuberculosis.
AB  - A 40-year-old male patient was admitted in the Intensive Care Unit with
      complicated pulmonary tuberculosis. After 4 days he developed an acute abdomen
      with free air as demonstrated on plain abdominal films. A laparotomy was
      performed and an ileal perforation was found, located just before the ileocaecal
      valve. A right hemicolectomy was carried out and the resected specimen was send
      for further patho-anatomical examination. Our suspicion of ileocaecal perforation
      due to tuberculosis was confirmed. Despite further extensive medical treatment,
      the patient died 15 days after admission to the hospital. At autopsy, the cause
      of death was confirmed as being due to fulminant pulmonary tuberculosis.

PMID- 10582079
TI  - Persistent mullerian duct syndrome with torsion of an intra-abdominal seminoma.
AB  - Persistent Mullerian Duct Syndrome (PMDS) is a particular form of male
      pseudohermaphroditism. Due to the absence or inactivity of Mullerian Inhibiting
      Substance (MIS), no regression is observed of the Mullerian ducts in a
      genotypical and phenotypical male individual. This leads to the development of
      fallopian tubes, uterus and proximal vagina. The testes often lie intra
      abdominally and are exposed to malignant degeneration. A case is described in
      which the diagnosis of PMDS was made by laparotomy for an acute abdomen, caused
      by torsion of a seminoma.

PMID- 10582080
TI  - Left middle lobe resection for bronchiectasis in Kartagener's syndrome.
AB  - We report the case of a young girl with Kartagener's syndrome who suffered from
      severe bronchiectasis confined to the left middle lobe. Due to chronic
      abscedation which failed to respond to medical therapy, resection of the left
      middle lobe was performed. Although there was an initial clinical benefit,
      afterwards she had to be treated again for recurrent infectious exacerbations.

PMID- 10582081
TI  - Abdominal aortic coarctation with splanchnic arterial occlusion.
AB  - Abdominal aortic coarctation is found in only 2% of aortic coarctation and is
      usually manifested by renovascular hypertension. Splanchnic arterial occlusive
      lesions occur in 22% of these patients and are exceptionally symptomatic. We
      present a case report of a young patient with abdominal aortic coarctation
      causing hypertension and visceral angina. The aetiopathogeny and treatment are
      discussed.

PMID- 10582082
TI  - Popliteal artery entrapment syndrome: specific aspect.
AB  - A case of popliteal artery entrapment syndrome (PAES) is reported. A non smoker,
      63-year-old man, consulted for severe claudication of the lower limb, with a
      sudden onset. There was no past history of vascular disease. Neither the
      arteriography nor the arterial doppler led to definite diagnosis. In our case,
      only the C.T. scan was contributive to the diagnosis. The age, 63, at which this
      abnormality became symptomatic, the abrupt appearance of ischaemic symptoms and
      the embryologic type of the arterial stenosis were particular. The surgical
      management was the only therapeutic option.

PMID- 10582083
TI  - New insights into glucocorticoid and mineralocorticoid signaling: lessons from
      gene targeting.

PMID- 10582084
TI  - Orphan nuclear receptors: an emerging family of metabolic regulators.

PMID- 10582085
TI  - Nuclear receptor coactivators.

PMID- 10582086
TI  - Cytokines and STAT signaling.

PMID- 10582087
TI  - Coordination of cAMP signaling events through PKA anchoring.

PMID- 10582088
TI  - G protein-coupled extracellular Ca2+ (Ca2+o)-sensing receptor (CaR): roles in
      cell signaling and control of diverse cellular functions.

PMID- 10582089
TI  - Pancreatic islet development.

PMID- 10582090
TI  - Genetic analysis of androgen receptors in development and disease.

PMID- 10582091
TI  - An antiprogestin regulable gene switch for induction of gene expression in vivo.

PMID- 10582092
TI  - Steroid receptor knockout models: phenotypes and responses illustrate
      interactions between receptor signaling pathways in vivo.

PMID- 10582093
TI  - Impact of yellow fever on the developing world.
AB  - Yellow fever (YF) has remained a disease of public health importance since it was
      first described in the fifteenth century. At different periods in human history,
      YF has caused untold hardship and indescribable misery among populations in the
      Americas, Europe, and Africa. It brought economic disaster in its wake,
      constituting a stumbling block to development. Yellow fever is an arboviral
      infection with three epidemiological transmission cycles between monkeys,
      mosquitoes, and humans. It is an acute infectious disease characterized by sudden
      onset, with two phases of development separated by a short period of remission.
      The clinical spectrum of YF varies from a very mild, nonspecific, febrile illness
      to a fulminating, sometimes fatal disease with pathognomonic features. In severe
      cases, jaundice and bleeding diathesis with hepatorenal involvement are common.
      The fatality rate of severe YF is 50% or higher. Despite landmark achievements in
      the understanding of the epidemiology of YF and the availability of a safe,
      efficacious vaccine, YF remains a major public health problem in both Africa and
      South America, where annually the disease affects an estimated 200,000 persons,
      causing an estimated 30,000 deaths. Since the 1980s epidemics of YF in Africa
      have affected predominantly children under the age of 15 years. The failure to
      control YF arises from a misapplication of public health strategies and
      insufficient political commitment by governments in YF endemic areas, especially
      in Africa, to control the disease.

PMID- 10582094
TI  - Impact of dengue/dengue hemorrhagic fever on the developing world.

PMID- 10582095
TI  - Human immunodeficiency viruses in the developing world.
AB  - AIDS has become a major burden in developing countries. At present, more than 90%
      of new HIV infections are emerging in Asia and Africa. Particularly ominous is
      the epidemic due to HIV-1 C in southern Africa, where about 25% of adults in
      several countries are infected. Although most of its spread apparently occurred
      during the 1990s, HIV-1 C currently accounts for one-half of the infections in
      the world. Both HIV-2, which is less virulent than HIV-1, and HIV-1 apparently
      spread to the human population from nonhuman African primates during the
      twentieth century. HIV-1 infection is usually lethal in the absence of
      antiretroviral therapy, but clinical disease occurs only after an induction
      period of several years. Some subtypes of HIV-1, such as C, E, and A, appear to
      be transmitted more efficiently than HIV-1 B, which is the major subtype in the
      United States and Europe. Molecular evolutionary changes that include receptor
      affinity, mediated by the env gene, and increased transcriptional activation,
      mediated by changes in the LTR and the tat gene, may account for some of the
      changes in transmission. Current therapies are prohibitively expensive for use in
      adults in most developing countries, although drugs for maternal-to-infant
      transmission are becoming accessible. A vaccine for HIV is desperately needed for
      the developing world.

PMID- 10582096
TI  - Rinderpest: the disease and its impact on humans and animals.
AB  - Rinderpest is an ancient plague of cattle and other large ruminants, with
      descriptions of its effects dating back to Roman times. It is caused by a
      morbillivirus closely related to human measles virus. Although a very effective
      vaccine is available, it is heat labile, and logistical and financial problems
      hamper its delivery to the remote areas of Africa and Asia where enzootic foci
      remain. Periodic epizootics emerge from these foci and spread into neighboring
      areas, mainly as a result of uncontrolled livestock movement and trading. This is
      particularly true during wars or civil disturbances when normal veterinary
      controls do not operate. The disease continues to cause devastating economic
      losses in domestic livestock in areas of the world where it remains endemic.

PMID- 10582097
TI  - Foot-and-mouth disease and international development.

PMID- 10582098
TI  - Plant virus disease problems in the developing world.

PMID- 10582099
TI  - Functional cDNA clones of the Flaviviridae: strategies and applications.

PMID- 10582100
TI  - Reverse genetics of picornaviruses.

PMID- 10582101
TI  - Reverse genetics of nodaviruses.

PMID- 10582102
TI  - Reverse genetics of the largest RNA viruses.

PMID- 10582103
TI  - Genetic engineering of influenza and other negative-strand RNA viruses containing
      segmented genomes.

PMID- 10582104
TI  - Redesign and genetic dissection of the rhabdoviruses.

PMID- 10582105
TI  - Reverse genetics of the Paramyxoviridae.

PMID- 10582106
TI  - Reverse genetics of dsRNA bacteriophage phi 6.

PMID- 10582107
TI  - Rescue systems for dsRNA viruses of higher organisms.

PMID- 10582108
TI  - Control of tobamovirus infections via pathogen-derived resistance.

PMID- 10582109
TI  - Applications of in situ hybridization techniques in the diagnosis of chronic
      sinusitis.
AB  - The clinical significance of positive bacterial cultures in chronic sinusitis is
      often difficult to assess. Contaminants from surface colonization of the sinus
      mucosa may be difficult to distinguish from true intramucosal or bone
      involvement. Furthermore, tissue Gram stains are frequently unable to demonstrate
      the presence of bacteria in tissue despite endoscopic evidence of active
      sinusitis. In situ hybridization (ISH) techniques using bacterial rRNA probes
      were applied to evaluate the presence of intramucosal and intraosseous bacteria
      in chronic sinusitis surgical specimens. A total of 22 specimens of chronically
      inflamed human ethmoid bone were evaluated by ISH and by Gram stain. In three
      specimens, ISH identified bacterial rRNA within sinus mucosa and mucin. Notably,
      in these three ISH-positive specimens, Gram stain was negative in two. No
      specimen showed evidence of bacterial rRNA within bone. These preliminary results
      suggest that in situ hybridization may be a useful adjunct to current methods of
      detecting microorganisms within chronically infected sinus tissue.

PMID- 10582110
TI  - Increased expression of IL-4, IL-5, IFN-gamma, IL-6, IL-8, and TGF-beta mRNAs in
      maxillary mucosa of patients with chronic sinusitis.
AB  - This study aimed to investigate expression of various cytokine mRNAs, including
      IL-6, IL-8, TGF-beta, IL-4, IL-5, and IFN-gamma in maxillary sinus mucosa of
      patients with chronic sinusitis. Maxillary sinus mucosae of six patients with
      chronic sinusitis and turbinate mucosae of six healthy subjects were obtained. We
      performed RT-PCR and Southern blot to examine gene expression of the cytokines IL
      6, IL-8, TGF-beta, IL-4, IL-5, and IFN-gamma in maxillary sinus mucosa and
      compared the results with cytokine gene expressions in normal turbinate mucosa.
      IL-6, IL-8, TGF-beta, IL-4, IL-5, and IFN-gamma mRNAs were expressed more
      frequently in maxillary sinus mucosa from patients with chronic sinusitis than in
      normal turbinate mucosa. All the maxillary sinus mucosa specimens revealed
      relatively higher mean density ratio for each cytokine investigated than did
      normal turbinate mucosa. IL-6, IL-8, TGF-beta, IL-4, IL-5, and IFN-gamma mRNAs
      were expressed simultaneously in maxillary sinus mucosa of chronic sinusitis.
      These cytokines may be responsible for recruitment of inflammatory cells and for
      mucosal thickening in chronic sinusitis, and thus chronicity of the disease.

PMID- 10582111
TI  - Correlation of allergy and severity of sinus disease.
AB  - Allergy is an important consideration in the evaluation of patients with
      rhinosinusitis. Several studies have addressed staging systems for rhinosinusitis
      based on the extent of disease present on computed tomography (CT) scanning. The
      severity and extent of sinus disease present on CT imaging helps guide decisions
      regarding medical and surgical treatment options. This study evaluates the
      severity of sinus disease in allergic and nonallergic patients. A total of 42
      patients at our institution underwent both modified RAST and coronal sinus CT
      scan in the evaluation of their rhinosinusitis symptoms. A single, blinded staff
      neuroradiologist staged all 42 CT scans using the Lund-Mackay staging system.
      None of the patients had undergone sinus surgery. Age, sex, co-morbidities,
      asthma, smoking, RAST score, total IgE, and CT staging score were analyzed.
      Allergic patients were found to have a higher CT scan score (mean score = 12)
      when compared to nonallergic patients (mean score = 6), indicating more extensive
      sinus disease (p = 0.03). We conclude that allergy is a significant factor in the
      development of rhinosinusitis, and allergic patients are more likely to
      demonstrate advanced disease on CT scan when compared to nonallergic patients.

PMID- 10582112
TI  - The relationship of nasal polyps, infection, and inflammation.
AB  - The role of infection as cause or effect in nasal polyps is debated. In
      experimentally induced sinusitis in rabbits, polyps are frequent. The initial
      polyp formation sequence involves multiple epithelial disruptions with
      proliferating granulation tissue. Regenerating epithelial branches spread into
      the underlying connective tissue, where intraepithelial microcavities give rise
      to a polyp body from the adjacent mucosa. Clinical as well as experimental
      studies indicate that nasal polyp formation and growth are activated and
      perpetuated by an integrated process of mucosal epithelium, matrix, and
      inflammatory cells, which in turn may be initiated by both infectious and
      noninfectious inflammation. The complexity of the pathophysiologic events in
      nasal polyposis is reinforced by the finding that epithelial desquamation,
      combined with infection or inflammation, will initiate polyp formation. Systemic
      glucocorticosteroids inhibit polyp formation as well as growth of pathogenic
      bacteria in the sinuses of rabbits with experimental infection. Therapeutic use
      of corticosteroids in polyp disease, combined with antibiotics or surgery, should
      be modified in relation to long-term progression, intensity variations, and
      predisposing conditions.

PMID- 10582113
TI  - Long-term efficacy of our surgical approach to turbinate hypertrophy.
AB  - In our department, chronically enlarged inferior turbinates (not responding to
      adequate medical therapy) are treated with the CO2-laser or by partial inferior
      turbinoplasty. In this work, the latter technique is described and the short- and
      long-term results (up to 9 years of follow-up) are evaluated. Relief of nasal
      obstruction was reported by 93.5% of the patients. There was a good correlation
      between this success rate and the objective measurements of the nasal resistance
      by active anterior rhinomanometry. Rhinorrhea or postnasal drip was still present
      in 32.5%. Atrophic changes of the nasal mucosa were not observed in any of the
      patients. Early postoperative epistaxis was found in 6.5% of the patients. Late
      postoperative epistaxis did not occur.

PMID- 10582114
TI  - The effects of adenoid hypertrophy and subsequent adenoidectomy on pediatric
      nasal airway resistance.
AB  - To investigate how adenoid hypertrophy and subsequent adenoidectomy affect
      pediatric airway resistance, we developed a prospective controlled study. Fifty
      children, aged 3 to 12 years, diagnosed with adenoid hypertrophy and selected for
      adenoidectomy, preoperatively had their nasal airway resistance assessed by
      active anterior rhinomanometry. Twenty-five of these children were subsequently
      followed up postoperatively, undergoing nasal resistance evaluations at 1 month,
      3 months, 6 months, and 12 months. Another 25 children, without chronic upper
      airway obstruction symptoms, were enrolled as a control group, and their airway
      resistance was assessed in the same fashion. We concluded that the children
      selected for adenoidectomy, compared to the control group and before surgery, had
      mean resistance values up to two- to threefold higher, in both untreated and
      decongested nose states. Surgery was found to dramatically reduce airway
      resistance, but only in children under the age of seven. However, the
      postoperative values still tended to remain higher than the control subjects
      results. If in a significant number of children the operation failed in
      completely resolving their complaints, no pre-operative rhinomanometric pattern
      could be found to specifically relate to a complete surgical success.

PMID- 10582115
TI  - Endonasal laser-assisted dacryocystorhinostomy.
AB  - Dacryocystorhinostomy is a procedure that is performed to allow drainage of tears
      from the lacrimal sac directly into the nasal cavity. Endonasal telescopes
      facilitate performance of this operation with better visualization and decreased
      morbidity. We present our experience with endoscopic laser-assisted DCR. In the
      last 31 months, we have performed 31 procedures on 23 patients with either the
      holmium:YAG laser or the argon:HGM laser. We have a 97% overall success rate with
      a mean follow-up of 16 months. Our series includes both adult and pediatric
      patients as well as five revision procedures after failed external DCR. We
      present our technique, results, and the reasons for our change in laser delivery
      systems. Most importantly, we discuss the technical factors that contribute to
      our overall success. These include a large rhinostomy size, simultaneous
      correction of intranasal and/or sinus pathology, the avoidance of laser use
      within the lacrimal sac, and close postoperative monitoring with intranasal
      debridement. We conclude that endoscopic laser-assisted DCR is a better
      alternative to standard external DCR because it avoids a cutaneous scar,
      excessive tissue injury, and postoperative morbidity.

PMID- 10582116
TI  - Changes in nasal resistance and nasal geometry using pressure and acoustic
      rhinometry in a feline model of nasal congestion.
AB  - This is the first report describing the use and pharmacological characterization
      of nasal patency by both pressure rhinometry and acoustic rhinometry (AcR) in an
      experimental cat model of nasal congestion. In pressure rhinometry studies,
      aerosolized compound 48/80 (0.1-3.0%), a mast cell liberator, increased nasal
      airway resistance (NAR) 1.2 +/- 0.6, 5.8 +/- 0.5, 8.6 +/- 1.1 and 7.9 +/- 1.5
      cmH2O.L/minute, respectively. Increases in NAR produced by compound 48/80 were
      associated with a 395% increase in histamine concentration found in the nasal
      lavage fluid. Pretreatment with the alpha-adrenoreceptor agonist,
      phenylpropanolamine (PPA; 0.1-3.0 mg/kg, i.v.), and the NO synthetase inhibitor,
      NG-nitro-L-arginine (L-NAME; 10 mg/kg, i.v.) attenuated the increases in NAR
      produced by compound 48/80. The histamine H1 antagonist chlorpheniramine (1.0
      mg/kg, i.v.) and the H2 antagonist, ranitidine (1.0 mg/kg, i.v.) had no
      decongestant activity. Also without decongestant activity were the muscarinic
      antagonist atropine, the cyclooxygenase inhibitor indomethacin, and the 5-HT
      blocker methysergide. Aerosolized histamine (0.1-1.0%) also produced a dose
      dependent increase in NAR. In studies using acoustic rhinometry (AcR), intranasal
      application of compound 48/80 (0.1-1.0%) elicited pronounced decreases in nasal
      cavity volumes and minimum cross-sectional area (Amin). Pretreatment with PPA (3
      mg/kg, i.v. or 10 mg/kg, p.o.) attenuated the decreases in nasal volume and Amin.
      The effects of topical intranasal histamine (0.1-1.0%) on nasal geometry were
      similar to compound 48/80. We conclude that the cat is a useful model for
      evaluating the pharmacological actions of potential nasal decongestants.
      Furthermore, we also conclude that AcR is a useful method for noninvasive
      assessment of nasal patency in a preclinical setting.

PMID- 10582117
TI  - Breathe Right nasal strips and the respiratory disturbance index in sleep related
      breathing disorders.
AB  - This investigation assesses the effects of Breathe Right nasal strips on the
      respiratory disturbance index (RDI) measured by polysomnography in patients
      suffering from obstructive sleep apnea and snoring. The positive effect of these
      strips on nasal ventilation was shown in earlier studies. Twenty-six patients
      with an RDI higher than 10 in an initial measurement underwent a second
      preoperative polysomnography with Breathe Right nasal strips in place. Nineteen
      of these 26 patients showed reduction of RDI during the second night of
      polysomnography using the nasal strips, indicating that nasal obstruction seems
      to be a predominant factor in the etiology of snoring and apnea in these
      individuals. Demographic data, medical history, rhinoscopy, clinical assessment
      of pharyngeal obstruction (Mueller's maneuver), as well as anterior
      rhinomanometry and acoustic rhinometry were used to identify typical findings
      correlating with a positive effect of the Breathe Right nasal strips on the RDI:
      1. Hyperplasia or hypertrophy of the lower turbinates, septal deviation, and/or
      allergic rhinitis. 2. None or only minor pharyngeal obstruction. 3. Age less than
      55 years. If a positive effect is seen during polysomnography with the strips in
      place, patients will most likely profit from an improvement of nasal ventilation.
      This may help to target more effectively septal or turbinate surgery if
      applicable. In other cases, if a significant RDI reduction is obtained by the use
      of the nasal strips, they could also offer a noninvasive modality of treatment,
      especially since the high degree of co-morbidity in this group of patients can
      sometimes make a surgical approach less favorable.

PMID- 10582118
TI  - Combined histamine H1 and H3 receptor blockade produces nasal decongestion in an
      experimental model of nasal congestion.
AB  - We studied the pharmacological actions of combined histamine H1/H3 receptor
      blockade on the increase in nasal airway resistance (NAR) and decrease in nasal
      cavity volume produced by nasal exposure to compound 48/80, a mast cell
      degranulator. In the anesthetized cat compound 48/80 (1%) produced a maximum
      increase in NAR of 9.1 +/- 0.7 cmH20.L/minute. The increase in NAR in animals
      pretreated with a combination of the H1 antagonist, chlorpheniramine (CTM; 0.8
      mg/kg i.v.) and increasing doses of the H3 antagonist, thioperamide (THIO; 1.0,
      3.0, and 10.0 mg/kg i.v.) were 6.1 +/- 2.1, 4.2 +/- 1.0 and 2.2 +/- 0.7
      cmH20.L/minute, respectively. A second H3 antagonist, clobenpropit (CLOB; 0.03,
      0.3, and 1.0 mg/kg i.v.) combined with CTM (0.8 mg/kg i.v.) also inhibited the
      nasal effects of compound 48/80. When the nonsedating H1 antihistamine,
      loratadine (3.0 mg/kg i.v.), was substituted for CTM, it also reduced nasal
      congestion when given in combination with THIO (10 mg/kg i.v.). In contrast,
      treatment with CTM (1.0 mg/kg i.v.) and the H2 antagonist, ranitidine (RAN; 1.0
      mg/kg i.v.) were without activity. Loratadine, CTM, CLOB, RAN, or THIO
      administered alone were inactive. The alpha-adrenergic agonist,
      phenylpropanolamine (PPA; 1.0 mg/kg i.v.) demonstrated decongestant effects, but
      in contrast to H1/H3 blockade, PPA produced a significant hypertensive effect.
      Using acoustic rhinometry (AcR) we found that combined i.v. CTM (1.0 mg/kg) and
      THIO (10 mg/kg) and combined oral CTM (10 mg/kg) and THIO (30 mg/kg) blocked the
      decrease in nasal cavity volume produced by intranasal compound 48/80 (1%, 50
      microL). We conclude that combined H1/H3 histamine receptor blockade enhances the
      efficacy of an H1 antagonist by conferring decongestant activity to the H1
      antihistamine. We propose that the decongestant activity of combined H1/H3
      blockade may provide a novel approach for the treatment of allergic nasal
      congestion without the hypertensive liability of current therapies.

PMID- 10582119
TI  - Normal adult values, diurnal variation, and repeatability of nasal nitric oxide
      measurement.
AB  - Reports of elevated nasal nitric oxide (NO) levels in allergic rhinitis suggest
      that nasal NO levels could be a valuable marker of upper airway inflammation,
      provided that the reproducibility of nasal NO measurement is acceptable. The aims
      of this study were to evaluate the precision with which nasal NO levels can be
      measured at single point in time, and to quantify within-day and between-day
      variation. Nasal NO was measured using a modified chemiluminescence analyzer.
      Population data were normally distributed, as judged by testing for skewness and
      kurtosis. NO levels were not related to age or gender, and there was no evidence
      of diurnal variation. Sampling rates of 250 mL/minute and 500 mL/minute at a
      single point in time had acceptable reproducibility (coefficients of variation
      10.2% and 6.6%, respectively). However, within-day variation (coefficient of
      variation 13.4%) and between-day variation (coefficient of variation 11.8%), at a
      sampling rate of 500 L/minute, were substantially higher. These findings
      highlight the importance of taking measurement variation into account, in the
      interpretation of NO levels, in clinical research and, potentially, in routine
      practice. In individual patients, an alteration of 20-25% in NO levels is
      required, to ensure that change is genuine and not ascribable to the noise of
      measurement.

PMID- 10582120
TI  - Acoustic rhinometry of the oriental nose.
AB  - Most studies have established normal values for acoustic rhinometric (AR)
      analysis of the nasal passage based on a primarily caucasian or mixed population.
      Because consistent anatomic differences do occur in anthropomorphic measurements
      of the nose of different races, AR analysis was performed on an Asian population
      to determine whether differences occurred in the minimum cross-sectional area
      (MCA). AR with expanded testing was performed on a non-Asian control group and an
      Asian study population containing 28 subjects, with 56 half-cavities (F: 20; M:
      8; age range 21-58), including 16 Vietnamese, 8 Korean, 4 Thai, all of whom had
      physically typical mesorrhine noses. In the Asian population, the mean MCA of
      each half-cavity was 0.56 +/- 0.16 cm2, and 39.3% of subjects had significant
      asymmetry between their two half-cavities. The mean MCA increased to 0.67 +/-
      0.12 cm2 after the placement of a Breathe Right Strip Dilator (BRSD) over the
      nasal bridge, which was a significant increase in 32% of subjects, and to 0.68 +/
      0.14 cm2 after the application of 1% Neosinephrine, a significant increase in
      34% of those tested compared to the resting state. The combination of BRSD and
      Neosinephrine produced an MCA of 0.72 +/- 0.11 cm2, which was a statistically
      significant increase in 24 half-cavities (43%). Compared to our non-Asian
      population, the Asian group had fewer subjects with significant asymmetry (39%
      versus 59%) before expanded testing and fewer responders to BRSD (48% versus
      79%).

PMID- 10582121
TI  - The septal mucosa decongests with naphazoline: a study of mucosal dynamics with
      sonography.
AB  - A new method using B-mode and power-Doppler-mode (pD) sonography for the
      investigation of changes in nasal mucosa swelling and perfusion was developed.
      The effect of naphazoline (0.25 mg/mL) on the nasal mucosa was visualized and
      recorded in 1-minute intervals in 40 patients. The effect of normal saline
      solution was studied in 27 healthy volunteers. The decongestant and normal saline
      were applied by flooding the anterior nasal cavity. A computer program
      automatically quantified pD color information. Normal saline solution induced a
      4.8 +/- 2.4% increase in perfusion (+/- SEM, n.s.) after 5 minutes. In the
      naphazoline group, changes in stereometry were measured on B-mode-sequences in 24
      (60%) and perfusion changes in 24 participants (60%). In 16 of 40 patients (40%),
      both stereometry and perfusion were analyzed. After 10 minutes, the septum and
      inferior turbinate mucosa thickness were reduced by 17 +/- 2.8% (p < 0.001) and
      25 +/- 2.6% (p < 0.001). Perfusion of the septum and inferior turbinate mucosa as
      visualized with pD-sonography decreased by 33 +/- 3.3% (p < 0.001). The reduction
      of bloodflow induced by naphazoline as visualized with pD-sonography is within
      the range of perfusion changes found in LDF and Xenon clearance studies.
      Decongestion of the septum mucosa demonstrates erectile properties of the septum,
      which may contribute to the increase of nasal patency after nasal decongestion.

PMID- 10582122
TI  - Glutamine and the immune system.
AB  - Glutamine is utilised at a high rate by cells of the immune system in culture and
      is required to support optimal lymphocyte proliferation and production of
      cytokines by lymphocytes and macrophages. Macrophage-mediated phagocytosis is
      influenced by glutamine availability. Hydrolysable glutamine dipeptides can
      substitute for glutamine to support in vitro lymphocyte and macrophage functions.
      In man plasma and skeletal muscle glutamine levels are lowered by sepsis, injury,
      burns, surgery and endurance exercise and in the overtrained athlete. The lowered
      plasma glutamine concentrations are most likely the result of demand for
      glutamine (by the liver, kidney, gut and immune system) exceeding the supply
      (from the diet and from muscle). It has been suggested that the lowered plasma
      glutamine concentration contributes, at least in part, to the immunosuppression
      which accompanies such situations. Animal studies have shown that inclusion of
      glutamine in the diet increases survival to a bacterial challenge. Glutamine or
      its precursors has been provided, usually by the parenteral route, to patients
      following surgery, radiation treatment or bone marrow transplantation or
      suffering from injury. In most cases the intention was not to stimulate the
      immune system but rather to maintain nitrogen balance, muscle mass and/or gut
      integrity. Nevertheless, the maintenance of plasma glutamine concentrations in
      such a group of patients very much at risk of immunosuppression has the added
      benefit of maintaining immune function. Indeed, the provision of glutamine to
      patients following bone marrow transplantation resulted in a lower level of
      infection and a shorter stay in hospital than for patients receiving glutamine
      free parenteral nutrition.

PMID- 10582123
TI  - Ion permeation properties of a cloned human 5-HT3 receptor transiently expressed
      in HEK 293 cells.
AB  - Human 5-HT3 receptors expressed in HEK 293 cells were studied using patch-clamp
      techniques. The permeability ratios of cations to Na+ were Li+, 1.16; K+, 1.04;
      Rb+, 1.11; Cs+, 1.11; NMDG+, 0.04; Ca2+, 0.49, and Mg2+, 0.37. The permeability
      sequence of the alkali metal cations was Li+ > Rb+ = Cs+ > K+ > Na+. Increased
      external concentrations of Ca2+ or Mg2- decreased 5-HT-induced currents at all
      potentials tested in a voltage-independent manner. The single-channel conductance
      of human 5-HT3 receptors measured by fluctuation analysis of whole-cell currents
      was 790 +/- 100 fS. Differences in the basic properties of 5-HT3 receptors
      between species may explain interspecies differences in pharmacological
      properties.

PMID- 10582124
TI  - Novel glutathione analogues containing the dithiol and disulfide form of the Cys
      Cys dyad.
AB  - The glutathione analogue gamma-(H-Glu-OH)-Cys-Cys-OH (5), containing the 8
      membered disulfide ring -Cys-Cys replacing the native-Cys-Gly fragment, has been
      synthesized and characterized together with its reduced dithiol form gamma-(H-Glu
      OH)-Cys-Cys-OH (6).

PMID- 10582125
TI  - Developmental aspects of polyamine-oxidizing enzyme activities in the mouse
      kidney. Effects of testosterone.
AB  - In the present study developmental patterns of renal polyamine-oxidizing enzymes
      polyamine oxidase (PAO) and diamine oxidase (DAO) in male and female ICR mice
      were demonstrated. The effects of testosterone (10 micrograms/100g body weight)
      on renal PAO and DAO activities were also studied. The differences between sexes
      in both PAO and DAO activities were most clearly expressed in the immature
      kidney. At the age of 20 days PAO and DAO activities were 1.52 fold (p < 0.01)
      and 1.75 (p < 0.02) respectively higher in male mouse kidney than in female.
      Maturational processes reflected in significant increases in polyamine-oxidizing
      enzyme activities mainly in female mouse kidney, comparable with the gain in the
      kidney wet weight. Our data show that testosterone is able to influence renal PAO
      and DAO activities in addition to the well-known stimulation of polyamine
      biosynthesis. The hormonal effects were sex and age dependent. The influence of
      testosterone on renal PAO activity was mainly age dependent. The slight
      stimulation of renal PAO activity observed in 20- and 50-day old mice, 24 h after
      testosterone administration, change with a decrease in the enzyme activity at the
      age of 70 days. The effects of testosterone on renal DAO activity were mainly sex
      dependent. Testosterone caused stimulation of DAO activity with a very close
      magnitude (nearly twice) in female mouse kidney, independently of the age of
      mice. In contrast, in male mice the hormone treatment resulted in a statistically
      significant increase in renal DAO activity at the age of 70 days (1.3 fold, p <
      0.05) only. It could be suggested that our data indicate the different
      contribution of renal PAO and DAO in androgen regulation of polyamine levels,
      depending on sex and the stage of the postnatal development.

PMID- 10582126
TI  - Alteration in the D-amino acid content of the rat pineal gland under anesthesia.
AB  - In a previous report (Hamase, K. et al., Biochim Biophys Acta 1134: 214-222
      (1997)), we showed that the rat pineal gland contains D-leucine (D-Leu) as well
      as D-aspartic acid (D-Asp). In this communication we report alterations in the
      content of these D-amino acids during anesthesia. The D-Asp content was
      significantly increased from 2.8 to 5.0, 4.8 and 5.8 nmol/pineal gland by
      administration of ether, urethane and pentobarbital, respectively. In contrast,
      the D-Leu content was decreased by administration of urethane or pentobarbital.
      The D-Leu content decreased from 4.2 to 2.2 pmol/pineal gland 4 hours after
      administration of urethane, although the content remained unchanged until 1.5
      hours after administration. The content of the L-enantiomers of these amino acids
      were not affected by anesthesia. The urethane-induced decrease in D-leucine
      content was almost completely suppressed by a beta-agonist, (-)-isoproterenol,
      whereas the agonist itself had no effect.

PMID- 10582127
TI  - Trypsin-catalyzed peptide synthesis with m-guanidinophenyl and m
      (guanidinomethyl)phenyl esters as acyl donor component.
AB  - Two series of inverse substrates, m-guanidinophenyl and m-(guanidinomethyl)phenyl
      esters derived from N-(tert-butyloxycarbonyl)-amino acid, were prepared as an
      acyl donor component for trypsin-catalyzed peptide synthesis. The kinetic
      behavior of these esters toward tryptic hydrolysis was analyzed. They were found
      to couple with an acyl acceptor such as L-alanine p-nitroanilide to produce
      dipeptide in the presence of trypsin. Streptomyces griseus trypsin was a more
      efficient catalyst than the bovine trypsin. Within the enzymatic peptide coupling
      methods, this approach was shown to be advantageous, since the resulting peptides
      are resistant to the enzymatic hydrolysis.

PMID- 10582128
TI  - Determination of the optical purity of threonine and hydroxyproline by capillary
      gas chromatography on a chiral stationary phase.
AB  - Experimental conditions for the derivatization and resolution by GLC of all
      stereoisomers of threonine and 4-hydroxyproline are reported. Threonine was in
      two steps converted to N,O-bisisobutoxycarbonyl 2,2,2-trifluoroethyl ester
      derivatives, the second of which was performed under anhydrous conditions. As
      such the enantiomers could pairwise be separated by capillary gas chromatography
      on a Chirasil-Val column. Since L- and D-threonine eluted much earlier than the
      corresponding allo forms, quantitative determination of the allothreonine content
      in D- or L-threonine down to the one percent level could be simply accomplished
      but also enantiomeric impurities could be determined. Unlike for threonine, the
      corresponding 4-hydroxyproline isomers could not all be resolved as N,O
      bisisobutoxycarbonyl 2,2,2-trifluoroethyl esters on this column. Although
      diastereomers could still be separated, the allo pair cochromatographed and the
      resolution for the L- and D-isomers was low. Complete separation of the 4
      hydroxyproline isomers could be accomplished as N,O-bisprotected isobutyl amides,
      the formation of which required three derivatization steps. These were used for
      the determination of allohydroxyproline.

PMID- 10582129
TI  - Taurine modulates expression of transporters in rat brain and heart.
AB  - In pro- and eucaryotic life, cellular and subcellular compartments are separated
      by membranes and the regulated and selective passage of specific molecules across
      these membranes is a basic and highly conserved principle. We were interested
      whether taurine, a naturally occurring amino acid, would be able to induce or
      suppress expression of transporters with the Rationale that taurine was shown to
      detoxify a series of endogenous toxins and xenobiotics of various chemically non
      related structures. For this purpose we used a gene hunting technique,
      subtractive hybridization, subtracting mRNAs of taurine-treated rat brain and
      heart from untreated controls. Subtracted mRNAs were then converted to cDNAs,
      amplified, sequenced and identified by gene bank data. We found five transporter
      transcripts, the phosphonate transport ATPase PHNC, multidrug transporter homolog
      MTH104, protein-export-membrane protein SECD, oligopeptide transporters oppA and
      oppD, in the brain and two: ABC-transporter BRAF-2 and cation-transport ATPase
      PACS, in the heart. Homologies of the sequences found were in any case > 50% thus
      permitting the identification of transporters with high probability. The
      biological meaning could be that a naturally occurring amino acid, taurine,
      modulates complex transport systems. The most prominent finding is the
      upregulation of a multidrug transporter transcript, explaining a mechanism for
      the nonselective detoxifying action of taurine.

PMID- 10582130
TI  - Urine glycyl-L-proline increase and skin trophicity.
AB  - Glycyl-L-proline (gly-pro) is an end product of collagen metabolism that is
      further cleaved by prolidase (EC 3.4.13.9); the resulting proline molecules are
      recycled into collagen or other proteins. We postulated a relationship between
      defective gly-pro hydrolysis, increased collagen degradation and skin
      destruction. This relationship was tested using HPLC to measure the gly-pro in
      urine. 24 hour urine samples were collected from 27 old people (86 +/- 6 years
      old), of whom 15 were suffering from skin pressure sores of the sacrum or
      calcaneus. The urine from patients with pressure sores contained significantly
      more gly-pro than the urine from the control. A cut-off at 7 mumol/mmol
      creatinine gave the test a positive predictive value of 70%. Collagen breakdown
      was also increased as indicated by the increase of hydroxyproline (hyp) in the
      urine. But this breakdown seemed to stop at the gly-pro step.

PMID- 10582131
TI  - The epidemiology of lung cancer.
AB  - Lung cancer is the most frequent cancer worldwide, accounting for about 12% of
      all new cancer diagnoses in the two sexes combined. During the 1950s and 1960s
      clear evidence emerged that smoking was the cause of striking lung cancer
      increases. Risk of lung cancer increases approximately with the fourth power of
      duration of smoking and the square of the number of cigarettes smoked daily.
      Between 1990 and 1994, lung cancer mortality rates showed first decreases in the
      US and several European countries, including Italy, in men although not in women.
      Marked shifts are, however, taking place in the incidence of different histologic
      types. Adenocarcinoma, which had always been the predominant type in women and
      non-smokers, is increasingly associated with tobacco smoking. Since the 1950s
      steady rises in the incidence of adenocarcinoma of the lung have been observed in
      many developed countries. Increases are similar in the two sexes and have
      followed a clear cohort pattern, paralleling changes in smoking habits and
      cigarette design more than diagnostic advances. Low-yield filter cigarettes tend
      to be inhaled more deeply than high-yield cigarettes in order to satisfy a
      craving for nicotine. The peripheral part of the lung, where most adenocarcinomas
      arise, is thus exposed to a disproportionately higher amount of smoke
      carcinogens. The hazards of light and ultra-light cigarettes tend to be
      underestimated, whereas the only safe cigarette is the non-smoked one.

PMID- 10582132
TI  - Molecular epidemiology of lung cancer.
AB  - Lung cancer occurs through a complex multistage process that results from the
      combination of carcinogen exposure and genetic susceptibilities. The primary
      etiology of lung cancer is tobacco smoking, but an understanding of why some
      smokers develop lung cancer, and others do not, remains unclear. Current studies
      focus on genetic susceptibilities to lung cancer, and how they modify the effects
      of tobacco smoke carcinogens. New assays are being developed to study other
      contributors to cancer risk, such as interindividual differences in DNA repair.
      There is current evidence to suggest that the risk of lung cancer for women,
      compared to men, is higher for the same level of smoking. Several biological
      differences for the types of lung cancer have been observed in women and men.
      Also, there appear to be differences in lung cancer between Caucasians and
      African-Americans. Molecular epidemiology tools are uniquely suited to study
      these biological differences. These studies will improve cancer risk assessments
      and focus cancer prevention strategies. Other studies also are focusing on
      tobacco addiction, in order to lead to improved smoking cessation strategies.

PMID- 10582133
TI  - The combination of etoposide and cisplatin in non-small-cell lung cancer (NSCLC).
AB  - The role of chemotherapy in the treatment of advanced non-small-cell lung cancer
      (NSCLC) has been a subject of debate for many years. Only recently, cisplatin
      based combination chemotherapy has been demonstrated to yield a small but
      definite survival benefit and to improve symptoms, performance status and quality
      of life in a substantial proportion of advanced NSCLC patients. The cisplatin
      etoposide (PE) regimen was developed in the early 1980s and has been one of the
      standard chemotherapy programs most extensively used in the clinical practice
      until a few years ago. More recently, several randomized trials have compared the
      efficacy of new cisplatin-containing combination chemotherapies including
      Paclitaxel or Gemcitabine with that of PE or PE-like regimens. Preliminary
      results are encouraging, indicating a small benefit in favor of the last
      generation of regimens which might therefore replace PE as 'gold standards' in
      the treatment of advanced NSCLC. However, the costs of these last generation
      regimens is higher and the entity of the benefit small. Therefore, PE
      chemotherapy can still be an option in selected situations.

PMID- 10582134
TI  - Anthracyclines in non-small-cell lung cancer: do they have a therapeutic role?
AB  - BACKGROUND: Owing to its low level of activity together with its potential
      cardiotoxicity, doxorubicin (DXR) has been considered as having a marginal role
      in the treatment of NSCLC. Its analogue, epirubicin (EPI), has also shown a poor
      antitumor activity in the treatment of NSCLC when used at 'standard' doses (= 90
      mg/m2). On the contrary, high-dose epirubicin (HD-EPI) (> 90 mg/m2) has
      demonstrated antitumor activity as a single agent in the treatment of advanced
      NSCLC in six small phase II studies (mean 25%, range 17%-36%). RESULTS: A series
      of consecutive studies on the activity of HD-EPI alone or in combination regimens
      were carried out at the Division of Medical Oncology of S. Orsola-M. Malpighi
      Hospital. After activity was confirmed in advanced disease with doses between 120
      and 165 mg/m2 (PR in 6 of 24 = 25%), a phase II study was carried out on the
      combination of HD-EPI 120 mg/m2 + cisplatinum (CP) 60 mg/m2 in stage IIIB-IV
      NSCLC. PR was achieved in 54% of 35 patients with a median survival of nine
      months. A subsequent multicenter phase III trial compared HD-EPI and vinorelbine
      (VNR), both combined with CP. Two hundred twenty-eight patients with locally
      advanced or metastatic NSCLC were randomized to receive either EPI 120 mg/m2 plus
      CP 60 mg/m2 on day 1 or VNR 25 mg/m2 on day 1 and 8 plus CP 60 mg/m2 on day 1.
      Both treatments were recycled every 21 days. Eligible patients were 212 and 210
      patients evaluable for objective response (100 on HD-EPI and 110 on VNR),
      respectively. The CR + PR rate was 32% vs. 26% (P = NS) for a median duration of
      nine and eight months, respectively. Median survival was 10 and 9.5 months,
      respectively. Grade III-IV leucopenia occurred in 38% and 21% on HD-EPI and VNR,
      respectively (P = 0.01), thrombocytopenia in 6% and 0% (P = 0.02), anemia in 8%
      and 7% (NS). Non-hematological toxicity was moderate and the only difference
      between the treatments was alopecia (88% vs. 33% on HD-EPI and VNR,
      respectively). Supraventricular arrhythmia occurred in three patients on HD-EPI;
      a > 15% LVEF decrease by MUGA scan was observed in 22.5% and 14% patients on HD
      EPI and VNR, respectively (NS). No congestive heart failure was observed.
      CONCLUSIONS: EPI can be safely administered at a dose of 120-135 mg/m2 in non
      pretreated patients showing a significant antitumor activity in NSCLC. If the
      cumulative dose of 800-900 mg/m2 is not exceeded, clinical manifestations of
      cardiotoxicity are very rare. However, grade 3-4 myelotoxicity and alopecia are
      very common and can limit the use of this drug in the palliative treatment of
      this disease. Interesting results are observed in an ongoing pilot study that
      employed HD-EPI + CP + VNR + G-CSF in the induction therapy of locally advanced
      NSCLC.

PMID- 10582135
TI  - Ifosfamide in non-small-cell lung cancer.
AB  - Ifosfamide has been used in combination with several drugs including cisplatin,
      giving rise to multiple doublets and triplets including the ifosfamide-cisplatin
      mitomycin regimen (Cullen's MIC regimen) that has been commonly used in Europe.
      However, new combinations are challenging the activity of the old chemotherapy
      regimens, especially in terms of objective response rate and time to progressive
      disease, as has been shown in several phase III randomized trials. Among these
      new combinations, ifosfamide-vinorelbine and ifosfamide-gemcitabine-cisplatin are
      especially promising. In this paper, several ifosfamide doublets and triplets are
      reviewed.

PMID- 10582136
TI  - Tirapazamine: a new drug producing tumor specific enhancement of platinum-based
      chemotherapy in non-small-cell lung cancer.
AB  - BACKGROUND: Tirapazamine (TPZ), a new anti-cancer drug activated to a toxic free
      radical under hypoxic conditions, produces a tumor specific potentiation of cell
      kill by cisplatin. In the present study we discuss the mechanism and clinical
      potential of this effect, as well as investigate the influence of p53 mutations
      on the activity of TPZ. MATERIALS AND METHODS: For in vitro experiments we have
      used mouse SCCVII tumor cells, minimally transformed mouse embryo fibroblasts
      (MEFs) from wild-type and p53 knockout mice, and several human NSCLC cell lines.
      For in vivo experiments we have used RIF-1 tumors implanted subcutaneously into
      C3H mice. RESULTS: Prior injection of TPZ into tumor-bearing mice markedly
      potentiated tumor cell kill by cisplatin, but produced no effect on systemic
      toxicity. The maximum potentiation occurred when TPZ was injected two to three
      hours prior to cisplatin administration. Experiments performed with cells in
      vitro showed a similar synergistic interaction between the two drugs when cells
      were exposed to TPZ under hypoxic conditions prior to exposure to cisplatin.
      Experiments with MEFs from either p53 wild-type or p53-knockout mice showed no
      influence of p53 on the sensitivity of cells to killing by TPZ under hypoxia. A
      similar lack of influence of p53 on the toxicity to TPZ was obtained for a panel
      of NSCLC cell lines. CONCLUSIONS: TPZ is a novel anticancer drug that produces
      tumor selective potentiation of cisplatin and carboplatin in both pre-clinical
      and clinical studies. The fact that the drug produces no potentiation of the
      systemic side effects of these drugs, or of other anticancer drugs used in
      combination with platinum in NSCLC, suggests that TPZ could become a useful agent
      in the treatment of lung cancer.

PMID- 10582137
TI  - Docetaxel (Taxotere) in combination chemotherapy and in association with thoracic
      radiotherapy for the treatment of non-small-cell lung cancer. Thoracic Oncology
      Program.
AB  - Docetaxel is one of the most active single agents for the treatment of non-small
      cell lung cancer. Given the preclinical indications for synergy and the lack of
      cross-resistance with other active agents in this disease, clinical trials of
      docetaxel combinations have been undertaken. Phase I and II clinical trials of
      docetaxel in combination with cisplatin, carboplatin, gemcitabine, vinorelbine,
      or thoracic radiation for patients with non-small-cell lung cancer were reviewed.
      The endpoint for phase I trials was to define the phase II doses for the
      docetaxel combinations where overall response rates, median and one year survival
      were the endpoints. Five phase I-II studies of docetaxel and cisplatin have
      reported response rates ranging from 21% to 48%. Median survival times ranged
      from 8 to 13 months, and one-year survivals from 32% to 58%. Combining docetaxel
      with vinorelbine resulted in a 37% response rate and a median survival of 9.4
      months. Docetaxel in combination with gemcitabine produced a response rate of
      53%. The adverse events of these combinations were manageable. Responses have
      also been reported in studies of docetaxel administered with carboplatin or
      thoracic radiation therapy. Combinations of docetaxel with platinum, vinorelbine,
      gemcitabine, and radiation were active in non-small-cell lung cancer with
      acceptable adverse effects. Phase III trials are currently in progress to further
      define the role of docetaxel combinations in the first-line treatment of this
      disease.

PMID- 10582138
TI  - Vinorelbine (Navelbine) in the treatment of non-small-cell lung cancer: studies
      with single-agent therapy and in combination with cisplatin.
AB  - Initial studies of vinorelbine (Navelbine) given as a single agent to patients
      with operable non-small-cell lung cancer (NSCLC) showed that overall response
      rates of the order of 30% could be obtained with a schedule of 30 mg/m2 given
      weekly. Although such high levels of response have seldom been obtained when
      vinorelbine is given alone in one arm of a comparative study, the level of
      activity is clearly worthwhile and represents a significant improvement over
      supportive care. Combination therapy with cisplatin has been highly successful,
      establishing Vinorelbine as a safe well-tolerated agent which provides
      considerable activity, and experience from large phase III studies suggests that
      the combination of vinorelbine and cisplatin could represent a reference schedule
      against which other therapy should be compared.

PMID- 10582139
TI  - Vinorelbine (navelbine) in the treatment of non-small-cell lung cancer: recent
      developments in combination chemotherapy and radiotherapy.
AB  - The investigation of the activity of vinorelbine in non-small-cell lung cancer
      (NSCLC) has continued beyond the initial studies which established its single
      agent activity and defined the combination of vinorelbine and cisplatin as one of
      the standard treatments for inoperable NSCLC. Alternative partners to cisplatin
      have been evaluated in combination therapy with vinorelbine with promising
      results emerging from combinations with carboplatin, ifosfamide, mitomycin C and
      gemcitabine. Three drug combinations such as vinorelbine, cisplatin and
      ifosfamide can clearly produce high response rates in patients with good
      performance status at the time of treatment. The ability of vinorelbine to
      contribute to disease reduction either alone or in combination with other
      cytotoxic drugs has made it possible to consider its use in neo-adjuvant therapy,
      while the synergistic action of vinorelbine with radiotherapy has encouraged the
      use of sequential or concomitant chemoradiotherapy producing high response rates
      after completion of both modalities. The possible role of post-operative adjuvant
      treatment with Vinorelbine either alone or in combination with cisplatin is being
      assessed in a prospective trial.

PMID- 10582140
TI  - The role of single-agent gemcitabine in the treatment of non-small-cell lung
      cancer.
AB  - Gemcitabine is a novel antimetabolite which has shown anti-tumor activity against
      a variety of tumors including non-small-cell lung cancer (NSCLC). Phase I
      clinical trials with gemcitabine revealed it was well tolerated and several phase
      II trials were conducted. This report will summarize the data from 15 phase I-II
      trials conducted in both untreated and treated patients with advanced lung
      cancer. Overall, single-agent gemcitabine was active with response rates in
      untreated patients ranging from 14%-33% and 0%-25% in previously treated
      patients. Grade 4 toxicities were infrequent with neutropenia reported in 2%-6%
      of patients and grade 4 thrombocytopenia was rate (1%). One randomized phase III
      trial comparing the efficacy and safety of gemcitabine to best supportive care
      confirmed the role of gemcitabine as an active agent for the treatment of NSCLC.
      Furthermore, gemcitabine was shown in several economic models to be cost
      effective. In summary single agent gemcitabine is active, minimally toxic, and
      cost-effective as a treatment regimen for patients with advanced lung cancer.
      Studies combining gemcitabine with other active agents are underway and have
      reported promising results. As monotherapy, gemcitabine may make a valuable
      contribution to those patients with a poor performance status or comorbid
      diseases desiring treatment studies in this setting should also be considered.

PMID- 10582141
TI  - Cisplatin and gemcitabine in non-small-cell lung cancer.
AB  - The nucleoside analogue, gemcitabine, has shown activity as a single agent in the
      treatment of metastatic non-small-cell lung cancer (NSCLC), producing consistent
      response rates of 20% and above. Because of its unique mechanism of action and
      its non-overlapping toxicity with other active agents, gemcitabine is an
      attractive candidate for trials in combination with other cytotoxic agents. In
      preclinical models, the cisplatin-gemcitabine combination suggested synergy
      between the two drugs. In phase I-II studies, response rates are as high as 54%
      when gemcitabine is combined with cisplatin, both in stage III and IV NSCLC. The
      gemcitabine-containing regimens showed a favourable safety-efficacy profile and
      compared well with standard regimens used in NSCLC. These preliminary results
      must be validated by large randomised trials comparing gemcitabine-containing
      regimens with NSCLC reference chemotherapy regimens.

PMID- 10582142
TI  - Paclitaxel-based therapy in non-small-cell lung cancer: improved third generation
      chemotherapy.
AB  - The newer or 'third generation' chemotherapeutic agents (paclitaxel, docetaxel,
      vinorelbine, gemcitabine, irinotecan, topotecan) have all recently been shown to
      have substantial activity against non-small-cell lung cancer (NSCLC). Many of
      these agents are now being incorporated into the therapy for patients with
      advanced disease. Paclitaxel was the first 'third generation' drug to be studied.
      The use of paclitaxel and carboplatin has proven to be a well tolerated and quite
      active regimen with one-year survival in patients with stage IV disease of about
      40% and two-year survival of about 20%. These survival rates are at least twice
      as good as previous platinum-based regimens. We have simplified the
      administration of paclitaxel by using a one-hour infusion and many other
      investigators and clinicians have followed suit. The results are equivalent to a
      three-hour infusion schedule. Given the degree of activity in patients with stage
      IV disease, it is imperative to begin neoadjuvant and adjuvant trials with the
      newer drugs and drug combinations. We and others have started a neoadjuvant
      strategy which has proven to be feasible and most patients tolerate surgery well.
      While the results are quite preliminary, we have seen some complete pathologic
      responses (about 20%) and are encouraged by these early data. In addition, we
      have routinely used adjuvant paclitaxel and carboplatin in patients with stage IB
      IIIA disease who have been previously resected. Radiotherapy and a weekly
      schedule of paclitaxel and carboplatin have been incorporated for patients with
      stages II-IIIB (selected IIIB patients). Randomized comparisons are certainly
      needed in the neoadjuvant and adjuvant arena and the other 'third generation'
      drugs need to be quickly evaluated. We have chosen to add a third agent to
      paclitaxel and carboplatin. The evaluation of several triple combinations
      including the addition of gemcitabine, vinorelbine and topotecan, respectively to
      the paclitaxel-carboplatin combination has been completed. Preliminary results
      from these trials will be briefly summarized and plans for additional studies of
      the newer agents will also be discussed. Studies to learn the appropriate
      combinations, doses and schedules of the newer drugs in concert with radiotherapy
      and/or resection are also urgently needed. Since the newer 'third generation'
      drugs appear to genuinely improve the survival of patients with stage IV disease,
      it is likely that incorporation of these more active agents into therapy for
      lower stages of disease will make an even greater impact on overall survival for
      patients with this common neoplasm.

PMID- 10582144
TI  - The role of surgery in integrated therapies for non-small-cell lung cancer.
AB  - Surgery represents the best treatment for early-stage non-small-cell lung cancer
      (NSCLC). In selected cases, even locally-advanced cancers may be suitable for
      surgical treatment. The combination of chemotherapy (with or without
      radiotherapy) and surgery has proved potentially useful in improving survival,
      but pre-operative treatment may represent a risk factor for the onset of post
      operative complications. Studies performed to date indicate the need for further
      multidisciplinary research with a view to identifying more advantageous treatment
      modalities, particularly for locally-advanced NSCLC.

PMID- 10582143
TI  - Docetaxel (Taxotere) in the neo-adjuvant setting in non-small-cell lung cancer.
AB  - BACKGROUND: There is a potential for neo-adjuvant chemotherapy to provide
      significant benefit in outcome for patients with locally advanced non-small-cell
      lung cancer (NSCLC). Patients with N2/T3 NSCLC have a poor prognosis when treated
      by surgery alone since micrometastases result in relapse in the majority of
      cases. The same is true of patients with N3/T4 disease treated only with
      radiotherapy. Systemic therapy is therefore required, and cisplatin-based
      induction chemotherapy prior to surgery or radiotherapy has been shown to improve
      survival when compared with surgery or radiotherapy alone. Docetaxel has been
      shown to have significant activity in stage IV NSCLC and ongoing phase III trials
      are comparing single agent docetaxel or doceatxel in combination with cisplatin
      or VP16 before local treatment to local treatment alone. DESIGN: Patients with
      locally-advanced (stage IIIa or IIIb) NSCLC receive three cycles of docetaxel
      (100 mg/m2) followed by appropriate local therapy, or local therapy alone. Local
      therapy for stage IIIa patients is surgery (with or without radiotherapy
      depending on completeness of resection) and for stage IIIb patients curative
      intent radiotherapy. In another on-going study in stage IIIa NSCLC, docetaxel (75
      mg/m2) is given in combination with cisplatin (40 mg/m2) followed by surgery.
      Patients must have histologically or cytologically confirmed NSCLC, have received
      no prior treatment for the disease and are suitable to undergo surgery or radical
      radiotherapy, as appropriate. RESULTS: Initial results from the phase III
      comparative study show that single agent docetaxel in the neo-adjuvant setting is
      effective and associated with acceptable toxicity. Two hundred of the planned two
      hundred ninety-two patients have been accrued to the single-agent docetaxel neo
      adjuvant study. In the first 49 evaluable patients in the docetaxel arm, 1 CR and
      18 PR have been achieved (response rate 39%) and no patients receiving docetaxel
      neo-adjuvant therapy have progressed. All patients were able to receive the full
      doses of docetaxel. CONCLUSION: The details of time-to-progression and survival
      in this study will eventually confirm the results from recent small trials of neo
      adjuvant chemotherapy in locally-advanced NSCLC.

PMID- 10582145
TI  - Chemoradiotherapy interactions and lung toxicity.
AB  - BACKGROUND: The combination of high-dose radiotherapy with intensive chemotherapy
      may improve the prognosis of patients with inoperable, locally advanced non-small
      cell lung cancer. In the design of suitable clinical protocols, potential
      interactions of drugs and radiation in the tumour, the lung and other critical
      normal tissues have to be considered. METHODS: From experimental data on
      chemotherapy radiotherapy interactions and based on knowledge about the biology
      of non-small cell lung cancer and the pathogenesis of radiation pneumopathy, the
      principles which should be considered in the design of treatment schedules are
      developed. RESULTS: For the increase in local tumour control, further escalation
      of radiation dose should be considered first. The most critical issue for lung
      toxicity may be the volume of the 30 Gy isodose. Yet, the most critical normal
      tissue which may limit the further increase in dose and dose intensity appears to
      be the oesophagus. CONCLUSIONS: Since the main cause of treatment failure remains
      local recurrence, further increase in locoregional cytotoxicity is the first
      priority in locally advanced non-small-cell lung cancer. This can best be
      achieved by increasing radiation dose and dose intensity further. Yet, there may
      also be a role for simultaneous radiochemotherapy, even if this would increase
      the lung volume which develops radiation pneumopathy and thus the severity of
      symptoms. This problem should be dealt with by reducing the irradiated lung
      volume by use of conformal treatment planning. The most critical side effects
      will then be due to increased severity of acute oesophagitis.

PMID- 10582146
TI  - Multidrug resistance in non-small-cell lung cancer.
AB  - Resistance to cytotoxic drugs is an important cause of treatment failure. The
      causes are complex and may be determined by a combination of the tumour
      characteristics, such as the proportion of resting cells, adequacy of blood
      supply, and specific cellular mechanisms, as in the multidrug resistance
      phenotype. In lung cancer four types of multidrug resistance have been defined on
      the basis of the cellular drug targets involved, i.e., classical multidrug
      resistance (MDR), non-P-glycoprotein MDR (also called MRP), atypical MDR
      (mediated through altered expression of topoisomerases II) and lung resistance
      related protein. In lung cancer the role of the different forms of multidrug
      resistance is complex and only partially understood.

PMID- 10582147
TI  - Therapy of non-small-cell lung cancer (NSCLC) in patients with HIV infection.
      GICAT. Cooperative Group on AIDS and Tumors.
AB  - Incidence and mortality of AIDS patients have significantly declined in the
      developed countries due to the very active anti-HIV combination therapy available
      today. Because of the prolongation of the survival expectancy of these patients,
      other non-AIDS defining tumours have been recently reported in several cohort
      studies with increased frequency. We want to report the clinico-pathological
      features and the outcome of 39 patients with lung cancer and HIV infection,
      collected by the Italian Cooperative Group on AIDS and Tumors (GICAT) between
      1986 and December 1997. As a control group, we decided to evaluate patients, less
      than 60 years of age, with lung cancer but without HIV infection seen at the CRO,
      Aviano, during 1995 and 1996. The median age of the study group patients was 38
      years (range 28-58) and 90% of them were males. Sixty-nine percent of patients
      were intravenous drug users and HIV infection was asymtomatic in 41% of patients.
      NSCLC was observed in 78% of patients, SCLC in 13% and mesothelioma in 8%. Among
      NSCLC, adenocarcinoma was the most frequently observed histological subtype
      (48%). No differences were found as regards the stage of disease at diagnosis and
      the histologic subtype in comparison with the control group. The median overall
      survival was significantly shorter for patients with HIV infection when compared
      to that of the control group (5 months vs. 10 months, P < 0.0001). In conclusion,
      the outcome of patients with SNCLC and HIV infection seems worse than that of the
      general population, suggesting a synergistic and/or addictive adverse effect of
      HIV on the outcome of lung cancer.

PMID- 10582148
TI  - Chemotherapy of non-small-cell lung cancer: role of erythropoietin in the
      management of anemia.
AB  - Main mechanisms involved in the development of chemotherapy-induced anemia are
      the direct bone marrow damage and the renal impairment with a secondary deficient
      production of erythropoietin. The first mechanism is induced by almost all
      cytotoxic drugs whilst the second one has been demonstrated with cisplatin
      treatment. NSCLC patients are generally treated with platinum-based chemotherapy
      and then both mechanisms are involved in the development of anemia which can be,
      as a consequence, more frequent and more severe compared to other cancer
      patients. Chemotherapy regimens such as MVP (mitomycin, vindesine, platin),
      cisplatin-etoposide and cisplatin-teniposide induce grade > or = 2 anemia in 64%,
      46% and 83% of patients, respectively, with grade 3-4 anemia occurring in 29%,
      15% and 24% of patients. New chemotherapy regimens are also associated with a
      high incidence of anemia. Carboplatin-paclitaxel induces grade 3-4 anemia in 34%
      of patients and 30% of patients need blood transfusions. Similarly, 33% of
      patients treated with cisplatin-gemcitabine require blood transfusions.
      Erythropoietin is able to correct anemia in nearly 60%-80% of patients receiving
      platinum-based chemotherapy and in nearly 40% of patients treated with regimens
      without platinum compounds, leading to a reduction in blood transfusion
      requirement. Moreover, erythropoietin is able to prevent anemia development in
      cancer patients. Due to the high incidence of anemia, erythropoietin may
      represent an important tool in the supportive care of NSCLC patients.
      Erythropoietin use is mainly limited by the economic cost and then efforts should
      be made to identify the subset of patients in whom this supportive therapy is
      cost-effective. Patient and disease characteristics, factors predicting the
      probability to be transfused as well as factors predicting the response to
      erythropoietin can be useful in selecting patients likely to benefit from
      erythropoietin therapy.

PMID- 10582149
TI  - Retinoids in lung cancer chemoprevention and treatment.
AB  - In this review, we aim to synthesize the emerging picture of retinoids in lung
      cancer through a summary of ongoing investigations in biology, chemoprevention
      and therapy settings, in an attempt to clarify the possible role of these agents
      in such a disease. Early work in head and neck cancer has evidenced the
      capability of retinoids to interrupt field carcinogenesis by reversing
      premalignant lesions and decreasing the incidence of second primary tumors
      (SPTs). At this time, the completed randomized trials in lung cancer have failed
      to demonstrate an evident chemopreventive effect of the tested agents on
      different study end points, although both a marginally significant benefit of
      retinol palmitate in time-to-development rates for smoke-related SPTs and a
      potential preventive effect of retinol supplementation against mesothelioma in
      selected populations of asbestos-exposed workers have been recently reported.
      Concerning the role of retinoids in lung cancer treatment, a moderate activity of
      13-cis-retinoic acid (13cRA) or all-transretinoic acid (ATRA) as single agents
      has been reported in small series of advanced, mostly pretreated lung cancer
      patients. More encouraging findings derive from combination studies, in which
      retinoids, especially ATRA, are added to either alpha-interferon or chemotherapy
      and radiotherapy. Major recent advances have been made towards the understanding
      of retinoids mechanisms of action; at this regard, the role of RAR-beta basal or
      treatment-induced levels seems to be of particular interest as intermediate end
      point and/or independent prognostic factor, besides their known importance in
      lung carcinogenesis. Future research for chemopreventive and therapeutic programs
      with retinoids in lung cancer should be focused on the investigation of new
      generation compounds with a specificity for individual retinoid nuclear
      receptors. Such selective molecules may have a greater activity against lung
      cancer, with a more favourable toxicity profile, as recently suggested by our
      preliminary data on Ro 41-5253.

PMID- 10582150
TI  - Prolog.

PMID- 10582151
TI  - What is your diagnosis? Amelanotic melanoma.

PMID- 10582152
TI  - What's eating you? Psocoptera (book lice, psocids).

PMID- 10582153
TI  - Childhood psoriasis.
AB  - Psoriasis is a common skin disease in infants, children, and adolescents. A
      review of the clinical, epidemiologic, genetic, and therapeutic aspects of
      childhood psoriasis is presented. Population studies indicate that the first
      signs of psoriatic lesions occur in the pediatric age group, birth to 18 years of
      age, and that both genetic and environmental factors interact to precipitate the
      development of psoriasis. Koebner reactions are the result of external or
      internal triggering factors, such as physical injury to the skin, low humidity,
      and certain drugs. The most frequently observed variant to psoriasis is the
      plaque type, followed by guttate psoriasis, and juvenile psoriatic arthritis.
      Pustular psoriasis and erythrodermic psoriasis are rare forms of the disease, but
      are seen in children from infancy to adolescence. The scalp is the most
      frequently affected site of involvement in pediatric psoriasis, followed by the
      appearance of lesions on the extensor surfaces of the extremities, trunk, and
      nails. Although not common in adult psoriasis, the face and ears are often
      involved. Topical medications such as corticosteroids, calcipotriol, coal tar
      preparations, anthralin formulations, and ultraviolet B are recommended in
      monotherapy or in combination therapy, whereas psoralen plus ultraviolet A,
      methotrexate, and retinoids should only be administered in crisis situations. The
      treatment objectives in childhood psoriasis are to preserve skin surfaces, to
      afford physical relief from the disease, and to employ treatments that do not
      endanger the health or future development of the child.

PMID- 10582154
TI  - Head lice.

PMID- 10582156
TI  - Progress in our understanding of the biology of psoriasis.
AB  - This review describes the progress made in our understanding of the basic biology
      of psoriasis and how newer, safer clinical approaches to control the disease may
      result from these developments. It reveals how epidermal hyperproliferation can
      be permanently induced using transgenic mouse models, how the discovery of
      methods to generate humanized mouse monoclonal antibodies may be used to control
      the synthesis of autocrine and paracrine growth factors, how programmed cell
      death (apoptosis) is regulated in the epidermis, and how the abnormal synthesis
      of superantigens, cytokines, and chemokines can result in immune dysfunction and
      generate increased angiogenesis, inflammation, and epidermal hyperproliferation.

PMID- 10582155
TI  - Topical corticosteroid therapy in psoriasis vulgaris: update and new strategies.
AB  - This is an update of a previous report on the use of topical steroids in the
      management of psoriasis vulgaris. The current focus is on new combination
      therapies that enhance the efficacy of corticosteroids while diminishing their
      potential side effects.

PMID- 10582157
TI  - Search for the psoriasis susceptibility gene: the Newfoundland Study.
AB  - The authors review early pioneering research on the genetics of psoriasis and
      recently published independent and collaborative investigations searching for the
      psoriasis susceptibility genes. We describe the research design and current plans
      for a joint pursuit between the Psoriasis Research Institute, the Memorial
      University of Newfoundland, and Chiroscience R&D, Inc., for susceptibility genes.
      A unique study sample from Newfoundland, drawn from affected and unaffected
      members of multiplex families and relatives, provides a nearly homogeneous
      isolated population. Families reflect English, Scottish, and Irish ancestry, and
      have been in residence in Newfoundland for over 300 years. The prevalence of
      psoriasis is estimated to be 2 to 3%. Familial psoriasis occurs in over 85% of
      families, with at least one affected member. The experimental strategy using
      linkage analysis and linkage disequilibrium analysis of the collected tissue bank
      are discussed, emphasizing prospects for the future outcome of the research
      findings.

PMID- 10582158
TI  - Methotrexate in the treatment of psoriasis.
AB  - Methotrexate is an important drug in the armamentarium available to physicians to
      treat patients with moderate to severe psoriasis. The drug has a 40-year track
      record and has proven to be effective in cases in psoriasis that are refractory
      to other intense forms of treatment. While it has proven efficacy, methotrexate
      also has the potential for both acute and chronic toxicity. Patients must be
      carefully selected and the drug administered according to specific guidelines to
      guard against the development of serious side effects. Methotrexate is best used
      by individuals very familiar with psoriasis and equally well-versed in the
      complexities of managing patients on antimetabolite therapy.

PMID- 10582159
TI  - The art of treating psoriasis: practical suggestions for improved treatment.
AB  - The author provides various perspectives on interacting with a psoriasis patient
      from both treatment and educational viewpoints. The value of employing
      monotherapeutic and polytherapeutic approaches is discussed, and written
      instructions on the course of treatment to ensure patient compliance are advised.
      Despite busy medical practice schedules, dermatologists and family physicians or
      their nursing staff are encouraged to keep in contact with a patient by phone two
      or three weeks following a visit to sustain the physician-patient relationship.

PMID- 10582160
TI  - Phototherapy: UVB and PUVA.
AB  - The following paper is a review of the benefits of natural and artificial
      ultraviolet light in psoriasis. Phototherapy has been administered alone or in
      combination with topical corticosteroids, tars, anthralin, calcipotriene, and
      tazarotene, and with systemic therapies, such as methotrexate, acitretin, and
      cyclosporine. The choice of treatment with ultraviolet light B or psoralen plus
      ultraviolet light A is based on a history of previous response to treatment, skin
      type, severity of psoriasis, and patient considerations, including compliance and
      responsibility for observing the precautions to avoid potential side effects.

PMID- 10582161
TI  - Treatment of psoriasis with retinoids: present status.
AB  - Oral retinoids such as etretinate/acitretin are well established for the
      treatment of severe generalized psoriasis. They are particularly useful for the
      management of pustular and erythrodermic variants and plaque-type psoriasis
      because they act synergistically with many other topical antipsoriatic agents
      (corticosteroids, anthralin, tar, and phototherapies). Oral regimens are dose
      dependent, and, if carefully administered, are manageable and tolerable. Long
      term toxicity is rare; however, teratogenicity restricts the use of oral
      retinoids and requires close monitoring in females. In recent years, a topical
      agent, tazarotene, has been developed and added to the armamentarium of psoriasis
      therapy.

PMID- 10582162
TI  - The "lost" skin biopsy: how to prevent it!

PMID- 10582163
TI  - Live attenuated Salmonella: a paradigm of mucosal vaccines.
AB  - Two key steps control immune responses in mucosal tissues: the sampling and
      transepithelial transport of antigens, and their targeting into professional
      antigen-presenting cells in mucosa-associated lymphoid tissue. Live Salmonella
      bacteria use strategies that allow them to cross the epithelial barrier of the
      gut, to survive in antigen-presenting cells where bacterial antigens are
      processed and presented to the immune cells, and to express adjuvant activity
      that prevents induction of oral tolerance. Two Salmonella serovars have been used
      as vaccines or vectors, S. typhimurium in mice and S. typhi in humans. S.
      typhimurium causes gastroenteritis in a broad host range, including humans, while
      S. typhi infection is restricted to humans. Attenuated S. typhimurium has been
      used successfully in mice to induce systemic and mucosal responses against more
      than 60 heterologous antigens. This review aims to revisit S. typhimurium-based
      vaccination, as an alternative to S. typhi, with special emphasis on the
      molecular pathogenesis of S. typhimurium and the host response. We then discuss
      how such knowledge constitutes the basis for the rational design of novel live
      mucosal vaccines.

PMID- 10582165
TI  - The B-cell system of human mucosae and exocrine glands.
AB  - The mucosae and exocrine glands harbour the largest activated B-cell system of
      the body, amounting to some 80-90% of all immunoglobulin (Ig)-producing cells.
      The major product of these immunocytes is polymeric (p)IgA (mainly dimers) with
      associated J chain. Both pIgA and pentameric IgM contain a binding site for the
      polymeric Ig receptor (pIgR), or secretory component (SC), which is a requirement
      for their active external transport through secretory epithelia. The pIgR/SC
      binding site depends on covalent incorporation of the J chain into the quaternary
      structure of the polymers when they are produced by the local immunocytes. This
      important differentiation characteristic appears to be sufficient functional
      justification for the J chain to be expressed also by most B cells terminating at
      secretory effector sites with IgD or IgG production; they probably represent a
      "spin-off" from sequential downstream CH switching on its way to pIgA expression,
      thus apparently reflecting a maturational stage of effector B-cell clones
      compatible with homing to these sites. Observations in IgA-deficient individuals
      suggest that the magnitude of this homing is fairly well maintained even when the
      differentiation pathway to IgA is blocked. Certain microenvironmental elements
      such as specific cytokines and dendritic cells appear to be required for
      induction of IgA synthesis, but it remains virtually unknown why this isotype
      normally is such a dominating product of local immunocytes and why they have such
      a high level of J chain expression. Also, despite the recent identification of
      some important requirements in terms of adhesion molecules (e.g. integrin alpha 4
      beta 7 and MAdCAM-1) that explain the "gut-seeking" properties of enterically
      induced B cells, the origin of regionalized homing of B cells to secretory
      effector sites outside the gut remains elusive. Moreover, little is known about
      immune regulation underlying the striking disparity of both the class (IgD, IgM)
      and subclass (IgA1, IgA2, IgG1, IgG2) production patterns shown by local
      immunocytes in various regions of the body, although the topical microbiota and
      other environmental stimuli might be important. Rational design of local vaccines
      will depend on better knowledge of both inductive and migratory properties of
      human mucosal B cells.

PMID- 10582164
TI  - Genetic vaccination strategies for enhanced cellular, humoral and mucosal
      immunity.
AB  - In this article, we describe several novel genetic vaccination strategies
      designed to facilitate the development of different types of immune responses.
      These include: i) the consecutive use of DNA and fowlpoxvirus vectors in "prime
      boost" strategies which induce greatly enhanced and sustained levels of both cell
      mediated immunity and humoral immunity, including mucosal responses; ii) the co
      expression of genes encoding cytokines and cell-surface receptors, and the use of
      immunogenic carrier molecules, for immune modulation and/or improved targeting of
      vector-expressed vaccine antigens; and iii) the expression of minimal immunogenic
      amino acid sequences, particularly cytotoxic CD8+ T-cell determinants, in
      "polytope" vector vaccines. The capacity to modulate and enhance specific immune
      responses by the use of approaches such as these may underpin the development of
      vaccines against diseases for which no effective strategies are currently
      available.

PMID- 10582167
TI  - A role for cytokines in potentiation of malaria vaccines through immunological
      modulation of blood stage infection.
AB  - Malaria is the world's major parasitic disease, for which effective control
      measures are urgently needed. One of the difficulties hindering successful
      vaccine design against Plasmodium is an incomplete knowledge of antigens
      eliciting protective immunity, the precise types of immune response for which to
      aim, and how these can be induced. A greater appreciation of the mechanisms of
      protective immunity, on the one hand, and of immunopathology, on the other,
      should provide critical clues to how manipulation of the immune system may best
      be achieved. We are studying the regulation of the balance between T helper 1
      (Th1) and T helper 2 (Th2) CD4+ T lymphocytes in immunity to asexual blood stages
      of malaria responsible for the pathogenicity of the disease. Protective immunity
      to the experimental murine malarias Plasmodium chabaudi and Plasmodium yoelii
      involves both Th1 and Th2 cells, which provide protection by different mechanisms
      at different times of infection characterised by higher and lower parasite
      densities, respectively. This model therefore facilitates a clearer understanding
      of the Th1/Th2 equilibrium that appears central to immunoregulation of all
      host/pathogen relationships. It also permits a detailed dissection in vivo of the
      mechanisms of antimalarial immunity. Here, we discuss the present state of
      malaria vaccine development and our current research to understand the factors
      involved in the modulation of vaccine-potentiated immunity.

PMID- 10582166
TI  - Polysaccharide vaccines as probes of antibody repertoires in man.
AB  - Antibodies specific for capsular polysaccharide epitopes mediate immunity to
      encapsulated bacterial pathogens, and accordingly, vaccine development has
      focused upon the induction of these specificities. Efficacious vaccines,
      consisting of either polysaccharide alone or polysaccharide coupled to protein
      carriers, have been developed for a number of pathogens. Their clinical
      importance notwithstanding, these vaccines serve as model antigens to study the
      genetic and somatic forces molding adaptive immunity in man. In this article we
      review progress aimed at delineating the structure and dynamics of the human
      antibody repertoire to the Haemophilus influenzae type b polysaccharide (Hib PS),
      a system which has been studied from infancy to old age. Collectively, the data
      reveal a repertoire which is encoded by a relatively large number of germline
      variable (V) region gene segments, but which is typically expressed within
      individuals as a markedly restricted, oligoclonal population. One particular V
      domain has attained canonical status because of its high penetrance at the
      population level and its predominance in individual repertoires. Although this
      combining site is assembled in early infancy and retains its prominence
      throughout life, its frequency of expression, affinity and protective function
      are dictated by the molecular form of the Hib PS immunogen (vaccine). The
      determinants of Hib PS binding affinity can include both germline and somatically
      acquired V region polymorphisms. We discuss how these properties of the Hib PS
      repertoire could impact immunity to Hib, and we consider the implications of
      these findings towards understanding the evolution of immunoglobulin germline V
      genes.

PMID- 10582168
TI  - Vaccination against helminth parasites--the ultimate challenge for
      vaccinologists?
AB  - Helminths are multicellular pathogens which infect vast numbers of human and
      animal hosts, causing widespread chronic disease and morbidity. Vaccination
      against these parasites requires more than identification of effective target
      antigens, because without understanding the immunology of the host-parasite
      relationship, ineffective immune mechanisms may be invoked, and there is a danger
      of amplifying immunopathogenic responses. The fundamental features of the immune
      response to helminths are therefore summarised in the context of vaccines to
      helminth parasites. The contention between type-1 and type-2 responses is a
      central issue in helminth infections, which bias the immune system strongly to
      the type-2 pathway. Evidence from both human and experimental animal infections
      indicates that both lineages contribute to immunity in differing circumstances,
      and that a balanced response leads to the most favourable outcome. A diversity of
      immune mechanisms can be brought to bear on various helminth species, ranging
      from antibody-independent macrophages, antibody-dependent granulocyte killing,
      and nonlymphoid actions, particularly in the gut. This diversity is highlighted
      by analysis of rodent infections, particularly in comparisons of cytokine
      depleted and gene-targeted animals. This knowledge of protective mechanisms needs
      to be combined with a careful choice of parasite antigens for vaccines. Many
      existing candidates have been selected with host antibodies, rather than T-cell
      responses, and include a preponderance of highly conserved proteins with
      similarities to mammalian or invertebrate antigens. Advantage has yet to be taken
      of parasite genome projects, or of directed searches for novel, parasite-specific
      antigens and targets expressed only by infective stages and not mature forms
      which may generate immunopathology. With advances under way in parasite genomics
      and new vaccine delivery systems offering more rapid assessment and development,
      there are now excellent opportunities for new antihelminth vaccines.

PMID- 10582169
TI  - The search for a vaccine against schistosomiasis--a difficult path but an
      achievable goal.
AB  - The search for an effective vaccine against schistosomiasis, a parasitic disease
      currently affecting over 200 million people, remains a desirable but as yet
      challenging and elusive goal. Progress in the area has been relatively slow but
      research demonstrating the ability of humans to acquire natural immunity to
      schistosome infection, together with the successful use in animals of attenuated
      vaccines, supplemented with encouraging results obtained with defined antigens,
      suggests that development of a vaccine is achievable. Noteworthy also are recent
      immune correlate findings which shed light on the complex, putatively protective
      immune responses in humans, which have improved the prospects of success. With
      the first human clinical trial having been completed with a schistosome vaccine
      candidate, this review examines current progress aimed at achieving the objective
      of a safe and effective vaccine for widespread use against schistosomiasis. The
      review emphasises work undertaken in the author's laboratory and those of his
      chief collaborators in the search for a vaccine against schistosomiasis japonica,
      a disease of major public health significance in The People's Republic of China
      and The Philippines. Schistosomiasis vaccines should not be considered as the
      panacea for schistosomiasis control as, when available, it is generally envisaged
      that they would be used as one component of an integrated strategy complementing
      currently available and effective tools such as chemotherapy, improvements to
      sanitation, piped water supply, effective sewage draining and health education.

PMID- 10582170
TI  - Experimental approaches to the development of a recombinant hookworm vaccine.
AB  - Hookworm infection is a major parasitic cause of morbidity in the developing
      nations of the tropics. Development of a genetically engineered vaccine would be
      a useful tool in the control of this infection in highly endemic areas.
      Recombinant polypeptides belonging to the Ancylostoma secreted protein (ASP)-1
      family have shown promise for reducing hookworm burdens after larval challenge
      infections in mice. Typically, these polypeptides are expressed in Escherichia
      coli and administered as an alum precipitate. Vaccine protection is antibody
      dependent. It is anticipated that a cocktail of different recombinant hookworm
      antigens may be required in order to effectively prevent heavy hookworm
      infections and disease. The progress of this work has been hampered by the
      absence of both a convenient laboratory animal with which to study hookworm
      infections resembling human infection, as well as the lack of easy availability
      of native hookworm antigens. In addition, useful human serologic correlates of
      antihookworm immunity are still poorly defined.

PMID- 10582171
TI  - Vaccines and passive immunological approaches for the control of fertility and
      hormone-dependent cancers.
AB  - Reviewed here is the development of a vaccine against the human chorionic
      gonadotropin that prevents pregnancy in sexually active women without impairment
      of ovulation or derangement of menstrual regularity. Also reviewed are the
      vaccines inducing antibodies against the luteinizing hormone-releasing hormone,
      which have immunotherapeutic potential in prostatic hypertrophy and other sex
      hormone-dependent male and female cancers. The adoption of passive immunization
      using humanized recombinant antihormone antibodies is advocated for assured
      efficacy and safe, prompt therapeutic action.

PMID- 10582172
TI  - Vaccine for contraception targeting sperm.
AB  - Development of a vaccine(s) based on sperm antigens represents a promising
      approach to contraception. The utility of a sperm antigen in immunocontraception
      is contingent upon its tissue specificity, involvement in fertility and on
      raising high antibody titer, especially locally in the genital tract, that is
      capable of inducing reversible infertility. Several sperm antigens, such as
      lactate dehydrogenase C4, PH-20, sperm protein (SP)-10, fertilization antigen
      (FA)-1, FA-2, cleavage signal (CS)-1, NZ-1, and NZ-2 have been proposed as
      potential candidates for the vaccine development. Spermzona pellucida (ZP)
      binding is a pivotal tissue- and mostly species-specific event in the
      fertilization process, and the molecules involved in this site constitute the
      most exciting candidates for immuno-contraception. FA-1 is a sperm-specific
      glycoprotein having receptor activity for ZP recognition and binding.
      Complementary DNA encoding for FA-1 antigen has been cloned and sequenced. Active
      immunization of animals with recombinant FA-1 antigen causes a long-lasting
      reversible inhibition in fertility by raising a sperm-specific immune response.
      This antigen is also involved in human immunoinfertility. The exciting findings
      from the recent trial in immunoinfertile couples indicate that the FA-1 antigen
      may have clinical application in the treatment of male infertility. A vaccine
      having most appropriate tissue-specific and effective recombinant and/or
      synthetic epitopes of various sperm antigens, such as the FA-1 antigen, in a
      single formulation may provide a highly immunogenic and efficacious antisperm
      vaccine for contraception. The advances made during the last 5 years suggest that
      it may be a realistic proposition.

PMID- 10582173
TI  - Evidence for a unique N-linked glycan associated with human infertility on sperm
      CD52: a candidate contraceptive vaccinogen.
AB  - A major objective in developing a sperm antigen-based contraceptive vaccine for
      humans is the discovery of sperm surface immunogens that are functionally
      relevant and sperm specific. The latter criterion is deemed essential to avoid
      the possibility of inducing autoimmune disease upon vaccination. This review
      presents evidence that a unique carbohydrate epitope is synthesized in the human
      epididymis, is attached to the core peptide of CD52, a lymphocyte differentiation
      marker, and is subsequently inserted into the sperm membrane via a
      glycosylphosphatidylinositol anchor. This unique CD52 glycoform is localized to
      the entire sperm surface, functions as a potent target for agglutinating and
      cytotoxic antibodies, and is one of the few well-defined sperm surface
      glycoproteins indicated in human antibody-mediated infertility.

PMID- 10582174
TI  - [Help in stopping smoking. The time for action has come].

PMID- 10582175
TI  - [Chronic varicose pelvic veins].
AB  - After a long period of neglect, pelvic vein pathology must be recognized today as
      a true pathological entity. It is easy to understand how fragile the veins are
      and how liable to poor venous return when the anatomical, histological and
      functional characteristics of the venous system of the pelvis are properly
      understood. Furthermore this pathology has an adverse effect on peripheral and
      underlying venous functions. Initially revealed by transuterine
      hysterophlebography, the morphological and functional disorders of the pelvic
      veins can now be shown by color Doppler ultrasonography, which is indeed the tool
      of first intention for diagnosis and therapeutic assessment, being capable of
      displaying the variations in calibre of the veins and more particularly of
      establishing their flow rates. Study of pelvic vascularization has two
      fundamental applications for gynecology: non specific chronic, pelvic pain which
      represents between 15 and 20% of reasons for patients consulting, and
      premenstrual syndrome dominated by congestive phenomena. The indispensable
      accompaniment to Doppler ultrasonography for investigation of persistent pelvic
      pain is laparoscopy, which confirms the venous dilatation involved, assesses any
      associated lesions also liable to slow venous flow and offers simple and
      efficient methods for treatment.

PMID- 10582176
TI  - [Measurement of monocyte activation: perspectives in clinical application in the
      investigation of the diabetic patient].
AB  - Monocytes play a pivotal role in the complex processes of inflammation,
      immunologic responses and atherothrombosis. Clinical studies essentially reported
      an increased procoagulant activity in diabetes and coronary disease, suggesting
      an overexpression of tissue factor. This was further confirmed by the direct
      measurement of tissue factor on monocyte membrane by flow cytometry. Many
      receptors can be measured on monocytes by flow cytometry: beta 2 integrins (CD 11
      a-b-c/CD 18) involved in adhesion, EPR-1 receptor, receptors for advanced
      glycation products, urokinase receptor U-PAR. Flow cytometry allows a cell
      analysis in whole blood. Modern methods allow a standardization of the procedures
      and a quantification of the number of sites expressed by the cell. However, the
      respect of preanalytical and analytical conditions is mandatory to obtain
      reliable data. Besides, clinical studies in diabetes should carefully define the
      subgroups of patients: type of diabetes, metabolic abnormalities, risk factors,
      infective complications.

PMID- 10582177
TI  - [Arterial complications of neurofibromatosis].
AB  - Type 1 neurofibromatosis (NF1) is the most frequently observed phacomatosis, but
      involvement of arterial trunks is uncommon. Expression depends on the
      localization and is not easily related to the causal condition. Seven patients
      with type 1 neurofibromatosis developed vascular manifestations (table I)
      disclosed by hypertension (n = 2) digestive angina (n = 1), arterial rupture (n =
      1) and aneurysm of the subrenal aorta (n = 1). The diagnosis of NF1 was clear in
      5 cases; in 2 cases, the diagnosis could only be established on the basis of
      pathology findings demonstrating dysplasia of the media with voluminous
      periadventitial hypertrophic nerves (table II). All the large arteries can be
      involved in NF1. A complete vascular work-up is needed to identify multiple
      arterial localizations as found in two of our cases. Thoraco-abdominal stenosis
      was observed in 5 cases leading, in 2 cases, to coarctation with a hemodynamic
      and functional impact requiring aortic revascularization. The most frequently
      observed localization involves the renal arteries: 3 of our patient had occlusive
      lesions of the renal arteries and in 2, aneurysms were observed. Three of our
      patients (including 2 of the preceding), had major occlusion of digestive
      arteries. Three other cases revealed an aneurysm of inflammatory subrenal aorta,
      a rupture of the iliac into the inferior vena cava and a rupture covered by a
      subclavian aneurysm. The indication for surgery depends on the arterial signs of
      associated complications (5 of our cases). In one case surgery was indicated to
      prevent rupture of a splenic artery aneurysm and an aneurysm of the subrenal
      abdominal aorta. Two cases were treated by exclusion (ilio-cava fistula) or
      excision (splenic aneurysm); renal or digestive revascularization was performed
      with arterial or venous autografts in young patients (3 cases). One extensive
      abdominal coarctation was repaired with a PTFE graft as were the subclavian and
      subrenal aorta aneurysms. One patient with an ilio-cava fistula died from
      collapsus. Long-term results of the revascularizations are satisfactory with good
      control of the hypertension and total regression of the digestive angina.
      Fibrodysplasia of the renal or digestive media occurring alone or thoraco
      abdominal coarctation should suggest NF1 and lead to a complete work-up to
      identify other arterial localizations. Patients should be followed regularly to
      prevent complications which in case of rupture can be life-threatening.

PMID- 10582179
TI  - [Results of a neurophysiologic consultation in patients with secondary lymphedema
      of the arm after breast cancer associated with neurological symptoms].
AB  - The aim of this study was to identify the nature of the nerve lesions found in
      patients with neurological complains and with lymphedema occurring after breast
      cancer treated by surgery and radiotherapy. Twelve patients treated in a
      specialised centre for lymphology had clinical and neurophysiological
      examinations. This study found 9 radiation-induced plexopathies, 1 neoplasic
      plexopathy, 2 carpal tunnel syndromes (one isolated), 1 cervical root disease and
      1 normal examination. The radiation-induced plexopathy is characterised by a
      chronic neurogenic involvement and the presence of (motor and sensory) proximal
      persistent conduction blocks. This study demonstrated that it is essential to
      identify with electrodiagnosis the exact nature of the nerve lesion to determine
      the most appropriate and effective treatment.

PMID- 10582178
TI  - [Platelet activation in cardiology: methods, indications and therapeutic
      perspectives].
AB  - Platelet activation and/or platelet reactivity have been reported to be
      associated with coronary heart disease. Whole blood flow cytometry allows to
      analyze platelets in their physiological environment, while other assays need
      platelet separation, susceptible to induce platelet modifications. But flow
      cytometric assay also have limitations. We studied preanalytical conditions in
      healthy volunteers, using two monoclonal antibodies directed against CD62 and
      CD63 (two specific markers of platelet degranulation), and two markers which
      recognize GPIIb/IIIa activation (PAC1 and bound fibrinogen). Preanalytical
      requirements were as follow: 1) whole blood samples need antagonists of platelet
      activation i.e., a mixture of theophylline, adenosine and dipyridamole, since
      artefactual platelet activation rapidly occurred in citrated whole blood, 2)
      whole blood should be immediately immunolabeled when samples arrived to
      laboratory, because fixation did not prevent artefactual time dependent
      activation, 3) the stability of immunolabeling was determined for each monoclonal
      antibody: paraformaldehyde as fixative solution was mandatory for both CD62 and
      CD63, whereas it enhanced bound fibrinogen and PAC1 expression, 4) platelets can
      be easily identified and gating on a dual scatter (forward scatter x side
      scatter) dot plot with no specified labeling. The whole blood flow cytometric
      assay must be standardized in future clinical studies, especially regarding to
      preanalytical requirements.

PMID- 10582180
TI  - [Essential thrombocythemia and cerebral ischemic accident: discussion of two
      cases].
AB  - Not only the total number of platelets but their normal or abnormal function are
      essential points to be analyzed in case of stroke associated with thrombocytemia.
      When possible the treatment of arterial episodes in thrombocytemia should not be
      surgical. Anti-platelet agents and the rigorous control of the different risk
      factors are warranted to limit the activation of abnormal platelets on early
      endothelial lesions and thereby limit the risk of recurrent accidents. We report
      two typical cases illustrating these different points.

PMID- 10582181
TI  - [Coronary revascularization provides confirmation of coronary and aortic giant
      cell vasculitis].
AB  - The present report describes a 58-year-old woman who had unstable angina pectoris
      28 months after the end of corticosteroid treatment prescribed for biopsy-proven
      temporal arteritis. Coronary angiogram disclosed critical left main coronary
      artery stenosis. Despite a 3-week corticosteroid regimen no improvement was
      obtained and an aortocoronary bypass was performed. Histological examination of
      the affected artery showed vasculitis. Corticosteroid treatment was continued.
      Six months later, symptoms had not recurred and the coronary bypass graft was
      permeable. The stress test was negative fifteen months after surgery and the
      patient remained clinically well thirty months later. For any patient with
      current or previous temporal arteritis, any cardiovascular manifestation might be
      a new episode of giant-cell arteritis.

PMID- 10582182
TI  - [Youthful popliteal aneurysm].
AB  - Popliteal artery aneurysms are not so clinically frequent but are the most common
      site of peripheral aneurysms. They usually affect men aged over sixty and are
      caused by atherosclerosis. Whenever they concern younger men, other more unusual
      aetiologies such trauma, infection, inflammatory arteritis or popliteal
      entrapment are responsible. The authors report the first written observation of
      small size popliteal aneurysm, revealed by intermittent claudication in a 33
      years old subject, of which the origin is accelerated atherosclerosis. The
      evolution after resection of the popliteal aneurysm and end-to-end anastomosis
      with saphenous vein was favorable. This observation reminds us of various
      popliteal aneurysm aetiologies, not excluding atherosclerosis due to young age
      and also underlines that the small size of these aneurysms does not protect
      against embolism risk.

PMID- 10582183
TI  - Assessing the evidence that antibiotic growth promoters influence human
      infections.

PMID- 10582184
TI  - Nosocomial infections in patients with HIV disease.
AB  - Throughout the AIDS epidemic, nosocomial infection in the patient with HIV
      disease has presented a constant problem--not only for the hospitalized patient
      but also for the clinic attender. The nosocomial spread of multidrug-resistant
      tuberculosis has emphasized the need for effective control of infection measures
      in dealing with the immunodeficient. Increased recognition of nosocomial
      bacterial pneumonias has raised questions about the place, if any, of
      antimicrobial prophylaxis in preventing Gram-negative and Legionella infection.
      The use of long-term indwelling venous catheters for the administration of
      parenteral therapy is associated with an increased risk of nosocomial bloodstream
      infection--particularly from staphylococci and Pseudomonas spp. Evidence now
      exists for the nosocomial spread of opportunistic infections, including
      Cryptosporidium parvum, Mycobacterium avium complex and Pneumocystis carinii. The
      delay between exposure and diagnosis, the atypical presentation of infections
      such as tuberculosis and repeated hospital admissions of AIDS patients can
      combine to confuse the issue with the result that a nosocomial infection may be
      mis-classified as community-acquired. It seems likely that the burden of
      nosocomial infection in HIV disease is continually underestimated.

PMID- 10582185
TI  - The genomic diversity of coagulase-negative staphylococci associated with
      nosocomial infections.
AB  - A total of 117 isolates of coagulase-negative staphylococci (CNS) were collected
      from patients in three medical centres. They were genotyped by pulsed-field gel
      electrophoresis (PFGE) following digestion with restriction enzymes SmaI and
      SstII. The isolates included Staphylococcus epidermidis, S. simulans, S. hominis,
      S. lugdunensis, S. capitis, S. saprophyticus, S. caprae and S. sciuri. They were
      collected at random from 82 patients and were associated with infected central
      venous lines, continuous ambulatory peritoneal dialysis (CAPD) catheters,
      endocarditis, osteomyelitis of prosthetic hips and internally fixed fractures.
      The genetic heterogeneity of the strains was demonstrated by PFGE profiles and
      two dendrograms. Though the strains were segregated into species, there was no
      clustering of the strains by type of infection, associated medical unit or
      geographical location of the patient. Numerous genotypes were identified,
      suggesting that no specific strains of CNS are associated with prosthetic related
      infection.

PMID- 10582186
TI  - Rapid emergence of resistant coagulase-negative staphylococci on the skin after
      antibiotic prophylaxis.
AB  - One approach for prosthetic vascular surgery is to continue antimicrobial
      prophylaxis while intravascular lines and catheters are in place. However this
      may give rise to antimicrobial resistance in the colonizing bacterial flora. We
      studied 37 patients undergoing vascular surgery, who received either co-amoxyclav
      for three days (group 1), ofloxacin plus metronidazole for three days (group 2)
      or for one day (group 3), respectively. Seventeen hospitalized patients not
      undergoing surgery or receiving antibiotics were studied as controls. In groups I
      and II there was a significant decline in susceptibility to cloxacillin (12.8%
      respectively 23.6%) and ofloxacin (0.5% and 85% respectively) in skin
      staphylococci. The results from group 3 were intermediate. Molecular typing
      showed that the patient's susceptible community-derived strains were replaced by
      genetically unrelated resistant strains, probably hospital derived. Long-term
      prophylaxis should be avoided as colonization occurs with resistant strains.

PMID- 10582187
TI  - Quantitative determination of endotoxins released by bacterial biofilms.
AB  - Residual endotoxins, commonly associated with bacterial biofilms colonizing
      reusable medical devices have been associated with pyrogenic reactions in
      patients. We have used a quantitative, sensitive and reproducible kinetic
      chromogenic adaptation of the Limulus Amebocyte Lysate assay to assess endotoxin
      recovery from an in-vitro bacterial biofilm. The 'recovery method' was based on a
      combination of physical treatment (vortexing and sonication) and chemical
      treatment (immersion in recovery solution). Five recovery solutions were
      investigated. The recovered endotoxin was greater when the biofilm was treated
      with a 1% SDS solution. The sensitive and reproducible method we have developed
      should allow the recovery and measurement of biofilm bacterial endotoxins on
      implanted and colonized medical devices. Moreover, the amount of endotoxin was
      sufficient (> 1000 endotoxin units/cm2 of substrate) to enable a substantial
      reduction by sterilization processes, the efficiency of which on biofilm
      endotoxins has yet to be proven.

PMID- 10582188
TI  - Pseudomonas aeruginosa strains obtained from patients with tracheal, urinary
      tract and wound infection: variations in virulence factors and virulence genes.
AB  - Pseudomonas aeruginosa produces several virulence factors including exotoxin A,
      exoenzyme S and elastase. In previous reports we have analysed several clinical
      isolates for the production of these three virulence factors and for possible
      heterogeneity within the genes that code for these factors (toxA, lasB and the
      exoS genes). The isolates were obtained from three specific sites (trachea,
      urinary tract and wounds). Although the isolates produced variable levels of
      these factors, isolates that were obtained specifically from urinary tract and
      wound infections produced increased levels of exotoxin A and exoenzyme S. In
      addition, a prolonged infection with P. aeruginosa appears to enhance exoenzyme S
      production. Restriction site polymorphism was very limited within the toxA, lasB,
      and exoS structural genes; however, the upstream region of toxA showed
      restriction site polymorphisms between the different isolates. The observed
      polymorphisms did not correlate with any variations in the levels of the
      virulence factors. In this article, we provide a short review of these studies.

PMID- 10582189
TI  - Properties of an enzyme-based low-level iodine disinfectant.
AB  - An enzyme-based iodine (EBI) disinfectant that continuously generates free
      molecular iodine in a controlled fashion was developed and evaluated for use in
      disinfecting flexible fibreoptic endoscopes (FFEs). EBI is a powder concentrate
      that produces iodine from sodium iodide and calcium peroxide when catalyzed by
      horseradish peroxidase. After dissolution in water, it delivers relatively high
      concentrations of free molecular iodine (> 15 ppm) at relatively low
      concentrations of total iodine (30-40 ppm). It demonstrates the ability to
      function as an effective low level iodine disinfectant by rapidly inactivating
      bacteria, fungi and viruses. A unique feature of the EBI system is the ability to
      reoxidize reduced iodine which results in a constant level of active (free
      molecular) iodine during use. EBI inactivates Mycobacterium bovis var BCG more
      rapidly than 2% glutaraldehyde (Cidex-7). Its sporicidal activity, however, was
      found to be slower than the aldehyde formulation. The qualification of EBI for
      use as a practical disinfectant was shown by its negligible toxicity in dermal,
      ocular, oral and inhalation studies on animals, which is attributed to the low
      level of total iodine in the solution.

PMID- 10582191
TI  - Interpreting the effectiveness of a national antibiotic policy and comparing
      antimicrobial use between countries.

PMID- 10582190
TI  - Rectal colonization with vancomycin-resistant enterococci among high-risk
      patients in an Israeli hospital.
AB  - The prevalence of rectal carriage of vancomycin-resistant enterococci (VRE) in
      two high-risk populations--61 patients admitted to ICU and 92 patients on renal
      dialysis--was studied longitudinally over a period of six months in a 650-bed
      general hospital. ICU patients were swabbed weekly and dialysis patients monthly.
      Enterococcal isolates were fully identified using the ATB identification system,
      and MICs were determined according to the NCCLS recommendations. Enterococci were
      isolated in 52 (83.6%) ICU patients and 86 (93.4%) dialysis patients. VRE were
      recovered at least once in 14 (27%) ICU patients and four (4.8%) dialysis
      patients. All VRE isolates (MIC of vancomycin > or = 256 micrograms/mL) were
      resistant to teicoplanin (MIC > or = 32 micrograms/mL; vanA phenotype), 87.5%
      were ampicillin-resistant, and 92% showed high-level resistance to gentamicin;
      88% were E. faecium. The main risk factors for acquisition of VRE included
      duration of hospitalization in the six months preceding entry into the study and
      during the survey (P = 0.009 and 0.007 respectively, for ICU patients), and
      duration of antibiotic administration (P = 0.005, for ICU patients). The impact
      of vancomycin was most prominent (P = 0.005 for receipt and 0.06 for duration of
      administration, in ICU patients). Six of the 18 VRE carriers developed
      bacteraemia, six isolates being vancomycin-susceptible and one vancomycin
      resistant (one patient had both). In this study, the first in Israel, a low
      rectal carriage rate occurred in renal dialysis patients and antibiotic use was
      the most important risk factor for VRE colonization.

PMID- 10582192
TI  - Fatal nosocomial Legionnaires' disease after heart transplantation: clinical
      course, epidemiology and prevention strategies for the highly immunocompromized
      host.

PMID- 10582193
TI  - Bench-top sterilizers and CSSD.

PMID- 10582194
TI  - Contamination of intravenous heparin infusions.

PMID- 10582196
TI  - Dust mites but not grass pollen are important sensitizers in asthmatic children
      in the Ecuadorian Andes.
AB  - Grass pollen is an important cause of asthma and rhinoconjunctivitis in Europe
      and the United States. In the high Andes however, the role this pollen plays in
      respiratory allergies is unknown. In this study, we tested the prevalence of
      grass pollen sensitization in comparison to other aeroallergens on 433 asthmatic
      children living in Quito, Ecuador (the Andes mountain range, 2,800 m above sea
      level). The skin prick test technique was used. We found that the least
      sensitizing allergens of all were grass pollen (12.2%) and molds (7.4%) with p <
      0.0001. A clear predominance of sensitization to the house dust mite
      Dermatophagoides pteronyssinus (77.8%) and Dermatophagoides farinae (76.9%), in
      comparison to the other aeroallergens tested, in terms of sensitization (p =
      0.00000) and papule size (p < 0.0002), was observed. The most highly sensitized
      group consisted of asthmatics between 5 and 15 years of age (D. pteronyssinus
      90.7%, D. farinae 87.5%, dog hair 37.4%, cat hair 43%, grass pollen 15.9% and
      molds 9.9%). In the total study group, males were only more sensitive than
      females to D. pteronyssinus (82.1% vs. 71.6%, p = 0.0009). We concluded that in
      the group of asthmatic children studied, grass pollen showed a low capacity of
      sensitization, even though it is widely found all over our city. The most
      sensitizing allergens were D. pteronyssinus and D. farinae, followed by cat and
      dog hair.

PMID- 10582195
TI  - Nasal provocation and immunotherapy.
AB  - Nasal mucosa is heavily exposed to inflammatory and allergic stimuli, rhinitis
      being the most common form of allergic respiratory disease. The nose is an easily
      accessible organ and a good model for the study of allergies as it makes it
      possible to monitor the effects of specific challenges as well as therapeutic
      interventions, namely specific immunotherapy (SIT). Injectable, nasal or
      sublingual SIT are useful therapeutic strategies in the management of allergic
      rhinitis patients. Monitoring the evolution of parameters such as clinical
      scores, nasal peak flow variation or drug requirements during SIT provides
      important information on its clinical efficacy. Laboratory measurement of
      tryptase and eosinophil cationic protein in the target organ after specific nasal
      provocation makes it possible to record changes in the release of mast cell and
      eosinophil mediators, thus providing objective evidence of the immunological
      efficacy of this therapy on these cell populations and providing data which
      eventually will contribute to a better understanding of the multiple mechanisms
      of action of allergen desensitization therapy.

PMID- 10582197
TI  - Comparison of two different dose regimens of nedocromil sodium with placebo in
      the management of childhood asthma.
AB  - According to the recent guidelines, persistent asthma requires daily
      antiinflammatory treatment with either nedocromil sodium, cromolyn sodium or
      inhaled corticosteroids. In choosing the most appropriate drug, it is wise to
      weigh the therapeutic advantages against possible side effects, particularly in
      patients at the milder end of disease spectrum and in children. Cromolyn sodium
      and nedocromil sodium both have strong safety profiles, and nedocromil sodium has
      been reported to have a broader spectrum of efficacy than cromolyn sodium. In an
      attempt to provide data for the efficacy of two different dose regimens of
      inhaled nedocromil sodium in childhood asthma, a placebo-controlled, randomized,
      double-blind, double-dummy, parallel group study was conducted in 38 subjects
      with mild to moderate persistent asthma. After a 2-week run-in period, patients
      were randomly allocated into one of the three study groups and treated with
      either placebo or with two times daily (4 mg b.i.d.) or four times daily (4 mg
      q.i.d.) regimens of inhaled nedocromil sodium for 8 weeks. Symptom scores,
      bronchodilator requirements, FEV1, daily PEFs and methacholine hyperreactivity
      were evaluated at study entry, before randomization and at weeks 4 and 8 of
      treatment. In the four times daily treatment group, slight but significant
      increases were observed in FEV1, peak expiratory flows and symptom scores (p <
      0.05 for each). However, there was no significant change in methacholine
      hyperreactivity and bronchodilator requirement. In the two times dose regimen and
      placebo groups, there were no improvements in any of the variables. The
      compliance, measured as the reduced weight of the canisters, was low, but was not
      different between the two nedocromil sodium treatment groups. The four times
      daily regimen of nedocromil sodium was effective in improving control of mild to
      moderate persistent asthma in children, whereas the two times daily regimen
      failed.

PMID- 10582198
TI  - Immunological changes during cockroach immunotherapy.
AB  - Data obtained in a 3-year survey of specific immunotherapy (SIT) with a
      Periplaneta americana antigen (Pa-1) are presented. Parameters such as serum IgE
      paperadioimmunosorbent test, specific IgE and IgG, interleukin (IL)-2, IL-4 and
      IL-4R levels were recorded before and after SIT. While serum IgE levels and IgE
      RAST-anti-Pa-1 did not change throughout SIT (p = not significant), IgG-RAST-anti
      Pa-1 showed a marked increase from the first year (p < 0.002 to p < 0.001). Only
      after 3 years of SIT did the serum levels of IL-2, IL-4 and IL-4R show lower
      values than before this period (p = 0.05, p = 0.05, p = 0.01, respectively). The
      comparative statistical analysis of the cytokine data between the nonatopic
      subjects and the atopic treated patients revealed no significant differences (p =
      0.02). The symptomatic scores showed significant results at the third year of SIT
      in sneezing attacks, nose blowing and nasal obstruction (p = 0.001, p < 0.001, p
      = 0.001, respectively).

PMID- 10582199
TI  - Sublingual immunotherapy and influence on urinary leukotrienes in seasonal
      pediatric allergy.
AB  - Sublingual immunotherapy has been suggested for the treatment of respiratory
      allergies. Many controversial studies have been reported on the efficacy of
      sublingual immunotherapy. The aim of this prospective study was to evaluate
      whether sublingual immunotherapy was effective according to clinical and
      laboratory results in pediatric allergies. Thirty-nine allergic, grass pollen
      sensitive children were admitted into the study. Sublingual immunotherapy was
      given over a 12-month period to 21 children (mean age 10.5 +/- 3.3 years), 10 of
      whom had seasonal allergic rhinitis and 11 seasonal allergic asthma. During the
      same period, 18 children (mean age 11.1 +/- 2.5 years), 10 with seasonal allergic
      rhinitis and eight with seasonal allergic asthma, received placebo. Symptom
      scores and drug requirements were recorded and urine samples were collected to
      detect urinary levels of leukotrienes (Uc-LTB4 and Uc-LTE4). In patients who
      received sublingual immunotherapy, the symptom scores of seasonal allergic
      rhinitis significantly decreased, but no statistically significant changes were
      observed in terms of symptoms of seasonal allergic asthma. Uc-LTE4 and Uc-LTB4
      levels of seasonal allergic rhinitis, with a geometric mean and 95% confidence
      interval (CI), were significantly decreased from 216 (103-464) and 61 (22-198)
      pmol/mmol creatinine to 78 (29-159) and 35 (12-118) pmol/mmol creatinine,
      respectively (p < 0.05 and p < 0.05). On the other hand, Uc-LTE4 and Uc-LTB4
      levels for seasonal allergic asthma were 180 (92-355) and 78 (44-258) pmol/mmol
      creatinine and decreased to 156 (72-402) and 69 (32-254) pmol/mmol creatinine,
      respectively. These changes were not statistically significant (p > 0.05).
      According to our clinical results and urinary levels of leukotrienes, which are
      mediators showing the severity of allergic inflammation, it can be suggested that
      sublingual immunotherapy may be useful in the treatment of seasonal allergic
      rhinitis but not of seasonal allergic asthma.

PMID- 10582200
TI  - The growing genetic links and the early onset of atopic diseases in children
      stress the unique role of the atopic march: a meta-analysis.
AB  - Allergic asthma and rhinitis, atopic dermatitis, urticaria and food allergy are
      genetic diseases present in infants and children. Several investigators have
      provided evidence for a genetic localization for atopy. Babies of atopic parents
      are at high risk of developing atopic diseases; however, the phenotypic
      expression of such diseases varies widely in that it can be very mild in some
      infants and children, severe and frustrating in many, even life-threatening in
      others, as well as also being common, disabling and chronic. A meta-analysis of
      all available studies on the age of onset of atopic march was carried out by
      selecting what appeared to be the most relevant articles in the literature rather
      than aiming for a comprehensive selection. It was found that in the first year of
      life, there is the onset of atopic dermatitis in 79.8% (60.2-100%) of babies, of
      cow's milk allergy in 72.7%, egg allergy in 71%, and fish allergy in 51.3%.
      Asthma starts in the first year of life in 41.8%, in the second in 49.3%, and
      within the eighth year in 92.5% of children. Allergic rhinitis begins in 35% of
      babies in the first year of life, and in 59% or 13-19% in those aged 2-5 years.
      It seems therefore that up until now the role of pediatric allergy and immunology
      has been somewhat obscured, as can be witnessed by atopic march. Instead,
      pediatric allergy and immunology have a substantial, unmatched role, focusing on
      the early and often very early onset of atopy, which requires strategic
      intervention in the very first months of life or even before birth. As the main
      goal of modern medicine is prevention of chronic and severe diseases, the
      possibility of preventing such disorders in predisposed children has stimulated
      the imagination of researchers since the beginning of the century, when atopic
      diseases were not as common as they are now.

PMID- 10582201
TI  - Immunotherapy with a mass unit Parietaria judaica extract: a tolerance study with
      evidence of immunological changes to the major allergen Par j 1.
AB  - Specific immunotherapy with Parietaria judaica pollen extract has been proven to
      be effective in the treatment of patients with respiratory allergy induced by
      this pollen. Nevertheless, there is some controversy about its tolerability. We
      conducted an open uncontrolled study to evaluate the tolerability of an aluminium
      adsorbed P. judaica pollen extract whose major allergen (Par j 1) content was
      known. Changes in immunological parameters to a complete P. judaica extract and
      to a purified Par j 1 preparation were monitored. Twenty-one patients (12 women,
      9 men; mean age 30.2 years) suffering from rhinoconjunctivitis and/or asthma due
      to Parietaria pollen were enrolled. The maximum dose was established at 10 BU/ml
      (0.6 microgram Par j 1). Skin and conjunctival reactivity as well as serum levels
      of specific IgE, IgG, IgG1 and IgG4 were evaluated before therapy (T0), when 1 BU
      was given (T1), 2 weeks after the maintenance dose was reached (T2) and after the
      pollen season (T3). Four-hundred and fifteen doses were administered during
      immunotherapy. Only one systemic reaction (0.24% of doses) and two local
      reactions were registered. Reactions occurred during the administration of the
      highest concentrated vial. Before immunotherapy, purified Par j 1 accounted for
      94.2% of the cutaneous response elicited by the complete extract. A statistically
      significant decrease in cutaneous response was detected after 8 weeks of
      treatment. There were no significant changes in conjunctival reactivity
      throughout the study. Specific IgG, IgG1 and IgG4 showed a pronounced and
      significant increase during the study, while specific IgE levels initially
      decreased and increased after the pollen season. The kinetics of specific
      antibodies to P. judaica complete extract and purified Par j 1 showed a parallel
      trend. The present study demonstrates that immunotherapy with P. judaica extract
      is well tolerated in patients suffering from rhinoconjunctivitis and/or asthma
      due to Parietaria pollen. This therapy induces specific changes in the
      immunological response to P. judaica and to purified Par j 1. These changes can
      be detected at very early stages of therapy.

PMID- 10582203
TI  - Anaphylaxis should be considered to be a potential cause of stuporous state.
AB  - Anaphylaxis is not considered to cause stupor. We studied the case of a 69-year
      old woman who lost consciousness after eating seafood. On her admittance to
      hospital she was in a state of stupor and elevated serum tryptase levels led us
      to the diagnosis of anaphylaxis.

PMID- 10582202
TI  - Anaphylaxis inhibitory factor in IgE-dependent mast cell stimulation.
AB  - We have previously demonstrated that there is a factor present in some human
      serum which inhibits the passive cutaneous anaphylaxis reaction mediated by IgE.
      The present study analyzes the effect of this factor on mast cell IgE-dependent
      tumor necrosis factor (TNF)-alpha release. Rat peritoneal mast cells and RBL-2H3
      cells treated with monoclonal mouse IgE anti-dinitrophenol (anti-DNP) followed by
      DNP-bovine serum albumin (DNP-BSA) were used and TNF-alpha release was measured
      at different time points. Similarly the percentage of rat peritoneal mast cell
      degranulation was determined. Results show a period of 30 min as optimal
      incubation time for TNF-alpha release in both mast cell populations. Human serum
      anaphylaxis inhibitory factor enriched fraction inhibited TNF-alpha release when
      it was in contact with IgE before the antigen treatment. Under these conditions
      the percentage of mast cell degranulation decreased. Mast cells incubated before
      IgE treatment with the factor alone do not release TNF-alpha and the percentage
      of degranulation increases due to a non-IgE-dependent process. A possible role of
      the inhibitory factor in the later phase reaction in addition to immediate
      hypersensitivity described previously is suggested.

PMID- 10582204
TI  - Desensitization to azathioprine.
AB  - Azathioprine is an immunosuppressant drug which is an analog to 6-mercaptopurine
      and has been used in the last 20 years to prevent organ transplant rejection. It
      has also been used in the treatment of some autoimmunological diseases. We
      present a case of a 24-year-old woman with systemic lupus erythematosus,
      suffering from nephritis, who developed angioedema after using azathioprine to
      control her illness. She had never reported similar episodes. The involvement of
      the drug was demonstrated by positive oral challenge test without changes in
      biochemical and complement blood determinations. She reached tolerance to the
      drug after a desensitization procedure (increasing 5 mg each day to reach 125 mg
      daily). We are not able to propose the involvement of an IgE-mediated mechanism,
      but rather a hypersensitive one with a non-dose-dependent effect. These
      desensitization procedures show great potential as therapeutic safeguards against
      harmful drugs in some patients. We have not found any other desensitization
      procedure for this drug.

PMID- 10582205
TI  - [Malonyl dialdehyde concentration in red blood cells of workers engaged in the
      production of iron-manganese alloys].
AB  - The increased concentration of malonyl dialdehyde (MDA) in peripheral blood red
      cells of workers engaged in the production of iron-manganese alloyes was found.
      That provide evidence that increased peroxidation of red blood cell lipids
      induced by the production of free radicals is due to factors present in the
      occupational environment.

PMID- 10582206
TI  - [The evaluation of the exposure of seamstresses to electromagnetic fields,
      emitted by sewing machines].
AB  - The authors present the results of the first phase of the studies on the risk of
      pregnancy complications in semesters and on their work environment with special
      reference to electromagnetic fields (EMF) emitted by various types of industrial
      sewing machines. EMF measurements were taken in the surrounding of 464 sewing
      machines used in five sewing works in the region of Lodz. The results obtained
      provided evidence that semesters++ working with industrial sewing machines were
      exposed to EMF of 60 Hz. Thirteen types of machines were identified. Having based
      on the statistical analysis (analysis of variance) it was found that individual
      types of sewing machines emit substantially different EMFs. Depending on the
      level of EMF emitted at a given workpost, all the machines were classified into
      three groups: those with weak (O A/m-1.5 A/m); medium (2 A/m-4 A/m); and strong
      (9 A/m-16 A/m) emissions.

PMID- 10582207
TI  - [The participation of psychological laboratories in the implementation of tasks
      assigned to district occupational health centers].
AB  - For many years psychologists have carried out examinations for the benefit of
      Occupational Health Services. In the past, they mostly focused on the
      qualification of persons to be employed at posts that require a good psychomotor
      performance. Since 1996 when the modified Labour Code, the Occupational Health
      Services Act, and regulations on preventive health examinations became effective,
      the scope of tasks and objectives to be accomplished by psychologists engaged in
      occupational health services have expanded greatly. The aim of the studies was to
      define the extent of responsibilities of and the task performance by
      psychological laboratories of district occupational health centres as well as to
      find out what changes should be introduced in order to best improve the
      functioning of these laboratories.

PMID- 10582208
TI  - [Attitudes of occupational medicine physician towards health promotion].
AB  - The objective of the survey was to judge the attitudes of occupational medicine
      physicians towards health promotion in the workplace. To this end, a special
      questionnaire has been developed. In total, 142 physicians qualified in
      preventive medicine were surveyed. Some of them have been working as occupational
      physicians for six years and some were in the course of specialisation in
      occupational medicine (the 1st and the 2nd grades). The survey yielded the
      following results: 84.5% of respondents considered that occupational medicine
      physicians should be involved in health promotion in the workplace, but only
      37.1% of them were ready to undertake individual actions in this area; a large
      majority of respondents listed the following factors as the main obstacles in
      initiating health promotion activities: (a) the lack of interest in health
      promotion among employers (27.5%), (b) the lack of interest in health promotion
      among employees (25.5%), (c) the lack of time (25.5%), (d) the ack of sufficient
      financial means for health promotion in the workplace. Only 2.8% of persons
      reported no problems encountered in their health promotion work in the workplace.
      In addition, 39.4% of respondents were interested in the organisation and
      coordination of health promotion programmes in conditions existing nowadays in
      Poland. To sum up the results of the survey, it is necessary to emphasise a
      positive observation that the majority of respondents want to participate in
      health promotion programmes, although they feel that 'know-how' knowledge,
      professional publications and medical equipment are still far from being
      satisfactory. Thus, it is deemed necessary to develop further health promotion
      programmes to encourage positive attitudes towards health promotion among
      employers and employees.

PMID- 10582209
TI  - [The toxic effect of mercury in occupational exposure].
AB  - The paper addresses the problems of environmental and occupational exposures to
      mercury compounds. Mercury and its compounds are very toxic. Occupational
      exposure and environmental pollution are the major sources of hazard to human
      health. Metallic mercury evaporates at room temperature producing inorganic and
      organic compounds, and forms amalgams with many metals. In more than 50
      professions, workers may be exposed to mercury, particularly in the mining and
      chemical industries and in agriculture. Occupational poisoning is rarely acute
      but it is usually chronic. The symptoms result from the damage to the central
      nervous system, and the kidney, as well as from the impairment of erythrocyte
      metabolism, coagulation and immune response. Mercury may also induce allergic
      reactions. Chronic mercury poisoning is diagnosed on the basis of the clinical
      picture in the presence of the occupational exposure. Inorganic mercury poisoning
      is treated specifically with chelating agents.

PMID- 10582210
TI  - [Epidemiology of Lyme borreliosis].
AB  - In this paper basic issues concerning epidemiology of Lyme disease were
      presented. The role of ticks and small mammals was emphasised. An increasing
      prevalence of Lyme disease especially among people working in forests was pointed
      out.

PMID- 10582211
TI  - [Prevention of Lyme disease].
AB  - Over the last decade many researchers have turned much attention to the vaccine
      against Lyme disease as the only effective preventive method. Recently two groups
      of researchers have published data on their trials carried out on humans. The
      vaccine given to volunteers consisted of recombinant outer surface protein
      (Osp)A. A two-year observation of the persons studies revealed that 79% of them
      had developed resistance to Borrelia burgdorferi infection. These data were
      evaluated by the FDA experts who recommended the vaccine for general use with the
      following reservations that have to be elucidated: too short observation of
      vaccinated persons, no possibility to vaccinate children and the problem of
      vaccinating people with undiagnosed Lyme disease.

PMID- 10582212
TI  - [Some aspects of drinking water fluoridation].
AB  - Increased fluoride concentration in different ecological systems results from
      cool combustion and fluoridation of water in the public supply system. In
      Wroclaw, water has been fluoridated for thirty years to achieve the concentration
      of 1 mg F per litre for dental caries protection. Over that time the
      concentration of fluoride ion has not been surveyed in serum or urine of the
      Wroclaw population. The prevention of dental caries using fluoride-containing
      tooth paste as well as fluoride tables and gels is strongly recommended.

PMID- 10582213
TI  - [The problem of correct assessment of risk of hearing loss in miners during their
      work at the mines].
AB  - This paper presents a modern approach to quantitative risk assessment of noise
      exposed miners. It is a twofold process involving the hazard assessment to
      determine the degree of potential harm posed by a given source of noise, and the
      exposure assessment to estimate the number of persons potentially exposed to
      harmful or annoying levels of noise emissions. In other words, to be accurate one
      has to retrieve the information on the characteristics of various standard
      populations; quantitatively assess the exposure at workplaces; and directly
      calculate the risk resulting from the exposure. It should be stressed that
      quantitative risk assessment of hearing loss is one of the essential steps in the
      Hearing Conservation Programme. The final aim of risk assessment is risk
      management which involves the selection of the most appropriate strategy to
      reduce the noise emission to the level required, and to limit the probability of
      harmful health effects.

PMID- 10582214
TI  - [Own experience in occupational evaluation of persons with hypertension].

PMID- 10582215
TI  - Pre- and postsynaptic mechanisms of the involvement of amygdaloid complex
      serotonin in the reproduction of a conditioned passive avoidance response in
      rats.
AB  - Serotonin metabolism and [3H]-serotonin radioligand receptor binding were studied
      in the amygdaloid complex of the rat brain at different stages of a conditioned
      passive avoidance response. Serotoninergic changes were specific for the process
      of reproduction of the conditioned response. The involvement of serotonin in the
      amygaloid complex during reproduction of memory traces consisted of a reduction
      in its postsynaptic receptor binding. The serotonin level in the amygaloid
      complex did not change, while changes in serotonin metabolism detected during
      reproduction of the conditioned avoidance response were associated with an
      increase in its deamination by monoamine oxidase and an increase in the active
      transport of 5-hydroxyindoleacetic acid from nerve terminals.

PMID- 10582216
TI  - The effects of a novel analog of the C-terminal fragment of vasopressin on the
      behavior of white rats.
AB  - The effects of an arginine-vasopressin fragment, Ac-D-MPRG, on the movement
      activity and orientational-investigative activity of white rats were studied.
      Peptide was given intranasally at doses of 0.001, 0.01, 0.1, 1, and 10
      micrograms/kg 1 h before testing. All peptide doses increased vertical movement
      activity in an open field test and hole board test and decreased grooming levels
      in both tests. The peptide had no effect on horizontal movement activity.
      Analysis of these results led to the conclusion that Ac-D-MPRG increases
      orientational-investigative activity, but, unlike arginine-vasopressin, does not
      affect non-motivated movement activity.

PMID- 10582217
TI  - The effects of atropine microinjections into the motor cortex of rats on the
      development of a motor habit.
AB  - Acetylcholine modulates the responses of motor cortex neurons during learning.
      Studies were carried out on the effects of atropine microinjections into the
      motor cortex on the development of a habit consisting of procuring food with the
      forelimbs in freely mobile rats. Animals received unilateral intracortical
      injections of atropine (5 and 15 micrograms in 0.6 microliter over 40 sec) in the
      forelimb representation area of the motor cortex. Rats were trained to procure
      food from a horizontal tube, using the forelimb contralateral to the injection
      site. Data were obtained which suggested that atropine has a dose-dependent
      effect on the development of this movement habit. The general effect of atropine
      doses consisted of suppressing the inhibition of concurrent movements during
      learning. The higher atropine concentration had a depressive effect on the
      initiation of the learned movement.

PMID- 10582219
TI  - A model of a neuronal network for detection of single bands and cross-like
      figures.
AB  - A model of a neuronal network is presented which, like a significant proportion
      of the neurons in the visual cortex, identifies not only the orientation of a
      single band, but also high selective sensitivity to cross-like figures. The model
      was used to study the properties of a "cross detector" constructed on the basis
      of convergence of excitatory connections with different weightings from elements
      with different orientational tuning. It is shown that a cross detector with
      monomodal orientational tuning needs an amplifier mechanism (a reverberator).

PMID- 10582218
TI  - Background activity of rabbit hippocampal neurons in conditions of functional
      exclusion of structures which regulate the theta rhythm.
AB  - The functional importance of theta modulation in the activity of hippocampal
      neurons was further analyzed using a method consisting of controlled sequential
      short-term (25-30 min) inclusion or exclusion of the theta rhythm by local
      administration of lidocaine into the median cervical nucleus and medial septal
      region respectively. Studies were carried out using conscious rabbits with
      extracellular recording of hippocampal neuron activity in field CA1.
      Administration of lidocaine into the medial septal nucleus and diagonal tract
      nucleus (MS-DT) led to complete inhibition of theta modulation in neuronal and
      total hippocampus activity. The mean frequency of background discharges underwent
      no change in most neurons, but decreased significantly in a limited group of
      cells with high-frequency activity (presumptive inhibitory neurons).
      Administration of lidocaine into the median cervical nucleus (MCN), the source of
      serotoninergic pathways to the MS-DT and hippocampus, was accompanied by
      increases in the stability and frequency of theta modulation of neuronal
      activity, induction of theta modulation in an additional group of neurons, and
      expression of a continuous theta rhythm in the electrical activity (EA) of the
      hippocampus. The mean frequency and regularity of discharges increased in most
      cells. These data support the existence of tonic inhibitory effects on the part
      of the MCN on the septa-hippocampal system generating the theta rhythm; in this
      regard, the MCN can be regarded as an antagonist of the activating reticular
      formation.

PMID- 10582220
TI  - The protective effects of negative air ions in acute stress in rats with
      different typological behavioral characteristics.

PMID- 10582221
TI  - Disorders of higher mental function due to single infarctions in the thalamus and
      in the area of the thalamofrontal tracts.
AB  - Nine patients (five female and four male, mean age 58 years) with small infarcts
      in the thalamus (TH) or in the region of the thalamofrontal tracts and producing
      acute mental disturbances which in the acute phase of insult consisted of
      dementia in seven cases and mild cognitive disturbances in two cases. The complex
      of mental changes was similar to that seen in "frontal syndrome" and was
      characterized largely by lack of spontaneity, adynamia, disorientation, loss of
      attention and memory, slowing of all mental processes, and lack of criticality
      and adequacy. Accompanying focal neurological symptoms were mild in seven
      patients and moderate or pronounced in two. In five patients, the severity of
      mental disturbances decreased with time. Computer tomography demonstrated small
      infarcts in the anterior or medial parts of the TH in seven patients and in the
      posteromedial parts of the anterior limb of the internal capsule, i.e., the
      thalamofrontal tracts, in two cases. In five cases, infarcts were located in the
      dominant hemisphere, with lesions in the non-dominant hemisphere in three and in
      both hemispheres in one. The positions of all foci corresponded to structures
      traversed by pathways connecting the TH and the lower part of the reticular
      formation to the frontal lobes. It is suggested that disconnection of these
      pathways leads to cognitive lesions or dementia because of functional
      inactivation of the frontal cortex.

PMID- 10582222
TI  - Quantitative changes in human cerebellar pyriform neurons from birth to the age
      of 20 years.

PMID- 10582223
TI  - Cell structure in the islands of Calleja in carnivore brains.

PMID- 10582224
TI  - The astrocyte glia of the motor cortex in conditions of application of
      acetylcholine.

PMID- 10582225
TI  - Experimentally induced actin depolymerization disrupts the adaptive state of
      neurons.

PMID- 10582227
TI  - Structural organization of the thoracic nucleus of the spinal cord of the cat
      after destruction of the amygdaloid body of the brain.

PMID- 10582226
TI  - Changes in the ratio of the rough and smooth endoplasmic reticulum in fish
      Mauthner neurons as a measure of compensatory processes occurring in response to
      sensory stimulation.

PMID- 10582228
TI  - The synaptology of two types of neurons in the sympathetic ganglia of the frog.

PMID- 10582229
TI  - The protective effect of nerve growth factor in nerve tissue cultures exposed to
      diphtheria toxin.

PMID- 10582230
TI  - Morphological features of cell death in various types of acute tick-borne
      encephalitis.

PMID- 10582231
TI  - Methods and methodological approaches to studies of isolated neurons of brain
      from adult animals (Lymnaea stagnalis) in tissue culture.

PMID- 10582232
TI  - The role of the hippocampal formation in controlling GABA release in the nucleus
      accumbens during an emotional conditioned response.
AB  - Intracerebral dialysis was used in living hooded rats in combination with high
      performance liquid chromatography with electrochemical detection to study the
      effects of lesions to the hippocampal formation on GABA release into the
      intercellular space of the medial part of the nucleus accumbens during an
      emotional conditioned response to situational stimuli. These experiments showed
      that the procedures of learning and performing the emotional conditioned response
      were accompanied by increases in GABA levels in the intercellular space of the
      nucleus accumbens. Lesioning of the hippocampal formation with ibotenic acid
      interfered with the performance of the emotional conditioned response and
      decreased the release of GABA in the nucleus accumbens induced by the behavioral
      test to levels not significantly different from those due to background release.
      These data suggest that the hippocampal formation has a role in reproducing
      memory traces produced by situational stimuli and that this role is mediated by
      its influence on the GABAergic system of the nucleus accumbens.

PMID- 10582233
TI  - Increases in the threshold for the development of epileptiform activity in field
      CA1 of Krushinskii-Molodnika rat hippocampal slices as an adaptive protective
      mechanism.
AB  - Studies were carried out into the chances of developing epileptiform activity in
      the neuronal network of hippocampal field CA1 in normal (Wistar) rats and in rats
      genetically predisposed to audiogenic convulsions (Krushinskii-Molodkina rats).
      The development of epileptiform activity was assessed in terms of the reduction
      in the threshold for development trains of epileptiform discharges in field CA1
      of hippocampal slices, which were induced using episodic increases in the
      extracellular K+ concentration ([K+]0) or decreases in the extracellular Mg2+
      concentration ([Mg2+]0). These experiments showed that the threshold for the
      development of trains of epileptiform discharges increased in field CA1 of
      hippocampal slices of Krushinskii-Molodkina rats, while the excitability of
      glutamatergic Schaffer collaterals/commissural fibers was decreased. In addition,
      Krushinskii-Molodkina rats showed no long-term potentiation of glutamatergic
      synaptic transmission or potentiation of the EPSP-spike system in pyramidal
      neurons, induced in field CA1 of hippocampal slices in Wistar rats by reductions
      in [Mg2+]0 and increases in [K+]0 respectively. It is suggested that this
      underlies the operation of an adaptive protective mechanism preventing the
      propagation of convulsive activity in the Krushinskii-Molodkina rat brain.

PMID- 10582234
TI  - Long-term increases in neuronal activity in the motor cortex evoked by
      simultaneous stimulation of the thalamus and somatosensory cortex in cats.
AB  - Experiments on anesthetized cats were used to study the activity of motor cortex
      neurons (field 4 gamma) in response to separate and simultaneous stimulation of
      the ventrolateral nucleus of the thalamus and the somatosensory cortex (field 2)
      of the brain. Long-term potentiation of motor cortex neuron activity in response
      to simultaneous stimulation of the ventrolateral nucleus and somatosensory cortex
      arose only in regions receiving corticocortical projections from the stimulation
      site in the somatosensory cortex of the brain, while regions lacking
      corticocortical projections from the somatosensory cortex showed no such effect.
      Experiments demonstrated that the duration of increased motor cortex neuron
      activity following stimulation of the ventrolateral nucleus of the thalamus and
      somatosensory cortex was greater than one hour after recording was started. These
      data led to the conclusion that simultaneous stimulation of corticocortical and
      thalamocortical afferents can alter the level of neuronal activity in the motor
      cortex only in regions with convergent sensory inputs from the thalamus and
      somatosensory cortex of the brain.

PMID- 10582235
TI  - Short-term memory processes in delayed visual differentiation in rhesus macaques
      after bilateral removal of field 7 of the parietal cortex.
AB  - Monkeys (Macaca mulatta) with preliminary removal of field 7 of the lower
      parietal cortex and previously trained to differentiate images differing in
      shape, color, size, orientation, and spatial relationships were used to study the
      processes involved in short-term storage of different types of information
      required for a delayed (by 0-8 sec) visual differentiation task and the effects
      on these processes of the antioxidant Oxymetacil. Significant differences were
      found in comparison with intact animals. Removal of field 7 sharply worsened
      short-term storage processes during visual differentiation of different types of
      images, including those differing in terms of properties such as color,
      geometrical shape, and the spatial relationships between image elements. There
      were significant reductions in the level of correct responses for all delay
      periods with significant increases in the motor reaction time, indicating a sharp
      reduction in the duration of short-term information storage, which suggests that
      the monkeys' short-term memory mechanisms were disrupted. Oxymetacil had a
      correcting effect only in relation to stimuli differing in terms of color and
      shape, but had no effect at all on the short-term storage of spatial information.
      It is suggested that these data suggest that field 7 has at least two functions.
      These are, firstly, a role in processes underlying the evaluation,
      differentiation, and storage of spatial information depending on visual
      vestibular interactions, and secondly, a role in the mechanisms underlying the
      attention system, which is disrupted by removal of field 7 and restored by
      treatment with the antioxidant when there is no need to differentiate spatial
      information, a process which depends on assessment of the body image and
      egocentric orientation based on visual-vestibular interactions.

PMID- 10582237
TI  - The Saccharomyces cerevisiae ubiquitin-proteasome system.
AB  - Our studies of the yeast ubiquitin-proteasome pathway have uncovered a number of
      general principles that govern substrate selectivity and proteolysis in this
      complex system. Much of the work has focused on the destruction of a yeast
      transcription factor, MAT alpha 2. The alpha 2 protein is polyubiquitinated and
      rapidly degraded in alpha-haploid cells. One pathway of proteolytic targeting,
      which depends on two distinct endoplasmic reticulum-localized ubiquitin
      conjugating enzymes, recognizes the hydrophobic face of an amphipathic helix in
      alpha 2. Interestingly, degradation of alpha 2 is blocked in a/alpha-diploid
      cells by heterodimer formation between the alpha 2 and a1 homeodomain proteins.
      The data suggest that degradation signals may overlap protein-protein interaction
      surfaces, allowing a straightforward steric mechanism for regulated degradation.
      Analysis of alpha 2 degradation led to the identification of both 20S and 26S
      proteasome subunits, and several key features of proteasome assembly and active
      site formation were subsequently uncovered. Finally, it has become clear that
      protein (poly) ubiquitination is highly dynamic in vivo, and our studies of yeast
      de-ubiquitinating enzymes illustrate how such enzymes can facilitate the
      proteolysis of diverse substrates.

PMID- 10582236
TI  - The proteasome: a macromolecular assembly designed for controlled proteolysis.
AB  - In eukaryotic cells, the vast majority of proteins in the cytosol and nucleus are
      degraded via the proteasome-ubiquitin pathway. The 26S proteasome is a huge
      protein degradation machine of 2.5 MDa, built of approximately 35 different
      subunits. It contains a proteolytic core complex, the 20S proteasome and one or
      two 19S regulatory complexes which associate with the termini of the barrel
      shaped 20S core. The 19S regulatory complex serves to recognize ubiquitylated
      target proteins and is implicated to have a role in their unfolding and
      translocation into the interior of the 20S complex where they are degraded into
      oligopeptides. While much progress has been made in recent years in elucidating
      the structure, assembly and enzymatic mechanism of the 20S complex, our knowledge
      of the functional organization of the 19S regulator is rather limited. Most of
      its subunits have been identified, but specific functions can be assigned to only
      a few of them.

PMID- 10582238
TI  - The 26S proteasome of the fission yeast Schizosaccharomyces pombe.
AB  - The 26S proteasome is the multiprotein complex that degrades proteins that have
      been marked for destruction by the ubiquitin pathway. It is made up of two
      multisubunit complexes, the 20S catalytic core and the 19S regulatory complex. We
      describe the isolation and characterization of conditional mutants in the
      regulatory complex and their use to investigate interactions between different
      subunits. In addition we have investigated the localization of the 26S proteasome
      in fission yeast, by immunofluorescence in fixed cells and live cells with the
      use of a GFP-tagged subunit. Surprisingly, we find that in mitotic cells the 26S
      proteasome occupies a discrete intracellular compartment, the nuclear periphery.
      Electron microscopic analysis demonstrates that the complex resides inside the
      nuclear envelope. During meiosis the localization showed a more dynamic
      distribution. In meiosis I the proteasome remained around the nuclear periphery.
      However, during meiosis II there was a dramatic relocalization: initially, the
      signal occupied the area between the dividing nuclei, but at the end of mitosis
      the signal dispersed, returning to the nuclear periphery on ascospore formation.
      This observation implies that the nuclear periphery is a major site of
      proteolysis in yeast during mitotic growth and raises important questions about
      the function of the 26S proteasome in protein degradation.

PMID- 10582239
TI  - SCF ubiquitin protein ligases and phosphorylation-dependent proteolysis.
AB  - Many key activators and inhibitors of cell division are targeted for degradation
      by a recently described family of E3 ubiquitin protein ligases termed Skp1-Cdc53
      F-box protein (SCF) complexes. SCF complexes physically link substrate proteins
      to the E2 ubiquitin-conjugating enzyme Cdc34, which catalyses substrate
      ubiquitination, leading to subsequent degradation by the 26S proteasome. SCF
      complexes contain a variable subunit called an F-box protein that confers
      substrate specificity on an invariant core complex composed of the subunits
      Cdc34, Skp1 and Cdc53. Here, we review the substrates and pathways regulated by
      the yeast F-box proteins Cdc4, Grr1 and Met30. The concepts of SCF ubiquitin
      ligase function are illustrated by analysis of the degradation pathway for the G1
      cyclin Cln2. Through mass spectrometric analysis of Cdc53 associated proteins, we
      have identified three novel F-box proteins that appear to participate in SCF-like
      complexes. As many F-box proteins can be found in sequence databases, it appears
      that a host of cellular pathways will be regulated by SCF-dependent proteolysis.

PMID- 10582241
TI  - Control of metaphase-anaphase progression by proteolysis: cyclosome function
      regulated by the protein kinase A pathway, ubiquitination and localization.
AB  - Ubiquitin-mediated proteolysis is fundamental to cell cycle progression. In the
      fission yeast Schizosaccharomyces pombe, a mitotic cyclin (Cdc13), a key cell
      cycle regulator, is degraded for exiting mitosis, while Cut2 has to be destroyed
      for the onset of sister chromatid separation in anaphase. Ubiquitination of these
      proteins requires the special destruction box (DB) sequences locating in their N
      termini and the large, 20S complex called the anaphase-promoting complex or
      cyclosome. Here we show that cyclosome function during metaphase-anaphase
      progression is regulated by the protein kinase A (PKA) inactivation pathway,
      ubiquitination of the cyclosome subunit, and cellular localization of the target
      substrates. Evidence is provided that the cyclosome plays pleiotropic roles in
      the cell cycle: mutations in the subunit genes show a common anaphase defect, but
      subunit-specific phenotypes such as in G1/S or G2/M transition, septation and
      cytokinesis, stress response and heavy metal sensitivity, are additionally
      produced, suggesting that different subunits take distinct parts of complex
      cyclosome functions. Inactivation of PKA is important for the activation of the
      cyclosome for promoting anaphase, perhaps through dephosphorylation of the
      subunits such as Cut9 (Apc6). Cut4 (Apc1), the largest subunit, plays an
      essential role in the assembly and functional regulation of the cyclosome in
      response to cell cycle arrest and stresses. Cut4 is highly modified, probably by
      ubiquitination, when it is not assembled into the 20S cyclosome. Sds23 is
      implicated in DB-mediated ubiquitination possibly through regulating de
      ubiquitination, while Cut8 is necessary for efficient proteolysis of Cdc13 and
      Cut2 coupled with cytokinesis. Unexpectedly, the timing of proteolysis is
      dependent on cellular localization of the substrate. Cdc13 enriched along the
      spindle disappears first, followed by decay of the nuclear signal, whereas Cut2
      in the nucleus disappears first, followed by decline in the spindle signal during
      metaphase-anaphase progression.

PMID- 10582240
TI  - Two distinct ubiquitin-proteolysis pathways in the fission yeast cell cycle.
AB  - The SCF complex (Skp1-Cullin-1-F-box) and the APC/cyclosome (anaphase-promoting
      complex) are two ubiquitin ligases that play a crucial role in eukaryotic cell
      cycle control. In fission yeast F-box/WD-repeat proteins Pop1 and Pop2,
      components of SCF are required for cell-cycle-dependent degradation of the cyclin
      dependent kinase (CDK) inhibitor Rum1 and the S-phase regulator Cdc18.
      Accumulation of these proteins in pop1 and pop2 mutants leads to re-replication
      and defects in sexual differentiation. Despite structural and functional
      similarities, Pop1 and Pop2 are not redundant homologues. Instead, these two
      proteins form heterodimers as well as homodimers, such that three distinct
      complexes, namely SCFPop1/Pop1, SCFPop1/Pop2 and SCFPop2/Pop2, appear to exist in
      the cell. The APC/cyclosome is responsible for inactivation of CDK/cyclins
      through the degradation of B-type cyclins. We have identified two novel
      components or regulators of this complex, called Apc10 and Ste9, which are
      evolutionarily highly conserved. Apc10 (and Ste9), together with Rum1, are
      required for the establishment of and progression through the G1 phase in fission
      yeast. We propose that dual downregulation of CDK, one via the APC/cyclosome and
      the other via the CDK inhibitor, is a universal mechanism that is used to arrest
      the cell cycle at G1.

PMID- 10582242
TI  - Mechanisms and regulation of the degradation of cyclin B.
AB  - The degradation of the cyclin B subunit of protein kinase Cdk1/cyclin B is
      required for inactivation of the kinase and exit from mitosis. Cyclin B is
      degraded by the ubiquitin pathway, a system involved in most selective protein
      degradation in eukaryotic cells. In this pathway, proteins are targeted for
      degradation by ligation to ubiquitin, a process carried out by the sequential
      action of three enzymes: the ubiquitin-activating enzyme E1, a ubiquitin-carrier
      protein E2 and a ubiquitin-protein ligase E3. In the system responsible for
      cyclin B degradation, the E3-like function is carried out by a large complex
      called cyclosome or anaphase-promoting complex (APC). In the early embryonic cell
      cycles, the cyclosome is inactive in the interphase, but becomes active at the
      end of mitosis. Activation requires phosphorylation of the cyclosome/APC by
      protein kinase Cdk1/cyclin B. The lag kinetics of cyclosome activation may be
      explained by Suc1-assisted multiple phosphorylations of partly phosphorylated
      complex. The presence of a Fizzy/Cdc20-like protein is necessary for maximal
      activity of the mitotic form of cyclosome/APC in cyclin-ubiquitin ligation.

PMID- 10582243
TI  - Molecular mechanism of autophagy in yeast, Saccharomyces cerevisiae.
AB  - Bulk degradation of cytosol and organelles is important for cellular homeostasis
      under nutrient limitation, cell differentiation and development. This process
      occurs in a lytic compartment, and autophagy is the major route to the lysosome
      and/or vacuole. We found that yeast, Saccharomyces cerevisiae, induces autophagy
      under various starvation conditions. The whole process is essentially the same as
      macroautophagy in higher eukaryotic cells. However, little is known about the
      mechanism of autophagy at a molecular level. To elucidate the molecules involved,
      a genetic approach was carried out and a total of 16 autophagy-defective mutants
      (apg) were isolated. So far, 14 APG genes have been cloned. Among them we
      recently found a unique protein conjugation system essential for autophagy. The C
      terminal glycine residue of a novel modifier protein Apg12p, a 186-amino-acid
      protein, is conjugated to a lysine residue of Apg5p, a 294-amino-acid protein,
      via an isopeptide bond. We also found that apg7 and apg10 mutants were unable to
      form an Apg12p-Apg5p conjugate. The conjugation reaction is mediated via Apg7p,
      E1-like activating enzyme and Apg10p, indicating that it is a ubiquitination-like
      system. These APG genes have mammalian homologues, suggesting that the Apg12
      system is conserved from yeast to human. Further molecular and cell biological
      analyses of APG gene products will give us crucial clues to uncover the mechanism
      and regulation of autophagy.

PMID- 10582244
TI  - Control of mitotic transitions by the anaphase-promoting complex.
AB  - Proteolysis controls key transitions at several points in the cell cycle. In
      mitosis, the activation of a large ubiquitin-protein ligase, the anaphase
      promoting complex (APC), is required for anaphase initiation and for exit from
      mitosis. We show that APC is under complex control by a network of regulatory
      factors, CDC20, CDH1 and MAD2. CDC20 and CDH1 are activators of APC; they bind
      directly to APC and activate its cyclin ubiquitination activity. CDC20 activates
      APC at the onset of anaphase in a destruction box (DB)-dependent manner, while
      CDH1 activates APC from late anaphase through G1 with apparently a much relaxed
      specificity for the DB. Therefore, CDC20 and CDH1 control both the temporal order
      of activation and the substrate specificity of APC, and hence regulate different
      events during mitosis and G1. Counteracting the effect of CDC20, the checkpoint
      protein MAD2 acts as an inhibitor of APC. When the spindle-assembly checkpoint is
      activated, MAD2 forms a ternary complex with CDC20 and APC to prevent activation
      of APC, and thereby arrests cells at prometaphase. Thus, a combination of
      positive and negative regulators establishes a regulatory circuit of APC,
      ensuring an ordered progression of events through cell division.

PMID- 10582245
TI  - Role of factors downstream of caspases in nuclear disassembly during apoptotic
      execution.
AB  - We used cytoplasmic extracts from chicken DU249 cells at various stages along the
      apoptotic pathway to analyse the events of apoptotic execution. So-called S/M
      extracts from morphologically normal 'committed-stage' cells induce apoptotic
      morphology and DNA cleavage in substrate nuclei. These apoptotic changes appear
      to require the function of multiple caspases (cysteine aspartases, a specialized
      class of proteases) acting in parallel. Extracts from 'execution-stage' apoptotic
      cells induce apoptotic events in added nuclei in a caspase-independent manner.
      Biochemical fractionation of these extracts reveals that a column fraction
      enriched in endogenous active caspases is unable to induce DNA fragmentation or
      chromatin condensation in substrate nuclei, whereas a caspase-depleted fraction
      induces both changes. 'Execution-stage' extracts contain an ICAD/DFF45
      inhibitable nuclease resembling CAD, plus another activity that is required for
      the apoptotic chromatin condensation. 'Committed-stage' S/M extracts lack these
      downstream activities. These observations reveal that caspases act in an
      executive fashion, serving to activate downstream factors that disassemble the
      nucleus rather than disassembling it themselves. They also suggest that
      activation of the downstream factors (rather than the caspases) is the critical
      event that occurs at the transition from the latent to the execution phase of
      apoptosis.

PMID- 10582247
TI  - Low kilovoltage, nonscreen mummy radiography.
AB  - In the past, radiographic studies of mummies relied on relatively high
      kilovoltage techniques with intensifying screens. This article discusses mummy
      radiographs produced using a low kilovoltage technique and a nonscreen film
      holder. The author compares images of a single mummy produced with both
      techniques, demonstrating that the low kilovoltage, nonscreen technique reveals
      soft tissue structures and the materials used to cover the mummy in greater
      detail.

PMID- 10582248
TI  - Contrast-enhanced MR angiography.
AB  - Contrast-enhanced magnetic resonance angiography (CE-MRA) is challenging
      conventional angiography as the primary diagnostic tool for vascular
      visualization. This article describes CE-MRA techniques, equipment and many of
      the applications currently in use, as well as applications under development. The
      advantages of CE-MRA also are discussed.

PMID- 10582249
TI  - Telemedicine and teleradiology.
AB  - Inherent challenges accompany the rapidly increasing use of teleradiology and
      other telemedicine applications. These challenges include the complex interaction
      of multiple technologies as well as new operational procedures and changes in the
      way health care is delivered. This article focuses on the operational issues
      surrounding telemedicine, teleradiology and the transition to a digital
      department. The legal implications of telemedicine and government's role in
      regulating it are emphasized, along with telemedicine's impact on rural health
      care.

PMID- 10582246
TI  - Control of NF-kappa B transcriptional activation by signal induced proteolysis of
      I kappa B alpha.
AB  - In unstimulated cells the transcription factor NF-kappa B is held in the
      cytoplasm in an inactive state by I kappa B inhibitor proteins. Ultimately
      activation of NF-kappa B is achieved by ubiquitination and proteasome-mediated
      degradation of I kappa B alpha and we have therefore investigated factors which
      control this proteolysis. Signal-induced degradation of I kappa B alpha exposes
      the nuclear localization signal of NF-kappa B, thus allowing it to translocate
      into the nucleus and activate transcription from responsive genes. An
      autoregulatory loop is established when NF-kappa B induces expression of the I
      kappa B alpha gene and newly synthesized I kappa B alpha accumulates in the
      nucleus where it negatively regulates NF-kappa B-dependent transcription. As part
      of this post-induction repression, the nuclear export signal on I kappa B alpha
      mediates transport of NF-kappa B-I kappa B alpha complexes from the nucleus to
      the cytoplasm. As nuclear export of I kappa B alpha is blocked by leptomycin B
      this drug was used to examine the effect of cellular location on susceptibility
      of I kappa B alpha to signal-induced degradation. In the presence of leptomycin
      B, I kappa B alpha is accumulated in the nucleus and in this compartment is
      resistant to signal-induced degradation. Thus signal-induced degradation of I
      kappa B alpha is mainly, if not exclusively a cytoplasmic process. An efficient
      nuclear export of I kappa B alpha is therefore essential for maintaining a low
      level of I kappa B alpha in the nucleus and allowing NF-kappa B to be
      transcriptionally active upon cell stimulation. We have detected a modified form
      of I kappa B alpha, conjugated to the small ubiquitin-like protein SUMO-1, which
      is resistant to signal-induced degradation. SUMO-1 modified I kappa B alpha
      remains associated with NF-kappa B and thus overexpression of SUMO-1 inhibits the
      signal-induced activation of NF-kappa B-dependent transcription. Reconstitution
      of the conjugation reaction with highly purified proteins demonstrated that in
      the presence of a novel E1 SUMO-1 activating enzyme, Ubch9 directly conjugated
      SUMO-1 to I kappa B alpha on residues K21 and K22, which are also used for
      ubiquitin modification. Thus, while ubiquitination targets proteins for rapid
      degradation, SUMO-1 modification acts antagonistically to generate proteins
      resistant to degradation.

PMID- 10582250
TI  - Forensic medicine: matters of life and death.
AB  - Forensic radiology uses medical imaging to answer a variety of legal questions,
      including questions about suspicious and violent deaths. This article traces the
      history of forensic medicine and forensic radiology and outlines radiology's role
      in investigating death. The authors discuss the physical changes that occur after
      death and the procedures involved in forensic autopsies, including radiography.

PMID- 10582251
TI  - R.T.s and the baccalaureate requirement.

PMID- 10582252
TI  - Demographics of the profession.

PMID- 10582253
TI  - Changes in health care compensation.

PMID- 10582254
TI  - JRCERT's strategic plan. Joint Review Committee on Education in Radiologic
      Technology.

PMID- 10582255
TI  - Using video to upgrade competencies.

PMID- 10582256
TI  - Evidence-based medicine and critical care.
AB  - Applying the best available scientific evidence to selecting the most appropriate
      action for the care of individual patients is not a novel concept. Nevertheless,
      in these times of exponential growth in medical literature, heavy time
      constraints on clinicians and increasing health care costs, this approach needed
      to be reemphasised. The promoters of evidence-based medicine have contributed
      significantly to this task, by making explicit the steps from the search for the
      best evidence (randomised controlled trials and meta-analyses) to its application
      to clinical practice. Moreover, they have developed and made available several
      invaluable tools for critical appraisal of the medical literature. To illustrate
      the usefulness of evidence-based medicine, we applied this approach to two
      clinical situations: (1) the decision whether to use NPPV instead of conventional
      ventilation in a patient with acute respiratory failure due to severe pneumonia;
      and (2) whether to administer albumin to critically ill patients with
      hypovolaemia, burns or hypoalbuninaemia. Finally, the limitations of evidence
      based medicine and its main instruments, i.e. randomised controlled trials and
      meta-analyses, are briefly discussed.

PMID- 10582257
TI  - Error in medicine: adverse events in intensive care.
AB  - Human error occurs in all walks of life, including medicine. Numerous studies
      demonstrate that iatrogenic complications account for many deaths, long-term
      disabilities and unnecessary expense. The study of these adverse events can be
      formalized in various ways in order to minimise the frequency and severity of
      complications. Incident monitoring borrows its methodology from the well proven
      airline, scuba diving and similar fields where "near miss" events are treated as
      seriously as actual events, because the near miss is often a pointer to a
      systematic problem which should be corrected. The areas of human performance
      psychology and the analysis of complex systems are of increasing relevance to the
      avoidance of error. These techniques have been incorporated into the Australian
      Incident Monitoring Program which developed in the anaesthetic forum but which
      has now been taken up by intensive care units and indeed hospital wide in many
      parts of Australia and New Zealand.

PMID- 10582258
TI  - [Quality assurance in intensive care: the situation in Switzerland].
AB  - The movement for quality in medicine is starting to take on the dimensions of a
      crusade. Quite logically it has also reached the intensive care community. Due to
      their complex multidisciplinary functioning and because of the high costs
      involved, ICUs are model services reflecting the overall situation in our
      hospitals. The situation of Swiss intensive care is particularly interesting,
      because for over 25 years standards for design and staffing of Swiss ICUs have
      been in effect and were enforced via onsite visits by the Swiss Society of
      Intensive Care without government involvement. Swiss intensive care thus defined
      its structures long before the word "accreditation" had even been used in this
      context. While intensive care in Switzerland is practised in clearly defined,
      well equipped and adequately staffed units, much less is known about process
      quality and outcomes of these services. Statistics on admissions, length of stay
      and length of mechanical ventilation, as well as severity data based on a simple
      classification system, are collected nationwide and allow some limited insight
      into the overall process of care. Results of intensive care are not
      systematically assessed. In response to the constant threat of cost containment,
      Swiss ICUs should increasingly focus on process quality and results, while
      maintaining their existing good structures.

PMID- 10582259
TI  - Is the gut responsible for multiple organ failure?
AB  - Multiple organ failure is the consequence of many pathological processes, an
      acute reduction in oxygen supply being one of the most important. The splanchnic
      region is particularly susceptible to hypoxic injury, and the ischaemic gut
      mucosa may act as a neutrophil activating site. This is followed by leukocyte
      adhesion to endothelium and migration into the tissues where cytotoxic chemicals
      are released, producing tissue injury. This process is aggravated by multiple and
      sequential physiological insults, some of which may not be evident using basic
      clinical monitoring. The factors which precipitate cell injury and organ failures
      may be amenable to relatively simple preventative interventions, but once damage
      has occurred the process becomes increasingly complex and self-sustaining.
      Natural defence systems may become pathologically hyperactive, or suppressed, at
      different stages in critical illness, making it difficult to target therapies
      directed at the immunoinflammatory cascade with any degree of accuracy or safety,
      explaining in part the failure of immunotherapy for sepsis. There are significant
      genetic and constitutional components to susceptibility to critical illness, the
      most important of which affect cardiac reserve and the ability to maximise tissue
      oxygen supply. Whether the gut is the most important target organ for oxygen
      delivery in stress is still the subject of continued research.

PMID- 10582260
TI  - [Is prevention of upper digestive system hemorrhage in intensive care
      necessary?].
AB  - Mucosal lesions are observed in 40 to 100% of critically ill patients. They are
      mainly due to gastric acid hypersecretion, biliary reflux, a decrease in mucosal
      defences, and digestive mucosal ischaemia. Acute upper gastrointestinal bleeding
      in intensive care unit (ICU) patients may occur, and if severe is associated with
      increased mortality and hospitalization costs. However, progress in the ICU
      management of patients, and especially in nutritional support, probably explains
      the low incidence of stress-induced gastrointestinal bleeding. Preventive
      strategies are indicated in high risk patients, i.e. when the risk of
      gastrointestinal bleeding is above 1%. Risk factors are not well defined
      presently, and probably include defective haemostasis and/or respiratory failure
      requiring prolonged ventilation assistance. Gastric hypersecretion can be well
      controlled with anti-H2 agents and sucralfate; these treatments improve the rate
      of complications but do not reduce overmortality related to gastrointestinal
      bleeding. Other drugs such as omeprazole are under investigation but due to
      insufficient clinical data and excessive cost, omeprazole cannot be recommended
      for this use. In addition, enteral nutritional support per se may efficiently
      prevent stress ulcers. Eradication of Helicobacter pylori has never been
      evaluated in this context. The selection of drugs today depends not only on
      efficacy and on costs, but also on possible adverse effects such as the putative
      risk of nosocomial pneumonia due to gastric bacterial overgrowth. Finally, only
      careful medico-economic evaluations of stress ulcer prophylaxis in ICUs will
      permit the implementation of valuable practice guidelines.

PMID- 10582261
TI  - History of high frequency oscillation.
AB  - The article describes the evolution of high frequency oscillation since its first
      use by Lunkenheimer through the initial failed NIH trial and subsequent more
      successful trials to its current widespread use in the neonatal population. The
      importance of oscillating at an optimal lung volume, achieved through a volume
      recruitment manoeuvre, is emphasised as is the efficacy with which oscillation
      clears CO2. The lack of adequate control of these two factors in the initial NIH
      trial is suggested as a possible cause of the trial's failure. Comment is made on
      optimising oscillator settings as well on elementary mechanics of high frequency
      oscillation and the effect of high frequency oscillation on surfactant
      degradation. Given the difficulty of recruiting lung volume in late RDS, a
      suggestion is made to combine high frequency oscillation with perfluorocarbon.
      The former as a mechanism for maintaining lung volume which has been recruited by
      the perfluorocarbon. The authors speculate that the use of high frequency
      oscillation will increase in both the paediatric and adult population.

PMID- 10582262
TI  - [Nutrition in acute pancreatitis].
AB  - Severe acute pancreatitis is a two-phase systemic disease. The first phase is a
      clinical response resulting from systemic effects of proinflammatory mediators
      called SIRS (systemic inflammatory response syndrome), that may lead to multiple
      organ failure and death. The second phase, if the process is not reversed by
      natural defences or treatment, may be accompanied by local complications such as
      infected pancreatic necrosis. The severity of the disease must be established
      early to identify patients requiring intensive monitoring and support. The
      clinico-biochemical score (Ranson score) is about 80% accurate at 48 hours but is
      not accurate before this time; the APACHE II system has the sensitivity to
      predict severe pancreatitis in 61% of patients on admission. Although not
      perfect, the prognostic systems of severity remain better than clinical
      judgement. SIRS followed by local complications is accompanied by increased
      energy requirements and, with the absence of oral intake, a persistently negative
      nitrogen balance and mineral and micronutrient deficiencies. Thus, early
      nutritional support is indicated. Formerly, total parenteral nutrition was the
      standard practice for providing exogenous nutrients avoiding pancreatic
      stimulation. The use of early enteral feeding has recently been evaluated.
      Gastric atony and obstruction of the duodenum by pancreatic oedema or necrosis
      have been overcome by delivering enteral nutrition to the jejunum, distal to the
      ligament of Treitz; in this position, regular diets do not stimulate pancreatic
      secretions. The efficacy, tolerance, clinical outcome and cost of enteral
      nutrition suggest that this feeding route should be preferred in patients with
      severe acute pancreatitis.

PMID- 10582263
TI  - Medical-ethical guidelines for the transplantation of human foetal tissue. Swiss
      Academy of Medical Sciences (SAMS).

PMID- 10582264
TI  - [Intestinal focal-nodular hyperplasia in "common variable immunodeficiency"].

PMID- 10582265
TI  - Primary macular amyloidosis: an ultrastructural approach to diagnosis.
AB  - Seven cases of primary macular amyloidosis were studied on skin biopsies. The
      Congo red stain was positive only in three cases, whereas the ultrastructural
      observation allowed for the detection of amyloid deposits in all biopsies.
      Fibrillary degeneration of basal keratynocytes was occasionally observed, and
      regressive changes of keratynocytes and dermal nerve bundles presumably related
      to the intensity of the scratch trauma were detected in one case. In six biopsies
      mast cell profiles exhibiting various degrees of degranulation were detected in
      the dermis. Melanosome aggregates were also observed consistently in dermal
      macrophages and occasionally in Schwann cells. A variable degree of structural
      alteration was observed in dermal unmyelinated nerve fibers. Even if the intimate
      mechanism of amyloid deposition was not explained by the ultrastructural study,
      this approach is a useful instrument in the differential diagnosis of cutaneous
      macular hyperpigmented lesions.

PMID- 10582266
TI  - Crystalloid inclusions in brain macrophages and hemopoietic tissue in GFAP-IL3
      mice resemble inclusions identified in multiple sclerosis.
AB  - Crystalloid inclusions or "pole bodies" observed in brain macrophages in human
      demyelinating disease represent a morphological enigma. Similar inclusions were
      detected in brain macrophages from the GFAP-IL3 mouse, a transgenic murine model
      for macrophage mediated demyelination. Mice also showed inclusions in
      hematopoietic tissue. They appear to be related to phagocytosis and secretion,
      respectively, as evidenced by the fact that in phagocytosing cells they often
      merged with lysozomes and that affected cells showed empty channels open to the
      interstitium. Based on ultrastructural and immunolocalization studies using
      chaperonin-10, lysozyme, and cathepsin the authors suggest that these inclusions
      are consistent with phagocytosis-related secretory products. This study may
      provide insight into the nature and significance of similar macrophage inclusions
      recently identified in multiple sclerosis.

PMID- 10582267
TI  - Angiogenic histogenesis of stromal cells in hemangioblastoma: ultrastructural and
      immunohistochemical study.
AB  - Controversy regarding the origin of characteristic stromal cells (SC) is
      responsible for the placement of hemangioblastoma as a single entity in the
      category of "tumors of uncertain histogenesis" in the current WHO classification
      of brain tumors. This subclassification of hemangioblastoma is, to a large
      extent, a consequence of a remarkable antigenic heterogeneity of SC demonstrated
      in many, often contradictory immunohistochemical studies. In contrast, most of
      the electron microscopic studies demonstrated a number of features indicating
      angiogenic nature of SC and, therefore, hemangioblastoma. This study reevaluated
      the histogenesis of SC, applying immunohistochemistry as well as electron
      microscopy and immunoelectron microscopy. Immunohistochemical studies confirmed
      most of the previous results indicating a very frequent expression of vimentin, S
      100 protein, neuron-specific enolase, and cytokeratins. SC were less commonly
      immunoreactive for desmin, factor XIIIa, and Ricinus communis lectin receptors,
      and only occasionally for factor VIII and Ulex europeus lectin. They were
      negative for other markers of endothelial, neuronal, glial, neuroendocrine, and
      smooth muscle differentiation. Approximately 1% of SC showed Ki67
      immunoreactivity, indicating their slight proliferative activity, consistent with
      the benign nature of the tumor. In contrast to the inconclusive results of the
      immunohistochemistry, electron microscopy demonstrated a clear relationship of SC
      to endothelial cells, smooth muscle cells, and pericytes. Occasional SC were
      found within the vascular lumina. SC often showed intracellular caveolae
      consistent with the formation of early capillary lumina. Moreover, occasional SC
      contained small Weibel-Palade bodies positive for factor VIII in immunoelectron
      microscopy. SC represent a heterogeneous population of abnormally differentiating
      mesenchymal cells of angiogenic lineage, with some morphological features of
      endothelium, pericytes, and smooth muscle cells. Occurrence of SC in
      hemangioblastoma could be related to a limited ability of angioformative stromal
      cells to develop an architecture of capillary lumina integrated with the vascular
      network of the tumor. Hemangioblastoma should be reclassified and included
      together with other vascular tumors of the central nervous system.

PMID- 10582268
TI  - Intraventricular neurocytoma with prominent myelin figures.
AB  - A case is reported of intraventricular neurocytoma that had characteristic light
      microscopic findings of neurocytoma with prominent intracytoplasmic concentric
      lamellar structures mimicking myelin sheaths. On routine H&E-stained sections,
      this tumor showed intracytoplasmic vesicular bleb-like structures having
      eosinophilic cores that were consistent with ultrastructural concentric lamellar
      structures. Immunohistochemically, this tumor was immunoreactive for
      synaptophysin and neurofilament, but negative for antibody to glial fibriallary
      acidic protein. Electron microscopic findings fulfilled the criteria for
      neurocytoma, with the presence of neurosecretory granules and neurotubules. These
      findings may suggest dual differentiation of this tumor into neurocytes and
      oligodendrocytes.

PMID- 10582269
TI  - Mucin-secreting cellular ependymoma: a light and electron microscopy study.
AB  - Mucin accumulation in ependymomas is thought to be limited to the myxopapillary
      variant and represents an important diagnostic feature. Similarly, signet-ring
      cells in ependymomas have been shown by electron microscopy to represent
      microrosette instead of mucin secretion. This study describes an infratentorial
      ependymoma largely composed of mucinous areas and signet-ring cells. The
      ependymal nature of mucin-secreting cells was confirmed by ultrastructural
      analysis. This case widens the variable spectrum of ependymal morphology. The
      value of electron microscopy in differentiating central nervous system neoplasms
      showing mucous secretion is stressed.

PMID- 10582270
TI  - Astroblastoma: ultrastructural observations on a case of high-grade type.
AB  - An astroblastoma of high-grade type arising in the brain of a 3-year-old child is
      reported. The first description of the ultrastructural, immunohistochemical, and
      cytogenetic findings in this rare tumor variant are presented.

PMID- 10582271
TI  - True histiocytic lymphoma of the esophagus in an HIV-positive patient: an
      ultrastructural study.
AB  - A 56-year-old white woman, seropositive for human immunodeficiency virus for 18
      months without signs of acquired immunodeficiency syndrome, presented with
      retrosternal pain and progressive dysphagia secondary to an exophytic esophageal
      mass. Biopsies of the tumor showed a malignant neoplasm composed of pleomorphic,
      noncohesive cells growing in a diffuse, sheet-like fashion.
      Immunohistochemically, tumor cells were nonreactive with epithelial, lymphoid,
      neural, and monocyte/macrophage markers. Despite the noncontributory
      immunohistochemical findings, ultrastructural study of the tumor cells revealed
      convincing histiocytic features. Individual cells possessed long, slender
      filopodial projections, prominent Golgi apparatus, residual bodies, rare
      lysosomes, and prelysosomes. Immunoglobulin heavy chain and T-cell receptor gamma
      gene rearrangement studies detected no evidence of a clonal gene rearrangement.
      The patient responded poorly to chemotherapy and died 5 months after her initial
      symptom of dysphagia.

PMID- 10582272
TI  - Fibrous meningioma with tyrosine-rich crystals.
AB  - A 58-year-old African-American woman presented with a 6-month history of
      headaches. A magnetic resonance imaging scan of the head revealed a 5-cm,
      enhancing dura-based mass in the left parietal region. The variably cellular
      tumor was composed of uniform spindle cells associated with intercellular
      collagen and numerous radially arranged "petal-shaped" clusters of eosinophilic
      crystals. The tumor was diagnosed by light microscopy as a fibrous meningioma.
      Ultrastructural examination disclosed cells with complex interdigitating
      processes connected by desmosome-like cell junctions, abundant intercellular
      collagen fibers, and prominent, densely osmiophilic crystals featuring radiating
      teardrop shaped petals emanating from a central core. A positive Millon reaction
      showed these crystals to consist at least in part of tyrosine. By morphology,
      histochemistry, and ultrastructure, the crystals resembled tyrosine-rich crystals
      occurring in salivary gland tumors. This is the first report of a fibrous
      meningioma containing tyrosine-rich crystals.

PMID- 10582273
TI  - Case for the panel Nephrotic syndrome with fibrillary and lipid deposits.

PMID- 10582274
TI  - Perivascular amorphous matrices containing laminin and type IV collagen not
      organized as a conventional basal lamina: identification by electron microscopy
      and implications for the control of cell biological processes.

PMID- 10582275
TI  - Local and global patterns during morphogenesis of the retinotectal topographical
      mapping in the vertebrate brain.
AB  - The highly ordered neuronal projections from the retina to the tectum
      mesencephali (optic tectum) in several vertebrate groups have been intensively
      studied. Several hypotheses so far have been proposed, suggesting mechanisms to
      explain the topographical and biochemical specificity of the retinotectal
      projections during ontogeny. In the present paper we compare the main hypotheses
      of retinotectal development with respect to the nature of specificity envisaged,
      the activity-dependence versus inheritance criterium and the strategy of
      argument, in casu the descriptive versus interferential type of argument.
      Matching of the current developmental hypotheses and mechanisms for elimination
      or persistence of contralateral, respectively ipsilateral connections, is
      attempted with respect to the known neuroanatomical connectivity data in the
      amphibian optic tectum and with respect to the symmetry relations between
      ipsilateral and contralateral connection patterns described in amphibians and
      other vertebrate groups. Local mechanisms influencing the survival potential of
      synaptic contacts between retinal afferents and tectal neurons are probably
      essential for generating global symmetry patterns. Finally, a global topological
      approach is discussed with respect to its applicability in the amphibian
      retinotectal projection system. Basic assumptions of topological modeling appear
      to rely on anatomical and functional properties of the visual system like left
      right symmetry, dichotomy, (absence of) convergence and segregation of fibers and
      neurons into columnar information units. It is concluded however, that more
      neuroanatomical, physiological and ultrastructural data are needed to establish a
      formalized operation model of the amphibian retinotectal system.

PMID- 10582276
TI  - Sequence mapping in a three-dimensional space by a numeric method and some of its
      applications.
AB  - In this work we report a simple way to assign a single numeric value in a three
      dimensional space to a given nucleotide sequence. The method reported allows for
      theoretical comparisons of naturally occurring nucleotide sequences.

PMID- 10582277
TI  - A radiation hybrid map of bovine chromosome one.
AB  - Radiation hybrid (RH) mapping has proven to be an extremely powerful approach to
      constructing high density maps of human chromosomes and is experiencing increased
      use in other animals, including cattle. A 5000 rad bovine whole-genome radiation
      hybrid panel was recently constructed in order to integrate existing cattle
      linkage maps with evolutionarily conserved genes and provide high resolution
      comparative maps relative to humans and mice. We utilized this panel to construct
      a 19 marker framework map of bovine chromosome 1 (BTA1), which included 8 Type I
      loci and 11 Type II loci ordered with at least 1000:1 odds. A 35 marker
      comprehensive map including 15 Type I loci and 20 Type II loci was also produced.
      Of the 15 Type I loci ordered on the comprehensive map, three are ordered on HSA3
      and five are ordered in three blocks on HSA21 on the human cytogenetic maps.

PMID- 10582278
TI  - Detection of QTL for milk production traits in cattle by application of a
      specifically developed marker map of BTA6.
AB  - Interval mapping was carried out to identify quantitative trait loci (QTL) for
      milk production traits in five granddaughter design families of the German
      Holstein population. Fourteen randomly generated markers spanning the whole of
      BTA6 and six targeted microsatellite markers from BTA6q21-31 were included in the
      analysis. In one family a QTL with effects on milk fat yield and milk protein
      yield was mapped to the interval TGLA37-FBN13 (3 CM proximal to FBN13, lodscore
      3.22) in the middle part of the chromosome. Although there are several reports
      about QTL with effects on milk production traits on BTA6 in the literature, a QTL
      with effects on milk fat and milk protein yield has not been previously
      described.

PMID- 10582279
TI  - Report of the International Equine Gene Mapping Workshop: male linkage map.
AB  - The goal of the First International Equine Gene Mapping Workshop, held in 1995,
      was the construction of a low density, male linkage map for the horse. For this
      purpose, the International Horse Reference Family Panel (IHRFP) was established,
      consisting of 12 paternal half-sib families with 448 half-sib offspring provided
      by 10 laboratories. Blood samples were collected and DNA extracted in each
      laboratory and sent to the Lexington laboratory (KY, USA) for dispatch in
      aliquots to 14 typing laboratories. In total, 161 markers (144 microsatellites,
      seven blood groups and 10 proteins) were tested for all families for which the
      sire was heterozygous. Genealogies and typing data were sent for analysis to the
      INRA laboratory (Jouy-en-Josas, France) according to a specific format and
      entered into a database with input verification and output processes. Linkage
      analysis was performed with the CRIMAP program. Significant linkage was detected
      for 124 loci, of which 95 were unambiguously ordered using a multipoint analysis
      with an average spacing of 14.2 CM. These loci were distributed among 29 linkage
      groups. A more comprehensive analysis including synteny group data and FISH data
      suggested that 26 autosomes out of 31 are covered. The complete map spans 936 CM.

PMID- 10582280
TI  - Estimations of the efficacy and reliability of paternity assignments from DNA
      microsatellite analysis of multiple-sire matings.
AB  - It is important for bovine DNA testing laboratories to provide the cattle
      industry with accurate estimates of the efficacy and reliability of DNA tests
      offered so that end users of this technology can adequately assess the cost
      benefits of testing. To address these issues for bovine paternity testing,
      paternity exclusion probability estimates were obtained from breed panel data and
      were predictive of the efficacy of the DNA tests used in 39 multiple-sire mating
      groups, involving 5960 calves and 505 bulls. Paternity testing of these mating
      groups has demonstrated that the majority involve a variable proportion of
      unknown sires and this impacts on the reliability of sire allocation.
      Mathematical models based on binomial or beta-binomial probability distributions
      were used to estimate the reliability of single-sire allocations from multiple
      sire matings involving unknown sires. Reliability of 98-99% is achieved when the
      exclusion probability is 0.99 or greater, after allowing for up to 20% unknown
      sires. When the exclusion probability drops below 0.90 and there are 20% unknown
      sires, the reliability is poor, bringing into question the benefits of testing.
      This highlights the need for DNA testing laboratories to offer paternity tests
      with an exclusion power of at least 99%.

PMID- 10582281
TI  - DNA sequence of SSCP haplotypes at the bovine growth hormone (bGH) gene.
AB  - Previous studies using SSCP and PCR-RFLP methodologies uncovered nine polymorphic
      sites within the bGH gene, defining eight intragenic haplotypes falling into two
      main groups. In the present study we report the DNA sequence of these eight
      haplotypes. A total of 1494 bp were sequenced uncovering a total of 12 sequence
      variants. Haplotypes within groups differed among themselves at one or two sites,
      compared across groups, haplotypes of the two groups differed consistently at six
      sites, each of which was monomorphic within the respective groups. This comes to
      4 differentiating sites per kb, suggesting that the two haplotype groups began to
      diverge about 400,000 years ago. This corresponds approximately to the estimated
      time of divergence of the Bos taurus and Bos indicus lineages, raising the
      possibility, supported by other evidence, that the two haplotype classes
      represent taurine and indicine haplotypes, respectively. Nucleotide sequence
      divergence of taurine and indicine genomes of this magnitude has far reaching
      implications with respect to QTL mapping and marker assisted selection in breeds
      derived from taurine x indicine crosses.

PMID- 10582282
TI  - Five new linkage groups in the canine linkage map.
AB  - Nineteen further polymorphic loci were typed on the DogMap reference panel. Five
      new linkage groups were identified. Additionally, five markers were added to
      earlier defined linkage groups. Three of the new linkage groups contain markers
      mapped earlier to specific dog chromosomes by physical mapping. These results
      make a further contribution to the canine genome map and provides more linkage
      groups physically assigned to known chromosomes.

PMID- 10582283
TI  - Bovine chromosome 4 workshop: consensus and comprehensive linkage maps.
AB  - The report of the bovine chromosome 4 (BTA4) workshop is presented. Six
      laboratories contributed a total of 30,168 informative meioses from 62 loci.
      Twenty-two loci were typed by at least two independent laboratories and were used
      to construct a consensus linkage map of BTA4. The remaining 40 loci were
      subsequently incorporated into a comprehensive map. The sex-averaged consensus
      map covered 131.4 cM. The female map was 124.3 cM in length, while the male map
      was 134.3 cM. The comprehensive sex-averaged map spanned 141.6 cM. The length of
      the female and male comprehensive maps were 123.1 cM and 156.4 cM, respectively.
      Average genetic distance between loci was 6 and 2.3 cM for the consensus and
      comprehensive linkage maps, respectively.

PMID- 10582284
TI  - Bovine UCP2 and UCP3 map to BTA15.
AB  - Two recently described uncoupling proteins, UCP2 and UCP3, may have important
      roles in determining feed conversion and/or maintenance energy requirements in
      livestock. Sequence was determined for the entire coding region and four of the
      six introns for bovine UCP3. A partial cDNA sequence was obtained for bovine
      UCP2. Radiation hybrid mapping was used to place UCP3 on BTA15, a chromosome
      previously shown to harbor a locus influencing meat tenderness. In order to place
      UCP3 in the existing linkage map, five single nucleotide polymorphisms (SNPs)
      were developed. Linkage analysis using one of five SNPs was used to place UCP3
      between 53.1 and 53.5 CM. No recombination was detected between UCP3 and IDVGA10,
      IDVGA32, and INRA145. The sequence of PCR products from a single BAC amplified
      with primers specific for either UCP2 or UCP3 indicate that UCP2 and UCP3 are
      separated by < 200 kb.

PMID- 10582285
TI  - Single strand conformational polymorphisms in the second exons of the ovine DMB,
      DYA and DYB genes.

PMID- 10582286
TI  - Use of the human transcript map to assign five loci to bovine chromosomes.

PMID- 10582287
TI  - RFLP markers in the bovine butyrophilin gene.

PMID- 10582288
TI  - A new allelic variant in the bovine prion protein gene (PRNP) coding region.

PMID- 10582289
TI  - Twelve novel cosmid-derived canine microsatellites.

PMID- 10582290
TI  - A molecular marker for the chicken myostatin gene (GDF8) maps to 7p11.

PMID- 10582291
TI  - A polymorphic CA-repeat at the porcine transferrin (TF) locus.

PMID- 10582292
TI  - A single nucleotide polymorphism and a (GA)n microsatellite in intron 6 of the
      canine endothelin receptor B (EDNRB) gene.

PMID- 10582293
TI  - A HaeIII PCR-RFLP in the ZFY/ZFX genes of horses.

PMID- 10582294
TI  - Characterization of 33 chicken microsatellite loci: 20 new locations on reference
      maps.

PMID- 10582295
TI  - Two highly polymorphic dinucleotide microsatellites in rainbow trout
      (Oncorhynchus mykiss): OmyRGT7TUF and OmyRGT8TUF.

PMID- 10582296
TI  - A single nucleotide polymorphism in the bovine kit oncogene (Hardy-Zuckerman 4
      feline sarcoma viral (v-kit) oncogene homolog).

PMID- 10582297
TI  - Five new polymorphic microsatellite markers for pig chromosome 6p.

PMID- 10582298
TI  - A new mutation in the bovine insulin-like growth factor binding protein-3.

PMID- 10582299
TI  - Linkage assignment of the last unmapped cattle erythrocyte antigen system, EAF.

PMID- 10582300
TI  - Molecular markers for the bovine gene encoding acidic seminal fluid protein
      precursor (spermadhesin 1, SPADH1) map to chromosome 26q23.

PMID- 10582301
TI  - Identification of a novel HaeIII PCR-RFLP in the SLA DQB gene.

PMID- 10582302
TI  - Thirteen new dinucleotide microsatellites in Alpaca.

PMID- 10582303
TI  - Dopamine receptor D2 maps to bovine chromosome 15.

PMID- 10582304
TI  - Six microsatellite markers for South American camelids.

PMID- 10582305
TI  - Genetic characterization and chromosomal location of a single locus GT
      microsatellite from Atlantic salmon.

PMID- 10582306
TI  - Identification of five point mutations, including an AluI RFLP, in the bovine
      butyrophilin gene.

PMID- 10582307
TI  - Evaluation of two cDNA-derived bovine tandem repeat sequences, BMON112 and
      BMON114.

PMID- 10582308
TI  - A Bsp143I PCR-RFLP in exon 3 of the ovine aromatase gene (CYP19).

PMID- 10582310
TI  - Mapping of the gene encoding a chicken homologue of the mammalian chemokine
      SCYA4.

PMID- 10582309
TI  - Assignment of a homologue of murine wingless-type MMTV integration site family
      member 3a (WNT3A) to chicken chromosome 2.

PMID- 10582311
TI  - Characterisation of a G-->A transition polymorphism within an Eco130I site of
      intron 3 of the insulin-like growth factor-1 (IGF1) gene of swamp buffaloes
      (Bubalus b. bubalis kerebau).

PMID- 10582312
TI  - Production of leukotriene B4 and prostaglandin E2 by turbot (Scophthalmus
      maximus) leukocytes.
AB  - Production of two eicosanoids derived from lipoxygenase and cyclooxygenase
      activities: leukotriene B4 (LTB4) and prostaglandin E2 (PGE2), respectively, have
      been simultaneously determined in turbot (Scophthalmus maximus) blood leucocyte
      and kidney macrophage supernatants by a reverse phase high performance liquid
      chromatography (HPLC) system coupled with a Diode-Array detector. Levels of LTB4
      after calcium ionophore challenge were 4.08 ng ml-1 in blood leukocyte
      supernatants and 0.25 ng ml-1 in kidney macrophage supernatants. The levels found
      for PGE2 were 428.23 and 606.67 ng ml-1 in blood leukocytes and kidney macrophage
      supernatants, respectively. When blood leukocytes were treated with the
      respective inhibitors for the enzymes implicated on the synthesis of both
      compounds an inhibition of 90.35% was observed for PGE2 and 76.44% for LTB4. The
      detection limit of the method was 0.15 ng ml-1 for LTB4 and 50 ng ml-1 for PGE2.

PMID- 10582313
TI  - Polyunsaturated fatty acids enhance the heat induced stress response in rainbow
      trout (Oncorhynchus mykiss) leukocytes.
AB  - The heat shock response has been studied extensively, yet the molecular signals
      that trigger the response remain elusive. The dogma of the heat shock response
      contends that denatured proteins initiate the response, but evidence is
      accumulating to point to a more complex system in which at least more than one
      signal is involved in this process. Thermal stress initiates changes in cellular
      phospholipid membrane physical state, which when acted upon by phospholipases may
      release lipid mediators that could serve as triggering signals during the heat
      shock response. We have examined the heat shock response in freshly isolated
      leukocytes from the pronephros of rainbow trout (Oncorhynchus mykiss). In this
      study, we show that leukocytes isolated from rainbow trout acclimated to 5 or 19
      degrees C express elevated levels of heat shock protein 70 (hsp70) mRNA when heat
      shocked at 5 degrees C above their respective acclimation temperature and
      supplementation with exogenous docosahexaenoic acid or arachidonic acid followed
      by heat shock enhanced levels of hsp70 mRNA. The time course for docosahexaenoic
      acid induced enhancement of hsp70 mRNA was accelerated compared with heat shock
      alone, and staurosporine inhibited the docosahexaenoic acid induced increase of
      hsp70 mRNA. We also provide evidence that phospholipase A2 is involved in the
      heat shock response.

PMID- 10582314
TI  - Cleavage specificity of a myofibril-bound serine proteinase from carp (Cyprinus
      carpio) muscle.
AB  - Previously, we reported the purification and characterization of a myofibril
      bound serine proteinase (MBP) from carp muscle (Osatomi K, Sasai H, Cao M-J, Hara
      K, Ishihara T. Comp Biochem Physiol 1997;116B:159-66). In the present study, the
      N-terminal amino acid sequence of the enzyme was determined, which showed high
      identity with those of other trypsin-like serine proteases. The cleavage
      specificity of MBP for dibasic and monobasic residues was investigated using
      various fluorogenic substrates and peptides. Analyses of the cleaved peptide
      products showed that the enzyme hydrolyzed peptides both at monobasic and dibasic
      amino acid residues. Monobasic amino acid residues were hydrolyzed at the
      carboxyl side; dibasic residues were cleaved either at the carboxyl side of the
      pair or between the two basic residues and the enzyme showed a cleavage
      preference for the Arg-Arg pair. Unexpectedly, MBP hydrolyzed lysyl-bradykinin
      and methionyl-lysyl-bradykinin at the carboxyl side of Gly fairly specifically
      and efficiently displaying a unique cleavage. Because MBP also degraded protein
      substrates such as casein and myofibrillar proteins, the substrate specificity of
      MBP appeared not to be strictly specific.

PMID- 10582315
TI  - Fatty acid composition of choline and ethanolamine glycerophospholipid subclasses
      in heart tissue of mammals and migratory and demersal fish.
AB  - The distribution and fatty acid composition of cardiac choline and ethanolamine
      glycerophospholipids in both migratory and demersal fish and bovine and pig were
      determined. Phospholipid contents (mg/g heart) were 4.7-9.4 in demersal fish,
      14.0-16.5 in migratory fish, and 16.8-20.6 in mammals. Phosphatidylcholine (PC)
      and phosphatidylethanolamine (PE) were the major components in the phospholipid
      fraction. Diacyl forms represented 50.2-88.1% of PC in all animals, while
      plasmalogens comprised 47.0% in bovine, 8.2% in pig and 6.2-7.2% in four species
      of fish. In PE, plasmalogens varied from 45.0% in bovine and 57.9% in pig to 26.1
      29.7% in fish. This glycerophospholipid subclass was identified as containing
      higher proportions of polyunsaturated fatty acids (PUFAs; 20:4, 20:5, and 22:6)
      than found in alkylacyl- and diacyl-glycerophospholipids. Qualitative and
      quantitative differences were found in PE-plasmalogen between land mammals and
      fish, especially with regard to n-3 fatty acid composition, but no significant
      difference was noted between migratory and demersal fish.

PMID- 10582316
TI  - Influence of a high ambient temperature on stearoyl-CoA-desaturase activity in
      the growing pig.
AB  - An experiment was conducted to determine the influence of a high ambient
      temperature on the stearoyl-CoA-desaturase activity and fatty acid composition of
      backfat, leaf fat, Longissimus dorsi muscle and liver, in the growing pig.
      Eighteen Large White X Landrace castrated pigs (20 kg body weight) were divided
      into three groups: I (31 degrees C, ad libitum), II (20 degrees C, pair-fed on
      the 31 degrees C group) and III (20 degrees C, ad libitum) until 35 kg body
      weight. At 20 degrees C, the level of feed intake had no effect on stearoyl-CoA
      desaturase activity, whatever the tissue (groups II and III). At similar levels
      of feeding, (groups I and II), the stearoyl-CoA-desaturase activity was lower at
      31 degrees C (P < 0.001) than at 20 degrees C, regardless of the tissue, with the
      exception of the hepatic stearoyl-CoA-desaturase activity, which was similar in
      all three groups. This reduction of the stearoyl-CoA-desaturase activity at 31
      degrees C could be related to a decrease in the monounsaturated fatty acid
      percentage in all the tissues, in hot conditions. The present results show that
      changes in fatty acid composition caused by environmental temperature, in the
      pig, may be attributed at least in part to an alteration in the stearoyl-CoA
      desaturase activity.

PMID- 10582317
TI  - Oxygen consumption by mitochondria from an endotherm and an ectotherm.
AB  - Comparisons of metabolic properties of mitochondria from an endothermic and an
      ectothermic vertebrate were performed. Oxygen (O2) consumption rates of liver
      mitochondria from laboratory mice and western fence lizard (Sceloporus
      occidentalis) were determined over a range of temperatures (10, 20, 30 and 37
      degrees C) and in the presence of a variety of substrates. At 37 degrees C the O2
      consumption rate of mouse mitochondria was 4-11 times higher than lizard
      mitochondria in the presence of five of eight substrates. This range of
      differences is similar to differences reported for O2 consumption of endothermic
      animals, tissues and cells over those of ectotherms. Thermal sensitivity of
      mitochondria was measured by calculation of Q10s for O2 consumption. Q10s were
      highest for mouse mitochondria overall. The range that showed the highest Q10s
      for the mouse mitochondria was 30-20 degrees C, whereas for the lizard
      mitochondria it was 20-10 degrees C. Thus, mitochondria from the ectotherm showed
      a lower degree of temperature sensitivity than did mitochondria from the
      endotherm. The preferred substrate for all mitochondria at all temperatures was
      succinate, but mouse mitochondria then showed some preference for alpha
      ketoglutarate and citrate, whereas lizard mitochondria showed a preference for
      pyruvate and malate + pyruvate.

PMID- 10582318
TI  - Comparison between site-specific DNA binding proteins of male and female
      Schistosoma mansoni.
AB  - Several amplicons with approximately 120 bp each, obtained from the upstream
      domain of Schistosoma mansoni female-specific gene F-10, were coupled to
      Dynabeads M-280 streptavidin. The beads were used as a matrix for affinity
      purification of nuclear proteins obtained from mixed populations of adult worms.
      A protein of approximately 12 kDa, bound to the DNA in a sequence-independent
      manner. In contrast, when the DNA matrix was narrowed down to smaller synthetic
      oligonucleotides, bearing sequences corresponding to the TATA box and the CAAT
      box, band-shift assays revealed that different nuclear proteins from either adult
      male or female worms formed complexes with the DNA adduct. In order to
      characterise the bound proteins, the same oligonucleotides were UV cross-linked
      to the male and female protein extracts. Whilst the band shift experiments showed
      that the proteins from each sex produced a distinct mobility pattern when the
      TATA box sequences were tested and a similar one when the CAAT box sequences were
      added to the proteins, UV cross-linking experiments revealed clear qualitative
      differences between both, male and female proteins and also between the proteins
      binding to the two motifs. These results are compatible with a model in which the
      differential expression of the F-10 gene might depend on individual sub-sets of
      proteins.

PMID- 10582319
TI  - Identification of differentially expressed genes in Con A-activated carp
      (Cyprinus carpio L.) leucocytes.
AB  - A cDNA library was constructed from the message RNA (mRNA) obtained from Con A
      induced head kidney (HK) leucocytes of carp (Cyprinus carpio L.). Differential
      screening of the cDNA was carried out by hybridization against the total cDNA
      probes from normal, Con A-uninduced HK leucocytes or Con A-induced HK leucocytes
      of carp. The differential expression patterns of certain cDNA clones were
      confirmed by Southern-blot and Northern-blot analysis. Single-pass of the
      sequencing analysis and homology search in Genbank (EMBL) revealed those
      differentially expressed cDNA clones encode for cytochrome c oxidase sub-unit II
      and III (COII and COIII), elongation factor-1 beta (EF-1 beta), bleomycin
      hydrolase (BH), heat shock cognate protein 70 (HSC70) and 16S ribosomal RNA (16S
      rRNA).

PMID- 10582320
TI  - Involvement of calcineurin in the signal transduction of PBAN in the silkworm,
      Bombyx mori (Lepidoptera).
AB  - In several moth species sex pheromone production in the pheromone gland is
      regulated by a neurohormone, pheromone biosynthesis activating neuropeptide
      (PBAN). In Bombyx mori it is suggested that PBAN, after binding to the cell
      surface receptor, primarily activates a plasma membrane receptor-activated Ca2+
      channel to increase cytosolic levels of Ca2+, and Ca2+/calmodulin complex
      directly or indirectly activates a phosphoprotein phosphatase, which in turn
      elicits activation of acyl CoA reductase (the key enzyme under PBAN control)
      through dephosphorylation, resulting in pheromone (bombykol) production. The
      effect of cyclosporin A (CsA) and FK 506, specific inhibitors of calcineurin
      (phosphoprotein phosphatase 2B) was studied on the sex pheromone production, in
      B. mori. The in vitro experiments showed that both chemicals exerted a dose
      dependent inhibitory action when they were co-incubated with TKYFSPRL amide (Hez
      PBAN fragment peptide). Practically, no difference was detected between the two
      chemicals in the tested doses (0.025-1250 microM). When effects of CsA or FK 506
      were studied on cell-free production of bombykol by using microsomal fraction no
      inhibition was detected. Since microsomal fraction contains the acyl CoA
      synthetase, the rate-limiting acyl CoA reductase and the precursor, bombykol is
      produced if supplied with CoA, ATP and NADPH. Thus, the inhibitory action of CsA
      and FK506 under in vitro conditions should occur before the step of acyl group
      reduction and the effect is likely to be attributable to the inhibition of
      calcineurin in the signal transduction cascade mechanism of PBAN, in B. mori. The
      existence of calcineurin in the pheromone gland by using Western blot analysis is
      also demonstrated.

PMID- 10582321
TI  - Cyclic AMP metabolism by swine adipocyte microsomal and plasma membranes.
AB  - Extracellular cyclic AMP is source of extracellular adenosine in brain and
      kidney. Whether this occurs in adipose tissue is unknown. The present study
      evaluated the capacity of swine adipocyte plasma membranes to metabolize cyclic
      AMP to AMP and adenosine, via phosphodiesterase (PDE) and 5'-nucleotidase (5'
      NT), respectively. Plasma membranes (PM) and microsomal membranes (MM) were
      isolated from over-the-shoulder subcutaneous adipose tissue of 3 month-old male
      miniature swine. The purity of the membrane fractions was determined and PDE and
      5'-NT activities in PM and MM fractions were corrected for cross-contamination.
      The maximal activity of MM-PDE was 7-fold greater than that of PM-PDE. MM-PDE was
      100% inhibited by 5 microM cilostamide, while PM-PDE was unaffected by this PDE3B
      inhibitor. Inhibitors of PDE1, PDE2, PDE4 and PDE5 also failed to inhibit PM-PDE.
      However, 1 mM DPSPX inhibited PM-PDE activity by 72%. When PM were incubated with
      0.8 microM cyclic AMP for 20 min, AMP accumulation was four times that of
      adenosine. These data demonstrate that cyclic AMP can be converted to AMP and
      adenosine by the PM-bound enzymes 5'-NT and PDE, and suggest that the PM-PDE
      responsible for extracellular cyclic AMP metabolism to AMP is distinct from the
      intracellular MM-PDE.

PMID- 10582322
TI  - Immunochemical analysis and immunocytochemical localization of crustacean
      hyperglycemic hormone from the eyestalk of Macrobrachium rosenbergii.
AB  - Heptapeptide (YANAVQV-NH2 = T-) and octapeptide (YANAVQTV-NH2 = T+), the putative
      C-terminus of crustacean hyperglycemic hormone (CHH) from the eyestalk of the
      giant freshwater prawn Macrobrachium rosenbergii, was synthesized by solid phase
      peptide synthesis and conjugated to bovine serum albumin, then used for
      immunization in swiss mice. Specificity of the antisera against both peptides was
      determined by indirect immunoperoxidase ELISA. The best response of antiserum
      against each peptide was used to determine the presence of the natural CHH in the
      eyestalk extract after separation by one step of RP-HPLC using dot-ELISA. The
      peptide immunoreactive substances were found in fraction 30 using anti-T-
      antiserum and in fraction 38 using anti-T+ antiserum. However, the CHH activity
      was found only in fractions 37-39. Immunocytochemical localization of peptide
      immunoreactive substances in the eyestalk of M. rosenbergii using the anti-T-
      antiserum did not show any specific staining. In contrast, the anti-T+ antiserum
      revealed specific staining on a group of 24 +/- 5 neurons in medulla terminalis
      ganglionic x-organ and their processes through the sinus gland. Similar results
      were also obtained using the eyestalk of another species, the giant tiger prawn
      Penaeus monodon, in which 34 +/- 4 neuronal cells were recognized. These results
      strongly indicate that the anti-T+ antibody can bind to the natural CHH while the
      anti-T- antibody can not; therefore, this isoform of CHH in M. rosenbergii should
      consist of 72 residues and threonine is predicted to be present at position 71.

PMID- 10582323
TI  - Fatty acid composition of Heterorhabditis sp. during storage.
AB  - The fatty acid composition of three North West European isolates of
      Heterorhabditis sp. from different geographical origins, UK211 (England), HF85
      (The Netherlands) and EU17 (Estonia) was assessed directly after harvest and, for
      UK211 and HF85, after 5 weeks storage in water at 20 degrees C. Lipid represented
      34-43% of the dry weight of fresh nematodes. Of this, neutral lipid (NL)
      comprised from 70% (HF85) to over 90% (UK211, EU17). The fatty acid patterns were
      similar between the three isolates. Oleic (C18:In-9), palmitic (C16:0), and
      linoleic (C18:2n-6) acid predominated with 51, 13 and 12%, respectively in the
      total lipid (TL) of fresh nematodes (average for the three isolates). Levels of
      unsaturation (U.I.) of fresh nematodes were on average 110, 112, 113 and 152 for
      the TL, NL, phospholipid and free fatty acid fractions, respectively. EU17 had a
      slightly lower U.I than the other two strains, despite its more northern origin.
      Changes in fatty acid composition due to storage were most significant in the NL
      fraction. The U.I. for the NL fraction increased during storage, suggesting a
      preferential use of saturated fatty acids.

PMID- 10582324
TI  - A novel, endogenous inhibitor of 7-ethoxyresorufin-O-deethylase activity isolated
      from liver cytosolic fractions of bream (Abramis brama L.).
AB  - The cytosolic supernatant of bream (Abramis brama L.) liver homogenates inhibits
      the 7-ethoxyresorufin-O-deethylase (EROD) activity of pike (Esox lucius)
      microsomal fractions. The inhibitor shows no activity against 7-ethoxycoumarin-O
      deethylase and benzo(a)pyrene hydroxylase indicating a high isoenzyme
      specificity. The inhibiting component is a heat-sensitive substance (56 degrees C
      for 5') which is not self regenerating after subsequent cooling. It can be
      isolated from the cytosolic fraction using two combined steps of ion exchange
      chromatography. The purification factor is 500-fold with a recovery rate of 70%.
      SDS-PAGE of the purified fractions indicate that electrophoretic purity was not
      achieved. However, a prominent band at about 97 kDa was present in all fractions
      in a close intensity activity relationship. The molecular weight of the native
      form of the purified protein was determined to be 175 +/- 35 kDa using gel
      filtration on a Sephacryl S 300 HR column. So far the inhibitor can be
      characterized as a protein. It shows strong tendencies to aggregate due to
      lipophilic interactions. These interactions can be repressed by the addition of
      1% sodium cholate. The inhibitor has an optimum activity at 25 degrees C and pH
      8.0. The inhibitor does not correspond to any of the known cytosolic, endogenous
      inhibitors of EROD activities in fish, including proteases, cytosolic
      phosphatases, kinases and resorufin reductase (e.g. DT-diaphorase), although a
      non-dicoumarol (10 microM)-inhibited menadione oxidoreductase activity of up to
      46.7 +/- 0.4 nmol/min per mg inhibitory protein was measured. Kinetic studies
      using Michaelis-Menten kinetics with purified inhibitor fractions prove a non
      competitive mode of inhibition. As this kind of inhibitor is not described yet it
      is named CERODIP (cytosolic, EROD-inhibiting protein).

PMID- 10582325
TI  - Importance of the role of calcium in programmed cell death: a review.
AB  - Calcium plays an important role in physiological cell death processes such as
      terminal differentiation and apoptosis. Cell injury occurs when the intracellular
      calcium pool is disturbed, which in turn may lead to cell death. Calcium in
      calcium-dependent enzymes, transglutaminases, various proteases, phosphorylases
      and kinase, is involved in the process of cell death. Examples of such enzymes
      involved in cell death, and the role of calcium levels in regulation of these
      enzymes, are described and discussed.

PMID- 10582326
TI  - Effect of triethyl lead on peristaltic contractile activity of the ileum of mice.
AB  - The effect of triethyl lead (TriEL) as triethyl lead chloride on the rhythmic
      peristaltic contractile activity of ileum isolated from Swiss white mice was
      investigated, with the aid of a tensiometer. The response was measured as a
      change in period duration and force amplitude. TriEL concentrations of < 40
      microM did not show any obvious effects on either of the parameters. In the
      concentration range between 40 and 120 microM, TriEL exclusively affected the
      rhythm of contractions in a concentration-dependent manner. It induced elongation
      of the period and reduction of the force amplitude. Concentrations of TriEL above
      120 microM induced irreversible dramatic changes in the ileum contractile
      activity, while 200 microM TriEL induced a strong contracture followed by an
      irreversible cessation of the oscillatory contractile activity. The results
      demonstrate that the measurement of rhythmic contractions may be a useful model
      for a toxicological screening system.

PMID- 10582327
TI  - Heat stable lipase activity of thermotolerant bacteria from hot springs at
      Orissa, India.
AB  - Thermotolerant bacteria (35 in toto) isolated from three hot springs (Atri,
      Taptapani and Deuljhari, Orissa), were screened for lipase activities. Of these,
      nine strains of Bacillus spp. and three strains of Pseudomonas spp. showed heat
      stable lipase activity at 60 degrees C. The hydrolytic activity of these bacteria
      was tested using Tween-20 and Tween-80 as substrates at different temperatures
      using plate assay and titration techniques. The hydrolytic activity at different
      pH values and salt concentrations was investigated.

PMID- 10582328
TI  - Heterochromatin patterns in triatomines of the genus Panstrongylus.
AB  - Spermatogenesis was analysed by C-banding in two species of triatomines,
      Panstrongylus megistus and P. herreri. Both species revealed interstitial and
      terminal bands in the autosomes, which is a common pattern in Heteroptera. The
      terminal bands corroborated the hypothesis that in holocentric chromosomes the
      heterochromatin is preferentially located at the telomere. The sex chromosomes in
      P. herreri were totally heterochromatic in spermatogenesis, and in P. megistus
      the X chromosomes alternated between positive and negative banding.

PMID- 10582329
TI  - Effect of ethyl methane sulphonate on biomass and protein production by Candida
      tropicalis.
AB  - Large doses of ethyl methanesulphonate (EMS) greatly increased the induction of
      auxotrophic mutants in Candida tropicalis. The maximum yield of biomass and
      protein was recorded in some mutants isolated after treatment with 60, 80 and 100
      ppm EMS. The electrophoretic protein profile revealed typical banding patterns
      for both C. tropicalis wild type and mutants.

PMID- 10582330
TI  - Regulation of hemopoietic system.
AB  - The regulation of the hemopoietic system is extremely complex. In this directed
      issue we have focussed on a few important control points, from extracellular
      growth factors binding to their cognate receptors and initiation of signalling
      cascades, to transcription factors and the pathway for hemoglobin synthesis.
      Major advances have been made in the field of hemopoiesis--critical new knowledge
      has been generated, much of which has been translated into clinical applications.
      The future for hemopoietic research is indeed bright and we eagerly await the
      next exciting installments.

PMID- 10582331
TI  - The iron transporter DMT1.
AB  - Divalent metal transporter 1 (DMT1) is the first mammalian transmembrane iron
      transporter to be identified. In 1997, parallel experiments from two groups
      provided compelling evidence of its function. Fleming and colleagues identified
      mutations in DMT1 (formerly known as Nramp2 and DCT1) in mice and rats with
      defects in intestinal iron absorption and red blood cell iron utilization.
      Gunshin and co-workers (H Gunshin, B MacKenzie, UV Berger, Y Gunshin, MF Romero,
      WF Boron, S. Nussberger, JL Gollan, MA Hediger, Cloning and characterization of a
      mammalian proton-coupled metal-ion transporter, Nature 388 (1997) 482-488.)
      isolated DMT1 through an expression cloning strategy looking for mRNAs that
      stimulated iron uptake by Xenopus oocytes. Taken together, these data indicate
      that the twelve transmembrane domain protein DMT1 transfers iron across the
      apical surface of intestinal cells and out of transferrin cycle endosomes. Human
      DMT1 may be a good target for pharmacological intervention in patients with iron
      overload disorders attributable to increased iron absorption.

PMID- 10582332
TI  - Ferrochelatase.
AB  - Ferrochelatase, the terminal enzyme of the heme biosynthetic pathway, catalyzes
      the insertion of ferrous iron into protoporphyrin IX. It is encoded by a single
      gene, and mutations in the human gene are associated with the inherited disorder,
      erythropoietic protoporphyria. With the development of heterologous
      overexpression systems and the ready availability of recombinant ferrochelatase,
      new structural elements have been identified and new aspects of the
      ferrochelatase-catalyzed reaction mechanism have been unraveled. Namely, a [2Fe
      2S] cluster is a prosthetic group in mammalian ferrochelatase, a conserved and
      essential histidine residue appears to be involved in the binding of the metal
      substrate and a conserved glutamate residue has been proposed to have a catalytic
      role. The three-dimensional structure for Bacillus subtilis ferrochelatase, the
      only known 'water-soluble' ferrochelatase, revealed that the protein contains two
      similar domains, each of which has a four-stranded beta-sheet flanked by alpha
      helices; the active site was modeled to be in a cleft defined by the two domains.
      The definition of the structure and catalytic mechanism of ferrochelatase should
      help in the interpretation of the impact caused by erythropoietic porphyria
      mutations.

PMID- 10582333
TI  - The erythropoietin receptor.
AB  - The erythropoietin (epo) receptor is a member of the cytokine receptor family. It
      is expressed almost exclusively on erythroid precursor cells and controls the
      development of red blood cells. The epo receptor has no intrinsic kinase
      activity, but binds intracellular tyrosine kinases to elicit its signals.
      Alterations in the transmission of the signalling cascade lead to clinically
      abnormal red blood cell production.

PMID- 10582334
TI  - SHIPs ahoy.
AB  - In 1996 three groups independently cloned a hemopoietic specific, src homology 2
      containing inositol 5'-phosphatase which, based on its structure, was called
      SHIP. More recently, a second more widely expressed SHIP-like protein has been
      cloned and called SHIP2. Both specifically hydrolyze phosphatidylinositol-3,4,5
      trisphosphate and inositol 1,3,4,5-tetrakisphosphate in vitro. Moreover, SHIP has
      been shown in vivo to be the primary enzyme responsible for breaking down
      phosphatidylinositol-3,4,5-trisphosphate to phosphatidylinositol-3,4-bisphosphate
      in normal mast cells and, as a result, limits normal and prevents inappropriate
      mast cell degranulation. Because of their ability to break down
      phosphatidylinositol-3,4,5-trisphosphate, the SHIPs have the potential to
      regulate many, if not all, phosphatidylinositol-3-kinase induced events
      including, proliferation, differentiation, apoptosis, end cell activation, cell
      movement and adhesion and will thus likely be the subject of intensive research
      over the next few years.

PMID- 10582335
TI  - The beta common chain (beta c) of the granulocyte macrophage-colony stimulating
      factor, interleukin-3 and interleukin-5 receptors.
AB  - The hematopoietic cytokines granulocyte-macrophage colony-stimulating factor (GM
      CSF), Interleukin (IL)-5 and IL-3 utilise a common receptor signalling molecule,
      the beta common chain (beta c). This shared receptor component explains, in part
      the overlapping actions of these cytokines. Mice lacking beta c have a low
      circulating eosinophil level, have impaired eosinophilic responses to parasitic
      infection and develop lung disease analogous to human pulmonary alveolar
      proteinosis (PAP). Surprisingly however, mature hematopoietic cell function is
      relatively intact, although all GM-CSF-mediated mature cell responses, including
      glucose transport are absent. Intriguing observations suggesting altered
      susceptibility to some infectious agents and amelioration of responses to
      inflammatory stimuli, require further clarification.

PMID- 10582336
TI  - The functional basis of granulocyte-macrophage colony stimulating factor,
      interleukin-3 and interleukin-5 receptor activation, basic and clinical
      implications.
AB  - The cytokines granulocyte-macrophage colony stimulating factor, interleukin-3 and
      interleukin-5 have overlapping activities on cells expressing their receptors.
      This is explained by their sharing a receptor signal transduction subunit, beta
      c. This communal signaling subunit is also required for high affinity binding of
      all three cytokines. Therapeutic approaches attempting to interfere or modulate
      haemopoietic cells using cytokines or their analogues can in some instances be
      limited due to functional redundancy amongst cytokines using shared receptor
      signaling subunits. Therefore, a better approach would be to develop therapeutics
      against the shared subunit. Studies examining the GM-CSF, IL-3 and IL-5 receptors
      have identified the key events leading to functional receptor activation. With
      this knowledge, it is now possible to identify new targets for the development of
      a new class of antagonist that blocks the biological activity of all the
      cytokines utilizing beta c. This approach may be extended to other receptor
      systems such as IL-4 and IL-13 where receptor activation is dependent on a common
      signaling and binding subunit.

PMID- 10582337
TI  - Thrombopoietin and the c-Mpl receptor: insights from gene targeting.
AB  - The availability of thrombopoietin (TPO) in recombinant form has revolutionized
      the study of megakaryocytopoiesis and provided an exciting new reagent for
      clinical evaluation. Through the application of gene targeting technology, the
      production of mice lacking TPO or its receptor c-Mpl has provided valuable
      insights into the physiological roles of TPO signalling. The near identical
      phenotype of c-mpl-/- and TPO-/- mice provides strong biological evidence that
      TPO is the sole c-Mpl ligand and uses no other additional receptor itself. TPO-/-
      and mpl-/- mice are severely thrombocytopenic indicating that TPO is the primary
      physiological regulator of platelet production in vivo. The physiological basis
      for this platelet deficiency has been further defined by analysis of
      megakaryocytes and committed progenitor cells, the numbers of which are also
      reduced in these mutants. The platelets that are produced in the absence of TPO
      signalling are morphologically and functionally normal and residual production is
      sufficient to prevent bleeding and allow a normal lifespan. Thus, TPO-/- and mpl
      /- mice also reveal that important TPO-independent mechanisms exist that control
      platelet production in vivo, and these mice are ideal models to explore the
      nature of these alternative regulators. The mechanisms regulating the circulating
      levels of TPO have also been elucidated in these mice, highlighting the central
      role of c-Mpl mediated internalisation and degradation. The unexpected
      observation that progenitor cells of all hemopoietic lineages are produced in
      reduced numbers in TPO-/- and mpl-/- mice has also led to studies that uncovered
      a central role for TPO signalling in hemopoietic stem cell regulation.

PMID- 10582338
TI  - The biology of stem cell factor and its receptor C-kit.
AB  - The receptor tyrosine kinase c-Kit and its ligand Stem Cell Factor (SCF) are
      essential for haemopoiesis, melanogenesis and fertility. SCF acts at multiple
      levels of the haemopoietic hierarchy to promote cell survival, proliferation,
      differentiation, adhesion and functional activation. It is of particular
      importance in the mast cell and erythroid lineages, but also acts on
      multipotential stem and progenitor cells, megakaryocytes, and a subset of
      lymphoid progenitors. SCF exists in soluble or transmembrane forms which appear
      to differ in function. Multiple isoforms of c-Kit also exist as a result of
      alternate mRNA splicing, proteolytic cleavage and the use of cryptic internal
      promoters in certain cell types. This review focuses on what is known about the
      regulation of c-Kit expression, the functions of SCF and c-Kit isoforms, and the
      nature of the biological responses elicited by this receptor-ligand pair with
      emphasis on the haemopoietic system.

PMID- 10582339
TI  - Early signaling pathways activated by c-Kit in hematopoietic cells.
AB  - c-Kit is a receptor tyrosine kinase that binds stem cell factor (SCF).
      Structurally, c-Kit contains five immunoglobulin-like domains extracellularly and
      a catalytic domain divided into two regions by a 77 amino acid insert
      intracellularly. Studies in white spotting and steel mice have shown that
      functional SCF and c-Kit are critical in the survival and development of stem
      cells involved in hematopoiesis, pigmentation and reproduction. Mutations in c
      Kit are associated with a variety of human diseases. Interaction of SCF with c
      Kit rapidly induces receptor dimerization and increases in autophosphorylation
      activity. Downstream of c-Kit, multiple signal transduction components are
      activated, including phosphatidylinositol-3-kinase, Src family members, the
      JAK/STAT pathway and the Ras-Raf-MAP kinase cascade. Structure-function studies
      have begun to address the role of these signaling components in SCF-mediated
      responses. This review will focus on the biochemical mechanism of action of SCF
      in hematopoietic cells.

PMID- 10582340
TI  - Activation of erythropoietin signaling by receptor dimerization.
AB  - The hormone erythropoietin (Epo) is essential for red blood cell development. Epo
      binds a high affinity receptor on the surface of erythroid progenitor cells,
      stimulating receptor dimerization and activation of the intracellular signal
      transduction pathways that support erythroid cell survival, proliferation and
      differentiation. Biochemical and structural analysis of the erythropoietin
      receptor (EpoR) is revealing the molecular mechanisms of EpoR function, leading
      the way to the development of small molecule Epo mimetics. This review focuses on
      the role EpoR dimerization plays in receptor function.

PMID- 10582341
TI  - Deregulation of erythropoiesis by the Friend spleen focus-forming virus.
AB  - The proliferation and differentiation of erythroid cells is a highly regulated
      process that is controlled primarily at the level of interaction of
      erythropoietin (Epo) with its specific cell surface receptor (EpoR). However,
      this process is deregulated in mice infected with the Friend spleen focus-forming
      virus (SFFV). Unlike normal erythroid cells, erythroid cells from SFFV-infected
      mice are able to proliferate and differentiate in the absence of Epo, resulting
      in erythroid hyperplasia and leukemia. Over the past 20 years, studies have been
      carried out to identify the viral genes responsible for the pathogenicity of SFFV
      and to understand how expression of these genes leads to the deregulation of
      erythropoiesis in infected animals. The studies have revealed that SFFV encodes a
      unique envelope glycoprotein which interacts specifically with the EpoR at the
      cell surface, resulting in activation of the receptor and subsequent activation
      of erythroid signal transduction pathways. This leads to the proliferation and
      differentiation of erythroid precursor cells in the absence of Epo. Although the
      precise mechanism by which the viral protein activates the EpoR is not yet known,
      it has been proposed that it causes dimerization of the receptor, resulting in
      constitutive activation of Epo signal transduction pathways. While interaction of
      the SFFV envelope glycoprotein with the EpoR leads to Epo-independent erythroid
      hyperplasia, this is not sufficient to transform these cells. Transformation
      requires the viral activation of the cellular gene Sfpi-1, whose product is
      thought to block erythroid cell differentiation. By understanding how SFFV can
      deregulate erythropoiesis, we may gain insights into the causes and treatment of
      related diseases in man.

PMID- 10582342
TI  - The transferrin receptor: role in health and disease.
AB  - The transferrin receptor is a membrane glycoprotein whose only clearly defined
      function is to mediate cellular uptake of iron from a plasma glycoprotein,
      transferrin. Iron uptake from transferrin involves the binding of transferrin to
      the transferrin receptor, internalization of transferrin within an endocytic
      vesicle by receptor-mediated endocytosis and the release of iron from the protein
      by a decrease in endosomal pH. With the exception of highly differentiated cells,
      transferrin receptors are probably expressed on all cells but their levels vary
      greatly. Transferrin receptors are highly expressed on immature erythroid cells,
      placental tissue, and rapidly dividing cells, both normal and malignant. In
      proliferating nonerythroid cells the expression of transferrin receptors is
      negatively regulated post-transcriptionally by intracellular iron through iron
      responsive elements (IREs) in the 3' untranslated region of transferrin receptor
      mRNA. IREs are recognized by specific cytoplasmic proteins (IRPs; iron regulatory
      proteins) that, in the absence of iron in the labile pool, bind to the IREs of
      transferrin receptor mRNA, preventing its degradation. On the other hand, the
      expansion of the labile iron pool leads to a rapid degradation of transferrin
      receptor mRNA that is not protected since IRPs are not bound to it. However, some
      cells and tissues with specific requirements for iron probably evolved mechanisms
      that can override the IRE/IRP-dependent control of transferrin receptor
      expression. Erythroid cells, which are the most avid consumers of iron in the
      organism, use a transcriptional mechanism to maintain very high transferrin
      receptor levels. Transcriptional regulation is also involved in the receptor
      expression during T and B lymphocyte activation. Macrophages are another example
      of a cell type that shows 'unorthodox' responses in terms of IRE/IRP paradigm
      since in these cells elevated iron levels increase (rather than decrease)
      transferrin receptor mRNA and protein levels. Erythroid cells contain the highest
      mass of the total organismal transferrin receptors which are released from
      reticulocytes during their maturation to erythrocytes. Hence, plasma contains
      small amounts of transferrin receptors which represent a soluble fragment of the
      extracellular receptor domain. Measurements of serum transferrin receptor
      concentrations are clinically useful since their levels correlate with the total
      mass of immature erythroid cells.

PMID- 10582343
TI  - Iron-regulatory proteins, iron-responsive elements and ferritin mRNA translation.
AB  - Iron plays a central role in the metabolism of all cells. This is evident by its
      major contribution to many diverse functions, such as DNA replication, bacterial
      pathogenicity, photosynthesis, oxidative stress control and cell proliferation.
      In mammalian systems, control of intracellular iron homeostasis is largely due to
      posttranscriptional regulation of binding by iron-regulatory RNA-binding proteins
      (IRPs) to iron-responsive elements (IREs) within ferritin and transferrin
      receptor (TfR) mRNAs. the TfR transports iron into cells and the iron is
      subsequently stored within ferritin. IRP binding is under tight control so that
      it responds to changes in intracellular iron requirements in a coordinate manner
      by differentially regulating ferritin mRNA translational efficiency and TfR mRNA
      stability. Several different stimuli, as well as intracellular iron levels and
      oxidative stress, are capable of regulating these RNA-protein interactions. In
      this mini-review, we shall concentrate on the mechanisms underlying modulation of
      the interaction of IRPs and the ferritin IRE and its role in regulating ferritin
      gene expression.

PMID- 10582344
TI  - Regulation of erythroid 5-aminolevulinate synthase expression during
      erythropoiesis.
AB  - Erythroid tissue is the major site of heme production in the body. The synthesis
      of heme and globin chains is coordinated at both the transcriptional and post
      transcriptional levels to ensure that virtually no free heme or globin protein
      accumulates. The key rate-controlling enzyme of the heme biosynthetic pathway is
      5-aminolevulinate synthase (ALAS) and an erythroid-specific isoform (ALAS2) is up
      regulated during erythropoiesis. Differentiation of embryonic stem cells with a
      disrupted ALAS2 gene has established that expression of this gene is critical for
      erythropoiesis and cannot be compensated by expression of the ubiquitous isoform
      of the enzyme (ALAS1). Interestingly, heme appears to be important for expression
      of globin and other late erythroid genes and for erythroid cell differentiation
      although the mechanism of this effect is not clear. Transcriptional control
      elements that regulate the human gene for ALAS2 have been identified both in the
      promoter and in intronic enhancer regions. Subsequent translation of the ALAS2
      mRNA is dependent on an adequate iron supply. The mechanism by which
      transcription of the gene for ALAS2 is increased by erythropoietin late in
      erythropoiesis remains an interesting issue. Erythropoietin action may result in
      altered levels of critical erythroid transcription factors or modulate the
      phosphorylation/acetylation status of these factors. Defects in the coding region
      of the gene for ALAS2 underlie the disease state X-linked sideroblastic anemia.
      In this review, we focus on the regulation and function of erythroid-specific 5
      aminolevulinate synthase during erythropoiesis and its role in the X-linked
      sideroblastic anemia.

PMID- 10582345
TI  - Basic Kruppel-like factor functions within a network of interacting
      haematopoietic transcription factors.
AB  - Basic Kruppel-like Factor (BKLF) is a recently recognized member of a small group
      of transcription factors that bind CACCC motifs in DNA, by means of three highly
      conserved C-terminal Kruppel-like (typically Cys-X2-4-Cys-X12-His-X3-4-His) zinc
      fingers. Together with Erythroid Kruppel-like Factor (EKLF), it is one of the
      most abundant CACCC-binding proteins in erythroid cells. In contrast to EKLF,
      BKLF can act to repress transcription and thus may serve to moderate EKLF
      activity in vivo. Interestingly, it has also been shown that BKLF expression in
      erythroid cells is dependent on EKLF. Analysis of proteins interacting with BKLF
      indicates that it represses transcription by recruiting the general co-repressor
      protein CtBP, a cofactor that also associates with other haematopoietic
      transcriptional repressors such as Evi-1 and ZEB/AREB6. The observation that mice
      deficient in BKLF exhibit a myeloproliferative disorder suggests that BKLF
      regulates important processes involved in haematopoietic differentiation.

PMID- 10582346
TI  - Erythroid Kruppel like factor: from fishing expedition to gourmet meal.
AB  - Erythroid Kruppel like factor (EKLF) is the founding member of a family of
      transcription factors which are defined by the presence of three C-terminal C2H2
      type zinc fingers. Since its discovery 6 years ago, the study of EKLF has been
      intense. In this review I will revisit the discovery of EKLF, and highlight
      recent advances in our understanding of how it interacts with other proteins to
      regulate erythroid gene transcription. The current knowledge of the biological
      role/s of EKLF in erythroid cell differentiation and globin gene switching are
      summarized.

PMID- 10582347
TI  - The stem cell leukaemia (SCL) gene: a critical regulator of haemopoietic and
      vascular development.

PMID- 10582348
TI  - New insights into the roles of ReL/NF-kappa B transcription factors in immune
      function, hemopoiesis and human disease.
AB  - In mammals, Rel/NF-kappa B proteins are a small family of transcription factors
      which serve as pivotal regulators of immune, inflammatory and acute phase
      responses. Pathways leading to the activation of Rel/NF-kappa B have recently
      been dissected in some detail and shown to converge on a unique high molecular
      weight cytoplasmic complex that includes several kinases and regulatory
      molecules. Moreover, gene targeting experiments have identified novel roles for
      Rel/NF-kappa B proteins in the development and maturation of hemopoietic
      precursors as well as in the function of mature cells in the immune system. These
      include regulating the cell cycle, controlling cell survival and providing a link
      between the innate and adaptive immune systems. Since the dysregulation of Rel/NF
      kappa B function is associated with various pathologies including inflammatory
      and neoplastic disease, new insights into the role of Rel/NF-kappa B in human
      disease may provide a basis for therapeutic strategies in the treatment of
      chronic inflammatory diseases and certain malignancies.

PMID- 10582349
TI  - Role of nuclear factor of activated T cells (NFAT) in the expression of
      interleukin-5 and other cytokines involved in the regulation of hemopoetic cells.
AB  - NFAT (nuclear factor of activated T cells) is a transcription factor that plays a
      role in the regulation of various cytokines, including those involved in the
      regulation of hemopoetic cells such as granulocyte-macrophage colony stimulating
      factor (GM-CSF), interleukin-4 (IL4), interleukin-3 (IL3), interleukin-13 (IL13)
      and interleukin-5 (IL5). In this report we provide a summary of the various
      locations in the promoters of each of these cytokines where NFAT has been shown
      or suggested to bind, and at which sites NFAT has been shown to be involved in
      transcriptional regulation. We also provide experimental data to show that the
      binding of NFAT to the nucleotides GAA at positions -113 to -111 of the human IL5
      promoter is associated with functional activity in human T cells.

PMID- 10582350
TI  - Plasticity in the haemopoietic system.

PMID- 10582351
TI  - Activated protein C resistance is uncommon in sudden death due to pulmonary
      embolism.
AB  - Activated protein C resistance (APC-R) is the most common inherited defect of the
      coagulation system known to date, affecting 3-5% of Americans. It is an autosomal
      dominant disorder associated with an increased risk of venous thrombosis and is
      reportedly found in 21% of individuals with deep venous thrombosis. Medical
      examiners are in a unique position to make the diagnosis since a fatal pulmonary
      embolism may be the first manifestation of the disorder. This study examines the
      prevalence of APC-R in individuals who die suddenly of pulmonary embolism to help
      medical examiners decide if routine testing is indicated. We examined 66 cases of
      sudden death due to pulmonary embolism seen at the Bexar County Forensic Science
      Center in San Antonio, Texas, from 1993-1997. The median age was 46 years with a
      range of 14 to 93 years. Fifty-three percent were Caucasian, 24% were African
      American, and 23% were Hispanic. Twenty-seven percent had no known risk factors
      for pulmonary embolism. Whole blood was tested for the factor V codon 506Q
      mutation responsible for APC-R using polymerase chain reaction. The prevalence of
      APC-R was 4.5%, which is similar to the prevalence of APC-R in the general
      American population. These data imply that individuals with APC-R are not in
      increased risk for sudden death due to pulmonary embolism, or, conversely, that
      most fatal pulmonary emboli seen in the medical examiner setting are not induced
      by APC-R. Routine postmortem testing for the factor V 506Q mutation does not
      appear indicated at this time, given the low prevalence and high cost of testing.

PMID- 10582352
TI  - Hypernatremia and subdural hematoma in the pediatric age group: is there a causal
      relationship?
AB  - Several researchers in the 1950's proposed that hypernatremia causes water to
      leave brain cells, shrinking the brain, thus tearing the bridging veins and
      resulting in subdural hematomas. Although the old literature suggests mechanisms
      linking the two in a cause and effect relationship, there is controversy as to
      whether hypernatremia leads to subdural bleeding or whether the reverse is true.
      This issue is important for forensic pathologists who must distinguish natural
      disease from trauma. An etiologic link between hypernatremia and subdural
      hematomas was suggested recently, and was proposed originally before Kempe's 1962
      paper "The Battered Child Syndrome" which widely disseminated the concepts of
      child physical abuse, and of subdural bleeding resulting from non-accidental
      injury. Our study is a multifaceted investigation of infants which includes: a
      literature review, retrospective chart reviews of both living and deceased
      hypernatremic infants, a retrospective review of infants hospitalized with
      subdural hematoma, and a prospective collection of head injured, hypernatremic
      children. We conclude that hypernatremia, if present in association with subdural
      hemorrhage, is most likely secondary to intracranial pathology, and that
      hypernatremia often develops in critically ill infants suffering from a variety
      of medical conditions.

PMID- 10582353
TI  - Drowning without aspiration: is this an appropriate diagnosis?
AB  - It has been reported that 10-15% of drowning victims do not aspirate water. We
      have revisited the original studies quoted to reach this conclusion and find it
      is without foundation. Sudden cardiac standstill is known to occur on land and,
      therefore, may also occur when the victim is in water. In the absence of the
      common finding of significant pulmonary edema in the victim's respiratory system,
      to conclude his or her death was caused by "drowning without aspiration" is
      unwise. All causes of sudden death that might occur in which respiration may not
      take place should receive serious consideration when examining bodies with such
      findings that are found in water.

PMID- 10582354
TI  - Estimating time of death of deer in Missouri; a comparison of three indicators.
AB  - Estimation of time of death (TOD) of white-tailed deer is important to wildlife
      law enforcement officers. The purpose of this study was to develop and test a
      model for estimating TOD of white-tailed deer in Missouri. We compare the utility
      of carcass temperature, pupil diameter, and rigor mortis as TOD indicators. The
      effects of body size, ambient temperature, and various carcass handling methods
      on the estimate were also examined. Data were collected from 1484 deer during the
      1995-96 and 1996-97 hunting seasons. Stepwise regression indicated that all three
      indicators were significant and that body size and ambient temperature could
      influence the model. Predictive equations were developed for various combinations
      of the indicators based on practicality and statistical probabilities. TOD was
      estimated for 28 animals where the exact TOD was known. There was no significant
      difference between the estimated and known TOD (p = 0.759) and the average of the
      absolute differences in 1 h and 28 min.

PMID- 10582355
TI  - Comparative studies on tissue distributions of organophosphorus, carbamate and
      organochlorine pesticides in decedents intoxicated with these chemicals.
AB  - This paper describes the tissue distributions of dichlorvos, an organophosphate,
      chlorpyrifos-methyl, an organophosphorothioate, methomyl, a carbamate, and
      endrin, an organochlorine, in three individuals (Cases 1-3) who died after
      ingesting insecticidal preparations containing these chemicals. In Case 1
      involving dichlorvos and chlorpyrifos-methyl, no dichlorvos was detected in most
      of the blood and tissue samples. Tiny amounts of dichlorvos (0.067 mg/L and 0.027
      mg/L) were detected in the vitreous humor and cerebrospinal fluid, respectively.
      The chlorpyrifos-methyl concentrations in the blood samples were very site
      dependent with a range of 0.615-2.24 mg/L. The tissue concentrations of
      chlorpyrifos-methyl were within the range 0.379-8.60 mg/kg. The total amounts of
      dichlorvos and chlorpyrifos-methyl in the stomach were 879 and 612 mg,
      respectively. The serum cholinesterase activity was 3 IU/L/37 degrees C. In Case
      2 involving methomyl, the methomyl concentrations in the blood samples were very
      site-dependent with a range of 0.56-4.75 mg/L. The tissue concentrations of
      methomyl were 2.61 mg/kg or less, no methomyl being detected in the spleen, liver
      and kidney. The methomyl concentrations in the cerebrospinal fluid and vitreous
      humor were 5.37 and 4.75 mg/L, respectively. The stomach contained 85 mg
      methomyl. The serum cholinesterase activity was 73 IU/L/37 degrees C. In Case 3
      involving endrin, the victim underwent medical treatment for 7 h after ingesting
      an endrin preparation. The differences in the endrin concentrations among the
      blood samples were small, with a range of 0.353-0.615 mg/L. The tissue
      concentrations of endrin were within the range 0.467-13.3 mg/kg. The endrin in
      the stomach (66 mg) was adsorbed almost completely on the activated charcoal that
      was administered for medical treatment.

PMID- 10582356
TI  - An evaluation of the significance of transfers of debris: criteria for
      association and exclusion.
AB  - Several criteria are proposed for making decisions about comparing sets of debris
      involving the transfer of non-component particles and fibers--those produced from
      something other than the item itself--using a model based upon rudimentary set
      theory. Decisions about the significance of an association or an exclusion based
      upon trace evidence require an evaluation of debris in its context; reference
      points for such evaluation are presented. Samples of debris from the sites
      relevant to the event under investigation must be available, as well as debris
      standards from the usual environments of the people involved, and must be
      adequate to permit a determination of normal versus foreign debris. Criteria are
      proposed for establishing contact based upon corresponding sets of particles and
      fibers, for excluding contact in the absence of corresponding particles or
      fibers, and for refraining from making either an association or an exclusion.
      Conditions for reaching qualified conclusions or other types of associations when
      these criteria are only partially met are also discussed; conclusions may
      sometimes be reached if potential sources for debris particles and fibers can be
      found. Decisions about the strength of an association or an exclusion based upon
      comparisons of non-component debris particles and fibers can be made by reference
      to the criteria for reaching a conclusion. The criteria can be tested via Bayes'
      Theorem. The analysis itself is based primarily upon light microscopy, although
      other methods may be used as well. Case examples are presented.

PMID- 10582357
TI  - Long PCR for VNTR analysis.
AB  - The Polymerase Chain Reaction (PCR) has revolutionized the analysis of DNA from a
      variety of sources. With its sensitivity and ability to amplify degraded DNAs and
      small quantities of samples, coupled with fast turn-around-time, PCR is often the
      analytical method of choice for DNA profiling in forensic laboratories. RFLP
      methods, while requiring larger amounts of high molecular weight DNA and needing
      approximately 6-8 weeks of analytical time, still provide a higher power of
      discrimination per locus than that achieved using the loci currently available
      for PCR. The combination of both RFLP and PCR would be advantageous for some
      applications. A new technique, Long PCR, allows for the effective amplification
      of long DNA targets from approximately 0.5 kb to > 20 kb of genomic DNA.
      Currently, several Long PCR systems are commercially available. Using a
      Taq/Pyrococcus DNA polymerase enzyme system and DNA isolated from bloodstains, we
      have successfully amplified 1-20 ng of Chelex-extracted DNA, an amount commonly
      used in Amp-FLP technology. The robustness of Long PCR in comparison to RFLP was
      also examined through the use of partially degraded blood samples. Long PCR was
      then used to amplify both D2S44 and D5S110 RFLP loci. Although all D2 and D5
      alleles were detected, the larger alleles were amplified at significantly lower
      levels than the smaller alleles.

PMID- 10582358
TI  - Comparative identity and homogeneity testing of the mtDNA HV1 region using
      denaturing gradient gel electrophoresis.
AB  - A denaturing gradient gel electrophoresis (DGGE) assay has been developed for
      comparative identity and homogeneity testing of the mtDNA HV1 region. A total of
      49 pairs of sequences, each pair differing by a single unique polymorphism, were
      tested to verify the reliability of the assay. Discrimination between all
      pairings was achieved as judged by the resolution of the mismatch-containing
      heteroduplexes from the fully base-paired homoduplexes. In all but two pairings,
      resolution of the fully base-paired homoduplexes was also obtained. Sequence
      pairs differing by multiple polymorphisms were also tested and resulted in a
      greater separation between the homo- and heteroduplexes. Additional information
      derived from the technique includes the identification of co-amplifying
      contaminating or heteroplasmic samples in the independent samples lanes. Thirteen
      heteroplasmic samples, six at positions distinct from those analyzed in the
      pairwise comparison study, were analyzed and the heteroplasmic positions
      identified unambiguously by sequencing the excised bands. The technique
      constitutes a conceptually simple, accurate, and inexpensive test for determining
      whether two sequences match within the mtDNA HV1 region, while providing a more
      definitive control for the identification of co-amplifying contaminating or
      heteroplasmic sequences than is presently available.

PMID- 10582359
TI  - A reevaluation of the sex prediction accuracy of the minimum supero-inferior
      femoral neck diameter for modern individuals.
AB  - The results of an independent test of the minimum supero-inferior femoral neck
      diameter as a sex predictor are presented. Seidemann et al. (1) generated
      discriminant functions for Caucasians, African-Americans, and a combined race
      sample from the Hamann-Todd skeletal collection. Jackknifed classification
      matrices and the use of independent, random validation samples indicated a sex
      prediction accuracy in the 90% range. This, combined with a high rate of
      preservation, makes the femoral neck a significant measure for forensic
      applications. However, the method has not been evaluated on a truly modern
      sample. Data were collected for 94 males and 49 females from the Documented
      Collection at the University of New Mexico. The sample consists of 94 Caucasians,
      33 African Americans, three modern Native Americans, two Hispanics, and 11
      individuals of unknown ancestry. All individuals were born after the turn of the
      century. We evaluate the accuracy of the discriminant functions generated from
      the Hamann-Todd control sample. For Caucasians, 83% were correctly classified,
      for African Americans 97% were correctly classified and for the combined race
      function 85% were correctly classified. This decrease in accuracy is the result
      of the increase in African American male and all female sample means. This
      effectively decreases the separation between males and females for the femoral
      neck diameter. We generate new discriminant functions from the modern data and
      jackknife the classification matrices. The Caucasian function was 84% accurate,
      the African-American function was 82% accurate and the combined sample function
      was 85% accurate. The femoral neck may provide a useful alternative to
      multivariate techniques for individuals who are poorly preserved.

PMID- 10582360
TI  - Validation of the use of a commercially available kit for the identification of
      prostate specific antigen (PSA) in semen stains.
AB  - PSA is currently being used to detect and monitor quantitatively the development
      of prostate cancer by serum levels of PSA and has also been found to be present
      in high concentrations in semen. Elegantly simple, sensitive, and reproducible
      methods have been developed for analysis of the presence of PSA, including the
      Tandem-E PSA Immunoenzymetric Assay. The most common procedures for the forensic
      identification of semen have focused on the microscopic detection of sperm, acid
      phosphatase activity, and immunoelectrophoretic methods for the detection of PSA.
      Although these methods have been used for many years, there are problems
      associated with each method. The Tandem-E PSA Immunoenzymetric Assay detected PSA
      in 100% of the forensic casework fabric samples, 80% of the forensic casework
      vaginal swabs and 100% of the vasectomized individuals tested. The cut-off value
      was determined to be 1.77 ng/mL. These results indicate that this method can be
      used to identify the presence of semen in forensically significant specimens.

PMID- 10582361
TI  - Detection of epithelial cells in dried blood stains by reverse transcriptase
      polymerase chain reaction.
AB  - The identification of menstrual blood stains can be improved by detection of
      messenger ribonucleic acid (mRNA) specific for epithelial (endometrial) cells.
      RNA molecules, however, are believed to be unstable and require careful sample
      processing. In this study, we have investigated the extraction of RNA suitable
      for reverse transcriptase-polymerase chain reaction (RT-PCR) from dried blood
      stains stored for up to six months. With a modified RNA isolation protocol, it
      was possible to obtain RNA from dried blood stains with at least 5 x 10(2)
      leukocytes. In an additional experiment, we evaluated the RNA isolation from
      mixed stains composed of leukocytes and T47D cells, a breast cancer-derived cell
      line with epithelial origin. Detection of 10(2) T47D cells in a total number of
      10(5) leukocytes was possible by amplification of cytokeratin 19 mRNA and
      progesterone receptor-mRNA specific for hormonally regulated epithelial cells. In
      both experiments amplification results were not dependent on storage time with
      similar data from one day to six months. Furthermore, it was possible to identify
      dried menstrual blood samples by showing the presence of mRNA specific for
      epithelial cells. These results demonstrate for the first time, that RNA suitable
      for RT-PCR, can be isolated from forensic specimens stored up to at least six
      months, and that a small number of epithelial (endometrial) cells can be
      identified in dried blood specimens. Using this method, it will be possible to
      identify the origin of small and partially degraded blood samples which can be
      especially useful in forensic evaluation of cases with sexual offense.

PMID- 10582362
TI  - Application of solid-phase microextraction to the profiling of an illicit drug:
      manufacturing impurities in illicit 4-methoxyamphetamine.
AB  - This article describes the application of solid-phase microextraction (SPME) to
      the recovery of manufacturing by-products and impurities from an illicit drug
      seizure. The preparation chosen for examination using this technique contained 4
      methoxyamphetamine, an hallucinogenic amphetamine that has been encountered
      frequently in South Australia. Compounds found in the PMA preparation included 4
      methoxyphenol, 4-methoxybenzaldehyde, 4-methoxyphenyl-2-propanone, 4
      methoxyphenyl-2-propanol, 4-methoxyphenyl-propene, and (tentatively) 4-methyl-5
      (4'-methoxyphenyl) pyrimidine. The presence of these compounds suggests that the
      active drug was prepared from 4-methoxybenzaldehyde via 4-methoxyphenyl-2
      propanone using a Leuckardt reductive amination. In this instance, SPME was found
      to be a simple, rapid, and non-destructive recovery technique that gave results
      complementary to those provided by conventional liquid-liquid extraction. There
      is an indication that SPME might find application in profiling of illicit drugs.

PMID- 10582363
TI  - TWGDAM validation of a nine-locus and a four-locus fluorescent STR multiplex
      system.
AB  - The Gene Print PowerPlex 1.1/Amelogenin and FFFL Fluorescent STR Systems have
      been validated following the recommendations presented by the Technical Working
      Group on DNA Analysis Methods (TWGDAM). The PowerPlex 1.1/Amelogenin System
      supports simultaneous amplification of eight short tandem repeat loci and the
      Amelogenin gender identification marker. The loci D16S539, D7S820, D13S317, and
      D5S818 are labeled with fluorescein (FL) while the loci CSF1PO, TP0X, TH01, vWA
      and Amelogenin are labeled with carboxy-tetramethylrhodamine (TMR). The FFFL
      Multiplex System is composed of the loci F13A01, FESFPS, F13B, and LPL, each
      labeled with fluorescein. We have observed no overlap of alleles across loci
      labeled with an individual fluorescent dye. Samples of each system were amplified
      and labeled in a single reaction, separated by electrophoresis through a
      denaturing polyacrylamide gel, and amplified alleles detected using a Hitachi
      FMBIO Fluorescent Scanner. Alterations from the standard amplification protocols
      in cycle number and annealing temperature generally produced excellent results.
      In experiments testing sensitivity as little as 0.2 ng of DNA template could be
      detected. As expected, different body fluids from the same individuals generated
      identical DNA profile results. Template DNA derived from blood-strains deposited
      on a variety of matrix supports displayed robust amplification except for
      material derived from deposits on wood and Japanese orchid leaves. Mixtures of
      DNA templates could be interpreted with the minor component present in as little
      as ten percent of the total sample. Monoplex and multiplex amplifications
      produced identical amplified allele patterns, indicating that STR multiplex
      systems save template and increase efficiency in the amplification procedure
      without loss of quality. Analyses of genotype frequencies in African-American,
      Caucasian-American and Hispanic-American populations using all twelve loci were
      used to determine matching probabilities smaller than 1 in 1.14 x 10(8) and 1 in
      2658 for the PowerPlex 1.1 and the FFFL Multiplex Systems, respectively. The
      matching probability achieved with the two systems combined is smaller than 1 in
      3.03 x 10(11). The independence of alleles within loci was generally demonstrated
      by applying the exact test to demonstrate Hardy-Weinberg Equilibrium. All of the
      studies performed indicate that the PowerPlex 1.1/Amelogenin and FFFL Multiplex
      Systems are powerful, robust, and reliable investigative tools that can be used
      in the analysis of forensic samples.

PMID- 10582364
TI  - Data on the PCR Turkish population based loci: LDLR, GYPA, HBGG, D7S8, and Gc.
AB  - Allele and genotype frequencies for the five PCR-based loci were analyzed in 157
      unrelated Turkish individuals. The five PCR-based loci included LDLR, GYPA, HBGG,
      D7S8, and Gc. The results of the chi-square and exact tests showed that the
      genotype distribution at the LDLR, GYPA, D7S8, and Gc loci did not significantly
      differ from the Hardy-Weinberg Expectation (HWE). However, the genotype
      distribution at the HBGG locus did not conform to HWE. Moreover, the genotype
      frequencies calculated in this study were compared with the published genotype
      frequencies of US African American and US Caucasian populations. The Turkish
      population was significantly different at the HBGG locus from the US Caucasian
      population. However, there were highly significant differences at the LDLR, HBGG,
      and Gc loci between the Turkish and African American populations.

PMID- 10582365
TI  - Population study of HUMTH01, HUMVWA31/A, HUMF13A1, and HUMFES/FPS systems in
      Azores.
AB  - The tetrameric short tandem repeat polymorphisms HUMTH01, HUMVWA31/A, HUMF13A1,
      and HUMFES/FPS were studied in blood stains obtained from a population of
      unrelated individuals from the Azores Archipelago (Portugal). Gene frequencies
      were determined and no deviation from the Hardy-Weinberg equilibrium was found.
      However, the allelic independence test between loci showed linkage disequilibrium
      between HUMVWA31/A and HUMFES/FPS. A combined discrimination power and chance of
      exclusion of, respectively, 0.9999 and 0.9534, reveal the high forensic interest
      of the four systems. No differences with other caucasoid populations were found,
      but comparison with some asiatic, eskimo, and amerindian populations showed
      significant statistical differences.

PMID- 10582366
TI  - Allele frequencies of six STR loci in Argentine populations.
AB  - Allele frequencies of six short tandem repeat (STR) loci were determined in a
      Caucasian urban sample of La Plata city and three Amerindian sample populations
      of Argentina. Allele frequencies showed differences between urbans and
      Amerindians, and among Amerindians as well. The degree of genetic differentiation
      of subpopulations was mainly due to the Amerindian contribution. Mapuche, Mocovi,
      and pooled Amerindian populations showed little evidence of HW disequilibrium,
      and association of alleles. In the urban sample, there is no evidence of
      population substructuring. Forensic probabilities of exclusion and matching
      showed high differences between the population groups. Finally, La Plata sample
      did not show differences with Caucasians from other geographic regions.

PMID- 10582367
TI  - A systematic analysis of secondary DNA transfer.
AB  - The Nature letter by R. van Oorschot and M. Jones (1) addressed two topics: the
      primary transfer of DNA from person to person or to various objects, and the
      secondary transfer of DNA through an intermediary. Forensic scientists have
      described the primary transfer of DNA and other biological evidence for many
      years. However, the authors also reported detecting secondary transfer of DNA
      from an object to a person's hands, which could adversely affect DNA typing in
      the forensic context. The prospect of secondary transfer raises questions of
      interest to both the legal and forensic communities. Therefore, we sought to
      evaluate parameters potentially leading to secondary DNA transfer. Our data do
      not support the conclusion that secondary transfer will compromise DNA typing
      results under typical forensic conditions.

PMID- 10582368
TI  - Frequencies of D8S384 alleles and genotypes in European, African-American,
      Chinese, and Japanese populations.
AB  - D8S384 is a tetranucleotide tandem repeat locus. In order to evaluate the
      forensic validation of D8S384, the genotype distributions and allele frequencies
      in ten populations from three main ethnic groups were investigated, including
      Germans, Slovakians, African Americans, Japanese, and Chinese (Jilin, Guangzhou,
      Nanning, Hailaer, Dali, and Chengdu). A total of 1011 unrelated individuals, 41
      pedigrees, 30 disputed paternity trios and three personal identification cases
      were analyzed for D8S384 by Amp-FLP technique. Many kinds of tissues, body
      fluids, secreta and stains have been tested. The alleles were determined by
      comparison with a human allele ladder. The results showed that D8S384 typing was
      both precise and reliable. There were eight alleles in these populations. The
      genotype distributions conformed to Hardy-Weinberg equilibrium predictions. No
      mutation events were observed. With a maximum likelihood method, the mutation
      rate was indirectly estimated as 2.14 x 10(-5). The heterozygosity was 0.704 +/-
      0.014 at D8S384 locus. All these results suggest that D8S384 locus is a useful
      marker for forensic identification and paternity analysis.

PMID- 10582369
TI  - Population data on the thirteen CODIS core short tandem repeat loci in African
      Americans, U.S. Caucasians, Hispanics, Bahamians, Jamaicans, and Trinidadians.
AB  - Allele distributions for 13 tetrameric short tandem repeat (STR) loci, CSF1PO,
      FGA, TH01, TPOX, VWA, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51,
      and D21S11, were determined in African American, United States Caucasian,
      Hispanic, Bahamian, Jamaican, and Trinidadian sample populations. There was
      little evidence for departures from Hardy-Weinberg expectations (HWE) in any of
      the populations. Based on the exact test, the loci that departed significantly
      from HWE are: D21S11 (p = 0.010, Bahamians); CSF1PO (p = 0.014, Trinidadians);
      TPOX (p = 0.011, Jamaicans and p = 0.035, U.S. Caucasians); and D16S539 (p =
      0.043, Bahamians). After employing the Bonferroni correction for the number of
      loci analyzed (i.e., 13 loci per database), these observations are not likely to
      be significant. There is little evidence for association of alleles between the
      loci in these databases. The allelic frequency data are similar to other
      comparable data within the same major population group.

PMID- 10582370
TI  - Positive identification of cremains recovered from an automobile based on
      presence of an internal fixation device.
AB  - We report on the use of a surgically implanted device, an EBI osteostimulator, as
      a means of establishing the identification of a homicide victim. The use of such
      an appliance for securing positive identification has not been previously
      reported. Additionally we stress the importance of intensive and accurate
      excavation at scenes involving intense burning where the potential for non
      skeletal contaminants is high.

PMID- 10582371
TI  - Fulminant liver failure in a young child following repeated acetaminophen
      overdosing.
AB  - Acetaminophen (paracetamol), a widely used analgetic drug, is well tolerated at
      therapeutic doses, but may cause severe hepatotoxicity when ingested in large
      overdose. Self-poisoning is still very popular in adults and accidental ingestion
      of one single overdose occurs occasionally in children. In contrast, lethal
      intoxication in children after repeated administration of therapeutic doses is a
      very rare event. This case report describes an iatrogenic acetaminophen
      overdosing in a 5-year-old child receiving 8.5 g acetaminophen in 48 h. Fulminant
      liver failure developed within 60 h. Autopsy findings included panlobular liver
      cell necrosis. Acetaminophen serum levels were rather low compared to cases with
      ingestion of one single overdose. Postmortem diagnosis of chronic acetaminophen
      intoxication as cause of death should include the clinical history as well as, if
      available, the calculated drug serum half-life.

PMID- 10582372
TI  - Traumatic rupture of an abdominal aortic aneurysm associated with the use of a
      seatbelt.
AB  - Injury to the abdominal aorta after blunt trauma continues to be a relatively
      infrequent occurrence. In this report, we describe a case of traumatic rupture of
      an abdominal aortic aneurysm associated with inappropriate seatbelt use.

PMID- 10582373
TI  - A case of suicidal hanging staged as homicide.
AB  - Suicides staged as homicides are rarely encountered by crime scene investigators.
      The case of one such staged homicide is presented in which the victim used
      restraints during a hanging. No other cases of suicidal hangings staged as
      homicides could be found in the forensic literature. Similar cases should be
      reported so additional data can be gained from these deaths to help reveal
      indicators of suicide rather than homicide.

PMID- 10582374
TI  - Detection of azide in forensic samples by capillary electrophoresis.
AB  - Azide salts are highly toxic compounds that have been difficult to detect in
      forensic samples. Here, anion analysis by capillary electrophoresis with indirect
      spectrophotometric detection was applied to detect azide in forensic specimens
      from two suicide victims. Gastric specimens from the victims were shown to have
      high azide concentrations; azide represented one of the major anionic components
      and no corresponding component occurred in normal gastric juice. Samples of blood
      and bile had low concentrations of azide near the limits of detection. The method
      described for azide analysis used simple steps for sample preparation and
      analysis time was less than 10 min per sample. It offers a simple and reliable
      method for detecting azide in biological fluids.

PMID- 10582375
TI  - Distribution of D1S80 alleles in the Bahrainian population.
AB  - This study demonstrates that the locus D1S80 is highly polymorphic in the
      Bahrainian population. There were 24 different D1S80 alleles and 51 distinct
      genotypes observed in 198 Bahrainians. There was one allele observed that was
      smaller than the 14 repeat allele. This data set meets the Hardy-Weinberg
      expectations (HWE) and could be a useful marker for parentage testing and
      forensic applications.

PMID- 10582376
TI  - Construction of cellulase hyperproducing strains derived from polyploids of
      Trichoderma reesei.
AB  - The mycelial mat of Trichoderma reesei strain QM 6a was treated with 0.1% (w/v)
      colchicine solution for 14 days and designated M14. The cellulase productivity of
      strain M14 was not much higher than that of the original strain. When conidia of
      M14 were treated with ethylmethane sulphonate (EMS) solution, the cellulase
      hyperproducers, M14-1 and M14-2, were isolated using a selection medium
      containing Avicel. The DNA content of M14-1 and M14-2 was higher than that of the
      original strain. Cellulase productivity per mycelium of these strains increased
      and was higher than that of the original strain. The cellulase productivity did
      not change through ten generations when these strains were cultivated
      successively on a medium containing Avicel. It was concluded that cellulase
      hyperproducers, whose cellulase productivity per mycelium increased, could be
      obtained when the conidia of strain M14 were treated with EMS.

PMID- 10582377
TI  - Bacterial degradation of hydrocarbons as evidenced by respirometric analysis.
AB  - The microbial biodegradability of mineral oil and other hydrocarbons, namely
      hexane, decane and tetradecane was determined using the Warburg constant volume
      respirometer. Results of oxygen uptake indicated that hexane and tetradecane were
      more degradable than mineral oil and decane. Rhodococcus erythropolis and Erwinia
      cancerogena showed the highest (0.866) and lowest (0.115) oxygen quotient (Qo2)
      values, respectively, when exposed to mineral oil. Staphylococcus warneri and
      Enterobacter cloacae showed the highest (2.895) and (2.816) Qo2 values,
      respectively, when exposed to hexane; whereas E. cloacae and E. cancerogena
      showed the lowest Qo2 values (1.289 and 1.824), respectively. Both R.
      erythropolis and E. cloacae had the highest Qo2 values (2.859 and 2.289),
      respectively, when exposed to tetradecane. More oxygen was consumed by R.
      erythropolis than the other bacterial cultures when exposed to all hydrocarbons.
      In contrast, less oxygen was taken by E. cancerogena than the other bacterial
      cultures when exposed to all hydrocarbons, except for hexane.

PMID- 10582378
TI  - Indigenous yeasts associated with two Vitis vinifera grape varieties cultured in
      southern Spain.
AB  - The yeast microbiota present on the surface of grapes of two Vitis vinifera
      varieties, Pedro Ximenez and Tempranillo de Rioja, grown in the Montilla-Moriles
      region of southern Spain was identified. The changes between veraison and the
      physiological ripeness time during 3 years were monitored. Overall, the yeast
      microbiota isolated was of oxidative metabolism. Sporobolomyces roseus and
      Cryptococcus albidus species occurred at all physiological stages, in the two
      Vitis vinifera varieties, and the three seasons studied. On the other hand,
      Kloeckera apiculata was never detected and Saccharomyces cerevisiae was scarcely
      isolated, it was only present, testimonial, in Tempranillo de Rioja grapes during
      the 1992 vintage. The widest variety of yeast species was observed in the 1992
      season, and in contrast, the lowest number of species in both varieties of Vitis
      was detected in the 1994 season.

PMID- 10582379
TI  - Isolation, identification and analysis of antibacterial activity of soil
      streptomycetes isolates from north Jordan.
AB  - A total of 90 different Streptomyces isolates were recovered from 36 soil samples
      and assessed for their antibacterial activity. Nine isolates were identified by
      the absence of an aerial mycelium. The rest were grouped into six colour series,
      namely grey, white, yellow, green, red and polymorphic colours (pink, orange or
      violet) with total numbers of 29, 18, 14, 8, 3 and 9, respectively. The isolates
      (68%) showed a reverse side culture pigmentation, 30% produced melanin and 25%
      produced other soluble pigments. Isolates (48%) were characterized by flexuous
      spore chains, 21% with spiral and 10% for each of the rectus and retinaculum
      apertum arrangement. The antibiotic activity against a wide range of bacteria was
      exhibited by 54% of the isolates which were effective against Bacillus subtilis
      (57%), Staphylococcus aureus (47%), Escherichia coli (24%), Klebsiella spp (16%),
      and Shigella spp (12%). The lowest activity (8%) was exhibited against
      Pseudomonas spp and Salmonella spp. The antibacterial activity of the isolates
      was divided into four groups according to the diameter of the inhibition zone
      produced. Groups 3 and 4 with larger inhibition zones indicated their potential
      as a possible source of novel antibiotics.

PMID- 10582380
TI  - Prevalence of enteroaggregative and other HEp-2 cell adherent Escherichia coli in
      asymptomatic rural south Indians by longitudinal sampling.
AB  - Enteroaggregative and other HEp-2 cell adherent Escherichia coli can produce
      acute and persistent diarrhoea in children and adults, but their prevalence in
      asymptomatic individuals in the community is not known. In this study, faecal
      specimens were obtained at 3-4 monthly intervals from 349 subjects constituting a
      20% age-stratified sample of a rural community for a period of two years. HEp-2
      cell adherent E. coli were found in 210 subjects, and repeat isolations of
      enteroaggregative E. coli belonging to the same serogroup were found in 12.6% of
      children less than 12 years of age, indicating that this organism can
      asymptomatically colonise the intestinal tract. These children may act as a
      reservoir of infection for the community.

PMID- 10582381
TI  - Mental health in the Oregon Health Plan: fragmentation or integration?
AB  - The Oregon Health Plan was implemented in 1994 with a 50% expansion of Medicaid
      enrollment to include some of the working poor. Over 75% of Oregon Medicaid
      clients are now enrolled in health maintenance organizations (HMOs). Outpatient
      chemical dependency services have been capitated since May 1995. Capitated mental
      health services have been provided for the 25% of eligibles who live in
      demonstration counties since January 1995. Expansion and capitation appear to
      have been achieved without major trauma. More challenging has been the attempted
      integration of public sector behavioral health services with private sector
      health plans. Stakeholders interviewed for this study were especially concerned
      about the long-term impact on Medicaid clients with chronic mental illness.
      Strong leadership and clear policies regarding the mixture of public, private
      nonprofit, and private for profit entities are necessary if the state is to
      achieve its aim of integration without fragmenting a system of care for people
      with severe mental illness.

PMID- 10582382
TI  - The rights of state hospital patients: from state hospitals to their
      alternatives.
AB  - During the 1980s and 1990s the locus of psychiatric treatment in many states
      shifted from state hospitals to the psychiatric units of general hospitals. The
      extent to which the rights guaranteed to psychiatric inpatients by state mental
      health agencies will survive this "privatization" process is unclear. The authors
      explore this issue by providing a "status report" of patient rights, identified
      through a national survey. They discuss the problems of preserving these rights
      as an ever greater proportion of care is provided in general hospitals under the
      mechanism of managed care.

PMID- 10582383
TI  - Predictors of psychiatric hospitalization: a multivariate analysis.
AB  - Inpatient treatment continues to be the most expensive form of mental health
      service. This study sought to improve the methodological weaknesses, e.g., poor
      statistical controls, in the literature by using multivariate statistics to
      predict hospitalization. Results revealed that aftercare, i.e., outpatient
      treatment, is an important factor in reducing the utilization of inpatient
      resources, even when controlling for demographic and psychiatric history
      variables. Further, background characteristics, while easily measured, are not
      important predictors of hospitalization.

PMID- 10582384
TI  - A provider assessment of the Massachusetts Medicaid Managed Behavioral Health
      Program: year four.
AB  - A stratified, random sample of 80 providers in the Massachusetts Medicaid Managed
      Mental Health/Substance Abuse Program were interviewed by phone to assess their
      views of the program in year four. Providers continued to believe that access and
      quality were the same or better than a year earlier, that client severity
      continued to increase while length of stay decreased, that readmissions and
      emergency room admissions were the same as a year earlier, and that aftercare was
      the same or better than a year earlier. Substantial problems were reported in the
      integration of services, in linkages with support services, and with
      administration of the program.

PMID- 10582385
TI  - Trends over a decade for a general hospital psychiatry unit.
AB  - This study examines the composition and delivery of services in a general
      hospital inpatient psychiatry unit during a 10-year period. Multiple regression
      techniques were used to assess the association of clinical, insurance, and
      demographic data with length of stay and likelihood of readmission for all
      admissions from 1985-1993. Two variables became progressively associated with
      readmission--Medicaid and psychotic diagnosis. The results indicate that: (1) the
      hospital is increasingly treating a poorer, sicker group of patients with shorter
      lengths of stay and more readmissions, and (2) the rise in readmissions,
      particularly within vulnerable populations, could represent an inadequate length
      of initial treatment. Future research should further investigate the
      generalizability of these results and implications for quality of inpatient care.

PMID- 10582386
TI  - Psychiatric hospitalization characteristics associated with insurance type.
AB  - This study examines the relationship among types of insurance and characteristics
      of inpatient psychiatric treatment. Data include 46,998 adult psychiatric or
      substance abuse cases from all 1991-1992 Washington State discharges from short
      stay general hospitals. Large and significant differences among payers exist in
      treatment characteristics, controlling for diagnosis and patient age. For
      example, length of stay is longest among commercial and Medicare payers.
      Emergency admissions are more common among public payers, and elective admissions
      are more common among private payers, including HMOs. Results and discussed in
      light of policy and administration issues that will arise as financing for mental
      health services comes under greater capitation.

PMID- 10582387
TI  - Definition of service areas for substance abuse treatment agencies.

PMID- 10582388
TI  - Housing for psychiatric survivors: values, policy and research.

PMID- 10582389
TI  - Offenders with mental illness: mental health and criminal justice best practices.

PMID- 10582390
TI  - NICE advises against prescribing zanamivir until further evidence emerges.

PMID- 10582391
TI  - [Prevalence of anti-HIV antibodies in patients at the Service of Human
      Reproduction Biology of the "20th November" National Medical Center].
AB  - At the service of Human Reproduction of the Centro Medico Nacional "20 de
      Noviembre" ISSSTE from January 94 to August 98, at the first visit, were
      performed routine screening for antibodies anti-HIV for both partners. Of 672
      samples 3 (0.44%) were positive for antibodies anti-HIV with ELISA and two
      confirmed by Western blot analysis.

PMID- 10582392
TI  - [Induction of labor in patients with premature rupture of membranes in term
      pregnancy using dinoprostone vs oxytocin. An aleatory study].
AB  - It was accomplished a random comparative study to evaluate the effects of
      dinoprostone in the Hospital de Gineco Obstetricia No. 60 of the Mexican
      Institute of the Social Security, from June of 1997 to December of the same year,
      in relationship to the inducement cervical repening and vaginal delivery in
      patients with score less than or equal Bishop to 4. They were studied a total of
      156 patients split into two groups: 78 patients who were administered by
      intracervical gel of Dinoprostone and to the remainders 78 were administered
      oxitocin with the same purpose, being this last the control group. We found that
      the duration time of induction with dinoprostone is 2 hours in average less than
      the inducement with oxitocin (p > 0.05). The were achieved 67 deliveries with
      dinoprostone and 65 deliveries with oxitocina, being not significantly. (p <
      0.05) The percentage of inducement defect was considered in relationship to the
      absence of cervical modifications in 12 hours of administration of dinoprostone
      or oxitocin, being only 3 patients in each group in these conditions. The
      observed complications were the same in both groups and the conditions of the
      newborn were better in the Dinoprostone group. The septic complications of
      mothers were smaller in Dinoprostone group than Oxitocin group and were
      significantly (p > 0.05). We can conclude that the dinoprostone intracervical
      application reduce the induction and expulsion time, with better conditions of
      the new born, and less percent of infectious complications, in relationship to
      the Oxitocin control group.

PMID- 10582393
TI  - [Changes in iron levels in non-anemic women 18-58 years of age].
AB  - The objective was to describe changes in serum ferritin (SF) in women residents
      in Mexico City. We evaluated prospectively, three groups of non-anemic, non
      pregnant women (< 20, 21-40 y 40-58 years old). Sociodemographic variables,
      hemoglobin (Hb) and erythrocyte index and SF values were registered. We included
      252 women in the study. There were no differences in Hb values (15.0, 14.6 and
      14.7 g/dL) or erythrocyte index between the three groups of women. We found
      significative differences (p < 0.001) in mean values of (32 and 34 micrograms/L),
      for group 1 and 2, with group 3 (SF 54 micrograms/L). In global sample, we
      observed low SF store, a normal or higher in 76 cases (30.2%), 163 (64.6%) and 13
      cases (5.2%), respectively. The women with SF lower than 20 micrograms/L were in
      proportion 0.54, 0.32 and 0.16. Elevated values in SF were found in a proportion
      0.04, 0.18 and 0.13, for groups 1, 2 and 3, with significative differences (p <
      0.001). We observed that non-anemic women in Mexico City, showed increase in SF
      concentrations beginning at 41 years of age, without any major variation in their
      erythocyte indexes. The prevalence in moderate-severe iron deficiency between 18
      to 40 years of years, decreasing progressively.

PMID- 10582394
TI  - [Effects of tibolone on lipid and glucose metabolism as well as insulin secretion
      in postmenopausal women].
AB  - Tibolone is a synthetic steroid with progestogenic, androgenic and estrogenic
      properties. In postmenopausal women it has been shown that improves climateric
      complaints and prevents osteoporosis, without impact on endometrial thickness and
      uterine fibroids volume. Tibolone administration decreases cholesterol and
      triglycerides. Although, the effects of hormonal replacement on insulin
      sensitivity and glucose metabolism has not been well established. The effect of
      tibolone 2.5 mg/day for 3 months was investigated in 10 healthy postmenopausal
      women. The results show that tibolone decreases tryglicerides and cholesterol
      levels along with an increase in fasting insulin levels. The oral glucose
      tolerance test was unaffected. This study suggests that tibolone reduces markers
      of cardiovascular disease.

PMID- 10582395
TI  - [Epidemiologic variables in postmenopausal women].
AB  - The objective was to know the characteristics of presentation, its clinical
      aspects and the modification in the diagnostic tools in a selected population of
      Mexican women with spontaneous menopause. The age at menarche, age at menopause,
      marital status, age at marriage, number of pregnancies and occupation of 1,099
      women with spontaneous menopause were studied. In 619 women which were not
      receiving nor had received hormone replacement therapy the clinical, laboratory
      such as glucose, lipids, hormones, bone remodeling biochemistry; and X ray
      studies such as densitometry and mammography were analyzed. The age average of
      menarche presentation was at 13 years, and that of spontaneous menopause at 48.1
      years 78% were married, with an age at marriage of 23 years, 66% had home duties.
      The screening tests showed that 30% of patients required cardiovascular
      evaluation, 40% showed alterations on lipids levels and at least 40% had some
      alteration on bone remodeling biochemistry or in densitometry. The mammography
      was normal in 81%. This study showed that most of the data in these group of
      women were similar to those of other populations, and many of them need intensive
      surveillance and adequate therapeutic prescriptions to diminish risk factors.

PMID- 10582396
TI  - [Doppler flowmetric fetal indices in low-risk pregnancies].
AB  - In order to measure the umbilical resistance and pulsatility Doppler indexes 60
      pregnant women with low risk pregnancies were studied in a descriptive,
      observational and prospective study carried out at the Hospital de Gineco
      Pediatria numero 48 del Instituto Mexicano del Seguro Social. Umbilical Doppler
      measurements were done of the fetal umbilical cord from the week 30 at the 40 of
      gestation. We carried out a total of 337 measurements and 178 (52.8%)
      corresponded to the resistance index and 159 (47.2%) to the pulsatility index.
      The average of the resistance index was 0.64 with a range average (average plus
      two standard deviations was 0.48-0.79) and the pulsatility index had an average
      value of 0.94 with an average range of 0.58-1.30. The percentil values of the
      resistance index were 0.52, 0.66 and 0.79 respectively in the percentil 5, 50 and
      95 whereas the percentil values of the pulsatility index were 0.64, 0.94 and 1.28
      respectively in the percentil 5, 50 and 95. The analysis of variance with the
      Bonferroni test for multiple comparisons showed that our found indexes can be
      applied from the week 31 to the 40 of gestation. Our findings are in according to
      reported by other authors and it should be kept in mind that the concept of
      normality of the Doppler velocimetry indexes is strictly statistical and that
      only its judicious use will offer the benefit to our pregnant patients to obtain
      products under good conditions of health.

PMID- 10582397
TI  - [Closure of the skin with cyanoacrylate in cesarean section].
AB  - The objective was to determine the usefulness of cyanocrilate when closing
      cesarean wounds, in comparison with silk and nylon usual sutures. 74 patients
      with cesarean without background of previous abdominal surgery or infection were
      observed. Patients were divided into two groups: the use of cyanocrilate to close
      skin on medium and Pfannenstiel incisions was practiced on 44 patients, and on
      the remaining 30 patients integrating the control group, silk or nylon suture was
      used. The population characteristics did not show differences. Evaluated
      parameters were as follows; both groups showed similar little to moderate pain.
      Pruritus predominated in the cyanocrilate group (CIAN) on about 18.1% vs 13.2% on
      the control group. Marks on the skin largely predominated on the control group
      with silk (75%), while there were no marks on the CIAN group. The reaction to a
      foreign body was greater in the CIAN group, 15.9% versus 6.6% in the control
      group. Superficial dehiscence on the CIAN group was 6%, while it was 10% on the
      control group. The CIAN group showed 2.2% of hematomas, and the group of control
      6.6%. Poorly coapted edges resulted in 4.5% on the CIAN group versus 20% on the
      control group. Skin closure average time on the CIAN was 62.8 sec and 283 on the
      control group. The use of cyanocrilate on the cesaran wounds closure showed:
      efficiency, safety and surgical time reduction, the scar aesthetics was improved
      and costs were reduced.

PMID- 10582398
TI  - [Posterior genital prolapse following the Burch method of colposuspension].
AB  - The aim of this paper was to know the prevalence of genital prolapse after the
      Burch procedure. Also to intend knowing if the associate surgery for vaginal
      relaxation used in our Urogynecologic Service is working well. Seventy four
      patients with more than six months after the Burch procedure were addressed from
      October 1995 to January 1996. Special attention was put to detect pelvis floor
      defects in specific vaginal sites (urethra, bladder, vaginal apex, cul de sac and
      distal posterior wall). The prevalence of urethrocele was 2.7%, cystocele 50.6%,
      almost of all were mild. None severe cystocele was detected. Cervical prolapse
      was present in 21.3%, vault prolapse in 9.3% and enterocele 41.9%. The posterior
      colporraphy seems to be useful to prevent the vault prolapse and the enterocele.
      On the contrary the Moschowitz procedure seems not to be useful in this aspect.
      In order to diminish the prevalence of genital prolapse posterior to Burch
      procedure it would be better to improve the preoperative vaginal examination in
      order to do segmentary prolapse diagnosis and also to stablish an individualized
      surgical treatment of them.

PMID- 10582399
TI  - [Risk of breast cancer of low differentiation in tumors with estrogen-negative
      receptors].
AB  - The risk for poorly differentiated invasive ductal carcinoma was evaluated in
      negative estrogen receptor tumors determined by immunohistochemical method. The
      results were correlated with the histological grade. The poorly differentiated
      tumors had a major risk (OR = 17.8) to be negative. A high risk of correlation
      was found between the estrogen receptor positivity and the well differentiated
      tumors (grade I), p = .0001. Our results are similar to other previous reports.
      The usefulness of this findings and its occasional role when it was not possible
      the determination of this receptor for lacking economical or technological
      resources is discussed.

PMID- 10582400
TI  - [Serological estimation of the occurrence of chlamydiosis in children with the
      upper respiratory tract inflammation and pneumonia in 1993-1996 in the area of
      Wroclaw].
AB  - The investigation were made of the seasonal occurrence of the upper respiratory
      tract inflammation and pneumonia probably caused by ch. trachomotis. The
      immunofluorescence tests of chlamydia trachomatis were done in the blood serum of
      1831 children aged from 2 weeks to 6 years hospitalised in Wroclaw. The research
      was conducted from 1993 to 1996. The obtained results allowed to assume that the
      occurrence of the infections confirmed by serologically positive reactions is not
      connected with the season predisposing the organism of child to the diminished
      immunity.

PMID- 10582401
TI  - [Carcinoma of the fallopian tube. Clinical analysis of 40 cases].
AB  - The results of clinical analysis of 40 cases of primary carcinoma of the
      fallopian tube are presented. All patients were treated with surgery and post
      operative external beam irradiation. Overall 5 years survival was 37% and symptom
      free survival 21%. The influence of following prognostic factors on the results
      of treatment had been evaluated: clinical stage, histologic grading and depth of
      infiltration of fallopian tube wall. Only the depth of infiltration proved to be
      statistically significant negative prognostic factor. The main cause of treatment
      failure was the intraperitonal dissemination of the disease. The results of
      treatment of recurrences was only palliative. No long term survivors were noted.

PMID- 10582402
TI  - [Extracellular matrix components in ovarian tumors].
AB  - This report describes the collagen, glycosaminoglycans and elastin--composition
      of ovarian tumours. Rearrangement of extracellular matrix in ovarian tumour has
      been found. There was an increase of total collagen content in comparison to
      control. Type I collagen was found to be predominant in both tissues. Both
      tissues, normal and neoplastic one, contain all known glycosaminoglycans. Among
      them dermatan sulphate was found to be the most abundant. In ovarian tumour an
      increase of this glycosaminoglycan content was observed.

PMID- 10582403
TI  - [The coexistence of endometrial cancer with second primary malignant neoplasms].
AB  - OBJECTIVE: An epidemiologic study of multiple primary malignant neoplasms with
      endometrial cancer patients is presented. Coexistence of endometrial carcinoma
      with second primary malignant neoplasms was evaluated and controlled for age,
      residence, civil status, education, parity, menarche age, last menstruation age,
      length of reproductive period, blood group, hypertension, diabetes, body mass
      index, sterility, histological subtype, grading, staging. DESIGN: From 1984-1998
      136 endometrial carcinomas have been evaluated in the Department of Gynecology &
      Obstetrics in Hospital of Slupsk retrospectively. All double and triple neoplasms
      have been histologically recorded, doubtful cases have been excluded. MATERIAL &
      METHODS: Of 136 endometrial carcinomas 16 (11.6%) were multiple malignant
      neoplasms. Of these neoplasms 9 (6.6%) occur together with breast cancer, 3
      (2.2%) with ovarian carcinoma, 1 (0.7%) with stomach carcinoma, 1 (0.7%) with
      rectum carcinoma, 1 (0.7%) with carcinoma in focus of endometriosis and 1 (0.7%)
      coexists with double neoplasms (bowel and endometriosis carcinoma) During the 14
      year period of study, 15 patients (11.0%) out of 136 patients diagnosed as having
      endometrial cancer had double and 1 (0.6%) had triple primary malignant
      neoplasms. There was not significant difference in age rate (p = 0.72), residence
      rate (p = 0.93), civil status rate (p = 0.76), education rate (p = 0.70), parity
      rate (p = 0.76), menarche age rate (p = 0.46), blood group rate (p = 0.45),
      hypertension rate (p = 0.94), diabetes rate (p = 1.0), not overweight status rate
      (BMI < 29) (p = 0.55), sterility rate (p = 0.45), histological subtype rate (p =
      0.39), grading rate (p = 0.67), staging rate (p = 0.26) between both patients
      group (with and without second primary malignant neoplasma). We observed
      statistically significant difference in body mass index (BMI > 32) rate (p =
      0.03), last menstruation age rate (p = 0.04), length of reproductive period rate
      (p = 0.04) between both patients group (with and without second primary malignant
      neoplasma). CONCLUSION: Patients with endometrial cancer should be carefully and
      regularly followed up by monitoring et every anatomic site, especially the
      breast, stomach, and colon, in order that the development of a second primary
      carcinoma can be detected as early as possible, and not be overlooked in
      examinations. Additional risk factors for endometrial carcinoma with multiple
      malignant neoplasma include: menopause occurring after age fifty-one; obese women
      with body mass index (BMI) higher than 32; reproductive period longer than 37
      years.

PMID- 10582404
TI  - [Primary malignant schwannoma in peritoneum of pelvis minoris: a case report].
AB  - There are reports of rare cases of malignant schwannoma of the small bowel, ovary
      or urinary bladder. We report a case of malignant schwannoma found in peritoneum
      without any other localisation in 66-year-old woman. The first diagnosis was
      tumor of right ovary. Laparotomy was performed and a big, solid tumor of urinary
      bladder involving the small bowel was found. There were some small tumors in
      peritoneum and parametrium. All the tumors were removed. The histological changes
      of the small lesions were described as malignant schwannoma. The mass in urinary
      bladder and small bowel was found to be of an inflammatory origin. The cases
      described by other authors suggest, that the diagnosis of malignant schwannoma in
      pelvis minoris is very difficult. Surgery is an adequate way of final diagnosis
      and management.

PMID- 10582405
TI  - [Neurofibroma of the transversal mesocolon previously diagnosed under clinical
      and ultrasound examinations as an ovarian tumor. A case report].
AB  - The authors presented an unusually rare case of the displaced transversal
      mesocolon tumor in 67 years old patient which had been earlier clinically
      diagnosed as an right ovary tumor.

PMID- 10582406
TI  - [Acute fatty liver of pregnancy: underestimated complication of the third
      trimester?].
AB  - Two cases of acute fatty liver of pregnancy (AFLP) are described. The liver
      function abnormalities have been ignored in the both cases. The review literature
      on this rare clinical entity unique to pregnancy is presented. The importance of
      clinical and biochemical findings in the diagnosis of disease is emphasized.
      Although etiology is unknown, deficiency of fatty acid beta-oxidation has been
      suggested.

PMID- 10582407
TI  - [Acute fatty liver in pregnancy: treatment, prognosis, rules of management].
AB  - Acute fatty liver of pregnancy (AFLP), rare and potentially fatal disease, is
      considered as obstetric emergency. The perinatologist must be familiar with this
      complication of pregnancy because early diagnosis, prompt delivery and supportive
      care is the mainstay of therapy. When pregnant woman has nausea or vomiting,
      abdominal pain and jaundice, increased transaminase activity, coagulopathy and
      hypoglycemia during third trimester AFLP should be suspected. Mothers who have
      experienced AFLP must be informed of the possibility recurrence and undergo close
      surveillance in the next pregnancy.

PMID- 10582408
TI  - [Psychotropic drugs used in pregnancy and breast-feeding period].
AB  - There are some specific problems connected with psychotropic drugs used in
      pregnancy and breast-feeding period shown in the article. The action of
      psychoactive drugs was discussed as well as side effects and danger of using.
      Teratogenic effect was especially pointed. Drugs were classified based on safety
      for fetus and new-born.

PMID- 10582409
TI  - [Evaluation of the value and the efficacy of operative hysteroscopy in cases of
      intrauterine pathology].

PMID- 10582410
TI  - [Evaluation of modern ultrasonography in diagnosis of uterine and adnexal
      neoplasms].

PMID- 10582411
TI  - Predicting vestibular, proprioceptive, and biomechanical control strategies in
      normal and pathological head movements.
AB  - Little is known of the functionality of the vestibulocollic reflex (VCR) and
      cervico-collic reflex (CCR) during head and neck movements caused by
      perturbations of the trunk. Previously, we formulated mathematical expressions
      for these neck reflexes and incorporated them into a model of horizontal plane
      head movements. The formalism of this neuromechanical model allowed us to examine
      separately the main components of head movement control. In the present study, we
      examine selected parameters within the main components of the model, and
      associate variations of these parameters with disease processes affecting head
      and neck movements, such as loss of sensory input or modification in central or
      motor function. Our simulations led us to several conclusions. First, the
      probable use of the VCR and CCR in yaw plane head movements is to tune the head
      response. In the time domain, they diminish natural head oscillations (head
      wobble) related to head mechanics. Equivalently, in the frequency domain, they
      reduce the amplitude of head wobble (resonances) around 2 Hz. Second, our
      simulations suggest that the VCR is about ten times stronger than the CCR in
      normal humans. Moreover, this disproportion is associated with only very minor
      contributions from the CCR in yaw. Third, head oscillations (or instability) can
      be generated by mechanical or neural changes in the head and neck system.
      Finally, readjustments of central nervous system dynamic operations could provide
      mechanisms to compensate for sensory and motor dysfunction caused by disease.

PMID- 10582412
TI  - The need for correct realistic geometry in the inverse EEG problem.
AB  - For accurate electroencephalogram-based localization of mesial temporal and
      frontal sources correct modeling of skull shape and thickness is required. In a
      simulation study in which results for matched sets of computed tomography and
      magnetic resonance (MR) images are compared, it is found that errors arising from
      skull models based on smooth and inflated segmented MR images of the cortex are
      of the order of 1 cm. These errors are comparable to those found when
      overestimating or underestimating skull conductivity by a factor of two.

PMID- 10582413
TI  - The magnetic field associated with a plane wave front propagating through cardiac
      tissue.
AB  - An action potential propagating through a two-dimensional sheet of cardiac tissue
      produces a magnetic field. In the direction of propagation, the intracellular and
      extracellular current densities are equal and opposite, so the net current is
      zero. However, because of the unequal anisotropy ratios in the intracellular and
      extracellular spaces, the component of the current density perpendicular to the
      direction of propagation does not, in general, vanish. This line of current
      produces the magnetic field. The amplitude of the magnetic field is zero only if
      the action potential propagates parallel to or perpendicular to the fiber
      direction, or if the tissue has equal anisotropy ratios.

PMID- 10582414
TI  - Performance estimation of diagnostic tests for cervical precancer based on
      fluorescence spectroscopy: effects of tissue type, sample size, population, and
      signal-to-noise ratio.
AB  - Fluorescence spectroscopy may provide a cost-effective tool to improve precancer
      detection. We describe a method to estimate the diagnostic performance of
      classifiers based on optical spectra, and to explore the sensitivity of these
      estimations to factors affecting spectrometer cost. Fluorescence spectra were
      obtained at three excitation wavelengths in 92 patients with an abnormal
      Papanicolaou smear and 51 patients with no history of an abnormal smear. Bayesian
      classification rules were developed and evaluated at multiple misclassification
      costs. We explored the sensitivity of classifier performance to variations in
      tissue type, sample size, tested population, signal to noise ratio (SNR), and
      number of excitation and emission wavelengths. Sensitivity and specificity could
      be evaluated within +/- 7%. Minimal decrease in diagnostic performance is
      observed as SNR is reduced to 15, the number of excitation-emission wavelength
      combinations is reduced to 15 or the number of excitation wavelengths is reduced
      to one. Diagnostic performance is compromised when ultraviolet excitation is not
      included. Significant spectrometer cost reduction is possible without
      compromising diagnostic ability. Decision-analytic methods can be used to rate
      designs based on incremental cost-effectiveness.

PMID- 10582415
TI  - EM field prediction inside lossy multilayer elliptic cylinders for biological
      body modeling and numerical-procedure testing.
AB  - In this paper, a biological model made up of a multilayer elliptic cylinder is
      considered. This canonical scattering problem is solved by a recursive procedure,
      which has been generalized to the case of lossy materials by using the analytical
      properties of Mathieu functions. Although it is a simplified model, this
      stratified configuration may simulate better than circular cylinders the local
      behavior of biological subsystems. In addition, it represents an effective tool
      for producing analytical data for testing direct-scattering numerical codes in
      biomedical applications and for the evaluation of reconstruction procedures in
      medical imaging.

PMID- 10582416
TI  - Effect of complex bolus-tissue load configurations on SAR distributions from dual
      concentric conductor applicators. Specific absorption rate.
AB  - Power deposition [specific absorption rate (SAR)] distributions from a two
      element array configuration of 4-cm-square 915-MHz dual concentric conductor
      (DCC) microwave antennas were characterized theoretically for several clinically
      realistic complex bolus-tissue load models using the finite difference time
      domain (FDTD) numerical method. The purpose of this effort was to determine the
      perturbing effects on SAR of three often unavoidable heterogeneities in the bolus
      tissue load. The three cases studied in this work consist of bone (two ribs
      spaced 1 cm apart) embedded 5-mm or 1-cm deep in muscle or layered fat-muscle
      tissue, small air bubbles trapped between the coupling bolus and tissue surface,
      and variable thickness water bolus layer due to sharply contoured anatomy.
      Results of the FDTD simulations demonstrate rather small effects on SAR
      distribution for both rib-sized bones > or = 5-mm deep in muscle and small air
      pockets < or = 1-mm thick. Larger air bubbles > 1-cm diameter by 3-mm depth
      showed a distinct concentration of SAR near the lateral sides of the air bubbles,
      and a blocking effect under the bubbles when located directly under the center of
      a DCC aperture where there is a higher normal E-field component. Variation from
      2.5- to 7.5-mm bolus thickness under the two aperture array produced only minor
      perturbation of the uniformity and penetration of SAR, along with minor reduction
      in SAR under the thicker bolus which should be accommodated sufficiently by
      changes in applied power to the array elements.

PMID- 10582417
TI  - Time-scale analysis of motor unit action potentials.
AB  - Quantitative analysis in clinical electromyography (EMG) is very desirable
      because it allows a more standardized, sensitive and specific evaluation of the
      neurophysiological findings, especially for the assessment of neuromuscular
      disorders. Following the recent development of computer-aided EMG equipment,
      different methodologies in the time domain and frequency domain have been
      followed for quantitative analysis. In this study, the usefulness of the wavelet
      transform (WT), that provides a linear time-scale representation is investigated,
      for describing motor unit action potential (MUAP) morphology. The motivation
      behind the use of the WT is that it provides localized statistical measures (the
      scalogram) for nonstationary signal analysis. The following four WT's were
      investigated in analyzing a total of 800 MUAP's recorded from 12 normal subjects,
      15 subjects suffering with motor neuron disease, and 13 from myopathy: Daubechies
      with four and 20 coefficients, Chui (CH), and Battle-Lemarie (BL). The results
      are summarized as follows: 1) most of the energy of the MUAP signal is
      distributed among a small number of well-localized (in time) WT coefficients in
      the region of the main spike, 2) for MUAP signals, we look to the low-frequency
      coefficients for capturing the average waveshape of the MUAP signal over long
      durations, and we look to the high-frequency coefficients for locating MUAP spike
      changes, 3) the Daubechies 4 wavelet, is effective in tracking the transient
      components of the MUAP signal, 4) the linear spline CH (semiorthogonal) wavelet
      provides the best MUAP signal approximation by capturing most of the energy in
      the lowest resolution approximation coefficients, and 5) neural network DY (DY)
      of Daubechies 4 and BL WT coefficients was in the region of 66%, whereas DY for
      the empirically determined time domain feature set was 78%. In conclusion,
      wavelet analysis provides a new way in describing MUAP morphology in the time
      frequency plane. This method allows for the fast extraction of localized
      frequency components, which when combined with time domain analysis into a
      modular neural network decision support system enhances further the DY to 82.5%
      aiding the neurophysiologist in the early and accurate diagnosis of neuromuscular
      disorders.

PMID- 10582418
TI  - Changes in the complex permittivity during spreading depression in rat cortex.
AB  - With recent developments in current density imaging (CDI), it is feasible to
      utilize this new technique in brain imaging applications. Since CDI's ability to
      measure changes in current density depends on a concomitant activity-dependent
      change in the conductivity of the brain tissue, we have examined the changes in
      complex conductivity during spreading depression (SD) in rodent neocortex using a
      coaxial probe. SD was chosen because it is often referred to as an animal model
      of cerebral ischemia and migraine with aura. The conductivity measurements
      revealed a change with short latency (30-60 s) followed by a change with a longer
      latency (200-300 s). This change in conductivity with short latency has not been
      reported before, and we conjecture that it may be the priming or triggering
      mechanism prior to the main SD episode. A 20% change in conductivity during SD is
      sufficiently large to be measured by CDI. Therefore, the ability to measure
      changes in the conductivity, as opposed to metabolic changes, makes CDI a viable
      approach to the study of ischemia and migraine with aura.

PMID- 10582419
TI  - Partitioning of respiratory mechanical impedance by absolute and differential
      body plethysmography.
AB  - We have recently demonstrated the feasibility of partitioning total respiratory
      impedance (Zrs) into its airway (Zaw) and tissular (Zti) components by measuring
      alveolar gas compression (Vpl) plethysmographically during pressure oscillations
      at the airway opening (Peslin et al.). The aim of this study was to comparatively
      evaluate an alternative approach: the measurement of Zrs and of the transfer
      function (FTF) between airway flow and body surface flow obtained by absolute
      body plethysmography. The two approaches are theoretically equivalent, provided
      thermal and other artifacts are properly eliminated. Zrs and Vpl (method 1) and
      Zrs and FTF (method 2) were measured in 11 healthy subjects from 4 to 29 Hz,
      using a pressure-type and a flow-type plethysmograph, respectively. Inspired gas
      was conditioned to body temperature and pressure, saturated with water vapor in
      both instances to minimize thermal factors. Zaw and Zti spectra computed from
      both sets of data were quite similar in shape. Neither airway resistance nor
      tissue compliance differed significantly; tissue resistance, however, was about
      14% lower with method 1, which may be due to imperfect gas conditioning. The
      reproducibility of the data was similar with the two approaches. We conclude that
      absolute body plethysmography is as reliable as differential body plethysmography
      to partition Zrs.

PMID- 10582420
TI  - Model creation and deformation for the automatic segmentation of the brain in MR
      images.
AB  - In this paper a method for the automatic segmentation of the brain in magnetic
      resonance images is presented and validated. The proposed method involves two
      steps 1) the creation of an initial model and 2) the deformation of this model to
      fit the exact contours of the brain in the images. A new method to create the
      initial model has been developed and compared to a more traditional approach in
      which initial models are created by means of brain atlases. A comprehensive
      validation of the complete segmentation method has been conducted on a series of
      three-dimensional T1-weighted magnetization-prepared rapid gradient echo image
      volumes acquired both from control volunteers and patients suffering from
      Cushing's disease. This validation study compares results obtained with the
      method we propose and contours drawn manually. Averages differences between
      manual and automatic segmentation with the model creation method we propose are
      1.7% and 2.7% for the control volunteers and the Cushing's patients,
      respectively. These numbers are 1.8% and 5.6% when the atlas-based method is
      used.

PMID- 10582421
TI  - Extraction of fluorescent dot traces from a scanning laser ophthalmoscope image
      sequence by spatio-temporal image analysis: Gabor filter and radon transform
      filtering.
AB  - The scanning laser ophthalmoscope (SLO) allows the tracking of fluorescent dot
      motion, thereby enabling the flow velocities in perimacular capillaries to be
      directly measured. These can serve as an important index of local retinal
      soundness or reflect the whole body circulation status in disorders such as
      diabetes. Although it is possible to perceive moving fluorescent dots with the
      human eye, they are so faint and unstable that it is difficult to detect them by
      conventional digital still-image processing methods. To solve this problem, we
      generated spatio-temporal images of the fluorescent dots in a capillary and
      applied Gabor filters tuned to the direction of the traces in order to detect
      them. Finally, by discriminating and integrating the output using two levels of
      threshold, we were able to extract their traces. Because the medium-size Gabor
      filter requires a considerable amount of time for two-dimensional convolution
      calculation, we prove that there is a certain equivalence between the Gabor
      filter, the radon transform, and the Hough transform. In the light of this, we
      propose a form of radon transform filtering that includes a radon transform Gabor
      filter as a very long Gabor filter. This allows a whole trace to be detected in a
      single step with a one-dimensional convolution, thereby shortening the processing
      time. In an experiment, 60% of the traces could be detected without error, which
      is sufficient to allow the mean flow velocity in a capillary to be measured.

PMID- 10582422
TI  - Automatic cardiac LV boundary detection and tracking using hybrid fuzzy temporal
      and fuzzy multiscale edge detection.
AB  - This paper describes a new fully automatic fuzzy multiresolution-based algorithm
      for cardiac left ventricular (LV) epicardial and endocardial boundary detection
      and tracking on a sequence of short axis (SA) echocardiographic images of a
      complete cardiac cycle. This is a necessary step for automatic quantification of
      cardiac function using echo images. The proposed method is a "center-based"
      approach in which epicardial and endocardial boundary edge points are searched
      for on radial lines emanating from the LV center point. The central point of the
      LV cavity is estimated using a fuzzy-based technique in which the "uncertain"
      spatial, morphological, and intensity information of the image are represented as
      fuzzy sets and then combined by fuzzy operators. Edge-detection stage uses
      multiscale spatial and temporal information in a fuzzy multiresolution framework
      to identify a single moving edge point for each one of the epicardial and
      endocardial boundaries over the M radii in the N frames of a complete cardiac
      cycle. The raw extracted edge points are then processed in the wavelet domain to
      reduce the effects of noise from the boundaries and papillary muscles from the
      endocardial boundary extraction process. Finally, a uniform cubic B-spline
      approximation method is used to define the closed LV boundaries. Experiments with
      simulated and real echocardiographic images are presented.

PMID- 10582423
TI  - A reconstruction algorithm for electrical impedance tomography data collected on
      rectangular electrode arrays.
AB  - A three-dimensional reconstruction algorithm in electrical impedance imaging is
      presented for determining the conductivity distribution beneath the surface of a
      medium, given surface voltage data measured on a rectangular array of electrodes.
      Such an electrode configuration may be desirable for using electrical impedence
      tomography to detect tumors in the human breast. The algorithm is based on
      linearizing the conductivity about a constant value. Here, we describe a simple
      implementation of the algorithm on a four-electrode--by-four-electrode array and
      the reconstructions obtained from numerical and experimental tank data. The
      results demonstrate significantly better spatial resolution in the plane of the
      electrodes than with respect to depth.

PMID- 10582424
TI  - Fast frequency-sweep analysis of RF coils for MRI.
AB  - A fast frequency-sweep technique is developed for the analysis of radio-frequency
      coils for magnetic resonance imaging. This technique applies the method of
      asymptotic waveform evaluation to the moment method solution of the integral
      equation for the original physical problem. Numerical examples show that the
      proposed technique can speed up the analysis by more than an order of magnitude.

PMID- 10582425
TI  - A tale of an inconsequential worm.

PMID- 10582426
TI  - Crash and learn: 21st century interdiciplinary medical approach to injuries and
      biomechanical trauma.

PMID- 10582427
TI  - Supracervical abdominal hysterectomy: a technique whose time has come (again!),
      including an opinion by the late Dr. David Nichols.

PMID- 10582428
TI  - Physicians newly licensed in Rhode Island during 1998.

PMID- 10582429
TI  - Hodgkin's disease in patients with HIV/AIDS: case report and literature review.

PMID- 10582430
TI  - Update on the SCRIPT Project.

PMID- 10582431
TI  - Lyme disease in Rhode Island, 1990-1998.

PMID- 10582432
TI  - TB: prevention and control issues, 1999.

PMID- 10582433
TI  - Left main coronary artery disease. Clinical and angiographic features. A
      retrospective study regarding two groups of patients with left main coronary
      artery disease and three-vessel disease.
AB  - BACKGROUND: The aim of this study was to assess the ability of clinical and
      instrumental features to identify patients with left main coronary artery disease
      (LMCD) compared with a three-vessel coronary artery disease group. METHODS: A
      cohort of 70 patients with LMCD was matched with another one of 66 patients with
      three-vessel disease. A history of angina before angiography was similar in both
      groups; the higher degrees of stable angina and the forms of unstable angina were
      moderately prevalent in the group with LMCD. RESULTS: In the last subgroup a
      significantly reduced incidence of previous acute myocardial infarction (AMI) was
      observed (p < 0.05). The resting electrocardiogram (ECG) showed higher incidence
      of atrial fibrillation (fa) and left bundle branch block (BBS) in the subjects
      with LMCD, with a statistic value (p < 0.05). The exercise test performed by a
      lot of patients appeared equally positive for inducible ischemia in the 2 groups.
      Significantly higher exercise peak load was achieved by the patients with three
      vessel disease (p < 0.05). The coronary angiography showed a prevalence of right
      dominant circulation in the 2 groups; significantly the collateral circulation
      was more represented in the subjects with three-vessel disease (p < 0.05). Most
      patients with LMCD underwent a bypass coronary artery graft surgery (CABG
      surgery) more frequently than the ones with three-vessel disease (p < 0.01). In
      the former group the cardiovascular mortality within an average 2-year follow-up
      proved higher as to the latter group even if without statistic significance.
      CONCLUSIONS: Nevertheless this retrospective study showed some limitations.
      Particularly the incidence of clinical and instrumental variables and their
      capacity to differentiate LMCD patients from those with three-vessel disease were
      not demonstrated.

PMID- 10582434
TI  - [Atrial stunning and pharmacologic cardioversion in idiopathic atrial
      fibrillation of recent onset].
AB  - BACKGROUND: Normal atrial mechanic function may not return immediately after the
      successful cardioversion of atrial fibrillation. It has been suggested that the
      delayed recovery of atrial contraction (atrial stunning) might be due to: 1. the
      energy delivered during direct current cardioversion 2. the time from the onset
      of atrial fibrillation 3. the left atrial size 4. the associated cardiac disease.
      This study evaluates "atrial stunning" in patients pharmacologically treated,
      with atrial fibrillation of recent onset, normal atrial size and without heart
      disease. Doppler echocardiography is well suited for assessment of atrial
      function due to the ability of recording the peak velocity of atrial contraction
      (A wave). METHODS: Twenty-five patients with no evidence of heart disease and M
      mode left atrial dimension less than 40 mm underwent successful pharmacologic
      cardioversion (pro-paphenon or flecainide 2 mg/kg/10 min) of atrial fibrillation
      of recent onset (less than 48 hours). After cardioversion an echocardiographic
      study was performed within 12 hours (ECO 1), on day 3 (ECO 2), on day 12 (ECO 3),
      and on day 30 (ECO 4). RESULTS: No significant difference of both left atrial
      size (37 +/- 3.9 mm; 38.22 +/- 3.8 mm; 38.02 +/- 4.7 mm; 38.2 +/- 4.14 mm) and
      peak E velocity (57.97 +/- 18.3 mm/sec; 59.4 +/- 18.3 mm/sec; 59.0 +/- 16 mm/sec;
      59.07 +/- 16.7 mm/sec) was demonstrated among serial echocardiographic
      evaluations. Both peak A velocity (mm/sec) and E/A ratio were significantly
      different in ECO 1 (60.29 +/- 12.3-1.0 +/- 0.37) than in ECO 2 (73.1 +/- 10.7, p
      < 0.005-0.82 +/- 0.27, p < 0.05); no statistical difference was found between ECO
      2 and ECO 3 (76.31 +/- 12-0.78 +/- 0.24 mm/sec)--ECO 4 (76.91 +/- 14.8-0.78 +/-
      0.21 mm/sec). CONCLUSIONS: This study suggests that patients with atrial
      fibrillation of recent onset have a delayed recovery of normal atrial systolic
      function after pharmacologic cardioversion.

PMID- 10582435
TI  - Patent ductus arteriosus. Follow-up of 677 operated cases 40 years later.
AB  - BACKGROUND: This review is about the patency of ductus arteriosus (PDA), with
      particular care concerning diagnosis, surgical techniques, survival and
      postoperative pregnancy in operated females. METHODS: a) Sperimental study: the
      research has been conducted retrospectively and the follow-up is 40 years. b)
      ENVIRONMENT: all the patients were operated on in the Division of Cardiac
      Surgery, University of Turin (public structure) and in the Italian Institution of
      Cardiac Surgery (private structure). c) PATIENTS: from 1958 to 1987, 677 patients
      were operated on: mean age was 11.5 +/- 8.7 years. A complete follow-up was made
      on 487 patients (72%). d) Technique of operation: left lateral thoracotomy was
      often performed; in younger children, however, the tying of PDA was frequently
      made within the pericardium by left anterior thoracotomy in the third intercostal
      space. In uncomplicated situations, PDA was tied more frequently than divided, by
      two purse string stitches and one or two transfixed ligatures. e) SURVEY: overall
      early and late mortality, the clinical conditions of all patients, pregnancies
      and preor postoperative miscarriages of operated women were examined. RESULTS:
      From 1958 to 1967 overall early mortality was 5%; during the following years,
      there was no hospital mortality. The recurrence of PDA occurred only in 4
      patients. 72% of the operated females became pregnant. CONCLUSION: Life
      expectancy is normal after surgical closure of an uncomplicated PDA in infancy or
      in childhood but premature death may not always be avoided operating on adults
      with long-standing chronic congestive heart failure. At least, postoperative
      pregnancy is not a risk factor for the mother and PDA seems not to be correlated
      to foetal transmission.

PMID- 10582436
TI  - Venous thromboembolism and renal cell carcinoma.
AB  - There is a vast amount of literature documenting the relationship between cancer
      and venous thromboembolism. Nevertheless, many aspects of this association remain
      obscure and the best approach to be taken towards a patient with apparently
      idiopathic venous thromboembolism has yet to be defined. We present a case of a
      patient with venous thromboembolism in whom abdominal ultrasonography, prescribed
      as a cautionary measure to rule out the presence of a tumour, revealed liver
      metastases, while the subsequent CAT scan showed hepatic angiomatosis and two
      small bilateral renal carcinomas. Although there are as yet no indications in the
      literature on screening patients with idiopathic venous thromboembolism for
      occult tumours, our case shows how the clinical decision to perform abdominal
      ultrasonography saved the patient's life.

PMID- 10582438
TI  - [Acute cardiotoxicity from 5-fluorouracil: un underestimated toxicity].
AB  - The most common toxicity in clinical trials with 5-FU, in mono or
      polychemotherapy, is stomatitis, diarrhea, hand-foot syndrome. In this case
      report, the 5-fluorouracil (5-FU) cardiotoxicity, an uncommon 5-FU-related
      toxicity, has been investigated. Cardiotoxicity reports are uncommon because the
      problem is not well known. This study is also a review of the recent literature
      and it recommend to take care in prescribing chemotherapy to patients with heart
      disease history.

PMID- 10582437
TI  - Erythropoietin in Jehova's witness heart surgery.
AB  - The patients, reported here, needed open heart surgery, but religion obliged them
      to refuse blood transfusion. Three of the four patients suffered from obstructive
      coronary diseases and one from mitral valvular disease, prevalently stenosis. All
      of them refused blood transfusions. One of the three patients presented, was
      refused by an other Cardiovascular Surgery Center because of his low blood values
      (Haemoglobin 9.2--Haematocrit 26.7). All these patients had been treated with
      subcutaneous injection of epoetin alfa 10,000 U twice a week and ferrous sulphate
      525 mg three time a day per os, for three weeks before operation. Haemoglobin,
      haematocrit and reticulocytes values were controlled in pre, postoperative and at
      discharge. With this treatment the authors found haemoglobin and haematocrit
      values so increased to allow surgery without blood transfusion during and in the
      post operative period.

PMID- 10582439
TI  - [Operationalized psychodynamic diagnosis in childhood and adolescence. Conference
      proceedings. Gottingen, September 1996].

PMID- 10582440
TI  - [Importance of developmental perspective for the construction of a diagnostic
      test battery for children and adolescents (OPD-KJ)].
AB  - In the following contribution, developmental aspects are highlighted which served
      as a framework for developing an diagnostic instrument for child and adolescent
      psychiatry. In operationalizing a psychodynamic instrument for assessing children
      and adolescent symptomatology, a developmental perspective is critically
      important. Compared to adult, developmental changes occur on most dimensions
      measured, for example with respect to coping with the illness and dealing with
      stressors and conflicts. In addition, relationships with parents and peers
      changed over time as well as the capacity of self-reflexion and empathy. Two
      important conceptualizations are presented, which deal with these changes, the
      concept of developmental lines and the theory of developmental tasks. These
      conceptualizations, together with the theory of cognitive development, served as
      a framework for an approach, which distinguish diagnostically between infants,
      pre-school children, schools aged children and adolescents.

PMID- 10582441
TI  - [Representation and structure from a developmental psychopathology perspective].
AB  - An attempt to define "psychic structure" leads to the conclusion, that
      "structure" provides adaptive behavioral strategies for the interaction of the
      person with a physical and social world by representing experiences of earlier
      interactions in memory processes. Compatibility of different definitions of
      "structure" in psychopathology and psychoanalysis is being discussed.
      Developmental aspects of a "theory of mind" in children and of different modes of
      representation have to be addressed. A "multiple code theory" of W. Bucci is
      introduced. Conclusions for diagnosis and therapy in psychodynamic approaches
      will be drawn. It has to be faced, that children represent optimal structures in
      each level of psychic development, noting the importance of age-relevant
      normative measures.

PMID- 10582442
TI  - [Significance of research with infants for operationalized psychodynamic
      diagnosis (OPD) during the first year of life].
AB  - The early development of the infant and of the infant-parent relationship
      contains complex processes. These processes are built on the relational
      competency of the infant and of the parents and are characterized by fast changes
      and affective integration. The developmental process can easily be disturbed.
      Early disturbances can have severe consequences for further development. The
      process of early diagnostic in infant psychiatry faces many difficulties: the
      fast changes during early development, the strong connection between individual
      and interactional processes, and the uncertainty of differentiating between
      normality and pathology during this early age. The operationalized psychodynamic
      diagnostic can better deal with this developmental phase than traditional
      classification systems, which only address the individual phenomenology, because
      in the OPD there is a special axis for the relational level. Modern theories and
      research results on early development and on the early parent-infant triad offer
      a favorable background for such a classification of relations.

PMID- 10582443
TI  - [Distinction between regression and retardation].
AB  - Retardation is an impairment of functioning, which has affected individual growth
      from the onset of life. Regression is a temporary developmental flaw which is
      more easily amenable to psychdynamic understanding and treatment. In reality both
      retardation and regression are interlaced in great complexity. The structural
      axis of the OPD system has for methodological reasons decided to assess both
      states separately. Once the developmental level has been assessed, the structural
      level can be determined. Difficulties of this procedure are discussed.

PMID- 10582444
TI  - [OPD-diagnostics of child play].
AB  - Up to now there have been only a few attempts at using child play as a diagnostic
      instrument for distinguishing different psychic disturbances. In this article the
      author proposes different dimensions of evaluating child play diagnostically,
      serving to classify the respective integration level. They are dimensions such as
      the relation reality/phantasy, bodily action, as if ability, play duration,
      contents and quality, and play development. Play is understood here essentially
      as a child's one-sided enactment. With case examples the author clarifies how
      child play is to be understood on different integration levels using the
      evaluation criteria.

PMID- 10582445
TI  - [Brief report of the working group OPD-CA (children and adolescents) Axis I:
      subjective dimensions, resources, and preconditions for treatment].
AB  - The progress of work in adaptation axis I of OPD (operationalized psychodynamic
      diagnostic) to axis I OPD-CA (children and adolescents) is delineated. The items
      are now classified as subjective dimensions, resources and preconditions for
      treatment. Overlapping with the multi-axial classification for children and
      adolescents as used in Germany (MAS) was eliminated and important items for child
      and adolescent psychiatric and psychotherapeutic treatment were added. In the
      field of personal dimensions only subjective impairment will be covered.
      Resources were accentuated for the benefit of peer relationships. Motivation for
      treatment is now differentiated between a more global motivation for change and
      motivation for psychotherapeutic treatment. In order to reduce ambiguity the term
      of compliance was transformed into ability for therapeutic agreement. The
      possibility of realization of therapeutic indication was added.

PMID- 10582446
TI  - [Brief report of the working group OPD-CA (children and adolescents) Axis II:
      interpersonal relations].
AB  - Operationalization of relations is tried out following an interpersonal circular
      model (SASB) using observation and description of behavior in dyadic and triadic
      relationship configurations. On a vertical and on a horizontal axis the amount of
      loving kindness versus hostile aggressivity and of independence versus control is
      determined. Different dyadic and triadic relationship configurations (e.g. child
      to mother or researcher to child) and also the emotional resonance of the
      investigating person will be rated according to anamnestic data, observed and
      videotaped sequences of interaction, play episodes or symbolic relationships in
      projective tests. Such ratings can be performed in a module like form and will be
      used not only in clinical practice but also in settings of scientific research.
      The minimal standard for a clinical examination consists of the evaluation of the
      child with his parents.

PMID- 10582447
TI  - [Brief report of the working group OPD-CA (children and adolescents) Axis III:
      conflict].
AB  - Conflict according to the OPD is understood as a lasting and unconscious inner
      conflict, which should be described on the background of the child's or
      adolescent's developmental state. In accordance with the adult OPD the following
      seven conflicts can be differentiated: Dependence versus autonomy, submission
      versus control, desire for care versus autarchy, conflicts of self-value
      (narcissistic conflicts, self-value versus object-value), conflicts of loyalty
      (guilt conflicts, egoistic versus pro-social tendencies), oedipal sexual
      conflicts, identity conflicts (identity versus dissonance). These conflicts have
      been operationalized for 6 domain of daily living--family, peers,
      kindergarten/school, property, play and illness--for the developmental phases (2
      5, 6-11, and older than 12 years) separately.

PMID- 10582448
TI  - [Brief report of working group OPD-CA (children and adolescents) Axis IV:
      structural standard].
AB  - Apart from the structural differentiation of the body and its functions, the
      enlargement of the child's repertoire of possibilities to make experiences and to
      act is a manifestation of the development of the child's psychic structure which,
      advancing in years, may be considered as a treasure of all the experiences one
      has made with oneself, with the world and with the others. Structure will develop
      along with the interactional experiences with the world around us and becomes
      manifest in one's behaviour which may be witnessed and observed. The description
      of the psychic structure comprises three dimensions (perception of the self and
      of the objects, control, communication and bonding) which will be described by
      certain capabilities and will be assessed with the help of an anchoring example
      typical for each age which serves the purpose of clinical illustration. The
      adaptational achievement may then be assessed on the basis of a structural
      standard independent of age and may be ranged on a structural level. It appears
      that the exemplary description of different scopes of tasks typically to be
      performed at certain ages which serves as a basis for the assessment of the
      adaptational competence during childhood and adolescence seems to be a good
      policy. The purpose of our studies is the development of a valid instrument which
      is easy to handle in practice and which has a high interrater-reliability.

PMID- 10582449
TI  - Diastolic heart function and dysfunction.

PMID- 10582450
TI  - Diastolic heart failure: identification and characterization. Epidemiology,
      prevalence and grounds for clinical suspicion.

PMID- 10582451
TI  - Diastolic heart failure: identification and characterization. Doppler
      echocardiography: the "old" approach.

PMID- 10582452
TI  - Diastolic heart failure: identification and characterization. Doppler tissue
      imaging: a "new" approach.

PMID- 10582453
TI  - Diastolic heart failure: identification and characterization. The role of
      radionuclide ventriculography.

PMID- 10582454
TI  - Diastolic heart failure: identification and characterization. Is there a role for
      invasive methods?

PMID- 10582455
TI  - A personal approach to identify and characterise diastolic heart failure in
      routine clinical practice.

PMID- 10582456
TI  - Dealing with a special group: hypertrophic cardiomyopathy. Etiology and
      prevalence: what is known today.

PMID- 10582457
TI  - Dealing with a special group: hypertrophic cardiomyopathy. Models of diastolic
      dysfunction in hypertrophic cardiomyopathy.

PMID- 10582458
TI  - Dealing with a special group: hypertrophic cardiomyopathy. Pharmacological
      treatment.

PMID- 10582459
TI  - Dealing with a special group: hypertrophic cardiomyopathy. The role of
      electrophysiology and pacing in hypertrophic cardiomyopathy.

PMID- 10582460
TI  - Dealing with a special group: hypertrophic cardiomyopathy. Surgical treatment:
      what for?

PMID- 10582461
TI  - Diastolic dysfunction in coronary artery disease.

PMID- 10582462
TI  - Other diseases with diastolic dysfunction: how to deal with? Hypertensive heart
      disease.

PMID- 10582463
TI  - Other diseases with diastolic dysfunction: how to deal with? Restrictive
      cardiomyopathy.

PMID- 10582464
TI  - Other diseases with diastolic dysfunction: how to deal with? Constrictive
      pericarditis.

PMID- 10582465
TI  - Left ventricular diastolic dysfunction in patients under periodic hemodialytic
      treatment.

PMID- 10582466
TI  - Noninvasive monitoring of pulmonary capillary wedge pressure in heart failure.

PMID- 10582467
TI  - Myocardial asynchrony in hypertrophic cardiomyopathy.

PMID- 10582468
TI  - Neurohormonal mechanisms in congestive heart failure with special reference to
      diastolic heart failure.

PMID- 10582469
TI  - Treating diastolic heart failure: the role of beta-blockers.

PMID- 10582470
TI  - Treating diastolic heart failure: the role of ACE inhibitors.

PMID- 10582471
TI  - Treating diastolic failure: the role of diuretics and nitrates.

PMID- 10582472
TI  - Treating diastolic heart failure: the role of calcium antagonists.

PMID- 10582473
TI  - How to treat diastolic heart failure: a personal point of view.

PMID- 10582474
TI  - [Medicine and contemporary mythologies].

PMID- 10582475
TI  - [In Process Citation]

PMID- 10582476
TI  - [Amiodarone and thyroid disorders--prospective study and review of the
      literature].
AB  - A well-known adverse effect of amiodarone is the induction of thyroid
      dysfunction. The numerous studies evaluating the incidence of amiodarone-induced
      thyroid dysfunction have given very dissimilar results, because of the
      variability in the criteria of hyper- and hypothyroidism, on the one hand, and in
      the iodine intake of the studied population on the other hand. The aim of our
      study was to evaluate the incidence of amiodarone-induced thyroid dysfunction.
      One hundred and twelve patients without prior thyroid dysfunction or anterior
      treatment with amiodarone were included in the study. Thirty-one patients were
      later excluded from the analysis because of a follow-up duration of less than
      four months. So our analysis concerned 81 patients (52 men and 29 women),
      followed for a mean period of 37.3 months. Amiodarone-Induced Thyrotoxicosis
      (AITT), diagnosed by the association of a low TSH and a high T4 (free and total
      T4), occurred in 13 patients (16%). Male sex proved to be a statistically
      significant risk factor of AITT. The normalization of the thyroid tests was
      obtained by the withdrawal of amiodarone and, for most of the patients, by the
      addition of thionamides. Amiodarone-Induced Hypothyroidism (AIHT), diagnosed by
      the elevation of TSH, occurred in 10 patients (12.3%). Female sex proved to be a
      statistically significant risk factor of AIHT.

PMID- 10582477
TI  - [Fenfluramines and cardiac valvular lesions].
AB  - We report cardiac valvulopathy occurring after prolonged intake of anorectic
      drugs containing fenfluramine (Fen) and/or dexfenfluramine (D-Fen) in 14 patients
      whose evolution was followed by Doppler echocardiography. A relation between
      these drugs and valvular regurgitation was first suspected after 4 cases reported
      in 1991-1992 and confirmed after 3 more patients in 1993-94-95, who were taken D
      Fen or Fen alone. All were women, aged 42 to 73 years. Patient 1 to 7 had been
      taking Fen and/or D-Fen for 14 to 52 months. Patients 8 to 14 had been taking a
      mixture of Fen and/or D-Fen, diethylpropion and chinese-herbs for 3 to 69 months.
      These last 7 patients developed renal failure requiring hemodialysis or
      peritoneal dialysis in 5 and subsequent renal transplantation in 4. All presented
      with cardiac murmur(s) and some with dyspnea or palpitations. An initial
      echocardiography was performed at the time of diagnosis, and was repeated
      annually for a follow-up period extending to 8 years. We conclude that a relation
      between Fen and/or D-Fen and the outbreak of valvular heart disease is identified
      in our patients, confirming previous findings. The nephrotoxicity observed in 7
      patients is due to the "chinese-herbs". When Fen and/or D-Fen are stopped and
      proper therapy initiated, the cardiac symptoms may stabilize or even subside,
      though slowly. Hemodynamic unstability and/or infection appear to be an
      aggravating factor. These patient's follow up must be prolonged for several years
      and is readily achieved with echocardiography. Systematic screening of all
      patients having taken Fen and/or D-Fen must be performed, as renal and urinary
      screening for all patients having taken chinese-herbs. Endocardial prophylaxis
      must always be prescribed.

PMID- 10582478
TI  - [Atorvastatin (Lipitor)].
AB  - Atorvastatin is a second generation synthetic statin, introduced in Belgium in
      May 1998. Its mechanism of action is similar to that of the other statins, i.e.
      the inhibition of HMG Co-A reductase, the key enzyme in cholesterol synthesis,
      which leads to the increase of LDL receptors. The prolonged half-life (20-30 H)
      of atorvastatin and its active metabolites, induces a prolonged inhibition of HMG
      Co-A reductase and a reduction of hepatitic apo B production. The biological
      efficacy of atorvastatin is high: 41 to 61% lowering of LDL depending of the
      dose. Atorvastatin is indicated in primary hypercholesterolemia, mixed
      hyperlipidemia and homozygous familial hypercholesterolemia. If necessary, a
      resin or even a fibrate may be added. The safety profile is good. The most common
      adverse effects are gastro-intestinal and transient. Liver tests or muscle
      enzymes are rarely modified. If clinical proof of reduction of CV morbidity and
      mortality in primary and secondary prevention is obtained, atorvastatin shall
      represent a major step forward in the treatment of hypercholesterolemia.

PMID- 10582479
TI  - [In vitro fertilization at the Erasme Hospital: 10 years and 1000 pregnancies
      later...].
AB  - This contribution summarize ten years of in vitro fertilization of clinical work.
      Activity growth, improvements of results (mean fertilization rate increased from
      45% to 58%, fertilization failure dropped from 18% to 7%, pregnancy chances gains
      9% to reach 44% per trial) and new treatments possibilities (severe male
      infertility) thanks to the ICSI technic were the major characteristics of this
      last ten years. The original anonymous oocyte donation program with donors
      permutation initiated as soon as 1990 has imposed itself due to it's exceptional
      efficiency with a pregnancy rate of 95% per oocyte pick up on a population of 46
      donors and 145 recipient cycles. Thanks to the large population studied (4028
      cycles, 1071 pregnancies), the tendencies in human fecundity (impact of age) and
      the risks linked to multiples pregnancies could be highlighted, stressing the
      importance of future developments presented in the other contributions following
      this general presentation of results.

PMID- 10582480
TI  - [Evolution of ovarian stimulation in in vitro fertilization].
AB  - This paper reviews the different treatments of ovarian stimulation for in vitro
      fertilization (IVF). It emphasizes the recent development of new molecules,
      including recombinant gonadotrophins and GnRH antagonists. Because of their
      higher purity, recombinant gonadotrophins are theoretically less immunogenic than
      the urinary forms. Their preparation mode ensures a better batch to batch
      consistency. Their clinical use in IVF seems to be associated with a higher
      number of developing follicules and retrieved oocytes, but pregnancy rates are
      comparable to those obtained after ovarian stimulation with urinary
      gonadotrophins. The GnRH antagonists induce a direct inhibition of the pituitary
      gonadotrophin secretion. In association with an ovarian stimulation with
      gonadotrophins, they efficiently prevent premature LH surges when administered
      during the end of the follicular phase. The GnRH antagonists are still in
      clinical evaluation phase and the optimal protocol and dose still to be defined.
      They should become available in the coming year. The risks related to the
      controlled hyperstimulation together with the reduction of the number of
      transferred embryos has recently led "soft stimulation" to a reevaluation of the
      stimulation protocols towards a simplified procedure. However, the validity of
      this attitude could be in opposition with the wish to limit the number of
      transferred embryos since embryo quality seems to be directly related to the
      total number of embryos.

PMID- 10582481
TI  - [Impact of the introduction of intracytoplasmic sperm injection (ICSI) on the
      treatment of severe male sterility].
AB  - The introduction of the Intracytoplasmic Single Sperm Injection (ICSI) has been a
      turning point for the treatment of severe male infertility. ICSI allowed not only
      to reduce fertilization failure from 35% to 0.7% but created at the same time the
      opportunity for a group of patients with extremely low sperm counts to procreate.
      The discovery that breaking the tail of the spermatozoon prior to the injection
      was the most important step is at the origin of major improvements: fertilization
      increased from 22% to 77%, pregnancy rate from 16% to 54% and the implantation
      rate from 7.4% to 26%. From October 1994 to April 1999, 835 ICSI cycles were
      performed and resulted in 312 ongoing pregnancies (37%), fertilization rate was
      75%, with a fertilization failure of only 0.7%. The use of ICSI and IVF on
      sibling oocytes for semen samples with doubtful fertilizing ability clearly
      illustrated the superiority of ICSI. No fertilization failures occurred after
      ICSI and the fertilization rate was 76% versus 27.8% (P < 0.01). Similar benefit
      of ICSI was shown for crytozoospermia up to then a hopeless situation. A total of
      26 pregnancies were obtained out of 87 cycles with a fertilization rate of 58.8%.
      Similar results were obtained when ICSI was combined with testicular sperm, 20
      pregnancies occurred after from 46 transfers (43%) including cycles with
      cryopreserved testicular sperm. It is now clear that ICSI is the method of choice
      for the treatment of severe male infertility.

PMID- 10582482
TI  - [Genetics of male sterility].
AB  - Infertility affects 10 to 15% of all couples, the man responsible being in
      approximately half of the cases. With the development of assisted reproductive
      technologies such as ICSI (Intracytoplasmic Sperm Injection), some infertile men
      can reproduce and transmit the infertility to their offspring. The genetic basis
      of male infertility has been extensively studied these last years. This article
      gives a non exhaustive overview of genetic defects associated with infertility,
      and emphasizes the importance of genetic screening, and possibly genetic
      counseling for these infertile males.

PMID- 10582483
TI  - [Diminishing the risk of multiple pregnancies in in vitro fertilization: from
      selective transfer of two embryos to that of one blastocyst?].
AB  - The risk of multiple pregnancy after IVF needs to be drastically reduced. Several
      policies can be applied including the transfer of a maximum of three embryos to
      all patients, the fertilization of a maximum of three oocytes or a selective
      reduction of the number of transferred embryos. The first policy previously
      applied at the Fertility Clinic at Erasme Hospital until 1996, transferred two
      good quality embryos to patients with at least three good embryos. If this policy
      demonstrated that patients with two transferred embryos had similar chances of
      pregnancies compared to patients with three transferred embryos, it failed to
      sufficiently decrease the number of multiple pregnancies. The second policy
      applied since 1997, transferring a maximum of two average or good embryos to all
      patients aged under 35 years and with less than 3 previous attempts, demonstrated
      that while preserving the chances of pregnancy for these patients, it decreased
      by 20% the number of multiple pregnancies and almost eliminated triplets. With
      the improvement of culture media, it is now possible to culture embryos in vitro
      for a longer period and therefore transfer embryos with proven viability at a
      time corresponding more to in vivo physiological conditions. The implantation
      rates for these embryos, for patients with at least 4 previous attempts can reach
      40%. If these results persist, it would be possible to transfer blastocysts to
      all patients and perhaps move on to the replacement of a single embryo, a policy
      that will practically eradicate all multiple pregnancies.

PMID- 10582484
TI  - [Aspects of scientific research and technical progress in human fertility].
AB  - The development of an outstanding in vitro fertilization program greatly benefits
      from the contribution of research because it remains an unfailing source of
      questions on human reproduction, as much in the fields of physiology and
      pathology as in those of psychology and sociology. This paper shows five major
      themes that are tackled by the laboratory of biology and psychology of human
      fertility and the Fertility Clinic, whether it's endocrinology (the ovarian renin
      and angiotensin regulation), cellular metabolism (embryo metabolism), genetics
      (preimplantation genetic diagnosis) or cancerology (ovarian tissue conservation
      before or after chemo- or radiotherapy), all of these are crossed by the fifth
      (the psychological and ethical aspects of in vitro fertilization) which gives a
      human dimension to the biological work, since it's a very special biology that
      it's our own reproduction, the very base of the specie's survival.

PMID- 10582485
TI  - [Pathology].

PMID- 10582486
TI  - [Autopsies: from the past to the future].

PMID- 10582487
TI  - [Malignant lymphomas--the end of a long dispute?].

PMID- 10582488
TI  - [Molecular pathology of colorectal cancer].
AB  - The identification of several types of familial colorectal cancer has led to the
      discovery of some of the genes involved in these diseases. It was subsequently
      shown that somatic mutations of these genes (APC, mismatch repair genes, TP53)
      also occur in sporadic colorectal cancer. Gradually, this molecular information
      is being incorporated into the standard histopathological analysis of colorectal
      cancer and can be used for the characterization of primary tumors. Although
      attempts have been made to use molecular parameters to better define dysplasia
      grades, differentiate between adenoma and carcinoma, and subtype carcinomas,
      histological parameters remain the standard for the classification of primary
      tumors. Nonetheless, molecular parameters may help define subgroups of colorectal
      carcinoma differing in prognosis and requiring individualized treatment regimens.
      Interesting possibilities are predicting the response of chemotherapy or
      radiotherapy at a molecular level and the search for metastasis by looking for
      molecular markers in lymph nodes or circulating blood. Other pathological tests
      being developed include the detection of K-ras, TP53 or APC mutations in stool
      and plasma. Such approaches will have a significant impact on the clinical
      management of colorectal cancer.

PMID- 10582489
TI  - [Role of anatomopathology in the surveillance of liver transplants].

PMID- 10582490
TI  - [Cytology: some new applications].

PMID- 10582491
TI  - [New techniques in cytology: liquid milieu and thin slides].

PMID- 10582492
TI  - [Inflammatory and infectious manifestations of the nervous system].
AB  - The Central Nervous System is the site of a wide variety of inflammatory and
      infectious diseases. Some disease entities have been in the focus of interest in
      recent years and progress has been achieved in our understanding of some chosen
      domains. We will review recent progress in our knowledge about transmissible
      spongiformes encephalopathies and AIDS-associated lesions, and briefly discuss
      cerebral vasculitis, granulomatous diseases and the most frequent infections by
      parasites.

PMID- 10582493
TI  - [Medical data in pathology--evaluation of a large collection. (530,000 diagnoses
      coded in SNOMED II)].
AB  - The paper is describing the design and the performance of the computerized
      system, from its introduction in 1982 until the present day. The first device,
      using the MUMPS language on a mini-computer, followed by a VAX computer with
      terminals have been replaced in 1996 by an application program, using ORACLE,
      based on the client-server concept. The content and the particularities of the
      different data groups are discussed, concerning the functional components of the
      data bank: 'PATIENTS', 'SPECIMEN', 'SENDERS', 'REPORT' and 'DIAGNOSES'. By means
      of examples, we demonstrate the chronological evolution of the registration of
      persons, the distribution of the diagnoses according to the organ systems, the
      possibilities to combine various lesions and an algorithm to assure that a given
      lesion is registered only once per patient. In first place, the efficiency and
      the reliability of manual coding by a pathologist using the Systematized
      Nomenclature of Medicine (SNOMED; 2nd edition [1979/1982]) is discussed. The data
      bank currently contains 530,000 diagnoses, distributed among on SNOMED's five
      main modules, obtained from 1500 autopsies, 140,000 surgical and 180,000
      cytological specimens. Concluding the article, an analysis is made of desirable
      developments in the future with the aim of a better integration of the acquired
      information in routine work and an enhanced use of the medical content for
      epidemiological research or statistical analysis.

PMID- 10582494
TI  - [Cancer registry: foundations and functioning].

PMID- 10582495
TI  - [Cardiac fibrosarcoma discovered by cerebral metastases].
AB  - Primary heart tumors are rare, and the fibrosarcomas are exceptional. We present
      the findings in a 78 year old female who has been hospitalized in April 1997 with
      a history of 4 months of malaise, headaches and weight loss. Clinical examination
      showed a right lateral homonymous hemi-anopsia. Computed tomography (CT-Scan) of
      the brain showed two lesions in the occipital and temporal lobe, consistent with
      metastasis. Thoracic and abdominal-pelvic CT-Scan revealed a voluminous mass of
      the left auricle that has been interpreted as a probable sarcoma. Biopsy specimen
      of one of the cerebral lesions, performed at the Centre hospitalier universitaire
      vaudois (CHUV) on April 29th 1997, revealed fragments of a poorly differentiated
      sarcoma. After referral back to Neuchatel, the patient suffered suddenly three
      weeks later from a cerebral vascular insult with instant onset of deep coma. She
      deceased on May 27. At autopsy we found a neoplastic lesion of the left auricle
      with invasion of the pulmonary veins. The histological appearance is similar to
      the appearance of the cerebral metastasis, showing a proliferation of spindled
      cells with a partial positivity for Vimentine. It was classified as a
      fibrosarcoma. Metastasis were found only in the brain with postoperative ischemic
      left occipitotemporal necrosis and neoplastic emboli.--We are discussing the
      various incidences of cardiac neoplasms in autopsies or biopsies.

PMID- 10582496
TI  - [All ankle traumas are not banal sprains...].

PMID- 10582497
TI  - [Dying in the hospital].

PMID- 10582498
TI  - Leishmania/HIV co-infection, south-western Europe, 1990-1998.

PMID- 10582499
TI  - Development of sizing systems for protective clothing for the adult male.
AB  - The aim of the study was to obtain comprehensive anthropometric data from which
      to develop a sizing system appropriate for inclusion in specifications for
      protective clothing; and for purchases of other selected equipment. Fifty-five
      body dimensions on a male sample of the New Zealand Fire Services (n = 691,
      approximately 7% of employees) were obtained by direct measurement. Descriptive
      statistics and selected percentiles (5th, 50th, 95th) are given. The body
      dimensions accounting for most of the variance in the data were established by
      factor analysis and are reported here. Size groups for various body sections
      based on the relevant measurements of that section were established by cluster
      analysis around a control variable.

PMID- 10582500
TI  - Spine loading and trunk kinematics during team lifting.
AB  - Two-person or team lifting is a popular method for handling materials under
      awkward or heavy lifting conditions. While many guidelines and standards address
      safe lifting limits for individual lifting, there are no such limits for team
      lifting, and these lifts are poorly understood. The literature associated with
      team lifting offers some interesting paradoxes. Many studies have indicated that
      people lift less per individual under team conditions compared with one-person
      lifting. Yet, at least one study has reported an increase in team-lifting
      capacity when subjects were height-matched. The current study explored the spine
      loading characteristics of one- and two-person lifting teams when subjects lifted
      under several sagittally symmetric and asymmetric conditions. Spine compression
      was lower for two person lifts for a given weight, while lifting in sagittally
      symmetric conditions whereas lateral shear became much greater for two-person
      lifts under asymmetric lifting conditions. This study has linked these changes to
      differences in trunk kinematic patterns adopted during one- versus two-person
      lifting.

PMID- 10582501
TI  - Perception of surface pressure applied to the hand.
AB  - The study aimed to determine the relationship between the physical magnitude and
      the subjective perception of applied pressure, and to determine discomfort and
      pain thresholds. Free modulus magnitude estimation of the subjective pressure
      level was made on three points: on the finger, the palm and the thenar area. The
      pressure was judged to be higher at the thenar point than at the finger and palm
      points. The slopes of the linear functions (log magnitude estimates as a function
      of log pressure) were 0.66, 0.78 and 0.76 for the finger, palm and thenar points
      respectively. The discomfort threshold was 38% of the pain pressure threshold at
      the finger point, 40% at the palm and 22% at the thenar point. The results are
      probably of importance in the performance of hand-intensive work, in particular
      in the design of hand tools.

PMID- 10582502
TI  - Manual handling performance: the effects of menstrual cycle phase.
AB  - Physiological and subjective responses to physical performance have been shown to
      interrelate with fluctuations in the female hormonal environment throughout the
      menstrual cycle. The aim of this study was to examine whether these fluctuations
      affect the strenuous performance required in manual handling. Seventeen
      eumenorrheic females performed lifting tasks in five phases of their menstrual
      cycle. These tasks were maximal isometric lifting strength (MILS) and an
      endurance lift at 45% MILS (t), at both knee and waist height; and the selection
      of a maximal acceptable load (MAL) to lift six times per min, for 10 min, in both
      the sagittal and asymmetric planes. Heart rate response (HR) and rating of
      perceived exertion (RPE) were recorded throughout each of the lifting tasks.
      MILS, t and the chosen MAL were unaffected by menstrual phase over both heights
      and planes of lift (p > 0.05). HR to the isometric endurance lift was greater
      following ovulation than prior to ovulation by approximately 7 beats.min-1 (p <
      0.05). This was true when the data were analysed at 50, 80 and 100% of the time
      to volitional fatigue, and by an area under the curve procedure. HR to the
      dynamic lifting tasks was also elevated by approximately 7 beats.min-1 following
      ovulation. This difference was non-significant due to the low power of the
      analysis. Re-analysis of the data by re-sampling 1000 matched comparisons
      produced significant phase variations (p < 0.05). The RPE for all of the lifting
      tasks was independent of menstrual phase (p > 0.05). The impact of the
      eumenorrheic menstrual cycle on lifting capability was negligible in the present
      study. However, the results of this study indicate that all further
      investigations utilizing HR data to produce recommendations for health and safety
      in manual handling tasks must control for menstrual cycle phase in female
      populations.

PMID- 10582503
TI  - Effects of keyboard tray geometry on upper body posture and comfort.
AB  - The effects of a downward-tilting (DT) keyboard tray on wrist posture, seated
      posture and self-assessed musculoskeletal discomfort were investigated in a field
      experiment. Thirty-eight professional office workers were studied. A pretest
      assessed how they typed using either a conventional keyboard on a desk or on an
      articulating keyboard tray, and with or without wrist rests. Workers were
      randomly allocated to a control (n = 15) or test group (n = 23) that used their
      existing keyboard in a DT system. A post-test was conducted 3 weeks later.
      Results showed no significant changes in wrist posture, seated posture or reports
      of musculoskeletal discomfort for the control group, and approximately 50% of
      typing wrist movements put the hand in a neutral zone. There were significant
      improvements in wrist posture, seated posture and upper body musculoskeletal
      discomfort for the test group using the DT system. Over 80% of typing wrist
      movements put the hand into a neutral zone with the DT arrangement. Reactions to
      using a conventional keyboard on a DT system were positive.

PMID- 10582504
TI  - Effects of computer mouse design and task on carpal tunnel pressure.
AB  - Computer mouse use has become an integral part of office work in the past decade.
      Intensive mouse use has been associated with increased risk of upper extremity
      musculoskeletal disorders, including carpal tunnel syndrome. Sustained, elevated
      fluid pressure in the carpal tunnel may play a role in the pathophysiology of
      carpal tunnel syndrome. Carpal tunnel pressure was measured in 14 healthy
      individuals while they performed tasks using three different computer mice.
      Participants performed a multidirectional dragging ('drag and drop') task
      starting with the hand resting (static posture) on the mouse. With one mouse, an
      additional pointing ('point-and-click') task was performed. All mice were
      associated with similar wrist extension postures (p = 0.41) and carpal tunnel
      pressures (p = 0.48). Pressures were significantly greater during dragging and
      pointing tasks than when resting the hand (static posture) on the mouse (p =
      0.003). The mean pressures during the dragging tasks were 28.8-33.1 mmHg,
      approximately 12 mmHg greater than the static postures. Pressures during the
      dragging task were higher than the pointing task (33.1 versus 28.0 mmHg),
      although the difference was borderline non-significant (p = 0.06). In many
      participants the carpal tunnel pressures measured during mouse use were greater
      than pressures known to alter nerve function and structure, indicating that jobs
      with long periods of intensive mouse use may be at an increased risk of median
      mononeuropathy. A recommendation is made to minimize wrist extension, minimize
      prolonged dragging tasks and frequently perform other tasks with the mousing
      hand.

PMID- 10582505
TI  - Effect of gloves on prehensile forces during lifting and holding tasks.
AB  - The effect of gloves on the spatio-temporal characteristics of prehensile forces
      during lifting and holding tasks was investigated. Participants (n = 10) lifted a
      force transducer equipped object (weight = 0.29 N) with various types of gloves
      and barehanded using a two-fingered precision grip. Rubber surgical gloves of
      varied thicknesses (0.24, 0.61 and 1.02 mm) were worn to examine the effect of
      glove thickness on a rayon surface. It was found that grip force increased with
      thickness because the participants employed a higher safety margin above the
      minimum force required to hold the object. The safety margin for the barehanded
      condition was the smallest. The performance time for lifting the object was not
      influenced by the variation of glove thickness. The findings suggest that glove
      thickness, which presumably modifies the cutaneous sensation, influences grip
      force regulation. The effect of glove material (rubber and cotton) was also
      examined in relation to slippery (rayon) and non-slippery (sandpaper) surfaces.
      It was found that the participants used a larger grip force with the cotton glove
      than the rubber glove for the slippery surface, but not with the non-slippery
      surface. With use of the rubber glove, a relatively low grip force level was
      maintained for both slippery and non-slippery surfaces. The performance time for
      the cotton glove was longer than that for the rubber glove. The findings suggest
      that the rubber glove provides better efficiency of force and temporal control
      than the cotton glove in precision handling of small objects.

PMID- 10582506
TI  - Legality of bowling actions in cricket.
AB  - An ergonomic methodology has been designed and developed to evaluate the legality
      of bowling actions in cricket. This paper describes the methodology and a case
      study related to an international cricket player with an unorthodox bowling
      action. Objective measurements were used to evaluate the action. An
      electrogoniometer and a force-sensing resistor (FSR) were used for this purpose.
      The electrogoniometer measured the elbow angles in the sagittal plane, while the
      FSR indicated the instant of ball release to assess the presence of any elbow
      'straightening' directly preceding delivery. The FSR was attached to a finger
      depending on the type of ball delivered. Angles and forces were sampled at 500 Hz
      and stored in a data logger. The information collected was downloaded on to a
      computer for further analyses. The angle information preceding ball release is a
      clear indicator of arm 'straightening' during bowling. The methodology has high
      reliability and accuracy in the evaluation of the legitimacy of bowling actions
      as defined by the International Cricket Council laws.

PMID- 10582508
TI  - Laser heart surgery update.

PMID- 10582507
TI  - Parental employment, school climate, and children's academic and social
      development.
AB  - Longitudinal data were used to examine the effects of parental employment status
      and school climate on children's academic and social development. Hierarchical
      regression, analyses of covariance, and latent growth modeling were used to
      assess various aspects of change as a function of work status and school climate
      with family income and education as control variables. Parental employment was
      associated with positive changes in social and academic progress even after
      controlling for prior developmental level, climate, and family income although
      effects were small and complex. School climate had minimal effect on the outcome
      variables. Income and education were related to various school outcomes.

PMID- 10582509
TI  - Antibiotic resistance: can we resist it?

PMID- 10582510
TI  - Where's the hair?

PMID- 10582511
TI  - Drugs plus counseling best for stubborn depression.

PMID- 10582512
TI  - Higher progesterone, less bleeding.

PMID- 10582513
TI  - Female vegetarians: short on iron?

PMID- 10582514
TI  - Melatonin no panacea for jet lag.

PMID- 10582515
TI  - The homocysteine-CVD connection.

PMID- 10582516
TI  - Higher BP, weaker bones?

PMID- 10582517
TI  - Benefits of the grape.

PMID- 10582518
TI  - Mite and mold control.

PMID- 10582519
TI  - New canker sore treatment.

PMID- 10582520
TI  - Nitric oxide production is decreased in the brain of the seizure susceptible EL
      mouse.
AB  - To investigate nitric oxide production in the brain of the EL mouse, an inbred
      mutant strain of the ddY mouse that is susceptible to convulsive seizures, we
      measured whole brain nitric oxide metabolites, and counted the number of nitric
      oxide-producing cells in the parietal cortex and striatum. Nitric oxide
      metabolites in the brain and serum were determined by measuring levels of nitrite
      plus nitrate. Nitric oxide-producing cells were demonstrated histochemically by
      staining for nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase.
      Levels of nitrite plus nitrate in the whole brain were significantly lower than
      those of the control mice, although levels of nitrite plus nitrate in the serum
      did not differ between groups. There were significantly fewer NADPH-diaphorase
      positive cells in the parietal cortex and striatum of the EL mouse compared to
      the ddY controls. These results suggest that lower nitric oxide production in the
      brain may be related to the susceptibility of the EL mouse to convulsive
      seizures.

PMID- 10582521
TI  - Selective alterations of glycosaminoglycans synthesis and proteoglycan expression
      in rat cortex and hippocampus in pilocarpine-induced epilepsy.
AB  - Proteoglycans and glycosaminoglycans are elements of matrix. In the nervous
      system, glycosaminoglycans modulate neurite outgrowth and are co-receptors for
      growth factors playing a crucial role in cell differentiation and synaptogenesis.
      The receptor of protein tyrosine phosphatase beta (RPTPbeta) is a chondroitin
      sulphate proteoglycan which plays an important role in neural morphogenesis and
      axon guidance mechanisms. Pilocarpine-treated rats present status epilepticus,
      which is followed by a seizure-free period (silent), by a period of spontaneous
      recurrent seizures (chronic), and the hippocampus of these animals exhibits cell
      loss and mossy fiber sprouting. Thus, the synthesis of heparan sulphate and
      chondroitin sulphate and the time course of RPTPbeta immunoreactivity were
      studied in the hippocampus and cerebral cortex during these phases of pilocarpine
      induced epilepsy. The results showed decreased synthesis of heparan sulphate
      during the acute phase and an increased synthesis of chondroitin sulphate during
      the silent period in the cortex and hippocampus. In control rats RPTPbeta
      immunoreactivity was detected only in glial cells. After 6 h of status
      epilepticus the RPTPbeta immunoreactivity was no longer detectable in the glial
      cells in both tissues and intense staining became evident in the matrix,
      surrounding CA3 and dentate gyrus and piriform cortex neurones. In the silent and
      chronic periods RPTPbeta immunoreactivity was mainly detected in neuronal somata
      and fibers of neurones of hippocampus and cortex. These changes show a selective
      variation of synthesis and expression of glycosaminoglycans and RPTPbeta in
      relation to epilepsy suggesting a molecular interplay between glia and neurones
      during seizures.

PMID- 10582522
TI  - Effects of testosterone on the synaptology of the medial preoptic nucleus of male
      Japanese quail.
AB  - The medial preoptic nucleus (POM) of male Japanese quail is a sexually dimorphic
      testosterone-dependent structure that plays a key role in the activation of male
      sexual behavior. Both the total volume of the nucleus and the size of the
      dorsolateral neurons are decreased in gonadectomized males. Immunocytochemical
      studies have revealed a complex pattern of innervation: immunopositive fibers for
      several neuropeptides and neurotransmitters have been detected in the POM; some
      of them (e.g. vasotocin-immunoreactive fibers) are sexually dimorphic and
      testosterone-dependent To understand the anatomical bases of these testosterone
      dependent neurochemical changes, we performed an ultrastructural study of the POM
      neuropil in intact sexually mature, gonadectomized, or testosterone-treated
      gonadectomized males. A complex synaptic organization of the POM neuropil was
      observed in intact male quail reflecting the heterogeneity of the
      neurotransmitters and neuropeptides present in this nucleus. Changes in this
      organization were observed after the endocrine manipulations. The number of
      axosomatic synapses per cell body decreased after gonadectomy and was restored to
      the level observed in the intact group after the administration of testosterone.
      By contrast, no significant change was observed in the density of axodendritic
      and axospinal synapses after hormonal manipulations which suggests that the total
      number of synapses in the nucleus should be affected by testosterone (constant
      density in a changing total volume). The cross-sectional area of synaptic boutons
      was also decreased by castration and restored to intact level by testosterone.
      The action of testosterone on the activation of male copulatory behavior in
      gonadectomized birds is hence paralleled by an extensive rearrangement of
      neuropil in the POM.

PMID- 10582524
TI  - Pyramidal neuron types in field CA2 of the guinea pig.
AB  - The aim of the present study was to obtain information about the pyramidal neuron
      types in hippocampal field CA2 of the guinea pig. The apical and basal dendritic
      trees and the somata of CA2 pyramidal neurons were analyzed and quantified in
      Golgi-stained brains of adult guinea pigs of both sexes. Most of field CA2
      pyramidal neurons (92%) had a single apical shaft (monoapical neurons) and very
      few neurons (8%) had two apical shafts (biapical neurons). The monoapical neurons
      were subdivided into three classes on the basis of the pattern of their apical
      tree. Morphometric analysis showed differences among the different neuron classes
      in the number of apical and basal dendritic branches, in the spread of the apical
      tree, in shaft dimensions and in soma diameters. Several morphometric sex
      differences were also found for two of the three monoapical neuron classes and
      for the biapical neurons. The results demonstrate that field CA2 of the guinea
      pig contains four different types of pyramidal neurons and that also this small
      hippocampal field is characterized, like the other hippocampal fields, by the
      presence of a heterogeneous population of pyramidal neurons.

PMID- 10582523
TI  - Reduction in somatostatin and substance P levels and choline acetyltransferase
      activity in the cortex and hippocampus of the rat after chronic
      intracerebroventricular infusion of beta-amyloid (1-40).
AB  - The present study investigated the neurochemical and behavioural sequelae
      following chronic intracerebroventricular infusion of beta-amyloid (1-40) in
      rats. beta-amyloid was either infused intermittently via implanted cannulae on
      the day of operation and subsequently on postsurgical days 4, 7, 10, and 13
      (Experiment 1), or continuously using osmotic pumps for 14 days (Experiment 2).
      The same amount of beta-amyloid was delivered under both infusion regimes. In
      both experiments, beta-amyloid infusion led to severe deficits in the acquisition
      of a spatial reference memory task conducted on postoperative days 10 to 14. The
      animals were sacrificed on the postoperative day 15 for neurochemical analyses.
      These included radioenzymatic and radioimmunoassays, designed to determine
      choline acetyltransferase activity and the contents of neuropeptides
      (somatostatin, substance P, and neuropeptide Y), respectively. Experiment 2 also
      included solution-hybridisation-RNAase protection assay for preprosomatostatin
      mRNA quantification. There was a significant reduction in choline
      acetyltransferase activity and in the levels of substance P as well as
      somatostatin and preprosomatostatin mRNA in the cortical mantle of beta-amyloid
      treated rats, compared to controls in both experiments. Appreciable reductions in
      choline acetyltransferase activity and somatostatin level were also apparent in
      the hippocampus. In contrast, beta-amyloid infusion did not significantly affect
      the brain level of neuropeptide Y. The present study demonstrated that chronic
      infusion of beta-amyloid can lead to a reduction in the levels of selected
      neuropeptides resembling the pattern seen in Alzheimer's disease patients.

PMID- 10582525
TI  - Impact of a preceding striatal excitotoxic lesion and treatment with ciliary
      neurotrophic factor on striatal graft survival.
AB  - The survival of grafted embryonic striatal tissue, dissected from the lateral
      ganglionic eminence, depends on the status of the host striatum. We found
      significantly larger volumes of surviving graft tissue and of striatal-like
      tissue (P-zone) within the graft, when the host striatum had been subjected to an
      excitotoxic lesion prior to transplantation surgery. Concomitantly the numbers of
      surviving grafted cells, assessed in both cresyl violet-stained sections and in
      sections stained with an immunohistochemical marker for striatal neurons,
      increased as compared to when graft tissue was placed in an intact unlesioned
      striatum. Finally, we examined the impact of treatment of the donor tissue with
      ciliary neurotrophic factor (CNTF) on graft survival. CNTF has previously been
      shown to protect striatal neurons against excitotoxic insults both in vitro and
      in vivo, but it did not improve striatal graft survival when added to the cell
      suspension prior to implantation.

PMID- 10582526
TI  - Ontogeny of puromycin-sensitive and insensitive aminopeptidase activities in
      several subcellular fractions of the rat brain.
AB  - Puromycin-sensitive and insensitive aminopeptidase (aminopeptidase M) activities
      are measured in several subcellular fractions of the rat brain cortex and
      subcortex during the first postnatal month. Tyr-beta-naphthylamide has been used
      as substrate and 20 microM puromycin as selective inhibitor. We have found that
      puromycin-sensitive aminopeptidase activity increases twofold in the synaptosomal
      and mitochondrial fractions in the first 6-9 postnatal days, just during the
      period of axonal and dendritic growth. This enzyme also has significant age
      related changes in the nuclear fraction. The developmental pattern is different,
      depending on the subcellular fraction analyzed. Significant developmental changes
      of puromycin-insensitive aminopeptidase (aminopeptidase M) are only found in the
      myelinic and microsomal fractions and they are less significant than those found
      in the puromycin-sensitive aminopeptidase. It has been suggested that these
      enzyme activities could be involved in processes of cell proliferation,
      differentiation, and maturation.

PMID- 10582527
TI  - Odor-induced fast waves in the dentate gyrus depend on a pathway through
      posterior cerebral cortex: effects of limbic lesions and trimethyltin.
AB  - Previous research has shown that the odor of a variety of organic solvents and of
      components of the anal scent gland excretions of various predators will elicit a
      burst of fast waves of about 20 Hz in the olfactory bulb, pyriform cortex, and
      dentate gyrus of the rat. The present experiments show that large lesions of the
      caudal cerebral cortex, involving particularly the entorhinal and subicular
      cortices and the angular bundle, abolish the olfactory fast wave response of the
      dentate gyrus, but not the similar response of the olfactory bulb. In
      confirmation of previous work, such a lesion also abolishes an average evoked
      response elicited in the dentate gyrus by electrical stimulation of the olfactory
      bulb. Systemic treatment with the neurotoxin trimethyltin abolished the olfactory
      fast wave response in the olfactory bulb and both the olfactory fast wave and the
      olfactory evoked potential in the dentate gyrus. Large lesions of the amygdala or
      the septal nuclei did not eliminate either the dentate olfactory evoked potential
      or the odor-induced dentate fast wave response. However, the septal lesion
      reduced the amplitude of both spontaneous and odor-induced dentate fast wave
      activity. It is suggested that olfactory stimuli elicit 20 Hz dentate fast waves
      via a pathway from the olfactory bulb through the entorhinal cortex and, further,
      that cholinergic interneurons in the dentate gyrus may be essential to the
      dentate fast wave response.

PMID- 10582528
TI  - Neonatal asphyxia, definitive markers and hearing loss.
AB  - A study of 56 severely asphyxiated infants (8 hearing impaired and 46 normally
      hearing) was designed to identify specific markers associated with asphyxia which
      could be related to hearing loss. Sixteen variables, including such items as: one
      and five-minute Apgar scores, muscle tone, use of a ventilator, prolonged stay
      in the NICU, hypoxic-ischemic encephalopathy (HIE), other organ damage, and intra
      uterine growth retardation (IUGR) were considered. Results suggested four factors
      related to asphyxia which are often found in the presence of hearing loss, but
      none of these was considered a definitive marker or predictor of such a
      disability. A combination of HIE, seizures, associated organ damage and IUGR
      should be considered a strong marker for the probability of a sensorineural
      hearing loss.

PMID- 10582529
TI  - Neonatal hearing screening with transient evoked otoacoustic emissions: a
      learning curve.
AB  - The present paper reports on the implementation of a neonatal hearing screening
      programme in a private hospital in Belgium. A maternity-based neonatal hearing
      screening project with transient evoked otoacoustic emissions (TEOAEs) was
      started in 1993. The cost of the test was not covered by the public health
      insurance, so the parents had to pay the full cost for screening their child
      (approximately 30 Euro). Since 1993 the programme strategies have been changed on
      several occasions to improve the quality and efficacy. A retrospective analysis
      was performed on: (1) the test pass rate; (2) the coverage; and (3) the number of
      children who become 'Lost to follow-up' after failing the initial test. The data
      show a steady learning curve with a time course of several years. They also
      demonstrate that it is worthwhile and feasible to run a high-quality screening
      programme in a private establishment.

PMID- 10582530
TI  - The acoustic reflex threshold: not predictive for loudness perception in normally
      hearing listeners.
AB  - The working hypothesis of an ongoing study is that the quick and reliable
      procedure of acoustic reflex threshold (ART) determination in conjunction with
      measurements of HTL may yield accurate estimates of loudness. The aim of this
      study was to investigate whether differences in loudness in normally-hearing
      subjects are reflected in the ARTs and to collect normal material with respect to
      pure-tone elicited ART and loudness categories. Categorical loudness scaling
      (CLS) and ART measurements were performed at frequencies of 0.5, 1, 2 and 4 kHz
      in 60 normally-hearing subjects (HTL<20 dB HL, 26 males, 34 females, aged 21-63
      years) with no history or sequelae of middle ear disease. Subjects reporting
      disturbing tinnitus were excluded. The results show that the ART is not a
      predictor of individual loudness perception for normally-hearing subjects. Using
      a numerical scale (HTL=0, 'very soft'=5, 'soft'=15, 'OK'=25, 'loud'=35, 'very
      loud'=45 and 'too loud'=50) loudness for pure tones grows almost linearly at
      approximately 0.4 arbitrary loudness units per dB below the 'loud' category.
      Above the 'loud' category the slope is around 1 unit per dB. The median ART was
      85 dB HL at frequencies of 0.5, 1, 2 and 4 kHz. No differences in loudness
      perception across frequencies were found.

PMID- 10582531
TI  - The relationship between the acoustic reflex threshold and levels of loudness
      categories in hearing-impaired listeners.
AB  - When applied as a tool for hearing aid fitting, categorical loudness scaling
      (CLS) is time consuming and not feasible in all subjects. It is therefore
      desirable to use objective measures for accurate prediction of loudness
      categories among hearing-impaired individuals. The present study aimed at
      exploring whether loudness perception at the ART is constant with varying hearing
      threshold. Seventy-five subjects with various degrees of hearing impairment,
      measurable acoustic reflex and normal middle ear function participated. The HTLs,
      ARTs and the levels of six loudness categories at frequencies 0.5, 1, 2 and 4 kHz
      were determined for all subjects. Loudness at the ART was found to be correlated
      with the amount of hearing loss. On the basis of these results, it is concluded
      that the ART cannot be used for accurate estimation of loudness in hearing
      impaired subjects.

PMID- 10582532
TI  - Separate and combined effects of a benzodiazepine (alprazolam) and noise on
      auditory brainstem responses in man.
AB  - Auditory brainstem responses (ABRs) were recorded in 60 male or female, anxious
      or anxiety-free university students, before and after separated or simultaneous
      intake of alprazolam and exposure to noise. A significant increase of the
      latencies of the ABRs was found when subjects took alprazolam. This effect is
      consistent with the presence of gamma-aminobutyric acid (GABA), one of the
      neurotransmitters at terminals of cochlear efferent fibres A significant increase
      of the latencies was observed after noise alone. In subjects taking alprazolam
      when they are exposed to noise, the effect of noise on the ABR latencies is
      reduced, but not abolished. The effects of alprazolam on the ABR are consistent
      with the presence of GABA in the medulla and pons. Significant effects of noise
      upon III-V and I-V intervals suggest that auditory 'fatigue' may involve a
      retrocochlear component. Differences due to sex appear to be abolished by
      anxiety.

PMID- 10582533
TI  - Contribution of click frequency bands to the human binaural interaction
      components.
AB  - The purpose of this study was to determine the contribution of click frequency
      bands (broad-band, >2000 Hz, <2000 Hz and <1000 Hz) to binaural interaction
      components (BICs) of the human auditory brainstem evoked potentials (ABEPs). The
      human BICs were studied by subtracting the potentials to binaural clicks from the
      algebraic sum of monaurally evoked potentials to either ear. Effective frequency
      bands were derived using clicks alone or clicks with ipsilateral or binaural
      masking noise, high- or low-pass filtered at different cut-off frequencies.
      Analysis included single-channel vertex-cervical spinous process VII derivation
      of BIC and ABEP, as well as estimating the single, centrally located dipole
      equivalent of the surface activity from three orthogonally positioned electrode
      pairs, using the three-channel Lissajous' trajectory (3-CLT) analysis. All BIC 3
      CLTs included three major components (labeled BdII, BeI, and BeII) approximately
      corresponding in latency to IIIn, V and VI ABEP peaks. All apex latencies of BIC
      3-CLT, except BeI, were longer in response to <2000 Hz and <1000 Hz (low
      frequency) effective clicks. Apex amplitude of components BeI and BeII of BIC 3
      CLT were smaller with low-frequency effective clicks than with broad-band or high
      frequency (>2000 Hz) clicks. We suggest that binaural interaction component BeI
      is mainly tuned to high frequencies, showing no frequency effect on latency, and
      decreasing in amplitude with decreasing click high frequency content. In
      contrast, BdII and BeII of the human BICs are evoked more synchronously by high
      frequency binaural inputs, but are also sensitive to low frequencies, increasing
      in latency according to the cochleotopic activation pattern. These differences
      between BIC components may reflect their roles in sound localization.

PMID- 10582534
TI  - Self-assessed hearing problems in Sweden: a demographic study.
AB  - A study of self-assessed hearing problems was performed comprising 48,680 Swedish
      inhabitants aged 16-84 years. The participants of the survey responded to
      personal interviews during the period 1986-1993. One of the questions in the
      interview concerned difficulties of hearing in background noise. The total
      prevalence of the reported hearing problems was 10.7 per cent, varying from 2.4
      per cent in the youngest age group to 30 per cent in the oldest. Men reported
      difficulties in hearing more often than women, except in the youngest age group.
      Hearing problems were more often reported by manual workers, unemployed and by
      those who had taken early retirement, than by non-manual employees and the self
      employed. Regional differences regarding hearing problems were observed. The
      prevalence of self-reported problems was lowest in metropolitan Stockholm (7.9
      per cent) and increased in the following order: other major cities (9.4 per
      cent), other cities (10.5 per cent), small population centres (12.5 per cent),
      agricultural areas (13.5 per cent) and sparsely populated forest areas (15 per
      cent). In summary, a number of factors related to ageing, socioeconomic status
      and domicile were related to self-assessed difficulties hearing a conversation.
      These factors obviously include determinants such as genetics, health status,
      gender-related differences, exposure to noise and possible conditioning effects
      of low-level noise exposure.

PMID- 10582535
TI  - First audiometric results with the Vibrant soundbridge, a semi-implantable
      hearing device for sensorineural hearing loss.
AB  - The Vibrant soundbridge is a semi-implantable hearing device. The implanted
      electromagnetic transducer is attached to the incus and it is linked by telemetry
      to the externally worn audio processor. In Nijmegen, this device has been applied
      to seven patients with moderate or severe sensorineural hearing loss (PTA between
      43 and 71 dB HL) who could not tolerate ear moulds. As the amplification of the
      device depends on the input level (amplifier with wide dynamic range
      compression), loudness scaling measurements were performed. The gain as a
      function of input level was determined from aided and unaided loudness growth
      curves. The mean gain was 21 dB at an input level of 40 dB SPL. The mean gain
      decreased to 5 dB at an input level of 90 dB SPL. Measured gain values were lower
      than target values prescribed by the FIG6 method, mainly however for the low
      frequency range and for low-level sounds. It was concluded that this device is
      very promising for patients who cannot tolerate an ear mould.

PMID- 10582536
TI  - Effectiveness of a single and a repeated screen for hearing loss in the elderly.
AB  - The aim of this study was to assess the value of repeated audiometric screens
      offered to elderly in general practice. In 1991, an audiometric screen was
      performed on 660 participants, aged 60 years and over, enlisted in one general
      practice near Rotterdam, the Netherlands. We repeated the audiometric screen 5
      years later in 80.2% (405/505) of the eligible participants of the first screen.
      After the first screen, 24.3% of those who were hearing impaired had discussed
      this with their general practitioner, 21.5% were referred to a specialist in
      otolaryngology and 12.1% had been prescribed a hearing aid. The effect of the
      repeated screen was lower as only 7.3% of the hearing impaired participants
      received a hearing aid. Efforts to screen on hearing loss will be fruitless and
      can best be avoided by general practitioners unless strategies are developed to
      increase the use of hearing aids after a positive screening result.

PMID- 10582538
TI  - Changes in serum apolipoprotein concentrations after L-thyroxine therapy in
      infants with congenital hypothyroidism.
AB  - To further characterize the impact of thyroid hormones on the serum lipid
      profile, we studied serum apolipoproteins in infants with congenital
      hypothyroidism before and after L-thyroxine (L-T4) replacement therapy. Serum
      high-density lipoprotein cholesterol (HDLC) decreased after L-T4 therapy. Total
      cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) levels did not
      change significantly after therapy. Two months after L-T4 replacement therapy,
      serum apolipoprotein A-I (apo A-I), C-III, and E declined and apo B increased
      significantly. No significant changes were observed for serum concentrations of
      apo A-II and C-II after L-T4 substitution. We conclude that in infants, thyroid
      hormone reduces serum levels of apo A-I, the principal protein component of HDLC,
      and this may contribute to the decline of serum HDLC concentrations after L-T4
      replacement therapy.

PMID- 10582537
TI  - Effect of pregnancy on insulin metabolism in spontaneously hypertensive rats.
AB  - Several lines of evidence suggest that insulin resistance and/or hyperinsulinemia
      may play an important role in the pathogenesis of hypertension. We studied the
      effect of pregnancy on insulin metabolism in spontaneously hypertensive rats
      (SHRs) and in Wistar-Kyoto rats (WKYs) as a control. Pregnancy markedly reduced
      blood pressure in both strains of rats, but insulin resistance as determined by
      the hyperinsulinemic glucose clamp (10 mU/kg/min) increased in SHRs and was
      unchanged in WKYs. The plasma insulin response to an intravenous glucose
      challenge in SHRs was low and did not change with pregnancy. Therefore, it is
      suggested that the regulation of blood pressure in these animals is linked to an
      unknown factor rather than to insulin resistance and hyperinsulinemia. Fetuses
      from SHRs had a lower body weight and plasma glucose level and higher plasma
      insulin and pancreatic insulin levels than those from WKYs. Thus, fetal
      hyperinsulinemia in the SHR may be linked to the development of hypertension in
      adulthood.

PMID- 10582539
TI  - Cochlear dysfunction in type 2 diabetes: a complication independent of neuropathy
      and acute hyperglycemia.
AB  - The effects of type 2 diabetes on evoked otoacoustic emissions (e-OAEs) elicited
      by clicks in subjects with normal hearing and the involvement of the central
      (CNS) and peripheral nervous system and acute hyperglycemia were investigated. In
      study 1, 110 type 2 diabetic patients and 106 control subjects matched for age
      and gender were investigated by e-OAEs. Central and peripheral neuropathy were
      evaluated respectively by auditory brainstem responses (ABRs) and according to
      San Antonio Consensus Conference criteria. In study 2, 10 healthy and 10 type 2
      diabetic men matched for age, all with normal e-OAEs, underwent a 5-hour
      hyperglycemic clamp study. e-OAE tests were performed before and during the
      hyperglycemic clamp. In study 1, e-OAEs were impaired in 51.8% (57 of 110) of the
      diabetic subjects, in comparison to 4.7% (five of 106) of the control group (P <
      .0001). Diabetics with impaired e-OAEs (e-OAEs-), in comparison to those with
      normal e-OAEs (e-OAEs+), were older (51.0+/-5.8 v 45.1+/-6.0 years, P < .001),
      had diabetes longer (11.5+/-4.4 v 7.0+/-3.9 years, P < .001), achieved poorer
      metabolic control as judged by hemoglobin A1c ([HbA1c] 6.9%+/-0.4% v 6.5%+/-0.3%,
      P < .001), and had more peripheral neuropathy (46% v 23%, P < .02). No difference
      was observed between e-OAEs- and e-OAEs+ subjects for retinopathy or nephropathy.
      Nevertheless, when the duration of diabetes was corrected by multiple regression
      analysis, the correlation between sensorineural damage and peripheral neuropathy
      lost significance (P = .12). Diabetic groups (e-OAEs+ and e-OAEs-) showed greater
      latency in waves I, III, and V and greater interwave latency for waves I to V
      than the control group, but there was no significant difference in ABRs between e
      OAEs+ and e-OAEs- subjects. In study 2, there were no significant changes in e
      OAE intensities compared with basal values during the entire hyperglycemic clamp
      in either type 2 diabetic or control subjects. No difference was observed between
      the two groups at each time of the clamp. Thus, type 2 diabetic subjects show a
      higher rate of compromised e-OAEs than healthy individuals. The e-OAE dysfunction
      does not associate with either an injury to the auditory nervous pathway or
      diabetic microvasculopathy. The apparent interference of peripheral neuropathy in
      e-OAEs loses significance when corrected for the duration of diabetes.

PMID- 10582540
TI  - Verapamil acute administration: a new dynamic test in hyperprolactinemic states.
AB  - We studied the effect of acute administration of the calcium-channel blocker
      verapamil (VER) in 27 patients with tumoral hyperprolactinemia ([THPRL]
      prolactinomas and pseudoprolactinomas). We also studied the effect of VER in
      seven patients with idiopathic hyperprolactinemia (IHPRL) and a small group of
      patients with normal prolactin (PRL) levels and minimal incidental anomalies
      shown by magnetic resonance imaging (MRI). The study was performed on 2 separate
      days: on the first day, all subjects received VER, and on the second they
      received placebo. Acute administration of VER evoked a remarkable increase in
      serum PRL in IHPRL (as in normal healthy subjects used as controls), but no
      response was shown in THPRL, with no overlap between the two conditions. Acute
      administration of VER stimulated PRL secretion in patients with minimal
      incidental lesions shown by MRI; however, this increase was smaller in patients
      whose PRL level consistently reached the upper-normal limit. Although the meaning
      of such minimal anomalies shown by MRI is unknown, this could suggest that the
      test is precociously altered. To further elucidate the action of VER on
      lactotropes, we investigated the effect of VER given intravenously (IV) and
      compared different oral formulations in healthy subjects. Our data show that the
      VER test is effective in distinguishing between THPRL and IHPRL, but
      unfortunately, like other tests, it is not able to individualize patients in whom
      THPRL is the result of diminished dopaminergic tone (pseudoprolactinoma). From a
      pathophysiological point of view, calcium influx would appear less important in
      PRL regulation in chronic disorders of PRL secretion. VER given IV did not
      stimulate PRL release in normal subjects. This suggests that IV administration
      could produce a peak with an inadequate duration or that oral formulations may
      act also by metabolites formed on first-pass metabolism in the liver.

PMID- 10582541
TI  - Effects of insulin and metformin on glucose metabolism in rat vascular smooth
      muscle.
AB  - Glucose metabolism in vascular smooth muscle cells (VSMCs) is characterized by
      substantial lactate production even in fully oxygenated conditions. Insulin and
      metformin, an insulin-sensitizing agent, have direct effects on the vascular
      tissue metabolism. We investigated whether insulin or metformin can induce a
      switch in VSMC glucose metabolism from lactate production to pyruvate oxidation,
      by measuring lactate oxidation as determined by the conversion of [1-14C]-D,L
      lactate to [1-14C]-pyruvate and subsequent oxidation to acetyl coenzyme A and
      14CO2 by pyruvate dehydrogenase (PDH). Lactate oxidation was measured in control
      rat aortic cultured VSMCs incubated for 30 minutes in media with and without
      additional glucose compared with VSMCs cultured in the presence of insulin or
      metformin. The addition of glucose to VSMCs decreased lactate oxidation (4.6+/
      1.7 v 9.6+/-2.4 pmol/cell/min, P < .001). In the absence of additional glucose,
      metformin decreased lactate oxidation in VSMCs compared with controls (4.9+/-1.4
      v 9.6+/-2.4 pmol/cell/min, P < .01). Metformin in the presence of glucose caused
      the greatest decline in lactate oxidation (2.5+/-0.4 pmol/cell/min, P < .001). In
      contrast to the effects of metformin, insulin increased lactate oxidation both
      with (12.9+/-1.5 pmol/cell/min, P < .001) and without (17.9+/-4.4, P < .01)
      additional glucose. This suggests that insulin facilitates VSMC utilization of
      lactate as a source of pyruvate and energy production even during noncontractile
      periods.

PMID- 10582542
TI  - Net mass transfer of plasma cholesteryl esters and lipid transfer proteins in
      normolipidemic patients with peripheral vascular disease.
AB  - The role of plasma cholesteryl ester transfer and lipid transfer proteins in
      atherosclerosis is unclear. Recent data suggest both antiatherogenic and
      atherogenic properties for cholesteryl ester transfer protein (CETP). The overall
      effect of CETP on atherosclerosis may thus vary depending on individual lipid
      metabolism. To test whether lipid transfer parameters are of importance even in
      patients without major lipid risk factors for atherosclerosis, CETP mass and
      activity, net mass transfer of cholesteryl esters between endogenous lipoproteins
      (CET), and phospholipid transfer protein (PLTP) activity were determined in
      plasma from 18 normolipidemic male patients with peripheral vascular disease and
      21 controls. Furthermore, lecithin: cholesterol acyltransferase (LCAT) activity
      was tested. The results show that CETP mass, CETP activity, and LCAT activity are
      not different between patients and controls. However, specific CETP activity
      (CETP activity/CETP mass) is lower in the patients (P < .02). On the contrary,
      higher CET is observed in patients' plasma (P < .001). Increased plasma PLTP
      activity (P = .052) is demonstrable in the patients. If the data of all subjects
      are combined, CET correlates positively with triglycerides ([TG], r = .45, P <
      .001) and with PLTP activity (r = .32, P < .05) but negatively with specific CETP
      activity (r = -.37 P < .05). CET and specific CETP activity remain significantly
      different in TG-matched patients and controls and are more strongly interrelated
      (r = -.71, P < .001), suggesting a higher and selective influence of lipid
      transfer inhibitor(s) on CET and CETP activity in the patients. CET allows the
      best discrimination between patients and controls in univariate and multivariate
      analysis. Eighty-eight percent of the subjects are correctly classified by CET as
      a single parameter. The results suggest that increased CET in the patients may
      reflect atherogenic alterations in TG metabolism and/or in lipid transfer protein
      activities despite normal fasting lipoprotein levels.

PMID- 10582543
TI  - Association of beta3-adrenergic receptor gene polymorphism with insulin
      resistance in Japanese-American men.
AB  - The Trp64Arg variant of the beta3-adrenergic receptor (beta3-AR) gene is
      relatively common in Japanese people. We hypothesized that this variant may be
      associated with obesity and insulin resistance when combined with a westernized
      lifestyle. To test this hypothesis, we investigated the relationships between the
      beta3-AR gene variant and obesity and insulin resistance in Japanese-American
      men, who are known to have a higher prevalence of type 2 diabetes mellitus (DM).
      The subjects were 152 Japanese-American men living in Hawaii, 83 with normal
      glucose tolerance (NGT), 40 with impaired glucose tolerance (IGT), and 29 with
      DM. The frequency of the Trp64Arg allele of the beta3-AR gene was 0.18, almost
      identical to that of the mainland Japanese. The prevalence of the Trp64Arg allele
      was 30.1% in NGT, 35.0% in IGT, and 41.4% in DM subjects (nonsignificant). The
      Trp64Arg variant of the beta3-AR gene showed no significant relationship with
      obesity or insulin resistance in NGT subjects. However, fasting and 2-hour
      insulin levels and insulin resistance as determined by homeostasis model
      assessment (HOMA) were significantly higher in IGT subjects with the Trp64Arg
      variant. Although indices of obesity were the same in IGT subjects with and
      without the Trp64Arg variant, differences in the body mass index (BMI) and
      percent body fat between NGT and IGT subjects were greater for individuals with
      the Trp64Arg variant. Thus, there is an association between the Trp64Arg variant
      of the beta3-AR gene and insulin resistance in Japanese-Americans with IGT.

PMID- 10582544
TI  - Changes in fat cell size and in vitro lipolytic activity of abdominal and gluteal
      adipocytes after a one-year cross-sex hormone administration in transsexuals.
AB  - We prospectively studied the effects of cross-sex hormone administration on fat
      cell size and in vitro lipolytic activity in subcutaneous abdominal and gluteal
      fat biopsies obtained from 19 male-to-female (M-F) transsexuals and 17 female-to
      male (F-M) transsexuals. The amount of subcutaneous fat at the abdominal and
      gluteal levels was quantified with the use of magnetic resonance imaging (MRI).
      Before cross-sex hormone administration, M-F transsexuals had less subcutaneous
      fat with smaller fat cells compared with F-M transsexuals, with a higher baseline
      in vitro lipolytic activity expressed as glycerol release per milligram of
      triglyceride (TG) in the abdominal region (P < .05). Before cross-sex hormone
      treatment, no differences in lipolytic activity stimulated with arterenol (ART),
      isoproterenol (ISO), or ISO + insulin (INS) were observed between groups or
      regions. After a 1-year treatment with estrogens and antiandrogens in M-F
      transsexuals, subcutaneous fat areas on MRI and fat cell size were increased (P <
      .001) and reductions were observed in the basal lipolytic activity of gluteal and
      abdominal fat biopsies (P < .05). Following administration of testosterone to F-M
      transsexuals, subcutaneous fat and fat cell size at the gluteal and abdominal
      depots were decreased (P < .01) and basal lipolysis was increased significantly
      at the abdominal level (P < .05) but not at the gluteal level. In both M-F and F
      M transsexuals, no effect of sex hormone administration was observed on
      stimulated lipolytic activities. In conclusion, regional sex differences in the
      amount of subcutaneous fat, adipocyte size, and in vitro basal lipolytic activity
      were demonstrated that could be largely reversed by cross-sex hormone treatment
      in adult subjects, providing evidence for their dependence on the sex steroid
      milieu.

PMID- 10582545
TI  - Leucine kinetics in reference to the effect of the feeding mode as three discrete
      meals.
AB  - In a recent study, we observed that the 24-hour leucine oxidation measured when
      three equal meals providing a generous intake of leucine (approximately 90 mg x
      kg(-1) x d(-1)) are eaten during the day is 16% lower (P < .01) than that for the
      same diet given as 10 hourly, equal meals. We hypothesized that the pattern of
      meal intake at a lower level of dietary leucine would affect the 24-hour rate of
      leucine oxidation and possibly improve the retention of dietary leucine. A total
      of 11 healthy adults participated in this investigation. The daily leucine intake
      was 182 micromol x kg(-1) x d(-1) (38 mg x kg(-1) x d(-1)) given with an L-amino
      acid diet. All subjects received three discrete meals daily for 6 days prior to a
      24-hour intravenous (IV) tracer infusion of L-[1-13C]-leucine on day 7 (study 1).
      Four of these subjects participated in two additional studies of similar design.
      Study 2 involved giving [1-13C]-leucine as a constant IV infusion together with
      tracer added to the amino acid mixture at each meal time. In study 3, subjects
      received the three meals with added [1-13C]-leucine tracer while [2H3]-leucine
      was given as a constant IV infusion. Total leucine oxidation in studies 1 and 2
      was 238+/-66 and 231+/-85 micromol x kg(-1) x d(-1), respectively. Leucine
      balance was positive, amounting to 18% of the total (diet + tracer) intake. The
      estimated mean nitrogen balance was +8 mg x kg(-1) x d(-1). Leucine oxidation was
      higher (P < .01) for breakfast than for the lunch meal. This difference was
      associated with lower insulin and higher plasma leucine concentrations at
      breakfast versus lunch periods. The results from study 3 suggest that the higher
      rate of leucine oxidation observed at breakfast as compared with lunch is not due
      to a difference in the immediate splanchnic fate of absorbed leucine from each
      meal. In comparison to our previous small frequent-meal studies, the pattern of
      meal feeding influences overall leucine utilization at both generous and limiting
      leucine intakes. Hence, it is possible that the pattern of meal feeding may
      affect estimations of amino acid requirements using the tracer-balance approach.
      Longer-term dietary studies will be needed to establish whether and the extent to
      which this is so.

PMID- 10582546
TI  - Insulin secretion in growth hormone-deficient adults: effects of 24 months'
      therapy and five days' acute withdrawal of recombinant human growth hormone.
AB  - Beta-cell function in growth hormone (GH)-deficient (GHD) adults is poorly
      documented. Beta-cell function was therefore studied in 10 GHD adults (age, 40+/
      3 years; weight, 79.3+/-4.8 kg; body mass index [BMI], 27.5+/-1.3 kg x m(-2))
      before and after 6- and 24-month recombinant human GH (rhGH) therapy (0.24 IU x
      kg(-1) x wk(-1)) compared with 10 age-, sex-, weight-, and BMI-matched control
      subjects. With rhGH therapy, fat-free mass (FFM) increased (48.2+/-4.9, 52.5+/
      4.8, and 59+/-6.8 kg, respectively) and fat mass (FM) decreased (33.8%+/-2.8%,
      28.0%+/-3.0%, and 29.4%+/-2.5%, respectively), as did serum cholesterol. Oral
      glucose tolerance initially deteriorated at 6 months, but improved toward the
      control value by 24 months. Fasting insulin (FI) increased significantly, as did
      the acute insulin response to oral glucose (deltaAIR(OGTT)/deltaG) at 30 minutes
      (FI: pretreatment 9.8+/-0.8, 6 months, 14.0+/-1.8, 24 months 12.5+/-1.6 v control
      11.4+/-1.9 mU x L(-1); deltaAIR(OGTT)/deltaG: pretreatment 201+/-24, 6 months
      356+/-41, 24 months 382+/-86 v control 280+/-47 mU x mmol(-1)). However, the
      acute insulin response to intravenous (IV) glucose (AIR(G)) and IV glucagon at
      euglycemia and hyperglycemia did not change with rhGH therapy and were similar to
      the control group values. Importantly, the expected reciprocal relationships (as
      observed for the control group) between the various insulin secretory parameters
      and insulin sensitivity (SI) either were not present or were statistically weak
      in GHD subjects, despite the 35% decrease in SI by 24 months of rhGH therapy. In
      particular, over time, there was an attenuation of insulin secretion with respect
      to the ongoing insulin resistance with rhGH therapy, particularly for AIR(G) at
      24 months. After 5 days of rhGH withdrawal, insulin secretion decreased and SI
      improved in GHD subjects. It is concluded that the current long-term rhGH
      treatment regimens appear to impact on insulin secretion such that the normal
      relationships between insulin secretion and SI are altered despite the favorable
      impact on body composition and serum lipid profiles.

PMID- 10582547
TI  - Release of proinflammatory cytokines by mitogen-stimulated peripheral blood
      mononuclear cells from critically ill multiple-trauma victims.
AB  - This study investigated the alterations in circulating proinflammatory cytokines
      and cytokine production by peripheral blood mononuclear cells (PBMCs) in response
      to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) after severe trauma.
      Plasma and PBMCs were collected from 17 severely injured trauma patients and 10
      healthy subjects. Plasma was stored at -80 degrees C and analyzed for cytokines.
      Isolated PBMCs from each subject were stimulated with LPS or PHA and incubated at
      5% CO2 for 24 hours. Supernatants were collected and analyzed for cytokines.
      There was no significant change in the plasma concentration of free TNF-alpha and
      IL-1beta between healthy subjects and trauma patients. Plasma IL-6, total TNF
      alpha, and total IL-1beta were significantly increased in severely traumatized
      patients compared with healthy control subjects. PBMCs from trauma patients
      produced higher levels of TNF-alpha in response to LPS but it showed no
      significant change in IL-1beta and IL-6 production in response to PHA or LPS in
      comparison to PBMCs from control subjects. We conclude that severe trauma results
      in a significant increase in plasma proinflammatory cytokine IL-6. Free TNF-alpha
      and IL-1beta in plasma remain at levels comparable to those in uninjured
      controls, while plasma free IL-6 levels in trauma patients remain high. Serious
      injury is associated with an enhanced production of TNF-alpha by PBMCs stimulated
      with LPS.

PMID- 10582548
TI  - Effect of dietary fish and exercise training on urinary F2-isoprostane excretion
      in non-insulin-dependent diabetic patients.
AB  - Despite the potential benefits of dietary treatment with marine omega3 fatty
      acids in cardiovascular disease, there remains concern with respect to their
      potential for increased lipid peroxidation. Thus far, data from in vivo studies
      are inconclusive. Increased lipid peroxidation has also been associated with
      acute exercise in some studies, but the methods have been nonspecific. The
      quantitation of F2-isoprostanes provides a more reliable and useful assessment of
      in vivo lipid peroxidation. We therefore aimed to assess the independent and
      combined effects of dietary omega3 fatty acids and aerobic exercise training on
      urinary F2-isoprostane levels in dyslipidemic non-insulin-dependent diabetic
      (NIDDM) patients. In a randomized controlled trial, 55 untrained, sedentary,
      dyslipidemic NIDDM patients were randomly assigned to a low-fat diet (30% of
      daily energy) with or without one daily fish meal (3.6 g omega3 fatty acids per
      day) and further randomized to either a moderate (55% to 65% maximal oxygen
      consumption [VO2max]) or light (heart rate <100 bpm) exercise training program
      for 8 weeks. Twenty-four-hour urine samples from 49 subjects were collected for
      measurement of urinary F2-isoprostanes by gas chromatography-mass spectrometry
      before and after intervention. The fish diets reduced urinary F2-isoprostanes by
      830+/-321 pmol/24 h (20%, P = .013) relative to the low-fat diet alone. This
      effect was independent of age, gender, and body weight change. Moderate exercise
      training did not alter F2-isoprostanes. These findings show that, at least in the
      short-term, exercise had no effect, whereas the inclusion of regular fish meals
      as part of a low-fat diet reduced in vivo lipid peroxidation in dyslipidemic
      NIDDM patients. This response could further complement the known benefits of
      omega3 fatty acids and exercise favoring a reduced cardiovascular risk in
      diabetic patients.

PMID- 10582549
TI  - Functional electrical stimulation exercise increases GLUT-1 and GLUT-4 in
      paralyzed skeletal muscle.
AB  - The study purpose was to determine the effect of functional electrical
      stimulation (FES)-leg cycle ergometer training (30 minutes on 3 d/wk for 8 weeks)
      on the GLUT-1 and GLUT-4 content of paralyzed skeletal muscle. Biopsy samples of
      vastus lateralis muscle were obtained pre- and post-training from five
      individuals with motor-complete spinal cord injury ([SCI] four men and one woman
      aged 31 to 50 years, 3 to 25 years postinjury involving C5-T8). Western blot
      analysis indicated that GLUT-1 increased by 52% and GLUT-4 increased by 72% with
      training (P < .05). This coincided with an increase in the muscle oxidative
      capacity as indicated by a 56% increase in citrate synthase (CS) activity (P <
      .05) and an improvement in the insulin sensitivity index as determined from oral
      glucose tolerance tests (P < .05). It is concluded that FES endurance training is
      effective to increase glucose transporter protein levels in paralyzed skeletal
      muscle of individuals with SCI.

PMID- 10582550
TI  - Depletion of total antioxidant capacity in type 2 diabetes.
AB  - The purpose of the study was to examine the relationship between antioxidant
      depletion, glycemic control, and development of chronic complications in a
      controlled population of type 2 diabetic patients. Fifty age-matched type 2
      diabetic patients receiving sulfonylureas but not insulin treatment were screened
      and assigned to two groups based on the presence or absence of proteinuria. A
      third group of normal subjects without diabetes were also enrolled in the study.
      All subjects in the three groups were Egyptians who were matched for body weight,
      and the two diabetic groups were also age-matched. Plasma glucose and
      fructosamine levels were higher in the two groups of diabetic patients versus the
      control group, but lipid peroxide levels were higher only in the patients with
      proteinuria. Compared with the control group, the total antioxidant capacity was
      depleted in the two diabetic groups, but the depletion was more severe in
      patients with proteinuria. Thus, the mean Trolox equivalent antioxidant capacity
      (TEAC) of the control group was 2.7+/-0.45, versus 1.7+/-0.5 (P < .001) in the
      patients without proteinuria. Furthermore, the TEAC measured in patients with
      proteinuria, who also had more diabetic complications, was lower (1.4+/-0.5, P <
      .001) than the TEAC in patients without urinary protein. In conclusion, a
      depletion of the total antioxidant capacity is associated with a higher incidence
      of diabetic complications.

PMID- 10582551
TI  - Differential effects of troglitazone and D-chiroinositol on glucosamine-induced
      insulin resistance in vivo in rats.
AB  - Troglitazone and D-chiroinositol have been shown to exert antidiabetic effects by
      either potentiating or mimicking insulin action. We studied whether pretreatment
      with these compounds can prevent the deleterious effects of glucosamine on
      insulin action that may play an important role in hyperglycemia-induced insulin
      resistance. Normal Wistar rats were pretreated with troglitazone (100 mg/kg/d), D
      chiroinositol (100 mg/kg/d), or placebo (saline) for 7 days. Glucosamine (50
      micromol/kg/min) was then infused for 210 minutes, and a euglycemic glucose clamp
      was performed during the last 120 minutes. Pretreatment with troglitazone or D
      chiroinositol had no effect on fasting plasma glucose or insulin or basal hepatic
      glucose output (HGO). Under the euglycemic-hyperinsulinemic (956+/-93 pmol/L)
      clamp condition, HGO in glucosamine-infused placebo-treated rats was not
      suppressed, but instead was increased over the basal level, indicative of hepatic
      insulin resistance. In contrast, HGO failed to increase during glucosamine
      infusion in rats pretreated with troglitazone but was not normally suppressed.
      This may indicate a partial improvement in the hepatic insulin resistance. D
      Chiroinositol pretreatment had no effect on the glucosamine-induced increase in
      HGO. The glucose disposal rate (GDR) was 25% lower in rats infused with
      glucosamine versus saline-infused rats (25.5+/-2.5 v 34.1+/-2.0 mg/kg/min),
      indicative of peripheral insulin resistance. Pretreatment with D-chiroinositol
      (34.5+/-2.3 mg/kg/min) prevented the glucosamine-induced decrease in the GDR,
      indicating an improvement in peripheral insulin resistance. Troglitazone (25.2+/
      3.3 mg/kg/min) was without effect. In conclusion, (1) in normal control rats,
      glucosamine infusion induced hepatic and peripheral insulin resistance; (2) D
      chiroinositol, but not troglitazone, pretreatment prevented glucosamine-induced
      peripheral insulin resistance; and (3) troglitazone, but not D-chiroinositol,
      partially blocked the glucosamine-induced hepatic insulin resistance. D
      Chiroinositol may provide a novel pharmacological approach to hexosamine-induced
      peripheral insulin resistance.

PMID- 10582552
TI  - Interrelationships of spontaneous growth hormone axis activity, body fat, and
      serum lipids in healthy elderly women and men.
AB  - Aging is associated with decreased growth hormone (GH) secretion and plasma
      insulin-like growth factor-I (IGF-I) levels, increased total and abdominal fat,
      total and low-density lipoprotein (LDL) cholesterol, and triglycerides, and
      reduced high-density lipoprotein (HDL) cholesterol. Similar changes in lipids and
      body composition occur in nonelderly GH-deficient adults and are reversed with GH
      administration. To examine whether GH/IGF-I axis function in the elderly is
      related to the lipid profile independently of body fat, we evaluated GH
      secretion, serum IGF-I and IGF binding protein-3 (IGFBP-3) levels, adiposity via
      the body mass index (BMI), waist to hip ratio (WHR), dual-energy x-ray
      absorptiometry (DEXA), and magnetic resonance imaging (MRI), and circulating
      lipids in 101 healthy subjects older than 65 years. Integrated nocturnal GH
      secretion (log IAUPGH) was inversely related (P < .005) to DEXA total and
      abdominal fat and MRI visceral fat in both genders. Log IAUPGH was inversely
      related to visceral fat in women (P < .005) and men (P < .0001), but was not
      significantly related to total fat in either gender. In women, log IAUPGH was
      related inversely to total and LDL cholesterol and positively to HDL cholesterol
      (P < .008). In men, log IAUPGH was inversely related to total cholesterol and
      triglycerides (P < .005). In women, HDL cholesterol was inversely related to the
      WHR (P < .005). In men, triglycerides were positively related (P < .001) to the
      WHR and DEXA abdominal and MRI visceral fat. Multivariate regression revealed log
      IAUPGH, but not DEXA total body fat, to be an independent determinant of total (P
      < .001 for women and P = .01 for men) and LDL (P < .007 and P = .05) cholesterol
      in both sexes and of HDL cholesterol (P < .005) and triglycerides (P < .03) in
      women. Log IAUPGH, but not DEXA abdominal fat, was related to total (P < .005 and
      P < .03) and LDL (P < .03 and P = .05) cholesterol in both genders and to HDL in
      women (P < .05). Log IAUPGH, but not MRI visceral fat, was related to total
      cholesterol (P < .03 and P = .05) in women and men. Age, IGF-I, and IGFBP-3 were
      not significantly related to any body fat or lipid measures, except for a
      positive correlation of IGF-I with triglycerides in men. Thus, endogenous
      nocturnal GH secretion predicts total, LDL, and HDL cholesterol levels
      independently of total or abdominal fat, suggesting that it is an independent
      cardiometabolic risk factor in healthy elderly people.

PMID- 10582553
TI  - Characterization of L-leucine transport system in brush border membranes from
      human and rabbit small intestine.
AB  - The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are
      beneficial to catabolic patients by improving hepatic protein synthesis and
      nitrogen economy, yet their transport from the intestinal lumen is not well
      defined. The leucine transport system in human and rabbit small intestine was
      characterized using a brush border membrane vesicle (BBMV) model. Sodium and pH
      dependence and transport activity along the longitudinal axis of the small bowel
      were determined. Transport kinetics and inhibition profiles were defined.
      Although previous studies in other tissues show leucine transport to be mostly a
      Na+-independent process, our studies show that leucine transport is a
      predominantly Na+-dependent process occurring mainly via a single saturable pH
      independent transporter resembling system B0 in the intestine. This system B0
      transporter demonstrates stereoisomeric specificity. There is also a minor Na+
      independent transport component (<6% in rabbits). Leucine uptake in both rabbits
      and humans is significantly greater than the uptake of other clinically relevant
      nutrients such as glutamine. In the rabbit, ileal leucine transport is
      significantly greater than jejunal uptake. While the affinities of the human and
      rabbit transporters are similar, the rabbit transporter has greater carrier
      capacity (maximal transport velocity [Vmax]). These findings suggest that the
      transport of leucine in the gut mucosa is significantly different from the
      transport in other tissues.

PMID- 10582555
TI  - Aging changes tissue-specific glucose metabolism in rats.
AB  - This study defines the tissue-specific changes in glucose metabolic flux that
      occur over time prior to the onset of whole-body insulin resistance in rats. Rats
      at 6 weeks of age were maintained on a high-carbohydrate diet for either 12 or 26
      weeks, at which time euglycemic clamps were performed at basal and
      midphysiological plasma insulin concentrations. Following death, insulin
      sensitive tissues were excised and frozen until assayed for the rate of glucose
      uptake, glycogenesis, and lipogenesis. Glucose metabolic flux, particularly
      through glycogenesis, was reduced between 18 and 32 weeks of age in all tissues
      except the adipose tissues. For example, the rate of glycogenesis in liver at 18
      weeks (117+/-10 nmol glucose incorporated/min/g) was more than double that
      observed at 32 weeks (54+/-8 nmol glucose incorporated/min/g, P < .01). Despite
      this, animals in the 32-week group displayed no impairment in whole-body glucose
      disposal, due to compensatory glucose uptake in white adipose tissue (WAT) and
      increased glucose flux through lipogenesis in brown adipose tissue (BAT). At 32
      weeks, the rate of glucose uptake in WAT (85.0+/-5.6 nmol 2-deoxy-D-glucose
      phosphate accumulated/min/g) was approximately double that at 18 weeks (46.6+/
      5.6 nmol 2-deoxy-D-glucose phosphate accumulated/min/g) was approximately double
      that at 18 weeks (46.6+/-5.6 nmol 2-deoxy-D-glucose phosphate accumulated/min/g,
      P < .01). These changes in insulin responsiveness in adipose tissue of older
      animals may underlie the increased adiposity that is currently thought to be the
      causative factor in the development of age-related insulin resistance.

PMID- 10582554
TI  - Contribution of fasting hyperinsulinemia to prediction of atherosclerotic
      cardiovascular disease status in 293 hyperlipidemic patients.
AB  - In a cross-sectional study of 293 nondiabetic patients (169 men and 124 women)
      referred for the diagnosis and treatment of hyperlipidemia, our specific aim was
      to determine whether fasting serum insulin independently contributes to the
      prediction of atherosclerotic cardiovascular disease (ASCVD) status. Of the 169
      men and 124 women, 65 (38%) and 44 (35%), respectively, had ASCVD with at least
      one of the following: unstable angina, myocardial infarction (MI), angioplasty,
      coronary artery bypass graft (CABG), claudication, transient ischemic attack, or
      ischemic stroke. In addition, 42% and 38% had fasting hyperinsulinemia (> or =20
      microU/mL). Fasting serum insulin of 20 microU/mL or higher was very common in
      women (59% to 100%) and men (67% to 88%) when hypertension, obesity, top-decile
      triglyceride (TG), and bottom-decile high-density lipoprotein cholesterol (HDLC)
      were concurrent in various combinations. ASCVD events (present or absent) were
      dependent variables in a stepwise logistic regression model with explanatory
      variables including age, gender, race, hypertension, cigarette smoking, ASCVD in
      first-degree relatives at age 55 years or less, Quetelet Index, fasting serum
      insulin, a gender x insulin interaction term, anticardiolipin antibodies (ACLAs)
      IgG and IgM, total cholesterol to HDLC ratio, TG, lipoprotein(a) [Lp(a)], and
      homocysteine. The risk odds ratio for ASCVD (109 events and 184 nonevents) for
      subjects with top-decile insulin (vthe bottom nine deciles) was 3.71, with a 95%
      confidence interval (CI) of 1.62 to 8.9 (P = .002). For patients with MI and/or
      CABG and/or angioplasty ([MCA] 63 events and 184 nonevents), the risk odds ratio
      for top-decile insulin versus the rest was 5.07 (95% CI, 1.83 to 14.8, P = .002).
      For patients with MCA at age 55 or less, the gender x insulin interaction term
      was significant (P = .0004); the risk odds ratio for men with top-decile insulin
      was 13.28 (95% CI, 3.82 to 51.65, P = .0001). Hyperinsulinemia is very common in
      nondiabetic hyperlipidemic women and men. Fasting serum insulin, a crude, simple,
      practical, and inexpensive measure, independently and uniformly improved the
      prediction of ASCVD status beyond traditional risk factors and lipid variables in
      patients referred for treatment of hyperlipidemia.

PMID- 10582556
TI  - Amelioration by KRP-297, a new thiazolidinedione, of impaired glucose uptake in
      skeletal muscle from obese insulin-resistant animals.
AB  - We examined the effect of KRP-297, a new thiazolidinedione derivative, on glucose
      uptake in the soleus muscle of two animal models of insulin resistance that show
      moderate (ob/ob mice) and severe (db/db mice) hyperglycemia. Insulin-stimulated 2
      deoxyglucose (2DG) uptake in soleus muscle was 53.8% lower in ob/ob mice versus
      lean mice (P < .05). When administered to ob/ob mice, KRP-297 (0.3 to 10 mg/kg)
      decreased plasma glucose and insulin levels and improved the impaired insulin
      stimulated 2DG uptake in soleus muscle in a dose-dependent manner. Soleus muscle
      from db/db mice exhibited defects in both basal (35.0% decrease, P < .01) and
      insulin-stimulated (50.5% decrease, P < .01) 2DG uptake. These defects were
      improved by treatment with KRP-297 (0.3 to 10 mg/kg). Moreover, KRP-297 prevented
      severe hyperglycemia and the marked decrease in pancreatic insulin content in
      db/db mice. These results suggest that KRP-297 treatment is useful to prevent the
      development of diabetic syndromes in addition to ameliorating the impaired
      glucose transport in skeletal muscle.

PMID- 10582557
TI  - Circadian variations in plasma and erythrocyte concentrations of glutamate,
      glutamine, and alanine in men on a diet without and with added monosodium
      glutamate.
AB  - Variations in plasma and erythrocyte concentrations of glutamate, glutamine, and
      alanine during the day were studied in 10 healthy men fed ordinary Taiwanese
      meals, first without and, 1 week later, with monosodium glutamate (MSG) added.
      MSG at a level of 15, 40, and 45 mg/kg (total, 100 mg/kg/d) was added,
      respectively, to the breakfast, lunch, and dinner meals. Heparinized blood
      samples were collected over 24 hours with 1- to 3-hour intervals. In both trials,
      plasma glutamate concentrations increased significantly after lunch and dinner.
      Although the circadian variations of plasma glutamate were small (between 32 and
      53 micromol/L), the levels nevertheless varied significantly as a function of the
      time of day in both trials. Considering that the dietary intake of glutamate was
      high when MSG was added, the low plasma glutamate concentration over 24 hours
      indicates that glutamate is actively metabolized. On the other hand, the
      concentrations of erythrocyte glutamate (507 to 631 micromol/L) and glutamine
      (427 to 613 micromol/L) did not show a significant postprandial increase or
      circadian variation. Nevertheless, the concentration of plasma glutamine (539 to
      657 micromol/L) varied significantly as a function of time in both trials. The
      plasma concentration of alanine (274 to 494 micromol/L) increased significantly
      after each meal and decreased significantly from 2:00 to 5:00 AM in both trials.
      Both plasma and erythrocyte alanine concentrations varied significantly as a
      function of time. These results show that the substantial amount of MSG intake
      had no apparent effect on the circadian variation profiles of blood glutamate,
      glutamine, and alanine.

PMID- 10582558
TI  - Effects of the pesticide amitraz and its metabolite BTS 27271 on insulin and
      glucagon secretion from the perfused rat pancreas: involvement of alpha2D
      adrenergic receptors.
AB  - The study purpose was to investigate the direct effect of amitraz, a formamidine
      insecticide/acaricide, and its active metabolite BTS 27271 on insulin and
      glucagon secretion from the perfused rat pancreas. Amitraz and BTS 27271 (0.01,
      0.1, 1, and 10 micromol/L) inhibited insulin secretion in a concentration
      dependent manner. Amitraz increased glucagon secretion at 10 micromol/L, whereas
      BTS 27271 increased glucagon secretion at 1 and 10 micromol/L. Amitraz- and BTS
      27271-induced decreases in insulin secretion and increases in glucagon secretion
      were not abolished during the 10-minute washout period. During the arginine
      treatment, both amitraz and BTS 27271 groups (0.1, 1, and 10 micromol/L) had
      lower insulin secretion and higher glucagon secretion than the control group.
      Idazoxan, an alpha2A/2D-adrenergic receptor (AR) antagonist, prevented the
      inhibitory effect of amitraz on insulin secretion in a concentration-dependent
      manner, but prazosin, an alpha1- and alpha2B/2C-AR antagonist, failed to
      antagonize the effect of amitraz. These results demonstrate that (1) amitraz and
      BTS 27271 inhibit insulin and stimulate glucagon secretion from the perfused rat
      pancreas, (2) amitraz inhibits insulin secretion by activation of alpha2D-ARs,
      since rats have alpha2D- but not alpha2A-ARs, and (3) amitraz and BTS 27271 may
      have a high binding affinity to the alpha2D-ARs of pancreatic islets.

PMID- 10582559
TI  - Insulin-induced vasodilatation of internal carotid artery.
AB  - The increase in leg and forearm blood flow induced by insulin could be secondary
      to its metabolic effect on glucose uptake. We therefore investigated whether
      insulin causes vasodilation of the internal carotid artery, since the brain is
      not dependent on insulin for glucose uptake, to demonstrate that the vasodilatory
      effect of insulin is primary and independent of its metabolic effect. Internal
      carotid artery diameter was continuously monitored using a 7.5-MHz transducer
      linked to an Acuson XP10 ultrasonograph (Mountainview, CA) during infusion of 125
      mL 10% dextrose mixed with 3 U regular insulin and 5 mmol potassium chloride over
      1 hour. The internal carotid artery diameter increased progressively with time
      from a mean of 5.4+/-1 mm to 5.7+/-1 mm at 15 minutes, 5.9+/-1.1 mm at 30
      minutes, 6+/-1.1 mm at 45 minutes, and 6.1+/-1.1 mm at 60 minutes (P < .05), an
      increase of 13% over baseline. Glucose was maintained between 93 and 106 mg/dL,
      and insulin increased from 15+/-14 microU/mL and was maintained between 34 and 47
      microU/mL. There was no change in mean arterial blood pressure (MABP) or heart
      rate during the infusion. We conclude that insulin dilates the internal carotid
      artery consistently at physiological concentrations, probably independently of
      glucose uptake by the brain. Alterations in this effect of insulin may be of
      relevance in the pathogenesis of abnormalities of cerebral blood flow in type 1
      and type 2 diabetics as described by our group previously.

PMID- 10582560
TI  - Differential effect of resistance training on the body composition and
      lipoprotein-lipid profile in older men and women.
AB  - The effects of a 12-week resistance exercise training (RT) program on body
      composition and serum lipid concentrations were assessed in weight-stable,
      moderately overweight older men (n = 18) and women (n = 17) aged 54 to 71 years
      with a body mass index (BMI) of 26 to 36 kg/m2. Following RT, the men had a
      significant increase in fat-free mass (FFM) and a decrease in percent body fat
      (%BF) and fat mass (FM), whereas the women demonstrated no change, resulting in
      significant time-by-sex interactions for FFM (P = .002), %BF (P = .006), and FM
      (P = .005). There were no changes in total cholesterol (Chol), low-density
      lipoprotein cholesterol (LDL-C), or triacylglycerol (Tg) due to RT. However,
      following RT, high-density lipoprotein cholesterol (HDL-C) increased (0.06+/-0.02
      mmol/L) in the men and decreased (0.09+/-0.03 mmol/L) in the women (time-by-sex
      interaction, P = .0004). The Chol/HDL-C ratio decreased (0.36+/-0.11) in the men
      and increased (0.29+/-0.10) in the women (time-by-sex interaction, P = .0001).
      For all subjects combined, the changes in HDL-C and the Chol/HDL-C ratio were not
      related to any changes in body fat stores (ie, %BF or FM), suggesting that RT may
      potentially alter the lipoprotein-lipid profile in older weight-stable men and
      women. In conclusion, although the changes in the lipoprotein-lipid profile were
      small, the men had a significantly increased HDL-C level and decreased Chol/HDL-C
      ratio, while the women demonstrated opposite changes.

PMID- 10582561
TI  - Comparing regularized and non-regularized nonlinear dipole fit methods: a study
      in a simulated sulcus structure.
AB  - The inverse problem arising from EEG and MEG is largely underdetermined. One
      strategy to alleviate this problem is the restriction to a limited number of
      point-like sources, the focal source model. Although the singular value
      decomposition of the spatio-temporal data gives an estimate of the minimal number
      of dipoles contributing to the measurement, the exact number is unknown in
      advance and noise complicates the reconstruction. Classical non-regularized
      nonlinear dipole fit algorithms do not give an estimate for the correct number
      because they are not stable with regard to an overestimation of this parameter.
      Too many sources may only describe noise but can still attain a large magnitude
      during the inverse procedure and may be indiscernible from the true sources. This
      paper describes a nonlinear dipole fit reconstruction algorithm with a new
      regularization approach for the embedded linear problem, automatically controlled
      by the noise in the data and the condition of the occuring least square problems.
      The algorithm is stable with regard to source components which "nearly" lie in
      the kernel of the projection or lead field operator and it thus gives an estimate
      of the unknown number parameter. EEG simulation studies in a simulated sulcus
      structure are carried out for an instantaneous dipole model and spatial
      resolution in the sulcus and stability of the new method are compared with a
      classical reconstruction algorithm without regularization.

PMID- 10582562
TI  - Local polynomial estimate of surface Laplacian.
AB  - This paper describes a method for estimating the surface Laplacian of brain
      potentials. The method consists of two steps: local surface approximation by its
      tangent plane and local polynomial fitting. Compared to previous methods for
      estimating surface Laplacian, this method has some new features. First, it can
      estimate the surface Laplacian at any point of the scalp, including the locations
      of the peripheral electrodes. Secondly, it estimates the brain potential and the
      surface Laplacian at any point simultaneously. This reduces the risk of error
      propagation, which occurs when the brain potential is interpolated first and the
      surface Laplacian is then computed based on the interpolated brain potential.
      Finally, the method automatically adapts to noisy data by using more or less
      measurements at neighboring electrodes based on estimated noise level.
      Simulations suggest that this method is effective. Application to event-related
      potentials are also presented.

PMID- 10582563
TI  - P300 and response selection: a new look using independent-components analysis.
AB  - PURPOSE: The most prevalent current view of the functional role of the P300
      component of the event-related potential (ERP) is that it indexes strategic
      processing related to context updating. Using independent-components analysis
      (ICA), the present study examined the role of P300 in the tactical process of
      response selection. METHODS: In a task crossing manipulations of perceptual
      difficulty (PD) and response-selection difficulty (R-SD), ICA was employed to
      measure not only P300 latency, but its onset and duration as well. RESULTS:
      Increased PD delayed P300 latency and onset in parallel, while increased R-SD
      lengthened P300 duration. CONCLUSIONS: The latency and onset results suggest that
      the often-cited covariation of P300 latency with stimulus-evaluation time is
      secondary to effects on processing stages preceding P300. The results for
      duration indicate that P300 is involved in response selection, suggesting that it
      is not a unitary phenomenon. While P300's well-known relation to stimulus
      probability indicates a strategic role, our findings indicate a tactical role as
      well.

PMID- 10582564
TI  - Determining working memory from ERP topography.
AB  - Event-related potentials were recorded during a delayed matching-to-sample design
      from 17 volunteers (5 f) using high-resolution (65 channels) EEG-recordings. In
      the two-stimulus paradigm, the 500-ms stimulus S1 comprised a visual pattern of
      two diamonds differing in size, angular rotation and location; in the delay
      period, Working Memory (WM) load was varied in the following way: a stimulus-free
      interval of 1 s was followed by a 6-s presentation either of a pattern identical
      to the S1 (low WM load) or of a pattern differing from S1 (high WM load). The 500
      ms stimulus S2 comprised one diamond; the subject's task was to indicate by left-
      or right-hand (respectively) button press, whether the S2 matched the (a) left-
      or (b) right-positioned S1-diamond, or (c) did not match at all (NoGo). The
      topographical distribution of activity in the time intervals (a) following S1
      offset, (b) during the WM manipulation interval and (c) prior to S2 were
      evaluated in the signal (scalp potential) and source (Minimum Norm) space.
      Following S1-offset the ERP pattern was characterised by negativity over
      posterior areas, slightly more so over the right hemisphere. In the subsequent 6
      s interval high WM load elicited a larger negative slow ERP than low WM load, the
      negativity increase due to high WM load being larger over frontal than central
      areas. Source modelling indicated activity in anterior areas under high, and
      posterior activity under low WM load. Asymmetry of activity, although indicating
      a shift to left-hemispheric activity under high compared to low WM load, varied
      considerably between subjects. Results suggest that high-resolution ERP
      recordings allow to examine cortical activity during WM challenge.

PMID- 10582565
TI  - Dipole source analysis in persistent mirror movements.
AB  - To elucidate the pathomechanism underlying persistent mirror movements (MM), we
      modelled the origin of electric brain activity associated with these movements.
      Movement-related cortical potentials (MRCP) in a group of subjects affected by
      persistent mirror movements were compared with those of a control group. The data
      of the normal subjects were best explained with two bilaterally active electric
      sources in the sensorimotor cortices with a clear preponderance of the hemisphere
      contralateral to the movement. In contrast, the MM subjects presented a fairly
      symmetric source activity in both hemispheres during unilateral intended
      movements. In the control group, the source representing the activity of the
      motor cortex ipsilateral to the moving finger reduced activity before the
      beginning of the movement; this was interpreted as an inhibition of the
      ipsilateral motor cortex during unilateral movement. In the MM group, however,
      this inhibition was not seen. Furthermore, while normal subjects demonstrated no
      relevant activity of an additional source placed near midline motor structures
      (supplementary motor area; SMA), subjects with MM showed considerable activity of
      this dipole source. These findings suggest that subjects with persistent MM have
      abnormal bilateral activation of the primary motor areas, probably together with
      an additional activation of mesial motor structures. This assumption fits well
      with the observation of an incomplete decussation of the pyramidal tract. The
      bilateral activation is then explained as a compensatory strategy in order to
      achieve sufficient force in the innervated target muscles.

PMID- 10582566
TI  - Fuzzy segmentation spatiotemporal patterns of cognitive potential into
      microstates.
AB  - Fuzzy c-mean algorithm was applied to segment spatiotemporal patterns of
      brainwave into microstates and memberships. The optimal clustering number was
      estimated with both the trends of objective function and the eigenvalue number of
      microstates. Comparable spatial patterns may occur at different temporal moments
      in consideration of fuzzy index that is beyond the limit of serial processing.
      Those techniques were illustrated with multichannel event-related potentials
      recorded from 9 subjects during Stroop test. Statistical parametric map of F
      value suggested that significant task (color decision and word decision) effect
      involve widespread cortical regions after stimulus onset 280 ms and this result
      supports the hypothesis that Stroop interference derives from response
      competition during post-perception stage. As significant stimulus (congruent
      stimulus and incongruent stimulus) effect only involves several separate visual
      regions within 100 ms after stimulus presentation, it may reflect top-down
      attentional regulation.

PMID- 10582567
TI  - Clustering gene expression patterns.
AB  - Recent advances in biotechnology allow researchers to measure expression levels
      for thousands of genes simultaneously, across different conditions and over time.
      Analysis of data produced by such experiments offers potential insight into gene
      function and regulatory mechanisms. A key step in the analysis of gene expression
      data is the detection of groups of genes that manifest similar expression
      patterns. The corresponding algorithmic problem is to cluster multicondition gene
      expression patterns. In this paper we describe a novel clustering algorithm that
      was developed for analysis of gene expression data. We define an appropriate
      stochastic error model on the input, and prove that under the conditions of the
      model, the algorithm recovers the cluster structure with high probability. The
      running time of the algorithm on an n-gene dataset is O[n2[log(n)]c]. We also
      present a practical heuristic based on the same algorithmic ideas. The heuristic
      was implemented and its performance is demonstrated on simulated data and on real
      gene expression data, with very promising results.

PMID- 10582568
TI  - Performance of threading scoring functions designed using new optimization
      method.
AB  - We present a new procedure for optimization of a threading scoring function. A
      scoring function is usually formulated in terms of the structural environment
      states that describe the protein fold model. We propose a method for the optimal
      selection of those structural environment states that naturally follows from the
      probabilistic description of the threading problem and is done prior to threading
      experiments. We demonstrate the selection of the optimal structural environment
      states for the solvent exposure of the amino acid position, and present the
      results of threading experiments performed using scoring functions designed with
      and without the optimization of the structural environment states. These results
      confirm that the optimal scoring function predicts the sequence-to-structure
      alignments most accurately. Threading experiments performed with 15 optimally
      designed scoring functions show that the correlation coefficient between the
      information content of the amino acid distribution that determines the scoring
      function and the accuracy of the optimal sequence-to-structure alignment is 0.94.

PMID- 10582569
TI  - Fast detection of common geometric substructure in proteins.
AB  - We consider the problem of identifying common three-dimensional substructures
      between proteins. Our method is based on comparing the shape of the alpha-carbon
      backbone structures of the proteins in order to find three-dimensional (3D) rigid
      motions that bring portions of the geometric structures into correspondence. We
      propose a geometric representation of protein backbone chains that is compact yet
      allows for similarity measures that are robust against noise and outliers. This
      representation encodes the structure of the backbone as a sequence of unit
      vectors, defined by each adjacent pair of alpha-carbons. We then define a measure
      of the similarity of two protein structures based on the root mean squared (RMS)
      distance between corresponding orientation vectors of the two proteins. Our
      measure has several advantages over measures that are commonly used for comparing
      protein shapes, such as the minimum RMS distance between the 3D positions of
      corresponding atoms in two proteins. A key advantage is that this new measure
      behaves well for identifying common substructures, in contrast with position
      based measures where the nonmatching portions of the structure dominate the
      measure. At the same time, it avoids the quadratic space and computational
      difficulties associated with methods based on distance matrices and contact maps.
      We show applications of our approach to detecting common contiguous substructures
      in pairs of proteins, as well as the more difficult problem of identifying common
      protein domains (i.e., larger substructures that are not necessarily contiguous
      along the protein chain).

PMID- 10582570
TI  - De novo peptide sequencing via tandem mass spectrometry.
AB  - Peptide sequencing via tandem mass spectrometry (MS/MS) is one of the most
      powerful tools in proteomics for identifying proteins. Because complete genome
      sequences are accumulating rapidly, the recent trend in interpretation of MS/MS
      spectra has been database search. However, de novo MS/MS spectral interpretation
      remains an open problem typically involving manual interpretation by expert mass
      spectrometrists. We have developed a new algorithm, SHERENGA, for de novo
      interpretation that automatically learns fragment ion types and intensity
      thresholds from a collection of test spectra generated from any type of mass
      spectrometer. The test data are used to construct optimal path scoring in the
      graph representations of MS/MS spectra. A ranked list of high scoring paths
      corresponds to potential peptide sequences. SHERENGA is most useful for
      interpreting sequences of peptides resulting from unknown proteins and for
      validating the results of database search algorithms in fully automated, high
      throughput peptide sequencing.

PMID- 10582571
TI  - Evolution of metabolisms: a new method for the comparison of metabolic pathways
      using genomics information.
AB  - The abundance of information provided by completely sequenced genomes defines a
      starting point for new insights in the multilevel organization of organisms and
      their evolution. At the lowest level enzymes and other protein complexes are
      formed by aggregating multiple polypeptides. At a higher level enzymes group
      conceptually into metabolic pathways as part of a dynamic information-processing
      system, and substrates are processed by enzymes yielding other substrates. A
      method based on a combination of sequence information with graph topology of the
      underlying pathway is presented. With this approach pathways of different
      organisms are related to each other by phylogenetic analysis, extending
      conventional phylogenetic analysis of individual enzymes. The new method is
      applied to pathways related to electron transfer and to the Krebs citric acid
      cycle. In addition to providing a more comprehensive understanding of
      similarities and differences between organisms, this method indicates different
      evolutionary rates between substrates and enzymes.

PMID- 10582572
TI  - Optimal reconstruction of a sequence from its probes.
AB  - An important combinatorial problem, motivated by DNA sequencing in molecular
      biology, is the reconstruction of a sequence over a small finite alphabet from
      the collection of its probes (the sequence spectrum), obtained by sliding a fixed
      sampling pattern over the sequence. Such construction is required for Sequencing
      by-Hybridization (SBH), a novel DNA sequencing technique based on an array (SBH
      chip) of short nucleotide sequences (probes). Once the sequence spectrum is
      biochemically obtained, a combinatorial method is used to reconstruct the DNA
      sequence from its spectrum. Since technology limits the number of probes on the
      SBH chip, a challenging combinatorial question is the design of a smallest set of
      probes that can sequence an arbitrary DNA string of a given length. We present in
      this work a novel probe design, crucially based on the use of universal bases
      [bases that bind to any nucleotide (Loakes and Brown, 1994)] that drastically
      improves the performance of the SBH process and asymptotically approaches the
      information-theoretic bound up to a constant factor. Furthermore, the sequencing
      algorithm we propose is substantially simpler than the Eulerian path method used
      in previous solutions of this problem.

PMID- 10582573
TI  - Disk-covering, a fast-converging method for phylogenetic tree reconstruction.
AB  - The evolutionary history of a set of species is represented by a phylogenetic
      tree, which is a rooted, leaf-labeled tree, where internal nodes represent
      ancestral species and the leaves represent modern day species. Accurate (or even
      boundedly inaccurate) topology reconstructions of large and divergent trees from
      realistic length sequences have long been considered one of the major challenges
      in systematic biology. In this paper, we present a simple method, the Disk
      Covering Method (DCM), which boosts the performance of base phylogenetic methods
      under various Markov models of evolution. We analyze the performance of DCM
      boosted distance methods under the Jukes-Cantor Markov model of biomolecular
      sequence evolution, and prove that for almost all trees, polylogarithmic length
      sequences suffice for complete accuracy with high probability, while polynomial
      length sequences always suffice. We also provide an experimental study based upon
      simulating sequence evolution on model trees. This study confirms substantial
      reductions in error rates at realistic sequence lengths.

PMID- 10582574
TI  - Efficient algorithms for protein sequence design and the analysis of certain
      evolutionary fitness landscapes.
AB  - Protein sequence design is a natural inverse problem to protein structure
      prediction: given a target structure in three dimensions, we wish to design an
      amino acid sequence that is likely fold to it. A model of Sun, Brem, Chan, and
      Dill casts this problem as an optimization on a space of sequences of hydrophobic
      (H) and polar (P) monomers; the goal is to find a sequence that achieves a dense
      hydrophobic core with few solvent-exposed hydrophobic residues. Sun et al.
      developed a heuristic method to search the space of sequences, without a
      guarantee of optimality or near-optimality; Hart subsequently raised the
      computational tractability of constructing an optimal sequence in this model as
      an open question. Here we resolve this question by providing an efficient
      algorithm to construct optimal sequences; our algorithm has a polynomial running
      time, and performs very efficiently in practice. We illustrate the implementation
      of our method on structures drawn from the Protein Data Bank. We also consider
      extensions of the model to larger amino acid alphabets, as a way to overcome the
      limitations of the binary H/P alphabet. We show that for a natural class of
      arbitrarily large alphabets, it remains possible to design optimal sequences
      efficiently. Finally, we analyze some of the consequences of this sequence design
      model for the study of evolutionary fitness landscapes. A given target structure
      may have many sequences that are optimal in the model of Sun et al.; following a
      notion raised by the work of J. Maynard Smith, we can ask whether these optimal
      sequences are "connected" by successive point mutations. We provide a polynomial
      time algorithm to decide this connectedness property, relative to a given target
      structure. We develop the algorithm by first solving an analogous problem
      expressed in terms of submodular functions, a fundamental object of study in
      combinatorial optimization.

PMID- 10582575
TI  - An anytime local-to-global optimization algorithm for protein threading in theta
      (m2n2) space.
AB  - This paper describes a novel anytime branch-and-bound or best-first threading
      search algorithm for gapped block protein sequence-structure alignment with
      general sequence residue pair interactions. The new algorithm (1) returns a good
      approximate answer quickly, (2) iteratively improves that answer to the global
      optimum if allowed more time, (3) eventually produces a proof that the final
      answer found is indeed the global optimum, and (4) always terminates correctly
      within a bounded number of steps if allowed sufficient space and time. It runs in
      polynomial space, which is asymptotically dominated by the theta(m2n2) space
      required by the lower bound computation. Using previously published data sets and
      the Bryant-Lawrence (1993) objective function, the algorithm found the true
      (proven) global optimum in less than 5 min in all search spaces size 10(25) or
      smaller (sequences to 478 residues), and a putative (not guaranteed) optimum in
      less than 5 hr in all search spaces size 10(60) or smaller (sequences to 793
      residues, cores to 42 secondary structure segments). The threading in the largest
      case studied was eventually proven to be globally optimal; the corresponding
      search speed in that case was the equivalent of 1.5 x 10(56) threadings/sec, a
      speed-up exceeding 10(25) over previously published batch branch-and-bound
      speeds, and exceeding 10(50) over previously published exhaustive search speeds,
      using the same objective function and threading paradigm. Implementation
      independent measures of search efficiency are defined for equivalent branching
      factor, depth, and probability of success per draw; empirical data on these
      measures are given. The general approach should apply to other alignment
      methodologies and search methods that use a divide-and-conquer strategy.

PMID- 10582576
TI  - A dictionary-based approach for gene annotation.
AB  - This paper describes a fast and fully automated dictionary-based approach to gene
      annotation and exon prediction. Two dictionaries are constructed, one from the
      nonredundant protein OWL database and the other from the dbEST database. These
      dictionaries are used to obtain O (1) time lookups of tuples in the dictionaries
      (4 tuples for the OWL database and 11 tuples for the dbEST database). These
      tuples can be used to rapidly find the longest matches at every position in an
      input sequence to the database sequences. Such matches provide very useful
      information pertaining to locating common segments between exons, alternative
      splice sites, and frequency data of long tuples for statistical purposes. These
      dictionaries also provide the basis for both homology determination, and
      statistical approaches to exon prediction.

PMID- 10582577
TI  - Phylogenetic invariants for genome rearrangements.
AB  - We review the combinatorial optimization problems in calculating edit distances
      between genomes and phylogenetic inference based on minimizing gene order
      changes. With a view to avoiding the computational cost and the "long branches
      attract" artifact of some tree-building methods, we explore the probabilization
      of genome rearrangement models prior to developing a methodology based on branch
      length invariants. We characterize probabilistically the evolution of the
      structure of the gene adjacency set for reversals on unsigned circular genomes
      and, using a nontrivial recurrence relation, reversals on signed genomes.
      Concepts from the theory of invariants developed for the phylogenetics of
      homologous gene sequences can be used to derive a complete set of linear
      invariants for unsigned reversals, as well as for a mixed rearrangement model for
      signed genomes, though not for pure transposition or pure signed reversal models.
      The invariants are based on an extended Jukes-Cantor semigroup. We illustrate the
      use of these invariants to relate mitochondrial genomes from a number of
      invertebrate animals.

PMID- 10582578
TI  - Dissimilarity-based algorithms for selecting structurally diverse sets of
      compounds.
AB  - This paper commences with a brief introduction to modern techniques for the
      computational analysis of molecular diversity and the design of combinatorial
      libraries. It then reviews dissimilarity-based algorithms for the selection of
      structurally diverse sets of compounds in chemical databases. Procedures are
      described for selecting a diverse subset of an entire database, and for selecting
      diverse combinatorial libraries using both reagent-based and product-based
      selection.

PMID- 10582579
TI  - Trends in computational biology: a summary based on a RECOMB plenary lecture,
      1999.
AB  - Computational biology, a term coined from analogy to the role of computing in the
      physical sciences, is now coming into its own as a major element of contemporary
      biological and biomedical research. Information science and computational science
      provide essential tools for next generation biological science efforts, from
      focusing the direction of experimental studies to providing knowledge and insight
      that can not otherwise be obtained. Going beyond the revolution in biology
      reflected in the successes of the genome project and driven by the power of
      molecular biology techniques, computational approaches will provide an
      underpinning for the integration of broad disciplines for development of a
      quantitative systems approach to understanding the mechanisms in the life of the
      cell.

PMID- 10582580
TI  - Mechanisms of synaptic vesicle recycling illuminated by fluorescent dyes.
AB  - The recycling of synaptic vesicles in nerve terminals involves multiple steps,
      underlies all aspects of synaptic transmission, and is a key to understanding the
      basis of synaptic plasticity. The development of styryl dyes as fluorescent
      molecules that label recycling synaptic vesicles has revolutionized the way in
      which synaptic vesicle recycling can be investigated, by allowing an examination
      of processes in neurons that have long been inaccessible. In this review, we
      evaluate the major aspects of synaptic vesicle recycling that have been revealed
      and advanced by studies with styryl dyes, focussing upon synaptic vesicle fusion,
      retrieval, and trafficking. The greatest impact of styryl dyes has been to allow
      the routine visualization of endocytosis in central nerve terminals for the first
      time. This has revealed the kinetics of endocytosis, its underlying sequential
      steps, and its regulation by Ca2+. In studies of exocytosis, styryl dyes have
      helped distinguish between different modes of vesicle fusion, provided direct
      support for the quantal nature of exocytosis and endocytosis, and revealed how
      the probability of exocytosis varies enormously from one nerve terminal to
      another. Synaptic vesicle labelling with styryl dyes has helped our understanding
      of vesicle trafficking by allowing better understanding of different synaptic
      vesicle pools within the nerve terminal, vesicle intermixing, and vesicle
      clustering at release sites. Finally, the dyes are now being used in innovative
      ways to reveal further insights into synaptic plasticity.

PMID- 10582581
TI  - Identification of a mammalian homologue of the fungal Tom70 mitochondrial
      precursor protein import receptor as a thyroid hormone-regulated gene in specific
      brain regions.
AB  - Thyroid hormone is an important regulator of mammalian brain maturation. By
      differential display PCR, we isolated a cDNA clone (S2) that is specifically up
      regulated in the striatum of neonatal hypothyroid rats. S2 was identified as
      KIAA0719, the first human gene distantly homologous to the fungal Tom70, which
      encodes a member of the translocase mitochondrial outer membrane complex involved
      in the import of preproteins into the mitochondria. By northern and in situ
      hybridization studies, KIAA0719 was found to be up-regulated in the striatum,
      nucleus accumbens, and discrete cortical layers of 15-day-old hypothyroid rats.
      In contrast, lower expression was found in the olfactory tubercle, whereas no
      differences were detected in other brain regions. Significantly, treatment of
      hypothyroid animals with single injections of thyroxine restored the normal
      levels of KIAA0719 expression. Moreover, treatment of control animals with
      thyroxine led to a reduced expression, demonstrating a negative hormonal
      regulation in vivo. Thus, KIAA0719 gene expression is regulated by thyroid
      hormone in the neonatal rat brain in a region-specific fashion. Given the role of
      the homologous Tom70 gene, the alteration of KIAA0719 expression may contribute
      to the changes in mitochondrial morphology and physiology caused by
      hypothyroidism in the developing rat brain.

PMID- 10582582
TI  - Genomic organization of human DLG4, the gene encoding postsynaptic density 95.
AB  - We have determined the exon-intron organization and characterized the 5'-flanking
      promoter region of DLG4. Encompassing approximately 30 kb, the DLG4 locus is
      composed of 22 exons that range in size from 28 to 1,218 nucleotides. All splice
      sites conform to the GT-AG rule, except for the splice acceptor site of intron 5,
      which is TG instead of AG. Three different exons of DLG4 were found to be
      alternatively spliced in a subset of tissues. Two of these variants result in
      altered postsynaptic density 95 (PSD95) isoforms that dramatically truncate the
      protein. The third splicing variant represents an extension of exon 4 that
      encodes an additional 33-amino acid segment. Analysis of the core promoter region
      for DLG4 suggests that the expression of this gene is controlled by a TATA-less
      promoter using a single transcriptional start site embedded within a CpG island.
      DLG4 maps to a region on chromosome 17p13.1 known to contain a locus for
      autosomal dominant cone dystrophy 5. Scanning for mutations in the DLG4 coding
      region and splice sites was performed in 15 cone dystrophy patients, including
      probands from five families showing linkage to the DLG4 region. No disease
      causing mutations were identified in any patients, suggesting that DLG4 is not
      the causative gene for this genetic eye disorder.

PMID- 10582583
TI  - Characterization of transcripts from the synapsin III gene locus.
AB  - Synapsin III, the most recently described member of the synapsin gene family,
      displays a gene structure and protein domain structure similar to those of
      synapsins I and II. In this report, however, we describe major differences in the
      temporal- and tissue-specific expressions of synapsin III. Whereas synapsins I
      and II each give rise to two isoforms that are expressed predominantly in adult
      brain, there are at least six synapsin III transcripts (synapsin IIIa-IIIf) that
      differ with respect to tissue- and developmental stage-specific expression. Three
      of the neuronal transcripts are detected in fetal and to a lesser extent in adult
      brain (IIa-IIIc), whereas one (IIId) is detected only in fetal brain. Two
      additional transcripts (IIIe and IIIf) are detected only in nonneuronal tissues.
      A putative second promoter, which is contained within an intron in the synapsin
      III gene locus, appears to generate the nonneuronal synapsin IIIe and IIIf
      transcripts. This level of genome complexity is far greater than that described
      previously for the synapsin I and II genes and suggests that synapsin III may
      have functions distinct from those described for synapsins I and II.

PMID- 10582584
TI  - Prolactin induction of nitric oxide synthase in rat C6 glioma cells.
AB  - We have examined the neuroimmunoregulatory function of prolactin (PRL) on
      astrocytic inducible nitric oxide synthase (iNOS) expression in the C6 glioma
      cell line. After 24 h of PRL (5-100 nM) stimulation, a concentration-dependent
      increase of NO release, evaluated as nitrite, was observed in C6 culture medium.
      Moreover, both NO release and iNOS expression induced by interferon-gamma (250
      U/ml) were enhanced by PRL (18-100 nM). PRL-induced NO release was inhibited by
      dexamethasone, an inhibitor of de novo iNOS synthesis. We used erbstatin (5
      microg/ml), a potent inhibitor of protein tyrosine kinases, to test whether these
      proteins were required for signaling events evoked by PRL in these cells. This
      inhibitor was able to inhibit completely the PRL-induced NO production and iNOS
      expression. In conclusion, we provide evidence that NO production in glial cells
      can be regulated not only by cytokines but also by neuroimmunoregulatory hormones
      such as PRL, which is present in normal brain but may be elevated in several
      pathological states.

PMID- 10582585
TI  - Staurosporine-induced activation of caspase-3 is potentiated by presenilin 1
      familial Alzheimer's disease mutations in human neuroglioma cells.
AB  - Familial Alzheimer's disease (FAD) mutant forms of presenilin 1 (PS1) and 2 have
      been shown to sensitize cells to apoptotic cell death. Here we explore the
      effects of FAD mutant forms of PS1 on caspase activation during apoptosis. We
      show that caspase activation leads to increased generation of alternative C
      terminal fragments (CTFs) from mutant as compared to wild-type (wt) PS1. For this
      purpose, very low expression levels of wt, A246E, L286V, and deltaE10 FAD mutant
      PS1 proteins in stably transfected human H4 neuroglioma cells were used to avoid
      artifactual induction of spontaneous apoptosis due to overexpression of PS1.
      Staurosporine treatment of these cells resulted in increased cell death and up to
      a 10-fold increase in caspase-3 activation in mutant versus wt PS1-expressing
      cell lines. Correspondingly, relative levels of caspase-cleaved PS1 CTFs were
      increased by five- to sixfold in the FAD mutant versus wt PS1 cells. Elevated
      caspase activation and caspase cleavage of FAD mutant PS1 suggest the possibility
      of either a direct proapoptotic effect of mutant PS1 or interference of mutant
      PS1 with antiapoptotic effects of wt PS1.

PMID- 10582586
TI  - CTCF is essential for up-regulating expression from the amyloid precursor protein
      promoter during differentiation of primary hippocampal neurons.
AB  - The transcriptional mechanism underlying amyloid precursor protein (APP)
      regulation in primary neurons during development was investigated. We observed an
      approximately threefold elevation of APP mRNA levels in differentiating rat
      hippocampal neurons between day 1 and day 7 in culture and in rat brain
      hippocampi between embryonic day 18 and postnatal day 3. When an APP promoter
      construct extending to position -2,832 upstream from the main transcriptional
      start site was transfected into primary rat hippocampal neurons, promoter
      activity increased from day 1 until reaching a maximum on day 7 in culture. This
      increase in APP promoter activity was correlated more closely with the time
      course of expression of the synaptic vesicle protein synaptophysin, an indicator
      of synaptogenesis, than with neurofilament accumulation, an indicator of
      neuritogenesis. Transfection of 5' APP promoter deletions and internal block
      mutations indicated that the CTCF binding domain designated APBbeta was the
      primary contributor to the increase in APP promoter activity. Furthermore, the
      binding of transcription factor CTCF to the APBbeta element increased
      approximately fivefold between day 1 and day 7, whereas the binding of USF to the
      APBalpha sequence increased only twofold. These results suggest that CTCF is
      pivotal for the up-regulation of APP expression during synaptogenesis in primary
      neurons.

PMID- 10582588
TI  - Monoamine oxidase and mitochondrial respiration.
AB  - Mitochondrial defects encompassing complexes I-IV of the electron transport chain
      characterize a relatively large number of neurodegenerative diseases. The
      relationships between mitochondrial lesions and recently described genetic
      alterations have not yet been defined. We describe a general mechanism whereby
      the enzymatic metabolism of neurotransmitters by monoamine oxidase (MAO) damages
      mitochondria, altering their protein thiol status and suppressing respiration. In
      these experiments, incubation of rat brain mitochondria with tyramine (a mixed
      MAO-A/MAO-B substrate) for 15 min at 27 degrees C suppressed state 3 respiration
      by 32.8% and state 5 respiration by 40.1%. These changes were accompanied by a 10
      fold rise in protein-glutathione mixed disulfides. Direct comparison of effects
      on respiration and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
      bromide] dye reduction during electron flow gave similar results. It is suggested
      that certain mitochondrial lesions may derive from the natural turnover of
      monoamine neurotransmitters in susceptible individuals.

PMID- 10582587
TI  - Lithium activates the c-Jun NH2-terminal kinases in vitro and in the CNS in vivo.
AB  - The therapeutic efficacy of lithium in the treatment of mood disorders is delayed
      and only observed after chronic administration, a temporal profile that suggests
      alterations at the genomic level. Lithium has been demonstrated to modulate AP-1
      DNA binding activity as well as the expression of genes regulated by AP-1, but
      the mechanisms underlying these effects have not been fully elucidated. In the
      present study, we found that the lithium-induced increases in AP-1 DNA binding
      activity were accompanied by increases in p-cJun and cJun levels in SH-SY5Y
      cells. Lithium also increased cJun-mediated reporter gene expression in a dose
      dependent manner, with significant effects observed at therapeutically relevant
      concentrations. Lithium's effects on cJun-mediated reporter gene expression in SH
      SY5Y cells were more pronounced in the absence of myo-inositol and were blocked
      by protein kinase C (PKC) inhibitors and by cotransfection with a PKCalpha
      dominant-negative mutant. Chronic in vivo lithium administration increased AP-1
      DNA binding activity in frontal cortex and hippocampus and also increased the
      levels of the phosphorylated, active forms of c-Jun NH2-terminal kinases (JNKs)
      in both brain regions. These results demonstrate that lithium activates the JNK
      signaling pathway in rat brain during chronic in vivo administration and in human
      cells of neuronal origin in vitro; in view of the role of JNKs in regulating
      various aspects of neuronal function and their well-documented role in regulating
      gene expression, these effects may play a major role in lithium's long-term
      therapeutic effects.

PMID- 10582589
TI  - The phosphatidylinositol 3-kinase inhibitor wortmannin alters the metabolism of
      the Alzheimer's amyloid precursor protein.
AB  - One of the hallmarks of Alzheimer's disease is the accumulation of senile plaques
      in brain, extracellular lesions comprised mostly of aggregates of the amyloid
      beta-peptide (Abeta). Abeta is proteolytically derived from the Alzheimer's
      amyloid precursor protein (APP). The generation of Abeta and nonamyloidogenic
      derivatives of APP involves utilization of alternative processing pathways and
      multiple subcellular compartments. To improve our understanding of the regulation
      of APP processing, we investigated the effects of wortmannin, a
      phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, on APP processing. PI3
      kinases form a multifaceted family of enzymes that represent converging points
      for multiple signal transduction pathways and also act as key regulators of
      vesicular trafficking. In N2a neuroblastoma cells expressing either wild-type APP
      or the "Swedish" familial Alzheimer's disease-associated mutant variant of APP,
      wortmannin treatment resulted in decreased release of both Abeta and soluble
      APPalpha. In parallel, full-length APP and both processed derivatives accumulated
      inside the cells. These effects were not present at nanomolar concentrations of
      wortmannin, but only at micromolar concentrations, implying the possible
      involvement of a recently described trans-Golgi network (TGN)-associated PI3
      kinase that is resistant to nanomolar concentrations of the inhibitor, but
      sensitive to micromolar concentrations. All effects were reversible when the drug
      was removed from the cell culture medium. Given the suspected site of action of
      this novel PI3-kinase activity at the TGN, it is tempting to speculate that the
      unexpected increase in the levels of both intracellular soluble APPalpha and
      intracellular Abeta might be due to wortmannin-induced covesiculation of APP
      together with its respective secretase enzymes within the TGN, leading to the
      execution of alpha-, beta-, and gamma-secretase reactions.

PMID- 10582590
TI  - Sublytic terminal complement complexes decrease P0 Gene expression in Schwann
      cells.
AB  - Complement cascade activation on peripheral nerve myelin can cause myelin
      destruction. Although terminal complement complexes (TCCs) are transiently
      detected on Schwann cells (SchCs) during inflammatory neuropathy, SchCs appear
      resistant to complement-mediated lysis, and little is known about the functional
      consequences of sublytic TCC deposition on SchCs. We studied the effects of
      sublytic complement in modulating myelin gene expression at the
      posttranscriptional and transcriptional levels. Cultured SchCs, stimulated to
      express protein zero (P0), were treated with sensitizing antibody (Ab) and normal
      human serum (NHS) complement. P0 mRNA content decreased by 71% during 12 h. In
      the presence of actinomycin D, P0 mRNA levels declined 50% following incubation
      with Ab plus 10% NHS over 6 h, compared with control levels, suggesting enhanced
      P0 mRNA degradation. The decreases, in part, reflected TCC formation because C7
      reconstitution of Ab plus C7-depleted human serum (C7dHS) or TCCs assembled from
      purified components down-regulated P0 mRNA 53 and 55% over that of Ab plus C7dHS
      or heat-activated components, respectively. Expression of a P0
      promoter/luciferase reporter construct transiently transfected into SchCs was
      reduced 70% by sublytic TCCs at 6 h, demonstrating that P0 gene transcription was
      also inhibited. c-jun mRNA was up-regulated within 30 min by sublytic TCCs,
      before the reduction in P0 mRNA expression. Our data suggest that sublytic
      complement activation on SchCs may contribute to peripheral nerve demyelination
      by decreasing expression of genes important in myelin formation and compaction.

PMID- 10582591
TI  - Association of the tyrosine phosphatase SHP-2 with transducin-alpha and a 97-kDa
      tyrosine-phosphorylated protein in photoreceptor rod outer segments.
AB  - Increasing evidence indicates that tyrosine phosphorylation, controlled by the
      concerted action of tyrosine kinases and protein tyrosine phosphatases (PTPs),
      plays important roles in retinal photoreceptor rod outer segments (ROS). We
      characterized PTP activity in isolated bovine ROS that is significantly inhibited
      by orthovanadate. Incubating ROS in the presence of exogenous Mg2+, ATP, and
      orthovanadate dramatically enhanced the tyrosine phosphorylation of several
      endogenous proteins. SHP-2, a PTP with two SH2 domains, was identified in ROS by
      immunoblot analysis and was found to associate with ROS membranes.
      Immunocytochemistry showed localization of SHP-2 in photoreceptor outer segments
      and possibly in the outer plexiform, inner nuclear, and inner plexiform cell
      layers of the retina as well. SHP-2 associated with transducin-alpha and a 97-kDa
      tyrosine-phosphorylated protein in ROS, suggesting the formation of a multimeric
      signaling complex. Based on its association with transducin-alpha and a 97-kDa
      protein, SHP-2 may regulate the tyrosine phosphorylation of endogenous proteins,
      including transducin-alpha, and may play a significant role in a novel signaling
      pathway in photoreceptors.

PMID- 10582592
TI  - Activity-dependent neurotrophic factor peptide (ADNF9) protects neurons against
      oxidative stress-induced death.
AB  - Activity-dependent neurotrophic factor (ADNF) and a 14-amino acid fragment of
      this peptide (sequence VLGGGSALLRSIPA) protect neurons from death associated with
      an array of toxic conditions, including amyloid beta-peptide, N-methyl-D
      aspartate, tetrodotoxin, and the neurotoxic HIV envelope coat protein gp120. We
      report that an even smaller, nine-amino acid fragment (ADNF9) with the sequence
      SALLRSIPA potently protects cultured embryonic day 18 rat hippocampal neurons
      from oxidative injury and neuronal apoptosis induced by FeSO4 and trophic factor
      withdrawal. Among the characteristics of this protection are maintenance of
      mitochondrial function and a reduction in accumulation of intracellular reactive
      oxygen species.

PMID- 10582594
TI  - Neuregulin-increased expression of acetylcholine receptor epsilon-subunit gene
      requires ErbB interaction with Shc.
AB  - Selective transcription of acetylcholine receptor (AChR) subunit genes by
      neuregulin is one of the mechanisms involved in the synaptic localization of
      AChRs to the neuromuscular junction. Neuregulin stimulates ErbB receptor tyrosine
      kinases and subsequently activates the Ras/ERK pathway, which is required for
      neuregulin-mediated induction of AChR subunit genes in muscle cells and synapse
      specific expression in vivo. Here we investigated the neuregulin transduction
      mechanism that leads to ERK activation after ErbB receptor tyrosine
      phosphorylation. Neuregulin increases the association of the adaptor proteins
      Grb2 and Shc with both ErbB2 and ErbB3 in C2C12 muscle cells. Dephosphorylation
      of the tyrosine-phosphorylated ErbB proteins abolished their association with
      both Grb2 and Shc, suggesting a tyrosine phosphorylation-dependent interaction.
      The interaction of Shc with the ErbB receptors is mediated by Shc's
      phosphotyrosine-binding domain. In addition, neuregulin increased tyrosine
      phosphorylation of Shc. Mutagenesis approaches demonstrated that tyrosine
      phosphorylation of Shc is required for neuregulin induction of AChR subunit gene
      expression. Taken together, these data indicate that the interaction of ErbB
      receptors with Grb2 alone is insufficient for neuregulin-activated transcription,
      but that ErbB receptor signaling via Shc is necessary and important.

PMID- 10582593
TI  - Glial and neuronal cells express functional chemokine receptor CXCR4 and its
      natural ligand stromal cell-derived factor 1.
AB  - Chemokines are a family of proteins that chemoattract and activate cells by
      interacting with specific receptors on the surface of their targets. The
      chemokine stromal cell-derived factor 1, (SDF1), binds to the seven-transmembrane
      G protein-coupled CXCR4 receptor and acts to modulate cell migration,
      differentiation, and proliferation. CXCR4 and SDF1 are reported to be expressed
      in various tissues including brain. Here we show that SDF1 and CXCR4 are
      expressed in cultured cortical type I rat astrocytes, cortical neurons, and
      cerebellar granule cells. In cortical astrocytes, prolonged treatment with
      lipopolysaccharide induced an increase of SDF1 expression and a down-regulation
      of CXCR4, whereas treatment with phorbol esters did not affect SDF1 expression
      and down-modulated CXCR4 receptor expression. We also demonstrated the ability of
      human SDF1alpha (hSDF1alpha) to increase the intracellular calcium level in
      cultured astrocytes and cortical neurons, whereas in the same conditions,
      cerebellar granule cells did not modify their intracellular calcium
      concentration. Furthermore, in cortical astrocytes, the simultaneous treatment of
      hSDF1alpha with the HIV-1 capside glycoprotein gp120 inhibits the cyclic AMP
      formation induced by forskolin treatment.

PMID- 10582595
TI  - High expression of the gamma5 isoform of G protein in neuroepithelial cells and
      its replacement of the gamma2 isoform during neuronal differentiation in the rat
      brain.
AB  - High concentrations of G proteins, which include multiple isoforms of each
      subunit, alpha, beta, and gamma, are expressed in the adult brain. In this study,
      we concentrated attention on changes of these isoforms during embryonic
      development in the rat brain. Concentrations of gamma2 as well as GoAalpha,
      GoBalpha, and beta2 were low in early embryogenesis and then increased, whereas
      expression of gamma5, in contrast, was initially high followed by a drop, with
      only very low levels observed throughout postnatal development. Among the other
      isoforms, Gi1alpha, G(s)alpha-short, G12alpha, G13alpha, beta4, gamma3, gamma7,
      and gamma12 were present in the embryonic brain at low levels, but their levels
      markedly increased after birth. In contrast, the levels of Gi2alpha, G(s)alpha
      long, Gq/11alpha, and beta1 were essentially constant throughout.
      Immunohistochemical staining of the brain vesicles in the embryos showed gamma5
      to be specifically expressed in the proliferative region of the ventricular zone,
      whereas gamma2 was mainly present in differentiated neuronal cells of the
      marginal zone. Furthermore, differentiation of P19 mouse embryonal carcinoma
      cells to neuronal cells with retinoic acid induced the expression of gamma2 and a
      decrease of gamma5, the major isoform in the undifferentiated state. These
      results suggest that neuronal differentiation is responsible for the on/off
      switch of the expression of gamma2 and gamma5 subunits.

PMID- 10582596
TI  - Dopamine D2 receptor isoforms expressed in AtT20 cells differentially couple to G
      proteins to acutely inhibit high voltage-activated calcium channels.
AB  - The dopamine D2 receptor belongs to the serpentine superfamily of receptors,
      which have seven transmembrane segments and activate G proteins. D2 receptors are
      known to be linked, through Galpha(o)- and Galpha(i)-containing G proteins, to
      several signaling pathways in neuronal and secretory cells, including inhibition
      of adenylyl cyclase and high voltage-activated Ca2+ channels (HVA-CCs). The
      dopamine D2 receptor exists in two alternatively spliced isoforms, "long" and
      "short" (D2L, and D2S, respectively), which have identical ligand binding sites
      but differ by 29 amino acids in the third intracellular loop, the proposed site
      for G protein interaction. This has led to the speculation that the two isoforms
      may interact with different G proteins. We have transfected the AtT20 cell line
      with either D2L (KCL line) or D2S (KCS line) to facilitate experimentation on the
      individual isoforms. Both lines show dopamine agonist-dependent inhibition of Q
      type HVA-CCs. We combined G protein antisense knock-down studies with
      multiwavelength fluorescence video microscopy to measure changes in HVA-CC
      inhibition to investigate the possibility of differential G protein coupling to
      this inhibition. The initial, rapid, K+ depolarization-induced increase in
      intracellular Ca2+ concentration is due to influx through HVA-CCs. Our studies
      reveal that both D2 isoforms couple to Galpha(o) to partially inhibit this
      influx. However, D2L also couples to Galpha(i)3, whereas D2S couples to
      Galpha(i)2. These data support the hypothesis of differential coupling of D2
      receptor isoforms to G proteins.

PMID- 10582597
TI  - Antisense-induced reduction of presenilin 1 expression selectively increases the
      production of amyloid beta42 in transfected cells.
AB  - Autosomal dominant mutations in the presenilin 1 (PS1) gene are associated with
      familial, early-onset Alzheimer's disease. Although the pathogenic mechanism of
      these mutations is unclear, their common feature is that they lead to an
      increased concentration of amyloid beta-peptide (Abeta) 42 in the plasma of early
      onset patients, in the conditioned media of transfected cells, and in the brains
      of transgenic mice that overexpress mutant PS1. To address the mechanism(s) by
      which the pathogenic PS1 mutations increase Abeta42, we constructed human cell
      lines expressing a doxycyclin (dox)-inducible antisense PS1 RNA and measured its
      effects on the levels of PS1, amyloid precursor protein (APP), and Abeta. In time
      course experiments, we observed a statistically significant (p = 0.0038) more
      than twofold elevation in secreted Abeta42 as early as 12 days after addition of
      dox. This correlated with an 80% decrease in the 46-kDa PS1 holoprotein and a 30%
      decrease in the 26-kDa N-terminal fragment (NTF). Furthermore, there was a
      significant fivefold (p = 0.002) increase in Abeta42 after 14-day dox treatment;
      this correlated with a >90% decrease in PS1 holoprotein and 60% decrease in NTF.
      At no time point did we observe significant changes in Abeta40, APP holoprotein,
      presenilin 2, or tubulin. Ten days after the removal of dox, we observed a return
      to constitutive levels for Abeta42, PS1 holoprotein, and NTF. These results
      suggest that in human cell lines, the reduction of normal PS1 activity results in
      the increased production of Abeta42. Furthermore, our results are consistent with
      a loss of function or dominant negative mechanism for the pathogenic PS1
      mutations.

PMID- 10582598
TI  - Effect of benzodiazepines on the epithelial and neuronal high-affinity glutamate
      transporter EAAC1.
AB  - EAAC1-mediated glutamate transport concentrates glutamate across plasma membranes
      of brain neurons and epithelia. In brain, EAAC1 provides a presynaptic uptake
      mechanism to terminate the excitatory action of released glutamate and to keep
      its extracellular concentration below toxic levels. Here we report the effect of
      well known anxiolytic compounds, benzodiazepines, on glutamate transport in EAAC1
      stably transfected Chinese hamster ovary (CHO) cells and in EAAC1-expressing
      Xenopus laevis oocytes. Functional properties of EAAC1 agreed well with already
      reported characteristics of the neuronal high-affinity glutamate transporter (Km
      D-Asp,CHO cells: 2.23+/-0.15 microM; Km D-Asp,oocytes: 17.01+/-3.42 microM). In
      both expression systems, low drug concentrations (10-100 microM) activated
      substrate uptake (up to 200% of control), whereas concentrations in the
      millimolar range inhibited (up to 50%). Furthermore, the activation was more
      pronounced at low substrate concentrations (1 microM), and the inhibition was
      attenuated. The activity of other sodium cotransporters such as the sodium/D
      glucose cotransporter SGLT1, stably transfected in CHO cells, was not affected by
      benzodiazepines. In electrophysiological studies, these drugs also failed to
      change the membrane potential of EAAC1-expressing Xenopus laevis oocytes. These
      results suggest a direct action on the glutamate transporter itself without
      modifying the general driving forces. Thus, in vivo low concentrations of
      benzodiazepines may reduce synaptic glutamate concentrations by increased uptake,
      providing an additional mechanism to modulate neuronal excitability.

PMID- 10582599
TI  - Amine weak bases disrupt vesicular storage and promote exocytosis in chromaffin
      cells.
AB  - The vesicular contents in bovine chromaffin cells are maintained at high levels
      owing to the strong association of its contents, which is promoted by the low
      vesicular pH. The association is among the catecholamines, Ca2+, ATP, and
      vesicular proteins. It was found that transient application of a weak base,
      methylamine (30 mM), amphetamine (10 microM), or tyramine (10 microM), induced
      exocytotic release. Exposure to these agents was also found to increase both
      cytosolic catecholamine and intracellular Ca2+ concentration, as measured by
      amperometry and fura-2 fluorescence. Amphetamine, the most potent amine with
      respect to evoking exocytosis, was found to be effective even in buffer without
      external Ca2+; however, the occurrence of spikes was suppressed when BAPTA
      acetoxymethyl ester was used to complex intracellular Ca2+. Amphetamine-induced
      spikes in Ca2+-free medium were not suppressed by thapsigargin or ruthenium red,
      inhibitors of the sarco(endo)plasmic reticulum Ca2+-ATPase and mitochondrial Ca2+
      stores. Atomic absorption measurements of amphetamine- and methylamine-treated
      vesicles reveal that intravesicular Ca2+ stores are decreased after a 15-min
      incubation. Taken together, these data indicate that amphetamine and methylamine
      can disrupt vesicular stores to a sufficient degree that Ca2+ can escape and
      trigger exocytosis.

PMID- 10582600
TI  - Dopamine neuronal transport kinetics and effects of amphetamine.
AB  - The dopamine (DA) transporter (DAT) regulates DA neurotransmission by recycling
      DA back into neurons. Drugs that interfere with DAT function, e.g., cocaine and
      amphetamine, can have profound behavioral effects. The kinetics of DA transport
      by DAT in isolated synaptosomal or single cell preparations have been previously
      studied. To investigate how DA transport is regulated in intact tissue and to
      examine how amphetamine affects the DAT, the kinetics of DA uptake by the DAT
      were examined in tissue slices of the mouse caudate-putamen with fast-scan cyclic
      voltammetry. The data demonstrate that inward DA transport is saturable and
      sodium-dependent. Elevated levels of cytoplasmic DA resulting from disruption of
      vesicular storage by incubation with 10 microM Ro 4-1284 did not generate DA
      efflux or decrease its uptake rate. However, incubation with 10 microM
      amphetamine reduced the net DA uptake rate and increased extracellular DA levels
      due to DA efflux through the DAT. In addition, a new, elevated steady-state level
      of extracellular DA was established after electrically stimulated DA release in
      the presence of amphetamine, norepinephrine, and exogenous DA. These results from
      intact tissue are consistent with a kinetic model of the DAT established in more
      purified preparations in which amphetamine and other transported substances make
      the inwardly facing DAT available for outward transport of intracellular DA.

PMID- 10582601
TI  - Activation and degradation of the transcription factor C/EBP during long-term
      facilitation in Aplysia.
AB  - Long-term facilitation (LTF) of the sensory-to-motor synapses that mediate
      defensive reflexes in Aplysia requires induction of the transcription factor
      Aplysia CCAAT/enhancer binding protein (ApC/EBP) as an early response gene. We
      examined the time course of ApC/ EBP DNA binding during the induction of LTF:
      Binding activity was detected within 1 h of the sensitization treatment with
      serotonin, reached a maximum at 2 h, and decreased after 6 h. How are DNA binding
      and the turnover of ApC/EBP regulated? We find that phosphorylation of ApC/EBP by
      mitogen-activated protein (MAP) kinase is essential for binding. MAP kinase
      appears to be activated through protein kinase C. We also showed that ApC/EBP is
      degraded through the ubiquitin-proteasome pathway but that phosphorylation by MAP
      kinase renders it resistant to proteolysis. Thus, phosphorylation by MAP kinase
      is required for ApC/EBP to act as a transcription activator as well as to assure
      its stability early in the consolidation phase, when genes essential for the
      development of LTF begin to be expressed.

PMID- 10582602
TI  - Botulinum neurotoxin E-insensitive mutants of SNAP-25 fail to bind VAMP but
      support exocytosis.
AB  - Neurotransmitter release from synaptic vesicles is mediated by complex machinery,
      which includes the v- and t-SNAP receptors (SNAREs), vesicle-associated membrane
      protein (VAMP), synaptotagmin, syntaxin, and synaptosome-associated protein of 25
      kDa (SNAP-25). They are essential for neurotransmitter exocytosis because they
      are the proteolytic substrates of the clostridial neurotoxins tetanus neurotoxin
      and botulinum neurotoxins (BoNTs), which cause tetanus and botulism,
      respectively. Specifically, SNAP-25 is cleaved by both BoNT/A and E at separate
      sites within the COOH-terminus. We now demonstrate, using toxin-insensitive
      mutants of SNAP-25, that these two toxins differ in their specificity for the
      cleavage site. Following modification within the COOH-terminus, the mutants
      completely resistant to BoNT/E do not bind VAMP but were still able to form a
      sodium dodecyl sulfate-resistant complex with VAMP and syntaxin. Furthermore,
      these mutants retain function in vivo, conferring BoNT/E-resistant exocytosis to
      transfected PC12 cells. These data provide information on structural requirements
      within the C-terminal domain of SNAP-25 for its function in exocytosis and raise
      doubts about the significance of in vitro binary interactions for the in vivo
      functions of synaptic protein complexes.

PMID- 10582603
TI  - Striatal dopamine metabolism in monoamine oxidase B-deficient mice: a brain
      dialysis study.
AB  - We have studied striatal dopamine (DA) metabolism in monoamine oxidase (MAO) B
      deficient mice using brain microdialysis. Baseline DA levels were similar in wild
      type and knock-out (KO) mice. Administration of a selective MAO A inhibitor,
      clorgyline (2 mg/kg), increased DA levels and decreased levels of its metabolites
      in all mice, but a selective MAO B inhibitor, l-deprenyl (1 mg/ kg), had no
      effect. Administration of 10 and 50 mg/kg L-DOPA, the precursor of DA, increased
      the levels of DA similarly in wild-type and KO mice. The highest dose of L-DOPA
      (100 mg/kg) produced a larger increase in DA in KO than wild-type mice. This
      difference was abolished by pretreating wild-type mice with l-deprenyl. These
      results suggest that in mice, DA is only metabolized by MAO A under basal
      conditions and by both MAO A and B at high concentrations. This is in contrast to
      the rat, where DA is always metabolized by MAO A regardless of concentration.

PMID- 10582604
TI  - D1 dopamine receptor-induced cyclic AMP-dependent protein kinase phosphorylation
      and potentiation of striatal glutamate receptors.
AB  - Dopamine receptor activation regulates cyclic AMP levels and is critically
      involved in modulating neurotransmission in the striatum. Others have shown that
      alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-type glutamate
      receptor-mediated current is potentiated by cyclic AMP-dependent protein kinase
      (PKA) activation. We made whole-cell patch clamp recordings from cultured
      striatal neurons and tested whether D1-type dopamine receptor activation affected
      AMPA receptor-mediated currents. After a 5-min exposure to the D1 agonist SKF
      81297 (1 microM), kainate-evoked current amplitude was enhanced in approximately
      75% of cells to 121+/-2.5% of that recorded prior to addition of drug. This
      response was inhibited by the D1 antagonist SCH 23390 and mimicked by activators
      of PKA. Moreover, by western blot analysis using an antibody specific for the
      phosphorylated PKA site Ser845 of GluR1, we observed a marked increase in
      phosphorylated GluR1 following a 10-min exposure of striatal neurons to 1 microM
      SKF 81297. Our data demonstrate that activation of D1-type dopamine receptors on
      striatal neurons promotes phosphorylation of AMPA receptors by PKA as well as
      potentiation of current amplitude. These results elucidate one mechanism by which
      dopamine can modulate neurotransmission in the striatum.

PMID- 10582605
TI  - Chronic delta9-tetrahydrocannabinol treatment produces a time-dependent loss of
      cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain.
AB  - Chronic treatment of rats with delta9-tetrahydrocannabinol (delta9-THC) results
      in tolerance to its acute behavioral effects. In a previous study, 21-day delta9
      THC treatment in rats decreased cannabinoid activation of G proteins in brain, as
      measured by in vitro autoradiography of guanosine-5'-O-(3-[35S]thiotriphosphate)
      ([35S]GTPgammaS) binding. The present study investigated the time course of
      changes in cannabinoid-stimulated [35S]GTPgammaS binding and cannabinoid receptor
      binding in both brain sections and membranes, following daily delta9-THC
      treatments for 3, 7, 14, and 21 days. Autoradiographic results showed time
      dependent decreases in WIN 55212-2-stimulated [35S]GTPgammaS and [3H]WIN 55212-2
      binding in cerebellum, hippocampus, caudate-putamen, and globus pallidus, with
      regional differences in the rate and magnitude of down-regulation and
      desensitization. Membrane binding assays in these regions showed qualitatively
      similar decreases in WIN 55212-2-stimulated [35S]GTPgammaS binding and
      cannabinoid receptor binding (using [3H]SR141716A), and demonstrated that
      decreases in ligand binding were due to decreases in maximal binding values, and
      not ligand affinities. These results demonstrated that chronic exposure to delta9
      THC produced time-dependent and region-specific down-regulation and
      desensitization of brain cannabinoid receptors, which may represent underlying
      biochemical mechanisms of tolerance to cannabinoids.

PMID- 10582606
TI  - Bax and Bcl-2 interaction in a transgenic mouse model of familial amyotrophic
      lateral sclerosis.
AB  - It has been proposed that mutations in copper/zinc-superoxide dismutase (SOD1),
      the only proven cause of amyotrophic lateral sclerosis (ALS), induce the disease
      by a toxic property that promotes apoptosis. Consistent with this, we have
      demonstrated that overexpression of Bcl-2, a protein that inhibits apoptosis,
      attenuates neurodegeneration produced by the familial ALS-linked SOD1 mutant G93A
      (mSOD1). Herein, we assessed the status of key members of the Bcl-2 family in the
      spinal cord of transgenic mSOD1 mice at different stages of the disease. In
      asymptomatic transgenic mSOD1 mice, expression of Bcl-2, Bcl-XL, Bad, and Bax
      does not differ from that in nontransgenic mice. In contrast, in symptomatic
      mice, expression of Bcl-2 and Bcl-XL, which inhibit apoptosis, is reduced,
      whereas expression of Bad and Bax, which stimulate apoptosis, is increased. These
      alterations are specific to affected brain regions and are caused by the mutant
      and not by the normal SOD1 enzyme. Relevant to the neuroprotective effects of Bcl
      2 in transgenic mSOD1 mice, overexpression of Bcl-2 increases the formation of
      Bcl-2:Bax heterodimers, which abolish the Bax proapoptotic property. This study
      demonstrates significant alterations in the expression of key members of the Bcl
      2 family associated with mSOD1 deleterious effects. That these changes contribute
      to the neurodegenerative process in this model of ALS is supported by our
      observations in double transgenic mSOD1/Bcl-2 mice in which the pernicious
      increase of Bax is tempered by an increase in formation of Bcl-2:Bax
      heterodimers. Based on these findings, it may be concluded that Bcl-2 family
      members appear as invaluable targets for the development of new neuroprotective
      therapies in ALS.

PMID- 10582607
TI  - Altered glial function causes neuronal death and increases neuronal
      susceptibility to 1-methyl-4-phenylpyridinium- and 6-hydroxydopamine-induced
      toxicity in astrocytic/ventral mesencephalic co-cultures.
AB  - Altered glial function in the substantia nigra in Parkinson's disease may lead to
      the release of toxic substances that cause dopaminergic cell death or increase
      neuronal vulnerability to neurotoxins. To investigate this concept, we examined
      the effects of subjecting astrocytes to lipopolysaccharide (LPS)-induced
      activation alone or combined with L-buthionine-[S,R]-sulfoximine-induced
      glutathione depletion or inhibition of complex I activity by 1-methyl-4
      phenylpyridinium (MPP+) on the viability of primary ventral mesencephalic
      neurones or susceptibility to MPP+ and 6-hydroxydopamine (6-OHDA) in co-cultures.
      LPS-activated astrocytes caused neuronal death in a time-dependent manner, but
      glutathione-depleted or complex I-inhibited astrocytes had no effect on neuronal
      viability. The neurotoxicity of LPS-activated astrocytes was inhibited by the
      inducible nitric oxide synthase inhibitor aminoguanidine, by the nitric oxide
      scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, and
      by reduced glutathione (GSH). MPP+-induced neuronal death was greater in ventral
      mesencephalic cultures previously cultured with LPS-activated, glutathione
      depleted, or complex I-inhibited astrocytes compared with co-cultures containing
      normal astrocytes. The increased neuronal susceptibility to MPP+ caused by LPS
      activated or complex I-inhibited astrocytes and glutathione-depleted astrocytes
      was inhibited by the NMDA/glutamate antagonist MK-801 and by GSH, respectively.
      Neuronal death caused by 6-OHDA was increased in ventral mesencephalic cultures
      previously cultured with LPS-activated and glutathione-depleted, but not complex
      I-inhibited astrocytes, compared with co-cultures containing normal astrocytes.
      Treatment of co-cultures with GSH prevented the increased neuronal susceptibility
      to 6-OHDA. These findings suggest that glial dysfunction may cause neuronal death
      or render neurones susceptible to toxic insults via a mechanism involving the
      release of free radicals and glutamate. Such a mechanism may play a role in the
      development or progression of nigrostriatal degeneration in Parkinson's disease.

PMID- 10582608
TI  - In vivo development of brain phosphocreatine in normal and creatine-treated
      rabbit pups.
AB  - To study the effects of creatine (Cr) on brain energy metabolism and on hypoxia
      induced seizures, 5- to 30-day-old rabbit pups were given subcutaneous Cr (3
      g/kg) for 3 days before exposure to 4% O2 for 8 min. In saline-treated controls,
      hypoxic seizures were most frequent at 15 days (80% of pups) and 20 days (60%) of
      age. Seizures were prevented at 15 days and reduced 60% at 20 days in Cr-treated
      pups. In surface coil-localized brain 31P nuclear magnetic resonance spectra,
      with signal from both cerebral gray (GM) and white (WM) matter, the
      phosphocreatine (PCr)/nucleoside triphosphate (NTP) ratio doubled between 5 and
      30 days of age in controls. In all Cr-injected pups, brain PCr/NTP increased to
      values seen in 30-day-old controls. When spectra were acquired in predominantly
      GM and WM slices in vivo, the PCr/NTP ratio was very low in GM at 5 days but
      reached adult levels by 15 days in controls. In WM, the ratio increased steadily
      from 5 to 30 days of age. In Cr-injected pups, PCr/NTP increased to mature levels
      in WM and in GM at all ages. In conclusion, hypoxic seizures occur midway in the
      time course of brain PCr/NTP increase in rabbit pups as previously described in
      rat pups. In both altricial pups, systemic Cr increases brain PCr/NTP ratio and
      prevents hypoxic seizures. These results suggest that mature levels of PCr and/or
      Cr in brain limit EEG activation either directly or indirectly by preventing
      hypoxic metabolic changes.

PMID- 10582609
TI  - Isoform pattern of 14-3-3 proteins in the cerebrospinal fluid of patients with
      Creutzfeldt-Jakob disease.
AB  - Two-dimensional polyacrylamide gel electrophoresis of CSF has been used in the
      diagnosis of Creutzfeldt-Jakob disease (CJD). One of the two diagnostic protein
      spots was identified as isoform(s) of the 14-3-3 family of abundant brain
      proteins. This has led to the development of one-dimensional 14-3-3 sodium
      dodecyl sulfate polyacrylamide gel electrophoresis immunoblot, which is currently
      used to support the diagnosis of CJD. In the present study employing western blot
      analysis, we have identified the panel of 14-3-3 isoforms that appear in the CSF
      of 10 patients with CJD compared with 10 patients with other dementias. The
      results clearly show that the 14-3-3 isoforms beta, gamma, epsilon, and eta are
      present in the CSF of patients with CJD and can be used to differentiate other
      dementias. 14-3-3eta also gave a baseline signal in all patients with other
      dementias, including six patients with Alzheimer's disease. The presence of 14-3
      3eta in the CSF of a patient with herpes simplex encephalitis was particularly
      noteworthy. This study has determined that isoform-specific 14-3-3 antibodies
      against beta, gamma, and epsilon should be considered for the neurochemical
      differentiation of CJD from other neurodegenerative diseases.

PMID- 10582610
TI  - Tumor necrosis factor-alpha increases lactoferrin transcytosis through the blood
      brain barrier.
AB  - Lactoferrin (Lf) is an iron-binding protein involved in host defense against
      infection and severe inflammation, which accumulates in the brain during
      neurodegenerative disorders. Prior to determining Lf function in pathological
      brain tissues, we investigated its transport through the blood-brain barrier
      (BBB) in inflammatory conditions. For this purpose, we used a reconstituted BBB
      model consisting of the coculture of bovine brain capillary endothelial cells
      (BBCECs) and astrocytes in the presence of tumor necrosis factor-alpha (TNF
      alpha). As TNF-alpha can be either synthesized by brain glial cells or present in
      circulating blood, BBCECs were exposed to this cytokine at their luminal or
      abluminal side. We have been able to demonstrate that in the presence of TNF
      alpha, whatever the type of exposure, BBCECs were activated and Lf transport
      through the activated BBCECs was markedly increased. Lf was recovered intact at
      the abluminal side of the cells, suggesting that increased Lf accumulation may
      occur in immune-mediated pathophysiology. This process was transient as 20 h
      later, cells were in a resting state and Lf transendothelial traffic was back to
      normal. The enhancement of Lf transcytosis seems not to involve the up-regulation
      of the Lf receptor but rather an increase in the rate of transendothelial
      transport.

PMID- 10582611
TI  - Activation of AP-1 and nuclear factor-kappaB transcription factors is involved in
      hydrogen peroxide-induced apoptotic cell death of oligodendrocytes.
AB  - H2O2-induced onset and execution of programmed cell death in mature rat brain
      oligodendrocytes in culture is accompanied by the induction and nuclear
      translocation of the transcription factors AP-1 and nuclear factor-kappaB (NF
      kappaB), both of which have been discussed as regulators of cell death and
      survival. Supershift analysis of nuclear extracts indicated that the AP-1 complex
      consists of c-Jun, c-Fos, JunD, and possibly JunB proteins, and that the NF
      kappaB complex contains p50, p65, and c-Rel proteins. The first signs of DNA
      fragmentation were seen already during the first hour after the treatment. DNA
      fragmentation could be prevented by the antioxidants pyrrolidine dithiocarbamate
      and vitamin E, by the nuclease inhibitor aurintricarboxylic acid, and by
      preincubation with the iron chelator deferoxamine (DFO). Additionally, DFO
      protected oligodendrocytes from H2O2-induced cytotoxic effects as assessed by the
      MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, and
      suppressed the formation of free radicals. DFO alone led to a slight increase and
      in combination with H2O2 synergistically induced DNA-binding activities of AP-1
      and NF-kappaB in oligodendrocytes. Our data suggest that although low levels of
      H2O2 directly activate AP-1 and NF-kappaB and might contribute to signal
      transduction pathways promoting cell survival, the formation and action of
      hydroxyl radicals promote cell death mechanisms that can be attenuated by the
      iron chelator DFO.

PMID- 10582612
TI  - Characterization of wild-type and mutants of recombinant human GTP cyclohydrolase
      I: relationship to etiology of dopa-responsive dystonia.
AB  - To explore the molecular etiology of two disorders caused by a defect in GTP
      cyclohydrolase I--hereditary progressive dystonia with marked diurnal fluctuation
      (HPD), also known as dopa-responsive dystonia (DRD), and autosomal recessive GTP
      cyclohydrolase I deficiency--we purified and analyzed recombinant human wild-type
      and mutant GTP cyclohydrolase I proteins expressed in Escherichia coli. Mutant
      proteins showed very low enzyme activities, and some mutants were eluted at a
      delayed volume on gel filtration compared with the recombinant wild-type. Next,
      we examined the GTP cyclohydrolase I protein amount by western blot analysis in
      phytohemagglutinin-stimulated mononuclear blood cells from HPD/DRD patients. We
      found a great reduction in the amount of the enzyme protein not only in one
      patient who had a frameshift mutation, but also in an HPD/DRD patient who had a
      missense mutation. These results suggest that a dominant-negative effect of
      chimeric protein composed of wild-type and mutant subunits is unlikely as a cause
      of the reduced enzyme activity in HPD/DRD patients. We suggest that reduction of
      the amount of the enzyme protein, which is independent of the mutation type,
      could be a reason for the dominant inheritance in HPD/DRD.

PMID- 10582613
TI  - Ethanol inhibits astroglial cell proliferation by disruption of phospholipase D
      mediated signaling.
AB  - The activation of phospholipase D (PLD) is a common response to mitogenic stimuli
      in various cell types. As PLD-mediated signaling is known to be disrupted in the
      presence of ethanol, we tested whether PLD is involved in the ethanol-induced
      inhibition of cell proliferation in rat cortical primary astrocytes. Readdition
      of fetal calf serum (FCS) to serum-deprived astroglial cultures caused a rapid,
      threefold increase of PLD activity and a strong mitogenic response; both effects
      were dependent on tyrosine kinases but not on protein kinase C. Ethanol (0.1-2%)
      suppressed the FCS-induced, PLD-mediated formation of phosphatidic acid (PA) as
      well as astroglial cell proliferation in a concentration-dependent manner.
      Moreover, exogenous bacterial PLD increased astroglial proliferation in an
      ethanol-sensitive manner, whereas exogenous PA or lysophosphatidic acid was less
      effective. Formation of PA and astroglial proliferation were strongly inhibited
      by 1-butanol (0.1-1%), a substrate of PLD, but were unaffected by t-butanol, a
      non-substrate; 2-butanol had intermediate effects. Platelet-derived growth factor
      and endothelin-1 mimicked the mitogenic effect of FCS; their effects were also
      inhibited by the butanols in the potency order 1-butanol > 2-butanol > tert
      butanol. Our results, in particular, the differential effects of 1-, 2-, and tert
      butanol with respect to PA formation and astroglial proliferation, strongly
      suggest that the antiproliferative effects of ethanol in glial cells are due to
      the disruption of the PLD signaling pathway. This mechanism may also contribute
      to the inhibition of astroglial growth and brain development observed in
      alcoholic embryopathy.

PMID- 10582614
TI  - Propofol hemisuccinate protects neuronal cells from oxidative injury.
AB  - Oxidative stress contributes to the neuronal death observed in neurodegenerative
      disorders and neurotrauma. Some antioxidants for CNS injuries, however, have yet
      to show mitigating effects in clinical trials, possibly due to the impermeability
      of antioxidants across the blood-brain barrier (BBB). Propofol (2,6
      diisopropylphenol), the active ingredient of a commonly used anesthetic, acts as
      an antioxidant, but it is insoluble in water. Therefore, we synthesized its water
      soluble prodrug, propofol hemisuccinate sodium salt (PHS), and tested for its
      protective efficacy in neuronal death caused by non-receptor-mediated, oxidative
      glutamate toxicity. Glutamate induces apoptotic death in rat cortical neurons and
      the mouse hippocampal cell line HT-22 by blocking cystine uptake and causing the
      depletion of intracellular glutathione, resulting in the accumulation of reactive
      oxygen species (ROS). PHS has minimal toxicity and protects both cortical neurons
      and HT-22 cells from glutamate. The mechanism of protection is attributable to
      the antioxidative property of PHS because PHS decreases the ROS accumulation
      caused by glutamate. Furthermore, PHS protects HT-22 cells from oxidative injury
      induced by homocysteic acid, buthionine sulfoximine, and hydrogen peroxide. For
      comparison, we also tested alpha-tocopherol succinate (TS) and methylprednisolone
      succinate (MPS) in the glutamate assay. Although TS is protective against
      glutamate at lower concentrations than PHS, TS is toxic to HT-22 cells. In
      contrast, MPS is nontoxic but also nonprotective against glutamate. Taken
      together, PHS, a water-soluble prodrug of propofol, is a candidate drug to treat
      CNS injuries owing to its antioxidative properties, low toxicity, and
      permeability across the BBB.

PMID- 10582615
TI  - A novel microtubule-associated protein-2 expressed in oligodendrocytes in
      multiple sclerosis lesions.
AB  - Elucidation of the mechanisms involved in the regeneration of oligodendrocytes
      and remyelination is a central issue in multiple sclerosis (MS) research. We
      recently identified a novel alternatively spliced, developmentally regulated
      oligodendrocyte-specific protein designated microtubule-associated protein-2+13
      [microtubule-associated protein-2 expressing exon 13 (MAP-2+13)]. MAP-2+13 is
      expressed in human fetal oligodendrocytes during process extension and
      myelination but is minimally expressed in normal mature CNS. To test the
      hypothesis that MAP-2+13 is reexpressed in regenerating oligodendrocytes in MS
      lesions, we examined the brains of MS patients for the expression of this
      protein. By immunocytochemistry using a series of monoclonal antibodies specific
      for MAP-2+13, we determined that MAP-2+13 expression was up-regulated in all 31
      lesions from 10 different MS brains. MAP-2+13 was expressed in regenerating
      oligodendrocytes associated with demyelinated lesions, with the highest counts
      found in regions of extensive remyelination. By electron microscopy, MAP-2+13 was
      localized to oligodendrocytes engaged in remyelination, evident by their process
      extension and association with thinly myelinated (remyelinated) and demyelinated
      axons. These results suggest a hitherto unsuspected role for this microtubule
      associated protein in oligodendrocyte function during development and myelin
      repair.

PMID- 10582616
TI  - Vesicular monoamine transporter 1 is responsible for storage of 5
      hydroxytryptamine in rat pinealocytes.
AB  - Vesicular monoamine transporters (VMATs) are involved in chemical transduction in
      monoaminergic neurons and various endocrine cells through the storage of
      monoamines in secretory vesicles. Mammalian pinealocytes contain more 5
      hydroxytryptamine (5-HT) than any other cells and are expected to contain VMAT,
      although no information is available so far. Upon the addition of ATP,
      radiolabeled 5-HT was taken up by a particulate fraction prepared from cultured
      rat pinealocytes. The 5-HT uptake was inhibited significantly by bafilomycin A1
      (an inhibitor of vacuolar H+-ATPase), 3,5-di-tert-butyl-4
      hydroxybenzylidenemalononitrile (a proton conductor), or reserpine (an inhibitor
      of VMAT). RT-PCR analysis suggested that VMAT type 1 (VMAT1), but not type 2, is
      expressed. Antibodies against VMAT1 recognized a single polypeptide with an
      apparent molecular mass of approximately 55 kDa, and specifically immunostained
      pinealocytes. VMAT1 immunoreactivity was high in the vesicular structures in the
      varicosities of long branching processes and was associated with 5-HT, but not
      with synaptophysin, a marker protein for microvesicles. The 5-HT immunoreactivity
      in the long branching processes disappeared upon incubation with reserpine. These
      results indicate that 5-HT, at least in part, is stored in vesicles other than
      microvesicles in pinealocytes through a mechanism similar to that of various
      secretory vesicles.

PMID- 10582617
TI  - Peroxynitrite- and nitrite-induced oxidation of dopamine: implications for nitric
      oxide in dopaminergic cell loss.
AB  - Increased nitric oxide (NO) production has been implicated in many examples of
      neuronal injury such as the selective neurotoxicity of methamphetamine and 1
      methyl-4-phenyl-1,2,3,6-tetrahydropyridine to dopaminergic cells, presumably
      through the generation of the potent oxidant peroxynitrite (ONOO). Dopamine (DA)
      is a reactive molecule that, when oxidized to DA quinone, can bind to and
      inactivate proteins through the sulfhydryl group of the amino acid cysteine. In
      this study, we sought to determine if ONOO could oxidize DA and participate in
      this process of protein modification. We measured the oxidation of the
      catecholamine by following the binding of [3H]DA to the sulfhydryl-rich protein
      alcohol dehydrogenase. Results showed that ONOO oxidized DA in a concentration-
      and pH-dependent manner. We confirmed that the resulting DA-protein conjugates
      were predominantly 5-cysteinyl-DA residues. In addition, it was observed that
      ONOO decomposition products such as nitrite were also effective at oxidizing DA.
      These data suggest that the generation of NO and subsequent formation of ONOO or
      nitrite may contribute to the selective vulnerability of dopaminergic neurons
      through the oxidation of DA and modification of protein.

PMID- 10582618
TI  - Chronic exposure to ammonia alters pathways modulating phosphorylation of
      microtubule-associated protein 2 in cerebellar neurons in culture.
AB  - Hyperammonemia is considered the main cause for the neurological alterations
      found in hepatic failure. However, the mechanisms by which high ammonia levels
      impair cerebral function are not well understood. It has been shown that chronic
      hyperammonemia impairs signal transduction pathways associated with NMDA
      receptors and also alters phosphorylation of some neuronal proteins. The aim of
      the present work was to analyze the effects of chronic exposure to ammonia on
      phosphorylation of microtubule-associated protein 2 (MAP-2) in intact neurons in
      culture and to assess whether modulation of MAP-2 phosphorylation by glutamate
      receptor-associated transduction pathways is altered in neurons chronically
      exposed to ammonia. It is shown that chronic exposure to ammonia increases basal
      phosphorylation of MAP-2 by approximately 70%. This effect seems to be due to a
      decreased tonic activation of NMDA receptors and of calcineurin. Chronic exposure
      to ammonia also alters the modulation of MAP-2 phosphorylation by NMDA receptors
      and metabotropic glutamate receptors. In neurons exposed to ammonia, treatment
      with NMDA for 30 min induced a significant decrease in phosphorylation of MAP-2.
      Activation of metabotropic glutamate receptors with (1S,3R)-1-aminocyclopentane
      1,3-dicarboxylic acid significantly increased phosphorylation of MAP-2 in control
      neurons, whereas in neurons exposed to ammonia the response was the opposite,
      with 1-aminocyclopentane-1,3-dicarboxylic acid inducing a dephosphorylation of
      MAP-2. These results indicate that ammonia alters significantly signal
      transduction pathways associated with different types of glutamate receptors.
      This would lead therefore to significant alterations in glutamatergic
      neurotransmission, which would contribute to the neurological alterations found
      in hyperammonemia and in hepatic encephalopathy.

PMID- 10582619
TI  - Stimulation of the brain NO/cyclic GMP pathway by peripheral administration of
      tetrahydrobiopterin in the hph-1 mouse.
AB  - Mutations in GTP-cyclohydrolase I (GTP-CH) have been identified as causing a
      range of inborn errors of metabolism, including dopa-responsive dystonia. GTP-CH
      catalyses the first step in the biosynthesis of tetrahydrobiopterin (BH4), a
      cofactor necessary for the synthesis of catecholamines and serotonin. Current
      therapy based on monoamine neurotransmitter replacement may be only partially
      successful in correcting the neurological deficits. The reason might be that BH4
      is also a cofactor for nitric oxide synthase. Using a strain of mutant GTP-CH
      deficient (hph-1) mice, we demonstrate that in addition to impaired monoamine
      metabolism, BH4 deficiency is also associated with diminished nitric oxide
      synthesis in the brain (as evaluated by measuring the levels of cyclic GMP), when
      compared with wild-type animals. We have found a decline in the levels of BH4
      with age in all animals, but no gender-related differences. We found a strong
      association between the levels of BH4 and cyclic GMP in hph-1 mice but not in
      wild-type animals. We also demonstrate that acute peripheral administration of
      BH4 (100 micromol/kg s.c.) in hph-1 mice significantly elevated the brain BH4
      concentration and subsequently cyclic GMP levels in cerebellum, with peaks at 2
      and 3 h, respectively. We suggest that BH4 administration should be considered in
      BH4 deficiency states in addition to monoamine replacement therapy.

PMID- 10582620
TI  - Serotonin-mediated increases in the extracellular levels of beta-endorphin in the
      arcuate nucleus and nucleus accumbens: a microdialysis study.
AB  - Although the involvement of both endogenous opioid and serotonergic systems in
      modulation of pain and emotion was suggested, the neurochemical interaction
      between these systems in the brain has not previously been studied directly.
      Herein, the effects of the local application of serotonin (5-HT) and fluoxetine
      (a 5-HT reuptake inhibitor) on extracellular levels of beta-endorphin in the
      arcuate nucleus and nucleus accumbens were assessed in freely moving rats using
      in vivo microdialysis. The mean basal concentrations of beta-endorphin in
      dialysates obtained from the arcuate nucleus and nucleus accumbens were 259.9 and
      143.3 pM, respectively. Specific lesion of the serotonergic system by 5,7
      dihydroxytryptamine (5,7-DHT) caused a significant decrease in these dialysate
      beta-endorphin levels. When 5-HT (0.25-5 microM) was added to the perfusion
      solution, the levels of beta-endorphin in the dialysate from the arcuate nucleus
      increased (186-296% of baseline), in a concentration-dependent manner. In the
      nucleus accumbens, 0.5 and 2 microM 5-HT in the perfusion fluid did not affect
      the levels of beta-endorphin in the dialysate, whereas 5 and 10 microM 5-HT
      caused an increase of approximately 190% of baseline. When fluoxetine (250
      microM) was present in the perfusing solution, the levels of beta-endorphin in
      the dialysates from the arcuate nucleus and nucleus accumbens increased two- to
      threefold. This effect was not obtained in the 5,7-DHT-lesioned rats. Thus, 5-HT,
      either endogenously or exogenously delivered, appears to facilitate the release
      of beta-endorphin in the arcuate nucleus and nucleus accumbens. This indication
      of an interaction between serotonergic and endorphinic systems may be relevant
      for assessing pain and mood disorder circuits and the mode of action of
      antidepressant drugs.

PMID- 10582621
TI  - The Na-G ion channel is transcribed from a single promoter controlled by distinct
      neuron- and Schwann cell-specific DNA elements.
AB  - Na-G is a putative sodium (or cationic) channel expressed in neurons and glia of
      the PNS, in restricted neuronal subpopulations of the brain, and in several
      tissues outside the nervous system, like lung and adrenal medulla. To analyze the
      mechanisms underlying tissue-specific expression of this channel, we isolated the
      5' region of the corresponding gene and show that Na-G mRNA transcription
      proceeds from a single promoter with multiple initiation sites. By transgenic
      mice studies, we demonstrate that 600 bp containing the Na-G proximal promoter
      region and the first exon are sufficient to drive the expression of a beta
      galactosidase reporter gene in neurons of both CNS and PNS, whereas expression in
      Schwann cells depends on more remote DNA elements lying in the region between 
      6,500 and -1,050 bp upstream of the main transcription initiation sites. Crucial
      elements for lung-specific expression seem to be located in the region between 
      1,050 and -375 bp upstream of the promoter. Using in vivo footprint experiments,
      we demonstrate that several sites of the Na-G proximal promoter region are bound
      specifically by nuclear proteins in dorsal root ganglion neurons, as compared
      with nonexpressing hepatoma cells.

PMID- 10582622
TI  - Increased expression of rat synuclein in the substantia nigra pars compacta
      identified by mRNA differential display in a model of developmental target
      injury.
AB  - Human alpha-synuclein was identified on the basis of proteolytic fragments
      derived from senile plaques of Alzheimer's disease, and it is the locus of
      mutations in some familial forms of Parkinson's disease. Its normal function and
      whether it may play a direct role in neural degeneration remain unknown. To
      explore cellular responses to neural degeneration in the dopamine neurons of the
      substantia nigra, we have developed a rodent model of apoptotic death induced by
      developmental injury to their target, the striatum. We find by mRNA differential
      display that synuclein is up-regulated in this model, and thus it provides an
      opportunity to examine directly whether synuclein plays a role in the death of
      these neurons or, alternatively, in compensatory responses. Up-regulation of mRNA
      is associated with an increase in the number of neuronal profiles immunostained
      for synuclein protein. At a cellular level, synuclein is almost exclusively
      expressed in normal neurons, rather than apoptotic profiles. Synuclein is up
      regulated throughout normal postnatal development of substantia nigra neurons,
      but it is not further up-regulated during periods of natural cell death. We
      conclude that up-regulation of synuclein in the target injury model is unlikely
      to mediate apoptotic death and propose that it may be due to a compensatory
      response in neurons destined to survive.

PMID- 10582623
TI  - A novel rat tetraspan protein in cells of the oligodendrocyte lineage.
AB  - The tetraspanin/transmembrane 4 superfamily gene superfamily encodes proteins
      that span the plasma membrane four times. Tetraspan proteins are implicated in
      proliferation, motility, and differentiation in various cell types, and in some
      cells they may link plasma membrane proteins into signalling complexes. Using a
      subtractive cDNA library prepared from oligodendrocytes and their progenitor
      cells, we have identified Tspan-2 as a member of this superfamily. In situ
      hybridization analysis revealed robust expression in cells of the oligodendrocyte
      lineage in comparison with the Plp gene, a well-characterized marker for myelin
      forming glia in the CNS. Rat Tspan-2 mRNA is restricted to the nervous system and
      is detectable by northern blot shortly after birth in the CNS. Subsequently the
      gene is up-regulated strongly between postnatal day 3 and 10, and expression
      levels continue to rise up to postnatal day 22. These data indicate that Tspan-2
      is likely to play a role in signalling in oligodendrocytes in the early stages of
      their terminal differentiation into myelin-forming glia and may also function in
      stabilizing the mature sheath.

PMID- 10582624
TI  - c-Jun contributes to amyloid beta-induced neuronal apoptosis but is not necessary
      for amyloid beta-induced c-jun induction.
AB  - The role of gene expression in neuronal apoptosis may be cell- and apoptotic
      stimulus-specific. Previously, we and others showed that amyloid beta (Abeta)
      induced neuronal apoptosis is accompanied by c-jun induction. Moreover, c-Jun
      contributes to neuronal death in several apoptosis paradigms involving survival
      factor withdrawal. To evaluate the role of c-Jun in Abeta toxicity, we compared
      Abeta-induced apoptosis in neurons from murine fetal littermates that were
      deficient or wild-type with respect to c-Jun. We report that neurons deficient
      for c-jun are relatively resistant to Abeta toxicity, suggesting that c-Jun
      contributes to apoptosis in this model. When changes in gene expression were
      quantified in neurons treated in parallel, we found that Abeta treatment
      surprisingly led to an apparent activation of the c-jun promoter in both the c
      jun-deficient and wild-type neurons, suggesting that c-Jun is not necessary for
      activation of the c-jun promoter. Indeed, several genes induced by Abeta in wild
      type neurons were also induced in c-jun-deficient neurons, including c-fos, fosB,
      ngfi-B, and ikappaB. In summary, these results indicate that c-Jun contributes to
      Abeta-induced neuronal death but that c-Jun is not necessary for c-jun induction.

PMID- 10582625
TI  - Human apolipoprotein E isoform-specific differences in neuronal sprouting in
      organotypic hippocampal culture.
AB  - The apolipoprotein E (ApoE) epsilon4 allele is a major risk factor for
      neurodegenerative conditions, including Alzheimer's disease. A role for ApoE is
      implicated in regeneration of synaptic circuitry after neural injury. In the in
      vitro mouse organotypic hippocampal slice culture system, we previously showed
      that cultures derived from ApoE-knockout mice are defective in mossy fiber
      sprouting into the dentate gyrus molecular layer. This sprouting defect was
      rescued in cultures from transgenic mice expressing ApoE3 under the control of
      the human promoter and in ApoE-knockout cultures treated with ApoE3-conditioned
      media. Although the ApoE3 transgene fully restored sprouting, ApoE4 restored
      sprouting to only 58% of ApoE3 levels. These data indicate that ApoE isoform
      specific effects on neuroregeneration may contribute to its genetic risk for
      Alzheimer's disease.

PMID- 10582626
TI  - Structural requirements of 5-hydroxytryptamine-moduline analogues to interact
      with the 5-hydroxytryptamine1B receptor.
AB  - 5-Hydroxytryptamine-moduline is an endogenous cerebral tetrapeptide that
      regulates the activity of 5-hydroxytryptamine1B receptors. Direct binding of 5
      [3H]hydroxytryptamine-moduline on rat brain homogenate evidenced the existence of
      two interacting sites for the peptide, very likely corresponding to different
      conformations of the 5-hydroxytryptamine1B receptor: The peptide first binds to a
      low-affinity state of the receptor (pIC50 = 7.68+/-0.14) and then induces (or
      stabilizes) a high-affinity complex (pIC50 = 11.62+/-0.18). This work focuses on
      the ability of 5-hydroxytryptamine-moduline analogues to recognize the high- and
      low-affinity sites for 5-hydroxytryptamine-moduline. The results obtained show
      that the two conformers of the 5-hydroxytryptamine1B receptor have similar but
      not identical binding pockets for 5-hydroxytryptamine-moduline. These two sites
      proved to be stereoselective and selective for tetrapeptides and favored the
      binding of peptides with hydrophobic amino acids in positions 1 and 4, serine in
      position 2, and a short amino acid in position 3. However, the serine in position
      2 seems to be more important for the interaction of the peptide with the low
      affinity site than the high-affinity one, which only needs a short hydrophobic
      amino acid in position 2.

PMID- 10582627
TI  - Is alpha-methyl-L-tryptophan a good tracer for brain serotonin synthesis
      measurements, and does the lumped constant vary in different structures of the
      rat brain?

PMID- 10582628
TI  - How effective are complementary therapies for HIV and AIDs?--A systematic review.
AB  - Complementary treatments are often used by HIV-infected individuals. Yet little
      is known about their effectiveness. The aim of this systematic review was
      therefore to summarize the published evidence for or against the effectiveness of
      complementary therapies in HIV-positive people. A comprehensive literature search
      was conducted to locate all randomized clinical trials (RCTs) of complementary
      therapies. Data were extracted in a standardized fashion and evaluated
      critically. Fourteen studies met our pre-defined inclusion/exclusion criteria; 2
      of herbal treatments, 5 of vitamins and other supplements, 5 of stress
      management, one of massage therapy, and one of acupuncture. They fall into 2
      broad categories of 'cure' and 'care'. While the former category yields few
      encouraging results, the latter group of studies is more promising. In
      particular, stress management may prove to be an effective way to increase the
      quality of life. It is concluded that few rigorous trials of complementary
      treatments for HIV exist. The domain of complementary medicine may lie in the
      care for HIV-infected individuals with a view of increasing their quality of
      life. This notion requires further rigorous investigation.

PMID- 10582629
TI  - Update on the treatment of sexually transmitted infections in pregnancy--2.

PMID- 10582630
TI  - Subtyping of high-level plasmid-mediated tetracycline resistant Neisseria
      gonorrhoeae isolated in Scotland between 1992 and 1998.
AB  - Tetracycline resistant Neisseria gonorrhoeae (TRNG) contain a 25.2 MDa TetM
      plasmid encoding a 68 KDa cytoplasmic protein which confers high-level
      tetracycline resistance. The aim of this study was to subtype all TRNG isolated
      in Scotland between 1992 and 1998. Subtyping was performed by a polymerase chain
      reaction (PCR) assay which characterizes the TetM plasmid as either the Dutch
      variant (443 base pair product) or the American variant (777 base pair product).
      Of the 78 TRNG isolates, 35 were the American variant and 43 were the Dutch
      variant. TRNG were distributed amongst 30 serovar/auxotype classes, the most
      common being 1A6/NR (11.5%), 1A6/P (14.1%) and 1B4/NR (14.1%). The country where
      infection was acquired was known for 36 of the 46 TRNG strains isolated between
      1996 and 1998. All infections acquired in Asia and South America were the Dutch
      variant whereas all infections acquired in Africa were the American variant. A
      penicillinase plasmid was present in 66% (23/35) of the American variant TRNG
      compared with 51% (22/43) of the Dutch variant: the 3.2 MDa penicillinase plasmid
      was found in 87% of the American variant TRNG whereas the 4.4 MDa penicillinase
      plasmid was found in 68% of the Dutch variant TRNG. We conclude that subtyping of
      TRNG by PCR is a useful tool in studying the epidemiology of gonococcal infection
      due to plasmid-mediated resistant isolates.

PMID- 10582631
TI  - Monitoring cytomegalovirus retinitis prevalence in an HIV-seropositive cohort:
      the assessment of improvements observed following the introduction of highly
      active antiretroviral triple therapy.
AB  - This paper concerns the ophthalmic assessment of patients with acquired
      immunodeficiency syndrome (AIDS) for a number of eye conditions and in particular
      cytomegalovirus (CMV) retinitis. CMV has been the most common opportunistic
      infection associated with AIDS and the leading cause of blindness among AIDS
      patients. There have been early indications of a widespread fall in CMV
      prevalence internationally following the introduction of a new highly active
      antiretroviral triple (HAART) therapy. Our study sought to assess the position
      for Ireland. Our cohort was the entire population of stage IV AIDS patients
      attending the country's leading referral centre. The total number of patients
      examined was 167 and the period of examination was 1 May 1995 to 30 April 1997.
      HAART was introduced in March 1996, so the data permitted a 'before and after'
      comparison of various clinical findings. The incidence of new CMV cases was found
      to be 4 among the 102 patients examined in the first 12-month period and one
      among 107 patients examined in the second 12-month period. There were
      accompanying declines in HIV-related noninfectious retinal vasculopathy (HIVR),
      keratitis and other conditions. The findings are promising, but we argue that
      caution is needed in assessing long-term trends. In the paper we discuss a number
      of methodological issues in the collection and analysis of the clinical data and
      in the interpretation of results.

PMID- 10582632
TI  - Sexually transmitted infections in the Russian Federation, the Baltic States and
      Poland.

PMID- 10582633
TI  - The control and management of the sexually transmitted diseases: a comparison of
      the United Kingdom and the Russian Federation.
AB  - During the last 20 years, both the United Kingdom and the Russian Federation have
      seen changes to clinical services for sexually transmitted diseases (STDs) health
      systems and other mechanisms through which STDs are controlled. In the UK these
      changes followed the description of the acquired immunodeficiency syndrome (AIDS)
      and the human immunodeficiency virus (HIV); its causal agent. In Russia, the
      breakdown of the Soviet Union following glasnost and perestroika, and its
      associated political, social and economic changes generated substantial
      developments to the ideological and legislative framework within which STD
      control is achieved as well as a revolution in the financial base upon which
      clinical STD services operate. The purpose of this paper is to sketch these
      developments in STD services within the 2 countries to provide a context for the
      series of papers presented in this edition.

PMID- 10582634
TI  - Syphilis and other sexually transmitted infections in the Russian Federation.
AB  - The countries of the former Soviet Union are currently experiencing major
      epidemics of sexually transmitted infections (STIs). By 1997 rates of syphilis
      notification in the Russian Federation had risen to 277 per 100,000 total
      population, a 43-fold increase over 1989 levels, with rises proportionally larger
      among young women. Epidemics of gonorrhoea occurred earlier in Russia with
      official notification rates rising from 105 per 100,000 in 1987 to 232 per
      100,000 in 1993; and exceeded one per 100 among both young men and young women in
      that year. The true incidence of gonorrhoea is certainly much higher. These STI
      epidemics cause direct suffering and may be important in significantly enhancing
      the transmission of human immunodeficiency virus (HIV), in the context of
      liberalization of sexual behaviour, and epidemics of injecting drug use and
      related HIV transmission. This paper reviews recent epidemiological trends in
      syphilis and other STIs in Russia against the background of existing mechanisms
      for the control of these infections.

PMID- 10582635
TI  - Sexually transmitted infections in Estonia.
AB  - Estonia, one of the Baltic countries, regained its independence in 1991, after
      the collapse of the USSR. This process led to great changes in every sphere of
      life--in politics, in the economy and in medicine. The service providing care for
      sexually transmitted infections (STIs) was involved in the process of these
      changes, too. However, freedom was followed not only by great happiness, but also
      by social destabilization and transformation of the old moral norms, the most
      evident features of which were the dramatic rise in crime, a sexual revolution
      and public prostitution. These 2 great simultaneous transformations in the STI
      care system and public mores led to the rapid increase of STIs in Estonia in the
      first half of the 1990s. Now some stabilization, and even a fall in incidence has
      occurred.

PMID- 10582636
TI  - Sexually transmitted diseases in Lithuania: some epidemiological and social
      aspects.
AB  - With political, economical and social changes in Lithuania following the break-up
      of the Soviet Union, the health-care system has changed. The old Soviet system
      has been abandoned and it has taken time to re-establish a system under the new
      government. Resources are limited in most aspects of health care, including
      sexually transmitted infections (STIs). This has, also limited the development of
      education packages on STIs which are so important when trying to combat the
      spread of HIV infection. Notifications of syphilis, in Lithuania, have increased
      52 fold between 1990 and 1996 although, since then, the incidence has started to
      decrease. Syphilis has been more reliably notified than other STIs and serves as
      the most reliable indicator of STI trends.

PMID- 10582637
TI  - HIV infection and sexually transmitted infections in Lithuania.
AB  - Lithuania is a small country with a population of 3.7 million. It has recently
      been released from the yoke of Soviet rule. HIV infection was first identified in
      1988 and while the numbers of cases are small, the incidence is beginning to rise
      precipitously. A National AIDS Centre has been established in the capital,
      Vilnius, and a nationwide epidemiological survey is underway. Efforts are being
      made to prevent HIV infection. Sixty one per cent of notified cases of HIV
      infection are in Klaipeda, a port city adjacent to the Kaliningrad region and the
      predominant mode of transmission is by intravenous drug use. The majority of
      cases of AIDS, however, are seen in Vilnius. Sexually transmitted infections
      (STIs) are poorly controlled and there is no national control strategy. While the
      incidence of gonorrhoea is declining, new cases of syphilis have been on the
      increase, reaching 101.4 cases per 100,000 of the population. Cases of congenital
      syphilis are still seen.

PMID- 10582638
TI  - Epidemiology of syphilis and gonorrhoea in eastern Poland in the years 1988-1997.
AB  - Because of the sexually transmitted diseases (STDs) epidemic in the former Soviet
      Union and the possibility of a rise in early syphilis and gonorrhoea in the
      eastern region of Poland it seemed important to calculate the incidence rates for
      early syphilis and gonorrhoea for 3 border regions (east, west and south) and the
      central part of the country in the last 10 years. In addition, data were analysed
      on patients and their sexual partners (from Poland and abroad), and the country
      where the contact took place obtained from 14 Provincial Skin-VD Out-Patients'
      Clinics of eastern Poland. The results from 1988/89 and 1996/97 were compared. It
      was shown that early syphilis morbidity significantly decreased in western and
      southern Poland, fell in the central part and rose in the east slightly.
      Gonorrhoea morbidity significantly decreased in all regions. However, the number
      of provinces with early syphilis and gonorrhoea incidence rates in the 1990s of
      the same value or higher than in the 1980s, or of the whole of Poland clearly
      increased in eastern and central regions. The early syphilis and gonorrhoea
      morbidity in east Poland in the 1990s in relation to 1980s was marked by
      significant increase in the percentage of the foreigners treated (12.2 vs 1.8,
      P<0.001 for early syphilis, and 10.0 vs 2.3, P<0.001 for gonorrhoea) and in
      sexual contacts with foreigners reported by Polish patients (23.7 vs 0.8, P<0.01
      for early syphilis and 17.7 vs 4.3, P<0.01 for gonorrhoea). Of the foreign
      contacts reported in 1996/97 by early syphilis and gonorrhoea patients, 60.4% and
      82.2%, respectively, were casual. Contact with foreigners took place, mainly, in
      the former Soviet Union. The study illustrates that there may be a danger of an
      increase in the incidence of syphilis and gonorrhoea in Poland due to the
      epidemics in the neighbouring countries.

PMID- 10582639
TI  - The name game: lamivudine-lamotrigine dispensing error presenting as human
      immunodeficiency virus-associated fever of unknown origin.

PMID- 10582640
TI  - Hepatitis as the presenting feature of an HIV seroconversion illness.

PMID- 10582641
TI  - Antiretroviral therapy in HIV infection: are we using resources appropriately and
      cost effectively?
AB  - The provision of antiretroviral therapy to HIV-positive patients attending the
      Department of Genitourinary Medicine at the Royal Infirmary of Edinburgh was
      assessed, to examine whether clinicians were offering treatment in line with the
      departmental protocol. A total of 195 patients attended in 1998, of whom 169
      fulfilled the protocol criteria for treatment. Although only 115 of these were on
      therapy, no patient who fulfilled treatment criteria and wished to be treated was
      denied treatment. Of the 26 patients not fulfilling any treatment criteria, 9 had
      transferred in from another unit already on treatment. The remaining 17 were not
      on treatment.

PMID- 10582642
TI  - An audit of antiretroviral prescribing in HIV patients. Yorkshire Audit Group for
      HIV-related diseases.

PMID- 10582643
TI  - A case of cat scratch disease masquerading as lymphogranuloma venereum.

PMID- 10582644
TI  - Progress of the basics.

PMID- 10582645
TI  - Effects of potentization in aqueous solutions.
AB  - Over the past two decades, research into structure formation and structure
      conservation in water has created a significant interest among the homeopathy
      research community. The formation of sustained static and dynamic structures in
      aqueous solutions is thought to be synonymous with the possible storage of
      information in associated liquids. Prominent models and experiments considering
      this possibility are presented in this paper, and some of their subtleties, which
      were not given much room in the respective original publications, will be
      elucidated in more detail here.

PMID- 10582646
TI  - Physical, chemical and biological assay of Tylophora indica mother tincture--a
      comparative study.
AB  - Successful use of homeopathic medicines is related to the purity and quality of
      crude and finished products. To maintain the quality of Tylophora indica mother
      tincture, a comparative study on physical, chemical and biological assay of five
      samples (reference laboratory and market) of Tylophora indica was carried out.
      The market sample showed different chromatographic characteristics and may have
      been prepared from a different species. T. indica has antispasmodic and
      hypotensive properties.

PMID- 10582647
TI  - The toxicology of Octopus maculosa: the blue-ringed octopus.
AB  - The biotoxicology of the Australian blue-ringed octopus is detailed with the view
      of introducing it as a remedy into the homoeopathic Materia Medica and
      stimulating the second step of proving this venom.

PMID- 10582648
TI  - The doctrine of signatures: a historical, philosophical and scientific view (I).
AB  - The evolution of the Doctrine of Signatures is presented, with reference to a
      physical as well as mental/spiritual mode of relating nature's medicinal
      substances to the human symptoms. Symbolism, intuition, biological observation,
      and the study of the medicinal properties serve as guides in the Doctrine of
      Signatures; modern science offers additional dimensions by relating physiological
      processes to physiology of disease.

PMID- 10582649
TI  - Biotypology II: modern concepts.
AB  - Modern concepts of biotypology are based on embryological concepts. Based on the
      work of Nebel and Vannier, described in part I of this article, Bernard related
      endoblast mesoblast and ectoblast to Carbonic, Sulphuric and Phosphoric
      constitutions respectively. These in turn are linked to particular morphologies
      and disease susceptibilities, and the question of an inherited tuberculous
      predisposition has been much debated. The reaction of particular biotypes to
      stress has been analysed in terms of Selye's Adaptation Syndrome. Bernard has
      also analysed the pathological progression of biotypes in terms of a sequence of
      salts: Calcium, Magnesium, Potassium, Sodium, Barium and Ammonium.

PMID- 10582650
TI  - 20 years ago: British Homoeopathic Journal, October 1979.

PMID- 10582651
TI  - The end of the Benveniste affair?

PMID- 10582652
TI  - Improving the Success of Homeopathy 2, London, 15-16 April 1999. Taking
      homeopathic research into the next millennium.

PMID- 10582653
TI  - Pressure to conform, the editorial by Dr Leckridge in April.

PMID- 10582654
TI  - Involvement of prostanoids in cigarette smoking-induced pathophysiological
      effects in the lung.

PMID- 10582655
TI  - Essential fatty acids, lipid peroxidation and apoptosis.
AB  - Essential fatty acids (EFAs) and their metabolites, especially gamma-linolenic
      acid, arachidonic acid, eicosapentaenoic acid and decosahexaenoic acid are known
      to induce apoptotic death of tumour cells. But the exact mechanism by which these
      fatty acids are able to induce apoptosis is not clear. Recent studies suggest
      that these fatty acids are able to induce apoptosis in cells over expressing
      cytochrome P450 following depletion of cellular glutathione and inhibition of
      carnitine palmitoyl transferase I (CPTI) activity. On the other hand, BCL-2
      prevented apoptosis induced by these long-chain fatty acids, where as n-3 fatty
      acids suppressed ras expression leading to suppression of development of overt
      neoplasia. Phosphorylation of BCL-2 inhibits its ability to interfere with
      apoptosis and enhances lipid peroxidation leading to the occurrence of apoptosis.
      Tumour cells treated with long-chain fatty acids show increase in lipid
      peroxidation process, depletion of antioxidants and phosphorylation of proteins.
      Based on these results, it is suggested that long-chain fatty acids induce
      apoptosis by enhancing lipid peroxidation, suppressing BCL-2 expression possibly
      by phosphorylation and augmentation of P450 activity. Thus, these long-chain
      fatty acids may, infact act at the level of gene/oncogene expression in producing
      their cytotoxic action on tumour cells.

PMID- 10582656
TI  - Multiple arachidonic acid metabolites inhibit sodium-dependent phosphate
      transport in OK cells.
AB  - The cytochrome P450-dependent monoxygenase pathway represents a major route for
      the metabolism of arachidonic acid (AA) in the kidney. In turn, AA metabolites
      have been shown to affect renal electrolyte metabolism, including sodium
      transport. Specifically AA, 20-HETE and 12-HETE inhibit sodium-dependent (Na+-Pi)
      uptake into renal culture cells, and both 12-HETE and 14,15 EET have been shown
      to reduce renin release from renal cortical slices. Since the bulk of Pi
      transport occurs in the proximal tubule (PT), and the PT is a major site of AA
      metabolism, we studied the effect of AA and several of its metabolites on Na+-Pi
      uptake into PT-like opossum kidney (OK) cells. Incubation of OK cells in AA (10(
      8) M) resulted in 17% inhibition of Pi uptake. Three metabolites of omega
      hydroxylation of AA induced significant decreases in Pi uptake: 19R-HETE (10(-8)
      M) by 36% (P=0.008), 19S-HETE (10(-8) M) by 24% (P=0.002) and 20-COOH-AA (10(-8)
      M), a metabolite of 20-HETE, by 25% (P<0.0001). 14,15 EET (10(-8) M), a breakdown
      product of AA by the epoxygenase pathway, had the greatest effect on Pi uptake in
      OK cells. It decreased Pi uptake by 47% (P < 0.0001). Addition of the P450
      inhibitor, 7-ER (10(-8) M), to OK cells resulted in a significant stimulation
      (28%) of Pi uptake (P=0.016). These results indicate that these AA metabolites
      have a significant inhibitory effect on Na+-Pi uptake in OK cells.

PMID- 10582657
TI  - Comparative study of the effects of polyunsaturated fatty acids and their
      metabolites on cell growth and tyrosine kinase activity in oesophageal carcinoma
      cells.
AB  - The effects of exogenous gamma-linolenic acid (GLA), arachidonic acid (AA),
      prostaglandin E2 (PGE2) and prostaglandin A2 (PGA2) were evaluated on cell growth
      in two squamous oesophageal carcinoma cell lines, WHCO1 and WHCO3 and normal
      monkey kidney (NMK) cells. In both cancer cell lines all four compounds inhibited
      cell growth significantly. Indomethacin (I) alone, or in combination with either
      GLA or AA, caused marked inhibition of cell growth in WHCO3. Total tyrosine
      kinase (TK) activity was determined after exposure of all three cell types to the
      lipid compounds. Negligible differences were observed in TK activity between
      treated and untreated NMK cells. Small increases were noticed in WHCO1. Marked TK
      stimulation was observed in WHCO3. Addition of indomethacin to WHCO3 also
      increased TK activity above control value. Tyrosine phosphorylation status of
      exposed cells indicated that a band of approximately 55 kDa (approximately 55
      kDa) was primarily influenced in both WHCO3 and WHCO1. PGA2 caused a decrease in
      tyrosine phosphorylation of the approximately 55 kDa protein in all three cell
      types. Negligible differences were observed in the tyrosine phosphorylation
      status of the approximately 55 kDa in NMK cells exposed to GLA, AA and PGE2
      respectively. However, tyrosine phosphorylation of a number of other proteins
      (21.5-97.4 kDa) was observed in NMK cells. Flow cytometry studies showed an
      increase in S phase and decrease in G1 phase in WHCO3 exposed to PGE2 and PGA2.
      Indomethacin alone, or in combination with GLA and AA, respectively, lead to an
      increase in G1 and a decrease in S phase. Induction of p53 levels was observed in
      WHCO3 cells exposed to GLA, AA, PGA2, indomethacin and the combination of
      indomethacin and GLA or AA.

PMID- 10582658
TI  - Semotiadil, a new calcium antagonist, is a very potent inhibitor of LDL
      oxidation.
AB  - The influence of semotiadil, a novel benzothiazine calcium antagonist on in-vitro
      copper-, 2,2azo-bis-(2,4 dimethylvaleronitrile)[AMVN]-, and 2,2azo-bis-(2
      amidinopropane) [AAPH]-induced low-density lipoprotein (LDL) oxidation was
      assessed. The following parameters were measured: lag-time of oxidation, maximal
      rate of oxidation, dienes formed through continuous monitoring of developing
      conjugated dienes, thiobarbituric acid reactive substances, isoprostane(8-iso
      PGF2alpha)-generation and relative electrophoretic mobility. The effect was
      compared with nifedipine, amlodipine and diltiazem. Besides the influence on
      isoprostane (8-iso-PGF2alpha)-generation where nifedipine was equipotent with
      semotiadil at 10(-3) M, semotiadil demonstrated a strong and significant effect
      in attenuating the indicated indices of LDL-oxidation, in particular, dose
      dependently (10(-3) M to 10(-7) M). These results indicate that semotiadil may
      have the strongest antioxidant activity on LDL among the calcium antagonists
      examined.

PMID- 10582659
TI  - Prostaglandin D2 induces interleukin-6 synthesis via Ca2+ mobilization in
      osteoblasts: regulation by protein kinase C.
AB  - We previously showed that prostaglandin (PG) D2 stimulates Ca2+ influx from
      extracellular space and activates phosphoinositidic (PI)-hydrolyzing
      phospholipase C and phosphatidylcholine (PC)-hydrolyzing phospholipase D
      independently from PGE2 or PGF2alpha in osteoblast-like MC3T3-E1 cells. In the
      present study, we investigated the effect of PGD2 on the synthesis of interleukin
      6 (IL-6) and its regulatory mechanism in MC3T3-E1 cells. PGD2 significantly
      stimulated IL-6 synthesis dose-dependently in the range between 10 nM and 10
      microM. The depletion of extracellular Ca2+ by EGTA reduced the PGD2-induced IL-6
      synthesis. TMB-8, an inhibitor of intracellular Ca2+ mobilization, significantly
      inhibited the PGD2-induced IL-6 synthesis. On the other hand, calphostin C, a
      specific inhibitor of protein kinase C (PKC), enhanced the synthesis of IL-6
      induced by PGD2. In addition, U-73122, an inhibitor of phospholipase C, and
      propranolol, a phosphatidic acid phosphohydrolase inhibitor, enhanced the PGD2
      induced IL-6 synthesis. These results strongly suggest that PGD2 stimulates IL-6
      synthesis through intracellular Ca2+ mobilization in osteoblasts, and that the
      PKC activation by PGD2 itself regulates the over-synthesis of IL-6.

PMID- 10582660
TI  - Modulation of palmitate-induced cardiomyocyte cell death by interventions that
      alter intracellular calcium.
AB  - The objective of this study was to investigate whether palmitate-induced cell
      death in cardiomyocytes was dependent on alterations of intracellular calcium
      ([Ca2+)I). Specifically, we sought to determine whether palmitate might produce a
      cellular calcium overload by increasing calcium influx into the cell or by
      altering sarcoplasmic reticulum (SR) calcium transport. We also determined
      whether palmitate's effects might be modulated by agents that alter [Ca2+]l.
      Treatment of chick embryonic cardiomyocytes in culture with palmitate (100 uM)
      produced a significant (P < 0.05) and 42.9 +/- 5.3% reduction in cell survival or
      increase in cell death. As determined by FURA-2 measurement of [Ca2+]I, the
      cytotoxicity of palmitate on cardiomyocytes did not appear to be mediated through
      acute increases in [Ca2+]l. In contrast, the unsaturated fatty acid, arachidonic
      acid increased [Ca2+]l. The calcium ionophore ionomycin significantly (P < 0.05)
      increased palmitate-induced cardiomyocyte cell death. The effects of ionomycin
      and palmitate, however, were additive, suggesting palmitate and ionomycin acted
      in an independent manner to induce cell death. Furthermore, in contrast to
      palmitate, an ionomycin-induced increase in [Ca2+]l was demonstrated in these
      cells. Inhibition of SR calcium reuptake by thapsigargin, which acutely increases
      [Ca2+]I, also significantly (P < 0.05) increased palmitate-induced cardiomyocyte
      death. Again, these two agents most likely acted in an independent manner because
      of the additive nature of the effect of palmitate and thapsigargin on cell
      viability. Palmitate-induced cardiotoxicity was not mediated through release of
      [Ca2+]I from SR or through voltage-operated channels on plasma membranes, as
      neither SR calcium depletion by low concentrations of ryanodine nor blockade of
      the voltage-operated calcium channel with nifedipine significantly altered
      palmitate-induced cardiomyocyte death. These data suggest that palmitate-induced
      cardiac cell death is enhanced by increases in [Ca2+]I and highlights the
      potential adverse effect of a combination of palmitate with conditions that
      increase [Ca2+]I in cardiomyocytes.

PMID- 10582661
TI  - F2-isoprostane excretion rate and diurnal variation in human urine.
AB  - 8-Iso-PGF2alpha is formed in vivo by non-enzymatic free radical catalysed
      oxidation of arachidonic acid. Urinary measurement of this compound has
      previously been shown to reflect the oxidative stress of the body in human and
      animal studies. To investigate the normal excretion rate and a possible diurnal
      variation of 8-iso-PGF2alpha excretion in humans urinary samples were collected
      from ten healthy volunteers of both sexes at different times during a day and as
      a 24-h urine sample. The samples were analyzed by a newly developed
      radioimmunoassay with a specific antibody against free 8-iso-PGF2alpha. There was
      no diurnal variation in the urinary levels of 8-iso-PGF2alpha during the day in
      this study. Neither was there any statistically significant difference between
      the 8-iso-PGF2alpha levels at any time of the day or in the morning urine samples
      compared to the 24-h urine samples. In conclusion, all urine samples collected at
      any time of the day, preferably a morning urine sample (representative urine from
      6-8 hours), can thus be used to obtain a reliable and adequate value of the
      amount of the 8-iso-PGF2alpha excretion in urine in healthy individuals.

PMID- 10582662
TI  - In vitro protection from cisplatin-induced neurotoxicity by amifostine and its
      metabolite WR1065.
AB  - Cisplatin-induced neuropathy is a major dose-limiting toxicity. Counteraction by
      amifostine and its metabolite WR1065 may reduce peripheral neurotoxicity in a
      number of patients. Using the nerve growth factor (NGF)-dependent neurite
      outgrowth from the PC12 pheochromocytoma cell line as an in vitro assay for
      neurotoxicity, the protective effects of amifostine and WR1065 against cisplatin
      action on neurite formation by PC12 cells were studied. Cisplatin in a
      concentration of 10 microg/ml significantly decreased the percentage of neurite
      forming cells from 84% to 40%. Amifostine in doses of 0.4 and 0.8 mM proved to
      protect significantly against the cisplatin-induced decrease in neurite
      formation, when co-incubated with cisplatin. Also the metabolite WR1065 protected
      significantly against cisplatin neurotoxicity in a dose of 0.12 mM. Our results
      show a significant protection by amifostine and its main metabolite WR1065
      against cisplatin-induced neurotoxicity using an in vitro model.

PMID- 10582663
TI  - Enhanced antitumor activity of sarCNU in comparison to BCNU in an extraneuronal
      monoamine transporter positive human glioma xenograft model.
AB  - A novel analogue of nitrosoureas, 2-chloroethyl-3-sarcosinamide-1-nitrosourea
      (SarCNU), has demonstrated increased anticancer effects in vitro and in vivo. Our
      previous work suggested that SarCNU enters cells via the extraneuronal monoamine
      transporter (EMT), that contributes to its enhanced cytotoxicity. In the present
      study, comparative activities of SarCNU and 1,3-bis(2-chloroethyl)-1-nitrosourea
      (BCNU) were evaluated in an EMT positive human glioma xenograft model. Athymic
      nude mice implanted subcutaneously or intracranially with human glioma SHG-44, a
      cell line that has been confirmed EMT positive by using reverse-transcription
      polymerase chain reaction (RT-PCR) assay, were treated with SarCNU at an optimal
      dose of 167 mg/kg, or BCNU at 20 mg/kg or 30 mg/kg, q4d x 3 intraperitoneally
      (i.p.). In 17 animals with subcutaneous tumor grafts treated with SarCNU, 9
      animals became tumor free and 8 demonstrated tumor regression. While in the BCNU
      treated group, there were only 2 out of 10 mice in the 20 mg/kg group and 2 out
      of 7 in the 30 mg/kg group, which demonstrated some tumor regression. There were
      4 drug related deaths in the BCNU (30 mg/kg) group, while there were no drug
      related deaths in the SarCNU group. In the intracranially implanted mice, the
      median survival time in the SarCNU group was more than 130 days, while in the
      BCNU treated group it was only 22 days which was similar to the control group (18
      days). This is the first demonstration that SarCNU, in comparison to BCNU, has
      enhanced anticancer activity in an EMT positive human glioma xenograft model.

PMID- 10582664
TI  - An indwelling brachytherapy balloon catheter: potential use as an intracranial
      light applicator for photodynamic therapy.
AB  - An indwelling balloon applicator developed for postoperative intracavity
      afterloading brachytherapy was evaluated for photodynamic therapy (PDT).
      Following tumor resection, the applicator is positioned in the center of the
      resultant cavity and the balloon is inflated with a scattering solution. The
      liquid-filled balloon stabilizes the resection cavity ensuring a constant and
      simple geometric shape during treatment. The catheter is brought out through the
      skin and adjusted so that 1-2 cm projects above the scalp surface. Measurements
      of light distribution in a phantom model surrounding the balloon catheter, show
      that it may be used to deliver sufficiently uniform light doses during PDT. The
      light distribution is uniform to within 5% when the balloon is filled with a
      scattering medium. Based on simple assumptions, it is shown that the applicator
      can be used to deliver a sufficient optical dose to brain tissue at a depth of 1
      cm in less than 1 h. The applicator has already been used for brachytherapy in 72
      patients with few complications. A new treatment protocol employing the
      combination of both fractionated intracavity brachytherapy and PDT is currently
      being planned.

PMID- 10582666
TI  - The p27/Kip1 locus shows no loss of heterozygosity in human pituitary adenomas.

PMID- 10582665
TI  - Expression of different extracellular matrix components in human brain tumor and
      melanoma cells in respect to variant culture conditions.
AB  - Local tumor invasion into the surrounding brain tissue is a major characteristic
      of malignant gliomas. These processes critically depend on the interaction of
      tumor cells with various extracellular matrix (ECM) components. Because only
      little quantitative information about expression of ECM gene products in general
      and expression in response to alterations of the surrounding environment is
      available, the present study was designed. Four human glioblastoma cell lines
      (U373MG, U138MG, U251MG, GaMG) as well as four human melanoma cell lines (MV3,
      BLM, 530, IF6) were tested with semiquantitative RT-PCR for their ability to
      express mRNA of different human ECM components (fibronectin, decorin, tenascin,
      collagen I, collagen IV, versican). In addition, two human medulloblastoma (MHH
      Med 1, MHH-Med 4) and two fibrosarcoma (HT1080, U2OS) cell lines were analyzed.
      Cells which were grown in DMEM medium containing 10% FCS expressed most of the
      analyzed protein components. When the same medium, but depleted of ECM proteins
      by filtrating through a membrane with cut-off at > 100 kD was used, basal mRNA
      expression of the ECM proteins was changed in most of the examined cell lines.
      Using serum free conditions, most of the cell lines again showed a variation in
      the expression pattern of mRNA encoding for the different ECM proteins compared
      to the other medium conditions. Comparing different cell lines from one tumor
      entity or different tumor groups, ECM expression was heterogeneous with regard to
      the different tumor entities as well as within the entities themselves. Migration
      assays revealed heterogeneous responses between the different cell lines, ECM
      components and culture conditions, making it difficult to correlate ECM
      expression patterns and migratory behavior. Our results revealed that all
      examined cell lines are able to produce ECM proteins in vitro. This suggests that
      tumor cells can modulate their microenvironment in vitro which has to be taken
      into consideration for studies related to migration and invasion.

PMID- 10582667
TI  - Leptomeningeal melanomatosis with multiple cutaneous pigmented nevi: tumor cell
      proliferation and malignant transformation in an autopsy case.
AB  - We experienced a rare case of leptomeningeal melanomatosis. The proliferative
      activity and nuclear accumulation of p53 in this tumor were examined, since the
      relationship between this tumor type and growth has not yet been elucidated. A 33
      year-old Japanese man was shown to have leptomeningeal melanomatosis with
      multiple cutaneous pigmented nevi. The autopsy findings showed the presence not
      only of benign diffuse melanosis of the leptomeninges but also of leptomeningeal
      melanomatosis in the subarachnoid space and brain parenchyma. In the brain
      parenchyma, the direct invasion of tumor cells from the subarachnoid space and
      Virchow-Robin spaces filled with melanoma cells were observed. Multiple
      hemorrhagic areas invaded by melanoma cells were also present.
      Immunohistochemical staining with a monoclonal antibody to melanoma cells showed
      positivity in the tumor cells. Proliferation analysis using the MIB-1 antibody
      demonstrated that the labeling index of tumor cells invading brain parenchyma
      (2.54%) was higher than that in other lesions of the inner (0.89%) and outer
      layer (0.76%) of the subarachnoid space. Nuclear accumulation of p53 protein was
      rarely seen in the tumor cells. We reported a case of leptomeningeal
      melanomatosis. Higher proliferative activity was found in invading cells of the
      brain parenchyma. Malignant transformation of the tumor did not appear to be
      associated with p53 gene mutation.

PMID- 10582668
TI  - Brain tumor masquerading as stroke.
AB  - Discriminating brain tumor from stroke in patients presenting with acute focal
      neurologic signs and symptoms is crucial to avoid improper treatment, or delay
      correct treatment of the brain tumor patient. Data from the era before computed
      tomography (CT) suggests that 3% of patients with brain tumors are initially
      thought to have had a stroke. Our goal was to see if this has improved in the CT
      era. We reviewed hospital charts of all patients admitted to the Johns Hopkins
      Hospital with a brain tumor during a one year period. Eleven (4.9%) of the 224
      patients discharged with a diagnosis of brain tumor were initially thought to
      have had a stroke. Seven had primary brain tumors and 4 had metastatic tumors.
      Patients who were originally misdiagnosed were significantly older (p = 0.01) and
      more likely to have a Glioblastoma Multiforme (p = 0.04) than those correctly
      diagnosed. Eighty-two percent of those misdiagnosed had no prior history of
      cancer compared to 59% of patients correctly diagnosed. Distinguishing the acute
      presentation of brain tumor and stroke remains an important diagnostic
      consideration. Physicians should recognize that while CT is frequently employed
      for acute neurologic deficits to exclude intracranial hemorrhage, CT may not be
      sufficient to exclude brain tumor. A prospective study is needed to confirm these
      findings.

PMID- 10582669
TI  - Resection and permanent I-125 brachytherapy without whole brain irradiation for
      solitary brain metastasis from non-small cell lung carcinoma.
AB  - We assessed a treatment plan of local therapy (resection and placement of
      permanent low dose-rate I-125 seeds) without whole brain irradiation in 15
      patients with solitary brain metastasis (SBM) from primary non-small cell lung
      cancer between January, 1991 and May, 1996. Thirteen lesions were confirmed as
      solitary by MRI scan, and 2 patients had CT scan only. With median follow up of
      14 months, 3 patients remain alive at 6, 33, and 62 months post-resection. Median
      survival is 14 months for all patients and 26 months for patients with SBM as the
      only site of disease. Five tumors failed in the brain: 2 solitary recurrences
      adjacent to the site of SBM, 2 multiple metastases outside the primary site, and
      1 multiple recurrence including the primary site. No failures were seen with SBM
      <2.5 cm. Only 2 of 13 patients with SBM confirmed with MRI experienced relapses
      elsewhere in the brain. Recurrence rates both adjacent and outside the area of
      the initial brain lesion are similar to studies employing resection plus whole
      brain irradiation (WBI), and the patient is spared the acute and potential late
      toxicity of WBI. This approach may be considered for selected patients with
      solitary brain metastases (SBMs), although further experience with larger patient
      numbers is needed.

PMID- 10582670
TI  - Phase II study of weekly dose-intensified cisplatin chemotherapy with oral
      etoposide in recurrent glioma.
AB  - BACKGROUND: In most patients with recurrent glioma chemotherapy is the only
      remaining treatment option. In general results of chemotherapy in these patients
      are poor, and trials on new regimens are indicated. Because relatively good
      results have been achieved with combinations of platin compounds and etoposide,
      we investigated a dose-intensified cisplatin regimen with oral etoposide.
      METHODS: Eligible patients, with recurrent glioma after surgery and radiation
      therapy were treated with two four week-cycles with cisplatin 70 mg/m2 on days 1,
      8 and 15, combined with oral etoposide 50 mg daily on days 1-15. In responding or
      stabilized patients, treatment was continued with six four week-cycles of oral
      etoposide 50 mg/m2 on days 1-21. Toxicity was assessed using the NCI Common
      Toxicity Criteria, a 50% decrease in contrast enhancing area on MRI scan was
      considered a partial response. Time to progression was measured from the start of
      chemotherapy. RESULTS: Sixteen patients were included, 11 were progressive during
      or immediately after the induction cycles. Two patients achieved a partial
      response with a time to progression of 42 and 58 weeks. Three patients were
      stable for 11, 14 and 15 weeks respectively. Toxicity was modest. DISCUSSION:
      This dose-intensified cisplatin regimen did not result in a significant number of
      objective responses and even the number of 'stable disease' was small. Given the
      low response rate of this intensive treatment, we consider this intensive regimen
      inappropriate for these patients.

PMID- 10582671
TI  - Penetration of idarubicin into malignant brain tumor tissue.
AB  - Anthracyclines are effective in breast cancer and have in vitro cytotoxicity in
      glioma. In patients with glioma anthracyclines are not effective possibly because
      the hydrophilic drugs do not reach cytotoxic levels in tumor tissue. Idarubicin
      is more lipophilic than the other anthracyclines and is more cytotoxic in glioma
      cell lines. The uptake of idarubicin and its major metabolite idarubicinol in
      brain tumor tissue were measured in a patient with a brain metastasis from breast
      cancer and in 4 patients with malignant glioma after an oral dose of idarubicin
      (45 mg/m2 in 1 patient; 25 mg/m2 in 4 patients), given 15-24 h before brain tumor
      resection. The concentrations of idarubicin and of idarubicinol in tumor tissue
      exceeded the concurrent plasma concentrations as well as the peak plasma
      concentrations in all cases. The median tumor:concurrent plasma ratio of
      idarubicinol was 5.7 (range 1.7-18). The concentration of idarubicinol in the
      marginal zone between brain and tumor tissue was lower than in central tumor
      tissue, but was still higher than the plasma concentration in 2 of the 3 examined
      cases. Bone marrow suppression (platelets CTC grade 2, granulocytes CTC grade 4)
      occurred after a single dose of 45 ml/m2. No toxicity was seen at a dose of 25
      mg/m2. These results, the in vitro activity of idarubicin in glioma, the
      convenience of oral administration, and its toxicity profile make clinical
      studies with idarubicin in malignant glioma, and perhaps also in brain metastases
      from breast cancer worthwhile.

PMID- 10582672
TI  - Treatment of intracranial nongerminomatous germ-cell tumor by high-dose
      chemotherapy and autologous stem-cell rescue.
AB  - Nongerminomatous germ-cell tumor (NGGCT) in the central nervous system (CNS) is
      still highly lethal. The present study evaluated the outcome of high-dose
      chemotherapy followed by autologous stem-cell rescue (ASCR). The patients
      included three cases of choriocarcinoma, two cases of embryonal carcinoma and one
      case of yolk sac carcinoma. High-dose cisplatin (200 mg/m2), etoposide (1250
      mg/m2) and ACNU (150 mg/m2) were administrated in combination with ASCR to
      patients at complete remission as a result of surgical removal, irradiation, and
      from four to seven courses of induction chemotherapy. All the patients treated
      with this therapy were alive from one to seven years after the diagnosis, living
      with good performance status. The patients have not required any additional
      treatments after ASCR. The myelosuppression period, characterized by fewer than
      500/microl peripheral neutrophils, ranged from 8 to 15 days (median, 11.5 days).
      Within seven days of ASCR, high fever was found in four patients. Although mild
      liver dysfunction was found in all patients, renal dysfunction was not observed.
      Hearing disturbance was found in 50% of the patients. This treatment regime will
      improve long-term survival for patients with NGGCT.

PMID- 10582673
TI  - Dose-intensive, time-compressed procarbazine, CCNU, vincristine (PCV) with
      peripheral blood stem cell support and concurrent radiation in patients with
      newly diagnosed high-grade gliomas.
AB  - The dose intensity of the PCV regimen can be doubled using peripheral blood stem
      cell (PBSC) support. This study sought to determine the feasibility of giving
      dose-intensive PCV concurrently with radiation therapy. Twelve patients, age 3.2
      22.7 years, median 7.5 years, with newly diagnosed high grade gliomas were
      enrolled. Diagnoses included diffuse intrinsic brainstem gliomas (BSG) (n = 6),
      glioblastoma (n = 4), anaplastic astrocytoma (n = 2). PBSCs were harvested prior
      to chemotherapy with G-CSF priming. Chemotherapy consisted of CCNU 130 mg/m2 and
      vincristine 1.5 mg/m2 on day 0, and procarbazine 150 mg/m2 on days 1-7. PBSCs
      were reinfused on day 9 of each course. Four courses of chemotherapy were
      administered every 28 days or when blood counts recovered. The first course was
      administered the week prior to RT, the second course began on week 3 of RT and
      the third and fourth course were given after RT. Hematologic toxicity was mild
      and the majority of courses were given on schedule. Five of six patients with
      diffuse BSG showed clinical improvement and three showed a radiographic response;
      however, only one remains alive 12+ months from diagnosis. All four patients with
      non-brainstem large-volume tumors showed clinical deterioration and radiographic
      progression during or shortly after RT. MRI scans showed massive edema and
      enhancement. Median time to radiographic progression was five months. Median
      overall survival was 11 months. We conclude that dose-intensive, time-compressed
      PCV given concurrently with large-volume RT appears to result in unacceptable
      toxicity in patients with large residual tumors.

PMID- 10582675
TI  - C6 rat glioma grown into the peritoneal cavity, a large source of tumoral cells
      for subcutaneous transplant of glioma.

PMID- 10582674
TI  - Short-course radiotherapy in elderly and frail patients with glioblastoma
      multiforme. A phase II study.
AB  - PURPOSE: To evaluate efficacy of short-course radiotherapy (RT) in elderly (> or
      = 60 years) and frail [Karnofsky performance status (KPS) 50-70] patients with
      glioblastoma multiforme (GBM). MATERIALS AND METHODS: Between January 1987 and
      June 1993, a total of 47 elderly and frail patients with histological diagnosis
      of GBM entered into a phase II study. RT alone was administered with tumor dose
      of 45 Gy in 15 daily fractions in 15 treatment days in 3 weeks to a target volume
      described as tumor visible on CT scan and a 2-cm margin. RESULTS: Forty-four
      patients were evaluable for this analysis. There were 15 (34%) CR and 11 (25%)
      PR, making the overall response rate of 60%. Median duration of response was 9
      months (range, 2-36 months). Improvement in pretreatment performance status was
      observed in 20/44 (45%) patients, 5 of which improved their KPS for 20%. Median
      survival time is 9 months, and 1-4 year survival rates are 39%, 6.8%, 4.5%, and
      0, respectively, while median time to tumor progression is 8 months, and 1-4 year
      progression-free survival rates are 30%, 4.5%, 4.5%, and 0, respectively. Females
      did significantly better than males, patients with KPS 60-70 did significantly
      better than those with KPS 50, patients having tumors 4-5 cm did significantly
      better than those with tumors 6-8 cm as well as did those with more radical
      surgery when compared to those with biopsy only. On multivariate analysis, only
      tumor size and extent of surgery were found to independently influence survival.
      Acute toxicity was generally assessed as mild. One of the 12 (8%) autopsied
      patients had RT-induced brain necrosis. CONCLUSION: This shortened RT appears to
      be an effective tool in palliation of elderly and frail patients with GBM.
      Further studies with more patients are needed before testing it against more
      aggressive treatment approaches in this patient population.

PMID- 10582676
TI  - Expression of cyclooxygenase-2 (COX-2) in human invasive transitional cell
      carcinoma (TCC) of the urinary bladder.
AB  - Cyclooxygenase (COX)-inhibiting drugs have antitumor activity in canine and
      rodent models of urinary bladder cancer. Two isoenzymes of COX have been
      identified, COX-1 and COX-2. The purpose of this study was to characterize COX-1
      and COX-2 expression in human invasive transitional cell carcinoma of the urinary
      bladder by immunohistochemistry and Western blot analysis. COX-2 was not
      expressed in normal urinary bladder samples but was detected in 25 of 29 (86%)
      invasive transitional cell carcinomas of the urinary bladder and in 6 of 8 (75%)
      cases of carcinoma in situ. These results indicate that COX-2 may play a role in
      bladder cancer in humans and support further study of COX-2 inhibitors as
      potential antitumor agents in human bladder cancer.

PMID- 10582677
TI  - NH2-terminal pentapeptide of endothelial interleukin 8 is responsible for the
      induction of apoptosis in leukemic cells and has an antitumor effect in vivo.
AB  - We have reported that endothelial interleukin 8 (IL-8) induces apoptosis in
      leukemic cells in vitro and in vivo, and that interaction between endothelial
      cells and leukemic cells causes induction of apoptosis through the release of
      endothelial IL-8 (Y. Terui et al., Biochem. Biophys. Res. Commun., 243: 407-411,
      1998; Y. Terui et al., Blood, 92: 2672-2680, 1998). Here, we examined whether a
      pentapeptide corresponding to the NH2-terminal region of endothelial IL-8 can
      induce apoptosis in leukemic cells. The NH2-terminal pentapeptide Ala-Val-Leu-Pro
      Arg (AVLPR) was found to significantly induce apoptosis in the leukemic cell
      lines K562, HL-60, Jurkat, and Daudi, as compared with the COOH-terminal
      pentapeptide Arg-Glu-Ala-Asn-Ser (REANS). Moreover, the NH2-terminal pentapeptide
      AVLPR significantly inhibited growth of i.p. and s.c. tumor masses of K562 cells
      and induced apoptosis in these cells in vivo. The active site of endothelial IL-8
      is the NH2-terminal pentapeptide AVLPR, and this may serve as a new therapy for
      hematological malignancies.

PMID- 10582678
TI  - In vivo gene expression profile analysis of human breast cancer progression.
AB  - The development and use of molecular-based therapy for breast cancer and other
      human malignancies will require a detailed molecular genetic analysis of patient
      tissues. The recent development of laser capture microdissection and high density
      cDNA arrays now provides a unique opportunity to generate gene expression
      profiles of cells from various stages of tumor progression as it occurs in the
      actual neoplastic tissue milieu. We report the combined use of laser capture
      microdissection and high-throughput cDNA microarrays to monitor in vivo gene
      expression levels in purified normal, invasive, and metastatic breast cell
      populations from a single patient. These in vivo gene expression profiles were
      verified by real-time quantitative PCR and immunohistochemistry. The combined use
      of laser capture microdissection and cDNA microarray analysis provides a powerful
      new approach to elucidate the in vivo molecular events surrounding the
      development and progression of breast cancer and is generally applicable to the
      study of malignancy.

PMID- 10582679
TI  - The association of chromosome 8p deletion and tumor metastasis in human
      hepatocellular carcinoma.
AB  - To understand the genetic mechanisms underlying the progression of hepatocellular
      carcinoma (HCC) metastasis, differences of genomic alterations between 10 pairs
      of primary HCC tumors and their matched metastatic lesions were analyzed by
      comparative genomic hybridization. Several chromosomal alterations including loss
      of 8p, 4q, 17p, and 19p, gain of 5p and high-level amplification of 1q12-q22 were
      detected in two or more cases. The most significant finding is the loss of 8p
      which was detected in 8 metastatic tumors but only in 3 corresponding primary
      tumors (P = 0.03). This result suggests that the deletion of chromosome 8p might
      contribute to the development of HCC metastasis. Another interesting result is
      the detection of a minimum high-level amplification region at 1q12-q22 in HCC.
      This result provides a candidate amplification region in HCC for further study to
      identify amplified oncogenes related to the development or progression of HCC.
      Finally, this study provides a practicable model to detect specific genetic
      alterations related to the tumor metastasis through comparing the primary tumor
      and its corresponding metastatic lesion using comparative genomic hybridization
      technique.

PMID- 10582680
TI  - Gender differences in p53 mutational status in small cell lung cancer.
AB  - Mutations in the p53 tumor suppressor gene have been demonstrated to be one of
      the most frequent genetic abnormalities in human cancers. Previous studies have
      shown that the frequency of p53 mutations is significantly higher in small cell
      lung cancer than in non-small cell lung cancer. However, this conclusion was
      based in large part on data derived from tumor cell lines and from studies with
      relatively small sample sizes and biased gender populations. To determine the
      mutational frequency in the p53 tumor suppressor gene and a potential difference
      in gender, we analyzed primary small cell lung cancer tumors from 65 patients (37
      males and 28 females) for p53 mutations between exons 5 and 9. Mutations were
      found in 37 of 65 tumors (57%) within the region of p53 analyzed. Interestingly,
      none of the tumors from females contained more than one mutation, whereas four of
      the tumors from males contained more than one mutation. The most common mutation
      in this population was an adenosine-to-guanine transition (27%), followed by
      guanine-to-thymidine transversion (17%) and guanine-to-adenosine transition
      (12%). The gender difference in p53 mutational rate identified in this study
      suggests that a higher proportion of female tumors may develop through pathways
      not involving p53 mutations.

PMID- 10582681
TI  - A new ligand for the peroxisome proliferator-activated receptor-gamma (PPAR
      gamma), GW7845, inhibits rat mammary carcinogenesis.
AB  - We have tested a new ligand for peroxisome proliferator-activated receptor-gamma,
      GW7845, as an inhibitor of experimental mammary carcinogenesis, using the classic
      rat model with nitrosomethylurea as carcinogen. Rats were first treated with a
      single dose of nitrosomethylurea (50 mg/kg body weight, i.p.). Starting 1 week
      later, they were fed GW7845, at either 60 or 30 mg/kg of diet, for 2 months. This
      agent significantly reduced tumor incidence, tumor number, and tumor weight at
      both doses. This is the first report of the use of a ligand for peroxisome
      proliferator-activated receptor-gamma to prevent experimental breast cancer.

PMID- 10582682
TI  - Point mutations and deletions of the Bcl10 gene in solid tumors and malignant
      lymphomas.
AB  - The Bcl10 gene, which encodes a protein with proapoptotic activity, recently has
      been identified on chromosome 1p22. In this study, we analyzed somatic mutations
      and deletions of the Bcl10 gene in a series of 439 tumor tissues from various
      histological origins that are known to have frequent loss of heterozygosity at
      chromosome 1p22. According to the LOH study at intragenic polymorphic sites,
      deletion of Bcl10 in informative cases was detected in 50% of malignant
      mesotheliomas, 33% of gastric carcinomas, 23% of breast carcinomas, 20% of
      hepatocellular carcinomas, 17% of lymphomas, 15% of colorectal carcinomas, 13% of
      laryngeal carcinomas, and 10% of male germ cell tumors (GCTs). In contrast, we
      detected Bcl10 mutations in 4 of 120 lymphomas (3.3%) and 2 of 78 GCTs (2.6%),
      respectively, but no mutation was found in the remaining solid tumors analyzed.
      Taken together, these data imply that Bcl10 may occasionally be involved in the
      pathogenesis of lymphoma and GCTs. However, the absence or low frequency of the
      mutation suggests that either Bcl10 is inactivated by other mechanisms or it is
      not the only target of chromosome 1p22 deletion in human tumors.

PMID- 10582684
TI  - Alterations of the DR5/TRAIL receptor 2 gene in non-small cell lung cancers.
AB  - Chromosome 8p21-22 is a frequent site of allelic deletions in many types of human
      tumors, including non-small cell lung cancer (NSCLC). Tumor necrosis factor
      related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) is a cell-surface
      receptor involved in cell death signaling. The TRAIL-R2 gene recently has been
      mapped to chromosome 8p21-22. To explore the possibility that the TRAIL-R2 gene
      might be the relevant gene to the frequent deletion of 8p21-22 in NSCLC, we have
      analyzed the entire coding region and all splice sites of TRAIL-R2 for the
      detection of the somatic mutations in a series of 104 NSCLCs. Overall, 11 tumors
      (10.6%) were found to have TRAIL-R2 gene mutations in the death domain known to
      be involved in the transduction of an apoptotic signal. Our data indicate that
      somatic mutation of TRAIL-R2 may play a role in the pathogenesis of some NSCLCs
      and that the TRAIL-R2 gene is one of the genes relevant to the frequent loss of
      chromosome 8p21-22 in NSCLC.

PMID- 10582683
TI  - TbetaR-I(6A) is a candidate tumor susceptibility allele.
AB  - We have previously described a type I transforming growth factor (TGF)-beta
      receptor (TbetaR-I) polymorphic allele, TbetaR-I(6A), that has a deletion of
      three alanines from a nine-alanine stretch. We observed a higher than expected
      number of TbetaR-I(6A) homozygotes among tumor and nontumor DNA from patients
      with a diagnosis of cancer. To test the hypothesis that TbetaR-I(6A) homozygosity
      is associated with cancer, we performed a case-control study in patients with a
      diagnosis of cancer and matched healthy individuals with no history of cancer and
      who were identical in their gender and their geographical and ethnic background
      to determine the relative germ-line frequencies of this allele. We found nine
      TbetaR-I(6A) homozygotes among 851 patients with cancer. In comparison, there
      were no TbetaR-I(6A) homozygotes among 735 healthy volunteers (P < 0.01). We also
      observed an excess of TbetaR-I(6A) heterozygotes in cancer cases compared to
      controls (14.6% versus 10.6%; P = 0.02, Fisher's exact test). A subset analysis
      revealed that 4 of 112 patients with colorectal cancer were TbetaR-I(6A)
      homozygotes (P < 0.01). Using mink lung epithelial cell lines devoid of TbetaR-I,
      we established stably transfected TbetaR-I and TbetaR-I(6A) cell lines. We found
      that, compared to TbetaR-I, TbetaR-I(6A) was impaired as a mediator of TGF-beta
      antiproliferative signals. We conclude that TbetaR-I(6A) acts as a tumor
      susceptibility allele that may contribute to the development of cancer,
      especially colon cancer, by means of reduced TGF-beta-mediated growth inhibition.

PMID- 10582686
TI  - Decreased insulin-like growth factor-II/mannose 6-phosphate receptor expression
      enhances tumorigenicity in JEG-3 cells.
AB  - The insulin-like growth factor-II/mannose-6 phosphate receptor (IGF-II/M6PR) is
      believed to bind and degrade the potent mitogen IGF-II, a growth factor for many
      tumors. This receptor has been shown to be mutated and/or lost in a significant
      percentage of a variety of tumors, implying that it may act as a negative
      regulator of cell growth. In this study, we demonstrate that down-regulation of
      this receptor, mediated by antisense IGF-II/M6PR cDNA transfection into JEG-3
      choriocarcinoma cells, results in increased growth rate in vitro and increased
      tumor growth rate in vivo. These findings demonstrate that a decrease in IGF
      II/M6PR expression results in a growth advantage in JEG-3 cells and are
      consistent with the hypothesis that the IGF-II/M6PR is an inhibitor of tumor
      growth.

PMID- 10582685
TI  - Chromosomal imbalances are associated with a high risk of progression in early
      invasive (pT1) urinary bladder cancer.
AB  - Many cytogenetic alterations are known to occur in urinary bladder cancer, but
      the significance of most of them is poorly understood. To define these
      chromosomal regions where clinically relevant genes may be located, a series of
      54 pT1 urinary bladder carcinomas with clinical follow-up information (median, 52
      months; range, 5-167 months) were examined by comparative genomic hybridization.
      The most frequent alterations included DNA sequence copy number gains at 1q22-24
      (33%), 20q11.2-ter (33%), 8q22 and 17q21 (28% each), and 6p22 (15%) as well as
      deletions at Y (37%), 9p (31%), 9q22-33 and 11p14-ter (28% each), 11q23 (26%), 8p
      (24%), 13q31 (19%), 2q35-ter (17%), and 2q22-33 (11%). Whereas the histological
      grade was unrelated to prognosis (P = 0.9752), the risk of tumor progression was
      significantly associated with the number of deletions per tumor (P = 0.0014).
      Individual cytogenetic alterations that were linked to subsequent tumor
      progression included gains of 3p22-24 (P = 0.0112) and 5p (P = 0.0003) as well as
      losses of 4p11-15 (P = 0.0052), 5q15-23 (P = 0.0410), 6q22-23 (P = 0.0090), 10q24
      26 (P = 0.0232), and 18q12-23 (P = 0.0005). Genes with a role for bladder cancer
      progression may be located at these regions.

PMID- 10582687
TI  - HMG-I(Y) recognizes base-unpairing regions of matrix attachment sequences and its
      increased expression is directly linked to metastatic breast cancer phenotype.
AB  - Base-unpairing regions (BURs) contain a specialized DNA context with an
      exceptionally high unwinding propensity, and are typically identified within
      various matrix attachment regions. A BUR affinity column was used to purify a
      doublet of Mr 20,000 proteins from human breast carcinoma cells. These proteins
      were identified as the high-mobility group (HMG) protein, HMG-I, and its splicing
      variant, HMG-Y. We show that HMG-I(Y) specifically binds BURs. Mutating BURs so
      as to abrogate their unwinding property greatly reduced their binding affinity to
      HMG-I(Y). Numerous studies have indicated that elevated HMG-I(Y) expression is
      correlated with more advanced cancers and with increased metastatic potential. We
      studied whether the expression of HMG-I(Y) responds to signaling through the
      heregulin (HRG)-erbB pathway and the extracellular matrix. HMG-I(Y) expression
      was increased in MCF-7 cells after stable transfection with an HRG expression
      construct that led cells to acquire estrogen independence and metastasizing
      ability. A high level of HMG-I(Y) expression was detected in metastatic MDA-MB
      231 cells, but the expression was virtually diminished, and the metastasizing
      ability was lost after cells were stably transfected with an antisense HRG cDNA
      construct. HMG-I(Y) was also decreased in MDA-MB-231 cells when treated with a
      chemical inhibitor for matrix metalloproteinase-9 that led to a reduction of
      invasive capability in vitro. The level of HMG-I(Y) expression, therefore, is
      dynamically regulated in human breast cancer cells in response to varying types
      of signaling that affect metastatic ability, including the HRG-erbB pathway and
      those from the extracellular matrix.

PMID- 10582688
TI  - Red meat and colon cancer: the cytotoxic and hyperproliferative effects of
      dietary heme.
AB  - The intake of a Western diet with a high amount of red meat is associated with a
      high risk for colon cancer. We hypothesize that heme, the iron carrier of red
      meat, is involved in diet-induced colonic epithelial damage, resulting in
      increased epithelial proliferation. Rats were fed purified control diets, or
      purified diets supplemented with 1.3 micromol/g of hemin (ferriheme),
      protoporphyrin IX, ferric citrate, or bilirubin (n = 8/group) for 14 days. Feces
      were collected for biochemical analyses. Fecal cytotoxicity was determined from
      the degree of lysis of erythrocytes by fecal water. Colonic epithelial
      proliferation was measured in vivo using [3H]thymidine incorporation into colonic
      mucosa. The colonic epithelial proliferation in heme-fed rats was significantly
      increased compared to control rats [55.2 +/- 5.8 versus 32.6 +/- 6.3 dpm/microg
      DNA (mean +/- SE); P < 0.05]. The fecal water of the heme group was highly
      cytotoxic compared to the controls (90 +/- 2% versus 2 +/- 1%; P < 0.001),
      although the concentrations of cytotoxic bile acids and fatty acids were
      significantly lower. Organic iron was significantly increased compared to the
      controls (257 +/- 26 versus 80 +/- 21, microM; P < 0.001). Spectrophotometric
      analyses suggest that this organic iron is heme-associated. Thiobarbituric acid
      reactive substances were greatly increased in the fecal water of heme-fed rats
      compared to the controls (177 +/- 12 versus 59 +/- 7 microM; P < 0.05). Heme
      itself could not account for the increased cytotoxicity because the addition of
      heme to the fecal water of the control group, which was equimolar to the organic
      iron content of the fecal water of the heme group, did not influence the
      cytotoxicity. Hence, an additional heme-induced cytotoxic factor is involved,
      which may be modulated by the generation of luminal-reactive oxygen species.
      Protoporphyrin IX, ferric citrate, and bilirubin did not increase proliferation
      and cytotoxicity. In conclusion, dietary heme leads to the formation of an
      unknown, highly cytotoxic factor in the colonic lumen. This suggests that, in
      heme-fed rats, colonic mucosa is damaged by the intestinal contents. This results
      in a compensatory hyperproliferation of the epithelium, which supposedly
      increases the risk for colon cancer.

PMID- 10582689
TI  - Transgenic mice overexpressing protein kinase Cdelta in the epidermis are
      resistant to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate.
AB  - To determine the role of protein kinase Cdelta in mouse skin carcinogenesis, we
      have developed transgenic FVB/N mouse lines expressing in the epidermis an
      epitope-tagged protein kinase Cdelta (T7-PKCdelta) regulated by the human keratin
      14 promoter. The untreated T7-PKCdelta mice displayed excessive dryness in the
      skin of the tail with a variable penetrance over time. Histologically, the tail
      skin showed hyperplasia with evidence of hyperkeratosis. The epidermis of the
      rest of the T7-PKCdelta mouse was unremarkable. Despite this mild phenotype, the
      effects of PKCdelta overexpression on mouse skin tumor promotion by 12-O
      tetradecanoylphorbol-13-acetate (TPA) were dramatic. Two independent lines of T7
      PKCdelta mice (16 and 37) expressing the T7-PKCdelta transgene were examined for
      responsiveness to skin tumor promotion by 7,12-dimethylbenz[a]anthracene and TPA.
      By immunoblot analysis, the T7-PKCdelta-16 and T7-PKCdelta-37 mice showed an 8-
      and 2-fold increase of PKCdelta protein. The T7-PKCdelta-16 mice averaged 300%
      more T7-PKCdelta activity than the T7-PKCdelta-37 mice did. The T7-PKCdelta-37
      mice did not manifest any difference in tumor burden or incidence. However, the
      reduction in papilloma burden at 25 weeks of promotion for the T7-PKCdelta-16
      mice relative to wild-type mice averaged 72 and 74% for males and females,
      respectively. The T7-PKCdelta-16 mice reached 50% papilloma incidence between 12
      and 13 weeks of promotion compared with 8 weeks for wild-type mice. Furthermore,
      the carcinoma incidence was also reduced in T7-PKCdelta-16 mice. Carcinoma
      incidence at 25 weeks of promotion treatment was: wild-type females, 78%; T7
      PKCdelta16 females, 37%; wild-type males, 45%; and T7- PKCdelta-16 males, 7%.
      Thus, PKCdelta when expressed at sufficient levels can suppress skin tumor
      promotion by TPA.

PMID- 10582690
TI  - Caveolin-1 expression in clinically confined human prostate cancer: a novel
      prognostic marker.
AB  - We demonstrated previously elevated caveolin-1 expression in metastatic mouse and
      human prostate cancer cells both in vitro and in vivo. In this study, we analyzed
      its prognostic value for progression of clinically confined human prostate
      cancer. Immunohistochemical staining with a caveolin-1-specific antibody was
      performed on routinely processed paraffin sections from 189 radical prostatectomy
      specimens. Caveolin-1 immunoreactivity was evaluated in association with
      patients' age, race, preoperative prostate-specific antigen, clinical stage, and
      pathological features including Gleason score, extraprostatic extension, status
      of surgical margins, and time to disease progression after surgery. Positive
      caveolin-1 immunostaining was detected in 47 of the 189 cancers (25%) and
      correlated positively with Gleason score, positive surgical margin, as well as
      lymph node involvement (P = 0.0071, 0.0267, and 0.0399, respectively). In lymph
      node-negative cancers (n = 162), caveolin-1 immunoreactivity predicts a shorter
      time to disease progression after surgery (P = 0.0033, univariate analysis).
      Multivariate analyses that included caveolin-1 and other prognostic pathological
      markers identified positive caveolin-1 immunostaining as an independent predictor
      for time to disease progression (P = 0.0186). Thus, our study establishes
      caveolin-1 as a novel prognostic marker for clinically confined human prostate
      cancer.

PMID- 10582692
TI  - Differential diagnosis of chronic pancreatitis and pancreatic cancer in brush
      cytology specimens.
AB  - Discrimination between chronic pancreatitis and pancreatic carcinoma can be
      complicated, particularly in brush cytology specimens. Previous studies have
      shown that the oxygen insensitivity of the histochemical reaction to detect
      glucose-6-phosphate dehydrogenase activity based on neotetrazolium reduction can
      be used for discriminating malignant cells from nonmalignant cells. In the
      present study, we investigated the value of the assay for differential diagnosis
      between the two pancreatic diseases. Oxygen insensitivity in ductal epithelial
      cells in normal human pancreas, chronic pancreatitis, and pancreatic carcinoma
      was determined by quantitative image analysis in sections of biopsies and in
      brush cytology preparations. In sections, the reaction in the absence of oxygen
      was a proper reflection of glucose-6-phosphate dehydrogenase activity, whereas in
      the presence of oxygen only malignant cells showed a significant reaction. Of 39
      brush cytology specimens, diagnosis of all 11 cases of pancreatitis and 28 cases
      of cancer with the oxygen insensitivity test were in agreement with independent
      measures of chronic pancreatitis and cancer. The oxygen insensitivity test is a
      simple and valuable tool in addition to conventional pathology for differential
      diagnosis between pancreatitis and pancreatic cancer, both in biopsies and in
      brush cytology specimens.

PMID- 10582691
TI  - Loss of KAI1 expression in the progression of colorectal cancer.
AB  - The transmembrane 4 superfamily member KAI1 (CD82) has been shown to inhibit
      pulmonary metastases in experimental metastasis models of prostate cancer and
      melanoma. KAI1 expression is decreased in the progression of common solid
      epithelial tumors of adulthood, including lung, prostate, breast, esophageal,
      gastric, pancreatic, and bladder cancers. The purpose of our study was to
      investigate KAI1 expression in the progression of human colorectal cancer. We
      first analyzed 20 colorectal cancer cell lines by immunoblot techniques. KAI1 was
      expressed heterogeneously, with the tumor cell lines having a more complex degree
      of glycosylation compared with that of the normal colonic tissue. KAI1 was highly
      expressed in the primary SW480 colon cancer cell line but was down-regulated 15
      fold in the matched metastatic SW620 cell line. We also investigated KAI1 protein
      expression by immunohistochemistry in tissues from 84 patients with colorectal
      cancer. Each tissue section was assigned a KAI1 mean score (KMS) from 0 to 300
      based on the product of the percentage of cells that stained for KAI1 and the
      intensity of the stain (1, 2, or 3). In 84 patients with colorectal cancer, KAI1
      was expressed at high levels in normal colonic mucosa (KMS 226) but was expressed
      at lower levels in the primary tumors (KMS 65; P < 0.0001). In a subset of 12
      patients with stage IV metastatic disease, we observed a progressive down
      regulation of KAI1, from the normal adjacent colonic mucosa (KMS 193) to the
      primary tumor (KMS 72; P = 0.0001) to the liver metastasis (KMS 25; tumor
      compared with metastasis, P = 0.0135). We found no correlation between loss of
      KAI1 expression and stage of disease. In 10 patients, we also noted loss of KAI1
      expression in the transition from normal colonic mucosa (KMS 237) to adenoma (KMS
      174) to carcinoma (KMS 62; P < 0.0167 for all three comparisons). We conclude
      that the down-regulation of KAI1 occurs early in the progression of colorectal
      cancer.

PMID- 10582693
TI  - Human uterine leiomyomata express higher levels of peroxisome proliferator
      activated receptor gamma, retinoid X receptor alpha, and all-trans retinoic acid
      than myometrium.
AB  - Uterine leiomyomata are the main indication for a hysterectomy in the United
      States and occur in 25% of women >35 years. Because uterine leiomyomata can form
      when ovariectomized guinea pigs are exposed to estradiol and retinoic acids, we
      tested whether human leiomyomata had high levels of retinoic acids and related
      nuclear receptors. Compared with normal human myometrium, leiomyomata had 3- to 5
      fold higher levels of peroxisome proliferator-activated receptor gamma
      (PPARgamma), retinoid X receptor alpha proteins, and all-trans retinoic acid, but
      only during the follicular phase of the menstrual cycle. 9-cis Retinoic acid was
      undetectable in either leiomyomata or myometrium. PPARgamma mRNA levels were
      lower in leiomyomata than myometrium, but only during the luteal phase of the
      cycle. A PPARgamma agonist, troglitazone, was given to guinea pigs along with
      estradiol and all-trans retinoic acid and produced the largest leiomyomata seen
      to date in this model. By contrast, no tumors formed when troglitazone was given
      alone or with estradiol or when troglitazone was given with estradiol and 9-cis
      retinoic acid. New therapies for human leiomyomata may emerge by combining
      antagonists for PPARgamma and retinoid X receptor alpha with selective estrogen
      receptor modulators.

PMID- 10582694
TI  - Phosphoinositide 3-hydroxide kinase blockade enhances apoptosis in the Ewing's
      sarcoma family of tumors.
AB  - Ewing's sarcoma family of tumors (ESFTs) affects patients between the ages of 3
      and 40 years, with most cases occurring in the second decade of life. These
      tumors contain a characteristic translocation, t(11;22), that produces a unique
      fusion protein, EWS/FLI-1. EWS/FLI-1 transforms mouse fibroblasts; this
      transformation requires intact EWS and FLI-1 domains as well as the insulin-like
      growth factor-I receptor (IGF-IR). The IGF-IR is a well-described transmembrane
      tyrosine kinase receptor that modulates transformation, cell growth, and
      survival. IGF-IR survival signaling is mediated through the downstream activation
      of phosphoinositide 3-OH kinase (PI 3-K) and Akt. Apoptosis, programmed cell
      death, progresses from a central death signal to a caspase cascade, including
      activation of caspase-3. Because the IGF-IR has been shown to play a role in the
      transformation and growth of ESFTs, we wanted to determine the role of downstream
      molecules in the cellular response to doxorubicin treatment. Doxorubicin
      increased caspase-3 activity in two ESFT cell lines, TC-32 and TC-71. Concomitant
      treatment of the doxorubicin-treated cells with IGF-I reduced caspase-3 activity
      8-fold in TC-32 and 4-fold in TC-71. To determine whether PI 3-K has a role in
      IGF-I-mediated survival in ESFTs, PI 3-K was then inhibited with wortmannin and
      LY294002. Doxorubicin treatment reduced cell number and enhanced apoptosis in PI
      3-K inhibited cells compared with noninhibited cells. Akt, a serine/threonine
      kinase activated downstream of PI 3-K, was investigated to determine whether its
      constitutive activation would render ESFT cells more resistant to doxorubicin. A
      constitutively activated Akt was stably transfected into ESFT and those cells
      with high levels of expression demonstrated increased resistance to doxorubicin
      induced caspase-3 activation. These results indicate that ESFT cell lines use an
      IGF-IR initiated signaling pathway through PI 3-K and Akt for survival when
      treated with doxorubicin.

PMID- 10582695
TI  - CHS 828, a novel pyridyl cyanoguanidine with potent antitumor activity in vitro
      and in vivo.
AB  - A new class of recently discovered antineoplastic agents, the pyridyl
      cyanoguanidines, exert a potent antitumor activity in rodents after oral
      administration. Optimization in vitro and in vivo has resulted in the selection
      of the lead candidate CHS 828 (N-(6-chlorophenoxyhexyl)-N'cyano-N"-4
      pyridylguanidine). CHS 828 was found to exert potent cytotoxic effects in human
      breast and lung cancer cell lines, with lesser effects on normal fibroblasts and
      endothelial cells. In a study using a panel of cell lines with different
      resistance patterns, the effects of CHS 828 showed a low correlation with the
      activity patterns of known anticancer agents, and no sensitivity to known
      mechanisms of multidrug resistance was observed. In nude mice bearing human tumor
      xenografts, CHS 828, at doses from 20 to 50 mg/kg/day p.o., inhibited the growth
      of MCF-7 breast cancer tumors and caused regression of NYH small cell lung cancer
      tumors. Oral administration of CHS 828 once weekly improved efficacy without
      increasing toxicity. CHS 828 was found to compare favorably with established
      chemotherapeutic agents such as cyclophosphamide, etoposide, methotrexate, and
      paclitaxel. In mice with NYH tumors, long-term survival (>6 months) was observed
      after treatment with CHS 828 was stopped. In conclusion, CHS 828 is an effective
      new antitumor agent, with a potentially new mechanism of action. CHS 828 is
      presently being tested in Phase I clinical trials in collaboration with the
      European Organization for Research and Treatment of Cancer.

PMID- 10582696
TI  - High thermal stability is essential for tumor targeting of antibody fragments:
      engineering of a humanized anti-epithelial glycoprotein-2 (epithelial cell
      adhesion molecule) single-chain Fv fragment.
AB  - The epithelial glycoprotein-2 is abundantly expressed on many solid tumors and is
      a suitable target for antibody-based therapy. In the present study, an
      antiepithelial glycoprotein-2 single-chain Fv (scFv) was derived from the
      hybridoma MOC31 by phage display. Despite its high affinity (KD = 3.9 x 10(-9)
      M), however, this antibody fragment failed to significantly enrich at lung tumor
      xenografts in mice, mostly because of its insufficient thermal stability. To
      overcome this limitation, the antigen-binding residues of the MOC31 scFv fragment
      were grafted onto the framework of the highly stable and well-folding anti-c
      erbB2 scFv 4D5. Further modification of the resulting 4D5 MOC-A, which was
      performed by transferring eight additional residues of the heavy chain variable
      domain core of the parent MOC31 antibody, produced 4D5 MOC-B, resulting in
      increased serum stability at 37 degrees C and also significantly improved
      expression behavior while retaining the antigen specificity and affinity of the
      parent MOC31 scFv. In mice, the scFv 4D5 MOC-B, which was radiolabeled with
      99mtechnetium using a new histidine-tag specific labeling method (Waibel et al.,
      Nature Biotechnol., 17: 897-901, 1999), showed favorable blood clearance and
      efficient enriches at lung tumor xenografts, with a tumor:blood ratio of 5.25 and
      a total dose of 1.47% injected dose per gram after 24 h. Biophysical properties
      such as high thermal stability are thus decisive for whether these molecules are
      useful in vivo, and our approach may provide a general strategy to solve this
      problem. This is also the first report of using a humanized anti-EGP-2 scFv in
      vivo for targeting solid tumors, which is a promising targeting moiety for the
      diagnostics and therapy of EGP-2-positive tumors in patients.

PMID- 10582697
TI  - Ceramide-beta-D-glucuronide: synthesis, digestion, and suppression of early
      markers of colon carcinogenesis.
AB  - Dietary sphingolipids inhibit chemically induced colon cancer in mice. The most
      likely mediators of this effect are the metabolites ceramide (Cer) and
      sphingosine, which induce growth arrest and apoptosis in transformed cells.
      Sphingolipids are digested in both the upper and the lower intestine; therefore,
      a more colon-specific method of delivery of sphingolipids might be useful. A Cer
      analogue with a D-glucuronic acid attached at the primary hydroxyl of N-palmitoyl
      D-sphingosine (Cer-beta-glucuronide) was synthesized and evaluated as a substrate
      for Escherichia coli beta-glucuronidase and colonic digestion, as well as for
      suppression of early events in colon carcinogenesis in CFI mice treated with 1,2
      dimethylhydrazine. Purified beta-glucuronidase (EC 3.2.1.31) and colonic segments
      (as a source of colonic enzymes and microflora) hydrolyzed Cer-beta-glucuronide
      to release Cer, as analyzed by tandem mass spectrometry. More than 75% of the Cer
      beta-glucuronide was cleaved in an 8-h incubation with the colonic segments. When
      Cer-beta-glucuronide was administered for 4 weeks as 0.025% and 0.1% of the diet
      (AIN 76A) to 1,2-dimethylhydrazine-treated mice, there were significant
      reductions in colonic cell proliferation, as determined by in vivo BrdUrd
      incorporation, and in the appearance of aberrant crypt foci. The effect of
      dietary Cer-beta-glucuronide on aberrant crypt foci correlated significantly with
      the length of the colon, which suggests that Cer-beta-glucuronide was most
      effective when there was a larger compartment for digestion. Thus, synthetic
      sphingolipids that target the colon for the release of the bioactive backbones
      offer a promising approach to colon cancer prevention.

PMID- 10582698
TI  - Inhibition of tumor growth correlates with the expression level of a human
      angiostatin transgene in transfected B16F10 melanoma cells.
AB  - Although the therapeutic value of angiostatin, a proteolytic fragment of
      plasminogen, has been recognized for the treatment of cancer, the production of
      bioactive angiostatin remains a difficult task. Here we report that expression of
      a cDNA encoding a secreted, four-kringle human angiostatin inhibited tumor growth
      of B16F10 melanoma cells in mice but did not suppress tumor cell growth in
      culture. After transfection and selection, stable expression of the angiostatin
      cDNA was demonstrated in several B16F10 clones by quantitative mRNA analysis
      using the Taqman method. Cells that expressed angiostatin at either a low,
      medium, or high level were injected into C57BL/6 mice. s.c. Growth of B16F10
      tumors was diminished by the angiostatin transgene, and the inhibition was
      directly proportional to the expression level of angiostatin in the transfected
      cells. However, suppression of s.c. tumor growth was transient, and eventually,
      tumors emerged with a strongly decreased expression of the transgene. Angiostatin
      expression also reduced lung metastasis from i.v.-injected B16F10 cells. Our data
      indicate that a cDNA encoding bioactive human angiostatin is potentially useful
      for gene therapy of human cancers, but the delivery of the transgene may require
      repeated dosing to achieve sustained dormancy of primary tumors and cancer
      metastases.

PMID- 10582699
TI  - Antitumor immune effector mechanisms recruited by phage display-derived fully
      human IgG1 and IgA1 monoclonal antibodies.
AB  - We have constructed a recombinant, fully human IgA1 monoclonal antibody, UBS
      54/IgA1, against the tumor-associated Ep-CAM molecule and compared its tumor
      killing capacity with its IgG1 counterpart in in vitro assays. The data show that
      phage display-derived fully human IgA1 antibodies efficiently recruit immune
      effector cells that express the Fc receptor for IgA, FcalphaRI (CD89). UBS
      54/IgA1-mediated killing of tumor cells by isolated polymorphonuclear cells
      (PMNs) and in whole blood was found to proceed without the necessity to
      preactivate effector cells with cytokines. In addition, the IgA1 anti-Ep-CAM
      human monoclonal antibody (huMab) triggered phagocytosis of tumor cells by
      monocyte-derived macrophages. Strikingly, simultaneous addition of IgA1 and IgG1
      anti-Ep-CAM antibodies did not result in enhancement of tumor cell killing unless
      the effector cells were stimulated with granulocyte colony-stimulating factor.
      The lack of an additive effect could be attributed to an inhibitory effect of IgG
      on IgA-mediated tumor cell killing through binding of IgG1 to the inhibitory
      FcgammaRIIb receptor expressed by PMNs. These results show that IgA1 antitumor
      huMabs are capable of recruiting the large population of peripheral blood PMNs
      for tumor cell killing. This population is not effectively recruited by IgG type
      antibodies, currently the antibodies most frequently used for clinical
      application. In addition, the data suggest that a combination of IgG1 and IgA1
      antitumor huMabs may collaborate in tumor cell killing in patients treated with
      granulocyte colony-stimulating factor.

PMID- 10582700
TI  - Two antigens recognized by autologous cytolytic T lymphocytes on a melanoma
      result from a single point mutation in an essential housekeeping gene.
AB  - We have pursued our analysis of antigens recognized by autologous cytolytic T
      lymphocytes (CTLs) on the melanoma cells of patient LB33. This patient enjoys an
      unusually favorable evolution, which is associated with a strong and sustained
      antitumor CTL response. We reported previously the analysis of two melanoma cell
      lines, MEL.A and MEL.B, which were derived from metastases removed from the
      patient at 5 years' distance. Autologous CTL clones derived from blood
      lymphocytes recognized several antigens presented by different HLA class I
      molecules on MEL.A. The MEL.B cells resisted lysis by these CTLs because they
      have lost expression of most HLA molecules, suggesting that they were selected in
      vivo by the anti-MEL.A CTL response. One of the MEL.A antigens was shown to
      result from a point mutation in the tumor. Here we report the cloning of a gene
      that encodes two other MEL.A antigens. This new gene, MUM-2, is expressed
      ubiquitously. In the melanoma cells of patient LB33, it contains a point mutation
      that changes one amino acid in the translated protein. Two different antigenic
      peptides, one presented to CTL by HLA-B44 molecules and another by HLA-C6
      molecules, overlap and contain the mutated residue. Gene MUM-2 is homologous to
      an essential yeast gene, bet5, that was recently shown to be implicated in the
      vesicular transport of proteins from the endoplasmic reticulum to the Golgi. In a
      mutant yeast with a disrupted bet5 gene, both the wild-type and the mutated MUM-2
      genes could complement for bet5 function. These results indicate that the
      antigenic mutation does not destroy the function of the protein, a function that
      is conserved in eukaryotic cells. The identification of these antigens suggests
      that point mutations could be the major cause of the strong immunogenicity of
      MEL.A cells.

PMID- 10582701
TI  - Human leukocyte antigen class I expression on squamous cell carcinoma cells
      regulates natural killer cell activity.
AB  - Human leukocyte antigen (HLA) class I molecules on hematopoietic cancers and
      melanomas inhibit attack by natural killer lymphocytes, but previous studies have
      not consistently demonstrated that carcinoma cells are protected by HLA class I
      expression. We investigated whether HLA class I molecules protect oral and
      pharyngeal squamous cell carcinoma cells from natural killer lymphocyte attack.
      Squamous cell carcinoma cell lines expressed varying levels of HLA class I, which
      correlated inversely with cytolysis by natural killer-enriched polyclonal
      lymphocytes. Cytolysis was increased by the presence of anti-HLA class I blocking
      monoclonal antibody (mAb). Subclones of the NK-92 human natural killer lymphoma
      cell line were derived by treatment with 5-aza-2'-deoxycytidine and limiting
      dilution cloning. NK-92 subclones expressed distinct sets of HLA class I-specific
      receptors. Some NK-92 subclones differentially lysed hematopoietic cells and
      squamous cell carcinoma cells, even in the presence of anti-HLA class I blocking
      mAb. This suggests that natural killer cells recognize different non-HLA ligands
      on hematopoietic and squamous cell carcinoma cells. In the presence of anti-HLA
      class I monoclonal antibody, other NK-92 subclones increased cytolysis of
      squamous cell carcinoma cells with moderate-to-high HLA class I levels. Anti-HLA
      class I mAb also increased natural killer cell attack of squamous cell carcinoma
      cells that were adherent to plastic. These data suggest that natural killer cell
      recognition of squamous cell carcinoma cells depends upon the balance of
      stimulatory and inhibitory ligands.

PMID- 10582702
TI  - A triad of costimulatory molecules synergize to amplify T-cell activation.
AB  - The activation of a T cell has been shown to require two signals via molecules
      present on professional antigen-presenting cells: signal 1, via a peptide/MHC
      complex; and signal 2, via a costimulatory molecule. Here, the role of three
      costimulatory molecules in the activation of T cells was examined. Poxvirus
      (vaccinia and avipox) vectors were used because of their ability to efficiently
      express multiple genes. Murine cells provided with signal 1 and infected with
      either recombinant vaccinia or avipox vectors containing a TRIad of COstimulatory
      Molecules (B7-1/ICAM-1/LFA-3, designated TRICOM) induced the activation of T
      cells to a far greater extent than cells infected with any one or two
      costimulatory molecules. Despite this T-cell "hyperstimulation" using TRICOM
      vectors, no evidence of apoptosis above that seen using the B7-1 vector was
      observed. Results using the TRICOM vectors were most dramatic under conditions of
      either low levels of first signal or low stimulator cell:T-cell ratios.
      Experiments using a four-gene construct also showed that TRICOM recombinants can
      enhance antigen-specific T-cell responses in vivo. These studies thus demonstrate
      for the first time the ability of vectors to introduce three costimulatory
      molecules into cells, thereby activating both CD4+ and CD8+ T-cell populations to
      levels greater than those achieved with the use of only one or two costimulatory
      molecules. This new threshold of T-cell activation has broad implications in
      vaccine design and development.

PMID- 10582703
TI  - PTEN suppresses breast cancer cell growth by phosphatase activity-dependent G1
      arrest followed by cell death.
AB  - PTEN/MMAC1/TEP1, a tumor suppressor gene, is frequently mutated in a variety of
      human cancers. Germ-line mutations of phosphatase and tensin homolog, deleted on
      chromosome ten (PTEN) are found in two inherited hamartoma tumor syndromes:
      Cowden syndrome, which has a high risk of breast, thyroid, and other cancers; and
      Bannayan-Zonana syndrome, a related disorder. PTEN encodes a phosphatase that
      recognizes both protein substrates and phosphatidylinositol-3,4,5-triphosphate.
      The lipid phosphatase activity of PTEN seems to be important for growth
      suppression through inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt
      signaling pathway. We established clones with stable PTEN expression controlled
      by a tetracycline-inducible system to examine the consequences of increased
      levels of wild-type and mutant PTEN expression in a well-characterized breast
      cancer line, MCF-7. When we overexpressed PTEN in MCF-7, growth suppression was
      observed, but only if PTEN phosphatase activity is preserved. The initial growth
      suppression was attributable to G1 cell cycle arrest, whereas subsequent growth
      suppression was attributable to a combination of G1 arrest and cell death. Of
      note, the decrease in Akt phosphorylation preceded the onset-of suppression of
      cell growth. Treatment of MCF-7 cells with wortmannin, a PI3K inhibitor, caused
      cell growth inhibition in a way similar to the effects of overexpression of PTEN
      in this cell. In general, the inverse correlation between PTEN protein level and
      Akt phosphorylation was found in a panel of breast cancer cell lines. Therefore,
      PTEN appears to suppress breast cancer growth through down-regulating PI3K
      signaling, which leads to the blockage of cell cycle progression and the
      induction of cell death, in a sequential manner.

PMID- 10582704
TI  - Bone morphogenetic protein-6 is a marker of serous acinar cell differentiation in
      normal and neoplastic human salivary gland.
AB  - Bone morphogenetic protein (BMP-6, also known as vegetal-pale-gene-related and
      decaplentaplegic-vegetal-related) is a member of the transforming growth factor
      beta superfamily of multifunctional signaling molecules. BMP-6 appears to play
      various biological roles in developing tissues, including regulation of
      epithelial differentiation. To study the possible involvement of BMP-6 in normal
      and neoplastic human salivary glands, we compared its mRNA and protein expression
      in 4 fetal and 15 adult salivary glands and in 22 benign and 32 malignant
      salivary gland tumors. In situ hybridization and Northern blot analysis indicated
      that BMP-6 transcripts are expressed at low levels in acinar cells of adult
      submandibular glands but not in ductal or stromal cells. BMP-6 was immunolocated
      specifically in serous acini of parotid and submandibular glands. None was found
      in primitive fetal acini or any other types of cell in adult salivary glands,
      including mucous acini and epithelial cells of intercalated, striated, and
      excretory ducts. All 16 cases of acinic cell carcinoma consistently exhibited
      cytoplasmic BMP-6 staining in the acinar tumor cells. Other cell types in these
      tumors, including intercalated duct-like cells, clear, vacuolated cells, and
      nonspecific glandular cells, exhibited no cytoplasmic BMP-6 staining. Other
      benign and malignant salivary gland tumors lacked BMP-6 immunoreactivity, except
      in areas of squamous differentiation. The results indicate that in salivary
      glands, BMP-6 expression is uniquely associated with acinar cell differentiation
      and suggest that BMP-6 may play a role in salivary gland function. More
      importantly, our experience of differential diagnostic problems related to
      salivary gland tumors suggests that the demonstration of consistent and specific
      BMP-6 immunoreactivity in acinic cell carcinoma is likely to be of clinical
      value.

PMID- 10582705
TI  - Hypoxia-induced elevation in interleukin-8 expression by human ovarian carcinoma
      cells.
AB  - The expression level of interleukin-8 (IL-8) directly correlates with the
      progression of human ovarian carcinomas implanted into the peritoneal cavity of
      nude mice, but the mechanism of induction is unknown. Because hypoxia induces
      expression of vascular endothelial growth factor/vascular permeability factor,
      which, like IL-8, is an angiogenesis-regulating molecule, we determined whether
      hypoxic conditions could regulate the expression of IL-8. Surgical specimens of
      human ovarian carcinomas were prepared for immunohistochemical and in situ
      hybridization analysis. Elevated levels of IL-8 mRNA and protein were found in
      tumor cells adjacent to necrotic zones. In vitro exposure of human ovarian
      carcinoma cell lines SKOV3 i.p.1 and Hey-A8 to hypoxia resulted in a time
      dependent increase in steady-state levels of IL-8 mRNA (Northern blot) and in
      increased production and secretion of IL-8 protein (ELISA). Hypoxia-mediated
      transient induction of IL-8 expression could be ascribed to both an increase in
      IL-8 mRNA stability and transcriptional activation of the IL-8 gene promoter.
      Detailed functional analysis of the IL-8 promoter revealed that the sequence
      between -133 and -98 bp relative to the transcription initiation site was
      primarily responsible for IL-8 gene transcriptional activation by hypoxia. Point
      mutated luciferase reporter studies indicated that AP-1 and NF-kappaB-like factor
      binding elements were mainly responsible for hypoxia-induced increase in IL-8
      gene expression in human ovarian cancer cells, and that IL-8 transcription
      activation by hypoxia required the cooperation of NF-kappaB and AP-1 binding
      sites.

PMID- 10582707
TI  - Diminished aqueous microviscosity of tumors in murine models measured with in
      vivo radiofrequency electron paramagnetic resonance.
AB  - Using very low frequency in vivo electron paramagnetic resonance (EPR), we have
      compared, for the first time, the average microviscosity of the total aqueous
      compartment of murine fibrosarcomas and that of normal leg tissue in a living
      animal. EPR spectra from dissolved nitroxide spin probes report the solvent
      microviscosity. The tumor aqueous microviscosity, 1.8 +/- 0.1 centipoise, was
      significantly lower than that of the corresponding normal tissue, 2.9 +/- 0.3
      centipoise, a difference of 38 +/- 7%. These results confirm the commonly
      observed increase in the water proton transverse relaxation times (T2) in
      magnetic resonance imaging of hyperproliferative states, for example, malignancy.
      The specificity of the localization of the EPR signal indicates a substantial
      portion of the T2 increase seen in magnetic resonance imaging derives from
      decreased bulk-water viscosity. The effect of this microviscosity differences may
      be the basis of several physiological differences between tumors and normal
      tissues which could confer a growth rate advantage to tumor tissue.

PMID- 10582706
TI  - Overexpression of hypoxia-inducible factor 1alpha in common human cancers and
      their metastases.
AB  - Neovascularization and increased glycolysis, two universal characteristics of
      solid tumors, represent adaptations to a hypoxic microenvironment that are
      correlated with tumor invasion, metastasis, and lethality. Hypoxia-inducible
      factor 1 (HIF-1) activates transcription of genes encoding glucose transporters,
      glycolytic enzymes, and vascular endothelial growth factor. HIF-1 transcriptional
      activity is determined by regulated expression of the HIF-1alpha subunit. In this
      study, HIF-1alpha expression was analyzed by immunohistochemistry in 179 tumor
      specimens. HIF-1alpha was overexpressed in 13 of 19 tumor types compared with the
      respective normal tissues, including colon, breast, gastric, lung, skin, ovarian,
      pancreatic, prostate, and renal carcinomas. HIF-1alpha expression was correlated
      with aberrant p53 accumulation and cell proliferation. Preneoplastic lesions in
      breast, colon, and prostate overexpressed HIF-1alpha, whereas benign tumors in
      breast and uterus did not. HIF-1alpha overexpression was detected in only 29% of
      primary breast cancers but in 69% of breast cancer metastases. In brain tumors,
      HIF-1alpha immunohistochemistry demarcated areas of angiogenesis. These results
      provide the first clinical data indicating that HIF-1alpha may play an important
      role in human cancer progression.

PMID- 10582708
TI  - Aberrant sphingolipid signaling is involved in the resistance of prostate cancer
      cell lines to chemotherapy.
AB  - Activation of the apoptosis program has been implicated in the response of cancer
      cells to chemotherapy. Therefore, we postulated that chemotherapy-resistant
      prostate cancer has developed a lesion in the apoptosis signal transduction
      cascade. In this study, we investigated the mechanism underlying the resistance
      of apoptosis-insensitive prostate cancer cells to apoptosis. We approached this
      by comparing the response of the androgen-sensitive LNCaP cell line and the
      androgen-insensitive PC3 cell line to treatment with the topoisomerase I
      inhibitor, camptothecin. We demonstrated that LNCaP cells are susceptible to
      camptothecin-induced cell death, and PC3 cells are resistant. Additional studies
      confirmed that the mode of cell death in the LNCaP cells was by apoptosis. We
      then determined that a component of the resistance to death in the apoptosis
      insensitive cells involved a defect in the generation of ceramide, a key lipid
      mediator of apoptosis. Specifically, we demonstrated that PC3 cells are unable to
      elevate ceramide in response to treatment with camptothecin. In contrast,
      elevations in ceramide levels occur in LNCaP cells in response to the same
      treatment. Significantly, additional studies showed that treatment with exogenous
      ceramide overcomes the lesion in the PC3 cells and induces apoptosis. In
      attempting to gain preliminary insight into the nature of the lesion in ceramide
      formation in the apoptosis-resistant cells, we established that generation of
      ceramide in LNCaP cells is independent of the de novo pathway. These studies
      present novel insights into the mechanism by which prostate cancer cells may be
      resistant to induction of apoptosis. The significance of this study lies in the
      fact that an understanding of the biological and molecular events contributing to
      the resistance of prostate cancer to therapy is crucial to the development of
      more effective regimens for advanced disease.

PMID- 10582709
TI  - Identification of breast cancer cell line-derived paracrine factors that
      stimulate osteoclast activity.
AB  - Metastatic breast cancer causes destruction of significant amounts of bone, and,
      although bone is the most likely site of breast cancer metastasis, little is
      understood about interactions between tumor cells and bone-resorbing osteoclasts.
      We have investigated the paracrine factors produced by breast cancer cells that
      are involved in increasing osteoclast activity. We have determined by immunoassay
      that the human breast cancer cell line MDA MB 231 (231) cultured in serum-free
      medium secretes transforming growth factors type beta(TGF-beta) 1 and 2,
      macrophage colony-stimulating factor (M-CSF), granulocyte macrophage colony
      stimulating factor (GM-CSF), interleukin (IL) -1 and -6, tumor necrosis factor
      alpha (TNF-alpha), insulin-like growth factor II (IGF II), and parathyroid
      hormone-related peptide. To determine which of these are involved in increased
      bone destruction, we have fractionated serum-free 231-conditioned media and
      measured these fractions for effects on osteoclast resorption activity using
      multiple activity assays. The pattern of responses was complex. Several fractions
      stimulated osteoclast resorption either by increasing the number of osteoclasts
      binding to the bone or by elevating the resorption activity of the individual
      osteoclasts. Other fractions inhibited osteoclast activity. Analysis of active
      fractions for the factors identified in the 231-conditioned medium revealed that
      the presence of TNF-alpha and IGF-II was restricted to separate fractions that
      stimulated osteoclast resorption activity. The fractions that inhibited
      osteoclast resorption activity contained M-CSF, IL-6, TGF-beta2, and GM-CSF. No
      TGF-beta1 or IL-1 was detected in any of the active fractions. Our data support
      the hypothesis that breast cancer cells modulate osteoclast activity using
      multiple regulatory factors that increase both the number of mature osteoclasts
      attached to the bone and the bone resorption activity of these individual
      osteoclasts. Once it is understood how metastatic breast cancer elevates
      osteoclast-mediated bone loss, effective therapies to slow the progression and/or
      prevent this bone loss will become possible.

PMID- 10582710
TI  - Correspondence re: N.N. Mahmoud et al., Genotype-phenotype correlation in murine
      Apc mutation: differences in enterocyte migration and response to sulindac.
      Cancer Res., 59: 353-359, 1999.

PMID- 10582711
TI  - Stevens-Johnson syndrome: getting ready for the year 2000 and beyond.

PMID- 10582712
TI  - Comparing pollen and spore counts collected with the Rotorod Sampler and Burkard
      spore trap.
AB  - BACKGROUND: The Rotorod Sampler and Burkard spore trap are air-sampling
      instruments commonly used by allergists in the United States. Although both
      devices are volumetric, their principles of operation and particle recoveries
      differ. OBJECTIVE: This review will develop some guidelines for interpreting and
      comparing pollen counts obtained with these instruments. DATA SOURCES:
      Investigations examining particle recovery by each device will be reviewed. Five
      studies where the Rotorod and Burkard were operated in parallel will also be
      assessed. RESULTS: The Rotorod's theoretical and empirical collection
      efficiencies are low for particles <10 microm but typically exceed 80% for
      particles above this threshold. This instrument has traditionally been considered
      insensitive to wind; experimental data present a mixed picture. The Burkard
      offers high collection efficiencies, particularly for small particles, when an
      aerosol's velocity is low. Bi-directional errors in collection efficiency occur
      as a function of increasing wind speed and particle size. Parallel trapping
      investigations demonstrated that the Burkard yielded a higher estimate of the
      atmospheric particle concentration for all particle sizes. Differences were
      widest for small fungus spores but narrowed for pollen-sized particles. Some
      recovery differences are readily explained by sampling theory. Other disparities
      may reflect over-sampling, under-sampling or each device's principles of
      operation. CONCLUSIONS: Both instruments appear to record the same relative
      changes in airborne particle concentrations. The Burkard appears to be a superior
      instrument for sampling particles <10 microm. The Rotorod appears to be equal or
      superior to the Burkard for collecting particles >10 microm. A rough empirical
      means for comparing differences in particle recovery is presented.

PMID- 10582713
TI  - Facial edema, oral ulcers, and a cutaneous eruption following a dental procedure
      utilizing diflunisal and mepivacaine.

PMID- 10582714
TI  - B-lymphocyte aggregates in alveoli from a child with hypersensitivity pneumonitis
      (bird breeders lung).
AB  - BACKGROUND: Hypersensitivity pneumonitis is an interstitial lung disease mediated
      through a patient's immunologic response to a variety of inhaled organic dusts.
      Studies of the cellular components of lavage fluid from patients with this
      disease show marked increases of CD8+ suppressor/cytotoxic T-lymphocytes.
      OBJECTIVE: In this study, we identified, in addition to the expected suppressor T
      cells and natural killer cells, follicle-like aggregates of B-cells in the lung
      interstitium of an affected patient. METHODS: The patient was an 11-year-old non
      asthmatic, Caucasian male who presented with a 4-month history of progressive
      dyspnea, cough, and fever. The home contained nine cockatiel and two doves.
      Admission pulmonary functions revealed a restrictive pattern with diminished
      diffusion capacity. Prior to a diagnosis, the patient underwent bronchoalveolar
      lavage and transbronchial biopsy. Serum precipitins were eventually positive to
      pigeon (which cross-reacts with dove) droppings. The symptoms resolved after a
      prolonged course of prednisone. RESULTS: Analysis of bronchoalveolar lavage
      lymphocyte population revealed a predominance of CD8+ cells (50%) with 85%
      expressing the activation marker HLA-DR. The percentage of CD4+ and CD56+ were
      32% and 16%, respectively. The transbronchial biopsy revealed CD20+ follicle-like
      aggregates within the lung interstitium. CONCLUSIONS: The histopathologic
      findings confirm that in hypersensitivity pneumonitis, the predominant immune
      response is an infiltrate of CD8+ T cells. The presence of B cell aggregates,
      however, may indicate that the local synthesis of antibody may be involved in an
      antibody-dependent cellular cytotoxic mechanism.

PMID- 10582715
TI  - Risk factors for death from asthma. Prairie Provinces Asthma Study Group.
AB  - BACKGROUND: Asthma mortality rates have increased in Canada and worldwide. Within
      Canada, the highest rates were seen in the prairie provinces. OBJECTIVE: The
      objective was to determine risk factors for fatal asthma by comparing those who
      died of an acute exacerbation with those who attended an emergency department for
      treatment of asthma. METHODS: The case-control study included all deaths from
      asthma among those aged 5 to 50 years in Alberta, Saskatchewan and Manitoba from
      November, 1992 through October, 1995 (cases). The 35 fatalities were matched to
      209 controls by age, gender, time of the index event and residence. RESULTS:
      Cases were more likely than controls to have had severe asthma, an unscheduled
      physician visit in the past year, a past hospitalization for asthma, and to have
      been intubated. Both groups reported frequent, regular asthma symptoms. Beta
      agonist bronchodilator use was more common among cases, as was use in excess of
      prescribed amounts. Use of inhaled steroids did not differ between groups. Prior
      to the index event controls were more likely to report a cold or flu (OR = 0.27;
      95% CI: 0.10 to 0.72) and that medications were "not working" (OR = 0.30; 95% CI:
      0.12 to 0.71). Cases were more often sad and depressed (OR = 2.88; 95% CI: 1.03
      to 8.05). Time between onset/recognition of symptoms and the event was
      significantly shorter for cases than controls. CONCLUSIONS: Both groups tolerated
      high levels of regular symptoms, suggesting poor management. Opportunities for
      intervention existed for both groups near the time of the event. The short time
      between recognition of symptoms and death suggests patients at increased risk
      should monitor their condition closely and take action in response to
      predetermined criteria.

PMID- 10582716
TI  - Asthma quality of life in a Southern practice: towards a new paradigm.
AB  - BACKGROUND: Quality of life (QOL) surveys are increasingly recognized as part of
      state-of-the-art asthma assessment. Disease-specific surveys quantitate total QOL
      and subscale domains which, along with changes in these measures, suggest asthma
      severity and effects of intervention. OBJECTIVES: This study was conducted to (1)
      compare regional variation in QOL and change in QOL in an allergy practice in the
      South and (2) to examine if one or a set of questions relating to asthma severity
      could estimate QOL thereby obviating the need for a complete survey. METHODS:
      Fifty-eight patients were administered an asthma specific quality of life (AQOL)
      questionnaire, the Marks et al Asthma Quality of Life survey, at baseline and
      surveyed in follow-up at 1 and 6 months. Additional questions were asked
      concerning bronchodilator use in a day and 1 week, missed work/school days,
      nocturnal wakening in 1 week due to asthma, emergency room visits in the previous
      month, and past hospitalizations in the last year. Spirometry was performed at
      each visit. RESULTS: Baseline AQOL is significantly (P < .05) related
      individually to nocturnal wakening, bronchodilator use in a day, work or school
      days missed, and hospitalization during the past year. A model combining these
      factors explains 49% of the variance, r2 = .49. The AQOL score between baseline
      and the first month shows a significant improvement (P < .0001) and this
      improvement is related (P = .002) to the reduction in nocturnal wakenings during
      that same time period. CONCLUSIONS: Specialty care intervention affected QOL
      similarly in the Southern practice compared with other regions/countries.
      Nocturnal wakening, bronchodilator use in a day, workdays missed, and
      hospitalization in the past year were all significantly correlated with AQOL.
      Number of nocturnal wakenings and bronchodilator use in a day may not only
      stratify asthma severity, they roughly stratify AQOL. The wide scatter of AQOL
      scores for a given indicator of asthma severity makes a limited combination of
      questions an indicator but not yet a reliable predictor of AQOL.

PMID- 10582717
TI  - Detection and clinical characterization of patients with oral allergy syndrome
      caused by stable allergens in Rosaceae and nuts.
AB  - BACKGROUND: A minority of patients with oral allergy syndrome (OAS) induced by
      Rosaceae or nuts are positive on skin prick tests with commercial food extracts.
      This suggests reactivity against distinct stable allergens. OBJECTIVES: (1) To
      define the prevalence of subjects positive on skin prick tests with commercial
      extracts among patients with OAS caused by Rosaceae and/or nuts and (2) To
      investigate whether commercial extracts-positive subjects show some peculiar
      clinical feature and may represent a specific subset with food allergy. METHODS:
      Skin prick tests were carried out with a large panel of commercial extracts of
      airborne allergens (Allergopharma) and of vegetable foods (Dome/Hollister-Stier)
      in 298 adults with OAS caused by Rosaceae (n = 237) and or nuts (n = 161),
      positive on skin prick tests with fresh offending foods. RESULTS: 25/237 (11%)
      patients were positive on prick tests with commercial plum extract. This subgroup
      showed a higher incidence of systemic symptoms (64% versus 6%; P < .001) and a
      lower incidence of birch pollen allergy (12% versus 99%; P < .001) than
      commercial extract-negative patients; moreover, 36% versus 0%, respectively, did
      not have respiratory allergy (P < .001). Apple and peach were the main offending
      foods among commercial extract-negative and commercial extract-positive patients,
      respectively (87% versus 44% for apple, P < .001; and 52% versus 88% for peach, P
      < .005). Eight of one hundred sixty-one (5%) nuts-sensitive patients were
      positive on prick test with commercial walnut extract. This subgroup showed a
      higher proportion of patients who experienced systemic symptoms (63% versus 6%, P
      < .001), a lower prevalence of birch pollen allergy (13% versus 97%, P < .001),
      and a higher prevalence of grass pollen allergy (88% versus 41%, P < .05) than
      commercial extract-negative subjects. Further, reactivity against commercial
      walnut extract was associated with skin reactivity against commercial extracts of
      peanut (88% versus 37%, P < .005), tomato (75% versus 5%, P < .001), and plum
      (63% versus 8%, P < .001), and inversely related with skin reactivity against
      fresh apple (P < .001). In most cases, high levels of IgE specific for peach,
      apple, and hazelnut were associated with peanut reactivity rather than with
      clinical sensitivity to specific foods. In a preliminary investigation, most
      commercial extract-positive patients reacted against a 10-kDa protein
      characterized as a lipid transfer protein (LTP). CONCLUSIONS: Skin prick tests
      with commercial extracts of plum and walnut may be usefully employed to detect
      patients with OAS reacting against stable allergens. The high prevalence of
      systemic symptoms in these patients suggests that allergens' stability is
      associated with a higher resistance to the gastrointestinal environment and
      strongly influences the clinical expression of vegetable food allergy. At least
      some stable allergens, namely lipid transfer protein might be shared by
      botanically unrelated fruits such as nuts, peanuts, legumes, tomato, and
      Prunoideae.

PMID- 10582718
TI  - Risk factors for development of bronchial asthma in children in Delhi.
AB  - BACKGROUND: Information on the magnitude of the problem of childhood asthma in
      India and the factors influencing its occurrence is inadequate. OBJECTIVE: To
      measure the prevalence of asthma in schoolchildren in Delhi and study the factors
      determining its occurrence. METHODS: A questionnaire-based study carried out in
      nine randomly selected schools in Delhi. The age range was 5 to 17 years. The
      questionnaires were distributed to all the children (n = 21,367) for answering by
      either parent. The key questions relate to complaints of recurrent wheezing in
      the past, during the immediate last 1-year, and also wheezing exclusively induced
      by exercise or colds. In all, 19,456 questionnaires were received back (response
      rate 91%). Out of these, 18,955 were complete and analyzed. RESULTS: The
      prevalence of current asthma was 11.9% while past asthma was reported by 3.4% of
      children. Exclusive exercise-induced asthma was reported by 2.1% while that
      associated with colds by 2.4% of children. Boys had a significantly higher
      prevalence of current asthma as compared with girls (12.8% and 10.7%,
      respectively). Multiple logistic regression analysis showed that male sex, a
      positive family history of atopic disorders, and the presence of smokers in the
      family were significant factors influencing the development of asthma while
      economic class, air pollution (total suspended particulates), and type of
      domestic kitchen fuel were not. CONCLUSIONS: The prevalence of current asthma in
      children in Delhi is 11.9%. Significant risk factors for its development are male
      sex, a positive family history of atopic disorders, and the presence of smokers
      in the family.

PMID- 10582719
TI  - Serious childhood respiratory infections and asthma in adult life. A population
      based study. ECRHS Italy. European Community Respiratory Health Survey.
AB  - BACKGROUND: A number of epidemiologic studies have tried to establish whether
      respiratory tract infections in early childhood cause obstructive pulmonary
      disease in adult life. OBJECTIVE: To determine whether reported serious
      respiratory infection before the age of 5 years (SRI) is a significant risk
      factor for subsequent development of bronchial asthma and/or bronchial
      hyperresponsiveness in adults. METHODS: We investigated a random population
      sample of 1,104 subjects (aged 20 to 40 years), participating in the European
      Respiratory Health Survey in Italy. Bronchial response to methacholine and
      answers to a standardized questionnaire were analyzed. RESULTS: The prevalence of
      SRI (ie, a positive response to the question "Have you ever had a serious
      respiratory infection before the age of 5 years?") was significantly higher in
      the subjects with a positive family history of allergic diseases than in those
      with a negative one (O.R. 1.89; 95% C.I. 1.24 to 2.87, P < .01). No relationship
      was found between SRI and current adult asthma; however, asthma in the past was
      found in 20.5% of the SRI positive subjects and in 9.1% of SRI negative subjects
      (O.R. 2.47; 95% C.I. 1.47 to 4.15, P < .05). No difference in the response to
      methacholine and in FEV1, FEV1/FVC values was found between SRI positive and SRI
      negative subjects. CONCLUSIONS: We suggest that a positive family history of
      atopy is associated with a significantly higher prevalence of SRI. Furthermore
      our results indicate that exposure to SRI is a risk factor for asthma in the past
      (ie, asthma in childhood and adolescence) but not for adult asthma or for the
      development of bronchial impairment in adult life.

PMID- 10582720
TI  - IgE antibody response to vertebrate meat proteins including tropomyosin.
AB  - BACKGROUND: Although meat is a main source of proteins in western diets, little
      information is available regarding allergy to vertebrate meats or the allergens
      implicated in these reactions. OBJECTIVE: To evaluate the in vitro IgE antibody
      response to different vertebrate meats in suspected meat-allergic subjects, as
      well as the possible role of tropomyosin in meat allergy and to analyze the cross
      reactivity between vertebrate meats and the effect of heating on the IgE-binding
      to meat proteins. METHODS: Fifty-seven sera from suspected meat-allergic subjects
      were tested by grid blot to extracts of beef, lamb, pork, venison, chicken, and
      turkey and to four mammalian tropomyosins of different origins. RESULTS: Meat
      allergic subjects have IgE antibodies to proteins in different mammalian meats
      (43/57 subjects); cross-reactivity with avian meat was limited: less than 50%
      (19/43) of meat positive sera reacted to chicken. In contrast, most of the
      poultry-positive sera also reacted to different mammalian meats. In general,
      there was stronger IgE reactivity to raw meats in comparison to cooked meats; an
      exception was six cases in which IgE reactivity to cooked poultry was stronger.
      Weak IgE reactivity to tropomyosin was detected in only 2/57 sera tested.
      CONCLUSIONS: Suspected meat-allergic subjects have serum IgE directed to meat
      proteins. In vitro cross-reactivity among mammalian meats appears to be
      important, while cross-reactivity to poultry is limited indicating mammalian
      specific proteins. Although cooking in general denatures meat proteins rendering
      them less allergenic, in some cases the process of cooking may result in the
      formation of new allergenic moieties. The muscle protein tropomyosin is not an
      important vertebrate meat allergen.

PMID- 10582721
TI  - Lupine-induced anaphylaxis.
AB  - BACKGROUND: Legumes are one of the most common foods causing allergic reactions
      in children and adults. Cross-reacting antibodies are frequently demonstrated in
      this family but the real clinical cross-reactivity is uncommon. OBJECTIVE: To
      report a case of lupine-induced anaphylaxis and to elucidate in vivo and in vitro
      cross-reactivity with some legumes. METHODS: Skin prick test (SPT) with some
      legumes were performed. Cap-IgE, ELISA-IgE, and immunoblotting were carried out.
      Open oral challenges with some legumes were performed. Cross-reactivity was
      studied by ELISA and immunoblotting inhibition. RESULTS: The results demonstrated
      type-I hypersensitivity reactions with lupine and some other legumes. Cap-IgE
      with peanut was positive but the SPT and ELISA-IgE were negative and the patient
      tolerated a peanut challenge. ELISA inhibition revealed a partial inhibition
      (62%) using lupine as the solid phase. Partial inhibition was demonstrated by
      immunoblotting inhibition. Open oral challenge with peanut and green bean were
      negative but positive with pea. CONCLUSION: We present a lupine sensitized
      patient with positive SPT and in vitro cross-reactivity with other legumes.
      Clinical cross-reactivity progressively developed over a 5-year period.
      Discrepancies were found between the clinical aspect and in vitro study of peanut
      allergy. Factors determining the wide variability in cross-reactivity among
      individuals are still obscure.

PMID- 10582722
TI  - Conditions in blood sampling procedures that extend the ex vivo stability of
      eosinophil activity markers in peripheral blood from allergic patients and
      healthy controls.
AB  - BACKGROUND: Serum-ECP, EG2-epitope on intracellular ECP and surface expression of
      CD9 and CD11b in peripheral blood eosinophils (PBE) are considered to be markers
      that mirror clinical parameters in allergic inflammation. OBJECTIVE: The aim was
      to investigate the impact of the blood sampling procedure on PBE markers and to
      identify optimal conditions for extended pre-analysis storage. METHODS: Blood,
      from healthy individuals and patients with allergic rhinitis/asthma, was
      collected in tubes with EDTA, citrate, or without anti-coagulant. The expression
      of EG2-epitope, CD9, and CD11b were analyzed in eosinophils and neutrophils after
      1, 5, and 24 hours of storage at +4 degrees C, according to the FOG-method and
      flow cytometry. In vitro stimulation with fMLP/PMA was used for metabolic
      activity analysis and CD11b mobilization. Following a 1-hour clotting period at
      +20 to 22 degrees C, samples were stored at +4 degrees C and serum-ECP levels
      were measured. RESULTS: The EG2-epitope, serum-ECP, and CD9 were stable in
      samples from both healthy controls and allergic patients at all storage
      conditions. The EG2-epitope, serum-ECP and PBE count were significantly increased
      in the patient group, whereas no differences were observed in the expression of
      CD9 or CD11b. Both granulocytes and monocytes retained their metabolic activity
      for 24 hours. Neutrophils in citrate-blood increased their ability to respond to
      fMLP, as compared with EDTA-blood. CONCLUSION: In vitro analysis of selected
      activity markers and functional tests could be performed on granulocytes from
      both healthy individuals and allergic patients after 24 hours storage at +4
      degrees C. The anticoagulant citrate seems to be preferable to EDTA when
      monocytes or CD11b expression are analyzed.

PMID- 10582723
TI  - Astemizole use with erythromycin.

PMID- 10582724
TI  - Aminophylline in the treatment of bronchial asthma.

PMID- 10582725
TI  - WHO position paper on oral (sublingual) immunotherapy.

PMID- 10582726
TI  - Primary sensitization in infants.
AB  - OBJECTIVE: It has become increasingly clear that the mechanisms by which an
      allergic immune response is generated are complex and may begin even before a
      baby is born. Genetic, environmental, nutritional, and immunologic factors acting
      during pregnancy all play a role in determining whether or not a baby is born
      with a propensity to develop allergic sensitization and subsequent allergic
      disease. The objective of the research described in this article is to determine
      whether manipulation of any or all of these could lead to prevention of disease.
      DATA SOURCES: The database used was Medline up to and including 1997. The
      Conference Proceedings of the XVth World Congress of Asthmology in Montpellier
      1996 are quoted. Many of the research hypotheses are generated from work
      performed in our own laboratories. STUDY SELECTION: The criteria used to select
      studies for review centered around a necessity for the data to have been
      collected in very early life with, if possible, a follow-up period to determine
      disease progression, or for the data to have been collected during pregnancy to
      elucidate primary mechanisms. RESULTS: It has been shown that a fetus is able to
      mount a proliferative response to a common allergic trigger (beta-lactoglobulin,
      house dust mite, etc) as early as 22 weeks of pregnancy. Maternal exposure to
      allergens influences her own IgG production which modulates the allergen exposure
      of the fetus resulting in either primary sensitization of T cells or "tolerance"
      to the allergen. Atopic mothers create a more Th2-orientated environment for the
      developing fetus than non-atopic mothers. CONCLUSIONS: Manipulation of the
      maternal immune response during pregnancy, either by altering her environment or
      controlling her allergic reactions, may be a method of preventing the development
      of allergic disease in infants.

PMID- 10582727
TI  - Linking upper and lower airways.
AB  - BACKGROUND: Upper and lower airways are similar in many ways, including common
      triggers, pathogenic mechanisms, and response to treatment. Explanations for the
      posed linkage between upper and lower airways include nasal-bronchial reflux,
      postnasal drainage of inflammatory material into the lower airways, and dry air
      impinging on the nasal mucosa. CONCLUSION: Treatment modalities such as
      antihistamines and corticosteroid aerosols by the nasal route improve both the
      upper and lower airways.

PMID- 10582728
TI  - Allergic inflammation in upper and lower airways.
AB  - OBJECTIVE: The primary reason for this review is to discuss the relationship
      between upper and lower airways at various levels with the emphasis on common
      pathophysiologic mechanisms, and how treatment of the upper airways will benefit
      the lower airways. DATA SOURCES: The main source of information is derived from
      original articles and books, with an extensive bibliography included. STUDY
      SELECTION: Studies were derived almost exclusively from articles and reviews in
      peer-reviewed journals. RESULTS: The prevalence of rhinitis and asthma are both
      increasing. Common to both the upper and lower airways are the triggers, many of
      the inflammatory cells and mediators, and the treatment modalities. By contrast,
      there are organ-specific differences in the reaction to various stimuli in the
      nose or lung, with each organ manifesting its own vocabulary of response.
      CONCLUSIONS: There are meaningful relationships between upper and lower airways
      at various levels of our understanding. Differential responses to medications
      help us better understand pathogenic mechanisms in rhinitis and asthma. Further,
      treatment of the upper airways provides additional benefit to the lower airways.

PMID- 10582729
TI  - Minimal persistent inflammation may be controlled by cetirizine.
AB  - OBJECTIVE: Recent pathophysiologic research demonstrated the crucial role played
      by adhesion molecules in recruiting and activating inflammatory cells during
      allergic reaction. DATA SOURCES: Intracellular adhesion molecule (ICAM-1)
      expression on nasal epithelial cells is involved in two main pathogenetic
      phenomena. The first is to allow leukocyte infiltration of respiratory mucosa,
      since they express LFA1 and Mac1, which are ligands of ICAM-1. This point is very
      important, because it has been demonstrated that patients with mite allergy (ie,
      continuously exposed to allergen) present a minimal persistent inflammation (MPI)
      both at nasal and conjunctival levels. This inflammation is characterized by the
      presence of leukocyte infiltration and ICAM-1 expression on epithelial cells and
      by a relationship between specific and nonspecific hyperreactivity in the absence
      of clinical symptoms. The second is that ICAM-1 is also the main receptor of the
      human rhinoviruses. This fact may partially explain the relationship among
      allergy, viral infections, and asthma attacks. STUDY SELECTION: Different studies
      have been performed to demonstrate the possible effects on the different clinical
      aspects of MPI exerted by an antiallergic drug. RESULTS: It has been demonstrated
      that cetirizine is able to reduce ICAM-1 expression on nasal epithelial cells and
      conjunctival nonspecific hyperreactivity in asthmatic asymptomatic children with
      MPI. CONCLUSIONS: The therapeutical strategy of mite allergy should be targeted
      to treat minimal persistent inflammation.

PMID- 10582730
TI  - Quality of life in allergic rhinitis.
AB  - OBJECTIVE: This review will furnish the reader current information on the
      importance of quality of life evaluation in patients suffering from allergic
      rhinitis, the different types of quality of life instruments used, and how they
      can be used in judging different pharmaceutical therapies. DATA SOURCES: Computer
      assisted MEDLINE searches for articles assessing "quality of life" and "outcomes"
      in rhinitis. Also MEDLINE searches evaluating health-related quality of life in
      relationship to different pharmacologic treatments in allergic rhinitis. STUDY
      SELECTIONS: Pertinent abstracts and articles in two broad areas were selected.
      The first groups were articles in the fields of outcomes, quality of life,
      allergic rhinitis, and its relationship to health-related quality of life. The
      second group of articles evaluated different pharmacologic agents' effect on the
      health-related quality of life of rhinitis patients. Both sets of articles were
      critically analyzed with important representative studies selected for this
      review. RESULTS: Health-related quality of life of patients with allergic
      rhinitis is impaired as measured by both generic and specific health-related
      quality of life instruments. Use of second generation antihistamines, intranasal
      corticosteroids, and intranasal ipratropium bromide have been shown to improve
      the health-related quality of life of sufferers of allergic rhinitis.
      CONCLUSIONS: The measuring of health-related quality of life is assuming a
      primary position in outcomes analysis in the patient with allergic rhinitis.
      Studies have documented the validity of using generic and specific health-related
      quality of life instruments in allergic rhinitis. Each type has its own
      weaknesses and strengths that the user needs to appreciate. Appraising the role
      of different pharmacologic agents in allergic rhinitis in improving the patient's
      quality of life is an important part of proving the medication's worth to the
      health care community.

PMID- 10582731
TI  - Impact of cetirizine on the burden of allergic rhinitis.
AB  - OBJECTIVE: The goals of this article include the reporting of the epidemiology,
      economic and medical impact of allergic rhinitis. In addition, the pharmacology
      and clinical profile of the therapeutic agent cetirizine are reviewed. DATA
      SOURCES: A detailed literature search was conducted. References are limited to
      the English language and human subjects and tissues. Studies considered relevant
      and important over the past 20 years are highlighted. STUDY SELECTION: Prevalence
      and morbidity data were chosen from more recent assessments. Because cetirizine
      is a relatively new compound, studies from the past several years from peer
      reviewed journals have been emphasized. RESULTS: Allergic rhinitis affects
      between 15% and 25% of the US general population. It shares common
      pathophysiologic mechanisms with conjunctivitis and asthma and predisposes to
      nasal infections, otitis media, sinusitis, nasal polyposis, and orthodontic
      malocclusions. Direct medical care costs amount to up to 3 billion dollars every
      year. In addition, the quality of life of affected individuals is substantially
      compromised. Cetirizine is a potent H1-receptor antagonist and has anti
      inflammatory properties. It does not interact with concomitantly administered
      medications, has no cardiac adverse effects, and does not appear to be associated
      with teratogenicity. Impairment of CNS function is comparable to other low
      sedating antihistamines at the recommended dose of 10 mg daily for adults. Its
      clinical efficacy for allergic respiratory diseases has been established in
      numerous trials. CONCLUSIONS: Allergic rhinitis causes considerable suffering.
      Cetirizine, with a fine risk-benefit ratio, can be a most valuable therapeutic
      option.

PMID- 10582732
TI  - Clinical aspects, epidemiology, and prognosis of atopic dermatitis.
AB  - OBJECTIVE: This review article examines the clinical aspects, epidemiology, and
      prognosis of atopic dermatitis. DATA SOURCES: These are studies and review
      articles from textbooks of dermatitis and allergy in general, as well as more
      recent epidemiologic surveys published in specialist journals of allergy and
      dermatology. STUDY SELECTION: Included studies meet the criteria of being a
      survey of the prevalence of atopic dermatitis published recently in a respected
      peer-reviewed journal. Particular emphasis is placed on those that examine both
      the prevalence of the problem and significant causative and associated factors.
      RESULTS: Atopic dermatitis is frequently a severe illness that develops in early
      infancy. It can persist beyond the childhood years and is often found in
      association with significant respiratory complications. The exact pathogenesis is
      unclear but it appears that it has a complex immunologic origin. Early surveys
      lack the methodologic refinements of more recent data from the mid-1990s,
      including the SCARPOL study. Collectively, these point to a high current
      prevalence rate of 10% to 15%, a figure that has risen steadily in the preceding
      decades. The most common associations of atopic dermatitis are a risk of
      developing respiratory disorders, such as allergic rhinitis and asthma (40% to
      60%), and a persistence rate after puberty (40% to 60%), which is indeed much
      higher than previously suspected. CONCLUSIONS: A clear recognition of the various
      disease subgroups along with intervention studies that evaluate reduction of risk
      are needed before more precise treatment strategies can be devised.

PMID- 10582733
TI  - Human skin mast cells: in vitro and in vivo studies.
AB  - OBJECTIVE: This short review surveys our current knowledge on the development and
      heterogeneity of human mast cells, the distribution of mast cells within human
      skin and the properties of human skin mast cells both in vitro and in vivo. It
      also examines the effects of antihistamines in the wheal-and-flare response in
      the skin provoked by bradykinin. RESULTS: Mast cells derive from mononuclear
      precursor cells which undergo their final phase of their differentiation in the
      tissues. In normal skin, mast cells, which are primarily of the MC(TC) subtype,
      occur in the greatest density in the superficial dermal zone. Like all other mast
      cells, human skin mast cells bind IgE with high affinity to specific FcepsilonRI
      receptors, but unlike those from lung, tonsils, adenoids or intestine, they also
      express the C5a receptor (CD88) and activation sites for substance P, VIP,
      somatostatin, and compound 48/80. Both IgE-dependent stimulation by activating
      tyrosine kinases, and non-immunologic stimulation by activating G-proteins induce
      a characteristic compound exocytosis resulting in the liberation of the preformed
      mediators. Production of prostaglandin D2 and leukotriene C4, however, occurs
      only with IgE-dependent stimulation. In vivo, dermal microdialysis and scanning
      laser Doppler imaging have been used to assess the role of histamine in the wheal
      and-flare response. These techniques were also used to show that low
      concentrations of intradermal bradykinin release negligible quantities of
      histamine. The results showed that although the resultant flare was inhibitable
      by antihistamines, low concentrations of bradykinin released negligible
      quantities of histamine. This suggests a potentially novel mechanism of action of
      antihistamines that requires further detailed investigation.

PMID- 10582734
TI  - Use of cetirizine in dermatologic disorders.
AB  - OBJECTIVE: This review is written to summarize the present state of knowledge on
      the use of cetirizine in dermatologic disorders, its efficiency, and concerns
      regarding the safety of the drug. DATA SOURCES AND STUDY SELECTION: A Medline
      search from 1980 until August 1997 was conducted. In addition, older literature
      especially concerning hydroxyzine was evaluated as well. The review considers all
      double-blind trials and in addition focuses on all information regarding the
      pharmacology and possible side effects of the drug. RESULTS: Peak plasma levels
      are reached within 1 hour after intake. Drug elimination occurs largely unchanged
      by renal excretion and drug interactions are not known. Cetirizine has no cardiac
      toxicity. No evidence for teratogenicity has been found. Possible adverse events
      include somnolence but are dose-dependent and mostly mild. At the dose of 10 mg
      no impairment of driving performance or response time was observed. In
      dermatology, cetirizine has proven to be effective in the treatment of various
      forms of urticaria and it reduces the pruritus of atopic eczema. For these
      conditions, frequently doses higher than 10 mg (up to 40 mg) are recommended to
      achieve the best benefit. In other pruritic dermatoses, cetirizine has been
      reported to be helpful but, with the exception of mosquito bites where 10 mg
      daily had a significant effect, controlled studies are missing. CONCLUSIONS:
      Cetirizine is a safe second generation antihistamine. It is effective especially
      in the treatment of urticaria and reduces significantly the pruritus of atopic
      dermatitis. An individual dosage should be chosen based on the severity of
      symptoms.

PMID- 10582735
TI  - H1-receptor antagonists: safety issues.
AB  - Histamine is an important neurotransmitter. Old (first-generation) H1-receptor
      antagonists such as chlorpheniramine, diphenhydramine, or triprolidine produce
      histamine blockade at H1-receptors in the central nervous system (CNS) and
      frequently cause somnolence or other CNS adverse effects. New (second generation)
      H1-antagonists such as cetirizine, fexofenadine, and loratadine represent an
      advance in therapeutics; in manufacturers' recommended doses, they enter the CNS
      in smaller amounts, produce relatively little somnolence or other CNS adverse
      effects, and do not exacerbate the adverse CNS effects of alcohol or other CNS
      active chemicals. Two H1-antagonists, astemizole and terfenadine, have been found
      to prolong the QTc interval and, rarely, to cause cardiac dysrhythmias after
      overdose or under other specific conditions. This has led to withdrawal of
      regulatory approval for them. An H1-antagonist absolutely free from adverse
      effects under all circumstances is not yet available for use.

PMID- 10582736
TI  - Therapeutic index of H1-antihistamines: example of cetirizine.
AB  - BACKGROUND: The second generation H1 antihistamines were considered to have an
      improved risk/benefit ratio because of their low penetration into the brain and
      their very low incidence of CNS depressant effects. Nevertheless, the cardiac
      rhythm disturbances described under terfenadine and astemizole intake drew the
      attention to the fact that the low penetration into the brain is only one limited
      item in the evaluation of their respective therapeutic indices. A correct
      evaluation of the therapeutic index should always comprise a large series of
      items: all desired and not desired effects and properties should be considered
      together with the physicobiochemical mechanisms of the drugs at cell and membrane
      levels.

PMID- 10582737
TI  - Comparison of two surgical techniques for renal transplantation in cats.
AB  - OBJECTIVE: To compare two surgical techniques for renal transplantation in cats
      with respect to graft warm ischemia time, total surgical time, operative and
      postoperative complications, and return to normal renal function based on
      measurement of plasma creatinine concentrations. STUDY DESIGN: Research study
      using normal cats. ANIMALS OR SAMPLE POPULATION: Fourteen adult, feline leukemia
      virus and feline immunodeficiency virus (FELV/FIV) negative, neutered male and
      spayed female cats. MATERIALS AND METHODS: Fourteen cats underwent heterotopic
      renal isograft transplantation with nephrectomy of the contralateral kidney.
      Renal arterial end-to-end anastomosis to the external iliac artery was performed
      in eight cats and renal arterial end-to-side anastomosis to the aorta was
      performed in six cats. Cats were monitored for 14 days after surgery. Renal
      function was evaluated by daily measurement of plasma creatinine concentrations.
      The cats' health was assessed by the daily recording of body weight, rectal
      temperature, postoperative complications, urine production, appetite, packed red
      blood cell volume, and total serum protein. Ultrasonographic assessment of the
      isograft was performed every third day. Animals were euthanatized or adopted 14
      days after surgery and histopathologic analysis of biopsies or whole isograft
      tissues was performed. RESULTS: Nine of fourteen cats survived the 14-day study
      period. Although not statistically significant, mean total surgical time and
      graft warm ischemia time was shorter for the arterial end-to-side anastomosis.
      Mean daily plasma creatinine concentrations were not significantly different
      between the two groups. Five of eight cats (62%) undergoing the arterial end-to
      end technique developed neuropraxia and lameness of the ipsilateral pelvic limb.
      Five cats died or were euthanatized because of other complications. CONCLUSIONS
      AND CLINICAL RELEVANCE: The arterial end-to-side technique appears to be the
      better method for renal transplantation in cats. Shorter graft warm ischemia and
      total surgical times, absence of pelvic limb complications, and an adequate
      return to normal renal function were associated with this technique.

PMID- 10582738
TI  - Reoperative neurosurgery in dogs with thoracolumbar disc disease.
AB  - OBJECTIVE: To characterize the subset of dogs in our neurosurgical practice that
      underwent spinal surgery for thoracolumbar (TL) disc herniation and subsequently
      underwent additional decompressive TL surgery. STUDY DESIGN: A retrospective case
      series. SAMPLE POPULATION: Thirty dogs that underwent reoperation for TL disc
      herniation. A comparison group of Dachshunds that underwent only one
      decompressive TL disc surgery was also studied. METHODS: Dogs that underwent
      reoperation were divided into two groups based on the interval between their
      first and second surgery. The early reoperation group included those dogs having
      a second surgery less than 4 weeks after the initial operation. The late
      reoperation group included those dogs having a second surgery more than 4 weeks
      after the initial operation. For each Dachshund in the late reoperation group,
      two Dachshunds that underwent only one decompressive TL disc surgery were
      selected and formed the comparison group. Dogs in the comparison group were
      matched with reoperated cases based on the severity of preoperative neurologic
      deficit and site of disc herniation. These two groups were compared to determine:
      (1) if age and body weight were risk factors for reoperation, and (2) if dogs had
      a poorer functional outcome after their second decompressive surgery than did
      those in the comparison group after their first (and only) decompressive surgery.
      RESULTS: A total of 30 of 467 (6.4%) dogs that underwent decompressive TL disc
      surgery were reoperated. In the early reoperative cases (n = 5 dogs), the
      inciting cause in all cases was residual compression from disc material at the
      site of the initial surgery. In the late reoperation group, 22 of 25 (88%) cases
      had a second disc herniation at a site distinct from the initial lesion.
      Dachshunds had a significantly higher risk for late reoperation (odds ratio and
      95% CI = 3.67, 1.46 to 10.03); other small and medium-sized breeds (<20 kg) were
      underrepresented. Age and body weight were not significant predictors for
      reoperation. A total of 21 of 23 (91%) dogs had functional recovery after late
      reoperation. Complete sensorimotor loss was a significant negative predictor of
      functional recovery in the late reoperative cases (P = .01). Likelihood of
      functional recovery in dogs after their second decompressive surgery was
      identical to the functional recovery of dogs in the comparison group. CONCLUSIONS
      AND CLINICAL RELEVANCE: Our results show that a second disc herniation occurring
      at a site distinct from the initial lesion is the most common cause for
      reoperation and that Dachshunds have a significantly greater risk than other
      breeds.

PMID- 10582739
TI  - Tenoscopic examination and proximal annular ligament desmotomy for treatment of
      equine "complex" digital sheath tenosynovitis.
AB  - OBJECTIVE: To determine the outcome of horses with "complex" digital
      tenosynovitis treated by tenoscopic proximal annular ligament desmotomy and
      resection of synovial masses or adhesions, or both, within the digital sheath.
      STUDY DESIGN: Retrospective evaluation. ANIMALS OR SAMPLE POPULATION: Twenty-five
      horses with a clinical and ultrasonographic diagnosis of palmar or plantar
      proximal annular ligament constriction and ultrasonographic evidence of synovial
      masses or adhesions within the digital tendon sheath. METHODS: Each horse had
      tenoscopic surgery for annular ligament desmotomy combined with adhesiolysis
      and/or synovial mass resection. Mean follow-up time was 3.4 years. Spearman's
      rank correlation was used to assess the relationship between functional outcome
      or cosmetic results and preoperative variables including duration of clinical
      signs, digital sheath synovial fluid total protein concentration and nucleated
      cell count, thickness of the palmar or plantar proximal annular ligament (PAL),
      severity of adhesions, severity of synovial masses, degree of synovial
      distention, or limb affected. RESULTS: A total of 18 (72%) horses returned to
      athletic soundness, 4 were improved but not sound, and 3 were not improved.
      Cosmetic outcome was normal in 10 horses, improved but not normal in 12, and not
      improved in 3 horses. Cosmetic and functional outcome were significantly
      adversely affected by the duration of clinical signs and the severity of synovial
      masses. CONCLUSIONS: With appropriate tenoscopic surgical attention, horses with
      complex tenosynovitis syndrome characterized by synovial masses, adhesions, or
      both adhesions and masses, and PAL constriction, have a good prognosis for return
      to athletic soundness. CLINICAL RELEVANCE: Horses with PAL constriction and
      additional digital tendon sheath pathology such as adhesions and synovial masses
      have a 72% chance of returning to sound athletic performance, however 60% of
      horses retain some degree of cosmetic blemish in the affected limb. There is an
      inverse relationship between the duration of clinical signs and outcome, and
      therefore, prompt surgical attention is advised.

PMID- 10582740
TI  - Management of hypertension controls postoperative neurologic disorders after
      renal transplantation in cats.
AB  - OBJECTIVES: To determine the prevalence and describe the management of
      hypertension and central nervous system (CNS) complications after renal
      transplantation in cats. We also compared the prevalence of CNS complications
      between cats monitored and treated for postoperative hypertension and a
      previously described, historical control group of cats not monitored or treated
      for postoperative hypertension. STUDY DESIGN: Retrospective clinical study.
      ANIMALS OR SAMPLE POPULATION: A total of 34 client-owned cats that received renal
      allografts for the treatment of end-stage renal failure. METHODS: Medical records
      were reviewed. Data obtained included preoperative and postoperative systolic
      blood pressures, antihypertensive therapy, response to treatment, neurologic
      signs, and clinical outcome. The results were compared with a historical control
      group of feline renal allograft recipients that were neither monitored nor
      treated for postoperative hypertension. RESULTS: Severe postoperative
      hypertension occurred in 21 of 34 of cats. Hypertension was treated in all 21
      cats with subcutaneously administered hydralazine which reduced systolic blood
      pressure to less than 170 mm Hg in 15 minutes in 20 of 21 cats; hydralazine
      produced hypotension in one cat and failed to control hypertension in 1 cat.
      After transplantation, seizures were observed in one cat and other neurologic
      complications (stupor, ataxia, and central blindness) were observed in three
      cats. The prevalence of seizures and neurologic complication-related deaths after
      transplantation was significantly reduced with treatment of postoperative
      hypertension. CONCLUSIONS AND CLINICAL RELEVANCE: Hypertension is a major
      contributing factor to postoperative seizure activity after renal transplantation
      in cats; treatment of hypertension reduces the frequency of neurologic
      complications.

PMID- 10582741
TI  - Comparison of incisional bursting strength of simple continuous and inverted
      cruciate suture patterns in the equine linea alba.
AB  - OBJECTIVE: To determine the bursting strength of ventral median abdominal
      incisions closed by either simple continuous or inverted cruciate suture
      patterns. STUDY DESIGN: Experimental. ANIMAL OR SAMPLE POPULATION: Twelve equine
      cadavers. METHODS: A 25 cm ventral median incision was made through the linea
      alba and a 200 L polyurethane bladder was placed within the abdomen. Either a
      simple continuous or an inverted cruciate pattern using 3 polyglactin 910 with a
      bite size and suture interval of 1.5 cm was used to close linea incisions.
      Closure time was recorded for each pattern. The bladder was inflated with air at
      40 L/min, and the pressure at body wall failure recorded. The length of suture
      used for wound closure and the wound failure modes were recorded. Deviation from
      the linea (cm), total suture length (cm), suture length to wound length ratio
      (SL:WL), closure time (min), bursting pressure (mm Hg), and failure modes were
      compared between groups using Welch-Aspin t-tests. The effects of independent
      subject variables were assessed for possible effects on bursting strength using
      analysis of covariance. RESULTS: Mean bursting pressure was significantly greater
      for the simple continuous pattern than for the inverted cruciate pattern (P =
      .01). Significantly less suture material (P = .0002) was required with the
      continuous pattern than with the inverted cruciate pattern. Mean closure time,
      SL:WL, deviation from the linea, and failure modes were not significantly
      different between groups. No significant effects were noted for independent
      variables in both groups on bursting strength. CONCLUSIONS: In this model, a
      simple continuous closure pattern for ventral median abdominal incisions was
      stronger than an inverted cruciate pattern. A simple continuous pattern leaves
      less foreign material in the wound, which may be of benefit in reducing
      incisional complications. CLINICAL RELEVANCE: Use of a continuous closure pattern
      for the linea alba may offer greater wound security during episodes of increased
      intra-abdominal pressure in horses.

PMID- 10582742
TI  - The effects of ketoconazole on the pharmacokinetics of cyclosporine A in cats.
AB  - OBJECTIVE: To determine the effects of ketoconazole (KC) on the pharmacokinetics
      of cyclosporine A (CsA) elimination in cats. STUDY DESIGN: Research study and
      prospective clinical trial. ANIMALS: Five healthy adult cats (pharmacokinetic
      studies) and 6 client-owned cats with chronic renal failure. METHODS: Blood CsA
      concentrations were measured after CsA (4 mg/kg i.v.) administration with or
      without concurrent oral KC (10 mg/kg). Subsequently, a combined CsA-KC
      immunosuppressive regimen was used in cats after kidney transplantation. Blood
      CsA concentrations were measured using high performance liquid chromatography.
      CsA elimination was analyzed using a computerized pharmacokinetics program.
      RESULTS: KC increased blood CsA concentrations 1.8-fold and 2.2-fold at 12 and 24
      hours after CsA administration. KC significantly decreased the mean systemic CsA
      clearance from 2.73 mL/min/kg to 1.22 mL/min/kg resulting in an increase in the
      terminal phase half-life from 10.7 to 22.2 hours. The volume of distribution of
      steady-state of CsA was unaffected by KC. In a series of clinical feline kidney
      transplant patients, a once-a-day CsA-KC regimen was able to be used in most of
      the cats and was effective for prevention of allograft rejection in all of these
      cats. CONCLUSION AND CLINICAL RELEVANCE: KC is an effective adjunct treatment for
      immunosuppression in feline kidney transplant patients. KC suppresses CsA
      elimination, which reduces the need for CsA and allows once daily administration
      of CsA.

PMID- 10582743
TI  - Microvascular transplantation of a free omental graft to the distal extremity in
      dogs.
AB  - OBJECTIVE: To assess the survival of a free omental graft applied to an
      experimentally created wound on the distal extremity in dogs. STUDY DESIGN: A
      free omental graft was evaluated as a primary method of treatment for dogs with
      distal extremity wounds in an experimental model. ANIMALS OR SAMPLE POPULATION:
      Five adult intact female mixed breed dogs weighing 21.8 kg to 25.0 kg. METHODS: A
      free omental graft was harvested from the abdomen and transferred to a wound bed
      overlying the medial aspect of the tibia. A microvascular anastomosis was
      performed between the graft vessels and vessels at the recipient site. Daily
      clinical assessment of graft viability was performed. Angiography and
      99mTechnetium labeled macroaggregated albumin (99mTc MAA) scintigraphic perfusion
      scans were performed on either day 4, 5, or 7. Postmortem collection of tissues
      for histopathologic analysis was performed immediately after imaging. Total
      operative time and graft ischemia time were evaluated for effects on graft
      survival. RESULTS: Two of seven grafts survived to the end of the study, three of
      seven grafts failed because of ischemia, and two of seven grafts failed because
      of self-trauma. There was no clinically significant morbidity associated with the
      abdominal portion of the procedure. Because of the small number of surviving
      grafts, the effects of operative time and graft ischemia time could not be
      statistically evaluated. CONCLUSIONS: Microvascular transplantation of a free
      omental graft can result in a viable tissue covering of a distal extremity wound,
      however, the failure rate is unacceptably high. CLINICAL RELEVANCE: A free
      omental graft may not have sufficient durability to be an acceptable wound
      covering by itself. Further studies combining omentum with a skin graft or other
      tissues may result in a clinically useful technique.

PMID- 10582744
TI  - Tissue reactivity to poliglecaprone 25 in the feline linea alba.
AB  - OBJECTIVE: To use poliglecaprone 25 for all ligations and closure in routine
      feline ovariohysterectomies and evaluate maintenance of tissue approximation and
      tissue reaction to the suture. STUDY DESIGN: Prospective, descriptive study.
      ANIMALS: Twenty four female cats. METHODS: Ovariohysterectomies were performed in
      all cats. Abdominal incisions were inspected on days 1, 3, 7, 14, and 28 for
      dehiscence and swelling. All cats were euthanatized postoperatively, group 1 on
      day 7; group 2 on day 14; and group 3 on day 28. The peritoneal cavity was
      inspected for adhesions and all abdominal incisions were collected en bloc. Each
      linea alba was histologically evaluated and the inflammatory reaction was
      characterized. RESULTS: Dehiscence did not occur in any of the 24 cats. The
      incisional swelling on day 1 was significantly smaller than on day 7, and the
      swelling on day 14 was significantly smaller than on days 1, 3, and 7 (P < .05).
      Intra-abdominal adhesions were found in all groups with the greatest number
      associated with the peritoneum at the incision site. Tissue reactions in group 1
      were pyogranulomatous or fibromononuclear, group 2 were granulomatous or
      fibromononuclear, and group 3 were pyogranulomatous, granulomatous,
      fibromononuclear or fibrous. Eosinophilic infiltration was seen in 3 of the 8
      cats in group 1. CONCLUSIONS: Incisional swelling and inflammatory reactions seen
      with poliglecaprone 25 were consistent with those anticipated after implantation
      of suture in a surgically created wound. CLINICAL RELEVANCE: Poliglecaprone 25
      appears to be an acceptable suture for use in feline ovariohysterectomy. It
      causes a relatively short-lived inflammatory response.

PMID- 10582745
TI  - Thoracoscopic versus open partial pericardectomy in dogs: comparison of
      postoperative pain and morbidity.
AB  - OBJECTIVE: To evaluate postoperative pain and morbidity in dogs undergoing open
      thoracotomy and partial pericardectomy versus thoracoscopic pericardectomy. STUDY
      DESIGN: Research study in normal dogs. ANIMALS OR SAMPLE POPULATION: Fourteen
      mixed breed healthy dogs. METHODS: Seven dogs had a partial pericardectomy
      through a standard left lateral thoracotomy at the fifth intercostal space. The
      remaining seven dogs underwent selective lung ventilation and thoracoscopic
      partial pericardectomy. Surgery sites in both groups were bandaged and each dog
      received a single postoperative dose of morphine (0.2 mg/kg, intramuscularly
      [i.m.]). Postoperative pain was evaluated using a standard pain score table at 1,
      5, 9, 17, 29, and 53 hours after surgery. Dogs receiving a pain score of six or
      greater received an additional dose of morphine. At each observation point, blood
      samples were taken to measure blood glucose and plasma cortisol concentrations.
      Pain scores, blood glucose, and plasma cortisol concentrations were compared
      between the two groups using two-way ANOVA. RESULTS: Blood glucose
      concentrations, plasma cortisol concentrations, and pain scores were
      significantly different between the two groups, with the thoracotomy dogs having
      higher values at 1, 5, and 9 hours postoperatively. Three of the open thoracotomy
      dogs required additional analgesia after the initial dose of morphine. In
      addition, two dogs that underwent open thoracotomy were lame in the left forelimb
      and two others developed dehiscence of their wounds. CONCLUSIONS AND CLINICAL
      RELEVANCE: Thoracoscopic partial pericardectomy has several advantages over open
      partial pericardectomy including decreased postoperative pain, fewer wound
      complications, and more rapid return to function.

PMID- 10582746
TI  - Vertebrectomy, bone allograft fusion, and antitumor vaccination for the treatment
      of vertebral fibrosarcoma in a dog.
AB  - OBJECTIVE: To describe the surgical technique of vertebrectomy with bone
      allograft fusion and the use of antitumor vaccine for the treatment of a primary
      vertebral neoplasm in a dog. STUDY DESIGN: Case Report. ANIMALS OR SAMPLE
      POPULATION: A 3 year old 32 kg female spayed mixed breed dog with progressive
      paraplegia. METHODS: Myelography was performed to identify an L5 lytic lesion
      with spinal cord compression. A dorsal laminectomy was performed to decompress
      the spinal cord and obtain biopsies. Pathologic fracture of the vertebral body
      two days later was treated with L5 vertebrectomy, cortical allograft
      implantation, and bilateral plating from L4 to L6. Tumor samples were used to
      create an autologous cytokine-gene-engineered tumor cell vaccine. Recheck
      radiographs and neurologic examinations were obtained 1, 2, 7, and 13 months
      after surgery. RESULTS: The histopathologic diagnosis was fibrosarcoma. Although
      slight osteopenia of the allograft was noted thirteen months after surgery, the
      allograft and plate fixation remained stable. The patient tolerated the antitumor
      vaccination protocol well. Two years after the procedures the dog was able to
      ambulate normally but remained urinary and fecal incontinent. CONCLUSIONS AND
      CLINICAL RELEVANCE: Vertebrectomy and cortical allograft implantation with
      plating permitted this patient to return to a functional lifestyle with its
      owners.

PMID- 10582747
TI  - Caudal vena cava obstruction and ascites in a cat treated by balloon dilation and
      endovascular stent placement.
AB  - OBJECTIVE: To present details of an unusual case of caudal vena caval obstruction
      and its management in a cat. STUDY DESIGN: Clinical case report. STUDY
      POPULATION: A 15 month old male castrated domestic shorthaired cat. RESULTS: The
      diagnostic evaluation included the use of digital subtraction angiography and
      ultrasonography to locate the caudal vena caval obstruction. Treatment initially
      involved puncture and balloon dilation of the obstructed area of the cava. After
      reobstruction, the stenotic area was redilated and stented. The cat was
      euthanatized 4 weeks later because of vomiting, anorexia, and abnormal behavior,
      presumed to be associated with liver disease. CONCLUSION AND CLINICAL RELEVANCE:
      Interventional radiography provided a minimally invasive way to manage this
      unusual vascular anomaly.

PMID- 10582748
TI  - Surgical repair of a thoracic meningocele in a foal.
AB  - A 6 week old American Paint filly was admitted for evaluation of a dorsal
      thoracic mass suspected to be a meningocele. The diagnosis was confirmed by plain
      and contrast enhanced computed tomography. Surgical repair was performed by
      dissection of the base of the meningocele followed by ligation. No postoperative
      complications occurred. Contrast enhanced computed tomography was useful to
      confirm the diagnosis of meningocele and rule out a meningomyelocele.

PMID- 10582749
TI  - Investigation into the use of the laryngeal mask airway in pentobarbital
      anesthetized dogs.
AB  - OBJECTIVE: To investigate the use of the laryngeal mask airway (LMA) in dogs.
      STUDY DESIGN: Prospective experimental study. ANIMALS: Eight healthy adult mixed
      breed dogs weighing from 15 to 20 kg. METHODS: The dogs were anesthetized with
      intravenous pentobarbital. An LMA was introduced after the induction of
      anesthesia and 1 L/min O2 plus 1 L/min air was delivered using a circle
      anesthetic system. Respiratory rate, tidal volume, arterial O2 saturation (pulse
      oximetry), end tidal CO2, inspired fraction of O2, pulse rate, and mean arterial
      blood pressure were measured after the insertion of the LMA and 30, 60, 90, and
      120 minutes afterwards. RESULTS: There were no changes in respiratory rate, tidal
      volume, arterial O2 saturation, and pulse rate during anesthesia. End tidal CO2
      decreased significantly by the end of anesthesia and ventilation appeared
      satisfactory. CONCLUSIONS: An LMA appeared to be an alternative option to
      maintain the patency of the airway in dogs. CLINICAL RELEVANCE: This device may
      allow safe maintenance of an airway in dogs when intubation is difficult or when
      it interferes with the procedure (eg, cervical myelography).

PMID- 10582750
TI  - Inhaled carbon monoxide concentration during halothane or isoflurane anesthesia
      in horses.
AB  - OBJECTIVE: The purpose of this study was to assess carbon monoxide (CO) exposure
      during equine anesthesia with either halothane (H) or isoflurane (I) delivered in
      a circle rebreathing system. STUDY DESIGN: Prospective clinical investigation.
      ANIMALS: Fifty client-owned horses. METHODS: Horses were randomly assigned for
      anesthetic maintenance with H (n = 26) or I (n = 24). Two large animal anesthetic
      machines were used and assigned to a single agent for 2-4 weeks at a time.
      Machines were disassembled and soda lime changed prior to switching anesthetic
      agents. Inhalant anesthetic concentration and CO concentration were measured in
      gas samples obtained from the inspiratory limb of the anesthetic circuit. Values
      were recorded at 15 minute intervals for 90 minutes. Soda lime status (new or
      used) and mode of ventilation (spontaneous or mechanical) were also recorded.
      Data were analyzed using a five-factor ANCOVA with repeated measures. RESULTS:
      Inspired CO concentration for H and I increased from 1 +/- 3 and 6 +/- 11 ppm at
      baseline to 54 +/- 33 and 21 +/- 18 ppm at 90 min, respectively (mean +/- sd). H
      was associated with significantly greater CO concentrations than I at 30 to 90
      min, although baseline CO was significantly greater in the I group than the H
      group. Oxygen flow rates were 9.9 +/- 0.5 L/min at baseline for H and I, and 5.0
      +/- 0.4 and 5.0 +/- 0.7 L/min at 90 min for H and I, respectively. There were no
      significant differences between groups for O2 flow at any time point. Neither
      mechanical ventilation nor new versus used soda lime affected CO concentration.
      CONCLUSIONS: Significantly higher concentrations of CO were recorded during the
      administration of H than I. CLINICAL RELEVANCE: Levels of CO observed during the
      administration of either H or I for 90 minutes to horses were not clinically
      significant.

PMID- 10582751
TI  - Total intravenous anesthesia in greyhounds: pharmacokinetics of propofol and
      fentanyl--a preliminary study.
AB  - OBJECTIVE: To evaluate concomitant propofol and fentanyl infusions as an
      anesthetic regime, in Greyhounds. ANIMALS: Eight clinically normal Greyhounds
      (four male, four female) weighing 25.58 +/- 3.38 kg. DESIGN: Prospective
      experimental study. METHODS: Dogs were premedicated with acepromazine (0.05
      mg/kg) by intramuscular (i.m.) injection. Forty five minutes later anesthesia was
      induced with a bolus of propofol (4 mg/kg) by intravenous (i.v.) injection and a
      propofol infusion was begun (time = 0). Five minutes after induction of
      anesthesia, fentanyl (2 microg/kg) and atropine (40 microg/kg) were administered
      i.v. and a fentanyl infusion begun. Propofol infusion (0.2 to 0.4 mg/kg/min)
      lasted for 90 minutes and fentanyl infusion (0.1 to 0.5 microg/kg/min) for 70
      minutes. Heart rate, blood pressure, respiratory rate, end-tidal carbon dioxide,
      body temperature, and depth of anesthesia were recorded. The quality of
      anesthesia, times to return of spontaneous ventilation, extubation, head lift,
      and standing were also recorded. Blood samples were collected for propofol and
      fentanyl analysis at varying times before, during and after anesthesia. RESULTS:
      Mean heart rate of all dogs varied from 52 to 140 beats/min during the infusion.
      During the same time period, mean blood pressure ranged from 69 to 100 mm Hg. On
      clinical assessment, all dogs appeared to be in light surgical anesthesia. Mean
      times (+/- SEM), after termination of the propofol infusion, to return of
      spontaneous ventilation, extubation, head lift and standing for all dogs were 26
      +/- 7, 30 +/- 7, 59 +/- 12, and 105 +/- 13 minutes, respectively. Five out of
      eight dogs either whined or paddled their forelimbs in recovery. Whole blood
      concentration of propofol for all eight dogs ranged from 1.21 to 6.77 microg/mL
      during the infusion period. Mean residence time (MRTinf) for propofol was 104.7
      +/- 6.0 minutes, mean body clearance (Clb) was 53.35 +/- 0.005 mL/kg/min, and
      volume of distribution at steady state (Vdss) was 3.27 +/- 0.49 L/kg. Plasma
      concentration of fentanyl for seven dogs during the infusion varied from 1.22 to
      4.54 ng/mL. Spontaneous ventilation returned when plasma fentanyl levels were
      >0.77 and <1.17 ng/mL. MRTinf for fentanyl was 111.3 +/- 5.7 minutes. Mean body
      clearance was 29.1 +/- 2.2 mL/kg/min and Vdss was 2.21 +/- 0.19 L/kg. CONCLUSION
      AND CLINICAL RELEVANCE: In Greyhounds which were not undergoing any surgical
      stimulation, total intravenous anesthesia maintained with propofol and fentanyl
      infusions induced satisfactory anesthesia, provided atropine was given to
      counteract bradycardia. Despite some unsatisfactory recoveries the technique is
      worth investigating further for clinical cases, in this breed and in mixed breed
      dogs.

PMID- 10582752
TI  - Effects of lumbosacral subarachnoid catheterization in horses.
AB  - OBJECTIVES: To evaluate the effects of long duration subarachnoid catheterization
      in horses on cerebrospinal fluid (CSF) cellularity and bacteriology, arterial
      blood pressure, heart rate, respiratory rate, rectal body temperature, and
      spontaneous locomotor activity. STUDY DESIGN: Prospective experimental study.
      ANIMAL: Five clinically normal healthy adults horses weighing 511 +/- 47 kg.
      METHODS: Subarachnoid catheters were placed using sedation and local anesthesia
      and maintained for 48 hours in standing horses. Cerebrospinal fluid samples were
      tested for cellularity and bacteria growth. Heart rate, respiratory rate,
      arterial blood pressure, and body temperature were recorded. Locomotor activity
      was graded. One-way repeated measures ANOVA and Bonferroni's test were used to
      statistically compare data from baseline to 12, 24, and 48 hours. RESULTS:
      Subarachnoid catheterization in horses produced an acute inflammatory reaction
      after 12 hours of catheterization, as evidenced by a statistically significant
      increase in CSF white blood cell count. No bacterial contamination was
      encountered. No significant differences were found in heart rate, respiratory
      rate, body temperature, and arterial blood pressure. The horses did not develop
      motor ataxia or proprioceptive deficits during 48 hours of catheterization.
      CONCLUSIONS: Results of this study suggest that 48 hours of subarachnoid
      catheterization in horses does not produce clinical signs of neurologic
      dysfunction or cardiovascular and respiratory changes, even though an
      inflammatory reaction occurred. CLINICAL RELEVANCE: Subarachnoid catheterization
      in horses is preferred for monitoring CSF pressure or for repeated collection.
      Understanding the effects of catheterization alone, allows the clinician to
      better interpret abnormalities in CSF collected.

PMID- 10582753
TI  - Dyspepsia--acid or stress? A study of controversy. Abandoned by experts,
      finalized in clinical practice?

PMID- 10582754
TI  - Short Barrett: prevalence and risk factors.
AB  - BACKGROUND: The incidence of adenocarcinoma at the gastro-oesophageal junction is
      on the increase. These carcinomas are usually diagnosed too late and thus have a
      poor prognosis. Only early diagnosis can improve the situation. Classical Barrett
      oesophagus (length, >3 cm) is a known precancerous condition. There is also
      specialized columnar epithelium (SCE) in the grossly unremarkable gastro
      oesophageal transitional zone (short Barrett). METHODS: To determine the
      frequency of SCE, 370 patients were investigated by gastroscopy (OGD)
      consecutively between September 1995 and February 1996. RESULTS: Classical
      Barrett oesophagus was found to have an incidence of 4.6%. In contrast,
      microscopic evidence of SCE was observed in 13.6% of the cases. Patients with
      short Barrett presented with reflux symptoms (odds ratio (OR), 4.7), irregular
      zona serrata ('tongues') in the cardia (OR, 2.8), and reflux oesophagitis
      significantly more frequently. Patients with reflux symptoms and concomitant
      'tongues', however, had an OR of 13.16. Careful history-taking, together with a
      subtle histologic work-up of the gastro-oesophageal transitional zone can improve
      the rate of detecting patients with short Barrett. CONCLUSION: Patients with
      reflux symptoms and irregular zona serrata should be selectively biopsied at the
      gastro-oesophageal junction, even when the latter presents a grossly normal
      appearance, with the aim of detecting patients at risk of developing a Barrett
      carcinoma.

PMID- 10582755
TI  - The rebleeding course and long-term outcome of esophageal variceal hemorrhage
      after ligation: comparison with sclerotherapy.
AB  - BACKGROUND: Endoscopic variceal ligation is widely accepted as the optimum
      endoscopic treatment for esophageal variceal hemorrhage. However, the rebleeding
      course and long-term outcome of patients with esophageal variceal hemorrhage
      after ligation have been poorly defined. Therefore, we conducted a long-term
      follow-up study to delineate the outcome of ligation and compare it with that
      after sclerotherapy. METHODS: One hundred and eighty-five liver cirrhotic
      patients with endoscopically proven esophageal variceal hemorrhage were
      randomized to undergo endoscopic variceal sclerotherapy or ligation. These
      patients received regular follow-up and detailed clinical assessment. RESULTS:
      Two patients developed hepatoma within 6 months of entry in each group and were
      excluded. Another six patients in the sclerotherapy group and seven patients in
      the ligation group were excluded because of poor compliance or lost to follow-up.
      Therefore, 84 patients in each group were analyzed. In this long-term follow-up
      (55.3 +/- 12.5 months) the rebleeding rate for ligation was lower than that for
      sclerotherapy, regardless of whether the rebleeding was analyzed by patient
      number or Kaplan-Meier analysis. With regard to the rebleeding risk of various
      periods, the sclerotherapy risk was higher than that of ligation within 4 weeks
      of the initial endoscopic treatment or before variceal eradication.
      Multifactorial analysis showed hematemesis, poor hepatic function, and
      sclerotherapy were the risk factors determining rebleeding. The annual
      hepatocellular carcinoma incidence was 4.9%. There was no difference in survival
      between sclerotherapy and ligation. Multifactorial analysis showed that poor
      hepatic function was the only factor determining survival. CONCLUSIONS: The
      rebleeding risk was higher in sclerotherapy than in ligation before variceal
      eradication, especially within 4 weeks of the initial endoscopic treatment. Long
      term survival was dependent on hepatic reserve regardless of the treatment
      method.

PMID- 10582757
TI  - Peptic ulcer bleeding: interaction between non-steroidal anti-inflammatory drugs,
      Helicobacter pylori infection, and the ABO blood group system.
AB  - BACKGROUND: Helicobacter pylori infection is found in almost all patients with an
      uncomplicated ulcer. Non-steroidal anti-inflammatory drug (NSAID) use is the main
      risk factor for bleeding peptic ulcer. In the older literature ABO blood groups
      were mentioned as a risk factor. There is continuing uncertainty about the
      interaction between these risk factors and the development of peptic ulcer
      bleeding. We therefore determined the separate and combined effect of NSAIDs, H.
      pylori infection, and the ABO blood group system in patients with a bleeding
      peptic ulcer. METHODS: The prevalence of NSAID use, H. pylori infection, and
      blood group O was determined in 227 patients who were admitted with a bleeding
      gastric or duodenal ulcer between 1990 and 1997. These results were compared with
      the expected frequency of these risk factors in the Dutch population. RESULTS:
      NSAID use was reported in 48.2% of the patients with a bleeding peptic ulcer. The
      H. pylori prevalence was 62.0%, whereas blood group O was present in 49.3% of the
      patients. NSAID use was the strongest risk factor for hemorrhage caused by a
      peptic ulcer (relative risk, 8.4), whereas the relative risk associated with H.
      pylori infection and blood group O was 1.5 and 1.2, respectively. With univariate
      analysis NSAID use and H. pylori infection seemed to be separate risk factors and
      did not really potentiate each other's effect. Moreover, blood group O did not
      potentiate the strong effect of NSAIDs. CONCLUSION: H. pylori infection may add
      only a little to the important risk of NSAID use in the development of bleeding
      peptic ulcers.

PMID- 10582756
TI  - Most gastric cancer occurs on the distal side of the endoscopic atrophic border.
AB  - BACKGROUND: The endoscopic atrophic border indicates the extent of atrophic
      gastritis. The aims of this study were to examine the relation of intestinal and
      diffuse types of gastric cancer to the atrophic border and to study the
      pathologic condition of the atrophic border. METHODS: In 83 patients with gastric
      cancer the extent of atrophic gastritis was assessed macroscopically. In 46
      patients gastric biopsy specimens were also taken, to compare the histologic
      features of gastritis proximal and distal to the atrophic border. RESULTS: Eighty
      five per cent of gastric cancers (including 93% of intestinal type) occurred on
      the distal side of the atrophic border. Early diffuse gastric cancer arose closer
      to the atrophic border than intestinal-type cancer and was more likely to be
      sited proximal to it. Histologically, the grade of polymorphonuclear cell
      infiltration (inflammatory activity) and Helicobacter pylori density were
      significantly greater on the proximal side (P < 0.05), whereas the grades of
      glandular atrophy and intestinal metaplasia were significantly greater distally
      (P < 0.001). CONCLUSIONS: The atrophic border delineates the area of atrophic
      gastritis and intestinal metaplasia, and it is within the distal part of the
      stomach that gastric cancer occurs most frequently. Endoscopists should observe
      the distal side particularly carefully to identify early gastric cancer. The
      relationship of the two histologic types of cancer to areas of intestinal
      metaplasia and 'active' inflammation may have implications for the pathogenesis
      of cancer and, if so, for the potential protective effect of H. pylori
      eradication.

PMID- 10582758
TI  - Butyrate hastens restoration of barrier function after thermal and detergent
      injury to rat distal colon in vitro.
AB  - BACKGROUND: Epithelial migration restores barrier function after superficial
      injury to any mucosa. The present study aimed to determine whether butyrate,
      important to colonic epithelial physiology in diverse ways, influences
      restoration of barrier function in the injured rat colon. METHODS: Rat distal
      colon was transiently exposed in vitro to heat (55 degrees C for 10 sec) or to
      detergent (deoxycholic acid, 7.5 mM, for 15 min), and tissue damage was verified
      histologically. Epithelial barrier function was assessed, in colon tissue mounted
      in Ussing chambers, by measuring electric resistance and passive serosa-to-mucosa
      fluxes of 22Na and of 14C PEG 4000 under voltage clamp conditions. Studies were
      done in the absence and presence of 25 mM butyrate in the bathing solutions.
      RESULTS: Heat exposure induced superficial epithelial damage, and the electric
      resistance decreased significantly. This was accompanied by increase in flux of
      14C PEG and increased passive flux of 22Na. Electric resistance was significantly
      higher, and PEG flux significantly lower, in tissues bathed with butyrate.
      Exposure to deoxycholic acid also induced superficial epithelial damage, reduced
      tissue electric resistance, and increased passive flux of Na and PEG. Electric
      resistance was significantly higher, and PEG flux significantly lower, in injured
      tissues bathed in butyrate, than in injured tissues bathed in butyrate-free
      solution. The effect of butyrate on restoration of electric resistance towards
      normal was seen in colon both from adult rats and from younger rats that were 2
      or 6 weeks old. CONCLUSIONS: Butyrate enhanced restoration of mucosal barrier
      function in rat distal colon in response to heat and detergent injury.

PMID- 10582759
TI  - Effects of gamma-aminobutyric acid and peripheral benzodiazepine ligands on
      duodenal bicarbonate secretion.
AB  - BACKGROUND: The effects of gamma-aminobutyric (GABA(A))-receptor ligands and
      peripheral-type benzodiazepine (BZ) ligands on duodenal mucosal bicarbonate
      secretion (DBS) were studied in thiobarbiturate-anesthetized rats. METHODS: A
      segment of proximal duodenum was perfused, and bicarbonate secretion was
      continuously titrated by pH-stat. In some experiments the vagus nerves were
      dissected free and cut at the neck level. RESULTS: Luminal GABA (10(-8) to 10(-6)
      M) increased (P < 0.01) DBS dose-dependently, and the GABA(A) antagonist (+)
      bicuculline (0.1-2.5 mg/kg intravenously) caused a similar increase (P < 0.01) in
      DBS. Vagotomy abolished the latter response, suggesting a centrally elicited
      nervous action of bicuculline mediated by the vagal nerves. This was supported by
      the absence of an effect of bicuculline administered intra-arterially close to
      the duodenum. The GABA(A) agonist muscimol had no effect on DBS when administered
      intravenously (0.01-0.25 mg/kg) or into a lateral brain ventricle (2 microg/kg/h)
      but counteracted any stimulation by subsequent intravenous bicuculline. The
      'peripheral-type' BZ agonist 4'-chlorodiazepam increased DBS when infused close
      intra-arterially but had no effect when administered intravenously. CONCLUSIONS:
      Inhibition of GABA(A) receptors related to cholinergic excitatory pathways in the
      central nervous system stimulates duodenal mucosal bicarbonate secretion and may
      increase the local mucosal defense. The stimulation by luminal GABA may reflect
      modulation of the local mucosal control of duodenal bicarbonate secretion.

PMID- 10582760
TI  - 31-43 amino acid sequence of the alpha-gliadin induces anti-endomysial antibody
      production during in vitro challenge.
AB  - BACKGROUND: Wheat gliadin is the culprit antigen of coeliac disease (CD). Two
      short sequences of NH2-terminal portion of gliadin seem to be responsible for CD.
      Antiendomysial antibodies (EMA), highly sensitive and specific for CD, are
      detectable in the culture media from treated CD patients, after in vitro
      challenge with peptic-tryptic (PT) digest of gliadin. In this study we detected
      EMA production after in vitro challenge with 31-43 peptide. We used 56-68
      peptide, lacking toxic sequences, as a negative control. METHODS: Duodenal
      samples from 11 treated CD patients and 9 control patients were cultured with 31
      43 and 56-68 peptides and PT gliadin. Indirect immunofluorescence analysis was
      used for EMA detection. RESULTS: EMA were detected in culture media of 10 of 11
      specimens challenged with PT-gliadin and in the media of all specimens challenged
      with 31-43 peptide. No EMA were detectable in any treated patients cultured with
      56-68 peptide or with medium alone. No EMA were observed in cultures of control
      specimens. DISCUSSION: The ability of the 31-43 sequence of the alpha-gliadin to
      induce EMA production suggests its involvement in the pathogenesis of CD.
      Furthermore, it may be a more useful antigenic substance than PT gliadin for both
      in vitro and in vivo studies of CD.

PMID- 10582761
TI  - Ultrasonography in the evaluation of extension, activity, and follow-up of
      ulcerative colitis.
AB  - BACKGROUND: The purpose of the study was to establish the clinical significance
      of bowel-wall thickening, measured by ultrasound, in ulcerative colitis (UC) and
      to evaluate the usefulness of ultrasonography (US) to define the extension, the
      severity, and the response to medical treatment of this pathologic condition.
      METHODS: Thirty consecutive patients with active UC were studied on two different
      occasions 2 months apart and after treatment with steroids. On both occasions the
      clinical, endoscopic, and biochemical activity of the disease and the
      ultrasonographic examination of the intestinal walls were evaluated. The maximum
      bowel wall thickness (BWT) was considered an index of ultrasonographic activity,
      and the presence of thickened bowel walls and the US appearance of loss of
      haustra coli were considered in the evaluation of the extension of disease. The
      extension of colitis was evaluated by means of a double-contrast barium enema in
      every patient at the beginning of the study. RESULTS: US correctly defined the
      extension of UC in 74% of the patients as defined by double-contrast barium
      enema. The degree of BWT was significantly correlated to the clinical,
      biochemical, and endoscopic activity of UC before and after the treatment.
      Moreover, BWT decreased significantly (7.3 +/- 1.9 mm versus 5.1 +/- 1.2 mm; P <
      0.001) in patients who experienced clinical improvement after treatment, and it
      did not change (7.0 +/- 1.5 mm versus 7.0 +/- 1.4 mm; P=NS) in patients showing
      no significant clinical improvement. The degree of pretreatment BWT did not
      differ between UC patient responders and non-responders. CONCLUSIONS: US
      evaluation of BWT may be useful in evaluating the extension of UC. The degree of
      BWT, as evaluated by US, correlates with the clinical, biochemical, and
      endoscopic activity of UC, both before and after treatment. This suggests that US
      may be useful to evaluate the response of UC patients to medical therapy.

PMID- 10582762
TI  - The relation between antioxidant status and alterations in fatty acid profile in
      patients with Crohn disease and controls.
AB  - BACKGROUND: A diminished antioxidant defence and alterations in the fatty acid
      profile may play a role in the pathophysiology of inflammation in Crohn disease
      (CD). METHODS: Antioxidant status (serum antioxidant vitamins and minerals,
      glutathione peroxidase, and superoxide dismutase activity), disease activity,
      dietary intake, and the fatty acid profile in plasma and erythrocyte
      phospholipids were studied in patients with active CD (n = 12), inactive CD (n =
      50), and controls (n = 70). Eight patients with active CD were re-evaluated
      during the subsequent phase of clinical remission. The relation between the
      variables was assessed by multiple linear regression. RESULTS: We observed a
      significantly diminished antioxidant status in patients with active CD compared
      with inactive CD and controls. Furthermore, the antioxidant defence was depleted
      in patients with inactive CD compared with controls. An aberrant fatty acid
      profile in plasma phospholipids was found in active and inactive CD compared with
      controls. Multivariate analysis showed that the plasma phospholipid fatty acid
      indices were significantly associated with several antioxidants (beta-carotene,
      vitamin E, and glutathione peroxidase) in CD patients but not in controls.
      CONCLUSION: The fatty acid profile in CD patients is significantly associated
      with disease activity and serum antioxidant concentrations. This observation,
      along with the diminished antioxidant defence in patients with active and
      inactive CD, indicates that antioxidants should be considered in the therapy of
      inflammation in CD.

PMID- 10582763
TI  - Aminoguanidine has both an anti-inflammatory effect on experimental colitis and a
      proliferative effect on colonic mucosal cells.
AB  - BACKGROUND: The aim of this study was to assess the effect of aminoguanidine (AG)
      on developed colitis and cell proliferation. METHODS: Colitis was induced by
      means of trinitrobenzene sulphonic acid (TNB) in male Wistar rats weighing about
      250 g. Seven days after induction of TNB colitis the rats were divided into two
      groups at random, and one group was orally treated with 1.5 micromol/kg AG each
      day. We assessed the effect of AG by measuring the mucosal damage, the ulcer
      area, myeloperoxidase (MPO) activity, inducible nitric oxide synthase (iNOs)
      activity, and nitrogen oxide in serum 7 days after the beginning of treatment.
      RESULTS: AG significantly ameliorated the macroscopic damage score (AG versus
      control, 5.25 +/- 0.80 versus 7.50 +/- 0.50), the microscopic damage score (5.88
      +/- 1.13 versus 9.25 +/- 0.31), ulcer area (0.57 +/- 0.14 versus 1.24 +/- 0.17
      cm2), decreased MPO activity (51.5 +/- 9.4 versus 192.2 +/- 60 units/g tissue),
      and nitrogen oxide in serum (27.2 +/- 1.4 versus 32.3 +/- 1.8 microM) but did not
      decrease iNOs activity (8732 +/- 435 versus 8672 +/- 357 cpm/g tissue). Moreover,
      AG accelerated T84 cell proliferation in a dose-dependent manner. CONCLUSIONS:
      These results suggest that AG ameliorates TNB colitis not only by its anti
      inflammatory effect but also by accelerating the proliferation of colonic mucosal
      cells. AG, accordingly, might well be a useful new medicine to ameliorate
      inflammatory bowel disease.

PMID- 10582764
TI  - Does analysis of the antigenic specificities of anti-neutrophil cytoplasmic
      antibodies contribute to their clinical significance in the inflammatory bowel
      diseases?
AB  - BACKGROUND: The clinical relevance of anti-neutrophil cytoplasmic antibodies
      (ANCA) in inflammatory bowel diseases is unclear. Definition of their antigenic
      specificities may improve their diagnostic significance. METHODS: We studied the
      target antigens of ANCA in 96 patients with ulcerative colitis (UC) and 112
      patients with Crohn disease (CD) by indirect immunofluorescence, antigen-specific
      enzyme-linked immunosorbent assays, and immunodetection on Western blot. We
      related the presence of antibodies of defined specificity to clinical symptoms.
      RESULTS: By indirect immunofluorescence, ANCA were present in 58% of UC patients
      and in 21% of CD patients. Major antigens were catalase, alpha-enolase, and
      lactoferrin. In UC, ANCA titers correlated with disease activity. In CD, both
      ANCA, by indirect immunofluorescence, and antibodies to lactoferrin were
      associated with colonic localization of the disease. Neither ANCA, by indirect
      immunofluorescence, nor antibodies of defined specificity were associated with
      duration of disease, use of medication, or a history of bowel resection.
      CONCLUSIONS: ANCA are useful as markers for UC and colonic localization in CD.
      Definition of the antigenic specificities of ANCA in inflammatory bowel disease
      does not significantly contribute to their clinical significance.

PMID- 10582765
TI  - Peripheral blood mononuclear cells promote intestinal epithelial restitution in
      vitro through an interleukin-2/interferon-gamma-dependent pathway.
AB  - BACKGROUND: Acute intestinal mucosal inflammation is associated with recruitment
      of peripheral blood mononuclear cells (PBMN) into the mucosa and migration across
      the epithelium. It has recently been shown that several PBMN-derived cytokines,
      including transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha
      (TNF-alpha), interleukin-2 (IL-2), and interferon-gamma (IFN-gamma) may modify
      intestinal epithelial cell function, resulting in rapid improvement of wound
      repair. Our aim was to characterize the modulating effects of PBMN on intestinal
      epithelial restitution, the initial step of wound healing. METHODS: PBMN were
      separated from whole blood, obtained from healthy volunteers, by using a density
      gradient. The effect of PBMN on intestinal epithelial restitution was assessed by
      using an in vitro coculture wounding model with non-transformed small-intestinal
      epithelial IEC-6 cells. RESULTS: Coculture of PBMN caused a significant
      enhancement of epithelial cell restitution in vitro. The modulatory effects of
      PBMN could be significantly blocked by adding immunoneutralizing anti-IL-2 or
      anti-IFN-gamma to the culture media, suggesting that PBMN may modulate intestinal
      epithelial migration through an IL-2- and IFN-gamma-dependent pathway. In
      contrast, PBMN-induced stimulation of intestinal epithelial restitution was not
      influenced by addition of anti-TGF-beta or anti-TNF-alpha, suggesting that these
      cytokines are not critical for the modulation of restitution by PBMN.
      CONCLUSIONS: These findings suggest that PBMN may promote intestinal epithelial
      wound repair by enhancing restitution through secretion of various cytokines,
      among them IL-2 and IFN-gamma, which are abundantly expressed in the course of
      several inflammatory diseases of the gut.

PMID- 10582766
TI  - Profile of circulating levels of interleukin-1 receptor antagonist and
      interleukin-6 in colorectal cancer patients.
AB  - BACKGROUND: Circulating levels of pro-inflammatory cytokines are associated with
      the disease status of cancer patients. We investigated the profile of circulating
      levels of interleukin (IL)-6 and its antagonist in colorectal cancer patients.
      METHODS: Serum concentrations of interkeukin-1 receptor antagonist (IL-1ra) and
      IL-6 in 80 colorectal cancer patients and tissue concentrations of IL-1ra and IL
      6 in 60 primary colorectal cancers and normal colonic mucosas were determined.
      The serum concentration of immunosuppressive acidic protein (IAP) was also
      determined. RESULTS: The serum concentrations of IL-1ra and IL-6 in the patients
      were significantly higher than those in the controls. The serum concentration of
      IL-1ra in the patients was associated with clinicopathologic factors including
      tumor size, liver metastasis, lymph node metastasis, vessel involvement, or serum
      level of carcinoembryonic antigen. Although the serum IL-1ra level increased in
      keeping with the increase of serum IL-6, the net balance between IL-1ra and IL-6
      was significantly lower than that in the controls. The serum IL-1ra to IL-6 ratio
      decreased in association with the patient's age, the rate of loss of body weight
      and the serum level of IAP. Although the serum level of IL-6 correlated with the
      IL-6 concentration in the cancer tissue, the serum level of IL-1ra did not
      correlate with the IL-1ra concentration in this tissue. CONCLUSIONS: Serum IL
      1ra, induced systemically by a marked activation of the IL-6 network in cancer
      tissue, may be a potent index that evaluates disease progression of colorectal
      carcinoma. Decreased serum IL-1ra to IL-6 ratio may reflect the deterioration of
      the systemic anti-inflammatory response that is associated with aging, tumor
      related malnutrition, or immunosuppression.

PMID- 10582767
TI  - Preoperative prediction model of outcome after cholecystectomy for symptomatic
      gallstones.
AB  - BACKGROUND: After cholecystectomy for symptomatic gallstone disease 20%-30% of
      the patients continue to have abdominal pain. The aim of this study was to
      investigate whether preoperative variables could predict the symptomatic outcome
      after cholecystectomy. METHODS: One hundred and two patients were referred to
      elective cholecystectomy in a prospective study. Median age was 45 years; range,
      20-81 years. A preoperative questionnaire on pain, symptoms, and history was
      completed, and the questions on pain and symptoms were repeated 1 year
      postoperatively. Preoperative cholescintigraphy and sonography evaluated
      gallbladder motility, gallstones, and gallbladder volume. Preoperative variables
      in patients with or without postcholecystectomy pain were compared statistically,
      and significant variables were combined in a logistic regression model to predict
      the postoperative outcome. RESULTS: Eighty patients completed all questionnaires.
      Twenty-one patients continued to have abdominal pain after the operation.
      Patients with pain 1 year after cholecystectomy were characterized by the
      preoperative presence of a high dyspepsia score, 'irritating' abdominal pain, and
      an introverted personality and by the absence of 'agonizing' pain and of symptoms
      coinciding with pain (P < 0.000001). In a constructed logistic regression model
      15 of 18 predicted patients had postoperative pain (PVpos = 0.83). Of 62 patients
      predicted as having no pain postoperatively, 56 were pain-free (PVneg = 0.90).
      Overall accuracy was 89%. CONCLUSION: From this prospective study a model based
      on preoperative symptoms was developed to predict postcholecystectomy pain. Since
      intrastudy reclassification may give too optimistic results, the model should be
      validated in future studies.

PMID- 10582768
TI  - 13C mixed-triglyceride breath test: isotope selective non-dispersive infrared
      spectrometry in comparison with isotope ratio mass spectrometry in volunteers and
      patients with chronic pancreatitis.
AB  - BACKGROUND: The 13C mixed-triglyceride breath test (MTB) has been proposed for
      the non-invasive assessment of duodenal pancreatic lipase activity. Until now,
      stable isotope analysis of CO2 of the MTB has been carried out with isotope ratio
      mass spectrometry (IRMS). The aim of the present study was to compare MTB results
      by using the new non-dispersive infrared spectrometry (NDIRS) and the IRMS.
      METHODS: Ten healthy volunteers and 10 patients with chronic pancreatitis and
      exocrine insufficiency were studied. After an overnight fast each subject
      received a test meal containing 250 mg 1,3 distearyl, 2[13C] octanoyl glycerol.
      Breath samples were taken at base line and at 30-min intervals over a period of 6
      h postprandially. The 13C/12C ratio was determined in each breath sample by NDIRS
      and CF-IRMS as delta values. Results were expressed as delta over base line (DOB
      (per 1000)) and as cumulative percentage dose of 13C recovered (cPDR (%)).
      Correlations between IRMS and NDIRS were tested by linear regression analysis.
      For measuring agreement an Altman-Bland plot was performed. RESULTS: A linear
      correlation was found (DOB: y = 0.645 +/- 0.040 x + 1.496 +/- 0.089, r = 0.70, P
      < 0.0001; cPDR: y = 1.269 +/- 0.031 x + 2.010 +/- 0.353, r = 0.93, P < 0.0001).
      For DOB the mean difference (d) was 1.0/1000, and the standard deviation (s) of
      the difference was 1.3/1000. The limits of agreement (d +/- 2 s) were -1.6/1000
      and 3.6/1000. CONCLUSION: The comparison of DOB and cPDR values by NDIRS and IRMS
      shows a moderate to good linear correlation. However, the distance of the limits
      of agreement is rather wide. Consequently, the validity of the MTB is diminished,
      which makes MTB by NDIRS less suitable for exact evaluation of non-invasive
      assessment of duodenal pancreatic lipase activity. Further studies are necessary
      to determine sensitivity and specificity of the MTB with NDIRS in larger study
      populations.

PMID- 10582769
TI  - Treatment of difficult intrahepatic stones by using extracorporeal and
      intracorporeal lithotripsy techniques: 10 years' experience in 55 patients.
AB  - BACKGROUND: Intrahepatic lithiasis still is a complicated disease and merits
      special attention during therapeutic intervention. Although resection of the
      affected liver lobe or segment is the best therapeutic option to completely
      remove the source of recurrent infection, the need for endoscopic treatment
      modalities is evident because hepatic resections are combined with a high
      morbidity and mortality rate. METHODS: Over a 10-year period (1988-1997) 55
      patients with intrahepatic stones that were not accessible to routine endoscopic
      extraction were treated at our department. These patients underwent either
      extracorporeal shock-wave lithotripsy (n=27) or intracorporeal electrohydraulic
      (n=12) or laser lithotripsy (n=16). RESULTS: Using these techniques, we achieved
      stone fragmentation in 33.3%, 41.6%, and 75%, respectively. With a combination of
      the different methods, more than 90% of intrahepatic stones could be removed
      endoscopically. Overall complication rate was 12.7%; complete recovery was
      achieved in all patients with conservative management. CONCLUSION: The endoscopic
      approach to intrahepatic lithiasis appears to be a useful alternative to surgery,
      with a lower morbidity and mortality. If endoscopic therapy fails, surgery is
      still possible.

PMID- 10582771
TI  - Nimesulide, a selective anti-inflammatory cyclooxygenase-2 inhibitor, does not
      affect polyp number and mucosal proliferation in familial adenomatous polyposis.

PMID- 10582770
TI  - A case of adenocarcinoma of the small intestine in a Japanese patient with Crohn
      disease: a report with immunohistochemical and oncogenic analyses.
AB  - We report a rare case of Crohn disease accompanied by a small-bowel carcinoma
      that developed in a 54-year-old Japanese man. The ulcerating tumor, which
      histologically proved to be a poorly differentiated adenocarcinoma and dysplasia
      surrounding the carcinoma, was located in the diseased ileum. The Ki-67
      immunoreactive epithelial cells were increased in regenerative mucosa as compared
      with values for normal mucosa. The Ki-67- and p53-positive cells were increased
      in dysplasia and carcinoma as compared with values for regenerative or normal
      mucosa. In contrast, the p21(WAF1/CIP1) immunoreactive cells were decreased in
      this order. Intense DCC (deleted in colorectal cancer) expression was constantly
      shown among normal, regenerative, dysplastic and cancerous tissues. No bcl-2
      expression and c-Ki-ras mutations were apparent. In conclusion, enhanced
      epithelial cell proliferation, p53 overexpression, and decrease of p21(WAF1/CIP1)
      expression may predispose the small-bowel mucosa to dysplasia and carcinoma
      development in Crohn disease.

PMID- 10582772
TI  - Insulin-like growth factor I: an attractive option for chronic heart failure?
AB  - Chronic congestive heart failure is a syndrome with a poor prognosis. Currently,
      the only therapy providing the possibility of long term survival is heart
      transplantation. Therefore, new therapeutic strategies continue to be
      investigated. One such new approach may be the application of recombinant human
      insulin-like growth factor (IGF)-1. IGF-1 has both acute and long term
      cardiovascular effects. Acute administration of IGF-1 resulted in a reduction in
      afterload and positive inotropic effects in patients with heart failure. In vitro
      and animal studies have demonstrated that IGF-1 can stimulate myofibril
      formation. In addition, IGF-1 administration has beneficial metabolic effects.
      The benefits of prolonged IGF-1 therapy have yet to be investigated.

PMID- 10582773
TI  - Epidemiology and drug treatment of epilepsy in elderly people.
AB  - Seizures are extremely common in the elderly, with an annual incidence reaching
      100 per 100000 people aged over 60 years. Most are precipitated by acute
      symptomatic illnesses such as stroke or systemic disease. Chronic neurological
      diseases such as Alzheimer's disease may also cause seizures. The aetiology of
      seizures in many patients is unknown. Seizures may be situational and subside
      quickly, but the prevalence of chronic seizures--epilepsy--is as high as 1% in
      the elderly. The majority of seizures are of partial onset, especially complex
      partial. Complex partial seizures at this age may be very subtle and hard to
      diagnose. Generalised-onset seizures also occur, perhaps as a result of diffuse
      changes with aging or degenerative disease or to a combination of genetic and
      environmental factors. The prognosis for complete seizure control in this
      population is relatively favourable. Physiological and disease-related changes
      with aging result in complex pharmacokinetics. Most changes lead to a need for
      gentler drug treatment with cautious initiation of drugs at lower dosages.
      Consideration must be given to renal and hepatic function, protein binding and
      drug interactions. Determinations of free (unbound) drug concentrations are
      helpful for highly protein bound drugs. The dosages of newer drugs excreted
      renally must be adjusted based on creatinine clearance. The dosage of most drugs
      is determined empirically by careful observation of seizure control and adverse
      effects. Carbamazepine, valproic acid (sodium valproate), gabapentin and
      lamotrigine have certain theoretical advantages, but comparative trials of
      anticonvulsants in the elderly are needed. The ideal drug for older patients
      would be effective, without neurological toxicity, with low protein binding, a
      nonparticipant in drug interactions and amenable to once daily administration.

PMID- 10582774
TI  - Aromatase inhibitors in the treatment of postmenopausal breast cancer.
AB  - Anastrozole, letrozole and vorozole are new aromatase inhibitors with a
      nonsteroidal structure (NSS), and have been demonstrated to be highly effective
      and better tolerated than standard endocrine therapy with megestrol (megestrol
      acetate) and aminoglutethimide (AG). These agents are very potent and selective:
      all of them are capable of suppressing estrone (E1) and estradiol (E2) to the
      limit of sensitivity methods, and plasma estrone sulfate (E1S) levels are also
      suppressed. However, the fact that this potency has not led to any greater
      clinical efficacy, and that there is no relationship between estrogen suppression
      and clinical response, suggests that aromatase inhibitors may have additional
      mechanisms of action. A number of international, multicentre clinical trials have
      compared anastrozole, letrozole and vorozole with megestrol 160 mg/day or AG 500
      mg/day plus hydrocortisone in patients with advanced breast cancer. Letrozole
      proved to be significantly more effective than megestrol but anastrozole had a
      greater effect on survival than either agent. However, letrozole therapy led to
      longer survival than that observed in patients treated with AG. The activity of
      vorozole was similar to that of megestrol and AG. These results have raised a
      number of questions. The first is how should the clinical results be evaluated,
      given that 'disease stabilisation lasting > or =6 months' has been considered a
      response? The second is how should these drugs be used, and whether there is a
      rationale for using them in combination or sequentially in the treatment of
      patients with advanced breast cancer? Finally, is the possible effect of
      formestane and vorozole on intratumoral aromatase an alternative or concomitant
      mechanism of action? Anastrozole, letrozole and vorozole will be compared with
      tamoxifen in postmenopausal patients with breast cancer in adjuvant and primary
      settings. However, we feel that concomitant biological and clinical studies
      should also be carried out in order to clarify the properties of these drugs and
      avoid possible risks for patients over time.

PMID- 10582775
TI  - New bisphosphonates in the treatment of bone diseases.
AB  - Bisphosphonates are pyrophosphate analogues, in which the oxygen in P-O-P has
      been replaced by a carbon, resulting in a P-C-P structure. They are characterised
      by a strong anti-osteoclastic activity and for this pharmacological property they
      are now considered the treatment of choice for Paget's disease of the bone,
      malignant hypercalcaemia and bone metastases. Etidronate, clodronate and
      pamidronate have been registered in several countries for these indications.
      Etidronate and alendronate are also extensively used for the prevention and
      treatment of postmenopausal and senile osteoporosis. In this article, we review
      the most recent findings on the newest bisphosphonates, which will become
      available in the near future. The aminobisphosphonate risedronate is undergoing a
      huge programme of clinical development for the treatment of osteoporosis. In a
      study of the prevention of early postmenopausal bone loss, oral risedronate 5 mg
      fully prevented the bone loss observed in the placebo group. Similar effects have
      been observed with an intermittent dosage regimen of oral risedronate 30 mg/day
      for 2 out of 12 weeks, which corresponds to 5 mg/day in terms of cumulative dose.
      With lower doses [5 mg on alternate fortnights (2 weeks)] the prevention of bone
      loss was half that observed with continuous 5 mg/day therapy, indicating that
      this might not yet be the maximum effective dose. The use of intermittent
      intravenous bisphosphonates for osteoporosis therapy has been pioneered by
      studies with clodronate, pamidronate and alendronate. This treatment regimen has
      been chosen for an extensive clinical development programme for ibandronate. In a
      phase 2 study, this new bisphosphonate was administered as an intravenous bolus
      (0.25, 0.5, 1 or 2 mg) every 3 months for a year, with increases in spinal bone
      mass of 5.2%. Tiludronate, alendronate and risedronate have been recently
      introduced for the treatment of Paget's disease of bone. Daily doses of
      tiludronate 400 mg, alendronate 40 mg and risedronate 30 mg for 3 to 6 months
      have been shown to be superior to etidronate 400 mg/day. The intravenous
      administration of ibandronate, zoledronate and alendronate (40 mg, 10 mg and 5
      mg, respectively) have achieved the normalisation of serum alkaline phosphatase
      in more than 70% of the patients and these treatments may provide an alternative
      for patients intolerant oral bisphosphonates. Intravenous ibandronate has been
      also developed for the treatment of hypercalcaemia of malignancy. The effective
      doses ranged from 2 to 4 mg. Zoledronate appears to be the most powerful
      bisphosphonate under investigation, and the effective doses used in cancer
      hypercalcaemia are as low as 1 to 2 mg. The new generation of bisphosphonates are
      likely to increase clinical options in terms of administration regimens, but
      their real advantage over those already available in terms of clinical efficacy
      remains uncertain.

PMID- 10582776
TI  - Preventing thromboembolic complications in older orthopaedic surgery patients:
      interventions and outcomes.
AB  - The aging of the population in developed countries has been associated with a
      growing burden of degenerative joint disease and hip fracture, and this has
      contributed to a progressive increase in the utilisation of major hip and knee
      arthroplasty. In the absence of effective thromboprophylaxis, patients undergoing
      major orthopaedic surgery are at high risk of deep vein thrombosis, which may in
      turn lead to life-threatening complications such as pulmonary embolism, as well
      as long term sequelae including the post-thrombotic syndrome. However, increasing
      age is also associated with an increased risk of venous thromboembolism, and
      older orthopaedic patients are, therefore, at particularly high risk. Randomised
      trials have demonstrated that the risk of venous thromboembolism in these
      patients, as demonstrated by venography, can be reduced by more than 50% with the
      use of effective thromboprophylaxis. However, antithrombotic agents such as low
      molecular weight heparin and warfarin, which are widely used for the prevention
      of venous thromboembolism, are also associated with an increased risk of bleeding
      complications, and selection of the most appropriate strategy should, therefore,
      involve consideration of the potential risks as well as benefits of the currently
      available interventions.

PMID- 10582778
TI  - Genital tract infection and infertility. Preface.

PMID- 10582777
TI  - Epirubicin: a review of its intravesical use in superficial bladder cancer.
AB  - The anthracycline epirubicin has been investigated for intravesical use in
      patients with superficial bladder cancer. In multicentre, randomised trials,
      prophylaxis with intravesical epirubicin 30 to 80 mg after transurethral
      resection (TUR) was more effective than no prophylaxis in the prevention of
      disease recurrence. Intravesical prophylaxis with epirubicin was as effective as
      that with equivalent dosages of doxorubicin after TUR. Data are conflicting
      concerning the relative efficacy of intravesical epirubicin and bacillus Calmette
      Guerin (BCG) in patients at intermediate risk of recurrence after TUR, but
      epirubicin was less effective than BCG in those at high risk. The efficacy and
      tolerability of prophylaxis with epirubicin relative to that with mitomycin is
      not yet established. The efficacy of epirubicin as prophylaxis after TUR in
      combination with BCG or interferon-alpha-2b, or as treatment in patients with
      superficial bladder cancer has been evaluated in small, noncomparative trials,
      but requires clarification. Adverse events associated with intravesical
      epirubicin were generally mild and transient. The most common adverse events were
      localised to the bladder (cystitis, haematuria and urinary tract infection).
      Systemic adverse events (cardiac, haematological or related to hypersensitivity)
      were not reported in many trials of intravesical epirubicin, and when reported
      generally occurred in < or =5% of patients who received the drug. Intravesical
      epirubicin was generally tolerated as well as intravesical doxorubicin and was
      associated with a lower incidence of mild chemical cystitis in 1 clinical trial.
      The incidence of adverse events associated with intravesical epirubicin was
      markedly lower than that associated with intravesical BCG. CONCLUSIONS:
      Intravesical epirubicin has shown efficacy in preventing disease recurrence after
      TUR of superficial bladder cancer. In comparison with equivalent dosages of
      doxorubicin, the efficacy of epirubicin for this indication is generally similar,
      and the tolerability profile may be more favourable. Epirubicin is less effective
      than BCG as intravesical prophylaxis in patients at high risk of recurrence after
      TUR; the relative efficacy of epirubicin and BCG after TUR in patients at
      intermediate risk is not yet clear. Intravesical epirubicin is generally
      tolerated better than BCG. Intravesical epirubicin may be used as prophylaxis
      after TUR in patients who are at low or intermediate risk of recurrence of
      superficial bladder cancer.

PMID- 10582779
TI  - Mechanisms and effects of male genital tract infection on sperm quality and
      fertilizing potential: the andrologist's viewpoint.
AB  - There are several mechanisms acting in synergism that can impair sperm
      characteristics of patients with accessory gland infection. In some cases,
      conventional sperm variables are disturbed with oligo and/or asthenozoospermia.
      In other patients, these sperm variables may appear normal, but the functional
      capacity of spermatozoa may be impaired. In particular, changes in the
      composition of the sperm membrane may result in reduced acrosome reactivity and
      capacity to fuse with the oolemma, and oxidative damage of the sperm DNA may
      induce mutagenesis. Changes in the biochemical make-up of seminal plasma can also
      reduce the in-vivo fertilizing capacity of spermatozoa, and infection-related
      disruption of the blood-testis barrier can induce the generation of anti-sperm
      antibodies and immunological infertility. Many of these functional abnormalities
      will not become evident upon 'basic semen analysis', which explains why some
      authors are unable to link infection of the accessory sex glands to subfertility.
      Also, functional and anatomical damage acquired as a result of infection is often
      permanent and not reversible by (antibiotic) treatment. Clearly, there are many
      more aspects of male accessory gland infection that require investigation.
      Available data should stimulate clinicians to place more emphasis on the
      prevention of infection-related infertility than on its treatment, as the latter
      is often unsuccessful.

PMID- 10582780
TI  - Infections in the male genital tract and reactive oxygen species.
AB  - In the male genital tract, reactive oxygen species (ROS) are generated by
      spermatozoa and leukocytes including neutrophils and macrophages. ROS are
      involved in the regulation of sperm functions such as capacitation and the
      acrosome reaction. Infections lead to an excessive ROS production, resulting in
      an 'oxidative burst' from neutrophils/macrophages as a first-line defence
      mechanism. This is modulated by several cytokines and the pro-oxidant mechanisms
      of bacteria and viruses. At the site of an infection, the degree of activation of
      leukocytes, i.e. the amount of ROS produced, and the available antioxidative
      systems determine whether spermatozoa are damaged or not. During an infection, an
      imbalance of pro- and antioxidants favouring the former results in oxidative
      stress which impairs the sperm functions mentioned, as well as motility and
      fertilization. ROS produced during infections of the testis and epididymis are
      especially harmful to spermatozoa due to the longer contact time and the lack of
      antioxidant protection. In the final ejaculate, only very high numbers of ROS
      producing leukocytes are detrimental to sperm functions. An infectious injury
      involving ROS in the prostate gland, seminal vesicles or epididymis could impair
      sperm functions indirectly. Pro- and antioxidative properties of therapeutics are
      currently receiving more attention as part of anti-infectious therapies. At
      present, there are many unresolved questions concerning the exact role of ROS
      during infections of the male genital tract because of the difficulty of
      specifically assessing the site of generation and the short-lived effects of ROS.
      New techniques may enable specific studies to fill this gap in the near future.

PMID- 10582781
TI  - Relevance of male accessory gland infection for subsequent fertility with special
      focus on prostatitis.
AB  - Infections of the male genitourinary tract may contribute to infertility to a
      various extent depending on the site of inflammation. Especially in prostatitis,
      the exact classification of the infection contributes to its impact on changes in
      the ejaculate. Similarly, in urethritis, epididymitis and orchitis, only a clear
      clinical diagnosis allows a rational approach to altered sperm parameters.
      Several inflammatory and reactive alterations of sperm quality seem to be proven;
      nevertheless, the impact of these findings on male fertility remains in many
      cases unclear. Even therapeutic trials do not provide more insights into the
      association of male genital infections and impaired fertility, although the
      efficacy of antibiotic trials seems to be proven. For the future, it may be
      decisive to evaluate inflammatory changes in the ejaculate not only on the basis
      of standard but also on functional parameters, thus providing new definitions of
      the interactions between male urogenital tract infection and disturbances of male
      fertility.

PMID- 10582782
TI  - Chlamydia trachomatis: impact on human reproduction.
AB  - Chlamydia trachomatis infections are the most prevalent bacterial sexually
      transmitted infections (STI) recognized throughout the world. Worldwide, the
      magnitude of morbidity associated with sexually transmitted chlamydial infections
      is enormous. C.trachomatis is a common cause of urethritis and cervicitis, and
      sequelae include pelvic inflammatory disease (PID), ectopic pregnancy, tubal
      factor infertility, epididymitis, proctitis and reactive arthritis. The sharp
      worldwide increase in the incidence of PID during the past two decades has led to
      the secondary epidemics of tubal factor infertility and ectopic pregnancy.
      Chlamydial PID is the most important preventable cause of infertility and adverse
      pregnancy outcome. Chlamydial infections, like STI in general, are primarily a
      woman's health care issue since the manifestations and consequences are more
      damaging to the reproductive health in women than in men. Based on the available
      evidence, approximately 20% of women with chlamydial lower genital tract
      infection will develop PID, approximately 4% develop chronic pelvic pain, 3%
      infertility, and 2% adverse pregnancy outcome. However, these estimates are based
      on relatively weak evidence. Research on the link between C.trachomatis and male
      aspects of infertility has been much more limited. Currently recommended
      treatment regimens include azithromycin in a single dose or doxycycline for 7
      days. These therapies are highly efficacious. Timely management of sex partners
      is essential for decreasing the risk for re-infection. Immunopathogenesis of
      C.trachomatis infection is one of the main focal points of current research into
      Chlamydia. Chlamydial infection fills the general prerequisites for disease
      prevention by screening, i.e. chlamydial infections are highly prevalent, usually
      asymptomatic, are associated with significant morbidity, can be reliably
      diagnosed, and are treatable. Screening programmes for C.trachomatis will be of
      paramount importance in the prevention of long-term sequelae. The cost of
      screening is only a fraction of the health care costs incurred due to
      complications resulting from undiagnosed and untreated chlamydial infections.
      Current strategies to control C.trachomatis still largely depend on clinic-based
      screening of symptomatic patients, and have not been successful. The development
      of highly sensitive and specific nucleic acid amplification tests for the
      diagnosis of chlamydial infections has been an important advance in the ability
      to conduct population-based screening programmes to prevent complications. Thus,
      the case for screening is clearly made, but much detail remains to be worked out.

PMID- 10582783
TI  - Treatment of retrograde ejaculation and anejaculation.
AB  - Treatment of retrograde ejaculation and anejaculation The various options for the
      treatment of retrograde ejaculation (RE) and anejaculation (AE) are discussed
      systematically in this review. A total of 88 studies dealing with patients with
      RE emphasize medical treatment for reversal of RE and retrieval of spermatozoa
      from urine. In 136 studies concerning patients with AE, the main emphasis is on
      medical treatment, electroejaculation (EE) and electrovibration stimulation (EVS)
      for the reversal of AE. Sperm quality in patients with RE and AE is often
      impaired. However, with the help of assisted reproduction techniques (ART)
      available today, both ejaculation disorders can be considered as treatable
      diseases. The major problem when analysing the studies was the uneven
      methodological quality of the original articles and the difficulties presented by
      different drugs and dosages, equipment and techniques, along with different
      criteria for success. In conclusion, controlled clinical trials comparing
      different treatment options appear urgently warranted.

PMID- 10582784
TI  - Critical analysis of intravenous immunoglobulin therapy for recurrent
      miscarriage.
AB  - Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage
      An alloimmune abnormality is believed to be the cause of recurrent miscarriage in
      couples in whom no other cause can be identified. Because of its
      immunosuppressive properties, intravenous immunoglobulin (IVIG) is used as a
      treatment for this disorder. The purpose of this study was to determine whether
      IVIG improves the chance of successful pregnancy in women with recurrent
      miscarriage by using individual patient data from efficacy trials. Detailed
      information on each patient enrolled in these trials was obtained to evaluate the
      efficacy of IVIG and investigate the effect of clinical variability on pregnancy
      outcome. Data from 125 patients in the IVIG group and 115 patients in the placebo
      group were available for analysis. Although the number of previous miscarriages
      and female age were both negative prognostic factors for successful outcome,
      there was no significant improvement in successful pregnancy or live birth rate
      with IVIG. Subgroup analyses indicated that timing of IVIG administration may be
      important. The results of the present study highlight the importance of
      stratification for known confounders, so that the role of IVIG can be evaluated
      in more detail. The collective evidence thus far indicates that IVIG does not
      have a therapeutic effect that is clinically meaningful.

PMID- 10582785
TI  - Premature ovarian failure: a systematic review on therapeutic interventions to
      restore ovarian function and achieve pregnancy.
AB  - Infertility is an important issue for patients with premature ovarian failure
      (POF). Although oocyte donation offers an alternative method to achieve a
      pregnancy, many patients seek to reproduce with their own gametes. We performed a
      literature search to evaluate the possibility of pregnancy following diagnosis,
      and the additional value of treatment strategies. We found 52 case reports, eight
      observational studies, nine uncontrolled studies and seven controlled trials. Due
      to a strong variability in study design, patient selection and mode of
      intervention, it was not possible to combine the data of the seven studies to
      perform a meta-analysis. None of the studies showed a statistically significant
      difference between both (or more) study groups. Due to a lack of incorporation of
      a placebo group, preference of any treatment over no treatment could not be
      established. Importantly, the collected data of observational, uncontrolled and
      controlled studies indicate that POF patients still have a 5-10% chance to
      conceive following diagnosis. Approximately 80% of the reported pregnancies
      resulted in the birth of a healthy child. There is no evidence that any treatment
      can enhance this pregnancy rate.

PMID- 10582786
TI  - Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary
      syndrome: rationale, results, reflections and refinements.
AB  - Low-dose follicle stimulating hormone (FSH) regimens for induction of ovulation
      for women with polycystic ovaries have succeeded in reducing the rate of ovarian
      hyperstimulation syndrome (OHSS) almost to nil and the rate of multiple
      pregnancies to a minimum of 6%. This has been achieved by reaching, but not
      exceeding, the threshold level of FSH, starting with a daily dose of 75 IU for 14
      days, using small incremental dose rises where necessary, and inducing
      uniovulation in 70% of cycles. Conception rates are as good, if not better, than
      those achieved with conventional therapy. The miscarriage rate is still
      relatively high (20-25%) and obese women fare worse. Serum oestradiol
      concentrations and the number of large and intermediate follicles on the day of
      human chorionic gonadotrophin administration are much lower, in parallel with
      lower serum FSH concentrations. Inhibin values increase with the rise in serum
      FSH concentrations but those of luteinizing hormone decrease steadily throughout
      the follicular phase. New data using recombinant hFSH (rhFSH), rather than
      urinary gonadotrophin as the ovarian stimulant, demonstrate that treatment time
      is shortened. However, the ideal regimen has still to be formulated.

PMID- 10582787
TI  - Trends in world population: how will the millenium compare with the past?
AB  - This paper reviews historical and projected trends in world population numbers,
      and the underlying determinants of those trends. Whereas the world's population
      has shown little change over most of its one million-year history, the past 200
      years have witnessed dramatic changes in fertility, mortality and population
      growth rates. Recent decades, in particular, have seen unprecedented demographic
      events, with more people added to the world's population in the past 50 years
      than in the preceding million. The demographic impact of HIV/AIDS, selective as
      it is to young adults and infants, is also unprecedented, with life expectancy
      among some populations reduced by almost 20 years. As we approach the end of the
      20th century, further demographic changes are underway with, for the first time
      in recent human history, a slowing down of world population growth. Nonetheless,
      world population is projected to grow from 6 billion currently to about 9.4
      billion by 2050 (medium fertility assumption), with ageing emerging as the most
      pressing demographic issue facing humanity in the millenium.

PMID- 10582788
TI  - Prophylactic contraceptives for HIV/AIDS.
AB  - The current pandemic of sexually transmitted human immunodeficiency virus (HIV)
      infection--the causative agent of acquired immunodeficiency syndrome (AIDS), has
      created an urgent need for a new type of contraceptive: one that is both a
      spermicide and a microbicide. Because most women at risk for HIV infection are of
      reproductive age (15-44 years), effective use of dual-function contraceptives is
      important to prevent HIV transmission and unintended pregnancies. In the absence
      of an effective prophylactic anti-HIV therapy or vaccine, new emphasis has been
      placed on the development of intravaginal microbicidal agents capable of reducing
      the transmission of HIV. Topical microbicidal spermicides would ideally provide a
      female-controlled method of self-protection against HIV as well as preventing
      pregnancy. However, several microbicides that are undergoing preclinical and
      human clinical trials contain detergent-type ingredients. The detergent-type
      spermicide, nonoxynol-9, the only recommended microbicide for protection against
      sexual transmission of HIV has been shown to cause lesions in vaginal and
      cervical epithelia leaving women more vulnerable to HIV infection. Therefore, a
      major challenge in microbicide research has been to design mechanism-based
      microbicides that are highly effective against pregnancy and HIV transmission
      while lacking detergent-type effects on epithelial cells and normal vaginal
      flora. We present an overview of current microbicide research and report on the
      identification and preclinical development of novel non-detergent spermicidal
      nucleoside and non-nucleoside inhibitors aimed at decreasing pregnancy and
      preventing sexual transmission of HIV.

PMID- 10582789
TI  - Clinical applications of colour Doppler energy imaging in the female reproductive
      tract and pregnancy.
AB  - This review describes the usefulness of colour Doppler energy (CDE) (or power
      Doppler) imaging to measure vascularization in the female reproductive tract. CDE
      imaging is characterized by an increased sensitivity to flow, and thus may be
      useful in low-flow states and when optimal Doppler angles cannot be obtained. In
      addition, longer segments of vessels and more individual vessels can be
      visualized with CDE imaging. The role of CDE imaging in the evaluation of stromal
      vasculature in normal and in polycystic ovaries is described, and the
      relationship between follicular vascularity and outcome following in-vitro
      fertilization are discussed, together with the findings obtained from the
      evaluation of thecal arteriole of corpus luteum in early pregnancy. The
      fundamental role of CDE imaging in differentiation among ovarian masses is also
      reviewed. We summarize the role of CDE imaging in pregnancy, and describe two new
      applications of three-dimensional power Doppler sonography and the use of
      ultrasound contrast media. In conclusion, CDE imaging can replace conventional
      colour Doppler when the information on the direction of flow is not useful.
      Moreover, the technique appears superior to others for describing microvascular
      architecture and determining the presence or absence of flow.

PMID- 10582790
TI  - Antenatal screening for Down's syndrome in assisted reproductive pregnancies.
AB  - The wide use of assisted conception methods has risen dramatically. The greater
      proportion of singletons, twins and high order of multiplicity conceived by those
      methods have already focused the medical community to various obstetric
      complications. Recently, there have been suggestions that the levels of mid
      gestation serum markers, particularly human chorionic gonadotrophin (HCG), might
      be affected by assisted conception, leading to higher false-positive results.
      Furthermore, women who conceived after assisted reproduction methods are on
      average older, and in many cases their current pregnancy was achieved after long
      standing infertility and might even be their last one. This is why they are
      extremely wary of any invasive fetal karyotyping. Therefore, every effort should
      be made to provide them with the most accurate screening of Down's syndrome (DS)
      risk. In this respect, nuchal translucency (NT) measurement, which has been
      reported to be another effective screening method, might be a more reliable
      marker in these pregnancies. This review explores the problematic issue of
      antenatal DS screening in assisted conception pregnancies. For the singletons and
      twins, a sequential NT and second-trimester serum marker screening can be
      offered, thus producing a single risk estimation which seems to be more accurate.
      For the high order of multiplicity, the NT offers additional important data,
      which can be taken in consideration both as a screening tool for DS and if fetal
      reduction is planned.

PMID- 10582791
TI  - Stem cell factor/c-kit system in spermatogenesis.
AB  - One of the major unresolved questions with male infertility is the identification
      of the molecular origin of a great majority of the spermatogenetic arrests
      currently diagnosed as idiopathic male infertility. During the past years,
      several families of regulating factors have been implicated in spermatogenesis
      defects observed essentially in animal models. Among these factors are signalling
      molecules, and particularly the stem cell factor (SCF)/c-kit system. The SCF and
      its receptor c-kit are an appropriate example to illustrate the role of
      signalling molecules in the physiology and pathology of spermatogenesis. The
      SCF/c-kit regulates primordial germ cell migration, proliferation and apoptosis
      during fetal gonadal development. The SCF/c-kit also regulates spermatogonia
      proliferation in the adult animal. In mutant mice, abnormalities of the SCF/c-kit
      gene expression, such as gene deletion, point mutation, alternative splicing
      defect, lead to different types of spermatogenesis alterations (e.g. decrease in
      primordial germ cell migration, decrease in spermatogonia proliferation). More
      recently, defects in SCF/c-kit gene expression have also been shown in human
      testicular dysfunctions. Indeed, a reduction in SCF/c-kit expression has been
      evidenced in oligozoospermia/azoospermia associated with an increase in the germ
      cell apoptosis process. In addition, c-kit seems to be a good marker of seminoma
      testicular tumours. This review reports a large number of data--obtained
      essentially in animal models--that suggest an important role for the SCF/c-kit
      system in spermatogenesis and, as a corollary, its potential involvement in
      spermatogenic defects.

PMID- 10582793
TI  - Penile vibratory stimulation for men with spinal cord injury.

PMID- 10582792
TI  - The fertility potential of women with a single ovary.
AB  - The incidence of having a single ovary is quite common in infertile patients and
      can reach up to 17% of women with severe tubal disease who require in-vitro
      fertilization (IVF) treatment. Data on the short- and long-term implications of
      having only one ovary are scarce, and patients in this situation are naturally
      concerned. This article reviews the effect of possessing a single ovary on the
      fertility potential and ovarian reserve of these women and their performance in
      assisted reproduction treatment.

PMID- 10582794
TI  - Development of the human dispermic embryo.
AB  - In a recent CD-ROM, we portrayed the microstructure of the pre-implantation human
      embryo (Sathananthan et al., 1999), which was a multimedia production with
      computer colour-enhanced electron micrographs of mainly monospermic embryos. This
      disk portrays light and electron micrographs of over 250 tripronuclear (3PN),
      dispermic, human embryos during pre-implantation development, viewed in thick and
      thin Araldite sections, as well as appearances of whole embryos flat embedded in
      Araldite blocks visualized with the light microscope. The 100 figures were
      computerized (IBM TIFF format), edited and labelled using Adobe Photoshop 5. Some
      of the figures were coloured on computer. The early development of 3PN embryos
      overtly resembles that of normal embryos but there are important differences in
      their microstructure which are portrayed in this presentation. This is a
      multicentric study involving researchers from four IVF centres.

PMID- 10582795
TI  - rCBF in neurodegenerative diseases as estimated by the autoradiographic (ARG)
      method and delayed I-123-IMP studies.
AB  - A total of 24 patients with a mean age of 45.8 +/- 20.8 were included in the
      study. The patients were grouped as Control (C), Degenerative Syndromes (DS),
      Degeneration Associated with External Factors (DEF), Degeneration Associated with
      Focal Neurologic Lesion (DFN) and Demyelinating Disease (DM). Imaging started 15
      minutes for early and 4 hours for delayed scans after i.v. infusion of I-123 IMP.
      The rCBF was calculated by the IMP autoradiographic (ARG) method. The wash-out
      ratio (WR) was calculated as the ratio of the Delay/Early count. In the rCBF of
      the various areas of the brain, significant differences were noted between
      various disease groups. No correlation was noted between rCBF and WR (r = -0.50).
      The WR of patients grouped according to various disease processes did not show a
      significant difference between various areas of the brain. In conclusion, the
      rCBF was effective in separating both various areas of the brain and disease
      entities. WR from a delayed study is less useful in neurodegenerative diseases.

PMID- 10582796
TI  - Cytosolic/microsomal redox pathway: a reductive retention mechanism of a PET
      oncology tracer, cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (cu-PTSM).
AB  - OBJECTIVE: To clarify the retention mechanism of a PET imaging agent Cu
      pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-62-PTSM) in tumor cells,
      reductive metabolism of non-radioactive Cu-PTSM in five cultured tumor cell
      lines, a tumor specimen and non-tumor tissues in vitro was evaluated by electron
      spin resonance spectrometry (ESR). RESULTS: In the brain, mitochondrial electron
      transport enzyme reduced Cu-PTSM specifically. On the other hand, Cu-PTSM was not
      reduced in tumor mitochondria. The mitochondrial electron transport enzyme in
      tumor cells was not damaged, but NADH was considered to be depleted. In
      compensation for that, the tumor cells acquired complementary reduction activity
      in the microsome/cytosol. The reduction was enzymatic and NADH-dependent,
      possibly similar to the activation mechanism of bioreductive anticancer drugs.
      CONCLUSION: Cu-PTSM and its derivatives are considered to be used as a marker for
      microsome/cytosol redox ability in PET oncology, although the physiological role
      of the redox enzyme system in tumor cells has not been clarified. The change in
      electron (NADH) flow in tumor cells might be a mechanism supporting aerobic
      glycolysis in tumor cells.

PMID- 10582797
TI  - Testicular lymphoma with bone/bone marrow metastases illustrated by scrotal
      sonography, spinal MRI, and total body Tc-99m HMDP and Tc-99m MIBI images.
AB  - An 83-year-old man with testicular lymphoma demonstrated progressive scrotal
      enlargement with non-homogeneity sonographically and abnormally increased uptake
      in the scrotum of Tc-99m HMDP and Tc-99m MIBI scintigraphically. Extensive
      bone/bone marrow metastases were exhibited by Tc-99m MIBI and Tc-99m HMDP
      scintigraphies and MRI of the spine. In addition, focal/tubular activity of the
      femoral bone marrow on Tc-99m MIBI imaging was consistent with skeletal
      scintigraphic findings. It is emphasized that Tc-99m MIBI total body imaging
      enabled the demonstration of testicular lymphoma as increased uptake and the
      illustration of skeletal/bone marrow metastases as diffuse and/or focal increased
      uptake, especially focal/tubular MIBI activity of the femoral marrow.

PMID- 10582798
TI  - Estimation of cardiac output by first-pass transit of radiotracers.
AB  - To evaluate cardiac function with various tracers to be used for radionuclide
      scintigraphy, we examined the validity of a simplified method to measure cardiac
      output (CO) by modifying the equation of Stewart-Hamilton in the radionuclide
      study. After a bolus injection of I-123 or Tc-99m tracer, the total injection
      dose and count in the pulmonary artery during the first transit of the tracer
      were measured to calculate the CO Index. The CO Index was obtained from the
      integral of the first transit of radiotracers in the pulmonary artery divided by
      the total injected count. CO was estimated from the regression formula which was
      obtained by comparing the CO Index with CO measured by the Doppler
      echocardiographic method. There were close correlations between the CO Index and
      CO measured by Doppler echocardiography both in the study with I-123 (n = 13, r =
      0.85, p < 0.001) and with Tc-99m (n = 17, r = 0.88, p < 0.001). The regression
      formula varied according to the radionuclide used for the study (CO = 2.29 x (CO
      Index)(0.634) for I-123 and CO = 3.18 x (CO Index)(0.518) for Tc-99m). CO
      measured by this method is useful for the assessment of cardiac function with
      various tracers in routine clinical studies, and this simple method may be
      utilized for assessment of organ blood flow on the basis of the microsphere
      model.

PMID- 10582799
TI  - The effect of tumor size on F-18-labeled fluorodeoxyglucose and
      fluoroerythronitroimidazole uptake in a murine sarcoma model.
AB  - The purpose of this study was to evaluate the effect of tumor size on the uptake
      of 18F-fluorodeoxyglucose (FDG) and fluoroerythronitroimidazole (FETNIM) in a
      murine sarcoma model. ICR mice were xenografted with sarcoma 180 cell line and
      tumors were allowed to grow to a weight of 0.26-5.82 grams. 18F-FDG and 18F
      FETNIM were injected intravenously in separate groups of mice, and after 1 hr,
      the tumors were excised and radiotracer uptake was measured. In another group of
      mice tumors were autoradiographically analyzed and subjected to H & E staining.
      In both the FDG and FETNIM group, per-gram radiotracer uptake by a tumor was
      inversely proportional to tumor weight. 18F-FETNIM correlated more (r = -0.593, p
      < 0.05) than 18F-FDG (r = -0.447, p < 0.05). Autoradiographic studies revealed
      that FDG accumulated in viable tumor areas, whereas FETNIM accumulated in both
      viable and partially necrotic areas. In the case of 18F-FETNIM, a direct
      correlation between tumor weight and the no-uptake-area to total-tumor-area was
      demonstrated. We concluded that increased tumor size is associated with decreased
      uptake of 18F-FDG and FETNIM, though this depends on the type of radiotracers and
      distribution of necrosis.

PMID- 10582800
TI  - Preserved benzodiazepine receptors in Alzheimer's disease measured with C-11
      flumazenil PET and I-123 iomazenil SPECT in comparison with CBF.
AB  - This study evaluates the regional cerebral blood flow (CBF) with H2(15)O-PET and
      the distribution of central benzodiazepine receptor (BZR) with C-11 flumazenil
      (FMZ) by PET and I-123 iomazenil (IMZ) by SPECT in Alzheimer's disease (AD). In
      AD, whereas the CBF was diminished in the frontal, temporal, parietal, and
      occipital cortex, the distribution volume of FMZ and delayed activity of IMZ were
      relatively preserved in these cortices, suggesting that the BZR reduction,
      reflecting neuronal loss, is less prominent than the CBF suppression. The mini
      mental state examination score (MMS) was weakly correlated with the CBF in the
      parietal cortex but not with BZR. It is speculated that the neuronal density
      reflected by BZR is less impaired than the neuronal function assessed with blood
      flow in the association cortex of AD. High correlation was found between the
      uptake of FMZ and the delayed activity of IMZ. The delayed image of IMZ-SPECT is
      clinically useful to evaluate the preservation of neuronal density in the
      affected temoporoparietal association cortex in AD.

PMID- 10582801
TI  - A new method for crosstalk correction in simultaneous dual-isotope myocardial
      imaging with Tl-201 and I-123.
AB  - We have developed a new method of crosstalk correction in simultaneous dual
      isotope imaging with Tl-201 and I-123 by using crosstalk ratios and a blurring
      filter. Single isotope myocardial studies (10 for Tl-201 and 7 for I-123) were
      performed with a dual energy window acquisition mode and two low energy general
      purpose collimators. Then two planar images acquired with dual energy windows for
      a Tl-201 line source and an I-123 line source were obtained to measure line
      spread functions (LSFs) and crosstalk ratios for each image. The line source
      experiments showed that the LSFs for the Tl-201 imaging window from the single Tl
      201 source were very similar to those for the I-123 imaging window from the
      single Tl-201 source, but the LSFs for the Tl-201 imaging window from the single
      I-123 source had broad shapes which differed from those for the I-123 imaging
      window from the single I-123. To obtain accurate I-123 crosstalk images in the Tl
      201 imaging window from the I-123 images in the I-123 imaging window, we designed
      a low-pass blurring filter. In 7 clinical I-123 MIBG studies, I-123 window images
      processed with this filter became very similar to the Tl-201 window image from
      the single I-123 source. The method proposed in this study can accurately correct
      the crosstalk in dual isotope studies with Tl-201 and I-123 and is easily
      applicable to conventional gamma camera systems with any dual energy window
      acquisition mode.

PMID- 10582802
TI  - Mammary lymphoscintigraphy with various radiopharmaceuticals in breast cancer.
AB  - Sentinel node biopsy (SNB) in breast cancer is a promising surgical technique
      that avoids unnecessary axillary lymph node dissection. To optimize lymphatic
      mapping with radiopharmaceuticals, mammary lymphoscintigraphy with 30-50 MBq of
      technetium-99m-diethylenetriamine pentaacetic acid human serum albumin (99mTc
      HSAD), technetium-99m-human serum albumin (99mTc-HSA), or technetium-99m-tin
      colloid (99mTc-TC) were investigated in 69 cases of primary breast cancer.
      Dynamic early images were obtained during the first 30 or 40 minutes, and static
      delayed images were obtained 6 hours after tracer injection. Hot spots as
      sentinel lymph nodes (SLNs) appeared in 51 of 69 cases (74%): in early images in
      27 cases and in delayed images in 24 cases. SLNs were visualized more frequently
      in 23 of the 26 cases (88%) treated with 99mTc-HSAD and in 21 of the 24 cases
      (88%) treated with 99mTc-HSA than in only 7 of the 19 cases (37%) treated with
      99mTc-TC. In 26 of the 51 cases, SLNs were identified as faint spots in delayed
      images. There was a significant difference in the first appearance of SLNs on the
      lymphoscintiscan between 43 cases of dense breast parenchyma and 26 cases of
      fatty breast parenchyma. These results suggest that 99mTc-HSAD or 99mTc-HSA is
      acceptable for lymphatic mapping, but in cases which have faint spots in delayed
      images or fatty breast parenchyma, gamma probe-guided SNB may result in failure
      or misleading false-negative SLNs.

PMID- 10582803
TI  - Effects of scatter correction on regional distribution of cerebral blood flow
      using I-123-IMP and SPECT.
AB  - The transmission dependent convolution subtraction method which is one of the
      methods for scatter correction of SPECT was applied to the assessment of CBF
      using SPECT and I-123-IMP. The effects of scatter correction on regional
      distribution of CBF were evaluated on a pixel by pixel basis by means of an
      anatomic standardization technique. SPECT scan was performed on six healthy men.
      Image reconstruction was carried out with and without the scatter correction. All
      reconstructed images were globally normalized for the radioactivity of each
      pixel, and transformed into a standard brain anatomy. After anatomic
      standardization, the average SPECT images were calculated for scatter corrected
      and uncorrected groups, and these groups were compared on pixel by pixel basis.
      In the scatter uncorrected group, a significant overestimation of CBF was
      observed in the deep cerebral white matter, pons, thalamus, putamen, hippocampal
      region and cingulate gyrus as compared with scatter corrected group. A
      significant underestimation was observed in all neocortical regions, especially
      in the occipital and parietal lobes, and the cerebellar cortex. The regional
      distribution of CBF obtained by scatter corrected SPECT was similar to that
      obtained by O-15 water PET. The scatter correction is needed for the assessment
      of CBF using SPECT.

PMID- 10582804
TI  - Limitations of spontaneous reperfusion and conventional medical therapy to afford
      myocardial protection through antecedent angina pectoris in acute myocardial
      infarction.
AB  - Despite the cardioprotective effect of rapid coronary reperfusion, the effects of
      spontaneous recanalization on myocardial viability and metabolism are unknown. We
      studied whether preinfarction angina affords cardioprotection when spontaneous
      coronary reperfusion occurred in acute infarct patients. Myocardial tomographies
      with thallium and I-123-labeled-beta-methyl-p-iodophenyl penta-decanoic acid
      (BMIPP) were performed in 27 acute myocardial infarct patients treated medically:
      15 patients had preexisting angina before infarction (group A) and 12 did not
      (group B). Thallium and BMIPP abnormalities and regional function were quantified
      by a polar map and contrast ventriculography, respectively. There was no
      significant difference between thallium and BMIPP in the severity index in groups
      A and B (89 +/- 97 vs. 85 +/- 68, 97 +/- 28 vs. 95 +/- 27, respectively), and no
      significant difference between the groups in the thallium or BMIPP severity
      index. The ratio of the thallium severity index to that of BMIPP and the regional
      wall-motion abnormality index were identical in groups A and B. Both patient
      groups were divided into 2 subgroups based on the presence or absence of
      spontaneous coronary reperfusion: subgroups A1 and A2, and subgroups B1 and B2,
      respectively. There were no significant differences among the 4 subgroups in
      severity indexes for both tracers, the thallium/BMIPP ratio, or the asynergy
      score. The BMIPP severity index correlated significantly with that of thallium in
      all subgroups, but no significant difference between the regression lines was
      found. It is therefore unlikely that spontaneous coronary recanalization affords
      beneficial effects through preservation of myocardial viability in an ischemia
      related zone, suggesting that the cardioprotective effect of preinfarction angina
      is a limited phenomenon in patients undergoing rapid coronary reperfusion.

PMID- 10582805
TI  - A case of diaphragm hernia containing accessory spleen and great omentum detected
      by Tc-99m phytate scintigraphy.
AB  - A rare case of diaphragm hernia containing an accessory spleen and great omentum
      is reported. Tc-99m phytate SPECT showed tracer accumulation in the accessory
      spleen and was useful in the evaluation of the disease.

PMID- 10582806
TI  - Sub-super bone scan caused by bone marrow involvement of prostate cancer.
AB  - A 67-year-old man presented with malaise and marked anemia. A diagnostic workup
      revealed severe pancytopenia on a complete blood count and diffuse sclerotic
      change in the axial skeleton on a plain abdominal radiograph. Bone metastases
      being suspected from these findings, bone scintigraphy was performed. The bone
      scan demonstrated uniformly increased skeletal activity with faint soft-tissue
      activity. The findings of the bone scan, however, appeared atypical of the super
      scan caused by diffuse bone metastases, without any decrease in radioactivities
      of the appendicular skeleton and kidneys. Bone marrow scintigraphy with In-111
      chloride demonstrated central marrow failure and peripheral expansion, which
      indicated the possibility of myelophthisis. The patient underwent bone marrow
      biopsy, which revealed replacement of the bone marrow by metastatic
      adenocarcinoma. Further examinations detected the primary lesion in the prostate.
      In this case, the findings of the bone scan were insufficient for the super scan,
      and might be categorized as a sub-super scan. It would be important to recognize
      this incomplete form of super scan as a rare scintigraphic pattern of diffuse
      bone marrow metastases.

PMID- 10582807
TI  - Functional imaging in reading epilepsy: a case report.
AB  - Reading epilepsy is an uncommon epileptic syndrome preferentially related to the
      temporoparietal region of the language dominant hemisphere. We report ictal and
      interictal brain perfusion SPECT images in a 28-year-old woman who was reading
      epilepsy.

PMID- 10582808
TI  - Accumulation of technetium-99m pertechnetate in a patient with metastases of
      thyroid carcinoma.
AB  - Accumulation of both Tc-99m pertechnetate and radioiodine upon scintigraphy in
      thyroid carcinoma and/or in its metastases is a rare occurrence. In this paper we
      describe a patient who was taken to surgery for left lobectomy of the thyroid
      with follicular adenocarcinoma and who had accumulation of both I-131 and Tc-99m
      pertechnetate in lung metastases. The accumulation of I-131 was less than that of
      Tc-99m pertechnetate. The use of Tc-99m pertechnetate for imaging for diagnosis
      of functioning thyroid metastases is discussed.

PMID- 10582809
TI  - Evaluation of transmyocardial laser revascularization (TMLR) by gated myocardial
      perfusion scintigraphy.
AB  - TMLR is a novel treatment for patients with coronary artery disease. It comprises
      the creation of transmyocardial channels thought to improve myocardial perfusion.
      Gated Tc-99m sestamibi scintigraphy was used to evaluate changes in myocardial
      perfusion after TMLR. Twelve patients underwent TMLR using a carbon dioxide
      laser. Sestamibi scans were carried out following a standard protocol prior to
      and 1, 3, 6, and 12 months after TMLR. Both visual and semi-quantitative
      assessment showed improvement in 4 patients, deterioration in 2 patients, and no
      change in the remaining 6 patients each. However, visual and semi-quantitative
      assessment were concordant in 6 patients and discordant in 6 patients. In 3 of
      these, semi-quantitative assessment suggested a better outcome, and in 3 patients
      visual assessment gave better results. Our findings in a small group of patients
      suggest that about a third benefited from TMLR. Gated myocardial perfusion
      scintigraphy using technetium-99m sestamibi is suitable for visual evaluation of
      changes in the lased area over time, but does not allow semi-quantitative
      evaluation in the patient population typically treated with TMLR. Further
      investigations using optimized imaging protocols, including positron emission
      tomography and three dimensional image presentation, are warranted.

PMID- 10582810
TI  - Unintentional human skeletal imaging with 99mTc-methylene diphosphonate 45 months
      beyond expiration.
AB  - Eight patients were inadvertently administered, and imaged with, 99mTc-labeled
      MDP which was 45 months expired. Two cases are presented. All patients were
      subsequently imaged with normal MDP. The images obtained with expired MDP were
      clinically acceptable. No differences in scan abnormalities were observed
      compared with normal MDP for any of the patients. None of the patients suffered
      any side effects attributable to the expired MDP.

PMID- 10582811
TI  - NCQA accreditation 2000 standards note pharmacist's role, need for DUE. National
      Committee for Quality Assurance.

PMID- 10582812
TI  - Minnesota researchers find few differences in HMO, fee-for-service care of acute
      myocardial infarction.

PMID- 10582813
TI  - Pharmacist on care team contributes to better outcomes in patients with heart
      failure.

PMID- 10582814
TI  - Drug addiction treatment guide released.

PMID- 10582815
TI  - Consumer group touts generics.

PMID- 10582816
TI  - Therapeutics research centers named by AHCPR.

PMID- 10582817
TI  - Pharmacists in all countries should join wider efforts to improve health, says
      FIP president. International Pharmaceutical Federation.

PMID- 10582818
TI  - Choosing what to post on a pharmacy intranet web page.

PMID- 10582819
TI  - Ganirelix acetate.

PMID- 10582820
TI  - Rabeprazole sodium.

PMID- 10582821
TI  - Influenza outbreak in a long-term-care facility: considerations for pharmacy.
AB  - The role played by a hospital pharmacy department in managing an influenza
      outbreak at an affiliated long-term-care facility is described. In February 1998
      an outbreak of influenza A was confirmed in a 570-bed long-term-care facility.
      During the outbreak, a total of 48 cases of influenza-like illness (ILI) were
      reported to infection control, and 62 staff members missed work because of ILI.
      Infection control measures included a recommendation for prophylaxis with
      amantadine. Pharmacists assumed responsibility for educating patients and
      families about amantadine prophylaxis, providing individualized dosing,
      evaluating reported adverse effects, and drug distribution. Pharmacists developed
      an information sheet on amantadine for patients and met with patients and their
      families. The overall acceptance rate for chemoprophylaxis was 91%. Of the 349
      patients receiving amantadine during the outbreak, 203 (58%) were given 100 mg
      daily, 136 (39%) were given 100 mg every other day, and 10 (3%) were prescribed
      100 mg weekly. Pharmacists confirmed a total of 22 adverse effects; generally the
      problem was solved by reducing the dosage rather than discontinuing the drug. In
      all cases, the first dose of amantadine was provided to the nursing units within
      three hours of an order being written. Pharmacists played an active role in
      managing an influenza A outbreak at a long-term-care facility.

PMID- 10582822
TI  - Quality of consumer drug information provided by four Web sites.
AB  - The quality of drug-specific information available to consumers on the Internet
      was studied. The 30 most commonly dispensed prescription drugs were selected to
      represent those medications for which consumers would be seeking information. A
      Web page evaluation form was developed to objectively evaluate each site in terms
      of sponsors, references, recency of updates, ease of use, overall organization,
      and other characteristics. A second form was developed to qualitatively and
      quantitatively assess the drug information provided by the sites. Four Internet
      sites, MedicineNet, RxList, Drug InfoNet, and thriveonline, were evaluated.
      Authors, contributors, and references were identified for three of the sites. All
      sites had disclaimers advising patients to seek the advice of a health care
      professional, all indexed drug information by both brand name and generic name,
      and all were well organized. Only RxList and MedicineNet contained information on
      all the drugs evaluated. For the drugs documented, RxList, MedicineNet, Drug
      InfoNet, and thriveonline contained 84%, 60%, 87%, and 72% of the 22 variables
      assessed, respectively. The accuracy of the information provided was greater than
      98% for all the sites. Only two of four Internet sites containing consumer drug
      information included all the prescription drugs being evaluated. Most but not all
      of the information on the four sites was accurate.

PMID- 10582823
TI  - Subcutaneous phytonadione for reversal of warfarin-induced elevation of the
      International Normalized Ratio.
AB  - The efficacy and safety of subcutaneous phytonadione in the treatment of patients
      with asymptomatic excessive International Normalized Ratio (INR) values secondary
      to warfarin therapy were evaluated. Patients at an outpatient anticoagulation
      clinic with an INR of 8 or more but less than 14 were given 1 mg of subcutaneous
      phytonadione, and patients with an INR of 14 or more but less than 20 received 2
      mg. The patients were instructed to withhold warfarin therapy for the next 24
      hours and to immediately report any bleeding complications. At subsequent visits,
      patients with an INR of 8 or more but less than 14 were given an additional 1 mg
      of subcutaneous phytonadione. Patients with an INR above 4.5 were instructed to
      withhold warfarin therapy for an additional 24 hours. Seventeen patients received
      the 1-mg dose (group 1), and four patients received the 2mg dose (group 2). In
      group 1, the mean INR reduction was 49% at 24 hours and 72% at 48 hours and the
      INR was below 4.5 in 93% of patients at 48 hours. In group 2, the mean INR
      reduction was 67% at 24 hours and 85% at 48 hours and the INR was below 4.5 in
      100% of patients at 48 hours. In four group-1 patients and one group-2 patient,
      the INR fell below 2.0 at 48 hours. No patients reported hemorrhagic or
      thrombotic complications. Subcutaneous phytonadione safely lowered excessively
      high INR values caused by warfarin therapy.

PMID- 10582824
TI  - Stability of levofloxacin in an extemporaneously compounded oral liquid.
AB  - The stability of levofloxacin in an extemporaneously compounded oral liquid was
      studied. A suspension of levofloxacin 50 mg/mL was prepared from commercially
      available 500-mg levofloxacin tablets and equal amounts of Ora-Plus and
      Strawberry Syrup, NF, to make a final volume of 60 mL. Six identical volumes of
      the suspension were prepared in amber plastic prescription bottles. Three bottles
      were stored at 23-25 degrees C, and three were stored at 3-5 degrees C.
      Immediately after preparation and at 8, 15, 29, and 57 days, samples were
      visually inspected and assayed in duplicate by high-performance liquid
      chromatography; pH was also determined. At least 99% of the initial levofloxacin
      concentration remained in all samples throughout the study period. The color,
      odor, and pH of all the samples did not change appreciably. An extemporaneously
      compounded oral liquid formulation of levofloxacin 50 mg/mL in a 1:1 mixture of
      Ora-Plus and Strawberry Syrup, NF, was stable at 23-25 or 3-5 degrees C for up to
      57 days.

PMID- 10582825
TI  - Pharmacist-coordinated program to improve use of pharmacotherapies for reducing
      risk of coronary artery disease in low-income adults.

PMID- 10582826
TI  - One-year experience with a pharmacist-coordinated nutritional support clinic.

PMID- 10582827
TI  - Delivery of omeprazole and lansoprazole granules through a nasogastric tube in
      vitro.

PMID- 10582828
TI  - Factors influencing students' attitudes toward pharmaceutical care.

PMID- 10582829
TI  - Can science measure art?

PMID- 10582830
TI  - A public-policy strategy for drug formularies: preparation or procrastination?

PMID- 10582831
TI  - Syndromes of abnormal fat redistribution and metabolic complications in HIV
      infected patients.

PMID- 10582832
TI  - Importance of identifying foreign drugs.

PMID- 10582833
TI  - More citizen-soldier pharmacists needed.

PMID- 10582834
TI  - High-dose amoxicillin in new guidelines for treatment of otitis media in
      children.

PMID- 10582835
TI  - A longitudinal study of mothers' overreactive discipline and toddlers'
      externalizing behavior.
AB  - The association between children's externalizing behavior problems and mothers'
      overreactive discipline was examined in a longitudinally assessed sample of
      toddlers and their mothers. Path analyses indicated that mothers' overreactive
      discipline and children's externalizing behaviors were significantly and
      similarly stable over a 2 1/2-year period. No evidence of a cross-time influence
      of either variable on the other was observed. Mothers' overreactive discipline at
      Time 2 had a significant effect on Time 2 externalizing behavior. No significant
      effects of children's behavior on mothers' discipline were found. Mothers'
      depressive symptomatology and marital discord predicted initial overreactivity
      and were related to externalizing problems through their relations to
      overreactivity. The results support the appropriateness of implementing parenting
      interventions for externalizing problems before age 2 years.

PMID- 10582837
TI  - Childhood peer relationship problems and young people's involvement with deviant
      peers in adolescence.
AB  - Using prospective longitudinal data from the Christchurch Health and Development
      Study, this article examined the relationship between children's peer
      relationship problems in middle childhood and their subsequent risk of forming
      deviant peer affiliations in adolescence. The analysis proceeded in three steps.
      First, a structural equation model demonstrated a moderate association between
      early peer relationship problems and later deviant peer affiliations (r = .27).
      Second, the model was extended to include a latent variable measure of early
      conduct problems. This analysis revealed that when the confounding effects of
      concurrently measured conduct problems were taken into account, peer relationship
      problems in middle childhood were no longer significantly related to young
      people's choice of deviant peers in adolescence. Third, the model was further
      extended to include lagged variables, permitting an examination of possible
      reciprocal relationships between early conduct problems and peer relationship
      problems. Results suggested that both early peer relationship problems and
      adolescent deviant peer involvement are symptomatic of early child behavioral
      adjustment. The implications of these findings for explanations of deviant peer
      selection are discussed.

PMID- 10582836
TI  - A longitudinal study of interparental conflict, emotional and behavioral
      reactivity, and preschoolers' adjustment problems among low-income families.
AB  - Researchers have begun to develop models that explain the processes by which
      interparental conflict impacts children's adjustment. The present study tested a
      model based on emotional security theory. The longitudinal relations among
      interparental conflict, boys' reactions to conflict, and internalizing and
      externalizing problems were examined in a sample of 129 mother-son dyads from low
      income, 2-parent families from the time sons were age 2 to 5. Results indicated
      that children exposed to interparental conflict were more likely to have
      concurrent and later behavior problems and that patterns of interparental
      conflict across time made unique contributions in predicting later problems.
      Children's emotional reactivity in response to conflict had no direct relation to
      interparental conflict and only modest relations to behavior problems. However,
      interparental conflict and reactivity factors interacted to predict behavior
      problems at ages 3 1/2 and 5. Thus, some support was demonstrated for emotional
      reactivity as a moderator in the development of young children's behavior
      problems.

PMID- 10582838
TI  - An initial look at sibling reports on children's behavior: comparisons with
      children's self-reports and relations with siblings' self-reports and sibling
      relationships.
AB  - The authors examined siblings' reports of children's depression, anxiety, and
      aggression, and their reports of the sibling relationship, and compared them with
      children's self-reports. In two samples, including 169 sibling pairs (age M =
      9.98 years, SD = 1.51), no significant differences emerged in the levels of
      depression and anxiety found in siblings' reports of children's behavior and
      children's self-reports, although siblings reported children to have
      significantly higher levels of aggression than the children self-reported. Age,
      the difference in ages between siblings, sex, and sibling sex were not related to
      siblings' reports of children's behavior. The relations between children's and
      siblings' reports of children's behavior were significant, yet moderate (average
      r = .22). Both siblings' self-reports of internalizing behavior and their
      perceptions of aspects of the sibling relationship (affection, rivalry,
      hostility, and satisfaction with the sibling relationship) explained significant,
      and unique, variance in siblings' reports of children's internalizing behavior.
      The findings for aggressive behavior were similar, although siblings' perceptions
      of affection in the sibling relationship were not significantly related to their
      reports of children's aggression. The potential uses and benefits of sibling
      reports of children's behavior, and sibling and family relationships, are
      discussed.

PMID- 10582839
TI  - The association between anxiety and psychopathy dimensions in children.
AB  - Although several theoretical models posit that low levels of anxiety are a risk
      factor for psychopathy and antisocial behavior, a number of studies have reported
      elevated levels of anxiety among antisocial individuals. Nevertheless, most
      investigators in this literature have not distinguished between fearfulness and
      trait anxiety or attempted to separate the antisocial lifestyle dimension from
      the callous and unemotional dimension of psychopathy. In a study of clinically
      referred children (N = 143), we found that (a) measures of trait anxiety and
      fearlessness (low fearfulness) exhibited low correlations; (b) conduct problems
      tended to be positively correlated with trait anxiety, whereas callous and
      unemotional traits tended to be negatively correlated with trait anxiety; and (c)
      controlling statistically for the effects of one dimension increased the
      divergent correlations of the other dimension with both trait anxiety and fearful
      inhibition. These findings bear potentially important implications for the
      diagnosis and etiology of psychopathy and antisocial behavior and suggest that
      distinctions between trait anxiety and fearful inhibition, as well as between the
      two dimensions of psychopathy, may help to clarify longstanding confusion in this
      literature.

PMID- 10582840
TI  - The ADHD response-inhibition deficit as measured by the stop task: replication
      with DSM-IV combined type, extension, and qualification.
AB  - Although response inhibition has been proposed as a core element of child
      attention-deficit hyperactivity disorder (ADHD), the literature is heavily
      reliant on studies using DSM-III-R diagnostic criteria, older methods of
      measuring response inhibition, samples of boys, and failing to control thoroughly
      for comorbid problems--both as diagnoses and as subclinical variation. The
      present study replicated a deficit in response inhibition in the ADHD combined
      type (DSM-IV, American Psychiatric Association, 1994) using samples matched on
      age and sex. The study replicated an effect size of approximately d = .6 in boys
      with ADHD, and observed an even larger effect size for girls, although the Sex x
      Group interaction was nonsignificant. Children with ADHD also had problems with
      response output, shown by variable responding. Excluding comorbid conduct
      disorder, reading disorder, generalized anxiety disorder, obsessive-compulsive
      disorder, major depression, and posttraumatic stress disorder from the sample did
      not alter the results. Correlations indicated that response inhibition was
      associated with both attentional problems and reading level. Covarying for
      reading problems did not eliminate the ADHD group effect, but the association of
      response inhibition with reading clearly requires further examination. Overall,
      the study supported the role of response inhibition in the DSM-IV ADHD combined
      type, but with key qualifications as to degree of specificity in reference both
      to comorbid problems and other executive functions.

PMID- 10582841
TI  - Development of sustained attention assessed using the continuous performance test
      among children 6-15 years of age.
AB  - The Continuous Performance Test (CPT) is a widely used measure of sustained
      attention, which may rely on the efficiency of cognitive inhibition. We examined
      the relationships of age and sex with CPT performance among 341 randomly selected
      school children 6-15 years of age. Multiple regression analyses revealed that the
      hit rate, false alarm rate, and sensitivity of both the undegraded and the
      degraded CPT were associated with age by a quadratic relationship. The age
      development curves for the hit rate and sensitivity were convex, whereas that for
      the false alarm rate was concave. Sex was associated with the hit rate and
      sensitivity on the degraded CPT only. Our findings are consistent with the
      hypothesis that sustained attention develops during the primary school ages. The
      data reported are essential for identifying children with conditions associated
      with sustained attention deficit, such as attention-deficit hyperactivity
      disorder, as well as those at an increased risk for developing schizophrenia.

PMID- 10582842
TI  - The diabetic foot: a personal experience of 50 years.

PMID- 10582843
TI  - Acute complications in the operative treatment of isolated ankle fractures in
      patients with diabetes mellitus.
AB  - Using a computer database, we conducted a retrospective review of all ankle
      fractures treated at our institution from March 1985 to October 1996. Twenty-one
      patients with diabetes mellitus and isolated ankle fractures that were treated
      operatively met all inclusion criteria. Seven had insulin-dependent diabetes, and
      14 had non-insulin-dependent diabetes. A randomly selected control group of 46
      patients without diabetes who also underwent operative treatment of ankle
      fractures during this same time period were matched for age, sex, and fracture
      severity. The complication rate was 43% with 13 complications in nine patients
      with diabetes. There were seven (15.5%) complications in the control group.
      Complications in the diabetic group included seven infections (five deep, two
      superficial) and three losses of fixation. The complications were more severe in
      our diabetic population, requiring seven additional procedures including two
      below-knee amputations; a third patient refused an amputation. No additional
      procedures were required in our control group. All complications in our control
      group resolved with treatment. The relative risk for postoperative complications
      in patients with diabetes who sustained ankle fractures that were treated
      operatively was 2.76 times greater than the control group's (95% confidence
      interval, 1.57-3.97).

PMID- 10582844
TI  - Guidelines for diabetic foot care. The Diabetes Committee of the American
      Orthopaedic Foot and Ankle Society.
AB  - Foot infection is the most common reason for hospital admission of patients with
      diabetes in the United States. Foot ulceration leads to deep infection, sepsis,
      and lower extremity amputation. Prophylactic foot care has been shown to decrease
      patient morbidity, decrease the utilization of expensive resources, and decrease
      the risk for amputation and premature death. The Diabetes Committee of the
      American Orthopaedic Foot and Ankle Society has developed guidelines for
      implementing this type of prophylactic foot care. The guidelines are arranged as
      follows: I. Screening for Patients Who Are at Risk for Developing Diabetic Foot
      Complications A. Risk Factors B. Components of Screening and Examination II.
      Patient Education III. Basic Treatment Guidelines A. Risk Categories B. Nail Care
      C. Ulcer Care IV. Referral Guidelines A. Vascular Surgery Consultation B.
      Orthopaedic Consultation C. Endocrinologist/Diabetologist Consultation D.
      Infectious Disease Consultation E. Radiologic Consultation F. Pedorthic
      Consultation V. Resources.

PMID- 10582845
TI  - American Orthopaedic Foot and Ankle Society shoe survey of diabetic patients.
AB  - A one-page written survey was completed by 402 randomly selected patients with
      diabetes in five cities during a scheduled visit to their endocrinologist.
      Patients averaged 61.5 years of age and had been diagnosed with diabetes for 27.3
      years. This study suggests that approximately 25% of adults with diabetes are at
      risk for developing foot ulcers, the precursor to deep infection leading to lower
      limb amputation. The goal at the inception of this project was to obtain
      benchmark data on the current level of prophylactic foot care being provided to
      adult patients with diabetes. The results of this survey suggest that most
      individuals with diabetes and their physicians are aware of potential diabetic
      foot morbidity, yet very few take advantage of prophylactic protective footware.
      Even fewer are presently taking advantage of benefits established through the
      Medicare Therapeutic Foot Bill. This survey highlights a substantial opportunity
      for improvement in the long-term care of individuals with diabetes.

PMID- 10582846
TI  - Arthroscopic findings associated with the unstable ankle.
AB  - Before lateral ankle stabilization, arthroscopic surgery was performed on 54
      patients (55 ankles) with chronic ankle instability. All patient charts, x-rays,
      operative reports, and surgical videotapes were reviewed. A detailed
      questionnaire was answered by all patients. The study population included 31
      males and 23 females, with a mean age of 31 years (range, 14-64 years). The right
      ankle was involved in 64% of cases. Average follow-up was 9.6 months.
      Arthroscopic surgery was performed using small joint instrumentation including 30
      degrees and 70 degrees 2.7-mm arthroscopes and a 30 degrees 1.9-mm arthroscope.
      At surgery, 51 ankles (93%) had intra-articular abnormalities including loose
      bodies (12), synovitis (38), osteochondral lesions of the talus (9), ossicles
      (14), osteophytes (6), adhesions (8), and chondromalacia (12). The most common
      arthroscopic procedures were synovectomy, removal of loose bodies and ossicles,
      excision and drilling of osteochondral lesions, debridement of the lateral
      gutter, excision of osteophytes, and removal of adhesions and scar tissue. There
      was a 25% incidence of chondral injuries, which differs considerably from the
      results of Taga et al., who found chondral injuries in 95% of ankles with lateral
      instability. Overall, there were excellent or good results in 96% of ankles. The
      incidence of excellent results was lower in the worker's compensation patients
      because of a greater incidence of complaints of pain with activity. There was no
      correlation between the presence of osteochondral lesions or amount of talar tilt
      and results.

PMID- 10582847
TI  - Reconstruction for chronic lateral ankle instability using the palmaris longus
      tendon: is reconstruction of the calcaneofibular ligament necessary?
AB  - The palmaris longus tendon was used to reconstruct the anterior talofibular
      ligament (ATFL) in 27 ankles with chronic lateral instability. The mean age of
      the patients at surgery was 23 years, and the follow-up was more than 2 years.
      The functional evaluation showed excellent or good results in all ankles. Twenty
      seven ankles were divided into two groups according to operative findings: group
      A consisted of 11 ankles with old isolated injury of the ATFL, and group B
      consisted of 16 ankles with old combined injuries of the ATFL and the
      calcaneofibular ligament. There were no significant differences in clinical
      results between group A and group B. The preoperative mean talar tilt angles on
      stress radiograph in group B were significantly larger than those in group A. At
      follow-up, there were no significant differences in the mean talar tilt angles
      between group A and group B. We demonstrate that reconstruction of the
      calcaneofibular ligament along with the ATFL is not necessary for patients with
      chronic combined lateral ligament instability.

PMID- 10582848
TI  - Effect of foot and ankle position on tarsal tunnel compartment pressure.
AB  - Tarsal tunnel intracompartment pressures were determined in 10 fresh-frozen
      normal human adult cadaver specimens. With the foot and ankle held in mild
      plantarflexion and neutral eversion-inversion, mean tarsal tunnel pressure was
      minimal (2 +/- 1 mmHg). However, when the foot and ankle were positioned in full
      eversion, mean tarsal tunnel pressure increased to 32 +/- 5 mmHg (P < or =
      0.005); in full inversion, mean pressure increased to 17 +/- 5 mmHg (P < or =
      0.05). There was no significant difference in mean tarsal tunnel pressure between
      the everted and inverted positions. These results support the hypothesis that
      increased pressure within the tarsal tunnel when the foot is moved into the
      everted or inverted position may aggravate posterior tibial nerve entrapment.
      These findings may also provide an explanation for clinically observed
      aggravation of symptoms in these positions, night pain, and improvement of
      symptoms with neutral immobilization in some patients with tarsal tunnel
      syndrome.

PMID- 10582849
TI  - Mesenchymal cells and growth factors in bunions.
AB  - Bunion formation in adults is an example of bone growth that occurs after physis
      closure. Bone is laid down secondary to mechanical irritation caused by foot
      deformity. It is a mechanism of ectopic bone formation unrelated to physeal
      growth. In this article, bone formation is analyzed using immunohistochemical and
      cell culture techniques. Using markers specific for mesenchymal cells (collagen
      type IIa and fibroblast growth factor receptor 3), a cell population is defined
      in the soft tissues that overlie the bunion and is isolated from explant
      cultures. The cells do not produce bone matrix in culture, and they do not
      express osteoblast-related antigens. Stimulation of the cells by fibroblast
      growth factor (FGF) 2 leads to rapid cell proliferation and phenotype change. The
      cells start to form humps and at the same time express alkaline phosphatase and
      collagen type I. Expression of collagen type IIa and fibroblast growth factor
      receptor 3 ceases. These series of experiments indicate that a specific
      population of mesenchymal cells occurs in the soft tissues that overlie the
      bunion. This population is capable of bone formation when stimulated by FGF, a
      common mediator of inflammatory processes. Thus, FGF stimulation of mesenchymal
      cells in soft tissues that overlie the head of the first metatarsal is a
      potential link between the biomechanical forces that cause hallux valgus and
      bunion formation.

PMID- 10582850
TI  - Tibiotalar motion--effect of fibular displacement and deltoid ligament
      transection: in vitro study.
AB  - The purpose of this study was to quantify tibiotalar translation and rotation
      under various stages of fibular displacement and injury to the syndesmotic and
      deltoid ligaments. Ten unpaired specimens amputated below the knee were studied
      using an unconstrained testing apparatus. The specimens were moved through a
      dorsiflexing and plantarflexing arc of 55 degrees (20 degrees dorsiflexion and 35
      degrees plantarflexion). Dorsiflexion of the intact lower leg was associated with
      an average of 4.2 degrees of external talar rotation, and plantarflexion was
      associated with an average of 1.4 degrees of internal talar rotation. Fibular
      osteotomy and displacement of the distal fibular fragment did not change the
      talar rotation significantly. Additional transection of the deltoid ligament,
      however, decreased external talar rotation significantly, to 1.4 degrees, and
      decreased talar internal rotation to 0.6 degrees. Talar shift was not affected in
      dorsiflexion or plantarflexion by fibular fracture, displacement of the distal
      fibular fragment, or transection of the deltoid ligament. These data may suggest
      that in dorsiflexion or plantarflexion, an intact lateral malleolus is not
      necessary for physiological talar tracking. They further suggest that in a
      fibular fracture with a significant injury to the deltoid ligament, healing of
      the ligament at its resting length is crucial to restoring physiological talar
      rotation.

PMID- 10582851
TI  - Filariasis of the ankle: magnetic resonance imaging.
AB  - Filariasis is a world health problem that is frequently seen in tropical and
      subtropical countries. In endemic areas, the clinical spectrum of extremity
      swelling, lymphangitis, or elephantiasis is usually recognized as filariasis. In
      the United States, diagnosis of the disease may be more difficult because of lack
      of familiarity with this infection. We present a case of filaremic arthropathy of
      the ankle joint and the magnetic resonance imaging (MRI) findings of this
      disease. It is the first reported case of MRI findings in a human patient. MRI
      has been done on animal models with filariasis, and the findings are similar.

PMID- 10582852
TI  - Pseudoaneurysm of the lateral malleolar artery after an ankle sprain: case report
      and review of the literature.
AB  - A pseudoaneurysm of the peroneal artery or one of its branches is rare after
      trauma. The diagnosis is frequently delayed, resulting in substantial morbidity
      to the patient. The infrequent occurrence of this condition has resulted in a
      lack of diagnostic and treatment guidelines. However, when recognized, prompt
      attention involving either surgical ligation or embolization of the injured
      arterial branch is the most reliable method of treatment. Presented is a report
      of a patient who developed a lateral malleolar arterial pseudoaneurysm after an
      ankle sprain, which was treated successfully with aneurysmal excision and
      surgical ligation of the injured arterial branch. A review of the literature and
      treatment recommendations follow.

PMID- 10582854
TI  - Correction augmentation and provisional fixation in proximal metatarsal
      osteotomies using Kirschner wires.

PMID- 10582853
TI  - Arthroscopy of the ankle: analysis of results and indications on a series of 75
      cases.
AB  - The purpose of this study was to evaluate the results of arthroscopy of the
      ankle. Of the 114 arthroscopies of the ankle that we performed between 1991 and
      1996, 13 were for diagnosis, 6 were associated with open surgery, and 10 were
      ankle arthrodeses. We report the results of the remaining 85 therapeutic
      arthroscopies. We identified five groups according to preoperative indications:
      (1) anterolateral synovitis after a sprained ankle (33 cases), (2) sequelae of
      fractured ankles (17 cases), (3) anterior impingement as a result of osteophytes
      (12 cases), (4) loose foreign bodies as a result of avulsion of fragments of bone
      (6 cases), and (5) osteochondral lesions of the talar dome (17 cases). In
      anterolateral synovitis, results were better when the pain followed a single
      sprain than when after chronic instability. In osteochondral lesions of the talar
      dome, results were better in anterolateral lesions than in posteromedial lesions.

PMID- 10582855
TI  - Fetal movement detection: comparison of the Toitu actograph with ultrasound from
      20 weeks gestation.
AB  - OBJECTIVE: This study evaluates the validity of Doppler-detected fetal movement
      by a commercially available monitor and investigates whether characteristics of
      maternal body habitus and the intrauterine environment affect its performance.
      METHODS: Fetal movement was evaluated in normal pregnancies using both ultrasound
      visualization and a fetal actocardiograph (Toitu MT320; Tofa Medical Inc.,
      Malvern, PA). Data were collected for 32 min on 34 fetuses stratified by
      gestational age (20-25 weeks; 28-32 weeks; 35-39 weeks). Fetal and maternal
      characteristics were recorded. Comparisons between ultrasound-detected trunk and
      limb movements and actograph records were conducted based both on 10-s time
      intervals and on detection of individual movements. RESULTS: Time-based
      comparisons indicated agreement between ultrasound and actograph 94.7% of the
      time; this association rose to 98% when movements of less than 1 s duration were
      excluded. Individual movements observed on ultrasound were detected by the
      actograph 91% of the time, and 97% of the time when brief, isolated movements
      were excluded. The overall kappa value for agreement was 0.88. The actograph was
      reliable in detecting periods of quiescence as well as activity. These findings
      did not vary by gestational age. The number of movements detected by the
      actograph, but not the single-transducer ultrasound, significantly increased over
      gestation. Maternal age, parity, weight, height, or body mass index were not
      consistently associated with actograph validity. Characteristics of the uterine
      environment, including placenta location, fetal presentation, and amniotic fluid
      volume also did not affect results. CONCLUSIONS: The Toitu actograph accurately
      detects fetal movement and quiescence from as early as 20 weeks gestation and has
      utility in both clinical and research settings. Actographs are most useful for
      providing objective and quantifiable measures of fetal activity level, including
      number and duration of movements, while visualization through ultrasound is
      necessary for studies of movement quality, source, or mechanics.

PMID- 10582856
TI  - Fetal Down syndrome screening: a cost effectiveness analysis of alternative
      screening programs.
AB  - OBJECTIVE: To compare the efficacy and cost effectiveness of different screening
      programs for fetal Down syndrome (DS). METHODS: Screening tools evaluated
      included maternal age, triple screening (TS), and ultrasound (U/S) for fetal
      markers of DS. Sensitivities used were TS: 55% <35 years, 80% > or = 35 years;
      U/S: 70%. Average regional fees used were TS: $80, U/S: $200, amniocentesis (AM):
      $1,000. Five screening programs were evaluated: 1) <35 years, no screening; > or
      = 35 years, AM; 2) <35 years, TS with AM for screen-positive subjects; > or = 35
      years, AM; 3) all patients, TS with AM for screen-positive subjects; 4) <35
      years, TS followed by U/S for screen-positive women, AM for women with fetal
      markers of DS on U/S; > or = 35 years TS with AM for screen-positive subjects; 5)
      all women, TS followed by U/S for screen-positive women, AM for women with fetal
      markers of DS on U/S. The sensitivity, total cost, cost/case DS detected
      (Cost/DS), AM losses, and residual risk (RR, undetected DS fetuses/women not
      receiving AM) were calculated for each screening program. Population analysis was
      performed using 1988 IL delivery statistics. RESULTS: It was estimated that 260
      cases of DS would occur in the population of 167,654 women (8.4% > or = 35 years
      at delivery). Sensitivity for programs 1-5 was 30, 69, 62, 51, and 36 percent,
      respectively, and cost/DS was 181,000, 203,000, 162,000, 151,000, and 194,000
      dollars, respectively. CONCLUSIONS: DS screening incorporating TS in all patients
      with program #4 and without program #3 selective U/S in women <35 years yield the
      best combination of sensitivity and cost effectiveness while minimizing the
      number of AM-related losses.

PMID- 10582857
TI  - Three-level view of fetal brain imaging in the prenatal diagnosis of congenital
      anomalies.
AB  - OBJECTIVE: To determine whether a systematic stream-lined approach could be
      routinely used in the evaluation of fetal intracranial anatomy. METHODS: Nine
      thousand six hundred uncomplicated pregnancies were evaluated using a three-level
      view of fetal brain imaging. An axial scan, which passed through the level of the
      lateral ventricles, was first obtained. This was followed by a second view
      passing through the cavum septum pellucidum anteriorly, the thalami medially, and
      the 3rd ventricle centrally. Finally, a third view was made passing through the
      posterior fossa. RESULTS: Although the fetus had different presentations, we were
      able to fully image the fetal brain in all three levels in most cases. The
      intracranial anatomy could be scrutinized in most cases. Ninety-six percent of
      abnormal cases (126/133) were diagnosed using Levels I, II, or III independently
      or in combination. CONCLUSIONS: The three-level view provides a comprehensive and
      systematic sonographic approach to the evaluation of the fetal intracranial
      anatomy, and for the diagnosis of anomalous fetal brain development.

PMID- 10582859
TI  - Impact of gestational age at delivery of the economics of triplet pregnancy.
AB  - OBJECTIVE: To establish the charges associated with triplet pregnancies managed
      at a single tertiary center, over a 5-year time period, and to evaluate the
      impact of prematurity on these charges. METHODS: All triplet pregnancies that
      reached at least 20 weeks gestation and received prenatal and neonatal care at
      our center from 1992 to 1996 were included. Charges for these mothers and
      neonates were extracted from two separate hospital billing computer systems,
      encompassing all inpatient, outpatient, technical, and professional charges.
      Linear regression was used to evaluate the relationship between gestational age
      at delivery and total charges. RESULTS: Fifty-five triplet pregnancies were
      included, resulting in the admission of 149 liveborn neonates. The median
      gestational age at delivery was 32.1 weeks. The mean charges per triplet mother
      were: $6,899 (professional), $3,959 (hospital outpatient), and $32,686 (hospital
      inpatient). The mean charges per neonatal sibling set were: $20,107
      (professional) and $124,163 (hospital inpatient). The mean charges per complete
      triplet pregnancy was $187,814 (maternal plus neonatal). There was a significant
      inverse relationship between gestational age at delivery and total charges per
      triplet family, with a decrease of $16,584 for each additional gestational week
      reached (P = 0.006). CONCLUSIONS: Triplet pregnancy charges averaged almost
      $190,000 each, which does not include charges associated with assisted
      reproductive technologies. These charges are almost all related to the expense of
      prolonged neonatal intensive care, and are significantly related to the
      gestational age at delivery. Efforts at containing these costs should focus on
      reducing the incidence of multiple gestation and preventing prematurity.

PMID- 10582858
TI  - Effect of meconium on the hemoglobin-oxygen association curve.
AB  - OBJECTIVE: Our purpose was to determine the effect of meconium-stained amniotic
      fluid on the hemoglobin-oxygen association curve of maternal whole blood.
      METHODS: Whole blood was obtained from term gravidas in active labor. Hemoglobin
      oxygen association curves were generated for blood incubated with meconium vs.
      controls. Oxygen association curves were determined at pH 7.4 and 37 degrees C
      utilizing an automated device consisting of a spectrophotometer cuvette fitted
      with a magnetic stirrer, gas exchange line, and a Clark oxygen electrode. The
      samples were deoxygenated with nitrogen and association curves recorded while
      reoxygenating. Data was analyzed with Sigma Plot and Sigma Stat software.
      Analysis included log transformation, linear regression, and paired t-test.
      RESULTS: Twenty-eight hemoglobin oxygen association curves were generated. In all
      14 pairs, meconium shifted the hemoglobin-oxygen association curve to the right.
      Partial pressures of oxygen required for various degrees of hemoglobin saturation
      were higher in meconium-exposed samples; P50 (30.1+/-0.6 vs. 27.8+/-0.4 mmHg, P <
      0.01); P75 (46.9+/-0.6 vs. 43.1+/-0.5 mmHg, P < .001); P90 (69.2+/-1 vs. 63.3+/-1
      mmHg, P < 0.01). CONCLUSIONS: Meconium-stained amniotic fluid causes a
      statistically significant, but clinically small, right shift in the hemoglobin
      oxygen association curve.

PMID- 10582860
TI  - Effect of cocaine on fetal kidney and bladder function.
AB  - OBJECTIVE: To study the relationship between the bladder cycle and urine output
      by the fetus and the effect of intrauterine exposure to cocaine on both. METHODS:
      Fetal hourly urine production rate and bladder cycle length were measured in two
      groups of pregnant women between 20 and 40 weeks of gestation. A control group of
      59 normal pregnancies were examined longitudinally to establish reference ranges.
      A study group of 36 women with a history of cocaine abuse; urine was positive for
      cocaine only. They were examined once. The diameters of fetal bladder were
      measured to calculate bladder volume and hourly urine output. The bladder cycle
      was the time interval between two successive acts of voiding by the fetus.
      RESULTS: In the normal group, fetal hourly urine production had a positive linear
      correlation with the gestational age, with mean urine volume of 3.38 ml/h at 20
      weeks and 48.36 ml/h at 40 weeks. The bladder cycle also had positive linear
      association with the advancing gestational age, with 26+/-4.76 min at 20 weeks
      and 65.2+/-14.85 min at 40 weeks. When compared with the corresponding
      gestational ages, the cocaine-exposed group showed a significant decrease (P <
      0.0001) in the hourly urine production and the bladder cycle. There was
      significant correlation (r = 0.95, P < 0.001) between bladder cycle and hourly
      urine output in the control group, but not in the cocaine group. CONCLUSION:
      Cocaine decreases fetal urine output and bladder cycle.

PMID- 10582861
TI  - Distribution of apolipoprotein(a) isoforms in normotensive and severe
      preeclamptic women.
AB  - OBJECTIVE: Preeclampsia is a pregnancy-related disorder constituting one of the
      primary causes of worldwide maternal and fetal mortality, but despite intensive
      research its pathogenesis remains unclear. Lipids have been implicated in the
      development of preeclampsia, although this possible association remains
      controversial and not yet fully investigated. This study set out to examine the
      potential association between lipoprotein(a) and the development of severe
      preeclampsia. The focus of this study was to investigate the potential utility of
      apolipoprotein(a) isoforms as possible diagnostic markers for identifying women
      at risk for developing preeclampsia. METHODS: Study participants included a
      control group of nonpregnant female volunteers (n = 59), a group of healthy
      pregnant (normotensive) female volunteers (n = 51), and a group of severe
      preeclamptic female volunteers (n = 59). Serum lipoprotein(a) concentrations were
      measured using double-antibody ELISA methods and were found to be 17.0+/-23.6
      mg/dl among nonpregnant controls (n = 51), 15.9+/-15.8 mg/dl among healthy
      pregnant normotensives (n = 51), and 16.2+/-16.7 mg/dl in the preeclamptic group
      (n = 59). In addition, apolipoprotein (a) isoforms were identified using high
      resolution SDS-agarose electrophoresis followed by immunoblotting. RESULTS: We
      detected no significant differences between the groups studied in the
      distribution of isoforms (Chi-square = 1.21, df = 4, P = 0.89); however, in a 1
      week interval we detected a 42.2% rise in Lp(a) levels as well as a 67.1% rise in
      C-reactive protein concentrations among 10 volunteers in the preeclamptic group
      (median = 9.6; P < 0.05). CONCLUSIONS: Although the exact mechanism of
      pathogenesis continues to elude investigators, our results suggest that
      lipoprotein(a) may act as an acute-phase reactant during preeclampsia. Although
      our results are preliminary, they are consistent with growing evidence
      implicating lipids as among those factors involved in the etiology of
      preeclampsia. Changes in apolipoprotein(a) may be among those important
      biochemical markers that are found to be useful in the early identification of
      high-risk women and warrant further study.

PMID- 10582862
TI  - Antepartum, transabdominal near infrared spectroscopy: feasibility of measuring
      photon migration through the fetal head in utero.
AB  - OBJECTIVE: We report the feasibility of measuring photon migration through the
      fetal head in utero using antepartum, transabdominal, near infrared (NIR)
      spectroscopy. METHODS: We developed a continuous wave (CW) spectrometer that
      incorporates a halogen light source, silicon photodetectors, and a differential
      processing circuit for antepartum, transabdominal, NIR spectroscopy. By placement
      of the light source and photodetector on the midline of the maternal abdomen
      above the fetal head at a separation (approximately 10 cm) large enough for the
      light to propagate through maternal and fetal tissues via multiple scattering
      events before being detected at the surface and the use of filtered illumination
      and detection at wavelengths (760 nm, 850 nm), which coincide with the absorption
      bands of oxygenated and deoxygenated hemoglobin in the NIR window, we performed
      studies to evaluate whether antepartum, transabdominal NIR spectroscopy can
      measure photon migration through the fetal head in utero. RESULTS: The results
      demonstrate that the CW spectrometer we developed can be employed to make NIR
      measurements from the maternal abdomen at a 10 cm source-detector separation,
      with an excellent signal-to-noise ratio. Furthermore, a variety of antepartum,
      transabdominal NIR measurements that we performed on patients undergoing a
      routine nonstress test demonstrate the feasibility of measuring photon migration
      through the fetal head in utero. CONCLUSIONS: Preliminary assessment of
      transabdominal NIR spectroscopy suggests that this technique can enable photon
      migration through the fetal head in utero. This is an important step towards the
      development of this technique for measuring and quantifying fetal cerebral blood
      oxygenation in utero.

PMID- 10582863
TI  - Tuberculous meningitis in pregnancy--implications for mother and fetus: case
      report and literature review.
AB  - The objective of this article is to report an illustrative case of tuberculous
      meningitis in pregnancy and review the recent literature outlining management and
      outcome of this devastating disease. A MEDLINE database search for English and
      French language articles dating back to 1966 was conducted and supplemented by
      reviewing the references of key articles and textbooks. An article was included
      if it described a case of tuberculous meningitis during pregnancy or explained
      the management of this disease. The search yielded a total of 17 articles, case
      reports, and reviews relating to tuberculous meningitis and/or pregnancy. Six
      authors describe cases and outcomes of tuberculous meningitis during pregnancy to
      give a total of 55 cases. Twenty-one patients died of their disease (38.2%),
      while 15 fetal or neonatal deaths have been reported (36.6%). Tuberculous
      meningitis is an insidious disease presenting a diagnostic challenge to even an
      astute practitioner. When recognized early and treated effectively with modern
      antituberculous medication, prognosis for mother and child is greatly improved.

PMID- 10582864
TI  - Successful management of fetal cervical teratoma using the EXIT procedure.
AB  - Fetal cervical teratoma is a cause of polyhydramnios, premature labor, and
      newborn airway obstruction. Formation of a multispecialty team and use of the
      EXIT procedure is essential for survival of the neonate. Without a team, there is
      little hope for fetal survival; mortality will be 80-100%. Early diagnosis and
      planning are essential. Cervical teratomas can contribute to pulmonary
      insufficiency and chondromalacia because of a mass effect in utero and
      underdevelopment of the fetal lungs.

PMID- 10582865
TI  - Activated protein C resistance and lupus anticoagulant in pregnancy.
AB  - Thrombophilias, both inherited and acquired, have been reported to be associated
      with thromboembolic events and severe obstetric complications. This case report
      examines the case of a patient with two thrombophilias, activated protein C
      resistance secondary to Factor V Leiden mutation and lupus anticoagulant.

PMID- 10582866
TI  - Second trimester therapeutic abortion using mifepristone and oral misoprostol in
      a woman with two previous caesarean sections and a cone biopsy.
AB  - Most regimes for medical termination use an antiprogesterone and a vaginal
      prostaglandin. Concern remains about its safety in women with previous caesarean
      births. We present a case of successful therapeutic mid-trimester termination in
      a woman with two previous caesarean births and cervical surgery using an
      antiprogesterone and an oral prostaglandin.

PMID- 10582867
TI  - Nomenclature for macrolide and macrolide-lincosamide-streptogramin B resistance
      determinants.

PMID- 10582868
TI  - Efficacies of high-dose fluconazole plus amphotericin B and high-dose fluconazole
      plus 5-fluorocytosine versus amphotericin B, fluconazole, and 5-fluorocytosine
      monotherapies in treatment of experimental endocarditis, endophthalmitis, and
      pyelonephritis due to Candida albicans.
AB  - We compared the efficacies of fluconazole (Flu), amphotericin B (AmB), and 5
      fluorocytosine (5FC) monotherapies with the combination of Flu plus 5FC and Flu
      plus AmB in a rabbit model of Candida albicans endocarditis, endophthalmitis, and
      pyelonephritis. The dose of Flu used was that which resulted in an area under the
      concentration-time curve in rabbits equivalent to that seen in humans who receive
      Flu at 1,600 mg/day, the highest dose not associated with central nervous system
      toxicity in humans. Quantitative cultures of heart valve vegetations, the choroid
      retina, vitreous humor, and kidney were conducted after 1, 5, 14, and 21 days of
      therapy. All untreated controls died within 6 days of infection; animals treated
      with 5FC monotherapy all died within 18 days. In contrast, 93% of animals in the
      other treatment groups appeared well and survived until they were sacrificed. At
      day 5, the relative decreases in CFU per gram in the vitreous humor were greater
      in groups that received Flu alone and in combination with 5FC or AmB than in
      groups receiving AmB or 5FC monotherapies (P < 0. 005) but were similar
      thereafter. In the choroid-retina, 5FC was the least-active drug. However, there
      were no differences in choroidal fungal densities between the other treatment
      groups. On days 5 and 14 of therapy, fungal densities in kidneys of AmB
      recipients were lower than those resulting from the other therapies (P < 0.001
      and P < or = 0.038, respectively) and AmB-plus-Flu therapy was antagonistic;
      however, all therapies for fungal pyelonephritis were similar by treatment day
      21. While fungal counts in cardiac valves of Flu recipients were similar to those
      of controls on day 5 of therapy and did not change from days 1 to 21, AmB therapy
      significantly decreased valvular CFUs versus Flu at days 5, 14, and 21 (P < 0.005
      at each time point). 5FC plus Flu demonstrated enhanced killing in cardiac
      vegetations compared with Flu or 5FC as monotherapies (P < 0. 03). Similarly, the
      combination of AmB and Flu was more active than Flu in reducing the fungal
      density in cardiac vegetations (P < 0.03). However, as in the kidney, AmB plus
      Flu demonstrated antagonism versus AmB monotherapy in the treatment of C.
      albicans endocarditis (P < 0.05, P = 0.036, and P < 0.008 on days 5, 14, and 21,
      respectively).

PMID- 10582869
TI  - Interaction between fluconazole and amphotericin B in mice with systemic
      infection due to fluconazole-susceptible or -resistant strains of Candida
      albicans.
AB  - The interaction between fluconazole (Flu) and amphotericin B (AmB) was evaluated
      in a murine model of systemic candidiasis for one Flu-susceptible strain (MIC,
      0.5 microg/ml), two strains with intermediate Flu resistance (Flu mid-resistant
      strains) (MIC, 64 and 128 microg/ml), and one highly Flu-resistant strain (MIC,
      512 microg/ml) of Candida albicans. Differences in fungal densities in kidneys of
      infected mice after 24 h of therapy and in survival rates at 62 days of mice
      treated with an antifungal drug or a combination of antifungal drugs for 4 days
      were compared. For the Flu-susceptible and Flu mid-resistant strains, the
      combination of Flu and AmB was antagonistic, as shown by both quantitative
      culture results and survival. The interaction was additive for the highly Flu
      resistant strain. These results suggest that the combination of Flu and AmB
      should be used with caution in infections due to fungi that are usually
      susceptible to both antifungal agents and as empirical antifungal drug therapy.

PMID- 10582870
TI  - Pharmacokinetics of cefepime in patients with thermal burn injury.
AB  - The pharmacokinetics of cefepime following administration of a single 2-g dose
      were evaluated for 12 adult patients with thermal burn injury and suspected or
      documented infection. Serial blood and urine samples for cefepime concentration
      determination were obtained for 24 h following drug administration. Serum and
      urine cefepime concentrations were determined by high-performance liquid
      chromatography and serum concentrations were fit to a two-compartment
      pharmacokinetic model. Mean (standard deviation [SD]) age, actual body weight
      (ABW), percent total body surface area burned, and days postburn at the time of
      study were 41 (13) years, 84 (22) kg, 36 (17)%, and 9 (3) days, respectively.
      Mean (SD) measured creatinine clearance (CL(CR)), total clearance (CL(T)), renal
      clearance (CL(R)), alpha phase half-life, beta phase half-life, and volume of
      distribution at steady state (V(SS)) were 135 (31) ml/min, 8.8 (2.4) liters/h,
      8.1 (2.0) liters/h, 0.33 (0.14) h, 2.8 (0.6) h, and 0.43 (0.10) liters/kg ABW,
      respectively. Cefepime CL(T) and CL(R) in burn patients were similar to
      previously reported values for healthy volunteers when normalized by CL(CR).
      Stepwise multiple regression was used to associate CL(T) with CL(CR) and days
      postburn (r(2) = 0.861), CL(R) with CL(CR) and days postburn (r(2) = 0.773),
      nonrenal clearance with percent third-degree (% 3 degrees ) burn and albumin
      concentration (r(2) = 0.550), and V(SS) only with % 3 degrees burn (r(2) =
      0.624). Simulated steady-state serum concentrations obtained by using the
      patients' pharmacokinetic parameters exceeded the susceptibility interpretive
      standard (breakpoint) of cefepime for at least 60% of the dosing interval with
      dosing regimens of 1 g every 8 h (q8h), 2 g q8h, and 2 g q12h. Despite
      differences in pharmacokinetic parameters between our patients and healthy
      volunteers, it appears that these dosing regimens may be adequate in similar burn
      patients.

PMID- 10582871
TI  - Pharmacokinetics of [(14)C]abacavir, a human immunodeficiency virus type 1 (HIV
      1) reverse transcriptase inhibitor, administered in a single oral dose to HIV-1
      infected adults: a mass balance study.
AB  - Abacavir (1592U89) ((-)-(1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2
      cyclopentene- 1-m ethanol) is a 2'-deoxyguanosine analogue with potent activity
      against human immunodeficiency virus (HIV) type 1. To determine the metabolic
      profile, routes of elimination, and total recovery of abacavir and metabolites in
      humans, we undertook a phase I mass balance study in which six HIV-infected male
      volunteers ingested a single 600-mg oral dose of abacavir including 100 microCi
      of [(14)C]abacavir. The metabolic disposition of the drug was determined through
      analyses of whole-blood, plasma, urine, and stool samples, collected for a period
      of up to 10 days postdosing, and of cerebrospinal fluid (CSF), collected up to 6
      h postdosing. The radioactivity from abacavir and its two major metabolites, a 5'
      carboxylate (2269W93) and a 5'-glucuronide (361W94), accounted for the majority
      (92%) of radioactivity detected in plasma. Virtually all of the administered dose
      of radioactivity (99%) was recovered, with 83% eliminated in urine and 16%
      eliminated in feces. Of the 83% radioactivity dose eliminated in the urine, 36%
      was identified as 361W94, 30% was identified as 2269W93, and 1.2% was identified
      as abacavir; the remaining 15.8% was attributed to numerous trace metabolites, of
      which <1% of the administered radioactivity was 1144U88, a minor metabolite. The
      peak concentration of abacavir in CSF ranged from 0.6 to 1.4 microg/ml, which is
      8 to 20 times the mean 50% inhibitory concentration for HIV clinical isolates in
      vitro (0.07 microg/ml). In conclusion, the main route of elimination for oral
      abacavir in humans is metabolism, with <2% of a dose recovered in urine as
      unchanged drug. The main route of metabolite excretion is renal, with 83% of a
      dose recovered in urine. Two major metabolites, the 5'-carboxylate and the 5'
      glucuronide, were identified in urine and, combined, accounted for 66% of the
      dose. Abacavir showed significant penetration into CSF.

PMID- 10582872
TI  - Comparison of in vitro activities of camptothecin and nitidine derivatives
      against fungal and cancer cells.
AB  - The activities of a series of camptothecin and nitidine derivatives that might
      interact with topoisomerase I were compared against yeast and cancer cell lines.
      Our findings reveal that structural modifications to camptothecin derivatives
      have profound effects on the topoisomerase I-drug poison complex in cells.
      Although the water-soluble anticancer agents topotecan and irinotecan are less
      active than the original structure, camptothecin, other derivatives or analogs
      with substitutions that increase compound solubility have also increased
      antifungal activities. In fact, a water-soluble prodrug appears to penetrate into
      the cell and release its active form; the resulting effect in complex with
      Cryptococcus neoformans topoisomerase I is a fungicidal response and also potent
      antitumor activity. Some of the compounds that are not toxic to wild-type yeast
      cells are extremely toxic to the yeast cells when the C. neoformans topoisomerase
      I target is overexpressed. With the known antifungal mechanism of a camptothecin
      topoisomerase I complex as a cellular poison, these findings indicate that drug
      entry may be extremely important for antifungal activity. Nitidine chloride
      exhibits antifungal activity against yeast cells through a mechanism(s) other
      than topoisomerase I and appears to be less active than camptothecin analogs
      against tumor cells. Finally, some camptothecin analogs exhibit synergistic
      antifungal activity against yeast cells in combination with amphotericin B in
      vitro. Our results suggest that camptothecin and/or nitidine derivatives can
      exhibit potent antifungal activity and that the activities of camptothecin
      derivatives with existing antifungal drugs may be synergistic against pathogenic
      fungi. These new compounds, which exhibit potent antitumor activities, will
      likely require further structural changes to find more selective activity against
      fungal versus mammalian cells to hold promise as a new class of antifungal
      agents.

PMID- 10582873
TI  - Azithromycin as treatment for disseminated Mycobacterium avium complex in AIDS
      patients.
AB  - This multicenter, randomized, dose-ranging study was performed to determine the
      safety and efficacy of two different doses of azithromycin for treating
      disseminated Mycobacterium avium complex (MAC) in patients with AIDS. Eighty
      eight AIDS patients with symptoms and blood cultures consistent with disseminated
      MAC were treated with 600 or 1,200 mg of azithromycin daily for 6 weeks; 62
      patients completed the entire 6 weeks of study. Of note, this study was done
      prior to the time when combination antiretroviral or anti-MAC regimens were the
      standard of care. Over the 6-week study period, symptomatic improvement was noted
      in both dose groups. Microbiological responses were comparable, with mean
      decreases of 1. 5 and 2.0 log CFU/ml in the high- and low-dose groups,
      respectively. Sterilization of blood cultures occurred in 54% of samples;
      patients with lower baseline colony counts were more likely to achieve culture
      negativity. Resistance developed in one patient. Gastrointestinal symptoms were
      the most common side effects and were more frequent in patients receiving 1,200
      mg. Azithromycin is a useful alternative treatment for disseminated MAC infection
      in AIDS patients. Symptomatic improvement correlates with measurable decreases in
      mycobacterial load.

PMID- 10582874
TI  - Activities of the oxazolidinones linezolid and eperezolid in experimental intra
      abdominal abscess due to Enterococcus faecalis or vancomycin-resistant
      Enterococcus faecium.
AB  - The in vivo effectiveness of oxazolidinones eperezolid (U-100592) and linezolid
      (U-100766) against one strain each of Enterococcus faecalis and vancomycin
      resistant Enterococcus faecium was examined in a rat model of intra-abdominal
      abscess. MICs of both drugs were 2 microg/ml for each strain. At doses of 25
      mg/kg of body weight twice daily intravenously or orally, linezolid produced
      small but statistically significant reductions in abscess bacterial density for
      E. faecalis. The reduction in viable cells observed would not likely be
      clinically relevant. Eperezolid was ineffective at this dose. At a dosage of 100
      mg/kg/day, linezolid treatment led to an approximately 100-fold reduction in
      viable cells per gram of abscess. Against E. faecium infections, intravenous
      eperezolid and oral linezolid were effective, reducing densities approximately 2
      log(10) CFU/g. Both oxazolidinones demonstrated activity against enterococci in
      this model. However, results were modest with the dosing regimens employed.

PMID- 10582875
TI  - Activities of tobramycin and six other antibiotics against Pseudomonas aeruginosa
      isolates from patients with cystic fibrosis.
AB  - The in vitro activity of tobramycin was compared with those of six other
      antimicrobial agents against 1,240 Pseudomonas aeruginosa isolates collected from
      508 patients with cystic fibrosis during pretreatment visits as part of the phase
      III clinical trials of tobramycin solution for inhalation. The tobramycin MIC at
      which 50% of isolates are inhibited (MIC(50)) and MIC(90) were 1 and 8 microg/ml,
      respectively. Tobramycin was the most active drug tested and also showed good
      activity against isolates resistant to multiple antibiotics. The isolates were
      less frequently resistant to tobramycin (5.4%) than to ceftazidime (11.1%),
      aztreonam (11.9%), amikacin (13.1%), ticarcillin (16.7%), gentamicin (19.3%), or
      ciprofloxacin (20.7%). For all antibiotics tested, nonmucoid isolates were more
      resistant than mucoid isolates. Of 56 isolates for which the tobramycin MIC was >
      or = 16 microg/ml and that were investigated for resistance mechanisms, only 7
      (12.5%) were shown to possess known aminoglycoside-modifying enzymes; the
      remaining were presumably resistant by an incompletely understood mechanism often
      referred to as "impermeability."

PMID- 10582876
TI  - Potentiation of vancomycin-induced histamine release by muscle relaxants and
      morphine in rats.
AB  - The intravenous injection of vancomycin sometimes causes anaphylactoid reactions,
      in which histamine release may play a major role. These reactions are more
      frequently manifested when vancomycin is injected into anesthetized patients. We
      examined the vancomycin-induced histamine release and the interaction of
      vancomycin with muscle relaxants or opioid in rats. In an in vitro study with rat
      peritoneal mast cells, treatment with vancomycin at concentrations of greater
      than 1.25 mM produced significant histamine release. Tubocurarine, vecuronium,
      pancuronium, succinylcholine, and morphine up to concentrations of 0.25, 1, 5,
      30, and 5 mM, respectively, produced no significant histamine release. However,
      the nonsignificant histamine release induced by 0.5 mM vancomycin was clearly
      enhanced by combining vancomycin with any of these agents. In the in vivo study,
      the intravenous injection of vancomycin significantly increased the plasma
      histamine levels in rats when vancomycin was injected at 200 mg/kg of body weight
      (63.2 +/- 34.0 ng/ml [mean +/- standard deviation]) but not when it was injected
      at 100 mg/kg (30.8 +/- 20.2 ng/ml) compared with that in the saline-treated rats
      (22.5 +/- 11.4 ng/ml). Although the subcutaneous administration of morphine (10
      mg/kg) never increased the plasma histamine levels, the intravenous injection of
      vancomycin (100 mg/kg) 30 min after this morphine treatment markedly increased
      the plasma histamine levels (56.0 +/- 26.9 ng/ml). These findings provide
      experimental evidence that the combination of muscle relaxants or an opioid with
      vancomycin may increase the risk of anaphylactoid reactions by enhancing the
      release of histamine.

PMID- 10582877
TI  - Hydroxyurea potentiates the antiherpesvirus activities of purine and pyrimidine
      nucleoside and nucleoside phosphonate analogs.
AB  - Hydroxyurea has been shown to potentiate the anti-human immunodeficiency virus
      activities of 2',3'-dideoxynucleoside analogs such as didanosine. We have now
      evaluated in vitro the effect of hydroxyurea on the antiherpesvirus activities of
      several nucleoside analogs (acyclovir [ACV], ganciclovir [GCV], penciclovir
      [PCV], lobucavir [LBV], (R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine [H2G],
      and brivudin and nucleoside phosphonate analogs (cidofovir [CDV] and adefovir
      [ADV]). When evaluated in cytopathic effect (CPE) reduction assays, hydroxyurea
      by itself had little effect on CPE progression and potentiated in a
      subsynergistic (herpes simplex virus type 1 [HSV-1]) to synergistic (HSV-2)
      fashion the antiviral activities of ACV, GCV, PCV, LBV, H2G, ADV, and CDV.
      Hydroxyurea also caused marked increases in the activities of ACV, GCV, PCV, LBV,
      and H2G (compounds that depend for their activation on a virus-encoded thymidine
      kinase [TK]) against TK-deficient (TK(-)) HSV-1. In fact, in combination with
      hydroxyurea the 50% effective concentrations of these compounds for inhibition of
      TK(-) HSV-1-induced CPE decreased from values of 20 to > or = 100 microg/ml (in
      the absence of hydroxyurea) to values of 1 to 5 microg/ml (in the presence of
      hydroxyurea at 25 to 100 microg/ml). When evaluated in a single-cycle virus yield
      reduction assay, hydroxyurea at a concentration of 100 microg/ml inhibited
      progeny virus production by 60 to 90% but had little effect on virus yield at a
      concentration of 25 microg/ml. Under these assay conditions hydroxyurea still
      elicited a marked potentiating effect on the antiherpesvirus activities of GCV
      and CDV, but this effect was less pronounced than that in the CPE reduction
      assay. It is conceivable that the potentiating effect of hydroxyurea stems from a
      depletion of the intracellular deoxynucleoside triphosphate pools, thus favoring
      the triphosphates of the nucleoside analogues (or the diphosphates of the
      nucleoside phosphonate analogues) in their competition with the natural
      nucleotides at the viral DNA polymerase level. The possible clinical implications
      of these findings are discussed.

PMID- 10582878
TI  - Expanded-spectrum nonnucleoside reverse transcriptase inhibitors inhibit
      clinically relevant mutant variants of human immunodeficiency virus type 1.
AB  - A research program targeted toward the identification of expanded-spectrum
      nonnucleoside reverse transcriptase inhibitors which possess increased potency
      toward K103N-containing mutant human immunodeficiency virus (HIV) and which
      maintain pharmacokinetics consistent with once-a-day dosing has resulted in the
      identification of the 4-cyclopropylalkynyl-4-trifluoromethyl-3, 4-dihydro
      2(1H)quinazolinones DPC 961 and DPC 963 and the 4-cyclopropylalkenyl-4
      trifluoromethyl-3, 4-dihydro-2(1H)quinazolinones DPC 082 and DPC 083 for clinical
      development. DPC 961, DPC 963, DPC 082, and DPC 083 all exhibit low-nanomolar
      potency toward wild-type virus, K103N and L100I single-mutation variants, and
      many multiply amino acid-substituted HIV type 1 mutants. This high degree of
      potency is combined with a high degree of oral bioavailability, as demonstrated
      in rhesus monkeys and chimpanzees, and with plasma serum protein binding that can
      result in significant free levels of drug.

PMID- 10582879
TI  - Activities of poloxamer CRL-1072 against Mycobacterium avium in macrophage
      culture and in mice.
AB  - Earlier studies reported that certain large hydrophobic poloxamer surfactants
      were able to inhibit the growth of Mycobacterium avium-M. intracellulare complex
      (MAI) in broth and to produce synergistic enhancement of the activity of
      rifampin. CRL-1072 was synthesized to have an optimal structure for antimicrobic
      effects and greater purity. Its MIC for MAI in broth was greater than 100
      microg/ml. Surprisingly, its MIC for MAI growing in human U937 monocytoid cells
      was much lower, 5 microg/ml. A still lower concentration, 0.1 microg/ml, produced
      synergistic enhancement of the activities of clarithromycin, rifampin, amikacin,
      streptomycin, and clindamycin, but not isoniazid, against MAI infecting
      monocytoid cells. Mice tolerated injection of doses of CRL-1072 as high as 125
      mg/kg of body weight. Pharmacokinetic analysis revealed that the copolymer had an
      elimination half-life of 60 h and suggested dosing regimens that might produce
      therapeutic concentrations in tissue. In a mouse model of acute MAI infection,
      CRL-1072 significantly enhanced the bactericidal activities of clarithromycin and
      rifampin when it was administered at 1.0 mg/kg intravenously (i.v.) three times
      per week. CRL-1072 given i.v. or orally also enhanced the bactericidal activity
      of clindamycin against MAI.

PMID- 10582880
TI  - Biochemical characterization of novel tetrahydrofuranyl 1beta-methylcarbapenems:
      stability to hydrolysis by renal dehydropeptidases and bacterial beta-lactamases,
      binding to penicillin binding proteins, and permeability properties.
AB  - The biochemical properties of tetrahydrofuranyl (THF) carbapenems, carbapenems
      with THF substituents, were evaluated with respect to enzyme stability, binding
      to penicillin-binding proteins (PBPs), and penetration into gram-negative
      organisms. THF carbapenems showed increased stability to hog renal
      dehydropeptidases (DHPs) compared to that of imipenem or meropenem and were more
      stable to human DHP than imipenem (<10% hydrolysis compared to that for
      imipenem). THF carbapenems were stable to hydrolysis by all serine beta
      lactamases tested. CL 191,121, a prototype THF carbapenem, was more stable to
      hydrolysis by carbapenem-hydrolyzing serine beta-lactamases such as IMI-1 and Sme
      1 than imipenem, with a relative k(cat) value of <20% for imipenem. Similar to
      imipenem and meropenem, THF carbapenems were not stable to the metallo beta
      lactamases CcrA and L1. However, CL 191,121 bound to all Staphylococcus aureus
      PBPs at concentrations that were less than or equal to the MICs. The THF
      carbapenems bound to PBPs from Escherichia coli and Pseudomonas aeruginosa, with
      the highest affinities being for PBPs 2 and 4, as noted with imipenem. The
      affinities for PBPs 1a and 1b in E. coli were reduced for the THF carbapenems
      compared to that for imipenem, even though the MICs of the THF carbapenems for E.
      coli strains were lower than those of imipenem. The penetrability of the THF
      carbapenems into Serratia marcescens S6, which produces the Sme-1 carbapenem
      hydrolyzing beta-lactamase, was 2.4 to 7.8 times less than that of imipenem.
      Compounds CL 190,294 and CL 188,624 showed good penetrability, with permeability
      coefficient values comparable to those of the rapidly penetrating agents
      cephaloridine, imipenem, meropenem, and biapenem. Decreased penetration into wild
      type P. aeruginosa was suggested by the high MICs of the THF carbapenems (MICs,
      16 to 32 microg/ml), despite equivalent or better binding to P. aeruginosa PBPs
      than that of imipenem. However, the MICs of the THF carbapenems for wild-type P.
      aeruginosa compared to that for an OprD2 mutant generally varied no more than 2
      fold, but those of imipenem and other carbapenems differed 16-fold. These data
      indicated that THF carbapenems do not appear to enter through protein OprD2. In
      conclusion, the THF carbapenems exhibited stability to hydrolysis by renal DHPs
      and serine beta-lactamases, exhibited strong binding to essential PBPs from E.
      coli and S. aureus, and penetrated gram-negative enteric bacteria at rates
      comparable to those for meropenem and biapenem.

PMID- 10582881
TI  - Efficacy of the triazole SCH 56592 against Leishmania amazonensis and Leishmania
      donovani in experimental murine cutaneous and visceral leishmaniases.
AB  - Current therapy for leishmaniasis is unsatisfactory. Efficacious and safe oral
      therapy would be ideal. We examined the efficacy of SCH 56592, an investigational
      triazole antifungal agent, against cutaneous infection with Leishmania
      amazonensis and visceral infection with Leishmania donovani in BALB/c mice. Mice
      were infected in the ear pinna and tail with L. amazonensis promastigotes and
      were treated with oral SCH 56592 or intraperitoneal amphotericin B for 21 days.
      At doses of 60 and 30 mg/kg/day, SCH 56592 was highly efficacious in treating
      cutaneous disease, and at a dose of 60 mg/kg/day, it was superior to amphotericin
      B at a dose of 1 mg/kg/day. The means of tail lesion sizes were 0.32 +/- 0.12,
      0.11 +/- 0.06, 0.17 +/- 0.07, and 0.19 +/- 0.08 mm for controls, SCH 56592 at 60
      and 30 mg/kg/day, and amphotericin B recipients, respectively (P = 0.0003, 0.005,
      and 0.01, respectively). Parasite burden in draining lymph nodes confirmed these
      efficacy findings. In visceral leishmaniasis due to L. donovani infection, mice
      treated with SCH 56592 showed a 0.5- to 1-log-unit reduction in parasite burdens
      in the liver and the spleen compared to untreated mice. Amphotericin B at 1
      mg/kg/day was superior to SCH 56592 in the treatment of visceral infection, with
      a 2-log-unit reduction in parasite burdens in both the liver and spleen. These
      studies indicate very good activity of SCH 56592 against cutaneous leishmaniasis
      due to L. amazonensis infection and, to a lesser degree, against visceral
      leishmaniasis due to L. donovani infection in susceptible BALB/c mice.

PMID- 10582882
TI  - Proteoglycan and collagen biochemical variations during fluoroquinolone-induced
      chondrotoxicity in mice.
AB  - Although fluoroquinolone antibacterials have a broad therapeutic use, with a
      relatively low incidence of severe side effects, they have been reported to
      induce lesions in the cartilage of growing animals by a mechanism that remains
      unclear. This study was undertaken to determine the potentially deleterious
      effect of a high dose of pefloxacin (400 mg/kg of body weight) on two main
      constituents of cartilage in mice, i.e., proteoglycans and collagen. Variations
      in levels of proteoglycan anabolism measured by in vivo [(35)S]sulfate
      incorporation into cartilage and oxidative modifications of collagen assessed by
      detection of carbonyl derivatives were monitored after administration of
      pefloxacin. Treatment of mice with 1 day of pefloxacin treatment significantly
      decreased the rate of biosynthesis of proteoglycan for the first 24 h. However,
      no difference was observed after 48 h. The decrease in proteoglycan synthesis was
      accompanied by a marked drop in serum sulfate concentration and a concomitant
      increase in urinary sulfate excretion. The decrease in proteoglycan synthesis,
      also observed ex vivo, may suggest a direct effect of pefloxacin on this process,
      rather than it being a consequence of a low concentration of sulfate. On the
      other hand, treatment with pefloxacin for 10 days induced oxidative damage to
      collagen. In conclusion, this study demonstrates, for the first time, that
      pefloxacin administration to mice leads to modifications in the metabolism and
      integrity of extracellular proteins, such as collagen and proteoglycans, which
      may account for the side effects observed. These results offer new insights to
      explain quinolone-induced disorders in growing articular cartilage.

PMID- 10582883
TI  - High-dose isoniazid therapy for isoniazid-resistant murine Mycobacterium
      tuberculosis infection.
AB  - The use of isoniazid (INH) for the treatment of INH-resistant Mycobacterium
      tuberculosis infection has been controversial. The purpose of the present studies
      was to determine if there is a dose response with INH for INH-susceptible M.
      tuberculosis Erdman (ATCC 35801), and whether high-dose INH (100 mg/kg of body
      weight) was more effective than standard-dose INH (25 mg/kg) for therapy of
      tuberculosis infections caused by INH-resistant mutants of M. tuberculosis
      Erdman. Six-week-old CD-1 mice were infected with approximately 10(7) viable
      mycobacteria. Early control groups of infected but untreated mice were euthanized
      by CO(2) inhalation 1 week later when treatment was initiated. INH (25, 50, 75,
      and 100 mg/kg) was given by gavage 5 days/week for 4 weeks. Late control groups
      of untreated mice and treated mice were sacrificed 2 days after the last dose of
      drug. Spleens and right lungs were removed aseptically and homogenized, and
      viable cell counts were determined by titration on 7H10 agar plates. In the next
      study, INH at 100 mg/kg was compared to INH at 25 mg/kg against an isogenic
      mutant of M. tuberculosis Erdman (INH MIC, 2 microg/ml) and the parent strain.
      This mutant was found to have a mutation in the KatG protein (Phe to Leu at
      position 183). In the first study, there was no dose response with increasing
      doses of INH. In the second study, there was no significant difference between
      the reduction of viable cell counts for mice treated with INH at 100 mg/kg and
      that for mice treated with INH at 25 mg/kg (parent or INH-resistant mutant).
      These preliminary results suggest that INH may be useful in combination therapy
      of M. tuberculosis infections caused by low-level INH-resistant organisms (INH
      MICs, 0.2 to 5 microg/ml) and that higher doses of INH are unlikely to be more
      efficacious than the standard 300-mg/day dose.

PMID- 10582884
TI  - Incidence and characterization of integrons, genetic elements mediating multiple
      drug resistance, in avian Escherichia coli.
AB  - Antibiotic resistance among avian bacterial isolates is common and is of great
      concern to the poultry industry. Approximately 36% (n = 100) of avian, pathogenic
      Escherichia coli isolates obtained from diseased poultry exhibited multiple
      antibiotic resistance to tetracycline, oxytetracycline, streptomycin,
      sulfonamides, and gentamicin. Clinical avian E. coli isolates were further
      screened for the presence of markers for class 1 integrons, the integron
      recombinase intI1 and the quaternary ammonium resistance gene qacEDelta1, in
      order to determine the contribution of integrons to the observed multiple
      antibiotic resistance phenotypes. Sixty-three percent of the clinical isolates
      were positive for the class 1 integron markers intI1 and qacEDelta1. PCR analysis
      with the conserved class 1 integron primers yielded amplicons of approximately 1
      kb from E. coli isolates positive for intI1 and qacEDelta1. These PCR amplicons
      contained the spectinomycin-streptomycin resistance gene aadA1. Further
      characterization of the identified integrons revealed that many were part of the
      transposon Tn21, a genetic element that encodes both antibiotic resistance and
      heavy-metal resistance to mercuric compounds. Fifty percent of the clinical
      isolates positive for the integron marker gene intI1 as well as for the
      qacEDelta1 and aadA1 cassettes also contained the mercury reductase gene merA.
      The correlation between the presence of the merA gene with that of the integrase
      and antibiotic resistance genes suggests that these integrons are located in
      Tn21. The presence of these elements among avian E. coli isolates of diverse
      genetic makeup as well as in Salmonella suggests the mobility of Tn21 among
      pathogens in humans as well as poultry.

PMID- 10582885
TI  - Multilocus genotypes and DNA fingerprints Do not predict variation in azole
      resistance among clinical isolates of Candida albicans.
AB  - If variation in azole resistance is due to inherent differences in strains of
      Candida albicans, as a predominantly clonal organism, then correlation between
      multilocus genotypes and drug resistance would be expected. A sample of 81
      clinical isolates from patients infected with human immunodeficiency virus in
      Toronto, Canada, plus 3 reference isolates were genotyped at 16 loci, distributed
      on all linkage groups, by means of oligonucleotide hybridizations specific for
      each of the alleles at each locus. These multilocus genotypes were significantly
      correlated with DNA fingerprints obtained with the species-specific probe 27A,
      indicating widespread linkage disequilibrium in the genome. There were 64
      multilocus diploid genotypes and 77 DNA fingerprint types delineated in this
      sample. Neither the multilocus genotyping nor DNA fingerprinting alone identified
      all of the 81 types identified by the combination of these two methods.
      Multilocus genotypes were not predictive of fluconazole resistance, suggesting
      that resistance is gained or lost too quickly to be predicted by linkage with
      neutral markers.

PMID- 10582886
TI  - A new method for assessing metronidazole susceptibility of Giardia lamblia
      trophozoites.
AB  - A quantitative, simple, and rapid assay has been developed to assess Giardia
      lamblia trophozoite sensitivity to metronidazole [1-(2-hydroxyetyl)-2-methyl-5
      nitroimidazole] (MTZ). This new assay utilizes the ability of live (surviving)
      trophozoites to take up oxygen after have been exposed to MTZ. The effect of MTZ
      on oxygen uptake was compared with its effect on viability as evaluated by a
      culture method and morphological assays. Oxygen uptake rates decreased in
      trophozoites treated with MTZ, and this effect was drug concentration dependent:
      O(2) uptake rates went from 3.04 microM O(2) min(-1) per 10(6) cells to 0.72
      microM O(2) min(-1) per 10(6) cells with increasing drug concentration (0.15 to
      0.6 mM) in the preincubation. Concentrations of the drug which inhibited oxygen
      uptake by 28 to 76% in trophozoites killed from 39 to 82% of trophozoites, as
      evaluated by the culture method, and altered the morphology of 21 to 86% of the
      trophozoites. Thus, the trophozoites killed by MTZ are nonmotile cells and do not
      take up oxygen. A good correlation was found between the inhibitory effects of
      MTZ, as evaluated by oxygen uptake, and cellular viability. Similar 50%
      inhibitory concentrations were obtained: 0.33 mM by oxygen uptake, 0. 26 mM by
      the culture method, and 0.35 mM by morphological criteria. Oxygen uptake appears
      to be a good indicator of parasite viability. Therefore, this new method can
      provide a convenient means to assess MTZ susceptibility in G. lamblia and can be
      applied for screening potential antigiardial agents.

PMID- 10582887
TI  - The pfmdr1 gene is associated with a multidrug-resistant phenotype in Plasmodium
      falciparum from the western border of Thailand.
AB  - On the western border of Thailand, Plasmodium falciparum has become resistant to
      almost all antimalarial agents. The molecular basis of resistance in these
      parasite populations has not been well characterized. This study assessed genetic
      polymorphisms in the pfmdr1 gene in 54 parasites collected from the western
      border of Thailand to determine the relationship of pfmdr1 copy number and codon
      mutations with parasite sensitivities to mefloquine, chloroquine, halofantrine,
      quinine, and artesunate assessed in vitro. A point mutation at codon 86
      (resulting in a change of Asn to Tyr) was associated with a significantly lower
      50% inhibitory concentration (IC(50)) of mefloquine (median, 9 ng/ml versus 52.4
      ng/ml; P = 0.003). Overall 35% of the isolates (19 of 54) had an increase in
      pfmdr1 copy number, and all 19 carried the wild-type allele at codon 86.
      Increased pfmdr1 copy number was associated with higher IC(50)s of mefloquine (P
      = 0.04) and artesunate (P = 0.005), independent of polymorphism at codon 86. The
      relationship between pfmdr1 and resistance to structurally distinct antimalarial
      agents confirms the presence of a true multidrug-resistant phenotype.

PMID- 10582889
TI  - Automated thermal cycling is superior to traditional methods for nucleotide
      sequencing of bla(SHV) genes.
AB  - Genes encoding SHV-1 and SHV-2 were sequenced by different methods. Nucleotide
      sequencing of the coding strand by standard dideoxy-chain termination methods
      resulted in errors in the interpretation of the nucleotide sequence and the
      derived amino acid sequence in two main regions which corresponded to nucleotide
      and amino acid changes that had been reported previously. The automated thermal
      cycling method was clearly superior and consistently resulted in the correct
      sequences for these genes.

PMID- 10582888
TI  - Proton-pumping-ATPase-targeted antifungal activity of a novel conjugated styryl
      ketone.
AB  - NC1175 (3-[3-(4-chlorophenyl)-2-propenoyl]-4-[2-(4-chlorophenyl)vinyle ne]-1-
      ethyl-4-piperidinol hydrochloride) is a novel thiol-blocking conjugated styryl
      ketone that exhibits activity against a wide spectrum of pathogenic fungi.
      Incubation of NC1175 with various concentrations of cysteine and glutathione
      eliminated its antifungal activity in a concentration-dependent fashion. Since
      NC1175 is a lipophilic compound that has the potential to interact with
      cytoplasmic membrane components, we examined its effect on the membrane-located
      proton-translocating ATPase (H(+)-ATPase) of yeast (Candida albicans, Candida
      krusei, Candida guilliermondii, Candida glabrata, and Saccharomyces cerevisiae)
      and Aspergillus (Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus,
      and Aspergillus nidulans) species. The glucose-induced acidification of external
      medium due to H(+)-ATPase-mediated expulsion of intracellular protons by these
      fungi was measured in the presence of several concentrations of the drug. NC1175
      (12.5 to 50 microM) inhibited acidification of external medium by Candida,
      Saccharomyces, and Aspergillus species in a concentration-dependent manner.
      Vanadate-inhibited hydrolysis of ATP by membrane fractions of C. albicans was
      completely inhibited by 50 microM NC1175, suggesting that the target of action of
      NC1175 in these fungi may include H(+)-ATPase.

PMID- 10582890
TI  - Determination of zidovudine triphosphate intracellular concentrations in
      peripheral blood mononuclear cells from human immunodeficiency virus-infected
      individuals by tandem mass spectrometry.
AB  - Nucleoside reverse transcriptase inhibitors (NRTIs) used against the human
      immunodeficiency virus (HIV) need to be activated intracellularly to their
      triphosphate moiety to inhibit HIV replication. Intracellular concentrations of
      these NRTI triphosphates, especially zidovudine triphosphate (ZDV-TP), are
      relatively low (low numbers of femtomoles per 10(6) cells) in HIV-infected
      patient peripheral blood mononuclear cells. Recently, several methods have used
      either high-performance liquid chromatography (HPLC) or solid-phase extraction
      (SPE) coupled with radioimmunoassay to obtain in vivo measurements of ZDV-TP. The
      limit of detection (LOD) by these methods ranged from 20 to 200 fmol/10(6) cells.
      In this report, we describe the development of a method to determine
      intracellular ZDV-TP concentrations in HIV-infected patients using SPE and HPLC
      with tandem mass spectrometry for analysis. The LOD by this method is 4.0
      fmol/10(6) cells with a linear concentration range of at least 4 orders of
      magnitude from 4. 0 to 10,000 fmol/10(6) cells. In hispanic HIV-infected
      patients, ZDV-TP was detectable even when the sampling time after drug
      administration was 15 h. Intracellular ZDV-TP concentrations in these patients
      ranged from 41 to 193 fmol/10(6) cells. The low LOD obtained with this method
      will provide the opportunity for further in vivo pharmacokinetic studies of
      intracellular ZDV-TP in different HIV-infected populations. Furthermore, this
      methodology could be used to perform simultaneous detection of two or more NRTIs,
      such as ZDV-TP and lamivudine triphosphate.

PMID- 10582891
TI  - Gatifloxacin activity against quinolone-resistant gyrase: allele-specific
      enhancement of bacteriostatic and bactericidal activities by the C-8-methoxy
      group.
AB  - Antibacterial activities of gatifloxacin (AM1155), a new C-8-methoxy
      fluoroquinolone, and two structurally related compounds, AM1121 and
      ciprofloxacin, were studied with an isogenic set of ten quinolone-resistant, gyrA
      (gyrase) mutants of Escherichia coli. To compare the effect of each mutation on
      resistance, the mutant responses were normalized to those of wild-type cells.
      Alleles exhibiting the most resistance to growth inhibition mapped in alpha-helix
      4, which is thought to lie on a GyrA dimer surface that interacts with DNA. The C
      8-methoxy group lowered the resistance due to these mutations more than it
      lowered resistance arising from several gyrA alleles located outside alpha-helix
      4. These data are consistent with alpha-helix 4 being a distinct portion of the
      quinolone-binding site of GyrA. A helix change to proline behaved more like
      nonhelix alleles, indicating that helix perturbation differs from the other
      changes at helix residues. Addition of a parC (topoisomerase IV) resistance
      allele revealed that the C-8-methoxy group also facilitated attack of
      topoisomerase IV. When lethal effects were measured at a constant multiple of the
      minimum inhibitory concentration for each fluoroquinolone to normalize for
      differences in bacteriostatic action, gatifloxacin was more potent than the C-8-H
      compounds, both in the presence and absence of protein synthesis (an exception
      was observed when alanine was substituted for aspartic acid at position 82).
      Collectively, these data show that the C-8-methoxy group contributes to the
      enhanced activity of gatifloxacin against resistant gyrase and wild-type
      topoisomerase IV.

PMID- 10582892
TI  - Characterization of a Pseudomonas aeruginosa efflux pump contributing to
      aminoglycoside impermeability.
AB  - Pseudomonas aeruginosa can employ many distinct mechanisms of resistance to
      aminoglycoside antibiotics; however, in cystic fibrosis patients, more than 90%
      of aminoglycoside-resistant P. aeruginosa isolates are of the impermeability
      phenotype. The precise molecular mechanisms that produce aminoglycoside
      impermeability-type resistance are yet to be elucidated. A subtractive
      hybridization technique was used to reveal gene expression differences between
      PAO1 and isogenic, spontaneous aminoglycoside-resistant mutants of the
      impermeability phenotype. Among the many genes found to be up-regulated in these
      laboratory mutants were the amrAB genes encoding a recently discovered efflux
      system. The amrAB genes appear to be the same as the recently described mexXY
      genes; however, the resistance profile that we see in P. aeruginosa is very
      different from that described for Escherichia coli with mexXY. Direct evidence
      for AmrAB involvement in aminoglycoside resistance was provided by the deletion
      of amrB in the PAO1-derived laboratory mutant, which resulted in the restoration
      of aminoglycoside sensitivity to a level nearly identical to that of the parent
      strain. Furthermore, transcription of the amrAB genes was shown to be up
      regulated in P. aeruginosa clinical isolates displaying the impermeability
      phenotype compared to a genotypically matched sensitive clinical isolate from the
      same patient. This suggests the possibility that AmrAB-mediated efflux is a
      clinically relevant mechanism of aminoglycoside resistance. Although it is
      unlikely that hyperexpression of AmrAB is the sole mechanism conferring the
      impermeability phenotype, we believe that the Amr efflux system can contribute to
      a complex interaction of molecular events resulting in the aminoglycoside
      impermeability-type resistance phenotype.

PMID- 10582893
TI  - Antibiotic-induced cell wall fragments of Staphylococcus aureus increase
      endothelial chemokine secretion and adhesiveness for granulocytes.
AB  - Antibiotics release inflammatory fragments, such as lipoteichoic acid (LTA) and
      peptidoglycan (PG), from the cell wall of Staphylococcus aureus. In this study,
      we exposed S. aureus cultures to a number of beta-lactam antibiotics (imipenem,
      flucloxacillin, and cefamandole) and protein synthesis-inhibiting antibiotics
      (erythromycin, clindamycin, and gentamicin) and investigated whether supernatants
      of these cultures differ in their capacity to stimulate endothelial cells (EC).
      After 24 h of incubation, endothelial adhesiveness for leukocytes, surface
      expression of various adhesion molecules, and secretion of the chemokines
      interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) were measured.
      Supernatants of beta-lactam-exposed cultures (designated beta-lactam
      supernatants) enhanced the adhesiveness of EC for granulocytes, whereas those of
      protein synthesis-inhibiting antibiotic-exposed cultures (designated protein
      synthesis-inhibitor supernatants) did not. This hyperadhesiveness coincided with
      a higher intercellular adhesion molecule-1 expression on the surface of the
      stimulated EC. In addition, EC stimulated with beta-lactam supernatants secreted
      significantly higher concentrations of the chemokines IL-8 and MCP-1 than those
      stimulated with protein synthesis-inhibitor supernatants. The finding that the
      concentrations of LTA and PG in beta-lactam supernatants were much higher than
      those in protein synthesis-inhibitor supernatants suggests that the observed
      differences in stimulatory effect between these supernatants are a result of
      differences in the release of cell wall fragments, although the presence of other
      stimulatory factors in the supernatants cannot be excluded. In conclusion, our
      results argue for a release of LTA and PG from S. aureus after exposure to beta
      lactam antibiotics that enhances the development of a systemic inflammatory
      response by stimulating EC such that adhesiveness for granulocytes is increased
      and large amounts of IL-8 and MCP-1 are secreted.

PMID- 10582894
TI  - Activities of a nitrofurazone-containing urinary catheter and a silver hydrogel
      catheter against multidrug-resistant bacteria characteristic of catheter
      associated urinary tract infection.
AB  - The in vitro inhibitory activity of a nitrofurazone-coated urinary catheter (NFC)
      against 86 recently obtained susceptible and multidrug-resistant (MDR) clinical
      isolates of Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii,
      Staphylococcus aureus, coagulase-negative staphylococci, and Enterococcus
      faecium, which are species implicated in catheter-associated urinary tract
      infection and which traditionally have been susceptible to nitrofuran
      derivatives, was determined using an agar diffusion assay. In a subset of these
      strains, the activity of the NFC was compared with that of a silver hydrogel
      urinary catheter (SHC), and the durability of each catheter's inhibitory activity
      was assessed during serial daily transfers of catheter segments to fresh culture
      plates. Except for vancomycin-resistant E. faecium, the NFC was active against
      all isolates tested and showed comparable inhibition zones with susceptible and
      MDR strains of each species. In contrast, the SHC inhibited only certain
      staphylococci (P < 0.01 versus the NFC), and among these strains, the SHC
      produced smaller inhibition zones than did the NFC (P < 0.01). Inhibition was
      evident for up to 5 days with the NFC, but for only 1 day (if at all) with the
      SHC (P < 0.01). These data document that, for most genera which traditionally
      have been susceptible to nitrofuran derivatives, the NFC remains active against
      contemporary MDR isolates. They also demonstrate that the in vitro antibacterial
      activity of the NFC is markedly superior to that of the SHC in several respects.
      Thus, the NFC shows promise for clinical use in the current era of MDR bacteria.

PMID- 10582895
TI  - In vitro activities of SCH27899 alone and in combination with 17 other
      antimicrobial agents.
AB  - SCH27899, an everninomicin antibiotic, was tested for its in vitro activity
      against 718 bacterial isolates representing 27 species. The Enterobacteriaceae
      and nonenteric gram-negative bacilli were resistant to > or = 8.0 microg/ml, but
      all others were inhibited by < or = 1.0 microg/ml. When tested in combination
      with 17 other antimicrobial agents against 110 strains, SCH27899 demonstrated no
      significant antagonism or synergy. Consequently, combination therapy is not
      contraindicated.

PMID- 10582896
TI  - Activity of gemifloxacin against penicillin- and ciprofloxacin-resistant
      Streptococcus pneumoniae displaying topoisomerase- and efflux-mediated resistance
      mechanisms.
AB  - Nine penicillin-resistant Streptococcus pneumoniae clinical isolates from
      Northern Ireland, resistant to ciprofloxacin (MICs, 2 to 64 microg/ml) through
      topoisomerase- and/or reserpine-sensitive efflux mechanisms, were highly
      susceptible to gemifloxacin (MICs, 0.03 to 0. 12 microg/ml). Two strains
      (requiring a ciprofloxacin MIC of 64 microg/ml) carried known quinolone
      resistance mutations in parC, parE, and gyrB, resulting in S79F, D435V, and E474K
      changes, respectively. Thus, gemifloxacin is active against clinical strains
      exhibiting altered topoisomerase and efflux phenotypes.

PMID- 10582897
TI  - Comparative in vitro antimicrobial activities of the newly synthesized quinolone
      HSR-903, sitafloxacin (DU-6859a), gatifloxacin (AM-1155), and levofloxacin
      against Mycobacterium tuberculosis and Mycobacterium avium complex.
AB  - We compared the in vitro antimycobacterial activity of a new fluoroquinolone, HSR
      903, with strong activity against gram-positive cocci with those of levofloxacin
      (LVFX), sitafloxacin (STFX), and gatifloxacin (GFLX). The MICs of the quinolones
      for Mycobacterium tuberculosis and Mycobacterium avium complex were in the order
      STFX approximately GFLX < LVFX <== HSR-903 and STFX <== GFLX <== HSR-903 <==
      LVFX, respectively. HSR-903 effectively eliminated intramacrophagial M.
      tuberculosis, as did LVFX, and exhibited bacteriostatic effects against M.
      tuberculosis replicating in type II alveolar cells.

PMID- 10582899
TI  - High-level aminoglycoside resistance in the beta-hemolytic group G Streptococcus
      isolate BM2721.
AB  - The beta-hemolytic group G Streptococcus clinical isolate BM2721 was resistant to
      high levels of aminoglycosides by synthesis of AAC(6')-APH(2"), APH(3')-III, and
      ANT(6) modifying enzymes. The corresponding genes were found to be adjacent as
      the result of a recombination event between Tn4001 and Tn5405, two transposons
      originating in staphylococci.

PMID- 10582898
TI  - Oral bioavailability and pharmacokinetics of trovafloxacin in patients with AIDS.
AB  - Trovafloxacin pharmacokinetics were evaluated in 12 subjects with AIDS. By using
      a randomized design, single 200-mg doses of oral trovafloxacin and intravenous
      alatrofloxacin were administered. The mean absolute bioavailability was 91%. The
      pharmacokinetics of trovafloxacin when administered orally as the active form or
      intravenously as the prodrug (alatrofloxacin) are not altered in subjects with
      AIDS compared to those in healthy adults.

PMID- 10582900
TI  - Characterization of a Mycobacterium smegmatis mutant lacking penicillin binding
      protein 1.
AB  - The ponA gene of Mycobacterium smegmatis encodes a 95-kDa penicillin binding
      protein, PBP1, that is similar to PBP1s of Mycobacterium tuberculosis and
      Mycobacterium leprae. Transposon disruption of ponA in M. smegmatis resulted in a
      PBP1-deficient mutant that was sensitive to beta-lactam antibiotics, was more
      permeable to glycine, and grew slowly in liquid culture.

PMID- 10582901
TI  - Distribution of beta-lactamases in actinomycetes.
AB  - The distribution of beta-lactamase activities in a collection of actinomycete
      strains was surveyed. Six of 127 strains were found to produce beta-lactamase.
      This low frequency was in contrast to the case with Streptomyces species. The
      producing strains were not related phylogenetically. MICs of benzylpenicillin did
      not correlate with beta-lactamase production.

PMID- 10582902
TI  - Genetic characterization of antimicrobial resistance in Canadian isolates of
      Salmonella serovar Typhimurium DT104.
AB  - PCR was used to identify antibiotic resistance determinants in 31 Canadian
      Salmonella serovar Typhimurium DT104 isolates. Genes encoding resistance to
      ampicillin (pse1 or blaP1), chloramphenicol (pasppflo-like), streptomycin
      spectinomycin (aadA2), sulfonamide (sulI), and tetracycline [tet(G)] were mapped
      to a 13-kb region of DNA of one isolate. Two copies of sulI were identified and
      mapped to the 3' end of either pse1 or aadA2 integrons. The two integrons were
      separated by the pasppflo-like gene and the tet(G) gene. The kanamycin resistance
      determinant (aphA-1) was present on a 2.0-MDa plasmid (five isolates) or on the
      chromosome (three isolates).

PMID- 10582903
TI  - Antimicrobial resistance of diarrheagenic Escherichia coli isolated from children
      under the age of 5 years from Ifakara, Tanzania.
AB  - Diarrhea caused by multidrug-resistant bacteria is an important public health
      problem among children in developing countries. The prevalence and antimicrobial
      susceptibility of diarrheagenic Escherichia coli in 346 children under 5 years of
      age in Ifakara, Tanzania, were studied. Thirty-eight percent of the cases of
      diarrhea were due to multiresistant enterotoxigenic E. coli, enteroaggregative E.
      coli, or enteropathogenic E. coli. Strains of all three E. coli categories showed
      high-level resistance to ampicillin, tetracycline, co-trimoxazole, and
      chloramphenicol but were highly susceptible to quinolones. Guidelines for
      appropriate use of antibiotics in developing countries need updating.

PMID- 10582904
TI  - Population pharmacokinetics of lamivudine in adult human immunodeficiency virus
      infected patients enrolled in two phase III clinical trials.
AB  - Lamivudine population pharmacokinetics were investigated by using nonlinear mixed
      effect modelling (NONMEM) analysis of data from 394 human immunodeficiency virus
      (HIV)-infected patients treated with lamivudine (150 to 300 mg every 12 h) in two
      large, phase III clinical efficacy-safety trials, NUCA3001 and NUCA3002. Analyses
      of 1,477 serum lamivudine concentration determinations showed that population
      estimates for lamivudine oral clearance (CL/F; 25.1 liters/h) and volume of
      distribution (V/F; 128 liters) were similar to values previously reported for HIV
      infected patients in phase I pharmacokinetic studies. Lamivudine CL/F was
      significantly influenced by the covariates creatinine clearance and weight and
      not affected by age, Centers for Disease Control and Prevention (CDC)
      classification, CD4(+) cell count, HIV type 1 (HIV-1) RNA PCR, or gender and race
      when CL/F was corrected for differences in patient weight. The population
      estimate for lamivudine V/F was not significantly influenced by the covariates
      gender, race, age, weight, renal function, HIV-1 RNA PCR, or CDC classification
      and CD4(+) cell count when creatinine clearance was included with CL/F in the
      model. Lamivudine disposition was significantly influenced by renal function.
      However, as only three patients had an estimated creatinine clearance of <60
      ml/min, dosage adjustments for patients with impaired renal function should not
      be determined based on the population parameters derived in this analysis.

PMID- 10582905
TI  - Comparative bacteriostatic and bactericidal activities of cefodizime against
      Borrelia burgdorferi sensu lato.
AB  - The MIC and MSC (minimum spirocheticidal concentration) and killing rate for
      Borrelia burgdorferi, the etiological agent of Lyme disease, were assessed for
      cefodizime in comparison with ceftriaxone, minocycline, azithromycin,
      roxithromycin, and ciprofloxacin. The range of cefodizime MICs was greater than
      those of azithromycin and roxithromycin but comparable to those of ceftriaxone
      and minocycline. The MSCs were 1 to 2 dilutions higher than the MICs of all of
      the tested compounds. The killing curves of cefodizime and ceftriaxone showed
      parallel courses. In conclusion, cefodizime exerted an activity comparable to
      that of ceftriaxone against B. burgdorferi.

PMID- 10582906
TI  - Beneficial effect of adjunctive azithromycin in treatment of mucoid Pseudomonas
      aeruginosa pneumonia in the murine model.
AB  - While a time-kill methodology noted no appreciable improvement in bactericidal
      activity with the addition of azithromycin (AZM) to a ceftazidime (CAZ) regimen,
      data from the murine pneumonia model showed that the addition of AZM
      significantly improved survival compared to treatment with CAZ alone. These data
      suggest that AZM might be a useful adjunctive therapy in the management of
      pneumonia resulting from mucoid isolates of Pseudomonas aeruginosa.

PMID- 10582907
TI  - Novel streptomycin and spectinomycin resistance gene as a gene cassette within a
      class 1 integron isolated from Escherichia coli.
AB  - The aadA genes, encoding resistance to streptomycin and spectinomycin, have been
      found as gene cassettes in different gram-negative and gram-positive bacterial
      species. The present study has revealed the sequence of a new gene, aadA5,
      integrated as a gene cassette together with the trimethoprim resistance gene dfr7
      in a class 1 integron. The integron was located on a plasmid and was identified
      in a pathogenic porcine Escherichia coli isolate.

PMID- 10582908
TI  - In vitro activities of ketolide HMR3647, macrolides, and other antibiotics
      against Lactobacillus, Leuconostoc, and Pediococcus isolates.
AB  - Testing of susceptibility to 13 antibiotics was performed with 90 isolates of
      Lactobacillus, Leuconostoc, and Pediococcus. MICs at which 90% of the isolates
      tested were inhibited by HMR3647, erythromycin, and ciprofloxacin were 0.015,
      0.125 and 32 microg/ml, respectively. The penicillin MIC was > or = 16 microg/ml
      against 26.2% of the studied Lactobacillus sp. isolates and 50% of Lactobacillus
      plantarum. HMR3647 showed excellent activity against these genera.

PMID- 10582909
TI  - Rigorous assessment of palliative care revisited. Wisdom and compassion are
      needed when evidence is lacking.

PMID- 10582910
TI  - Vaccination policies: individual rights v community health. We can't afford to be
      half hearted about vaccination programmes.

PMID- 10582911
TI  - Learning from the NHS. NHS continues to be an important test bed for reform in
      health care.

PMID- 10582912
TI  - Medicine must change to serve an ageing society. Eradicate age discrimination and
      increase resources.

PMID- 10582913
TI  - Cardiac troponins in chest pain can help in risk stratification.

PMID- 10582915
TI  - First human chromosome is sequenced

PMID- 10582914
TI  - Study shows growing inequalities in health in Britain.

PMID- 10582916
TI  - Papillomavirus DNA in smear test raises risk of cervical cancer

PMID- 10582918
TI  - In brief

PMID- 10582917
TI  - England plans measures to cut outpatient waits.

PMID- 10582919
TI  - Agencies urge end to global trade restrictions on essential medicines

PMID- 10582920
TI  - No redress for failed sterilisations.

PMID- 10582921
TI  - Israel health minister bans AIDS campaign promoting condoms.

PMID- 10582922
TI  - Family compensated for death after illegible prescription.

PMID- 10582923
TI  - Survey finds that 1 in 10 children has a mental disorder.

PMID- 10582924
TI  - High coffee intake increasesrisk of miscarriage

PMID- 10582925
TI  - Babies sleeping with parents: case-control study of factors influencing the risk
      of the sudden infant death syndrome. CESDI SUDI research group.
AB  - OBJECTIVE: To investigate the risks of the sudden infant death syndrome and
      factors that may contribute to unsafe sleeping environments. DESIGN: Three year,
      population based case-control study. Parental interviews were conducted for each
      sudden infant death and for four controls matched for age, locality, and time of
      sleep. SETTING: Five regions in England with a total population of over 17
      million people. SUBJECTS: 325 babies who died and 1300 control infants. RESULTS:
      In the multivariate analysis infants who shared their parents' bed and were then
      put back in their own cot had no increased risk (odds ratio 0.67; 95% confidence
      interval 0.22 to 2.00). There was an increased risk for infants who shared the
      bed for the whole sleep or were taken to and found in the parental bed (9.78;
      4.02 to 23.83), infants who slept in a separate room from their parents (10.49;
      4.26 to 25.81), and infants who shared a sofa (48.99; 5.04 to 475.60). The risk
      associated with being found in the parental bed was not significant for older
      infants (>14 weeks) or for infants of parents who did not smoke and became non
      significant after adjustment for recent maternal alcohol consumption (>2 units),
      use of duvets (>4 togs), parental tiredness (infant slept </=4 hours for longest
      sleep in previous 24 hours), and overcrowded housing conditions (>2 people per
      room of the house). CONCLUSIONS: There are certain circumstances when bed sharing
      should be avoided, particularly for infants under four months old. Parents
      sleeping on a sofa with infants should always be avoided. There is no evidence
      that bed sharing is hazardous for infants of parents who do not smoke.

PMID- 10582927
TI  - The SCOFF questionnaire: assessment of a new screening tool for eating disorders.

PMID- 10582926
TI  - Increase in congenital rubella occurrence after immunisation in Greece:
      retrospective survey and systematic review.
AB  - OBJECTIVE: To describe the events leading to the epidemic of congenital rubella
      syndrome in Greece in 1993 after a major rubella epidemic. DESIGN: Retrospective
      survey and systematic review. SETTING: Greece (population 10 million), 1950-95.
      SUBJECTS: Children, adolescents, and women of childbearing age. RESULTS: Around
      1975 in Greece the measles, mumps, and rubella vaccine started being given to
      boys and girls aged 1 year without policies to attain high vaccination coverage
      and to protect adolescents and young women. During the 1980s, vaccination
      coverage for rubella remained consistently below 50%, and the proportion of
      pregnant women susceptible to rubella gradually increased. In 1993 the incidence
      of rubella in young adults was higher than in any previous epidemic year. The
      epidemic of congenital rubella that followed, with 25 serologically confirmed
      cases (24.6 per 100 000 live births), was probably the largest such epidemic in
      Greece after 1950. CONCLUSIONS: With low vaccination coverage, the immunisation
      of boys and girls aged 1 year against rubella carries the theoretical risk of
      increasing the occurrence of congenital rubella. This phenomenon, which has not
      been previously reported, occurred in Greece.

PMID- 10582928
TI  - A small united nations

PMID- 10582929
TI  - Socioeconomic inequalities in mortality and importance of perceived control:
      cohort study.

PMID- 10582930
TI  - Cost effectiveness analysis of inhaled anticholinergics for acute childhood and
      adolescent asthma.

PMID- 10582931
TI  - Unforeseen consequences

PMID- 10582932
TI  - Does hospital at home for palliative care facilitate death at home? Randomised
      controlled trial.
AB  - OBJECTIVE: To evaluate the impact on place of death of a hospital at home service
      for palliative care. DESIGN: Pragmatic randomised controlled trial. SETTING:
      Former Cambridge health district. PARTICIPANTS: 229 patients referred to the
      hospital at home service; 43 randomised to control group (standard care), 186
      randomised to hospital at home. INTERVENTION: Hospital at home versus standard
      care. MAIN OUTCOME MEASURES: Place of death. RESULTS: Twenty five (58%) control
      patients died at home compared with 124 (67%) patients allocated to hospital at
      home. This difference was not significant; intention to treat analysis did not
      show that hospital at home increased the number of deaths at home. Seventy three
      patients randomised to hospital at home were not admitted to the service.
      Patients admitted to hospital at home were significantly more likely to die at
      home (88/113; 78%) than control patients. It is not possible to determine whether
      this was due to hospital at home itself or other characteristics of the patients
      admitted to the service. The study attained less statistical power than initially
      planned. CONCLUSION: In a locality with good provision of standard community care
      we could not show that hospital at home allowed more patients to die at home,
      although neither does the study refute this. Problems relating to recruitment,
      attrition, and the vulnerability of the patient group make randomised controlled
      trials in palliative care difficult. While these difficulties have to be
      recognised they are not insurmountable with the appropriate resourcing and
      setting.

PMID- 10582933
TI  - National electronic Library for Health (NeLH)

PMID- 10582934
TI  - Instant wisdom

PMID- 10582936
TI  - Dangers for surgeons

PMID- 10582937
TI  - ABC of complementary medicine. Complementary medicine and the patient.

PMID- 10582938
TI  - It's all in the definition

PMID- 10582935
TI  - Management of Crohn's disease.

PMID- 10582939
TI  - Improving NHS performance: human behaviour and health policy.

PMID- 10582941
TI  - Plagiarism

PMID- 10582940
TI  - Calculating the number needed to treat for trials where the outcome is time to an
      event.

PMID- 10582942
TI  - Improving access to medical care. General practice cooperatives are coping well.

PMID- 10582943
TI  - North-South research in developing countries must respond to community's
      priorities.

PMID- 10582944
TI  - Managing drug misuse in general practice. Republic of Ireland has set up scheme
      to regulate methadone prescribing by GPs.

PMID- 10582945
TI  - Stillbirth as risk factor for depression and anxiety in subsequent pregnancy.
      References were misinterpreted.

PMID- 10582946
TI  - Clinical review overstates genetic case for schizophrenia.

PMID- 10582947
TI  - Folic acid supplementation before pregnancy remains inadequate.

PMID- 10582948
TI  - Legal safeguards for audit process are a bad idea.

PMID- 10582949
TI  - Obstacles in organisation of service delivery reduce potential of epidural
      analgesia.

PMID- 10582950
TI  - Ethnic and sex differences in selection for admission to medical school. Don't
      let's discriminate against academic brilliance.

PMID- 10582951
TI  - Study did not mention preregistration year in general practice.

PMID- 10582952
TI  - Increase in staff numbers may reduce doctors' "presenteeism".

PMID- 10582954
TI  - GMC agrees a change in culture is needed

PMID- 10582953
TI  - Sir melville arnott

PMID- 10582956
TI  - Pocket PDR: medical book system

PMID- 10582955
TI  - Dictionary of health economics

PMID- 10582958
TI  - Netlines

PMID- 10582957
TI  - The whole brain atlas

PMID- 10582959
TI  - Hollywood hails a tobacco whistleblower

PMID- 10582960
TI  - Eating disorders

PMID- 10582961
TI  - Time for a sinister practice

PMID- 10582963
TI  - Places to die and sleep, and "the forces of conservatism"

PMID- 10582962
TI  - The lords medical

PMID- 10582965
TI  - Inconsistent immunisation policies increase incidence of congenital rubella
      syndrome

PMID- 10582964
TI  - Where should babies sleep-alone or with parents?

PMID- 10582966
TI  - Hospital at home scheme did not increase likelihood of dying at home

PMID- 10582967
TI  - SCOFF questionnaire identifies people with eating disorders

PMID- 10582968
TI  - Low perceived control contributes substantially to socioeconomic differences in
      mortality

PMID- 10582969
TI  - Adding anticholinergics in acute childhood and adolescent asthma is cost
      effective

PMID- 10582970
TI  - Ischemic stroke subtypes: a population-based study of incidence and risk factors.
AB  - BACKGROUND AND PURPOSE: There is scant population-based information on incidence
      and risk factors for ischemic stroke subtypes. METHODS: We identified all 454
      residents of Rochester, Minn, with a first ischemic stroke between 1985 and 1989
      from the Rochester Epidemiology Project medical records linkage system. We used
      Stroke Data Bank criteria to assign infarct subtypes after reviewing medical
      records and brain imaging. We adjusted average annual incidence rates by age and
      sex to the US 1990 population and compared the age-adjusted frequency of stroke
      risk factors across ischemic stroke subtypes. RESULTS: Age- and sex-adjusted
      incidence rates (per 100 000 population) were as follows: large-vessel cervical
      or intracranial atherosclerosis with >50% stenosis, 27; cardioembolic, 40;
      lacuna, 25; uncertain cause, 52; other or uncommon cause, 4. Sex differences in
      incidence rates were detected only for atherosclerosis with stenosis (47 [95% CI,
      34 to 61] for men; 12 [95% CI, 7 to 17] for women). There was no difference in
      prior transient ischemic attack and hypertension among subtypes, and diabetes was
      not more common among patients with lacunar infarction than other common
      subtypes. CONCLUSIONS: The age-adjusted incidence rate of stroke due to stenosis
      of the large cervicocephalic vessels is nearly 4 times higher for men than for
      women. There is no association between preceding transient ischemic attack and
      stroke mechanism. Diabetes and hypertension are not more common among patients
      with lacunae. Age- and sex-adjusted incidence rates for ischemic stroke subtypes
      in this population can be compared with similarly determined rates from other
      populations.

PMID- 10582971
TI  - Incidence rates of first-ever ischemic stroke subtypes among blacks: a population
      based study.
AB  - BACKGROUND AND PURPOSE: The aim of this study was to determine the incidence
      rates of ischemic stroke subtypes among blacks. METHODS: Hospitalized and
      autopsied cases of stroke and transient ischemic attack among the 187 000 blacks
      in the 5-county region of greater Cincinnati/northern Kentucky From January 1,
      1993, through June 30, 1993, were identified. Incidence rates were age- and sex
      adjusted to the 1990 US population. Subtype classification was performed after
      extensive review of all available imaging, laboratory data, clinical information,
      and past medical history. Case-control comparisons of risk factors were made with
      age-, race-, and sex-matched control subjects. RESULTS: Annual incidence rates
      per 100 000 for first-ever ischemic stroke subtypes among blacks were as follows:
      uncertain cause, 103 (95% confidence interval [CI], 80 to 126); cardioembolic, 56
      (95% CI, 40 to 73); small-vessel infarct, 52 (95% CI, 36 to 68); large vessel, 17
      (95% CI, 8 to 26); and other causes, 17 (95% CI, 9 to 26). Of the patients
      diagnosed with an infarct of uncertain cause, 31% underwent echocardiography, 45%
      underwent carotid ultrasound, and 48% had neither. Compared with age-, race-, and
      sex- (proportionally) matched control subjects from the greater
      Cincinnati/northern Kentucky region, the attributable risk of hypertension for
      all causes of first-ever ischemic stroke is 27% (95% CI, 7 to 43); for diabetes,
      21% (95% CI, 11 to 29); and for coronary artery disease, 9% (95% CI, 2 to 16).
      For small-vessel ischemic stroke, the attributable risk of hypertension is 68%
      (95% CI, 31 to 85; odds ratio [OR], 5.0), and the attributable risk of diabetes
      is 30% (95% CI, 10 to 45; OR, 4.4). For cardioembolic stroke, the attributable
      risk of diabetes is 25% (95% CI, 4 to 41; OR, 3.1). CONCLUSIONS: Stroke of
      uncertain cause is the most common subtype of ischemic stroke among blacks.
      Cardioembolic stroke and small-vessel stroke are the most important, identifiable
      causes of first-ever ischemic stroke among blacks. The incidence rates of
      cardioembolic and large-vessel stroke are likely underestimated because
      noninvasive testing of the carotid arteries and echocardiography were not
      consistently obtained in stroke patients at the 18 regional hospitals. Most small
      vessel strokes in blacks can be attributed to hypertension and diabetes.

PMID- 10582972
TI  - Incidence and occurrence of total (first-ever and recurrent) stroke.
AB  - BACKGROUND AND PURPOSE: It has recently been hypothesized that the figure of
      approximately half a million strokes substantially underestimates the actual
      annual stroke burden for the United States. The majority of previously reported
      studies on the epidemiology of stroke used relatively small and homogeneous
      population-based stroke registries. This study was designed to estimate the
      occurrence, incidence, and characteristics of total (first-ever and recurrent)
      stroke by using a large administrative claims database representative of all 1995
      US inpatient discharges. METHODS: We used the Nationwide Inpatient Sample of the
      Healthcare Cost and Utilization Project, release 4, which contains approximately
      20% of all 1995 US inpatient discharges. Because the accuracy of International
      Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) coding
      is suboptimal, we performed a literature review of ICD-9-CM 430 to 438 validation
      studies. The pooled results from the literature review were used to make
      appropriate adjustments in the analysis to correct for some of the inaccuracies
      of the diagnostic codes. RESULTS: There were 682 000 occurrences of stroke with
      hospitalization (95% CI 660 000 to 704 000) and an estimated 68 000 occurrences
      of stroke without hospitalization. The overall incidence rate for occurrence of
      total stroke (first-ever and recurrent) was 259 per 100 000 population (age- and
      sex-adjusted to 1995 US population). Incidence rates increased exponentially with
      age and were consistently higher for males than for females. CONCLUSIONS: We
      conservatively estimate that there were 750 000 first-ever or recurrent strokes
      in the United States during 1995. This new figure emphasizes the importance of
      preventive measures for a disease that has identifiable and modifiable risk
      factors and for the development of new and improved treatment strategies and
      infrastructures that can reduce the consequences of stroke.

PMID- 10582973
TI  - Stable stroke occurrence despite incidence reduction in an aging population:
      stroke trends in the danish monitoring trends and determinants in cardiovascular
      disease (MONICA) population.
AB  - BACKGROUND AND PURPOSE: A stroke register was established at the Glostrup
      Population Studies in 1982 with the objective to monitor stroke occurrence in the
      population continuously during a 10-year period and contribute data to the WHO
      Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) Project.
      The purpose of the current analysis was to estimate temporal trends in stroke
      occurrence. METHODS: All stroke events in the study population were ascertained
      and validated according to standardized criteria outlined by the WHO MONICA
      Project. The study population comprised all subjects > or = 25 years of age.
      Stroke was defined by the clinical presentation. A total of 5262 stroke events in
      >2 million person-years were analyzed. Age-adjusted rates for first-ever stroke
      and for all stroke events were calculated and temporal trends estimated by means
      of Poisson regression. RESULTS: The overall annual stroke attack rate per 100,000
      person-years in the age range > or = 25 years was 272 in men and 226 in women.
      Age-adjusted stroke attack rates decreased among men by 3.9% per year and by 4.1%
      among women. Age-adjusted stroke incidence rates declined by 2.9% in men and by
      3. 1% in women. The trends were statistically significant in both sexes. However,
      the proportion of elderly people in the study population increased during the
      time period of the study. Hence the numbers of stroke victims in the population
      remained largely unaltered. CONCLUSIONS: Decreasing age-adjusted stroke incidence
      rates point to a reduction of stroke risk during the time period of the study.
      Cardiovascular prevention, in particular improved hypertension control, is
      believed to have contributed to the incidence reduction. However, the burden of
      stroke on the healthcare system did not substantially diminish. The gain likely
      achieved from reduction of preventable risk factors was almost counterbalanced by
      population aging.

PMID- 10582974
TI  - Different risk factors for different stroke subtypes: association of blood
      pressure, cholesterol, and antioxidants.
AB  - BACKGROUND AND PURPOSE: Blood pressure is an important risk factor for stroke,
      but the roles of serum total and HDL cholesterol, alpha-tocopherol, and beta
      carotene are poorly established. We studied these factors in relation to stroke
      subtypes. METHODS: Male smokers (n=28 519) aged 50 to 69 years without a history
      of stroke participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention
      (ATBC) Study, a controlled trial to test the effect of alpha-tocopherol and beta
      carotene supplementation on cancer. From 1985 to 1993, a total of 1057 men
      suffered from primary stroke: 85 had subarachnoid hemorrhage; 112, intracerebral
      hemorrhage; 807, cerebral infarction; and 53, unspecified stroke. RESULTS:
      Systolic blood pressure > or = 160 mm Hg increased the risk of all stroke
      subtypes 2.5 to 4-fold. Serum total cholesterol was inversely associated with the
      risk of intracerebral hemorrhage, whereas the risk of cerebral infarction was
      raised at concentrations > or = 7.0 mmol/L. The risks of subarachnoid hemorrhage
      and cerebral infarction were lowered with serum HDL cholesterol levels > or =
      0.85 mmol/L. Pretrial high serum alpha-tocopherol decreased the risk of
      intracerebral hemorrhage by half and cerebral infarction by one third, whereas
      high serum beta-carotene doubled the risk of subarachnoid hemorrhage and
      decreased that of cerebral infarction by one fifth. CONCLUSIONS: The risk factor
      profiles of stroke subtypes differ, reflecting different etiopathology. Because
      reducing atherosclerotic diseases, including ischemic stroke, by lowering high
      serum cholesterol is one of the main targets in public health care, further
      studies are needed to distinguish subjects with risk of hemorrhagic stroke. The
      performance of antioxidants needs confirmation from clinical trials.

PMID- 10582975
TI  - Autoantibodies against oxidatively modified LDL do not constitute a risk factor
      for stroke: a nested case-control study.
AB  - BACKGROUND AND PURPOSE: Autoantibodies against oxidatively modified LDL have been
      shown to be associated with atherosclerosis. Their possible pathogenic role is
      not yet fully understood, and earlier published data are inconsistent. In this
      prospective study, we have investigated the association of these antibodies with
      future stroke. METHODS: A prospective case-control study in which 44 725 men and
      women from the World Health Organization Multinational Monitoring of Trends and
      Determinants in Cardiovascular Disease (MONICA) project and the Vasterbotten
      Intervention Program (VIP) were enrolled and followed from January 1, 1985, to
      August 31, 1996. One hundred nineteen cases of stroke (male 75, female 44) were
      noted and compared with 233 age- and sex-matched controls from the same
      population. Antibodies against oxidatively modified LDL (copper-oxidized LDL and
      malonaldehyde [MDA]-LDL) were analyzed by ELISA. RESULTS: There was no difference
      in the levels or in the prevalence of IgG, IgA, and IgM autoantibodies against
      copper-oxidized LDL or MDA-LDL between patients and controls. Risk ratios for
      these antibodies, when adjusted for diabetes mellitus, hypertension, and smoking
      habits, did not confer a risk of stroke. Serum triglycerides (1.7 versus 1.4
      mmol/L, P=0.01), fasting blood sugar, and systolic and diastolic blood pressures
      were significantly higher in the patient group than in the control group, as was
      the prevalence of hypertension (51.8% versus 27.4%, P<0.0001) and diabetes
      mellitus (9.6% versus 0.8%, P<0.001). CONCLUSIONS: Autoantibodies against
      oxidatively modified LDL do not constitute a risk factor for stroke in an adult
      population.

PMID- 10582976
TI  - Markers of thrombin and platelet activity in patients with atrial fibrillation:
      correlation with stroke among 1531 participants in the stroke prevention in
      atrial fibrillation III study.
AB  - BACKGROUND AND PURPOSE: Markers of thrombin generation and platelet activation
      are often elevated in patients with nonvalvular atrial fibrillation, but it is
      unclear whether such markers usefully predict stroke. Therefore, we undertook the
      present study to assess the relationship between prothrombin fragment F1.2
      (F1.2), beta-thromboglobulin (BTG), fibrinogen, and the factor V Leiden mutation
      with stroke in atrial fibrillation. METHODS: Specimens were obtained from 1531
      participants in the Stroke Prevention in Atrial Fibrillation III study. The
      results were correlated with patient features, antithrombotic therapy, and
      subsequent thromboembolism (ischemic stroke and systemic embolism) by
      multivariate analysis. RESULTS: Increased F1.2 levels were associated with age
      (P<0.001), female sex (P<0.001), systolic blood pressure (P=0.006), and heart
      failure (P=0.001). F1.2 were not affected by aspirin use and were not associated
      with thromboembolism after adjustment for age (P=0. 18). BTG levels were higher
      with advanced age (P=0.006), coronary artery disease (P=0.05), carotid disease
      (P=0.005), and heart failure (P<0.001), lower in regular alcohol users (P=0.05),
      and not significantly associated with thromboembolism. Fibrinogen levels were not
      significantly related to thromboembolism but were associated with elevated BTG
      levels (P<0.001). The factor V Leiden mutation was not associated with
      thromboembolism (relative risk 0.5, 95% CI 0.1 to 3.8). CONCLUSIONS: Elevated
      F1.2 levels were associated with clinical risk factors for stroke in atrial
      fibrillation, whereas increased BTG levels were linked to manifestations of
      atherosclerosis. In this large cohort of patients with atrial fibrillation who
      were receiving aspirin, F1.2, BTG, fibrinogen, and factor V Leiden were not
      independent, clinically useful predictors of stroke.

PMID- 10582977
TI  - Measurement of hemostatic indexes in conjunction with transcranial doppler
      sonography in patients with ventricular assist devices.
AB  - BACKGROUND AND PURPOSE: Clinical thromboembolism (TE) remains an impediment to
      the chronic application of ventricular assist devices (VADs). Microembolic
      signals (MES) have been detected by transcranial Doppler ultrasound (TCD) in
      patients with VADs, although their origin and relation to TE remain undefined. We
      have investigated the hypothesis that hemostatic alterations are related to MES
      and that MES are associated with TE in a group of 27 VAD patients. METHODS:
      Indexes of coagulation, fibrinolysis, and cellular activation and aggregation
      were measured before and during the VAD implantation period in conjunction with
      TCD. Groups were defined on the basis of presence of MES, degree of MES
      showering, and incidence of TE. RESULTS: MES were observed in 67 (58%) of 115 of
      individual postoperative TCD measurements and in 21 (78%) of 27 patients. Of
      patients with TE, 10 (83%) of 12 had detectable MES compared with 11 (73%) of 15
      patients without TE (P=0.66). MES were significantly associated with elevated
      thrombin generation during the implantation period, as reflected by plasma
      prothrombin fragment F1.2. Elevations in indexes of coagulation, platelet
      activation, and fibrinolysis relative to normal control subjects were found for
      patients with VADs with and without detected MES. CONCLUSIONS: Although no
      significant relation between MES and TE in VAD patients was found, the data
      support the hypothesis that MES are related to increased hemostatic activity in
      this patient group despite aggressive anticoagulant therapy.

PMID- 10582978
TI  - Hormone replacement therapy and intima-media thickness of the common carotid
      artery: the Rotterdam study.
AB  - BACKGROUND AND PURPOSE: Observational data suggest that hormone replacement
      therapy (HRT) reduces morbidity and mortality from cardiovascular disease in
      healthy postmenopausal women. The mechanisms underlying this protection are not
      entirely clear but may include inhibition of the atherosclerotic process.
      METHODS: We studied the association between ever use of HRT and intima-media
      thickness (IMT) of the common carotid artery in 1103 naturally menopausal women,
      aged 55 to 80 years, in the Rotterdam Study, a community-based cohort study in a
      suburban area of Rotterdam, Netherlands. Mean and maximum IMT of the common
      carotid artery were measured noninvasively with B-mode ultrasound. RESULTS: Ever
      use of HRT for >/=1 year was associated with a decreased mean and maximum IMT
      compared with never users (mean IMT, 0.719 mm [SE 0.01] versus 0. 742 mm [SE
      0.004], P=0.03; maximum IMT, 0.952 mm [SE 0.015] versus 0. 983 mm [SE 0.006],
      P=0.04), after adjustment for age, smoking, educational level, systolic blood
      pressure, and body mass index. No association was found for use <1 year (mean
      IMT, 0.739 mm [SE 0.013] versus 0.742 mm [SE 0.004], P=0.69; maximum IMT, 0.990
      mm [SE 0.019] versus 0.983 mm [SE 0.006], P=0.75). Additional adjustment for
      diabetes, frequency of visits to healthcare facilities, or total and HDL
      cholesterol did not change these results. CONCLUSIONS: The findings of this
      population-based study show that ever use of HRT is associated with a decreased
      IMT in the common carotid artery in elderly women.

PMID- 10582980
TI  - Stroke treatment economic model (STEM): predicting long-term costs from
      functional status.
AB  - BACKGROUND AND PURPOSE: Stroke is a debilitating disease with long-term social
      and economic consequences. As new therapies for acute ischemic stroke are
      forthcoming, there is an increasing need to understand their long-term economic
      implications. To address this need, a stroke economic model was created. METHODS:
      The model consists of 3 modules. A short-term module incorporates short-term
      clinical trial data. A long-term module composed of several Markov submodels
      predicts patient transitions among various locations over time. The modules are
      connected via a bridge component that groups the survivors at the end of the
      short-term module according to their functional status and location. Examples of
      analyses that can be conducted with this model are provided with the use of data
      from 2 international trials. For illustration, UK unit costs were estimated.
      RESULTS: With the trial data in the short-term module, the short-term management
      cost is estimated to be pound8326 (US $13,649 [USD]). Hospital stay was the major
      cost driver. By the end of the trials, there was a pronounced difference in the
      distribution of patient locations between functional groups. It is predicted in
      the long-term module that the subsequent cost amounts to pound75 985 (124,564
      USD) for a major and pound27,995 (45,893 USD) for a minor stroke. CONCLUSIONS:
      Linking functional recovery at the end of short-term treatment with patients'
      treatment and residential locations allows this model to estimate the long-term
      economic impact of stroke interventions. Using patient location instead of the
      more common natural history as the model foundation allows quantification of the
      long-term impact to become data driven and hence increases confidence in the
      results.

PMID- 10582981
TI  - Helicopter transfer offers a potential benefit to patients with acute stroke.
AB  - BACKGROUND AND PURPOSE: Rapid transport of patients to specialized centers is
      widely used in the management of myocardial infarction, trauma, and more
      recently, acute stroke. We evaluated the role of helicopter transportation as it
      relates to the availability of acute stroke therapies and patients' perceptions
      of care. METHODS: We reviewed records of all patients transferred to a university
      hospital within 24 hours of stroke onset from January 1996 to December 1997. Data
      were collected on demographics, neurological deficit, treatment, and outcome. In
      addition, a questionnaire was sent to all patients with items about perceived
      reasons for helicopter transfer, expected and actual treatment, outcome, and
      overall impression. RESULTS: Helicopter transfer was used for 73 stroke patients.
      Before transfer, 8 patients (11%) received tissue plasminogen activator (tPA). On
      arrival, no patient received tPA, 38 patients (52%) were enrolled in acute stroke
      studies, and 35 patients (48%) received no specific medication. All but 2
      patients were managed in a specialized stroke unit. Of the 35 patients who
      received no specific therapy, 24 (69%) were ineligible for treatment or study
      enrollment owing to 1 or more exclusion criteria, but rarely (3%) because of
      time. Of the 45 respondents to the survey, most (84%) were transferred at the
      suggestion of the physician at the originating hospital because of a possible
      treatment that was unavailable there. Most patients (93%) believed that there was
      a benefit from emergent helicopter transfer to a stroke center, although 40% of
      respondents received no specific therapy. CONCLUSION: Interhospital transfer by
      air may benefit a substantial number of acute stroke patients by offering
      potential therapies and intensive management not available elsewhere.

PMID- 10582979
TI  - Stroke location is not associated with return to work after first ischemic
      stroke.
AB  - BACKGROUND AND PURPOSE: In prior studies, age, race, job category, disability,
      and cortical functions such as praxis, language, and memory have been associated
      with vocational outcome, but the influence of stroke location on return to work
      has never been critically examined. METHODS: We examined the influence of stroke
      location on vocational outcome in patients with clinically confirmed acute
      ischemic stroke from the National Institute of Neurological Disorders and Stroke
      Stroke Data Bank. RESULTS: Of 143 patients working full time at the time of first
      ischemic stroke, 23 patients were dead and 120 were alive at 1 year. Employment
      status was known in 109 (mean age, 55 years; 51 [47%] were white, and 82 [75%]
      were male). Fifty-eight (53%) had returned to work; most (85%) worked full time.
      Younger age was positively associated with return to work (P<0.05). In an age
      adjusted analysis, stroke severity as measured by the Barthel Index 7 to 10 days
      after stroke was negatively associated with return to work (P<0.001). Higher
      household income and absence of cortical neurological dysfunction 7 to 10 days
      after stroke were positively but less strongly associated with return to work
      (P<0.08). Stroke location, sex, and depression at time of stroke were not
      associated with vocational outcome. CONCLUSIONS: Our data suggest that stroke
      location may be less important than other more easily measured factors in
      predicting vocational outcome.

PMID- 10582982
TI  - Randomized controlled trial of a comprehensive stroke education program for
      patients and caregivers.
AB  - BACKGROUND AND PURPOSE: We report the findings of a randomized controlled trial
      to determine the effectiveness of a multidisciplinary Stroke Education Program
      (SEP) for patients and their informal carers. METHODS: Two hundred four patients
      admitted with acute stroke and their 176 informal carers were randomized to
      receive an invitation to the SEP or to receive conventional stroke unit care. The
      SEP consisted of one 1-hour small group educational session for inpatients
      followed by six 1-hour sessions after discharge. The primary outcome measure was
      patient- and carer-perceived health status (SF-36) at 6 months after stroke.
      Knowledge of stroke, satisfaction with services, emotional outcome, disability,
      and handicap and were secondary outcome measures. RESULTS: Only 51 of 108 (47%)
      surviving patients randomized to the SEP completed the program, as did 20 of 93
      (22%) informal carers of surviving patients. Perceived health status (Short Form
      36 [SF-36] health survey) scores were similar for SEP patients and controls.
      Informal carers in the control group scored better on the social functioning
      component of the SF-36 than the SEP group (P=0.04). Patients and informal carers
      in the SEP group scored higher on the stroke knowledge scale than controls
      (patients, P=0.02; carers, P=0. 01). Patients in the SEP group were more
      satisfied with the information that they had received about stroke (P=0.004).
      There were no differences in emotional or functional outcomes between groups.
      CONCLUSIONS: Although the SEP improved patient and informal carer knowledge about
      stroke and patient satisfaction with some components of stroke services, this was
      not associated with an improvement in their perceived health status. Indeed, the
      social functioning of informal carers randomized to the SEP was less than in the
      control group.

PMID- 10582983
TI  - A randomized efficacy trial of citicoline in patients with acute ischemic stroke.
AB  - BACKGROUND AND PURPOSE: Citicoline (cytidine-5'-diphosphocholine; CDP-choline)
      may reduce central nervous system ischemic injury by stabilizing cell membranes
      and reducing free radical generation. A previous dose-comparison trial in
      patients with acute stroke found that 500 mg of citicoline appeared to improve
      neurological outcome with minimal side effects. METHODS: The current trial was a
      33-center, randomized, double-blind, efficacy trial in 394 patients comparing
      placebo (n=127) with citicoline (n=267) (500 mg po daily) for 6 weeks, with a 6
      week posttreatment follow-up period. Patients with acute (24 hours) ischemic
      strokes clinically assessed to be in the middle cerebral artery territory with
      National Institutes of Health Stroke Scale (NIHSS) > or = 5 were enrolled.
      RESULTS: Mean time to treatment was 12 hours, and mean age was 71 for placebo and
      70 for citicoline. Although mean baseline NIHSS were similar for both groups,
      there was a higher percentage of placebo patients with NIHSS <8 (34% vs 22%;
      P<0.01). The incidence and type of side effects were similar between the groups.
      The planned primary analysis (logistic regression: 5 categories Barthel) failed
      the proportional odds assumption and was rendered unreliable. There were no
      between-group differences seen on the planned secondary assessment analyses at 90
      days, including the Barthel Index > or = 95 at 12 weeks (last observation carried
      forward: placebo 40%; citicoline 40%) or mortality rate (placebo 18%; citicoline
      17%). However, post hoc analyses in a subgroup of patients with baseline NIHSS >
      or = 8 found that citicoline-treated patients were more likely to have a full
      recovery (Barthel > or = 95): placebo 21%; citicoline 33%; P=0.05; whereas no
      difference was seen in patients with baseline NIHSS<8 (placebo 77%; citicoline
      69%; P>0.1. CONCLUSIONS: The results of this study indicate that citicoline was
      safe but ineffective in improving the outcome of patients with acute ischemic
      stroke who were enrolled in this trial. Post hoc analyses indicate that there may
      be a subgroup of patients with moderate to severe strokes who would benefit.

PMID- 10582984
TI  - Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of
      acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial.
AB  - BACKGROUND AND PURPOSE: The purpose of this study was to test the feasibility,
      efficacy, and safety of combined intravenous (IV) and local intra-arterial (IA)
      recombinant tissue plasminogen activator (r-TPA) therapy for stroke within 3
      hours of onset of symptoms. METHODS: This was a double-blind, randomized, placebo
      controlled multi-center Phase I study of IV r-TPA or IV placebo followed by
      immediate cerebral arteriography and local IA administration of r-TPA by means of
      a microcatheter. Treatment activity was assessed by improvement on the National
      Institutes of Health Stroke Scale Score (NIHSSS) at 7 to 10 days. The Barthel
      Index, modified Rankin Scale, and the Glasgow Outcome Scale measured 3-month
      functional outcome. Arterial recanalization rates and their relation to total r
      TPA dose and time to lysis were measured. Rates of life-threatening bleeding,
      intracerebral hemorrhage (ICH), or other bleeding complications assessed safety.
      RESULTS: Thirty-five patients were randomly assigned, 17 into the IV/IA group and
      18 into the placebo/IA group. There was no difference in the 7- to 10-day or the
      3-month outcomes, although there were more deaths in the IV/IA group. Clot was
      found in 22 of 34 patients. Recanalization was better (P=0. 03) in the IV/IA
      group with TIMI 3 flow in 6 of 11 IV/IA patients versus 1 of 10 placebo/IA
      patients and correlated to the total dose of r-TPA (P=0.05). There was no
      difference in the median treatment intervals from time of onset to IV treatment
      (2.6 vs 2.7 hours), arteriography (3.3 vs 3.0 hours), or clot lysis (6.3 vs 5.7
      hours) between the IV/IA and placebo/IA groups, respectively. A direct relation
      between NIHSSS and the likelihood of the presence of a clot was identified. Eight
      ICHs occurred; all were hemorrhagic infarctions. There were no parenchymal
      hematomas. Symptomatic ICH within 24 hours occurred in 1 placebo/IA patient only.
      Beyond 24 hours, symptomatic ICH occurred in 2 IV/IA patients only. Life
      threatening bleeding complications occurred in 2 patients, both in the IV/IA
      group. Moderate to severe bleeding complications occurred in 2 IV/IA patients and
      1 placebo/IA patient. CONCLUSIONS: This pilot study demonstrates combined IV/IA
      treatment is feasible and provides better recanalization, although it was not
      associated with improved clinical outcomes. The presence of thrombus on initial
      arteriography was directly related to the baseline NIHSSS. This approach is
      technically feasible. The numbers of symptomatic ICH were similar between the 2
      groups, which suggests that this approach may be safe. Further study is needed to
      determine the safety and effectiveness of this new method of treatment. Such
      studies should address not only efficacy and safety but also the cost-benefit
      ratio and quality of life, given the major investment in time, personnel, and
      equipment required by combined IV and IA techniques.

PMID- 10582985
TI  - Association of the platelet glycoprotein IIb HPA-3 polymorphism with survival
      after acute ischemic stroke.
AB  - BACKGROUND AND PURPOSE: The role of polymorphisms of the platelet glycoprotein
      (GP) IIb/IIIa receptor in the development of cardiovascular disease has been the
      subject of intensive research. The aim of this study was to determine the
      association of the HPA-3 polymorphism of platelet GPIIb with ischemic stroke and
      subsequent survival and to identify possible interactions of HPA-3 with classic
      risk factors. METHODS: HPA-3 genotype was determined by restriction fragment
      length polymorphism in 515 patients with ischemic stroke and 423 healthy, age
      matched control subjects. RESULTS: There was no significant difference in the
      genotype distribution of patients and controls, nor was there any difference when
      patients were subclassified into small- and large-vessel disease. The genotype
      distribution of the 231 patients subsequently dying during 2.8 years of follow-up
      (aa=45.0%, ab=46.8%, bb=8.2%) was significantly different from that of those
      still alive (aa=37.0%, ab=48.2%, bb=14. 8%) (P=0.03). In a Cox regression model,
      the relative risks for poststroke mortality in patients of aa and ab genotype
      compared with those of bb genotype were 2.42 (95% CI, 1.24 to 4.71) and 2.13 (95%
      CI, 1.09 to 4.17), respectively, after we accounted for confounding factors. In
      addition, significant interactions of HPA-3 with the Pl(A) polymorphism of GPIIIa
      (P=0.002) and with fibrinogen (P=0.01) were identified in relation to mortality.
      CONCLUSIONS: HPA-3 is related to poststroke mortality, and the significant
      interaction of HPA-3 with Pl(A) and fibrinogen suggests that it may in some way
      influence the interaction of GPIIb/IIIa with fibrinogen, particularly in the
      presence of high fibrinogen.

PMID- 10582986
TI  - Functional polymorphism in the matrix metalloproteinase-9 promoter as a potential
      risk factor for intracranial aneurysm.
AB  - BACKGROUND AND PURPOSE: There is convincing evidence that susceptibility to
      intracranial aneurysms (ICAs) has a genetic component. However, few studies have
      sought to identify functional variation in specific candidate genes that may
      predispose individuals to develop an ICA. METHODS: ICA cases and controls were
      genotyped for a simple length polymorphism in the promoter of matrix
      metalloproteinase-9 (MMP-9) to test for association between variation in the
      promoter and the occurrence of ICA. Alternative alleles were cloned into an in
      vitro reporter vector, transfected into human HT1080 fibroblasts, and assayed for
      promoter activity by beta-gal and luciferase assays. Electrophoretic gel shift
      assays were used to assess nuclear factor binding. RESULTS: A length polymorphism
      in the promoter of MMP-9 was nonrandomly associated with the occurrence of ICA in
      a case-control study. This polymorphism was shown, by direct sequencing of 36
      individuals, to be the only sequence variation within a 736-base pair region
      proximal to the transcriptional start site of the gene. Variation in the length
      of this repetitive element was shown to modulate promoter activity in an in vitro
      reporter assay, with the highest promoter activity being observed in constructs
      bearing the longest [(CA)23] element. Electrophoretic mobility shift assays were
      used to show that the (CA) element is bound by a sequence-specific DNA-binding
      protein. CONCLUSIONS: Genetic variation in the promoter of the MMP-9 gene results
      in variation in its expression at the level of transcription. This may result in
      subtle differences in MMP-9 activity within the circle of Willis, leading to
      increased susceptibility to ICA formation.

PMID- 10582987
TI  - Outcome after endovascular treatment of Hunt and Hess grade IV or V aneurysms:
      comparison of anterior versus posterior circulation.
AB  - BACKGROUND AND PURPOSE: The most common cause of poor treatment outcome in
      patients suffering aneurysmal subarachnoid hemorrhage is cerebral vasospasm,
      especially in cases of poor Hunt and Hess grades (IV and V). A further prognostic
      factor in surgically treated patients is aneurysm localization. The aim of the
      present retrospective study is to compare the endovascular treatment outcome in
      such poor-grade patients according to aneurysm localization in either the
      anterior (AC) or posterior (PC) circulation. METHODS: Forty poor-grade patients
      admitted between 1993 and July 1998 were treated by endovascular approach within
      23 days after aneurysm rupture. Eighteen had aneurysms in the AC, 22 in the PC.
      Mean treatment delay was 4 days after rupture and median, 2 days. One patient
      showed multiple aneurysms. In 36 cases, aneurysms were occluded by Guglielmi
      detachable coils; in 4 cases, by parent vessel balloon occlusion. RESULTS: The
      incidence of delayed ischemic neurological dysfunction or cerebral infarct due to
      vasospasm did not differ significantly between the AC and PC groups. Two
      procedure-related complications with clinical effect were observed in each group.
      At 6 months' follow-up, the result was good in 5 patients and poor in 13 in the
      AC group and good in 11 patients and poor in 11 in the PC group. CONCLUSION:
      Given comparable incidence of vasospasm in poor-grade patients, a tendency toward
      better treatment outcome was found in patients with aneurysms in the posterior
      circulation (chi(2)=2.04; P=0.15) than in the anterior circulation. Endovascular
      therapy for poor-grade patients is recommended, as are further studies to
      determine treatment differences.

PMID- 10582988
TI  - Distributions of local oxygen saturation and its response to changes of mean
      arterial blood pressure in the cerebral cortex adjacent to arteriovenous
      malformations.
AB  - BACKGROUND AND PURPOSE: To test the hypothesis that neither "steal" as cortical
      ischemia caused by reduced perfusion pressure nor "breakthrough" on the grounds
      of loss of pressure autoregulation exist in brain tissue surrounding
      arteriovenous malformations (AVMs), we established patterns of cortical oxygen
      saturation (SO(2)) adjacent to AVMs and its behavior after alterations of mean
      arterial blood pressure. METHODS: With a microspectrophotometer, SO(2) was
      scanned in the cortex around AVMs of 44 patients before and after resection and
      in that of a non-AVM group (n=42) before transsylvian dissection. Autoregulation
      was evaluated by linear regression analysis after elevation of mean arterial
      blood pressure (5 microg/min IV noradrenaline). SO(2) values were calculated as
      medians, percentage of critical values (<25% SO(2)), and coefficients of variance
      (approximate heterogeneity of SO(2) distributions). All values are given as
      mean+/-SD. RESULTS: Forty patients with AVM had an uneventful postoperative
      course (group A). Four hyperemic complications ("breakthrough") occurred (group
      B). Autoregulation was tested intact in all groups at all times. Preoperative
      SO(2) distributions in groups A and C (non-AVMs) were identical. In group B,
      significantly (P<0.05) lower medians (group A, 52.9+/-16.3%; group B, 44.2+/
      17.1%; group C, 51.9+/-11.5% SO(2)), more critical values (group A, 6.5+/-5.1%;
      group B, 14.7+/-11.1%; group C, 7.1+/-4.9%), and heterogeneous SO(2)
      distributions (group A, 20.2+/-12.7%; group B, 27.9+/-12.4%; group C, 26.8+/
      10.9%) were seen. Increase of median values was significantly higher in group B
      (76.3+/-10.4% SO(2)) than in group A (65.9+/-13.4% SO(2)) after resection.
      CONCLUSIONS: Severely hypoxic areas are uncommon in the cortex adjacent to AVMs
      and occur predominantly in patients prone to hyperemic complications. Reduced
      perfusion pressure is compensated in most cases, and moderate hyperemia prevails
      after excision. Reperfusion into unprotected capillaries of severely hypoxic
      cortical areas results in "breakthrough," for which vasoparalysis appears not to
      be the underlying mechanism.

PMID- 10582989
TI  - Neurological deterioration in acute ischemic stroke: potential predictors and
      associated factors in the European cooperative acute stroke study (ECASS) I.
AB  - BACKGROUND AND PURPOSE: The present study was undertaken to identify potential
      predictors of and factors associated with early and late progression in acute
      stroke. We performed secondary analysis of the clinical, biochemical, and
      radiological data recorded in the acute phase of stroke patients enrolled in the
      European Cooperative Acute Stroke Study (ECASS) I. METHODS: Early progressing
      stroke (EPS) was diagnosed when there was a decrease of > or = 2 points in
      consciousness or motor power or a decrease of > or = 3 points in speech scores in
      the Scandinavian Neurological Stroke Scale from baseline to the 24-hour
      evaluation, and late progressing stroke (LPS) was diagnosed when 1 of these
      decreases occurred between the 24-hour evaluation and the evaluation at day 7.
      Using logistic regression analyses, we looked for baseline variables that
      predicted EPS and LPS and for factors measured after the early or late acute
      phase and associated with the 2 clinical courses. RESULTS: Of the 615 patients
      studied, 231 (37.5%) worsened during the first 24 hours after inclusion. The
      overall incidence of EPS was 37% in the placebo group and 38% in the recombinant
      tissue plasminogen activator group (P=0.68, Fisher's Exact Test). Focal
      hypodensity (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.3 to 2.9) and
      hyperdensity of the middle cerebral artery sign (OR, 1.8; 95% CI, 1.1 to 3.1) on
      baseline computed tomography, longer delay until treatment (OR, 1.2; 95% CI, 1.1
      to 1. 4) and history of coronary heart disease (OR, 1.7; 95% CI, 1.1 to 2. 8) and
      diabetes (OR, 1.8; 95% CI, 1.0 to 3.1) were independent prognostic factors for
      EPS. Extent of hypodensity >33% in the middle cerebral artery territory (OR, 2.5;
      95% CI, 1.6 to 4.0) and brain swelling (OR, 1.8; 95% CI, 1.1 to 3.2) on CT at 24
      hours but not hemorrhagic transformation of cerebral infarct nor decrease in
      systolic blood pressure within the first 24 hours after treatment were associated
      with EPS in multivariate analyses. LPS was observed in 20.3% of patients. Older
      age, a low neurological score, and brain swelling at admission independently
      predicted late worsening. CONCLUSION: In the setting of a multicenter trial, EPS
      and LPS are mainly related to computed tomographic signs of cerebral edema.
      Treatment with recombinant tissue plasminogen activator, hemorrhagic
      transformation, and moderate changes in systolic blood pressure did not influence
      the early clinical course.

PMID- 10582990
TI  - Clinical severity in CADASIL related to ultrastructural damage in white matter:
      in vivo study with diffusion tensor MRI.
AB  - BACKGROUND AND PURPOSE: CADASIL is a newly recognized cause of subcortical
      ischemic strokes that progressively leads to dementia associated with
      pseudobulbar palsy and severe motor disability. This deleterious progression and
      the severity of clinical presentation are widely variable among affected
      subjects. The exact role played by MRI white-matter abnormalities, a hallmark of
      the disease, in the severity of the clinical phenotype remains poorly understood.
      METHODS: To address this issue, we used diffusion tensor imaging (DTI), a new MRI
      technique highly sensitive to white-matter microstructural changes, in 16
      symptomatic patients and 10 age-matched controls. Mean diffusivity and anisotropy
      of diffusion were measured within hyperintensities identified on T2-weighted
      images (T2WI) and outside these lesions on 4 slices at the level of centrum
      semiovale. RESULTS: We found a 60% increase of water mean diffusivity and a
      parallel loss of diffusion anisotropy in hyperintensities identified on T2WI. The
      same pattern of diffusion changes, but of lesser intensity, was found in the
      normal-appearing white matter on T2WI. Mean diffusivity in regions with increased
      signal on T2WI was higher in patients with severe clinical disability compared
      with those with no or mild deficit (1.33+/-0.11 versus 1.13+/-0.11 10(-3)
      mm(2)/s, P<0.01). Furthermore, diffusion measured within T2 hyperintensities
      correlated with both the Mini-Mental State Examination and Rankin scale scores.
      In patients with a severe clinical status, the increase of water diffusion in
      these regions exceeded 70% in comparison with values obtained in the normal white
      matter in control subjects. CONCLUSIONS: These results indicate that DTI is able
      to detect important ultrastructural changes in regions with increased signal on
      T2WI and within the normal-appearing white matter in CADASIL. The diffusion
      changes might be related to both neuronal loss and demyelination. The degree of
      the underlying ultrastructural alterations is related to the severity of the
      clinical status with a possible threshold level of white-matter damage above
      which severe neurological impairment may occur in this disease. DTI appears to be
      a promising technique for monitoring disease progression in CADASIL.

PMID- 10582991
TI  - Diffusion-weighted imaging identifies a subset of lacunar infarction associated
      with embolic source.
AB  - BACKGROUND AND PURPOSE: Small infarcts in the territory of penetrator arteries
      were described as causing a number of distinct clinical syndromes. The vascular
      pathophysiology underlying such infarcts is difficult to ascertain without
      careful pathological study. However, the occurrence of multiple, small infarcts,
      linked closely in time but dispersed widely in the brain, raises the possibility
      of an embolic mechanism. The current study determines the frequency and clinical
      characteristics of patients with well-defined lacunar syndromes and the diffusion
      weighted imaging (DWI) evidence of multiple acute lesions. METHODS: Sixty-two
      consecutive patients who presented to the emergency room with a clinically well
      defined lacunar syndrome were studied by DWI within the first 3 days of
      admission. RESULTS: DWI showed multiple regions of increased signal intensity in
      10 patients (16%). A hemispheric or brain stem lesion in a penetrator territory
      that accounted for the clinical syndrome ("index lesion") was found in all. DWI
      hyperintense lesions other than the index lesion ("subsidiary infarctions") were
      punctate and lay within leptomeningeal artery territories in the majority. As
      opposed to patients with a single lacunar infarction, patients with a subsidiary
      infarction more frequently (P<0.05) harbored an identifiable cause of stroke.
      CONCLUSIONS: Almost 1 of every 6 patients presenting with a classic lacunar
      syndrome has multiple infarctions demonstrated on DWI. This DWI finding usually
      indicates an identifiable cause of stroke and therefore may influence clinical
      decisions regarding the extent of etiologic investigations and treatment for
      secondary prevention.

PMID- 10582992
TI  - Primary somatosensory cortex activation is not altered in patients with
      ventroposterior thalamic lesions: a PET study.
AB  - BACKGROUND AND PURPOSE: We know remarkably little about the mechanisms underlying
      cortical activation. Such mechanisms might be better understood by studying the
      effect of well-localized lesions on the cortical activations in simple paradigms.
      METHODS: We used H(2)(15)O and positron emission tomography to measure regional
      cerebral blood flow (rCBF) at rest and during hand vibration in 7 patients with
      unilateral thalamic lesion involving the ventroposterior (VP) somatosensory
      thalamic relay nuclei. We compared the results with those obtained in 6 patients
      with thalamic lesions sparing the VP nuclei and 6 healthy controls. RESULTS: The
      patients with VP lesions had a selective hypoperfusion at rest in the
      ipsilesional primary sensorimotor cortex (SM1). This hypoperfusion was
      significantly correlated with the degree of contralateral somatosensory deficit.
      This abnormality may reflect the deafferentation of SM1 from its somatosensory
      thalamic input. Despite this deafferentation, the ipsilesional SM1 was normally
      activated by the vibration of the hypoesthetic hand. CONCLUSIONS: The fact that a
      lesion of the somatosensory thalamic relay nuclei alters the rCBF at rest in SM1
      but not its activation by hand vibration indicates that the mechanism of cortical
      activation is complex, even in the case of simple sensory stimulation. In
      addition, a dissociation may occur between obvious neurological deficits and
      apparently normal activation patterns, which suggests that activation studies
      should be interpreted cautiously in patients with focal brain lesions.

PMID- 10582993
TI  - High-resolution EEG in poststroke hemiparesis can identify ipsilateral generators
      during motor tasks.
AB  - BACKGROUND AND PURPOSE: Multimodal neuroimaging with positron emission tomography
      (PET) scanning or functional MRI can detect and display functional reorganization
      of the brain's motor control in poststroke hemiplegia. We undertook a study to
      determine whether the new modality of 128-electrode high-resolution EEG,
      coregistered with MRI, could detect changes in cortical motor control in patients
      after hemiplegic stroke. METHODS: We recorded movement-related cortical
      potentials with left and right finger movements in 10 patients with varying
      degrees of recovery after hemiplegic stroke. All patients were male, and time
      since stroke varied from 6 to 144 months. All patients were right-handed. There
      was also a comparison group of 20 normal control subjects. RESULTS: Five of 8
      patients with left hemiparesis had evidence of ipsilateral motor control of
      finger movements. There were only 2 cases of right hemiparesis; in addition, 1
      patient had a posteriorly displaced motor potential originating behind a large
      left frontal infarct (rim). CONCLUSIONS: Reorganization of motor control takes
      place after stroke and may involve the ipsilateral or contralateral cortex,
      depending on the site and size of the brain lesion and theoretically, the
      somatotopic organization of the residual pyramidal tracts. Our results are in
      good agreement with PET and functional MRI studies in the current literature.
      High-resolution EEG coregistered with MRI is a noninvasive imaging technique
      capable of displaying cortical motor reorganization.

PMID- 10582994
TI  - Absence of response to early transcranial magnetic stimulation in ischemic stroke
      patients: prognostic value for hand motor recovery.
AB  - BACKGROUND AND PURPOSE: Transcranial magnetic stimulation (TMS) has been proposed
      as a prognostic tool in stroke patients. Most of the previous studies agree in
      considering the presence of motor-evoked potentials (MEPs) in the first days
      after a stroke as an indicator of good outcome. In the present study, we have
      assessed the prognostic value of the absence of response to early TMS on hand
      motor recovery in stroke patients with complete hand palsy at onset due to
      ischemia in the area of the middle cerebral artery. METHODS: Fifteen patients
      submitted to TMS within 48 hours of stroke onset (defined as day 1) and again
      after 1 year. They were also evaluated clinically on day 1 by a scale derived
      from the Medical Research Council (MRC) and by the National Institutes of Health
      (NIH) stroke scale; they were reevaluated by the same scales and by Barthel Index
      on day 365. RESULTS: On day 1, all the patients had complete hand palsy and no
      response to TMS; their NIH scores showed great variability. After 1 year, 6 of 15
      patients regained small and prolonged MEPs, together with a very poor and not
      functionally useful motor recovery. NIH scores were significantly improved.
      Barthel Index scores showed large interindividual differences and were not
      correlated with MRC scores. CONCLUSIONS: We conclude that in patients with
      complete hand palsy, the absence of response to TMS in the first hours is
      predictive of absent or very poor, not useful, hand motor recovery.

PMID- 10582995
TI  - Circle of Willis collateral flow investigated by magnetic resonance angiography.
AB  - BACKGROUND AND PURPOSE: The circle of Willis (CW) is considered an important
      collateral pathway in maintaining adequate cerebral blood flow in patients with
      internal carotid artery (ICA) obstruction. We aimed to investigate the anatomic
      variation of the CW in patients with severe symptomatic carotid obstructive
      disease and to analyze diameter changes of its components in relation to varying
      grades of ICA obstruction and in relation to the presence or absence of
      (retrograde) collateral flow. METHODS: Seventy-five patients with minor disabling
      neurological deficits and with ICA stenoses or occlusions were categorized into 4
      groups according to the severity of ICA obstruction. This patient population
      reflected a relatively favorable subgroup of cerebral infarction (considering
      their minor neurological deficits). All subjects underwent magnetic resonance
      angiography, including magnetic resonance angiography sensitive to flow
      direction. CW morphology and the size of its components were determined and
      compared with those values in control subjects (n=100). RESULTS: Compared with
      control subjects, patients demonstrated a significantly higher percentage of
      entirely complete CW configurations (55% versus 36%, P=0.02), complete anterior
      configurations (88% versus 68%, P=0.002), and complete posterior CW
      configurations (63% versus 47%, P=0.04). Patients with severe ICA stenosis did
      not show significantly increased CW vessel diameters. Patients with ICA occlusion
      demonstrated a high prevalence of collateral flow through the anterior CW and
      significantly increased diameters of the communicating channels. Patients with
      bilateral ICA occlusion relied on collateral flow via the posterior CW and
      demonstrated a bilateral increase in posterior communicating artery diameters
      (P<0.05). CONCLUSIONS: The anatomic and functional configuration of the CW
      reflects the degree of ICA obstruction.

PMID- 10582996
TI  - Cerebral microembolism in acute myocardial infarction.
AB  - BACKGROUND AND PURPOSE: This study was undertaken to determine the frequency of
      cerebral microemboli (high-intensity transient signals; HITS) detected by
      transcranial Doppler (TCD) in patients with acute myocardial infarction (AMI) and
      to relate them to the various putative risk factors and clinical embolic events.
      METHODS: We investigated 112 consecutive patients within 72 hours of admission to
      an acute coronary care unit using TCD to monitor for cerebral microemboli. Twelve
      patients were excluded because of failure of ultrasound insonation. All patients
      had 2-dimensional echocardiograms within the study period. RESULTS: HITS were
      detected in 17% of patients, with significantly higher frequency in patients with
      reduced (<65%) left ventricular (LV) ejection fraction (P=0. 019), akinetic LV
      segments (P=0.002), and LV thrombus (P=0.015). A marginally significant (P=0.059)
      increase of HITS was found in patients with anterior AMI. Stroke was
      significantly more frequent in patients with cerebral microemboli (P=0.01).
      CONCLUSIONS: HITS were detected in 17% of patients in spite of adequate
      antithrombotic therapy and were increased in patients with reduced LV function,
      akinetic myocardial segments, and LV thrombus. They were present in all 3
      patients with stroke and may represent a predictor of clinical embolic events.

PMID- 10582997
TI  - Association between large aortic arch atheromas and high-intensity transient
      signals in elderly stroke patients.
AB  - BACKGROUND AND PURPOSE: Aortic arch atheromas (AAs) have been shown to be a risk
      factor for ischemic stroke (IS) in the elderly because of their potential for
      cerebral embolization. However, the association between AAs and the presence of
      cerebral microemboli has not been clearly established. The aim of this study was
      to determine whether large AAs are associated with an increased frequency of high
      intensity transient signals (HITS) in elderly patients with IS. METHODS: We
      performed bitemporal simultaneous HITS monitoring of both middle cerebral
      arteries in 62 consecutive elderly patients with acute IS (mean age 72.5+/-8.8
      years, 65% men). In 16 patients, one or both temporal windows were inadequate;
      therefore, the analysis of HITS was performed in the remaining 46 patients. All
      patients underwent omniplane transesophageal echocardiography (TEE), and they had
      no significant extracranial or intracranial artery disease and no cardiac
      prosthetic valves. Large AA was defined as > or = 4 mm in thickness. Complex AA
      was defined as ulcerated or mobile, regardless of plaque thickness. HITS
      monitoring was performed within 24 hours of TEE and analyzed by an experienced
      neurologist-sonographer blinded to TEE findings. A 9-dB threshold was chosen to
      discriminate HITS from background Doppler signal. The HITS counts in the left and
      in the right middle cerebral arteries were added and reported as a total number
      of HITS in 30 minutes. RESULTS: HITS were detected in 14 (78%) of 18 patients
      with large AAs versus 8 (29%) of 28 patients with no or small AAs (odds ratio
      [OR] 8.8, 95% CI 2.2 to 34.8; P=0. 001). The association was also present in 27
      patients with no other cardiac embolic sources, such as atrial fibrillation,
      patent foramen ovale, spontaneous echo contrast, and thrombus (7 of 10 patients
      with large AAs versus 3 of 17 patients with small or no AA; OR 10.9, 95% CI 1.7
      to 68.5; P=0.013). Complex AAs were associated with a higher frequency of HITS
      than were noncomplex AAs (6 of 6 patients with complex AAs versus 15 of 39
      patients with noncomplex AAs; OR 2. 6, 95% CI 1.7 to 3.9; P=0.005). CONCLUSIONS:
      HITS are significantly associated with large AAs in elderly stroke patients. This
      observation may support the causal role of large AAs in IS.

PMID- 10582999
TI  - Reference values for vertebral artery flow volume by duplex sonography in young
      and elderly adults.
AB  - BACKGROUND AND PURPOSE: Vertebrobasilar ischemia has been attributed to a
      reduction of net vertebral artery flow volume, the product of mean flow velocity
      and the cross-sectional area of the vessel. It can be determined by duplex
      sonography. There are no reference values for vertebral artery flow volume in an
      age group representative of patients with cerebrovascular disease. METHODS: We
      examined 50 nonvascular neurological patients (age 55.8+/-14.0 years). Flow
      velocities and vessel diameters were recorded in the intertransverse (V2)
      segments bilaterally, and the flow volume was calculated according to the
      following equations: (1) Q1=time-averaged mean velocity times area and (2)
      Q2=(time-averaged maximum velocity/2)times area. RESULTS: Flow velocities and
      vessel diameters tended to be lower on the right side, resulting in a lower flow
      volume. Flow volumes (according to Equation 1) were 77.2+/-29.8 mL/min on the
      right side, 105.3+/-46.4 mL/min on the left side, and 182.0+/-56.0 mL/min net.
      Side-to-side differences were not significant. Flow volumes calculated with the 2
      equations did not differ significantly. An age dependence could not be shown, but
      vessel diameters and net vertebral artery flow volumes were significantly lower
      in women than in men. The normal range for net vertebral artery flow volume
      defined by the 5th to 95th percentiles is between 102.4 and 301.0 mL/min. This
      wide range is due to the high interindividual variability of the parameters.
      CONCLUSIONS: On the basis of the reference values presented here, the association
      of decreased vertebral artery flow volume and vertebrobasilar ischemia should be
      reevaluated. Additional areas for investigation include the quantification of
      collateral flow in the vertebral arteries in carotid artery occlusive disease and
      their contribution to overall cerebral blood flow volume.

PMID- 10582998
TI  - Transcranial doppler detection of fat emboli.
AB  - BACKGROUND AND PURPOSE: The fat embolism syndrome (FES) is characterized by the
      simultaneous occurrence of pulmonary and neurological symptoms as well as skin
      and mucosal petechiae in the setting of long-bone fractures or their surgical
      repair. Its pathophysiology is poorly understood, and effective treatments are
      lacking. We present 5 patients with long-bone fractures in whom in vivo
      microembolism was detected by transcranial Doppler. METHODS: Five patients with
      long-bone fractures were monitored with transcranial Doppler for microembolic
      signals (MESs) after trauma. Two patients also had intraoperative monitoring. A
      TC-2020 instrument equipped with MES detection software was used. Detected
      signals were saved for subsequent review. Selected signals satisfied criteria
      defined previously and were categorized as large or small. RESULTS: Cerebral
      microembolism was detected in all 5 patients and was transient, resolving within
      4 days of injury. Intraoperative monitoring revealed an increase in MESs during
      intramedullary nail insertion. The characteristics of MESs after injury varied
      among patients, with large signals being more frequent in the only patient with a
      patent foramen ovale. CONCLUSIONS: Cerebral microembolism after long-bone
      fractures can be detected in vivo and monitored over time. These findings may
      have potential diagnostic and therapeutic implications.

PMID- 10583000
TI  - Sensory sequelae of medullary infarction: differences between lateral and medial
      medullary syndrome.
AB  - BACKGROUND AND PURPOSE: A comparison between long-term sensory sequelae of
      lateral medullary infarction (LMI) and medial medullary infarction (MMI) has
      never been made. METHODS: We studied 55 patients with medullary infarction (41
      with LMI and 14 with MMI) who were followed up for >6 months. We examined and
      interviewed the patients with the use of a structured format regarding the most
      important complaints, functional disabilities, and the presence of sensory
      symptoms. The nature and the intensity of sensory symptoms were assessed with the
      modified McGill-Melzack Pain Questionnaire and the visual analog scale,
      respectively. RESULTS: There were 43 men and 12 women, with an average age of 59
      years. Mean follow-up period was 21 months. The sensory symptoms were the most
      important residual sequelae in LMI patients and the second most important in MMI
      patients. In LMI patients, the severity of residual sensory symptoms was
      significantly related to the initial severity of objective sensory deficits
      (P<0.05). Sensory symptoms were most often described by LMI patients as numbness
      (39%), burning (35%), and cold (22%) in the face, and cold (38%), numbness (29%),
      and burning (27%) in the body/limbs, whereas they were described as numbness
      (60%), squeezing (30%) and cold (10%), but never as burning, in their body/limbs
      by MMI patients. LMI patients significantly (P<0.05) more often cited a cold
      environment as an aggravating factor for the sensory symptoms than did the MMI
      patients without spinothalamic sensory impairment. The subjective sensory
      symptoms were frequently of a delayed onset (up to 6 months) in LMI patients,
      whereas they usually started immediately after the onset in MMI patients.
      CONCLUSIONS: Our study shows that sensory symptoms are major sequelae in both LMI
      and MMI patients. However, the nature, the mode of onset, and aggravating factors
      are different between the 2 groups, which probably is related to a selective
      involvement of the spinothalamic tract by the former and the medial lemniscus by
      the latter. We suggest that the mechanisms for the central poststroke pain or
      paresthesia may differ according to the site of damages on the sensory tracts
      (spinothalamic tract versus medial lemniscal tract).

PMID- 10583001
TI  - Delayed treatment with AM-36, a novel neuroprotective agent, reduces neuronal
      damage after endothelin-1-induced middle cerebral artery occlusion in conscious
      rats.
AB  - BACKGROUND AND PURPOSE: AM-36 is a novel arylalkylpiperazine with combined
      antioxidant and Na(+) channel blocking actions. Individually, these properties
      have been shown to confer neuroprotection in a variety of in vitro and in vivo
      animal models of stroke. Preliminary studies have shown that AM-36 is
      neuroprotective in vivo. The purpose of the present study was to assess the
      neuroprotective and behavioral outcome after delayed administration of AM-36 in
      an endothelin-1-induced, middle cerebral artery model of cerebral ischemia in
      conscious rats. METHODS: Conscious male hooded Wistar rats were subjected to
      middle cerebral artery occlusion by perivascular microinjection of endothelin-1
      via a previously implanted cannula. AM-36 (6 mg/kg IP) or vehicle was
      administered intraperitoneally 30, 60, or 180 minutes after middle cerebral
      artery occlusion. Functional outcome was determined 24, 48, and 72 hours after
      stroke by neurological deficit score, motor performance, and sensory hemineglect
      tests. Rats were killed at 72 hours, and infarct area and volume were determined
      by histology and computerized image analysis. RESULTS: Endothelin-1-induced
      middle cerebral artery occlusion resulted in marked functional deficits and
      neuronal damage. AM-36 significantly reduced cortical damage when administration
      was delayed until 30, 60, or 180 minutes after stroke. Interestingly, neuronal
      damage was time-dependently reduced, with the greatest protection found when AM
      36 was administered 180 minutes after stroke. Striatal damage was significantly
      reduced after treatment with AM-36 at 180 minutes after stroke. Functional
      outcome paralleled histopathology. Rota-rod performance, sensory hemineglect, and
      neurological deficit scores returned to preischemia levels in AM-36-treated rats
      by 72 hours after stroke when administration was delayed by 180 minutes after
      stroke. CONCLUSIONS: AM-36 potently protects against both neuronal damage and
      functional deficits even when administered up to 180 minutes after induction of
      stroke. In fact, the greatest protection was found when administration was
      delayed by 180 minutes after stroke. The possible mechanisms of action of AM-36
      are discussed. The present findings suggest that AM-36 may have great promise in
      the acute treatment of human stroke.

PMID- 10583002
TI  - Mitochondrial potassium channel opener diazoxide preserves neuronal-vascular
      function after cerebral ischemia in newborn pigs.
AB  - BACKGROUND AND PURPOSE: N-Methyl-D-aspartate (NMDA) elicits neuronally mediated
      cerebral arteriolar vasodilation that is reduced by ischemia/reperfusion (I/R).
      This sequence has been preserved by pretreatment with the ATP-sensitive potassium
      (K(ATP)) channel opener aprikalim, although the mechanism was unclear. In the
      heart, mitochondrial K(ATP) channels (mitoK(ATP)) are involved in the ischemic
      preconditioning-like effect of K(+) channel openers. We determined whether the
      selective mitoK(ATP) channel opener diazoxide preserves the vascular dilation to
      NMDA after I/R. METHODS: Pial arteriolar diameters were determined with the use
      of closed cranial window/intravital microscopy in anesthetized piglets. Vascular
      responses to NMDA were assessed before and 1 hour after 10 minutes of global
      cerebral ischemia induced by raising intracranial pressure. Subgroups received 1
      of the following pretreatments before I/R: vehicle; 1 to 10 micromol/L diazoxide;
      and coapplication of 100 micromol/L 5-hydroxydecanoic acid (5-HD), a K(ATP)
      antagonist with diazoxide. RESULTS: NMDA-induced dose-dependent pial arteriolar
      dilation was not affected by diazoxide treatment only but was severely attenuated
      by I/R. In contrast, diazoxide dose-dependently preserved the NMDA vascular
      response after I/R; at 10 micromol/L, diazoxide arteriolar responses were
      unaltered by I/R. The effect of diazoxide was antagonized by coapplication of 5
      HD with diazoxide. Percent preservation of 100 micromol/L NMDA-induced
      vasodilation after I/R was 53+/-19% (mean+/-SEM, n=8) in vehicle-treated controls
      versus 55+/-10%, 85+/-5%, and 99+/-15% in animals pretreated with 1, 5, and 10
      micromol/L diazoxide (n=8, n=8, and n=12, respectively) and 60+/-15% in the group
      treated with 5-HD+diazoxide (n=5). CONCLUSIONS: The mitoK(ATP) channel opener
      diazoxide in vivo preserves neuronal function after I/R, shown by pial arteriolar
      responses to NMDA, in a dose-dependent manner. Thus, activation of mitoK(ATP)
      channels may play a role in mediating the protective effect of other K(+) channel
      openers.

PMID- 10583003
TI  - Combination of intraischemic and postischemic hypothermia provides potent and
      persistent neuroprotection against temporary focal ischemia in rats.
AB  - BACKGROUND AND PURPOSE: It is not known whether a combination of intraischemic
      and postischemic mild hypothermia provides extra neuroprotection and if so,
      whether the neuroprotection is persistent. METHODS: Sixty-eight Sprague-Dawley
      rats were used. In group 1, ischemia and reperfusion were performed under
      normothermic (N) conditions (control, N-N). In group 2, ischemia was induced and
      maintained under hypothermic conditions (33 degrees C for 2 hours) and
      reperfusion was performed under normothermic conditions, H-N. In group 3, both
      ischemia and reperfusion were performed under hypothermic conditions for an
      additional 21 hours after the surgery, H-22H. In group 4, ischemia was induced
      and maintained under hypothermic conditions and reperfusion was performed under
      hypothermic conditions only for the initial 3 hours (H-3H). In group 5, ischemia
      was induced and maintained under normothermic conditions and reperfusion was
      performed under hypothermic conditions (33 degrees C) (N-22H). All rats were
      perfused 48 hours after the induction of ischemia. In addition, the normothermic
      or hypothermic therapy used for groups 1, 3, and 4 was performed again, and these
      rats were killed 30 days after the induction of ischemia. Furthermore,
      neurological deficits were monitored in groups N-N and H-22H for 4 weeks.
      RESULTS: In the H-3H and H-22H groups, the total infarct volume was significantly
      reduced by 41% or 66%, respectively, assessed 48 hours after ischemia. The
      significant reduction in group H-22H was again confirmed 30 days after ischemia,
      ie, 50% reduction was observed. In contrast, the reduction in group H-3H (31%)
      was not significant. The neurological deficits were significantly more severe in
      the N-N group than in the H-22H group during week 4. CONCLUSIONS: The
      neuroprotective effects against temporary focal ischemia evaluated by infarct
      volume and neurological functions by the combination therapy with intraischemic
      and prolonged postischemic mild hypothermia were persistent in rats. Appropriate
      design of mild hypothermia therapy extending into the late reperfusion period is
      important to maximize the neuroprotective effects of hypothermia.

PMID- 10583004
TI  - Contribution of 20-HETE to vasodilator actions of nitric oxide in the cerebral
      microcirculation.
AB  - BACKGROUND AND PURPOSE: The present study examined the contributions of a rise in
      cGMP versus a fall in 20-HETE levels to the vasodilator response to nitric oxide
      (NO) in the cerebral circulation of the rat. METHODS: Intact rat middle cerebral
      and basilar arteries were bathed in physiological saline solution containing
      indomethacin (5 micromol/L) and baicalein (0.5 micromol/L) and pressurized at 90
      mm Hg. Relaxations to sodium nitroprusside (SNP) were studied before and after
      addition of [1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one] (ODQ, a guanylyl
      cyclase blocker), 8R,9S, 11S-(-)-9-methoxy-carbamyl-8-methyl-2,3,9,10-tetrahydro
      8, 11-epoxy-1H,8H,11H-2,7b,11a-trizadibenzo-(a,g)-cycloocta-(c, d, e)-trinden-1
      one (KT5823, a protein kinase G blocker), and 20-hydroxyeicosatetraenoic acid (20
      HETE). Cerebral blood flow was measured by using a laser Doppler flow probe over
      a thin cranial window in anesthetized rats, and the effects of
      intracerebroventricular infusion of 1-hexamine, 6-(2-hydroxy-1-methyl-2
      nitrosohydrazino)N-methyl (MAHMA nonoate) and dibromododecenyl methylsulfimide
      (DDMS) were determined. RESULTS: SNP-induced dilation of serotonin-preconstricted
      (0.2 micromol/L) middle cerebral arteries (10(-7) to 10(-3) mol/L) was attenuated
      in arteries treated with ODQ (10 micromol/L) or KT5823 (1 micromol/L) by 52% and
      27%, respectively. Preventing the NO-induced fall in intracellular 20-HETE, by
      adding 20-HETE (100 nmol/L) to the bath, reduced the dilation to SNP by 62%.
      Simultaneous administration of ODQ and 20-HETE markedly attenuated the SNP
      induced dilation by 90%. In basilar arteries, ODQ (10 micromol/L) alone
      completely blocked the response to SNP. Infusion of MAHMA nonoate (10 nmol/min
      ICV) in anesthetized rats increased cerebral blood flow by 52% before and 8%
      after blockade of the endogenous production of 20-HETE with DDMS (50 pmol/min).
      CONCLUSIONS: These results suggest that NO dilates cerebral arteries through both
      cGMP-dependent and cGMP-independent pathways and that inhibition of 20-HETE
      formation contributes to the cerebral vasodilator response to NO both in vitro
      and in vivo.

PMID- 10583005
TI  - Role of the cerebrovascular and metabolic responses in the delayed phases of
      injury after transient cerebral ischemia in fetal sheep.
AB  - BACKGROUND AND PURPOSE: Perinatal hypoxic-ischemic injuries can trigger a cascade
      of events leading to delayed deterioration and cell death several hours later.
      The objective of this study was to characterize the cerebral blood flow responses
      and the changes in extracellular glucose and lactate during the delayed phases of
      injury and to determine their relationships with the pathophysiological events
      after hypoxic-ischemic injury. METHODS: Two groups of near-term chronically
      instrumented fetal sheep were subjected to 30 minutes of cerebral hypoperfusion.
      In the first group, regional cerebral blood flow was measured over the next 24
      hours with radiolabeled microspheres. In the second, cortical extracellular
      glucose and lactate were measured by microdialysis. Parietal
      electrocorticographic activity and cortical impedance were recorded continuously
      in both groups, and the extent of neuronal loss was determined histologically at
      72 hours after injury. RESULTS: Cerebral blood flow was transiently impaired in
      the cortex during reperfusion, whereas during the delayed phase, there was a
      marked increase in cerebral blood flow. The severity of cortical neuronal loss
      was related to the degree of hypoperfusion in the immediate reperfusion period
      and inversely related to the magnitude of the delayed hyperperfusion. Cortical
      extracellular lactate was elevated after injury, and both glucose and lactate
      secondarily increased during the delayed phase of injury. CONCLUSIONS: The
      delayed phase is accompanied by a period of hyperperfusion that may protect
      marginally viable tissue.

PMID- 10583006
TI  - Experimental model of small deep infarcts involving the hypothalamus in rats:
      changes in body temperature and postural reflex.
AB  - BACKGROUND AND PURPOSE: Intraluminal middle cerebral artery (MCA) occlusion in
      rats has been reported to cause hyperthermia assumed to be caused by hypothalamic
      damage. To clarify the effects of hypothalamic ischemia on body temperature and
      to obtain a model simulating lacunar infarction, we attempted to produce small
      infarcts in deep structures (including the hypothalamus). METHODS: A surgical
      suture was advanced to occlude the origin of the hypothalamic (HTA) and/or
      anterior choroidal arteries (AChA) without compromise of the anterior or middle
      cerebral artery origins. After treatment, rectal temperature and postural reflex
      were examined repeatedly for 3 days under nonanesthetic conditions. The AChA and
      HTA and their link with small deep infarction were then confirmed by TTC,
      hematoxylin and eosin, and TUNEL stains and by microsurgical dissection after
      colored silicone perfusion into the cerebral arteries. RESULTS: Advancement of
      the suture near to but not occluding the MCA origin (0.5 to 1.9 mm proximal)
      produced small, deep, nonneocortical strokes in 25 of 36 animals without
      producing MCA ischemic changes. These infarctions mainly affected the
      hypothalamus in 13 animals (HTA area: infarct volume 6+/-1 mm(3)) and involved
      both the internal capsule and hypothalamus in 12 animals (HTA+AChA area infarct
      volume 48+/-10 mm(3)). Rats with HTA infarction alone exhibited persistent
      hyperthermia for 72 hours; some also had transient mild postural abnormality. The
      AChA+HTA infarct group showed a transient elevation of body temperature for 24
      hours and definitive postural abnormality. In the remaining 11 animals, the
      suture was inadvertently advanced across the MCA origin, producing a large
      infarct that affected both the neocortex (MCA territory) and nonneocortical
      structures (volume 381+/-30 mm(3), n=11). The MCA infarct group displayed a
      transient hyperthermia and severe postural abnormality. CONCLUSIONS: When
      properly positioned, the intraluminal suture method permits selective AChA and/or
      HTA obstruction without inducing MCA territory ischemia. This model confirms that
      selective hypothalamic infarction produces significant and sustained temperature
      regulation abnormalities. The model also may be useful in investigating the
      pathophysiology of small, deep, end-vessel infarction.

PMID- 10583008
TI  - Treatment for ruptured aneurysms and screening for unruptured aneurysms.

PMID- 10583007
TI  - Recommendations for standards regarding preclinical neuroprotective and
      restorative drug development.
AB  - The plethora of failed clinical trials with neuroprotective drugs for acute
      ischemic stroke have raised justifiable concerns about how best to proceed for
      the future development of such interventions. Preclinical testing of
      neuroprotective drugs is an important aspect of assessing their therapeutic
      potential, but guidelines concerning how to perform preclinical development of
      purported neuroprotective drugs for acute ischemic stroke are lacking. This
      conference of academicians and industry representatives was convened to suggest
      such guidelines for the preclinical evaluation of neuroprotective drugs and to
      recommend to potential clinical investigators the data they should review to
      reassure themselves that a particular neuroprotective drug has a reasonable
      chance to succeed in an appropriately designed clinical trial. Without rigorous,
      robust, and detailed preclinical evaluation, it is unlikely that novel
      neuroprotective drugs will prove to be effective when tested in large, time
      consuming, and expensive clinical trials. Additionally, similar recommendations
      are provided for drugs with the potential to enhance recovery after acute
      ischemic stroke, a burgeoning new field with great potential but little currently
      available data. The suggestions contained in this document are meant to serve as
      overall guidelines that must be adapted to the individual characteristics related
      to particular drugs and their preclinical and clinical development needs.

PMID- 10583009
TI  - Small chronic hemorrhages and ischemic lesions in association with spontaneous
      intracerebral hematomas.

PMID- 10583010
TI  - Diffusion MR imaging and transient ischemic attacks.

PMID- 10583011
TI  - Noninvasive vascular assessment in suspected acute basilar artery occlusion.

PMID- 10583012
TI  - Cerebrovascular reactivity in internal carotid artery occlusion.

PMID- 10583014
TI  - Abstracts of literature

PMID- 10583013
TI  - Computed tomographic findings and prediction of malignant middle cerebral artery
      infarction.

PMID- 10583015
TI  - Acetylcholinesterase inhibitors in Alzheimer's disease.

PMID- 10583016
TI  - Nicotine treatment for ulcerative colitis.

PMID- 10583017
TI  - An oral formulation of nicotine for release and absorption in the colon: its
      development and pharmacokinetics.
AB  - AIMS: Ulcerative colitis is predominantly a disease of nonsmokers and transdermal
      nicotine has therapeutic value in active disease; however side-effects are
      troublesome. The aim of this study was to develop an oral formulation of nicotine
      which would be slowly released in the colon over 6 h, and to examine its
      pharmacokinetic profile in 12 healthy volunteers, with measurements of serum
      nicotine and cotinine, its principal metabolite. METHODS: Nicotine was combined
      with a polyacrylic carbomer, Carbopol 974P which was incorporated into 13
      different vehicles and their release profiles examined in vitro. The
      polyglycolized glyceride, Gelucire 50/13, was chosen for subsequent kinetic
      studies because it consistently produced a suitable release pattern which was
      linear. Capsules containing 3 mg nicotine, combined with carbomer in Gelucire
      50/13, were coated with an acrylic resin Eudragit L; this ensured the capsule
      would remain intact until the ileum. On 2 separate days, 6 and 15 mg nicotine,
      contained in 2 and 5 capsules, respectively, were administered to 12 subjects,
      all nonsmokers, mean age 28 years. Serial blood measurements were taken for 36 h,
      serum nicotine and cotinine concentrations were measured by gas liquid
      chromatography. RESULTS: There was considerable intersubject variability in the
      nicotine and cotinine values. Plasma nicotine levels began to rise about 4 h
      after ingestion of the capsules, corresponding with the oro-caecal transit time.
      Cmax nicotine values were 2.2 and 5 ng ml-1, obtained 7 h after the ingestion of
      6 and 15 mg, respectively, of the formulation. The corresponding Cmax values for
      cotinine were 37 and 94.4 ng ml-1, occurring after 9-10 h. The mean for
      elimination half-lives in the 24 studies, including the 6 and 15 mg doses, for
      nicotine were 4.3+/-2.7 h and for cotinine 16.8+/-7.5 h. With 6 mg nicotine
      carbomer, only 1 of 12 volunteers had possible side-effects, but with the 15 mg
      dose 11 out of the 12 reported adverse effects which were systemic or
      gastrointestinal in nature-their timing corresponded with peak serum
      concentrations of nicotine. CONCLUSIONS: An oral formulation of nicotine has been
      developed; in the ileum and colon, this becomes available for slow linear release
      over 6 h and delivers high concentrations of nicotine for topical effect on the
      colon. 6 mg Nicotine was well tolerated, whilst 15 mg gave both systemic and
      gastrointestinal side-effects. High concentrations of topical nicotine in the
      colon are achieved with relatively low systemic bioavailablity-reflected by the
      Cmax and AUC values for nicotine. This, or comparable formulations, may be of
      therapeutic value in ulcerative colitis.

PMID- 10583018
TI  - Stereoselective pharmacokinetics of ketoprofen and ketoprofen glucuronide in end
      stage renal disease: evidence for a 'futile cycle' of elimination.
AB  - AIMS: To assess if futile cycling of ketoprofen occurs in patients with decreased
      renal function. METHODS: Ketoprofen was administered to six haemodialysis
      dependent patients with end-stage renal disease as single (50 mg) or multiple
      doses (50 mg three times daily, for 7 days). Plasma and dialysate concentrations
      of the unconjugated and glucuronidated R- and S-enantiomers of ketoprofen were
      determined using h.p.l.c. following the single and multiple dosing. RESULTS: The
      oral clearance was decreased and terminal elimination half-lives of R- and S
      ketoprofen and the corresponding acyl glucuronides were increased in functionally
      anephric patients compared with healthy subjects. In contrast with the R-isomers,
      S-ketoprofen and S-ketoprofen glucuronide exhibited an unexpected accumulation
      (2.7-3. 8 fold) after repeated dosing achieving S:R ratios of 3.3+/-1.7 and
      11.2+/-5.3, respectively. The plasma dialysis clearances for R- and S-ketoprofen
      glucuronides were 49.4+/-19.8 and 39.0+/-15.9 ml min-1, respectively, and 10.8+/
      17.6 and 13.3+/-23.5 ml min-1 for unconjugated R- and S-ketoprofen. CONCLUSIONS:
      The selective accumulation of S-ketoprofen and its acyl glucuronide are
      consistent with amplification of chiral inversion subsequent to futile cycling
      between R-ketoprofen and R-ketoprofen glucuronide. Severe renal insufficiency,
      and possibly more modest decrements, results in a disproportionate increase in
      systemic exposure to the S-enantiomer which inhibits both pathologic and
      homeostatic prostaglandin synthesis.

PMID- 10583019
TI  - Pharmacokinetics and pharmacodynamics of allopurinol in elderly and young
      subjects.
AB  - AIMS: The prevalence of hyperuricaemia and gout increases with age as does the
      incidence of adverse effects to allopurinol, the major uric acid lowering drug.
      The present study was performed to compare the disposition and effects of
      allopurinol and its active metabolite oxipurinol in elderly and young subjects
      without major health problems. METHODS: Ten elderly (age range 71-93 years) and
      nine young subjects (24-35 years) received an oral dose of 200 mg allopurinol in
      an open, single dose, cross sectional design. Four of these individuals were
      additionally dosed with 200 mg allopurinol intravenously. Plasma and urine
      concentrations of allopurinol, oxipurinol, hypoxanthine, xanthine, and uric acid
      were measured by h. p.l.c. RESULTS: Total clearance of allopurinol was not
      different in elderly (15.7+/-3.8 ml min-1 kg-1, mean+/-s.e. mean) and young
      subjects (15.7+/-2.1), whereas total clearance of oxipurinol was significantly
      reduced in the aged (0.24+/-0.03) compared with young controls (0.37+/-0.05) as
      was the distribution volume of oxipurinol (0.60+/-0.09 and 0.84+/-0.07 l kg-1,
      respectively). Oxipurinol was eliminated primarily by the kidneys, allopurinol by
      metabolism. Fractional peroral bioavailability of allopurinol was 0.81+/-0.16
      (n=4, two elderly and two young subjects). Although maximal plasma concentrations
      of oxipurinol were significantly higher in elderly (5. 63+/-0.83 microgram ml-1 )
      than in young persons (3.75+/-0.25) as was the area under the oxipurinol plasma
      concentration-time curve, AUC (260+/-46 and 166+/-23 microgram ml-1 h,
      respectively), the pharmacodynamic effect of oxipurinol was smaller in elderly
      than young subjects (time-dependent decrease of plasma uric acid 83+/-30
      microgram ml-1 h in elderly compared with 176+/-21 in young controls). Oxipurinol
      increased the renal clearance of xanthine, suggesting inhibition of tubular
      xanthine reabsorption by oxipurinol. CONCLUSIONS: Although allopurinol
      elimination is not reduced in the aged, that of its active metabolite oxipurinol
      is because of an age-dependent decline in renal function. Xanthine oxidase
      inhibition by oxipurinol appears to be reduced in old age. In addition to its
      uricostatic action, oxipurinol has a xanthinuric effect which is also diminished
      in the elderly.

PMID- 10583020
TI  - Pharmacokinetic-pharmacodynamic analysis of mnesic effects of lorazepam in
      healthy volunteers.
AB  - AIMS: To describe the pharmacokinetic-pharmacodynamic modelling of the
      psychomotor and mnesic effects of a single 2 mg oral dose of lorazepam in healthy
      volunteers. METHODS: This was a randomized double-blind, placebo-controlled two
      way cross-over study. The effect of lorazepam was examined with the following
      tasks: choice reaction time, immediate and delayed cued recall of paired words
      and immediate and delayed free recall and recognition of pictures. RESULTS: The
      mean calculated EC50 values derived from the PK/PD modelling of the different
      tests ranged from 12.2 to 15.3 ng ml-1. On the basis of the statistical
      comparison of the EC50 values, the delayed recall trials seemed to be more
      impaired than the immediate recall trials; similar observations were made
      concerning the recognition vs recall tasks. CONCLUSIONS: The parameter values
      derived from PK/PD modelling, and especially the EC50 values, may provide
      sensitive indices that can be used, rather than the raw data derived from
      pharmacodynamic measurements, to compare CNS effects of benzodiazepines.

PMID- 10583021
TI  - Metabolism and excretion of tolcapone, a novel inhibitor of catechol-O
      methyltransferase.
AB  - AIMS: To investigate the rate of excretion and routes of metabolism of tolcapone,
      a novel inhibitor of catechol-O-methyltransferase (COMT). METHODS: Six healthy
      male volunteers were given 200 mg [14C]-tolcapone (approximately 50 muCi) orally.
      To assess excretion balance and to identify metabolites, urine and faeces were
      collected before administration and until radioactivity fell below 75 d min-1 ml
      1 (urine) and 100 d min-1 mg-1 (faeces). Blood samples were collected frequently
      before and after administration to determine plasma radioactivity, to identify
      tolcapone metabolites and to measure plasma tolcapone and its methylated
      derivative 3-O-methyltolcapone (3-OMT). RESULTS: The mean proportion of the dose
      excreted in urine was 57.3% and in faeces 40.5%. Excretion was almost complete
      (more than 95%) in all participants after 9 days. The major early metabolite
      present in plasma was the 3-O-beta, d-glucuronide conjugate, which was detectable
      within 2 h after dosing. The major late metabolite in plasma was 3-OMT. The 3-O
      beta, d-glucuronide was also the most abundant metabolite in urine and faeces,
      accounting for 27% and 33%, respectively, of the total radioactivity excreted by
      these routes and for 26% of the original dose. Reduction of the nitro moiety
      yields an amine derivative, detected in both urine and faeces, with subsequent
      modifications, such as acetylation of the amine group and conjugation with
      glucuronic acid or sulphate, or both. Oxidative reactions due to cytochrome P450
      enzymes are of small significance, as is 3-O-methylation by COMT. CONCLUSIONS:
      Tolcapone is almost completely metabolized and excreted in urine and faeces (only
      0.5% of tolcapone was excreted unchanged); glucuronidation is the most important
      route of metabolism. The relatively long duration of excretion is caused by the
      long half-life of 3-OMT.

PMID- 10583022
TI  - Distribution and excretion of fluoxetine and norfluoxetine in human milk.
AB  - AIMS: To characterize milk/plasma (M/P) ratio and infant dose, for fluoxetine and
      norfluoxetine, in breast-feeding women taking fluoxetine for the treatment of
      depression, and to determine the plasma concentration of these drugs in their
      infants. METHODS: Fourteen women (mean age 32.2 years) taking fluoxetine (mean
      dose 0.51 mg kg-1 day-1 ) and their infants (mean age 3.4 months) were studied.
      Fluoxetine and norfluoxetine in plasma and milk were measured by high-performance
      liquid chromatography over a 24 h dose interval in four patients, and by single
      point data collection in 10 patients. Infant exposure was estimated as the
      product of estimated milk production, and average drug concentration in milk,
      normalized to body weight and expressed as a percentage of the weight-adjusted
      maternal dose. RESULTS: Mean M/P values of 0.68 (95% CI 0.52-0.84) and 0.56 (95%
      CI 0.35-0.77) were calculated for fluoxetine and norfluoxetine, respectively.
      Mean total infant exposure (fluoxetine equivalents) was estimated to be 6.81%
      (range 2.15-12%) of the weight-adjusted maternal dose of fluoxetine.
      Contributions from fluoxetine and norfluoxetine were approximately equal.
      Fluoxetine (range 20-252 microgram l-1 ) was detected in five of the nine infants
      from whom samples were collected, and norfluoxetine (range 17-187 microgram l-1 )
      was detected in seven of the nine infants. The highest of these concentrations
      was about 70% of the maternal plasma concentrations. CONCLUSIONS: The mean
      combined dose of fluoxetine and norfluoxetine transmitted to infants via breast
      milk is below the 10% notional level of concern. However, there was considerable
      interpatient variability in estimated infant dose and in some of the patients,
      the dose was >10%. Further, since adverse effects have been observed in breast
      fed infants, careful monitoring of the infants is mandatory. Neonates exposed to
      these drugs in utero had higher concentrations of fluoxetine and norfluoxetine
      and are at greater risk of adverse effects.

PMID- 10583023
TI  - Identification of the human cytochrome P450 enzymes involved in the in vitro
      metabolism of artemisinin.
AB  - AIMS: The study aimed to identify the specific human cytochrome P450 (CYP450)
      enzymes involved in the metabolism of artemisinin. METHODS: Microsomes from human
      B-lymphoblastoid cell lines transformed with individual CYP450 cDNAs were
      investigated for their capacity to metabolize artemisinin. The effect on
      artemisinin metabolism in human liver microsomes by chemical inhibitors selective
      for individual forms of CYP450 was investigated. The relative contribution of
      individual CYP450 isoenzymes to artemisinin metabolism in human liver microsomes
      was evaluated with a tree-based regression model of artemisinin disappearance
      rate and specific CYP450 activities. RESULTS: The involvement of CYP2B6 in
      artemisinin metabolism was demonstrated by metabolism of artemisinin by
      recombinant CYP2B6, inhibition of artemisinin disappearance in human liver
      microsomes by orphenadrine (76%) and primary inclusion of CYP2B6 in the tree
      based regression model. Recombinant CYP3A4 was catalytically competent in
      metabolizing artemisinin, although the rate was 10% of that for recombinant
      CYP2B6. The tree-based regression model suggested CYP3A4 to be of importance in
      individuals with low CYP2B6 expression. Even though ketoconazole inhibited
      artemisinin metabolism in human liver microsomes by 46%, incubation with
      ketoconazole together with orphenadrine did not increase the inhibition of
      artemisinin metabolism compared to orphenadrine alone. Troleandomycin failed to
      inhibit artemisinin metabolism. The rate of artemisinin metabolism in recombinant
      CYP2A6 was 15% of that for recombinant CYP2B6. The inhibition of artemisinin
      metabolism in human liver microsomes by 8-methoxypsoralen (a CYP2A6 inhibitor)
      was 82% but CYP2A6 activity was not included in the regression tree. CONCLUSIONS:
      Artemisinin metabolism in human liver microsomes is mediated primarily by CYP2B6
      with probable secondary contribution of CYP3A4 in individuals with low CYP2B6
      expression. The contribution of CYP2A6 to artemisinin metabolism is likely of
      minor importance.

PMID- 10583024
TI  - The effect of dosing regimen on the pharmacokinetics of risedronate.
AB  - AIMS: To examine the effect of timing of a risedronate dose relative to food
      intake on the rate and extent of risedronate absorption following single-dose,
      oral administration to healthy male and female volunteers. METHODS: A single
      dose, randomized, parallel study design was conducted with volunteers assigned to
      four treatment groups (31 or 32 subjects per group, 127 subjects total). Each
      subject was orally administered 30 mg risedronate. Group 1 was fasted for 10 h
      prior to and 4 h after dosing (fasted group); Groups 2 and 3 were fasted for 10 h
      and were dosed 1 and 0.5 h, respectively, before a high-fat breakfast; and Group
      4 was dosed 2 h after a standard dinner. Blood and urine samples were collected
      for 168 h after dosing. Pharmacokinetic parameters were estimated by simultaneous
      analysis of risedronate serum concentration and urinary excretion rate-time data.
      RESULTS: Extent of risedronate absorption (AUC and Ae ) was comparable (P=0.4) in
      subjects dosed 2 h after dinner and 0.5 h before breakfast; however, a
      significantly greater extent of absorption occurred when risedronate was given 1
      or 4 h prior to a meal (1.4- to 2.3-fold greater). Administration 0.5, 1, or 4 h
      prior to a meal resulted in a significantly greater rate of absorption (Cmax 2.8
      , 3.5-, and 4.1-fold greater, respectively) when compared with 2 h after dinner.
      CONCLUSIONS: The comparable extent of risedronate absorption when administered
      either 0.5-1 h before breakfast or 2 h after an evening meal support previous
      clinical studies where risedronate was found to have similar effectiveness using
      these dosing regimens. This flexibility in the timing of risedronate
      administration may provide patients an alternative means to achieve the desired
      efficacy while maintaining their normal daily routine.

PMID- 10583025
TI  - Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated
      transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice
      components.
AB  - AIMS: Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) are both expressed
      in the intestinal mucosa and present a barrier to oral drug delivery. CYP3A4 and
      P-gp share both overlapping tissue distribution and substrate specificity.
      Grapefruit juice interactions with CYP3A4 substrates are well documented and
      occur as a consequence of down regulation of intestinal CYP3A4. The aim of the
      present study was to screen grapefruit juice components against the CYP3A4
      mediated metabolism and P-gp mediated transport of the HIV-1 protease inhibitor
      saquinavir. METHODS: Five grapefruit juice components: quercetin, naringin,
      naringenin, 6', 7'-dihydroxybergamottin and bergamottin were screened as
      potential inhibitors of the metabolism of saquinavir by human liver microsomes.
      The known CYP3A4 inhibitor ketoconazole was also screened for inhibitory
      potential. These compounds were also screened as modulators of P-gp activity by
      assessing the directional transport of saquinavir across Caco-2 cell monolayers
      which express P-gp. The effect of verapamil, a known modulator of P-gp function,
      was also determined in these cell lines. RESULTS: On preincubation, 6', 7'
      dihydroxybergamottin and bergamottin inhibited the metabolism of saquinavir, with
      IC50 values of 0.33+/-0.23 muM and 0.74+/-0.13 muM, respectively (n=3).
      Ketoconazole achieved an IC50 of 0. 55+/-0.12 muM (n=4). The other compounds
      studied failed to reach IC50 at concentrations of up to 100 muM. The transport of
      saquinavir in the basolateral-->apical (BL-->AP) direction exceeded that in the
      apical -->basolateral direction (AP-->BL), with apparent permeability
      coefficients of 199.2+/-15.8x10-7 cm s-1 and 8.00+/-1. 13x10-7 cm s-1,
      respectively (n=3) which is indicative of a polarized efflux mechanism. The ratio
      of BL-->AP/AP-->BL for saquinavir was 25, but in the presence of verapamil and
      ketoconazole this ratio was reduced to 3.6 and 4.0, respectively (n=3),
      indicating extensive inhibition of P-gp mediated saquinavir efflux. Of the
      grapefruit juice components studied only naringin and 6', 7'-dihydroxybergamottin
      had any appreciable effect, reducing the ratio to 7.6 and 7.1, respectively
      (n=3); but this was due solely to increased AP-->BL transport. CONCLUSIONS:
      Grapefruit juice components inhibit CYP3A4-mediated saquinavir metabolism and
      also modulate, to a limited extent, P-gp mediated saquinavir transport in Caco-2
      cell monolayers. The in vivo effects of grapefruit juice coadministration are
      most likely the result of effects on CYP3A4 (inhibition and down regulation) and
      only to a minor extent on modulation of P-gp function.

PMID- 10583026
TI  - Fluoxetine inhibits the metabolism of tolterodine-pharmacokinetic implications
      and proposed clinical relevance.
AB  - AIMS: To investigate the change in disposition of tolterodine during
      coadministration of the potent cytochrome P450 2D6 (CYP2D6) inhibitor fluoxetine.
      METHODS: Thirteen patients received tolterodine l-tartrate 2 mg twice daily for
      2.5 days, followed by fluoxetine 20 mg once daily for 3 weeks and then
      concomitant administration for an additional 2.5 days. They were characterized as
      extensive metabolizers (EM1 with one functional CYP2D6 gene, EM2 with two
      functional genes) or poor metabolizers (PM). RESULTS: Nine patients, three EM2
      and four EM1 and two PM, completed the trial. Following tolterodine
      administration, the area under the serum concentration-time curve (AUC) of
      tolterodine was 4.4-times and 30-times higher among EM1 and PM, respectively,
      compared with EM2. The AUC of the 5-hydroxymethyl metabolite (5-HM) was not
      quantifiable in PM. Fluoxetine significantly decreased (P<0.002) the oral
      clearance of tolterodine by 93% in EM2 and by 80% in EM1. The AUC of 5-HM
      increased in EM2 and decreased in EM1. However, the exposure to the active moiety
      (unbound tolterodine +5-HM) was not significantly increased in the two
      phenotypes. The subdivision of the EM group showed a 2.1-fold increase in active
      moiety in EM2 but the exposure was still similar to EM1 compared with before the
      interaction. CONCLUSIONS: The study suggests a difference in the pharmacokinetics
      of tolterodine and its 5-hydroxymethyl metabolite depending on the number of
      functional CYP2D6 genes. Fluoxetine significantly inhibited the hydroxylation of
      tolterodine. Despite the effect on the pharmacokinetics of tolterodine in
      extensive metabolizers, the clinical effect is expected to be within normal
      variation.

PMID- 10583027
TI  - Ketoconazole inhibits the metabolism of tolterodine in subjects with deficient
      CYP2D6 activity.
AB  - AIMS: To investigate the pharmacokinetics and safety of tolterodine and
      tolterodine metabolites after single-and multiple-dose administration in the
      absence and presence of ketoconazole, an inhibitor of cytochrome P450 (CYP) 3A4,
      in healthy volunteers with deficient CYP2D6 activity, i.e. poor metabolisers of
      debrisoquine. METHODS: Eight healthy volunteers received single oral doses (2 mg)
      of tolterodine l-tartrate. Following a wash-out period of about 3 months, six of
      the subjects participated in a multiple-dose (1 mg twice daily) phase of the
      study. Ketoconazole 200 mg was given once daily for 4-4.5 days during both the
      single and multiple dose tolterodine administration phases. Blood samples were
      drawn and the pharmacokinetics of tolterodine and its metabolites were
      determined. RESULTS: A decrease (P<0.01) in apparent oral clearance of
      tolterodine, from 10- 12 l h-1 to 4.3-4.7 l h-1, was obtained during concomitant
      administration of ketoconazole, yielding at least a two-fold increase in the area
      under the serum concentration-time curve after single as well as after multiple
      doses following single dose administration of tolterodine. The mean (+/-s.d.)
      terminal half-life increased by 50% from 9.7+/-2.7 h to 15+/-5.4 h in the
      presence of ketoconazole. CONCLUSIONS: CYP3A4 is the major enzyme involved in the
      elimination of tolterodine in individuals with deficient CYP2D6 activity (poor
      metabolisers), since oral clearance of tolterodine decreased by 60% during
      ketoconazole coadministration. This inhibition resulted in 2.1-fold increase in
      AUC.

PMID- 10583028
TI  - Lymphocyte-sensitivity to glucocorticoid correlates with the sensitivity to
      cyclosporin A and tacrolimus in chronic renal failure patients.
AB  - AIMS: Association between lymphocyte-sensitivity to immunosuppressants in
      transplant recipients in vitro and clinical outcomes has been demonstrated. In
      general, renal transplant recipients are treated with a combination of
      immunosuppressants such as either glucocorticoid/cyclosporin A (CsA) or
      glucocorticoid/tacrolimus (FK506) but the pharmacological complementarity of
      these drugs is still controversial. We examined relationships between the
      lymphocyte-sensitivities to these immunosuppressants. METHODS: We examined
      lymphocyte-sensitivities to prednisolone (PSL), CsA, and FK506 in vitro in a
      total of 190 chronic renal failure (CRF) patients and 140 healthy subjects. The
      lymphocyte-sensitivity was evaluated from the IC50 value against mitogen
      stimulated lymphocyte-blastogenesis in vitro. RESULTS: Statistically significant
      correlations of the IC50 values in CRF patients between the following pairs of
      drugs were observed: PSL and CsA (P<0.0001; n=129, r=0.419), PSL and FK506
      (P<0.001; n=54, r=0. 441), and CsA and FK506 (P<0.0001; n=45, r=0.608). Similar
      correlations were also observed in lymphocytes from healthy subjects. The
      population of CRF patients who exhibited high IC50 values (low sensitivities) to
      PSL and FK506 was significantly larger than that of healthy subjects (P<0.05).
      CONCLUSIONS: Patients who showed low lymphocyte-sensitivity to either of the
      drugs also may exhibit low sensitivity to the others, and thus they may have a
      high risk of unsatisfactory outcome under combination therapy after renal
      transplantation. To overcome this risk, the selection of immunosuppressants is
      recommended to be restricted according to individual lymphocyte-sensitivities to
      these drugs in vitro, or alternatively, by addition of other drugs with different
      mechanisms for immunosuppression.

PMID- 10583029
TI  - Short-term dose-response relationships for the relative systemic effects of oral
      prednisolone and inhaled fluticasone in asthmatic adults.
AB  - AIMS: To determine the systemic dose-response relationships with oral
      prednisolone and inhaled fluticasone propionate administered in a putative 11:1
      mg equivalent basis, in terms of effects on adrenal, bone and haematological
      markers. METHODS: Twelve asthmatic patients mean (s.e.) age, 28.8 [3.3] years,
      FEV1 94.7 [3.6]% predicted, FEF(25-75) 65.5 [6.1]% predicted were studied in a
      double-blind, double dummy randomised crossover design comparing placebo, inhaled
      fluticasone propionate via volumatic spacer given twice a day (ex actuator dose
      0.44 mg day-1, 0.88 mg day-1, 1.76 mg day-1 ) and oral prednisolone given once
      daily (5 mg day-1, 10 mg day-1, 20 mg day-1 ). All treatments were for 4 days at
      each dose level with a 7-day washout at crossover. Measurements were made at
      08.00 h after the last dose of each dose level for plasma cortisol, serum
      osteocalcin and blood eosinophil count. RESULTS: There were significant dose
      related effects for suppression of all three endpoints with both prednisolone and
      fluticasone propionate. Parallel slope analysis revealed a calculated dose ratio
      for relative potency of 8. 5:1 mg (95% CI 5.7-11.2) comparing Pred with FP for
      morning cortisol. The magnitude of suppression with FP was less for osteocalcin
      and eosinophils than for cortisol. CONCLUSIONS: Systemic tissues exhibit
      different dose-response relationships for the effects of inhaled and oral
      corticosteroids with suppression of cortisol being greater than osteocalcin or
      eosinophils. For cortisol suppression we observed an 8.5:1 mg relative potency
      ratio comparing prednisolone with fluticasone propionate. Patients taking high
      dose inhaled fluticasone propionate should therefore be screened for evidence of
      impaired adrenal reserve.

PMID- 10583030
TI  - Evaluation of noninvasive blood pressure recording by photoplethysmography in
      clinical studies using angiotensin challenges.
AB  - AIMS: Continuous noninvasive blood pressure measurement by photoplethysmography
      has been regularly used in the experimental paradigm of angiotensin challenges,
      applied to the phase I clinical testing of angiotensin-converting enzyme
      inhibitors and angiotensin receptor antagonists. This work aims to evaluate the
      performance of this measurement method, in terms of reliability, reproducibility
      and dependence on technical settings. METHODS: Data have been gathered from 13
      clinical studies on antihypertensive drugs, using the Finapres device for
      measuring the response to exogenous angiotensin challenges. The agreement between
      simultaneous recordings at different fingers and the influence of the reading
      method are assessed. A literature review addresses the question of the
      concordance between results obtained noninvasively and through arterial
      cannulation. RESULTS: The relative precision of blood pressure monitoring by
      photoplethysmography allows reproducible determination of angiotensin-induced
      blood pressure peaks (agreement limits for systolic and diastolic peaks: 12 and 6
      mmHg respectively). The reading method influences the results to a similar
      extent. As compared with blood pressure measured intra-arterially, the difference
      is usually within limits of clinical acceptability. CONCLUSIONS: In the context
      of phase I studies using the angiotensin challenges methodology, the reliability
      and reproducibility of noninvasive blood pressure measurement appear
      satisfactory, despite the technical limitations of this method. The impact of
      selected changes in the settings and reading methods is limited.

PMID- 10583031
TI  - Evaluation of the angiotensin challenge methodology for assessing the
      pharmacodynamic profile of antihypertensive drugs acting on the renin-angiotensin
      system.
AB  - AIMS: The performance of the experimental paradigm of angiotensin challenges with
      continuous non-invasive blood pressure measurement was evaluated. Angiotensin
      dose-response relationships were characterized, along with the influence of
      clinical covariates. The stability of angiotensin-induced peaks and the
      variability of the angiotensin doses were assessed. Finally, the predictive value
      of studies based on angiotensin challenges to determine drug doses effective in
      therapeutics was evaluated. METHODS: The data were gathered from 13 clinical
      studies on nine angiotensin II receptor antagonists, one ACE inhibitor and one
      dual ACE-NEP inhibitor, using Finapres for measuring the response to exogenous
      angiotensin challenges. Modelling of angiotensin dose-response curves and
      determination of the inter and intrasubject variability were performed by
      nonlinear regression (NONMEM). The different sources of variations in angiotensin
      I and II doses and angiotensin-induced peaks were evaluated by analyses of
      variance. The dose of ACE inhibitors and angiotensin II receptor antagonists
      inhibiting blood pressure increase by at least 75%, as measured by this method,
      was chosen for comparison with the labelled starting dose. RESULTS: Angiotensin
      challenges exhibited a clear dose-response relationship which can be
      characterized both by an Emax or a log linear model. The log linear model gave an
      average systolic/diastolic response of 24+/-6/20+/-5 mmHg for a unit dose of 1
      microgram of angiotensin II equivalents, and an increase of 6/6 mmHg for each
      doubling of the dose. The angiotensin ED50 calculated values were 0.67 microgram
      for systolic and 0.84 microgram for diastolic blood pressure. The angiotensin
      doses for eliciting a given response and the angiotensin induced peaks were
      fairly constant between period and subject, but vary significantly between
      studies. Based on an inhibition of blood pressure by 75%, the agreement was good
      between the doses of ACE inhibitors and angiotensin receptor antagonists
      predicted from studies using the methodology of angiotensin challenges and the
      doses shown to be clinically efficacious, in spite of high intersubject and
      intrasubject variabilities. CONCLUSIONS: This experimental method represents a
      valid surrogate for the therapeutic target and a useful tool for the
      pharmacokinetic and pharmacodynamic profiling of drugs acting on the renin
      angiotensin system.

PMID- 10583033
TI  - Enhanced cholesterol reduction by simvastatin in diltiazem-treated patients.
AB  - AIMS: To investigate whether an interaction between diltiazem and the 3-hydroxy-3
      methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin may enhance
      the cholesterol-lowering response to simvastatin in diltiazem-treated patients.
      METHODS: One hundred and thirty-five patients attending the Sheffield
      hypertension clinic who started consecutively on simvastatin for primary or
      secondary prevention of coronary heart disease (CHD) during the 2 years June,
      1996-May 1998 were surveyed. From the clinic records we extracted and recorded
      absolute and percentage cholesterol responses to the starting dose of simvastatin
      and coprescription of diltiazem. RESULTS: The cholesterol reduction for the 19
      patients on diltiazem was 33.3% compared with 24.7% in the remaining 116 patients
      (median difference 8.6%, 95% CI 1.1-12.2%, P<0.02). The interindividual
      variability of cholesterol response to simvastatin was greater for patients not
      taking diltiazem than for those patients taking diltiazem. The ratio of the
      variances in response for the nondiltiazem group relative to the diltiazem group
      was 1.34 at 10 mg simvastatin daily (not significant, 95% CI 0.16-4.11), and 3.42
      at 20 mg daily (P<0.01, 95% CI 1.26-7.18). Concurrent diltiazem therapy (P<0.04),
      age (P=0.001) and starting dose of simvastatin (P=0.002) were found to be
      significant independent predictors of percentage cholesterol response.
      CONCLUSIONS: Patients who take both simvastatin and diltiazem may need lower
      doses of simvastatin to achieve the recommended reduction in cholesterol. The
      pharmacokinetic and pharmacodynamic aspects of this interaction need further
      study to confirm an enhanced effect on cholesterol reduction, and exclude an
      increased risk of adverse events.

PMID- 10583032
TI  - Acarbose is an effective adjunct to dietary therapy in the treatment of
      hypertriglyceridaemias.
AB  - AIMS: In diabetics, acarbose causes a reduction of blood glucose and triglyceride
      levels. The aim of this study was to assess the effect of this drug in non
      diabetic subjects with hypertriglyceridaemia. METHODS: Thirty non diabetic
      patients with hypertriglyceridaemia type IIb or IV (24 males, six females; mean
      age 51.1+/-10.2 years) were studied. They were stratified into two groups
      depending on their basal triglyceride concentration (group A: triglyceride values
      </=4.5 mmol l-1; group B triglyceride values >4.5 mmol l-1 ). Treatment consisted
      of 4 week courses of diet plus acarbose (50 mg twice daily) alternating with 4
      weeks of diet alone for a total period of 16 weeks. RESULTS: Mean triglyceride
      values decreased significantly during the first and third cycles of therapy, i.e.
      diet plus acarbose treatment cycles in both patient groups. Group A also had
      significant reductions in total cholesterol and HDL cholesterol concentrations
      after completion of the acarbose treatment. Reduction of triglyceride levels was
      observed after both acarbose courses in patients affected by
      hypertriglyceridaemia type IIb. A marked reduction of triglyceride concentrations
      was achieved by patients affected by hypertriglyceridaemia type IV after the
      second acarbose course only. CONCLUSIONS: Diet alone did not reduce triglyceride
      concentrations to normal values in our patients. The data suggest that acarbose
      is a useful adjunct to dietary control in non-diabetic patients affected by
      severe hypertriglyceridaemia.

PMID- 10583034
TI  - Impact of guidelines implemented in a paris university hospital: application to
      the use of antiemetics by cancer patients.
AB  - AIMS: To assess the impact with time of guidelines on antiemetic use in an 850
      bed Paris university hospital with a high proportion of cancer patients. METHODS:
      Guidelines on the use of antiemetics available in cancer chemotherapy were
      drafted according to the Delphi technique. Their implementation was based upon a
      patient-specific antiemetic prescription form. To assess the impact of guideline
      implementation over time, discrepancies between current practice and the
      guidelines were compared before guideline implementation (between March and
      August 1995) and after implementation (between March and August 1997, and March
      and August 1998). RESULTS: Before the Delphi panel's guidelines were implemented,
      5-HT3 antagonists were inappropriately administered in 70% of cases. After
      guideline implementation, this proportion dropped significantly (P<0.0001,
      Fisher's exact test) to 22% between March and August 1997 and 28% between March
      and August 1998. CONCLUSIONS: Implementation of guidelines seems to have resulted
      in significant changes with time, although a causal relationship has not been
      demonstrated. The development of guidelines by our hospital's multidisciplinary
      working group helped the various consultants to adjust medical practices to take
      account of these changes.

PMID- 10583035
TI  - Attitudinal survey of voluntary reporting of adverse drug reactions.
AB  - AIMS: Voluntary adverse drug reaction (ADR) reporting schemes have operated since
      the early sixties in many Western countries. It is generally recognized, however,
      that only a small proportion of ADRs is actually reported. The current survey was
      conducted to assess attitudes towards reporting of ADRs, and to study which types
      of ADRs are reported. METHODS: A questionnaire seeking reasons for nonreporting
      was sent to a random sample of 10% of medical practitioners in The Netherlands in
      October 1997. After 6 weeks, a reminder was sent to those who had not responded.
      RESULTS: One thousand four hundred and forty-two (73%) questionnaires were
      returned, of which 94% were complete. The percentage of GPs (51%) which had ever
      reported an ADR to the national reporting centre was significantly higher than
      the percentage of specialists (35%), who reported more often to the
      pharmaceutical industry (34% vs 48%). 86% of GPs, 72% of surgical specialists and
      81% of medical specialists had ever diagnosed an ADR, which they had not
      reported. Uncertainty as to whether the reaction was caused by a drug (72%), the
      ADR being trivial (75%) or too well known (93%) were the most important reasons
      for not reporting. 18% were not aware of the need to report ADRs, 22% did not
      know how to report ADRs, 38% did not have enough time, 36% thought that reporting
      was too bureaucratic and only 26% of Dutch physicians knew which ADRs to report.
      A serious ADR, an unlabelled ADR, an ADR to a new drug, history of reporting of
      one or more ADRs, and specialty were all independently associated with reporting
      of 16 hypothetical ADRs. Surgical and medical specialists tended to report less
      often than GPs. CONCLUSIONS: There is a considerable degree of underreporting,
      which might partly be explained by lack of knowledge and misconceptions about
      spontaneous reporting of adverse drug reactions.

PMID- 10583036
TI  - Persistence of anti-hypertensive effect after missed dose of perindopril.
AB  - AIMS: To assess the persistence of the antihypertensive effect of the ACE
      inhibitor perindopril after one missed dose. METHODS: After a placebo run-in
      period, 10 hypertensive patients were started on perindopril 4 mg once daily in
      the morning, increased to 8 mg once daily after 4 weeks if office diastolic BP
      >85 mmHg. 24 h BP monitoring was performed at the end of the placebo run-in
      period and during active treatment in week 9 and 10 on either active treatment or
      a placebo-day using a double-blind, randomized, cross-over design. RESULTS:
      Office BP decreased from 155+/-3/100+/-2 mmHg at the end of placebo to 139+/
      3/89+/-2 mmHg (P<0.05 vs placebo) after 8 weeks of active treatment. After 2
      months of active treatment, 24 h ABP showed significant decreases in day BP by 
      11+/-1/-7+/-1 mmHg and in night BP by -11+/-2/-7+/-1 mmHg while on active
      treatment. During the placebo-day, daytime BP showed decreases by -10+/-1/-5+/-1
      and night BP by -8+/-2/-6+/-1 mmHg (NS vs active treatment day). CONCLUSIONS:
      Perindopril 4-8 mg day-1 causes a persistent decrease in BP during the 24 h
      dosing interval, which is mostly maintained over the 24-48 h after dosing.

PMID- 10583037
TI  - Fenoterol stimulates human erythropoietin production via activation of the renin
      angiotensin system.
AB  - AIMS: The present study assessed the hypothesis that the beta2 sympathomimetic
      fenoterol influences the production of erythropoietin (EPO) by activation of the
      renin angiotensin system (RAS), i.e. angiotensin II. METHODS: In an open,
      parallel, randomized study healthy volunteers received i.v. either placebo
      (electrolyte solution), fenoterol or fenoterol in combination with an oral dose
      of the AT1-receptor antagonist losartan. RESULTS: Compared with placebo treatment
      AUCEPO(0,24 h) was significantly increased after fenoterol application by 48%
      whereas no increase in the group receiving fenoterol and losartan could be
      detected. The rise of PRA was statistically significant under fenoterol and
      fenoterol plus lorsartan. CONCLUSIONS: Stimulation of EPO production during
      fenoterol infusion appears to be angiotensin II-mediated. Thus, angiotensin II
      may be considered as one important physiological modulator of EPO production in
      humans.

PMID- 10583038
TI  - Absorption of sunscreens across human skin: an evaluation of commercial products
      for children and adults.
AB  - AIMS: Topical sunscreens are routinely applied to the skin by a large percentage
      of the population. This study assessed the extent of absorption of a number of
      common chemical sunscreen agents into and through human skin following
      application of commercially available products. METHODS: Sunscreen products were
      applied to excised human epidermis in Franz diffusion cells with the amount
      penetrating into and across the epidermis assessed by h.p.l.c. for 8 h following
      application. RESULTS: All sunscreen agents investigated penetrated into the skin
      (0.25 g m-2 or 14% of applied dose), but only benzophenone-3 passed through the
      skin in significant amounts (0.08 g m-2 or 10% of the applied dose). With one
      exception, suncreen agents in corresponding products marketed for adults and
      children had similar skin penetration profiles. CONCLUSIONS: Whilst limited
      absorption across the skin was observed for the majority of the sunscreens
      tested, benzophenone-3 demonstrated sufficiently high penetration to warrant
      further investigation of its continued application.

PMID- 10583040
TI  - Editorial comments

PMID- 10583041
TI  - The british association of dermatologists guidelines for the management of skin
      disease

PMID- 10583039
TI  - Possible enhancement of the first-pass metabolism of phenacetin by ingestion of
      grape juice in Chinese subjects.
AB  - AIMS: This serendipitous study revealed an unexpected effect of Jufeng grape
      juice on the CYP1A2-mediated metabolism of phenacetin. Investigation of the
      inhibition of CYP1A2 by grapefruit juice was involved but a translation error led
      to the grape juice substitution. METHODS: Twelve healthy subjects took a single
      oral dose of phenacetin (900 mg) on two randomized occasions together with 200 ml
      water or grape juice. Plasma phenacetin and paracetamol concentrations were
      assessed by h.p.l.c. RESULTS: Ingestion of grape juice was associated with
      reduced plasma phenacetin concentrations, while paracetamol levels were
      unaffected. Paracetamol to phenacetin AUC ratios increased from 13.9+/-3.1 to
      24.3+/-3.8 after ingestion of grape juice. CONCLUSIONS: These findings suggest
      enhanced first-pass metabolism of phenacetin, due to CYP1A2 activation by grape
      juice or to desaturation of CYP1A2 isoenzymes secondary to a slower rate of
      phenacetin absorption.

PMID- 10583042
TI  - The psychosocial consequences of androgenetic alopecia: a review of the research
      literature.
AB  - Androgenetic alopecia is a common dermatological condition, with potentially
      adverse psychosocial sequelae. The present review critically examines scientific
      evidence concerning the effects of androgenetic hair loss on social processes and
      psychological functioning, as well as the psychosocial outcomes of medical
      treatments. Research confirms a negative but modest effect of visible hair loss
      on social perceptions. More importantly, androgenetic alopecia is typically
      experienced as a moderately stressful condition that diminishes body image
      satisfaction. Deleterious effects on self-esteem and certain facets of
      psychological adjustment are more apparent among women than men and among
      treatment-seeking patients. Various 'risk factors' vis-a-vis the psychological
      adversity of androgenetic alopecia are identified. Medical treatments, i.e.
      minoxidil and finasteride, appear to have some psychological efficacy. A
      conceptual model is delineated to explain the psychological effects of hair loss
      and its treatment. Directions for needed research are discussed. Strategies are
      presented for the clinical management of psychological issues among these
      patients.

PMID- 10583043
TI  - Characterization of photosensitivity in the Smith-Lemli-Opitz syndrome: a new
      congenital photosensitivity syndrome.
AB  - Photosensitivity has recently been reported as a feature of the Smith-Lemli-Opitz
      syndrome (SLO). The aim of this study was to establish the photobiological
      features of this disorder and to examine the hypothesis that the photosensitivity
      is caused by the high levels of 7-dehydrocholesterol found in SLO. All known
      cases of SLO in the U.K. were reviewed and clinical details of photosensitivity
      were recorded in detail. The action spectrum of the photosensitive eruption was
      defined by monochromator light testing. Thirteen of the 23 subjects (57%) had
      severe photosensitivity, and in 10 there was no photosensitivity. No correlation
      was identified between levels of 7-dehydrocholesterol and severity of
      photosensitivity, suggesting that the photosensitivity in SLO is not caused by a
      direct phototoxic effect mediated by 7-dehydrocholesterol. A novel pattern of
      photosensitivity was observed, with onset of a sunburn-like erythema on sun
      exposed skin within minutes of sun exposure, which persisted in most cases for up
      to 24-48 h before fading. Monochromator light testing in three subjects showed an
      ultraviolet (UV) A-mediated photosensitivity eruption with greatest
      photosensitivity at 350 nm. Photosensitivity is a common and prominent feature of
      SLO and appears to be UVA-mediated. Elucidation of its biochemical basis may
      provide insight into normal cutaneous protective mechanisms against UVA-induced
      photodamage, and also sun sensitivity in general.

PMID- 10583044
TI  - Guidelines for the management of basal cell carcinoma. British Association of
      Dermatologists.
AB  - These guidelines on the management of basal cell carcinoma have been prepared for
      dermatologists on behalf of the British Association of Dermatologists. They
      present evidence-based guidance for treatment, with identification of the
      strength of evidence available at the time of preparation of the guidelines, and
      a brief overview of epidemiological aspects, diagnosis and investigation.

PMID- 10583045
TI  - The British Association of Dermatologists audit of atopic eczema management in
      secondary care. Phase 1: audit of service structure.
AB  - This first comprehensive study of atopic eczema management describes an audit of
      service structure (phase 1), process (phase 2) and outcome (phase 3) in the U.K.
      This paper describes the phase 1 results. Service structure was audited by a
      single-page questionnaire containing 10 questions on outpatient facilities. This
      was sent to the lead dermatologist at 187 dermatology centres throughout the
      U.K., and a final response rate of 98% was achieved. Although the percentage of
      centres reporting the presence of recommended facilities did not reach the 100%
      working standard for any one specific criterion, about half of the recommended
      items, such as provision of height and weight measuring facilities, access to a
      dietician, patch testing and photochemotherapy, was reported in over 90% of
      centres. Areas of service structure which were infrequently reported to be in
      place were issuing of new appointment letters asking patients to bring their
      treatment details to clinic (52% of centres) and access to nurses with
      dermatology experience on paediatric wards (57% of centres). Some audit measures,
      e.g. access to counselling services, showed wide regional variation (range 33-94%
      of centres), and these variations could not be explained simply in terms of
      provision of specialists. Some of the elements of service structure, such as
      access to nurses with dermatology experience on paediatric wards, may be
      difficult to change in the short term because of funding and staffing
      constraints, but others, such as provision of growth charts, are easy to change
      at little cost. This preliminary audit serves as a framework for future audits of
      atopic eczema management.

PMID- 10583046
TI  - Luteinizing hormone/human chorionic gonadotrophin receptors in various epidermal
      structures.
AB  - Two different monoclonal antibodies recognizing different epitopes were used to
      study the localization of luteinizing hormone/human chorionic gonadotrophin
      (LH/hCG) receptors in human skin. Immunolabelling was observed only in the
      epidermis and derived structures but not in the dermis. The basal, spinal and
      granular layers were stained, whereas no receptors were detected in the non
      nucleated horny cells. In the growing (anagen) hair, immunostaining was found in
      the inner root sheath below the level of the sebaceous glands and in the outer
      root sheath above this level. In the resting (telogen) hair, only the latter
      staining was observed. In the sebaceous glands, only the thin cells close to the
      walls of the ducts were immunolabelled. In the eccrine sweat glands, the external
      clear cells were stained in the secretory portion of the gland, whereas only the
      cells close to the lumen were labelled in the ducts. The distribution of LH/hCG
      receptors was compared with that of steroidogenic enzymes (side chain cleavage
      cytochrome P450, adrenodoxin, 3-beta-hydroxy-5-ene steroid dehydrogenase Delta5
      Delta4 isomerase, 17-hydroxylase cytochrome P450 and cytochrome P450 aromatase).
      Only partial overlaps were observed. The presence of LH receptor mRNA in the skin
      was confirmed by reverse transcription-polymerase chain reaction. Monoclonal
      antibodies raised against the human follicle-stimulating hormone receptor failed
      to detect the latter in the epidermal structures and in the dermis. The role of
      LH and hCG in skin modifications occurring during pregnancy and after the
      menopause is unknown. These hormones may possibly act by regulating steroidogenic
      enzymes or by modulating cell growth and differentiation.

PMID- 10583047
TI  - Epimorphin expression during human foetal hair follicle development.
AB  - Epimorphin is a mesenchymal protein expressed in several organs and known to have
      an essential role in epithelial tissue organization, including hair follicle
      morphogenesis, in mice. Although about 90% homology has been reported between
      human and mouse epimorphin exon sequences, there is no information about
      expression and function of epimorphin in hair follicle development in humans. In
      order to elucidate the expression pattern of epimorphin in human hair follicle
      morphogenesis and to compare it with the distribution of tenascin and neural cell
      adhesion molecule (NCAM), skin samples from human foetuses of a series of
      estimated gestational ages (EGAs) (46-168 days EGA) were studied using monoclonal
      anti-epimorphin antibody MC-1, anti-tenascin antibody and anti-human NCAM
      antibody. Epimorphin was detected in the mesenchymal cell condensation at the
      pregerm stage (< 75 days EGA), and there was strong expression of epimorphin in
      the perifollicular mesenchymal cells around the hair germ (75-84 days EGA). At
      the hair peg stage (85-104 days EGA), epimorphin was around the hair peg with the
      strongest staining in the neck portion. This sequence of staining patterns was
      similar to that of tenascin. In the bulbous hair peg (105-134 days EGA), the
      perifollicular dermal mesenchymal cells were evenly positive for epimorphin.
      Mesenchymal cells underneath the follicle bulb prior to formation of the dermal
      papilla were also positive for epimorphin. In the lanugo hair follicle (> 134
      days EGA), dermal papilla cells expressed epimorphin as well as tenascin and
      NCAM. These results indicate that epimorphin expression is closely linked to
      developing hair follicles in human foetuses. This suggests that epimorphin may
      have an important part in induction of morphogenesis during human foetal hair
      follicle development.

PMID- 10583048
TI  - Role of endogenous cathepsin D-like and chymotrypsin-like proteolysis in human
      epidermal desquamation.
AB  - Even though the skin surface is acidic (about pH 5), most in vitro studies on
      desquamation have been performed at alkaline pH. We demonstrate that the standard
      in vitro model system, which achieves squame shedding upon incubation of plantar
      stratum corneum for 1 day in an alkaline buffer that must include a chelating
      agent, can be extended to a more realistic model in which the incubation is for 4
      days, at varying pHs from 5 to 8, without exogenous chelators. Desmoglein I from
      stratum corneum was degraded by the squames shed at pH 5 as well as at pH 8.
      Squame shedding was inhibited to varying extents by the addition of proteinase
      inhibitors, whose specificity suggested that the crucial enzymatic activity at pH
      8 was a chymotrypsin-like serine proteinase, while a similar activity at pH 5 was
      accompanied by an aspartic proteinase activity of comparable strength. Four
      degradation peaks were observed when the insulin B chain was reacted with shed
      squames at pH 5. Two of these peptides were suppressed by the addition of
      phenylmethylsulphonyl fluoride, the other two by pepstatin A; chymostatin
      inhibited all four, but E-64 and leupeptin showed no effect. The implied
      specificity was confirmed by reacting the insulin (without squames) with the
      standard enzymes human liver cathepsin D and pancreatic chymotrypsin, reproducing
      the expected degradation products. These results suggest that epidermal
      desquamation at acidic pH requires two proteolytic activities, one of which is an
      analogue of chymotrypsin and the other of cathepsin D. Endogenous proteinases
      corresponding to these activities have been previously identified, namely the
      stratum corneum chymotryptic enzyme and the mature active form of cathepsin D.

PMID- 10583049
TI  - Cytochrome P450, CYP26AI, is expressed at low levels in human epidermal
      keratinocytes and is not retinoic acid-inducible.
AB  - Retinoids, and their synthetic analogues, are well-established regulators of the
      squamous differentiation programme both in vivo and in vitro. Despite this, very
      few studies have focused on the mechanism by which retinoid action is terminated,
      e.g. metabolism. Recently, a new cytochrome P450 family member (CYP26AI) was
      cloned. CYP26AI was reported to have substrate specificity for retinoids and to
      be retinoid-inducible. In this study, we have examined the expression and
      retinoic acid (RA) inducibility of CYP26AI in human epidermis and cultured
      keratinocytes. We found very low levels of CYP26AI mRNA expression in both
      epidermis and keratinocytes. Furthermore, we found no evidence for RA
      inducibility of CYP26 mRNA expression. This lack of RA inducibility was not due
      to inactivity of the retinoids, as we show that transglutaminase was still
      repressed by RA in the same cultures. Despite the low levels of CYP26AI
      expression in the keratinocytes, the keratinocytes were still capable of
      significant RA metabolism. In conclusion, our study reports, for the first time,
      that CYP26AI is unlikely to contribute to RA metabolism in keratinocytes. These
      studies also indicate that as yet unknown isoforms of cytochrome P450 may be
      involved in RA metabolism in keratinocytes.

PMID- 10583050
TI  - The irritancy of anthralin is inhibited by repeat applications of a subirritant
      concentration.
AB  - Anthralin is a safe, effective treatment for psoriasis, but its efficacy is
      hampered by the side-effects of irritation and staining of the uninvolved skin.
      To avoid burning, it is customary to start at low concentrations and increase
      every 48-72 h until the therapeutically effective concentration is reached, which
      takes time and appears to prolong treatment. We felt that if the minimal erythema
      concentration (MEC) of anthralin could be determined initially in an individual,
      this ought to be near or at the final achievable therapeutic concentration.
      Hence, by analogy with ultraviolet therapy, treatment could start just below this
      concentration and thus avoid delay. A series of concentrations of anthralin in
      Lassar's paste was applied to the back for 3 h, and erythemal responses assessed
      at 24 and 48 h. MECs (0.015-0.03%) were far below those usually reached during
      normal therapy. To test the possibility that the skin was adapting to anthralin,
      we pretreated areas of skin with a subirritant concentration of anthralin
      (0.007%) for 3 h on 2 consecutive days prior to application of the full dose
      series. On the pretreated areas, the MEC increased fourfold from 0. 015% to 0.06%
      (P < 0.01); the concentration of anthralin required to produce the mid-point on
      the dose-response curve increased from 0. 06% to 0.25% (P = 0.01), demonstrating
      a clear adaptive response. One pretreatment produced a 52% reduction in erythema
      compared with control challenge, and maximal 61% inhibition was seen after three
      applications. Pretreatment with a subirritant concentration of a control
      irritant, croton oil, had no effect on the response to anthralin and vice versa.
      Pretreatment of skin with danthron, the non-irritant oxidation product of
      anthralin, had no effect, suggesting that the attenuation effect is specific to
      native anthralin. To see whether the attenuation might be due to modulation of
      xenobiotic metabolizing enzymes, skin was pretreated with inducers and inhibitors
      of the cytochrome P450 and NADPH-dependent quinone reductase (NDQR) enzyme
      systems. However, no effect was seen. In conclusion, we have shown that the
      irritant response to anthralin is attenuated by repeated applications of a
      subirritant concentration of anthralin; this is not a non-specific response to
      all irritants, but a specific property of native anthralin, and the enzymes P450
      and NDQR are apparently not responsible for this effect.

PMID- 10583051
TI  - Defining target antigens in linear IgA disease using skin from subjects with
      inherited epidermolysis bullosa as a substrate for indirect immunofluorescence
      microscopy.
AB  - Identification of target antigens in immunobullous disorders usually involves
      laborious techniques such as immunoblotting and immunoprecipitation, which do not
      always provide conclusive data. This is particularly true of linear IgA disease
      (LAD) in which the target antigen has often proved difficult to identify. As an
      alternative means of antigen identification in five adult patients with LAD, we
      performed indirect immunofluorescence (IIF) microscopy on a panel of skin samples
      taken from subjects with different forms of inherited epidermolysis bullosa (EB).
      Skin samples were selected that showed a complete absence of immunostaining for a
      specific basement membrane zone (BMZ) molecule (type VII collagen, laminin 5 or
      the 180-kDa bullous pemphigoid antigen BP180). In each case, the underlying
      genetic mutations had been defined and shown to consist of premature termination
      codons on both alleles of the particular gene, resulting in total ablation of the
      encoded protein. Two epidermal-binding LAD sera showed BMZ fluorescence on all
      substrates except BP180-deficient skin, suggesting that the target antigen was
      BP180, or a closely related molecule. In contrast, two dermal-binding LAD sera
      were positive on all substrates except the type VII collagen-deficient skin,
      suggesting that the target antigen was likely to be type VII collagen. One LAD
      serum sample, which showed combined dermal and epidermal fluorescence on normal
      salt-split skin, was also positive on all substrates tested, suggesting a target
      antigen other than type VII collagen, laminin 5 or BP180. The study confirms that
      LAD is a heterogeneous disorder and illustrates that IIF using a panel of skin
      samples which lack specific BMZ molecules, taken from subjects with inherited EB,
      is a relatively simple and useful tool to help identify target antigens in
      immunobullous disorders.

PMID- 10583052
TI  - Immunohistochemical localization of types 1 and 2 5alpha-reductase in human
      scalp.
AB  - The predominant form of 5alpha-reductase (5aR) in human scalp is 5aR1. None the
      less, clinical studies have shown that finasteride, a selective inhibitor of
      5aR2, decreases scalp dihydrotestosterone and promotes hair growth in men with
      androgenetic alopecia. Immunolocalization studies were thus carried out to
      examine 5aR isozyme distribution within scalp and, in particular, to determine
      whether 5aR2 might be associated with hair follicles. 5aR2 was localized using
      both a rabbit polyclonal and a mouse monoclonal antibody. 5aR1 was detected with
      a mouse monoclonal antibody. The specificity of these reagents was demonstrated
      both by immunofluorescence and Western blot analyses of COS cells overexpressing
      human 5aR1 or 5aR2. When cryosections of scalp from men with androgenetic
      alopecia were stained with antibody against 5aR2, using immunoperoxidase avidin
      biotin complex methodology, immunostaining was observed in the inner layer of the
      outer root sheath and, in more proximal regions of the follicle, in the inner
      root sheath. Staining was also prominent in the infundibular region of the
      follicle, with less intense staining extending throughout the granular layer of
      the epidermis. Some staining was also seen in sebaceous ducts. Similar results
      were obtained with both the polyclonal and monoclonal 5aR2 antibodies. In
      contrast, in scalp cryosections stained with antibody to 5aR1, no immunostaining
      was observed within hair follicles. Intense staining for the type 1 isozyme was,
      however, detected within sebaceous glands. Our immunolocalization data suggest
      that the results seen in clinical trials of men with male pattern hair loss
      treated with finasteride may be due, at least in part, to local inhibition of
      5aR2 within the hair follicle.

PMID- 10583054
TI  - Trioxsalen bath PUVA did not increase the risk of squamous cell skin carcinoma
      and cutaneous malignant melanoma in a joint analysis of 944 Swedish and Finnish
      patients with psoriasis.
AB  - It has been suggested that trioxsalen bath and ultraviolet (UV) A (PUVA) is
      associated with a very low or no risk of non-melanoma skin cancer, but the
      numbers of patients in individual studies have been limited. In order to attain
      statistically relevant information about the cancer risk associated with
      trioxsalen bath PUVA, two follow-up studies were combined and the joined cancer
      incidence was analysed among 944 Swedish and Finnish patients with psoriasis. The
      mean follow-up time for skin cancer was 14.7 years. Standardized incidence ratios
      (SIR) were calculated as a ratio of observed and expected numbers of cases. The
      expected numbers of cases were based on the national cancer incidence rates in
      the respective countries. There was no excess of squamous cell skin carcinoma
      [SIR 1.1, 95% confidence interval (CI) 0.2-3.2] or malignant melanoma (SIR 0.9,
      95% CI 0.1-3.2) in the combined cohort. Basal cell skin carcinoma was not
      studied. The incidence of all non-cutaneous cancers was not increased (SIR 1.1,
      95% CI 0.8-1.4). A threefold excess risk of squamous cell skin carcinoma after
      trioxsalen bath PUVA could therefore be excluded, which is a markedly lower risk
      than that associated with oral 8-methoxypsoralen PUVA. The result needs to be
      confirmed in a future follow-up, however, as the number of patients with high
      PUVA exposures was low.

PMID- 10583053
TI  - No evidence for a role of human herpesvirus type 8 in sarcoidosis: molecular and
      serological analysis.
AB  - The aim of this study was to analyse the association between human herpesvirus
      type 8 (HHV8) and sarcoidosis. Using nested polymerase chain reaction (PCR), we
      tested the presence of HHV8 DNA sequences in 13 skin specimens and peripheral
      blood mononuclear cells from eight patients suffering from sarcoidosis. We also
      looked for the presence of HHV8 antibodies in the sera of 28 patients with
      sarcoidosis using three techniques: two indirect immunofluorescence assays and an
      enzyme-linked immunosorbent assay with recombinant capsid protein fragment
      encoded by open-reading frame 65. HHV8 PCR analysis was negative while HHV8
      serological studies showed an overall prevalence of 18% among patients suffering
      from sarcoidosis: 43% in patients from sub-Saharan Africa, 17% in patients from
      Northern Africa, 12.5% in patients from the French West Indies and 0% in French
      patients. In conclusion, our results do not indicate an association between HHV8
      and sarcoidosis but reflect the seroepidemiology of this virus in different
      geographical regions.

PMID- 10583055
TI  - Sun protection factor measurement of sunscreens is dependent on minimal erythema
      dose.
AB  - This study investigates the influence of skin colour and minimal erythema dose
      (MED) on the in vivo determination of sunscreen sun protection factors (SPFs).
      The MEDs of groups of 10-20 subjects were measured on the lower back with a 1000
      W solar-simulated xenon arc lamp. Five sunscreens, with commercially measured
      SPFs ranging from 4 to 30 + were then tested on the different groups, and their
      SPFs were correlated with volunteers' MEDs. We found that the sunscreens had
      higher SPF values when tested on subjects with lower MEDs and paler skin. The SPF
      values obtained with our ultraviolet (UV) source were lower than the SPF values
      reported with commercially used solar simulators. We conclude that while SPF
      tests with artificial UV sources and pale-skinned volunteers can and should be
      used to rank the efficacy of various sunscreens in preventing sunburn, they
      should not be interpreted as measures of a sunscreen's absolute level of sun
      protection. Factors such as the differences in skin colour and MED between
      subjects used for SPF testing and the general population, the spectral
      differences between sunlight and artificial UV, as well as the tendency of the
      public to apply only small amounts of sunscreen and to re-apply it infrequently,
      mean that laboratory and sunlight SPFs may be markedly different.

PMID- 10583056
TI  - Evidence for double resistance to permethrin and malathion in head lice.
AB  - A rising prevalence of head lice among school children and rising sales of
      insecticides with anecdotal evidence of their treatment failure, led us to
      examine whether head lice in Bristol and Bath were resistant to the insecticides
      available for treating head lice. Ten schools in Bristol and Bath were visited to
      collect field samples of head lice. A comparison was made of the survival rates
      of fully sensitive laboratory reared body lice and field samples of head lice on
      insecticide exposure. To confirm the in vitro relevance of these tests we
      performed supervised treatments of affected subjects with malathion or
      permethrin. There were significant differences (P < 10-6 Fishers exact test)
      between head and body lice survival for malathion and permethrin exposure, but
      not for carbaryl. There was an 87% failure rate for permethrin and a 64% failure
      rate for malathion with the topical treatment of a selected number of infested
      school children. We conclude that there is a high resistance to permethrin and
      malathion, but head lice remain fully sensitive to carbaryl. This is the first
      report of doubly resistant head lice. As permethrin, phenothrin (a very similar
      synthetic pyrethroid) or malathion are the active ingredients in all the over-the
      counter head lice treatments in the U.K., then it is likely that head lice
      prevalence will continue to increase. The resistance against permethrin employed
      by the head louse is probably the kdr (knockdown resistance) mechanism, and an
      enzyme-mediated malathion-specific esterase is the likely mechanism against
      malathion.

PMID- 10583057
TI  - A study of the spectrum of skin disease occurring in a black population in south
      east London.
AB  - We recorded the diagnosis made in 461 black patients (187 children and 274
      adults) attending a dermatology clinic between January and March 1996. In the
      childhood population, atopic eczema and tinea capitis were the most frequent
      dermatoses, comprising 63% of diagnoses recorded. In the adult population, acne
      and acne keloidalis nuchae were seen most frequently. Other conditions observed
      commonly were eczema, psoriasis, keloid scarring, pityriasis versicolor and
      postinflammatory changes. Our study demonstrates a wide spectrum of skin disease
      and includes disorders more common in black skin, disorders unique to black skin,
      those which present a greater cosmetic disability, and normal findings which have
      been mistaken for pathological disease.

PMID- 10583058
TI  - Dermatology in general practice.
AB  - A significant percentage of the workload of a general practitioner is
      dermatological. This study has analysed the cases seen by one partner in a
      semirural practice over a 5-year period. Of a total of 11,191 patients seen, 2386
      had a dermatological diagnosis (21%). There was a preponderance of females (1604,
      67%) and the most common skin diseases seen were viral warts, eczema and benign
      tumours. Surgical intervention was carried out in 707 cases, an atypical
      situation for most general practitioners. It was only because of additional
      training as a hospital practitioner in dermatology that the partner treated both
      benign and malignant tumours where she felt confident to do so. The incidence of
      skin cancer was 3% and 22 patients were referred to a dermatology outpatient
      department.

PMID- 10583059
TI  - Diffuse female hair loss: are androgens necessary?
AB  - Diffuse hair loss in women is generally regarded as the female equivalent of male
      balding and is often referred to as female androgenetic alopecia. In this article
      we report the case of a young woman with hypopituitarism who presented with the
      clinical and histological features of female androgenetic alopecia in the absence
      of detectable levels of circulating androgens or other signs of postpubertal
      androgenization, showing that this pattern of hair loss is not necessarily
      androgen dependent.

PMID- 10583060
TI  - Benign familial Degos disease worsening during immunosuppression.
AB  - We describe a 61-year-old woman with skin lesions consistent with those found in
      Degos disease, both in clinical and in histological appearance. She had had
      several of these lesions for many years, as had her mother, sister and niece. In
      1991, she underwent cadaveric renal transplantation and was treated with
      immunosuppression: prednisolone, azathioprine and cyclosporin. At that time, she
      developed many more characteristic skin lesions, and these were slightly larger
      and more noticeable than those she had had previously. She and the other affected
      family members appear to fit into the more benign subgroup of Degos disease, and
      it seems that her immunosuppression aggravated her cutaneous disease.

PMID- 10583061
TI  - Pneumocystis carinii pneumonia in patients receiving immunosuppressive drugs for
      dermatological diseases.
AB  - In recent years, Pneumocystis carinii pneumonia (PCP) has been increasingly
      reported in patients without human immunodeficiency virus (HIV) infection. The
      increased occurrence of PCP in non-HIV-immunocompromised subjects has been
      attributed to several factors: use of stronger immunosuppressive regimens, higher
      awareness of PCP, advanced diagnostic technology and nosocomial spread of P.
      carinii. Appearance of PCP subsequent to the use of immunosuppressive drugs has
      been noticed in many inflammatory diseases such as rheumatoid arthritis, systemic
      lupus erythematosus and ulcerative colitis. Dermatologists frequently use
      immunomodulating agents, but the occurrence of PCP in patients receiving
      immunosuppressive drugs for skin diseases is largely unknown. We report four
      cases where PCP appeared following the use of immunosuppressive drugs primarily
      for cutaneous diseases, namely pemphigus, cutaneous necrotizing vasculitis (two
      cases) and Behcet's syndrome. These cases were identified in a computerized
      database study (1979-95) to evaluate the occurrence of PCP among
      immunocompromised hosts without HIV infection.

PMID- 10583062
TI  - Cardiac involvement and molecular staging in a fatal case of mycosis fungoides.
AB  - Polymerase chain reaction (PCR) amplification of T-cell receptor-gamma gene
      rearrangement was used for molecular staging in a case of primary cutaneous T
      cell lymphoma (CTCL) with fatal evolution. Although initial evaluation was
      negative for systemic involvement, the patient died due to heart failure. Autopsy
      findings revealed lymphomatous myocardial infiltration, but other tissues and
      organs examined, including lymph nodes, liver, spleen, lung and bone marrow,
      appeared to be free of disease. Molecular analysis from frozen samples obtained
      during the initial evaluation, as well as paraffin-embedded material obtained
      during autopsy, revealed the presence of clonal rearranged bands in all tissues
      examined except the bone marrow. Subsequent hybridization of PCR products with a
      tumour-specific oligoprobe confirmed the PCR results, suggesting widespread
      dissemination of the lymphomatous process. The use of molecular analysis can add
      significant information about the extent of disease in patients with CTCL and may
      be helpful in the establishment of therapeutic options.

PMID- 10583063
TI  - Successful treatment of recalcitrant cicatricial pemphigoid with a combination of
      plasma exchange and cyclophosphamide.
AB  - We describe two patients with severe oral cicatricial pemphigoid, one of whom
      also had severe pharyngeal involvement. Both patients were resistant to treatment
      with corticosteroids and other standard immunosuppressive therapies. Plasma
      exchange alone proved to be only temporarily effective, but the combination of
      plasma exchange with subsequent cyclophosphamide resulted in a remission in both
      patients. Both patients experienced mild side-effects during the plasma exchange
      treatment (urticaria and mild hypotension). At present, at follow-up of 6 and 9
      years, respectively, the patients have no symptoms of active disease and have not
      required any further immunosuppressive treatment.

PMID- 10583064
TI  - Pyoderma gangrenosum with liver, spleen and bone involvement in a patient with
      chronic myelomonocytic leukaemia.
AB  - Pyoderma gangrenosum is a neutrophilic dermatosis of unknown aetiology. Visceral
      involvement by pyoderma gangrenosum is rare, the lung being the most frequent
      site of extracutaneous disease. We describe a 73-year-old man with pyoderma
      gangrenosum and chronic myelomonocytic leukaemia in whom aseptic hepatosplenic
      abscesses and bony lesions were associated.

PMID- 10583065
TI  - Netherton's syndrome: increased likelihood of diagnosis by examining eyebrow
      hairs.
AB  - Netherton's syndrome is a rare autosomal recessive condition with variable
      expression. It comprises an ichthyosiform dermatitis and erythroderma of variable
      intensity and manifestations, associated with hair abnormalities. The
      pathognomonic finding (required for diagnosis) is that of trichorrhexis
      invaginata identified by light and scanning electron microscopic examination of
      hair shafts. This may be difficult to establish because the hair is sparse and
      not all hairs exhibit abnormalities. In one patient, cutaneous and hair problems
      had existed since infancy, and despite repeated examination of scalp hairs, the
      definitive diagnosis was made only by examining eyebrow hairs at the age of 30
      years. We subsequently compared the number of diagnostic lesions found on scalp
      and eyebrow hairs from two other patients with previously diagnosed Netherton's
      syndrome. The density of lesions was greater in eyebrow than scalp hair, and
      furthermore, all eyebrow hairs had at least one lesion. It is proposed that
      microscopic examination, if possible, of both scalp and eyebrow hair from
      patients in whom Netherton's syndrome is suspected would increase the chance of a
      positive diagnosis.

PMID- 10583066
TI  - Congenital erythropoietic porphyria affecting two brothers.
AB  - We report two brothers, aged 5 and 2 years, with typical features of congenital
      erythropoietic porphyria. The elder did not receive medical attention until the
      age of 2 years, even though his urine had been red almost from birth, and despite
      severe scarring of the hands and face. The younger brother suffered haemolysis at
      birth. The uroporphyrinogen III cosynthase (URO IIIS) enzyme activity of red
      blood cells was 2% and 1.2% in the brothers, and genetic studies showed two
      different mutations of the URO IIIS gene, C73R and P248Q. The latter is a
      recently described mutation.

PMID- 10583067
TI  - Keratotsis punctata of the palmar creases: report of two cases associated with
      ichthyosis vulgaris.
AB  - Two patients with keratosis punctata of the palmar creases are described. The
      association with ichthyosis vulgaris and other disorders of keratinization is
      discussed. In both cases, histopathology revealed a close relation between the
      keratotic plug and the sweat glands. The role of genetic factors and manual
      activity in the pathogenesis is discussed. Treatment with oral etretinate
      resulted in a good improvement in the first patient, but prolonged low-dose
      maintenance therapy was required to prevent recurrence.

PMID- 10583068
TI  - Mycobacterium avium infection of the skin associated with lichen scrofulosorum:
      report of three cases.
AB  - We report three Japanese children with Mycobacterium avium infection of the skin
      who also developed lichen scrofulosorum, a previously undescribed association.
      They were healthy except for the presence of several noduloulcerative lesions
      associated with multiple asymptomatic papules on the trunk and extremities.
      Histology of the ulcerative lesions showed features of mixed-cell granuloma,
      whereas the papular lesions showed features consistent with lichen scrofulosorum.
      M. avium was identified by polymerase chain reaction-aided DNA-DNA hybridization
      analysis in specimens obtained from the noduloulcerative lesions. Both the
      noduloulcerative and the papular lesions responded well to combination
      chemotherapy consisting of antituberculous agents and antibiotics.

PMID- 10583069
TI  - Micrococcus folliculitis in HIV-1 disease.
AB  - Organisms with little pathogenic potential in immunocompetent hosts may produce
      disease in HIV-1 + patients. We describe three HIV-1 + patients in late disease
      who presented with pruritic papules with central ulceration over the face and
      arms. In all the patients the eruptions had been present for months, and the
      patients did not develop sepsis. Biopsy specimens in all the patients showed
      large Gram-positive cocci, forming tetrads. Colony morphology, catalase
      positivity and coagulase negativity, and resistance to nitrofurantoin were used
      to separate micrococci from staphylococci. Micrococcus species are usually
      considered normal inhabitants of the skin; however, in patients with HIV-1
      disease, Micrococcus species can produce localized cutaneous infections.

PMID- 10583070
TI  - Oleogranulomatous response in lymph nodes associated with emollient use in
      Netherton's syndrome.
AB  - Paraffin-based emollients are widely used in dermatological practice and are not
      usually absorbed through the skin. We report a case where transcutaneous transfer
      did occur in the context of damaged skin in Netherton's syndrome, resulting in a
      reversible lymphadenopathy.

PMID- 10583071
TI  - The HECA-452 epitope is highly expressed on lymph cells derived from human skin.
AB  - The cutaneous lymphocyte-associated antigen (CLA), recognized by the monoclonal
      antibody HECA-452, is a cell surface glycoprotein that binds specifically to E
      selectin. CLA is present on most T cells at sites of cutaneous immune response
      and has been shown to be important in lymphocyte homing to the skin. It is
      expressed only by a minor subset of peripheral T cells and is absent on
      thymocytes. We have analysed (using a FACScan flow cytometer) the expression of
      CLA on human lymph cells derived from normal skin, from ultraviolet (UV)
      irradiated skin and from allergic contact dermatitis. Whereas in the peripheral
      blood CLA was expressed on < 20% of CD4 +, CD8 + and CD56 + cells (natural killer
      cells), > 60% of CD4 +, CD8 + and CD56 + cells isolated from skin-derived lymph
      expressed CLA. Furthermore, > 90% of CD1a + dendritic lymph cells were positive
      for CLA. UV irradiation of the skin and induction of an allergic contact
      dermatitis did not change CLA expression on lymph cells, although lymph flow and
      cell output increased. These results provide further evidence for an important
      role of CLA in cell homing to the skin.

PMID- 10583072
TI  - An audit to identify the optimum referral rate to a contact dermatitis
      investigation unit.
AB  - The principle of patch testing is to identify individuals with a contact allergy
      of relevance to their disorder and to provide avoidance advice in an attempt to
      improve or resolve their condition. We aimed to define an optimum referral rate
      to a centralized contact dermatitis unit using a retrospective analysis of data
      relating to 10 consultants. The results showed no significant difference (P =
      0.21) in the percentage of relevant positive individuals identified between the
      consultants. However, a linear relationship (r = 0.99) was seen between the
      number of relevant positive allergic reactions and the number referred by
      individual consultants. We propose that the minimal annual referral rate for
      patch testing from a predominately urban population in a developed country is one
      in 700 of the population.

PMID- 10583073
TI  - Granular cell tumour with histological signs of malignancy: report of a case and
      comparison with 10 benign and 4 atypical cases.

PMID- 10583074
TI  - Expression of p53, pRb, p16 and proliferating cell nuclear antigen in squamous
      cell carcinomas arising on a giant porokeratosis.

PMID- 10583076
TI  - Correspondence

PMID- 10583075
TI  - Bowenoid papulosis transforming into squamous cell carcinoma of the genitalia.

PMID- 10583077
TI  - Hypercalcaemia of malignancy associated with invasive cutaneous squamous cell
      carcinoma.

PMID- 10583078
TI  - Dermal metastasis from vaginal squamous cell carcinoma.

PMID- 10583079
TI  - Photodynamic diagnosis of basal cell carcinoma on the lower eyelid using topical
      5-aminolaevulinic acid and desferrioxamine.

PMID- 10583080
TI  - Eruptive disseminated blue naevi of the scalp.

PMID- 10583081
TI  - Melanocyte colonization associated with malignant transformation of eccrine
      poroma.

PMID- 10583082
TI  - Successful treatment of recalcitrant penicillamine-induced pemphigus foliaceus by
      low-dose intravenous immunoglobulins.

PMID- 10583083
TI  - Pemphigoid excoriee: a further variant of bullous pemphigoid?

PMID- 10583084
TI  - Cutaneous relapse in acute promyelocytic leukaemia following treatment with all
      trans retinoic acid.

PMID- 10583085
TI  - Dermatotmal chronic cutaneous graft-versus-host disease at the site of prior
      herpes zoster.

PMID- 10583086
TI  - Sunbeds and the need to know.

PMID- 10583087
TI  - Porphyria cutanea tarda presenting as solar urticaria.

PMID- 10583088
TI  - Pseudoporphyria and propionic acid non-steroidal anti-inflammatory drugs.

PMID- 10583089
TI  - Melasma of the arms associated with hormone replacement therapy.

PMID- 10583090
TI  - Melasma of the arms associated with hormone replacement therapy.

PMID- 10583091
TI  - Isolated periocular 'dermatitis'.

PMID- 10583092
TI  - The prevalence of necrobiosis lipoidica diabeticorum in children with type 1
      diabetes.

PMID- 10583093
TI  - Needle evacuation of eruptive vellus hair cysts.

PMID- 10583094
TI  - Light cautery of macrocomedones under general anaesthesia.

PMID- 10583095
TI  - The treatment of acne agminata with clofazimine.

PMID- 10583096
TI  - Skin eruption to generic prednisolone.

PMID- 10583097
TI  - Cutaneous reactions to henna and associated additives.

PMID- 10583098
TI  - Urticarial vasculitis following cocaine use.

PMID- 10583099
TI  - Human papillomavirus type 60 plantar warts are predominately pigmented when
      discovered after early adulthood.

PMID- 10583100
TI  - The treatment of Darier's disease with topical tazarotene.

PMID- 10583101
TI  - Treatment of superficial white onychomycosis with topical terbinafine cream.

PMID- 10583103
TI  - Trichophyton erinacei: an unusual cause of kerion.

PMID- 10583102
TI  - Localized skin infection due to Scedosporium apiospermum: report of two cases.

PMID- 10583104
TI  - Sublamina densa-type linear IgA bullous dermatosis successfully treated with oral
      tetracycline and niacianamide.

PMID- 10583105
TI  - Streptococcal necrotizing fasciitis and the dermatologist.

PMID- 10583106
TI  - p21Wafl/Cipl and p53 expression in the skin - intertwined but not inseparable.

PMID- 10583107
TI  - X-linked ichthyosis: an update.
AB  - X-linked ichthyosis is a genetic disorder of keratinization characterized by a
      generalized desquamation of large, adherent, dark brown scales. Extracutaneous
      manifestations include corneal opacity and cryptorchidism. Since 1978 it has been
      known that a deficit in steroid sulphatase enzyme (STS) is responsible for the
      abnormal cutaneous scaling, although the exact physiological mechanism remains
      uncertain. The STS gene has been mapped to the distal part of the short arm of
      the X chromosome. Interestingly, this region escapes X chromosome inactivation
      and has the highest ratio of chromosomal deletions among all genetic disorders,
      complete deletions having been found in up to 90% of patients. Diagnosis of
      patients with X-linked ichthyosis and female carriers is based on biochemical and
      genetic analysis. The latter currently seems to be the most accurate method in
      the majority of cases.

PMID- 10583108
TI  - Nail melanoma: a review of the literature with recommendations to improve patient
      management.
AB  - In this review, the current state of knowledge concerning nail melanoma is
      summarized. The pathogenesis, histological findings, clinical presentation,
      treatment and prognosis of this rare form of cutaneous melanoma are discussed.
      Important clinical clues to the early diagnosis of nail melanoma are highlighted
      and recommendations to improve the management of patients are suggested.

PMID- 10583109
TI  - Guidelines for management of Bowen's disease. British Association of
      Dermatologists.
AB  - These guidelines for management of Bowen's disease have been prepared for
      dermatologists on behalf of the British Association of Dermatologists. They
      present evidence-based guidance for treatment, with identification of the
      strength of evidence available at the time of preparation of the guidelines, and
      a brief overview of epidemiological aspects, diagnosis and investigation.

PMID- 10583110
TI  - Effect of topical tazarotene in the treatment of congenital ichthyoses.
AB  - The clinical efficacy and tolerability of the topical receptor-selective retinoid
      tazarotene in the treatment of congenital ichthyoses was investigated. Twelve
      consecutive patients with different forms of congenital ichthyosis were enrolled
      in an open, non-randomized, intraindividually controlled, half-side pilot study.
      Diagnoses were X-linked recessive ichthyosis, non-erythrodermic autosomal
      recessive lamellar ichthyosis, autosomal dominant ichthyosis vulgaris and
      ichthyosis bullosa of Siemens (IBS). Tazarotene 0.05% gel was applied
      unilaterally daily on a defined body area measuring 10% of the body surface area.
      The contralateral side was treated with an ointment containing 10% urea. After 14
      days, application frequency was reduced to three times a week, and stopped after
      another 2 weeks. The follow-up period was 3 months. Reduction in scaling and
      roughness was used to assess the clinical response in the tazarotene-treated area
      compared with the control area. Clinical and laboratory assessments were
      performed every 14 days during the trial. Unilateral improvement in favour of the
      tazarotene-treated side was observed in nine of 12 patients (75%). Four patients
      (33%) achieved an excellent response and four (33%) achieved a good response. No
      therapeutic effect was seen in patients with IBS. The remission persisted during
      the reduction phase and after discontinuation for up to 2 months. Local
      irritation in three patients was the only side-effect detectable. Short-term
      topical application of tazarotene 0.05% gel is a very effective and well
      tolerated treatment modality in different forms of congenital ichthyoses and may
      be an alternative to systemic retinoid therapy.

PMID- 10583111
TI  - Overexpression of p2lWaf1/Cip1 immunohistochemical staining in Bowen's disease,
      but not in disseminated superficial porokeratosis.
AB  - Disseminated superficial porokeratosis (DSP) consists of multiple small lesions
      of porokeratosis. Although the pathogenesis of DSP remains unclear, localized
      cloning of abnormal epidermis has been hypothesized. Malignant cutaneous
      neoplasms, especially Bowen's disease, have been frequently reported in DSP.
      Immunopositive p53 has been demonstrated in a variety of human malignant tumours,
      and its role in oncogenesis and tumour progression is thought to be important.
      p21Waf1/Cip1 is thought to mediate the signal of p53 induced by DNA damaging
      agents to arrest the cell cycle. To clarify the role of p53 and p21Waf1/Cip1 in
      Bowen's disease and DSP, we analysed 12 cases of Bowen's disease and eight cases
      of DSP by immunohistochemistry. In five of the 12 Bowen's disease patients and
      two of the eight DSP patients, positive p53 staining was detected. In contrast,
      whereas p21Waf1/Cip1 overexpression was detected in all Bowen's disease patients,
      it was not seen in DSP. The present data suggest that p53 immunostaining provides
      relevant information concerning the pathogenesis of Bowen's disease and DSP.
      Furthermore, high p21Waf1/Cip1 expression appears to be a useful indicator of
      tumour activity in Bowen's disease.

PMID- 10583112
TI  - Effects of protein kinase inhibitors on radiation-induced WAF1 accumulation in
      human cultured melanoma cells.
AB  - To examine whether protein kinase C (PKC) and A (PKA) contribute to WAF1
      induction by ionizing radiation (IR) in cultured human melanomas, the effect of
      PK inhibitors 1-(5'-isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride
      (H7), bisindolylmaleimide (GF) and N-[2(p-dromocinnamylamino)ethyl]-5
      isoquinolinesulphonamide (H89) on IR-induced WAF1 accumulation was analysed by
      Western blot analysis. Gamma-ray-induced accumulation of WAF1 showed a peak at 6
      Gy in all the cell lines. After gamma-ray irradiation of 6 Gy, a peak of WAF1
      accumulation was observed at 6 h in SK-Mel-26, G361 and HM6KO cells, and at 3 h
      in MeWo cells. In MeWo and SK-Mel-26 cells, the X-ray-induced WAF1 accumulation
      was decreased by PK inhibitors, GF (PKC inhibitor) or H89 (PKA inhibitor); this
      did not occur in G361 and HM6KO. In all the cell lines, accumulation of WAF1
      induced by X-ray irradiation was suppressed by H7 (PKC and PKA inhibitor). In
      addition, polymerase chain reaction-single strand conformational polymorphism
      analysis detected no aberrations in the p53 gene of the four cell lines used.
      These results suggest that IR-induced WAF1 expression involves PKC and/or PKA
      activity depending on cell type.

PMID- 10583113
TI  - Changes in the expression and distribution of fibronectin, laminin and tenascin
      by cultured fibroblasts from skin lesions of patients with tuberous sclerosis.
AB  - Fibronectin, laminin and tenascin play an important part in the assembly of the
      extracellular matrix and the interaction of cells with it. In this study, changes
      in their expression and distribution associated with tuberous sclerosis are
      reported. Fibroblasts from three different tuberous sclerosis skin lesions
      (forehead plaque, neck fibroma and ungual fibroma) secreted more fibronectin and
      tenascin into their culture medium than did normal skin fibroblasts.
      Immunohistochemistry and flow cytometry showed that cells from an ungual fibroma
      which secreted most of each of these glycoproteins also retained more of them,
      associated mainly with the cell surface and a perinuclear area. Laminin was also
      produced by all fibroblasts but only in those from the neck fibroma was more both
      secreted and retained. The proportions of fibronectin/laminin/tenascin secreted
      by the skin lesion fibroblasts were markedly different from normal. The results
      suggest that the characteristic tissue hardening of skin lesions in tuberous
      sclerosis may result, at least in part, from differences in the expression and
      distribution of these critical components of the extracellular matrix and its
      consequent abnormal assembly.

PMID- 10583114
TI  - Characterization of dermal type I collagen of C3H mouse at different stages of
      the hair cycle.
AB  - Hair follicles develop or regress in accordance with the hair cycle. In this
      study, we partially characterized fibrillar type I collagen, the predominant
      component in the dermis, at two stages of the hair cycle: anagen and telogen.
      Skin samples were obtained from the backs of two groups of 11-week-old C3H mice:
      one at anagen stage induced by shaving and the other at telogen stage. The amount
      of neutral salt-soluble (newly synthesized) collagen obtained from anagen skin
      was about twofold that from telogen skin, while the level of acid-soluble
      collagen was not significantly different between the two groups. The degree of
      lysine hydroxylation of pepsinized type I collagen obtained from anagen skin was
      significantly higher than that in telogen (5.0% higher in alpha1 chain, and 15.6%
      higher in alpha2 chain). Proline hydroxylation at the anagen stage was also
      slightly higher than in the telogen stage. Two major collagen cross-links were
      found in both groups of skin; dehydro-hydroxylysinonorleucine and dehydro
      histidinohydroxymerodesmosine. The concentration of the latter, a complex
      tetravalent cross-link, was significantly lower in anagen skin when compared with
      telogen skin (mean +/- SD 0.64 +/- 0. 07 vs. 0.78 +/- 0.06 mol/mol collagen). The
      former showed no significant difference between the two groups. In addition, a
      significant amount of lysyl-aldehyde (a cross-link precursor) was found in anagen
      (0.16 +/- 0.02 mol/mol collagen), while it was 0.12 mol/mol collagen in telogen.
      These results indicate that the remodelling of collagen is more active in anagen
      skin than in telogen, and that characteristic post-translational modifications of
      dermal collagen seen in anagen may play a part in facilitating an environment
      around hair follicles for their migration and growth.

PMID- 10583115
TI  - Effects of repeated skin exposure to low nickel concentrations: a model for
      allergic contact dermatitis to nickel on the hands.
AB  - We studied the effects of repeated daily exposure to low nickel concentrations on
      the hands of patients with hand eczema and nickel allergy. The concentrations
      used were chosen to represent the range of trace to moderate occupational nickel
      exposure. The study was double-blinded and placebo controlled. Patients immersed
      a finger for 10 min daily into a 10-p.p.m. nickel concentration in water for the
      first week, and during the second week into a 100-p.p.m. nickel concentration.
      This regimen significantly increased (P = 0.05) local vesicle formation and blood
      flow (P = 0.03) as compared with a group of patients who immersed a finger into
      water. The nickel concentrations used also provoked significant inflammatory skin
      changes on sodium lauryl sulphate (SLS)-treated forearm skin of the patients,
      whereas inflammatory skin changes were not observed in healthy volunteers without
      hand eczema and nickel allergy, either on normal or on SLS-treated forearm skin.
      The present study strongly suggests that the changes observed were specific to
      nickel exposure. Standardized methods to assess trace to moderate nickel exposure
      on the hands, and the associated effects in nickel-sensitized subjects, are
      needed.

PMID- 10583116
TI  - Hypersensitivity to gold in gold sodium thiomalate-induced dermatosis.
AB  - Gold compounds are widely used in the treatment of rheumatoid arthritis.
      Mucocutaneous side-effects leading to the discontinuation of medication are
      common with these drugs. We investigated whether allergic mechanisms are involved
      in dermatosis induced by gold sodium thiomalate (GSTM). Thirteen gold dermatosis
      patients, 15 arthritis patients without any side-effects from GSTM and 11 healthy
      controls participated in the study. Venous blood lymphocytes from these subjects
      were cultured with GSTM and gold sodium thiosulphate (GSTS) in the lymphocyte
      proliferation test (LPT). In some cases, interferon-gamma-producing cells were
      enumerated in vitro (T-cell ELISpot). The subjects were also patch-tested with
      GSTM and GSTS. The LPT to either GSTM, GSTS or both was positive in 12 of 13
      patients with gold dermatosis. In the arthritis patient group without side
      effects from gold, the LPT gave two false-positive results and in the healthy
      control group the LPT was falsely positive with one subject. T-cell ELISpot was
      positive in four of six gold dermatosis patients and negative in the arthritis
      and healthy control groups. Only one patient who also developed contact
      dermatitis from gold jewellery was positive to gold in the patch test. These
      results indicate that gold dermatosis is mediated, at least in part, by allergic
      mechanisms and that the LPT is of value in the diagnosis of gold dermatosis.

PMID- 10583117
TI  - T-lymphocyte cytokine profiles in compositae airborne dermatitis.
AB  - Compositae airborne dermatitis is a well-recognized disorder characterized by
      erythematosquamous lesions and papules on light-exposed areas. The presence of
      positive patch test reactions and the absence of specific serum IgE suggest
      delayed-type hypersensitivity, the murine model of which is characterized by a
      Th1 cytokine production profile [high amounts of interferon (IFN)-gamma and
      interleukin (IL)-2; little or no IL-4 and IL-5]. The aim of this study was to
      evaluate the cytokine profile of T-cell lines and T-cell clones from peripheral
      blood in a 38-year-old non-atopic male woodcutter affected by seasonal airborne
      contact dermatitis. The patient showed positive patch test reactions to several
      Compositae extracts (Achillea millefolium, Chamomilla recutita, Tanacetum
      parthenium, T. vulgare) and sesquiterpene lactone mix. On prick testing with
      Compositae and other plants, serum-specific IgE levels and phototesting were
      negative or normal. Allergen-specific T-cell lines produced with Compositae
      extracts showed a good in vitro cell proliferation only to C. recutita extract.
      Serial cloning performed using the C. recutita-specific T-cell lines revealed an
      alphabeta+CD4+ phenotype with high amounts of IFN-gamma and IL-4 in T-cell
      clones. Thus, these cells expressed a preferential Th0 phenotype. These data
      suggest that in addition to IFN-gamma, other T-cell derived cytokines, such as IL
      4, may play a part in the immunopathogenesis of contact dermatitis.

PMID- 10583118
TI  - Blood lipid concentrations of dioxins and dibenzofurans causing chloracne.
AB  - Chloracne is caused by exposure to certain halogenated polycyclic hydrocarbons
      such as polychlorinated dibenzodioxins (PCDDs) and dibenzofurans (PCDFs). In
      chronic exposure it is not known what level of intoxication, represented by the
      level in blood lipids, is sufficient to cause chloracne. Blood levels of the
      congeners of PCDD/Fs were determined in four groups of humans. One group had
      clinically visible chloracne due to exposure in a hexachlorobenzene workshop of a
      large chemical factory. A second group was exposed in the same workshop, but had
      no skin changes. There were two control groups: one non-exposed group of
      maintenance workers from the same chemical factory, and one group of healthy
      individuals living elsewhere. Blood levels were converted to toxicity equivalents
      of tetrachlorodibenzo-p-dioxin (TCDD). In the chloracne group blood levels in
      toxicity equivalents (TEQs) ranged from 1168 to 22,308 pg/g blood lipid. In the
      exposed without chloracne this ranged from 424 to 662 pg/g. It is concluded that
      the level to develop chloracne is between 650 and 1200 pg/g TEQ. The contribution
      of TCDD was rather small, and the main causative congeners were the
      hexachlorinated dibenzodioxins and dibenzofurans (HxCDD/Fs); lipid-based blood
      levels in absolute amounts that may cause chloracne are in the range of 2-3.5
      ng/g HxCDD, and 2-5 ng/g HxCDF.

PMID- 10583119
TI  - Measuring health-related quality of life in patients with mild to moderate eczema
      and psoriasis: clinical validity, reliability and sensitivity to change of the
      DLQI. The Cavide Research Group.
AB  - The aim of this study was to assess the feasibility, validity, reliability and
      sensitivity to change of a Spanish version of the Dermatology Life Quality Index
      (DLQI) in patients with mild to moderate eczema and psoriasis who were treated
      with topical corticosteroids. The final study sample comprised 237 patients (48%
      eczema). Discriminant validity was tested by comparing patients' scores with
      those of a random sample of the general population (n = 100), and convergent
      validity by analysing correlations between DLQI scores, measures of clinical
      severity, and domain scores on the Nottingham Health Profile (NHP). Internal
      consistency and test-retest reliability were tested in clinically stable patients
      (n = 94), and responsiveness in a clinically unstable group (n = 143) initiating
      treatment with topical corticosteroids. Patient scores were significantly higher
      than general population scores (4.3 vs. 0. 27, P < 0.001). Correlations with NHP
      domains ranged from 0.12 to 0. 32, and there was significant correlation with
      clinical measures (r = 0.26, P < 0.001). Reliability was good (Cronbach's alpha =
      0.83; intraclass correlation coefficient = 0.88), and the instrument proved
      responsive to change (effect size for the total group of de novo patients =
      0.70), though the great majority of changes occurred in items 1 and 2. The NHP
      Emotional Reactions and Mobility domains were more responsive than some DLQI
      domains. In clinical trials of treatments for mild to moderate eczema and
      psoriasis, it is likely that only items 1 and 2 of the DLQI will be needed, and
      it is probably advisable to include generic instruments alongside the DLQI.

PMID- 10583120
TI  - The long-term results of cartilage removal alone for the treatment of
      chondrodermatitis nodularis.
AB  - Cartilage excision alone has been demonstrated to be an effective technique in
      the treatment of chondrodermatitis nodularis (CDN), and in the short term is
      associated with an 80% cure rate. The objective of this study was to demonstrate
      that long-term disease control could be achieved using this surgical technique.
      Set in three hospital dermatology departments, 94 patients with CDN affecting the
      helix and antihelix were contacted by postal questionnaire at least 6 months
      after surgery. Replies were received from 77; 11 patients had died and six could
      not be traced. The main outcome measure was the identification of those patients
      in remission and those with disease recurrence. Sixty-two helix lesions were
      followed up for a mean of 52 months (range 8-99). There was recurrence in 10
      patients (all men; 16%). Twenty antihelix lesions were followed up for a mean of
      55 months (range 8-93). There was recurrence in five patients (all women; 25%).
      In conclusion, this study confirms that only cartilage needs to be excised for
      the long-term effective treatment of CDN. The only relevant aetiological factor
      identified was that all except one patient slept on the same side as the CDN. We
      believe that pressure on the ear during sleep causes CDN. This is most evident on
      the most protuberant part of the ear.

PMID- 10583121
TI  - Primary CD56 + nasal-type T/natural killer-cell subcutaneous panniculitic
      lymphoma: presentation as haemophagocytic syndrome.
AB  - Natural killer (NK) cells are large granular lymphocytes that mediate cytotoxic
      reactions which are not restricted by the major histocompatibility complex. In
      recent years it has become apparent that a minor proportion of malignant
      lymphomas expresses an NK-cell phenotype defined by its reactivity with the CD56
      antibody. Primary purely cutaneous CD56 + lymphomas have rarely been reported.
      They share a generally aggressive course and are highly associated with Epstein
      Barr virus. We describe a patient with a primary cutaneous nasal-type T/NK-cell
      lymphoma that presented as a haemophagocytic syndrome and showed an aggressive
      clinical course.

PMID- 10583122
TI  - Adult-onset Still's disease with persistent plaques.
AB  - Adult-onset Still's disease (AOSD) is a systemic disorder characterized by
      intermittent fever, evanescent rash, arthralgias or arthritis and predominantly
      neutrophilic leucocytosis. We report on a 16-year-old woman with Still's disease
      who developed, in addition to the typical rash, persistent papular lesions on her
      face, neck and upper and lower back. Although the presence of fixed skin lesions
      is not a characteristic feature of AOSD, their appearance at the onset of the
      disease and their evolution suggest that they represent a specific manifestation
      of the disease.

PMID- 10583123
TI  - Malignant acanthosis nigricans: potential role of chemotherapy.
AB  - Acanthosis nigricans is an uncommon skin condition characterized by
      hyperkeratosis and skin hyperpigmentation. Most causes are benign, but it may
      also be associated with gastrointestinal and other malignancies. When associated
      with malignant disease, the skin pathology may be more severe and treatment often
      unsuccessful. We describe a 66-year-old man with acanthosis nigricans associated
      with carcinoma of the stomach, with distressing generalized cutaneous, perioral
      and perineal disease, whose skin condition resolved completely with combination
      chemotherapy. In patients with malignant acanthosis, chemotherapy may relieve
      many of the distressing cutaneous symptoms. A close liaison between
      gastroenterologists, dermatologists and oncologists is required.

PMID- 10583124
TI  - Acquired streptococcal necrotizing fasciitis following excision of malignant
      melanoma.
AB  - Necrotizing fasciitis is an uncommon condition which may complicate any surgical
      procedure, including 'minor' dermatological procedures. However, it may arise de
      novo in the absence of any discernible trauma. We report a patient who acquired a
      fulminant form of this condition following excision of a malignant melanoma. The
      development of necrotizing fasciitis in association with melanoma has not
      previously been reported.

PMID- 10583125
TI  - Lupus erythematosus with antiphospholipid syndrome and erythema multiforme-like
      lesions.
AB  - The occurrence of erythema multiforme (EM) in patients with lupus erythematosus
      (LE) has been described previously as a coincidental association. In contrast, LE
      with EM-like lesions and a peculiar immunological pattern, including positive
      rheumatoid factor, antinuclear antibodies and a serum antibody against an extract
      of human tissues recently recognized as similar to Ro (SSA), constitutes an
      established entity named Rowell's syndrome. We describe a woman with LE and long
      standing widespread vesiculobullous and necrotic haemorrhagic EM-like lesions in
      combination with Ro (SSA) and scl-70 antibodies and the typical laboratory
      findings of the antiphospholipid syndrome (APS), namely lupus anticoagulant,
      anticardiolipin antibodies and prolonged activated partial thromboplastin time.
      This case could conceivably be consistent with a diagnosis of Rowell's syndrome,
      if the latter is regarded as a clinicopathological spectrum. However, the
      coexistence of LE, persistent EM-like disease and incomplete APS may also fulfil
      the diagnostic criteria for the 'multiple autoimmune syndromes'. We speculate
      that the laboratory markers of APS play a pivotal part in such an unusual
      clinical presentation.

PMID- 10583126
TI  - Persistent ulcerated necrobiosis lipoidica responding to treatment with
      cyclosporin.
AB  - We report two patients with severe ulcerated necrobiosis lipoidica (NL) who
      responded to cyclosporin. One patient had suffered persistent ulceration for a
      period of 7 years and the other had NL of recent onset. In both cases, ulceration
      healed completely after 4 months of therapy, and both patients have remained free
      of ulceration since discontinuing therapy. The possible mode of action of
      cyclosporin in the context of this debilitating disease is discussed.

PMID- 10583127
TI  - Disseminated epidermolytic acanthoma probably related to trauma.
AB  - Epidermolytic acanthoma is a rare benign tumour, which may occur in both isolated
      and disseminated forms. Only seven cases of disseminated epidermolytic acanthoma
      (DEA) have been described. This entity should be distinguished from other
      hereditary or acquired conditions which involve epidermolytic hyperkeratosis and
      other benign acanthomas. On the basis of the clinical history and the
      histological findings, we diagnosed a case of DEA which was probably secondary to
      repeated trauma.

PMID- 10583128
TI  - Global nail dystrophy associated with human papillomavirus type 57 infection.
AB  - Verrucae vulgares frequently induce nail dystrophy when infection of the nail
      matrix occurs. Classic periungual warts are easily recognized by the experienced
      physician. We report a very unusual presentation of human papillomavirus (HPV)
      infection of the nail matrix and nail bed involving all 20 nails in an otherwise
      immunocompetent patient. Viral typing by in situ hybridization revealed HPV type
      57. To our knowledge, this is the first association between dystrophy of all 20
      nails and HPV infection. However, as the ease of HPV typing improves, a variety
      of previously unrecognized cutaneous lesions is likely to be associated with HPV
      infection.

PMID- 10583129
TI  - The perils and pitfalls of penile injections.
AB  - We describe a 45-year-old man who presented with an indurated penile nodule
      following self-injection of acyclovir tablets which he had dissolved in hydrogen
      peroxide solution. This is a hazardous procedure which may be complicated by
      permanent deformity and functional disability due to the irritant nature of the
      tablets' constituents and their propensity to cause foreign body reactions in the
      skin.

PMID- 10583130
TI  - Graft-versus-host disease-like immunophenotype and apoptotic keratinocyte death
      in paraneoplastic pemphigus.
AB  - Paraneoplastic pemphigus (PP) is an autoimmune disease, which is frequently
      associated with non-Hodgkin's lymphoma. Autoantibodies against components of the
      cytoplasmic plaque of epithelial desmosomes are usually present in the sera and
      are believed to play a major pathogenic part in acantholysis and suprabasal
      epidermal blistering. However, another typical histological feature of PP,
      interface dermatitis with keratinocyte dyskeratosis, is shared with skin diseases
      that involve epithelial damage mediated by T cells. Here, we present the detailed
      characterization of the cutaneous T-cell response in a patient with PP and
      demonstrate a selective epidermal accumulation of activated CD8+ T cells together
      with an increased local production of interferon-gamma and tumour necrosis factor
      alpha, and a strong expression of HLA-DR and ICAM-1 on keratinocytes. Apoptosis
      was identified as a key mechanism of keratinocyte death, and appeared independent
      of the FAS/FAS ligand (FAS-L) pathway, as epidermal expression of FAS was not
      increased compared with normal skin, and FAS-L was undetectable on the protein
      and mRNA level. Triple therapy with high-dose corticosteroids, cyclophosphamide
      and intravenous immunoglobulins reduced levels of pemphigus-like autoantibodies
      and reversed the cutaneous inflammatory reaction leading to long-standing
      clinical remission. Our findings support the concept of a major contribution of
      cytotoxic T lymphocytes to the immunopathology of paraneoplastic pemphigus.

PMID- 10583131
TI  - A recurrent keratin 14 mutation in Dowling-Meara epidermolysis bullosa simplex.

PMID- 10583132
TI  - Annular epidermolytic ichthyosis.

PMID- 10583133
TI  - Vermiculate atrophoderma in a boy with Marfan syndrome.

PMID- 10583134
TI  - Acroangiodermatitis in a carrier of the thrombophilic 20210A mutation in the
      prothrombin gene.

PMID- 10583135
TI  - Microvenular haemangioma in a patient with Wiskott-Aldrich syndrome.

PMID- 10583136
TI  - A case of herpetiform pemphigus coexisting with psoriasis vulgaris.

PMID- 10583137
TI  - Bullous pemphigoid induced by fluoxetine.

PMID- 10583138
TI  - Vancomycin-induced linear IgA bullous disease.

PMID- 10583139
TI  - Oral trimethoprim: a relatively safe and successful third-line treatment for acne
      vulgaris.

PMID- 10583140
TI  - Trigeminal trophic syndrome: successful treatment with carbamazepine.

PMID- 10583141
TI  - Disseminated superficial actinic porokeratosis in a patient with systemic lupus
      erythematosus.

PMID- 10583142
TI  - Rapid diagnosis of clinically atypical basal cell carcinoma by cytomorphology.

PMID- 10583143
TI  - Follow up for cutaneous malignant melanoma.

PMID- 10583144
TI  - Scratching and fasting: a study of pruritus and anorexia nervosa.

PMID- 10583145
TI  - Erosive pustular dermatosis of the scalp following radiation therapy for solar
      keratoses.

PMID- 10583146
TI  - Treatment of lichen planus of the penis with photodynamic therapy.

PMID- 10583147
TI  - Erythema elevatum diutinum/Sweet's syndrome overlap with gastrointestinal and
      oral involvement.

PMID- 10583148
TI  - Sezary syndrome revealed by routine blood examination.

PMID- 10583149
TI  - Human herpesvirus type 8 is not detected in cutaneous lesions of sarcoidosis.

PMID- 10583151
TI  - Linear melorheostotic scleroderma with hypertrichosis sine melorheostosis.

PMID- 10583150
TI  - Exanthematic pityriasis rubra pilaris.

PMID- 10583152
TI  - A case of lingual chondroma.

PMID- 10583153
TI  - Oestrogen urticaria associated with pregnancy.

PMID- 10583154
TI  - Graphite foreign body granuloma.

PMID- 10583155
TI  - Effector cells in cutaneous graft-versus-host disease. Who? What? When? Where?
      How?

PMID- 10583156
TI  - Why are there delays in patients presenting with melanoma?

PMID- 10583157
TI  - Awareness and early detection of cutaneous melanoma: an analysis of factors
      related to delay in treatment.
AB  - Factors associated with the detection of cutaneous melanomas and reasons for
      delay in diagnosis were investigated in 429 patients with histologically proven
      melanoma operated on between January 1993 and June 1996. Patients were
      interviewed using a standardized questionnaire. In 25% of patients, treatment was
      delayed for more than 1 year from the time they first noticed a suspicious
      pigmented lesion. Melanoma was detected by the patients themselves in 67% of
      women and 45% of men. The three predominant clinical symptoms of melanoma were
      change in colour (darker), increase in size and increase in elevation of a
      pigmented lesion. The role of sun exposure and of naevi as risk factors for
      melanoma, as well as the potential benefit of early treatment, were known by 87%,
      66% and 82% of the patients, respectively. However, melanoma awareness had no
      impact on the time period between first observation of skin changes and
      treatment. Among the factors associated with delay in melanoma diagnosis, an
      initial incorrect diagnosis as a benign lesion by the physician first visited (in
      18% of all cases) had the highest significance. Patients detecting their lesions
      themselves were treated significantly later than patients in whom others had
      remarked on changes in a naevus. Furthermore, melanomas of the head and neck were
      treated later than melanomas at other body sites. Further efforts to educate both
      the public and the medical profession are essential to ensure earlier treatment
      for cutaneous melanomas.

PMID- 10583158
TI  - Dermatoscopic pitfalls in differentiating pigmented Spitz naevi from cutaneous
      melanomas.
AB  - Epiluminescence microscopy (ELM, skin surface microscopy, dermoscopy,
      dermatoscopy) is a valuable method for improving the diagnostic accuracy in
      pigmented skin lesions. Specific ELM criteria are already recognized for
      differentiating pigmented Spitz naevi (PSN) from cutaneous melanomas (CM). Our
      purpose was to describe the ELM appearance of a series of PSN with emphasis on
      PSN and CM with overlapping features. Thirty-six consecutive patients with PSN,
      and three cases of CM (selected from a larger database) exhibiting ELM 'spitzoid'
      features, were evaluated clinically, dermatoscopically and histopathologically.
      Most PSN (27 of 36; 75%) displayed two typical ELM patterns, namely, the
      starburst (19 of 36; 53%) or the globular pattern (eight of 36; 22%), which were
      correlated to different histopathological findings. In nine of 36 (25%) PSN,
      atypical ELM features which are more commonly seen in CM were observed. These PSN
      with an atypical pattern were characterized by an uneven distribution of colours
      and structures, and an irregular diffuse pigmentation resembling blue-white veil
      or irregular extensions (black blotches). These atypical lesions mostly occurred
      in children and showed no history of growth. In contrast, in three examples of
      CM, the typical ELM criteria of malignancy were less recognizable and either the
      characteristic starburst or globular pattern usually seen in PSN was present.
      These three lesions occurred in adults and had a recent history of change in
      colour, shape or size. The overlap in ELM features of some PSN and CM represents
      a major diagnostic pitfall when ELM examination is considered alone. In these
      atypical cases, clinical history including the age of the patient may be the only
      clue to enable a correct diagnosis.

PMID- 10583159
TI  - Attachment and chemotaxis of melanocytes after ultraviolet irradiation in vitro.
AB  - Because ultraviolet (UV) radiation is able to influence the spatial distribution
      of melanocytes in melanocytic naevi in vivo, we investigated the influence of UV
      radiation on the ability of melanocytes to adhere to the extracellular matrix
      proteins fibronectin, laminin and collagen type IV in vitro. In addition,
      chemotaxis of melanocytes was studied using both fibronectin and the supernatants
      from irradiated, as well as non-irradiated, keratinocytes and fibroblasts as
      attractants. Melanocyte attachment to fibronectin was significantly increased 48
      h after a single UV irradiation at 30 mJ/cm2 in comparison with that of non
      irradiated melanocytes, whereas attachment to laminin and collagen type IV showed
      only minor changes after UV exposure. The UV-induced increase in attachment to
      fibronectin was suppressed by preincubation with antibodies against alpha5beta1
      or alphavbeta3 integrin. Both immunohistochemistry and flow cytometric analysis
      showed an increase in alpha5beta1 integrin expression on melanocytes after UV
      exposure. The chemotaxis of melanocytes to fibronectin was not influenced by UV
      exposure. A decreasing migration rate of melanocytes towards the supernatants of
      UVA-irradiated fibroblasts was observed with increasing UVA doses. The
      chemotactic effects of conditioned medium of keratinocytes towards melanocytes
      was not influenced either by UVB or by UVA. The results indicate that UV
      radiation may alter the ability of melanocytes to adhere to certain substrates by
      modification of integrin expression. Because fibronectin, as the major target
      protein of UV-altered attachment, is located in the dermis, the UV-induced
      morphological changes in melanocytic lesions, with an increase in suprabasally
      located melanocytes within the epidermis, may be due to other changes in the
      adhesive properties of melanocytes.

PMID- 10583160
TI  - Growth inhibition of psoriatic keratinocytes by quinazoline tyrosine kinase
      inhibitors.
AB  - Psoriasis is characterized by hyperproliferation of keratinocytes associated with
      an inflammatory infiltrate in the epidermis. Among factors which may be related
      to hyperplasia of psoriatic keratinocytes is the persistent autocrine stimulation
      of the epidermal growth factor receptor (EGFR) by transforming growth factor
      alpha. Owing to the pivotal role of the EGFR in driving the growth of human
      psoriatic keratinocytes, we examined two selective inhibitors of EGFR kinase
      activity: 4-(3-bromophenylamino)-6, 7-dimethoxyquinazoline (AG1517/SU5271) and 4
      (3-chlorophenylamino)-6, 7-dimethoxyquinazoline (AG1478) on psoriatic
      keratinocytes. SU5271 potently inhibits ligand-induced autophosphorylation of
      EGFR, and downstream signal transduction events, including DNA replication and
      cell cycle progression. SU5271, at micromolar concentrations, inhibited the
      proliferation of keratinocytes isolated from psoriatic lesions in excellent
      correlation with its EGFR kinase inhibitory activity in these cells. Biologically
      active concentrations of SU5271 penetrated human cadaver skin, suggesting that
      this compound is a strong candidate as an antipsoriatic agent.

PMID- 10583161
TI  - Development of autologous human dermal-epidermal composites based on sterilized
      human allodermis for clinical use.
AB  - The aim of this study was to identify a sterilization technique for the
      preparation of human allodermis which could be used as a dermal component in
      wound healing and as the dermal base for production of dermal-epidermal
      composites for one-stage grafting in patients. We report that it is possible to
      produce dermal-epidermal composites which perform well in vitro and in vivo using
      a standard ethylene oxide sterilization methodology. Prevention of ethylene oxide
      induced damage to the dermis was achieved using gentle dehydration of the skin
      prior to ethylene oxide sterilization. The issue of whether viable fibroblasts
      are required for composite production was examined in comparative studies using
      glycerol vs. ethylene oxide sterilized dermis. Where good collagen IV retention
      was achieved following preparation of acellular de-epidermized dermis there was
      no advantage to having fibroblasts present in vitro or in vivo; however, where
      collagen IV retention was poor or where keratinocytes were initially expanded in
      culture then there was a significant advantage to introducing fibroblasts to the
      composites during their preparative 10-day period in vitro. The requirement for
      fibroblasts became less evident when composites were grafted on to nude mice. In
      conclusion, we report a protocol for the successful sterilization of human
      allodermis to achieve an acellular dermis with good retention of collagen IV.
      This acellular dermis would be appropriate for clinical use as a dermal
      replacement material. It can also be used for the production of dermal-epidermal
      composites using autologous keratinocytes (with or without fibroblasts).

PMID- 10583162
TI  - Colocalization of basic fibroblast growth factor and CD44 isoforms containing the
      variably spliced exon v3 (CD44v3) in normal skin and in epidermal skin cancers.
AB  - Previous in vitro studies have shown CD44 isoforms containing the alternatively
      spliced exon v3 (CD44v3) to be modified with heparan sulphate (HS) and to bind HS
      binding basic fibroblast growth factor (bFGF). Here, we demonstrate that
      exogenously added bFGF is also bound in vivo by CD44v3-positive keratinocytes in
      normal skin and by tumour cells in basal cell carcinoma and squamous cell
      carcinoma (SCC), two skin cancers of keratinocyte origin. bFGF binding and CD44v3
      expression were colocalized in cultured human normal keratinocytes (HNK) and on
      the SCC cell line A431. By contrast, benign or malignant tumours of melanocyte
      origin failed to express CD44v3 and bound no bFGF. The bFGF binding to normal or
      transformed keratinocytes in vivo and in vitro was dependent on HS modification,
      as it was completely eliminated by pretreatment with heparitinase or by blocking
      with free heparin, whereas chondroitinase had no effect. In addition, specific
      removal of CD44v3 by antibody-induced shedding also diminished bFGF binding to
      keratinocytes. Furthermore, bFGF stimulated the proliferation of CD44v3-positive
      HNK and A431 in a dose-dependent fashion. This bFGF effect was again completely
      abolished by heparitinase or free heparin, but not by chondroitinase. In
      aggregate, our results suggest that a function of HS-modified CD44 isoforms such
      as CD44v3 in skin is to present the HS-binding growth factor bFGF, thereby
      stimulating the proliferation of normal or transformed keratinocytes.

PMID- 10583163
TI  - Pretibial dystrophic epidermolysis bullosa: a recessively inherited COL7A1 splice
      site mutation affecting procollagen VII processing.
AB  - Pretibial epidermolysis bullosa (PEB) is a rare form of localized epidermolysis
      bullosa dystrophica (EBD), a heterogeneous group of inherited, blistering
      diseases characterized by scarring, loss of dermal-epidermal adhesion and altered
      anchoring fibrils (AF). Mutations in the type VII collagen gene (COL7A1) underlie
      EBD and in a dominant PEB family a glycine substitution mutation has been
      identified. We report a 33-year-old man affected by PEB showing abnormal AF and
      reduced immunostaining for type VII collagen. Mutation search in the COL7A1 gene
      revealed a 14 bp deletion in the 115 exon-intron boundary (33563del14), which
      resulted in the in-frame skipping of exon 115 with elimination of 29 amino acids
      from the pro-alpha1(VII) polypeptide chain. As a consequence, procollagen VII
      failed to be processed to mature collagen VII and accumulated at the dermal
      epidermal junction, as revealed by immunofluorescence staining using a NC-2
      domain-specific antibody. The proband's father was a clinically unaffected
      heterozygous carrier of mutation 33563del14, whereas the maternal pathogenetic
      mutation has still not been identified. This represents the first report of a
      recessive deletion mutation in PEB and extends the range of EBD phenotypes
      associated with mutation 33563del14.

PMID- 10583164
TI  - Expression of mRNA for androgen receptor, 5alpha-reductase and 17beta
      hydroxysteroid dehydrogenase in human dermal papilla cells.
AB  - In order to determine whether adrenal and gonadal weak androgens are utilized to
      form active androgens in human hair, we studied the expression of mRNA for
      androgen receptor (AR), 5alpha-reductase and 17beta-hydroxysteroid dehydrogenase
      (17beta-HSD) in cultured dermal papilla cells (DPCs) from various body sites. AR
      mRNA was expressed in beard (Be) and axillary hair (Ax) DPCs from both sexes, but
      only at a low level in DPCs from occipital scalp hair (OS). Type I 5alpha
      reductase mRNA was expressed by all DPCs. Type II 5alpha-reductase mRNA was
      identified in beard DPCs, but was absent from OS and Ax DPCs. Type II 17beta-HSD
      mRNA was strongly expressed in outer root sheath cells (ORSCs), while DPCs except
      for male Ax expressed no type II 17beta-HSD mRNA. In contrast, type III 17beta
      HSD mRNA was strongly expressed in Be DPCs and Ax DPCs from both sexes; ORSCs
      showed a low level of expression. Expression of type III 17beta-HSD mRNA was not
      regulated by androgen in DPCs. These results suggest that the sensitivity of
      hairs to androgen is partially controlled by the site-specific expression of AR,
      5alpha-reductase and 17beta-HSD in DPCs.

PMID- 10583165
TI  - Corticosteroid treatment of prolidase deficiency skin lesions by inhibiting
      iminodipeptide-primed neutrophil superoxide generation.
AB  - We studied the pathogenetic role of iminodipeptides, and the effects of
      corticosteroids on the skin lesions of two adult female siblings with prolidase
      deficiency. The elder sister had had severe skin ulcers and mental retardation
      since childhood, while the younger sister had shown milder clinical
      manifestations since late adolescence. The ulcers showed vascular wall thickening
      and neutrophil infiltration. Oral prednisolone at moderate doses was not
      effective, but corticosteroid pulse therapy followed by a moderate dose of
      prednisolone improved the preulcerative indurated lesions and ulcers. A 2-year
      follow-up of the younger patient indicated that N-formyl methionyl leucyl
      phenylalanine-induced neutrophil superoxide generation was elevated, in parallel
      with an increase in the serum iminodipeptide level, when the skin ulcers and
      preulcerative indurated lesions were most active. Corticosteroid pulse therapy
      downregulated the superoxide generation by neutrophils. The serum iminodipeptide
      level, however, did not decrease during 25 days after pulse therapy. These
      findings suggest that iminodipeptides may play an important part in aggravating
      the skin lesions by priming neutrophil superoxide generation, and that high-dose
      corticosteroids improve the skin lesions, probably by inhibiting the
      infiltration, and superoxide generation by, neutrophils. Neutrophil superoxide
      generation was more prominent in the elder sister, suggesting that clinical
      severity may depend on the response of neutrophils to the iminodipeptides.
      Chronic stimulation by superoxide may cause thickening of cerebral blood vessels
      and eventual mental retardation.

PMID- 10583166
TI  - Factors affecting the adherence of Candida albicans to human buccal epithelial
      cells in human immunodeficiency virus infection.
AB  - Adherence to host surfaces is an essential prerequisite for colonization and
      infection. We compared the adherence of 15 oral isolates of Candida albicans
      harvested from human immunodeficiency virus (HIV)-infected individuals and 12
      isolates from HIV-free individuals to buccal epithelial cells (BECs) from HIV
      free individuals, and the adherence of a reference strain of C. albicans to BECs
      from HIV-infected as well as HIV-free individuals. C. albicans from HIV-infected
      individuals showed adherence values similar to those from HIV-free individuals.
      The clinical and laboratory parameters of the subjects from whom the Candida were
      isolated did not correlate with adherence. A reference strain of C. albicans (GDH
      1957), however, adhered more readily to BECs from HIV-infected individuals than
      to cells from an HIV-free cohort. Several variables were found to be associated
      with the adherence of C. albicans to BECs from HIV-infected individuals: use of
      zidovudine, antibacterials and antiparasitics was associated with increased
      adhesion, while haemophilia, heterosexuality, bisexuality, increased age,
      decreased CD4 + count and use of folate were associated with a decreased candidal
      adhesion (all P < 0.05). Our data suggest that the quality of BECs including
      their receptivity to Candida may play an important part in increasing the oral
      yeast carriage in HIV infection.

PMID- 10583167
TI  - IgA1 is the major IgA subclass in cutaneous blood vessels in Henoch-Schonlein
      purpura.
AB  - Henoch-Schonlein purpura (HSP) is characterized by palpable purpura predominantly
      involving the lower extremities. On direct immunofluorescence IgA can be seen
      deposited in the blood vessel walls of the superficial dermis. The subclass
      distribution of antibodies to this IgA was studied in the biopsies of 28 patients
      with HSP by direct immunofluorescence using anti-IgA1 and anti-IgA2 specific
      monoclonal antibodies. All 28 patients' biopsies demonstrated deposition of IgA1
      while only one patient had IgA2 deposition. Positive and negative controls
      stained appropriately. This demonstrates that IgA1 is the dominant IgA subclass
      found in the skin in Henoch-Schonlein purpura.

PMID- 10583168
TI  - The prevalence of corticosteroid allergy in two U.K. centres: prescribing
      implications.
AB  - Allergic contact dermatitis to topical corticosteroids is a common problem, seen
      in up to 6% of patients undergoing patch testing. Rates of steroid allergy vary
      widely both within and between countries. It has previously been shown that non
      fluorinated steroids degrade and react with arginine more rapidly in an in vitro
      system and may therefore be more likely to sensitize than fluorinated steroids.
      We have compared the rates of steroid allergy and corticosteroid prescribing
      habits in two different areas in England to observe the relationship between
      these factors. The results suggest that predominant use of non-fluorinated
      corticosteroids (hydrocortisone, hydrocortisone-17-butyrate and budesonide)
      results in a higher prevalence of corticosteroid contact allergy in comparison
      with those areas using a greater proportion of fluorinated corticosteroids.

PMID- 10583169
TI  - Adult linear IgA disease and chronic bullous disease of childhood: the
      association with human lymphocyte antigens Cw7, B8, DR3 and tumour necrosis
      factor influences disease expression.
AB  - Linear IgA disease and chronic bullous disease of childhood are both subepidermal
      autoimmune blistering diseases. Class I and II major histocompatibility locus
      (MHC) antigen typing was performed on 60 patients (26 chronic bullous disease of
      childhood, 34 adult linear IgA disease), and the findings were correlated with
      the clinical course. The typing was performed using a lymphocyte
      microcytotoxicity assay, and the results were compared with a reference
      population of U.K. organ donors. Analysis of the tumour necrosis factor (TNF)
      locus was performed using sequence-specific oligonucleotides on a dot blot in 51
      patients and compared with a random control population and human lymphocyte
      antigen (HLA) DR3 matched controls. The disease was found to be significantly
      associated with HLA Cw7 (chi2 = 19.24, P = 0.001), B8 (chi2 = 9.89, P = 0.04) and
      DR3 (chi2 = 10.47, P = 0.014), all components of the common Caucasian haplotype.
      There was also a close association between the disease and possession of HLA DR2
      or 3 (chi2 = 16.34, P = 0.001). A reduction in the incidence of DR1 and DR4
      (alleles carrying the rheumatoid motif) was observed, which is more marked in the
      children (chi2 = 8.34, P = 0.039). In the childhood group there was an increased
      frequency of B8, DR3 and DQ2 compared with the adults which included five of 26
      who were homozygous for these antigens, a feature not seen in the adults, which
      may account for the differences seen between the two groups. Possession of HLA
      B8, DR3 and DQ2 probably facilitates earlier presentation of the disease as there
      is no evidence from our results that the adults and children differ fundamentally
      in their MHC associations. The rare TNF2 allele was found in 29 of 51 patients
      (expected 8.2, chi2 = 18. 3, P = 0.0001). This was more marked in the children
      (19 of 26). Patients with the TNF2 allele had a longer disease duration (5.3
      years TNF2, 3.0 years TNF1).

PMID- 10583170
TI  - Clinical measurement of dimensions of basal cell carcinoma: effect of waiting for
      elective surgery.
AB  - Fifty well-defined basal cell carcinomas (BCCs) on the face, outside the central
      T, were studied to establish change in size between initial assessment and
      surgery. The major and minor diameters were measured at presentation and when the
      patients attended for elective excision 21-155 days later (mean 70). The median
      change in major diameter was an increase of 0.5 mm (range - 3 to + 4, P < 0.05).
      The median change in area was 4.71 mm2 (range - 54 to + 64, P < 0.05). Although
      there is a statistically significant increase in major diameter and area, it was
      small in clinical terms. The major axis increased by > 1 mm in 8% of cases. In no
      case was treatment or completeness of excision compromised by waiting. A mean
      delay of 10 weeks between review and surgery does not appear to compromise the
      outcome of treatment of BCC in patients with well-defined BCCs of the face
      outside the central T.

PMID- 10583171
TI  - International Nomenclature cosmetic ingredient awareness in Scotland.

PMID- 10583172
TI  - Unique immunobullous disease in a child with a predominantly IgA response to
      three desmosomal proteins.
AB  - We report the case of a 15-year-old girl who presented at 11 years of age with an
      interesting, acquired and, to our knowledge, unique blistering disease. It
      involved both skin and mucous membranes with extensive oral and periungual
      lesions, clinically resembling paraneoplastic pemphigus. Skin biopsy showed an
      inflammatory cell infiltrate in the upper dermis with numerous leucocytoclastic
      nuclear fragments, neutrophilic papillary microabscesses and a small subepidermal
      bulla. Direct and indirect immunofluorescence studies showed marked intercellular
      staining with IgA and less prominent staining with IgG. Granular deposition of
      IgA and, to a lesser extent IgG and C3, was also seen along the basement membrane
      zone. Immunoblotting and enzyme-linked immunosorbent assay studies showed both
      IgG and IgA antibodies to desmocollin, desmoglein 3 and desmoplakin. However,
      despite extensive investigation, no underlying neoplasm was found. Treatment with
      dapsone and sulphapyridine proved ineffective but methylprednisolone and
      azathioprine have reduced the blistering. We believe that this patient is unique
      for her combination of IgA and IgG antibodies to desmoplakin, desmocollin and
      desmoglein 3, although further studies may provide further clarification.

PMID- 10583173
TI  - Ocular involvement in IgA-epidermolysis bullosa acquisita.
AB  - Epidermolysis bullosa acquisita (EBA) is an autoimmune bullous disease with
      frequent ocular involvement, but visual loss is rare. In contrast, EBA patients
      with predominant IgA autoantibodies more frequently develop severe ocular
      involvement, which tends to be refractory to therapy. We report two patients with
      'IgA-EBA' with ocular involvement. Both initially presented with a generalized
      bullous disease, and direct immunofluorescence microscopy demonstrated IgA in the
      basement membrane zone of the skin, and in the conjunctiva and cornea of patient
      1. On salt-split patient skin, IgA was found predominantly on the dermal side of
      the artificial split in both patients. Direct immunoelectron microscopy
      demonstrated IgA below the lamina densa in close association with the anchoring
      fibrils in both patients. In patient 1, who had a prolonged course of the
      disease, the skin disorder responded well to treatment with cyclosporin, but the
      ocular involvement ended in bilateral blindness despite repeated surgical
      treatment. In patient 2, the blister formation and scarring conjunctivitis was
      stopped by a combination of prednisolone and colchicine. These patients show that
      in subepithelial blistering diseases, early delineation of disease nosology is
      critical to detect subtypes with severe ocular involvement such as 'IgA-EBA'. In
      addition, colchicine may be a valuable alternative in the treatment of EBA with
      ocular involvement.

PMID- 10583174
TI  - Lupus erythematosus vegetans.
AB  - A 29-year-old woman with known systemic lupus erythematosus presented with
      exudative and vegetative plaques bilaterally on her groins. The clinical and
      histological findings indicated a diagnosis of pyodermatitis vegetans. Direct
      immunofluorescence studies revealed the presence of a definite basement membrane
      zone band for IgG, IgM and C3, favouring lupus erythematosus. We propose the term
      lupus erythematosus vegetans for this combination of clinicopathological and
      immunohistological findings.

PMID- 10583175
TI  - A case of dermatomyositis that developed after delivery: the involvement of
      pregnancy in the induction of dermatomyositis.
AB  - A relationship between dermatomyositis (DM) and pregnancy has rarely been
      documented, and most cases have been reported from the viewpoint of the
      management of high-risk pregnancy. We report a patient with DM which developed
      after the delivery of a healthy infant. This case, with support from a literature
      review, suggests that pregnancy could be a trigger for the development of DM.
      Furthermore, it is suggested that there are at least two types of pregnancy
      related DM: in one type, the disease activity is provoked during pregnancy and
      tends to improve after delivery, while the other type (including the present
      case) has onset in the postpartum period.

PMID- 10583176
TI  - Cutaneous lesions as the presenting sign of acute graft-versus-host disease
      following liver transplantation.
AB  - Acute graft-versus-host disease (GVHD) is a frequent complication of bone marrow
      transplantation but is only rarely observed after solid organ transplantation. We
      describe a 68-year-old man who developed a maculopapular eruption 7 days
      following orthotopic liver transplantation for cirrhosis with malignant
      transformation due to haemochromatosis. At day 20, the patient complained of
      nausea, vomiting, diarrhoea and fever. Skin biopsy revealed a lymphocytic
      infiltrate at the dermoepidermal interface, vacuolization of basal cells and
      epidermal dyskeratosis. Immunohistochemistry showed HLA-DR and intercellular
      adhesion molecule-1 expression of lesional keratinocytes. HLA-typing of
      peripheral blood lymphocytes demonstrated circulating lymphocytes of donor
      origin. Endoscopy revealed extensive erosions of the oesophagus, stomach and
      duodenum that on histology disclosed multifocal loss of crypts, lymphocytic
      infiltrates and epithelial cell death. A diagnosis of acute GVHD was made, and
      high-dose immunosuppressive therapy with azathioprine and methylprednisolone was
      instituted. The skin and gastrointestinal symptoms subsided within 4 weeks, but
      the patient died from severe infectious complications 105 days after
      transplantation. We conclude that acute GVHD is a rare but potentially fatal
      complication of liver transplantation. Skin lesions are an early sign of acute
      GVHD and thus represent an important tool for early diagnosis.

PMID- 10583177
TI  - Papular mucinosis associated with generalized morphoea.
AB  - A 67-year-old white man is described who had large sclerotic plaques with a
      violaceous border on his back and abdomen and a scleroderma-like induration on
      the legs, sparing the feet. Additionally, he had multiple skin-coloured, large,
      sometimes centrally depressed papules and nodules on the nape of the neck, back
      and upper limbs. These occurred in both the normal and sclerotic areas.
      Histologically, large amounts of focal mucin were seen in the upper dermis
      consistent with the diagnosis of papular mucinosis and associated with typical
      underlying features of scleroderma. No paraproteinaemia was found. We excluded
      scleromyxoedema on clinical, histopathological and laboratory grounds and
      diagnosed our patient as having generalized morphoea with papular mucinosis. We
      are aware of only two reports of large cutaneous deposits of mucin associated
      with scleroderma.

PMID- 10583178
TI  - Meningeal involvement by a transformed mycosis fungoides following Hodgkin's
      disease.
AB  - A 58-year-old man had long-standing lesions of presumed large plaque
      parapsoriasis. Following treatment for nodal Hodgkin's disease (HD), these became
      more infiltrated, with a diagnosis of mycosis fungoides (MF). A few months later,
      nodules appeared on the right leg, which was lymphoedematous after inguinal
      irradiation for HD. Histopathological examination showed CD3+, CD30-, CD15- large
      pleomorphic lymphocytes, leading to the diagnosis of transformed MF. The
      cutaneous lesions were successfully treated with topical nitrogen mustard and
      interferon alfa-2b then methotrexate, but his general health worsened with
      depression and malaise, without specific neurological symptoms or extracutaneous
      spreading of the lymphoma. Cerebral computed tomographic scan revealed a
      cerebellar subdural collection, arachnoid cyst and quadriventricular
      hydrocephaly, initially considered to be non-specific. After a few weeks,
      clinical symptoms of intracranial hypertension appeared, and a cerebrospinal
      fluid (CSF) examination revealed meningeal involvement by the lymphoma. These
      cells were CD3-negative and the diagnosis was confirmed by polymerase chain
      reaction (PCR) study, which revealed an identical clonal rearrangement of the T
      cell receptor gamma gene between cutaneous biopsies and the CSF. Repeated
      intrathecal injections of methotrexate and cranial irradiation were performed and
      the patient was still alive after 13 months. This case illustrates the possible
      meningeal involvement of MF that may be preceded by atypical and mild
      neurological or psychiatric symptoms, which may be dissociated from the evolution
      of the cutaneous lesions. Moreover, PCR study may be useful for both diagnosis
      and monitoring.

PMID- 10583179
TI  - Relapse of cutaneous leishmaniasis in a patient with an infected subcutaneous
      rheumatoid nodule.
AB  - Cutaneous leishmaniasis is a protozoal infection generally considered to be
      limited to the skin. In Israel, the disease is common in geographically defined
      areas and is caused predominantly by Leishmania major. Sporotrichoid subcutaneous
      spread has been reported but is uncommon. We describe a patient with rheumatoid
      arthritis, treated with methotrexate and prednisone, in whom numerous rheumatoid
      nodules concomitant with cutaneous leishmaniasis were found, mimicking
      sporotrichoid spread of the disease. In a rheumatoid nodule that was examined by
      electron microscopy, Leishmania parasites were found at intracellular and
      extracellular locations. This observation supports the hypothesis that cutaneous
      leishmaniasis parasites persist after clinical cure of the disease and may re
      emerge as a result of immunosuppression.

PMID- 10583180
TI  - Crusted (Norwegian) scabies in a patient with dystrophic epidermolysis bullosa.
AB  - A 13-year-old girl with severe non-mutilating recessive dystrophic epidermolysis
      bullosa (EB) was admitted to hospital because of a Staphyloccus aureussepsos,
      deterioration of her general condition and worsening of her skin disease, which
      itched severely. In addition to the blisters and erosions normally seen, she was
      covered from head to toe with scales and hyperkeratotic crusts. Despite intensive
      topical therapy, her skin condition did not improve significantly until scabies
      was detected and treated 1 week after admission. Because of the huge number of
      mites found and the crusted appearance, a diagnosis of crusted (Norwegian)
      scabies was made. She was successfully treated with two doses of ivermectin
      orally and one application of lindane ointment. Permethrin cream was not
      tolerated. In this patient crusted scabies may have developed because of: (i) a
      modified host response due to malnourishment; (ii) inability to scratch because
      of the absence of fingernails; and (iii) abnormal scratching behaviour because of
      the vulnerability of EB skin, or a combination of these factors. Limited
      isolation measures were taken on admission and full measures were taken
      immediately after the diagnosis of crusted scabies was made. Prophylactic
      treatment of ward personnel was not undertaken. Fortunately, there was not an
      outbreak of scabies in the hospital.

PMID- 10583181
TI  - Common blue naevus with satellite lesions: possible perivascular dissemination
      resulting in a clinical resemblance to malignant melanoma.
AB  - We report a case of common blue naevus with polymorphous guttate and linear
      satellite lesions, thereby mimicking peripherally spreading malignant melanoma.
      Histopathologic examination showed that the naevus cells are clustered around
      blood vessels in the primary as well as satellite lesions, suggestive of
      spreading of the naevus cells along the perivascular space. Such biological
      behaviour resulting in a clinical manifestation of a malignant melanoma-like
      lesion is a rarity in common blue naevus, a benign cutaneous disorder that is
      devoid of a malignant potential, and has not been described before.

PMID- 10583182
TI  - Dermatomyositis with the features of inclusion body myositis associated with
      carcinoma of the bladder.
AB  - Inclusion body myositis (IBM) is a unique category of inflammatory myopathy. It
      is characterized histologically by the presence of muscle fibres with rimmed
      vacuoles and abnormal intracellular accumulations of proteins. We report here a
      62-year-old patient with bladder carcinoma, where the signs of IBM overlapped
      with clinical features of dermatomyositis (DM). A combination of cutaneous
      changes typical for DM with histological and other features of IBM is exceedingly
      rare, and has not been previously addressed in dermatological literature. To the
      best of our knowledge this is also the first description of the association of
      DM/IBM with internal malignancy.

PMID- 10583183
TI  - Passive transfer of contact hypersensitivity to rubber following allogeneic bone
      marrow transplantation.

PMID- 10583184
TI  - Hypertrichosis due to porphyria cutanea tarda associated with blastic
      transformation of myelofibrosis.

PMID- 10583185
TI  - Treatment of epidermolysis bullosa acquisita with mycophenolate mofetil and
      autologous keratinocyte grafting.

PMID- 10583186
TI  - Mycophenolate mofetil monotherapy for pemphigus vulgaris.

PMID- 10583187
TI  - Osteoporosis in a patient with recessive dystrophic epidermolysis bullosa.

PMID- 10583188
TI  - Complete remission of advanced cutaneous leiomyosarcoma following isolated limb
      perfusion with high-dose tumour necrosis factor-alpha and melphalan.

PMID- 10583189
TI  - Efficacy of topical photodynamic therapy of a giant keratoacanthoma demonstrated
      by partial irradiation.

PMID- 10583190
TI  - An acral 'inflammatory' cutaneous metastasis of oesophageal carcinoma.

PMID- 10583191
TI  - Metastatic squamous cell carcinoma of the nail bed: a presenting sign of lung
      cancer.

PMID- 10583192
TI  - Carcinoma erysipeloides of the facial skin in a patient with metastatic breast
      cancer.

PMID- 10583193
TI  - Myotonic dystrophy and basal cell carcinoma-a true association?

PMID- 10583195
TI  - Propylthiouracil-induced antineutrophil cytoplasmic antibodies in a patient with
      Graves' disease and a neutrophilic dermatosis.

PMID- 10583194
TI  - Lack of evidence of human herpesvirus 8 DNA sequences in HIV-negative patients
      with systemic plasmacytosis.

PMID- 10583196
TI  - Acute severe acne in a female patient (acne fulminans?)

PMID- 10583198
TI  - Eccrine syringofibroadenoma: the simultaneous occurrence of two histopathological
      variants (conventional and clear-cell type) in one patient.

PMID- 10583197
TI  - Isotretinoin treatment for acne vulgaris and its cutaneous and ocular side
      effects.

PMID- 10583199
TI  - Porokeratosis of Mibelli associated with dermal amyloid deposits.

PMID- 10583200
TI  - A case of clear cell acanthoma presenting as nipple eczema.

PMID- 10583201
TI  - Extramammary Paget's disease in two siblings.

PMID- 10583202
TI  - Kerion formation due to Trichophyton rubrum.

PMID- 10583203
TI  - Non-professional identification of malignant melanoma: are wives more attentive?

PMID- 10583204
TI  - Naevocentric erythema multiforme associated with herpes labialis.

PMID- 10583205
TI  - Images in haematology. The peripheral blood in metastatic melanoma.

PMID- 10583206
TI  - The continuing challenge of treatment for non-Hodgkin's lymphoma in children.

PMID- 10583207
TI  - Can antimicrobial central venous catheters prevent associated infection?

PMID- 10583208
TI  - Historical review. Inherited bone marrow failure: the men behind the empty space.

PMID- 10583209
TI  - Spatial and temporal mapping of c-kit and its ligand, stem cell factor expression
      during human embryonic haemopoiesis.
AB  - Receptor tyrosine kinases (RTKs) mediate cellular responses to the extracellular
      signals involved in the regulation of cell differentiation and proliferation.
      Ligand binding initiates a cascade of events, such as receptor dimerization and
      tyrosine phosphorylation. The c-kit gene encodes an RTK for stem cell factor
      (SCF), (c-kit ligand, KL), both of which play a critical role in the
      differentiation and growth of haemopoietic stem cells (HSCs). We investigated the
      expression of the c-kit and SCF genes and the presence of the corresponding
      proteins in haemopoietic tissues during human embryogenesis. We have examined c
      kit and SCF transcripts levels in human embryonic yolk sac, the AGM region, and
      liver at different stages of gestation (days 25 to 63), using RT-PCR
      amplification combined with PhosphorImager quantitative analysis and RNase
      Protection Assay (RPA). Weak levels of SCF gene expression were observed in the
      AGM region (days 25 to 34) and high levels were found in the early-stage liver
      (day 34). The expression of c-kit transcript was observed in all studied tissues,
      but at various levels. The restricted presence of SCF protein following mRNA
      expression was demonstrated in embryonic liver CD38+ haemopoietic cells by
      immunocytochemistry. These observations suggest that the biological function of
      the c-kit receptor plays an important role in the early stages of human
      haemopoiesis, and that c-kit/SCF signalling is particularly involved in early
      human definitive haemopoiesis.

PMID- 10583210
TI  - WASP is involved in proliferation and differentiation of human haemopoietic
      progenitors in vitro.
AB  - The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder
      characterized by thrombocytopenia, immunodeficiency and eczema. X-linked
      thrombocytopenia (XLT) is a mild form of WAS with isolated thrombocytopenia. Both
      phenotypes are caused by mutation of the Wiskott-Aldrich syndrome protein (WASP)
      gene. In this study we investigated the role of WASP in the differentiation of
      CD34-positive (CD34+) cells isolated from the bone marrow of patients with WAS (n
      = 5) or with XLT (n = 4). Megakaryocyte colony formation was significantly
      decreased in patients with WAS when compared with normal controls. The formation
      of granulocyte-macrophage colonies and erythroid bursts were also decreased in
      WAS patinets. In contrast, in XLT patients, formation of all these colonies was
      normal. However, in vitro proplatelet formation of megakaryocytes induced by
      thrombopoietin was markedly decreased in both XLT and WAS. Electron microscopic
      examination revealed that megakaryocytes obtained from WAS or XLT patients grown
      in vitro had abnormal morphologic features, which seemed to be caused by
      defective actin cytoskeletal organization, including labyrinth-like structures of
      the demarcation membrane system and deviated distribution of the alpha-granules
      and demarcation membrane system. These observations indicate that WASP is
      involved in the proliferation and differentiation of CD34+ haemopoietic
      progenitor cells probably by its participation in signal transduction and in the
      regulation of the cytoskeleton.

PMID- 10583211
TI  - Time-course expression of polypeptides carrying blood group antigens during human
      erythroid differentiation.
AB  - The time course expression of blood group antigens was examined by flow cytometry
      using a two-phase liquid culture system that supports the proliferation and
      maturation of human erythroid progenitors from adult peripheral blood. The
      progression towards erythroid differentiation was followed by the expression
      changes of the transferrin receptor (CD71++) and glycophorin A (GPA+). Four main
      categories of blood group markers were identified: (i) those characterized by an
      early expression like ABO (A), Kell (K:2) and Rh50 which were detected in the Epo
      independent phase 1, (ii) those including GPC (Gerbich, Ge antigens) and Fy6
      which were expressed in the late phase 1, (iii) GPA (MN antigens), Wrb (Band
      3/GPA interaction), Rh(D, Cc/Ee) and LW which appeared during the Epo-dependent
      phase 2 and (iv) those like Jk3 and Lub which were expressed in late phase 2.
      Regarding blood group molecules exhibiting adhesive properties (LW/ICAM-4, Oka
      and Lu) the most significant event was a sharp decrease of Oka (neurothelin)
      expression with the concomitant loss of ICAMs expression during the later stage
      of differentiation. These studies suggest that Oka, ICAMs and LW might contribute
      to the adhesive interactions involved in the formation of erythroblastic islands
      and attachment to stroma cells and the extracellular matrix. We also noted an
      asynchronous expression of the proteins that compose the core of the Rh complex,
      since Rh50 glycoprotein was expressed earlier than Rh(D, CE) proteins.

PMID- 10583212
TI  - Propagation and senescence of human marrow stromal cells in culture: a simple
      colony-forming assay identifies samples with the greatest potential to propagate
      and differentiate.
AB  - Marrow stromal cells (MSCs) were isolated from bone marrow obtained by aspirates
      of the iliac crest of normal volunteers. The cells were isolated by their
      adherence to plastic and then passed in culture. Some of the samples expanded
      through over 15 cell doublings from the time frozen stocks were prepared. Others
      ceased replicating after about four cell doublings. The replicative potential of
      the cells in culture was best predicted by a simple colony-forming assay in which
      samples from early passages were plated at low densities of about 10 cells per
      cm2. Samples with high colony-forming efficiency exhibited the greatest
      replicative potential. The colonies obtained by plating early passage cells at
      low density varied in size and morphology. The large colonies readily
      differentiated into osteoblasts and adipocytes when incubated in the appropriate
      medium. As samples were expanded in culture and approached senescence, they
      retained their ability to differentiate into osteoblasts. However, the cells
      failed to differentiate into adipocytes. The loss of multipotentiality following
      serial passage in culture may have important implications for the use of expanded
      MSCs for cell and gene therapy.

PMID- 10583213
TI  - Metabolism and functional effects of sphingolipids in blood cells.
AB  - We examined the sphingolipid metabolism of peripheral blood cells, i. e.
      platelets, erythrocytes, neutrophils and mononuclear cells. A distinguishing
      characteristic of sphingolipid metabolism in these highly differentiated cells
      was their high sphingosine (Sph) kinase activity. The occurrence of
      [3H]sphingosine 1-phosphate (Sph-1-P) from [3H]Sph (actively incorporated from
      the outside) in the blood cells was strong, long-lasting, and independent of cell
      activation. Hence, the possibility of Sph-1-P playing a second messenger role is
      remote in these cells. About 40% of platelet Sph-1-P could be released
      extracellularly by 12-O-tetradecanoylphorbol 13-acetate, possibly through
      mediation by protein kinase C. On the other hand, in erythrocytes, neutrophils
      and mononuclear cells a significant percentage of Sph-1-P formed inside the cell
      was discharged without stimulation, whereas the stimulation-dependent release was
      marginal. In contrast to active [3H]Sph conversion to [3H]Sph-1-P, formation of
      [3H]sphingomyelin was barely detectable in the blood cells; this was especially
      true for anucleate platelets and erythrocytes. The Sph --> Sph-1-P pathway may
      become predominant over the Sph --> Cer --> sphingomyelin pathway during late
      stage differentiation into platelets or erythrocytes. Sph and its methylated
      derivative, N, N-dimethylsphingosine, induced apoptosis not only in neutrophils
      but also in mononuclear cells, whereas Sph-1-P elicited Ca2+ mobilization in
      platelets. Our results suggest that all blood cells may remove plasma Sph, which
      is harmful or suppressive to cellular functions, and change it into Sph-1-P,
      acting as the source of plasma Sph-1-P, which may play a variety of important
      roles in blood vessels.

PMID- 10583214
TI  - Retinoic acid stimulates plasminogen activator inhibitor 2 production by blood
      mononuclear cells and inhibits urokinase-induced extracellular proteolysis.
AB  - Retinoids have been shown to modulate several functions of mononuclear
      phagocytes. We investigated the in vitro effect of all-trans-retinoic acid (ATRA)
      on the production of two major fibrinolytic components, urokinase-type
      plasminogen activator (u-PA) and PA inhibitor 2 (PAI-2), by human blood
      mononuclear cells (MNC). ATRA caused a dose-dependent (range 0.01-10 microM)
      accumulation of PAI-2 antigen and activity into the cell culture medium, with a
      maximal increase (about 5-fold over control) at a concentration of 1-10 microM.
      Similarly, a dose-dependent increase in PAI-2 antigen was observed in cell
      extracts upon ATRA stimulation. Northern blot analysis showed a parallel increase
      in the amount of PAI-2 mRNA in ATRA-treated cells. Time-course experiments with 1
      microM ATRA showed enhanced PAI-2 mRNA expression as early as 2 h, reaching a
      maximum at 4-6 h and then declining at 18-24 h, and a time-dependent increase in
      PAI-2 antigen in the cell culture medium. At variance with PAI-2, u-PA was not
      influenced by the drug. To establish whether ATRA-induced changes influenced the
      fibrinolytic process, we evaluated the effect of MNC stimulated with ATRA on u-PA
      induced degradation of diluted plasma clots. ATRA-treated cells markedly
      inhibited clot lysis induced by low concentrations of u-PA. The effect was due to
      enhanced extracellular PAI-2 accumulation since it was observed with conditioned
      medium from ATRA-treated cells; it was abolished by the addition of neutralizing
      anti-PAI-2 antibodies and was negligible when single-chain t-PA was used instead
      of u-PA. Since monocyte/macrophage-mediated, plasminogen-dependent extracellular
      proteolysis has been proposed as an important mechanism of tissue damage in
      several inflammatory states, our findings might contribute to better explain the
      anti-inflammatory properties of retinoids.

PMID- 10583215
TI  - Phosphatidylserine-related adhesion of human erythrocytes to vascular
      endothelium.
AB  - In pathological conditions such as sickle cell disease, falciparum malaria and
      diabetes, an abnormal adherence of erythrocytes to endothelium is concomitant
      with loss of phospholipid asymmetry resulting in phosphatidylserine (PS)
      exposure. We have investigated the involvement of PS in this interaction by
      studying adhesion of human erythrocytes, treated with Ca2+-ionophore A23187 in
      combination with N-ethylmaleimide, to human umbilical vein endothelial cells in a
      flow-based assay. Results showed that erythrocytes which exposed PS, massively
      adhered to HUVEC in a Ca2+-dependent manner. This adhesion was inhibited by PS
      liposomes and by annexin V, giving clear evidence of the PS dependence of these
      interactions.

PMID- 10583216
TI  - Further characterization of antibody and antigen in heparin-induced
      thrombocytopenia.
AB  - Patients with immune heparin-induced thrombocytopenia (HIT) possess antibodies
      that bind to a complex of platelet factor 4 (PF4) and heparin. We observed that
      HIT antibodies will also bind to PF4 alone adsorbed on polystyrene ELISA wells
      but not to soluble PF4 in the absence of heparin. Having developed a technique to
      affinity-purify anti-PF4-heparin HIT IgG, we are able to provide the first
      estimates of the avidity of HIT IgG. HIT IgG displayed relatively high functional
      affinity for both PF4-heparin (Kd = 7-30 nM) and polystyrene adsorbed PF4 alone
      (Kd = 20-70 nM). Furthermore, agarose beads coated with PF4 alone were almost as
      effective as beads coated with PF4 plus heparin in depleting HIT plasmas of anti
      PF4-heparin antibodies. We conclude that the HIT antibodies which bind to
      polystyrene adsorbed PF4 without heparin are largely the same IgG molecules that
      bind PF4-heparin and therefore most HIT antibodies bind epitope(s) on PF4 and not
      epitope(s) formed by part of a PF4 molecule and part of a heparin molecule.
      Binding of PF4 to heparin (optimal) or polystyrene/agarose (suboptimal) promotes
      recognition of this epitope.

PMID- 10583217
TI  - Hereditary thrombocythaemia in a Japanese family is caused by a novel point
      mutation in the thrombopoietin gene.
AB  - Hereditary thrombocythaemia (HT) with clinical features very similar to essential
      thrombocythaemia (ET) has been found to be transmitted as an autosomal dominant
      trait in several families. Here we studied the pathogenesis of HT in a previously
      described Japanese kindred. We found markedly elevated thrombopoietin (TPO) serum
      levels in all affected individuals and identified a novel point mutation in the
      TPO gene, a G --> T transversion at position 516 of the TPO mRNA (G516T) that co
      segregated with the HT phenotype in all affected family members. This mutation is
      located in the 5'-untranslated region (5'-UTR) of the TPO mRNA and when assayed
      in reticulocyte lysates, improved translational efficiency of in vitro
      transcribed TPO mRNA. Cell lines transfected with the mutant TPO cDNA secreted up
      to 8-fold more TPO protein than cells transfected with the normal cDNA. We
      provide a molecular model of how the mutation partially disables the physiologic
      repression of TPO translation and thereby causes thrombocytosis. This is the
      third family in which HT has been caused by the loss of translational inhibition
      of TPO mRNA.

PMID- 10583218
TI  - A novel missense mutation in the human plasmin inhibitor (alpha2-antiplasmin)
      gene associated with a bleeding tendency.
AB  - Heterozygosity for a G --> A mutation converting Val384(GTG) to Met(ATG)
      associated with plasmin inhibitor (alpha2-antiplasmin) deficiency was identified
      in three family members with bleeding tendency. The proband had traumatic breast
      haematoma and per-/postoperative bleeds. An affected daughter required a blood
      transfusion after a normal delivery and a son had prolonged bleeding after tooth
      extraction. The plasma plasmin inhibitor activities of the affected family
      members were reduced to 49-66% of normal. The antigenic concentrations determined
      by electroimmunoassay were reduced to 57-68% of normal. Crossed
      immunoelectrophoresis of plasma from the proband showed a normal pattern. The
      amino acid Val384 is located eight residues C-terminal (P8') of the P1 residue
      (Arg376) in the reactive site. The P8' residues of bovine and mouse plasmin
      inhibitor are both Val. Among other serpins the P8' residue is unconserved. The
      mutation was not present in the non-affected family member or 30 blood donors. In
      addition to the Val384Met mutation two new polymorphisms Ala-26(GCG)/Val(GTG) and
      Arg407(AGG)/Lys(AAG) and one previously reported polymorphism Arg6(CGG)/Trp(TGG)
      were identified in the plasmin inhibitor gene of the family. The allelic
      frequencies among 30 blood donors with normal values of plasma plasmin inhibitor
      (functional) were 0.84/0.16 for C/T in codon -26, 0.81/0.19 for C/T in codon 6
      and 0.83/0.17 for G/A in codon 407.

PMID- 10583219
TI  - Phospholipid binding of factor VIII in different therapeutic concentrates.
AB  - Binding to anionic phospholipid (PL) is essential for the biological function of
      factor VIII (FVIII). We have developed a method to study the level of PL binding
      of FVIII in a variety of therapeutic concentrates, using the BIACORETM system
      which utilizes the Surface Plasmon Resonance (SPR) phenomenon. A HPA sensor chip
      was employed on to which synthetic phospholipid unilamellar vesicles were
      adsorbed to form a 3:1 phosphatidylcholine: phosphatidylserine lipid monolayer.
      Using this surface the interaction of unlabelled FVIII in concentrates was
      observed from which direct kinetic data (kon, koff and KD values) were obtained
      in real-time. Marked differences in the binding to PL, as measured by KD values,
      between different products were observed. These fell into three categories: two
      recombinant FVIII products showed high affinities for PL with KD values around 0.
      05-0.14 nM; four high-purity plasma derived products, two prepared by monoclonal
      antibody and two prepared by ion-exchange chromatography, had 6-8-fold lower
      affinities, and two intermediate-purity products had 34-60-fold lower affinities
      with KD values in the nM region. Measurements of kon and koff values for each
      product showed that the differences in the KD values expressed were primarily due
      to the differences in their respective kon values, although the recombinant
      products showed changes in the koff values. The study showed that the assessment
      of binding to PL by FVIII in concentrates was possible without prior purification
      and gave KD values in the range reported previously for other methods. The
      difference between the products requires further investigation but may be partly
      due to other proteins present, in particular the content and quality of von
      Willebrand factor which is known to affect PL binding of FVIII.

PMID- 10583220
TI  - Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony
      stimulating factor is an effective treatment for aplastic anaemia patients
      unresponsive to a first course of intensive immunosuppressive therapy. Gruppo
      Italiano Trapianto di Midollo Osseo (GITMO)
AB  - About 30% of patients with severe aplastic anaemia (SAA) unresponsive to one
      course of immunosuppressive (IS) therapy with antithymocyte or antilymphocyte
      globulin can achieve complete or partial remission after a second IS treatment.
      Among various second-line treatments, rabbit ATG (r-ATG) could represent a safe
      and effective alternative to horse ALG (h-ALG). In a multicentre study, 30
      patients with SAA (17 males and 13 females, median age 21 years, range 2-67) not
      responding to a first course with h-ALG plus cyclosporin (CyA) and granulocyte
      colony stimulating factor (G-CSF), were given a second course using r-ATG (3.5
      mg/kg/d for 5 d), CyA (5 mg/kg orally from day 1 to 180) and G-CSF (5 microg/kg
      subcutaneously from day 1 to 90). The median interval between first and second
      treatment was 151 d (range 58-361 d). No relevant side-effects were observed, but
      one patient died early during treatment because of sepsis. Overall response,
      defined as transfusion independence, was achieved in 23/30 (77%) patients after a
      median time of 95 d (range 14-377). Nine patients (30%) achieved complete
      remission (neutrophils >/=2.0 x 109/l, haemoglobin >/=11 g/dl and platelets
      >/=100 x 109/l). The overall survival rate was 93% with a median follow-up of 914
      d (range 121-2278). So far, no patient has relapsed. Female gender was
      significantly associated with a poorer likelihood to respond (P = 0.0006). These
      data suggest that r-ATG is a safe and effective alternative to h-ALG for SAA
      patients unresponsive to first-line IS treatment.

PMID- 10583221
TI  - Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia
      (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita
      gene, DKC1.
AB  - Hoyeraal-Hreidarsson (HH) syndrome is a multisystem disorder affecting boys
      characterized by aplastic anaemia (AA), immunodeficiency, microcephaly,
      cerebellar-hypoplasia and growth retardation. Its pathogenesis is unknown. X
      linked dyskeratosis congenita (DC) is an inherited bone-marrow-failure syndrome
      characterized by skin pigmentation, nail dystrophy and leucoplakia which usually
      develop towards the end of the first decade of life. AA occurs in >90% of cases
      of DC. We speculated that mutations in the gene responsible for X-linked DC
      (DKC1) may account for the HH syndrome, due to the phenotypic similarities
      between the disease in respect of AA and gender bias. We therefore analysed the
      DKC1 gene in two HH families. In one family a nucleotide change at position 361(A
      --> G) in exon 5 was found in both affected brothers; in the other family a
      nucleotide change at position 146(C --> T) in exon 3 was found in the affected
      boys. The finding of these two novel missense DKC1 mutations demonstrates that HH
      is a severe variant of DC. They also show that mutations in DKC1 can give rise to
      a very wide clinical spectrum of manifestations. Boys with unexplained AA or
      immunodeficiency should be tested for mutations in DKC1 even though they may lack
      diagnostic features of DC.

PMID- 10583222
TI  - Characterization of 12p molecular events outside ETV6 in complex karyotypes of
      acute myeloid malignancies.
AB  - Acute myeloid disorders with rearrangements of 12p outside the ETV6 gene were
      characterized by fluorescence in situ hybridization (FISH) with a panel of DNA
      probes. Seven patients with de novo acute myeloid leukaemia (AML), one with
      secondary acute myeloid leukaemia (sAML), and one in the blast phase of chronic
      myeloid leukaemia (CML-BP) were enrolled in the study. All AML cases showed
      multiple karyotypic changes. Chromosome 5 and/or 7 deletions were the most
      frequent accompanying changes. FISH revealed amplification, cryptic
      translocation, and fragmentation of chromosome 12, not discernible at karyotypic
      level. Different karyotypic rearrangements of 12p showed a common molecular
      event. Among the seven cases in which breakpoints could be determined, six were
      telomeric and one centromeric to ETV6. In three AML cases a new recurrent
      breakpoint in the telomeric region was identified distally to locus D12S158 and
      to pac 922B22 which is the most telomeric probe available for 12p. Accompanying
      cryptic deletions were also detected in five patients and the commonly deleted
      region, of around 700 kb, included the ETV6 gene and the D12S391 locus.

PMID- 10583223
TI  - Surface CD14 positivity in B-cell chronic lymphocytic leukaemia is related to
      clinical outcome.
AB  - The aberrant expression of the myelomonocytic antigen CD14 was investigated in
      128 untreated patients diagnosed with B-cell chronic lymphocytic leukaemia (B
      CLL). A cut-off value of 5 x 10(9)/l CD14-positive cells was chosen for
      statistical analysis because it showed the best discriminating power among
      patients with different clinical features. 56 cases had a CD14+ cell count >5 x
      10(9)/l. A significant correlation was found between Rai and Binet stages and
      total tumour mass (TTM) score on one hand, and the absolute CD14+ cell cut-off,
      on the other. This relationship was more evident in Rai 0-II and Binet A-B
      stages, where a CD14+ cell count >5 x 10(9)/l was preferentially distributed
      among patients with a higher tumoral mass. In univariate analysis the survival
      probability at 5 and 10 years showed a significant correlation with Rai and Binet
      stages, TTM score, CD14+ absolute cell count and median age. The median overall
      survival (OS) was 63 months for patients with a CD14+ cell count >5 x 10(9)/l and
      136 months for those with a CD14+ cell count < 5 x 10(9)/l. In the multivariate
      Cox regression model, Rai stage, age and CD14+ cell count were independent
      significant factors for the prediction of OS. Finally, when the same analysis was
      restricted to Rai stages 0-II, CD14+ cell count was the only significant
      independent parameter influencing OS, with a relative death risk of 3.8. In
      conclusion, these data reveal that CD14+ represents an important marker for
      predicting OS in B-CLL patients and, therefore, we suggest that it should be
      included in the immunological characterization of B-CLL.

PMID- 10583224
TI  - Hepatitis B and C virus infection in Romanian non-Hodgkin's lymphoma patients.
AB  - We determined the hepatitis C virus (HCV) antibodies (anti-HCV) and the hepatitis
      B virus (HBV) surface antigen (HBsAg) in a cohort of 68 consecutive non-Hodgkin's
      lymphoma (NHL) patients diagnosed and treated in our institution between December
      1997 and March 1999. 27 cases were diagnosed as low-grade, 33 as intermediate
      grade, and eight as high-grade NHL. In 35 cases (51.4%) we found evidence of
      either HCV or HBV infection. Anti-HCV antibodies were found in 20 patients
      (29.5%) and HBsAg was found in 21 patients (30.8%). In six patients both anti-HCV
      and HBsAg were present. Anti-HCV were present in 12/27 low-grade NHL cases
      (44.4%) and in 8/41 intermediate/high-grade (aggressive) NHL cases (19.5%, P <
      0.03). HBsAg was found in 10/27 low-grade NHL cases (37%) and in 11/41 aggressive
      NHL cases (26.8%). Evidence of liver disease, as reflected by elevated
      aminotransferases or typical alterations at liver biopsy, was present in eight
      patients. Cryoglobulins were present in six patients, all anti-HCV positive and
      with low-grade NHL. The prevalence of both HCV antibodies and HBsAg was
      significantly higher (P < 0.0001) in our NHL cases than in a sample of the
      general Romanian population, where the prevalence of anti-HCV was 4.9% and that
      of HBsAg was 6.3%. It is difficult to say whether either HCV or HBV had actually
      been involved in lymphomagenesis or if alpha-interferon treatment would be
      effective in this subset of patients.

PMID- 10583225
TI  - Identification of patient-specific peptides for detection of M-proteins and
      myeloma cells.
AB  - We have taken advantage of the selection power of phage display technology to
      define specific peptide mimotopes that recognize individual M-proteins, isolated
      from patients with multiple myeloma. Preferred amino acid motifs of phages
      binding to M-proteins were identified in 6/9 patients investigated. Chemically
      synthesized peptides, corresponding to the phage-displayed peptide inserts, were
      used to verify the specificity of binding in competition assays. The peptides
      were able to bind to the M-proteins, as well as the myeloma cells, with high
      sensitivity and specificity. Employing simple immunological techniques, < 0.01
      g/l of M-protein could be quantified, suggesting a novel way for monitoring
      minimal residual disease in the production of guidelines for adjusting or
      reintroducing conventional chemotherapy. The peptide mimotopes defined by this
      technology may be useful as tumour-specific targeting agents and as a tool for
      purging cells in autologous bone marrow transplantation.

PMID- 10583226
TI  - BCR-ABL influences the antileukaemic efficacy of alkylphosphocholines.
AB  - We have compared the antileukaemic efficacy of a series of new i.v. injectable
      alkylphosphocholines (APC) with their clinically used congeners miltefosine and
      perifosine. The test system consisted of four leukaemic cell lines carrying the
      bcr-abl rearrangement (K-562, LAMA-84, CML-T1 and BV-173) and two other leukaemic
      cell lines (HL-60 and SKW-3) without this genetic alteration. The prototype of
      i.v. injectable APC, erucylphosphocholine, was more active against BCR-ABL
      positive cell lines than the two reference APC. It induced programmed cell death
      in HL-60 and SKW-3 cells after exposure for 24 h, and in bcr-abl expressing cells
      after a prolonged incubation period (48 h). LAMA-84 cells responded to i.v.
      injectable APC with increased conversion to an adherent, fibroblast-like
      phenotype. Experiments with a cell-free system showed that the target structures
      of APC are localized within the cytoplasmic compartment. Blockade of ceramide
      synthase by fumonisin B1 was insufficient to prevent oligonucleosomal DNA
      fragmentation. Using RT-PCR we confirmed that K-562 and LAMA-84 cells carry the
      b3a2 fusion type, and CML-T1 and BV-173 the b2a2 variant. BV-173 cells had the
      lowest level of bcr-abl mRNA which correlated with their increased sensitivity.
      Transfection of K-562 cells with antisense oligonucleotides directed against bcr
      abl caused a specific suppression of K-562 clonogenicity. Our data indicated that
      i.v. injectable alkylphosphocholines are potent inducers of apoptosis and display
      increased antileukaemic efficacy against BCR-ABL-positive blasts as compared with
      miltefosine and perifosine. The expression of BCR-ABL cannot prevent apoptosis
      but delays erucylphosphocholine-induced programmed cell death. Transfection with
      bcr-abl directed antisense oligonucleotides reduces the clonogenicity of K-562
      cells.

PMID- 10583227
TI  - Plasma IL-8 and IL-6 levels can be used to define a group with low risk of
      septicaemia among cancer patients with fever and neutropenia.
AB  - The standard therapy for patients with fever and chemotherapy-related neutropenia
      is hospitalization and infusion of broad-spectrum antibiotics. Early discharge of
      a defined group of patients at low risk for septicaemia would be of great
      advantage for these patients. In this study plasma interleukin-8 (IL-8) and
      interleukin-6 (IL-6) levels measured at start of fever (n = 72) could define a
      low-risk group of febrile patients with neutropenia due to chemotherapy. For this
      purpose we collected and analysed data on 72 fever episodes from 53 patients with
      chemotherapy-related neutropenia, aged between 1 and 66 years. Of the 72
      episodes, 18 were classified as bacteraemia and/or clinical sepsis (sepsis
      group). The IL-6 and IL-8 plasma concentration were significantly increased in
      patients with chemotherapy-related neutropenia and fever due to bacteraemia
      versus fever of non-bacterial origin (P = 0.043 and P = 0.022 respectively).
      Logistic regression analysis, with sepsis as the outcome variable, revealed
      significant effects of age combined with either IL-6 or IL-8. Sepsis occurrence
      was lowest for patients <16 years and highest in patients between 16 and 50
      years, and was higher in patients with increased IL-6 (P = 0.032) or IL-8 (P =
      0.049). No significant effect of leucocyte count, C-reactive protein, sex or
      underlying malignancy at presentation was detected. The plasma IL-6 and IL-8
      levels were fairly strongly correlated (Pearson r = 0.62). Using a cut-off value
      with 100% sensitivity, both IL-8 and IL-6 could define a low-risk group of
      neutropenic patients of 28% (CI 15-40%) at the start of the febrile period.
      Intervention studies are warranted to confirm this result and to investigate
      whether an early discharge based on IL-8 or IL-6 measurement is safe, increases
      the quality of life, and results in cost savings.

PMID- 10583228
TI  - Clonal selection of CD56+ t(8;21) AML blasts: further suggestion of the adverse
      clinical significance of this biological marker?
AB  - Although patients with acute myelogenous leukaemia (AML) and t(8;21)(q22;q22)
      have a favourable prognosis, a subset die despite receiving appropriate
      treatment. Recent reports suggest that expression of the CD56 antigen might
      predict for both extramedullary disease and poor outcome in these patients. We
      describe a patient who presented with CD56-negative t(8;21) AML who achieved a
      complete remission and was subsequently treated with three consolidative courses
      of high-dose cytarabine therapy. She relapsed 9 months later with extramedullary
      and bone marrow involvement of CD56-positive t(8;21) AML. This case demonstrates
      clonal evolution and provides further support that blast expression of CD56 might
      be an unfavourable prognostic factor in t(8;21) AML.

PMID- 10583229
TI  - Bcl10 in chronic lymphocytic leukaemia and T-cell prolymphocytic leukaemia.
AB  - Bcl10 is a cancer gene recently identified in B-cell lymphomas of mucosa
      associated lymphoid tissues. It has been suggested as a target for mutation in
      multiple types of tumour including follicular lymphoma, T-cell acute
      lymphoblastic leukaemia and Sezary syndrome. To evaluate further the role of
      Bcl10 in human adult haematological cancers, we screened for mutations samples
      from 24 patients with B-cell chronic lymphocytic leukaemia (CLL) and 18 samples
      from patients with T-cell prolymphocytic leukaemia (T-PLL). No pathogenic
      mutations were detected in any of the samples analysed, strongly suggesting that
      Bcl10 is not involved in the development of CLL or T-PLL and that its involvement
      may be restricted to other haematological malignancies.

PMID- 10583230
TI  - Acute tumour lysis syndrome: a case in AL amyloidosis.
AB  - Tumour lysis syndrome (TLS) in plasma cell dyscrasias is extremely rare. TLS has
      been described in eight cases of multiple myeloma undergoing high-dose therapy
      with autologous stem cell transplant (ASCT). Recently, clinical trials of
      intensive chemotherapy followed by autologous or allogeneic stem cell support has
      been shown to offer potential benefit in AL (amyloid light-chain) amyloidosis.
      TLS in primary AL amyloidosis in this setting has not been previously reported.
      We report a case of TLS in a patient with AL amyloidosis which developed after
      high-dose melphalan chemotherapy supported by ASCT.

PMID- 10583231
TI  - Tumour necrosis factor polymorphisms and susceptibility to follicular lymphoma.
AB  - Follicular lymphoma is characterized in 85% of patients by the presence of a
      t(14;18) chromosomal translocation that results in overproduction of BCL2. In
      this study the distribution of high and low expressing TNF alleles at the TNF (
      308) and LTalpha (+252) polymorphic sites in 121 patients with follicular
      lymphoma and 88 control individuals has been analysed. A reduction in high
      expressing haplotypes in patients compared to normal controls was found (P =
      0.055), with no significant difference observed in response rate or overall
      survival between patients with high or low expressing haplotypes. These results
      suggest that the TNF locus, or an adjacent locus within the MHC region, is an
      important genetic risk factor in this disease.

PMID- 10583232
TI  - Mcl-1 and Bcl-xL are co-regulated by IL-6 in human myeloma cells.
AB  - Multiple myeloma (MM) is a slowly proliferative malignancy in which malignant
      plasma cells accumulate within the bone marrow. The expression of several anti
      apoptotic proteins was evaluated by immunoblotting in human myeloma cell lines
      and in highly purified native myeloma cells. Expression of Bcl-xL, Mcl-1 and Bcl
      2 was found in most of the samples; expression of Bcl-xL and Mcl-1 seemed to be
      related on myeloma cells. In a system of apoptosis by growth factor deprivation
      on myeloma cells, we showed that the effect of Bcl-2 seemed minimal whereas Mcl-1
      and Bcl-xL were tightly regulated by interleukin (IL)-6. These findings underline
      the important role of Mcl-1 and Bcl-xL instead of Bcl-2 in IL-6-induced survival
      of myeloma cells.

PMID- 10583233
TI  - Molecular remission of chronic myeloid leukaemia following a non-myeloablative
      allogeneic peripheral blood stem cell transplant: in vivo and in vitro evidence
      for a graft-versus-leukaemia effect.
AB  - Two patients with chronic myeloid leukaemia (CML) received a non-myeloablative
      preparative regimen of cyclophosphamide and fludarabine, followed by an
      unmanipulated, G-CSF-mobilized, peripheral blood stem cell transplant from an HLA
      identical sibling. Chimaerism, evaluated in myeloid and T-lymphoid lineages by
      PCR of minisatellite variable regions, showed day 14 post-transplant haemopoietic
      recovery to be 90% autologous in both patients. On day 30 the bone marrow showed
      only 1/20 and 2/18 donor metaphases. By day 100 post transplant both had 100%
      donor myeloid and lymphoid lineages as assessed by karyotype and minisatellite
      chimaerism analysis. They subsequently became RT-PCR negative for BCR-ABL. Both
      survive 7 and 14 months post transplant in molecular remission of CML. In one,
      donor T cells, stimulated with pre-transplant CML cells, induced 30-50%
      inhibition of pre-transplant leukaemic CFU-GM, but did not inhibit CFU-GM in the
      day 60 marrow (46% Ph-negative recipient, 54% donor). These results show that a
      non-myeloablative allotransplant can induce molecular remissions of CML through a
      graft-versus-leukaemia effect.

PMID- 10583234
TI  - Enhanced retroviral gene transfer into CML and normal bone marrow, and CML and
      mobilized peripheral blood CD34+ cells using the recombinant fibronectin fragment
      CH-296.
AB  - Autologous stem cell transplantation is a therapeutic alternative for many
      chronic myeloid leukaemia (CML) patients ineligible for the only curative
      treatment of allogeneic bone marrow transplantation. In this study the retroviral
      transduction of CD34+ progenitor cells isolated from the bone marrow (BM) and
      peripheral blood (PB) of patients with CML was compared to that of CD34+ cells
      isolated from the BM and PB of normal individuals and patients with non
      haematological malignancies. A highly significant increase in transduction of all
      cell types was achieved in the presence of the recombinant fibronectin fragment,
      CH-296 (P < 0.05). In the absence of fibronectin, centrifugation produced a
      marginal improvement in the transduction of all cell types, which was significant
      only for CMLBM progenitor cells (P < 0.05). There was no significant additive
      effect when centrifugation was included in the fibronectin infection protocol. In
      the presence of CH-296, combinations of three or more cytokines improved
      transduction for all cell types. The same degree of transduction was observed for
      both normal and CML cells, irrespective of the variations employed in the
      infection protocol, suggesting that both leukaemic and non-leukaemic progenitors
      are equally susceptible to retroviral infection. These results demonstrate that
      CH-296 has a universal beneficial effect on the transduction of haemopoietic
      progenitor cells, with clear potential for future clinical trials.

PMID- 10583235
TI  - Factors affecting the outcome of allogeneic bone marrow transplantation for adult
      patients with refractory or relapsed acute leukaemia.
AB  - We evaluated the outcome of allogeneic bone marrow transplantation (BMT) for
      advanced acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) in
      383 adult patients in nine Australian adult BMT centres between 1981 and 1997.
      The median overall survival for the group was 4.8 months, with an estimated 5
      year survival of 18%. 28% of patients died of transplant-related toxicities
      within the first 100 d. Progressive disease was responsible for 48% of deaths.
      Multi-factor analysis demonstrated that AML (v ALL), disease status (second
      complete remission [CR2] v others), age (< 40 years) and duration of prior first
      complete remission (CR1) (> 6 months) were pre-transplant variables significantly
      associated with improved survival. Acute graft-versus-host disease (GVHD) of any
      grade reduced the rate of relapse in both AML and ALL, but only grades I-II were
      associated with improved survival. Both limited and extensive chronic GVHD were
      associated with increased survival. Only patients with AML in untreated first
      relapse or CR2, with a duration of CR1 > 6 months, or patients with T ALL, had a
      5-year survival > 20%. Transplants for AML in induction failure or pre-B ALL in
      untreated first relapse or CR2 had an intermediate outcome, with 5-year survival
      of 10-20%. A 5-year survival of < 10% was observed for patients transplanted for
      ALL in induction failure or for pre-B ALL or AML in refractory first relapse or
      beyond CR2. These results suggest that for most adult patients with advanced
      acute leukaemia an allograft offers only a small chance of cure.

PMID- 10583236
TI  - Selection and transplantation of autologous CD34+ B-lineage negative cells in
      advanced-phase multiple myeloma patients: a pilot study.
AB  - The feasibility of sequential positive and negative selection of mobilized CD34+
      B-lineage negative cells to achieve tumour-free autografts in multiple myeloma
      (MM) patients was evaluated. Peripheral blood stem cells (PBSC) of 14 patients
      with advanced disease were mobilized. CD34+ cells were enriched in 12 of the
      patients by the avidin-biotin immunoabsorption technique. Subsequently, CD10+,
      CD19+, CD20+ and CD56+ cells (B-lin cells) were removed by immunomagnetic
      depletion. Minimal residual disease (MRD) was detected by flow cytometry and PCR
      based molecular analysis of the patient specific IgH complementary-determining
      region III (CDRIII). Positive selection of stem cells produced a median recovery
      of 54.7% of the initial content of CD34+ cells (median purity 71.9%). Negative
      depletion of B-lineage cells reduced the number of CD34+ cells to 33.3% of the
      baseline value (median purity 72.7%). However, long-term culture assays showed
      the recovery of >60% of primitive haemopoietic progenitor cells after depletion
      of the B-lineage-positive cells. All evaluable patients had detectable disease in
      PBSC collections. The first step of positive selection of CD34+ cells resulted in
      >2 logs of tumour cell purging. However, molecular assessment showed the
      persistence of the disease in 6/7 cases. Immunofluorescence analysis demonstrated
      1 additional log of B-cell purging by negative depletion. More importantly,
      molecular evaluation of IgH CDRIII region showed the disappearance of myeloma
      cells in 6/7 patients. 12 patients received a median of 3.9 x 106 CD34+ B-lin-
      cells/kg after conditioning with high-dose melphalan and showed a rapid
      reconstitution of haemopoiesis. These results were similar to two similar cohorts
      of patients who received either unmanipulated PBSC or positively selected CD34+
      cells after the same conditioning regimen. Severe extrahaematological toxicity
      was limited to mucositis; no late infections were observed. We concluded that
      autotransplantation of purified CD34+ B-lin- cells was associated with a rapid
      and sustained recovery of haemopoiesis and low peritransplant morbidity.
      Sequential positive and negative enrichment of stem cells reduced tumour cell
      contamination in B-cell malignancies below the lower limit of detection of
      molecular analysis.

PMID- 10583237
TI  - Comparative serial quantitative measurements of chimaerism following
      unmanipulated allogeneic transplantation of peripheral blood stem cells and bone
      marrow.
AB  - Serial samples were collected from 38 patients following allogeneic
      transplantation using either unmanipulated peripheral blood stem cells (PBSC) (n
      = 18) or bone marrow (BM) (n = 20) to assess the incidence of mixed chimaerism
      using PCR amplification of five VNTR regions. After amplification, products were
      analysed using the Applied Biosystems ABI PRISM 377 Automated DNA Sequencer and
      GeneScan software GenoTyper program to determine a quantitative measure of
      chimaerism. The sensitivity of detection using this method was 0.1%. In the
      immediate post-transplant period (up to day 30) a significantly lower incidence
      of mixed chimaerism (MC) occurred in recipients of PBSC compared to BM (P <
      0.0005). Between 1 and 6 months there was a significantly lower incidence of low
      level MC in patients receiving PBSCT compared to BMT (4/14 v 8/11 respectively, P
      = 0.04) in patients who had not rejected their grafts or relapsed. Similarly,
      beyond 6 months 0/9 PBSCT patients compared to 4/9 BMT patients showed MC (P =
      0.02). Beyond day 30 13/33 (39%) patients showed intermittent low-level MC, but
      this was not predictive for subsequent relapse. A rapidly increasing proportion
      of recipient haemopoiesis was predictive of graft rejection or relapse. Stable
      continuous MC without relapse was seen in one patient transplanted with PBSC for
      severe aplastic anaemia. These results suggest that the incidence of intermittent
      low-level MC is relatively high in the first 6 months following unmanipulated
      haemopoietic stem cell transplantation but reduces with time and is significantly
      lower in recipients of PBSC.

PMID- 10583238
TI  - Cord blood progenitor cells have greater transendothelial migratory activity and
      increased responses to SDF-1 and MIP-3beta compared with mobilized adult
      progenitor cells.
AB  - When cord blood is used as a source of haemopoietic stem cells for
      transplantation, fewer cells are required per kg of recipient. This greater
      engraftment efficiency of cord blood cells may relate to an increased ability to
      traverse sinusoidal endothelium, a crucial step in the homing of stem cells. We
      report that freshly isolated cord blood progenitors migrated more efficiently
      than mobilized adult cells. Cord blood progenitors responded rapidly to growth
      factor stimulation with an increase in migratory ability within 24 h whereas
      mobilized adult cells responded only after 72 h (P < 0.01). Cord blood cells also
      exited G0/G1 rapidly; after 24 h of growth factor exposure, 20.2 +/- 1.2% of cord
      blood CD34+ cells were in S + G2/M compared to 6.9 +/- 1.2% of adult CD34+ cells
      (P < 0.01). Proliferating CFC migrated more efficiently (13.3 +/- 3.4% for GM
      CFC) than non-proliferating CFC (1.4 +/- 0.5%, P < 0.01) as determined using a 3H
      thymidine suicide assay. Cord blood progenitor cells also demonstrated a greater
      transmigratory response to chemokine stimulation compared with adult cells; this
      was manifested as a differential response of freshly isolated cells to SDF-1, and
      of growth factor activated cells to MIP-3beta. Finally, cord blood CD34+ cells
      express higher levels of the chemokine receptor for SDF-1, CXCR4, when compared
      with mobilized adult CD34+ cells (P < 0. 05).

PMID- 10583239
TI  - Intracellular cytokine production and cytokine receptor interaction of cord
      mononuclear cells: relevance to cord blood transplantation.
AB  - A 'cytokine storm' consisting of IL-1, IL-2, IL-12, IFNgamma and TNFalpha is
      considered important in the development of graft-versus-host disease (GvHD).
      These cytokines activate effector cells or damage host tissues. Cord blood
      transplantation has been associated with a low incidence of GvHD. We hypothesized
      that the low incidence of GvHD relates to the cord mononuclear cells being poor
      producers of pro-inflammatory cytokines. The cytokine profile (IL-1alpha/beta, IL
      2, IL-4, IL-6, IL-8, IL-10, IL-12, IFNgamma and TNFalpha) of cord blood cells
      induced by immune stimuli was determined in heparinized whole blood. Compared to
      adult, cord blood CD3+ and NK cells produced less IFNgamma, less cord blood CD3+
      cells and monocytes produced TNFalpha and less monocytes produced IL-1alpha/beta.
      Although more cord T cells produced IL-2 compared to adult T cells at 4 h, adult
      T cells produced more at 24 h. Cord blood had similar proportions of monocytes to
      adult producing IL-6, IL-10 and IL-12. Both adult and cord mononuclear cells
      constitutively expressed receptors for IFNgamma and TNFalpha but not IL-12. In
      contrast to the adult cells, cord CD3+ and NK cells did not express IL-12
      receptor but did up-regulate IL-10 receptor after mitogenic stimulation. The
      findings of this study indicate that the cord blood cytokine-receptor network is
      biased towards anti-inflammatory activity compared to adult and helps to explain
      the decreased incidence of GVHD in cord blood transplantation.

PMID- 10583240
TI  - A bone marrow biopsy technique suitable for use in neonates.
AB  - Thrombocytopenia and neutropenia are common among neonates in intensive care
      units. Bone marrow aspirations are sometimes performed as part of their
      evaluation. However, marrow biopsies have not been reported from living neonates.
      Since architecture and cellularity cannot generally be accurately assessed from
      marrow aspirates, we devised a biopsy technique which we successfully applied to
      five cytopenic neonates (three with severe persistent thrombocytopenia and two
      with idiopathic neutropenia). This technique used a 19 gauge, half-inch Osgood
      needle to obtain bone marrow clots from the tibias of small preterm neonates
      which enabled the assessment of marrow cellularity and architecture. On the basis
      of our initial experience we have ceased using the traditional bone marrow
      aspiration technique in neonates and now use this technique exclusively.

PMID- 10583241
TI  - Simultaneous occurrence of follicular lymphoma in two monozygotic twins.

PMID- 10583242
TI  - Serum M-CSF levels in Kawasaki disease.

PMID- 10583244
TI  - The frequency of the haemochromatosis C282Y mutation in the ethnic Hungarian and
      Romany populations of eastern Hungary.

PMID- 10583243
TI  - Elevated serum LDH in patients with non-Hodgkin's lymphoma: not always an ominous
      sign.

PMID- 10583245
TI  - Invasive aspergillosis of the heart.

PMID- 10583246
TI  - Factor XIII deficiency.

PMID- 10583247
TI  - The pathology, diagnosis, and treatment of hepatic veno-occlusive disease:
      current status and novel approaches.

PMID- 10583248
TI  - CD82 (KAI1), a member of the tetraspan family, is expressed on early haemopoietic
      progenitor cells and up-regulated in distinct human leukaemias.
AB  - CD82 (KAI1) is a member of the tetraspan transmembrane protein family which has
      been cloned from lymphoblastoid variant cell lines. However, a role for CD82 in
      early normal and malignant haemopoiesis has not yet been characterized. We
      studied the CD82 expression in 33 normal donor samples and 98 leukaemias by
      fluorescence activated cell sorting (FACS) and reverse transcriptase polymerase
      chain reaction (RT-PCR). We demonstrated that CD82 was moderately expressed in
      the vast majority of normal granulocytes and monocytes. In contrast, only about
      one third of the peripheral blood lymphocytes were weakly CD82 positive (CD82+).
      Interestingly, judgement of the CD82 transcription and expression in various
      leukaemias revealed that CD82 was overexpressed in chronic myeloid leukaemia
      (CML) patients in accelerated or blastic phase (CML-AP/BP) as well as in acute
      myeloid leukaemia (AML) and chronic lymphocytic leukaemia (CLL) patients.
      Analysis of AML patients with CD34+/CD82+ blasts prompted us to expand our
      studies on haemopoietic CD34+ progenitor cells. Intriguingly, 84-95% of the CD34+
      cells isolated from healthy bone marrow, cord blood or peripheral blood were
      highly CD82+. CD82 was abundantly expressed on primitive as well as on committed
      haemopoietic progenitor cells. After in vitro induction of myeloid
      differentiation in CD34+ peripheral blood progenitor cells (PBPC), the expression
      of CD82 decreased to levels similar to those found on peripheral blood
      granulocytes. These observations suggest for the first time a role for CD82 in
      normal and malignant haemopoiesis.

PMID- 10583249
TI  - Coexistence of normal and clonal haemopoiesis in aplastic anaemia patients
      treated with immunosuppressive therapy.
AB  - Cytogenetic abnormalities and paroxysmal nocturnal haemoglobinuria (PNH)
      phenotype are frequent findings in aplastic anaemia patients treated with
      immunosuppressive therapy (IST). In this study we investigated whether the
      appearance of clonal haemopoiesis influences patient outcome and survival. 97
      patients entered this study and were followed from the onset of the disease for a
      median follow-up (FU) of 53 months. 93% are alive, 56% achieved complete
      remission, 30% partial remission, both transfusion independent, and 14% did not
      respond. Three groups were identified: (A) patients without evidence of emerging
      clones (71/97); (B) patients who acquired chromosomal abnormalities (13/97); (C)
      patients who showed low expression of glycosyl phosphatidylinositol anchored
      proteins (GPI-AP) (PNH phenotype) at presentation or later (16/97). Three
      patients showed both PIG-AP deficiency and chromosomal abnormalities. The
      actuarial survival of patients without clonal haemopoiesis (n = 71) at 6 years
      was 95%, for patients with chromosomal abnormalities (n = 13), 88%, and for
      patients with PIG-AP deficiency (n = 16), 89%. There was no difference in the
      probability of becoming transfusion independent in the three groups (93%, 92% and
      88% respectively). This study confirmed that a proportion of severe aplastic
      anaemia (SAA) patients exhibit clonal markers during the time after IST, often
      coexisting with cytogenetically or phenotypically normal haemopoiesis. There was
      no significant clinical impact of these abnormalities on transfusion independence
      and survival at the median follow-up of 4 years.

PMID- 10583250
TI  - Neutrophil hypersegmentation in iron deficiency anaemia: a case-control study.
AB  - Neutrophil hypersegmentation (NH) is an important haematological feature of
      cobalamin or folate deficiency. As iron deficiency and folate deficiency often
      occur in the same target groups it is important to establish whether iron
      deficiency alone is a cause of NH. We report a case-control study which addresses
      this issue. Two groups of hospital patients were studied. Group 1 comprised 50
      patients with iron deficiency anaemia (IDA). Group II comprised 50 control age-
      and sex-matched patients who were haematologically normal without evidence of
      iron deficiency from the iron studies. Patients with other factors which could
      affect the degree of neutrophil segmentation (cobalamin/folate deficiency, renal
      failure, infection and drug exposures) were excluded from the study. A total of
      10 000 neutrophils were examined, 100 from each patient. NH was defined as the
      presence of five or more five-lobed neutrophils per 100, or any neutrophils with
      six or more lobes. The results were as follows: IDA, mean neutrophil lobe count
      3.36; number of patients with NH 31/50 (62%): controls, mean neutrophil lobe
      count 2.96, number of patients with NH 2/50 (4%). These differences were
      statistically significant. We conclude that NH is common in IDA. The mechanism
      whereby iron deficiency results in NH is not clear.

PMID- 10583251
TI  - The erythrocyte effects of haemoglobin O(ARAB).
AB  - To test the hypothesis that HbOARAB induces an increase in red cell mean
      corpuscular haemoglobin concentration (MCHC), we studied members of four Tunisian
      families who were either homo- or heterozygous for HbOARAB or were double
      heterozygotes for HbS and HbOARAB. The alpha-gene status was also tested. The
      findings included: (1) Distinctive variation in red cell density (MCHC) as
      determined by separation of red cells on isopycnic gradients: (a) All red cells
      from patients homozygous for HbOARAB were denser than normal red cells, as is
      observed for homozygous HbC patients. (b) In patients heterozygous for HbOARAB,
      red cell density was strongly influenced by the presence of alpha-thalassaemia.
      The coexistence of -alpha/alphaalpha resulted in an average red cell density
      slightly greater than normal (AA) red cells. Patients heterozygous for HbOARAB
      with a normal complement of four alpha genes had denser red cells similar to
      sickle cell disease with some cells of normal density but with most cells very
      dense. (c) Finally, the double heterozygotes for HbS and HbOARAB had significant
      haemolytic anaemia and red cells denser than normal with some as dense as the
      densest cells found in sickle cell anaemia. (2) Reticulocytes in patients
      homozygous for HbOARAB were found in the densest density fraction of whole blood.
      (3) Cation transport in patients homozygous for HbOARAB was abnormal, with K:Cl
      cotransport activity similar to that of HbS-Oman and only somewhat lower than in
      sickle cell anaemia red cells. The activity of the Gardos channel was
      indistinguishable from that found in HbS, HbC and HbS-Oman cells. We conclude
      that the erythrocytic pathogenesis of HbOARAB involves the dehydration of red
      cells due, at least in part, to the K:Cl cotransport system. The similarity of
      the charge and consequences of the presence of both HbC and HbOARAB, which are
      the products of mutations at opposite ends of the beta-chain, raises the
      possibility that this pathology is the result of a charge-dependent interaction
      of these haemoglobins with the red cell membrane and/or its cytoskeleton and that
      this abnormality is present early in red cell development.

PMID- 10583252
TI  - Determinants of iron status and bilirubin levels in congenital dyserythropoietic
      anaemia type I.
AB  - Seven untransfused patients with congenital dyserythropoietic anaemia type I were
      investigated to assess the determinants of both iron overload and serum bilirubin
      levels. The serum ferritin concentration was increased in all patients and non
      transferrin-bound iron (NTBI) was increased in all but one patient. None of the
      patients showed the C282Y mutation in the hereditary haemochromatosis gene, HFE.
      One patient was homozygous for the H63D mutation in this gene. The data indicated
      that differences in the extent of iron overload were not mediated by co
      inheritance of the C282Y mutation in the HFE gene but could largely be explained
      by differences in the severity of anaemia and ineffective erythropoiesis, and in
      the age of the patient. In one patient an unusually high plasma bilirubin level
      was associated with the variant A[TA]7TAA configuration in the TATA box of the
      uridine diphosphate glucuronosyltransferase (UGT-1A) gene promoter, the mutation
      found in most patients with mild Gilbert's syndrome.

PMID- 10583253
TI  - Accessibility of abciximab to megakaryocytes and endothelial cells in the bone
      marrow compartment: studies on a patient receiving antithrombotic therapy.
AB  - Abciximab, chimaeric Fab fragments of the monoclonal antibody 7E3 (c7E3 Fab), has
      achieved widespread use as an anti-platelet agent for blocking GP IIb-IIIa
      (alphaIIbbeta3) function and preventing ischaemic complications after coronary
      artery angioplasty. However, its accessibility to the bone marrow compartment
      during therapy is unknown, as is its ability to bind alphavbeta3 in vivo. Using
      electron microscopy and immunogold labelling, we have looked for abciximab in the
      bone marrow of a patient who became thrombocytopenic during treatment. The
      presence of abciximab was assessed on ultrathin frozen sections of a marrow
      aspirate, the drug being revealed by a rabbit antibody to c7E3 Fab. Labelling was
      maximal on fragmenting megakaryocytes (MK) and proplatelets in the vascular sinus
      and in direct access to the blood compartment. Not only the plasma membrane but
      also the demarcation membrane system (DMS) and the membranes of alpha-granules
      were labelled. Abciximab was also revealed on the luminal surface of endothelial
      cells lining the marrow sinuses, thereby confirming for the first time its
      ability to bind to alphavbeta3 in vivo. The study revealed no signs that
      abciximab had accumulated in the marrow.

PMID- 10583254
TI  - p38 MAPK is activated but not necessary in porcine von Willebrand factor
      dependent platelet activation.
AB  - We have investigated the role of p38 mitogen-activated protein kinase (MAPK) in
      von Willebrand factor (VWF)-dependent platelet activation. The interaction of
      platelets with subendothelial VWF, especially under high shear stress, is
      considered to be the first activation step which primes platelets for subsequent
      haemostatic events. As a model of VWF-dependent platelet activation, porcine VWF
      was employed. Porcine VWF induced p38 MAPK activation by 1 min post-addition;
      assessed by phosphorylation of a recombinant p38 MAPK fusion protein substrate
      termed glutathione S-transferase-MAPK activated protein kinase-2. To determine if
      p38 MAPK was necessary for porcine VWF-induced platelet activation, we
      functionally inhibited p38 MAPK activity with SB203580 before exposure of the
      platelets to porcine VWF. Inhibition of p38 MAPK had no effect on VWF-induced
      platelet alpha or lysozomal granule release, expression of activated GPIIb IIIa,
      modulation of membrane glycoprotein CD41, expression of phosphatidylserine as
      assessed by annexin V binding, microparticle formation, or platelet
      agglutination. It was concluded that SB203580-inhibitable p38 MAPK activity
      induced by porcine VWF is not necessary for platelet activation.

PMID- 10583255
TI  - Cys97-->Tyr mutation in the glycoprotein IX gene associated with Bernard-Soulier
      syndrome.
AB  - Bernard-Soulier syndrome (BSS) is an autosomal recessive bleeding disorder due to
      quantitative or qualitative abnormalities in the glycoprotein (GP) Ib/IX/V
      complex, the platelet receptor for von Willebrand factor. We describe here the
      genetic basis of the disorder in a patient with BSS. Flow cytometric analysis of
      the patient's platelets showed a greatly reduced GPIbalpha and completely absent
      GPIX surface expression. Immunoblot analysis disclosed greatly reduced GPIbalpha
      and residual amounts of GPIbbeta and GPIX in the platelets. DNA sequencing
      analysis revealed the patient to be homozygous for a novel missense mutation in
      the GPIX gene that converts Cys (TGT) to Tyr (TAT) at residue 97. Transient
      transfection studies confirmed that mutant GPIX was not expressed on the
      transfected cells, showing that the mutation was responsible for the BSS
      phenotype observed in the patient.

PMID- 10583256
TI  - Characterization of platelet glycoproteins and platelet/endothelial cell
      antibodies in patients with thrombotic thrombocytopenic purpura.
AB  - Platelets and sera from 12 patients with thrombotic thrombocytopenic purpura
      (TTP) and 12 healthy normal control subjects were examined. As determined by
      quantitative flow cytometry, prior to plasma exchange therapy platelet surface
      glycoprotein (GP) Ib levels were similar in TTP patients and normal controls
      (mean 20 188 and 20 226 molecules/platelet, respectively). Platelets from
      patients with TTP did, however, have significantly reduced levels of GPIIb/IIIa
      prior to plasmapheresis (mean 36 348 v 52 505 molecules/platelet in controls; P =
      0.0004) and of GPIV (mean 13 321 v 26 212 molecules/platelet in controls; P =
      0.0002). An increase in activated platelets, as determined by CD62 expression,
      was observed in 82% of patients. Increased platelet-associated immunoglobulins
      and/or complement was also seen in approximately 60% of the patients. In general,
      with return of platelet counts to normal levels following seven plasmaphereses,
      the above abnormalities were reversed, although often not to normal levels.
      Western blot analysis indicated the presence of antibodies reactive to platelet
      GPIV (88 kD) in 70% of pretreatment sera from patients with TTP; a similar band
      was observed in 80% of patient sera against microvascular endothelial cells.
      Immunofluorescence microscopic examination indicated the presence of antibody in
      pretreatment sera from patients with TTP to microvascular (73%) and large vessel
      (36%) endothelial cells. As measured by an indirect flow cytometric assay,
      pretreatment sera from 55% of patients with TTP were reactive with large vessel
      endothelial cells and 100% reacted with microvascular endothelial cells;
      reactivity was significantly greater against the microvascular endothelial cells
      (P = 0.0048) and was reduced following plasma exchange therapy. These results
      indicate abnormalities in platelet glycoprotein expression in TTP and suggest
      that anti-platelet and anti-endothelial cell antibodies play a role in the
      thrombocytopenia and vasculitis characteristic of this disorder.

PMID- 10583257
TI  - Increased bleeding associated with protease inhibitor therapy in HIV-positive
      patients with bleeding disorders.
AB  - The use of protease inhibitor (PI) drugs in treatment regimens for HIV-infected
      patients with hereditary bleeding disorders has been associated with an increased
      bleeding tendency. To characterize the nature of this bleeding tendency, a
      retrospective case record analysis was performed on 67 HIV-positive patients with
      hereditary bleeding disorders who had been treated with PI therapy. 34 patients
      (51%) developed an increased bleeding tendency on PI therapy, usually within the
      first few weeks of treatment. As well as an increase in usual joint bleeds,
      patients developed spontaneous atypical small joint, soft tissue and muscle
      bleeds. Haematuria was also common. Bleeding episodes tended to respond
      suboptimally to factor concentrate replacement. Ritonavir was most likely to be
      associated with bleeding. Nine patients switched first-line PI therapy as a
      direct consequence of bleeding and seven had no further bleeding problem on their
      second PI. Factor concentrate usage was significantly increased during the first
      6 months of PI therapy compared to the 6 months preceeding treatment. PI therapy
      is frequently associated with increased bleeding in patients with hereditary
      bleeding disorders. The mechanism of the bleeding tendency remains to be
      elucidated.

PMID- 10583258
TI  - Grandpaternal mosaicism in a family with isolated haemophilia A.
AB  - About one third of cases of haemophilia A have no family history of the disorder,
      and 20% are thought to be due to a new mutation. In the family reported here, a 3
      bp deletion was detected in DNA from the proband at the 3' end of exon 15. Direct
      sequencing of genomic DNA prepared from blood and buccal cells of the grandfather
      revealed both normal and mutant sequences, suggesting that he is a mosaic for
      this mutation. This highlights the usefulness of mutation detection, both for
      accurate genetic counselling and to determine the origin of new mutations of
      haemophilia.

PMID- 10583259
TI  - Allelic distribution of the glycoprotein Ia (alpha2-integrin) C807T/G873A
      dimorphisms among caucasian venous thrombosis patients and six racial groups.
AB  - Two linked silent dimorphisms, 807 C --> T (Phe224) and 873 G --> A (Thr246)
      within the glycoprotein Ia (GPIa) gene have been correlated with low and high
      platelet receptor density, respectively, and associated with vascular disease. A
      multiplexed allele-specific PCR assay was used to determine the GPIa 807T/873A
      allele frequency among 331 Caucasian venous thrombosis patients and 3571
      unrelated individuals belonging to six different racial groups. The 807T/873A
      allele frequencies were 54%, 51%, 39%, 39%, 38%, 34% and 30% among Native
      Americans, Hispanics, Caucasians, Caucasian venous thrombosis patients, Asian
      Indians, African-Americans, and Koreans, respectively. Significant differences in
      the GPIa allele frequency among racial groups were revealed which emphasized the
      need for appropriate controls in studies evaluating the association of GPIa
      genotype to vascular disease.

PMID- 10583260
TI  - Specific analysis of the intron 22 XbaI polymorphism of the human factor VIII
      gene using long-distance PCR.
AB  - A rapid, non-radioactive, PCR-based method to genotype the XbaI restriction
      fragment length polymorphism of the human factor VIII gene is described. The
      method uses long-distance PCR followed by XbaI restriction digestion and agarose
      gel electrophoresis. The 6.6 kb amplification product includes a constant XbaI
      site, which provides a digestion control. The specificity of the method was
      challenged by a blind experiment with 16 genomic DNA samples previously genotyped
      by Southern blot analysis: a perfect correlation was obtained between genotypes
      determined using Southern blot and PCR.

PMID- 10583261
TI  - The methylenetetrahydrofolate reductase gene C677T polymorphism in patients with
      homozygous sickle cell disease and stroke.
AB  - Homozygosity for the methylenetetrahydrofolate reductase (MTHFR) gene C677T
      polymorphism may cause hyperhomocysteinaemia, a recognized risk factor for
      stroke, in individuals with folate deficiency. Homozygous sickle cell (SS)
      disease is associated both with increased demands for folic acid and a tendency
      to develop stroke. We therefore investigated a possible role of the MTHFR C677T
      polymorphism in SS disease patients with stroke. Investigation of the frequency
      of the polymorphism in 48 patients with stroke and in 48 age-, sex- and racially
      matched SS controls without stroke failed to reveal a difference between the
      groups (Fisher exact test, P = 0.99). Homozygosity for the MTHFR C677T
      polymorphism is unlikely to be a risk factor for stroke in this population with
      SS disease.

PMID- 10583262
TI  - Expression of AC133 and CD117 on candidate normal stem cell populations in
      childhood B-cell precursor acute lymphoblastic leukaemia.
AB  - To identify residual candidate normal progenitor/stem cell populations in
      childhood B-cell precursor acute lymphoblastic leukaemia (ALL), expression of
      AC133 and CD117 was analysed on the leukaemic cell clone and on immature B
      lineage-negative CD34+CD19- bone marrow cells. 10/25 patients (40%) had no
      detectable expression of AC133 within the leukaemic cell clone. 24/26 patients
      (92%) lacked expression of CD117 on the leukaemic blast cell population. In
      contrast, a distinct AC133-positive cell population was found in 8/8 children
      with AC133-negative ALL and a CD117-positive cell population could be identified
      in 12/12 children with CD117-negative ALL, within the CD34+CD19- progenitor/stem
      cell compartment. These observations provide further evidence that in B-cell
      precursor ALL, unlike in acute myelogenous leukaemia, it may be possible to
      distinguish residual normal progenitor/stem cells from the leukaemic cell clone.

PMID- 10583263
TI  - Chronic myelogenous leukaemia with p185(BCR/ABL) expression: characteristics and
      clinical significance.
AB  - We investigated the significance of p185BCR/ABL expression in patients with
      chronic myelogenous leukaemia (CML) in relation to disease features, therapy and
      outcome. Results of Western blot analysis for 1384 patients referred with a
      diagnosis of CML to our institution from 1989 to 1997 were reviewed. Clinical
      characteristics, results of cytogenetic analysis and RT-PCR for BCR rearrangement
      were analysed. Five patients with Ph-positive CML expressing the p185BCR/ABL
      hybrid protein were identified. By RT-PCR, bone marrow specimens of these
      patients were confirmed to have an e1a2 junction. The median age at diagnosis of
      these patients was 55 years (range 43-76). All had elevated white cell counts at
      diagnosis (median 50 x 109/l, range 11.7-163 x 109/l). Four patients had
      monocytosis (range 10-16%) with a low neutrophil/monocyte ratio in the peripheral
      blood (range 3.4-5.7). Patients presented with various stages of the disease (two
      in chronic-phase CP, two in accelerated-phase AP, and one in blastic-phase BP).
      The clinical course and therapy of the patients varied, with one patient
      receiving hydroxyurea only, three patients receiving hydroxyurea followed by
      interferon-alpha based regimens and bone marrow transplantation. The patient
      presenting in BP was treated with combination chemotherapy. The clinical outcome
      of the patients was also varied with one patient alive and in complete remission
      (with complete cytogenetic remission after transplant) and four patients dead
      after progression to more advanced stages. We conclude that patients with Ph
      positive p185BCR/ABL CML frequently present with monocytosis and a low
      neutrophil/monocyte ratio in the peripheral blood, aiding the speculation that
      the presence of the p185BCR/ABL hybrid protein may contribute to a phenotype
      intermediate between CML and CMML. Of interest, the only other specific clinical
      feature identified was the absence of splenomegaly in four of five patients.
      There was no definite association with transformation to lymphoid blast phase.

PMID- 10583264
TI  - Monitoring chronic myeloid leukaemia therapy by real-time quantitative PCR in
      blood is a reliable alternative to bone marrow cytogenetics.
AB  - We have developed a rapid real-time quantitative PCR method for measuring BCR-ABL
      mRNA levels in peripheral blood in chronic myeloid leukaemia (CML). The technique
      was used to monitor minimal residual disease for the early detection of relapse
      and as an assessment of treatment response. Normal BCR mRNA was quantitated to
      control for RNA degradation and the results reported as a percentage of BCR
      ABL/BCR. Every patient measured at diagnosis (n = 21) had increased expression of
      BCR-ABL of up to 5-fold above the normal BCR levels. With effective treatment the
      BCR-ABL levels decreased. The molecular data was correlated with Philadelphia
      chromosome levels in bone marrow and a good correlation was found when treatment
      induced a cytogenetic response (Spearman correlation = 0.94, P < 0.0001, n = 67
      samples). In patients receiving interferon-alpha therapy we found a significant
      difference in the BCR-ABL levels between cytogenetic response groups. The method
      was sensitive, reproducible, and readily detected a change in BCR-ABL transcript
      levels in serial blood samples. Sample throughput was high because post PCR
      processing was unnecessary. We conclude that real-time quantitative PCR
      monitoring of peripheral blood can be used to reliably monitor disease response
      in CML.

PMID- 10583265
TI  - Molecular heterogeneity of the NUP98/HOXA9 fusion transcript in myelodysplastic
      syndromes associated with t(7;11)(p15;p15).
AB  - The reciprocal translocation t(7;11)(p15;p15) has been reported as occurring
      mainly in acute myelogenous leukaemia (AML) and the acute phase of chronic
      myelogenous leukaemia (CML). This translocation in AML involves both the
      nucleoporin gene NUP98 on 11p15 and the homeobox gene HOXA9 on 7p15. The
      invariant chimaeric NUP98/HOXA9 transcripts are a result of the fact that each
      breakpoint of the NUP98 and the corresponding breakpoint of the HOXA9 gene
      cluster occur within the same intron. Only one patient with myelodysplastic
      syndromes (MDS) carrying this chromosome aberration has been reported, but this
      study did not involve molecular analysis. We describe two patients with MDS
      associated with t(7;11): patient 1 was a Japanese man diagnosed with chronic
      myelomonocytic leukaemia; patient 2 was a Japanese woman with refractory anaemia
      with excess of blasts in transformation. Within a year both patients developed
      AML and showed multidrug resistance to chemotherapy. Southern blot analysis
      showed rearrangements of the NUP98 gene of the two patients and the HOXA9 gene of
      patient 2. Patient 1 had two types of the novel NUP98/HOXA9 fusion transcripts.
      Each of them lacked the common 141 bp NUP98 exon which was contained in the
      NUP98/HOXA9 fusion transcripts detected in patient 2 and the reported AML cases.
      These data indicated that t(7;11) could determine the development of various
      myeloid leukaemias and that the resultant chimaeric transcripts are heterogenous.

PMID- 10583266
TI  - Increased serum levels of vascular endothelial growth factor predict risk of
      progression in early B-cell chronic lymphocytic leukaemia.
AB  - The present study is the first to evaluate serum levels of vascular endothelial
      growth factor (VEGF) in B-cell chronic lymphocytic leukaemia (CLL). All 68 B-cell
      CLL patients and 31 control subjects analysed had detectable serum levels of
      VEGF, with no statistically significant difference between two proups. An
      aberrant increase of circulating levels of VEGF was found in only 17.6% of cases.
      B-cell CLL patients whose serum VEGF levels were higher than the median (i.e.
      194.8 pg/ml) or 75th percentile (i.e. 288.5 pg/ml) values were more frequently at
      an advanced clinical stage. In contrast, no correlation with other clinico
      biological features representative of either tumour mass [bone marrow (BM)
      histology, peripheral blood (PB) lymphocytosis, beta-2 microglobulin (beta-2m),
      LDH, interleukin-6 (IL-6)] or disease-progression (DP) [lymphocyte doubling time
      (LDT)] was found. Serum levels of VEGF predicted the risk of DP in early CLL.
      Among 41 patients in Binet stage A, progression-free survival (PFS) was
      significantly shorter in those patients whose VEGF serum concentrations were
      above the median value. Interestingly, characteristics of stage A patients
      stratified according to the median value of VEGF were similar with respect to
      many clinico-biological features, thus suggesting a possible independent
      prognostic role for such a marker. Finally, when added to the Rai
      subclassification, VEGF serum levels identified two groups with different PFS
      within stages I-II. We conclude that increased serum levels of VEGF can be
      considered useful for predicting the risk of DP and add prognostic information to
      the Rai subclassification of stage A CLL.

PMID- 10583267
TI  - Antisense-mediated suppression of Bcl-2 highlights its pivotal role in failed
      apoptosis in B-cell chronic lymphocytic leukaemia.
AB  - Although advances have been made in the development of more effective treatment
      modalities, B-cell chronic lymphocytic leukaemia (B-CLL) remains incurable due to
      the development of drug resistance. Defective programmed cell death mechanisms
      rather than dysregulation of cell cycle appears to predominate in B-CLL and it is
      likely that a failure to initiate apoptosis contributes to chemoresistance. Most
      B-CLL cells contain high levels of the anti-apoptotic protein Bcl-2 and high Bcl
      2/Bax ratios have been associated with in vitro resistance to cytotoxic agents.
      In this study we evaluated the cellular responses to a Bcl-2 antisense
      oligonucleotide in terms of Bcl-2 mRNA and protein expression and the induction
      of apoptosis. The antisense molecule induced a specific reduction in Bcl-2 mRNA
      and protein expression over the 48 h culture period and was associated with
      increased apoptosis. The study indicates that Bcl-2 protein is central to the
      mediation of resistance to apoptosis in B-CLL. Therefore Bcl-2 antisense
      oligonucleotides might be useful in the treatment of B-CLL.

PMID- 10583268
TI  - VH gene usage by family members affected with chronic lymphocytic leukaemia.
AB  - The excess risk of chronic lymphocytic leukaemia (CLL) in the first-degree
      relatives of affected patients suggests that familial CLL might constitute a
      useful model to study the pathogenesis of this disease, as has been demonstrated
      in numerous other neoplastic disorders. Previous studies have shown non-random
      utilization of immunoglobulin genes in CLL, some germline in sequence and others
      containing numerous somatic mutations. To investigate whether familial cases of
      CLL exhibit similarities in the composition of the B-cell receptor repertoire to
      the pattern expressed by CLL patients as a whole, we have studied 25 CLL patients
      belonging to 12 different families (four French and eight Italian), each of which
      contained at least two affected members. Among familial cases, VH gene segment
      utilization proved non-random and diverged from the frequencies previously
      reported among unrelated patients with CLL. Specifically, although the 4-34 and 5
      51 gene segments were found repeatedly, the 1-69 and 4-39 gene segments were used
      sparingly and the 3-23 gene segment presented with increased frequency. Following
      the pattern detected in studies of unrelated patients, the single 1-69 expressing
      CLL contained an unmutated H chain sequence and included a long HCDR3 interval.
      In contrast, 3-23 containing H chains all used JH4, retained at most 93% homology
      with germline sequence, and included only short HCDR3 intervals. The vast
      majority of the CLL variable domains contained a high degree of somatic mutation
      and exhibited an excess of replacement mutations in the CDR intervals. These
      findings suggest that familial CLL cases may preferentially derive from B-cell
      progenitors that have responded to antigen.

PMID- 10583269
TI  - The genetic variability of the VH genes in follicular lymphoma: the impact of the
      hypermutation mechanism.
AB  - Follicular lymphoma (FL) cells have inherited an activated hypermutation
      mechanism from their origin of germinal centre B cells. Based on today's
      knowledge of the intrinsic properties related to this mechanism and the VH base
      composition, reconsideration of previous reports should be made on a broader
      range of samples. The present study examined the mutation pattern of the VH genes
      expressed by 55 cases of FL. FL VH genes showed evidence of antigenic selection
      in 30% of cases with 88% carrying a functional sIg and 78.2% showing intraclonal
      variation. VH family and gene segment utilization was found to be roughly similar
      to that of normal B lymphocytes. FL VH genes revealed extensive variations. 17%
      of the VH exons harboured a total of five deletions, three duplications and two
      insertions as compared to the most homologous germline counterpart. The VH genes
      of one tumour displayed three populations with varying CDR3 length at diagnosis.
      At relapse, emergence of a differently mutated gene, additional mutations
      reminiscent of ongoing mutations or no variation was prominent. From this study
      the heterogeneity of FLs is well established and ongoing mutations are seen in
      the scope of the activated status of the hypermutation mechanism rather than
      antigen-stimulated tumour growth.

PMID- 10583270
TI  - X-chromosome inactivation analysis of isolated Reed-Sternberg cells in nodular
      sclerosing Hodgkin's disease.
AB  - In spite of several studies of immunoglobulin (Ig) gene rearrangements in whole
      Hodgkin's disease (HD) tissues and in isolated single Reed-Sternberg (RS) cells,
      the issue of clonality of the RS cell in HD remains incompletely resolved.
      Analysis of X-chromosome inactivation patterns (XCIPs) can be used to determine
      whether cell populations are clonal in origin. By PCR amplification of the human
      androgen receptor (HUMARA) loci using nested primers, we have studied XCIPs in
      six cases of HD of the nodular sclerosing (NS) subtype in which individual RS
      cells were isolated by micromanipulation from formalin-fixed, paraffin-embedded
      tissue sections immunostained with CD30 or CD15. In order to assess whether a
      clonal population of RS cells might be present in NSHD tissues, we compared the
      XCIPs obtained from whole NSHD tissues with those obtained from single RS cells
      harvested from the same tissues. Whole tissues from all six cases of NSHD showed
      balanced HUMARA allelic patterns, whereas an average of 83% (range 77-91%) of
      single RS cells from each of the six tissues expressed the same high- or low
      molecular weight allele, suggesting that a clonal population of RS cells was
      likely to be present in each case. These data are consistent with the presence of
      a clonal population of RS cells in NSHD tissues.

PMID- 10583271
TI  - Generation of anti-idiotype immune responses following vaccination with idiotype
      protein pulsed dendritic cells in myeloma.
AB  - Myeloma cells produce immunoglobulin which is unique to the malignant clone and
      presents antigenic determinants, or idiotypes, which may function as a tumour
      specific antigen. The availability of significant quantities of idiotype protein
      in the serum makes immunotherapeutic strategies utilizing this protein to
      generate an anti-idiotype immune response an attractive prospect. We treated two
      patients with advanced refractory myeloma with a series of four vaccinations
      using autologous idiotype-protein pulsed dendritic cells combined with adjuvant
      GM-CSF. The vaccinations were well tolerated with a mild fever post-vaccination
      in one patient. An idiotype-specific T-cell proliferative response developed in
      both patients. This T-cell response was associated with the production of gamma
      interferon, indicating a TH-1-like response. Furthermore, one patient developed
      anti-idiotype IgM antibodies. However, no idiotype-specific cytotoxic T-cell
      response could be demonstrated. Further investigation is warranted to define the
      optimal conditions for dendritic cell culture and priming to maximize the anti
      tumour immune response.

PMID- 10583272
TI  - Complete remission rate and outcome after intensive treatment of 177 patients
      under 75 years of age with IgG myeloma defining a circumscribed disease entity
      with a new staging system.
AB  - Because the presence of IgG paraprotein in the blood is clear cut, it makes IgG
      myeloma a more circumscribed disease than myeloma as a whole in which to study
      treatment efficacy, particularly relating to complete remission (CR). Between May
      1989 and December 1997, 177 consecutive patients with IgG myeloma who were <75
      years old were seen, of whom 153 entered a sequential therapy (ST) programme of
      initial courses of C-VAMP infusional chemotherapy (IC), high-dose treatment (with
      or without stem cell rescue) (119 patients) and maintenance interferon (87
      patients). 74/153 (48.4%) patients entered CR. Median overall survival (OS) and
      event-free survival (EFS) were 4.9 and 2.1 years, respectively. Multivariate
      analysis at presentation showed OS was significantly prolonged for beta2M <2.7
      mg/l and age <median 52, whilst beta2M <2.7 mg/l and Hb >8.5 g/dl predicted for
      longer EFS. For CR patients, age <median 51 years, absence of Bence-Jones
      proteinuria (BJP), male sex and white blood cells (WBC) <7 x 109/l predicted for
      a longer OS. Longer length of first CR was predicted by absence of BJP at
      presentation (P = 0.03) and fewer than five courses of IC (P = 0.02) to attain
      CR. We have therefore been able to refine the use of ST in IgG myeloma, redefine
      CR as a 'macro' endpoint, and propose a new staging system for IgG myelomas.
      Analysis of 41 comparable IgA patients showed IgG to be a distinct entity.

PMID- 10583273
TI  - Low frequency of the TEL/AML1 fusion gene in acute lymphoblastic leukaemia in
      Spain.
AB  - We report on a series of Spanish patients with acute lymphoblastic leukaemia in
      whom the t(12;21) [TEL/AML1] translocation could not be identified with two
      sensitive techniques: reverse transcript-polymerase chain reaction (RT-PCR) and
      fluorescence in-situ hybridization (FISH). 101 cases were analysed: 38 children
      (29 B-cell precursor; nine T-cell precursor) and 63 adults (48 B-cell precursor;
      15 T-cell precursor). Specific RT-PCR to amplify the TEL/AML1 fusion transcript
      was negative in all 101 cases. Moreover, all 38 paediatric samples were also
      negative by interphase FISH analysis for the presence of the TEL/AML1 fusion.
      These results suggest the existence of geographic/race variations in the genotype
      of acute lymphoblastic leukaemia (ALL).

PMID- 10583274
TI  - Multiple autoimmune haemopoietic disorders and insidious clonal proliferation of
      large granular lymphocytes.
AB  - We report a patient with clonal proliferation of CD3+8+TCRalphabeta+ large
      granular lymphocytes (LGL) presenting multiple episodes of autoimmune cytopenia,
      including autoimmune neutropenia, idiopathic thrombocytopenic purpura, autoimmune
      haemolytic anaemia, and pure red cell aplasia. Each disorder appeared separately
      or as a combination during an 11-year clinical course. The increase of blood
      CD3+8+TCRalphabeta+ LGL was detected 6 years after the initial diagnosis of
      cytopenia, but the absolute number of LGL cells was always < 1.0 x 109/l. LGL
      cells were of monoclonal origin and had a chromosomal abnormality. LGL cells
      transiently responded to cyclosporine A therapy, which was also effective on all
      of these autoimmune cytopenias. Accordingly, an undetectable level of
      proliferation of a clonal LGL population could cause various autoimmune
      haemopoietic disorders.

PMID- 10583275
TI  - NG2 expression in MLL rearranged acute myeloid leukaemia is restricted to
      monoblastic cases.
AB  - Expression of NG2 has been reported in the majority of paediatric acute leukaemia
      (AL) cases with MLL rearrangement. We demonstrated 7. 1 positivity in 2/3
      paediatric and 4/11 adult MLL rearranged acute myeloid leukaemia (AML) but in
      0/28 adult AML without MLL rearrangement, thus extending the 100% specificity to
      adult cases. Positivity correlated with stage of maturation arrest since it was
      found in 0/6 immature AML but in 6/8 monoblastic cases. These data demonstrate
      that, if NG2 expression in AL is the (in)direct result of MLL rearrangement, such
      activation is restricted to a monoblastic population in AML. They also have
      practical implications for NG2 diagnostic screening strategies.

PMID- 10583276
TI  - Successful use of recombinant FVIIa (Novoseven) in the management of intractable
      post-surgical intra-abdominal haemorrhage.

PMID- 10583277
TI  - Centralization of surgery for periampullary malignancy.

PMID- 10583278
TI  - Anal intraepithelial neoplasia.

PMID- 10583279
TI  - Popliteal artery entrapment syndrome.
AB  - BACKGROUND: Popliteal artery entrapment syndrome (PAES) is rare and may be
      underdiagnosed. Improved specialized, non-invasive imaging techniques are
      producing detailed topographical evidence of the anomaly. METHODS: A historical
      review of the literature and Medline search was performed with reference to the
      diagnosis and treatment of the condition. In addition, embryologically based
      theories for the condition have been postulated. RESULTS AND CONCLUSION: PAES may
      be the result of abnormal development of the popliteal artery or a consequence of
      excessive cranial migration of the medial head of the gastrocnemius muscle.
      Magnetic resonance imaging appears to be the most useful single investigation to
      demonstrate the anomaly. Popliteal artery release alone or with vein bypass is
      the treatment of choice when intervention is indicated.

PMID- 10583280
TI  - Surgical management of severe secondary peritonitis.
AB  - BACKGROUND: Despite advances in diagnosis, surgery, antimicrobial therapy and
      intensive care support, the mortality rate associated with severe secondary
      peritonitis remains unacceptably high. This article presents various surgical
      treatment strategies for severe secondary peritonitis, emphasizing the role of
      open management of the abdomen and planned relaparotomies. METHODS: Material was
      identified from previous review articles, references cited in original papers and
      a Medline search of the literature. RESULTS AND CONCLUSION: Surgical treatment of
      severe secondary peritonitis is highly demanding and very complex. The
      combination of improved surgical techniques, antimicrobial therapy and intensive
      care support has improved the outcome of such peritonitis following perforation
      or anastomotic disruption of the digestive tract, or infected necrotizing
      pancreatitis. However, aggressive surgical treatment strategies, such as open
      management of the abdomen and planned relaparotomies, may have reached their
      limits.

PMID- 10583281
TI  - Digest

PMID- 10583282
TI  - Randomized clinical trial of early laparoscopy in the management of acute non
      specific abdominal pain.
AB  - BACKGROUND: Abdominal pain of uncertain aetiology (non-specific abdominal pain;
      NSAP) is the commonest reason for emergency surgical admission. The aim of this
      study was to examine the role of early laparoscopy in the management of NSAP.
      METHODS: Some 120 patients, admitted between November 1995 and October 1998 with
      acute abdominal pain of uncertain aetiology, were randomized into two groups:
      group 1 had laparoscopy during the first 18 h of admission and group 2 had close
      observation, conventional investigation and surgical intervention if signs of
      peritonism developed. Outcome measures were diagnosis, operative procedures,
      duration of hospital stay, readmission rate, morbidity and death, patient
      satisfaction and total number of investigations performed. RESULTS: Median
      hospital stay was 2 (range 1-13) days in both groups (P = 0.87). A diagnosis was
      established in 48 (81 per cent) of 59 patients in group 1 compared with 22 (36
      per cent) of 61 in group 2 (P < 0.0001). The morbidity rate was 14 (24 per cent)
      of 59 in group 1 and 19 (31 per cent) of 61 in group 2 (P = 0.3629). The
      readmission rate at a median follow-up of 21 (range 1-35) months was 17 (29 per
      cent) of 59 in group 1 compared with 20 (33 per cent) of 61 in group 2 (P = 0.
      6375). Well-being scores improved from 134 on admission to 149 of 177 6 weeks
      later in group 1 (P = 0.007) and from 132 to 143 of 177 in group 2 (P = 0.089).
      CONCLUSION: Early laparoscopy provided a higher diagnostic accuracy and improved
      quality of life in patients with NSAP.

PMID- 10583283
TI  - Electronic evaluation of the value of double gloving.
AB  - BACKGROUND: Breakdown of the surgeon-patient barrier represents a risk for
      transmission of infectious disease. Such breakdowns are frequently not recognized
      by the surgical team. The protection afforded by double gloving under normal
      operating conditions was evaluated. METHODS: An electronic device detected
      breakdown of the surgeon-patient barrier in a series of 80 surgical procedures,
      randomly assigned to either double or single gloving. Fluid contact due to glove
      perforation, porosity or gown wetting was recorded during 151 individual surgeon
      episodes covering 238 operator-hours. Surgical procedures were called superficial
      for incisions of less than 10 cm. RESULTS: Double gloving reduced the number of
      perforation and porosity alarms twofold in both superficial and deep surgical
      procedures. Deep procedures carried a sevenfold increased risk of barrier
      breakdown compared with superficial procedures, the risk being greatest for the
      principal operator. CONCLUSION: Without electronic detection, a large majority of
      barrier breakdowns would remain undetected by the surgical team and lead to
      prolonged contact with potentially contaminating body fluids. The use of double
      gloving provides real protection against such contamination risks.

PMID- 10583284
TI  - Hepatitis viral status in patients undergoing liver resection for hepatocellular
      carcinoma.
AB  - BACKGROUND: Hepatitis B and C viruses are the main causative agents of
      hepatocellular carcinoma (HCC). The influence of hepatitis viral status on liver
      resection for HCC remains undetermined. METHODS: Patients who underwent curative
      resection for HCC were divided into four groups: group 1, seronegative for
      hepatitis B surface antigen (HBsAg) and antihepatitis C antibody (HCVAb); group
      2, seropositive for HBsAg only; group 3, seropositive for HCVAb only; and group
      4, seropositive for HBsAg and HCVAb. The clinicopathological characteristics and
      surgical results of the four groups were compared. Resection of HCC was
      determined according to liver functional reserve and tumour extent. RESULTS:
      There were 40, 131, 70 and 20 patients in groups 1, 2, 3 and 4 respectively. Due
      to patient selection bias, there were significant differences in some background
      features, resectional extent and pathological characteristics among the four
      groups. Postoperative morbidity and mortality, as well as the Union Internacional
      Contra la Cancrum tumour node metastasis stages, did not differ. Patients in
      group 1 had a higher disease-free survival rate than those in group 2 (P = 0.
      02). The actuarial survival rates of patients in groups 2 and 4 were lower than
      those of groups 1 and 3. CONCLUSION: With careful patient selection, the
      hepatitis viral status does not influence the surgical risks of hepatectomy for
      HCC. After liver resection for HCC, the long-term survival rate of patients
      seronegative for HBsAg is greater than that of patients seropositive for HBsAg.

PMID- 10583285
TI  - Laparoscopy extends the indications for liver resection in patients with
      cirrhosis.
AB  - BACKGROUND: Clinical or biological evidence of liver failure is usually
      considered a contraindication to open liver surgery as it is associated with a
      prohibitive risk of postoperative death. METHODS: This report describes three
      patients who had resection of a superficial hepatocellular carcinoma suspected
      either to be ruptured, or at high risk of rupture, using the laparoscopic
      approach. All three patients had intractable ascites, in two superimposed on
      active hepatitis. Surgery was per- formed under continuous carbon dioxide
      pneumoperitoneum with intermittent clamping of the hepatic pedicle. RESULTS:
      Intraoperative blood loss was between 100 and 400 ml; no blood transfusion was
      required. The postoperative course was uneventful except for a transient leak of
      ascites through the trocar wounds. Duration of in-hospital stay was 6-10 days.
      Liver function tests had returned to preoperative values within 1 month of
      surgery in all patients. CONCLUSION: The laparoscopic approach may enable liver
      resection in patients with cirrhosis and evidence of liver failure that would
      contraindicate open surgery.

PMID- 10583286
TI  - Early evaluation of renal reperfusion injury after prolonged cold storage using
      proton nuclear magnetic resonance spectroscopy.
AB  - BACKGROUND: Proton nuclear magnetic resonance (NMR) spectroscopy can be used as a
      non-invasive tool to measure renal damage. In the present investigation, proton
      NMR spectroscopy of urine was assessed in order to detect cellular damage after
      different periods of cold ischaemia in two standard preservation solutions.
      METHODS: The isolated perfused pig kidney was used to assess initial renal
      function after in situ cold flush and cold storage (CS) for 24 or 48 h in two
      standard preservation solutions: EuroCollins (EC) and University of Wisconsin
      (UW) solutions. Kidneys flushed with cold heparinized saline and immediately
      perfused were used as a control group. Kidneys were perfused for 2 h at 37.5
      degrees C for functional evaluation. During reperfusion, renal perfusion flow
      rate was measured. Glomerular filtration rate (GFR), tubular reabsorption of
      sodium ions, and lactate dehydrogenase (LDH) and N-acetyl-beta-D-glucosaminidase
      (NAG) excretion were determined. Impairment caused by ischaemia and reperfusion
      was also determined by histological techniques and proton NMR spectroscopy.
      RESULTS: The perfusion flow rate, GFR and tubular reabsorption of sodium were
      significantly decreased in experimental groups compared with the control group.
      There was no significant difference between experimental groups after 24 h of CS.
      The perfusion flow rate was significantly decreased in the EC group after 48 h of
      cold ischaemia compared with that in the UW group. After 48 h of CS, GFR and
      tubular reabsorption of sodium were significantly reduced in the EC group
      compared with those in the UW group. The release of LDH into the effluent and the
      urinary excretion of NAG were not significantly different after 24 h of CS. After
      more than 45 and 60 min of reperfusion respectively, LDH and NAG excretion was no
      different in the 48-h CS groups. The most relevant resonances determined by
      proton NMR spectroscopy were of citrate, trimethylamine-N-oxide, lactate, acetate
      and amino acids. Excretion of these markers was significantly more accurate and
      efficient to assess renal ischaemia-reperfusion injury than that of biochemical
      markers. A resonance (P) detected particularly in the EC group after 48 h of CS
      was identified and correlated well with renal dysfunction. After CS for 48 h and
      2 h of reperfusion, renal injury was histologically more pronounced in EC groups
      than in UW groups. However, the difference was not significant after CS for 24 h.
      CONCLUSION: NMR spectroscopy, which is a non-invasive and non-destructive
      technique, is more accurate and efficient when assessing kidney damage after cold
      ischaemia and reperfusion when compared to conventional histological and
      biochemical analysis.

PMID- 10583287
TI  - Kupffer cell blockade, tumour necrosis factor secretion and survival following
      endotoxin challenge in experimental biliary obstruction.
AB  - BACKGROUND: Gram-negative sepsis and its sequelae frequently complicate invasive
      procedures in patients with obstructive jaundice. In response to endotoxin,
      Kupffer cells secrete tumour necrosis factor (TNF), a pivotal early mediator of
      sepsis. An investigation was carried out into the specific role of Kupffer cell
      TNF secretion following endotoxin challenge in obstructive jaundice. METHODS:
      Survival following intraperitoneal administration of endotoxin (2.0, 0.02 and
      0.0002 mg per 100 g) was determined in rats following bile duct ligation (BDL) or
      sham operation. Plasma TNF concentration was quantified following endotoxin
      administration (0.0002 mg per 100 g) at 1, 2 and 6 h. Subsequently, the effect of
      Kupffer cell blockade by gadolinium chloride on survival and plasma TNF
      concentration was assessed. RESULTS: Jaundiced animals showed a significantly
      increased mortality rate following intraperitoneal injection of endotoxin 2.0 mg
      per 100 g (BDL 100 per cent versus sham 0 per cent) and 0.02 mg per 100 g (BDL 70
      per cent versus sham 0 per cent; P = 0. 002, Fisher's exact test). Median plasma
      TNF concentration was significantly greater in jaundiced animals 1 h after
      endotoxin administration (BDL 943 (interquartile range (i.q.r.) 211-3900) pg/ml
      versus sham 64 (i.q.r. 47-127) pg/ml; P = 0.002, Mann-Whitney U test). Kupffer
      cell blockade with gadolinium chloride increased the survival rate following
      endotoxin administration in BDL animals (BDL-GdCl3 100 per cent versus BDL-saline
      40 per cent; P = 0.0003, Fisher's exact test) and decreased median plasma levels
      of TNF (BDL-GdCl3 88 (i.q.r. 0-1065) pg/ml versus BDL-saline 16 550 (1255-29 360)
      pg/ml; P = 0.002, Mann-Whitney U test). CONCLUSION: Kupffer cell blockade
      improved survival and suppressed systemic TNF activity after endotoxin challenge.
      In obstructive jaundice, hypersecretion of TNF by Kupffer cells may supplement
      systemic cytokine production and be responsible for significant complications.

PMID- 10583288
TI  - Value of percutaneous transhepatic portography before hepatectomy for hilar
      cholangiocarcinoma.
AB  - BACKGROUND: The diagnostic value of percutaneous transhepatic portography (PTP)
      for assessing cancer invasion of the portal bifurcation in patients with hilar
      cholangiocarcinoma has not been studied previously. METHODS: From April 1977 to
      March 1998 combined hepatobiliary and portal vein resection was performed in 45
      patients. In 25 patients, PTP was carried out before operation and the resected
      portal bifurcation was examined histologically. Correlation between portographic
      and microscopic findings at the portal bifurcation was studied retrospectively.
      RESULTS: Portographic and microscopic findings were classified into three groups
      (type A, B or C, and grade 0, I or II respectively) according to the findings at
      the portal bifurcation. There was a significant correlation between the
      portographic type and degree of cancer invasion (P = 0.0001). In seven of the
      eight patients with type A portograms, there was no microscopic cancer invasion
      of the portal bifurcation. In 15 of the 17 patients with type B or C portograms,
      cancer invasion was found microscopically. All patients with microscopic grade II
      invasion had type C portograms. CONCLUSION: PTP can be used to evaluate cancer
      invasion of the portal bifurcation with sufficient reliability for preoperative
      staging of hilar cholangiocarcinoma.

PMID- 10583289
TI  - Comparison of intra-arterial digital subtraction angiography, magnetic resonance
      angiography and duplex ultrasonography for measuring carotid artery stenosis.
AB  - BACKGROUND: Duplex ultrasonography and magnetic resonance angiography (MRA) are
      becoming competitive alternatives to angiography for determining the degree of
      internal carotid artery (ICA) stenosis. Varying reports have been published
      regarding the suitability of each technique for grading ICA disease. This
      retrospective study compared the merits of these three modalities for measuring
      ICA stenosis. METHODS: One hundred and eleven patients being considered for
      carotid endarterectomy underwent intra-arterial digital subtraction angiography
      (DSA) via arch injection. Duplex imaging was performed in all patients and MRA in
      50. The degree of carotid stenosis estimated by the three modalities was
      compared. RESULTS: There was good correlation between subjectively graded MRA and
      DSA images (r = 0.87, P < 0.001, n = 82 carotids) but poor correlation for
      objective estimates. MRA tended to underestimate the degree of stenosis (bias -
      4.5 per cent) compared with DSA, but showed good correlation with duplex
      ultrasonography estimates (r = 0. 86, P < 0.001, n = 87 carotids). Both non
      invasive modalities produced high values of sensitivity and specificity in
      estimating stenoses of greater than 70 per cent. MRA was less sensitive for
      distinguishing between severe stenosis and complete occlusion. CONCLUSION: This
      study did not resolve the debate regarding the method of choice as both MRA and
      duplex ultrasonography were accurate for imaging carotid stenoses.

PMID- 10583290
TI  - Role of nitric oxide in intestinal ischaemia-reperfusion injury studied using
      electron paramagnetic resonance.
AB  - BACKGROUND: The role of nitric oxide in intestinal ischaemia-reperfusion (I/R)
      remains poorly defined, partly because of difficulty in detecting the nitric
      oxide free radical. In this study nitric oxide production was assessed during
      intestinal I/R by direct measurement using electron paramagnetic resonance (EPR),
      and the production of nitric oxide in jejunum and ileum was correlated with their
      different abilities to resist I/R injury. METHODS: Rats were given an electron
      spin trapper (diethyldithiocarbamate/ferrous citrate) by intraperitoneal
      injection. Thirty-six segments each of jejunum and ileum were subjected to 15-90
      min of ischaemia and 25 min of reperfusion. Tissue samples were analysed for EPR
      signals using a spectrometer. RESULTS: Mean(s.d.) basal nitric oxide level was
      significantly higher in ileum (3.39(1.42) units) than jejunum (0. 65(0.05) units)
      (P = 0.0005). Increasing ischaemic times in the ileum resulted in decreasing
      nitric oxide levels (85, 32 and 13 per cent of basal level at 30, 60 and 90 min
      respectively); reperfusion resulted in further nitric oxide reduction (mean
      decrease 26 per cent). Severe (grade 3) histological damage was observed in low
      nitric oxide states (after 15 min of I/R in jejunum, 60 min of I/R in ileum).
      CONCLUSION: Nitric oxide can be measured in intestinal tissues directly by EPR.
      The findings support a protective role for nitric oxide in I/R, and offer an
      explanation for the greater resistance to I/R of ileum.

PMID- 10583291
TI  - Improved management of infrainguinal bypass graft infection with methicillin
      resistant Staphylococcus aureus.
AB  - BACKGROUND: There is considerable debate over the management of infected
      infrainguinal grafts. This report describes recent experience in this field and
      documents the change in clinical practice needed to deal with methicillin
      resistant Staphylococcus aureus (MRSA). METHODS: All infected infrainguinal
      grafts between January 1991 and July 1997 were reviewed. In the light of the
      findings, clinical practice was modified considerably. A further 1 year was
      audited prospectively up to August 1998. RESULTS: Twenty-six patients were
      treated for 27 infrainguinal graft infections (25 prosthetic, two vein). Twenty
      were treated by complete graft excision as the initial therapy; graft
      preservation was attempted in six patients. Before 1995, the infecting organisms
      were predominantly Pseudomonas aeruginosa or methicillin-sensitive staphylococci.
      Subsequently all 14 patients treated up to 1997 had infection with MRSA. The
      overall amputation rate was 17 of 26; ten amputations were in patients with MRSA.
      Four patients died, all with MRSA sepsis. As a result of this experience a policy
      of complete isolation was adopted for all patients infected with MRSA. In the 12
      months since this policy was introduced, 77 infrainguinal grafts (61 vein, 16
      prosthetic) have been inserted. Two grafts (3 per cent) have become infected,
      necessitating graft excision and amputation. CONCLUSION: MRSA infection of an
      infrainguinal graft is a serious complication with high associated amputation and
      mortality rates. Isolation and barrier nursing appeared to contain the problem.

PMID- 10583292
TI  - Venous ulcer healing by four-layer compression bandaging is not influenced by the
      pattern of venous incompetence.
AB  - BACKGROUND: Previous studies have related deep venous incompetence to reduced
      venous ulcer healing rates. The aim of this study was to determine the
      relationship between the pattern of venous incompetence and ulcer healing.
      METHODS: A total of 198 legs with venous ulceration were investigated with colour
      venous duplex imaging to determine the presence and site of venous incompetence.
      All were treated initially with the four-layer bandage technique. RESULTS: At 6
      months, 74 per cent of the venous ulcers had healed using the four-layer bandage
      technique. There was no significant correlation between the pattern of
      incompetence and the healing rate of the ulcer. Previous deep vein thrombosis
      (DVT), increased size of the ulcer and previous episodes of ulceration were
      associated with a poor healing rate. CONCLUSION: The four-layer bandage technique
      achieved an ulcer healing rate of 74 per cent after 6 months, irrespective of the
      pattern of venous incompetence. Patients with a large ulcer, previous DVT or
      previous episodes of ulceration had delayed healing, supporting the previous
      literature.

PMID- 10583293
TI  - Influence of systemic factors on pre-existing intimal hyperplasia and their
      effect on the outcome of infrainguinal arterial reconstruction with vein.
AB  - BACKGROUND: The association between raised levels of homocysteine, fibrinogen and
      lipoprotein (a), and the presence of pre-existing intimal hyperplasia (IH) in
      vein has not been assessed. The positive association between such hyperplasia and
      graft failure following infrainguinal arterial reconstruction, and between
      lipoprotein (a) and graft failure, is disputed. The influence of homocysteine on
      outcome has not been investigated prospectively. METHODS: Fifty-seven patients
      (63 grafts) undergoing infrainguinal arterial reconstruction with saphenous vein
      were studied. Homocysteine, fibrinogen and lipoprotein (a) levels were measured,
      and a vein biopsy was taken at operation. Patients underwent graft surveillance
      and outcome at 12 months was determined. RESULTS: Fifty-seven per cent of
      patients had hyperhomocysteinaemia. Patients with pre-existing IH had
      significantly higher homocysteine levels. There was no association between
      homocysteine and outcome, or between fibrinogen and pre-existing IH or outcome.
      Lipoprotein (a) levels were significantly lower in patients with pre-existing
      disease, and were lower, but not significantly, in those whose grafts failed. The
      correlation between pre-existing IH and vein graft failure was highly
      significant. CONCLUSION: Hyperhomocysteinaemia is associated with peripheral
      vascular disease and the development of pre-existing IH in vein, which itself is
      associated with vein graft failure.

PMID- 10583294
TI  - Surgery may be curative for patients with a localized perforation of rectal
      carcinoma.
AB  - BACKGROUND: Perforation at the time of operation adversely affects the prognosis
      of rectal cancer. These procedures have been termed 'palliative' or 'non
      curative'. The long-term outcome of generalized perforations may be different
      from that of localized or contained perforations. Although the oncological
      results may be compromised when the tumour is perforated, results in cases where
      the perforation is contained may not be as bad as previously thought. An attempt
      was made to examine the intermediate and long-term results for locally contained
      perforated rectal cancers. METHODS: Some 848 patients with rectal cancer were
      operated on between March 1989 and December 1995. Of these, 42 (5 per cent) had a
      locally contained perforation of the rectum. Median follow-up was 23 (range 12
      74) months. RESULTS: The survival of patients with locally contained tumour
      perforation who underwent resection without macroscopic residual disease (40 per
      cent at 5 years) was significantly better than that of patients with metastatic
      disease at the time of surgery (zero at 4 years) (P < 0.01). The survival of
      patients in whom the tumour was inadvertently perforated during operation was
      similar to that of patients with locally contained spontaneous tumour
      perforations. The incidence of local recurrence in these perforated cases was low
      provided that a wide tumour clearance was achievable at the time of operation.
      Operative mortality and morbidity rates were not significantly different but the
      incidence of postoperative wound infection was marginally higher among patients
      with perforation. CONCLUSION: If clear margins can be obtained at the time of
      operation the prognosis of locally contained perforated rectal cancers is good
      and approaches that of a potentially curative resection.

PMID- 10583295
TI  - Experimental study of neorectal physiology after formation of a transverse
      coloplasty pouch.
AB  - BACKGROUND: A novel transverse coloplasty pouch (TCP) with a larger neorectal
      volume than a straight coloanal anastomosis (CAA) but a smaller volume than a
      short colonic J pouch (CJP) may improve short-term function after rectal
      excision. METHODS: Twelve pigs were investigated 6 weeks after complete rectal
      excision followed by reconstruction with a CAA, CJP or TCP. The results were
      compared with findings in the normal pig rectum. RESULTS: The colonic transit
      times assessed by radio-opaque marker transit were 24 h for CAA, 60 h for CJP and
      32 h for TCP. Non-operated control pigs had a mean transit time of 46 h. Pigs
      that had a CJP developed colonic dilatation and substantial faecal impaction.
      Colonic electrostimulation induced an adaptive relaxation in the normal rectum
      but a pressure increase in all neorecta, particularly after CAA. The neorectal
      longitudinal smooth muscle layer in pigs with a TCP was significantly thicker
      than that in pigs with a CAA or CJP; its thickness was closest to that of the
      normal pig rectum. Colonic smooth muscle layers 10 cm proximal to the coloanal
      anastomosis, above the neorecta, were significantly thicker after CJP than after
      CAA or TCP formation. No significant difference in microcirculation was observed
      between the three restorative procedures. CONCLUSION: Accelerated colonic transit
      and a lack of adequate relaxation upon endoluminal pressure increase was
      associated with urgency and incontinence after CAA. Delayed colonic transit,
      faecal impaction and ineffective muscular hypertrophy due to pouch dilatation and
      constipation indicated evacuation problems after CJP construction. Functional and
      morphometric data for TCPs suggested almost normal defaecation. Of the three
      restorative procedures, the data for TCPs were most similar to those obtained in
      the normal pig rectum at short-term follow-up.

PMID- 10583296
TI  - Multicentre study of ultrasonographically guided axillary node biopsy in patients
      with breast cancer.
AB  - BACKGROUND: Axillary lymph node dissection is still performed as a staging
      procedure since lymph node status is the most important prognostic factor in
      patients with breast cancer. Sentinel node biopsy may replace routine axillary
      lymphadenectomy, especially in patients with small breast cancers. This study
      investigated whether ultrasonographically guided fine-needle aspiration cytology
      (FNAC) of the axillary lymph nodes in clinically node-negative patients was an
      accurate staging procedure to select patients for sentinel node biopsy. METHODS:
      One hundred and eighty-five consecutive patients were included. All had axillary
      ultrasonography and detected nodes were categorized according to their dimensions
      and echo patterns. Ultrasonographically guided FNAC was carried out if
      technically possible. These results were compared with the results of the
      sentinel node biopsy and subsequent axillary dissection. RESULTS: In 116 patients
      no lymph nodes were detected by ultrasonographic imaging. Of 69 patients with
      visible nodes, 31 had malignant cells on FNAC. There were no false-positive
      results. Some 87 of 185 patients had axillary metastases on definitive
      histological examination. Ultrasonography was sensitive in patients with
      extensive nodal involvement. Failure of the examination was caused by problems
      learning the method, difficulty in puncturing small lymph nodes and sampling
      error. CONCLUSION: In patients without palpable axillary nodes, a sentinel node
      biopsy could be avoided in 17 per cent since ultrasonography combined with FNAC
      had already diagnosed axillary metastases. The method is particularly valuable in
      larger breast cancers.

PMID- 10583297
TI  - In vitro DNA synthesis in freshly separated human breast cancer cells assessed by
      tritiated thymidine incorporation assay: relationship to the long-term outcome of
      patients.
AB  - BACKGROUND: Tumour growth rate has a significant effect on the clinical course of
      various malignancies. The present study was designed to assess whether in vitro
      DNA synthesis in freshly separated breast cancer cells is a useful marker in
      evaluating growth rates and in predicting the clinical outcome of patients.
      METHODS: From 1982 to 1992, DNA synthesis was assessed by [3H]thymidine
      incorporation in 97 samples of primary lesions from 94 patients with breast
      cancer. The patients were followed for 5-15 years and their outcome was surveyed
      in January 1998. RESULTS: The level of DNA synthesis did not correlate with the
      patients' age, clinical stage or expression of oestrogen receptor. However, it
      correlated significantly with the histological grade. In 89 patients, whose
      outcome was reported, the survival rate in the group with a high rate of DNA
      synthesis (log10c.p.m. 3.0 or more) was significantly lower than that in the low
      level group; the 5- and 10-year survival rates were 84 and 74 per cent for the
      low synthesis group (n = 46), and 60 and 46 per cent for the high synthesis group
      (n = 43) respectively. This was also noted in patients with stage 1 or 2 cancers,
      for whom the 5- and 10-year survival rates were 100 and 90 per cent for the low
      synthesis group (n = 25), and 75 and 70 per cent for the high synthesis group (n=
      35). Multivariate analysis supported this significant correlation for DNA
      synthesis in the prognosis of patients after mastectomy. Furthermore, the level
      of DNA synthesis was significantly higher in 18 patients who died from a
      recurrence within 3 years after operation than in 56 survivors, and the level of
      DNA synthesis also correlated significantly with the survival period in the 33
      patients who died. CONCLUSION: The level of DNA synthesis in breast cancer was
      variable, and was independent of the clinical stage or oestrogen receptor status.
      However, a high level of DNA synthesis was a positive indicator of a high risk of
      recurrence after operation, especially for stage 1 or 2 breast cancer. In vitro
      DNA synthesis may account for some of the clinical characteristics of breast
      cancers.

PMID- 10583298
TI  - Endoscopic technique for the localization of intraduct papillomas.

PMID- 10583299
TI  - 24-h pH monitoring is necessary to assess acid reflux suppression in patients
      with Barrett's oesophagus undergoing treatment with proton pump inhibitors.
AB  - BACKGROUND: Control of acid reflux is the main objective of treatment for
      Barrett's oesophagus. However, as these patients have a reduced sensitivity to
      acid reflux, disappearance of symptoms may not correlate with efficient control
      of acid reflux. The aim of this study was to determine in a group of patients
      with Barrett's oesophagus whether treatment with proton pump inhibitors
      suppressed pathological acid reflux once the symptoms of reflux had been
      controlled and the associated inflammatory lesions cured. METHODS: Eighteen
      consecutive patients with Barrett's oesophagus were studied, all of whom
      presented with heartburn. Twenty-four-hour oesophageal pH monitoring before
      treatment showed pathological acid reflux in all cases: median percentage of
      total time with pH less than 4, 22 (range 8-52) per cent. All patients received
      proton pump inhibitors (dose 20-60 mg/day) until symptoms were controlled.
      RESULTS: While on therapy, pH was reduced (median percentage of total time with
      pH less than 4, 3 versus 22 per cent; P < 0.001). However, three patients had
      persistent pathological rates of acid reflux. CONCLUSION: Disappearance of
      symptoms is not a good indicator of control of pathological acid reflux in
      patients with Barrett's oesophagus. Twenty-four-hour pH monitoring should be
      performed for proper adjustment of the dose of medication.

PMID- 10583301
TI  - Scientific surgery

PMID- 10583300
TI  - Role of superficial venous surgery in the treatment of venous ulceration.

PMID- 10583302
TI  - Hypogonadotrophic hypogonadism: a unique biological opportunity.

PMID- 10583303
TI  - Postmenopausal osteoporosis is more related to hormonal aberrations than to
      lifestyle factors.
AB  - OBJECTIVE: Serum insulin-like growth factor-1 (IGF-1) decreases with increasing
      age and this process is more pronounced in women after the menopause in parallel
      with the increasing prevalence of osteoporosis. This study was designed to
      compare IGF-1 concentrations, vitamin D, intact parathyroid hormone (PTH) and
      lifestyle factors in postmenopausal, osteoporotic women with and without
      oestrogen replacement therapy (HRT), with an age-matched random population sample
      of women. DESIGN: Case control study. PATIENTS: Postmenopausal, osteoporotic
      women, n = 128, mean age 59 +/- 6 years, were compared with a female random
      population sample matched for age, n = 227, mean age 59 +/- 5 years, from the WHO
      MONICA Project, Goteborg, Sweden. Osteoporotic fractures had occurred in 56% of
      the patients compared with 4% of the controls (P < 0.001). MEASUREMENTS:
      Anthropometry, occupation, smoking habits, physical activity, blood pressure, IGF
      1, vitamin D, intact PTH, blood lipids. RESULTS: There were no differences in
      occupational class, current or previous smoking habits, degree of physical
      activity during occupational or leisure time between the patients and controls.
      Osteoporotic women had lower body weight and body mass index than the controls (P
      < 0.001). Height, waist/hip ratio and osteocalcin were similar. 25(OH) vitamin D
      and 1,25(OH)2 vitamin D were lower (P < 0.05 and P < 0.01, respectively), PTH was
      higher (P < 0.001) and IGF-1 lower (P < 0.01) in osteoporotic women compared with
      the controls. IGF-1 was lower (P < 0.05), in spite of similar bone mineral
      density, in osteoporotic women without HRT than in those with HRT, who had IGF-1
      concentrations similar to those of the population sample, of whom fewer than 10%
      had HRT. Among patients, IGF-1 did not correlate with serum oestradiol or bone
      mineral density. PTH correlated negatively to bone mineral density at the femoral
      site (r = - 0.29; P = 0.003). CONCLUSION: Osteoporosis in postmenopausal women is
      more related to hormonal aberrations than to lifestyle factors.

PMID- 10583304
TI  - Increased prevalence of type 2 diabetes mellitus and impaired glucose tolerance
      in first-degree relatives of girls with a history of precocious pubarche.
AB  - OBJECTIVE: To assess whether abnormal responses to an oral glucose load,
      dyslipidaemia and hyperandrogenaemia, which are commonly found in girls with a
      history of precocious pubarche, can also be detected in first-degree relatives of
      these patients. PATIENTS AND DESIGN: Sixty first-degree relatives (age, 41.4 +/-
      4.4 years; BMI, 26.9 +/- 3.3 kg/m2) of girls diagnosed with precocious pubarche
      were studied. The prevalence of gestational diabetes mellitus and the hirsutism
      score were assessed in the females. The study was performed during the early
      follicular phase of the menstrual cycle in females and at random in males.
      MEASUREMENTS: All subjects underwent a standard 75 g 2-h oral glucose tolerance
      test (OGTT). Serum lipids and lipoproteins were measured in baseline blood
      samples in all subjects, while serum testosterone, sex hormone-binding globulin
      (SHBG) levels and the free androgen indices were determined only in females.
      Impaired glucose tolerance (IGT) and type 2 diabetes mellitus were diagnosed
      according to the criteria of the Expert Committee on the Diagnosis and
      Classification of Diabetes Mellitus. RESULTS: Seven subjects (11.6%) had type 2
      diabetes while a further 14 (23.3%) had IGT; prevalences significantly higher
      than those reported for the present population of the same age (type 2 diabetes,
      2.5% and IGT, 7. 5%; P < 0.001 and P < 0.001, respectively). BMIs were similar in
      patients with either normal or abnormal glucose tolerance. Abnormal levels of at
      least two lipid parameters were found in 40% of subjects. Four out of 10 hirsute
      women and six non-hirsute women reported gestational diabetes. Mean serum SHBG
      levels were lower in female relatives compared with population controls (P <
      0.0005). CONCLUSIONS: First-degree relatives of girls with precocious pubarche
      are at a higher risk of impaired glucose tolerance and type 2 diabetes which, in
      most cases, is accompanied by an unfavourable lipid profile. Hyperandrogenism and
      an increased prevalence of gestational diabetes mellitus are frequent among
      females. These data may prove useful in identifying a specific subset of the
      population at increased risk of developing metabolic disturbances known to
      predispose to cardiovascular disease.

PMID- 10583305
TI  - RAD51 as a candidate parathyroid tumour suppressor gene on chromosome 15q:
      absence of somatic mutations.
AB  - OBJECTIVE: Loss of heterozygosity (LOH) at chromosome 15q is frequent in
      parathyroid adenomas, but no tumour suppressor gene of importance to parathyroid
      tumour development has been isolated from this region. The RAD51 gene has been
      localized to chromosome 15q and possesses regulatory functions involving DNA
      stability and cell proliferation, suggesting its possible role in tumorigenesis.
      Additionally, mutations in the RAD51 gene cause reduced resistance to ionizing
      radiation, which is a major risk factor for primary hyperparathyroidism. RAD51
      was therefore analysed as a candidate tumour suppressor gene in a group of
      parathyroid adenomas for which mutations in a 15q tumour suppressor should be
      most readily detectable. PATIENTS AND DESIGN: From a total of 55 parathyroid
      adenomas, nine were selected based on their LOH pattern showing DNA loss at
      chromosome 15q in the vicinity of the RAD51 gene. RAD51 mRNA expression was
      investigated by reverse transcription-polymerase chain reaction (RT-PCR), and
      sequence analysis of the entire coding region of the RAD51 cDNA was performed in
      all nine adenomas. RESULTS: RAD51 mRNA expression was substantiated in all
      parathyroid adenomas. Compared with the normal RAD51 cDNA sequence, no point
      mutations or microdeletions could be found in the parathyroid tumor cDNA.
      CONCLUSION: These observations suggest that somatic inactivating mutations of the
      RAD51 gene are uncommonly, if ever, associated with parathyroid tumourigenesis.

PMID- 10583306
TI  - Acute dexamethasone administration enhances GH responsiveness to GH releasing
      peptide-6 (GHRP-6) in man.
AB  - OBJECTIVE: Acute administration of glucocorticoids stimulates GH secretion
      probably by a decrease in hypothalamic somatostatin release. GHRP-6 is a
      synthetic hexapeptide that increases GH secretion by a mechanism of action not
      yet fully known, but apparently not by inhibition of hypothalamic somatostatin
      release. The aim of this study was to evaluate the effect of acute dexamethasone
      administration on GH responsiveness to GHRP-6 in man. DESIGN: One group of
      subjects received iv GHRP-6 (1 microg/kg), GH-releasing hormone (GHRH; 100
      microg), GHRH plus GHRP-6 or saline 3.5 h after oral acute dexamethasone
      administration (4 mg; at 0600 h). A second study group was treated with GHRP-6,
      GHRH or GHRP-6 plus GHRH after placebo ingestion, following the same protocol.
      PATIENTS: Sixteen normal subjects (mean age: 29 +/- 3.3 years), with normal BMI
      (22.4 +/- 2.0 kg/m2), were studied. Eight subjects received dexamethasone and the
      other eight were treated with placebo. MEASUREMENTS: Serum GH was measured by a
      two site monoclonal antibody immunofluorometric assay. RESULTS: In the placebo
      treated subjects, mean peak GH (mU/l; mean +/- SE) and AUC (mU.min/l) values
      after GHRP-6 administration (peak: 43.8 +/- 9.0; AUC: 2262.0 +/- 459. 2) did not
      differ from those observed after GHRH injection (peak: 49. 8 +/- 12.0; AUC:
      2903.4 +/- 872.6). The association of the two peptides markedly increased GH
      levels (peak: 172.4 +/- 34.2; AUC: 10393.0 +/- 1894.8) compared with the isolated
      administration of GHRP-6 or GHRH. In the subjects who received dexamethasone 3.5
      h before saline injection, GH baseline values were significantly higher than
      those observed after 90 min of sampling (12.4 +/- 9.4 vs. 4.6 +/- 2.0). Mean GH
      peak and AUC values after GHRP-6 (peak: 78.8 +/- 11.0; AUC: 4114.6 +/- 588.2) and
      after GHRH administration (peak: 46.8 +/- 16.0; AUC: 3006.8 +/- 1010.0) did not
      differ significantly in the dexamethasone-treated subjects. In this study group,
      the administration of the two peptides together caused a significant increase in
      both peak (119.2 +/- 16.0) and AUC values (7377.0 +/- 937.2) compared with the
      response obtained after each peptide alone. When the two groups were compared, a
      significant increase in GH responsiveness to GHRP-6 was observed after
      dexamethasone administration compared with placebo. No differences in GH response
      to GHRH, or to the administration of the two peptides together, were seen between
      the two groups. CONCLUSIONS: Oral dexamethasone, at a dose of 4 mg, enhances GH
      releasing peptide-6-induced GH release when administered 3.5 h earlier. These
      results suggest that dexamethasone and GHRP-6 could act at different sites of GH
      releasing mechanisms. Further studies are necessary to elucidate these findings.

PMID- 10583307
TI  - Effects of short-term hormone replacement on serum leptin levels in
      postmenopausal women.
AB  - OBJECTIVE: Leptin is a hormone which is secreted by adipocytes and appears to
      influence the reproductive axis. Previous studies have demonstrated higher leptin
      levels in relation to body fat mass in women compared to men, higher levels in
      normally cycling compared to postmenopausal women, and a decrease in leptin
      levels with increased age. The purpose of this study was to determine whether
      oestrogen replacement with or without progesterone increases serum leptin levels
      in postmenopausal women, independently of changes in body fat, and to determine
      if ageing affects leptin levels at baseline or in response to hormone
      replacement. PATIENTS: Twenty-one healthy postmenopausal women on no hormone
      replacement were studied at baseline, after 1 month of oestrogen (E2: estraderm
      50 microg/day) and after a further month of oestrogen and 7 days of progesterone
      (P: progesterone 100 mg per vagina bid) designed to achieve physiological hormone
      levels. Subjects included 11 younger (45-55 years) and 10 older (70-80 years)
      postmenopausal women. RESULTS: The relationship between leptin and the absolute
      fat mass (% body fat x weight [kg]) at baseline was not different between the
      younger and older postmenopausal women. The adequacy of physiological hormone
      replacement was confirmed in all subjects. Despite the absence of an effect of
      hormone replacement on weight, body mass index (BMI), % and absolute fat mass
      (bioimpedance) or waist-hip ratio, there was an increase in serum leptin levels
      with hormone replacement (15.4 +/- 1.7, 17.6 +/- 1.7, and 18.1 +/- 1.6 microg/l;
      mean +/- SEM at baseline, with E2, and with E2 + P, respectively; P < 0.001 vs.
      baseline) for the group as a whole. An increase in leptin with hormonal treatment
      was seen in both the younger (15.1 +/- 2.1, 18.1 +/- 2.4, and 18.5 +/- 1.9
      microg/l; P < 0.01) and the older (15.7 +/- 2.8, 17.0 +/- 2.5, 17.7 +/- 2.8
      microg/l; P = 0.06) postmenopausal women. CONCLUSIONS: (1) Short-term
      physiological oestrogen replacement increases serum leptin levels in
      postmenopausal women independently of changes in fat mass; and (2) physiological
      progesterone replacement does not influence leptin levels in postmenopausal
      women.

PMID- 10583308
TI  - The insulin-like growth factor-I (IGF-I) gene in individuals born small for
      gestational age (SGA).
AB  - OBJECTIVE: To investigate the association of genetic variation of the insulin
      like growth factor-I (IGF-I) gene with birth size small for gestational age
      (SGA). SUBJECTS: We have studied a cohort of 120 SGA patients and 147 appropriate
      for gestational age (AGA) controls from Haguenau, France. METHODS: PCR-SSCP
      analysis was performed to detect sequence variation in the coding region of the
      IGF-I gene. Microsatellite markers near the IGF-I gene (intronic and D12S78) were
      selected and amplified to perform further analysis by association studies.
      RESULTS: A novel polymorphism in intron 2 was discovered, but allele-specific PCR
      analysis in the 120 SGA patients and 147 AGA controls found no association
      between this polymorphism and birth size SGA. Chi squared (chi2) analysis found
      no statistically significant association between the allele distribution of the
      microsatellite markers in the SGA subjects and the AGA controls. Power
      calculations estimate that the D12S78 marker has an 80% chance of detecting a 10
      15% difference. CONCLUSIONS: These studies suggest that genetic variation of IGF
      I alone does not result in birth size small for gestational age in this
      population. Thus, if this gene influences fetal size, it plays only a minor role
      in a multifactorial disorder which involves other genetic and environmental
      factors.

PMID- 10583309
TI  - Postpartum thyroid dysfunction: clinical assessment and relationship to
      psychiatric affective morbidity.
AB  - OBJECTIVE: Postpartum thyroid dysfunction (PPTD), diagnosed using biochemical
      criteria, is usually transient with a wide range of reported prevalence rates.
      The specific clinical and psychiatric morbidity associated with PPTD is still
      uncertain. The aims of the study were to determine the point prevalence of PPTD
      in Australian women at 6 months postpartum and to assess the specific clinical
      and psychiatric morbidity in these women. DESIGN: Women who were Caucasian, aged
      20-45 years and 4.5-5.5 months postpartum, were randomly selected and invited
      into the study. The respondents were assessed for biochemical and psychiatric
      morbidity. PPTD for this study was defined as TSH or free T4 outside the adult
      reference range. A double blind clinical assessment of PPTD women and their
      matched controls used standardized clinical hypo- and hyperthyroid clinical
      indices. PATIENTS: From the total randomly selected sample size of 1816 women,
      748 participated. MEASUREMENTS: Biochemical measurements were serum TSH, free T4,
      microsomal antibody (MsAb) and thyroid peroxidase antibody (TPOAb), and thyroid
      receptor antibodies (only in women with low TSH). Psychiatric assessment involved
      screening all participants using the General Health Questionnaire 28, followed by
      classifying and quantifying severity of cases using DSM-III-R categories for
      depression and anxiety. Clinical signs and symptoms of hypo- and hyper-thyroidism
      were measured using weighted standardized indices. Thyroid size was assessed by
      palpation. Achilles tendon reflex time was measured by photomotograph. RESULTS:
      The prevalence of PPTD in the participants was 11.5% (95% CI 9.2-13. 8%), giving
      a minimum prevalence for the randomly selected sample of 4.7% (95% CI 3.7-5.7%).
      In the PPTD women, 54% had an elevated TSH, 30% had a suppressed TSH and the
      remainder had a low fT4 and normal TSH. Positive thyroid autoantibody titres in
      the PPTD group were 46. 5% for microsomal antibody (MsAb) and 63.9% for thyroid
      peroxidase antibody (TPOAb), and in the non-PPTD group were 1.7% and 4.9%,
      respectively. The 6 month point prevalence rates of depression, generalized
      anxiety disorder and panic disorder and/or agoraphobia were 9.4%, 1.4% and 3.1%,
      respectively. No relationship was found between PPTD status and the diagnosis of
      current depression or between thyroid antibody status and current depression. In
      women who were diagnosed as anxious at the time of assessment, the number of
      anxiety symptoms was higher in the PPTD group (P < 0.05). There was no difference
      in signs and symptom scores for the hypo- and hyper-thyroid clinical indices
      between PPTD women and their controls. CONCLUSION: This study has shown a high
      prevalence of postpartum thyroid dysfunction but there was no difference in the
      clinical and psychiatric signs and symptoms between cases and controls. In the
      social, psychological, physical and endocrine setting of the postpartum period,
      women with postpartum thyroid dysfunction are identifiable by the attending
      physician only by their abnormal thyroid function tests.

PMID- 10583310
TI  - Abnormal circadian rhythm and increased non-pulsatile secretion of thyrotrophin
      in Sheehan's syndrome.
AB  - OBJECTIVE: It has previously been shown that patients with postpartum pituitary
      necrosis (Sheehan's syndrome, SS) have paradoxically increased TSH levels and
      loss of the nocturnal TSH surge. This study sought to determine the circadian and
      pulsatile characteristics of TSH secretion underlying those abnormalities. DESIGN
      AND PATIENTS: Chronobiological and cluster analyses of 24-h TSH profiles were
      performed in nine SS patients (43-61 years, median = 52 years) and nine healthy
      female controls (33-47 years, median = 42 years). MEASUREMENTS: Serum
      concentrations of T3, T4, free T4 (fT4) and cortisol were measured by
      radioimmunoassay; TSH, GH, PRL and LH were determined by immunometric assays.
      RESULTS: All patients and controls showed significant circadian TSH rhythms, but
      the percentage amplitude was decreased (7.5% vs. 21.3%, P < 0.0001) and the
      acrophase was markedly displaced in SS patients, occurring between 0315 h and
      1515 h in seven/nine patients and in two/nine controls (P = 0.057). Patients
      showed increased total 24-h TSH secretion (6054 +/- 2293 vs. 2193 +/- 340
      mU/l/min, mean +/- SE, P = 0.04) due to increased non-pulsatile or tonic 24-h TSH
      secretion (5631 +/- 2105 vs. 1925 +/- 301 mU/l/min, P = 0.026), but no difference
      was detected in pulsatile secretion (424 +/- 191 vs. 268 +/- 41, P = 0.82). The
      contribution of non-pulsatile to total TSH secretion was also increased in SS
      patients (93.8% vs. 87.6%, P = 0. 002). No significant changes were found in TSH
      pulse frequency, amplitude, duration or interpeak interval. When cluster
      parameters were individually analysed in two distinctive 12-h periods
      corresponding to acrophase and nadir, patients showed increased non-pulsatile TSH
      secretion in both periods, but no differences were found in pulsatile TSH
      secretion, pulse frequency or amplitude. The increment of TSH secretion during
      the acrophase in SS patients was exclusively due to increased non-pulsatile TSH
      secretion, as opposed to controls who displayed significant increments in both
      non-pulsatile and pulsatile TSH secretions. CONCLUSIONS: Sheehan's syndrome
      patients have increased total TSH secretion due to increased tonic TSH secretion.
      A circadian TSH rhythm is still present in these patients, but shows decreased
      magnitude and markedly displaced acrophase.

PMID- 10583311
TI  - Effects of administration of 17beta-oestradiol on serum leptin levels in healthy
      postmenopausal women.
AB  - OBJECTIVE: Women have higher leptin levels than men at a certain degree of
      adiposity. The role of oestrogens in the regulation of serum leptin levels
      remains inconclusive. The aim of the present study was to investigate the effect
      of unopposed oestrogen replacement therapy, during two months, on serum leptin
      levels in postmenopausal women. DESIGN: A double-blind, placebo-controlled,
      randomized study. SUBJECTS: Twenty-five healthy postmenopausal women were studied
      (mean (+/- SD) age: 52.9 +/- 2.7 years, range of age: 48.7-57.4 years; mean body
      mass index (BMI): 26.4 +/- 4.2 kg/m2, range of BMI: 21.0-39.0 kg/m2). Twelve of
      these women were treated with 2 mg 17beta-oestradiol daily, and 13 postmenopausal
      women received placebo. MEASUREMENTS: Before and at the end of a 2-month study
      period, anthropometric and bio-electrical impedance measurements were performed,
      and fasting blood samples were taken, to determine serum levels of sex hormones
      and leptin. RESULTS: During the 2-month study period, body weight had increased
      significantly in the placebo group compared with the treatment group, but no
      significant changes were observed in percentage of body fat or the amount of body
      fat in kg between the groups. Following administration of 17beta-estradiol, the
      median leptin level increased from 17.6 microg/l to 24.1 microg/l after 2 months
      (P = 0. 008 compared with baseline). This increase was significantly different
      from the placebo group (P = 0.019), which showed no change in circulating leptin
      levels. CONCLUSION: This study demonstrates that unopposed oestrogen replacement
      therapy during 2 months in postmenopausal women slightly, but significantly,
      increases total serum leptin levels. This observation suggests a role for
      oestrogens in the regulation of leptin.

PMID- 10583312
TI  - Sexual dimorphism in circulating monomeric and dimeric inhibins in normal boys
      and girls from birth to puberty.
AB  - BACKGROUND AND OBJECTIVE: Inhibins are peptides, mainly of gonadal origin, that
      suppress FSH production. Dimeric forms of inhibin (A and B) have been proposed as
      peripheral markers of Sertoli and granulosa cell function. The aim of this study
      was to establish the relationship between circulating dimeric and monomeric
      inhibins, and gonadotrophins and sex steroids, in normal boys and girls from
      birth to puberty. SUBJECTS: One hundred and forty-six normal children (females:
      57; males: 89) were studied. MEASUREMENTS: Serum LH and FSH were measured by an
      immunofluorometric assay. Serum oestradiol and testosterone were measured by
      radioimmunoassay. Serum inhibin A and B, and Pro-alphaC, were measured by
      specific two-site enzyme-linked immunosorbent assays. RESULTS: In boys from birth
      to 6 months of age, the mean serum inhibin B concentration was as high (477 +/-
      53.7 ng/l) as that found at puberty (400 +/- 70.2 ng/l). After the first year,
      inhibin B gradually decreased to reach its lowest concentration (153 +/- 23.6
      ng/l) at age 4-6 years. At approximately age 10, it rose progressively to reach
      pubertal concentrations. Pro-alphaC showed a similar pattern but at lower
      concentrations. Inhibin A was not detected at any age. In girls from birth to 6
      months, inhibin B levels (83.0 +/- 18.3 ng/l) were approximately 50% lower than
      those found at puberty (181 +/- 25.7 ng/l). After 6 months of age, these levels
      dropped (17.5 +/- 1.6 ng/l) and remained low until the prepubertal years.
      Thereafter, they increased to pubertal concentrations. The serum inhibin A
      concentration after birth (29.9 +/- 8.7 ng/l) was similar to that found at
      puberty (18.3 +/- 5.7 ng/l); after 6 months, it fell to undetectable levels until
      the prepubertal years. CONCLUSION: The sex difference in serum levels of
      gonadotrophins is associated with sex differences in the levels and proportions
      of circulating dimeric and monomeric inhibins.

PMID- 10583313
TI  - Iopanoic acid-induced decrease of circulating T3 causes a significant increase in
      GH responsiveness to GH releasing hormone in thyrotoxic patients.
AB  - OBJECTIVE: Thyroid hormones participate in GH synthesis and secretion, and an
      impaired GH response to many pharmacological stimuli, including GH releasing
      hormone (GHRH), has been found in thyrotoxicosis. Although the mechanisms
      involved in this process have not been fully elucidated, there is evidence that
      thyroid hormones could act at both hypothalamic and pituitary levels. There are
      no data in the literature about the effect of an acute reduction of circulating
      T3 levels on GH secretion in hyperthyroidism. The GH responsiveness to GHRH was
      therefore evaluated in a group of hyperthyroid patients during short-term
      treatment with iopanoic acid. Iopanoic acid is a compound that induces a rapid
      decrease in serum T3 levels, mainly by inhibition of peripheral conversion of T4
      to T3. To the authors' knowledge, there is no evidence of a direct effect of
      iopanoic acid on GH secretion. DESIGN: Hyperthyroid patients were submitted to a
      GHRH test (100 microg, i.v.) before (day 0), and on days 4, 7 and 15 after oral
      treatment with iopanoic acid (3 g every 3 days) and propylthiouracil (200 mg
      every 8 h). A group of normal control subjects was also submitted to a single
      GHRH test (100 microg, i.v.). PATIENTS: Nine patients with thyrotoxicosis (eight
      women, one man), with a mean age of 34 years, were studied. All patients had high
      serum levels of total T3 and total T4, and suppressed TSH levels. None of them
      had taken any medication for at least 3 months before the study. The patients
      were compared with a group of nine control subjects (five women, four men) with a
      mean age of 31 years. MEASUREMENTS: GH and TSH were measured by
      immunofluorometric assays. Total T3, total T4 and IGF-I were determined by
      radioimmunoassay. Albumin levels were measured by a colorimetric method. RESULTS:
      Iopanoic acid induced a rapid and maintained decrease in serum T3 concentrations,
      with a significant reduction on days 4, 7 and 15 compared with pre-treatment
      values. In hyperthyroidism, peak GH levels (mean +/- SE mU/l) after GHRH were
      significantly higher on day 15 (24.4 +/- 3.8) than those observed on days 0 (14.2
      +/- 1.6), 4 (15.2 +/- 3.0) and 7 (19.6 +/- 5.0). There was a 79% increase in this
      response on day 15 compared with the pre-treatment period. Hyperthyroid patients
      had a blunted GH response to GHRH on days 0, 4 and 7 in comparison with control
      subjects. However, on day 15, no differences were observed between the area under
      the curve (mean +/- SE mU/l.120 min) in thyrotoxic patients (1770 +/- 306) and in
      the control group (3300 +/- 816). IGF-I and albumin levels did not change during
      iopanoic acid administration. CONCLUSIONS: The results show that an acute
      reduction in serum T3 levels elicits an increase in GH responsiveness to GHRH in
      hyperthyroidism. Although the mechanisms involved in this process are still
      unknown, it is possible that T3 influences GH responsiveness to GHRH via
      hypothalamic somatostatin release. Alternatively, T3 could have a direct effect
      at the pituitary somatotroph, modulating GHRH intracellular pathways.

PMID- 10583314
TI  - Extrusion of testosterone pellets: a randomized controlled clinical study.
AB  - BACKGROUND: It has previously been shown that testosterone implantation is an
      effective and well accepted form of androgen replacement therapy, but that pellet
      extrusion was the most frequent side-effect. The present study aimed to reduce
      the extrusion rate. OBJECTIVE: To determine whether the washing of testosterone
      pellets to remove potentially surface-adherent particles decreased the rate of
      extrusion of pellet implants. DESIGN: Prospective, randomized parallel group
      design in a single centre with consecutive procedures to be randomized (1 : 1)
      into a wash or control group. PATIENTS: The study included 251 testosterone
      implantation procedures in men with known androgen deficiency. MEASUREMENTS: The
      primary endpoint, extrusion rate per procedure, was evaluated prospectively by
      telephone contact at 1 week and then 3 and 6 month intervals. Secondary end
      points included peri-procedure adverse events (bleeding, skin reaction, excessive
      discomfort) noted at the time of implant. Bruising, bleeding and infection were
      also evaluated as later adverse events by telephone and personal follow-up.
      Explanatory variables recorded as possible covariables included the number of
      implants used, production batch number of the implants, the operator, as well as
      other demographic and medical factors. RESULTS: In the wash group, the extrusion
      rate was 12% per procedure (19 pellets from 15 subjects) whereas in the control
      group, the extrusion rate was 11.1% per procedure (18 pellets from 14 subjects),
      indicating no evidence of any benefit of the wash procedure (OR = 1. 09 [95% CI
      0.47-2.6] per procedure). There was no evidence of benefit in secondary endpoints
      including total adverse events (7.1%, OR 1.28 [0.44-3.9], bleeding/bruising
      (8.8%, 1.23 [0.47-3.3]) and infection (4.0%, 1.54 [0.35-7.6]) per procedure.
      Among men reporting an infection requiring antibiotic treatment according to
      their own general practitioners, six/ten (60%) subsequently experienced an
      extrusion. There were no significant differences in extrusion rate between four
      different operators (P = 0.24) nor among 12 different batches of pellets used
      during the course of the study (P = 0.77). CONCLUSIONS: The pellet washing
      procedure used during implantation does not reduce the subsequent extrusion rate.
      The higher rate of both primary and secondary adverse events in this prospective
      study compared with the previous retrospective survey may reflect either more
      rigorous follow-up or a secular trend.

PMID- 10583315
TI  - Assessment of cortisol and ACTH responses to the desmopressin test in patients
      with Cushing's syndrome and simple obesity.
AB  - OBJECTIVE: The desmopressin test has recently been introduced in clinical
      practice as an adjunctive tool in the differential diagnosis of ACTH-dependent
      Cushing's syndrome (CS). It has been reported that the majority of patients with
      pituitary-dependent CS (Cushing's disease, CD) respond to desmopressin, while no
      such response is usually observed in other forms of this syndrome. In the present
      study, the responsiveness of the HPA axis to desmopressin was studied in a group
      of obese subjects. In addition, the ability of desmopressin administration to
      differentiate between patients with obesity and the various forms of Cushing's
      syndrome was investigated. DESIGN AND SUBJECTS: Cortisol and ACTH responses to
      the administration of desmopressin (10 microg bolus i.v.) were examined in 20
      consecutive patients with obesity (14 women and six men; BMI range: 34.5-66.7
      kg/m2). Obese subjects had no clinical stigmata of CS. In all obese patients,
      either an overnight (dex 1 mg at 2300 h) (n = 8) or a formal low-dose (dex 0.5 mg
      6-hourly for 2 days) (n = 12) dexamethasone suppression test was performed for
      the exclusion of Cushing's syndrome. Three of eight subjects showed failure of
      cortisol suppression (i.e. F > 28 nmol/l) to the overnight dexamethasone
      suppression test, but they had undetectable cortisol levels (< 28 nmol/l) on
      further testing with the formal 2-day test. All but two of the remaining subjects
      had undetectable cortisol levels (< 28 nmol/l) following the formal 2-day, low
      dose, dexamethasone suppression test. For comparison, desmopressin responses were
      also tested in 33 patients with CS of varied aetiologies (25 patients with
      pituitary-dependent CS, three patients with occult ectopic ACTH secretion and
      five patients with primary adrenal CS). A positive response was considered to be
      an increment greater than 20% and 50% from baseline levels of cortisol and ACTH,
      respectively. RESULTS: Mean cortisol (F) and ACTH levels did not differ from the
      baseline at any time point following desmopressin administration in the obese
      group (basal F: 417 +/- 41, peak F: 389 +/- 32 nmol/l, P > 0.05; basal ACTH: 33.5
      +/- 4.3, peak ACTH: 50.6 +/- 16.6 ng/l, P > 0.05), or in patients with occult
      ectopic or primary adrenal CS. In contrast, in the group of patients with CD,
      there was a significant rise in the mean ACTH and F levels from baseline (basal
      F: 725 +/- 50, peak F: 1010 +/- 64 nmol/l, P < 0.01; basal ACTH: 88.6 +/- 11.8,
      peak ACTH: 351 +/- 64 ng/l, P < 0.01). Cortisol responses greater than 20% from
      baseline were observed in 21/25 (84%) patients with CD, but in only 3/20 (15%) of
      the obese patients. With regard to ACTH, increments greater than 50% over
      baseline were observed in 23/25 (92%) of patients with CD, and in only 3/20 (15%)
      of the obese patients. As previously reported, none of the patients with occult
      ectopic ACTH secretion or primary adrenal CS had a positive response.
      CONCLUSIONS: The prevalence of subjects who met the criteria adopted to define
      positive cortisol and ACTH responses to the desmopressin test was significantly
      higher in the group of patients with Cushing's disease than in the group of
      patients with obesity. It is therefore suggested that this test may be
      occasionally useful in the differentiation between simple obesity and the
      pituitary-dependent form (but not other forms) of Cushing's syndrome.

PMID- 10583316
TI  - GH substitution does not alter the pulsatile pattern of LH in amenorrhoeic growth
      hormone deficient women.
AB  - OBJECTIVE: GH substitution in GH-deficient (GHD) children promotes pubertal
      development. In some GHD women, secondary amenorrhoea occurs after
      discontinuation of GH treatment. This study was designed to investigate whether
      GH substitution directly influences the GnRH pulse generator. For this reason,
      the pulsatile release of LH was studied in amenorrhoeic GHD women before and
      during GH substitution. DESIGN: GH deficiency was confirmed by an insulin
      tolerance test. During a 24-h period, blood samples were drawn every 10 min for
      determination of LH, FSH and GH levels. Oestradiol and IGF-1 were determined at
      1000 h and 2200 h. After the first test day, patients started with GH
      substitution, 0.25 IU/kg/week. During month 6 of GH treatment, the 24 h blood
      sampling was repeated. SUBJECTS: Ten amenorrhoeic GH-deficient women participated
      in the trial. All were diagnosed as GH deficient during childhood or adolescence.
      Eight of them had been treated with GH during childhood. Seven women suffered
      from primary amenorrhoea and three from secondary amenorrhoea. Six women were
      started with GH substitution after the first test day (according to randomization
      in a larger study). MEASUREMENTS: LH and GH were determined every 10 min and FSH
      every 60 min. LH pulse detection was conducted using a validated statistical
      method. RESULTS: Prior to GH treatment, the LH pulse interval did not show a
      diurnal pattern as found during normal pubertal development. During GH treatment,
      IGF-1 levels rose significantly. No differences were found in mean LH, LH pulse
      amplitude and LH pulse interval before and during GH treatment. Oestradiol levels
      did not change either. CONCLUSIONS: GH substitution in amenorrhoeic GH-deficient
      women does not alter the pulsatile pattern of LH. This may suggest that GH
      treatment does not influence central nervous system control of gonadotropin
      secretion in GHD patients.

PMID- 10583317
TI  - Enhancement of the GH responsiveness to GH releasing stimuli by lysine
      vasopressin in type 1 diabetic subjects.
AB  - OBJECTIVE: We tested the possibility that lysine vasopressin (LVP) changes the GH
      responsiveness to exogenously administered GH-RH (at its minimal and maximal
      doses), clonidine (which is thought to stimulate endogenous GH-RH release) and
      arginine (which is thought to inhibit somatostatin) in patients with type 1
      diabetes mellitus and normal subjects. DESIGN AND PATIENTS: Normal male subjects
      (NC) and age- and weight-matched insulin-dependent diabetic men (DM) with good
      metabolic control were studied. An iv bolus of LVP at a dose (15 microg/kg body
      weight (BW)) lower than the minimal GH releasing effective dose was injected just
      before the I.V. injection of the minimal effective dose of GH-RH (0.035 microg/kg
      BW) in 10 NC and 10 DM, the I.V. injection of the maximal effective dose of GH-RH
      (100 microg) in 7 NC and 7 DM, the I.V. infusion of arginine (30 g over 30 min)
      in 7 NC and 8 DM or the oral administration of clonidine (150 microg) in 7 NC and
      8 DM. On different occasions, GH stimuli, LVP or normal saline were given alone
      to the same normal and diabetic subjects. MEASUREMENTS: GH responses in the
      presence and absence of LVP were measured and compared within each group and
      between normal and diabetic groups. RESULTS: LVP or normal saline administration
      did not modify the basal concentrations of GH in any subject. The administration
      of GH-RH (at the minimal dose), arginine or clonidine alone induced significantly
      higher GH responses in the diabetic subjects than in the normal controls. At the
      maximal dose GH-RH induced similar GH responses in normal and diabetic subjects.
      The simultaneous administration of LVP did not change the GH response to any
      challenging stimulation in the normal controls; in contrast, GH-RH- (at both
      minimal and maximal dose), arginine- and clonidine-induced GH increments were
      significantly enhanced by LVP in the diabetic subjects. CONCLUSIONS: These data
      show that in diabetic, but not in normal subjects LVP enhances the GH
      responsiveness to secretagogues, such as GH-RH, clonidine and arginine, which act
      through three different mechanisms. These findings suggest that in diabetes
      mellitus, vasopressin functions as a primer for various GH responses.

PMID- 10583318
TI  - Osteoporosis and fractures in Turner syndrome-importance of growth promoting and
      oestrogen therapy.
AB  - OBJECTIVE: Turner syndrome (TS) is a chromosomal aberration (45,X) characterized
      by endogenous oestrogen deficiency and short stature. The aim was to study body
      composition, bone mineral density, fracture frequency, social and life style
      factors and biochemical bone markers, as well as hormones, in adults with TS in
      comparison with a female random population sample. PATIENTS: Seventy women with
      TS responded to questionnaires. They underwent physical examination, bone mineral
      density measurement with Dual Energy X-ray Absorptiometry (DEXA) and blood
      sampling. Mean age was 31 +/- 12 (range 16-71) years. A random population sample
      of women from the WHO MONICA Project, Goteborg (25-64 years) served as controls
      (n = 740). RESULTS: Women with TS were shorter than the controls and had lower
      body weight and lean body mass (P < 0.0001). Body mass index and waist/hip
      circumference ratio were higher in TS (P < 0.0001). Osteoporosis was present in
      seven TS women, six above 45 years of age. None of these had received oestrogen
      substitution continuously. Fractures (all types) were reported by 11 (16%) TS
      women (six (50%) above 45 years) compared with 5% in the population sample (P <
      0. 001). Four TS women with fractures had osteoporosis, all above 45 years of
      age. Osteoporosis and fractures did not differ between women with the 45,X
      karyotype and those with mosaicism. Impaired hearing was reported by 40%, and 73%
      wore glasses. Six percent among TS were smokers compared with 25% in the
      population (P < 0.001). TS women reported a lower degree of leisure time physical
      activity than controls (P < 0.001). Parathyroid hormone and osteocalcin were
      higher among TS (P < 0.02 and 0.001). Insulin-like growth factor-I was similar.
      Ninety-one percent of all TS had oestrogen substitution and 96% of TS below 25
      years of age had received growth hormone treatment. CONCLUSION: Osteoporosis and
      fractures were common above, but not below, 45 years of age in Turner syndrome.
      It is probable that modern therapy, including growth promoting and continuous
      oestrogen therapy, will prevent osteoporotic fractures in the future.

PMID- 10583319
TI  - The course of Graves' ophthalmopathy is not influenced by near total
      thyroidectomy: a case-control study.
AB  - OBJECTIVE: The relationship between the method of treatment of hyperthyroidism
      due to Graves' disease and the course of Graves' ophthalmopathy is debated.
      Antithyroid drug therapy is associated with no change, or even amelioration, of
      ophthalmopathy. Although controversial, radioiodine may be followed by
      progression of eye disease, preventable by glucocorticoid administration. Whether
      thyroidectomy affects the course of ophthalmopathy is uncertain. DESIGN: In a
      case control study, the course of non-severe Graves' ophthalmopathy after
      thyroidectomy was investigated and the results compared with those observed in
      patients treated with methimazole. PATIENTS: Thirty patients with Graves'
      hyperthyroidism and non-severe/absent ophthalmopathy were treated with near-total
      thyroidectomy (Group 1, Tx), after achievement of euthyroidism with methimazole.
      After surgery, all patients started levothyroxine replacement therapy. Sixty
      patients treated with methimazole, matched for age, sex, duration of
      hyperthyroidism, degree of ocular involvement and smoking habits, were used as
      controls (Group 2, MMI). MEASUREMENTS: Patients were seen every 1-2 months for 12
      months for thyroid tests and ocular evaluation. RESULTS: In Group 1, ocular
      parameters did not change in 17 of 18 patients with pre-existing ophthalmopathy,
      and in 12 patients without ophthalmopathy. Eye manifestations worsened only in
      one (3.3%) patient with pre-existing ophthalmopathy. In Group 2, ocular
      parameters did not change in 58 patients (33 with, and 25 without
      ophthalmopathy), while new ophthalmopathy occurred in two without pre-existing
      eye disease. One of the 30 patients treated by surgery (3.3%) had permanent
      hypoparathyroidism. CONCLUSIONS: Treatment of Graves' hyperthyroidism with near
      total thyroidectomy in patients with non-severe or absent pre-existing
      ophthalmopathy is not associated in the short term with significant effects on
      the course of ophthalmopathy.

PMID- 10583320
TI  - Sensitivity and specificity of the fine needle aspiration biopsy of the thyroid:
      clinical point of view.
AB  - INTRODUCTION: The rates of sensitivity and specificity of fine needle aspiration
      biopsy (FNAB) for the diagnosis of thyroid malignancy differ considerably among
      various reported series. These values are influenced by three factors: (a)
      whether only clearly positive and negative results are considered, or whether the
      commonly encountered 10-20% of indeterminate/suspicious ones are included; (b)
      whether adenomas are considered as neoplasms in one group with carcinomas; and
      (c) whether only histologically proven cases are used in calculations or whether
      patients with benign clinical follow-up are included. AIM: The aim of the study
      was to evaluate the sensitivity and specificity of FNABs performed at this
      institution in the last 7 years from the clinical point of view, considering only
      benign vs. suspicious/malignant FNAB results (indicating surgery), and benign
      (including adenomas) vs. malignant definitive histology. STUDY DESIGN:
      Retrospective study comparing pre-operative FNAB results with definitive
      histological examination after operation. PATIENTS: A total of 2492 FNABs were
      performed in 2100 patients (1875 women and 225 men); their ages ranged from 9 to
      85 years, with a median of 46 years. Clinical diagnosis was multinodular goitre
      in 1330, single nodule in 591, Hashimoto's thyroiditis in 147 and subacute
      thyroiditis in 32 cases. In 148 instances, the nodule was cystic. A history of
      previous treatment for carcinoma of the thyroid was present in 12 patients. Five
      hundred and thirty-six patients subsequently underwent thyroid surgery.
      STATISTICS: The values of sensitivity, specificity, positive predictive value
      (PPV), negative predictive value (NPV) and diagnostic accuracy were calculated.
      RESULTS: The sensitivity was 86%, specificity 74%, PPV 34%, NPV 97% and
      diagnostic accuracy 75%. CONCLUSIONS: The specificity and positive predictive
      value are low when fine needle aspiration biopsy results are divided into two
      categories only (these being indication for surgery or not), and when only
      suspicious/malignant fine needle aspiration biopsies with subsequent malignant
      histology are considered to be true positive. Nevertheless, the ability to
      discriminate 11.7% of patients with a 34% probability of malignancy
      (suspicious/malignant cytology) from 81.2% of patients (benign cytology) with a
      probability of only 3% is very helpful.

PMID- 10583321
TI  - Role of oestrogen in male sexual behaviour: insights from the natural model of
      aromatase deficiency.
AB  - OBJECTIVE: In order to evaluate the role of oestrogens on human male sexual
      behaviour, the gender-identity, psychosexual orientation and sexual activity of a
      man with a congenital lack of oestradiol resulting from an inactivating mutation
      of the aromatase P450 gene was investigated. The psychosexual and sexual
      behavioural evaluations were performed before and during testosterone treatment
      and before oestradiol treatment, during three phases of different dosages of
      oestradiol treatment. DESIGN: The study was performed before (phase A) and during
      (phase B) testosterone enanthate treatment (250 mg i.m. every 10 days, for 6
      months), during testosterone withdrawal (phase C), and during each of the
      following transdermal oestradiol treatments: 50 microg twice a week for 6 months
      (phase D); 25 microg twice a week for 9 months (phase E), and 12.5 microg twice a
      week for 9 months (phase F). MEASUREMENTS: Sexual behaviour was investigated by a
      sexological interview and by a 2-month self-reported daily diary performed during
      each phase of the protocol study. Furthermore, during each oestradiol treatment
      (phase C, D, E and F), a study of depression, anxiety trait and sexual behaviour
      was performed by the Beck Depression Inventory (BDI), the Spielberger Trait
      Anxiety Inventory (STAI) and the Golombok-Rust Inventory of Sexual Satisfaction
      (GRISS), respectively. Sexual orientation and gender-identity were evaluated by
      the BEM Sex Role Inventory (BSRI). Serum testosterone and oestradiol were
      measured during each phase of the study. RESULTS: Before oestradiol treatment
      (phase C), serum oestradiol was undetectable, while it rose to 356.1, 88.1 and
      55.1 pmol/l during phases D, E and F, respectively. Before any oestradiol
      treatment, during phase D, phase E and phase F serum testosterone was 18.13,
      0.72, 14.3 and 18.51 nmol/l, respectively. The patient's gender-identity as
      assessed by BSRI and by the sexological interview was clearly male. The
      psychosexual orientation evaluated by BSRI, by the sexological interview and by
      the analysis of the self-filled diary was heterosexual. Relevant modification of
      the patient's sexual behaviour occurred only during oestrogen treatment. This was
      more evident during both phase E and phase F, and concerned the behavioural
      parameters with an increase of libido, frequency of sexual intercourse,
      masturbation and erotic fantasies. A reduction of BDI and STAI scores was
      detected during the oestrogen phases. CONCLUSIONS: The study of the sexual
      behaviour in this man with aromatase deficiency suggests that oestrogens in
      humans do not affect gender-identity and sexual orientation but could have a role
      in male sexual activity.

PMID- 10583323
TI  - EDITORIAL: Fractions of unity and thousands.

PMID- 10583324
TI  - Neonatal screening for haemoglobinopathies.

PMID- 10583322
TI  - Gordon Holmes spinocerebellar ataxia: a gonadotrophin deficiency syndrome
      resistant to treatment with pulsatile gonadotrophin-releasing hormone.
AB  - The Gordon Holmes spinocerebellar ataxia syndrome (GHS) is associated with
      idiopathic hypogonadotrophic hypogonadism (IHH). There are conflicting reports in
      the literature as to whether the primary neuroendocrine defect is of hypothalamic
      GnRH secretion, as with most causes of IHH, or of pituitary resistance to GnRH
      action. Because of the anatomical inaccessibility of the hypophyseal portal
      circulation, direct measurement of GnRH levels in human subjects is not possible.
      Previous investigators have attempted to unravel this problem through the use of
      GnRH stimulation tests and the limitations of this approach may explain the
      differing results obtained. We used the more physiological approach of treating a
      male GHS patient for four weeks with GnRH, 7-10 microg/pulse, delivered
      subcutaneously at 90 minute frequency via a portable minipump. This therapy
      failed to induce any rise in plasma gonadotrophin and testosterone
      concentrations. By contrast, eight weeks treatment with exogenous gonadotrophins
      maintained physiological plasma testosterone concentrations and induced
      testicular enlargement with induction of spermatogenesis. The data indicate that
      the primary endocrinopathy in GHS is of pituitary gonadotrophin secretion and not
      of hypothalamic GnRH. Moreover, the patient did not harbour any mutation of the
      GnRH receptor gene. Two clinical observations are consistent with progressive
      involution of gonadotrophic function, rather than a congenital gonadotrophin
      deficiency. First, the patient's development was arrested at early mid-puberty at
      the time of original presentation and, second, effective spermatogenesis was
      induced extremely rapidly during gonadotrophin treatment, suggesting prior
      exposure of the testes to FSH. Both spinocerebellar ataxia and pituitary
      dysfunction might thus have been in evolution since late childhood.

PMID- 10583325
TI  - Diagnosis of malaria: a review of alternatives to conventional microscopy.
AB  - Malaria causes significant morbidity and mortality worldwide, including countries
      with mainly imported malaria. In developing nations, scarce resources lead to
      inadequate diagnostic procedures. In affluent countries, poor familiarity with
      malaria may cause clinical and laboratory misdiagnosis. Microscopy of Giemsa
      stained thick and thin films remains the current standard for diagnosis. Although
      it has good sensitivity and allows species identification and parasite counts, it
      is time consuming, requires microscopical expertise and maintenance of equipment.
      Microscopy with fluorescent stains (QBC), dipstick antigen detection of HRP2 and
      pLDH (Parasight-F, ICT Malaria Pf, OptiMAL), polymerase chain reaction assays and
      some automated blood cell analysers offer new approaches and are reviewed here,
      with emphasis on clinical relevance and their potential to complement
      conventional microscopy, especially in countries with imported malaria.

PMID- 10583326
TI  - Haemoglobinopathy analyses in the Netherlands: a report of an in vitro globin
      chain biosynthesis survey using a rapid, modified method.
AB  - The paper reports the results obtained from the study of 949 patients examined
      for a suspected alpha- or beta-thalassaemia using a rapid modified method of in
      vitro biosynthesis determination. Part of the results have been evaluated in
      correlation with the different molecular defects, defects combinations and with
      the presence of abnormal haemoglobins. The validity of the method for diagnosis
      of thalassaemia and particularly for the analysis of complex defects combinations
      which may occur in multiethnic populations is illustrated. The technology of the
      modified method is thoroughly described and the influence of the factors
      interfering with the reliability of the experiments is discussed.

PMID- 10583327
TI  - Pseudo-reticulocytosis as a result of malaria parasites.
AB  - Recently fully automated methods for enumerating reticulocytes have become
      available as an integral function in routine haematology analysers. In such
      methods, all intraerythrocytic nucleic acid is stained and can be regarded as
      representing reticulocytes. It has previously been shown that Howell-Jolly bodies
      may be counted as reticulocytes in automated flow cytometric methods. In the
      present paper, data from two patients are described indicating that severe
      malaria infection may lead to falsely increased reticulocyte counts, at least in
      the CELL-DYN(R) 4000 haematology analyser. In this instrument, the
      intraerythrocytic nuclear material of the parasites will be stained and counted
      as reticulocytes. This phenomenon appears to be independent of the type of
      Plasmodium infection. Clinical haematology laboratories should be aware of this
      potential source of pseudo-reticulocytosis.

PMID- 10583328
TI  - Interference of Hb-H disease in automated reticulocyte counting.
AB  - Hb-H disease is a form of alpha-thalassemia commonly found in south-east Asia. In
      this condition, numerous Hb-H bodies are found in erythrocytes using reticulocyte
      staining preparations. This is the first study addressing the possible
      interference of Hb-H inclusions in automated reticulocyte counting. In this
      study, seven Hb-H disease samples were tested. Results obtained by the visual
      method and the Technicon H*3 automated method agreed relatively well. This was in
      contrast to the Coulter STKS automated method which generally gave lower results.
      Furthermore, when the incubation time was extended to 180 min in the Coulter STKS
      method, two Hb-H disease samples gave results several-fold higher than those
      obtained using the 60 min incubation time. These discrepant results were likely
      to have been caused by the analyser using the wrong threshold to separate
      reticulocytes and mature erythrocytes. High and low interference in Hb-H disease
      samples was observed in the Coulter STKS automated reticulocyte method.
      Laboratories should be aware of this potential problem, particularly when samples
      are from patients of Asian origin.

PMID- 10583329
TI  - The effect of G-CSF on the composition of human bone marrow.
AB  - The effects on bone marrow cellularity and morphology of 6 days' treatment with
      granulocyte colony-stimulating factor (G-CSF) in 35 patients were studied.
      Examination of trephine biopsies showed a highly significant increase in
      cellularity (P < 10-13). Assessment of aspirates revealed an increase in the
      myeloid to erythroid (M : E) ratio (P = 0.00006), the proportion of myeloid cells
      (P < 10-8), myelocytes (P = 0.00007), metamyelocytes (P = 0.04), band forms (P =
      0.0005) and neutrophils (P = 0.02). This study presents a comprehensive analysis
      of the effects of six days' administration of G-CSF on human bone marrow.

PMID- 10583330
TI  - Circulating thrombopoietin in reactive conditions behaves like an acute phase
      reactant.
AB  - In a recent study we found elevated thrombopoietin (TPO) levels along with a
      trend toward correlation between serum TPO and some acute phase reactants (APR)
      in patients with reactive thrombocytosis. In order to further clarify the
      behaviour of TPO in reactive conditions and to highlight the eventual drawbacks
      of serum TPO (sTPO) against plasma TPO (pTPO) measurements, serial measurements
      were made of sTPO, pTPO, interleukin (IL)-6, C-reactive protein (CRP), fibrinogen
      (FBG), and erythrocyte sedimentation rate (ESR) in 12 patients before and at the
      3rd, 7th, 14th, 45th day after hip replacement surgery. Platelet count, sTPO and
      pTPO were also measured in 30 healthy donors. As expected sTPO were significantly
      higher than pTPO levels (approximately 30% on average) both in controls (P <
      0.00001) and in patients (P < 0.00001). Overall a very good correlation (r =
      0.975, P < 0.00001) was found between serum and plasma TPO, whereas no
      correlation was found between platelet count and the sTPO/pTPO ratio indicating
      that the difference between sTPO and pTPO is independent from platelet count. So
      both serum and plasma seem to be suitable samples for TPO measurement if it is
      taken into account that sTPO are about 30% higher than pTPO. All the parameters
      we measured in our patients increased during the post-surgery period and returned
      to the basal value at the 45th day. pTPO levels peaked at the 3rd day, preceding
      by 11 days the peak in platelet count. A significant correlation was found
      between pTPO and ESR (P = 0.012), pTPO and FBG (P = 0.044), pTPO and CRP (P =
      0.033), and a nearly significant correlation between pTPO and IL-6 (P = 0. 054).
      These results indicate that, in the course of reactive conditions, an early rise
      in TPO precedes and probably induces a later increase in platelet count.
      Moreover, the significant correlations along with the similarity in the
      chronological variations between TPO and some APRs suggest that TPO behave like
      an APR.

PMID- 10583331
TI  - The clinical significance of apoptotic cells in peripheral blood smears.
AB  - Apoptosis as introduced by Kerr and colleagues describes a distinct set of
      morphological features that represent programmed cell death. Apoptosis frequently
      arises owing to genetic programming, cytotoxic drugs and physical stimuli. In
      order to ascertain whether all of the natural triggers of apoptosis have been
      identified, we looked for the presence of apoptotic cells in all routine blood
      films throughout a 5-month period. Patients with known malignant disease or on
      chemotherapy were excluded from the study. Forty-nine blood films, from 10,000
      examined in this period, showed apoptosis. The number of apoptotic cells ranged
      from the occasional cell to 20%. Apoptotic cells were either mainly lymphoid (34
      of 49) or mainly myeloid (15 of 49). All 34 cases with lymphoid apoptotic cells
      were seen in patients with suspected infectious mononucleosis (IM). In patients
      with IM, the presence of large numbers of apoptotic cells was associated with a
      prolonged, severe clinical course. Myeloid apoptotic cells were found in a
      variety of conditions, including one patient who had persistent apoptosis and was
      found to have myelodysplasia. Unexplained persistent apoptosis in blood films
      requires further investigation.

PMID- 10583332
TI  - Development of an internal restriction control in the PCR detection of the
      prothrombin 20210A mutation.
AB  - Detection of the presence of the 20210A/G allele in the human prothrombin gene is
      easily achieved by amplification using primers designed to span this region. The
      downstream primer creates a HindIII restriction site if the 20210A variant is
      present. A new forward upstream primer was designed to incorporate a naturally
      occurring HindIII site that, as it is present in both alleles, serves as an
      internal restriction control. Using this technique, the DNA of 292 unselected
      patients with venous thromboembolic disease was analysed. Of the 149 white
      patients, 4.7% were heterozygous for this mutation but none of the African Black
      patients were positive.

PMID- 10583334
TI  - Azathioprine-associated acute myeloid leukaemia with trilineage dysplasia and
      complex karyotype: a case report and review of the literature.
AB  - A 66-year-old female with dermatomyositis (DM) who had received immunosuppressive
      therapy with azathioprine developed acute myeloid leukaemia (AML). Cytogenetic
      analysis revealed a complex karyotype including monosomy 7, and trilineage
      dysplastic features strongly suggestive of a treatment-related aetiology. The
      literature on azathioprine-associated AML is reviewed.

PMID- 10583333
TI  - Immature reticulocyte fraction as a criterion for marrow engraftment. Evaluation
      of a semi-automated reticulocyte counting method.

PMID- 10583335
TI  - Double esterase staining of the bone marrow contributes to lineage identification
      in a case of minimally differentiated acute myeloid leukaemia (AML M0).
AB  - Minimally differentiated acute myeloid leukaemia (AML-M0) may pose difficulty in
      diagnosis since morphological criteria alone are not reliable. Other studies such
      as electron microscopy, immunocytochemistry and surface marker analysis are
      needed. The role of cytochemistry has been limited to the negative staining of
      blasts for Sudan Black B and myeloperoxidase. An abnormal morphology and
      cytochemistry of bone marrow maturing cells may indicate the myeloid nature of
      acute leukaemia. In this case of AML-M0, increased numbers of maturing and mature
      bone marrow granulocytic cells staining simultaneously for both specific and non
      specific esterase (double esterase) are described. In acute leukaemia, this
      abnormal cytochemical finding seems to be specific for myeloid leukaemia and may
      be used as supplementary evidence of myeloid differentiation of morphologically
      undifferentiated blasts in cases of AML-M0.

PMID- 10583336
TI  - Assessment of intermittent claudication: a comparison of questionnaire, visual
      analogue scale and subjective estimate information with post-exercise ankle
      brachial pressure index.
AB  - In order to assess two simple methods of evaluation of claudication, a standard
      questionnaire and visual analogue scale, a comparison was made between them and
      the post-exercise pressure index used as a gold standard. Fifty-eight consecutive
      stable claudicants were recruited to the study, 51/58 having arterial
      insufficiency according to post-exercise pressure measurements. Both methods
      appeared to correlate rather poorly with post-exercise pressures. Thus visual
      analogue scale cannot be used alone to assess walking tolerance but as it offers
      qualitative information it may be used to supplement pressure measurements in the
      assessment of incapacity caused by intermittent claudication.

PMID- 10583337
TI  - The effect of high- and low-frequency H-wave therapy upon skin blood perfusion:
      evidence of frequency-specific effects.
AB  - The current study was designed to assess the putative physiological effects of H
      wave therapy (HWT, a mode of therapeutic electro-stimulation) on skin blood flow
      in humans and to determine the relevance of frequency to any such effects. Laser
      Doppler flowmetry was used to record changes in blood perfusion on the dominant
      forearm of healthy human volunteers (n=36), who were each assigned, under
      randomized double blind conditions, to one of three experimental groups: placebo
      or HWT at 2 or 60 Hz. HWT stimulation was applied for 20 min, during which time
      concomitant skin temperature was recorded using three surface skin thermistors.
      Statistical analysis of perfusion measurement and skin temperature changes pre-,
      during and for up to 18 min post-HWT stimulation showed a highly significant
      increase in skin blood flow in the 2 Hz group when compared to placebo and 60 Hz
      (P<or/ = 0.01). This was associated with a significant increase in skin
      temperature during the period of stimulation (P<or/ = 0.05). No such differences
      were observed in the 60 Hz group. These results provide evidence that low
      frequency HWT may produce direct localized effects on cutaneous blood flow, a
      finding relevant for clinicians working in the field of tissue repair.

PMID- 10583338
TI  - Rhythms and complexity of respiration during sleep in pre-term infants.
AB  - The aim of this study is to test rhythmic and complex properties of respiratory
      control in former ventilated, pre-term infants during quiet and active sleep. The
      children had a higher risk for sudden infant death due to bronchopulmonary
      dysplasia (BPD). Twelve infants suffering from BPD and 12 control infants,
      matched regarding their post-conceptional age, were examined polygraphically
      during quiet (QS) and active sleep (AS). The respiratory rate (RR), the ratio
      (LF/HF) between the low-frequency power (LF) and the high-frequency power (HF) of
      the spectra of the thoracic respiratory effort, and the frequency of the dominant
      peak within LF (LFF) and HF (HFF) were computed. The correlation dimension (D2)
      of the respiratory signal was calculated to determine the complexity of the
      respiratory control. The transcutaneous pO2 (tcpO2) and pCO2 and the oxygen
      saturation (sO2) were analysed. Infants with BPD had significantly higher RR and
      HFF during QS (median: BPD 48 breaths min-1; control 32 breaths min-1). tcpO2 and
      sO2 were significantly lower in the BPD group. No differences were found in
      LF/HF, LFF or D2 between groups, either in QS or in AS. D2 ranged between 1.8 and
      3.8, showing significantly higher values during AS. LFF was found to be lower
      during active sleep (AS 0.04-0.05 Hz; QS about 0.06 Hz). We propose that in
      infants with BPD the lower lung compliance and the higher resistance, and
      possibly also the hypoxaemia, contribute to the acceleration of breathing. The
      behaviour of RR, spectral parameters and D2 indicates a specific, functional
      setting rather than a regulatory impairment in infants with BPD.

PMID- 10583339
TI  - Is routine echocardiography useful in patients hospitalized for chest pain?
      Evidence of areal myocardial dysfunction detected only by echocardiography.
AB  - To assess the diagnostic value of routine two-dimensional echocardiography in the
      coronary care unit setting, we studied 81 unselected patients admitted for acute
      chest pain. Using electrocardiography (ECG), clinical history and serum markers
      of myocardial injury, the patients were retrospectively diagnosed as having had
      definite acute myocardial infarction (AMI) with (n=13) or without (n=31) previous
      infarction, possible AMI with (n=14) or without (n=15) previous infarction, and
      non-coronary cardiac or other causes of chest pain (n=8). Abnormal wall motion
      was observed in 75/77 patients with a cardiac origin of symptoms (sensitivity
      97%), and there were no false-positive wall motion findings. In the 73 patients
      who were finally diagnosed with coronary artery disease (CAD), echocardiography
      showed wall motion abnormality in at least one additional coronary territory area
      in which there were no diagnostic ECG changes for 56% of patients with CAD
      (41/73) (P<0. 001). These areas were considered to be indicative of the presence
      of myocardium at risk for future cardiac events. We conclude that in addition to
      being a sensitive and accurate tool for detection of ischaemic wall motion
      abnormalities, two-dimensional echocardiography can give valuable information
      about the area of myocardium at risk. Therefore, therapeutic decisions can be
      affected by the findings of the routine echocardiographic examination, which is
      recommended even in unselected coronary care unit patients.

PMID- 10583341
TI  - Noise reduction of renograms: a new algorithm applied to simulated renograms for
      evaluation of the renal retention function.
AB  - Physiological information about an organ may be assessed from the retention
      function as derived by deconvolution analysis. However, noise in data may cause
      distortion of the retention curve and potentially induce methodological errors.
      To take full advantage of all parts of the retention function, i.e. even the
      vascular part, we have developed a non-linear noise reduction algorithm. The
      algorithm is an adaptive polynomial fit (APF) in a sliding segment over the
      renogram to be deconvoluted. Each segment is modelled by the lowest polynomial
      resulting in a root of mean square error lower than a pre-set value. APF was
      tested in comparison with conventional repetitive 1:2:1 smoothing and rectangular
      window smoothing, using a set of simulated retention functions and corresponding
      renograms with superimposed artificial noise. The outcome was evaluated by
      comparing the generated retention functions with the simulated ones. The
      conventional smoothing algorithms, as well as APF, induced some distortion of the
      retention function, but the deviation from the true retention function is
      essentially lower in the case of APF. In addition, APF seems to be more robust in
      cases of essentially reduced renal function and thereby relative high noise
      levels. APF reduces noise in data, leading to retention functions with reliable
      information in terms of a tracer's first passage, uptake and outflow.

PMID- 10583340
TI  - Regional VA/Q ratios in man using 133Xe and single photon emission computed
      tomography (SPECT) corrected for attenuation.
AB  - We describe a technique to obtain non-invasively regional pulmonary ventilation
      perfusion ratios (VA/Q) using single photon emission computed tomography (SPECT)
      and continuous infusion of 133Xe. Single photon transmission tomography was used
      for attenuation correction, for delineation of the lungs and for VA/Q
      calculations. Data are presented for six normal subjects and compared to those
      for two patients with moderate chronic obstructive pulmonary disease (COPD). The
      mean VA/Q for the whole lung of the normal subjects ranged from 0.49 to 0.65,
      group mean 0.56 +/- 0.07 (1 SD), and there was no significant difference between
      the right and left lung. The consistently too low VA/Q values are related to the
      inability to measure regional blood volume and the low resolution of the
      scintillation camera, giving an under-estimation of tracer input. For the normal
      subjects, the dispersion of VA/Q, as defined by the standard deviation of the
      individual distribution functions, ranged from 0.12 to 0.19. One of the patients
      was characterized by a low mean VA/Q of 0.35, and the other patient had a wide
      dispersion (SD) of VA/Q of 0.37. In the normal subjects, a consistent VA/Q
      gradient was found only in the ventrodorsal direction. 133Xe and SPECT can be
      used to obtain meaningful biological information regarding ventilation/perfusion
      relationships of potential clinical value.

PMID- 10583342
TI  - Wide-band spectral analysis of blood pressure and RR interval variability in
      borderline and mild hypertension.
AB  - The aim of this study was firstly to investigate whether indices of wide-band
      spectral analysis in borderline hypertensive (BHT) or mildly hypertensive (HT)
      subjects differ from those in normotensive (NT) subjects, and secondly to assess
      the predictive value of these indices for future hypertension. Electrocardiogram
      and intra-arterial 24 h ambulatory blood pressure (BP) were recorded in 32 NT, 29
      BHT and 30 HT middle-aged men. From the recordings, a 16 h period was extracted
      for wide-band spectral analysis. A single spectrum of BP and RR interval (RRI)
      variability was computed for each period by the fast Fourier transform method.
      The slopes of the spectra were assessed on a log-log scale by linear fitting of
      the spectral values. Power spectral densities were calculated over regions of 0
      0.003, 0.003-0.04, 0.04-0.15, 0.15-0.40 and 0-0.4 Hz. No between-group
      differences were found in the slopes of BP and RRI spectra. The between-group
      differences in spectral powers for BP variability were almost invariably
      significant. The spectral powers for RRI variability did not show between-group
      differences. Five years later, 22 NT, 22 BHT and 18 HT subjects were re-assessed
      using casual BP measurements. In a logistic regression model for the combined
      group of NT and BHT subjects who became HT (22 of 44) during the five-year
      period, none of the parameters of wide-band spectrum predicted the development of
      hypertension. In conclusion, parameters of wide-band spectral analysis may not be
      useful in predicting future hypertension in NT and BHT subjects. Because the BP
      level is a major factor influencing BP variability, the between-group differences
      in wide-band spectral powers in BP may be due to differences in BP level rather
      than differences in cardiovascular regulatory mechanisms.

PMID- 10583343
TI  - Myocardial SPET: artificial neural networks describe extent and severity of
      perfusion defects.
AB  - Artificial neural networks are computer programs that learn from examples. They
      have been successfully used to detect coronary artery disease from myocardial
      perfusion images. The purpose of the present study was to develop neural networks
      that could classify myocardial scintigrams regarding reversibility, localization,
      severity and extent of perfusion defects. Rest/exercise technetium-99m sestamibi
      scintigrams from 338 patients were studied. The classifications of two experts
      were employed as the gold standard. Artificial neural networks were trained to
      classify both reversible (ischaemia) and non-reversible (infarct) defects in
      three vascular territories, corresponding to the main coronary arteries. The
      extent (small or large) and severity (mild or severe) of the defects were
      described by the networks. After the training process, separate test sets were
      used to compare the neural networks with one of the experts who reclassified the
      scintigrams two months later. The neural networks made correct classifications in
      71% of the test cases and the human expert in 70% (P=0.10). It was concluded that
      artificial neural networks can be trained to make clinical interpretations of
      myocardial perfusion scintigrams. The results indicate that networks can assist
      physicians in achieving correct interpretations and thereby improve the
      diagnostic accuracy of medical imaging.

PMID- 10583344
TI  - An 18oxygen inhalation method for determination of total body formation of nitric
      oxide in humans.
AB  - The formation of nitric oxide (NO) and the subsequent conversion of the NO formed
      into nitrate require molecular oxygen. Based on this fact, we have recently
      developed a method using inhalation of the stable oxygen isotope, i.e. 18O2, to
      determine total formation of NO in small laboratory animals. The method has now
      been further developed to be applicable also in humans. Five healthy awake male
      subjects inhaled a gas mixture of unlabelled and 18-labelled oxygen (approximate
      ratio 4:1) in nitrogen from a closed breathing system equipped with eliminators
      for carbon dioxide and water vapour. The ratio of unlabelled to 18-labelled
      oxygen, as well as the total oxygen concentration during the inhalation, were
      monitored. Venous blood samples were taken before and after the inhalation for
      analysis of unlabelled and 18O-labelled nitrate by gas chromatography/mass
      spectrometry. The procedure was repeated with the same protocol on a later
      occasion, during ongoing treatment with the NO synthesis inhibitor NG-monomethyl
      L-arginine (L-NMMA). The average nitrate level in plasma in the absence of L-NMMA
      was 26 micromol l-1. The rate of total synthesis of NO was estimated to be 0.38
      +/- 0.06 mu mol kg-1 h-1, corresponding to a total body formation of 600-700 mu
      mol/24 h in an adult male. Infusion of L-NMMA caused an increase in mean arterial
      blood pressure from 86 +/- 4 to 99 +/- 5 mmHg (P<0.05). The average plasma level
      of nitrate during infusion of L-NMMA was 24 mu mol l-1. NO formation during
      infusion of L-NMMA was 0.17 +/- 0.03 mu mol kg-1 h-1, i.e. significantly (P<0.05)
      lower than in the absence of L-NMMA. We suggest that the described method allows
      direct determination of total NO formation in man. The method may be useful in
      the study of various experimental and pathophysiological conditions affecting NO
      formation.

PMID- 10583345
TI  - Transperitoneal transport in diabetic and non-diabetic patients on peritoneal
      dialysis.
AB  - To investigate differences in the transport characteristics of the peritoneal
      membrane between diabetic and non-diabetic patients on chronic peritoneal
      dialysis, a study was conducted in 21 non-diabetic and 18 diabetic patients.
      Transperitoneal transport of small solutes was evaluated in terms of the mass
      transfer area coefficients (urea, creatinine and glucose), ultra-filtration
      sieving coefficients (urea and creatinine) and by peritoneal equilibration test
      results. The capacity of the peritoneal membrane to transport macromolecules was
      evaluated by albumin mass transfer rates and clearances of albumin.
      Transperitoneal water transport was evaluated by the ultra-filtration properties
      and the lymphatic flow rates. Finally, the whole-body capillary permeability was
      estimated by measuring the unidirectional flux of albumin across the capillary
      wall, i.e. the transcapillary escape rate of 125I-labelled human albumin. Despite
      a significantly increased transcapillary escape rate of albumin in the diabetic
      patients, no differences in peritoneal membrane characteristics could be
      demonstrated between diabetic and non-diabetic patients on peritoneal dialysis.

PMID- 10583347
TI  - Assessment and appraisal: much ado about something.

PMID- 10583346
TI  - Measurement of lung density by photon transmission for monitoring intravascular
      and extravascular fluid volume changes in the lungs.
AB  - Left ventricular (LV) heart failure increases pulmonary blood volume (PBV) and
      interstitial fluid volume. Continuous measurements of lung density may be a
      simple non-invasive method for monitoring of the LV function as the lung density
      should reflect the changes in the PBV and extravascular lung water. The purpose
      of the study was to optimize transmission measurements of the lung with a gamma
      camera and a planar source. Another aim was to assess the possibility of
      transmission monitoring in normal subjects at rest and during exercise and to
      compare the results with simultaneous measurements of PBV changes. Transmission
      measurements were made in a water-filled phantom containing lungs of different
      density. A gamma camera and a planar 57Co source were used. The coefficient of
      variation in density determination owing to counting statistics in a lung area
      was calculated for different energy windows, acquisition times and collimation.
      Dynamic measurements in normal subjects were carried out in a sitting and a
      supine position at rest and during exercise. Pulmonary blood volume was monitored
      simultaneously using 99mTc-labelled red blood cells and the registered blood pool
      activity was corrected for attenuation. Highest precision in relative density
      determination was obtained with large energy window and uncollimated source. A
      precision of 1.0% was obtained with 1 min measuring time. About 10% change in
      transmission corresponding to a 15% change in density was observed during
      exercise. Changes in blood pool and lung density covariated. We conclude that
      lung density changes can be monitored with a high degree of statistical precision
      in a few minutes and with a low radiation dose of radiation using a gamma camera
      and a planar source.

PMID- 10583348
TI  - Immediate effects of aortic valve replacement on left ventricular function and
      its determinants.
AB  - Replacement of the aortic valve exposes the left ventricle to myocardial
      ischaemia and imposes on it abrupt changes in loading conditions and geometry. We
      studied the immediate changes in the left ventricular function of patients
      undergoing aortic valve replacement by transoesophageal echocardiography.
      Patients with aortic regurgitation responded to surgery with a decrease in global
      systolic function associated with a fall in preload. Patients with aortic
      stenosis showed an impairment in myocardial contractility and ventricular
      filling, and their global systolic function did not improve despite the marked
      reduction in afterload. This can be a consequence of inadequate myocardial
      protection and intra-operative ischaemic injury of the hypertrophic myocardium.
      Information provided by transoesophageal echocardiography contributes to optimal
      and individualized management of the period immediately after aortic valve
      replacement.

PMID- 10583349
TI  - Ondansetron is more effective than metoclopramide for the treatment of opioid
      induced emesis in post-surgical adult patients. Ondansetron OIE Post-Surgical
      Study Group.
AB  - Nausea and vomiting are common side effects of opioids administered for pain
      control. This double-blind, randomized, parallel-group study evaluated the anti
      emetic efficacy and tolerability of single intravenous (i.v.) doses of
      ondansetron 8 mg, ondansetron 16 mg and metoclopramide 10 mg in the treatment of
      opioid-induced emesis. Adult patients undergoing low emetogenic surgical
      procedures, using a standardized anaesthesia regimen were assessed for 24 h
      following administration of study anti-emetic to treat established post-surgical
      opioid-induced emesis. A total of 4511 patients were enrolled of whom 1366
      experienced opioid-induced emesis and received randomized study medication.
      Ondansetron 8 mg and 16 mg were significantly better than metoclopramide 10 mg (P
      < 0.05) for both complete control of emesis, complete control of nausea and other
      efficacy measures. There were no significant differences between the two
      ondansetron groups. All three treatments were well tolerated. In conclusion, this
      large, multicentre study demonstrates that ondansetron is more effective than
      metoclopramide in the treatment of opioid-induced emesis following administration
      of post-surgical opioids to control pain.

PMID- 10583350
TI  - A rational approach to the control of sedation in intensive care unit patients
      based on closed-loop control.
AB  - Optimal control of long-term sedation during therapy in the intensive care unit
      is difficult to achieve in a number of patients when based on commonly used
      clinical sedation scores alone. We therefore used the median frequency of the EEG
      power spectrum as a quantitative measure for closed-loop administration of
      propofol in 21 artificially ventilated patients (nine trauma, 12 non-trauma). The
      EEG setpoint was correlated with a clinical sedation score and defined such, that
      mechanical ventilation was tolerated. The sedative therapy was given for 31 +/-
      30 h. Non-trauma patients required sedation with an EEG median frequency between
      2 and 3 Hz (propofol consumption: 1.4 +/- 0.8 mg kg-1 h-1) and sedation seemed to
      follow some circadian patterns, whereas trauma patients needed significantly
      deeper sedation (EEG median frequency: 1-2 Hz; propofol consumption: 2.6 +/- 0.8
      mg kg-1 h-1). We conclude that the EEG closed-loop system could safely and
      reliably administer propofol to maintain a predetermined level of sedation for
      patients in intensive care unit over a protracted time.

PMID- 10583351
TI  - Prevention of post-operative nausea and vomiting with combined granisetron and
      droperidol in women undergoing thyroidectomy.
AB  - We have compared the efficacy and safety of combined granisetron and droperidol
      with each anti-emetic alone for preventing post-operative nausea and vomiting
      after thyroidectomy. In a prospective, randomized, double-blind study, 180 women
      received granisetron 40 micrograms kg-1, droperidol 20 micrograms kg-1, or
      granisetron 40 micrograms kg-1 plus droperidol 20 micrograms kg-1 (n = 60 of
      each) intravenously immediately before induction of anaesthesia. A standard
      general anaesthetic technique and post-operative analgesia were used. A complete
      response, defined as no post-operative nausea and vomiting and no need for
      another rescue anti-emetic, during the first 24 h after anaesthesia occurred in
      88%, 60% and 98% of patients who had received granisetron, droperidol and
      granisetron plus droperidol (P < 0.05; overall Fisher's exact probability test).
      No clinically important adverse events due to the drugs were observed in any of
      the groups. In summary, prophylactic use of combined granisetron and droperidol
      is more effective than each drug alone for the prevention of post-operative
      nausea and vomiting in female patients undergoing thyroidectomy.

PMID- 10583352
TI  - Effects of epidural anaesthesia on microcirculatory blood flow in free flaps in
      patients under general anaesthesia.
AB  - It has been suggested that epidural anaesthesia may increase blood flow in free
      flaps on the lower extremity. The objective of the present study was to test this
      hypothesis in 21 patients undergoing reconstructive surgery of the lower
      extremity with free muscle (n = 8), fasciocutaneous (n = 6) or musculocutaneous
      (n = 7) flaps. Microcirculatory blood flow was measured continuously with a
      multichannel laser Doppler flowmetry, both in muscle and skin of the free flap as
      well as in the intact skin and muscle on the same extremity. After completion of
      surgery, general anaesthesia was continued and the epidural block was induced by
      an injection of 2% lignocaine-hydrochloride into a pre-operatively inserted and
      tested epidural catheter. The epidural block caused no change in microcirculatory
      flow in the intact skin and muscle, however, it resulted in a marked decrease in
      microcirculatory blood flow in all the free flaps studied (20-30%; P < 0.05). The
      epidural block also caused a significant decrease in mean arterial blood
      pressure, from 85 (+/- 2.8) mmHg to 68 (+/- 2.8) mmHg (P < 0.01). It was
      concluded that epidural anaesthesia may decrease microcirculatory blood flow in
      free flaps on the lower extremity by diverting flow away from the flap to normal
      intact tissues (a steal phenomenon).

PMID- 10583353
TI  - The laryngeal mask airway in fresh cadavers versus paralysed anaesthetized
      patients: ease of insertion, airway sealing pressure, intracuff pressures and
      anatomic position.
AB  - We compared the performance of the size 5 laryngeal mask airway in 20 paralysed
      anaesthetized male patients and 20 male cadavers (6-24 h post-mortem). Groups
      were matched for height and weight. Airway sealing pressure, in vivo intracuff
      pressure and anatomical position (judged fibre-optically) were documented at zero
      volume and after each additional 10 mL up to 40 mL. All laryngeal mask airways
      were inserted at the first attempt and insertion times were similar. There were
      no differences in airway sealing pressure, in vivo intracuff pressure or fibre
      optic position between the groups. We conclude that the performance of the
      laryngeal mask airway is similar for fresh cadavers and paralysed anaesthetized
      patients. This may have implications for laryngeal mask airway research and
      training.

PMID- 10583354
TI  - No reduction in the sufentanil requirement of elderly patients undergoing
      ventilatory support in the medical intensive care unit.
AB  - The aim of the study was to test the hypothesis that the requirement of
      sufentanil is reduced in elderly patients when the opiate is primarily used to
      facilitate mechanical ventilation in a medical intensive care unit. A further aim
      was to study whether elderly patients developed withdrawal symptoms after
      discontinuing prolonged sufentanil administration. We have studied prospectively
      two groups of patients requiring mechanical ventilation for more than 96 h; group
      1 age < 60 years (n = 316 or 68%) and group 2 age > 70 years (n = 150 or 32%). In
      all patients sufentanil and midazolam were administered continuously in order to
      facilitate ventilatory support. After an initial intravenous bolus injection of
      sufentanil 3.0-8.0 micrograms kg-1, the dosage was adjusted to the patients needs
      (0.75-1.0 microgram-1 kg-1 h) using a modified Ramsey score by accepting between
      3b and 4a as the end point. The amount of sufentanil administered and side
      effects were recorded at 24-h intervals. Seventy-two hours following the start of
      sedation with sufentanil/midazolam the dose of sufentanil required for sedation
      increased significantly (P < 0.05) in both groups when compared with the first 24
      h. There was no statistical difference between the two groups in sufentanil
      requirement at any time during the study. This suggests that tachyphylaxis
      develops to a similar degree in patients in both age groups. In addition, weaning
      in the elderly was characterized by a similar degree of withdrawal-like symptoms
      suggesting that independent of age, there are similar receptor related reactions
      once the opiate is withdrawn.

PMID- 10583355
TI  - Comparison of intra-articular fentanyl and intra-articular bupivacaine for post
      operative pain relief after knee arthroscopy.
AB  - A randomized double-blinded study consisting of 107 patients was conducted to
      compare the effect on post-operative pain relief of intra-articular fentanyl and
      intra-articular bupivacaine after knee arthroscopy. The results showed that intra
      articular bupivacaine produced superior analgesia in the immediate post-operative
      period. At 2 h post-operatively, the intra-articular bupivacaine group had a mean
      pain score of 2.0 (standard deviation 2.1, P < 0.05) compared with the intra
      articular fentanyl group which had a mean pain score of 3.2 (standard deviation
      2.3, P < 0.05). After 2 h post-operatively, intra-articular bupivacaine and intra
      articular fentanyl had a similar effect on pain scores. The mean pain score 18 h
      post-operatively was 2.7 for the intra-articular bupivacaine group (standard
      deviation 2.2, P value 0.6) compared with the intra-articular fentanyl group
      which had a mean pain score of 2.8 (standard deviation 1.9, P value 0.6).

PMID- 10583356
TI  - Does aprotinin modify the effects of ischaemia-reperfusion on the myocardial
      performance of a blood perfused isolated rabbit heart?
AB  - Aprotinin has been reported to influence positively or negatively the process of
      ischaemia-reperfusion. However, it is a complex drug acting on platelets,
      neutrophils and coagulation, which may also have a direct effect by inhibiting
      intracellular proteases and free radical generation. The goal of this study was
      to determine the direct effects of aprotinin on the myocardial performances of an
      isolated blood perfused rabbit heart preparation after normothermic global
      ischaemia. Two groups of 10 hearts were studied. The control group (ischaemia)
      underwent 30 min of global normothermic ischaemia. In the aprotinin group,
      (aprotinin) 200 KUI mL-1 of aprotinin was added to the perfusate before
      ischaemia. Measurements were obtained at base-line, 10, 30 and 60 min after
      reperfusion. Normothermic ischaemia significantly decreased myocardial
      performance in both groups. After 60 min reperfusion, myocardial contractility
      significantly recovered in the aprotinin group compared with the ischaemia group.
      Aprotinin contributes significantly by limiting the consequences of ischaemia on
      myocardial performances. This effect may be due to a direct action of the drug
      because leucocytes and plasma proteins were removed in this preparation.

PMID- 10583357
TI  - Searching for a general anaesthesia protocol for rapid detoxification from
      opioids.
AB  - The technique for ultra rapid opioid detoxification is designed to shorten the
      detoxification period by precipitating withdrawal by the administration of opioid
      antagonists such as naloxone or naltrexone. This procedure is performed under
      deep sedation or general anaesthesia to ensure that the patient does not
      consciously experience the acute withdrawal phase. This strategy has aroused
      controversy regarding the risk of sedation or anaesthesia in this situation. In
      the present study, ultra rapid opioid detoxification was carried out in 12 opiate
      addicted patients by infusion of naloxone 4 mg for a period of 5 h using
      controlled ventilation during general anaesthesia, induced and maintained with
      midazolam, propofol and atracurium. Invasive cardiovascular and respiratory
      monitoring was performed, and withdrawal signs were evaluated using a graduated
      scale. Anaesthesia was maintained for another hour after the completion of the
      naloxone infusion. The validity of this anaesthesia protocol was confirmed by the
      relative lack of change in the patients' haemodynamic values associated with mild
      signs of withdrawal.

PMID- 10583358
TI  - Management of peri-operative pulmonary hypertension in a patient presenting for a
      portosystemic shunt.
AB  - We report the successful management of intra-operative pulmonary hypertension in
      a patient with mitral valve insufficiency and portal hypertension. A 48-year-old
      male with portal hypertension presented for a portosystemic shunt. Previously
      undiagnosed mitral valve insufficiency and pulmonary hypertension complicated his
      anaesthetic management. His intra-operative course was marked by systolic
      hypotension, pulmonary hypertension and a reduction in cardiac output. The use of
      nitric oxide in this patient reduced right ventricular afterload, increased
      cardiac output, without exacerbating pre-existing systolic hypotension.

PMID- 10583359
TI  - Thiamine for the treatment of nucleoside analogue-induced severe lactic acidosis.
AB  - Nucleoside analogue-induced lactic acidosis is an often fatal condition in
      patients with HIV. There is only one report of successful treatment with
      riboflavin. We describe a 30-year-old female with AIDS and nucleoside analogue
      induced lactic acidosis that exacerbated shortly after introducing total
      parenteral nutrition and reversed within hours after the addition of thiamine.
      Successful treatment of nucleoside analogue-induced lactic acidosis with a high
      dose of thiamine supports the hypothesis that vitamin deficiency is an important
      cofactor in the development of this rare and unpredictable condition in patients
      with HIV. We suggest that high dose B-vitamins should be given to any patient
      presenting with lactic acidosis under nucleoside analogue treatment.

PMID- 10583361
TI  - Pre-operative assessment: role of the anaesthetist as a peri-operative physician.

PMID- 10583360
TI  - Tropisetron or ondansetron for the prevention of post-operative nausea and
      vomiting (PONV)

PMID- 10583362
TI  - Correspondence.

PMID- 10583364
TI  - Isolation and characterization of Neurospora crassa nucleoside diphosphate kinase
      NDK-1.
AB  - We have previously reported that phosphorylation of a 15-kDa protein increased
      after blue-light irradiation in Neurospora crassa. In this study, the 15-kDa
      protein was purified using four columns; DEAE-cellulose, Blue-Sepharose, SP
      Sepharose and Mono Q. The 15-kDa protein was shown to be homologous with
      nucleoside diphosphate kinase by amino acid sequencing and was also shown to
      possess nucleoside diphosphate kinase activity. A gene encoding N. crassa
      nucleoside diphosphate kinase, ndk-1, was isolated from the mycelial cDNA and
      genomic libraries. The deduced amino acid sequence of NDK-1 was identical to that
      of the 15-kDa protein. Northern blot analysis suggested that WC-1 and WC-2, the
      key factors of blue-light signal transduction in N. crassa, did not regulate NDK
      1 at the transcriptional level. NDK-1 also showed rapid autophosphorylation
      activity and protein kinase activity against myelin basic protein with a Km value
      of 0.36 mM. These results suggest that NDK-1 acts as a signal transducer by
      phosphorylating proteins.

PMID- 10583363
TI  - Evolution of oligomeric proteins. The unusual case of a dimeric ribonuclease.
AB  - The model system made up of a monomeric and a dimeric ribonuclease of the
      pancreatic-type superfamily has recently attracted the attention of investigators
      interested in the evolution of oligomeric proteins. In this system, bovine
      pancreatic ribonuclease (RNase A) is the monomeric prototype, and bovine seminal
      ribonuclease (BS-RNase) is the dimeric counterpart. However, this evolutionary
      case is unusual, as BS-RNase is the only dimeric member of the whole large
      superfamily comprising more than 100 identified members from amphibia, aves,
      reptilia and mammalia. Furthermore, although the seminal-type RNase gene can be
      traced back to the divergence of the ruminants, it is expressed only in a single
      species (Bos taurus). These unusual findings are discussed, as well as previous
      hypotheses on the evolution of seminal RNase. Furthermore, a new 'minimalist'
      hypothesis is proposed, in line with basic principles of structural biology and
      molecular evolution.

PMID- 10583365
TI  - Biochemical properties of a minimal functional domain with ATP-binding activity
      of the NTPase/helicase of hepatitis C virus.
AB  - The RNA-stimulated nucleoside triphosphatase (NTPase) and helicase of hepatitis C
      virus (HCV) consists of three domains with highly conserved NTP binding motifs
      located in the first domain. The ATP-binding domain was obtained by limited
      proteolysis of a greater fragment of the HCV polyprotein, and it was purified to
      homogenity by column chromatography. The identity of the domain, comprising amino
      acids 1203 to 1364 of the HCV polyprotein, was confirmed by N- and C-terminal
      sequencing and by its capability to bind 5'-fluorosulfonylbenzoyladenosine
      (FSBA). The analyses of the kinetics of ATP binding revealed a single class of
      binding site with the Kd of 43.6 microM. The binding is saturable and dependent
      on Mn2+ or Mg2+ ions. Poly(A) and poly(dA) show interesting properties as
      regulators of the ATP-binding capacity of the domain. Polynucleotides bind to the
      domain and enhance its affinity for ATP. In addition, ATP enhances the affinity
      of the domain for the polynucleotides. Different compounds, which are known to
      interact with nucleotide binding sites of various classes of enzymes, were tested
      for their ability to inhibit the binding of ATP to the domain. Of the compounds
      tested, two agents behaved as inhibitors: paclitaxel, which inhibits the ATP
      binding competitively (IC50 = 22 microM), and trifluoperazine, which inhibits the
      ATP binding by a noncompetitive mechanism (IC50 = 98 microM). Kinetic experiments
      with the NTPase/helicase indicate that both compounds inhibit the NTPase activity
      of the holoenzyme by interacting with its ATP-binding domain.

PMID- 10583367
TI  - Internal regulation of ATP turnover, glycolysis and oxidative phosphorylation in
      rat hepatocytes.
AB  - Previously [Ainscow, E.K. & Brand, M.D. (1999) Eur. J. Biochem. 263, 671-685],
      top-down control analysis was used to describe the control pattern of energy
      metabolism in rat hepatocytes. The system was divided into nine reaction blocks
      (glycogen breakdown, glucose release, glycolysis, lactate production, NADH
      oxidation, pyruvate oxidation, mitochondrial proton leak, mitochondrial
      phosphorylation and ATP consumption) linked by five intermediates (intracellular
      glucose 6-phosphate, pyruvate and ATP levels, cytoplasmic NADH/NAD ratio and
      mitochondrial membrane potential). The kinetic responses (elasticities) of
      reaction blocks to intermediates were determined and used to calculate control
      coefficients. In the present paper, these elasticities and control coefficients
      are used to quantify the internal regulatory pathways within the cell. Flux
      control coefficients were partitioned to give partial flux control coefficients.
      These describe how strongly one block of reactions controls the flux through
      another via its effects on the concentration of a particular intermediate. Most
      flux control coefficients were the sum of positive and negative partial effects
      acting through different intermediates; these partial effects could be large
      compared to the final control strength. An important result was the breakdown of
      the way ATP consumption controlled respiration: changes in ATP level were more
      important than changes in mitochondrial membrane potential in stimulating oxygen
      consumption when ATP consumption increased. The partial internal response
      coefficients to changes in each intermediate were also calculated; they describe
      how steady state concentrations of intermediates are maintained. Increases in
      mitochondrial membrane potential were opposed mostly by decreased supply, whereas
      increases in glucose-6-phosphate, NADH/NAD and pyruvate were opposed mostly by
      increased consumption. Increases in ATP were opposed significantly by both
      decreased supply and increased consumption.

PMID- 10583366
TI  - Specificity of starch synthase isoforms from potato.
AB  - In higher plants several isoforms of starch synthase contribute to the extension
      of glucan chains in the synthesis of starch. Different isoforms are responsible
      for the synthesis of essentially linear amylose chains and branched, amylopectin
      chains. The activity of granule-bound starch synthase I from potato has been
      compared with that of starch synthase II from potato following expression of both
      isoforms in Escherichia coli. Significant differences in their activities are
      apparent which may be important in determining their specificities in vivo. These
      differences include affinities for ADPglucose and glucan substrates, activation
      by amylopectin, response to citrate, thermosensitivity and the processivity of
      glucan chain extension. To define regions of the isoforms determining these
      characteristic traits, chimeric proteins have been produced by expression in E.
      coli. These experiments reveal that the C-terminal region of granule-bound starch
      synthase I confers most of the specific properties of this isoform, except its
      processive elongation of glucan chains. This region of granule-bound starch
      synthase I is distinct from the C-terminal region of other starch synthases. The
      specific properties it confers may be important in defining the specificity of
      granule-bound starch synthase I in producing amylose in vivo.

PMID- 10583368
TI  - alpha-fetoprotein causes apoptosis in tumor cells via a pathway independent of
      CD95, TNFR1 and TNFR2 through activation of caspase-3-like proteases.
AB  - alpha-Fetoprotein (AFP) is an oncoembryonal protein with multiple cell growth
      regulating, differentiating and immunosuppressive activities. Previous studies
      have shown that treatment of tumor cells in vitro with 1-10 microM AFP produces
      significant suppression of tumor cell growth by inducing dose-dependent
      cytotoxicity, but the molecular mechanisms underlying these AFP functions are
      obscure. Here, we show that AFP cytotoxicity is closely related to apoptosis, as
      shown by cell morphology, nuclear DNA fragmentation and caspase-3-like activity
      resulting in cleavage of poly(ADP-ribose) polymerase. Apoptosis was significantly
      inhibited by a CPP32 family protease inhibitor whereas a general caspase
      inhibitor had no inhibitory effect, showing some enhancement of AFP-mediated cell
      death. Using fluorogenic caspase substrates, we found that caspase-3-like
      proteases were activated as early as 4 h after treatment of Raji cells with 15
      microM AFP, whereas caspase-1, caspase-8, and caspase-9-like activity was not
      detected during the time interval 0.5-17 h. AFP treatment of Raji cells increased
      Bcl-2 protein, showing that AFP-induced apoptosis is not explained by
      downregulation of the Bcl-2 gene. This also suggests that AFP operates downstream
      of the Bcl-2-sensitive step. AFP notably decreased basal levels of soluble and
      membrane-bound Fas ligand. Incubation of AFP-sensitive tumor cells (HepG2, Raji)
      with neutralizing anti-Fas, anti-tumor necrosis factor receptor (TNFR)1 or anti
      TNFR2 mAb did not prevent AFP-induced apoptosis, demonstrating its independence
      of Fas-dependent and TNFR-dependent signaling. In addition, it was found that
      cells resistant to TNF-induced (Raji) or Fas-induced (MCF-7) apoptosis are,
      nevertheless, sensitive to AFP-mediated cell death. In contrast, cells sensitive
      to Fas-mediated cell death (Jurkat) are completely resistant to AFP. Taken as a
      whole, our data demonstrate that: (a) AFP induces apoptosis in tumor cells
      independently of Fas/Fas ligand or TNFR/TNF signaling pathways, and (b) AFP
      mediated cell death involves activation of the effector caspase-3-like proteases,
      but is independent of upstream activation of the initiator caspase-1, caspase-8,
      and caspase-9-like proteases.

PMID- 10583369
TI  - Capsular polysaccharide produced by the thermophilic cyanobacterium Mastigocladus
      laminosus. Structural study of an undecasaccharide obtained by lithium
      degradation.
AB  - The capsular polysaccharide produced by the thermophilic cyanobacterium
      Mastigocladus laminosus has been subjected to a specific degradation with lithium
      in ethylenediamine. The released undecasaccharide attached to one unit of
      tetrahydroxycyclopentanecarboxylic acid has been characterized by a combination
      of 2D nuclear magnetic resonance spectroscopy, mass spectrometry, monosaccharidic
      composition and linkage analyses. From the overlap of the structure of this
      oligosaccharide with previously identified di-, tri- and pentasaccharides
      released by mild acid hydrolysis, the capsular polysaccharide was deduced to have
      a pentadecasaccharide repeating unit with the following structure:

PMID- 10583370
TI  - Reaction of neuronal nitric oxide synthase with the nitric oxide spin-trapping
      agent, iron complexed with N-dithiocarboxysarcosine.
AB  - A water-soluble iron complex with N-dithiocarboxysarcosine (Fe-DTCS) has been
      developed as an ESR spin-trapping agent for NO and successfully applied to ESR
      imaging of endogenous NO production in mice. We attempted to measure NO produced
      by purified neuronal NO synthase (nNOS) by this method, but could not detect NO.
      We speculated that Fe-DTCS inhibits NOS activity. In fact, it markedly inhibited
      NOS activity with an IC50 value of 9.7 +/- 0.7 microM in the citrulline-formation
      assay. DTCS alone did not inhibit the activity. An iron complex with N-methyl-D
      glucamine dithiocarbamate, a similar spin-trapping agent for NO, also inhibited
      the activity, with an IC50 value of 25.1 +/- 2.9 microM. Fe-DTCS suppressed
      cytochrome c and ferricyanide reductase activities of nNOS, and markedly
      increased nNOS-mediated NADPH oxidation. Concomitantly, it accelerated oxygen
      consumption caused by activated nNOS. These results suggest that the ESR spin
      trapping agent Fe-DTCS inhibits NO synthesis by interfering with the
      physiological electron flow from NADPH to nNOS heme iron.

PMID- 10583371
TI  - Lectinochemical characterization of a GalNAc and multi-Galbeta1-->4GlcNAc
      reactive lectin from Wistaria sinensis seeds.
AB  - An agglutinin that has high affinity for GalNAcbeta1-->, was isolated from seeds
      of Wistaria sinensis by adsorption to immobilized mild acid-treated hog gastric
      mucin on Sepharose 4B matrix and elution with aqueous 0.2 M lactose. The binding
      property of this lectin was characterized by quantitative precipitin assay (QPA)
      and by inhibition of biotinylated lectin-glycan interaction. Of the 37 glycoforms
      tested by QPA, this agglutinin reacted best with a GalNAcbeta1-->4 containing
      glycoprotein (GP) [Tamm-Horsfall Sd(a+) GP]; a Galbeta1-->4GlcNAc containing GP
      (human blood group precursor glycoprotein from ovarian cyst fluid and asialo
      human alpha1-acid GP) and a GalNAcalpha1-->3GalNAc containing GP (asialo bird
      nest GP), but poorly or not at all with most sialic acid containing
      glycoproteins. Among the oligosaccharides tested, GalNAcalpha1-->3GalNAcbeta1-
      >3Galalpha1-->4Galbeta 1-->4Glc (Fp) was the most active ligand. It was as active
      as GalNAc and two to 11 times more active than Tn cluster mixtures, Galbeta1-->
      3/4GlcNAc (I/II), GalNAcalpha1-->3(L-Fucalpha1-->2)Gal (Ah), Galbeta1-->4Glc (L),
      Galbeta1-->3GalNAc (T) and Galalpha1--> 3Galalpha-->methyl (B). Of the
      monosaccharides and their glycosides tested, p-nitrophenyl betaGalNAc was the
      best inhibitor; it was approximately 1.7 and 2.5 times more potent than its
      corresponding alpha anomer and GalNAc (or Fp), respectively. GalNAc was 53.3
      times more active than Gal. From the present observations, it can be concluded
      that the Wistaria agglutinin (WSA) binds to the C-3, C-4 and C-6 positions of
      GalNAc and Gal residues; the N-acetyl group at C-2 enhances its binding
      dramatically. The combining site of WSA for GalNAc related ligands is most likely
      of a shallow type, able to recognize both alpha and beta anomers of GalNAc. Gal
      ligands must be Galbeta1-->3/4GlcNAc related, in which subterminal beta1-->3/4
      GlcNAc contributes significantly to binding; hydrophobicity is important for
      binding of the beta anomer of Gal. The decreasing order of the affinity of WSA
      for mammalian structural carbohydrate units is Fp >/= multi-II > monomeric II >/=
      Tn, I and Ah >/= E and L > T > Gal.

PMID- 10583372
TI  - In vitro translation in a cell-free system from Trypanosoma brucei yields
      glycosylated and glycosylphosphatidylinositol-anchored proteins.
AB  - African trypanosomes escape many cellular and unspecific immune reactions by the
      expression of a protective barrier formed from a repertoire of several hundred
      genes encoding immunologically distinct variant surface glycoproteins (VSGs). All
      mature VSGs are glycosylphosphatidylionositol-anchored and N-glycosylated. To
      study trypanosome-specific post-translational modifications of VSG, a cell-free
      system capable of in vitro translation, translocation into the rough endoplasmic
      reticulum, N-glycosylation and glycosylphosphatidylinositol-anchor addition was
      established using lysates of the bloodstream form of Trypanosoma brucei.
      Monitoring protein synthesis by [35S]methionine incorporation, labeled protein
      bands were readily detected by fluorography following SDS/PAGE. Appearance of
      these bands increased during a time-course of 45 min and was sensitive to
      cycloheximide but not chloramphenicol treatment. Efficiency of this system, in
      terms of incorporation of radiolabeled amino acids into newly formed proteins, is
      similar to reticulocyte lysates. The system does not, however, allow initiation
      of protein synthesis. Depending on the clone used, immunoprecipitation revealed
      one or two newly formed VSG bands. Upon digestion with N-glycosidase F these
      bands resulted in a single band of a lower apparent molecular mass, indicating
      that newly synthesized VSG underwent translocation and glycosylation in the cell
      free system. Biotinylation of VSG and a combination of precipitation with
      immobilized avidin and detection of VSG using antibodies specific for clones and
      cross-reacting determinants revealed that newly formed VSG contained the
      glycosylphosphatidylinositol anchor.

PMID- 10583373
TI  - Binding to human dipeptidyl peptidase IV by adenosine deaminase and antibodies
      that inhibit ligand binding involves overlapping, discontinuous sites on a
      predicted beta propeller domain.
AB  - Dipeptidyl peptidase IV (DPPIV) is an atypical serine protease that modifies the
      biological activities of certain chemokines and neuropeptides. In addition, human
      DPPIV, also known as the T-cell activation antigen CD26, binds adenosine
      deaminase (ADA) to the T-cell surface, thus protecting the T-cell from adenosine
      mediated inhibition of proliferation. Mutations were engineered into DPPIV (five
      point, 16 single point and six deletion mutations) to examine the binding of ADA
      and 19 monoclonal antibodies. Deletions of C-terminal residues from the 738
      residue extracellular portion of DPPIV showed that the 214 residues C-terminal to
      Ser552 were not required for ADA binding and that peptidase activity could be
      ablated by deletion of 20 residues from the C-terminus. Point mutations at either
      of two locations, Leu294 and Val341, ablated ADA binding. Binding by six anti
      DPPIV antibodies that inhibited ADA binding was found to require Leu340 to Arg343
      and Thr440/Lys441 but not the 214 residues C-terminal to Ser552. The 13 other
      antibodies studied bound to a truncated DPPIV consisting of amino acids 1-356.
      Therefore, the binding sites on DPPIV of ADA and antibodies that inhibit ADA
      binding are discontinuous and overlapping. Moreover, the 47 and 97 residue
      spacing of amino acids in these binding sites concords with their location on a
      beta propeller fold consisting of repeated beta sheets of about 50 amino acids.

PMID- 10583374
TI  - Molecular cloning of the Lon protease gene from Thermus thermophilus HB8 and
      characterization of its gene product.
AB  - The gene encoding Lon protease was isolated from an extreme thermophile, Thermus
      thermophilus HB8. Sequence analysis demonstrated that the T. thermophilus Lon
      protease gene (TT-lon) contains a protein-coding sequence consisting of 2385 bp
      which is approximately 56% homologous to the Escherichia coli counterpart. As
      expected, the G/C content of TT-lon was 68%, which is significantly higher than
      that of the E. coli lon gene (52% G/C). The amino acid sequence of T.
      thermophilus Lon protease (TT-Lon) predicted from the nucleotide sequence
      contained several unique sequences conserved in other Lon proteases: (a) a
      cysteine residue at the position just before the putative ATP-binding domain; (b)
      motif A and B sequences required for composition of the ATP-binding domain; and
      (c) a serine residue at the proteolytic active site. Expression of TT-lon under
      the control of the T7 promoter in E. coli produced an 89-kDa protein with a yield
      of approximately 5 mg.L-1. Recombinant TT-Lon (rTT-Lon) was purified to
      homogeneity by sequential column chromatography. The peptidase activity of rTT
      Lon was activated by ATP and alpha-casein. rTT-Lon cleaved succinyl-phenylalanyl
      leucyl-phenylalanyl-methoxynaphthylamide much more efficiently than succinyl
      alanyl-alanyl-phenylalanyl-methoxynaphthylamide, whereas both peptides were
      cleaved with comparable efficiencies by E. coli Lon. These results suggest that
      there is a difference between TT-Lon and E. coli Lon in substrate specificity.
      rTT-Lon most effectively cleaved substrate peptides at 70 degrees C, which was
      significantly higher than the optimal temperature (37 degrees C) for E. coli Lon.
      Together, these results indicate that the TT-lon gene isolated from T.
      thermophilus HB8 actually encodes an ATP-dependent thermostable protease Lon.

PMID- 10583375
TI  - Azide binding to the trinuclear copper center in laccase and ascorbate oxidase.
AB  - Azide binding to the blue copper oxidases laccase and ascorbate oxidase (AO) was
      investigated by electron paramagnetic resonance (EPR) and pulsed electron-nuclear
      double resonance (ENDOR) spectroscopies. As the laccase : azide molar ratio
      decreases from 1:1 to 1:7, the intensity of the type 2 (T2) Cu(II) EPR signal
      decreases and a signal at g approximately 1.9 appears. Temperature and microwave
      power dependent EPR measurements showed that this signal has a relatively short
      relaxation time and is therefore observed only below 40 K. A g approximately 1.97
      signal, with similar saturation characteristics was found in the AO : azide (1:7)
      sample. The g < 2 signals in both proteins are assigned to an S = 1 dipolar
      coupled Cu(II) pair whereby the azide binding disrupts the anti-ferromagnetic
      coupling of the type 3 (T3) Cu(II) pair. Analysis of the position of the g < 2
      signals suggests that the distance between the dipolar coupled Cu(II) pair is
      shorter in laccase than in AO. The proximity of T2 Cu(II) to the S = 1 Cu(II)
      pair enhances its relaxation rate, reducing its signal intensity relative to that
      of native protein. The disruption of the T3 anti-ferromagnetic coupling occurs
      only in part of the protein molecules, and in the remaining part a different
      azide binding mode is observed. The 130 K EPR spectra of AO and laccase with
      azide (1:7) exhibit, in addition to an unperturbed T2 Cu(II) signal, new features
      in the g parallel region that are attributed to a perturbed T2 in protein
      molecules where the anti-ferromagnetic coupling of T3 has not been disrupted.
      While these features are also apparent in the AO : azide sample at 10 K, they are
      absent in the EPR spectra of the laccase : azide sample measured in the range of
      6-90 K. Moreover, pulsed ENDOR measurements carried out at 4.2 K on the latter
      exhibited only a reduction in the intensity of the 20 MHz peak of the 14N
      histidine coordinated to the T2 Cu(II) but did not resolve any significant
      changes that could indicate azide binding to this ion. The lack of T2 Cu(II)
      signal perturbation below 90 K in laccase may be due to temperature dependence of
      the coupling within the trinuclear : azide complex.

PMID- 10583376
TI  - Solution structure of a new hypothalamic neuropeptide, human hypocretin-2/orexin
      B.
AB  - Orexin-A and orexin-B (also called hypocretin-1 and hypocretin-2, respectively)
      are novel hypothalamic neuropeptides encoded by a single mRNA transcript; they
      stimulate food intake. We have determined the three-dimensional solution
      structure of human hypocretin-2/orexin-B using two-dimensional 1H-NMR data and
      dynamical simulated annealing calculations. On the basis of NOEs, 3JHNalpha
      coupling constants and hydrogen-deuterium exchange rates together with chemical
      shift indices, human hypocretin-2/orexin-B was deduced to consist of two alpha
      helices connected with a short linker in both H2O and 30% trifluoroethanol
      solutions. The helical axis of helix I is oriented about 60-80 degrees relative
      to helix II. Hybrid distance geometry and simulated-annealing protocols were used
      to generate an ensemble of 30 structures with no constraint violations greater
      than 0.03 nm for distances and 3 degrees for angles. In addition, human
      hypocretin-2/orexin-B shares a similar secondary-structural motif with human
      neuropeptide Y. This result can form the basis for further study on ligand
      receptor recognition of human orexin receptors.

PMID- 10583377
TI  - 2'-carboxy-D-arabitinol 1-phosphate protects ribulose 1, 5-bisphosphate
      carboxylase/oxygenase against proteolytic breakdown.
AB  - Trypsin-catalysed cleavage of purified ribulose 1,5-bisphosphate
      carboxylase/oxygenase (Rubisco) and the resultant irreversible loss of
      carboxylase activity were prevented by prior incubation with the naturally
      occurring nocturnal Rubisco inhibitor 2'-carboxy-D-arabitinol 1-phosphate (CA1P),
      as well as with ribulose 1,5-bisphosphate (RuBP), Mg2+ and CO2. CA1P also
      protected Rubisco from loss of activity caused by carboxypeptidase A. When
      similar experiments were carried out using soluble chloroplast proteases, CA1P
      was again able to protect Rubisco against proteolytic degradation and the
      consequent irreversible loss of catalytic activity. Thus, CA1P prevents the
      proteolytic breakdown of Rubisco by endogenous and exogenous proteases. In this
      way, CA1P may affect the amounts of Rubisco protein available for photosynthetic
      CO2 assimilation. Rubisco turnover (in the presence of RuBP, Mg2+ and CO2) may
      confer similar protection against proteases in the light.

PMID- 10583378
TI  - Characterization of two bifunctional Arabdopsis thaliana genes coding for
      mitochondrial and cytosolic forms of valyl-tRNA synthetase and threonyl-tRNA
      synthetase by alternative use of two in-frame AUGs.
AB  - We characterized two Arabidopsis thaliana cDNAs coding for class I valyl-tRNA
      synthetase and class II threonyl-tRNA synthetase. The proteins display
      characteristics of cytosolic enzymes, yet possess an N-terminal extension
      relative to their prokaryotic homologs. The proximal part of the N-terminal
      extension is a mitochondrial-targeting signal. Through transient expression of
      GFP fusions in tobacco cells, we demonstrated that both genes encode the
      cytosolic and mitochondrial forms of the enzymes by alternative use of two in
      frame initiation codons. A long, mitochondrial form of the enzyme is translated
      from a first initiation codon at reduced levels because of a poor sequence
      context and a shorter, cytosolic form is translated from a second in-phase AUG,
      which is in a better context for translation initiation. Primer extension
      experiments revealed several transcript ends mapping upstream of the first AUG
      and between the two AUGs. Distal to the mitochondrial transit peptide both valyl
      tRNA synthetase and threonyl tRNA synthetase possess an NH2-appended domain
      compared with their prokaryotic counterparts. This domain's amphiphilic helix is
      conserved between yeast and A. thaliana valyl-tRNA synthetase, suggesting an
      important role in translation. Based on the high structural similarities between
      yeast and A. thaliana valyl-tRNA synthetase, we propose that the acquisition of
      bifunctionality of valyl-tRNA synthetase predates the divergence of these two
      organisms.

PMID- 10583379
TI  - Anti-proliferative effect of two novel palmitoyl-carnitine analogs, selective
      inhibitors of protein kinase C conventional isoenzymes.
AB  - Previous studies have shown that palmitoyl-carnitine is an anti-proliferative
      agent and a protein kinase C inhibitor. Two new palmitoyl-carnitine analogs were
      synthesized by replacing the ester bond with a metabolically more stable ether
      bond. An LD50 value in the nM range was found in anti-proliferative assays using
      HL-60 cells and was dependent on the alkyl-chain length. The inhibitory action of
      these water-soluble compounds on protein kinase C in vitro was greatly increased
      with respect to palmitoyl-carnitine and was dependent on the length of the alkyl
      chain. Its effect was mediated by an increase in the enzyme's requirement for
      phosphatidylserine. Inhibition of the in situ phosphorylation of a physiological
      platelet protein kinase C substrate and of phorbol ester-induced differentiation
      of HL-60 cells was also observed. Finally, to test for isoenzyme selectivity,
      several human recombinant protein kinase C isoforms were used. Only the Ca2+
      dependent classic protein kinase Cs (alpha, betaIota, betaIotaIota and gamma)
      were inhibited by these compounds, yet the activities of casein kinase I,
      Ca2+/calmodulin-dependent kinase and cAMP-dependent protein kinase were
      unaffected. Thus, these novel inhibitors appear to be both protein kinase C and
      isozyme selective. They may be useful in assessing the individual roles of
      protein kinase C isoforms in cell proliferation and tumor development and may be
      rational candidates for anti-neoplasic drug design.

PMID- 10583380
TI  - Extensive regulation compromises the extent to which DNA gyrase controls DNA
      supercoiling and growth rate of Escherichia coli.
AB  - As DNA gyrase is the only enzyme to supercoil DNA actively, we address here the
      question of whether it does play the expected dominant role in controlling the
      level of DNA supercoiling and growth rate in Escherichia coli. We modulated the
      expression of DNA gyrase around its wild-type level, and measured the effect on
      plasmid supercoiling and growth rate. As both the activity and the transcription
      rate of DNA gyrase are sensitive to DNA supercoiling we distinguish two types of
      control (with control defined as the percentage change observed on a 1%
      modulation of a parameter). The first type of control, here named inherent
      control, quantifies the effect of a sustained modulation of the transcription
      rate of gyrase. At its wild-type expression level this inherent control exerted
      by DNA gyrase on growth rate was very low, i.e. c mu/gyrase = 0.05 - 0.00, as was
      the inherent control on DNA supercoiling, c aLK/gyrase = 0.2. The second type of
      control, here named global control, quantifies the effect of a change in gyrase
      activity whilst allowing the cell to respond by readjusting gyrase transcription.
      Both types of control are linked via the sensitivity of gyrase transcription to
      DNA supercoiling, as determined from the inherent control by gyrase of the gyrase
      promoter activity using a chromosomal gyrB:lacZ fusion. As expected, the latter
      control was negative, but small, i.e. c gyr promoter/gyrase=-0.3. The global
      control by gyrase of active linking number was 0.1. These results show that
      although gyrase is an essential enzyme it does not have a high control, on either
      growth rate or DNA supercoiling. Homeostatic regulation of physiological DNA
      structure appears to dominate. At low degrees of DNA supercoiling, the control by
      DNA gyrase and by the other topoisomerases is much stronger.

PMID- 10583381
TI  - Activation of human neutrophils by a synthetic anti-microbial peptide,
      KLKLLLLLKLK-NH2, via cell surface calreticulin.
AB  - We previously reported that a synthetic anti-bacterial peptide, KLKLLLLLKLK-NH2
      (L5), showed significant chemotherapeutic activity in methicillin-resistant
      Staphylococcus aureus-infected mice, and its ability to activate human
      neutrophils was related to its chemotherapeutic activity. In this study, we found
      that activation of neutrophils by L5 was inhibited by pertussis toxin, suggesting
      that GTP-binding protein (G-protein) participates in this process. We isolated an
      L5-binding protein, which turned out to be human calreticulin, with a molecular
      mass of 60 kDa from neutrophil membranes. From experiments using an anti
      calreticulin antibody, we proposed that calreticulin is partly localized on the
      surface of neutrophils, and L5-bound calreticulin transmits a signal into cells
      via G-protein to activate neutrophils to generate superoxide anion.

PMID- 10583382
TI  - Different mechanisms of protection against apoptosis by valproate and Li+.
AB  - Acute treatment with valproate and Li+ was found to protect cultured cerebellar
      granule cells against apoptosis induced by low K+ (5 mM). Because the protection
      was unaffected by MK801 (N-methyl-D-aspartate receptor inhibitor), an increase in
      glutamate release cannot be responsible for the observed neuroprotection. Insulin
      also protects against low-K+-induced apoptosis of cerebellar granule cells. This
      protection is totally dependent on LY294002 (a phosphatidylinositol 3-kinase
      inhibitor). These results suggest a role for phosphatidylinositol 3-kinase in the
      neuroprotection induced by insulin. Likewise, and in contrast with the results
      observed with Li+, the protection induced by valproate is also dependent on
      insulin and LY294002. Moreover, valproate (a branched-chain fatty acid) does not
      change the plasma membrane microviscosity under physiological conditions. These
      results suggest that valproate protects against low-K+-induced apoptosis by
      acting in the phosphatidylinositol 3-kinase/protein kinase B pathway. The
      protection by Li+ is independent of this transduction pathway.

PMID- 10583383
TI  - Enovin, a member of the glial cell-line-derived neurotrophic factor (GDNF) family
      with growth promoting activity on neuronal cells. Existence and tissue-specific
      expression of different splice variants.
AB  - Glial cell-line-derived neurotrophic factor (GDNF), neurturin and persephin are
      neurotrophic factors involved in neuroneal differentiation, development and
      maintenance. They act on different types of neuroneal cells and signal through a
      receptor complex composed of a specific ligand-binding subunit of the GDNF family
      receptor alpha (GFRalpha) family together with a common signaling partner, the
      cRET protein tyrosine kinase. We describe the molecular cloning, expression,
      chromosomal localization and functional characterization of enovin, a fourth GDNF
      family member almost identical to the recently described artemin. We show the
      occurence in most tissues of several differently spliced mRNA variants for
      enovin, of which only two are able to translate into functional enovin protein.
      Some tissues seem to express only nonfunctional transcripts. These observations
      may underlie a complex transcriptional regulation pattern. Enovin mRNA expression
      is detectable in all adult and fetal human tissues examined, but expression
      levels are highest in peripheral tissues including prostate, placenta, pancreas,
      heart and kidney. This tissue distribution pattern is in accordance with that of
      GFRalpha-3, which here is shown to be the preferred ligand-binding receptor for
      enovin (Kd = 3.1 nM). The human enovin gene is localized on chromosome 1, region
      p31.3-p32. In vitro, enovin stimulates neurite outgrowth and counteracts taxol
      induced neurotoxicity in staurosporine-differentiated SH-SY5Y human neuroblastoma
      cells. The peripheral expression pattern of enovin and its receptor together with
      its effects on neuroneal cells suggest that enovin might be useful for the
      treatment of neurodegenerative diseases in general and peripheral neuropathies in
      particular.

PMID- 10583385
TI  - Activation of the rod G-protein Gt by the thrombin receptor (PAR1) expressed in
      Sf9 cells.
AB  - Functional coupling of the human thrombin receptor PAR1 (protease-activated
      receptor 1) with the retinal rod G-protein transducin (Gt, a member of the Gi
      family) was studied in a reconstituted system of membranes from Sf9 cells
      expressing the thrombin receptor and purified Gt from bovine rod outer segments.
      TRAP6-agonist-activated PAR1 interacts productively with the distant G-protein.
      Agonist-dependent Gt activation was measured using a real-time fluorimetric
      GTP[S]-binding assay and membranes from Sf9 cells. To characterize nucleotide
      exchange catalysis by PAR1, we analyzed dependence on nucleotides, temperature
      and pH. Activation was inhibited by low GDP concentrations (IC50 = 5.2 +/- 1.5
      microM at 5 microM GTP[S]), indicating that receptor-Gt coupling, followed by
      instantaneous GDP release, is rate limiting under the conditions (25 degrees C).
      Arrhenius plots of the temperature dependence reflect an apparent Ea of 60 +/-
      3.5 kJ.mol-1. Evaluation of the pH/rate profiles of Gt activation indicates that
      the activating conformation of the receptor is determined by protonation of a
      titratable group with an apparent pKa of 6.4. This supports the idea that the
      active state of agonist-bound PAR1 depends on forced protonation, indicating
      possible analogies to the scheme established for rhodopsin.

PMID- 10583384
TI  - The NAD-linked aromatic alpha-hydroxy acid dehydrogenase from Trypanosoma cruzi.
      A new member of the cytosolic malate dehydrogenases group without malate
      dehydrogenase activity.
AB  - Trypanosoma cruzi, the protozoan parasite causing Chagas disease, contains a
      novel aromatic alpha-hydroxy acid dehydrogenase. This enzyme is responsible,
      together with tyrosine aminotransferase, for the catabolism of aromatic amino
      acids, which leads to the excretion of aromatic lactate derivatives into the
      culture medium. The gene encoding the aromatic alpha-hydroxy acid dehydrogenase
      has been cloned through a combined approach using screening of an expression
      genomic library with antibodies, peptide sequencing and PCR amplification. Its
      sequence shows high similarity to the cytosolic malate dehydrogenases. However,
      the enzyme has no malate dehydrogenase activity. The gene seems to be present in
      a single copy per haploid genome and is differentially expressed throughout the
      parasite's life cycle, the highest levels being found in the insect forms of T.
      cruzi. The purified recombinant enzyme, expressed in Escherichia coli, was unable
      to reduce oxaloacetate and had kinetic constants similar to those of the natural
      aromatic alpha-hydroxy acid dehydrogenase. Sequence comparisons suggest that the
      aromatic alpha-hydroxy acid dehydrogenase derives from a cytosolic malate
      dehydrogenase no longer present in the parasite, made redundant by the presence
      of a glycosomal malate dehydrogenase as a member of a shuttle device involving
      the mitochondrial isoenzyme.

PMID- 10583386
TI  - Generation of epitope-specific antibodies to rat GHBP in the sheep using an
      interspecies switching strategy involving site-directed mutagenesis of ovine
      GHBP.
AB  - Site-directed antibodies to the growth hormone receptor could be potentially
      useful as growth hormone mimics but, in previous attempts, we found that antisera
      generated using peptides derived from growth hormone receptor sequences failed to
      recognize the intact protein. As an alternative approach to this problem, we have
      now adopted a strategy of epitope-switching between rat and ovine growth hormone
      receptors to produce rat epitopes in the correct structural context. Using site
      directed mutagenesis, we altered the two dominant linear epitopes in the ovine
      growth hormone binding protein to the analogous sequences in rat growth hormone
      binding protein. Site A, between Thr28 and Leu34, is equivalent to epitope 1 in
      ovine growth hormone binding protein and site B, between Ser121 and Asp124,
      corresponds to epitope 5. The wild-type ovine growth hormone binding protein and
      the two mutant proteins were bacterially expressed, refolded and, following
      purification by metal-chelate affinity chromatography, used to raise antisera in
      sheep. We showed using RIA, in which wild-type ovine growth hormone binding
      protein acted as a competitor for the binding of rat growth hormone binding
      protein, that only the site A mutant protein elicited a specific anti-rat growth
      hormone binding protein response. This was confirmed in subsequent RIA studies
      using the antiserum to the site A mutant protein in which only peptides
      corresponding to the site A sequences in mutant ovine growth hormone binding
      protein and rat growth hormone binding protein, but not that in wild-type ovine
      growth hormone binding protein, were able to act as competitors for rat growth
      hormone binding protein. Antibodies specific for rat growth hormone binding
      protein could be separated from the antiserum to the site A mutant protein by
      means of affinity chromatography using immobilized wild-type ovine growth hormone
      binding protein to remove antibodies which cross-reacted with the ovine protein.
      The work lays the foundations for further studies in which the biological effects
      of these antibody fractions will be investigated and demonstrates an approach
      with general applicability in the production of antibodies directed towards
      specific epitopes on protein molecules.

PMID- 10583387
TI  - Identification and characterization of a melanocyte-specific novel 65-kDa
      peripheral membrane protein.
AB  - In order to study proteins of the melanosome, we developed a panel of antisera
      against various protein fractions of melanosomes from B16 melanoma cells. An
      antiserum raised against a Triton X-100 insoluble fraction of melanosomes
      recognized a 65-kDa protein in melanocytes from mice homozygous for the buff
      mutation, but not in their wild type counterparts. Further studies were conducted
      using a specific, second generation antiserum raised against the purified
      protein. The protein was also detected in melanocytes cultured from albino mice,
      but absent in cultured mouse cell lines not of melanocyte origin. Density
      gradient centrifugation of subcellular organelles and indirect immunofluorescent
      cell staining, indicated that the protein was associated with melanosomes and
      vesicles. The protein on intact organelles could be made soluble using sodium
      carbonate, and digested with proteases in the absence of detergent suggesting
      that it was a peripheral membrane protein localized on the cytosolic face of
      organelle membranes. Metabolic labelling of cells and N-glycosidase F digestion
      of cell extracts indicated that the protein was not N-glycosylated. Based on its
      intracellular localization and biochemical defects in the buff mouse, a potential
      role has been suggested for the 65-kDa protein in intracellular membrane
      trafficking.

PMID- 10583388
TI  - Both G-type domains of protein S are required for the high-affinity interaction
      with C4b-binding protein.
AB  - Anticoagulant protein S interacts with the complement regulatory protein C4b
      binding protein (C4BP) via its sex-hormone-binding globulin (SHB6)-like region,
      which contains two globular (G) domains. Similar G domains are found in Gas6, a
      protein homologous to protein S, which is not known to bind C4BP or to have any
      anticoagulant activity. To determine the relative importance of the two G domains
      in protein S for C4BP protein binding, three recombinant protein S chimeras were
      produced having either of the two globular domains, or the whole SHB6-like
      globulin region, replaced by corresponding parts from Gas6. The chimeras were
      tested for binding to immobilized C4BP using surface-plasmon-resonance technology
      and microtiter plate-based assays. In both systems, chimeras containing either
      only globular domains G1 or G2 from protein S were found to bind C4BP. Binding
      was stimulated by Ca2+ in a manner similar to that found for wild-type protein S.
      The affinities for C4BP of both chimeras containing individual G domains from
      protein S, were lower than that of wild-type protein S. Chimera II, containing
      the G1 domain from protein S, consistently bound C4BP more efficiently than
      chimera I, which had the protein S-derived G2 domain. The chimera containing the
      whole SHB6-like globulin region from Gas6 interacted considerably more weakly
      with C4BP. Our results demonstrate that both G domains of protein S are involved
      in the interaction between protein S and C4BP and that full affinity binding is
      dependent on contributions from both domains.

PMID- 10583389
TI  - Extracellular calcium stimulates DNA synthesis in synergism with zinc, insulin
      and insulin-like growth factor I in fibroblasts.
AB  - In serum-starved mouse NIH 3T3 fibroblasts cultured in 1.8 mM Ca2+-containing
      medium, addition of 0.75-2 mM extra Ca2+ stimulated DNA synthesis in synergism
      with zinc (15-60 microM), insulin and insulin-like growth factor I. Extra Ca2+
      stimulated phosphorylation/activation of p42/p44 mitogen-activated protein
      kinases by an initially (10 min) zinc-independent mechanism; however, insulin,
      and particularly zinc, significantly prolonged Ca2+-induced mitogen-activated
      protein kinase phosphorylation. In addition, extra Ca2+ activated p70 S6 kinase
      by a zinc-dependent mechanism and enhanced the stimulatory effect of zinc on
      choline kinase activity. Insulin and insulin-like growth factor I also commonly
      increased both p70 S6 kinase and choline kinase activities. In support of the
      role of the choline kinase product phosphocholine in the mediation of mitogenic
      Ca2+ effects, cotreatments with the choline kinase substrate choline (250 microM)
      and the choline kinase inhibitor hemicholinium-3 (2 mM) enhanced and inhibited,
      respectively, the combined stimulatory effect of extra Ca2+ (3.8 mM total) and
      zinc on DNA synthesis. In various human skin fibroblast lines, 1-2 mM extra Ca2+
      also stimulated DNA synthesis in synergism with zinc and insulin. The results
      show that in various fibroblast cultures, high concentrations of extracellular
      Ca2+ can collaborate with zinc and certain growth factors to stimulate DNA
      synthesis. Considering the high concentration of extracellular Ca2+ in the dermal
      layer, Ca2+ may promote fibroblast growth during wound healing in concert with
      zinc, insulin growth factor-I insulin, and perhaps other growth factors.

PMID- 10583390
TI  - Isolation, characterization and immunolocalization of phosphorylcholine
      substituted glycolipids in developmental stages of Caenorhabditis elegans.
AB  - Caenorhabditis elegans displays three neutral glycosphingolipids with structural
      homology to glycosphingolipids from the porcine nematode parasite, Ascaris suum.
      The present findings extend the degree of structural conservation between the two
      nematode species to glycosphingolipids with a phosphodiester substitution. Using
      a combination of hydrofluoric acid pretreatment, immunochemical characterization
      and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry,
      three zwitterionic, phosphorylcholine-substituted glycosphingolipids could be
      identified in the neutral glycolipid fraction of C. elegans. The components were
      isolated as their zwitterionic, phosphorylcholine-substituted, pyridylaminated
      oligosaccharides by HPLC. Structural analysis was performed using hydrofluoric
      acid treatment, partial acid hydrolysis, methylation analysis, gas chromatography
      mass spectrometry, cleavage with exoglycosidases and matrix-assisted laser
      desorption/ionization time-of-flight mass spectrometry. Their chemical structures
      are proposed as: component Nz1, GalNAc(beta1-4)[phosphorylcholine]GlcNAc(beta1
      3)Man(beta1-4)Glc-cera mide; component Nz2, Gal(alpha1-3)GalNAc(beta1
      4)[phosphorylcholine]-GlcNAc(beta1-3)Man(be ta1-4)Glc-ceramide; and component
      Nz3, Gal(beta1-3)- Gal(alpha1-3)GalNAc(beta1-4)[phosphorylcholine]GlcNAc(beta1
      3)Man(bet a1-4)Glc-ceramide. The oligosaccharide core is characteristic of the
      biosynthetic arthro-carbohydrate series of protostomial glycosphingolipids. The
      ceramide moiety was specified by a d17 : 1 sphingoid-base with iso-branching and
      anteiso-branching, and 2-hydroxy, saturated fatty acids as represented by
      docosanoic and tetracosanoic acids. Analysis of the spatial and temporal
      expression of the phosphorylcholine epitope, during embryonic and postembryonic
      development, showed it to be localized predominantly in seam cells and basement
      membranes, respectively. In early embryonic ontogenesis the phosphorylcholine
      epitope was only lipid bound, while in late embryonic and postembryonic
      development this epitope was both lipid bound and protein bound.

PMID- 10583392
TI  - The chimeric peptide [Lys(-2)-Arg(-1)]-sarafotoxin-S6b, composed of the
      endothelin pro-sequence and sarafotoxin, retains the salt-bridge staple between
      Arg(-1) and Asp8 previously observed in [Lys(-2)-Arg(-1)]-endothelin.
      Implications of this salt-bridge in the contractile activity and the oxidative
      folding reaction.
AB  - The chimeric peptide [Lys(-2)-Arg(-1)]-sarafotoxin-S6b (KR-SRTb) designed from
      the Lys-2-Arg-1 dipeptide of the endothelin pro-sequence and the sarafotoxin-S6b
      sequence was synthesized. Its contractile activity was found to be decreased
      markedly when compared with that of the parent SRTb. In contrast, the extension
      by the Lys-Arg dipeptide was found to increase the formation of the native
      disulfide isomer (82/18 versus 96/4) when the reaction was carried out in the
      presence of redox reagents. The solution structure of KR-SRTb was determined by
      NMR as a function of pH. In the carboxylic acid state, the structure consists of
      the cystine-stabilized alpha-helical motif, with the alpha-helical part spanning
      residues 9-15, and of an unstructured C-terminal tail. In the carboxylate state,
      the structure is characterized by a salt-bridge between Arg(-1) and Asp8, which
      we identified previously in the [Lys(-2)-Arg(-1)]-endothelin-1 peptide (KR-ET-1).
      The fact that this salt-bridge is commonly observed in KR-SRTb and KR-ET-1,
      despite the 33% sequence difference between the corresponding parental peptides,
      highlights the remarkable adaptability of the Lys-Arg extension for the formation
      of a special salt-bridge. As a consequence, this salt-bridge, which does not
      depend on either the 4-7 sequence of the loop or the C-terminal sequence, appears
      to be particularly well suited to improve the stability of the cystine-stabilized
      alpha-helical motif. Therefore, because of its high yield in the native disulfide
      arrangement and its high permissiveness for sequence mutation in the 4-7 loop,
      such a stabilized cystine-stabilized alpha-helical motif could be a valuable
      scaffold for the presentation of a library of constrained short peptides.

PMID- 10583391
TI  - Implications of hemolin glycosylation and Ca2+-binding on homophilic and cellular
      interactions.
AB  - Insects are useful models for the study of innate immune mechanisms because of
      their lack of antibodies and receptors involved in adaptive immune response.
      Nevertheless, hemolin cloned from moths is a soluble and membrane associated Ig
      related molecule that is up-regulated during immune response [Lanz-Mendoza, H. &
      Faye, I. (1999) Dev. Comp. Immunol. 23, 359-374]. The hemolin monomeric form has
      four, pair-wise, interacting Ig-domains, forming a strongly bent horseshoe
      structure [Su, X.-D., Gastinel, L.N., Vaughn, D.E., Faye, I., Poon, P. &
      Bjorkman, P. (1998) Science 281, 991-995]. To elucidate the nature of its
      homophilic and cellular interactions, the glycosylation and Ca2+-binding
      properties of hemolin were investigated. We used Hyalophora cecropia hemolin
      isolated from hemolymph of bacteria-injected pupae, or produced as a recombinant
      protein in a baculovirus/insect cell system. Both types of hemolin contain N
      acetylglucosamine and probably sialic acid, as indicated by peptide:N-glycosidase
      F and neuraminidase digestion and glycosylation detection by Western-blotting
      analysis. The N-acetylglucosamine residues on hemolin were confirmed with the use
      of specific lectins. In addition, hemolin was shown to specifically bind calcium
      when spotted onto nitrocellulose and treated as for 45Ca2+ autoradiography.
      Earlier studies demonstrated that hemolin can bind to hemocytes and this was
      tested for its dependence on calcium and carbohydrates, using hemolin-coated
      fluorescent microspheres. A greater level of attachment of microspheres occurred
      in the presence of calcium than if calcium was absent. Furthermore, this binding
      was inhibited by EGTA and N-acetylglucosamine or N-acetylneuraminic acid,
      implying that carbohydrates and calcium are crucial factors in homophilic binding
      and cell-adhesion events mediated by this Ig-superfamily molecule.

PMID- 10583393
TI  - Proteome mapping, mass spectrometric sequencing and reverse transcription-PCR for
      characterization of the sulfate starvation-induced response in Pseudomonas
      aeruginosa PAO1.
AB  - A set of proteins induced in Pseudomonas aeruginosa PAO1 during growth in the
      absence of sulfate was characterized by differential two-dimensional
      electrophoresis and MS. Thirteen proteins were found to be induced de novo or
      upregulated in P. aeruginosa grown in a succinate/salts medium with sodium
      cyclohexylsulfamate as the sole sulfur source. Protein spots excised from the two
      dimensional gels were analysed by N-terminal Edman sequencing and MS sequencing
      (MS/MS) of internal protein fragments. The coding sequences for 11 of these
      proteins were unambiguously identified in the P. aeruginosa genome sequence.
      Expression of these genes was investigated by reverse transcription-PCR, which
      confirmed that repression in the presence of sulfate was acting at a
      transcriptional level. Three classes of sulfur-regulated proteins were found. The
      first class (five proteins) were high-affinity periplasmic solute-binding
      proteins with apparent specificity for sulfate and sulfonates. A second class
      included enzymes involved in sulfonate and sulfate ester metabolism (three
      proteins). The remaining three proteins appeared to be part of a more general
      stress response, and included two antioxidant proteins and a putative
      lipoprotein. This study demonstrates the power of the proteomics approach for
      direct correlation of the responses of an organism to an environmental stimulus
      with the genetic structures responsible for that response, and the application of
      reverse transcription-PCR significantly increases the conclusions that can be
      drawn from the proteomic study.

PMID- 10583394
TI  - Analysis of natural and synthetic sphingomyelins using high-performance thin
      layer chromatography.
AB  - The chromatographic behaviour of molecular species of sphingomyelin on HPTLC was
      investigated. Sphingomyelin gave a double band pattern on HPTLC plates developed
      using chloroform/methanol/acetic acid/water (25 : 15 : 4 : 2, v/v) or
      chloroform/methanol/water (25 : 10 : 1.1, v/v). HPTLC analysis of acyl chain
      defined sphingomyelins showed that the Rf values increased linearly with the
      length of the N-linked acyl chain. A double-banded pattern was therefore seen for
      natural sphingomyelins with a bimodal fatty acid composition. Racemic
      sphingomyelins also gave a double band pattern on HPTLC, where the lower band
      represented the Derythro and the upper band the Lthreo isomer. We also showed
      that Derythro-N-16:0-dihydrosphingomyelin migrated faster on HPTLC than Derythro
      N-16:0-sphingomyelin. The upper and lower band sphingomyelins from two different
      cell lines (human skin fibroblasts and baby hamster kidney cells) were separately
      scraped off the HPTLC plates and the fatty acid and long-chain base profiles were
      studied using GC-MS. The lower bands contained short-chain fatty acids and most
      of the fatty acids in the upper bands were long. The predominant long-chain base
      was sphingosine, which was found in both upper and lower bands, but sphinganine
      was found only in the upper bands. To conclude, there are at least three possible
      reasons for the sphingomyelin double bands on HPTLC; acyl chain length, long
      chain base composition and stereochemistry. These reasons might sometimes overlap
      and, therefore, HPTLC alone is insufficient for complete analysis of the
      molecular species of sphingomyelin.

PMID- 10583395
TI  - The CCKB/gastrin receptor is coupled to the regulation of enzyme secretion,
      protein synthesis and p70 S6 kinase activity in acinar cells from ElasCCKB
      transgenic mice.
AB  - In order to determine which physiological functions can be regulated by the
      pancreatic CCKB/gastrin receptor, studies were carried out on pancreatic acini
      from mice expressing transgenic CCKB/gastrin receptors in the exocrine pancreas
      (ElasCCKB mice). Acini were stimulated by sulfated gastrin in the presence of SR
      27897 (1.8 microM), blocking endogenous CCKA receptors. After 30 min incubation
      with gastrin, the secretion of chymotrypsinogen and amylase showed superimposable
      monophasic dose-response curves. Enzyme secretion was detectable and maximal at
      100 pM and 1 nM of gastrin, respectively. No increase in chymotrypsinogen and
      amylase mRNAs was detected for doses of gastrin which specifically occupy the
      CCKB/gastrin receptor. In contrast, gastrin stimulated total protein synthesis in
      isolated acini from ElasCCKB mice. [35S]Methionine incorporation into total
      proteins was increased dose-dependently to a maximum for 30 pM gastrin and
      inhibited with higher doses (> 300 pM). Gastrin stimulated p70 S6 kinase activity
      for concentrations ranging from 10 pM to 1 nM. Gastrin-stimulated p70 S6 kinase
      activity and protein synthesis were blocked by rapamycin and wortmannin.
      Therefore, in ElasCCKB mice acinar cells, the CCKB/gastrin receptor mediates
      enzyme release and protein synthesis. However, a more efficient coupling of the
      CCKB/gastrin receptor to protein synthesis than to enzyme secretion was
      demonstrated. CCKB/gastrin receptor-stimulated protein synthesis likely results
      from an enhancement of mRNA translation and involves phosphatidyl inositol 3
      kinase and p70 S6 kinase.

PMID- 10583397
TI  - The antimicrobial peptide trichogin and its interaction with phospholipid
      membranes.
AB  - The interaction of the antimicrobial peptide trichogin GA IV with phospholipid
      bilayers has been studied. A series of analogs of trichogin was synthesized in
      which the nitroxide spin label, 4-amino-4-carboxy-2,2,6,6-tetramethylpiperidino-1
      oxyl (TOAC), replaced one of the three alpha-aminoisobutyric acid (Aib) residues
      in the sequence. These modified peptides were used to assess the location of
      different residues of the peptide in a phospholipid bilayer composed of egg
      phosphatidylcholine containing 0.4 mol% of a fluorescently labelled phospholipid.
      We demonstrate that the substitution of Aib residues with TOAC does not alter the
      manner in which the peptide affects membrane curvature or induces vesicle
      leakage. The proximity of the nitroxide group on the peptide to the 4,4-difluoro
      4-bora-3a,4a-diaza-S-indacene (BODIPY) fluorophore attached to the phospholipid
      was estimated from the extent of quenching of the fluorescence. By this criterion
      it was concluded that the peptide penetrates into the bilayer and that Aib4 is
      the most deeply inserted of the Aib residues. The results suggest that the helix
      axis of the peptide is oriented along the plane of the membrane. All of the
      peptides were shown to raise the bilayer to the hexagonal phase transition
      temperature of dipalmitoleoylphosphatidylethanolamine, indicating that they
      promote positive membrane curvature. This is a property observed with peptides
      that do not penetrate deeply into the bilayer or are oriented along the bilayer
      normal. We also demonstrate trichogin-promoted leakage of the aqueous contents of
      liposomes. These results indicate that the peptides cause bilayer
      destabilization. The extent of leakage induced by trichogin is very sensitive to
      the peptide to lipid ratio over a narrow range.

PMID- 10583396
TI  - Analysis of lissencephaly-causing LIS1 mutations.
AB  - Mutations in the LIS1 gene may result in severe abnormalities of brain cortical
      layering known as lissencephaly. Most lissencephaly-causing LIS1 mutations are
      deletions that encompass the entire gene, therefore the mechanism of the disease
      is regarded as haploinsufficiency. So far, 13 different intragenic mutations have
      been reported: one point mutation, H149R; deletion of exon 9, which results in
      deleted acids Delta301-334; deletion of exon 4, which results in deleted amino
      acids Delta40-64; 10 mutations resulting in truncated proteins and one predicted
      to result in extra amino acids. We studied the consequences of the point
      mutation, deletion mutation and one of the reported truncations. In order to
      study LIS1 structure function, we introduced an additional point mutation and
      other truncations in different regions of the protein. The consequences of these
      mutations to protein folding were studied by gel filtration, sucrose density
      gradient centrifugation and measuring resistance to trypsin cleavage. On the
      basis of our results, we suggest that all truncation mutations and lissencephaly
      causing point mutations or internal deletion result in a reduction in the amount
      of correctly folded LIS1 protein.

PMID- 10583398
TI  - The self-association of protein SV-IV and its possible functional implications.
AB  - The protein SV-IV, a major protein secreted from the rat seminal vesicle
      epithelium, is a basic protein with immunomodulatory, anti-inflammatory, and
      procoagulant activity. Predictions suggested that this protein is very flexible,
      with its three tyrosyl residues presumably located in water-exposed segments of
      the primary structure. The solution behaviour of the protein was investigated by
      two types of spectroscopic techniques. Modifications of the spectral
      characteristics of tyrosyl residues induced by changes of protein concentration
      were demonstrated by absorption and fluorescence experiments. In addition,
      secondary structure rearrangements associated with a possible self-association
      equilibrium were highlighted by far-UV CD spectra. The equilibrium, confirmed by
      chromatographic techniques, appears to control some biological properties of the
      protein.

PMID- 10583399
TI  - Ca2+/calmodulin-dependent protein kinase II isoenzymes gamma and delta are both
      present in H+/K+-ATPase-containing rabbit gastric tubulovesicles.
AB  - Ca2+/calmodulin-dependent protein kinase II is thought to participate in M3
      muscarinic receptor-mediated acid secretion in gastric parietal cells. During
      acid secretion tubulovesicles carrying H+/K+-ATPase fuse with the apical
      membrane. We localized Ca2+/calmodulin-dependent protein kinase II from highly
      purified rabbit gastric tubulovesicles using Ca2+/calmodulin-dependent protein
      kinase II isoform-specific antibodies, in vitro phosphorylation and
      pharmacological inhibition of Ca2+/calmodulin-dependent protein kinase II
      activity by the potent Ca2+/calmodulin-dependent protein kinase II inhibitor KN
      62. The presence of Ca2+/calmodulin-dependent protein kinase II in tubulovesicles
      was shown by immunoblot detection of both Ca2+/calmodulin-dependent protein
      kinase II-gamma (54 kDa) and Ca2+/calmodulin-dependent protein kinase II-delta
      (56.5 kDa). The immunoprecipitated Ca2+/calmodulin-dependent protein kinase II
      from tubulovesicles showed Ca2+/calmodulin-dependent protein kinase activity by
      phosphorylating autocamtide-II, a specific synthetic Ca2+/calmodulin-dependent
      protein kinase II substrate. KN-62 inhibited the in vitro autophosphorylation of
      tubulovesicle-associated Ca2+/calmodulin-dependent protein kinase II (IC50 = 11
      nM). During the search for potential Ca2+/calmodulin-dependent protein kinase II
      substrates we identified different proteins associated with tubulovesicles, such
      as synaptophysin and beta-tubulin immunoreactivity, which were identified using
      specific antibodies. These targets are known to participate in intracellular
      membrane traffic. Ca2+/calmodulin-dependent protein kinase II is thought to play
      an important role in regulating tubulovesicular motor activity and therefore in
      acid secretion.

PMID- 10583400
TI  - Prediction of protein (domain) structural classes based on amino-acid index.
AB  - A protein (domain) is usually classified into one of the following four
      structural classes: all-alpha, all-beta, alpha/beta and alpha + beta. In this
      paper, a new formulation is proposed to predict the structural class of a protein
      (domain) from its primary sequence. Instead of the amino-acid composition used
      widely in the previous structural class prediction work, the auto-correlation
      functions based on the profile of amino-acid index along the primary sequence of
      the query protein (domain) are used for the structural class prediction.
      Consequently, the overall predictive accuracy is remarkably improved. For the
      same training database consisting of 359 proteins (domains) and the same
      component-coupled algorithm [Chou, K.C. & Maggiora, G.M. (1998) Protein Eng. 11,
      523-538], the overall predictive accuracy of the new method for the jackknife
      test is 5-7% higher than the accuracy based only on the amino-acid composition.
      The overall predictive accuracy finally obtained for the jackknife test is as
      high as 90.5%, implying that a significant improvement has been achieved by
      making full use of the information contained in the primary sequence for the
      class prediction. This improvement depends on the size of the training database,
      the auto-correlation functions selected and the amino-acid index used. We have
      found that the amino-acid index proposed by Oobatake and Ooi, i.e. the average
      nonbonded energy per residue, leads to the optimal predictive result in the case
      for the database sets studied in this paper. This study may be considered as an
      alternative step towards making the structural class prediction more practical.

PMID- 10583403
TI  - Atlantic salmon (Salmo salar L.) skin contains a novel kininogen and another
      cysteine proteinase inhibitor.
AB  - We describe the purification and characterization of two novel cysteine
      proteinase inhibitors found in Atlantic salmon skin. One of these, salmon
      kininogen, has a molecular mass of 52 kDa as determined by matrix-assisted laser
      desorption/ionization time-of-flight MS, is multiply charged with pI values of
      4.0, 4.2 and 4.6 and shows homology to kininogens including the bradykinin motif.
      The other, salarin, has a molecular weight of 43 kDa, a pI of 5.1 and shows weak
      homology to cysteine proteinases. Both proteins are N- and O-glycosylated and
      inhibit papain and ficin but not trypsin.

PMID- 10583402
TI  - The role of cysteine residues in structure and enzyme activity of a maize beta
      glucosidase.
AB  - The maize Zm-p60.1 gene encodes a beta-glucosidase that can release active
      cytokinins from their storage forms, cytokinin-O-glucosides. Mature catalytically
      active Zm-p60.1 is a homodimer containing five cysteine residues per a subunit.
      Their role was studied by mutating them to alanine (A), serine (S), arginine (R)
      or aspartic acid (D) using site-directed mutagenesis, and subsequent heterologous
      expression in Escherichia coli. All substitutions of C205 and C211 resulted in
      decreased formation and/or stability of the homodimer, manifested as accumulation
      of high levels of monomer in the bacterial expression system. Examination of urea
      and glutathione-induced dissociation patterns of the homodimer to the monomers,
      HPLC profiles of hydrolytic fragments of reduced and oxidized forms, and a
      homology-based three-dimensional structural model revealed that an intramolecular
      disulfide bridge formed between C205 and C211 within the subunits stabilized the
      quaternary structure of the enzyme. Mutating C52 to R produced a monomeric enzyme
      protein, too. No detectable effects on homodimer formation were apparent in C170
      and C479 mutants. Given the Km values for C170A/S mutants were equal to that for
      the wild-type enzyme, C170 cannot participate in enzyme-substrate interactions.
      Possible indirect effects of C170A/S mutations on catalytic activity of the
      enzyme were inferred from slight decreases in the apparent catalytic activity,
      k'cat. C170 is located on a hydrophobic side of an alpha-helix packed against
      hydrophobic amino-acid residues of beta-strand 4, indicating participation of
      C170 in stabilization of a (beta/alpha)8 barrel structure in the enzyme. In
      C479A/D/R/S mutants, Km and k'cat were influenced more significantly suggesting a
      role for C479 in enzyme catalytic action.

PMID- 10583401
TI  - Production and activation of recombinant hK2 with propeptide mutations resulting
      in high expression levels.
AB  - Human glandular kallikrein 2 (hK2) is a serine protease expressed mainly by the
      prostate gland with 80% identity in primary structure to prostate specific
      antigen (PSA). hK2 has proven to be a useful marker of prostate cancer which can
      be used in combination with PSA to better discriminate between prostate cancer
      and benign prostate hyperplasia. The studies on hK2 have been hampered by its
      very low phyciological levels (6 microgram.mL-1), its close similarity to PSA,
      and the low expression levels obtained using recombinant procedures to produce
      hK2 (0.7 mg.L-1). We have now generated propeptide mutations of hK2 which can be
      used to isolate stable, inactive prohK2 mutants. Compared with wild-type hK2,
      expression of the propeptide hK2 mutants increases the expression levels up to 15
      40-fold giving 10-30 mg hK2.L-1. These results indicate that the low expression
      levels of wild-type hK2 are related to the activation or autoactivation of the
      wild-type enzyme and the instability of the active protease in cell culture and
      possibly also in tissue. The purified mutant hK2 may be activated by either
      enterokinase or factor Xa to generate an enzyme for use in functional studies
      with the characteristics of the original wild-type protein. Further, the stable
      inactive mutant hK2 protein may be used for immunizations to generate novel
      monoclonal antibodies, used as standard material for clinical assays or in
      crystallization studies where large quantities of protein are required.

PMID- 10583404
TI  - Impact of amino acids 22-27 of Rho-subfamily GTPases on glucosylation by the
      large clostridial cytotoxins TcsL-1522, TcdB-1470 and TcdB-8864.
AB  - Here we report data describing some principles of the interaction between small
      GTP-binding proteins and large Clostridial cytotoxins (LCTs). Our investigation
      was based on the differential glucosylation of Rac1 versus RhoA by LCTs TcsL
      1522, TcdB-1470 and TcdB-8864. Chimeric RhoA/Rac1 proteins and GTPases mutated at
      defined regions or single amino acids were used as substrates. Starting with
      chimeric Rac/Rho proteins we demonstrated that proteins containing the N-terminal
      73 amino acids of Rac1 (but not those of RhoA) were efficiently glucosylated.
      Within this stretch, three regions differ significantly in Rac1 and RhoA. Regions
      containing amino acids 41-45 and 50-54 had no effect on toxin induced
      glucosylation, whereas amino acids 22-27 had a drastic impact on the potential of
      all three toxins to covalently modify the GTPases. Point mutations K25T of RhoA
      (numbering according to Rac1) and K27A of Cdc42 significantly increased
      glucosylation by the cytotoxins; introduction of lysines at the equivalent
      positions of Rac1 hindered modification. Our experiments demonstrate the
      influence of this charged residue on GTPase-LCT interactions. Amino acids 22-27
      are part of the transition between the alpha1-helix to the switch I region of
      small GTP-binding proteins; both are known structures for specificity
      determination of the interactions with physiologic partners. Comparing these
      structures with data from our investigation we suggest that TcsL-1522, TcdB-1470
      and TcdB-8864 mimic aspects of the physiologic interactions of small GTP-binding
      proteins.

PMID- 10583405
TI  - Circular dichroism and fluorescence spectroscopic properties of the major core
      protein of feline immunodeficiency virus and its tryptophan mutants. Assignment
      of the individual contribution of the aromatic sidechains.
AB  - The gene coding for the major capsid protein of feline immunodeficiency virus
      (FIV) has been cloned into the expression vector pQE60, which allows protein
      purification by affinity chromatography on a nitrilotriacetic acid/Ni/agarose
      column. The gene was expressed in Escherichia coli and the resultant soluble
      protein (FIV-rp24) purified to electrophoretic homogeneity. The amino-acid
      composition of the recombinant protein is almost identical to that predicted from
      the DNA sequence. This protein has two tryptophan residues at positions 40 and
      126 that have been replaced by phenylalanine by site-directed mutagenesis to
      obtain two single mutants and a double mutant. Circular dichroism and
      fluorescence spectroscopy were employed to study the structural features of FIV
      rp24 protein and its tryptophan mutants. The analysis of the CD spectra indicated
      that alpha-helix is the major secondary structural element (48-52%) and that the
      overall three-dimensional structure is not modified by the mutations. The
      fluorescence emission spectra showed that both tryptophan residues occupy a
      highly hydrophobic environment. Moreover, the different tyrosine fluorescence
      intensities of wild-type and mutant proteins are indicative of the existence of
      resonance energy transfer processes to nearby tryptophan. The individual
      contributions of each tryptophan residue to the spectroscopic properties of the
      wild-type protein were obtained from the spectra of all these proteins. Thermal
      denaturation studies indicate that the two tryptophan residues do not contribute
      equally to the stabilization of the three-dimensional structure.

PMID- 10583406
TI  - Molecular characterization of the Caenorhabditis elegans Rho GDP-dissociation
      inhibitor.
AB  - GDP-dissociation inhibitors (GDIs) form one of the classes of regulatory proteins
      that modulate the cycling of the Ras superfamily of GTPases between active GTP
      bound and inactive GDP-bound states. We report here the characterization of the
      Caenorhabditis elegans RhoGDI (CeRhoGDI) as part of our investigations into Rho
      GTPase signalling pathways that are involved in nematode development. CeRhoGDI is
      a 23-kDa protein that is localized predominantly in the cytosol. CeRhoGDI
      interacts only with the lipid-modified forms of C. elegans Rho-GTPases, CeRhoA,
      CeRac1 and Cdc42Ce, in vitro and is able to solubilize the membrane-bound forms
      of these GTPases. CeRhoGDI recognizes the GTPases in both GTP- and GDP-bound
      forms; hence it inhibits both the guanine-nucleotide dissociation and GTP
      hydrolysis activities. The inhibitory activity towards the GTP-bound GTPases is
      weak compared with that towards GDP-bound GTPases. CeRhoGDI is expressed
      throughout development and is highly expressed in marginal and vulval epithelial
      cells, in sperm cells and spicules. Taken together, our results suggest that
      CeRhoGDI may be involved in specific morphogenetic events mediated by the C.
      elegans Rho-GTPases.

PMID- 10583407
TI  - Interactions of Alzheimer amyloid-beta peptides with glycosaminoglycans effects
      on fibril nucleation and growth.
AB  - Proteoglycans and their constituent glycosaminoglycans are associated with all
      amyloid deposits and may be involved in the amyloidogenic pathway. In Alzheimer's
      disease, plaques are composed of the amyloid-beta peptide and are associated with
      at least four different proteoglycans. Using CD spectroscopy, fluorescence
      spectroscopy and electron microscopy, we examined glycosaminoglycan interaction
      with the amyloid-beta peptides 1-40 (Abeta40) and 1-42 (Abeta42) to determine the
      effects on peptide conformation and fibril formation. Monomeric amyloid-beta
      peptides in trifluoroethanol, when diluted in aqueous buffer, undergo a slow
      random to amyloidogenic beta sheet transition. In the presence of heparin,
      heparan sulfate, keratan sulfate or chondroitin sulfates, this transition was
      accelerated with Abeta42 rapidly adopting a beta-sheet conformation. This was
      accompanied by the appearance of well-defined amyloid fibrils indicating an
      enhanced nucleation of Abeta42. Incubation of preformed Abeta42 fibrils with
      glycosaminoglycans resulted in extensive lateral aggregation and precipitation of
      the fibrils. The glycosaminoglycans differed in their relative activities with
      the chondroitin sulfates producing the most pronounced effects. The less
      amyloidogenic Abeta40 isoform did not show an immediate structural transition
      that was dependent upon the shielding effect by the phosphate counter ion.
      Removal or substitution of phosphate resulted in similar glycosaminoglycan
      induced conformational and aggregation changes. These findings clearly
      demonstrate that glycosaminoglycans act at the earliest stage of fibril
      formation, namely amyloid-beta nucleation, and are not simply involved in the
      lateral aggregation of preformed fibrils or nonspecific adhesion to plaques. The
      identification of a structure-activity relationship between amyloid-beta and the
      different glycosaminoglycans, as well as the condition dependence for
      glycosaminoglycan binding, are important for the successful development and
      evaluation of glycosaminoglycan-specific therapeutic interventions.

PMID- 10583408
TI  - Chicken cystatin stimulates nitric oxide release from interferon-gamma-activated
      mouse peritoneal macrophages via cytokine synthesis.
AB  - Cystatins are natural tight-binding, reversible inhibitors of cysteine proteases.
      We have shown that cystatins also stimulate nitric oxide (NO) production by
      interferon-gamma-activated mouse peritoneal macrophages [Verdot, L., Lalmanach,
      G., Vercruysse, V., Hartman, S., Lucius, R., Hoebeke, J., Gauthier F. & Vray, B.
      (1996) J. Biol. Chem. 271, 28077-28081]. The present study was undertaken to
      further document this new function. Macrophages activated with interferon-gamma
      and then stimulated with interferon-gamma plus chicken cystatin generated
      increased amounts of NO in comparison with macrophages only activated with
      interferon-gamma. Interferon-gamma-activated macrophages must be incubated with
      chicken cystatin for at least 8 h to upregulate NO production. NO induction was
      due to increased inducible nitric oxide synthase protein synthesis. Macrophages
      incubated with chicken cystatin alone or with interferon-gamma plus chicken
      cystatin produced increased amounts of both tumor necrosis factor alpha and
      interleukin 10. The addition of recombinant murine tumor necrosis factor alpha
      alone or in combination with recombinant murine interleukin-10 mimicked the
      effect of chicken cystatin. The addition of neutralizing anti-(tumor necrosis
      factor alpha) antibodies reduced sharply NO production by chicken
      cystatin/interferon-gamma-activated mouse peritoneal macrophages. Taken together,
      these data suggest that chicken cystatin induces the synthesis of tumor necrosis
      factor alpha and interleukin 10. In turn, these two cytokines stimulate the
      production of NO by interferon-gamma-activated macrophages. The findings point to
      a new relationship between cystatins, cytokines, inflammation and the immune
      response.

PMID- 10583410
TI  - Effect of modified nucleotides on Escherichia coli tRNAGlu structure and on its
      aminoacylation by glutamyl-tRNA synthetase. Predominant and distinct roles of the
      mnm5 and s2 modifications of U34.
AB  - Overproducing Escherichia coli tRNAGlu in its homologous host results in the
      presence of several distinctly modified forms of this molecule that we name
      modivariants. The predominant tRNAGlu modivariant in wild-type E. coli contains
      five modified nucleosides: Psi13, mnm5s2U34, m2A37, T54 and Psi55. Four other
      overproduced modivariants differ from it by, respectively, either the presence of
      an additional Psi, or the presence of s2U34, or the lack of A37 methylation
      combined with either s2U34 or U34. Chemical probing reveals that the anticodon
      loop of the predominant modivariant is less reactive to the probes than that of
      the four others. Furthermore, the modivariant with neither mnm5s2U34 nor m2A37
      has additional perturbations in the D- and T-arms and in the variable region. The
      lack of a 2-thio group in nucleoside 34, which is mnm5s2U in the predominant
      tRNAGlu modivariant, decreases by 520-fold the specificity of E. coli glutamyl
      tRNA synthetase for tRNAGlu in the aminoacylation reaction, showing that this
      thio group is the identity element in the modified wobble nucleotide of E. coli
      tRNAGlu. The modified nucleosides content also influences the recognition of ATP
      and glutamate by this enzyme, and in this case also, the predominant modivariant
      is the one that allows the best specificity for these two substrates. These
      structural and kinetic properties of tRNAGlu modivariants indicate that the
      modification system of tRNAGlu optimizes the stability of tRNAGlu and its action
      as cofactor of the glutamyl-tRNA synthetase for the recognition of glutamate and
      ATP.

PMID- 10583409
TI  - Striatum- and testis-specific phosphodiesterase PDE10A isolation and
      characterization of a rat PDE10A.
AB  - PDE10A, a phosphodiesterase (PDE) exhibiting properties of a cAMP PDE and a cAMP
      inhibited cGMP PDE, was cloned and investigated in detail in rats. PDE10A
      transcripts were abundant in the brain and testis. In situ hybridization analysis
      using a PDE10A riboprobe demonstrated the presence of PDE10A transcripts in the
      neurons of the striatum and the olfactory tubercle regions of the brain. Rat
      PDE10A cDNAs were isolated from a brain cDNA library and nucleotide sequence
      analysis revealed several N-terminal variants. The deduced amino-acid sequence of
      one of the major variant forms contained 794 amino acids, and it was 96%
      identical to that of the human PDE10A2. The other major form has a distinct N
      terminal sequence that is not found in humans. PDE10A was partially purified from
      rat striatum and testis, and characterized with respect to Km, inhibitor
      sensitivity and immunoreactivity to an anti-PDE10A serum. These findings indicate
      that PDE10A functions in these tissues.

PMID- 10583411
TI  - Self-assembly and catalytic activity of the pyruvate dehydrogenase multienzyme
      complex from Bacillus stearothermophilus.
AB  - The pyruvate dehydrogenase multienzyme complex from Bacillus stearothermophilus
      was reconstituted in vitro from recombinant proteins derived from genes over
      expressed in Escherichia coli. Titrations of the icosahedral (60-mer)
      dihydrolipoyl acetyltransferase (E2) core component with the pyruvate
      decarboxylase (E1, alpha2beta2) and dihydrolipoyl dehydrogenase (E3, alpha2)
      peripheral components indicated a variable composition defined predominantly by
      tight and mutually exclusive binding of E1 and E3 with the peripheral subunit
      binding domain of each E2 chain. However, both analysis of the polypeptide chain
      ratios in complexes generated from various mixtures of E1 and E3, and
      displacement of E1 or E3 from E1-E2 or E3-E2 subcomplexes by E3 or E1,
      respectively, showed that the multienzyme complex does not behave as a simple
      competitive binding system. This implies the existence of secondary interactions
      between the E1 and E3 subunits and E2 that only become apparent on assembly.
      Exact geometrical distribution of E1 and E3 is unlikely and the results are best
      explained by preferential arrangements of E1 and E3 on the surface of the E2
      core, superimposed on their mutually exclusive binding to the peripheral subunit
      binding domain of the E2 chain. Correlation of the subunit composition with the
      overall catalytic activity of the enzyme complex confirmed the lack of any
      requirement for precise stoichiometry or strict geometric arrangement of the
      three catalytic sites and emphasized the crucial importance of the flexibility
      associated with the lipoyl domains and intramolecular acetyl group transfer in
      the mechanism of active-site coupling.

PMID- 10583412
TI  - Insulin-like growth factor-I (IGF-I)-dependent activation of pp42/44 mitogen
      activated protein kinase occurs independently of IGF-I receptor kinase activation
      and IRS-1 tyrosine phosphorylation.
AB  - The proliferation and metabolism of H4IIE hepatoma cells is apparently mediated
      through the insulin receptor. These cells, however, also have high-affinity
      binding sites for insulin-like growth factor-I (IGF-I). Addition of insulin to
      H4IIE cells increased RNA synthesis, DNA synthesis and cell number. IGF-I, on the
      other hand, was ineffective at concentrations equivalent to the lowest effective
      insulin dose, although stimulation was observed with concentrations 100-fold
      higher. Similar results were obtained when glucose uptake was measured. Western
      blot analysis demonstrated that tyrosine phosphorylation patterns produced by
      insulin and IGF-I differed. In particular, phosphorylation of insulin receptor
      substrate-1 (IRS-1) was evident after treatment with insulin, but not after
      treatment with IGF-I. Correspondingly, insulin, but not IGF-I, stimulated
      receptor tyrosine kinase activity. In contrast with these results, both insulin
      and IGF-I induced mitogen-activated protein (MAP) kinase phosphorylation and
      activity at a concentration of 10 nM. The correlation between insulin-dependent
      and IGF-I-dependent MAP kinase activation was confirmed by Western blot analysis
      of phosphorylated MAP kinase kinase (MEK). These results suggest that
      phosphorylation of IRS-1 is essential for both cell proliferation and glucose
      metabolism, but is uncoupled from the MAP kinase cascade. Furthermore,
      stimulation of MEK and MAP kinase is independent of receptor tyrosine kinase
      activity.

PMID- 10583413
TI  - Biochemical and molecular characterization of the [NiFe] hydrogenase from the
      hyperthermophilic archaeon, Thermococcus litoralis.
AB  - Thermococcus litoralis is a hyperthermophilic archaeon that grows at temperatures
      up to 98 degrees C by fermentative metabolism and reduces elemental sulfur (S0)
      to H2S. A [NiFe] hydrogenase, responsible for H2S or H2 production, has been
      purified and characterized. The enzyme is composed of four subunits with
      molecular mass 46, 42, 34 and 32 kDa. Elemental analyses gave approximate values
      of 22 Fe, 22 S and 1 Ni per hydrogenase. EPR spectra at 70 and 5 K indicated the
      presence of four or five [4Fe-4S] and one [2Fe-2S] type clusters. The optimal
      temperature for both H2 evolution and oxidation, using artificial electron
      carriers, was around 80 degrees C. The operon encoding the T. litoralis enzyme is
      composed of four genes forming one transcriptional unit, and transcription is not
      regulated by S0. An unusual transcription-initiation site is located 139 bp
      upstream from the translational start point. Sequence analyses indicated the
      presence of new putative nucleotide-binding domains. Upstream from the
      hydrogenase operon, ORFs probably encoding a molybdopterin oxidoreductase enzyme
      have been identified. Based on sequence, biochemical and biophysical analyses, a
      model of the enzyme and the pathway of electron flow during catalysis is
      proposed.

PMID- 10583414
TI  - Role of the Src homology 2 domains and interdomain regions in ZAP-70
      phosphorylation and enzymatic activity.
AB  - The protein tyrosine kinase ZAP-70, which mediates T-cell antigen receptor (TCR)
      signalling, contains three distinct functional modules, two tandemly arranged SH2
      domains, a kinase domain and a linker region (interdomain B) that connects them.
      ZAP-70 enzymatic activation is strictly dependent on the binding, via its SH2
      domains, to the triggered TCR and on tyrosine phosphorylation. Here we utilized
      recombinant ZAP-70 and carried out a mutational analysis to understand the
      structural requirements for its activation. We show that deletion of both SH2
      domains corresponding to the first 254 residues moderately increases ZAP-70
      enzymatic activity on an exogenous substrate in vitro, results in increased
      tyrosine phosphorylation and produces subtle conformational changes, as judged by
      altered SDS/PAGE migration. Mutation of Tyr292, 315 and 319 to Phe in the
      interdomain B region, which constitute the major phosphorylation sites both in
      vitro and in vivo, did not affect ZAP-70 enzymatic activity. Moreover, deletion
      analysis of the interdomain B region established residues 320-619 as a minimal
      region endowed with full kinase activity. We propose that binding of ZAP-70 to
      the TCR promotes, through conformational changes, its extensive phosphorylation
      on tyrosine. However, Tyr292, 315 and 319 do not affect ZAP-70 enzymatic activity
      and may influence ZAP-70 signalling only indirectly by mediating its association
      with intracellular transducers.

PMID- 10583415
TI  - 600 MHz NMR studies of human articular cartilage keratan sulfates.
AB  - The use of high-field two-dimensional 1H-correlation data is described for the
      detailed comparison of intact keratan sulfate polymer chains derived from human
      articular cartilage sources as a function of age. For fetal material the
      nonreducing chain termini are shown to be sparsely capped by sialyl groups which,
      if present, are exclusively (alpha2-3)-linked to an unsulfated galactose residue.
      The asialo capping segment has the structure: Gal-GlcNAc6S-Gal-GlcNAc6S-.
      Examination of keratan sulfate from 10-year-old cartilage shows that capping by
      sialyl groups is complete, with (alpha2-3)-linkages predominant; for both this
      and the 38-year-old cartilage the three capping structures: NeuAc(alpha2-3)-Gal
      GlcNAc6S-Gal-GlcNAc6S-, NeuAc(alpha2-3)-Gal-GlcNAc6S-Gal6S-GlcNAc6S-, and
      NeuAc(alpha2-3)-Gal6S-GlcNAc6S-Gal6S-GlcNAc6S- are clearly recognizable. The
      level of (alpha2-6)-linked chain capping sialyl groups is significant for 38-year
      old cartilage keratan sulfate. Structural information concerning the linkage
      region to protein and the distribution of galactose environments is readily
      obtained from the spectra. Signal complexities severely limit the usefulness of
      two-dimensional correlation spectroscopy at 600 MHz for the examination of N
      acetylglucosamine residues within the poly(N-acetyllactosamine) repeat sequence
      and signals representing fucose placements remain undifferentiated. This
      nondestructive approach complements current degradative methods for the
      structural examination of keratan sulfates.

PMID- 10583416
TI  - Identification and characterization of potential new therapeutic targets in
      inflammatory and autoimmune diseases.
AB  - The isoxazole derivative Leflunomide (HWA 486) is a novel immunoregulatory and
      anti-inflammatory drug. Affinity chromatography was used to purify and identify
      Leflunomide binding proteins, which might play a role as potential cellular
      targets in the molecular mode of action. The Leflunomide derivative A 0273 was
      covalently coupled to a Fractogel(R) matrix. This column was used to separate a
      cytosolic protein extract of the macrophage cell line RAW 264.7 by several
      selected and specific gradient elution steps. Proteins that were specifically
      eluted through the active metabolite of Leflunomide, A 1726, were identified by
      subsequent protein sequence analysis. This allowed us to specify 10 cytosolic
      proteins, which bind with high affinity to this matrix. Three of them,
      glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase and phosphoglycerate
      mutase belong to the second part of the glycolytic pathway. The binding
      specificity of these protein/drug interactions was further evaluated using
      BIAcore(R) analysis. Kd values of glyceraldehyde 3-phosphate dehydrogenase,
      pyruvate kinase and lactic dehydrogenase were similar to the Kd value of a known
      Leflunomide target protein, dihydroorotate dehydrogenase. In order to elucidate
      the features as well as the overall relevance of these results, cytosolic
      fractions of three additional cell lines MOLT-4, A20.2J, HeLa were compared using
      the same chromatographic protocol. The elution profiles as well as subsequent
      Western blot analyses confirmed the data obtained previously for the macrophage
      cell line RAW 264.7.

PMID- 10583417
TI  - Determination of solution conformations of PrP106-126, a neurotoxic fragment of
      prion protein, by 1H NMR and restrained molecular dynamics.
AB  - Experimental two-dimensional 1H NMR data have been obtained for PrP106-128 under
      the following solvent conditions: deionized water/2, 2,2-trifluoroethanol 50 : 50
      (v/v) and dimethylsulfoxide. These data were analyzed by restrained molecular
      mechanics calculations to determine how changes in solvation affect the
      conformation of the peptide. In deionized water at pH 3.5, the peptide adopted a
      helical conformation in the hydrophobic region spanning residues Met112-Leu125,
      with the most populated helical region corresponding to the Ala115-Ala119 segment
      ( approximately 10%). In trifluoroethanol/H2O, the alpha-helix increased in
      population especially in the Gly119-Val122 tract ( approximately 25%). The
      conformation of this region was found to be remarkably sensitive to pH, as the
      Ala120-Gly124 tract shifted to an extended conformation at pH 7. In
      dimethylsulfoxide, the hydrophobic cluster adopted a prevalently extended
      conformation. For all tested solvents the region spanning residues Asn108-Met112
      was present in a 'turn-like' conformation and included His111, situated just
      before the starting point of the alpha-helix. Rather than by conformational
      changes, the effect of His111 is exerted by changes in its hydrophobicity,
      triggering aggregation. The amphiphilic properties and the pH-dependent ionizable
      side-chain of His111 may thus be important for the modulation of the
      conformational mobility and heterogeneity of PrP106-126.

PMID- 10583418
TI  - Mutational analysis of Asp51 of Anabaena azollae glutamine synthetase. D51E
      mutation confers resistance to the active site inhibitors L-methionine-DL
      sulfoximine and phosphinothricin.
AB  - The role of Asp51 in the catalytic activity of glutamine synthetase from the
      cyanobacterium Anabaena azollae has been analyzed. Five mutant enzymes, D51S,
      D51A, D51E, D51N and D51R, were constructed by site-directed mutagenesis and
      characterized. Asp51 appears to participate in the binding of ammonium ion, as
      affinity for this substrate was affected in all cases, although it varied
      according to the charge and/or size of the amino-acid residue, decreasing in the
      order Glu > Asn > Ser > Ala. The replacement of Asp51 by Glu (D51E) conferred
      besides a high resistance to the herbicides L-methionine-DL-sulfoximine and
      phosphinothricin, as a result of a decreased phosphorylation ability.

PMID- 10583420
TI  - Complement activation by oxidatively modified low-density lipoproteins.

PMID- 10583419
TI  - Solution structure of a recombinant mouse major urinary protein.
AB  - Major urinary proteins (MUPs) form an ensemble of protein isoforms which are
      expressed and secreted by sexually mature male mice only. They belong to the
      lipocalin superfamily and share with other members of this family the capacity to
      bind hydrophobic molecules, some of which are odorants. MUPs, either associated
      with or free of their natural ligands, play an important role in the reproductive
      cycle of these rodents by acting as pheromones. In fact, they are able to
      interact with receptors in the vomeronasal organ of the female mice, inducing
      hormonal and physiological responses by an as yet unknown mechanism. In order to
      investigate the structural and dynamical features of these proteins in solution,
      one of the various wild-type isoforms (rMUP: 162 residues) was cloned and
      subsequently isotopically labeled. The complete 1H, 13C and 15N resonance
      assignment of that isoform, achieved by using a variety of multidimensional
      heteronuclear NMR experiments, has been reported recently. Here, we describe the
      refined high-resolution three-dimensional solution structure of rMUP in the
      native state, obtained by a combination of distance geometry and energy
      minimization calculations based on 2362 NOE-derived distance restraints. A
      comparison with the crystal structure of the wild-type MUPs reveals, aside from
      minor differences, a close resemblance in both secondary structure and overall
      topology. The secondary structure of the protein consists of eight antiparallel
      beta-strands forming a single beta-sheet and an alpha-helix in the C-terminal
      region. In addition, there are several helical and hairpin turns distributed
      throughout the protein sequence, mostly connecting the beta-strands. The tertiary
      fold of the beta-sheet creates a beta-barrel, common to all members of the
      lipocalin superfamily. The shape of the beta-barrel resembles a calyx, lined
      inside by mostly hydrophobic residues that are instrumental for the binding and
      transport of small nonpolar ligand molecules.

PMID- 10583421
TI  - Metabolic effects of glucocorticoids: the unfinished story.

PMID- 10583422
TI  - Angiotensin II increases erythropoietin production in healthy human volunteers.
AB  - BACKGROUND: A number of animal studies and our own clinical trials point towards
      a possible influence of the renin-angiotensin-system (RAS) on erythropoietin
      (EPO) production. In this study we investigated the role of angiotensin II in the
      regulation of EPO production in humans. METHODS: After a hemorrhage of 750 ml as
      a basic physiological stimulus 72 healthy male volunteers received in a parallel
      design either placebo (physiologic electrolyte solution) for 6 h, angiotensin II
      i.v. for 6 h (1-3 microgram min-1, sufficient to increase systolic blood pressure
      by 20 mmHg), the selective AT1-receptor antagonist losartan, the ACE-inhibitor
      captopril, angiotensin II + losartan, or angiotensin II + captopril. RESULTS:
      Administration of angiotensin II alone and in combination with captopril resulted
      in a significantly higher Cmax EPO (67% higher vs. placebo, P < 0.05) and AUCEPO
      (0-24h) (40% higher vs. placebo, P < 0.05). In the groups receiving losartan or
      captopril alone or the combination of angiotensin II + losartan no significant
      difference of Cmax EPO and AUCEPO(0-24h) compared to placebo could be detected.
      CONCLUSIONS: This study shows in a model of controlled, basic physiological
      stimulation of renal EPO production that angiotensin II is able to increase EPO
      levels in humans. This effect of angiotensin II can be blocked by the specific
      AT1-receptor antagonist losartan but not by the ACE-inhibitor captopril. The
      result may be interpreted as a hint that one signal for the control of EPO
      production in humans may be mediated by angiotensin II (AT1)-receptors.

PMID- 10583423
TI  - Detection of WT1 mRNA in urine from patients with kidney diseases.
AB  - Detachment of glomerular epithelial cells (GEC) from glomerular basement membrane
      (GBM) could account for a part of the pathogenic mechanism of proteinuria seen in
      primary and secondary renal diseases. The Wilms' tumour suppresser gene (WT1) is
      strictly expressed in GEC in the adult kidney. Mutations of WT1 gene have been
      implicated in progressive renal damage. Utilizing nested RT-PCR we detected mRNA
      of WT1 in the urine of patients with renal diseases. Seven of 20 (35%) chronic
      glomerulonephritis (CGN), eight of 20 (40%) diabetes mellitus (DM) with
      proteinuria, and two of 24 (8.3%) rheumatic diseases were WT1 positive.
      Interestingly, only one of 51 (2%) DM without proteinuria was WT1 positive. None
      of the healthy volunteers or cystitis patients were WT1 positive. This is the
      first report describing the detection of endogenous WT1 mRNA, an important gene
      in progressive renal failure, from patients' urine. This technique could be a
      powerful tool in the search for information about glomerular damage in clinical
      settings as well as for WT1 mutations or isoform imbalance at the research level
      without renal biopsy.

PMID- 10583424
TI  - Differences between men and women in the response of serum cholesterol to dietary
      changes.
AB  - BACKGROUND: Hypercholesterolaemia is initially treated by diet. However, most
      studies of diet and cholesterol response have been carried out in men, and it is
      not known whether women react to diet to the same extent as men do. We therefore
      studied sex differences in the response of serum cholesterol and lipoproteins to
      diet. MATERIALS AND METHODS: We measured the responses of serum cholesterol to a
      decrease in dietary saturated fat in seven trials involving 126 men and 147
      women, to a decrease in dietary trans fat in two trials (48 men and 57 women) and
      to a decrease in dietary cholesterol in eight trials (74 men and 70 women). We
      also measured responses to the coffee diterpene cafestol, which occurs in
      unfiltered coffee, in nine trials (72 men and 61 women). All subjects were lean
      and healthy. RESULTS: The response of total cholesterol (+/- standard deviation)
      to a decrease in the intake of saturated fat was greater in men (-0.62 +/- 0.39
      mmol L-1) than in women (-0.48 +/- 0.39 mmol L-1; 95% confidence interval, 0.04
      0.23 mmol L-1). The response of total cholesterol to a decrease in the intake of
      cafestol was also larger in men (-1.01 +/- 0.49 mmol L-1) than in women (-0.80 +/
      0.49 mmol L-1; 95% confidence interval, 0. 04-0.39 mmol L-1). Responses to trans
      fat and to dietary cholesterol did not differ between men and women. CONCLUSION:
      Men have larger responses of total and low-density lipoprotein cholesterol to
      saturated fat and cafestol than women do.

PMID- 10583425
TI  - Complement activation by oxidatively modified low-density lipoproteins.
AB  - BACKGROUND: Oxidatively modified low-density lipoproteins (LDLs) have been
      implicated in the pathogenesis of atherosclerosis and are found in human vascular
      lesions. There is increasing evidence that complement activation may also play a
      role in atherogenesis. Activated complement proteins have been demonstrated to be
      present in early atherosclerotic lesions, and lipids isolated from lesions have
      been shown to activate complement, hence their designation as lesion complement
      activator (LCA). The question now arose whether oxidized LDLs would also activate
      complement. MATERIAL AND METHODS: The complement-activating capacity of a lesion
      complement activator preparation and of minimally as well as heavily oxidized LDL
      was investigated by measuring SC5b-9 formation in normal human serum. In
      addition, C3 conversion was followed using two-dimensional immunoelectrophoresis.
      RESULTS: Minimally and heavily oxidized LDL generated small but significant
      amounts of SC5b-9 (7.9 microgram mL-1, SD 3.5, and 10.8 microgram mL-1, SD 1.2,
      respectively; n = 6) compared with native LDL (3.3 microgram mL-1, SD 1.4; P <
      0.05), whereas LCA generated substantially larger amounts of the terminal complex
      (32.0 microgram mL-1, SD 3.2). Both oxidized LDL preparations caused only minor
      C3 conversion. CONCLUSIONS: These findings show that oxidation does not confer
      relevant complement-activating properties on LDL, suggesting that the lesion
      complement activator is not directly related to oxidized LDL. Oxidized LDL is
      probably of minor importance for complement activation in atherosclerotic
      lesions.

PMID- 10583426
TI  - Insulin: new roles for an ancient hormone.
AB  - Recent research has greatly expanded the domain of insulin action. The classical
      action of insulin is the control of glucose metabolism through the dual feedback
      loop linking plasma insulin with plasma glucose concentrations. This canon has
      been revised to incorporate the impact of insulin resistance or insulin
      deficiency, both of which alter glucose homeostasis through maladaptive responses
      (namely, chronic hyperinsulinaemia and glucose toxicity). A large body of
      knowledge is available on the physiology, cellular biology and molecular genetics
      of insulin action on glucose production and uptake. More recently, a number of
      newer actions of insulin have been delineated from in vitro and in vivo studies.
      In sensitive individuals, insulin inhibits lipolysis and platelet aggregation. In
      the presence of insulin resistance, dyslipidaemia, hyper-aggregation and anti
      fibrinolysis may create a pro-thrombotic milieu. Preliminary evidence indicates
      that hyperinsulinaemia per se may be pro-oxidant both in vitro and in vivo.
      Insulin plays a role in mediating diet-induced thermogenesis, and insulin
      resistance may therefore be implicated in the defective thermogenesis of
      diabetes. In the kidney, insulin spares sodium and uric acid from excretion; in
      chronic hyperinsulinaemic states, these effects may contribute to high blood
      pressure and hyperuricaemia. Insulin hyperpolarises the plasma membranes of both
      excitable and non-excitable tissues, with consequences ranging from baroreceptor
      desensitisation to cardiac refractoriness (prolongation of QT interval). Under
      some circumstances insulin is vasodilatory-the mechanism involving both the
      sodium-potassium pump and intracellular calcium transients. Finally, by crossing
      the blood-brain barrier insulin exerts a host a central effects (sympatho
      excitation, vagal withdrawal, stimulation of corticotropin releasing factor),
      collectively resembling a stress reaction. Description and understanding of these
      new roles, their interactions, the interplay between insulin resistance and
      hyperinsulinaemia, and their implications for cardiovascular disease have only
      begun.

PMID- 10583427
TI  - Hypoleptinemia in female and male elite gymnasts.
AB  - BACKGROUND: Elite gymnasts favour low body fat mass as the current aesthetic
      ideal required for complex movements in this sports discipline. Pubertal
      development and growth are retarded in juvenile gymnasts. Leptin, the protein
      product of the ob-gene, is secreted by fat cells. Besides its role in regulation
      of body weight, leptin also stimulates the reproductive axis. We investigated
      various serum hormones including leptin, body composition and nutrition in
      cohorts of female and male elite gymnasts to elucidate if there is a relationship
      between leptin levels and delayed puberty in elite gymnasts. MATERIALS AND
      METHODS: Twenty-two female and 18 male elite gymnasts were enrolled in this
      study. Pubertal stage, various hormonal levels and body composition were
      determined and nutritional intake was assessed. Leptin was analysed using a
      specific RIA. RESULTS: Pubertal development and growth were delayed in the study
      group, especially in girls. The percentage of body fat was reduced as compared to
      a normal age-matched population: 14.4% versus 21.9% in girls and 10.4% versus
      15.1% in boys. Serum leptin levels were decreased, especially in pubertal girls,
      and did not show the normal developmental pattern with a steady increase in girls
      and a peak in boys of pubertal stage 2. In all gymnasts leptin levels correlated
      with the amount of fat mass (r = 0.6, P = 0.005 in girls; r = 0.44, P = 0.038 in
      boys). When leptin levels were transformed into standard deviation scores (SDS)
      it became obvious that the gymnasts, especially pubertal females, had
      significantly lower values than normal controls of the same sex, pubertal stage
      and body mass index (BMI): leptin SDS (BMI) = -1.21 and -3.99 in prepubertal and
      pubertal girls, - 0.94 and -0.91 in prepubertal and pubertal boys, respectively.
      When leptin SDS were based on % body fat instead of BMI, mean values were still
      significantly decreased compared to normal controls: -1.05 in girls (P < 0.001)
      and -0.60 in boys (P = 0. 025). CONCLUSIONS: Adjustment of serum leptin levels in
      elite gymnasts for gender, pubertal stage and BMI or % body fat reveals
      inappropriately low values. The reason for this hypoleptinemia is most probably
      insufficient caloric intake. The data suggest that hypoleptinemia in turn causes
      delayed puberty and growth in this particular group of athletes.

PMID- 10583428
TI  - Acute methylprednisolone administration induces a transient alteration of glucose
      tolerance and pyruvate dehydrogenase in humans.
AB  - BACKGROUND: Glucocorticoid administration induces alteration of glucose
      tolerance, and impairment of glucose oxidation may contribute to glucocorticoid
      induced derangement of glucose metabolism. We investigated glucose tolerance
      following methylprednisolone administration in humans. In the same model, we
      evaluated pyruvate dehydrogenase (PDH), the rate limiting enzyme of glucose
      oxidation, in peripheral blood mononuclear cells. MATERIALS AND METHODS:
      Methylprednisolone (2 x 40 mg, iv, one dose every 12 h) was administered to six
      healthy volunteers. Glucose tolerance was evaluated through an oral glucose
      tolerance test (oGTT, 75 g glucose) at least a week before and after drug
      administration (2 and 24 h post-drug). To assess modifications of lipid
      metabolism circulating free fatty acids (FFA) and glycerol were measured, during
      fasting and oGTT. The active form of PDH (PDHa) was evaluated in peripheral blood
      mononuclear cells, both as ex vivo activity and as in vitro response to insulin
      (30 pmol l-1). RESULTS: Methylprednisolone induced an alteration of glucose
      tolerance 2 h after its administration. Such alteration was completely reversed
      at 24 h. Alteration of glucose tolerance was accompanied by decreased ex vivo
      PDHa activity. PDH responsiveness to insulin in vitro was also impaired.
      Circulating FFA were unmodified, but decreased glycerol levels suggested a slight
      inhibition of lipolysis. CONCLUSIONS: Acute methylprednisolone administration in
      humans induced a transient decrease of glucose tolerance 2 h after drug
      administration, accompanied by hyperinsulinaemia, inhibition of ex vivo PDH
      activity and its response to insulin in vitro. These alterations were completely
      abolished at 24 h, suggesting that methylprednisolone can be safely administered
      acutely. Furthermore, methylprednisolone induced only minor modifications of
      circulating FFA and glycerol, indicating minimal impact on lipid metabolism.

PMID- 10583429
TI  - Comparative inhibitory potential of differently modified antisense
      oligodeoxynucleotides on hepatitis C virus translation.
AB  - BACKGROUND: A completely modified phosphorothioate antisense oligodeoxynucleotide
      (cS-ODN 4) directed against nucleotides 326-348 of the hepatitis C virus (HCV) 5'
      non-coding region (NCR) efficiently inhibits viral gene expression. As cS-ODN
      exerts undesired side-effects in vivo, we synthesized partially modified ODN 4
      that contained only six modified nucleotides which are located at the ODN termini
      or are scattered along the molecule. The tested modifications were polar
      phosphorothioates (S) and non-polar methyl- (M) or benzylphosphonates (B).
      RESULTS: In an in vitro translation system, specific inhibition of HCV gene
      expression by M-ODN 4 or B-ODN 4 was observed if terminally modified ODN were
      used; the maximal inhibition was 92.3% +/- 1.9% and 87.1% +/- 3.7%, respectively,
      at 10 microgram mol L-1 concentration. S-ODN 4 specifically suppressed viral
      translation irrespective of the location of the modifications, resulting in a
      maximal inhibition of 86.3% +/- 3.3%. For all terminally modified ODNs the
      therapeutic index was high, with tB-ODN 4 the second best at 3.8. Inhibition
      correlated with efficient RNase H-associated cleavage of target RNA. In transient
      co-transfection experiments of HepG2 cells with a reporter gene construct and the
      ODN, terminally modified B-ODN 4 was the most effective and specific inhibitor.
      At a concentration of 5 microgram mol L-1 the suppression of HCV translation was
      96.3% +/- 0.7%. CONCLUSION: These data demonstrate that terminally modified B-ODN
      4 is a potent inhibitor of HCV gene expression in vitro and in HepG2 cell culture
      and may be valuable for future antiviral treatment.

PMID- 10583430
TI  - The type and time of menopause as decisive factors for bone mass changes.
AB  - BACKGROUND: Early menopause, whether it be natural or surgical, is one of the
      established risk factors for osteoporosis. Surgical menopause, however, differs
      from natural menopause owing to the abrupt cessation of estrogen secretion. This
      study attempts to investigate the influence of menopause type on bone mineral
      density (BMD) changes. METHODS: Four groups, each consisting of 30 women, were
      compared: early menopause (EMP), surgical menopause (SUMP) and two groups of
      natural menopause. The two groups share a similar number of years since menopause
      (YSM) but have a different chronological age (NMPO), or share a similar age but
      different YSM (NMPY) to the EMP and SUMP. BMD was measured by the DXA method at
      L2-L4 vertebrae and proximal femur. RESULTS: Mean vertebral BMD of EMP was lower
      than that of SUMP (P < 0.05) and of NMPY (P < 0.001) women. Femoral neck BMD did
      not differ between SUMP and EMP women but both exhibited significantly lower BMD
      than either natural menopause groups. BMD of SUMP and vertebral BMD of NMPY women
      was inversely correlated to chronological age and to number of YSM. Pertaining to
      T-score values according to the osteoporotic range, NMPO, EMP and SUMP women
      being homogeneous exhibited significantly lower values than NMPY in the vertebrae
      (F-ratio = 7.84, P < 0.001). Whereas, in the femoral neck and the trochanter
      major, EMP and SUMP categories presented significantly lower T-score values than
      the NMPO and NMPY (F = 3.61, P < 0.01 and 2.8, P < 0.05 respectively).
      CONCLUSION: Women with early menopause exhibit lower vertebral BMD than women of
      similar age after either surgical or natural menopause. In women of similar age,
      surgical menopause results in lower vertebral and femoral neck densities compared
      to natural menopause. Chronological age and the interval after menopause
      negatively affects bone density in women with similar age whether in surgical or
      natural menopause.

PMID- 10583431
TI  - Mitochondrial myopathies and encephalomyopathies.
AB  - Defects of mitochondrial metabolism result in a wide variety of human disorders,
      which can present at any time from infancy to late adulthood and involve
      virtually any tissue either alone or in combination. Abnormalities of the
      electron transport and oxidative phosphorylation (OXPHOS) system are probably the
      most common cause of mitochondrial diseases. Thirteen of the protein subunits of
      OXPHOS are encoded by mitochondrial DNA (mtDNA) and mutations of this genome are
      important causes of OXPHOS deficiency. The link between genotype and phenotype
      with respect to mtDNA mutations is not clear: the same mutation may result in a
      variety of phenotypes, and the same phenotype may be seen with a variety of
      different mtDNA mutations. The pathogenesis of mtDNA mutations is unclear
      although OXPHOS and ATP deficiency, and free radical generation, are thought to
      contribute to tissue dysfunction. There is now strong evidence for mitochondrial
      dysfunction in neurodegenerative disorders. In some cases, e.g. Friedreich's
      ataxia, hereditary spastic paraplegia, this is a result of a mutation of a
      nuclear gene encoding a mitochondrial protein, whilst in others, e.g.
      Huntington's disease, amyotrophic lateral sclerosis, the OXPHOS defect is
      secondary to events induced by a mutation in a nuclear gene encoding a non
      mitochondrial protein. In yet a third group, e.g. Parkinson's disease,
      Alzheimer's disease, the relationship of the mitochondrial defect to aetiology
      and pathogenesis is unclear.

PMID- 10583433
TI  - Carbohydrate deficient transferrin is not a useful marker for the detection of
      chronic alcohol abuse

PMID- 10583432
TI  - Carbohydrate-deficient transferrin is a useful marker for the detection of
      chronic alcohol abuse.

PMID- 10583434
TI  - Left atrial systolic function is depressed in idiopathic and preserved in
      ischemic dilated cardiomyopathy.
AB  - BACKGROUND: Left atrial systolic dysfunction, unexplained by altered loading
      conditions, has been reported in idiopathic dilated cardiomyopathy suggesting
      left atrial involvement in the myopathic process. MATERIALS AND METHODS:
      Seventeen patients with idiopathic dilated cardiomyopathy, 16 with ischemic
      dilated cardiomyopathy and 18 normal controls were studied with transthoracic
      echocardiography and cardiac catheterization. Transmitral diastolic flow was
      evaluated with pulsed Doppler. Left atrial volume (cm3/m2) at mitral valve
      opening (maximal, Vmax.), onset of atrial systole (P wave of the
      electrocardiogram, Vp), and mitral valve closure (minimal, Vmin. ) was determined
      with two-dimensional echocardiography using the biplane area-length method. The
      left atrial active emptying fraction (ACTEF = [Vp-Vmin.] x 100/Vp) served as an
      index of systolic function. RESULTS: The peak early diastolic transmitral flow
      velocity (cm/sec) was similar in the three groups (idiopathic: 60 +/- 16,
      ischemic: 58 +/- 20, control: 56 +/- 22; P = NS), whereas the late diastolic
      transmitral flow velocity was lower but not significantly different in idiopathic
      compared to ischemic cardiomyopathy, and in both was lower than control (26 +/-
      12 vs. 34 +/- 13 vs. 44 +/- 14, respectively; P < 0.05). Vmax. and Vp were
      similar in idiopathic and ischemic cardiomyopathy and greater than control (44.6
      +/- 13.6 vs. 48.2 +/- 18.3 vs. 26.9 +/- 6.2; P < 0.05, and 34.6 +/- 13.4 vs. 30.8
      +/- 10.9 vs. 16.7 +/- 3.7, respectively; P < 0.05). ACTEF was lower in idiopathic
      than in ischemic cardiomyopathy and in the latter it was similar to control (18
      +/- 10% vs. 32 +/- 10% vs. 36 +/- 10%, respectively; P < 0.05). Moreover, ACTEF
      was inversely related to left atrial tension at end-of atrial systole both in
      idiopathic and in ischemic cardiomyopathy (r2 = 0.52, P = 0.001 and r2 = 0.57, P
      = 0.0007, respectively). However, at any given level of left atrial tension at
      end of atrial systole, ACTEF was lower in idiopathic than ischemic
      cardiomyopathy. CONCLUSION: Left atrial systolic function is depressed in
      idiopathic and preserved in ischemic dilated cardiomyopathy despite similar left
      atrial loading conditions. This finding suggests left atrial myopathy in the
      former, and may be related to the differences in the response to medical
      treatment and clinical outcome observed between the two conditions.

PMID- 10583435
TI  - Short-term hormone replacement therapy: reduced plasma levels of soluble adhesion
      molecules.
AB  - BACKGROUND: Epidemiological data have suggested that the use of hormone
      replacement therapy (HRT) is associated with a decreased risk of cardiovascular
      disease. Vascular endothelium and adhesion molecules play an important role in
      the initiation and progression of atherosclerosis. MATERIAL AND METHODS:
      Prospective, randomized, placebo-controlled 12-week study. Sixty healthy,
      normotensive postmenopausal women received either micronised oestradiol 2 mg
      alone (n = 16, E2 group), or sequentially combined with a progestagen; E2 + P
      groups trimegestone 0.5 mg (E2 + T, n = 14) or dydrogesterone 10 mg (E2 + D
      group, n = 14) or placebo (n = 16). Data were collected at baseline and at 4 and
      12 weeks. RESULTS: Twelve weeks of treatment with E2 or E2 + P was associated
      with a significant decrease in the plasma concentrations of soluble intercellular
      adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and
      thrombomodulin (sTM). The average decrease in these markers was about 9%. In
      women treated with trimegestone the decreases were larger than in those treated
      with dydrogesterone; for sICAM-1 (-15% vs. -2%; P < 0.0001), sVCAM-1 (-15% vs.
      +3%; P = 0. 003) and sTM (-9% vs. -4%; P = 0.11). Plasma levels of endothelin-1
      (ET-1) decreased (by 13%) only in women treated with E2 + P. In the E2 group,
      flow-mediated, endothelium-dependent vasodilatation increased by 6 percentage
      points after 12 weeks (P = 0.07 vs. baseline, P = 0.02 vs. E2 + P, and P = 0.17
      vs. placebo). CONCLUSION: Short-term treatment with E2 or E2 + trimegestone
      reduces plasma levels of sICAM-1, sVCAM-1 and sTM. ET-1 decreased only in the E2
      + P groups. Different types of progestagens may differentially affect sICAM-1,
      sVCAM-1 and sTM levels, which may be relevant for the choice of type HRT.

PMID- 10583436
TI  - Performance of the [13C]-acetate gastric emptying breath test during physical
      exercise.
AB  - BACKGROUND: The gastric emptying rate of liquids can be determined non-invasively
      using the [13C]-acetate breath test at rest. The aims of our study were to
      validate this test during physical exercise against the double-sampling method
      and to evaluate the time needed for intestinal absorption and the delay between
      absorption and appearance of 13CO2 in breath, both at rest and during exercise.
      DESIGN: Fifteen well-trained male subjects were investigated. Gastric emptying
      was determined simultaneously measuring the 13CO2 breath enrichment after
      intragastric administration of 0.5 L of carbohydrate solution with 150 mg of
      [13C]-acetate added and by the double-sampling technique (n = 9). In separate
      tests, 150 mg of [13C]-acetate was also applied intraduodenally and intravenously
      (n = 6), both at rest and during exercise. Time-to-peak (TTP) 13CO2 enrichment
      was determined using a curve fit and was considered as the parameter for gastric
      emptying. RESULTS: TTP enrichment derived from the breath test significantly
      correlated with the gastric emptying half-time obtained from the gastric
      aspirates. During exercise, median TTP enrichment values after intragastric,
      intraduodenal (i.d.) and intravenous (i.v.) administration of [13C]-acetate were
      22.3, 10.3 and 5.4 min respectively. During exercise, i.d. and i.v. values were
      reached significantly earlier than at rest. CONCLUSION: The [13C]-acetate breath
      test can be used as a non-invasive method to determine relative gastric emptying
      rates of liquids during exercise, but the results are influenced by the rate of
      absorption and the time needed for subsequent oxidation of [13C]-acetate and
      exhalation of 13CO2.

PMID- 10583437
TI  - Anti-neutrophil cytoplasmic antibodies in a rat model of trinitrobenzenesulphonic
      acid-induced liver injury.
AB  - BACKGROUND: In sera from patients with autoimmune liver diseases, e. g. primary
      sclerosing cholangitis (PSC) and autoimmune hepatitis, anti-neutrophil
      cytoplasmic antibodies (ANCAs) can be found. Until now, no animal model of ANCA
      induction in liver disease has been described. In this study, we describe a novel
      rat model of acute liver injury and subsequent ANCA production. MATERIALS AND
      METHODS: The hapten reagent 2,4,6-trinitrobenzenesulphonic acid (TNBS) was
      injected into the portal vein of female Lewis rats. Two experimental groups were
      studied: group A (TNBS/ethanol) received different TNBS concentrations; control
      animals of group B (ethanol) were injected with 10% (v/v) ethanol/0.9% (w/v)
      NaCl. RESULTS: A dose-dependent acute necrotizing liver injury occurred after
      injection of TNBS. Histopathological examination revealed acute hepatic injury
      with confluent parenchymal necrosis, mild bile duct proliferation and periportal
      infiltration. The periportal infiltration consisted mainly of macrophages and T
      lymphocytes. ANCAs were found in an allogenic test system between 1 and 8 weeks
      after TNBS injection in 11 out of 28 (39%) TNBS-treated rats (group A) and did
      not correlate with the extent of liver injury or TNBS dose. Autoantibody
      specificities of IgG type were directed against catalase (29%), myeloperoxidase
      (14%) and actin (7%), as detected by enzyme-linked immunosorbent assay and
      Western blotting. Moreover, autoantibodies against the asialoglycoprotein
      receptor were observed. Peripheral blood mononuclear cells and spleen lymphocytes
      from TNBS-treated rats were shown to produce ANCAs. CONCLUSION: In summary, we
      were able to show that intraportal administration of the hapten reagent TNBS
      induces an acute necrotizing liver injury with subsequent ANCA production in
      Lewis rats. ANCA specificities were mainly directed against catalase, an
      autoantigen that has recently been identified in sera from patients with primary
      sclerosing cholangitis and autoimmune hepatitis. This animal model offers the
      opportunity to study the pathomechanisms of ANCA production in necrotizing liver
      injury.

PMID- 10583438
TI  - Hepatitis C virus core protein does not inhibit apoptosis in human hepatoma
      cells.
AB  - BACKGROUND: Viral persistence is a major problem after infection with the
      hepatitis C virus. Recently, it has been reported that hepatitis C virus core
      protein inhibits cis-platin induced apoptosis in human cervical carcinoma cells
      and apoptosis induced by overexpression of c-myc in Chinese hamster ovary cells.
      MATERIALS AND METHODS: This study investigated whether different variants of
      hepatitis C virus core or E2 protein interfere with tumour necrosis factor alpha
      or Fas (CD95/ APO-1) antibody-induced programmed cell death in transiently
      transfected human hepatoma (HepG2) cells. RESULTS: While neither full length or C
      terminally truncated variants of hepatitis C virus core protein nor hepatitis C
      virus E2 protein inhibited tumour necrosis factor alpha- or Fas antibody-induced
      apoptosis, a strong inhibition was observed with the cowpox virus cytokine
      response modifier A protein. CONCLUSIONS: Thus, it is unlikely that hepatitis C
      virus core or E2 protein inhibit apoptosis mediated by apoptosis-signalling
      pathways sensitive to cytokine response modifier A protein. Discrepancies to
      previous reports probably reflect specific effects of hepatitis C virus core
      protein on different apoptotic pathways and/ or cell lines.

PMID- 10583439
TI  - Amino acid concentration in the interstitium of human skeletal muscle: a
      microdialysis study.
AB  - BACKGROUND: The microdialysis technique has been widely used for in vivo
      monitoring of the interstitial composition of several tissues. Remarkably high
      concentrations of taurine and glycerol were reported in a recent human study. As
      taurine and glycerol are predominantly present in the intracellular space,
      cellular trauma after probe insertion may have resulted in elevated interstitial
      concentrations. With the present study we wanted to investigate the impact of the
      initial trauma on the interstitial concentrations of amino acids and glycerol.
      METHODS: Microdialysis probes were inserted into the vastus lateralis muscle in
      eight subjects. Using a slow perfusion rate of 0.3 muL min-1, dialysate samples
      were collected in five 75-min periods. Simultaneously, plasma samples were taken
      from a peripheral vein for amino acid determination. RESULTS: During the first
      collection period, the dialysate concentration for 21 measured amino acids was on
      average 180% +/- 51% higher than the concentration in plasma water. This
      difference decreased to 52% +/- 15%, 32% +/- 8%, 37% +/- 8% and 31% +/- 7% during
      periods 2, 3, 4 and 5 respectively. Carnosine, which is not present in plasma,
      was detected in high concentrations in the interstitium during the first
      collection period and decreased subsequently. CONCLUSION: In the post-absorptive
      phase, the concentrations of most amino acids in muscle interstitium are slightly
      higher than in venous plasma water. The leakage of intracellular amino acids,
      because of probe insertion, will initially lead to an overestimation of the
      actual interstitial concentration of amino acids. Therefore, reliable baseline
      values of amino acids cannot be obtained until 120-150 min after probe insertion.
      The dialysate concentration of carnosine may be used as a marker of cellular
      leakage.

PMID- 10583440
TI  - Inhaled nitric oxide does not influence bleeding time or platelet function in
      healthy volunteers.
AB  - BACKGROUND: Bleeding time has been reported to increase during gaseous nitric
      oxide (NO) inhalation in healthy volunteers and patients, and it has been
      speculated that inhaled NO inhibits platelet function. However, results have not
      been unanimous, and we have been unable to document any effects of inhaled NO on
      circulating platelets. MATERIALS AND METHODS: We performed a double-blind,
      placebo controlled cross-over study in which healthy volunteers (n = 15) inhaled
      NO (30 ppm, 30 min) or control gas. Aspirin (640 mg x 1 orally) was used as
      positive control on the third occasion (n = 14). Bleeding time was measured, and
      platelet function was determined flow cytometrically by measuring the expression
      of P-selectin on circulating platelets and locally activated platelets in wound
      blood. Skin perfusion close to the site for bleeding time incisions was assessed
      by laser Doppler flowmetry. RESULTS: Bleeding time was unaffected by NO, as there
      were slight increases during both NO and control inhalation (+20% and +14%
      respectively, P = 0.9). Similarly, NO inhalation had no effect on platelet P
      selectin expression in either systemic or wound blood, or on skin perfusion.
      Aspirin pretreatment, on the other hand, prolonged bleeding time (P < 0.001) and
      decreased P-selectin expression of platelets in wound blood (P = 0.03).
      CONCLUSIONS: This first placebo-controlled study indicates that inhaled NO does
      not influence either bleeding time, platelet activity or skin perfusion. Thus, it
      is unlikely that treatment of critically ill patients with inhaled NO will
      aggravate haemostatic disturbances, which has previously been feared, by
      influencing platelet function.

PMID- 10583441
TI  - Persistent symptoms in former UNTAC soldiers are not associated with shifted
      cytokine balance.
AB  - BACKGROUND: The pathogenesis of post-combat syndromes, such as Gulf War syndrome,
      is poorly understood. Recently, it has been postulated that the symptoms of
      veterans with such syndromes are due to a disturbed cytokine balance shifted
      towards a T-helper (Th) 2 profile. We investigated this hypothesis in 21
      symptomatic former UNTAC soldiers and compared their results with those obtained
      in 21 healthy former UNTAC soldiers matched for age, sex and military force.
      DESIGN: The numbers of intracellular interleukin 4 (IL-4) and interferon gamma-
      (IFN-gamma) producing CD4+ and CD8+ T lymphocytes (CD3+) were determined after in
      vitro stimulation with phorbol myristate acetate and calcium ionophore in the
      presence of brefeldin to block secretion of induced cytokines. Circulating
      concentrations and lipopolysaccharide- (LPS) or phytohaemagglutinin- (PHA)
      stimulated whole-blood production of the proinflammatory cytokines IL-1beta, IL
      1ra, tumour necrosis factor alpha (TNF-alpha) and IL-10 and IFN-gamma were
      measured. RESULTS: The numbers of CD4+ and CD8+ T lymphocytes positive for IL-4
      or IFN-gamma production were not significantly different in patients and control
      subjects. After stimulation with LPS or PHA, the in vivo circulating
      concentration and concentration of IL-10 and IFN-gamma were also similar.
      CONCLUSIONS: The present study demonstrates that there is no shift in cytokine
      balance towards a Th2 profile in former UNTAC soldiers with symptoms similar to
      those of the Gulf War syndrome.

PMID- 10583442
TI  - The growth and the control of human immunodeficiency virus in the lung:
      implications for highly active antiretroviral therapy.
AB  - In recent years, it has become apparent that the lung is an important niche for
      the proliferation of human immunodeficiency virus (HIV), which may have
      implications for highly active antiretroviral therapy (HAART). The lung itself is
      a major site for the opportunistic infections associated with the progression to
      acquired immune deficiency syndrome (AIDS), specifically Pneumocystis carinii,
      Myobacterium tuberculosis and pyogenic bacteria. These cases of active pulmonary
      complications are direct indicators of enhanced progression to AIDS-defining
      illness and increased morbidity and mortality. It is therefore essential that the
      interaction between the lung and HIV is fully understood. Recent research
      indicates the lung may be a major sanctuary for the virus, with distinct
      evolution and replication in contrast to other target organs for HIV. In this
      review, we will discuss the recent findings of HIV infection, evolution, host
      factors involved in the control of HIV within the lung and the impact this may
      have on current therapy.

PMID- 10583444
TI  - Nef protein induces differential effects in CD8+ cells from HIV-1-infected
      patients.
AB  - BACKGROUND: The Nef protein of HIV-1 is suspected to play a role in the depletion
      of uninfected CD4+ lymphocytes that leads to AIDS. By contrast its effect on CD8+
      cells, whose functions are also deregulated during HIV-1 infection, is presently
      unclear. Here we describe a number of derangements induced in vitro by Nef in
      CD8+ cells from HIV-1-infected patients. DESIGN: Peripheral lymphocytes from 16
      HIV-1+ subjects and 9 uninfected individuals were cultivated on a Nef-transfected
      mouse fibroblast layer exposing the carboxyl-terminal region of the viral protein
      on cell membrane. The cultures were then measured for both apoptosis and
      proliferation by subdiploid DNA content and Ki67 expression, respectively,
      whereas the molecular analysis of purified CD8+ cells investigated the Fas-L mRNA
      levels in Nef-treated CTLs. In addition, we evaluated the Nef-induced variation
      in the extent of CD8+/HLA-DR+ subset, which includes non cytotoxic cells
      secreting T-cell antiviral factor (CAF) and a soluble factor inhibiting the HIV-1
      replication. RESULTS: The viral protein induced in peripheral blood lymphocytes
      (PBL) a moderate tendency to proliferate, as measured by the increment of Ki67
      antigen, particularly on the CD8+ subset of HIV-1 infected individuals (P <
      0.05). This profile was particularly evident in cultures from patients with
      severe CD4+ lymphopenia and paralleled an apparent expansion of the CD8+/CD57+
      suppressor cell subset. Molecular analysis of purified CD8+ cells revealed a
      defective expression of Fas-L mRNA in Nef-cultured CTLs, whereas the viral
      protein exerted a down modulatory effect on the CD8+/HLA-DR+ subset (P < 0.05),
      thus suggesting a potential inhibition of CAF. CONCLUSIONS: These results support
      a potential role of Nef in the progression of HIV-1 infection as a number of
      cellular functions are affected in the CD8+ subset. In particular, the defective
      functions of CD8+ cells induced by the viral protein could contribute, at least
      partly, to the escape of HIV-1 from the immune control of these cells.

PMID- 10583443
TI  - Anti-PR-3 antibodies induce endothelial IL-8 release.
AB  - BACKGROUND: It has been shown that interaction of anti-PR-3 antibodies with human
      endothelial cells (EC) leads to an activation of EC in vitro, i.e. induction of
      adhesion molecules like E-selectin, VCAM-1 and tissue factor. The aim of this
      study was to investigate the effect of anti-PR-3 antibodies on endothelial IL-8
      expression. MATERIALS AND METHODS: EC were cultured in 96-well plates and
      stimulated with TNF-alpha and IL-1beta for 1 h to induce membrane expression of
      endothelial PR-3. Anti-PR-3 antibodies were purified from sera from patients with
      clinically active Wegener's granulomatosis. Purified anti-Ro, anti-centromere,
      anti-dsDNA antibodies and a monoclonal anti-PR-3 antibody (WGM2) served as
      controls. Induction of IL-8 mRNA was detected by RT-PCR. IL-8 was measured in the
      supernatant of EC by ELISA. In addition, induction of NFkappaB was investigated
      by PAGE of nuclear extracts of EC and Western blot with ab against p65. RESULTS:
      In contrast to controls, interaction of anti-PR-3 antibodies (patients and WGM2)
      with cytokine activated EC led to the highest amount of IL-8 synthesis. Priming
      of EC with cytokines alone induced a markedly lower IL-8 level. The lowest levels
      of IL-8 could be measured after incubation of unprimed EC with anti-PR-3
      antibodies. Anti-PR-3 antibody induced endothelial IL-8 expression could be
      inhibited by cycloheximide. In addition, we established that the activation of NF
      kappaB is critically involved in anti-PR-3 antibody induced endothelial IL-8
      production. CONCLUSION: In summary, we were able to show that anti-PR-3
      antibodies induce endothelial IL-8 synthesis by activating NF-kappaB. As IL-8
      represents a powerful neutrophil chemoattractant, our data provide further
      evidence for a direct pathogenic effect of anti-PR-3 antibodies in ANCA related
      diseases.

PMID- 10583445
TI  - High serum laminin concentrations in patients with Candida sepsis.
AB  - BACKGROUND: Laminin, a major component of the basement membrane, plays a critical
      role in normal cell adhesion and also during tissue invasion of pathogenic
      microorganisms. MATERIALS AND METHODS: Serum laminin concentrations were
      determined in 19 patients with Candida albicans sepsis, in 13 patients with
      bacterial sepsis and in 20 noninfectious controls. RESULTS: Serum laminin
      concentrations of both, patients with candidal and bacterial sepsis, were
      significantly elevated compared to the controls (486 ng mL-1 [155-924], median
      [range]; P < 0.01). Laminin concentrations were significantly higher in patients
      with Candida sepsis than in patients with bacterial sepsis on day 1 (2565 ng mL-1
      [659-6064] vs. 994 ng mL-1 [386-2064]; P < 0.01), day 7 (1594 ng mL-1 [607-4611]
      vs. 684 ng mL-1 [284-1920]; P < 0.05) and day 14 (1444 ng mL-1 [202-2131] vs. 386
      ng mL-1 [180-1658]; P < 0.05). CONCLUSIONS: Laminin serum concentrations might be
      useful to differentiate nonbacterial, bacterial and fungal etiology.

PMID- 10583446
TI  - The p22 phox polymorphism C242T is not associated with CHD risk in Asian Indians
      and Chinese.
AB  - BACKGROUND: Oxygen free radicals such as superoxide anion have been implicated in
      the pathogenesis of atherosclerosis and coronary heart disease (CHD). The
      nonglycosylated 22 kDa alpha-subunit of the NADH/NADPH oxidase (p22 phox) of the
      vasculature acts as the final electron transporter in the generation of
      superoxide anion. Recently, a common polymorphism (C242T) at codon 72 in the p22
      phox gene has been reported to be associated with CHD risk. STUDY DESIGN: We
      examined the role of the C242T polymorphism with the risk of CHD in a biracial
      sample of Asian Indians and Chinese from Singapore. The sample comprised
      angiographically confirmed CHD patients (126 Asian Indians and 151 Chinese) and
      age- and sex-matched healthy control subjects (154 Asian Indians and 167
      Chinese). RESULTS: The frequency of the T allele was significantly higher in
      Asian Indian control subjects than in Chinese control subjects (0.38 vs. 0.09; P
      < 0. 0001). However, there was no difference in the frequency of this allele
      between case patients and control subjects either in Chinese (0.10 vs. 0.09) or
      Asian Indians (0.38 vs. 0.40). This polymorphism was also not associated with
      plasma lipid and apolipoprotein levels in any group. CONCLUSIONS: The p22 phox
      codon 72 polymorphism is not associated with the risk of CHD in the present
      samples of Asian Indians and Chinese.

PMID- 10583447
TI  - Methylenetetrahydrofolate reductase polymorphism, plasma homocysteine and age.
AB  - BACKGROUND: Elevated fasting levels of total homocysteine are now accepted as an
      independent risk factor for the development of arteriosclerotic vascular
      diseases. A polymorphism in the gene encoding methylenetetrahydrofolate reductase
      (MTHFR), caused by the C677T point mutation, leads to increased thermolability of
      the enzyme, with reduced enzyme activity. We studied the frequency of this
      mutation in different groups of the Swiss adult population. PATIENTS AND METHODS:
      DNA from 361 subjects was screened for the thermolabile MTHFR variant with PCR.
      Included were healthy subjects without vascular disease (n = 118), older healthy
      subjects (n = 106), patients with coronary artery disease (CAD, n = 75), and
      patients with peripheral arterial occlusive disease (PAOD, n = 63). RESULTS: In
      the different groups studied, homozygosity for the mutation ranged from 4.8 to
      16.2%, with a frequency of 16.2% in the healthy cohort. The allele frequencies of
      the thermolabile allele were 38.5 and 27.3 in young and old controls, and 37.3
      and 33.3 in CAD and PAOD patients. In the healthy younger subjects the mutant
      allele was 1.4 times more frequent compared to the older subjects (P = 0.01). No
      difference in either MTHFR genotype distribution (P = 0.33) or allele frequencies
      (P = 0.48) between patients and controls was found. Except for the PAOD group
      with elevated tHcy levels for the +/+ carriers compared to the other genotypes,
      no statistically significant difference was found comparing homocysteine levels
      with genotype. CONCLUSION: This study shows no link between the mutation and the
      occurrence of vascular disease but we found evidence pointing to a correlation
      between the mutation and longevity in our population.

PMID- 10583448
TI  - Renal hemodynamic changes during smoking: effects of adrenoreceptor blockade.
AB  - BACKGROUND: Cigarette smoking accelerates progression of renal failure in
      diabetic and nondiabetic renal disease. Renal hemodynamics during smoking are
      characterised by a reversible decrease in glomerular filtration rate (GFR) and
      filtration fraction (FF) accompanied by increased renovascular resistance (RVR),
      systemic blood pressure, heart rate and plasma catecholamine concentrations.
      MATERIALS AND METHODS: To further assess the role of sympathetic overactivity we
      compared the effects of different pharmacological interventions on smoking
      induced changes of renal hemodynamics in occasional smokers. In a first series,
      placebo pretreatment plus smoking was compared to Prazosin pretreatment (3 mg)
      plus smoking. In a second study, placebo pretreatment plus smoking was compared
      to Atenolol pretreatment (50 mg) plus smoking. RESULTS: Basal blood pressure was
      significantly lower with Prazosin and Atenolol. On placebo, GFR and FF decreased
      significantly during smoking and RVR increased. With Prazosin pretreatment
      compared to placebo pretreatment no statistically significant differences for the
      changes of GFR, FF, RPF and RVR were seen. In contrast, with Atenolol
      pretreatment compared to placebo pretreatment, the smoking-induced changes in
      active renin, GFR and RVR were significantly smaller. CONCLUSION: It is suggested
      that the acute renal hemodynamic effects of smoking are mediated, at least in
      part, via increased sympathetic activity operating mainly through beta-1
      adrenergic mechanisms.

PMID- 10583449
TI  - Pretreatment renal vascular tone predicts the effect of specific renin inhibition
      on natriuresis in essential hypertension.
AB  - BACKGROUND: In essential hypertension an elevated renal vascular resistance (RVR)
      may be a marker of renin-angiotensin-aldosterone system-mediated impairment of
      renal sodium excretion. This hypothesis was tested by investigating whether, in
      subjects with essential hypertension, the natriuretic response to specific renin
      angiotensin-aldosterone system (RAAS) blockade by renin-inhibitor remikiren could
      be predicted from pretreatment renal vascular tone. MATERIALS AND METHODS: Renal
      hemodynamics, and the effects of single (n = 17) and multiple doses (n = 8, 8
      days) of remikiren (600 mg day-1) on sodium excretion were studied under
      conditions of carefully controlled sodium balance. RESULTS: Pretreatment renal
      vascular tone showed considerable individual differences: filtration fraction
      (FF) ranged from 21.2 to 30.3% and RVR from 18.8 to 33.5 10-2 mmHg min mL-1 in
      the single dose study, and FF from 20.8 to 24.9% and RVR from 14.8 to 28.8 10-2
      mmHg min mL-1 in the multiple dose study. Remikiren induced a fall in blood
      pressure, FF and RVR, with considerable interindividual variability in
      natriuretic response. During single dose, cumulative sodium loss was 5.1 mmol per
      5 h (-8.8 to +24.6), whereas after 8 days treatment cumulative sodium loss was 72
      +/- 30 mmol (-46 to +187). The natriuretic response to remikiren during single as
      well as multiple dose significantly correlated with pretreatment renal vascular
      tone (estimated from FF and RVR) but not with remikiren-induced changes in renal
      hemodynamics or in hormonal parameters. Cumulative sodium loss was largest in
      patients with a higher pretreatment FF and RVR (r = 0.74, P < 0.001 and r = 0.52,
      P < 0.05, respectively, single dose; and r = 0.75, P < 0.05 and r = 0.73, P <
      0.05, respectively, multiple dose). CONCLUSION: These data support the hypothesis
      that in essential hypertension an elevated renal vascular tone is a marker of
      RAAS-mediated impairment of sodium excretion.

PMID- 10583450
TI  - Vitamin E supplementation in hyperlipidaemic patients: effect of increasing doses
      on in vitro and in vivo low-density lipoprotein oxidation.
AB  - BACKGROUND: Vitamin E supplementation is associated with a reduced risk of
      developing atherosclerotic events; probably because it inhibits low-density
      lipoprotein (LDL) oxidation, an initial step in atherosclerosis. Metal ion
      dependent LDL oxidation is a commonly used method to estimate oxidizability of
      LDL, but the effect of antioxidant supplementation on the levels of
      autoantibodies to oxidised LDL (ox-LDL), an in vivo indicator of LDL oxidation,
      is unknown. DESIGN: This double-blind, placebo-controlled study investigated the
      susceptibility of LDL to copper induced oxidation and malondialdehyde (MDA)
      derivatized-LDL (MDA-LDL) in hyperlipidaemic patients on supplements of vitamin
      E. The vitamin E group (n = 20) took vitamin E 100 IU daily and the dose was
      doubled at six-weekly intervals to 1600 IU daily. The control group (n = 17)
      received placebo in the same fashion. Blood samples were obtained at baseline and
      each subsequent visit to measure vitamin E status and oxidation of LDL. RESULTS:
      A significant increase in both alpha-tocopherol levels and the lengths of lag
      phase was seen in the vitamin E group after first week of supplementation (100 IU
      day-1). This continued to rise in a dose-dependent fashion with a doubling of the
      lag phase on 1600 IU daily. However, the titre of antibodies to MDA-LDL was not
      altered. CONCLUSIONS: The results suggest that although regarded as an in vivo
      marker of LDL oxidation, antibodies to MDA-LDL may not be a suitable measure to
      evaluate the effect of short-term antioxidant supplementation. The failure of
      autoantibody titres to fall despite reduced oxidizability of LDL may possibly be
      attributable to a long half-life of the antibody or, once initiated, a continuous
      immunological response to ox-LDL contained in atherosclerotic lesions of the
      arterial wall.

PMID- 10583451
TI  - Capillary permeability is increased in normo- and microalbuminuric type 1
      diabetic patients: amelioration by ACE-inhibition.
AB  - BACKGROUND: Capillary leakage of sodium-fluorescein (NaF) in the skin reflects
      capillary permeability and may be a marker of diabetes-associated
      microcirculatory abnormalities. DESIGN: We evaluated transcapillary skin NaF
      leakage by fluorescence videodensitometry in 10 normoalbuminuric, 10
      microalbuminuric Type 1 diabetic men (diabetes duration > 10 years) and 10
      healthy subjects. The microalbuminuric patients were restudied after 6 weeks
      treatment with the ACE-inhibitor enalapril, 10 mg once daily. All measurements
      were performed at a blood glucose level of 5 mmol L-1. RESULTS: Transcapillary
      NaF leakage was strongly increased in normoalbuminuric Type 1 diabetic patients
      compared to healthy subjects (P < 0.001) and was still further increased in
      microalbuminuric Type 1 diabetic patients (P < 0.01 compared to normoalbuminuric
      patients). Enalapril reduced NaF leakage (P < 0.05), mean arterial blood pressure
      (P < 0.05) and microalbuminuria (P < 0. 05). After treatment, NaF leakage was not
      different from that in normoalbuminuric patients. CONCLUSIONS: Capillary
      permeability, as determined by NaF leakage, is elevated in normoalbuminuric Type
      1 diabetic patients with long-standing disease, and the excess elevation in
      microalbuminuric Type 1 diabetic patients is ameliorated by ACE-inhibition. Skin
      NaF videodensitometry seems a useful tool to document capillary permeability in
      intervention studies.

PMID- 10583452
TI  - Changes of plasma total homocysteine levels during the menstrual cycle.
AB  - BACKGROUND: It is known that plasma total homocysteine (tHcy) levels are lower in
      premenopausal and pregnant women compared with postmenopausal women. To confirm
      the suggestion that sex steroid hormones are nongenetic factors affecting
      homocysteine metabolism, we investigated the effect of natural steroid hormone
      levels on the fasting plasma tHcy in healthy women during the menstrual cycle.
      MATERIALS AND METHODS: Fifteen premenopausal women were enrolled in this study.
      Plasma tHcy, estradiol, progesterone and cortisol concentrations were measured in
      the luteal and follicular phase. The plasma tHcy concentration was determined by
      high performance liquid chromatography with fluorescence detection, and the
      steroid hormones by RIA methods. RESULTS: Mean homocysteine values increased from
      7.8 micromol L-1 in the luteal phase to 8.9 micromol L-1 in the follicular phase
      (P < 0.000005, Student's paired t-test). We also found slight negative but
      insignificant correlations of homocysteine levels with estradiol in both phases
      of the menstrual cycle. In the case of cortisol and progesterone, no significant
      correlations with plasma homocysteine were found. CONCLUSION: The study provides
      the first evidence of significant differences in plasma homocysteine
      concentration during the menstrual cycle. From our observed findings it is
      necessary to account for the phase of the menstrual cycle when determining
      homocysteine in premenopausal women.

PMID- 10583453
TI  - Suppression of the nocturnal rise in growth hormone reduces subsequent lipolysis
      in subcutaneous adipose tissue.
AB  - BACKGROUND: The aim of this study was to examine the effect of the nocturnal rise
      in growth hormone (GH) concentration on lipolysis in adipose tissue the following
      morning. METHODS: Eight healthy subjects were studied on two occasions (control
      vs. suppression of GH secretion) and six were studied on a third occasion
      (control vs. replacement of GH). Lipolysis in the whole body was assessed by
      measurement of systemic glycerol turnover. Lipid metabolism in the subcutaneous
      adipose tissue of the anterior abdominal wall was studied by measurement of
      arterio-venous differences. RESULTS: Suppression of the nocturnal rise in GH did
      not affect systemic glycerol turnover. However, in subcutaneous abdominal adipose
      tissue it led to a significant reduction in the veno-arterial differences in
      nonesterified fatty acid (NEFA, P = 0.041) and glycerol (P = 0. 014)
      concentrations, reflecting a reduction in intracellular lipolysis (P = 0.011).
      Although arterialized plasma triacylglycerol (TG) concentrations were reduced in
      the absence of the nocturnal GH pulse, the extraction of TG in subcutaneous
      abdominal adipose tissue remained unchanged. CONCLUSION: We conclude that the
      normal nocturnal rise in plasma GH concentration leads to site-specific
      regulation of lipolysis in adipose tissue on the following day, with preferential
      fat mobilization from central depots.

PMID- 10583454
TI  - Does jejunal feeding activate exocrine pancreatic secretion?
AB  - BACKGROUND: The upper small bowel is of pivotal importance for the stimulation of
      exocrine pancreatic secretion in response to a meal. We hypothesize that more
      distal delivery of nutrients into the small intestine will result in less
      activation of pancreatic secretion. MATERIALS AND METHODS: Eight healthy subjects
      (3 male, 5 female; age 23 +/- 1 years) participated in two experiments, performed
      in random order. Subjects were intubated with a 4-lumen tube. Duodenal outputs of
      pancreatic enzymes and bilirubin were measured by aspiration using a recovery
      marker. The distal opening was used for continuous administration of a mixed
      liquid meal and located at either the ligament of Treitz or 60 cm further
      distally. Gallbladder volume was measured and blood samples were drawn for
      determination of gastrointestinal hormones. The duration of each experiment was 4
      h; with 1 h fasting and 3 h continuous administration of nutrients. RESULTS:
      During proximal jejunal feeding, pancreatic enzyme output increased significantly
      over basal levels. No significant increase over basal levels was observed during
      distal jejunal feeding. Bilirubin output and gallbladder contraction were
      significantly (P < 0.05) reduced during distal compared to proximal jejunal
      feeding. No significant differences were found in plasma levels of CCK, PYY and
      neurotensin between proximal and distal jejunal feeding. CONCLUSION: Continuous
      feeding in the distal jejunum does not stimulate exocrine pancreatic secretion
      but maintains gallbladder contraction, although to a lesser extent. These effects
      are not related to hormonal changes but probably reduced activation of the
      enteropancreatic reflexes.

PMID- 10583455
TI  - Creatine corrects muscle 31P spectrum in gyrate atrophy with hyperornithinaemia.
AB  - BACKGROUND: Eye fundus destruction and type II muscle fiber atrophy in gyrate
      atrophy of the choroid and retina with hyperornithinaemia (GA) may be mediated by
      elevated ornithine concentrations which strongly inhibit creatine biosynthesis.
      This results in deficiency of creatine phosphate (PCr), a key intracellular
      energy source, as we have demonstrated in skeletal muscle of the patients by 31P
      magnetic resonance spectroscopy (31P MRS). MATERIALS AND METHODS: Possible
      correction of the relative PCr deficiency by long-term daily exogenous
      supplementation of creatine or its precursors was investigated in four GA
      patients receiving creatine and in five patients treated with guanidinoacetic
      acid-methionine combination. The relative PCr concentration, expressed as PCr/Pi
      (Pi; inorganic phosphate) or as PCr/ATP ratios, was compared with the values of
      untreated GA patients, and matched healthy volunteers. RESULTS: Muscle PCr/Pi
      ratios (mean +/- SD) of the untreated and creatine supplemented GA patients and
      controls were 4.9 +/- 1.4, 7.9 +/- 0.4 and 8.4 +/- 1.3. Guanidinoacetate
      methionine combination was similarly effective (respective PCr/Pi ratios: 4.9 +/-
      0.7, 6.3 +/- 1.1 and 10.7 +/- 2.8). CONCLUSION: Supplementation with creatine or
      creatine precursors almost normalised low muscle PCr/Pi ratios of patients with
      GA.

PMID- 10583456
TI  - Review article: platelet-collagen interactions: membrane receptors and
      intracellular signalling pathways.
AB  - Platelet adhesion to and activation by exposed subendothelial collagen plays a
      critical role in normal haemostasis and pathological thrombosis. Recent advances
      in elucidating the mechanisms underlying platelet-collagen interaction support a
      'two-site, two-step' model. Direct platelet binding to integrin alpha2beta1
      mainly sustains adhesion and allows recognition of glycoprotein VI. The latter
      interaction is responsible for characteristic intracellular signalling events
      leading to p72Syk and PLCgamma2 activation. The present review describes the
      known collagen receptors on platelets and discusses the current understanding of
      signal transduction promoted by collagen.

PMID- 10583457
TI  - L-selectin in trauma patients: a marker for organ dysfunction and outcome?
AB  - BACKGROUND: Systemic inflammatory response syndrome (SIRS) and multiple organ
      dysfunction syndrome (MODS) are important factors affecting morbidity and
      mortality after trauma. Adhesion molecules, e.g. L-selectin (CD62 L), play
      crucial roles in both conditions. PATIENTS AND METHODS: In 51 multiple trauma
      patients, CD62 L surface expression on granulocytes, monocytes, lymphocytes, as
      well as sCD62 L plasma concentrations were determined during the first 6 days
      after trauma, starting at the site of accident. Clinical parameters were severity
      of injury scores (ISS, APACHE II), requirement of red blood cell transfusion,
      acute lung or liver failure, development of MODS or SIRS, early (< or = 6 d) or
      late (> 6 d), and outcome. RESULTS: CD62 L expression was reversibly elevated on
      granulocytes, T cells and monocytes in comparison with initial values. sCD62 L
      plasma concentrations did not show temporal variations but were depressed
      throughout observation period, in comparison with healthy controls. Lung failure
      within the first 6 days was associated with increased CD62 L expression on
      monocytes and B cells on admission and increased sCD62 L concentrations after 12
      and 24 h. Patients with more severe injuries (APACHE II > 20 points) had higher
      sCD62 L concentrations after 24 h. Non-survivors had decreased sCD62 L (on
      admission) and T-cell CD62 L expression (after 4 h). Patients with early MODS or
      SIRS showed increased monocyte CD62 L expression after 6 days. CONCLUSIONS: In
      multiple trauma patients, severe organ dysfunction is associated with altered
      CD62 L expression on leukocytes and circulating sCD62 L plasma concentrations.
      However, the obvious complexity of the pattern currently restricts use of CD62 L
      quantitation for clinical purposes.

PMID- 10583458
TI  - Polymorphism of DR52-associated haplotypes in a Croatian population.
AB  - We investigated DR52 haplotype polymorphism in a population of 78 Croatian
      families with at least one parent and one offspring positive for a DR52
      associated allele, using the PCR-SSOP method. The haplotypes DRB1*0301-DQA1*0501
      DQB1*0201, DRB1*11-DQA1*0501-DQB1*0301 and DRB1*1201-DQA1*0501-DQB1*0301 seem to
      be conserved haplotypes in this Croatian population, while DRB1*13 haplotypes
      showed high diversity. Among 10 different DRB1*13 haplotypes, four consist of
      common alleles, while six have an unusual combination of DRB1-DQA1-DQB1 alleles.
      Three haplotypes (DRB1*1301-DQA1*0103-DQB1*0503, DRB1*1302-DQA1*0102-DQB1*0502
      and DRB1*1303-DQA1*0102-*DQB1*0502) have not been reported. These results on DR52
      associated haplotype polymorphisms in a Croatian population must be taken into
      consideration in organ transplantation, especially when searching for unrelated
      bone marrow donors.

PMID- 10583459
TI  - HLA class II polymorphism in Thai patients with non-Hodgkin's lymphoma.
AB  - The distribution of HLA-DRB1 alleles and DQB1 alleles in 100 Thai patients with
      non-Hodgkin's lymphoma (NHL) was analysed using the polymerase chain reaction
      with sequence-specific primer (PCR-SSP) method, and the association between the
      disease and the presence of certain HLA class II alleles was investigated. The
      frequencies of HLA-DRB1*1502 and DRB1*09012 were increased while those of
      DRB1*0404, DRB1*0803 and DRB1*1106 were decreased. On the other hand, the
      incidence of HLA-DQB1 alleles was similar to that in the normal population.
      Interestingly, only HLA-DRB1*1502 showed a significant positive association with
      NHL, especially in patients < or / = 45 years and in male patients. It is
      concluded that the DRB1*1502 allele may contribute to NHL susceptibility in the
      Thai population. However, further studies on the functional roles of the HLA
      class II alleles are necessary to elucidate NHL susceptibility.

PMID- 10583460
TI  - Human platelet antigens: typing by PCR using sequence-specific primers and their
      distribution in blood donors resident in Wales.
AB  - We developed and validated HPA-1 to HPA-6 typing by PCR-SSP using a combination
      of established, modified and newly designed sequence-specific primers. We
      confirmed that the PCR primer mixtures functioned under the same PCR conditions
      as our standard HLA-A, -B, -C, -DR, -DQ PCR-SSP typing system. This allows
      concurrent testing for both HPA and HLA specificities and is therefore the system
      of choice for both clinical and large-scale blood donor panel HPA and HLA typing
      by PCR-SSP. Test validation included typing a population of blood donors living
      in Wales. These HPA frequencies were consistent with those of other European
      Caucasoid populations. HPA-4b and -6b were absent and HPA-5b, which shows some
      frequency variation, had a phenotype frequency of 18.9% (allele frequency 0.
      0973), being close to that of the Dutch (19.7%) and Austrian (20.4%) populations
      and almost twice that found in Finns (10.0%). HPA genotype frequencies showed a
      good fit to Hardy-Weinberg equilibrium, further supporting the validity of our
      typing method.

PMID- 10583461
TI  - Novel intronic variants of MICB (MHC class I chain-related gene B).
AB  - We report an eight-nucleotide duplication in intron 4 of the MICB allele 01021,
      which was found in samples from different ethnic backgrounds and in association
      with several HLA-B alleles. We suggest that this new MICB allele is
      evolutionarily older than HLA-B alleles.

PMID- 10583462
TI  - Towards understanding the origin and dispersal of Austronesians in the Solomon
      Sea: HLA class II polymorphism in eight distinct populations of Asia-Oceania.
AB  - HLA class II nucleotide sequence polymorphisms were examined in eight ethnic
      groups of Asia-Oceania using DNA typing methods. Allele frequencies and
      characteristic DR/DQ haplotypes were determined and compared with those of other
      populations of Asia-Oceania. Genetic distances were measured to show the genetic
      relationship within the studied populations as well as between the studied
      populations and previously published populations. Phylogenetic trees were
      constructed based on HLA allele frequencies using the neighbour-joining method.
      The populations, mainly Trobriand Islanders, Roro, Tolai, Western Samoans and
      Taiwanese Aborigines, are characterized by a reduced diversity at the HLA loci
      examined, especially for DPB1. The high frequency of the 'Asian'-specific
      DPB1*0501 allele in Trobrianders and Roro, but also in Western Samoans and
      Taiwanese Aborigines, was the most striking result. The prevalence of DPB1*0501
      and the short genetic distance from Trobriander and Roro to Taiwanese Aborigines
      provide evidence that the origin of the Austronesian odyssey is south-east Asia,
      and Taiwan could be an important part of it. The relatedness of Trobrianders to
      the Polynesian population from Western Samoa indicates a probable recent common
      ancestor. The observed lack of diversity may reflect bottleneck(s) and/or limited
      diversity of the founding population. Analysis of HLA class I antigens, together
      with mt-DNA and Y-chromosomal studies, will give us further information about the
      settlement of the Trobriand and other islands during the colonization of the
      Pacific.

PMID- 10583463
TI  - Mitochondrial DNA polymorphism in the Vietnamese population.
AB  - The mitochondrial DNA variation was screened in a sample of 50 unrelated
      individuals of the Vietnamese population originating from Hanoi. A combination of
      long and standard PCR and restriction endonuclease digests with the enzymes HpaI,
      BamHI, HaeII, MspI, AvaII and HincII were used to reveal mtDNA variation. Twenty
      enzyme morphs were detected, three of which (HaeII-13Viet, MspI-19Viet and MspI
      20Viet) are new and are produced by a single mutational event in already known
      enzyme morphs. Ten already known and four new mitotypes [93Viet (1-1-2-4-1),
      94Viet (2-1-13Viet-1-1), 95Viet (2-1-13Viet-19Viet-1) and 96Viet (1-1-2-20Viet
      12)] were found in the Vietnamese population. The 9-bp deletion occurring in the
      COII/tRNALys region of the mitochondrial genome was also analysed and 10 samples
      were found to have this deletion. The comparison of the Vietnamese with other
      East Asian populations showed a close genetic relationship of the population
      under investigation with other Orientals. However, the Vietnamese population can
      be differentiated by the significantly higher frequency of the enzyme morph
      HincII-5 and by seven new markers. These results strongly support the hypothesis
      of a dual ethnic origin of the Vietnamese population from the Chinese and Thai
      Indonesian populations based on HLA markers and linguistic evidence.

PMID- 10583464
TI  - Confirmation of the detection of HLA-A*0104N in a family: a PCR-SSP reaction for
      the allelic detection of HLA-A*0104N.
AB  - The allele A*0104N has been detected in a family with a patient requiring a bone
      marrow transplant. The allele was found as a consequence of a discrepant result
      when family members were typed using serology and polymerase chain reaction using
      sequence-specific primers (PCR-SSP). Serological typing gave an apparent HLA-A
      'blank' while PCR-SSP revealed the presence of an A*01 allele in three family
      members who were serologically negative for A1. Sequencing-based typing (SBT) was
      then used to establish that the allele was A*0104N. A PCR-SSP reaction was
      subsequently designed and used for the allelic detection of A*0104N. The study
      highlights the potential risks involved if molecular technology is used for
      typing, unless all non-expressed alleles are specifically detected.

PMID- 10583465
TI  - Nomenclature for factors of the HLA system, update July/August 1999.

PMID- 10583466
TI  - Brain somatostatin: a candidate inhibitory role in seizures and epileptogenesis.
AB  - Recent evidence shows that neuropeptide expression in the CNS is markedly
      affected by seizure activity, particularly in the limbic system. Changes in
      neuropeptides in specific neuronal populations depend on the type and intensity
      of seizures and on their chronic sequelae (i.e. neurodegeneration and spontaneous
      convulsions). This paper reviews the effects of seizures on somatostatin
      containing neurons, somatostatin mRNA and immunoreactivity, the release of this
      peptide and its receptor subtypes in the CNS. Differences between kindling and
      status epilepticus in rats are emphasized and discussed in the light of an
      inhibitory role of somatostatin on hippocampal excitability. Pharmacological
      studies show that somatostatin affects electrophysiological properties of
      neurons, modulates classical neurotransmission and has anticonvulsant properties
      in experimental models of seizures. This peptidergic system may be an interesting
      target for pharmacological attempts to control pathological hyperactivity in
      neurons, thus providing new directions for the development of novel
      anticonvulsant treatments.

PMID- 10583467
TI  - FAK+ and PYK2/CAKbeta, two related tyrosine kinases highly expressed in the
      central nervous system: similarities and differences in the expression pattern.
AB  - Focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2/cell adhesion
      kinase beta (PYK2/CAKbeta) are related, non-receptor, cytoplasmic tyrosine
      kinases, highly expressed in the central nervous system (CNS). In addition, FAK+
      is a splice isoform of FAK containing a 3-amino acid insertion in the carboxy
      terminal region. In rat hippocampal slices, FAK+ and PYK2/CAKbeta are
      differentially regulated by neurotransmitters and depolarization. We have studied
      the regional and cellular distribution of these kinases in adult rat brain and
      during development. Whereas PYK2/CAKbeta expression increased with postnatal age
      and was maximal in the adult, FAK+ levels were stable. PYK2/CAKbeta mRNAs,
      detected by in situ hybridization, were expressed at low levels in the embryonic
      brain, and became very abundant in the adult forebrain. Immunocytochemistry of
      the adult brain showed a widespread neuronal distribution of FAK+ and
      PYK2/CAKbeta immunoreactivities (ir). PYK2/CAKbeta appeared to be particularly
      abundant in the hippocampus. In hippocampal neurons in culture at early stages of
      development, FAK+ and PYK2/CAKbeta were enriched in the perikarya and growth
      cones. FAK+ extended to the periphery of the growth cones tips, whereas
      PYK2/CAKbeta appeared to be excluded from the lamellipodia. During the
      establishment of polarity, a proximal-distal gradient of increasing PYK2/CAKbeta
      ir could be observed in the growing axon. In most older neurons, FAK+-ir was
      confined to the cell bodies, whereas PYK2/CAKbeta-ir was also present in the
      processes. In vitro and in vivo, a subpopulation of neurons displayed neurites
      with intense FAK+-ir. Thus, FAK+ and PYK2/CAKbeta are differentially regulated
      during development yet they are both abundantly expressed in the adult brain,
      with distinctive but overlapping distributions.

PMID- 10583468
TI  - Differential projections from the anterior and posterior divisions of the
      accessory olfactory bulb to the medial amygdala in the opossum, Monodelphis
      domestica.
AB  - The vomeronasal sensory epithelium of mammals contains apical and basal cell
      populations expressing different G proteins and putative pheromone receptors,
      which project, respectively, to the anterior and posterior divisions of the
      accessory olfactory bulb (AOB). In order to analyse whether these segregated
      pathways are preserved in the connections between the AOB and the amygdala,
      conjugated dextran-amines were iontophoretically injected into the anterior and
      posterior divisions of the AOB. We found that efferent projections from both
      divisions essentially overlap throughout the vomeronasal recipient amygdala. In
      the medial amygdaloid complex, both divisions project to lamina 1A of layer 1 of
      the anterodorsal, anteroventral, posterodorsal and posteroventral nuclei. The
      posterior division alone, however, projects to lamina 1B and layers 2 and 3 of
      the anterodorsal, anteroventral and posteroventral nuclei. These results
      constitute a link between molecular, anatomical and functional approaches on the
      study of the vomeronasal system. Molecular and functional studies support that
      the two segregated pathways between the vomeronasal organ and the AOB are
      functionally different. Similarly, the anatomical approaches to the further
      connections of this system indicate that the medial amygdala possesses ventral
      and dorsal divisions that are hodologically and functionally different. The
      present results demonstrate a differential projection from the posterior AOB to
      the ventral division of the medial amygdala. These findings indicate that the
      segregated pathways of the vomeronasal system continue to the level of the
      amygdala, and they provide some clues about the functional implications.

PMID- 10583469
TI  - Granule cell dispersion is restricted across transverse boundaries in mouse
      chimeras.
AB  - The granular layer of the developing and adult cerebellum is marked by the
      presence of several transverse boundaries, revealed in gene expression patterns
      or as a consequence of genetic mutations. It is unclear whether these boundaries
      represent fundamental differences between granule cell populations or if they are
      a secondary response to regional differences in the underlying Purkinje cells.
      One possibility is that boundaries mark different spatial domains of granule
      cells in a lineage-dependent fashion. To test this hypothesis, we have analysed a
      series of murine embryonic stem cell chimeras marked by the constitutive
      expression of beta-galactosidase in donor granule cells. The chimeras show a
      consistent spatial restriction boundary, located in the granular layer of lobule
      VI in the vermis and extending laterally into crus I of the hemispheres. A second
      boundary was found separating lobules IX and X in the vermis. No correlation was
      found between the genotypes of molecular layer interneurons and the underlying
      granule cells, suggesting that they arise independently. No transverse boundaries
      were observed for the molecular layer interneurons, consistent with the
      hypothesis that they are not generated from precursors in the external granular
      layer. These results indicate that the granular layer of the cerebellum comprises
      cellular domains with different histories separated by consistent spatial
      restriction boundaries.

PMID- 10583470
TI  - Inferior olivary-induced expression of Fos-like immunoreactivity in the
      cerebellar nuclei of wild-type and Lurcher mice.
AB  - Earlier behavioural studies have shown that the expression of the immediate-early
      gene c-fos, as visualized by the immunohistochemical detection of Fos, in the
      inferior olive (IO) correlated closely with expression in related areas of the
      cerebellar nuclei. It has been speculated that the expression of c-fos within the
      cerebellar nuclei may be induced by enhanced spiking activity of the
      immunopositive neurons in the inferior olive. Two potential mechanisms may play a
      role in this process: a direct induction by way of the collaterals of the olivary
      climbing fibres to the cerebellar nuclei, or indirectly, by climbing fibre
      activity-induced depression of mossy fibre-parallel fibre-induced simple spike
      frequency of the Purkinje cells resulting in a subsequent disinhibition of the
      related parts of the cerebellar nuclei. In an attempt to distinguish between
      these possible mechanisms, we analysed Fos immunoreactivity in the
      olivocerebellar system of wild-type mice and in the mutant mouse Lurcher which
      lacks Purkinje cells. The tremorgenic agent harmaline, which is known to induce
      enhanced and rhythmic firing of olivary neurons was given intraperitoneally to
      anaesthetized mice of both genotypes. Harmaline application coincides with the
      induction of Fos-immunoreactive neurons in most areas of the IO in both wild-type
      and Lurcher mice. Both types of mice also showed enhanced expression in the
      larger neurons of the cerebellar nuclei. However, in the smaller, GABAergic
      nucleo-olivary neurons, increased c-fos expression was only observed in the wild
      type mice. We conclude that: (i) increased olivary activity indeed may result in
      increased c-Fos expression in related areas of the cerebellar nuclei; (ii)
      because the indirect mode of induction is not operative in Lurcher mice, the
      olivary collateral innervation of the cerebellar nuclei is sufficient for c-fos
      induction in the larger nucleobulbar neurons in Lurcher and potentially also in
      wild-type mice; however (iii) for the nucleo-olivary cells an intact cerebellar
      cortical input is necessary to evoke increased expression of c-fos following
      harmaline application.

PMID- 10583471
TI  - 5-HT1A and 5-HT1B receptors control the firing of serotoninergic neurons in the
      dorsal raphe nucleus of the mouse: studies in 5-HT1B knock-out mice.
AB  - The characteristics of the spontaneous firing of serotoninergic neurons in the
      dorsal raphe nucleus and its control by serotonin (5-hydroxytryptamine, 5-HT)
      receptors were investigated in wild-type and 5-HT1B knock-out (5-HT1B-/-) mice of
      the 129/Sv strain, anaesthetized with chloral hydrate. In both groups of mice, 5
      HT neurons exhibited a regular activity with an identical firing rate of 0.5-4.5
      spikes/s. Intravenous administration of the 5-HT reuptake inhibitor citalopram or
      the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) induced a
      dose-dependent inhibition of 5-HT neuronal firing which could be reversed by the
      selective 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2
      pyridinyl)cyclohe xane carboxamide (WAY 100635). Both strains were equally
      sensitive to 8-OH-DPAT (ED50 approximately 6.3 microgram/kg i.v.), but the
      mutants were less sensitive than wild-type animals to citalopram (ED50 = 0.49 +/-
      0.02 and 0.28 +/- 0.01 mg/kg i.v., respectively, P < 0.05). This difference could
      be reduced by pre-treatment of wild-type mice with the 5-HT1B/1D antagonist 2'
      methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carbox yli c acid [4
      methoxy-3-(4-methyl-piperazine-1-yl)-phenyl]amide (GR 127935), and might be
      accounted for by the lack of 5-HT1B receptors and a higher density of 5-HT
      reuptake sites (specifically labelled by [3H]citalopram) in 5-HT1B-/- mice. In
      wild-type but not 5-HT1B-/- mice, the 5-HT1B agonists 3-(1,2,5, 6-tetrahydro-4
      pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94253, 3 mg/kg i.v.) and 5-methoxy-3
      (1,2,3, 6-tetrahydropyridin-4-yl)-1H-indole (RU 24969, 0.6 mg/kg i.v.) increased
      the firing rate of 5-HT neurons (+22.4 +/- 2.8% and +13.7 +/- 6.0%, respectively,
      P < 0.05), and this effect could be prevented by the 5-HT1B antagonist GR 127935
      (1 mg/kg i.v.). Altogether, these data indicate that in the mouse, the firing of
      5-HT neurons in the dorsal raphe nucleus is under both an inhibitory control
      through 5-HT1A receptors and an excitatory influence through 5-HT1B receptors.

PMID- 10583472
TI  - The mouse Ptprr gene encodes two protein tyrosine phosphatases, PTP-SL and
      PTPBR7, that display distinct patterns of expression during neural development.
AB  - The protein tyrosine phosphatases PTP-SL and PTPBR7 differ only in the length of
      their N-terminal domain. We show here that PTP-SL and PTPBR7 are isoforms derived
      from a single gene (Ptprr) through developmentally regulated use of alternative
      promoters. Isoform-specific reverse transcriptase-polymer chain reaction (RT-PCR)
      and RNA in situ hybridization experiments reveal that PTPBR7 is expressed during
      early embryogenesis in spinal ganglia cells as well as in developing Purkinje
      cells. Post-natally, PTPBR7 is expressed in various regions of the adult mouse
      brain, but expression in Purkinje cells has ceased and is replaced by the PTP-SL
      specific transcript. In transient transfection experiments it is confirmed that
      PTPBR7 is a type I transmembrane protein tyrosine phosphatase (PTPase). PTP-SL,
      however, appears to be a cytosolic membrane-associated PTPase that is located at
      perinuclear vesicular structures that partly belong to the endosomal compartment.
      Thus, during maturation of Purkinje cells, a gene-promoter switch results in the
      replacement of a receptor-type PTPase by a cytosolic vesicle-associated isoform.

PMID- 10583473
TI  - Astroglia inhibit the proliferation of neocortical cells and prevent the
      generation of small GABAergic neurons in vitro.
AB  - We quantitatively studied the dynamics of rat neocortical precursor proliferation
      in vitro, and additionally examined the effects of neuron-glia interactions on
      the proliferation and differentiation of neurons, and particularly of gamma
      aminobutyric acid (GABA)-containing cells. In cultures grown on glia-free
      substrate, cellular proliferation was detected at least until the end of the
      second week in vitro, but most neurons which expressed detectable amounts of
      microtubule-associated protein at 12 days in vitro were generated early during
      the first week. Further double-labelling experiments, combining 5'-bromo-2'
      deoxyuridine with GABA or beta-tubulin III immunohistochemistry, provided direct
      evidence that neuronal proliferation continued through the second week in vitro,
      and that a population of small GABAergic neurons was generated between 3 and 12
      days in vitro. Culturing cells on a glial substrate significantly reduced the
      generation of small GABAergic cells and strongly inhibited the total cell
      proliferation. Inhibition also occurred if astrocytes were added to the culture
      after 6 days in vitro, but was significantly decreased if cells were grown on a
      fixed glial substrate, suggesting that the effect might be at least partially
      mediated by active interactions between neurons and glia. In conclusion, our
      results show that the sustained proliferation of precursor cells in neocortical
      cultures is necessary for the differentiation of small GABAergic neurons, and
      that mature astroglia effectively inhibit the proliferation of neocortical
      precursors thereby affecting the appearance of a population of GABAergic cells.

PMID- 10583474
TI  - 3-Hydroxykynurenine potentiates quinolinate but not NMDA toxicity in the rat
      striatum.
AB  - L-3-Hydroxykynurenine (L-3-HK) and quinolinate (QUIN) are two metabolites of the
      kynurenine pathway, the major route of tryptophan degradation in mammals. L-3-HK
      is a known generator of highly reactive free radicals, whereas QUIN is an
      endogenous excitotoxin acting specifically at N-methyl-D-aspartate (NMDA)
      receptors. This study was designed to examine possible synergistic interactions
      between L-3-HK and QUIN in the rat brain in vivo. Intrastriatal coinjection of 5
      nmol L-3-HK and 15 nmol QUIN, i.e. doses which caused no or minimal
      neurodegeneration on their own, resulted in substantial neuronal loss, determined
      both behaviourally (apomorphine-induced rotations) and histologically
      (quantitative assessment of lesion size). The excitotoxic nature of the lesion
      was verified by tyrosine hydroxylase immunohistochemistry, showing the survival
      of dopaminergic striatal afferents. There was also a relative sparing of large
      striatal neurons, and neurodegeneration was prevented both by NMDA receptor
      blockade (using CGP 40116) and free radical scavenging [using N-tert-butyl-alpha
      (2-sulphophenyl)-nitrone, S-PBN]. The pro-excitotoxic features of L-3-HK were
      especially pronounced at low QUIN doses and were not observed when QUIN was
      substituted by NMDA. Notably, the effect of L-3-HK was not due to its
      intracerebral conversion to QUIN and was duplicated by equimolar D,L-3-HK. These
      data indicate that an elevation of L-3-HK levels constitutes a significant hazard
      in situations of excitotoxic injury. Pharmacological interventions aimed at
      decreasing L-3-HK formation may therefore be particularly useful for the
      treatment of neurological diseases which are associated with an abnormally
      enhanced flux through the kynurenine pathway.

PMID- 10583475
TI  - Time-dependent induction of depotentiation in the dentate gyrus of freely moving
      rats: involvement of group 2 metabotropic glutamate receptors.
AB  - Depotentiation comprises a reversal of tetanization-induced long-term
      potentiation (LTP) which occurs following low-frequency stimulation (LFS) in the
      hippocampus in vivo. Although depotentiation has been consistently demonstrated
      in the CA1 region, no positive reports of the existence of depotentiation in the
      dentate gyrus in vivo have occurred. This study therefore investigated whether
      depotentiation is possible in the dentate gyrus in vivo. We found that
      depotentiation can be induced, but it is very tightly dependent on the interval
      between tetanization and LFS. Thus, LFS given 2 or 5 min following tetanization
      produced significant depotentiation, whereas LFS given 10-30 min following
      tetanization had no significant effect on the expression of LTP. Depotentiation
      occurred in two phases: a transient depression of evoked responses to below pre
      tetanization values, which occurred in the first 60 min following LFS, and a
      recovery of this response to a stable level of synaptic transmission which
      comprised a significant reduction in the magnitude of LTP. Group 2 metabotropic
      glutamate receptors (mGluRs) play an important role in the expression of long
      term depression in vivo. We therefore investigated whether group 2 mGluRs
      contribute to depotentiation. The group 2 antagonist (2S)-alpha-ethylglutamic
      acid (EGLU) inhibited the early transient depression at a concentration which
      inhibits LTD in vivo, but did not block the expression of depotentiation. EGLU
      also inhibited the transient depression induced by 5 Hz given alone. Increasing
      the concentration of EGLU prevented depotentiation, however. The group 2 agonist
      (S)-4-carboxy-3-hydroxyphenyl- glycine (4C3HPG) inhibited LTP and enhanced
      depotentiation. These data suggest a role for group 2 mGluRs in depotentiation.

PMID- 10583476
TI  - NT-3 promotes growth of lesioned adult rat sensory axons ascending in the dorsal
      columns of the spinal cord.
AB  - The regeneration capacity of spinal cord axons is severely limited. Recently,
      much attention has focused on promoting regeneration of descending spinal cord
      pathways, but little is known about the regenerative capacity of ascending axons.
      Here we have assessed the ability of neurotrophic factors to promote regeneration
      of sensory neurons whose central axons ascend in the dorsal columns. The dorsal
      columns of adult rats were crushed and either brain-derived neurotrophic factor
      (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3)
      or a vehicle solution was delivered continuously to the lesion site for 4 weeks.
      Transganglionic labelling with cholera toxin beta subunit (CTB) was used to
      selectively label large myelinated Abeta fibres. In lesioned rats treated with
      vehicle, CTB-labelled fibres were observed ascending in the gracile fasciculus,
      but these stopped abruptly at the lesion site, with no evidence of sprouting or
      growth into lesioned tissue. No CTB-labelled terminals were observed in the
      gracile nucleus, indicating that the lesion successfully severed all ascending
      dorsal column axons. Treatment with BDNF did not promote axonal regeneration. In
      GDNF-treated rats fibres grew around cavities in caudal degenerated tissue but
      did not approach the lesion epicentre. NT-3, in contrast, had a striking effect
      on promoting growth of lesioned dorsal column axons with an abundance of fibre
      sprouting apparent at the lesion site, and many fibres extending into and beyond
      the lesion epicentre. Quantification of fibre growth confirmed that only in NT-3
      treated rats did fibres grow into the crush site and beyond. No evidence of
      terminal staining in the gracile nucleus was apparent following any treatment.
      Thus, although NT-3 promotes extensive growth of lesioned axons, other factors
      may be required for complete regeneration of these long ascending projections
      back to the dorsal column nuclei. The intrathecal delivery of NT-3 or other
      neurotrophic molecules has obvious advantages in clinical applications, as we
      show for the first time that dorsal column axonal regeneration can be achieved
      without the use of graft implantation or nerve lesions.

PMID- 10583477
TI  - Stimulation of adenosine A1 receptors attenuates dopamine D1 receptor-mediated
      increase of NGFI-A, c-fos and jun-B mRNA levels in the dopamine-denervated
      striatum and dopamine D1 receptor-mediated turning behaviour.
AB  - Adenosine A1 receptors antagonistically and specifically modulate the binding and
      functional characteristics of dopamine D1 receptors. In the striatum this
      interaction seems to take place in the GABAergic strionigro-strioentopeduncular
      neurons, where both receptors are colocalized. D1 receptors in the strionigro
      strioentopeduncular neurons are involved in the increased striatal expression of
      immediate-early genes induced by the systemic administration of psychostimulants
      and D1 receptor agonists. Previous results suggest that a basal expression of the
      immediate-early gene c-fos tonically facilitates the functioning of strionigro
      strioentopeduncular neurons and facilitates D1 receptor-mediated motor
      activation. The role of A1 receptors in the modulation of the expression of
      striatal D1 receptor-regulated immediate-early genes and the D1 receptor-mediated
      motor activation was investigated in rats with a unilateral lesion of the
      ascending dopaminergic pathways. The systemic administration of the A1 agonist N6
      cyclopentyladenosine (CPA, 0.1 mg/kg) significantly decreased the number of
      contralateral turns induced by the D1 agonist SKF 38393 (3 mg/kg). Higher doses
      of CPA (0.5 mg/kg) were necessary to inhibit the turning behaviour induced by the
      D2 agonist quinpirole (0.1 mg/kg). By using in situ hybridization it was found
      that CPA (0.1 mg/kg) significantly inhibited the SKF 38393-induced increase in
      the expression of NGFI-A and c-fos mRNA levels in the dopamine-denervated
      striatum. The increase in jun-B mRNA expression could only be inhibited with the
      high dose of CPA (0.5 mg/kg). A stronger effect of the A1 agonist was found in
      the ventral striatum (nucleus accumbens) compared with the dorsal striatum
      (dorsolateral caudate-putamen). The results indicate the existence of
      antagonistic A1-D1 receptor-receptor interactions in the dopamine-denervated
      striatum controlling D1 receptor transduction at supersensitive D1 receptors.

PMID- 10583478
TI  - Abnormal expression of neurofilament proteins in dysmyelinating axons located in
      the central nervous system of jimpy mutant mice.
AB  - Myelination in the peripheral nervous system is considered to increase the
      phosphorylation level of neurofilament proteins in the axon, resulting in an
      increase in axonal calibre. To understand the relationship between myelination
      and neurofilament proteins in axons, we examined jimpy mutant mice with a point
      mutation in the proteolipid protein gene and dysmyelination in the central
      nervous system. The jimpy mice exhibited a characteristic similarity in
      neurofilament nature to the myelin-deficient mice in the peripheral nervous
      system reported previously. The following novel results were obtained in the
      jimpy mice: dysmyelinated axons, in which the amount of non-phosphorylated
      neurofilament-H was drastically increased without a significant reduction of the
      phosphorylated form, compared with the control myelinated axons, did not suffer
      any decrease in their diameters. Expression levels of all neurofilament subunit
      proteins and their mRNAs were enhanced in the central nervous system tissue.
      Because the above biochemical data were obtained from the cytoskeletal fraction,
      at least some of the increased neurofilament-H and -M proteins appeared to be
      coassembled into neurofilaments but remained non-phosphorylated. Axonal
      neurofilaments of the jimpy were, probably due to this abnormal stoichiometry and
      phosphorylation state in neurofilaments, more compact and random in alignment
      with less prominent cross-bridges than those of the control, providing possible
      evidence for disturbing the axonal transport of other organelles. These results
      suggest that myelination regulates both the expression and phosphorylation of
      neurofilament proteins, and is essential for the cytoplasmic organization of
      myelinated axons.

PMID- 10583479
TI  - Nerve growth factor (NGF) induces motoneuron apoptosis in rat embryonic spinal
      cord in vitro.
AB  - Recent studies have demonstrated that nerve growth factor (NGF) induces apoptosis
      of several cell types in the central nervous system through its low-affinity p75
      neurotrophin receptor (p75NTR). To test the effect of NGF on embryonic motoneuron
      survival, we developed an organotypic culture system which allowed the in vitro
      development of intact embryonic rat spinal cords. In our system, neural tubes
      were taken and cultured at E13, just before the onset of physiological motoneuron
      death. After 2 days in vitro (DIV), motoneurons underwent apoptosis over a time
      course similar to that in vivo. In this system, the addition of NGF (200 ng/mL)
      for 2 days enhanced the number of apoptotic motoneurons by 37%. This pro
      apoptotic effect was completely reversed by the blocking anti-p75NTR (REX)
      antibody which inhibits NGF binding to p75NTR. Other neurotrophins, e.g. brain
      derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4/5
      (NT4/5) did not have any effect, while glial cell-derived neurotrophic factor
      (GDNF) promoted motoneuron survival. Anti-BDNF blocking antibodies enhanced
      motoneuron death indicating that endogenous BDNF promotes motoneuron survival in
      explants. Our results demonstrate, for the first time, that NGF can induce
      embryonic motoneuron apoptosis through its receptor p75NTR.

PMID- 10583480
TI  - Vasopressin in the lateral septum promotes elemental conditioning to the
      detriment of contextual fear conditioning in mice.
AB  - Previous experiments using a classical fear conditioning paradigm have provided
      evidence that the processing of contextual conditional stimuli (CSs) by the
      hippocampus would be controlled by the amygdala through a modulation of
      hippocampal-lateral septal (H-LS) excitability. More specifically, our suggestion
      was that vasopressin release into the LS would occur in an elemental conditioning
      case [pairing CS-US (unconditional stimulus) procedure] and would result in less
      hippocampal-dependent contextual stimuli processing (i.e. overshadowing of CSs by
      the simple CS). Conversely, when an unpairing CS-US procedure is used, this would
      result in more contextual stimuli processing through a decrease in vasopressin
      release into the LS. The aim of the present experiment was to test this
      hypothesis using intraseptal injection of vasopressin or its V1/V2 antagonist. In
      agreement with this hypothesis, results suggest that vasopressin release into the
      LS would constitute a device by which priority is given to the more salient
      simple stimulus to the detriment of contextual information.

PMID- 10583481
TI  - The cortical visual area V6: brain location and visual topography.
AB  - The brain location and topographical organization of the cortical visual area V6
      was studied in five hemispheres of four awake macaque monkeys. Area V6 is located
      in the caudal aspect of the superior parietal lobule (SPL). It occupies a 'C'
      shaped belt of cortex whose upper branch is in the depth of the parieto-occipital
      sulcus (POS) and lower one is in the depth of the medial parieto-occipital sulcus
      (POM), with the medial surface of the brain as a zone of junction between the two
      branches. Area V6 contains a topographically organized representation of the
      contralateral visual field up to an eccentricity of at least 80 degrees. The
      lower visual field representation is located dorsally, in the ventral part of
      POS, and the upper field ventrally, in the dorsal wall of POM. The representation
      of the horizontal meridian forms the posterior border of V6. It is adjacent to
      area V3 in POS as well as in the caudal part of POM, on the ventral convexity of
      the brain. The lower vertical meridian forms the anterior border of V6, adjacent
      to area V6A. The upper vertical meridian is in the depth of POM. The
      representation of the central visual field is not magnified relative to that of
      the periphery. The central visual field (below 20-30 degrees of eccentricity) is
      represented in the medial-most aspect of the annectant gyrus, in the lateral part
      of the posterior bank of POS. The visuotopic organization of area V6 suggests a
      role in the analysis of the flow field resulting from self-motion, in selecting
      targets during visual searching as well as in the control of arm-reaching
      movements towards non-foveated targets.

PMID- 10583482
TI  - The paleocortical ventricle is the origin of reelin-expressing neurons in the
      marginal zone of the foetal human neocortex.
AB  - The subpial granular layer (SGL) is a transient cell layer in the cortical
      marginal zone during the period of neuronal migration into the cortical plate.
      The origin of the SGL has been studied by immunocytochemistry for calretinin (CR)
      and reelin in human foetuses from 11 to 40 gestational weeks (GW). At 11 GW, the
      paleocortical ventricle, a rostral dilatation of the lateral ventricle, gives
      rise to two fountainheads: a medial fountainhead provides neurons for the
      marginal zone (MZ) of the rostral cortex and rostral hippocampal rudiment, while
      multiple cell streams migrate from a lateral fountainhead into the MZ of the
      paleocortex and insula. The latero-medial gradient of neuronal packing density in
      the neocortical MZ indicates that migration extends farther into the neocortex.
      Neurons express CR already in the retrobulbar ventricular zone; they express
      reelin only as they approach the MZ of the paleocortex and rostral archicortex.
      At 16/17 GW, large numbers of CR-immunoreactive granule cells originate from the
      same fountainheads, and then direct medially, toward the surface of the anterior
      perforated substance, and laterally, into the paleocortical MZ, from where they
      continue into the neocortical SGL following a ventrolateral to dorsomedial
      gradient. From 13 to 18 GW, reelin is expressed by a subpopulation of granule
      cells and by Cajal-Retzius-like neurons. By 22 GW, the paleocortical ventricle
      undergoes regression and no longer supplies the SGL. Our results show that the
      paleocortical ventricle gives rise to a stream of neurons which extends over the
      cortical MZ as the subpial granular layer. The fact that SGL derivatives express
      reelin suggests that this transient cell layer may play a significant role in the
      establishment of the complex cytoarchitecture of the cerebral cortex.

PMID- 10583483
TI  - Improved auditory spatial acuity in visually deprived ferrets.
AB  - We have examined the effects on auditory spatial acuity in the horizontal plane
      of depriving ferrets of patterned visual cues by binocular eyelid suture in
      infancy or for a comparable period in adulthood. Minimum audible angles (MAAs)
      were measured for 500-, 100- and 40-ms broadband noise bursts at the midline and
      at 45 degrees to one side. A logistic regression analysis revealed no consistent
      difference between the midline MAAs of normal and infant lid-sutured ferrets.
      However, the lateral field MAAs of the infant-deprived group were significantly
      smaller and showed less inter-subject variability than those of normal-sighted
      ferrets. The animals deprived in adulthood were tested in the lateral field only,
      firstly 6 months after binocular eyelid suture and again after a further 10
      months. For the first test, the MAAs achieved by these animals with 500- and 100
      ms noise bursts were significantly smaller than the normal values and no
      different from those of the infant-deprived group. A significant improvement in
      performance at the two shortest stimulus durations (100 and 40 ms) was observed
      when the adult-deprived animals were re-tested. Their second-test MAAs did not
      differ from those of the infant-deprived group at any of the three stimulus
      durations used, and both groups achieved significantly better scores than the
      normal-sighted control animals. These results show that prolonged visual
      deprivation in both juvenile and adult ferrets can lead to a significant
      improvement in auditory spatial acuity in the lateral sound field. This is
      consistent with reports that congenitally blind humans can localize peripheral
      sounds more accurately than normal controls.

PMID- 10583484
TI  - Stimulation of nicotinic receptors in the lateral septal nucleus increases
      anxiety.
AB  - The present study investigated the role of nicotinic receptors in the lateral
      septum in the modulation of anxiety. The effects of direct injections of nicotine
      into the lateral septum were first investigated in two tests of anxiety, social
      interaction and elevated plus-maze tests. Intra-septal injection of nicotine (1
      and 4 microgram) induced consistent anxiogenic effects in both tests. The
      reversal of nicotinic effects with mecamylamine was then studied in the social
      interaction test. Intra-septal injection of mecamylamine at a low dose (15 ng)
      induced an anxiolytic effect, suggesting the presence of intrinsic cholinergic
      tone increasing anxiety. At higher doses (30-50 ng), mecamylamine was without
      effect in the social interaction test, but blocked the anxiogenic effects of
      nicotine (4 microgram). These findings provide further evidence for the role of
      the lateral septum in the modulation of anxiety and suggest that cholinergic
      projections to this brain area facilitate anxiety through nicotinic receptors.

PMID- 10583486
TI  - The spatial representation of chemical structures in the antennal lobe of
      honeybees: steps towards the olfactory code.
AB  - Odours are represented by specific ensembles of activated glomeruli in a
      combinatorial manner within the olfactory bulb of vertebrates or the antennal
      lobe (AL) of insects. Here, we optically measured glomerular calcium activities
      in vivo in the honeybee Apis mellifera during olfactory stimulation with 36 pure
      chemicals differing systematically in carbon chain length (C-5-10) and functional
      group (aldehyde, ketone, alcohol, carboxylic acid and alkane). We show their
      glomerular representations in 38 morphologically identified glomeruli out of the
      honeybee's 160. We measured the molecular receptive range of identified glomeruli
      averaging up to 21 individuals. Of the 38 glomeruli measured, 23 show maximal
      activity in a specific range of chain length. Glomeruli preferentially responding
      to a functional group are also always broadly tuned to particular chain lengths.
      Furthermore, glomeruli with similar response spectra are often direct neighbours.
      The results allow conclusions about the interactions between olfactory receptors
      and odour molecules, and about the AL network.

PMID- 10583485
TI  - Postnatal loss of Merkel cells, but not of slowly adapting mechanoreceptors in
      mice lacking the neurotrophin receptor p75.
AB  - Merkel cells are specialized epidermal cells which are abundantly found in touch
      sensitive areas and which are innervated by slowly adapting mechanosensitive
      afferent fibres with large myelinated (Abeta) axons. The role of Merkel cells in
      mechanosensation, their developmental regulation and their influence on sensory
      neuron function are, however, incompletely understood. Here, we used mice lacking
      the neurotrophin receptor p75 which is expressed on Merkel cells to investigate
      their postnatal development and that of their innervating sensory neurons. Using
      morphological studies we now show that Merkel cells develop normally in both
      hairy and glabrous skin in these animals until 2 weeks old, but are progressively
      lost thereafter and have almost completely disappeared 2 months after birth.
      Using standard extracellular electrophysiological recording techniques we find
      that despite the profound loss of Merkel cells there is no corresponding
      reduction in the number of myelinated slowly adapting afferent fibres. Moreover,
      the mean mechanical threshold of these neurons and their average stimulus
      response function to suprathreshold mechanical stimuli does not change during the
      time period when more than 99% of Merkel cells are lost. We conclude that Merkel
      cells require p75 during the late postnatal development. However, neither the
      survival nor the mechanical sensitivity of slowly adapting mechanoreceptive Abeta
      fibres depends on the presence of Merkel cells.

PMID- 10583487
TI  - Role of the corpus callosum in the somatosensory activation of the ipsilateral
      cerebral cortex: an fMRI study of callosotomized patients.
AB  - To verify whether the activation of the posterior parietal and parietal opercular
      cortices to tactile stimulation of the ipsilateral hand is mediated by the corpus
      callosum, a functional magnetic resonance imaging (fMRI, 1.0 tesla) study was
      performed in 12 control and 12 callosotomized subjects (three with total and nine
      with partial resection). Eleven patients were also submitted to the tactile
      naming test. In all subjects, unilateral tactile stimulation provoked a signal
      increase temporally correlated with the stimulus in three cortical regions of the
      contralateral hemisphere. One corresponded to the first somatosensory area, the
      second was in the posterior parietal cortex, and the third in the parietal
      opercular cortex. In controls, activation was also observed in the ipsilateral
      posterior parietal and parietal opercular cortices, in regions anatomically
      corresponding to those activated contralaterally. In callosotomized subjects,
      activation in the ipsilateral hemisphere was observed only in two patients with
      splenium and posterior body intact. These two patients and another four with the
      entire splenium and variable portions of the posterior body unsectioned named
      objects explored with the right and left hand without errors. This ability was
      impaired in the other patients. The present physiological and anatomical data
      indicate that in humans activation of the posterior parietal and parietal
      opercular cortices in the hemisphere ipsilateral to the stimulated hand is
      mediated by the corpus callosum, and that the commissural fibres involved
      probably cross the midline in the posterior third of its body.

PMID- 10583489
TI  - Behavioural trait of reactivity to novelty is related to hippocampal
      neurogenesis.
AB  - The hippocampal formation is one of the brain areas where neurogenesis persists
      during adulthood, with new neurons being continuously added to the population of
      dentate granule cells. However, the functional implications of this neurogenesis
      are unknown. On the other hand, the hippocampal formation is particularly
      concerned with the detection of novelty, and there are indications that dentate
      granule cells play a significant role in this function. Recently, the existence
      of inter-individual differences in behavioural reactivity to novelty has been
      evidenced, related to differences in the reactivity of the hypothalamic-pituitary
      adrenal axis (HPA). Rats that are highly reactive to novelty (HR) exhibit a
      prolonged corticosterone secretion in response to novelty and to stress when
      compared with low reactive rats (LR). Taking advantage of the existence of these
      inter-individual differences, we investigated whether neurogenesis in the dentate
      gyrus is correlated with the behavioural trait of reactivity to novelty. Rats
      were first selected according to their locomotor reactivity to a novel
      environment. Two weeks later, cell proliferation, evaluated by the incorporation
      of 5-bromo-2'-deoxyuridine (BrdU) in progenitors, was studied by
      immunohistochemistry. We found that cell proliferation in the dentate gyrus was
      negatively correlated with locomotor reactivity to novelty. Indeed, cell
      proliferation in LR rats was twice that observed in HR rats. In contrast,
      survival of nascent neurons was not influenced by the behavioural trait of
      reactivity to novelty. Using an unbiased stereology, we show that LR rats had
      more cells within the granule cell layer of the dentate gyrus than did HR rats.
      These results demonstrate the existence of inter-individual differences in
      neurogenesis and total granule cell number within the dentate gyrus. These
      differences in hippocampal plasticity can be predicted by the behavioural trait
      of reactivity to novelty.

PMID- 10583488
TI  - The modulation of calcium current by GABA metabotropic receptors in a sub
      population of pallidal neurons.
AB  - Globus pallidus (GP) receives an abundant GABAergic (gamma-aminobutyric acid)
      pathway from the corpus striatum. Several evidences suggested that alterations of
      this pathway might underlie the development of movement disorders. Classical
      models on Parkinsonism are centred on the increased excitability of GABAergic
      striatofugal neurons impinging GP and, therefore, on the presumed hypoactivity of
      GP neurons, but very few electrophysiological studies have addressed the
      activation of GABA receptors in mammalian GP. We have isolated calcium currents
      in GP neurons dissociated from the adult rat brain and analysed GABA-mediated
      responses. In the presence of bicuculline, the fast, chloride-mediated,
      ionotropic responses were obscured and GABA produced a large (>/= 35%) inhibition
      of calcium currents. The GABA-induced inhibition of calcium currents strongly
      desensitized was mimicked by baclofen and prevented by hydroxy-saclofen,
      supporting the involvement of GABAB receptors. The baclofen-mediated modulation
      was: (i) associated with slowing of activation kinetics; (ii) relieved by
      prepulse facilitation; and (iii) G-protein-mediated. The response was slow in
      onset, requiring the mobilization of intracellular cAMP, and was abolished by the
      combination of N-type and P-type calcium channel blockers. The GABAB-mediated
      effect, however, was confined to a particular subtype of GP neurons, identified
      by relatively small to medium soma. Differently, in cells characterized by larger
      somata and capacitance, the baclofen response was negligible. Intriguingly, these
      baclofen-resistant, larger neurons manifested a consistent low-voltage-activated
      (LVA) calcium current, not detected in baclofen-sensitive cells, at least when
      recorded in whole-cell mode. This study demonstrates that GP neurons express
      functional GABAA and GABAB receptors. In a subset of GP neurons, the activation
      of GABAB receptors induces a large modulation of high-voltage-activated (HVA)
      calcium currents, which may strongly influence basal ganglia circuitry and
      partially explain some discrepancies of classical models of extrapyramidal
      disorders.

PMID- 10583490
TI  - Late embryonic expression of AMPA receptor function in the CA1 region of the
      intact hippocampus in vitro.
AB  - Studies in slices suggest that alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionic acid (AMPA) receptor-mediated synaptic currents are not
      present in CA1 (Cornu ammonis) pyramidal neurons at birth (P0). We have re
      examined this issue in the rat intact hippocampal formation (IHF) in vitro.
      Injections of biocytin or carbocyanine show that the temporo-ammonic, commissural
      and Schaffer collateral pathways are present at birth in the marginal zone of
      CA1. Electrical stimulation of these pathways evoked field excitatory
      postsynaptic potentials (fEPSPs) in the marginal zone of CA1 from embryonic day
      19 (E19) to postnatal day 9 (P9). These fEPSPs are mediated by synaptic AMPA
      receptors as they are reduced or completely blocked by: (i) tetrodotoxin; (ii)
      high divalent cation concentrations; (iii) the adenosine A1 receptor agonist CPA;
      (iv) anoxic episodes; (v) the selective AMPA receptor antagonist 1-(4
      aminophenyl)-3-methylcarbamyl-4-methyl-7, 8-methylenedioxy-3,4-dihydro-5H-2,3
      benzodiazepine (GYKI-53655) or the mixed AMPA-kainate receptor antagonists 6
      cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6-nitro-7
      sulphamoylbenzo[f]quinoxaline-2,3-dione (NBQX). The amplitude of the fEPSPs is
      also reduced by D(-)-2-amino-5-phosphonopentanoic acid (D-APV) and its duration
      is increased by bicuculline suggesting the participation of N-methyl-D-aspartate
      (NMDA) and GABAA (gamma-aminobutyric acid) receptors. Finally, AMPA receptor
      mediated fEPSPs are also recorded in P0 slices, but they are smaller and more
      labile than in the IHF. Our results suggest that in embryonic CA1 neurons,
      glutamate acting on AMPA receptors already provides a substantial part of the
      excitatory drive and may play an important role in the activity-dependent
      development of the hippocampus. Furthermore, the IHF may be a convenient
      preparation to investigate the properties of the developing hippocampus.

PMID- 10583491
TI  - Neuronal correlates of real and illusory contour perception: functional anatomy
      with PET.
AB  - Illusory contours provide a striking example of the visual system's ability to
      extract a meaningful representation of the surroundings from fragmented visual
      stimuli. Psychophysical and neurophysiological data suggest that illusory
      contours are processed in early visual cortical areas, and neuroimaging studies
      in humans have shown that Kanizsa-type illusory contours activate early
      retinotopic visual areas that are also activated by real contours. It is not
      known whether other types of illusory contours are processed by the same
      mechanisms, nor is it clear to what extent attentional effects may have
      influenced these results, as no attempt was made to match the salience of real
      and illusory stimuli in previous imaging studies. It therefore remains an open
      question whether there are any brain regions specifically involved in the
      perception of illusory contours. To address these questions, we have used 15O
      butanol positron emission tomography (PET) and a novel kind of illusory contour
      stimulus that is induced only by aligned line ends. By employing a form
      discrimination task that was matched for attention and stimulus salience across
      conditions we were able to directly contrast perception of real and illusory
      contours. We found that the regions activated by illusory contour perception were
      the same as those activated by real contours. Only one region, located in the
      right fusiform gyrus, was significantly more strongly activated by perception of
      illusory contours than by real contours. In addition, a principal component
      analysis suggested that illusory contour perception is associated with a change
      in the correlation between V1 and V2. We conclude that different kinds of
      illusory contours are processed by the same cortical regions and that these
      regions overlap extensively with those involved in processing of real contours.
      At the regional level, perception of illusory contours thus appears to differ
      from perception of real contours by the degree of involvement of higher visual
      areas as well as by the nature of interaction between early visual areas.

PMID- 10583492
TI  - Brain activity underlying stereotyped and non-stereotyped retrieval of learned
      stimulus-response associations.
AB  - When humans retrieve learned stimulus-response associations in a stereotyped
      manner the necessary brain structures may differ from those required when the
      same associations must be retrieved and adapted to new circumstances. We tested
      this hypothesis by means of tasks that resembled those employed in monkeys, using
      positron emission tomography (PET). Stimuli consisted of abstract two-dimensional
      shapes. Stereotyped retrieval of learned stimulus-response associations was
      studied by the use of a concurrent discrimination task with fixed pairing. This
      was contrasted with conditions requiring retrieval and adaptation of learned
      associations: forced-choice recognition, response reversal and concurrent
      discrimination with random pairing. Visuomotor control, passive viewing and
      fixation conditions were also included. During concurrent discrimination with
      fixed pairing, the left lower precentral gyrus and rostral anterior cingulate
      demonstrated higher blood flow levels in comparison with recognition, concurrent
      discrimination with random pairing, and to a lesser degree, response reversal. In
      the left lower precentral gyrus these blood flow levels were also higher in
      comparison with control conditions. Conversely, during recognition, concurrent
      discrimination with random pairing and reversal, a single region within the right
      inferior frontal gyrus demonstrated higher blood flow levels in comparison with
      concurrent discrimination with fixed pairing and control conditions. This right
      inferior frontal gyrus activation did not depend on the need for active
      familiarity judgements or response inhibition. To conclude, the left lower
      precentral gyrus is more active during stereotyped retrieval of learned stimulus
      response associations and the right inferior prefrontal cortex is more active
      when a learned stimulus-response association must be retrieved and adapted to new
      circumstances.

PMID- 10583493
TI  - Long-term enhancement of REM sleep by the pituitary adenylyl cyclase-activating
      polypeptide (PACAP) in the pontine reticular formation of the rat.
AB  - In rats, rapid eye movement (REM) sleep can be elicited by microinjection of
      vasoactive intestinal polypeptide (VIP) into the oral pontine reticular nucleus
      (PnO). In the present study, we investigated whether this area could also be a
      REM-promoting target for a peptide closely related to VIP: the pituitary adenylyl
      cyclase-activating polypeptide (PACAP). When administered into the posterior part
      of the PnO, but not in nearby areas, of freely moving chronically implanted rats,
      PACAP-27 and PACAP-38 (0.3 and 3 pmol) induced a marked enhancement (60-85% over
      baseline) of REM sleep for 8 h that could be prevented by prior infusion of the
      antagonist PACAP-(6-27) (3 pmol) into the same site. Moreover, injections of
      PACAP into the centre of the posterior PnO resulted in REM sleep enhancement
      which could last for up to 11 consecutive days. Quantitative autoradiography
      using [125I]PACAP-27 revealed the presence in the PnO of specific binding sites
      with high affinity for PACAP-27 and PACAP-38 (IC50 = 2.4 and 3.2 nM,
      respectively), but very low affinity for VIP (IC50 > 1 microM). These data
      suggest that PACAP within the PnO may play a key role in REM sleep regulation,
      and provide evidence for long-term (several days) mechanisms involved in such a
      control. PAC1 receptors which have a much higher affinity for PACAP than for VIP
      might mediate this long-term action of PACAP on REM sleep.

PMID- 10583494
TI  - Prior short-term synaptic disinhibition facilitates long-term potentiation and
      suppresses long-term depression at CA1 hippocampal synapses.
AB  - Long-term potentiation (LTP) and long-term depression (LTD) are two main forms of
      activity-dependent synaptic plasticity that have been extensively studied as the
      putative mechanisms underlying learning and memory. Current studies have
      demonstrated that prior synaptic activity can influence the subsequent induction
      of LTP and LTD at Schaffer collateral-CA1 synapses. Here, we show that prior
      short-term synaptic disinhibition induced by type A gamma-aminobutyric acid
      (GABA) receptor antagonist picrotoxin exhibited a facilitation of LTP induction
      and an inhibition of LTD induction. This effect lasted between 10 and 30 min
      after washout of picrotoxin and was specifically inhibited by the L-type voltage
      operated Ca2+ channel (VOCC) blocker nimodipine, but not by the N-methyl-D
      aspartate (NMDA) receptor antagonist D-2-amino-5-phosphopentanoic acid (D-APV).
      Moreover, this picrotoxin-induced priming effect was mimicked by forskolin, an
      activator of cyclic adenosine monophosphate (cAMP)-dependent protein kinase
      (PKA), and was blocked by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)
      9H-purin-6-amine (SQ 22536) and the PKA inhibitor Rp-adenosine 3',5'-cyclic
      monophosphothioate (Rp-cAMPS). It was also found that following picrotoxin
      application, CA1 neurons have a higher probability of synchronous discharge in
      response to a population of excitatory postsynaptic potential (EPSP) of fixed
      slope (EPSP/spike potentiation). However, picrotoxin treatment did not
      significantly affect paired-pulse facilitation (PPF). These findings suggest that
      a brief of GABAergic disinhibition can act as a priming stimulus for the
      subsequent induction of LTP and LTD at Schaffer collateral-CA1 synapses. The
      increase in Ca2+ influx through L-type VOCCs in turn triggering a cAMP/PKA
      signalling pathway is a possible molecular mechanism underlying this priming
      effect.

PMID- 10583495
TI  - The cerebellum and cognition: cerebellar lesions do not impair spatial working
      memory or visual associative learning in monkeys.
AB  - Anatomical studies in non-human primates have shown that the cerebellum has
      prominent connections with the dorsal, but not the ventral, visual pathways of
      the cerebral cortex. Recently, it has been shown that the dorsolateral prefrontal
      cortex (DPFC) and cerebellum are interconnected in monkeys. This has been cited
      in support of the view that the cerebellum may be involved in cognitive
      functions, e.g. working memory. Six monkeys (Macaca fascicularis) were therefore
      trained on a classic test of working memory, the spatial delayed alternation
      (SDA) task, and also on a visual concurrent discrimination (VCD) task.
      Excitotoxic lesions were made in the lateral cerebellar nuclei, bilaterally, in
      three of the animals. When retested after surgery the lesioned animals were as
      quick to relearn both tasks as the remaining unoperated animals. However, when
      the response times (RT) for each task were directly compared, on the SDA task the
      monkeys with cerebellar lesions were relatively slow to decide where to respond.
      We argue that on the SDA task animals can prepare their responses between trials
      whereas this is not possible on the VCD task, and that the cerebellar lesions may
      disrupt this response preparation. We subsequently made bilateral lesions in the
      DPFC of the control animals and retested them on the SDA task. These monkeys
      failed to relearn the task. The results show that, unlike the dorsal prefrontal
      cortex, the cerebellum is not essential for working memory or the executive
      processes that are necessary for correct performance, though it may contribute to
      the preparation of responses.

PMID- 10583496
TI  - Neuroactive steroids and the constraint of memory.
AB  - Different normo- and pathophysiological conditions are associated with large
      variations in plasma and brain concentrations of neuroactive steroids. In an
      attempt to specify the possible role of these steroids in memory processes, we
      examined the ability of pregnanolone, a positive modulator of the gamma
      aminobutyric acid type A (GABAA) receptor complex, to sustain state dependence in
      rats. Animals treated with either saline or different doses of pregnanolone were
      trained to complete a fixed ratio 10 (FR10) schedule of lever presses for milk
      reward within 120 s, and were tested for the retention of this response 48 h
      later while treated with the same or a different treatment. The data indicate
      that saline-to-drug as well as drug-to-saline state changes produced robust
      failures to recall the response. Furthermore, animals trained with pregnanolone
      showed transfer of the response when tested with the benzodiazepine
      chlordiazepoxide and vice versa. The partial benzodiazepine inverse agonist N
      methyl-beta-carboline-3-carboxamide (FG-7142) antagonized the states produced by
      both pregnanolone and chlordiazepoxide. State changes constitute a mechanism of
      action that may operate endogenously; the release of neuroactive steroids in
      response to various physiological conditions may act to contain but also to
      constrain memories associated with these events, rendering these memories
      inaccessible on other occasions. The apparent memory impairment that can so be
      produced may render the effects of past experience available in a manner that is
      appropriately selective.

PMID- 10583497
TI  - AMPA-receptor involvement in c-fos expression in the medial prefrontal cortex and
      amygdala dissociates neural substrates of conditioned activity and conditioned
      reward.
AB  - Exposure to an environment, previously conditioned to amphetamine (1 mg/kg,
      i.p.), induced locomotor activity and c-fos expression (a marker for neuronal
      activation) in the mouse medial prefrontal cortex (mPFC) and amygdala; acute or
      repeated amphetamine (1 mg/kg, i.p.) administration induced c-fos expression
      additionally in the nucleus accumbens. An alpha-amino-3-hydroxy-5-methyl-4
      isoxazole propionate (AMPA)-receptor antagonist, 2, 3-dihydroxy-6-nitro-7
      sulphamoyl-benzo(f)quinoxaline (NBQX), blocked expression of conditioned
      activity, and prevented the increase in c-fos expression in mPFC, implicating
      mPFC AMPAergic transmission in the conditioned component of behavioural
      sensitization to amphetamine. NBQX failed to block the expression of amphetamine
      conditioned place preference, a measure of conditioned reward, or conditioned c
      fos expression in the amygdala, an area implicated in the expression of
      conditioned place preference. These findings indicate that the conditioned
      components of behavioural sensitization depend on AMPA-receptor-mediated
      activation in mPFC, but that conditioned reward does not.

PMID- 10583498
TI  - Functional heterogeneity of the rat medial prefrontal cortex: effects of discrete
      subarea-specific lesions on drug-induced conditioned place preference and
      behavioural sensitization.
AB  - While the principal components of the brain reward system, the nucleus accumbens
      septi and the ventral tegmental area have received much attention, their efferent
      and afferent structures have not been investigated to the same degree. One major
      input to this system originates from the medial prefrontal cortex (mPFC) which is
      not a homogenous structure but can be divided into different subareas that can be
      distinguished on anatomical and possibly functional grounds. We examined the
      effects of discrete bilateral quinolinic acid lesions (45 nmol/0.5 micro(L)) of
      each of the mPFC subareas, the infralimbic (il), prelimbic (pl) and the anterior
      cingulate (cg) mPFC, on the conditioned place preference (CPP) and psychomotor
      activation induced by several drugs. Lesions of the il mPFC blocked CPP induced
      by morphine (10 mg/kg) and CGP37849 [DL-(E)-2-amino-4-methyl-5-phosphono-3-pentic
      acid, a competitive N-methyl-D-aspartate receptor antagonist; 10 mg/kg]. Lesions
      of the pl mPFC blocked CPP induced by cocaine (15 mg/kg) and CGP37849, and
      lesions of the cg mPFC only blocked CGP37849-induced CPP. Lesions of the whole
      mPFC blocked morphine-, cocaine- and CGP37849-induced CPP. None of the lesions
      affected DL-amphetamine (4 mg/kg)-induced CPP. During the conditioning period,
      none of the lesions affected amphetamine-induced psychomotor activation and
      sensitization, whereas both phenomena were attenuated by pl and whole mPFC
      lesions in the case of cocaine, and by il and whole mPFC lesions in the case of
      morphine. These results show that the different mPFC subregions have distinct
      functional roles in the generation of behavioural effects produced by different
      classes of drugs. This heterogeneity should be taken into account in future
      studies addressing the role of the mPFC in drug reward and sensitization.

PMID- 10583499
TI  - Synchronization of GABAergic interneuronal networks during seizure-like activity
      in the rat horizontal hippocampal slice.
AB  - We studied the contribution of GABAergic (gamma-aminobutyric acid)
      neurotransmission to epileptiform activity using the horizontal hippocampal rat
      brain slice. Seizure-like (ictal) activity was evoked in the CA1 area by applying
      high-frequency trains (80 Hz for 2 s) to the Schaffer collaterals. Whole-cell
      recordings from stratum oriens-alveus interneurons revealed burst firing with
      superimposed high-frequency spiking which was synchronous with field events and
      pyramidal cell firing during ictal activity. On the other hand, interictal
      interneuronal bursts were synchronous with large-amplitude inhibitory
      postsynaptic potentials (IPSPs) in pyramidal cells. Excitatory and inhibitory
      postsynaptic potentials were simultaneously received by pyramidal neurons during
      the ictal afterdischarge, and were synchronous with interneuronal bursting and
      field potential ictal events. The GABAA receptor antagonist bicuculline greatly
      reduced the duration of the ictal activity in the CA1 layer, and evoked rhythmic
      interictal synchronous bursting of interneurons and pyramidal cells. With intact
      GABAergic transmission, interictal field potential events were synchronous with
      large amplitude IPSPs (9.8 +/- 2.4 mV) in CA1 pyramidal cells, and with
      interneuronal bursting. Simultaneous dual recordings revealed synchronous IPSPs
      received by widely separated pyramidal neurons during ictal and interictal
      periods, indicative of widespread interneuronal firing synchrony throughout the
      hippocampus. CA3 pyramidal neurons fired in synchrony with interictal field
      potential events recorded in the CA1 layer, and glutamate receptor antagonists
      abolished interictal interneuronal firing and synchronous large amplitude IPSPs
      received by CA1 pyramidal cells. These observations provide evidence that the
      interneuronal network may be entrained in hyperexcitable states by GABAergic and
      glutamatergic mechanisms.

PMID- 10583500
TI  - Perirhinal cortex input to the hippocampus in the rat: evidence for parallel
      pathways, both direct and indirect. A combined physiological and anatomical
      study.
AB  - The possibility of a direct projection from the perirhinal cortex (PER) to areas
      CA1 and subiculum (SUB) in the hippocampus has been suggested on the basis of
      tracer studies, but this projection has not unequivocally been supported by
      physiological studies. The demonstration of such a functional pathway might be
      important to understand the functioning of the hippocampal memory system. Here we
      present physiological and further anatomical evidence for such a connection
      between PER and the hippocampus. Electrical stimulation of PER in vivo evoked
      field potentials (EFPs) at the border area of CA1/SUB, consisting of a short
      latency and a longer latency component. Current source density analysis revealed
      that the sink of the short latency component was situated in the molecular layer
      of area CA1/SUB, while the longer latency component had its sink in the outer
      molecular layer of the dentate gyrus (DG). Anterograde tracer injections in PER
      showed labelled fibres in the border area of CA1/SUB, but anatomical evidence for
      a projection of PER to DG was not found. When synaptic transmission in the
      entorhinal cortex was partly blocked, the amplitude of the longer latency
      component of the recorded EFPs in the hippocampus was decreased while the short
      latency component was not affected, which suggests that the indirect pathway
      originating in PER is mediated through a synaptic relay in the entorhinal cortex.
      From the present results we conclude that information originating in PER reaches
      area CA1/SUB by parallel, direct and indirect, routes. The existence of this
      parallel organization appears to form an essential feature for the proper
      function of the medial temporal lobe memory system.

PMID- 10583501
TI  - Manipulation of synaptic sign and strength with divalent cations in the
      vertebrate retina: pushing the limits of tonic, chemical neurotransmission.
AB  - At the first synaptic level of the vertebrate retina, photoreceptor light
      responses are transmitted to second order neurones through a chemical synapse
      based on a tonic release of neurotransmitter modulated by graded changes of
      presynaptic potential. The possibility that such synapses could work through a
      Ca2+-independent process had been proposed by previous authors, based on the
      persistence of transmission process in low Ca2+ media containing Co2+ or Ni2+
      ions. Recently, we were able to explain these results within the framework of the
      classical calcium-hypothesis of synaptic transmission by taking into account the
      modifications of presynaptic surface potential brought about by changes of
      divalent cation concentrations. Here we report data showing how a surface-charge
      hypothesis could account for several apparently paradoxical effects of divalent
      cation manipulations such as: the enhancement of neurotransmitter release induced
      by low Ca2+ media; the transmission "unblocking" effect of Zn2+, Co2+ and Ni2+;
      and the reversal of transmission polarity induced by application of low Ca2+
      media containing Cd2+ or Mg2+ ions.

PMID- 10583502
TI  - Analysis of neurotrophic effects of hepatocyte growth factor in the adult
      hypoglossal nerve axotomy model.
AB  - Recent studies have shown that hepatocyte growth factor (HGF) promotes the
      survival of embryonic motor neurons. However, it remains unclear whether HGF has
      trophic effects on mature motor neurons. In the present study, we examined the
      effects of HGF on adult motoneurons using the hypoglossal nerve transection
      model. In adult rats, neurons in the hypoglossal nucleus show a dramatic loss of
      choline acetyltransferase (ChAT) protein and mRNA after the axotomy. This
      reduction of ChAT was markedly prevented when HGF was administered continuously
      at the cut end of the nerve using an osmotic pump. The HGF receptor, c-met,
      protein and mRNA, which were faintly expressed in hypoglossal neurons under
      normal conditions, gradually increased and reached maximal levels 2 weeks after
      the axotomy. Administration of HGF reduced this c-met upregulation almost to
      normal levels. We also quantified HGF mRNA in the tongue and hypoglossal nucleus.
      The tongue contained abundant HGF mRNA, whereas the nucleus contained only low
      levels. Interestingly, the HGF mRNA level in the nucleus did not increase after
      the axotomy. These findings suggest that HGF is principally produced in the
      tongue and contributes to maintain ChAT expression in the nucleus. HGF produced
      in the hypoglossal nucleus alone after disconnection from the tongue may not be
      sufficient for the maintenance of the motor neuron function. Thus, exogenously
      applied HGF was effective to prevent the downregulation of ChAT activities. These
      findings provide a strong rationale for the potential clinical use of HGF for the
      treatment of motor neuron degenerative disease.

PMID- 10583503
TI  - Induction of stable long-term depression in vivo in the hippocampal-prefrontal
      cortex pathway.
AB  - We studied excitatory field potentials in the medial prefrontal cortex (mPFC,
      prelimbic area) to electrostimulation of the ventral hippocampus (CA1/subicular
      region) in the anaesthetized rat. Nine hundred stimulus trains (5 pulses at 250
      Hz) applied at 1 Hz to the ventral hippocampus significantly and persistently
      depressed the amplitude and maximal slope ( approximately 55% for each index) of
      the prelimbic field potentials, but did not change the latency of the maximal
      slope or peak negativity. Twelve stimulus trains (50 pulses at 250 Hz) applied
      subsequently at 0.1 Hz restored the depression back to control level, and this
      reversible depression was maintained for at least 13 h. Cumulative depressive
      effects on the prelimbic field potential amplitude and maximal slope were
      observed upon addition of stimulus trains in the hippocampus. An important
      implication of the results is that the direct pathway from the hippocampus to the
      mPFC in the rat retains long-term depression (LTD) as a neuroplastic form in
      vivo. This form could cooperate with long-term potentiation (LTP) and such a bi
      directional synaptic plasticity in the prefrontal cortex contributes to how
      cortical neural networks store information.

PMID- 10583504
TI  - Transposition of IS1 circles.
AB  - BACKGROUND: IS1, the smallest active transposable element in bacteria, encodes
      transposase. IS1 transposase promotes transposition as well as production of
      miniplasmids from a plasmid carrying IS1 by deletion of the region adjacent to
      IS1. The IS1 transposase also promotes production of IS1 circles consisting of
      the entire IS1 sequence and a sequence, 6-9 bp in length, as a spacer between
      terminal inverted repeats of IS1. The biological significance of the generation
      of IS1 circles is not known. RESULTS: Plasmids carrying an IS1 circle with a
      spacer sequence 6-9 bp long transposed to target plasmids at a very high
      frequency when transposase was produced from a co-resident plasmid. The products
      were target plasmids with the donor plasmid inserted at the ends of IS1 in the
      IS1 circle. This insertion accompanied the removal of the spacer sequence and
      duplication of the sequence at the target site. IS1 circles with a much longer
      spacer sequence transposed less frequently. The SOS response was induced in cells
      harbouring a plasmid with an IS1 circle owing to transposase. IS1 circles could
      transpose in the strain deficient in H-NS, a nucleoid-associated DNA-binding
      protein known to be required for the transposition of IS1. CONCLUSIONS: IS1
      circles appear to act as intermediates for simple insertion into the target DNA
      via cleavage of the circles which induces the SOS response. H-NS may function in
      promoting the assembly of an active IS1 DNA-transposase complex at the terminal
      inverted repeats.

PMID- 10583505
TI  - Presence of telomeric G-strand tails in the telomerase catalytic subunit TERT
      knockout mice.
AB  - BACKGROUND: Telomerase consists of two essential subunits, the template RNA (TR;
      telomerase RNA) and the catalytic subunit TERT (telomerase reverse
      transcriptase). Knockout mice with a mTR (mouse TR) deletion have been described
      and well characterized. However, mice with a mTERT (mouse TERT) deletion have not
      been reported. RESULTS: mTERT-knockout mice have been constructed. The first
      generation mTERT -/- mice were fertile, and did not show any noticeable
      macroscopic or microscopic phenotypic change. All tissue cells derived from mTERT
      -/- mice that were examined lacked telomerase activity, indicating that mTERT is
      the only gene encoding the telomerase catalytic subunit. Pulse field gel
      electrophoresis (PFGE) and nondenaturing in-gel hybridization analyses showed
      that mouse telomeric DNA has G-strand 5'-overhangs, as demonstrated for human and
      yeast cells. This telomeric single-stranded G-tail was also observed in MEF
      (mouse embryonic fibroblast) and liver cells derived from mTERT -/- mice.
      CONCLUSIONS: mTERT-knockout mice show phenotypes that are apparently normal at
      least during the early generations. This observation is similar to that obtained
      with the mTR-knockout mice. The presence of the telomeric G-strand tails in mTERT
      -/- mice suggests that these telomeric 5'-overhangs are produced by telomerase
      independent mechanisms, as has been proposed for yeast and human.

PMID- 10583506
TI  - Similar and differential behaviour between the nectin-afadin-ponsin and cadherin
      catenin systems during the formation and disruption of the polarized junctional
      alignment in epithelial cells.
AB  - BACKGROUND: We have recently identified a novel cell-cell adhesion system, named
      NAP system, which is localized at cadherin-based cell-cell adherens junctions
      (AJs). The NAP system is composed of at least nectin, afadin and ponsin. Nectin
      is an immunoglobulin-like cell adhesion molecule. Afadin is an actin filament
      binding protein which associates nectin with the actin cytoskeleton. Ponsin is an
      afadin-binding protein which furthermore binds to vinculin and provides a
      possible linkage of nectin-afadin to cadherin-catenin through vinculin. We
      compared here the behaviour of the NAP and cadherin-catenin systems during the
      formation and disruption of the polarized junctional alignment in epithelial
      cells. RESULTS: At the early stage of the formation of the polarized junctional
      alignment in MTD-1 A cells, primordial spot-like junctions were formed at the
      tips of thin cellular protrusions radiating from adjacent cells. Nectin, afadin,
      ponsin, cadherin and catenin were simultaneously recruited to these junctions. As
      the cell polarization proceeded, the spot-like junctions were gradually fused to
      form belt-like AJs where all these proteins were concentrated. The disruption of
      cell-cell AJs in MDCK cells by culturing at a low Ca2+ concentration caused rapid
      endocytosis of cadherin, but not that of nectin or afadin. Addition of 12-O
      tetradecanoylphorbol-13-acetate to the cells formed a tight junction-like
      structure where nectin and afadin, but not cadherin, accumulated. CONCLUSION:
      These results indicate that the NAP and cadherin-catenin systems show similar and
      differential behaviour during the formation and disruption of the polarized
      junctional alignment in epithelial cells.

PMID- 10583507
TI  - Smad8B, a Smad8 splice variant lacking the SSXS site that inhibits Smad8-mediated
      signalling.
AB  - BACKGROUND: Members of the TGF-beta superfamily of ligands bind to and activate
      surface serine/threonine-kinase receptors. Transduction of these signals requires
      the Smad proteins, which transiently interact with the activated receptor complex
      and are phosphorylated on their C terminus, SSXS site, by the type I receptor.
      Smad8 is a downstream signalling mediator of ALK2/ActRIA. RESULTS: We have cloned
      a splice variant of Smad8, designated Smad8B. The Smad8 and Smad8B cDNAs are
      identical in sequence, except that Smad8B lacks a portion encoding 47 amino
      acids, including the SSXS phosphorylation site, in the C-terminal MH2 region.
      Both Smad8 and Smad8B were expressed in many of the same cell types. Smad8B was
      capable of specific complex formation with either Smad8 or Smad4 in mammalian
      cells. In cells expressing constitutively activated ALK2, Smad8B was localized to
      the cytoplasmic region, whereas Smad8 was translocated into the nucleus. In
      mammalian cells, Smad8B acted as a dominant inhibitor of BMP signalling.
      CONCLUSIONS: Smad8B, a splice variant of Smad8, was isolated and found to
      specifically associate with both Smad8 and Smad4. Smad8B inhibited BMP
      signalling. Smad8 and Smad8B thus represent novel signal transduction proteins
      that may regulate the BMP signalling pathway.

PMID- 10583508
TI  - Cloning and characterization of two neural-salient serine/arginine-rich (NSSR)
      proteins involved in the regulation of alternative splicing in neurones.
AB  - BACKGROUND: In neurones, alternative splicing regulates the functions of many
      gene products. However, the molecular basis of neural-specific splicing, and how
      splicing regulation is modulated in different neurones remains to be determined.
      RESULTS: We cloned two new SR proteins, Neural-salient SR proteins (NSSR) 1 and
      2, which are present at higher levels in brain and testis. During the
      differentiation, NSSR 1 is detected only in the neuronal stage. Both the purified
      recombinant NSSR 1 and 2 proteins enhance the in vitro splicing activity of
      nuclear extract. Moreover, recombinant NSSR 1 protein enhances the assembly of
      ribonucleoprotein complexes with S100 fraction. Over-expression of NSSR 2
      prevents the inclusion of either the Flip or Flop exons in the splicing of the
      GluR-B gene, resulting in an increase in the abnormal exon-skipping product. In
      contrast, transient transfection with NSSR 1 promotes the inclusion of the Flip
      exon so that the abnormal product is spliced to the mature spliced form. This
      suppression of exon skipping by NSSR 1 is observed even with co-transfection of
      NSSR 2. CONCLUSIONS: NSSR 1 and 2 were cloned from mouse cDNA libraries. Results
      indicate that NSSR 1 may play a crucial role in the regulation of alternative
      splicing in neurones.

PMID- 10583509
TI  - Haemophilia therapy: assessing the cumulative risk of HIV exposure by
      cryoprecipitate.
AB  - Most of the world's haemophilia population live in countries with developing or
      emerging economies. As such, they do not have access to viral inactivated
      clotting product. Many are treated with cryoprecipitate made from locally
      supplied blood. The rationale for using cryoprecipitate instead of viral
      inactivated products is based on an implicit belief that because blood banks can
      provide reasonably safe products by using modern testing procedures, transmission
      of HIV and other blood-borne viruses is rare. However, the risk of acquiring a
      blood-borne infection is cumulative, and haemophilia patients treated with
      cryoprecipitate or fresh-frozen plasma are exposed to hundreds or thousands of
      donors during their lifetime. The risk that an HIV-infected person will be a
      donor during the 'window period' is directly related to the incidence of HIV in
      the country where the donation occurs. To illustrate the extent of this problem,
      we devise a model for estimating the risk that a person with haemophilia will
      encounter HIV-contaminated cryoprecipitate as a function of years of treatment
      and the underlying incidence rate of HIV among blood donors. We apply the model
      to two countries with different incidence rates of HIV, Venezuela and the USA.
      Over a lifetime of treatment (60 years), the cumulative risk of HIV exposure for
      a person with haemophilia receiving monthly infusion of cryoprecipitate prepared
      from plasma of 15 donors is significant, 2% in the USA and 40% in Venezuela.
      Considering the cumulative risk for transmitting HIV to patients with haemophilia
      through cryoprecipitate treatment, medical care providers should carefully
      evaluate the use of cryoprecipitate in any but emergency conditions or when no
      virally inactivated products are available.

PMID- 10583510
TI  - Factor replacement for haemophilia--should cryoprecipitate be used?

PMID- 10583512
TI  - von Willebrand disease and bleeding in women.
AB  - Menorrhagia is a common health problem in women, particularly those with bleeding
      disorders. Little is known about the course of menorrhagia or other bleeding
      symptoms in women with the most common congenital bleeding disorder, von
      Willebrand disease (vWD). We determined the prevalence of menorrhagia, bleeding
      symptoms and coagulation abnormalities associated with vWD, including factor VIII
      activity, von Willebrand factor (vWF) antigen, ristocetin cofactor and bleeding
      time (BT), on a cohort of 38 females with type 1 vWD referred for diagnosis and
      medical care. Menorrhagia was the most common bleeding symptom in females with
      vWD, occurring in 93.1% of adult women. Menorrhagia was also the most common
      initial bleeding symptom, occurring in 53.1% of adult women in all of whom it
      began at menarche, median 14 years of age. There was a delay from initial
      bleeding symptoms, at median age 12 years, to diagnosis, at median age 16 years,
      P=0.0049. Although 94% undergoing surgery had previous bleeding, a vWD diagnosis
      was known preoperatively in only 6.2%, resulting in potentially preventable
      bleeding. In summary, menorrhagia is the most common bleeding symptom in females
      with vWD and begins at menarche. Obtaining a personal and family bleeding history
      promotes early diagnosis, potentially prevents postoperative bleeding, and
      improves the health of women with vWD.

PMID- 10583511
TI  - Prevalence and incidence of intracranial haemorrhage in a population of children
      with haemophilia. The Hemophilia Growth and Development Study.
AB  - The prevalence of intracranial haemorrhage (ICH) in our population of
      haemophiliacs was 12%. The incidence of ICH was approximately 2% per year. At
      entry, 7% (21/309) had clinical histories of ICH without MRI evidence of old
      haemorrhage, indicating that either the haemorrhages had completely resolved,
      that routine MRI sequences are not particularly sensitive for the detection of
      old blood products, or a combination of both of these factors. One half (4/8) of
      the ICHs documented by entry MRI were clinically silent, and three of the 11
      incident cases documented by MRI were clinically silent. HIV infection did not
      increase the risk of ICH.

PMID- 10583513
TI  - Acquired von Willebrand syndrome--report of 10 cases and review of the
      literature.
AB  - Acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder with clinical
      and laboratory features closely resembling hereditary von Willebrand disease
      (vWD), arising in previously haemostatically normal individuals. We present a
      retrospective review of 10 cases with AvWS diagnosed over 17 years. The severity
      of the bleeding tendency varied from mild to severe forms. Multimers
      electrophoresis showed that 8/10 patients had a normal pattern similar to type 1
      vWD, 1/10 had a type 2A vWD pattern (with absence of high and intermediate
      molecular weight multimers) and 1/10 had a type 3 vWD pattern. An inhibitor
      screen was performed in 6/10 patients and autoantibodies against von Willebrand
      factor were found in only two cases. The underlying cause/associated conditions
      were identified in 8/10 patients. Treatment of the bleeding diathesis was
      successfully achieved with desmopressin or clotting factor concentrates.
      Resolution of underlying hypothyroidism (in two cases) and multiple myeloma (in
      one case) led to normalization of the coagulation parameters. The report on this
      cohort of 10 patients with AvWS illustrates the complexity of AvWS and its
      multifactorial aetiology. A brief review of the recent literature on AvWS is also
      presented, with emphasis on the current opinions in pathogenesis and treatment.
      Acquired von Willebrand syndrome (AvWS) is an acquired bleeding disorder,
      characterized by a phenotype similar to the inherited von Willebrand disease
      (vWD), with a prolonged bleeding time and low plasma levels of factor VIII - von
      Willebrand factor (vWF) measurements. It occurs in patients with no family
      history of vWD, who present with recent onset of bleeding symptoms. AvWS appears
      to be associated mainly with lymphoproliferative disorders, immunological
      conditions and neoplasia. AvWS is a rare condition and it is difficult to conduct
      prospective studies, therefore it is important to document the experience with
      such cases. The aim of this paper is first, to report 10 cases of AvWS identified
      at our Haemophilia Centre during the past 17 years. Second, to present a brief
      review of the recent literature on AvWS - outlining the salient features,
      associated disorders, mechanisms of acquisition and the available options of
      treatment.

PMID- 10583514
TI  - Audit of clinical management of von Willebrand disease during 1997 at a single
      institution and review of treatment patterns between 1980 and 1997.
AB  - In 1997 the UK Haemophilia Centre Directors Organization published the guidelines
      for diagnosis and management of von Willebrand disease (vWD). The guidelines
      stated that desmopressin (DDAVP) should be used in type 1 and type 2N vWD, that
      it might be useful in other types 2 vWD and that it is ineffective in type 3 vWD.
      If patients are unresponsive to DDAVP or if it is contraindicated, the treatment
      of choice is clotting factor concentrates (CFC). In the light of these
      guidelines, we audited our practice for 1997. Furthermore, we undertook a
      retrospective review of the changing patterns of treatment of vWD between 1980
      and 1997. During 1997, 10 patients with vWD received DDAVP and another 30
      patients were treated with CFC (a total of 1.2 million IU): Haemate P (Centeon,
      Germany) and/or 8Y (BPL, Elstree, UK). Few patients had clear contraindications
      to DDAVP, but several patients with type 1 and 2 vWD received CFC on the basis of
      age or reduced levels of von Willebrand factor - where DDAVP was considered
      suboptimal for adequate haemostasis. However, this assumption was made without a
      preliminary test dose to assess the response to DDAVP. The analysis of treatment
      of vWD for the past 17 years showed that cryoprecipitate was discontinued from
      use in the early 1990s and that both DDAVP and CFC usage has been on the
      increase. In conclusion, the audit illustrated a general good adherence to
      guidelines but it highlighted the need for a DDAVP test before using CFC.

PMID- 10583515
TI  - Highly sensitive and species-specific assay for quantification of human transgene
      expression levels.
AB  - During the past few years great efforts have been made to construct and to test
      human factor VIII (hFVIII) and IX (hFIX) vectors suitable for haemophilia gene
      therapy in vivo. However, little is known about the molecular mechanisms of
      persistence and shut-off of transgene expression in the target organs after gene
      transfer using recombinant adenoviral vectors. To evaluate low transgene mRNA
      levels in different tissues, especially at long times after the gene transfer,
      the common northern blot method is often not sensitive enough. For this reason we
      developed a new, highly sensitive and species-specific method for hFIX mRNA
      quantification and employed it in mice treated with an adenoviral vector
      (Ad5CMVFIX) expressing human FIX. In addition to its very high sensitivity
      (lowest detection level=1 fg RNA), the method was shown to be strictly species
      specific, since hFIX mRNA signals were never detected in untreated mice. In a
      long-term study of 18 vector-treated mice we compared the human FIX:Ag levels in
      the mouse plasma, the human FIX mRNA levels and human FIX vector DNA
      concentrations in the mouse liver. We found that a slow but continuous decrease
      of hFIX:Ag levels in mouse plasma was associated with a corresponding decrease of
      hFIX mRNA levels in the liver. However, the Ad5CMVFIX vector DNA levels did not
      decrease to a comparable degree, suggesting that the decrease of human FIX:Ag
      levels in mouse plasma is, to a significant extent, also caused by CMV promotor
      shut-off and only to a minor degree by loss of vector DNA.

PMID- 10583516
TI  - In vivo evaluation of a novel epitope-tagged human factor VIII-encoding
      adenoviral vector.
AB  - Haemophilia A is caused by a deficiency in coagulation factor VIII (FVIII) and is
      an attractive target for gene therapy. Adenoviral vectors encoding a human B
      domain deleted (BDD) FVIII cDNA have been shown previously to mediate expression
      of high levels of human FVIII and correct the bleeding defect in haemophiliac
      mice and dogs. While vector assessment in a non-human primate model would have a
      significant preclinical benefit, a haemophiliac non-human primate model is not
      available, and assays that distinguish human FVIII from monkey FVIII have not
      been developed successfully. As a first step to enable vector evaluation in non
      human primates, we have constructed an epitope-tagged FVIII molecule by the
      addition of 16 amino-acids to the carboxy terminus of the BDD protein (BDD-E).
      Following vector administration to normal mice, therapeutic levels of BDD-E FVIII
      were expressed for at least 20 weeks. Treatment of haemophiliac mice revealed
      that the BDD-E protein was biologically active in vivo. To distinguish the BDD-E
      protein from non-human primate FVIII, a sensitive immunoprecipitation/Western
      assay was developed that reproducibly detected 1 ng mL-1 of the epitope-tagged
      human FVIII in the presence of monkey plasma. These data demonstrate that the
      addition of an epitope tag had no effect on FVIII function or immunogenicity, and
      suggest that the BDD-E vector will be an effective reagent for non-human primate
      studies.

PMID- 10583517
TI  - Teaching parents advanced clinical skills.
AB  - The management of haemophilia, in common with many other inherited, chronic
      disorders, has witnessed enormous advances and improvements. The quality of life
      enjoyed by children with haemophilia is excellent. To realize these benefits,
      however, expectations are placed on parents to administer intravenous treatment
      at home. The frequency of required treatment can be as often as alternate days.
      The role of implantable venous access devices has made venous access in young
      children at home a realistic procedure. This is a highly complex skill for the
      lay person to undertake, and comprehensive parental teaching and standardized
      written information are necessary. A teaching package has been created that
      commences with theoretical instruction and moves onto practical training. On
      going assessment is then carried out at regular intervals in the home
      environment. Not only does this package provide a formal framework for
      instruction, it also facilitates emotional support for both the child and
      parents, which can be given in a planned manner. Nurses are professionally
      accountable for the information and teaching they give. This package documents
      the process of training undertaken and standardizes the level of information
      given. Thereby providing reassurance to nurses that they have fulfilled the
      professional requirements placed on them. Currently, there is no other source of
      information about implantable venous access devices for the lay carer. This
      package could be of value in other chronic conditions that incorporate an element
      of intravenous home care.

PMID- 10583518
TI  - Changes in hepatitis B serologic titers in HIV+ and HIV- children with
      haemophilia.
AB  - This longitudinal study examines differences in hepatitis B immune titres in
      children and adolescents with haemophilia to determine if they are dependent on
      how immunity was acquired (vaccination or natural infection), and whether they
      are related to the child's HIV status and/or are influenced by HIV disease
      progression. Serologic titres (HBcAb, HBsAb) and HBsAg were measured
      prospectively at baseline, and at years 1, 2 and 3 of follow-up in 126 HIV- and
      207 HIV+ children and adolescents with haemophilia. Analyses were performed to
      assess the impact of HIV status on the measured titres, and for HIV+ subjects to
      examine the association with CD4+ lymphocyte counts and p24 antigen status. The
      results show that HIV+ children were more likely than HIV- children to lose
      vaccine-induced immunity as indicated by the loss of HBsAb. There was an
      increased risk of losing HBsAb with higher CD4+ counts and younger age. Re
      immunization was not successful in seven of eight HIV+ children. Two subjects
      (one HIV+, one HIV-) entered the study HBsAg- but became HBsAg+ over the course
      of follow-up. Seven HIV+ subjects lost natural immunity as indicated by the loss
      of HBcAb. The loss of either HBsAb or HBcAb in HIV--subjects was negligible to
      absent. In conclusion, because of the loss of immunity in HIV+ children the viral
      safety of factor replacement concentrates for these children is an important
      consideration. HIV- children rarely lose immunity, therefore frequent measures of
      HBsAb are not necessary.

PMID- 10583519
TI  - Therapeutic embolization and surgical excision of haemophilic pseudotumour.
AB  - Haemophilic pseudotumour is a rare complication of haemophilia. Few cases of
      iliac haemophilic pseudotumour have been reported in the literature. These
      tumours can act as a focus for infection and cause cutaneous fistulas. When they
      present perforations and infections of endogenous origin their course is usually
      fatal. Suitable treatment has been investigated on numerous occasions, most of
      the literature agreeing that the only curative treatment is surgical resection.
      We present a case of haemophilic pseudotumour of the iliac and caecum with
      cutaneous fistulas, with a septic process of endogenous origin. It was treated
      with surgical resection after performing arterial embolization to reduce the
      vascularization of the pseudotumour, thereby reducing its size and the risk of
      bleeding complications during surgery.

PMID- 10583521
TI  - Economic aspects of haemophilia care

PMID- 10583520
TI  - Haemophilia following successful in vitro fertilization.

PMID- 10583522
TI  - Probabilities, costs, and outcomes: methodological issues in modelling
      haemophilia treatment.
AB  - Economic analyses in haemophilia care are at present limited, but are
      increasingly being used to examine the costs and outcomes associated with various
      treatment regimens. The assignment of probabilities and costs in these models can
      be challenging, and the use and development of new quality-of-life instruments
      for haemophilia have yet to be fully investigated. These methodological issues
      need to be addressed to expand research in the area of the economics of
      haemophilia care.

PMID- 10583523
TI  - Assessing health-related quality-of-life in individuals with haemophilia.
AB  - The objectives of this study were to analyse current levels of health-related
      quality-of-life (HR-QoL) in individuals with severe haemophilia and to assess the
      scope for these levels to improve. To do this, 249 individuals with severe,
      moderate and mild haemophilia were asked to complete Medical Outcomes Study (MOS)
      Short-Form 36 (SF-36) and EuroQol (EQ-5D) questionnaires. Access was also gained
      to two appropriate normative data sets. The results from these questionnaires
      showed that HIV status, history of orthopaedic surgery and bleeding frequency in
      the previous calendar year were not strong predictors of HR-QoL for individuals
      with severe haemophilia. However, for the majority of scales, age was found to be
      a strong predictor of HR-QoL for this patient group. The results from the
      analysis also showed that compared to individuals with moderate/mild haemophilia
      and the UK male normative population, individuals with severe haemophilia
      generally recorded poorer levels of HR-QoL. These results suggest, therefore,
      that individuals with severe haemophilia have reduced levels of HR-QoL compared
      to individuals with moderate/mild haemophilia and the general population,
      irrespective of differences in age. The results also suggest that the scope for
      primary prophylaxis to increase HR-QoL in individuals with severe haemophilia is
      significant.

PMID- 10583524
TI  - Financial aspects of haemophilia care in Puerto Rico and other Latin American
      countries.
AB  - The present cost of optimal care in haemophilia is very high. The paradigm of
      comprehensive care approach, including the essential elements of continuous
      integrated multidisciplinary health services and the provision of home care with
      early use of antihaemophilic products requires abundant economic resources that
      usually are not readily available in nonaffluent countries. A cost-effective
      comprehensive paediatric haemophilia programme has been operating in Puerto Rico
      during the last 15 years that provides quality care to over 90% of paediatric
      haemophiliacs, and is financed mainly by the local government health system.
      Efforts are also being made to provide and/or coordinate health care to all adult
      haemophilic patients through the Puerto Rico Pediatric Hemophilia Treatment
      Center. Information on the haemophilia care available in Latin American countries
      is scanty. The data available indicate that with a few exceptions, haemophilia
      care in this vast region is suboptimal. Apparently, early diagnosis is not
      common, there is lack of accessibility of services in most countries,
      comprehensive care is not the rule, safe high-purity AHF concentrates are used
      infrequently, and home care is used rarely. The main antihaemophilic products
      used are fresh frozen plasma and cryoprecipitate due to the high cost of modern
      antihaemophilic factor concentrates. The average per capita income of the main
      Latin American countries is about one-quarter of that of the USA and Canada. The
      existing economic situation of most Latin American countries would make it very
      difficult for them to purchase modern antihaemophilic products regularly and
      provide quality comprehensive care to their haemophilia patients, unless they
      make special efforts and get some type of external help. As a result of this
      study recommendations are made to improve the quality and accessibility of
      services to haemophilia patients in Latin America and other nonaffluent
      countries.

PMID- 10583525
TI  - Fibrin glue and clinical impact on haemophilia care.
AB  - Fibrin glues, a kind of biological sealant, have been used for enhancement of
      local haemostasis, tissue sealing and wound healing for haemophilia and similar
      disorders. Commercial viral-inactivated fibrin glue products are available in
      Europe and have recently been approved in the USA. Using fibrin glue,
      hospitalization, medical cost, viral transmission risk and factor supplementation
      will be reduced. In the near future, the role of fibrin glues will be increased
      in the haemophilia field.

PMID- 10583526
TI  - Hemophilia. Treatment of patients with inhibitors: cost issues.
AB  - The management of bleeding episodes and surgery in haemophilia patients who
      develop inhibitors is specially difficult and also has major impact on
      therapeutic costs. We assessed the costs of coagulation factors in noninhibitor
      haemophilia A and B patients (0 Inh; n=103), patients with low responding
      inhibitors (LR; n=24), patients with high responding inhibitors (HR; n=17) in our
      centre between 1988 and 1998 during two periods: 1988-1995 and 1996-1998, before
      and after the introduction of recombinant factor VIIa in France (1996). From 1988
      to 1995 the mean annual cost of 0 inh and LR patients was 43 234 and 49 422,
      respectively, with more than 90% as home treatment, whereas the mean cost of HR
      patients was 56 262 (1.3 time more than 0 Inh), half of this cost being related
      to treatment administered in hospital. From 1996 to 1998, the mean cost of HR
      patients was 186 482, approximately three times more than that of 0 Inh (59 887)
      and LR patients (54 226) with half of the cost due to treatment administered in
      hospital. So rFVIIa seems to exert a major economic effect on both the cost of
      home treatment and treatment administered in hospital. It must be pointed out
      that particularly severe bleeding episodes were effectively treated with rFVIIa
      during this period and that rFVIIa allowed surgery to be undertaken: including
      two elective orthopaedic surgeries. So there is no doubt that rFVIIa offers new
      perspectives in the therapeutic management of HR patients, but creates a new
      economic situation which needs further evaluation.

PMID- 10583527
TI  - The economic aspects of hepatitis C-- implications for haemophilia.
AB  - This paper considers the literature relating to the course of hepatitis C
      infection and its implications for those with haemophilia. It goes on to discuss
      a model that assessed the economic aspects of treating hepatitis C cases with
      interferon-alpha, discusses recent changes in recommended treatment of hepatitis
      C and critically reviews the model and its application to patients with
      haemophilia.

PMID- 10583528
TI  - Current practices regarding newborn intracranial haemorrhage and obstetrical care
      and mode of delivery of pregnant haemophilia carriers: a survey of obstetricians,
      neonatologists and haematologists in the United States, on behalf of the National
      Hemophilia Foundation's Medical and Scientific Advisory Council.
AB  - We undertook this survey to determine institutional practices of obstetricians,
      neonatologists and haematologists regarding care of pregnant haemophilia carriers
      and newborns with haemophilia and intracranial haemorrhage (ICH). Our purpose was
      also to determine whether institutions had written guidelines to manage such
      patients. Questionnaires were sent to 1000 obstetricians and through the
      Haemophilia Treatment Centres (HTC) to 180 paediatric haematologists and 180
      neonatologists, each representing an institution. Twenty-three per cent of
      obstetricians, 22% of neonatologists and 16% of paediatric haematologists
      returned completed surveys. Over 94% of the respondents had no written guidelines
      for management of pregnant haemophilia carriers or their newborns or for
      neurologic assessment of newborns. For known haemophilia carriers, 57% of the
      obstetricians routinely preferred vaginal delivery and 11% preferred caesarean
      section. Availability of perinatal services influenced prenatal management (P <
      0.05). In term newborns with documented ICH, only 23% of neonatologists would
      evaluate for haemophilia, whereas in pre-term newborns with ICH, this number
      dropped even further to 3%. For all newborns with haemophilia, 40% preferred
      routine administration of clotting factor concentrates (CFC) immediately
      following birth to offset the trauma of delivery and 89% of paediatric
      haematologists favoured early prophylaxis with CFC. Guidelines are needed for
      management of pregnant haemophilia carriers as well as newborns with haemophilia.
      Physicians need to be made aware that ICH may be a presenting sign of haemophilia
      in both term as well as pre-term newborns, so that appropriate therapy can be
      instituted early in the event of a bleed.

PMID- 10583530
TI  - Safety and efficacy of high-purity concentrates in haemophiliac patients
      undergoing surgery by continuous infusion.
AB  - In this study we explore the feasibility of high-purity double-inactivated
      concentrates by continuous infusion for the treatment of haemophiliacs in a group
      of patients undergoing different surgical procedures. The patients were enrolled
      in the study on the basis of their transfusion history, which was well known due
      to their long-term follow up at our Haemophilia Center. We did not perform a pre
      operative pharmacokinetic study because one of the aims of this study was to
      demonstrate that continuous infusion can become a first choice standard treatment
      in patients with haemophilia. Fourteen haemophilia A and one haemophilia B
      patients who needed at least 5 days of replacement therapy were monitored for
      haemostatic efficacy, post-operative factor VIII and factor IX levels and
      evaluated for safety and flexibility of the products. The infusion rate of 3 IU
      kg-1 h-1 was demonstrated to be sufficient to ensure haemostasis and patients did
      not need additional bolus infusion during the post-operative period. Our study
      demonstrates the safety and feasibility of high-purity concentrates in patients
      undergoing surgery by continuous infusion, also in the absence of a previous
      pharmacokinetic study.

PMID- 10583529
TI  - Immunosuppressive effects of factor IX products: an in vitro study.
AB  - The effects of a recombinant factor IX product (BeneFix), and of five plasma
      derived factor IX products, AlphaNine, Immunine, Konyne, Mononine and Replinine
      on in vitro peripheral blood mononuclear cell (PBMC) immune function were
      compared in a blinded study. We assessed the effects of these products on Con-A
      induced lymphocyte proliferation and interleukin-2 and interleukin-10 secretion,
      expression of lymphocyte activation markers, and nitric oxide secretion by
      stimulated mouse peritoneal macrophages. At 1 mL-1 for 48 h, Konyne reduced Con-A
      induced mitogenesis by 50% (P < 0.05); AlphaNine, Mononine and BeneFix had no
      effect. At 10 IU mL-1, Con-A-induced mi- togenesis was at control levels with
      Mononine and BeneFix, but was reduced to <15% (P < 0.05) with each of the other
      products. IL-2 and IL-10 secretion by Con-A-stimulated lymphocytes was also
      markedly depressed by all the products tested except Mononine and BeneFix.
      Dialysis of these products did not substantially affect these results. Flow
      cytometric analysis of lymphocyte activation markers following Con-A stimulation
      showed that Konyne also decreased IL-2 receptor alpha and beta chain (CD25 and
      CD122) induction on PBMC. Konyne also inhibited nitric oxide secretion to levels
      <18% of controls. These results indicate that certain factor IX products,
      including some of purported higher purity, substantially depress in vitro immune
      function. The importance of these findings to in vivo immune function in
      haemophilia B patients remains to be established.

PMID- 10583531
TI  - Induction of immune tolerance with recombinant factor VIII in haemophilia A
      patients with inhibitors.
AB  - We report on 11 patients (nine unrelated and a brother pair) with severe
      haemophilia A and factor VIII (FVIII) inhibitor, in whom immune tolerance (IIT)
      was induced with recombinant FVIII (r-FVIII). Their age ranged from 11 months to
      47 years. The number of exposure days (ED) at inhibitor detection varied from 11
      to 130. Nine of the 11 patients were high responders ?>10 Bethesda units (BU)
      with peak inhibitor levels ranging from 10 to 566 BU. The other two were low
      responders with peak levels between 0.7 and 2 BU. Before inhibitor detection, the
      patients had been receiving products of various purities. The IIT regimens were
      very heterogeneous, and the treatment schedule varied from a short period with 50
      IU kg-1 every 2 days, followed by 100 IU kg-1 every 2 days and then 220 IU kg-1
      daily. The outcome was considered successful when the inhibitor level fell to 0.6
      BU or lower after IIT treatment. The outcome overall was successful in nine out
      of 11 patients (81.8%), with the nine successful cases comprising seven of the
      nine high responders (77.8%) and the two low responders. Definite failure of IIT
      was observed in one high responder after two different IIT regimens. A second
      high responder is still on IIT treatment. All patients in whom IIT was successful
      are currently receiving r-FVIII on demand or prophylactically at various dosages.
      Despite the variability of the patient characteristics and the IIT schedules,
      this study demonstrates that r-FVIII represents an effective alternative for the
      eradication of inhibitors through IIT.

PMID- 10583532
TI  - Incidence and treatment of hepatitis C virus infection in children with
      haemophilia in Poland.
AB  - In 80% of children with haemophilia treated in our department, screening tests
      showed the presence of antibodies against the hepatitis C virus (HCV). HCV RNA
      was detected in serum in 41% of cases. In 20% of cases there were periodic
      increases in the level of alanine aminotransferase (ALT) activity, and in these
      cases liver biopsy was performed after factor concentrate replacement. No
      haemorrhagic complications or pain complaints were reported either during the
      biopsy or immediately afterwards. In all cases histopathological examination
      revealed chronic hepatitis type C - chronic mild hepatitis and chronic minimal
      hepatitis. Eight boys were treated with interferon (INF) alpha. In two cases this
      therapy was successful. No HCV RNA was detected in serum and transaminase
      activity was normal during the year following interferon treatment.

PMID- 10583533
TI  - Major surgery for a gastric cancer in a haemophilic with high inhibitor titre
      successfully performed by the use of recombinant FVIIa.
AB  - A total gastrectomy with omentectomy and resection of the distal oesophagus in a
      69-year-old haemophilia A patient with high inhibitor of 128 Bethesda units is
      described. Surgery was successfully performed after infusion of 112 microg kg-1
      bw of recombinant FVIIa. Ninety-two microg kg-1 were given thereafter at time
      intervals of 2 h until 12 h, then every 3 h until 24 h, and every 4 h until 48 h
      after surgery. Doses were gradually reduced in the following days and finally
      discontinued on day 28 after surgery. The complete treatment schedule required
      the administration of a total of 708 mg of recombinant FVIIa. Using this
      approach, we observed normal haemostasis, and there were no signs of excessive
      postoperative bleeding or wound haematoma. No clinical side-effects or evidence
      of systemic activation of coagulation occurred during the treatment. As judged
      from the clinical course of this major surgery, recombinant FVIIa appears to be
      highly efficacious and safe and should be used as first line treatment in high
      titre inhibitor patients with cross-reactivity to porcine factor VIII, undergoing
      surgery.

PMID- 10583534
TI  - Severe haemophilia A in a female: a compound heterozygote with nonrandom X
      inactivation.
AB  - We report a case of severe haemophilia A (<1% factor VIII level) in a female
      resulting from an interesting and improbable combination of events. The patient
      inherited a factor VIII intron 22 inversion from her carrier mother, as well as a
      second factor VIII inversion involving intron 22 that arose de novo on her
      paternally derived X chromosome. In addition, the patient's paternally derived X
      chromosome had been preferentially inactivated in 95+% of her somatic cells. The
      patient's mother, who was clinically unaffected, carried an intron 22 inversion
      as well and also showed nonrandom X-inactivation. The patient's mother had a
      brother with severe haemophilia A. It is therefore likely that the mother's
      inversion was on her maternally derived X chromosome. Since she was unaffected,
      it is likely that her inversion-bearing X was the one that was preferentially
      inactivated.

PMID- 10583535
TI  - Gas gangrene in a patient with severe haemophilia A.
AB  - The haemophilia patient tends to live a more protected life than his normal
      counterpart, this is particularly so in underdeveloped and developing countries
      where due to poor health infrastructure, financial constraints and
      nonavailability of factor concentrates, patients quickly learn that they need to
      live a protected life. Under such circumstances, gas gangrene seems to be a very
      unusual infection for this group of patients. We report here a 25-year-old male
      with severe haemophilia who developed gas gangrene due to inadequate medical
      management following a road traffic accident. Subsequently, his affected limb was
      salvaged by conservative therapy. A literature search failed to reveal any
      reports of similar patients in the English literature.

PMID- 10583536
TI  - Polymorphisms associated with the factor IX gene in Chinese people.

PMID- 10583537
TI  - Transgressive segregation, adaptation and speciation.
AB  - The production of extreme or 'transgressive' phenotypes in segregating hybrid
      populations has been speculated to contribute to niche divergence of hybrid
      lineages. Here, we assess the frequency of transgressive segregation in hybrid
      populations, describe its genetic basis and discuss the factors that best predict
      its occurrence. From a survey of 171 studies that report phenotypic variation in
      segregating hybrid populations, we show that transgression is the rule rather
      than the exception. In fact, 155 of the 171 studies (91%) report at least one
      transgressive trait, and 44% of 1229 traits examined were transgressive.
      Transgression occurred most frequently in intraspecific crosses involving inbred,
      domesticated plant populations, and least frequently in interspecific crosses
      between outbred, wild animal species. Quantitative genetic studies of plant
      hybrids consistently point to the action of complementary genes as the primary
      cause of transgression, although overdominance and epistasis also contribute.
      Complementary genes appear to be common for most traits, with the possible
      exception of those with a history of disruptive selection. These results lend
      credence to the view that hybridization may provide the raw material for rapid
      adaptation and provide a simple explanation for niche divergence and phenotypic
      novelty often associated with hybrid lineages.

PMID- 10583538
TI  - Microsporogenesis in a citrus interspecific tetraploid somatic hybrid and its
      fusion parents
AB  - Microsporogenesis was analysed in a tetraploid somatic hybrid (SH) (2n=4x=36) of
      Citrus and its diploid fusion parents (2n=2x=18), Valencia sweet orange (C.
      sinensis L. Osbeck) and Femminello lemon (C. limon L. Burm. f.). Intergenomic
      pairing between lemon and orange occurred in the somatic hybrid which showed
      multivalent chromosome associations in diakinesis, although one quadrivalent was
      definitely because of a reciprocal translocation present in Valencia. The
      behaviour of univalents was variable in the somatic hybrid and its parents. In
      the somatic hybrid and Valencia, the univalents preferentially formed micronuclei
      and polyads whereas, in Femminello, they were generally enclosed in a nucleus
      although distributed randomly. The somatic hybrid showed a rate of pollen
      stainability of 64% and germinability of 41%. The chromosomally unbalanced pollen
      from the tetraploid SH was presumed viable and able to fertilize because
      different nuclear DNA contents were found in the back-cross progeny. Moreover,
      meiotic nuclear restitution mechanisms, which could be mainly dependent on the
      abnormal orientation of the spindles in meiosis II, are described.

PMID- 10583539
TI  - Mitochondrial DNA sequence variation in ixodes pacificus (Acari: ixodidae).
AB  - The western black-legged tick, Ixodes pacificus, is a primary vector of the
      spirochaete, Borrelia burgdorferi, that causes Lyme disease. We used variation in
      a 355-bp DNA portion of the mitochondrial cytochrome oxidase III gene to assess
      the population structure of the tick across its range from British Columbia to
      southern California and east to Utah. Ixodes pacificus showed considerable
      haplotype diversity despite low nucleotide diversity. Maximum parsimony and
      isolation-by-distance analyses revealed little genetic structure except between a
      geographically isolated Utah locality and all other localities. Loss of mtDNA
      polymorphism in Utah ticks is consistent with a post-Pleistocene founder event.
      The pattern of genetic differentiation in the continuous part of the range of
      Ixodes pacificus reinforces recent recognition of the difficulties involved in
      using genetic frequency data to infer gene flow and migration.

PMID- 10583540
TI  - The relationship between the effects of UV light and thermal shock on gametes and
      the viability of early developmental stages in a marine teleost fish, the sea
      bass (Dicentrarchus labrax L.).
AB  - To improve the efficiency of gynogenetic induction, the effects of UV light and
      thermal shock on gametes were investigated in the sea bass. Exposure of sperm to
      UV light (>/=15 000 erg mm-2) reduced the amount of motile spermatozoa, without
      affecting the duration of motility in the spermatozoa that remained motile. The
      Hertwig effect was elicited in eggs fertilized with sperm exposed to >/=35 000
      erg mm-2 of UV light, indicating the inactivation of the DNA of the spermatozoa
      while retaining their ability to trigger development. Resulting embryos (24
      chromosomes; one NOR) exhibited the haploid syndrome and died at hatch. Diploidy
      was restored in eggs fertilized with irradiated sperm by blocking meiosis II with
      a thermal shock (0 +/- 0.5 degrees C for 10 min, starting 5 min after
      fertilization). Resulting larvae ( approximately 35% survival at hatching) had 48
      chromosomes, one or two NOR and no paternal chromosome fragments (gynogenetic
      diploids). In eggs fertilized with sperm not exposed to UV light, the same
      thermal shock induced 100% triploidy (72 chromosomes; one, two or three NOR),
      with 70% survival at hatching. Multifactorial ANOVA showed that, compared to
      external factors (sperm diluent, UV light and thermal shock), the contribution of
      broodstock to the viability of the early developmental stages was not significant
      (P > 0.05). Effects of the thermal shock were most evident after fertilization
      (30.7%) but disappeared (0%) at hatching, suggesting that the lower survival of
      triploids is a consequence of handling, not of the triploid condition per se.
      However, effects of UV light increased through development (42.5-69.7%), probably
      reflecting cumulative deficits in protein synthesis.

PMID- 10583541
TI  - Growth temperature and reaction norms of morphometrical traits in a tropical
      drosophilid: Zaprionus indianus.
AB  - Ten isofemale lines of Zaprionus indianus were analysed to study the reaction
      norms of five morphometrical traits (wing and thorax length, body weight,
      sternopleural bristle and ovariole number) in relation to growth temperature. All
      these traits exhibited nonlinear concave reaction norms and were characterized by
      the coordinates of their maximum: MV (maximum value), and TMV (temperature of
      maximum value). Wing/thorax ratio, which is related to flight capacity, was also
      calculated and exhibited a monotonically decreasing reaction norm. Intraclass
      correlations were on average quite low, with no significant differences between
      traits, temperature or sex; a highly significant trait-temperature interaction
      was, however, observed. Sex dimorphism was very low in Zaprionus, contrasting
      with data previously obtained in other species. MVs among lines were positively
      correlated for the three size-related traits, whereas sternopleural bristle and
      ovariole number were genetically independent. TMVs were different between the
      traits, but higher than in D. melanogaster and other cold-adapted species, in
      agreement with the hypothesis that the norm shape evolves according to species
      thermal adaptation. MVs and TMVs were never correlated, indicating that mean
      values and plasticity are genetically independent. Some positive correlations
      were observed among TMVs of different traits, suggesting that the same genetic
      system might regulate plasticity of different traits.

PMID- 10583542
TI  - Population structure in the malaria vector, Anopheles arabiensis patton, in East
      Africa.
AB  - The population structure of the malaria vector Anopheles arabiensis was
      investigated using data from six microsatellite loci in samples from localities
      in Mozambique and Tanzania. Genotype frequencies were neither significantly
      different between houses in a village in Tanzania nor between villages within a
      20-km radius in Mozambique. Thus a deme has an area greater than 20 km in radius.
      At five of the six loci the heterozygosity of the population from Mozambique was
      lower than that from Tanzania, implying a lower effective population size (Ne) at
      this southern edge of the species range. There were significant differences in
      genotype frequencies between the Tanzanian and Mozambique populations at five of
      the six loci (P<0.05). Values for both FST (mean=0.069) and RST (mean=0.025) were
      significantly different from zero (P<0.05) at four and three out of five loci,
      respectively, but there was no significant correlation between the two
      statistics. The wide variation in values of FST and RST across loci suggests that
      care should be taken in interpreting values derived from averaging across loci.
      Whether the variation results from sampling effects or selectional constraints on
      some loci is unclear. Although there is evidence for significant differentiation
      between these populations, estimates of gene flow (Nm) calculated from mean FST
      and RST statistics were relatively high, 3.4 and 4.9, respectively. We argue that
      this is more likely to reflect recent separation of these populations and/or
      large effective population size rather than large-scale present day migrations.

PMID- 10583543
TI  - Genetic divergence and the mating system in the endangered and geographically
      restricted species, lambertia orbifolia gardner (Proteaceae)
AB  - Population genetic structure and the mating system were investigated in the
      endangered plant Lambertia orbifolia. This species is geographically restricted
      with two disjunct groups of populations. Twelve out of 19 allozyme loci were
      polymorphic and four were suitable for mating system studies. Levels of genetic
      variation within populations were comparable to other long-lived woody shrub
      endemics. Genetic divergence between population groups was very high (D = 0.252)
      and the FST over all populations was 0.441. Gene flow estimates within population
      groups were low even though the maximum geographical distance between any pair of
      populations is 15 km and could be attributed to the localized movement of bird
      pollinators. Mating system studies on four populations showed consistently low
      levels of outcrossing, compared with other Proteaceae. Correlations of outcrossed
      paternity were moderately high and all were significantly greater than zero.
      Values ranged from rp = 0.33, in the two largest and very dense populations, to
      the highest value of rp = 0.54 in a smaller low-density population. The current
      population genetic structure in L. orbifolia is probably the result of local
      extinction of intervening populations because of Pleistocene climatic change and
      increased aridity, and extended isolation of the two remnants. It is proposed
      that the phylogenetically distinct Narrikup population group be recognized as a
      separate conservation unit and be given high priority for conservation action.

PMID- 10583545
TI  - Common origin of B chromosome variants in the grasshopper eyprepocnemis plorans
AB  - Nine B chromosome variants, from seven different populations of Eyprepocnemis
      plorans collected at four localities in Spain and three in Morocco, have been
      shown to be mainly composed of two DNA sequences, i.e. a 180-bp tandem repeat and
      ribosomal DNA. B types, however, differ in the relative amounts of the two
      sequences. The most widespread one (B1) bears about the same amount of rDNA and
      180 bp repeat, but three other variants that have reached a polymorphism by
      replacing B1 in smaller areas (B2, B5 and B24) carry a conspicuously larger
      amount of the 180 bp repeat. In Morocco, the most widespread B variant is also
      B1, and a rare variant that appeared in a single individual is also built with
      the same two DNA sequences. All these data point to a common origin for these B
      chromosomes, with B1 probably being the original one. The origin of the different
      B types and the possible relationship of the relative amount of 180 bp DNA repeat
      with B drive are discussed.

PMID- 10583544
TI  - The B chromosome polymorphism of the grasshopper eyprepocnemis plorans in north
      africa. I. B variants and frequency
AB  - Polymorphism for B chromosomes has been detected in all nine populations of the
      grasshopper Eyprepocnemis plorans ssp. plorans sampled in Morocco. The most
      frequent B chromosome in all populations showed a C-banding pattern and size
      similar to those of the B1 variant found in the Iberian Peninsula. In addition,
      other B chromosome variants (B1iso1, B1iso2, B1d1, B1di1, B3 and B1dd1) were
      discovered in these populations, although at a very low frequency. No significant
      differences in B chromosome frequency were found either in the nine populations
      or, for some of them, in up to three consecutive years. These results are
      discussed in the light of current hypotheses on the evolution of this B
      chromosome polymorphism in the Iberian Peninsula.

PMID- 10583546
TI  - Predicting correlated responses in natural populations: changes in JHE activity
      in the bermuda population of the sand cricket, gryllus firmus
AB  - Quantitative genetic methods have been used to examine selection responses in
      domesticated organisms but there are few cases of their application to predict
      changes in natural populations: there are, to our knowledge, no cases in which
      correlated responses to selection have been predicted. In the present paper we
      use quantitative genetic parameters estimated from a half-sib experiment to
      predict the changes expected in juvenile hormone esterase (JHE) activity in the
      Bermuda population of the wing dimorphic cricket, Gryllus firmus. JHE activity is
      genetically correlated with wing form in this cricket and hence changes in the
      proportion of macroptery (volant morph) are predicted to bring about a correlated
      response in JHE activity. The Bermuda population has a higher proportion of
      macropterous individuals (95%) compared to the stock (35%, originally from
      Florida) from which the heritabilities and correlations were estimated. The
      quantitative genetic analysis makes three predictions which were tested both
      qualitatively and quantitatively. In all cases the null hypothesis that the
      observed results correspond to those predicted cannot be rejected. As predicted,
      in the Bermuda population there is: (i) an increase in the population mean JHE
      activity; (ii) a leftwards shift in the curve relating the probability of
      microptery (flightless morph) to JHE activity; and (iii) a decrease in the mean
      JHE activity within each morph.

PMID- 10583547
TI  - A polymorphic duplicated locus for cytosolic PGI segregating in sheep's fescue
      (Festuca ovina L.)
AB  - Normally sheep's fescue (Festuca ovina) carries a single locus encoding the
      cytosolic enzyme phosphoglucoisomerase (PGI). However, at several localities in
      southern Sweden plants with more than two different alleles have been found by
      isozyme studies. Crossing experiments and subsequent progeny analyses revealed
      two unlinked loci. The additional locus was polymorphic for two alleles with
      different electrophoretic mobilities. Two of the numerous alleles at the primary
      locus had the same mobility. A complex gene coding for both electrophoretic types
      was also found to map to the additional locus, but no such complex gene has been
      found at the primary locus. The genes at the additional locus can be lacking, or
      present in hemizygous or homozygous form. Allozymes encoded by the additional
      locus readily form heterodimers with those encoded by the primary locus, thus
      giving rise to multibanded isozyme patterns. This segregating, polymorphic gene
      duplication may well represent a rare case where the initial stage of the
      evolution of a new gene can be directly studied.

PMID- 10583549
TI  - Wolbachia infection in the terrestrial isopod oniscus asellus: sex ratio
      distortion and effect on fecundity
AB  - Maternally inherited Wolbachia bacteria are widespread in arthropods where they
      are responsible for various reproductive alterations. In terrestrial isopods
      (woodlice), Wolbachia may induce feminization or cytoplasmic incompatibility
      (CI), but their effect remains unknown in most host species. To increase our
      understanding of host/symbiont interactions in terrestrial isopods, the effect of
      Wolbachia was investigated in the oniscidean Oniscus asellus, mainly to
      discriminate between feminization and CI. The Wolbachia infection was not linked
      with a CI phenomenon, but females infected with Wolbachia produced female-biased
      broods compared with uninfected females. The fecundity of infected females was
      slightly lower than that of uninfected, but the number of young at the adult
      stage was similar between the two female categories. The experimental transfer of
      the symbiont into uninfected strains showed that Wolbachia was responsible for
      the feminization of a number of genetic males. In female-biased broods, Wolbachia
      were vertically transmitted to around 88% of the offspring, but the transmission
      rate was lower in the few male-biased progenies. The feminizing activity of these
      symbionts was not systematic, as many phenotypic males were infected. These
      results contrasted with what is known in another woodlouse species, and indicated
      that feminization has evolved in different ways in terrestrial isopods.

PMID- 10583548
TI  - The role of fertility restoration in the maintenance of the inversion In(2L)t
      polymorphism in drosophila melanogaster.
AB  - In order to explain the worldwide latitudinal distribution and seasonal
      fluctuations in In(2L)t frequencies in Drosophila melanogaster, fitness
      differences among In(2L)t and Standard (ST ) homo- and heterokaryotypes under
      high-temperature conditions were determined. Viabilities were measured for high
      temperature treatment started at different juvenile stages. The capacity to
      restore fertility after high-temperature treatment was measured for adults and
      juveniles. Furthermore, genetic adaptation for increased temperature resistance
      for these traits was determined for strains which were reared at 33 degrees C for
      10 generations. Whereas larva-pupa survival rates were high, highest juvenile
      mortalities and strongest karyotypic effects were observed during the pupal stage
      when preceding larval stages were reared at 33 degrees C. ST karyotypes showed
      lowest viabilities. Although mating rate was hardly influenced, sterility was
      induced for females and males after high-temperature treatment of adults as well
      as juveniles. Subsequent transfer to 25 degrees C, however, resulted in restored
      fertility in some of the individuals, depending on the length of the recovery
      period. Fertility restoration was significantly higher for heterokaryotype males
      and females. Heterokaryotype superiority for restored fertility as well as for
      viability was positively correlated with severity of the treatment. Ten
      generations of selection at 33 degrees C resulted in significant improvement of
      juvenile survival and fertility restoration for all karyotypes. These fitness
      components were positively correlated (r=0.91; P < 0.001), which might suggest
      pleiotropic effects. It is concluded that the capacity to restore fertility after
      heat stress is an important fitness component, especially with respect to the
      In(2L)t polymorphism. The observed heterokaryotypic superiority fits with the
      idea that the latitudinal distribution of In(2L)t frequencies is maintained by
      balancing selection, with equilibrium values decreasing with latitude.

PMID- 10583550
TI  - Genetic diversity in peripheral and subcentral populations of corrigiola
      litoralis L. (Illecebraceae)
AB  - Genetic diversity and differentiation were studied in Corrigiola litoralis L., an
      annual plant species growing on seasonally flooded river banks. Plant species
      that are restricted to river systems may consist of highly isolated populations.
      For this species, pronounced genetic differentiation among rivers was expected.
      Plants were sampled from the river Loire (France) representing subcentral
      populations and the rivers Rhine, Weser and Elbe (Germany) representing
      peripheral ones. Allozyme electrophoresis revealed 17 putative loci in 11 enzyme
      systems. At the species level, percentage polymorphic loci, mean number of
      alleles, observed heterozygosity and expected heterozygosity were P=29%, A=1.5 +/
      0.2, Ho=0.007 +/- 0.005 and He=0.065 +/- 0.035, respectively. Peripheral
      populations were smaller in number and showed decreased levels of genetic
      diversity relative to central populations. Corrigiola litoralis was highly
      inbreeding as indicated by a mean FIS of 0.755. Genetic differentiation among
      populations was high with a mean FST-value of 0.585. Hierarchical F-statistics
      revealed that genetic variability was partitioned at 57% among sites, 52% among
      countries and 11% among sites within countries. Genetic distances between French
      and German populations were 0.08, indicative of considerable differentiation at
      the intraspecific level. The overall low level of allozyme diversity is
      attributed to the breeding system and to habitat conditions homogenized by
      regular flooding. The decrease in diversity from subcentral to peripheral
      populations is considered to be a result of drift and founder effects during
      postglacial recolonization. Peripheral populations were characterized by a single
      fixed allele at locus IDH, thus representing an evolutionarily significant unit.

PMID- 10583551
TI  - On the methods for predicting the effective size of populations under selection.
AB  - Inconsistencies between equations for the effective population size under
      selection obtained by two different approaches are explained. In one approach,
      the effective population size is predicted from the drift in the frequency of a
      neutral allele, accounting for the accumulation of selective advantage over
      generations. The second approach is based on the rate of inbreeding, using the
      concept of long-term genetic contributions. It is shown that the long-term
      genetic contribution approach leads to an identical result to the drift approach,
      if the effect of mates on the long-term genetic contributions is correctly
      accounted for.

PMID- 10583552
TI  - Microsatellite DNA analysis of population structure in Atlantic herring (Clupea
      harengus), with direct comparison to allozyme and mtDNA RFLP analyses.
AB  - Previous attempts to test for small-scale stock structuring within Atlantic
      herring (Clupea harengus L.) with molecular markers have been hampered by
      uninformative levels of genetic variation. Here we report the first application
      of microsatellite DNA markers to investigate population subdivision in Atlantic
      herring from Norwegian waters and the Barents Sea, and also examine
      microsatellite differentiation between C. harengus and Pacific herring (C.
      pallasi). Results from four microsatellite loci indicate high, and informative,
      variation compared to molecular markers used previously: number of alleles per
      locus=18-41; mean expected heterozygosity within samples=0.90-0.93. Significant
      genetic differences were detected between almost all samples representing
      postulated Icelandic summer-spawner, Norwegian spring-spawner and Norwegian fjord
      stocks, using Fisher's exact test, FST and RST values. Levels of allele frequency
      differentiation between Atlantic and Pacific herring overlapped the range seen
      among Atlantic herring samples, indicating that microsatellites are poor
      indicators of the degree of species differentiation. Comparison with allozyme and
      mitochondrial DNA restriction fragment length polymorphism (RFLP) datasets from
      the same samples suggests that microsatellites may detect structuring at a finer
      scale, but are less informative at larger scales of divergence.

PMID- 10583553
TI  - DCIS grading schemes and clinical implications.
AB  - The frequency with which ductal carcinoma in situ (DCIS) is detected has
      increased greatly since the introduction of mammographic screening. The number of
      treatment options has also increased and mastectomy has been extensively replaced
      by local excision with or without radiotherapy. DCIS is generally unicentric, as
      evidenced by the rarity with which it is bilateral and the location of
      recurrences at the site of previous surgery. Complete excision is thus curative
      but assessing adequacy of excision is beset with significant technical problems
      and consequently margin involvement does not correlate very well with the
      presence of residual disease in the breast or the development of clinical
      recurrence. Lesion size is related to recurrence but is also often difficult to
      measure. At the histological level, DCIS is a heterogeneous group of
      proliferations varying in cytological and architectural features, some of which
      are related to clinical outcome. The traditional method of classification was by
      growth pattern but was found to lack reproducibility and prognostic power. As a
      consequence, several new classifications have been proposed in recent years. Some
      have been assessed more rigorously than others in terms of the consistency with
      which they can be applied and their ability to predict clinical outcome. There is
      strong evidence, however, that nuclear grade is the best predictor of recurrence
      and the time scale over which it is likely to occur although presently it can be
      determined with only fair to moderate consistency. Necrosis is also a useful
      feature when used in combination with nuclear grade, but specifically recognizing
      a comedo pattern appears to have little clinical value and is associated with
      significant diagnostic inconsistency. No histological features to date have been
      found to predict the development of invasive disease. Histological assessment
      alone is insufficient to determine how patients with DCIS should be managed,
      which should also take account pathological assessment of excision margins and
      lesion size as well as radiological and clinical features.

PMID- 10583554
TI  - The fraction of fields showing neoplastic tubules: a practical estimate of
      tubular differentiation in breast cancer.
AB  - AIMS: The purpose of the study is to evaluate histological measurement methods
      for quantitative assessment of the degree of tubular differentiation in breast
      cancer. METHODS AND RESULTS: We evaluated tubular differentiation in 20 cases of
      invasive breast cancer by four different assessment methods. Method 1 was the
      traditional subjective evaluation of the amount of malignant tubules in each
      sample. Method 2 evaluated the fraction of fields presenting tubular
      differentiation by registering the presence or absence of neoplastic tubular
      structures in each microscopic field. In method 3 the area fraction of malignant
      epithelial cells presenting tubular differentiation was assessed field-by-field
      and expressed as an average of the whole tumour area. Method 4 applied point
      counting for evaluating the fraction of malignant epithelial cells in tubular
      structures. By correlation and reproducibility analyses, method 1 was inferior to
      the other methods. Method 4 was accurate but too laborious and time-consuming for
      clinical use. Methods 2 and 3 were both efficient and reproducible and could be
      used interchangeably. With the time and effort used in the measurements taken
      into consideration method 2 was best applicable to clinical practice. CONCLUSION:
      Accurate evaluation of tubular differentiation in breast cancer is possible by
      defining the presence or absence of tubular differentiation in microscopic fields
      of a histological section. Assessment of the fraction of fields with tubular
      differentiation (FTD) is simple, unambiguous, objective and fast--even a large
      sample can be screened in less than 10 min. In our results, FTD has clear
      advantages over subjective or point counting-based evaluation methods of tubular
      differentiation.

PMID- 10583555
TI  - Primary alveolar soft part sarcoma of bone.
AB  - AIMS: Alveolar soft part sarcoma is a distinct, rare soft tissue tumour occurring
      primarily within the skeletal muscles or musculofascial planes in young adults.
      Primary involvement of bone is extremely rare. We report on six patients with
      alveolar soft part sarcoma occurring primarily in bone. METHODS AND RESULTS:
      Thorough clinical and radiographic examinations were done to rule out any other
      primary site. The patients were four women and two men aged 17-35 years (mean,
      24.5 years). The primary site of the tumour was the femur in three patients, the
      ilium in one and the fibula in two. In one of the patients with fibular
      involvement, the tibia was also involved by direct extension. Of the long bone
      lesions, three were centred in the metaphysis and one in the diaphysis.
      Radiographically, all of the lesions demonstrated an osteolytic pattern of bone
      destruction with ill-defined margins and a wide zone of transition between the
      lesion and adjacent normal bone. Microscopically, all tumours showed the typical
      histological pattern of alveolar soft part sarcoma. Diastase-resistant, periodic
      acid-Schiff-positive crystalline structures were identified within the cytoplasm
      and confirmed ultrastructurally. Immunohistochemically, a keratin stain was
      negative in all cases; there was positive staining for MyoD1 in the cytoplasm but
      not the nuclei. Distant metastasis developed in four patients; one died.
      CONCLUSION: Alveolar soft part sarcoma arising in bone is extraordinarily rare
      but should be considered in the differential diagnosis of metastatic
      hypernephroma in a young patient.

PMID- 10583556
TI  - Scarring in papillary carcinoma of the thyroid: report of two new cases with
      exuberant nodular fasciitis-like stroma.
AB  - AIMS: To describe two new cases of papillary carcinoma of the thyroid with
      exuberant nodular fasciitis-like stroma, one of which was characterized by
      previously unreported transformation into a poorly differentiated lesion.
      Moreover, we explore the presence of TGF-beta to help to clarify the pathogenesis
      of the collagen formation. METHODS AND RESULTS: The case characterized by an
      aggressive behaviour exhibited areas of transformation into a poorly
      differentiated (insular) carcinoma of the thyroid. In both cases, as revealed by
      immunohistochemistry, neoplastic cells produced and secreted high amounts of TGF
      beta. On the contrary, TGF-beta immunoreaction was never present in the normal
      thyroid or in papillary carcinomas without collagen bundles, while a weak,
      exclusively intracellular reaction was present in a patchy manner in cases
      showing intratumoral fibrous bundles. CONCLUSIONS: The rare variant of papillary
      thyroid carcinoma characterized by exuberant stroma may give rise to more
      aggressive lesions, as do other histotypes of differentiated thyroid carcinomas.
      TGF-beta, the fundamental cytokine which mediates scarring and activation of
      myofibroblasts, most probably induces the exuberant stroma.

PMID- 10583557
TI  - Ultrastructural localization of E-cadherin and alpha-/beta-catenin in adenoid
      cystic carcinoma.
AB  - AIMS: To investigate the disturbance of intercellular adhesion in adenoid cystic
      carcinoma (ACC), we examined the ultrastructural localization of E-cadherin (E
      cad), alpha-catenin (alpha-cat) and beta-catenin (beta-cat) in ACC, and compared
      it with that in the normal labial gland. METHODS AND RESULTS: Using immuno
      electron microscopy, in the normal labial gland, E-cad was found to be uniformly
      distributed along the plasmalemma, where cells were in close contact with each
      other, with junctional complexes, desmosomes and interdigitations; expression of
      alpha-cat and beta-cat was also detected. In ACC, which was classified into
      tubular, cribriform and trabecular types, E-cad expression seemed not to be
      uniform, but was observed to be along the plasmalemma where cell-to-cell contact
      was made. On the other hand, expression of alpha-cat or beta-cat was uneven in
      the trabecular-type cells which were very slender and grew in an infiltrative
      scattered pattern into the extracellular matrix; that was absent in the
      cribriform-type cells which made contact with each other mostly at the tip of the
      cytoplasmic processes. CONCLUSION: These findings suggest that the neoplastic
      cells of ACC express E-cad for use in intercellular adhesion, but the cadherin
      catenin complex might not operate properly, which is the cause of neoplastic cell
      dissociation, followed by invasion and metastasis.

PMID- 10583558
TI  - Metaplastic (infarcted) Warthin's tumour of the parotid gland: a possible
      consequence of fine needle aspiration biopsy.
AB  - AIMS: The metaplastic (or infarcted) variant of Warthin's tumour is characterized
      by replacement of much of the original oncocytic epithelium by metaplastic
      squamous cells, along with areas of extensive necrosis, fibrosis and inflammatory
      change. The pathogenesis is unknown, but it is most likely to be vascular in
      origin. An association with a previous fine needle aspiration (FNA) has been
      suggested, and this is explored further. METHODS AND RESULTS: Nine metaplastic
      Warthin's tumours were collected from several centres: all arose in the parotid
      gland, and all showed the characteristic histological features. Eight had
      previously undergone FNA some 1-4 months before surgery; the other case had had
      an incisional biopsy. CONCLUSIONS: It is important to recognize metaplastic
      Warthin's tumour, because the differential diagnoses of this benign neoplasm
      include mucoepidermoid and squamous carcinoma, both primary and metastatic. The
      tumours in this study followed FNA or biopsy, and we believe this association is
      unlikely to be coincidental. Although many metaplastic Warthin's tumours clearly
      arise spontaneously, we conclude that the balance of probabilities favours the
      view that FNA is capable of causing metaplastic change in a Warthin's tumour, and
      may have done so in these cases. If so, this previously unusual subtype will
      become increasingly common, as FNA becomes more widely used (and its value
      appreciated) in the investigation of patients with a mass in the neck.

PMID- 10583559
TI  - Intravascular tumour in intra-oral pleomorphic adenomas: a diagnostic and
      therapeutic dilemma.
AB  - AIMS: Intravascular tumour has been described very rarely in pleomorphic
      adenomas. The aim of this study was to establish the frequency of intravascular
      tumour in pleomorphic adenomas arising in minor salivary glands and to determine
      the biological significance of this phenomenon. METHODS AND RESULTS:
      Representative sections of 67 widely excised pleomorphic adenomas were examined
      for the presence of intravascular tumour. Sixty-two cases were derived from the
      palate while the remaining five were from the cheeks and lips. In instances where
      intravascular tumour was identified, multiple serial sections were assessed and
      immunohistochemical stains were performed. None of these cases showed cytological
      evidence of malignancy. Solid cords of intravascular tumour were present in six
      palatal tumours (8.9%) and consisted of plasmacytoid myoepithelial cells
      permeating muscular walled blood vessels and capillaries both within the tumour
      and capsule. Immunoperoxidase staining confirmed that the intravascular cells
      were phenotypically identical to those of the tumour being S100- and smooth
      muscle actin (SMA) positive. There is some evidence that this phenomenon
      represents true vascular invasion although artefactual spillage cannot be
      excluded. CONCLUSIONS: Although the biological significance of intravascular
      tumour in pleomorphic adenomas of minor salivary glands remains unknown, the
      occurrence of metastatic disease has not been demonstrated nor have aggressive
      behaviour or recurrences.

PMID- 10583560
TI  - Inflammatory aetiology of primary oesophageal achalasia: an immunohistochemical
      and ultrastructural study of Auerbach's plexus.
AB  - AIM: Achalasia is a disease of the oesophagus characterized by increased lower
      oesophageal sphincter (LOS) tone, absence of LOS relaxation with swallowing and
      aperistalsis of the body of the oesophagus. The aetiology and pathogenesis of
      idiopathic achalasia is still controversial. METHODS AND RESULTS: We examined 16
      oesophageal biopsies and one low oesophagectomy specimen from patients with
      achalasia. The control group was composed of five autopsy cases with no history
      of oesophageal disorders, three cases of diffuse oesophageal spasm, one of gastro
      oesophageal reflux disease and one patient with oesophageal carcinoma. Sections
      were immunostained for neurofilaments NF70 and NF200, S100 protein and neurone
      specific enolase. Biopsies with inflammatory infiltrates, were in addition
      immunostained with antibodies against leucocyte common antigen as well as for
      CD20, CD43, CD68 and CD45RO. All biopsies were examined after plastic embedding,
      and electron microscopy (EM) was performed on samples containing autonomic
      plexus. An inflammatory infiltrate of varying intensity was present along the
      nerve fascicles and around ganglion cells in 90% of the cases of achalasia. T
      lymphocytes predominated in all these cases. The autonomic nerves showed loss of
      fibres and degenerative changes which were discernible only by EM. Although there
      was no convincing neuronal loss or signs of active neuronal degeneration in
      biopsied cases, the oesophagectomy specimen revealed total absence of neurones
      and significant loss of nerve fibres. The control group showed normal plexuses
      and no inflammation. CONCLUSION: Degeneration and significant loss of nerve
      fibres associated with predominant T-cell lymphocytic inflammatory infiltrate
      around the myenteric plexus support the concept for the inflammatory, probably
      autoimmune, aetiology of autonomic nervous system injury in primary achalasia.

PMID- 10583561
TI  - Small epithelial cells in extrahepatic biliary atresia: electron microscopic and
      immunoelectron microscopic findings suggest a close relationship to liver
      progenitor cells.
AB  - AIMS: It is still unclear whether hepatic stem cells that give rise to both
      biliary epithelial cells and hepatocytes exist in the human liver. The aim of
      this study was to investigate whether cells with ultrastructural and
      immunophenotypical features similar to those of the oval cells of rodents or the
      small epithelial cells (SEC) described recently in hepatoblastoma, i.e. putative
      hepatic progenitor cells, are found in the liver of patients with extrahepatic
      biliary atresia. METHODS AND RESULTS: Liver biopsies from 10 infants with
      extrahepatic biliary atresia were investigated by transmission electron
      microscopy. Single and double immunolabelling for cytokeratin 7, a marker of
      biliary differentiation, and albumin, a marker of hepatocytic differentiation,
      was investigated by immunoelectron microscopy. Electron microscopy revealed SEC
      that were ultrastructurally similar to the oval cells and coexpressed albumin and
      cytokeratin 7. The SEC exhibited a spectrum of differentiation that, in addition
      to relatively undifferentiated cells, included cells that exhibited morphological
      and immunophenotypical signs of differentiation towards biliary epithelial cells
      and hepatocytes. CONCLUSIONS: The findings demonstrate that SEC with
      morphological and immunophenotypical features of the oval cells of rodents and
      the SEC described in hepatoblastoma are found in the liver of patients with
      extrahepatic biliary atresia. The data further support the hypothesis that the
      SEC represent possible candidates for hepatic progenitor cells.

PMID- 10583562
TI  - A neural network approach to the biopsy diagnosis of early acute renal transplant
      rejection.
AB  - AIMS: To develop and test a neural network to assist in the histological
      diagnosis of early acute renal allograft rejection. METHODS AND RESULTS: We used
      three sets of biopsies to train and test the network: 100 'routine' biopsies from
      Leicester; 21 selected difficult biopsies which had already been evaluated by
      most of the renal transplant pathologists in the UK, in a study of the Banff
      classification of allograft pathology and 25 cases which had been classified as
      'borderline' according to the Banff classification in a review of transplant
      biopsies from Oxford. The correct diagnosis for each biopsy was defined by
      careful retrospective clinical review. Biopsies where this review did not provide
      a clear diagnosis were excluded. Each biopsy was graded for 12 histological
      features and the data was entered into a simple single layer perception network,
      designed using the MATLAB neural network toolbox. Results were compared with
      logistic regression using the same data, and with 'conventional' histological
      diagnosis. If the network was trained only with the 100 'routine' cases, its
      performance with either of the other sets was poor. However, if either of the
      'difficult' sets was added to the training group, testing with the other
      'difficult' group improved dramatically; 19 of the 21 'Banff' study cases were
      diagnosed correctly. This was achieved using observations made by a trainee
      pathologist. The result is better than was achieved by any of the many
      experienced pathologists who had previously seen these biopsies (maximum 18/21
      correct), and is considerably better than that achieved by using logistic
      regression with the same data. CONCLUSION: A neural network can provide a
      considerable improvement in the diagnosis of early acute allograft rejection,
      though further development work will be needed before this becomes a routine
      diagnostic tool. The selection of cases used to train the network is crucial to
      the quality of its performance. There is scope to improve the system further by
      incorporating clinical information. Other related areas where this approach is
      likely to be of value are discussed.

PMID- 10583563
TI  - Microinvasive carcinoma of the breast: can it be diagnosed reliably and is it
      clinically significant?
AB  - Deciding whether in-situ breast carcinoma is associated with microinvasion is a
      common problem. Histological features resembling invasion can be simulated by in
      situ carcinoma distorted by inflammatory and reparative changes. Having expended
      the effort to diagnose genuine microinvasion, just how useful is this diagnosis
      in planning further treatment and follow-up? In the following articles, Hoda et
      al. comment on the utility of immunohistochemistry in resolving uncertainty about
      the presence of microinvasion, and Ellis et al. critically appraise the
      definition of microinvasion and its clinical significance.

PMID- 10583564
TI  - Microinvasive carcinoma of the breast: diagnostic criteria and clinical
      relevance.

PMID- 10583565
TI  - Clear cell change in colonic adenocarcinoma: an equally unusual finding.

PMID- 10583566
TI  - E-cadherin changes in gastric carcimona.

PMID- 10583567
TI  - Chondrolipoma of the breast: a case report with cytological and histological
      examination.

PMID- 10583569
TI  - Melanotic oncocytic metaplasia of the nasopharynx.

PMID- 10583568
TI  - Eosinophilic granulomatous vasculitis mimicking a gastric neoplasmn.

PMID- 10583570
TI  - Lipoma of the endocervix.

PMID- 10583571
TI  - Clear cell atypical fibroxanthoma.

PMID- 10583572
TI  - Predicting the future: a critical appraisal of cancer prognosis studies.
AB  - Many studies have attempted to define useful prognostic and predictive factors in
      cancer but few have achieved acceptance in clinical practice because of
      methodological weaknesses. These include failure to test clearly formulated
      hypotheses, inadequate sample size, inappropriate multiple significance testing,
      arbitrary definition of patient groups, inadequately reproducible assays, and
      failure to verify prognostic factors with data independent of the data which
      suggested the original hypothesis. This unsatisfactory situation will persist
      until critical attention is routinely paid to study design and prospective
      validation of supposed prognostic and predictive factors, without which classical
      approaches will be suboptimally exploited and the flood of data from new
      molecular technologies will not be used effectively. We propose that prognostic
      factors should be evaluated in three phases: I, assay definition; II,
      retrospective testing; III, prospective testing, ideally as a designed part of
      clinical trials.

PMID- 10583573
TI  - Cribriform adenocarcinoma of the tongue: a hitherto unrecognized type of
      adenocarcinoma characteristically occurring in the tongue.
AB  - AIMS: We report a review of our institutional and consultation files in order to
      select cases of hitherto unrecognized type of adenocarcinoma occurring in the
      tongue. MATERIALS AND RESULTS: Eight cases of a characteristic adenocarcinoma of
      the tongue resembled solid and follicular variants of the papillary carcinoma of
      the thyroid. All the tumours were unencapsulated and were divided by fibrous
      septa into lobules. Major parts of the lesions were composed of areas with solid
      and microcystic growth patterns. The most striking cytological feature was that
      the tumour nuclei were pale-staining with a 'ground glass' quality, and they
      often appeared to overlap. Immunohistochemically, the tumours expressed
      cytokeratin and S100 protein and, focally, actin; thyroglobulin was negative.
      Ultrastructurally the cells had clefted nuclei, and the cytoplasm contained a few
      mitochondria, lysosomes and Golgi apparatus. Many tumour cells had combined
      features of both myoepithelial and secretory differentiation-well formed
      microvilli on their apical borders and bundles of microfilaments. At first
      presentation, all eight patients had metastases in the regional neck lymph nodes,
      but all are alive 2-6 years after the initial excision and irradiation.
      CONCLUSION: We describe a distinctive type of adenocarcinoma of the tongue, for
      which we propose the name cribriform adenocarcinoma of the tongue (CAT). CAT
      usually presents with metastases in the neck lymph nodes at the time of
      presentation. We hypothesize that the tumour might arise from the thyroglossal
      duct anlage.

PMID- 10583574
TI  - Phenotypes in canalicular adenoma of human minor salivary glands reflect the
      interplay of altered secretory product, absent neuro-effector relationships and
      the diversity of the microenvironment.
AB  - AIMS: Uncertainty about the factors influencing phenotypes in salivary
      canalicular adenoma prompted the present investigation. METHODS AND RESULTS:
      Specimens of canalicular adenoma from 15 patients were examined with the use of
      histology, histochemistry for protein, mucosubstances and pigments, nerve
      staining and immunocytochemistry for cytoskeleton components. The tumours
      consisted largely of simple cells lining tubules that were occasionally cystic or
      branching and budding, and were set in loose, vascular and often haemorrhagic
      stroma. Other phenotypes recognized were mucous cells, apocrine-like cells,
      pigmented cells, microliths and stromal macrophages, detected in 26.6%, 20%,
      33.3%, 20% and 53. 3% of the patients, respectively. Simple cells showed moderate
      levels of -SH groups and strong immunoreactivity for 'simple' epithelial
      phenotype cytokeratin. The simple cells lining cystic tubules showed additional
      immunoreactivity for 'stratified' epithelial phenotype cytokeratin, possibly an
      adaptation to mechanical pressure. Lumina showed variable levels of neutral and
      carboxylated glycoproteins, and chondroitin sulphate. Stroma showed high levels
      of chondroitin sulphate and hyaluronic acid. Mucous cells showed high levels of 
      SS- groups and nonsulphated glycoproteins. Apocrine-like cells contained
      lipofuscin. Pigmented cells contained haemosiderin, possibly a consequence of
      localized iron overload. Microliths contained mucosubstances. Macrophages often
      contained lipofuscin. No nerves were found in relation to the tumours.
      CONCLUSIONS: The results suggest that, contrary to popular belief, phenotypes in
      canalicular adenoma do not reflect histogenetic concepts but rather may derive
      from the interplay between an altered secretory product, consisting of
      glycosaminoglycan and an immature form of glycoprotein, the lack of neuro
      effector relationships and the different microenvironments throughout the tumour.

PMID- 10583575
TI  - Expression of MUC1 and MUC2 mucin gene products in Barrett's metaplasia,
      dysplasia and adenocarcinoma: an immunopathological study with clinical
      correlation.
AB  - AIMS: Changes in the histochemical characteristics of the surface epithelial
      mucins is the hallmark of Barrett's metaplasia. The study investigated the
      pattern of expression of MUC1 and MUC2 mucin gene products in Barrett's
      metaplasia, dysplasia and adenocarcinoma as possible indicators of increased
      malignant potential. METHODS AND RESULTS: Tissue sections from 51 patients with
      Barrett's intestinal metaplasia, nine with dysplasia (three indefinite) and 28
      resected adenocarcinomas were stained with monoclonal antibodies to MUC1 and
      MUC2. The majority of the patients were men (70/88, 80%) who were treated over a
      period of 3 years. None of the patients with dysplasia or carcinoma were under
      surveillance at the time of presentation. All 51 biopsies with Barrett's
      metaplasia expressed MUC2 and MUC1 was consistently absent. Neither MUC1 or MUC2
      were expressed in the dysplastic epithelium whether in its pure form (6/6) or
      when associated with carcinoma (26/28) (P < 0.005). Three biopsies which were
      initially classified as high-grade dysplasia expressed MUC1 and these turned out
      to be carcinomas on further investigations. MUC1 was also expressed in 12/28
      (43%) of the adenocarcinomas and majority of these were poorly differentiated
      stage 3 tumours (P < 0.05). MUC2 was only positive in mucin-secreting carcinomas
      (4/28; 14%) irrespective of the tumour stage. CONCLUSION: Despite the large
      number of patients with Barrett's metaplasia and carcinoma, very few patients
      presented with dysplasia, implying that Barrett's oesophagus is a silent disease
      in the community presenting late as carcinoma. The study has demonstrated
      aberrant expression of MUC2 (an intestinal mucin) in Barrett's metaplasia and
      this expression is lost when the cells become dysplastic. The lack of MUC1 in
      dysplastic epithelium and its expression in carcinoma could be utilized as a
      marker which could differentiate dysplasia from carcinoma in mucosal biopsies.
      Furthermore, expression of MUC1 in advanced stage oesophageal cancers (as in
      breast cancer) suggests an unfavourable prognosis.

PMID- 10583576
TI  - Sinus histiocytosis with massive lymphadenopathy: evidence for its relationship
      to macrophages and for a cytokine-related disorder.
AB  - AIMS: Sinus histiocytosis with massive lymphadenopathy (SHML) or Rosai-Dorfman
      disease is a rare histiocytic disorder of unknown origin. Immunophenotypically
      the histiocytes of SHML express intensively the S100 protein and in addition a
      panel of macrophage-associated antigens. Their exact relationship to either
      monocytes/macrophages or immune accessory dendritic cells is, however, still
      controversial. METHODS AND RESULTS: In this report recurrent nodal and extranodal
      manifestations of SHML of a 70-year-old patient were analysed by differential
      phenotyping using a panel of monoclonal and polyclonal antibodies to macrophage
      and immune accessory dendritic cell related antigens and by applying
      nonradioactive in-situ hybridization. CONCLUSIONS: We conclude that stimulation
      of monocytes/macrophages via macrophage colony stimulating factor (M-CSF) leading
      to immune suppressive macrophages represents a main mechanism for the
      pathogenesis of SHML. The study further provides evidence for the
      monocyte/macrophage but not dendritic cell differentiation of SHML histiocytes.

PMID- 10583577
TI  - Mycobacterial cervical lymphadenitis: the histological features of non
      tuberculous mycobacterial infection.
AB  - AIMS: The distinction between nontuberculous mycobacterial (NTM) lymphadenitis
      and other causes of cervical lymphadenitis is critical, as different entities
      call for different treatments. Despite modern diagnostic techniques for NTM
      infections their prompt and accurate diagnosis is still difficult. We assessed
      the value of different histological features in diagnosing clinically suggestive
      NTM cervical lymphadenitis in cases of granulomatous cervical lymphadenitis.
      METHODS AND RESULTS: A retrospective study of 30 patients with a clinical
      diagnosis of NTM cervical lymphadenitis was carried out. The patients were
      divided into three subgroups and several histological parameters were examined in
      each subgroup. A comparison was made with cases of proven tuberculous
      lymphadenitis. Four histological features (presence of microabscesses, ill
      defined granulomas, noncaseating granulomas and a small number of giant cells)
      were found with significant statistical difference when comparison was made
      between the NTM group and the tuberculosis group. CONCLUSIONS: A rapid and
      accurate diagnostic procedure for NTM lymphadenitis is not yet available.
      Therefore, in the presence of a suggestive clinical picture for NTM
      lymphadenitis, we propose four histological features which support this
      diagnosis, thus allowing prompt therapeutic intervention.

PMID- 10583578
TI  - Genotypic and phenotypic alterations in Epstein-Barr virus-associated lymphoma.
AB  - AIMS: Epstein-Barr virus (EBV) is associated with numerous reactive and
      neoplastic lymphoproliferative disorders. In vitro, EBV infection can transform B
      lymphocytes and induce phenotypic alterations. This study presents the
      clinicopathological features of four cases with malignant lymphoma, which showed
      phenotypic and/or genotypic alterations during the course of the disease. METHODS
      AND RESULTS: To determine the type of EBV genotype, we performed polymerase chain
      reaction (PCR) for lymphocyte-defined membrane antigen (LYDMA) of EBV, subtype
      A/B and latent membrane protein (LMP)-1 deletion. In addition, we analysed the
      terminal repeat (TR) band of EBV and receptor genes (T-cell receptor gene, TCR;
      immunoglobulin gene heavy chain, IgH) for EBV-infected cell clonality. Double
      staining of cell markers (B, T-lymphocytes; histiocytes), and in-situ
      hybridization (ISH) for EBV were performed using tissues obtained during the
      course of the disease. The first case showed genotypic and phenotypic alterations
      of T-cell type to B-cell type. The first TCR rearrangement and T-cell markers
      (CD3+, CD4+, CD8-) were lost and IgH rearrangement and B-cell markers (CD19+,
      CD20+) were identified. During the course of the disease, EBV-TR bands changed in
      size; however, the EBV genotype type B, LMP1 deletion type, and single LYDMA band
      remained the same. The initial T-cell lymphoma clone was considered to be
      different from the latter B-cell lymphoma clone. The second case showed
      phenotypic alterations. The first B-cell marker (CD19+, CD20+, CD68-) changed to
      histiocytic markers (CD19-, CD20-, CD68+). However, IgH rearrangement and EBV-TR
      bands remained the same throughout the course of the disease and EBV genotype
      type A, LMP1 deletion type, and single LYDMA band remained unchanged. The third
      case showed phenotypic alterations. The B-cell marker (CD20+) was lost; however,
      IgH rearrangement of PCR and EBV genotype remained the same. In the second and
      third cases, the initial lymphoma clones were considered to be same as the latter
      clones. The last case showed lineage alterations from Hodgkin's disease to
      natural killer (NK) cell leukaemia. However, EBV genotype did not change. The
      second case and Hodgkin's disease showed LMP expression, but the first and third
      cases showed no LMP, and EBNA2 was not detected in all cases. CONCLUSIONS: We
      report the genotypic and/or phenotypic alterations in four patients with EBV
      associated lymphoma/leukaemia. However, EBV genotype did not change in all four.
      These findings suggest that EBV might induce the cell marker and lineage
      alteration in vivo, as in vitro.

PMID- 10583579
TI  - Mucinous epithelial cysts of the spleen associated with pseudomyxoma peritonei.
AB  - AIMS: We report two rare cases of neoplastic pseudomyxoma peritonei associated
      with splenic mucinous epithelial cysts and review previously reported cases of
      splenic mucinous lesions in order to investigate the extent and implications of
      such an association. METHODS AND RESULTS: The majority of mucinous lesions of the
      spleen appear to be associated with pseudomyxoma peritonei. The
      clinicopathological profile of these cases conforms to that of neoplastic
      pseudomyxoma peritonei, showing a similar age of onset, outcome and histological
      features. Most of the cases were associated with a confirmed or suspected
      appendiceal primary. The immunophenotype (cytokeratin 7 negative; cytokeratin 20
      and CEA positive) of the lesions of both our cases, including those in the ovary,
      was suggestive of a gastrointestinal origin. CONCLUSIONS: Splenomegaly due to
      cystic intrasplenic mucinous epithelial lesions may occasionally be the
      presenting feature of pseudomyxoma peritonei or herald tumour recurrence.
      Mucinous epithelial cysts of the spleen may also precede the development of
      pseudomyxoma peritonei. All cases of pseudomyxoma peritonei should be
      investigated for splenic involvement and, conversely, a primary mucinous neoplasm
      sought elsewhere in the abdomen in all cases of splenic mucinous cysts.

PMID- 10583580
TI  - Spinal melanotic schwannoma: a tumour with poor prognosis.
AB  - AIM: To clarify the prognosis of melanotic schwannoma. This is a rare tumour
      which is generally considered as a benign lesion, reported in many cases with a
      short follow-up only. METHODS AND RESULTS: Five cases of spinal melanotic
      schwannoma were retrospectively studied. The tumours were examined using standard
      histological, immunohistochemical and ultrastructural methods. No features of
      malignancy (high mitotic count, atypia or necrosis) were found in the primary
      tumours. The follow-up period ranged from 3 to 7 years. Malignant clinical
      behaviour was clear-cut in four cases: three patients died from metastases to
      various sites and one presented several discrete spinal tumours of the same type
      seven years after the first operation. Only one patient presented no recurrence
      and was free of disease 6 years after initial diagnosis. The review of 57 cases
      of the literature (including our cases), showed that 15% of the cases had
      recurrences and 26.3% were complicated by metastasis. Only 53% of the cases
      followed for more than 5 years, were free of disease vs. 67.5% of the cases with
      shorter follow-up. Twenty additional cases had no follow-up. CONCLUSION:
      Appropriate long-term follow-up is required for all melanotic schwannomas, as it
      may recur or metastasize after more than 5 years, even in the absence of overt
      malignant histological features.

PMID- 10583582
TI  - Ljubljana classification of epithelial hyperplastic laryngeal lesions.

PMID- 10583583
TI  - Authors' reply

PMID- 10583581
TI  - Morphological evidence for field effect as a mechanism for tumour spread in
      mammary Paget's disease.
AB  - AIMS: The histogenesis of mammary Paget's disease is controversial. The purpose
      of this study was to investigate the mechanism of tumour spread in the nipple
      epidermis by examining 28 cases of mammary Paget's disease associated with
      underlying intraductal carcinoma. METHODS AND RESULTS: The atypical cells in the
      epidermis displayed a spectrum of cytological changes ranging from small-sized
      atypical cells located in the basal cell layer to large-sized atypical cells
      characteristic of Paget's cells in the upper layer of the epidermis. Serial
      sectioning revealed the presence of isolated, scattered and small atypical cells
      in the basal cell layer at the periphery of the epidermal lesion. The atypical
      cells, including those in the basal cell layer showed positive immunostaining for
      cytokeratin 7 and Her2/neu oncoprotein. Electron microscopy examination
      demonstrated the presence of intercellular junctions of desmosomal-like or
      desmosomal types between tumour cells and adjacent squamous cells. Furthermore,
      examination of the intraductal carcinoma of the breast tissue in cases of Paget's
      disease as well as control cases of intraductal carcinoma also revealed areas of
      skip lesions of intraductal carcinoma. CONCLUSIONS: In view of these changes, it
      is unlikely that tumour expansion or tumour cell motility are sufficient
      explanations to account for the pattern of tumour spread in both the epidermis
      and the duct epithelium with skip lesions. A 'field effect' in the duct system
      harbouring intraductal carcinoma and the adjacent epidermis may play an important
      role in the tumour cell spread in the epidermis as well as in the ductal
      epithelium.

PMID- 10583584
TI  - Typing breast cancer following primary chemotherapy.

PMID- 10583585
TI  - Intramammary lymph nodes as a cause of bilateral breast enlargement in a man.

PMID- 10583586
TI  - Recurrent isolated amyloid lymphadenopathy due to primary plasmacytoma of lymph
      nodes.

PMID- 10583587
TI  - Extramammary Paget's disease arising in a mature cystic teratoma of the ovary.

PMID- 10583588
TI  - NOS2-derived nitric oxide regulates the size, quantity and quality of granuloma
      formation in Mycobacterium avium-infected mice without affecting bacterial loads.
AB  - Granuloma formation in response to mycobacterial infections is associated with
      increased expression of inducible nitric oxide synthase (NOS2) within granuloma
      macrophages and increased levels of nitrate/nitrite in the sera of infected mice.
      Continuous treatment with 5 mm or 10 mm l-N6-(1-imino-ethyl)-lysine (L-NIL), a
      selective NOS2-inhibitor, in acidified drinking water for up to 7 weeks
      consistently reduced infection-induced nitrate/nitrite to background levels in
      mycobacteria-infected BALB/c mice. Oral treatment with 5 mm L-NIL initiated at
      the time of infection significantly exacerbated growth of Mycobacterium
      tuberculosis, but had no effect on Mycobacterium avium colony-forming unit
      development in the liver, spleen and lungs of intravenously infected mice. In
      order to examine the role of nitric oxide in mycobacteria-induced granulomatous
      inflammation in the absence of any effect on the bacterial load, M. avium
      infected mice were treated with 5 mm L-NIL from day 1 through 38 and the
      development of granulomatous lesions in the liver was assessed by histology,
      immunohistology and reverse-transcription-polymerase chain reaction (RT-PCR).
      Computer- and video-assisted morphometry performed at 4 and 7 weeks post
      infection showed that treatment with L-NIL led to markedly increased number,
      cellularity and size of granulomatous lesions in infected mice regardless of the
      virulence of the M. avium isolate used for infection. Immunohistology of the
      liver revealed that in mice treated with L-NIL, the numbers of CD3+ T cells,
      CD21/35+ B cells, CD11b+ macrophages and RB6-8C5+ granulocytes associated with
      granulomatous lesions was increased. RT-PCR of the liver showed that in L-NIL
      treated mice infected with M. avium, mRNA levels of tumour necrosis factor,
      interleukin-12p40, interferon-gamma, interleukin-10 and interferon-gamma
      inducible protein-10 (IP-10) were up-regulated, while mRNA levels of interleukin
      4, monocyte chemotactic protein-1 (MCP-1) and MCP-5 were similar to those in
      untreated control infected mice. When M. avium-infected mice were treated with 5
      mm L-NIL between the 5th and 12th weeks of infection, similar changes in
      granuloma number and size were found in the absence of any effect on the
      bacterial load. These findings demonstrate that nitric oxide regulates the
      number, size and cellular composition of M. avium-induced granulomas
      independently of antibacterial effects by modulating the cytokine profile within
      infected tissues.

PMID- 10583589
TI  - Granuloma formation is required to contain bacillus growth and delay mortality in
      mice chronically infected with Mycobacterium tuberculosis.
AB  - Previous studies in this laboratory have shown that mice with a gene disruption
      to the intracellular adhesion molecule-1 (ICAM-K/O) express normal cell-mediated
      immunity but cannot mount delayed-type hypersensitivity reactions following
      Mycobacterium tuberculosis infection. However, even in the absence of any
      appreciable granuloma formation, these mice control bacterial growth for at least
      90 days. While not required to control the infection initially, we hypothesized
      that granuloma formation was required to control chronic infection, acting by
      surrounding infected cells to prevent bacterial dissemination. To test this, ICAM
      1 knockout mice were infected with a low dose aerosol of M. tuberculosis Erdman
      and were found to succumb to infection 136+/-30 days later, displaying highly
      elevated bacterial loads compared to wild-type mice. Lung tissue from ICAM-K/O
      mice displayed extensive cellular infiltration and widespread tissue necrosis,
      but no organized granulomatous lesions were evident, whereas the control mice
      displayed organized compact granulomas. These data demonstrate that while a
      granulomatous response is not required initially to control M. tuberculosis
      infection, absence of granulomas during chronic infection leads to increased
      bacterial growth and host death. Thus these data support the hypothesis that
      granuloma formation is required to control chronic infection, acting by
      surrounding and walling off sites of infection to prevent bacterial dissemination
      and maintain a state of chronic infection.

PMID- 10583590
TI  - Systemic mycobacterial infection inhibits antigen-specific immunoglobulin E
      production, bronchial mucus production and eosinophilic inflammation induced by
      allergen.
AB  - As the burden of infectious diseases becomes reduced in many countries, a
      remarkable increase in the incidence of allergies has occurred. The basis for the
      rise in atopic disorders as a correlate of the decline in infectious diseases has
      not been defined. In the present study, we tested experimentally whether prior
      systemic infection with Mycobacterium bovis bacillus Calmette Guerin (BCG) had
      any effect on ovalbumin (OVA) Al(OH)3 (alum)-induced immunoglobulin E (IgE)
      production, airway mucus production and eosinophilic inflammation. The data
      showed that allergen-specific IgE production and OVA-induced eosinophilia and
      goblet cell development were significantly inhibited by prior infection with BCG.
      Correspondingly, following immunization with OVA alum, BCG-infected mice
      exhibited significantly higher levels of allergen-driven interferon-gamma (IFN
      gamma) production than the mice without infection. The ratio of IFN-gamma:
      interleukin (IL)-4 production was higher in OVA-sensitized mice with prior BCG
      infection than in those without infection. The abrogation of OVA-induced mucus
      production and pulmonary eosinophilia in BCG-infected mice correlated with
      significantly decreased IL-5 production and increased IFN-gamma and IL-12
      production. These data provide direct evidence that intracellular bacterial
      infection (i.e. BCG) can inhibit antigen-specific IgE and airway reactivity
      induced by environmental allergen. Furthermore, the results suggest that changes
      in cytokine-producing patterns of T lymphocytes and other cells may be the
      mechanism by which infections influence allergies.

PMID- 10583591
TI  - Low dose of orally administered antigen down-regulates the T helper type 2
      response in a murine model of dust mite hypersensitivity.
AB  - One of the main goals of immunotherapy of allergic diseases is the down
      regulation of the type I hypersensitivity reaction. We investigated in this study
      the effect of oral administration of varying doses (0.25, 1.0, 4.0 and 10 mg) of
      dust mite extract (Dermatophagoides pteronyssinus, Dp) in sensitized A/Sn mice. A
      marked decrease of the allergen-specific immunoglobulin E (IgE) response was
      observed with all antigen doses. The mice orally tolerized with low Dp dose (0.25
      mg) had a significant decrease in the total serum IgE and in the immunoglobulin
      G1 (IgG1), IgG2a and IgG2b antibody levels. The higher Dp dose (10.0 mg),
      however, enhanced the IgG1 antibody response, suggesting the stimulation of a pre
      existing immune response of the sensitized animals. Animals fed with the low Dp
      dose had a significant decrease in the frequency of interleukin-4 (IL-4)
      secreting cells. These animals also showed a significant decrease in the
      frequency of Dp-specific IgE- and IgG1-positive plasma cells. Our data suggest
      that feeding dust mite extract to Dp-sensitized mice down-regulates the
      development of type I hypersensitivity, by inhibition of the T helper 2 response.

PMID- 10583592
TI  - C57BL/6 mice are more susceptible to antigen-induced pulmonary eosinophilia than
      BALB/c mice, irrespective of systemic T helper 1/T helper 2 responses.
AB  - Inflammatory response differences between C57BL/6 and BALB/c mice following
      ovalbumin (OVA) sensitization and a single challenge were investigated. Serum
      immunoglobulin (Ig)E and IgG1 levels were higher in C57BL/6 mice than in BALB/c
      mice. In contrast, IgG2a levels in C57BL/6 mice were lower than in BALB/c mice.
      Furthermore, the number of eosinophils infiltrating into lungs in C57BL/6 mice
      was significantly higher than in BALB/c mice after OVA challenge. The levels of
      the T helper 2 (Th2)-type cytokines interleukin (IL)-4 and IL-5, generated in
      challenged C57BL/6 lung tissue, were also higher than in BALB/c lung tissue. The
      participation of IL-4 and IL-5 in the induction of eosinophil infiltration into
      the lungs was confirmed in both strains of mice by injection of anti-IL-4 and
      anti-IL-5 monoclonal antibodies (mAbs). However, following OVA stimulation, in
      vitro IL-4 and IL-5 production in splenocyte cultures from C57BL/6 mice was lower
      than in splenocyte cultures from BALB/c mice. These results indicate that C57BL/6
      mice induce Th2-type responses in the lungs, while BALB/c mice induce T helper 1
      (Th1)-type responses in the lungs, despite considerable production of IL-4 and IL
      5 from splenocytes. Therefore, local immune responses are more important in the
      induction of allergic inflammation in the lungs and are different from systemic
      immune responses, which are thought to depend on genetic background.

PMID- 10583593
TI  - Age-related changes in dermal mast cell prevalence in BALB/c mice: functional
      importance and correlation with dermal mast cell expression of Kit.
AB  - Differences in dermal mast cell prevalence for adult mice of different strains
      have been reported previously. In this study, the dermal mast cell prevalence for
      BALB/c and C57BL/6 mice at 6 weeks of age was similar but as BALB/c mice matured
      from 6 to 10 weeks of age, their dermal mast cell prevalence halved. In contrast,
      there was no significant difference in the dermal mast cell prevalence of 6- and
      10-week-old C57BL/6 mice. These differences determined the degree of
      susceptibility of BALB/c and C57BL/6 mice of different ages to UVB (UV radiation
      of wavelength 280-320 nm)-induced systemic immunosuppression. Expression of the
      receptor for stem cell factor, Kit protein, was examined on mast cells under
      conditions in which the dermal mast cell prevalence varied. A significant
      correlation was observed between Kit expression by mast cells from adult BALB/c,
      DBA/2 and C57BL/6 mice and dermal mast cell prevalence. In BALB/c mice, mast cell
      Kit expression decreased as the mice matured from 6 to 10 weeks of age and
      correlated with the reduction in dermal mast cell numbers. Kit levels on dermal
      mast cells from C57BL/6 mice were consistently higher than on mast cells from
      BALB/c mice although significant reductions in Kit were also measured with ageing
      from 6 to 10 weeks. We hypothesize that regardless of the extent of Kit
      expression, the dermal mast cell populations were maximally expanded in C57BL/6
      mice. We suggest that BALB/c mice of 6 and 10 weeks of age are useful hosts in
      which to quantitatively evaluate mast cell involvement in a range of functional
      assays involving skin.

PMID- 10583594
TI  - Both adhesion to immobilized vitronectin and FcepsilonRI cross-linking cause
      enhanced focal adhesion kinase phosphorylation in murine mast cells.
AB  - Murine mast cells adhere spontaneously to plate-bound vitronectin (VNPB) via
      alphav-containing integrins, and this adhesive interaction results in an
      augmented interleukin-3 (IL-3)-dependent mast-cell proliferation. In this report
      we demonstrate that the activation of murine mast cells through alphav-integrin,
      as well as through the high affinity immunoglobulin E (IgE) receptor
      (FcepsilonRI), results in enhanced tyrosine phosphorylation of focal adhesion
      kinase (FAK), a cytoplasmic protein tyrosine kinase involved in mitogenic and
      oncogenic signal transduction. While mast cell adhesion to VNPB resulted in
      enhanced FAK phosphorylation, treatment with soluble vitronectin (VNSOL) failed
      to do so. Spontaneous mast cell adhesion to entactin (EN) did not induce tyrosine
      phosphorylation of FAK, demonstrating that not all adhesive interactions lead to
      the same sequence of biochemical events. Because FAK has intrinsic tyrosine
      kinase activity, we examined whether activating mast cells via alphav-integrins,
      or via FcepsilonRI-cross-linking stimulated the in vitro kinase activity of FAK.
      Both pathways were found independently to activate FAK in mast cells and together
      appeared additive. Protein kinase C depletion in mast cells and calcium depletion
      in the medium caused decreased tyrosine phosphorylation of FAK, indicating that
      optimal tyrosine phosphorylation of FAK is regulated by both pathways. These data
      are consistent with the conclusion that the tyrosine phosphorylation of FAK
      represents at least one example of a point of convergence in the intracellular
      tyrosine phosphorylation cascades induced by alphav integrin-and FcepsilonRI
      mediated signal transduction pathways in mast cells.

PMID- 10583595
TI  - Nitric oxide and macrophage antiviral extrinsic activity.
AB  - In this study we evaluated the relationship between nitric oxide (NO) and
      macrophage antiviral extrinsic activity. Macrophages activated by intraperitoneal
      injection of herpes simplex virus-2 (HSV-2), showed both extrinsic antiviral
      activity and high nitrite production in contrast to non-activated, resident
      macrophages. The extrinsic antiviral activity was observed in cultures of Vero
      cells infected with HSV-1 and HSV-2. The NO inhibitor N-monomethyl-l-arginine
      acetate (l-NMA) impaired the antiviral activity of HSV-elicited macrophages. The
      effect was dose dependent and correlated with a reduction of nitrite in the
      culture media. The effect of l-NMA was reversed by the addition of l-arginine.
      These data indicate that NO could be responsible for the described activity.
      Furthermore, l-NMA treatment resulted in the aggravation of HSV-1-induced
      keratitis in the mouse model, supporting a defensive role of NO in the
      pathogenesis of HSV-1 corneal infection.

PMID- 10583597
TI  - Kinetics of interferon-gamma secretion and its regulatory factors in the early
      phase of acute graft-versus-host disease.
AB  - Increased serum levels of interferon-gamma (IFN-gamma) have been observed in
      acute graft-versus-host disease (GVHD). Recent in vitro studies have demonstrated
      that interleukin-12 (IL-12) and interleukin-18 (IL-18) synergistically up
      regulate IFN-gamma secretion. In this communication, we investigated the factors
      relevant to IFN-gamma secretion in acute GVHD. A murine model of acute GVHD was
      established by injecting donor spleen cells into severe combined immunodeficiency
      (SCID) mice. A series of specimens, including sera, livers and spleens derived
      from the GVHD mice, were investigated with histological examination, enzyme
      linked immunosorbent assay (ELISA), flow cytometry, and semiquantitative reverse
      transcription-polymerase chain reaction (RT-PCR). IFN-gamma secretion increased
      in serum 3 days after spleen cell transfer, peaked on day 7, and then gradually
      decreased close to the baseline level by day 35. A synchronized increase of
      activated T cells and mRNA expression of IL-12, IL-18 and their respective
      receptors was observed after spleen cell transfer. However, only the kinetic
      expression pattern of IL-12 receptor (IL-12R) beta2 chains was closely correlated
      with that of IFN-gamma, while IL-12 dropped to the baseline level earlier than
      IFN-gamma. Therefore, IFN-gamma expression in the early phase of acute GVHD is a
      mono-peak and self-restricted pattern. Its secretion is closely related with T
      cell activation, the presence of IL-12, IL-18 and their respective receptors.
      However, the limiting factors for IFN-gamma secretion seem to be IL-12 and IL-12R
      beta2 chains.

PMID- 10583596
TI  - Regulation of murine dendritic cell functions in vitro by taurine chloramine, a
      major product of the neutrophil myeloperoxidase-halide system.
AB  - Taurine chloramine (TauCl) is a major chloramine generated in activated
      neutrophils as a result of the reaction of highly toxic hypochlorous acid and
      taurine, the most abundant free amino acid in cytosol. In this study we have
      tested the influence of TauCl on the properties of murine dendritic cells (DC),
      the major cell population involved in the initiation of an adaptive immune
      response against pathogenic organisms. N418+, MHC II+, B7-2+ dendritic cells,
      generated from the mouse bone marrow cells cultured in the presence of
      granulocyte-macrophage colony-stimulating factor, were stimulated by interferon
      gamma and lipopolysaccharide to produce nitric oxide, reactive oxygen species,
      interleukin-6 (IL-6), tumour necrosis factor-alpha, and IL-12, in the presence of
      different doses of TauCl. TauCl differently inhibited the generation of these
      inflammatory mediators in a dose-dependent manner. Furthermore, TauCl selectively
      modulated the ability of DC to induce the release IL-2 and IL-10 from T cells.
      These results suggest that neutrophil-derived mediators, such as TauCl, at a site
      of inflammation, may affect the functions of sentinel DC and macrophages, and
      play a role in maintaining the balance between the inflammatory response and the
      induction of an antigen-specific immune response.

PMID- 10583598
TI  - Up-modulation of interferon-gamma mediates the enhancement of spontanous
      cytotoxicity in prolactin-activated natural killer cells.
AB  - Prolactin (PRL) has been shown to participate in lymphocyte activation. In
      particular, the constitutive natural killer (NK) and the lymphokine-activated
      killer (LAK) cytotoxicity of CD56+ CD16+ cells is increased by its physiological
      to supraphysiological concentrations. As PRL has been shown to up-regulate the
      production of interferon-gamma (IFN-gamma) by peripheral blood mononuclear cells,
      we studied its effect on IFN-gamma production by NK cells as a possible mechanism
      of autocrine activation of cytotoxicity. Released and intracellular IFN-gamma, as
      well as IFN-gamma mRNA expression, were increased by pituitary and recombinant
      human PRL, which stimulated optimal NK and LAK cytotoxicity. Treatment with
      blocking anti-IFN-gamma monoclonal antibody (mAb) selectively affected PRL
      increased killing of K562 targets, demonstrating that PRL-mediated enhancement of
      spontaneous cytotoxicity depends, at least in part, on up-regulation of IFN
      gamma.

PMID- 10583599
TI  - Nitric oxide selectively decreases interferon-gamma expression by activated human
      T lymphocytes via a cGMP-independent mechanism.
AB  - The role of exogenous nitric oxide (NO) on the expression of interleukin (IL)-2,
      IL-4, IL-5 and interferon-gamma (IFN-gamma) by freshly isolated human T
      lymphocytes was investigated. The presence of NO, generated from any of the NO
      donor compounds, S-nitroso-N-acetyl-D,L-penicillamine (SNAP), DPTA-nonoate (DPTA)
      or DETA-nonoate (DETA), added 15 min prior to T-cell stimulation (for 24 hr) with
      anti-CD3/anti-CD28 monoclonal antibodies (mAbs), resulted in up to 50% inhibition
      of IL-4, IL-5 and IFN-gamma secretion. In contrast, IL-2 secretion was not
      inhibited. Using the guanylate cyclase inhibitor, LY83583, it was shown that the
      inhibition of IL-4 and IL-5 was cGMP dependent, whereas additional mechanisms
      mediated the inhibition of IFN-gamma. Exposure of T cells to the NO-donor
      compounds for 24 hr prior to stimulation resulted in a more pronounced inhibition
      of IFN-gamma secretion by DPTA and DETA (P < 0.01), despite the fact that NO
      generation could no longer be detected. Under these conditions, IL-4 secretion
      was not inhibited and IL-5 secretion was inhibited to a lesser extent (P < 0.01
      for SNAP and DPTA, P > 0.05 for DETA). IL-2 secretion was inhibited after 24 hr
      of preincubation with the NO-donor compounds, whereas it was not directly
      affected by NO. The increased inhibitory effects on IFN-gamma and IL-2 secretion
      could not be accounted for by the antiproliferative effects of the NO-donor
      compounds, which were diminished after 24 hr of preincubation relative to 15 min
      of preincubation. For IFN-gamma, the inhibition was at least partially effected
      at the transcriptional level as shown by decreased mRNA accumulation. These data
      show that NO can modulate the balance between the expression, by human T
      lymphocytes, of T helper 1- and T helper 2-type cytokines, through selective and
      persistent inhibition of the expression of IFN-gamma via a cGMP-independent
      mechanism.

PMID- 10583600
TI  - Putative role for interleukin-7 in the maintenance of the recirculating naive
      CD4+ T-cell pool.
AB  - The capacity of the immune system to respond efficiently to new antigens depends
      upon a continuous source of naive CD4+ T cells. Such cells exit from the thymus
      and join the recirculated T-cell pool. Factors present at the sites of naive CD4+
      T-cell circulation must be responsible for their survival, since upon removal
      from their host, naive CD4+ T cells die. However, such factors remain unknown.
      The presence of the cytokine interleukin-7 (IL-7) in secondary lymphoid organs
      and the continuous expression of its receptor on naive CD4+ T cells prompted us
      to examine the possibility that IL-7 might be a survival factor for naive CD4+ T
      cells. Using naive CD4+ T cells isolated from cord blood we show that IL-7, but
      not IL-2, can maintain naive CD4+ T-cell viability in vitro for at least 15 days.
      In addition, we find that IL-7 can induce modest proliferation of naive CD4+ T
      cells without affecting either their cell surface phenotype or their ability to
      respond to antigenic stimulation. We also find that after anti-CD3 stimulation,
      naive CD4+ T cells lose that ability to respond to IL-7. However, if cells are
      primed with IL-7 prior to antigenic stimulation, their proliferative responses
      are enhanced. Together, these data suggest a novel and important role for IL-7 in
      the maintenance and maturation of naive CD4+ T cells, ensuring that they can
      respond maximally when they first meet antigen in secondary lymphoid tissue.

PMID- 10583601
TI  - Interleukin-12 modulates T-cell responses to microfilariae but fails to abrogate
      interleukin-5-dependent immunity in a mouse model of onchocerciasis.
AB  - Infection of mice with microfilariae of Onchocerca lienalis induces high levels
      of protective immunity to reinfection, which is dependent on interleukin (IL)-5
      but not IL-4. Here, we have investigated the effect of exogenous IL-12
      administration during either the priming or effector phases of the immune
      response. When administered during priming, IL-12 induced down-regulation of
      parasite-specific serum immunoglobulin (Ig)E and up-regulation of IgG2a. Antigen
      specific IL-4 responses were strongly suppressed, whilst blood eosinophil levels
      were partially reduced. When administered during a challenge infection, IL-12 did
      not significantly influence the balance of antibody isotypes, but partially
      reduced eosinophil production. Antigen-specific IL-4 responses were again
      completely ablated. Unusually, interferon-gamma (IFN-gamma) responses were not
      significantly affected following IL-12 administration, either during priming or
      after challenge infections. Moreover, despite a fall in antigen-specific IL-5
      production, the expression of IL-5-dependent immunity, as determined by reduction
      in worm recoveries, was fully maintained. These data demonstrate that parasite
      induced IL-4 can be abrogated without affecting protective immunity to Onchocerca
      microfilariae in mice. In view of the established role of IL-4 in pathogenesis,
      this may have important implications for the development of immunoprophylaxis
      aimed at microfilariae and the alleviation of pathology in onchocerciasis.

PMID- 10583602
TI  - Interaction of CTLA-4 (CD152) with CD80 or CD86 inhibits human T-cell activation.
AB  - Occupancy of CTLA-4 (cytotoxic T-lymphocyte antigen-4 or CD152) negatively
      regulates the activation of mouse T lymphocytes, as indicated by the fate of CTLA
      4-deficient mice, by the impact of anti-CTLA-4 monoclonal antibodies (mAbs) on
      mouse T-cell activation in vitro and by the impact of CTLA-4 blockade on the
      course of experimental tumoral, autoimmune, alloimmune or infectious disease in
      this animal. The function of human CTLA-4, however, remains less clear. The
      expression and function of human CTLA-4 were further explored. CTLA-4 was
      expressed under mitogenic conditions only, its expression being, at least
      partially, dependent on the secretion of interleukin-2. Memory T cells expressed
      CTLA-4 with faster kinetics than naive T cells. The functional role of human CTLA
      4 was assessed utilizing a panel of four anti-CTLA-4 mAbs that blocked the
      interaction between CTLA-4 and its ligands. These mAbs, in immobilized form,
      profoundly inhibited the activation of T cells by immobilized anti-CD3 mAb in the
      absence of anti-CD28 mAb, but co-stimulated T-cell activation in the presence of
      anti-CD28 mAb. Finally, and importantly, blockade of the interaction of CTLA-4
      with its ligands using soluble anti-CTLA-4 mAbs, in intact form or as Fab
      fragments, enhanced T-cell activation in several polyclonal or alloantigen
      specific CD80- or CD80/CD86-dependent assays, as measured by cytokine production,
      cellular proliferation or cytotoxic responses. It is concluded that interaction
      of CTLA-4 with its functional ligands, CD80 or CD86, can down-regulate human T
      cell responses, probably by intracellular signalling events and independent of
      CD28 occupancy.

PMID- 10583603
TI  - L-selectin expression on thymic emigrants defines two distinct tissue-migration
      pathways.
AB  - We have studied the appearance and phenotype of recent thymic emigrants in blood,
      spleen and lymph nodes (LN) of neonatal lambs. Using in situ labelling of
      thymocytes with fluoroscein isothiocyanate (FITC), we examined the expression of
      the LN homing receptor L-selectin on alphabeta and gammadelta subsets of recent
      thymic emigrants 24 hr after labelling. There were marked differences in the
      proportions of CD4+, CD8+ and gammadelta T-cell receptor (TCR+) cells exported
      from the thymus to spleen compared to lymph nodes. Spleen was enriched in CD8+
      and gammadelta TCR+ emigrants while LN were enriched in CD4+ emigrants. There
      were also marked differences in the expression of L-selectin by emigrants homing
      to spleen compared with those homing to lymph nodes. While the majority of thymic
      emigrants in LN expressed L-selectin, considerably fewer emigrants in spleen were
      L-selectin+. The presence of large numbers of CD8+ L-selectin- and gammadelta
      TCR+ L-selectin- thymic emigrants homing to spleen raises the possibility that
      unique homing receptor specificities underpin the migration of T cells to spleen
      as distinct from lymph nodes.

PMID- 10583604
TI  - CD44 is involved in selective leucocyte extravasation during inflammatory central
      nervous system disease.
AB  - Clinical signs of experimental autoimmune encephalomyelitis (EAE) are associated
      with the selective recruitment of CD4+ memory (CD45RBlow CD44high) T cells into
      the central nervous system (CNS). However, we have found that many of these
      recently recruited memory cells are CD44low, suggesting that the CD44 antigen may
      be involved in, and transiently lost during, the extravasation process. Indeed,
      administration of a CD44-specific antibody (IM7.8.1) induced leucocyte CD44
      shedding and both prevented the development and ameliorated the severity of
      established EAE by inhibiting mononuclear cell infiltration into the CNS.
      Trafficking of cells into lymph nodes, however, a property mainly of naive cells,
      was essentially unaffected. In contrast, treatment with antibody to very late
      activation antigen-4 (VLA-4) prevented homing to both the CNS and to lymph nodes.
      This study contests previous reports that dismissed a role for CD44 in
      inflammation of the CNS and, coupled with observations in murine dermatitis and
      arthritis, suggests that CD44 is involved in the homing of primed lymphocytes to
      sites of inflammation. CD44 should therefore be considered a target for
      immunotherapy of T-cell-mediated inflammatory diseases, such as multiple
      sclerosis.

PMID- 10583605
TI  - Immunomodulatory effect of a plasmid expressing CD40 ligand on DNA vaccination
      against human immunodeficiency virus type-1.
AB  - CD40 ligand is a costimulatory molecule which acts a potent immunomodulator. We
      found the mice inoculated with human CD40 ligand expression plasmid (pMEhCD40L)
      combined with human immunodeficiency virus type-1 (HIV-1) DNA vaccine exhibited
      both humoral and cellular antigen-specific immunological enhancement. The
      expression of hCD40L induced predominantly antigen-specific immunoglobulin G
      (IgG) antibody response while it failed to induce mucosal IgA response. Delayed
      type hypersensitivity (DTH) and cytotoxic T lymphocyte (CTL) activity were
      induced in a dose-dependent manner. Examination of the relative levels of the two
      IgG subclasses showed that co-injection of pMEhCD40L enhanced IgG2a response
      without suppressing IgG1 response. Similarly, the expression of pMEhCD40L
      enhanced not only T helper 1 (Th1)- but also Th2-type cytokine production. In
      conclusion, co-inoculation of pMEhCD40L with DNA vaccine was shown to be a useful
      way to enhance CTL responses without suppressing the humoral immune response in
      acquired immune deficiency syndrome (AIDS) patients.

PMID- 10583607
TI  - Acidic pH increases the avidity of FcgammaR for immune complexes.
AB  - The interaction of immunoglobulin G (IgG) antibodies with FcgammaR constitutes a
      critical mechanism through which IgG antibody effector functions are mediated. In
      the current work we have examined whether human neutrophil FcgammaR exhibit pH
      dependence in their association with IgG. Binding assays were performed in
      culture medium adjusted to different pH values. It was found that the binding of
      either heat-aggregated human IgG (AIgG), soluble immune complexes (sIC) or IgG
      coated erythrocytes (IgG-E) was markedly higher at pH 6.5 than at pH 7.3. This
      effect was not observed when saturation of FcgammaR was achieved, suggesting that
      acidic pH increases the avidity of FcgammaR for IC without modifying the total
      binding capacity. Similar results were observed for the binding of AIgG to either
      monocytes, natural killer (NK) or K562 cells, suggesting that acidic pH increases
      the avidity of both, FcgammaRII and FcgammaRIII. Additional experiments were
      performed to analyse whether the binding of IgG to FcgammaRI also showed pH
      dependence. To this aim, we employed interferon-gamma-treated human neutrophils
      and mouse inflammatory macrophages, previously incubated with blocking antibodies
      directed to FcgammaRII and FcgammaRIII. Acidic pH did not enhance the binding of
      AIgG nor monomeric IgG under these experimental conditions. Further studies are
      required to determine whether the enhancement of FcgammaR avidity for IC could be
      attributed to titration of histidine(s) residues on the Fc fragment of IgG.

PMID- 10583606
TI  - Large clonal expansions of human virus-specific memory cytotoxic T lymphocytes
      within the CD57+ CD28- CD8+ T-cell population.
AB  - The proportion of human peripheral blood CD8+ T cells that are CD57+ CD28- is low
      at birth but increases with age and in individuals infected with human
      cytomegalovirus (HCMV) or human immunodeficiency virus (HIV). These CD57+ CD28-
      CD8+ T cells contain large oligoclonal T-cell expansions whose antigen
      specificity is unknown. We identified clonal expansions of virus-specific memory
      cytotoxic T-lymphocyte precursors (CTLp) in both healthy carriers of HCMV and in
      asymptomatic HIV-infected subjects. In each subject, from the T-cell receptor
      (TCR) beta-chain hypervariable sequence of each immunodominant CTL clone, we
      designed complementary oligonucleotide probes to quantify the size and phenotypic
      segregation of individual virus-specific CTL clones in highly purified
      populations of peripheral blood CD8+ T cells. We found large clonal expansions of
      virus-specific CTL clonotypes in CD57+ CD28- CD8+ T cells. Using limiting
      dilution analysis, we found functional peptide-specific CTLp at high frequency in
      CD57+ CD28- cells. Thus, memory CTL specific for persistent viruses account for
      many oligoclonal expansions within CD57+ CD28- CD8+ T cells.

PMID- 10583608
TI  - Histidine-rich glycoprotein prevents the formation of insoluble immune complexes
      by rheumatoid factor.
AB  - In previous studies we have shown that histidine-rich glycoprotein (HRG), a
      relatively abundant plasma protein, can bind to immunoglobulin G (IgG) and
      inhibit the insolubilization of IgG-containing immune complexes (IC). It was of
      interest, therefore, to determine whether HRG can inhibit the formation of
      insoluble IC (IIC) resulting from the interaction of rheumatoid factor (RF) with
      human IgG-containing IC. Light scattering techniques were used to examine the
      effect of HRG on the formation of IIC between RF and IC containing human IgG
      according to three different models. In all three models physiological
      concentrations of HRG could block the formation of IIC induced by RF. Optical
      biosensor studies of the RF-IgG interaction also revealed that HRG can mask the
      epitopes on IgG recognized by RF. Additional studies examined whether HRG can
      solubilize already formed IIC and demonstrated that HRG can, in fact, partially
      solubilized IIC. These data indicate that HRG can regulate the formation of IIC
      induced by RF at three levels: namely by inhibiting the initial recognition of
      IgG containing IC by RF, by inhibiting the subsequent insolubilization of IgG
      containing IC by RF and by solubilizing already formed IIC. Collectively, these
      findings suggest that HRG may be an important inhibitor of the formation of
      pathogenic IC in diseases such as systemic lupus erythematosus and rheumatoid
      arthritis.

PMID- 10583609
TI  - Rat complement factor I: molecular cloning, sequencing and expression in tissues
      and isolated cells.
AB  - Factor I (FI) is a regulatory serine protease of the complement system which
      cleaves three peptide bonds in the alpha-chain of C3b and two bonds in the alpha
      chain of C4b thereby inactivating these proteins. The human protein and the
      recently characterized mouse factor I are heterodimers of about 88,000 MW which
      consist of a non-catalytic heavy chain of 50,000 MW which is linked to a
      catalytic light chain of 38,000 MW by a disulphide bond. For the screening of a
      rat liver cDNA library we used a hybridization probe produced by polymerase chain
      reaction (PCR) using degenerated primers which corresponded to conserved parts of
      the human and the murine factor I nucleotide sequences. One of the identified
      sequences, which had a length of 2243 base pairs (bp), contained the complete
      coding region and the whole 3' untranslated region. The length of the coding
      region in rat consisted of 1812 bp followed by a 3' untranslated region of 207 bp
      including the polyadenylation signal and the beginning of the poly A tail.
      Comparison of the rat cDNA-derived coding sequence revealed identities of 87% to
      the mouse and of 78% to the human FI nucleotide sequence. The translation product
      of rat FI mRNA was 604 amino acid residues (aa) in length with an identity of 85%
      to the mouse (603 aa) and 69% to the human protein (583 aa). The comparison of
      the molecular mass predicted by the primary structure and derived from rat FI
      isolated from rat serum as detected in immunoblot analyses suggested a
      glycosylation of more than 20% of the total mass of the FI protein. Expression
      studies using reverse transcription (RT)-PCR assays indicated that FI-specific
      mRNA could neither be identified in B cells, nor in T cells, monocytes or
      granulocytes from rat and human peripheral blood nor in rat peritoneal
      macrophages. These data were in agreement with the results of RT-PCR obtained
      with several human lymphoma cell lines (Jurkat, MOLT-4, HUT102, Wil 2-NS, Ramos,
      Raji, U937) all of which were devoid of FI-specific mRNA. In accord with our data
      from two rat hepatoma cell lines (FAO and H4IIE) and one from man (HepG2) only
      isolated rat hepatocytes (HC) but neither Kupffer cells (KC), hepatic stellate
      cells (HSC; Ito cells) nor sinusoidal endothelial cells (SEC) expressed FI
      specific mRNA. FI mRNA was also detected in human umbilical vein endothelial
      cells (HUVEC) and in the uterus and small intestine of the rat. Spleen and lymph
      nodes did not contain any detectable FI-specific mRNA.

PMID- 10583610
TI  - The effect on immunoglobulin glycosylation of altering in vivo production of
      immunoglobulin G.
AB  - The effect on murine immunoglobulin G (IgG) glycosylation of altering IgG
      production in vivo was assessed in interleukin (IL)-6 transgenic and CD4 knockout
      mice. C57BL/6 mice carrying the IL-6 transgene showed increased levels of
      circulating IgG. This was associated with decreased levels of galactose on the
      IgG oligosaccharides. No decrease in beta4-galactosyltransferase mRNA or in
      enzyme activity was seen in IL-6 transgenic mice. MRL-lpr/lpr mice normally have
      elevated levels of circulating IgG, again accompanied by decreased levels of IgG
      galactose. Disruption of the CD4 gene in MRL-lpr/lpr mice led to a substantial
      decrease in the concentration of circulating IgG, but IgG galactose levels
      remained low. Thus, an enforced decrease in IgG levels in the lymphoproliferative
      MRL-lpr/lpr mice did not alter the percentage of agalactosyl IgG in these mice,
      suggesting that agalactosyl IgG production is not simply caused by excessive IgG
      synthesis leading to an insufficient transit time in the trans-Golgi, but rather
      to a molecular defect in the interaction between galactosyltransferase and the
      immunoglobulin heavy chain.

PMID- 10583611
TI  - Wood's light in dermatology.

PMID- 10583612
TI  - Current therapies for wound healing: electrical stimulation, biological
      therapeutics, and the potential for gene therapy.

PMID- 10583613
TI  - Linear IgA bullous dermatosis.

PMID- 10583614
TI  - Routine office procedures.

PMID- 10583615
TI  - Tzanck smear, an old test for the new millennium: when and how.

PMID- 10583616
TI  - The diagnostic role of the in vitro drug-induced interferon-gamma release test in
      Stevens-Johnson syndrome.
AB  - BACKGROUND: Drug-related T-cell activity in cutaneous drug reactions may be
      assessed by in vitro cytokine release tests. The diagnostic role of in vitro drug
      induced interferon-gamma (IFN-gamma) release was evaluated in a patient with
      Stevens-Johnson syndrome. CASE REPORT: Stevens-Johnson syndrome was diagnosed in
      a 58-year-old man, treated with colchicine (1 mg daily for 39 days) and
      allopurinol (300 mg daily for 13 days). Based on a clinical-epidemiologic score,
      allopurinol was more likely to be the causative agent. In vitro drug-induced IFN
      gamma release test was conducted on this patient and on two controls, using an
      enzyme-linked immunoabsorbent assay (ELISA) technique. Increased IFN-gamma
      release was observed following an in vitro challenge of the patient's lymphocytes
      with allopurinol, but not following in vitro challenge with colchicine. An in
      vitro challenge with allopurinol in two control patients, treated with
      allopurinol without adverse drug reactions, did not induce a significant increase
      in IFN-gamma release. CONCLUSIONS: The role of allopurinol as the drug
      responsible for the induction of Stevens-Johnson syndrome in our patient was
      confirmed by in vitro allopurinol-induced IFN-gamma release, which may indicate a
      drug-specific immune response.

PMID- 10583617
TI  - Cutaneous sarcoidosis in black South Africans.
AB  - BACKGROUND: It has been observed that, in the USA, sarcoidosis is more common in
      African-Americans than in other races. It has also been noted that sarcoidosis in
      African-Americans is characterized by more severe extrapulmonary involvement and
      more exuberant skin lesions. There is little information on sarcoidosis in black
      Africans. METHODS: Fifty-four black South African patients with cutaneous lesions
      of sarcoidosis proven by biopsy were prospectively studied. Dermatologic and
      ophthalmologic examinations and chest X-rays were performed in all patients.
      Other investigations relevant in the diagnosis of extracutaneous sarcoidosis were
      also performed in a variable number of patients. RESULTS: In 40 patients (71%),
      systemic sarcoidosis was found with lung, eye, and acral bone involvement being
      most common. Great variations in the morphology of skin lesions were observed. In
      one-quarter of patients, atypical cutaneous lesions (hypopigmented,
      ichthyosiform, lymphedematous, mutilating, ulcerative, verrucous) were found.
      Lupus pernio, once thought to be confined to Northern Europe, was observed in
      five patients in the subtropical milieu of South African Transvaal. Sarcoidal
      dactylitis with nail changes was seen in eight patients. Fibrinoid necrosis was
      found in 12% of the biopsies. CONCLUSIONS: Sarcoidosis in black South Africans is
      characterized by extensive cutaneous involvement. The lesions are morphologically
      extremely variable, frequently atypical, and often demonstrate fibrinoid necrosis
      on histology.

PMID- 10583618
TI  - Chromoblastomycosis in India.
AB  - BACKGROUND: Four patients with chromoblastomycosis are presented. An additional
      30 infected Indian patients are reviewed. RESULTS: These 34 patients ranged in
      age from 12 to 80 years with a male to female ratio of 5.8 : 1. Onset before the
      age of 20 years was seen in 24% of cases which was comparatively high. Culture
      was positive in 72% of cases and sclerotic bodies were observed in 84% of cases.
      A relatively higher prevalence (15%) of Fonsecaea compacta was observed. Unusual
      cutaneous sites afflicted were the penile shaft, vulva, and ala of the nose, and
      unusual extracutaneous spread was seen in the pleural cavity, ileocecal region,
      laryngotracheal area, and tonsils. Extracutaneous involvement was seen in 24% of
      cases. Overlapping infection with another fungus, Geotrichum candidum, was seen
      in one case. CONCLUSIONS: Combination therapy with two azoles was attempted with
      some success for clinical cure.

PMID- 10583619
TI  - Basal cell carcinoma of the lower extremities.
AB  - BACKGROUND: The most common malignancy in the USA is basal cell carcinoma. It is
      most prevalent on the head and neck, but can occur elsewhere. We sought to
      determine the frequency of basal cell carcinomas arising on the lower
      extremities, as well as the gender of affected patients, the histologic subtype,
      and the specific sites of involvement. METHODS: We reviewed cases submitted to
      the Vanderbilt Dermatopathology Service between 1994 and 1997 which were
      diagnosed as basal cell carcinoma. A subset of 150 cases which arose on the lower
      extremities and a control group of 150 cases which arose at other anatomic sites
      were studied further. RESULTS: A significantly greater number of basal cell
      carcinomas of the lower extremities arose in women, were of the superficial
      subtype, and were found below the knee; 59% of basal cell carcinomas in both
      sexes arose on the right limb. CONCLUSION: Basal cell carcinomas of the lower
      extremities occur more often in women in the USA and are of the superficial
      subtype. This may be due to differing patterns of dress and exposure to the sun.

PMID- 10583620
TI  - Partial agenesis of corpus callosum in LEOPARD syndrome.

PMID- 10583621
TI  - Fibrofolliculomas with acne scar-like appearance.

PMID- 10583622
TI  - Hypercalcemia and parathyroid hormone related protein expression in cutaneous T
      cell lymphoma.

PMID- 10583623
TI  - Tinea versicolor treated with terbinafine 1% solution.

PMID- 10583624
TI  - Management of vitiligo. Results of a questionnaire among dermatologists in The
      Netherlands.
AB  - BACKGROUND: Several therapeutic options are available for the treatment of
      vitiligo. Concern exists that there is no uniform approach towards the management
      of vitiligo among Dutch dermatologists. METHODS: A written survey concerning the
      management of vitiligo was sent to 332 dermatologists in The Netherlands.
      RESULTS: The response rate was 86%. "Giving information and reassurance
      concerning the nature of disease" was regarded by most dermatologists (68%) as
      being the most important goal in the management of vitiligo. Only 16% of the
      dermatologists aimed for active treatment in vitiligo. The reported therapy
      choices in children resembled those of adults, except that slightly more
      dermatologists did not prescribe active therapy in children. Nine different
      therapeutic modalities were mentioned as first choice therapies. Topical
      corticosteroids were indicated by most dermatologists as first choice therapy
      (241 out of 266, i.e. 91%); however, only 2% indicated that 50% or more of the
      patients achieved a successful treatment; 66% found that less than 25% of the
      patients were successfully treated with topical corticosteroids. Only 15% of the
      respondents reported that 50% or more of the patients were treated successfully
      with narrow-band UVB. The observed response profile to broad-band UVB therapy was
      found to be comparable with that of narrow-band UVB. The classical therapy with
      oral psoralen plus UVA (PUVA) was prescribed as first choice therapy by only 12%
      (32 out of 266) of the dermatologists. Only 6% of these respondents observed that
      50% or more of the patients achieved successful therapy using oral PUVA. The
      recommended maximum treatment duration for topical corticosteroids, oral PUVA,
      and UVB therapy was found to vary from 3 to 12 months. CONCLUSIONS: Most
      dermatologists in The Netherlands do not offer active treatment in vitiligo,
      probably because the estimated effectiveness of (nonsurgical) repigmentation
      therapy is low. In cases where treatment is prescribed, there appears to be no
      consensus on the choice of therapies and treatment strategies. The development of
      practice guidelines may be helpful in reducing inappropriate care and improving
      treatment outcome.

PMID- 10583625
TI  - Creeping eruption due to Gnathostoma hispidum--one way to find the causative
      parasite with artificial digestion method.

PMID- 10583627
TI  - Cardiovascular pathology in the year 2000: a series of reviews in honour of
      professor neville woolf

PMID- 10583626
TI  - Subcutaneous pheohyphomycosis caused by Phoma species.

PMID- 10583628
TI  - Cardiotrophin-1 (CT-1): a novel hypertrophic and cardioprotective agent.
AB  - Cardiotrophin-1 (CT-1) is a member of the IL-6 family of cytokines which was
      originally discovered as a factor which can induce hypertrophy of cardiac
      myocytes both in vitro and in vivo. Subsequently, CT-1 has been shown to have a
      wide variety of different effects on cardiac and non cardiac cells including the
      ability to stimulate the survival of both cardiac and neuronal cells.
      Interestingly, whilst activation of the p42/p44 MAP kinase pathway is necessary
      for the survival promoting effects of CT-1 in cardiac cells, it is not required
      for its hypertrophic effect which is likely to involve activation of the Jak/STAT
      3 pathway. CT-1 may therefore be of use as a novel cardio-protective agent,
      particularly if its hypertrophic effect can be specifically inhibited.

PMID- 10583629
TI  - Vascular smooth muscle cell apoptosis in atherosclerosis.

PMID- 10583630
TI  - Acinar cell apoptosis and the origin of tubular complexes in caerulein-induced
      pancreatitis.
AB  - The interrelationship between acinar cell apoptosis and tubular complex formation
      was examined in caerulein-induced pancreatitis using histology,
      immunohistochemistry, electron microscopy and DNA gel electrophoresis. Rats were
      given 8 hourly subcutaneous injections of caerulein, 24 micrograms/kg, for up to
      2 days. Morphologically and biochemically typical apoptosis affected 4.6 and 8.9%
      of acinar cells at 1 and 2 days, respectively, resulting in removal of most
      acinar cells by 2 days. Consequently, pancreatic ducts, the lining cells
      expressing bcl-2 and therefore resistant to apoptosis, became much more closely
      approximated to form the basis of tubular complexes; small numbers of
      immunohistochemically discrete acinar cells in their lining were either pre
      apoptotic resistant to it or newly formed. Proliferation of duct-like lining
      cells was associated with apoptosis, an increase in islet cells and acinar cell
      regeneration. There was evidence of duct to acinar cell differentiation but the
      main increase in acinar cell numbers appeared to derive from proliferation of
      newly formed acinar cells.

PMID- 10583631
TI  - Massive acinar cell apoptosis with secondary necrosis, origin of ducts in
      atrophic lobules and failure to regenerate in cyanohydroxybutene pancreatopathy
      in rats.
AB  - Cyanohydroxybutene (CHB), a glycosinolate breakdown product, causes pancreatic
      injury when given to animals in large amounts. To determine the course of CHB
      induced pancreatopathy, rats were given a single subcutaneous dose of CHB and the
      pancreas weighed and examined by light and electron microscopy and
      immunohistochemistry at intervals from 2 h to 28 days. The pancreatic lesion was
      unusual in that there was marked early oedema with limited inflammatory cell
      infiltration, rapid synchronous onset of acinar cell apoptosis and early advanced
      atrophy engendering only a limited regenerative response. Acinar cell apoptosis
      was atypical in that cell fragmentation was limited and phagocytosis delayed,
      resulting in extensive secondary necrosis. As ducts were unaffected by CHB, the
      crowded ducts making up the epithelial component of atrophic lobules could be
      clearly shown to derive from their condensation and proliferation, not the
      redifferentiation of pre-existing acinar cells, widely held to produce this
      lesion. Although the basis of CHB selectivity and toxicity for pancreatic acinar
      cells remains unknown, the potential therapeutic benefit of such an agent in
      patients with pancreatitis or pancreatic tumours warrants further investigation.

PMID- 10583632
TI  - Effects of vitamin E on human platelet and mononuclear cell responses in vitro.
AB  - Recent epidemiological studies have provided evidence supporting the potential
      benefits of antioxidants in coronary prevention. We have investigated the effects
      of vitamin E on platelets, monocytes and endothelial cells in vitro. Pre
      incubation of platelets with vitamin E inhibited subsequent thrombin- (P < 0.05,
      n = 5), collagen- (P < 0. 0001, n = 5) and ADP-(P < 0.05, n = 4) induced platelet
      aggregation measured using a microtitre plate method, or conventional
      aggregometry. The adhesion of thrombin-activated platelets to collagen was also
      inhibited by vitamin E (P < 0.05, n = 8), but not by vitamin C (P > 0.05, n = 8);
      nor was the adhesion of unstimulated platelets significantly affected (P > 0.05,
      n = 8). Pre-incubation of monocytes with vitamin E inhibited their subsequent
      adhesion to plastic (P < 0.05, n = 9), and was also associated with an 18%
      reduction in adhesion to EA.hy 926 endothelial cells (n = 8), although this
      failed to reach statistical significance. Pre-incubation of the endothelial cells
      with vitamin E also significantly reduced subsequent mononuclear cell adhesion by
      56% (P < 0.05, n = 3).

PMID- 10583633
TI  - Farewell from the founding editor.

PMID- 10583634
TI  - Depot neuroleptics, schizophrenia and the role of the nurse: is practice evidence
      based? A review of the literature.
AB  - Nurses are expected to justify their practice with research based evidence.
      Community psychiatric nurses (CPNs) are under pressure to concentrate more on the
      'seriously mentally ill', particularly those with a diagnosis of schizophrenia.
      Neuroleptic medicines are a recommended therapy in schizophrenia. The
      administration and monitoring of these drugs is a central part of the CPN's role.
      The CPN also often assumes an important position as patient advocate in relation
      to prescribing practices. Neuroleptics are commonly given in depot form to
      promote compliance, prevent relapse and be of benefit to the patient. This
      literature review considers the research evidence that these aims are achieved
      through current practice and reflects on the implications for nursing. In the
      absence of definitive research work, it may be that important decisions are based
      on received wisdom rather than research evidence. Whilst the data supporting the
      use of depots are inconclusive, there is an increasing body of knowledge
      demonstrating the efficacy of nursing approaches to drug therapy which seek to
      empower the patient.

PMID- 10583635
TI  - Inequalities in service provision: an examination of institutional influences on
      the provision of district nursing care to minority ethnic communities.
AB  - This paper reports on the selected findings from a larger ethnographic study of
      the provision of district nursing care to patients from different ethnic
      backgrounds. The two-stage study was undertaken in an English community National
      Health Service (NHS) trust serving an ethnically diverse population. The first
      stage comprised an organizational profile in order to analyse the local policy
      context, including specific responses to ethnic diversity. Data were collected by
      means of in-depth interviews with managers. The second stage entailed a
      participant observational study focusing on six district nursing teams. Purposive
      sampling was used to identify four teams with high minority ethnic caseloads and
      two teams with predominately white ethnic majority caseloads. Interview
      transcripts and field-notes were analysed by drawing upon the principles of
      dimensional analysis. The paper focuses upon institutional influences on the
      provision of care to minority ethnic communities. An analysis of the allocation
      of district nursing resource to different general practitioner (GP) practices
      identified marked inequalities in the district nursing provision which impacted
      upon the services provided to minority ethnic patients. Single-handed, inner city
      GP practices with a large minority ethnic practice population received a much
      smaller allocation of nursing staff than single group practices serving a smaller
      and predominately white practice population. The reasons why this situation
      existed are explored and an explanation offered as to why it had not been
      rectified. Observation of caseload management indicated that despite differences
      in the size of the practice populations served by the respective teams, all
      patients referred for nursing care received it. However, several covert processes
      appeared to limit the caseload size of those teams with large practice
      populations so that it remained manageable within the limited nursing resource
      available. It is concluded that although nurses at an individual level did not
      appear overtly to disadvantage minority ethnic patients, institutional forces
      conspired to perpetuate the disadvantage experienced by minority ethnic
      communities.

PMID- 10583636
TI  - The power of women as nurses in South Africa.
AB  - An epistemological analysis of the power of women as nurses in one of the larger
      and more deprived regions of South Africa, KwaZulu-Natal, was carried out. The
      premises of the standpoint theory were used as a justificatory strategy for
      participant selection. A fourth premise of rurality was added to the existing
      three premises of race, class and gender. A phenomenological research approach
      incorporating two to three in-depth interviews with each participant following a
      flexible guideline was utilized. Key concepts and realities such as
      powerlessness, powerfulness and empowerment were explored and a total of 44 audio
      taped interviews was transcribed. Data analysis was aided by a software programme
      for qualitative data analysis (NUD. IST) and focused on the exploration and
      development of themes, categories, relationships and condensed forms of outcomes.
      Detailed attention was given to ethical considerations such as anonymity, freedom
      of expression and rapport. The credibility of the study was enhanced through
      prolonged engagement, thick descriptions and the input of three experienced
      researchers. In reflecting on powerlessness, women as nurses belonging to the
      enrolled category were alienated as they were severed from the nursing profession
      and from the ruling gender of men. They were lost in routine activities, were
      misused, maternalized and domesticated at home and at work. These phenomena were
      voiced more strongly by the rural group of women. Registered nurses created their
      own freedom, often away from their men as in divorce, and sought solutions
      concerning powerlessness in more distant terms. They communicated a sense of
      empowerment in terms of education and personal qualities. Culture rather than
      race was emphasized as an essence of women's oppression. Recommendations of the
      study focused on ways to limit categorial division, of aligning scope of
      practices with current health care practices in South Africa and further research
      regarding the value of the fourth premise of the standpoint theory is suggested.

PMID- 10583637
TI  - The role of nursing partnership interventions in improving the health of
      disadvantaged women.
AB  - This paper describes a project which assessed the contribution that nursing
      professionals are making to improving the health of deprived women living in
      Northern Ireland. The study is set within the context of the Targeting Health and
      Social Need (THSN) Initiative an important theme within the Northern Ireland
      Regional Strategy entitled Health and Well-being into the Next Millennium - A
      Regional Strategy for Health and Social Well-being 1997-2002 which is concerned
      with addressing inequalities in health status and social well-being. The paper
      describes the results of a survey (n=1,000, response rate 39%) and the criteria
      used to select 22 interventions to provide evidence of 'effective practice'
      within THSN. The study highlights the work of previous reviews in the area and
      provides evidence concerning effective interventions in practice. Although the
      interventions described may be lacking in 'pure scientific' method and may not
      meet the rigorous inclusion criteria of systematic review methodologies, there is
      evidence to suggest that nurses are using well-designed more qualitative
      evaluation methods and demonstrating improvements in health and social need for
      women in the lowest socio-economic groups. In terms of equity the case studies
      show that community nursing may be a powerful vehicle for researching people
      previously neglected by the formal health care system. Health policies such as
      THSN can now articulate the methods needed for reform or change, setting
      directions and articulating the barriers to implementation and achievement.

PMID- 10583638
TI  - User involvement in identifying health needs and shaping and evaluating services:
      is it being realised?
AB  - The rhetoric of user involvement has featured in health policy documents for over
      a decade. However, there is mixed evidence as to the extent to which it is being
      achieved. This paper explores what is meant by user involvement, proposing that
      it exists at a series of levels ranging from information giving to true
      empowerment. Examples are presented from two practice development projects. The
      first sought to develop multidisciplinary audit in primary care, attempting to
      involve users in defining health needs and determining services. Although the
      project co-ordinators were highly committed to user involvement this was only
      achieved to a limited extent. It was concluded that there was a resistance to
      user involvement grounded in the fear that such involvement would increase user
      expectations and add to the pressures of overworked primary care teams. The
      second project used interviews with service users to assess the effectiveness of
      a team building initiative. Users were found to be knowledgeable about
      practitioner roles and how to access the care they required. The overall
      conclusion is that there needs to be a shift from rhetoric to reality at
      governmental and practitioner level if true user involvement is to be achieved.

PMID- 10583639
TI  - 'A heavy and blessed experience': a psychoanalytic study of community Macmillan
      nurses and their roles in serious illness and palliative care.
AB  - This paper explores the psychoanalytic ideas of containment as described by
      Wilfred Bion and applies them to the work of community Macmillan nurses and to
      the ways in which they might understand and structure therapeutic conversations
      with people that are seriously ill. Case vignettes show the application of
      psychoanalytic thinking in context. The discussion offers the idea that the
      impact of physical illness is such that the emotional issues of patients, their
      families and fellow palliative care workers can saturate nurses. To protect
      themselves, nurses and other health workers might assimilate the emotional
      traumas of others into physical symptoms, and so they are ignored or overlooked
      in favour of drug therapies, pre-occupations with breaking through silences and
      other concrete or demonstrable methods of treatment. An environment is needed in
      which a person with serious illness and his or her family member is helped to
      make sense of their experiences and so integrate them into a meaningful life
      continuum. Similar provisions are needed for nurses. Appropriate methods of
      clinical supervision might help these important provisions.

PMID- 10583640
TI  - Grief and social support after the death of a spouse.
AB  - The death of a spouse is one of the most stressful events in a person's life.
      Social support has been shown to be widely beneficial in moderating the effects
      of both chronic and acute stress. The answers of Finnish widows and widowers
      (n=318) were analysed in order to investigate the sources of social support, what
      is the nature of support received, and whether social support is connected with
      coping with grief. The Hogan Grief Reactions Checklist was used to describe the
      grief as well as answers to open-ended questions about what helped the widowed
      persons cope with their grief. Kahn's theory of social support was used as a
      framework in the content analysis of the open-ended answers. The results showed
      that Finnish widows and widowers receive social support most often from their own
      family and friends. They perceived the received support most helpful, but also
      the support that the grieving person can give to other family members is seen as
      important. Results suggest that those who had had social support were able to
      grieve by allowing themselves to disorganize and experience panic behaviour.

PMID- 10583641
TI  - The biopsychosocial impact of end-stage renal disease: the experience of dialysis
      patients and their partners.
AB  - This phenomenological study was conducted to investigate the biopsychosocial
      impact of end-stage renal disease on dialysis patients and their partners. Forty
      four participants were interviewed separately (22 patients and their partners) by
      way of two open-ended questions, and multiple themes were identified from
      verbatim transcripts. Both the patients and partners viewed their relationship
      very positively, and both were overwhelmed by the impact of dialysis on their
      lives. Anger, depression and hopelessness were evident in the patients, whilst a
      pervasive sadness, resentment, guilt and loss were prevalent in the partners.
      This study gives a unique perspective on the negative impact which dialysis can
      have on couples, yet it also suggests that some are able to cope in a positive
      way despite the many life-style adjustments required by dialysis. The results of
      this study indicate that nurses need to recognize and respond to the tremendous
      emotional impact that chronic illness and its treatment can have on families in
      an era where it is possible to sustain life for years with the use of life
      support technology.

PMID- 10583642
TI  - An embedded decisional model of stress and coping: implications for exploring
      treatment decision making by women with breast cancer.
AB  - Treatment decision making by women with breast cancer has been recognized to be
      an inherently stressful process. However, past decisional theory and research has
      failed to fully elucidate the personal, transactional, and relational nature of
      choice behaviour. The purpose of this paper is to explore an embedded decisional
      model of stress and coping that locates key assumptions of Janis & Mann's (1977)
      conflict-theory model of decision making within Lazarus & Folkman's (1984)
      transactional framework. Through combining decisional and stress and coping
      theories, a model is developed that addresses the theoretical limitations of the
      conflict-theory model and provides greater specificity within decision-making
      research. The paper examines the complexity of treatment decision making within
      the context of the constructs of causal antecedents, primary appraisal, secondary
      appraisal, coping, and adaptational outcomes. Examples specific to women with
      breast cancer are provided to illustrate the potential application of the
      embedded model. The implications of this inclusive and comprehensive decisional
      theory for future knowledge development and research in the area of treatment
      decision making are also discussed.

PMID- 10583643
TI  - Experience of social support in rehabilitation: a phenomenological study.
AB  - The progressive muscular weakness brought on by muscular dystrophy causes the
      sufferer many problems in everyday life. Earlier studies in Sweden have shown
      that adults with hereditary muscular dystrophy often have difficulty in gaining
      access to rehabilitation. For this reason a special rehabilitation programme was
      drawn up and carried out, extending over a period of 18 months. The purpose of
      the study is to describe the participants' experience of social support in
      connection with the programme. Thirty-seven participants (21 women and 16 men)
      were interviewed. The analytical method was phenomenological, incorporating
      validation by independent judges. Nine overall themes emerged from the
      interviews: psychosocial support, meeting other people with muscular dystrophy,
      knowledge and learning, adjustment in daily life, coping with illness-related
      problems, adjustment at work, management of physical disability, medical
      examination and treatment, and involvement of relatives. The results indicate
      that the participants encountered staff with a sense of commitment and felt
      themselves to be 'seen and confirmed'. From the discussions and the contact with
      others in the same situation there arises a sense of affinity and a better
      understanding of one's own situation. There was appreciation of the education
      about the disease, its hereditary aspect, technical aids, grants and physical
      training. Hardly any of the participants spoke of knowing such things before. In
      conclusion there was approval of the received support, and recognition that
      persons with muscular dystrophy should be given access to recurrent
      rehabilitation.

PMID- 10583644
TI  - Transitions in the lives of elderly women who have sustained hip fractures.
AB  - Hip fractures represent a major health problem within the older population,
      especially for elderly, white women. As the older woman transitions through the
      recovery process following hip fracture, her ability to meet basic needs, fulfil
      usual roles, and maintain well-being is threatened. Despite the rehabilitation
      provided to these women, studies suggest that hip fractures frequently result in
      permanent decline in functional status. Little is known about what characterizes
      those few elderly women who do recover to their previous level of functioning. In
      this context, a study was designed to identify factors which promote function and
      enable a successful transition following hip fracture. A total of 15 women
      ranging in age from 72 to 82, who had returned home alone following care in a
      Midwestern subacute unit, participated in three focus groups. The data were
      analysed using the grounded theory method. The findings revealed that the women
      were confronted with an array of problems, which were labelled function
      inhibiting factors. To overcome these problems, the women mobilized their
      adaptive approaches to life. In addition, they identified various
      interdisciplinary interventions, labelled function-promoting factors, which
      helped to provide a successful transition. From these findings, a programme of
      interdisciplinary interventions was identified which could be implemented in
      subacute units and tested to establish its effectiveness in promoting a
      successful transition following hip fracture.

PMID- 10583645
TI  - An evaluation of patients' quality of life before, 6 weeks and 6 months after
      total hip replacement surgery.
AB  - Annually, throughout the world, more than 800,000 primary total hip replacement
      surgery procedures are performed on patients suffering from hip joint arthrosis.
      Since 1991, approximately 11,000 of these procedures are performed annually in
      Sweden. This study aimed to investigate any changes in the patients' life quality
      6 weeks and 6 months after their total hip replacement surgery had been
      performed, compared to that immediately prior to the operation. It also aimed to
      examine the reason for surgery, the types of prostheses used, postoperative pain,
      complications and the actual usage of ambulation support. The Sickness Impact
      Profile self-appraisal instrument, together with personal patient interviews have
      been used as the basis of the research. A total of 51 patients responded to the
      quality of life instrument prior to their operation, 47 of these participated 6
      weeks after the operation, and 40 patients 6 months after the operation.
      Significant differences in patients' total, physical and psychosocial quality of
      life 6 months postoperatively compared to the situation prior to the operation
      were found, but not between the situation before and 6 weeks after the total hip
      replacement surgery. The majority of patients were of the opinion that it was
      more important that the pain had disappeared or decreased, than any overall
      increase in the quality of life. Postoperative complications occurred within 6
      weeks, and even after 6 months some patients still suffered from these.

PMID- 10583646
TI  - The first line of response for people who self-poison: exploring the options for
      gut decontamination.
AB  - The trend for increasing numbers of self-poisoning incidents has been noted and a
      variety of policy initiatives have been launched. Nurses, particularly in
      emergency room environments occupy a pivotal place in the chain of response to
      such acts. Any such response needs to be firmly rooted in evidence-based practice
      yet the initial management of self-poisoning often involves a consideration of
      procedures, the application of which can vary enormously. This paper offers some
      contextual information prior to a critical perspective of management modes,
      namely emesis, lavage, the use of activated charcoal and whole bowel irrigation.
      A comparison of the relative advantages and disadvantages of each mode precedes
      suggestions for nursing practice.

PMID- 10583647
TI  - A description of health care professionals' experiences of encounters with
      patients in clinical settings.
AB  - The aim of this study was to describe health care professionals' way of
      experiencing their encounters with in- or outpatients, while working in acute
      medical care hospitals. One main question was addressed: What are the experiences
      which health care professionals have of their encounters with in- or outpatients
      in clinical settings? Eleven health care professionals (physicians, registered
      nurses and enrolled nurses) were interviewed and a phenomenographic approach was
      used, where data were analysed qualitatively. The results indicate that the
      health care professionals' way of experiencing their encounters with patients in
      acute medical care hospitals could be separated into three categories of
      description: a gain in personal knowledge and understanding of the patients'
      different 'ways' of communicating experienced suffering; making the patient feel
      confident and; focusing on the medical problems, not understanding the patient's
      different 'ways' of communicating their experienced suffering. The first two
      categories of description showed encounters where the health care professionals
      felt that they could understand the patients' expressions of suffering. The third
      showed encounters where the health care professionals experienced difficulty in
      understanding the patients' expressions of suffering. There is a need therefore
      to support health care professionals in improving their understanding of
      patients' suffering.

PMID- 10583648
TI  - Practitioner-centred research: an evaluation of the implementation of the bedside
      hand-over.
AB  - A practitioner-based enquiry (PBE) or 'practitioner-centred-research' (Rolfe
      1998), was undertaken using action research to examine the concept of 'nursing
      hand-over'. The move away from the traditional style of hand-over (which involved
      either one or two people verbally relaying 'all' information to those nurses
      coming onto duty) to a hand-over that is based at the bedside with the patient
      and involves the patient and only those nurses accountable for that individual's
      care, was the focus of the study reported here. The study was carried out on a
      medical ward for people aged 65 and over and aimed to identify whether after 6
      months (post-implementation of the new style of hand-over) all staff felt that
      key issues identified in a 3-month evaluation based primarily on quantitive data
      collection, had been addressed by using an action research methodology. Although
      reference will be made to the 3-month evaluation as it formed a vital part of the
      process of assessing the change to practice, the focus of the analysis will be
      the evaluation that took place after 6 months. The key objective was to assess
      the effectiveness of the planned implementation of hand-over at the bedside and
      the subsequent change to current nursing practice.

PMID- 10583649
TI  - Nursing science: the transformation of practice.
AB  - World-wide transformations in nursing practice are evolving as more nurses are
      embracing extant nursing theories and frameworks in order to fortify their unique
      contributions to the healthcare system. This article specifies the importance of
      and the ethical considerations arising when using nursing knowledge from within
      the school of thought of the discipline to guide practice. The ideas set forth
      are in stark contrast to the general nursing process with its medical model
      driven diagnostic systems now proliferating in nursing practice in the global
      healthcare community. Both challenges and opportunities are present in the
      transformation of practice to a nursing knowledge base.

PMID- 10583650
TI  - Caring: theoretical perspectives of relevance to nursing.
AB  - Caring as a central concept within nursing has led to the development of several
      caring theories, the most well known being Madeleine Leininger's Theory of
      Culture Care and Jean Watson's Theory of Human Caring, both of which were
      formulated in the 1970s. This paper explores a total of four caring theories: the
      two established theories presented by Leininger and Watson, Simone Roach's theory
      developed in the 1980s, and a recent caring theory developed by Boykin &
      Schoenhofer. A comparison of these theories is presented drawing on a number of
      criteria, namely: origin of theory, scope of theory, definition of caring,
      description of nursing, key concepts of the theory, and goal/outcome.
      Additionally, simplicity as a central component of internal structure is examined
      in relation to each. Based on this analysis, similarities and differences are
      highlighted, concluding with a discussion of the utility of the caring theories
      within nursing practice.

PMID- 10583651
TI  - Respite care for frail older people and their family carers: concept analysis and
      user focus group findings of a pan-European nursing research project.
AB  - This paper provides a concept analysis of respite care for frail older people and
      their family carers. The authors re-examine the broader conceptualization of
      respite care delineated by Nolan & Grant, namely, users' needs for information,
      education and support about respite care, based on a review of recent literature
      and on a user focus group study. This work was undertaken by the Sheffield arm of
      the ACTION Project research team. ACTION is a 36-month project (1997-1999),
      involving Northern Ireland, The Republic of Ireland, Portugal, Sweden and England
      and is the largest nurse-led project to have received funding from the European
      Union TIDE sector (DGXIII Telematics Applications Programme, Disabled and
      Elderly). The authors discuss the key elements of respite and, more specifically,
      how they can be successfully used so that the potential of respite may be
      realized fully by family carers. Recommendations within the context of the ACTION
      research project are put forward to enable family carers and the persons they
      care for to make informed choices about respite care.

PMID- 10583652
TI  - Can a standardized needs assessment be used to improve the care of people with
      severe mental disorders? A pilot study of 'needs feedback'.
AB  - The care programme approach (CPA) was introduced in the United Kingdom in 1991 to
      ensure that the needs of people with mental health problems are met
      appropriately. Many community psychiatric nurses (CPNs) act as 'key workers'
      under the CPA. Recent evidence suggests that the CPA is not particularly
      effective at meeting the needs of this vulnerable group, but it might be possible
      to enhance the CPA by introducing a more 'needs-led' approach to the planning of
      nursing care. 'Needs feedback' is a technique for enhancing the CPA. Needs
      feedback begins with a standardized assessment of patients' psychiatric and
      social needs by a nurse specialist. The patient's CPN is then provided with
      information on: (a) the needs identified; (b) why these needs have been
      identified; (c) the interventions required to meet the identified needs; and (d)
      how these interventions may be obtained. In the pilot study reported in this
      paper, 20 patients with severe mental disorder were evaluated before and after
      their CPN received needs feedback. All patients were living in the community and
      being managed by CPNs under the CPA. Outcome was assessed 6 months after the
      feedback in terms of: mental state, social behaviour and number of 'unmet' needs.
      Needs feedback was found to be compatible with the CPA in that it proved
      acceptable to CPNs and patients. Significant improvements were seen in the number
      of 'unmet' needs and the level of anxious/depressive symptoms. Improvements
      approaching significance were seen for social functioning and negative
      psychiatric symptoms, but not for positive psychiatric symptoms. This pilot study
      suggests that needs feedback may improve the quality of nursing assessment and
      care planning within the CPA. Further controlled investigations of needs feedback
      are justified.

PMID- 10583653
TI  - The Childbirth Self-Efficacy Inventory: a replication study.
AB  - In 1993 Lowe developed the Childbirth Self-Efficacy Inventory (CBSEI). This is a
      self-administered, 62-item, Likert tool which measures women's confidence in
      their ability to cope with labour. The tool is valid and reliable for use in
      American culture but had not been tested in Northern Ireland, therefore a
      replication study was deemed necessary. The research study set out to replicate
      Lowe's study and to test the potential application of this tool in clinical
      midwifery practice. A convenience sample comprising a cohort of 126 women
      attending an urban maternity unit in Northern Ireland formed the study population
      and a response rate of 64% was achieved. The tool was administered antenatally,
      intranatally and postnatally. The predictive validity of the instrument was
      tested to determine actual coping behaviours in labour (Pearson's r=0.3963, P <
      0.00 for active labour; r=0.5149, P < 0.00 for second stage labour). This work
      confirms the CBSEI as a measurement of confidence in women's ability to cope in
      labour. The authors recommend the utility of the CBSEI in midwifery practice as a
      tool for the identification of women who will require extra support in labour and
      pregnancy.

PMID- 10583655
TI  - Evaluation of an innovative curriculum: nursing education in the next century.
AB  - The present research focused on an interim evaluation of a new nursing curriculum
      made by first- and second-year undergraduates. Study 1 examined the assessments
      made by 90 students of the new, actual programme of their studies, as well as an
      ideal one, on 21 bipolar criteria reflecting the developing changes in health
      care practices and higher educational processes in western society. The results
      of study 1 indicated that students perceived the actual programme as compatible
      with health care changes, but lacking in terms of the learning process. Study 2
      investigated the same assessments among 105 registered nurses who evaluated the
      traditional nursing programme under which they were trained as well as an ideal
      one. The results of study 2 showed that registered nurses perceived past
      curricula as lower than the ideal on both health care and process of learning.
      The results of this interim evaluation imply that the new nursing curriculum
      follows health care trends, but a shift in the educational process is required.

PMID- 10583654
TI  - A comparison of three strategies for risk-adjustment of outcomes for AIDS
      patients hospitalized for Pneumocystis carinii pneumonia.
AB  - BACKGROUND: The need for risk-adjustment of patient outcomes has been driven by
      the competitive health care market and the subsequent increase in comparative
      outcome reporting among health care institutions, among managed care plans, and
      among individual providers for some procedures (e.g. coronary artery bypass graft
      surgery). However, if the outcomes reported do not take into account patient
      characteristics that can be considered dimensions of risk for poor clinical
      outcomes or increased utilization of services, there is the possibility that
      inaccurate conclusions will be drawn about the quality of care provided.
      OBJECTIVE: The specific purpose of this study was to examine the ability of four
      measures, APACHE III - acute physiology scale, Quality Audit Marker - ambulation
      score, Quality Audit Marker - self-care ability score, and Nursing Severity
      Index, to predict mortality and hospital length of stay in a convenience sample
      of 140 males with Pneumocystis carinii pneumonia. METHODS: The study utilized a
      descriptive, longitudinal design. RESULTS: APACHE III - acute physiology scale (P
      = 0.006, odds ratio = 1.40), and Quality Audit Marker - ambulation (P = 0.037,
      odds ratio = 0.50), were significant predictors of hospital mortality and the
      APACHE III - acute physiology scale was also a predictor of mortality within 3 (P
      = 0.004, odds ratio = 1.13) and 6 months (P = 0.009, odds ratio = 1.10) following
      hospitalization. Only Quality Audit Marker - ambulation (P = 0.0001) was a
      significant predictor of length of stay. CONCLUSIONS: The findings of this study
      confirm the findings of other investigators that measures of acute clinical
      stability and functional status have utility as risk-adjustment approaches for
      the outcomes of mortality and length of stay. Further research is needed that
      compares the utility of generic vs. disease-specific measures for prediction of
      outcomes in HIV/AIDS.

PMID- 10583656
TI  - Planning for information technology key skills in nurse education.
AB  - New recruits to courses in nursing, midwifery and health visiting come from a
      wide range of educational backgrounds and it is reasonable to expect that this
      diversity will also be reflected in the range of their experience and competence
      with information technology (IT). Accommodating such variety can make the
      planning of appropriate training to enhance and develop their IT skills
      difficult. In order to explore the likely extent of diversity in IT experience
      and skills in today's recruits, the project reported here examined the
      competence, attitudes and previous IT training of two consecutive cohorts of new
      entrants to a higher diploma programme. The surveys add weight to the view that
      nurse educators do face a considerable diversity in new students' competence and
      experience with IT. Further analysis has also shown that subgroups of the
      cohorts, characterized by their age, gender, education or previous IT training,
      differed significantly in a 'knowledge of computers' score but not in their
      attitudes to IT. Arising from the results, the paper argues that, in seeking to
      develop a consistent level of IT literacy, core IT competence should be
      identified and all courses should have the clear objective of raising students'
      confidence in using computers.

PMID- 10583657
TI  - Students' perceptions of their psychiatric mental health clinical nursing
      experience: a personal construct theory exploration.
AB  - Personal construct theory and repertory grid technique provides a suitable
      framework for exploring Registered Nursing students' perceptions of their
      psychiatric practicum. This descriptive research was designed to understand
      students' own ways of constructing knowledge during their mental health clinical
      experience. A constructivist conceptual perspective and George Kelly's personal
      construct psychology were the theoretical bases of the research. A qualitative
      case study methodology allowed creation of and reflection on personal construct
      changes as provided in participants' review of repertory grid ideas about
      psychiatric nursing. The participants were six Canadian second-year nursing
      students in a Baccalaureate programme that integrated psychiatric and medical
      surgical nursing curricula. The following three overarching themes were
      identified and are used to explain and describe significant features of the
      psychiatric clinical experience: 1) students' anxiety related more to feeling
      unable to help than to interactions with mentally ill patients; 2) students'
      feelings of a lack of inclusion in staff nurse groups; 3) student emphasis on the
      importance of nonevaluated student-instructor discussion time.

PMID- 10583658
TI  - Experiential learning: issues for supervision.
AB  - This paper reports on an evaluation of work-based learning within a
      postregistration community health nursing degree programme. Work-based learning
      is primarily concerned with the process of learning and with encouraging the
      individual to be explicit about how and what they learn so that their
      experiential learning may be assessed and accredited. The methodology of
      Illuminative Evaluation was adopted, with case studies (n=6) used as the means of
      exploring in depth the different perspectives of the major stakeholders (that is,
      the students, their workplace supervisors and their academic supervisors). The
      data comprised documentation, participant and nonparticipant observation,
      interviews and focus groups. The initial aim was to examine the potential
      benefits of work-based learning to students and to describe its impact on their
      practice. However, what emerged through the course of inquiry was a gap between
      the educational philosophy of work-based learning and the way in which work-based
      learning was delivered within the department concerned. Work-based learning
      provides educators with an opportunity to debate openly fundamental issues about
      the nature of educational practice; in particular, about the role of the
      supervisor in facilitating students' learning. As the evaluation highlights, if
      this debate does not occur, existing educational practice remains unchanged and
      the potential benefits to students of this new educational philosophy are not
      realized. Furthermore, it is by engaging in a reflective process in relation to
      their own experience that educators can begin to understand how to facilitate
      that process in others.

PMID- 10583659
TI  - Celebrating nursing's past...claiming the future. Conference organized and hosted
      by the Royal College of Nursing of the United Kingdom to celebrate the centenary
      of the foundation of the International Council of Nurses, held in London,
      England, 27 June-1 July 1999.

PMID- 10583660
TI  - Media reviews

PMID- 10583661
TI  - Media reviews

PMID- 10583662
TI  - Media reviews

PMID- 10583663
TI  - Media reviews

PMID- 10583664
TI  - Media reviews

PMID- 10583665
TI  - Media reviews

PMID- 10583666
TI  - Media reviews

PMID- 10583667
TI  - Media reviews

PMID- 10583668
TI  - Media reviews

PMID- 10583669
TI  - Media reviews

PMID- 10583670
TI  - Media reviews

PMID- 10583671
TI  - Media reviews

PMID- 10583672
TI  - Forthcoming contents of volume 31, number 1, january 2000

PMID- 10583673
TI  - Comparison of different methods for diagnosis of bovine tuberculosis from
      tuberculin- or interferon-gamma-reacting cattle in Spain.
AB  - Of 1479 cattle from herds in Northwestern Spain previously diagnosed as
      tuberculosis (TB) positive, 218 animals which gave a positive tuberculin or
      interferon-gamma reaction were examined at the slaughterhouse. Medial
      retropharyngeal and caudal mediastinal lymph nodes, and any tissues containing
      lesions suspected to be tuberculous, were removed and submitted to the
      laboratory. Three techniques for diagnosis of TB were used: post mortem
      examination (PME), smear staining by means of auramine O method (AOM), and
      culture isolation in Coletsos and Lowenstein-Jensen media followed by
      confirmation of M. tuberculosis complex organisms using PCR (CIM-PCR). Only 123
      (29.9%) of the 412 samples collected showed typical tuberculous lesions.
      Confirmed M. tuberculosis complex organisms were isolated in 144 cases, 114 of
      which were from tissues showing lesions (success rate of 92.8%). Smears were
      found positive in 113 cases, 96 of which came from lesions suspected to be
      tuberculous (success rate of 78.0%). The sensitivities of CIM-PCR compared with
      those of PME and AOM were 92.7% and 85.7%, respectively. Statistical analysis
      revealed that PME and AOM are good indicators of the presence of M. tuberculosis
      complex organisms in tuberculin- or interferon-gamma reacting cattle.

PMID- 10583674
TI  - Identification and environmental detection of Rhodococcus species by 16S rDNA
      targeted PCR.
AB  - Bacteria of the genus Rhodococcus can degrade a wide range of organic pollutants
      and catalyse many useful biotransformations. There is a need for improved tests
      to identify Rhodococcus species. PCR-based methods for species identification
      offer advantages in terms of speed and accuracy over traditional methods and can
      allow direct detection of microbes in environmental samples., PCR tests, using
      primers targeted at species-specific sequences in the 16S rRNA gene, were
      successfully developed for R. globerulus, R. erythropolis, R. opacus and R.
      ruber. These tests gave positive results with all or most strains of target
      species but did not generally cross-react with other species. Cases of apparent
      cross-reaction were shown to be due to prior misclassification of strains of R.
      opacus as R. erythropolis and of strains of R. ruber as R. rhodochrous. A simple
      and rapid method for the extraction and purification of DNA from soil was
      developed and successfully applied to the PCR detection of indigenous R.
      erythropolis in an environmental sample. Cell lysis in the samples was achieved
      by lysozyme and sarkosyl treatment, aided by freeze-thaw cycles. Removal of humic
      compounds inhibitory to PCR was accomplished by CTAB treatment with solvent
      extraction and, if necessary, passage of extracts through Sepharose CL-6B in a
      spun-column format. Extracts prepared using a tris-EDTA buffer were much clearer
      than those prepared using a sodium phosphate buffer, indicating lower levels of
      humic compounds. A detection limit of 104 cfu g-1 of soil was achieved and the
      use of a secondary PCR allowed detection of 1 cfu g-1.

PMID- 10583675
TI  - Enterotoxigenic profiles and polymerase chain reaction detection of Bacillus
      cereus group cells and B. cereus strains from foods and food-borne outbreaks.
AB  - Bacillus cereus is one of the important food pathogens. Since B. cereus group
      cells, such as B. cereus, B. thuringiensis, B. anthracis and B. mycoides, share
      many phenotypical properties and a high level of chromosomal sequence similarity,
      it is interesting to investigate the virulence profiles for B. cereus group
      cells, including B. cereus strains isolated from foods and samples associated
      with food-poisoning outbreaks. For this investigation, the presence of
      enterotoxin genes, such as those of haemolysin BL, B. cereus enterotoxin T and
      enterotoxin FM, were assayed by polymerase chain reaction (PCR) methods.
      Meanwhile, their enterotoxin activities were assayed using the BCET-RPLA kit,
      haemolytic patterns on sheep blood agar and their cytotoxicity to Chinese hamster
      ovary (CHO) cells. Results showed that there were 12 enterotoxigenic profiles for
      the 98 B. cereus group strains collected. In addition, if any of the three types
      of enterotoxins was present in the B. cereus group cells, these cells were shown
      to be cytotoxic to the CHO cells. Similar enterotoxigenic profiles could be found
      among strains of B. cereus, B. mycoides and B. thuringiensis. Thus, all B. cereus
      group strains may be potentially toxigenic and the detection of these cells in
      foods is important. We thus designed PCR primers, termed Ph1/Ph2, from the
      sphingomyelinase gene of B. cereus cells. These primers were specific for all B.
      cereus group strains and could be used for the detection of B. cereus cells
      contaminated in food samples.

PMID- 10583676
TI  - Validating predictive models of food spoilage organisms.
AB  - The accuracy and bias of a predictive model for the maximum specific growth rate
      of Pseudomonas spp. were studied by means of percentage discrepancy and bias
      indicators. These were calculated for observations obtained both in laboratory
      media and in food. When independent pseudomonad data generated in broth were
      compared with model predictions, the error was smaller than in the case of food.
      The extent to which the food structure and composition of the microflora
      contribute to the overall error of the model was quantified.

PMID- 10583678
TI  - Production of Aspergillus xylanase by lignocellulosic waste fermentation and its
      application.
AB  - Strains of Aspergillus terreus and A. niger, known to produce xylanase with
      undetectable amounts of cellulase, were studied for xylanase (EC 3.2.1.8)
      production on various lignocellulosic substrates using solid state fermentation.
      Of the lignocellulosic substrates used, wheat bran was the best for xylanase
      production. The effects of various parameters, such as moistening agent, level of
      initial moisture content, temperature of incubation, inoculum size and incubation
      time, on xylanase production were studied. The best medium for A. terreus was
      wheat bran moistened with 1:5 Mandels and Strenberg mineral solution containing
      0.1% tryptone, at 35 degrees C, and at inoculum concentration 2x107-2x108 spores
      5 g-1 substrate; for A. niger, the best medium was wheat bran moistened with 1:5
      Mandels and Strenberg mineral solution containing 0.1% yeast extract, at 35
      degrees C, and at an inoculum concentration of 2x107-2x108 spores 5 g-1
      substrate. Under these conditions, A. terreus produced 68.9 IU ml-1 of xylanase,
      and A. niger, 74.5 IU ml-1, after 4 d of incubation. A crude culture filtrate of
      the two Aspergillus strains was used for the hydrolysis of various
      lignocellulosic materials. Xylanase preparations from the two strains selectively
      removed the hemicellulose fraction from all lignocellulosic materials tested.

PMID- 10583677
TI  - Production and utilization of polyclonal antibodies against nisin in an ELISA and
      for immuno-location of nisin in producing and sensitive bacterial strains.
AB  - Specific nisin polyclonal antibodies (PAb) were produced in rabbits using nisin Z
      produced by Lactococcus lactis subsp. lactis biovar diacetylactis UL 719.
      Antisera were obtained from white female New Zealand rabbits that were first
      immunized with a nisin Z-keyhole limpet haemocyanin conjugate and boosted with
      free nisin Z. Nisin-specific PAb were purified by affinity chromatography with a
      yield of 15 mg specific antinisin 100 ml-1 serum. The detection limit of the
      ELISA test for nisin Z was 0.75 ng ml-1 in buffer but was 1.7 and 3.5 ng ml-1 in
      milk and complex media broth spiked (5, 10, 20 microg ml-1) with nisin Z,
      respectively. In nisin Z-spiked samples, the average concentration was between 90
      and 107% of actual added amount. In contrast, when the bioassay (microtitration
      method) was used, only 50-63% of nisin Z biological activity could be detected.
      In addition, the affinity-purified nisin PAb, antirabbit IgG gold conjugate and
      transmission electron microscopy were successfully used to locate nisin Z on
      producing cells and to observe its bactericidal effects against sensitive cells.

PMID- 10583679
TI  - Zygosaccharomyces lentus: a significant new osmophilic, preservative-resistant
      spoilage yeast, capable of growth at low temperature.
AB  - Zygosaccharomyces lentus is a yeast species recently identified from its
      physiology and 18S ribosomal sequencing (Steels et al. 1999).The physiological
      characteristics of five strains of this new yeast so far isolated were
      investigated, particularly those of technical significance for a spoilage yeast,
      namely temperature range, pH range, osmotolerance, sugar fermentation, resistance
      to food preservatives such as sorbic acid, benzoic acid and dimethyldicarbonate
      (DMDC; Velcorin). Adaptation to benzoic acid, and growth in shaking and static
      culture were also investigated. Zygosaccharomyces lentus strains grew over a wide
      range of temperature (4-25 degrees C) and pH 2.2-7.0. Growth at 4 degrees C was
      significant. Zygosaccharomyces lentus strains grew at 25-26 degrees C in static
      culture but were unable to grow in aerobic culture close to their temperature
      maximum. All Z. lentus strains grew in 60% w/v sugar and consequently, are
      osmotolerant. Zygosaccharomyces lentus strains could utilize sucrose, glucose or
      fructose as a source of fermentable sugar, but not galactose. Zygosaccharomyces
      lentus strains were resistant to food preservatives, growing in sorbic acid up to
      400 mg l-1 and benzoic acid to 900 mg l-1 at pH 4.0. Adaptation to higher
      preservative concentrations was demonstrated with benzoic acid. Resistance to
      DMDC was shown to be greater than that of Z. bailii and Saccharomyces cerevisiae.
      This study confirms that Z. lentus is an important food spoilage organism
      potentially capable of growth in a wide range of food products, particularly low
      pH, high sugar foods and drinks. It is likely to be more significant than Z.
      bailii in the spoilage of chilled products.

PMID- 10583680
TI  - Sorbitol-fermenting bifidobacteria as indicators of diffuse human faecal
      pollution in estuarine watersheds.
AB  - Sorbitol fermenting bifidobacteria were evaluated as indicators of non-point
      source human faecal pollution to three sub-estuaries with elevated faecal
      coliform densities. Human-specific bifidobacteria correlated with identifiable
      human sanitary deficiencies in feeder streams to estuarine creeks in two of three
      watersheds examined, one rural and one moderately developed. Sorbitol-fermenting
      bifidobacteria were recovered at densities ranging from 1 to 90 colony-forming
      units 100 ml-1 in 11 of 258 water samples but were undetected in sediment (n =
      68) and scat from resident wildlife (deer, muskrat and raccoon, n = 20). Failure
      to detect sorbitol-fermenting bifidobacteria in water samples during the summer
      months was consistent with laboratory microcosm results showing non
      recoverability of Bifidobacterium adolescentis after 5-9 d in membrane-filtered
      estuarine water at 23 and 30 degrees C, but persistence for 4 weeks at 10 degrees
      C. Persistence of sewage-derived bifidobacteria in membrane-filtered freshwater
      at 15 degrees C was also observed. Recovery of sorbitol-fermenting bifidobacteria
      was complicated by high background levels of Gram-positive rods and cocci. Use of
      propionic acid and reduced pH (pH = 5.0), or use of a two-step resuscitation
      protocol using non-selective and selective media, did not improve recovery.
      Although human specific bifidobacteria hold promise as indicators of diffuse
      faecal contamination, methodological constraints now limit its application to
      situations of gross contamination, or sampling potential sources during
      environmental conditions conducive to bifid persistence.

PMID- 10583681
TI  - Salmonella infection in children from the wastewater-spreading zone of Marrakesh
      city (Morocco).
AB  - The available circumstantial evidence gained from epidemiological and
      microbiological investigations suggests that the use of untreated wastewater
      causes an excess of Salmonella infection among children living in El Azzouzia
      (the wastewater-spreading area of Marrakesh city, Morocco) compared with those
      from a control area that does not practice sewage irrigation (Sidi Moussa). The
      prevalence in the exposed group (32.56%) was significantly (P < 0. 001) higher
      than for the control group (1.14%). Serogroups B and C were the most commonly
      isolated. Boys were at greater risk (37.61%) of contracting Salmonella infection
      than girls (26.66%). Age-specified rates showed that children of less than 10
      years old were infected at a higher rate than older children in the area (exposed
      group), with 40.32% and 19.72% rates of infection, respectively. Crop irrigation
      with untreated wastewater caused a significantly higher rate of infection with
      Salmonella in the children of agricultural workers (39.33%) than in the children
      of non-agriculturists (24.58%).

PMID- 10583682
TI  - The effect of alpha-lactalbumin and beta-lactoglobulin hydrolysates on the
      metabolic activity of Escherichia coli JM103.
AB  - Bovine milk proteins alpha-lactalbumin (alpha-la) and beta-lactoglobulin (beta
      lg) were hydrolysed with seven different proteolytic enzymes, and the effect of
      various hydrolysates on a genetically modified luminous Escherichia coli JM103
      was tested in vitro with a bioluminescence assay for bacterial growth and
      metabolism. Undigested proteins did not inhibit the activity of tested E. coli
      JM103 at a concentration as high as 0.1 g ml-1. At the same concentrations, alpha
      la hydrolysed with pepsin or trypsin and beta-lg hydrolysed with alcalase, pepsin
      or trypsin, showed a lower metabolic activity during the first 8 h of growth. The
      activity of E. coli JM103 in the presence of 25 mg ml-1 alpha-la or beta-lg
      hydrolysed with pepsin and trypsin was only 21% of the control after incubation
      for 6 h. The preliminary results indicated that ultrafiltration through 10 kDa
      and 1 kDa molecular mass cut-off membranes may be used to enrich bacteriostatic
      properties.

PMID- 10583683
TI  - A study of dextran production from maltodextrin by cell suspensions of
      Gluconobacter oxydans NCIB 4943.
AB  - This study investigated dextran synthesis from a commercial maltodextrin
      substrate using cell suspensions of G. oxydans NCIB 4943 as catalysts.
      Experiments were arranged according to a central composite statistical design.
      The effects of substrate concentration (10-100 g l-1), cell concentration (0.32
      32.0 g wet weight l-1), time of reaction (8-48 h) and pH (3.5-5.5), each at three
      levels, on dextran yield and dextran molecular weight (MW), were investigated.
      Response surface methodology was used to assess factor interactions, and
      empirical models describing the two responses were fitted. Most of the variance
      in dextran yield could be explained by the fitted model (R2 = 0.96). Dextran
      yield ranged from 1.21 to 41.69%. The presence of significant negative quadratic
      effects of cell concentration and time indicated that dextran yield reached a
      plateau and thus, optimum levels of cell concentration and time could be
      identified to maximize dextran yield. Dextran MW ranged from 6.6 to 38 kDa and
      was characterized by the significant interactions of reaction time with substrate
      concentration and cell concentration. The model, however, could account for only
      60% of the variance in dextran MW. Possible reasons for this are discussed.

PMID- 10583684
TI  - Purification and partial characterization of an extracellular serine-proteinase
      of Streptomyces cyaneus isolated from Brazilian cerrado soil.
AB  - Streptomyces cyaneus, a micro-organism isolated from Brazilian cerrado soil,
      produces an extracellular proteinase (SCP), which was purified 22-fold to
      homogeneity from culture supernatant fluid, using a single aprotinin-agarose
      affinity chromatography step. It is produced at a level corresponding to
      approximately 15% of total protein, but its physiological function has yet to be
      determined. The molecular mass of this S. cyaneus proteinase was estimated to be
      120 kDa by gel filtration high performance liquid chromatography, and it migrates
      by SDS-PAGE as a single band of 30 kDa. It was optimally active at 25 degrees C
      and pH 9.0, and was fully inhibited by the serine-proteinase inhibitors PMSF and
      TPCK. A Km value of 1. 86 x 10-5 mmol l-1, and Vmax of 2.0 x 10-2 mmol l-1
      (Abs247 nm microg-1 min-1), were calculated for alpha-N-p-tosyl-L-arginine-methyl
      ester (TAME) as substrate.

PMID- 10583686
TI  - Molecular and physiological characterization of dominant bacterial populations in
      traditional mozzarella cheese processing
AB  - The development of the dominant bacterial populations during traditional
      Mozzarella cheese production was investigated using physiological analyses and
      molecular techniques for strain typing and taxonomic identification. Analysis of
      RAPD fingerprints revealed that the dominant bacterial community was composed of
      25 different biotypes, and the sequence analysis of 16S rDNA demonstrated that
      the isolated strains belonged to Leuconostoc mesenteroides subsp. mesenteroides,
      Leuc. lactis, Streptococcus thermophilus, Strep. bovis, Strep. uberis,
      Lactococcus lactis subsp. lactis, L. garviae, Carnobacterium divergens, C.
      piscicola, Aerococcus viridans, Staphylococcus carnosus, Staph. epidermidis,
      Enterococcus faecalis, Ent. sulphureus and Enterococcus spp. The bacterial
      populations were characterized for their physiological properties. Two strains,
      belonging to Strep. thermophilus and L. lactis subsp. lactis, were the most
      acidifying; theL. lactis subsp. lactis strain was also proteolytic and eight
      strains were positive to citrate fermentation. Moreover, the molecular techniques
      allowed the identification of potential pathogens in a non-ripened cheese
      produced from raw milk.

PMID- 10583685
TI  - The effect of zinc oxide supplementation on the stability of the intestinal flora
      with special reference to composition of coliforms in weaned pigs.
AB  - The effect of a dietary supplementation of zinc oxide (ZnO) on the stability of
      the intestinal flora and on the composition of coliforms in weaned pigs was
      investigated. Faecal floras were characterized by their metabolic activities and
      fermentative capacity (FC) using the Phene Plate generalized microplate.
      Coliforms were characterized by conventional enumeration and by the Phene Plate
      RS plates. The latter measured FC, phenotypic diversity, persistence of each
      coliform strain in piglets, and similarity among the coliform populations within
      groups. From weaning onwards, the control pigs (n = 5) were fed a basal diet ad
      libitum, while experimental pigs (n = 5) were given the same food supplemented
      with 2500 ppm ZnO. Metabolic fingerprinting of faecal floras indicated marked
      differences between the composition of floras of treated and control pigs during
      the first 2 weeks post-weaning. The FC of faecal flora in both groups decreased
      as pigs aged, but it was significantly (P </= 0.0001) lower in control pigs
      during the first 2 weeks post-weaning. Neither the number of coliforms, nor their
      FC-values, differed between the groups. However, during the first 2 weeks post
      weaning, there was a significant increase in both variety (P = 0.019) and
      diversity (P </= 0.001) of coliforms in control pigs compared with the ZnO
      treated group. Homogeneity between coliform populations of piglets was high
      during the suckling period, indicating the presence of many identical strains
      among piglets. This, however, decreased in control pigs during the first 2 weeks
      post-weaning. Several coliform strains that colonized the gut at the early stage
      of the pigs' life were found to be resident in animals of both groups. It is
      concluded that supplementation of ZnO to weaned pigs helped to maintain the
      stability of the intestinal microflora and the diversity of coliforms during the
      first 2 weeks post-weaning, but not later, and that ZnO supplementation to creep
      feed should be restricted to the first 2 weeks post-weaning in veterinary
      practice.

PMID- 10583687
TI  - Anaerobic lactic acid degradation during ensilage of whole crop maize inoculated
      with lactobacillus buchneri inhibits yeast growth and improves aerobic stability
AB  - Aerobic deterioration of silages is initiated by (facultative) aerobic micro
      organisms, usually yeasts, that oxidize the preserving organic acids. In this
      study, a Lactobacillus buchneri strain isolated from maize silage was evaluated
      for its potential as a bacterial inoculant that enhances aerobic stability of
      silages. In four experiments, chopped whole crop maize (30-43% dry matter (DM))
      was inoculated with Lact. buchneri and ensiled in laboratory silos. Uninoculated
      silages served as controls. Analysis of silages treated with Lact. buchneri at
      levels of 103-106 cfu g-1 after about 3 months of anaerobic storage showedthat
      acetic acid and 1-propanol contents increased with inoculum levels above 104 cfu
      g-1,whereas lactic acid decreased. Propionic acid, silage pH and DM loss
      increased withinoculum levels above 105 cfu g-1. Time course experiments with
      maize inoculated with Lact. buchneri at 4 x 104-2 x 105 cfu g-1 showed that up to
      7-14 d after ensiling, Lact. buchneri had no effect on silage characteristics.
      Thereafter, the lactic acid content of the inoculated silages declined and,
      simultaneously, acetic acid and, to a lesser extent, propionic acid and 1
      propanol, accumulated. Inoculation reduced survival of yeasts during the
      anaerobic storage phase and inhibited yeast growth when the silage was exposed to
      O2, resulting in a substantial improvement in aerobic stability. The results
      indicate that the use of Lact. buchneri as a silage inoculant can enhance aerobic
      stability by inhibition of yeasts. The ability of the organism to ferment lactic
      acid to acetic acid appears to be an important underlying principle of this
      effect.

PMID- 10583688
TI  - Microbiological characteristics of anevato: a traditional greek cheese
AB  - Nine batches of Anevato, raw goat milk cheese, were examined throughout a 60 day
      storage time at three different periods within the lactation season of the goat.
      High mean log counts per gram of cheese for aerobic bacteria (7.92-9.56), lactic
      acid bacteria (7. 78-9.32), Gram-negative organisms 5.64-9.67), psychrotrophs
      (7.90-11. 79) and proteolytic bacteria (7.57-9.36) were found.
      Enterobacteriaceae, coliforms and yeasts were considerably lower.
      Enterobacteriaceae and coliforms in the curd of cheese made in May were lower by
      approximately 3.0 log10 cfu g-1 than counts in curd made in January, and were
      lower by about 2.5 log10 cfu g-1 than those in cheese made in March. This
      coincided with lower pH and higher counts of lactic acid bacteria in cheese made
      in March and May. Yeast populations were affected by the season and were higher
      in May than March and/or January. Lactococci dominated in the cheese until 15
      days, but lactobacilli became predominant after 30 days. Lactococcus lactis was
      the most abundant species of lactic acid bacteria found in Anevato cheese.
      Results suggest the need for improving milk quality and/or using heat-treated
      milk to produce Anevato cheese; the use of L. lactis as a starter would possibly
      eliminate or suppress the growth of undesirable organisms.

PMID- 10583689
TI  - Genetic diversity in Helicobacter pullorum from human and poultry sources
      identified by an amplified fragment length polymorphism technique and pulsed
      field gel electrophoresis.
AB  - Helicobacter pullorum was first isolated from the faeces and carcasses of poultry
      and has been associated with human gastroenteritis. The aim of this study was to
      examine interstrain genetic diversity within H. pullorum. Two fingerprinting
      techniques were used: amplified fragment length polymorphism (AFLP) and pulsed
      field gel electrophoretic (PFGE) analysis. The 20 strains examined were from four
      countries and comprised 13 human isolates and seven poultry isolates. Their
      identity was confirmed by a species-specific PCR assay. The human and poultry
      isolates had distinct genotypes and most strains showed a high degree of genetic
      diversity. Genotyping also indicated a clonal origin for two strains from the
      same poultry flock, and established a close relatedness between three chicken
      carcass isolates from a processing plant. It is concluded that these two
      genotyping techniques will provide a useful basis for future epidemiological
      investigations of H. pullorum in poultry, and may provide a link with its
      possible causal role in human gastrointestinal infections.

PMID- 10583690
TI  - Influence of growth phases and desiccation on the degrees of unsaturation of
      fatty acids and the survival rates of rhizobia
AB  - The influence of growth phase on the evolution of cellular fatty acids (CFA) and
      survival of Sinorhizobium and Bradyrhizobium during desiccation and storage at
      different levels of relative humidity (R. H.) was studied. Lactobacillic, cis
      vaccenic and palmitic acids were the major fatty acids of S. meliloti RCR 2011,
      B. elkanii USDA 120 and B. japonicum 3.2, whatever the growth phase. An exchange
      of cis vaccenic with lactobacillic acid was observed during the course of growth.
      The degree of unsaturation (% unsaturated CFA/% saturated CFA = u/s ratio) was
      significantly higher during the mid logarithmic phase of growth. Survival rates
      immediately after desiccation were unaffected by the growth phase and the R.H.
      Furthermore, no correlation was found between survival rate and u/s ratio. During
      the course of desiccation, the u/s ratio of rhizobia decreased but the decrease
      was largely independent of the R.H. Optimum R.H. values for storage were in the
      range 22-67.8%, and S. meliloti was significantly more tolerant than the
      bradyrhizobia. Cells of rhizobia harvested in the lag phase of growth were more
      resistant to protracted storage than cells at other growth phases. Again, no
      correlation was found between u/s ratio and survival rates, despite the expected
      practical significance for screening for drought-tolerant micro-organisms.

PMID- 10583691
TI  - Monoclonal antibodies against AsaP1, a major exotoxin of the fish pathogen
      Aeromonas salmonicida subsp. achromogenes, and their application in ELISA.
AB  - Two monoclonal antibodies (Mabs) binding to a toxic extracellular metallo
      proteinase of Aeromonas salmonicida subsp. achromogenes, AsaP1, were produced.
      Both reacted with common epitopes of the native enzyme and recognized this 20 kDa
      antigen on Western blots. One of these Mabs had an inhibitory effect on the
      caseinase activity of the exotoxin. A Mab-based ELISA was set up and evaluated
      for serological detection of AsaP1 in bacterial culture filtrates. The exotoxin
      was identified serologically in the extracellular products of 11 of 26 atypical
      Aer. salmonicida isolates, including the type strain for subsp. achromogenes
      NCIMB 1110. The ELISA was approximately 100-fold more sensitive in detecting
      AsaP1 compared with an azocasein assay. The established serological test enables
      AsaP1 to be quantified reliably with a lower detection limit of about 0.12 ng ml
      1 and has a potential use for the phenotypic differentiation of atypical Aer.
      salmonicida isolates.

PMID- 10583692
TI  - Hormonal emergency contraception: moving over the counter?

PMID- 10583693
TI  - Omeprazole-induced leukopenia. A case report.
AB  - BACKGROUND: Omeprazole has been marketed in France since 1989, for the healing of
      peptic ulcers, erosive reflux oesophagitis, and the Zollinger-Ellison syndrome.
      However, the drug has been associated with serious adverse reactions, including
      haemolytic anaemia and acute interstitial nephritis. More recently, an autoimmune
      syndrome induced by omeprazole has been described. OBJECTIVE: We present here a
      clinical history and an in vitro test of cytotoxicity linking leukopenia to
      omeprazole. RESULTS: A 37-year-old woman was hospitalized in the intensive care
      unit of our hospital with acute pulmonary insufficiency secondary to pneumonia.
      72 h after starting omeprazole treatment, a decrease in leucocyte count was
      observed. The leukopenia was maximal on day 22: total white cell count was 2.
      1x109/l, and neutrophil count was less than 0.75x109/l. In order to find the
      cause of this leukopenia, an in vitro cytotoxicity test was performed. The test
      was positive only when patient neutrophils and patient serum were in the presence
      of omeprazole. This cytotoxicity seems to be complement-dependent, as in the
      presence of heated serum, the omeprazole toxic effect was substantially reduced.
      CONCLUSION: This case report suggests that the leukopenia was associated with
      omeprazole.

PMID- 10583694
TI  - Update: genetic polymorphism of drug metabolizing enzymes in humans.
AB  - The cytochrome P450 (P450 or CYP) monooxygenases, CYP2D6, CYP2C19, CYP2E1 and
      CYP2C9, and non-P450 monooxygenases, N-acetyltransferase, thioprine
      methyltransferases and dihydropyrimidine dehydrogenase, all display polymorphism.
      CYP2D6 and CYP2C19 have been studied extensively and, despite their low abundance
      in the liver, they have been found to catalyse the metabolism of many drugs.
      CYP2D6 has many allelic variants, whereas CYP2C19 has only two. Most variants are
      translated into inactive, truncated proteins or fail to express protein. There
      is, as yet, no clear information about CYP2E1 polymorphism. In addition, genetic
      differences in certain foreign-compound metabolizing enzymes, such as Phase II
      enzymes, have been shown to be associated with an increased risk of developing
      environmentally and occupationally related diseases such as cancer. When two
      drugs that are substrates of a polymorphic CYP enzyme are administered
      concomitantly during drug therapy, each will compete for that enzyme and
      competitively inhibit the metabolism of the other substrate. This can result in
      toxicity. Patients who are poor metabolizers (PMs), extensive metabolizers (EMs)
      and ultrarapid metabolizers (URMs) can be identified. Having such information
      will help in determining the appropriate dosage of certain drugs when treating
      patients with an inherited abnormality of a drug-metabolizing enzyme. In view of
      the remarkable progress in this particular field, it is to be expected that more
      genetic polymorphisms will be discovered in the near future.

PMID- 10583695
TI  - Can lowering homocysteine levels reduce the incidence of stroke?
AB  - Hyperhomocysteinaemia has been identified as an independent risk factor for
      atherosclerotic and thromboembolic diseases such as cerebro-vascular diseases,
      coronary artery disease and venous thrombosis. This review will discuss the role
      of high levels of plasma homocysteine in stroke disease.

PMID- 10583696
TI  - Gender-related differences in pharmacokinetics and their clinical significance.
AB  - In this review I have attempted to summarize gender differences in
      pharmacokinetics involving the cytochrome P450 (CYP) isozymes of young and mature
      adults, excluding the effects of the menstrual cycle, use of oral contraceptives
      and pregnancy. Sex differences in drug metabolism and elimination are mainly
      related to steroid hormone levels. CYP3A4, responsible for the metabolism of over
      50% of therapeutic drugs, exhibits higher activity in women than in men.
      Nonetheless, the absence of a sex difference has been reported by some workers.
      The activity of several other CYP (CYP2C19, CYP2D6, CYP2E1) isozymes and the
      conjugation (glucuronidation) activity involved in drug metabolism may be higher
      in men than in women. Drug metabolism in women is affected by sex-specific
      factors (menopause, pregnancy and menstruation) in addition to the cigarette
      smoking, drug ingestion and alcohol consumption that are more commonly observed
      factors in men. Furthermore, they are affected by physiological factors such as
      drug absorption, protein binding and elimination. Thus, careful attention should
      be paid to the side-effects and toxicity arising from sex differences in drug
      metabolism in clinical situations. Although there are specific ethical
      considerations regarding carrying out drug trials in women, the relationship
      between the side-effects and toxicity that may be influenced by hormones during
      drug metabolism and drug treatment needs further study.

PMID- 10583697
TI  - Clinically significant pharmacokinetic drug interactions with benzodiazepines.
AB  - The reports of interactions between benzodiazepines (BZPs) and other drugs (e.g.,
      antidepressants, selective serotonin reuptake inhibitors, antiulcer drugs,
      antiepileptic drugs, macrolide antibiotics) during their combined use are
      reviewed. In general, metabolism of BZPs is delayed when combined with a number
      of other drugs but some reports have suggested otherwise. In recent years, the
      cytochrome P450 (P450 or CYP) isoenzyme that catalyses the metabolism of BZPs has
      also been identified. BZPs are mainly catalysed by CYP3A4. When published reports
      are studied, it appears necessary to be exceptionally careful about interactions
      mainly between BZPs and selective serotonin reuptake inhibitors, cimetidine,
      antiepileptic drugs, macrolide antibiotics and antimycotics. More information is
      necessary to identify individuals at greatest risk of drug interactions and
      adverse events.

PMID- 10583698
TI  - The impact of nursing home patients on prescribing costs in general practice.
AB  - OBJECTIVES: To compare the costs of prescribing for older people in nursing homes
      with older people living at home and to compare patterns of prescribing between
      these two groups. DESIGN: Retrospective case-control study. SETTING: Nine general
      practices in Nottinghamshire. SUBJECTS: Two hundred and seventy patients aged 65
      years and over living in nursing homes matched for age, sex and general practice,
      with 270 patients living in their own homes. MAIN OUTCOME MEASURES: A comparison
      of the costs of prescriptions, the number of items on prescription and the types
      of drugs prescribed between the cases and controls. RESULTS: The mean cost of
      prescriptions per patient month was almost three times higher for nursing home
      patients than controls (45.27 pounds compared to 16.46 pounds). The mean number
      of items prescribed per patient month was also higher in nursing home patients
      (5.60 compared to 2.55). Total costs of prescriptions for nursing home patients
      were higher than for controls (P < 0.0001), as were total numbers of prescription
      items (P < 0.001). There were differences in the types of medication prescribed
      between the two groups, including considerably higher costs for central nervous
      system drugs, ulcer healing drugs, laxatives and enteral nutrition in nursing
      home residents. CONCLUSIONS: When calculating general practice prescribing
      budgets, nursing home patients should have a greater weighting than other
      patients of similar age and sex.

PMID- 10583699
TI  - Stability of methacholine chloride in isotonic sodium chloride using a capillary
      electrophoresis assay.
AB  - OBJECTIVE: To investigate the stability of methacholine chloride in 0.9% sodium
      chloride solutions. METHOD: Methacholine powder was mixed with diluent to a final
      concentration of 5 and 10 mg/ml. Duplicates of each admixture were divided and
      stored in glass vials at 25 degrees C, 4 degrees C and -20 degrees C for 12
      months. At appropriate times intervals, samples were removed from solutions and
      analysed. Methacholine concentrations were measured using a high performance
      capillary electrophoresis assay. RESULTS: No colour or other visual changes were
      seen in any sample. However, an additional peak was observed in some samples.
      CONCLUSION: Methacholine chloride solutions 5 mg/ml were stable in isotonic
      sodium chloride after refrigeration or freezing over a period of one year;
      methacholine chloride solutions 10 mg/ml were stable for one year after freezing.
      The solutions stored at ambient temperature were stable for 35 days and for less
      than 14 days, respectively, for the 5 and the 10 mg/ml solutions.

PMID- 10583700
TI  - Piracetam in the treatment of schizophrenia: implications for the glutamate
      hypothesis of schizophrenia.
AB  - OBJECTIVE: There is a growing interest in investigating the role of glutamate
      receptors in the pathophysiology of schizophrenia. Indeed, the hyperdopaminergic
      theory of schizophrenia can explain only the positive symptoms of schizophrenia,
      whereas the glutamate hypothesis may provide a more comprehensive view of the
      illness. We undertook a trial to investigate whether the combination of
      haloperidol with piracetam, a nootropic agent which modulates the glutamate
      receptor positively was more effective than haloperidol alone. METHODS: Thirty
      patients who met the DSM IV criteria for schizophrenia completed the study.
      Patients were allocated in a random fashion, 14 to haloperidol 30 mg/day plus
      piracetam 3200 mg/day and 16 to haloperidol 30 mg/day plus placebo. RESULTS:
      Although both protocols significantly decreased the score of the positive
      symptoms, the negative symptoms, the general psychopathological symptoms and the
      total score of PANSS scale over the trial period, the combination of haloperidol
      and piracetam showed a significant superiority over haloperidol alone in the
      treatment of schizophrenic patients. CONCLUSION: Piracetam, a member of the
      nootropic class of drugs and a positive modulator of glutamate receptor, may be
      of therapeutic benefit in treating schizophrenic patients in combination with
      typical neuroleptics. However, a larger study to confirm our results is warranted

PMID- 10583701
TI  - Digoxin: use pattern in Estonia and bioavailability of the local market leader.
AB  - BACKGROUND: In comparison with neighbouring Scandinavian countries, the use of
      digoxin in Estonia is high. The present study was carried out to determine the
      use pattern of digoxin in Estonia and bioavailability of the local market leader
      preparation in comparison with Lanoxin. METHOD: Drug use data were evaluated from
      the annual reports of wholesale companies. For the bioequivalence study, a single
      blind cross-over randomised two-way single-dose comparative bioavailability study
      was performed using 14 healthy volunteers. Digoxin concentrations in serum
      samples and urine were measured by chemiluminescent competitive immunoassay.
      RESULTS: The use of digoxin in Estonia has increased by 35% during the period
      1994-97. The steady market leader was the local generic drug. No statistically
      significant differences were found in any pharmacokinetic parameter between the
      generic preparation and Lanoxin. All parameters showed considerable variability.
      The total amount of drug excreted was the parameter with lowest inter- individual
      variation. CONCLUSION: The present study indicates that the generic digoxin
      preparation studied is bioequivalent to Lanoxin. The increasing use of digoxin in
      Estonia is not caused by low bioavailability of the local market leader but by
      therapeutic traditions.

PMID- 10583702
TI  - Optimization of phenytoin therapy in adults with epilepsy in the Western Cape,
      South Africa.
AB  - OBJECTIVE: To assess the extent to which adults with epilepsy were optimized and
      individualized on phenytoin monotherapy in the Western Cape, South Africa and to
      estimate the average optimized dose and serum phenytoin concentration, and the
      therapeutic range for this patient group. METHODS: Patients were considered to be
      optimized on phenytoin if they were seizure-free or the best compromise was
      achieved between seizure reduction and side-effects. RESULTS: 538 (233 black and
      305 coloured) adult people with epilepsy were treated at nine epilepsy clinics as
      outpatients. Of these patients, 332 (226 male and 106 female, 149 black and 183
      coloured) were included in the data analysis as they were considered to have
      reliable phenytoin levels. Phenytoin doses and steady-state serum concentrations
      were predicted using the Michaelis-Menten equation. Patients attended a clinical
      pharmacokinetic service for 7.7+/-5.3 (range 1-22) months. The average optimized
      dose was 305.8 (range 100-500) mg/day and the average optimized level was 62.7+/
      23.9 (range 15-133) micromol/l. Most patients (61.9%) were optimized in the
      therapeutic range 40-79 micromol/l; 21.1% were optimized above and 17% below this
      range. In 1.6% of patients serum concentrations above 120 micromol/l were
      required. Dosage adjustments were made in 47.0% of patients, increased in 31.9%
      and reduced in 15.1%. CONCLUSION: These findings indicate that many patients
      (47%) attending outpatient clinics were not optimized on phenytoin therapy.

PMID- 10583703
TI  - Evaluation of the in-line filters for the intravenous infusion of amphotericin B
      fluid.
AB  - OBJECTIVE: To evaluate the effects of four types of in-line filters on filtration
      rate, amphotericin B concentration and particulate matter. METHODS: Filtration
      rates of amphotericin B fluid through in-line filters under maximum gravity flow
      were examined. The concentrations of amphotericin B and the particulate matter in
      the non-filtered and filtered amphotericin B fluid at the flow rate of 500 ml/24
      h were measured. RESULTS: Filtration through a 1.2 microm or 0.2 microm
      polyethersulphone (PES) filter under maximum gravity flow took less than 40 min.
      The 0.2 microm positively charged nylon 66 and 0.2 microm nylon 66 filters took
      70 and 100 min, respectively, to filter 500 ml of amphotericin B fluid. The 0.2
      microm positively charged nylon 66 filter and the 0.2 microm nylon 66 filter, but
      not the PES filter (1.2 and 0.2 microm), decreased the concentrations of
      amphotericin B in the filtered fluid by 100% within 1 h and by 66% within 24 h
      after the start of filtration, respectively. The particulate count in the non
      filtered amphotericin B fluid was 27+/-5 particles/ml, exceeding the limit
      defined by USP XXIII. The 1.2 microm and 0.2 microm PES filters significantly
      decreased particulate matter by 83 and 97%, respectively, just after filtration.
      CONCLUSION: The present results indicate that the 0.2 microm PES filter is
      optimal for intravenous infusion of amphotericin B fluid to minimize the
      introduction of particulate matter, microbial contaminants and endotoxin into
      patients.

PMID- 10583704
TI  - The effects of light to moderate drinking on cardiovascular diseases.

PMID- 10583705
TI  - Postprandial lipoprotein metabolism and atherosclerosis.
AB  - Postprandial lipids and lipoproteins have been associated with the presence of
      cardiovascular disease in a large number of case-control studies. Because the
      metabolic perturbations around the postprandial situation is a key driving force
      for cholesterol flux between lipoproteins and tissues, together with the
      augmented generation of potentially atherogenic cholesterol-rich remnant
      lipoproteins, several hypotheses have been formulated to link excessive
      lipoproteinaemic response to fat intake with cardiovascular disease. Recent
      information on the regulation of lipoprotein remnant formation and its relation
      to atherosclerosis will enable us to test a pertinent clinical question: is there
      a direct relationship between repeated elevations of postprandial lipoproteins
      and development of atherosclerosis?

PMID- 10583706
TI  - The effect of various hormonal preparations and calcium supplementation on bone
      mass in early menopause. Is there a predictive value for the initial bone density
      and body weight?
AB  - OBJECTIVES: To compare the effect of various oestrogen and oestrogen/progestin
      preparations on bone density over a 2-year follow-up period in early
      postmenopausal women. SETTING: A retrospective study on 315 women followed in a
      menopause clinic. DESIGN: Antero-posterior lumbar spine bone densitometry was
      performed at baseline and between 18 and 24 months (mean 22 months) after
      initiation of hormone therapy. Participants were divided into six groups: women
      taking conjugated equine oestrogen (CEE) (n = 30); CEE plus sequential monthly
      medroxyprogesterone acetate (MPA) (n = 52); CEE plus sequential bimonthly MPA (n
      = 51); oral estradiol plus sequential monthly norethisterone acetate (n = 52);
      transdermal estradiol plus sequential monthly MPA (n = 30). A control group (n =
      100) was composed of nonusers of hormones. RESULTS: Hormone users, as a whole (n
      = 215), increased their bone mineral density (BMD) by 2.9% (4.8) as compared to
      the controls who lost 3.5% (3.4; P < 0. 001). There were similar gains in BMD
      amongst the five study groups. Calcium supplementation was associated with better
      results in all women: users of hormones and calcium had a gain in BMD of 4.5%
      (4.8) compared to only 1.5% (4.5) in those on hormones but without calcium (P <
      0.001); amongst the controls, women using calcium lost 1.4% (2. 4), whilst
      nonusers of calcium lost 3.7% (2.4; P < 0.001). A dose-response curve was found
      between basal BMD and the effect of hormone therapy: women with osteoporosis (T
      score <75%) demonstrated the largest increase in BMD - 6.3% (4.6), osteopenia (T
      score 75-85%) was associated with a gain of 3.2% (5.6), low-borderline values (T
      score 86-100%) gave a modest increase of 1.3% (4.3), and those with more than
      average BMD values (T-score >100%) actually lost bone despite hormone treatment [
      2.1% (4.1)]. CONCLUSIONS: All hormone regimens had a similar bone conserving
      effect. Basal BMD value may serve as a predictor for the success of treatment.
      Calcium supplementation should be recommended in all postmenopausal women.

PMID- 10583707
TI  - Ventricular arrhythmias during 24-h ambulatory ECG recording: incidence, risk
      factors and prognosis in men with and without a history of cardiovascular
      disease.
AB  - OBJECTIVE: To study incidence, prognosis and risk factors of ventricular
      arrhythmias in men with and without asymptomatic non-invasively detected
      cardiovascular disease (CVD). DESIGN: Prospective cohort study with 11 years'
      follow-up. The subjects went through 24-h ambulatory electrocardiographic (ECG)
      registrations and non-invasive examinations of leg and carotid arteries at the
      baseline examination. SETTING: Malmo, Sweden. SUBJECTS: Four hundred and forty
      three randomly selected 68-year-old men. MAIN OUTCOME MEASURES: Mortality and
      cardiac event rates during an 11-year period. RESULTS: Frequent or complex
      arrhythmias (Lown class 2-5) were common in men both with and without CVD.
      However, the associated prognoses were different. In men with CVD, frequent or
      complex arrhythmias were associated with increased cardiac event rates (P =
      0.001) and increased mortality (P = 0.054). This pattern was also found in men
      with asymptomatic leg and carotid artery disease, although the frequency of
      arrhythmia in Lown class 2-5 was similar to that in men without CVD. Men with
      angina pectoris or previous myocardial infarction in combination with leg or
      carotid artery disease had the most arrhythmias and the worst prognosis. No
      relationship between frequent or complex arrhythmias and mortality or cardiac
      events was found in men without CVD. In a logistic regression, smoking and
      diabetes mellitus were significant and independent determinants of frequent or
      complex arrhythmias in men with CVD. High alcohol consumption was associated with
      arrhythmias in men without CVD. CONCLUSION: Ambulatory ECG recording is a
      feasible method to improve risk assessment in men with CVD. In this group,
      frequent or complex arrhythmias are associated with smoking and diabetes
      mellitus.

PMID- 10583708
TI  - Can one really measure magnesium deficiency using the short-term magnesium
      loading test?
AB  - OBJECTIVE: To compare a 1-h-version of a magnesium-loading-test (MLT) designed
      for outpatients in healthy controls with the 8-h standard; to establish the test
      in patients after renal transplantation prone to develop magnesium (Mg)
      deficiency; to correlate femur Mg-concentration and percentage retention of the
      given load. DESIGN: Comparison of mean values from healthy controls with
      respective from the literature; a prospective, randomized, controlled 4-month
      study; an intra-individual correlation of Mg-serum values and loading-test data
      with femur-Mg concentrations. SETTING: One centre study in a medical university;
      outpatients from the transplant unit; inpatients from the orthopedic unit.
      SUBJECTS: Twenty-four healthy controls aged 36.7 +/- 7.4 years; 34 patients after
      renal transplantation (46.5 +/- 14.3 years); 41 patients with hip replacement
      therapy (63.9 +/- 18.6 years). INTERVENTION: Baseline Mg values were measured by
      atomic absorption spectroscopy (AAS) in serum and urine. An intravenous Mg load
      with 0.1 mmol Mg-aspartate hydrochloride per kilogram bodyweight was given during
      1 h. In 24 h-urine, the amount of excreted Mg was measured by AAS and the
      percentage retention of the given load calculated according to the formula: 1 -
      [Mg 24 h-urine/Mg test dose] x 100. Femur Mg was measured by AAS in a peace of
      the femur neck. Patients after renal transplantation were randomized after the
      first Mg load to either obtain daily 5 mmol Mg-aspartate hydrochloride per
      kilogram bodyweight, or placebo. Four months later a second loading-procedure was
      performed. MAIN OUTCOME MEASURE: Serum Mg, percentage retention of the given Mg
      load (%Ret) and femur Mg concentration. RESULTS: Mean serum Mg values were within
      the normal range. In controls, %Ret was -18 +/- 21 and not different from the
      literature. In the first MLT after renal transplantation, %Ret was 47 +/- 43. In
      patients under Mg medication it decreased significantly to 16 +/- 26, but was 58
      +/- 27 in the placebo group. Femur Mg concentration was 62.6 +/- 20.9 mmol kg-1
      dry substance and the corresponding %Ret was 14 +/- 28 with r = - 0.7093.
      CONCLUSION: The short-term version of the MLT is as good as the standard and was
      easily applied in outpatients. The indication from the good correlation between
      bone-Mg and %Ret and a marked decrease in %Ret in patients after Mg medication
      was that one can really measure magnesium deficiency.

PMID- 10583709
TI  - The cost of inappropriate admissions: a study of health benefits and resource
      utilization in a department of internal medicine.
AB  - OBJECTIVES: High rates of inappropriate hospital admissions have been found in
      numerous studies, suggesting that a high percentage of hospital resources are, in
      effect, wasted. The degree to which this is true depends on how costly
      inappropriate admissions are compared to other admissions. This study aimed to
      estimate both the percentage and cost of inappropriate admissions. SETTING:
      Department of internal medicine at a teaching hospital. SUBJECTS: Consecutively
      admitted patients during a six-week study period. MAIN OUTCOME MEASURES:
      Assessments of inappropriateness were based on estimates of health benefit and
      necessary care level. These estimates were made by expert panels using a
      structured consensus method. Health benefit was estimated as gain in quality
      adjusted life years, or degree of short-term improvement in quality of life
      during or shortly after the hospital stay. The direct costs to the hospital of
      each stay were estimated by allocating the costs of labour, 'hotel' and overhead
      according to length of stay and adding to this the cost of ancillary resources
      used by each individual patient. RESULTS: A total of 422 admissions were
      included. The 102 (24%) judged to be inappropriate had a lower mean cost (US$
      2532) than the other 320 (US$ 5800) (difference 3268; 95% confidence interval
      1025-5511). The inappropriate admissions accounted for 12% of the total costs.
      CONCLUSIONS: Denying care for inappropriate admissions does not generate cost
      reductions of the same magnitude. Policy makers should be cautious in projecting
      the cost savings potential of excluding inappropriate admissions.

PMID- 10583710
TI  - Antibodies to platelet-activating factor are associated with borderline
      hypertension, early atherosclerosis and the metabolic syndrome.
AB  - OBJECTIVE: Platelet-activating factor (PAF) is a phospholipid inflammatory
      mediator which is synthesized by a variety of cells, including monocytes and
      endothelial cells, and PAF can be retained in activated endothelial cell
      membranes. Furthermore, PAF-like lipids are produced in other phospholipid
      membranes as in oxidized LDL. Atherosclerosis is a chronic inflammation in the
      artery wall, but little is known about the role of immune reactions in the early
      stages of development of cardiovascular disease. In the present study we
      investigated if there are antibodies to PAF (aPAF) that may play a role in
      borderline hypertension and early atherosclerosis. DESIGN: Seventy-three men with
      borderline hypertension (BHT) and 73 age-matched normotensive (NT) men (diastolic
      blood pressure 85-94 and <80 mmHg, respectively) were recruited from a population
      screening programme. Antibody levels were determined by use of ELISA. Carotid
      intima-media (IM)-thickness and atherosclerosis was determined by B-mode
      ultrasonography. RESULTS: BHT men had 49.3% higher aPAF levels of IgG class than
      NT controls (P = 0.0007). Antibodies to the biologically inactive lysoPAF did not
      differ between BHT and NT group. aPAF levels were associated with IM-thickness in
      the left (P = 0.02) and right (P = 0.009) carotid artery. Furthermore, aPAF
      levels were enhanced in individuals with the metabolic syndrome (n = 44) as
      compared to those without (n = 102; P = 0.009), and also significantly associated
      with insulin levels (P = 0.02) and insulin resistance (P = 0.02). CONCLUSIONS:
      aPAF antibodies may reflect early vascular changes and thus serve as novel
      markers for disease, and they may also be pathogenic, by eliciting an
      inflammatory reaction in the vascular wall.

PMID- 10583711
TI  - Deoxycholic acid treatment in patients with cholesterol gallstones: failure to
      detect a suppression of cholesterol 7alpha-hydroxylase activity.
AB  - Hillebrant C-G, Nyberg B, Angelin B, Axelson M, Bjorkhem I, Rudling M, Einarsson
      C (Huddinge University Hospital and Karolinska Hospital, Karolinska Institute,
      Stockholm, Sweden). Deoxycholic acid treatment in patients with cholesterol
      gallstones: failure to detect a suppression of cholesterol 7alpha-hydroxylase
      activity. J Intern Med 1999; 246: 399-407. OBJECTIVES: Based on animal studies,
      hydrophobic bile acids have been postulated to be particularly strong inhibitors
      of bile acid synthesis. The present study was undertaken to characterize in
      humans the effects of one of the most hydrophobic of the common bile acids,
      deoxycholic acid (DCA), on the transcriptional regulation and activity of the
      cholesterol 7alpha-hydroxylase, on hepatic cholesterol metabolism and on biliary
      lipid metabolism and plasma lipids. DESIGN, SUBJECTS AND SETTINGS: Thirteen
      patients with cholesterol gallstone disease were treated with DCA (750 mg day-1)
      for 3 weeks prior to cholecystectomy. Blood samples were collected before and
      during treatment. At operation, a liver biopsy and gallbladder bile were
      obtained. Twenty-eight untreated gallstone patients undergoing cholecystectomy
      served as controls. The study was carried out at a university hospital. RESULTS:
      Deoxycholic acid comprised 72 +/- 6% (mean +/- SEM) of total biliary bile acids
      in DCA-treated patients (n = 8), and 21 +/- 2% in the controls (n = 16; P <
      0.001). Cholesterol saturation of gallbladder bile averaged 102% in both treated
      (n = 7) and untreated (n = 16) patients. Cholesterol 7alpha-hydroxylase and HMG
      CoA reductase activities and mRNA levels were not different between DCA-treated
      and untreated gallstone patients. The LDL receptor mRNA levels were similar in
      both groups of patients. Plasma levels of total cholesterol were lowered by 10%
      upon DCA treatment (P < 0.05). CONCLUSIONS: Treatment with DCA did not
      significantly affect mRNA levels and activity of hepatic cholesterol 7alpha
      hydroxylase or HMG CoA reductase in patients with cholesterol gallstones. There
      was no effect on the saturation of gallbladder bile, Thus, the present study
      could not verify that the hydrophobicity of the bile acid pool is a major factor
      regulating human hepatic cholesterol 7alpha-hydroxylase activity.

PMID- 10583712
TI  - Leptin is associated with increased risk of myocardial infarction.
AB  - OBJECTIVES AND DESIGN: Leptin is involved in the regulation of bodyweight and
      metabolism in man and might also be involved in the pathophysiology of the
      insulin resistance syndrome, which is associated with the development of
      cardiovascular diseases. We tested whether leptin is a risk factor for acute
      myocardial infarction (AMI) in a nested case-referent study. SUBJECTS AND
      METHODS: Sixty-two men with first-ever AMI were identified who, prior to AMI, had
      participated in population-based health surveys in Northern Sweden. Referents
      were matched for sex, age, date and type of health survey, and geographical
      region. Blood pressure, body mass index (BMI) and the presence of smoking,
      diabetes and hypertension were recorded. Total cholesterol, apolipoprotein A-1
      (apo A-1), apolipoprotein B (apo B), plasminogen activator inhibitor (PAI-1),
      insulin, and leptin were analysed in stored samples. Their influences on first
      ever AMI were analysed by conditional logistic regression analysis. RESULTS: Men
      with first-ever AMI had higher BMI, plasma insulin and leptin, and diastolic
      blood pressure than the referents. Furthermore, they had lower plasma apo A-1 and
      were more often smokers. Smoking, high leptin, PAI-1 and cholesterol, and low apo
      A-1 levels were significant risk factors for first-ever AMI in univariate
      analysis. High leptin (OR 8.97; 95% CI: 1.73-46.5) and cholesterol (OR 5.18; 95%
      CI: 1.34-20.0) levels remained significant risk factors for AMI in a multivariate
      model. High apo A-1 was protective (OR = 0.13; 95% CI: 0.03-0.55). The
      combination of high leptin and low apo A-1 was associated with a particularly
      pronounced increased risk for AMI. CONCLUSION: Plasma leptin strongly predicts
      first-ever AMI. Our data support the hypothesis that leptin is an important link
      in the development of cardiovascular disease in obesity.

PMID- 10583713
TI  - Increased glucose intolerance related to digoxin treatment in patients with type
      2 diabetes mellitus.

PMID- 10583714
TI  - Total homocysteine and cardiovascular disease.
AB  - Recent data have shown that an elevated plasma level of the amino acid
      homocysteine (Hcy) is a common, independent, easily modifiable and possibly
      causal risk factor for cardiovascular disease (CVD) which may be of equal
      importance to hypercholesterolemia, hypertension and smoking. This paper reviews
      the biochemical, clinical, epidemiological and experimental data underlying this
      conclusion and is critically questioning whether elevated tHcy is a causal
      factor.

PMID- 10583715
TI  - Chronic fatigue syndrome: new insights and old ignorance.
AB  - Chronic fatigue syndrome (CFS) is a condition characterized by impairment of
      neurocognitive functions and quality of sleep and of somatic symptoms such as
      recurrent sore throat, muscle aches, arthralgias, headache, and postexertional
      malaise. A majority of patients describe an infectious onset but the link between
      infections and CFS remains uncertain. Findings show an activation of the immune
      system, abberations in several hypothalamic-pituitary axes and involvement of
      other parts of the central nervous system. The origin is bound to be complex and
      it may well be that the solution will come together with a more generally altered
      view about mind-body dualism, and the concept of illness and disease.

PMID- 10583716
TI  - Plasma thrombopoietin levels in liver cirrhosis and kidney failure.
AB  - BACKGROUND: Recently, c-Mpl ligand (thrombopoietin, TPO) has been cloned by
      several groups and found to be a primary regulator of thrombopoiesis. Its mRNA
      expression has been detected in several organs including kidneys, bone marrow
      stroma cells, muscles, and is very strongly expressed in the liver. OBJECTIVE: To
      clarify thrombopoiesis and the regulation of TPO in severe liver and renal
      failure. DESIGN: We analysed plasma TPO levels in patients with biopsy verified
      liver cirrhosis (n = 18; mean platelet count 115 +/- 54 x 109 L-1), in patients
      on chronic haemodialysis as a result of end-stage renal failure (n = 20; mean
      platelet count 295 +/- 94 x 109 L-1), and in healthy individuals (n = 20; mean
      platelet count 250 +/- 40 x 109 L-1). Plasma was prepared from EDTA
      anticoagulated whole blood and a commercially available ELISA kit was used for
      the analysis. RESULTS: The mean plasma TPO concentration amongst the normal
      individuals was 50 +/- 14 pg mL-1. In the patients with liver cirrhosis and in
      patients on haemodialysis the mean TPO levels were 62 +/- 19 pg mL-1 and 46 +/-
      17 pg mL-1, respectively. The mean plasma TPO concentration for the cirrhotic
      patients was significantly higher than the mean recorded for the healthy
      volunteers (P = 0.031), whereas no statistically significant differences in
      plasma TPO were seen between the group of end-stage renal failure and normals.
      CONCLUSION: Our results suggest that TPO production is maintained in liver
      cirrhosis and in renal failure, and that the thrombocytopenia in liver cirrhosis
      is not due to an impaired TPO production.

PMID- 10583717
TI  - Reduced transcapillary fluid absorption from skeletal muscle and skin during
      hypovolaemia in insulin-dependent diabetes mellitus.
AB  - OBJECTIVES: Diabetes mellitus is associated with a high cardiovascular morbidity
      which has been linked to disturbances in microvascular function. This study was
      designed to examine the transcapillary fluid absorption during experimental
      hypovolaemia in type 1 diabetes. SUBJECTS: Twelve males with type 1 diabetes (age
      25 +/- 3 years, duration 8 +/- 1 years) with no clinical microangiopathy and 12
      healthy males (22 +/- 2 years). INTERVENTIONS: As a model for hypovolaemic
      circulatory stress, lower body negative pressure (LBNP: 15, 30 and 60 cmH2O) was
      used. Transcapillary fluid absorption from tissue to blood in the upper arm, as
      well as forearm blood flow, was measured by volumetric technique. RESULTS:
      Resting forearm blood flow, heart rate and blood pressure were similar in
      diabetic patients and controls. Basal plasma noradrenaline was reduced in the
      diabetics compared with controls (0.75 +/- 0.06 vs. 1.09 +/- 0.10 pmol L-1, P <
      0.05), but the increase in plasma noradrenaline in response to LBNP was similar
      in the two groups. The haemodynamic responses to LBNP in the two groups were
      equal, showing a reduction of pulse pressure, an increase in heart rate and in
      peripheral resistance with a concomitant blood flow reduction. The transcapillary
      fluid absorption (mL 100 mL-1 min-1) was significantly reduced in the diabetic
      patients: LBNP 15 cmH2O, 0.024 +/- 0.004 vs. 0.036 +/- 0. 002; 30 cmH2O, 0.041 +/
      0.003 vs. 0.056 +/- 0.005; and 60 cmH2O, 0. 057 +/- 0.007 vs. 0.091 +/- 0.008
      (diabetic patients vs. controls, P < 0.001). CONCLUSIONS: The transcapillary
      fluid absorption from tissue to blood during hypovolaemic circulatory stress in
      type 1 diabetic patients is reduced by one-third compared with controls, which
      indicates impaired plasma volume regulation. This basic mechanism for plasma
      volume control is affected before clinical microcirculatory complications are
      found and could be one of the causes of the increased cardiovascular morbidity
      and mortality in IDDM.

PMID- 10583718
TI  - Insulin sensitivity and haemostatic factors in men at high and low cardiovascular
      risk. The Risk Factor Intervention Study Group.
AB  - OBJECTIVE: To investigate the relationship between variables of the coagulation
      and fibrinolysis system and insulin sensitivity in non-diabetic men at high and
      low risk of cardiovascular disease. DESIGN: Cross-sectional study. SETTING:
      Outpatient clinic in city hospital. PATIENTS: Thirty-five men at high risk for
      atherosclerotic disease (hypertension and at least one the following factors:
      hypercholesterolaemia and smoking) and an age-matched low-risk group (n = 23)
      with no cardiovascular risk factors. MAIN OUTCOME MEASURES: Insulin-mediated
      glucose disposal (hyperinsulinaemic euglycaemic clamp) adjusted for lean body
      mass and fibrinogen, von Willebrand factor, prothrombin fragment 1 + 2,
      thrombin/antithrombin complex and plasminogen activator inhibitor activity were
      determined. RESULTS: Insulin-mediated glucose disposal adjusted for lean body
      mass was significantly lower in the high-risk group than in the low-risk group.
      Glucose disposal was significantly negatively associated with plasminogen
      activator inhibitor activity (PAI) in the high-risk group and with von Willebrand
      factor in the low-risk group. In the whole study group, fibrinogen and PAI were
      significantly associated with glucose disposal. After adjusting for confounding
      factors, glucose disposal was independently negatively associated with PAI in the
      high-risk group (P < 0.001) and in the whole group (P < 0.001). CONCLUSIONS: High
      risk men were significantly more insulin-resistant than the low-risk group.
      Glucose disposal adjusted for lean body mass was associated with an impaired
      fibrinolytic activity in the high-risk group. Fibrinogen was associated with
      insulin resistance in the whole study group. The negative relationship between
      von Willebrand factor levels and glucose disposal in the low-risk group may
      indicate that insulin resistance can induce an endothelial dysfunction even in
      non-diabetic subjects.

PMID- 10583719
TI  - Quality of self-care in patients on replacement therapy with hydrocortisone.
AB  - OBJECTIVES: To assess the quality of self-care in patients receiving replacement
      therapy with hydrocortisone for primary or secondary adrenal insufficiency.
      DESIGN: A questionnaire-based survey. SETTING: The outpatient Clinic of
      Endocrinology at the University Hospital in Herlev, Denmark. SUBJECTS: Ninety
      seven patients identified from the case reports of the clinic. All patients had
      received repeated oral information about hydrocortisone treatment and dose
      adjustments. Eighty-four (87%) patients completed the questionnaire. MAIN OUTCOME
      MEASURES: Ability to act appropriately in case of physical stress, possession of
      a 'Steroid warning card', number and nature of episodes of physical stress during
      the past year and self-experienced level of information was recorded. RESULTS:
      Thirty-nine (46%) of the patients were not sufficiently skilled in coping with
      physical stress. This was more prominent in the elderly patients. Seventeen (20%)
      did not possess a 'steroid warning card'. Thirty-seven (44%) had experienced at
      least one febrile episode and 24 (29%) had been admitted to hospital during the
      past year. Fifty (60%) felt themselves to be well informed, but this did not
      correlate with the ability to act appropriately. CONCLUSIONS: The study shows the
      need for continuous education of patients with adrenal insufficiency. Oral
      instructions should be supplemented with written information or a more detailed
      and structured education.

PMID- 10583720
TI  - Do ACE-inhibitors suppress tumour necrosis factor-alpha production in advanced
      chronic renal failure?
AB  - OBJECTIVES: The serum levels of the catabolic cytokine TNF-alpha are often raised
      in malnourished chronic heart failure patients as well as in chronic renal
      failure (CRF) patients. Angiotensin-converting enzyme (ACE) inhibitors are often
      used in these patients and may decrease TNF-alpha and IL-1beta levels in vitro
      and in vivo. The aim of this study was to find out whether CRF patients with
      ongoing ACE-inhibitor treatment have lower TNF-alpha levels. DESIGN: Cross
      sectional study. SETTING: Tertiary Referral Center and University Hospital.
      SUBJECTS: Ninety-six predialysis patients (mean age 52 +/- 1 years) with advanced
      CRF (glomerular filtration rate 7 +/- 1 mL min-1). MAIN OUTCOME MEASURES: Plasma
      levels of TNF-alpha, subjective global assessment of nutritional status and data
      on ongoing antihypertensive treatment (ACE-inhibitors, beta blockers, calcium
      channel blockers and angiotensin II (AII) receptor blockers). RESULTS: Patients
      treated with ACE-inhibitors (n = 44) had significantly lower plasma TNF-alpha
      levels (18.5 +/- 1.2 vs. 26.6 +/- 2.2 pg mL-1; P < 0.01) and were less frequently
      malnourished, relative to 52 patients not treated with ACE-inhibitors. No
      significant difference in TNF-alpha levels were observed when comparing patients
      with or without treatment with beta, calcium channel, or AII receptor blockers,
      respectively. CONCLUSIONS: The present data suggest that the use of ACE
      inhibitors is associated with lower plasma TNF-alpha and CRP levels as well as a
      lower prevalence of malnutrition in patients with advanced CRF. Further studies
      are needed to establish if there is a casual relationship between these findings
      and, if so, the molecular mechanism(s).

PMID- 10583721
TI  - A case of neurofibromatosis type 1 with an aldosterone-producing adenoma of the
      adrenal.
AB  - Neurofibromatosis type 1 is a phacomatosis. Neurofibromas are the most common
      tumours associated with the disease, and along with other tumours, make
      neurofibromatosis type 1 the most common tumour predisposing syndrome in humans.
      Hypertension may be coincidental, but at least two specific neurofibromatosis
      related causes must be considered, namely neurofibromatous involvement of the
      renal artery and pheochromocytoma. We have described the first known case of a
      patient with neurofibromatosis type 1 who developed hypertension due to an
      aldosterone-producing adenoma of the adrenal. The question of whether this
      association was coincidental or due to the tumour predisposition of
      neurofibromatosis type 1 was debated.

PMID- 10583722
TI  - Recurrent malignant hypertension: a report of two cases and review of the
      literature.
AB  - Malignant hypertension (MHT) is a rare and life-threatening condition which is
      defined clinically as severe hypertension accompanied by bilateral retinal
      haemorrhages and/or hard exudates, with or without papilloedema. If untreated,
      the prognosis of MHT is poor. With MHT being a relatively rare condition, it
      would be unusual to see it on more than one occasion in the same patient. We
      describe in detail two cases from a disease register of 400 cases of MHT seen in
      one medical centre over 33 years.

PMID- 10583723
TI  - Essential thrombocythemia in young adults: treatment and outcome of 16
      pregnancies.

PMID- 10583724
TI  - Sex- and age-specific differences in human brain CYP11A1 mRNA expression.
AB  - While the presence of CYP11A1 (P450SCC, cholesterol side-chain cleavage enzyme)
      has been well established in the brain of rodents, limited information is
      available on CYP11A1 expression in human brain. In both species, little is known
      regarding postnatal changes or sex specific differences in cerebral CYP11A1
      expression. In the present study, we used a sensitive competitive reverse
      transcriptase polymerase chain reaction (RT-PCR) assay to quantify the amount of
      CYP11A1 mRNA in a large number of human brain tissue specimens obtained at
      neurosurgery. CYP11A1 mRNA is expressed approximately 200 times lower in the
      temporal lobe, frontal lobe and hippocampus than in adrenal tissue, known for
      high CYP11A1 mRNA expression. During childhood CYP11A1 mRNA concentrations in the
      temporal lobe increase markedly and reach adult levels at puberty. CYP11A1 mRNA
      is significantly higher in the temporal and frontal lobe cortex of women than in
      that of men. Our data demonstrate for the first time an age and sex dependent
      expression of CYP11A1 mRNA in the human brain.

PMID- 10583725
TI  - Stimulatory role of prolactin on the development of tuberoinfundibular
      dopaminergic neurones in prepubertal female rats: studies with cysteamine and
      somatostatin.
AB  - Cysteamine, a potent depletor of prolactin and somatostatin, was used to
      determine the role of prolactin and somatostatin in the control of central
      dopamine neurones in prepubertal rats. Cysteamine (100 mg/kg, i.p., twice daily)
      was injected for 7, 14 or 21 days in 28-day-old Sprague-Dawley female rats in one
      study and for 3 days in 35-day-old rats in another. In control rats, the 3, 4
      dihydroxyphenylacetic acid (DOPAC) levels in the median eminence increased
      threefold from day 35 to day 49, and serum prolactin concentration increased
      about 50%. Cysteamine lowered serum prolactin concentrations to 20%, and median
      eminence DOPAC and dopamine levels to 32-50% of control levels in both studies.
      The DOPAC levels in the nucleus accumbens and striatum were also lowered, while
      both DOPAC and dopamine in the paraventricular nucleus and periventricular
      nucleus (A14) were increased by cysteamine. A single injection of rat prolactin
      (0.01, 0.1 or 1 mg/kg) significantly increased DOPAC or DOPA levels in the median
      eminence, nucleus accumbens and striatum, but not in the paraventricular nucleus
      or A14 at 14 h later in 28-day old female rats or in 40-day-old rats pretreated
      with cysteamine. In contrast, central injection of somatostatin dose (0.001-1
      microg/rat) and time (30-90 min) dependently decreased the DOPAC levels in the
      median eminence, paraventricular nucleus and A14 and increased those in the
      nucleus accumbens and striatum of adult female rats. These results indicate that
      serum prolactin is important for the maturation and maintenance of dopamine
      systems in the median eminence, nucleus accumbens and striatum, while
      somatostatin exhibits inhibitory and stimulatory effects on hypothalamic and
      midbrain dopamine systems, respectively.

PMID- 10583726
TI  - GHRP-6-induced changes in electrical activity of single cells in the arcuate,
      ventromedial and periventricular nucleus neurones [correction of nuclei] of a
      hypothalamic slice preparation in vitro.
AB  - Previously, we demonstrated that systemic injection of the growth hormone
      secretagogue, growth hormone-releasing peptide (GHRP)-6, selectively activated
      cells in the hypothalamic arcuate nucleus, as reflected by increased electrical
      activity and induction of the immediate early gene c-fos. The growth hormone
      secretagogue receptor distribution is not confined to the arcuate nucleus,
      suggesting that additional sites of action may exist. In the present study we
      characterized the electrophysiological responses of cells in the arcuate nucleus,
      ventromedial nucleus and periventricular nucleus in an in-vitro hypothalamic
      slice preparation, following bath application of GHRP-6. Additionally, since
      central somatostatin administration has been shown to attenuate the induction of
      the c-fos gene by GHRP-6, we sought to determine whether the arcuate cells
      activated by GHRP-6 are also somatostatin-sensitive. Male Wistar rats (100-150 g
      body weight (BW)) were anaesthetized (urethane; 1.2 g/kg BW) and the brains
      removed. Coronal sections (400 microm thickness) were cut through a block of
      hypothalamus and were transferred to a slice chamber perfused with artificial
      cerebrospinal fluid. Forty-one arcuate nucleus cells were tested with bath
      application of 15 microm GHRP-6 for 10 min, 16 of which were tested subsequently
      (>30 min later) with application of 10 microM somatostatin. Following GHRP-6
      administration, 19 cells (46. 3%) showed a significant increase in firing rate
      during the 15-min period after GHRP-6 application (P<0.001), 17 cells (41.5%) did
      not respond and the remaining five cells (12.2%) were significantly inhibited.
      Six of the eight arcuate nucleus cells that were excited by GHRP-6 were
      significantly inhibited by somatostatin. By contrast, five of the six arcuate
      nucleus cells that were unresponsive to GHRP-6 were also unresponsive to
      somatostatin. In the ventromedial nucleus, of 19 cells tested, eight cells
      (42.1%) were excited by GHRP-6, eight cells (42.1%) were unresponsive and the
      remaining three cells (15.8%) were significantly inhibited. Of 19 cells recorded
      in the periventricular nucleus, 13 (68.4%) were unresponsive to GHRP-6 and six
      (31.6%) were significantly inhibited. Thus, electrophysiological studies in vitro
      suggest that: (1) neurones in the hypothalamic arcuate nucleus, ventromedial
      nucleus and periventricular nucleus show changes in electrical activity in
      response to GHRP-6; and (2) the arcuate nucleus cells excited by GHRP-6 are also
      subject to inhibitory control by somatostatin.

PMID- 10583727
TI  - The influence of postnatal handling on adult neuroendocrine and behavioural
      stress reactivity.
AB  - Environmental stimuli during early stages of life can influence the development
      of an organism and may result in permanent changes in adult behaviour and
      physiology. In the present study we investigated the influence of early postnatal
      handling on adult neuroendocrine and behavioural stress reactivity in Wistar
      rats. Pups were subjected to handling from postnatal day 1-21. The young were
      taken from the nest every day for 15 min and each of the pups was handled
      separately. Control nests were left undisturbed. When the animals had reached an
      adult age of 3-4 months they were individually housed and subjected to a series
      of tests to measure their stress reactivity. In the first experiment we
      established adult behavioural coping with stressors and anxiety in the following
      series of tests: open field test, shock prod defensive burying test, elevated
      plus maze and conditioned fear test. Collectively, the data clearly indicate that
      handled animals are characterized by a lower stress-induced anxiety. Yet, handled
      and control animals do not differ in their general way of coping with stressors.
      Although the lower anxiety in handled animals is often reflected in a higher
      activity, they are not more active per se. In a second experiment, animals were
      provided with a permanent jugular vein canula for repeated blood sampling to
      determine stress hormones: noradrenaline, adrenaline, prolactin and
      corticosterone. Animals were subjected to a novelty test and a conditioned fear
      test. The neuroendocrine response profile is consistent with the conclusion that
      handled animals are less anxious than controls but are not different in their
      general strategy of coping with stressors. The handled animals showed an
      attenuated adrenaline, prolactin and corticosterone response. Yet, in neither of
      the two tests there was a difference in noradrenaline response, a typical marker
      for an active coping strategy. Interestingly, the differences in neuroendocrine
      reactivity already appeared in response to a mild novelty challenge when there
      were no clear behavioural differences yet. The neuroendocrine measures are in
      line with the behavioural data but more sensitively reflect the differences
      between handled and control animals.

PMID- 10583728
TI  - Transgenic expression of green fluorescent protein in mouse oxytocin neurones.
AB  - Routine targeting of neurones for expression of exogenous genes would facilitate
      our ability to manipulate their internal milieu or functions, providing insight
      into physiology of neurones. The magnocellular neurones of the paraventricular
      and supraoptic nuclei of the hypothalamus have been the objects of limited
      success by this approach. Here we report on the placement of the enhanced green
      fluorescent protein (eGFP) coding sequence at various locations within an
      oxytocin transgene. Placement within the first exon yielded little to no
      expression, whereas placement in the third exon (as an in-frame fusion with the
      carboxyl terminus of the oxytocin preprohormone) resulted in cell-specific
      expression of eGFP in oxytocin neurones. Furthermore, placement of the eGFP
      sequence downstream of a picornavirus internal ribosomal entry site (IRES), also
      in the third exon, allowed expression of the eGFP as a separate protein. Other
      coding sequences should now be amenable to expression within oxytocin neurones to
      study their physiology.

PMID- 10583729
TI  - N-terminal splice variants of the type I PACAP receptor: isolation,
      characterization and ligand binding/selectivity determinants.
AB  - Three full-length cDNAs encoding functional splice variants of the pituitary
      adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1) were
      isolated from Y-79 retinoblastoma cells and human cerebellum. Although the third
      intracellular loops of the three splice variants were identical, their N-terminal
      extracellular domains differed. The first full-length PAC1 variant, PAC1normal
      (PAC1n), encoded the entire N-terminus, whereas the second variant named
      PAC1short (PAC1s) was deleted by 21 amino acids (residues 89-109). Finally, the
      third variant, named PAC1very short (PAC1vs), was deleted by 57 amino acids
      (residues 53-109). Using semiquantitative reverse transcriptase polymerase chain
      reaction (RT-PCR) analysis, it was established that all three variants were
      expressed in neuronal tissues. Binding- and cAMP studies using human embryonic
      kidney 293 (HEK293) cells stably transfected with PAC1n, PAC1s and PAC1vs showed
      significant differences in the affinities and selectivities towards PACAP38,
      PACAP27 and VIP. PAC1n bound PACAP38 and PACAP27 with affinities in the low
      nanomolar range whereas VIP was bound with up to 400-fold lower affinity. PAC1vs
      preferentially bound PACAP38 (Ki=121 nM) and PACAP27 (Ki=129 nM) over VIP
      (Ki>1000 nM) but with 100-fold lower affinity than PAC1n. Surprisingly, PAC1s
      unselectively bound all three ligands with high affinity. These data indicate
      that residues 53-88 within the N-terminal domain of the PAC1 are important for
      high affinity ligand binding, whereas residues 89-109 determine the receptor's
      ligand selectivity.

PMID- 10583730
TI  - Perinatal developmental changes in expression of the neuropeptide genes preoptic
      regulatory factor-1 and factor-2, neuropeptide Y and GnRH in rat hypothalamus.
AB  - The preoptic regulatory factor genes, PORF-1 and PORF-2, are expressed in the rat
      brain in a regional-, age- and gender-dependent fashion. They are also expressed
      in the testis, where PORF-2 mRNA localizes to dividing germ cells while PORF-1
      mRNA is associated with newly differentiated sperm. This suggests that PORF-1 and
      PORF-2 may play distinct roles in cell growth and differentiation. Moreover, the
      two preoptic regulatory factors are also highly expressed in the immature and
      mature rat hypothalamus, and their expression is modulated by gonadal hormones.
      Therefore, in the present study we investigated the expression of these two
      factors in neuroendocrine regions of the developing rat brain by addressing the
      following questions. First, are PORF-1 and PORF-2 mRNAs expressed during
      perinatal development in the preoptic area-anterior hypothalamus (POA-AH) and
      medial basal hypothalamus (MBH), and how do their levels vary? Second, are there
      gender differences in their expression? We also compared expression of the PORF
      mRNAs with those of neuropeptide Y (NPY) and gonadotropin-releasing hormone
      (GnRH), which play critical neuroendocrine roles, in these brain regions. PORF-1,
      PORF-2, and NPY mRNAs in the POA-AH and MBH, and GnRH mRNA in the POA-AH, were
      quantified by RNase protection assay at embryonic day (E) 18-19, and postnatal
      days (P) 0, 5, 10 and 15 in male and female rats. The results show that the four
      neuropeptide genes are regulated differentially during the perinatal-prepubertal
      period. PORF-1 mRNA shows age-related increases in expression from E18-E19 to P15
      in POA-AH and MBH, without significant gender differences. In contrast, PORF-2
      mRNA shows both age and gender differences in expression in these brain regions,
      with decreases occurring during the same time period in development. NPY mRNA
      increases similarly in males and females with age in POA-AH and MBH during this
      period. GnRH mRNA does not change during this period. Taken together with
      previous studies, the results suggest possible roles for PORF-1 and NPY in the
      pubertal process, since their expression is maximal from the prepubertal to the
      early pubertal period. The observation of highest levels of expression of PORF-2
      in embryonic neuroendocrine tissues suggests a possible involvement of this
      neuropeptide in prenatal/neonatal developmental events.

PMID- 10583731
TI  - Regulation of corticotropin-releasing factor-binding protein expression in
      amygdalar neuronal cultures.
AB  - Corticotropin-releasing factor-binding protein (CRF-BP) is known to regulate the
      bioavailability of CRF and may also play a role in stress behaviours. CRF-BP has
      been localized in the pituitary as well as central nervous system (CNS) limbic
      and cortical areas, including the amygdala. The signal transduction pathways
      which regulate amygdalar CRF-BP are not well understood. In this report, we have
      examined the effect of protein kinase A and C activators, CRF, dexamethasone and
      interleukin-6 (IL6) on CRF-BP mRNA and protein expression in dissociated fetal
      amygdalar cultures. CRF-BP mRNA levels were determined by Northern analysis
      following 12 h treatment with the following agents: forskolin (1-30 microM), CRF
      (1-1000 nM), phorbol-12-myristate-13-acetate (TPA; 1-50 nM), dexamethasone (1-100
      nM) and IL6 (10-500 pM). Significant increases in CRF-BP mRNA were observed in
      response to forskolin (30 mM), CRF (100, 1000 nM), IL6 (100, 500 pM), TPA (50 nM)
      and dexamethasone (100 nM; P<0.05 for all; n=3-6 for all). We extended our
      observations of CRF-BP expression to the protein level by performing
      semiquantitative Western analysis of total cellular protein after treatment with
      the same agents. Twenty-four hour treatment with 30 microM forskolin, 1000 nM
      CRF, 50 nM TPA, 100 pM IL6 or 100 nM dexamethasone significantly increased CRF-BP
      expression (P<0.05, n=3 for each treatment). The primary cultures were then
      transfected with a rat CRF-BP-reporter construct containing 3500 base pairs of
      CRF-BP 5' flanking DNA. Treatment with all five agents produced statistically
      significant increases above control (P<0.05; n=3 for each). The results suggest
      that CRF-BP in the amygdala is stimulated by numerous pathways which may play a
      significant role in promoting behavioural changes.

PMID- 10583732
TI  - Meeting report: 1999 World Congress on Neurohypophysial Hormones.

PMID- 10583733
TI  - Advances in biomaterials from 1957 to 1997.
AB  - The developments in biomaterials over the past 40 years were listed in a
      questionnaire. Groups of dentists with and without a Master's degree ranked each
      development on the basis of the impact they believed it has had on the practice
      of dentistry. The results of the questionnaires were analysed and the rankings
      were discussed and used as a guide to the projection of the probable future needs
      and developments in biomaterials, based on the needs of current and future dental
      patients.

PMID- 10583734
TI  - pH changes of glass-ionomer lining materials at various time intervals.
AB  - The purpose of this in vitro study was to evaluate pH changes of resin modified
      glass-ionomer (RMGI) and conventional glass-ionomer liners at short-term
      intervals after mixing to relate the timing of light activation on the acidity of
      RMGI lining materials. The RMGI liners tested were Vitrebond (3M), Variglass VLC
      (Dentsply), Fuji Lining LC (GC Dental Industrial Corp.) compared to a traditional
      glass-ionomer liner: Lining Cement (GC, control). Light activation of liners was
      carried out at different time intervals after mixing. The pH changes of each
      liner were evaluated immediately after mixing and thereafter every minute for 8
      min using a surface pH meter. All liners tested exhibited a gradual increase in
      surface pH over time. The delay of light activation of RMGI lining materials
      after mixing did not significantly decrease the acidity of the liner during the
      first 9 min post-mixing.

PMID- 10583735
TI  - Effects of the solvents on bond strength of resin bonded porcelain.
AB  - Clinical trials of porcelain veneers for chairside colour modifications may
      require the use of a trial resin with various colours of tints. The bond strength
      effects of four different solvents used for removal of trial resin from etched
      porcelain specimens were investigated. Fifty-six porcelain specimens were
      fabricated, flattened by a metallurgically standard method, etched with
      hydrofluoric acid and silane treated. The specimens were divided into four groups
      at random. The trial resin material was cleaned with different solvents prior to
      bonding of a dual cure resin composite button. After bonding the specimens were
      stored in water at 37 degrees C for 7 days. Shear bond strength results were as
      follows: acetone (control) group, 12.9+/-2.9 MPa; ethanol group, 15.1+/-4.6 MPa;
      methanol group, 11.5+/-2.9 MPa; methylene chloride group, 11.3+/-2.4 MPa. No
      significant differences were measured (ANOVA, P>0.05). The results indicated that
      the resin-porcelain bond strengths were not affected by the type of solvent used
      to remove trial resin. This procedure is recommended for clinical cases when
      resin composite is used for the try-in of etched porcelain bonded restorations.

PMID- 10583736
TI  - Masseter muscle activity during the whole day in children and young adults.
AB  - Changes in size and shape of the craniofacial skeleton during growth may be
      related to the masticatory muscle function in daily life. The purpose of this
      study was to measure the masseter muscle activity during the whole day in
      children and to investigate the differences between children and young adults.
      Fifteen children (7.8-13.0 years of age) and 30 young adults (20.3-34.7 years of
      age), who had acceptable occlusions without any remarkable skeletal discrepancy
      or temporomandibular disorder, were used as the subjects. In both children and
      young adults, most high-amplitude bursts of masseter muscle appeared mainly
      during mealtime, whereas a substantially larger number of low-amplitude ones were
      widely distributed throughout the whole day. The number and total duration of
      bursts of masseter muscle activity during the whole day was greater in children
      than in young adults, although significant differences were not found between the
      sexes. During daytime and sleep, both the number and total duration of bursts
      were greater in children. During mealtime, no significant differences in the
      number of bursts were found between children and young adults, however, the
      duration of bursts tended to be longer in children. It is concluded that the
      masseter muscle activity during the whole day is greater in children than in
      young adults.

PMID- 10583737
TI  - Electrognathographic and electromyographic observations on jaw depression during
      neck extension.
AB  - Albeit never substantiated through experimental and clinical evidence, the
      theoretical linchpin of the mechanics of a so-called whiplash injury of the
      temporomandibular joint (TMJ) is the postulate that a pre-existing depressor
      force (continual anchoring force), generated by the anterior suprahyoid (SH)
      muscles, will always act on the mandible and cause traumatic mouth opening
      (anterior acceleration of the TMJ condyles) when the neck is extended (posterior
      acceleration of the head). To test aspects of this postulate, six subjects
      assumed the positions of neutral (0 degrees ), medium (32 degrees ) and maximum
      (58 degrees ) neck extension while the mandible was in its postural positions of
      rest and light centric occlusion. By means of surface electromyography, it was
      shown that the relative contractile activities of the anterior SH muscles never
      exceeded 7.3% of the contractile activity required to anchor the mandible in a
      position of maximum depression. By means of electrognathography, it was shown
      that the maxillary and mandibular incisors were never separated by more than 2.6
      mm during neutral, medium, and maximum extension of the neck. In other words,
      during neck extensions there was no evidence of a continual or induced voluntary
      or involuntary depressor force that would and could anchor the mandible in a
      position of traumatic mouth opening. Accordingly, and in agreement with other
      biophysical and biomedical evidence, it was concluded that there is no foundation
      for the pseudoscientific speculations and unsubstantiated opinions offered in
      support of a concept and diagnosis of a so-called TMJ whiplash injury.
      Additionally, this study found co-activation of cervical flexor muscles and
      mandibular elevator as well as depressor muscles.

PMID- 10583738
TI  - Adhesive bonding of noble metal alloys with a triazine dithiol derivative primer
      and an adhesive resin.
AB  - The purpose of this study was to evaluate the bond strength and durability of a
      metal adhesive system bonded to noble metal alloys. Disc specimens were cast from
      type IV gold (type IV, Casting Gold M. C., metal-ceramic gold (Au-Pt-Pd, Degudent
      Universal, metal-ceramic palladium (Pd-Ga-Co, PTM 88 silver-indium (Ag-In-Zn,
      Salivan Hard and silver-palladium-copper-gold (Ag-Pd-Cu, S12) alloys and pure
      silver (pure Ag). The specimens were air-abraded with 50 micron alumina,
      conditioned with a thiol-based primer designed for noble alloys (V-Primer), and
      then bonded with an adhesive resin (Super-Bond Opaque Ivory). Shear bond
      strengths were determined after repeated thermocycling (4-60 degrees C, 1 min
      each, 100 000 cycles). The average bond strengths in MPa (n=8) were 30.9 for the
      type IV alloy, 29.0 for the Ag-Pd-Cu alloy, 28.0 for the Au-Pt-Pd alloy, 26.3 for
      the pure Ag, 26.0 for the Pd-Ga-Co alloy and 9.3 for the Ag-In-Zn alloy. The Ag
      In-Zn alloy exhibited significantly lower bond strength than the other alloys,
      whereas the bond strengths of the other four alloys and pure Ag were comparable
      (P<0.05). It is concluded that the combined use of the thiol derivative primer
      and the adhesive resin is effective for bonding the noble metal alloys examined,
      with the exception of the Ag-In-Zn alloy.

PMID- 10583739
TI  - Size of the mandibular jaw angle related to age, tooth retention and gender.
AB  - The size of the gonial angle was measured in cephalograms of 431 adults attending
      the Department of Prosthodontics, School of Dentistry, University of Bergen,
      Norway. The purpose of the work was to conduct a study of the variables often
      related to the development of the size of the gonial angle, i.e. age, degree of
      tooth retention, and gender. Descriptive data showed that the edentulous
      participants had the largest mean angle, the participants in possession of all
      teeth had the smallest angle, and the partially dentate participants had a jaw
      angle size between that of the aforementioned groups. Preliminary results of the
      analysis (ANOVA) showed that the number of teeth had a decisive influence on the
      size of the gonial angle. The correlation coefficients between size of the gonial
      angle and age showed that age explained approximately 8-16% of the variation of
      the angle through its relation with age. Sex differences in age and size of the
      gonial angle were not statistically significant in any of the three tooth
      retention categories. Future multiple regression analysis may explain a greater
      part of the variation of the angle if the analysis is carried out in separate age
      groups of the three categories.

PMID- 10583740
TI  - The effects of oscillating forces upon the flow of dental cements.
AB  - The aim of this study was to evaluate the effect of oscillating forces upon the
      flow of five dental cements. A laboratory investigation was carried out using a
      crown and die. It showed that the application of oscillating forces improved the
      flow of the tested dental cements when combined with low static loads and wide
      crown-die separations. The oscillating forces enhanced the late, particle
      dominated phase of cement flow. Further investigations characterised the nature
      of the oscillating forces applied in this experiment and revealed yield stress
      behaviour shown by one cement.

PMID- 10583741
TI  - Head, neck and trunk movements accompanying jaw tapping.
AB  - Several studies have examined the functional relationship between mandibular
      movement and head or body posture, but head and body motion during jaw movement
      have not been extensively investigated. Ten healthy participants performed
      repetitive jaw tapping movement. Piezoelectric accelerometers were attached on
      the surfaces of the participant's forehead, mentum, and over the spinous
      processes of the sixth cervical, twelfth thoracic and third lumbar vertebrae. The
      direction in which the antero-posterior acceleration signals appeared around the
      onsets of jaw opening and closing were observed for the period from the 6th to
      the 25th strokes of the jaw tapping. Around the onset of jaw opening, the
      forehead and the lumbar vertebra tended to move posteriorly, but the cervical and
      thoracic vertebrae moved anteriorly with significant frequencies. The directions
      of the motions of these locations reversed themselves at the beginning of jaw
      closing; so the motions of the forehead and the lumbar vertebra were opposed
      again to the ones of the cervical and thoracic vertebrae. The results suggest
      that the head extend-flex motion often accompanied the jaw open-close movement,
      and the motions of the neck and trunk existed, which would serve the purpose of
      promoting the mandible to move smoothly.

PMID- 10583742
TI  - Occlusal contact area, occlusal pressure, bite force, and masticatory efficiency
      in patients with anterior disc displacement of the temporomandibular joint.
AB  - The occlusal contact area, occlusal pressure, bite force, and masticatory
      efficiency were measured in 48 patients with anterior disc displacement (ADD) of
      the temporomandibular joint (TMJ). The results were compared with those of 30
      normal controls without TMJ dysfunction. The values of occlusal contact area,
      bite force, and masticatory efficiency measured in patients with ADD were
      significantly smaller than those measured in the controls, although there was no
      difference in occlusal pressure between the two groups. The results of the
      measurements of 22 patients with ADD with reduction were also compared with those
      of 26 patients with ADD without reduction. There was no difference in any
      measurement between these patients subgroups. The analysis of occlusal contact
      area, bite force, and masticatory efficiency appeared to be useful methods in
      documenting the fact that masticatory function was impaired in patients with ADD
      of the TMJ.

PMID- 10583743
TI  - The periodontal response to cantilevered resin-bonded bridgework.
AB  - This study investigated 84 cantilevered resin-bonded bridges (CRBB) in 60
      patients. These CRBB (single retainer, single pontic) had been in place for an
      average of 43.6 months. Periodontal health was assessed on abutment teeth and
      contralateral control teeth. Periodontal indices utilized were Plaque Index (PI),
      Gingival Index (GI), Bleeding Index (BI), Pocket Depth (PD) and mobility. The
      marginal adaptation, the gingival extension of the retainers and the presence or
      absence of caries around each retainer margin were also assessed. Information
      about the history of debonding was collected and a success rate of 93% was
      reported. PI, GI and mean PD compared statistically significantly, less
      favourably, with scores of the control teeth. Marginal adaptation of the
      retainers was of a high standard and caries did not appear to be a problem.

PMID- 10583744
TI  - Incidence of occlusal contacts with complete dentures during mastication using a
      6-channel telemetry system: preliminary measurements.
AB  - The purpose of this study was to observe the incidence of occlusal contact with
      complete dentures during mastication using a 6-channel telemetry system whose
      accuracy had been improved. The telemetry system consisted of the transmitter
      unit and the receiver unit. The transmitter unit was embedded in the lower
      complete denture. This system detects occlusal contacts by the shift of frequency
      in 100 kHz. The transmitter allowed 6 channels for the occlusal contacts. The
      data was telemetered by a time division multiplex communication method. A special
      switch was designed to measure excursive movement on the occlusal surface. After
      careful occlusal adjustment, the special switches were inserted in the lower
      first molars. On the basis of preliminary measurements on a 64-year-old
      edentulous male, it appears that the width of the gliding on the occlusal surface
      at the lower first molar was mostly 0.2-1.2 mm and the majority of the excursive
      movements ended at the centric occlusal position.

PMID- 10583745
TI  - Survival ability of cytotoxic strains of motile Aeromonas spp. in different types
      of water.
AB  - The ability of motile Aeromonas spp. to survive in drinking water (mineral and
      tap water) and in sea water was experimentally tested. Clinically isolated
      cytotoxic strains of A. hydrophila, A. caviae and A. sobria were selected for
      this study. After contamination of water samples, the survival of Aeromonas
      strains was studied for at least three months using viable counts. The results
      obtained show that the survival of the Aeromonas spp. varies considerably
      depending on species and water type. For all three species, the survival time was
      longest in mineral water, where viable bacteria of each strain were still
      detected after 100 d. Moreover, A hydrophila and A. caviae also re-grew on the
      first day. In tap water all strains showed marked survival, although to a lesser
      extent than in mineral water. Aeromonas cells showed a rapid decline in sea water
      (90% reduction in viable cells after about two d) and thus seem to be more
      sensitive to saline/marine stress than chlorination.

PMID- 10583746
TI  - An automated method for the detection of staphylococcal heat stable
      deoxyribonuclease in dairy products.
AB  - An automated sandwich immunoassay with specific polyclonal antibodies for the
      detection of Staphylococcus aureus thermostable nuclease (DNase) is described. To
      evaluate this assay, different quantities of purified S. aureus nuclease were
      added to dairy products. Additionally, staphylococcal counts and nuclease
      activity of milk samples inoculated with S. aureus were determined. Different
      extraction procedures were performed and compared. The results indicated that the
      automated test was a reliable method for detecting DNase activity in milk
      products. The procedure was completed in 2 h and detected 1 ng of DNase ml-1.
      Detection of the DNase was especially useful in cheeses and could be used to
      confirm positive enterotoxin results.

PMID- 10583747
TI  - Formation of L-malic acid by yeasts of the genus Dipodascus.
AB  - The yeast strains of the genus Dipodascus were used for the bioconversion of
      fumaric acid to L-malic acid. Under nongrowth conditions, the fumarase activity
      in the intact cells or in the cell-free extract of Dipodascus was 10 times higher
      than that of Saccharomyces cerevisiae cells. Pretreatment of the Dipodascus with
      malonate was not necessary because succinate was not detected as a by-product.
      The fumarase activity in Dipodascus magnusii CCM 8235 was increased approximately
      100% when Triton X-305 (0.1%) was added to the reaction mixture.

PMID- 10583748
TI  - Morphological changes (including filamentation) in Escherichia coli grown under
      starvation conditions on silicon wafers and other surfaces.
AB  - Using a scanning electron microscope, pleomorphism (notably filamentation) was
      seen when Escherichia coli was grown under starvation conditions for 14 d on
      microporous silicon wafers, titanium, glass and plastic discs. Under these
      conditions, the 'standard', rod shaped cell (1-3 microns) failed to separate
      after division and filaments developed, some as long as 50 microns, with many
      showing bulbous tips. Filamentation began to occur 5 d after the imposition of
      starvation conditions. Dumbbell shaped cells were also observed, although
      apparent 'Y' and 'V'-shaped cells proved to be artefacts, caused by overlapping
      rods. The implications of the appearance of pleomorphism in E. coli, when grown
      under starvation conditions, is discussed in relation to its pathogenicity and
      growth in the environment.

PMID- 10583749
TI  - Effects of temperature and heat activation on germination of individual spores of
      Bacillus subtilis.
AB  - Phase intensity changes of individual germinating spores of Bacillus subtilis
      were determined by phase-contrast light microscopy and image analysis. Two
      germination phases were investigated. The length of the time period before a
      change in phase brightness was evident and the duration of the phase intensity
      change until a constant greylevel was maintained. The incubation temperature (37
      and 20 degrees C) and heat activation (10 min at 65 degrees C) had a distinct
      effect on both phases. At 37 degrees C, spores of B. subtilis 604 started to show
      a decrease in brightness in L-alanine buffer after 3-39 min and needed 10-39 min
      to complete the phase change. At 20 degrees C, lag times of 10-100 min were
      observed and the spores needed 30-100 min to reach a constant greylevel. Heat
      activation and subsequently exposure to L-alanine buffer at 20 degrees C reduced
      the lag phase to 6-90 min and the phase change was finished after 30-60 min. Our
      results indicate enzymatic involvement before and during the phase intensity
      change of germinating spores.

PMID- 10583750
TI  - Pressure- vs. heat-induced bacterial stress in cooked poultry sausages: a
      preliminary study.
AB  - Vacuum-packaged poultry cooked sausages were pressure-treated at 500 MPa by
      combinations of time (5-45 min) and temperature (2-80 degrees C) and later stored
      at 6-8 degrees C for 12 we. Mesophile and psychrotrophe counts were determined 1
      d, 3, 6, 9 and 12 we after treatment and compared with those of cooked sausages
      pasteurized at 80-85 degrees C for 40 min. Both pressure and heat treatments
      offer great possibilities for preservation. Sausages pressurized at 65 degrees C
      for 15 min showed mesophile numbers below 2 log cfu g(-1) throughout the chill
      storage. Pressurization, unlike heat treatment, causes a reversible bacterial
      stress. Thus, injured cells recovered during storage and, at 6 and 12 we, after a
      temperature abuse (room temperature for approx. 24 h), counts increased up to 6.5
      - 7.5 log units. Psychrotrophes were more sensitive to both treatments; no growth
      was detected the day after (a lethality of more than 4 log units).

PMID- 10583751
TI  - Inhibitory effects of some spice essential oils on Aspergillus ochraceus NRRL
      3174 growth and ochratoxin A production.
AB  - Inhibitory effects of essential oils of oregano (Origanum vulgare), mint (Menta
      arvensis), basil (Ocimum basilicum), sage (Salvia officinalis) and coriander
      (Coriandrum sativum), on the mycelial growth and ochratoxin A production by
      Aspergillus ochraceus NRRL 3174 were studied. Cultures were incubated on yeast
      extract-sucrose (YES) broth, at concentrations of 0, 500, 750 and 1000 p.p.m. of
      essential oils during 7, 14 and 21 d at 25 degrees C. At 1000 p.p.m., oregano and
      mint completely inhibited the fungal growth and ochratoxin A production up to 21
      d, while basil was only effective up to 7 d. At 750 p.p.m., oregano was
      completely effective up to 14 d, whereas mint allowed fungal growth but no
      ocratoxin A production up to 14 d. At 500 p.p.m., no evident inhibition could be
      in observed with any of the essential oils under analysis. Sage and coriander
      showed no important effect at any of the concentrations studied. These inhibitory
      effects are interesting in connection with the prevention of mycotoxin
      contamination in many foods and they could be used instead of synthetic
      antifungal products.

PMID- 10583752
TI  - Enhanced biodegradation of phenanthrene by a marine bacterium in presence of a
      synthetic surfactant.
AB  - The biodegradation of phenanthrene by the marine strain Sphingomonas sp. 2MPII
      (DSMZ 11572) was enhanced by the solubilizating properties of the nonionic
      surfactant Tween 80. After 197 h of incubation, 85 +/- 4% of the initial amount
      of phenanthrene (0.4 g l-1) was biodegraded in presence of Tween 80 (0.5 g l-1)
      as opposed to 52 +/- 5% without this synthetic surfactant. These results confirm
      that the activity of the strain 2MPII is limited by the bioavailability of the
      polycyclic aromatic hydrocarbon (PAH) substrate in the aqueous phase. Tween 80
      appears to be efficient in increasing the bioavailability of hydrophobic
      compounds such as PAHs.

PMID- 10583753
TI  - The same species of sulphate-reducing Desulfomicrobium occur in different oil
      field environments in the north sea.
AB  - Several metabolic types of sulphate-reducing bacteria, including mesophiles and
      thermophiles, were successfully obtained from four samples from two different
      North Sea oil fields. The Gram-negative, rod-shaped, sulphate-reducing strains
      MM6, EF2, FM2, and GF2 were isolated from drain water, and from drilling muds E,
      F, and G, respectively. All four isolates grew on lactate, pyruvate, glycerol,
      and ethanol, with optimal growth temperatures between 25 degrees C and 35 degrees
      C and at salinities between 0 and 5% NaCl. They were capable of using sulphate,
      thiosulphate or sulphite, but not nitrate, as electron acceptors. These isolates
      were tentatively identified to be the same species of Desulfomicrobium based on
      physiological and biochemical characterization, and 16S rRNA gene analysis.
      Therefore, the same Desulfomicrobium species was present in different samples
      from distant oil fields. This result suggests that these microorganisms are
      likely to be widespread throughout oil field systems, and possibly play an
      important role in the generation of sulphide.

PMID- 10583754
TI  - A comparison of different culture media for the membrane filter quantification of
      Aeromonas in water.
AB  - A comparative assessment of culture media for the membrane filter enumeration of
      Aeromonas spp. in water was performed, testing the effects of different
      incubation conditions (aerobic and anaerobic), temperatures (30 and 37 degrees C)
      and times (24 and 48 h). Different water samples seeded with test suspensions of
      Aeromonas spp., fecal material or raw sewage were examined. Results indicate
      clearly that plates should be incubated aerobically at 30 degrees C for 24 h. If
      the bacterial contamination is likely to be low, the use of most sensitive
      culture media, such as SAA, mA, ADA or PADE Agar, is recommended. By contrast,
      samples with an expected high level of background microbial flora should be
      analysed through more selective media, such as MIX Agar. However, the low
      selectivity of all media tested and the high likelihood of false negatives based
      upon the macroscopic examination of colonies means that further research directed
      to the development of more efficient media is needed.

PMID- 10583755
TI  - Characterization of 'faecal streptococci' as indicators of faecal pollution and
      distribution in the environment.
AB  - The recent revision of the taxonomy of 'faecal streptococci' prompted us to
      verify the importance of identifying the species of this group of cocci. During a
      study carried out to assess the hygienic quality of environmental samples from a
      variety of sources, we isolated 198 strains named faecal streptococci on the
      basis of conventional international tests (EVA broth multiple tube test) used for
      Public Health purposes. The predominant species were Enterococcus faecalis (39%)
      and Ent. faecium (29%), followed by Ent. durans/hirae, Ent.
      casseliflavus/gallinarum, Ent. raffinosus, with a different prevalence of the
      species depending on the source. Eighty-four per cent of isolates were true
      faecal species. Only one isolate was identified as belonging to the Streptococcus
      genus. The authors stress the opportunity to identify the species. This may help
      to clarify the ecological and epidemiological characteristics of intestinal
      enterococci and streptococci in the environment, in drinking and recreational
      waters and their meaning as indicators of faecal pollution. All isolates were
      tested for their susceptibility to some antimicrobial agents widely used in
      medical therapy and the pattern was compared with the pattern of isolates from
      clinical specimens.

PMID- 10583756
TI  - Production of bacteriocin by Bacteriodes fragilis and partial characterization.
AB  - The ability of Bacteroides fragilis strains, isolated from various sources, to
      produce bacteriocin was evaluated. All strains isolated from intestinal
      infections were producers in high levels and less susceptible to the others.
      Strains from other origins were found to produce bacteriocin at a medium level
      and they were variably susceptible. Some properties of one bacteriocin produced
      by the Bact. fragilis 079298-3 strain were analysed, providing evidence of its
      protein nature, with stability over a wide range of pH and retained inhibitory
      activity after heating. This variability seems to suggest that bacteriocin typing
      is a good method for this species.

PMID- 10583758
TI  - Medical education in South Africa.

PMID- 10583757
TI  - Rapid detection of Salmonella in field samples by nested polymerase chain
      reaction.
AB  - A simple and universal protocol for the rapid detection of Salmonella spp. in
      various samples using nested polymerase chain reaction (PCR) was developed. The
      protocol takes advantage of the rapid purification and concentration of
      Salmonella by centrifugation onto a layer of 60% sucrose solution. DNA was
      released by treatment with proteinase K and Triton X-100. Even without pre
      enrichment, the detection limit for the nested PCR was 10(5) CFU g-1 of faeces.
      After pre-enrichment, it was possible to detect Salmonella in faeces where their
      original concentration was approximately 10(2) CFU g-1 of faeces and in meat
      samples, it was possible to detect Salmonella in samples where their original
      concentration was less than 10 cells g-1 of minced meat.

PMID- 10583759
TI  - Medical education challenges in South Africa.

PMID- 10583760
TI  - The current status and future needs of education and training in family medicine
      and primary care in South Africa.
AB  - South Africa is undergoing tremendous political and social change affecting every
      sphere of society, including medical education and the delivery of health
      services. The legacy of its history created a health system that in some respects
      can be compared to the best in the world, but one also characterized by inequity,
      discrimination and lack of access to even basic services for the rural and the
      poor. Its medical education system trails behind modern trends such as problem
      based learning, community-based education and the utilizing of general/family
      practitioners as trainers. Vocational training in family practice is not
      compulsory for independent practice. The discipline of family practice has
      nevertheless developed the programmes and core infrastructure for such a future
      undertaking in the form of masters programmes in family medicine at all medical
      schools. The recently introduced system of compulsory recertification through
      continuous professional development provides a window of opportunity to develop
      locally relevant curricula and appropriate education and training methods for
      family practitioners. Challenges for family practice include the establishment of
      the role and value of the discipline in a developing country with a health system
      based on a nurse-driven primary care service and the re-orientation of family
      medicine teachers, trained in a biomedical paradigm, to the patient-centred
      approach. The aspirations of family practice are to define the core content of
      the discipline, establish and nurture a culture of research in primary care, and
      to develop and introduce appropriate under and postgraduate training programmes
      for the new generation of family doctors.

PMID- 10583761
TI  - Medical education in the community--the UNITRA experience.
AB  - The creation of the independent black state of Transkei, under the apartheid
      regime, resulted in inadequate allocation of resources to the region. These
      inequalities were translated into health care. Despite these limitations, over
      the last five years an innovative community-based educational programme involving
      medical students, nurses and health educators is evolving at the relatively new
      medical school in this region. This programme, however, has not been free of
      difficulties. There is an urgent need to address these issues using a combination
      of administrative, educational and research approaches. This would provide a
      strong basis for the further development of this educational programme that could
      serve as a unique South African example of medical education in the community.

PMID- 10583762
TI  - Community-based training in family medicine--a different paradigm.
AB  - INTRODUCTION: Community-based education is an important strategy for training
      students appropriately for delivering primary health care services. A community
      based training rotation in Family Medicine and Primary Care was introduced at the
      University of Stellenbosch, South Africa, in January 1998. OBJECTIVE: The aim of
      this study was to explore the perceptions of final year medical students about
      the new rotation and to provide feedback on the value of this experience to the
      Faculty. In this article we explore the influence of differing world views held
      by biomedically oriented training institutions and the systems view of life
      adhered to by the discipline of Family Medicine on attempts to reform medical
      education. METHOD: Quantitative and qualitative curriculum evaluation methods,
      including a questionnaire and focus groups discussions, were used. Students rated
      the value of the block as 7.8 out of 10. RESULTS: Eighty-eight percent of
      students felt that there should be an earlier exposure to Family Medicine and
      Primary Care in their training. The main themes identified from the qualitative
      results supported the literature findings and included the difference in type of
      practice between tertiary and primary levels of care and the value of learning a
      new approach to patient care. Despite the fact that the results emphasized the
      importance of including community-based training in Family Medicine and Primary
      Care at an early stage in the medical curriculum, resistance to implementation
      was encountered. This led to reflection on possible reasons on why the
      recommendations of the study were not immediately adopted into the curriculum.

PMID- 10583763
TI  - Practical skills and valued community outcomes: the next step in community-based
      education.
AB  - OBJECTIVES: Community-based medical education (CBE) has clear value. However,
      there are aspects of CBE where improvement is possible. First, communities do not
      generally receive valued outcomes in exchange for participation in the CBE
      process. Secondly, students are usually not trained to influence health in the
      community using methods that are realistic in busy clinical practice. DESIGN: A
      CBE rotation was designed to address these problems. Rotation activities were
      structured to facilitate development of a health programme desired by the
      community while giving students practical skills for later use. Working with
      community residents and health staff, sequential groups of students carried out,
      in turn, problem analysis, resource identification, planning and implementation
      activities aimed at establishing a community tuberculosis (TB) control programme.
      SETTING: The University of Natal in Durban, South Africa. SUBJECTS: Final-year
      medical students. RESULTS: At the end of the academic year, the TB control
      programme was approximately 60% in place, and 90% of TB patients cared for by the
      students were completing treatment. Overall, students rated the experience good
      for learning about health care in community settings and about methods for
      community health programme development. Student ratings were significantly higher
      for those groups whose activities brought them into greater contact with
      community residents. The 'real-time' nature of planning the sequential student
      groups' work created logistical problems and, as an isolated activity, the
      rotation had little impact on student attitudes toward community-based careers.
      CONCLUSIONS: Expanding the goals for CBE is both feasible and important. Further
      work should focus on refining designs for this next step in CBE.

PMID- 10583764
TI  - Evaluating problem-based learning in a multilingual student population.
AB  - OBJECTIVES: The University of Natal Medical School in South Africa provides
      training for a student body composed of two groups: one with English as a first
      language and the other with an African language as a first language and English
      as the second. A new methodology was developed to evaluate an innovative course
      using modified problem-based learning techniques in this heterogeneous
      environment. DESIGN: The learning model proposed required achieving a balance of
      three components: content, enquiry/learning process and social interaction/group
      process. A multidimensional system, felt to be consistent with this educational
      philosophy, was developed using seven different quantitative and qualitative
      techniques. SETTING: The University of Natal Medical School. SUBJECTS: First-year
      multilingual medical students. RESULTS: The results revealed that social
      interaction was highly successful in reducing barriers between the student groups
      and between students and facilitators. However, the emphasis on group
      participation may have overshadowed the enquiry process, leading to superficial
      discussions of problems and feelings of repetitiveness. During the course
      students and facilitators expressed concern that the innovative assessments used
      did not assess the course content adequately. While the group presentations and
      projects were useful exercises for consolidation and group interaction, they did
      not enable facilitators to identify struggling students. CONCLUSIONS: The outcome
      of the evaluation stressed the need of achieving an appropriate balance both in
      the curriculum and assessments of the three components of the learning model,
      particularly in a setting where student backgrounds and language ability differ.
      Multidimensional methodology is needed for effective evaluation that promotes
      critical reflection.

PMID- 10583765
TI  - An audit of clinical teaching in paediatric surgery to interns and surgical
      registrars.
AB  - OBJECTIVES: The study aimed to assess the knowledge increment in paediatric
      surgery of interns (pre-registration) after a 1-month period of training and of
      registrars after a 6-month rotation. A comparison of the knowledge base of
      interns from different universities was included. DESIGN: A standard
      questionnaire was completed by all interns and registrars on the first day of
      their appointment and again at the end of rotation. Knowledge increment was
      assessed for each student and each question. SETTING: King Edward VIII Hospital,
      Durban, South Africa. SUBJECTS: Interns (equivalent to pre-registration house
      officers) and registrars (registered practitioners) undergoing general surgical
      training. RESULTS: Both registrars and interns improved their test scores after
      their training period. However, satisfactory exit scores were achieved by interns
      in only 72% of questions. CONCLUSIONS: This study forms the basis for assessing
      future educational strategies and has identified areas of teaching weakness which
      can be remedied. The reduction in exposure of interns to clinical paediatric
      surgery must be balanced by more efficient use of teaching time.

PMID- 10583766
TI  - A home visit programme to teach medical students about children with special
      needs.
AB  - OBJECTIVES: During an 8-week clinical rotation in paediatrics and child health,
      fifth-year medical students at the University of Cape Town are required to visit
      children with special needs in their homes. The home visit allows students to
      learn, first-hand, from children with special needs and their families about
      living with chronic disease and disability. DESIGN: During 1998 students
      anonymously completed home visit evaluation questionnaires (90% response rate,
      160/177). Through verbal presentations, students are assessed on their ability to
      make a comprehensive evaluation of the impact of chronic disease and disability
      on a child and family. SETTING: University of Cape Town Medical School. SUBJECTS:
      Fifth-year medical students. RESULTS: A content analysis of verbal presentations
      found students were more likely to identify medical, psychosocial and economic
      than spiritual and ethical issues. As a learning experience, 37% (n=57) of
      students rated the home visit as 'extremely worthwhile', 62% (n=100) found it
      'worthwhile' and only 2% (n=3) felt it was 'a waste of time'. Most (97%, n=155)
      students felt the programme should continue in the future. CONCLUSIONS: As an
      educational tool, home visiting grounds learning in families' experience and
      encourages reflection beyond the medical aspects of care for children with
      special needs.

PMID- 10583767
TI  - Impact of training on PBL facilitators.

PMID- 10583768
TI  - Letter from a junior doctor.

PMID- 10583769
TI  - Use of student-centred, computer-mediated communication to enhance the medical
      school curriculum.
AB  - OBJECTIVES: While it is clear that computers will play an important role in the
      study and practice of medicine their introduction into the curriculum remains
      controversial. Computer purchase has been made compulsory for incoming students.
      DESIGN: Members of the incoming class were allowed to purchase any computer and
      modem capable of using the communication program chosen by the school. No formal
      computer training was given. Students were encouraged to call for assistance or
      bring in their computers for configuration. The primary object of the system was
      for communication between the students and between students and faculty. SETTING:
      The School of Medicine of the University of New Mexico. SUBJECTS: First-year
      medical students. RESULTS: The vast majority of students set up their computers
      and connected to the system with little assistance. At the end of the first week
      of studies all the students were connected. Most of the students used the system
      on a daily basis. The greatest interest was in discussions concerning
      examinations with 93% of students reading these postings. The least-used aspect
      of the system was the exchange of learning issues from small group case
      discussions. Students also downloaded the curricular material provided but were
      discriminating in accessing this content. CONCLUSIONS: The student use of the
      computer as a communication tool has been a success. Students used the system in
      a variety of ways and by so doing also learned the basics of computer use and
      maintenance. The area of faculty training is often ignored but is considered
      crucial to the success of such a project.

PMID- 10583770
TI  - Medical informatics education in paediatric residency training.
AB  - OBJECTIVES: The objective of this study was to determine whether Medical
      Informatics education among house staff is included in the current residency
      curriculum, and to present ways in which this type of education may be improved.
      DESIGN: During autumn 1996 a mailed survey was distributed to chief residents of
      American paediatric residency programmes. Questions included the resident's use
      of computers, the influence of Informatics-trained faculty members on programme
      education and plans for curriculum expansion. SETTING: Division of General
      Paediatrics, University of Alabama, United States. SUBJECTS: Paediatric chief
      residents. RESULTS: Eighty programmes (63%) returned a survey. An average of 97%
      of residents use the computer for looking up patient laboratory results, while
      70% use it for Medline searches. Less than half of all residents use the Internet
      or computer-based learning programmes. Thirty-seven per cent of programmes
      provided formal lectures on computer topics, and 22% of programmes provided hands
      on Internet training. There was no association between the presence if
      Informatics faculty and current programmes; however, programmes with Informatics
      faculty were more likely to have future curriculum plans (P=0.04). Some of the
      programmes' future plans are described. CONCLUSIONS: We felt that an overall
      description of what is currently being done with computers would be helpful as a
      baseline for other programmes considering new curricula changes. Residents use
      the computer often to check patient laboratory results but not as much for self
      education. Many programmes are expanding their Informatics curriculum. Faculty
      without formal Informatics training can take part in basic computer education for
      residents. A self-study approach by the residents has been received positively.

PMID- 10583771
TI  - Medical education in China for the 21st century.
AB  - Drastic changes are occurring in medical education around the world. Medicine and
      medical technologies are developing rapidly and expanding beyond the
      multidisciplinary area. The needs of medical care and medical education are
      different even from those of several years ago. In order to cope with these
      increasing social needs, the innovation of medical education in China has become
      an urgent and important problem. This study is an attempt to answer the question
      of how to develop medical education in China for the 21st century, based on a
      historical review of the development of medical education. This development might
      be divided into three periods: (1) before the Cultural Revolution; (2) the
      Cultural Revolution (1966-76); and (3) post-Cultural Revolution (1977-present) in
      modern China, and based on problem analysis of the curriculum, teaching methods,
      education evaluation, systems and policies and the balance between educational
      needs and supplies. We concentrate on the discussion of how to solve these
      problems, and have designed a new strategy for the further development of medical
      education in China. This discussion and newly developing strategy focuses on the
      main targets and priorities and adoption of suitable measures according to the
      conditions of the country. The purposes are to elevate the quality of medical
      education, to train qualified doctors to meet continuously increasing needs and
      to maintain the development of medical education for the 21st century in China.

PMID- 10583772
TI  - The teaching of immediate cardiac and trauma care to general practitioners in a
      skills-based outreach format: an assessment in terms of information gain.

PMID- 10583773
TI  - The impact of guidelines and different dissemination strategies on GPs' knowledge
      of magnetic resonance imaging.

PMID- 10583775
TI  - M brownell anderson

PMID- 10583776
TI  - Report and comment on 'Clinical governance: the educational Agenda' 12 march
      1999, society of chemical industry, london

PMID- 10583774
TI  - An international course for faculty development in family medicine: the Slovenian
      model.

PMID- 10583777
TI  - No carrot, no stick, no project--lessons learnt from a postgraduate group
      research project.

PMID- 10583778
TI  - Waiving fees does not improve academic performance.

PMID- 10583780
TI  - In this issue

PMID- 10583779
TI  - When are medical school libraries open? A postal survey of the opening times of
      medical school libraries in the United Kingdom.

PMID- 10583781
TI  - Educational needs after completion of vocational training in general practice.

PMID- 10583782
TI  - Setting standards for tomorrow's doctors.

PMID- 10583783
TI  - Primary care education in the United States--trends and prospects.

PMID- 10583784
TI  - Managed care and graduate medical education in the United States.

PMID- 10583785
TI  - Research and development in community-based teaching: where next?

PMID- 10583786
TI  - A lesson from the introduction of a problem-based, graduate entry course: the
      effects of different views of self-direction.
AB  - OBJECTIVES: Difficulties in the early years of a new curriculum are to be
      expected as staff and students come to terms with new structures, and with
      different approaches to teaching and learning. During the first year of
      implementation of the Graduate Medical Course at the Graduate School of Medicine,
      The University of Queensland, we experienced our share of 'teething troubles'.
      One source of difficulty was different interpretations of the concept of 'self
      directed learning' as it was to be applied in the new course. This paper presents
      an analysis of the effects of these differences on the development of the
      curriculum. DESIGN: An orientation programme was designed to introduce students
      to staff, facilities and the PBL process. SETTING: The University of Queensland.
      SUBJECTS: Problem-based learning (PBL) tutors, medical students. RESULTS: The
      overall effect was to place in jeopardy the achievement of student self-direction
      and commitment to lifelong learning as a goal of the course. To counter the
      undesirable effects of different interpretations, we have developed a conceptual
      framework to promote an agreed understanding of the meaning of self-direction,
      and to guide review and further development of the curriculum. A further paper
      describes the framework. CONCLUSIONS: Consistency in interpretation of key
      concepts is an important factor in the success of problem-based curricula.

PMID- 10583787
TI  - The impact of student-generated learning issues on individual study time and
      academic achievement.
AB  - OBJECTIVES: The aim of this study was twofold. The first question concerns the
      way students make use of the learning issues they generate (as strict guidelines
      or as global guidelines) and whether this changes across years of training. The
      second question concerned the relationship between the way students make use of
      learning issues and the time spent on individual study and achievement on two
      tests of knowledge. DESIGN: A questionnaire was developed, containing seven items
      that measured to what extent students study strictly according to the student
      generated learning issues and six items that measured to what extent students
      study beyond the student-generated learning issues. The questionnaire also
      contained one question in which students had to estimate the mean time spent on
      individual study. Achievement was measured by two forms of tests of knowledge, a
      block test assessing course content and a progress test assessing long-term
      functional knowledge. SETTING: Medical School of Maastricht University, the
      Netherlands. SUBJECTS: Medical students (response=69%) from the problem-based
      curriculum at the Maastricht University. RESULTS: During their first year
      students study strictly according to the content of the learning issues, whereas
      in later years students studied more according to their own learning needs and
      interests. In addition, students who tended to study beyond the generated
      learning issues spent more time on individual study and achieved better on both
      tests. CONCLUSIONS: Students in a problem-based curriculum seem to become better
      self-directed learners during the years of training.

PMID- 10583788
TI  - Assessing the ability of medical students to apply evidence in practice: the
      potential of the OSCE.
AB  - OBJECTIVES: Critical analysis and application of evidence-based practice are key
      skills for students to master. Assessment of these skills can be undertaken by
      written examination. Regardless of how knowledge of the appraisal process may be
      assessed, written examinations ignore assimilation of that evidence into everyday
      practice. DESIGN: A combined clinical and communication skills station was used
      in an objective structured clinical examination where the ability to appraise
      evidence critically was assessed along with the application of that evidence in
      managing a common clinical problem. SETTING: University of Liverpool. SUBJECTS:
      Undergraduate medical students. RESULTS: The results from 156 undergraduate
      medical students demonstrated that it is possible to assess the application of
      evidence in practice, both in terms of outcome and patient assessment of the
      encounter. CONCLUSIONS: Assessment is a powerful tool in promoting learning and
      adoption of such assessment strategies may help to address concerns surrounding
      apparent poor effect of critical appraisal training.

PMID- 10583789
TI  - Assessment of student performance in problem-based learning tutorial sessions.
AB  - OBJECTIVES: To assess student performance during tutorial sessions in problem
      based learning (PBL). DESIGN: A 24-item rating scale was developed to assess
      student performance during tutorial sessions in problem-based learning (PBL) as
      conducted during the pre-clinical years of Medical School at the National
      Autonomous University of Mexico. Items were divided into three categories:
      Independent study, Group interaction and Reasoning skills. Fourteen tutors
      assessed 152 first and second-year students in 16 tutorial groups. An exploratory
      factor analysis with an Oblimin rotation was carried out to identify the
      underlying dimensions of the questionnaire. SETTING: Medical School at the
      National Autonomous University of Mexico. SUBJECTS: Medical students. RESULTS:
      Factor analysis yielded four factors (Independent study, Group interaction,
      Reasoning skills, and Active participation) which together accounted for 76.6% of
      the variance. Their Cronbach reliability coefficients were 0.95, 0.83, 0.94 and
      0. 93, respectively, and 0.96 for the scale as a whole. CONCLUSIONS: It was
      concluded that the questionnaire provides a reliable identification of the
      fundamental components of the PBL method as observable in tutorial groups and
      could be a useful assessment instrument for tutors wishing to monitor students'
      progress in each of these components.

PMID- 10583790
TI  - Brief problem-solving questions in medical school examinations: is it necessary
      for students to explain their answers?
AB  - OBJECTIVE: To compare outcomes when answers to objective type problem-solving
      questions are marked with and without consideration of students' explanations of
      their answers. DESIGN: Students answered six multiple-part problem-solving
      questions on the final examination for a course in clinical biochemistry. Each
      part required a choice from a list, a number or a few words, plus an explanation
      or justification. Scores were determined independently for the answers alone and
      for the answers plus explanations. The outcomes of the two marking methods were
      compared. SETTING: Department of Pathology, University of Otago Medical School,
      Dunedin, New Zealand. SUBJECTS: Final year preclinical medical students. RESULTS:
      Marks were slightly higher for answers alone than for answers plus explanations
      (overall mean, 82.1%; standard deviation, 9.8% vs. 77.1%; 9.3%; P < 0.001 by
      paired t-test). There was a very high correlation between scores derived from the
      two methods (r=0. 87). Consideration of the answers alone (without explanations)
      was about as good as answers plus explanations in identifying students who
      performed at different levels overall on the examination and in identifying the
      weakest students. CONCLUSIONS: The data suggest that when students arrived at the
      correct answers, their information and reasons were usually correct and that
      answers alone discriminate adequately among students with different levels of
      knowledge and ability. By dispensing with the requirement for explanations, we
      would be able to ask more questions and mark objectively, so competent students
      should not be disadvantaged by the lack of opportunity to explain their
      reasoning.

PMID- 10583791
TI  - Students' attitudes towards computer testing in a basic science course.
AB  - OBJECTIVES: The introduction of computerized testing offers several advantages
      for test administration, however, little research has examined students'
      attitudes toward computerized testing. This paper, reports the attitudes of 202
      students in a first year cell biology and histology course toward computerized
      testing and its influence on their study habits over a three year period. DESIGN
      AND METHODS: Multiple choice and image-based extra credit examinations and
      summative image-based examinations have been successfully administered in the
      course. The results indicate that students readily accept computer exams and that
      their study habits were influenced in a positive manner by the computer
      administered extra-credit examinations. RESULTS: Our results provide further
      evidence that medical students like the use of computer administered examinations
      and that the examinations may actually accentuate the learning experience.

PMID- 10583792
TI  - Reliability and credibility of an angoff standard setting procedure in progress
      testing using recent graduates as judges.
AB  - INTRODUCTION: Progress testing is an assessment method that samples the complete
      domain of knowledge that is considered pertinent to undergraduate medical
      education. Because of the comprehensive nature of this test, it is very difficult
      to set a passing score. We obtained a progress test standard using an Angoff
      procedure with recent graduates as judges. This paper reports on the reliability
      and credibility of this approach. METHODS: The Angoff procedure was applied to a
      sample of 146 progress test items. The items were judged by a panel of eight
      recently graduated students. Generalizability theory was used to investigate the
      reliability as a function of the number of items and judges. Credibility was
      judged by comparing the pass/fail rates resulting from the standard arrived at by
      the Angoff procedure with those obtained using a relative and a fixed standard.
      RESULTS: The results indicate that an acceptable error score can be achieved,
      yielding a precision within one percentage on the scoring scale, by using 10
      judges on a full-length progress test (i.e. 250 items). The pass/fail rates
      associated with the Angoff standard came closest to those of the relative
      standard, which takes variations in test difficulty into account. A high
      correlation was found between item-Angoff estimates and the item P-values.
      CONCLUSION: The results of this study suggest that the Angoff procedure, using
      recently graduated students as judges, is an appropriate standard setting method
      for a progress test.

PMID- 10583793
TI  - Extending community involvement in the medical curriculum: lessons from a case
      study.
AB  - OBJECTIVES: Recent reports have stressed the importance of developing medical
      students' understanding of primary and community care and their ability to work
      in health-care teams. DESIGN: An innovative 3-year project aimed to achieve this
      understanding by broadening the range of health-care professionals and community
      organizations contributing to the medical curriculum. SETTING: King's College
      School of Medicine, London. SUBJECTS: Undergraduate medical students. RESULTS:
      Through partnerships with three local community health care trusts, non-medical
      health care disciplines in the teaching hospital and a range of voluntary and
      statutory services, students have been introduced to a broader spectrum of care.
      This has taken place both within the core curriculum and through the development
      of special study modules. CONCLUSIONS: Involving teachers and organizations which
      have not traditionally contributed to medical education raises philosophical
      issues around the aims and rationale of their involvement and practical issues
      such as gaining curriculum time, recruiting suitable teachers and gaining
      credibility for the courses. We analyse the benefits and difficulties inherent in
      broadening the curriculum in this way and assess the lessons our experience
      provides for the future expansion of such learning, both locally and nationally.

PMID- 10583794
TI  - Measuring instructional quality in community-orientated medical education:
      looking into the black box.
AB  - OBJECTIVES: Decentralizing medical education to community settings has raised
      issues of instructional quality. The need to evaluate community-based instruction
      accents the need to adopt a systems perspective, moving beyond factors known to
      comprise general clinical teaching effectiveness to include factors that focus on
      instruction as a process. Application of evaluation models using traditional
      input-output analysis can be flawed. This approach--dubbed the 'black box'-
      typically examines inputs and outputs, but often ignores throughputs. DESIGN: In
      this article we open the black box, using theory to examine the underlying
      processes that define community-based medical education. We first describe the
      components and processes of an instructional model that is framed by the
      philosophy of quality and grounded in experiential learning theory. Without
      examining the critical processes at work inside the black box - i.e. how students
      come to acquire clinical knowledge and how behaviours are influenced - it is
      difficult to assess which programme features contribute to success. Tensions
      created by the absence of consensus on the outcomes of instruction and the
      challenge of developing adequate measures are highlighted. SETTING: State
      University of New York at Buffalo. SUBJECTS: Clinician-teachers, learners and
      patients in the environment. RESULTS AND CONCLUSIONS: We conclude with describing
      a tool for evaluating community-based instruction that is guided by the context
      of our model.

PMID- 10583796
TI  - David prideaux

PMID- 10583797
TI  - 'Really good stuff': new ideas in medical education

PMID- 10583795
TI  - A managed care curriculum: developing a managed care curriculum for primary care
      residents.
AB  - INTRODUCTION: Managed care in its numerous forms is continuing to change the face
      of the healthcare system in the United States. IMPACT OF MANAGED CARE ON MEDICAL
      EDUCATION: As managed care continues to invade the market, it has a substantial
      influence in shaping the parameters of graduate medical education. Various
      surveys have shown that residents are under-trained in managed care principles
      and practice. There is a clear need for a residency curriculum that fully
      prepares students to keep pace with modern markets. EDUCATIONAL METHODOLOGY: This
      manuscript describes a curriculum which emphasizes the role of the primary care
      physician, cost-effective practice, multidisciplinary practice and evidenced
      based strategies. Educational methods and concepts presented here are based on
      the recommendations of healthcare educators, extensive literature searches and
      United States advisory panels. After the curriculum is completed, the resident
      will: 1. Practice cost-effectively under 100% capitation and learn proper risk
      management. 2. Utilize epidemiological thinking and community-oriented primary
      care. 3. Function as a part of healthcare team and understand how to achieve cost
      effective care for patients. 4. Practice the principles of continuous quality
      improvement and assess patient satisfaction. 5. Practice and adopt evidence-based
      medicine and guidelines. 6. Become skilled with computers including facility with
      literature searches, databases and the internet. 7. Practice a full spectrum of
      primary care emphasizing patient education and psychosocial health. 8. Understand
      the ethical issues pertinent to managed care practices. EVALUATION: The residency
      curriculum committee will evaluate the managed care curricular elements on an on
      going basis. CONCLUSION: This comprehensive curriculum for primary care residents
      can help ensure success in the new healthcare marketplace.

PMID- 10583798
TI  - Ratcliffe J, Gask L, Creed F, Lewis B. Psychiatry training for family doctors:
      what do GP registrars want and can a brief course provide this? Medical Education
      1999; 33;434-438.

PMID- 10583799
TI  - Selecting medical students in Colombia.

PMID- 10583800
TI  - In this issue

PMID- 10583801
TI  - From the editor

PMID- 10583802
TI  - Clinical governance: the ethical challenge to medical education.

PMID- 10583804
TI  - An illustrated guide for the young non-clinically qualified millennialist medical
      educator (NOCQUAME)

PMID- 10583803
TI  - Fit for the future--are medical schools going to produce the doctors the health
      service needs?

PMID- 10583806
TI  - More of the same, only different

PMID- 10583805
TI  - Three shots in the dark

PMID- 10583807
TI  - Medical school for sale

PMID- 10583808
TI  - The hitch-hiker's guide to medical education

PMID- 10583809
TI  - Career choices at the end of the pre-registration year of doctors who qualified
      in the united kingdom in 1996.
AB  - OBJECTIVE: To report the career intentions one year after qualification of
      doctors who qualified in the United Kingdom (UK) in 1996, and to compare their
      intentions with those of 1993 qualifiers at the same stage. DESIGN: Postal
      questionnaires. SETTING: United Kingdom. SUBJECTS: All doctors who qualified in
      the UK in 1996. MAIN OUTCOME MEASURES: Choices of eventual career expressed one
      year after qualifying. RESULTS: We report on detailed choices of long-term
      careers for all specialties. Only 20% of 1996 respondents chose general practice
      compared with 25.8% of 1993 respondents. The percentage choosing general practice
      fell more sharply among women, from 34.0% to 25.2%, than among men, from 17.5% to
      14.1%. Choices for surgical specialties rose from 16.9% of 1993 respondents to
      21. 4% of 1996 respondents. The percentage choosing the surgical specialties rose
      among women, from 7.8% to 11.6%, compared with a rise among men from 26.1% to
      32.2%. The percentage of respondents who definitely or probably intended to
      pursue a long-term career in the UK was 77.7% compared with 75.7% of 1993
      respondents. Most of the home-based respondents who had doubts about practising
      in the United Kingdom were considering practising abroad. Only 1% made an
      explicit first choice for a non-medical career. However, in all, 9. 4% said that
      there was a possibility that they might leave medicine. CONCLUSION: The
      substantial decline in intentions to enter general practice among newly qualified
      doctors, seen in the 1993 qualifiers, is continued in the 1996 qualifiers. A
      shortfall in recruitment of UK-trained doctors to general practice is the likely
      outcome. The rise in choices for the surgical specialties, particularly among
      women, may herald a renewed interest in hospital specialist training following
      the Calman changes. It is worrying that almost a quarter of respondents indicated
      some doubts about pursuing a medical career in the UK.

PMID- 10583810
TI  - Evidence-based education: development of an instrument to critically appraise
      reports of educational interventions.
AB  - OBJECTIVES: Educational interventions may ultimately impact on patient care as
      well as affecting individuals' learning. Critical evaluation of educational
      literature by those involved in designing and developing educational
      interventions is therefore important. A checklist instrument for critically
      appraising reports of educational interventions is described. DESIGN: The
      instrument was developed by an iterative process and piloted. The instrument
      consists of nine questions: 1. Is there a clear question which the study seeks to
      answer? 2. Is there a clear learning need which the intervention seeks to
      address? 3. Is there a clear description of the educational context for the
      intervention? 4. Is the precise nature of the intervention clear? 5. Is the study
      design able to answer the question posed by the study? 6. Are the methods within
      the design capable of appropriately measuring the phenomena which the
      intervention ought to produce? 7. Are the outcomes chosen to evaluate the
      intervention appropriate? 8. Are there any other explanations of the results
      explored in the study? 9. Are any unanticipated outcomes explained? A worked
      example is given to illustrate how the instrument can be used in practice.
      SETTING: The Department of General Practice in Glasgow. SUBJECTS: Young general
      practitioners and the Educational Journal Club. RESULTS: The instrument was
      feasible. CONCLUSIONS: The use of the checklist allows the reader to critically
      appraise reports of educational interventions and helps in the practice of
      evidence-based education.

PMID- 10583811
TI  - A qualitative study of pre-registration house officers in general practice.
AB  - OBJECTIVES: To evaluate a unique pre-registration house officer (PRHO) rotation
      involving half a week in general practice over a 4-month period. House officers'
      and supervisors' views were sought on the value of this type of rotation. DESIGN:
      Qualitative study using semi-structured interviews. SETTING: A four-partner
      postgraduate training practice in a deprived urban part of North-east England.
      SUBJECTS: Pre-registration house officers and supervisors. RESULTS: House
      officers gained in educational and clinical terms from their period in general
      practice. They had a high level of individual supervision and teaching and
      encountered a wider spectrum of illness than in hospital. They found certain
      aspects of general practice stressful. The supervision required was greater than
      that needed for a registrar. The supervision of house officers requires support
      and possibly further education for the supervisor. CONCLUSIONS: General practice
      can provide valuable supervised experience at this stage of a doctor's career.

PMID- 10583812
TI  - Profiles of effective tutors in problem-based learning: scaffolding student
      learning.
AB  - OBJECTIVES: Research on tutoring in problem-based learning has not focused so far
      on the variation in tutoring and how this variation can be interpreted by
      conceptions about effective tutoring. DESIGN: This study focuses on the profiles
      of tutors generated by means of an instrument, the so-called Tutor Intervention
      Profile (TIP), and tries to determine which profiles are more or less effective.
      The TIP contains four dimensions of tutor behaviour: (1) elaboration; (2)
      directing the learning process; (3) integration of knowledge; and (4) stimulating
      interaction and individual accountability. SETTING: The medical school of the
      University of Maastricht, The Netherlands. SUBJECTS: Sixty-seven tutors who run
      67 tutorial groups across three units (courses) in the academic year 1996-97.
      RESULTS: It appeared that high, average and low performing tutors differ in their
      performance on each of the four dimensions of the TIP. Several different profiles
      of tutor performance could be distinguished, which were more or less effective.
      One group of tutors demonstrated a tutor intervention profile that was
      characterized as relying more on the use of expert knowledge, whereas another
      group of tutors was characterized as relying more on their abilities to stimulate
      the learning process in the tutorial group. The tutor intervention profile that
      was perceived by students as most effective showed high scores on each of the
      four dimensions, as expected. Notably, a tutor stressing the learning process in
      the tutorial group was perceived as more effective than a tutor stressing content
      (expert tutor). This is especially true for a relatively poor scoring tutor.
      CONCLUSIONS: The results of this study are consistent with research on human
      tutoring and research on tutoring in problem-based learning.

PMID- 10583813
TI  - Audit encourages an evidence-based approach to medical practice.
AB  - OBJECTIVES: This study was designed in order to identify any changes taking place
      in students' ability to incorporate research evidence into clinical practice
      after the introduction of an evidence-based medicine session into their audit
      teaching. DESIGN: We chose to look at the references cited in students' audit
      projects as a way of making a retrospective assessment of their ability to use
      evidence. Each of a sample of 221 projects was analysed for the number and
      accuracy of references, the phase of the audit cycle in which the references were
      cited, the topic chosen and the use of computers. A smaller sample were assessed
      for quality. SETTING: The Department of General Practice at Glasgow University.
      SUBJECTS: Final-year medical students. RESULTS: We found that there was an
      increase in quality and quantity of citation of references by the students over a
      3-year period which corresponded with changes in teaching methods. CONCLUSIONS:
      It is possible that this increase in the quantity and quality of reference
      citation by final-year students was in response to a change in the content of
      teaching sessions, but there may be other reasons for this. The experience of
      researching and carrying out the projects has given students first-hand
      experience of the techniques of evidence-based medicine. Requiring students to
      state their information sources and include a copy of the abstracts from cited
      papers would assist further studies of this kind.

PMID- 10583815
TI  - Seasonal quiz

PMID- 10583814
TI  - 'Hello, my name is Gabriel, I am the house officer, may I examine you?' or the
      Objective Santa Christmas Examination (OSCE).
AB  - OBJECTIVE: To design a clinical examination of high content validity suitable for
      use as a formative assessment tool with pre-registration house officers (PRHO'S)
      towards the end of their first house officer post. DESIGN: A multicentre
      collaboration between four UK medical schools who offer undergraduate curricula
      which are problem-based, systems-based, patient-orientated, student-centred,
      jargon-laden and utterly staff-bewildering. MAIN OUTCOME: An objective structured
      clinical examination (OSCE) which is suitable for use with graduates of UK
      medical schools. It assesses the knowledge, skills and attitudes essential for
      future careers in a hierarchical system where protecting the senior staff from
      all forms of irritation is paramount. RESULTS: PRHO'S who excel in this
      examination get better references. CONCLUSION: The OSCE format can be used to
      provide 'real-life' scenarios appropriate to the season.

PMID- 10583817
TI  - Charles george

PMID- 10583816
TI  - Differences in curriculum emphasis in US undergraduate and generalist residency
      education programmes.
AB  - OBJECTIVES: Little attention has been paid to the differential emphasis
      undergraduate and graduate medical education programmes place on the broad
      competencies that will be needed for practice in an increasingly managed health
      care environment. The purpose of this study was to determine differences in
      emphasis that undergraduate and primary care graduate medical education
      programmes are currently placing on 33 broad practice competencies, compared with
      the emphasis they ideally would like to give them, and the barriers they perceive
      to curriculum change. DESIGN: Subjects were surveyed by mailed questionnaire. A
      reminder postcard and follow-up mailing were sent to non-respondents. SETTING: US
      allopathic medical schools. SUBJECTS: Academic deans identified by the
      Association of American Medical Colleges (AAMC) and generalist (family medicine,
      internal medicine, paediatrics and obstetrics-gynaecology) residency programme
      directors identified by the American Council on Graduate Medical Education
      (ACGME). RESULTS: Findings revealed that residency programmes placed greater
      emphasis on the study's broad curriculum topics than did undergraduate medical
      education programmes. Statistically significant differences were found in current
      emphasis for 12 topics and ideal emphasis for six topics. Both groups identified
      an already crowded curriculum and inadequate funding as the top two barriers to
      curriculum change. CONCLUSIONS: The differences in curriculum emphases and
      perceived barriers to curriculum change most probably reflect the different
      realities of undergraduate and graduate medical education programmes, i.e.
      academics vs. a focus on immediate practice realities.

PMID- 10583818
TI  - Improving induction day for pre-registration house officers.

PMID- 10583819
TI  - Letters to the editor

PMID- 10583821
TI  - Genetic structure of the world's polar bear populations.
AB  - We studied genetic structure in polar bear (Ursus maritimus) populations by
      typing a sample of 473 individuals spanning the species distribution at 16 highly
      variable microsatellite loci. No genetic discontinuities were found that would be
      consistent with evolutionarily significant periods of isolation between groups.
      Direct comparison of movement data and genetic data from the Canadian Arctic
      revealed a highly significant correlation. Genetic data generally supported
      existing population (management unit) designations, although there were two cases
      where genetic data failed to differentiate between pairs of populations
      previously resolved by movement data. A sharp contrast was found between the
      minimal genetic structure observed among populations surrounding the polar basin
      and the presence of several marked genetic discontinuities in the Canadian
      Arctic. The discontinuities in the Canadian Arctic caused the appearance of four
      genetic clusters of polar bear populations. These clusters vary in total
      estimated population size from 100 to over 10 000, and the smallest may merit a
      relatively conservative management strategy in consideration of its apparent
      isolation. We suggest that the observed pattern of genetic discontinuities has
      developed in response to differences in the seasonal distribution and pattern of
      sea ice habitat and the effects of these differences on the distribution and
      abundance of seals.

PMID- 10583822
TI  - Population structure delineated with microsatellite markers in fragmented
      populations of a tropical tree, carapa guianensis (Meliaceae)
AB  - Deforestation and selective logging in the tropics may have serious consequences
      on genetic processes in tropical tree populations, affecting long-term survival
      of a given species as well as tropical forest communities. Because understanding
      the effects of human-induced changes on genetic processes is of utmost importance
      in formulating sound conservation and management plans for tropical forest
      communities, we developed microsatellite or simple sequence repeat (SSR) markers
      for the tropical tree Carapa guianensis (Meliaceae) and assessed the polymorphism
      of SSRs in adult and sapling populations in a large contiguous forest and in
      selectively logged and fragmented forests. The number of alleles in polymorphic
      loci ranged between 4 and 28. No inbreeding was detected in saplings or adult
      cohorts, but the allelic richness was lower in the sapling cohort of the isolated
      fragment. Genetic distances, Nei's D and (delta&mgr;)2, and RST values among
      saplings were greater than among adult cohorts, suggesting restriction of gene
      flow due to deforestation and habitat fragmentation. These SSR loci may be used
      to address many related questions regarding the population and conservation
      genetics of tropical trees.

PMID- 10583820
TI  - Discordant patterns of morphological and molecular change in broadtail madtoms
      (genus Noturus).
AB  - Two morphologically distinct forms of an undescribed madtom catfish (Noturus sp.)
      occur in the rivers and lakes of southeastern USA. 'Lake' broadtail madtoms are
      endemic to Lake Waccamaw and are probably related to nearby 'river' broadtail
      populations. To investigate phylogenetic relationships, we surveyed mitochondrial
      DNA (mtDNA) sequence variation in 'lake' and 'river' broadtails and other members
      of the genus Noturus. Mitochondrial rDNA data suggest a sister group relationship
      between broadtail madtoms and N. insignis, not N. leptacanthus as posited
      previously. Population-level analyses using additional mtDNA characters (NADH
      dehydrogenase subunit 2 (ND2) and cytochrome b (Cytb)) identified two highly
      divergent genetic lineages within broadtail madtoms that do not correspond to the
      morphological designations 'river' and 'lake'.

PMID- 10583823
TI  - Rangewide variation of the maritime pine bast scale matsucoccus feytaudi duc.
      (Homoptera: matsucoccidae) in relation to the genetic structure of its host
AB  - The bast scale Matsucoccus feytaudi is a specific pest of maritime pine, but the
      damage inflicted by the insect on the host trees is variable, ranging from no
      apparent effect to severe decline of the maritime pine stands. Rangewide
      variation of mitochondrial DNA among M. feytaudi populations was analysed by
      polymerase chain reaction-restriction fragment length-single-strand conformation
      polymorphism (PCR-RFLP-SSCP) analysis and the results compared with the genetic
      information already available for its host. Three main nonoverlapping lineages
      can be distinguished in M. feytaudi. The phylogeography of the pest population is
      clearly related to the history of its host. Most local associations could result
      from common evolution while others must be interpreted as intraspecific host
      shifts. Because the distribution of cultivated tree species is greatly influenced
      by humans, much may be learned concerning their genetic structure from the
      indirect study of their specific pests.

PMID- 10583824
TI  - Mitochondrial DNA analysis of sympatric morphotypes of bottlenose dolphins
      (genus: Tursiops) in Chinese waters.
AB  - The classification within the bottlenose dolphin (genus Tursiops) is
      controversial. Although many morphological variants exist, most authors have
      concluded that the genus is composed of a single species, Tursiops truncatus
      (Montagu 1821). Two distinct morphotypes of bottlenose dolphins, which have been
      referred to as T. truncatus and T. aduncus, exist in sympatry in Chinese waters.
      Comparisons of a 386-bp fragment of the mitochondrial DNA (mtDNA) control region
      (n = 47) indicated that the two sympatric morphotypes were genetically distinct,
      with seven fixed site differences and a sequence divergence of approximately
      4.4%. Phylogenetic analyses using maximum likelihood, neighbour-joining and
      maximum parsimony approaches showed that the truncatus-type dolphins from Chinese
      waters were more closely related to Atlantic Ocean truncatus-type than to the
      sympatric aduncus-type dolphins. The Atlantic truncatus-type dolphins also shared
      the same diagnostic sites that separated Chinese truncatus-type from aduncus-type
      dolphins. The molecular data agreed completely with the morphological
      classifications of the specimens. This congruence is strong evidence that the
      sympatric morphotypes in Chinese waters are reproductively isolated and comprise
      two distinct species. These findings have important implications for the
      conservation of bottlenose dolphins in Chinese waters.

PMID- 10583825
TI  - Phylogeographical population structure of tiger quolls Dasyurus maculatus
      (Dasyuridae: Marsupialia), an endangered carnivorous marsupial.
AB  - Tiger quolls, Dasyurus maculatus, are the largest carnivorous marsupials still
      extant on the mainland of Australia, and occupy an important ecological niche as
      top predators and scavengers. Two allopatric subspecies are recognized, D.m.
      gracilis in north Queensland, and D.m. maculatus in the southeast of the mainland
      and Tasmania. D.m. gracilis is considered endangered while D.m. maculatus is
      listed as vulnerable to extinction; both subspecies are still in decline.
      Phylogeographical subdivision was examined to determine evolutionarily
      significant units (ESUs) and management units (MUs) among populations of tiger
      quolls to assist in the conservation of these taxa. Ninety-three tiger quolls
      from nine representative populations were sampled from throughout the species
      range. Six nuclear microsatellite loci and the mitochondrial DNA (mtDNA) control
      region (471 bp) were used to examine ESUs and MUs in this species. We
      demonstrated that Tasmanian tiger quolls are reciprocally monophyletic to those
      from the mainland using mtDNA analysis, but D.m. gracilis was not monophyletic
      with respect to mainland D.m. maculatus. Analysis of microsatellite loci also
      revealed significant differences between the Tasmanian and mainland tiger quolls,
      and between D.m. gracilis and mainland D.m. maculatus. These results indicate
      that Tasmanian and mainland tiger quolls form two distinct evolutionary units but
      that D.m. gracilis and mainland D.m. maculatus are different MUs within the same
      ESU. The two marker types used in this study revealed different male and female
      dispersal patterns and indicate that the most appropriate units for short-term
      management are local populations. A revised classification and management plan
      are needed for tiger quolls, particularly in relation to conservation of the
      Tasmanian and Queensland populations.

PMID- 10583827
TI  - Small effective population size in the long-toed salamander.
AB  - The effective population sizes (Ne) of six populations of the long-toed
      salamander (Ambystoma macrodactylum) from Montana and Idaho, USA were estimated
      from allozyme data from samples collected in 1978, 1996 and 1997 using the
      temporal allele frequency method. Five of the six estimates ranged from 23 to 207
      (mean = 123 +/- 79); one estimate was indistinguishable from infinity. In order
      to infer the actual Ne of salamander populations, we compared the frequency
      distribution of our observed Ne estimates with distributions obtained from
      simulated populations of known Ne. Our observed Ne estimate distribution was
      consistent with distributions from simulated populations with Ne values of 10,
      25, and 50, suggesting an actual Ne for each of the six salamander populations of
      less than 100. This Ne estimate agrees with most other Ne estimates for
      amphibians. We conclude by discussing the conservation implications of small Ne
      values in amphibians in the context of increasing isolation of populations due to
      habitat fragmentation.

PMID- 10583828
TI  - Comparison of the population genetics and densities of five pinanga palm species
      at kuala belalong, brunei
AB  - This study investigated the effect of population density on the population
      genetic structure of five co-occurring congeneric understorey palm species:
      Pinanga aristata, P. sp. aff. brevipes, P. dumetosa, P. tenella var. tenella and
      P. veitchii, all endemic to northern Borneo. The average population densities of
      the study species varied across a wide spectrum, ranging from 343 (plants per ha)
      in P. tenella to 10 (plants per ha) in P. veitchii. All species of Pinanga palms
      studied had quite high levels of genetic diversity (HE: 0.379, 0.256, 0.294,
      0.133, 0.352). Genetic diversity (HE) was correlated with population density (D;
      rs = - 0.433, P < 0.01) and the average distance to the nearest conspecific
      neighbour (NN; rs = 0.576, P < 0.001) such that the most-dense species had less
      genetic diversity and the less-dense species had greater genetic diversity. Gene
      flow (Nm) among populations approximately followed a gradient of increasing
      species density and abundance, such that the most common species P. dumestosa had
      the greatest gene flow (Nm = 2.268) between its populations and the rarest, most
      sparsely distributed species P. sp. aff. brevipes had the lowest (Nm = 0.698).
      All species of Pinanga were effectively inbred (F: 0.760, 0.856, 0.640, 0.753,
      0.674). The amount of homozygosity and inbreeding (HO, F) were not correlated (P
      > 0.05) with population density (D) or the distance between nearest neighbouring
      plants of the same species (NN).

PMID- 10583826
TI  - Comparisons of mitochondrial DNA (mtDNA) sequences (16S rRNA gene) between
      oviparous and viviparous strains of Lacerta vivipara: a preliminary study.
AB  - The lizard Lacerta vivipara has allopatric oviparous and viviparous populations.
      The mitochondrial DNA (mtDNA) gene coding for the 16S rRNA was sequenced for
      several viviparous lizard populations from France, Switzerland, Bulgaria, Czech
      Republic, The Netherlands, Sweden, and for oviparous lizard populations from the
      Pyrenean and Cantabric Mountains. Seven distinct groups (three oviparous and four
      viviparous) were identified. The net nucleotide divergence between oviparous and
      viviparous haplotypes was 1.3% +/- 0.5 (mean +/- standard deviation). These
      results on mtDNA, together with other data obtained previously, led us to
      formulate a biogeographical scenario that could be tested by further research.

PMID- 10583829
TI  - Microevolution, low clonal diversity and genetic affinities of parthenogenetic
      sitobion aphids in new zealand
AB  - In sharp contrast to their southeast Asian and European counterparts, Sitobion
      miscanthi and S. near fragariae aphids in Australia exhibit a complete absence of
      sexual reproduction. This demands an explanation within the context of the
      evolution and maintenance of sex and parthenogenesis. Accordingly, we executed a
      genetic analysis of the two species in neighbouring New Zealand. Microsatellites
      and single-stranded conformation polymorphism/sequence analysis of the nuclear
      gene elongation factor 1alpha were used to identify aphid clones and confirm
      species identification, respectively. Karyotypic variation was also investigated.
      The New Zealand fauna showed few (nonrecombining) genotypes and appears to have
      received migrants from both Australia and Asia. Other genotypes have apparently
      arisen in situ in New Zealand, exhibiting stepwise mutation of microsatellite
      alleles and also karyotypic change. Thus, these data represent rare evidence of
      evolution within wild-living parthenogenetic lineages. Karyotypic changes appear
      to occur at a rate even greater than that of microsatellite evolution. Strong
      geographical partitioning of genotypes/karyotypes was found, with certain ones
      predominating over large areas. These data suggest that clonal selection could be
      important in the distribution and patterning of genetic variation. We present a
      model to explain the genetic patterns, with particular reference to the absence
      of sexual reproduction in Sitobion aphids in New Zealand and Australia.

PMID- 10583830
TI  - Colonization history and introduction dynamics of capsella bursa-pastoris
      (Brassicaceae) in north america: isozymes and quantitative traits
AB  - Multilocus isozyme genotypic composition for aspartate aminotransferase (AAT),
      leucine aminopeptidase (LAP) and glutamate dehydrogenase (GDH) was studied for
      Capsella in the source continent, Europe (9000 plants from 593 populations), and
      in the colonized continent, North America (2700 plants from 88 populations).
      North America was depauperate in the number of genotypes (by approximately 50%),
      but in terms of frequencies, a few genotypes were common and shared by both
      continents. Although some, very rare, genotypes were, however, unique for North
      America, our data provided no evidence to indicate that the introduced gene pools
      were reconstructed on a multilocus genetic basis after introduction. Instead,
      they argued for a considerable number of independent introduction events.
      Geographical distribution patterns of multilocus genotypes in Europe and North
      America were pronounced and enabled us to trace the colonization history of
      Californian Capsella back to Spanish ancestral populations and those of temperate
      North America back to temperate European gene pools. A random-block field
      experiment with 14 Californian populations from different climatic regions
      revealed that variation patterns of quantitative traits reflect ecotypic
      variation, and the ecological amplitude of Capsella in North America is similar
      to that in Europe, which can be traced back to the introduction of preadapted
      genotypes. It appears that certain multilocus isozyme genotypes are associated
      with certain ecotypes. The variable European gene pool of Capsella was
      essentially introduced into North America without major genetic changes.

PMID- 10583831
TI  - A phylogeographical analysis of the bemisia tabaci species complex based on
      mitochondrial DNA markers
AB  - Mitochondrial 16S ( approximately 550 bp) and cytochrome oxidase I (COI) (
      approximately 700 bp) sequences were utilized as markers to reconstruct a
      phylogeography for representative populations or biotypes of Bemisia tabaci. 16S
      sequences exhibited less divergence than COI sequences. Of the 429 characters
      examined for COI sequences, 185 sites were invariant, 244 were variable and 108
      were informative. COI sequence identities yielded distances ranging from less
      than 1% to greater than 17%. Whitefly 16S sequences of 456 characters were
      analysed which consisted of 298 invariant sites, 158 variable sites and 53
      informative sites. Phylogenetic analyses conducted by maximum parsimony, maximum
      likelihood and neighbour-joining methods yielded almost identical phylogenetic
      reconstructions of trees that separated whiteflies based on geographical origin.
      The 16S and COI sequence data indicate that the B-biotype originated in the Old
      World (Europe, Asia and Africa) and is most closely related to B-like variants
      from Israel and Yemen, with the next closest relative being a biotype from Sudan.
      These data confirm the biochemical, genetic and behavioural polymorphisms
      described previously for B. tabaci. The consideration of all global variants of
      B. tabaci as a highly cryptic group of sibling species is argued.

PMID- 10583832
TI  - Random amplified polymorphic DNA variation among remnant big bluestem (Andropogon
      gerardii vitman) populations from Arkansas' grand prairie
AB  - Random amplified polymorphic DNA (RAPD) analysis was used to characterize genetic
      diversity and genetic distinctiveness of Andropogon gerardii from remnant
      Arkansas prairies. Six oligonucleotide primers, which generated 37 RAPD bands,
      were used to analyse 30-32 plants from six Grand Prairie populations, Baker
      Prairie (Arkansas Ozarks), two Illinois prairies and two cultivars. Genetic
      diversity of the Arkansas remnants ranged from 82.7 to 99.3%, with 89% of the
      total genetic variation within and 11% among populations. The partitioning of
      genetic variation was consistent with that reported for other outcrossing
      perennial grasses, using the more conservative allozyme markers. Principal
      component analysis indicated a northern and southern association within Arkansas'
      Grand Prairie. Although there was no genetic structuring at the landscape level,
      the Illinois prairies and cultivars were different from all Arkansas prairies
      tested. There was significant within-population structuring in four of the seven
      Arkansas remnants, with a negative relationship between genetic similarity and
      geographical distance. The three nonstructured populations were from a linear
      railroad remnant, suggesting different population-level dynamics from nonlinear
      prairies. The results of this study indicated that small isolated remnant big
      bluestem populations were not genetically depauperate and that genetic
      relationships among populations could not be predicted solely on geographical
      proximity.

PMID- 10583833
TI  - Potential of microsatellites for individual assignment: the North Atlantic
      redfish (genus Sebastes) species complex as a case study.
AB  - We used the four redfish taxa (genus Sebastes) from the North Atlantic to
      evaluate the potential of multilocus genotype information obtained from
      microsatellites in assigning individuals at two different levels of group
      divergence. We first tested the hypothesis that microsatellites can
      diagnostically discriminate individual redfish from different groups. Second, we
      compared two different methods to quantify the effect of number of loci and
      likelihood stringency levels on the power of microsatellites for redfish group
      membership. The potential of microsatellites to discriminate individuals from
      different taxa was illustrated by a shared allele distance tree in which four
      major clusters corresponding to each taxa were defined. Concomitant with this
      strong discrimination, microsatellites also proved to be powerful in
      reclassifying specimens to the taxon of origin, using either an empirical or
      simulated method of estimating assignment success. By testing for the effect of
      both the number of loci and the level of stringency on the assignment success, we
      found that 95% of all specimens were still correctly reclassified with only four
      loci at the most commonly used criterion of log0. In contrast, the results
      obtained at the population level within taxa highlighted several problems of
      assignment that may occur at low levels of divergence. Namely, a drastic decrease
      of success with increasing stringency illustrated the lack of power of our set of
      loci. Strong discrepancy was observed between results obtained from the empirical
      and simulated methods. Finally, the highest assignment success was obtained when
      reducing the number of loci used, an observation previously reported in studies
      of human populations.

PMID- 10583834
TI  - Population, habitat and genetic correlates of mycorrhizal specialization in the
      'cheating' orchids corallorhiza maculata and C. mertensiana
AB  - Unlike photosynthetic plants, several distantly related nonphotosynthetic plants
      are highly specialized toward their mycorrhizal fungi. It is unknown whether this
      specialization varies geographically or is influenced by the environment. We have
      investigated these questions in the nonphotosynthetic orchids Corallorhiza
      maculata and C. mertensiana by amplifying fungal internal transcribed spacer
      (ITS) fragments from widespread mycorrhiza samples and then discriminating
      putative fungal species using ITS restriction fragment length polymorphisms
      (RFLPs). Three fungal species were found across 27 plants representing seven
      populations of C. mertensiana; 20 species were found across 104 plants and 21
      populations of C. maculata. All fungi belonged to the Russulaceae, an
      ectomycorrhizal family. Partitioning of Simpson's diversity showed that 48% of
      the variance in occurrences of fungal species coincided with population
      boundaries in C. mertensiana, vs. 68% in C. maculata. This differentiation
      coincided with geography but not habitat in C. mertensiana. In contrast,
      likelihood ratio tests showed strong associations between fungal occurrence and
      both habitat and phenotype in C. maculata. For example, C. maculata populations
      growing under oaks had no fungi in common with nearby populations growing under
      conifers, and those above 2000 m had no fungi in common with those below 2000 m.
      However, plant genetic differentiation may underlie some of these patterns. C.
      mertensiana and C. maculata never shared fungal species, even when growing
      intermixed at the same site, demonstrating genetic control that was independent
      of habitat. Similarly, intermixed normal and pale-coloured variants of C.
      maculata had no fungal species in common. These results demonstrate fine-scale
      genetic influences and geographical mosaicism in a mycorrhizal interaction.

PMID- 10583835
TI  - Impact of gene flow from cultivated beet on genetic diversity of wild sea beet
      populations
AB  - Gene flow and introgression from cultivated plants may have important
      consequences for the conservation of wild plant populations. Cultivated beets
      (sugar beet, red beet and Swiss chard: Beta vulgaris ssp. vulgaris) are of
      particular concern because they are cross-compatible with the wild taxon, sea
      beet (B.vs. ssp. maritima). Cultivated beet seed production areas are sometimes
      adjacent to sea beet populations; the numbers of flowering individuals in the
      former typically outnumber those in the populations of the latter. In such
      situations, gene flow from cultivated beets has the potential to alter the
      genetic composition of the nearby wild populations. In this study we measured
      isozyme allele frequencies of 11 polymorphic loci in 26 accessions of cultivated
      beet, in 20 sea beet accessions growing near a cultivated beet seed production
      region in northeastern Italy, and 19 wild beet accessions growing far from seed
      production areas. We found one allele that is specific to sugar beet, relative to
      other cultivated types, and a second that has a much higher frequency in Swiss
      chard and red beet than in sugar beet. Both alleles are typically rare in sea
      beet populations that are distant from seed production areas, but both are common
      in those that are near the Italian cultivated beet seed production region,
      supporting the contention that gene flow from the crop to the wild species can be
      substantial when both grow in proximity. Interestingly, the introgressed
      populations have higher genetic diversity than those that are isolated from the
      crop. The crop-to-wild gene flow rates are unknown, as are the fitness
      consequences of such alleles in the wild. Thus, we are unable to assess the long
      term impact of such introgression. However, it is clear that gene flow from a
      crop to a wild taxon does not necessarily result in a decrease in the genetic
      diversity of the native plant.

PMID- 10583836
TI  - Armadillos exhibit less genetic polymorphism in North America than in South
      America: nuclear and mitochondrial data confirm a founder effect in Dasypus
      novemcinctus (Xenarthra).
AB  - Heterozygosity at eight nuclear enzymatic loci and mitochondrial DNA control
      region (D-loop) sequence polymorphism was compared between North and South
      American nine-banded armadillos (Dasypus novemcinctus: Xenarthra, Dasypodidae).
      All markers revealed a striking genetic homogeneity amongst Texas, Louisiana, and
      Mississippi individuals, vs. the usual level of polymorphism for the French
      Guiana population. This may reflect a founder effect during colonization of North
      America. Occurrence of polymorphism in the D-loop microsatellite motif of North
      American armadillos suggests a recent recovery of mitochondrial variability.
      Phylogeographic analyses using Dasypus kappleri as outgroup provides evidence for
      a clear separation between North and South American control region haplotypes.

PMID- 10583837
TI  - Noninvasive methods for collecting fresh hair tissue.

PMID- 10583838
TI  - The accuracy of heterozygous base calling from diploid sequence and resolution of
      haplotypes using allele-specific sequencing.

PMID- 10583839
TI  - Microsatellite loci to determine population structure of the Patagonian toothfish
      Dissostichus eleginoides.

PMID- 10583840
TI  - Interspecific variation in microsatellites isolated from tuco-tucos (Rodentia:
      Ctenomyidae).

PMID- 10583841
TI  - Microsatellites in grayling (Thymallus thymallus): comparison of two
      geographically remote populations from the Danubian and Adriatic river basin in
      Slovenia.

PMID- 10583842
TI  - Polymorphic microsatellite markers in Ictalurus punctatus and related catfish
      species.

PMID- 10583843
TI  - Isolation and characterization of long compound microsatellite repeat loci in the
      land snail, Cepaea nemoralis L. (Mollusca, Gastropoda, Pulmonata).

PMID- 10583844
TI  - Polymorphic microsatellite markers for Atlantic halibut, Hippoglossus
      hippoglossus.

PMID- 10583845
TI  - Characterization and isolation of microsatellite loci from the endangered North
      Atlantic right whale.

PMID- 10583846
TI  - Microsatellites from the Amazonian tree Dinizia excelsa (Fabaceae).

PMID- 10583847
TI  - Amplifying dolphin mitochondrial DNA from faecal plumes.

PMID- 10583848
TI  - Interaction between blood flow and motility in normal and inflamed ileum.
AB  - The alterations in local and superior mesenteric blood flow during ileal
      inflammation and their correlations with motility in the normal and the inflamed
      ileum were investigated in the conscious state. Ileal inflammation decreased the
      local mesenteric blood flow but had no significant effect on the superior
      mesenteric blood flow. A significant reduction or an increase in local mesenteric
      blood flow in the normal or the inflamed ileum had no effect on local contractile
      activity. The vascular reactivity to vaso-dilators and vaso-constrictors was
      significantly reduced during inflammation. Local mesenteric blood flow increased
      significantly in the descending segment ahead of a caudal propagating giant
      migrating contraction. The local mesenteric blood flow oscillated during a
      migrating motor complex (MMC) cycle. We conclude that a several-fold increase or
      decrease in local mesenteric blood flow lasting for several minutes does not
      affect contractility. Ileal inflammation decreases local mesenteric blood flow
      but does not affect the total blood flow to the small intestine.

PMID- 10583850
TI  - The effect of physical exercise on parameters of gastrointestinal function.
AB  - Exercise decreases splanchnic bloodflow. Therefore exercise may induce
      alterations in gastrointestinal (GI) function. In the present study we
      investigated the effect of high-intensity exercise on oesophageal motility,
      gastro-oesophageal reflux, gastric pH, gastric emptying, orocaecal transit time
      (OCTT), intestinal permeability and glucose absorption simultaneously, using an
      ambulatory protocol. Ten healthy well-trained male subjects underwent a rest
      cycling-rest, and a rest-rest-rest protocol (60-90-210 min). Oesophageal
      motility, gastro-oesophageal reflux and intragastric pH was measured using a
      trans-nasal catheter. OCTT was measured via breath H2 measurement. A sugar
      absorption test was applied to determine intestinal permeability and glucose
      absorption. Gastric emptying was measured using the 13C-acetate breath test.
      Peristaltic velocity was increased during cycling, compared to rest (4.92 (2.86)
      vs. 4.03 (1. 48) cm s-1, P = 0.015). Peristaltic contraction pressure at the mid
      oesophagus and the duration of the peristaltic contractions at the mid- and
      distal oesophagus was lower during cycling. There were no differences between the
      pre-exercise, the exercise and the post-exercise episodes for gastric pH or for
      both the number and duration of reflux episodes, in both the rest and cycling
      trials. Neither gastric emptying nor OCTT showed differences between rest and
      cycling. The lactulose/rhamnose ratio and intestinal glucose absorption were
      significantly decreased in the cycling trial. Our model enables multiple GI
      measurements during exercise. Cycling at 70% Wmax does not lead to differences in
      reflux, gastric pH or gastrointestinal transit in healthy trained individuals.
      The distal oesophageal pressure decreases and peristaltic velocity increases. The
      lactulose/rhamnose ratio and jejunal glucose absorption are decreased during
      exercise.

PMID- 10583849
TI  - Effect of an o-raffinose cross-linked haemoglobin product on oesophageal and
      lower oesophageal sphincter motor function.
AB  - The present experiments evaluate the effects on oesophageal motility of an o
      raffinose cross-linked haemoglobin-based oxygen carrier (HBOC) purified from
      outdated donated human blood cells (HemolinkTM), with attention to dose-response
      (0.6-2.4 g kg-1), oxygenation status and low molecular weight components (4.4
      36.4% 64 kDa or less). In ketamine-anaesthetized cats, lower oesophageal
      sphincter (LES) function and oesophageal peristalsis were monitored 0.5 h before,
      during and up to 3.5 h after HBOC infusion, and in some cats at 24 h. (1) All
      products significantly inhibited LES relaxation and increased peristaltic
      velocity in the distal smooth muscle oesophagus, without consistently altering
      resting LES pressure. (2) Effects on peristaltic velocity reached a maximum at
      the smallest dose, whereas the effects on LES relaxation had a maximum effect at
      1.2 g kg-1. (3) Effects were not significantly altered by the haemoglobin
      oxygenation status or presence of low molecular weight components. (4) Repetitive
      oesophageal contractions occurred. In the cat, an o-raffinose cross-linked human
      haemoglobin product produces changes in oesophageal body and LES function, which
      are independent of the HBOC oxygenation status and composition of the low
      molecular weight components tested. Changes may persist for at least 24 h. These
      motility changes are likely due to scavenging of nitric oxide by the haemoglobin.

PMID- 10583851
TI  - Isopower maps of the electrogastrogram (EGG) after total gastrectomy or total
      colectomy.
AB  - Isopower or topographic electrogastrograms (EGG) correspond to topographic
      electroencephalograms. Both project the topographic localizations of the spectral
      frequencies on the abdominal surface or scalp. This paper compares the pre
      operative control isopower EGG maps with those of total gastrectomy or total
      colectomy. EGGs were recorded simultaneously at 27 locations on the epigastro
      abdominal surface. Spectral analysis by the maximal entropy method (MEM) was
      performed and the ensemble means of pre-prandial and post-prandial spectra were
      calculated. The spectral frequencies were arbitrarily classified into five
      groups, 1 cycle per minute (cpm) (0-2.4 cpm), 3 cpm (2.5-4.9 cpm), 6 cpm (5.0-7.4
      cpm), 8 cpm (7.5-9.9 cpm) and 10 cpm (10.0-12.9 cpm). Maximal power peaks in each
      spectral group, and electrode locations which were expressed by x-y coordinates
      were the indicators for making the isopower EGG maps by using a contour map
      program. Thereafter, the maximal power spots or foci in each spectral group were
      determined. The pre-operative maximal power foci of the 1, 8 and 10 cpm groups
      were distributed rather evenly on the epigastro-abdominal surface. Those of the 3
      and 6 cpm groups, mainly concentrated in the epigastric region, were absent in
      almost all patients who had undergone total gastrectomy. The infra-umbilical foci
      of the 3 and 6 cpm groups completely disappeared after total colectomy. The infra
      umbilical foci of the 3 and 6 cpm groups (2.5-7.4) may reflect the colonic
      activities and the epigastric 3 cpm foci, the gastric activities. The pre
      operative maximal power of the 3 cpm foci decreased significantly after total or
      sub-total gastrectomy.

PMID- 10583852
TI  - Effect of gastrin on proximal gastric motor function in humans.
AB  - The present study was performed to investigate the effect of gastrin on proximal
      gastric motor and sensory function. Ten healthy volunteers participated in three
      experiments performed in random order during: (A) continuous intravenous infusion
      of saline (control) or (B) gastrin (15 pmol kg-1 h-1) reaching postprandial serum
      gastrin levels or (C) gastrin infusion (15 pmol kg-1 h-1) preceded by acute acid
      inhibition with intravenous omeprazole. Proximal gastric function was evaluated
      using a barostat with stepwise pressure and volume distensions and volume
      measurements during set pressure (MDP + 2 mmHg). Gastrin significantly increased
      the intragastric volume compared to control during MDP + 2 mmHg (276 +/- 39 mL
      vs. 159 +/- 9 mL; P < 0.01) and reduced phasic slow volume wave frequency (from
      1.4 +/- 0.1 to 0.7 +/- 0.1 per min; P < 0.01). During isobaric distensions
      gastrin increased gastric compliance (42 +/- 4 mL mmHg-1 vs. 31 +/- 3 mL mmHg-1;
      P < 0.05). These effects of gastrin infusion were completely abolished by
      pretreatment with omeprazole. Symptom perception decreased during gastrin
      infusion and was more dependent on pressure and wall tension than on volume. IN
      CONCLUSION: gastrin may have a role in regulating proximal gastric mechanics by
      inducing fundic relaxation and increasing gastric wall compliance. The effect of
      gastrin is dependent on acid secretion.

PMID- 10583853
TI  - Involvement of 5-HT3 and 5-HT4 receptors in the motor activity of isolated
      vascularly perfused rat duodenum.
AB  - The involvement of serotonin (5-HT) receptor subtypes in motor activity of the ex
      vivo vascularly perfused rat duodenum was investigated. Clusters of phasic
      contractions (CPCs), migrating in an oral to anal direction, were obtained
      without any stimulation. Drug effects were evaluated by changes in different
      components of the pressure waves, such as motor index (MI), frequency, amplitude
      and duration of the CPC. The effect of 5-HT depletion on motor activity was
      examined in animals treated with p-chlorophenylalanine (PCPA). The MI, frequency
      and duration of CPC were decreased by PCPA, but the amplitude was not affected,
      suggesting that endogenous 5-HT may play an important role in regulation of the
      motor activity of the rat intestine. The importance of the 5-HT receptor subtypes
      in the regulation of motor activity was examined. Neither the nonselective 5-HT1
      and 5-HT2 receptor antagonist, methysergide, nor the 5-HT2 receptor antagonist,
      ketanserin, affected motor activity. However, the 5-HT3 receptor antagonists,
      granisetron and azasetron, decreased percentage MI, frequency, percentage
      amplitude and percentage duration of CPC. The 5-HT4 receptor antagonist,
      SB204070, exerted both excitatory and inhibitory actions, with a higher dose (10
      nM) stimulating percentage MI, frequency, percentage amplitude and percentage
      duration, and a lower dose (0.1 nM or 1 nM) decreasing percentage MI and
      percentage duration of CPC. These results suggest that endogenous 5-HT regulates
      the motor activity of the rat duodenum through 5-HT3 and 5-HT4 receptors, with
      the former mediating the stimulatory influence and the latter mediating both
      stimulatory and inhibitory influences.

PMID- 10583854
TI  - Activation of an adrenergic and vagally-mediated NANC pathway in surgery-induced
      fundic relaxation in the rat.
AB  - The aim of this study was to pharmacologically characterize and investigate the
      possible contribution of adrenergic and nonadrenergic noncholinergic (NANC)
      pathways involved in the relaxation of the rat gastric fundus following abdominal
      surgery. Using an intragastric balloon, the effect of skin incision (SI),
      laparotomy (LT) and manipulation of the small intestine followed by caecal
      resection (M + R) on fundic pressure was evaluated. SI resulted in a brief
      relaxation of the gastric fundus abolished by guanethidine and blocked by
      hexamethonium and the combination of phentolamine, propranolol and atropine
      (PPA). LT induced a longer lasting relaxation which was abolished by guanethidine
      and hexamethonium. It was blocked by PPA and the combination of ganglionectomy
      and vagotomy, but unaffected by atropine, vagotomy or ganglionectomy. M + R
      induced a long-lasting relaxation which was only partly blocked by guanethidine
      or PPA, illustrating an inhibitory NANC component. Vagotomy combined with
      guanethidine completely abolished the relaxation following M + R, whereas it was
      significantly blocked by hexamethonium and the combination of ganglionectomy with
      vagotomy. These results indicate that SI, LT and M + R induce inhibition of
      fundic motility via an adrenergic mechanism. During M + R, an additional vagally
      mediated inhibitory NANC pathway is activated. Finally, we suggest that LT and M
      + R inhibit the gastric fundus via both a splanchnic and a vagal reflex pathway.

PMID- 10583855
TI  - Hemozoin is a key factor in the induction of malaria-associated
      immunosuppression.
AB  - Infection-associated immunoincompetence during malaria might result from
      macrophage dysfunction. In the present study, we investigated the role of
      macrophages as target for immunosuppression during infection, using the murine
      Plasmodium c. chabaudi model. Special attention has been paid to the analysis of
      processing/presentation of protein antigens and presentation of peptides, using
      cocultures of peritoneal exudate cells (PECs) from infected mice and antigen
      specific T-cell hybridomas. The results obtained indicate a defective processing
      of protein antigens that becomes maximal at acute parasitemias. In addition,
      macrophages from acutely infected mice suppress the interleukin-2 production by
      the antigen-activated T-cell hybridomas. This effect was independent of
      prostaglandin and nitric oxide production by the macrophage. The possible role of
      parasite components in the impaired accessory cell function of PECs was
      investigated and hemozoin, the end-product of the hemoglobin catabolism by
      intraerythrocytic malaria parasites, was found to induce similar infection
      associated deficiencies in vitro. Moreover, hemozoin, was shown to mimic the
      immunosuppressive effects induced in PECs during in-vivo infections with P.
      chabaudi. In conclusion, we propose that hemozoin is a key factor in the malaria
      associated immunosuppression, affecting both the antigen processing and
      immunomodulatory functions of macrophages.

PMID- 10583856
TI  - Opsonization of Toxoplasma gondii tachyzoites with nonspecific immunoglobulins
      promotes their phagocytosis by macrophages and inhibits their proliferation in
      nonphagocytic cells in tissue culture.
AB  - We have recently shown that Toxoplasma gondii tachyzoites grown in in vitro
      culture can bind unspecific immunoglobulin (Ig) through their Fc moiety. We show
      now that Fc receptors are also present on T. gondii within the host animal, and
      that intraperitoneal parasites in immunocompetent mice are saturated with
      unspecific Ig. We have also investigated the effect of the parasite's Fc receptor
      on the interaction of tachyzoites with mammalian cells, using the Vero cell line
      as a model for nonphagocytic host cells and murine peritoneal macrophages in
      primary culture as a model for phagocytic cells. Coating of tachyzoites with
      parasite-unrelated Ig did not enhance their invasive capacity in either target
      cell type, but slightly decreased the parasite proliferation. Moreover,
      phagocytosis by macrophages was increased by approximately 50% when parasites
      were coated with unspecific Ig. These results indicate that the Fc receptor on T.
      gondii affects the balance between invasion and phagocytosis in a way that is
      detrimental to the parasites.

PMID- 10583857
TI  - Reversal in microfilarial density and T cell responses in human lymphatic
      filariasis.
AB  - This study reports reversals in microfilarial density and the accompanying
      changes in cellular immune responses to filarial antigens of 39 individuals (11
      microfilaria-positives, 22 microfilaria-negatives and six converters) living in
      an area endemic for brugian filariasis. Microfilarial counts decreased from
      April, the end of the rainy season to July, middle of the dry season (g.m. 88
      mf/ml and 38 mf/ml, respectively; P = 0.001) and subsequently increased in
      November, the beginning of the rainy season (P = 0.088). Whereas the
      proliferative responses remained low throughout the study period in
      microfilaraemic individuals, in amicrofilaraemics these responses changed in the
      opposite direction to that of microfilarial densities. In three converters,
      proliferation changed in the opposite direction to the presence or absence of
      microfilariae. Cytokine analysis in the converters revealed that interferon-gamma
      was most affected by the shifts in microfilarial densities. In contrast,
      interleukin-4 responses showed little correlation with changes in parasite
      densities.

PMID- 10583858
TI  - Immunogenicity of malaria transmission-blocking vaccine candidate, y230.CA14
      following crosslinking in the presence of tetanus toxoid.
AB  - Proteolytically processed 310 kDa form of Plasmodium falciparum gamete surface
      antigen, Pfs230, is the target of malaria transmission-blocking monoclonal
      antibodies. To design a recombinant malaria transmission-blocking subunit
      vaccine, the amino terminus of the 310 kDa surface-exposed form of Pfs230 was
      mapped to amino acids (aa) 522 and 584 using a series of peptides and recombinant
      proteins encoding distinct regions of Pfs230. Antiserum generated against an
      Escherichia coli-produced recombinant protein, spanning the Pfs230 processing
      site and extending into the cysteine domains, r230/MBP.C (aa 443-1132), reduced
      parasite infectivity by 71.2-89.8%. To determine if the region spanning the
      cleavage site blocked malaria transmission when produced as a secreted protein by
      Saccharomyces cerevisiae, y230.CA14 (aa 467-584) was generated, purified,
      emulsified in adjuvant and used to vaccinate mice. In contrast to E. coli
      produced r230/MBP.C, the immune response generated against y230. CA14 was very
      weak. To enhance the response, y230.CA14 was mixed with tetanus toxoid,
      chemically crosslinked, repurifed, and its immunogenicty compared with
      unconjugated y230.CA14. Conjugated-y230. CA14/TT required fewer booster
      injections to induce an immune response against Pfs230 and the antibodies
      generated reacted with the surface of intact gametes and immunoprecipitated
      radiolabelled Pfs230 extracted from 125I surface-labelled gametes to a greater
      extent. After seven injections, all y230.CA14 vaccinated mice developed anti
      Pfs230 antibodies and the isotype profile was the same. In addition to enhancing
      the initial immune response generated against y230.CA14, conjugation focuses the
      immune response toward epitopes within the region of Pfs230 present on the
      surface of the gamete.

PMID- 10583859
TI  - Characterization of murine Th1 clones specific to egg antigen of Schistosoma
      japonicum and their interaction with cytokines.
AB  - T cell clones (B1, B21, B7, A25) specific to the soluble egg antigen (SEA) of
      Schistosoma japonicum were established from C3H/He mice immunized with SEA. These
      clones belonged to CD3+, CD4+ and CD8-Th1 cells, showing TCR-gamma delta-, TCR
      alpha beta+ and Vbeta10b+. The molecular weights of target antigens recognized by
      the clones ranged from 51 to 80 kDa. Interleukin-2 (IL-2) and IL-12 could
      vigorously increase the proliferation response of the T clones to SEA; while IL
      10 and transforming growth factor-beta1 (TGF-beta1) strongly inhibited the
      response. IL-12 activity was detected in the culture supernatant of T clones
      stimulated with SEA in the presence of APC (antigen presenting cells). This
      stimulation also upregulated the expression of the IL-12 receptor on the T
      clones. IL-12 from APC served as a costimulatory factor for the SEA induced
      proliferation of the T clone cells. Clone B1 was able to induce granuloma
      formation both in vivo and in vitro. These data provide further insight into the
      complicated interaction among SEA, T cell and cytokine at a clonal level in S.
      japonicum infection.

PMID- 10583860
TI  - Parasite-derived immunoregulatory molecules.

PMID- 10583861
TI  - Adversarial relationship between the leishmania lipophosphoglycan and protein
      kinase C of host macrophages.
AB  - The dominant glycoconjugate on the cell surface of all Leishmania promastigotes
      is an unusual glycoconjugate named lipophosphoglycan (LPG). Its relative
      abundance, unique structure, and cellular location have implicated LPG as an
      essential virulence determinant. One feature of LPG resides in its strong
      inhibitory effect on the activity of protein kinase C (PKC) of host macrophages.
      This article summarizes the evidence that LPG is inhibitory toward PKC activation
      in macrophages and discusses the implication of such inhibition on
      intramacrophage survival of the parasite.

PMID- 10583862
TI  - Immunomodulatory properties of a phosphorylcholine-containing secreted filarial
      glycoprotein.
AB  - ES-62 is a phosphorylcholine (PC)-containing glycoprotein which is secreted by
      the rodent filarial nematode Acanthocheilonema viteae. A homologue exists in the
      human filarial nematode Brugia malayi and indeed PC is found attached to
      glycoproteins of many, if not all, filarial species. At concentrations equivalent
      to those found for PC-containing molecules in the bloodstream of parasitized
      humans, ES-62 is able to polyclonally activate certain protein tyrosine kinase
      and mitogen-activating protein kinase signal-transduction elements in B and T
      lymphocytes following in-vitro exposure. Although this interaction is
      insufficient to cause lymphocyte proliferation per se, it serves to desensitize
      the cells to subsequent activation of the phosphoinositide-3-kinase, protein
      kinase C and Ras mitogen-activating protein kinase pathways and hence also to
      proliferation via the antigen receptors. The active component of ES-62 appears to
      be PC, as the results obtained with ES-62 are broadly mimicked by PC conjugated
      to BSA or PC alone. Although PC can also be shown to desensitize B cells
      following in-vivo administration, not all cells are affected, as it is still
      possible to generate an antibody response. Dissection of this response indicates
      that it is of the Th2 type.

PMID- 10583864
TI  - Experimental Ascaris suum infection in the pig: protective memory response after
      three immunizations and effect of intestinal adult worm population.
AB  - The protective immune response to larval migration in pigs, with or without adult
      intestinal worm populations, 10 weeks after 3 weekly Ascaris suum inoculations,
      was studied in 45 pigs. Controlled adult worm populations were achieved by oral
      transfer of 10 adult worms to previously immunized pigs after anthelmintic
      drenching. A significant reduction in larval recovery from lungs on day 7, and
      small intestine on day 14, was observed in immunized pigs compared with
      previously uninfected control pigs after challenge inoculation. The strong
      anamnestic response to larval migration was characterized by blood eosinophilia
      and specific immune responses measured by peripheral blood enzyme-linked
      immunospot and immunosorbent assays using larval excretory-secretory products and
      adult body fluid as well as Western blotting with a panel of stage-specific A.
      suum antigens. Immune detection of a previously unreported 10 kDa band, specific
      to the L2 larval stage and egg hatch fluid, emerged in all pigs after challenge,
      while the major adult body fluid constituent, ABA-1, remained unrecognized. No
      significant effect of an intestinal adult worm burden on the larval recovery
      after a challenge inoculation or on the immune response before or after challenge
      inoculation could be detected. These results indicate that a significant
      protective memory immune response to A. suum challenge inoculation can be induced
      in pigs, and that this protective immunity is not significantly modulated by the
      presence of adult parasites in the gut.

PMID- 10583863
TI  - Specificity in signal transduction among glycosylphosphatidylinositols of
      Plasmodium falciparum, Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.
AB  - Glycosylphosphatidylinositols (GPIs) and related glycoconjugates of parasite
      origin have been shown to regulate both the innate and acquired immune systems of
      the host. This is achieved through the activation of novel GPI-dependent
      signalling pathways in macrophages, lymphocytes and other cell types. Parasite
      GPIs impart at least two distinct signals to host cells through the structurally
      distinct inositolphosphoglycan (IPG) and fatty acid domains. Binding of IPG to as
      yet uncharacterized cell surface receptor(s) leads to activation of src-family
      protein tyrosine kinases: depending upon structure, GPI-derived fatty acids can
      either activate or antagonize protein kinase C, and may enter the
      sphingomyelinase pathway. The degree of fatty acid saturation may also contribute
      to signalling activity. Thus, variation in structure of parasite GPIs imparts
      different properties of signal transduction upon this class of glycolipid. The
      divergent activities of GPIs from various protozoal taxa reflect global aspects
      of the host/parasite relationship, suggesting that GPI signalling is a central
      determinant of disease in malaria, leishmaniasis and both American and African
      trypanosomiases.

PMID- 10583865
TI  - In utero sensitization in Chagas' disease leads to altered lymphocyte phenotypic
      patterns in the newborn cord blood mononuclear cells.
AB  - Neonates are sensitized in utero to maternal circulating antigens and idiotypes
      that eventually cross the placental barrier. We believe that children born of
      mothers under long lasting antigenic stimulation, as in a chronic infection,
      would be affected by these maternal influences and show differences in the
      phenotypic repertoire of lymphocytes. To test this hypothesis, we evaluated flow
      cytometry studies in cord blood mononuclear cells (CBMC) from children born of
      chagasic mothers without congenital disease, with special attention to T and B
      cells and expression of activation markers. We have also evaluated the peripheral
      blood mononuclear cells (PBMC) of these children 6 months after delivery. We show
      that CBMC of children born of infected mothers have high proliferative responses
      to antigenic stimulation, significantly lower mean percentages of CD3+ T cells,
      CD4+ T cells and diminished expression of the costimulatory molecule CD28 in the
      CD8+ T cell subset. Interestingly, this subpopulation has an increased expression
      of the MHC class II gene product as evidenced by the expression of HLADR. It is
      noteworthy that the patterns observed in CBMC T lymphocyte populations of these
      children closely resemble earlier findings on lymphocytic profiles of chronic
      chagasic adult patients and those of their mothers. We also show that, 6 months
      after delivery, some alterations observed at birth are reversed to levels
      observed in noninfected individuals.

PMID- 10583866
TI  - Paramyosin is a major target of the human IgA response against Schistosoma
      japonicum.
AB  - Human resistance and susceptibility to schistosomiasis is associated with age and
      specific antibody isotype responses against worm (SWAP) and egg (SEA) antigens.
      In a cross-sectional study of 176 individuals infected with Schistosoma japonicum
      in the Philippines, strikingly similar isotype response patterns against SWAP and
      SEA was observed when compared to other endemic areas. Interestingly, IgA titres
      to SWAP correlated with older age among S. japonicum-infected individuals (n =
      176, P < 0.01), suggesting a role for this isotype in protective immunity. To
      identify the molecular targets of human IgA, 17 high-IgA/SWAP responders were
      identified from the said population. IgA antibodies from the majority (14/17) of
      these individuals recognized a band of 97 kDa (Sj97), comigrating in immunoblots
      with the myofibrillar protein paramyosin. The antigen was confirmed as paramyosin
      by expressed sequence tag (EST)-analysis of four clones obtained by screening an
      adult S. japonicum cDNA library with pooled IgA antisera and mouse antiparamyosin
      polyclonal antibodies. The identification of paramyosin as a major target of
      human IgA raises its potential as a vaccine candidate that targets mucosal immune
      responses. Since this antigen is exposed on the parasite surface only during the
      lung stages, we propose that human IgA contributes to parasite attrition during
      schistosome migration in the lungs.

PMID- 10583867
TI  - Infection of mice by a Toxoplasma gondii isolate from an AIDS patient: virulence
      and activation of hosts' immune responses are independent of parasite genotype.
AB  - Virulence of a Toxoplasma gondii isolate from an AIDS patient (designated as PTN)
      was compared with that of PLK, a variant of P-strain. Virulence was assessed in
      term of host survival upon inoculation in different strains of mice. All C57BL/6
      mice died of acute toxoplasmosis by 7-10 days following intraperitoneal infection
      with 1 x 105 tachyzoites of PTN and 40% of BALB/c died on day 23 of infection,
      whereas 100% CBA/J infected with the same dose of PTN survived, as did outbred
      Swiss Webster mice. All C57BL/6, BALB/c, CBA/J, or Swiss Webster died of acute
      toxoplasmosis by 3-9 days postinfection upon inoculation with same dose of
      tachyzoites of the PLK strain. Further studies in CBA/J mice demonstrated that
      mice infected with PTN elicited a significantly higher lymphoproliferative
      response to crosslinked anti-CD3 mAb or Con A than PLK infected mice, and
      augmented production of TNFalpha, lower levels of nitrite and a higher number of
      NK cells. Genetical analysis indicated that both PLK and PTN strains of T. gondii
      are from type ll. Interestingly, being of the same genotype, the later showed
      less virulence upon inoculation in mice and had greater capacity to activate host
      immune system than the PLK strain.

PMID- 10583882
TI  - Alternatives to standard blood transfusion: availability and promise.
AB  - Largely due to concerns over safety, a wide variety of alternatives to the
      conventional blood bank products of red cells, platelet concentrates, plasma and
      fractionated plasma products are under development. This review attempts to
      survey the alternative therapies that are being developed, whether they provide
      viable solutions and what impact they might have on transfusion practice.

PMID- 10583883
TI  - Robotic selective sampling and total automation for anti-CMV screening.
AB  - The provision of anti-cytomegalovirus (CMV)-negative blood products causes the
      blood banking community considerable logistical problems. This is due firstly to
      the fact that only a select group of patients require anti-CMV-negative units,
      namely the immunocompromised. Secondly, the prevalence of CMV antibody in the
      blood donor population is high and, thirdly, the demand for anti-CMV-negative
      blood components continues to increase. To address this problem, a system of
      robotic selective sampling and total assay automation for anti-CMV screening has
      been developed. An in-house computer program generates a worklist from the
      donation database of samples requiring screening to meet clinical demand.
      Algorithms incorporated in the program ensure that the minimum number of samples
      possible are selected for provision of anti-CMV-negative products. This
      'intelligent' selection of samples substantially reduces reagent cost. Robotic
      pipetting from the electronically derived worklist, masterplate to test plate
      robotic transfer and use of an automated assay processor maintains specific
      sample identification throughout. Results are read mechanically and transmitted
      directly to the main computer system. Robotic selective sampling and total assay
      automation produces an efficient, secure, auditable and completely traceable
      system for the provision of anti-CMV-negative units. The system produced a
      substantial reduction in labour costs with a 40% reduction in reagent usage. This
      system can be readily adapted for screening other markers on a selective basis.

PMID- 10583884
TI  - Epitope-specific glutamic acid decarboxylase-65 autoantibodies in intravenous
      immunoglobulin preparations.
AB  - Intravenous immunoglobulin (IVIG) has been used to treat many autoimmune
      disorders including Stiff-Man Syndrome (SMS). SMS is a neurological disorder
      associated with an immune-mediated deficiency of gamma-aminobutyric acid (GABA)
      due to autoantibodies against the GABA synthesizing enzyme glutamic acid
      decarboxylase-65 (GAD65). GAD65 autoantibodies are present among 1-2% of healthy
      individuals. It can therefore not be excluded that GAD65 autoantibodies may be
      present in IVIG, which is prepared from multiple blood donors. We report here
      that GAD65 but not IA-2 autoantibodies were present in commercial IVIG
      preparations. The presence of autoantibodies may affect the outcome of IVIG
      treatment and screening commercial preparations of IVIG for GAD65 autoantibodies
      is therefore recommended before treating patients.

PMID- 10583885
TI  - Volume-dependent collection of peripheral blood progenitor cells during large
      volume leukapheresis for patients with solid tumours and haematological
      malignancies.
AB  - We investigated the efficacy of peripheral blood progenitor cell (PBPC)
      collection during large-volume leukapheresis (LVL) in patients with solid tumours
      and haematological malignancies (n = 18). The time- and volume-dependent harvest
      of leucocytes (WBC), mononuclear cells (MNC), CD34+ cells and colony-forming
      cells (CFU-GM) during LVL was analysed in six sequentially filled collection bags
      processing four times the patient's blood volumes. The amounts of leucocytes
      (WBC) and the purity of mononuclear cells (MNC%) did not show any significant
      changes during LVL. The percentage of CD34+ cells remained constant for the first
      three bags but consecutively decreased from initially 1.71% CD34+ cells in the
      beginning of LVL to finally 1.34% CD34+ cells (P = 0.02). The mean numbers of
      colony-forming cells (CFU-GM) decreased from 74 microL-1 to 59 microL-1 during
      LVL (P = 0.16). Furthermore, the comparison of volume-dependent PBPC collection
      for patients with high, medium and low total yields of CD34+ cells showed similar
      kinetics on different levels for the three groups. We concluded that - relative
      to the initial total amount of PBPC harvested - comparable numbers of progenitor
      cells can be collected during all stages of LVL with a slight decreasing trend
      processing four times the patient's blood volumes.

PMID- 10583887
TI  - Monitoring the clearance of fetal RhD-positive red cells in FMH following RhD
      immunoglobulin administration.
AB  - Anti-RhD immunoglobulin was administered to RhD-negative women based on estimates
      of fetal bleed size obtained using a direct immunofluorescence flow cytometric
      technique employing a FITC-conjugated monoclonal human anti-D (BRAD 3). The
      effectiveness of the dose administered was assessed by (i) measuring the fraction
      of RhD-positive fetal cells in the maternal circulation at d0, and between d2 and
      d10 post RhD Ig administration, (ii) quantifying the amount of anti-D detectable
      in maternal plasma following RhD Ig injection in the perinatal period and (iii)
      assessing maternal serum for the presence of immune anti-D in follow-up samples
      taken 3 months to 3 years after delivery. Fifty-four women were assessed, 29
      having fetal bleeds in excess of 4 mL. Follow-up samples were received from 20/29
      mothers after RhD Ig administration; 43-99% and 69-99% of fetal cells had been
      cleared by d2/3 and d5/6, respectively, in 14/20 mothers, whereas less than 50%
      had been cleared in the remaining mothers. Long-term follow-up samples were
      obtained from eight of the 29 mothers (four with bleeds >/=20 mL, two with bleeds
      >95 mL): none had detectable anti-D in the serum 4 months to 3 years after
      delivery despite the persistence of up to 36% fetal RhD-positive cells in the
      maternal circulation six days after delivery.

PMID- 10583886
TI  - Prenatal treatment of severe fetomaternal alloimmune thrombocytopenia.
AB  - Prenatal treatment of fetomaternal alloimmune thrombocytopenia (FMAIT) in
      previously affected families is of great clinical importance. We report here our
      experience in the prenatal treatment of 15 severely thrombocytopenic fetuses.
      Thrombocytopenia was in 13 cases due to immunization to HPA-1a, in one case to
      HPA-5b, and in one case to HPA-6b. Thirteen fetuses received altogether 34
      intrauterine platelet transfusions, seven of them in combination with maternal
      administered intravenous gammaglobulin (IVIG) and two in combination with IVIG
      and prednisone. Six of the 13 fetuses had only one transfusion just prior to
      delivery. In our experience, IVIG seemed to be less effective than reported; only
      two fetuses of eight treated initially with weekly maternal-administered IVIG
      responded, and these were the mildest affected cases in the study. On the other
      hand, owing to the short survival time, weekly platelet transfusions could only
      partly maintain a safe platelet count in the four fetuses treated with serial
      intrauterine platelet transfusions. The number of transfusions needed to be
      limited because of the high cumulative risk associated with repeated procedures.
      Three of 34 intrauterine platelet transfusions were associated with near-loss of
      three different fetuses due to prolonged fetal bradycardia after the transfusion.
      In conclusion, overall neonatal outcome was good, with no mortality; among the
      study group there was no intracranial haemorrhage (evaluated by postnatal
      ultrasonography) compared with one case in their untreated siblings. However, the
      problem of the optimal treatment of FMAIT remains to be solved. For the moment,
      the treatment of choice is a combination of maternal IVIG and platelet
      transfusions in severely affected cases. Serial fetal blood samplings (FBS) are
      needed in order to monitor the fetus with sufficient care.

PMID- 10583888
TI  - A chemiluminescence test for predicting the outcome of transfusing incompatible
      blood.
AB  - A chemiluminescent test (CLT) which measures the metabolic response of human
      monocytes to sensitized red cells was developed to distinguish antibodies capable
      of causing the increased destruction of transfused incompatible red cells from
      antibodies which are clinically benign. Thirty sera containing IgG antibodies to
      high-frequency antigens were tested; 27 of these sera were also tested using the
      monocyte monolayer assay (MMA). The clinical significance of antibodies in 14 of
      the sera was known: three (anti-Ata (two), -JMH) caused accelerated clearance of
      51Cr-labelled cells, five (anti-'MiIII', -Yta, three unidentified) caused
      haemolytic transfusion reactions and six (anti-Yta, -Ge, -JMH, -Xga, -Kna (two))
      did not appear to affect red cell survival. Overall, results from the MMA and CLT
      showed good agreement; seven sera were negative in both assays, 18 sera were
      positive in both assays and two sera were positive in the MMA but negative in the
      CLT. There was no clear relationship between the activity of different antibodies
      and the level of sensitization as determined by flow cytometry. Antibody activity
      could be either increased or decreased by incubation of sensitized red cells with
      fresh serum. MMA results were in concordance with the clinical significance of
      antibodies where known in eight of 10 cases. CLT results were in concordance with
      clinical significance in 12 of 14 cases. Both assays gave false-positive results
      with serum from a patient with anti-Kna who had received red cell transfusions
      without adverse effect. This appeared to be due to the ability of anti-Kna to
      cross-link complement receptor 1 (CR1) on red cells to CR1 on monocytes; negative
      results were obtained using autologous monocytes.

PMID- 10583889
TI  - A method for drying red blood cells for solid-phase immunoassay.
AB  - To develop a simpler and quicker alloantibody screening method, red cell stroma
      were bound and dried to microplate wells for use in magnetic-mixed passive
      haemagglutination (M-MPHA) tests. In the procedure of drying stroma, the Triton X
      100-based haemolysing method gave lowest denaturation of red blood cells, and
      this method gave increased reactivity to Kidd and Rh antigens and clinically
      significant antibodies were detected as well as with the M-MPHA test. But long
      incubation with Triton X-100 and using high concentrations of Triton X-100 gave
      rise to some reduction in antigenicity, so the precise conditions for haemolysis
      are critical. This dried stroma-coated microplate can be stored for longer and
      more easily at room temperature than nondried intact red blood cells. The new
      system gave good sensitivity and the overall test time was shortened and should
      give a particular advantage for mass screening and for automation of this test.

PMID- 10583890
TI  - Proceedings of the International Seminar, Royal College of Pathologists, 13
      November 1998. Altruism: is it alive and well?

PMID- 10583891
TI  - Variant Creutzfeldt-Jakob disease is not related to underlying IgA deficiency.

PMID- 10583892
TI  - Evaluation of an enzyme-linked immunosorbent assay kit (GTI PakPlus) for the
      detection of antibodies against human platelet antigens.

PMID- 10583893
TI  - Evaluation of an enzyme-linked immunosorbent assay kit (GTI PakPlus(R)) for the
      detection of antibodies against human platelet antigens

PMID- 10583894
TI  - Geographical information systems (GIS) and the tuberculosis DOTS strategy.

PMID- 10583895
TI  - Spatial implications of the tuberculosis DOTS strategy in rural South Africa: a
      novel application of geographical information system and global positioning
      system technologies.
AB  - We used GIS/GPS technology to document and quantify improved access to
      tuberculosis treatment through a community-based programme in Hlabisa, South
      Africa. We plotted tuberculosis supervision points used by the district health
      system in 1991 (programme's first year) and 1996 (programme fully established),
      and quantified access by using GIS to measure the mean distance from each
      homestead in the district to hospital, clinics, community health workers (CHW)
      and volunteer supervisors. While the tuberculosis caseload tripled, the number of
      community supervision points used increased from 37 in 1991 to 147 in 1996.
      Adding clinics and then CHWs to the hospital as treatment points reduced the mean
      distance from homestead to treatment point from 29.6 km to 4.2 km and to 1.9 km,
      respectively. Adding volunteers further decreased the distance to 800 m. GIS/GPS
      effectively documents and quantifies the impact of community-based tuberculosis
      treatment on access to treatment.

PMID- 10583896
TI  - Short report: lack of specificity of Beilstein test in detecting pyrethroid
      insecticide on coloured mosquito nets.

PMID- 10583897
TI  - A community perspective on the efficacy of malaria treatment options for children
      in Lundazi district, Zambia.
AB  - In 1996, Zambia's Ministry of Health made sulfadoxine-pyrimethamine (SP)
      available as a second-line antimalarial. SP differs from chloroquine (CQ) in ways
      that might affect parents' acceptance of the drug, resulting in possible delays
      in seeking treatment if parents perceive SP as less efficacious. A multifaceted
      study consisting of a rapid community ethnographic assessment to examine local
      attitudes and perceptions toward malaria, a 14-day in vivo drug efficacy study
      comparing clinical and parasitological efficacy of CQ, SP, and SP with
      paracetamol (PCM) in children under five, and a qualitative study examining
      caretakers' perceptions of drug efficacy helped to guide implementation of the
      new drug policy. The rapid ethnographic study indicated that the community was
      aware of malaria as an illness best treated with modern medicines, particularly
      CQ. The drug efficacy study demonstrated a 25% level of clinical failures
      compared to none with SP, and 30% of the children treated with CQ had either RIII
      or RII parasitological failures whereas none occurred in children treated with
      SP. Most parents perceived that their children were improving and that the drugs
      were working. Parents in the SP groups were most pleased and readily accepted SP
      as a new drug. The addition of PCM did not improve perceptions of SP efficacy,
      contradicting conventional wisdom regarding the need for direct antipyretic
      action for parents to perceive a drug as efficacious. The combined results
      reflected a community that was in the beginning stages of evaluating a new
      malaria therapy mostly unknown to them. Perceptions of efficacy of CQ were
      beginning to shift, indicating a readiness for accepting a new drug based on its
      shown biological efficacy. Parasitological and clinical failure rates reinforced
      the need to fully implement the changed national policy as soon as possible, and
      to consider a change in first-line therapy.

PMID- 10583898
TI  - Epidemiological features and case management practices of imported malaria in
      northern Italy 1991-1995.
AB  - We report the results of a retrospective analysis of the clinical charts of
      imported malaria cases notified during the period 1991-95 in the Lombardy region
      of northern Italy. We analysed 694 admissions related to 683 individuals. The
      proportion of immigrants increased during the observation period from 34.4% in
      1991 to 59.9% in 1995 (P = 0.002). P. falciparum was the causative species in 534
      cases (78. 2%), and 591 (90.1%) of 656 cases with a full travel history had
      travelled to Africa. Information on chemoprophylaxis was available in 604 cases:
      429 (71.0%) reported no drug intake, 140 (23.2%) an incomplete, and 35 (5.8%) a
      complete chemoprophylactic course. The proportion of subjects who had initiated
      malaria chemoprophylaxis was significantly lower among immigrants (7.4%) than
      nonimmigrants (50.2%) (P < 0.001). Severe disease was diagnosed in 26 (4.7%) of
      551 cases of falciparum malaria, with a significantly lower incidence among
      immigrants (1.3% vs. 9.2%; P < 0.001). Eight deaths were recorded, all among
      nonimmigrants, whose fatality rate was significantly higher (P = 0.02).
      Mefloquine treatment of cases of uncomplicated falciparum malaria was associated
      with a significantly shorter fever clearance time (2.8 days +/- 1.5 vs. 3.5 days
      +/- 1.9; P < 0.001) and mean hospital stay (5.9 days +/- 4.4 vs. 8.3 days +/-
      5.1; P < 0.001) compared to quinine treatment.

PMID- 10583899
TI  - Detection of Trypanosoma brucei gambiense in sleeping sickness suspects by PCR
      amplification of expression-site-associated genes 6 and 7.
AB  - We have developed a sensitive and specific method to identify Trypanosoma brucei
      ssp. using PCR to amplify conserved expression-site-associated gene 6 and 7 DNA
      target sequences. Amplification of 10% of the DNA in a single trypanosome
      produced sufficient PCR product to be visible as a band in an agarose gel stained
      with ethidium bromide. We analysed 59 blood samples of serologically positive
      cases of sleeping sickness by PCR, and directed parasitological examination of
      tissue fluids. The PCR test detected 87% of the parasitologically positive cases,
      with a specificity of 97%. In 5 cases, the parasite was demonstrated by the PCR
      test 4-6 months prior to parasitological detection. This result shows the
      potential of the assay in early diagnosis of actual T. b. gambiense infections in
      apparently aparasitaemic sleeping sickness patients.

PMID- 10583900
TI  - [A foci of Schistosomiasis mekongi rediscovered in Northeast Cambodia: cultural
      perception of the illness; description and clinical observation of 20 severe
      cases].
AB  - In 1992 a foci of Schistosomiasis mekongi was rediscovered in the province of
      Kracheh in Northeast Cambodia. Severe clinical signs due to portal hypertension,
      which were frequently observed in this population, allowed the discovery of this
      'forgotten' focus. Elements of the perception of the population and clinical
      observations of 20 severe cases due to S. mekongi infections are presented.
      Interviews with patients and villagers of the area of Kracheh showed severe
      psychosocial impact including fear from death, infirmity and invalidity. The
      symptoms of schistosomiasis were well known by the population and were reported
      to have increased in frequency in the last two decades. They have received
      traditional names and specific traditional treatment. The description of the
      clinical cases illustrates the severe pathology, which was observed in the
      hospital of Sambour, in the north of the province of Kracheh. It shows the
      pathogenic potential of S. mekongi in all age groups (from 7 to 58 years old):
      cachexia, hepatosplenomegaly, stunting and retardation of puberty, decompensation
      of portal hypertension with ascites and rupture of oesophagual varicies. The
      efficacy of the treatment in the severe stages varies. A follow-up after 30
      months showed that 5 patients died, 5 initially improved but then relapsed, 3
      remained unchanged and only 5 patients clearly improved. Two patients could not
      be followed-up. The clinical observations and interviews show severe pathology
      with impact at both individual and community level. The infection with S. mekongi
      is the main factor but additional concomitant factors are responsible for this
      fact. At a certain stage of the disease the prognosis for successful treatment is
      very low. These observations show the importance of the foci in the Province of
      Kracheh, Cambodia and underline the need for a long-term global intervention.

PMID- 10583901
TI  - Foci of Schistosomiasis mekongi, Northern Cambodia: II. Distribution of infection
      and morbidity.
AB  - In the province of Kracheh, in Northern Cambodia, a baseline epidemiological
      survey on Schistosoma mekongi was conducted along the Mekong River between
      December 1994 and April 1995. The results of household surveys of highly affected
      villages of the East and the West bank of the river and of school surveys in 20
      primary schools are presented. In household surveys 1396 people were examined. An
      overall prevalence of infection of 49.3% was detected by a single stool
      examination with the Kato-Katz technique. The overall intensity of infection was
      118.2 eggs per gram of stool (epg). There was no difference between the
      population of the east and west shore of the Mekong for prevalence (P = 0.3) or
      intensity (P = 0.9) of infection. Severe morbidity was very frequent.
      Hepatomegaly of the left lobe was detected in 48.7% of the population.
      Splenomegaly was seen in 26.8% of the study participants. Visible diverted
      circulation was found in 7.2% of the population, and ascites in 0.1%.
      Significantly more hepatomegaly (P = 0.001), splenomegaly (P = 0. 001) and
      patients with diverted circulation (P = 0.001) were present on the west bank of
      the Mekong. The age group of 10-14 years was most affected. The prevalence of
      infection in this group was 71.8% and 71.9% in the population of the West and
      East of the Mekong, respectively. The intensity of infection was 172.4 and 194.2
      epg on the West and the East bank, respectively. In the peak age group
      hepatomegaly reached a prevalence of 88.1% on the west and 82.8% on the east
      bank. In the 20 schools 2391 children aged 6-16 years were examined. The overall
      prevalence of infection was 40.0%, ranging from 7.7% to 72.9% per school. The
      overalls mean intensity of infection was 110.1 epg (range by school: 26.7-187.5
      epg). Both prevalence (P = 0.001) and intensity of infection (P = 0.001) were
      significantly higher in schools on the east side of the Mekong. Hepatomegaly
      (55.2%), splenomegaly (23.6%), diverted circulation (4. 1%), ascites (0.5%),
      reported blood (26.7%) and mucus (24.3%) were very frequent. Hepatomegaly (P =
      0.001), splenomegaly (P = 0.001), diverted circulation (P = 0.001) and blood in
      stool (P = 0.001) were significantly more frequent in schools of the east side of
      the Mekong. Boys suffered more frequently from splenomegaly (P = 0.05), ascites
      (P = 0.05) and bloody stools (P = 0.004) than girls. No difference in sex was
      found for the prevalence and intensity of infection and prevalence of
      hepatomegaly. On the school level prevalence and intensity of infection were
      highly associated (r = 0. 93, P = 0.0001). The intensity of infection was
      significantly associated only with the prevalence of hepatomegaly (r = 0.44, P =
      0. 05) and blood in stool (r = 0.40, P = 0.02). This comprehensive
      epidemiological study documents for the first time the public health importance
      of schistosomiasis mekongi in the Province of Kracheh, Northern Cambodia and
      points at key epidemiological features of this schistosome species, in particular
      the high level of morbidity associated with infection.

PMID- 10583902
TI  - Detection of circulating E/S antigens in the sera of patients with fascioliasis
      by IELISA: a tool of serodiagnosis and assessment of cure.
AB  - An IELISA was developed to evaluate the performance of Fasciola E/S antigens in
      diagnosis and cure assessment of human Fasciola infection. Twenty patients with
      acute (prepatent) fascioliasis and another 20 with patent infection were enrolled
      in the study. Patients were treated with TCZ and followed at 1, 3 and 6 months
      after therapy. At inspection, the sensitivity of the test to diagnose prepatent
      cases was 100% compared to 70% for patent infections. There was a gradual
      decrease of antigenaemia over the follow-up period in acute cases. In chronic
      cases antigen disappeared from 13 cases (65%) at 1 month; this proportion did not
      change at 3 or 6 months.

PMID- 10583903
TI  - Circulating antibodies and antigens correlate with egg counts in human
      fascioliasis.
AB  - We explored the relationships between specific IgG antibody levels and
      circulating E/S antigen to intensity of Fasciola infection in the human host.
      Twenty patients with patent infection and six healthy individuals were enrolled
      in the study. Intensity of infection was determined by repeated egg counts in
      stools, while IgG antibodies against adult Fasciola gigantica somatic FI, FII and
      against E/S antigens were measured as ELISA O.D. readings. The level of
      circulating E/S antigens was determined by IELISA. Positivity as well as levels
      of antibodies and antigen correlated with infection intensity. These findings may
      disclose in the future a relation between morbidity in the acute phase and worm
      load.

PMID- 10583904
TI  - Where health care has no access: the nomadic populations of sub-Saharan Africa.
AB  - Nomadic and seminomadic pastoralists make optimal use of scarce water and pasture
      in the arid regions south of the Sahara desert, spreading from Mauretania in the
      west to Somalia in East Africa. We attempted to summarize the fragmentary
      evidence from the literature on the health status of these populations and to
      assess the best ways to provide them with modern health care. Infant mortality is
      higher among nomadic than among neighbouring settled populations, but childhood
      malnutrition is less frequent. Nomads often avoid exposure to infectious agents
      by moving away from epidemics such as measles. Trachoma is highly prevalent due
      to flies attracted by cattle. The high prevalence of tuberculosis is ascribed to
      the presence of cattle, crowded sleeping quarters and lack of health care;
      treatment compliance is generally poor. Guinea worm disease is common due to
      unsafe water sources. Helminth infections are relatively rare as people leave
      their waste behind when they move. Malaria is usually epidemic, leading to high
      mortality. Sexually transmitted diseases spread easily due to lack of treatment.
      Leishmaniasis and onchocerciasis are encountered; brucellosis occurs but most
      often goes undetected. Drought forces nomads to concentrate near water sources or
      even into relief camps, with often disastrous consequences for their health.
      Existing health care systems are in the hands of settled populations and rarely
      have access to nomads due to cultural, political and economic obstacles. A
      primary health care system based on nomadic community health workers is outlined
      and an example of a successful tuberculosis control project is described. Nomadic
      populations are open to modern health care on the condition that this is not an
      instrument to control them but something they can control themselves.

PMID- 10583905
TI  - The juxtamembrane domain of cadherin regulates integrin-mediated adhesion and
      neurite outgrowth.
AB  - Axons are guided along their trajectories during development by many different
      systems of adhesion, attraction, and repulsion. Thus, many distinct, and
      potentially competing, receptor systems respond to environmental cues, and the
      information must be coordinated inside the growth cone to ensure that extension
      follows the appropriate path. In this brief review we bring together two studies,
      each of which has defined different aspects of a pathway through which N-cadherin
      regulates beta1-integrin function allowing for coordinated responses to
      environmental cues during neurite extension. First we review progress in defining
      the binding to cells and the subsequent effects on adhesion and neurite outgrowth
      of the chondroitin sulfate proteoglycan, neurocan. Neurocan binds to a cell
      surface glycosyltransferase associated with N-cadherin (but not integrin),
      initiating a signal which results in loss of cadherin and integrin-function
      suggesting that these two adhesion receptor systems engage in cross-talk,
      allowing coordinate regulation. Second, we review the use of "Trojan" peptides,
      peptides which mimic specific sequences in the cytoplasmic domain of N-cadherin
      attached to a cell permeation sequence, to reveal protein-protein interactions
      critical to cadherin-integrin cross-talk. One peptide mimicking a 20 amino acid
      sequence in the juxtamembrane region of N-cadherin has the same effect as
      neurocan, blocking both cadherin- and integrin-mediated adhesion and neurite
      outgrowth. Both neurocan and the peptide cause the release of the non-receptor
      tyrosine kinase Fer from the cadherin complex and its binding to the integrin
      complex. These data define an epigenetic pathway through which environmental cues
      are capable of coordinately regulating the activity of two developmentally
      important adhesion systems.

PMID- 10583906
TI  - Mouse oligospheres: from pre-progenitors to functional oligodendrocytes.
AB  - To study the biology and repair capacities of mouse oligodendroglial cells, we
      established cultures of cells purified from neonatal wild-type and 9.6-kb MBP
      LacZ transgenic newborn mice cerebral hemispheres as free-floating aggregates in
      the continuous presence of neuroblastoma conditioned medium (N1-B104). In vitro
      analysis indicated that the initial cell preparations were enriched in
      oligodendrocyte pre-progenitors that expressed PSA-NCAM and GAP-43 but not GD3,
      O4, NF68 or glial fibrillary acidic protein (GFAP) markers. These pre-progenitors
      required increased concentrations of insulin and progesterone to allow their
      survival in vitro. With time in culture, spheres composed of oligodendrocyte pre
      progenitors became oligospheres enriched in oligodendrocyte progenitors
      expressing GAP-43 and GD3. As well as conserving bipotentiality in vitro, these
      spheres were able to form myelin in vivo after transplantation into the neonatal
      shiverer mouse brain. Thus, the oligosphere strategy is a powerful method for
      generating large populations of mouse oligodendrocyte pre-progenitors and
      progenitors. The ability to generate oligospheres from transgenic mice will be
      instrumental in the further dissection of the molecular and cellular mechanisms
      of myelination and remyelination of the central nervous system.

PMID- 10583907
TI  - Completion of myelin compaction, but not the attachment of oligodendroglial
      processes triggers K(+) channel clustering.
AB  - The characteristic localization of ion channels is crucial for the propagation of
      saltatory conduction in myelinated nerves. Voltage-gated Na(+) channels are
      located at nodes of Ranvier while voltage-gated K(+) channels are mainly found at
      juxtaparanodal regions. Recently, a humoral factor secreted by oligodendrocytes
      has been reported to induce clustering of Na(+) channels in CNS axons. However,
      the molecular mechanisms for K(+) channel clustering as well as the role of
      oligodendrocytes are still uncertain. To clarify whether myelin sheath itself can
      induce the distinct distribution of K(+) channels, we have investigated the
      localization of K(+) channels in adult and developing mouse optic nerves. The CNS
      axons from chronic demyelinating and hypomyelinating mice were also examined to
      determine if myelin sheaths were required for the maintenance of clusters. In all
      cases, the K(+) channel clustering correlated well with compact myelin, but not
      with the presence of oligodendrocytes, suggesting that, in contrast to Na(+)
      channel clustering, the formation of compact myelin is required for initiation as
      well as maintenance of K(+) channel clustering. In addition, postsynaptic density
      protein-95 (PSD-95) or its highly related protein was found colocalized with K(+)
      channels, suggesting that it may interact with K(+) channels to form clusters at
      juxtaparanodal regions.

PMID- 10583908
TI  - Characterization of the signal transduction pathways mediating noradrenaline
      stimulated MAPK activation and c-fos expression in oligodendrocyte progenitors.
AB  - In examining the signaling transduction pathway of adrenoceptors in
      oligodendrocyte progenitors, we have found that stimulation of alpha(1)
      adrenoceptors with norepinephrine (NE), in the presence of 3 microM propranolol,
      increased the activity of mitogen-activated protein kinases (MAPKs). This
      stimulation was concentration- and time-dependent, with maximal response after 10
      min of exposure to 10 microM NE. Pertussis toxin (PTX) blocked NE-mediated MAPK
      activation, suggesting that alpha(1)-adrenoceptor activates MAPK through a PTX
      sensitive G-protein. In the presence of U73122, an inhibitor of phospholipase C
      (PLC), MAPK activation was blocked. In oligodendrocyte progenitor cultures,
      chronic treatment with phorbol-12-myristate-13-acetate (PMA) down-regulated
      protein kinase C (PKC) and blocked NE-mediated MAPK activation. The response to
      NE was also significantly decreased by the PKC inhibitors H7 and
      bisindolylmaleimide GF109203X. Similarly, the effect of NE on MAPK activation was
      not observed in a calcium-free medium. Furthermore, attenuation of MAPK activity
      was observed when cultures were pretreated with LY294002 and wortmannin,
      inhibitors of phosphatidylinositol-3 kinase (PI3K). These results suggest that
      alpha(1)-adrenoceptor-mediated activation of MAPK involves a PTX-sensitive G
      protein, PLC, PI3K, and 1,2-diacyl glycerol (DAG)-dependent PKC isozyme.
      Stimulation of oligodendrocyte progenitors with NE also resulted in an increase
      in c-fos expression, which was mediated by both alpha(1)- and beta-adrenoceptor
      and was calcium-, PKC-, and protein kinase A (PKA)-dependent. Interestingly, in
      the presence of PD 098059, a specific inhibitor of MAPK kinase (MEK), both MAPK
      activity and c-fos expression were blocked. This suggests that MAPK is implicated
      in the transmission of the signal from alpha(1)-adrenoceptor to c-fos gene
      expression.

PMID- 10583909
TI  - Borrelia burgdorferi induces matrix metalloproteinases by neural cultures.
AB  - Matrix metalloproteinases (MMPs) are associated with chronic neurologic diseases
      such as multiple sclerosis and senile dementia. Lyme disease is a multisystemic
      infection involving the nervous system, skin, joints, and heart. Neurologic
      manifestations of chronic Lyme disease include encephalopathy and cranial and
      peripheral neuropathy. Borrelia burgdorferi, the spirochaete causing Lyme
      disease, has been cultured from the cerebrospinal fluid (CSF), and B. burgdorferi
      DNA is frequently detected in the CSF of patients with Lyme neuroborreliosis. We
      used cerebral and cerebellar primary cultures to determine whether B. burgdorferi
      induces the production of MMPs by primary neural cultures. B. burgdorferi in a
      dose- and time-dependent manner induced the expression of MMP-9 by primary neural
      cultures but had no effect on the expression of MMP-2. Human and rat type I
      astrocytes expressed MMP-9 when incubated with B. burgdorferi in the same manner
      as primary neural cultures. This response may play a role in the symptomatology
      and the pathogenesis of Lyme neuroborreliosis.

PMID- 10583910
TI  - Shaw-like potassium currents in the auditory rhombencephalon throughout
      embryogenesis.
AB  - The Shaw subfamily of potassium channel genes, including Kv3.1, are highly
      expressed within the auditory nuclei of the brainstem, where they have been
      implicated in the characteristic response properties of particular types of
      neurons. Potassium currents carried by Kv3.1 are voltage-dependent, have a high
      activation threshold, are slow to inactivate, and are very sensitive to 4
      aminopyridine (4-AP) and tetraethylammonium (TEA). We have investigated the
      developmental appearance of potassium currents in cell cultures from nucleus
      magnocellularis and its precursor neuroblasts from the acoustico-vestibular
      anlage of the chicken. Whole-cell patch recordings revealed that high-threshold,
      sustained, outward currents were present in 91% of neuroblasts. These currents
      displayed high sensitivities to TEA and 4-AP. The remaining 9% of neuroblasts
      exhibited only transient outward currents. Most cells (74%) had both a sustained
      and an initial transient component of outward current. These current types were
      observed throughout embryogenesis, beginning with the earliest ages (embryonic
      day [E]2). During proliferation and migration, and early neuronal
      differentiation, current levels were low; they incremented gradually during the
      time when the first synapses occur on dendrites and increased 2- to 3-fold just
      before hatching, when axosomatic synapses form. These findings suggest that the
      Shaw subfamily of channels in nucleus magnocellularis may be involved in early
      neuronal development, as well as in synaptic function later on.

PMID- 10583911
TI  - Role in neuronal cell migration for high-threshold potassium currents in the
      chicken hindbrain.
AB  - We have investigated the influence of voltage-dependent, potassium conductances
      on the migration of embryonic neurons, using a culture preparation taken from the
      acoustico-vestibular anlage long before the onset of electrical excitability and
      synaptic function. Whole-cell patch clamp recordings from migrating neuroblasts
      at Hamburger-Hamilton stage 28 (E 5.5) revealed the exclusive expression of
      voltage-dependent, high-threshold, outward currents, activating at potentials
      positive to -20 mV. These currents were completely suppressed by the potassium
      channel blockers, 1.0 mM tetraethylammonium chloride (TEA) or 1.0 mM 4
      aminopyridine (4-AP). In control media, the active migration of individual
      neuroblasts was recorded at 27 +/- 6 microm per hr. Within minutes after adding
      either drug to the culture, normal migration completely stopped for several
      hours. Calcium channel blockers, omega-conotoxin (3 microM) or cadmium chloride
      (100 microM), slowed, but did not halt, migration, while nickel chloride (100
      microM) or N-methyl-D-glucamine (1 mM) had no effect. However, within 8 hr after
      TEA exposure, migratory activity usually returned. This recovery was associated
      with the appearance of a previously undetected, low-threshold and 4-AP- sensitive
      potassium conductance. We suggest that high-threshold, TEA/4-AP-sensitive
      potassium channels may normally support the migration of these neurons, while
      their chronic blockade can be compensated by the appearance of novel potassium
      channels. Potassium currents may act in concert with N-type calcium channels to
      regulate neuronal migration.

PMID- 10583912
TI  - Neuroprotective effects of estradiol in the adult rat hippocampus: interaction
      with insulin-like growth factor-I signalling.
AB  - We have previously shown that 17-beta-estradiol protects neurons in the dentate
      gyrus from kainic acid-induced death in vivo. To analyse whether this effect is
      mediated through estrogen receptors and through cross-talk between steroid and
      insulin-like growth factor (IGF) systems, we have concomitantly administered
      antagonists of estrogen receptor (ICI 182,780) or the IGF-I receptor (JB1) with
      estradiol. In addition, we have also administered IGF-I with or without the
      estrogen receptor antagonist. JB1 (20 microg/ml), ICI 182,780 (10(-7) M), and IGF
      I (100 microg/ml) were delivered into the left lateral ventricle of young
      ovariectomized rats via an Alzet osmotic minipump (0.5 microl/hr) for 2 weeks.
      All rats received kainic acid (7 mg/Kg b.w.) or vehicle i.p. injections at day 7
      after minipump implant. Also on day 7, rats treated i.c. v.with only ICI 182,780
      or JB1 received a single i.p. injection of 17-beta-estradiol (150 microg/rat) or
      vehicle. On day 14 after minipump implant, the rats were killed, brains
      processed, and the number of surviving hilar neurons estimated by the optical
      disector technique. Both IGF-I and estradiol treatments resulted in over 90%
      survival of hilar neurons. The neuroprotective action of estradiol was blocked by
      ICI 182,780 and by JB1. Furthermore, IGF-I enhancement of neuronal survival was
      significantly reduced by ICI 182,780. These results indicate that in this model
      of hippocampal lesion, the neuroprotective effect of estradiol depends both on
      estrogen receptors and IGF-I receptors, while the protection exerted by IGF-I
      depends also on estrogen receptors. In conclusion, an interaction of estrogen
      receptor and IGF-I receptor signalling may mediate neuroprotection in the adult
      rat hippocampus.

PMID- 10583913
TI  - 4-hydroxynonenal increases neuronal susceptibility to oxidative stress.
AB  - Increased levels of reactive oxygen species occur in neurodegenerative disorders
      and may promote neuron death. The lipid peroxidation product 4-hydroxynonenal
      (HNE) is increased in neurons following oxidative stress and promotes neuron
      death in vitro and in vivo. The present study examined the possibility that HNE
      can increase neuron vulnerability to oxidative stress. Application of low
      concentrations of HNE (50-500 nM) increased neuron death induced by beta-amyloid
      or glutamate when added within 3 hr of injury. In addition, treatment with HNE
      exacerbated mitochondrial reactive oxygen species formation and loss of
      mitochondrial membrane potential in response to beta-amyloid and glutamate. The
      ability to exacerbate oxidative stress, mitochondrial dysfunction, and neuron
      death appears to be specific to HNE, because application of other lipid
      peroxidation products had no effect. These data indicate a role for low levels of
      HNE in promoting reactive oxygen species accumulation and neuron degeneration by
      altering mitochondrial homeostasis. In addition, the present study indicates a
      possible mechanism for reactive oxygen species and lipid peroxidation toxicity in
      neurodegenerative conditions.

PMID- 10583915
TI  - Professional organizations, medical journals, and editors. A dynamic tension.

PMID- 10583914
TI  - Fast, convenient, and effective method to transiently transfect primary
      hippocampal neurons.
AB  - Transfection of primary neurons in culture has proven to be experimentally
      challenging in the past. To overcome these limitations, we present a detailed
      transfection protocol for hippocampal neurons based on DNA/Ca(2+)-phosphate
      coprecipitation. The main advantages being (1) the speed and convenience, (2) the
      remarkable efficiency of transfection for mature neurons, and (3) consistent
      health of the neurons upon transfection allowing subsequent manipulations. The
      strength of this protocol is convincingly demonstrated by the fact that the
      expressed protein can be detected biochemically on Western blots.

PMID- 10583916
TI  - A portrait in history. Thomas Hodgkin.

PMID- 10583917
TI  - Outpatient order accuracy. A College of American Pathologists Q-Probes study of
      requisition order entry accuracy in 660 institutions.
AB  - CONTEXT: Laboratory test order entry errors potentially delay diagnosis, consume
      resources, and cause patient inconvenience. OBJECTIVE: To evaluate the frequency
      and causes of computer order entry errors in outpatients. DESIGN: Cross-sectional
      survey and prospective sample of errors. Participants answered questions about
      their test order entry policies and practices. They then examined a sample of
      outpatient requisitions and compared information on the requisition with
      information entered into the laboratory computer system. Order entry errors were
      divided into 4 types: tests ordered on the requisition, but not in the computer;
      tests performed but not ordered on the requisition; physician name discrepancies;
      and test priority errors. PARTICIPANTS: Six hundred sixty laboratories enrolled
      in the College of American Pathologists Q-Probes program. MAIN OUTCOME MEASURE:
      Overall order entry error rate. RESULTS: A total of 5514 (4.8%) of 114 934
      outpatient requisitions were associated with at least 1 order entry error. The
      median participant reported 1 or more order errors on 6.0% of requisitions; 10%
      of institutions reported errors with at least 18% of requisitions. Of the 4
      specific error types, physician name discrepancies had the highest error rate,
      and test priority errors the lowest error rate. Four institutional factors were
      significantly associated with higher overall error rates: orders verbally
      communicated to the laboratory; no policy requiring laboratory staff to compare a
      printout or display of ordered tests with the laboratory requisitions to confirm
      that orders had been entered correctly; failure to monitor the accuracy of
      outpatient order entry on a regular basis; and a higher percentage of occupied
      beds (ie, a busier hospital). CONCLUSIONS: Computer order entry errors are
      common, involving 5% of outpatient requisitions. Laboratories may be able to
      decrease error rates by regularly monitoring the accuracy of order entry,
      substituting written and facsimile orders for verbal orders, and instituting a
      policy in which orders entered into computer systems are routinely rechecked
      against orders on requisitions.

PMID- 10583918
TI  - DNA technology in the clinical laboratory.
AB  - OBJECTIVES: To review the advances in clinically useful molecular biological
      techniques and to identify their applications in clinical practice, as presented
      at the Eighth Annual William Beaumont Hospital Symposium. DATA SOURCES: The 10
      manuscripts submitted were reviewed, and their major findings were compared with
      literature on the same topic. STUDY SELECTION: Two manuscripts addressed specimen
      (nucleic acid) stability, 2 described novel analytic approaches, 3 discussed
      detection of B- or T-cell clonality in lymphoproliferative disorders, and 3
      reported the frequency of a variety of genetic polymorphisms found in cardiac
      disorders. DATA SYNTHESIS: DNA from dried blood spots is stable and may be
      purified rapidly for amplification and mutation analysis. RNA is much less
      stable, and a variety of methods may be used to reduce ribonuclease degradation
      of enteroviral RNA. False-negative reactions may be reduced by genomic
      amplification of ligated padlock probes by cascade rolling circle or polymerase
      chain reaction. A multiplex polymerase chain method using fluorescence-labeled
      products that separate both the wild-type and mutant hemochromatosis gene alleles
      by capillary gel electrophoresis represents another approach for detecting the 2
      major missense mutations (C282Y and H63D) in hemochromatosis. Southern blotting
      and polymerase chain reaction have been used to detect B- and T-cell clonality in
      lymphoproliferative diseases, including mantle cell lymphoma and lymphoma of the
      breast. Genetic polymorphisms in a variety of coagulation factors and platelet
      glycoprotein IIIa are associated with ischemic heart disease. CONCLUSIONS: As the
      Human Genome Project continues to define disease-associated mutations, the number
      of clinically useful molecular pathologic techniques and assays will expand.
      Clinical outcome analysis is still required to document a decrease in the
      patient's length of stay to offset the cost of introducing molecular biological
      assays in the routine clinical pathology laboratory.

PMID- 10583919
TI  - Optimization of an automated DNA purification protocol for neonatal screening.
AB  - CONTEXT: Collection of blood from newborns is a standard clinical procedure used
      for genetic screening. Typically, blood from a heel prick is absorbed onto
      standard collection paper and dried before analysis of metabolites, proteins,
      hormones, and more recently DNA. OBJECTIVE: To evaluate strategies to purify DNA
      for use with automated workstations. DESIGN: Two factors were used to evaluate
      several DNA purification protocols: residual heme contamination and amplification
      yield. The protocol that produced DNA with the lowest heme content and the
      highest amplification yield was selected. In combination with those two
      performance factors, the protocol with the fewest number of steps was chosen to
      reduce reagent use and processing time. SETTING: Industrial research and
      development laboratory. RESULTS: Robust amplification of DNA isolated from dried
      blood spots was demonstrated using both fluorescence and agarose gel-based
      detection methods. In addition, the samples had consistent DNA volumes and had no
      detectable cross-contamination. Suggested instrument settings, equipment, and
      supplies were included for automated processing of DNA from dried blood spots.
      CONCLUSION: A 4-step DNA processing protocol was developed for dried blood spots.
      The protocol could be performed in either a manual or automated format, making it
      possible to process hundreds of samples in 1 day.

PMID- 10583920
TI  - Reverse-transcription polymerase chain reaction detection of the enteroviruses.
AB  - OBJECTIVE: This review focuses on commercial and in-house-developed reverse
      transcription polymerase chain reaction (RT-PCR) assays used for the detection of
      enteroviral infections. In addition to providing details on the performance of RT
      PCR, its specificity, and sensitivity, the clinical utility of this diagnostic
      method with specific reference to its impact on hospitalization and cost savings
      is addressed. DATA SOURCES: MEDLINE was searched for reports relating to RT-PCR
      detection of the enteroviruses in adults and children. The search was restricted
      to studies reported in English language journals. STUDY SELECTION: Reports
      documenting detailed information regarding the RT-PCR conditions, primers,
      sensitivity, specificity and, if relevant, clinical impact were selected for
      analysis. DATA EXTRACTION: Details regarding method of extraction of the
      enteroviral genome, the primers used, RT-PCR conditions, and sensitivity and
      specificity of the assay were extracted from the literature. For reports
      detailing the use of RT-PCR in the clinical management of enteroviral infections
      in children, the reduction in duration of hospitalization and health care cost
      savings were recorded. DATA SYNTHESIS: Reverse-transcription PCR can increase the
      yield of detection of enteroviruses from cerebrospinal fluid by a mean of
      approximately 20% over tissue culture. Reverse-transcription PCR of cerebrospinal
      fluid has been shown to exhibit sensitivity and specificity values of 86% to 100%
      and 92% to 100%, respectively. Reductions of 1 to 3 days of hospitalization per
      patient are predicted if RT-PCR is used to diagnose enteroviral meningitis in
      children. CONCLUSIONS: Reverse-transcription PCR detection of enteroviral
      infections is an extremely rapid, sensitive, and specific diagnostic modality.
      Both commercial assays and assays developed in-house appear to be equivalent with
      regard to sensitivity and specificity. Reverse-transcription PCR diagnosis of
      enteroviral infections in children could reduce the length of hospitalization and
      result in significant health care cost savings.

PMID- 10583921
TI  - Amplification of padlock probes for DNA diagnostics by cascade rolling circle
      amplification or the polymerase chain reaction.
AB  - CONTEXT: Padlock probes are highly specific reagents for DNA diagnostics that can
      discriminate gene sequences with single base mutations. When the 3' and 5'
      terminal regions of the oligonucleotide probes are juxtaposed on a target DNA
      sequence, they can be circularized by enzymatic ligation and become topologically
      locked to the target. However, to be useful in solution-based diagnostics, the
      sensitivity of padlock probes must be markedly enhanced. OBJECTIVE: To describe
      two methods for geometric amplification of circularized padlock probes. DESIGN:
      Cascade rolling circle amplification is an isothermal system that uses generic
      primers and a DNA polymerase with strong strand displacement activity to amplify
      circularized probes by a mechanism combining rolling circle replication and
      strand displacement synthesis. One of the primers was designed as an energy
      transfer-labeled primer, which generates a fluorescence signal only when
      incorporated into the amplified product, enabling a direct means of detection.
      RESULTS: Using pUC19 as a model target to circularize an 89-base probe, a 10
      billion-fold amplification was achieved with Bst DNA polymerase (large fragment)
      within 1 hour starting with as few as 10 probe molecules. The polymerase chain
      reaction was also used to amplify ligated padlock probes in a rare target
      detection system. In mixing experiments containing both normal and mutant p53 or
      c-Ki-ras2 gene target sequences, mutant targets were easily detected in the
      presence of a 500-fold excess of normal target copies. CONCLUSION: These results
      indicate that padlock probes can be amplified to the high levels required for
      solution-based DNA diagnostics.

PMID- 10583923
TI  - Mantle cell lymphoma.
AB  - OBJECTIVE: This article summarizes the most useful ancillary immunohistochemical
      and molecular assays for use in the diagnosis of mantle cell lymphoma. DATA
      SOURCES: The English language literature was surveyed, with an emphasis on recent
      publications, for articles presenting key advances in the molecular
      characterization of mantle cell lymphomas and for series of cases testing the
      utility of molecular diagnostic tests. The authors' series of 26 small B-cell
      lymphomas, analyzed for the cyclin D1 protein by paraffin immunohistochemistry
      and for t(11;14) by polymerase chain reaction, is included. CONCLUSIONS: Mantle
      cell lymphoma, a B-cell lymphoma now recognized in the 1994 Revised European
      American Classification of Lymphoid Neoplasms (REAL) classification, is a
      relatively aggressive lymphoma with a poor prognosis. Its characteristic
      t(11;14)(q13;q32) translocation has a role in oncogenesis and has been exploited
      for molecular diagnostic tests, but these tests vary in sensitivity, specificity,
      and ease of use. Improved immunohistochemical tests are sufficient to confirm the
      diagnosis in most cases. Conventional cytogenetics and molecular diagnostic tests
      for t(11;14)-Southern blot and polymerase chain reaction analysis-may be helpful
      in selected cases, but are laborious or of limited sensitivity. Other methods,
      such as fluorescence in situ hybridization, need further development to provide
      faster, more sensitive diagnosis.

PMID- 10583922
TI  - HFE genotyping using multiplex allele-specific polymerase chain reaction and
      capillary electrophoresis.
AB  - CONTEXT: Hereditary hemochromatosis is recognized as one of the most common
      autosomal recessive disorders, with a prevalence of 1 in 200 to 400 in the white
      population. Early detection and treatment are completely effective in preventing
      pathology. It is anticipated that testing for hereditary hemochromatosis will
      increase, as will the need for a technology that can handle the demand.
      OBJECTIVE: To describe a high-throughput, single-tube, allele-specific multiplex
      polymerase chain reaction assay for identifying the 2 mutations in the HFE gene
      associated with hereditary hemochromatosis. DESIGN: Fluorescence-labeled
      polymerase chain reaction products from a multiplex polymerase chain reaction are
      analyzed by automated capillary electrophoresis. DATA ANALYSIS: The assay was
      validated by analysis of 25 blinded samples, and results were concordant with an
      established laboratory assay. CONCLUSION: The assay described offers a
      significant improvement over manual laboratory assays in throughput, reduced
      technologist time, and cost.

PMID- 10583924
TI  - Overview of the role of molecular methods in the diagnosis of malignant
      lymphomas.
AB  - OBJECTIVE: To review the role of molecular genetics in the diagnosis of malignant
      lymphomas. DATA SOURCES AND STUDY SELECTION: Primary research studies and reviews
      published in the English literature that focus on molecular genetics and
      malignant lymphoma, in particular, clonality, chromosomal translocations, tumor
      suppressor genes, and Hodgkin disease. DATA EXTRACTION AND SYNTHESIS: Molecular
      genetics has an important role in the assessment of malignant lymphomas.
      Clonality, detected by Southern blot analysis or the polymerase chain reaction,
      is helpful for establishing the diagnosis of lymphoma in lesions with ambiguous
      morphologic and immunophenotypic findings. Southern blot analysis is the "gold
      standard" for clonality assessment, but the process is labor-intensive and time
      consuming. Polymerase chain reaction analysis is more convenient, but a
      potentially significant false-negative rate exists in the analysis of some
      antigen receptor genes as a result of using consensus primers and the process of
      somatic hypermutation. Chromosomal translocations, which result in oncogene
      activation, occur in many types of B- and T-cell lymphomas, and their detection
      is helpful in classification as well as in establishing a diagnosis of
      malignancy. Gene rearrangements and chromosomal translocations also can be used
      to monitor minimal residual disease. Tumor suppressor genes, although their
      analysis is relatively less useful for diagnosis, are involved in both
      pathogenesis and tumor progression and will be more important diagnostically as
      this field continues to expand. Molecular genetic analysis has played a major
      role in improving our understanding of Hodgkin disease. CONCLUSIONS: Molecular
      genetic tests are currently important ancillary tools for the diagnosis and
      classification of malignant lymphomas, and their role is likely to increase in
      the future.

PMID- 10583925
TI  - Lymphoma of the breast. A clinicopathologic study of primary and secondary cases.
AB  - BACKGROUND: Primary lymphomas of the breast are rare, accounting for 1.7% to 2.2%
      of extranodal lymphomas and 0.38% to 0.7% of all non-Hodgkin lymphomas. Although
      secondary breast lymphomas are also rare, they represent the largest group of
      metastatic tumors of the breast. OBJECTIVES: To investigate the clinicopathologic
      and immunophenotypic characteristics of breast lymphomas, the relative frequency
      of primary and secondary mammary lymphomas, and in selected cases, the role of
      gene rearrangement analysis in diagnosis and staging of these lymphomas. RESULTS:
      We conducted a retrospective review of 22 cases of breast lymphoma diagnosed at
      William Beaumont Hospital, Royal Oak, Mich, during a 30-year period (1963-1994).
      Eleven of the 22 cases fulfilled the criteria for primary breast lymphoma; these
      cases represented 0.6% of all non-Hodgkin lymphomas seen in our hospital. Of the
      11 cases, 5 were diffuse large B-cell lymphomas, 2 were follicle center
      lymphomas, 2 were marginal zone B-cell lymphomas (mucosa-associated lymphoid
      tissue type), 1 was a lymphoplasmacytoid lymphoma, and 1 was a peripheral B-cell
      neoplasm, unclassified. Using a panel of immunohistochemical stains (CD45RO,
      CD45RA, CD43, CD3, CD20, CD30, CD68, and HLA-DR), 8 cases demonstrated
      unequivocal B-cell phenotype and 3 cases had equivocal or weak staining patterns
      for B-cell markers. We identified no cases of T-cell lymphoma. Of 7 cases that
      had bone marrow biopsies for staging, 3 were positive morphologically for bone
      marrow involvement. Molecular analysis of B- and T-cell gene rearrangement was
      used to exclude bone marrow involvement in one case with bone marrow lymphoid
      aggregates and to confirm negativity in a case that was morphologically negative.
      Of the 11 secondary breast lymphomas, 5 were diffuse large B-cell lymphomas; 1
      was diffuse large B-cell, primary mediastinal subtype; and 5 were follicle center
      lymphomas. CONCLUSIONS: Breast lymphomas represented 1.2% of all non-Hodgkin
      lymphomas in this study; the frequency of primary and secondary cases was equal.
      In both groups, right breast lesions were predominant, and the most frequent
      morphologic type was diffuse large B-cell lymphoma. Gene rearrangement analysis
      is helpful in selected cases to rule out bone marrow involvement, especially in
      older patients, in whom lymphoid aggregates are common.

PMID- 10583926
TI  - An overview of genetic factors influencing plasma lipid levels and coronary
      artery disease risk.
AB  - BACKGROUND: Coronary artery disease (CAD) is a major cause of morbidity and
      mortality in most Western countries and its origin involves a significant genetic
      component. METHODS: Genetic and epidemiologic studies have been performed to
      identify factors that influence the CAD risk in the population. RESULTS: The
      primary loci that have been demonstrated to be associated with increased CAD risk
      owing to genetic mutations include the low-density lipoprotein receptor,
      apolipoprotein B-100, and lipoprotein(a). Additional implicated loci include
      lipoprotein lipase, apolipoprotein CII, cholesteryl ester transfer protein,
      apolipoprotein AI, and lecithin-cholesterol acyl transferase. CONCLUSIONS:
      Numerous mutations in known genes exert a major effect on CAD risk in some
      patients. However, in most patients with CAD, the genetic component is believed
      to be attributable to the aggregate effect of loci that, individually, exert only
      a minor influence on lipoprotein levels.

PMID- 10583927
TI  - Higher prevalence of GPIIIa PlA2 polymorphism in siblings of patients with
      premature coronary heart disease.
AB  - BACKGROUND: The Pl(A2) polymorphism of GPIIIa has been associated with unstable
      coronary syndromes in some studies, but the association has remained debated.
      None of the previous studies have focused on families at high risk. Risk factors
      tend to cluster within kindreds with high prevalence of premature coronary heart
      disease (CHD). Therefore, a heightened prevalence of the Pl(A2) polymorphism
      among siblings of patients with CHD would support the hypothesis that Pl(A2) is
      linked, directly or indirectly, to CHD. OBJECTIVES: To measure the prevalence of
      the Pl(A2) polymorphism among siblings of patients with CHD before the age of 60
      years and to seek an association between the Pl(A2) polymorphism and established
      atherosclerotic and thrombogenic risk factors. METHODS: From January 1994 to
      April 1996, we genotyped 116 asymptomatic siblings (60 Caucasians, 56 Afro
      Caribbeans) of patients with CHD manifestations before the age of 60 years for
      the Pl(A) polymorphism (also called HPA-1). A control cohort was used for
      comparison, consisting of individuals that were matched for race and geographic
      area but were free of CHD (n = 268, 168 Caucasians and 100 Afro-Caribbeans). In
      addition, we have characterized the sibling cohort for other atherogenic and
      thrombogenic risk factors. RESULTS: The prevalence of Pl(A2)-positive individuals
      (Pl(A2)[+], Pl(A1/A2) heterozygotes plus Pl(A2/A2) homozygotes) in the sibling
      cohort was high: 41.4%. When analyzed separately, the prevalence of Pl(A2)(+)
      siblings was 53.3% among Caucasians and 28.6% among Afro-Caribbeans. There was no
      association between Pl(A2) and other established atherogenic or thrombogenic risk
      factors. Interestingly, the clustering of other risk factors was lesser among
      Pl(A2)(+) siblings than their Pl(A1) counterparts. CONCLUSIONS: This study
      supports the hypothesis that the prevalence of Pl(A2)(+) individuals is high in
      kindreds with premature CHD. Hence, like the established risk factors that tend
      to cluster in families with premature CHD and contribute strongly to the
      accelerated atherosclerotic process affecting these individuals, the Pl(A2)
      polymorphism of GPIIIa may represent an inherited risk that promotes the
      thromboembolic complications of CHD. That these asymptomatic Pl(A2)(+) siblings
      had overall less established risk factors than their Pl(A1) counterparts might
      represent an explanation for why they remained asymptomatic despite their Pl(A2)
      positivity.

PMID- 10583928
TI  - Polymorphisms in the genes for coagulation factors II, V, and VII in patients
      with ischemic heart disease.
AB  - BACKGROUND: Cardiovascular disease remains the leading cause of mortality in the
      United States, accounting for approximately 33% of all deaths in this country. Of
      these deaths, most are due to acute myocardial infarctions (AMIs), which are
      associated with thrombotic coronary artery obstruction and/or occlusion. These
      events could potentially be due to alterations in genes coding for coagulation
      factors. Several polymorphisms have been described in the factor II, V, and VII
      genes, which may predispose one to increased risk for ischemic heart disease
      (IHD). OBJECTIVE: To determine if mutations in 3 coagulation factor genes could
      predispose an individual to increased risk for arterial thrombosis as a mechanism
      for developing unstable angina (UA) or AMI. METHODS: We examined 125 hospitalized
      patients (mean age, 53 +/- 6 years, 79 men and 46 women), including 32 with AMI,
      68 with UA, and 25 noncardiac controls, for a genetic predisposition for
      increased risk of IHD. EDTA-anticoagulated whole blood was collected at the time
      of hospital admission. DNA was extracted, and the polymorphisms were detected by
      polymerase chain reaction amplification of these genes with subsequent
      restriction enzyme digestion and gel electrophoresis. RESULTS: Our results showed
      that 3 (9.4%), 3 (4.4%), and 1 (4%) individuals were heterozygous for prothrombin
      G20210A and 3 (9.4%), 5 (7.4%), and 1 (4%) individuals were heterozygous for
      factor V Leiden in the AMI, UA, and control groups, respectively. The following
      genotype frequencies for the factor VII R353Q polymorphism were identified: 25
      (78.1%), 56 (82.4%), and 18 (72%) with RR and 7 (21.9%), 12 (17. 6%), and 7 (28%)
      with RQ in the AMI, UA, and control groups, respectively. No QQ homozygotes were
      identified. For the HVR4 size polymorphism, the following genotypes were
      identified: 3 (9.4%), 4 (5.9%), and 5 (20%) individuals with H7H7; 11 (34.4%), 33
      (48.5%), and 12 (48%) with H6H7; and 18 (56.2%), 31 (45.6%), and 8 (32%) with
      H6H6 genotypes in the AMI, UA, and control groups, respectively. There were no
      H7H5 and H6H5 genotypes found in this study. CONCLUSIONS: Although the frequency
      differences of these polymorphisms in patients with AMI and UA were not
      statistically significant from those in controls, several trends are consistent
      with what has been reported in the literature. Although any of these or other
      undefined genetic abnormalities may result in IHD, it is possible that phenotypic
      predisposition to IHD initially presents as UA. A larger population study
      addressing the significance of these polymorphisms in the sequence of events that
      lead to IHD, including cases of UA, is warranted.

PMID- 10583929
TI  - Primary cutaneous T-cell-rich B-cell lymphomas with flow cytometric
      immunophenotypic findings. Report of 3 cases and review of the literature.
AB  - BACKGROUND: Primary cutaneous T-cell-rich B-cell lymphoma is a relatively rare
      entity that has been diagnosed most commonly using immunohistochemical and
      molecular techniques. Flow cytometric immunophenotyping (FCI) has not been
      described in this entity. We report the demonstration of B-cell monoclonality by
      FCI in 3 cases of primary cutaneous T-cell-rich B-cell lymphoma. METHODS:
      Clinical and pathologic data were recorded for 3 cases of primary cutaneous T
      cell-rich B-cell lymphoma. Immunohistochemical and FCI data were available in all
      cases; DNA analysis was performed in 1 case. RESULTS: Flow cytometric
      immunophenotyping revealed a monoclonal B-cell population exclusively in the
      monocyte (large cell) region in all 3 cases. Immunohistochemistry confirmed the T
      cell richness of the infiltrates within the cutaneous lymphomas; T cells
      accounted for 65% to greater than 90% of the cells within the infiltrates. DNA
      analysis by polymerase chain reaction in 1 case did not demonstrate a monoclonal
      rearrangement of the immunoglobulin heavy-chain gene. CONCLUSIONS: Flow
      cytometric immunophenotyping in primary cutaneous T-cell-rich B-cell lymphoma may
      be useful in demonstrating monoclonality in these cases, especially if there is
      selective gating on the relatively small population of cells in the large cell
      region. The FCI data should be correlated with histology and
      immunohistochemistry.

PMID- 10583930
TI  - Relevance of apolipoprotein E polymorphism for coronary artery disease in the
      Saudi population.
AB  - BACKGROUND: The apolipoprotein E alleles epsilon2 and epsilon4 have been reported
      as independent risk factors for coronary artery disease (CAD) and as predictors
      for the development of atherosclerosis. METHODS AND RESULTS: We determined by
      polymerase chain reaction the distribution of apolipoprotein E polymorphism in
      320 Saudi blood donors (BD), 96 CAD patients, and 40 control subjects who had
      undergone angiography. Compared to controls, only epsilon4 was elevated in CAD
      patients. More than 61% (P <.0001) of the patients had angina, and 52.1% (P <.05)
      were diabetic; both of these factors were strongly associated with the presence
      of allele epsilon2. The epsilon2 allele was also associated with hypertension,
      elevated serum triglycerides, and total cholesterol. On the other hand, the
      allele epsilon4 appeared to be associated with increased risk of CAD and was also
      associated with hypertension, 3-vessel disease, and restenosis. CONCLUSIONS:
      Accordingly, epsilon4 may be associated with increased risk of CAD, whereas
      epsilon2 appears to be a predictor of several risk factors for atherosclerosis.

PMID- 10583931
TI  - Molecular pathology of soft tissue and bone tumors. A review.
AB  - OBJECTIVE: To present recent concepts on the molecular pathogenesis of tumors of
      soft tissue and bone, and on the use of molecular genetic methods, including
      their significance as diagnostic markers and prognostic indicators. DATA SOURCES
      AND STUDY SELECTION: Reports on tumors of bone and/or soft tissue published in
      the English language literature and observations made using specimens available
      at the Departments of Pathology at Albany Medical College and Loyola University
      Medical Center. DATA EXTRACTION AND SYNTHESIS: Studies on bone and soft tissue
      tumors containing chromosomal or genetic evaluation were selected for further
      analysis. Specific chromosomal abnormalities, such as numerical aberrations or
      translocations with production of fusion genes, were classified according to the
      tumor of origin. Data were also collected on mutations in tumor suppressor genes,
      genes coding for growth factors or their receptors, and genes coding for tyrosine
      kinases. Also noted were mutations of uncertain significance, for which the
      pathogenic connection between tumor production and mutated gene function is still
      unclear. CONCLUSIONS: In general, the mutations reported interfere with the
      action of peptide growth factors coordinating mesenchyme proliferation and
      differentiation, although membrane-bound receptors expressing the intracellular
      signaling modifier, tyrosine kinase activity, have also been involved. Functional
      types of genes most commonly affected include tumor suppressors, oncogenes, and
      nuclear transcription factors. Thus, the mutations involved in the pathogenesis
      of soft tissue and bone tumors have affected multiple genes. Moreover, aberrant
      fusion gene products may be formed in tumoral tissue and may then act as
      transcription regulators stimulating cellular proliferation. Cytogenetic studies
      help at the clinical level by demonstrating aneuploidy and increased ploidy,
      which may correlate with malignant behavior. Diagnostic tumor-specific
      chromosomal translocations may be detected with Southern hybridization analysis,
      polymerase chain reaction, reverse-transcription polymerase chain reaction, or
      with the fluorescence in situ hybridization technique. Notably, early metastatic
      disease may be detectable in blood specimens using polymerase chain reaction or
      reverse-transcription polymerase chain reaction techniques.

PMID- 10583932
TI  - Immunohistochemical detection of p53 protein could improve the management of some
      patients with Barrett esophagus and mild histologic alterations.
AB  - OBJECTIVE: To determine the usefulness of p53 immunostaining in identifying the
      subgroup of patients with Barrett esophagus who may be at increased risk of
      developing adenocarcinoma of the esophagus. MATERIALS AND METHODS: Tissue samples
      of 41 patients with Barrett esophagus and available sequential histologic data
      were processed for p53 immunostaining. Results from each patient were compared
      over time, and the results of a subset of patients were compared with each other.
      RESULTS: We observed a significant correlation between the percentage of samples
      with p53 expression and the severity of dysplasia. Moreover, in a subset of
      patients with mild dysplasia (cases classified as showing indefinite dysplasia),
      we observed a statistically significant difference in the percentage of p53
      positive samples between the group that progressed to more severe dysplasia and
      the group that did not progress. CONCLUSION: Our results suggest that this
      procedure, which is technically simple, economical, and quick, could play a role
      in the evaluation and follow-up of patients with Barrett esophagus.

PMID- 10583934
TI  - Presence of human herpesvirus 8 DNA sequences in renal transplantation-associated
      pleural Kaposi sarcoma.
AB  - OBJECTIVE: To describe one case of symptomatic skin and pleural Kaposi sarcoma
      (KS) associated with kidney transplantation. Diagnosis was supported by
      morphologic study and human herpesvirus 8 (HHV-8) detection in both tissues.
      Pulmonary involvement was not present. DESIGN: The presence of HHV-8 DNA
      sequences was proved using polymerase chain reaction (PCR), Southern blot
      hybridization, and in situ hybridization. SETTING: Human herpesvirus 8 is found
      in most KS from patients with and without the acquired immunodeficiency syndrome.
      Clinically significant pulmonary infiltration by KS is diagnosed uncommonly
      antemortem, and pleural disease is exceptional. PATIENT: A 49-year-old man who
      had renal transplant with immunosuppressive therapy (tacrolimus and prednisone)
      and developed a cutaneous KS. A pleural effusion appeared without pulmonary
      involvement. Both lesions disappeared when immunosuppressive drugs were
      suspended. Later, the pleural effusion and the cutaneous lesions reappeared.
      Pleural biopsy specimens showed KS infiltration. OUTCOME: The patient refused
      treatment and was lost to follow-up. RESULTS: The skin and pleural biopsies
      showed a proliferation of spindle-shaped cells positive for CD34. The HHV-8
      sequences were detected by nested PCR. No amplification was detected in
      uninvolved skin from the patient or in peripheral blood mononuclear cells from 10
      healthy individuals used as controls. The Southern blot hybridization confirmed
      these results. CONCLUSIONS: To our knowledge, this is the first report of HHV-8
      in symptomatic pleural KS, which was probably associated with immunosuppression
      after kidney transplantation. The demonstration of HHV-8 DNA in biopsy material
      in the appropriate cells could be diagnostic when the morphologic setting is
      consistent with KS.

PMID- 10583935
TI  - Pheochromocytoma associated with neuroendocrine carcinoma. A new type of
      composite pheochromocytoma.
AB  - The coexistence of pheochromocytoma and other tumor types in a single adrenal
      gland has been rarely documented. This type of pheochromocytoma is designated
      "composite" or "mixed," depending on whether the pheochromocytoma and the
      nonpheochromocytoma components show the same embryologic origin. The
      nonpheochromocytoma components reported in the composite pheochromocytoma include
      ganglioneuroma, ganglioneuroblastoma, neuroblastoma, and malignant schwannoma.
      The components found in the mixed pheochromocytoma include adrenal cortical
      neoplasms and spindle cell sarcoma. We report a unique case of composite
      pheochromocytoma in which the nonpheochromocytoma element is a neuroendocrine
      carcinoma. The histologic and the immunohistochemical profiles of the 2 distinct
      components of this tumor were typical for those of pheochromocytoma and
      neuroendocrine carcinoma. This dual differentiation was also supported by
      ultrastructural findings. This case not only broadens the morphologic spectrum of
      composite pheochromocytoma but also provides some additional insight into the
      histogenesis of this rare but fascinating type of tumor.

PMID- 10583936
TI  - Mucinous tumor of the gallbladder with a separate nodule of anaplastic carcinoma.
AB  - A case of mucinous tumor of the gallbladder with a separate nodule of anaplastic
      carcinoma is reported. The patient was an 83-year-old Japanese man who underwent
      cholecystectomy under the preoperative diagnosis of a mucus-producing gallbladder
      tumor. A mucinous tumor was found in the neck and distal body of the gallbladder,
      associated with a separate nodule in the fundus. The latter nodule was initially
      diagnosed as a benign xanthogranulomatous lesion. However, the
      immunohistochemical study revealed that the atypical cells in the superficial
      part of the nodule were positive for cytokeratin and epithelial membrane antigen,
      confirming the diagnosis of anaplastic carcinoma. Although the occurrence of
      mural nodules in mucinous cystic tumors of the ovary and pancreas is well
      reported, to our knowledge, this is the first report on the occurrence of a
      mucinous tumor with a nodule of anaplastic carcinoma in the gallbladder.

PMID- 10583933
TI  - Expression of bcl-2 in enteric neurons in normal human bowel and Hirschsprung
      disease.
AB  - OBJECTIVE: The bcl-2 protein has the functional role of blocking apoptosis, ie,
      programmed cell death. This protein is widely expressed in the developing central
      and peripheral nervous systems. The purpose of this study was to map bcl-2
      expression in the human enteric nervous system, as this has not previously been
      done. METHODS: Rectal specimens were obtained at autopsy of 13 fetuses at 13 to
      31 weeks of gestation. Normal colon was also obtained from 5 children and 2
      adults, and, in addition, ganglionic and aganglionic bowel resected in 11
      patients with Hirschsprung disease was examined. Specimens were fixed in
      formalin, embedded in paraffin, and analyzed with immunohistochemical methods,
      using antibodies raised against bcl-2 and neuron-specific enolase (NSE). RESULTS:
      The bcl-2 protein was expressed in myenteric and submucous ganglion cells in
      fetuses, children, and adults. Nerve fibers of the enteric plexuses that were bcl
      2 immunoreactive were few compared with the number of NSE-immunoreactive nerve
      fibers. In aganglionic bowel no bcl-2-or NSE-immunoreactive ganglion cells were
      revealed. Results of NSE immunohistochemistry showed clearly stained hypertrophic
      nerve bundles, known to be of extrinsic origin, which were only weakly bcl-2
      immunoreactive. CONCLUSION: Expression of bcl-2 in enteric ganglion cells of the
      myenteric and submucous plexuses is displayed in the fetus and during childhood
      and is also retained in adult bowel. Immunohistochemical analysis of bcl-2
      provides a good marker for identification of ganglion cells in Hirschsprung
      disease and may also be valuable for the diagnosis of disorders characterized by
      hypoganglionosis or hyperganglionosis.

PMID- 10583937
TI  - Pathologic quiz case. Renal mass in a 36-year-old woman. Diagnosis: metanephric
      adenoma.

PMID- 10583938
TI  - Pathologic quiz case. Pulmonary mass in a patient presenting with a hemothorax.
      Diagnosis: primary pulmonary biphasic synovial sarcoma.

PMID- 10583940
TI  - Systematic review of cost-effectiveness research of stroke evaluation and
      treatment

PMID- 10583939
TI  - Marfan syndrome and intracranial aneurysms.

PMID- 10583941
TI  - Clearance of psoriasis following agranulocytosis.

PMID- 10583942
TI  - Pentoxyfylline in toxic epidermal necrolysis and Stevens-Johnson syndrome.

PMID- 10583943
TI  - Setting the standards: quality control in the secretory pathway.
AB  - A variety of quality control mechanisms operate in the endoplasmic reticulum and
      in downstream compartments of the secretory pathway to ensure the fidelity and
      regulation of protein expression during cell life and differentiation. As a rule,
      only proteins that pass a stringent selection process are transported to their
      target organelles and compartments. If proper maturation fails, the aberrant
      products are degraded. Quality control improves folding efficiency by retaining
      proteins in the special folding environment of the endoplasmic reticulum, and it
      prevents harmful effects that could be caused by the deployment of incompletely
      folded or assembled proteins.

PMID- 10583944
TI  - Posttranslational quality control: folding, refolding, and degrading proteins.
AB  - Polypeptides emerging from the ribosome must fold into stable three-dimensional
      structures and maintain that structure throughout their functional lifetimes.
      Maintaining quality control over protein structure and function depends on
      molecular chaperones and proteases, both of which can recognize hydrophobic
      regions exposed on unfolded polypeptides. Molecular chaperones promote proper
      protein folding and prevent aggregation, and energy-dependent proteases eliminate
      irreversibly damaged proteins. The kinetics of partitioning between chaperones
      and proteases determines whether a protein will be destroyed before it folds
      properly. When both quality control options fail, damaged proteins accumulate as
      aggregates, a process associated with amyloid diseases.

PMID- 10583945
TI  - Quality control mechanisms during translation.
AB  - Translation uses the genetic information in messenger RNA (mRNA) to synthesize
      proteins. Transfer RNAs (tRNAs) are charged with an amino acid and brought to the
      ribosome, where they are paired with the corresponding trinucleotide codon in
      mRNA. The amino acid is attached to the nascent polypeptide and the ribosome
      moves on to the next codon. The cycle is then repeated to produce a full-length
      protein. Proofreading and editing processes are used throughout protein synthesis
      to ensure the faithful translation of genetic information. The maturation of
      tRNAs and mRNAs is monitored, as is the identity of amino acids attached to
      tRNAs. Accuracy is further enhanced during the selection of aminoacyl-tRNAs on
      the ribosome and their base pairing with mRNA. Recent studies have begun to
      reveal the molecular mechanisms underpinning quality control and go some way to
      explaining the phenomenal accuracy of translation first observed over three
      decades ago.

PMID- 10583946
TI  - Quality control by DNA repair.
AB  - Faithful maintenance of the genome is crucial to the individual and to species.
      DNA damage arises from both endogenous sources such as water and oxygen and
      exogenous sources such as sunlight and tobacco smoke. In human cells, base
      alterations are generally removed by excision repair pathways that counteract the
      mutagenic effects of DNA lesions. This serves to maintain the integrity of the
      genetic information, although not all of the pathways are absolutely error-free.
      In some cases, DNA damage is not repaired but is instead bypassed by specialized
      DNA polymerases.

PMID- 10583947
TI  - The crystal structure of a T cell receptor in complex with peptide and MHC class
      II.
AB  - The crystal structure of a complex involving the D10 T cell receptor (TCR), 16
      residue foreign peptide antigen, and the I-Ak self major histocompatibility
      complex (MHC) class II molecule is reported at 3.2 angstrom resolution. The D10
      TCR is oriented in an orthogonal mode relative to its peptide-MHC (pMHC) ligand,
      necessitated by the amino-terminal extension of peptide residues projecting from
      the MHC class II antigen-binding groove as part of a mini beta sheet.
      Consequently, the disposition of D10 complementarity-determining region loops is
      altered relative to that of most pMHCI-specific TCRs; the latter TCRs assume a
      diagonal orientation, although with substantial variability. Peptide recognition,
      which involves P-1 to P8 residues, is dominated by the Valpha domain, which also
      binds to the class II MHC beta1 helix. That docking is limited to one segment of
      MHC-bound peptide offers an explanation for epitope recognition and altered
      peptide ligand effects, suggests a structural basis for alloreactivity, and
      illustrates how bacterial superantigens can span the TCR-pMHCII surface.

PMID- 10583949
TI  - Complex Shear Wave Velocity Structure Imaged Beneath Africa and Iceland.
AB  - A model of three-dimensional shear wave velocity variations in the mantle reveals
      a tilted low velocity anomaly extending from the core-mantle boundary (CMB)
      region beneath the southeastern Atlantic Ocean into the upper mantle beneath
      eastern Africa. This anomaly suggests that Cenozoic flood basalt volcanism in the
      Afar region and active rifting beneath the East African Rift is linked to an
      extensive thermal anomaly at the CMB more than 45 degrees away. In contrast, a
      low velocity anomaly beneath Iceland is confined to the upper mantle.

PMID- 10583948
TI  - Predicting the evolution of human influenza A.
AB  - Eighteen codons in the HA1 domain of the hemagglutinin genes of human influenza A
      subtype H3 appear to be under positive selection to change the amino acid they
      encode. Retrospective tests show that viral lineages undergoing the greatest
      number of mutations in the positively selected codons were the progenitors of
      future H3 lineages in 9 of 11 recent influenza seasons. Codons under positive
      selection were associated with antibody combining site A or B or the sialic acid
      receptor binding site. However, not all codons in these sites had predictive
      value. Monitoring new H3 isolates for additional changes in positively selected
      codons might help identify the most fit extant viral strains that arise during
      antigenic drift.

PMID- 10583950
TI  - A Lower Mantle Source for Central European Volcanism.
AB  - Cenozoic rifting and volcanism in Europe have been associated with either passive
      or active mantle upwellings. Tomographic images show a low velocity structure
      between 660- and 2000-kilometer depth, which we propose to represent a lower
      mantle upwelling under central Europe that may feed smaller upper-mantle plumes.
      The position of the rift zones in the foreland of the Alpine belts and the
      relatively weak volcanism compared to other regions with plume-associated
      volcanism are probably the result of the past and present subduction under
      southern Europe.

PMID- 10583951
TI  - Transition States Between Pyramids and Domes During Ge/Si Island Growth.
AB  - Real-time observations were made of the shape change from pyramids to domes
      during the growth of germanium-silicon islands on silicon (001). Small islands
      are pyramidal in shape, whereas larger islands are dome-shaped. During growth,
      the transition from pyramids to domes occurs through a series of asymmetric
      transition states with increasing numbers of highly inclined facets. Postgrowth
      annealing of pyramids results in a similar shape change process. The transition
      shapes are temperature dependent and transform reversibly to the final dome shape
      during cooling. These results are consistent with an anomalous coarsening model
      for island growth.

PMID- 10583952
TI  - Global Warming and Northern Hemisphere Sea Ice Extent.
AB  - Surface and satellite-based observations show a decrease in Northern Hemisphere
      sea ice extent during the past 46 years. A comparison of these trends to control
      and transient integrations (forced by observed greenhouse gases and tropospheric
      sulfate aerosols) from the Geophysical Fluid Dynamics Laboratory and Hadley
      Centre climate models reveals that the observed decrease in Northern Hemisphere
      sea ice extent agrees with the transient simulations, and both trends are much
      larger than would be expected from natural climate variations. From long-term
      control runs of climate models, it was found that the probability of the observed
      trends resulting from natural climate variability, assuming that the models'
      natural variability is similar to that found in nature, is less than 2 percent
      for the 1978-98 sea ice trends and less than 0.1 percent for the 1953-98 sea ice
      trends. Both models used here project continued decreases in sea ice thickness
      and extent throughout the next century.

PMID- 10583953
TI  - Satellite Evidence for an Arctic Sea Ice Cover in Transformation.
AB  - Recent research using microwave satellite remote sensing data has established
      that there has been a reduction of about 3 percent per decade in the areal extent
      of the Arctic sea ice cover since 1978, although it is unknown whether the nature
      of the perennial ice pack has changed. These data were used to quantify changes
      in the ice cover's composition, revealing a substantial reduction of about 14
      percent in the area of multiyear ice in winter during the period from 1978 to
      1998. There also appears to be a strong correlation between the area of multiyear
      ice and the spatially averaged thickness of the perennial ice pack, which
      suggests that the satellite-derived areal decreases represent substantial rather
      than only peripheral changes. If this apparent transformation continues, it may
      lead to a markedly different ice regime in the Arctic, altering heat and mass
      exchanges as well as ocean stratification.

PMID- 10583954
TI  - Domain movement in gelsolin: a calcium-activated switch.
AB  - The actin-binding protein gelsolin is involved in remodeling the actin
      cytoskeleton during growth-factor signaling, apoptosis, cytokinesis, and cell
      movement. Calcium-activated gelsolin severs and caps actin filaments. The 3.4
      angstrom x-ray structure of the carboxyl-terminal half of gelsolin (G4-G6) in
      complex with actin reveals the basis for gelsolin activation. Calcium binding
      induces a conformational rearrangement in which domain G6 is flipped over and
      translated by about 40 angstroms relative to G4 and G5. The structural
      reorganization tears apart the continuous beta sheet core of G4 and G6. This
      exposes the actin-binding site on G4, enabling severing and capping of actin
      filaments to proceed.

PMID- 10583955
TI  - Linking spontaneous activity of single cortical neurons and the underlying
      functional architecture.
AB  - The relation between the activity of a single neocortical neuron and the dynamics
      of the network in which it is embedded was explored by single-unit recordings and
      real-time optical imaging. The firing rate of a spontaneously active single
      neuron strongly depends on the instantaneous spatial pattern of ongoing
      population activity in a large cortical area. Very similar spatial patterns of
      population activity were observed both when the neuron fired spontaneously and
      when it was driven by its optimal stimulus. The evoked patterns could be used to
      reconstruct the spontaneous activity of single neurons.

PMID- 10583956
TI  - Stimulation of bone formation in vitro and in rodents by statins.
AB  - Osteoporosis and other diseases of bone loss are a major public health problem.
      Here it is shown that the statins, drugs widely used for lowering serum
      cholesterol, also enhance new bone formation in vitro and in rodents. This effect
      was associated with increased expression of the bone morphogenetic protein-2 (BMP
      2) gene in bone cells. Lovastatin and simvastatin increased bone formation when
      injected subcutaneously over the calvaria of mice and increased cancellous bone
      volume when orally administered to rats. Thus, in appropriate doses, statins may
      have therapeutic applications for the treatment of osteoporosis.

PMID- 10583957
TI  - Requirement for B cell linker protein (BLNK) in B cell development.
AB  - Linker proteins function as molecular scaffolds to localize enzymes with
      substrates. In B cells, B cell linker protein (BLNK) links the B cell receptor
      (BCR)-activated Syk kinase to the phosphoinositide and mitogen-activated kinase
      pathways. To examine the in vivo role of BLNK, mice deficient in BLNK were
      generated. B cell development in BLNK-/- mice was blocked at the transition from
      B220+CD43+ progenitor B to B220+CD43- precursor B cells. Only a small percentage
      of immunoglobulin M++ (IgM++), but not mature IgMloIgDhi, B cells were detected
      in the periphery. Hence, BLNK is an essential component of BCR signaling pathways
      and is required to promote B cell development.

PMID- 10583958
TI  - An essential role for BLNK in human B cell development.
AB  - The signal transduction events that control the progenitor B cell (pro-B cell) to
      precursor B cell (pre-B cell) transition have not been well delineated. In
      evaluating patients with absent B cells, a male with a homozygous splice defect
      in the cytoplasmic adapter protein BLNK (B cell linker protein) was identified.
      Although this patient had normal numbers of pro-B cells, he had no pre-B cells or
      mature B cells, indicating that BLNK plays a critical role in orchestrating the
      pro-B cell to pre-B cell transition. The immune system and overall growth and
      development were otherwise normal in this patient, suggesting that BLNK function
      is highly specific.

PMID- 10583959
TI  - Perforin gene defects in familial hemophagocytic lymphohistiocytosis.
AB  - Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, rapidly fatal,
      autosomal recessive immune disorder characterized by uncontrolled activation of T
      cells and macrophages and overproduction of inflammatory cytokines. Linkage
      analyses indicate that FHL is genetically heterogeneous and linked to 9q21.3-22,
      10q21-22, or another as yet undefined locus. Sequencing of the coding regions of
      the perforin gene of eight unrelated 10q21-22-linked FHL patients revealed
      homozygous nonsense mutations in four patients and missense mutations in the
      other four patients. Cultured lymphocytes from patients had defective cytotoxic
      activity, and immunostaining revealed little or no perforin in the granules.
      Thus, defects in perforin are responsible for 10q21-22-linked FHL. Perforin-based
      effector systems are, therefore, involved not only in the lysis of abnormal cells
      but also in the down-regulation of cellular immune activation.

PMID- 10583960
TI  - A pair of related genes with antagonistic roles in mediating flowering signals.
AB  - Flowering in Arabidopsis is promoted via several interacting pathways. A
      photoperiod-dependent pathway relays signals from photoreceptors to a
      transcription factor gene, CONSTANS (CO), which activates downstream meristem
      identity genes such as LEAFY (LFY). FT, together with LFY, promotes flowering and
      is positively regulated by CO. Loss of FT causes delay in flowering, whereas
      overexpression of FT results in precocious flowering independent of CO or
      photoperiod. FT acts in part downstream of CO and mediates signals for flowering
      in an antagonistic manner with its homologous gene, TERMINAL FLOWER1 (TFL1).

PMID- 10583961
TI  - Activation tagging of the floral inducer FT.
AB  - FLOWERING LOCUS T (FT), which acts in parallel with the meristem-identity gene
      LEAFY (LFY) to induce flowering of Arabidopsis, was isolated by activation
      tagging. Like LFY, FT acts partially downstream of CONSTANS (CO), which promotes
      flowering in response to long days. Unlike many other floral regulators, the
      deduced sequence of the FT protein does not suggest that it directly controls
      transcription or transcript processing. Instead, it is similar to the sequence of
      TERMINAL FLOWER 1 (TFL1), an inhibitor of flowering that also shares sequence
      similarity with membrane-associated mammalian proteins.

PMID- 10583962
TI  - Organogenic role of B lymphocytes in mucosal immunity.
AB  - Follicle-associated epithelium (FAE) in the intestinal Peyer's patches contains M
      cells that deliver pathogens to organized lymphoid tissue. Development of Peyer's
      patches, FAE, and M cells was found to be impaired in mice that had no B cells.
      Transgenic expression of membrane-bound immunoglobulin M restored B cells and FAE
      development. The lack of M cells abrogated infection with a milk-borne
      retrovirus. Thus, in addition to secretion of antibodies and presentation of
      antigens, B cells are important for organogenesis of the mucosal immune barriers.

PMID- 10583963
TI  - Use of chemokine receptors by poxviruses.
AB  - Chemokine receptors serve as portals of entry for certain intracellular
      pathogens, most notably human immunodeficiency virus (HIV). Myxoma virus is a
      member of the poxvirus family that induces a lethal systemic disease in rabbits,
      but no poxvirus receptor has ever been defined. Rodent fibroblasts (3T3) that
      cannot be infected with myxoma virus could be made fully permissive for myxoma
      virus infection by expression of any one of several human chemokine receptors,
      including CCR1, CCR5, and CXCR4. Conversely, infection of 3T3-CCR5 cells can be
      inhibited by RANTES, anti-CCR5 polyclonal antibody, or herbimycin A but not by
      monoclonal antibodies that block HIV-1 infection or by pertussis toxin. These
      findings suggest that poxviruses, like HIV, are able to use chemokine receptors
      to infect specific cell subtypes, notably migratory leukocytes, but that their
      mechanisms of receptor interactions are distinct.

PMID- 10583964
TI  - Fungi from geothermal soils in Yellowstone National Park.
AB  - Geothermal soils near Amphitheater Springs in Yellowstone National Park were
      characterized by high temperatures (up to 70 degrees C), high heavy metal
      content, low pH values (down to pH 2.7), sparse vegetation, and limited organic
      carbon. From these soils we cultured 16 fungal species. Two of these species were
      thermophilic, and six were thermotolerant. We cultured only three of these
      species from nearby cool (0 to 22 degrees C) soils. Transect studies revealed
      that higher numbers of CFUs occurred in and below the root zone of the perennial
      plant Dichanthelium lanuginosum (hot springs panic grass). The dynamics of fungal
      CFUs in geothermal soil and nearby nongeothermal soil were investigated for 12
      months by examining soil cores and in situ mesocosms. For all of the fungal
      species studied, the temperature of the soil from which the organisms were
      cultured corresponded with their optimum axenic growth temperature.

PMID- 10583965
TI  - Soluble methane monooxygenase gene clusters from trichloroethylene-degrading
      Methylomonas sp. strains and detection of methanotrophs during in situ
      bioremediation.
AB  - The soluble MMO (sMMO) gene clusters from group I methanotrophs were
      characterized. An 8.1-kb KpnI fragment from Methylomonas sp. strain KSWIII and a
      7.5-kb SalI fragment from Methylomonas sp. strain KSPIII which contained the sMMO
      gene clusters were cloned and sequenced. The sequences of these two fragments
      were almost identical. The sMMO gene clusters in the fragment consisted of six
      open reading frames which were 52 to 79% similar to the corresponding genes of
      previously described sMMO gene clusters of the group II and group X
      methanotrophs. The phylogenetic analysis of the predicted amino acid sequences of
      sMMO demonstrated that the sMMOs from these strains were closer to that from M.
      capsulatus Bath in the group X methanotrophs than to those from Methylosinus
      trichosporium OB3b and Methylocystis sp. strain M in the group II methanotrophs.
      Based on the sequence data of sMMO genes of our strains and other methanotrophs,
      we designed a new PCR primer to amplify sMMO gene fragments of all the known
      methanotrophs harboring the mmoX gene. The primer set was successfully used for
      detecting methanotrophs in the groundwater of trichloroethylene-contaminated
      sites during in situ-biostimulation treatments.

PMID- 10583966
TI  - Cloning, overexpression, and mutagenesis of the Sporobolomyces salmonicolor
      AKU4429 gene encoding a new aldehyde reductase, which catalyzes the
      stereoselective reduction of ethyl 4-chloro-3-oxobutanoate to ethyl (S)-4-chloro
      3-hydroxybutanoate.
AB  - We cloned and sequenced the gene encoding an NADPH-dependent aldehyde reductase
      (ARII) in Sporobolomyces salmonicolor AKU4429, which reduces ethyl 4-chloro-3
      oxobutanoate (4-COBE) to ethyl (S)-4-chloro-3-hydroxybutanoate. The ARII gene is
      1,032 bp long, is interrupted by four introns, and encodes a 37,315-Da
      polypeptide. The deduced amino acid sequence exhibited significant levels of
      similarity to the amino acid sequences of members of the mammalian 3beta
      hydroxysteroid dehydrogenase-plant dihydroflavonol 4-reductase superfamily but
      not to the amino acid sequences of members of the aldo-keto reductase superfamily
      or to the amino acid sequence of an aldehyde reductase previously isolated from
      the same organism (K. Kita, K. Matsuzaki, T. Hashimoto, H. Yanase, N. Kato, M. C.
      M. Chung, M. Kataoka, and S. Shimizu, Appl. Environ. Microbiol. 62:2303-2310,
      1996). The ARII protein was overproduced in Escherichia coli about 2, 000-fold
      compared to the production in the original yeast cells. The enzyme expressed in
      E. coli was purified to homogeneity and had the same catalytic properties as ARII
      purified from S. salmonicolor. To examine the contribution of the dinucleotide
      binding motif G(19)-X-X-G(22)-X-X-A(25), which is located in the N-terminal
      region, during ARII catalysis, we replaced three amino acid residues in the motif
      and purified the resulting mutant enzymes. Substrate inhibition of the G(19)-->A
      and G(22)-->A mutant enzymes by 4-COBE did not occur. The A(25)-->G mutant enzyme
      could reduce 4-COBE when NADPH was replaced by an equimolar concentration of
      NADH.

PMID- 10583967
TI  - Influence of different electron donors and acceptors on dehalorespiration of
      tetrachloroethene by Desulfitobacterium frappieri TCE1.
AB  - Strain TCE1, a strictly anaerobic bacterium that can grow by reductive
      dechlorination of tetrachloroethene (PCE) and trichloroethene (TCE), was isolated
      by selective enrichment from a PCE-dechlorinating chemostat mixed culture. Strain
      TCE1 is a gram-positive, motile, curved rod-shaped organism that is 2 to 4 by 0.6
      to 0.8 microm and has approximately six lateral flagella. The pH and temperature
      optima for growth are 7.2 and 35 degrees C, respectively. On the basis of a
      comparative 16S rRNA sequence analysis, this bacterium was identified as a new
      strain of Desulfitobacterium frappieri, because it exhibited 99.7% relatedness to
      the D. frappieri type strain, strain PCP-1. Growth with H(2), formate, L-lactate,
      butyrate, crotonate, or ethanol as the electron donor depends on the availability
      of an external electron acceptor. Pyruvate and serine can also be used
      fermentatively. Electron donors (except formate and H(2)) are oxidized to acetate
      and CO(2). When L-lactate is the growth substrate, strain TCE1 can use the
      following electron acceptors: PCE and TCE (to produce cis-1,2-dichloroethene),
      sulfite and thiosulfate (to produce sulfide), nitrate (to produce nitrite), and
      fumarate (to produce succinate). Strain TCE1 is not able to reductively
      dechlorinate 3-chloro-4-hydroxyphenylacetate. The growth yields of the newly
      isolated bacterium when PCE is the electron acceptor are similar to those
      obtained for other dehalorespiring anaerobes (e.g., Desulfitobacterium sp. strain
      PCE1 and Desulfitobacterium hafniense) and the maximum specific reductive
      dechlorination rates are 4 to 16 times higher (up to 1.4 micromol of chloride
      released. min(-1). mg of protein(-1)). Dechlorination of PCE and TCE is an
      inducible process. In PCE-limited chemostat cultures of strain TCE1,
      dechlorination is strongly inhibited by sulfite but not by other alternative
      electron acceptors, such as fumarate or nitrate.

PMID- 10583968
TI  - Cloning and characterization of an Aspergillus nidulans gene involved in the
      regulation of penicillin biosynthesis.
AB  - To identify regulators of penicillin biosynthesis, a previously isolated mutant
      of Aspergillus nidulans (Prg-1) which carried the trans-acting prgA1 mutation was
      used. This mutant also contained fusions of the penicillin biosynthesis genes
      acvA and ipnA with reporter genes (acvA-uidA and ipnA-lacZ) integrated in a
      double-copy arrangement at the chromosomal argB gene. The prgA1 mutant strain
      exhibited only 20 to 50% of the ipnA-lacZ and acvA-uidA expression exhibited by
      the wild-type strain and had only 20 to 30% of the penicillin produced by the
      wild-type strain. Here, using complementation with a genomic cosmid library, we
      isolated a gene (suAprgA1) which complemented the prgA1 phenotype to the wild
      type phenotype; i.e., the levels of expression of both gene fusions and
      penicillin production were nearly wild-type levels. Analysis of the suAprgA1 gene
      in the prgA1 mutant did not reveal any mutation in the suAprgA1 gene or unusual
      transcription of the gene. This suggested that the suAprgA1 gene is a suppressor
      of the prgA1 mutation. The suAprgA1 gene is 1,245 bp long. Its five exons encode
      a deduced protein that is 303 amino acids long. The putative SUAPRGA1 protein was
      similar to both the human p32 protein and Mam33p of Saccharomyces cerevisiae.
      Analysis of the ordered gene library of A. nidulans indicated that suAprgA1 is
      located on chromosome VI. Deletion of the suAprgA1 gene resulted in an
      approximately 50% reduction in ipnA-lacZ expression and in a slight reduction in
      acvA-uidA expression. The DeltasuAprgA1 strain produced about 60% of the amount
      of penicillin produced by the wild-type strain.

PMID- 10583969
TI  - Dynamic interaction of Trichoderma reesei cellobiohydrolases Cel6A and Cel7A and
      cellulose at equilibrium and during hydrolysis.
AB  - The binding of cellobiohydrolases to cellulose is a crucial initial step in
      cellulose hydrolysis. In the search for a detailed understanding of the function
      of cellobiohydrolases, much information concerning how the enzymes and their
      constituent catalytic and cellulose-binding domains interact with cellulose and
      with each other and how binding changes during hydrolysis is still needed. In
      this study we used tritium labeling by reductive methylation to monitor binding
      of the two Trichoderma reesei cellobiohydrolases, Cel6A and Cel7A (formerly CBHII
      and CBHI), and their catalytic domains. Measuring hydrolysis by high-performance
      liquid chromatography and measuring binding by scintillation counting allowed us
      to correlate activity and binding as a function of the extent of degradation.
      These experiments showed that the density of bound protein increased with both
      Cel6A and Cel7A as hydrolysis proceeded, in such a way that the adsorption points
      moved off the initial binding isotherms. We also compared the affinities of the
      cellulose-binding domains and the catalytic domains to the affinities of the
      intact proteins and found that in each case the affinity of the enzyme was
      determined by the linkage between the catalytic and cellulose-binding domains.
      Desorption of Cel6A by dilution of the sample showed hysteresis (60 to 70%
      reversible); in contrast, desorption of Cel7A did not show hysteresis and was
      more than 90% reversible. These findings showed that the two enzymes differ with
      respect to the reversibility of binding.

PMID- 10583971
TI  - cis-chlorobenzene dihydrodiol dehydrogenase (TcbB) from Pseudomonas sp. strain
      P51, expressed in Escherichia coli DH5alpha(pTCB149), catalyzes enantioselective
      dehydrogenase reactions.
AB  - cis-Chlorobenzene dihydrodiol dehydrogenase (CDD) from Pseudomonas sp. strain
      P51, cloned into Escherichia coli DH5alpha(pTCB149) was able to oxidize cis
      dihydrodihydroxy derivatives (cis-dihydrodiols) of dihydronaphthalene, indene,
      and four para-substituted toluenes to the corresponding catechols. During the
      incubation of a nonracemic mixture of cis-1,2-indandiol, only the (+)-cis-(1R,2S)
      enantiomer was oxidized; the (-)-cis-(S,2R) enantiomer remained unchanged. CDD
      oxidized both enantiomers of cis-1,2-dihydroxy-1,2,3, 4-tetrahydronaphthalene,
      but oxidation of the (+)-cis-(1S,2R) enantiomer was delayed until the (-)-cis
      (1R,2S) enantiomer was completely depleted. When incubated with nonracemic
      mixtures of para-substituted cis-toluene dihydrodiols, CDD always oxidized the
      major enantiomer at a higher rate than the minor enantiomer. When incubated with
      racemic 1-indanol, CDD enantioselectively transformed the (+)-(1S) enantiomer to
      1-indanone. This stereoselective transformation shows that CDD also acted as an
      alcohol dehydrogenase. Additionally, CDD was able to oxidize (+)-cis-(1R,2S)
      dihydroxy-1, 2-dihydronaphthalene, (+)-cis-monochlorobiphenyl dihydrodiols, and
      (+)-cis-toluene dihydrodiol to the corresponding catechols.

PMID- 10583970
TI  - Ubiquity and diversity of dissimilatory (per)chlorate-reducing bacteria.
AB  - Environmental contamination with compounds containing oxyanions of chlorine, such
      as perchlorate or chlorate [(per)chlorate] or chlorine dioxide, has been a
      constantly growing problem over the last 100 years. Although the fact that
      microbes reduce these compounds has been recognized for more than 50 years, only
      six organisms which can obtain energy for growth by this metabolic process have
      been described. As part of a study to investigate the diversity and ubiquity of
      microorganisms involved in the microbial reduction of (per)chlorate, we
      enumerated the (per)chlorate-reducing bacteria (ClRB) in very diverse
      environments, including pristine and hydrocarbon-contaminated soils, aquatic
      sediments, paper mill waste sludges, and farm animal waste lagoons. In all of the
      environments tested, the acetate-oxidizing ClRB represented a significant
      population, whose size ranged from 2.31 x 10(3) to 2.4 x 10(6) cells per g of
      sample. In addition, we isolated 13 ClRB from these environments. All of these
      organisms could grow anaerobically by coupling complete oxidation of acetate to
      reduction of (per)chlorate. Chloride was the sole end product of this reductive
      metabolism. All of the isolates could also use oxygen as a sole electron
      acceptor, and most, but not all, could use nitrate. The alternative electron
      donors included simple volatile fatty acids, such as propionate, butyrate, or
      valerate, as well as simple organic acids, such as lactate or pyruvate. Oxidized
      minus-reduced difference spectra of washed whole-cell suspensions of the isolates
      had absorbance maxima close to 425, 525, and 550 nm, which are characteristic of
      type c cytochromes. In addition, washed cell suspensions of all of the ClRB
      isolates could dismutate chlorite, an intermediate in the reductive metabolism of
      (per)chlorate, into chloride and molecular oxygen. Chlorite dismutation was a
      result of the activity of a single enzyme which in pure form had a specific
      activity of approximately 1,928 micromol of chlorite per mg of protein per min.
      Analyses of the 16S ribosomal DNA sequences of the organisms indicated that they
      all belonged to the alpha, beta, or gamma subclass of the Proteobacteria. Several
      were closely related to members of previously described genera that are not
      recognized for the ability to reduce (per)chlorate, such as the genera
      Pseudomonas and Azospirllum. However, many were not closely related to any
      previously described organism and represented new genera within the
      Proteobacteria. The results of this study significantly increase the limited
      number of microbial isolates that are known to be capable of dissimilatory
      (per)chlorate reduction and demonstrate the hitherto unrecognized phylogenetic
      diversity and ubiquity of the microorganisms that exhibit this type of
      metabolism.

PMID- 10583972
TI  - Swimming marine Synechococcus strains with widely different photosynthetic
      pigment ratios form a monophyletic group.
AB  - Unicellular marine cyanobacteria are ubiquitous in both coastal and oligotrophic
      regimes. The contribution of these organisms to primary production and nutrient
      cycling is substantial on a global scale. Natural populations of marine
      Synechococcus strains include multiple genetic lineages, but the link, if any,
      between unique phenotypic traits and specific genetic groups is still not
      understood. We studied the genetic diversity (as determined by the DNA-dependent
      RNA polymerase rpoC1 gene sequence) of a set of marine Synechococcus isolates
      that are able to swim. Our results show that these isolates form a monophyletic
      group. This finding represents the first example of correspondence between a
      physiological trait and a phylogenetic group in marine Synechococcus. In
      contrast, the phycourobilin (PUB)/phycoerythrobilin (PEB) pigment ratios of
      members of the motile clade varied considerably. An isolate obtained from the
      California Current (strain CC9703) displayed a pigment signature identical to
      that of nonmotile strain WH7803, which is considered a model for low-PUB/PEB
      ratio strains, whereas several motile strains had higher PUB/PEB ratios than
      strain WH8103, which is considered a model for high-PUB/PEB-ratio strains. These
      findings indicate that the PUB/PEB pigment ratio is not a useful characteristic
      for defining phylogenetic groups of marine Synechococcus strains.

PMID- 10583973
TI  - Disruption of TRI101, the gene encoding trichothecene 3-O-acetyltransferase, from
      Fusarium sporotrichioides.
AB  - We screened a Fusarium sporotrichioides NRRL 3299 cDNA expression library in a
      toxin-sensitive Saccharomyces cerevisiae strain lacking a functional PDR5 gene.
      Fourteen yeast transformants were identified as resistant to the trichothecene
      4,15-diacetoxyscirpenol, and each carried a cDNA encoding the trichothecene 3-O
      acetyltransferase that is the F. sporotrichioides homolog of the Fusarium
      graminearum TRI101 gene. Mutants of F. sporotrichioides NRRL 3299 produced by
      disruption of TRI101 were altered in their abilities to synthesize T-2 toxin and
      accumulated isotrichodermol and small amounts of 3, 15-didecalonectrin and 3
      decalonectrin, trichothecenes that are not observed in cultures of the parent
      strain. Our results indicate that TRI101 converts isotrichodermol to
      isotrichodermin and is required for the biosynthesis of T-2 toxin.

PMID- 10583974
TI  - Attributes of atmospheric carbon monoxide oxidation by Maine forest soils.
AB  - CO, one of the most important trace gases, regulates tropospheric methane,
      hydroxyl radical, and ozone contents. Ten to 25% of the estimated global CO flux
      may be consumed by soils annually. Depth profiles for (14)CO oxidation and CO
      concentration indicated that CO oxidation occurred primarily in surface soils and
      that photooxidation of soil organic matter did not necessarily contribute
      significantly to CO fluxes. Kinetic analyses revealed that the apparent K(m) was
      about 18 nM (17 ppm) and the V(max) was 6.9 micromol g (fresh weight)(-1) h(-1);
      the apparent K(m) was similar to the apparent K(m) for atmospheric methane
      consumption, but the V(max) was more than 100 times higher. Atmospheric CO
      oxidation responded sensitively to soil water regimes; decreases in water content
      in initially saturated soils resulted in increased uptake, and optimum uptake
      occurred at water contents of 30 to 60%. However, extended drying led to
      decreased uptake and net CO production. Rewetting could restore CO uptake, albeit
      with a pronounced hysteresis. The responses to changing temperatures indicated
      that the optimum temperature for net uptake was between 20 and 25 degrees C and
      that there was a transition to net production at temperatures above 30 degrees C.
      The responses to methyl fluoride and acetylene indicated that populations other
      than ammonia oxidizers and methanotrophs must be involved in forest soils. The
      response to acetylene was notable, since the strong initial inhibition was
      reversed after 12 h of incubation; in contrast, methyl fluoride did not have an
      inhibitory effect. Ammonium did not inhibit CO uptake; the level of nitrite
      inhibition was initially substantial, but nitrite inhibition was reversible over
      time. Nitrite inhibition appeared to occur through indirect effects based on
      abiological formation of NO.

PMID- 10583975
TI  - Biosynthesis of novel exopolymers by Aureobasidium pullulans.
AB  - Aureobasidium pullulans ATCC 42023 was cultured under aerobic conditions with
      glucose, mannose, and glucose analogs as energy sources. The exopolymer extracts
      produced under these conditions were composed of glucose and mannose. The molar
      ratio of glucose to mannose in the exopolymer extract and the molecular weight of
      the exopolymer varied depending on the energy source and culture time. The
      glucose content of exopolymer extracts formed with glucose and mannose as the
      carbon sources was between 91 and 87%. The molecular weight decreased from 3.5 x
      10(6) to 2.12 x 10(6) to 0.85 x 10(6) to 0.77 x 10(6) with culture time. As the
      culture time increased, the glucose content of the exopolymer extract formed with
      glucosamine decreased from 55 +/- 3 to 29 +/- 2 mol%, and the molecular weight
      increased from 2.73 x 10(6) to 4.86 x 10(6). There was no evidence that
      glucosamine was directly incorporated into exopolymers. The molar ratios of
      glucose to mannose in exopolymer extracts ranged from 87 +/- 3:13 +/- 3 to 28 +/-
      2:72 +/- 2 and were affected by the energy source added. On the basis of the
      results of an enzyme hydrolysis analysis of the exopolymer extracts and the
      compositional changes observed, mannose (a repeating unit) was substituted for
      glucose, which gave rise to a new family of exopolymer analogs.

PMID- 10583976
TI  - Osmoprotection of Escherichia coli by peptone is mediated by the uptake and
      accumulation of free proline but not of proline-containing peptides.
AB  - The effect of meat peptone type I (Sigma) on the growth of Escherichia coli cells
      under hyperosmotic stress has been investigated. Peptone is a complex mixture of
      peptides with a small content of free amino acids, which resembles nutrients
      found in natural environments. Our data showed that peptone enhances the growth
      of E. coli cells in high-osmolarity medium to levels higher than those achieved
      with the main compatible solute in bacteria, glycine betaine. The mechanism of
      osmoprotection by peptone comprises the uptake and accumulation of the compatible
      solute, proline. The main role of the peptides contained in peptone is the
      provision of nutrients rather than the intracellular accumulation of osmolytes.
      In contrast to Listeria monocytogenes (M. R. Amezaga, I. Davidson, D. McLaggan,
      A. Verheul, T. Abee, and I. R. Booth, Microbiology 141:41-49, 1995), E. coli does
      not accumulate exogenous peptides for osmoprotection and peptides containing
      proline do not lead to the accumulation of proline as a compatible solute. In
      late-logarithmic-phase cultures of E. coli growing at high osmolarity plus
      peptone, proline becomes the limiting factor for growth, and the intracellular
      pools of proline are not maintained. This is a consequence of the low
      concentration of free proline in peptone, the catabolism of proline by E. coli,
      and the inability of E. coli to utilize proline-containing peptides as a source
      of compatible solutes. Our data highlight the role that natural components in
      food such as peptides play in undermining food preservation regimes, such as high
      osmolarity, and also that the specific mechanisms of osmoprotection by these
      compounds differ according to the organism.

PMID- 10583977
TI  - Removal of mercury from chloralkali electrolysis wastewater by a mercury
      resistant Pseudomonas putida strain.
AB  - A mercury-resistant bacterial strain which is able to reduce ionic mercury to
      metallic mercury was used to remediate in laboratory columns mercury-containing
      wastewater produced during electrolytic production of chlorine. Factory effluents
      from several chloralkali plants in Europe were analyzed, and these effluents
      contained total mercury concentrations between 1.6 and 7.6 mg/liter and high
      chloride concentrations (up to 25 g/liter) and had pH values which were either
      acidic (pH 2.4) or alkaline (pH 13.0). A mercury-resistant bacterial strain,
      Pseudomonas putida Spi3, was isolated from polluted river sediments. Biofilms of
      P. putida Spi3 were grown on porous carrier material in laboratory column
      bioreactors. The bioreactors were continuously fed with sterile synthetic model
      wastewater or nonsterile, neutralized, aerated chloralkali wastewater. We found
      that sodium chloride concentrations up to 24 g/liter did not inhibit microbial
      mercury retention and that mercury concentrations up to 7 mg/liter could be
      treated with the bacterial biofilm with no loss of activity. When wastewater
      samples from three different chloralkali plants in Europe were used, levels of
      mercury retention efficiency between 90 and 98% were obtained. Thus, microbial
      mercury removal is a potential biological treatment for chloralkali electrolysis
      wastewater.

PMID- 10583978
TI  - Leaching of zinc sulfide by Thiobacillus ferrooxidans: bacterial oxidation of the
      sulfur product layer increases the rate of zinc sulfide dissolution at high
      concentrations of ferrous ions.
AB  - This paper reports the results of leaching experiments conducted with and without
      Thiobacillus ferrooxidans at the same conditions in solution. The extent of
      leaching of ZnS with bacteria is significantly higher than that without bacteria
      at high concentrations of ferrous ions. A porous layer of elemental sulfur is
      present on the surfaces of the chemically leached particles, while no sulfur is
      present on the surfaces of the bacterially leached particles. The analysis of the
      data using the shrinking-core model shows that the chemical leaching of ZnS is
      limited by the diffusion of ferrous ions through the sulfur product layer at high
      concentrations of ferrous ions. The analysis of the data shows that diffusion
      through the product layer does not limit the rate of dissolution when bacteria
      are present. This suggests that the action of T. ferrooxidans in oxidizing the
      sulfur formed on the particle surface is to remove the barrier to diffusion by
      ferrous ions.

PMID- 10583979
TI  - PCR detection, characterization, and distribution of virulence genes in Aeromonas
      spp.
AB  - We found 73.1 to 96.9% similarity by aligning the cytolytic enterotoxin gene of
      Aeromonas hydrophila SSU (AHCYTOEN; GenBank accession no. M84709) against
      aerolysin genes of Aeromonas spp., suggesting the possibility of selecting common
      primers. Identities of 90 to 100% were found among the eight selected primers
      from those genes. Amplicons obtained from Aeromonas sp. reference strains by
      using specific primers for each gene or a cocktail of primers were 232 bp long.
      Of hybridization group 4/5A/5B (HG4/5A/5B), HG9, and HG12 or non-Aeromonas
      reference strains, none were positive. PCR-restriction fragment length
      polymorphism (PCR-RFLP) with HpaII yielded three types of patterns. PCR-RFLP 1
      contained two fragments (66 and 166 bp) found in HG6, HG7, HG8, HG10, and HG11.
      PCR-RFLP 2 contained three fragments (18, 66, and 148 bp) found in HG1, HG2, HG3,
      and HG11. PCR-RFLP 3, with four fragments (7, 20, 66, and 139 bp), was observed
      only in HG13. PCR-amplicon sequence analysis (PCR-ASA) revealed three main types.
      PCR-ASA 1 had 76 to 78% homology with AHCYTOEN and included strains in HG6, HG7,
      HG8, HG10, and HG11. PCR-ASA 2, with 82% homology, was found only in HG13. PCR
      ASA 3, with 91 to 99% homology, contained the strains in HG1, HG2, HG3, and HG11.
      This method indicated that 37 (61%) of the 61 reference strains were positive
      with the primer cocktail master mixture, and 34 (58%) of 59 environmental
      isolates, 93 (66%) of 141 food isolates, and 100 (67%) of 150 clinical isolates
      from around the world carried a virulence factor when primers AHCF1 and AHCR1
      were used. In conclusion, this PCR-based method is rapid, sensitive, and specific
      for the detection of virulence factors of Aeromonas spp. It overcomes the
      handicap of time-consuming biochemical and other DNA-based methods.

PMID- 10583980
TI  - Transformation of Escherichia coli with DNA from Saccharomyces cerevisiae cell
      lysates.
AB  - We developed a system to monitor the transfer of heterologous DNA from a
      genetically manipulated strain of Saccharomyces cerevisiae to Escherichia coli.
      This system is based on a yeast strain that carries multiple integrated copies of
      a pUC-derived plasmid. The bacterial sequences are maintained in the yeast genome
      by selectable markers for lactose utilization. Lysates of the yeast strain were
      used to transform E. coli. Transfer of DNA was measured by determining the number
      of ampicillin-resistant E. coli clones. Our results show that transmission of the
      Amp(r) gene to E. coli by genetic transformation, caused by DNA released from the
      yeast, occurs at a very low frequency (about 50 transformants per microg of DNA)
      under optimal conditions (a highly competent host strain and a highly efficient
      transformation procedure). These results suggest that under natural conditions,
      spontaneous transmission of chromosomal genes from genetically modified organisms
      is likely to be rare.

PMID- 10583981
TI  - Lignin-modifying enzymes of the white rot basidiomycete Ganoderma lucidum.
AB  - Ganoderma lucidum, a white rot basidiomycete widely distributed worldwide, was
      studied for the production of the lignin-modifying enzymes laccase, manganese
      dependent peroxidase (MnP), and lignin peroxidase (LiP). Laccase levels observed
      in high-nitrogen (HN; 24 mM N) shaken cultures were much greater than those seen
      in low-nitrogen (2.4 mM N), malt extract, or wood-grown cultures and those
      reported for most other white rot fungi to date. Laccase production was readily
      seen in cultures grown with pine or poplar (100-mesh-size ground wood) as the
      sole carbon and energy source. Cultures containing both pine and poplar showed 5-
      to 10-fold-higher levels of laccase than cultures containing pine or poplar
      alone. Since syringyl units are structural components important in poplar lignin
      and other hardwoods but much less so in pine lignin and other softwoods, pine
      cultures were supplemented with syringic acid, and this resulted in laccase
      levels comparable to those seen in pine-plus-poplar cultures. Sodium dodecyl
      sulfate-polyacrylamide gel electrophoresis of concentrated extracellular culture
      fluid from HN cultures showed two laccase activity bands (M(r) of 40,000 and 66,
      000), whereas isoelectric focusing revealed five major laccase activity bands
      with estimated pIs of 3.0, 4.25, 4.5, 4.8, and 5.1. Low levels of MnP activity (
      approximately 100 U/liter) were detected in poplar-grown cultures but not in
      cultures grown with pine, with pine plus syringic acid, or in HN medium. No LiP
      activity was seen in any of the media tested; however, probing the genomic DNA
      with the LiP cDNA (CLG4) from the white rot fungus Phanerochaete chrysosporium
      showed distinct hybridization bands suggesting the presence of lip-like sequences
      in G. lucidum.

PMID- 10583982
TI  - A study of deep-sea natural microbial populations and barophilic pure cultures
      using a high-pressure chemostat.
AB  - Continuous cultures in which a high-pressure chemostat was used were employed to
      study the growth responses of (i) deep-sea microbial populations with the
      naturally occurring carbon available in seawater and with limiting concentrations
      of supplemental organic substrates and (ii) pure cultures of copiotrophic
      barophilic and barotolerant deep-sea isolates in the presence of limiting carbon
      concentrations at various pressures, dilution rates, and temperatures. We found
      that the growth rates of natural populations could not be measured or were
      extremely low (e.g., a doubling time of 629 h), as determined from the difference
      between the dilution rate and the washout rate. A low concentration of
      supplemental carbon (0.33 mg/liter) resulted in positive growth responses in the
      natural population, which resulted in an increase in the number of cells and
      eventually a steady population of cells. We found that the growth responses to
      imposed growth pressure by barophilic and barotolerant pure-culture isolates that
      were previously isolated and characterized under high-nutrient-concentration
      conditions were maintained under the low-nutrient-concentration limiting
      conditions (0.33 to 3.33 mg of C per liter) characteristic of the deep-sea
      environment. Our results indicate that deep-sea microbes can respond to small
      changes in substrate availability. Also, barophilic microbes that are
      copiotrophic as determined by their isolation in the presence of high carbon
      concentrations and their preference for high carbon concentrations are versatile
      and are able to compete and grow as barophiles in the low-carbon-concentration
      oligotrophic deep-sea environment in which they normally exist.

PMID- 10583983
TI  - Characterization of unexpected growth of Escherichia coli O157:H7 by modeling.
AB  - Modeling of batch kinetics in minimal synthetic medium was used to characterize
      Escherichia coli O157:H7 growth, which appeared to be different from the
      exponential growth expected in minimal synthetic medium and observed for E. coli
      K-12. The turbidimetric kinetics of 14 of the 15 O157:H7 strains tested (93%)
      were nonexponential, whereas 25 of the 36 other E. coli strains tested (70%)
      exhibited exponential kinetics. Moreover, the anomaly was almost corrected when
      the minimal medium was supplemented with methionine. These observations were
      confirmed with two reference strains by using plate count monitoring. In mixed
      cultures, E. coli K-12 had a positive effect on E. coli O157:H7 and corrected its
      growth anomaly. This demonstrated that commensalism occurred, as the growth curve
      for E. coli K-12 was not affected. The interaction could be explained by an
      exchange of methionine, as the effect of E. coli K-12 on E. coli O157:H7 appeared
      to be similar to the effect of methionine.

PMID- 10583984
TI  - Listeria monocytogenes Scott A: cell surface charge, hydrophobicity, and electron
      donor and acceptor characteristics under different environmental growth
      conditions.
AB  - We determined the variations in the surface physicochemical properties of
      Listeria monocytogenes Scott A cells that occurred under various environmental
      conditions. The surface charges, the hydrophobicities, and the electron donor and
      acceptor characteristics of L. monocytogenes Scott A cells were compared after
      the organism was grown in different growth media and at different temperatures;
      to do this, we used microelectrophoresis and the microbial adhesion to solvents
      method. Supplementing the growth media with glucose or lactic acid affected the
      electrical, hydrophobic, and electron donor and acceptor properties of the cells,
      whereas the growth temperature (37, 20, 15, or 8 degrees C) primarily affected
      the electrical and electron donor and acceptor properties. The nonlinear effects
      of the growth temperature on the physicochemical properties of the cells were
      similar for cells cultivated in two different growth media, but bacteria
      cultivated in Trypticase soy broth supplemented with 6 g of yeast extract per
      liter (TSYE) were slightly more hydrophobic than cells cultivated in brain heart
      infusion medium (P < 0.05). Adhesion experiments conducted with L. monocytogenes
      Scott A cells cultivated in TSYE at 37, 20, 15, and 8 degrees C and then
      suspended in a sodium chloride solution (1.5 x 10(-1) or 1.5 x 10(-3) M NaCl)
      confirmed that the cell surface charge and the electron donor and acceptor
      properties of the cells had an influence on their attachment to stainless steel.

PMID- 10583985
TI  - Agar underlay method for recovery of sublethally heat-injured bacteria.
AB  - A method of recovering sublethally heat-injured bacteria was developed. The
      procedure (termed the agar underlay method) uses a nonselective agar underlaid
      with a selective medium. In a two-chambered petri dish, the Lutri plate (LP), a
      nonselective agar is inoculated with a population of sublethally heat-injured
      bacteria. After a 2-h repair incubation period, selective agar is added to the
      bottom chamber of the LP and incubated. By diffusing through the nonselective top
      agar, selective agents from the underlay medium impart selectivity to the system.
      By the agar underlay method, recovery rates of the heat-injured food-borne
      pathogens Escherichia coli O157:H7 and Salmonella typhimurium were not different
      (P > 0. 05) from recovery rates determined with nonselective media. Sublethally
      heat-injured cells (60 degrees C for 1.5 min in buffer or 80 degrees C for 30 s
      on meat surfaces) grew and produced a typical colony morphology and color
      reaction when the agar underlay procedure was used with the appropriate
      respective selective agars. Unlike agar overlay methods for injury repair, the
      agar underlay procedure allows the typical selective-medium colony morphology to
      develop and allows colonies to be more easily picked for further
      characterization. Higher recovery rates of heat-injured fecal enterococci from
      bovine fecal samples and total coliforms from animal waste lagoons were obtained
      by the agar underlay method with selective agars than by direct plating on the
      respective selective media.

PMID- 10583986
TI  - A unique chitinase with dual active sites and triple substrate binding sites from
      the hyperthermophilic archaeon Pyrococcus kodakaraensis KOD1.
AB  - We have found that the hyperthermophilic archaeon Pyrococcus kodakaraensis KOD1
      produces an extracellular chitinase. The gene encoding the chitinase (chiA) was
      cloned and sequenced. The chiA gene was found to be composed of 3,645
      nucleotides, encoding a protein (1,215 amino acids) with a molecular mass of
      134,259 Da, which is the largest among known chitinases. Sequence analysis
      indicates that ChiA is divided into two distinct regions with respective active
      sites. The N-terminal and C-terminal regions show sequence similarity with
      chitinase A1 from Bacillus circulans WL-12 and chitinase from Streptomyces
      erythraeus (ATCC 11635), respectively. Furthermore, ChiA possesses unique chitin
      binding domains (CBDs) (CBD1, CBD2, and CBD3) which show sequence similarity with
      cellulose binding domains of various cellulases. CBD1 was classified into the
      group of family V type cellulose binding domains. In contrast, CBD2 and CBD3 were
      classified into that of the family II type. chiA was expressed in Escherichia
      coli cells, and the recombinant protein was purified to homogeneity. The optimal
      temperature and pH for chitinase activity were found to be 85 degrees C and 5.0,
      respectively. Results of thin-layer chromatography analysis and activity
      measurements with fluorescent substrates suggest that the enzyme is an endo-type
      enzyme which produces a chitobiose as a major end product. Various deletion
      mutants were constructed, and analyses of their enzyme characteristics revealed
      that both the N-terminal and C-terminal halves are independently functional as
      chitinases and that CBDs play an important role in insoluble chitin binding and
      hydrolysis. Deletion mutants which contain the C-terminal half showed higher
      thermostability than did N-terminal-half mutants and wild-type ChiA.

PMID- 10583987
TI  - Molecular analysis of the 18S rRNA gene of Cryptosporidium serpentis in a wild
      caught corn snake (Elaphe guttata guttata) and a five-species restriction
      fragment length polymorphism- based assay that can additionally discern C. parvum
      from C. wrairi.
AB  - An adult wild-caught corn snake (Elaphe guttata guttata) was presented for humane
      euthanasia and necropsy because of severe cryptosporidiosis. The animal was
      lethargic and >5% dehydrated but in good flesh. Gastric lavage was performed
      prior to euthanasia. Histopathologic findings included gastric mucosal
      hypertrophy and a hemorrhagic erosive gastritis. Numerous 5- to 7-microm-diameter
      round extracellular organisms were associated with the mucosal hypertrophy. A
      PCR, acid-fast stains, Giemsa stains, and an enzyme immunoassay were all positive
      for Cryptosporidium spp. PCR and restriction fragment length polymorphism (RFLP)
      analysis on gastric lavage and gastric mucosal specimens, and subsequent
      sequencing of the 18S rRNA gene, enabled a distinct molecular characterization of
      the infecting organism as Cryptosporidium serpentis. Until recently, studies on
      snake Cryptosporidium have relied on host specificity and gross and
      histopathologic observations to identify the infecting species. A multiple
      alignment of our sequence against recently published sequences of the 18S rRNA
      gene of C. serpentis (GenBank accession no. AF093499, AF093500, and AF093501 [L.
      Xiao et al., unpublished data, 1998]) revealed 100% homology with the C.
      serpentis (Snake) sequence (AF093499) previously described by Xiao et al. An RFLP
      method to differentiate the five presently sequenced strains of Cryptosporidium
      at this locus was developed. This assay, which uses SpeI and SspI, complements a
      previously reported assay by additionally distinguishing the bovine strain of
      Cryptosporidium from Cryptosporidium wrairi.

PMID- 10583988
TI  - The presence of salt and a curing agent reduces bacteriocin production by
      Lactobacillus sakei CTC 494, a potential starter culture for sausage
      fermentation.
AB  - The specific conditions in the batter of raw fermented sausages may reduce the
      efficiency of bacteriocin-producing starter cultures. In this work, using in
      vitro fermentation, we found that sodium chloride and sodium nitrite interfere
      with the growth of Lactobacillus sakei CTC 494, an organism which produces the
      antilisterial bacteriocin sakacin K. Because sakacin K production follows primary
      metabolite kinetics, a decrease in cell formation resulted in a decrease in
      sakacin K production as well. Sodium chloride dramatically influenced bacteriocin
      production by decreasing both biomass production and specific bacteriocin
      production. Sodium nitrite, however, had no effect on specific bacteriocin
      production and decreased bacteriocin production only because of its effect on
      cell growth. Moreover, sodium nitrite enhanced the toxic effect of lactic acid on
      bacterial growth.

PMID- 10583989
TI  - Utilization of heterologous siderophores enhances levels of iron available to
      Pseudomonas putida in the rhizosphere.
AB  - Pseudomonas spp. have the capacity to utilize siderophores produced by diverse
      species of bacteria and fungi, and the present study was initiated to determine
      if siderophores produced by rhizosphere microorganisms enhance the levels of iron
      available to a strain of Pseudomonas putida in this natural habitat. We used a
      previously described transcriptional fusion (pvd-inaZ) between an iron-regulated
      promoter (pvd) and the ice nucleation reporter gene (inaZ) to detect alterations
      in iron availability to P. putida. Ice nucleation activity (INA) expressed from
      the pvd-inaZ fusion by P. putida N1R or N1R Pvd(-), a derivative deficient in the
      production of a pyoverdine siderophore, was inversely related to the
      concentration of ferric citrate in a culture medium. In culture, INA expressed by
      N1R Pvd(-) (pvd-inaZ) was reduced in the presence of the ferric complex of
      pseudobactin-358, a pyoverdine siderophore produced by P. putida WCS358 that can
      be utilized as a source of iron by N1R Pvd(-). In the rhizosphere of cucumbers
      grown in sterilized soil, N1R Pvd(-) (pvd-inaZ) expressed INA, indicating that
      iron availability was sufficiently low in that habitat to allow transcription of
      the iron-regulated pvd promoter. Coinoculation with WCS358 or N1R significantly
      decreased INA expressed by N1R Pvd(-) (pvd-inaZ) in the rhizosphere, whereas
      coinoculation with a pyoverdine-deficient mutant of WCS358 did not reduce INA
      expressed by N1R Pvd(-) (pvd-inaZ). These results indicate that iron availability
      to N1R Pvd(-) (pvd-inaZ) in the rhizosphere was enhanced by the presence of
      another strain of P. putida that produces a pyoverdine that N1R Pvd(-) (pvd-inaZ)
      was able to utilize as a source of iron. In culture, strain N1R Pvd(-) also
      utilized ferric complexes of the siderophores enterobactin and aerobactin as
      sources of iron. In the rhizosphere of cucumbers grown in sterilized soil, INA
      expressed by N1R Pvd(-) (pvd-inaZ) was reduced in the presence of strains of
      Enterobacter cloacae that produced enterobactin, aerobactin, or both
      siderophores, but INA expressed by N1R Pvd(-) (pvd-inaZ) was not altered in the
      presence of a mutant of E. cloacae deficient in both enterobactin and aerobactin
      production. Therefore, the iron status of P. putida was altered by siderophores
      produced by an unrelated bacterium coinhabiting the rhizosphere. Finally, we
      demonstrated that INA expressed by N1R containing pvd-inaZ in the rhizosphere
      differed between plants grown in sterilized versus nonsterilized field soil. The
      results of this study demonstrate that (i) P. putida expresses genes for
      pyoverdine production and uptake in the rhizosphere, but the level of gene
      expression is influenced by other bacteria that coexist with P. putida in this
      habitat, and (ii) diverse groups of microorganisms can alter the availability of
      chemical resources in microbial habitats on root surfaces.

PMID- 10583990
TI  - Effects of pulsed electric fields on inactivation kinetics of Listeria innocua.
AB  - The effects of pulsed electric field (PEF) treatment and processing factors on
      the inactivation kinetics of Listeria innocua NCTC 11289 were investigated by
      using a pilot plant PEF unit with a flow rate of 200 liters/h. The electric field
      strength, pulse length, number of pulses, and inlet temperature were the most
      significant process factors influencing the inactivation kinetics. Product
      factors (pH and conductivity) also influenced the inactivation kinetics. In
      phosphate buffer at pH 4.0 and 0.5 S/m at 40 degrees C, a 3. 0-V/microm PEF
      treatment at an inlet temperature of 40 degrees C resulted in > or = 6.3 log
      inactivation of strain NCTC 11289 at 49.5 degrees C. A synergistic effect between
      temperature and PEF inactivation was also observed. The inactivation obtained
      with PEF was compared to the inactivation obtained with heat. We found that heat
      inactivation was less effective than PEF inactivation under similar time and
      temperature conditions. L. innocua cells which were incubated for a prolonged
      time in the stationary phase were more resistant to the PEF treatment, indicating
      that the physiological state of the microorganism plays a role in inactivation by
      PEF. Sublethal injury of cells was observed after PEF treatment, and the injury
      was more severe when the level of treatment was increased. Overall, our results
      indicate that it may be possible to use PEF in future applications in order to
      produce safe products.

PMID- 10583991
TI  - Molecular analysis of the microbial diversity present in the colonic wall,
      colonic lumen, and cecal lumen of a pig.
AB  - Random clones of 16S ribosomal DNA gene sequences were isolated after PCR
      amplification with eubacterial primers from total genomic DNA recovered from
      samples of the colonic lumen, colonic wall, and cecal lumen from a pig. Sequences
      were also obtained for cultures isolated anaerobically from the same colonic-wall
      sample. Phylogenetic analysis showed that many sequences were related to those of
      Lactobacillus or Streptococcus spp. or fell into clusters IX, XIVa, and XI of
      gram-positive bacteria. In addition, 59% of randomly cloned sequences showed less
      than 95% similarity to database entries or sequences from cultivated organisms.
      Cultivation bias is also suggested by the fact that the majority of isolates
      (54%) recovered from the colon wall by culturing were related to Lactobacillus
      and Streptococcus, whereas this group accounted for only one-third of the
      sequence variation for the same sample from random cloning. The remaining
      cultured isolates were mainly Selenomonas related. A higher proportion of
      Lactobacillus reuteri-related sequences than of Lactobacillus acidophilus- and
      Lactobacillus amylovorus-related sequences were present in the colonic-wall
      sample. Since the majority of bacterial ribosomal sequences recovered from the
      colon wall are less than 95% related to known organisms, the roles of many of the
      predominant wall-associated bacteria remain to be defined.

PMID- 10583992
TI  - Influence of different functional elements of plasmid pGT232 on maintenance of
      recombinant plasmids in Lactobacillus reuteri populations in vitro and in vivo.
AB  - Plasmid pGT232 (5.1 kb), an indigenous plasmid of Lactobacillus reuteri 100-23,
      was determined, on the basis of nucleotide and deduced protein sequence data, to
      belong to the pC194-pUB110 family of plasmids that replicate via the rolling
      circle mechanism. The minimal replicon of pGT232 was located on a 1.7-kb sequence
      consisting of a double-strand origin of replication and a gene encoding the
      replication initiation protein, repA. An erythromycin-selectable recombinant
      plasmid containing this minimal replicon was stably maintained (>97% erythromycin
      resistant cells) without antibiotic selection in an L. reuteri population under
      laboratory growth conditions but was poorly maintained (<33% resistant cells) in
      the L. reuteri population inhabiting the murine gastrointestinal tract. Stable
      maintenance (>90% resistant cells) of pGT232-derived plasmids in the
      lactobacillus population in vivo required an additional 1.0-kb sequence which
      contained a putative single-strand replication origin (SSO). The SSO of pGT232 is
      believed to be novel and functions in an orientation-specific manner.

PMID- 10583993
TI  - Reverse transcription-PCR differential display analysis of Escherichia coli
      global gene regulation in response to heat shock.
AB  - A reverse transcription (RT)-PCR technique was developed to analyze global gene
      regulation in Escherichia coli. A novel combination of primers designed
      specifically for the start and stop regions of E. coli genes (based on the
      findings of Fislage et al. [R. Fislage, M. Berceanu, Y. Humboldt, M. Wendt, and
      H. Oberender, Nucleic Acids Res. 25:1830-1835, 1997]) was used as an alternative
      to the poly(T) primers often used in eukaryotic RT-PCR. The validity of the
      technique was demonstrated by applying it to heat shock analysis. Specifically,
      RT-PCR-amplified total RNA from heat-shocked and non-heat-shocked cells were
      hybridized with slot blots of the Kohara set (U. Kohara, K. Akiyama, and K.
      Isono, Cell 50:495-508, 1987; S. Chuang, D. Daniels, and F. Blattner, J.
      Bacteriol. 175:2026-2036, 1993). The signals obtained for heat-shocked and
      control cultures of each clone were compared, and differences in intensity were
      evaluated by calculating induction ratios. Clones that were considered
      significantly induced were subsequently mapped by the Southern blot technique in
      order to determine specific gene upregulation. Also, for several genes, Northern
      blotting and total RNA dot blotting were performed to confirm that the transcript
      levels in the original RNA samples were different. This technique extended
      previously described methods for studying global gene regulation in E. coli by
      incorporating a PCR amplification step in which global, mRNA-specific primers
      were used. In addition, the method employed here can be easily extended to study
      E. coli global gene regulation in response to additional environmental stimuli.

PMID- 10583994
TI  - Fate of pGFP-bearing Escherichia coli O157:H7 in ground beef at 2 and 10 degrees
      C and effects of lactate, diacetate, and citrate.
AB  - Although beef has been implicated in the largest outbreaks of Escherichia coli
      O157:H7 infection in the United States, studies on the fate of this pathogen have
      been limited. Problems in such studies are associated with detection of the
      pathogen at levels considerably lower than the levels of the competing
      microorganisms. In the present study, a green fluorescent protein-expressing E.
      coli O157:H7 strain was used, and the stable marker allowed us to monitor the
      behavior of the pathogen in ground beef stored aerobically from freshness to
      spoilage at 2 and 10 degrees C. In addition, the effects of sodium salts of
      lactate (SL) (0.9 and 1.8%), diacetate (SDA) (0.1 and 0.2%), and buffered citrate
      (SC) (1 and 2%) and combinations of SL and SDA were evaluated. SC had negligible
      antimicrobial activity, and SL delayed microbial growth, while SDA and SL plus
      SDA were most inhibitory to the total-aerobe population in the meat. At 2 degrees
      C, the initial numbers of E. coli O157:H7 (3 and 5 log(10) CFU/g) decreased by
      approximately 1 log(10) CFU/g when spoilage was manifest (>7 log(10) CFU of total
      aerobes/g), irrespective of the treatment. There was no decline in the numbers of
      the pathogen during storage at 10 degrees C. Our results showed that the pathogen
      was resistant to the salts tested and confirmed that refrigerated meat
      contaminated with the pathogen remains hazardous.

PMID- 10583995
TI  - Mitochondrial function in cell wall glycoprotein synthesis in Saccharomyces
      cerevisiae NCYC 625 (Wild type) and [rho(0)] mutants.
AB  - We studied phosphopeptidomannans (PPMs) of two Saccharomyces cerevisiae NCYC 625
      strains (S. diastaticus): a wild type strain grown aerobically, anaerobically,
      and in the presence of antimycin and a [rho(0)] mutant grown aerobically and
      anaerobically. The aerobic wild-type cultures were highly flocculent, but all
      others were weakly flocculent. Ligands implicated in flocculation of mutants or
      antimycin-treated cells were not aggregated as much by concanavalin A as were
      those of the wild type. The [rho(0)] mutants and antimycin-treated cells differ
      from the wild type in PPM composition and invertase, acid phosphatase, and
      glucoamylase activities. PPMs extracted from different cells differ in the
      protein but not in the glycosidic moiety. The PPMs were less stable in
      mitochondrion-deficient cells than in wild-type cells grown aerobically, and this
      difference may be attributable to defective mitochondrial function during cell
      wall synthesis. The reduced flocculation of cells grown in the presence of
      antimycin, under anaerobiosis, or carrying a [rho(0)] mutation may be the
      consequence of alterations of PPM structures which are the ligands of lectins,
      both involved in this cell-cell recognition phenomenon. These respiratory chain
      alterations also affect peripheral, biologically active glycoproteins such as
      extracellular enzymes and peripheral PPMs.

PMID- 10583996
TI  - Linking toluene degradation with specific microbial populations in soil.
AB  - Phospholipid fatty acid (PLFA) analysis of a soil microbial community was coupled
      with (13)C isotope tracer analysis to measure the community's response to
      addition of 35 microg of [(13)C]toluene ml of soil solution(-1). After 119 h of
      incubation with toluene, 96% of the incorporated (13)C was detected in only 16 of
      the total 59 PLFAs (27%) extracted from the soil. Of the total (13)C-enriched
      PLFAs, 85% were identical to the PLFAs contained in a toluene-metabolizing
      bacterium isolated from the same soil. In contrast, the majority of the soil
      PLFAs (91%) became labeled when the same soil was incubated with [(13)C]glucose.
      Our study showed that coupling (13)C tracer analysis with PLFA analysis is an
      effective technique for distinguishing a specific microbial population involved
      in metabolism of a labeled substrate in complex environments such as soil.

PMID- 10583997
TI  - Quantification of bias related to the extraction of DNA directly from soils.
AB  - In recent years, several protocols based on the extraction of nucleic acids
      directly from the soil matrix after lysis treatment have been developed for the
      detection of microorganisms in soil. Extraction efficiency has often been
      evaluated based on the recovery of a specific gene sequence from an organism
      inoculated into the soil. The aim of the present investigation was to improve the
      extraction, purification, and quantification of DNA derived from as large a
      portion of the soil microbial community as possible, with special emphasis placed
      on obtaining DNA from gram-positive bacteria, which form structures that are
      difficult to disrupt. Furthermore, we wanted to identify and minimize the biases
      related to each step in the procedure. Six soils, covering a range of pHs, clay
      contents, and organic matter contents, were studied. Lysis was carried out by
      soil grinding, sonication, thermal shocks, and chemical treatments. DNA was
      extracted from the indigenous microflora as well as from inoculated bacterial
      cells, spores, and hyphae, and the quality and quantity of the DNA were
      determined by gel electrophoresis and dot blot hybridization. Lysis efficiency
      was also estimated by microscopy and viable cell counts. Grinding increased the
      extracellular DNA yield compared with the yield obtained without any lysis
      treatment, but none of the subsequent treatments clearly increased the DNA yield.
      Phage lambda DNA was inoculated into the soils to mimic the fate of extracellular
      DNA. No more than 6% of this DNA could be recovered from the different soils. The
      clay content strongly influenced the recovery of DNA. The adsorption of DNA to
      clay particles decreased when the soil was pretreated with RNA in order to
      saturate the adsorption sites. We also investigated different purification
      techniques and optimized the PCR methods in order to develop a protocol based on
      hybridization of the PCR products and quantification by phosphorimaging.

PMID- 10583998
TI  - Precise detection and tracing of Trichoderma hamatum 382 in compost-amended
      potting mixes by using molecular markers.
AB  - Randomly amplified polymorphic DNA (RAPD) analysis and the PCR assay were used in
      combination with dilution plating on a semiselective medium to detect and
      enumerate propagules of Trichoderma hamatum 382, a biocontrol agent utilized in
      compost-amended mixes. Distinct and reproducible fingerprints were obtained upon
      amplification of purified genomic DNA of T. hamatum 382 with the random primers
      OPE-16, OPH-19, and OPH-20. Three amplified DNA fragments of 0.35 (OPE-16(0.35)),
      0.6 (OPH-19(0.6)), and 0.65 (OPH-20(0.65)) kb were diagnostic for T. hamatum 382,
      clearly distinguishing it from 53 isolates of four other Trichoderma spp. tested.
      Some isolates of T. hamatum shared these low-molecular-weight fragments with T.
      hamatum 382. However, RAPD analysis of isolates of T. hamatum with all three
      random primers used in consecutive PCR tests distinguished T. hamatum 382 from
      other isolates of T. hamatum. These three RAPD amplicons were cloned and
      sequenced, and pairs of oligonucleotide primers for each cloned fragment were
      designed. Use of the primers in the PCR assay resulted in the amplification of
      DNA fragments of the same size as the cloned RAPD fragments from genomic DNA of
      T. hamatum 382. A combination of dilution plating on a semiselective medium for
      Trichoderma spp. and PCR, with the RAPD primers OPH-19, OPE-16, and OPH-20 or the
      three sequence-characterized primers, was used successfully to verify the
      presence of T. hamatum 382 propagules in nine different soil, compost, and
      potting mix samples. All 23 Trichoderma isolates recovered on semiselective
      medium from commercial potting mixes fortified with T. hamatum 382 were
      identified as T. hamatum 382, whereas 274 Trichoderma isolates recovered from the
      other nine samples were negative in the PCR assay. Thus, this highly specific
      combination of techniques allowed detection and enumeration of propagules of T.
      hamatum 382 in fortified compost-amended potting mixes. Sequence-characterized
      amplified region markers also facilitated the development of a very simple
      procedure to amplify DNA of T. hamatum 382 directly from fortified compost
      amended potting mixes.

PMID- 10583999
TI  - Cloning, sequencing, and characterization of genomic subtracted sequences from
      Listeria monocytogenes.
AB  - Individual sequences of a genomic subtracted, PCR-amplified, mixed-sequence probe
      (GS probe) were cloned and sequenced. The GS probe differentiated restriction
      fragment length polymorphism patterns for Listeria monocytogenes but did not
      hybridize with members of other bacterial genera. Sequence analysis identified
      several L. monocytogenes sequences already present in the GenBank database; the
      putative identities of other sequences were inferred from homology data, and
      still other sequences did not exhibit significant levels of homology with any
      GenBank sequences.

PMID- 10584000
TI  - Secretion of cryparin, a fungal hydrophobin.
AB  - Cryparin is a cell-surface-associated hydrophobin of the filamentous ascomycete
      Cryphonectria parasitica. This protein contains a signal peptide that directs it
      to the vesicle-mediated secretory pathway. We detected a glycosylated form of
      cryparin in a secretory vesicle fraction, but secreted forms of this protein are
      not glycosylated. This glycosylation occurred in the proprotein region, which is
      cleaved during maturation by a Kex2-like serine protease, leaving a mature form
      of cryparin that could be isolated from both the cell wall and culture medium.
      Pulse-chase labeling experiments showed that cryparin was secreted through the
      cell wall, without being bound, into the culture medium. The secreted protein
      then binds to the cell walls of C. parasitica, where it remains. Binding of
      cryparin to the cell wall occurred in submerged culture, presumably because of
      the lectin-like properties unique to this hydrophobin. Thus, the binding of this
      hydrophobin to the cell wall is different from that of other hydrophobins which
      are reported to require a hydrophobic-hydrophilic interface for assembly.

PMID- 10584001
TI  - The hemolytic enterotoxin HBL is broadly distributed among species of the
      Bacillus cereus group.
AB  - The prevalence of the hemolytic enterotoxin complex HBL was determined in all
      species of the Bacillus cereus group with the exception of Bacillus anthracis.
      hblA, encoding the binding subunit B, was detected by PCR and Southern analysis
      and was confirmed by partial sequencing of 18 strains. The sequences formed two
      clusters, one including B. cereus and Bacillus thuringiensis strains and the
      other one consisting of Bacillus mycoides, Bacillus pseudomycoides, and Bacillus
      weihenstephanensis strains. From eight B. thuringiensis strains, the enterotoxin
      gene hblA could be amplified. Seven of them also expressed the complete HBL
      complex as determined with specific antibodies against the L(1), L(2), and B
      components. Eleven of 16 B. mycoides strains, all 3 B. pseudomyoides strains, 9
      of 15 B. weihenstephanensis strains, and 10 of 23 B. cereus strains carried hblA.
      While HBL was not expressed in the B. pseudomycoides strains, the molecular
      assays were in accordance with the immunological assays for the majority of the
      remaining strains. In summary, the hemolytic enterotoxin HBL seems to be broadly
      distributed among strains of the B. cereus group and relates neither to a certain
      species nor to a specific environment. The consequences of this finding for food
      safety considerations need to be evaluated.

PMID- 10584002
TI  - Biochemical and phylogenetic analyses of a cold-active beta-galactosidase from
      the lactic acid bacterium Carnobacterium piscicola BA.
AB  - We are investigating glycosyl hydrolases from new psychrophilic isolates to
      examine the adaptations of enzymes to low temperatures. A beta-galactosidase from
      isolate BA, which we have classified as a strain of the lactic acid bacterium
      Carnobacterium piscicola, was capable of hydrolyzing the chromogen 5-bromo-4
      chloro-3-indolyl beta-D-galactopyranoside (X-Gal) at 4 degrees C and possessed
      higher activity in crude cell lysates at 25 than at 37 degrees C. Sequence
      analysis of a cloned DNA fragment encoding this activity revealed a gene cluster
      containing three glycosyl hydrolases with homology to an alpha-galactosidase and
      two beta-galactosidases. The larger of the two beta-galactosidase genes, bgaB,
      encoded the 76.8-kDa cold-active enzyme. This gene was homologous to family 42
      glycosyl hydrolases, a group which contains several thermophilic enzymes but none
      from lactic acid bacteria. The bgaB gene from isolate BA was subcloned in
      Escherichia coli, and its enzyme, BgaB, was purified. The purified enzyme was
      highly unstable and required 10% glycerol to maintain activity. Its optimal
      temperature for activity was 30 degrees C, and it was inactivated at 40 degrees C
      in 10 min. The K(m) of freshly purified enzyme at 30 degrees C was 1.7 mM, and
      the V(max) was 450 micromol. min(-1). mg(-1) with o-nitrophenyl beta-D
      galactopyranoside. This cold-active enzyme is interesting because it is
      homologous to a thermophilic enzyme from Bacillus stearothermophilus, and
      comparisons could provide information about structural features important for
      activity at low temperatures.

PMID- 10584003
TI  - Permeabilization of fungal membranes by plant defensins inhibits fungal growth.
AB  - We used an assay based on the uptake of SYTOX Green, an organic compound that
      fluoresces upon interaction with nucleic acids and penetrates cells with
      compromised plasma membranes, to investigate membrane permeabilization in fungi.
      Membrane permeabilization induced by plant defensins in Neurospora crassa was
      biphasic, depending on the plant defensin dose. At high defensin levels (10 to 40
      microM), strong permeabilization was detected that could be strongly suppressed
      by cations in the medium. This permeabilization appears to rely on direct peptide
      phospholipid interactions. At lower defensin levels (0.1 to 1 microM), a weaker,
      but more cation-resistant, permeabilization occurred at concentrations that
      correlated with the inhibition of fungal growth. Rs-AFP2(Y38G), an inactive
      variant of the plant defensin Rs-AFP2 from Raphanus sativus, failed to induce
      cation-resistant permeabilization in N. crassa. Dm-AMP1, a plant defensin from
      Dahlia merckii, induced cation-resistant membrane permeabilization in yeast
      (Saccharomyces cerevisiae) which correlated with its antifungal activity.
      However, Dm-AMP1 could not induce cation-resistant permeabilization in the Dm
      AMP1-resistant S. cerevisiae mutant DM1, which has a drastically reduced capacity
      for binding Dm-AMP1. We think that cation-resistant permeabilization is binding
      site mediated and linked to the primary cause of fungal growth inhibition induced
      by plant defensins.

PMID- 10584004
TI  - Isolation and characterization of the epoxide hydrolase-encoding gene from
      Xanthophyllomyces dendrorhous.
AB  - The epoxide hydrolase (EH)-encoding gene (EPH1) from the basidiomycetous yeast
      Xanthophyllomyces dendrorhous was isolated. The genomic sequence has a 1,236-bp
      open reading frame which is interrupted by eight introns that encode a 411-amino
      acid polypeptide with a calculated molecular mass of 46.2 kDa. The amino acid
      sequence is similar to that of microsomal EH and belongs to the alpha/beta
      hydrolase fold family. The EPH1 gene was not essential for growth of X.
      dendrorhous in rich medium under laboratory conditions. The Eph1-encoding cDNA
      was functionally expressed in Escherichia coli. A sixfold increase in specific
      activity was observed when we used resting cells rather than X. dendrorhous. The
      epoxides 1,2-epoxyhexane and 1-methylcyclohexene oxide were substrates for both
      native and recombinant Eph1. Isolation and characterization of the X. dendrorhous
      EH-encoding gene are essential steps in developing a yeast EH-based epoxide
      biotransformation system.

PMID- 10584005
TI  - Polyphasic study of the spatial distribution of microorganisms in Mexican pozol,
      a fermented maize dough, demonstrates the need for cultivation-independent
      methods to investigate traditional fermentations.
AB  - The distribution of microorganisms in pozol balls, a fermented maize dough, was
      investigated by a polyphasic approach in which we used both culture-dependent and
      culture-independent methods, including microbial enumeration, fermentation
      product analysis, quantification of microbial taxa with 16S rRNA-targeted
      oligonucleotide probes, determination of microbial fingerprints by denaturing
      gradient gel electrophoresis (DGGE), and 16S ribosomal DNA gene sequencing. Our
      results demonstrate that DGGE fingerprinting and rRNA quantification should allow
      workers to precisely and rapidly characterize the microbial assemblage in a
      spontaneous lactic acid fermented food. Lactic acid bacteria (LAB) accounted for
      90 to 97% of the total active microflora; no streptococci were isolated, although
      members of the genus Streptococcus accounted for 25 to 50% of the microflora.
      Lactobacillus plantarum and Lactobacillus fermentum, together with members of the
      genera Leuconostoc and Weissella, were the other dominant organisms. The overall
      activity was more important at the periphery of a ball, where eucaryotes,
      enterobacteria, and bacterial exopolysacharide producers developed. Our results
      also showed that the metabolism of heterofermentative LAB was influenced in situ
      by the distribution of the LAB in the pozol ball, whereas homolactic fermentation
      was controlled primarily by sugar limitation. We propose that starch is first
      degraded by amylases from LAB and that the resulting sugars, together with the
      lactate produced, allow a secondary flora to develop in the presence of oxygen.
      Our results strongly suggest that cultivation-independent methods should be used
      to study traditional fermented foods.

PMID- 10584006
TI  - Phototrophs in high-iron-concentration microbial mats: physiological ecology of
      phototrophs in an iron-depositing hot spring.
AB  - At Chocolate Pots Hot Springs in Yellowstone National Park the source waters have
      a pH near neutral, contain high concentrations of reduced iron, and lack sulfide.
      An iron formation that is associated with cyanobacterial mats is actively
      deposited. The uptake of [(14)C]bicarbonate was used to assess the impact of
      ferrous iron on photosynthesis in this environment. Photoautotrophy in some of
      the mats was stimulated by ferrous iron (1.0 mM). Microelectrodes were used to
      determine the impact of photosynthetic activity on the oxygen content and the pH
      in the mat and sediment microenvironments. Photosynthesis increased the oxygen
      concentration to 200% of air saturation levels in the top millimeter of the mats.
      The oxygen concentration decreased with depth and in the dark. Light-dependent
      increases in pH were observed. The penetration of light in the mats and in the
      sediments was determined. Visible radiation was rapidly attenuated in the top 2
      mm of the iron-rich mats. Near-infrared radiation penetrated deeper. Iron was
      totally oxidized in the top few millimeters, but reduced iron was detected at
      greater depths. By increasing the pH and the oxygen concentration in the surface
      sediments, the cyanobacteria could potentially increase the rate of iron
      oxidation in situ. This high-iron-content hot spring provides a suitable model
      for studying the interactions of microbial photosynthesis and iron deposition and
      the role of photosynthesis in microbial iron cycling. This model may help clarify
      the potential role of photosynthesis in the deposition of Precambrian banded iron
      formations.

PMID- 10584007
TI  - Biodegradation of free phytol by bacterial communities isolated from marine
      sediments under aerobic and denitrifying conditions.
AB  - Biodegradation of (E)-phytol [3,7,11, 15-tetramethylhexadec-2(E)-en-1-ol] by two
      bacterial communities isolated from recent marine sediments under aerobic and
      denitrifying conditions was studied at 20 degrees C. This isoprenoid alcohol is
      metabolized efficiently by these two bacterial communities via 6,10, 14
      trimethylpentadecan-2-one and (E)-phytenic acid. The first step in both aerobic
      and anaerobic bacterial degradation of (E)-phytol involves the transient
      production of (E)-phytenal, which in turn can be abiotically converted to 6,10,14
      trimethylpentadecan-2-one. Most of the isoprenoid metabolites identified in vitro
      could be detected in a fresh sediment core collected at the same site as the
      sediments used for the incubations. Since (E)-phytenal is less sensitive to
      abiotic degradation at the temperature of the sediments (15 degrees C), the major
      part of (E)-phytol appeared to be biodegraded in situ via (E)-phytenic acid. (Z)-
      and (E)-phytenic acids are present in particularly large quantities in the upper
      section of the core, and their concentrations quickly decrease with depth in the
      core. This degradation (which takes place without significant production of
      phytanic acid) is attributed to the involvement of alternating beta
      decarboxymethylation and beta-oxidation reaction sequences induced by
      denitrifiers. Despite the low nitrate concentration of marine sediments,
      denitrifying bacteria seem to play a significant role in the mineralization of
      (E)-phytol.

PMID- 10584008
TI  - Partitioning effects during terminal carbon and electron flow in sediments of a
      low-salinity meltwater pond near Bratina Island, McMurdo Ice Shelf, Antarctica.
AB  - A study of anaerobic sediments below cyanobacterial mats of a low-salinity
      meltwater pond called Orange Pond on the McMurdo Ice Shelf at temperatures
      simulating those in the summer season (<5 degrees C) revealed that both sulfate
      reduction and methane production were important terminal anaerobic processes.
      Addition of [2-(14)C]acetate to sediment samples resulted in the passage of label
      mainly to CO(2). Acetate addition (0 to 27 mM) had little effect on
      methanogenesis (a 1.1-fold increase), and while the rate of acetate dissimilation
      was greater than the rate of methane production (6.4 nmol cm(-3) h(-1) compared
      to 2.5 to 6 nmol cm(-3) h(-1)), the portion of methane production attributed to
      acetate cleavage was <2%. Substantial increases in the methane production rate
      were observed with H(2) (2.4-fold), and H(2) uptake was totally accounted for by
      methane production under physiological conditions. Formate also stimulated
      methane production (twofold), presumably through H(2) release mediated through
      hydrogen lyase. Addition of sulfate up to 50-fold the natural levels in the
      sediment (interstitial concentration, approximately 0.3 mM) did not substantially
      inhibit methanogenesis, but the process was inhibited by 50-fold chloride (36
      mM). No net rate of methane oxidation was observed when sediments were incubated
      anaerobically, and denitrification rates were substantially lower than rates for
      sulfate reduction and methanogenesis. The results indicate that carbon flow from
      acetate is coupled mainly to sulfate reduction and that methane is largely
      generated from H(2) and CO(2) where chloride, but not sulfate, has a modulating
      role. Rates of methanogenesis at in situ temperatures were four- to fivefold less
      than maximal rates found at 20 degrees C.

PMID- 10584009
TI  - Regulation of the feruloyl esterase (faeA) gene from Aspergillus niger.
AB  - Feruloyl esterases can remove aromatic residues (e.g., ferulic acid) from plant
      cell wall polysaccharides (xylan, pectin) and are essential for complete
      degradation of these polysaccharides. Expression of the feruloyl esterase
      encoding gene (faeA) from Aspergillus niger depends on D-xylose (expression is
      mediated by XlnR, the xylanolytic transcriptional activator) and on a second
      system that responds to aromatic compounds with a defined ring structure, such as
      ferulic acid and vanillic acid. Several compounds were tested, and all of the
      inducing compounds contained a benzene ring which had a methoxy group at C-3 and
      a hydroxy group at C-4 but was not substituted at C-5. Various aliphatic groups
      occurred at C-1. faeA expression in the presence of xylose or ferulic acid was
      repressed by glucose. faeA expression in the presence of ferulic acid and xylose
      was greater than faeA expression in the presence of either compound alone. The
      various inducing systems allow A. niger to produce feruloyl esterase not only
      during growth on xylan but also during growth on other ferulic acid-containing
      cell wall polysaccharides, such as pectin.

PMID- 10584010
TI  - Induction and transcription studies of the dextransucrase gene in Leuconostoc
      mesenteroides NRRL B-512F.
AB  - Dextransucrase production by Leuconostoc mesenteroides NRRL B-512F in media
      containing carbon sources other than sucrose is reported for the first time.
      Dextransucrases were analyzed by gel electrophoresis and by an in situ activity
      assay. Their polymers and acceptor reaction products were also compared by (13)C
      nuclear magnetic resonance and high-performance liquid chromatography techniques,
      respectively. From these analyses, it was found that, independently of the carbon
      source, L. mesenteroides NRRL B-512F produced dextransucrases of the same size
      and product specificity. The 5' ends of dextransucrase mRNAs isolated from cells
      grown under different culture conditions were identical. Based on this evidence,
      we conclude that dextransucrases obtained from cells grown on the various carbon
      sources result from the transcription of the same gene. The control of expression
      occurs at this level. The low dextransucrase yields from cultures in D-glucose or
      D-fructose and the enhancement of dextransucrase gene transcription in the
      presence of sucrose suggest that an activating phenomenon may be involved in the
      expression mechanism. Dextransucrase mRNA has a size of approximately 4.8 kb,
      indicating that the gene is located in a monocistronic operon. The transcription
      start point was localized 34 bp upstream from the ATG start codon. The -10 and 
      35 sequences found, TATAAT and TTTACA, were highly homologous to the only
      glycosyltransferase promoter sequence reported for lactic acid bacteria.

PMID- 10584011
TI  - Production of sulfur flavors by ten strains of Geotrichum candidum.
AB  - Ten strains of Geotrichum candidum were studied on a liquid cheese model medium
      for the production of sulfur compounds which contribute to the aroma of cheeses.
      The volatile components produced by each cultured strain were extracted by
      dynamic headspace extractions, separated and quantified by gas chromatography
      (GC), and identified by GC-mass spectrometry. It was shown that four strains of
      this microorganism produced significant quantities of S-methyl thioacetate, S
      methyl thiopropionate, S-methyl thiobutanoate, S-methyl thioisobutanoate, S
      methyl thioisovalerate, and S-methyl thiohexanoate. This is the first example of
      the production of these compounds by a fungus. In addition, dimethyldisulfide,
      dimethyltrisulfide, dimethylsulfide, and methanethiol, which are more commonly
      associated with the development of cheese flavor in bacterial cultures, were also
      produced by G. candidum in various yields, depending on the strain selected. The
      potential application of these strains in cultured microbial associations to
      produce modified cheeses with more desirable organoleptic properties is
      discussed.

PMID- 10584012
TI  - Electrochemical studies of a truncated laccase produced in Pichia pastoris.
AB  - The cDNA that encodes an isoform of laccase from Trametes versicolor (LCCI), as
      well as a truncated version (LCCIa), was subcloned and expressed by using the
      yeast Pichia pastoris as the heterologous host. The amino acid sequence of LCCIa
      is identical to that of LCCI except that the final 11 amino acids at the C
      terminus of LCCI are replaced with a single cysteine residue. This modification
      was introduced for the purpose of improving the kinetics of electron transfer
      between an electrode and the copper-containing active site of laccase. The two
      laccases (LCCI and LCCIa) are compared in terms of their relative activity with
      two substrates that have different redox potentials. Results from electrochemical
      studies on solutions containing LCCI and LCCIa indicate that the redox potential
      of the active site of LCCIa is shifted to more negative values (411 mV versus
      normal hydrogen electrode voltage) than that found in other fungal laccases. In
      addition, replacing the 11 codons at the C terminus of the laccase gene with a
      single cysteine codon (i.e., LCCI-->LCCIa) influences the rate of heterogeneous
      electron transfer between an electrode and the copper-containing active site
      (k(het) for LCCIa = 1.3 x 10(-4) cm s(-1)). These results demonstrate for the
      first time that the rate of electron transfer between an oxidoreductase and an
      electrode can be enhanced by changes to the primary structure of a protein via
      site-directed mutagenesis.

PMID- 10584013
TI  - Determining sources of fecal pollution in a rural Virginia watershed with
      antibiotic resistance patterns in fecal streptococci.
AB  - Nonpoint sources of pollution that contribute fecal bacteria to surface waters
      have proven difficult to identify. Knowledge of pollution sources could aid in
      restoration of the water quality, reduce the amounts of nutrients leaving
      watersheds, and reduce the danger of infectious disease resulting from exposure
      to contaminated waters. Patterns of antibiotic resistance in fecal streptococci
      were analyzed by discriminant and cluster analysis and used to identify sources
      of fecal pollution in a rural Virginia watershed. A database consisting of
      patterns from 7,058 fecal streptococcus isolates was first established from known
      human, livestock, and wildlife sources in Montgomery County, Va. Correct fecal
      streptococcus source identification averaged 87% for the entire database and
      ranged from 84% for deer isolates to 93% for human isolates. To field test the
      method and the database, a watershed improvement project (Page Brook) in Clarke
      County, Va., was initiated in 1996. Comparison of 892 known-source isolates from
      that watershed against the database resulted in an average correct classification
      rate of 88%. Combining all animal isolates increased correct classification rates
      to > or = 95% for separations between animal and human sources. Stream samples
      from three collection sites were highly contaminated, and fecal streptococci from
      these sites were classified as being predominantly from cattle (>78% of
      isolates), with small proportions from waterfowl, deer, and unidentified sources
      ( approximately 7% each). Based on these results, cattle access to the stream was
      restricted by installation of fencing and in-pasture watering stations. Fecal
      coliforms were reduced at the three sites by an average of 94%, from prefencing
      average populations of 15,900 per 100 ml to postfencing average populations of
      960 per 100 ml. After fencing, <45% of fecal streptococcus isolates were
      classified as being from cattle. These results demonstrate that antibiotic
      resistance profiles in fecal streptococci can be used to reliably determine
      sources of fecal pollution, and water quality improvements can occur when efforts
      to address the identified sources are made.

PMID- 10584014
TI  - Initial reactions in anaerobic alkane degradation by a sulfate reducer, strain AK
      01.
AB  - An alkane-degrading, sulfate-reducing bacterial strain, AK-01, isolated from a
      petroleum-contaminated sediment was studied to elucidate its mechanism of alkane
      metabolism. Total cellular fatty acids of AK-01 were predominantly C even when it
      was grown on C-even alkanes and were predominantly C odd when grown on C-odd
      alkanes, suggesting that the bacterium anaerobically oxidizes alkanes to fatty
      acids. Among these fatty acids, some 2-, 4-, and 6-methylated fatty acids were
      specifically found only when AK-01 was grown on alkanes, and their chain lengths
      always correlated with those of the alkanes. When [1,2-(13)C(2)]hexadecane or
      perdeuterated pentadecane was used as the growth substrate, (13)C-labeled 2-Me
      16:0, 4-Me-18:0, and 6-Me-20:0 fatty acids or deuterated 2-Me-15:0, 4-Me-17:0,
      and 6-Me-19:0 fatty acids were recovered, respectively, confirming that these
      monomethylated fatty acids were alkane derived. Examination of the (13)C-labeled
      2-, 4-, and 6-methylated fatty acids by mass spectrometry showed that each of
      them contained two (13)C atoms, located at the methyl group and the adjacent
      carbon, thus indicating that the methyl group was the original terminal carbon of
      the [1, 2-(13)C(2)]hexadecane. For perdeuterated pentadecane, the presence of
      three deuterium atoms, on the methyl group and its adjacent carbon, in each of
      the deuterated 2-, 4-, and 6-methylated fatty acids further supported the
      hypothesis that the methyl group was the terminal carbon of the alkane. Thus,
      exogenous carbon appears to be initially added to an alkane subterminally at the
      C-2 position such that the original terminal carbon of the alkane becomes a
      methyl group on the subsequently formed fatty acid. The carbon addition reaction,
      however, does not appear to be a direct carboxylation of inorganic bicarbonate. A
      pathway for anaerobic metabolism of alkanes by strain AK-01 is proposed.

PMID- 10584015
TI  - Estimation of methanogen biomass by quantitation of coenzyme M.
AB  - Determination of the role of methanogenic bacteria in an anaerobic ecosystem
      often requires quantitation of the organisms. Because of the extreme oxygen
      sensitivity of these organisms and the inherent limitations of cultural
      techniques, an accurate biomass value is very difficult to obtain. We
      standardized a simple method for estimating methanogen biomass in a variety of
      environmental matrices. In this procedure we used the thiol biomarker coenzyme M
      (CoM) (2-mercaptoethanesulfonic acid), which is known to be present in all
      methanogenic bacteria. A high-performance liquid chromatography-based method for
      detecting thiols in pore water (A. Vairavamurthy and M. Mopper, Anal. Chim. Acta
      78:363-370, 1990) was modified in order to quantify CoM in pure cultures,
      sediments, and sewage water samples. The identity of the CoM derivative was
      verified by using liquid chromatography-mass spectroscopy. The assay was linear
      for CoM amounts ranging from 2 to 2,000 pmol, and the detection limit was 2 pmol
      of CoM/ml of sample. CoM was not adsorbed to sediments. The methanogens tested
      contained an average of 19.5 nmol of CoM/mg of protein and 0.39 +/- 0.07 fmol of
      CoM/cell. Environmental samples contained an average of 0.41 +/- 0.17 fmol/cell
      based on most-probable-number estimates. CoM was extracted by using 1% tri-(N)
      butylphosphine in isopropanol. More than 90% of the CoM was recovered from pure
      cultures and environmental samples. We observed no interference from sediments in
      the CoM recovery process, and the method could be completed aerobically within 3
      h. Freezing sediment samples resulted in 46 to 83% decreases in the amounts of
      detectable CoM, whereas freezing had no effect on the amounts of CoM determined
      in pure cultures. The method described here provides a quick and relatively
      simple way to estimate methanogenic biomass.

PMID- 10584016
TI  - The bglA gene of Aspergillus kawachii encodes both extracellular and cell wall
      bound beta-glucosidases.
AB  - We cloned the genomic DNA and cDNA of bglA, which encodes beta-glucosidase in
      Aspergillus kawachii, based on a partial amino acid sequence of purified cell
      wall-bound beta-glucosidase CB-1. The nucleotide sequence of the cloned bglA gene
      revealed a 2,933-bp open reading frame with six introns that encodes an 860-amino
      acid protein. Based on the deduced amino acid sequence, we concluded that the
      bglA gene encodes cell wall-bound beta-glucosidase CB-1. The amino acid sequence
      exhibited high levels of homology with the amino acid sequences of fungal beta
      glucosidases classified in subfamily B. We expressed the bglA cDNA in
      Saccharomyces cerevisiae and detected the recombinant beta-glucosidase in the
      periplasm fraction of the recombinant yeast. A. kawachii can produce two
      extracellular beta-glucosidases (EX-1 and EX-2) in addition to the cell wall
      bound beta-glucosidase. A. kawachii in which the bglA gene was disrupted produced
      none of the three beta-glucosidases, as determined by enzyme assays and a Western
      blot analysis. Thus, we concluded that the bglA gene encodes both extracellular
      and cell wall-bound beta-glucosidases in A. kawachii.

PMID- 10584017
TI  - Visualization and enumeration of marine planktonic archaea and bacteria by using
      polyribonucleotide probes and fluorescent in situ hybridization.
AB  - Fluorescent in situ hybridization (FISH) using rRNA-specific oligonucleotide
      probes has emerged as a popular technique for identifying individual microbial
      cells. In natural samples, however, the signal derived from fluor-labeled
      oligonucleotide probes often is undetectable above background fluorescence in
      many cells. To circumvent this difficulty, we applied fluorochrome-labeled
      polyribonucleotide probes to identify and enumerate marine planktonic archaea and
      bacteria. The approach greatly enhanced the sensitivity and applicability of FISH
      with seawater samples, allowing confident identification and enumeration of
      planktonic cells to ocean depths of 3,400 m. Quantitative whole-cell
      hybridization experiments using these probes accounted for 90 to 100% of the
      total 4',6-diamidino-2-phenylindole (DAPI)-stained cells in most samples. As
      predicted in a previous study (R. Massana, A. E. Murray, C. M. Preston, and E. F.
      DeLong, Appl. Environ. Microbiol. 63:50-56, 1997), group I and II marine archaea
      predominate in different zones in the water column, with maximal cell densities
      of 10(5)/ml. The high cell densities of archaea, extending from surface waters to
      abyssal depths, suggest that they represent a large and significant fraction of
      the total picoplankton biomass in coastal ocean waters. The data also show that
      the vast majority of planktonic prokaryotes contain significant numbers of
      ribosomes, rendering them easily detectable with polyribonucleotide probes. These
      results imply that the majority of planktonic cells visualized by DAPI do not
      represent lysed cells or "ghosts," as was suggested in a previous report.

PMID- 10584018
TI  - Requirement for phosphoglucose isomerase of Xanthomonas campestris in
      pathogenesis of citrus canker.
AB  - A mutant (XT906) of Xanthomonas campestris pv. citri, the causal agent of citrus
      canker, was induced by insertion of the transposon Tn5tac1 and isolated. This
      mutant did not grow or elicit canker disease in citrus leaves but was still able
      to induce a hypersensitive response in a nonhost plant (the common bean). The
      mutant was also unable to grow on minimal medium containing fructose or glycerol
      as the sole carbon source. A 2.5-kb fragment of wild-type DNA that complemented
      the mutant phenotype of XT906 was isolated. Sequence analysis revealed that this
      DNA fragment encoded a protein of 562 amino acids that shows homology to
      phosphoglucose isomerase (PGI). Enzyme activity assay confirmed that the encoded
      protein possesses PGI activity. Analysis of the activity of the promoter of the
      pgi gene revealed that it was inhibited by growth in complex medium but induced
      by culture in plant extract. These results demonstrate that PGI is required for
      pathogenicity of X. campestris pv. citri.

PMID- 10584019
TI  - Anastomosis formation and nuclear and protoplasmic exchange in arbuscular
      mycorrhizal fungi.
AB  - We observed anastomosis between hyphae originating from the same spore and from
      different spores of the same isolate of the arbuscular mycorrhizal fungi Glomus
      mosseae, Glomus caledonium, and Glomus intraradices. The percentage of contacts
      leading to anastomosis ranged from 35 to 69% in hyphae from the same germling and
      from 34 to 90% in hyphae from different germlings. The number of anastomoses
      ranged from 0.6 to 1.3 per cm (length) of hyphae in mycelia originating from the
      same spore. No anastomoses were observed between hyphae from the same or
      different germlings of Gigaspora rosea and Scutellospora castanea; no
      interspecific or intergeneric hyphal fusions were observed. We monitored
      anastomosis formation with time-lapse and video-enhanced light microscopy. We
      observed complete fusion of hyphal walls and the migration of a mass of particles
      in both directions within the hyphal bridges. In hyphal bridges of G. caledonium,
      light-opaque particles moved at the speed of 1.8 +/- 0.06 microm/s. We observed
      nuclear migration between hyphae of the same germling and between hyphae
      belonging to different germlings of the same isolate of three Glomus species. Our
      work suggests that genetic exchange may occur through intermingling of nuclei
      during anastomosis formation and opens the way to studies of vegetative
      compatibility in natural populations of arbuscular mycorrhizal fungi.

PMID- 10584020
TI  - Molecular characterization of a toluene-degrading methanogenic consortium.
AB  - A toluene-degrading methanogenic consortium enriched from creosote-contaminated
      aquifer material was maintained on toluene as the sole carbon and energy source
      for 10 years. The species in the consortium were characterized by using a
      molecular approach. Total genomic DNA was isolated, and 16S rRNA genes were
      amplified by using PCR performed with kingdom-specific primers that were specific
      for 16S rRNA genes from either members of the kingdom Bacteria or members of the
      kingdom Archaea. A total of 90 eubacterial clones and 75 archaeal clones were
      grouped by performing a restriction fragment length polymorphism (RFLP) analysis.
      Six eubacterial sequences and two archaeal sequences were found in the greatest
      abundance (in six or more clones) based on the RFLP analysis. The relative
      abundance of each putative species was estimated by using fluorescent in situ
      hybridization (FISH), and the presence of putative species was determined
      qualitatively by performing slot blot hybridization with consortium DNA. Both
      archaeal species and two of the six eubacterial species were detected in the DNA
      and FISH hybridization experiments. A phylogenetic analysis of these four
      dominant organisms suggested that the two archaeal species are related to the
      genera Methanosaeta and Methanospirillum. One of the eubacterial species is
      related to the genus Desulfotomaculum, while the other is not related to any
      previously described genus. By elimination, we propose that the last organism
      probably initiates the attack on toluene.

PMID- 10584021
TI  - Molecular phylogenetic analysis of archaeal intron-containing genes coding for
      rRNA obtained from a deep-subsurface geothermal water pool.
AB  - Molecular phylogenetic analysis of a naturally occurring microbial community in a
      deep-subsurface geothermal environment indicated that the phylogenetic diversity
      of the microbial population in the environment was extremely limited and that
      only hyperthermophilic archaeal members closely related to Pyrobaculum were
      present. All archaeal ribosomal DNA sequences contained intron-like sequences,
      some of which had open reading frames with repeated homing-endonuclease motifs.
      The sequence similarity analysis and the phylogenetic analysis of these homing
      endonucleases suggested the possible phylogenetic relationship among archaeal
      rRNA-encoded homing endonucleases.

PMID- 10584022
TI  - Involvement of manganese in conversion of phenylalanine to benzaldehyde by lactic
      acid bacteria.
AB  - We examined the involvement of Mn(II) in the conversion of phenylalanine to
      benzaldehyde in cell extracts of lactic acid bacteria. Experiments performed with
      Lactobacillus plantarum demonstrated that Mn(II), present at high levels in this
      strain, is involved in benzaldehyde formation by catalyzing the conversion of
      phenylpyruvic acid. Experiments performed with various lactic acid bacterial
      strains belonging to different genera revealed that benzaldehyde formation in a
      strain was related to a high Mn(II) level.

PMID- 10584023
TI  - Cooccurrence of elevated urea levels and dinoflagellate blooms in temperate
      estuarine aquaculture ponds.
AB  - In hybrid striped bass aquaculture ponds, dinoflagellate blooms were found on 10
      of 14 occasions to co-occur with concentrations of urea in excess of 1.5 microM
      nitrogen. When urea levels were <1.5 microM nitrogen, on seven occasions, no
      evidence of dinoflagellate blooms was observed in these ponds.

PMID- 10584024
TI  - Growth of facultatively heterofermentative lactobacilli on starter cell
      suspensions.
AB  - The growth of facultatively heterofermentative lactobacilli (FHL) on cell
      suspensions of the homofermentative Lactobacillus helveticus was investigated.
      Osmotic lysis of L. helveticus led to a significant increase of ribose. It
      decreased steadily in parallel with the growth of FHL, strongly suggesting that
      the bacteria used ribose as a growth substrate.

PMID- 10584025
TI  - Escherichia coli resistance to chlorine and glutathione synthesis in response to
      oxygenation and starvation.
AB  - Reduced glutathione (GSH) levels and resistance to chlorine were measured for two
      isogenic Escherichia coli strains stressed by oxygenation and/or starvation. The
      E. coli mutant deficient in GSH was not more sensitive to the oxidant than its
      parent strain when the bacteria were cultured with a low oxygenation rate.
      Starvation or oxygenation increased the resistance of the parent strain to
      chlorine, while the resistance of the deficient strain remained unchanged.

PMID- 10584026
TI  - Polyphosphates in intraradical and extraradical hyphae of an arbuscular
      mycorrhizal fungus, Gigaspora margarita.
AB  - The amount of polyphosphate in the intraradical and extraradical hyphae of
      Gigaspora margarita was estimated from successive extractions with
      trichloroacetic acid (TCA), EDTA, and phenol-chloroform (PC). In the intraradical
      hyphae, most of the polyphosphate was present in TCA- and EDTA-soluble (short
      chain and long-chain) fractions, whereas most of the polyphosphate in the
      extraradical hyphae was present in EDTA- and PC-soluble (long-chain and granular)
      fractions.

PMID- 10584027
TI  - Isolation of Terrabacter sp. strain DDE-1, which metabolizes 1, 1-dichloro-2,2
      bis(4-chlorophenyl)ethylene when induced with biphenyl.
AB  - Terrabacter sp. strain DDE-1, able to metabolize 1,1-dichloro-2, 2-bis(4
      chlorophenyl)ethylene (DDE) in pure culture when induced with biphenyl, was
      enriched from a 1-1-1-trichloro-2, 2-bis(4-chlorophenyl)ethane residue
      contaminated agricultural soil. Gas chromatography-mass spectrometry analysis of
      culture extracts revealed a number of DDE catabolites, including 2-(4'
      chlorophenyl)-3,3-dichloropropenoic acid, 2-(4'-chlorophenyl)-2-hydroxy acetic
      acid, 2-(4'-chlorophenyl) acetic acid, and 4-chlorobenzoic acid.

PMID- 10584028
TI  - Hemolytic activity and siderophore production in different Aeromonas species
      isolated from fish.
AB  - The hemolytic activity and siderophore production of several strains of motile
      aeromonads were determined. The hemolytic activity of Aeromonas caviae and
      Aeromonas eucrenophila was enhanced after trypsinization of the samples. The
      enhancement of hemolysis was observed in strains that carried an aerolysin-like
      gene, detected by a PCR procedure. Siderophore production was demonstrated in all
      but one strain of Aeromonas jandaei. No apparent relationship was observed
      between the presence of plasmid DNA and hemolysis or siderophore production.

PMID- 10584029
TI  - Comparative survival of free shiga toxin 2-encoding phages and Escherichia coli
      strains outside the gut.
AB  - The behavior outside the gut of seeded Escherichia coli O157:H7, naturally
      occurring E. coli, somatic coliphages, bacteriophages infecting O157:H7, and
      Shiga toxin 2 (Stx2)-encoding bacteriophages was studied to determine whether the
      last persist in the environment more successfully than their host bacteria. The
      ratios between the numbers of E. coli and those of the different bacteriophages
      were clearly lower in river water than in sewage of the area, whereas the ratios
      between the numbers of the different phages were similar. In addition, the
      numbers of bacteria decreased between 2 and 3 log units in in situ survival
      experiments performed in river water, whereas the numbers of phages decreased
      between 1 and 2 log units. Chlorination and pasteurization treatments that
      reduced by approximately 4 log units the numbers of bacteria reduced by less than
      1 log unit the numbers of bacteriophages. Thus, it can be concluded that Stx2
      encoding phages persist longer than their host bacteria in the water environment
      and are more resistant than their host bacteria to chlorination and heat
      treatment.

PMID- 10584030
TI  - Engineering of a stable whole-cell biocatalyst capable of (S)-styrene oxide
      formation for continuous two-liquid-phase applications.
AB  - Recombinant strains of Pseudomonas putida KT2440 carrying genetic expression
      cassettes with xylene oxygenase- and styrene monooxygenase-encoding genes on
      their chromosomes could be induced in shaking-flask experiments to specific
      activities that rivaled those of multicopy-plasmid-based Escherichia coli
      recombinants. Such strains maintained the introduced styrene oxidation activity
      in continuous two-liquid-phase cultures for at least 100 generations, although at
      a lower level than in the shaking-flask experiments. The data suggest that
      placement of target genes on the chromosome might be a suitable route for the
      construction of segregationally stable and highly active whole-cell biocatalysts.

PMID- 10584031
TI  - Molecular detection of Norwalk-like caliciviruses in sewage.
AB  - In this study, Norwalk-like virus (NLV) RNA was detected by reverse transcriptase
      PCR (RT-PCR) in sewage water concentrates. Sequence analysis of the RT-PCR
      products revealed identical sequences in stools of patients and related sewage
      samples. In 6 of 11 outbreak-unrelated follow-up samples, multiple NLV genotypes
      were present. Levels as high as 10(7) RNA-containing particles per liter were
      found. These data show that high loads of NLVs may be present in sewage and
      warrant further studies addressing the efficacy of NLV removal by sewage water
      treatment processes.

PMID- 10584032
TI  - Seasonal enumeration of fecal coliform bacteria from the feces of ring-billed
      gulls (Larus delawarensis) and Canada geese (Branta canadensis).
AB  - Water suppliers have often implicated roosting birds for fecal contamination of
      their surface waters. Geese and gulls have been the primary targets of this blame
      although literature documenting the fecal coliform content of these birds is
      quite limited. To determine the actual fecal coliform concentrations of these
      birds, fecal samples from 249 ring-billed gulls and 236 Canada geese in
      Westchester County, N.Y., were analyzed over a 2-year period. Results indicate
      that gull feces contain a greater average concentration of fecal coliform
      bacteria per gram (3.68 x 10(8)) than do goose feces (1.53 x 10(4)); however,
      average fecal sample weights of the geese were more than 15 times higher than
      those of the gulls.

PMID- 10584033
TI  - Characterization of a bacteriocin-like substance produced by a vaginal
      Lactobacillus salivarius strain.
AB  - A novel bacteriocin-like substance produced by vaginal Lactobacillus salivarius
      subsp. salivarius CRL 1328 with activity against Enterococcus faecalis,
      Enterococcus faecium, and Neisseria gonorrhoeae was characterized. The highest
      level of production of this heat-resistant peptide or protein occurred during the
      late exponential phase. Its mode of action was shown to be bactericidal. L.
      salivarius subsp. salivarius CRL 1328 could be used for the design of a probiotic
      to prevent urogenital infections.

PMID- 10584034
TI  - Regiospecific internal desaturation of aliphatic compounds by a mutant
      Rhodococcus strain.
AB  - A mutant Rhodococcus strain lacking the ability to utilize 1-chlorohexadecane was
      found to cis-desaturate aliphatic compounds, such as 1-chlorohexadecane, n
      hexadecane, and heptadecanonitrile, yielding corresponding products with a double
      bond mainly at the ninth carbon from the terminal methyl groups. A new oxidative
      pathway involving the cis-desaturation step was suggested for alkane utilization
      by Rhodococcus spp.

PMID- 10584035
TI  - Enzymatic function of the nor-1 protein in aflatoxin biosynthesis in Aspergillus
      parasiticus.
AB  - The nor-1 gene is involved in aflatoxin biosynthesis in Aspergillus parasiticus
      and was predicted to encode a norsolorinic acid ketoreductase. Recombinant Nor-1
      expressed in Escherichia coli converted the 1' keto group of norsolorinic acid to
      the 1' hydroxyl group of averantin in crude E. coli cell extracts in the presence
      of NADPH. The results confirm that Nor-1 functions as a ketoreductase in vitro.

PMID- 10584036
TI  - Low-fat diets, lipoprotein subclasses, and heart disease risk.

PMID- 10584037
TI  - Harbingers of coronary heart disease: dietary saturated fatty acids and
      cholesterol. Is chocolate benign because of its stearic acid content?

PMID- 10584038
TI  - Assorted monounsaturated fatty acids promote healthy hearts.

PMID- 10584039
TI  - Using stable isotopes to assess mineral absorption and utilization by children.
AB  - Adequate mineral intake is a crucial part of a healthy diet for children-it
      supports appropriate growth and development and provides protection against
      childhood conditions like anemia and helps to prevent future adult diseases such
      as osteoporosis. Challenges in performing and interpreting studies in infants and
      children have hampered the accurate assessment of their mineral utilization. Many
      of the most powerful techniques used in adults, such as radioisotope testing, are
      not appropriate for use in children. In recent years, advanced mineral stable
      isotope techniques have been developed to fill this gap. Pediatric applications
      include studies of calcium absorption and kinetics during puberty and evaluation
      of the calcium-iron interaction in infants and toddlers. The effects of genetics
      in determining calcium absorption and bone turnover may become an important
      research area. The goals and methods of ongoing mineral stable-isotope research
      in infants and children are examined in this report. In the past, the cost and
      difficulties in obtaining isotopes have limited such research. This situation has
      improved considerably, although relatively few nutrition research laboratories
      are prepared to perform sample analyses.

PMID- 10584040
TI  - Weight-loss attempts and risk of major weight gain: a prospective study in
      Finnish adults.
AB  - BACKGROUND: The effects of weight-loss attempts on long-term weight gain remain
      unclear. OBJECTIVE: The objective was to study prospectively how attempts to lose
      weight relate to future risk of major weight gain (>10 kg) and whether familial
      factors affect this relation. DESIGN: Participants in the Finnish Twin Cohort
      (3536 men and 4193 women aged 18-54 y at baseline) were followed up for 6-15 y.
      The role of familial factors was studied in 1705 twin pairs in this cohort who
      were discordant for weight-loss attempts at baseline. Baseline (1975) and follow
      up (1981 and 1990) data-including weight, weight-loss attempts (dieting), and
      selected confounders-were obtained via mailed questionnaires. RESULTS: Average
      weight gain was at most weakly associated with weight-loss attempts. The risk of
      major weight gain for subjects attempting to lose weight at baseline was greatest
      among initially young (18-29 y) men (over 6 and 15 y, respectively-odds ratios:
      2.01 and 1.74; 95% CI: 1.13, 3.57 and 1.11, 2.75) and middle-aged (30-54 y) women
      (over 6 and 15 y, respectively-2.43 and 1.52; 1.33, 4.42 and 1.06, 2.22) and
      persisted after potential confounders were controlled for. These risks decreased
      and became nonsignificant in the pairwise twin analysis, suggesting that the
      relation between dieting and subsequent major weight gain may also have a
      familial component. CONCLUSIONS: Weight-loss attempts may be associated with
      subsequent major weight gain, even when several potential confounders are
      controlled for. Genetic and familial factors may contribute to this association.

PMID- 10584041
TI  - Are olive oil diets antithrombotic? Diets enriched with olive, rapeseed, or
      sunflower oil affect postprandial factor VII differently.
AB  - BACKGROUND: The incidence of ischemic heart disease (IHD) in Crete was lower than
      expected on the basis of blood lipid concentrations of participants in the Seven
      Countries Study. A favorable effect of a high intake of olive oil on
      thrombogenesis may have contributed to this finding. OBJECTIVE: We compared the
      effects of virgin olive oil with those of rapeseed and sunflower oils on blood
      coagulation factor VII (FVII), a key factor in thrombogenesis. DESIGN: In a
      randomized and strictly controlled crossover study, 18 healthy young men consumed
      diets enriched with 5 g/MJ (19% of total energy) olive oil, sunflower oil, or
      rapeseed oil for periods of 3 wk. On the final day of each period, participants
      consumed standardized high-fat meals (42% of energy as fat). Fasting and
      nonfasting blood samples were collected after each period. RESULTS: Mean (+/-SEM)
      nonfasting peak concentrations of activated FVII (FVIIa) were 11.3 +/- 5.1 U/L
      lower after olive oil than after sunflower oil, an 18% reduction (P < 0.05).
      Olive oil also tended to cause lower FVIIa peak concentrations than did rapeseed
      oil (mean difference: 8.6 U/L, a 15% reduction; P = 0.09). There were no
      significant differences between diets with respect to nonfasting factor VII
      coagulant activity (FVII:c), prothrombin fragment 1+2 (F1+2), and tissue factor
      pathway inhibitor (TFPI) concentrations, or with respect to fasting plasma values
      of FVII protein, FVII:c, FVIIa, F1+2, or TFPI. CONCLUSION: A background diet rich
      in olive oil may attenuate the acute procoagulant effects of fatty meals, which
      might contribute to the low incidence of IHD in Mediterranean areas.

PMID- 10584042
TI  - Modified milk fat reduces plasma triacylglycerol concentrations in normolipidemic
      men compared with regular milk fat and nonhydrogenated margarine.
AB  - BACKGROUND: A modified milk fat with reduced cholesterol was developed by
      fractionation technology. OBJECTIVE: The effect of this modified milk fat on the
      lipoprotein profile of 21 normolipidemic men was compared with that of regular
      milk fat and nonhydrogenated margarine. DESIGN: A crossover design was used for
      the administration of the 3 experimental diets, which provided 13240 kJ as 16%
      protein, 51% carbohydrates, 33-34% lipids, and 21 g fiber/d. The ratio of
      polyunsaturated to saturated fat was 1.3:1 for the margarine diet and 0.3:1 for
      the milk-fat diets. The cholesterol content of the modified milk-fat and
      margarine diets was similar (248 and 254 mg/d, respectively), but was
      significantly higher (428 mg/d) for the regular milk-fat diet. RESULTS: Modified
      and regular milk fats did not change plasma total and LDL cholesterol
      significantly, but margarine did (P < 0.01). Furthermore, modified milk fat
      maintained initial HDL(2)-cholesterol concentrations, but margarine reduced this
      variable significantly (P < 0.05). These results can be explained by the lower
      ratio of polyunsaturated to saturated fat in the modified and regular milk-fat
      diets than in the margarine diet. Men who ingested modified milk fat had
      significantly (P < 0.05) lower total and VLDL-triacylglycerol and VLDL
      cholesterol concentrations than did those who ingested either regular milk fat or
      margarine. This may have been, in part, because of the lower intestinal fat
      absorption with modified milk fat than with regular milk fat and margarine
      arising from changes in the melting properties of milk fat with fractionation.
      CONCLUSION: A reduction in plasma triacylglycerol concentrations after the
      consumption of modified milk fat may prevent the onset of
      hypertriacylglycerolemia.

PMID- 10584043
TI  - HDL-subpopulation patterns in response to reductions in dietary total and
      saturated fat intakes in healthy subjects.
AB  - BACKGROUND: Little information is available about HDL subpopulations during
      dietary changes. OBJECTIVE: The objective was to investigate the effect of
      reductions in total and saturated fat intakes on HDL subpopulations. DESIGN:
      Multiracial, young and elderly men and women (n = 103) participating in the
      double-blind, randomized DELTA (Dietary Effects on Lipoproteins and Thrombogenic
      Activities) Study consumed 3 different diets, each for 8 wk: an average American
      diet (AAD: 34.3% total fat,15.0% saturated fat), the American Heart Association
      Step I diet (28.6% total fat, 9.0% saturated fat), and a diet low in saturated
      fat (25.3% total fat, 6.1% saturated fat). RESULTS: HDL(2)-cholesterol
      concentrations, by differential precipitation, decreased (P < 0.001) in a
      stepwise fashion after the reduction of total and saturated fat: 0.58 +/- 0.21,
      0.53 +/- 0.19, and 0.48 +/- 0.18 mmol/L with the AAD, Step I, and low-fat diets,
      respectively. HDL(3) cholesterol decreased (P < 0.01) less: 0.76 +/- 0.13, 0.73
      +/- 0.12, and 0.72 +/- 0.11 mmol/L with the AAD, Step I, and low-fat diets,
      respectively. As measured by nondenaturing gradient gel electrophoresis, the
      larger-size HDL(2b) subpopulation decreased with the reduction in dietary fat,
      and a corresponding relative increase was seen for the smaller-sized HDL(3a, 3b),
      and (3c) subpopulations (P < 0.01). HDL(2)-cholesterol concentrations correlated
      negatively with serum triacylglycerol concentrations on all 3 diets: r = -0.46, 
      0.37, and -0.45 with the AAD, Step I, and low-fat diets, respectively (P <
      0.0001). A similar negative correlation was seen for HDL(2b), whereas HDL(3a,
      3b), and (3c) correlated positively with triacylglycerol concentrations. Diet
      induced changes in serum triacylglycerol were negatively correlated with changes
      in HDL(2) and HDL(2b) cholesterol. CONCLUSIONS: A reduction in dietary total and
      saturated fat decreased both large (HDL(2) and HDL(2b)) and small, dense HDL
      subpopulations, although decreases in HDL(2) and HDL(2b) were most pronounced.

PMID- 10584044
TI  - Dietary saturated fats and their food sources in relation to the risk of coronary
      heart disease in women.
AB  - BACKGROUND: Metabolic studies suggest that saturated fatty acids differ in their
      effects on blood lipids. OBJECTIVE: The objective was to examine the associations
      between intakes of individual saturated fatty acids and their food sources in
      relation to the risk of coronary heart disease (CHD). DESIGN: This was a
      prospective cohort study of 80082 women in the Nurses' Health Study aged 34-59 y.
      Subjects had no known cardiovascular disease, cancer, hypercholesterolemia, or
      diabetes, and completed validated food-frequency questionnaires in 1980. RESULTS:
      During 14 y of follow-up, we documented 939 incident cases of major CHD events.
      In multivariate analyses in which age, smoking, and other covariates were
      controlled for, intakes of short- to medium-chain saturated fatty acids (4:0
      10:0) were not significantly associated with the risk of CHD. In contrast,
      intakes of longer-chain saturated fatty acids (12:0-18:0) were each separately
      associated with a small increase in risk. The multivariate RR for a 1% energy
      increase from stearic acid was 1.19 (95% CI: 1.02, 1.37). The ratio of
      polyunsaturated to saturated fat was strongly and inversely associated with CHD
      risk (multivariate RR for a comparison of the highest with the lowest deciles:
      0.58; 95% CI: 0.41, 0.83; P for trend < 0.0001). Conversely, higher ratios of red
      meat to poultry and fish consumption and of high-fat to low-fat dairy consumption
      were associated with significantly greater risk. CONCLUSION: A distinction
      between stearic acid and other saturated fats does not appear to be important in
      dietary advice to reduce CHD risk, in part because of the high correlation
      between stearic acid and other saturated fatty acids in typical diets.

PMID- 10584045
TI  - High-monounsaturated fatty acid diets lower both plasma cholesterol and
      triacylglycerol concentrations.
AB  - BACKGROUND: Low-fat diets increase plasma triacylglycerol and decrease HDL
      cholesterol concentrations, thereby potentially adversely affecting
      cardiovascular disease (CVD) risk. High-monounsaturated fatty acid (MUFA),
      cholesterol-lowering diets do not raise triacylglycerol or lower HDL cholesterol,
      but little is known about how peanut products, a rich source of MUFAs, affect CVD
      risk. OBJECTIVE: The present study compared the CVD risk profile of an Average
      American diet (AAD) with those of 4 cholesterol-lowering diets: an American Heart
      Association/National Cholesterol Education Program Step II diet and 3 high-MUFA
      diets [olive oil (OO), peanut oil (PO), and peanuts and peanut butter (PPB)].
      DESIGN: A randomized, double-blind, 5-period crossover study design (n = 22) was
      used to examine the effects of the diets on serum lipids and lipoproteins: AAD
      [34% fat; 16% saturated fatty acids (SFAs), 11% MUFAs], Step II (25% fat; 7%
      SFAs, 12% MUFAs), OO (34% fat; 7% SFAs, 21% MUFAs), PO (34% fat; 7% SFAs, 17%
      MUFAs), and PPB (36% fat; 8% SFAs, 18% MUFAs). RESULTS: The high-MUFA diets
      lowered total cholesterol by 10% and LDL cholesterol by 14%. This response was
      comparable with that observed for the Step II diet. Triacylglycerol
      concentrations were 13% lower in subjects consuming the high-MUFA diets and were
      11% higher with the Step II diet than with the AAD. The high-MUFA diets did not
      lower HDL cholesterol whereas the Step II diet lowered it by 4% compared with the
      AAD. The OO, PO, and PPB diets decreased CVD risk by an estimated 25%, 16%, and
      21%, respectively, whereas the Step II diet lowered CVD risk by 12%. CONCLUSION:
      A high-MUFA, cholesterol-lowering diet may be preferable to a low-fat diet
      because of more favorable effects on the CVD risk profile.

PMID- 10584046
TI  - Lifestyle and cardiovascular disease risk factors as determinants of total
      cysteine in plasma: the Hordaland Homocysteine Study.
AB  - BACKGROUND: Plasma total homocysteine (tHcy) is a cardiovascular disease risk
      factor and is related to several components of the established cardiovascular
      disease risk profile. Cysteine is structurally and metabolically related to
      homocysteine, but data on its association with cardiovascular disease and
      cardiovascular disease risk factors are sparse. OBJECTIVE: Our objective was to
      search for the determinants of plasma total cysteine (tCys) and compare them with
      those of tHcy. DESIGN: In this cross-sectional study, we studied 7591 healthy men
      and 8585 healthy women aged 40-67 y with no history of hypertension, diabetes
      mellitus, coronary heart disease, or cerebrovascular disease. RESULTS: In the
      group aged 40-42 y, tCys was significantly higher in men (&mean;: 273 micromol/L;
      2.5-97.5 percentile: 219-338 micromol/L) than in women (253 micromol/L; 202-317
      micromol/L) (P < 0.001). In the group aged 65-67 y, there was no significant sex
      difference in tCys: men (296 micromol/L; 233-362 micromol/L) and women (296
      micromol/L; 234-361 micromol/L). As with tHcy, tCys was positively associated
      with age, total cholesterol concentration, diastolic blood pressure, and coffee
      consumption. Body mass index was a strong determinant of tCys but was not related
      to tHcy. Several factors known to influence tHcy, including smoking status,
      folate and vitamin intake, heart rate, and physical activity, were not associated
      or were only weakly associated with tCys. CONCLUSION: Plasma tCys is strongly
      related to several factors that constitute the cardiovascular disease risk
      profile. This should be an incentive to determine the role of tCys in
      cardiovascular disease.

PMID- 10584047
TI  - Longitudinal changes in adult fat-free mass: influence of body weight.
AB  - BACKGROUND: Almost all of the data on changes in body composition during aging
      are cross-sectional in nature. These show that fat-free mass (FFM) declines with
      age. OBJECTIVE: The goal was to analyze results of assays done in the author's
      laboratory of the FFM of normal adults studied at intervals for >/=2 decades to
      ascertain longitudinal changes. DESIGN: (40)K counting was used to estimate FFM
      in adult university personnel (15 men, 5 women) over periods ranging from 21 to
      38 y. No advice was given about diet or exercise. RESULTS: There was considerable
      variation in the change of FFM over time. Some subjects lost FFM as the years
      went by, whereas others actually gained FFM. Analysis of the data showed that
      change in body weight was a prime factor in determining the magnitude and
      direction of the FFM change (R(2) = 0.54). Adults who maintained their weight
      lost an average of 1.5 kg FFM per decade and so gained an equal amount of fat;
      those who lost weight lost even more FFM, whereas those who gained weight either
      gained FFM or lost it more slowly than the others. Data from the literature
      confirmed this trend. CONCLUSIONS: FFM loss is not inevitable during adulthood-at
      least up to age 81 y, the oldest age yet studied. The magnitude and direction of
      the FFM change, be it positive or negative, is strongly influenced by change in
      body weight.

PMID- 10584048
TI  - Effects of an omnivorous diet compared with a lactoovovegetarian diet on
      resistance-training-induced changes in body composition and skeletal muscle in
      older men.
AB  - BACKGROUND: Very limited data suggest that meat consumption by older people may
      promote skeletal muscle hypertrophy in response to resistance training (RT).
      OBJECTIVE: The objective of this study was to assess whether the consumption of
      an omnivorous (meat-containing) diet would influence RT-induced changes in whole
      body composition and skeletal muscle size in older men compared with a
      lactoovovegetarian (LOV) (meat-free) diet. DESIGN: Nineteen men aged 51-69 y
      participated in the study. During a 12-wk period of RT, 9 men consumed their
      habitual omnivorous diets, which provided approximately 50% of total dietary
      protein from meat sources (beef, poultry, pork, and fish) (mixed-diet group).
      Another 10 men were counseled to self-select an LOV diet (LOV-diet group).
      RESULTS: Maximal strength of the upper- and lower-body muscle groups that were
      exercised during RT increased by 10-38% (P < 0.001), independent of diet. The RT
      induced changes in whole-body composition and skeletal muscle size differed
      significantly between the mixed- and LOV-diet groups (time-by-group interactions,
      P < 0. 05). With RT, whole-body density, fat-free mass, and whole-body muscle
      mass increased in the mixed diet group but decreased in the LOV- diet group. Type
      II muscle fiber area of the vastus lateralis muscle increased with RT for all men
      combined (P < 0.01), and the increase tended to be greater in the mixed-diet
      group (16.2 +/- 4.4 %) than in the LOV diet group (7.3 +/- 5.1%). Type I fiber
      area was unchanged with RT in both diet groups. CONCLUSION: Consumption of a meat
      containing diet contributed to greater gains in fat-free mass and skeletal muscle
      mass with RT in older men than did an LOV diet.

PMID- 10584049
TI  - Efficacy of a green tea extract rich in catechin polyphenols and caffeine in
      increasing 24-h energy expenditure and fat oxidation in humans.
AB  - BACKGROUND: Current interest in the role of functional foods in weight control
      has focused on plant ingredients capable of interfering with the sympathoadrenal
      system. OBJECTIVE: We investigated whether a green tea extract, by virtue of its
      high content of caffeine and catechin polyphenols, could increase 24-h energy
      expenditure (EE) and fat oxidation in humans. DESIGN: Twenty-four-hour EE, the
      respiratory quotient (RQ), and the urinary excretion of nitrogen and
      catecholamines were measured in a respiratory chamber in 10 healthy men. On 3
      separate occasions, subjects were randomly assigned among 3 treatments: green tea
      extract (50 mg caffeine and 90 mg epigallocatechin gallate), caffeine (50 mg),
      and placebo, which they ingested at breakfast, lunch, and dinner. RESULTS:
      Relative to placebo, treatment with the green tea extract resulted in a
      significant increase in 24-h EE (4%; P < 0.01) and a significant decrease in 24-h
      RQ (from 0.88 to 0.85; P < 0.001) without any change in urinary nitrogen. Twenty
      four-hour urinary norepinephrine excretion was higher during treatment with the
      green tea extract than with the placebo (40%, P < 0.05). Treatment with caffeine
      in amounts equivalent to those found in the green tea extract had no effect on EE
      and RQ nor on urinary nitrogen or catecholamines. CONCLUSIONS: Green tea has
      thermogenic properties and promotes fat oxidation beyond that explained by its
      caffeine content per se. The green tea extract may play a role in the control of
      body composition via sympathetic activation of thermogenesis, fat oxidation, or
      both.

PMID- 10584050
TI  - Incorporation of urea and ammonia nitrogen into ileal and fecal microbial
      proteins and plasma free amino acids in normal men and ileostomates.
AB  - BACKGROUND: The importance of urea nitrogen reutilization in the amino acid
      economy of the host remains to be clarified. OBJECTIVE: The objective was to
      explore the transfer of (15)N from orally administered [(15)N(2)]urea or
      (15)NH(4)Cl to plasma free and intestinal microbial amino acids. DESIGN: Six men
      received an L-amino acid diet (167 mg N*kg(-)(1)*d(-)(1); 186 kJ*kg(-)(1)*d(
      )(1)) for 11 d each on 2 different occasions. For the last 6 d they ingested
      [(15)N(2)]urea or, in random order, (15)NH(4)Cl (3.45 mg (15)N*kg(-)(1)*d(-)(1)).
      On day 10, a 24-h tracer protocol (12 h fasted/12 h fed) was conducted with
      subjects receiving the (15)N tracer hourly. In a similar experiment, (15)NH(4)Cl
      (3.9 mg (15)N*kg(-)(1)*d(-)(1)) was given to 7 ileostomates. (15)N Enrichments of
      urinary urea and plasma free and fecal or ileal microbial protein amino acids
      were analyzed. RESULTS: (15)N Retention was significantly higher with (15)NH(4)Cl
      (47.7%; P < 0.01) than with [(15)N(2)]urea (29.6%). Plasma dispensable amino
      acids after the (15)NH(4)Cl tracer were enriched up to 20 times (0. 2-0.6 (15)N
      atom% excess) that achieved with [(15)N(2)]urea. The (15)N-labeling pattern of
      plasma, ileal, and fecal microbial amino acids (0.05-0.45 (15)N atom% excess) was
      similar. Appearance of microbial threonine in plasma was similar for normal
      subjects (0.14) and ileostomates (0.17). CONCLUSION: The fate of (15)N from urea
      and NH(4)Cl differs in terms of endogenous amino acid metabolism, but is similar
      in relation to microbial protein metabolism. Microbial threonine of normal and
      ileostomy subjects appears in the blood plasma but the net contribution to the
      body threonine economy cannot be estimated reliably from the present data.

PMID- 10584051
TI  - Behavioral and hematologic consequences of marginal iron-zinc nutrition in
      adolescent monkeys and the effect of a powdered beef supplement.
AB  - BACKGROUND: The adolescent growth spurt and menarche increase iron and zinc needs
      and could precipitate functional deficiencies if dietary sources are inadequate.
      OBJECTIVE: The effects of mild, combined zinc and iron deprivation during the
      growth spurt and the ability of meat as a common dietary source of zinc and iron
      to reverse these effects was studied. DESIGN: Pubertal female rhesus monkeys were
      fed control diets (n = 8) or diets marginally deficient in zinc (2 microg/g diet;
      n = 8) and iron (10 microg/g diet; n = 8) for 3 mo. A powdered beef supplement
      (104 microg Zn/g and 43 microg Fe/g, 11 +/- 2 g/d) was then fed daily to half of
      the deprived group for 3 additional months. RESULTS: Growth and hematology were
      not affected significantly by iron-zinc deprivation, but plasma zinc and iron
      were somewhat lower in the deprived group than in the control group after 3 mo.
      The deprived monkeys reduced their participation in behavioral testing, responded
      more slowly and less frequently to test stimuli, and were less active. The beef
      supplement increased participation in testing and stabilized activity levels, but
      response times remained depressed. Plasma ferritin was lower in the
      nonsupplemented deprived monkeys than in the controls by the end of the
      experiment. Four of 8 of the deprived monkeys had iron deficiency anemia compared
      with none of the controls and 1 of 8 who received the beef supplement.
      CONCLUSIONS: Marginal zinc and iron deprivation in early adolescence can lead to
      behavioral and hematologic dysfunction in nonhuman primates and dietary beef
      supplements can prevent and reverse some of these effects.

PMID- 10584052
TI  - Green and yellow vegetables can maintain body stores of vitamin A in Chinese
      children.
AB  - BACKGROUND: Vitamin A activity of plant provitamin A carotenoids is uncertain.
      OBJECTIVE: The objective was to determine whether plant carotenoids can sustain
      or improve vitamin A nutrition during the fall season in kindergarten children in
      the Shandong province of China. DESIGN: The serum vitamin A concentration of 39%
      of the children was <1.05 micromol/L and of 61% of the children was > or = 1.05
      micromol/L. For 5 d/wk for 10 wk, 22 children were provided approximately 238 g
      green-yellow vegetables/d and 34 g light-colored vegetables/d. Nineteen children
      maintained their customary dietary intake, which included 56 g green-yellow
      vegetables/d and 224 g light-colored vegetables/d. Octadeuterated and
      tetradeuterated vitamin A were given before and after the interventions,
      respectively, and their enrichments in the plasma were determined by gas
      chromatography-mass spectrometry. Serum retinol and carotenoid concentrations
      were measured by HPLC. RESULTS: Carotenoid nutrition improved after consumption
      of green-yellow vegetables. Serum concentrations of retinol were sustained in the
      group fed green-yellow vegetables but decreased in the group fed light-colored
      vegetables (P < 0.01). The isotope-dilution tests confirmed that total-body
      vitamin A stores were sustained in the group fed green-yellow vegetables, but
      decreased 27 micromol (7700 microg retinol) per child, on average, in the group
      fed light-colored vegetables (P < 0.06). CONCLUSION: Green-yellow vegetables can
      provide adequate vitamin A nutrition in the diet of kindergarten children and
      protect them from becoming vitamin A deficient during seasons when the provitamin
      A food source is limited.

PMID- 10584053
TI  - Dietary factors in relation to rheumatoid arthritis: a role for olive oil and
      cooked vegetables?
AB  - BACKGROUND: Although several studies showed that risk of rheumatoid arthritis
      (RA) is inversely associated with consumption of n-3 fatty acids, the one study
      showing that olive oil may have a protective role has not yet been confirmed.
      OBJECTIVE: We examined the relation between dietary factors and risk of RA in
      persons from southern Greece. DESIGN: We studied 145 RA patients and 188 control
      subjects who provided information on demographic and socioeconomic variables,
      prior medical and family history, and present disease status. Subjects responded
      to an interviewer-administered, validated, food-frequency questionnaire that
      assessed the consumption of >100 food items. We calculated chi-square statistics
      for linear trend and odds ratios (ORs) for the development of RA in relation to
      the consumption of olive oil, fish, vegetables, and a series of food groups
      classified in quartiles. RESULTS: Risk of developing RA was inversely and
      significantly associated only with cooked vegetables (OR: 0.39) and olive oil
      (OR: 0.39) by univariate analysis. A significant trend was observed with
      increasing olive oil (chi-square: 4.28; P = 0.03) and cooked vegetable (chi
      square: 10. 48; P = 0.001) consumption. Multiple logistic regression analysis
      models confirmed the independent and inverse association between olive oil or
      cooked vegetable consumption and risk of RA (OR: 0.38 and 0.24, respectively).
      CONCLUSIONS: Consumption of both cooked vegetables and olive oil was inversely
      and independently associated with risk of RA in this population. Further research
      is needed to elucidate the underlying mechanisms of this finding, which may
      include the antioxidant properties or the high n-9 fatty acid content of the
      olive oil.

PMID- 10584054
TI  - Interaction of body weight and ethnicity on risk of gestational diabetes
      mellitus.
AB  - BACKGROUND: The James Bay Cree of Canada have one of the highest recorded rates
      of gestational diabetes mellitus (GDM) among aboriginal people worldwide; the
      reasons for this elevated risk remain to be documented. OBJECTIVE: Our objective
      was to compare predictors and risk of GDM between the James Bay Cree and non
      Native Canadians. DESIGN: Risk for GDM was compared between Cree and non-Native
      women by 1) adjusting statistically for differences in age, parity, pregravid
      weight, and smoking status (n = 402 Cree, 7718 non-Natives), and 2) matching Cree
      women with non-Native women for age and pregravid weight (n = 394 Cree, 788 non
      Natives). Dietary and physical activity information was available for a subset of
      Cree women (n = 152). RESULTS: Age and pregravid weight were independent
      predictors of GDM in both Cree and non-Native women. After these predictors were
      controlled for, normal-weight (</=77 kg) Cree women were not at increased risk of
      GDM (OR: 1.42; 95% CI: 0.67, 2.71) but overweight Cree women had a higher risk
      than did overweight non-Native women (OR: 2.25; 95% CI: 1.32, 3.80). CONCLUSIONS:
      Overweight Cree women are at increased risk of GDM. Given the high prevalence of
      pregravid overweight among the Cree, the burden of GDM is higher than among non
      Native Canadians.

PMID- 10584055
TI  - Receiver operating characteristic analysis of body mass index, triceps skinfold
      thickness, and arm girth for obesity screening in children and adolescents.
AB  - BACKGROUND: Valid and practical methods based on health-related criteria for
      obesity screening in children and adolescents are not available. Arbitrarily
      defined body mass index (BMI) cutoffs have been proposed to select adolescents at
      high risk of developing obesity in adulthood. OBJECTIVE: We assessed the
      usefulness of BMI, triceps skinfold thickness, and upper arm girth for screening
      for obesity by using a health-related definition of obesity (> or = 25% body fat
      in boys and > or = 30% body fat in girls) and a criterion method (dual-energy X
      ray absorptiometry) that estimates percentage fat without the potential bias
      associated with other methods in adolescents. DESIGN: This was a cross-sectional
      study of Portuguese boys (n = 165) and girls (n = 163) aged 10-15 y.
      Nonparametric receiver operating characteristic (ROC) analysis was used to define
      the best tradeoff between true-positive and false-positive rates. RESULTS: True
      positive rates ranged from 67% to 87% and from 50% to 100% in girls and boys,
      respectively, and false-positive rates ranged from 0% to 19% and from 5% to 26%,
      respectively. For children aged 10-11 y, the areas under the curves (AUCs) for
      ROCs, an index of diagnostic accuracy, were close to 1.0, suggesting very good
      accuracy. For older boys and girls, AUCs for triceps skinfold thickness were
      similar to or greater than AUCs for BMI and upper arm girth. CONCLUSIONS: The
      results suggest that triceps skinfold thickness gives the best results for
      obesity screening in adolescents aged 10-15 y. BMI and upper arm girth were
      reasonable alternatives, except in 14-15-y-old boys, in whom both indexes were
      only marginally able to discriminate obesity.

PMID- 10584056
TI  - Digestion and absorption of 2 fat emulsions with different droplet sizes in the
      human digestive tract.
AB  - BACKGROUND: The extent of fat emulsification affects the activity of digestive
      lipases in vitro and may govern digestion and absorption of dietary fat.
      OBJECTIVE: We investigated the effect of the fat globule size of 2 enteral
      emulsions on fat digestion and assimilation in humans. DESIGN: Healthy subjects
      received intragastrically a coarse (10 microm) and a fine (0.7 microm) lipid
      emulsion of identical composition in random order. Gastric and duodenal aspirates
      were collected throughout digestion to measure changes in fat droplet size,
      gastric and pancreatic lipase activities, and fat digestion. Blood lipids were
      measured postprandially for fat assimilation. RESULTS: Despite an increase in
      droplet size in the stomach (2.75-6.20 microm), the fine emulsion retained
      droplets of smaller size and its lipolysis was greater than that of the coarse
      emulsion (36.5% compared with 15.8%; P < 0.05). In the duodenum, lipolysis of the
      fine emulsion was on the whole higher (73.3% compared with 46.3%). The overall 0
      7-h plasma and chylomicron responses given by the areas under the curve were not
      significantly different between the emulsions, but the triacylglycerol peak was
      delayed with the fine emulsion (3 h 56 min compared with 2 h 50 min).
      CONCLUSIONS: Fat emulsions behave differently in the digestive tract depending on
      their initial physicochemical properties. A lower initial fat droplet size
      facilitates fat digestion by gastric lipase in the stomach and duodenal
      lipolysis. Overall fat assimilation in healthy subjects is not affected by
      differences in initial droplet size because of efficient fat digestion by
      pancreatic lipase in the small intestine. Nevertheless, these new observations
      could be of interest in the enteral nutrition of subjects suffering from
      pancreatic insufficiency.

PMID- 10584057
TI  - Refined-cereal intake and risk of selected cancers in italy.
AB  - BACKGROUND: Although consumption of whole-grain foods seems to reduce the risk of
      several types of neoplasms, the potential influence of a diet rich in starches
      and refined grains is less clear. OBJECTIVE: We studied the relation between the
      frequency of consumption of refined cereals (bread, pasta, or rice) and the risk
      of selected neoplasms. DESIGN: This was an integrated series of case-control
      studies conducted in northern Italy between 1983 and 1993. The subjects were
      patients admitted to the major teaching and general hospitals in Milan and
      Pordenone with incident, histologically confirmed cancers: 343 with cancer of the
      oral cavity and pharynx, 94 with cancer of the esophagus, 146 with cancer of the
      larynx, 745 with cancer of the stomach, 955 with cancer of the colon, 625 with
      cancer of the rectum, and 428 with cancer of the thyroid. The control subjects
      were 3526 patients admitted to the same network of hospitals for acute
      nonneoplastic conditions unrelated to long-term modification of diet. Odds ratios
      (ORs) for consecutive tertiles of refined-cereal consumption were computed after
      allowance for sociodemographic variables, education, smoking status, alcohol
      consumption, body mass index, and consumption of fruit, vegetables, and whole
      grain foods. RESULTS: The ORs for the highest tertile of refined-cereal intake
      were 1.6 for cancer of the oral cavity, pharynx, esophagus, or larynx; 1.5 for
      stomach cancer; 1.5 for colon cancer; 1.3 for cancer of the rectum; and 2.0 for
      thyroid cancer. The trends in risk were significant for all neoplasms considered.
      CONCLUSION: Consumption of refined cereals was associated with an increased risk
      of cancers of the large bowel, the stomach, and other selected digestive and
      nondigestive sites.

PMID- 10584058
TI  - Low-fat, high-sugar diet and lipoprotein profiles.

PMID- 10584059
TI  - Coronary artery disease risk factors in south Asian and American premenopausal
      women.

PMID- 10584060
TI  - Treatment of severe psoriasis with fumaric acid esters: scientific background and
      guidelines for therapeutic use. The German Fumaric Acid Ester Consensus
      Conference.
AB  - Fumaric acid ester (FAE) therapy has proved to be safe and effective in patients
      with severe psoriasis vulgaris. This treatment was introduced nearly 30 years
      ago, but is only now gaining renewed interest among dermatologists. FAE therapy
      is licensed in Germany and registration is pending in many European countries.
      Multicentre trials have confirmed the beneficial effect of FAE in psoriasis and
      have defined the spectrum of its adverse effects. Although the mode of action of
      FAEs in the treatment of psoriasis is not fully understood, recent experimental
      data point towards a skewing of the Th1-dominated T-cell response in psoriasis to
      a Th2-like pattern, and inhibition of proliferation of keratinocytes. This
      article reviews the experimental and clinical information on FAEs in psoriasis
      and provides guidelines for the clinical use of FAEs derived from a consensus
      meeting of leading experts.

PMID- 10584061
TI  - Theoretical study of the electrostatically driven step of receptor-G protein
      recognition.
AB  - This study proposes a theoretical model describing the electrostatically driven
      step of the alpha 1 b-adrenergic receptor (AR)-G protein recognition. The
      comparative analysis of the structural-dynamics features of functionally
      different receptor forms, i.e., the wild type (ground state) and its
      constitutively active mutants D142A and A293E, was instrumental to gain insight
      on the receptor-G protein electrostatic and steric complementarity. Rigid body
      docking simulations between the different forms of the alpha 1 b-AR and the
      heterotrimeric G alpha q, G alpha s, G alpha i1, and G alpha t suggest that the
      cytosolic crevice shared by the active receptor and including the second and the
      third intracellular loops as well as the cytosolic extension of helices 5 and 6,
      represents the receptor surface with docking complementarity with the G protein.
      On the other hand, the G protein solvent-exposed portions that recognize the
      intracellular loops of the activated receptors are the N-terminal portion of
      alpha 3, alpha G, the alpha G/alpha 4 loop, alpha 4, the alpha 4/beta 6 loop,
      alpha 5, and the C-terminus. Docking simulations suggest that the two
      constitutively active mutants D142A and A293E recognize different G proteins with
      similar selectivity orders, i.e., G alpha q approximately equal to G alpha s > G
      alpha i >> G alpha t. The theoretical models herein proposed might provide useful
      suggestions for new experiments aiming at exploring the receptor-G protein
      interface.

PMID- 10584062
TI  - Enzyme polarization of substrates of dihydrofolate reductase by different
      theoretical methods.
AB  - We have investigated the importance of polarization by the enzyme dihydrofolate
      reductase (DHFR) on its substrates, folate and dihydrofolate, using a series of
      quantum mechanical (QM) techniques (Hartree-Fock (HF), Moller-Plesset second
      order perturbation theory (MP2), local density approximation (LDA) and
      generalized gradient approximation (GGA) density functional theory (DFT)
      calculations) in which the bulk enzyme is included in the calculations as point
      charges. Polarization, in terms of both charges on components (residues) of the
      folate and dihydrofolate molecules and changes in the electron density,
      particularly of the pterin ring of the substrates, and the implications for the
      catalytic reduction are discussed. Significant differences in polarization
      behavior are observed for the different theoretical methods employed. The
      consequences of this, particularly for choosing an appropriate model for quantum
      mechanical/molecular mechanical (QM/MM) calculations, are pointed out. The HF and
      MP2 QM methods show small polarizations (approximately 0.04 electrons) of the
      pterin ring but quite large polarizations with both LDA and GGA DFT methods (0.3
      0.5 electrons). This large difference in polarization for both folate and
      dihydrofolate arises as a result of substantial differences between the charge
      distributions for the gasphase DFT and HF calculations, specifically the charges
      on the dianionic glutamate side chain. Some recent literature reports of
      incorrect representation of anionic systems by DFT methods are noted. The DFT
      results are similar to the previously reported LDA DFT results of Bajorath et al.
      predicting a large polarization of the pterin ring of folate (Proteins 9:217-224,
      1991) and dihydrofolate (PNAS 88:6423-6426, 1991) of approximately 0.5-0.6
      electrons.

PMID- 10584063
TI  - Automated docking of maltose, 2-deoxymaltose, and maltotetraose into the soybean
      beta-amylase active site.
AB  - In this study, products and substrates were docked into the active site of beta
      amylase using the simulated annealing algorithm AutoDock. Lowest-energy
      conformers reproduced known crystallographic atom positions within 0.4 to 0.8 A
      rmsd. Docking studies were carried out with both open and closed configurations
      of the beta-amylase mobile flap, a loop comprising residues 96 to 103. Ligands
      with two rings docked within the cleft near the active site when the flap was
      open, but those with four rings did not. The flap must be closed for alpha
      maltotetraose to adopt a conformation allowing it to dock near the
      crystallographically determined subsites. The closed flap is necessary for
      productive but not for nonproductive binding, and therefore it plays a essential
      role in catalysis. The gain in total binding energy upon closing of the flap for
      alpha-maltose docked to subsites -2, -1 and +1, +2 is about 22 kcal/mol,
      indicating more favorable interactions are possible with the flap closed. Larger
      intermolecular interaction energies are observed for two alpha-maltose molecules
      docked to subsites -2, -1 and +1, +2 than for one alpha-maltotetraose molecule
      docked from subsites -2 to +2, suggesting that it is only upon cleavage of the
      alpha-1,4 linkage that optimal closed-flap binding can occur with the
      crytallographically determined enzyme structure.

PMID- 10584064
TI  - Homology modeling and substrate binding study of human CYP2C9 enzyme.
AB  - The CYP2C subfamily of human liver P450 isozymes is of major importance in drug
      metabolism. The most abundant 2C isozyme, CYP2C9, regioselectively hydroxylates a
      wide variety of substrates. A major obstacle to understanding this specificity in
      human CYP2C9 is the absence of a 3D structure. A 3D model of CYP2C9 was built,
      assessed, and used to characterize explicit enzyme-substrate complexes using
      methods previously developed in our laboratory. The 3D model was assessed by
      determining its stability to unconstrained molecular dynamics and by comparison
      of specific properties with those of known protein structures. The CYP2C9 model
      was then used to characterize explicit enzyme complexes with three structurally
      and chemically diverse substrates: (S)-naproxen, phenytoin, and progesterone.
      Each substrate was found to bind to the enzyme with a favorable interaction
      energy and to remain in the binding site during unconstrained molecular dynamics.
      Moreover, the mode of binding of each substrate led to calculated preferred
      hydroxylation sites consistent with experiment. Binding-site residues identified
      for the models included Arg 105 and Arg97 as key cationic residues, as well as
      Asn 202, Asp 293, Pro 101, Leu 102, Gly 296, and Phe 476. Site-specific mutations
      are proposed for further integrated computational and experimental study.

PMID- 10584065
TI  - Structure modelling and site-directed mutagenesis of the rat aromatic L-amino
      acid pyridoxal 5'-phosphate-dependent decarboxylase: a functional study.
AB  - The pyridoxal-5'-phosphate-dependent enzymes (B6 enzymes) are grouped into three
      main families named alpha, beta, and gamma. Proteins in the alpha and gamma
      families share the same fold and might be distantly related, while those in the
      beta family exhibit specific structural features. The rat aromatic L-amino acid
      decarboxylase (AADC; EC(4.1.1.28)) catalyzes the synthesis of two important
      neurotransmitters: dopamine and serotonin. It binds the cofactor pyridoxal-5'
      phosphate and belongs to the alpha family. Despite the low level of sequence
      identity (approximately 10%) shared by the rat AADC and the sequences of the
      enzymes belonging to the B6 enzymes family, including the known three-dimensional
      structures, a multiple sequence alignment was deduced. A model was built using
      segments belonging to seven of the eleven known structures. By homology, and
      based on knowledge of the biochemistry of the aspartate aminotransferase,
      structurally and functionally important residues were identified in the rat AADC.
      Site-directed mutagenesis of the conserved residues D271, T246, and C311 was
      carried out in order to confirm our predictions and highlight their functional
      role. Mutation of D271A and D271N resulted in complete loss of enzyme activity,
      while the D271E mutant exhibited 2% of the wild-type activity. Substitution of
      T246A resulted in 5% of the wild-type activity while the C311A mutant conserved
      42% of the wild-type activity. A functional model of the AADC is discussed in
      view of the structural model and the complementary mutagenesis and labelling
      studies.

PMID- 10584066
TI  - Homology modeling and substrate binding study of human CYP2C18 and CYP2C19
      enzymes.
AB  - It is well established that the variable binding-site architecture and
      composition of the P450 metabolizing heme proteins are major modulators of
      substrate and product specificity. Even the three closely related human liver
      isozymes, CYP2C9, CYP2C18, and CYP2C19, do not share all substrates and do not
      always lead to the same preferred hydroxylation products. The lack of knowledge
      of their three-dimensional (3D) structures has hindered efforts to understand the
      differences in their specificities. Building on previous work for the CYP2C9
      enzyme, 3D models of CYP2C18 and 2C19 have been constructed and validated by
      computational methods developed and tested in our laboratory. They were used to
      characterize explicit enzyme-substrate complexes using the isoform-specific
      substrates progesterone and (S)-mephenytoin for 2C19 and 2-[2,3-dichloro-4-(3
      hydroxypropyloxy)benzoyl]thiophene for 2C18. The results allowed both common and
      unique binding-site residues to be identified in each model. The calculated
      preferred hydroxylation site was obtained for each substrate and was found to be
      consistent with experimental observation. Comparisons were made among the 2C9,
      2C18, and 2C19 model binding sites to investigate the subtle differences among
      them. These models can be used as structure-based guides for mutagenesis studies
      and screening of potential pharmaceuticals or toxins.

PMID- 10584067
TI  - Modelling the catalytic reaction in human aldose reductase.
AB  - Aldose reductase (ALR2) has received considerable attention due to its possible
      link to long-term diabetic complications. Although crystal structures and kinetic
      data reveal important aspects of the reaction mechanism, details of the catalytic
      step are still unclear. In this paper a computer simulation study is presented
      that utilizes the hybrid quantum mechanical and molecular mechanical (QM-MM)
      potential to elucidate the nature of the hydride and proton transfer steps in the
      reduction of D-glyceraldehyde by ALR2. Several reaction pathways were
      investigated in two models with either Tyr48 or protonated His110+ acting as the
      potential proton donor in the active site. Calculations show that the substrate
      binds to ALR2 through hydrogen bonds in an orientation that facilitates the
      stereospecific catalytic step in both models. It is established that in the case
      that His110 is present in the protonated form in the native complex, it is the
      energetically favored proton donor compared with Tyr48 in the active pocket with
      neutral His110. The reaction mechanisms in the different models are discussed
      based on structural and energetic considerations.

PMID- 10584068
TI  - Evaluation of the FLEXX incremental construction algorithm for protein-ligand
      docking.
AB  - We report on a test of FLEXX, a fully automatic docking tool for flexible
      ligands, on a highly diverse data set of 200 protein-ligand complexes from the
      Protein Data Bank. In total 46.5% of the complexes of the data set can be
      reproduced by a FLEXX docking solution at rank 1 with an rms deviation (RMSD)
      from the observed structure of less than 2 A. This rate rises to 70% if one looks
      at the entire generated solution set. FLEXX produces reliable results for ligands
      with up to 15 components which can be docked in 80% of the cases with acceptable
      accuracy. Ligands with more than 15 components tend to generate wrong solutions
      more often. The average runtime of FLEXX on this test set is 93 seconds per
      complex on a SUN Ultra-30 workstation. In addition, we report on "cross-docking"
      experiments, in which several receptor structures of complexes with identical
      proteins have been used for docking all cocrystallized ligands of these
      complexes. In most cases, these experiments show that FLEXX can acceptably dock a
      ligand into a foreign receptor structure. Finally we report on screening runs of
      ligands out of a library with 556 entries against ten different proteins. In
      eight cases FLEXX is able to find the original inhibitor within the top 7% of the
      total library.

PMID- 10584069
TI  - Computational studies of the domain movement and the catalytic mechanism of
      thymidine phosphorylase.
AB  - Thymidine phosphorylase (TP) is a dual substrate enzyme with two domains. Each
      domain binds a substrate. In the crystal structure of Escherichia coli TP, the
      two domains are arranged so that the two substrate binding sites are too far away
      for the two substrates to directly react. Molecular dynamics simulations reveal a
      different structure of the enzyme in which the two domains have moved to place
      the two substrates in close contact. This structure has a root-mean-square
      deviation from the crystal structure of 4.1 A. Quantum mechanical calculations
      using this structure find that the reaction can proceed by a direct nucleophilic
      attack with a low barrier. This mechanism is not feasible in the crystal
      structure environment and is consistent with the mechanism observed for other N
      glycosidic enzymes. Important catalytic roles are found for the three highly
      conserved residues His 85, Arg 171, and Lys 190.

PMID- 10584070
TI  - Fluorescence quenching in the DsbA protein from Escherichia coli: complete
      picture of the excited-state energy pathway and evidence for the reshuffling
      dynamics of the microstates of tryptophan.
AB  - The disulfide oxidoreductase DsbA is a strong oxidant of protein thiols and is
      required for efficient disulfide bond formation in the bacterial periplasm. DsbA
      contains two tryptophans: W76 and W126. The fluorescence of W76 changes upon
      reduction of the disulfide bridge, as analyzed previously (Hennecke et al.,
      Biochemistry 1997;36:6391-6400). The fluorescence of W126 is highly quenched. The
      only two potential side chain quenchers are Q74 and N127, and these were replaced
      by alanine, resulting in a threefold increase in fluorescence intensity. The
      fluorescence intensity increase is not due to the removal of dynamic quenchers
      but to an increase in the population with the longest lifetime. In this report,
      the possibility of a change in the conformation of W126 is investigated
      theoretically by using molecular mechanics and dynamic simulations and
      experimentally by using a reaction with N-bromosuccinimide. This reacts
      preferably with the most exposed microstate of tryptophan, which is responsible
      for the longest lifetime. The simulations and the experimental results reveal
      that the amino acid replacements allow W126 to increase the population of its
      antiperpendicular conformation. The selectivity of the N-bromosuccinimide
      reaction allows the visualization of the reshuffling kinetics at exhausting
      reagent concentration. To the authors' knowledge, this is the first time that the
      kinetics of Trp population reshuffling have been measured.

PMID- 10584071
TI  - Dictionary building via unsupervised hierarchical motif discovery in the sequence
      space of natural proteins.
AB  - Using Teiresias, a pattern discovery method that identifies all motifs present in
      any given set of protein sequences without requiring alignment or explicit
      enumeration of the solution space, we have explored the GenPept sequence database
      and built a dictionary of all sequence patterns with two or more instances. The
      entries of this dictionary, henceforth named seqlets, cover 98.12% of all amino
      acid positions in the input database and in essence provide a comprehensive
      finite set of descriptors for protein sequence space. As such, seqlets can be
      effectively used to describe almost every naturally occurring protein. In fact,
      seqlets can be thought of as building blocks of protein molecules that are a
      necessary (but not sufficient) condition for function or family equivalence
      memberships. Thus, seqlets can either define conserved family signatures or cut
      across molecular families and previously undetected sequence signals deriving
      from functional convergence. Moreover, we show that seqlets also can capture
      structurally conserved motifs. The availability of a dictionary of seqlets that
      has been derived in such an unsupervised, hierarchical manner is generating new
      opportunities for addressing problems that range from reliable classification and
      the correlation of sequence fragments with functional categories to faster and
      sensitive engines for homology searches, evolutionary studies, and protein
      structure prediction.

PMID- 10584072
TI  - Searching for frameshift evolutionary relationships between protein sequence
      families.
AB  - The protein sequence database was analyzed for evidence that some distinct
      sequence families might be distantly related in evolution by changes in frame of
      translation. Sequences were compared using special amino acid substitution
      matrices for the alternate frames of translation. The statistical significance of
      alignment scores were computed in the true database and shuffled versions of the
      database that preserve any potential codon bias. The comparison of results from
      these two databases provides a very sensitive method for detecting remote
      relationships. We find a weak but measurable relatedness within the database as a
      whole, supporting the notion that some proteins may have evolved from others
      through changes in frame of translation. We also quantify residual homology in
      the ordinary sense within a database of generally unrelated sequences.

PMID- 10584073
TI  - Local-scale repetitiveness in amino acid use in eukaryote protein sequences: a
      genomic factor in protein evolution.
AB  - We showed previously that the use of arginine versus lysine residues in eukaryote
      proteins is correlated positively with local GC content of the genome within
      approximately 50 residues. Cumulative analyses show that the tendency for self
      clustering (or repetitive use) generally is the case for all types of amino acids
      except for certain hydrophobic types. The degree to which each of the amino acids
      is used recurrently is weak for ancient proteins (or protein domains), those that
      are conserved through both eukaryotes and prokaryotes, but strong for modern
      proteins, which are unique to organisms of particular phyla. These findings
      support the idea that repetitiveness occurs due to a propensity of genomic DNA to
      cause tandem genomic duplication. A protein sequence with high repetitiveness
      tends to be unique in the homology search, which may indicate the weaker
      constraints and, hence, more arbitrary use of amino acids. Simulation analyses
      suggest that tandem gene duplications on a very small scale (1 or 2 codons) is an
      important causal factor in maintaining repetitiveness in the presence of
      concomittant occurrence of substitutive point mutation. For yeast proteins,
      approximately 1.3 duplication events per 1,000 residues on average are likely to
      occur, whereas 10 events of substitution mutation occur. It also is suggested
      that duplication enhances the probability of occurrence of some peptide motifs,
      such as those found in zinc fingers and segments with extreme physicochemical
      characteristics, and, thus, that local repetitiveness is a genomic factor
      influencing the evolution of eukaryote proteins.

PMID- 10584074
TI  - The function of conserved amino acid residues adjacent to the effector domain in
      elongation factor G.
AB  - Bacterial elongation factor G (EF-G) physically associates with translocation
      competent ribosomes and facilitates transition to the subsequent codon through
      the coordinate binding and hydrolysis of GTP. In order to investigate the amino
      acid positions necessary for EF-G functions, a series of mutations were
      constructed in the EF-G structural gene (fusA) of Escherichia coli, specifically
      at positions flanking the effector domain. A mutated allele was isolated in which
      the wild-type sequence from codons 29 to 47 ("EFG2947") was replaced with a
      sequence encoding 28 amino acids from ribosomal protein S7. This mutated gene was
      unable to complement a fusAts strain when supplied in trans at the nonpermissive
      temperature. In vitro biochemical analysis demonstrated that nucleotide
      crosslinking was unaffected in EFG2947, while ribosome binding appeared to be
      completely abolished. A series of point mutations created within this region,
      encoding L30A, Y32A, H37A, and K38A were shown to give rise to fully functional
      proteins, suggesting that side chains of these individual residues are not
      essential for EF-G function. A sixth mutant, E41A, was found to inefficiently
      rescue growth in a fusAts background, and was also unable to bind ribosomes
      normally in vitro. In contrast E41Q could restore growth at the nonpermissive
      temperature. These results can be explained within the context of a three
      dimensional model for the effector region of EF-G. This model indicates that the
      effector domain contains a negative potential field that may be important for
      ribosome binding.

PMID- 10584075
TI  - Multifunctional enzymes and evolution of biosynthetic pathways: retro-evolution
      by jumps.
AB  - A likely scenario of evolution of biosynthetic pathways is believed to have
      occurred by retro-evolution through recruitment of existing enzymes rather than
      generation of de novo classes. It had been proposed that such retro-evolution
      occurred in steps as a response to depletion of an essential metabolite and
      availability of another related substance in the environment. In this article, I
      argue that because of instability of many such extant intermediates, it is
      unlikely that retro-evolution had occurred in steps. I further propose that such
      evolution in many cases has taken place by jumps, i.e., by recruitment of a
      multifunctional enzyme capable of catalyzing several steps at a time, albeit
      inefficiently. I further speculate that in some cases one primordial multienzyme
      may have catalyzed the whole sequence of reaction of a biosynthetic pathway,
      i.e., the pathway may have evolved by a single leap. Gene duplications and
      further evolution to more efficient enzymes led to extant pathways. Such a
      mechanism predicts that some or all enzymes of a pathway must have descended from
      a common ancestor. Sequence and structural homologies among extant enzymes of a
      biosynthetic pathway have been examined.

PMID- 10584076
TI  - Role of metal ions on the secondary and quaternary structure of alkaline
      phosphatase from bovine intestinal mucosa.
AB  - Alkaline phosphatase (EC 3.1.3.1) from bovine intestinal mucosa (BIAP) is an
      homodimeric metalloenzyme, containing one Mg2+ and two Zn2+ ions in each active
      site. ApoBIAP, prepared using ion-chelating agents, exhibited a dramatic decrease
      of its hydrolase activity, concomittant to conformational changes in its
      quaternary structure. By rate-zonal centrifugation and electrophoresis, we
      demonstrated, for the first time, that the loss of divalent ions leads to some
      monomerization process for a metal-depleted alkaline phosphatase. Divalent ions
      are also involved in the secondary and tertiary structures. Metal-depletion
      induced more exposure of some Trp residues and hydrophobic regions to the solvent
      (as proved by intrinsic and ANS fluorescences). These changes might correspond to
      the disappearance of alpha-helices and/or turns with a concomittant appearance of
      unordered structures and beta-sheets (as probed by FTIR spectroscopy). For BIAP,
      three steps of temperature-induced changes were exhibited, while for apoBIAP,
      only one step was exhibited at 55 degrees C. Our work on BIAP showed two main
      differences with alkaline phosphatase from Escherichia coli. The loss of the
      divalent ions induces protein monomerization and the total recovery of enzyme
      activity by divalent ion addition to apoBIAP was not obtained.

PMID- 10584077
TI  - Medecins sans frontieres: bearing witness.

PMID- 10584078
TI  - Reaching a consensus on irritable bowel syndrome.

PMID- 10584079
TI  - To test or not to test.

PMID- 10584080
TI  - What's in a name?

PMID- 10584081
TI  - Methadone treatment.

PMID- 10584082
TI  - Methadone treatment.

PMID- 10584083
TI  - Methadone treatment.

PMID- 10584084
TI  - Violence in the emergency department: a survey of health care workers.
AB  - BACKGROUND: Violence in the workplace is an ill-defined and underreported concern
      for health care workers. The objectives of this study were to examine perceived
      levels of violence in the emergency department, to obtain health care workers'
      definitions of violence, to determine the effect of violence on health care
      workers and to determine coping mechanisms and potential preventive strategies.
      METHODS: A retrospective written survey of all 163 emergency department employees
      working in 1996 at an urban inner-city tertiary care centre in Vancouver. The
      survey elicited demographic information, personal definition of violence,
      severity of violence, degree of stress as a result of violence and estimate of
      the number of encounters with violence in the workplace in 1996. The authors
      examined the effects of violence on job performance and job satisfaction, and
      reviewed coping and potential preventive strategies. RESULTS: Of the 163 staff,
      106 (65%) completed the survey. A total of 68% (70/103) reported an increased
      frequency of violence over time, and 60% (64/106) reported an increased severity.
      Most of the respondents felt that violence included witnessing verbal abuse (76%)
      and witnessing physical threats or assaults (86%). Sixty respondents (57%) were
      physically assaulted in 1996. Overall, 51 respondents (48%) reported impaired job
      performance for the rest of the shift or the rest of the week after an incident
      of violence. Seventy-seven respondents (73%) were afraid of patients as a result
      of violence, almost half (49%) hid their identities from patients, and 78 (74%)
      had reduced job satisfaction. Over one-fourth of the respondents (27/101) took
      days off because of violence. Of the 18 respondents no longer working in the
      emergency department, 12 (67%) reported that they had left the job at least
      partly owing to violence. Twenty-four-hour security and a workshop on violence
      prevention strategies were felt to be the most useful potential interventions.
      Physical exercise, sleep and the company of family and friends were the most
      frequent coping strategies. INTERPRETATION: Violence in the emergency department
      is frequent and has a substantial effect on staff well-being and job
      satisfaction.

PMID- 10584085
TI  - Response of paramedics to terminally ill patients with cardiac arrest: an ethical
      dilemma.
AB  - BACKGROUND: In an environment characterized by cuts to health care, hospital
      closures, increasing reliance on home care and an aging population, more
      terminally ill patients are choosing to die at home. The authors sought to
      determine the care received by these patients when paramedics were summoned by a
      911 call and to document whether do-not-resuscitate (DNR) requests influenced the
      care given. METHODS: The records of a large urban emergency medical services
      system were reviewed to identify consecutive patients with cardiac arrest over
      the 10-month period November 1996 to August 1997. Data were abstracted from
      paramedics' ambulance call reports according to a standardized template. The
      proportion of these patients described as having a terminal illness was
      determined, as was the proportion of terminally ill patients with a DNR request.
      The resuscitative efforts of paramedics were compared for patients with and
      without a DNR request. RESULTS: Of the 1534 cardiac arrests, 144 (9.4%) involved
      patients described as having a terminal illness. The mean age of the patients was
      72.2 (standard deviation 14.8) years. Paramedics encountered a DNR request in 90
      (62.5%) of these cases. Current regulations governing paramedic practice were not
      followed in 34 (23.6%) of the cases. There was no difference in the likelihood
      that cardiopulmonary resuscitation (CPR) would be initiated between patients with
      and those without a DNR request (73% v. 83%; p = 0.17). In patients for whom CPR
      was initiated, paramedics were much more likely to withhold full advanced cardiac
      life support if there was a DNR request than if there was not (22% v. 68%; p <
      0.001). INTERPRETATION: Paramedics are frequently called to attend terminally ill
      patients with cardiac arrest. Current regulations are a source of conflict
      between the paramedic's duty to treat and the patient's right to limit
      resuscitative efforts at the time of death.

PMID- 10584086
TI  - Temporal changes in the outcomes of acute myocardial infarction in Ontario, 1992
      1996.
AB  - BACKGROUND: There is relatively little information available on recent population
      based trends in the outcomes of patients who have had an acute myocardial
      infarction (AMI). We, therefore, conducted a study of temporal trends in the
      outcomes of AMI patients in Ontario, Canada, between the 1992 and 1996 fiscal
      years. METHODS: 114,618 AMI patients were discharged from hospitals in Ontario
      between Apr. 1, 1992, and Mar. 31, 1997. After specific exclusion criteria were
      applied the final sample of 89,456 patients was divided into 5 cohorts according
      to the fiscal year of discharge. As part of the Ontario Myocardial Infarction
      Database project the linked administrative data pertaining to these patients were
      used to examine cohort characteristics, cardiac procedures used and mortality
      rates for each of the 5 cohorts over time. RESULTS: There was a significant
      increase in the percentage of patients in Ontario receiving coronary angiography,
      percutaneous transluminal coronary angioplasty and coronary artery bypass
      grafting surgery (p < 0.001) after an AMI between 1992 and 1996. In addition, the
      overall 30-day risk-adjusted mortality rate declined from 15.5% in 1992 to 14.0%
      in 1996 (p = 0.001) and the 1-year risk-adjusted mortality rate declined from
      23.7% in 1992 to 22.3% in 1996 (p = 0.017). Virtually all of the improvement
      occurred within 30 days of admission. The absolute decline in 1-year mortality
      rates was significant for patients under the age of 65 (2.3%, 95% confidence
      interval [CI] 1.4% to 3.2%) and for males (1.2%, 95% CI 0.2% to 2.2%); absolute
      declines were not significant for patients 65 years of age or older (0.7%, 95% CI
      -0.6% to 2.0%) and for female patients (-0.1%, 95% CI -1.7% to 1.5%).
      Interestingly, post-infarction coronary angiography and coronary artery bypass
      grafting rates were consistently lower in the older and the female patients
      throughout the study period. INTERPRETATION: There was a modest improvement in
      the short- and long-term survival of patients in Ontario after an AMI between
      1992 and 1996. The Ontario experience suggests that recent advances in AMI
      management have been of more benefit to younger and male AMI patients.

PMID- 10584087
TI  - Abuse of emergency department workers: an inherent career risk or a barometer of
      the evolving health care system?

PMID- 10584088
TI  - Dignified death or legislated resuscitation?

PMID- 10584089
TI  - Drug-drug interactions: how scared should we be?

PMID- 10584090
TI  - Tuberculosis: 11. Nosocomial disease.

PMID- 10584091
TI  - Drug interactions and the statins.
AB  - Drug interactions commonly occur in patients receiving treatment with multiple
      medications. Most interactions remain unrecognized because drugs, in general,
      have a wide margin of safety or because the extent of change in drug levels is
      small when compared with the variation normally seen in clinical therapy. All
      drug interactions have a pharmacokinetic or pharmacodynamic basis and are
      predictable given an understanding of the pharmacology of the drugs involved.
      Drugs most liable to pose problems are those having concentration-dependent
      toxicity within, or close to, the therapeutic range; those with steep dose
      response curves; those having high first-pass metabolism or those with a single,
      inhibitable route of elimination. Knowing which drugs possess these intrinsic
      characteristics, together with a knowledge of hepatic P-450 metabolism and common
      enzyme-inducing and enzyme-inhibiting drugs, can greatly assist physicians in
      predicting interactions that may be clinically relevant. This article reviews the
      pharmacology of drug interactions that can occur with hydroxymethylglutaryl
      coenzyme A (HMG-CoA) reductase inhibitors (statins) to illustrate the scope of
      the problem and the ways in which physicians may manage this important
      therapeutic class of drugs.

PMID- 10584092
TI  - Tennis anyone? The lungs as a new court for systemic therapy.

PMID- 10584093
TI  - Xenotransplantation: an animal future?

PMID- 10584094
TI  - Radiation techniques for the 21st century.

PMID- 10584095
TI  - Intraoperative MRI: a moving magnet.

PMID- 10584096
TI  - Molecular diagnosis of infections in the new millennium.

PMID- 10584097
TI  - Developing a code of conduct for the Web.

PMID- 10584098
TI  - The Chaoulli case: one-tier medicine goes on trial in Quebec.

PMID- 10584099
TI  - Task force seeks solutions for "senior squalor".

PMID- 10584100
TI  - Unique health needs of elderly women being ignored, symposium told.

PMID- 10584101
TI  - The Yukon takes native health a step further at Whitehorse hospital.

PMID- 10584102
TI  - Emergency department evaluation and treatment of the neck and cervical spine
      injuries.
AB  - In the United States, nearly 5 million patients per year require spinal
      immobilization. The emergency physician (EP) must be able to efficiently and
      effectively manage these patients. To do so, the EP must have an understanding of
      cervical spine anatomy, spinal immobilization techniques, specific injury
      patterns, optimal imaging studies, and associated injuries and treatment
      modalities. This article addresses these important issues and discusses other
      challenges in the management of cervical spine injuries.

PMID- 10584103
TI  - Emergency department evaluation and treatment of hand injuries.
AB  - This article focuses on disorders of the hand most commonly presented to the
      practitioner in an emergency setting. An initial review of functional anatomy is
      followed by discussions of the clinical findings and treatment of fractures,
      tendon injuries, infections, nailbed injuries, high-pressure injection injuries,
      and nerve injuries. The information presented in this article provides a basis
      for proper evaluation, diagnosis, and treatment of hand injuries.

PMID- 10584104
TI  - Emergency department evaluation and treatment of wrist injuries.
AB  - This article provides the emergency physician a thorough understanding of the
      basic and surface anatomy required to accurately diagnose wrist injuries in the
      emergency department. Functional and neurologic examinations are discussed in
      detail as they increase precision in diagnosis. Special radiographic studies,
      guided by exam findings, are often crucial in adequately visualizing an otherwise
      occult injury. Radiographic evidence of injury is not present at time of initial
      evaluation in a small but noteworthy percentage of significant injuries. For
      these reasons, the appropriate use of radiographic studies is included. Finally,
      a rationale for performing conservative mobilization and promptly referring a
      suspected occult fracture is provided.

PMID- 10584105
TI  - Emergency department evaluation and treatment of elbow and forearm injuries.
AB  - This article reviews the anatomy of the elbow and discusses several different
      types of elbow fractures and dislocations. A review of forearm anatomy and common
      injuries, trauma, and fractures follows. Methods for treatment and management for
      both elbow and forearm injuries are discussed.

PMID- 10584106
TI  - Emergency department evaluation and treatment of the shoulder and humerus.
AB  - The shoulder girdle is a versatile anatomic structure with a wide range of
      mobility and function. Its soft tissue and skeletal components are subject to a
      variety of injuries spanning from overuse syndromes to acute trauma. This article
      reviews the key historical and physical examination techniques of the shoulder,
      and special attention is paid to proper imaging in the emergency department,
      which aids in the diagnosis of specific disorders. This article also reviews the
      various therapeutic options, including surgery.

PMID- 10584107
TI  - Emergency department evaluation and treatment of back pain.
AB  - Patients with back pain commonly present in the emergency department for
      evaluation and treatment. Because it is a common syndrome with a generally benign
      origin, the examiner may overlook markers of serious disease. This article
      reviews the important historical and physical factors to consider, with an
      emphasis on the red flags of serious disease. This article also reviews the
      management of acute lumbosacral strain, sciatica, and disc herniation, cauda
      equina syndrome and spinal cord compression, and back pain in the patient with a
      history of cancer.

PMID- 10584108
TI  - Emergency department evaluation and treatment of pediatric orthopedic injuries.
AB  - Orthopedic injuries in children are unique in terms of the mechanisms of injury,
      pathophysiology, and healing. This article reviews the pediatric fracture
      patterns and common pediatric injuries or complaints seen in the emergency
      department, with an emphasis on management in the emergency department.
      Additionally, the approach to pediatric cervical spine injuries and child abuse
      will be described as it pertains to the emergency physician.

PMID- 10584109
TI  - [Audit on the quality of medical records in oncology at the Lyon civic hospices].
AB  - OBJECTIVE: Assess the quality of information contained in the medical files of
      patients with cancer pathology. PATIENTS AND METHODS: Eighty medical files from
      patients cared for in the cancerology units of the Lyons civil hospices were
      retrospectively analyzed to determine information quality. Prior to the audit,
      the health care teams established a set of consensus standards to compared with
      observed procedures. After data collection and analysis of the results, observed
      departures from the standards led to propositions for guidelines designed to
      improve points where significant deviations were observed. RESULTS: For certain
      items, the medical files did not always contain the expected data. Significant
      deviations were observed for important data such as postal code of birth, pTNM
      classification, presence of pathology report, codified evaluation of general
      status. CONCLUSION: Management of these patients requires more rigorous record
      keeping and classing of appropriate data. A unique data sheet is proposed for all
      cancer. This should be a computerized sheet with a cancerology reference in each
      medical unit.

PMID- 10584110
TI  - [Pediatric medical emergencies: clinical classification on basis of severity of
      illness, distribution between work days and non-working days].
AB  - OBJECTIVES: Assess one year of activity in a pediatric medical emergency unit of
      a non-university hospital to detail the degree of gravity of patients admitted to
      pediatric wards and the distribution of non-programmed activity between and work
      days and non-work days. METHODS: Prospective classification into 5 degrees of
      emergency of all admitted children and count of non-programmed medical and
      surgical activity. RESULTS: A significantly growing number of consultations for
      minor problems was observed during non-work days. Most hospitalizations were for
      problems of a rather relative emergency nature. CONCLUSION: The creation of a
      "day-hospital" would allow evaluation and/or treatment of a large number of
      pediatric patients without requiring hospitalization. The problem of controlling
      the flow of consultations to the hospital remains a difficult problem. The many
      reasons leading to hospital consultation are poorly assessed. It appears
      indispensable to promote population "education" and development of closer
      physician's office-hospital collaboration.

PMID- 10584111
TI  - [Chemical odor intolerance. 5 cases].
AB  - BACKGROUND: Chemical odor intolerance is a benign, non-specific, generally
      subjective syndrome triggered by inhalation of non-toxic doses of chemical
      compounds or products which had been previously well tolerated. We report five
      characteristic cases and discuss current data. CASE REPORTS: Five patients (3
      women, 2 men; age range 23-52 years) presented the basic criteria of chemical
      odor intolerance: acquired syndrome, non-specific signs (headache, nausea,
      vertigo ...) triggered by the odor of one or more chemical substances. Physical
      examination and exploratory tests were normal. In 3 cases, the course was
      favorable after evicting the causal substances. For the other 2 cases,
      intolerance spread to other compounds. Four of the patients changed their work
      situation because of the chemical odor intolerance. DISCUSSION: The diagnosis is
      clinical. Different pathogenic hypotheses have been put forward in the
      literature: immunological, toxic, neurobiological, psychological, and psychiatric
      mechanisms have been proposed. The mechanism is probably multifactorial but
      psychological factors appear to play an important role either as predisposing or
      triggering factors. CONCLUSION: Due to the social and occupational consequences
      of chemical odor intolerance, better knowledge of its prevalence and mechanism
      would be most helpful in managing these patients.

PMID- 10584112
TI  - [Unrecognized cause of recurrent icterus: idiopathic ductopenia].

PMID- 10584113
TI  - [Behcet disease and corticotherapy].

PMID- 10584114
TI  - [Apropos of Plasmodium falciparum malaria].

PMID- 10584115
TI  - [Neurologic complications of Gougerot-Sjogren syndrome].

PMID- 10584116
TI  - [Risk of breast cancer in women with palpable cysts].

PMID- 10584117
TI  - [Treatment of arterial hypertension in the aged. Comparison of recent national
      and international guidelines. ANAES (National Agency for Health Evaluation)].

PMID- 10584118
TI  - [Hospital care of adolescents after attempted suicide. November 1998].

PMID- 10584119
TI  - [Cutaneous complications after organ transplant].
AB  - FREQUENT DIVERSE COMPLICATIONS: Skin problems in organ recipients mainly result
      from the induced immunosuppression but also from specific adverse effects of
      immunosuppressive drugs. The degree of extension and gravity of the clinical
      manifestations are often proportional to the intensity and/or duration of the
      immunosuppressive therapy. Immunodepression mainly leads to infectious and
      neoplastic complications. INFECTIONS: Viral and fungal infections are the most
      frequently encountered. Herpes simplex and zoster infections require treatment to
      prevent visceral involvement. Human papillomavirus infections occur in 80% of
      patients 5 years after transplantation and can lead to malignant transformation.
      Fungal infections include pityriasis versicolor and often extensive
      dermatophytosis. CANCER: Increased rate of cancer occurs especially in patients
      with viral disease. Skin cancers involving papillomavirus are the most frequent
      cancers observed in transplant recipients, occurring in half of the long-term
      survivors. Squamous cell carcinoma of exposed areas are the most common; they are
      often more aggressive than in non-immunodepressed patients (multiple sites,
      recurrence). Exposure to sun is a proven inducer. There is a 500-fold higher risk
      of Kaposi disease linked to HHV8 virus. This disease can regress simply after
      reducing the immunosuppressive treatment. Other more uncommon tumors such as
      lymphomas, melanomas, sarcomas and Merkel cell tumors also appear to occur at an
      increased rate in transplant recipients. PREVENTION: Most malignant skin tumors
      are the expression of marked immunodepression and their prognosis is improved
      with reduction in immunosuppressive therapy. Prevention requires regular
      dermatology work-ups and counseling about strict protection from sun exposure.

PMID- 10584120
TI  - [Decubitus sores in geriatric medicine. Local and general treatment of pressure
      sores in the aged].
AB  - LOCAL CARE: Local antiseptics and antibiotics must be avoided to preserve the
      local bacterial ecosystem of the wound. If surgical debridement is not possible,
      hypercolloid, alginate or hydrogel dressings should be applied to achieve natural
      autolytic cleansing. The budding and epithelization phases are also treated
      either with oily or humid dressings or more modern hypercellular, hydrocolloid
      and polyurethane film dressings. Other treatments under evaluation include
      physical means (negative pressure, electrical stimulation) or use of recombinant
      growth factors. GENERAL TREATMENT: Surgical repair with flaps or grafts is not
      usually indicated in fragile elderly patients. Special attention must be given to
      all associated diseases (diabetes, heart failure, etc.) as well as protein
      calorie nutrition. The objective is 35 cal/kg/d including 1.25-1.5 g
      protein/kg/d. TREATMENT OF COMPLICATIONS: Wound infection should be suspected in
      case of an inflammatory induration around the wound, fever, or delayed healing.
      Systemic antibiotics are indicated as for cellulitis. The wound is generally
      colonized by germs found on local bacteriological samples. Osteitis should be
      suspected if the wound is in contact with bone. In case of biopsy proven osteitis
      with positive culture, prolonged oral antibiotics are indicated. Tendon
      retractions should benefit from rehabilitation exercises and surgery in case of
      medical failure. Antalgesics may be required, either continuously or when making
      the dressings.

PMID- 10584121
TI  - [Prevention of decubitus scars in the elderly].
AB  - IDENTIFYING RISK: Groups of elderly patients at risk of pressure sores must be
      carefully identified for effective prevention. Recommended risk scales are
      insufficiently used in everyday practice. Preventive measures must be rapidly
      implemented in order to reduce or eliminate factors contributing to the
      development of pressure sores. Risk factors include, among others, prolonged or
      heavy pressure, friction, shearing force, malnutrition, and bowel incontinence.
      POSITION: The position of patients with severe sensorial disorders should be
      changed every 2 or 3 hours. Bed rest should be interrupted as soon as possible,
      using a cushioned chair. Reclining in the strictly lateral position (with
      pressure on the trochanter) must be avoided. A 30 degrees dorsal inclination in
      the lateral position is preferable. The reclining-sitting position with a greater
      than 30 degrees inclination should be avoided as it increases the shearing forces
      applied to the sacrum. The ventral position is inappropriate for the elderly.
      PREVENTION AIDS: Mattresses, mattress covers, cushions and various other aids
      have been developed specifically for the prevention of pressure sores but the
      evaluation and choice of material requires careful assessment using pressure
      sensors. GENERAL MEASURES: Instruments designed to facilitate position changing
      help reduce the risk of friction. The general practice of massage, widely used in
      France, is not based on confirmed arguments of efficacy. On the contrary, certain
      studies would show that such methods can have unfavorable effects. Prevention of
      undernutrition and renutrition cannot be overlooked. Maintaining the patient in a
      dry environment (particularly in case of incontinence) and use of emollients to
      prevent skin drying are recommended. Written prevention protocols for education
      of patients, family, and health care personnel are indispensable.

PMID- 10584122
TI  - [Epidemiology and cost of pressure sores in the aged].
AB  - PREVALENCE: The prevalence of pressure sores reaches 10-20% in hospitalized
      elderly subjects. Higher rates are observed in units providing mid-term nursing.
      Rates recorded in long-term units are inversely lower. The prevalence of pressure
      sores in the elderly population living at home is poorly known. FAVORING FACTORS:
      Very old age is a favoring factor due to associated diseases. Insufficient
      mobility, incontinence, undernutrition, mental disorders, and skin fragility
      increase the risk. All these factors must be taken into consideration when using
      risk scales to adapt preventive measures. NATURAL HISTORY: Pressure sores
      generally develop in the hospital, generally within one week of admission. For
      patients who do not die shortly thereafter, healing is generally achieved within
      3 to 5 months. Pressure sores are a source of pain and infection. They also
      prolong the hospital stay. Overmortality is associated with pressure sores,
      basically resulting from the effect of comorbid states. COST: The economic impact
      of pressure sores is considerable but it is quite difficult to extract the
      individual cost of prevention, or treatment, from the overall cost of care due to
      the associated deficiencies and incapacities. It would be advisable to apply
      evidence-based protocols to reduce the incidence of pressure sores and also
      reduce the economic cost, both in terms of prevention and treatment.

PMID- 10584123
TI  - [Radiotherapy of benign diseases: a pattern of care study in Germany].
AB  - BACKGROUND: Radiation therapy of benign diseases is controversially discussed and
      rarely applied in Anglo-American countries, while in other parts of the world,
      especially Central and East Europe, it is commonly practised for several benign
      disorders. Similar to the European Society of Therapeutic Radiology and Oncology
      survey, a patterns of care study was performed in Germany. METHOD: A
      questionnaire was mailed in 3 years (1994, 1995, 1996) to all radiation
      facilities in Germany, which assessed equipment, indications, number of patients
      and treatment concepts. A total of 134 (88%) institutions returned all requested
      data: 22 in East and 112 in West Germany; 30 in university and 104 in
      community/private hospitals. The average data of each institution and of all
      institutions were analyzed for frequencies and ratios between different regions
      and institutions. RESULTS: A mean of 2 (range 1 to 7) megavoltage (Linac/Cobalt
      60) and 1.4 (range 0 to 4) orthovoltage units were available per institution; 32
      (24%) institutions had no orthovoltage equipment. A mean of 20,082 patients were
      treated per year: 456 (2%) for inflammatory diseases (221 hidradenitis, 78 nail
      bed infection, 23 parotitis, 134 not specified), 12,600 (63%) for degenerative
      diseases (2,711 peritendinitis humeroscapularis, 1,555 epicondylitis humeri,
      1,382 heel spur, 2,434 degenerative osteoarthritis, 4,518 not specified), 927
      (5%) for hypertrophic diseases (146 Dupuytren's contracture, 382 keloids, 155
      Peyronie's disease, 244 not specified), 1,210 (6%) for functional disorders (853
      Graves' orbitopathy, 357 not specified), and 4,889 (24%) for other disorders
      (e.g. 3,680 heterotopic ossification prophylaxis). In univariate analysis, there
      were significant geographical (West vs East Germany) differences in the use of
      radiotherapy for inflammatory and degenerative disorders and institutional
      differences (university vs community/private hospitals) in the use of
      radiotherapy for hypertrophic and functional disorders (p < 0.05). The prescribed
      dose concepts were mostly in the low dose range (< 10 Gy), but varied widely and
      inconsistently within geographic regions and institution types. CONCLUSION:
      Radiotherapy is a well accepted and frequently practised treatment for several
      benign diseases in Germany, however, there are significant geographical and
      institutional differences. As the number of orthovoltage units decreases, an
      increasing patient load is in demand of more megavoltage units, which may
      compromise the cost-effectiveness of this treatment. Only 4% of all clinical
      institutions are involved in controlled clinical trials. To maintain a high level
      of radiotherapy service to other disciplines, radiotherapy treatment guidelines,
      quality control and continuing medical education are required.

PMID- 10584124
TI  - [Postoperative radiotherapy in endometrial carcinoma. A retrospective analysis of
      541 cases].
AB  - PURPOSE: This retrospective study was designed to evaluate the role of adjuvant
      radiotherapy for surgically treated endometrial carcinoma. PATIENTS AND METHODS:
      From 1980 through 1988, 541 patients were treated with either intravaginal cuff
      irradiation with a high-dose-rate (HDR) Iridium-192 remote afterloading technique
      (n = 294) or with combined HDR-brachytherapy and additional external pelvic
      irradiation to 54 Gy (n = 247) after surgery for endometrial cancer. Afterloading
      irradiation was administered in 4 fractions 4 to 6 weeks after surgery. A dose of
      30 Gy was delivered at a depth of 0.5 cm from the vaginal mucosa. RESULTS:
      Patients with HDR-brachytherapy alone showed a 5-year survival of 94.3% for Stage
      I and 73.6% for Stage II (p = 0.0007). Patients who received both brachytherapy
      and additional external pelvic irradiation had a 5-year survival of 94.1% for
      Stage I, 81.1% for Stage II, 70.4% for Stage III and 46.9% for Stage IV (p =
      0.0001). The main predictors for survival in a multivariate analysis were stage
      and grading. Patients with combined radiotherapy had a local recurrence rate of
      3.2%, whereas patients with brachytherapy alone who were better selected and had
      more favorable prognostic factors showed a recurrence rate of 2%. Low-risk
      patients (Stage I, Grade 1, low infiltration) in the HDR-brachytherapy group had
      6 relapses, mainly caused by insufficient treatment on the basis of papillary
      histology. High-risk patients with poorly differentiated tumors, which infiltrate
      more than half the myometrial wall might benefit from additional external
      radiotherapy in terms of reduction of local recurrence and better survival. Five
      year actuarial survival rate was 93.6% after combined radiotherapy vs 86.7% after
      brachytherapy alone. Complications were graded according to the RTOG scoring
      system. Severe late complications were fistulas of bladder and/or bowel, which
      occurred in 2.8% in the combined radiotherapy group, and 0.7% in the HDR
      brachytherapy group. CONCLUSIONS: Low-risk patients should be generally treated
      postoperative with HDR-brachytherapy alone. Combined radiotherapy decreased
      pelvic relapses for high-risk patients with overall low complication rates. We
      conclude that an individually adjusted postoperative radiotherapy allows a well
      tolerated treatment with excellent results.

PMID- 10584125
TI  - Localized prostate cancer in elderly patients. Outcome after radiation therapy
      compared to matched younger patients.
AB  - PURPOSE: To detect a difference in outcome (disease-specific survival, local
      tumor progression, late toxicity, quality of life) after curative radiotherapy
      for localized prostate cancer in elderly as compared to younger patients.
      PATIENTS AND METHODS: In a retrospective analysis 59 elderly patients (> 74 years
      old) were matched 1:2 with younger patients from the data base according to tumor
      stage, grading, pre-treatment PSA values and year of radiotherapy. Surviving
      patients were contacted to fill in a validated questionnaire for quality of life
      measurement (EORTC QLQ-C30). Median follow-up for elderly and younger patients
      was 5.2 and 4.5 years, respectively. RESULTS: Overall survival at 5 years was 66%
      for the elderly and 80% for younger patients. Intercurrent deaths were observed
      more frequently in the elderly population. There was no age-specific difference
      in disease-specific survival (78% vs 82%), late toxicity or quality of life.
      Clinically meaningful local tumor progression was observed in 15% and 14%,
      respectively, corresponding to data from the literature following hormonal
      ablation. CONCLUSIONS: There is no obvious difference in outcome including
      disease-specific survival, late toxicity and quality of life in elderly patients,
      compared to a matched younger population. A clinically meaningful local tumor
      progression following radiotherapy or hormonal ablation only is rare. Local
      radiotherapy or, alternatively, hormonal ablation is recommended to preserve
      local progression-free survival in elderly patients except for very early stage
      of disease (i.e. T1 G1-2 M0).

PMID- 10584126
TI  - [Changes in hemoglobin concentrations in combined radio- and chemotherapy in
      locally advanced ORL tumors].
AB  - BACKGROUND: Despite multimodality treatment strategies of locally advanced head
      and neck cancers long-term results leave much to be desired. There is evidence
      that oxygenation status of head and neck tumors is directly influenced by the
      hemoglobin concentration. The aim of this study was to verify changes in the
      hemoglobin level during combined radio-chemotherapy of locally advanced head and
      neck tumors. PATIENTS AND METHODS: Sixty-eight patients with locally advanced
      head and neck cancer had primary or adjuvant radiotherapy with doses of 60 to 74
      Gy in combination with cisplatin- (+/- 5-FU) or carboplatin chemotherapy in the
      first and fifth week of treatment. Hemoglobin levels were analyzed before and at
      the end of radiotherapy. RESULTS: In 41% of all patients the initial hemoglobin
      concentration was below normal levels. The mean hemoglobin values in all patients
      dropped significantly from 12.9 +/- 1.7 g/dl before to 11.6 +/- 1.6 g/dl at the
      end of treatment. In 12 cases (18%) allogeneic erythrocytes had to be transfused
      during treatment. At the end of treatment 76% of all patients had anemic
      hemoglobin levels. In the groups of patients with cisplatin and carboplatin
      chemotherapy a significant decrease in hemoglobin levels was seen without
      meaningful statistical difference between these 2 groups. CONCLUSIONS: In
      patients with locally advanced head and neck cancer a high initial rate of anemia
      was registered (41%): This rate was nearly doubled during chemoradiation (76%).
      Since several studies have shown a correlation between hemoglobin levels and
      local tumor control, there is evidence, that this group might benefit from
      correcting anemia before combined radio-chemotherapy.

PMID- 10584127
TI  - 13-cis retinoic acid in combination with interferon-alpha enhances radiation
      sensitivity of human squamous cell carcinoma cells of the oral cavity.
AB  - BACKGROUND: Preclinical and clinical trials demonstrated the antiproliferative
      and chemopreventive potential of 13-cis retinoic acid in combination with
      interferon-alpha. The present study was designed to determine the
      radiosensitizing potential of both drugs after single and combined treatment of
      human squamous-cell carcinoma cells of the oral cavity in vitro. MATERIAL AND
      METHODS: The study was performed using the human squamous-cell carcinoma cell
      line SCC4, which was originally established from a tumor of the oral cavity.
      Based on clonogenic assays, the inhibition of clonogenic activity and
      radiosensitizing potential of 13-cis retinoic acid and interferon-alpha after
      single or combined treatment without and with subsequent irradiation was
      determined. RESULTS: 13-cis retinoic acid (10 microM) and interferon-alpha (50
      IU/ml) showed significant inhibition of clonogenic activity after single
      treatment. A combined treatment protocol resulted at least in a highly
      significant additive inhibition of clonogenicity. Treatment with both drugs (5
      microM 13-cis retinoic acid, 25 IU/ml IFN-alpha) prior and post irradiation of
      the cells resulted in a pronounced enhancement of radiation toxicity resulting in
      significantly decreased SF2- and alpha-values. Combined treatment with both drugs
      was significantly more effective than single drug treatment. CONCLUSIONS: The
      data presented indicate that pre- and post-irradiation treatment with 13-cis
      retinoic acid and interferon-alpha significantly enhance the radiosensitivity of
      human squamous-cell carcinoma cells, SCC4, in vitro. Therefore, they support the
      initiation of clinical trials to test the radio-oncological value of such a
      treatment regime for squamous-cell carcinomas.

PMID- 10584128
TI  - [Development and application of dynamic MR imaging in the evaluation of perfusion
      changes in rectal carcinoma during radiotherapy in clinical routine. Preliminary
      results].
AB  - PURPOSE: This study was aimed at measuring microcirculatory parameters and
      contrast medium accumulation within the rectal carcinoma during fractionated
      radiotherapy in the clinical setting. MATERIAL AND METHODS: Perfusion data were
      observed in patients with rectal carcinoma (n = 8) who underwent a pre-operative
      combined chemo/radiotherapy. To acquire perfusion data, an ultrafast T1 mapping
      sequence was carried out on a 1.5-Tesla whole body imager to obtain T1 maps at
      intervals of 14 or 120 seconds. The overall measurement time was 40 minutes. The
      transaxial slice thickness (5 mm) was chosen in such a way that both arterial
      vessels and the tumor could be clearly identified. The gadolinium-DTPA (Gd-DTPA)
      concentration time curve was evaluated for arterial blood and tumor after
      intravenous constant rate infusion. The method allows a spatial resolution of 2 x
      2 x 5 mm and a temporal resolution of 14 seconds. Patients underwent MR imaging
      before and at constant intervals during fractionated radiotherapy. RESULTS:
      Spatial and temporal resolution of dynamic T1 mapping was sufficient to reveal
      varying CM accumulation levels within the tumor and to identify the great
      arteries in the pelvis. In 6 patients Gd-DTPA concentration-time-curves were
      evaluated within the tumor during radiation. Pi index of Gd-DTPA versus radiation
      dose showed a significant increase in the first or second week of treatment, then
      either returned slowly to pretreatment level or a renewed increase was observed.
      The average Pi-value at the beginning was 0.16 (+/- 0.049), reaching highest
      level of 0.23 (+/- 0.058). In all groups the rise from the Pi-value to the Pi
      maximum was statistically significant. The relative increase in perfusion ranged
      between 20 to 83%. CONCLUSION: The results show, that the ultrafast MR-technique
      described above provide a suitable tool for monitoring tumor microcirculation
      during therapeutic interventions and offers the potential for an individualized
      optimization of therapeutic procedures.

PMID- 10584129
TI  - [Contour defects after breast preserving therapy of breast carcinoma. Primary and
      secondary possibilities of correction].
AB  - BACKGROUND: Breast conserving treatment is increasing for primary treatment of
      breast carcinoma because of the importance of the cosmetic outcome. PATIENTS AND
      METHOD: We examined 195 patients after breast conserving therapy which was
      performed between 1983 and 1992. For evaluation of the cosmetic result symmetry,
      contour of the breast and location of the areola were examined. Radiation effect
      on breast tissue was evaluated by the Lent score. 72% of the patients had been
      treated with quadrantectomy and 28% with lumpectomy. RESULTS: Deformities of the
      contour were visible in 59% of the patients depending on the primary location of
      the tumor. Lumpectomy from medial quadrants caused poor results. Dislocation of
      the areola of more than 2 cm was detected in 32% of the patients. The dislocation
      depended on the primary kind of incision and resulted in 89% of the patients
      after a radial incision and only in 11% after curvilinear incisions.
      Telangiectasias were absent in 84% of the patients, the others showed
      telangiectasias Grade 1 to 3. In 48% of the patients no signs of fibrosis could
      be detected, in 49% fibrosis Grade 1 to 2 was found. 68% of the patients
      estimated the cosmetic result as very good or good. Only 10% of the patients
      estimated the result as fair or bad. The examiner estimated the results as good
      or very good in 28%. Examples of operative procedures for primary and secondary
      correction are demonstrated. CONCLUSIONS: Our results showed an adverse effect of
      long radial incisions. For lumpectomy and axillary node dissection separate
      incisions should be used. Correction of contour deformities should be done
      primarily in breast conserving procedures. This is possible by using modified
      reduction mammaplasties, local flaps of the breast tissue or switching a
      latissimus dorsi muscle flap. For secondary correction of defects after breast
      conserving treatment a latissimus dorsi muscle can be used as well as z-plasty
      for scar contracture.

PMID- 10584130
TI  - [Thin-layer spiral CT is superior to MRI in the diagnosis of local extent of
      pancreatic carcinoma].

PMID- 10584131
TI  - [New data on cytoprotection in radiotherapy].

PMID- 10584132
TI  - [Alteration of radiation-induced hematotoxicity by amifostine (ethyol)].
AB  - BACKGROUND: Radiotherapy--even of small volumes--can decrease leukocyte counts.
      We examined whether the radio-protector amifostine can reduce this
      hematotoxicity. PATIENTS AND METHODS: Twenty-six patients (Table 1) undergoing
      radiotherapy for squamous cell carcinoma of the head and neck were evaluated. All
      were given 60 (to 70) Gy 5 x 2 Gy per week in standard radiation techniques.
      Thirteen patients are randomized to receive 200 mg/m2 amifostine i.v., 30 minutes
      before radiation. Blood counts and differentials were determined before, during
      and following radiotherapy. Differences of these parameters are calculated and
      compared by t-test. RESULTS: The blood hemoglobin and the thrombocyte levels did
      not change during the radiotherapy course, neither for the amifostine treated,
      nor the control patients. Similarly the leukocyte counts of amifostine treated
      patients did not change during irradiation. The control patients, however, had a
      decrease of leukocytes from 8.4 to 6.0 x 10(3)/microliter, p = 0.03 (Table 2),
      and the reduction of the neutrophilic granulocyte count was more impressive for
      these patients. CONCLUSION: In this explorative study amifostine diminished
      radiation induced leukocyte toxicity.

PMID- 10584133
TI  - Radioprotection of salivary glands by amifostine in high-dose radioiodine
      treatment. Results of a double-blinded, placebo-controlled study in patients with
      differentiated thyroid cancer.
AB  - BACKGROUND AND PURPOSE: Parenchymal impairment of salivary glands following high
      dose radioiodine treatment is a well-known side effect in general caused by free
      radicals. Therefore, the radioprotective effect of the radical scavenger
      amifostine was evaluated prospectively in patients receiving high-dose
      radioiodine treatment. PATIENTS AND METHODS: Parenchymal function was assessed by
      quantitative salivary gland scintigraphy performed in 50 patients with
      differentiated thyroid cancer prior to and 3 months after high-dose radioiodine
      treatment with either 3 GBq 131I (n = 21) or 6 GBq 131I (n = 29) in a double
      blinded, placebo-controlled study. Twenty-five patients treated with 500 mg/m2
      amifostine intravenously prior to high-dose radioiodine treatment were compared
      to 25 control patients receiving physiological saline solution. Xerostomia was
      graded according to WHO-criteria. RESULTS: In 25 control patients high-dose
      radioiodine treatment significantly (p < 0.001) reduced parenchymal function of
      parotid and submandibular glands by 40.2 +/- 14.1% and 39.9 +/- 15.3%,
      respectively. Nine out of these 25 patients developed Grade I and 2 Grade II
      xerostomia. In contrast, in 25 amifostine-treated patients there was no
      significant (p = 0.691) decrease in parenchymal function following high-dose
      radioiodine treatment, and xerostomia did not occur in any of them. CONCLUSION:
      Parenchymal damage of salivary glands induced by high-dose radioiodine treatment
      can be significantly reduced by amifostine which may improve quality of life of
      patients with differentiated thyroid cancer.

PMID- 10584134
TI  - [Outcome of primary combined radio-chemotherapy in head and neck tumors with
      simultaneous salivary gland protection by amifostine].
AB  - AIM: Demonstration and critical evaluation of the use of cytoprotective agents in
      radiation therapy. PATIENTS AND METHODS: In 1996 9 patients with head and neck
      tumors were irradiated with a mean dose of 66 Gy and simultaneous application of
      amifostine. Primaries were in the oropharynx (3), tongue (2), tonsils (2) as well
      as nasopharynx and soft palate. Parallel carboplatin was administered 6 times
      with a dose of 100 mg/week and amifostine twice a week with 500 mg over 6 weeks.
      The evaluation was performed clinically and by sialoscintigraphy (Figure 1).
      RESULTS: There were no lasting side effects, but episodes of hypotension in 7 of
      9 patients and nausea. Radiogenic acute toxicity was nearly uneffected,
      complaints from xerostomia, however, were diminished. All patients showed
      increased dermal pigmentation and dermatitis. Sialoscintiraphies 6 months after
      therapy proved better salivary gland function with correlated better patient
      condition. CONCLUSION: Amifostine might gain a role in the prevention of lasting
      radiogenic xerostomia. The required dose is not yet clear. A broader use of
      amifostine would be favored by lower costs of the substance.

PMID- 10584135
TI  - [Side effects of postoperative radiochemotherapy with amifostine versus
      radiochemotherapy alone in head and neck tumors. Preliminary results of a
      prospective randomized trial].
AB  - PURPOSE: Experimental and clinical data suggest a reduction of radiation-induced
      acute toxicity by amifostine. We investigated this issue in a randomized trial
      comparing radiochemotherapy (RCT) versus radiochemotherapy and amifostine (RCT +
      A) in patients with head and neck cancer. PATIENTS AND METHODS: Forty-seven
      patients with pharyngeal or laryngeal cancer (T1-2 N1-2 G3, T3-4 N0-2 G1-3) were
      randomized to receive RCT alone (21 patients) or RCT + A (21 patients). Patients
      were irradiated up to 60 Gy (R0) or 70 Gy (R1/2). Chemotherapy consisted of 70
      mg/m2 carboplatin and was administered over 5 days in the 1st and 5th week of the
      radiotherapy course. 250 mg amifostine were applied daily just before each
      radiotherapy session. Acute toxicity was evaluated according to the Common
      Toxicity Criteria (CTC). As for xerostomia no patients with laryngeal cancer were
      assessed because in these cases only small volumes of the salivary glands were
      within the treatment volume. To evaluate the overall toxicity a summarized CTC
      score of all observed side effects was calculated. RESULTS: Forty-two patients
      were evaluable. Clinical characteristics (age, sex, Karnofsky index, tumor
      staging) were well balanced in both treatment groups (Tables 2 and 3). Amifostine
      provided reduction in xerostomia and mucositis (Figures 5 and 6) but had no
      obvious influence on Karnofsky index, body weight, cutaneous side effects and
      alopecia (Figures 1 to 4). CONCLUSIONS: According to our preliminary results
      amifostine has a radioprotective effect on salivary glands. Mucositis can be
      reduced during radiochemotherapy. At this point of patient accrual the difference
      between both groups are statistically not significant. To improve the
      radioprotective effects of amifostine in clinical practice the application of a
      higher dose (> 250 mg) seems to be necessary.

PMID- 10584136
TI  - Supportive use of amifostine in patients with head and neck tumors undergoing
      radio-chemotherapy. Is it possible to limit the duration of the application of
      amifostine?
AB  - BACKGROUND: Amifostine is a new cancer-supporting agent to protect normal tissue
      in patients receiving radio-chemotherapy. The main question of our study is
      whether the application of amifostine can be limited on the duration of
      chemotherapy in patients with advanced head and neck tumors undergoing radio
      chemotherapy. PATIENTS AND METHODS: In a randomized study 14 patients were
      treated with amifostine (500 mg, day 1 to 5 and 29 to 33) during concurrent radio
      chemotherapy with carboplatin (70 mg/m2, day 1 to 5 and 29 to 33), 14 patients
      were treated without amifostine. The analyzed parameters were dermatitis,
      mucositis, skin temperature, white blood and platelet count, creatinine and
      scintigram of salivary glands. Median survival of the amifostine group was 19
      months, of the control group 10 months. RESULTS: There were no relevant
      differences in all analyzed parameters between both arms of the study.
      CONCLUSION: Our form of amifostine application is probably not able to obtain a
      relevant reduction of the toxicity of radio-chemotherapy.

PMID- 10584137
TI  - Amifostine--a radioprotector in locally advanced head and neck tumors.
AB  - PURPOSE: There are some preliminary informations about the beneficial use of
      amifostine in avoiding side effects in patients with head and neck tumors who
      underwent radiotherapy. PATIENTS AND METHOD: Amifostine was given as daily
      intravenous application (500 mg) 10 to 15 minutes prior to radiotherapy in 20
      patients. The results were compared with another collective of patients which was
      similar. RESULTS: According to the WHO score mucositis became manifest in 10
      patients (Grade I) and 4 patients (Grade II) in the amifostine group vs 9
      patients (Grade II), 6 patients (Grade III) and 1 patient (Grade IV) in the
      control group. Xerostomia has been seen in 15 patients (Grade I) and 5 patients
      (Grade II) after administration of amifostine. Without the drug 2 patients
      suffered from xerostomia (Grade I), 8 patients (Grade II) and 8 patients (Grade
      III), respectively. Administering amifostine had been feasible and non
      problematic. Only a small rate of toxic side effects like nausea (11%) or emesis
      (4%) was documented. CONCLUSIONS: Amifostine is an effective radioprotector
      decreasing acute and late side effects in patients with head and neck tumors.

PMID- 10584138
TI  - [Cytoprotection with amifostine in radiotherapy or radio-chemotherapy of head and
      neck tumors].
AB  - BACKGROUND: A considerable amount of experimental and clinical data prove the
      cytoprotective effect of amifostine on normal tissue exposed to different types
      of antineoplastic treatments. The present study examines its influence on the
      short-term toxicity of either radiotherapy alone or combined radio-chemotherapy
      in patients with advanced head and neck cancer. PATIENTS AND METHODS: Twenty
      three patients with advanced head and neck cancer, mainly Stage III and IV, were
      treated with preoperative radiation (n = 1), pre- as well as postoperative
      radiotherapy (n = 5), postoperative radiation (n = 9) or combined postoperative
      radio-chemotherapy (n = 6). Before each radiation application a total dose of 500
      mg amifostine was administered intravenously over 15 minutes. The documentation
      of this unselected patient group was compared retrospectively to a historical
      control group comprising 17 patients. RESULTS: In 15 patients (65%) of the
      amifostine group, therapy induced side effects such as mucositis and dermatitis
      of WHO Grade < or = 2 were detected, requiring interruptions of the radiotherapy
      (mean: 6.5, maximum 17 days). No mucosa or dermatologic toxicity of WHO Grade 3
      or 4 was observed in this group. Significantly more acute toxicity was detected
      in the historical control group. Stomatitis or epitheliolysis of WHO Grade 3
      occurred in 7 patients (41%). The side effects induced by the antineoplastic
      therapy caused an interruption of treatment in 15 patients (88%) (mean: 16,
      maximum 40 days; p = 0.0016). CONCLUSION: The application of amifostine before
      each radiation treatment seems to result in a distinct reduction of short-term
      toxicity of radiotherapy or combined radio-chemotherapy in patients with head and
      neck cancer, allowing for a better adherence to the planned radiation time
      schedule.

PMID- 10584139
TI  - Radioprotection of human endothelial cells with amifostine.
AB  - MATERIALS AND METHODS: We studied the effect of amifostine on radiation
      sensitivity of human endothelial cells and several tumor cell lines (HeLa, MIA
      PaCa-2 and BxPC-3). The cells were incubated in medium with a concentration of 1
      microgram/microliter amifostine and after 1 hour irradiated with 10 or 20 Gy
      single dose. Proliferation index was measured by BrdU assay after another 8 and
      24 hours. RESULTS: The results show a higher proliferation rate of endothelial
      cells following radiation plus amifostine, compared with radiation alone.
      Amifostine induced an increase of proliferation in the control/non-irradiated
      human endothelial cells. After irradiation with 10 Gy single dose the
      proliferation of amifostine treated human endothelial cells was still higher.
      Amifostine exerts no apparent proliferative effect on the tumor cells.
      CONCLUSIONS: The results presented indicate that amifostine acts as an activation
      of proliferation of the human endothelial cells in a simple in-vitro system and
      indicate that amifostine supplementation prior to radiation therapy might exert a
      radioprotective effect to healthy tissue without spurring tumor growth.

PMID- 10584140
TI  - [Cytoprotection with amifostine in the framework of radiochemotherapy in
      previously irradiated head and neck carcinoma].
AB  - PURPOSE: The radiotherapeutic possibilities are limited for patients with a
      recurrent or second head and neck cancer if the patient was already irradiated in
      the first therapy. In the presented study we investigated the changes of this
      situation due to the usage of amifostine in the case of re-irradiation
      (simultaneous radio-chemotherapy). PATIENTS AND METHODS: Between 1995 and 1997 we
      treated 14 patients with a recurrent or second malignancy of the head and neck
      region by a simultaneous radio-chemotherapy (20 x 1.5 Gy, Carboplatin 70 mg/m2
      BSA on days 1 to 5 and 16 to 20, 500 mg amifostine prior to every carboplatin
      infusion). Six out of 14 patients got an additional brachytherapy (10 to 15 Gy)
      to increase the local dose because of a residual tumor. In 4 cases the treatment
      was an adjunctive one, following the surgical tumor debulking. RESULTS: We have
      seen 3 complete remissions (21.4%), and 8 partial remissions (57.1%). The median
      time of observation is 13 months now. Three out of 14 patients died, 2 because of
      the tumor. Hematological toxicities: side effects Grade 2 WHO were seen only in 1
      patient. Acute non-hematological toxicities: mucositis Grade 0/1 in 7 patients,
      mucositis Grade 2 in 7 patients, dysphagia Grade 0/1 in 9 patients, dysphagia
      Grade 2 in 5 patients, xerostomia Grade 1 in 9 patients, xerostomia Grade 2 in 3
      patients. We registrated only 1 serious late toxicity due to radio-chemotherapy:
      4 months after brachytherapy a patient (with laryngectomy) developed a submental
      fistula. CONCLUSION: These first results suggest that the usage of amifostine
      offers new potential ways for re-irradiation of patients with recurrent or second
      malignancies in the head neck region.

PMID- 10584141
TI  - [Pleural cytopathology: diagnosis of primary and metastatic tumors].

PMID- 10584142
TI  - [Bronchoalveolar lavage and alveolar hemorrhage].

PMID- 10584143
TI  - [Vesicular lesions of the thyroid].

PMID- 10584144
TI  - [Inflammatory lesions of the breast].

PMID- 10584145
TI  - [Ovarian puncture: supposed functional cysts].

PMID- 10584146
TI  - [Diagnostic pitfalls in urinary cytology].

PMID- 10584147
TI  - [Diagnosis of pancreatic lesions by fine needle aspiration: present status and
      pitfalls].

PMID- 10584148
TI  - [Role of cytology in the diagnosis of nodular hepatic lesions].

PMID- 10584149
TI  - [Diagnostic pitfalls in CSF cytology].

PMID- 10584150
TI  - [False negatives and quality assurance in cervico-uterine cytology].
AB  - Determining the false negative rate of cervical smear interpretation is an
      important part of quality assessment and a necessary step for any improvement
      program. We report our experience of negative smear rescreening of 522
      histologically proven high-grade lesions or cancers, over a 5 to 7 year preceding
      period. False negative rate was 6.88% as calculated with a narrow definition of
      error, i.e. intra-epithelial lesions and atypical squamous cells of undetermined
      significance. It was 10.78% as calculated with a broad definition of error,
      including minor anomalies such as repair and parakeratosis. Bibliographic data
      account for 0 to 94% false negative diagnoses, owing to great disparities in
      calculating the false negative rate as well as in rescreening. However, a 10%
      traditionally calculated and standardised false negative rate is a reasonable and
      achievable goal in a view of quality improvement. Systematic random rescreening
      of 10% of negative smears is ineffective.

PMID- 10584151
TI  - [Transthoracic aspiration. Evaluation of cytologic and histologic diagnosis in a
      pulmonary nodule by retrospective comparison of 2 series of 267 cytoaspirations
      and 292 coaxial needle aspirations].
AB  - Percutaneous fine-needle aspiration is a well established method for the
      diagnosis of peripheral lung lesion. In order to compare different methods of
      aspiration, we analyze retrospectively two different series: 267 fine needle
      aspirations (FNA) compared with the histological diagnosis on surgical specimens
      and 292 lung biopsies using a coaxial technique with comparison between
      cytological diagnosis--smears and imprints--and histological diagnosis
      simultaneously obtained on the same specimen. The sensitivity (91%), the
      specificity (90%) and the overall typing accuracy related to the histological
      types obtained by FNAB are equivalent to those of the literature. The low rate of
      pneumothorax in the series (6%) is related to the use of immediate interpretation
      of the specimen. Automated biopsy with a coaxial cutting needle provide
      cytological specimens--smears and imprint--with a high rate of sensibility
      (95.3%) and of sensibility (98%). The overall sensitivity of the cytological
      methods alone is better than biopsy (95.3% vs. 92.9%), but the typing accuracy is
      not as good as biopsy alone (98% vs. 100%). False-positive and false-negative
      diagnoses are the same in both series. In conclusion the percutaneous aspiration
      method choose to establish a morphological diagnosis in lung lesion depends now
      on the habits of the radiologist and the pathologist.

PMID- 10584152
TI  - Relationship between genetic anomalies of different levels and deviations in
      dermatoglyphic traits. Part 4: Dermatoglyphic peculiarities of males and females
      with Down syndrome. Family study.
AB  - The present study was carried out in order to evaluate the effect of chromosomal
      morbidity (trisomy 21) in males and females with Down's Syndrome (DS) based on
      dermatoglyphic traits (DT) and their indices of diversity and asymmetry. The
      results were compared between parents and control groups of women and men whose
      data are detailed in our publication (Kobyliansky et al. 1999). The general aim
      of the study was to explore the possibility of using DT of the parents of DS
      patients to predict the likelihood of the disease appearing in the offspring. The
      samples were of DS patients (198 males and 140 females) and their parents (84
      fathers and 153 mothers), all Israeli Jews. The prints were collected in the
      Genetic Institute of the Sheba Hospital, Ramat-Gan, Israel, and were validated by
      chromosomal examination. Interpretation of the prints was done according to
      Cummins & Midlo (1961) and Penrose (1968) and included identification of
      patterns, ridge counts and the measurements of distances and angles in the palm
      of the hands; 79 DT for every individual: 28 continuous traits, 9 discrete
      traits, 11 indices of intraindividual diversity (Div), 15 indices of directional
      asymmetry (DA) and 16 indices of fluctuating asymmetry (FA) were estimated. This
      study supports the hypothesis that the magnitude of FA in groups with low
      developmental stability (groups with chromosomal aberrations) or other birth
      defects, is elevated, compared with FA in healthy controls. The present study
      found proof of the existence of an additive genetic component in the FA of DT,
      while an increased FA was observed in parents of DS patients in comparison to
      control groups. The DT which are typical to DS patients were confirmed also in
      parents. The decrease in sexual dimorphism of the DT was found in DS patients and
      their parents in comparison with the control.

PMID- 10584153
TI  - [The Gepiden of Viminacium during population migration. An anthropological
      contribution].
AB  - The archaeological excavations at the cemetry Vise Grobalja on Viminacium were
      finished in the year 1985. Altogether 94 skeletons which were attributed to the
      Gepiden were examined anthropologically. The graveyard was dated about the middle
      of the 6th century. Of special importance were the 31 artificial deformed skulls.
      The deformation was done with a circular bandaging which is graphically
      illustrated. Farkas (1973), Winkler (1979) and Schroter (1988) identified the
      same type of bandaging on skulls of the ethnic migration period. The
      anthropological examination identified 46 as male and 27 as female skeletons: 16
      were determined as infants and juveniles. About 5 skeletons were indeterminable
      because of their bad state of preservation. There was a deficit of women and
      infants. The average lifespan was less than 33 years. The influence or the
      presence of other anthropological types was not identified. But there should be
      further proof why, for example these groups of Gepiden from Viminacium have
      disappeared relatively rapidly from the historical stage and the Balkan.

PMID- 10584154
TI  - Lower and upper limb length of urban and rural 7-11 years old Turkish school
      children.
AB  - This study was carried out on 779 male and 755 female 7-11 years old children,
      who are students of the primary schools in Diyarbakir city center and center
      connected areas. The average values of lower and upper extremity lengths of
      children in center and rural primary schools have been compared, and the results
      have been analyzed with the Student t-test. The relation between lower and upper
      extremity length averages and height is shown by correlation coefficients. It is
      observed that in the 11 years old boy's group and in the 9 years old girl's group
      of the center primary schools the total arm lengths are longer (p < 0.01). Upper
      and lower extremity lengths are increasing parallel to height. Iliospinal heights
      are obviously longer in the 11 year old group of boys and the 7, 9 and 11 year
      group of girls in the center primary school.

PMID- 10584155
TI  - Pioneering aspects of psychiatry.

PMID- 10584156
TI  - Curriculum renewal in child psychiatry.
AB  - OBJECTIVE: To ensure uniform design and evaluation of a clerkship curriculum for
      child and adolescent psychiatry teaching common disorders and problems in an
      efficient manner across 5 teaching sites and to include structures for continuous
      improvement. METHOD: The curriculum committee selected for course inclusion
      disorders and problems of child psychiatry that were commonly encountered by
      primary care physicians. Instruction methods that encouraged active student
      learning were selected. Course coordination across sites was encouraged by
      several methods: involving faculty, adopting a centralized examination format,
      and aligning teaching methods with examination format. Quantitative and
      qualitative methods were used to measure students' perceptions of the course's
      value. These evaluative results were reviewed, and course modifications were
      implemented and reevaluated. RESULTS: The average adjusted student return rate
      for course evaluation questionnaires for the 3-year study period was 63%. Clerks'
      ratings of course learning value demonstrated that the course improved
      significantly and continually across all sites, according to a Scheffe post-hoc
      analysis. Analysis of student statements from focus-group transcripts contributed
      to course modifications, such as the Brief Focused Interview (BFI). CONCLUSIONS:
      Our curriculum in child psychiatry, which focused on common problems and used
      active learning methods, was viewed as a valuable learning experience by clinical
      clerks. Curriculum coordination across multiple teaching sites was accomplished
      by including faculty in the process and by using specific teaching and
      examination strategies. Structures for continuous course improvement were
      effective.

PMID- 10584157
TI  - Exploring the longitudinal course of psychotic illness: a case-study approach.
AB  - OBJECTIVE: Thirty-three patients with a diagnosis of a psychotic disorder
      (schizophrenia, bipolar disorder, atypical psychosis) according to the Diagnostic
      and Statistical Manual of Mental Disorders (DSM-III-R) were studied to
      qualitatively assess the longitudinal course of the disorder using a case-study
      approach. METHODS: Weekly fluctuations in patient symptomatology and overall
      social and personal functioning using the Global Assessment Scale were assessed
      following index hospitalization. Patients were followed for 1 year. RESULTS: The
      emergent courses showed no relationship to diagnosis but followed 3 general
      trends: 1) positive incline; 2) fluctuating; and 3) stable. Individual
      representations of each course were examined closely, and biological and
      psychosocial factors associated with each were evaluated. CONCLUSIONS: The
      results supported the longitudinal patterns and individual interactions of
      Strauss's Interactive Developmental Model. The clinical course of psychotic
      disorders may be represented by 3 patterns. Key factors in the interaction
      between patient and environment that generate important changes in the evolution
      of each illness were illustrated.

PMID- 10584158
TI  - Retention rates in placebo- and nonplacebo-controlled clinical trials of
      schizophrenia.
AB  - OBJECTIVE: To determine if the inclusion of a placebo control in clinical trials
      of schizophrenia affects retention rates in the first 35 days of inclusion
      relative to trials that did not have a placebo control. METHOD: This was a
      retrospective study of 8 double-blind clinical trials, 5 of which had a placebo
      control while 3 did not. Using survival analysis, retention rates between the
      placebo-controlled trials (PCTs) and the nonplacebo-controlled trials (NPCTs)
      were compared. Screening and percentage improvement on Brief Psychiatric Rating
      Scale and Positive and Negative Syndrome Scale scores were compared. RESULTS:
      Significantly more patients were retained in the 35-day period for NPCTs. Also,
      the PCT group had significantly more psychopathology at screening than did the
      NPCT group. CONCLUSIONS: Differences in retention rates between PCTs and NPCTs
      cannot be uniquely attributed to placebo itself.

PMID- 10584159
TI  - An exploration of the psychometric properties of the French version of the
      Positive and Negative Syndrome Scale.
AB  - The psychometric properties of the French version of the Positive and Negative
      Syndrome Scale (PANSS) were studied in a population of 85 patients diagnosed with
      schizophrenia in accordance with Diagnostic and Statistical Manual of Mental
      Disorders (DSM-III-R) criteria. The results of the study of the properties
      (internal consistency and principal-component analysis) of the initial structure
      with 3 scales (positive, negative, and general psychopathology) led us to
      investigate other factorial structures. We thus isolated a 5-factor structure
      (negative, hostility, positive, disorganization, and anxiety), explaining 54.7%
      of the total variance. The internal consistency of the 5 factors isolated was
      good (0.79, negative factor; 0.71, hostility factor; 0.77, positive factor; 0.66,
      disorganization factor; and 0.61, anxiety factor). The 3-subscale structure of
      the PANSS is discussed.

PMID- 10584160
TI  - [Alcoholic father, adolescent drug abuse and protective factors].
AB  - OBJECTIVES: To compare the children of alcoholic fathers who do not develop
      alcohol or drug problems in adolescence (that is, resilient children) to those
      who do, focusing on characteristics of personality and family. Various
      behavioural traits are examined as resilience factors, as are certain educational
      practices of the parents. METHOD: Resilience factors were studied throughout
      childhood, from age 6 to 12 years. The presence or absence of alcohol or drug
      problems was assessed at the age of 15 or 16 years. RESULTS: Close to 1000
      children of both sexes participated in the study. As expected, paternal
      alcoholism was an important risk factor in the development of substance abuse
      problems in adolescence. The risk, however, diminishes with personality traits
      such as low thrill-seeking behaviour and a propensity for inhibition. These
      traits cannot be considered resilience factors, however, because their effect is
      as present in children of nonalcoholic fathers as in children of alcoholic
      fathers. Parental supervision proves to be a protective influence and was found
      to reduce the risk of substance abuse in children of alcoholic fathers.
      CONCLUSION: These results indicate that, above and beyond personality variables,
      the presence of an alcoholic father constitutes a high risk factor for adolescent
      drug addiction. Nevertheless, parental supervision may attenuate this risk and is
      therefore an important means of intervention.

PMID- 10584161
TI  - Hospital days in risperidone-treated patients.
AB  - OBJECTIVE: To compare inpatient hospital days of a group of "real world"
      schizophrenia-spectrum patients for 3 years prior to and 3 years after
      risperidone initiation. METHOD: This is a retrospective cohort study using a
      mirror-image design of hospital days in 120 patients over a 6-year period.
      Hospital admission and discharge information was obtained from chart review and
      database extraction at 3 outpatient treatment sites. The sample comprised all
      patients attending these clinics who were prescribed risperidone during the first
      year of the drug's release. RESULTS: Patients separated into 3 treatment groups:
      those who were prescribed risperidone for 3 uninterrupted years (N = 35), those
      who interrupted but resumed risperidone use and were prescribed the drug at 3
      years (N = 8), and those who discontinued risperidone during the 3-year follow-up
      period (N = 77). The group continuing risperidone to 3 years demonstrated a
      significant decrease in hospital days after risperidone treatment, in contrast to
      the other 2 groups. The reduction in inpatient days for the total sample was not
      statistically significant. CONCLUSION: In this outpatient clinic sample, the 29%
      of patients who continued on risperidone showed a significant reduction in
      inpatient hospital days, from an average of 17.2 days per year in the 3 years
      before risperidone treatment to an average of 2.1 days per year for the 3 years
      of risperidone treatment.

PMID- 10584162
TI  - The effects of hypnosis on dissociative identity disorder: a reexamination of the
      evidence.
AB  - OBJECTIVE: To examine the possibility that hypnosis has significant iatrogenic
      effects on dissociative identity disorder (DID). METHOD: This paper reexamines
      previously published data that have been interpreted as indicating that hypnosis
      does not exert significant iatrogenic effects on DID. RESULTS: The use of
      hypnosis is associated with differences in DID phenomenology and number of DID
      patients in treatment. CONCLUSION: Hypnosis may have significant iatrogenic
      effects on DID.

PMID- 10584163
TI  - Tardive dyskinesia from risperidone and olanzapine in an alcoholic man.

PMID- 10584164
TI  - Re: Predictors of outcome in electroconvulsive therapy.

PMID- 10584165
TI  - Electroconvulsive therapy, personality structure, and suicide.

PMID- 10584166
TI  - Abnormal clotting and production of factor VIII inhibitor in a patient treated
      with venlafaxine.

PMID- 10584167
TI  - Gender of victims and motivation of filicidal parents: is there a relationship?

PMID- 10584168
TI  - Nefazodone-induced visual disturbances.

PMID- 10584169
TI  - Antidepressants and sexual dysfunction.

PMID- 10584170
TI  - Is olanzapine a mood stabilizer?

PMID- 10584171
TI  - Group treatment of substance abuse for patients with schizophrenia or related
      disorders.

PMID- 10584172
TI  - CT of the brain: how useful is it in general psychiatry?

PMID- 10584173
TI  - Forty years of PRCs--what have we learned?
AB  - What are phase-response curves (PRCs)? How can they be measured? How should they
      be plotted? These questions and many other fascinating facets of PRCs are
      addressed in this review, including research topics in which phase-resetting data
      have provided crucial insights: entrainment, phototransduction, pacemaker
      mechanism, phase markers of the pacemaker, and gauges of oscillator amplitude.
      PRCs have enlightened us and will continue to be a valuable tool in clock
      research.

PMID- 10584174
TI  - Organotypic suprachiasmatic nuclei cultures of adult voles reflect locomotor
      behavior: differences in number of vasopressin cells.
AB  - This study is the first to demonstrate organotypic culturing of adult
      suprachiasmatic nuclei (SCN). This approach was used to obtain organotypic SCN
      cultures from adult vole brain with a previously determined state of behavioral
      circadian rhythmicity. We examined vasopressin (AVP) immunoreactivity in these
      organotypic slice cultures. AVP is one of the major neuropeptides produced by the
      SCN, the main mammalian circadian pacemaker. AVP immunoreactivity in the SCN of
      adult common voles in vivo has been shown to correlate with the variability in
      expression of circadian wheel-running behavior. Here, cultures prepared from
      circadian rhythmic and nonrhythmic voles were processed immunocytochemically for
      AVP. Whereas in all cultures AVP could be observed, AVP immunoreactivity differed
      considerably between vole SCN cultures. SCN cultures from rhythmic voles
      contained significantly lower numbers of AVP immunoreactive (AVPir) cells per
      surface area than cultures from nonrhythmic voles. The correlation between timing
      of behavior and AVP immunoreactivity in vitro is similar to the correlation found
      earlier in vivo. Apparently, such correlation depends on intrinsic AVP regulation
      mechanisms of SCN tissue, and not on neural or hormonal input from the
      environment, as present in intact brain.

PMID- 10584175
TI  - Aging alters properties of the circadian pacemaker controlling the locomotor
      activity rhythm in males of Drosophila nasuta.
AB  - Effects of aging on the circadian rhythm of locomotor activity in males of
      Drosophila nasuta were investigated. The adult life of males was divided in 1-3
      stages according to spontaneous changes in free-running period tau in constant
      darkness (DD): stage 1, days 1-19; stage 2, days 20-36; stage 3, days 37-43.
      Stage 1 was characterized by a bimodal activity pattern with a short light
      induced morning peak and a prolonged evening peak when the flies were entrained
      to light-dark cycles of 12 hours of light, 12 hours of darkness (LD 12:12). The
      morning peak had a phase angle difference psi m (psi, the time from lights on in
      LD 12:12 cycles to the onset of morning peak) of about 0.1 h, while psi e (psi of
      evening peak) was about 9 h at stage 1. The transient morning peak was curtailed
      at the end of stage 1. At stage 2, the psi e was about 10 h, and the activity end
      was delayed by an addition of about 3 h of activity in the scotophase. The
      changes in tau during DD free runs were determined in two groups of flies: flies
      reared in LD 12:12 and flies reared in DD. In both groups, tau increased from
      about 23 h at stage 1 to about 25 h at stage 2. Stage 3 was characterized by
      arrhythmicity associated with highest mean activity level (total number of
      passes/fly/day) in the entrained and both free-running groups. The mean activity
      level increased significantly from stage 1 to stage 3 in all three groups of
      flies.

PMID- 10584176
TI  - Survival of rats undergoing continuous bile drainage depends on maintenance of
      circadian rhythm of bile secretion.
AB  - It is very difficult to collect bile secretions from animals for extended periods
      of time. We compared the use of saline or water as drinking fluids to sustain the
      animals, which were being continuously drained of bile. Complete bile drainage
      was performed in 16 male Wistar rats by surgical intervention. After surgery, 8
      rats were given tap water, and the other 8 were given normal saline for water.
      The rats that received water rapidly lost weight after bile drainage, and all
      died within 8 days after the operation. In contrast, all rats that drank saline
      maintained their body weight and survived 14 days or longer after surgery. Serum
      biochemistry of the rats with water intake on the third day after bile drainage
      revealed hyponatremia, hypochloremia, and acute renal failure resulting in
      hyperkalemia. In contrast, electrolyte balance and renal function were normal in
      the rats with saline intake, and bile was secreted continuously with a circadian
      rhythm. These results clearly demonstrate that saline as drinking water is
      essential to the replacement of lost fluids and loss of electrolytes due to bile
      drainage. Further, saline proved efficacious for sustaining experimental animals
      undergoing continuous bile collection.

PMID- 10584177
TI  - Circadian phase-dependent antinociceptive reaction in mice determined by the hot
      plate test and the tail-flick test after intravenous injection of dalargin-loaded
      nanoparticles.
AB  - Peptides normally do not cross the blood-brain barrier (BBB). Previously, it has
      been shown that the hexapeptide enkephalin analogue dalargin with polysorbate-80
      coated nanoparticles (DAL/NP) can be transported across the BBB and is able to
      exhibit an antinociceptive effect in mice. In the present study, the circadian
      time and dose dependencies of the antinociceptive effect of different dalargin
      preparations were investigated. The active preparation (DAL/NP, 5 mg/kg, 10
      mg/kg), as well as a dalargin solution in phosphate buffered saline (DAL/SOL, 10
      mg/kg) were injected intravenously to groups of 10-12 inbred DBA/2 mice at 12
      different circadian times; mice were synchronized to a light-dark (LD) 12:12
      regimen. The antinociceptive effect was determined 15 minutes postinjection by
      the hot-plate test. Experiments with DAL/NP were repeated using the tail-flick
      test system at two selected times (08:00 and 20:00) to test for dose dependency
      (2.5, 5, 7.5, 10 mg/kg). Hot-plate latencies were rhythmic under baseline and
      after DAL/SOL, with acrophases in the dark phase; DAL/SOL did not influence
      latency time. In contrast, DAL/NP significantly increased reaction time dose
      dependently; the maximal possible effect was rhythmic with the 10 mg/kg
      preparation, with a peak effect in the early light phase. Results were confirmed
      by the tail-flick test. The experiments demonstrate that an enkephalin analogue
      coated with nanoparticles can easily cross the BBB and is able to display a dose-
      and time-dependent antinociceptive effect.

PMID- 10584178
TI  - Biological-time-dependent differences in effect of verapamil on rat aorta and
      influence of endothelium.
AB  - The biological-time-dependent variation in the vasodilator effect of verapamil on
      rat thoracic aorta was assessed in both endothelium-intact and denuded
      preparations. Groups of adult male rats were housed in light from 08:00 to 20:00
      and in darkness from 20:00 to 08:00 and sacrificed at six different times of the
      day (1, 5, 9, 13, 17, and 21 hours after lights on; HALO). Verapamil caused
      concentration-dependent relaxations in both endothelium-intact and denuded aortic
      rings precontracted with phenylephrine (Phe). In endothelium-intact rings,
      neither the AUC nor the EC50 values for verapamil exhibited significant
      biological-time-dependent effects, as determined by one-way analysis of variance
      (ANOVA). In endothelium-denuded rings, AUC values did vary in a statistically
      significant manner according to the biological time of study, while the EC50
      values did not. Endothelium denudation led to an increase in EC50 values at
      almost every time point. Statistically significant interactions between the
      biological time of study and treatment (intact vs. denuded endothelium) in both
      AUC and EC50 values were documented by two-way ANOVA; this indicated differences
      in the clock-time staging of verapamil-induced relaxation in endothelium-denuded
      versus intact aortic rings.

PMID- 10584179
TI  - Assessment of the effects of nocturnal exposure to 50-Hz magnetic fields on the
      human circadian system. A comprehensive study of biochemical variables.
AB  - The proposed laboratory investigation was designed to evaluate the effects of
      acute exposure to both continuous and intermittent magnetic fields (MFs) (50 Hz
      10 microT) on the circadian rhythm of clinical chemistry variables in humans:
      electrolytes (magnesium, calcium, phosphorus, sodium, potassium, and chloride),
      enzymes (amylase, lipase, aldolase, gamma glutamyl-transferase [GGT], lactate
      dehydrogenase [LDH], aspartate aminotransferase [ASAT], and alkaline phosphatase
      [ALP]), lipids (cholesterol, high-density lipoprotein [HDL], apolipoprotein A1
      [ApoA1], and ApoB), proteins (total proteins and albumin), nitrogen substances
      (uric acid, urea, and creatinine), iron, glycemia, and transferrin. Young
      volunteers (32 subjects; 16 exposed and 16 sham exposed) were selected according
      to the screening criteria. Each subject participated in two sessions held within
      a 4-week period. In the first session, one group of volunteers (16 subjects) was
      exposed to a continuous MF and then, in the second session, to an intermittent
      MF. The second group (16 subjects) served as a control for both sessions. At each
      session, blood samples were collected at 3 h intervals from 11:00 to 20:00 and
      hourly from 22:00 to 08:00. The results indicate that both continuous and
      intermittent 50-Hz linearly polarized MFs of 10 microT intensity have no effects
      on the circadian rhythms or on the levels of the variables studied here.

PMID- 10584180
TI  - Is there seasonal periodicity in the prevalence of Helicobacter pylori?
AB  - The objective of the present study was to evaluate seasonal periodicity in the
      prevalence of Helicobacter pylori. A prospective study was performed on 1076
      consecutive patients who were investigated in our hospital over a 3-year span
      because of epigastric complaints. Our findings indicate a significant
      accumulation of positive Helicobacter pylori tests in October. Gastric acidity,
      gender, and age did not influence Helicobacter pylori infection significantly.
      There was no significant correlation between potential seasonal influence on the
      diagnosis of ulcer disease and the seasonal fluctuation of Helicobacter pylori
      infection. The seasonality was confirmed by cosinor analysis for the absolute
      frequencies of H. pylori infections and also for the number of cases positive for
      H. pylori per number of presenting patients per month. A seasonal concept of a
      sensitivity threshold for positive Helicobacter pylori testing is introduced,
      taking into account such factors as immune system, nutrition, and medication
      status.

PMID- 10584181
TI  - Administration-time differences in the pharmacokinetics of gentamicin
      intravenously delivered to human beings.
AB  - Administration-time differences of gentamicin pharmacokinetics were studied by
      crossover design after a single intravenous administration of gentamicin (80 mg)
      to 10 human subjects at 09:00 (morning time) and 22:00 (nighttime). The profiles
      of serum gentamicin concentration showed a significant statistical difference
      between 09:00 and 22:00, suggesting circadian variations of pharmacokinetic
      behaviors. A significant circadian rhythm of pharmacokinetic parameters as a
      function of time of day was noted in human subjects, showing lower total body
      clearance Clt and higher serum area under the curve (AUC) when given at
      nighttime. The half-life t1/2 was shorter in the morning (2.82 h +/- 0.43 h) when
      compared to the nighttime (2.97 h +/- 0.36 h), but the difference was not
      statistically significant. The AUC was significantly greater in the morning (23.4
      +/- 3.84 micrograms-h/mL) than that in the nighttime (26.3 +/- 5.79 micrograms
      h/mL) (p < .05), most likely because the Clt was significantly higher when
      gentamicin was given in the morning (3.51 +/- 0.57 L/h) versus in the nighttime
      (3.18 +/- 0.65 L/h). Although the volume of distribution Vd decreased when given
      at nighttime, it was independent of the dosing time. From this study, there was
      an administration-time difference of gentamicin pharmacokinetics in human beings.
      The optimized dosing regimen of gentamicin can be decided by considering
      circadian rhythm and rest-activity routine so that minimized toxicity and
      effective therapy are established for patients. The current findings also can be
      applied to other drugs with circadian rhythms of pharmacokinetics and narrow
      therapeutic windows in clinical chronotherapeutics.

PMID- 10584182
TI  - New legislation of night and shiftwork in Brazil.

PMID- 10584183
TI  - Anesthetic considerations in pediatric laparoscopic and thoracoscopic surgery.
AB  - Minimally-invasive surgery does not equate with minimally-invasive anesthesia in
      children undergoing laparoscopic and thoracoscopic surgery. Knowledge of the
      associated pathophysiological changes, appropriate monitoring and good planning
      allow the safe provision of anesthesia for children subjected to these otherwise
      advantageous surgical techniques.

PMID- 10584184
TI  - Laparoscopic fundoplication in children--an audit of fifty cases.
AB  - Critical evaluation of new laparoscopic procedures in childhood are essential.
      The aim of this study was to audit fifty laparoscopic fundoplications in
      children. METHOD: Evaluation of the financial implications, hospital stay,
      analgesia requirements, operative morbidity and symptom control was undertaken.
      RESULTS: 50 laparoscopic fundoplications were performed on children (6 months to
      13 years) with a median follow-up period of 31.8 months. The conversion rate to
      an open procedure was 8%. The median length of opiate requirement for opiate
      analgesia was 1 day (range 1-5), post-operative stay 2 days (range 2-15). The
      operative morbidity was 8% (respiratory infection, pneumothorax, two patients,
      oesophageal perforation one patient). The recurrences rate was 6%. Whilst a
      prospective randomised trial is essential to satisfy the requirements of evidence
      based medicine, the results of our review of laparoscopic fundoplication are
      encouraging.

PMID- 10584185
TI  - Nissen fundoplication and Boix-Ochoa antireflux procedure: comparison between two
      surgical techniques in the treatment of gastroesophageal reflux in children.
AB  - Over a period of 19 years an antireflux procedure was performed for
      gastroesophageal reflux in 59 children. Thirty-two patients underwent Nissen
      fundoplication and 27 children underwent the Boix-Ochoa antireflux procedure. Six
      patients died between two and 15 months post surgery of unrelated causes. Follow
      up period from six months to 18 years was available in 45 (85%) of the surviving
      patients. This report summarizes the complications and long-term results with the
      two surgical procedures and their comparisons. The follow-up evaluation included
      parental interview and physical examination. Upper GI series and pH monitoring
      were performed only in children with signs and symptoms of recurrent GER or other
      post-operative complications. At follow-up with a mean period of 8.7 years
      following Nissen fundoplication, 87.5% showed good results without any residual
      symptoms. However, the overall complication rate was as high as 50%. Following
      the Boix-Ochoa antireflux procedure, 17 (81%) children showed excellent results
      while four children had recurrent GER. This occurred in two neurologically
      impaired children and two patients following esophageal atresia repair. No other
      post-operative complications were encountered with the Boix-Ochoa antireflux
      procedure. In our experience, the Boix-Ochoa antireflux procedure should be the
      procedure of choice in the surgical treatment of GER in otherwise normal children
      while the Nissen fundoplication is preferable in neurologically impaired children
      and in patients with GER following esophageal atresia repair.

PMID- 10584186
TI  - Laparoscopy combined with conventional operative techniques.
AB  - In order to establish minimal invasive methods further, it should be guaranteed
      that laparoscopy is not only performed in a few pediatric surgical centers. A
      simple approach to gain experience would be the performance of diagnostic
      laparoscopy. However, benefit could be increased if the surgeon combines the
      minimal invasive laparoscopy to establish the diagnosis with the conventional
      surgical technique to continue. This approach for example applies to complicated
      cases of appendicitis. In a combined procedure, even bowel resections and tumor
      extirpations can be performed with minimal invasion. In twenty-seven cases--11
      appendicectomies, 14 resections of cystic ovarian tumors and 2 resections of
      Meckel's diverticulum--we applied this technique and found no complications so
      far. The surgical method presented is convenient and safe.

PMID- 10584187
TI  - Laparoscopically assisted performance of gastrostomy--a simple, safe and minimal
      invasive technique.
AB  - We developed a new and simple technique for a gastrostomy, which combines the
      benefits of the laparoscopic and open approach: under visual control, the correct
      site at the gastric wall is defined laparoscopically and, via a second trocar,
      the stomach is pulled out onto the abdominal wall to insert a Kasper catheter and
      place the sutures. Evaluated in a rat model, this procedure demonstrates safety
      and surgical feasibility on the grounds of a minimal invasive access. The case
      report of a 1-year-old boy may also prove the clinical benefit.

PMID- 10584188
TI  - Cardiac achalasia in children. Dilatation or surgery?
AB  - Surgical treatment of cardiac achalasia in children is still the main line of
      treatment with a success rate of 70-80%. Balloon dilatation is less widely used
      due to inappropriate size of balloons. The authors report on their experience in
      11 children with cardiac achalasia over the last 7 years using balloon dilatation
      as the treatment of choice, 8 boys and 3 girls with ages ranging from 1.5-14
      years (average 7.5 years) were investigated. One family (brother and sister)
      presented with no glucocorticoid deficiency or other anomalies, one patient had
      mental retardation, the rest had no associated anomalies. All patients presented
      with vomiting, 7 with dysphagia, 6 with loss of weight, 5 with recurrent chest
      infection and 2 with retrosternal pain. Radiological diagnosis was accurate in
      all patients, endoscopy with biopsy were done to confirm diagnosis and exclude
      other pathology, manometry yielded positive results in 4 patients. Dilatation was
      done under general anesthesia with fluoroscopic control, balloons were used over
      a guide wire (balloon sizes were 18-35 mm). Seven patients had 2 sessions and 4
      had 3 sessions with radiological follow-up after the second dilatation. Follow-up
      ranged from 2-7 years: excellent results were achieved in 8 patients (72.7%) with
      disappearance of symptoms and marked radiologic improvement, 2 still have mild
      symptoms with overall success (90.9%), one had mild gastroesophageal reflux,
      controlled medically, and one had mild dysphagia but his status was improved
      compared to that before dilatation. One patient had recurrent dysphagia
      necessitating cardiomyotomy (9.1%). Results were not related to age or sex. The
      authors recommend balloon dilatation in children with cardiac achalasia as the
      treatment of choice or even as the only feasible treatment.

PMID- 10584189
TI  - Are patients with antenatally diagnosed hydronephrosis being over-investigated
      and overtreated?
AB  - BACKGROUND: It is usually recommended that neonates with antenatally diagnosed
      hydronephrosis are put on prophylactic antibiotics and undergo the following
      investigations--ultrasound, MCU and a radio-isotope renogram. OBJECTIVE: To
      question the need for such an extensive protocol in antenatally diagnosed
      hydronephrosis on the basis of an improved understanding of this condition.
      METHODS: Over a 3-year-period, persistent postnatal hydronephrosis was seen in 42
      neonates; in 12 it was bilateral. Antibiotic prophylaxis was stopped in the
      unilateral cases. An MCU was done mainly in the following circumstances:
      bilateral hydronephrosis, dilated ureter(s) or presence of UTI. A renogram was
      avoided if the AP diameter of the renal pelvis was below 15 mm and the calyces
      were not dilated. RESULTS: 1) The AP diameter of the pelvis was recorded in 40
      renal units as follows--< 15 mm--22, 15-20 mm--10, 20-40 mm--6, > 40 mm--2. Both
      the patients in the latter group needed a pyeloplasty--their AP diameter exceeded
      8 cms and an RNS showed depressed function. 2) In those patients who did not
      receive antibiotics or had a MCU, none has had a UTI. 3) Four unilateral
      hydronephrotic kidneys showed a paradoxical supranormal function, ranging from 54
      60%. The contralateral kidney was completely normal on the RNS. CONCLUSION: 1)
      The vast majority of antenatally diagnosed hydronephrosis have a benign course,
      only 2/54 or 3.7% required a pyeloplasty. 2) Invasive investigations like an MCU
      are not necessary in most cases. 3) Routine antibiotic prophylaxis is not
      required in all unilateral cases and in bilateral ones after VUR has been
      excluded.

PMID- 10584190
TI  - Long-term prognosis of renal function in boys treated for posterior urethral
      valves.
AB  - This paper discusses the long-term prognosis of renal function in 84 boys treated
      for posterior urethral valves and followed up for a period ranging from 1-21
      years. Thirty-one of the 84 patients (39.3%) were either adolescents or had
      crossed adolescence and this study highlights the changes through adolescence and
      puberty. Serum creatinine was found to be raised in 53% patients at presentation
      and 22.5% patients eventually progressed to chronic renal failure. Serum
      creatinine value 1 year after appropriate decompression of the urinary tract was
      a more accurate predictor of the eventual renal outcome rather than serum
      creatinine at presentation. Decompensation at puberty was detected in 3 patients
      in this study. The predisposing factors identified were the persistence of gross
      hydroureteronephrosis with voiding dysfunction after treatment in one patient and
      renal parenchymal disease in the other 2 patients. The "risk factors" for
      predicting a poor eventual renal function were persistently raised serum
      creatinine 1 year after decompression by diversion or fulguration, bilateral high
      grade vesicoureteral reflux, persistent severe upper tract dilatation after
      treatment, voiding dysfunction and delayed presentation. This study emphasizes
      the need to diagnose and intervene early, to investigate post-treatment
      persistent upper tract dilatation for vesicoureteral junction obstruction and for
      detrusor dysfunction by a complete urodynamic evaluation and to follow up these
      patients carefully through adolescence and adulthood.

PMID- 10584191
TI  - Is bilateral congenital anorchia genetically determined?
AB  - Bilateral congenital anorchia (BCA) can be defined as complete absence of
      testicular tissue in a patient with male normal phenotype and karyotype. On the
      basis of familial occurrences of BCA a possible genetic aetiology has been
      hypothesised, i.e. mutations of the SRY gene which initiates the genetic cascade
      leading to testis development in mammals. The aim of the study is to assess this
      hypothesis. Eight boys affected by BCA have been studied; a normal monozygotic
      twin of one of the patients, a boy and a girl acted as controls. A normal 46, XY
      karyotype was detected in all patients; 3 had hypoplasia of the scrotum and 2 of
      the penis. Hormonal data were available for 5 patients: Prader's stimulation test
      to HCG showed in all lack of testosterone response, and 4 out of 5 had elevated
      FSH and LH levels. Complete absence of testicular tissue was confirmed in all by
      surgical exploration. DNA was sampled by Jeanpierre modified extraction method
      and amplification by polymerase chain reaction. The expected segment of 750
      basepairs of the SRY gene, included between the two oligonucleotide primers Xes
      10 and Xes 11, was found in all patients. SRY gene is present in our BCA patients
      as well as in normal boys, and therefore BCA does not seem related to an anomaly
      of the opening reading frame sequence of the SRY gene. Nevertheless, familial
      occurrences of BCA continue to suggest a genetic aetiology: further studies must
      therefore evaluate the possibility of punctiform mutations of the SRY gene, by
      direct sequentiation, and exclude abnormalities in the critical region DSS/AHC of
      the X chromosome, recently discovered as one of the loci involved in the
      differentiation of the male gonad.

PMID- 10584192
TI  - Multiple trauma in children patterns of injury--treatment strategy--outcome.
AB  - TOPIC OF THE STUDY: In 1994 more than 50,000 children under 15 years were
      involved in a road accident in Germany. About one third of them received major
      injuries and 431 children died. These data obviously show the importance of
      multiple trauma in children in a developed country. METHODS: Between 1985 and
      1990, 64 multi-traumatized children were evaluated after receiving treatment at
      the Aachen University Hospital. It was possible to evaluate 66% of the patients
      at the follow-up examination after 1 and 5 years. The results have been measured
      with the ALOS (Aachen long-term outcome score) and the GOS (Glasgow outcome
      score) in relation to the degree of trauma. OWN RESULTS: 12.5% died mainly from
      the effects of a cerebral injury. 25% developed different complications. Again
      the effects of craniocerebral trauma determined the long-term outcome. All other
      injuries can be managed by aggressive treatment without major consequences.
      CONCLUSIONS: In multi-traumatized children, craniocerebral trauma is the key
      injury regarding both lethality and long-term outcome. Therefore, prevention is
      of primary importance. Aggressive treatment of thoracic and abdominal trauma can
      usually help to cure completely these injuries. Especially osteosynthetic
      procedures, exerting little strain and performed as appropriate for children,
      have made injuries of the limbs less critical.

PMID- 10584193
TI  - Aicardi syndrome associated with palatal hemangioma.
AB  - An 1-day-old female newborn who had typical clinical features of Aicardi
      syndrome, such as agenesis of the corpus callosum, ocular abnormalities and
      infantile spasm associated with a palatal hemangioma is reported. The intraoral
      mass, which occluded incompletely the oropharynx and right side of the
      nasopharynx, was partially excised under general anesthesia. This is the first
      reported patient with Aicardi syndrome with palatal hemangioma, according to the
      med-line search.

PMID- 10584194
TI  - Barrett's esophagus and chemotherapy, a case report.
AB  - There have been few reports of Barrett's esophagus associated with chemotherapy
      in children. We report the case of a 3-year-old patient diagnosed with acute
      lymphoblastic leukemia who developed Barrett's esophagus after BMF-90
      chemotherapeutic regimen. A stricture appeared as a complication of Barrett's
      metaplasia and Nissen fundoplication was performed. Symptoms improved shortly
      after surgery and regression of Barrett's esophagus was observed 2 years later.
      Children treated with antileukemic chemotherapy may develop Barrett's esophagus
      without previous clinical apparent gastroesophageal reflux. Endoscopic
      surveillance has been advised in these patients. Barrett's esophagus may regress
      after antireflux surgery.

PMID- 10584195
TI  - Massive true thymic hyperplasia.
AB  - A case of massive true thymic hyperplasia in a child of eleven months is
      described. This rare disorder must be included in the differential diagnosis of a
      mediastinal mass in children. Diagnosis and management are discussed and the
      relevant literature is reviewed.

PMID- 10584196
TI  - Congenital lung cyst.
AB  - This case report describes a congenital lung cyst presenting as a brilliantly
      transilluminant mass in the left supraclavicular region. Clinically, it was
      mistakenly thought to be a cervical cystic hygroma with intrathoracic extension.
      X-ray and CT scan of the neck and chest confirmed the diagnosis. The lung cyst
      was treated by surgical excision with excellent results.

PMID- 10584197
TI  - Biliary pseudolithiasis in childhood: a case report.
AB  - Cholelithiasis is uncommon in childhood and usually associated with any
      predisposing factors such as congenital abnormalities of biliary tract, hemolytic
      diseases, TPN administration and diseases of terminal ileum. Recent studies
      demonstrated ceftriaxone inducing reversible precipitations in gallbladder that
      mimic cholelithiasis. This complication is termed "biliary pseudolithiasis" or
      "reversible cholelithiasis". In this paper we describe a patient who developed
      biliary pseudolithiasis after six days of ceftriaxone therapy which completely
      resolved eleven days after the end of the treatment, and discuss the indication
      for cholecystectomy.

PMID- 10584198
TI  - Antenatal diagnosis of biliary atresia (noncorrectable cyst type): a case report.
AB  - At 32 weeks of gestation a cystic mass was identified in the hepatic hilum of a
      fetus by maternal sonography. Laparotomy was performed at 39 days of life after a
      diagnosis of correctable type of biliary atresia (Type I). A cystically dilated
      extrahepatic duct, in which the proximal and distal sides of the common bile duct
      were occluded (Type III with cyst, noncorrectable type), was identified by
      operative cholangiography. A standard Kasai operation was performed, and 1 year
      after operation the patient was doing well and was jaundice-free. From this
      experience in routine maternal sonography, a cystic mass in the hepatic hilum may
      also suggest Type III biliary atresia with a cyst.

PMID- 10584199
TI  - Association of inflammatory pseudotumor of the liver and Papillon-Lefevre
      syndrome--case report.
AB  - A case of hepatic inflammatory pseudotumor mimicking malignancy in a 4-year-old
      girl with the Papillon-Lefevre syndrome (PLS) is reported. Only recently, an
      association between this inherited syndrome and liver abscesses has been found.
      Its possible pathogenesis is discussed and immunologic defects resulting from the
      Papillon-Lefevre syndrome are presented. The development of inflammatory
      pseudotumor of the liver might be caused by immunologic disturbances and
      staphylococcal infection. The picture of the hepatic tumor on imaging in patients
      with PLS should be attributed rather to inflammatory than neoplastic process.

PMID- 10584200
TI  - Epigastric heteropagus: a case report with review of the literature.
AB  - Incomplete conjoined twinning or heteropagus attached at the autosite's
      epigastrium is an extremely rare form of conjoined twinnings. We report a case of
      epigastric parasitic twinning in which the parasite has a well developed lower
      trunk and pelvis with rudimentary lower limbs, and well developed upper
      extremities without shoulder girdles and thoracic cage. The clinical features of
      this rare entity are discussed with a literature review. We emphasize that in
      spite of monstrous appearance, autosite component of epigastric heteropagus can
      be treated successfully with minor surgery. This fact should be kept in mind
      during the intrauterine evaluation of these type of anomalies in order to avoid
      needless terminations.

PMID- 10584201
TI  - An unusual complication of appendicitis in childhood.
AB  - Mesenteric venous thrombosis has not been reported after an appendicectomy in the
      pediatric literature. We report on a special and very unusual complication in a
      girl who presented mesenteric venous thrombosis (MVT) following an appendicectomy
      for gangrenous appendicitis. The early diagnosis of this entity is vital in order
      to start the anticoagulation treatment which could allow preservation of bowel
      viability. The therapy should be continued for a long time to decrease the risk
      of relapse.

PMID- 10584202
TI  - Combined antiviral therapy reduces HIV-1 plasma load and improves CD4 counts but
      does not interfere with ongoing lymphocyte apoptosis.
AB  - The progression of HIV-1 disease appears associated with an unregulated Fas
      mediated apoptosis of lymphocytes that involves the activation of ICE protease
      and ceramide generation and antiviral therapy may not be fully effective in the
      absence of a relevant impact on apoptosis. Six drug-naive HIV-1-infected
      symptomless patients with advanced immunodeficiency were treated with combined
      AZT and ddl for 4 months; plasma HIV-1 RNA levels, the counts of CD4 cells, CD4
      and CD8 apoptotic lymphocytes, Fas-positive cells and ICE-positive cells, and
      intracellular ceramide levels were measured at base-line and after 7, 45 and 120
      days of treatment. There was a prompt reduction in plasma viremia and a secondary
      increase in CD4 counts, but the treatment had no impact on apoptotic CD4 and CD8
      lymphocytes, Fas-positive cells and ICE-positive cells, and on the intracellular
      levels of ceramide. A discrepancy exists between the positive impact of combined
      AZT and ddl treatment on plasma viral load and CD4 counts and the lack of any
      effect on the process of lymphocyte apoptosis. We suggest to use the measurement
      of apoptotic lymphocytes as a surrogate marker to predict, in combination with
      viral load and CD4 counts, a large proportion of the clinical effect of antiviral
      therapy.

PMID- 10584203
TI  - Apoptotic cell death induced by taxol is inhibited by nitric oxide in human
      leukemia HL-60 cells.
AB  - Taxol, an antineoplastic drug, increases the fraction of cells in G2/M phases of
      cell cycle, induces apoptosis of leukemic cells, and activates macrophages to
      produce nitric oxide (NO) in response to interferon-gamma. NO has been found to
      play roles as pro-apoptotic or anti-apoptotic effector molecules. In this study,
      we investigate effects of NO on taxol-induced apoptosis in human myeloid leukemia
      cell, HL-60. Incubation of the cells with taxol for 24 hr induced marked DNA
      fragmentation of HL-60 cells. Treatment of the cells with S-nitrosogluthathione
      (GSNO), a NO-generating agent, protected the cells against taxol-induced
      apoptosis. Cell cycle analysis showed that treatment of the cells with 100 nM
      taxol for 12 hr rendered the cells to be accumulated in G2/M phase, but the
      cotreatment of the cells with taxol and 0.1 mM GSNO decreased the accumulation of
      the cell in G2/M phases, suggesting that NO might interfere entering of taxol
      treated cells into G2/M phases. Deferoxamine or mimosine, which can arrest cells
      mainly at G1/S phases, also decreased taxol-induced apoptosis and reduced the
      number of the taxol-treated cells arresting in G2/M phases. Thus, we conclude
      that a protective effect of NO on taxol-treated cells from apoptosis may be
      partially caused by interfering entering of the taxol-treated cells into G2/M
      phases.

PMID- 10584204
TI  - Protein-A activates membrane bound multicomponent enzyme complex, NADPH oxidase
      in human neutrophils.
AB  - Protein-A, 42KD cell wall glycoprotein of S. aureus Cowan I enhance mononuclear
      and polymorphonuclear cell counts in vivo and possesses antitoxic, antitumor,
      properties. In order to explain the mechanism of its function, the respiratory
      burst phenomenon in cell and cell free system was studied using lucigenin
      dependent chemiluminescence technique. A dose dependent increase in protein A
      mediated generation of superoxide radical was observed in resting and PMA
      stimulated neutrophils. Superoxide dismutase (SOD) was used to confirm the
      production of superoxide radicals (O2-). To understand the mechanism of protein-A
      induced O2- generation; NADPH oxidase activity was measured in cell free system
      using NADPH as a substrate. A significant increase in NADPH oxidase activity was
      observed in the membrane and post-nuclear supernatant fraction of activated human
      neutrophils. Cytosolic fraction showed slight enzyme activation. Protein A (SpA)
      induced NADPH oxidase activation in the membrane fraction was observed even in
      the absence of the substrate NADPH. These data indicate that protein A attenuate
      the NADPH oxidase system to produce O2- radicals.

PMID- 10584205
TI  - Effect of Withania somnifera on cytokine production in normal and
      cyclophosphamide treated mice.
AB  - Administration of an extract from the powdered root of the plant Withania
      somnifera (Family: Solanaceae) enhanced the levels of Interferon gamma (IFN
      gamma) (75.87 pg/ml), Interleukin-2 (IL-2) (14.16 pg/ml) and Granulocyte
      macrophage colony stimulating factor (GM-CSF) (49.22 pg/ml) in normal Balb/c
      mice. The lowered levels of IFN gamma--(30 pg/ml), IL-2 (4.5 pg/ml) and GM-CSF
      (19.12 pg/ml) after treatment with cyclophosphamide (CTX) was reversed by the
      administration of Withania somnifera extract (IFN gamma--74 pg/ml; IL-2 7.5
      pg/ml; GM-CSF 35.47 pg/ml). Withania extract lowered the levels of Tumour
      necrosis factor alpha (TNF alpha) production. Administration of bonemarrow cells
      from donor mice treated with Withania extract increased the spleen nodular
      colonies in irradiated mice (8.33) compared to those treated with normal
      bonemarrow cells (3.03). The number of nodular colonies increased significantly
      when these animals were continued with Withania extract treatment. These results
      indicate the immunopotentiating and myeloprotective effect of Withania somnifera
      as seen from the enhancement of cytokine production and stem cell proliferation
      and its differentiation.

PMID- 10584207
TI  - Pancreatic phospholipase A2 induces bacterial translocation in rats.
AB  - The importance of pancreatic enzymes, particularly phospholipase A2 (PLA2), for
      bacterial translocation, which is considered to be one of the aggravating causes
      of acute pancreatitis, was investigated. Male rats were administered an
      intraperitoneal or intravenous injection of normal saline, PLA2, or amylase. Four
      days later, the mesenteric lymph nodes (MLNs) and portal blood of the animals
      were cultured. None of the animals had a positive portal blood culture. The MLNs
      contained enteric bacteria in 78% of the animals given 50 mg/kg of PLA2
      intraperitoneally. 5 mg/kg of PLA2 intraperitoneally, 50 mg/kg of amylase
      intraperitoneally, or 50 mg/kg of PLA2 intravenously showed positive cultures in
      25%, 20%, and 11%, respectively. None of the animals given intraperitoneal or
      intravenous normal saline had positive cultures of their MLNs. Intraperitoneal
      injection of 25 mg/kg of nafamostat mesilate just before intraperitoneal PLA2 (50
      mg/kg) resulted in a reduction of positive MLNs from 70% to 30%. The cecal
      myeroperoxidase (MPO) activity of animals administered 50 mg/kg of PLA2
      intraperitoneally was significantly higher compared with animals administered
      saline intraperitoneally. These results indicate that intraperitoneal leakage of
      PLA2 plays an important role in bacterial translocation during acute pancreatitis
      and that administration of a protease inhibitor may be effective against the
      bacterial translocation.

PMID- 10584206
TI  - Effect of Schizonepeta tenuifolia extract on mast cell-mediated immediate-type
      hypersensitivity in rats.
AB  - We investigated the effect of an aqueous extract of Schizonepeta tenuifolia
      (STAE) on mast cell-mediated immediate-type hypersensitivity. STAE inhibited
      systemic allergic reaction induced by compound 48/80 in rats dose-dependently.
      STAE also inhibited plasma histamine levels induced by compound 48/80. STAE
      inhibited local allergic reaction activated by anti-dinitrophenyl (DNP) IgE. In
      addition, STAE does-dependently inhibited histamine release from rat peritoneal
      mast cells (RPMC) activated by compound 48/80 or anti-DNP IgE. However, STAE had
      a significant enhancing effect on anti-DNP IgE-induced tumor necrosis factor
      alpha (TNF-alpha) production from RPMC. These results indicate that STAE inhibits
      immediate-type hypersensitivity and suggest that STAE can selectively activate
      the TNF-alpha production from RPMC.

PMID- 10584208
TI  - Soluble HLA class I antigens in chronic hepatitis C: a disease-associated
      manifestation or molecules modulating immunoresponsiveness?
AB  - The occurrence of high levels of soluble human leukocyte class I antigens (sHLA
      I) represents an usual finding during the course of different clinical
      conditions, such as viral infections and autoimmune disorders. On the other hand,
      the well known property of sHLA-I to modulate T cell responsiveness could be
      taken as an advantage to improve long-term allograft acceptance. Recent data have
      pointed out that subjects with chronic hepatitis C virus (HCV) infection exhibit
      high amounts of sHLA-I, a pattern which has also been used for monitoring host
      responsiveness to interferon alpha (IFN-alpha) therapy. However, the lack of
      correlation between lymphocyte infiltration at liver site and disease biological
      activity suggests a potential role for sHLA-I in T cell dysfunction during
      chronic hepatitis C. sHLA-I antigens may, in fact, either interact with T cell
      receptor delivering an inhibitory signal or trigger cytotoxic T lymphocyte
      apoptosis by inducing CD95 ligand expression. Both events seem to favour HCV
      replication and liver tissue damage progression. Alltogether, these findings
      indicate that, besides viral variant generation and HCV core-mediated
      immunosuppression, sHLA-I may contribute to the imbalance of immunoresponsiveness
      during chronic HCV infection.

PMID- 10584209
TI  - Stimulation of mouse macrophage antigen presentation by cocaine.
AB  - Cocaine has been demonstrated to have multiple effects on the immune system.
      Here, we determined the effects of cocaine on macrophage antigen presentation,
      using an in vitro antigen presentation assay after macrophages were treated with
      cocaine both in vitro and in vivo. Our results showed that in vitro treatment of
      macrophages with cocaine significantly enhanced macrophage's ability to present
      ovalbumin (OVA) and the enhancement was also demonstrated in the macrophages of
      cocaine-injected mice. The presentation of an OVA-derived antigenic peptide
      (OVA323-339), however, was not affected. In vitro cocaine treatment neither
      affected antigen uptake nor major histocompatibility complex (MHC) II expression
      and the expression of co-stimulatory molecules B7. These results suggest that
      cocaine may act on an early event in the antigen handling by accessory cells.

PMID- 10584211
TI  - Influence of berberine on T-cell mediated immunity.
AB  - The protoberberine alkaloid berberine is isolated as a main alkaloid from the
      roots and bark of Berberis vulgaris. Berberine strongly inhibited in vitro the
      proliferative response of mouse spleen cells to T-dependent mitogens concanavalin
      A (Con A) and phytochemagglutinin (PHA). Spleen cells obtained from berberine
      treated mice (10 mg/kg/3 days) expressed enhanced proliferative response to both
      mitogens. Berberine was applied to mice at different intervals before or after
      the induction of adjuvant arthritis (AIA) and Candida albicans (C. albicans)
      infection. The application of the alkaloid to new born mice (5 days after birth
      at a dose of 5 mg/kg/3 days) did not change the course of AIA and C. albicans
      infection. Its application at three 10 day intervals (5 mg/kg), starting from the
      5 day after birth increased the joint inflammation in AIA. The host resistance to
      C. albicans infection was not affected, while the delayed type hypersensitivity
      (DTH)-reaction against the pathogen was enhanced. The alkaloid inhibited the
      development of AIA when applied after its onset (10 mg/kg from day +3 to +12
      day). Berberine treatment during the ongoing infection did not influence its
      outcome (from +2 to +10 day).

PMID- 10584210
TI  - Effect of short-term cocaine administration on the immune system of young and old
      C57BL/6 female mice.
AB  - It has been shown that either cocaine or aging alone can alter the immune system.
      Our objective was to study if the immune system of aging mice was more
      susceptible to the effect of cocaine than the immune system of young mice. We
      used a short term (20 days) cocaine daily administration protocol. Cocaine only
      decreased the absolute number of Thy 1+, CD4+, CD8+, IL-2R+, Mac 1+ and B cells,
      in the spleen of old mice. Old untreated mice had a lower number of Thy 1+ cells
      in the thymus, and a higher number of cells expressing IL-2R. Cocaine decreased
      the number of Thy 1+ cells in the thymus of both age groups. Old mice showed a
      lower number of IgA+ plasma cells in the intestinal lamina propria (ILP) than
      young mice. Short term cocaine administration provoked a decrease in the number
      of CD4+ cells in young mice ILP and of CD8+ cells in old mice ILP. Our data
      suggest that cocaine can potentiate the effect of aging on the thymus and on the
      mucosal immune system. Taken together, our findings indicate that aging and
      cocaine can potentiate each other to impairing the host immune system.

PMID- 10584212
TI  - Benzodiazepine receptors and avian macrophage activity: diazepam decreases
      spreading and phagocytosis.
AB  - The complex interrelations between the nervous system and the immune system have
      led to the creation of a new research area denoted neuroimmunology. The effects
      of stress on the immune response have long been observed in chickens. Since
      benzodiazepine receptors are involved in the stress reaction, we proposed to
      assess the importance of these receptors in the activity of chick peritoneal
      macrophages. We used 420 viable embryonated eggs of the commercial Hubbard
      broiler line treated through the chorioallantoid membrane on the 11th day of
      incubation: falsely manipulated (Sham group), with 40% propyleneglycol (PG) in
      simple Ringer solution (Vehicle group), and treated with diazepam (DZ), 8 mg/kg
      (DZ group). After hatching, the chicks were housed in metal rearing cages of the
      "battery" type for 5 weeks. At 36 days of age, 24 chicks from each treated group
      were divided at random into two groups of 12 animals each which were treated with
      DZ (2 mg/kg) or with 40% PPG in an equal volume once a day by the oral route for
      4 days. Peritoneal macrophages were collected and submitted to the spreading an
      phagocytosis tests. Data were analyzed statistically using the SAS software (p <
      0.05). Administration of DZ in ovo did not cause a significant decrease in egg
      hatchability, birth weight or performance parameters during the 5 weeks of
      assessment. However, the rate of macrophage spreading and phagocytosis was
      reduced. When administered at 40 days of age, DZ did not change the spreading
      rate but reduced the phagocytosis rate. There was no interaction between
      treatments. These results indicate that benzodiazepine receptors seem to be
      important for macrophage activity also in birds, as previously observed in
      rodents and primates. Since benzodiazepine receptors are involved in the response
      to stress, it is possible that the effects of stress on avian immunity may be
      mediated in part by these receptors.

PMID- 10584213
TI  - Helicobacter pylori infection and host cell responses.
AB  - It is well known that Helicobacter pylori is able to colonize the gastric mucosa,
      causing a chronic and persistent infection with complications, such as peptic
      ulcer and gastric cancer. This review places emphasis on some epidemiological
      aspects of Helicobacter pylori infection and its mode of transmission. At the
      same time, invasive and non-invasive methods of diagnosis of Helicobacter pylori
      infection are illustrated. More space is devoted to the host response following
      invasion of the stomach. In this respect, the role played by different growth
      factors and polyamines in the course of Helicobacter pylori disease is discussed
      also in relation to the result of eradicating treatment. On the other hand, an
      accurate description of the host immune responses against Helicobacter pylori
      organism and/or their components (e.g. lipopolysaccharides) is reported. Finally,
      since Helicobacter pylori has been classified as a class I carcinogen, current
      researches are focussed on the Helicobacter pylori-induced carcinogenesis.

PMID- 10584214
TI  - The sensitivity of the results of molecular docking to induced fit effects:
      application to thrombin, thermolysin and neuraminidase.
AB  - This paper describes the application of PRO_LEADS to the flexible docking of
      ligands into crystallographically derived enzyme structures that are assumed to
      be rigid. PRO_LEADS uses a Tabu search methodology to perform the flexible search
      and an empirically derived estimate of the binding affinity to drive the docking
      process. The paper tests the extent to which the assumption of a rigid enzyme
      compromises the accuracy of the results. All-pairs docking experiments are
      performed for three enzymes (thrombin, thermolysin and influenza virus
      neuraminidase) based on six or more ligand-enzyme crystal structures for each
      enzyme. In 76% of the cases, PRO_LEADS can successfully identify the correct
      ligand conformation as the lowest energy configuration when the enzyme structure
      is derived from that ligand's crystal structure, but the methodology only docks
      49% of the cases successfully when the ligand is docked against enzyme crystal
      structures derived from other ligands. Small movements in the enzyme structure
      lead to an under-prediction in the energy of the correct binding mode by up to 14
      kJ/mol and in some cases this under-prediction can lead to the native mode not
      being recognised as the lowest energy solution. The type of movements responsible
      for mis-docking are: the movement of sidechains as a result of changes in C alpha
      position; the movement of sidechains without changes in C alpha position; the
      movement of flexible portions of main chains to facilitate the formation of
      hydrogen bonds; and the movement of metal atoms bound to the enzyme active site.
      The work illustrates that the assumption of a rigid active site can lead to
      errors in identification of the correct binding mode and the assessment of
      binding affinity, even for enzymes which show relatively small shift in atomic
      positions from one ligand to the next. A good docking code, such as PRO_LEADS,
      can usually dock successfully if there is induced fit in relatively rigid enzymes
      but there remains the need to develop improved strategies for dealing with enzyme
      flexibility. The work implies that treatments of enzyme flexibility which focus
      only on sidechain rotations will not deal with the critical shifts responsible
      for mis-docking of ligands in thrombin, thermolysin and neuraminidase. The paper
      demonstrates the utility of all pairs docking experiments as a method of
      assessing the effectiveness of docking methodologies in dealing with enzyme
      flexibility.

PMID- 10584215
TI  - Quantitative structure-activity relationships and comparative molecular field
      analysis of TIBO derivatised HIV-1 reverse transcriptase inhibitors.
AB  - Quantitative structure-activity relationships (QSAR) and Comparative Molecular
      Field Analysis (CoMFA) have been applied in order to explain the structural
      requirements of HIV-1 reverse transcriptase (HIV-1 RT) inhibitory activity of
      TIBO derivatives on the MT-4 cells. The best QSAR model is satisfactory in both
      statistical significance and predictive ability. The derived structural
      descriptors indicate the importance of electronic contributions toward the HIV-1
      RT inhibition of this class of compounds. However, it could not reveal any
      hydrophobic influence because of high collinearity between C2 and log P
      variables. In order to cope with steric interaction in the correlation, 3D-QSAR
      was performed using CoMFA. The obtained CoMFA model shows high predictive
      ability, rcv2 = 0.771, and clearly demonstrates its potential in the steric
      feature of the molecules through contour maps, explaining a majority (81.8%) of
      the variance in the data. Consequently, these results can be useful in
      identifying the structural requirements of TIBO derivatives and helpful for
      better understanding the HIV-1 RT inhibition. Eventually, they provide a
      beneficial basis to design new and more potent inhibitors of HIV-1 RT.

PMID- 10584216
TI  - A model for the binding of low molecular weight inhibitors to the active site of
      thrombin.
AB  - This paper describes the construction, validation and application of an active
      site model of the serine protease thrombin. Initial use was made of medium
      resolution X-ray crystallographic structures of thrombin complexed with low
      molecular weight, non-specific inhibitors to create a computationally useable
      active site shell of the enzyme. Molecular mechanics methods were then applied to
      dock known ligands into the active site region in order to derive a model that
      would accurately predict binding conformations. Validation of the modelling
      process was achieved by comparison of the predicted enzyme-bound conformations
      with their known, crystallographic binding conformations. The resultant model was
      used extensively for predictive purposes prior to obtaining confirmatory crystal
      data relating to a ligand possessing a novel and unexpected binding component
      complexed to thrombin. The data served both to confirm the accuracy of the
      binding site model and to provide information for the further refinement of the
      model.

PMID- 10584217
TI  - Hydrogen bonding and dimeric self-association of 2-pyrrolidinone: an ab initio
      study.
AB  - Ab initio calculations on the different associated structures of 2-pyrrolidinone
      with water and with itself were carried out using 3-21G and 6-31G* basis sets at
      the Hartree-Fock level, including electron correlation using second-order Moller
      Plesset perturbation theory. The calculated free energy changes for the
      intermolecular hydrogen bonded dimer and hydrated species indicated that the
      molecular systems with cyclic dimerization and association with two water
      molecules are dominant. The results are compared to the available experimental
      data in the literature.

PMID- 10584218
TI  - Facet diagrams for quantum similarity data.
AB  - The objective of this work is to demonstrate that an appropriate treatment of
      quantum similarity matrices can reveal hidden data grouping related to relevant
      structural features and even to biological properties of interest. Classical
      scaling is used here to extract the information contained in the similarity
      relationships between the elements of a molecular set. Facet theory is invoked to
      relate, in a qualitative way, the spatial regions to structural characteristics
      as well as to properties of interest. Two application examples are discussed: the
      Cramer steroid set and a benzene, toluene and xylene derivatives set.

PMID- 10584219
TI  - Application of multivariate data analysis methods to comparative molecular field
      analysis (CoMFA) data: proton affinities and pKa prediction for nucleic acids
      components.
AB  - Multivariate data analysis methods (Principal Component Analysis (PCA) and
      Partial Least Squares (PLS)) are applied to the analysis of the CoMFA
      (Comparative Molecular Field Analysis) data for several nucleic acids components.
      The data set includes nitrogenated bases, nucleosides, linear nucleotides, 3', 5'
      cyclic nucleotides and oligonucleotides. PCA is applied to study the structure of
      the CoMFA data and to detect possible outliers in the data set. PLS is applied to
      correlate the CoMFA data with either calculated AM1 proton affinities or with
      experimental pKa values. The possibility of making a prediction of pKa values
      directly from 3D structures of the monomers for polynucleotides is also shown.
      The influence of the superposition criteria and of conformational changes along
      the glycosidic bond on the pKa prediction are studied as well.

PMID- 10584220
TI  - Visualisation and integration of G protein-coupled receptor related information
      help the modelling: description and applications of the Viseur program.
AB  - G Protein-Coupled Receptors (GPCRs) constitute a superfamily of receptors that
      forms an important therapeutic target. The number of known GPCR sequences and
      related information increases rapidly. For these reasons, we are developing the
      Viseur program to integrate the available information related to GPCRs. The
      Viseur program allows one to interactively visualise and/or modify the sequences,
      transmembrane areas, alignments, models and results of mutagenesis experiments in
      an integrated environment. This integration increases the ease of modelling
      GPCRs: visualisation and manipulation improvements enable easier databank
      interrogation and interpretation. Unique program features include: (i) automatic
      construction of 'Snake-like' diagrams or hyperlinked GPCR molecular models to
      HTML or VRML and (ii) automatic access to a mutagenesis data server through the
      Internet. The novel algorithms or methods involved are presented, followed by the
      overall complementary features of the program. Finally, we present two
      applications of the program: (i) an automatic construction of GPCR snake-like
      diagrams for the GPCRDB WWW server, and (ii) a preparation of the modelling of
      the 5HT receptor subtypes. The interest of the direct access to mutagenesis
      results through an alignment and a molecular model are discussed. The Viseur
      program, which runs on SGI workstations, is freely available and can be used for
      preparing the modelling of integral membrane proteins or as an alignment editor
      tool.

PMID- 10584221
TI  - Ethics in contemporary medicine and society.

PMID- 10584222
TI  - Adolescent sexuality and teen pregnancy prevention. The National Commission on
      Adolescent Sexual Health.

PMID- 10584223
TI  - Menstrual and premenstrual issues in female military cadets: a unique population
      with significant concerns.
AB  - CONTEXT: There is a strong need to determine what effect, if any, menstruation
      has on the performance of duty as a Cadet at the United States Military Academy
      (USMA) at West Point, and to determine what impact, if any, the USMA environment
      has on the menstrual cycle. STUDY OBJECTIVES: To study menstrual function and
      premenstrual symptoms in a structured, rigorous military environment; determine
      the perceived impact of menstrual and premenstrual symptoms on academic,
      physical, and military activities; and evaluate the difficulties inherent to
      menstruation in a military setting. DESIGN, SETTING, AND PARTICIPANTS: A survey
      about high school menstrual and premenstrual function, and the Premenstrual
      Assessment Form (PAF), were completed by all 158 freshman female Cadets in July
      1991. In May 1992, 83 participants completed a survey assessing menstrual and
      premenstrual symptoms, including interference with activities during the year.
      MAIN OUTCOME MEASURES: Menstrual regularity, premenstrual symptoms, interference
      with activities. RESULTS: Participants reported menstrual patterns and
      premenstrual symptoms in high school similar to other females their age. Most
      (62%) predicted a change in menstruation at the USMA, half were worried that
      physical symptoms would interfere with activities, one-fourth were worried that
      premenstrual symptoms would interfere with activities, and one-fourth were
      worried that obtaining and changing menstrual materials would interfere with
      activities. Almost all respondents (91%) reported changes in menstruation during
      the year, most commonly less regular, less frequent, shorter, lighter, and less
      crampy periods. Menstrual and premenstrual symptoms interfered with physical
      activities (66.2%, 61.4% respectively) more so than academic (50.6%, 45.7%
      respectively) or military activities (39.8%, 47.0% respectively). Female Cadets
      described significant difficulties with changing (62.6%), obtaining (51.8%), and
      disposing of (38.5%) menstrual materials. CONCLUSIONS: The data demonstrate major
      changes in menstrual function in over 90% of female Cadets; a significant
      perceived impact of menstrual and premenstrual symptoms on academic, physical,
      and military activities; and difficulties in obtaining, changing, and disposing
      of menstrual materials in a military setting. These findings have implications
      for females in the military, as well as for young women generally.

PMID- 10584224
TI  - Should gynecologic maturity change the management of cervical cytologic atypia
      during adolescence?
AB  - STUDY OBJECTIVE: To test the hypothesis that atypical cytology (ASCUS) portends
      ominous histologic diagnoses during adolescence. METHODS: The prevalence of
      squamous intraepithelial lesions (SILs) was determined in a racially diverse
      group of thirty-six 14- to 21-year-olds who were undergoing colposcopic
      evaluation of ASCUS cytology. The prevalence of 10 widely accepted risk factors
      for SIL was also qualified. RESULTS: SILs were detected in biopsies obtained from
      20 (56%) of the 36 study subjects. There were 15 (39%) low-grade SILs and 5 (17%)
      high-grade SILs. No single risk factor or combination of risk factors
      distinguished subjects with SIL histology from those with more benign diagnoses.
      CONCLUSION: The hypothesis was supported. More than half (56%) of the adolescents
      we studied with ASCUS cytology had SIL histology. The findings suggest that
      immediate colposcopic evaluation may be prudent for adolescents with ASCUS
      cytology that cannot be attributed to concurrent lower genital tract infections.

PMID- 10584225
TI  - Premenarchal and postmenarchal girls with insulin-dependent diabetes mellitus:
      ovarian and other organ-specific autoantibodies, menstrual cycle.
AB  - STUDY OBJECTIVE: To estimate various organ-specific autoantibodies and detect
      other endocrine autoimmune disorders and menstrual cycle characteristics in girls
      with Type 1 insulin dependent diabetes mellitus (IDDM). DESIGN: Prospective
      cohort study from 1993 to 1998, duration 4.5 years. SETTING: Diabetes & Endocrine
      Clinic of the University Hospital, Motol, Prague. PATIENTS: 53 IDDM girls (group
      A--43 postmenarchal, group B--10 premenarchal), 15.5 +/- 2.5 (8-19) years old,
      6.2 +/- 4.3 years after IDDM onset. MAIN OUTCOME MEASURES: Ovarian autoantibodies
      directed to ooplasm, zona pellucida, membrana granulosa, theca folliculi interna,
      and lutein cells, insulin autoantibodies, thyroid peroxidase and thyroglobulin
      autoantibodies. Menstrual cycle character, endocrine glands disturbance. Diabetes
      control, body mass index, duration of IDDM. RESULTS: Ovarian autoantibodies in at
      least one of the followed structures were found in 67.9% of the IDDM girls. In
      the control group of 21 healthy girls of corresponding age, the positive findings
      in lutein cells were found in only 4.8% of the girls (P < 0.01 versus IDDM
      girls). The lutein cells commonly associated with theca folliculi interna cells
      were the most frequent immunopositive structures in diabetic girls (P < 0.05
      versus another positive ovarian autoimmune structure). Autoantibodies directed to
      ovarian steroid producing cells were frequent in IDDM patients with both
      irregular and normal menstrual cycles. Irregular menstrual cycles were diagnosed
      in 27.9% of IDDM girls, polymenorrhea in half of them, and oligomenorrhea in the
      remainder. Diabetes control in our patients (glycosylated hemoglobin HbA1c in
      postmenarchal girls 10.1 +/- 2.0%) did not differ between those with regular and
      those with irregular menstrual cycles. Over a follow-up period one-third of the
      girls with oligomenorrhea and a long-term noncompliance (HbA1c 13.5%) developed
      secondary amenorrhea. Insulin autoantibodies were found in 67.8%, thyroid
      peroxidase autoantibodies in 12.5%, and thyroglobulin autoantibodies in 10.4% of
      the IDDM girls. Autoimmune thyroiditis was diagnosed in 5 IDDM patients (9.4%);
      hypothyroidism developed in 3 of them. Menstrual cycle was irregular in 4 of the
      5 girls with autoimmune thyroiditis (polymenorrhea in 1, oligomenorrhea in
      another 3 girls). CONCLUSIONS: An increased incidence of various circulating
      autoantibodies may be markedly demonstrated in IDDM girls. Their reproductive
      function might have an important relationship to an evidence of ovarian
      autoantibodies. Menstrual cycle disturbances could be linked to the poor diabetes
      control, to the presence of ovarian and other autoantibodies, and also to other
      autoimmune disease.

PMID- 10584226
TI  - Pediatric and Adolescent Gynecology experience in academic and community OB/GYN
      residency programs in Michigan.
AB  - OBJECTIVES: The purpose of this study is to assess training in Pediatric and
      Adolescent Gynecology (PAG) at the Obstetrics and Gynecology (OB/GYN) resident
      level. SETTING: Two large Michigan programs were studied: a university-based,
      inner-city program, and a suburban, community-based program. Seventy-one
      questionnaires were distributed to the residents, and descriptive and inferential
      analysis of answers to demographic, training, attitude, and knowledge-based
      questions regarding PAG was performed. RESULTS: Sixty-one questionnaires were
      returned, a response rate of 86%. The majority of respondents reported no PAG
      rotations or clinics and recalled limited didactic sessions with only 0-2
      lectures. Ninety-eight percent of university residents and 94% of community
      residents requested more PAG training. Comfort levels about PAG issues were
      assessed on a 5 point scale (1 = low, 5 = high comfort); university residents
      scored 3.7 with pediatric patients and 4.4 with adolescents, and community
      residents scored 4.0 with the pediatric age group and 4.3 with adolescents.
      However, both groups responded with familiarity to knowledge based questions only
      61% of the time. CONCLUSIONS: OB/GYN residents in both academic and community
      programs report little experience and scant training in PAG but express interest
      in obtaining the skills and information needed. It is concerning that residents
      lack the basic knowledge that is required for the routine daily care of this
      patient population. More emphasis needs to be placed on these issues in OB/GYN
      residency training programs.

PMID- 10584227
TI  - A survey of pregnant women's knowledge about sexual abuse.
AB  - STUDY OBJECTIVE: To assess pregnant women's understanding of sexual abuse
      prevalence and perpetrator characteristics. DESIGN: A multiple choice
      questionnaire concerning knowledge about sexual abuse prevalence and an
      understanding of potential perpetrators was presented to patients. Comparisons
      were made based on participant's age, educational status, and personal
      involvement in the care of children. SETTING: Prenatal clinic, Department of
      OB/GYN, James H. Quillen College of Medicine, East Tennessee State University,
      Johnson City, Tennessee. PARTICIPANTS: Patients presenting for new obstetrical
      evaluation (N = 289). MAIN OUTCOME MEASURES: Responses to the questionnaire.
      RESULTS: Less than half of the subjects correctly answered questions about sexual
      abuse prevalence. Only 22% of patients understood the potential youthfulness of
      juvenile sex offenders. Neither age nor child care responsibilities affected
      response. Subjects with greater than 12 years of formal education achieved
      significantly higher scores than those with less education, 59% of respondents
      were interested in more information. CONCLUSION: Pregnant women's knowledge about
      the dangers of sexual abuse was suboptimal in this population. The majority of
      patients were interested in more information.

PMID- 10584228
TI  - Surgery for ovarian masses during childhood and adolescence: a report of 79
      cases.
AB  - STUDY OBJECTIVE: Abdominal pain is a common symptom in female children and
      adolescents that may be caused by appendicitis, other gastrointestinal or
      urological conditions, or gynecological problems. This study evaluates
      retrospectively the preoperative work-up and the operative treatment of ovarian
      masses in young girls at our institution. SETTINGS: The medical records of all
      female patients aged 17 years or less operated on for an ovarian mass in 1971
      1995 at the Tampere University Hospital were reviewed. RESULTS: Seventy-nine
      patients were identified. In the 1970's preoperative sonography was done on only
      15% of the patients. In the 1990's the figure was 65%. Thirty-seven (47%) of all
      operations were emergency procedures; of these, 41% were performed by a
      gynecologist. Seven of the tumors were malignant. Thirty-four patients had a
      benign neoplasm and 26 had functional ovarian cysts. Eight patients were operated
      on for an adnexal torsion and four patients had other adnexal conditions.
      Unilateral salpingo-oophorectomy was performed on 20 patients, unilateral
      oophorectomy on 12 patients, and ovarian resection on 27 patients. An occasional
      appendectomy was performed on 37 patients. CONCLUSIONS: Surgery for benign
      neoplasms and functional lesions seems to be too extensive. This is likely to be
      due to inadequate preoperative work-up and to the fact that many of the
      operations were performed on an emergency basis and by non-gynecologists. A
      gynecological examination with sonography should be included in the diagnostic
      work-up of a young girl's abdominal complaints. With a proper preoperative work
      up adequate treatment, which often consists of expectation, can be chosen for the
      patient and subsequent problems related to fertility and abdominal complaints can
      be avoided.

PMID- 10584229
TI  - In support of emergency contraception.

PMID- 10584231
TI  - Management quandary. Persistent vaginal bleeding at menarche.

PMID- 10584230
TI  - Emergency contraception: is it always justifiable?

PMID- 10584232
TI  - Evaluating and managing acute genital trauma in premenarchal girls.

PMID- 10584233
TI  - [Antiretroviral agent nevirapine: its pharmacological action and potential for
      clinical use].
AB  - Nevirapine (NVP) is a potent noncompetitive inhibitor of the reverse
      transcriptase enzyme, which is necessary for HIV replication. NVP selectively
      inhibits HIV-1 but not HIV-2 and any of the human DNA polymerases. NVP is active
      against ZDV-resistant HIV-1 and synergistic with nonnucleoside reverse
      transcriptase inhibitors. NVP has a favorable pharmacokinetic profile, becomes
      widely distributed throughout body tissues including the central nervous system,
      and is active in the adult at an oral dose of 200 mg administered twice daily
      after a 2 week lead-in dose of 200 mg/day due to its long elimination half life.
      Although the currently used protease inhibitors (PIs) may undergo more rapid
      rates of metabolism because NVP induces CYP3A, No dosage adjustments are required
      when NVP is taken in combination with PIs so far. When administered in triple
      combinations with antiretroviral agents, the antiviral effect of NVP has been
      profound and sustained in HIV-infected patients, particularly in naive patients
      to antiretroviral therapy. Resistance to NVP is rapid when given as monotherapy,
      but this is altered and made less clinically relevant when NVP is administered as
      a triple combination. NVP has a safety profile that does not overlap with other
      antiretroviral therapies, the most common treatment-limiting reaction being rash.
      It seems that NVP would be a very useful option in combination with
      antiretroviral agents.

PMID- 10584234
TI  - [Pharmacological profiles of sildenafil (VIAGRA) in the treatment of erectile
      dysfunction: efficacy and drug interaction with nitrate].
AB  - Penile erection follows relaxation of the corpus cavernosum in which nitric oxide
      (NO) released during sexual stimulation from non-adrenergic non-cholinergic nerve
      endings and from endothelial cells of the corpus cavernosum plays a crucial role.
      Sildenafil (VIAGRA) selectively inhibited phosphodiesterase type 5 (PDE5)
      activity in the human corpus cavernosum and increased cGMP concentrations in the
      rabbit cavernosum in the presence of NO. Sildenafil enhanced the NO-dependent
      relaxation of the isolated human corpus cavernosum and the intracavernosal
      pressure in the anesthetized dog without affecting systemic blood pressure and
      heart rate. In the patients with erectile dysfunction, an orally administered
      sildenafil enhanced the penile rigidity during visual sexual stimulation.
      Sildenafil did not affect the phenylephrine-induced contraction of the isolated
      rabbit aorta, but enhanced the relaxant effect of glyceryl trinitrate. The
      pharmacodynamic interaction with glyceryl trinitrate was also observed in human
      studies where sildenafil potentiated the hypotensive effect of the nitrate. These
      results indicate that sildenafil, which enhances the physiological process of
      penile erection during sexual arousal, is a novel orally effective treatment for
      erectile dysfunction. It should be noted, however, that sildenafil enhanced the
      hypotensive effect of glyceryl trinitrate, as a result of inhibition of PDE5 in
      vascular smooth muscle. Therefore, administration of sildenafil to patients who
      are using nitrates and NO donors is contraindicated.

PMID- 10584235
TI  - [Pharmacological review of tropisetron].
AB  - Tropisetron is used as an anti-emetic agent against chemotherapy-induced nausea
      and vomiting. Tropisetron shows strong 5-HT3 antagonist and weak 5-HT4 antagonist
      activities in vitro. In the various animal models of vomiting including
      chemotherapy- or radiotherapy-induced emesis in the dog and ferret, tropisetron
      is reported to inhibit the emetic episodes. The potent anti-emetic activity of
      oral tropisetron rather than the i.p. administered drug suggests that it can act
      directly from the intestinal lumen as well as from the blood stream after its
      absorption. Moreover, the anti-emetic activity of tropisetron may involve the 5
      HT4-receptor mechanism in addition to the 5-HT3-receptor mechanism. Tropisetron
      has several pharmacological activities other than anti-emesis such as the
      stimulation of the gastric emptying and the inhibition of the diarrhea, visceral
      pain and anxiety. These effects of tropisetron may contribute to the high
      clinical efficacy of tropisetron against chemotherapy-induced emesis.

PMID- 10584236
TI  - [Investigation of the atrial pacemaker site and rate of the dog heart by the
      multi-electrodes mapping system].
AB  - The site of impulse origin in the right atrium is generally considered to be a
      single static locus within the sinoatrial (SA) node. However, it has been
      recognized that the pacemaker site may shift as a consequence of changes in
      physiological and pathological conditions. To determine the role of the atrial
      pacemaker complex including the superior pacemaker site, SA node and inferior
      pacemaker site quantitatively, we investigated atrial rate and the earliest
      activation region (EAR) from the isochronal activation sequence map by 48
      unipolar electrodes and the mapping system. The epicardial activation sequence of
      the right atrium including the SA node region was obtained from the 48
      electrodes, which were fixed to two flexible templates made of soft plastic
      plates. Using the mapping system, we found that (1) the EAR was shifted by the
      sympathetic or parasympathetic neural activity, (2) parasympathetic activity
      predominates over the sympathetic activity not only on heart rate, but also on
      the location of the EAR, and (3) the role of the inward Ca2+ current,
      hyperpolarization inward current and delayed rectifier K+ current, of the
      pacemaker cells distributed in the atrial pacemaker complex is different in the
      dog heart in situ.

PMID- 10584237
TI  - [Effect of liver hydrolysate on hepatic proliferation in regenerating rat liver].
AB  - The effect of liver hydrolysate (LH) derived from bovine liver on rat liver
      regeneration after partial hepatectomy (PH) were investigated. Oral
      administration of LH increased rat liver weight dose-dependently at 24 h after
      PH. Hepatic ornithine decarboxylase (ODC) activity and proliferating cell nuclear
      antigen (PCNA) labeling index were measured in regenerating rat liver as markers
      of cell proliferation. ODC activities at 4 and 24 h after PH were significantly
      increased by LH administration. PCNA labeling index at 24 h after PH were also
      increased by LH administration. These results suggest that LH stimulates liver
      regeneration in partially hepatectomized rats.

PMID- 10584238
TI  - [Merits and demerits of nitric oxide].

PMID- 10584239
TI  - [The importance of headaches in neurology clinics. Study groups of neurologists
      of Aragon].
AB  - OBJECTIVE: To analyze the patients sent to Neurology Clinics for headache and to
      investigate the differences in epidemiology, clinical findings and therapeutics
      as compared with those consulting for other neurological disorders. PATIENTS AND
      METHODS: Eighteen neurologists from all the Outpatient Departments of the
      Community of Aragon Health Service were analysed using a specially designed
      questionnaire for all the patients who attended the Neurology Clinics for the
      first time during a period of three months. RESULTS: Of 3,489 patients assessed,
      25.5% complained of headache. Of these, 70% were women of an average age of 41.2
      +/- 18.8 years. In 42% the consultation was for migraine followed by chronic
      tension headache in 30.1%. Family doctors sent 86.7% of the patients and
      requested complementary tests for 31.1%. Cerebral TAC (12.4%) and EEG (7.6%) were
      the investigations most often requested. Treatment was given to 68.6% of the
      patients with headache. Calcium-antagonists and anti-depressants were the drugs
      most used. CONCLUSIONS: Headache is the commonest cause for consulting a
      neurologist. It affects young adults, with marked predominance of the female sex.
      There are significative differences in clinical attention (fewer complementary
      tests are requested and less follow-up is necessary, although more treatment is
      given) than for other neurology patients.

PMID- 10584240
TI  - [Quantitative and cytomorphometric analysis of glial population in the frontal
      cortex of contralaterally lesioned rats].
AB  - INTRODUCTION: In the last years, the changes in glial cells during different
      alterations in the Central Nervous System have been studied. It is known that
      astrocytes and microglial cells are the glial cells which present the major
      reactivity. OBJECTIVE: The aim of this work was to analyze the glial cell changes
      induced by a lesion. MATERIAL AND METHODS: We studied the quantitative and
      morphometric changes observed in glial cells in the different layers of
      contralateral frontal cortex using micrometric techniques and image analysis.
      RESULTS: In contralateral side to the lesions, we observed an increase in the
      total glial cells in all the cortical layers. The astrocytes only increased their
      number in cortical layer I, but microglia and oligodendrocytes increased in all
      the layers. In the cytomorphometric analysis an increase in the nucleus area of
      astrocytes was observed. CONCLUSION: The glial cell response to the lesions is
      different for astrocytes, microglia and oligodendrocytes but these changes
      affected to all the cortical layers.

PMID- 10584241
TI  - [The characteristics of evoked potentials due to omission of stimuli in a
      sequence of rhythmic auditory tones].
AB  - INTRODUCTION: The detection of absence of a stimulus from a sequence of rhythmic
      stimuli generates potentials which may express different cognitive processes from
      the P300 wave. PATIENTS AND METHODS: In nine healthy subjects we studied the
      differences between the P300 wave obtained by the 'odd ball' paradigm and the
      potentials evoked by random omission of an auditory tone in a rhythmic sequence
      of tones of 1,000 Hz. Stimulation was biaural at a frequency of 0.7 Hz and a
      proportion of stimuli were frequent/infrequent or omitted 3/1. The subjects
      indicated appearance of an infrequent stimulus or its omission by moving a
      finger. The potentials were registered on all the points of the international
      system 10-20. RESULTS: All the subjects evoked potentials P300 and P3o with a
      range of maximum latencies between 212 and 424 ms, without any differences
      between the two conditions being observed. The amplitude of P3o was significantly
      less than that of the P300 for all the electrodes. The topographical distribution
      of both waves, although predominantly in the midline, was more posterior in the
      case of P3o with lateralization to the left parietal region. CONCLUSION: The
      potentials omitted show some differences from the P300 wave and this may be
      derived from the process of estimation and production of a time interval, which
      is essential in detecting omission of a stimulus, and is useful in the study of
      time perception and the generation of internal rhythms.

PMID- 10584242
TI  - [Clinical manifestation and molecular identification of patients with Leber's
      hereditary optic neuropathy in a national reference center for neuro
      ophthalmology in Cuba].
AB  - INTRODUCTION: Leber's hereditary optic neuropathy (LHON) is a mitochondrial
      disorder, confirmed at a molecular level 10 years ago. This had permitted better
      understanding of the condition. Since 1998, the Instituto de Neurologia y
      Neurocirugia has used these techniques for the study of mutations which are
      considered to be the origin of the disorder. PATIENTS AND METHODS: We describe
      the characteristics of 14 cases from 10 families with LHON and the molecular
      confirmation found between 1994 and 1998 in the Instituto de Neurologia
      Neurocirugia de Cuba. We also review the few cases seen in the previous 18 years.
      These were from only two families. They were diagnosed on clinical grounds and in
      view of maternal inheritance. RESULTS AND CONCLUSIONS: In 80% of the families in
      which the presence of primary mutations was investigated there was A117789, and
      in 20% A3460G. The average age of appearance was 28 years. The ages of onset were
      within the limits of 11 years and 48 years. There were 43% women. Two cases were
      considered to be sporadic. The clinical features corresponded to those described
      in such cases, with severe visual defects, central scotomas, very reduced colour
      vision and severely altered visual evoked potentials, with normal diffuse light
      and pattern electroretinograms. An improvement in visual acuity of 0.2 was seen
      in two cases. Microangiopathy, described as characteristic of the early stages of
      this disorder was detected in five cases, in at least one eye. The others had
      different degrees of optic atrophy. Two generations of one complete family, all
      with mutation 3460, were studied. In several families with this mutation
      alterations were found in the colour vision test of Farnsworth Munsell Hue 100
      and also microangiospathy of the retina.

PMID- 10584243
TI  - [Intracranial collections of pus. A review of 100 cases].
AB  - INTRODUCTION: In recent decades, important scientific advances have been made,
      leading to modification of the diagnosis and the treatment of intracranial
      collections of pus (ICP). OBJECTIVES: To analyze the changes in various
      clinicopathological aspects of ICP during the twenty years studied. PATIENTS AND
      METHODS: We present a retrospective analysis of 100 cases of ICP diagnosed
      between 1979 and 1998 in the Hospital General de Galicia. We divided the patients
      into two groups: A (1979-1988) and B (1989-1998), and analyzed the similarities
      and differences between them. RESULTS: In these two decades, there was a
      predominance of men over women (4/1) ENT infections (30/100) and surgical-trauma
      (25/100) were the commonest causes. The diagnosis was established during the week
      the symptoms started in 40% of group A and 58.1% of group B. The most frequent
      site for abscesses was in the frontal lobes (28.5%) and temporal lobes (26.1%)
      and was closely related to the origin of the infection. Culture was positive in
      45% of group A and in 60.3% of group B. The commonest micro-organisms found were
      Streptococcus (38%) and Staphylococcus (26%). More anaerobes were observed in the
      second decade. The most usual surgical treatment was excision (86%). Mortality
      was 33.3% in the first decade and 5.4% in the second. CONCLUSION: Technological
      improvements permit earlier, more reliable radiological and micro-biological
      diagnosis as well as lower morbi-mortality figures for ICP.

PMID- 10584244
TI  - [Reversible dementia in neurology outpatient clinics].
AB  - INTRODUCTION: The dementias are one of the commonest conditions seen in Neurology
      Clinics. Potentially reversible causes are described amongst the various
      aetiologies although there are doubts as to whether the use of indiscriminate
      testing to detect them is worthwhile. OBJECTIVE: In a group of demented persons
      to determine how many had a potentially reversible condition and how many
      improved, in a prospective, descriptive study in a Neurology Outpatient Clinic.
      PATIENTS AND METHODS: Using the Mini-Mental State Examination of Folstein and the
      DSM-III-R criteria for dementia, 121 demented patients were selected. An ordinary
      biochemical study was made (vitamin B12, thyroid hormones), serology (lues) and
      neuroimaging (cerebral CT), and when a potentially reversible condition was
      found, each case was treated. The patients treated were followed-up periodically
      for an average of 9.6 months (range 2 to 24 months). RESULTS: A potentially
      reversible condition was seen in 19.8% of the patients. On prospective evaluation
      only 3.3% had reversible symptoms and in no case were these completely reversed.
      Improvement was seen in conditions of depressive pseudo-dementia. CONCLUSIONS:
      Since some causes of dementia are reversible, the neurologist is obliged to
      investigate and seek these possible aetiologies. This study should be
      individualized according to clinical criteria to improve profitability of the
      complementary tests. Our results suggest that there are doubts as to the
      usefulness of indiscriminate investigation of possible reversible causes of the
      cases of dementia referred to Outpatient neurologists.

PMID- 10584245
TI  - [Early diagnosis of a serious form of Pelizaeus-Merzbacher's disease confirmed by
      molecular analysis of the gene for proto-lipoproteins].
AB  - INTRODUCTION: Pelizaeus-Merzbacher's disease involves extensive demyelination of
      the Central Nervous System. This is due to a defect in the gene for
      proteolipoproteins, found on the X chromosome. It appears early as marked axial
      hypotonia, stridor, nystagmus and anomalous movements of the head, and later as
      variable pyramidal, extrapyramidal and cerebellar involvement. CLINICAL CASE: A
      three year old boy, with no unusual family history, was seen for psychomotor
      retardation. He had marked hypotonia, absence of evidence of social contact,
      inspiratory stridor, nystagmus and horizontal nodding movements of the head. MR
      at 4 months showed absence of supratentorial and infratentorial myelinization.
      Analysis of the gene for proteolipoproteins showed a specific mutation on the
      exon 5 C227Y. At eight and a half years there was persistence of the severe axial
      hypotonia with minimal visual function and social contact was maintained through
      hearing. CONCLUSIONS: It is possible to make an early diagnosis of Pelizaeus
      Merzbacher's disease in the first weeks of life, on the typical clinical picture
      and MR findings of marked extensive hypomyelination, although assessment of
      myelination is difficult at this age. Early diagnosis is very important, since
      molecular analysis of the proteolipoproteins gene permits confirmation of the
      diagnosis, identification of heterozygotes and the establishment of prenatal
      diagnosis.

PMID- 10584246
TI  - [Neuromuscular pathology in a critical pediatric patient].
AB  - OBJECTIVE: To describe and provide diagnosis guidelines for the neuromuscular
      pathology of the pediatric critical patients, manifested as extubation
      difficulty, based in our experience. CLINICAL CASES: A retrospective study has
      been performed on three patients in the Pediatric Intensive Care Unit that were
      diagnosed by using clinical, analytical and electromyographical findings. In the
      three patients the presence of the disorder was suspected due to the extubation
      difficulty and the hypotony. All them received vecuronium as neuromuscular
      blockage while dexamethasone was provided to one of them due to a nodal
      tachycardia. Myopathic causes were discarded in view of the normally of the
      muscular enzymes. The electromyography showed an axonal disorder in all three
      child. Neither lumbar puncture nor muscular biopsy were performed in any of them.
      CONCLUSIONS: The three patients were diagnosed for a drug neuropathy
      (neuromuscular blocked and/or corticotheraphy). There were described another
      causes of the critical patient polyneuropathy in the literature, but we didn't
      find any of them.

PMID- 10584247
TI  - [Late infantile and juvenile form of GM2-gangliosidosis variant B1].
AB  - INTRODUCTION: Variant B1 is a rare form of GM2-gangliosidosis characterized by
      the presence of a mutation in the hexosaminidase A gene (HEXA) leading to a
      defect in the catalytic region of the alpha-subunit of beta-hexosaminidase A
      (alpha beta heterodymer). The mutated Hex A has almost normal activity against
      the natural synthetic substrates (4-methylumbelliferyl-N-acetyl-beta-D
      glucosamine, 4MU-NAG) but is unable to hydrolyse GM2-ganglioside and the
      sulphated synthetic substrates (4MU-NAGS). The first and more frequent mutation
      described in the alpha-subunit gene associated to B1 variant GM2-gangliosidosis
      was a G533-->A transition (DN allele) resulting in Arg178His substitution.
      CLINICAL CASES: Here, we report the clinical, enzymatic and molecular
      characterization in two variant B1 late infantile and juvenile cases. Both cases
      presented regression of mental skills leading to dementia, epilepsy and severe
      motor impairment with dystonic involuntary movements and quadriplegia. In the
      late infantile case (death at 5 years and 8 months), cherry-red spot was also
      present. Enzymatic assays were performed in fibroblasts, leukocytes and serum and
      confirmed the abnormally low beta-hexosaminidase A activity against sulphated
      substrate despite a normal or nearly normal total hexosaminidase activity
      (unsulphated substrates). The patient with the late infantile phenotype was found
      to be compound heterozygote for the DN allele whilst the juvenile form was
      homozygote for that mutation. CONCLUSION: Variant B1 form of GM2-gangliosidosis
      is a rare and heterogeneous condition that must be kept in mind when evaluating
      neurodegenerative disorders associated with speech or gait disturbances,
      dystonia, seizures and pyramidal features.

PMID- 10584248
TI  - [Nerve growth factor: possibilities and limitations of its clinical application].
AB  - INTRODUCTION: The use of neurotrophic factors for the treatment of degenerative
      disorders of the nervous system opens up promising new perspectives. DEVELOPMENT:
      Nerve growth factor (NGF) represents the most known and studied trophic factor,
      which acts on sensory and sympathetic neurons of the peripheral nervous system,
      and on basal forebrain and striatal cholinergic neurons of the central nervous
      system. The specificity and trophic actions of NGF on these neuronal populations
      and its efficacy at preventing neurodegeneration have led to its proposal of
      evaluation in the treatment of neurological diseases such as: Alzheimer's
      disease, diabetic neuropathies and Huntington's diseases. Preclinical and
      clinical studies carried out in animal models and patients with diagnosis of
      these diseases have revealed satisfactory results. The difficulties of the NGF
      central chronic infusion, and the NGF detrimental effects arising from the
      stimulation of other sensitive neuronal population have stimulated active efforts
      for the development of more efficacious delivery strategies. Besides, it has also
      promoted further studies on the relation between the neuropathological stage, the
      dose and the effects of NGF administration. CONCLUSION: The NGF is a potential
      therapeutic agent in the treatment of neurodegenerative diseases.

PMID- 10584249
TI  - [Measurement of the quality of life in stroke survivors].
AB  - OBJECTIVE: The aim of this article is to describe methods of evaluation of the
      quality of life in relation to health after a stroke, methodological
      considerations and criteria for the use of scales. DEVELOPMENT: The terms
      affected person, disability and handicap are defined. We discuss the indices of
      functional evaluation used in the study of strokes: activities of daily life
      (ADL), instrumental activities and the generic health questionnaires used to
      study quality of life. Ideally, these should all be reliable, valid and sensitive
      to change. The profile of the consequences of the illness, the SF-36 and
      Nottingham health questionnaires are valid instruments for evaluation of the
      quality of life of people with strokes. The Barthel index is a reliable, valid
      index for measurement of ADL in patients with strokes. The Rankin scale is used
      to evaluate disability and handicap. The indicia of activity of these instruments
      involve a cultural bias due to their original design. The risk of falls, painful
      shoulders, the presence of dysphagia or of urinary incontinence are specific
      complications of stroke patients. Difficulty in returning to work or driving are
      factors affecting the quality of life after stroke. CONCLUSION: In the follow-up
      survivors with strokes it is necessary to include quality of life instruments for
      measurement of the dimensions of health not covered by ADL indices, especially
      social and emotional functions and functional state.

PMID- 10584250
TI  - [Neurocysticercosis].
AB  - INTRODUCTION: This paper review current literature about neurocysticercosis with
      emphasis on recent advances on diagnosis and therapy. DEVELOPMENT: Cysticercosis
      is the most common parasitic disease of the nervous system. The disease occurs
      when humans become the intermediate host in the life cycle of Taenia solium by
      ingesting its eggs from contaminated food. Endemic in developing countries of
      Latin America, Asia and Africa, massive immigration of people to industrialized
      nations caused a recent increase in the number of patients with cysticercosis in
      the United States of America and in some European countries. Neurocysticercosis
      is a pleomorphic disease due to individual differences in the number, size, and
      location of the parasites within the nervous system as well as to differences in
      the severity of the host's immune reaction against the parasite. Epilepsy, focal
      neurological signs, and intracranial hypertension are the most common clinical
      manifestations of neurocysticercosis. Since the diagnosis is not possible on
      clinical grounds, it is necessary the practice of complementary exams in every
      suspected case. Neuroimaging studies (CT or MRI) usually permit the diagnosis as
      they show objective evidence of the parasites and the inflammatory changes
      induced in the surrounding nervous tissue. Immunological tests developed to
      detect anticysticercal antibodies in serum or CSF present many problems inherent
      to the lack of specificity or sensibility; therefore, they should not be used by
      themselves to confirm or exclude the disease. Two drugs, albendazole and
      praziquantel, have been used with success to destroy most intracranial parasites;
      however, surgery still play a role in the management of some forms of the
      disease, particularly hydrocephalus and intraventricular cysts. CONCLUSIONS:
      Development of modern diagnostic tests and introduction of potent cestocidal
      drugs have increased our knowledge on neurocysticercosis and have improved its
      prognosis. Nevertheless, some patients still have torpid clinical courses despite
      proper therapy.

PMID- 10584251
TI  - [Epilepsy in the Spanish Renaissance. The work of Perez Cascales of Alcala].
AB  - INTRODUCTION: During the Renaissance, the University of Alcala de Henares
      represented the most best of Spanish medical humanism. A return to the classics
      after mediaeval religious obscurantism meant a 'modern' spirit of reconsideration
      of the major neurological disorders. DEVELOPMENT: In 1611 Francisco Perez
      Cascales, trained at this university, wrote the first great Spanish treatise on
      paediatrics, Liber de affectionibus puerorum, which included a long chapter on
      epilepsy (alferecia). The author, considered to be a 'Hippocratic galenist'
      critically reviewed, with data from empirical observations, the Greek theory of
      humours. Following the Galenic tradition, he distinguished three types of
      epilepsy: primary or originating in the brain, and by 'consensus' (originating in
      another region but with secondary cerebral involvement) either of the stomach or
      other parts of the body. CONCLUSION: The work of Perez Cascales is one of the
      most complete contributions to the under understanding of epilepsy at his time.

PMID- 10584252
TI  - [Neurology and Internet].
AB  - The internet currently offers a powerful, but underused, substructure for fluid
      contact between neurologists all over the world. For improved exploitation of
      these resources, Thematic Virtual Communities are necessary to organize the
      information and to make available the tools which the necessary for the best use
      of it. The internet represents a great advantage for investigation and also for
      clinical practice, since it permits free, universal access to data bases and the
      interchange of texts, images and videos. Thus it facilitates multicentric trials,
      the circulation of scientific journals, long-distance education and telemedicine.

PMID- 10584253
TI  - [Systems of biomedical information on the internet: bibliographic contents and
      electronic magazines].
AB  - OBJECTIVE: In this article we review two of the main Internet information
      services for seeking references to bibliography and journals, and the electronic
      publications on the Internet, with particular emphasis on those related to
      neurosciencs. DEVELOPMENT: The main indices of bibliography are: 1. MEDLINE. By
      definition, this is the bibliography database. It is an 'on line' version of the
      magazine with a smaller format, published weekly with the title pages and
      summaries of most of the biomedical journals. It is based on the Index Medicus, a
      bibliographic index (on paper) which annually collects references to the most
      important biomedical journals. 2. EMBASE (Excerpta Medica). It is a direct
      competitor to MEDLINE, although it has the disadvantage of lack of government
      subsidies and is privately financed only. This bibliographic database, produced
      by the publishers Elsevier of Holland, covers approximately 3,500 biomedical
      journals from 110 countries, and is particularly useful for articles on drugs and
      toxicology. 3. Current Contents. It publishes the index Current Contents, a
      classic in this field, much appreciated by scientists in all areas: medicine,
      social, technology, arts and humanities. At present, it is available in an on
      line version known as CCC (Current Contents Connect), accessible through the web,
      but only to subscribers. CONCLUSIONS: There is a growing tendency towards the
      publication of biomedical journals on the Internet. Its full development, if
      correctly carried out, will mean the opportunity to have the best information
      available and will result in great benefit to all those who are already using new
      information technology.

PMID- 10584254
TI  - [Quo vadis telemedicine?].
AB  - INTRODUCTION: Telemedicine, i.e. the set of diagnostic, terapheutic or social
      medicine actions, done using electronic transmission methods, is thieving and
      shows an amazing and disquieting near future. Let us review the actual situation
      and analyze the future perspectives. DEVELOPMENT: It is now a reality in
      different scopes and centres such as Teleradiology, Telepathology,
      Teleophthalmology, and so, and terms like Telepresence or Robotic Surgery, are
      making its way. Meanwhile, by now, Internet doesn't support critical applications
      where the patient's life is at risk, the boom of telecommunications at planetary
      level is changing our habits and rhythms, ... our lifes. It's the immediate
      transmission of information without intermediaries being able of manipulate it,
      it's the universal, easy, free and immediate communication between persons. A
      media without government, without censure, hard to legislate, that implies the
      fading out of diverse social beings that are nowadays under constraints of time
      and space, and the fading in of new beings free of that sort of constraints. We
      are seeing the born and growing up of a new culture that will impose itself-it is
      already doing so-like it has happened before with the press, or vaccines. It is
      in our hands to cooperate in the positive development of these new technologies,
      of this new culture, and to protect it from irresponsible governments, from
      unscrupulous commercials, and from the people trying to convert it in new social
      barriers. But we have reasons to be optimist, one of them is the existence of a
      lot of intelligent, passionated, usually very young people, extremely experts in
      computer science and communications, that are working hard in these fields,
      knowing that the ones who have the control of communications will rulethe future
      world. CONCLUSIONS: It is important that telemedicine helps improving medical
      sciences, the patients, the doctor and the society and we can-we must-work to
      this end.

PMID- 10584255
TI  - [Internet in scientific investigation].
AB  - INTRODUCTION: In the United States all universities, public libraries and most
      colleges are equipped with rooms containing computers connected to the internet,
      with free access for both investigators and pupils. The web is the new frontier
      of telecommunications, particularly regarding science and especially medicine.
      DEVELOPMENT: One of the applications giving most popularity to the Internet is
      the World Wide Web system, a graphic environment which permits users to explore
      the information contained on the Internet, and which grows daily. The rapid
      access to well organized information is essential for genetic, epidemiological
      and clinical studies. Today, for instance, genetic investigation is unimaginable
      without the Internet. In the literature, one often finds specialized
      investigation which has been developed using the Internet, from which
      epidemiological data, examples of analysis or sophisticated programs for the
      presentation of results were obtained, or volunteers recruited for
      pharmacological studies. The internet gives access to articles published in 5,000
      medical journals alone on the databases Medline and Embase. CONCLUSIONS: The
      availability of information and the ease of communication using the Internet is a
      prerequisite for scientific work and investigation in many disciplines. Internet
      is a means of enrichment, and in the future will be even more so, when the
      information which it contains can be more strictly selected by the users.

PMID- 10584256
TI  - [The Net 'a la carte': virtual communities of users and integrated thematic
      telematic services].
AB  - INTRODUCTION: Internet and its society of information and communication should be
      considered to be a smaller society evolving--others would say is trapped--within
      our society. Therefore, it should be considered not only from a technical or
      technological point of view but also regarding its human, cultural, social and
      intellectual aspects. DEVELOPMENT: This article starts with a general view of the
      present situation on the Internet. We also define the concept of a Virtual
      Community of Users (VCU). In view of this concept, debate centers on the
      communities of scientific, professional and academic communities using the
      Internet, analyzing the present situation, its needs and problems. We continue
      with the concepts of Virtual Thematic Service (VTS) and Integrated Virtual
      Thematic Services (IVTS) introduced as a means to solve the needs and problems of
      VCU. Finally, we describe a real pilot study, based on the IVTS paradigm, known
      as UniNet.

PMID- 10584257
TI  - [Vacuolar myelopathy associated with AIDS: premortem diagnosis by MRI].

PMID- 10584258
TI  - [Epilepsy and coma as the presentation of vitamin B12 deficiency].

PMID- 10584259
TI  - [Torticollis as a cause of consultation in neuropediatrics].
AB  - INTRODUCTION AND OBJECTIVE: Torticollis is a very non-specific symptom occurring
      in different conditions and may therefore be the reason for consultation in many
      specialties including neuropaediatrics. Analysis of torticollis as a cause for
      consultation in neuropaediatrics may contribute to the establishment of a
      suitable strategy for diagnosis. PATIENTS AND METHODS: We review, from the
      diagnostic point of view, the clinical histories of cases in which the reasons
      for consultation included torticollis. These cases were included in the database
      of all the patients assessed by the neuropaediatric department of the Hospital
      Miguel Servet in Zaragoza between May 1990 and February 1999. RESULTS: Of the
      4,138 new patients evaluated during the period studied, in 60 patients
      torticollis was either the sole symptom or was one of the symptoms leading to
      consultation. The diagnoses established were: 30 congenital torticollis (50%), 6
      secondary to space-occupying intracranial lesions (10%), 5 benign paroxystic
      torticollis (8.3%), 4 post-traumatic, 3 secondary to ocular disorders, 3 Sandifer
      syndrome, 1 focal dystonia of the neck, 1 secondary to a submandibular adeno
      phlegmon, 1 secondary to an epidural hematoma of the cervical spine, 1 to
      encephalomyelitis and 1 to spondylodiscitis, with 4 cases unclassified.
      CONCLUSIONS: The clinical history, physical examination and follow-up of the
      course of the disorder orientate or permit the diagnosis to be established in
      many cases of torticollis. The indications for complementary investigations,
      particularly neuroimaging, should be considered individually in each case.

PMID- 10584260
TI  - [Genotype-phenotype correlation in myotonic dystrophy and prediction of clinical
      seriousness].
AB  - INTRODUCTION: Since description of the expansion of the number of CTG
      trinucleotides on the long arm of chromosome 19 in the 19 q 13.2-13.3 interval as
      being responsible for myotonic dystrophy (DM), many studies have established a
      direct relationship between the size of the expansion and the severity of the
      manifestations. OBJECTIVES: To evaluate the clinico-genetic correlation in a
      population with DM in Eastern Andalucia and to establish the predictive value of
      the increase in number of CTG repetitions with regard to clinical gravity.
      PATIENTS AND METHODS: A transverse study of persons from families known to have
      members with DM, classified with regard to the clinical gravity of their illness.
      Diagnosis was by means of clinical neurological, ophthalmological and
      neurophysiological examination and subsequently by genetico-molecular study,
      Southern blot, PCR, oligonucleotide CTC hybridization and Northern blot. RESULTS:
      Genetic studies confirmed the previous clinical diagnosis of DM in 78 persons, of
      the 145 studied, who came from 32 families. The average size of the mutation was
      1-5 kb. There was close correlation between the size of the expansion and the
      clinical condition. Logistic repression studies permitted adequate classification
      in function of the size of the expansion in 87.23% of the cases of clinically
      relevant illness and in 90% of the cases in which the condition was not
      clinically relevant. CONCLUSIONS: There is a strong association between the
      clinical features of DM and the magnitude of the mutation. The size of the
      expansion has considerable predictive value in prognosis of the disorder. This
      may be useful when making decisions during prenatal diagnosis.

PMID- 10584261
TI  - [P300 and auditory information processing during natural sleep].
AB  - INTRODUCTION: The P300 is elicited, in the waking state and during an 'attention
      condition', in response to deviant stimuli of an oddball paradigm. This component
      of event related potentials (ERP) may be a useful research tool in the assessing
      of cortical sensory processing during normal sleep since a subject does not need
      to be awake or totally conscious in order to generate a measurable response.
      OBJECTIVE: This study used an classical oddball paradigm as a means to assess the
      auditory information processing during sleep. PATIENTS AND METHODS: The auditory
      ERP were registered in twelve healthy volunteers during the waking state and
      sleep stages II, III-IV and REM. The amplitude, latency and scalp distribution
      parameters of the positivity observed were contrasted with the results obtained
      in the waking state. RESULTS: A 'P300-like' with a significantly smaller peak
      amplitude and an increment of latency was elicited during stage II and the REM
      stage of sleep. As in the waking state, the positivity during this sleep stages
      was maximal at central-parietal regions. CONCLUSIONS: The response obtained seems
      to correspond both for the morphology of the potential as for the centro-parietal
      predominance with a waking P3b component. These results suggest that certain
      processes of attention and memory-related operations involved in the auditory
      processing of simple signals remain operative during these sleep stages.

PMID- 10584262
TI  - [Epileptic crisis and multiple sclerosis: anatomo-clinical correlation].
AB  - INTRODUCTION: The prevalence of epilepsy in multiple sclerosis (MS) is low and
      the occurrence of an epileptic seizure as a first sign of this illness is even
      more infrequent. The relationship between both these illnesses is not clear; as
      epilepsy is a common condition, a coincidental association only could exist
      between the two diseases. OBJECTIVE: To establish a nexus of causality between
      epilepsy an MS. Clinical case. We present one case of epileptic seizures as the
      first manifestation of MS. The patient was a woman of 25 years old. The only
      result of the clinical examination was a right homonymous inferior
      cuadrantanopsy. The patient presented a high Tibbling index, lesions of
      demyelination in the subcortical occipital region and semioval centrum in the MRI
      and a pathological electroencephalogram; also, the visual and auditory evoked
      potential latency were delayed. CONCLUSIONS: We related he results of the
      neuroimaging, the clinical examination and the complementary tests of the
      patient. The appears to be a causal association between epilepsy and MS.

PMID- 10584263
TI  - [Thyrotoxic periodic paralysis. A report of 2 cases].
AB  - INTRODUCTION: Thyrotoxic hypokalemic periodic paralysis is characterized by
      recurrent episodes of motor weakness of variable intensity associated with
      thyroid overactivity. It is usually associated with low plasma potassium levels
      and is often precipitated by physical activity or ingestion of carbohydrates.
      CLINICAL CASES: We describe two men, aged 33 and 50, who complained of several
      episodes of muscular paralysis in the context of previously undiagnozed
      hyperthyroidism and associated with low plasma potassium levels. There were
      clearly raised levels of T3, T4 and free T4 and TSH was depressed due to
      hyperactive diffuse goitre. In one patient the precipitating factor was known to
      have been a large intake of carbohydrates and intense physical exercise.
      Antithyroid treatment, and the resulting correction of hyperthyroid function,
      prevented any further episodes of muscular weakness in both patients.
      CONCLUSIONS: Thyrotoxic periodic paralysis should be considered in the
      differential diagnosis of all acute episodes of motor paralysis in young
      patients. Determination of the plasma levels of potassium and thyroid hormones
      helps diagnosis. Early diagnosis is important so as to be able to establish
      antithyroid treatment and avoid further episodes of weakness.

PMID- 10584264
TI  - [Neurotoxicity, neuroprotection and therapeutic window in cerebral ischemia].

PMID- 10584265
TI  - [Neuronal death mechanisms in cerebral ischemia].
AB  - INTRODUCTION: Morphological and biochemical studies have shown an apoptotic
      component in neurons following either focal or global ischemia in adults, or
      hypoxia-ischemia during development. DEVELOPMENT: Different factors, including
      transcription factors, members of the Bcl-2 family, caspases and trophic factors,
      participate in the cascade of events leading to cell death. Transcription factor
      c-Jun is induced and expressed in the three models of ischemia as a non-specific
      response to the ischemic stress. The role played by the different members of the
      Bcl-2 family is not clear in cerebral ischemia. It is feasible that Bcl-2
      expression is not sufficient to protect nerve cells from dying in those animals
      with physiological dotations of this protein. Yet Bcl-xS may have a role in
      ischemia-induced cell death following global ischemia in the adult or hypoxia
      ischemia during development. Recent studies have also shown a similar putative
      role of caspase 1 and caspase 3 following cerebral ischemia. Finally, the
      ischemic insult is usually accompanied by modifications in the expression of
      neurotrophins and receptors. CONCLUSIONS: Brain-derived neurotrophic factor
      (BDNF) administration preserves nerve cells from dying following focal or global
      ischemia in adults, and hypoxia-ischemia during development. This positive effect
      is probably dependent on the cross-signaling between BDNF and its specific
      receptor TrkB. Cumulative evidence in experimental models indicates BDNF as a
      putative agent in the treatment of cerebral ischemia in humans.

PMID- 10584266
TI  - [Factors determining the therapeutic window in acute ischemic stroke:
      characteristics of PET studies].
AB  - OBJECTIVE: To make a brief review of the use of PET in the study of patients with
      acute ischemic stroke. DEVELOPMENT: In the cerebral cortex PET may be used to
      detect a series of changes which permit the definition of three types of patients
      with different prognoses. The patients of type 1 (severe fall in cerebral blood
      flow and CMRO2) have an unfavorable prognosis and do not benefit from
      fibrinolytic treatment and/or neuroprotection to assist recovery of areas of
      penumbra. Patients of type 2 (marked drop in cerebral blood flow with moderate
      reduction of CMRO2) have a doubtful prognosis and are those which, in theory,
      might benefit from fibronolytic and/or neuroprotector treatment to help recovery
      of zones of penumbra. The patients of type 3 (focal hyperperfusion with CMRO2
      maintained) have a favorable spontaneous prognosis. CONCLUSIONS: This technique
      also shows that the therapeutic window should be individually analyzed in each
      case. This data is of great interest when planning therapeutic clinical studies.

PMID- 10584267
TI  - [Neuronal death mechanisms in cerebral ischemia: laboratory at the clinic].
AB  - In this article we review the different stages in the development of a
      neuroprotector drug, such as cytocholine, starting with the initial experimental
      stage and ending with its effects when used clinically in humans. It has been
      confirmed experimentally that the drug has neuroprotector, neuro-repair and
      neurocognitive effects which are also observed when it is used to treat patients
      with acute ischaemic cerebrovascular accidents.

PMID- 10584268
TI  - [Current situation of neuroprotection in stroke].
AB  - Focal and global brain ischemic injury represents one of the most important
      causes of human neurological disability and mortality in developed countries. It
      has been long recognized that the two major therapeutic approaches to ischemic
      stroke involve improving blood flow and the reduction or blockade of the cellular
      and subcellular consequences of ischemic injury. The important advances
      experienced during the last decade on the knowledge of pathophysiological
      mechanisms of brain ischemia and the development of new drugs give us a glimmer
      of hope in the treatment and they allow us to reject the nihilistic attitudes. We
      review the new pharmacological approaches to cytoprotective therapy for acute
      ischemic stroke and the results of reported clinical trials.

PMID- 10584269
TI  - [The objective of acute stroke therapy and neuroprotective therapeutic
      approaches].
AB  - In this article we review the concept of ischemic penumbra and emphasize the
      potentially reversible aspect as a function of time, which is the basis of the
      concept of a therapeutic window. Also, we briefly consider the physiopathology of
      the ischemic cascade, emphasizing the levels at which the different
      neuroprotector drugs under investigation have their effect.

PMID- 10584270
TI  - [Neurological complications of peri-spinal block in regional anesthesia].
AB  - INTRODUCTION: A perispinal block (intradural and/or epidural) is a technique
      which is considered to be safe under certain conditions. Nevertheless,
      neurological complications are possible and may be associated with transient or
      permanent sequelae, as is shown by symptoms ranging from minor alterations (most
      commonly) to major neurological defects (rarely). DEVELOPMENT: In this article we
      describe a review of the bibliography on physiopathological mechanisms
      (ischaemia, compression, trauma per se, neurotoxicity of the anesthetic drugs and
      infection), and also the risk factors associated with the development of these
      complications. CONCLUSION: Knowledge permits the use of a series of preventive
      measures to be followed before, during and after carrying out the technique.

PMID- 10584271
TI  - [Monotherapy with gabapentin ++].
AB  - INTRODUCTION AND OBJECTIVE: Gabapentin is an anti-epileptic drug approved in the
      USA in December 1993 as an additional treatment for patients with crises of
      partial onset. Recently it has been approved for use as monotherapy. We review
      the characteristics of this molecule as an anti-epileptic drug and the clinical
      trials which have permitted approval of the current indications. DEVELOPMENT: We
      review the particular difficulties of designing trials using monotherapy, both
      for ethical reasons (problems with the use of a placebo) and for technical
      reasons and those of interpretation (problems comparing two drugs with equivalent
      results) and analyze the trials in which attempts were made to overcome these
      difficulties. A trial designed to replace polytherapy in drug-resistant patients
      by monotherapy did not show conclusive results, although they were suggestive. A
      trial of patients admitted for pre-surgical studies permitted verification of the
      efficacy and safety of higher doses (3,600 mg/day) than those previously used
      (800-2,400 mg/day). Another trial, this time of newly diagnosed patients,
      permitted verification of the efficacy and safety of gabapentin used in different
      dosages. CONCLUSIONS: Gabapentin is effective when used as monotherapy. The dose
      recommended for the initial treatment of newly-diagnosed patients is 900 mg/day.
      It has a better safety profile than carbamazepine and is indicated in simple and
      complex partial crises with or without secondary generalization.

PMID- 10584272
TI  - [Tropical spastic myelopathy-paraparesis due to human lymphotropic virus 1 (HTLV
      1)].

PMID- 10584273
TI  - [Answer to "Memory disorders in the epidemic neuropathy"].

PMID- 10584274
TI  - [Lower extremity monoparesis as complication of abdominal aortic aneurysm
      rupture: a case report].

PMID- 10584275
TI  - [Late onset epilepsy. Further comments].

PMID- 10584276
TI  - [Pathogenesis of alpha/theta coma].

PMID- 10584277
TI  - [Percutaneous decompression with ND:YAG laser in disc hernias].

PMID- 10584278
TI  - [Multiple post-traumatic cerebral infarcts. A case report].

PMID- 10584279
TI  - [Neuropsychiatric disorders and macroprolactinoma].

PMID- 10584280
TI  - [Cerebral paralysis with dystonic components. A presentation of nine cases].

PMID- 10584281
TI  - [Specific immunotherapy (desensitization)].

PMID- 10584282
TI  - [Methods for monitoring of therapeutic efficacy in immunotherapy of allergic
      rhinitis].
AB  - Efficacy monitoring of immunotherapy (IT) is performed to adjust the therapy
      according to the patient's reactions, to collect data for scientific studies and
      to evaluate the efficacy of IT. A decrease of allergy symptoms and of drug use
      are the main parameters. For this, allergy diaries are most suitable. Pollen
      exposition should be monitored with Burkhard traps. Wheal and flare reactions in
      skin tests can be measured by visual inspection with quantification of the
      diameter on transparent foils or by means of laser scanners. Nasal provocation
      testing leads to subjective and objective (rhinomanometry, acoustic rhinometry)
      results. A change in the threshold concentration of allergen, which is needed to
      provoke a positive test reaction, can be used to evaluate the success of an IT.
      Additionally, systemic or local side-effects should be carefully revealed.
      Cytologic measures can be achieved by nasal lavages. Cotton samplers, cytology
      brushes and suction techniques are used to collect cells and nasal secretions.
      Early and late allergic reactions can be evaluated. Specific cell activation
      markers like ECP or tryptase are useful parameters in nasal secretions. T
      lymphocyte subpopulations and T-cell-lymphokine-profiles can be detected. During
      IT, a change from a dominating TH2-cytokine-profile to a dominating TH1-cytokine
      profile can be seen. For the reason of their expense, those methods are
      restricted to scientific investigations and only rarely used for routine
      diagnostics.

PMID- 10584283
TI  - [Short-term immunotherapy--a survey of current studies].
AB  - Immunotherapy (IT) plays a central role in the therapy of allergic rhinitis as it
      was proved to be causal and preventive. IT induces humoral and cellular changes
      in the immune system, a reduction of symptoms and a prophylactic effect regarding
      a possible expansion of the allergene spectrum and of involved organ systems.
      Regular therapeutic schedules include allergen injections starting immediately
      after the pollen season and ending just before the expected beginning of a
      season. Additionally, perseasonal and perennial therapy schemes have been used.
      In all these, a phase of dose-increase is followed by an individually adjusted
      steady-state preservation-phase. In perseasonal and perennial scheme the
      injections are given during the pollen season. The preseasonal shortterm
      immunotherapy is another schedule. The increase of the injected allergen-dose is
      made very fast (most commonly during seven weeks), so that the phase of dose
      increase is shortened considerably, and a preservation-phase does not take place.
      This shortterm-immunotherapy has been developed for patients who consult their
      doctor shortly before the start of the pollen season. The preseasonal shortterm
      immunotherapy has been shown to be efficient regarding allergic rhinitis caused
      by grass-, rye-, birch-, hazel- and alder-pollen. Clinical and experimental data
      of two placebo-controlled trials and one open study are presented and the role of
      this new immunotherapy approach is discussed.

PMID- 10584284
TI  - [WHO position paper (summary)--allergen-immunotherapy: therapeutic vaccines for
      allergic diseases].
AB  - From January 27 to 29, 1997, experts on allergen immunotherapy from various
      geographic locations throughout the world met at the headquarter of the World
      Health Organization (WHO) in Geneva, Switzerland to reach a consensus on
      international guidelines. Guidelines or indications for immunotherapy with
      inhalant allergens and venoms have been published before by the WHO, the European
      Academy of Allergy and Clinical Immunology (EAACI), the International Consensus
      Report on Asthma, the Global Strategy for Asthma Management and Prevention, the
      International Consensus Report on Rhinitis, the British Society for Allergy and
      Clinical Immunology, the American Academy of Allergy, Asthma and Immunology
      (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI). The
      committee wrote a position paper based on scientific articles reviewed for data
      before April 1, 1997. These guidelines should result in a better understanding of
      the science and rationale for using allergen immunotherapy as well as improve the
      safety of such therapy. The document also defines new techniques being developed
      which may result in better efficacy and less risk for allergen immunotherapy as
      well as recommends areas of additional and necessary research.

PMID- 10584285
TI  - [Theories on the mode of action of desensitization].
AB  - Specific immunotherapy (SIT) has been practised successfully for about 80 years.
      In classic immunotherapy, an allergen-extract is repeatedly injected
      subcutaneously in increasing doses. A large number of clinically controlled
      studies have proved the efficacy of this kind of immunotherapy, while its mode of
      action is not precisely known yet. A successful SIT leads to an impairment of
      allergic symptoms (symptom score), and a concordant decrease in drug use.
      Furthermore, a reduced reactivity in specific dermal, nasal and bronchial
      provocation tests is induced as well as a diminished unspecific reagibility in
      the affected tissues. Several studies showed reduced values for allergen-specific
      IgE (serum) that followed an initial increase. A reduced immigration of
      eosinophils was found, both after provocation with allergen and during the pollen
      season, as well as diminished values of markers for the activity of eosinophils,
      e.g. eosinophil cationic protein (ECP). Also, a reduced allergen-induced
      histamine-liberation from mast cells and basophils has been reported. The
      underlying mechanism for these effects of SIT might be a reorientation of the
      allergen-induced lymphokine-production to a dominant TH1-cytokine-profile.
      Because the relation between the quantity of IL-4 and its regulator IFN-gamma
      controls the extent of IgE-synthesis by B-cells, the reorientation leads to a
      diminished production of IgE. IFN-gamma inhibits the differentiation of TH2
      cells; by this less TH2-cells are present to help B-cells to produce IgE
      antibodies, and to induce the differentiation of mast cells and basophils as well
      as immigration, differentiation and activation of eosinophils. Thus, the positive
      effects of SIT can be explained by the reorientation T-cell lymphokine profile.
      The mechanism under discussion for explaining this reorientation include: 1) an
      increased differentiation of allergen-specific CD4+ precursor-cells or a
      reorientation of established TH2-cells to the production of IFN-gamma, 2) the
      differentiation of IFN-gamma-producing CD8+ T-cells and of T-cells with receptors
      for T-cell-antigenes of the gamma, delta-type; and 3) the induction of an energy
      in TH2-cells.

PMID- 10584286
TI  - [Desensitization of allergy to hymenoptera venoms].
AB  - Hyposensitization (immunotherapy) of hymenoptera venom allergy has been practised
      for 70 years. About 20 years ago the use of ineffective whole-body extracts was
      abandoned, as effective therapy with preparations of bee venom and wasp venom
      became available. The diagnosis of hymenoptera venom allergy is based on history,
      skin tests and determination of venom specific IgE-antibodies in the serum. Only
      rarely other tests are needed (histamine or leukotriene release tests,
      immunoblot, specific IgG antibodies). To achieve a definite diagnosis, all
      findings have to be considered carefully, as "false positive" and "false
      negative" results can occur in all test systems. Hyposensitization is indicated
      in all patients with systemic IgE-mediated immediate type reactions, only in
      children with exclusive skin symptoms it may not be needed. Contraindications of
      hyposensitization are to be considered. Allergen preparations for subcutaneous
      injection are available as aqueous preparations or as aluminium hydroxide
      adsorbed depot extracts. Various rush or conventional treatment protocols are
      used to reach the maintenance dose of usually 100 micrograms venom/four weeks.
      The most frequent side effects are large local reactions, which are observed in
      almost all patients. Systemic anaphylactic side effects also occur in up to 40%,
      in most cases the symptoms are mild. To identify patients who are not protected
      by the usual maintenance dose, a sting challenge test with a living insect should
      be performed. By this, about 80 to 100% of the patients are found to be protected
      from systemic symptoms, and in those still reacting an increased dose of 200
      micrograms (or even higher) eventually induces protection. Hyposensitization may
      be stopped if it lasted at least for 3 to 5 years, if systemic side-effects did
      not occur and if the patient has tolerated a sting challenge or a field-sting
      without systemic symptoms. In patients intensely exposed to hymenoptera or in
      those with an increased risk of severe reactions, longer treatment has to be
      considered.

PMID- 10584287
TI  - [Therapeutic measures for anaphylactic reactions in the course of allergen
      specific immunotherapy].
AB  - Allergologic emergencies that are caused by an overwhelming immunologic systemic
      reaction during immunotherapy are guessed to occur in 1:1,000,000 to 1:100,000.
      These anaphylactic or anaphylactoid reactions are induced by the liberation of
      different mediators. The symptoms are determined by the kind, the quantity and
      the relation of these mediators and by the individual predisposition. In general,
      these symptoms can be detected on the skin, the lungs, the cardiovascular system
      and the gastrointestinal tract. The early treatment of circulatory and pulmonary
      disturbances is decisive for the prognosis of the patient. The severity of
      symptoms is graded from 1 to 4. An adequate therapy has to be given immediately
      according to the severity of the symptoms in a step-wise approach. Initially, an
      interruption of the allergen exposition is important, as is an oxygen supply and
      placement of intravenous accesses. In the specific drug-therapy a few substances
      have proved to be reliable. Catecholamines (adrenaline, dopamine, noradrenaline),
      histamine-antagonists, glucocorticosteroids, theophylline and volume substitutes
      belong to this group, but not the intravenous application of calcium.

PMID- 10584288
TI  - Oral and sublingual immunotherapy: general aspects and critical considerations.
AB  - Local routes for immunotherapy (IT) such as oral (OIT) and sublingual (SLIT) have
      the primary aim of avoiding or minimizing the risk of adverse events and of
      improving the compliance of the patients with IT itself. About the possible
      mechanisms of action, only few information are available since local IT has been
      deeply studied only in the last ten years. The current data about
      pharmacokinetics are controversial and not conclusive, since they are mostly
      derived from animal models. However, very recent studies have demonstrated that
      the sublingual/swallow modality is the most promising way of mucosal
      immunotherapy. Thus, SLIT could be shown to lead to systemic immunological
      effects and to a decreased responsiveness of target organs. Furthermore, no
      severe adverse events were reported in the SLIT-studies. Some studies indicate
      that SLIT is as effective as subcutaneous IT, whilst OIT is not recommended for
      the clinical practice. SLIT would appear particularly suitable for pediatric
      patients. Administration schedules include a build-up phase and a maintenance
      phase which can be administered either preseasonally or continuously, and rush
      schedules for preseasonal IT are also available. Furthermore, SLIT reduces time
      and money expenses usually required by SIT since it is self-administered.

PMID- 10584289
TI  - [Immunological mechanisms in allergen-specific immunotherapy: impact on future
      trends in type-1 allergy management].
AB  - Specific immunotherapy (SIT) is the only treatment of Type-I allergy that leads
      to a modulation of the immune response to the eliciting allergen. The repeated
      administration of high doses of antigen induces a state of "antigen-specific non
      responsiveness", i.e. immunologic tolerance to the injected antigen. Accordingly,
      during and after SIT the proliferative response of allergen-specific T
      lymphocytes in response to the administered antigen are significantly reduced.
      According to recent publications, this effect is due to the production of the
      immunosuppressive cytokine interleukin (IL)-10, which is induced during the
      treatment. On the other hand, a distinct change in the quality of the immune
      response to the injected allergen can be observed: the production of the IgE
      inducing cytokine IL-4 by T helper cells decreases. Moreover, the release of
      other proinflammatory cytokines and inflammatory mediators is suppressed.
      Together, these events result in a marked decrease of symptoms during allergen
      exposure and reduced reactivity during challenge.

PMID- 10584290
TI  - PAT--the Preventive Allergy Treatment Study design and preliminary results.
AB  - The Preventive Allergy Treatment Study, the PAT Study, is a European multi-center
      study. The end-point is to show in what capacity allergen specific subcutaneous
      immunotherapy can reduce the outcome of asthma in children with allergic
      rhinoconjunctivitis sensitized to birch and/or timothy pollen. Two hundred and
      ten children aged from 5 to 13 years were included in the study. Children were
      randomized to the active treatment group receiving allergen specific
      immunotherapy with birch and/or timothy pollen allergen extract or to the control
      group receiving the optimal pharmacotherapy. Immunotherapy was given for the
      course of three years. Preliminary data show that immunotherapy has been
      effective, it has been safe and statistically significantly less children in the
      actively treated group had asthmatic symptoms than children in the control group.
      Data have not been evaluated from all centers at the moment. The study is a
      prospective follow-up study, the patients' data will be evaluated next time in
      the year 2002.

PMID- 10584291
TI  - [Costs of allergy therapy].

PMID- 10584292
TI  - [Desensitization with allergens: early, specific, effective therapy of immune
      system almost without side effects. Interview by Dr. Barbara Scholtissek].

PMID- 10584293
TI  - [Recombinant allergens; allergy vaccine in the future?. Interview by Dr. Barbara
      Scholtissek].

PMID- 10584294
TI  - Onset of the sliding movement of an actin filament on myosin molecules: from
      isotropic to anisotropic fluctuations.
AB  - An actin filament contacting myosin molecules increased the fluctuation intensity
      of the filamental displacement as the ATP concentration increased. In particular,
      fluctuations in the filamental displacement in the planar plane in which the
      sliding movement takes place were isotropic at a low ATP concentration, and
      became anisotropic as the concentration increased. The build-up of the sliding
      movement of an actin filament was associated with the transformation from
      isotropic to anisotropic fluctuations of the filamental displacement.

PMID- 10584295
TI  - Important amino acid properties for enhanced thermostability from mesophilic to
      thermophilic proteins.
AB  - Understanding the role of various interactions in enhancing the thermostability
      of proteins is important not only for clarifying the mechanism of protein
      stability but also for designing stable proteins. In this work, we have analyzed
      the thermostability of 16 different families by comparing mesophilic and
      thermophilic proteins with 48 various physicochemical, energetic and
      conformational properties. We found that the increase in shape, s (location of
      branch point in side chain) increases the thermostability, whereas, an opposite
      trend is observed for Gibbs free energy change of hydration for native proteins,
      GhN, in 14 families. A good correlation is observed between these two properties
      and the simultaneous increases of -GhN and s is necessary to enhance the
      thermostability from mesophile to thermophile. The increase in shape, which tends
      to increase with increasing number of carbon atoms both for polar and non-polar
      residues, may generate more packing and compactness, and the position of beta and
      higher order branches may be important for better packing. On the other hand, the
      increase in -GhN in thermophilic proteins increases the solubility of the
      proteins. This tendency counterbalances the increases in insolubility and
      unfolding heat capacity change due to the increase in the number of carbon atoms.
      Thus, the present results suggest that the stability of thermophilic proteins may
      be achieved by a balance between better packing and solubility.

PMID- 10584296
TI  - Polyketides from dinoflagellates: origins, pharmacology and biosynthesis.
AB  - Dinoflagellates, unicellular marine protists, produce some of the largest and
      most complex polyketides identified to date. The biological activities of these
      compounds are quite diverse. Compounds having potential therapeutic value as anti
      cancer agents as well as deadly neurotoxins, whose production has resulted in
      severe public health hazards and economic hardships, are represented in this
      group of secondary metabolites. Stable isotope feeding experiments have firmly
      established the polyketide origins of representative compounds from each of the
      three structural classes, the polyether ladders, the macrocycles and the linear
      polyethers. Yet some unusual labeling patterns have been observed in each class.
      Pendant methyl groups are most often derived from C-2 of acetate and deletions of
      C-1 of acetate are common. Studies on the biosynthesis of dinoflagellate derived
      polyketides at the genomic level have not been reported, in part due to the
      peculiarities of the dinoflagellate nucleus and the lack of a dinoflagellate
      transformation system. Nevertheless, a fundamental understanding of the genetics
      of polyketide biosynthesis by dinoflagellates could be the catalyst for
      developing several fruitful avenues of research. Dinoflagellate derived
      polyketides are reviewed with special emphasis on pharmacology and biosynthesis.

PMID- 10584297
TI  - Comparative aspects of milk caseins.
AB  - The caseins comprise the major protein component of milk of most mammals and are
      secreted as micelles that also carry high concentrations of calcium. They are
      phosphoproteins that represent the products of four genes, equivalent to those
      that encode the bovine alpha s1, alpha s2, beta, and kappa-caseins. There is
      considerable variation in the relative proportions of the particular caseins
      across species. The primary sequences of the alpha s1, alpha s2, and beta-caseins
      also show considerable species variation consistent with rapidly evolving genes
      that are proposed to have a common precursor. In contrast, the kappa-caseins
      exhibit features that demonstrate a separate origin and function where they are
      proposed to stabilise the micelle structure. This review focuses on comparative
      aspects of the caseins across a number of species for which information is now
      available.

PMID- 10584298
TI  - The Antarctic toothfish (Dissostichus mawsoni) lacks plasma albumin and utilises
      high density lipoprotein as its major palmitate binding protein.
AB  - Plasma from the Antarctic toothfish, Dissostichus mawsoni, a member of the
      advanced teleost Nototheniidae family, was analysed. Agarose gel electrophoresis
      showed a major diffuse anionic protein that bound [14C]palmitic acid but not
      63Ni2+, and two more cationic proteins that bound 63Ni2+ but not palmitate. Oil
      Red O staining following cellulose acetate electrophoresis indicated that the
      palmitate binding protein was a lipoprotein. Two-dimensional electrophoresis
      showed that this palmitate binding band was composed of three proteins with M(r)
      of 11, 30, and 42 kDa, without any trace of material at approximately 65 kDa, the
      mass of albumin. N-terminal sequencing of the palmitate binding band gave a major
      sequence of DAAQPSQELR-, indicating a high degree of homology to apolipoprotein A
      I (apo-AI), the major apolipoprotein of high density lipoprotein (HDL). N
      terminal sequencing of the major nickel binding band produced a sequence with no
      homology to albumin. When ultracentrifugation was used to isolate the
      lipoproteins from Antarctic toothfish plasma, the palmitate binding protein was
      found solely in the lipoprotein fraction. In competitive binding experiments,
      added human albumin did not prevent palmitate binding to toothfish HDL. In
      conclusion, there is no evidence for albumin in Antarctic toothfish plasma and
      HDL assumes the role of fatty acid transport.

PMID- 10584299
TI  - Apolipoprotein CIII from guinea pig (Cavia porcellus) is shorter and less
      homologous than apolipoprotein CIII from other mammals.
AB  - Apolipoprotein (apo) CIII plays an important role in metabolism of triglyceride
      rich lipoproteins as a regulator of lipolysis and/or lipoprotein-receptor
      interaction. With the method of RT-PCR, the cDNA of guinea pig apo CIII was
      cloned and sequenced. The deduced amino acid sequence of 91 amino acids residues
      consists of a highly conserved signal peptide of 20 residues and a mature protein
      of 71 residues. Compared to mouse, rat, dog, bovine and human apo CIII, guinea
      pig apo CIII has a deletion of eight or nine amino acids at its C-terminus and it
      shows the lowest degree of homology to the presently known apo CIII sequences.
      Interestingly, the most conserved areas of guinea pig apo CIII are found in two
      regions, residues 16-33 and residues 50-69. Corresponding regions in human and
      dog apo CIII were previously predicted to form amphipathic helices, which are
      assumed to play important roles in the inhibition of lipoprotein lipase (LPL) and
      binding to lipid. Our present study could be helpful for the future elucidation
      of the structure-function relationships and evolution of apo CIII.

PMID- 10584300
TI  - Efflux of T4 from the in situ perfused liver of rainbow trout: effect of T4,
      dithiothreitol and cysteine in the perfusate.
AB  - A Cortland saline-perfused rainbow trout (Oncorhynchus mykiss) liver model was
      used to study aspects of T4 efflux from the intact organ system. There was a
      consistent efflux of T4 in the absence of T4 in the perfusate, and the T4 efflux
      was increased in the presence of T4 in the perfusate, but the efflux was not T4
      dose dependent. The addition of the thiol-containing compound dithiothreitol
      (DTT, 2 mM) to the perfusate had no significant effect on the flux of T4 from the
      liver, whereas the addition of cysteine (2 mM), a thiol-containing amino acid
      suppressed T4 efflux. The results are consistent with the known mechanisms of
      thyroid hormone trafficking across cell membranes, and suggest that organ
      systems, such as the liver, may act as a major reserve of hormone, thus
      participating in plasma thyroid hormone homeostasis.

PMID- 10584301
TI  - The glyoxylate cycle: does it function in the dormant or active bear?
AB  - The presence of or induction of an active glyoxylate cycle (GC) in the dormant
      black bear whose sole source of energy is body fat is an attractive concept which
      would allow lipid (acetate) to be directed from oxidation via the tricarboxylic
      acid cycle to many biosynthetic pathways. However, in spite of earlier claims,
      the present report establishes that isocitrate lyase and malate synthetase, GC
      marker enzymes, could not be detected in liver or kidney of active or dormant
      bears; liver peroxisome numbers were similar. The absence of brown fat (by light
      microscopy) and of the GC enzymes in the dormant bear raises questions about the
      prior report.

PMID- 10584302
TI  - Adenylate kinase is tightly bound to axonemes of Tetrahymena cilia.
AB  - Cilia of Tetrahymena thermophila possess adenylate kinase [ATP:AMP
      phosphotransferase, EC 2.7.4.3] activity. More than 95% of the total activity was
      recovered in the axonemal fraction when cilia were demembranated with 0.2%
      Nonidet P-40. There was no loss of the specific activity of adenylate kinase when
      axonemes were thoroughly washed with HMEK solution (10 mM HEPES, 5 mM MgCl2, 0.1
      mM EDTA, and 0.1 M KCl, pH 7.4). These results suggest that adenylate kinase is
      tightly bound to axoneme. Solubilization of adenylate kinase was markedly
      increased when axonemes were incubated in HME buffer (10 mM HEPES, 1 mM MgCl2,
      0.1 mM EDTA, pH 7.4) containing concentrations of NaCl (or KCl) exceeding 1 M.
      Therefore, routine isolation of adenylate kinase from axonemes involved pre
      extracting axonemes with 0.5 M NaCl in HME buffer followed by extraction in HME
      buffer containing 1.5 M NaCl. Native-gel electrophoresis of the high salt extract
      revealed two protein bands (band I and band III). An active staining for
      adenylate kinase showed a single active band corresponding to the position of
      band III. Two-dimensional gel electrophoresis using native-gel electrophoresis in
      the first dimension and SDS-PAGE in the second dimension suggests that band III
      protein contains at least nine polypeptides ranging from 21 to 110 kDa.

PMID- 10584303
TI  - Vitellins and vitellogenins of Dysdercus koenigii (Heteroptera: Pyrrhocoridae)-
      identification, purification and temporal pattern.
AB  - Two vitellins, VtA and VtB, were purified from the eggs of Dysdercus koenigii by
      gel filtration and ion exchange chromatography. VtA and VtB have molecular
      weights of 290 and 260 kDa, respectively. Both Vts are glycolipoproteinaceous in
      nature. VtA is composed of three polypeptides of M(r) 116, 92 and 62 kDa while
      VtB contained an additional subunit of M(r) 40 kDa. All subunits except the 116
      kDa subunit are glycolipopolypeptides. Polyclonal antibody raised against VtA
      (anti-VtA antibody) cross-reacted with VtB and also with vitellogenic haemolymph
      and ovaries and pre-vitellogenic fat bodies, but not with haemolymph from either
      adult male, fifth instar female, or pre-vitellogenic females demonstrating sex
      and stage specificity of the Vts. Immunoblots in the presence of anti-VtA
      revealed two proteins (of 290 and 260 kDa) in both vitellogenic haemolymph and
      pre-vitellogenic fat bodies that are recognised as D. koenigii Vgs. In newly
      emerged females, Vgs appeared on day 1 in fat bodies and on day 3 in haemolymph
      and ovaries. Vg concentration was maximum on day 2 in fat body, day 4 in
      haemolymph and day 7 in ovary. Although the biochemical and temporal
      characteristics of these proteins show similarity to some hemipterans, they are
      strikingly dissimilar with those of a very closely related species.

PMID- 10584304
TI  - Effect of tumour necrosis factor-alpha on total myofibrillar and sarcoplasmic
      protein synthesis and polysomal aggregation in rat skeletal muscles.
AB  - The total sarcoplasmic and myofibrillar protein synthesis was reduced in
      incubated fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus of
      rat after in vivo tumour necrosis factor-alpha treatment at 50 micrograms/kg/day
      for 5 days. The rate of protein synthesis in the myofibrillar fraction was
      inhibited more severely (41% in EDL and 34% in soleus) than that in the
      sarcoplasmic fraction (23% in EDL and 14% in soleus). Sucrose density gradient
      centrifugation analysis indicated that TNF-alpha treatment impaired polysomal
      aggregation in rat diaphragm muscle. Compared with the control muscles, the ratio
      of 40S and 60S subunits to polysomes was higher in TNF-alpha treated muscles.
      These findings suggest a role for TNF-alpha in the translational regulation of
      protein synthesis in rat skeletal muscle.

PMID- 10584305
TI  - Molecular genetic mapping of three X-linked avirulence genes, vH6, vH9 and vH13,
      in the Hessian fly.
AB  - Three X-linked avirulence genes, vH6, vH9, and vH13 in the Hessian fly, Mayetiola
      destructor, confer avirulence to Hessian fly resistance genes H6, H9, and H13 in
      wheat. We used a combination of two- and three-point crosses to determine the
      order of these genes with respect to each other, the white eye mutation and three
      X-linked molecular markers, G15-1, 020, and 021, developed from genomic lambda
      clones, lambda G15-1, lambda 020, and lambda 021. The gene order was determined
      to be vH9-vH6-G15-1-w-vH13-020-021. In situ hybridization of lambda G15-1, lambda
      020, and lambda 021, on the polytene chromosomes of the Hessian fly salivary
      gland established their orientation on Hessian fly chromosome X1. Based on the
      size of the Hessian fly genome, and the genetic distances between markers, the
      relationship of physical to genetic distance was estimated at no more than 300
      kb/cM along Hessian fly chromosome X1, suggesting that map-based cloning of these
      avirulence genes will be feasible.

PMID- 10584306
TI  - Two highly divergent 5S rDNA unit size classes occur in composite tandem array in
      European larch (Larix decidua Mill.) and Japanese larch (Larix kaempferi (Lamb.)
      Carr.).
AB  - The 5S ribosomal DNA unit structure and organization have been investigated in
      Larix decidua and Larix kaempferi using selective amplification of gene and
      spacer, sequence analysis and homologous probe hybridization. Two highly
      divergent unit size classes of approximately 650 and 870 bp were detected in both
      species. Sequence analysis in Larix decidua revealed that length variations occur
      in the middle spacer region and are the result of duplications (in the long
      spacers) and considerable sequence heterogeneity. Conversely, the transcribed
      region is of uniform length (120 bp), and the nucleotide sequence of one Larix
      decidua clone is similar to that reported for other gymnosperms. Sequence
      comparison of the larch spacers with two other Pinaceae species (Pinus radiata
      and Picea glauca) showed that the 5' and 3' regions flanking the gene (40 and 60
      bp, respectively) are quite conserved, suggesting a regulatory role. Moreover, a
      small element of about 70 bp located in the middle spacer region was found to be
      common to the larch long units and the six Pinus radiata spacer clones previously
      sequenced (64% sequence identity). The short and long unit size classes are
      mainly organized in composite tandem array(s) with evidence of extensive zones of
      strict alternation in both species. Mechanisms underlying this unusual
      association of divergent units in larch 5S rDNA arrays are discussed.

PMID- 10584307
TI  - Sequence analysis and gene identification in a set of mapped RFLP markers in
      barley (Hordeum vulgare).
AB  - The "Igri/Franka" (I/F) map ranks among the most comprehensive genetic linkage
      maps of barley (Hordeum vulgare), containing a large number of markers derived
      from cDNA and genomic PstI clones. Fourty-three cDNA clones and 259 genomic
      clones were at least partially sequenced and compared with the major data bases
      of protein and nucleic acid sequences. Of the cDNA clones, 53% show significant
      similarity to known sequences in protein data bases. A comparison of sequences
      from genomic clones to nucleic acid sequence data bases revealed similarities for
      9% of the clones. For cDNA sequences analyzed the same way, significant
      similarities were observed for 35% of the clones. These results show that genomic
      PstI clones, although containing genes at a significant frequency, represent an
      inappropriate source for an efficient, systematic gene identification in barley.
      Sequence information obtained in the context of the present study provides a
      resource for the conversion of these markers into sequence-tagged site (STS)
      markers and their use in PCR assays.

PMID- 10584308
TI  - The 5S rRNA gene in wall barley (Hordeum murinum L. sensu lato): sequence
      variation among repeat units and relationship to the Y haplome in the genus
      Hordeum (Poaceae: Triticeae).
AB  - The molecular diversity of the 5S rDNA units in 13 accessions of wall barley,
      which include Hordeum murinum, H. leporinum, and H. glaucum, is reported. Our
      analyses, based on 54 sequenced clones, indicate the presence of two sequence
      classes not previously seen in other barley species; namely, the long Y1 unit
      class and the short Y1 unit class. In addition, the accumulation of new sequence
      information has allowed us to refine previous groups. Using these new results,
      along with previously published work, we present a summary of all the unit
      classes described to date and potential correspondences between 5S rDNA unit
      classes and haplomes identified previously. In H. murinum, we found the long H1
      and long X2 unit classes, and in one of six accessions referable to H. glaucum we
      found the unique short Y1 unit class. Our cladistic analyses, using orthologous
      sequences, provide support for the current model for the relationships among
      several species within the Triticeae.

PMID- 10584309
TI  - Satellite DNA in the ant Messor structor (Hymenoptera, Formicidae).
AB  - This paper is the first record of the satellite DNA of Formicidae. The satellite
      DNA of the ant Messor structor is organized in a tandem repeat of monomers of 79
      bp. Like satellite DNAs of other insects, it is AT rich and presents direct and
      inverted internal repeats. Restriction analysis of the total DNA with methylation
      sensitive enzymes strongly suggests that this DNA is undermethylated. The
      presence of this repetitive DNA in other species of the genus Messor is also
      tested.

PMID- 10584310
TI  - Identification and analysis of homoeologous segments of the genomes of rice and
      Arabidopsis thaliana.
AB  - Using contiguous genomic DNA sequences of Arabidopsis thaliana, we were able to
      identify a region of conserved structure in the genome of rice. The conserved,
      and presumptive homoeologous segments, are 194 kb and 219-300 kb in size in
      Arabidopsis and rice, respectively. They contain five homologous genes,
      distinguished in order by a single inversion. These represent the first
      homoeologous segments identified in the genomes of a dicot and a monocot,
      demonstrating that fine-scale conservation of genome structure exists and is
      detectable across this major divide in the angiosperms. The conserved framework
      of genes identified is interspersed with non-conserved genes, indicating that
      mechanisms beyond segmental inversions and translocations need to be invoked to
      fully explain plant genome evolution, and that the benefits of comparative
      genomics over such large taxonomic distances may be limited.

PMID- 10584311
TI  - Molecular characterization and distribution of a 145-bp tandem repeat family in
      the genus Populus.
AB  - This report aims to describe the identification and molecular characterization of
      a 145-bp tandem repeat family that accounts for nearly 1.5% of the Populus
      genome. Three members of this repeat family were cloned and sequenced from
      Populus deltoides and P. ciliata. The dimers of the repeat were sequenced in
      order to confirm the head-to-tail organization of the repeat. Hybridization-based
      analysis using the 145-bp tandem repeat as a probe on genomic DNA gave rise to
      ladder patterns which were identified to be a result of methylation and (or)
      sequence heterogeneity. Analysis of the methylation pattern of the repeat family
      using methylation-sensitive isoschizomers revealed variable methylation of the C
      residues and lack of methylation of the A residues. Sequence comparisons between
      the monomers revealed a high degree of sequence divergence that ranged between 6%
      and 11% in P. deltoides and between 4.2% and 8.3% in P. ciliata. This indicated
      the presence of sub-families within the 145-bp tandem family of repeats.
      Divergence was mainly due to the accumulation of point mutations and was
      concentrated in the central region of the repeat. The 145-bp tandem repeat family
      did not show significant homology to known tandem repeats from plants. A short
      stretch of 36 bp was found to show homology of 66.7% to a centromeric repeat from
      Chironomus plumosus. Dot-blot analysis and Southern hybridization data revealed
      the presence of the repeat family in 13 of the 14 Populus species examined. The
      absence of the 145-bp repeat from P. euphratica suggested that this species is
      relatively distant from other members of the genus, which correlates with
      taxonomic classifications. The widespread occurrence of the tandem family in the
      genus indicated that this family may be of ancient origin.

PMID- 10584312
TI  - Constitutive heterochromatin DNA polymorphisms in diploid Medicago sativa ssp.
      falcata.
AB  - A Giemsa C-banding technique was used to study the amount and location of
      constitutive heterochromatin in diploid (2n = 2x = 16) Medicago sativa ssp.
      falcata (L.) Arcangeli. Most accessions had the standard C-banding pattern with
      centromeric bands on all the chromosomes and a prominent heterochromatic band at
      the nucleolar organizer regions (NOR) of the satellited (SAT) chromosomes.
      However, we observed in various accessions that constitutive heterochromatic C
      bands can exist at the telomeric ends of all the chromosomes. Interstitial bands
      occurred on the short arms of all chromosomes except for chromosome 3 and on the
      long arms of chromosomes 1, 2, 3, and 6, only. Rearranged chromosomes such as
      isochromosomes have been observed for the short arms of chromosomes 2 and 6. This
      is the first report on the existence of C-banding polymorphisms and the detection
      of putative isochromsomes in the chromosomes of diploid ssp. falcata which could
      have contributed to the variation observed in cultivated alfalfa.

PMID- 10584313
TI  - RFLP- and RAPD-based genetic relationships of seven diploid species of Avena with
      the A genome.
AB  - Relatively few molecular analyses are available for diploid oat species, which
      constitute the majority of the wild species of Avena and, therefore, the
      principal natural reservoir of variability. The present work reports an RAPD
      (random amplified polymorphic DNA) and RFLP-(restriction fragment length
      polymorphism) based study of the intra- and interspecific variability of seven
      diploid A-genome oat species. Both types of markers resulted in valid tools for
      identifying polymorphisms both within and between species. The two statistical
      analyses, UPGMA (unweighted pair group method, arithmetic mean) and PCoA
      (principal coordinate analysis), computed on the basis of genetic similarities
      estimated from RAPDs and RFLPs, showed that the different accessions grouped
      according to species, but the similarity coefficients were consistently higher in
      the RFLP analysis. Furthermore, slight differences were observed in the intra-
      and interspecific relationships found with the two types of markers. This may
      support the hypothesis that the polymorphisms revealed by the two types of
      markers may associate with regions of the genome having different evolutionary
      rates. The relationships among species are not identical to those deduced from
      previous karyotypic and morphological studies, thus suggesting a partially
      different evolutionary pathway in oat speciation.

PMID- 10584314
TI  - Development of simple sequence repeat markers in rye (Secale cereale L.).
AB  - Simple sequence repeats (SSRs), also referred to as microsatellites, represent a
      PCR-based marker system that has been described in mammalian and plant genomes in
      recent years. In self-pollinating crop plants they have been shown to be superior
      to other DNA markers with respect to their level of polymorphism. The technical
      advantages compared with RFLP markers should also facilitate marker analysis in
      outcrossing crops like rye. In order to determine the usefulness of SSR markers
      in rye genetics and breeding, several genomic libraries were screened for
      (CT/GA)n and (GT/CA)n dinucleotide repeats. It was estimated that these motifs
      occur at a frequency of one per 268-519 kb. Seventy four out of 182 positive
      clones were sequenced, and the majority (56.8%) revealed perfect repeats,
      predominantly of the type (GT/CA)n (61.9%). Fifty seven primer pairs were
      designed and 27 (47.4%) resulted in specific SSR markers, of which 20 were
      genetically mapped or assigned to chromosomes or chromosome arms, respectively.
      The level of polymorphism of four SSR and three RFLP markers was assessed in two
      open-pollinated rye cultivars. On average, the SSR markers showed larger values
      of expected heterozygosity (0.62 vs. 0.43) and allele number (5.9 vs. 3.4) than
      RFLP markers in both cultivars.

PMID- 10584315
TI  - Phylogeny in the genus Hordeum based on nucleotide sequences closely linked to
      the vrs1 locus (row number of spikelets).
AB  - The phylogenetic relationship between four basic genomes designated H, I, Xa, and
      Xu in the genus Hordeum was studied using a nuclear DNA sequence. The sequence,
      cMWG699, is single copy in the H. vulgare genome, and tightly linked to the vrs1
      locus which controls two- and six-rowed spikes. DNA fragments homologous to
      cMWG699 were amplified from diploid Hordeum species and the nucleotide sequences
      were determined. A phylogeny based on both base substitutions and an insertion
      deletion event showed that the H- and Xa-genome groups are positioned in one
      monophyletic group indicating that the Xa-genome taxa should be included in the H
      genome group. The large H-genome group is highly homogeneous. The I and Xu
      genomes are distinctly separated from H and Xa, and form sister groups. Another
      phylogeny pattern based on data excluding the insertion-deletion gave a result
      that the Xa genome forms a sister group to the H-genome group. The difference
      between the H and Xa genomes was affected only by a single base insertion
      deletion event, thus the H and Xa genomes are likely to be closely related. The I
      and Xu genomes were again distinctly separated from the H and Xa genomes.

PMID- 10584316
TI  - Clustering of the human CLCA gene family on the short arm of chromosome 1 (1p22
      31).
AB  - The CLCA gene family is a novel family of calcium-activated chloride channels.
      Several family members have recently been cloned from different mammalian species
      with distinct, highly tissue-specific expression patterns. Here, we describe
      radiation hybrid mapping of the human CLCA2 and CLCA3 genes using the Genebridge
      4 panel. Both genes were mapped to adjacent loci on the short arm of chromosome 1
      (1p22-31), a region to which the human CLCA1 had been assigned earlier. The
      results show clustering of all human CLCA family members known so far despite
      their moderately low levels of sequence homology and their heterogeneous
      expression patterns.

PMID- 10584317
TI  - Conservatism and defense style.
AB  - The dynamic theory of conservatism suggests that conservatism can be described as
      an ego-defensive behavior. Furthermore, the theory of defense style suggests that
      defensive behaviors are revealed in individuals' attitude structures. The present
      study was designed to examine the relationship between conservatism and defense
      style. Measures of conservatism, anal personality traits, and defense style were
      completed by 238 university students (103 men, 134 women, 1 unidentified). The
      measure of anal personality traits was included to replicate factors previously
      discovered with similar conservatism measures. A principal components analysis
      with oblimin rotation indicated that conservatism and anal personality traits
      loaded alongside mature defense style. The findings suggest that conservatism can
      be located within the theoretical model of defense style. However, it is
      suggested that the match between liberal attitudes and mature defense style be
      investigated in future research.

PMID- 10584318
TI  - Characteristics of preschool and school-age children with imaginary companions.
AB  - The authors investigated the prevalence and characteristics of children who
      experience or who have experienced imaginary companions. For the study, a self
      administered questionnaire that sought information regarding the characteristics
      of children with and without imaginary companions was completed by 478 parents of
      children within the age range of 3 to 9.5 years. A significantly larger number of
      children with imaginary companions were reported to be first-born children, to be
      very imaginative, to incorporate myth in their play, and to explain events as
      magical. Overall, these results are interpreted to indicate that birth order,
      combined with characteristics such as imaginativeness and a predisposition to
      engage in fantasy, characterizes children with imaginary companions.

PMID- 10584319
TI  - Women's characteristics and gender role attitudes: support for father involvement
      with children.
AB  - Women's (N = 364) personal characteristics and gender role attitudes were
      examined in relation to their support for father involvement with children. The
      respondents completed measures of trust, attitudes toward women, hostility, self
      esteem, and father involvement. Nontraditional gender role attitudes, positive
      ratings of their own interpersonal trust, and low hostility toward men were
      predictive of the respondents' support for father involvement. Participant
      demographics (including age, marital status, and number of children) were
      unrelated to their views of father involvement. Results indicate the importance
      of considering the characteristics and attitudes women bring to the co-parental
      relationship in the examination of factors influencing father involvement with
      children. Findings are discussed within the context of mothers' primary child
      care and gatekeeping roles.

PMID- 10584320
TI  - Children's understanding of inferential knowledge.
AB  - The understanding of inference as a source of knowledge for 4- and 6-year-old
      children was investigated. Children and a puppet were shown 2 toys of different
      colors. The toys were hidden in separate plastic cans. After the puppet looked
      into 1 of the cans, 6-year-olds, but not 4-year-olds, usually judged that the
      puppet knew the color of the toy in the other can as well. The finding that 6
      year-olds attributed inferential knowledge to another observer is interpreted as
      evidence that children begin to understand the role of cognitive processes in
      knowledge acquisition around the age of 6 years.

PMID- 10584321
TI  - Self-concepts of mountain children of Nepal.
AB  - The authors explored the basis of the self-concepts of young children from
      impoverished villages high in the mountains of Nepal by having them respond to
      the How I See Myself questionnaire (A. Juhasz, 1985). The participants were 101
      children, 7 to 14 years old, from the Sherpa and Tamang ethnic groups. The
      results provide evidence for questioning the appropriateness of the content of
      Western self-esteem instruments for such children. The authors argue that items
      about satisfying basic physical needs may be most appropriate for assessing the
      self-esteem of such children.

PMID- 10584322
TI  - Experimenter effects on children's understanding of false drawings and false
      beliefs.
AB  - Two experiments were conducted in which a variant of J. McGarrigle and M.
      Donaldson's (1975) "Naughty Teddy" intervention was applied to children's
      understanding of false drawings and false beliefs. The results showed that
      preschool children's understanding of the contents of an out-of-date drawing
      improved when the drawing was made by a capricious agent ("Naughty Snakey" glove
      puppet) rather than by the experimenter. The children's performance on a false
      belief task also improved when the events that set up the false belief were the
      result of the actions of the glove puppet. The results are discussed in terms of
      the role of children's sensitivity to the pragmatics of interactions in their
      development of a theory of mind.

PMID- 10584323
TI  - Characteristics of children who interact in groups or in dyads.
AB  - Little research within the field of developmental or educational psychology has
      addressed teachers' perceptions of the characteristics of children who interact
      in different types of peer organizations. This study was designed to examine
      teachers' perceptions of the characteristics of boys and girls who interact in
      groups or in dyads. Participants (teachers and children) were recruited from 10
      classes from all grade levels of 2 elementary schools. The children were asked to
      name those in their classes who played together frequently. On the basis of
      participants' responses, 2 categories of target children were identified: those
      who played with at least 3 other children (group) and those children who played
      with 1 other child (dyad). Two teachers then rated each target child on 6
      characteristics. The results indicated that, compared with children who played in
      dyads, target children who played in groups were rated by teachers as being more
      competitive, receiving more attention from peers, valuing their friends more, and
      being more emotionally expressive. No differences were found between target
      children who played in groups or dyads in empathy or self-confidence. In
      addition, no interaction between sex and type of social organization was found
      for any of the measures. Results are discussed in terms of the relation between
      social organization and functions of peer relations.

PMID- 10584324
TI  - Dieting and body image in the child's world: conceptualization and behavior.
AB  - The authors examined children's (N = 431, aged 7 years to 10 years 9 months)
      understanding of and reasons for dieting, to validate recent research indicating
      that perceived body-image dissatisfaction and restrictive eating behaviors occur
      in pre-adolescent populations. Scores on 2 sentence-completion tasks confirmed
      that the children do have a clear understanding of what dieting means in terms of
      intent and behavior (defined, in this study, as intentional restrictive eating
      behaviors). The results indicated that children as young as 7 years of age report
      dissatisfaction with their current body size and deliberately engage in
      restrictive eating behaviors. These findings provide validation of previous
      research and emphasize children's capacity to engage in deleterious health
      behaviors. Given that extreme dieting behaviors are harmful to a child's physical
      and psychological well-being, the authors concluded that research exploring (a)
      the genesis of these attitudes and behaviors and (b) their continuity or
      discontinuity across childhood is required.

PMID- 10584325
TI  - Attachment and social support among adolescents.

PMID- 10584326
TI  - Unknown identification using reference mass spectra. Quality evaluation of
      databases.
AB  - The high success of the "uncertified" mass spectrometry spectral collection
      started in 1956 demonstrated qualitatively that a partial reference mass
      spectrum, even one measured routinely, can be of real value. Correct matchings
      were still possible despite reference errors, which almost never led to close
      matches that were incorrect. This study shows quantitatively that the number of
      different compounds, not the number of peaks in a spectrum, is by far the most
      important determinant of database efficiency for identifying a "global" unknown.
      A statistical evaluation of matching performance shows that only 6, 12, and 18
      peaks in a reference spectrum are 13%, 67%, and 96%, respectively, as valuable as
      hundreds of peaks. Also, a separately measured second spectrum of the same
      compound is 50% as valuable as the first. Database expansion that tripled the
      number of possible wrong answers only reduced the proportion of correct
      identifications by 5%. Corrections of a mass or abundance error in each of six
      reference spectra increase the database matching performance by as much as the
      addition of one spectrum of a new compound. A new "matching quality index" based
      statistically on these values indicates that the largest database is also by far
      the most effective for matching unknowns.

PMID- 10584327
TI  - Studies of structure and mechanism in acetonitrile chemical ionization tandem
      mass spectrometry of polyunsaturated fatty acid methyl esters.
AB  - Recently it has been shown that acetonitrile chemical ionization tandem mass
      spectrometry (CI-MS/MS) is a rapid, on-line means to determine double bond
      position in fatty acid methyl esters (FAME). The mechanism of this gas phase
      condensation reaction has been studied. Evidence of the (1-methyleneimino)-1
      ethenylium ion (m/z 54), formed upon the reaction of acetonitrile with itself,
      adding across the double bond in a [2 + 2] cycloaddition reaction is observed.
      When this nascent complex undergoes collision-induced dissociation, two
      diagnostic ions emerge. One of these ions results from loss of the hydrocarbon
      end of the FAME, whereas the other ion results from loss of the methyl ester end,
      and when considered together, the diagnostic ions localize the positions of the
      double bonds in the FAME. Several labeling and MS/MS/MS experiments on the two
      diagnostic ions were performed to determine a plausible fragmentation mechanism
      of the stable (1-methyleneimino)-1-ethenylium-FAME complex. The first generation
      product ions, or diagnostic ions, appear to be formed though a charge-driven
      mechanism, whereas the second generation product ions are formed via charge
      remote fragmentations. Plausible mechanisms for the formation and subsequent
      dissociation of the diagnostic ions are presented for the monounsaturated,
      diunsaturated, and polyunsaturated (3 or more double bonds) FAME.

PMID- 10584328
TI  - Sheathless preconcentration-capillary zone electrophoresis-mass spectrometry
      applied to peptide analysis.
AB  - A reliable capillary zone electrophoresis-electrospray ionization-tandem mass
      spectrometry system has been developed for the sensitive analysis and sequencing
      of peptides. The system comprises (1) a zero dead volume on-line sample
      preconcentration interface allowing over 100-fold increase in sample volume
      introduction and (2) a zero-dead volume, durable electrospray emitter yielding
      stable, low background electrospray signals, both proving not to compromize the
      electrophoretic performance. Sub-fmol sensitivities were obtained in applications
      to complex peptide samples derived from tryptic digestion of proteins and
      naturally processed major histocompatibility complex class I associated peptides.

PMID- 10584329
TI  - High-throughput sample preparation and analysis using 96-well membrane solid
      phase extraction and liquid chromatography-tandem mass spectrometry for the
      determination of steroids in human urine.
AB  - A 96-well solid-phase extraction (SPE) system is used to rapidly prepare human
      urine samples for high-throughput quantitative analysis of two steroids,
      equilenin and progesterone, by liquid chromatography-tandem mass spectrometry
      using deuterated estrone as the internal standard. We define high-throughput here
      as analysis of 384 samples in a 24 h period. A total of 384 samples and standards
      were extracted by an individual in one day and subsequently analyzed within a 24
      h period. The inter- and intratray accuracy and precision obtained over the
      course of these injections was within 8% coefficient of variation when analyzed
      by atmospheric pressure chemical ionization mass spectrometry using positive ion
      detection. A semiautomated sample processing workstation was used to add internal
      standard and then process 96 samples at a time. The recovery of the analytes from
      the SPE was approximately 85%. The accuracy and precision obtained was comparable
      to that ordinarily obtained using manual sample preparation techniques.

PMID- 10584330
TI  - Fingerprint patterns from laser-induced azido photochemistry of spin-labeled
      photoaffinity ATP analogs in matrix-assisted laser desorption/ionization mass
      spectrometry.
AB  - The photochemical reaction of azide derivatives induced by ultraviolet (UV) laser
      in matrix-assisted laser desorption/ionization mass spectrometry (MALDI) is
      reported. A novel synthesized class of azide aromatic derivatives, spin-labeled
      photoaffinity non-nucleoside adenosine triphosphate (ATP) analogs which are
      useful probes in study of muscle contraction mechanism, is used in this
      investigation. In the negative ion MALDI spectra of these ATP analogs,
      "fingerprint" peaks corresponding to [M - 10 - 1]-, [M - 12 - 1]-, [M - 16 - 1]-,
      [M - 26 - 1]-, [M - 28 - 1]-, [M - 41 - 1]-, and [M - 42 - 1]- were observed with
      relative intensities depending on the MALDI matrix. Only the [M - 16 - 1]- is
      present in the similar mass spectra of the analog in which the azido group is
      replaced by a hydrogen. A model is suggested for the photochemical reactions of
      azide derivatives under UV laser irradiation. The photoreaction fingerprint
      information is diagnostically useful in characterization of azido compounds,
      especially for spin-labeled photoaffinity non-nucleoside ATP analogs.

PMID- 10584331
TI  - The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in
      bacteria, algae and higher plants.

PMID- 10584332
TI  - Lantibiotics: biosynthesis, mode of action and applications.

PMID- 10584333
TI  - Bioactive natural products with carbon-phosphorus bonds and their biosynthesis.

PMID- 10584334
TI  - Diterpenoid and steroidal alkaloids.

PMID- 10584335
TI  - 'Small worlds' and the evolution of virulence: infection occurs locally and at a
      distance.
AB  - Why are some discases more virulent than others? Vector-borne diseases such as
      malaria and water-borne diseases such as cholera are generally more virulent than
      diseases spread by direct contagion. One factor that characterizes both vector-
      and water-borne diseases is their ability to spread over long distances, thus
      causing infection of susceptible individuals distant from the infected
      individual. Here we show that this ability of the pathogen to infect distant
      individuals in a spatially structured host population leads to the evolution of a
      more virulent pathogen. We use a lattice model in which reproduction is local but
      infection can vary between completely local to completely global. With completely
      global infection the evolutionarily stable strategy (ESS) is the same as in mean
      field models while a lower virulence is predicted as infection becomes more
      local. There is characteristically a period of relatively moderate increase in
      virulence followed by a more rapid rise with increasing proportions of global
      infection as we move beyond a 'critical connectivity'. In the light of recent
      work emphasizing the existence of 'small world' networks in human populations,
      our results suggests that if the world is getting 'smaller'--as populations
      become more connected--diseases may evolve higher virulence.

PMID- 10584336
TI  - Transmission dynamics of a zoonotic pathogen within and between wildlife host
      species.
AB  - The transmission dynamics of the cowpox virus infection have been quantified in
      two mixed populations of bank voles (Clethrionomys glareolus) and wood mice
      (Apodemus sylvaticus), through analyses of detailed time-series of the numbers of
      susceptible, infectious and newly infected individuals. The cowpox virus is a
      zoonosis which circulates in these rodent hosts and has been shown to have an
      adverse effect on reproductive output. The transmission dynamics within species
      is best described as frequency dependent rather than density dependent, contrary
      to the 'mass action' assumption of most previous studies, both theoretical and
      empirical. Estimation of a transmission coefficient for each species in each
      population also allows annual and seasonal variations in transmission dynamics to
      be investigated through an analysis of regression residuals. Transmission between
      host species is found to be negligible despite their close cohabitation. The
      consequences of this for the combining ability of hosts as zoonotic reservoirs,
      and for apparent competition between hosts, are discussed.

PMID- 10584337
TI  - Kin discrimination and female mate choice in the naked mole-rat Heterocephalus
      glaber.
AB  - Naked mole-rats are fossorial, eusocial rodents that naturally exhibit high
      levels of inbreeding. Persistent inbreeding in animals often results in a
      substantial decline in fitness and, thus, dispersal and avoidance of kin as mates
      are two common inbreeding avoidance mechanisms. In the naked mole-rat evidence
      for the former has recently been found. Here we address the latter mechanism by
      investigating kin recognition and female mate choice using a series of choice
      tests in which the odour, social and mate preferences of females were determined.
      Discrimination by females appears to be dependent on their reproductive status.
      Reproductively active females prefer to associate with unfamiliar males, whereas
      reproductively inactive females do not discriminate. Females do not discriminate
      between kin and non-kin suggesting that the criterion for recognition is
      familiarity, not detection of genetic similarity per se. In the wild, naked mole
      rats occupy discrete burrow systems and dispersal and mixing with non-kin is
      thought to be comparatively rare. Thus, recognition by familiarity may function
      as a highly efficient kin recognition mechanism in the naked mole-rat. A
      preference by reproductively active females for unfamiliar males is interpreted
      as inbreeding avoidance. These findings suggest that, despite an evolutionary
      history of close inbreeding, naked mole-rats may not be exempt from the effects
      of inbreeding depression and will attempt to outbreed should the opportunity
      arise.

PMID- 10584338
TI  - Positive identification of the puberty-accelerating pheromone of the house mouse:
      the volatile ligands associating with the major urinary protein.
AB  - Five structurally diverse small ligands, all binding to the major urinary protein
      (MUP) of the male house mouse, show individually puberty-accelerating pheromonal
      activity in the recipient females. A recombinant MUP (identical structurally to
      the natural protein) has shown no biological activity. While four of these
      ligands were previously implicated in oestrus synchronization (Whitten effect),
      the same chemosignals now appear responsible for both sexual maturation and
      cycling in adult females.

PMID- 10584339
TI  - Uniformity of colour vision in Old World monkeys.
AB  - It is often assumed that all Old World monkeys share the same trichromatic colour
      vision, but the evidence in support of this conclusion is sparse as only a small
      fraction of all Old World monkey species have been tested. To address this issue,
      spectral sensitivity functions were measured in animals from eight species of Old
      World monkey (five cercopithecine species and three colobine species) using a non
      invasive electrophysiological technique. Each of the 25 animals examined had
      spectrally well-separated middle- and long-wavelength cone pigments. Cone
      pigments maximally sensitive to short wavelengths were also detected, implying
      the presence of trichromatic colour vision. Direct comparisons of the spectral
      sensitivity functions of Old World monkeys suggest there are no significant
      variations in the spectral positions of the cone pigments underlying the
      trichromatic colour vision of Old World monkeys.

PMID- 10584340
TI  - Sensory and intrinsic coordination of movement.
AB  - A recently generalized theory of perceptual guidance (general tau theory) was
      used to analyse coordination in skilled movement. The theory posits that (i)
      guiding movement entails controlling closure of spatial and/or force gaps between
      effectors and goals, by sensing and regulating the tau s of the gaps (the time-to
      closure at current closure rate), (ii) a principal way of coordinating movements
      is keeping the tau s of different gaps in constant ratio (known as tau-coupling),
      and (iii) intrinsically paced movements are guided and coordinated by tau
      coupling onto a tau-guide, tau g, generated in the nervous system and described
      by the equation tau g = 0.5 (t-T 2/t) where T is the duration of the body
      movement and t is the time from the start of the movement. Kinematic analysis of
      hand to mouth movements by human adults, with eyes open or closed, indicated that
      hand guidance was achieved by maintaining, during 80 85% of the movement, the tau
      couplings tau alpha-tau r and tau r-tau g, where tau r is tau of the hand-mouth
      gap, tau alpha is tau of the angular gap to be closed by steering the hand and
      tau g is an intrinsic tau-guide.

PMID- 10584341
TI  - [The travel of urology: from scalpel to restriction enzymes].

PMID- 10584342
TI  - [Indications for BCG in surface tumors of the bladder].
AB  - Overall view of Bacille de Calmette-Guerin (BCG) immunotherapy in the prophylaxis
      and treatment of surface cancer of the bladder. A series of issues, on some of
      which a consensus has been reached while controversy is still frequent in others
      are discussed. Intravesical instillation of BCG as the single route has been
      considered to best mode of administration. With regard to the BCG strain to be
      used, there is still no consensus after the analysis of the data provided by the
      studies conducted. Relative to the treatment schedule, it appears clear that
      maintenance therapy is superior to an exclusively induction regime. No consensus
      has been reached about optimal dosage or the possibility to reduce toxicity.
      Although some studies support the belief that intravesical immunotherapy with BCG
      is superior to chemotherapy, further data is required to confirm such assumption.
      In conclusion, although treatment with BCG has proven to be effective in patients
      with surface tumours of the bladder, it should not be considered a panacea to be
      indiscriminately used in any patient with this malignancy.

PMID- 10584343
TI  - [Comparative population-based survey as evaluation method of prostate disease
      changes].
AB  - A survey-based comparative study was conducted to evaluate the changes on the
      prostate pathology in two male populations separated by a time interval of two
      years (1st and 3rd Week of Prostate Health). A total of 2056 respondents in the
      1st Week, and 2126 in the 3rd Week were evaluated. The questionnaire included
      questions relative to prostate awareness, impact of urinary complaints on daily
      like activities, Spanish validated IPSS and selective questions for prostate
      patients. The comparison between both surveys disclosed visits to the urologist
      at earlier age and longer-standing symptoms. The most prevalent symptoms continue
      to be decreased calibre of the urinary stream, pollakiuria and urgency. IPSS/L
      and IPSS/age ratios remained unchanged. There was increased number of visits by
      mildly symptomatic patients (IPSS < 8), increased periodical revisions, and in
      the number of patients seen and treated by the urologist. A significant
      approximation to the diagnostic testing criteria established by the WHO for BPH
      was demonstrated. The number of patients who received treatment raised and there
      was also a significant improvement in the outcome. Comparative populational
      studies could allow to assess changes in the awareness status of the prostate,
      changes in symptomatic levels and quality of life of the population requesting
      health care, as well as changes in the diagnostic and therapeutical schemes in
      patients suspected of having BPH.

PMID- 10584344
TI  - [Progression and prognosis of in situ carcinoma of the bladder treated with BCG].
AB  - OBJECTIVES: In situ carcinoma (isT) of the bladder is a poor prognostic tumour
      with a natural progressive evolution. Treatment with BCG achieves a significant
      improvement in survival. This paper analyses our experience in the management of
      isT patients with endovesical BCG. MATERIAL AND METHODS: Between 1983 and 1997
      the Urology Unit in the Mostoles Hospital saw 636 patients with transitional
      carcinoma of the bladder. Of these, 498 (78%) were surface tumours, and 138 (22%)
      were infiltrant. isT: 80 patients (13%), 14 of which were primary (17%), 37
      associated to a surface tumour (46%), and 29 to infiltrant tumours (36%). All
      surface tumours: isT was present in 51 patients (10%) 44 of which were managed
      with 2 courses of BCG Connaught (81 mg), for 6 weeks each followed by vesical
      reassessment. Quarterly follow-up was conducted during a 2-year period. Patients
      not managed with BCG were treated with radical cystectomy. An analysis was made
      of patients without complete response to BCG, as well as actuarial analysis of
      disease-free survival (DFS), survival until progression (SUP) and specific
      survival (SS). All possible prognostic factors are analyzed: sex, focal isT (a
      single focus) or diffuse isT (more than one focus). Primary or secondary isT and
      association to G1, G2 or G3 tumours. RESULTS: In all 44 patients managed with
      BCG: males 37 (84%), females 7 (16%), primary 14 (32%), focal 22 (50%), diffuse
      22 (50%). Six patients died (5 because of the tumour). Mean follow-up of living
      patients: 3.7 years (0.5-7.5 years). After the 2 BCG courses, 36 (82%) showed
      complete response. Thirteen patients (30%) had no complete response during follow
      up, and 11 (85%) continued to progression. In total 7 patients underwent
      cystectomy. Of 5 patients directly cystectomized due to persistence of isT or
      T1G3 tumour at monitoring after BCG, 2 (40%) had infiltrant tumour and one (20%)
      nodular metastasis. Three patients with persistent isT or T1G3 after BCG were not
      initially cystectomized: two that were treated with other endovesical therapies
      because of their age progressed, and the third one underwent a third BCG course
      and required cystectomy due to tumour persistency. 5-year DFS: 56%, being diffuse
      isT vs. focal isT (p = 0.0206) was an unfavourable prognostic factor. 5-year SUP:
      63%, no significant prognostic factor. 5-year SS: 79%, being a female was an
      unfavourable prognostic factor (p = 0.0201). CONCLUSIONS: Based on our results
      and the analysis of the literature we recommend treatment with 2 BCG courses of
      all isTs of the bladder that present some of the following factors: Diffuse
      cancer associated to T1G3, involvement of prostatic urethra or overexpression of
      p53 over 20%. In the rest of vesical tumours, one BCG course followed by a second
      one if lack of response to the first. After failure of both BCG courses,
      cystectomy must be performed in both groups.

PMID- 10584345
TI  - ["Evanescent" prostate carcinoma].
AB  - Occurrence of prostatectomy sections with minimum or no tumour volume have been
      increasingly seen over the last few years in spite of a preoperative histology
      based diagnosis of adenocarcinoma with a needle biopsy ("evanescent cancer
      phenomenon" ECP). Our group has reviewed 145 prostatectomies performed in our
      hospital between January 1988 and October 1997, and found 3 cases of ECP (2%). To
      explain this phenomenon patients must be divided into two groups. In those who
      receive preoperative hormonal blockade, treatment may result in a drastic
      reduction of tumoral volume as well as microscopic changes that make malignancy
      recognition more difficult. ECP occurs in less than 5% of these prostatectomies.
      In patients with no previous hormonal treatment, ECP is extremely rare and any
      explanation comes as a consequence of the extended use of screening methods that
      lead to the detection of very small tumours, probably of little clinical
      relevance, that are found in the needle biopsy. Subsequently, however, no
      residual neoplasia is seen in the section either due to technical limitations of
      the pathoanatomical methods or because of a true, complete ablation of the lesion
      through the biopsy.

PMID- 10584346
TI  - [Early diagnosis of prostate cancer in patients with prostate symptoms by DRE,
      PSA, TRU and DPSA].
AB  - Presentation of our experience in the early diagnosis of prostate cancer in
      patients with signs and symptoms of prostatism. Over a one year period (96-97),
      316 patients underwent biopsy based on clearly defined criteria according to the
      diagnostic algorithm used in our centre: suspicious DRE and/or PSA > or = 10
      ng/mL, and in patients with PSA between 4 and 10 ng/mL in the presence of
      suspicious TRU or when DPSA was > or = 0.15. The ratio of the 136 (43%) prostate
      cancer diagnosed relative to biopsy +/- was 1:1.32. It is concluded that early
      diagnosis in a selected population is useful and shows good diagnostic yield. The
      diagnostic algorithm used is more than acceptable with 43% positive biopsies and
      a good ratio between biopsy +/-. With a cutoff of 0.15 DPSA is a good method to
      improve PSA significance in patients in the difficult PSA range of 4 to 10 ng/mL.

PMID- 10584347
TI  - [Radical prostatectomy in prostate adenocarcinoma. Clinical factors influencing
      the pathological stage. Diagnostic model].
AB  - MATERIAL AND METHODS: Study on the efficacy of stage diagnosis, how to support it
      based on clinical objective data and description of a prognostic model. Analysis
      of 160 patients diagnosed with localized prostate adenocarcinoma undergoing
      radical prostatectomy in the Clinica Universitaria de Navarra between 1988-1997.
      The statistical study used Fisher's or Pearson's tests for the comparison of
      qualitative variables. A logistic regression multivariate analysis was run to
      avoid confounding factors in the pathological stage. RESULTS: 85/160 (53%) were
      correctly staged. Incorrect staging occurred in patients with higher clinical
      stage (T1-T2a: 25%; T2bc: 65%). The univariate study shows that the pathological
      stage is significantly correlated to: a) serum PSA levels (15 ng/mL in P2 vr. 25
      ng/mL in P3-4), the most suitable cutoff value being 15 ng/mL. b) digital rectal
      examination and Gleason. Negatively influencing factors in the multivariate study
      were: PSA greater than 15 ng/mL, Gleason greater than 5 and a T2bc clinical
      stage. Risk groups: 4 risk groups are established based on the above factors
      (inclusion in group 1 involves an 8% risk of having P3, 30% in group 2, 56% in
      group 3 and 84% in group 4). CONCLUSIONS: The clinical factors with influence in
      the pathological stage are PSA, Gleason and clinical stage. The reliability of
      the risk groups established based on these factors is remarkable.

PMID- 10584348
TI  - [Trigonocervicoprostatomy. Indications and results from 100 case reports].
AB  - Trigonocervicotomy is a barely invasive technique for the treatment of
      infravesical obstruction, first introduced in the 60's by Turner-Warkic and
      Orandi. To achieve good results with this procedure, the selection criteria must
      take into account a series of parameters such as age, sexual activity, PSA,
      prostate weight (below 30 grams) and others. In addition to its low morbidity, a
      larger percentage of patients preserve ejaculation than with the use of other
      techniques, also the neck sclerosis rate being lower as seen in all our series
      and expertise. The efficacy of this technique was studied on 100 patients.

PMID- 10584349
TI  - [Use of the appendix in urology: analysis of findings and incidental
      appendicectomy in urological patients].
AB  - In spite of the long-standing use of the appendage in urological reconstructive
      surgery, it wasn't until the 80's that became popular. Anatomical and
      histological normality is the major consideration to allow use of the appendage
      in autografting. Over a 9-year period, performance of incidental appendicectomies
      in abdominal major surgery in adult patients was included as a surgical routine
      practice in our service. This paper describes the pathoanatomical findings of
      incidentally removed appendages, discussing the relevance of such findings in the
      incorporation of the appendage to the urinary tract.

PMID- 10584350
TI  - [Suprarenal myelolipoma: an "incidental" disease].
AB  - With the development and improvement of imaging techniques, we are witnessing a
      greater number of disease diagnoses considered uncommon only a few years ago.
      When the diagnosis of a tumoral disease occurs "incidentally" while performing an
      imaging examination for other reasons, we name the condition "INCIDENTALOMA". A
      clear example of these in suprarenal conditions is the myelolipoma. Myelolipoma
      is a benign and non-functioning tumour originating in the suprarenal cortex and
      histologically consisting of mature fat and haemopoietic tissue. Given its benign
      and usually inactive nature, the current approach is a conservative attitude.
      Surgical exeresis is only accepted when large tumoral masses are present or in
      complicated cases. This paper presents a new case of a 10 cm suprarenal
      myelolipoma incidentally diagnosed during routine ultrasound examination in a 47
      year old male patient. Subsequent exeresis of the suprarenal mass and
      pathohistological study confirmed the diagnosis.

PMID- 10584351
TI  - [Mucinous prostate adenocarcinoma initially presented as an intestinal
      subocclusive picture].
AB  - Mucinous prostate adenocarcinoma is an infrequent tumour, with no more that 50
      cases described to date. This paper contributes a new case of the entity. Rather
      than on the rarity of the tumour, the interest in our case focuses in the unusual
      nature of its clinical presentation. It initially appeared as a presumable
      rectoanal neoplasia but the pathoanatomical examination discovered the prostatic
      origin of the tumoration.

PMID- 10584352
TI  - [Metastatic prostate adenocarcinoma in hernial sac. Contribution of one case].
AB  - Presentation of a case of stage D2 prostatic adenocarcinoma, diagnosed through a
      chance finding of micrometastasis in the pathohistological study of the hernial
      sac of a patient undergoing inguinal herniorrhaphy. Most usual sites for prostate
      cancer metastasis are lymph nodes, bones, lungs, liver, and brain. During our
      revision of unusual anatomical sites for prostatic carcinoma metastasis, we found
      references of metastasis on the uvea, larynx, orbit and maxillary sinus. The
      peritoneal cavity was not found to be a common site for metastatic implants. It
      was also found that such peritoneal spread was usually diagnosed after a
      postmortem examination.

PMID- 10584353
TI  - [Clear cell renal carcinoma outside of the usual age group].
AB  - We report a case of a 17 year old woman with a clear cell sarcoma of kidney
      treated at the Division of Urology of Hospital General de Agudos Dr. Jose M.
      Ramos Mejia dependent of Government of Buenos Aires City. This report is based on
      the unusual age of tumor presentation and its good course and results after
      radiotherapy and chemotherapy, with 10 years survival after surgery.

PMID- 10584354
TI  - [Relapse in brucella orchiepididymitis].
AB  - This paper describes a case of systemic brucellosis accompanied by brucellar
      orchitis that resolved favourably. There was however a relapse at the testicular
      level inappropriately treated that triggered a new episode of systemic
      brucellosis.

PMID- 10584355
TI  - [Hydatidosis in a single location].
AB  - Hydatidosis in our country an important health problem because of its high
      prevalence. We present a case of renal Hydatidosis in which we point out the
      renal single location of the disease and emphasize that MRI helped us to find a
      correct preoperative diagnosis.

PMID- 10584356
TI  - [Laparoscopic approach of Dielt's syndrome].
AB  - Dielt's syndrome is generally known as nephritic colic due to the dilation of the
      urinary tract that results from a renal ptosis. In spite of renal ptosis being a
      commonly seen occurrence, sometimes it can be the cause of a serious painful
      clinical manifestation. This paper presents one case successfully treated through
      laparoscopic nephropexy. It also includes a discussion on the various diagnostic
      and therapeutical techniques.

PMID- 10584357
TI  - [Cerebral oximetry in pediatric anesthesiology].
AB  - A new method, spectroscopy in a spectrum approximating the infrared, was used in
      children during total anesthesia for evaluating the oxygen status and blood
      content of the brain. This method shows in the real time mode the content of
      total hemoglobin and its fractions oxyhemoglobin and deoxyhemoglobin in brain
      tissue. Oxidative (RedOx) status of cerebral cell cytochrome oxidase was
      assessed. A total of 128 children aged 7 months to 14 years were observed
      throughout total anesthesia. The method is highly informative and can be used for
      monitoring the degree of oxygenation, tissue respiration, and blood filling of
      the brain during total anaesthesia in children and for evaluating the effects of
      various anesthetics on these parameters.

PMID- 10584358
TI  - [Evaluation of the effectiveness of slow-flow anesthesia in children].
AB  - Combined total anesthesia by a slow flow of fresh gas (slow-flow anesthesia) was
      used in 98 children aged 1-14 years with various surgical diseases. The
      advantages of this method consist in a lower loss of humor and heat from the
      child's airways during surgery, a lower contamination of the air in the operation
      room, and a lower cost of anesthesia. If properly monitored, such anesthesia is a
      sufficiently effective and safe method of inhalation anesthesia, which can be
      used with good results in routine pediatric surgery.

PMID- 10584359
TI  - [Electroencephalographic monitoring in intravenous anesthesia using propofol in
      children].

PMID- 10584360
TI  - [Evaluation of the effectiveness of a new myorelaxant nimbex (cisatracurium
      besilate) in children].
AB  - Cisatracurium besilate was used in 21 children aged 2-12 years (ASA classes I-II)
      for intravenous anesthesia anesthetic + nitrous oxide + oxygen (group 1, 11 pts)
      and halothane + nitrous oxide + oxygen (group 2, 11 pts). In group 1 the initial
      nimbex dose was 0.15 mg/kg, in group 2 0.12 mg/kg, which created good or
      excellent conditions for intubation within 2 min and induced a neuromuscular
      blocking (NMB) for 44.2 +/- 4.7 and 37.6 +/- 5.9 min, respectively. NMB was
      maintained by bolus injections of nimbex in doses of 0.03 mg/kg (group 1) and
      0.02 mg/kg (group 2). The duration of myoplegia was 18.6 +/- 3.6 and 13.2 +/- 2.3
      min, respectively. Clinically the relaxation was sufficient throughout the
      operation. Neuromuscular conduction recovered spontaneously in all cases,
      extubation was carried out 42.2 +/- 3.8 min after the last bolus injection of
      nimbex in group 1 and after 35.4 +/- 7.4 min in group 2. No appreciable
      fluctuations of hemodynamic parameters or other side effects (skin hyperemia or
      bronchial spasm) were observed during anesthesia. Studies of the benzyl
      isoquinoline myorelaxant cisatracurium besilate demonstrated that this effective
      and safe drug with an average duration of effect can be used in pediatric
      anesthesiology.

PMID- 10584361
TI  - [A comparative study of 2 methods of neuromuscular function monitoring,
      electromyography and acceleromyography, during anesthesia in children].
AB  - The responses of m. adductor pollici to TOF stimulation of the ulnar nerve were
      recorded by electromyography (EMG) and acceleromyography (AMG) in 36 children
      aged 2-12 years with ASA classes I-II during 36 planned surgeries. In 14 children
      myoplegia was attained by intravenous bolus and infusion atracurium (Tracrium)
      and in 22 by cisatracurium (nimbex). The data on the function of this muscle
      after the initial bolus injection of myoplegics do not provide reliable
      information on the function of the larynx and respiratory muscles during
      intubation and do not allow a conclusion on the possibility of endotracheal
      intubation. The threshold sensitivities of EMG and AMG recording of the
      neuromuscular function starting from the fifth minute after the myorelaxant
      injection till the end of anesthesia are different. EMG permits evaluating the
      recovery of neuromuscular conduction early after the infusion of myoplegics;
      complete recovery of the block is shown virtually simultaneously by AMG and EMG.
      EMG as a more accurate method is preferable for research, while AMG is a simpler
      and stable method, preferable for routine practice.

PMID- 10584362
TI  - [Characteristics of anesthesia in trauma surgery in children with severe burn
      injuries].
AB  - The authors analyze total anesthesia in 347 children with thermal injuries,
      subjected to traumatic operations involving massive blood loss. A characteristic
      feature of total anesthesia in children subjected to early necrectomies was a
      lower dose or refusal from cholinolytics for premedication, endotracheal
      multicomponent narcosis with ketamine, fentanyl (promedole) in the minimal doses
      in parallel with inhalation anesthesia by fluothane traces and a nitrous oxide
      oxygen mixture with at least 50% oxygen. The optimal initial dose of
      nondepolarized myorelaxants in burnt children is 30-50% higher than the
      recommended dose and is determined by the size and depth of injury. For
      controlled myoplegia, the doses of nondepolarized myorelaxants for subsequent
      injections should be 1.5-2.5 times lower than the initial dose. The duration of
      pancuronium and arduan effects depended on hepatorenal function. Tracrium
      provided regulated myorelaxation in children with burns even in cases with
      hepatorenal dysfunction. A high rate of massive blood loss and early development
      of multiple organ failure in children with thermal injuries prompted us to
      develop infusion-transfusion therapy for traumatic operations involving massive
      blood loss. The volume of blood loss is estimated from the area of necrotic
      tissues removed and the type of necrectomy. Qualitative composition of
      transfusion mixture and the rate of transfusion is determined by the rate and
      volume of blood loss, level of hemoglobin and hematocrit, and metabolic disorders
      during the operation. Prolonged ventilation of the lungs is recommended for
      children with thermal injuries after operations involving blood loss of 1
      circulating blood volume or more. These measures decreased the incidence and
      severity of complications involving the hemodynamics, oxygen status and
      metabolism in tissues, and improved the reparation.

PMID- 10584363
TI  - [Effects of changes in body posture on hemodynamics in patients with infantile
      cerebral palsy during general anesthesia with preservation of spontaneous
      respiration].
AB  - The central hemodynamics was examined in 40 patients with infantile cerebral
      paralysis aged 9-14 years. The studies were carried out under halothane +
      ketamine analgesia with spontaneous respiration. The central hemodynamic
      parameters were evaluated by tetrapolar rheography after Kubicek with the patient
      lying supine and turning on the right and left side. The primary hemodynamic
      reactions are universally directed during turning on the left and right side, but
      more pronounced during turning on the right side.

PMID- 10584364
TI  - [Induction of anesthesia in ambulatory surgery in children].
AB  - The studies were carried out in 163 children aged 3-16 years operated in a one
      day hospital. The patients were divided into 3 groups administered different
      types of induction anesthesia: 1) ethrane inhalation up to 3 vol% and N2O with O2
      in 1:1 ratio (56 children); 2) fluothane up to 3.5 vol% and N2O with O2 in 2:1
      ratio (87 children); and 3) intravenous calipsol in a dose of 2-4 mg/kg (20
      children). Central hemodynamic parameters, cardiointervalograms, and external
      respiration function were analyzed. Induction with ethrane was longer (4-12 min)
      than with fluothane (3-5 min). The reaction of central hemodynamics was less
      expressed after induction anesthesia with ethrane and fluothane in combination
      with N2O and O2 than after calipsol, leading to a decrease in the sympathetic
      tone and a higher activity of the parasympathetic component of the autonomic
      nervous system. Calipsol induction was associated with the predominance of the
      sympathetic component of the autonomic nervous system.

PMID- 10584365
TI  - [Complications of anesthesia and their prevention in children with spastic
      cerebral palsy during ambulatory surgery].
AB  - A total of 8000 anesthesias with ketamine or ketamine + halothane in children
      with infantile cerebral paralysis, operated in a one-day hospital, are analyzed.
      The complications were as follows: tachycardias in 12%, hypotonia in 8%, repeated
      vomiting in 5%, postnarcosis depression in 10%, psychomotor excitation in 9%, and
      painful syndrome in 7%. The most incident combination of complications was
      hypotonia, tachycardia, repeated vomiting, and postnarcosis depression.
      Complications occurred in 14.2% cases in ketamine anesthesia and in 4.3% cases in
      halothane + ketamine anesthesia.

PMID- 10584366
TI  - [Effects of trigger flow artificial ventilation of the lungs in newborn with
      respiratory distress syndrome].

PMID- 10584367
TI  - [Artificial ventilation of the lungs in pulmonary hypertension in newborn infants
      with congenital defects].

PMID- 10584368
TI  - [Prolonged blocking of the brachial plexus by axillary approach in children].
AB  - Surgical interventions were carried out under combined total anesthesia with
      prolonged blocking of the brachial plexus via axillary approach in 40 children
      aged 4-14 years with surgical diseases of the arms. Prolonged axillary blockade
      maintained adequate analgesia in the lower third of the brachial bone, ulnar
      joint, forearm, and hand for 24-48 h. The proposed protocols of lidocaine and
      bupivacaine infusion into the axillary space of the brachial plexus caused no
      toxic reactions in children of this age group. The method can be used in children
      during and after surgery.

PMID- 10584369
TI  - [High thoracic epidural analgesia in the postoperative period after correction of
      congenital heart defects in children].
AB  - The effects and side effects of thoracic epidural analgesia on the respiratory
      response, awakening time, and cooperation with nurses were studied. Forty
      children received epidural analgesia after open-heart surgery. Lidocaine was
      injected in a dose of 1.5-2 mg/kg every 1.5-2 h. Controls (16 pts) received
      intravenous fentanyl + diazepam analgesia. Respiratory response and awakening
      were significantly earlier (p < 0.001) in the epidural group. Cooperation with
      nurses was much better in this group, too. No side effects were observed in the
      epidural group. Therefore, thoracic epidural analgesia is a safe and effective
      method of postoperative analgesia for children subjected to open-heart surgery.

PMID- 10584370
TI  - [Postoperative epidural analgesia using local anesthetics in combination with
      morphine in children].
AB  - Epidural analgesia with lidocaine (trimecaine) in combination with the minimum
      morphine doses is an effective method for regional pain relief in children. It
      maintains a long postoperative analgesia with 5-10 times lower doses of
      narcotics.

PMID- 10584371
TI  - [Use of laser irradiation in intensive care of children during the postoperative
      period].
AB  - Homeostasis parameters, level of endotoxicosis, free radical lipid peroxidation,
      and antiradical defense were studied in young children administered laser
      exposures and antioxidants unithiol and vitamin E within the protocol of
      intensive case for pyoinflammatory diseases. The patients were divided into three
      groups with different protocols of treatment. Clinical and biochemical findings
      indicate the efficacy of laser therapy and antioxidants.

PMID- 10584372
TI  - [Experience in the use of EMLA ointment in analgesia of children operated on in
      one-day surgical hospital].

PMID- 10584374
TI  - [Characteristics of anesthesiological care in adenotonsillectomy in children].

PMID- 10584373
TI  - [Pediatric regional anesthesia: rational approaches and practical aspects].
AB  - Regional anesthesia in children is to be carried out with due consideration for
      anatomy, physiology (specifically, neurophysiology), pharmacology of local
      anesthetics, and detailed knowledge of pediatric protocols of numerous regional
      blockades. Age-specific differences in the pharmacokinetics of local anesthetics
      should be borne in mind when choosing safe doses and protocols. The
      pharmacokinetic factors may involve the risk of toxic reactions to local
      anesthetics. The protocols of central neuroaxial blockades in children are
      characterized by certain differences, concerning the indications, anatomic
      reference points, choice of special equipment, doses, and schemes of
      administration.

PMID- 10584375
TI  - [Current problems in anesthesia and intensive care in pediatrics].

PMID- 10584377
TI  - [Pilot study of interferon alpha-2b tolerance in patients with stage III
      melanoma].
AB  - GOAL: Evaluation of interferon alpha-2b adjuvant treatment (INF alpha-2b)
      toxicity by monitoring biologic parameters in patients with stage III melanoma.
      METHOD: Between January 7th till October 29th 1998, we administered 674
      injections of INF alpha-2b to eight patients who previously had undergone surgery
      for stage III melanoma. Patients received 20 MU/m2/d IV for a month and 10
      MU/m2/d sub-cutaneously three time a week for 48 weeks. All these patients were
      followed with at least one complete blood count and hepatic profile every week.
      Interferon alpha-2b doses were changed accordingly. RESULTS: Patients received on
      average 51.5% of the total dose. Doses were decreased in patients with
      neutropenia or hepatic profiles anomalies. Only one patient could received 100%
      of the total regimen. In four patients treatment was discontinued. In three out
      of four patients this was due to disease progression, and in one out of four
      patients this was due to hepatic toxicity. CONCLUSION: INF alpha-2b is less well
      tolerated than initially thought. Dosage was frequently decreased due to
      hematologic and hepatic toxicities. This could compromise the treatments
      efficacity. The minimal dose required to obtain an optimal response will thus
      have to be defined.

PMID- 10584376
TI  - [Hypertrichosis and gingival hypertrophy regression in renal transplants
      following the substitution of cyclosporin by tacrolimus].
AB  - Gingival Hyperplasia (GH) and hypertrichosis (HT) are two sides effects
      associated with the usage of cyclosporine (CyA) but not with tacrolimus (FK 506).
      The aim of this study is to evaluate the efficacy and security of the conversion
      from CsA to FK 506 to treat those two complications. From August 1996 to May
      1997, 15 patients (9 males, 6 females) aged from 23 to 63 years old (38 +/- 14,
      mean +/- SD) were switched from CsA to FK 506, 12 for GH, 2 for HT and one for
      combined presentation. FK 506 was first initiated at a dose of 0.15 mg/kg/day and
      then adjusted to a level target of 8 ng/ml. The conversion was done on an out
      patient basis at average 35 (5-83) months after transplantation. Patients were
      followed prospectively for 12 months. There was a significant reduction in GH in
      all patients within 3 months. Five out 13 patients had a complete resolution of
      GH within three months of conversion, 9/12 within 6 months and all by 12 months.
      HT resolved completely within 6 months. No rejection episode occurred and the
      serum creatinin remain stable over one year post conversion. Conversion from CsA
      to FK 506 is thus a safe and valid option to treat CsA induced GH and HT.

PMID- 10584378
TI  - [Systemic coronary surgery in the beating heart. Experience in 250 cases].
AB  - OBJECT: To report our recent experience with off-pump coronary artery
      revascularization in multi-vessel disease. METHODS: Between October 1996 and
      August 1998, 250 off-pump (OP) procedures were completed at the Montreal Heart
      Institute, representing more than 90% of all procedures done during the same time
      frame (97% for 1998). These patients have been compared to 1870 patients operated
      upon under cardiopulmonary bypass during the years 1995-1996 (CPB). RESULTS: Mean
      age, sexe distribution, and preoperative risk factors were comparable for both
      groups. On average 2.89 +/- 0.8 and 2.84 +/- 0.6 grafts/patient were completed in
      OP and CPB groups respectively. A majority (70%) of patients had either a triple
      or quadruple bypass. Coronary anastomoses were achieved with myocardial
      mechanical stabilization and heart "verticalization". Ischemic time was shorter
      in the OP group (29.8 +/- 0.9 vs 45 +/- 0.4 min, p < 0.05). Similarly, need for
      transfusion was significantly less (OP: 34 vs CPB: 66%, p < 0.005). Use of
      postoperative intra-aortic counterpulsation as well as the raise of CK-MB were
      lesser in the OP group. Operative mortality (OP: 1.6%, vs CPB: 2%, p = ns) and
      perioperative myocardial infarction rate (OP: 3.6% vs CPB: 4.2) were comparable
      for both groups. CONCLUSION: Off-pump complete coronary artery revascularization
      is an acceptable alternative to conventional surgery in a majority of patients
      with good results given progressive experience, rigorous technique, and adequate
      coronary artery stabilization.

PMID- 10584379
TI  - [Left main coronary artery stenosis and revascularization in the beating heart.
      Short- and long-term experience].
AB  - OBJECT: To determine the safety of surgical revascularization without
      cardiopulmonary bypass in left main coronary artery stenosis. METHODS: Between
      October 1996 and October 1998, 67 patients with a left main stem stenosis (LMS)
      (> 50%) underwent revascularization on beating heart surgery (BHS) and were
      compared to a cohort of 192 patients with LMS disease that were operated on under
      cardiopulmonary bypass (CPB) during 1996. RESULTS: Mean age and sex distribution
      and prevalence of preoperative risk factors were the same in both groups as well
      as the average number of grafts per patient was 3.1 +/- 0.7 and 2.9 +/- 0.7 in
      BHS and CPB groups respectively. Perioperative infarction rate (defined
      arbitrarily as a CK-MB > 100 IUL) was 2.9% in BHS group and 3.1% in CPB group.
      Postoperative blood transfusion requirements were less in BHS group (38%)
      compared to CPB group (64%), p < 0.05. Inotropic requirements postoperatively
      were similar in both groups. Hospital stay was shorter in BHS group (6.8 days)
      compared to CPB group (7.6 days) although not significant. There was no operative
      mortality in BHS group whereas 4.7% died postoperatively in CPB group.
      CONCLUSION: Our experience suggests that non-bypass surgical revascularization is
      a feasible and safe alternative to conventional cardiopulmonary bypass.

PMID- 10584380
TI  - [Hemodynamic changes during bypass surgeries in the beating heart].
AB  - OBJECT: To study the effect of surgical manipulations on patient hemodynamics
      during beating-heart CABG surgery. METHODS: We continuously monitored the
      systemic arterial pressure (SAP, n = 31), the pulmonary arterial pressure (PAP, n
      = 31) and the mixed venous oxygen saturation (SvO2, n = 6) using an Oxymetrix
      catheter. RESULTS: Patients age ranged from 53 to 85 years old (mean 66.4 +/-
      8.5) to whom 3.0 +/- 0.8 distal anastomoses were performed per patient.
      Stabilization of the heart were done using a "fork-type" stabilizator in all
      patients, and the target coronaries were clamped proximally and distally to the
      anastomosis site without pre-conditioning. A SAP decrease was found during the
      procedure and differed on the coronary territory being worked on: left anterior
      descending (LAD) (-11 +/- 19%), diagonal (Diag) (-13 +/- 27%), circumflex
      marginal (CM) (-19 +/- 17%) and right coronary (RC) or posterior descending
      artery (PDA) (-17 +/- 14%). PAP increase was maximal with the Diag (+47 +/- 84%)
      and was more important during LAD (+30 +/- 36%) and CM (+21 +/- 48%) than RC/PDA
      revascularization (+10 +/- 24%). On the other hand, SvO2 changes were found
      unchanged with any coronary territory. These changes occurred during the
      stabilization period before vessel occlusion, and were well tolerated by all
      patients, whom rarely needed inotropic support. No correlation between SvO2, SAP,
      PAP and occlusion time was found. CONCLUSION: The mobilization and stabilization
      of the heart using a "fork-type" stabilizator, rather than clamping the
      coronaries, during beating-heart CABG surgery were responsible for a decreased in
      SvO2, the SAP and an increase of the PAP. The marked elevation of PAP during
      revascularization of the diagonal and LAD territory may be explained by a
      compression of the left ventricle outflow tract. The Trendelenburg maneuver used
      during revascularization of the marginal and PDA territories may improve
      hemodynamics by relieving such pressure on the outflow tract and improve venous
      return.

PMID- 10584382
TI  - [Aortic valve stenosis in children. Surgical valvuloplasty long-term results].
AB  - From 1960 through 1992, 67 children with congenital aortic stenosis aged 6-228
      months (M 105.7 +/- 52) were submitted to aortic valvuloplasty at our
      institution. There was no hospital mortality. During the follow-up of 127.5 +/-
      66.7 months, there were two late valve related deaths. Eight patients (11.9%)
      developed aortic regurgitation 5 to 125 months (M 66.6 +/- 35) following surgical
      valvuloplasty and one of them required aortic valve replacement. Because of
      restenosis, 15 patients required a second operation. Of them five children
      underwent a second aortic valvuloplasty without mortality and, in four of them,
      the functional result has been excellent after a mean follow-up of 75.4 +/- 12
      months. Ten patients required an aortic valve replacement 62 to 208 months post
      op (M 100.9 +/- 50.8). Mechanical prosthesis were used in 6 and bioprosthesis in
      4. Two patients required a Konno and one patient a Ross procedure. There were no
      early nor late deaths following reoperations. The 20 year survival rate following
      the first valvuloplasty was 94%, the freedom from reoperation 63% and the freedom
      from aortic valve replacement 73% for the same time period. Our results
      demonstrate that congenital aortic valvar stenosis in children can be surgically
      well controlled until adulthood. Our study also illustrates that surgical
      valvuloplasty is a safe and efficacious procedure and that its beneficial effect
      is maintained over 20 years in the majority of children.

PMID- 10584381
TI  - [Ebstein's anomaly: valvular replacement in pediatric patients].
AB  - The surgical treatment of Ebstein's anomaly is still controversial. Therefore we
      have retrospectively studied the results of tricuspid valve replacement (TVR)
      performed for this anomaly at Sainte Justine Hospital. From October 1977 to
      December 1997, 9 patients with Ebstein's anomaly, aged from 31 to 248 months
      (mean 176 +/- 66), have undergone TVR. Eight children were in functional class
      III or IV (NYHA), while one was in class II. Seven patients underwent plication
      of the atrialized right ventricular segment. Eight bioprostheses (ranging in
      diameter from 31 to 35 mm) and one mechanical prosthesis (21 mm) were used. The
      valve was implanted on the tricuspid annulus in six cases. There was no operative
      death, nor postoperative complete heart block. Follow-up ranged from 11 to 264
      months (mean 91 +/- 84). One late death occurred unrelated to surgery. The
      probability of 20 years survival is 88%. One patient required a second TVR 162
      months after the first surgery because of bioprosthesis failure. Seven of the
      surviving patients are in functional class I, while one patient is in class II.
      This experience suggests that TVR with bioprosthesis is a good therapeutical
      option for children with Ebstein's anomaly since the operative risk is low, the
      functional status improved in all patients and the durability of bioprosthesis in
      tricuspid position has been good.

PMID- 10584383
TI  - [Results of surgery after failed mitral percutaneous dilatation].
AB  - OBJECTIVES: Percutaneous balloon mitral valve commissurotomy (BMC) is an
      alternative to surgical commissurotomy. Complications following BMC includes
      mitral regurgitation, iatrogenic atrial septal defect, residual mitral stenosis,
      and pericardial hemorrhage. This study analyzes the outcomes of surgery following
      failed BMC for mitral stenosis. METHODS: In a series of 298 patients treated with
      BMC, 53 patients (17.7%) had a complication that necessitated a surgical
      treatment. Twenty-eight patients needed an immediate surgery before the discharge
      (group I) and 25 patients were operated on an elective basis (group II). RESULTS:
      In group I, 27 patients have been operated and one died before the operation. In
      21 patients an acute mitral regurgitation occurred, 3 patients had a residual
      mitral stenosis, and 3 had a left atrial perforation. The operation consisted of
      26 mitral valve replacements, 20 concomitant reparations of iatrogenic atrial
      septal defect, and one open mitral valve commissurotomy. Operative mortality was
      3.7% (1 out of 27). In group II, 25 patients have been operated at a mean 18 +/-
      14 months after BMC. In the 25 patients the operation was indicated for
      significant mitral regurgitation (2 + and more). The operation consisted of 25
      mitral valve replacements, 9 concomitant reparations of iatrogenic atrial septal
      defect, 3 patients had also coronary artery bypasses. The operative mortality was
      8% (2 out of 25). The echocardiographic score was similar for both groups, it was
      8.4 +/- 2.0 in group I and 8.0 +/- 1.5 in group II (P = NS). Despite these
      complications following failed BMC, surgery appears a safe procedure with an
      acceptable mortality.

PMID- 10584384
TI  - [Treatment of diaphyseal femoral fractures in children: a clinical study].
AB  - Many therapeutic modalities have been reported for the management of femoral
      shaft fractures in children and young adolescents but there is no consensus on
      the preferable method. PURPOSE: To compare the malunion rate of femoral shaft
      fractures in children treated either by traction and spica cast or traction and
      functional brace. MATERIAL AND METHODS: Between 1982 and 1984 a prospective study
      was carried out in a tertiary pediatric university hospital on 43 patients (24
      boys, 19 girls) with a closed femoral shaft fracture. The patient's age ranged
      from 5 to 13 years old. Open, pathologic, subtrochanteric and physeal fractures
      were excluded. Fifteen (15) patients were treated by a functional brace and 28
      were treated by a spica cast. Clinical and radiological assessments of all
      patients were performed 5 years or more after the fracture by an independent
      observer. A malunion occurred if one of these criteria were met: an angulation >
      or = 10 degrees in the coronal plane, an angulation > or = 15 degrees in the
      sagittal plane, a malrotation > or = 15 degrees by opposition to the other leg,
      and a discrepancy > or = 10 mm between femur's length. RESULTS: A malunion was
      found in 17 patients, 6 in the functional brace and 11 in the spica cast group (p
      > 0.05). The leg length discrepancy was the most common type of malunion. The
      length of stay was not significantly different between both treatment groups. The
      functional brace was worn longer than the spica cast. CONCLUSION: There was no
      statistical difference between the malunion rate of children treated by traction
      spica cast and traction-functional brace. The functional brace appears to be a
      good alternative for the treatment for femoral shaft fracture in children
      allowing an earlier ambulation than spica cast.

PMID- 10584385
TI  - [Mechanical evaluation of a ligament fixation system for ACL reconstruction at
      the tibia in a canine cadaver model].
AB  - OBJECT: Excellent fixation of an artificial ligament in bone is mandatory for
      initial stability. ACL reconstruction with the LARS artificial ligament may fail
      if anchorage to bone is inadequate. The weak metaphyseal bone of the proximal
      tibia is prone to inadequate fixation. This study evaluates the initial
      mechanical stability of two techniques with an interference screw on the tibial
      side of an ACL reconstruction with the LARS ligament. METHODS: Six left tibias
      were obtained from 1 to 3 year old mongrel dog weighing 20 to 26 kg. ACL straight
      line reconstruction according to the technique described by J.P. Laboureau was
      performed with a 4.5 mm drill. Two tunnels were created in the tibia, one oblique
      and one transverse, the latter 2 cm below the former. Reconstruction was done
      with a 30-fiber LARS ligament and a 5.2 mm x 15 mm conical titanium cannulated
      interference screw. Group I had an interference screw in the oblique tunnel and
      group II had an interference screw in the transverse tunnel. Pull-out tests were
      performed parallel to the oblique tunnel on an Instron 8521 machine at a speed of
      5 mm per minute until failure. The oblique tunnel was tested first then the
      transverse tunnel. RESULTS: Group I (n = 6): sliding value = 238 +/- 115 N. Group
      II (n = 6): sliding value = 998 +/- 148 N. This is statistically significant (p <
      0.001, student t-test). CONCLUSION: One interference screw in a transverse tibial
      tunnel for ACL reconstruction with the LARS ligament is 4 times more resistant on
      loading and impact than an oblique screw.

PMID- 10584386
TI  - [Simulation of lateral bending tests using a musculoskeletal model of the trunk].
AB  - INTRODUCTION: The lateral bending test is used for the preoperative evaluation of
      scoliotic patients in order to determine the type of spinal curvatures as well as
      to assess spine flexibility and possible corrections. However, very few
      biomechanical studies have been dedicated to the analysis of lateral bending. In
      this article, a biomechanical model of the human trunk has been used in order to
      evaluate the possibility of simulating lateral bending tests. METHODS: This model
      includes elements representing the osseo-ligamentous structures of the spine, rib
      cage and pelvis, as well as 160 muscle fascicles represented by bilinear cable
      elements. For 4 scoliotic patients (right thoracic and left lumbar curvatures),
      3D upright standing and bending reconstructions were generated from calibrated x
      rays and used to calculate the displacements of the vertebrae T1 and L5. These
      displacements were applied to the model in standing position in order to simulate
      lateral bending. The resulting geometry of the deformed model was compared to the
      reconstructed geometry in lateral bending for the other vertebral levels (T2 to
      L4). RESULTS: The model allows the reproduction of the thoracic Cobb angle
      modifications with an accuracy superior to 2 degrees, as well as the vertebral
      rotations in the frontal plane (agreement greater than 85%). The positions of the
      vertebral body centroids following the simulations showed an agreement of over
      77% with reconstructed positions. The direction of the axial angulation for the
      thoracic and lumbar apical vertebrae is correctly reproduced by the model. The
      axial rotation for these vertebrae does not result in a common pattern for the 4
      patients, which is consistent with the diversity of published data concerning the
      direction of this coupling. CONCLUSIONS: This study shows the feasibility of
      simulating lateral bending tests using a 3D biomechanical model integrating
      muscles. The effect of muscle forces on trunk stiffness and intersegmental
      mobility can also be assessed using this approach. Future developments should
      enable the evaluation of the biomechanical properties of scoliotic deformities,
      thus providing a useful tool for preoperative surgical planning.

PMID- 10584387
TI  - [Comparison of the reliability of two 3D acquisition systems used for the study
      of anthropometric and postural parameters].
AB  - The goal of this study is to compare the between trials and between session
      reliability of the postural geometry (PG) and anthropometrical evaluations,
      obtained by the FreePoint (FP) system and the Motion Analysis System (MA). The
      potential of automatization of the anthropometric evaluation is also evaluate
      through the comparison of height measurements obtained by the two 3D systems and
      traditional anthropometrical tools. The PG of 15 adult control subjects (x: 25
      years, SD: 6) evaluated on two occasions (1 week interval) and a mannequin on one
      occasion were evaluated with both systems. Each evaluation involved the
      identification of 52 anatomical landmarks followed by the acquisition of 5 trials
      with each system. The 3 dimensional position of the anatomical landmarks serves
      to define a postural model including the shoulder girdle, spinous processes (T1
      to S1), thorax, pelvis, lower extremities and base of support. Postural
      parameters were calculated, including rotations, tilts, versions, kyphosis,
      lordosis, right and left Cobb, anteroposterior shifts, (AP), mediolateral shifts
      (ML) and vertical heights. The between trials and between session results
      demonstrate a strong correspondence of the 15 anthropometric heights and the 20
      postural parameters between the three systems, permitting the proposal of a
      broadened clinical utilisation of the FreePoint system. However, the validity of
      these measures is influenced by the reliability of the anthropometric
      landmarking, natural oscillation of the body and the intra-specific variation of
      the posture of each subject.

PMID- 10584388
TI  - [Back muscle activity during flexions/extensions in a second group of normal
      subjects].
AB  - Natural trunk movements and back muscle electromyographic (EMG) activity are
      seldom studied but are pertinent to daily life activities, which can lead to low
      back pain. In this study, ten normal subjects performed trunk flexion/extensions
      (F/E) without any restraining apparatus. Duration of the F/E was either free, or
      at 3, 2.25 and 1.5 s. A fatiguing task consisted of continuous F/E movements
      accomplished at 1.5 s intervals during 90 s. Photodiodes were placed on the skin
      to obtain kinematics of the trunk. EMG signals of the back were recorded with 10
      pairs of surface electrodes located at 3 levels of the erector spinae. It was
      found that the F/E movement duration chosen by the subjects varied between 4.07
      and 2.07 s and the flexion amplitude varied between 55 degrees and 118 degrees.
      Similar variations in the amplitude of flexions were found for the tasks realized
      at fixed periods. The level of fatigue induced in the fatigue task was evaluated
      by comparing the energy of its EMG signals with those of the 1.5 s task. With
      this index, fatigue was detected in a few subjects only. Due to the length of the
      fatigue task (90 s long), it would seem that most of the subjects became adapted
      to the movements and could produced them more effectively (i.e. with less EMG)
      than during the 1.5 s task which was repeated only for few seconds.

PMID- 10584389
TI  - [Experimental scoliosis in the minipig: study of vertebral deformations].
AB  - The purpose of this study was to attempt an induction of a scoliotic deformation
      in the minipig by means of unilateral epiphysiodesis of the neurocetral cartilage
      (NCC) of 5 consecutive vertebrae, in order to understand the vertebral
      deformities genesis in the scoliotic pathology. The vertebral deformities induced
      in this quadruped have been compared to those of the pseudo-biped (chicken:
      induction of the scoliosis by means of pinealectomy) and to the known vertebral
      deformities in the human idiopathic scoliosis. MATERIAL AND METHODS: Eight
      Yucatan minipigs (1 month old) have been used. In the tested group (4 minipigs)
      underwent an epiphysiodesis (compression with a screw) on the NCC from T5 to T9.
      The control group (2 minipigs) underwent a perforation of the NCC without a screw
      placement from T5 to T9. The sham group (2 minipigs) underwent only a sus
      periosted vertebral muscles clearing on the right side at the thoracic level. An
      X-ray follow-up at 1, 6 and 12 months has been performed. The minipigs have been
      sacrificed between 12 an 13 months post-operatively. The vertebrae were dissected
      for the macroscopic anatomic analysis. RESULTS: The X-ray follow-up shows an
      unfinished resorption of the curvature after one year post-operatively. The
      horizontal deformity of the vertebrae was more marked in those with the
      compressed (screw) NCC. The vertebral deformities in the minipig are similar to
      those found in the human and chicken. CONCLUSIONS: Although the curvatures are
      benign and often spontaneously resolvent, the comparison of the induced vertebral
      deformities to those obtained in a chicken (post-pinealectomie) and the human
      suggest that the NCC is likely involved in the vertebral deformities in the
      horizontal plan. Therefore the minipig does not seem to be a good experimental
      model for the scoliosis.

PMID- 10584390
TI  - [Reductibility of idiopathic scoliosis during orthopedic treatment].
AB  - Non-operative treatment of idiopathic scoliosis is long and difficult. For the
      patient and the therapist it is particularly important to define early the
      therapeutic prognosis. The goal of this study is to verify if the initial
      reducibility at the beginning of treatment with the dynamic corrective brace
      (Spinecor) would be valid as a prognostic factor, allowing a more effective
      prognostic judgement of the final outcome treatment. This is a prospective study
      which includes 99 scoliosis patients (88 female, 11 male), with a mean age of new
      12.6 years, treated by the dynamic corrective brace for progressive idiopathic
      scoliosis curves (29 degrees mean Cobb angle). The initial Cobb angle was
      compared to the pre-therapeutic Cobb angle. The results demonstrate that the
      reducibility of the scoliotic curves with the brace at the beginning of treatment
      provides a significant global prognostic index but is difficult to apply
      individually. Other factors should be considered, such as the impact of growth
      velocity on the spinal deformity at the onset of the adolescent growth spent as
      well as vertebral deformities diagnosed around the apex.

PMID- 10584391
TI  - [Comparison between clinical Cobb angles and measurements performed on vertebral
      bodies, pedicle centroids and spinous processes].
AB  - GOAL: Evaluate the relations between the clinical Cobb angle measured on
      radiographic images and the computerized Cobb angles measured on curves passing
      through: 1) the vertebral body centroids, 2) the pedicle centroids and 3) the
      spinous process tips, in the frontal plane, the sagittal plane and the plane of
      maximum curvature. MATERIAL AND METHODS: A bi-planar radiographic technique was
      used to reconstruct in 3D the spine geometry for 39 adolescent girls having
      double-curved idiopathic scoliosis. The Cobb angles were measured clinically on
      the radiographs and were computed on the 3 curves. RESULTS: Every relation was
      found significant and their determination coefficient (R2) was between 0.38 and
      0.98. Linear relations were established between clinical and computerized angles.
      Angles measured on the curve passing through the pedicle centroid correlated best
      with clinical indices. CONCLUSIONS: The computerized measurements of Cobb angles
      from 3D models can be used with confidence and are interchangeable, provided the
      appropriate conversion factor is used.

PMID- 10584392
TI  - [Correlation study between spinal curvatures and vertebral and disk deformities
      in idiopathic scoliosis].
AB  - Idiopathic scoliosis involves complex tridimensional (3D) deformations of the
      spine associated with intrinsic alterations (wedging) of vertebral bodies (VB)
      and intervertebral disks (ID). This study intends to evaluate analytically in
      vivo 2D and 3D scoliotic descriptors, based on clinical data from 40 thoracic
      curves of scoliotic adolescents, and to establish relationships between the
      regional curve deformations and the local VB and ID deformities. A multiplanar
      radiographic technique provided 3D positioning of vertebral landmarks. Cobb angle
      in the postero-anterior (PA) view, in the plane of maximum deformity (CobbP.Max)
      and the angular orientation of the plane of maximum deformity were used as
      regional descriptors. Vertebral body endplates were modeled as 3D oriented
      ellipses. Axial rotation, global PA and local frontal wedgings (inclinations of
      projected ellipses in the global and vertebral frontal planes), 3D maximum
      wedging (real inclination of adjacent ellipses) as well as the angular
      orientation of 3D wedging were calculated to characterize local deformations at
      the thoracic apex. Mean values for CobbPA, CobbP.Max and the angular orientation
      of the maximum deformity (with respect to the sagittal plane) reached 44 degrees,
      48 degrees and 67 degrees respectively. On average, vertebral axial rotation,
      global PA, local frontal and 3D wedging angles were respectively 15 degrees, 8.3
      degrees, 8.2 degrees and 9.7 degrees. Analyses indicated statistical correlation
      between: a) Cobb angles and vertebral wedging; b) the orientations of the maximum
      deformity and of 3D vertebral wedging; c) the axial rotation and CobbPA; d) the
      axial rotation and the angular orientation of 3D vertebral wedging. At the
      thoracic level, statistical analyses indicated that vertebral wedging and axial
      rotation increase with curve progression. Scoliosis severity, as measured by Cobb
      angles, evolves simultaneously to a coronalization of the plane of maximum
      deformity, revealing an hypokyphotic phenomenon, and to a real vertebral wedging
      shifting towards the frontal plane of the vertebra. These 3D in vivo analyses
      allowed interpretation of spatial relationships between regional and local
      scoliotic deformities. Compared to 2D in vivo or 3D in vitro analyses alone, this
      3D in vivo study provides a more complete assessment of spinal curve progression
      to fully interpret the real 3D curvature and intrinsic deformations as well as
      their evolution processes.

PMID- 10584393
TI  - [Perioperative radiographic reconstruction of the scoliotic vertebral column].
AB  - We have developed a new per-operative three dimensional (3D) reconstruction
      technique to evaluate the 3D correction of a scoliotic spine induced by surgery
      using Cotrel-Dubousset instrumentation. A small object with 15 embedded markers
      was used to calibrate the radiographic system. During surgery, the calibration
      object was sterilized and fixed to the patient just before the acquisition of two
      pairs of posterior-anterior and sagittal radiographs; one pair before the
      rotation maneuver of the rod and one pair after the maneuver. The markers were
      digitized on each radiograph and their relative 3D positions were measured to
      establish the relation between the 3D positions of the anatomical structures and
      their 2D positions on the radiographs. This relation was used to calculate the 3D
      position of six anatomical landmarks per vertebra (the centers of the superior
      and inferior vertebral body endplates and the proximal and distal bodies of both
      pedicles) from the identification of these landmarks on each radiograph. We made
      a 3D representation of the thoracic and lumbar spine of three patients with
      idiopathic scoliosis undergoing corrective surgery by the posterior approach.
      Clinical indices (Cobb angle, axial rotation and the plane of maximum curvature)
      computed from the 3D reconstruction of the spine obtained before and after the
      rotation maneuver of the rod were compared to evaluate the 3D correction
      performed during the surgery. The new proposed approach allows the surgeon to
      evaluate the per-operative shape of the spine. This approach is simpler, faster
      and less risky for the patient than the previous method which employed an
      electromagnetic digitizer to measure the 3D coordinates of anatomical landmarks
      located on the posterior part of the spine. Furthermore, the 3D representation of
      the spine visualized from different points of view gives the surgeon an accurate
      evaluation of the 3D correction during the surgical procedure.

PMID- 10584394
TI  - Age-related changes in body composition of 3- to 6-year-old Japanese children.
AB  - This study was undertaken to establish an approach for the investigation of age
      related changes in indices of body composition during childhood in Japan. It
      provides current reference values for total body fat mass (TBFM) and lean body
      mass (LBM) as indices of body composition in an urban population of 3- to 6-year
      old Japanese children. Moreover, we assessed the age-specific patterns of body
      fat distribution [subcutaneous fat mass (SFM) and internal fat mass (IFM)] during
      childhood. Measurements of body composition by bioelectrical impedance were made
      in 141 boys and 139 girls, all apparently healthy, aged 3-6 years. Determinations
      of impedance were made using a four-terminal impedance analyzer (TP-95K; Toyo
      Physical, Inc., Fukuoka, Japan). LBM was calculated using the equation of Kushner
      et al. (1992) and Goran et al. (1993). SFM was calculated using a modification of
      the equation derived by Skerjl et al. (1953). IFM was calculated as the
      difference between TBFM and SFM. From ages 3 through 6 years, the mean LBM
      increased with age in boys and girls, and showed significant age differences.
      Between the ages of 3 and 6, the average increment in LBM was 5.1 kg in boys and
      4.4 kg in girls. On average, boys gained 0.5 kg of TBFM each year, whereas girls
      gained 0.4 kg of TBFM each year. Furthermore, both groups gained 0.3 kg of SFM
      each year. Percentage body fat decreased in both genders until approximately the
      age of 5, and increased again slightly at the age of 6. The age-specific pattern
      of fat accumulation during childhood was characterized by an almost linear
      increase in SFM in girls, but a transient decrease in IFM in boys. We conclude
      that further research is required, including longitudinal assessment of body
      composition variables, in order to unravel the dynamics of body composition
      change in Japanese children.

PMID- 10584395
TI  - Change of footwear insulation at various sweating rates.
AB  - Moisture inside the footwear can considerably affect the thermal insulation. In
      this study with a thermal foot model there was simulated three sweat rates (3, 5
      and 10 g/h). Five types of footwear with various insulation levels (dry
      insulation from 0.19 to 0.50 m2. K/W) were tested. The footwear insulation
      reduction was calculated for 1.5 hour period. The reduction in insulation was
      related to sweating rate and initial insulation. The footwear with high
      insulation lost even in percentile more insulation than thin boots under the same
      conditions (9-19% at 3 g/h, 13-27% at 5 g/h and 19-36% at 10 g/h). A relationship
      between insulation decrease and sweating rate was established. An 8-hour sweating
      test (5 g/h) and a test for determining evaporative heat, losses were carried out
      in addition. The insulation reduction during the first 1.5 hours of the 8-hour
      test answered for more than half of the total reduction.

PMID- 10584396
TI  - Characteristics of ADL ability on partially dependent older adults: comparison
      among different ambulatory activities levels.
AB  - The purpose of the present study was to clarify the characteristics of ADL
      ability among different ambulatory level groups. The subjects were 448 partially
      dependent older adults (PD; 126 male, 81.7 +/- 8.22 year; 322 female, 82.5 +/-
      7.25 year) over 60 years of age, and they were divided into 3 groups based on
      ambulatory activity level; G1 could not walk without assistance; G2 could walk
      with a stick; G3 could walk without assistance. The PD were asked 17 ADL
      questionnaires representing seven ADL domains to evaluate the ADL ability. Total
      and domain ADL scores, and achievement rates for each item were calculated, and
      compared among different ambulatory activity groups. It is confirmed that ADL
      ability level in PD significantly relates to ambulatory level and becomes
      gradually higher as the ambulatory activity level advances. It is considered that
      in the G1, lower limb ability level is low, and the contribution of ability level
      regarding changing posture and manual activities to total ADL ability level is
      high. On the other hand, in the G3 the achievement levels in manual activities
      and high-difficulty ADLs using lower limbs reflects the differences in the ADL
      ability level among individuals. Gender differences for ADL ability are not found
      in any ADL domain, while age differences are found in only the G3. It is inferred
      that for the G1, the achievement levels of ADLs are largely influenced by disease
      morbidity and age contributes very little to the decline of ability level.

PMID- 10584397
TI  - Ambient air, oxygen and nitrox effects on cognitive performance at altitude.
AB  - The effects on cognitive performance of breathing air, oxygen and nitrox gas
      mixtures at surface ambient pressures were investigated during an expedition to
      the Everest region of Nepal. A slight improvement in grammatical reasoning at
      altitude was found under nitrox (p < 0.05) and mathematical reasoning showed
      improvement at altitude on air (p < 0.05), oxygen (p < 0.01) and nitrox (p <
      0.01). There were non-significant trends towards decreasing mathematical ability,
      coupled with an increase in variance on both grammatical and mathematical test
      performance, with increasing pO2 (all p > 0.05). The results suggest that there
      is a subtle interaction on cognition as indicated by a significant three-way
      interaction between subject x altitude x gas (p < 0.05).

PMID- 10584398
TI  - Effect of low-intensity leg exercise on ventilatory threshold during incremental
      arm exercise.

PMID- 10584399
TI  - [Measurement and evaluation of three-dimensional acceleration signals for rate
      adaptation of cardiac pacemakers].
AB  - The aim of this study was to determine which of the one-dimensional acceleration
      signals best correlates with the heart rate under the conditions of daily
      activities, or whether such correlation is shown by three-dimensional
      acceleration signals. A commercially available biosignal system (ZAK, Germany)
      was used to record electrographic data and acceleration caused by body movements
      in the three directions vertical, sagittal and lateral. The evaluation was
      performed on 12 young healthy volunteers and 4 elderly volunteers with
      cardiovascular disorders but adequate chronotropic function. Informed consent was
      given by all participants. Activity signals and heart rate were recorded while
      walking under two different conditions. For analysis, the pathways were divided
      into segments with different gradients. All the acceleration signals were
      analysed statistically and temporally with regard to peak-to-peak value, root
      mean square value, and step frequency by means of cross correlation. Both
      statistical and temporal analysis showed that the correlation of heart rate and
      all one-dimensional acceleration signals and the three-dimensional acceleration
      signal was relatively low (r < or = 0.6). Walking uphill even showed a negative
      correlation between acceleration signals and heart rate. Despite the widespread
      use of activity-controlled pacemakers, the correlation between heart rate and
      acceleration signals is not satisfactory.

PMID- 10584400
TI  - [Transcranial Doppler ultrasonography: stereotactically guided examinations using
      magnetic resonance angiography].
AB  - The accurate localization of specific intracranial blood vessels is a major
      difficulty with transcranial Doppler sonography (TCD). It was the purpose of this
      study to develop a system enabling stereotactic navigation during a TCD
      examination on the basis of high-resolution three-dimensional magnetic resonance
      angiographic (MRA) data. During TCD, the examiner is provided--on a computer
      screen--with a projected view of the respective intracranial vessel anatomy. With
      the aid of an optoelectronic localization system, the spatial orientation and
      localization of the US probe is determined in real time, and correlated with the
      patient's MRA data using a dedicated stereotactic mask. Subsequently, the US beam
      and the points of insonation are displayed on the screen overlaid on the vessel
      anatomy. In this way the examiner gains real time control of the localization of
      the respective intracranial vessel insonated. Points of insonation can be stored
      and recalled for follow-up examinations. In addition to the successful
      verification of the system, it was shown that, in comparison with conventional
      TCD, stereotactic navigation distinctly improves the reproducibility of repeat
      TCD examinations.

PMID- 10584401
TI  - 1H and 31P NMR characterisation of a double breast coil for spectroscopic
      measurements and imaging.
AB  - For the first time a double turn breast coil has been described which can be used
      for 1H imaging, 1H spectroscopy and 31P spectroscopy. The paper describes basic
      technical features of the coil, coil design, B1 field/excitation field
      distribution for 1H and 31P, sensitivity, and feasibility for 31P spectroscopic
      in vivo studies. The main advantage of the double frequency tuneable coil is that
      1H imaging for tumor localization and 31P spectroscopy for response control can
      be done without an additional repositioning of the patient.

PMID- 10584402
TI  - [Effects of extracorporeal shock waves (ESW) on human bone marrow cell cultures].
AB  - INTRODUCTION: Extracorporeal shockwave therapy (ESWT) is a new method of treating
      insertion tendopathy and pseudo-arthrosis, the clinical importance of which
      cannot yet be definitively assessed, and the underlying mechanisms of which are
      still unclear. AIM: To develop an experimental set-up enabling the standardised
      application of ESWT to human bone marrow cell culture and the determination of
      the effect of ESWT. MATERIAL AND METHODS: After 14 days incubation, human bone
      marrow cell cultures were subjected to ESWT using 200/500 pulses at an energy
      flux densities ED + of 0.03, 0.04, 0.07, 0.11 and 0.25 millijoule/mm2. Samples
      were obtained for LDH measurement 15 minutes, 4 h and 18 h after ESWT.
      Transmission light microscopy was carried out before and after ESWT to determine
      cell numbers and for morphological analysis. RESULTS: Gaps in the cellular tissue
      first appear at an energy of 0.01 millijoule/mm2. At energies of 0.25
      millijoule/mm2, morphologically altered cells, thinned out cellular tissue with a
      cell-free focal zone are found. At low energy levels, defects have been repaired
      ca. 1 week after ESWT. No significant increase in LDH was detected at any of the
      energy levels applied. CONCLUSION: Increasing energy and higher pulse frequency
      is associated with an increase in the size and number of holes in cellular tissue
      and in cell separation. Regeneration capability (regrowth, sprouting, normal cell
      form) decreases as the energy level increases. Changes can be detected even at
      the lowest energy flux densities, which up until now had been assumed to have no
      effect on cell morphology or number. The standardised application of ESWT to
      human bone marrow cell cultures provides reproducible results that can be
      controlled by a placebo ESWT application.

PMID- 10584403
TI  - [A simplified procedure for mechanical testing of lumbar spinal fixation
      implants].
AB  - On the basis of the current ASTM and ISO standard proposals, a simplified test
      procedure for spinal fixation implants has been developed. It comprises static
      and dynamic tests aimed at evaluating the stiffness and strength of various
      different internal implants. Different methods of mounting the pedicle screws to
      the test device are shown to significantly affect the characteristic values and
      failure mechanisms of the implants. The feasibility of the procedure was
      investigated by comparing 7 different internal fixation implants. The
      reproducible results revealed general differences associated with the material,
      dimensions and design, which latter in particular correlated with the specific
      failure mechanisms. For longer-term in situ duration, testing of these implants
      should be expanded to include an analysis of wear and corrosion properties.

PMID- 10584404
TI  - [Light-induced control of polymerization shrinkage of dental composites by
      generating temporary hardness gradients].
AB  - Irradiation of light-curing dental filling materials in a single direction
      results in a temporary hardness gradient in the direction of the irradiation. The
      photoactivated polymerisation process begins at the site of the highest light
      intensity. In the simplest possible model, the polymerizing composites irradiated
      in a single direction shows three adjacent co-existing phases: an almost
      hardened, a gelled and a still plastic phase. As long as all three phases are
      present, any shrinking of the contracting phases can be compensated by the
      plastic phase. A knowledge of the distribution of these phases and their spatial
      and temporal modulation by the selection of suitable curing light parameters
      provides simple techniques for reducing shrinkage gaps around voluminous fillings
      in large dental cavities.

PMID- 10584405
TI  - Diagnosis of papillary and follicular thyroid cancers.
AB  - In general, thyroid cancer patients are usually presented with asymptomatic neck
      nodules. A differential diagnosis between malignant and benign thyroid disorder
      is very important for these patients. In the preoperative diagnosis, thyroid
      ultrasonography has been proven to be quite useful in the detection of thyroid
      lesions. There are two major reasons to perform thyroid ultrasonography before
      fine needle aspiration cytology (FNAC): to detect deep-seated small nodules, and
      to realize the nature of the clinically palpable nodules. Despite the limitations
      of aspiration cytology in the diagnosis of primary neoplasms, using this method
      can increase diagnostic accuracy to 92.89% in thyroid malignancy cases. Most
      thyroid malignancies can be diagnosed with FNAC, except for cases involving
      follicular thyroid cancer and Hurthle cell carcinoma. Although the serum
      thyroglobulin level has been used as a post-operative, well-differentiated
      thyroid cancer tumor marker, the assay cannot be used for preoperative diagnosis
      of thyroid carcinoma. Two dimensional gels electrophoresis has also been used as
      a diagnostic tool to elucidate tumor-specific proteins in the detection of well
      differentiated thyroid cancers. The results of this technique need further
      investigation. In conclusion, and at the present time, FNAC is considered a
      useful tool in the pre-operative diagnosis of most thyroid cancers. For patients
      with follicular or Hurthle cell carcinomas, we need to develop further specific
      tumor markers for differentiating them between benign and malignant nodules.

PMID- 10584406
TI  - Subcutaneous tumors of mice treated with rhodamine-123 and laser irradiation.
AB  - BACKGROUND: Treatment involving photosensitizers and laser irradiation (LIR) in
      cancer therapy is known as photodynamic therapy (PDT). The purpose of our study
      was to assess the therapeutic effect of PDT using rhodamine-123 (Rh123) and LIR
      on subcutaneous tumors (ST) in mice. METHODS: Sarcoma-180 cells (1 x 10(7)) were
      implanted subcutaneously into the breast area of strain Cr1:CD-1-ICR (BR) female
      mice. Mice bearing ST were treated with Rh123 or LIR alone, or a combination of
      both, once a day for 3 successive days. RESULTS: The best therapeutic effect was
      observed in the group treated with 7.5 mg Rh123 per kilogram of body weight,
      combined with 75 J/cm2 laser irradiation energy. The group's mortality rate,
      tumor control rate, mean survival time, and increase in lifespan within 120 days
      after treatment were 16.7%, 83.3%, 109.4 days, and 135.8%, respectively. The most
      inhibitory effect on tumor cells was found in the group treated with 15 mg/kg
      Rh123 and 90 J/cm2 laser irradiation. The biosyntheses of DNA, RNA, and protein
      in tumor cells of this group was obviously inhibited. CONCLUSION: PDT with the
      photosensitizer Rh123 and laser irradiation was therapeutically effective in
      treating subcutaneous tumors of mice. The tumor cells and the syntheses of DNA,
      RNA, and protein of the tumor cells in these PDT treated mice were obviously
      inhibited.

PMID- 10584407
TI  - Effects of glycyrrhizae and glycyrrhizic acid on cellular immunocompetence in low
      dose gamma-ray irradiated mice.
AB  - BACKGROUND: For both animals and human beings, it is important to prevent damage
      from ionizing radiation and to restore immunocompetence following irradiation.
      The present study was conducted to investigate the effects of glycyrrhizae (GL)
      and glycyrrhetinic acid (GA) on cellular immunocompetence in low dose gamma-ray
      irradiated mice. METHODS: Six- to 8-week-old ICR strain' Crl:CD-1-ICR (BR) strain
      male mice, bred in the Institute of Cancer Research, U.S.A., were chosen and
      divided into four groups. Group A was the normal control. Group B, the
      experimental control, received 1 Gy of whole body gamma-ray irradiation. Groups C
      and D, the experimental groups, were treated with 500 mg/kg of GL (orally) and 5
      mg/kg body weight of GA (i.p.), respectively, once a day, 5 days a week for 2
      weeks after gamma-irradiation. The tested mice were killed, at 6 different
      intervals to measure their leukocyte and differential counts. Cellular
      immunocompetence was measured by the 3H-thymidine uptake in each group. RESULTS:
      One gray of gamma-ray irradiation had evident inhibition on the leukocyte and
      differential counts and the cellular immunity of mice. GL and GA could help to
      restore the decreased leukocyte counts and the cellular immunocompetence in low
      dose gamma-irradiated mice. CONCLUSION: GL and GA could help to restore decreased
      leukocyte counts and the cellular immunocompetence in low-dose gamma-ray
      irradiated mice.

PMID- 10584408
TI  - Maxillary growth after palatal denudation: an animal experiment.
AB  - BACKGROUND: Palate surgery at an early age may cause retardation of maxillary
      growth. The second intention healing of the raw bone surface created on the
      palate is considered to be the cause of the growth retardation. The animal
      experiment in this study was designed to evaluate this effect. METHODS: Four-week
      old Sprague-Dawley rats were divided into 3 groups. In the first group, a strip
      of mucoperiosteum was excised on both sides of the hard palate. A second group of
      rats received a sham surgery in which bilateral mucoperiosteal flaps were raised
      and redraped. The third group served as controls with no surgery. Flap elevation
      with and without excision was performed under an operative microscope to
      facilitate the delicate manipulation of tissue and to avoid injury to the
      underlying bone. The animals were killed 11 weeks later and the skulls were
      prepared for measurements, which included the palatal inter-molar width,
      maxillary height, and maxillary length. RESULTS: The results revealed
      statistically significant decreases in palatal width and maxillary length in the
      experimental group (excision of mucoperiosteum). No differences were observed in
      the vertical height of the maxilla. CONCLUSION: This study confirms that
      surgically created bone denudation of the palate causes maxillary growth
      disturbances.

PMID- 10584409
TI  - Endoscopic carpal tunnel release.
AB  - BACKGROUND: Endoscopic carpal tunnel release was developed by Okutsu and Chow in
      1989. Many reports have indicated that endoscopic carpal tunnel release
      diminishes postoperative pain and accelerates the recovery time. METHODS: In a
      series of 1278 carpal tunnel release procedures (in 948 patients), 1214 were
      performed with a modified Menon endoscopic method and the remaining 64 with an
      open procedure. The patients with idiopathic carpal tunnel syndrome were followed
      for at least 3 months. RESULTS: Of the endoscopic release patients, 80.9%
      recovered grip strength equal to or greater than preoperative levels within 4
      weeks, whereas in the open procedure group, the rate was only 59.3%. The
      difference was statistically significant (p = 0.00011). An immediate complication
      was one median motor nerve severance. There were 24 conversions to a conventional
      open procedure during endoscopic release. In the endoscopic group, 81% developed
      scar tenderness over the thenar crease, 31% developed new sensory disturbance,
      and 4% developed pillar pain. CONCLUSION: Endoscopic release facilitated the
      recovery of grip strength and diminished the frequency of scar tenderness.
      However, neurovascular injury should be carefully prevented.

PMID- 10584410
TI  - Neutrophil adherence to lung epithelial cells induce interleukin-8 release.
AB  - BACKGROUND: Neutrophil recruitment to the lungs and transmigration through the
      pulmonary epithelium to reach the respiratory tract are characteristics of airway
      inflammation. Interleukin-8 (IL-8) plays a critical role in the recruitment of
      neutrophils to epithelial cells. We investigated the effect of neutrophil
      adherence to epithelial cells on cytokine secretion. METHODS: The production of
      IL-8 from cultured A549 epithelial cells was assayed and neutrophil adherence
      assay in the presence or absence of interferon-gamma (IFN-gamma) plus tumor
      necrosis factor-alpha (TNF-alpha) plus interleukin-1 beta (IL-1 beta) stimulation
      was studied on cultured A549 epithelial cells. The role of an adhesion molecule
      in the modulation of neutrophil adherence was examined by pretreatment with
      intercellular adhesion molecule-1 (ICAM-1) blocking antibody. RESULTS: There was
      an increase in IL-8 release from epithelial cells that was time-dependent and in
      the magnitude of neutrophil adherence to the epithelial cells. Stimulation of
      epithelial cells with IFN-gamma +TNF-alpha +IL-1 beta significantly increased IL
      8 release and neutrophil adherence. The spontaneous or IFN-gamma +TNF-alpha +IL-1
      beta-induced IL-8 release was significantly augmented after the addition of
      neutrophils. The inhibition of neutrophil adherence to epithelial cells by ICAM-1
      blocking antibody downregulated the augmented release of IL-8 with or without IFN
      gamma +TNF-alpha +IL-1 beta stimulation. Placing a membrane filter on cultured
      epithelial cells to prevent neutrophil adherence significantly decreased IL-8
      release from epithelial cells with IFN-gamma +TNF-alpha +IL-1 beta stimulation.
      CONCLUSION: Our results indicate that lung epithelial cells not only provide a
      harboring site for neutrophils to be activated, but also amplify the neutrophil
      sequestration in the lung by releasing IL-8. Moreover, the release of IL-8 is
      dependent on the adherence between neutrophils and lung epithelial cells.

PMID- 10584411
TI  - Does the use of clinical paths improve the efficiency and quality of care under
      the case payment system for inguinal herniorrhaphy or transurethral
      prostatectomy?
AB  - BACKGROUND: We evaluated the effects of implementing clinical paths for both
      inguinal herniorrhaphy (IH) and transurethral prostatectomy (TURP) on the
      efficiency and quality of medical care under the case payment system. METHODS:
      Patients undergoing IH or TURP were treated using the guidelines for clinical
      paths under the case payment system (CPUCP). The results of treatment after
      implementation of CPUCP were compared with results for patients treated before
      implementation of CPUCP. We also compared results using eight quality indicators
      both before and after implementation of CPUCP. RESULTS: The post-CPUCP length of
      hospital stay decreased significantly in patients who underwent either IH (p <
      0.001) or TURP (p = 0.008). The post-CPUCP total admission charges decreased (p =
      0.001) by 7.5% in the IH group alone. Two quality indicators in the IH group and
      three quality indicators in the TURP group were significantly improved after
      implementation of CPUCP. The percentage of patients who completed treatment
      without deviation as recommended by the guidelines for CPUCP was about 60% in the
      IH group and about 70% in the TURP group. CONCLUSION: The results of this study
      indicate that the implementation of clinical paths under the case payment system
      for patients undergoing inguinal herniorrhaphy or transurethral prostatectomy can
      improve the efficiency and quality of medical care.

PMID- 10584412
TI  - High-risk human papillomavirus deoxyribonucleic acid as an adjunct marker in
      cervical cytology.
AB  - BACKGROUND: This study was designed to determine whether screening for high-risk
      human papillomaviruses testing could improve the detection of cervical dysplasia
      and cancer in assistance with conventional Papanicoloau (Pap) smears. METHODS:
      The study was based on 114 patients with abnormal Pap smears referred for
      colposcopy from Feb. 1997 to Dec. 1997. The presence of high-risk human
      papillomavirus (HPV) DNA was determined with the Hybrid Capture method (including
      HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). Cytologic
      examination by Papanicolaou smear was based on the Bethesda system and cervical
      biopsy was done via colposcopy. RESULTS: Cytologic examination demonstrated high
      grade squamous intraepithelial lesions (HSIL) in 24 patients with HPV positive
      (75%), low-grade squamous intraepithelial lesions (LSIL) in 38 with 61% HPV
      positive, and atypical squamous cells of undetermined significance (ASCUS) in 52
      with 37% HPV positive. Among patients with a cytologic diagnosis of borderline
      abnormalities (ASCUS or LSIL), those with who were HPV positive were
      significantly more likely to have cervical dysplasia (both p < 0.05). The
      sensitivity of combined HPV assay and/or cytology for detection of noninvasive
      precursor (91%) was significantly greater than those of cytology (68%) or HPV
      assay (81%) alone. CONCLUSION: The addition of the hybrid capture high-risk HPV
      DNA assay to cytologic examination of cervical smears appears to increase the
      sensitivity of cervical screening. Our findings suggest that HPV DNA may be a
      useful adjunct marker for early detection of cervical dysplasia in women with
      minimally abnormal Pap smears (ASCUS/low-grade SIL).

PMID- 10584413
TI  - Upregulation of IL-5 receptor expression on bone marrow-derived CD34+ cells from
      patients with asthma.
AB  - BACKGROUND: Interleukin-5 (IL-5) is a potent eosinophilopoietic factor implicated
      in the chronic inflammatory cell accumulation accompanying bronchial asthma. We
      studied the expression of the IL-5 receptor alpha-subunit (IL-5R alpha) on bone
      marrow-derived cluster of differentiation molecule 34 positive (CD34+) progenitor
      cells in asthmatics to prove the ability of progenitor cells to respond to IL-5
      more readily. METHODS: Non-adherent non-T cells (NANT) were separated from
      heparinized bone marrow blood from 6 asthmatics and 3 normal subjects, loaded
      with CD34+ and IL-5R alpha monoclonal antibodies conjugated with
      immunofluorescence and then analyzed by flow cytometry. Colonies grown from
      progenitor cells cultured in methylcellulose were determined for 14 days in the
      presence or absence of growth factors, including granulocyte-monocyte colony
      stimulating factor, stem cell factor, and interleukin-3. RESULTS: The proportion
      of IL-5R alpha expression on the CD34+ cell surface was significantly increased
      in asthmatics (12.9 +/- 3.3%, n = 6, p = 0.0163) compared to normal subjects (1.8
      +/- 0.6%, n = 3). A significantly greater number of colonies committed to
      eosinophilic differentiation were found in the asthmatic subjects. CONCLUSION: We
      demonstrated an increased expression of IL-5R alpha on bone marrow-derived
      progenitor cells in asthmatics. This supports the concept that bone marrow
      derived progenitor cells are ready for eosinophilopoiesis.

PMID- 10584414
TI  - Low dose flutamide in the treatment of acne vulgaris in women with or without
      oligomenorrhea or amenorrhea.
AB  - BACKGROUND: In the skin, the expression of androgen action is dependent on the
      reduction of testosterone to dihydrotestosterone mediated by the enzyme 5 alpha
      reductase. Additionally, an exaggeration of this peripheral metabolism has been
      associated with acne in women. METHODS: Fifty-two women with acne vulgaris but
      without hirsutism were recruited in this study, including 42 with oligomenorrhea
      or amenorrhea (Group 1) and 10 with regular menstrual cycles (Group 2). As a
      control, another 15 oligomenorrheic women without acne were also studied (Group
      3). Flutamide combined with sequential estrogen-progestogen preparations was
      given to patients in Group 1. In Group 2, flutamide alone was administered. In
      Group 3, the women were treated with sequential estrogen-progestogen. RESULTS: In
      Groups 1 and 2, a significant decrease in the number of inflammatory lesions was
      found at the end of 3 and 6 months of treatment, and even after discontinuation
      of therapy for 6 months. Before treatment, patients in Group 1 showed signs of
      biochemical hyperandrogenism, including elevated levels of serum testosterone
      (T), androstenedione (A), and dehydroepiandrosterone sulfate (DHEA-S), as well as
      a decreased level of sex hormone-binding globulin (SHBG). A decrease in
      circulating T and A, and an elevation in serum SHBG were found 3 and 6 months
      after treatment in Group 1. In Group 2, clinical improvement of acne was achieved
      by flutamide alone without alteration in circulating androgens (including T, A,
      and DHEA-S). Similarly, no change in serum androgens was observed in the women of
      Group 3 after treatment. CONCLUSION: A low dose of flutamide (250 mg/day) in
      association with or without estrogen-progestogen is effective for the clinical
      improvement of acne vulgaris in women with or without oligomenorrhea or
      amenorrhea. However, the effectiveness on hyperandrogenic symptoms by
      antiandrogens may or may not be reflected by the suppression of serum androgens.

PMID- 10584415
TI  - Development of a device for immobilization of head and correlation of functional
      anatomical brain images.
AB  - BACKGROUND: The excellent resolution of brain imaging modalities has important
      contributions in the diagnosis of brain diseases. However, involuntary movement
      by the patient may cause poor image quality. In this study, we developed a device
      to help keep a patient's head immobilized during brain image acquisition, for
      comparison between each follow-up study, and for functional-anatomical image
      correlation. METHODS: This device includes an acrylic material head supporter and
      a thermoplastic material facemask. The head supporter and the facemask can be
      firmly attached as a whole to support the head in a fixed position. Two capillary
      tubes filled with technetium-99m solution were placed perpendicularly on one side
      of the facemask as fiducial for imaging correlation between different studies.
      Ten patients, who each had two technetium-99m hexamethyl propyleneamine oxime
      (99mTc-HMPAO) brain single photon emission computer tomography (SPECT), were
      tested with this device for imaging. RESULTS: Three-dimensional cine motion and
      sectional imaging were displayed and confirmed head immobilization in all of
      these studies. In addition, the 99mTc fiducial were useful in the comparison of
      head positions among the different studies. In five subjects, the device also
      proved to be useful in functional-anatomical correlation among SPECT, magnetic
      resonance imaging (MRI), and computed tomography (CT) images. CONCLUSION: In
      conclusion, this device has been developed and found to be useful in (1) keeping
      patient's head immobilization, (2) keeping consistent head position for follow-up
      studies, and (3) SPECT, MRI and CT functional-anatomical imaging correlation.

PMID- 10584416
TI  - Local supplementation of ketoprofen reduces the incidence of low back pain after
      lumbar epidural anesthesia.
AB  - BACKGROUND: Backache is a common postoperative complaint after lumbar epidural
      anesthesia. Our study was aimed to compare the effect of the local addition of
      ketoprofen on the incidence of postepidural backache after nonobstetric surgery.
      METHODS: One thousand patients scheduled for hemorrhoidectomy were randomly given
      4 ml of 1% lidocaine with ketoprofen 1:400 (ketoprofen group) or without
      ketoprofen (control group) for local skin infiltration prior to epidural needle
      placement. Each of them received a single epidural injection of 25 ml 2%
      lidocaine with epinephrine 1:200000, and was interviewed 24, 48, and 72 hours
      postoperatively using a standard visual analog scale (VAS) for evaluation of
      postepidural backache. RESULTS: The incidence of postepidural backache in the
      ketoprofen-group patients for the 3 days was 9.8%, 4.6%, and 1.8%, all rates
      which were significantly less than those observed in the control-group patients
      (22.8%, 17.4%, and 9.2%, p < 0.001). There was also a significant association
      between postepidural backache and multiple attempts at epidural needle insertion.
      CONCLUSION: In summary, the local addition of ketoprofen reduced the incidence
      and severity of postepidural backache.

PMID- 10584418
TI  - Hyperglycemic hyperosmolar non-ketotic syndrome in hemodialysis patients.
AB  - BACKGROUND: Hyperglycemic hyperosmolar non-ketotic syndrome (HHNK) is an
      emergency complication of diabetes mellitus. The conventional treatment modality
      often includes massive fluid supplementation. In maintenance hemodialysis
      patients, dehydration via the renal route may not occur, and fluid management is
      rather complicated. In this study, we investigated the precipitating factors,
      treatment modalities, clinical course and prognosis of HHNK patients who received
      maintenance hemodialysis. METHODS: From January 1988 through August 1998, 16
      diabetic patients who had developed HHNK were enrolled. Eight of them were end
      stage renal disease (ESRD) patients on maintenance hemodialysis, and another
      group included 8 acute renal failure (ARF) diabetes mellitus patients who
      received their first hemodialysis during the HHNK episode. We retrospectively
      reviewed their medical charts and recorded each patient's age, treatment
      modalities, especially fluid supplementation, predisposing factors, and
      biochemical data during the HHNK episode. Complications and the final outcome
      were also recorded. RESULTS: There were no significant differences in biochemical
      data and patients' ages between the two groups (p > 0.05). The major predisposing
      factor for the ARF patients was infection, but irregular use of or discontinuing
      oral hypoglycemic agents (OHA) or insulin was the major predisposing factor for
      the ESRD patients. Less fluid supplementation was given in the ESRD group as
      compared to the ARF group and no deaths occurred in the ESRD group of patients.
      However, 6 patients expired in the ARF group of patients. CONCLUSION: Regular
      medical care, early diagnosis and recognition, and easier management of fluid
      administration explain the rather smooth course and better prognosis in the ESRD
      group of patients.

PMID- 10584417
TI  - Diagnosis and management of 34 Hurthle cell tumors.
AB  - BACKGROUND: Controversies still exist around the diagnosis and management of
      Hurthle cell tumors. The aim of this study is to reexamine our experience to
      improve our methods in the future. METHODS: We treated 34 patients with verified
      Hurthle cell carcinoma and adenoma at Chang Gung Memorial Hospital, Linkou from
      1990 through 1996. Clinical characteristics, thyroid ultrasonogram, 131I, 201Tl,
      99mTc-methoxy-isobutyl-isonitrile (MIBI) and 99mTc-thyroid scan, fine needle
      aspiration cytology (FNAC) and histology results were analyzed. RESULTS: Female
      predominance (82.4%) was noticed among our Hurthle cell tumors. Nine (26.5%)
      patients had carcinoma. The median size of carcinoma was 4.0 cm, which was
      significantly larger than the median 3.0 cm for adenoma. No significant
      differences were found between gender, age, multiplicity or echogenicity between
      two groups. All 12 adenoma and 3 carcinoma patients who received pre-operative
      99mTc and/or 131I thyroid scan showed cold nodules. The sensitivity and
      specificity of detection Hurthle cell carcinoma as indeterminate and malignant
      using FNAC was 78% and 18% respectively. These improved to 100% and 86% using
      frozen sections. One carcinoma patient developed neck lymph node metastasis, with
      normal serum thyroglobulin, negative 131I but positive 201Tl and 99mTc-MIBI whole
      body scans. Another one showed mediastinum metastasis with elevated serum
      thyroglobulin, detected using 131I scan, revealed successful regression after
      131I therapeutic scan. CONCLUSION: Tumor size of carcinoma is significantly
      larger than adenoma. All patients with FNAC suggestive of Hurthle cell tumors
      should receive surgery for histological diagnosis to differentiate carcinoma from
      adenoma. Therapeutic radioiodine ablation is indicated whenever there is 131I
      uptake by tumor cells.

PMID- 10584419
TI  - Identification of familial hypercholesterolemia in Taiwan: report of eleven
      cases.
AB  - BACKGROUND: Familial hypercholesterolemia is associated with a very high risk of
      premature coronary heart disease. In order to identify cases of familial
      hypercholesterolemia in Taiwan, we screened the hyperlipidemic patients in our
      metabolic clinics. METHODS: Hyperlipidemic patients were screened in the
      metabolic outpatient department and the cases which fulfilled the clinical
      criteria of definitive or possible familial hypercholesterolemia were further
      analyzed. Their clinical characteristics, including age, gender, physical
      findings, past history of coronary heart disease or cerebrovascular accident
      (CVA), family history, and lipid profiles before and after medical treatment,
      were reviewed. RESULTS: Eight women and 3 men fulfilled the diagnostic criteria.
      The mean age at diagnosis was 51.1 +/- 11.9 years old. Tendon xanthomas were
      found in 5 patients with definitive familial hypercholesterolemia. Coronary heart
      disease was confirmed in one patient and old CVA was noted in another 2 patients.
      The mean total cholesterol level was 390.3 +/- 88.9 mg/dl and the mean low
      density lipoprotein-cholesterol (LDL-cholesterol) level was 309.6 +/- 89.9 mg/dl
      before treatment. After a mean treatment duration of 45.2 months, the mean total
      cholesterol level and LDL-cholesterol level were 326.8 +/- 87.8 mg/dl and 249.1
      +/- 91.1 mg/dl, respectively. CONCLUSION: Clinically diagnosed familial
      hypercholesterolemia indeed exists in Taiwan. As compared to other reports, the
      mean age at diagnosis in our series was older and the majority of patients were
      women. Most patients were not vigorously treated and the family members were not
      thoroughly screened. Adequate treatment of patients with familial
      hypercholesterolemia in clinical practice and screening their family members are
      crucial in preventing new or recurrent coronary heart disease.

PMID- 10584420
TI  - Acute fish liver intoxication: report of three cases.
AB  - The livers of some larger fish such as shark, tuna and seabass have been reported
      to be responsible for a peculiar poisoning causing headaches and desquamation.
      This type of poisoning can also be induced by ingestion of the livers of the sea
      whale, the polar bear and the seal. Since these animals contain an extremely
      large quantity of vitamin A in their livers and the symptoms of poisoning in the
      patients resembled those of patients with acute hypervitaminosis A, the poisoning
      was believed to have been caused by excessive vitamin A intake. We observed an
      episode of acute fish liver intoxication in which 3 man experienced dizziness,
      headache, blurred vision, nausea, vomiting, fever, and desquamation after
      ingesting the liver of the grouper fish Cephalopholis boenak (C. boenak). One of
      the patients had full-blown symptoms and presented with a high fever, headache,
      dizziness, generalized aching pain, and superficial vesicles and bullae of the
      skin. The treatment was mainly supportive. In the follow-up period, he
      subsequently developed hair loss and diffuse peeling of the skin on his palms and
      soles. Acute fish liver intoxication is rare, especially in subtropical regions.
      Symptomatologically, the clinical pictures of these patients were comparable to
      acute hypervitaminosis A or retinoid intoxication. The average vitamin A content
      in the grouper (C. boenak) is high enough to cause acute vitamin A intoxication.
      Moreover, ethanol may play a potentiating role in this type of event.

PMID- 10584421
TI  - Primary stenting of the left main coronary artery in acute myocardial infarction
      complicated by cardiogenic shock: case report.
AB  - Although acute left main coronary artery (LMCA) occlusion is a rare angiographic
      finding, it carries a very high mortality rate and most of the patients with this
      clinical condition die from sudden death or cardiogenic shock due to malignant
      arrhythmia or pump failure. The high mortality rate and tendency to lead rapidly
      to death are chiefly related to extensive myocardial injury. We report a case of
      cardiogenic shock resulting from acute myocardial infarction. Emergency cardiac
      catheterization was performed and coronary angiography showed a totally occluded
      LMCA. Prompt revascularization by means of primary LMCA stenting was successful
      and the patient was discharged 2 weeks later with only mild congestive heart
      failure. We suggest that the rapid performance of angiographic studies in this
      patient with cardiogenic shock was the turning point in saving her life. We also
      suggest primary LMCA stenting as an effective procedure for saving lives because
      it may reverse cardiogenic shock and prevent a probable fatal outcome.

PMID- 10584422
TI  - Multiple pregnancy with adnexal torsion after in vitro fertilization: case
      report.
AB  - Assisted reproductive techniques (ART) are widely accepted procedures for
      infertile couples. Rare complications, like heterotopic pregnancy, bilateral
      tubal pregnancy, and adnexal torsion during pregnancy, have been diagnosed with
      increasing frequency after ART. We present a case of an early triplet pregnancy
      complicated with adnexal torsion. The patient was pregnant through in vitro
      fertilization. Early ultrasound examination revealed a triplet pregnancy within
      the uterine cavity. At 7 weeks' gestational age, an acute onset of lower
      abdominal pain, progressive abdominal distension, and massive internal bleeding
      prompted emergency laparotomy. The right ovary was enlarged, twisted, necrotic
      and hemorrhagic. Attempts to preserve the ovary failed because of the friable
      nature of the affected ovary, and an oophorectomy had to be performed. Although
      the removed ovary contained a corpus luteum, the pregnancy continued smoothly
      after only short luteal support. A precise pre-surgery diagnosis in our case was
      difficult based on the patient's initial clinical presentation. However, with
      high clinical suspicion in addition to color Doppler ultrasound, the physician
      should be able to make an early decision for an exploratory laparotomy or
      laparoscopy, gaining the benefit of more conservative treatment.

PMID- 10584423
TI  - Primary hepatic epithelioid hemangioendothelioma: case report.
AB  - Hepatic epithelioid hemangioendothelioma (HEH) is a very rare vascular tumor of
      the liver. It usually affects adult women and presents as multiple hepatic
      nodules with mainly peripheral distribution. It poses special difficulties for
      clinicians in its diagnosis and treatment because of its non-specific clinical
      manifestations and findings on imaging, and it is easy to be misdiagnosed
      pathologically. Its clinical course and prognosis are variable but supposed to be
      intermediate between hemangioma and angiosarcoma. The primary treatments of
      choice are radical resection or liver transplantation. We report a 62-year-old
      man with right upper quadrant abdominal pain of several days' duration, who was
      initially misdiagnosed as having a liver abscess. Finally, HEH was diagnosed on
      the basis of positive immunohistochemical staining for factor VIII-related
      antigen in tumor cells. This case could serve to highlight the pitfalls in
      diagnosing this rare tumor. Increasing the index of suspicion and familiarity
      with the radiological and histological characteristics of this tumor would
      facilitate the accurate diagnosis and thus avoid unnecessary interventions.

PMID- 10584424
TI  - Recurrent fetal thyrotoxicosis in a woman with Graves' disease: case report.
AB  - The thyroid stimulating immunoglobulins are generally believed to be the cause of
      hyperthyroidism in Graves' disease. Placental transfer of these antibodies from a
      mother with autoimmune thyroid disease can result in fetal thyroid disorders. We
      report the case of a 31-year-old woman who had a history of Graves' disease. She
      received thyroxine therapy for post thyroidectomy hypothyroidism. Two years after
      the thyroidectomy, she became pregnant. Unfortunately, intrauterine fetal death
      occurred in midgestation. One year later, she became pregnant again. In the 26th
      week of gestation, fetal thyrotoxicosis was diagnosed using clinical pictures,
      including fetal tachycardia and cardiomegaly, and a hormonal evaluation of a
      periumbilical blood sampling (T4: 18 micrograms/dl, T3: 65.3 ng/dl, TSH: < 0.03
      microU/ml) was performed. Antimicrosomal antibodies were not detectable in either
      the maternal or fetal blood. In this case, high levels of TBII were detected
      during pregnancy and crossed the placenta to result in a thyrotoxic fetus in the
      second pregnancy. We recommend that both the regular monitoring of the
      thyrotropin receptor antibodies of pregnant women with a history of autoimmune
      thyroid disease, and routine measurements of the fetal heart rate and
      intrauterine growth during gestation be mandatory for the early detection of
      fetal thyroid disorders. Cordocentesis for measuring fetal thyroid function is
      helpful in reaching a definite diagnosis and for guiding therapy.

PMID- 10584425
TI  - Acute postoperative aggravation of radiculopathy as a complication of free fat
      transplantation in lumbar disc surgery: case report.
AB  - This case report illustrates a rare case of motor weakness caused by a free fat
      graft herniation. A 40-year-old woman who had undergone surgery for a herniated
      lumbar intervertebral disc experienced right lower leg weakness. On magnetic
      resonance image (MRI) a herniated free fat graft was noted. An emergent operation
      was performed and the herniated fat graft was removed. Postoperatively, the
      patient recovered well with improvement of the motor weakness. MRI is a good
      method for diagnosis of fat graft herniation. The mechanisms of this complication
      have been documented, and the size of the fat graft plays an important role. The
      methods for prevention of this herniation are also discussed. Although the
      transplantation of adipose tissue has many advantages, including the prevention
      of postoperative epidural fibrosis, great care is needed when applying a fat
      graft intra-operatively. When a postoperative neurologic deficit develops,
      herniation of the fat graft must be considered. An emergent operation is the
      treatment of choice for this particular complication.

PMID- 10584426
TI  - Anterior tarsal tunnel syndrome: case report.
AB  - Anterior tarsal tunnel syndrome is a rare entrapment neuropathy involving the
      deep peroneal nerve beneath the inferior extensor retinaculum of the ankle and
      foot. This syndrome may be a clinically under-recognized entity, thus making a
      missed diagnosis and delayed treatment likely. We present the case of a 53-year
      old woman who for many years had experienced the clinical symptoms of anterior
      tarsal tunnel syndrome, including pain in the dorsum of the right foot with
      numbness radiating to the first web space. Roentgenograms of the foot revealed
      osteophytes on the dorsum of the talus as it articulated with the navicular bone.
      During surgery, the osteophytes were found to be irritating the deep peroneal
      nerve. After surgical decompression of the anterior tarsal tunnel, the patient
      had a significant reduction of symptoms. One year later, she was noted to be
      asymptomatic with normal physical findings. We believe that this case points to
      the necessity of more thoughtful attention to this syndrome and its diagnosis.
      That is to say, a thorough knowledge of the pathogenesis and a comprehensive
      physical examination are the prerequisites for correct diagnosis and appropriate
      treatment.

PMID- 10584427
TI  - Vibrio parahemolyticus bacteremia: case report.
AB  - Vibrio parahemolyticus (V. parahemolyticus) is a halophilic gram-negative
      bacillus that lives in the ocean. It is the leading cause of infectious diarrhea
      in Taiwan and sometimes produces soft tissue infections, but it is rarely a cause
      of bacteremia. There have been only 11 cases reported in the literature. Most of
      the cases involved a history of ingestion of seafood or exposure to seawater. In
      addition, those patients were all immunosuppressed, especially with leukemia and
      cirrhosis. We report a 60-year-old male patient with chronic hepatitis C and
      adrenal insufficiency. He developed V. parahemolyticus bacteremia following
      ingestion of seafood one week prior to admission. His condition was complicated
      with neck and right lower leg soft tissue infection, as well as multiple organ
      failure. The patient survived after intravenous ceftazidime, oral doxycycline,
      and surgical debridement. To our knowledge, this is the 12th reported cases on
      Medline, and the second bacteremic case in Taiwan. After reviewing the
      literature, we suggest that all patients with immunosuppressed conditions or
      adrenal insufficiency should eat foods that are well cooked and avoid raw
      seafood. Moreover, when patients who are at risk to develop fever, diarrhea, and
      soft tissue infection after ingestion of seafood, V. parahemolyticus infection
      should be suspected. All culture specimens should be inoculated on Vibrios
      selective media.

PMID- 10584428
TI  - Recurrent herpetic keratitis induced by laser iridectomy: case report.
AB  - The mechanism for herpetic keratitis reactivation remains unclear. When observed
      clinically, the reactivation may be associated with a variety of endogenous and
      exogenous stimuli, such as strong sunlight, fever, menstruation, and psychiatric
      disturbances. In experimental studies, most methods of inducing recurrence have
      involved some degree of corneal trauma, inflammation, neuronal stimulation, or
      damage to the nerves that innervate the cornea. Although corneal damage after
      laser iridectomy (LI) is well documented, recurrent herpetic keratitis induced by
      LI has never been reported. Here we present an unusual case of recurrent herpetic
      keratitis induced by LI. The location of the bullous keratopathy was strongly
      correlated to the site of laser iridectomy. Clinical findings as well as the
      dramatic response to antiviral treatment supported the diagnosis. Although the
      energy for laser iridectomy is relatively safe for most circumstances, the
      possibility of inducing herpetic keratitis cannot be ignored. Therefore it is
      important for clinicians to beware of this potential complication.

PMID- 10584429
TI  - Retinal detachment in postpartum preeclampsia and eclampsia: report of two cases.
AB  - Retinal detachment is an unusual complication of hypertensive disorder in
      pregnancy. It has been reported in 1% to 2% of patients with severe preeclampsia
      and in 10% of patients with eclampsia. Choroidal ischemia may be the cause of
      retinal detachment. We know that mild arteriolar spasm involving the bulbar
      conjunctival vessels has been observed in the normal pregnancy, but in pregnancy
      induced hypertension the vasospasm may be severe and result in choroidal
      ischemia. Most patients with retinal detachment in pregnancy-induced hypertension
      have had full spontaneous resolution within a few weeks, and they did not have
      any sequelae. Medical treatment with antihypertensive drugs and steroids may be
      helpful. We report two rare cases of retinal detachment and persistent
      hypertension in association with postpartum eclampsia and post-cesarean section
      preeclampsia. These patients had normotension throughout pregnancy. Preeclampsia
      or eclampsia developed after delivery, and blurred vision, headache, and reduced
      vision accompanied serous retinal detachment. The serous retinal detachment
      disappeared within 3 weeks. Good outcomes were found in the follow-up
      examinations in both of these cases. For women who had been normotensive at the
      time of delivery and then complained in the postpartum period of blurred vision,
      headaches, nausea and vomiting, we should consider the possibility of retinal
      detachment and perform fundoscopy.

PMID- 10584430
TI  - Tracheal neurilemmoma mimicking bronchial asthma--a dilemma of difficult
      diagnosis: case report.
AB  - Tracheal tumors are often overlooked as a cause of pulmonary symptoms until they
      reach an advanced state. They are often presented with a prolonged cough and
      shortness of breath. Most tracheal tumors in adults are cancerous (80% to 90%).
      Benign tracheal tumors are rare in adult patients. A case history is presented of
      a 19-year-old patient with a rare tracheal neurilemmoma. He was treated as having
      bronchial asthma initially, but his signs and symptoms did not improve with
      traditional therapy. The possibility of the presence of an upper airway
      obstruction was not raised until the typical "inspiratory tubular sound" was
      heard. Flow-volume loop testing, bronchoscopy, and three-dimensional computed
      tomography (3-D CT) confirmed the diagnosis of upper airway obstruction caused by
      a tracheal tumor. Therefore, surgical intervention rather than bronchoscopic
      removal was performed without difficulty. The patient was leading a stable life 8
      months after a surgical resection. The presence of an upper airway obstruction
      can be proven by flow-volume loop testing and 3-D CT. Further pathologic
      confirmation can be accomplished by bronchoscopy. High suspicion of an upper
      airway obstruction such as a tracheal lesion should be raised when bronchial
      asthma patients fail to respond to conventional treatment.

PMID- 10584431
TI  - Aberrant infrarenal inferior vena cava as a hindrance to percutaneous transvenous
      mitral valvuloplasty in a patient with mitral stenosis: case report.
AB  - Cardiac catheterization and percutaneous transvenous mitral commissurotomy using
      the Inoue technique were attempted in a 44-year-old woman with mitral stenosis.
      The pulmonary arterial wedge pressure was 25 mmHg, mean transmitral diastolic
      pressure gradient 20.3 mmHg, cardiac index 1.80 L/min/m2, and mitral valve area
      0.70 cm2. After the diagnostic catheterization, the guide wire for the
      transseptal procedure was checked in the middle of the inferior vena cava (IVC).
      A 7-French end-holed Bermann catheter was then used to detect the course of the
      IVC. It was found that the IVC coursed along the left border of the 4th and 5th
      lumbar vertebrae, to the left of the abdominal aorta. At the upper border of the
      third lumbar vertebra, the IVC returned to the right side of the vertebra. In
      consideration of the inability to pass the Brockenbrough needle through the
      detoured infrarenal IVC and the risk of rupturing the vessel, the transseptal
      procedure and attempted percutaneous transvenous mitral commissurotomy were
      aborted. Therefore, the patient underwent open mitral commissurotomy instead.

PMID- 10584432
TI  - Ankylosing spondylitis with severe chondrocalcinosis: case report.
AB  - The term chondrocalcinosis is often used to describe the radiological or
      pathological features of calcified joint cartilage, and it usually indicates the
      deposition in cartilage of calcium pyrophosphate dihydrate. The prevalence of
      chondrocalcinosis increases with age, with dramatic increases occurring in the
      decades past age 60. In younger patients with chondrocalcinosis, either clinical
      evidence of associated metabolic diseases leading to the chondrocalcinosis or
      familial disease occurrence usually can be detected. We report a 42-year-old
      Chinese woman with ankylosing spondylitis and arthritis involving multiple
      peripheral joints. Severe chondrocalcinosis was detected incidentally in this
      patient, however, subsequent studies revealed no associated metabolic disease or
      familial susceptibility and the clinical features of this patient were different
      from those of ankylosing chondrocalcinosis (pseudoankylosing spondylitis). The
      cause of chondrocalcinosis in this patient remains unknown, but joint damage and
      repair could have been initiating or aggravating factors of the
      chondrocalcinosis.

PMID- 10584433
TI  - Sequential sonographic changes of the gallbladder in hemobilia: case report of a
      patient with intrahepatic duct stones.
AB  - The sonographic features of hemobilia in the gallbladder have been reported with
      variation, including an echogenic mass, hypoechoic mass, and scattered
      intraluminal echoes. The sequential sonographic changes of hemobilia in the
      gallbladder were observed in a 59-year-old male patient with bilateral
      intrahepatic duct stones. The sonograms of hemobilia in the distended gallbladder
      initially showed a hyperechoic, homogeneous, movable mass-like lesion, 36 hours
      before the onset of upper gastrointestinal (UGI) bleeding. A hypoechoic mass-like
      lesion with a hyperechoic ring was found 5 days after the onset of UGI bleeding.
      A faint hypoechoic mass-like lesion was found 7 days after the onset of UGI
      bleeding (the day of no further bleeding). Scattered echoic densities were found
      9 days after the onset of UGI bleeding, then disappearance of the lesion was
      noted 12 days after the onset of UGI bleeding. The sonographic patterns of
      hemobilia in the gallbladder vary depending on the timing of lysis of the blood
      clot. It should be differentiated from gallbladder cancer, a stone, a polyp,
      sludge, acute gangrenous cholecystitis, and gallbladder empyema.

PMID- 10584434
TI  - Breast cancer management, its triumphs and challenges.

PMID- 10584435
TI  - Mammography for senior women: an overview.

PMID- 10584436
TI  - "Help us save your life".

PMID- 10584437
TI  - Current imaging modalities for the diagnosis of breast cancer.
AB  - Although mammography still remains the gold standard for breast cancer screening
      and diagnosis, it typically cannot differentiate benign from malignant disease
      and is less accurate in patients with dense glandular breasts. This article is an
      overview of imaging modalities that have emerged to augment mammography and
      improve the accuracy of non-invasive breast cancer diagnosis. Ultrasound is
      currently used to differentiate breast masses and guide aspirations and biopsies.
      Magnetic resonance imaging has excellent sensitivity in demonstrating breast
      cancer but a low specificity. Nuclear medicine studies have recently emerged that
      detect the increased metabolic rate and vascularity of breast cancers. Other
      modalities, such as thermography and computed tomography, have a more limited
      utility for breast cancer diagnosis. Digital mammography is among other emerging
      technological advancements that will continue to develop and improve the accuracy
      of breast cancer diagnosis in the future.

PMID- 10584438
TI  - Screening for life: helping Delaware women receive lifesaving services.

PMID- 10584439
TI  - Early detection reminder systems a boon for cancer screenings.

PMID- 10584440
TI  - Drugs can reduce the incidence of breast cancer: now what?

PMID- 10584441
TI  - SLN biopsy in breast cancer: Christiana care experience. May 1998-February 1999.

PMID- 10584442
TI  - Aesthetic advances in TRAM flap breast reconstruction: the skin-sparing
      mastectomy technique.

PMID- 10584443
TI  - Preliminary but promising: the value of limited studies.

PMID- 10584444
TI  - The effects of economic circumstances on British students' mental and physical
      health.
AB  - Three-hundred sixty British university students completed a questionnaire
      providing information on demographic characteristics, financial circumstances,
      smoking, and drug and alcohol use. A 14-item inventory of physical symptoms, the
      short form 36 health survey (SF-36), and the General Health Questionnaire (GHQ
      12) were used to assess their physical and psychological well-being. Except for
      physical functioning, all subscales of the SF-36 and the GHQ indicated levels of
      health significantly below population norms matched for age and sex. Poorer
      mental health was related to longer working hours outside the university and
      difficulty in paying bills. Students who had considered abandoning study for
      financial reasons had poorer mental health, lower levels of social functioning
      and vitality, and poorer physical health as indicated by variables on the SF-36.
      They were also heavier smokers. Students' personal debt was significantly
      associated with their knowing people involved in prostitution, crime, or drug
      dealing to help support themselves financially.

PMID- 10584445
TI  - Prevalence of alcohol-use disorders and alcohol-related problems in a college
      student sample.
AB  - Most studies of alcohol consumption patterns and alcohol-related problems among
      college students have failed to include a diagnostic measure based on Diagnostic
      and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria. Applying the DSM
      IV standards would facilitate an analysis of the prevalence of alcohol-use
      disorders and individual symptoms of those disorders. A structured diagnostic
      interview based on DSM-IV criteria (the alcohol section of the Substance Abuse
      Module) and several alcohol screening instruments were administered to 306
      undergraduate students at an urban commuter campus. The prevalence of current and
      lifetime alcohol-use disorders, individual symptoms of those disorders, and other
      alcohol-related problems are reported, as well as data regarding alcohol
      consumption patterns and binge drinking. The data are analyzed in terms of
      demographic variables, including sex, ethnicity, year in school, age, and marital
      status of those in the sample.

PMID- 10584446
TI  - Serum cholesterol levels in college students: opportunities for education and
      intervention.
AB  - Elevated serum cholesterol levels have been shown to be associated with premature
      atherosclerosis in adolescents and young adults. The National Cholesterol
      Education Program recommends cholesterol screening for all adults aged 20 years
      or older, but normative data on the college-age population are limited. At a
      university where lipid profiles are made available to students in selected
      health/wellness courses, the authors analyzed and summarized lipid profiles on
      1,088 undergraduates. Mean total cholesterol levels were similar for men (165 +/-
      33 mg/dL) and women (168 +/- 27 mg/dL). The men, however, had significantly lower
      high-density lipoprotein (HDL) cholesterol and higher low-density lipoprotein
      (LDL) cholesterol than the women. One hundred twenty-one students (11.1% of the
      sample) had elevated serum cholesterol levels (LDL-C > or = 130 mg/dL).
      Cholesterol screening can be used as an educational tool for college students to
      reinforce the link between lipid levels and health habits.

PMID- 10584447
TI  - African American female basketball players: an examination of alcohol and drug
      behaviors.
AB  - The use of drugs and alcohol by National Collegiate Athletic Association Division
      I African American female basketball players and their reasons for using these
      substances were examined. The investigation is part of a broader study
      investigating the use of alcohol, weight-loss products, tobacco, amphetamines,
      and anabolic steroids by female college athletes. Of the 50 athletes in this
      study, 72% reported having consumed alcoholic beverages, and 46% had engaged in
      binge drinking. Only 8% reported using either weight-loss or tobacco products,
      and there were no reports of using amphetamines or anabolic steroids. Usage
      patterns indicated that the athletes in the study were aware of the short-term
      negative effects of alcohol and tobacco; those respondents who did use these
      products greatly reduced their consumption during the competitive season. Factors
      found to influence use include social and peer influences and coaches' rules.

PMID- 10584448
TI  - An examination of common coping strategies used to combat driver fatigue.
AB  - Driver fatigue is recognized as an important highway safety risk. Many
      organizations have published recommendations for coping with driver fatigue. The
      authors explored the effectiveness of 10 common coping strategies, using a case
      controlled design to examine the use of coping strategies among a random sample
      of college students (N = 301). The students were questioned about their use of
      coping strategies for driver fatigue and their record of having experienced a
      dozing-related incident. Odds ratios were calculated and 4 strategies--taking a
      walk, drinking caffeinated beverages, stopping for a nap, and chewing ice--were
      found to predict an incident. Three other strategies, snacking, rolling the
      window down, and talking with a passenger, were found to be protective.

PMID- 10584449
TI  - Setting up a CLIA-certified laboratory in a student health services clinic.
AB  - Performing some laboratory tests on site at a student health service clinic may
      increase efficiency and cut costs for patients. However, with the passage of the
      Clinical Laboratory Improvement Amendments (CLIA) of 1988, many laboratories in
      physician offices and clinics have shut down because of increased regulatory
      requirements. The personnel in one SHS laboratory found that the guidelines
      proposed by CLIA help assure quality care and are not prohibitive. In this
      article, the process of applying for and receiving a CLIA certificate in the
      student health clinic setting is explored.

PMID- 10584450
TI  - Youth violence? Let's call it what it is.

PMID- 10584451
TI  - Postherpetic neuralgia in a patient with a lesion involving the dorsal horn of
      the cervical spinal cord.

PMID- 10584452
TI  - Re: Dyspnea in the advanced cancer patient.

PMID- 10584453
TI  - Re: Visual disturbances in advanced cancer patients.

PMID- 10584454
TI  - Validation of the Brief Pain Inventory in a Taiwanese population.
AB  - Assessment of pain in cancer patients is very important to all health care
      professionals. This paper describes the development of a Taiwanese version of the
      Brief Pain Inventory (BPI-T) and discusses its psychometric properties in Taiwan.
      The BPI-T was developed from the original BPI using back-translation and
      committee review. A total of 534 cytologically or pathologically diagnosed cancer
      patients in three medical centers in Taiwan were interviewed between July 1992
      and October 1997. The intraclass correlation coefficient for the test-retest
      reliability was 0.79 for the pain severity scale and 0.81 for the pain
      interference scale. The explained variance for the within-scale factor analyses
      was larger than 60% in both scales. The coefficient alpha for the internal
      reliability was 0.81 for the severity scale and 0.89 for the interference scale.
      Confirmatory factor analysis of the BPI-T clearly identified the same two scales
      (severity and interference scales) in the 299 adult patients (age between 20-64)
      with high education (education years > 9) or patients at an early stage of
      disease. However, in the 235 nonadult patients with distant metastasis or low
      education patients with distant metastasis, the "most severe pain" item loaded
      more to the interference scale than the severity scale. Convergent validity of
      the pain severity was demonstrated by significant correlations with stage of
      disease (National Cancer Institute's Surveillance, Epidemiology, and End Results
      Program [SEER]), performance status (Eastern Cooperative Oncology Group [ECOG]),
      and pain interference. In conclusion, interviewer-administered BPI-T was a
      reliable instrument for cancer pain severity and its interference in Taiwan.
      Additionally, it was a valid instrument on adult cancer patients with high
      education or patients at an early stage of disease.

PMID- 10584455
TI  - Continuous subcutaneous administration of high-dose salmon calcitonin in bone
      metastasis: pain control and beta-endorphin plasma levels.
AB  - This prospective nonrandomized trial was performed to evaluate the efficacy of
      salmon calcitonin (sCT) in controlling pain related to bone metastasis in cancer
      patients and the relation of sCT's analgesic efficacy with beta-endorphin blood
      levels. The study group consisted of 22 cancer patients with bone metastases
      (male 13 and female 9, age range 38-77 years). Pain control was first achieved by
      continuous subcutaneous (s.c.) morphine administration. The next increase in pain
      was managed with continuous s.c. administration of 400 IU/day sCT. Beta-endorphin
      blood levels were measured before and during sCT administration. The first
      measurement was taken before sCT administration; subsequent measurement occurred
      at 12, 24, and 48 hours and 7 days after the commencement of treatment. Pain
      scores were monitored by a visual analogue scale. A complete blood count and a
      biochemical screening profile were taken before the administration of calcitonin
      and also on the seventh and the fifteenth day of the administration. The results
      showed a satisfactory analgesic effect. The mean pain score before the calcitonin
      administration was 4.43 and the score on the seventh day was 1.17. The gradual
      reduction of pain score was associated with an increase in beta-endorphin blood
      levels (increase to 147.2% of baseline on the seventh treatment day). In three
      cases, no satisfactory analgesic effect was obtained and pain control was
      achieved by increasing the continuous s.c. morphine dosage. No significant side
      effects were observed. These data suggest that sCT in high doses may be a useful
      adjuvant analgesic when combined with low doses of morphine in continuous s.c.
      administration for the management of metastatic bone pain.

PMID- 10584456
TI  - Disclosure of the cancer diagnosis as it relates to the quality of pain
      management among patients with cancer pain in Taiwan.
AB  - This study was designed to explore: (1) who is responsible for disclosing to
      Taiwanese cancer patients the diagnosis of cancer, (2) the extent of disclosure,
      and (3) the relationship between the disclosure of the cancer diagnosis and the
      quality of cancer pain management as perceived by the patients experiencing
      cancer pain. One hundred twelve cancer patients with pain were recruited from
      three teaching hospitals in Taiwan. The major findings in this study were as
      follows: the majority of the patients with pain (79%) had been informed that the
      diagnosis was cancer, and for the majority (89%) the disclosure of cancer had
      been made by their physicians; older patients and those with lower levels of
      education were less likely to be told that they had been diagnosed with cancer;
      and patients to whom it was disclosed that the diagnosis was cancer tended to
      experience lower levels of pain intensity, lower levels of pain interference, and
      higher levels of satisfaction with pain management provided by clinicians. These
      findings provide significant implications for disclosure practice for Taiwanese
      oncology clinicians.

PMID- 10584457
TI  - Contributing factors to physical symptoms in terminally-ill cancer patients.
AB  - Prediction of future suffering could improve palliative care. To identify the
      factors contributing to physical symptoms, a prospective study was performed on
      two series of hospice inpatients with cancer (n = 150 and n = 200, respectively).
      Physical symptoms, patients' characteristics, and tumor locations were recorded
      using a structured protocol on admission and throughout the clinical course.
      Common symptoms on admission and during the patient's course were pain (65%,
      88%), general malaise (58%, 77%), anorexia (57%, 94%), constipation (33%, 71%),
      dyspnea (33%, 66%), nausea/vomiting (29%, 48%), cough/sputum (29%, 48%), edema
      (27%, 65%), fever (26%, 70%), abdominal swelling (26%, 42%), and dry mouth (25%,
      61%), respectively. The mean number of symptoms was 5.7 +/- 3.0 on admission and
      9.6 +/- 3.1 during the course. Factors that contributed to the symptoms were
      young age (pain, abdominal swelling, dry mouth), performance status (anorexia,
      general malaise, edema, dyspnea), brain tumor (paralysis), neoplasms of
      lung/pleura (dyspnea, cough/sputum, death rattle), bone metastasis (pain,
      paralysis), gastric/pancreas cancer (abdominal swelling), peritoneal metastasis
      (general malaise, edema, nausea/vomiting, abdominal swelling, dry mouth), opioids
      (constipation, dry mouth, myoclonus), anticholinergics (dry mouth), and
      antidopaminergics (myoclonus). Opioid requirement was positively correlated with
      the presence of bone metastasis, and negatively correlated with age and brain
      involvement. Additional opioids were frequently used in the final 48 hours in
      cases with lung/pleura neoplasms. These data suggest that terminal symptoms in
      cancer patients are determined by local and/or general factors. Clinicians can
      predict the probability of future symptoms from patients' characteristics,
      general condition, tumor locations, and medications.

PMID- 10584459
TI  - Homeopathic prophylaxis of headaches and migraine? A systematic review.
AB  - Homeopathy is often advocated as a prophylaxis of migraine and headaches. The aim
      of this systematic review was to evaluate the clinical trials, testing the
      efficacy of homeopathy for these indications. Independent computerized literature
      searches were carried out in 4 databases. Only randomized, placebo-controlled
      trials were included. Four such studies were found. Their methodological quality
      was variable but, on average, satisfactory. One study suggested that homeopathic
      remedies were effective. The other, methodologically stronger trials did not
      support this notion. It is concluded that the trial data available to date do not
      suggest that homeopathy is effective in the prophylaxis of migraine or headache
      beyond a placebo effect.

PMID- 10584458
TI  - Investigation of an opioid response categorization in advanced cancer patients.
AB  - The aim of this study was to investigate a possible distinction in three
      categories of opioid response and to identify possible factors associated with a
      poor response. A prospective survey was carried out in 105 consecutive patients
      requiring morphine for at least 4 weeks before death. Mean pain intensity, opioid
      doses and symptom intensity at weekly intervals, pain syndromes, and the presence
      of psychological distress were assessed. Opioid escalation index (OEI%) was
      calculated from the parameters recorded. Three categories were considered,
      including (1) patients with slow increments of opioid dose and a mean analgesic
      10-cm visual analogue scale (VAS) less than 4 (responders), (2) patients with an
      OEI% more than 5 but a mean VAS less than 4 (partial responders), and (3)
      patients with a mean VAS more than 4 (poor responders). Treating physicians were
      asked to make a judgment on the pain treatment difficulties on a numerical scale
      (0-10). Significant differences in opioid starting dose (OSD), opioid dose at--4
      weeks, nausea and vomiting at--1 week, opioid maximum doses, mean VAS, and OEI
      were found in the three categories of response. Significant correlations with the
      physician judgment were found for opioid maximum dose, mean VAS, VAS at the
      different time intervals, the doses used at the different intervals, OEI, and
      confusion. Neuropathic pain was significantly associated with a judgment of poor
      pain outcome. The correlation between the physician judgment and the categories
      of opioid response was highly significant. Seven of the 12 patients in the third
      category (poor response) were considered as having a relevant psychological
      distress. The categorization of the opioid response used in this study could be
      used in clinical research and as an audit tool, and could be tested in other
      settings to compare different treatments.

PMID- 10584460
TI  - Barriers to effective cancer pain management: a review of the literature.
AB  - As many as 90% of patients with cancer-related pain can attain satisfactory
      relief through available pharmacological and medical means. However, as many as
      45% of patients in the earlier stages of cancer and 75% of patients in the
      advanced stages experience at least some pain. Although published guidelines are
      available, the research literature suggests that health care providers continue
      to hold some negative misconceptions about cancer pain and its treatment.
      Patients also harbor similar misconceptions that contribute to ineffective
      management. Interventions have been discussed in the literature, and although
      some have proven successful, much still needs to be done to remedy this problem.
      This review outlines the published guidelines for cancer pain management and
      describes the literature related to provider and patient barriers, as well as
      some interventions designed to facilitate effective cancer pain management.

PMID- 10584461
TI  - Methadone: outpatient titration and monitoring strategies in cancer patients.
AB  - Methadone can be an effective drug for cancer pain but it can also be difficult
      to use safely. It has been recommended that rotation to methadone from other
      opioids be undertaken in a hospital setting. The purpose of the study was to
      characterize the safety, toxicities, and outcomes of outpatient rotation to
      methadone for severe cancer pain in a heavily pretreated cohort of cancer
      patients. Data were collected through a retrospective review of consecutive
      patients from a tertiary level cancer pain clinic. Twenty-nine patients were
      rotated to methadone, 13 (45%) due to opioid toxicity and 16 (55%) because of
      either cost or difficulty swallowing their prior opioid. Eleven of 29 patients
      (38%) failed methadone due to rapidly progressive cancer, dose-limiting side
      effects, or other reasons, but the other patients were successfully rotated to
      methadone. Pain usually improved following rotation to methadone, but drowsiness
      from methadone was common. On average, it took 32 days to successfully rotate to
      methadone in the outpatient setting. Cancer patients with advanced disease and
      severe pain can be safely and effectively rotated to methadone in the outpatient
      setting. It takes considerably longer to stabilize these patients than patients
      on lower doses of opioid or those titrated in the inpatient setting. A careful
      monitoring system is needed to screen for evidence of toxicity.

PMID- 10584462
TI  - Use of transcutaneous electrical nerve stimulation in a young child with pain
      from open perineal lesions.
AB  - Transcutaneous electrical nerve stimulation (TENS) has been shown to be an
      effective treatment modality in adults experiencing pain associated with a
      variety of conditions. Therapeutic measures that are effective with adults can
      often be used with children. However, the benefit of TENS for children has not
      been well established since few research or clinical data have been published in
      the literature. This case report of a 4-year-old female with open perineal skin
      lesions who received TENS as an adjuvant therapy for painful dressing changes
      illustrates that TENS can be an effective treatment in children. In addition to
      the pain reduction seen in our patient, TENS therapy also had an opioid-sparing
      effect.

PMID- 10584463
TI  - The use of mirtazapine in a patient with chronic pain.
AB  - Antidepressant drugs that act on serotonin and noradrenergic systems may be
      analgesic. The newer antidepressant mirtazapine (Remeron) has activity on
      noradrenergic and serotonergic transmission and is approved for the treatment of
      a Major Depressive Disorder. This paper describes a case that suggests that
      mirtazapine may also be useful in the treatment of chronic pain.

PMID- 10584464
TI  - Immune system of the gut and the feeding of infants.

PMID- 10584465
TI  - Aminoaciduria in calcium-deficiency rickets in northern Nigeria.
AB  - Generalized aminoaciduria is associated with vitamin D-deficiency rickets in
      humans, but there is little information regarding aminoaciduria in rickets caused
      by primary calcium deficiency. In contrast to rickets in other parts of the
      world, this bone disease in Nigeria is caused primarily by inadequate intake of
      dietary calcium. We conducted a clinical trial in Jos, Nigeria in 10 children
      with radiographically and biochemically proven rickets; an equal number of non
      rachitic healthy children from the same area served as controls. Serum and 24 h
      urine samples were obtained at baseline and at 24 h, 1 week, 4 weeks, and 12
      weeks after initiation of calcium supplementation (1000 mg/day) and were analysed
      for their content of amino acids. Serum calcium, phosphorus, intact parathyroid
      hormone (PTH), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were also
      measured at each time point. In the rachitic subjects urinary amino acid
      concentrations were elevated from 2- to 16-fold at baseline, while serum amino
      acid levels increased 1.5- to 3.8-fold compared to controls. After 12 weeks of
      calcium supplementation, serum and urine amino acids decreased. There was no
      correlation between the degree of aminoaciduria and serum PTH or 1,25
      dihydroxyvitamin D concentrations. We conclude that the aminoaciduria in these
      rachitic children was related to their calcium status and not to their vitamin D
      or PTH status.

PMID- 10584466
TI  - Use of V3 loop peptide-specific antibody evaluation for subtyping HIV-1: results
      of a vertical transmission study from Sao Paulo, Brazil.
AB  - Plasma samples obtained from 97 children enrolled in a longitudinal study of HIV
      1 perinatal transmission in Sao Paulo, Brazil, were tested for the presence of
      specific V3-loop antibodies in order to determine the HIV-1 subtype circulating
      among them. A set of seven synthetic peptides representative of the predominant
      HIV-1 subtypes detected in Brazil was employed in an in-house enzyme immunoassay
      (EIA) using two different protocols, one of which permits identification of high
      avidity antibodies (HAAb). Using these approaches we were able to detect
      antibodies in 64 out of 97 children, independently of the HIV-1 infection status,
      indicating the presence of subtype B in all cases, except one, which could be
      considered to be of subtype F. Among subtype B cases, half of the samples reacted
      with the GWGR motif (type W is representative of Brazilian B strains). In the
      main, concordant results were obtained between peptide-EIA and HIV-1 status among
      infants, although in several cases of truly HIV-1 infected children, negative
      results could be observed. Thirteen mother-child pairs and four fathers were also
      evaluated, and the results confirmed subtype B to be the prevalent one among
      them, showing similar proportions of P and W types. Taken together, the results
      obtained identified subtype B (W and P) uniformly among adults and HIV-1 infected
      children from Sao Paulo, Brazil, and confirm vertical and sexual transmission of
      the predominant strains.

PMID- 10584467
TI  - Molecular typing of multiresistant Klebsiella pneumoniae isolated from children
      from northern Jordan.
AB  - Twenty-nine clinical isolates of community acquired Klebsiella pneumoniae
      obtained from 17 children with malnutrition were characterized by antibiotic
      susceptibility, plasmid analysis, and random amplified polymorphic DNA (RAPD)
      techniques. Disc diffusion methodology was used to test the susceptibility of the
      isolates to 13 antibiotics: amoxycillin, cephapirin, ceftazidime, cefoxitin,
      cefotaxime, aztreonam, gentamicin, ciprofloxacin, chloramphenicol, erythromycin,
      nalidixic acid, trimethoprim and amoxycillin-clavulanic acid. All the isolates
      showed multiresistance patterns (15 patterns) ranging from resistance to two
      antibiotics to resistance to 10 antibiotics. All isolates were resistant to
      amoxycillin and erythromycin. Ten K. pneumoniae isolates producing extended
      spectrum beta-lactamases (ESBLs) as evidenced by the double-disc diffusion
      synergy test were isolated sporadically from six patients. Six of these 10
      isolates were hyperproducers of ESBL, which resulted in increased resistance to
      the beta-lactam-beta-lactamase inhibitor combination amoxycillin-clavulanic acid.
      Plasmid analysis showed plasmid ranging in size from 48 kilobases (kb) to 1.4 kb.
      All the 29 isolates shared the same plasmid 26 kb. There was a consistent
      relationship between antibiotype and plasmid profiles for each pair of isolates
      obtained from five individual patients. RAPD analysis using a single (10-mer)
      primer demonstrated that the isolates that have the same antibiotype and the same
      plasmid profile had different RAPD fingerprint patterns. These results
      demonstrate that the RAPD technique is better than antibiotype characterization
      and a plasmid analysis profile for typing K. pneumoniae as well as for revealing
      strain differences.

PMID- 10584468
TI  - Low birthweight babies in the Third World: maternal nursing versus professional
      nursing care.
AB  - Severe nursing shortage adds to the high mortality of low birthweight babies in
      developing countries. To study the efficacy of maternal nursing care we conducted
      a prospective matched case-control study. Outcome was compared in low birthweight
      babies nursed by mothers (mothers' group, n = 151, cases), versus professional
      nurses (nurses' group, n = 211, controls). Irrespective of condition on
      admission, weight gain was significantly higher (p < 0.001) and overall mortality
      rate significantly lower (p < 0.001) in the mothers' group. Mortality was also
      lower in the mothers' group for babies with pathological jaundice, skin/umbilical
      sepsis, and no disease except low birthweight (p < 0.001). Intercurrent
      diarrhoea, aspiration pneumonia, and septicaemia did not differ. Training mothers
      to nurse their low birthweight babies can significantly reduce mortality rates
      and decrease workload on nurses. Policy formulation using this approach can save
      costs in developing countries.

PMID- 10584469
TI  - Acquired microcephaly after low Apgar score in Zimbabwe.
AB  - Serial head circumference measurements were made on 165 African babies born with
      a 5 min Apgar score of 5 or less. Measurements were taken at birth and at 4, 9,
      and 12 months of age. In the majority of infants the onset of microcephaly could
      be diagnosed as early as 4 months of age. Twenty-five of the 142 infants were
      microcephalic at 1 year. Neurological development was impaired in 19 of the 25
      (76 per cent) microcephalic infants and in 18 of the 117 (15 per cent)
      normocephalic infants. Fourteen of the 16 (88 per cent) infants with severe
      quadriplegia developed microcephaly before the age of 4 months. A decreased rate
      of head growth during the first 4 months of life in African infants born with a
      low Apgar score correlates closely with the development of microcephaly. Infants
      with an acquired microcephaly have a high probability of developing neurologic
      impairment by the age of 1 year. Serial head circumference measurement in low
      Apgar score babies in developing countries is an easy, simple, and inexpensive
      method to detect microcephaly.

PMID- 10584470
TI  - Typhoid hepatitis in children.
AB  - Liver involvement is commonly observed in patients with typhoid fever. However, a
      hepatitis-like picture with fever and jaundice is unusual and infrequently
      reported in the paediatric literature. Our aim was to characterize the clinical
      picture, biochemical features, and prognosis of typhoid hepatitis. One hundred
      cases of typhoid fever (age 0 to 12 years), proven by positive blood cultures to
      Salmonella typhi, were studied with special reference to hepatic dysfunction. Of
      these, eight patients were found to have hepatitis during the course of their
      illness. All had high fever, tender hepatomegaly, elevated serum bilirubin (in
      the range of 2.5-5.8 mg/dl), and elevated serum alanine transaminase levels (in
      the range 100-620 IU/l). All the eight patients showed complete clinical and
      biochemical recovery in response to appropriate antibiotics. The clinical picture
      of typhoid hepatitis frequently mimics acute viral hepatitis. In tropical areas,
      the differential diagnosis of a child presenting with fever and jaundice should
      include typhoid hepatitis.

PMID- 10584471
TI  - Nutritional rickets without vitamin D deficiency in Bangladesh.
AB  - To understand nutritional rickets in Bangladesh better, 14 rachitic and 13
      'unaffected' children were evaluated. Seventy per cent of children with active
      rickets had no evidence of either vitamin D deficiency or familial rickets.
      Rickets in Bangladesh is probably related to calcium deficiency. Abnormalities in
      'unaffected' children suggest that subclinical calcium insufficiency is common.

PMID- 10584472
TI  - Plasma and urine carnitine levels and carnitine supplementation in children with
      malnutrition.
AB  - The purpose of the present investigation was to determine serum and urinary
      carnitine levels in children suffering from protein-energy malnutrition (PEM)
      before and after dietary treatment and carnitine supplementation, and to compare
      them with those in healthy children. Plasma and urine carnitine levels were lower
      in patients with marasmus and kwashiorkor than in controls. There was no
      statistical difference between groups with and without carnitine supplementation
      on the first day. On the fifth day, in groups receiving carnitine
      supplementation, plasma and urine carnitine levels were significantly higher than
      in groups without supplementation (p < 0.01). On the 15th day there was no
      statistical significance between groups with PEM and controls.

PMID- 10584473
TI  - Stability of saliva for measuring HIV in the tropics.
AB  - If HIV is to be detected among pregnant women in remote regions of the tropics,
      HIV antibodies need to remain stable until specimens arrive at the laboratory.
      Our objective was to assess the stability of HIV antibodies in saliva held for up
      to 1 month at ambient temperature in Yangon, Myanmar. We gathered 10 saliva
      specimens from each of 102 HIV-infected persons with the Omni-Sal collection
      device (Saliva Diagnostic Systems, Inc.), and for each subject, divided the
      saliva into 15 portions. During 33 days, the 102 saliva specimens, kept at
      ambient temperature, were tested every 2-3 days for HIV antibodies (total 1530
      assays) with the GACELISA (Murex Diagnostics Ltd), a highly sensitive test
      designed for use with saliva. We observed no reduction in test performance over
      33 days, indicating that the antimicrobial and antiproteolytic transport medium
      in the Omni-Sal device can preserve HIV antibodies without refrigeration for up
      to a month before saliva specimens reach the laboratory.

PMID- 10584474
TI  - Surrogate markers of disease progression in HIV-infected children in Rio de
      Janeiro, Brazil.
AB  - In order to test the predictive value of immune complex-dissociated p24
      antigenaemia (ICD-p24Ag), beta 2 microglobulin (beta 2-M), and neopterin as
      markers of disease progression, 53 HIV-1 infected children (mean age 68 months)
      and nine HIV-negative controls (mean age 65 months) were studied prospectively
      for 9 months. Five were classified in category E (CDC-1994) and seroreverted
      during the study, 14 in category A, nine in category B, and 25 in category C (CDC
      1994). Blood samples were taken at medium intervals of 61 days and tested for ICD
      p24Ag, beta 2 microglobulin, and neopterin. The results were correlated with
      clinical outcome and CD4-lymphocyte counts. All three groups (A, B, C) of
      symptomatic children had similar positivity in an ICD-p24Ag test (48.1, 58.8, and
      51.0 per cent, respectively), and all in group E had negative p24 antigenaemia.
      beta 2 microglobulin and neopterin tests showed no correlation with clinical
      stages of HIV-1 infection. There was no significant correlation between these
      three tests with age-matched CD4 lymphocyte counts (p > 0.05). In contrast, the
      CD4 lymphocyte count correlated well with disease stages. These data suggest that
      the markers evaluated in the present study do not correlate well with clinical
      findings or with CD4 lymphocyte counts. Of all the markers tested, CD4 count was
      the best to predict prognosis of HIV disease in this cohort.

PMID- 10584475
TI  - Relationship between nutritional status and histologic findings in small bowel
      mucosa of children presenting with diarrhoea of more than 14 days' duration.
AB  - In order to study the eventual effects of malnutrition on small intestinal
      mucosa, we evaluated 85 children with diarrhoea of more than 14 days' duration,
      aged from 4 to 114 months (median 17 months). A proximal small intestinal biopsy
      was obtained and villus height, crypt depth, mucosal thickness, and total mucosal
      thickness were measured. Gomez, Waterlow, and Z score criteria were applied.
      Statistical analyses were performed with the Spearman correlation test and the
      non-parametrical tests of Wilcoxon, Mann-Whitney, and Kruskal-Wallis. A value of
      p < 0.05 was considered significant. Average villus height was 269.2 microns (+/-
      87.5 microns); crypt depth 113.0 microns (+/- 33.8 microns); mucosal thickness
      210.5 microns (+/- 73.2 microns); total mucosal thickness 485.9 microns (+/-
      111.8 microns); and villus height/crypt depth ratio 2.5:1 (+/- 0.8:1). Five
      children had kwashiorkor and 13 had marasmus. Villus height for kwashiorkor
      children ranged from 151 microns to 353.3 microns (average 286.7 microns), crypt
      depth from 90.3 microns to 154 microns (average 111.11 microns). According to
      Gomez criteria, as malnutrition increased, mucosal thickness and the villus/crypt
      ratio decreased. Waterlow criteria had no relation to mucosal sizes. When
      distributed in sequential decrease according to their nutritional state, the Z
      score for weight for age and weight for height indices showed a positive
      correlation with villus height, total mucosal thickness, and villus/crypt ratio.

PMID- 10584477
TI  - Haematological abnormalities in children with tuberculosis.
AB  - Over a 16 month period 307 children with suspected tuberculosis (TB) and an
      available full blood count (FBC) seen at Tygerberg Hospital in South Africa were
      evaluated and categorized as confirmed (A), probable (B), and no TB (C) according
      to WHO criteria. There was no difference in the mean age of the 168 group A (33.6
      months), 83 group B (34.4 months), and the 56 group C (31.6 months) children. A
      lower mean haemoglobin (Hb 10.2 vs. 10.8 g/dl) was the only significantly
      different haematological parameter in children with TB compared with the
      comparison group (Group C). There were no differences in median total white cell
      count, neutrophils, lymphocytes, monocytes, platelets, or the proportion of
      children in each group with anaemia, microcytosis, neutrophilia, neutropenia,
      lymphocytosis, lymphopenia, monocytosis, thrombocytosis or thrombocytopenia. The
      most common haematological abnormalities in children with TB were the presence of
      anaemia, neutrophilia, and monocytosis but these changes were found with equal
      frequency in control patients. Although haematological abnormalities are fairly
      common in children with TB, in a developing country these abnormalities also
      occur frequently in children with other non-tuberculosis respiratory infections.
      An FBC has no diagnostic predictive value when investigating a child for TB.

PMID- 10584476
TI  - Early dexamethasone treatment in preterm infants treated with surfactant: a
      double blind controlled trial.
AB  - The objective of the study was to test the hypothesis that early postnatal
      dexamethasone administration (days 1-5) in preterm infants with respiratory
      distress syndrome would improve acute respiratory status and therefore decrease
      long-term neonatal morbidity. This was a prospective, blind randomized controlled
      trial. Eligible neonates were preterm infants with birthweight < or = 1500 g who
      developed respiratory distress syndrome requiring mechanical ventilation and
      surfactant. A 5-day course of dexamethasone or placebo was initiated within the
      first 6 h after birth. The starting dose of dexamethasone was 0.5 mg/kg/day and
      it was tapered progressively. Results were analysed with t-test chi 2, Wilcoxon
      test, and ANOVA. Twenty-nine infants (n = 15 of early dexamethasone and n = 14 of
      placebo group) fulfilled the inclusion criteria. The dexamethasone group
      exhibited a significant improvement in arterial to alveolar oxygen ratio only
      between postnatal days 2 and 5 (p = 0.02). This initial improvement was not
      associated with long-term benefits. Infants who received dexamethasone had
      increased systolic blood pressure (p = 0.0001), diastolic blood pressure (p =
      0.001), blood sugar (p = 0.02, serum urea (p = 0.03), and creatinine level (p =
      0.02). All these side-effects were resolved by postnatal day 7. We concluded that
      a 5-day course of early postnatal dexamethasone was associated with only a
      transient improvement in oxygenation with no long-term benefits. Side-effects
      were more common in the dexamethasone group.

PMID- 10584478
TI  - Poliovirus cultures in acute flaccid paralysis.

PMID- 10584479
TI  - Cephalo-caudal progression of jaundice: a reliable, non-invasive clinical method
      to assess the degree of neonatal hyperbilirubinaemia.

PMID- 10584480
TI  - A case study of factors affecting anemia during weaning period in an Okinawan
      village, Japan.

PMID- 10584481
TI  - Measles skin changes and their relationship to morbidity and pre-illness
      nutritional status in Vietnamese children with measles.

PMID- 10584482
TI  - Are breastfeeding promotion messages influencing mothers in Bangladesh? Results
      from an urban survey in Dhaka, Bangladesh.
AB  - Despite the launching of a national breastfeeding promotion campaign in
      Bangladesh in 1989, exclusive breastfeeding rates remain low. To understand
      mothers' perceptions of the campaign messages and the reasons for current
      practices, a random sample of 1100 lower middle class mothers in Dhaka, with
      infants aged 0-6 months, were interviewed in 1995. Although 99 per cent of
      mothers fed colostrum within 3 days of delivery, 92 per cent also gave one or
      more traditional prelacteals, and 68 per cent gave postlacteals. This could be
      due to ambiguity of the message, which simply advocated giving colostrum without
      indicating its exclusive use, thereby appearing compatible with traditional
      perceptions that colostrum alone is insufficient. Ninety-nine per cent of mothers
      reported hearing the breastfeeding messages or receiving advice, and 97 per cent
      stated that they understood the meaning of exclusive breastfeeding. But this
      concept was not correctly understood, as many thought it meant feeding breastmilk
      and water. The prevalence of exclusive breastfeeding was 15 per cent, and
      complementary foods were introduced early (median 30 days). Many mothers doubted
      the message that breastmilk alone is sufficient for 5 months. Messages to promote
      improved breastfeeding practices in Bangladesh need to be revised to clear
      misconceptions.

PMID- 10584483
TI  - [The meaning of gastric secretion intestinal phase disorders in the pathogenesis
      of ulcers and their surgical correction].
AB  - The data concerning the disorder of the gastric secretion intestinal phase in
      patients with complicated forms of ulcer disease and with recurrent ulcer as well
      are presented. The mechanism was shown, which if noneliminated can cause
      nonfavourable result of the operation performed for the ulcer disease
      complications. The data presented trust the necessity of more meticulous studying
      of disorders of the gastric acidproducing intestinal phase in surgical
      gastroenterology.

PMID- 10584484
TI  - [Prognosis and prophylaxis of postop inflammatory-purulent complications in
      patients with acute gastroduodenal ulcerative bleeding].
AB  - Basing on retrospective analysis of the cases records of 254 patients, suffering
      an acute gastroduodenal hemorrhage of ulcerative genesis, operated on in the
      clinic, the group of high degree risk was delineated for occurrence of
      inflammatory-purulent complications. This have permitted to prognosticate the
      complications occurrence and to suggest the ways of their prophylaxis. High
      efficacy of perftoran in the postoperative infusional-transfusional therapy
      complex was established.

PMID- 10584485
TI  - [The application of electronic microscopic studies in the diagnosis of the degree
      of inflammation in necrotic pancreatitis].
AB  - The electron-microscopical investigation of the pancreatic gland necrosis region
      had permitted to determine the organ inflammation character.

PMID- 10584486
TI  - [Surgical treatment of thoracic esophageal obstruction of neoplastic genesis].
AB  - The results of operative treatment of 126 patients with esophageal cancer,
      localized on different level, were analysed. In 73 of them the thoracic esophagus
      affection was revealed. Radical operations were performed in 46 and the
      palliative--in 27 patients. As a rule, one-staged esophagoplasty was done, using
      stomach and colon. The original method of the gastric transplant lengthening was
      proposed, permitting to perform one-staged retrosternal esophagoplasty with
      construction of cervical esophagogastroanastomosis. Complications have occurred
      in 6 patients.

PMID- 10584487
TI  - [Immediate and late follow-up results of the combined treatment of patients with
      esophageal and gastroesophageal cancer by intravascular laser irradiation of
      blood].
AB  - The method of intravascular laser irradiation of the blood was applied in complex
      treatment of 41 patient with thoracic esophagus cancer and in 31 patient with
      gastroesophageal cancer. Incorporating of photoimmunotherapy to the complex of
      treatment of patients had promoted the lowering of the postoperative
      complications rate, mortality and of the three-year survival indexes.

PMID- 10584488
TI  - [Pathophysiology, prophylaxis and treatment of reperfusion syndrome in the
      surgery of abdominal aorta aneurysm].
AB  - The peroxidal oxidation of the lipids state was studied up, as well as of the
      whole blood neutrophils functional activity, hemodynamics and microcirculation of
      lower extremities in surgical treatment of the abdominal aorta aneurysm. The main
      significance in the reperfusional syndrome pathophysiology, caused by temporary
      overcompression of aorta, has the neutrophils activation, their interrelationship
      with the endothelium cells and the activity lowering of the tissue antioxidant
      system, manifestated by vascular spasm, which is mostly expressed in the patients
      with stenotic affection of the lower extremities arteries. Positive effect was
      noted in application of preparation corvitin, which has antioxidant action.

PMID- 10584489
TI  - [Rehabilitation of patients undergoing surgery for bronchiectasis].
AB  - The results of resection operations on 94 patients with bronchiectatic disease
      were analyzed. Clinical research or proof remission was marked for 81.3%, the
      restoration of working ability--for 85.3% of patients. After the operation
      complications were revealed in 25.5% of patients. The most of them were
      concerning the increased exudation in pleural cavity and its infection. For
      proving of the rehabilitation outcomes before the operation carry out the course
      of complex therapy, including the sanation of bronchial tree.

PMID- 10584490
TI  - [Causes of ineffective chemotherapy of pulmonary tuberculosis in patients with
      diabetes mellitus].
AB  - The causes of unsatisfactory result of treatment in 125 patients with pulmonary
      tuberculosis and diabetes mellitus (DM) are presented. In every patient were
      revealed 2-4 and more nonfavourable factors, influencing the chemotherapy
      inefficacy. The main of them are: the severity of the DM course and of its
      complications, the patient's noncompliance of the treatment, the spreading of
      tuberculosis, the resistance of the tuberculosis Mycobacterium to preparations.

PMID- 10584491
TI  - [Secondary bronchopulmonary complications and their treatment in vascular ring
      anomaly in children].
AB  - In 47 children aged from 1.5 mo to 14 years with various variants of the vascular
      ring anomaly the peculiarities of diagnosis and treatment of secondary
      bronchopulmonary complications were studied. In untimely diagnosis of vascular
      ring the chronical inflammatory bronchopulmonary diseases may occur, up to
      bronchiectases formation, demanding correction not only of vascular pathology but
      the affected part of pulmonum resection as well.

PMID- 10584492
TI  - [The role of microorganisms of the wound in postop complications].
AB  - Sensitivity of mostly wide-spread pathogenic microorganisms to modern antibiotics
      of the wide spectrum of action (Tienam, Mefoxin, Cifran), and to antibiotics,
      widely applied in everyday clinical practice was studied.

PMID- 10584493
TI  - [Postop abdominal hernia, occurring in the Pfannenstiel access location].
AB  - The peculiarities of surgical treatment of postoperative abdominal hernia,
      occurring in the Pfannenstiel access location, are enlighted.

PMID- 10584494
TI  - [Endoprosthesis of the knee joint].
AB  - The experience of primary total endoprosthesis of a knee joint for restoration of
      its motility and stability was presented. Prostheses "Zimmer MG II", "Zimmer I B
      II", "Richards-Genesis", "Richards-Trigon-C", "Aesculap Mul. II", "Howmedica
      kinematics" were implanted in 16 patients with gonarthrosis and rheumatoid
      arthritis stage III. One to four-year follow-up result after the operation was
      excellent in 68.75% patients, good--in 25%, fair--in 6.25%.

PMID- 10584495
TI  - [The use of endoscopic assistive devices in intracerebral hematoma surgery with
      the access formation via osteoplastic craniotomy].
AB  - The experience of the supratentorial intracerebral hematoma removal using
      endoscopical assisting technique with osteoplastic craniotomic access was
      presented. Rigid endoscopes with different technical characteristics were
      applied. In all observations the diagnosis was confirmed by data of computeric
      tomography of the brain.

PMID- 10584496
TI  - [Treatment of transitional synovitis of coxofemoral joint in children].
AB  - The experience of treatment of 164 children with transitional synovitis of
      coxofemoral joint was summarized. The complex, pathogenetically substantiated
      method of the disease treatment was suggested. The recovery of all the children
      was guaranteed during (14.3 +/- 2.6) days due to the elaborated curative
      algorithm application. The disease recurrency was not observed.

PMID- 10584497
TI  - [The causes of unsatisfactory results of treatment of open trauma of the hand
      under conditions of central regional hospital].
AB  - The main causes, influencing the result of treatment of open trauma of the hand
      were established. The unsatisfactory result rate was 39.4%.

PMID- 10584498
TI  - [Intensification of surgical stage of combined treatment in patients with ovarian
      cancer using pathogenetically directed correction of homeostasis disorders].
AB  - The surgical intervention performance in patients with wide-spread ovarial cancer
      is escorted by the intoxication severity raising, liposuperoxidation disorders,
      the antioxidants lacking, pronounced immunodepression. Application of
      pathogenetically directed program of complex correction of the homeostasis
      disorders promotes compensation of these disorders occurring.

PMID- 10584499
TI  - [Contemporary concepts of embryology and surgical anatomy of the thyroid gland].

PMID- 10584500
TI  - [The importance and methods of treatment of chronic osteomyelitis].

PMID- 10584501
TI  - [Pathogenesis, diagnosis and treatment of early functional postop ileus].

PMID- 10584502
TI  - [The administration of Docetaxel (taxoter): a new stage in chemotherapy of
      cancer].

PMID- 10584503
TI  - [Observation of successful treatment of patient with subtotal colonic necrosis
      occurring due to mesenteric thrombosis].

PMID- 10584504
TI  - [Observation of neuroblastoma transformation into ganglioneuroma in a child].

PMID- 10584505
TI  - [The administration of sandostatin in the combined treatment of acute
      pancreatitis and its complications].
AB  - Experience of application of the somatostatin synthetic analog sandostatin
      ("Novartis" firm) in treatment of 212 patients, including 84--with an acute
      pancreatitis (AP), 41--with postoperative AP (APP), 15--with external pancreatic
      fistula and 72--with high risk of the APP occurrence for prophylaxis was
      summarized. The significant inhibiting action of preparation on endocrine
      pancreatic function was noted. High efficacy of sandostatin in patients with AP
      and its complications was determined.

PMID- 10584506
TI  - [The status of ascorbate oxidation-reduction system of blood in patients with
      chronic pancreatitis throughout parenteral nutrition].
AB  - There was conducted operative treatment of patients with complicated chronic
      pancreatitis. Intravenous infusion of aminoacid cocktail with enhanced content of
      glutamine, methionine with the selenium addition was applied in the complex of
      therapy. Under the influence of modified cocktail during 3 days there was
      observed more complete restoration of the ascorbic acid (AA) level and lowering
      of her oxidated forms content. This effect became more potent in addition of AA
      (0.75 per one infusion).

PMID- 10584507
TI  - [Prognostic role trypsinogen-activating peptide in an acute pancreatitis].
AB  - The level of trypsinogenactivating peptide (TAP) in the blood serum of patients
      with an acute pancreatitis was investigated. In patients with severe necrotic
      pancreatitis the TAP content was the highest one.

PMID- 10584508
TI  - [Clinical effectiveness of trental and thiotriazolinum in the treatment of acute
      pancreatitis].
AB  - More earlier break off of the disease clinical symptoms, laboratory indexes
      normalization, the shortening of the patients stationary treatment duration were
      promoted by trental and thiotriazolin inclusion in the acute pancreatitis complex
      of treatment.

PMID- 10584509
TI  - [The use of efferent approach of detoxication and immunologic correction in the
      combined treatment of acute sepsis].
AB  - In 90 patients with an acute sepsis application of cryopreserved hepatocytes and
      splenic sections had promoted detoxication and immunocorrection, improved the
      rehabilitational indexes significantly.

PMID- 10584510
TI  - [Surgical treatment of giant posterior ampullar duodenal ulcer with bleeding in
      the elderly and senile patients].
AB  - There was experimentally elaborated and introduced to clinical practice the
      method of surgical treatment of giant retroampullar ulcer of duodenal posterior
      wall with hemorrhage in elderly and senile patients. Physiological
      exteriorization of ulcer out of duodenal borders and original method of tamponage
      using the small intestine wall with complete coverage of duodenal lumen and
      restoration of intestinal passability performing gastroenteroanastomosis
      antecolica anterior and Brown anastomosis are the main advantages of this method.
      The method guarantees the ulcer healing, prophylaxes the recurrency rise due to
      distribution of the contents motion in two streams.

PMID- 10584511
TI  - [Diagnostic and surgical approach in the combined thoracic trauma complicated by
      pulmonary and heart contusion].
AB  - Experience of treatment of 782 injured persons with combined thoracic trauma was
      summarized. Of the total number of injured persons with pulmonary contusion 177
      (control group) were treated using conventional methods and 165 (basic group)--an
      early active operative tactics. Of the total number of injured persons in 150
      with heart contusion (basic group) the cardiotropic therapy conduction was
      started from the hospitalization moment and in 134 (control group)--from the
      second day and later. Mortality while pulmonary contusion in control group was
      43% and in the basic one--31%; in the heart contusion--46 and 12% accordingly.

PMID- 10584512
TI  - [The causes of inefficacy of chemotherapy and the role of pulmonary resection in
      the treatment of patients with destructive tuberculosis and diabetes mellitus].
AB  - Retrospective analysis of the case records, roentgenograms of 128 patients with
      destructive pulmonary tuberculosis and diabetes mellitus was conducted. Nontimely
      diagnosis of pulmonary tuberculosis, the diabetes mellitus course severity,
      nonadequate correction of metabolic disorders, resistance of Micobacterium
      tuberculosis to chemopreparations, bad compliance of preparations, scornful
      attitude of patients to treatment were the main causes of the conservative
      therapy low efficacy. In the majority of patients 2-4 causes coexisted, leading
      to lack of the therapy efficacy.

PMID- 10584513
TI  - [Pseudochylothorax].
AB  - Pseudochylothorax--a rare disease, occurring in prolonged persistence of exudate
      in the cavity of fibrotically changed pleura. Three observations of
      pseudochylothorax, including as the complication of viral hepatitis A, are
      adduced. Diagnosis was established after biochemical analysis of exudate,
      obtained during pleural puncture.

PMID- 10584514
TI  - [Aspects of the onset and clinical course of pulmonary abscess].
AB  - The causes of formation and variants of clinical course of chronic pulmonary
      abscess were analysed in 166 patients. The main cause of the disease transition
      into chronic stage is nontimely and nonadequate therapy with insufficient usage
      of pathogenetic and instrumental methods.

PMID- 10584515
TI  - [The influence of laser and electrophoresis of myramistin on dehydrogenases
      activity of the blood neutrophils in complex treatment of purulent complications
      in abdominal surgery].
AB  - It was established in clinical and experimental investigations that while the
      purulent postoperative complication occurrence the activity of succinate
      dehydrogenase, alpha-glycerophosphatedehydrogenase, glucoso-6
      phosphatedehydrogenase is reducing and the activity of the blood neutrophils
      lactatedehydrogenase is rising. Application of a laser and electrophoresis with
      Miramistin had promoted the normalization of these enzymes activity,
      substantiating its usage in complex therapy of purulent complications of the
      operation wound healing.

PMID- 10584516
TI  - [The application of combined antibacterial preparation Unazin for the prophylaxis
      of purulent postop complications at the clinic of thoracic oncology].
AB  - Antimicrobal preparation Unazin, combining sodium sulbactam and sodium
      ampicillin, characterized by broad antibacterial spectrum and potency to overcome
      the microorganisms stability, was applied in 15 patients in the early
      postoperative period after operations for pulmonary, esophageal, cardial cancers
      and mediastinal tumor. In these patients purulent-septic complications were not
      noted. According to the retrospective analysis data, of 846 patients, operated
      earlier, the complications have occurred in 131 (13.2%).

PMID- 10584517
TI  - [Disorders of acid-alkaline status and electrolyte composition in appendicitis
      related peritonitis in a child].
AB  - In children with diffuse appendicular peritonitis the disorders of acidic
      alkaline state (AAS) and the electrolytes composition (EC) of venous blood were
      studied. Before the operation in patients with extended peritonitis metabolic and
      respiratory alkalosis dominated, with general one--metabolic acidosis. In diffuse
      local peritonitis the conduction of ethiotropic antibacterial therapy and
      intravenous infusion of 2.5% thiotriazolin solution was effective; in extended
      peritonitis without concurrent pathology the application of potassium chloride
      was the method of choice. After the laparostomy conduction with programmed
      sanation the prolonged therapy using 2.5% thiotriazolin solution in maximal
      concentration was administered, in patients with general peritonitis and closed
      abdominal cavity the sittings of hyperbaric oxygenation were applied. Application
      of proposed differential complex correction of the AAS and EC disorders in
      conjunction with surgical methods of treatment had permitted to avoid mortality
      as a complication of appendicular peritonitis in last decade.

PMID- 10584518
TI  - [Differential diagnostic criteria of patient selection for surgical intervention
      for degenerative dystrophy of lower extremities].
AB  - Differential-diagnostical distinctions of deforming coxarthrosis and the head of
      femur aseptic necrosis of vertebral etiology and similar affection of other
      origin are adduced.

PMID- 10584519
TI  - [Detoxication properties of enterosgel in the treatment of purulent peritonitis].
AB  - It was established in experiment that under the influence of enterosorpent
      Enterosgel, brought into abdominal cavity, the adhesions are forming, thats why
      the preparation usage in containers is recommended, alone or in combination with
      gentamycini sulfas.

PMID- 10584520
TI  - [Application of greater omentum for regeneration of bronchial stump].
AB  - The regeneration processes in bronchial stump with participation of the great
      omentum tissue, located in pleural cavity with preservation of vascular peduncle
      of created strand were studied in experiment. The data concerning the course of
      healing of bronchial stump under condition of nonviable great omentum tissue are
      adduced.

PMID- 10584521
TI  - [The evaluation of severity status and prognosis of outcome in patients with
      surgery-related illnesses].

PMID- 10584522
TI  - [Electrical activity of the colonic muscles in humans: methods and results of
      electrophysiological investigation and possibilities for their clinical
      application].

PMID- 10584523
TI  - [Etiology and clinico-morphological classification of thyroid tumors].

PMID- 10584525
TI  - [Damages of sacro-iliac joint].

PMID- 10584524
TI  - [Problems of herniotomy for inguinal hernias in boys].

PMID- 10584526
TI  - [Method of transcutaneous microjejunostomy].

PMID- 10584527
TI  - [The application of anterolateral access in radical correction of the secondary
      interatrial septum defect].

PMID- 10584528
TI  - [Aspects of oxygen delivery and consumption in the congenital heart defect
      correction with the application of artificial blood circulation].

PMID- 10584529
TI  - [Combined treatment of patients with destructive pancreatitis].

PMID- 10584530
TI  - [Experience in cryo-ultrasound treatment of patients with epithelial head and
      neck tumors].

PMID- 10584532
TI  - [Surgical issues in yersiniosis].

PMID- 10584531
TI  - [Rare localization of teratoma in children].

PMID- 10584533
TI  - [Capronohernioplasty of gigantic hernia in a female patient with diabetes
      mellitus].

PMID- 10584534
TI  - [Risk of neurological injury after nitrous oxide anesthesia. Rare, but probably
      unreported adverse effect].

PMID- 10584535
TI  - [An open letter to Swedish health care politicians: don't concentrate on primary
      health care--concentrate on general practice!].

PMID- 10584536
TI  - [A basic program for school health services is required to achieve "care
      equity"].

PMID- 10584537
TI  - [Influenza--do vaccinate, but wait with the use of Relenza!].

PMID- 10584538
TI  - [Is mammography screening efficient?].

PMID- 10584539
TI  - [Recreation of tissue--the plastic surgeon's spring-board in to the 21st
      century].
AB  - During recent years, a new field has appeared, in which the principles of life
      sciences and engineering are applied to the development of methods of
      regenerating human tissue and organs. Since the emergence of this
      interdisciplinary field, plastic surgeons have been deeply involved in its
      development, both in the early stages and in introducing the methods into
      clinical practice. The article consists in discussion of the possibilities these
      methods offer and the impact they may have on the field of plastic and
      reconstructive surgery.

PMID- 10584540
TI  - [CATCH22 or 22q11 deletion syndrome. An underdiagnosed and misunderstood disease
      category with a variable clinical picture].
AB  - Patients with CATCH 22 or 22q11 deletion syndrome constitute a fast growing
      category in Sweden as it is still underdiagnosed. In a series of 54 patients the
      predominant features were found to be speech and language difficulties, cardiac
      malformations, susceptibility to infection, learning and behavioural problems,
      hypoparathyroidism, minor motor deficits, and characteristic facies. The severity
      of these problems varied individually, but as the patients had numerous symptoms
      and disabilities the overall degree of handicap was considerable. Thus, regular
      evaluation of the patient's condition and overall need of care is important.

PMID- 10584541
TI  - [Recommendations from a Swedish meeting of experts. Hepatitis C is to be treated
      with the combination of interferon and ribavirin].

PMID- 10584542
TI  - [Nitrous oxide can cause cobalamin deficiency. Vitamin B12 is a simple and cheap
      remedy].
AB  - Nitrous oxide may cause neurological and haematological signs and symptoms, as a
      result of its tendency to form complex with cobalt(I) in methylcobalamin, the
      cofactor for methionine synthase (EC 2.1.1.13), resulting in irreversible
      oxidation of the cofactor and inactivation of the enzyme protein. Formation of
      active enzyme requires new protein synthesis, as well as cobalamin supply
      (vitamin B12). Patients with low or marginal cobalamin depots (commonly found in
      the elderly) are at risk. The risk may be avoided by giving vitamin B12 to
      patients with confirmed or suspected cobalamin deficiency in good time before
      surgery involving nitrous oxide anaesthesia.

PMID- 10584543
TI  - [The immune system is affected by psychological factors. High stress levels can
      change susceptibility to infection and allergy].
AB  - The article consists in a review of the evidence of psychological and neural
      influences on the aetiology and severity of allergy. Histamine release in
      response to symbolic stimuli and behavioural conditioning of allergy-related
      immune variables suggest the existence of links via which psychological factors
      can affect the allergic cascade. Although this has been established in animal
      species, and is supported by evidence of neuro-immune communication pathways,
      convincing evidence of its occurrence in humans is sparse. Although asthma and
      stress symptoms seem to be related, the causal direction of such relationship
      remains unclear. In view of the occurrence of undocumented allergy and the
      importance of symptom perception as a basis for optimal medication, the
      assessment of subjective allergy symptoms is a cogent issue.

PMID- 10584544
TI  - [Being on call at a small hospital].

PMID- 10584545
TI  - [Patient empowerment--the aim is better health and stronger right to decide].

PMID- 10584546
TI  - [To sedate a dying patient--an ethical dilemma].

PMID- 10584548
TI  - [What is your diagnosis? Familial hypercholesterolemia].

PMID- 10584547
TI  - [Pain analysis is basis for correct choice of therapeutic method].

PMID- 10584549
TI  - [The drama of hyperextension trauma--chronic whiplash syndrome with its
      neuropsychological and psychiatric findings. An analysis of 80 cases from expert
      assessment].
AB  - The problem "whiplash associated disorder" was studied in a multidisciplinary
      analysis of 80 patients who all had a "simple whiplash-accident", this means a
      whiplash-accident without concomitant head trauma apart from contact with the car
      seat and without unconsciousness. The opinions of a rheumatologist and of a
      psychiatrist were considered in each case, and in 47 patients, a
      neuropsychological expertise was present. 43% of the patients who had been
      neuropsychologically tested revealed specific cognitive deficits as they are
      described after mild traumatic brain injuries and after whiplash accidents.
      Symptoms related to a pretraumatic cognitive disease were not found in any of the
      cases. Most patients had been professionally active at the time of the accident,
      some performing activities requiring a high level of cognitive skill. 66% percent
      of the study group showed psychological disturbances reducing the working
      capacity. There was no evidence for preexisting traumatic psychiatric symptoms.
      In many cases the psychiatric disturbances were accident-related, either reactive
      to the cognitive deficiencies or resulting from chronic pain. We assume that the
      "simple whiplash-accident" can cause chronic disturbances of brain function. In
      the etiology, a mild traumatic brain damage must be considered, this means an
      organic damage and not only a functional brain disorder. These brain function
      disturbances are often masked by the pure psychiatric symptoms, therefore they
      must be carefully searched for. Injured patients, who do not regain their working
      capacity after the accident, should be explored in a neuropsychological as well
      as in a psychiatric mode as early as possible after the accident.

PMID- 10584551
TI  - [X chromosome dominant hereditary nephritis: characterization by pedigree
      analysis and simple studies in general practice].
AB  - A family with chronic renal disease in the Bernese Oberland (Switzerland) is
      described. Most family members were directly evaluated by the author. The
      clinical syndromes identified in different family members are quite variable,
      reaching from asymptomatic glomerular microhematuria to segmental sclerosing
      glomerulonephritis with end stage renal failure. Based on the observation of the
      pedigree over five generations, the disorder appears to be transmitted as an x
      chromosomal dominant trait. Together with the ultrastructural diagnosis, the
      disorder corresponds to an Alport's syndrome Typ IV Atkien.

PMID- 10584550
TI  - [Cutaneous paraneoplastic syndrome as an immunologic phenomenon exemplified by
      paraneoplastic subacute cutaneous lupus erythematosus].
AB  - Two case reports and a review of the literature on paraneoplastic figurate
      erythemas with lupus erythematosus (LE)-specific histolopathology illustrate
      cutaneous paraneoplasia as an immunological phenomenon. Subacute cutaneous lupus
      erythematosus (SCLE) is characterized by photosensitive, annular or
      papulosquamous skin lesions with LE-specific histopathology in association with
      circulating anti-SS-A (Ro) auto-antibodies. The SS-A (Ro) antigen is a complex of
      cytoplasmic ribonucleoproteins that translocate to the surface of keratinocytes
      under UV irradiation. Sequestered cytosolic antigen that is expressed on the cell
      surface is presented to T lymphocytes by professional antigen presenting cells in
      the context of specific MHC class II molecules. The initiation of the specific
      immune response, the expansion of antigen-specific T helper cells, and the
      differentiation of B cells to antibody producing plasma cells depend on the
      further interaction with antigen. The risk of a self-perpetuating autoimmune
      response relies on further release of auto-antigen. It is conceivable that in
      paraneoplastic SCLE tumor antigen with homology to SS-A (Ro) leads to
      photosensitive autoreactivity. The review of the literature reveals 9 other cases
      of SCLE associated with internal malignancy. The most common associated tumors
      were bronchial and mammary carcinoma. The latency between the appearance of skin
      lesions and the diagnosis of an underlying tumor was between one month and three
      years (mean: 10 months). In all cases, skin lesions improved with cancer therapy,
      in three cases they (re)appeared in association with relapse of tumor.

PMID- 10584552
TI  - [Examining the shoulder in general practice].
AB  - When the cause of pain or the loss of function lies in the shoulder area itself,
      in most cases it can be related to a certain anatomical structure by means of a
      precise clinical examination. The individual tests are depicted in illustrations
      and concise texts. As a memory aid, the structure being tested has been added in
      each picture. Also, the clinically most relevant trigger points are depicted,
      along with their corresponding pseudoradicular symptomatology (referred pain).
      The aim of this article is to assist in the day-to-day treatment of common
      shoulder problems.

PMID- 10584554
TI  - [With magic bullets against syphilis: Paul Ehrlich (1845-1915) and "Salvarsan"].

PMID- 10584553
TI  - [Inoperable non-small-cell bronchial carcinoma: macroscopic and microscopic tumor
      behavior during and after radiotherapy with curative intent].
AB  - The supervision of the efficacy of therapy with curative aim in inoperable NSCLC
      focus on clinical and radiological parameters and the survival rate. But the
      decision about the local tumour elimination lies in the microscopic area, which
      cannot be controlled neither by laboratory tests nor by radiological
      examinations. About twenty years ago with support of our pneumologist we carried
      out bronchoscopies and biopsies depending on the applied radiation dose. It was
      our intention to take the remission noted by endoscopy as measure for the
      reaction of the whole irradiated target volume. The bronchoscopies and biopsies
      were provided at dose levels of 60 and 80 Gy. 90.9% (340/374) of repeated
      bronchoscopies were realized after a dose of 60 to 80 Gy. The analysis covers 253
      bronchoscopies before and 374 between or after radiotherapy with 623 histological
      or cytological examinations on a total of 253 patients. At the begin of the
      radiotherapy 50.2% (127/253) had tumour between trachea and a lobar bronchus,
      after 60 Gy only 13% and after 80 Gy still 1.2% (1/81) had tumour in this area.
      The macroscopical tumour elimination rose from 41.4% (80/193) after 60 Gy to
      79.3% (65/82) after 80 Gy. In contrast and unexpectedly the microscopic
      negativity decreased from 73.4% (141/192) to 71.6% (58/82). Partially this result
      is a consequence of the fact that "necrosis" may be either a part of an untreated
      malignoma or an effect of an irradiation. The combination of macro- and
      microscopic tumour elimination rose from 20.5% (7/34) after a dose of 60 Gy to
      64% (16/25) after total doses of 80 Gy. Only combined negativity had a
      consequence for local relapse free survival (p = 0.034) and overall survival (p =
      0.0002) in comparison with the patients with persistent macro- and/or
      microscopically detected endoluminal tumour at the final bronchoscopy. The
      assessment of endoluminal tumour regression as part of the whole irradiated
      malignoma permits conclusions about the total dose needed. This is a new approach
      providing at least more local security without augmentation of side effects in
      comparison with the conventional guidelines.

PMID- 10584555
TI  - Heavy heat shock induced retrotransposon transposition in Drosophila.
AB  - The phenomenon of transposition induction by heavy heat shock (HHS) was studied.
      Males of a Drosophila isogenic line with a mutation in the major gene radius
      incompletus (ri) were treated by HHS (37 degrees C for 1 h followed by 4 degrees
      C for 1 h, with the cycle repeated three times) and crossed to untreated females
      of the same line. The males were crossed 5 d after heat shock, and also 9 d after
      HHS. Many transpositions were seen in the F1 larvae by in situ hybridization. The
      rate of induced transposition was at least 2 orders of magnitude greater than
      that of the control sample, and was estimated to be 0.11 events per transposable
      element copy per sperm. Two 'hot' subdivisions for transpositions, induced
      probably during the post-meiotic stage of spermiogenesis, were found: 43B and
      97DE. Three-quarters of all transpositions were localized in these positions. In
      other sites the rates of induced transpositions were (1.3-3.2) x 10(-2) events
      per occupied segment per sperm, 1 order of magnitude greater than those of the
      control.

PMID- 10584556
TI  - Genetic variation affecting heart rate in Drosophila melanogaster.
AB  - Heart rate in pre-pupae of Drosophila melanogaster is shown to vary over a wide
      range from 2.5 to 3.7 beats per second. Quantitative genetic analysis of a sample
      of 11 highly inbred lines indicates that approaching one-quarter of the total
      variance in natural populations can be attributed to genetic differences between
      flies. A hypomorphic allele of the potassium channel gene ether-a-gogo, which is
      homologous to a human long-QT syndrome susceptibility gene (HERG), has a heart
      rate at the low end of the wild-type range, but this effect can be suppressed in
      certain wild-type genetic backgrounds. This study provides a baseline for
      investigation of pharmacological and other physiological influences on heart rate
      in the model organism, and implies that quantitative genetic dissection will
      provide insight into the molecular basis for variation in normal and arrhythmic
      heart function.

PMID- 10584557
TI  - Co-adaptation of pheromone production and behavioural responses in Drosophila
      melanogaster males.
AB  - In Drosophila melanogaster, male courtship behaviour is genetically controlled
      and is influenced by sex pheromones. 7-tricosene (7-T) induces a dose-dependent
      inhibition of male-male courtship, whereas 7,11-dienes stimulate male courtship
      of females. There is a geographical quantitative variation in the production of
      two predominant male hydrocarbons, 7-T and 7-pentacosene (7-P). We have
      previously found that 7-P, the main hydrocarbon from males of West African
      strains, stimulates males that mainly produce 7-T. Using both 'natural' and
      genetically engineered strains, we find that genetic factors coding for low
      levels of 7-P in males have co-evolved with factor(s) coding for male responses
      to high levels of 7-P. These two phenotypes are coded by factors on different
      chromosomes: the intraspecific polymorphism for the production of 7-T and 7-P is
      largely controlled by chromosome 2, whereas the variation in courtship towards 7
      P-rich males is largely controlled by chromosome 3. The polymorphism of male
      courtship towards 7-P-rich males shows no correlation with the variation in male
      responses to female flies.

PMID- 10584558
TI  - Genetic variants of the tuberous sclerosis 2 tumour suppressor gene in mouse t
      haplotypes.
AB  - The murine t complex on chromosome 17 contains a number of homozygous lethal and
      semi-lethal mutations that disrupt development of the mouse embryo. We recently
      characterized an embryonic lethality in the rat that results from a germ-line
      mutation in the tuberous sclerosis 2 (Tsc-2) tumour suppressor gene (the Eker
      mutation). Remarkably, mouse embryos homozygous for tw8 mutation display cranial
      defects reminiscent of those observed in rat embryos homozygous for the Eker
      mutation. To determine whether the Tsc-2 gene, which is in the t complex, is
      mutated in tw8 or other t haplotypes, we characterized this gene in a series of t
      haplotype mice. Four Tsc-2 polymorphisms were identified: three in the coding
      region and one intronic that appeared to be common to all t haplotypes analysed.
      No evidence was found to argue that the Tsc-2 gene is altered in tw8 haplotype
      mice. However, in the tw5 haplotype we found a G to T mutation in Tsc-2 that was
      present only in this t haplotype. In contrast to other polymorphisms within the
      Tsc-2 coding region which did not result in amino acid changes in Tsc-2 gene
      product tuberin, this mutation substituted a phenylalanine for a conserved
      cysteine in tw5 tuberin. Within the t complex, the Tsc-2 gene and the putative
      tw5 locus appeared to map to different positions, complicating identification of
      Tsc-2 as a candidate for the tw5 locus and suggesting that the G to T mutation in
      the Tsc-2 gene may have arisen independently of the tw5 functional mutation.

PMID- 10584559
TI  - Dynamics of inbreeding depression due to deleterious mutations in small
      populations: mutation parameters and inbreeding rate.
AB  - A multilocus stochastic model is developed to simulate the dynamics of mutational
      load in small populations of various sizes. Old mutations sampled from a large
      ancestral population at mutation-selection balance and new mutations arising each
      generation are considered jointly, using biologically plausible lethal and
      deleterious mutation parameters. The results show that inbreeding depression and
      the number of lethal equivalents due to partially recessive mutations can be
      partly purged from the population by inbreeding, and that this purging mainly
      involves lethals or detrimentals of large effect. However, fitness decreases
      continuously with inbreeding, due to increased fixation and homozygosity of
      mildly deleterious mutants, resulting in extinctions of very small populations
      with low reproductive rates. No optimum inbreeding rate or population size exists
      for purging with respect to fitness (viability) changes, but there is an optimum
      inbreeding rate at a given final level of inbreeding for reducing inbreeding
      depression or the number of lethal equivalents. The interaction between selection
      against partially recessive mutations and genetic drift in small populations also
      influences the rate of decay of neutral variation. Weak selection against mutants
      relative to genetic drift results in apparent overdominance and thus an increase
      in effective size (Ne) at neutral loci, and strong selection relative to drift
      leads to a decrease in Ne due to the increased variance in family size. The
      simulation results and their implications are discussed in the context of
      biological conservation and tests for purging.

PMID- 10584560
TI  - [Genetic background in carcinogenesis].
AB  - Carcinogenesis comprises both genetic and environmental factors. The genetic
      factor for cancer is most closely associated with familial cancer. Familial
      cancer makes up only a few percent of total cancer cases. Recently, various
      candidate genes for familial cancer have been identified by analyzing patients'
      family histories and genetically testing them. Most of these cancer
      susceptibility genes are frequently mutated or deleted on sporadic cancer cells.
      The study of these genes is very useful for explaining the molecular mechanisms
      of non-familial cancer. Various polymorphic mutations exist in normal phenotypes
      in human. Most of them are single nucleotide polymorphisms (SNPs) and intronic
      variations, but sometimes they are large gene alterations or chromosomal
      abnormalities. Human genetic polymorphisms can now be more easily analyzed by
      using computed biotechnology (DNA tips, microarray). Detailed examination of
      human DNA polymorphisms will advance the study of genetic background in
      carcinogenesis in the future.

PMID- 10584561
TI  - [Descriptive and analytical epidemiology of second primaries in Osaka, Japan].
AB  - With the improvement in survival of cancer patients, the incidence of second
      primaries has been increasing. Data from the Osaka Cancer Registry showed that
      the incidence of metachronous second primaries was associated with gender (male),
      age and calendar year at diagnosis of the first cancer. The 10-year cumulative
      risk was estimated at around 10% for those who developed their first cancer in
      their sixties in 1978-83. The observed number (O) of second primaries (including
      synchronous) was compared with the expected number (E). The O/E ratios among
      those who developed their first cancer at ages 0-14 and 15-29 years old were much
      higher than the ratios among all age groups. Patients who had developed cancer of
      the colon, larynx, lung, bladder, or breast (1978-86) showed a significantly
      higher than expected risk of developing second primaries during the 1-4 years
      after diagnosis of the first cancer. Based on the hospital cancer registry data
      from Osaka Medical Center for Cancer and Cardiovascular Diseases, associations
      between adjuvant chemo-immunotherapy and the risk of second primaries were
      examined among 1,925 gastric cancer patients who underwent curative gastrectomy.
      The sex-, age-, and stage-adjusted hazard rate ratio of second primaries was 1.04
      for patients who underwent chemotherapy and 0.70 for patients who underwent chemo
      immunotherapy, when compared with the risk for patients who did not receive
      adjuvant chemo-immunotherapy. Some chemotherapeutic agents appeared to increase
      the risk of second primaries. Second primaries among 2,824 breast cancer patients
      were examined and their associations with adjuvant chemo-immuno-radiotherapy were
      analyzed. The O/E ratio for cancers of all sites was 1.28, significantly higher
      than 1.0. Cancer of the stomach, colon, lung and ovary were frequently observed
      as a second primary among them. Among 117 patients who developed second
      primaries, 4 developed cancer of the corpus uteri. This corresponded to 1.89
      times the expected, however, only one of the 4 patients underwent tamoxifen
      treatment. The O/E ratio for non-Hodgkin's lymphoma was 3.40, significantly
      higher than 1.0. These results suggest associations between the risk for non
      Hodgkin's lymphoma and chemotherapy.

PMID- 10584563
TI  - [Secondary leukemias: their clinical features, incidence among populations at
      risk, mechanisms and new strategy for prediction].
AB  - Clinically distinct features in both alkylating agents--and topoisomerase II
      (topo II)-induced secondary leukemias (SL) are reviewed with special reference to
      the increasing frequencies observed in relation to advances in modern cancer
      chemotherapy. Topo II interacts with, and then stabilizes the cleavable complex
      that ultimately results in double strand breaks. In patients with SL, breakpoints
      in MLL gene are clustered within SARs of 3' bcr. However, mechanisms by which the
      former type of SL is caused remain to be elucidated. Since alkylating agents
      often induce profound marrow dysplasia, long-lived lesions induced on
      hematopoietic stem cells are of potential relevance to the development of SL.
      This process may be partially demonstrated by the variety of mitotic
      modifications found in MDS. Recently, the association has been investigated
      between certain enzyme polymorphisms related to activation or detoxification of
      anticancer agents and SL. These studies have potential importance, since
      individuals with a certain genotype may be at increased risk for SL.

PMID- 10584562
TI  - [Mechanism of occurrence of secondary tumors by antitumor drugs].
AB  - Due to the innovations in various aspects of cancer therapy, the time has come
      when more than half of cancer patients survive 5 years. However, secondary
      cancer, especially leukemias arising among the survivors and threatening their
      lives, has become a serious problem. In the present paper I focus on
      chemotherapeutics, especially DNA topoisomerase II inhibitors such as etoposide
      and adriamycin, presumed to be the causative agents, and their mode of
      intervention in the catalytic action of this enzyme. I describe the molecular
      basis of chromosomal translocations inherent in therapy-related secondary
      leukemias, and present a hypothesis for the molecular mechanism underlying the
      occurrence of the disease; namely, that poison-type topoisomerase II inhibitors
      stabilize the reaction intermediate covalent enzyme-DNA cleavage complexes,
      called "cleavable complexes," which in turn trigger the mobilization of various
      DNA damage repair and recombination systems to cope with the damage. The
      recombinant which acquires a growth advantage over others then overproliferates
      to become the leukemogenic population.

PMID- 10584564
TI  - [Second primary malignancy after surgical adjuvant therapy for gastric cancer].
AB  - Immunopotentiators are expected to intensify the effects of chemotherapy, but
      anticancer agents are in greater or lesser degree carcinogenic in humans. The
      carcinogenic risk after adjuvant chemo-immunotherapy was examined in 786 gastric
      cancer patients who underwent curative gastrectomy between 1963 and 1981. They
      consisted of 420 patients without any chemo- or immunotherapy (cont group), 302
      with chemotherapy (chem group) with mitomycin C and/or fluorinated pyrimidines,
      and 64 with chemo-immunotherapy (chem-immu group) with both chemotherapy and
      immuno-potentiator (s), levamisole or PSK and/or OK-432. The incidence of cancers
      other than gastric cancer 5 or more years after gastrectomy was 9 out of 64 in
      the chem-immu group (14.1%), which was higher than the 25 out of 302 in the chem
      group (8.3%) and significantly higher than the 27 out of 420 in the cont group
      (6.4%) (p < 0.05). The 5/10-year survival rate after gastrectomy was 76.0%/72.5%
      in the chem-immu group, which was significantly higher than the 66.1% /59.4% in
      the chem group and the 64.7%/59.3% in the cont group (p < 0.05). Among 215
      patients under 50 years of age, the survival rate was 72.7%/65.6% in the chem
      group, which was significantly lower than the 75.0%/71.7% in the cont group (p <
      0.01) and lower than the 81.9%/81.9% in the chem-immu group. However, the
      incidence of a second malignancy showed a tendency to increase in the order of
      the cont, chem and chem-immu groups.

PMID- 10584565
TI  - [Radiation-induced cancers following radiotherapy].
AB  - Improved radiotherapy for cancer has produced a large population of long-term
      survivors. These survivors, however, appear to have a greater risk of second
      primary cancers than would be expected based on the incidence of first primary
      cancers in the general population. The etiology of radiation-induced cancer is
      multifactorial and incompletely understood, and there is no firm diagnostic
      criteria for radiation-induced cancer because there are no specific
      histopathological findings. The incidence of radiation-induced cancers following
      radiotherapy was estimated to be about 0.3% in 5-year survivors, based on mail
      surveys (in 1979 & 1984) in Japan. It seems that the benefit of treatment
      outweighs the risk of developing secondary tumors. However, we should avoid
      excess treatment of patients with Hodgkin's disease or many pediatric
      malignancies who will be able to survive a long time after treatment. The
      relative carcinogenicity of various combinations of radiation and
      chemotherapeutic agents is now being established. Chemoradiotherapy is now
      frequently used for treatment of various malignancies which are considered to be
      uncontrollable by chemotherapy or radiotherapy alone. We should minimize their
      carcinogenic effects and the risk of developing secondary treatment-related
      tumors, to produce an optimal therapeutic gain. Long-term close follow-up is
      necessary for these patients.

PMID- 10584566
TI  - [Treatment of testicular and second cancer].
AB  - Since the advent of cisplatin-based chemotherapy in the 1970s, the majority of
      metastatic testicular cancer patients can be cured with chemotherapy followed by
      surgery. The high-curability of testicular cancer, along with young age of
      afflicted patients, can result in patients living for many years after the
      initial treatment. The development of second cancer represents one of the most
      severe long-term complications in these patients. Patients who have achieved a
      long-term disease-free status have an increased risk of developing germ-cell
      tumor in the contralateral testis. Late relapse (occurring more than 2 years
      after initial treatment) of germ-cell tumor at any site has also been found in
      approximately 3% of all patients. Patients receiving radiotherapy or chemotherapy
      for testicular cancer a have small, but clearly identifiable, risk of developing
      second malignancies. Radiotherapy is associated with a two- to threefold
      increased risk for second solid cancer. Chemotherapy, especially high-dose
      etoposide regimens, is associated with increased risk for second leukemia.
      Although the incidence of second malignancies is rather low, it is important to
      monitor the carcinogenic potential of therapy, and to develop a preventive
      approach for second cancer.

PMID- 10584567
TI  - [Study on CAF + medroxyprogesterone acetate (MPA) therapy for advanced or
      recurrent breast cancer--comparison between MPA 600 mg and 1,200 mg. Kyushu CAFT
      Therapy Study Group (Third Study)].
AB  - To find the optimal dose of MPA for combined use with CAF therapy for advanced or
      recurrent breast cancer, a randomized comparative study with a MPA 1,200 mg group
      and 600 mg group was carried out multi-institutionally. The response rate of
      complete cases was 37.5% (12/32) in the 1,200 mg group and 36.6% (15/41) in the
      600 mg group, showing no difference between the two groups. There were no
      differences in either the duration of response or the survival term. The major
      adverse effects and abnormal laboratory test values included alopecia, nausea and
      vomiting, general fatigue, anorexia and leukopenia, with no difference in
      incidence between the groups. Moon face, genital hemorrhage and body weight
      increase, which are thought to be caused by MPA, were found in both groups
      without a significant difference in incidence. The results of this study revealed
      no differences in effectiveness or safety between MPA 1,200 mg and 600 mg,
      suggesting that MPA for combined use with CAF is fully effective at a dose of 600
      mg.

PMID- 10584568
TI  - [Docetaxel as a single agent in cases of advanced/recurrent breast cancer
      previously treated with anthracycline].
AB  - Docetaxel 60 mg/m2 was administered via 1-hour intravenous infusion every 3-4
      weeks to 20 patients with advanced/recurrent breast cancer who had previously
      received anthracycline therapy. The overall response rate was 30.0% (6/20), with
      1 complete remission and 5 partial remissions. The median response duration was
      120 days. Response rates classified by recurrence site were soft tissues 43.0%,
      liver 33.3%, lung 33.3%, and bone 23.1%, respectively. Stable disease (prolonged
      NC) which continued more than 6 months was observed in patients with bone
      metastasis. Grade 3-4 leukocytopenia and neutropenia were observed in 45.0% and
      55.0%, respectively. Grade 3-4 leukocytopenia and neutropenia were frequently
      seen in patients who had received anthracycline of more than 500 mg/body as first
      line chemotherapy. Docetaxel thus seems to be effective in patients with
      advanced/recurrent breast cancer who are refractory to anthracycline therapy.

PMID- 10584569
TI  - [Effect of combination chemotherapy with multiple drugs (FLMP therapy) based on
      the circadian rhythms of the human body in advanced recurrent gastric cancer].
AB  - Combination chemotherapy with multiple drugs (FLMP therapy), in which the drugs
      were determined based on biochemical modulation and the dosing schedule was
      established in accordance with the circadian rhythms of the human body, was
      performed in cases of advanced recurrent gastric cancer. The drugs were
      administered according to the following schedule: 500 mg of 5-FU (continuous) on
      days 1-5 (the dose was increased during the night), 20 mg of LV on days 1-5 (at 6
      PM), 2 mg of MMC on day 5 (at 9 AM) and 60-80 mg of CDDP on day 5 (at 6 PM). A
      five-day course was administered by intravenous drip or hepatic arterial infusion
      at intervals of 4 weeks. Of 14 patients treated, the effect was estimated to be
      CR in 3, PR in 6, NC in 3, and PD in 2. The effectiveness rate was 62.3% overall,
      and the rate by administration route was 6/10 (60.0%) for i.v. and 3/4 (75.0%)
      for i.a. The side effects were slight. Those of grade 3 or more included anorexia
      in 5%, nausea and vomiting in 1%, stomatitis in 1% and leukopenia in 1%. This
      therapy, administered in accordance with the theory of chronotherapy, caused few
      side effects, and thus is considered a promising treatment for gastric cancer.

PMID- 10584570
TI  - [Late phase II clinical study for bropirimine (U-54461S) in situ carcinoma of the
      bladder: follow-up investigation. Bropirimine Study Group].
AB  - A follow-up investigation was conducted on a Late Phase II clinical study of
      bropirimine for carcinoma in situ (CIS) of the bladder. We previously reported
      that 48 patients were enrolled and 17 patients achieved complete remission (CR)
      in the Late Phase II study. Of the 17 CR patients, 5 had recurrence, but 9 were
      recurrence free for a year and 5 have remained so for more than 2 years (median
      follow-up: 29.1 +/- 4.2 months). The 1-year and 2-year recurrence-free rates
      calculated using the Kaplan-Meier method were 70.3% and 61.5% respectively. Of
      all the 47 bropirimine-treated patients, 11 underwent total cystectomy (median
      follow-up: 31.8 +/- 5.2 months). The rates of bladder preservation after 1 year,
      2 years, and 3 years calculated using the Kaplan-Meier method were 87.2%, 80.7%,
      and 74.0% respectively. Of the 39 patients who did not respond to bropirimine or
      suffered from recurrence after bropirimine treatment, 19 received subsequent
      intravesical bacillus Calmette-Guerin (BCG) therapy and 13 achieved CR (68.4%).
      This suggests that bropirimine does not decrease the efficacy of BCG therapy. In
      the present study, the prognosis was confirmed to be favorable after bropirimine
      therapy. Bropirimine would thus seem to be a useful oral anticancer agent for
      bladder CIS.

PMID- 10584571
TI  - [Evaluation of 389 cases with a central venous access device inserted
      peripherally in the forearm].
AB  - We describe the technique and the long-term results of a central venous access
      device inserted peripherally in the forearm. From July, 1994, 411 central venous
      access devices were implanted in 389 patients (365 patients with malignant
      disease and 24 with benign disease). The insertion was successful in 384 cases
      (99.0%). The mean follow up duration was 116.5 days (range 3 to 859 days) after
      insertion. Complications were observed in 90 cases (21.8%); drip insufficiency in
      42 (10.2%), phlebitis in 15 (3.6%), local infection in 9 (2.2%), catheter
      obstruction in 8 (1.9%), skin defect in 6 (1.5%), thrombosis of the subclavian
      vein in 4 (1.0%), system destruction in 4 (1.0%), and subcutaneous injection in 2
      (0.5%). The system was removed in 23 cases (5.6%). We conclude that this method
      is safe and effective and should be widely used for the management of
      outpatients.

PMID- 10584572
TI  - [Effects of HCFU and TNP 470 on liver metastasis of BALB/c retroperitoneal
      sarcoma (LMFS)].
AB  - Combination therapy using HCFU and TNP 470, which inhibits angiogenesis, was
      examined for effectiveness against the footpad injection model of LMFS tumor.
      This LMFS, a retroperitoneal sarcoma of BALB/c mice, proliferated at the
      inoculation site (100% take) and all mice operated on after day 15 had
      spontaneous metastatic nodules in the liver. Mice with the LMFS tumor were given
      HCFU and 5-FU (5 days/week), and/or TNP 470 (3 days/week) from day 3 for 3 weeks
      and sacrified at day 28 under anesthesia. Seven of 10 mice receiving 5-FU and TNP
      470 died from the side effects of the drugs. Mean tumor weight and liver
      metastatic nodules were determined and compared with a control group. The results
      were as follows: HCFU group: 94.6%, 11.8%, 5 FU group: 73.9%, 28.8%, TNP 470
      group: 67.6%, 44%, HCFU and TNP 470 group: 33.3%, 6.4%. Mice with LMFS were given
      HCFU and/or TNP 470 from day 3 for 4 weeks. The foot on the injected side was
      amputated on day 15, and the animals were sacrified on day 35. Liver metastatic
      nodules compared with those of the operation (OP) group as follows: OP + HCFU
      group: 14.4%, OP + TNP group: 39.1%, and OP + HCFU + TNP 470 group: 5.4%.
      Histologically, 5 of 5 mice of the OP group, 3 of 5 of the OP + HCFU group, 4 of
      5 of the OP + TNP 470 group and 1 of 5 of the OP + HCFU + TNP 470 group had liver
      metastases. These results show that while either HCFU or TNP 470 is effective by
      itself, a combination of these drugs is more effective against liver metastasis.

PMID- 10584573
TI  - [A case report of gastric carcinoma with complete remission of paraaortic lymph
      node metastasis by 5'-DFUR and MMC administration after resection of primary
      tumor].
AB  - A 53-year-old man was referred to our hospital with Borrmann type 2 advanced
      gastric cancer with a Virchow's node metastasis. A CT scan revealed a paraaortic
      lymph node metastasis. Because the tumor was diagnosed as being a poor candidate
      for curative resection, only a total gastrectomy was done. After surgery,
      administration of 5'-DFUR and MMC was begun. As a result, the paraaortic lymph
      node metastasis disappeared and the Virchow's node metastasis was reduced. The
      patient is well with no sign of recurrence 20 months after the operation.

PMID- 10584574
TI  - [A case of advanced gastric cancer with abdominal para-aortic lymph node
      metastasis successfully treated with FLP therapy].
AB  - A 73-year-old woman was admitted to our hospital in June 1998, suffering from
      upper abdominal pain. The upper G-I series and endoscopic examination revealed
      stenosis of the pylorus and antrum by a type 2 cancer, and a poorly
      differentiated adenocarcinoma and a signet-ring cell carcinoma were confirmed on
      endoscopic biopsy. A CT scan showed the enlargement of many regional and
      abdominal para-aortic lymph nodes. FLP therapy combined with cisplatin (50 mg/m2
      drip i.v., day 1-8), 5-fluorouracil (333 mg/m2 drip i.v.) and leucovorin (30
      mg/body i.v., day 1-8) was planned for neoadjuvant chemotherapy (NAC) in order to
      reduce or eliminate the tumor and increase curability. After two cycles of the
      FLP therapy, the tumor size shrunk remarkably and the enlargement of the para
      aortic lymph nodes disappeared. Distal gastrectomy with extended lymphadenectomy
      and cholecystectomy was performed. The histological findings of the primary tumor
      and metastatic lymph nodes demonstrated massive cancer cell degeneration such as
      pycnosis and vacuolation, xanthogranulomatous inflammation and dense fibrosis.
      The effect of NAC was judged to be grade 2 histologically. FLP therapy is an
      effective and safe regimen for NAC.

PMID- 10584575
TI  - [Case of stage IVb gastric cancer in which favorable anti-tumor effect and good
      QOL were observed due to UFTP therapy after low-dose CDDP-tegafur therapy].
AB  - A patient with stage IVb advanced gastric cancer, who was Group 4 lymph node
      metastasis positive, underwent two postoperative courses of low-dose CDDP-tegafur
      therapy (800 mg/body/day of tegafur + 5 mg/body/5 administrations, 2 days of
      rest, of cisplatin). UFTP therapy (400 mg/body/day of UFT + 5 mg/body/twice
      weekly of cisplatin) was thereafter given on an outpatient basis. The patient has
      now been receiving this therapy for one year and six months. The anti-tumor
      effect has been maintained and the tumor has been reduced in size by 89% without
      any adverse reactions. A good QOL has been observed. The present therapy can be
      performed safely at home and appears to be a favorable treatment from the
      viewpoint of QOL.

PMID- 10584576
TI  - [Effects of low-dose FP therapy for advanced gastric cancer cases].
AB  - The clinical application of low-dose FP therapy has spread rapidly in Japan. We
      examined the effects of this form of chemotherapy on patients with advanced
      gastric carcinoma in China. One cycle of this therapy consisted of intermittent
      infusion of CDDP (10 mg/body/3 hr), followed by intermittent infusion of 5-FU
      (250 mg/body/6 hr) and suppository administration of tegafur (500 mg) at night
      for 5 days with 2-day intervals. As a result, a partial response for the primary
      lesion and lymph nodes was obtained in some cases, 2 of which are described in
      this paper. No serious side effects were noted, although administration continued
      over a long period. Our results suggest that neoadjuvant chemotherapy with low
      dose FP may be useful as an inductive approach for advanced gastric cancer, and
      that the regimen can become a standard therapy for gastric cancer.

PMID- 10584577
TI  - [Successful treatment of pleuritis carcinomatosa using combination therapy of 5'
      DFUR, MPA and CPA as maintenance therapy].
AB  - A 44-year-old female patient with inoperable, local advanced left breast cancer
      was treated with 3 cycles of high dose CAF therapy followed by combination
      therapy of 5'-DFUR, MPA and CPA. The patient was discharged after receiving 3
      cycles of high-dose CAF therapy and continued to receive daily oral doses of 5'
      DFUR (800 mg), MPA (800 mg), and CPA (100 mg) for 15 months. After 3 cycles of
      high-dose CAF therapy, tumor marker (CEA, CA 15-3) levels were reduced. Six
      months later, after 3 cycles of high-dose CAF therapy, the tumor marker levels
      were within the normal range. No serious side effects were observed during
      chemotherapy. The patient enjoyed a good quality of life. We thus confirmed that
      this combination regimen was effective as a maintenance therapy for local
      advanced breast cancer.

PMID- 10584579
TI  - [A case of uterine cervical cancer in which UFT was an effective preoperative
      treatment].
AB  - We report a case in which UFT was effective as a preoperative treatment for stage
      II b cervical cancer. The patient was a 66-year-old female whose chief complaint
      was brown vaginal discharge. Following cytological, histological and CT
      examinations, a diagnosis was made of papillary squamous cell carcinoma invading
      the vagina and left parametrium. We administered UFT (600 mg/day, for 5 days) as
      one course, and conducted two courses with an interval of 2 days. The tumor had
      shrunk 2 weeks later and a radical hysterectomy was performed after additional
      treatment with intraarterial cisplatin (120 mg/body) infusion. Thymidylate
      synthase (TS) and dihydropyrimidine dehydrogenase (DPD), which are enzymes in 5
      FU metabolism, and the labeling index (ID) of DNA fragmentation in the tumor were
      estimated before and after UFT. The results showed that TS was 0.69 pmol/g tissue
      and DPD 39.98 pmol/mg/min before UFT, and that LI of DNA fragmentation was 21.8
      +/- 5.0% before UFT and 37.9 +/- 16.2% after UFT. We suggest that preoperative
      UFT administration is an effective treatment for cervical cancer, and that TS,
      DPD and LI of DNA fragmentation might be useful biomarkers to estimate the
      sensitivity of UFT.

PMID- 10584578
TI  - [Administration of docetaxel in cases of recurrent breast carcinoma with
      malignant pleural effusion controlled by intrapleural administration of OK-432].
AB  - Docetaxel is an anti-tumor agent which promotes the congregation and
      stabilization of microtubules, there by preventing cell division. It is reported
      to have anti-tumor activity against breast or non-small cell lung carcinomas
      which have been resistant to other anti-tumor agents. On the other hand, it
      causes peripheral edema and effusion in the pleural or peritoneal cavities. Thus,
      pleural or peritoneal effusions, which require drainage have been considered to
      be contraindications for the administration of docetaxel. OK-432 is an agent
      which causes adhesion by evoking a local inflammatory reaction. We experienced
      two cases of recurrent breast carcinoma with malignant pleural effusion. We
      successfully managed their pleural effusion with the intrapleural administration
      of OK-432. Thereafter, we safely administered docetaxel, and obtained good
      outcomes. The present paper also discussed the synergistic action between these
      agents.

PMID- 10584580
TI  - [Genetic and epigenetic alterations associated with cancer metastasis].
AB  - It is now well accepted that cancer is attributed to the accumulation of genetic
      alterations in the cells. Thus, to understand the molecular mechanisms of cancer
      metastasis, it is indispensable to identify the genes whose alterations
      accumulate during cancer progression as well as the genes whose expression is
      responsible for invasion and metastasis. Two different molecular approaches have
      been taken to identify such genes. One is the identification of genes whose
      alterations accumulate during cancer progression. The other is the identification
      of genes whose expression is responsible for the acquisition of metastatic
      potential in cancer cells. Molecular analyses of cancer cells in various stages
      of progression have revealed that alterations of tumor suppressor genes and
      oncogenes accumulate during cancer progression and correlate with the clinical
      aggressiveness of cancer cells. Comparative analyses of gene expression profiles
      between high-metastatic and non-metastatic cells have also revealed that various
      genes are differentially expressed in association with the metastatic potential
      of cancer cells. In the near future, the information obtained from these studies
      can be applied to the diagnosis, treatment and prevention of metastases.

PMID- 10584581
TI  - Symposium on natural products toxicology.

PMID- 10584582
TI  - Causes, epidemiology, and clinical evaluation of suspected herbal poisoning.

PMID- 10584583
TI  - Alternative medicines toxicology: a review of selected agents.

PMID- 10584584
TI  - Three new herbal hepatotoxic syndromes.

PMID- 10584585
TI  - Essential oil poisoning.

PMID- 10584586
TI  - Position statement and practice guidelines on the use of multi-dose activated
      charcoal in the treatment of acute poisoning. American Academy of Clinical
      Toxicology; European Association of Poisons Centres and Clinical Toxicologists.
AB  - In preparing this Position Statement, all relevant scientific literature was
      identified and reviewed critically by acknowledged experts using agreed criteria.
      Well-conducted clinical and experimental studies were given precedence over
      anecdotal case reports and abstracts were not usually considered. A draft
      Position Statement was then produced and subjected to detailed peer review by an
      international group of clinical toxicologists chosen by the American Academy of
      Clinical Toxicology and the European Association of Poisons Centres and Clinical
      Toxicologists. The Position Statement went through multiple drafts before being
      approved by the Boards of the two societies. The Position Statement includes a
      summary statement for ease of use and is supported by detailed documentation
      which describes the scientific evidence on which the Statement is based. Although
      many studies in animals and volunteers have demonstrated that multiple-dose
      activated charcoal increases drug elimination significantly, this therapy has not
      yet been shown in a controlled study in poisoned patients to reduce morbidity and
      mortality. Further studies are required to establish its role and the optimal
      dosage regimen of charcoal to be administered. Based on experimental and clinical
      studies, multiple-dose activated charcoal should be considered only if a patient
      has ingested a life-threatening amount of carbamazepine, dapsone, phenobarbital,
      quinine, or theophylline. With all of these drugs there are data to confirm
      enhanced elimination, though no controlled studies have demonstrated clinical
      benefit. Although volunteer studies have demonstrated that multiple-dose
      activated charcoal increases the elimination of amitriptyline,
      dextropropoxyphene, digitoxin, digoxin, disopyramide, nadolol, phenylbutazone,
      phenytoin, piroxicam, and sotalol, there are insufficient clinical data to
      support or exclude the use of this therapy. The use of multiple-dose charcoal in
      salicylate poisoning is controversial. One animal study and 2 of 4 volunteer
      studies did not demonstrate increased salicylate clearance with multiple-dose
      charcoal therapy. Data in poisoned patients are insufficient presently to
      recommend the use of multiple-dose charcoal therapy for salicylate poisoning.
      Multiple-dose activated charcoal did not increase the elimination of astemizole,
      chlorpropamide, doxepin, imipramine, meprobamate, methotrexate, phenytoin, sodium
      valproate, tobramycin, and vancomycin in experimental and/or clinical studies.
      Unless a patient has an intact or protected airway, the administration of
      multiple-dose activated charcoal is contraindicated. It should not be used in the
      presence of an intestinal obstruction. The need for concurrent administration of
      cathartics remains unproven and is not recommended. In particular, cathartics
      should not be administered to young children because of the propensity of
      laxatives to cause fluid and electrolyte imbalance. In conclusion, based on
      experimental and clinical studies, multiple-dose activated charcoal should be
      considered only if a patient has ingested a life-threatening amount of
      carbamazepine, dapsone, phenobarbital, quinine, or theophylline.

PMID- 10584587
TI  - Activated charcoal reduces the need for N-acetylcysteine treatment after
      acetaminophen (paracetamol) overdose.
AB  - BACKGROUND: The evidence for efficacy of gastric lavage and activated charcoal
      for gastrointestinal decontamination in poisoning has relied entirely on
      volunteer studies and/or pharmacokinetic studies and evidence for any clinical
      benefits or resource savings is lacking. AIM OF STUDY: To investigate the value
      of gastrointestinal decontamination using gastric lavage and/or activated
      charcoal in acetaminophen (paracetamol) poisoning. PATIENTS AND METHODS: We
      analyzed a series of 981 consecutive acetaminophen poisonings. These patients
      were treated with gastric lavage and activated charcoal, activated charcoal
      alone, or no gastrointestinal decontamination. The decision as to which treatment
      was received was determined by patient cooperation, the treating physician,
      coingested drugs, and time to presentation after the overdose. RESULTS: Of 981
      patients admitted over 10 years, 10% (100) had serum concentrations of
      acetaminophen that indicated a probable or high risk of hepatotoxicity. The risk
      of toxic concentrations for patients ingesting less than 10 g of acetaminophen
      was very low. In patients presenting within 24 hours, who had ingested 10 g or
      more, those who had been given activated charcoal were significantly less likely
      to have probable or high risk concentrations (Odds ratio 0.36, 95% CI 0.23-0.58,
      p < 0.0001). Gastric lavage, in addition to activated charcoal, did not further
      decrease the risk (Odds ratio 1.12, 95% CI 0.57-2.20, p = 0.86). CONCLUSIONS:
      Toxic concentrations of serum acetaminophen (paracetamol) are uncommon in
      patients ingesting less than 10 g. In those ingesting more, activated charcoal
      appears to reduce the number of patients who achieve toxic acetaminophen
      concentrations and thus may reduce the need for treatment and hospital stay.

PMID- 10584588
TI  - Oral or intravenous N-acetylcysteine: which is the treatment of choice for
      acetaminophen (paracetamol) poisoning?
AB  - BACKGROUND: The optimal route and duration of administration for N-acetyl
      cysteine in the management of acetaminophen (paracetamol) poisoning are
      controversial. It has been stated on the basis of a selected post-hoc analysis
      that oral N-acetylcysteine is superior to intravenous N-acetylcysteine in
      presentations later than 15 hours. AIM OF STUDY: To investigate the efficacy of
      intravenous or oral N-acetylcysteine. PATIENTS AND METHODS: We analyzed a series
      of acetaminophen poisonings treated with a protocol including activated charcoal
      and intravenous N-acetylcysteine. The outcomes assessed included use of N
      acetylcysteine, adverse effects of intravenous N-acetylcysteine, and the
      occurrence of hepatotoxicity (transaminase > 1000 U/L). We incorporated these
      results in a meta-analysis of previously reported series of acetaminophen
      poisonings to compare the outcomes from intravenous and oral N-acetylcysteine
      use. RESULTS: Of 981 patients admitted over 10 years, 4% (40) presented later
      than 24 hours and 10% (100) had concentrations of acetaminophen that indicated a
      probable or high risk of hepatotoxicity. The 30 patients who developed
      hepatotoxicity presented later, took larger amounts, had higher concentrations,
      and received N-acetylcysteine later than those who did not. No patients received
      a liver transplant but 2 patients died (one after referral to a transplant unit
      and one just before). Adverse reactions to intravenous N-acetylcysteine occurred
      in 6% (12/205) of patients but none prevented completion of the treatment. In the
      meta-analysis, those with probable or high risk concentrations had similar
      outcomes with intravenous (pooled n = 341) and oral N-acetylcysteine (pooled n =
      1462) administration. Rates of hepatotoxicity for those treated within 10 hours
      (3 and 6%), late (10-24 hours: 30 and 26%), and overall (0-24 hours: 16 and 19%)
      were all similar. The proportion of patients classified as presenting later than
      10 hours is much greater in the oral N-acetylcysteine studies (64%) than in many
      of the intravenous N-acetylcysteine studies (38%, 44%, and 63%). CONCLUSIONS: The
      differences claimed between oral and intravenous N-acetylcysteine regimes are
      probably artifactual and relate to inappropriate subgroup analysis. A shorter
      hospital stay, patient and doctor convenience, and the concerns over the
      reduction in bioavailability of oral N-acetylcysteine by charcoal and vomiting
      make intravenous N-acetylcysteine preferable for most patients with acetaminophen
      poisoning.

PMID- 10584589
TI  - Predictive properties of a qualitative urine acetaminophen screen in patients
      with self-poisoning.
AB  - OBJECTIVE: Screening for acetaminophen toxicity is recommended in almost all
      cases of self poisoning. We compared a qualitative urine acetaminophen screen to
      the quantitative serum acetaminophen to test the hypothesis that a negative urine
      acetaminophen screen would be predictive of a negative serum acetaminophen level.
      METHODS: All adults with intentional ingestions evaluated in our Emergency
      Department during 1995 were retrospectively identified based on Emergency
      Department International Classification of Disease--9th edition codes. Laboratory
      data from each patient including serum and urine toxicologic assays were
      examined. Predictive properties of urine acetaminophen screens for serum
      acetaminophen were evaluated. RESULTS: A total of 88 patients were identified who
      had both a serum acetaminophen and a urine acetaminophen performed. The
      sensitivity of the urine acetaminophen screen was 100% (95% CI 72-100%) and the
      specificity was 87% (95% CI 80-95%). All patients with negative urine
      acetaminophen screens had negative serum acetaminophen levels (negative
      predictive value 100%; 95% CI 96-100%). Accuracy of the urine acetaminophen
      screen was 89%. CONCLUSION: A negative urine acetaminophen screen was highly
      predictive of negative serum acetaminophen levels. It is possible that negative
      urine acetaminophen screens may obviate the need for 4-hour quantitative serum
      levels. Further validation in a prospective study is needed.

PMID- 10584590
TI  - Triethylene glycol poisoning treated with intravenous ethanol infusion.
AB  - INTRODUCTION: Poisoning with triethylene glycol has been rarely reported in
      humans. Triethylene glycol is thought to be metabolized by alcohol dehydrogenase
      to acidic products resulting in the production of a metabolic acidemia.
      Triethylene glycol metabolism has previously been shown to be inhibited by
      fomepizole (4-methyl pyrazole) administration. We report a case of triethylene
      glycol ingestion, presenting with a metabolic acidemia, treated with intravenous
      ethanol administration. CASE REPORT: A 23-year-old female presented to the
      emergency department approximately 1-1.5 hours following ingestion of a gulp of
      triethylene glycol (99%) brake fluid with coma (GCS-3) and metabolic acidemia (pH
      7.03, PCO2 44 mm Hg, Bicarbonate 11 mmol/L, anion gap 30 mmol/L, serum creatinine
      90 mumol/L). She was intubated and given 100 mmol of intravenous sodium
      bicarbonate. An ethanol loading dose was administered followed by an infusion to
      maintain serum ethanol at 100 mg/dL. Acidemia gradually resolved over the next 8
      hours and she was extubated 12 hours later. The ethanol infusion was continued
      for a total of 22 hours. There was no recurrence of acidemia. Serum ethanol,
      ethylene glycol, and methanol levels were nondetectable on presentation, as was
      serum salicylate. Urine drug of abuse screen and thin-layer chromatography
      revealed no other coingested substances. The patient was discharged to a
      psychiatric ward 36 hours postingestion. CONCLUSION: Pure triethylene glycol
      poisoning results in coma and metabolic acidemia and may be treated with alcohol
      dehydrogenase inhibitors such as ethanol.

PMID- 10584591
TI  - Fomepizole (4-methylpyrazole) in fatal methanol poisoning with early CT scan
      cerebral lesions.
AB  - BACKGROUND: Methanol poisoning, potentially fatal, is generally treated with the
      combination of ethanol as antidote, and hemodialysis. Fomepizole, a competitive
      inhibitor of alcohol dehydrogenase, has more recently been used, and is capable
      of blocking the toxic metabolism of methanol. To our knowledge, its use has never
      been reported as an antidote in severe methanol poisoning requiring hemodialysis.
      CASE REPORT: We report a case of fatal methanol poisoning (1.9 g/L on admission)
      suspected due to the combined presence of coma and severe metabolic acidosis with
      normokalaemia. CONCLUSION: The fomepizole treatment protocol (10 mg/kg by i.v.
      infusion over 1 hour before dialysis, repeated 12 hours later in combination with
      1.5 mg/kg/h during dialysis) was simple to use and appeared effective in
      eliminating methanol in combination with hemodialysis. The case is also unusual
      in terms of severity and the early onset of cerebral lesions demonstrated by
      computed tomography (CT) scan.

PMID- 10584592
TI  - Overdose of Rogaine Extra Strength for Men topical minoxidil preparation.
AB  - CASE REPORT: Minoxidil is a potent arterial vasodilator used in the treatment of
      hypertension. A side effect, hypertrichosis, has prompted the marketing of a
      topical preparation, Rogaine, for the treatment of male-pattern baldness.
      Recently, a 5% solution of minoxidil became available over-the-counter as Rogaine
      Extra Strength For Men Hair Regrowth Treatment. We describe an oral overdose of
      minoxidil 3 g as the Rogaine Extra Strength preparation. Toxicity manifested as
      profound hypotension, requiring vasopressor support, intubation, prolonged
      tachycardia, and fluid overload with pleural effusions, requiring several days of
      therapy with furosemide. This is the largest reported ingestion of minoxidil and
      the first reported overdose of the extra strength 5% solution.

PMID- 10584593
TI  - Acute potassium dichromate poisoning: a toxicokinetic case study.
AB  - CASE REPORT: A 48-year-old man drank 150 mL of an aqueous solution containing
      potassium dichromate 22.5 g in a suicidal attempt and was admitted 7 hours after
      the ingestion. Hemodialysis was promptly undertaken and chromium concentrations
      in serum, erythrocytes, and dialysate were determined during the treatment.
      Chromium elimination in urine was monitored during hemodialysis and the
      subsequent 400 hours. The total chromium eliminated via hemodialysis and urine
      was calculated as 36.7 mg or 0.16% of the ingested dose. Spontaneous urinary
      elimination proceeded according to an open one-compartment model. The elimination
      half-life was 71.37 hours +/- 17.13 hours (95% CI). Chromium elimination from
      serum followed an open two-compartment model, with the half-lives of 3.16 hours
      +/- 2.63 hours for phase 1 and 50 hours +/- 27 hours (95% CI) for phase 2.
      Calcium-EDTA therapy had no influence on erythrocyte, serum, or urine chromium
      level. It contributed, however, to a significant increase in chromium elimination
      rate in the dialysate. Serum zinc was very low at admission and serum zinc,
      copper, and magnesium were controlled during the initial 30 hours.

PMID- 10584594
TI  - The history of poisoning in the future: lessons from Star Trek.
AB  - BACKGROUND: The Arts are replete with examples of presaged events of the future.
      Since a unique glimpse of the 23rd century is afforded by the television series
      Star Trek, a survey of the toxin-related events as chronicled by the crew of the
      USS Starship Enterprise may provide insight to prepare toxicologists for the
      future. METHODS: An investigation of the logs of the Enterprise was undertaken
      for the years 2266 to 2269 which were part of its first 5-year mission. Internet
      sites, published databases, and selected recorded episodes from the original Star
      Trek television series were searched for poisonings or toxin-related incidents.
      RESULTS: Out of the 79 Star Trek episodes, 28 (35%) involved toxin-related
      incidents. A total of 31 poisoning incidents were documented with 13
      environmental, 9 intentional, 5 unintentional, and 4 homicidal circumstances.
      Biotoxins (10 incidents) were the most frequently involved toxin followed by
      neurotoxins (9), radiation (3), cytotoxins (3), temporal toxins (3), acids (2),
      and phytotoxins (1). Of these cases, 2 involved hazardous materials incidents, 1
      was contamination of food, and 3 involved therapeutic misadventures. CONCLUSIONS:
      Many of the circumstances encountered in poisonings of the future will likely be
      similar to contemporary reasons, but the nature of the toxins will differ.
      Clinical toxicologists should prepare for the future by increasing their study of
      molecular biology, comparative medicine, physics, and history.

PMID- 10584595
TI  - Fatal potassium permanganate intoxication in an infant.

PMID- 10584596
TI  - The MedWatch Program.

PMID- 10584597
TI  - Principles of screening.
AB  - Preventive medicine is an increasingly important area of clinical practice.
      Conceptually, preventive medicine involves three tasks of the clinician:
      screening, counseling, and immunization/prophylaxis. This opening article reviews
      some of the basic tenets underlying screening including basic epidemiologic
      principles, characteristics of a good screening situation, barriers to screening,
      and some of the potential hazards of screening.

PMID- 10584598
TI  - Screening for cardiovascular disease. Concepts, conflicts, and consensus.
AB  - CVD in the United States is prevalent, costly, and disabling. Wherever in the
      arterial tree atherosclerosis occurs, the process appears to begin in youth, to
      develop under the influence of the same risk factors, and to be amenable to the
      same interventions. The relationship between CVD and its associated risk factors
      is continuous, is graded, and extends below thresholds previously defined as
      normal. This observation, in turn, is based on an appreciation that in our
      society, the gap between normal and optimal can be considerable. CVD is a
      multifactorial process, often related to modifiable lifestyle choices; we focus
      on any single risk factor to the exclusion of others puts patients in danger.
      Because risk factors rarely occur in isolation, risk assessment must be as
      multifactorial as the underlying disease process. By understanding differences
      between risk factors in terms of the impact of their modification on the
      underlying disease, targeted interventions become possible that are tailored to
      the likelihood of an individual patient acquiring CVD. To change the overall
      prevalence of an epidemic disease such as CVD, however, such a high-risk approach
      must be applied in concert with a population strategy that seeks to effect
      smaller degrees of change in the large segment of society that may be at only
      moderate risk but--because of their great numbers--bears most of the morbidity
      and mortality of CVD. Finally, despite the remarkable progress that has been made
      in our understanding of the pathophysiology of CVD and the effectiveness of risk
      factor modification, significant gaps remain between knowledge and behavior.
      Fewer than 50% of diabetics are even aware that they have the disease. Only a
      third of those whose lipid levels qualify them for treatment receive intervention
      of any kind, including dietary advice. Only 27% of hypertensives have their blood
      pressure adequately controlled. The potential impact of more vigorous screening
      practices in the primary care setting on the health of individuals and
      communities cannot be overstated.

PMID- 10584599
TI  - Screening for coronary artery disease.
AB  - Unidentified coronary artery disease remains a significant cause of premature
      death and morbidity during the prime of life. The availability of effective
      interventions for the management of ischemia has provoked new interest in
      screening for this condition in asymptomatic patients, in the hope of reducing
      the burden of this condition. Although widespread use of stress testing is
      ineffective, the use of imaging techniques may offer better accuracy for
      detection of ischemia. Other tests that identify evidence of atheroma in the
      peripheral or coronary circulation may be useful to identify patients at risk.

PMID- 10584600
TI  - Colorectal cancer screening.
AB  - Colorectal cancer is an important problem in the United States, with over 130,000
      new cases and 55,000 deaths each year. There is now strong evidence that
      screening for colorectal cancer with fecal occult blood testing can decrease
      mortality, and additional evidence that removing benign adenomas can decrease
      cancer incidence. Evidence-based screening guidelines depend on colorectal cancer
      risk. Individuals at higher risk because of a personal or family history deserve
      more intensive screening than asymptomatic individuals over age 50.

PMID- 10584601
TI  - Screening for prostate cancer. The challenge of promoting informed decision
      making in the absence of definitive evidence of effectiveness.
AB  - Evidence demonstrating the burden of prostate cancer upon men in the United
      States is incontrovertible; less compelling, however, is proof of benefit from
      early detection efforts. Nevertheless, the absence of definitive evidence does
      not lessen the interest of men in prostate testing or the obligation of
      physicians to help interested men make well-informed decisions, which integrate
      personal circumstance and preference with the best available data. This article
      provides the counseling physician with the information required to frame the
      current prostate testing debate and an approach to support informed decision
      making by men who can benefit from their assistance.

PMID- 10584602
TI  - Breast cancer screening.
AB  - Breast cancer is the most common malignancy among women in the United States;
      however, recent data demonstrates a decline in the mortality rate, which may be
      attributed to early detection from screening programs combined with effective
      therapies for early stage disease. As a result of the prevalence of breast cancer
      and its association with highly emotional issues, screening recommendations have
      aroused debate in the scientific, public, and legislative domains. A general
      consensus supports breast cancer screening among women between the ages of 50 and
      70; however, much controversy exists regarding screening for women age 40 to 49
      or above age 70. This article explores the issues involved in determining breast
      cancer screening recommendations among asymptomatic women with average risk in
      the United States.

PMID- 10584603
TI  - Screening for gynecologic cancer.
AB  - Screening for cervical cancer with the Pap test has significantly reduced
      mortality from the disease. Although screening for ovarian and endometrial cancer
      is desirable, suggested strategies have not demonstrated efficacy. For the
      present time, educating patients with regard to the symptoms associated with
      these diseases and prompt evaluation of women who present with these symptoms
      helps limit unnecessary diagnostic delay.

PMID- 10584604
TI  - Risk assessment of the menopausal patient.
AB  - Menopause is a physiologic event that gives a woman the opportunity to become
      involved in a preventive health program. Menopause is not a disease; however, it
      does cause symptoms in a significant percentage of women. Medical evaluation with
      an emphasis on health maintenance and lifestyle measures is important for
      menopausal women. Tailoring an individual program for women, which may include
      HRT and other therapeutic options, is guided by the menopausal risk assessment.

PMID- 10584605
TI  - Geriatric assessment.
AB  - A comprehensive geriatric assessment involves the evaluation of the physical,
      psychosocial, and environmental factors affecting the health of an elderly
      person. In the office setting a geriatric assessment is best accomplished by the
      use of screening questions, which are incorporated into the patient's medical
      questionnaire; the use of validated, brief screening tests that measure the
      patient's performance of daily living activities, cognition, nutritional status,
      and risk of falls; and a review of the patient's personal values and social
      support network. The screening assessment can be completed in an average of ten
      minutes by using self-administered questionnaires and brief performance-based
      measures of physical functioning. The comprehensive assessment performed on the
      initial visit with an elderly patient will help to (1) improve diagnostic
      accuracy, (2) guide the selection of interventions to restore or preserve health,
      (3) recommend an optimal environment for care, (4) predict health outcomes, and
      (5) monitor clinical change over time. The effectiveness of geriatric assessment
      has been demonstrated in clinical trials and is likely to be most effective when
      conducted by the patient's primary care physician.

PMID- 10584606
TI  - Nutrition screening and assessment.
AB  - Both undernutrition and overnutrition contribute to increased risk of morbidity
      and mortality. Marasmus, kwashiorkor, and decreased micronutrient status are
      types of nutritional deficiencies, whereas obesity and problems resulting from
      dietary supplements are examples of overnutrition. Screening for malnutrition can
      be performed in the ambulatory, hospital, and institutional populations, each
      with methods appropriate for the target population. For patients determined to be
      at high risk, further nutrition assessment can be performed to help arrive at
      specific nutritional treatment goals. Identifying and treating malnutrition can
      potentially have an important impact on decreasing morbidity and mortality in the
      population.

PMID- 10584607
TI  - Screening for alcohol problems in primary care.
AB  - Alcohol problems are common among patients seen in primary care settings, yet
      they are often missed by physicians. This article offers a model for alcohol
      screening designed to facilitate early identification of alcohol problems. This
      approach emphasizes the heterogeneity of alcohol problems and looks at alcohol
      use along a spectrum, with different risks depending on where in the spectrum a
      patient falls. The authors provide practical suggestions on integrating alcohol
      screening and early intervention into routine care.

PMID- 10584608
TI  - Preoperative screening.
AB  - In screening the preoperative patient, several sources of risk, each with
      potentially modifiable components, must be considered. These include risks
      related to the proposed procedure, anesthetic, and medical illnesses present in
      the patient. To screen effectively, one must look for potential factors in each
      area that may affect perioperative morbidity and mortality. Once risk areas are
      identified, it is helpful to quantify them further through a focused testing
      approach, especially when the anticipated surgical or anesthetic risks are high.
      Data obtained through this process should guide the optimization of the patient's
      medical status to modify risks when possible. Sharing information obtained during
      the preoperative assessment with both anesthesiologists and surgeons helps to
      refine plans for management and may better ensure patient safety in the
      perioperative period.

PMID- 10584609
TI  - The preplacement evaluation.
AB  - Over the past 25 years, the preplacement evaluation has undergone considerable
      evolution under the influence of regulatory and economic pressures. Formally used
      by some employers to screen out applicants who might have represented the mere
      possibility of a future work-related injury, the modern-day preplacement
      evaluation is legally restricted to only two determinations: (1) whether the
      individual can perform essential job functions with or without accommodation and
      (2) whether the individual represents a direct threat to himself or herself or
      others. Truly enlightened companies also recognize that other benefits accrue
      from a properly designed, conscientiously performed preplacement evaluation,
      perhaps the most important of which is to promote worker health, in the certain
      recognition that healthy employees are more productive ones. This benefit may be
      the true purpose of the preplacement evaluation and its most enduring, tangible
      benefit.

PMID- 10584610
TI  - Host defense mechanisms in urinary tract infections.
AB  - The host response to urinary tract infections is directed against both bacterial
      surface antigens, as well as bacterial products. The local response is perhaps
      the most important, with prevention of binding and tissue invasion as the
      hallmarks. Once an infection is established, the humoral immune system is most
      active in curtailing the damage and clearing the infecting organism. The prostate
      has a specialized complex of defenses that serves to reduce the incidence of
      infections in males.

PMID- 10584611
TI  - Gram-negative bacterial sepsis and the sepsis syndrome.
AB  - Gram-negative sepsis syndrome is an increasingly common complication in medical
      and surgical patients. The molecular and cellular mechanisms underlying this
      dreaded complication are yielding to investigation. These studies have led to a
      multiplicity of targets for novel therapies. Despite highly promising results in
      many animal studies, clinical studies have been disappointing.

PMID- 10584612
TI  - Fungal infections of the genitourinary system: manifestations, diagnosis, and
      treatment.
AB  - There is an increasing pool of immunocompromised patients who are at an increased
      risk to fungi infections, which now cause 8% of nosocomial infections. Premature
      infants and elderly, transplant, and HIV patients are prime candidates for
      invasive fungal infections. The genitourinary system can be a source or target of
      disseminated fungal infection. Although candidal species are the most frequent
      pathogen, other species such as aspergila, cryptoccoccus have become major
      pathogens. "Environmental fungi," which include blastomyces, coccidioides and
      histoplasma, have become more aggressive in the vulnerable patient.

PMID- 10584613
TI  - Evaluation and management of pediatric urinary tract infections.
AB  - Urinary tract infections (UTIs) are relatively common in children. We describe
      the evaluation and management of children with UTIs, as well as the risks and
      consequences related to the UTI. This article describes a rational approach to
      the evaluation and management of childhood UTIs with the relation to the natural
      history and risk factors.

PMID- 10584614
TI  - Management of lower urinary tract infections and cystitis.
AB  - It is possible to understand the pathophysiology, diagnostic laboratory
      methodology, and appropriate medical and surgical management of urinary tract
      infections in today's modern medical world. The foundation of success lies within
      an appropriate determination of the presence of mitigating complications, careful
      documentation of invading organisms, and judicious selection and administration
      of modern antimicrobial agents. Virtually all urinary tract infections begin in
      the lower system through bacterial exposure and adherence phenomena, creating
      simple uncomplicated infections in otherwise healthy hosts and serious
      complicated infections in others. Not all bacteriuria should be treated, and not
      all infections should be treated equally; knowing the difference is the secret.

PMID- 10584615
TI  - Prostatitis: evolving management strategies.
AB  - Concepts regarding the etiology, diagnosis, and management of prostatitis have
      changed more in the last 3 years than they have in the last 3 decades. Urologists
      (and all physicians) no longer need to avoid patients with this disease. It is
      hoped that the new management strategies that are evolving will eventually
      benefit the majority of patients sustaining prostatitis.

PMID- 10584616
TI  - Management of pyelonephritis and upper urinary tract infections.
AB  - The most frequent cause of upper urinary tract infection remains E. coli. Other
      organisms are found in complicated infections associated with diabetes mellitus,
      instrumentation, stone, and immunosuppression. The pathogenesis of acute
      pyelonephritis is reviewed herein, with an emphasis on the virulence factors
      responsible for its initiation, including urothelial adhesion by P-fimbriae of E.
      coli and other common factors including hemolysin and aerobactin. Renal damage
      does not always ensue following such infection. It is seen when toxic oxygen
      radicals are released during the ischemic episode and the respiratory burst of
      phagocytosis is marked and prolonged. These events occur when effective
      antibacterial treatment is delayed when the diagnosis is not made early or when
      socioeconomic factors prevent treatment. The scarring of chronic pyelonephritis
      leads to the loss of renal tissue and function and may progress to end-stage
      renal disease. With effective antibacterial therapy, the immune response by both
      T and B lymphocytes leads to antibodies that assist in bacterial eradication.
      Therapy must be both rapid and effective. In many instances, antibacterial agents
      may be used as outpatient therapy. If the Gram stain shows only gram-negative
      organisms and if the infection is community acquired, oral outpatient therapy
      with trimethoprim/sulfamethoxazole or a fluoroquinolone may suffice if the
      patient has no nausea. When the patient is septic, hospitalization and treatment
      with parenteral antibiotics are needed. Both ceftriaxone and gentamycin are cost
      effective parenteral therapy because only once-daily dosing is needed. If gram
      positive organisms are found, an enterococcus should be suspected, and a beta
      lactam penicillin such as piperacillin or a third-generation cephalosporin such
      as ceftriaxone is indicated. If penicillin allergy exists, vancomycin should be
      used. If the patient does not improve rapidly, diagnostic studies including
      ultrasound and CT will assist in the diagnosis of obstruction, abscess, or
      emphysematous pyelonephritis. Most of these complications are now rapidly treated
      percutaneously, with surgical therapy following as needed. Complicated
      infections, such as those occurring in patients with anatomic abnormalities,
      stone, or immunosuppression, are often caused by organisms other than E. coli,
      and long-term antibacterial therapy often leads to fungal infections such as
      candidiasis. A recrudescence of tuberculosis is occurring, often with resistance
      to antituberculous drugs. The increased incidence has been associated with the
      immunosuppression of AIDS but is also occurring in intravenous drug users,
      perhaps because of poor nutrition but also owing to noncompliance with treatment.
      The symptoms of renal tuberculosis are usually limited to fever, frequency,
      urgency, and dysuria. Hematuria with sterile pyuria is the usual laboratory
      finding. The young urologist should remember this renal disease in the
      differential diagnosis of hematuria, because medical therapy can provide a cure.

PMID- 10584617
TI  - Nonsurgical management of infection-related renal calculi.
AB  - Struvite calculi can be a debilitating affliction for which the cure is mainly
      surgical. If left untreated, infection-related calculi can cause failure to
      thrive, anemia, chronic renal insufficiency, renal failure and death. There has
      been much research aimed at non-surgical intervention and prevention of these
      calculi especially in this "non-invasive" era. The historic and current non
      surgical treatment modalities of struvite calculi are discussed.

PMID- 10584618
TI  - Urinary tract infections in pregnancy.
AB  - Although pregnancy does not increase the prevalence of ASB in women, it does
      enhance the progression rate from asymptomatic to symptomatic disease.
      Furthermore, ASB is associated with preterm delivery. Given the fact that
      identification and eradication of ASB in pregnant women can lower the likelihood
      of pyelonephritis and prevent preterm delivery, every gravida should be
      systematically screened for ASB and appropriately treated. In the authors'
      opinion, a first-trimester urine culture remains the screening test of choice;
      reliance on symptoms to prompt screening is inadequate because the state of
      pregnancy can provoke frequency and nocturia. Multiple antibiotic regimens for
      ASB are safe during pregnancy and effective.

PMID- 10584619
TI  - Asymptomatic bacteriuria in spinal cord patients and the elderly.
AB  - The prevalence and incidence of symptomatic and asymptomatic bacteriuria will
      remain high for many years to come. Antimicrobial agents are necessary to treat
      symptomatic UTI because no natural methods have been shown to be effective.
      Treatment of ABU is not appropriate. There is growing resistance to antibiotics,
      biocides, and antiseptics and, simultaneously, a decreasing rate of introduction
      of new antibacterial agents; thus the problem of resistance is magnified and
      potentially complicates the management of patients with SCI and elderly persons.
      New options of managing health and of preventing ABU and UTI and the
      complications arising from these diseases must be investigated vigorously and
      urgently. In particular, further study of the role of bacterial biofilms, the
      normal microflora, the influence of diet and hygiene, and the importance of the
      host immune response in the process of urinary tract colonization and infection
      is relevant and necessary.

PMID- 10584620
TI  - HPV in the male patient.
AB  - Human papillomavirus (HPV) is a DNA-containing virus associated with a wide
      variety of clinical and subclinical diseases. These HPV lesions may resolve
      spontaneously or progress to benign (condyloma acuminata) or malignant (genital
      carcinoma) neoplasms. The incidence of HPV genital infection has risen
      dramatically over the past 30 years, and it is now the most common viral sexually
      transmitted disease. Many therapeutic options are available to the urologist with
      new treatments currently being investigated. The history, etiology, pathogenesis,
      carcinogenesis, and guidelines for evaluation and management are discussed.

PMID- 10584621
TI  - Strategies of antiretroviral therapy in adults.
AB  - Recent progress in antiretroviral treatment has led to dramatic improvements in
      HIV-related morbidity and mortality. These improvements have been fostered by
      advances in our understanding of HIV-related pathogenesis, the use of plasma HIV
      RNA levels to monitor patients, and the availability of 13 licensed
      antiretroviral drugs. Numerous drug combinations, especially those containing
      three or more agents, can suppress plasma HIV RNA levels below the lower limit of
      detection in the majority of treated patients. Urologists should be familiar with
      the limitations of this therapeutic response: patient adherence, drug resistance,
      a residual burden of chronically infected cells which are refractory to
      treatment, an unknown impact on HIV in genital secretions, and potential
      transmissibility through sexual contact.

PMID- 10584622
TI  - Hospital-acquired urinary tract infections associated with the indwelling
      catheter.
AB  - Indwelling urethral catheters are commonly used in patients admitted to acute
      care hospitals. Forty percent of nosocomial infections occur in the urinary
      tract, and greater than 80% of these infections are secondary to an indwelling
      urethral catheter. Fortunately, the majority of catheters are left indwelling for
      a short period of time. The duration of catheterization is directly related to
      the development of bacteriuria, nosocomial infection, and possible bacteremia
      with sepsis. A relatively low percentage of patients become infected during the
      first 3 to 5 days if sterile technique and proper maintenance of a closed system
      are performed. Bacteria may grow in the urine (planktonic) and ascend via the
      lumen, or bacteria in the biofilm around the outside of the catheter may infect
      the bladder. Most organisms are from the patient's intestinal flora, but
      exogenous sources on or near the patient may be involved. The major morbid events
      associated with the catheter are fever and the possible progression to bacteremia
      and sepsis. Early recognition of complications and arresting their progression,
      especially in the high-risk patient, are essential. Current research is directed
      at developing ways to reduce infection beyond the sterile closed system.

PMID- 10584623
TI  - Management of prosthesis infections in urologic surgery.
AB  - Prosthetic devices are a cornerstone of urologic surgical care. The most
      disastrous complication of these surgical procedures is infection. The
      prevention, identification, and management of infections are critical to
      maintaining functional urologic prosthetic devices. Although the incidence is
      low, rapid identification of infections once they occur and proper management
      with antibiotics, surgical intervention, irrigation, and salvage procedures can
      maintain the function of urologic prosthetic devices despite clinical infection.

PMID- 10584624
TI  - Fournier's disease.
AB  - Fournier's gangrene is an aggressive synergistic fasciitis of the perineum. The
      disease can no longer be considered to be idiopathic; in most cases a urologic,
      colorectal, or cutaneous source can be identified. Despite antibiotics and
      aggressive debridement, the mortality rate remains high, particularly in the
      elderly, in patients with renal failure, and in patients with extensive disease.
      The presentation is highly variable, necessitating a high index of suspicion.
      High-risk patients include diabetics, alcoholics, and debilitated and
      immunosuppressed individuals. As the AIDS population increases, the incidence of
      Fournier's gangrene may increase as well. In questionable cases, imaging
      modalities should be performed to allow early diagnosis and to reduce missed
      diagnoses. Broad-spectrum antibiotics and aggressive debridement remain the
      hallmarks of treatment. Hyperbaric oxygen therapy and improved local wound care
      may decrease the extent of tissue destruction. Reconstructive techniques afford
      better cosmetic results. With early recognition, prompt treatment, improved wound
      care, and reconstructive efforts, the mortality rates and cosmetic results should
      continue to improve.

PMID- 10584625
TI  - Early ovarian carcinoma surgical staging and prognostic factors.

PMID- 10584626
TI  - Total abdominal hysterectomy: a randomized study comparing two techniques.
AB  - BACKGROUND: Abdominal hysterectomy is the most frequent operation performed by
      gynecologists. The most commonly used techniques are intrafascial, extrafascial
      and supracervical hysterectomy; in our department we mainly use the first method.
      A variant of this technique, because during the operation we use only an Allis
      clamp, simplifies the operation and maintains certain anatomical relationships
      between neighbouring pelvic structures. METHODS: To compare two different
      surgical techniques between 1/1/1991 and 31/12/95, 262 women were randomized pre
      operatively: 133 by the intrafascial technique of Richardson and 129 by the
      variant hysterectomy technique. The difference between the two techniques
      (Richardson versus variant hysterectomy technique), as performed in our
      department, was investigated regarding the clamping of uterine vessels, the
      resection of uterosacral and cardinal ligament. The two-tailed student test was
      used for continuous data and chi2 analysis for discrete data. RESULTS: Less blood
      loss occurred in the variant than in the Richardson group (P<0.01) and no
      intrasurgical complications occurred as compared to one case of ureter lesion in
      the Richardson group. There were no differences in the number of days of
      hospitalization. No particular post-surgical complications occurred in the follow
      up period, which has now elapsed. After 36 months of follow-up the variant group
      showed a reduced incidence (not significant) of vaginal vault prolapse. The
      patients who underwent the variant hysterectomy technique reported better
      compliance with regard to sexual intercourse and urinary function than the
      Richardson group. CONCLUSION: We conclude that the variant hysterectomy technique
      is as valid as the Richardson technique, giving the surgeon the possibility of
      maintaining certain anatomical relationships between neighbouring pelvic
      structures. It also has minor delayed complications.

PMID- 10584627
TI  - Uterine curettage following second trimester abortion by extraovular instillation
      of prostaglandin E2. A prospective-randomized trial.
AB  - OBJECTIVE: To evaluate the benefits associated with routine uterine curettage
      following complete second trimester termination of pregnancy by extraovular
      prostaglandin E2. STUDY DESIGN: Fifty-five patients between 15 and 24 weeks'
      gestation who had undergone complete termination of pregnancy by continuous
      extraovular instillation of prostaglandin E2 (PGE2), were randomly assigned into
      either no further intervention (n=25), or uterine curettage under general
      anesthesia (n=30). The need for late uterine curettage, clinical and
      ultrasonographic parameters at 1 and 42 days follow-up, as well as the incidence
      of the minor and major complications, were compared between groups. RESULTS:
      Baseline and post-abortion clinical and ultrasonographic characteristics were
      similar in both groups. Mean (+/- Standard error of the mean) number of post
      abortion bleeding days in the curettage group was 8.9+/-1.8 versus 10.1+/-2.6
      days in the non-curettage group (P=NS). No patient in the former group, compared
      to three patients in the latter group, needed late uterine curettage, (P=NS).
      Major and minor complications rates in the curettage and in the no-curettage
      groups were not significantly different. Considerably more patients in the
      curettage group needed analgesic agents following the abortion compared to the no
      curettage group (60% vs. 3.3%, respectively; P<0.001). CONCLUSIONS: Routine
      uterine curettage in patients undergoing complete second trimester termination of
      pregnancy by extraovular instillation of PGE2, exerts no benefit.

PMID- 10584629
TI  - Nonlinear analysis of biomagnetic signals recorded from the umbilical artery in
      normal and pre-eclamptic pregnancies.
AB  - OBJECTIVE: In this study we investigated the hemodynamics of the feto-placental
      circulation in normal and pre-eclamptic near term pregnancies using the
      biomagnetometer SQUID. Thirteen abnormal and 25 normal pregnancies were included
      in this study. STUDY DESIGN: The biomagnetic signals were analyzed using
      nonlinear analysis in order to differentiate these two types of pregnancies.
      RESULTS: The application of nonlinear analysis reveal a clear saturation
      dimension value for pre-eclamptic and non-saturation for normal pregnancies.
      These findings were statistically significant and were correlated with fetal
      heart rate monitoring, pH and Apgar score: high biomagnetic cases (140-300
      fT/square root Hz) were related with normal patterns, pH>7.25 and Apgar >7, while
      low biomagnetic recordings (50-110 fT/square root Hz) were connected with
      abnormal patterns, pH<7.25 and Apgar <7. CONCLUSIONS: It is suggested that the
      biomagnetic measurements with SQUID and the application of nonlinear analysis, is
      a promising procedure in assessing fetal health, especially in high risk
      pregnancies.

PMID- 10584628
TI  - Risk factors associated with early-onset sepsis in premature infants.
AB  - OBJECTIVE: To define perinatal factors associated with early-onset neonatal
      sepsis. STUDY DESIGN: Maternal and neonatal variables were analysed
      retrospectively in 343 infants born before 35 weeks using univariate and
      multivariate statistical analysis. RESULTS: Logistic regression analysis
      identified risk factors for probable neonatal sepsis: gestational age at delivery
      (odds ratio 0.9, 95% confidence interval (CI) 0.91-0.96), premature rupture of
      the membranes (odds ratio 2.9, 95% CI 1.004-8.56), Apgar score after 1 min (odds
      ratio 0.7, 95% CI 0.53-0.96), and histological chorioamnionitis and/or funisitis
      (odds ratio 4.1, 95% CI 1.36-12.12). There was a strong association between
      probable sepsis and intracranial haemorrhage of the infant (odds ratio 4.3, 95%
      CI 1.07-17.40). Funisitis had a high specificity (91%) and positive predictive
      value (82%) for the detection of neonatal sepsis < or =32 weeks. CONCLUSIONS:
      Independent obstetrical risk factors for early-onset neonatal sepsis in premature
      infants may help to identify newborns who benefit from maternal antibiotic
      prophylaxis before birth. The histological examination of the umbilical cord can
      be used as an additional diagnostic test to detect newborns at risk of infection.

PMID- 10584630
TI  - Interobserver variability of the neurological optimality score.
AB  - OBJECTIVE: To assess the interobserver reliability of the neurological optimality
      score. STUDY DESIGN: The neurological optimality score of 21 full term healthy,
      neurologically normal newborn infants was determined by two well trained
      observers. RESULTS: The interclass correlation coefficient was 0.31. Kappa for
      optimality (score of 58 or higher) was 0.19. A systematic difference of 1.3
      points between the two observers was present. CONCLUSIONS: The interobserver
      variability of the neurological optimality score of the newborn infant is
      substantial. The subtle judgement of elicited responses as optimal or non-optimal
      proved to be especially critical in this concordance study. A difference of at
      least two points in the score is considered as a valid endpoint for comparative
      studies. If two or more observers are involved in the neurological examination of
      the newborn infant in a study to assess influences on perinatal morbidity,
      frequent re-instruction sessions are recommended.

PMID- 10584631
TI  - Brachmann-de Lange syndrome: a cause of early symmetric fetal growth delay.
AB  - Brachmann-de Lange syndrome is characterized by pre- and postnatal growth
      retardation, microbrachycephaly, hirsutism, various visceral and limb anomalies
      and a typical face. A sonographic prenatal diagnosis at mid-trimester is reported
      in a case of severe, symmetrical fetal growth delay at 20 weeks gestation, with a
      thickened skin on the forehead, a small nose and a marked depressed nasal bridge,
      a long philtrum, micrognathia and a persistently flexed right forearm, with a
      single bone associated to oligodactyly. Due to the severe mental impairment with
      a commonly estimated intelligence quotient under 60, the pregnancy was terminated
      after parental consent.

PMID- 10584632
TI  - Severe uterine diastolic notch as a prognostic factor in preeclamptic women.
AB  - OBJECTIVE: To investigate the usefulness of grade II uterine diastolic notch to
      predict maternal or perinatal outcome during conservative management of
      preeclampsia. STUDY DESIGN: We reviewed medical charts of 35 pregnant women
      admitted for hypertension and > or =1+ urine dipstick protein determination and
      who had a uterine Doppler examination at admission. Grade I notch was defined as
      a 'nadir' in early diastole higher than half of peak diastolic notch velocity.
      Grade II diastolic notch was defined as a 'nadir' in early diastole lower than
      half of peak diastolic notch velocity. RESULTS: Thirty-one preeclamptic women
      were admitted at 30.1+/-3 weeks. Of them, 23 had a grade I notch (group I) and
      eight a grade II notch (group II). Rates of abruptio placenta, eclampsia,
      thrombocytopenia, stillbirth, birth weight < or = 3rd centile, fetal distress
      before delivery and neonatal death were similar in the two groups. Rates of
      delivery before 32 weeks and newborn spending more than 48 h in neonatal
      intensive care unit were significantly higher in group II. Admission-to-delivery
      interval was significantly lower in group II (2.6+/-1.5 vs. 9.4+/-8.7 days,
      P<0.05). CONCLUSION: Grade II notch seems to identify in preeclamptic women those
      with a higher risk of early pregnancy termination.

PMID- 10584633
TI  - Cerebral MRI on fetuses submitted to repeated cocaine administration during the
      gestation: an ovine model.
AB  - The aim of this study was to determine the role of Magnetic Resonance Imaging
      (MRI) in investigating fetal cerebral lesions induced by long term exposure to
      cocaine during sheep pregnancy. Cerebral Magnetic Resonance Imaging was performed
      on two groups of fetuses at 125 days of gestation (normal gestation: 145 days).
      The control group consisted of eight fetuses of four pregnant ewes. The study
      group consisted of eight fetuses of four pregnant ewes receiving daily 140 mg/kg
      injection of cocaine from day 60 until delivery. The following MR sequences were
      applied: T1-weighted FLASH, and T2-weighted Fast-Spin-Echo. Cerebral images were
      evaluated semi quantitatively using the following criteria: Heterogenicity,
      contrast between grey and white matter, contours irregularity, hyposignal,
      lateral ventricle sizes. The brightness distribution and homogenicity of the
      images were analysed by means of edge pair distributions using a new computerized
      method originally designed for ultrasound images analysis developed by Ultrasight
      inc (USA). (1) Flash T1: Heterogenic areas and irregular contours were more
      frequent in cocaine exposed fetuses. The contrast between grey and white matter
      was more important in the cocaine group. Hyposignal was found only in the cocaine
      group. Enlarged lateral ventricle occurred more frequently in the cocaine group.
      (2) Spin echo T2: The contrast between grey and white matter was higher and the
      contours of the brain more irregular in the cocaine group. Heterogenicity and
      hyposignal were also more frequent in this group but the difference with the
      control group was not significant. The computerized analysis of the contrast
      density on the cerebral images showed that 88% of the areas exceeding the
      reference level concerned the cocaine group, while only 14% of the areas
      exceeding the reference level concerned the control group. Long term exposure to
      cocaine induces cerebral tissue modifications, in favor of an advanced maturation
      and the development of hypoxic lesions. The histology of the brains confirmed in
      the cocaine group, the existence of hypoxic lesions with gliosis, perivascular
      edema and hemorrhages, and neuronal death.

PMID- 10584634
TI  - Routine prenatal care in Europe: the comparative experience of nine departments
      of gynaecology and obstetrics in eight different countries.
AB  - OBJECTIVE: The aim of this study was to compare routine prenatal care in nine
      European obstetrics and gynaecology departments. STUDY DESIGN: A survey was
      performed between October 1992 and November 1993 by means of a questionnaire. The
      questionnaire comprised 118 questions covering clinical examinations and
      investigations systematically performed during the pregnancy. RESULTS: The survey
      revealed a certain number of differences between the types of prenatal care
      performed by each department. Thus, one notices differences to do the serological
      testing (toxoplasmosis, AIDS and hepatitis B) at the first visit and in the
      practice of vaginal examination, systematic ultrasound examination or
      cardiotocography. CONCLUSION: The differences observed in the prenatal care
      furnished are only a reflection of our uncertainties concerning the validity of
      the various tests used to monitor pregnancies. At a time when financial
      restrictions impose choices, we consider an evaluation of the efficacy and cost
      of prenatal care to be essential.

PMID- 10584635
TI  - Pulsatile vs. continuous parenteral tocolysis: comparison of side effects.
AB  - Bolus tocolysis has been developed to reduce the dose of fenoterol compared to
      continuous tocolysis. Whereas the high efficacy of pulsatile application of
      fenoterol has been shown, the proof of reduced side effects is still lacking. A
      total of 59 patients with preterm labor were divided in three groups: (1)
      continuous tocolysis and oral application of magnesium (n=19), (2) continuous
      tocolysis and parenteral application of magnesium (n=20), (3) pulsatile tocolysis
      (bolus tocolysis) and oral application of magnesium (n=20). Heart rate, systolic
      and diastolic blood pressure, serum K+ and serum Mg++ were quantified before
      tocolysis and after 2, 8 and 24 h. Beta-blockers and water balance were recorded
      over 24 h. Subjective side effects were quantified using a questionnaire with
      scales graduated covering palpitations, tremor, diaphoresis, thirst,
      precardialgia and nausea/vomiting. The analysis of the data revealed
      significantly fewer side effects concerning heart rate, plasma K+ level and the
      subjective side effects among patients treated with bolus tocolysis than among
      those treated with continuous tocolysis. Between the latter two groups, no
      significant difference was found. Concerning blood pressure and need for beta
      blockers, no significant differences were found between the three groups. The
      results of the present study show that especially the side effects subjectively
      found to be disagreeable by the patients are reduced by pulsatile tocolysis,
      whereas other side effects show only slight differences between the study groups.

PMID- 10584636
TI  - Lipid peroxidation and antioxidants in preeclampsia.
AB  - OBJECTIVE: To determine the changes in plasma levels of lipid peroxide, vitamin E
      and vitamin C in women with preeclampsia and to investigate their relationship
      with diastolic blood pressure. STUDY DESIGN: Cross sectional study consisting of
      22 preeclamptic and 21 healthy pregnant women. Fasting venous blood samples were
      collected during the antepartum period and plasma levels of malondialdehyde,
      alpha-tocopherol and ascorbic acid were measured. RESULTS: In the preeclamptic
      group malondialdehyde, a lipid peroxidation product, was significantly increased,
      while vitamins E and C were significantly decreased compared to healthy pregnant
      women. A strong correlation was detected between malondialdehyde and antioxidant
      factors (vitamins E and C) with blood pressure. CONCLUSION: Our findings are
      consistent with previous studies suggesting that lipid peroxidation is an
      important factor in the pathogenesis of preeclampsia. In preeclampsia,
      antioxidant nutrients are excessively utilised to counteract the cellular changes
      mediated by free radicals.

PMID- 10584637
TI  - Amniotic fluid nitric oxide metabolites, cyclic guanosine 3',5' monophosphate and
      dimethylarginine in alloimmunized pregnancies.
AB  - OBJECTIVE: To determine the relationship between gestational age or the Liley
      index (the severity of fetal hemolysis) and the amniotic fluid total nitrite
      (NOx), cyclic guanosine 3',5 'monophosphate (cGMP) and dimethylarginine (DMA)
      concentrations. We hypothesized that the concentrations of these components
      change because of fetal growth or adaptation to fetal anemia. STUDY DESIGN:
      Amniotic fluids (n=64) were obtained between 23 and 37 weeks from fifty-three
      patients at risk for alloimmunization. Amniotic fluids from the pregnancies with
      a Liley index=1 were considered as controls (n=17). Creatinine (C, microMol) was
      determined with the Jaffe reagent, nitrite (NOx, microMol) with the Griess
      reagent, cGMP (nMol) by an enzyme immunoassay and DMA (microMol) after HPLC.
      Multiple regression analysis was used for separating the effects of growth and
      the estimated degree of anemia. RESULTS: The concentration of NOx, cGMP and DMA
      was not related to the Liley index or whether or not the fetuses needed blood
      transfusions. The concentrations of creatinine (C), NOx and cGMP increased during
      pregnancy (in weeks;W) (C=-69.2+6.28W; r2=0.532; P<0.0001, NOx=-17.6+1.29W;
      r2=0.106; P=0.01, cGMP=-20.9+1.05W; r2=0.414; P<0.0001). The DMA concentration
      (3.8+/-0.8(SD) and the NOx/creatinine ratio (181+/-110 mM/M) did not change with
      gestational age. The cGMP/creatinine ratios (microM/M) increased (cGMP/C=
      41.8+4.31W; r2=0.134; P=0.007) whereas the DMA/creatinine ratio (mM/M) declined
      during pregnancy (DMA/C=73.1-1.34W; r2=0.278; P=0.0002). Consequently, the
      NOx/DMA and cGMP/DMA ratios increased (NOx/DMA=-6.96+0.43W; r2=0.105; P=0.02,
      cGMP/DMA=-5.9+0.29W; r2=0.391; P<0.0001). CONCLUSIONS: The concentrations in
      amniotic fluid of cGMP and NOX, but not of DMA increase during gestation. The
      cGMP/creatinine ratio increases also whereas that of DMA decreases. The changes
      in products of the NO-cGMP pathway are independent of mild to moderate fetal
      hemolysis and may result from fetal growth as well as from reduced inhibition of
      NO synthase by DMA. Gestational age related effects should be taken into account
      when analyzing nitric oxide metabolites in amniotic fluids.

PMID- 10584638
TI  - Conception and pregnancy in several examples from Croatian sacral patrimony.
AB  - Starting from the viewpoint of the history of medicine, the authors analyze the
      themes of conception and pregnancy in examples from canonical and apocryphal
      iconography of the lives of Mary and Jesus. St. Anne's and St. Joachim's
      assignation and kiss at the Golden Portal is a symbolic moment of St. Mary's
      conception. Jesus' conception has been represented in the theme of the
      Annunciation. The physical perception of pregnancy is experienced by St. Mary in
      the Visitation to Elizabeth. Several paintings, wall paintings and mosaics
      created in the area of today's Croatia in the period from the 6th to the 17th
      centuries were chosen for explicit illustration of the themes.

PMID- 10584639
TI  - Decision-making in the colposcopy clinic--a critical analysis.
AB  - OBJECTIVE: To consider the omission of several diagnostic steps from the
      management of patients with high-grade squamous intraepithelial lesion (SIL) by
      analyzing the role of each step on the choice of treatment. STUDY DESIGN: Each
      diagnostic procedure was correlated to the treatment and outcome in 87 women with
      high-grade SIL. Treatments considered were large loop excision of the
      transformation zone (LLETZ) cold knife conization, and CO2 laser vaporization.
      RESULTS: Unsatisfactory colposcopy (P< or =0.01) and positive endocervical
      curettage (ECC) specimen (P< or =0.01) were essential for choice of treatment.
      CIN2 diagnoses of the preoperative cervical biopsy were rediagnosed as CIN3 based
      on the surgical specimen in 57% of the cases. The margins of 33 and 23% of
      surgical specimens removed by LLETZ or knife conization, respectively, displayed
      CIN involvement. Forty and 47% of these patients, respectively, later developed
      recurrent CIN. CONCLUSIONS: Omission of colposcopy and ECC could have resulted in
      sub-optimal treatment in many cases. Excision by LLETZ or knife conization is
      recommended for cases of CIN2 and CIN3. Follow up is imperative for patients with
      involvement of the margins.

PMID- 10584640
TI  - Anaerobic glycolysis. The metabolism of the preovulatory human oocyte.
AB  - OBJECTIVES: The aim of the study was to investigate the process of glycolysis in
      gonadotropic, hyperstimulated, human ovarian follicles. STUDY DESIGN: Follicular
      fluid (FF) lactate and glucose concentrations were measured in 26 patients with
      tubal factor infertility undergoing in vitro fertilization treatment. RESULTS:
      The mean FF lactate and glucose concentrations were 3.17+/-0.90 mM with positive,
      and 3.39+/-0.91 mM with negative correlations to follicular size. FF lactate
      concentration correlated negatively to glucose levels. CONCLUSIONS: Our study
      confirms in vivo the anaerobic glycolysis in gonadotropic, hyperstimulated human
      ovarian follicles.

PMID- 10584641
TI  - May-Hegglin anomaly and pregnancy.
AB  - A hypertensive patients with thrombocytopenia is reported who had two pregnancies
      complicated by preeclampsia and cesarean deliveries without hemorrhage. During
      her first pregnancy corticosteroids were given for presumed autoimmune
      thrombocytopenia. Thereafter she was splenectomised. Ten years later May-Hegglin
      anomaly and renal failure were diagnosed. One of her children had easy bruising.

PMID- 10584642
TI  - Corticosteroid therapy for conservative management in marginally-viable pregnancy
      complicated by HELLP syndrome.

PMID- 10584643
TI  - Uterine fibroid embolization: measurement of health-related quality of life
      before and after therapy.
AB  - OBJECTIVE: To determine the change in health-related quality of life associated
      with uterine fibroid embolization (UFE). MATERIALS AND METHODS: A health-related
      quality-of-life questionnaire was administered before and after therapy. The
      questionnaire contained validated scales from the Medical Outcomes Study, with
      additional domains and symptom items specific to fibroids. Patients treated with
      UFE for symptomatic uterine leiomyomata completed a health-related quality of
      life questionnaire before therapy. A follow-up quality of life questionnaire and
      an additional brief questionnaire to assess symptom improvement were completed 3
      and 6 months postprocedure. Confirmatory reliability and validity testing was
      also conducted. Mean scores for each scale on the quality of life questionnaire
      were calculated and change scores were computed. RESULTS: Fifty women were
      enrolled in the study and completed the baseline assessment. Health-related
      quality of life scores improved in all instances at follow-up. Mean change scores
      were statistically significant for all domains between baseline and month 3 (P <
      .01) and between baseline and month 6 (P < .05) except backache (P = .12).
      CONCLUSION: Patients undergoing UFE report significant improvements in health
      related quality of life and fibroid-specific symptoms. These findings suggest
      that the measurement of health-related quality of life may be an effective means
      of comparing the outcome of UFE with other fibroid therapies.

PMID- 10584644
TI  - MR imaging-guided percutaneous nephrostomy and use of MR-compatible catheters in
      the nondilated porcine urinary tract.
AB  - PURPOSE: To investigate technique and practicability of MR-guided percutaneous
      nephrostomy (MRPCN) and to test magnetic resonance (MR)-compatible catheters
      inside the urinary tract. MATERIALS AND METHODS: In 10 healthy pigs, a
      percutaneous nephrostomy tube was placed into the nonobstructed pelvicaliceal
      system with use of exclusive MR guidance with a standard 1.5-T magnet. The
      urinary tract was visualized by intravenous injection of Gd-DTPA in combination
      with low-dose furosemide. The procedure was controlled with use of a T1-weighted
      turbo gradient-echo sequence in two orthogonal planes. The equipment for MRPCN
      included an 18-gauge MR-compatible puncture needle, a nitinol guide wire, and
      different 5-F MR catheters. RESULTS: In all 10 animals, the puncture needle was
      safely directed into the nondilated target calix. Slight deviations of the needle
      were detected on both MR image planes, which enabled immediate correction. This
      technique achieved a "first attempt" puncture of the targeted calix in each
      animal. MR images accurately demonstrated the dysprosium labelled tip of the
      different inserted catheters. It proved essential to inject a gadolinium-insaline
      solution via these catheters to preserve the endoluminal contrast enhancement as
      long as necessary. Balloon catheters were directed and inflated inside the ureter
      under exclusive MR guidance. Complications such as perforation and leakage were
      visualized by MR imaging. CONCLUSIONS: MRPCN is a promising technique for
      puncturing the pelvicaliceal system. The ability to successfully enter the
      urinary tract, even when it is nondilated, underscores the accuracy achievable
      with multiplanar MR imaging.

PMID- 10584645
TI  - Intraarterial gadolinium-enhanced 2D and 3D MR angiography: a preliminary study.
AB  - PURPOSE: To evaluate, in phantom and canine models, intraarterial gadolinium
      enhanced two-dimensional (2D) and three-dimensional (3D) magnetic resonance
      angiography (MRA). MATERIALS AND METHODS: The in vitro experiments examined
      gadodiamide solutions ranging in gadolinium (Gd) concentration from 0.1% to 100%.
      A spoiled gradient-recalled echo (SPGR) sequence was used with various repetition
      time/echo time (TR/TE) parameters. Signal was measured to determine which
      concentration yielded the highest signal. For in vivo experiments, pigtail
      catheters were placed in the abdominal aortae of two dogs. Intraarterial
      injections of 20-30 mL of 0.5%-25% Gd solutions were performed. We acquired
      images with use of 2D and 3D SPGR techniques. Depiction of the abdominal aortae
      and renal vessels was assessed qualitatively and quantitatively. RESULTS: Phantom
      experiments demonstrated that a 2%-6% solution of Gd produced the highest MR
      signal, depending on the imaging parameters. In the canine model, a 2% Gd
      solution was best for 2D techniques, whereas 7%-14% Gd solutions were optimal for
      3D techniques. CONCLUSIONS: Intraarterial contrast material-enhanced 2D and 3D
      MRA can be successfully implemented with use of dilute Gd. Dilution permits the
      administration of more intraarterial injections per day, without exceeding the
      dose limit, compared with intravenous Gd-enhanced MRA. Intraarterial injections
      also limit scan synchronization and contrast material dispersion issues. This
      technique may have application in MR-guided endovascular procedures.

PMID- 10584646
TI  - Diagnostic yield of MR-guided liver biopsies compared with CT- and US-guided
      liver biopsies.
AB  - PURPOSE: To compare diagnostic yield and complication rates of magnetic resonance
      (MR)-guided versus computed tomography (CT)- and ultrasound (US)-guided liver
      biopsies. MATERIALS AND METHODS: MR-, CT-, and US-guided liver biopsies performed
      between 9/96 and 9/98 were compared. Sixty patients (21 men and 39 women, mean
      age 60 years) underwent MR-guided biopsy of liver lesions. Thirty patients (16
      men and 14 women, mean age 59 years) underwent CT-guided biopsy. Eighteen
      patients (seven men and 11 women, mean age 50 years) underwent US-guided biopsy.
      MR procedures were performed in an open-configuration 0.5-T Signa SP MR unit.
      Lesion localization used standard T1 and T2 sequences, whereas biopsies were
      performed with multiplanar spoiled gradient recalled echo and fast gradient
      recalled echo sequences. A coaxial system with an MR-compatible 18-gauge
      stabilizing needle and a 21-gauge aspiration needle was used to obtain all
      samples. In CT and US procedures, a 19-gauge stabilizing needle and a 21-gauge
      aspiration or a 20-gauge core biopsy needle were used. A cytotechnologist was
      present to determine the adequacy of samples. RESULTS: MR had a diagnostic yield
      of 61%. CT and US had diagnostic yields of 67% and 61%, respectively. No serious
      complications were reported for MR and US procedures. Two CT biopsies resulted in
      postprocedural hemorrhage. One patient required surgical exploration and died.
      CONCLUSIONS: MR-guided biopsy of liver lesions with use of a 0.5-T open
      configuration magnet is safe and accurate when compared with CT and US. No
      statistical difference was observed between the diagnostic yield of biopsies
      performed with MR, CT, and US guidance. MR enabled biopsy of a number of lesions
      in the hepatic dome and lesions with low contrast, which would normally be
      difficult to sample safely with use of CT or US.

PMID- 10584648
TI  - Continuous arterial infusion therapy for severe acute pancreatitis: correlation
      between CT arteriography and therapeutic effect.
AB  - PURPOSE: This study evaluates the relationship between the therapeutic effect of
      arterial infusion therapy for severe acute pancreatitis and drug distribution on
      CT-arteriography (CTA). MATERIALS AND METHODS: Eleven patients with severe acute
      pancreatitis were treated by arterial infusion with use of protease inhibitor and
      antibiotics. Ten patients had an inflammation of the entire pancreas, while one
      had pancreatitis localized to the body and tail of the pancreas. The arterial
      infusion drugs were infused into the celiac artery, splenic artery, inferior
      pancreaticoduodenal artery, and common hepatic artery. The drug distributions
      were evaluated by CTA in 10 patients. The duration of arterial infusion ranged
      from 3 to 39 days. The relationship between the distribution on the CTA and the
      change in clinical grading of pancreatitis as evaluated by an APACHE II score was
      studied. RESULTS: Of the nine patients with inflammation of the entire pancreas,
      six showed the distribution of contrast material to the entire area of pancreatic
      inflammation (a good distribution) on the CTA, and the remaining three did not
      show the distribution of contrast material to cover the entire area of pancreatic
      inflammation (a poor distribution). One patient with localized pancreatitis
      showed a good distribution. In seven patients with a good distribution, the
      APACHE II score was decreased from 11.7 points to 4.3 points during follow-up. In
      the remaining three patients with a poor distribution, the APACHE II score was
      decreased from 12.3 points to nine points, but was decreased to five points after
      the additional interventions. One patient without CTA showed a marked improvement
      in the APACHE II score. No clinically important complications were observed.
      CONCLUSION: The present study findings suggest that arterial infusion is
      effective in the treatment of severe acute pancreatitis. A good drug distribution
      to the area of inflammation is needed to ensure a proper therapeutic effect.

PMID- 10584647
TI  - Weekly prophylactic urokinase instillation in tunneled central venous access
      devices.
AB  - PURPOSE: To determine the safety and efficacy of weekly prophylactic urokinase
      therapy in tunneled central venous access devices (VADs). MATERIALS AND METHODS:
      A prospective, randomized study was performed in 105 patients who underwent
      tunneled VAD placement between March 1997 and April 1998. The patients were
      randomized to receive either twice-daily heparin flushes (14 heparin flushes per
      week; group A, n = 52) or twice-daily heparin flushes with once-weekly urokinase
      (UK) instillation (13 heparin flushes, one UK flush per week; group B, n = 53).
      Patients were followed up by examination and/or interview at 1, 3, and 6 months
      for signs and symptoms of delayed catheter-related complications. RESULTS: The
      total number of indwelling catheter-days was similar between groups (5,450 in
      group A, 5,276 in group B). The total number of infectious complications and
      fibrin sheaths formed was greater for group A (n = 11; 21.1%) than group B (n =
      3; 5.7%) (P = .02). There were no side effects noted from the prophylactic UK
      administrations. CONCLUSION: Prophylactic UK is advantageous in preventing
      delayed catheter-related complications.

PMID- 10584649
TI  - Analysis of radiation scatter during angiographic procedures: evaluation of a
      phantom model and a modified radiation protection system.
AB  - PURPOSE: To study the radiation scattering associated with the digital
      subtraction angiography (DSA) unit in angiographic procedures and to design an
      effective radiation protection shield based on these data. MATERIALS AND METHODS:
      The number of scattered photons was measured at three points relative to the
      operator's position. Anteroposterior abdominal and lateral cranial fluoroscopy
      were evaluated. As protective devices, a lead curtain, sliding shields, and a
      brim-shaped image intensifier (II) hood were designed. RESULTS: In abdominal
      fluoroscopy, radiation was found to scatter to the operator's lower limbs from
      the underside of the catheter table, to the abdomen from the side of the
      patient's body, and to the head and neck from the table surface adjacent to the
      patient. The use of protective devices reduced exposure from 2.89 to 0.058 mR/min
      for the operator's lower limbs, from 0.987 to 0.069 mR/min for the operator's
      abdomen, and from 0.696 to 0.139 mR/ min for the operator's head and neck area.
      With lateral cranial fluoroscopy, radiation was detected to scatter to the
      operator's lower limbs from the underside of the catheter table, to the abdomen
      from the patient's temporal area, and to the head and neck from the patient's
      face. The use of protective devices reduced exposure from 0.248 to 0.010 mR/min
      for the operator's lower limbs, from 0.129 to 0.010 mR/min for the operator's
      abdomen, and from 0.162 to 0.018 mR/min for the operator's head and neck area.
      CONCLUSIONS: The characteristic directions of scattering to the operator were
      identified. An effective modified radiation protection system was designed based
      on this information.

PMID- 10584650
TI  - Cutaneous complications of hepatic chemoembolization via extrahepatic
      collaterals.
AB  - PURPOSE: To report cutaneous complications occurring after chemoembolization of
      hepatic tumors via extrahepatic collaterals. METHODS: Five patients underwent
      chemoembolization via the internal mammary (n = 3), intercostal (n = 1), or
      multiple extrahepatic collateral vessels supplying liver metastases. RESULTS:
      Painful induration and discoloration of the skin in the distribution of the
      superior epigastric or intercostal arteries occurred in four patients, with
      transmural necrosis in two. One required surgical excision. One patient developed
      a radiation burn after 12 procedures and eventually developed a squamous cell
      carcinoma at the site, which required resection and skin grafting. CONCLUSION:
      Cutaneous injury can occur after chemoembolization of extrahepatic collaterals.
      Scrupulous technique is required to avoid nontarget embolization of
      chemotherapeutic drugs. High cumulative radiation doses to localized areas of
      skin can occur in patients undergoing multiple procedures.

PMID- 10584651
TI  - Selective transcatheter hepatic arterial chemoembolization for hemobilia from
      hepatocellular carcinoma: report of three cases.

PMID- 10584652
TI  - Polyarteritis nodosa presenting as spontaneous perirenal hemorrhage: angiographic
      diagnosis and treatment with microcoil embolization.

PMID- 10584653
TI  - US-guided percutaneous catheter drainage of a deep retropharyngeal abscess.

PMID- 10584654
TI  - Stent-grafts for de novo TIPS: technique and early results.
AB  - PURPOSE: To evaluate the potential benefits of placing a polytetrafluoroethylene
      (PTFE)-covered stent-graft during initial creation of a transjugular intrahepatic
      portosystemic shunt (TIPS) in clinical practice. MATERIALS AND METHODS: De novo
      TIPS were created with a PTFE stent-graft in four male and four female patients
      with symptomatic portal hypertension awaiting liver transplant. Their ages ranged
      from 35 to 62 (mean, 47) years. Patients were followed with TIPS ultrasound (US)
      and/or venography until liver transplantation or death; one remains under active
      study. Six recovered specimens underwent gross and microscopic evaluation.
      RESULTS: All TIPS placements were successful. Six shunts were primarily patent,
      with a mean patency of 289 days, through completion of the study. Five were found
      to be patent at transplant and one was found to be patent at autopsy. Explant
      evaluation revealed a smooth, thin layer of neointima and exclusion of biliary
      secretions. Three patients developed a total of four stenoses (one tandem lesion)
      during follow-up, leading to revision in two patients. Mean primary and total
      patency in these patients was achieved after 279 and 463 days, respectively. A
      previously occult moderate stenosis was detected after explant in another
      patient. Only one (nonsignificant) stenosis clearly developed in an area covered
      by PTFE. CONCLUSION: Placement of a de novo PTFE stent-graft during TIPS creation
      is feasible and may extend primary shunt patency. Appropriate positioning of the
      stent-graft is critical.

PMID- 10584655
TI  - Stent placement of gastroenteric anastomoses formed by magnetic compression.
AB  - PURPOSE: To evaluate the use of stents for prolonging the patency of
      gastroenteric anastomoses (GEA) induced by magnet compression. MATERIALS AND
      METHODS: Rare earth magnets were inserted perorally and serially in 15 dogs so as
      to mate across the gastric and jejunal walls. After magnet excretion, the
      resulting GEA was identified endoscopically, dilated (n = 1), and stented with
      bare (n = 2) or partially covered (n = 6) flared 10-mm or 12-mm Z stents. The GEA
      was followed at 2-4-week intervals for patency; malfunctioning shunts were
      irrigated, or dilated with angioplasty balloons. Gross and histologic examination
      of the anastomotic tissues was performed in 14 animals. RESULTS: Magnet pairs
      were excreted in 5-7 days. Of the 19 magnet placements in 15 animals, stent
      placement was not possible because of early GEA closure (n = 6), failure to
      locate (n = 2), pancreatic abscess (n = 1), and magnet perforation with
      peritonitis (n = 1). Estimated duration of GEA patency was 19 days after balloon
      dilation, 40-64 days with bare Z stents, and 58-147 days (mean, 90 days) with
      partially covered Z stents. Shunt function was commonly hindered by bezoars.
      Stent narrowing or occlusion was caused by tissue overgrowth through bare stents
      (n = 2), between covered stent struts and through partially detached membrane (n
      = 2). Serious morbidity (n = 2) was due to malpositioned magnets across the
      pancreas in one animal and gastric perforation in the other. One dog was
      euthanized because of unsuspected kidney infection. CONCLUSION: Partially covered
      stents significantly extend the anatomic patency rate of magnetic GEA to 7 weeks
      or more. Functional patency is frequently impaired by bezoars. Ongoing
      improvements in covered stent design should provide longer-term GEA patency.

PMID- 10584656
TI  - Patency and complications of percutaneously inserted metallic stents in malignant
      biliary obstruction.
AB  - PURPOSE: The aim of this study was to analyze the patency of percutaneously
      inserted metallic stents in malignant biliary obstruction and to evaluate all the
      complications associated with the stents and the reinterventions needed.
      MATERIALS AND METHODS: Thirty-nine patients with 42 malignant strictures were
      treated percutaneously with 55 metallic self-expandable stents. Forty-eight were
      Wallstents and seven were Memotherm stents. Twenty-five strictures were hilar, 16
      were in the common bile duct, and one was in the hepaticojejunal anastomosis. The
      patients were followed until death and the mean follow-up was 6.4 months.
      RESULTS: Stent insertion was successful in 97% of the patients. Thirty percent
      had early complications (<30 days), and as many as 66% had late complications,
      including stent occlusions, which were seen in 10 patients. The patency rates of
      patients with cholangio-carcinoma were significantly lower than those of the
      patients with other diagnoses. There was also a tendency toward obstruction with
      less dilation of the stents, Y, T or tandem-style stent placement, an increasing
      number of stents, longer strictures, and hilar strictures. Thirty-one percent of
      the patients alive after the first 30 days had late reinterventions. CONCLUSIONS:
      Although metallic stents offer an alternative in the palliation of malignant bile
      duct obstruction, there seem to be numerous early and late complications.

PMID- 10584657
TI  - Endoluminal biopsy of the bile duct with a biliary manipulation catheter.

PMID- 10584658
TI  - Local administration of ramiprilat is less effective than oral ramipril in
      preventing restenosis after balloon angioplasty in an animal model.
AB  - PURPOSE: To test the hypothesis that local administration of angiotensin
      converting enzyme (ACE) inhibitor via a microporous balloon catheter would be
      more effective than oral administration of ACE inhibitor in preventing neointima
      formation after balloon angioplasty. MATERIALS AND METHODS: Neointima formation
      was induced by balloon denudation followed by 0.5% cholesterol diet in 29 New
      Zealand White rabbits. Directly after denudation, local administration of 1.8 mg
      of ramiprilat (n = 7) or saline (n = 7) with a microporous balloon catheter at a
      pressure of 3 atm was performed. Both groups additionally received ramipril
      orally (1 mg/d). Seven animals were treated exclusively with oral ramipril. The
      control group was fed a 0.5% cholesterol diet and given no medication (n = 8).
      Six weeks after intervention, the animals were killed and morphometric and
      immunohistologic analyses were performed. RESULTS: Oral administration of
      ramipril resulted in a significant reduction of placque area (-66%, P < .05).
      Oral and local administration of the ACE inhibitor was followed by a
      nonsignificant reduction of the neointimal area (-17%). Local administration of
      saline combined with oral ramipril failed to prevent neointimal formation
      (reduction of 6%, NS). CONCLUSION: Oral administration of ramipril resulted in a
      significant reduction of neointimal proliferation in New Zealand White rabbits.
      The possible benefit of an additional administration of local ramiprilat was
      diminished by an excessive neointimal hyperplasia, which was most likely caused
      by the inherent vessel trauma with use of the microporous balloon catheter.

PMID- 10584659
TI  - Reporting standards for percutaneous interventions in dialysis access. Technology
      Assessment Committee.

PMID- 10584660
TI  - Air embolism during tunneled central catheter placement performed without general
      anesthesia in children: a potentially lethal complication.

PMID- 10584661
TI  - Effectiveness and complications of treating neuroendocrine metastases,
      embolization versus chemoembolization.

PMID- 10584662
TI  - A complication of vascular access for hemodialysis-related interventions.

PMID- 10584663
TI  - Levodopa in the treatment of Parkinson's disease: a consensus meeting.

PMID- 10584664
TI  - A video review of the diagnosis of psychogenic gait: appendix and commentary.
AB  - The gait and other clinical features of 22 patients presenting to our hospital
      over the last 10 years are shown on video. In 12 patients, a diagnosis of
      psychogenic gait was made; in the remainder, the gait abnormality was the result
      of a neurologic disease. Psychogenic gaits are compared and contrasted with
      "organic" gaits. In one patient, the psychogenic gait occurred in the setting of
      a neurologic disease. The "traditional" approach to psychogenic gait, attempting
      to exclude underlying neurologic and psychiatric disease and seeking evidence for
      primary and secondary gain, was found to be of limited value. More useful were
      the features of the gait itself, in particular, exaggerated effort, extreme
      slowness, variability throughout the day, unusual or uneconomic postures,
      collapses, convulsive tremors, and distractibility; certain aspects of the
      history were also helpful. A list of comments is provided. The diagnosis of
      psychogenic gait, particularly in the elderly, remains fraught with hazard, and a
      balance has to be sought between subjecting an anxious patient to needless
      investigations and yet not losing sight of the fact that the patient may be
      elaborating on symptoms of genuine disease. The bizarre gait of some neurologic
      disorders, particularly dystonia and chorea, may be a pitfall for the unwary.

PMID- 10584665
TI  - Excessive daytime sleepiness and sleep benefit in Parkinson's disease: a
      community-based study.
AB  - The objective of this study was to investigate the frequency of excessive daytime
      sleepiness (EDS) and the beneficial effect of sleep on motor performance in an
      unselected community-based sample of patients with Parkinson's disease (PD).
      Furthermore, we wanted to identify possible risk factors to these phenomena.
      Detailed information on somnolence and sleep during daytime, as well as sleep
      benefit (SB) on awakening, was collected through a questionnaire among 245
      patients with PD. Daytime somnolence was graded in groups of no somnolence, mild
      daytime sleepiness, and EDS. In addition, the occurrence of somnolence in the
      patients with PD was compared with the occurrence among control groups of
      patients with diabetes mellitus and of healthy elderly subjects. The correlations
      between EDS and SB and various motor- and non-motor symptoms of PD were
      evaluated. Among the patients with PD, 15.5% experienced EDS, significantly more
      than in the patients with diabetes mellitus (4%) and the healthy control subjects
      (1%). The frequency of mild daytime sleepiness was similar (10%) in patients with
      PD and control subjects. The patients with EDS had significantly higher staging
      of PD, were more disabled, and showed a higher frequency of cognitive decline
      compared with the patients without somnolence. They also had been using levodopa
      for a longer time and had more hallucinations. The occurrence of nocturnal
      sleeping problems and the use of sleeping pills was similar in the two groups, as
      was the mean age at examination, duration of PD, and presence of fluctuations and
      dyskinesias. SB was found in 42.2% of the patients with PD. These patients had
      been using levodopa for significantly longer and had significantly more
      fluctuations and dyskinesias compared with the patients without SB. Our results
      suggest that mild daytime sleepiness may be a result of normal aging, whereas
      more severe EDS can be explained by the neuropathologic changes of PD. The data
      from this community-based study confirms the previously reported high frequencies
      of SB.

PMID- 10584666
TI  - Environmental risk factors in Parkinson's disease.
AB  - We studied the environmental risk factors of Parkinson's disease (PD) in Finland,
      particularly those related to rural environment, in a prevalence material in
      1992. The population numbered 196,864 people, including urban and rural areas. In
      this community-based study, we used a case-control method with personal
      investigation of the case subjects (n = 123) and matched control subjects (n =
      246). Analyses were carried out by conditional logistic regression model. Case
      subjects had far fewer domestic animals at home during their lifetime, including
      cows, sheep, pigs, and chickens. The difference was even more obvious in those
      under the age of 20 years, including also cats and horses, but diminished after
      20 years. The number of different animal species was smaller with case subjects
      as was the duration of animal contacts. Case subjects found their work physically
      heavier and exercised more. The mean age at onset in ever-smoking men was
      significantly higher than in never-smoking men. No special reason for non-smoking
      increased, and a physical reason decreased the risk of PD. Area of birth or
      living, farming and other occupations, types of drinking water, pesticide and
      herbicide use, head injuries, use of alcohol, education, and carbon monoxide
      poisonings were similar among case subjects and control subjects. In conclusion,
      domestic animals, or something that is connected with the animals, may have a
      protecting effect against PD. Alternatively, the observed negative associations
      of domestic animals at home and subsequent PD may only be a marker of other
      environmental conditions or lifestyles.

PMID- 10584667
TI  - The effect of dopamine agonist therapy on dopamine transporter imaging in
      Parkinson's disease.
AB  - Single-photon emission computed tomography (SPECT) imaging with the dopamine
      transporter ligand, [123I] beta-CIT (2beta-carboxymethoxy-3beta-[4-iodophenyl]
      tropane), has been proposed as a means of measuring Parkinson's disease (PD)
      progression. To be useful in this role, however, [123I] beta-CIT imaging should
      not be influenced by the medications used to treat PD, including the dopamine
      agonist drugs such as pergolide. We assessed the effect of adjunctive pergolide
      administration on [123I] beta-CIT uptake in 12 patients with PD, who were being
      treated with levodopa, initiating pergolide therapy for motor fluctuations.
      Patients underwent [123I] beta-CIT imaging at baseline, subsequently while on
      pergolide therapy (6 weeks), and again 4 weeks after pergolide wash-out. Uptake
      in the striatum was averaged for the two sides and expressed as (striatum -
      occipital)/occipital, with similar calculations for putamen and caudate.
      Consistent with PD, the patients' mean striatal and putamen uptake ratios at
      baseline were significantly less (p <0.001) than the mean values from 26 normal
      control subjects of similar age. During pergolide treatment, the striatal and
      putamen [123I] beta-CIT uptake ratios were each statistically similar to
      baseline, although there was a slight trend toward an increased striatal value
      (8% higher on pergolide; p = 0.105). Caudate [123I] beta-CIT uptake was 11%
      higher on pergolide therapy (nominal p = 0.042, but not significant when adjusted
      for multiple comparisons: p = 0.126). After pergolide wash-out, the striatal,
      putamen, and caudate uptake ratios did not differ from baseline. Therefore, we
      found that pergolide therapy did not significantly affect [123I] beta-CIT SPECT
      imaging but we cannot exclude a small influence.

PMID- 10584668
TI  - Progression of falls in postmortem-confirmed parkinsonian disorders.
AB  - Although falls are known to occur in several parkinsonian disorders, such as
      Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy
      bodies (DLB), corticobasal degeneration (CBD), and progressive supranuclear palsy
      (PSP), differences in the evolution of this feature have not been studied
      systematically in pathologically confirmed cases. Seventy-seven cases with
      pathologically confirmed parkinsonian disorders (PD: n = 11, MSA: n = 15, DLB: n
      = 14, CBD: n = 13, PSP: n = 24), collected up to 1994, formed the basis for a
      multicenter clinicopathologic study organized by the National Institute of
      Neurological Disorders and Stroke to improve differential diagnosis of
      parkinsonian disorders. In the present study, we determined the time course, that
      is, the duration from first symptom to onset (latency) and duration from onset to
      death, of recurrent falls. Furthermore, we analyzed the diagnostic validity of a
      predefined latency to onset of recurrent falls within 1 year of symptom onset.
      Significant group differences for latency, but not duration, of recurrent falls
      were observed. Latencies to onset of falls were short in PSP patients,
      intermediate in MSA, DLB, and CBD, and long in PD. Recurrent falls occurring
      within the first year after disease onset predicted PSP in 68% of the patients.
      Our study demonstrates for the first time that latency to onset, but not
      duration, of recurrent falls differentiates PD from other parkinsonian disorders.
      Whereas early falls are important for the diagnosis of PSP, the addition of other
      features increases its diagnostic predictive value.

PMID- 10584669
TI  - Unilateral pallidotomy in advanced Parkinson's disease: a retrospective study of
      26 patients.
AB  - OBJECTIVE: To evaluate the effects of unilateral pallidotomy in patients with
      Parkinson's disease (PD). PATIENTS AND METHODS: Twenty-six patients with PD and
      disabling dyskinesias, painful and/or disabling dystonia, and/or pain as part of
      PD despite optimal pharmacotherapy underwent unilateral pallidotomy. For
      assessment, the Unified Parkinson's Disease Rating Scale (UPDRS; part II and
      III), Hoehn and Yahr staging, the Schwab and England scale, a Dyskinesia Rating
      Scale, and timed tests were used. Assessment was performed in defined "off' and
      "on," and on average 2 months before and 7.5 months after the unilateral
      pallidotomy. Adverse effects were classified as transient or permanent and as
      major or minor. RESULTS: In the "off' phase, the median UPDRS II score improved
      from 26.5 to 20.5 (23%) and the median UPDRS III score improved from 47.5 to 33.0
      (31%). In the "on" phase, dyskinesias contralateral to the side of the procedure
      improved with 88% ipsilateral dyskinesias improved only temporarily, and the
      total UPDRS II and III scores remained unchanged. Thirteen patients had transient
      adverse effects, three patients had permanent, and two patients had a combination
      of transient and permanent adverse effects. The transient adverse effects in two
      patients were classified as major. CONCLUSION: Stereotactic unilateral
      pallidotomy can improve symptoms and disability in the "off' phase. In the "on"
      phase, dyskinesias disappeared at the side contralateral to the procedure.
      Permanent minor complications of pallidotomy occurred in 19% of the patients.

PMID- 10584670
TI  - Does deep brain stimulation of the nucleus ventralis intermedius affect postural
      control and locomotion in Parkinson's disease?
AB  - The purpose of this study was to evaluate the effect of unilateral stimulation of
      the nucleus ventralis intermedius (VIM) on parkinsonian signs like postural
      stability and locomotion with respect to the severity of Parkinson's disease
      (PD). Seven patients with idiopathic PD were included in the study. Changes in
      visual cues on postural stability and step initiation were assessed on a fixed
      platform system with VIM stimulation switched either on (VIM ON) or off (VIM
      OFF), and compared with a control group of seven age-matched normal individuals.
      Sway scores (area and path) were significantly (p <0.05) higher in the
      parkinsonian patients with VIM OFF than with VIM ON as well as compared with the
      control subjects. No correlation was obtained between extent of sway scores and
      severity of contralateral tremor after cessation of VIM stimulation. Locomotion
      parameters, by contrast, were not influenced by VIM stimulation: latency until
      step initiation and walking-cycle time were the same among parkinsonian patients
      as among normal individuals, both in the presence and in the absence of VIM
      stimulation. In conclusion, our results indicate that tremor suppression by VIM
      stimulation improves postural stability.

PMID- 10584671
TI  - Changes in handwriting resulting from bilateral high-frequency stimulation of the
      subthalamic nucleus in Parkinson's disease.
AB  - High-frequency stimulation of the subthalamic nucleus (STN) is a promising
      therapeutic approach in patients with severely disabling Parkinson's disease
      (PD). Whereas STN stimulation improves the cardinal signs of PD, little is known
      about the effects of STN stimulation on fine manual skills like handwriting.
      Therefore, the present study investigated the changes in handwriting during
      bilateral STN stimulation in 12 patients with advanced PD. Dopaminergic
      medication was discontinued at least 12 hours before the study. The patients were
      asked to write a standardized sentence repetitively. Five samples of the
      patient's script were recorded during effective bilateral STN stimulation and 1
      hour after both stimulators had been switched off. The movements of the tip of
      the pencil were recorded using a digitizing tablet. Handwriting movements were
      segmented into subsequent up- and down-strokes, and a stroke-based kinematic
      analysis of handwriting was performed. During high-frequency STN stimulation,
      handwriting movements became faster and smoother indicating a partial restoration
      of an "open-loop" automatic performance. In addition, STN stimulation gave rise
      to a significant increase in the mean vertical stroke length demonstrating a
      stimulation-related reduction in micrographia. The present data underscores the
      importance of the STN in "open-loop" performance of highly skilled sequential
      hand movements.

PMID- 10584672
TI  - Oxidative DNA damage in the aging mouse brain.
AB  - The brain exhibits regional vulnerabilities to many insults, and age itself has
      differential effects on neuronal populations as exemplified by the age-dependent
      loss of dopaminergic neurons in the nigrostriatal system. We hypothesized that
      oxidative damage to DNA was more likely to occur in the nigrostriatal system
      which undergoes significant neurochemical and functional changes with age. To
      test this hypothesis, oxidative damage to DNA, indicated by levels of 8-hydroxy2'
      deoxyguanosine (oxo8dG), was measured in pons-medulla (PM), midbrain (MB),
      caudate-putamen (CP), hippocampus (HP), cerebellum (CB), and cerebral cortex (CX)
      at 3, 18, and 34 months of age in C57/b1 mice. Steady-state levels of oxo8dG
      increased significantly with age in MB, CP, and CB, but not in PM, HP, or CX.
      Manganese superoxide dismutase (MnSOD) activity decreased with age in MB, CP, and
      HP, but not in PM, CB, or CX. Regional activities of Cu/Zn superoxide dismutase
      (Cu/Zn SOD) and glutathione peroxidase (Glut Px) did not change significantly
      with age. Concomitant with the regional alterations in DNA damage, there was a
      significant age-dependent decline in locomotor activity, motor coordination, and
      striatal dopamine content especially during the interval between 18 and 34
      months. In conclusion, oxyradical-associated damage to DNA did not accumulate
      uniformly across brain regions with age and was highest in brain regions that
      subserve spontaneous locomotor activity and motor coordination.

PMID- 10584673
TI  - Neuroendocrine responses to levodopa in multiple system atrophy (MSA).
AB  - Hypothalamic dopaminergic pathways are involved in the regulation of growth
      hormone and prolactin release from the anterior pituitary. Neuroendocrine studies
      in patients with multiple system atrophy (MSA), in whom there is a reported loss
      of hypothalamic dopamine, are few and contradictory. We therefore studied the
      neuroendocrine responses to 250 mg levodopa (plus 25 mg carbidopa) in subjects
      with MSA (n = 15), and compared them with age- and sex-matched healthy control
      subjects (n = 8). There were no significant differences in basal or post-levodopa
      levels of growth hormone (GH), growth hormone-releasing hormone (GHRH), glucose,
      insulin-like growth factor (IGF-1), or thyroid-stimulating hormone (TSH) between
      the groups. In patients with MSA, basal levels of prolactin were elevated (21.1
      +/- 5.2 ng/mL [mean +/-standard error]) compared with control subjects (12.1 +/-
      1.7, p <0.05), and after L-dopa there was increased variability in prolactin
      response with less suppression compared with control subjects. In conclusion, in
      patients with MSA, the GHRH and GH responses to L-dopa were preserved and were
      similar to responses in age-matched control subjects. In contrast, there was
      impaired dopaminergic suppression of prolactin secretion. In patients with MSA
      this may represent a selective dysfunction, rather than generalized loss, of
      tubero-infundibular dopaminergic neurones.

PMID- 10584674
TI  - Visuomotor performance in patients with essential tremor.
AB  - Essential tremor (ET) is the most prevalent extrapyramidal disorder, yet its
      diagnosis is still controversial. This article introduces new findings that
      pertain to this diagnostic problem. Twenty-three patients with ET were studied.
      Patients with parkinsonism, cerebellar signs, severe head injury, or those under
      neuroleptic medication were excluded. Twenty-five normal subjects served as
      control subjects. Visuomotor tests involving tracking and tracing along three
      different paths with both the right and left hands, were used. Performance was
      assessed by measuring test duration, directional error, the proportion of the
      cumulative test time during which directional error exceeded half the maximal
      possible level (PT50%), the mean distance from the model path, the velocity of
      the hand movement, and the number of tracking interruptions. In 15 of 23 patients
      performance was the same as in the control subjects. These patients were defined
      as having a "simple condition" of ET (ETs). Considerable visuomotor impairment
      was found in eight patients who were regarded as having a "complex condition" of
      ET (ETc). Patients with ETc had significantly lower tracking speed, more tracking
      interruptions, longer test duration, greater directional error, greater PT50%,
      and greater distance from path than patients with ETs or control subjects. Most
      patients with ET appear to have normal visuomotor capabilities (ETs) but some
      display significant visuomotor disturbances (ETc). Considering the presence of
      similar impairments in patients with early Parkinson's disease and the increased
      prevalence of parkinsonism in patients with ET, it is possible that preclinical
      parkinsonism exists in patients with ETc. Further follow up of patients with ETc
      is necessary to verify this possibility.

PMID- 10584675
TI  - Trick maneuvers in cervical dystonia: investigation of movement- and touch
      related changes in polymyographic activity.
AB  - Antagonistic gestures or trick maneuvers are well-known clinical features to
      reduce or abolish dystonic posturing in cervical dystonia (CD). The maneuvers
      typically consist of a finger touch to the facial skin but their physiology
      remains unknown. To determine the temporal profile of geste maneuver performance,
      25 patients with idiopathic CD were studied by means of polymyography of six
      cervical muscles prior to any botulinum toxin treatment. Two piezoelectric
      elements fixed to a fingertip of the hand involved in the trick maneuver and to
      the facial target region, respectively, were used to relate the essential points
      of the trick maneuver time course (start of geste-arm movement, facial contact,
      end of contact, end of movement) to changes in polymyographic activity. Thirteen
      patients (52%) showed marked reductions of electromyographic (EMG) activity (> or
      =50% in at least one muscle) during arm movement, definitely prior to contact
      between fingers and facial target area; in the remaining 12 patients (48%), geste
      related EMG effects were confined to facial-finger contact. These results might
      indicate different physiological mechanisms in clinically indistinguishable
      antagonistic gestures.

PMID- 10584676
TI  - Further studies on periodic limb movement disorder and restless legs syndrome in
      children with attention-deficit hyperactivity disorder.
AB  - Fourteen consecutive children who were newly diagnosed with attention-deficit
      hyperactivity disorder (ADHD) and who had never been exposed to stimulants and 10
      control children without ADHD underwent polysomnographic studies to quantify
      Periodic Limb Movements in Sleep (PLMS) and arousals. Parents commonly gave both
      false-negative and false-positive reports of PLMS in their children, and a sleep
      study was necessary to confirm their presence or absence. The prevalence of PLMS
      on polysomnography was higher in the children with ADHD than in the control
      subjects. Nine of 14 (64%) children with ADHD had PLMS at a rate of >5 per hour
      of sleep compared with none of the control children (p <0.0015). Three of 14
      children with ADHD (21%) had PLMS at a rate of >20 per hour of sleep. Many of the
      PLMS in the children with ADHD were associated with arousals. Historical sleep
      times were less for children with ADHD. The children with ADHD who had PLMS
      chronically got 43 minutes less sleep at home than the control subjects (p =
      0.0091). All nine children with ADHD who had a PLMS index of >5 per hour of sleep
      had a long-standing clinical history of sleep onset problems (>30 minutes) and/or
      maintenance problems (more than two full awakenings nightly) thus meeting the
      criteria for Periodic Limb Movement Disorder (PLMD). None of the control children
      had a clinical history of sleep onset or maintenance problems. The parents of the
      children with ADHD were more likely to have restless legs syndrome (RLS) than the
      parents of the control children. Twenty-five of 28 biologic parents of the
      children with ADHD and all of the biologic parents of the control children were
      reached for interview. Eight of twenty-five parents of the children with ADHD
      (32%) had symptoms of RLS as opposed to none of the control parents (p = 0.011).
      PLMS may directly lead to symptoms of ADHD through the mechanism of sleep
      disruption. Alternative explanations for the association between ADHD and
      RLS/PLMS are that they are genetically linked, they share a common dopaminergic
      deficit, or both.

PMID- 10584677
TI  - Decreased concentration of annexin V in parkinsonian cerebrospinal fluid:
      speculation on the underlying cause.
AB  - Circumstantial evidence suggests that increased apoptosis is responsible for the
      loss of dopaminergic nigrostriatal neurons in Parkinson's disease (PD). It is
      impossible to perform high-quality studies on human postmortem material because
      of the low quality of tissue preservation, and the fact that apoptosis has a
      duration of only hours, and that the duration of the agonal period itself will
      lead to massive neuronal cell death. We measured, as epiphenomenon of neuronal
      cell death ex vivo, the Annexin V concentration in cerebrospinal fluid (CSF) in
      patients with PD and control subjects. The Annexin V concentration in CSF of
      patients with PD was significantly lower compared with control subjects. Annexin
      V concentrations of the CSF did not correlate with dementia, duration of
      symptoms, age, sex, or treatment of PD. The rationale for measurement of Annexin
      V in CSF is the fact that Annexin V adheres to dying cells. It is tempting to
      suppose that the decrease of Annexin V in CSF of PD is the result of consumption
      of this protein during neuronal apoptosis as has been demonstrated to occur in
      the midbrain in PD.

PMID- 10584678
TI  - Worsening of motor performance in patients with Parkinson's disease following
      transdermal nicotine administration.
AB  - Nicotine has been reported to have positive effects on motor performance in
      patients with Parkinson's disease. In this study, motor performance was evaluated
      in 16 patients with idiopathic Parkinson's disease during a practical off-period
      using the motor part of the Unified Parkinson's Disease Rating Scale after 12
      hours' exposure to a transdermal patch containing 35 mg nicotine or placebo. The
      study was performed using a double-blind crossover design. In contrast to
      previous reports, nicotine exposure was followed by a worsening of symptoms
      compared with placebo. A negative response to subthreshold dopaminergic
      stimulation, resulting from an inhibitory effect of low striatal dopamine
      concentrations acting on a subset of dopamine receptors, might possibly account
      for this finding.

PMID- 10584679
TI  - Worsening of motor features of parkinsonism with olanzapine.
AB  - Clozapine is the current treatment of choice for drug-induced psychosis (DIP)
      occurring in Parkinson's disease. However, alternative medications have been
      sought because of the small but significant risk of agranulocytosis and the need
      for frequent blood testing. The new "atypical" antipsychotic olanzapine (OLZ) has
      recently been proposed as a safe and effective option for treating psychosis in
      this setting. To investigate this, we retrospectively evaluated all 12 of our
      patients treated with OLZ for DIP. Symptoms of psychosis were improved in nine of
      12 patients, but nine of 12 patients also experienced worsening of motor
      functioning while on OLZ. The worsening was considered dramatic in six of these
      patients. Overall, there was no significant increase in levodopa doses on OLZ.
      Only one patient remained on OLZ at the time of the analysis. Nine patients were
      switched to alternative treatment for DIP. We conclude that although OLZ may
      improve symptoms of psychosis in parkinsonian patients, it can also worsen motor
      functioning. In some patients, the degree of motor worsening may be intolerable.

PMID- 10584680
TI  - Combined use of type A and F botulinum toxins for blepharospasm: a double-blind
      controlled trial.
AB  - Type A botulinum toxin has widened its clinical range of applications, but the
      risk of developing antibodies limits the repeated use of high-dose injection. To
      minimize the risk, mixing different types of toxin might reduce the antigenic
      presentation of a specific toxin and associated proteins. At the same time,
      inhibition of the neuromuscular release process at the multiple sites might
      potentiate the clinical response or the duration of action. We compared the
      effectiveness of a mixture of type A and type F botulinum toxins with that of
      type A or type F toxin alone for treating patients with blepharospasm in a double
      blind study. Fifty-four patients had 10 units of toxin injection, a mixture of
      type A and F toxins (including 5 units of each) on one side and either type A or
      F toxin on the other side of the orbicularis oculi muscle. Clinical evaluation at
      4 and 10 weeks after the injection revealed that the peak clinical effect at 4
      weeks was similar among the three preparations. The duration of action of the
      mixture was intermediate between type A and type F alone, as assessed at 10
      weeks, when there was a tendency of conserving the beneficial effect on one eye
      at the expense of that on the other. Although there was no apparent potentiation
      of the clinical efficacy, the combination of these different types of toxin might
      be used for decreasing the risk of antibody development.

PMID- 10584681
TI  - Segmental facial myoclonus in moebius syndrome.
AB  - Moebius syndrome is characterized by sixth and seventh nerve palsy and is usually
      the result of bilateral hypoplasia or aplasia of the respective brain stem
      nuclei. There have been no reports of involuntary facial movements associated
      with this malformative complex. We report on a 6-year-old boy affected by Moebius
      syndrome with asymmetric involvement and segmental facial myoclonus with onset at
      age 2 years, affecting the side with partially conserved motility. Clinical
      presentation included congenital peripheral palsy of the right seventh cranial
      nerve and left-sided rhythmic rising of the upper lip and eyebrow. Surface
      electromyography (EMG) of the left levator labii and frontalis muscles showed
      rhythmic bursting (duration: 150-450 ms; frequency: 1-3 Hz).
      Electroencephalographic (EEG)-polygraphic recordings and burst-locked EEG
      averaging failed to show any consistent EEG activity preceding the EMG bursts.
      Study of the blink reflex, somatosensory and motor-evoked potentials showed
      findings consistent with pontine pathology. Segmental facial myoclonus, although
      extremely rare in children, must be differentiated from several other paroxysmal
      motor manifestations associated with structural lesions involving the brain stem.
      Segmental facial myoclonus stem-Structural lesion.

PMID- 10584683
TI  - Primary writing tremor treated by chronic thalamic stimulation.

PMID- 10584682
TI  - Striatal D2 dopamine receptor status in Parkinson's disease: an [18F]dopa and
      [11C]raclopride PET study.

PMID- 10584684
TI  - A case of myoclonic cortical tremor after extirpation of a parietal meningioma.

PMID- 10584685
TI  - Arm elevation in Huntington's disease: dystonia or levitation?

PMID- 10584686
TI  - Nabilone increases choreatic movements in Huntington's disease.

PMID- 10584687
TI  - Concordant late onset of craniocervical dystonia in a pair of monozygotic twins.

PMID- 10584688
TI  - Painful cervical dystonia: clinical features and response to treatment with
      botulinum toxin.

PMID- 10584689
TI  - Blepharospasm induced by an LED flashlight.

PMID- 10584690
TI  - Localized neuromyotonia of neck muscles after radiotherapy for for nasopharyngeal
      carcinoma.

PMID- 10584691
TI  - Slow rhythmic dyskinesia of the shoulder: one idopathic and two symptomatic
      cases.

PMID- 10584692
TI  - Shoulder girdle dyskinesia following local surgery.

PMID- 10584693
TI  - Painful legs and moving toes associated with neuropathy in HIV-infected patients.

PMID- 10584694
TI  - Sporadic acetazolamide-responsive episodic ataxia.

PMID- 10584695
TI  - Treatment of drooling in Parkinson's disease with botulinum toxin.

PMID- 10584696
TI  - Pallidotomy and generalized dystonia.

PMID- 10584697
TI  - Focal nodular hyperplasia of the liver: a comprehensive pathologic study of 305
      lesions and recognition of new histologic forms.
AB  - Atypical histologic variants of focal nodular hyperplasia have been reported and
      are sometimes difficult to recognize. To characterize the morphologic spectrum of
      focal nodular hyperplasia, we studied 305 lesions surgically resected from 168
      patients. Clinicomorphologic correlations were established by statistical
      analyses. The patients included 150 women and 18 men (sex ratio, 8:1; median age,
      38 years). One hundred twenty-eight (76.2%) patients had solitary lesions, and 40
      (23.8%) had 2 to 30 lesions. All 305 lesions measured 1 mm to 19 cm in diameter.
      Only 49% of these lesions had one to three macroscopic scars. Histologically, 245
      (80.3%) lesions were of classical form, and 60 (19.7%) lesions were nonclassical.
      The latter were classified as focal nodular hyperplasia of telangiectatic form
      (47 lesions), of mixed hyperplastic and adenomatous form (five lesions), and with
      atypia of large cell type (eight lesions). Several benign or malignant tumors
      were found in association with these lesions. This large retrospective series of
      focal nodular hyperplasia shows the relative incidence of its classical and
      nonclassical forms. The absence of a central scar could explain the difficult
      preoperative diagnosis of some of the cases. The morphologic diagnostic criteria
      in this study require further prospective evaluation.

PMID- 10584699
TI  - Heterotopic mesenteric ossification ('intraabdominal myositis ossificans'):
      report of five cases.
AB  - Intraabdominal heterotopic ossification is a very uncommon disorder. We report
      five new cases, review the previous literature, and discuss the clinical and
      pathologic features of these lesions. The clinical features of the current cases
      and of those previously reported are remarkably similar. All patients were middle
      aged to elderly men (range, 43-80 years; mean, 61 years) who had small bowel
      obstruction associated with heterotopic bone formation in the small bowel
      mesentery, often after one or more abdominal operations. In one case, an initial
      diagnosis of extraosseous osteosarcoma was considered. This unusual reactive
      process shares many of the clinical and pathologic features of myositis
      ossificans, as classically described in somatic soft tissues. We propose to
      designate this condition heterotopic mesenteric ossification.

PMID- 10584698
TI  - Clear cell sarcoma of kidney in an adolescent and in young adults: a report of
      four cases with ultrastructural, immunohistochemical, and DNA flow cytometric
      analysis.
AB  - Clear cell sarcoma of the kidney is a distinct, highly malignant pediatric
      neoplasm. Its occurrence in adults is extremely rare and the subject of isolated
      case reports. We present a series of four cases (three males and one female)
      identified in an adolescent and in young adults (16, 18, 20, and 25 years) with
      flank mass (three cases), hematuria (two cases), flank pain (two cases), and
      hypertension (one case). Three patients had stage III disease and one had stage I
      disease (National Wilms' Tumor Study staging system). All tumors had
      predominantly or exclusively the classic histology of a monotonous proliferation
      of uniform small round cells with evenly distributed fine chromatin, although
      focal microcyst formation (two cases) and spindled architecture (one case)
      (variant patterns) were also noted. Therapy in all cases consisted of surgery and
      chemotherapy with or without radiation. Follow-up data (29-202 months) showed
      distant metastases in all four cases, including the lung (four cases), bone (two
      cases), and the liver (two cases). Three patients died of disease at 29, 59, and
      63 months (mean, 50.3 months), and one patient is alive with no evidence of
      disease at 202 months. Ultrastructural features included scattered primitive
      junctions, short and irregular cytoplasmic extensions, and scant to a moderate
      amount of mitochondria. Immunohistochemical study (three cases) showed
      immunoreactivity with vimentin (two cases) and no reaction with cytokeratin,
      epithelial membrane antigen, S-100 protein, or desmin. Flow cytometric analysis
      showed diploid DNA content in three primary tumors and tetraploidy in one
      metastatic tumor. The proliferative activity (S-phase fraction) was low to
      intermediate (mean, 9.8%). Our data suggest that clear cell sarcoma of the kidney
      in the young adult age group resembles its pediatric counterpart in
      ultrastructural and immunohistochemical characteristics, proclivity for skeletal
      and visceral metastasis, DNA diploid status with relatively low S-phase, and
      aggressive clinical course. Clear cell sarcoma of the kidney in adult patients,
      although rare, must be differentiated from sarcomatoid carcinoma, sarcomas, and
      round cell tumors because of its unique characteristics in comparison to other
      renal neoplasms.

PMID- 10584700
TI  - Ductal adenocarcinoma of the prostate diagnosed on needle biopsy: correlation
      with clinical and radical prostatectomy findings and progression.
AB  - Ductal adenocarcinoma of the prostate, previously referred to as endometrioid
      cancer, is typically diagnosed on transurethral resection. When treated by
      radical prostatectomy (RP), it pursues a more aggressive clinical course than
      usual acinar prostate cancer does. The significance of prostate cancer with
      ductal features found on needle biopsies from the peripheral zone is unknown. We
      reviewed 58 prostate needle biopsy cases with ductal adenocarcinoma for which we
      were able to obtain clinical information. Patients had a mean age of 69 years
      (range, 50-89 years) and had a wide range of levels of serum prostate-specific
      antigen (median, 7.9 ng/mL) and clinical stages. Six (10%) had metastases at the
      time of diagnosis. Cribriform or papillary structures or a mixture of the two
      patterns were seen in 86% of cases, whereas in the remaining cases, discrete
      glands composed of tall columnar cells were present. Stromal fibrosis accompanied
      the ductal carcinoma in 67% of the cases. A coexisting acinar carcinoma component
      was identified in 48% of the biopsy specimens. On biopsy, the ductal component
      composed a mean of 82% of the tumor. Of the 20 tumors treated by RP, 63% had
      extraprostatic spread of tumor and 20% had positive margins. Two (10%) cases
      showed seminal vesicle invasion, but none had lymph node metastases. The number
      of positive needle cores correlated with RP margin status (p<0.004) and with
      likelihood of clinical progression (p<0.02), but not with organ-confined status.
      Tumor volume calculated on the 11 extensively sampled RPs ranged from 0.15 cm3 to
      20.3 mL (mean, 2.8 cm3). Two years after therapy, the actuarial risk of
      progression was between 34% (RP patients) and 42% (all patients). A shortened
      average time to progression was observed relative to a previous study group of
      men with acinar carcinoma. Serum prostate-specific antigen levels correlated with
      neither RP organ-confined status nor tumor volume. We conclude that prostatic
      ductal adenocarcinoma seen on needle biopsy implies more advanced cancer with a
      shortened time to progression.

PMID- 10584702
TI  - Patterns of local horizontal spread of melanomas: consequences for surgery and
      histopathologic investigation.
AB  - Understanding local spreading patterns of melanomas is a precondition for the
      localized surgical treatment and histopathologic investigation. We used
      hematoxylin and eosin-stained paraffin sections for a two-phase, cellular and
      microscopic study of patterns of lateral spread in superficial spreading
      melanomas (SSMs), nodular melanomas (NMs), lentigo maligna melanomas (LMMs), and
      acral lentiginous melanomas (ALMs). Complete histologic examination of vertical
      excisional margins was carried out with paraffin sections 5 mm beyond the
      clinical tumor border of 1395 SSMs, 376 NMs, 179 LMMs, 46 ALMs, and 37 acrally
      located SSMs or NMs. Further sections of embedded material were analyzed when
      tumor-positive margins were found. In case of continuous tumor spread,
      reoperations were continued until the tissue was free of tumor cells. In case of
      noncontinuity, a final excision was made to a minimum safety margin of 10 to 20
      mm. Concentrically consecutive, 5-microm thick hematoxylin and eosin-stained
      sections were taken from the outside of a 10-mm safety margin inward to the
      clinical borders of 34 SSMs, five NMs, 10 LMMs, and five ALMs. Noncontinuous
      subclinical spread was found in all SSMs and NMs in the form of few isolated cell
      nests at the epidermis-dermis junction. Ninety-two percent of these were located
      within 6 mm of the central tumor. All LMMs and ALMs showed a clearly
      demonstrable, uninterrupted spread into the periphery at the epidermis-dermis
      junction, too, usually in groups of outgrowths. The probability of finding these
      outgrowths 5 mm beyond the clinical tumor border was 54% in LMM and ALM. Complete
      histologic examination of vertical excisional margins (micrographic surgery) is
      therefore the therapy of choice only for LMM and ALM and is inefficient for SSM
      and NM.

PMID- 10584701
TI  - Retroperitoneal liposarcoma with combined well-differentiated and myxoid
      malignant fibrous histiocytoma-like myxoid areas.
AB  - To broaden the knowledge of myxoid morphology in liposarcoma, eight cases of
      unusual liposarcoma with combined well-differentiated and myxoid malignant
      fibrous histiocytoma (MFH)-like myxoid areas are reported. The tumors arose as
      huge retroperitoneal masses in elderly patients, except for one that occurred in
      the spermatic cord. Three cases had local recurrences, and one of the seven
      patients who were followed up had died of the tumor. Grossly, the tumors were
      mostly confluent and multinodular and showed a glistening myxoid appearance in
      variable proportions, which merged gradually into or were juxtaposed to yellow
      fatty or sclerotic whitish areas. Microscopically, in addition to areas of well
      differentiated lipoma-like or sclerosing liposarcoma, all the tumors contained
      myxoid portions characterized by scattered multinucleated or bizarre giant cells
      and a prominent plexiform vascular pattern that resembled myxoid MFH or
      myxofibrosarcoma. The myxoid areas were associated with discernible lipogenesis.
      High-grade dedifferentiation was present in one tumor. Cytogenetically, in one
      case, the myxoid lesion had nonrandom chromosomal aberrations, such as ring and
      marker chromosomes, characteristic of a well-differentiated variant of
      liposarcoma. In a nested reverse transcription-polymerase chain reaction analysis
      using archival paraffin-embedded tissue, it was seen that none of the eight
      tumors with myxoid MFH-like features had TLS/FUS-CHOP fusion transcripts
      characteristic of myxoid and round cell liposarcomas. These clinicopathologic and
      molecular features suggest that the current myxoid tumors are more closely
      related to well-differentiated liposarcoma rather than to ordinary myxoid
      liposarcoma despite their unequivocal myxoid morphology. Missense point mutations
      of the p53 gene were detected in two (25%) cases by single-strand conformation
      polymorphism and sequence analyses. Immunohistochemical expressions of p53 and
      mdm2 were observed in 75% of the cases, in which immunoreactive tumor cells were
      seen more often in the myxoid MFH-like areas. Thus, altered p53 pathways, such as
      p53 gene mutation and mdm2-mediated inactivation of p53, may play a pathogenetic
      role in this form of tumor progression showing myxoid MFH-like morphology in
      liposarcoma, as has been suggested in dedifferentiated liposarcoma.

PMID- 10584703
TI  - Metastatic malignant melanoma resembling malignant peripheral nerve sheath tumor:
      report of 16 cases.
AB  - We report 16 cases of metastatic malignant melanoma presenting clinically as
      lymphadenopathy or a soft-tissue mass and histologically resembling malignant
      peripheral nerve sheath tumor (MPNST). In two cases, the metastatic malignant
      melanoma was preceded by a primary cutaneous malignant melanoma; in four cases,
      it presented synchronously with such a tumor; and in 10 cases, there was no
      evidence of a previous or concomitant malignant skin lesion. Histologically, the
      tumors were characterized by a malignant-appearing spindle cell proliferation
      arranged in fascicles, often accompanied by a peritheliomatous growth pattern,
      alternating hypercellular and hypocellular areas, numerous mitoses, and foci of
      necrosis. In nine cases, there was residual lymph node tissue. In none of the
      cases was there evidence of an anatomic connection with a nerve, a coexistent
      neurofibroma, or the stigmata of neurofibromatosis. Fourteen of the cases showed
      strong and generally diffuse immunoreactivity for S-100 protein, and five cases
      showed positivity for HMB-45. Four of eight patients with follow-up information
      died of the disease. Tumors with a microscopic appearance compatible with MPNST
      but showing strong diffuse S-100 protein staining and featuring remnants of lymph
      node may represent metastatic malignant melanomas and should elicit a search for
      a previous or concomitant tumor in the skin and other sites. The similarities
      these tumors share with MPNST are probably related to their common
      neuroectodermal histogenesis.

PMID- 10584705
TI  - Carcinosarcomas of the lung: a clinicopathologic study of 66 patients.
AB  - Carcinosarcoma is a malignant tumor having a mixture of carcinoma and sarcoma
      containing differentiated mesenchymal elements, such as malignant cartilage,
      bone, and skeletal muscle. These tumors have been linked histogenetically to
      pleomorphic carcinomas; it is unclear whether their clinical behavior is
      significantly different. To investigate this issue, we studied 66 cases of
      carcinosarcomas of the lung and compared them with cases from a previously
      published series of pleomorphic carcinomas. Carcinosarcomas show a male-to-female
      ratio of 7.25:1, with a mean and median age of 65 years. They most often present
      as solitary masses in the upper lobes and average 7 cm in diameter. Most (62%)
      were endobronchial or central tumors, whereas 38% were described as peripheral.
      The most frequent epithelial component was squamous cell carcinoma (46%),
      followed by adenocarcinoma (31%) and adenosquamous carcinoma (19%), whereas
      sarcomatous elements most frequently included rhabdomyosarcoma, chondrosarcoma,
      osteosarcoma, or combinations of these elements. Survival of patients with
      carcinosarcomas of lung was poor, with a 5-year survival rate of 21.3%. Of
      several clinical and pathologic parameters, only increased tumor size (with 6 cm
      as the optimal cutoff point) appeared to be related to reduced survival (p =
      0.0195). In comparison with patients with pleomorphic carcinoma, patients with
      carcinosarcomas had no significant difference in the size of their tumors (p =
      1.0), stage at presentation (p = 0.883), location in the lung (p = 0.073), or
      their overall survival (21.3% vs 15.0%) (p = 0.1038). A significantly greater
      proportion of patients with carcinosarcoma had squamous cell (p = 0.004) or
      adenosquamous (p = 0.016) carcinoma, whereas patients who had pleomorphic
      carcinoma showed a significantly greater frequency of adenocarcinoma (p = 0.029)
      and large cell carcinoma. The histologic differences between these two types of
      tumor suggest that they may be different entities with similar behavior, but
      additional studies are warranted to investigate this hypothesis.

PMID- 10584704
TI  - Cutaneous melanoma with myxoid features: twelve cases with differential
      diagnosis.
AB  - Substantial myxoid change can occur in malignant melanoma, but its importance in
      primary disease has not been systematically evaluated. This report describes the
      clinical, microscopic, histochemical, and immunohistochemical findings in 12
      patients with primary cutaneous malignant melanoma with myxoid features. The
      tumors presented as solitary lesions situated on the limbs (six lesions), trunk
      (four lesions), and head and neck (two lesions). The patients included six women
      and six men, whose ages ranged from 26 to 95 years, with a mean of 63 years.
      Breslow thickness varied from 0.48 mm to more than 12 mm, with a mean of more
      than 3.2 mm. Clinical follow-up for an average of 22 months showed one local
      recurrence, but no evidence of metastases yet. In all cases, there was a
      combination of myxoid and nonmyxoid areas. A minimum of 15% myxoid cross
      sectional area was required for inclusion in the study, and up to 80% was
      observed. The pale blue mucin identified on hematoxylin and eosin staining was
      sensitive to hyaluronidase and positive for alcian blue in the 10 cases stained.
      Immunohistochemical staining was positive for S-100 in all 9 cases stained,
      positive for HMB-45 in 9 (90%) of 10, and negative for cytokeratin in all 9 cases
      in which myxoid melanoma remained in the block after previous sections. The
      presence of myxoid stroma did not define a biologically significant subgroup of
      melanoma. Only in cases with extensive (>50%) myxoid stromal effacement of the
      melanoma was there a major diagnostic hurdle. The diagnosis of primary cutaneous
      melanoma with myxoid features was seldom as problematic as metastatic myxoid
      melanoma. Positive S-100 stains, negative cytokeratin immunohistochemical stains,
      and hyaluronidase-sensitive alcian blue staining assisted in the diagnosis of
      this entity.

PMID- 10584706
TI  - Lysosomal inclusions in gastric parietal cells in mucolipidosis type IV: a novel
      cause of achlorhydria and hypergastrinemia.
AB  - Mucolipidosis type IV (ML-IV) is an autosomal recessive lysosomal storage disease
      that causes severe neurologic abnormalities. The brain disease is characterized
      by pigmented cytoplasmic granules in neurons and accumulation of lamellated
      membrane structures in lysosomes. The gastrointestinal disease in ML-IV was not
      previously recognized. Clinical examination of 20 patients with ML-IV (age range,
      2-23 years) at the National Institutes of Health showed hypergastrinemia and
      constitutive achlorhydria. Endoscopic biopsy specimens from the gastric fundus,
      body, and antrum and from the duodenum of four such patients (ages 4, 6, 7, and
      22 years) were evaluated histologically and by electron microscopy.
      Histologically, all gastric fundus and body biopsy specimens showed parietal
      cells in normal numbers. However, a striking cytoplasmic vacuolization of
      parietal cells was seen on hematoxylin and eosin stain. Electron microscopy
      showed the parietal cells to be markedly distended by large lysosomes containing
      lamellar, concentric, and cystic membranous inclusions. Additionally, chronic
      atrophic gastritis and enterochromaffin-like (ECL) cell hyperplasia were
      observed. Foveolar and chief cells in stomach and duodenum biopsy specimens were
      normal. We conclude that the cytoplasmic lysosomal inclusions in gastric parietal
      cells is a unique histologic feature of gastric biopsy in ML-IV.

PMID- 10584707
TI  - Differential diagnosis between monomorphic clear cell adenocarcinoma of salivary
      glands and renal (clear) cell carcinoma.
AB  - Clear cell adenocarcinoma of salivary glands (CCASG) is a relatively rare tumor,
      composed entirely of clear cells of putative ductal origin. It bears striking
      morphologic similarities to renal cell carcinoma (RCC) of clear cell type on
      hematoxylin and eosin stains. Differentiation between CCASG and metastatic RCC to
      the salivary glands has been considered problematic or even impossible on
      morphologic grounds. We examined three cases of CCASG and 12 cases of RCC (6
      primary and 6 metastatic) by hematoxylin and eosin staining,
      immunohistochemistry, and electron microscopy. Two distinctive
      immunohistochemical and ultrastructural patterns emerged from this analysis.
      CCASG showed positivity for high molecular weight cytokeratin and
      carcinoembryonic antigen and ultrastructurally showed prominent squamoid
      differentiation, glycogen pools, and absence of lipid. In contrast, RCC was
      characterized by positivity for vimentin and complete absence of staining for
      high molecular weight cytokeratin and carcinoembryonic antigen. On
      ultrastructural studies, RCC lacked any squamoid differentiation, and the tumor
      cells contained abundant cytoplasmic lipid in addition to glycogen. Thus, based
      on the consistent differences on the immunohistochemical staining patterns and
      their characteristic subcellular morphology, CCASG and RCC can be distinguished
      on pathologic evaluation. The different direction of differentiation of the cells
      in CCASG and RCC (i.e., ductal in the former and renal tubular and mesodermal in
      the latter) results in their distinctive immunophenotypical and ultrastructural
      features.

PMID- 10584708
TI  - The pathology of interstitial lung disease in nylon flock workers.
AB  - Flocking is a widely used industrial process in which short lengths of synthetic
      fibers are applied to backing fabric to produce plush material. In response to an
      apparent outbreak of interstitial lung disease in flock workers, the Centers for
      Disease Control hosted a clinical-pathological workshop to identify the defining
      characteristics of the disease and possible etiologic agents. Six pathologists
      reviewed 15 biopsies of 15 cases (out of a clinical caseload of 20 patients) and
      assessed the pattern, extent and degree of pulmonary inflammation, fibrosis, and
      other changes. A consensus clinical-pathologic diagnosis was reached for each
      patient and correlated with clinical and radiologic findings. Four of eight open
      lung biopsies and one of seven closed (transbronchial) lung biopsies demonstrated
      a characteristic pattern to which the descriptive terminology lymphocytic
      bronchiolitis and peribronchiolitis with lymphoid hyperplasia was applied. The
      other biopsies showed nonspecific inflammatory changes, airspace organization,
      and diffuse alveolar damage. One open lung biopsy demonstrated respiratory
      bronchiolitis with lymphoid hyperplasia. None of the lung biopsies showed more
      than mild interstitial fibrosis and no granulomas were identified. The consensus
      of the workshop was that lymphocytic bronchiolitis and peribronchiolitis with
      lymphoid hyperplasia was a characteristic and distinctive pattern of injury in
      the flock workers' lung biopsies. Although the etiology of this disease remains
      undefined at present, the injury pattern and environmental studies suggest a
      chronic immunologic response to inhaled material.

PMID- 10584709
TI  - Testicular biopsy in patients with obstructive azoospermia.
AB  - The present report studies the testicular biopsy lesions (histologic and
      semiquantitative) in a series of 48 patients with obstructive azoospermia of
      known etiology (vasectomy, congenital absence of vas deferens, herniorrhaphy,
      hydrocelectomy, Young's syndrome, and ejaculatory duct obstruction) in order to
      establish objective testicular data that permit the pathologist to diagnose an
      obstructive process, which should not be mistaken with a primary testicular
      lesion. The semiquantitative study included determinations of the average numbers
      of spermatogonia, primary spermatocytes, young spermatids (Sa + Sb), and
      differentiated spermatids (Sc + Sd). According to this study, the testes were
      classified into the following groups: (1) normal testes whose germ cell numbers
      were within normal limits (27 testes); (2) testes with lesions in the adluminal
      compartment; these lesions comprise two subgroups: (2a) late sloughing of primary
      spermatocytes (both spermatid types were greatly reduced in number while the
      other germ cell types were in normal numbers) (45 testes); and (2b) early
      sloughing of primary spermatocytes (normal spermatogonial number, reduced number
      of spermatocytes, and scanty spermatids) (9 testes); and (3) lesions in the basal
      compartment; these lesions comprise two subgroups: (3a) pure hypospermatogenesis
      (a proportionate decrease in the numbers of all germ cell types) (8 testes); and
      (3b) hypospermatogenesis associated with sloughing of primary spermatocytes
      (decreased numbers of all germ cell types with a very scanty number spermatids)
      (4 testes). Two testes appeared hyalinized and one testis was removed owing to
      cryptorchidism. The most frequent testicular lesion observed (alteration in the
      adluminal compartment of seminiferous tubules) seems to be related to the
      increase in hydrostatic pressure in the tight compartment formed by seminiferous
      tubules, rete testis, efferent ducts, the epididymal duct, and the initial
      portion of the vas deferens. The severity of the lesions is probably related to
      the cause and span of the obstruction. In addition, two azoospermic men without
      obstructive azoospermia and whose testicular biopsy study revealed meiotic
      anomalies (with the subsequent bad prognosis) were also studied for comparison.
      The semiquantitative study of these patients permitted the differential diagnosis
      between two lesion types. Testes with meiotic anomalies had a disproportionately
      elevated number of primary spermatocytes, and an extremely low number of young
      spermatids.

PMID- 10584710
TI  - Anatomic pathology image capture using a consumer-type digital camera.
AB  - Low-cost, high-quality consumer-type digital cameras are now on the market. They
      can be used for taking photomicrographs by simply placing the camera over the
      eyepiece of a conventional light microscope and pressing a button. Similar
      techniques can be used for capturing digital images through various types of
      viewing instruments. The quality of the digital images obtained is surprisingly
      high. With this low-cost approach, the uses of digital imaging in the author's
      anatomic pathology department have widely expanded.

PMID- 10584711
TI  - Columnar cell hyperplasia is associated with lobular carcinoma in situ and
      tubular carcinoma.

PMID- 10584712
TI  - Double jeopardy for women in cervical screening.

PMID- 10584713
TI  - Meta-style and expert review.

PMID- 10584714
TI  - Importance of position in which patients are nursed in intensive-care units.

PMID- 10584715
TI  - Safety of outpatient dental anaesthesia for children.

PMID- 10584716
TI  - Is simple clinical assessment adequate for cardiac risk stratification before
      elective non-cardiac surgery?

PMID- 10584717
TI  - Albumin infusion for spontaneous bacterial peritonitis.

PMID- 10584718
TI  - New treatments for pulmonary fibrosis?

PMID- 10584719
TI  - Myocarditis and cardiomyopathy associated with clozapine.
AB  - BACKGROUND: Clozapine is effective for resistant schizophrenia. After two sudden
      deaths in physically well young men soon after starting clozapine, we
      investigated the cardiovascular complications for this drug. METHODS: From
      January, 1993, to March, 1999, 8000 patients started clozapine treatment in
      Australia, and were registered with a mandatory monitoring service. We identified
      cases of myocarditis and cardiomyopathy from voluntary reports to the Australian
      Adverse Drug Reaction Committee and sought details of the relevant diagnostic
      studies, necropsies that had been done in suspicious cases, or both. FINDINGS: 23
      cases (20 men, three women, mean age 36 years [SD 9]) were identified: 15 of
      myocarditis and eight of cardiomyopathy associated with clozapine treatment. Six
      patients died. All cases of myocarditis (five deaths) occurred within 3 weeks of
      starting clozapine. Cardiomyopathy (one death) was diagnosed up to 36 months
      after clozapine was started. Necropsy results showed mainly eosinophilic
      infiltrates with myocytolysis, consistent with an acute drug reaction.
      INTERPRETATION: Clozapine therapy may be associated with potentially fatal
      myocarditis and cardiomyopathy in physically healthy young adults with
      schizophrenia.

PMID- 10584721
TI  - Supine body position as a risk factor for nosocomial pneumonia in mechanically
      ventilated patients: a randomised trial.
AB  - BACKGROUND: Risk factors for nosocomial pneumonia, such as gastro-oesophageal
      reflux and subsequent aspiration, can be reduced by semirecumbent body position
      in intensive-care patients. The objective of this study was to assess whether the
      incidence of nosocomial pneumonia can also be reduced by this measure. METHODS:
      This trial was stopped after the planned interim analysis. 86 intubated and
      mechanically ventilated patients of one medical and one respiratory intensive
      care unit at a tertiary-care university hospital were randomly assigned to
      semirecumbent (n=39) or supine (n=47) body position. The frequency of clinically
      suspected and microbiologically confirmed nosocomial pneumonia (clinical plus
      quantitative bacteriological criteria) was assessed in both groups. Body position
      was analysed together with known risk factors for nosocomial pneumonia. FINDINGS:
      The frequency of clinically suspected nosocomial pneumonia was lower in the
      semirecumbent group than in the supine group (three of 39 [8%] vs 16 of 47 [34%];
      95% CI for difference 10.0-42.0, p=0.003). This was also true for
      microbiologically confirmed pneumonia (semirecumbent 2/39 [5%] vs supine 11/47
      [23%]; 4.2-31.8, p=0.018). Supine body position (odds ratio 6.8 [1.7-26.7],
      p=0.006) and enteral nutrition (5.7 [1.5-22.8], p=0.013) were independent risk
      factors for nosocomial pneumonia and the frequency was highest for patients
      receiving enteral nutrition in the supine body position (14/28, 50%). Mechanical
      ventilation for 7 days or more (10.9 [3.0-40.4], p=0.001) and a Glasgow coma
      scale score of less than 9 were additional risk factors. INTERPRETATION: The
      semirecumbent body position reduces frequency and risk of nosocomial pneumonia,
      especially in patients who receive enteral nutrition. The risk of nosocomial
      pneumonia is increased by long-duration mechanical ventilation and decreased
      consciousness.

PMID- 10584720
TI  - Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2.
AB  - BACKGROUND: Early age at first full-term pregnancy and increasing parity are
      associated with a reduced risk of breast cancer. However, whether pregnancy
      decreases the risk of early-onset hereditary breast cancer is unknown. There is
      concern that pregnancy may increase breast-cancer risk in carriers of BRCA1 and
      BRCA2 germline mutations. We aimed to establish whether pregnancy is a risk
      factor for hereditary breast cancer. METHODS: We did a matched case-control study
      of breast cancer in women who carry deleterious BRCA1 or BRCA2 mutations. Cases
      were carriers who developed breast cancer by age 40 years, and controls were
      carriers of the same age without breast cancer, or who were diagnosed with breast
      cancer after age 40 years. Women who had undergone preventive mastectomy,
      hysterectomy, or oophorectomy, or who were diagnosed with ovarian cancer before
      the age at which breast cancer was diagnosed in the matched case were excluded.
      Information about pregnancies and pregnancy outcome was derived from a
      questionnaire completed by women in the course of genetic counselling. FINDINGS:
      A higher proportion of cases than controls had had a full term pregnancy (173/236
      vs 146/236; odds ratio 1.71 [95% CI 1.13-2.62], p=0.01). The mean number of
      births was also greater for cases than for controls (1.62 vs 1.38, p=0.04). The
      risk increased with the number of births and did not diminish with time since
      last pregnancy. There were no significant differences in age at first birth or
      age at last birth between cases and controls. INTERPRETATION: Carriers of the
      BRCA1 and BRCA2 mutations who have children are significantly more likely to
      develop breast cancer by age 40 than carriers who are nulliparous. Each pregnancy
      is associated with an increased cancer risk. An early first pregnancy does not
      confer protection for carriers of BRCA1 or BRCA2 mutations.

PMID- 10584722
TI  - Comparison of microwave endometrial ablation and transcervical resection of the
      endometrium for treatment of heavy menstrual loss: a randomised trial.
AB  - BACKGROUND: Various new endometrial ablation techniques have emerged for the
      treatment of menorrhagia. We undertook a randomised controlled trial comparing
      one new technique, microwave endometrial ablation (MEA), with a proven procedure,
      transcervical resection of the endometrium (TCRE), for women with heavy menstrual
      loss. METHODS: 263 eligible and consenting women, referred for endometrial
      ablative surgery, were randomly assigned MEA (Microsulis plc, Waterlooville,
      Hampshire, UK; n=129) or TCRE (n=134). 230 participants were needed to give 80%
      power of demonstrating a 15% difference in satisfaction with treatment. All
      procedures were done under general anaesthesia 5 weeks after endometrial thinning
      with goserelin 3.6 mg. Questionnaires were completed at recruitment and at 12
      months' follow-up. The primary outcome measures were patients' satisfaction with
      and the acceptability of treatment. Analysis was by intention to treat among
      women followed up to 12 months (n=116 MEA, n=124 TCRE). FINDINGS: At 12 months,
      89 (77%) women in the MEA group and 93 (75%) in the TCRE group were totally or
      generally satisfied with their treatment (95% CI for difference -12 to 17) and
      109 (94%) versus 112 (90%) found it acceptable (-11 to 35). Mean operating times
      were shorter for MEA than for TCRE (11.4 vs 15.0 min, p=0.001) and the
      postoperative stay slightly but not significantly shorter. One blunt perforation
      occurred in each study group resulting in one immediate hysterectomy (TCRE
      group). Of eight health-related quality of life dimensions, all were improved
      after MEA (six significantly) and seven were improved after TCRE (all
      significantly). INTERPRETATION: Both techniques achieved high rates of
      satisfaction and acceptability and both improved quality of life after 1 year.
      However, we cannot exclude a difference in satisfaction between the groups of
      less than 15%. MEA seems a suitable alternative to TCRE.

PMID- 10584723
TI  - Cardiac arrhythmias in children during outpatient general anaesthesia for
      dentistry: a prospective randomised trial.
AB  - BACKGROUND: Deaths in children associated with outpatient general dental
      anaesthesia may be attributable to sudden cardiovascular collapse precipitated by
      ventricular arrhythmias. A causal link between halothane anaesthesia, ventricular
      arrhythmias, and deaths has been suggested. We did a prospective, randomised
      trial to investigate the frequency and character of arrhythmias during
      anaesthesia with halothane and the alternative anaesthetic agent, sevoflurane.
      METHODS: 150 children, aged 3-15 years, who needed dental extraction under
      general anaesthesia were randomly assigned sevoflurane or halothane
      supplementation of 66% nitrous oxide in oxygen with spontaneous ventilation. The
      halothane group (n=50) received halothane introduced in 0.75% increments, every
      two to three breaths, to a maximum of 3.0%, with maintenance at 1.5%. The
      incremental sevoflurane group (n=50) received sevoflurane introduced in 2%
      increments increased to a maximum of 8%, with maintenance at 4%. The 8%
      sevoflurane group (n=50) received sevoflurane introduced at 8%, with maintenance
      at 4%. FINDINGS: 24 (48%) children receiving halothane had arrhythmias compared
      with four (8%) receiving incremental sevoflurane (difference 40% [95% Ci for
      differences 24-56] p<0.0001), and eight (16%) receiving 8% sevoflurane
      (difference 32% [15-50] p=0.0013). Halothane-associated arrhythmias occurred
      during dental extraction or emergence and were mainly ventricular. Six (12%)
      children in the halothane group had ventricular tachycardia. The methods of
      sevoflurane administration did not differ significantly for the frequency of
      arrhythmias (p=0.357). Sevoflurane-associated arrhythmias were mainly single
      supraventricular ectopic beats. INTERPRETATION: There was a strong association
      between halothane and ventricular arrhythmias, especially ventricular
      tachycardia. The use of sevoflurane in preference to halothane could contribute
      to a decline in morbidity and mortality associated with dental anaesthesia.

PMID- 10584725
TI  - Fever, cough, and nodules on ankles.

PMID- 10584724
TI  - Neuroanatomy of comorbid schizophrenia and learning disability: a controlled
      study.
AB  - BACKGROUND: Reasons for the higher frequency of schizophrenia in learning
      disabled populations are uncertain. We investigated the neuroanatomical basis for
      this phenomenon by structural magnetic resonance imaging (MRI) in patients with
      learning disability and schizophrenia, learning-disabled patients, and patients
      with schizophrenia. METHODS: Age-matched and sex-matched patients with learning
      disability (20 cases), schizophrenia (25), and both disorders (23) underwent MRI
      scans of the brain. Whole brain areas and specific regions of interest were
      examined. 29 normal controls were also scanned. FINDINGS: The scans of the group
      with both disorders were closely similar to those of the schizophrenic group, in
      terms of both general structures and the structure of the amygdala-hippocampus.
      However, the amygdala-hippocampus was significantly smaller on both sides than
      that of normal controls (left 4.1 vs 4.5 cm3, p=0.011; right 4.2 vs 4.99 cm3,
      p<0.0001). The brains of learning-disabled patients were generally smaller than
      those of the other three groups, but the amygdalohippocampal complexes were
      larger. INTERPRETATION: In terms of brain structure, patients with comorbid
      learning disability and schizophrenia resemble patients with schizophrenia and
      not those with learning disability. We suggest that the higher frequency of
      schizophrenia in learning-disabled patients is due to a greater tendency of
      schizophrenic patients to develop cognitive deficits, and that within the
      learning-disabled population there may be individuals whose deficits result from
      undiagnosed schizophrenia.

PMID- 10584726
TI  - Colorectal hyperplastic polyps and risk of recurrence of adenomas and
      hyperplastic polyps. Polyps Prevention Study.
AB  - We examined data from two large colorectal chemoprevention trials for possible
      associations of hyperplastic polyps and adenomas with subsequent development of
      these lesions. Hyperplastic polyps do not predict metachronous adenomas.

PMID- 10584727
TI  - Epidemic of obesity in UK children.
AB  - Data from a nationally representative sample of 2630 English children show that
      the frequency of overweight ranged from 22% at age 6 years to 31% at age 15 years
      and that of obesity ranged from 10% at age 6 years to 17% at age 15 years.

PMID- 10584728
TI  - Association between cerebral palsy and coagulase-negative staphylococci.
AB  - Coagulase-negative staphylococci were cultured from the space between the
      placental membranes at delivery in four of five neonates who were later diagnosed
      with cerebral palsy, and in 26 of 102 neonates who were not found to have the
      disorder (p=0.02).

PMID- 10584730
TI  - Suicide among patients with cancer cared for at home by palliative-care teams.
AB  - Patients with terminal cancer are thought to be at high risk of committing
      suicide. In a population of 17,964 patients with terminal cancer cared for at
      home by 12 palliative-care teams, five patients committed suicide. We speculate
      that continuing care made up by symptomatic treatment and psychosocial support
      given to these patients may reduce the risk.

PMID- 10584731
TI  - Role of microvascular decompression in trigeminal neuralgia and multiple
      sclerosis.
AB  - An excellent outcome after microvascular decompression for medically intractable
      trigeminal neuralgia in patients with multiple sclerosis is reported in seven of
      15 cases. A dual cause could be hypothesised in some patients with multiple
      sclerosis and trigeminal neuralgia, and that microvascular decompression can be a
      therapeutic option.

PMID- 10584732
TI  - Treatment of traumatic bleeding with recombinant factor VIIa.
AB  - Surgical intervention failed to stop life-threatening bleeding caused by injury
      complicated by severe coagulopathy. Administration of recombinant factor VIIa
      immediately corrected the coagulopathy and bleeding stopped.

PMID- 10584733
TI  - Topical N-acetylcysteine for lamellar ichthyosis.
AB  - The antioxidant N-acetylcysteine has an antiproliferative effect on a culture of
      human keratinocytes. We report a patient with lamellar ichthyosis satisfactorily
      treated with topical N-acetylcysteine.

PMID- 10584734
TI  - Data accrue on "visionary" agent to interrupt addiction.

PMID- 10584735
TI  - Probiotics strain for credibility.

PMID- 10584736
TI  - Old cash problems in Labour's new National Health Service.

PMID- 10584737
TI  - HIV/AIDS cases in 1999 set to keep increasing into the next century.

PMID- 10584738
TI  - Condoms banned from Israel's anti-AIDS campaign.

PMID- 10584739
TI  - Needle exchange advocated for Canada's prisons.

PMID- 10584740
TI  - How the World Trade Organisation is shaping domestic policies in health care.
AB  - High up on the agenda of the World Trade Organisation (WTO) is the privatisation
      of education, health, welfare, social housing and transport. The WTO's aim is to
      extend the free market in the provision of traditional public services.
      Governments in Europe and the US link the expansion of trade in public services
      to economic success, and with the backing of powerful medico-pharmaceutical,
      insurance, and service corporations, the race is on to capture the share of gross
      domestic product that governments currently spend on public services. They will
      open domestic European services and domestic markets to global competition by
      government procurement agreements, dispute-settlement procedures, and the
      investment rules of global financial institutions. The UK has already set up the
      necessary mechanisms: the introduction of private-sector accounting rules to
      public services; the funding of public-sector investment via private-public
      partnerships or the private finance initiative; and the change to capitation
      funding streams, which allows the substitution of private for public funds and
      services. We explain the implications of these changes for European public-health
      care systems and the threat they pose to universal coverage, solidarity through
      risk-pooling, equity, comprehensive care, and democratic accountability.

PMID- 10584741
TI  - Global trade and access to medicines: AIDS treatments in Thailand.

PMID- 10584742
TI  - Improving the quality of reports of meta-analyses of randomised controlled
      trials: the QUOROM statement. Quality of Reporting of Meta-analyses.
AB  - BACKGROUND: The Quality of Reporting of Meta-analyses (QUOROM) conference was
      convened to address standards for improving the quality of reporting of meta
      analyses of clinical randomised controlled trials (RCTs). METHODS: The QUOROM
      group consisted of 30 clinical epidemiologists, clinicians, statisticians,
      editors, and researchers. In conference, the group was asked to identify items
      they thought should be included in a checklist of standards. Whenever possible,
      checklist items were guided by research evidence suggesting that failure to
      adhere to the item proposed could lead to biased results. A modified Delphi
      technique was used in assessing candidate items. FINDINGS: The conference
      resulted in the QUOROM statement, a checklist, and a flow diagram. The checklist
      describes our preferred way to present the abstract, introduction, methods,
      results, and discussion sections of a report of a meta-analysis. It is organised
      into 21 headings and subheadings regarding searches, selection, validity
      assessment, data abstraction, study characteristics, and quantitative data
      synthesis, and in the results with "trial flow", study characteristics, and
      quantitative data synthesis; research documentation was identified for eight of
      the 18 items. The flow diagram provides information about both the numbers of
      RCTs identified, included, and excluded and the reasons for exclusion of trials.
      INTERPRETATION: We hope this report will generate further thought about ways to
      improve the quality of reports of meta-analyses of RCTs and that interested
      readers, reviewers, researchers, and editors will use the QUOROM statement and
      generate ideas for its improvement.

PMID- 10584743
TI  - Infant-feeding patterns and HIV-1 transmission.

PMID- 10584744
TI  - Infant-feeding patterns and HIV-1 transmission.

PMID- 10584745
TI  - Infant-feeding patterns and HIV-1 transmission.

PMID- 10584746
TI  - Infant-feeding patterns and HIV-1 transmission.

PMID- 10584747
TI  - Obstructive uropathies.

PMID- 10584748
TI  - Obstructive uropathies.

PMID- 10584749
TI  - Non-diabetic nephropathies and ACE inhibition.

PMID- 10584750
TI  - Male infertility and increased risk of diseases in future generations.

PMID- 10584751
TI  - Male infertility and increased risk of diseases in future generations.

PMID- 10584752
TI  - Hormone replacement therapy and C-reactive protein.

PMID- 10584753
TI  - Monetary incentives and community-directed health programmes in some less
      developed countries.

PMID- 10584754
TI  - Diagnosis and frequency of brain death.

PMID- 10584755
TI  - Eradication of poliomyelitis.

PMID- 10584756
TI  - Paracelsus on wound treatment.

PMID- 10584757
TI  - 50th anniversary of Ridley's pioneering procedure.

PMID- 10584758
TI  - The Nobel chronicles. 1982: Sune Karl Bergstrom (b 1916); Bengt Ingemar
      Samuelsson (b 1934); John Robert Vane (b 1927).

PMID- 10584759
TI  - Molecular neurobiology for practicing psychiatrists, part 3: how second
      messengers "turn on" genes by activating protein kinases and transcription
      factors.
AB  - One of the most important advances in molecular neurobiology of relevance to the
      practicing psychiatrist is how an intracellular second messenger can "turn on"
      genes by activating first a protein kinase enzyme and then a transcription
      factor. Failure to turn on the right genes may lead to psychiatric illnesses.
      Causing the appropriate genes to turn on may be the therapeutic mechanism of
      action of many current and future psychotropic drugs.

PMID- 10584760
TI  - A history of substance abuse complicates remission from acute mania in bipolar
      disorder.
AB  - BACKGROUND: Substance abuse frequently complicates the course of bipolar illness,
      promotes mixed states, and contributes to poor outcome in mania. Preliminary open
      trials suggest that anticonvulsant mood stabilizers may enhance remission rates
      and outcome for bipolar patients with substance abuse. This study compared
      remission patterns for mixed or pure manic episodes among bipolar inpatients with
      or without substance abuse histories. METHOD: Hospital records were
      retrospectively reviewed for 204 DSM-III-R bipolar I inpatients. Clinical
      features were compared for those with or without substance abuse/dependence
      histories predating the index manic episode. Time until remission was analyzed by
      Kaplan-Meier survival analysis. Naturalistic treatment outcome with lithium or
      anticonvulsant mood stabilizers was compared for those with or without past
      substance abuse. RESULTS: Past substance abuse was evident in 34% of the bipolar
      sample and comprised most often alcoholism (82%), followed by cocaine (30%),
      marijuana (29%), sedative-hypnotic or amphetamine (21%), and opiate (13%) abuse.
      Substance abuse was more common among men (p < .05) and those with mixed rather
      than pure mania (p < .05). Remission during hospitalization was less likely among
      patients with prior substance abuse (p < .05), especially alcohol or marijuana
      abuse, and among mixed manic patients with past substance abuse (p < .05).
      Bipolar patients with substance abuse histories who received divalproex or
      carbamazepine remitted during hospitalization more often than did those who
      received lithium as the sole mood stabilizer (p < .05). CONCLUSION: These
      findings support previous reports suggesting that bipolar patients with past
      substance abuse have poorer naturalistic treatment outcomes, but may show a
      better response to anticonvulsant mood stabilizers than lithium.

PMID- 10584761
TI  - Antidepressant treatment of depression in HIV-seropositive women.
AB  - BACKGROUND: This study aimed to assess the effectiveness of fluoxetine and
      sertraline in treating depressed women who are seropositive for the human
      immunodeficiency virus (HIV) and to document barriers to study participation.
      METHOD: Ambulatory HIV-seropositive women with DSM-IV depressive disorders were
      enrolled in an 8-week, open trial of fluoxetine (N = 21) or sertraline (N = 9)
      initiated at standard dosages. Outcome measures included the Clinical Global
      Impressions-Improvement scale (CGI), Hamilton Rating Scale for Depression (HAM
      D), Beck Depression Inventory (BDI), physical function ratings, and CD4 count.
      RESULTS: Thirty-six women were screened for the study and 30 were enrolled. Mean
      age was 35.5 years and HIV risk was primarily intravenous drug use (N = 16; 53%)
      or heterosexual contact (N = 12; 40%). Sixteen (53%) were Hispanic, 11 (37%) were
      African American, and 3 (10%) were white. Mean +/- SD CD4 count was 463+/-312
      cells/microL, and 30% had acquired immunodeficiency syndrome (AIDS). Eighteen
      women (60%) completed the trial (14 fluoxetine: dose range, 10-40 mg/day; 4
      sertraline: dose range, 25-100 mg/day). Of completers, 14 (78%) were clinical
      responders by CGI and reduction in HAM-D > 50%. Statistically significant
      reductions were seen in HAM-D and BDI scores, but not in measures of physical
      function or CD4 count. The most frequent adverse effects were anxiety,
      overstimulation, and insomnia. Reasons for nonparticipation or dropout included
      refusal to accept antidepressants on account of negative bias, preferring
      psychotherapy alone, adverse effects, and relapse to illicit drugs. CONCLUSION:
      While HIV-seropositive women may benefit from antidepressant treatment, multiple
      barriers to successful treatment exist. Aggressive outreach, education, and
      attention to the complex psychosocial needs of HIV-seropositive women are
      essential components of depression treatment in this population.

PMID- 10584762
TI  - Depressive and anxiety symptoms in patients with schizophrenia and
      schizophreniform disorder.
AB  - BACKGROUND: Symptoms of depression and anxiety are frequently encountered in the
      course of schizophrenia and are of considerable clinical importance. They may
      compromise social and vocational functioning, and they are associated with an
      increased risk of relapse and suicide. Various treatment approaches have been
      reported to be successful. METHOD: The sample comprised 177 patients with DSM-III
      R or DSM-IV schizophrenia or schizophreniform disorder who were participants in
      multinational clinical drug trials at our academic psychiatric unit over a 7-year
      period and who were assessed by means of the Positive and Negative Syndrome Scale
      (PANSS). Analysis was performed on baseline PANSS scores. The depression/anxiety
      score was compared in the men and women, first-episode and multiple-episode
      patients, and those with predominantly positive and negative syndromes.
      Correlations were sought between depression/anxiety scores and age, total PANSS
      score, positive score, negative score, general psychopathology score, and
      treatment outcome. Multivariate analysis was applied to determine contributions
      of individual variables toward depression/anxiety and outcome scores. RESULTS:
      Depression and anxiety symptoms were more severe in women (p = .007), first
      episode patients (p = .02), and those with predominantly positive symptoms (p <
      .0001). Depression/anxiety scores were significantly correlated to age (r = 
      0.31, p < .0001), PANSS positive scores (r = 0.39, p < .0001), and treatment
      outcome (r = 0.25, p = .006). Multivariate analysis bore out these results, with
      the exception that first episode was not a significant predictor of depression
      and anxiety scores. CONCLUSION: PANSS depressive/anxiety scores were generally
      low in our sample, perhaps because patients with schizoaffective disorder were
      excluded. The finding that these symptoms were more prominent in women and first
      episode patients is in keeping with previous literature. The higher scores in
      first-episode patients are likely due to the higher positive symptom scores in
      these patients. The association between depressive/anxiety scores and positive
      symptoms but not with negative symptoms points to a specific relationship between
      affective symptoms and the positive symptom domain of schizophrenia. The presence
      of depressive and anxiety symptoms may predict a more favorable outcome to
      treatment, although this may only apply to the acute exacerbations of the
      illness.

PMID- 10584763
TI  - Relationship between borderline personality disorder and Axis I diagnosis in
      severity of depression and anxiety.
AB  - BACKGROUND: This study tested the hypothesis that subjects with borderline
      personality disorder irrespective of the presence or absence of an Axis I mood or
      anxiety disorder would exhibit greater severity of depression and anxiety than
      subjects with either a personality disorder other than borderline personality
      disorder or no personality disorder. METHOD: Two hundred eighty-three subjects
      from an outpatient psychiatry clinic were administered the following assessments:
      the Structured Clinical Interview for DSM-III-R (SCID) for Axes I and II, the
      Hamilton Rating Scales for Depression and Anxiety, the Beck Depression Inventory,
      and the Spielberger State-Trait Anxiety Inventory. Subjects were categorized into
      borderline personality disorder, other personality disorder, and no personality
      disorder categories and into present versus absent categories on Axis I diagnosis
      of depression and of anxiety. A 2-factor multiple analysis of variance compared
      personality disorder status and Axis I diagnosis on severity of depression by
      observer rating and self-report. The analysis was repeated for anxiety. RESULTS:
      As hypothesized, significant main effects were found for borderline personality
      disorder and for both depression and anxiety. Subjects with borderline
      personality disorder showed greater severity on both depression and anxiety
      rating scales than did patients with another personality disorder, who showed
      greater severity than did patients with no personality disorder. Axis I diagnosis
      was also associated with greater severity on depression or anxiety rating scales.
      These differences were found for both observer ratings and self-report. An
      interaction was also found for depression: Subjects with borderline personality
      disorder but without an Axis I diagnosis of depression rated themselves as more
      severely depressed on the Beck Depression Inventory than did subjects with
      another or no personality disorder who also had an Axis I diagnosis of
      depression. CONCLUSION: Implications from the study are discussed including the
      need to assess for borderline personality disorder in research studies of
      depression and anxiety and to integrate treatments for borderline personality
      disorder into depression and anxiety treatment to maximize clinical outcomes.

PMID- 10584764
TI  - Tiagabine appears not to be efficacious in the treatment of acute mania.
AB  - BACKGROUND: Because a GABAergic hypofunction has been implied in the
      pathophysiology of mania, we have tested the antimanic properties of the GABA
      transporter 1 inhibitor tiagabine. METHOD: An open trial was conducted in 8
      acutely manic inpatients with DSM-IV bipolar I disorder, 2 of them with tiagabine
      monotherapy and 6 with tiagabine as an add-on to previously insufficient mood
      stabilizing medication. The study duration was 14 days. Changes in
      psychopathology were assessed by the Bech-Rafaelsen Mania Rating Scale. RESULTS:
      None of the patients showed clear-cut relief from manic symptoms during the 2
      week observation period. In 2 patients, we saw pronounced side effects (nausea
      and vomiting in one and a generalized tonic-clonic seizure in the other).
      CONCLUSION: The results from this open trial suggest that tiagabine seems to have
      no pronounced antimanic efficacy compared with standard treatments such as
      valproate, lithium, or neuroleptics. It also appears that rapid dosage increases
      for antimanic treatment can cause potentially severe side effects.

PMID- 10584765
TI  - A follow-up study of premenstrual syndrome.
AB  - BACKGROUND: Previous data suggest that premenstrual syndrome (PMS) and affective
      disorder are related. The purpose of this preliminary study was to ascertain (1)
      whether women with PMS have an increased risk for future major depressive
      episodes compared with controls and (2) whether PMS is a stable diagnosis over
      time. METHOD: Patients with prospectively confirmed PMS, along with retrospective
      DSM-IV premenstrual dysphoric disorder, and asymptomatic controls were studied at
      5- to 12-year follow-up using a structured clinical interview. Additionally,
      those women who still had regular cycles and were medication-free were asked to
      complete 2 months of prospective daily ratings. RESULTS: Women with PMS (N = 27)
      had a nonsignificantly higher incidence of new-onset depressive episodes (DSM-III
      R and Schedule for Affective Disorders and Schizophrenia-Lifetime Version [SADS
      L] criteria) during a 5- to 12-year follow-up compared with controls (N = 21).
      Differences in incidence disappeared when patients and controls without prior
      history of depression were compared. Prospective ratings completed during follow
      up confirmed original diagnoses of PMS patients (N = 7) and controls (N = 11).
      CONCLUSION: While preliminary, these results suggest that the higher rate of
      major depression in patients with PMS during follow-up reflects the higher risk
      attendant to the history of major depression that existed at baseline.
      Additionally, at least in a small subsample, PMS appears to be a stable diagnosis
      over time.

PMID- 10584766
TI  - Olanzapine increases weight and serum triglyceride levels.
AB  - BACKGROUND: Previous studies have suggested that clozapine is associated with
      increases in both weight and serum triglyceride (but not cholesterol) levels.
      Because of the pharmacologic similarities between clozapine and olanzapine, we
      decided to evaluate if olanzapine use was associated with an increase in
      triglycerides. METHOD: Twenty-five inpatients (21 men, 4 women) were treated with
      olanzapine, and their outcomes were tracked prospectively in a medication
      utilization evaluation study. RESULTS: After 12 weeks on a mean +/- SD dose of
      13.8+/-4.4 mg/day, weight increased a mean of 12 lb (5.4 kg; from 190+/-37 lb
      [85.5+/-16.7 kg] to 202+/-30 lb [90.9+/-13.5 kg]), while fasting triglycerides
      increased a mean of 60 mg/dL (from 162+/-121 mg/dL to 222+/-135 mg/dL). Both
      increases were significant at p < .05. Fasting total cholesterol did not
      increase. The triglyceride increase was even larger when we excluded 8 patients
      who received various interventions to lower lipid levels (e.g., pravastatin, low
      fat diet) during the olanzapine trial. There was a strong association between
      weight change and triglyceride change (p < .02); after controlling for weight,
      analysis of covariance showed no independent increase in triglycerides.
      CONCLUSION: These results suggest olanzapine has significant effects on weight
      and serum triglyceride levels. Clinical implications are discussed.

PMID- 10584767
TI  - A dose-outcome analysis of risperidone.
AB  - BACKGROUND: Although the establishment of appropriate dosage ranges for
      antipsychotics has important ramifications for both short-term treatment and long
      term therapeutic outcomes, difficulties in dosing persist. Evidence exists that
      initial dosing recommendations for the titration of risperidone to 6 mg/day in 3
      days are excessive. This study examines dosage trends of risperidone and further
      examines the relationship between dose and outcome by determination of discharge
      rates among individuals receiving varying doses of the drug. METHOD: Records of
      individuals receiving risperidone in Maryland state psychiatric facilities from
      March 1994 through February 1997 (N = 1056) were examined. Discharge rates and
      time to discharge were measured by Kaplan-Meier survival curve analysis. RESULTS:
      As risperidone use has risen each year since its introduction, mean doses in both
      inpatients and discharged patients have steadily declined. Additionally,
      risperidone doses for discharged patients were significantly lower than those for
      patients remaining in the hospital. Furthermore, patients receiving 2 and 4
      mg/day were significantly more likely to be discharged than those receiving 6
      mg/day (log-rank chi2 = 13.54, df = 2, p = .0011). This difference was seen in
      patients with similar diagnoses, ages, and racial status. CONCLUSION: Patients
      treated with doses less than the 6-mg/day initial dosing recommendations have
      better outcomes in terms of discharge. This finding should encourage clinicians
      to utilize adequate trials of risperidone aimed at stabilizing patients on doses
      in the 2- to 4-mg/day range before proceeding to higher doses.

PMID- 10584768
TI  - Metrifonate: update on a new antidementia agent.
AB  - OBJECTIVE: To review preclinical and clinical studies of metrifonate, a
      cholinesterase inhibitor relevant to the treatment of Alzheimer's disease. DATA
      SOURCES: English-language literature identified by MEDLINE using the term
      metrifonate was reviewed, and bibliography-sorted searches were conducted. STUDY
      FINDINGS: Metrifonate is an organophosphate cholinesterase inhibitor effective in
      the treatment of the cognitive symptoms of Alzheimer's disease and currently
      under review by the U.S. Food and Drug Administration. The active metabolite of
      metrifonate, 2,2-dimethyldichlorovinyl phosphate (DDVP), irreversibly inhibits
      the acetylcholinesterase enzyme. Although the elimination half-life of DDVP is 2
      3 hours, the half-life of cholinesterase inhibition by DDVP is stable (26 days).
      Metrifonate can be administered once daily. Animal studies demonstrate its
      efficacy in enhancing memory in animals that have cholinergic deficits. Double
      blind, placebo-controlled studies have shown the benefit of metrifonate compared
      with placebo in improving scores on the Clinical Global Impression of Change
      scale, the Alzheimer's Disease Assessment Scale-cognitive subscale, and the
      Neuropsychiatric Inventory. CONCLUSION: Metrifonate is a useful addition to our
      limited armamentarium of agents helpful against the cognitive deficits of
      Alzheimer's disease.

PMID- 10584769
TI  - Different influences of classical antipsychotics and clozapine on glucose-insulin
      homeostasis in patients with schizophrenia or related psychoses.
AB  - BACKGROUND: The aim of this study was to investigate the influence of classical
      antipsychotics and the atypical antipsychotic agent clozapine on glucose-insulin
      homeostasis to explain possible mechanisms behind weight gain associated with
      antipsychotic treatment. METHOD: Twenty-eight patients on therapy with classical
      antipsychotics and 13 patients treated with clozapine (all meeting DSM-III-R
      criteria for schizophrenia or related psychoses) were studied. Fasting blood
      samples for glucose and insulin, as well as for 2 markers of the glucose-insulin
      homeostasis, i.e., the growth hormone (GH)-dependent insulin-like growth factor I
      (IGF-I) and the insulin-dependent insulin-like growth factor binding protein-1,
      were analyzed. Body mass index (BMI) was calculated and serum concentrations of
      the different antipsychotic drugs were measured. In addition, the relationship
      between the endocrine parameters and drug serum concentrations was examined.
      RESULTS: The insulin levels were positively correlated to the serum concentration
      of clozapine, whereas no correlations were found between insulin and the serum
      concentrations of perphenazine (N = 12) or zuclopenthixol (N = 9). Insulin
      elevation was seen in the patients receiving clozapine more frequently than in
      the patients receiving classical antipsychotics. In addition, the median level of
      IGF-I was significantly lower in the patients receiving clozapine than in the
      patients receiving classical antipsychotics. No significant difference in BMI was
      found between the 2 patient groups, and all patients but 1 were normoglycemic.
      CONCLUSION: The correlation between insulin and the clozapine concentration
      indicates a probable influence of clozapine on insulin secretion. The normal
      blood glucose levels in the clozapine group support the theory that clozapine
      induces concentration-dependent insulin resistance with secondary increased
      insulin secretion. In addition, lower median level of IGF-I in patients receiving
      clozapine compared with patients receiving classical antipsychotics points to a
      lower GH secretion in the clozapine group. This impaired GH secretion together
      with the clozapine-induced insulin resistance might be mechanisms behind weight
      gain during clozapine therapy.

PMID- 10584771
TI  - Treatment of kleptomania with paroxetine.

PMID- 10584770
TI  - Safety of sildenafil for antidepressant-related sexual dysfunction.

PMID- 10584772
TI  - Self-amputation of left hand: a case report.

PMID- 10584773
TI  - Recommended haloperidol and risperidone doses in first-episode psychosis.

PMID- 10584774
TI  - Paroxetine for primary insomnia: possible placebo effect?

PMID- 10584775
TI  - Once-daily venlafaxine XR compared with fluoxetine in outpatients with depression
      and anxiety.

PMID- 10584776
TI  - Bright light therapy: side effects and benefits across the symptom spectrum.
AB  - BACKGROUND: Bright light therapy has been established for treatment of winter
      depression, or seasonal affective disorder (SAD). Analysis of side effects most
      often have focused on a narrow set of suspected symptoms, based on clinical
      observation (e.g., headache, eyestrain, nausea, insomnia, and hyperactivity).
      This study broadens the purview to a set of 88 physical and subjective symptoms
      that might emerge, remit, or remain unchanged relative to baseline, thus reducing
      bias toward assessment of presumed side effects. METHOD: Eighty-three patients
      with SAD (DSM-III-R criteria for mood disorders with seasonal pattern [winter
      type] and National Institute of Mental Health criteria for SAD) received bright
      light therapy at 10,000 lux for 30 minutes daily in the morning or evening for 10
      to 14 days. They completed a questionnaire (Systematic Assessment for Treatment
      Emergent Effects), rating symptom severity before and after treatment. Results
      were compared for morning or evening treatment and for responders and
      nonresponders. RESULTS: Several side effects emerged--mostly mildly--including
      jumpiness/jitteriness (8.8%), headache (8.4%), and nausea (15.9%), mirroring
      findings of past studies with a less inclusive scope. In most cases, remission
      rate equalled or exceeded emergence rate. Several nondepressive symptoms also
      showed large improvement, including poor vision and skin rash/itch/irritation.
      Being overactive/excited/elated showed greater emergence under morning light and
      greater remission under evening light. Emergence of nausea was greater than
      remission in responders. CONCLUSION: The dominant effect of light treatment was
      improvement in bothersome symptoms. Although patients should be advised of side
      effects and guided in dose manipulations to reduce them, attention also should be
      drawn to the substantial benefit-to-risk ratio. Improvement of symptoms outside
      the depressive cluster, seen in both responders and nonresponders, may point to
      new therapeutic uses of light therapy.

PMID- 10584777
TI  - Alternative diagnoses: the story behind the helical CT story.

PMID- 10584778
TI  - Malpractice issues in radiology. American College of Radiology Standard for
      Communication.

PMID- 10584779
TI  - Introduction to clinical prediction rules for radiologists.

PMID- 10584781
TI  - Noninterpretive skills for radiology residents. Introduction to series.

PMID- 10584780
TI  - Trends in the use of unenhanced helical CT for acute urinary colic.
AB  - OBJECTIVE: Unenhanced helical CT for urolithiasis detection is a limited CT
      examination that was designed specifically for the detection of urolithiasis. The
      purpose of this study was to repeat a prior study to assess whether clinicians
      had broadened the indications and changed the yield and findings of unenhanced
      helical CT. MATERIALS AND METHODS: One hundred consecutive patients with
      suspected renal colic or flank pain referred for unenhanced helical CT were
      selected for this study. We reviewed the original radiographic reports for each
      patient and recorded the presence of ureteral calculi. Other urinary
      abnormalities and extraurinary lesions were also recorded and compared with the
      results of the previous study. RESULTS: In this study, 56% of the patients who
      underwent unenhanced helical CT had symptoms of urinary colic, and 44% of
      patients had unspecified flank pain, compared with 100% of patients with symptoms
      of urinary colic 1 year earlier. The sensitivity and specificity of unenhanced
      helical CT in detecting ureteral calculi were 96% and 99%, respectively. Ureteral
      calculi were identified in only 28% of the patients versus 49% of patients (p <
      .01) 1 year earlier. Extraurinary lesions were identified in 45% of the patients
      versus 16% (p < .01) 1 year before. CONCLUSION: As clinicians developed
      familiarity with this technique, the indications for performance of unenhanced
      helical CT were expanded with a consequent reduction in the rate of detection of
      stone disease and identification of an increased number of extraurinary lesions,
      which suggests a demand for emergency abdominal CT studies.

PMID- 10584782
TI  - Noninterpretive skills for radiology residents. Job search and contracting
      issues.

PMID- 10584783
TI  - Diffusion-weighted MR imaging in acute stroke: theoretic considerations and
      clinical applications.
AB  - The major clinical use of diffusion-weighted imaging to date has been in
      evaluation of cerebral infarction, at which it excels. However, diffusion
      weighted imaging has also shown promise for other applications, ranging from
      quantitative analysis of biologic changes that are not apparent from simple
      visual inspection of images (but are detectable after using regions of interest
      on apparent diffusion coefficient maps) to better characterization of other
      intracranial abnormalities (e.g., abscess and tumor). Both the clinical and
      research applications of diffusion-weighted imaging can be expected to increase,
      providing fresh insights into physiologic characteristics of both normal and
      abnormal tissue.

PMID- 10584784
TI  - MR angiography as a screening tool for intracranial aneurysms: feasibility, test
      characteristics, and interobserver agreement.
AB  - OBJECTIVE: MR angiography may be an appropriate tool to screen for unruptured
      intracranial aneurysms. Feasibility, test characteristics, and interobserver
      agreement in evaluation of MR angiograms were assessed by members of the MARS
      (Magnetic resonance Angiography in Relatives of patients with Subarachnoid
      hemorrhage) Study Group. SUBJECTS AND METHODS: We screened 626 first-degree
      relatives of a consecutive series of 193 patients with subarachnoid hemorrhage
      examined at two institutions. We used MR imaging and MR angiography (three
      dimensional time-of-flight imaging at both institutions and additional three
      dimensional phase-contrast imaging at one institution). Three observers
      independently assessed the MR angiograms. Conventional angiography was performed
      in relatives with possible or definite aneurysms on MR angiography and was
      considered the standard of reference. RESULTS: Thirty-three aneurysms were found
      in 25 (4%; 95% confidence interval [CI], 3-6%) of 626 relatives. Thirteen (8%) of
      169 relatives who refused screening had MR-related reasons; an additional six
      persons could not be screened because of contraindications for MR imaging
      (pregnancy, n = 1; claustrophobia, n = 5). The positive predictive value of MR
      angiography was 100% (95% CI, 79-100%) for "definite" aneurysms and 58% (95% CI,
      28-85%) for "possible" aneurysms. Sensitivity of MR angiography was estimated at
      83% (95% CI, 65-94%) and specificity at 97% (95% CI, 94-98%). Interobserver
      agreement in the evaluation of MR angiograms was poor (kappa < .30), probably
      because different diagnostic strategies used by individual observers resulted in
      different use of the assessment category "possible aneurysm." CONCLUSION: MR
      angiography is a feasible screening tool for detection of intracranial aneurysms.
      Positive predictive value, sensitivity, and specificity are acceptable when at
      least two neuroradiologists independently assess MR angiograms.

PMID- 10584785
TI  - MR imaging of the brain: findings in asymptomatic patients with thalassemia
      intermedia and sickle cell-thalassemia disease.
AB  - OBJECTIVE: The purpose of this study was to evaluate the spectrum of MR findings
      of the brain in asymptomatic patients affected with thalassemia intermedia or
      sickle cell-thalassemia disease to prevent brain damage by identifying patients
      at risk for stroke so that transfusional or pharmacologic treatment could be
      implemented. SUBJECTS AND METHODS: Forty-one asymptomatic patients who were
      younger than 50 years and were affected by minor hemoglobinopathies underwent MR
      imaging of the brain. Ischemic lesions were classified as small, medium, or large
      and as single or multifocal. Atrophic changes were graded subjectively as mild,
      moderate, or severe. A grade of brain damage was assigned to every patient. The
      frequency and severity of brain damage were correlated with the number of sickle
      cell crises per year, hemoglobin level, sickling hemoglobin level, platelet
      count, sex, and age. RESULTS: Of the patients with thalassemia intermedia, 37.5%
      showed asymptomatic brain damage, and 52% of those with sickle cell-thalassemia
      disease showed asymptomatic brain damage. In the thalassemia intermedia group,
      atrophy was always mild and ischemic lesions were generally small (25%) and
      single (25%). Among the patients with sickle cell-thalassemia disease, 24% had
      small, 16% had medium, and 12% had large ischemic lesions. Multifocal lesions
      were twice as common in the patients with sickle cell-thalassemia disease (20%)
      as in those with thalassemia intermedia (12.5%). Only in the patients with
      thalassemia intermedia did the frequency of brain damage increase with age.
      Moreover, brain damage inversely correlated with hemoglobin level in patients
      with thalassemia intermedia but not in those with sickle cell-thalassemia
      disease. Brain damage was more severe in patients with sickle cell-thalassemia
      disease who had more crises per year. CONCLUSION: This study suggests that
      patients with thalassemia intermedia and those with sickle cell-thalassemia
      disease may have asymptomatic brain damage. Our results suggest that MR imaging
      is useful in identifying patients at risk for stroke so that they can be treated
      with transfusional or pharmacologic therapy.

PMID- 10584786
TI  - CT of the brain: a comparison of transportable and fixed-platform scanners.
AB  - OBJECTIVE: The purpose of this study was to determine whether an in-hospital
      transportable CT scanner can provide diagnostic brain images and to compare the
      quality of these images with those from a conventional fixed-platform CT scanner.
      SUBJECTS AND METHODS: Twenty-seven patients with known or suspected intracranial
      pathology underwent imaging on a transportable scanner and a fixed-platform
      scanner within 1 hr of each other. Images from each CT examination were evaluated
      independently by two neuroradiologists who were unaware of patient history.
      Conspicuousness of intracranial pathology and normal anatomy were rated on a 5
      point scale (1 point, optimal; 5 points, poor or not visualized). Statistical
      comparisons were made using nonparametric tests. RESULTS: Seven CT scans were
      interpreted as showing normal findings and 20 scans revealed intracranial
      pathology on both CT scanners. Image quality was higher on the fixed scanner
      (average rating, 2.42 points; SE = .12) than on the transportable scanner
      (average rating, 3.10 points; SE = .12) (p = .001). Depiction of the cerebellum,
      midbrain, and supratentorial gray-white matter was better on the fixed scanner (p
      < .05). However, we found no significant differences in detection of intracranial
      pathology between scanners. Both radiologists found images from both scanners to
      be diagnostic in all 27 patients. CONCLUSION: Images of the brain on the
      transportable CT scanner were less clear than those on a fixed scanner. However,
      images from the transportable CT scanner were diagnostic in 27 consecutive
      patients. The implications of this finding are important for the provision of CT
      services for critically ill patients who cannot be transported to the radiology
      department.

PMID- 10584787
TI  - CT and MR imaging of neurocysticercosis.

PMID- 10584788
TI  - Assessment of cerebral microcirculation in a patient with hypertensive
      encephalopathy using MR perfusion imaging.

PMID- 10584789
TI  - Diffuse cerebral vasculitis with normal results on brain MR imaging.

PMID- 10584790
TI  - A prospective comparative study of MR sialography and conventional sialography of
      salivary duct disease.
AB  - OBJECTIVE: The purpose of this study was to determine the diagnostic accuracy of
      MR sialography in the examination of patients with salivary duct disease.
      SUBJECTS AND METHODS: Forty-nine patients (23 males and 26 females; 16-78 years
      old; mean age, 47 years) with symptoms related to the salivary glands underwent
      both conventional sialography and MR sialography. The latter was performed using
      a heavily T2-weighted, two dimensional, fast spin-echo technique and a 12-cm
      circular surface coil. Contiguous 3-mm axial images with frequency-selective fat
      suppression were acquired through the symptomatic gland. The MR sialography
      findings were compared with the final diagnoses determined by conventional
      sialography. RESULTS: Conventional sialography showed calculus disease (n = 13),
      stricture (n = 12), sialectasis (n = 4), cast (n = 3), neoplasm (n = 2), and
      normal duct (n = 16). MR sialography alone had a sensitivity of 69% in revealing
      calculus disease. However, the sensitivity increased to 100% when MR sialograms
      were combined with control radiographs. MR sialography was sufficient to
      accurately reveal stricture, sialectasis, and neoplasm and to direct therapy on
      the basis of its findings. Overall, MR sialography combined with control
      radiographs had a sensitivity, specificity, and diagnostic accuracy of 100%, 88%,
      and 96%, respectively, in revealing salivary duct abnormalities. CONCLUSION: MR
      sialography alone is not sufficiently sensitive to reveal salivary duct stones.
      Caution must be exercised when excluding calculus disease. MR sialography, when
      combined with control radiographs, is accurate and has the potential to replace
      conventional sialography.

PMID- 10584791
TI  - Pneumocephalus and Brown-Sequard's Neurologic injury caused by a stab wound to
      the neck.

PMID- 10584792
TI  - Surveillance CT and the prompt use of CT-guided fine-needle aspiration in
      patients with head and neck cancer who have undergone surgery.
AB  - OBJECTIVE: The purpose of this study was to assess the usefulness of prompt CT
      guided fine-needle aspiration in the evaluation of suspected tumor recurrence
      seen on surveillance images of patients who had undergone surgery for head and
      neck cancer. SUBJECTS AND METHODS: We reviewed 32 patients who had undergone CT
      guided fine-needle aspiration after surgery for head and neck cancer. CT-guided
      fine-needle aspiration was performed with a 22-gauge spinal needle and a
      cytopathologist was present to assess the adequacy of the biopsy sample. As many
      as five needle passes were made. RESULTS: Of the 32 cases, pathologic findings
      revealed squamous cell carcinoma (n = 27), mucoepidermoid carcinoma (n = 2),
      neuroendocrine carcinoma (n = 1), papillary thyroid carcinoma (n = 1), and
      adenocarcinoma (n = 1). In 20 cases (62.5%) the results of CT-guided fine-needle
      aspiration were positive for tumor recurrence, whereas in 11 cases (34.4%) the
      results were negative. In one case (3.1%) the results were nondiagnostic. Of the
      11 patients with negative findings on CT-guided fine-needle aspiration, two
      patients had a subsequent recurrence that was not at the biopsy site. There were
      no complications from the procedure. CONCLUSION: When a radiologist who is
      trained in head and neck imaging identifies with CT a possible early recurrence
      of tumor, the prompt use of CT-guided fine-needle aspiration is an effective way
      to diagnose these tumors so that appropriate treatment can be initiated.

PMID- 10584793
TI  - Teardrop superior mesenteric vein: CT sign for unresectable carcinoma of the
      pancreas.
AB  - OBJECTIVE: Our objective was to investigate whether a tethered, teardrop-shaped
      superior mesenteric vein (SMV) is a reliable CT indicator of unresectable
      adenocarcinoma of the head of the pancreas. MATERIALS AND METHODS: CT scans of 92
      patients with high suspicion for pancreatic head adenocarcinoma were
      retrospectively reviewed by two radiologists who were unfamiliar with the
      patients' outcomes. The reviewers were asked to assess whether the teardrop SMV
      sign was present or not; agreement was reached by consensus. Teardrop SMV was
      considered absent in patients with an obstructed vessel. RESULTS: Of 92 patients,
      30 had a normal pancreas without a teardrop SMV. A mass in the head of the
      pancreas was seen in all 62 patients with cancer. Of these 62 patients, 30 (seven
      with teardrop SMV) were deemed to have inoperable disease by standard CT or
      clinical criteria. The remaining 32 patients underwent surgery; only 15 of these
      32 had successful pancreatoduodenectomies. No patient with resectable tumor had
      an unequivocal teardrop SMV sign. In 17 patients (13 with teardrop SMV),
      resection of the tumor could not be accomplished because of vascular encasement
      (n = 12) or metastasis (n = 5). Added to conventional signs, teardrop SMV
      significantly increased CT's sensitivity (from 60% to 91%) and accuracy (from 79%
      to 95%) without significantly changing its specificity (from 100% to 98%) for
      resectability of pancreatic head cancer. CONCLUSION: The teardrop SMV is a
      reliable sign for predicting unresectability of adenocarcinoma of the head of the
      pancreas and can significantly contribute to preoperative planning.

PMID- 10584794
TI  - Adenocarcinoma of the head of the pancreas: determination of surgical
      unresectability with thin-section pancreatic-phase helical CT.
AB  - OBJECTIVE: This study was conducted to evaluate newly introduced criteria for
      unresectability of pancreatic cancer with thin-section pancreatic-phase helical
      CT. MATERIALS AND METHODS: Twenty-five patients with adenocarcinoma in the head
      of the pancreas underwent thin-section pancreatic-phase helical CT. The major
      peripancreatic vessels were categorized on a scale of 1-4, according to the
      degree of circumferential involvement by tumor. The maximum diameters of the
      small peripancreatic veins--gastrocolic trunk, anterosuperior pancreaticoduodenal
      vein, and posterosuperior pancreaticoduodenal vein--were recorded. Findings on CT
      were compared with the results of surgery in each patient. RESULTS: Sixteen
      patients had surgically resectable tumors, and nine patients had surgically
      unresectable tumors. CT and surgical correlation was available for 98 major
      peripancreatic vessels; 85 were resectable and 13 were unresectable. Of category
      1 vessels, 72 (97%) of 74 were resectable at surgery. Of category 2 vessels, 12
      (71%) of 17 were resectable. One (50%) of two category 3 vessels and none (0%) of
      five category 4 vessels were resectable at surgery. CT showed a dilated
      gastrocolic trunk in two patients; one of these patients had a surgically
      resectable tumor, but the other patient had a surgically unresectable tumor.
      CONCLUSION: In patients with adenocarcinoma in the head of the pancreas, the
      degree of circumferential vessel involvement by tumor as shown by CT is useful in
      predicting which patients will have surgically unresectable tumors. A dilated
      gastrocolic trunk should not be used as an independent sign of surgical
      unresectability.

PMID- 10584795
TI  - Evaluation of the pancreas: a comparison of single thick-slice MR
      cholangiopancreatography with multiple thin-slice volume reconstruction MR
      cholangiopancreatography.
AB  - OBJECTIVE: The purpose of this study was to assess abilities of single thick
      slice MR cholangiopancreatography and multiple thin-slice multiprojection volume
      reconstruction (MPVR) MR cholangiopancreatography to evaluate diseases in and
      around the pancreas. SUBJECTS AND METHODS: Eighty-nine patients underwent both
      single and MPVR MR cholangiopancreatography using a single-shot fast spin-echo
      technique. Image quality (five-point scale), visualization of the common bile and
      pancreatic ducts (three-point scale), stenotic, dilatational, or cystic changes
      of the pancreatic ducts, and other pathologic findings were evaluated. RESULTS:
      Image quality was high for single and MPVR MR cholangiopancreatography (4.1+/-0.7
      and 4.5+/-0.6, respectively). Misregistration was noted in 19 patients with MPVR
      MR cholangiopancreatography. Ducts on and around the greater duodenal papilla and
      the common bile duct were revealed better using MPVR than single MR
      cholangiopancreatography (p < .05). Overall sensitivity, specificity, and
      accuracy for detection of stenosis of the main pancreatic ducts were 83.3%,
      93.6%, and 88.8%, respectively, using single MR cholangiopancreatography and
      76.2%, 97.9%, 87.6%, respectively, using MPVR MR cholangiopancreatography.
      Dilatation of the pancreatic ducts (100%) and cystic changes (n = 17 and n = 19,
      respectively) were well seen using either single or MPVR MR
      cholangiopancreatography. Although stenotic changes of the nondilated main
      pancreatic ducts and their branches were difficult to evaluate using single
      (62.5% and 14.3%, respectively) or MPVR (43.8% and 21.4%, respectively) MR
      cholangiopancreatography, single MR cholangiopancreatography better depicted
      ductal continuity. CONCLUSION: For evaluation of the pancreas, single and MPVR MR
      cholangiopancreatography provide complementary data; thus, we recommend using a
      combination of these two MR cholangiopancreatography techniques.

PMID- 10584796
TI  - Role of MR cholangiopancreatography in patients with failed or inadequate ERCP.
AB  - OBJECTIVE: The purpose of our study was to evaluate the usefulness of MR
      cholangiopancreatography in the diagnosis and further treatment of patients with
      failed or inadequate ERCP. SUBJECTS AND METHODS: Fifty-eight patients with failed
      or inadequate ERCP underwent MR cholangiopancreatography using a two-dimensional
      heavily T2-weighted multislice fast spin-echo technique. The final diagnosis was
      made on the basis of a second ERCP (n = 4), percutaneous transhepatic
      cholangiopancreatography (n = 19), intraoperative cholangiography (n = 6),
      percutaneous biopsy (n = 3), surgical findings (n = 5), or clinical follow-up (n
      = 21) for a mean period of 22 months (range, 7-31 months). RESULTS: MR
      cholangiopancreatography was technically successful in 57 patients and resulted
      in a sensitivity, specificity, and diagnostic accuracy of 97.1%, 100%, and 98.2%,
      respectively. Overall, MR cholangiopancreatography gave clinically useful
      information that contributed to patient management in 56 (96.6%) of the 58
      patients. On the basis of the MR cholangiopancreatography findings, patients were
      managed using a second ERCP (n = 4), combined percutaneous and endoscopic
      procedure (n = 2), percutaneous biliary stent insertion (n = 13), surgery (n =
      12), chemotherapy (n = 1), or conservative treatment (n = 24). CONCLUSION: MR
      cholangiopancreatography was found to have a unique and valuable role in the
      investigation of patients in whom ERCP failed or was inadequate. MR
      cholangiopancreatography helped us avoid using invasive procedures such as
      percutaneous transhepatic cholangiography in the diagnosis of bile duct disease
      after failed ERCP.

PMID- 10584797
TI  - Pancreatic changes in primary sclerosing cholangitis: evaluation with MR imaging.
AB  - OBJECTIVE: The purpose of this study was to determine the frequency and the
      spectrum of MR imaging findings of pancreatic abnormalities in patients with
      primary sclerosing cholangitis. MATERIALS AND METHODS: MR images in 24 patients
      with primary sclerosing cholangitis were retrospectively reviewed for evidence of
      pancreatic abnormalities, including abnormalities of signal intensity; changes in
      size and morphology; abnormalities of pancreatic ducts; presence of focal
      lesions, pseudocysts, and peripancreatic edema or fluid; and contrast-enhancement
      pattern if dynamic studies were available. RESULTS: Eleven patients with
      pancreatic abnormalities on MR images (case patients) and 13 patients with normal
      MR findings of the pancreas (cohort patients) were identified. The most common
      finding in case patients was increased signal intensity of the pancreas on T2
      weighted images (73%), followed by decreased signal intensity on T1-weighted
      images (55%) and decreased enhancement on arterial-phase contrast-enhanced images
      (50%). Other findings included marked enlargement of the pancreas (27%),
      narrowing of pancreatic ducts (27%), and peripancreatic edema or fluid (27%). The
      mean value of the anteroposterior diameter of the pancreatic head in the case
      patients was significantly greater than that in the cohort patients (p = .039).
      The mean signal-intensity ratio on the T2-weighted images was significantly
      higher in the case patients than in the cohort patients (p = .007). CONCLUSION:
      Increased signal on T2-weighted images, decreased signal on T1-weighted images,
      enlargement of the pancreas, and decreased contrast-enhancement were MR findings
      of pancreatic disease associated with primary sclerosing cholangitis.

PMID- 10584798
TI  - Percutaneous biliary drainage in patients with nondilated intrahepatic bile
      ducts.
AB  - OBJECTIVE: We evaluated the technical success and complications of percutaneous
      transhepatic biliary drainage in patients with nondilated intrahepatic bile
      ducts. MATERIALS AND METHODS: Between January 1, 1996, and August 31, 1998, 130
      percutaneous transhepatic biliary drainage procedures were performed on patients
      with nondilated intrahepatic bile ducts. This group comprised primarily patients
      who had received liver transplants or who had sustained iatrogenic bile duct
      injuries. Access in all procedures was performed using a one-step system
      consisting of a 21-gauge needle and an .018-inch guidewire. The technical success
      and complications of the procedures were evaluated. RESULTS: Percutaneous biliary
      drainage was successful in 117 (90%) of 130 attempts. In four patients, two
      attempts were required to place a drainage catheter. The overall complication
      rate was 9%. There were seven (5%) minor complications and five major
      complications (4%). No procedure-related deaths occurred. CONCLUSION:
      Percutaneous biliary drainage can be performed with a high success rate in
      patients with nondilated intrahepatic ducts. The incidence and types of
      complications in this population were similar to those reported in patients with
      intrahepatic ductal dilatation.

PMID- 10584799
TI  - MR imaging findings in recurrent pyogenic cholangitis.

PMID- 10584800
TI  - CO2 digital subtraction angiography for renal artery angioplasty in high-risk
      patients.
AB  - OBJECTIVE: The efficacy of CO2 digital subtraction angiography for performing
      renal artery angioplasty in high-risk patients was evaluated. SUBJECTS AND
      METHODS: From January 1997 to July 1998, 21 high-risk patients underwent 29 renal
      artery angioplasties using carbon dioxide as the principal contrast agent. Six
      patients had a known allergy to iodinated contrast material and 15 had elevated
      levels of creatinine. Iodinated contrast material was used only if necessary. All
      periprocedural allergic reactions were recorded. Before and 24 hr after the
      procedure, serum creatinine levels were obtained. If the creatinine level had
      become significantly elevated (>0.5 mg/dl), the creatinine level was acquired a
      second time. RESULTS: Twenty-one patients (13 men and eight women) underwent 29
      angioplasties (two were bilateral and six were repeated). Four kidney
      transplantation patients had ostial stenosis and the remaining 17 patients had
      nonostial stenosis. For all patients except one angioplasty initially was a
      technical success, as defined by a residual stenosis of less than 30%.
      Supplemental iodinated contrast material was used in only six patients (average
      dose, 8.5 ml). A range of 80-200 ml of carbon dioxide per procedure was used
      (average dose, 114.6 ml). One renal artery dissection occurred, which was
      unrelated to the carbon dioxide. There were no allergic reactions. The level of
      serum creatinine remained the same after 11 procedures, decreased after 12
      procedures, and increased minimally after four procedures (<0.5 mg/dl).
      CONCLUSION: On the basis of our preliminary findings in a small group of
      patients, using carbon dioxide as an intravascular contrast agent to perform
      renal artery angioplasty in patients who have an allergy to iodinated contrast
      material or who suffer from renal insufficiency is safe and efficacious.

PMID- 10584801
TI  - Recanalization of thrombosed superficial femoral arteries with a hydraulic
      thrombectomy catheter in a canine model.
AB  - OBJECTIVE: This experiment was conducted to evaluate efficacy and safety of the
      Oasis thrombectomy catheter on arterial thrombosis in dogs. MATERIALS AND
      METHODS: Thrombosis was induced in 18 femoral arteries of nine mongrel dogs.
      Recanalization of the thrombosed femoral artery was performed using a
      thrombectomy catheter 7-10 days after thrombus induction. Pre- and postprocedural
      arterial status was documented by angiography. After mechanical thrombectomy, the
      animals were sacrificed and the femoral arteries were harvested and examined
      macro- and microscopically. Additionally, in vitro fragmentation was carried out
      to determine particle size and distribution from the recovered effluent. RESULTS:
      Subacute thrombosis was successfully created in 15 femoral arteries. Full
      recanalization was achieved in 80% (12/15) of the thrombosed femoral arteries
      without any residual thrombus. No significant downstream embolization was
      documented angiographically. Endothelial denudation was observed in all the
      treated arteries along with occasional disruption of the internal elastic lamina.
      No medial injury was seen. Ninety-eight percent of thrombus was liquefied,
      defined as particles smaller than 15 microm, by the catheter. Particles larger
      than 400 microm represented 0.27% of the original clot weight. CONCLUSION:
      Occluded femoral arteries with 7- to 10-day-old thrombus can be efficiently
      recanalized with the Oasis catheter in dogs without any significant complication.
      This thrombectomy catheter appears to be highly effective and safe and requires
      no sophisticated equipment. Blood loss was our major concern regarding use of
      this catheter but can be minimized by strictly controlling activation time and
      restricting the inflow into the vascular segment being treated.

PMID- 10584802
TI  - Quantification of hemodynamic improvement after superficial femoral artery
      angioplasty by cine phase contrast MR angiography.

PMID- 10584804
TI  - X-linked adrenoleukodystrophy in children: review of genetic, clinical, and MR
      imaging characteristics.

PMID- 10584805
TI  - Children with congenital pulmonary lymphangiectasia: after infancy.
AB  - OBJECTIVE: The objective of this original report is to describe the
      characteristic chest imaging findings in children with primary congenital
      pulmonary lymphangiectasia who survive infancy. CONCLUSION: In children with
      primary congenital pulmonary lymphangiectasia, increased interstitial markings
      decrease over time and increased hyperinflation is associated with persistent
      patchy areas of ground-glass opacity.

PMID- 10584803
TI  - Sonographically guided compression repair of pseudoaneurysms: further experience
      from a single institution.
AB  - OBJECTIVE: Our purpose was to perform a comprehensive review of our experience
      with compression of postcatheterization groin pseudoaneurysms. MATERIALS AND
      METHODS: Two hundred eighty-one patients underwent 306 sonographically guided
      compression procedures on 297 groin pseudoaneurysms after femoral artery
      catheterization. The medical records, cardiac catheterization reports, and
      sonographic images were reviewed to determine patient demographics, type of
      catheterization procedure performed, sheath size, access site, interval from
      sheath removal to compression, anticoagulation status, pseudoaneurysm dimensions,
      complications, and follow-up information. Statistical analysis was performed
      using Pearson's chi-square and Kendall tau tests. RESULTS: The success rate for
      the initial compression attempt was 72.1%. Of the 83 failed compression attempts,
      12 patients underwent a second attempt, of which seven attempts were successful.
      Therefore, counting both first and second attempts, the success rate was 74.4%. A
      strong negative correlation existed between anticoagulation status and success,
      with a 70% failure rate in patients with anticoagulated blood. Smaller
      pseudoaneurysm size was strongly correlated with success. Of the 83 failed cases,
      49 ultimately underwent surgical repair. Eleven complications (3.6%) occurred,
      including three patients with rupture during compression. No deaths occurred as a
      result of compression repair. CONCLUSION: We conclude that sonographically guided
      pseudoaneurysm compression repair is an effective alternative to surgical repair,
      though nearly one third of compression attempts will fail and most of those
      patients will ultimately require surgery. The procedure is less effective when
      the patient's blood is anticoagulated and when the pseudoaneurysm is large. The
      procedure carries an overall complication rate of 3.6% and a risk for rupture of
      1%.

PMID- 10584806
TI  - Correlation between findings on chest radiography and survival in neonates with
      congenital diaphragmatic hernia.
AB  - OBJECTIVE: Predictors of survival are helpful when deciding on aggressiveness of
      care of neonates with congenital diaphragmatic hernia and respiratory failure. We
      evaluated findings on chest radiography as potential predictors of survival in
      these patients. MATERIALS AND METHODS: Findings on chest radiographs of neonates
      less than 24 hr old with congenital diaphragmatic hernia were evaluated.
      Radiographic findings analyzed included percentage of aerated ipsilateral lung,
      percentage of aerated contralateral lung, mediastinal shift, and hernia contents.
      Each finding was compared with survival (equated with hospital discharge) using a
      Mantel-Haenszel chi-square test. Survival was also determined using the total
      number of poor prognostic findings present in any one patient. RESULTS: In the 73
      neonates with congenital diaphragmatic hernia in our study, the overall survival
      rate was 55%. There were statistically significant relationships between survival
      rate and percentage of ipsilateral aeration (p = 0.001), percentage of
      contralateral aeration (p = 0.016), and mediastinal shift (p = 0.026). The
      survival rate for multiple poor prognostic factors was 0% with four of four
      factors and 20% with three of four factors (p = 0.001). Survival rate was not
      influenced by prematurity (p = 0.102), sex (p = 0.104), or side of hernia (p =
      0.895). CONCLUSION: Findings on initial chest radiography are helpful in
      predicting survival in neonates with congenital diaphragmatic hernia.

PMID- 10584807
TI  - Abnormalities of the chest wall in pediatric patients.
AB  - A variety of focal processes and diffuse abnormalities are found predominantly in
      children. In addition, thoracic manifestations of trauma differ in children
      because of increased chest wall compliance. Familiarity with both these
      abnormalities as well as the common normal variations provides optimal imaging
      evaluation.

PMID- 10584808
TI  - Sonography compared with radiography in revealing acute rib fracture.
AB  - OBJECTIVE: This study was undertaken to compare the sensitivities of sonography
      and radiography for revealing acute rib fracture. SUBJECTS AND METHODS: Chest
      radiography and rib sonography were performed on 50 patients with suspected rib
      fractures. Sonography was performed with a 9- or 12-MHz linear transducer.
      Fractures were identified by a disruption of the anterior margin of the rib,
      costochondral junction, or costal cartilage. The incidence, location, and degree
      of displacement of fractures revealed by radiography and sonography were
      compared. Sonography was performed again after 3 weeks in 37 subjects. RESULTS:
      At presentation, radiographs revealed eight rib fractures in six (12%) of 50
      patients and sonography revealed 83 rib fractures in 39 (78%) of 50 patients.
      Seventy-four (89%) of the 83 sonographically detected fractures were located in
      the rib, four (5%) were located at the costochondral junction, and five (6%) in
      the costal cartilage. Repeated sonography after 3 weeks showed evidence of
      healing in all reexamined fractures. Combining sonography at presentation and
      after 3 weeks, 88% of subjects had sustained a fracture. CONCLUSION: Sonography
      reveals more fractures than does radiography and will reveal fractures in most
      patients presenting with suspected rib fracture. Further scientific studies are
      needed to clarify the appropriate role for sonography in rib fracture detection.

PMID- 10584809
TI  - Helical CT of diaphragmatic rupture caused by blunt trauma.
AB  - OBJECTIVE: The purpose of this study was to determine the diagnostic sensitivity
      and specificity of helical CT with sagittal and coronal reformatted images in
      detecting diaphragmatic rupture after blunt trauma. MATERIALS AND METHODS: Chest
      and abdominal helical CT scans obtained in 41 patients with suspected
      diaphragmatic injury after major blunt trauma were reviewed by three observers
      who were unaware of surgical findings. Coronal and sagittal reformatted images
      were reviewed for each patient as well. Findings consistent with diaphragmatic
      injury, such as waistlike constriction of abdominal viscera (i.e., the "collar
      sign"), intrathoracic herniation of abdominal contents, and diaphragmatic
      discontinuity were recorded. Sensitivity and specificity of helical CT were
      calculated on the basis of surgical findings and clinical follow-up. RESULTS:
      Helical CT was performed preoperatively in 23 patients with diaphragmatic rupture
      (left, n = 17; right, n = 5; bilateral, n = 1). An additional 18 patients
      underwent helical CT to further evaluate suspicious findings seen on chest
      radiography at admission and were found to have an intact diaphragm. Sensitivity
      for detecting left-sided diaphragmatic rupture was 78% and specificity was 100%.
      Sensitivity for the detection of right-sided diaphragmatic rupture was 50% and
      specificity was 100%. The most common CT finding of diaphragmatic rupture was the
      collar sign, identified in 15 patients (sensitivity, 63%; specificity, 100%).
      Diaphragmatic discontinuity was seen in four patients. CONCLUSION: Helical CT,
      especially with the aid of reformatted images, is useful in the diagnosis of
      acute diaphragmatic rupture after blunt trauma. Helical CT can be used to detect
      78% of left-sided and 50% of right-sided injuries.

PMID- 10584810
TI  - Respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung
      disease, and desquamative interstitial pneumonia: different entities or part of
      the spectrum of the same disease process?
AB  - OBJECTIVE: Our objective was to assess high-resolution CT findings of respiratory
      bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease,
      and desquamative interstitial pneumonia and to determine whether these three
      entities could be reliably differentiated by radiologic criteria. MATERIALS AND
      METHODS: CT scans (1- to 3-mm collimation) were reviewed in 40 patients with
      pathologically proven respiratory bronchiolitis (n = 16), respiratory
      bronchiolitis-associated interstitial lung disease (n = 8), or desquamative
      interstitial pneumonia (n = 16). All patients with respiratory bronchiolitis and
      respiratory bronchiolitis-associated interstitial lung disease were cigarette
      smokers, and 85% of the patients with desquamative interstitial pneumonia had a
      history of smoking. CT scans were independently reviewed by two radiologists who
      assessed the pattern and distribution of abnormalities. RESULTS: The predominant
      abnormalities in respiratory bronchiolitis were centrilobular nodules (12 [75%]
      of 16 patients) and ground-glass attenuation (six [38%] of 16). No single
      abnormality predominated in the respiratory bronchiolitis-associated interstitial
      lung disease group; findings included ground-glass attenuation (four [50%] of
      eight), centrilobular nodules (three [38%] of eight), and mild fibrosis (two
      [25%] of eight). All patients with desquamative interstitial pneumonia showed
      ground-glass attenuation, and 10 (63%) of the 16 showed evidence of fibrosis.
      CONCLUSION: The significant overlap between the CT findings of respiratory
      bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease,
      and desquamative interstitial pneumonia is consistent with the concept that they
      represent different degrees of severity of small airway and parenchymal reaction
      to cigarette smoke.

PMID- 10584811
TI  - High-resolution CT findings of diffuse bronchioloalveolar carcinoma in 38
      patients.
AB  - OBJECTIVE: The purpose of this study was to analyze the high-resolution CT
      features of diffuse bronchioloalveolar carcinoma and determine the useful
      findings in differential diagnosis. MATERIALS AND METHODS: High-resolution CT
      scans of 38 patients with pathologically proven diffuse bronchioloalveolar
      carcinoma were reviewed. Sequential CT scans were obtained in 15 patients. The
      high-resolution CT findings were compared with those of eosinophilic pneumonia (n
      = 22), multiple pulmonary metastases (n = 12), and tuberculosis (bronchogenic: n
      = 22; miliary: n = 12). RESULTS: High-resolution CT findings of diffuse
      bronchioloalveolar carcinoma included ground-glass opacity (n = 29),
      consolidation (n = 29), nodules (n = 28), centrilobular nodules (n = 26),
      peripheral distribution (n = 19), and air bronchogram (n = 18). According to the
      major features, high-resolution CT findings of diffuse bronchioloalveolar
      carcinoma could be classified into three patterns: predominantly ground-glass (n
      = 4), consolidative (n = 22), and multinodular (n = 12). Most patients with
      diffuse bronchioloalveolar carcinoma had a mixture of these findings. The
      frequency of findings of diffuse bronchioloalveolar carcinoma on high-resolution
      CT was not different from that of tuberculosis, but the predominant distribution
      of the nodules and areas of ground-glass attenuation differed between the two.
      Difference in distribution between bronchioloalveolar carcinoma and bronchogenic
      tuberculosis included ground-glass opacity remote from the consolidation and a
      lower lung predominance. CONCLUSION: Although these high-resolution CT findings
      are not specific, the combination of consolidation and nodules and the
      coexistence of centrilobular nodules and remote areas of ground-glass attenuation
      are characteristic of diffuse bronchioloalveolar carcinoma.

PMID- 10584812
TI  - Thoracic manifestations of neurofibromatosis-I.
AB  - The intrathoracic manifestations of neurofibromatosis-I are protean and can, on
      occasion, mimic those of malignancy. Many of the intrathoracic findings are
      characteristic of the disease and can be expected to be present. Knowledge of the
      full spectrum of radiologic findings can thus be useful in preventing diagnostic
      error. Furthermore, an unexpected finding, such as rapid growth of a neural
      tumor, should be recognized as an atypical feature (suspicious for malignant
      degeneration) and result in further evaluation.

PMID- 10584813
TI  - Pulmonary tuberculosis in patients with systematic lupus erythematosus.
AB  - OBJECTIVE: The purpose of our study was to describe radiologic manifestations of
      pulmonary tuberculosis in patients with systemic lupus erythematosus. CONCLUSION:
      The prevalence of pulmonary tuberculosis was high in patients with systemic lupus
      erythematosus. Imaging of these patients showed miliary dissemination and patchy
      consolidation. However, cavitation was rare. These findings may reflect impaired
      immune response against tuberculous bacilli.

PMID- 10584814
TI  - Mammographic determination of breast volume: comparing different methods.
AB  - OBJECTIVE: The purpose of this study was to compare the accuracy and
      reproducibility of different methods for calculating breast volume when using
      measurements made on mammograms. MATERIALS AND METHODS: The volumes of 32 breasts
      were determined by pathologic evaluation of mastectomy specimens. Two
      radiologists independently measured breast height and width on the preoperative
      craniocaudal mammograms and measured height, width, and width at half-height on
      mediolateral oblique mammograms. Compression thicknesses used on the craniocaudal
      and mediolateral oblique projections were recorded. Volume was then calculated
      using six different formulas. The accuracy of each method was determined and
      compared using bivariate and univariate linear regression analyses. Interobserver
      variability in measurement was also assessed. RESULTS: The most accurate method
      for calculating breast volume was the one that assumed a half-elliptic cylinder
      shape for the compressed breast in the craniocaudal projection. Measurements made
      on the craniocaudal view were more reproducible than those made on the
      mediolateral oblique view. CONCLUSION: Breast volume can be accurately and
      reproducibly determined on mammograms by making two measurements on the
      craniocaudal view and knowing the compression thickness. This information may be
      useful to plastic surgeons, investigators who study parenchymal patterns, and
      physicians who examine cancer patients being considered for breast conservation
      surgery.

PMID- 10584815
TI  - Effect of age and breast density on screening mammograms with false-positive
      findings.
AB  - OBJECTIVE: The objective of this study was to examine the effect of breast
      density and age on screening mammograms with false-positive findings. MATERIALS
      AND METHODS: The study sample was taken from the Washington State Mammography
      Tumor Registry, which links data from participating radiologists with the Puget
      Sound Cancer Surveillance System and the Washington State Cancer Registry.
      Participants (n = 73,247) were women 35 years old and older who underwent
      screening mammography for which an assessment and a four-category density rating
      were coded. A total of 46,340 mammograms were sampled to avoid interpreter bias.
      In this study of false-positive mammograms, only women with no diagnosis of
      breast cancer within 12 months of the index mammogram were included. Logistic
      regression was used to estimate the odds ratios of a false-positive mammogram
      being associated with each category of breast density or age, adjusting for the
      other factor as a covariate. RESULTS: After controlling for breast density, we
      found that the risk of a false-positive mammogram was not affected by age (p =
      27). However, the trend of increasing risk of a false-positive mammogram with
      increasing breast density was highly significant (p < .001). Women with extremely
      dense breast tissue were almost two times more likely to have a false-positive
      mammogram than were women with fatty breast tissue. This effect persisted after
      controlling for age. CONCLUSION: Breast density, not age, is an important factor
      when predicting risk of a false-positive mammogram. Breast density should be
      considered when educating individual women on the risks and benefits of screening
      mammography.

PMID- 10584817
TI  - Compartmental anatomy: relevance to staging and biopsy of musculoskeletal tumors.
AB  - A thorough understanding of compartmental anatomy is essential for accurate
      staging of a suspected musculoskeletal tumor with MR imaging and for avoiding
      potentially devastating biopsy-related complications. Imaging-guided,
      percutaneous needle biopsy is a safe and cost-effective technique but requires
      careful planning in conjunction with the surgeon who will perform the definitive
      surgery because it constitutes the final step in the staging process and the
      first step in surgical therapy.

PMID- 10584816
TI  - Focal fibrosis: a common breast lesion diagnosed at imaging-guided core biopsy.
AB  - OBJECTIVE: Focal fibrosis is a benign breast lesion commonly diagnosed by imaging
      guided core biopsy. The goal of this study is to determine the frequency of focal
      fibrosis diagnosed at core biopsy and to describe its imaging features. MATERIALS
      AND METHODS: A consecutive series of 894 imaging-guided breast core biopsies were
      reviewed, and all cases of focal fibrosis were selected. The imaging features of
      each lesion were characterized. All lesions had been reviewed during radiologic
      histologic review sessions to assess for accurate needle positioning and
      concordant results. Follow-up imaging and histologic data were reviewed to
      document lesion stability. RESULTS: Focal fibrosis was diagnosed in 80 (8.9%) of
      894 imaging-guided core biopsies: 20 (8.7%) of 229 sonographically guided
      biopsies and 60 (9.0%) of 665 mammographically guided biopsies. Of 75
      mammographically visible lesions, 39 (52%) were masses, 29 (39%) were densities,
      and seven (9.3%) were clusters of calcifications. Thirty-five hypoechoic lesions
      were visualized on sonography: 29 (80%) were oval, and six (17%) were irregularly
      shaped. Six (21%) of the 28 oval masses showed posterior enhancement, four (14%)
      posterior shadowing, and 19 (68%) neither feature. Fifty-two (65%) of 80 patients
      with focal fibrosis had routine imaging follow-up; all had stable findings (mean
      follow-up period, 27 months). No false-negative cases were identified.
      CONCLUSION: Focal fibrosis most commonly appears as an enlarging solid mass or
      developing density on mammography or as an oval mass on sonography. Our data
      suggest that focal fibrosis accounts for 9% of lesions that undergo imaging
      guided core biopsy and that the diagnosis can be accurately reached using imaging
      guided biopsy.

PMID- 10584818
TI  - Conventional radiography, CT, and MR imaging in patients with hyperflexion
      injuries of the foot: diagnostic accuracy in the detection of bony and
      ligamentous changes.
AB  - OBJECTIVE: The goal of this study was to compare the capabilities of conventional
      radiography, CT, and MR imaging in revealing ligamentous and bony changes in
      patients after hyperflexion injuries. SUBJECTS AND METHODS: Forty-nine patients
      with hyperflexion injuries of the foot were included in our study. Conventional
      radiography, weight-bearing radiography, CT, and MR imaging were performed. All
      images were reviewed with respect to ligamentous and bony abnormalities and
      alignment alterations. Eleven patients with joint malalignment underwent surgery,
      which is considered the gold standard in these patients. Five patients with joint
      malalignment refused surgery. RESULTS: For all 49 patients, conventional
      radiographs revealed 33 metatarsal and 20 tarsal fractures. Eight patients
      presented with tarsometatarsal joint (Lisfranc's joint) malalignment. Weight
      bearing radiographs showed joint malalignment in the same eight patients only. CT
      showed 41 tarsal fractures and 53 metatarsal fractures. Joint malalignment was
      evident in 16 patients. MR imaging revealed 41 metatarsal fractures and 18
      metatarsal bone bruises. Tarsal bones were fractured at 39 sites and there were
      nine tarsal bone bruises. Metatarsal fractures were mostly localized in the
      second metatarsal bone; tarsal fractures, in the cuboid. Joint malalignment was
      evident in 16 patients; in 11 of these 16 patients, Lisfranc's ligament was
      disrupted. Surgery confirmed bony and ligamentous changes and joint malalignment
      in 11 patients. CONCLUSION: Conventional radiographs including weight-bearing
      images are not sufficient for routine diagnostic workup of patients with acute
      hyperflexion injuries of the foot. CT should serve as the primary imaging
      technique for such patients.

PMID- 10584819
TI  - Hyperextension vertebral body fractures in diffuse idiopathic skeletal
      hyperostosis: a cause of intravertebral fluidlike collections on MR imaging.
AB  - OBJECTIVE: We describe an intravertebral fluidlike collection observed on MR
      images in five of six patients who sustained vertebral body fracture through a
      segment of the spine ankylosed by diffuse idiopathic skeletal hyperostosis. The
      mechanism of injury, clinical course, conventional radiographs, CT scans, and
      other MR imaging findings are analyzed. CONCLUSION: Intravertebral fluidlike
      collections were associated with hyperextension injury of the spine. Well
      delineated borders, anterior widening, and associated posterior-element injury
      are the main MR imaging characteristics of this trauma-related intravertebral
      fluidlike collection.

PMID- 10584821
TI  - Imaging features of primary lymphoma of bone.
AB  - OBJECTIVE: Our objective was to describe the imaging appearances of primary
      lymphoma of bone, including conventional radiographic, scintigraphic, CT, and MR
      imaging features. MATERIALS AND METHODS: We retrospectively reviewed 237
      pathologically proven cases of primary lymphoma of bone. Evaluation included
      patient age, sex, lesion location, and pattern of bone destruction. Pathologic
      type, periosteal reaction, sequestrum, soft-tissue mass, extension across joints,
      and pathologic fracture were also noted. RESULTS: The study population included
      151 males and 86 females (ratio 1.8:1; range, 2-88 years; mean age, 42 years).
      Common locations were the distal femoral diametaphysis; proximal metadiaphysis of
      the tibia, femur, and humerus; and femoral mid shaft. Long bones were involved
      more often than flat bones (71% versus 22%). Common appearances were a lytic
      (70%) or mixed-density (28%) lesion with most cases showing a permeative or moth
      eaten pattern (74%). Periosteal reaction was seen in 58% of the long bones.
      Sequestra were found in 37 patients (16%). Soft-tissue masses were present in 113
      patients (48%). Extension across joints was seen in nine patients (4%).
      Pathologic fractures occurred in 53 patients (22%). Radionuclide (n = 56), CT (n
      = 45), and MR (n = 20) features were usually nonspecific. Pathologic types
      included non-Hodgkin's (n = 223) and Hodgkin's (n = 14) lymphoma. CONCLUSION:
      Primary lymphoma of bone most often involves the diametaphysis of a major long
      bone and has an aggressive pattern of lytic bone destruction and associated soft
      tissue mass. CT and MR imaging can suggest the diagnosis, particularly when a
      large soft-tissue mass and abnormal marrow attenuation or signal intensity is
      seen without extensive cortical destruction.

PMID- 10584820
TI  - Acute osteoporotic vertebral collapse: open study on percutaneous injection of
      acrylic surgical cement in 20 patients.
AB  - OBJECTIVE: The aim of this study was to determine the efficacy of percutaneous
      vertebroplasty in treating painful spinal osteoporotic collapse. SUBJECTS AND
      METHODS: Twenty-three cases of vertebral collapse were evaluated with CT and MR
      imaging to determine osteoporotic origin and recent evolution. Percutaneous
      vertebroplasties were performed using CT guidance. The 20 patients included in
      the study (17 women, 3 men; 62-92 years old) had acute pain of less than 1
      month's duration that hindered ambulation and required treatment with narcotic
      drugs. They underwent this procedure for analgesic purposes. The analogic visual
      scale of Huskisson was used for pain when scoring assessment. RESULTS: In 15
      patients (75%), pain relief was complete within 24 hr after injection. Analgesic
      administration was stopped in 14 patients. Mild pain persisted in three (15%) of
      the remaining five patients. In one other patient (5%), crural pain was observed
      with cement leakage in the psoas muscle. In the fifth patient (5%), pain recurred
      after the patient was lifted. The pain was related to a new acute collapse of an
      adjacent vertebrae. CONCLUSION: Vertebroplasty for the treatment of osteoporotic
      vertebral collapse is a minimally invasive procedure that provides immediate pain
      relief and enables the patient to become quickly mobile.

PMID- 10584822
TI  - Imaging findings in tumors of the sacrum.

PMID- 10584823
TI  - When is large core breast biopsy really large core?

PMID- 10584824
TI  - Radiation hazards involved in CT dacryocystography.

PMID- 10584825
TI  - Which primary diagnostic tool should be used for blunt abdominal trauma?

PMID- 10584826
TI  - Residents learning and applying research methodology.

PMID- 10584827
TI  - Hydroxyapatite-associated arthritis of a thoracic costovertebral joint.

PMID- 10584828
TI  - Profound neocortical atrophy after prolonged, continuous status epilepticus.

PMID- 10584829
TI  - Incidentally diagnosed Marchiafava-Bignami disease.

PMID- 10584830
TI  - Choledochal cyst and adult intestinal malrotation: a rare association.

PMID- 10584831
TI  - Splenic extramedullary hematopoiesis: large focal lesion in a patient with
      thalassemia.

PMID- 10584832
TI  - Endobronchial lipoma: helical CT diagnosis.

PMID- 10584833
TI  - Localization of hand motor activation in Broca's pli de passage moyen.
AB  - OBJECT: The object of this study was to identify a reliable surface landmark for
      the hand motor area and to demonstrate that it corresponds to a specific
      structural component of the precentral gyrus. METHODS: Positron emission
      tomography (PET) activation studies for hand motor function were reviewed in 12
      patients in whom magnetic resonance imaging results were normal. Each patient
      performed a hand opening and closing task. Using a computer-assisted three
      dimensional reconstruction of the surface of each hemisphere studied, the
      relationship of the hand motor area with cortical surface landmarks was
      evaluated. CONCLUSIONS: The region of hand motor activation can be reliably
      identified on the surface of the brain by assessing anatomical relationships to
      nearby structures. After identification of the central sulcus, the superior and
      middle frontal gyrus can be seen to arise from the precentral gyrus at a
      perpendicular angle. A bend or genu in the precentral gyrus is constantly seen
      between the superior and middle frontal gyrus, which points posteriorly
      (posteriorly convex). The location of hand motor function, identified using PET
      activation studies, is within the central sulcus at the apex of this posteriorly
      pointing genu. The apex of the genu of the precentral gyrus leads to a deep
      cortical fold connecting the pre- and postcentral gyri and elevating the floor of
      the central sulcus. This deep fold was described by Paul Broca as the pli de
      passage fronto-parietal moyen, and the precentral bank of the pli de passage
      represents the anatomical substratum of hand motor function. Observers blinded to
      the results of the activation studies were able to identify the hand motor area
      reliably after instruction in using these surface landmarks.

PMID- 10584834
TI  - A prospective comparison between three-dimensional magnetic resonance imaging and
      ventriculography for target-coordinate determination in frame-based functional
      stereotactic neurosurgery.
AB  - OBJECT: The purpose of this prospective study was to compare stereotactic
      coordinates obtained with ventriculography with coordinates derived from
      stereotactic computer-reconstructed three-dimensional magnetic resonance (3D-MR)
      imaging in functional stereotactic procedures. METHODS: In 15 consecutive
      patients undergoing functional stereotactic procedures, both preoperative frame
      based stereotactic 3D-MR imaging and intraoperative ventriculography were
      performed. Differences between 3D-MR imaging and ventriculography in X, Y, and Z
      coordinates of the anterior commissure (AC), posterior commissure (PC), and
      target area were calculated, as well as the 3D distance between the position of
      AC, PC, and target within stereotactic space as obtained using both methods. The
      position of the stereotactic MR imaging fiducial markers measured using 3D-MR
      imaging compared well with the markers' known position embedded in the software
      (mean error 0.4 mm, maximal error for an individual slice 1.2 mm). For the
      individual coordinates, only for Y-PC was a difference found between 3D-MR
      imaging and ventriculography that significantly exceeded half the size of a
      pixel, the theoretical limit of precision when using a digitized imaging
      technique. However, the mean difference was smaller than 1 mm. The mean 3D
      distance between the 3D-MR imaging- and ventriculography-derived coordinates was
      1.09 mm for AC, 1.13 mm for PC, and 1.29 mm for the targets. CONCLUSIONS: With
      these data it is shown that there is sufficient agreement between
      ventriculography-derived and 3D-MR imaging-derived stereotactic coordinates to
      justify the use of 3D-MR imaging target determination in frame-based functional
      stereotactic neurosurgery.

PMID- 10584835
TI  - Presurgical motor and somatosensory cortex mapping with functional magnetic
      resonance imaging and positron emission tomography.
AB  - OBJECT: Accurate identification of eloquent cortex is important to ensure that
      resective surgery in the region surrounding the central sulcus is performed with
      minimum risk of permanent neurological deficit. Functional localization has
      traditionally been accomplished using intraoperative cortical stimulation (ICS).
      However, this technique suffers from several disadvantages that make the
      development and validation of noninvasive methods desirable. Functional
      localization accomplished by activation studies in which positron emission
      tomography (PET) scanning and the tracer [15O]H2O have been used has been shown
      to correlate well with the results of ICS. Another noninvasive method for
      functional localization is functional magnetic resonance (fMR) imaging. We
      compared the locations of activation peaks obtained in individual patients using
      fMR and [15O]H2O PET imaging. METHODS: Twenty-six combined PET activation-fMR
      imaging studies were performed in 11 patients who were admitted for evaluation
      before undergoing surgery in the region surrounding the central sulcus. The PET
      scans were obtained using bolus injections of the cerebral blood flow tracer
      [15O]H2O (10 mCi). Multislice T2*-weighted gradient-echo echoplanar images were
      acquired using a 1.5-tesla MR imaging system. Activation maps were aligned with
      anatomical MR images and transformed into stereotactic space, after which the
      locations of activation peaks obtained using both modalities were compared. The
      average distance between activation peaks obtained using fMR imaging and those
      obtained using PET imaging was 7.9+/-4.8 mm (p>0.05), with 96% of the peaks being
      located on either the same or adjacent sulci and gyri. Overlapping of voxels
      activated by each modality occurred in 92% of the studies. Functional MR imaging
      failed to activate the primary sensorimotor cortex in one study and produced
      results that were ambiguous in the clinical setting in three cases. CONCLUSIONS:
      Overall, fMR imaging produced activation that correlated well with that obtained
      using PET scanning. Discrepancies between the sites of activation identified
      using these two techniques may reflect differences in their physiological bases.

PMID- 10584836
TI  - Identification of motor pathways during tumor surgery facilitated by multichannel
      electromyographic recording.
AB  - OBJECT: The goal of this study was to determine the usefulness of
      electromyographic (EMG) recording in locating motor pathways near the central
      sulcus or internal capsule during surgery. METHODS: Multichannel EMG recordings
      were compared with visual observation of contralateral body movement that was
      elicited by direct cortical or subcortical stimulation used to identify motor
      pathways before and during tumor resection. The EMG recordings were more
      sensitive than visual observation alone in identifying motor responses: in 30% of
      cases, responses were identified by EMG recording alone at some point during the
      operation and, in 9% of cases, EMG responses were the only responses observed.
      Additionally, EMG recordings often detected seizure activity resulting from
      electrical stimulation of the cortex that could not be appreciated on visual
      inspection. No new motor deficits were seen postoperatively in 88% of the
      patients in this series. CONCLUSIONS: Using EMG recording in addition to motor
      pathway mapping results in greater sensitivity, allowing the use of lower
      stimulation levels and facilitating detection of stimulation-induced seizure
      activity.

PMID- 10584837
TI  - Noninvasive evaluation of the malignant potential of intracranial meningiomas
      performed using proton magnetic resonance spectroscopy.
AB  - OBJECT: Controversy exists about correlations between histological tumor grade
      and magnetic resonance (MR) spectroscopy data. The authors studied single-voxel
      proton MR spectroscopy as a noninvasive way to evaluate grade of malignancy in
      intracranial meningiomas. METHODS: The authors compared the results of MR
      spectroscopy with those derived by the MIB-1 staining index (SI) in 29
      meningiomas. Proton MR spectroscopy was performed using stimulated echo
      acquisition and volume-localized solvent-attenuated proton nuclear MR sequences
      before surgery or other therapy. Twenty-four tumors were histologically benign
      (13 meningothelial, three fibrous, four transitional, three angiomatous, and one
      chordoid); four were atypical (Grade II), and one was papillary (Grade III). The
      mean MIB-1 SI in the benign group was significantly lower than those in the other
      groups (p = 0.0041). The mean choline-containing compound (Cho)/ creatine and
      phosphocreatine (Cr) ratios in the benign and nonbenign groups were 2.56+/-1.26
      and 7.85+/-3.23, respectively (p = 0.0002). A significant linear correlation was
      observed between the Cho/Cr ratio and the MIB-1 SI (r0.05 = 0.74, p<0.001).
      Necrosis was present histologically in four of the five meningiomas classified
      either as atypical or papillary. Magnetic resonance spectroscopy revealed a
      methylene signal in these meningiomas that was not detected in benign
      meningiomas. Of the five meningiomas in which only a lactate signal was observed,
      two were benign and the MIB-1 SI in these two benign meningiomas was higher than
      the mean value for the benign group. Alanine, detected in 12 of 30 meningiomas,
      did not correlate with either tumor grade or Cho/Cr ratio. CONCLUSIONS: Proton MR
      spectroscopy is a useful diagnostic method for determining the proliferative or
      malignant potential of meningiomas according to the Cho/Cr ratio. A lactate
      and/or methylene signal suggests a high-grade tumor.

PMID- 10584838
TI  - Apoptotic elimination of peripheral T lymphocytes in patients with primary
      intracranial tumors.
AB  - OBJECT: Patients with gliomas exhibit severe T lymphopenia during the course of
      the disease. This study was conducted to determine the mechanism(s) responsible
      for the lymphopenia. METHODS: Using two-color fluorescent staining techniques,
      the authors show that significant numbers of T cells undergo apoptosis in the
      peripheral blood of patients with gliomas. To determine whether a glioma-derived
      factor(s) induces this apoptosis, rosette-purified T cells obtained from healthy
      donors were treated with glioma cell culture supernatant (GCCS) and examined for
      apoptosis. It is demonstrated that treatment of normal T cells with GCCS induced
      apoptosis only with concurrent stimulation of the T-cell receptor/CD3 complex.
      The addition of neutralizing antibodies to interleukin (IL)-10, IL-4,
      transforming growth factor alpha, or tumor necrosis factor-beta (lymphotoxin) did
      not rescue these T cells from apoptosis. Experiments were also conducted in which
      the degree of monocyte involvement in the induction of T-cell apoptosis was
      explored. The U937 cells were pretreated for 20 hours with a 1:20 dilution of
      GCCS. After the removal of GCCS, the U937 cells were cultured in transwell assays
      with stimulated T cells. Although control U937 cells did not induce apoptosis of
      the activated T cells, GCCS-pretreated U937 cells induced appreciable apoptosis
      in normal, stimulated T-cell cultures. CONCLUSIONS: These data indicate that one
      mechanism by which gliomas cause immunosuppressive effects is the induction of
      monocytes to release soluble factors that promote activated T-cell apoptosis. The
      loss of activated T cells leads to T lymphopenia and contributes to the
      deficiencies in cell-mediated immunity that have been observed during testing of
      glioma patients' immune function.

PMID- 10584839
TI  - Improved efficiency of hypervolemic therapy with inhibition of natriuresis by
      fludrocortisone in patients with aneurysmal subarachnoid hemorrhage.
AB  - OBJECT: To reduce the risk of ischemic complications in patients with
      subarachnoid hemorrhage (SAH), hypervolemic therapy is generally advocated.
      However, such conventional treatment cannot always ensure the maintenance of an
      effective intravascular volume expansion, because excessive natriuresis and
      osmotic diuresis occur after SAH. In this prospective study the authors examined
      the effects of inhibition of natriuresis with fludrocortisone acetate on
      intravascular volume expansion during hypervolemic therapy. METHODS: Thirty
      patients with SAH were randomized and divided into two groups: controls (Group 1,
      15 patients) and patients treated with 0.3 mg/day of fludrocortisone (Group 2, 15
      patients). In all patients sodium and fluid intake levels were in excess of
      maintenance requirements in an attempt to maintain a positive water balance and a
      central venous pressure (CVP) of 8 to 12 cm H2O. The mean sodium and water intake
      levels for 14 days after SAH were significantly reduced by fludrocortisone in
      Group 2 (487+/-34.52 mEq/day and 5159.2+/-249.29 ml/day, respectively; p<0.01)
      compared with Group 1 (634.2+/-42.86 mEq/day and 6611.7+/-365.67 ml/day).
      Fludrocortisone significantly reduced the urinary sodium excretion (p<0.01) and
      urine volume (p<0.01) in parallel, and effectively prevented a negative shift in
      the sodium as well as water balance (p<0.01). The serum sodium level tended to
      decrease in Group 1, reaching 135 mEq/L on average, but not in Group 2 (p<0.01).
      Hyponatremia in Group 1 was always observed at the optimal range of CVP values. A
      decrease in serum potassium level within the range of 2.8 to 3.5 mEq/L was
      transiently noted in 11 patients (73.3%) of Group 2, but was easily corrected.
      Possible side effects of fludrocortisone, such as pulmonary edema, were not
      encountered. CONCLUSIONS: Intravascular volume expansion in the presence of
      excessive natriuresis requires a large sodium and water intake and is often
      associated with hyponatremia. Inhibition of natriuresis with fludrocortisone can
      effectively reduce the sodium and water intake required for hypervolemia and
      prevent hyponatremia at the same time.

PMID- 10584840
TI  - Ventricular pressure monitoring during bilateral decompression with dural
      expansion.
AB  - OBJECT: The management of massive brain swelling remains an unsolved problem in
      neurosurgery. Despite newly developed medical and pharmacological therapy, the
      rates of mortality and morbidity caused by massive brain swelling remain high.
      According to many recent reports, surgical decompression with dural expansion is
      superior to medical management in patients with massive brain swelling. To show
      the quantitative effect of decompressive surgery on intracranial pressure (ICP),
      the authors performed a ventricular puncture and measured the ventricular ICP
      continuously during decompressive surgery and the postoperative period. METHODS:
      Twenty patients with massive brain swelling who underwent bilateral decompressive
      craniectomy with dural expansion were included in this study. In all patients,
      ventricular puncture was performed at Kocher's point on the side opposite the
      massive brain swelling. The ventricular puncture tube was connected to the
      continuous monitor via a transducer device. The ventricular pressure was
      monitored continuously, during the bilateral decompressive procedures and
      postoperative period. The initial ventricular ICP was variable, ranging from 16
      to 65.8 mm Hg. Immediately after the bilateral craniectomy, the mean ventricular
      ICP decreased to 50.2+/-16.6% of the initial ICP (range 5-51.5 mm Hg). Additional
      opening of the dura decreased the mean ICP by an additional 34.5% and reduced the
      ventricular pressure to 15.7+/-10.7% of the initial pressure (range 0-15 mm Hg).
      Ventricular pressure measured postoperatively in the neurosurgical intensive care
      unit was lowered to 15.1+/-16.5% of the initial ICP. The ventricular ICP trend in
      the first 24 hours after decompressive surgery was an important prognostic
      factor; if it was greater than 35 mm Hg, the mortality rate was 100%.
      CONCLUSIONS: Bilateral decompression with dural expansion is an effective
      therapeutic modality in the control of ICP. To obtain favorable clinical outcomes
      in patients with massive brain swelling, early decision making and proper patient
      selection are very important.

PMID- 10584841
TI  - Empty sella syndrome: does it exist in children?
AB  - OBJECT: The empty sella syndrome (ESS) is well documented in adults, and although
      the same phenomenon of herniation of the arachnoid space into the enlarged sella
      turcica has been noted in children, it is not widely known that children suffer
      from this syndrome. Therefore, the aims of this paper are to increase
      neurosurgeons' awareness of the existence of this phenomenon in children and to
      add to the scant body of literature on the subject. METHODS: The authors treated
      12 children, ranging in age between 2 and 8 years, in whom neuroradiological
      studies demonstrated an enlarged sella turcica filled with cerebrospinal fluid
      and herniation of suprasellar and arachnoid spaces. The causes of ESS in these
      children were high intracranial pressure, neglected or improperly treated
      hydrocephalus, and suprasellar arachnoid cyst. Primary ESS was found as well.
      Most of the children presented with headache, abnormal body weight (the majority
      being underweight), and short stature. The results of hormone assays were normal
      in all children. CONCLUSIONS: If undiagnosed and untreated, ESS in children may
      lead to serious consequences, including impairment of pituitary and hypothalamic
      function and damage to the optic chiasm. It is important to raise awareness in
      the neurosurgical community about the existence of ESS in children so that it can
      be diagnosed and treated at an early stage. A classification system for the
      diaphragma sellae is recapitulated.

PMID- 10584842
TI  - Neuroendoscopic approach to tectal tumors: a consecutive series.
AB  - OBJECT: The authors report a consecutive series of 10 patients who presented with
      signs and symptoms caused by tectal tumors. Clinical findings, radiographic
      features, neuroendoscopic management strategies, and histological findings are
      reported and discussed. METHODS: Since January 1990, 11 neuroendoscopic
      procedures were performed in 10 patients who harbored tectal tumors. The patients
      were followed for an average of 5 years (range 2 months-11 years), and a
      retrospective study was conducted in which case notes, radiological findings,
      operative notes, and histopathological findings were assessed. Magnetic resonance
      (MR) imaging was performed, and the images were used to classify patients into
      three groups: those with hypertrophy of the tectum in whom isointensity appeared
      on T1-weighted images (Group 1); those with a tectal tumor occupying the cerebral
      aqueduct in whom decreased signal intensity appeared on T1-weighted images, as
      well as no enhancement after gadolinium administration (Group 2); and those with
      a tectal tumor in whom mixed signal intensity and conspicuous evidence of
      contrast enhancement appeared on T1-weighted images (Group 3). The results of
      histological examination were consistent with MR imaging features: in Group 1,
      glial tissue or gliosis; in Group 2, benign astrocytoma; and in Group 3,
      malignant astrocytoma. Cerebrospinal fluid diversion was the only surgical
      treatment that provided relief from obstructive hydrocephalus. One patient in
      Group 3 underwent radiotherapy and subsequent partial tumor removal under
      neuroendoscopic guidance. Thereafter, the tumor remained in decline. All patients
      had normal intellectual status after undergoing surgery in which a neuroendoscope
      was used. CONCLUSIONS: Neuroendoscopic procedures can provide histological
      diagnosis, define the tumor-midbrain interrelationship, and be highly effective
      in treating obstructive hydrocephalus and in removing tectal tumors. This
      procedure may receive clinical application as a new management strategy for
      tectal glioma.

PMID- 10584843
TI  - Medulloblastoma with extensive nodularity: a variant with favorable prognosis.
AB  - OBJECT: Some medulloblastomas (MBs) are characterized by extreme nodularity and
      intranodular nuclear uniformity in a fine fibrillary background. These lesions
      have also been designated as "cerebellar neuroblastoma." Although numerous
      reports have been published in which their morphological features have been
      investigated, only a few studies have been focused on their neuroradiological
      appearance, biological behavior, and response to therapy. The goal of this study
      was to gather more information about these lesions. METHODS: The authors present
      11 cases of MB with extensive nodularity. Five patients were boys and six were
      girls; all but one were 24 months of age or younger at diagnosis. Magnetic
      resonance imaging disclosed a peculiar grapelike architecture in eight cases.
      Surgical tumor removal was complete in nine cases and partial in one. In the
      other case a biopsy sample of the tumor was obtained after a preoperative course
      of chemotherapy. After surgery, two children were treated with radiotherapy alone
      and one with craniospinal irradiation followed by systemic chemotherapy. Eight
      patients were treated with chemotherapy only. All the patients in the study are
      presently alive with a median follow up of 66 months. Eight patients (73%) are in
      complete remission at 35 to 156 months. Three patients treated with chemotherapy
      alone postsurgery relapsed; however, all underwent successful retreatment (two
      with craniospinal irradiation and one with further surgery plus high-dose
      chemotherapy) and are in complete remission. A review of the literature revealed
      that patients in 11 of 12 reported cases were younger than 3 years of age and
      that seven of eight in whom follow-up information was available were alive and
      well, with survival times ranging from 6 to 84 months. CONCLUSIONS:
      Medulloblastomas with extensive nodularity represent a variant that is
      characterized by: 1) occurrence in very young children; 2) a peculiar grapelike
      appearance on neuroimaging; and 3) an apparently favorable outcome.

PMID- 10584844
TI  - Characterization of a model of hydrocephalus in transgenic mice.
AB  - OBJECT: The purpose of this study was to elucidate the pathophysiological
      characteristics of hydrocephalus in a new transgenic model of mice created to
      overproduce the cytokine transforming growth factor-beta1 (TGFbeta1) in the
      central nervous system (CNS). METHODS: Galbreath and colleagues generated
      transgenic mice that overexpressed TGFbeta1 in the CNS in an effort to examine
      the role of this cytokine in the response of astrocytes to injury. Unexpectedly,
      the animals developed severe hydrocephalus and died. The authors have perpetuated
      this transgenic colony to serve as a model of congenital hydrocephalus, breeding
      asymptomatic carrier males that are heterozygous for the transgene with wild-type
      females. One hundred twelve (49.6%) of 226 mice developed clinical manifestations
      of hydrocephalus, characterized by dorsal doming of the calvaria, spasticity,
      limb tremors, ataxia, and, ultimately, death. The presence of the TGFbeta1
      transgene was determined by performing polymerase chain reaction (PCR) analysis
      of sample tail slices. Animals with the hydrocephalic phenotype consistently
      carried the transgene, although some animals with the transgene did not develop
      hydrocephalus. Animals without the transgene did not develop hydrocephalus.
      Alterations in brain structure were characterized using magnetic resonance (MR)
      imaging, gross and light microscopic analysis, and immunocytochemical studies.
      Magnetic resonance imaging readily distinguished hydrocephalic animals from
      nonhydrocephalic controls and demonstrated an obstruction at the outlets of the
      fourth ventricle. Gross and light microscopic examination confirmed the MR
      findings. The results of immunofluorescent staining of brain tissue slices
      revealed the presence of the TGFbeta1 cytokine and its receptor preferentially in
      the meninges and subarachnoid space in both hydrocephalic and control mice.
      Reverse transcriptase-PCR analysis demonstrated tissue-specific expression of the
      TGFbeta1, gene in the brains of transgenic mice, and enzyme-linked immunosorbent
      assay confirmed overexpression of the TGFbeta1 cytokine in brain, cerebrospinal
      fluid, and plasma. CONCLUSIONS: The transgenic murine model provides a
      reproducible representation of congenital hydrocephalus. The authors hypothesize
      that overexpression of TGFbeta1 in the CNS causes hydrocephalus by altering the
      environment of the extracellular matrix and interfering with the circulation of
      cerebrospinal fluid. A model of hydrocephalus in which the genetic basis is known
      should be useful for evaluating hypotheses regarding the pathogenesis of this
      disorder and should also help in the search for new treatment strategies.

PMID- 10584845
TI  - Effects of N-6 essential fatty acids on glioma invasion and growth: experimental
      studies with glioma spheroids in collagen gels.
AB  - OBJECT: Intracranial infusions of gamma-linolenic acid (GLA), an essential fatty
      acid, have been used as an adjuvant therapy following malignant glioma resection;
      however, little is known about the dose response of glioma cells to this therapy.
      In this in vitro study the authors address this important pharmacological
      question. METHODS: Glioma spheroids derived from U87, U373, MOG-G-CCM, and C6
      cell lines were grown in collagen gel and exposed to a range of GLA
      concentrations (0-1 mM) for 5 days. The diameter of glioma spheroids was
      measured, the apoptotic index was assessed using both the terminal
      deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling
      technique and cell morphological testing, and the levels of proliferating cell
      nuclear antigen were also measured. CONCLUSIONS: The dose-response patterns were
      similar for all four glioma spheroids. Low concentrations of GLA (<100 microM)
      increased both apoptosis and proliferation with a net increase in tumor growth
      and invasion, whereas high-dose GLA (>100 microM) significantly impaired spheroid
      cell growth. The proliferative effects of low-dose GLA could be a hazard in the
      clinical treatment of malignant glioma; however, because of the low toxicity of
      GLA against normal cells, local delivery of millimolar doses of GLA could
      significantly reduce tumor size.

PMID- 10584846
TI  - Enhanced radiosensitivity of malignant glioma cells after adenoviral p53
      transduction.
AB  - OBJECT: The goal of this study was to determine whether adenoviral vector
      mediated expression of human wildtype p53 can enhance the radiosensitivity of
      malignant glioma cells that express native wild-type p53. The p53 gene is thought
      to function abnormally in the majority of malignant gliomas, although it has been
      demonstrated to be mutated in only approximately 30%. This has led to studies in
      which adenoviral transduction with wild-type human p53 has been investigated in
      an attempt to slow tumor cell growth. Recent studies suggest that reconstitution
      of wild-type p53 can render cells more susceptible to radiation-mediated death,
      primarily by p53-mediated apoptosis. METHODS: Rat RT2 glioma cells were analyzed
      for native p53 status by reverse transcriptase-polymerase chain reaction and
      sequence analysis and for p53 expression by Western blot analysis. Clonogenic
      survival and the terminal deoxynucleotidyl transferase-mediated deoxyuridine
      triphosphate nick-end labeling assay were used to characterize RT2 cell
      radiosensitivity and apoptosis, respectively, with and without prior transduction
      with p53-containing and control adenoviral vectors. Animal survival length was
      monitored after intracerebral implantation with transduced and nontransduced RT2
      cells, with and without cranial radiation. The RT2 cells were demonstrated to
      express native rat wild-type p53 and to markedly overexpress human p53 following
      adenoviral p53 transduction. The combination of p53 transduction followed by
      radiation resulted in marked decreases in RT2 cell survival and increases in
      apoptosis at radiation doses from 2 to 6 Gy. Animals receiving cranial radiation
      after intracerebral implantation with RT2 cells previously transduced with p53
      survived significantly longer than control animals (p<0.01). CONCLUSIONS: The
      ability to enhance the radiosensitivity of malignant glioma cells that express
      wild-type p53 by using adenoviral transduction to induce overexpression of p53
      offers hope for this approach as a therapeutic strategy, not only in human
      gliomas that express mutant p53, but also in those that express wild-type p53.

PMID- 10584847
TI  - Induction of cyclooxygenase-2 messenger RNA after transient and permanent middle
      cerebral artery occlusion in rats: comparison with c-fos messenger RNA by using
      in situ hybridization.
AB  - OBJECT: Recently, two different cyclooxygenase (COX) genes, COX-1 and -2, were
      identified. In this study, topographic and chronological profiles of COX-2
      messenger (m)RNA and c-fos mRNA expression were investigated using in situ
      hybridization after focal cerebral ischemia. METHODS: Rats undergoing permanent
      ischemia were decapitated at 30 and 90 minutes and at 2, 4, 8, and 24 hours after
      middle cerebral artery (MCA) occlusion, and rats undergoing transient ischemia
      were decapitated at 4, 8, and 24 hours after MCA occlusion that lasted for either
      30 or 90 minutes. After brief transient MCA occlusion, c-fos mRNA was induced in
      the whole MCA territory, adjacent cortex (cingulate cortex), and distant brain
      regions such as the hippocampus and substantia nigra. In contrast, COX-2 mRNA was
      not induced in the ischemic core (lateral striatum) but only in the penumbral
      area (MCA cortex). Long transient and permanent MCA occlusion did not induce c
      fos and COX-2 mRNAs in the ischemic core but strongly induced both mRNAs in the
      penumbral area (medial striatum and periphery of MCA cortex) and adjacent cortex
      (cingulate cortex). In brain regions distant from the ischemic territory,
      although c-fos mRNA was induced in the thalamus, substantia nigra, and
      hippocampus after extended transient and permanent occlusion, COX-2 mRNA was only
      induced in the bilateral hippocampi. The induction of COX-2 mRNA persisted in all
      locations even at 24 hours after MCA occlusion. CONCLUSIONS: The distribution of
      COX-2 mRNA induction was apparently different from that of c-fos mRNA after MCA
      occlusion. These results pertaining to COX-2 mRNA agree well with the previous
      observations of changes in prostaglandin metabolism induced by focal cerebral
      ischemia. However, whether this induction of the COX-2 gene contributes to the
      histopathological outcome of cerebral ischemia remains to be elucidated.

PMID- 10584848
TI  - Early alterations in cerebral hemodynamics, brain metabolism, and blood-brain
      barrier permeability in experimental intracerebral hemorrhage.
AB  - OBJECT: The authors sought to ascertain the nature of the hemodynamic and
      metabolic derangement underlying acute pathophysiological events that occur after
      intracerebral hemorrhage (ICH). METHODS: Cerebral perfusion pressure (CPP), flow
      velocity (FV) of the middle cerebral artery, and the arteriovenous contents of
      oxygen and lactate were investigated in 24 dogs subjected to sham operations
      (Group A, four animals) or intracerebral injections of 3 ml (Group B, 11 animals)
      or 5 ml (Group C, nine animals) autologous arterial blood. Twelve additional dogs
      received intravenous injections of 2% Evans blue or trypan blue dye to evaluate
      blood-brain barrier (BBB) changes. Within 1 hour, animals with ICH exhibited a
      rise in FV associated with significant reductions (p<0.05) in CPP and the
      arteriovenous content difference (AVDO2). In Group C animals significant
      increases in lactate concentration were found in arterial and superior sagittal
      sinus (SSS) samples compared with those in the other two groups (p<0.05).
      Additionally, perihematomal dye extravasation was observed in animals subjected
      to ICH and trypan blue dye injections, with profound and mild leakages in Group C
      and Group B animals, respectively, but not in Group A and Evans blue dye-injected
      animals. During the subsequent 4 hours, the FV and AVDO2 returned to normal in
      Group B animals, indicating a balanced cerebral metabolic rate for oxygen (CMRO2)
      compared with a deranged CMRO2 in Group C animals due to their lowered FV and
      AVDO2. However, no coupling increase in brain lactate clearance in Group C
      animals accounted for either the early lactate elevation in SSS or the decrease
      in CMRO2. CONCLUSIONS: Profound reductions in CPP and brain oxygenation after ICH
      may rapidly exhaust hemodynamic compensation and, thus, impede cerebral
      homeostasis; however, these reductions only modestly enhance anaerobic
      glycolysis. Furthermore, the data suggest that a selective increase in
      permeability, rather than anatomical disruption, of the BBB is involved in the
      acute pathophysiological events that occur after ICH, which may provide a
      possible gateway for systemic arterial lactate entering the SSS.

PMID- 10584849
TI  - Quantification of increased exposure resulting from orbital rim and
      orbitozygomatic osteotomy via the frontotemporal transsylvian approach.
AB  - OBJECT: Use of orbital rim and orbitozygomatic osteotomy has been extensively
      reported to increase exposure in neurosurgical procedures. However, there have
      been few attempts to quantify the extent of additional exposure gained by these
      maneuvers. Using a novel laboratory technique, the authors have attempted to
      measure the increase in the "area of exposure" that is gained by removal of the
      orbital rim and zygomatic arch via the frontotemporal transsylvian approach.
      METHODS: The authors dissected five cadavers bilaterally. The area of exposure
      provided by the frontotemporal transsylvian approach was determined by using a
      frameless stereotactic device. With the tip of a microdissector placed on targets
      deep within the exposure, the position of the end of the microdissector handle
      was measured in three-dimensional space as the microdissector was rotated around
      the periphery of the operative field. This maneuver was performed via the
      frontotemporal approach alone as well as with orbital rim and orbitozygomatic
      osteotomy approaches. After data manipulation, the areas of exposure
      corresponding to the polygons used to define these handle positions were
      calculated and directly compared. On average, the area of exposure provided by
      the frontotemporal transsylvian approach was increased 26 to 39% (p<0.05) by
      adding orbital rim osteotomy and an additional 13 to 22% (not significant) with
      removal of the zygomatic arch. CONCLUSIONS: Significant and consistent increases
      in surgical exposure were obtained by using orbital osteotomy, whereas zygomatic
      arch removal produced less consistent gains. Both maneuvers may be expected to
      improve surgical access. However, because larger and more consistent gains were
      afforded by orbital rim removal, the threshold for removal of this portion of the
      orbitozygomatic complex should be lower.

PMID- 10584850
TI  - The anatomy of the Berrettini branch: implications for carpal tunnel release.
AB  - OBJECT: Dissections were performed in 100 fresh cadaver palms to determine the
      frequency with which superficial palmar communication between the median and
      ulnar nerves occurs and to what extent it might incur iatrogenic injury during
      endoscopic carpal tunnel release. METHODS: Superficial palmar communication
      between the median and ulnar nerves was present in 81% of the dissected hands.
      Superficial palmar communication, also known as the Berrettini branch, has been
      classified into four distinct types by Ferrari and Gilbert. Twelve hands were
      classified as Group 1 (communication in an oblique course from the ulnar to the
      median nerve originating >4 mm above the distal margin of the transverse carpal
      ligament [TCL]), 16 hands were classified as Group 2 (communication parallel to
      the distal margin of the TCL), and 53 hands were classified as Group 3
      (communication in an oblique course from the ulnar nerve to the third common
      digital nerve, originating below the distal margin of the TCL). No hand fit the
      Group 4 classification (atypical communication). CONCLUSIONS: The Berrettini
      branch can be considered a normal anatomical finding. In 28% of the hands in this
      study, the branch was proximal to the edge of the distal ligament and, therefore,
      prone to iatrogenic injury in both one-portal and two-portal endoscopic surgery.

PMID- 10584851
TI  - Ruptured cerebral pseudoaneurysm caused by the removal of a ventricular catheter.
      Case report.
AB  - A rare case of cerebral pseudoaneurysm located at the internal carotid artery
      (ICA) was caused by the removal of a ventricular catheter in an infant. This 4
      month-old girl underwent ventriculoperitoneal shunt revision, during which the
      old ventricular catheter was removed from the posterior horn of the left lateral
      ventricle, but the choroid plexus was pulled out by the tip of the catheter.
      Intraventricular hemorrhage (IVH) and subarachnoid hemorrhage were observed
      postoperatively. Magnetic resonance (MR) angiography performed on the 12th
      postoperative day revealed ICA stenosis and aneurysm formation at the C1 portion
      of the left ICA. Contrast-enhanced computerized tomography (CT) scans obtained on
      the 21st postoperative day revealed recurrent IVH and enlargement of the lesion.
      The patient underwent surgery for treatment of the aneurysm. Operative findings
      revealed a pseudoaneurysm arising from the left ICA at the proximal end of the
      anterior choroidal artery (AChA). The aneurysm was removed and the wall of the
      ICA was reconstructed. Postoperative three-dimensional CT scanning and MR
      angiography demonstrated disappearance of the aneurysm and preservation of the
      ICA. The patient was discharged without additional neurological deficits. Many
      complications, including IVH, are associated with removal of a ventricular
      catheter. This case shows that pseudoaneurysm formation can occur in a remote
      region due to avulsion of the AChA from the ICA. In most circumstances a
      ventricular catheter can be removed without difficulty. However, precision and
      caution should be exercised when removing a ventricular catheter.

PMID- 10584852
TI  - Intraosseous orbitosphenoidal cavernous angioma. Case report.
AB  - Primary orbital intraosseous angiomas are rare. The authors report the case of a
      55-year-old man who harbored a multifocal cavernous angioma in an unusual
      sphenoorbital location. The lesion was responsible for unilateral exophthalmos
      and blindness. Characteristic imaging findings, which included a honeycomb
      pattern on plain x-ray films and computerized tomography scans, a heterogeneous
      high signal intensity on T2-weighted magnetic resonance images, and slowly
      flowing venous lakes on power Doppler ultrasonograms and angiograms, are
      presented and discussed.

PMID- 10584853
TI  - Histiocytic lesion mimicking intrinsic brainstem neoplasm. Case report.
AB  - This 10-year-old girl presented with a 1-month history of progressive bulbar
      palsy and a solitary enhancing mass originating within the floor of the fourth
      ventricle. Results of initial imaging studies and presentation were suggestive of
      neoplasia. Subtotal resection was performed and pathological examination revealed
      the mass to be a histiocytic lesion, with no evidence of a glioma. The patient
      had no other stigmata of histiocytosis and was treated with steroid medications,
      resulting in prolonged resolution of the lesion. This case demonstrates that for
      discrete brainstem lesions the differential diagnosis includes entities other
      than glioma for which treatment is available. Biopsy sampling should be
      considered when technically feasible.

PMID- 10584854
TI  - Glioblastoma multiforme at the site of metal splinter injury: a coincidence? Case
      report.
AB  - The authors report the case of a man who had suffered a penetrating metal
      splinter injury to the left frontal lobe at 18 years of age. Thirty-seven years
      later the patient developed a left-sided frontal tumor at the precise site of the
      meningocerebral scar and posttraumatic defect. Histological examination confirmed
      a glioblastoma multiforme adjacent to the dural scar and metal splinters. In
      addition, a chronic abscess from which Propionibacterium acnes was isolated was
      found within the glioma tissue. The temporal and local association of metal
      splinter injury with chronic abscess, scar formation, and malignant glioma is
      highly suggestive of a causal relationship between trauma and the development of
      a malignant brain tumor.

PMID- 10584855
TI  - En bloc resection of an intracavernous oculomotor nerve schwannoma and grafting
      of the oculomotor nerve with sural nerve. Case report and review of the
      literature.
AB  - A case in which a left oculomotor nerve schwannoma treated by en bloc resection
      of the lesion and grafting of the oculomotor nerve with sural nerve is presented.
      Recovery of nerve function was partial, but useful and cosmetically good. The
      last follow-up examination performed 2 years after surgery revealed recovery of
      function in the elevator muscle of the upper eyelid, together with slight
      vertical movement of the eye.

PMID- 10584856
TI  - Quantitative assessment of vessel flow integrity for aneurysm surgery. Technical
      note.
AB  - Quantitative measurement of blood flow in cerebral vessels during aneurysm
      surgery can help prevent ischemic injury and improve patient outcome. The authors
      report a case of a superior cerebellar artery (SCA) aneurysm in which
      perivascular microflow probes were used to measure blood flow quantitatively in
      both the SCA and the posterior cerebral artery before and after aneurysm
      clipping. Following aneurysm clipping, blood flow in the SCA was reduced to less
      than 25% of its initial baseline value. Prompt detection of compromised blood
      flow gave the surgeon the opportunity to adjust the clip and restore SCA flow to
      its preclipping value within 5 minutes of initial clip placement. Quantitative
      vessel-flow measurements were integral to the safe progression of the operation
      and may have prevented an adverse neurological outcome in this patient. The
      recommended surgical technique and the principle of operation are described.

PMID- 10584857
TI  - Size-adjustable titanium plate for reconstruction of the sella turcica. Technical
      note.
AB  - A size-adjustable plate constructed of pure titanium is proposed for use in the
      reconstruction of the sella turcica. The plate is composed of two semicircular
      pieces that are connected by a hinge located at the top of the plate. Using an
      applicator, the plate is inserted into the sella turcica in a closed position.
      The same applicator is then used to open and secure the plate. The titanium
      causes minimal ferromagnetic artifacts on postoperative magnetic resonance
      imaging. Preliminary findings indicate a possible clinical use for this plate in
      the reconstruction of the sella turcica when no suitable piece of bone is
      available.

PMID- 10584858
TI  - Osteoblastic meningioma of the lateral ventricle. Case illustration.

PMID- 10584859
TI  - Central nervous system metastasis from gallbladder carcinoma mimicking a
      meningioma. Case illustration.

PMID- 10584860
TI  - Rapid gas-forming brain abscess due to Klebsiella pneumoniae. Case illustration.

PMID- 10584861
TI  - Blister or berry aneurysm.

PMID- 10584862
TI  - Microvascular decompression.

PMID- 10584863
TI  - Vascularized pedicle graft.

PMID- 10584864
TI  - Brain tissue oxygenation.

PMID- 10584866
TI  - Prevention of hepatocellular cancer: one of the most cost-effective ways to
      reduce adult mortality?

PMID- 10584865
TI  - Endoscopy for cysts.

PMID- 10584867
TI  - BRCA1, BRCA2 and their possible function in DNA damage response.

PMID- 10584868
TI  - Chromosome alterations and E-cadherin gene mutations in human lobular breast
      cancer.
AB  - We have studied a set of 40 human lobular breast cancers for loss of
      heterozygosity (LOH) at various chromosome locations and for mutations in the
      coding region plus flanking intron sequences of the E-cadherin gene. We found a
      high frequency of LOH (100%, 31/31) at 16q21-q22.1. A significantly higher level
      of LOH was detected in ductal breast tumours at chromosome arms 1p, 3p, 9p, 11q,
      13q and 18q compared to lobular breast tumours. Furthermore, we found a
      significant association between LOH at 16q containing the E-cadherin locus and
      lobular histological type. Six different somatic mutations were detected in the E
      cadherin gene, of which three were insertions, two deletions and one splice site
      mutation. Mutations were found in combination with LOH of the wild type E
      cadherin locus and loss of or reduced E-cadherin expression detected by
      immunohistochemistry. The mutations described here have not previously been
      reported. We compared LOH at different chromosome regions with E-cadherin gene
      mutations and found a significant association between LOH at 13q and E-cadherin
      gene mutations. A significant association was also detected between LOH at 13q
      and LOH at 7q and 11q. Moreover, we found a significant association between LOH
      at 3p and high S phase, LOH at 9p and low ER and PgR content, LOH at 17p and
      aneuploidy. We conclude that LOH at 16q is the most frequent chromosome
      alteration and E-cadherin is a typical tumour suppressor gene in lobular breast
      cancer.

PMID- 10584869
TI  - Deletions at 14q in malignant mesothelioma detected by microsatellite marker
      analysis.
AB  - Previous molecular cytogenetic studies by comparative genomic hybridization (CGH)
      on primary tumours of human malignant mesothelioma have revealed that loss of
      genetic material at chromosome 14q is one of the most frequently occurring
      aberrations. Here we further verify the frequency and pattern of deletions at 14q
      in mesothelioma. A high-resolution deletion mapping analysis of 23 microsatellite
      markers was performed on 18 primary mesothelioma tumours. Eight of these had
      previously been analysed by CGH. Loss of heterozygosity or allelic imbalance with
      at least one marker was detected in ten of 18 tumours (56%). Partial deletions of
      varying lengths were more common than loss of all informative markers, which
      occurred in only one tumour. The highest number of tumours with deletions at a
      specific marker was detected at 14q11.1-q12 with markers D14S283 (five tumours),
      D14S972 (seven tumours) and D14S64 (five tumours) and at 14q23-q24 with markers
      D14S258 (five tumours), D14S77 (five tumours) and D14S284 (six tumours). We
      conclude from these data that genomic deletions at 14q are more common than
      previously reported in mesothelioma. Furthermore, confirmation of previous CGH
      results was obtained in all tumours but one. This tumour showed deletions by
      allelotyping, but did not show any DNA copy number change at 14q by CGH. Although
      the number of tumours allelotyped was small and the deletion pattern was complex,
      14q11.1-q12 and 14q23-q24 were found to be the most involved regions in
      deletions. These regions provide a good basis for further molecular analyses and
      may highlight chromosomal locations of tumour suppressor genes that could be
      important in the tumorigenesis of malignant mesothelioma.

PMID- 10584870
TI  - Differential regulation of MAP kinase cascade in human colorectal tumorigenesis.
AB  - Hyper-activation of mitogen-activated protein kinase (MAPK) has recently been
      reported in several human cancers and activation of MAPK in those cancers may be
      associated with carcinogenesis through aberrant cell proliferation. To understand
      the roles of the MAPK pathway in colorectal tumorigenesis, we examined the status
      of extracellular signal-regulated protein kinases (ERK1/2) in 21 colorectal
      tumour specimens and compared it with that of paired normals. The specific MAPK
      activities were two- to tenfold lower in 71% (15 out of 21 cases) of colorectal
      tumours compared to those in paired normals. The individual MAPK kinase (MEK)
      correlated with MAPK activities (P = 0.006). Reduction of the MAPK and MEK
      activities in colorectal tumours was also observed in adenomas. These results
      suggested that down-regulation of the MAPK cascade may be caused by early genetic
      event(s) and that it may be related to the loss of normal growth control.
      Although MAPK activities were down-regulated both in adenomas and carcinomas,
      activities of the MAPKs in carcinomas were higher than those of paired adenomas.
      These results suggested that MAPK activities may be increased in the adenoma-to
      carcinoma sequence and that it may play a role in the tumour progression.
      Observation of the differential regulation of MAPK activities in colorectal
      tumorigeneis suggested roles for the MAPK pathway in both positive and negative
      controls of cell growth.

PMID- 10584871
TI  - Inhibiting tumorigenic potential by restoration of p16 in nasopharyngeal
      carcinoma.
AB  - The p16 gene, encodes a key checkpoint protein p16 in the cell cycle, has been
      reported inactivation in a wide variety of human cancers. We have previously
      demonstrated high frequency of p16 alterations in primary nasopharyngeal
      carcinoma (NPC), xenografts and cell lines. The finding implied that inactivation
      of the p16 gene may play an important role in the NPC development. To investigate
      the tumour suppressor function of p16 in NPC, we transfected p16-deficient NPC
      cell line, NPC/HK-1, with a wild-type p16 expression construct, and evaluated
      growth and tumorigenic properties of the clones stably expressing exogenous p16.
      Expression of the exogenous wild-type p16 significantly inhibited cell growth by
      more than 70% when compared to that of the parental and empty vector-transfected
      cells. This growth inhibition was attributable to a significant proportion of p16
      expressing cells arrested at G1 phase in the cell cycle as revealed by flow
      cytometric analysis. By anchorage-independent colony forming assay, we found that
      the ability to form colonies in soft agar was highly reduced in cells expressing
      p16. NPC/HK1 cells expressing functional p16 also showed suppressed
      tumorigenicity in athymic nude mice. Taken together, our results provide strong
      evidence for a tumour suppressor role of p16 in NPC.

PMID- 10584872
TI  - Does reductive metabolism predict response to tirapazamine (SR 4233) in human non
      small-cell lung cancer cell lines?
AB  - The bioreductive drug tirapazamine (TPZ, SR 4233, WIN 59075) is a lead compound
      in a series of potent cytotoxins that selectively kill hypoxic rodent and human
      solid tumour cells in vitro and in vivo. Phases II and III trials have
      demonstrated its efficacy in combination with both fractionated radiotherapy and
      some chemotherapy. We have evaluated the generality of an enzyme-directed
      approach to TPZ toxicity by examining the importance of the one-electron reducing
      enzyme NADPH:cytochrome P450 reductase (P450R) in the metabolism and toxicity of
      this lead prodrug in a panel of seven human non-small-cell lung cancer cell
      lines. We relate our findings on TPZ sensitivity in these lung lines with our
      previously published results on TPZ sensitivity in six human breast cancer cell
      lines (Patterson et al (1995) Br J Cancer 72: 1144-1150) and with the sensitivity
      of all these cell types to eight unrelated cancer chemotherapeutic agents with
      diverse modes of action. Our results demonstrate that P450R plays a significant
      role in the activation of TPZ in this panel of lung lines, which is consistent
      with previous observations in a panel of breast cancer cell lines (Patterson et
      al (1995) Br J Cancer 72: 1144-1150; Patterson et al (1997) Br J Cancer 76: 1338
      1347). However, in the lung lines it is likely that it is the inherent ability of
      these cells to respond to multiple forms of DNA damage, including that arising
      from P450R-dependent TPZ metabolism, that underlies the ultimate expression of
      toxicity.

PMID- 10584873
TI  - 8-Cl-cAMP antagonizes mitogen-activated protein kinase activation and cell growth
      stimulation induced by epidermal growth factor.
AB  - The growth factor-activated mitogenic pathways are often disregulated in tumour
      cells and, therefore, they can provide specific molecular targets for novel anti
      tumour approaches. 8-Chloro-cAMP (8-Cl-cAMP), a synthetic cAMP analogue, is a
      novel anti-tumour agent that has recently undergone clinical evaluation. We
      investigated the effects of 8-Cl-cAMP on the epidermal growth factor (EGF)/EGF
      receptor (EGF-R) signalling in human epidermoid cancer KB cells, which are
      responsive to the mitogenic stimulus of EGF. We found that the growth-promoting
      activity of EGF was completely abolished when EGF treatment was performed in
      combination with 8-Cl-cAMP. The inhibition of the EGF-induced proliferation by 8
      Cl-cAMP was paralleled by the blockade of the EGF-stimulated activation of
      mitogen-activated protein kinases (MAPK), ERK-1 and ERK-2. Conversely, we found
      an increase of EGF-R expression and EGF-R tyrosine phosphorylation when KB cells
      were growth inhibited by 8-Cl-cAMP. Moreover, the activity of Raf-1 and MEK-1
      protein kinases, the activators upstream MAPK in the phosphorylation cascade
      induced by EGF, was not modified in 8-Cl-cAMP-treated cells. We concluded that
      the impairment of KB cell response to EGF, induced by 8-Cl-cAMP, resides in the
      specific inhibition of MAPK/ERKs activity while the function of the upstream
      elements in the EGF-R signalling is preserved.

PMID- 10584874
TI  - Breast tumour cell-induced down-regulation of type I collagen mRNA in
      fibroblasts.
AB  - This study investigated the modulation of type I collagen gene expression in
      normal fibroblasts by breast tumour cells. Northern analysis of total RNA
      extracted from stages I, II and III breast tumour tissue revealed that collagen
      mRNA levels were elevated in stage I tumours compared to the adjacent normal
      breast tissues, whereas they were decreased in stages II and III breast tumours.
      This aberrant collagen gene expression was confirmed by non-radioactive RNA:RNA
      in situ hybridization analysis of 30 breast carcinomas which localized the
      production of type I collagen mRNA to the stromal fibroblasts within the vicinity
      of the tumour cells. In order to determine whether the tumour cells were directly
      responsible for this altered collagen production by the adjacent fibroblasts,
      breast tumour cell lines were co-cultured with normal fibroblasts for in vitro
      assessment of collagen and steady-state collagen RNA levels. Co-culture of tumour
      cells and normal fibroblasts in the same dish resulted in down-regulation of
      collagen mRNA and protein. Treatment of the fibroblasts with tumour-cell
      conditioned medium also resulted in decreased collagen protein levels but the
      mRNA levels, however, remained unaltered. These results suggested that the tumour
      cells either secrete a labile 'factor', or express a cell surface protein
      requiring direct contact with the fibroblasts, resulting in down-regulation of
      collagen gene expression. Modulation of the ECM is a common characteristic of
      invading tumour cells and usually involves increased production of collagenases
      by the tumour cells or stromal fibroblasts. This study showed that tumour cells
      were also able to modulate collagen mRNA production by stromal fibroblasts, which
      may facilitate tumour cell invasion and metastasis.

PMID- 10584875
TI  - Evidence for an ependymoma tumour suppressor gene in chromosome region 22pter
      22q11.2.
AB  - Ependymomas are glial tumours of the brain and spinal cord. The most frequent
      genetic change in sporadic ependymoma is monosomy 22, suggesting the presence of
      an ependymoma tumour suppressor gene on that chromosome. Clustering of
      ependymomas has been reported to occur in some families. From an earlier study in
      a family in which four cousins developed an ependymoma, we concluded that an
      ependymoma-susceptibility gene, which is not the NF2 gene in 22q12, might be
      located on chromosome 22. To localize that gene, we performed a segregation
      analysis with chromosome 22 markers in this family. This analysis revealed that
      the susceptibility gene may be located proximal to marker D22S941 in 22pter
      22q11.2. Comparative genomic hybridization showed that monosomy 22 was the sole
      detectable genetic aberration in the tumour of one of the patients. Loss of
      heterozygosity studies in that tumour revealed that, in accordance to Knudson's
      two-hit theory of tumorigenesis, the lost chromosome 22 originated from the
      parent presumed to have contributed the wild-type allele of the susceptibility
      gene. Thus, our segregation and tumour studies collectively indicate that an
      ependymoma tumour suppressor gene may be present in region 22pter-22q11.2.

PMID- 10584876
TI  - Specific binding of TES-23 antibody to tumour vascular endothelium in mice, rats
      and human cancer tissue: a novel drug carrier for cancer targeting therapy.
AB  - The tissue distribution of anti-tumour vascular endothelium monoclonal antibody
      (TES-23) produced by immunizing with plasma membrane vesicles from isolated rat
      tumour-derived endothelial cells (TECs) was assessed in various tumour-bearing
      animals. Radiolabelled TES-23 dramatically accumulated in KMT-17 fibrosarcoma,
      the source of isolated TECs after intravenous injection. In Meth-A fibrosarcoma,
      Colon-26 adenocarcinoma in BALB/c mice and HT-1080 human tumour tissue in nude
      mice, radioactivities of 125I-labelled TES-23 were also up to 50 times higher
      than those of control antibody with little distribution to normal tissues. The
      selective recognition of TES-23 to TECs was competitively blocked by
      preadministration of unlabelled TES-23 in vivo. Furthermore, immunostaining of
      human tissue sections showed specific binding of TES-23 on endothelium in
      oesophagus cancers. These results indicate that tumour vascular endothelial cells
      express common antigen in different tumour types of various animal species. In
      order to clarify the efficacy of TES-23 as a drug carrier, an immunoconjugate,
      composed of TES-23 and neocarzinostatin, was tested for its anti-tumour effect in
      rats bearing KMT-17 fibrosarcomas. The immunoconjugate (TES-23-NCS) caused marked
      regression of the tumour, accompanied by haemorrhagic necrosis. Thus, from a
      clinical view, TES-23 would be a novel drug carrier because of its high
      specificity to tumour vascular endothelium and its application to many types of
      cancer.

PMID- 10584877
TI  - Expression of testicular genes in haematological malignancies.
AB  - The gene expression of a new group of tumour antigens known as cancer/testis (CT)
      antigens is now well-recognized in some solid tumours. However, their expression
      in haematological malignancies remained unclear. In this study, we have used
      reverse transcription polymerase chain reaction and Southern blot analysis to
      examine the presence of transcripts for the three CT antigens, NY-ESO-1, SSX2 and
      SCP1 in haematological malignant cells. We found that transcripts for SCP1 could
      be detected in 10% of myeloma, 5.7% of acute myeloid leukaemia and 23% of chronic
      myeloid leukaemia. In contrast, NY-ESO-1 and SSX2 were not detected in any of the
      107 tumour samples.

PMID- 10584878
TI  - Detection of circulating tumour cells in patients with breast or ovarian cancer
      by molecular cytogenetics.
AB  - Detection of micrometastases in patients with solid tumours may aid the
      establishment of prognosis and development of new therapeutic approaches. This
      study was designed to investigate the presence and frequency of tumour cells in
      the peripheral blood (PB) of patients with breast or ovarian cancer by using a
      combination of magnetic activated cell sorting (MACS) and fluorescence in situ
      hybridization (FISH). Separated tumour cell and PB-samples from 48 patients (35
      breast cancers, 12 ovarian tumours, one uterine sarcoma) were analysed for the
      presence of numerical aberrations of chromosomes 7, 12, 17 and 17 q11.2-q12.
      Twenty-five patients had primary disease and 23 had relapsed. The technique
      allows the detection of one tumour cell in 106 normal cells. Circulating tumour
      cells were detected in 35/48 cases (17 patients had relapsed and 13 primary
      carcinoma with lymph node or solid metastases) by the expression of anti
      cytokeratin and the presence of numerical chromosomal abnormalities. PB-tumour
      cells of patients with a primary carcinoma and without solid metastases had a
      significantly lower percentage of chromosomal aberrations, especially for
      chromosome 12 (P = 0.035; P = 0.038) compared to those with relapsed disease and
      solid metastases. Detection and quantification of minimal residual disease may
      monitor the response to cytotoxic or hormonal therapy and may identify women at
      risk of relapse.

PMID- 10584879
TI  - Expression and subcellular localization of cyclin D1 protein in epithelial
      ovarian tumour cells.
AB  - The expression of cyclin D1 protein in tumour sections from 81 patients with
      epithelial ovarian cancer was analysed using immunohistochemistry. The tumours
      that overexpressed cyclin D1 in more than 10% of neoplastic cells were considered
      positive. Thus overexpression of cyclin D1 was observed in 72/81 (89%) of the
      cases examined. Protein was detected in both the nucleus and the cytoplasm in
      24/81 (30%) and localized exclusively in the cytoplasm in 48/81 (59%) of the
      tumours. Cyclin D1 was overexpressed in both borderline and invasive tumours.
      There was no association between protein overexpression and tumour stage and
      differentiation. Furthermore, no correlation between cyclin D1 expression and
      clinical outcome was observed. However, in tumours overexpressing cyclin D1 (n =
      72), the proportion displaying exclusively cytoplasmic localization of protein
      was higher in those with serous compared with non-serous histology (P = 0.004,
      odds ratio 4.8, 95% confidence interval 1.4-19.1). Western analysis using a
      monoclonal antibody to cyclin D1 identified a 36 kDa protein in homogenates from
      seven tumours displaying cytoplasmic only and one tumour demonstrating both
      nuclear and cytoplasmic immunostaining. Using restriction fragment length
      polymorphism polymerase chain reaction and PCR-multiplex analysis, amplification
      of the cyclin D1 gene (CCND1 was detected in 1/29 of the tumours demonstrating
      overexpression of cyclin D1 protein. We conclude that deregulation of CCND1
      expression leading to both cytoplasmic and nuclear protein localization is a
      frequent event in ovarian cancer and occurs mainly in the absence of gene
      amplification.

PMID- 10584880
TI  - Epstein-Barr virus expression in Hodgkin's disease in relation to patient
      characteristics, serum factors and blood lymphocyte function.
AB  - Epstein-Barr virus (EBV) expression was investigated by immunohistochemistry
      (latent membrane protein 1 [LMP-1]) and in situ hybridization (EBV encoded RNA
      [EBER]) in biopsies from 95 patients with untreated Hodgkin's disease (HD).
      Tumour EBV status was related to EBV antibody titres, spontaneous and
      concanavalin A induced blood lymphocyte DNA synthesis, serum levels of soluble
      (s) CD4, sCD8, sCD25, sCD30, sCD54, beta2-microglobulin, thymidine-kinase,
      routine chemistry, patient characteristics, complete remission and survival. The
      median follow-up time was 145 months (range 60-257). Tumour EBV-positive (n = 30;
      33%) and negative (n = 62; 67%) patients did not differ with regard to sex, age,
      stage, presence of bulky disease or B-symptoms, remission rate or survival. The
      proportion of EBV+ cases was significantly higher among patients with mixed
      cellularity histopathology (58%) as compared to the nodular sclerosis subtype
      (18%; P < 0.001). The total white blood cell (WBC) counts were significantly
      lower in EBV+ patients (P < 0.01), who also had significantly higher levels of
      sCD54 (P < 0.02) and a tendency towards lower levels of sCD30 (P = 0.056).
      Patients in the tumour EBV+ group had significantly higher IgG antibody titres to
      restricted early antigen (EA-R) (P < 0.02). Hence, clinical features and outcome
      were not related to tumour EBV status. However, HD patients with EBV+ tumours had
      elevated sCD54 levels, higher antibody titres to EA-R and decreased total WBC
      counts. A potential causal relationship between EBV tumour status and these
      findings needs to be further explored.

PMID- 10584882
TI  - Physical and psychological symptoms of quality of life in the CHART randomized
      trial in head and neck cancer: short-term and long-term patient reported
      symptoms. CHART Steering Committee. Continuous hyperfractionated accelerated
      radiotherapy.
AB  - The randomized multicentre trial of continuous hyperfractionated accelerated
      radiotherapy (CHART) versus conventional radiotherapy in patients with advanced
      head and neck cancer showed no good evidence of a difference in any of the major
      clinical outcomes of survival, freedom from metastases, loco-regional control and
      disease-free survival. Therefore an assessment of the effect of treatment on
      physical and psychological symptoms is vital to balance the costs and benefits of
      the two treatments. A total of 615 patients were asked to complete a Rotterdam
      Symptom Checklist and the Hospital Anxiety and Depression Scale, which cover a
      variety of physical and psychological symptoms, at a total of ten time points.
      The data consisted of short-term data (the initial 3 months) and long-term data
      (1 and 2 years). The short-term data was split into an exploratory data set and a
      confirmatory data set, and analysed using subject-specific and group-based
      methods. Differences were only claimed if hypotheses generated in the exploratory
      data set were confirmed in the confirmatory data set. The long-term data was not
      split into two data sets and was analysed using a group-based approach. There was
      evidence of significantly worse symptoms of pain at day 21 in those treated with
      CHART and significantly worse symptoms of cough and hoarseness at 6 weeks in
      those treated conventionally. There was also evidence to suggest a higher degree
      of decreased sexual interest at 1 year and sore muscles at 2 years in those
      treated with conventional radiotherapy. There is no clear indication that one
      regimen is superior to the other in terms of 'quality of life', generally the
      initially more severe reaction in the CHART group being offset by the longer
      duration of symptoms in the conventionally treated group.

PMID- 10584881
TI  - Glycan composition of serum alpha-fetoprotein in patients with hepatocellular
      carcinoma and non-seminomatous germ cell tumour.
AB  - Although estimation of serum alpha-fetoprotein (AFP) is widely used in the
      diagnosis of hepatocellular carcinoma (HCC) and non-seminomatous germ cell
      tumours (NSGCT), the clinical usefulness of this test is limited by a low
      specificity. However, there exist glycoforms of AFP which may be more specific
      for particular tumours. Previously, detailed analysis has been prevented by the
      low levels of AFP in human serum. We report here the application of fluorescence
      labelling, sequential exoglycosidase digestion, high-performance liquid
      chromatography and matrix-assisted laser desorption ionization in time-of-flight
      mass spectrometry, to determine the glycan structures of purified serum AFP from
      patients with HCC and NSGCT. Eleven major glycans were found, of which seven were
      N-linked, and four were O-linked, to the protein backbone. The structure of the N
      linked glycans (all of bi-antennary complex-type with varying degrees of
      sialylation, fucosylation and galactosylation) were consistent with those
      previously reported. The O-linked glycans (three mucin O-GalNAc type glycans with
      variable degrees of sialylation, one O-HexNAc monosaccharide glycan) have not
      previously been reported. The finding of mucin O-GalNAc type glycans was
      supported by the prediction of potential O-GalNAc glycosylation sites on the
      protein backbone by analysis of the AFP structure by molecular modelling. With
      knowledge of these structures it may be possible to develop more specific assays
      for the detection of HCC and NSGCT.

PMID- 10584883
TI  - Prognostically orientated multimodality treatment including surgery for selected
      patients of small-cell lung cancer patients stages IB to IIIB: long-term results
      of a phase II trial.
AB  - Following mediastinoscopy, a prognostically orientated multimodality approach was
      chosen in selected small-cell lung cancer (SCLC) patients with hyperfractionated
      accelerated chemoradiotherapy (Hf-RTx) and definitive surgery (S). Stage IB/IIA
      patients had four cycles of cisplatin/etoposide (PE) and surgery. Stage IIB/IIIA
      patients had three cycles PE followed by one cycle concurrent chemoradiation
      including Hf-RTx and surgery. Most stage IIIB patients were not planned for
      surgery and had CTx followed by sequential RTx or one cycle concurrent CTx/RTx.
      Of 46 consecutive patients (stage IB six, IIA two, IIB/IIIA 22, IIIB 16) 43 (94%)
      showed an objective response. Twenty-three of patients (72%) planned for
      inclusion of S were completely resected (R0) (IB 6/6, IIA 2/2, IIB/IIIA 13/22,
      IIIB 2/2). Overall toxicity was acceptable--one patient died of septicaemia, no
      perioperative deaths occurred. Median follow-up of patients alive (n = 21) is 52
      months (30+ - 75+). Median survival and 5-year survival rate of all patients are
      36 months and 46%, in R0 patients 68 months and 63% (R0-IIB/IIIA/IIIB: not yet
      reached and 67%). This multimodality treatment including surgery proved highly
      effective with 100% local control and remarkable long-term survival after
      complete resection, even in locally advanced SCLC stages IIB/IIIA patients.

PMID- 10584884
TI  - Immunocytochemical assessment of bone marrow aspirates for monitoring response to
      chemotherapy in small-cell lung cancer patients.
AB  - Recent reports have suggested that tumour cell immunodetection in bone marrow of
      small-cell lung cancer patients is by far more frequent than found
      cytohistologically and may have clinical relevance. This study evaluates
      primarily the efficacy of chemotherapy as method of in vivo purging, but also the
      relationship of marrow involvement with survival. A total of 112 bone marrow
      aspirates from 30 chemo-naive patients were stained twice using anti-NCAM
      antibodies, first at diagnosis and then after chemotherapy (24 patients) or at
      disease progression (six patients). Marrow contamination was associated with
      lower survival (P = 0.002), and was also detected in 7/17 patients conventionally
      staged as having limited disease. At multivariate analysis, marrow involvement
      was an independent factor of unfavourable prognosis (P = 0.033). The amount of
      tumour contamination, before and after chemotherapy, remained unchanged also in
      responders and even in the subset of patients with apparent limited disease.
      Following chemotherapy, bone marrow became tumour negative only in 25% of
      initially positive responders and in none of non-responders. Our results indicate
      that (i) chemotherapy is not effective in purging bone marrow even in chemo
      responsive patients and (ii) a subset of patients with limited disease and
      negative bone marrow aspirates might have a more favourable prognosis.

PMID- 10584885
TI  - Biological markers of risk in nipple aspirate fluid are associated with residual
      cancer and tumour size.
AB  - We previously demonstrated that nipple aspirate fluid (NAF) can be obtained from
      virtually all non-Asian women between the ages of 30 and 72. The focus of this
      report is to (1) determine the association of candidate markers of breast cancer
      risk in NAF obtained from fresh mastectomy specimens with residual breast
      carcinoma, and (2) evaluate the association of the markers with breast tumour
      progression. Nipple aspiration was performed on 97 specimens. Cytology, DNA index
      (including % hypertetraploid cells), cell cycle parameters (S phase fraction, %
      cells in G2/M), prostate-specific antigen (PSA), epidermal growth factor (EGF),
      testosterone, carcinoembryonic antigen (CEA) and prostaglandin D synthase (PGDS)
      were evaluated in NAF for their association with (1) residual ductal carcinoma in
      situ (DCIS) or invasive cancer, and (2) pathologic tumour size. NAF was obtained
      from 99% (96/97) of specimens. Atypical and malignant NAF cytology were
      significantly associated with residual DCIS or invasive cancer (P = 0.001) and
      with larger tumours (P = 0.004). One hundred per cent and 88% of subjects with
      malignant and atypical NAF cytology, respectively, had residual carcinoma. The
      percentage of cells in G2/M and DNA index were associated both with risk of
      residual carcinoma (P = 0.01 for each) and larger tumour size (DNA index, P =
      0.03; G2/M, P = 0.05), although neither biomarker improved the ability of NAF
      cytology, to predict residual breast cancer. Higher DNA index was associated with
      atypical cytology (P = 0.0001). In summary, atypical and malignant NAF cytology
      are associated with larger tumour size, and are highly predictive of residual
      carcinoma after needle or excisional biopsy of the breast.

PMID- 10584886
TI  - Tobacco and the risk of acute leukaemia in adults.
AB  - Self-reported smoking histories were collected during face-to-face interviews
      with 807 patients with acute leukaemia and 1593 age- and sex-matched controls.
      Individuals who had smoked regularly at some time during their lives were more
      likely to develop acute leukaemia than those who had never smoked (odds ratio
      (OR) = 1.2, 95% confidence interval (CI) 1.0-1.4). The association was strongest
      for current smokers, defined here as smoking 2 years before diagnosis (OR = 1.4,
      95% CI 1.1-1.7). With respect to the numbers of years smoked, risk estimates were
      raised in all groups except those who had smoked for fewer than 10 years.
      Similarly, the odds ratio decreased as the number of years 'stopped smoking'
      increased, falling to one amongst those who had given up smoking for more than 10
      years. No significant linear trends were found, however, with either the numbers
      of years smoked or the numbers of years stopped smoking, and no significant
      differences were found between AML and ALL.

PMID- 10584887
TI  - Serum carotenoids and vitamins and risk of cervical dysplasia from a case-control
      study in Japan.
AB  - The relationships between risk of cervical dysplasia and dietary and serum
      carotenoids and vitamins were investigated in a case-control study. Cases were
      156 women who attended Papanicolaou test screening in nine institutes affiliated
      with Japan Study Group of Human Papillomavirus (HPV) and Cervical Cancer and had
      cervical dysplasia newly histologically confirmed. Age-matched controls were
      selected from women with normal cervical cytology attending the same clinic.
      Blood sample and cervical exfoliated cells were obtained for measuring serum
      retinol, alpha-carotene, beta-carotene, zeaxanthin/lutein, cryptoxanthin,
      lycopene and alpha-tocopherol and for HPV detection. Higher serum level of alpha
      carotene was significantly associated with decreased risk of cervical dysplasia
      after controlling for HPV infection and smoking status (odds ratio (OR) = 0.16,
      95% confidence interval (CI) 0.04-0.62 for the highest as compared with the
      lowest tertile). Decreased risk for the highest tertile of serum lycopene (OR =
      0.28) was marginally significant. Decreased risks observed for the highest
      tertiles of beta-carotene (OR = 0.65) and zeaxanthin/lutein (OR = 0.53), were not
      statistically significant.

PMID- 10584888
TI  - Prostate cancer risk and consumption of fish oils: a dietary biomarker-based case
      control study.
AB  - Experimental studies suggest that the risk of prostate cancer is reduced with the
      intake of long-chain n-3 polyunsaturated fatty acids derived from marine foods,
      such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, few
      human studies have been conducted due to difficulties in assessing the dietary
      intake of these fatty acids. The authors examined the relationship between
      prostate cancer risk and EPA and DHA in erythrocyte biomarkers in a population
      based case-control study in Auckland, New Zealand during 1996-1997 involving 317
      prostate cancer cases and 480 age-matched community controls. Reduced prostate
      cancer risk was associated with high erythrocyte phosphatidylcholine levels of
      EPA (multivariate relative risk = 0.59; 95% confidence interval 0.37-0.95, upper
      vs lowest quartile) and DHA (multivariate relative risk = 0.62; 95% confidence
      interval 0.39-0.98, upper vs lowest quartile). These analyses support evidence
      from in vitro experiments for a reduced risk of prostate cancer associated with
      dietary fish oils, possibly acting via inhibition of arachidonic acid-derived
      eicosanoid biosynthesis.

PMID- 10584889
TI  - A cost-effectiveness analysis of a residential radon remediation programme in the
      United Kingdom.
AB  - As residential radon programmes of identification and remediation have proceeded,
      so questions have been raised about their costs and benefits. This study presents
      a generalizable model for estimating the cost-effectiveness of a radon mitigation
      programme using the methodological framework now considered appropriate in the
      economic evaluation of health interventions. Its use will help to inform future
      discussion of radon remediation and lung cancer prevention programmes. Data from
      Northamptonshire were analysed, resulting in a societal cost-effectiveness ratio
      of Pounds Sterling 13250 per life-year gained in 1997. The percentage of houses
      found to be over the action level, and the percentage of householders who decide
      to remediate are shown to be important parameters for the cost-effectiveness
      analysis. Questions are raised about the particular importance of perspective in
      this type of analysis and suggestions are made for future research directions.

PMID- 10584890
TI  - Soya foods and breast cancer risk: a prospective study in Hiroshima and Nagasaki,
      Japan.
AB  - The association between soya foods and breast cancer risk was investigated in a
      prospective study of 34759 women in Hiroshima and Nagasaki, Japan. Women
      completed dietary questionnaires in 1969-1970 and/or in 1979-1981 and were
      followed for incident breast cancer until 1993. The analysis involved 427 cases
      of primary breast cancer in 488989 person-years of observation. The risk for
      breast cancer was not significantly associated with consumption of soya foods:
      for tofu, relative risks adjusted for attained age, calendar period, city, age at
      time of bombings and radiation dose to the breast were 0.99 (95% CI 0.80-1.24)
      for consumption two to four times per week and 1.07 (0.78-1.47) for consumption
      five or more times per week, relative to consumption once a week or less; for
      miso soup, relative risks were 1.03 (0.81-1.31) for consumption two to four times
      per week and 0.87 (0.68-1.12) for consumption five or more times per week,
      relative to consumption once a week or less. These results were not materially
      altered by further adjustments for reproductive variables and were similar in
      women diagnosed before age 50 and at ages 50 and above. Among 17 other foods and
      drinks examined only dried fish (decrease in relative risk with increasing
      consumption) and pickled vegetables (higher relative risk with higher
      consumption) were significantly related to breast cancer risk; these associations
      were not prior hypotheses and, because of the large number of comparisons made,
      they may be due to chance.

PMID- 10584891
TI  - High-risk mammographic parenchymal patterns and anthropometric measures: a case
      control study.
AB  - Mammographic parenchymal patterns are related to breast cancer risk and are also
      affected by anthropometric measure. We carried out a case-control study
      comprising 200 cases with high-risk (P2 and DY) mammographic parenchymal pattern
      and 200 controls with low-risk (N1 and P1) patterns in order to investigate the
      effect of body size and shape and breast size on mammographic patterns. Women in
      the highest quartile of body mass index (BMI) distribution were significantly
      less likely to have a high-risk pattern (odds ratio (OR) = 0.21, 95% confidence
      interval (CI) 0.08-0.52, P-value for trend = 0.001) compared to those in the
      lowest quartile. Relative to women with a waist to hip ratio (WHR) of less than
      0.75, the OR of having a high-risk pattern in women with a WHR greater than 0.80
      was 0.30 (95% CI 0.14-0.63). Breast size as measured by cup size was
      significantly and negatively related to high-risk pattern. Our study indicates
      that both BMI and WHR are negatively associated with high-risk patterns. However,
      both phenomena are associated with increased risk of breast cancer in
      postmenopausal women. This negative confounding of two positive risk factors
      means that the effect of parenchymal patterns on risk will tend to be
      underestimated when not adjusted for BMI and WHR and vice versa. Thus we may have
      underestimated the importance of BMI and mammographic parenchymal patterns in the
      past. Further studies are needed to determine a measure of parenchymal density
      that is independent of anthropometric measures and breast size.

PMID- 10584893
TI  - Vancomycin resistance: status quo and quo vadis.
AB  - The prevalence of vancomycin resistance is steadily rising among clinical
      isolates of Enterococcus spp., thereby limiting the treatment options for
      infections caused by vancomycin-resistant enterococci. The precise nature of the
      glycopeptide resistance genes has been elucidated, and many studies on gene
      reservoirs and strain-versus-resistance-gene epidemiology have been performed.
      The prevalence of vancomycin-resistant enterococci in various clinical and
      environmental settings in relation to nosocomial and veterinary applications of
      antimicrobial glycopeptides is discussed in detail in this review. Novel
      molecular tools for the identification of vancomycin-resistant enterococci
      genomes or the various resistance genes have been applied in order to expand
      current insight into the overall epidemiology of the resistance trait itself. The
      risk of the spread of vancomycin resistance to other bacterial species was
      recently underscored by the emergence of staphylococci showing clinical
      resistance to vancomycin. The topics mentioned above are elaborated on and
      discussed in light of the increasing medical concern on the future detection of
      microbial infections beyond chemotherapeutic cure.

PMID- 10584894
TI  - Presence of Staphylococcus aureus with reduced susceptibility to vancomycin in
      Germany.
AB  - A total of 457 Staphylococcus aureus strains from the culture collection of the
      National Reference Center for Staphylococci in Bonn, Germany, were screened for
      susceptibility to vancomycin because some Staphylococcus aureus strains are able
      to form subpopulations that show intermediate resistance to vancomycin. Two
      methicillin-resistant Staphylococcus aureus strains (isolated in 1993) exhibited
      intermediate resistance. One of these, Staphylococcus aureus 137-93, which
      displayed the genomic DNA fragment pattern of the northern German epidemic
      strain, appeared homogeneously resistant. Neither of these strains had been
      identified by routine susceptibility testing. The resistance of the German
      isolates was lower than that of the Japanese isolate Mu50. To determine whether a
      similar mechanism confers vancomycin resistance in Staphylococcus aureus Mu50 and
      137-93, the intracellular cell wall precursor concentration was measured and was
      not found to be comparably increased in Staphylococcus aureus 137-93. In
      conclusion, strains showing intermediate resistance have been present in Germany
      for some time (at least since 1993), but the subpopulations with decreased
      sensitivity were overlooked during antibiotic susceptibility testing.

PMID- 10584892
TI  - Geographic clustering of testicular cancer incidence in the northern part of The
      Netherlands.
AB  - Geographic variations in testicular cancer incidence may be caused by differences
      in environmental factors, genetic factors, or both. In the present study,
      geographic patterns of age-adjusted testicular cancer incidence rates (IRs) in 12
      provinces in The Netherlands in the period 1989-1995 were analysed. In addition,
      the age-adjusted IR of testicular cancer by degree of urbanization was evaluated.
      Cancer incidence data were obtained from the Netherlands Cancer Registry. The
      overall annual age-adjusted IR of testicular cancer in The Netherlands in the
      period 1989-1995 was 4.4 per 100000 men. The province Groningen in the north of
      the country showed the highest annual IR with 5.8 per 100000 men, which was
      higher (P < 0.05) than the overall IR in The Netherlands (incidence rate ratio
      (IRR) 1.3, 95% confidence interval (CI) 1.1-1.6). The highest IR in Groningen was
      seen for both seminomas and non-seminomas. In addition, Groningen showed the
      highest age-specific IRs in all relevant younger age groups (15-29, 30-44 and 45
      59 years), illustrating the consistency of data. The province Friesland, also
      situated in the northern part of the country, showed the second highest IR of
      testicular cancer with 5.3 cases per 100000 men per year (IRR 1.2, 95% CI 1.0
      1.5, not significant). This mainly resulted from the high IR of seminoma in
      Friesland. Analysis of age-adjusted IRs of testicular cancer by degree of
      urbanization in The Netherlands showed no urban-rural differences at analysis of
      all histological types combined, or at separate analyses of seminomas and non
      seminomas. Geographic clustering of testicular cancer seems to be present in the
      rural north of The Netherlands with some stable founder populations, which are
      likely to share a relatively high frequency of genes from common ancestors
      including genes possibly related to testicular cancer. Although this finding does
      not exclude the involvement of shared environmental factors in the aetiology of
      testicular cancer, it may also lend support to a genetic susceptibility to
      testicular cancer development. Testicular cancer cases in stable founder
      populations seem particularly suitable for searching for testicular cancer
      susceptibility genes because such genes are likely to be more frequent among
      affected men in such populations.

PMID- 10584895
TI  - Incidence of Lyme borreliosis in the Wurzburg region of Germany.
AB  - To assess the incidence of Lyme borreliosis in Central Europe, a 12-month,
      prospective, population-based surveillance study of Lyme borreliosis was
      conducted in the Wurzburg region of central Germany, following an aggressive
      awareness campaign. The diagnosis of Lyme borreliosis required the presence of
      (i) erythema migrans (diameter > or =5 cm); (ii) lymphocytoma; or (iii) another
      specific manifestation including Lyme arthritis, neuroborreliosis, carditis or
      acrodermatitis chronica atrophicans in conjunction with serological confirmation.
      A total of 313 cases of Lyme borreliosis was diagnosed, giving an incidence of
      111 cases/100000 inhabitants, the highest rates occurring in children and elderly
      adults living in wooded as opposed to agricultural areas. The incidence in city
      dwellers and inhabitants of rural areas was not significantly different. Erythema
      migrans was the only manifestation in 279 (89%) patients. Of the 34 patients with
      manifestations other than erythema migrans alone, 15 had arthritis, nine
      neuroborreliosis, six lymphocytoma, four acrodermatitis chronica atrophicans and
      one carditis. Children were more likely than adults to have manifestations other
      than erythema migrans alone. Lyme borreliosis was very common in central Germany,
      and one of the most frequent bacterial infections. The observation of more cases
      of arthritis than neuroborreliosis was similar to that in the USA. These results
      may be representative for many parts of central Europe and suggest the need for
      development of a vaccine against borreliosis caused by European strains of
      Borrelia species.

PMID- 10584896
TI  - Influence of socioeconomic status on features and outcome of community-acquired
      pneumonia.
AB  - The influence of socioeconomic status on the features and evolution of community
      acquired pneumonia in 107 consecutive hospitalized patients was investigated.
      Thirty-four (31.8%) patients were considered to have a low socioeconomic status.
      These patients were more likely immigrants, middle-aged, with fewer comorbid
      illnesses, and were more often tobacco, alcohol, or drug consumers (P<0.01). The
      distribution of etiologies was significantly different according to socioeconomic
      status, with tuberculosis occurring more frequently in the low socioeconomic
      group (P < 0.05). Low socioeconomic status was not associated with a more severe
      presentation or outcome of pneumonia but was an independent factor that predicted
      a significantly longer length of hospitalization (5.9 days longer; 95% confidence
      interval, 2.2-9.5 days; P<0.003), entailing a substantial excess cost per
      hospital stay.

PMID- 10584897
TI  - Response to interferon alfa-2b therapy in mutitransfused children with beta
      thalassemia and chronic hepatitis C.
AB  - Hepatitis C virus is responsible for the majority of cases of post-transfusion
      non-A non-B hepatitis in patients with thalassemia major. Interferon alfa is an
      effective treatment for patients with chronic hepatitis C. Response to therapy is
      related to the duration of treatment, the viral load in serum, and the hepatitis
      C virus genotype. The purpose of this study was to estimate the response of
      multitransfused children with beta-thalassemia and chronic hepatitis C to
      interferon alfa-2b therapy. Thirteen patients with beta-thalassemia and chronic
      hepatitis C, (mean age+/-SD, 14.1 +/- 1.7 years) participated in the study. Liver
      biopsy, estimation of HCV RNA, and virus genotyping were performed before onset
      of treatment. All patients were positive for HCV RNA in a low concentration; two
      patients carried the la genotype, four had genotype 3, and seven had genotype 4.
      Patients were treated with 3 x 10(6) U of subcutaneous interferon alfa-2b three
      times weekly. Eleven of 13 patients received therapy for 18 months; the remaining
      two underwent therapy for 6 months. Six of 13 patients responded completely to
      therapy, four responded partially, and three did not respond at all. The grade of
      inflammation and stage of fibrosis was lower in complete responders. Complete
      responders had lower ferritin values compared with the values for partial and
      nonresponders before starting therapy. The results suggest that interferon
      therapy should be recommended for children with beta-thalassemia major
      complicated by a low viral concentration of hepatitis C.

PMID- 10584898
TI  - Diagnostic relevance of the detection of Legionella DNA in urine samples by the
      polymerase chain reaction.
AB  - Urine samples from 317 patients with pneumonia and from 242 patients without
      pneumonia were tested using a polymerase chain reaction (PCR) system for
      detection of the Legionella 5S rRNA gene. The results were compared with findings
      obtained using the established methods for diagnosis of legionellosis. Of the 317
      patients with pneumonia, 58 had confirmed legionellosis, 35 had a presumptive
      Legionella infection, and 224 had no evidence of Legionella infection as
      determined by conventional methods using published criteria. The PCR was positive
      for 42 patients with confirmed infections, yielding a sensitivity of 72.4%.
      Furthermore, 16 (47%) patients with presumptive legionellosis and five (2.2%)
      patients without other evidence of Legionella infection had positive results. All
      samples from 242 patients without pneumonia were PCR-negative. When the results
      for all patients were considered, the specificity of the assay was > or =98.9%.
      The results demonstrate that the sensitivity and specificity values of urinary
      PCR are in the same range as those of established methods. The use of PCR in
      urine complements the repertoire of rapid diagnostic methods, especially for
      infections caused by legionellae not belonging to Legionella pneumophila
      serogroup 1, in which tests for detection of urinary antigen often fail.

PMID- 10584899
TI  - Outbreak of bloodstream infections associated with dialysis machine waste ports
      in a hemodialysis facility.
AB  - Eight cases of gram-negative bloodstream infection without a clinically evident
      source occurred at a hemodialysis unit in Jerusalem between February and
      September 1997. All infections could be traced to three of the 13 dialysis
      machines in use. Epidemiological investigation, including pulsed-field gel
      electrophoretic characterization of organisms isolated from the patients and
      dialysis machines, implicated the Waste Handling Option system of the machines as
      the source of the infections. Discontinuation of the Waste Handling Option system
      use was associated with prompt cessation of the outbreak.

PMID- 10584900
TI  - Rapid improvement of intracranial tuberculomas after addition of ofloxacin to
      first-line antituberculosis treatment.
AB  - Reported here is the case of a 9-year-old girl presenting with disseminated
      tuberculosis, the manifestations of which included mediastinal adenopathy, an
      osteolytic parietal lesion with a large associated scalp abscess, cerebral
      empyema, meningoencephalitis, and tuberculomas. No clear improvement was observed
      after 4 weeks of first-line antituberculosis treatment (10 mg/kg rifampin, 15
      mg/kg isoniazid, 30 mg/kg ethambutol, 30 mg/kg pyrazinamide). The isolation of an
      isoniazid-resistant organism prompted institution of ofloxacin. Introduction of
      this drug was associated with dramatic improvement. Its good penetration into the
      central nervous system and its distribution into macrophages suggest that this
      drug may be of interest for the treatment of intracranial tuberculomas,
      particularly those due to isoniazid-resistant strains.

PMID- 10584901
TI  - Response to standard syphilis treatment in patients infected with the human
      immunodeficiency virus.
AB  - In a study designed to evaluate the efficacy of penicillin in HIV-infected
      patients with syphilis and to determine the clinical and laboratory responses
      after treatment, 13 patients with HIV infection and syphilis were assessed at
      enrollment and at the last follow-up examination (median time of 21 months). The
      Venereal Diseases Research Laboratory (VDRL) test, the Treponema pallidum
      hemaglutination test, and leukocyte counts in cerebrospinal fluid were evaluated
      both at enrollment and at the last follow-up visit, and the polymerase chain
      reaction for Treponema pallidum DNA and the rabbit infectivity test were
      performed on cerebrospinal fluid samples at the last follow-up visit. Primary
      syphilis was confirmed in four patients, latent syphilis in five, and
      neurosyphilis in four. After penicillin treatment, all patients were
      asymptomatic. The serum rapid plasma reagin test became negative in five
      patients, and titers declined in eight. The VDRL test, Treponema pallidum DNA,
      and the rabbit infectivity test were negative in all 13 patients. Except for one
      patient whose serological titer was slow to decline, all patients had good
      clinical and serological responses to penicillin. In certain settings, factors
      other than penicillin treatment failure should be considered in HIV-infected
      patients with suspected relapse of syphilis.

PMID- 10584902
TI  - Reduction of immune system activation in HIV-1-infected patients undergoing
      highly active antiretroviral therapy.
AB  - The aim of this work was to analyze the effects of highly active antiretroviral
      therapy on the chronically activated immune system of 26 antiretroviral-naive HIV
      1-infected patients. Samples from baseline to week 24 or 36 of treatment were
      tested for serum levels of beta2-microglobulin, tumor necrosis factor alpha and
      soluble tumor necrosis factor alpha receptor type II, as well as for human
      leukocyte antigen-DR expression on T cells. After starting therapy, the mean HIV
      1 RNA serum levels decreased and the mean CD4 + cell counts increased from
      baseline to week 36 (P< 0.001). Mean levels of tumor necrosis factor alpha
      receptor type II, tumor necrosis factor alpha and beta2-microglobulin as well as
      expression of human leukocyte antigen-DR were significantly reduced at the end of
      follow-up (P<0.01). Deactivation kinetics of these parameters was similar in
      patients with CD4+ counts>200 cells/microl at baseline versus those with CD4 +
      counts < 200 cells/microl at baseline, despite higher activation at baseline in
      the group with <200 cells/microl. In summary, this study shows that highly active
      antiretroviral therapy is able to induce a strong deactivation of the immune
      system of HIV-1-infected patients.

PMID- 10584903
TI  - Post-traumatic course complicated by cutaneous infection with Absidia
      corymbifera.
AB  - Cutaneous mucormycosis is a rare but serious infection in trauma patients.
      Reported here is the case of a young patient with cutaneous mucormycosis due to
      Absidia corymbifera probably caused by a soil-contaminated wound. Despite daily
      surgical debridement and amphotericin B therapy, cure could be achieved only by
      amputation of the lower limb.

PMID- 10584904
TI  - Usefulness of immunochromatographic detection of antibodies to Mycobacterium
      tuberculosis as an adjunct to auramine staining for rapid diagnosis of
      tuberculosis in a low-prevalence setting.
AB  - A novel immunochromatographic membrane-based assay for the detection of specific
      IgG antibodies to Mycobacterium tuberculosis was evaluated in patients with
      active tuberculosis in a low-prevalence population. The sensitivity of the test
      for detecting active tuberculosis was 41.5% (17/41 patients positive); its
      specificity in a group of patients with other lung diseases was 91.4% (3/35 false
      positive), while in a group of 47 healthy controls it was 100%. The sensitivity
      of the immunochromatographic test equaled that of auramine staining, but
      different subsets of tuberculosis patients were detected by the two tests. The
      suboptimal sensitivity of this immunochromatographic test implies that, even
      though it could be a useful adjunct, it cannot be a replacement for the diagnosis
      of tuberculosis by other microbiological methods along with clinical and
      radiological data.

PMID- 10584905
TI  - Cefotaxime-hydrolysing beta lactamases in Morganella morganii.
AB  - The frequency of enterobacterial isolates with high resistance to expanded
      spectrum beta-lactam antibiotics (mainly cefotaxime or ceftriaxone) has increased
      notoriously in Argentina, mainly because of the spread of extended-spectrum beta
      lactamases. The aim of this work was the study of extended-spectrum beta
      lactamases in several Morganella morganii isolates with unusually high resistance
      to ceftriaxone. These strains produced at least two beta-lactamases, of apparent
      pIs of 5.4 and 8.2, molecular weight 23 000, well inhibited by clavulanate,
      compatible with a broad-spectrum beta-lactamase - perhaps TEM-1 - and an extended
      spectrum beta-lactamase, respectively. The extended-spectrum beta-lactamase was
      identified as a CTX-M-type beta-lactamase - probably CTX-M-2 - by polymerase
      chain reaction, restriction profile analysis and DNA-DNA hybridisation. The
      remaining isolates studied produced either the broad-spectrum beta-lactamase plus
      the ubiquitous AmpC beta-lactamase (13 strains), or the AmpC beta-lactamase only
      (10 strains).

PMID- 10584906
TI  - Semiquantitative polymerase chain reaction enzyme immunoassay for the diagnosis
      of pertussis.
AB  - The two most commonly used targets for diagnosis of pertussis by the polymerase
      chain reaction have been the pertussis toxin promoter and the repeated insertion
      sequence IS481. A comparative assessment of these primers was performed on
      routinely collected nasopharyngeal swabs, stored at -20 C, using novel
      semiquantitative enzyme immunoassays. Both sets of primers behaved similarly with
      bacterial suspensions, and the 17 culture-positive nasopharyngeal swabs were also
      positive with the pertussis toxin promoter primers, with one exception, which had
      been subject to prolonged storage. Significantly more of the 69 culture-negative
      swabs were positive with the pertussis toxin promoter primers (n = 36) than with
      the IS481 primers (n = 18). To determine the effect of inhibitors, a comparative
      assessment of three primer pairs against human DNA (beta-globin and
      glyceraldehyde-3-phosphate dehydrogenase) was also performed.

PMID- 10584907
TI  - An alleged outbreak of methicillin-resistant Staphylococcus aureus in a Dutch
      nursing home.

PMID- 10584908
TI  - A case of oesophageal leishmaniasis indicating visceral leishmaniasis in a
      patient with AIDS.

PMID- 10584910
TI  - Evaluation of modern agglutination tests for identification of methicillin
      susceptible and methicillin-resistant Staphylococcus aureus.

PMID- 10584909
TI  - Failure of indinavir to inhibit Candida albicans in vitro.

PMID- 10584911
TI  - Communication strategies for the intrapartum nurse.
AB  - Communication is a dynamic process involving the use of verbal and nonverbal
      techniques. The intrapartum nurse must use effective communication techniques
      when eliciting information during the initial interview and throughout the labor
      and delivery process. The use of effective communication techniques positively
      affects the clients birth outcome and satisfaction with the birthing experience.
      This article provides an overview of communication techniques and illustrates
      specific communication interventions useful in the clinical setting.

PMID- 10584912
TI  - Factors explaining lack of response to heel stick in preterm newborns.
AB  - OBJECTIVE: To determine factors explaining lack of response by preterm newborns
      to heel stick for blood sampling. DESIGN: A cross-sectional design based on
      secondary analysis of the control session of a randomized crossover design.
      SETTING: Four Level III neonatal intensive-care units of university teaching
      hospitals. PARTICIPANTS: 120 preterm newborns with an average age of 28 weeks
      postconceptional age. INTERVENTION: 24 newborns who showed a "no change" response
      according the Premature Infant Pain Profile were compared to the remaining 96
      newborns who had shown a pain response. MAIN OUTCOME MEASURES: Age
      (postconceptional age at birth, postnatal age at study), Apgar score at 5
      minutes, severity of illness, sex, race, wake/sleep state, previous study
      sessions, total number of painful procedures since birth, and time since last
      painful procedure. RESULTS: After stepwise logistic regression analysis the
      variables remaining in the final model that explained the difference between the
      groups were postnatal age at time of study, postconceptional age at birth, time
      since last painful procedure, and wake/sleep state. CONCLUSIONS: Newborns who
      were younger, asleep, and had undergone a painful event more recently were less
      likely to demonstrate behavioral and physiologic indicators of pain.

PMID- 10584913
TI  - Mother's perceptions of postpartum stress and satisfaction.
AB  - OBJECTIVE: To examine mothers' postpartum perceptions of stress and satisfaction.
      DESIGN: Methodologic triangulation with quantitative and qualitative data in a
      nonexperimental design. PARTICIPANTS AND SETTING: A convenience sample of 95
      women was obtained during normally scheduled postpartum appointments at a health
      maintenance organization. MAIN OUTCOME MEASURES: The self-administered
      questionnaire included the Mothers' Information Tool (MIT), What Being the Parent
      of a Baby Is Like (WPL-R), and the Brief Symptom Inventory (BSI). Open-ended MIT
      items revealed mothers' perceptions of stress and satisfaction. The WPL-R
      provided maternal satisfaction scores, and the BSI yielded Global Stress Index
      scores. RESULTS: Content analysis identified the following categories: Roles,
      Tasks, Resources, and Relationships. Subcategories identified as areas of stress
      were Work/School, Sleep/Rest, Adjustment/Own Needs, Health/Body Image,
      Organization of Life, Child Care, Day Care, Housework, Future Challenges,
      Finances, Housing, Time, Partner, and Family. Subcategories identified as areas
      of satisfaction were Participating in Relationships, Sharing the Future, Being
      Proud to Be a Mother, Enjoying a Healthy Baby, and Caring for a Child. Levels of
      stress and satisfaction of mothers who scored high and low on quantitative
      measures were compared. CONCLUSION: The outcomes contribute to the knowledge
      concerning postpartum women's perceptions of the mothering experience and suggest
      approaches to nursing assessment and intervention to prevent postpartum
      adjustment difficulties.

PMID- 10584914
TI  - Psychosocial and demographic factors related to health behaviors in the 1st
      trimester.
AB  - OBJECTIVE: To explore the relationship of psychosocial and demographic variables
      to health behaviors in early pregnancy. DESIGN: First trimester findings
      presented from a prospective study of weight gain in pregnancy. SETTING: A
      comprehensive health care system in central Texas. PARTICIPANTS: 114 pregnant
      women (75% white, 13% African American, 10% Hispanic, 2% Asian) of 12 weeks
      gestation or less. OUTCOME MEASURE: Self-Care Inventory, which includes
      diet/eating, substance abuse, recklessness, hygiene-related practices,
      sleep/rest, and exercise behaviors. RESULTS: In regression analysis the final
      model of demographic and psychosocial variables showed that higher depressive
      symptoms, lower internal locus of control for fetal health, and lower family
      income were related to poorer health behaviors in the 1st trimester of pregnancy.
      CONCLUSIONS: Health behaviors in early pregnancy may be affected by psychosocial
      factors such as depressive symptoms. Greater emphasis should be given to such
      factors in research and prenatal assessments.

PMID- 10584915
TI  - Methadone treatment during pregnancy.
AB  - OBJECTIVE: To review the literature on methadone use by pregnant women. DATA
      SOURCES: A search was conducted on CINAHL, MEDLINE, and PSYCHINFO under
      "pregnancy" and "methadone." STUDY SELECTION: Articles published between 1988
      1998 were reviewed and chosen based upon relevance to the objective. DATA
      EXTRACTION: Data were extracted and organized under the following headings:
      effects of methadone on pregnancy outcome, management of the pregnant woman on
      methadone, and implications of social and political policies for pregnant women
      who use opiates. DATA SYNTHESIS: Methadone treatment is most effective for
      pregnant women who receive care in a comprehensive service center. Few systematic
      investigations exist concerning methadone maintenance during pregnancy, thus no
      formal guidelines for management exist. Changes in federal policies for drug
      treatment and welfare regulations will challenge health care professionals who
      provide treatment for opiate-dependent pregnant women. CONCLUSIONS: Treatment
      with methadone is the standard of care for the opiate-using pregnant woman,
      despite findings challenging its benefits and efficacy in women who continue to
      use illicit drugs.

PMID- 10584916
TI  - Adolescent pregnancy and substance use.
AB  - OBJECTIVE: To review the literature on adolescent pregnancy and substance use for
      the purpose of identifying practice and research implications. DATA SOURCES:
      Computerized searches were done using MEDLINE and CINAHL, as well as references
      cited in the articles reviewed. Key words used in the search were adolescent
      pregnancy and substance use; teen pregnancy and substance abuse; adolescent risk
      behaviors; pregnant adolescent and drug addiction; and perinatal substance use.
      STUDY SELECTION: Articles and comprehensive works from indexed journals in the
      English language published after 1986 were reviewed. DATA EXTRACTION: Data were
      extracted and organized using these headings: motivation for drug use; common
      drugs used; cigarette smoking; alcohol; and other drugs. DATA SYNTHESIS: This
      review identifies factors associated with drug use in adolescent pregnancy, risk
      factors for the teenaged mother and her developing fetus, and suggestions of
      health care providers who have studied adolescent pregnancy and substance use.
      CONCLUSIONS: Nurses who care for pregnant adolescents are in an ideal position to
      assess for signs and symptoms of substance abuse, provide education, initiate
      interventions and referrals, and provide follow-up care. Early identification of
      substance abuse is a key factor in the prevention of pregnancy complications and
      poor fetal outcome.

PMID- 10584917
TI  - Drugs and uterine motility.
AB  - Nurses who care for pregnant and laboring women are faced with an increasingly
      frequent use of pharmaceutical agents that facilitate initiation of labor
      (uterotropins), augment labor (uterotonics), or potentially stop labor
      (tocolytics). The choice of the drug, administration, side effects, and
      complications varies. Knowledge about uterine physiology helps the clinician
      understand the action of these agents. Knowledge of the differences and
      similarities among oxytoxics, ergots, prostaglandins, and the various drugs used
      as tocolytics is essential for safe and effective care of women and their fetuses
      who may be exposed to these agents.

PMID- 10584918
TI  - Antimicrobial agents: pharmacology and clinical application in obstetric,
      gynecologic, and perinatal infections.
AB  - The pharmacology of selective antimicrobial agents and their role in the
      treatment of obstetric, gynecologic, and neonatal infections is the focus of this
      clinical review. Defining and refining the use of antimicrobial therapy is
      significant on both an individual and a global level because the emergence of
      resistant organisms is a public health concern. Heath care providers must be
      knowledgeable about the risks and benefits of initiating pharmacologic treatment
      based on clinical evidence with regard to an agent's spectrum of activity,
      efficacy, and side effects.

PMID- 10584919
TI  - Pharmacology of antihypertensive drugs.
AB  - The wide variety of first-line agents available for managing high blood pressure
      include diuretics, beta adrenergic receptor blockers, alpha adrenergic receptor
      blockers, angiotensin converting enzyme inhibitors, and calcium channel blockers.
      Supplemental agents used for second-line therapy and special indications, such as
      pregnancy and hypertensive emergencies, include angiotensin receptor blockers,
      central-acting agents, direct vasodilators, and adrenergic neuron inhibitors.
      Selection of agents for particular patients requires consideration of research
      based evidence for positive long-term outcomes and of the unique patient profile
      of age, race, co-morbidities, and lifestyle. A thorough understanding of the
      pharmacology (mechanism, pharmacokinetics, adverse effects and drug interactions,
      clinical use) of antihypertensive agents is an essential foundation for nursing
      practice in women's health.

PMID- 10584920
TI  - Targeting human papillomavirus type 16 E7 to the endosomal/lysosomal compartment
      enhances the antitumor immunity of DNA vaccines against murine human
      papillomavirus type 16 E7-expressing tumors.
AB  - DNA vaccination is an attractive approach for tumor immunotherapy because of its
      stability and simplicity of delivery. Advances demonstrate that helper T cell
      responses play a critical role in initiating immune responses. The aim of the
      current study is to test whether targeting HPV-16 E7 to the endosomal/lysosomal
      compartment can enhance the potency of DNA vaccines. We linked the lysosome
      associated membrane protein 1 (LAMP-1) to HPV-E7 to construct a chimeric DNA,
      Sig/E7/LAMP-1 DNA. For in vivo tumor prevention experiments, mice were vaccinated
      with E7 DNA or Sig/E7/LAMP-1 DNA via gene gun, followed by tumor challenge. For
      in vivo tumor regression experiments, mice were first challenged with tumor cells
      and then vaccinated with E7-DNA or Sig/E7/LAMP-1 DNA. Intracellular cytokine
      staining with flow cytometry analysis, cytotoxic T lymphocyte (CTL) assays,
      enzyme-linked immunoabsorbent assay (ELISA), and enzyme-linked immunospot
      (ELISPOT) assays were used for in vitro E7-specific immunological studies. In
      both tumor prevention and tumor regression assays, Sig/E7/LAMP-1 DNA generated
      greater antitumor immunity than did wild-type E7 DNA. In addition, mice
      vaccinated with Sig/E7/LAMP-1 DNA had greater numbers of E7-specific CD4+ helper
      T cells, higher E7-specific CTL activity, and greater numbers of CD8+ T cell
      precursors than did mice vaccinated with Sig/E7 or wild-type E7 DNA. Sig/E7
      generated a stronger E7-specific antibody response than did Sig/E7/LAMP-1 or wild
      type E7 DNA. Our results indicate that linkage of the antigen gene to an
      endosomal/lysosomal targeting signal may greatly enhance the potency of DNA
      vaccines.

PMID- 10584921
TI  - Systemic antitumor immunity in experimental brain tumor therapy using a
      multimutated, replication-competent herpes simplex virus.
AB  - Replication-competent, attenuated herpes simplex virus (HSV) vectors have been
      developed for viral oncolytic therapy of primary and metastatic malignant brain
      tumors. However, the role of the host immune responses in the brain has not been
      elucidated. N18 neuroblastoma cells were used as a tumor model in syngeneic A/J
      mice to test the therapeutic efficacy of G207, a conditionally replicating HSV
      vector, in an immunocompetent condition. G207 inoculated intraneoplastically
      exhibited a prominent oncolytic antitumor effect in mice harboring N18 tumors in
      the brain or subcutaneously, and, in addition, elicited a systemic antitumor
      immune response. Subcutaneous tumor therapy with G207 caused regression of a
      remote, established tumor in the brain or in the periphery, which was potentially
      mediated by the systemic antitumor immune response, and provided persistent tumor
      specific protection against N18 tumor rechallenge in the brain as well as in the
      periphery. Antitumor immunity was associated with an elevation of specific CTL
      activity against N18 tumor cells that persisted for at least 13 months. The
      results suggest that the oncolytic antitumor action of replication-competent HSV
      may be augmented by induction of specific and systemic antitumor immunity
      effective both in the periphery and in the brain.

PMID- 10584922
TI  - Disabled infectious single-cycle herpes simplex virus as an oncolytic vector for
      immunotherapy of colorectal cancer.
AB  - New modalities of treatment for colorectal cancer are required to support and
      improve those currently available. One such approach is immunotherapy by transfer
      of immunostimulatory genes to tumor cells. Here, we report the use of a herpes
      simplex virus (HSV) vector that is capable of a single round of infection
      (disabled infectious single-cycle [DISC]-HSV) as a gene transfer vehicle for
      colorectal cancer. This vector has potential advantages over other vectors for
      cancer immunotherapy in that it lyses infected tumor cells. Infection with DISC
      HSV inhibited tumor cell growth both in vitro and in vivo. In addition, DISC-HSV
      mediated cell killing occurs by both apoptotic and necrotic mechanisms. A range
      of colorectal tumor cell lines could be rapidly transduced with DISC-HSV/lacZ (14
      90% in 4 hr). Both tumor prevention and tumor therapy protocols showed clear
      antitumor effects with DISC-HSV/mGM-CSF. In the prophylactic approach, an
      infected/irradiated whole cell vaccine protected up to 80% of mice from
      rechallenge. In addition, intratumoral injection of established tumors with DISC
      HSV/GM-CSF caused rejection in 40% of mice and generated some protection from
      subsequent rechallenge. In both cases, however, it is clear that a dominant
      therapeutic effect of the DISC-HSV vector derives from its oncolytic properties,
      irrespective of the transduced gene. As a prelude to taking these studies forward
      to human clinical trials, we demonstrate that tumor cells could be successfully
      grown from freshly obtained human colorectal cancer resections (within 1 week of
      surgery), were transduced with DISC-HSV/hGM-CSF, and secreted the cytokine. This
      study provides the preclinical basis for trials of immunotherapy of colorectal
      cancer using DISC-HSV.

PMID- 10584923
TI  - Characterization of the P140K, PVP(138-140)MLK, and G156A O6-methylguanine-DNA
      methyltransferase mutants: implications for drug resistance gene therapy.
AB  - The G156A O6-alkylguanine-DNA alkyltransferase (AGT) mutant protein, encoded by
      the G156A O6-methylguanine-DNA methyltransferase gene (MGMT), is resistant to O6
      benzylguanine (BG) inactivation and, after transduction into hematopoietic
      progenitors, transmits remarkable resistance to BG and BCNU. As a result, a
      clinical trial, in which the MGMT gene is transduced into CD34+ cells of patients
      with cancer, has been approved. A newly identified AGT mutation, P140K, generates
      dramatically increased BG resistance relative to G156A, and suggests that gene
      transfer of P140K may confer improved hematopoietic cell protection. To address
      this hypothesis, we measured BG + BCNU and BG + TMZ resistance in G156A, P140K,
      or P138M/V139L/P140K (MLK) MGMT-transduced K562 cells. In addition, we performed
      a detailed characterization of individual properties including BG resistance,
      activity, and protein stability of these mutants in human hematopoetic K562 cells
      and E86 retroviral producer cells. In K562 cell extracts, the MLK and P140K
      mutants retained full activity at doses up to 1 mM BG, while G156A had a BG ED50
      of 15 microM, compared with 0.1 microM for wtAGT. In the absence of BG, the G156A
      protein possessed a 56% reduction in specific O6-methyltransferase activity
      compared with wtAGT. MLK, P140K, and wtAGT all possessed similar specific
      activities, although the O6-methyl repair rate of all mutants was reduced 4- to
      13-fold relative to wtAGT. The wtAGT, MLK, and P140K proteins were stable, with
      half-lives of greater than 18 hr. In contrast, only 20% of the G156A protein was
      stable after 12 hr in cycloheximide and, interestingly, the remaining protein
      appeared to retain most of the activity present in non-cycloheximide-treated
      cells. Differences in BG resistance, activity, and stability between P140K, MLK,
      and G156A suggest that P140K may be the optimal mutant for drug resistance gene
      transfer. However, hematopoietic K562 cells transduced with MFG-G156A, P140K, or
      MLK had similar degrees of BG and BCNU as well as BG and TMZ resistance when
      treated with concentrations of BG (< or =25 microM) achieved in clinical trials,
      suggesting similar efficacy in many in vivo applications.

PMID- 10584924
TI  - Hematologic recovery in mice transplanted with bone marrow stem cells expressing
      anti-human immunodeficiency virus genes.
AB  - We have used a mouse bone marrow transplantation (BMT) model to study the safety
      of retrovirus-mediated transfer of anti-HIV genes (RevM10 and HIV-1 pol
      antisense) into hematopoietic stem/progenitor cells (HSPCs). In particular, we
      have monitored the hematologic recovery post-BMT and transgene expression in
      myeloid and lymphoid lineages, and analyzed tissue sections for evidence of any
      transgene-related pathological condition. Expression of anti-HIV genes had no
      effect on kinetics of hematologic recovery post-BMT. The average time to reach
      20% of normal cell counts was 15-17 days for white blood cells and 12-14 days for
      platelets, and the average time to reach complete recovery was 42-56 days for
      leukocytes and 104-161 days for platelets. Hematocrit levels were not
      significantly affected by irradiation and transplantation procedures. Donor
      chimerism was uniformly > or =90% in all transplanted animals. At 4-5 weeks post
      BMT transgene expression was detected in peripheral blood leukocytes in 100% of
      the animals and ranged from 4.5 to 44.7%. In a majority of the animals the
      percentage of transgene-expressing cells in circulation decreased over time but
      remained detectable for the length of the study (>6 months). Expression was
      detected in all analyzed cell lineages (RBCs, platelets, monocytes, granulocytes,
      and T and B cells). Relative counts of various leukocytes (Mac1+ monocytes, Gr1+
      granulocytes, CD3+ T cells, and B220+ B cells) were normal. There were no
      treatment-related histopathological changes in a wide range of tissues examined.
      In addition, there were no treatment effects on differential leukocyte counts,
      and morphology of peripheral blood and bone marrow brush smears. In summary,
      transfer and expression of the RevM10 and the HIV-1 antisense genes into
      hematopoietic stem/progenitor cells in vivo appears safe. We propose that the
      mouse bone marrow transplantation model could be used to evaluate some safety
      aspects of HSPC-based gene therapies.

PMID- 10584925
TI  - Polarized secretion of transgene products from salivary glands in vivo.
AB  - Previously (Kagami et al. Hum. Gene Ther. 1996;7:2177-2184) we have shown that
      salivary glands are able to secrete a transgene-encoded protein into serum as
      well as saliva. This result and other published data suggest that salivary glands
      may be a useful target site for vectors encoding therapeutic proteins for
      systemic delivery. The aim of the present study was to assess in vivo if
      transgene-encoded secretory proteins follow distinct, polarized sorting pathways
      as has been shown to occur "classically" in cell biological studies in vitro.
      Four first-generation, E1-, type 5 recombinant adenoviruses were used to deliver
      different transgenes to a rat submandibular cell line in vitro or to rat
      submandibular glands in vivo. Subsequently, the secretory distribution of the
      encoded proteins was determined. Luciferase, which has no signal peptide, served
      as a cell-associated, negative control and was used to correct for any
      nonspecific secretory protein release from cells. The three remaining transgene
      products tested, human tissue kallikrein (hK1), human growth hormone (hGH), and
      human alpha1-antitrypsin (halpha1AT), were predominantly secreted (>96%) in
      vitro. Most importantly, in vivo, after a parasympathomimetic secretory stimulus,
      both hK1 and hGH were secreted primarily in an exocrine manner into saliva.
      Conversely, halpha1AT was predominantly secreted into the bloodstream, i.e., in
      an endocrine manner. The aggregate results are consistent with the recognition of
      signals encoded within the transgenes that result in specific patterns of
      polarized protein secretion from rat submandibular gland cells in vivo.

PMID- 10584926
TI  - Combined ultrafiltration-transduction in a hollow-fiber bioreactor facilitates
      retrovirus-mediated gene transfer into peripheral blood lymphocytes from patients
      with mucopolysaccharidosis type II.
AB  - The process of growing and transducing large quantities of human primary
      peripheral blood lymphocytes (PBLs) with high gene transfer efficiency continues
      to be one of the major challenges for clinical and experimental gene therapy.
      Toward developing a clinical trial of lymphocyte gene therapy for
      mucopolysaccharidosis type II (i.e., Hunter syndrome), we investigated a novel
      method that exploited the innate capability of a hollow-fiber bioreactor system
      to filter large quantities of vector supernatant and facilitate transduction. An
      aliquot (5 x 10(7)) of PBL apheresis product was precultured in a gas-permeable
      culture bag or a bioreactor, and then transduced with a retroviral vector L2SN
      containing the iduronate-2-sulfatase (IDS) and neomycin resistance genes. We
      observed that the total number of PBLs could be expanded up to 187-fold, yielding
      up to 10(10) cells at the end of a 7-day culture period. The multiplicity of
      infection could be increased (up to 20-fold) by ultrafiltrating a large volume of
      vector supernatant through the semipermeable membrane of this system. A high
      level of transduction efficiency (up to 57%) was achieved, resulting in IDS
      enzyme activity as high as 1250 U/mg/hr in transduced PBL(MPS) 15 days after
      transduction. This level was markedly increased from that of nontransduced cells
      (<3 U/mg/hr) and was even greater than that of normal PBLs (mean, 809; n = 10).
      After 12 days of G418 selection, PBL(MPS) transductants exhibited a proviral IDS
      enzyme level approximately threefold higher than that in normal PBLs. These
      results indicated that the hollow-fiber bioreactor could be used to culture and
      transduce human primary PBLs in clinically useful quantities with relatively high
      gene transfer efficiency and transgene expression.

PMID- 10584927
TI  - Selection of keratinocytes transduced with the multidrug resistance gene in an in
      vitro skin model presents a strategy for enhancing gene expression in vivo.
AB  - In gene therapy studies, achieving prolonged, high-level gene expression in a
      significant percentage of cells has been difficult. One solution to enhance
      expression would be to select for cells expressing both the desired gene and a
      linked selectable marker gene in a bicistronic vector. As a potential target
      tissue, the skin is easily accessible for safe topical application of a selecting
      agent that could lead to significant gene expression in a high percentage of
      keratinocytes. To test the feasibility of such an approach, a skin raft culture
      model was developed. Human keratinocytes were transduced with the multidrug
      resistance (MDR) gene, which confers resistance to a variety of cytostatic and
      antimitotic compounds, such as colchicine. While growing on acellular dermis,
      transduced keratinocytes were treated with various doses of colchicine (10-50
      ng/ml). Colchicine treatment increased the percentage of keratinocytes expressing
      MDR to almost 100% in raft cultures, Significantly, keratinocytes in colchicine
      treated, MDR-transduced raft cultures were able to proliferate normally and form
      a stratified, differentiated epidermis. This model suggests that topical
      selection for MDR-expressing keratinocytes in vivo should be feasible without
      hampering the biologic integrity of skin. Thus, topical selection leading to
      enhanced expression of a desired gene, linked to a resistance gene, holds future
      promise for skin gene therapy.

PMID- 10584928
TI  - Cellular immune responses of healthy individuals to intradermal administration of
      an E1-E3- adenovirus gene transfer vector.
AB  - In animals, Ad-mediated gene transfer initiates anti-Ad host immune responses
      that vary, depending on vector design, dose, host, and transgene. To begin to
      understand whether the anti-Ad vector responses in humans simulate those in
      animals, Ad(GV)CD.10, an E1-E3- Ad5 vector encoding the E. coli cytosine
      deaminase gene, was administered by the intradermal route to six normal
      individuals (8 x 10(7) to 8 x 10(9) particle units, each dose administered to two
      sites; n = 2 per group). No adverse events were observed. Polymerase chain
      reaction/Southern analysis demonstrated vector genome in the skin through 28 days
      in all individuals except one of two at the lowest dose. Local induration,
      independent of vector dose and baseline systemic anti-Ad5 neutralizing
      antibodies, developed in all subjects (6 to 17 mm, peak by day 3). Biopsies
      revealed a mild to moderate T cell (CD3+, CD4+, CD8+), B cell, and macrophage
      infiltrate at day 3, all decreased by day 28. Langerhans cells accumulated
      primarily in the papillary dermis. The day 3 cellular response was dose
      independent. On day 28, CD4+ and CD8+ T lymphocytes and macrophages showed dose
      dependency. There was minimal systemic Ad5-specific lymphocyte proliferation
      induced by Ad vector administration in three individuals studied, and no Ad5
      specific cytotoxic T lymphocytes (evaluated in two subjects) could be detected.
      Thus, intradermal administration of an E1-E3- Ad vector to normal subjects
      induces mild/moderate local cellular responses, even in Ad-immunized individuals.
      These observations provide a baseline to determine if these human anti-Ad vector
      host responses can be circumvented by using "stealth" vectors and/or
      immunosuppression.

PMID- 10584929
TI  - Adenoviral vector-mediated gene therapy in the mouse lung: no role of Fas-Fas
      ligand interactions for elimination of transgene expression in bronchioepithelial
      cells.
AB  - The early successes of adenoviral vector-mediated gene therapies in the lung have
      been hampered by the immune response directed against viral proteins and
      transgene product. Intratracheal administration of adenovirus vector in immune
      competent mice transduces bronchioepithelial cells of lung extremely efficiently;
      however, transgene expression is eliminated within 2 weeks. Extinction of
      transgene expression has been attributed to infiltrating cytotoxic T lymphocytes
      (CTLs). Fas-Fas ligand (Fas-FasL) interactions play a critical role in the
      effector function of the CTL killing. We have previously demonstrated that this
      interacting pair of molecules plays a critical role in elimination of transgene
      expression in mouse liver. In this study we investigated the role of Fas-FasL
      interactions in CTL effector functions in vivo in mouse lung. Analyses of these
      molecules in lung showed constitutive expression of Fas in bronchiooepithelial
      cells. On the other hand, FasL was inducible in the bronchioepithelial cells
      after adenovirus vector treatment. The in vivo role of the Fas-FasL interactions
      was determined by adoptive transfer of splenocytes from normal immune-competent
      mice to Fas-deficient mice (B6-lpr); likewise, the function of FasL on CTLs was
      analyzed by the ability of splenocytes from FasL-deficient mice (B6-gld) to
      eliminate transgene expression in Rag1-deficient mice. These studies demonstrate
      that despite expression of Fas and FasL in bronchioepithelial cells and CTLs,
      these interacting molecules do not play a critical role in elimination of
      transgene expression in the lung.

PMID- 10584930
TI  - Inhibition of bcr-abl oncogene expression by novel deoxyribozymes (DNAzymes).
AB  - Deoxyribozymes, or DNA enzymes (DNAzymes), are novel nucleic acids that have the
      ability to bind to specific sequences of RNA, and to cleave the target site
      catalytically. DNAzymes are smaller and more efficient enzymatically than
      ribozymes (RZs), which are catalytic nucleic acids synthesized from
      ribonucleotides. We have designed three DNAzymes that specifically target the two
      variants of the p210 bcr-abl gene (splice 1, b3a2; splice 2, b2a2) and the p190
      variant (ela2). The cleavage sites for these DNAzymes are located 5 nucleotides
      (nt) 5' from the fusion site for b3a2, and only 1 nt 5' from the fusion sites for
      b2a2 and e1a2. We have shown in cell-free in vitro cleavage assays that these
      DNAzymes efficiently cleave their respective substrates. Mutated DNAzymes, in
      which only one critical base has been altered, do not cleave these targets. We
      have used a serum-resistant cytofectin (GS 2888; Gilead) to transfect the
      DNAzymes into target K562 cells, which express p210bcr-abl. In short-term
      transfection assays, the DNAzymes specifically inhibited p210bcr-abl protein
      expression by K562 cells by about 40%, and inhibited cell growth by more than 50%
      in a 6-day liquid culture assay. We have also transfected freshly isolated CD34+
      bone marrow cells from patients with CML with the DNAzymes, which specifically
      inhibited the growth of bcr-abl-positive CFU-Mix colonies by 53-80%. The
      potential advantages of anti-bcr-abl DNAzymes over RZs include the following:
      DNAzymes are much less expensive to synthesize; they are more resistant to serum;
      and the anti-b2a2 DNAzyme cleaves at a site only 1 nt away from the fusion site,
      whereas its hammerhead RZ counterpart cleaves this target at a site 8 nt 3' to
      the fusion site, well within abl exon 2. DNAzymes are novel RNA-cleaving
      molecules that may significantly improve our ability to inhibit bcr-abl oncogene
      expression in Ph-positive target cells.

PMID- 10584931
TI  - Increased gene transfer into human cord blood cells by centrifugation-enhanced
      transduction in fibronectin fragment-coated tubes.
AB  - We investigated whether transduction of human cord blood progenitor cells can be
      increased by spinoculation in fibronectin fragment CH-296 (FN)-coated tubes.
      Bicistronic vectors PA317/LgEIN, containing the enhanced green fluorescent
      protein (EGFP) and neomycin phosphotransferase (neo) genes, and PG13/LgDIN,
      containing the dihydrofolate reductase and neo genes, were used to transduce CD34
      enriched human cord blood cells. Transduction by spinoculation in FN-coated tubes
      (spin/FN+) was compared with spinoculation in noncoated tubes (spin/FN-) and
      transduction in plates coated with FN (plate/FN+). Antibody to TGF-beta was added
      to spin/FN+ to evaluate its impact on transduction. Using producer cell line
      PA317/LgEIN for transduction of CD34+ cord blood cells, FACS analysis for
      expression of EGFP revealed mean transduction of 30.6+/-4.3, 9.1+/-1.6, and
      21.1+/-6.5% of CD34+ cells in the spin/FN+, spin/FN-, and plate/FN+ arms,
      respectively. Transduction of CD+CD38low cells was also higher in the spin/FN+
      arm as compared with transduction in the spin/FN- arm. These results were
      corroborated by colony-forming assays. Antibody to TGF-beta did not further
      increase transduction. Using a different producer cell line, PG13/pLgDIN, a
      higher number of G418-resistant CFU-GM was observed in the spin/FN+ as compared
      with the plate/FN+ and spin/FN-arms. NOD/SCID mice were transplanted with
      transduced, CD34-enriched human cord blood cells, and persistence of transduced
      human cells was analyzed in the mice marrows after 6-8 weeks: 32.8, 6.0, and
      23.9% human G418-resistant CFU-GM colonies were observed in the spin/FN+, spin/FN
      , and plate/FN+ arms, respectively. These results suggest that spinoculation in
      FN-coated tubes increases transduction of early human cord blood progenitor cells
      as compared with spinoculation in noncoated tubes.

PMID- 10584932
TI  - Corticosteroid administration does not affect viral oncolytic activity, but
      inhibits antitumor immunity in replication-competent herpes simplex virus tumor
      therapy.
AB  - A multimutated, conditionally replicating herpes simplex virus type 1, G207, has
      been developed as an effective means of treating human malignant brain tumors. We
      have shown that intraneoplastic inoculation of G207 induces a specific and
      systemic antitumor immune response that plays an important role in the antitumor
      activity, in addition to the direct oncolytic action of G207. Since a large
      number of malignant brain tumor patients are treated with corticosteroids, it is
      important to evaluate whether the therapeutic efficacy of G207 is affected by
      corticosteroid-induced immunosuppression. For a tumor model, we used G207
      permissive N18 murine neuroblastoma cells implanted subcutaneously in syngeneic
      A/J mice. Intraneoplastic inoculation of G207 (10(7) PFU) induced significant
      suppression of tumor growth whether or not dexamethasone (5 mg/kg) was given.
      When dexamethasone was given for an extensive time (16 days starting on day -2),
      all G207-treated mice showed tumor growth despite initial shrinkage, whereas in
      the saline group, four of eight of the G207-treated mice were cured.
      Dexamethasone administration significantly reduced serum neutralizing antibodies
      against G207 at 14 and 21 days after intraneoplastic G207 inoculation. However,
      there was no difference between the dexamethasone and saline groups in terms of
      the amount of infectious G207 isolated from tumors. Dexamethasone administration
      completely abolished G207-induced cytotoxic T lymphocyte activity against N18
      cells. These results indicate that the oncolytic activity of G207 is retained
      under corticosteroid administration. However, intensive immunosuppression may
      diminish the long-term efficacy of G207 owing to suppression of tumor-specific
      cytotoxic T lymphocyte induction.

PMID- 10584933
TI  - Congenital radius deficiency: radiographic outcome and survivorship analysis.
AB  - The experience with congenital radius deficiency, or radial hemimelia, at the
      Shriners' Hospital for Children, Los Angeles Unit, was reviewed. A cohort of 29
      limbs in 23 patients was identified with an average follow-up period of 50
      months. Radiographic parameters were assessed using the hand-forearm angle, hand
      forearm position, and ulnar bow. We compared radialization to modified
      centralization, assessed the efficacy of ulnar osteotomy, and assessed the effect
      of age, preoperative deformity, ulnar osteotomy, and Bayne's type on the final
      result. Revisions were noted and a survivorship analysis performed. The cohort
      had statistically significant correction of hand-forearm angle and hand-forearm
      position. Radialization was similar to modified centralization in the final
      outcome. Ulnar osteotomy was an efficacious way to correct ulnar deformity. Age,
      preoperative deformity, performance of an ulnar osteotomy, and Bayne's type did
      not affect the final wrist position. Survivorship analysis was performed using
      revision as the end point, with a survivorship rate at 5 years of 67%.
      Significant risk factors for revision included radial or positive hand-forearm
      angle and young age at the time of the index procedure. There was a suggestion
      that small postoperative hand-forearm position, or radial translation, increased
      the risk of revision. Preoperative deformity, performance of an ulnar osteotomy,
      and Bayne's type did not affect the risk of revision. These data offer support
      for the hypothesis that a more ulnar translation and an ulnar angulation of the
      wrist is a means of reducing the radial lever arm and thus the incidence of
      deformity recurrence and need for revision.

PMID- 10584934
TI  - The spectrum of radial longitudinal deficiency: a modified classification.
AB  - The records of 119 patients with 196 extremities with radial longitudinal
      deficiency seen between 1923 and 1996 were reviewed. We propose a global
      classification system that includes the spectrum of pathology affecting the
      radial side of the extremity, including deficiency of the radius, carpal
      abnormalities, and hypoplastic thumbs. Radial deficiency could be classified for
      181 extremities of 104 patients using this classification system. Type N has a
      normal length radius and a normal carpus with thumb hypoplasia, type O has a
      normal length radius and radial side carpal abnormalities, type 1 has more than 2
      mm shortening of the radius, type 2 has a hypoplastic radius, type 3 has a
      partial radius with absence of the distal physis, and type 4 has complete absence
      of the radius. All patients had thumb hypoplasia. Eighty-two percent of
      extremities with thumb hypoplasia but no deficiency of the radius that were
      available for carpal bone classification had carpal anomalies, including absence,
      hypoplasia, and coalitions. All the extremities with type 1 radial deficiency had
      carpal anomalies. Carpal abnormalities could not be determined for types 2, 3,
      and 4 deficiency because most had a prior centralization. Proximal radioulnar
      synostosis or congenital dislocation of the radial head was seen in 44% of
      extremities with type 1 radial deficiency. This classification includes carpal
      anomalies and thereby links isolated thumb hypoplasia and deficiency of the
      radius into one system.

PMID- 10584935
TI  - Trigger finger in children.
AB  - At the Texas Scottish Rite Hospital for Children, 239 trigger digits in 176
      children were seen and treated surgically over a 10-year period. Trigger fingers
      accounted for 33 (14%) of these digits in 18 (10%) of the patients. In 8 of 18
      patients (44%) the fingers continued to trigger after A-1 pulley release. In
      children, trigger fingers are different from trigger thumbs. Trigger fingers in
      children are uncommon and have variable causes, and an A-1 pulley release alone
      will not always correct the triggering. Additional treatments, such as resection
      of one or both limbs of the sublimis tendon or an A-3 pulley release, may be
      required. An awareness of other contributing factors and readiness to explore the
      entire flexor mechanism should help prevent failure of surgical treatment.

PMID- 10584936
TI  - Trigger fingers in children.
AB  - Twelve children with triggering of 17 digits other than the thumb were seen in
      our department during an 8-year period. There were 8 children with single-finger
      involvement; the remaining patients had more than 1 triggering finger. Seven
      fingers in 5 children were not treated surgically; 1 of these patients had
      residual triggering in all 3 involved fingers. Ten fingers in 7 children were
      treated surgically. In contrast to the operative findings in children with
      triggering thumbs, no nodules were found in these cases. The surgical procedure
      necessary to relieve the triggering was often more extensive than an incision of
      the A-1 pulley alone and required separation of the inserting slips of the flexor
      digitorum superficialis tendon and release of the proximal A-2 pulley.

PMID- 10584937
TI  - Comparison of nail bed repair versus nail trephination for subungual hematomas in
      children.
AB  - Fifty-three fingers in 52 children were divided into 2 groups, operative and
      nonoperative, after fingernail crush injury. Criteria for inclusion into the
      study were an intact nail and nail margin with subungual hematoma and no previous
      nail abnormality. The length of the follow-up period averaged longer than 2 years
      for each group. Twenty-six fingers in 26 children were treated by nail removal,
      exploration, and repair of nail bed lacerations (operative group). Twenty-seven
      fingers in 26 children were treated by evacuation of hematoma by nail
      trephination without nail removal in 11 fingers and by observation in the other
      16 fingers (nonoperative group). In the operative group, transient abnormalities
      (nail depression or hypertrophy), which resolved by 4 months, occurred in 3
      patients. In the group treated by simple decompression, there were no
      complications except for 1 transient nail depression at 3 months. The average
      cost to the operative group was $1,263 compared with $283 to the trephination
      group. Although formal nail bed reconstruction has been advocated for hematomas
      larger than 25%, we found no notable difference in outcome between the 2 groups
      regardless of hematoma size, presence of fracture, injury mechanism, or age.
      Charges, however, were 4 times greater for the operative group. Based on the
      results of this study, we do not feel that nail removal and nail bed exploration
      is indicated or justified for children with subungual hematoma and an intact nail
      and nail margin.

PMID- 10584938
TI  - Anatomic variations in sensory innervation of the hand and digits.
AB  - Anatomic dissections under microscopic magnification were performed on 30 fresh
      cadaveric hands to depict the course and interconnections of the sensory nerves
      to the digits. The dissections included the median nerve, the ulnar nerve, the
      superficial branch of the radial nerve, the dorsal branch of the ulnar nerve, and
      the dorsal branch of the proper digital nerve. The communicating branches between
      the median and ulnar nerves in the palm were found in 20 of the 30 (67%)
      specimens. The dorsal branch of the proper digital nerve was found to arise at or
      proximal to the A1 pulley zone in 62% of the long digits, more proximally than
      previously reported. The dorsal sensory nerves (the terminal branch of radial or
      ulnar sensory nerves) extending to the nail bed area were found in 46% of the
      digits, thus confirming that sensory supply to the dorsum of the distal phalanx
      and nail bed also arises from the dorsal sensory nerves. Four types of palmar
      dorsal interconnections, located in the middle of the proximal phalanx, were
      found in the digits but not in the thumb. The presence of these branches
      indicates dual innervation of the dorsal and palmar side of the distal areas of
      the digits. These anatomic findings may help hand surgeons interpret
      discrepancies in sensory loss after either dorsal or palmar injuries.

PMID- 10584939
TI  - Reconstruction of high ulnar nerve lesions by distal double median to ulnar nerve
      transfer.
AB  - Ulnar nerve lesions around the elbow often carry an unfavorable prognosis due to
      insufficient sensory and intrinsic muscle recovery. We present a series of 7
      cases in which restoration of ulnar innervated intrinsic muscles of the hand and
      of skin sensibility was achieved. This was accomplished by a distal connection of
      the anterior interosseous nerve and the superficial sensory palmar branch of the
      median nerve to the motor and sensory components of the ulnar nerve at Guyon's
      canal. The length of the follow-up period ranged from 1 to 3.5 years. Results
      were graded by the Highet-Zachary scale. Good motor and sensory recovery was
      obtained in 6 cases; only return of protective sensation occurred in the
      remaining case.

PMID- 10584940
TI  - Results of treatment of carpal tunnel syndrome with associated hourglass
      deformity of the median nerve.
AB  - Two hundred twenty-seven successive cases of carpal tunnel syndrome confirmed by
      abnormal electrodiagnostic studies were reviewed. All cases underwent open carpal
      tunnel release by a single surgeon over a 3-year period. Thirty-two hands (14% of
      all cases) in 29 patients demonstrated an hourglass deformity at the time of
      surgery. Electrodiagnostic tests revealed no evidence of any other type of
      peripheral neuropathy in any patient. Postoperative electrodiagnostic studies
      were obtained in all cases on completion of therapy. The length of the follow-up
      period averaged 11 months (range, 3-35 months). The duration of preoperative
      symptoms ranged from 2 years to more than 10 years. Twenty-eight of the 32 hands
      (88%) with hourglass deformities demonstrated subjective clinical improvement or
      complete resolution of symptoms. Chronicity of symptoms and electrophysiologic
      severity did not correlate with the presence of the hourglass deformity. Presence
      of hourglass compression of the median nerve in carpal tunnel syndrome is
      therefore not a negative prognostic indicator.

PMID- 10584941
TI  - Distal scaphoid resection arthroplasty for the treatment of degenerative
      arthritis secondary to scaphoid nonunion.
AB  - Nineteen patients with chronic scaphoid nonunion and associated degenerative
      arthritis between the distal fragment and the radial styloid were treated by
      resection of the distal fragment. All patients had a dorsal intercalated segment
      instability wrist collapse pattern with an average radiolunate angle of -32
      degrees and a 10% reduction in the carpal height, both of which changed minimally
      during the follow-up period. The duration of the nonunion averaged 12 years and
      the follow-up period averaged 49 months. Range of motion improved 85% and grip
      improved 134%. Thirteen of the patients experienced complete pain relief. One
      patient required additional surgery and elected wrist arthrodesis. Resection of
      the distal fragment is not recommended for patients with capitolunate arthritis.
      Two of the 4 patients with capitolunate arthritis had persistent symptoms; 3 had
      progressive degenerative changes.

PMID- 10584942
TI  - Retrograde compression screw fixation of acute proximal pole scaphoid fractures.
AB  - Seventeen consecutive patients with acute unstable proximal pole scaphoid
      fractures were managed over the past 5 years with open reduction and internal
      fixation. Four fractures were displaced, with greater than 1 mm of fragment
      offset and intercarpal malalignment. The operative technique consisted of a
      dorsal approach to the scaphoid, radius bone grafting, and freehand retrograde
      Herbert compression screw fixation. The patients were evaluated at an average of
      37 months (range, 12-63 months) after surgery. All fractures healed within 13
      weeks (average, 10 weeks). Functional wrist range of motion and grip strength
      were achieved in all patients. No patients developed osteonecrosis or
      radioscaphoid arthritis. Open reduction and internal fixation rather than primary
      casting is a better means of reducing the complications of delayed union,
      nonunion, and irreparable osteonecrosis that often occur after acute proximal
      pole scaphoid fracture treated with cast immobilization.

PMID- 10584943
TI  - Scaphoid nonunion and flexor pollicis longus tendon rupture.
AB  - Four patients presented with a rupture of the flexor pollicis longus tendon that
      was associated with a longstanding scaphoid nonunion. A radiocarpal arthrosis was
      present in 3 of the 4 patients and a dorsiflexed intercalated segment instability
      deformity was also seen in 3 of the 4 patients. Three patients underwent surgery
      consisting of an osteosynthesis with an iliac bone graft for the scaphoid
      nonunion and a palmaris longus tendon graft for the ruptured flexor pollicis
      longus tendon. An osseous union of the scaphoid and a functional active range of
      motion of the thumb interphalangeal joint (33 degrees on average) was attained in
      all 3 of the patients treated surgically. Preoperative radiologic examinations
      and intraoperative findings suggest that the volarly protruding distal scaphoid
      segment is the cause of the rupture.

PMID- 10584944
TI  - Scaphotrapezoid arthritis: prevalence in thumbs undergoing trapezium excision
      arthroplasty and efficacy of proximal trapezoid excision.
AB  - Between June 1995 and May 1998, 37 patients underwent trapezium excision
      arthroplasty. Preoperative radiographic assessment for scaphotrapezoid arthritis
      was performed. At the time of surgery intraoperative inspection of the
      scaphotrapezoid joint allowed calculation of the true prevalence of arthritis as
      well as sensitivity and specificity of the radiographic diagnosis. The true
      prevalence of scaphotrapezoid arthritis was 62%. The sensitivity of the
      radiographic diagnosis was 44% and the specificity was 86%. Comparison of
      surgical results in 23 patients who underwent both trapezium excision
      arthroplasty and proximal trapezoid excision, with 14 patients who underwent the
      former procedure, only showed that there was no morbidity associated with the
      latter. Because of the potential that scaphotrapezoid arthritis may cause
      residual symptoms following trapezium excision arthroplasty, and in light of the
      low sensitivity of radiographs, routine intraoperative assessment of the joint is
      recommended so that proximal trapezoid excision can be performed if degenerative
      change is present.

PMID- 10584945
TI  - Treatment of a traumatic osteochondral defect in the thumb carpometacarpal joint
      with a periosteal autograft.
AB  - We report a case in which an autogenous periosteal autograft was used to
      resurface a large osteochondral defect in the thumb carpometacarpal joint of a
      young woman. Good results were found at 4-year follow-up examination.

PMID- 10584946
TI  - Long-term assessment of proximal row carpectomy for chronic perilunate
      dislocations.
AB  - Twelve patients with chronic stage III or stage IV perilunate dislocations were
      managed over the past 7 years by proximal row carpectomy. All dislocations were
      untreated or incompletely reduced for a minimum of 8 weeks after injury. The mean
      time from injury to definitive treatment was 15 weeks (range, 8 weeks to 6
      months). Surgical management was inclusive of a dual dorsal and volar approach.
      Median nerve decompression, lunate excision, and capsuloligament repair was
      performed volarly and scaphoid and triquetrum carpectomy was accomplished
      dorsally. Temporary radio capitate K-wire fixation during early soft tissue
      healing was uniformly performed. All patients were evaluated at an average
      postoperative duration of 40 months (range, 28 months to 7 years). Marked relief
      of wrist pain and median nerve dysesthesias was routinely achieved. Effective
      wrist range of motion and grip strength were restored. Untreated stage III and IV
      chronic perilunate dislocation treated by proximal row carpectomy eliminates pain
      and restores function to a severely injured wrist.

PMID- 10584947
TI  - Radiologic measurement of the scapholunate joint: implications of biologic
      variation in scapholunate joint morphology.
AB  - To determine the optimal location for measurement of the scapholunate (SL) joint
      intercortical width, normal biologic variation in SL joint morphology was
      evaluated in 40 normal, skeletally mature wrists (16 volunteers, 24 cadavers)
      using thin-section 1.5T magnetic resonance imaging performed in the axial and
      coronal planes. The integrity of the SL ligaments was confirmed by magnetic
      resonance imaging and verified with anatomic dissection of the cadaver wrists.
      Patterns of SL articular morphology were qualitatively determined using
      similarity grouping. Scapholunate interval measurements were made at 3 locations
      each on the mid-SL joint image from both the axial and coronal planes: the
      articular margins (dorsal-palmar and proximal-distal) and midjoint. Three
      patterns of midjoint space cortical conformation were observed: parallel
      congruent (78%), inverted Y (15%), and point-like (8%). The most consistent and
      narrowest distance between the scaphoid and lunate was found at midjoint: coronal
      1.45 mm (44% coefficient of variation) and axial 1.00 mm (22% coefficient of
      variation). This study demonstrated that measurement of the apparent SL joint
      interval in an inappropriate site, as with extended or flexed clenched fist
      views, may provide inaccurate SL joint interval distance assessments. Regardless
      of SL joint configuration, the midportion of the SL joint shows only moderate
      biologic variation and the least absolute measurement variance in width and
      should be the most precise part of the joint to measure. On magnetic resonance
      imaging, the normal SL joint interval measures less than 2 mm.

PMID- 10584948
TI  - Hand function following single ray amputation.
AB  - We retrospectively studied primary and reconstructive single ray resection at 16
      to 150 months after surgery (median, 41 months) in 25 patients (18 males) whose
      average age was 28 years. Cases were reviewed 16 to 154 months after surgery
      (median, 41 months). The injuries involved 14 dominant and 11 nondominant hands.
      Twelve patients had primary ray resection (< or =2 weeks after injury) and 13 had
      secondary/reconstructive amputation of 18 border and 7 central digits.
      Examinations and functional testing by Minnesota rate of manipulation and timed
      grooved pegboard tests were done and x-rays were reviewed. The majority of
      patients were subjectively satisfied with the appearance and function of the
      hand. Patients lost an average of 13 weeks of work (range, 2-24 weeks); those
      with primary resection were out of work 9 weeks (range, 2-17 weeks) and patients
      who had secondary resection lost a total of 16 weeks of work (range, 7-24 weeks).
      Twenty-one of the 25 patients returned to their preinjury occupation. Evaluation
      of nonwork plus settled workers' compensation cases versus nonsettled
      compensation/litigation cases showed that there were statistically significant
      differences in grip strength, key pinch, oppositional pinch, and Minnesota rate
      of manipulation test results. Primary ray removal limits the total costs
      associated with injury and disability; unsettled compensation/litigation issues
      produce statistically disparate and otherwise physically inexplicable
      differences.

PMID- 10584949
TI  - Ring avulsion injuries: a biomechanical study.
AB  - The biomechanics of ring avulsion injuries was studied in a cadaveric simulation
      model. Custom-fitted metal rings attached to a rigid frame were placed over the
      proximal phalanx of fresh or thawed fresh-frozen specimens. Ring avulsion
      injuries in 44 fingers were produced with a standardized force applied to the
      proximal ulna. The progress of injury was evaluated with simultaneous high-speed
      cinematography and continuous force measurements. The injured digits were x-rayed
      and categorized according to Urbaniak's classification. Continuous force
      measurements produced similar curves for all classes of injuries. The average
      maximum force resulting in class I injuries was 80 N. The average maximum force
      producing amputation in class III injuries was 154 N, a force much lower than
      expected. Force measurements for class II injuries were nearly identical to those
      of class III. This surprisingly minimal force resulting in digit amputation was
      explained by high-speed cinematography, which showed that the rings tilt on the
      digits concentrating disruption forces as a result of ring angulation on the
      finger. Incomplete amputations were due to loss of ring purchase by skin flap
      eversion. Finally, comparison of high-speed cinematography with force curves
      suggests that skin rupture rather than skeletal or tendon disruption accounted
      for the maximum force during ring avulsion injury.

PMID- 10584950
TI  - Dynamic treatment of displaced proximal phalangeal fractures.
AB  - We report a splint system for a protected mobilization program (termed dynamic
      treatment) of proximal phalangeal fractures. This program can be used for
      nonoperative treatment or after operative treatment. Intra-articular fractures of
      the proximal phalanx at the metacarpophalangeal joint were included. The custom
      molded 2-component thermoplastic splint allows motion of the proximal and distal
      interphalangeal joints. It was developed to allow bone healing and recovery of
      motion at the same time. We evaluated the clinical and radiologic results of a
      consecutive series of 48 displaced proximal phalangeal fractures in 45 patients
      who received dynamic treatment. Fracture consolidation was achieved in all
      patients and bone healing and recovery of full active motion was achieved
      simultaneously in all but 4 patients by 6 weeks. The advantage of this splint
      system is the variability of its application. The splint can be used both for
      nonsurgical and surgical management. It can be removed to change dressings and
      for radiologic evaluations. The period of dynamic treatment can be determined
      individually in each case.

PMID- 10584951
TI  - Treatment of triplane fractures of the head of the proximal phalanx.
AB  - We report the morphology and treatment of 2 cases of a triplane intra-articular
      bicondylar fracture of the head of the proximal phalanx. Fracture lines in the
      coronal, sagittal, and transverse planes characterize this fracture, making it
      highly unstable. Open reduction and internal fixation using two 1.5-mm
      interfragmentary screws oriented in a dorsal to volar direction resulted in
      anatomic restoration of the articular surfaces and satisfactory functional
      results. In 1 case, autogenous cancellous bone graft was harvested from the
      ipsilateral radial styloid to support the articular fragments.

PMID- 10584952
TI  - Treatment of unstable distal radius fractures with cancellous allograft and
      external fixation.
AB  - Unstable fractures of the distal radius continue to pose a challenge to the hand
      surgeon. Adjunctive bone grafting is often required to augment structural
      integrity and aid healing. Because of the risks inherent to bone autograft
      harvest, however, freeze-dried, irradiated cancellous bone allograft has been
      used to treat unstable distal radius fractures with severe metaphyseal
      comminution. Seventeen patients with such fractures (mean age, 70 years; 2 males
      and 15 females) were treated with bone allograft and external fixation with or
      without internal fixation. The outcome was evaluated using the modified Mayo
      wrist score, demonstrating 3 excellent, 8 good, 6 fair, and no poor results on
      follow-up examination (mean follow-up period, 23 months; range, 7-43 months). The
      patients were requested to return for follow-up review between 1997 and 1998.
      These results show that cancellous bone allograft is a useful adjunct to external
      fixation in the treatment of unstable distal radius fractures.

PMID- 10584953
TI  - Delayed rupture of the flexor pollicis longus tendon after inappropriate
      placement of the pi plate on the volar surface of the distal radius.
AB  - The pi plate (Synthes Ltd, Paoli, PA) was designed to fit the unique contour of
      the dorsal aspect of the distal radius. Complications of pi plate fixation of the
      dorsal distal radius have been previously reported to include both extensor
      tenosynovitis and delayed extensor tendon rupture. We report a case of rupture of
      the flexor pollicis longus tendon associated with inappropriate placement of the
      pi plate on the volar surface of the distal radius.

PMID- 10584954
TI  - Atraumatic palmar midcarpal dislocation in a skeletally immature adolescent with
      hemiatrophy.
AB  - We report a late presentation of a palmar midcarpal dislocation in an adolescent
      female with open growth plates who had no history of antecedent wrist injury.
      Midcarpal arthrodesis improved function and eliminated progressive pain.

PMID- 10584955
TI  - Avulsion of both extensor carpi radialis tendons: a case report.
AB  - Closed traumatic avulsion of both extensor carpi radialis tendons is reported in
      a young healthy patient. Early diagnosis important because the tendons tend to
      retract and anatomic repositioning is more difficult to perform with passing
      time. Diagnostic markers are the inability to actively extend the wrist and the
      presence of dorsal bone fragments on the lateral radiograph of the wrist. We
      recommend fixation of the avulsed fragments to restore the length and strength of
      the wrist extensors.

PMID- 10584956
TI  - Forearm compartment pressures: an in vitro analysis of open and endoscopic
      assisted fasciotomy.
AB  - Pressure reduction for standard open fasciotomy and a novel endoscopic fascial
      release were compared in experimental conditions of elevated forearm compartment
      pressures by continuously monitoring intracompartmental pressures in 22 cadaver
      forearms. Both methods were effective in diminishing tissue pressures.
      Intracompartmental pressures were reduced to significantly lower levels following
      open versus endoscopic assisted fasciotomy (2.9 mm Hg vs. 13.2 mm Hg). In the
      endoscopic group a statistically significant second decrease in pressure was
      observed after dermatomy, reducing intracompartmental tissue pressures from 13.2
      mm Hg to 3.1 mm Hg. The results of this study suggest that endoscopic assisted
      fasciotomy can reduce elevated tissue pressures, confirming previous findings
      that fascial release is of primary importance in decreasing intracompartmental
      tissue pressures. Open fasciotomy, however, gave significantly greater
      decompression than the endoscopic technique, a difference that may be even more
      substantial in the clinical setting due to several limiting factors of this in
      vitro model. Our results also suggest that immediate skin closure following
      fasciotomy increased tissue pressure and therefore should be avoided.

PMID- 10584957
TI  - Recurrent giant cell tumors of the tendon sheath.
AB  - Seventy patients underwent surgical excision of a giant cell tumor of the tendon
      sheath. The patients were monitored for an average of 3 years 4 months. Nineteen
      of the 70 patients (27%) had a surgically and histologically documented
      recurrence at an average of 2 years 3 months (range, 3 months to 10 years)
      following the initial procedure. Eight of 19 patients (42%) with recurrence had a
      prior recurrence. Statistically significant risk factors for recurrence included
      presence of adjacent degenerative joint disease, location at the distal
      interphalangeal joint of the finger or interphalangeal joint of the thumb, and
      radiographic presence of an osseous pressure erosion. Age, gender, size, and
      location within the digit (volar vs. dorsal) were not risk factors for
      recurrence. Awareness of these associations should be reflected in the surgeon's
      approach and preoperative discussion with the patient.

PMID- 10584958
TI  - Split flexor pollicus longus tendon transfer for stabilization of the thumb
      interphalangeal joint: a cadaveric and clinical study.
AB  - The split flexor pollicus longus (FPL) tendon transfer is a surgical technique
      using the radial half of the FPL tendon rerouted dorsally and inserted into the
      extensor pollicis longus tendon for correction of Froment's sign. A cadaveric
      model was designed to investigate the effects of the split FPL tendon transfer on
      pinch strength. Pinch strength was compared for extrinsic thumb flexion (1)
      without the split FPL and (2) with the split FPL, tensioned at 3 different
      positions (0 degrees flexion, 30 degrees flexion, and 60 degrees flexion). We
      report the clinical results of key pinch strength using split FPL tendon transfer
      as part of thumb reconstruction for 12 thumbs in 10 patients at an average follow
      up time of 2 years. The cadaveric study showed no significant difference in pinch
      force between specimens with or without split FPL transfer or when comparing
      tensioning at 0 degrees versus 30 degrees versus 60 degrees. Froment's sign wa s
      reproduced in all cadavers with pinch activation without split FPL transfer and
      was eliminated in all specimens after the split FPL transfer. In the clinical
      portion of this study 12 transfers in 10 patients had an average follow-up pinch
      strength of 33.7 N (range, 18-80 N) and no evidence of Froment's sign. We
      conclude that the split FPL tendon transfer is an effective method for correction
      of Froment's sign due to intrinsic paralysis of the thumb.

PMID- 10584959
TI  - Extensor triggering in de Quervain's stenosing tenosynovitis.
AB  - Extensor triggering is an uncommon but recognized component of de Quervain's
      stenosing tenosynovitis. In a retrospective review of 827 patients with the
      diagnosis of de Quervain's disease over a 5-year period, 11 patients with 13
      affected wrists were identified who had demonstrable triggering by both history
      and physical examination (prevalence of 1.3%). One wrist underwent surgical
      release without conservative treatment. The remaining 12 wrists were initially
      treated with nonoperative modalities. Failure of conservative treatment as
      defined by recurrent triggering and pain occurred in 7 wrists, of which 5
      underwent surgical release. At the time of surgery, all wrists were noted to have
      synovitis, separate compartments for the extensor pollicis brevis and abductor
      pollicis longus tendons, and no intratendinous nodules. After an average follow
      up period of 42 months (range, 5.7-94.5 months) there were no recurrences of
      triggering after surgical treatment. Seven of 12 wrists with triggering de
      Quervain's stenosing tenosynovitis failed nonoperative treatment. Triggering or
      locking in extension is an uncommon symptom in de Quervain's stenosing
      tenosynovitis and demonstrates a more recalcitrant course when treated
      nonoperatively.

PMID- 10584960
TI  - A comparative analysis of the six-strand double-loop flexor tendon repair and
      three other techniques: a human cadaveric study.
AB  - The ideal zone II flexor tendon repair would be easy to perform, cause minimal
      scarring, and be strong enough to allow early active motion. A 6-strand loop
      suture technique devised by the senior author (T.M.T.) was studied in vitro.
      Forty flexor tendons were harvested from fresh-frozen human hands and divided
      into 4 groups of 10 tendons each. Each group of tendons was repaired with a
      specific technique: group 1, the modified Kirchmayr (modified Kessler) technique;
      group 2, the single-loop 2-strand technique described by Tsuge; group 3, Tsai's
      double-loop 4-strand modification of Tsuge's technique; and group 4, Tsai's
      double-loop 6-strand modification of Tsuge's technique. Gap resistance of each
      repair technique was recorded on a computer using a Differential Variable
      Reluctance Transducer (MicroStrain, Burlington, VT) and on videotape to record
      first gap formation, 1-mm and 2-mm gap formation, and maximum load. Statistically
      significant differences between groups were as follows: at first gap formation
      between the 2-strand and 6-strand loop suture techniques, and at maximum load
      between the modified Kessler and 4-strand, modified Kessler and 6-strand, 2
      strand and 4-strand, and 2-strand and 6-strand loop suture techniques. The 6
      strand double-loop suture technique had a higher tensile strength than the other
      techniques, as measured in this model at each stage in our experiment. The 6
      strand double-loop suture technique simplifies flexor tendon repair. It improves
      the repair's strength and its resistance to gapping without increasing tendon
      handling or bulk. This increased repair strength allows us to pursue a more
      aggressive rehabilitation program.

PMID- 10584961
TI  - Bone resorption of the proximal phalanx after tendon pulley reconstruction.
AB  - A 35-year-old male worker sustained a degloving injury of the left hand. An
      abdominal flap was used for skin coverage. Tenolysis and reconstruction of the A2
      pulley was done using a procedure based on the 3-loop technique, which was
      modified by putting the tendon loop under the extensor apparatus and periosteum.
      X-ray revealed hourglass-shaped bone resorption around the proximal phalanx, just
      under the reconstructed pulley. Diaphyseal narrowing remained present in follow
      up x-rays obtained 9 and 10 years later. The remodeling of the resorption was
      poor. Too much pressure may have caused this bone resorption from the shortened
      pulley and the circulatory deprivation may have been caused by the dissected
      periosteum and blocking by the surrounding tendon loop. The degloving injury,
      which also deprived the digits of a blood supply, may have been an additional
      underlying risk factor. We recommend that future comparative studies of pulley
      reconstruction take into account mechanical effectiveness as well as force
      distribution.

PMID- 10584962
TI  - Sesamoiditis of the index finger presenting as acute suppurative flexor
      tenosynovitis.
AB  - Sesamoiditis involving the hand is uncommon, usually reported in the thumb, and
      has not been reported in the index finger. As rare as this clinical entity
      remains, its presentation simulating an acute suppurative flexor tenosynovitis is
      even more rare. We report a patient who presented with Kanavel's 4 cardinal signs
      of acute suppurative tenosynovitis who was subsequently found to have an acute
      sesamoiditis of the index finger. This finding was supplemented by a cadaveric
      and radiographic study to better delineate the anatomy of the index sesamoid and
      further explain the clinical presentation.

PMID- 10584963
TI  - Repair of a multiply recurrent giant cell reparative granuloma of the hand with
      wide resection and fibular grafting.
AB  - A patient with multiply recurrent giant cell reparative granuloma of the third
      metacarpal is reported. Three prior excisions failed to prevent recurrence. A
      wide resection and replacement with a nonvascularized fibular bone graft resulted
      in elimination of the tumor at the 7-year follow-up visit.

PMID- 10584964
TI  - Elbow revision arthroplasty in the situation of bone loss using an unlinked long
      stem prosthesis.
AB  - The results of 16 first-revision operations using an unlinked cemented long-stem
      elbow arthroplasty in the situation of major bone loss are presented. Fifteen
      patients with a mean age of 62 years and longstanding polyarthritis were
      monitored for a mean period of 31 months (range, 6-62 months). Seven revision
      arthroplasties showed a good result and 7 a fair result with improvement of
      function and pain. Two patients with postoperative instability requiring further
      surgery had a poor result, with one infected prosthesis and one elbow with
      persistent instability and ulnar nerve hypersensitivity. Using a visual analog
      scale, patients documented good pain relief, good subjective independence, and a
      high level of satisfaction. In the follow-up SF-36 health survey, patients scored
      low physical function but good mental function. These results show that in the
      absence of infection and instability, revision elbow arthroplasty, even in the
      situation of major bone loss, can be a successful treatment option using this
      unlinked cemented long-stem system.

PMID- 10584965
TI  - The effects of wrist distraction on carpal kinematics.

PMID- 10584966
TI  - Surgical treatment for radial tunnel syndrome.

PMID- 10584967
TI  - Mechanisms underlying the anti-epileptic efficacy of the ketogenic diet.
AB  - The clinical efficacy of the ketogenic diet (KD) has now been well-documented.
      However, the underlying bases of KD antiepileptic efficacy are still a matter of
      speculation. A number of suggestions regarding underlying mechanisms have been
      offered, but all require rigorous testing. Development of appropriate animal
      model systems, and clear statement of experimentally testable hypotheses, are
      needed. Among the general hypotheses of interest are the following: (1) the KD
      alters the nature, and/or degree, of energy metabolism in the brain -- therefore
      altering brain excitability; (2) the KD leads to changes in cell (neuronal and
      perhaps glial) properties, which decrease excitability and dampen epileptiform
      discharge; (3) the KD induces changes in neurotransmitter function and synaptic
      transmission -- thus altering inhibitory-excitatory balance and discouraging
      hyper-synchronization; (4) the KD is associated with changes in a variety of
      circulating factors which act as neuromodulators that can regulate CNS
      excitability; and (5) the KD gives rise to alterations in brain extracellular
      milieu, which serve to depress excitability and synchrony. An understanding of
      the mechanism underlying KD antiepileptic efficacy will help us not only to
      optimize the clinical use of the ketogenic diet, but also to develop novel
      antiepileptic treatments.

PMID- 10584968
TI  - Clinical efficacy of the ketogenic diet.
AB  - The ketogenic diet is an effective alternative therapy used to control
      intractable seizures. It was originally described in 1921 as a way to duplicate
      and prolong the beneficial effects that fasting appeared to have on seizure
      control. It involves consuming a calorie-restricted diet in which the
      fat:carbohydrate + protein ratio ranges from 2:1 to 5:1. Recent prospective
      studies in children demonstrate that about 50% of children will continue on the
      diet for at least a year, with 40-50% of those starting the diet having a >50%
      reduction in seizures after 12 months. When the diet is discontinued it is
      usually due to lack of efficacy. The diet is a radical medical therapy and
      nutritional well-being is a constant concern. Renal stones have occurred in 5-8%
      of children on the diet; lipids are elevated, but the significance of this is not
      known. The mechanism of action of the diet remains unknown, and it is difficult
      to assess which biochemical parameters should be monitored as adjustments are
      made to the diet.

PMID- 10584969
TI  - Metabolic and endocrine aspects of the ketogenic diet.
AB  - The ketogenic diet (KD) is designed to simulate the biochemical effects of
      fasting by maintaining a state of ketosis. The complex interplay of endocrine and
      metabolic factors requires that a continuous ingestion of a diet high in lipid
      calories is necessary to achieve such a state and yet maintain body weight. The
      resulting condition provides for much of the cerebral energy requirements in the
      form of ketone bodies. We review energy metabolism with special emphasis on fatty
      acid oxidation to provide the readers with a foundation that facilitates
      identification of patients who will especially benefit from this diet, as well as
      to assist clinicians in screening candidates who may experience a catastrophic
      outcome if fasted and placed on this diet. The review includes a discussion of
      the role of carnitine in mitochondrial fatty acid metabolism, and the criteria
      for carnitine supplementation. Only limited information is available regarding
      the interaction of the diet with the commonly used antiepileptic drugs.

PMID- 10584971
TI  - Age-dependent pathways of brain energy metabolism: the suckling rat, a natural
      model of the ketogenic diet.
AB  - As a consequence of the high fat content of maternal milk, the suckling rat may
      be viewed as a 'natural model' of the ketogenic diet. Changes in energy
      metabolism during this period of development may give us some clues into the
      antiepileptic properties of the ketogenic diet. We have, therefore studied the
      postnatal evolution of local cerebral metabolic rates for glucose (LCMRglcs) and
      of regional rates of cerebral uptake of beta-hydroxybutyrate (betaHB) in the
      developing rat between postnatal day (PN) 10 and 35. LCMRglcs were low and
      homogeneous at PN10. They increased significantly in four auditory regions
      between PN10 and PN14, at the time of maturation of auditory function. Between
      PN14 and PN17, they increased further in two auditory regions, one visual area
      (the lateral geniculate nucleus), three limbic and three motor areas. These
      increases occurred simultaneously with the maturation of vision and the
      development of locomotion and general exploratory behavior. Between PN17 and
      PN21, LCMRglcs increased by 28-97% (depending on brain area) and by a mean value
      of 25% in all areas studied. In contrast to the function-related increases in
      LCMRglcs, regional rates of cerebral betaHB uptake underwent a generalized non
      specific increase between PN1O and PN14, and stayed at a high level until PN17.
      Between PN17 and PN21, rates of cerebral betaHB uptake decreased significantly in
      all brain regions studied, and reached very low levels by PN35. Thus, even in the
      suckling rat, whose cerebral metabolic activity depends upon both glucose and
      ketone bodies, it is the postnatal increases in LCMRglcs that appear to be
      critical for the acquisition of new functions and neurological competence.
      Conversely, the homogeneous increase in cerebral betaHB uptake occurring between
      PN10 and PN17 at a period of active brain growth may rather reflect non-specific
      mechanisms of cell growth.

PMID- 10584970
TI  - Endocrine regulation of neurotransmitter transporters.
AB  - Aminergic signalling in the CNS is terminated by clearance of neurotransmitters
      from the synapse via high affinity transporter molecules in the presynaptic
      membrane. Relatively recent sequence identification of these molecules has now
      permitted the initiation of studies of regulation of transporter function at the
      cellular and systems levels. In vitro studies provide evidence that the
      transporters for dopamine, serotonin, and gamma-aminobutyric acid (GABA) may be
      substrates for regulation by protein kinase C and protein kinase A signalling.
      Changes in energy balance and metabolic status, such as starvation, result in
      major shifts in hormonal output. It is now recognized that metabolic hormones
      such as insulin or the adrenal steroids can have significant acute and chronic
      effects on several aspects of CNS function. Data from this laboratory and others
      now provide evidence that insulin and adrenal and gonadal steroid hormones may
      regulate the synthesis and activity of the transporters. Future studies should
      permit elucidation of the cellular basis for endocrine regulation of
      neurotransmitter clearance, and thus, the role of endocrines in the maintenance
      of normal CNS aminergic signalling. The potential relevance of transporter
      regulation for the ketogenic diet is discussed.

PMID- 10584973
TI  - Age-dependent differences in flurothyl seizure sensitivity in mice treated with a
      ketogenic diet.
AB  - Despite strong clinical data confirming the anticonvulsant efficacy of a
      ketogenic diet (KGD) in pediatric patients, corroborative experimental data in
      young animals are limited. In the present study, the effects of a KGD on
      flurothyl seizure susceptibility were examined in normal juvenile mice after a
      dietary duration of 3, 7, or 12 days, and in adult mice for 15 days. In all
      groups of KGD-treated mice, blood beta-hydroxybutyrate levels were significantly
      elevated over those measured in controls. The present KGD was anticonvulsant
      (i.e. delayed onset) against the first (clonic) flurothyl-induced seizure for
      juvenile mice treated for either 7 or 12 days, but not for juvenile mice and
      adult mice fed the diet for 3 and 15 days, respectively. While this KGD was not
      anticonvulsant against the second (tonic extension) seizure induced by flurothyl
      in any of the juvenile groups, it significantly delayed tonic extension in the
      adult group. In addition, juvenile mice fed a KGD exhibited a lower mortality
      rate following flurothyl-induced seizures compared to mice fed a standard diet.
      In our discussion of animal models of the KGD, we highlight the need to
      understand better the impact of important variables such as dietary composition,
      genetic background, and mode of seizure induction in the study of the KGD.

PMID- 10584972
TI  - Blood-brain barrier, ion homeostatis and epilepsy: possible implications towards
      the understanding of ketogenic diet mechanisms.
AB  - The finding that epileptic seizures alter blood-brain barrier (BBB) properties
      has stimulated interest into the possibility that phenotypic changes in brain
      endothelium may constitute a pathological initiator leading to seizures. Recent
      evidence obtained from epileptic patients undergoing cortical resection,
      demonstrated abnormal expression of glucose transporter molecules (GLUT1), while
      [18F]deoxyglucose PET studies demonstrated regions of decreased glucose uptake
      and hypometabolism in seizure foci. The properties of other 'nonexcitable CNS
      cells' are also altered in epileptic tissue, and glial cells from epileptic brain
      displayed diminished capacity for ionic homeostasis; voltage-dependent mechanisms
      were primarily affected, increasing reliance on energy-dependent mechanisms.
      Diminished ion homeostasis together with increased metabolic demand of
      hyperactive neurons may further aggravate the neuropathological consequences of
      BBB loss of glucose uptake mechanisms. Since ketone bodies can provide an
      alternative to glucose to support brain energy requirements, it is hypothesized
      that one of the mechanisms of the ketogenic diet in epilepsy may relate to
      increased availability of beta-hydroxybutyrate, a ketone body readily transported
      at the BBB. This hypothesis is supported by the fact that the ketogenic diet is
      the treatment of choice for the glucose transporter protein syndrome and pyruvate
      dehydrogenase deficiency, both associated with cerebral energy failure and
      seizures.

PMID- 10584974
TI  - Animal models of the ketogenic diet: what have we learned, what can we learn?
AB  - Despite its clinical use as a therapy for refractory epilepsy for more than 75
      years, the ketogenic diet (KD) remains a therapy in search of an explanation. The
      mechanism of action of the KD is unclear and the optimal indications for its
      clinical use are incompletely defined. Animal models could help to elucidate
      these questions. Surprisingly, there have been very few animal studies of the KD,
      and those that have been performed are difficult to compare because of wide
      discrepancies in experimental methods. Earlier models concentrated on the effect
      of the KD on acute seizure threshold in normal (i.e. nonepileptic) animals.
      Recent studies are beginning to examine the longer term effects of the KD and its
      role in epileptogenesis. Some features of clinical experience have been
      replicated in animal models, including the role of ketosis, elevation of seizure
      threshold by both classic ketogenic and medium chain triglyceride diets, better
      effectiveness at younger ages, and rapid reversal of the seizure protective
      effect when the diet is discontinued. These parallels raise hope that pertinent
      clinical questions can be addressed in the more controlled setting of the
      research laboratory. As in the clinical arena, there has been a recent resurgence
      of interest in pursuing basic questions related to the ketogenic diet, using
      techniques of modern neuroscience. Experimental approaches such as brain slice
      neurophysiology, genetic models, dissection of metabolic pathways, and
      neurohistological techniques hold much promise in the effort to understand this
      intriguing alternative to standard anticonvulsants.

PMID- 10584975
TI  - Gender differences in pharmacokinetics and pharmacodynamics.
AB  - Several years ago regulatory authorities requested to include women in all phases
      of clinical drug development in order to thoroughly investigate potential gender
      differences in the pharmacokinetics and pharmacodynamics of newly developed
      therapeutic agents. Since then, numerous reports have been published that
      evaluate the potential existence and impact of gender differences on all aspects
      of clinical pharmacology. With regard to pharmacokinetics, differences in
      absorption rate and duration have been reported for several drugs, but generally
      lack to have major clinical relevance. Differences in oral bioavailability,
      however, seem to be more important and are usually caused by sex differences in
      the activity of major intestinal and hepatic metabolic enzymes. Distributional
      differences have also been identified for numerous compounds. Although the
      majority of these findings were merely weight effects as women generally have a
      lower body weight, some of the gender-specific distribution differences persisted
      after normalization for weight. Possible explanations are differences in body
      composition between men and women and/or physiological changes during the
      menstrual cycle as well as differences in plasma protein binding secondary to
      hormonal characteristics. Frequent and sometimes clinically relevant gender
      differences could be identified for drug elimination processes and were
      predominantly linked to the sex-specific expression of metabolic enzyme systems,
      e.g. CYP3A4 and CYP1A2. In contrast, gender-related differences in renal
      elimination are generally only of minor importance. With regard to
      pharmacodynamics, gender differences have been observed in baseline
      characteristics as well as in drug response, which might both, at least in part,
      be the consequence of modulation by sex hormones. Some of the most striking
      examples identified were in pain therapy and perception, glucose management and
      arrhythmia susceptibility. Since clinical endpoints of efficacy and toxicity are
      often difficult to monitor and are frequently substituted by surrogate markers
      that might increase variability and thus mask gender effects, sex-specific
      differences in pharmacodynamic characteristics can often remain uncovered and
      further intensive research in this area seems imperative. For the majority of
      investigated drugs in the past few years, however, no or only very minor gender
      differences could be detected in pharmacokinetics and/or pharmacodynamics. In
      addition, the clinical significance of those gender differences identified seem
      very limited and was only very rarely linked to treatment success or failure.
      Hence, it is undoubtedly necessary to include women in the clinical drug
      development process, but it seems questionable whether women of child-bearing
      capability should be exposed to potential risks in early phase I clinical trials.

PMID- 10584976
TI  - Pharmacokinetics and bioequivalence testing of generic ondansetron preparations
      in healthy Thai male volunteers.
AB  - SUBJECTS, MATERIAL AND METHODS: Pharmacokinetics and bioequivalence of oral
      preparations of generic ondansetron were investigated in healthy Thai males. The
      test preparations were Vomitron 8 and Vomitron 4, the reference was Zofran. The
      three products were administered as an 8 mg single oral dose, in a three-period
      four-sequence cross-over design with one-week washout period. An intravenous 8 mg
      Zofran was administered on the forth visit. Plasma ondansetron concentrations
      were determined by HPLC and the pharmacokinetic parameters were analyzed by non
      compartmental analysis. RESULTS: Following i.v. ondansetron, the mean values of
      its elimination half-life, its plasma clearance, and its volume of distribution
      were 4.5 hours, 398 ml/min, and 130 liters, respectively. Its oral
      bioavailability averaged 67%, and the elimination half-life after oral
      administration was 5.6 hours. The time to reach the maximal concentration (Tmax,
      hour) of Zofran (1.21 +/- 0.26) was statistically faster than that of Vomitron 8
      (1.33 +/- 0.54) and Vomitron 4 (1.46 +/- 0.50). The 90% confidence intervals of
      the AUC0-infinity and Cmax ratios muT/muR for (Vomitron 8/Zofran) were 0.88 -
      1.12 and 0. 85 - 1.08, respectively. Similarly the 90% CI of the-AUC0-infinity
      and Cmax ratios for (Vomitron 4/Zofran) were 0.96 - 1.17 and 1.01 - 1.19,
      respectively. CONCLUSION: These values were within the acceptable range of 0.80 -
      1.25, thus our study demonstrated the bioequivalence of Vomitron and Zofran with
      respect to the rate (Cmax) and extent of absorption (AUC0-infinity).

PMID- 10584977
TI  - Mean time concept and component analysis in pharmacokinetics.
AB  - In 1958, F.H. Dost [1958] defined the mean life-span ("mittlere Lebensdauer") of
      a total number of N molecules as the arithmetic mean of all times "z(i)" of any
      one of the N molecules residing in a pharmacokinetic system. This pharmacokinetic
      characteristic did not attract special interest for several years. Almost
      simultaneously Yamaoka et al. [1978], Cutler [1978], van Rossum [1978], Benet and
      Galeazzi [1979], and von Hattingberg and Brockmeier [1979] recommended the mean
      residence time (MRT) or mean time (MT) as a useful summarizing characteristic for
      complex pharmacokinetic systems. One of the most useful properties of the
      statistical analysis (also called "moment analysis" or "statistical moment
      analysis") of concentration-time data and in vitro dissolution profiles using
      moments is the additivity of mean times [von Hattingberg and Brockmeier 1978,
      1979]. The very simple and compelling logic of additivity can be explained by the
      following example: considering an oral administration of a readily available
      dosage form, the distribution of each individual molecule within the body and the
      elimination from the body must be preceded by absorption of this molecule, which
      is trivial. However, as a consequence, the total transit time of an individual
      molecule through this system is the sum of its time up to absorption into the
      central circulation z(i).abs and the time the molecule spends in any part of the
      volume the molecule can reach z(i).vss. Therefore, the total mean time of all
      drug molecules available is the sum of the mean absorption time MT(abs) and the
      mean time in the steady-state volume of distribution MTvss. It is obvious that we
      can estimate the two components of the total mean time, i.e. MTabs and MTvss, by
      an appropriate experimental setting giving the drug once intravenously and
      determining MTvss and once giving the drug as an oral solution and deducing MTabs
      = MTtotal - MTvss. Because of this very useful property of the statistical
      analysis of concentration-time data by moments, this approach has been entitled
      "component analysis" [von Hattingberg et al. 1984].

PMID- 10584978
TI  - Effect of fusidic acid on the hepatic cytochrome P450 enzyme system.
AB  - OBJECTIVE: To investigate the effects of fusidic acid therapy on the hepatic
      cytochrome P450 (CYP450) enzyme system. METHODS: Thirty HIV-seropositive L
      methadone-substituted i.v. drug abusers (stage CDC/WHO B2 - 3 with CD4+-counts
      ranging from 65 to 293/microl) were randomized into 3 groups (A - C). Ten
      patients were treated with fusidic acid 500 mg/day over a period of 14 (group A)
      or 28 days (group B), respectively. Patients in group C served as a control group
      and did not receive any medication apart from L-methadone. In order to
      investigate the hepatic monooxygenase system, pharmacokinetics were determined in
      all patients before initiation and 14 and 28 days after starting therapy with
      fusidic acid. The concentration of antipyrine and its 3 main metabolites
      (norantipyrine (NORA), 4-hydroxyantipyrine (OHA), 3-hydroxymethylantipyrine
      (HMA)) in plasma and urine were measured by high-performance liquid
      chromatography (HPLC). RESULTS: No effects on antipyrine pharmacokinetics and
      pharmacokinetics of antipyrine metabolites were found in group A after 14 days of
      fusidic acid intake and in the control group without therapy. However, in
      contrast an activation of the CYP450 enzyme system was observed in group B after
      28 days of fusidic acid therapy with an increase of total antipyrine clearance
      (43.0 +/- 7.62 ml/min to 51.0 +/- 9.03 ml/min) as well as clearances to all
      metabolites (NORA 7.11 +/- 1.75 to 8.60 +/-2.10 ml/min, OHA 11.5 +/- 2.89 to 14.0
      +/- 3.97 ml/min, HMA 4.05 +/- 0.99 to 4.94 +/- 1.27 ml/min). Antipyrine half-life
      was significantly reduced (12.3 +/- 2.8 h to 9.4 +/- 2.2 h) and some patients
      developed clinical signs of L-methadone underdosage. CONCLUSIONS: Our results
      suggest that fusidic acid has a time-dependent activating effect on the CYP450
      enzyme system. Especially in treatment of patients who are frequently under
      multidrug regimens such as HIV-positive patients drug interactions should be
      taken into consideration.

PMID- 10584979
TI  - Omeprazole weakly inhibits CYP1A2 activity in man.
AB  - BACKGROUND AND OBJECTIVES: Omeprazole is an inducer of human cytochrome P450 1A
      (CYP1A) enzymes, but shows inhibitory effects on CYP2C19 and CYP3A4. In this
      study, a potential inhibitory effect of omeprazole on caffeine metabolism, a
      validated CYP1A2 marker, was examined. METHODS: A randomized, balanced crossover
      single-dose study was conducted in 16 healthy volunteers comprising 12 extensive
      (EM) and 4 poor metabolizers (PM) for CYP2C19. All volunteers received a 40 mg
      omeprazole dose or placebo 0.5 h prior to caffeine 3 mg/kg body weight. Six EMs
      were re-tested with 80 mg of omeprazole. In vitro, effects of omeprazole on
      caffeine N3-demethylation were determined in human liver microsomes. RESULTS: In
      vivo, non-parametric point estimates (90% confidence intervals) for the ratios of
      caffeine pharmacokinetics with/without co-administration of the 40 mg omeprazole
      dose were: AUC 1.08 (1.04 - 1.13), MRT 1.09 (0.99 - 1.19), and plasma ratio of
      paraxanthine/caffeine 6 h post-dose 0.91 (0.80 - 1.00). Inhibition of caffeine N3
      demethylation by omeprazole was slightly more pronounced in PM than in EM of
      CYP2C19. Estimates for the 80 mg omeprazole dose were: AUC 1.12 (1.05 -1.18), MRT
      1.18 (1.07 - 1.30), and paraxanthine/caffeine ratio 0.83 (0.74 -0.94). In vitro,
      omeprazole was mainly a competitive CYP1A2 inhibitor with K(i) values of around
      150 microM. CONCLUSIONS: Omeprazole exerts a concentration-dependent inhibition
      of CYP1A2 activity in man. However, even after single oral doses up to 80 mg,
      this effect is weak and without clinical relevance.

PMID- 10584980
TI  - Novel hyperactive mitogen to endothelial cells: human decidual NKG5.
AB  - PROBLEM: The purpose of this study was the isolation and characterization of
      decidual extract proteins that exhibit mitogenicity on endothelial cells. METHOD
      OF STUDY: A partially purified extract (F1 fraction) was obtained from human
      decidua of the first trimester of pregnancy. F1 was separated by heparin
      sepharose column and showed significant mitogenicity on bovine brain capillary
      endothelial (BBCE) cells in vitro, using methylene blue stain nuclear assay.
      Sodium-dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) revealed
      four fractions with MW less than 30 KDa. RESULTS: Mitogenic fraction, E11-12
      (eluted at 1.5 M NaCl) was identified as basic fibroblast growth factor (bFGF).
      Vascular endothelial growth factor (VEGF) and acidic (a)FGF were not identified
      as one of the mitogenic fractions. However, fractions E5-6, and E7-8 induced
      statistically significant mitogenicity at concentration of 1 pg/mL, which is
      10(3) times lower than bFGF. Sequencing of E5-6 fraction identified NKG5 protein,
      a putative secreted polypeptide derived from human natural killer (NK) cells and
      activated T cells of unknown function. CONCLUSION: This work demonstrates that
      NKG5 stimulates mitogenicity of endothelial cells and may be involved in
      angiogenesis.

PMID- 10584981
TI  - Mitogen-induced cytokine responses of maternal peripheral blood lymphocytes
      indicate a differential Th-type bias in normal pregnancy and pregnancy failure.
AB  - PROBLEM: Profiles of Th1- and Th2-type cytokines were studied in women with a
      history of successful pregnancy and in women with a history of unexplained
      recurrent spontaneous abortions (RSA) with the objective of elucidating Th1- and
      Th2-type bias in normal pregnancy and pregnancy failure. METHOD OF STUDY:
      Peripheral blood mononuclear cells (PBMCs) from 54 women with a history of normal
      pregnancy and 23 women with a history of unexplained RSA, obtained at delivery or
      on the day of abortion, respectively, were stimulated with phytohemagglutinin
      (PHA), followed by the estimation of four Th2 cytokines and four Th1 cytokines.
      RESULTS: Significantly greater levels of Th2 cytokines were produced by the
      normal group than by the RSA group. On the other hand, significantly higher
      levels of Th1 cytokines were produced by the RSA group than by the normal
      pregnancy group. CONCLUSIONS: These data support the concept that unexplained
      recurrent spontaneous abortion is associated with an increase in Th1-type
      reactivity, while Th2 dominance is a feature of successful pregnancy.

PMID- 10584982
TI  - Natural killer cell activity and cytokine production after in vitro
      immunoglobulin treatment of lymphocytes derived from pregnant women with or
      without risk for spontaneous abortion.
AB  - OBJECTIVE: To investigate the possible mechanism of action effective in
      immunoglobulin G (IgG) treatment of recurrent spontaneous abortion (RSA). The
      effect in vitro of a commercially available intravenous immunoglobulin (IvIg) on
      the rate of interleukin (IL)-10 and IL-12 positive cells (Th1/Th2 balance) and on
      natural killer (NK) cell activity in populations of peripheral lymphocytes of
      healthy pregnant women and women at risk for premature pregnancy termination was
      studied. Primary habitual aborters as well as women showing clinical symptoms
      (bleeding or regular uterine contractions) of threatened premature pregnancy
      termination were included. METHODS: Lymphocytes of 20 pregnant women were tested.
      Five different batches of an IvIg with reported immunomodulatory potential were
      used at a concentration of 10 mg/mL. Cytokine profiles of the lymphocytes were
      determined by immunocytochemistry. For testing of NK cell activity, the 4 hr
      single cell cytotoxicity assay was used. RESULTS: Incubation with IgG of
      lymphocytes from recurrent spontaneous aborters concomitantly and significantly
      decreased the rate of IL-12 positive cells (P < 0.01) and increased the rate of
      IL-10 positive cells (P < 0.01), whereas such treatment had no significant effect
      on lymphocytes of pregnant women not at risk of abortion. Dialysis or heat
      treatment (56 degrees C, 30 min) of the IgG preparations did not modify the
      effect. Elevated NK cell activity of women at risk for premature pregnancy
      termination significantly decreased after IgG incubation of cells in all cases,
      whereas NK cell activity of normal pregnancy lymphocytes was not altered.
      CONCLUSION: This study suggests that incubation of peripheral lymphocytes from
      RSA patients with polyclonal polyspecific IgG alters cytokine profiles and NK
      activity while the same treatment does not affect lymphocytes of healthy pregnant
      women. These data might add to the understanding of mechanisms of action of IvIg
      in prevention of recurrent pregnancy loss.

PMID- 10584983
TI  - Controlled ovarian hyperstimulation: a state of neutrophil activation.
AB  - PROBLEM: To investigate if controlled ovarian hyperstimulation (COH) affects the
      expression of neutrophil adhesion molecules and if a correlation exists between
      neutrophil activation and serum sex-steroid levels. METHOD OF STUDY: The pilot
      study was carried out in the in vitro fertilization (IVF) unit of our department,
      and required no modification of our routine IVF protocol. Four patients arriving
      for baseline hormonal profile on day 1 of the menstrual cycle before initiation
      of COH (control group) and 11 patients admitted for oocyte recovery (study group)
      were included. Venous blood was obtained from all patients and examined for
      hormonal profile and neutrophil activation. The latter was performed by staining
      for the surface adhesion molecules beta2 integrin and L-selectin. Positive cell
      count and mean fluorescence intensity were determined by flow cytometry. RESULTS:
      While neutrophil L-selectin was significantly lower in the study group than in
      the control group, neutrophil beta2 integrin was nonsignificantly higher. Though
      no significant correlations were found between neutrophil adhesion molecules and
      patient age, serum estradiol level, and human chorionic gonadotropin level;
      neutrophil L-selectin was negatively correlated with serum progesterone levels.
      CONCLUSIONS: COH leads to neutrophil activation, which correlates with the degree
      of luteinization. Further studies are required to elucidate the relationship
      between the immune system and COH. These may lead to new strategies for promoting
      fertility and preventing complications of COH.

PMID- 10584984
TI  - The possible role of antiovary antibodies in repeated in vitro fertilization
      failures.
AB  - PROBLEM: The study was conducted to investigate the possible role of circulating
      ovarian autoantibodies (ov-ab) in patients with repeated in vitro fertilization
      embryo transfer (IVF-ET) failure and to evaluate the effectiveness of
      immunosuppression treatment in these patients. METHOD OF STUDY: The study group
      comprised 80 IVF patients who had five or more failed treatment cycles (mean
      10.2; range 7-22). The presence of ov-ab was compared between these women and 1)
      50 IVF patients who conceived during the first three treatment cycles; 2) 50
      healthy nulligravidae. All participants were seronegative to nonorgan-specific
      and antithyroid autoantibodies. Patients in the study group who were positive for
      ov-ab were treated with 10 mg/day prednisone starting 1 month before ovulation
      induction. Embryo grading was compared in the IVF cycles before and after
      treatment. RESULTS: Ov-ab were found in ten patients (12.5%) in the study group,
      compared to none in the control groups (P = 0.01). Nine of the patients positive
      for ov-ab were treated with prednisone for their following cycle. A statistically
      significant improvement in embryo grading was noted. Three patients conceived
      after treatment (33%), with a take-home baby rate of 22%, compared to only six
      patients (8.6%) who conceived among the rest of the seronegative study group,
      with a take-home baby rate of 7.1% (P = 0.05). CONCLUSIONS: Ov-ab are a possible
      marker of an autoimmune disorder that may be one of the causes of repeated IVF
      failures. Immunosuppression treatment may prove efficient in ov-ab seropositive
      patients with repeated IVF failures by improving embryo grading and pregnancy
      rate.

PMID- 10584985
TI  - An inverse relation between the expression of tumor necrosis factor alpha (TNF
      alpha) and TNF-alpha receptor in human endometrium.
AB  - PROBLEM: To determine whether the expression of tumor necrosis factor (TNF-alpha)
      correlates with TNF-alpha receptor expression in human endometrium. METHOD OF
      STUDY: A multiprimer synthetic cDNA standard template containing complimentary
      sequences for several cytokines including TNF-alpha and TNF-alpha receptor type 2
      was constructed and used in quantitative reverse transcription polymerase chain
      reaction (Q-RT-PCR). RESULTS: Endometrium from proliferative phase of the
      menstrual cycle expresses higher levels of TNF-alpha mRNA (2.35 +/- 0.2 x 10(5)
      copies/microg of total cellular RNA) than secretory phase ([1.3 +/- 0.08 x 10(5)
      copies] P < 0.05), with a significant reduction during menses (1.2 +/- 0.1 x
      10(4) copies) and postmenopausal period (8.1 +/- 1.6 x 10(4) copies [P < 0.05]).
      In contrast, TNF-alpha type 1 receptor mRNA expression was higher in endometrium
      from the secretory phase (6.6 +/- 0.6 x 10(7) copies) compared to the menses (5.1
      +/- 0.5 x 10(6) copies), proliferative phase (1.9 +/- 0.1 x 10(6) copies) and
      postmenopausal period (5.8 +/- 0.7 x 10(4) copies [P < 0.05]). Comparatively, TNF
      alpha receptor type 2 is expressed 10 to 100 fold higher in the endometrium than
      TNF-alpha (P < 0.05). CONCLUSION: The data confirm that human endometrium
      expresses TNF-alpha; and provide the first evidence that TNF-alpha expression is
      inversely related to TNF-alpha type 1 receptor expression during the menstrual
      cycle. Such an inverse relation between TNF-alpha and TNF-alpha receptor
      expression may provide a regulatory mechanism necessary to overcome the
      detrimental effect of high levels of TNF-alpha on various endometrial cell types.

PMID- 10584986
TI  - The expression of granulocyte macrophage-colony stimulating factor (GM-CSF) and
      receptors in human endometrium.
AB  - PROBLEM: To determine the temporal and spatial expression of granulocyte
      macrophage-colony stimulating factor (GM-CSF) and GM-CSF alpha and beta receptor
      mRNA and protein in human endometrium. METHOD OF STUDY: The endometrial
      expression of GM-CSF and GM-CSF receptor mRNA and protein was determined using
      competitive quantitative reverse transcription polymerase chain reaction (Q-RT
      PCR), in situ hybridization, and immunohistochemistry. RESULTS: Endometrium
      expresses GM-CSF and GM-CSF alpha receptor mRNA with maximal expression occurring
      during the mid-secretory phase (21.1 +/- 4.2 and 32.2 +/- 7.7 x 10(6) mRNA
      copies/microg total RNA) compared to the proliferative phase (1.46 +/- 0.4 and
      7.5 +/- 0.5 x 10(6) copies) of the menstrual cycle, with a significant reduction
      (0.67 +/- 0.1 and 1.7 +/- 0.2 x 10(6) mRNA copies) during the post-menopausal
      period (P < 0.05). The endometrium expresses a significantly lower level of GM
      CSF beta receptor mRNA (approximately 0.01 x 10(5) mRNA copies). Endometrial
      luminal and glandular epithelial cells are the primary site of GM-CSF mRNA and
      protein expression, while arteriole endothelial, stromal, and inflammatory cells
      are the primary site of GM-CSF alpha receptor protein. GM-CSF beta receptor
      protein has a similar cellular distribution as GM-CSF. CONCLUSION: Temporal and
      spatial expression of GM-CSF and GM-CSF receptors in human endometrium during the
      menstrual cycle suggests that epithelial-derived GM-CSF in an autocrine/paracrine
      manner may influence various endometrial biological activities, local
      inflammatory response, and macrophage survival.

PMID- 10584987
TI  - Progesterone directly and indirectly affects perforin expression in cytolytic
      cells.
AB  - PROBLEM: Decidual lymphocytes (DL) expressing the cytolytic molecule perforin
      represent approximately 55% of DL in the first trimester of human pregnancy.
      Progesterone dominates this phase of pregnancy and controls the production of
      uterine cytokines and growth factors. The aim of this study was to investigate
      the role of progesterone and progesterone-induced blocking factor (PIBF) on
      perforin expression in DL and peripheral blood lymphocytes (PBL). METHOD OF
      STUDY: Perforin expression was analyzed in PBL and DL incubated either in culture
      medium or with decidual adherent cells (DAC) and peripheral blood adherent cells
      (PBAC) and their supernatants with or without progesterone or PIBF. Perforin was
      detected by flow cytometry in PB and in decidual first trimester pregnancy
      lymphocytes. RESULTS: Progesterone in high concentrations directly affects
      perforin expression in DL but not in PBL. Progesterone in a concentration
      dependent manner indirectly blocks perforin expression in DL and PBL cultured
      with adherent cells or their supernatants. PIBF blocked upregulation of perforin
      expression of DL cultured with DAC, but none of those cultured with PBAC.
      Similarly, PIBF was inefficient when PBL or DL were cultured with PBAC.
      CONCLUSION: Progesterone present in a high concentration locally at the maternal
      fetal interface modulates perforin expression in the first trimester pregnancy
      DL.

PMID- 10584988
TI  - F4/80-positive cells rapidly accumulate around tubuli recti and rete testis
      between 3 and 4 weeks of age in the mouse: an immunohistochemical study.
AB  - PROBLEM: Previous studies demonstrated that F4/80 antigen (murine macrophage
      specific antigen)-positive cells in testes of normal adult mice accumulate
      particularly in the interstitium adjacent to the tubuli recti and rete testis
      (i.e., the central region). However, it remains unknown whether this accumulation
      is a congenital or acquired phenomenon. METHOD OF STUDY: The distribution of
      F4/80-positive cells on frozen sections of testes obtained from various aged mice
      was immunohistochemically examined to determine when the positive cells
      specifically accumulate in the central region. RESULTS: F4/80-positive cells were
      homogeneously distributed throughout the testicular interstitium with no specific
      accumulation until 2 weeks of age. However, at 3 weeks of age, the density of
      positive cells in the central region became slightly, but significantly, higher
      than that in the interstitium between the seminiferous tubules. Between 3 and 4
      weeks of age, the cell density in the central region increased rapidly, the
      density at 4 weeks of age reaching the level of the mature testes of 8-week-old
      mice. CONCLUSION: These results demonstrate that the specific accumulation of
      F4/80-positive cells in the central region is an acquired phenomenon, which
      starts and ends before puberty.

PMID- 10584989
TI  - Understanding and managing hyperphosphatemia in patients with chronic renal
      disease.
AB  - Controlling serum phosphorus levels continues to be a challenge in patients with
      chronic renal disease. Hyperphosphatemia is implicated in the development and
      worsening of secondary hyperparathyroidism and renal osteodystrophy (ROD) through
      its effects on serum calcium and calcitriol levels, parathyroid hormone (PTH)
      overproduction, and parathyroid cell hyperplasia. In the past serum phosphorus
      control with aluminum-containing phosphate binders was associated with insidious
      but serious development of aluminum toxicity. More recent approaches using non
      aluminum-containing calcium salts as phosphate binders are limited because of the
      excessive calcium load resulting from concomitant enhanced intestinal calcium
      absorption. Moreover serum phosphorus does not only result from dietary phosphate
      intake but also from enhanced bone breakdown due to secondary
      hyperparathyroidism. Strategies for managing ROD including early control of serum
      phosphorus and PTH, prevention of parathyroid hyperplasia; establishment of
      optimal PTH levels for bone health, and the availability of new therapeutic tools
      for controlling phosphorus may help prevent complications and improve patient
      outcomes.

PMID- 10584990
TI  - Studies of glomerular permeability factor (GPF) in focal segmental glomerular
      sclerosis and the relationship between GPF and vascular permeability factor
      (VPF).
AB  - BACKGROUND: We previously demonstrated that the supernatants of cultured
      concanavalin-A (con-A) stimulated peripheral blood mononuclear cells (PBMC) from
      patients with minimal change nephrotic syndrome (MCNS) increased the urinary
      protein excretion in injected rats and suggested that PBMC released a factor,
      which we called glomerular permeability factor (GPF), changes in the glomerular
      permeability and thus resulted in proteinuria in MCNS. MATERIAL AND METHODS: In
      this study we investigated the GPF activity in focal segmental glomerular
      sclerosis (FGS) and other conditions of chronic glomerulonephritis (CGN), and
      also the relationship between GPF and vascular permeability factor (VPF). In
      experiment 1 the supernatants of the cultured con-A stimulated PBMC from patients
      with 10 FGS, 5 other CGN and 10 controls were tested regarding their ability to
      produce GPE The GPF activity was defined as positive when the 8-hour urinary
      protein excretion after the injection of the supernatant in Sprague-Dawley rats
      exceeded the mean value plus 2 standard deviations (M + 2 SD) of that before
      injection. RESULTS: Three out of 10 FGS patients and 1 membranous nephropathy
      patient out of the 5 other CGN patients were positive for GPF activity. In
      experiment 2 the relationship between GPF and VPF was analyzed using culture
      supernatants of PBMC from 10 nephrotic MCNS patients and 15 controls. The VPF
      activity was measured following the method developed by Ovary [1975]. All 7 cases
      that were positive for GPF activity were simultaneously positive for VPF
      activity. On the other hand, 16 cases that were positive for VPF activity were
      not always positive for GPF activity (7 cases were positive and 9 were negative
      for VPF activity). CONCLUSION: Experiments 1 and 2 thus suggested that GPF was
      not active in MCNS alone, but also in other CGN conditions and it was therefore
      not considered to be the same factor/substance(s) as VPF.

PMID- 10584991
TI  - The "point of no return" and the rate of progression in the natural history of
      IgA nephritis.
AB  - BACKGROUND: Based on the observation of 7 patients with chronic IgA nephritis and
      on a course to end-stage renal failure after several years, D'Amico et al. [1993]
      reported on a "point of no return" at 2.5 to 3 mg/dl serum creatinine. After
      exceeding this limit all 7 patients exhibited an irreversible progressive renal
      failure. PATIENTS AND METHODS: Therefore, 115 patients with IgA nephritis from
      the "German Glomerulonephritis Therapy Study" were examined in order to look for
      the existence of such a "point of no return". RESULTS: Three different courses
      could be distinguished: a stable chronic course with constantly normal or only
      minor elevated serum creatinine lasting for years (91 patients), a progressive
      course with continuously increasing serum creatinine (22 patients), and a rare
      (only 2 patients) early acute course with a short-term increase of serum
      creatinine followed by a rapid return to the normal range. After exceeding 3
      mg/dl serum creatinine no remissions were observed in the progressive cases.
      Sixteen patients showed a rapid, continuously progressive course until end-stage
      renal failure with exactly the same progression as the 7 patients of D'Amico et
      al. Six patients of the 22 progressors were not observed long enough. The serum
      creatinine level doubled on average from 3 to 6 mg/dl within 10 months.
      CONCLUSION: Our study confirmed the existence of a "point of no return" at 3
      mg/dl (265 micromol/l) during the natural course of chronic IgA nephritis.

PMID- 10584992
TI  - Clinicopathological study of myeloperoxidase anti-neutrophil cytoplasmic antibody
      associated glomerulonephritis.
AB  - AIMS: To investigate the potential prognostic factors for myeloperoxidase anti
      neutrophil cytoplasmic antibody- (MPO-ANCA) associated glomerulonephritis.
      MATERIALS: The clinical and pathological findings were reviewed in 17 patients
      with this type of glomerulonephritis. METHODS: The relationship between the
      outcome and various clinical and pathological factors were assessed. The
      relationship between the blood MPO-ANCA level and cellular crescent formation was
      also investigated. RESULTS: Patients who died had a significantly lower serum
      albumin and creatinine clearance than those who survived, but there were no
      differences of age, blood MPO-ANCA, urinary protein, and serum creatinine levels
      or cellular crescent formation between the two groups. There was a close
      relationship between blood MPO-ANCA levels and cellular crescent formation.
      CONCLUSIONS: Hypoalbuminemia and renal dysfunction may be indicators of a poor
      prognosis in MPO-ANCA-associated glomerulonephritis. Patients with high blood
      levels of this antibody and increased cellular crescent formation appear to have
      active disease, but these factors are not statistically associated with a fatal
      outcome. Therefore, aggressive treatment may be indicated in patients with active
      disease initially.

PMID- 10584993
TI  - White coat hypertension in adolescents.
AB  - BACKGROUND: Although white coat hypertension (WCH) seems to occur in 20% or more
      of the adult hypertensive population, this clinical condition has rarely been
      described in adolescents. DESIGN: Routine use of ambulatory blood pressure
      monitoring (ABPM) procedure as part of the investigation of arterial hypertension
      in adolescents. METHODS: Office blood pressure was checked after 5 minutes of
      rest in the seated position by the auscultation method and ABPM was performed
      with oscillometrical equipment (SpaceLabs 90207, Redmond, Washington, USA).
      RESULTS: In the present study 6 adolescents (5 females, 3 white), suspected to
      suffer from arterial hypertension as judged by office blood pressure
      measurements, mean age 15.1 years (12.2 - 17.7), mean height 164.5 cm, mean
      weight 77.2 kg, mean body mass index 28.8 kg/m2 (25 - 35.2), were diagnosed with
      WCH using ambulatory blood pressure monitoring (ABPM). CONCLUSION: White coat
      hypertension should also be considered in the evaluation of arterial hypertension
      in adolescents.

PMID- 10584994
TI  - Influence of hemodialysis on intravascular volume and vasoactive hormones.
AB  - BACKGROUND: The posthemodialysis plasma level of atrial natriuretic peptide (ANP)
      has been proposed as an index for an adequate fluid state in hemodialysis (HD)
      patients. PATIENTS AND METHODS: We investigated the effect of fluid removal
      during HD on the interaction between intravascular volume and the vasoactive
      hormones ANP, vasopressin, adrenaline, noradrenaline, renin and aldosterone in 16
      HD patients. Intravascular volume was examined with the 131I-labeled albumin
      method for blood volume (BV) and ultrasound for measurement of inferior vena cava
      diameter (IVCD). RESULTS: There was a significant decrease in BV, IVCD and ANP,
      but not in the other vasoactive hormones. Based on BV and IVCD measurements, the
      predialysis plasma ANP levels in the normovolemic and hypovolemic patients were
      significantly higher than in the hypervolemic patients. There was no significant
      difference between the postdialysis ANP levels in the hypervolemic and
      normovolemic patients and no significant correlations between ANP and BV and
      IVCD, respectively, but postdialysis ANP correlated significantly with the
      ultrafiltration rate (r = -0.51, p < 0.05), noradrenaline (r = 0.54, p < 0.05)
      and change in vasopressin (r = -0.50, p < 0.05). There were also correlations
      between ANP and age before HD (r = 0.50, p < 0.05) and after HD (r = 0.70, p <
      0.0025). CONCLUSION: We conclude that the usefulness of the plasma ANP level for
      assessment of the fluid state in HD patients is limited, since age and other
      factors than those directly related to volume influence the concentration of ANP.

PMID- 10584995
TI  - Is dialysis membrane type responsible for increased circulating adhesion
      molecules during chronic hemodialysis?
AB  - BACKGROUND: Patients with chronic renal failure under maintenance hemodialysis
      (HD) present with numerous adverse effects including immunologic alterations.
      Serious abnormalities of neutrophil function have been reported to be associated
      with disturbed cell adhesiveness. These adhesion processes are mediated by
      cytokines and different adhesion molecules. PATIENTS AND METHODS: In this study,
      serum concentrations of the intercellular adhesion molecule ICAM-1, vascular cell
      adhesion molecule VCAM-1 and endothelial leukocyte adhesion molecule E-selectin
      were investigated during employment of different dialysis membranes (cuprophane:
      n = 23, cellulose: 8, polysulfone: 26, acrylonitrile: 7). These adhesion
      parameters from 64 patients before and after a hemodialysis session were
      investigated parallel to the serum levels of circulating cytokines and their
      inhibitors. RESULTS: Circulating ICAM-1 levels were not elevated in low-flux
      membranes and most of the high-flux HD membranes, except for one high-flux
      polysulfone membrane. cVCAM-1 levels were significantly elevated both in low- and
      high-flux dialysis membranes, whereas cE-selectin was not increased. cICAM-1
      levels were not different before and after hemodialysis in the entire study
      group. In contrast, cVCAM-1 and cE-selectin levels increased significantly during
      HD in the entire study group (both p < 0.001). Serum levels did not correlate
      with the duration of end-stage renal failure and hemodialysis. Levels of
      circulating cytokine antagonists/inhibitors (Il-lra, Il-2R, TNFsRp55/75) were
      significantly increased in all patients before and after HD, whereas the serum
      concentrations of the corresponding circulating cytokines (I1-1beta, Il-1, TNF
      alpha) were within normal ranges. CONCLUSION: Increased levels of cVCAM-1 which
      suggest an important role for immunological alterations in HD and cytokine
      independent changes during HD sessions in all membranes without alterations of
      cICAM-1 in most membranes and unchanged cE-selectin indicate that processes such
      as uremia are responsible for these effects rather than membrane characteristics.
      The level of circulating adhesion molecules does not serve as an appropriate
      marker of membrane biocompatibility.

PMID- 10584996
TI  - Comparison of different routes of administration of nadroparin in hemodialysis.
AB  - AIM: In an open, crossover, randomized study in hemodialysis patients, we
      investigated possible differences of the effect of the low molecular weight
      heparin (LMWH) nadroparin/fraxiparine in relation to the route of administration.
      PATIENTS AND METHODS: The effect of nadroparin, administered by the venous line
      or by the arterial line after priming of the extracorporeal circuit with a part
      of the total dose administered, was compared with administration of the same dose
      by the arterial line as recommended by the manufacturer. Twelve stable, chronic
      hemodialysis patients were studied during 3 dialysis sessions for each treatment
      option. Concomitant medication was kept constant. RESULTS: Results obtained after
      administration of nadroparin by the venous line were comparable to those obtained
      after administration by the arterial line. When a part of the dose was added to
      the priming solution, the anti-Xa activity, measured after 2 hours of dialysis,
      was somewhat lower (p = 0.09). There was also a tendency towards longer manual
      compression time in this group. There was no difference in hemoglobin, serum urea
      and creatinine before the study and at the end of each treatment option.
      CONCLUSION: We therefore conclude that the safety and efficacy of administration
      of LMWH by the arterial and by the venous route are identical. There is no need
      for addition of a small dose of LMWH to the priming fluid.

PMID- 10584997
TI  - Henoch Schoenlein nephritis.

PMID- 10584998
TI  - Reversible peritoneal calcification in a patient treated by CAPD.
AB  - The patient, a female, aged 65 years, developed diffuse peritoneal calcification
      nine years after commencing CAPD therapy. No abdominal symptoms or evidence of
      peritonitis were discovered during this period. Before peritoneal calcification
      was detected, a dialysate with a high glucose concentration (3.86%) had been used
      once daily for 16 months. In the case of this patient, it was not possible to
      discover any of the previous indicated etiologies of peritoneal calcification
      such as significantly elevated values for the product Ca x P, overt secondary
      hyperparathyroidism, or relapsing peritonitis. It was realized that the use of a
      high-glucose dialysate in a patient on long-term CAPD treatment had been one
      causative factor. After peritoneal calcification had been confirmed, the calcium
      concentration of the dialysate changed from 3.5 mEq/l to 2.5 mEq/l and the
      patient was put on a regime of 2.0 g alumigel (aluminum-containing phosphate
      binders) a day. Eight months later, a CT scan was taken. The peritoneal
      calcification has clearly been mitigated. At present, CAPD therapy is being
      continued in the absence of any abdominal symptoms.

PMID- 10584999
TI  - Effects of astragalus on IL-2/IL-2R system in patients with maintained
      hemodialysis.

PMID- 10585000
TI  - Use of a desferrioxamine "microdose" to chelate aluminum in hemodialysis
      patients.

PMID- 10585001
TI  - PTH decrease after radioiodine treatment in a patient with end-stage renal
      disease.

PMID- 10585002
TI  - A brief historical review of the development of chemotherapy for the treatment of
      advanced non-small cell lung cancer: why we should look beyond platinum.
AB  - We are approaching the end of the fifth decade and the most productive period in
      the development of chemotherapy for the treatment of advanced non-small cell lung
      cancer. We began this decade by establishing cisplatin-based combination
      chemotherapy regimens of the 1980s as effective at improving survival for
      patients with advanced disease. The observed improvement in survival from these
      trials appears to be primarily attributed to cisplatin. Furthermore, this decade,
      unlike the prior, has identified an abundance of novel active agents for the
      treatment of this disease. Vinorelbine, gemcitabine, docetaxel, paclitaxel, and
      irinotecan are all new chemotherapeutic agents which have shown promising
      activity in this disease. In contrast to the cisplatin-based chemotherapy trials
      of the 1980s, these newer chemotherapeutic agents when given in combination with
      cisplatin add to the survival outcomes for these patients. With these survival
      advances has come a focus on chemotherapy-induced adverse events, lung cancer
      symptom management, and overall quality of life. The results of the cisplatin
      combination trials will be discussed.

PMID- 10585003
TI  - Modulation of apoptosis signaling pathways and cell cycle regulation.
AB  - Apoptosis can be described as multiple pathways converging from numerous
      different initiating events and insults, such as anticancer agents. These
      pathways converge on a common irreversible execution phase in which proteases and
      nucleases digest the doomed cell. Counteracting the signals to die are a variety
      of pathways that enhance cell survival and that may become constitutively active
      as a result of oncogenic transformation. Studies of apoptosis have identified
      many cellular factors that play a role in the decision as to whether a cell lives
      or dies. These factors include the p53 tumor suppressor, the Bcl-2 family of
      proteins, and a variety of intracellular signal transduction pathways, all of
      which may provide novel therapeutic targets. It also is possible to take
      advantage of the defect in cell cycle regulation that occurs in cells with mutant
      p53; such cells are susceptible to agents that inhibit DNA damage-induced cell
      cycle checkpoints at S and G2 phase. Cell cycle perturbation occurs following
      treatment with all anticancer drugs and a knowledge of the kinetics of such
      events should facilitate design of synergistic rather than antagonistic
      schedules. These concepts have been developed in cell culture models and it is
      essential to determine whether the mechanisms defined also occur in patients
      receiving therapy. Accordingly, tumors need to undergo serial biopsies during
      therapy and be analyzed for perturbation in cell cycle or apoptosis-regulating
      proteins. The results of such studies should facilitate the rational design of
      chemotherapy combinations.

PMID- 10585004
TI  - Docetaxel in the treatment of non-small cell lung cancer: review of single-agent
      trials.
AB  - Several phase II studies have evaluated docetaxel, administered as a 1-hour
      intravenous infusion at a dose of 100 mg/m2 every 3 weeks, for chemotherapy-naive
      patients with advanced non-small cell lung cancer. Results have been consistent
      across numerous trials, with an overall response rate in the range of 23% to 38%
      and a median survival of 9 months. Results of a multicenter phase III trial of
      docetaxel versus best supportive care for the first-line treatment of non-small
      cell lung cancer are pending. In the second-line setting, after failure of first
      line platinum-based chemotherapy, four phase II studies of docetaxel 100 mg/m2
      have achieved response rates ranging from 16% to 22%, with encouraging median
      survival times of 30 to 42 weeks. Preliminary results of a large, multicenter,
      randomized phase III trial also indicated an advantage for docetaxel over control
      with regard to response, time to progression, survival, and quality of life.
      Results of a multicenter phase III trial of docetaxel versus best supportive care
      as second-line treatment will be reported soon. Weekly docetaxel has been well
      tolerated in phase I studies, with dose-limiting toxicity being asthenia rather
      than myelosuppression. Phase II trials of a dosage of 36 mg/m2/wk in elderly
      patients with advanced non-small cell lung cancer are ongoing. Docetaxel is a
      potent radiosensitizer. The dose-limiting toxicity of docetaxel when administered
      weekly with concurrent chest radiation at 50 to 64 Gy is esophagitis. Phase II
      trials of weekly docetaxel plus concomitant chest radiotherapy are in progress at
      the recommended phase II dosage of 20 to 30 mg/m2/wk.

PMID- 10585005
TI  - Phase II trials of vinorelbine and docetaxel in the treatment of advanced non
      small cell lung cancer.
AB  - Both vinorelbine and docetaxel are effective as single agents in non-small cell
      lung cancer, with response rates of 25% to 30%. Several in vitro and in vivo
      models demonstrate schedule-dependent synergy between these agents. In phase II
      clinical trials of the combination, response rates and median survivals ranged
      from 27% to 49% and 5 to 9 months, respectively. Common toxicities included
      neutropenia, febrile neutropenia, and mucositis. With prolonged therapy, severe
      onycholysis and eye irritation also have been noted. In conclusion, docetaxel and
      vinorelbine are active together and offer one alternative to cisplatin-based
      therapy for patients with adequate performance status.

PMID- 10585006
TI  - Docetaxel and gemcitabine combinations in non-small cell lung cancer.
AB  - Docetaxel and gemcitabine have been shown to be active as single agents in a
      variety of solid tumors. These two agents have been studied in combination with
      several different treatment schedules. Two phase I studies used a novel 2-week
      administration schedule that involved a 1-hour infusion of 35 mg/m2 to 65 mg/m2
      docetaxel and gemcitabine administered as either a 30-minute infusion (2,000 to
      4,000 mg/m2) or a 10 mg/m2/min infusion (1,000 to 1,200 mg/m2 total dose).
      Another novel phase I study evaluated the effect of drug sequence on toxicities.
      Patients received 30 to 40 mg/m2 docetaxel and 800 to 1,250 mg/m2 gemcitabine on
      days 1 and 8 every 21 days. Two phase I studies of a monthly docetaxel regimen
      have been conducted. Patients received 800 mg/m2 gemcitabine on days 1, 8, and 15
      and 100 mg/m2 docetaxel on day 1 of a 28-day cycle. Finally, in a phase II study,
      patients received 900 mg/m2 gemcitabine on days 1 and 8 and 100 mg/m2 docetaxel
      on day 8, with granulocyte colony-stimulating factor administered on days 9
      through 15. In these studies, antitumor responses were observed in lung cancer as
      well as a number of other histologies. Neutropenia was the most frequent dose
      limiting toxicity and no difference in clinical toxicity was observed with either
      sequence of administration. The emerging evidence suggests, therefore, that the
      combination of gemcitabine and docetaxel is active in a variety of solid tumors
      and is well tolerated.

PMID- 10585007
TI  - Docetaxel and irinotecan, alone and in combination, in the treatment of non-small
      cell lung cancer.
AB  - Single-agent activity has been observed for both docetaxel and irinotecan in
      several solid tumors, including non-small cell lung cancer (NSCLC). Compilation
      of data from phase II trials of single-agent docetaxel therapy in NSCLC yielded
      overall response rates of 26% and a 1-year survival rate of 52%. Furthermore, a
      recent study that combined radiotherapy with concurrent docetaxel treatment
      reported an overall response rate of 77%. The most important adverse effect of
      docetaxel therapy is neutropenia Phase II trials of single-agent irinotecan for
      NSCLC patients resulted in response rates of 15% to 31%. The main toxicities were
      neutropenia and diarrhea. Investigators have begun to explore the efficacy of
      combining docetaxel and irinotecan. The results of preclinical studies suggest
      that schedule and order of administration may be important. A Japanese study
      evaluated the combination in previously untreated patients with NSCLC, and found
      eight partial responses in 26 patients (32%). A recent phase I study at the Mayo
      Clinic showed partial responses in three of five patients who received irinotecan
      followed by docetaxel. In a phase I study conducted at Yale Cancer Center,
      escalating doses of docetaxel (25 to 40 mg/m2) were given before irinotecan (50
      mg/m2) for 4 weeks followed by a 2-week rest. There was one partial response
      among five evaluable patients with NSCLC (one of four among patients who had
      received no prior chemotherapy). The results of these studies suggest that the
      combination of docetaxel and irinotecan shows promise in the treatment of NSCLC.
      Irinotecan also has been used in combination with other chemotherapeutic agents.
      The irinotecan/etoposide combination has been less extensively evaluated but thus
      far appears to be associated with considerable toxicity, particularly
      myelosuppression, without clear therapeutic advantage. One report of the use of
      the triple combination of irinotecan/cisplatin/etoposide resulted in 16 partial
      responses in 42 NSCLC patients (38%). Like docetaxel, irinotecan has been used
      effectively in conjunction with radiation therapy, with partial response rates in
      some studies of more than 70%.

PMID- 10585008
TI  - Single-agent gemcitabine and gemcitabine/irinotecan combination (irimogem) in non
      small cell lung cancer.
AB  - Gemcitabine is a fluoridated pyrimidine related to cytosine arabinoside that has
      significant activity in solid tumor models. Irinotecan is a camptothecin analog
      with an active metabolite, SN-38, which inhibits topoisomerase I activity by
      stabilizing the topoisomerase I-DNA cleavable complex. Gemcitabine studies in non
      small cell lung cancer conducted in the United States, as well as an
      international collaboration and clinical trials from Europe and Japan, found
      overall response rates of 20% to 26%, a median duration of response between 5 to
      9 months, and a median duration of survival ranging from 7 to 12.3 months.
      Gemcitabine also has been shown to be more effective than best supportive care in
      non-small cell lung cancer. In a phase I trial of irinotecan (50, 75, 100, and
      115 mg/m2) in combination with 1,000 mg/m2 gemcitabine, three patients had
      documented partial responses: one with pancreas cancer at irinotecan 100 mg/m2,
      one with pancreas cancer, and one with metastatic carcinoma of unknown primary at
      irinotecan 115 mg/m2. Three of five non-small cell lung cancer patients had
      stable disease for four or more cycles at irinotecan doses of 50, 75, and 100
      mg/m2; no non-small cell lung cancer patients were treated at irinotecan 115
      mg/m2. We recommend that a combination of gemcitabine 1,000 mg/m2 and irinotecan
      100 mg/m2 given on days 1 and 8 every 3 weeks be used as the starting dose in
      future phase II studies. Furthermore, based on the absence of severe
      nonhematologic toxicity or grade IV hematologic toxicity in the majority of
      patients treated at the highest dose, escalation of irinotecan to 115 mg/m2 may
      be considered for subsequent cycles in patients who do not experience > or =grade
      I hematologic or non-hematologic toxicity during the first cycle of
      gemcitabine/irinotecan combination chemotherapy.

PMID- 10585009
TI  - Single-agent paclitaxel and paclitaxel/non-platinum combination therapy in
      advanced non-small cell lung cancer.
AB  - Cumulative experience with single-agent paclitaxel in advanced metastatic non
      small cell lung cancer (NSCLC) suggests that it is a highly active cytotoxic
      agent. The consistent finding of a 35% to 40% 1-year survival rate is notable.
      The major toxicities include neutropenia, neuropathy, and myalgia/arthralgia
      syndrome. Paclitaxel has been used in combination with several other nonplatinum
      agents for the treatment of NSCLC. Order of administration and schedule are
      clearly relevant in these combinations. For example, in one study, etoposide and
      paclitaxel given simultaneously proved ineffective, with substantial grade IV
      neutropenia Another schedule with an identical dose of etoposide, given daily for
      3 days, followed by paclitaxel achieved a response rate of 41%, with markedly
      diminished neutropenia A variety of phase I studies have evaluated
      gemcitabine/paclitaxel, with response rates ranging from 22% to 30%.
      Paclitaxel/vinorelbine also has proven feasible in both small cell lung cancer
      and NSCLC, with a response rate of 17%. Investigators have combined paclitaxel
      with ifosfamide at full dose with response rates of 21% and 23%. The three-drug
      nonplatinum combination of paclitaxel/ifosfamide/vinorelbine also has been
      studied. The maximum tolerated dose for ifosfamide was 1.2 g/m2 on days 1 through
      3, for vinorelbine 20 mg/m2 on days 1 through 3, and for paclitaxel 175 mg/m2 on
      day 1. The response rate of 16% was disappointing. Median survival was 6.1 months
      and toxicity was substantial. Paclitaxel/non-platinum combinations may prove to
      be reasonable alternatives for NSCLC patients who cannot tolerate cisplatin and
      for relapsed patients and patients with compromised performance status.

PMID- 10585010
TI  - Single-agent vinorelbine in the treatment of non-small cell lung cancer.
AB  - Vinorelbine, a vinca alkaloid, was the first drug in over 20 years to be approved
      by the Food and Drug Administration for treatment of advanced non-small cell lung
      cancer (NSCLC). The drug's nonhematologic toxicities are usually mild; its dose
      limiting toxicity is neutropenia. Vinorelbine has been studied in many phase II
      trials. As a single agent it has produced objective response rates of 8% to 37%
      and median survivals ranging from 33 to 40.1+ weeks. Several phase III trials
      have included single-agent vinorelbine as one of the study arms. In a trial that
      compared vinorelbine with 5-fluorouracil and leucovorin, the vinorelbine
      recipients had better responses, median and 1-year survival rates, and
      improvement in cancer-related symptoms. In a large multicenter European trial
      single-agent vinorelbine was compared with vinorelbine/cisplatin and
      vindesine/cisplatin. Although the vinorelbine/cisplatin combination was superior
      to the other treatment arms with regard to response rate and median survival,
      single-agent vinorelbine was equivalent to the European standard of cisplatin and
      vindesine and was much less toxic. Vinorelbine is a reasonable alternative for
      patients not suited for cisplatin-containing regimens. Because of its favorable
      toxicity profile, vinorelbine has been investigated as a treatment for elderly
      patients with advanced NSCLC. In a multicenter randomized trial vinorelbine was
      compared with best supportive care in this particular patient group. Treated
      patients had a better survival and a trend toward improved quality of life.
      Single-agent vinorelbine has been used as second-line treatment for NSCLC but has
      not been particularly effective. Future directions for vinorelbine in the
      treatment of NSCLC include novel combinations with other agents as well as with
      radiation therapy in the treatment of locally advanced disease.

PMID- 10585011
TI  - Gemcitabine and vinorelbine combinations in the treatment of non-small cell lung
      cancer.
AB  - Combinations of vinorelbine with other nonplatinum agents show promising results
      in phase I and phase II trials in non-small cell lung cancer (NSCLC). In two
      phase II studies the efficacy and safety of vinorelbine/gemcitabine in patients
      with advanced NSCLC were assessed. In the first study, 32 chemotherapy-naive
      patients were treated with gemcitabine 1,250 mg/m2 and vinorelbine 25 mg/m2 on
      days 1 and 8 every 21 days The overall response rate was 25% (all partial
      responses) and median survival time was 8.3 months, with a 1-year survival rate
      of 38%; patients with performance status 0-1 had median survival of 11.7 months
      and a 1-year survival rate of 48%. In the second study, previously untreated and
      treated patients received gemcitabine/vinorelbine on days 1, 8, and 15 of a 28
      day cycle. Because myelosuppression was observed in the first eight patients
      treated sequentially with 1,000 mg/m2 gemcitabine and 30 mg/m2 vinorelbine, the
      doses were subsequently reduced to 900 and 25 mg/m2, respectively. Of the 23
      evaluable treatment-naive patients, in this preliminary analysis (presented at
      the 1999 American Society of Clinical Oncology meeting) 43% had partial
      responses, 31% had stable disease, and 22% experienced disease progression;
      estimated median survival was 11 months. Of 29 evaluable previously treated
      patients, 14% had partial responses, 28% had stable disease, and 41% experienced
      disease progression; estimated median survival was 9.2 months.
      Vinorelbine/gemcitabine is an active and well-tolerated regimen for patients with
      advanced NSCLC, with response and survival rates at least comparable to those
      with standard platinum-based regimens. Future directions for vinorelbine in the
      treatment of NSCLC include combinations with other agents and with radiation
      therapy in the treatment of locally advanced disease.

PMID- 10585012
TI  - The future beyond platinum for the treatment of advanced non-small cell lung
      cancer.
AB  - The development of chemotherapy for advanced non-small cell lung cancer has been
      most productive in its fifth decade. We began this decade by establishing
      cisplatin-based combination chemotherapy regimens of the 1980s as effective at
      improving survival for patients with advanced disease. The observed improvement
      in survival from these trials appears to be primarily attributed to cisplatin.
      Furthermore, this decade, unlike the prior, has identified an abundance of novel
      active agents for the treatment of this disease. Vinorelbine, gemcitabine,
      docetaxel, paclitaxel, and irinotecan are all new chemotherapeutic agents which
      have shown promising activity and their cisplatin combinations have further
      advanced survival for these patients. In contrast to the cisplatin-based
      chemotherapy trials of the 1980s, these newer chemotherapeutic agents, when given
      in combination with cisplatin, add to the survival outcomes for patients with
      advanced non-small cell lung cancer. With these survival advances has come a
      focus on chemotherapy-induced adverse events, lung cancer symptom management, and
      overall quality of life. Is it feasible to use these novel chemotherapeutic drugs
      as single-agents, sequentially or as nonplatinum combinations to prolong
      survival, minimize adverse events, control symptoms, and improve the quality of
      life for patients with this disease? The goal of this symposium will be to
      present the results of the single-agent and nonplatinum combination studies of
      these newer therapies with a focus on survival, symptom management, and quality
      of life. This symposium is intended to introduce the next decade of care for
      advanced non-small cell lung cancer, namely "Non-platinum-Based Chemotherapy."

PMID- 10585013
TI  - Influence of bone-lead stores on the observed effectiveness of lead hazard
      intervention.
AB  - Lead hazard interventions have reduced children's blood-lead concentrations, but
      do not eliminate lead altogether from the bloodstream. Several studies suggest
      that blood-lead concentrations, measured 6 to 12 months after such interventions,
      decline by approximately 25%. The Environmental Protection Agency is preparing to
      promulgate a rule prescribing residential lead levels in paint, dust, and soil
      that constitute a lead-based paint hazard. Such a rule will prompt interventions
      of primary prevention character (i.e., precluding exposure before it occurs)
      rather than the secondary prevention character interventions (i.e., alleviating
      exposure after it has adversely affected the resident child) documented in the
      literature. It is important to attempt to estimate the efficacy achieved from the
      primary prevention interventions prompted by the rule's promulgation. As bone
      lead stores represent the principal confounding factor to relating secondary
      prevention results to primary prevention, this paper addresses the impact of lead
      stored in bone, which may later be released to the blood and other parts of the
      child's body. A simple, but thoroughly documented, modeling exercise is presented
      to estimate the maximum length of time for which bone-lead stores alone could
      account for continuing elevated blood-lead levels observed in children following
      an intervention. The approach is based on a two-compartment model for the
      transfer of lead between blood and bone tissues within the body and the
      elimination of lead from the body. Modeling results suggest that bone-lead
      mobilization can impact blood-lead levels of young children for considerably long
      periods following an intervention. These results may explain the seemingly
      contradictory fact that low declines in blood-lead concentrations are observed
      despite the significant reduction in residential dust-, paint-, and soil-lead
      levels observed following lead hazard interventions. An intervention which
      reduces a 5-year-old child's total lead exposure by 50% might, due to mobilized
      bone-lead stores, produce only a 25% decline in the child's blood-lead
      concentrations measured 12 months following the intervention. The results also
      suggest, however, that those intervention strategies for which less than 25%
      declines were observed 12 months following the intervention likely eliminated
      less than 50% of the children's total lead exposure.

PMID- 10585014
TI  - Acute health problems among the people engaged in the cleanup of the Nakhodka oil
      spill.
AB  - To determine if the Nakhodka oil spill and subsequent cleanup efforts had any
      health effects on the residents along the oil-contaminated coast, we investigated
      the health status of Anto residents who resided nearest to the coast where the
      bow ran aground. Two hundred eighty-two men and women involved in the cleanup
      activities between January 7 and January 20 were interviewed and examined by
      public health nurses to determine whether they suffered physical symptoms after
      exposure to the oil spill. Urine examinations for hydrocarbon toxicological
      markers were performed on 97 residents. The average number of days worked on
      cleanup activities was 4.7 days for men and 4.3 for women. Seventeen percent of
      the subjects had worked on cleanup activities for more than 10 days. Protective
      equipment was used against direct exposure to oil during the cleanup jobs and
      consisted of gloves used by almost 100% of the subjects and masks used by 87.1%
      of women and by only 35.4% of men. Glasses were worn by less than 30% of the
      subjects. Many symptoms emerged after the beginning of cleanup activities. The
      principal symptoms included low back pain and leg pain, headache, and symptoms of
      eyes and throat. Among the subjects undergoing urine tests, only three people
      showed a higher level of hippuric acid, although they returned to normal in the
      second examination. Accordingly, the exposure to the oil and the subsequent
      cleanup efforts were suggested to inflict acute health problems on local
      residents.

PMID- 10585015
TI  - Strategies to assess validity of self-reported exposures during the Persian Gulf
      War. Portland Environmental Hazards Research Center.
AB  - Research in the area of Persian Gulf War Unexplained Illnesses (PGWUI) is heavily
      dependent on self-reports of exposures. The Portland Environmental Hazards
      Research Center (PEHRC) conducted a population-based case-control study utilizing
      techniques to measure the magnitude of potential error in self-reports of
      exposure. While it is impossible to verify most exposures in the Persian Gulf War
      (PGW), results of our study reveal significant overreporting of exposures that
      can be verified based on the time period served in the Persian Gulf. Test-retest
      reliability estimates indicate inconsistency in frequency and rate of self
      reported exposures during the PGW. Unexplained illness in PGW veterans has
      received much political and scientific attention. Self-reported exposures in
      surveys returned preceding and following media reports on particular exposure
      such as nerve gas or pesticides are presented. These results are useful in the
      interpretation of findings related to the PGWUI and in the design of future
      investigations.

PMID- 10585016
TI  - Persistent health effects of dioxin contamination in herbicide production.
AB  - A total of 159 cases of chloracne reported in 1969-1975 in TCDD-contaminated
      production of the herbicide 2,4,5-T have been followed for mortality and
      morbidity up to 1996 when blood and urine tests were performed on 50 survivors of
      these exposed chemical workers and matched controls. In exposed, the most
      frequent cause of sick leave was chloracne which persisted in 32%. Neurological
      symptoms were reported frequently (44% sleep disturbance, 32% headache, 30%
      neuralgia). BSR, leucocytes, gamma-GT, SGOT, and SGPT were significantly higher
      in exposed than in controls. The effects of exposure (P= 0.002) and alcohol (P=
      0.002) on gamma-GT were found to be independent of each other. Comparisons within
      the chloracne cohort showed significantly exposed TCDD per gram blood lipid in
      patients with a history of liver disease (mean 801 pg/g) than without (mean 407
      pg/g). Other congeners were not found elevated but some higher chlorinated furans
      and PCBs were found reduced in patients with liver disease. In multiple
      regression analysis with the factors age, alcohol, and log TCDD, the effects of
      TCDD and its interaction with age were found significant, indicative of chronic
      liver damage after high TCDD exposure at a young age. The prevalence of
      neurological symptoms and signs of chronic liver disease were related to TCDD in
      blood and abnormal poryphyrins in urine. In 48% coproporphyrin I > III ratio was
      elevated, this group showing increased TCDD (mean 719 pg/g). These results
      contribute to the evidence that chloracne is not the only chronic disease which
      can be related to TCDD exposure, even 23 years after exposure and despite high
      intersubject variability of TCDD half-life and other exposures.

PMID- 10585017
TI  - Gulf War unexplained illnesses: persistence and unexplained nature of self
      reported symptoms.
AB  - Most published reports of health symptoms among Gulf War (GW) veterans have been
      based on self-reported questionnaire data. The presence of these symptoms at the
      time of a clinical evaluation and the unexplained nature of the symptoms have not
      been described. We report the findings of a sample of symptomatic veterans that
      were examined as part of a population-based case-control study of GW unexplained
      illnesses. Participants in the case-control study were selected from responders
      to a cross-sectional survey of a random sample of GW veterans residing in the
      northwestern United States. The initial survey questionnaire solicited
      information on the presence of fatigue and psychological/cognitive,
      gastrointestinal, musculoskeletal, and dermatological problems. The persistence
      of the symptoms and possible explanatory diagnoses were explored at the time of
      the clinical evaluation. Findings from the first 225 participants who completed
      clinical examinations indicate significant differences between self-reported
      symptoms on the survey questionnaire and those confirmed at the time of clinical
      exam. The agreement between symptoms reported both on the survey and at the time
      of examination varies across the symptom groups. While self-reported unexplained
      fatigue was confirmed at the time of clinical encounter in 79% of participants,
      self-reported gastrointestinal symptoms were confirmed at the clinical encounter
      in only 20% of participants. Differences between symptoms reported on the survey
      questionnaire and those confirmed at the time of clinical encounter were
      attributable to finding a clinical diagnosis for the symptom, resolution of
      symptom(s) between time of questionnaire and clinical exam, and inadvertent
      endorsement of the symptom on the questionnaire. These findings suggest that due
      to the possibility of outcome misclassification, inappropriate conclusions may be
      drawn about the association between exposures and unexplained illnesses in GW
      veterans from data derived solely from self-administered questionnaires.

PMID- 10585018
TI  - Air pollution and respiratory drug sales in the City of Le Havre, France, 1993
      1996.
AB  - The aim of this study is to evaluate ambulatory respiratory drug sales data as
      health indicators for the short-term effects of ambient air pollution in the city
      of Le Havre. Daily respiratory drug sales data were crossed with daily ambient
      air concentrations of sulfur dioxide (SO2), nitrogen dioxide (NO2), and black
      smoke (BS) using an autoregressive Poisson regression model adjusting for time
      trends, seasonal variations, influenza epidemics, and weather. Relative risks
      (RR) were expressed for an increase of two standard deviations above the mean of
      each pollutant. Respiratory drug sales were associated with most pollutants
      studied with lags varying from 1 to 9 days. For daily mean concentrations of BS,
      RR = 1.037 (95% confidence interval (CI) 1.009-1.066) for lag 1 and RR = 1.052
      (95% CI 1.023-1.081) for lag 8. For daily mean concentrations of N02, RR = 1.033
      (95% CI 1.001-1.066) for lag 1 and RR = 1.046 (95% CI 1.014-1.079) for lag 8. RR
      observed with a daily 1 h maximum of SO2 were RR= 1.027 (95% CI 1.004-1.051) for
      lag 3 and RR= 1.032 (95% CI 1.009-1.056) for lag 9. Our study concludes that
      ambulatory respiratory drug sales data could be useful for epidemiological
      surveillance of air pollutant health effects.

PMID- 10585019
TI  - Air pollution and daily mortality in the Coachella Valley, California: a study of
      PM10 dominated by coarse particles.
AB  - Many epidemiological studies provide evidence of an association between airborne
      particles, measured as PM10 (particulate matter less than 10 microm in diameter),
      and daily morbidity and mortality. Most of these studies have been conducted in
      urban areas where PM10 consists primarily of fine particles (<2.5 microm in
      diameter). Few studies have investigated impacts associated with coarse mode
      particles (>2.5 microm in diameter). We investigated associations between PM10
      and daily mortality in the Coachella Valley, a desert resort and retirement area
      east of Los Angeles, where coarse particles of geologic origin typically comprise
      approximately 50-60% of PM10 and can exceed 90% during wind events. Our analysis
      utilized daily data on mortality from 1989 through 1992 as well as several
      pollutant and meteorological variables, including PM10, nitrates, sulfates,
      ozone, nitrogen dioxide, carbon monoxide, temperature, and relative humidity.
      Outcome variables included several measures of daily mortality, including all
      cause, cardiovascular and respiratory mortality, and counts of deaths for those
      above age 50. Multivariate Poisson regression models were used to explain these
      health endpoints, controlling for temperature, humidity, day of the week, season,
      and time, using locally weighted smoothing techniques. The analysis indicated
      statistically significant associations between PM10 (2- or 3-day lags) and each
      measure of mortality. The results were robust to various model specifications,
      correction for autocorrelation and overdispersion, and analysis of influential
      observations. A 10 microg/m3 change in daily PM10 was associated with an
      approximately 1% increase in mortality, which is of similar magnitude to particle
      associated impacts identified in urban areas. Thus, our findings provide evidence
      for a mortality effect of PM10 in an area where the particulate mass is dominated
      by coarse particles.

PMID- 10585020
TI  - Association between indoor and outdoor air pollution and adolescent asthma from
      1995 to 1996 in Taiwan.
AB  - The study aim was to estimate the contribution of indoor and outdoor air
      pollution to the 1-year prevalence of adolescent asthma after personal
      susceptibility and other potential risk factors were taken into account. A large
      scaled cross-sectional study was conducted among 165,173 high school students
      aged 11 to 16 years in the different communities of Kaohsiung and Pintong in
      Taiwan, from October 1995 to June 1996. Each student and his/her parents
      participating in the study completed a video and a written International Study of
      Asthma and Allergies in Childhood (ISAAC) questionnaire about symptoms of
      wheezing and allergies, passive smoking, and demographic variables. After
      adjustment for potential confounders, adolescents exposed to cigarette smoking
      (odds ratio = 1.29, 95% confidence interval (CI), 1.17-1.42) and environmental
      tobacco smoke (odds ratio = 1.08, 95% CI, 1.05-1.12) were found to suffer from
      asthma at an increased frequency. We observed a statistically significant
      association between outdoor air pollution and asthma, after controlling for
      potential confound variables. Total suspended particulate, nitrogen dioxide,
      carbon monoxide, ozone, and airborne dust particles all displayed an independent
      association with asthma, respectively. There were no selection biases in this
      community-based study, which provides evidence that passive smoking and long
      term, high average outdoor air pollution are independent risk factors of asthma.

PMID- 10585021
TI  - Elevated TCDD in chicken eggs and farm-raised catfish fed a diet with ball clay
      from a Southern United States mine.
AB  - The U.S. Food and Drug Administration (FDA) terminated the use of ball clay from
      a mine in Mississippi as an additive in animal feed after discovering nanogram
      per gram concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD).
      The FDA collected chicken eggs and farm-raised catfish in affected areas and
      throughout the remaining continental United States to assess levels of 2,3,7,8
      TCDD. A new method using quadrupole ion storage tandem-in-time mass spectrometry
      (QISTMS) measured the 2,3,7,8-TCDD levels in 42 catfish fillet composites, 3
      Tilapia fillet composites, 46 chicken egg samples, and 6 chicken feeds. Six
      catfish composites and 20 egg samples had 2,3,7,8-TCDD concentrations
      significantly above 1.0 pg/g wet weight of fillet or whole egg. Farm-raised
      catfish not exposed to feed containing ball clay had a mean 2,3,7,8-TCDD
      concentration of 0.12 pg/g. The TCDD isomer pattern in ball clay differed from
      the TCDD isomer pattern in a fly ash sample and from the "chick edema factor"
      TCDD pattern in a sample of reference toxic fat used as a feed ingredient in the
      1950s.

PMID- 10585022
TI  - Bradykinin pretreatment improves ischemia tolerance of the rabbit heart by
      tyrosine kinase mediated pathways.
AB  - BACKGROUND: Depressed myocardial performance is an important clinical problem
      after open-heart surgery. We hypothesized that: (1) pretreating the heart with
      bradykinin improves postischemic performance, and (2) bradykinin activates
      protein tyrosine kinase (TK). METHODS: Twenty-seven adult rabbit hearts underwent
      retrograde perfusion with Krebs-Henseleit buffer (KHB) followed by 50 min of 37
      degrees C cardioplegic ischemia with St. Thomas' cardioplegia solution (StTCP).
      Ten control hearts received no pretreatment. Ten bradykinin-pretreated hearts
      received a 10-minute infusion of 0.1 microM bradykinin-enriched KHB and
      cardioplegic arrest with 0.1 microM bradykinin-enriched StTCP. Seven others
      received 40 microM Genistein (Research Biochemicals, Natick, MA), a selective
      inhibitor of TK, added to both the 0.1-microM bradykinin-enriched KHB and 0.1
      microM bradykinin-enriched StTCP solutions. RESULTS: Bradykinin pretreatment
      significantly improved postischemic myocardial performance and coronary flow (CF)
      compared with control (left ventricular developed pressure: 53 +/- 5 vs 27 +/- 4
      mm Hg; +dP/dt(max): 1,025 +/- 93 vs 507 +/- 85 mm Hg/s; CF: 31 +/- 3 vs 22 +/- 2
      mL/min; p < 0.05). Inhibition of TK with Genistein prevented this improvement in
      myocardial function, resulting in recovery equivalent to untreated controls.
      CONCLUSIONS: Bradykinin pretreatment may be an important new strategy for
      improving myocardial protection during heart surgery. The molecular mechanism of
      action may be similar to those activated by ischemic preconditioning.

PMID- 10585023
TI  - Sinus of Valsalva aneurysm or fistula: management and outcome.
AB  - BACKGROUND: Few large or long-term series exist regarding the management of
      patients with sinus of Valsalva aneurysms or fistulas (SVAFs). METHODS: Between
      1956 and 1997, 129 patients presented with a ruptured (64 cases; 49.6%) or
      nonruptured (65 cases; 50.4%) SVAF. The patients included 88 men and 41 women,
      with a mean age of 39.1 years. Associated findings included a history of
      endocarditis (42 cases; 32.6%), a bicuspid aortic valve (21 cases; 16.3%), a
      ventricular septal defect (15 cases; 11.6%), and Marfan's syndrome (12 cases;
      9.3%). Operative procedures included simple plication (61 cases; 47.3%), patch
      repair (52 cases; 40.3%), aortic root replacement (16 cases; 12.4%), and aortic
      valve replacement/repair (75 cases; 58.1%). RESULTS: There were five in-hospital
      deaths (3.9%): four due to preexisting sepsis and endocarditis and one that
      followed dehiscence of the repair in a patient with Marfan's syndrome. Two
      patients (1.6%) had strokes during the early postoperative period. The survivors
      were followed up for 661.1 patient-years (5.3 years/patient). The following late
      complications occurred: prosthetic valve malfunction (5 cases; 3.9%), prosthetic
      valve endocarditis (3 cases; 2.3%), SVAF recurrence (2 cases; 1.6%), thrombosis
      (1 case; 0.8%), and anticoagulation-related bleeding (1 case; 0.8%). CONCLUSIONS:
      Resection and repair of SVAF entails an acceptably low operative risk and yields
      long-term freedom from symptoms. Early, aggressive treatment is recommended to
      prevent endocarditis or lesional enlargement, which causes worse symptoms and
      necessitates more extensive repair.

PMID- 10585024
TI  - Platelet-activating factor receptor antagonism improves cerebral recovery after
      circulatory arrest.
AB  - BACKGROUND: The aim of this study was to determine the effects of antagonism of
      platelet-activating factor receptors on cerebral recovery after deep hypothermic
      circulatory arrest (DHCA). METHODS: Fourteen 1-week-old piglets were randomly
      assigned to either placebo (n = 7), or 10 mg/kg intravenous ginkgolide B
      (BN52021), a naturally occurring platelet-activating factor receptor antagonist.
      All piglets had cardiopulmonary bypass, cooling to 18 degrees C, 60 minutes of
      circulatory arrest followed by 60 minutes of reperfusion and rewarming. Global
      and regional cerebral blood flow, cerebral oxygen metabolism and renal blood flow
      were determined at baseline before DHCA and after 60 minutes of reperfusion.
      RESULTS: Blood flow was significantly reduced in all regions of the brain (p <
      0.001) and the kidneys (p = 0.02) after DHCA in control animals. Cerebral oxygen
      metabolism was also significantly reduced after DHCA to 59.2% +/- 3.2% of the pre
      DHCA value (p = 0.0003). In the ginkgolide B group, recovery of global cerebral
      blood flow to 60.4% +/- 2.8% of pre-DHCA level and of global cerebral oxygen
      metabolism to 77.1% +/- 5.8% of pre-DHCA value were significantly higher than the
      recovery in the control group (p < 0.02). Regional recovery of cerebral blood
      flow and oxygen metabolism in the gingkolide B group was greatest in the
      cerebellum and brainstem. Renal blood flow did not decrease significantly after
      DHCA in the gingkolide B group (p = 0.23). CONCLUSIONS: These results suggest
      that production of platelet-activating factor is increased in the brain after
      DHCA. Platelet-activating factor receptor antagonism with ginkgolide B before the
      circulatory arrest period can significantly improve recovery of cerebral blood
      flow and oxygen metabolism and renal blood flow after DHCA.

PMID- 10585025
TI  - Is distal anastomosis only to the true channel in chronic type B aortic
      dissection justified?
AB  - BACKGROUND: We investigated long-term outcomes of the distal false lumen of the
      aorta and aortic branches after distal anastomosis of the graft only to the true
      lumen in chronic type B aortic dissection. METHODS: From November 1979 until June
      1998, we treated 98 patients without Marfan syndrome who had chronic type B
      aortic dissection and underwent replacement of the descending aorta, 79 of whom
      had distal anastomosis to the true lumen only. The celiac artery originated from
      the false lumen in 11 patients, superior mesenteric artery in 5, right renal
      artery in 19, and left renal artery in 16. RESULTS: There were 12 (15.1%) early
      deaths. Spinal cord ischemia was detected in 5 patients. Postoperative follow-up
      was achieved in 67 patients, and 13 patients died. Postoperative survival at 10
      years was 67.6% +/- 7.1%. Eight patients had complete occlusion of the distal
      false lumen, 54 patients had occlusion of the false lumen down to the celiac
      artery, and 5 patients had a patent false lumen. Four patients required further
      replacement of the thoracoabdominal aorta. CONCLUSIONS: In non-Marfan patients
      with chronic type B aortic dissection, the false lumen distal to the graft
      anastomosis was likely to be thrombosed when the graft was anastomosed to the
      true lumen only. Postoperative visceral circulation was not compromised, but
      spinal cord ischemia is a problem that remains to be solved.

PMID- 10585026
TI  - Alabama coronary artery bypass grafting Cooperative Project: baseline data.
      Alabama CABG Cooperative Project Study Group.
AB  - BACKGROUND: The Alabama Cooperative CABG Project is a statewide process-oriented
      analysis of coronary artery bypass grafting (CABG). The purpose of this report is
      to present the first information generated by this analysis, which will serve as
      a baseline for subsequent quality improvement projects. METHODS: Medical records
      of Medicare beneficiaries from Alabama, a comparison state, and a national random
      sample who had isolated CABG between July 1, 1995, and June 30, 1996, were
      examined. Fifty-six demographic, procedural, and outcome variables were
      abstracted. Quality indicators identified by the Alabama Quality Assurance
      Foundation Study Group included: internal mammary artery use, prescription of
      aspirin at discharge, duration of postoperative intubation, use of intraaortic
      balloon pump, readmission to intensive care unit, hospital readmission within 30
      days, return to the operating room for bleeding, and in-patient mortality.
      Benchmark performance rates for quality indicators reflecting care processes were
      calculated. RESULTS: Alabama, the comparison state, and the national sample
      consisted of 4,092, 2,290, and 1,119 patients, respectively. The processes of
      care and outcome, including risk-adjusted mortality, for CABG across the state of
      Alabama are generally similar to other states and nationwide samples. However,
      there was considerable variation at the local hospital level in Alabama for each
      quality indicator. CONCLUSIONS: The data provide a "snapshot" of practice
      patterns for CABG in Alabama. A specific quality indicator (duration of
      intubation) was identified as a focus for statewide improvement. Hospital
      specific variations in quality indicators suggested opportunities for improvement
      in other indicators at a number of hospitals.

PMID- 10585027
TI  - Oral amiodarone reduces incidence of postoperative atrial fibrillation.
AB  - BACKGROUND: Atrial fibrillation (AF) is a common occurrence after heart
      operations that use cardiopulmonary bypass. It can cause life-threatening
      complications as well as delay discharge and increase hospitalization costs. The
      purpose of this study was to evaluate the effect of orally administered low-dose
      amiodarone on the incidence of new onset postoperative AF. METHODS: In this
      prospective study, 226 consecutive adult patients (group A) who had various heart
      operations utilizing cardiopulmonary bypass between April and November of 1998 at
      the University of Miami/Jackson Memorial Hospital, were given oral amiodarone
      (200 mg three times a day), starting immediately after arrival in the intensive
      care unit until the day of hospital discharge. The incidence of new AF in this
      group of patients was assessed and compared with a historical group of 239
      patients (group B) who had had cardiac operations with cardiopulmonary bypass in
      the preceding 9 months at the same institution. RESULTS: Preoperative patient
      characteristics and procedure types were similar in the two groups. Among the 226
      patients in group A, 13 (5.7%) had history of AF. Of the remaining 213 patients,
      new-onset AF occurred postoperatively in 10 (4.7%). Among the 239 patients in
      group B, 16 (6.7%) had history of AF. Of the remaining 223 patients, 44 (19.7%)
      developed new-onset AF (p < 0.001). Group A patients had a shorter length of
      hospital stay than those in group B (6.5 versus 7.8 days) but had a similar
      incidence of complications other than AF (23 of 226 patients in group A versus 24
      of 239 in group B). The drug was well tolerated. CONCLUSIONS: Postoperative low
      dose amiodarone given orally to patients who had cardiopulmonary bypass was well
      tolerated and appeared to reduce the incidence of new-onset AF and decrease the
      length of hospital stay.

PMID- 10585028
TI  - Right ventricular dysfunction after cardiac transplantation: primarily related to
      status of donor heart.
AB  - BACKGROUND: It is unclear whether right ventricular dysfunction after
      transplantation is due to donor brain death-related myocardial injury or
      recipient pulmonary hypertension. METHODS: A canine donor model of brain death
      and a monocrotaline pyrrole-induced chronic pulmonary hypertension recipient
      model were established, and used for 30 orthotopic bicaval cardiac
      transplantations divided into three groups: Controls (group A, normal
      donor/recipient), group B (brain-dead donors/normal recipient), and group C
      (normal donor/recipients with pulmonary hypertension). Right ventricular function
      was measured before transplant and brain death, 4 hours after brain death, and
      after transplant (1 hour off bypass) by load-independent means plotting stroke
      work versus end-diastolic volume during caval occlusion. Right ventricular total
      power and pulmonary vascular impedance were determined by Fourier analysis.
      RESULTS: In comparison to the control group right ventricular preload-recruitable
      stroke work and total power decreased significantly after brain death and
      transplant in group B (from 22.7 x 10(3) erg (+/-1.2) at baseline to 15.6 x 10(3)
      (+/-0.9) after brain death and to 11.3 x 10(3) (+/-0.9) after transplant). In
      group C there was a significant increase in pulmonary artery pressure, impedance,
      right ventricular preload-recruitable stroke work, total power after transplant.
      CONCLUSIONS: Normal donor hearts adapt acutely to the recipient's elevated
      pulmonary vascular resistance by increasing right ventricular power output and
      contractility. Brain death caused significant right ventricular dysfunction and
      power loss, which further deteriorated after graft preservation and
      transplantation. The effects of donor brain death on myocardial function
      contribute to right ventricular dysfunction after cardiac transplantation.

PMID- 10585029
TI  - Exclusive Y graft operation for multivessel coronary revascularization.
AB  - BACKGROUND: The pedicled (in-situ) left internal mammary artery grafted to the
      left anterior descending artery has a very high late patency and reduces late
      mortality following coronary artery bypass surgery. A technique is described
      which achieves total arterial revascularization in patients with multivessel
      coronary disease and which is also entirely pedicled. METHODS: Using the left
      internal mammary artery and radial artery joined as a composite Y graft, all
      coronary territories may be grafted. RESULTS: One in-hospital death from 464
      patients (0.2%) occurred. Age (mean +/- standard error) was 64.7 +/- 0.5 years
      and number of distal anastomoses 3.4 +/- 0.04. Of 1,681 patients from Royal
      Melbourne Hospital, 346 had this operation. Comparison found no preoperative
      selection bias and no postoperative differences in complications. Actuarial
      survival was 0.98 +/- 0.01 at 36.1 +/- 0.3 months. CONCLUSIONS: Total arterial
      revascularization may be performed using the left internal mammary artery and
      radial artery as a composite Y graft. There was no increase in complications.
      This technique preserves the left internal mammary artery to left anterior
      descending artery graft.

PMID- 10585030
TI  - Blood flow in composite arterial grafts and effect of native coronary flow.
AB  - BACKGROUND: Total arterial coronary revascularization can be achieved by joining
      arteries together as a composite graft with the proximal left internal mammary
      artery as the only source of blood inflow. Proof of the capacity of this
      composite conduit to provide adequate blood flow to the coronary circulation is
      required. METHODS: The radial artery was anastomosed to the left internal mammary
      artery as a Y graft in 17 patients and all coronary arteries grafted.
      Intraoperative blood flow through the composite grafts was evaluated by the
      transit-time Doppler technique. RESULTS: Against no resistance, blood flow in the
      left internal mammary artery alone was 99 +/- 9 mL/min and rose to 173 +/- 16
      mL/min when the radial artery was anastomosed as a Y graft. Composite-graft flow
      following grafting was 88 +/- 9 mL/min, 49 +/- 6 mL/min when the aortic clamp was
      removed and native coronary flow restored and 82 +/- 13 mL/min following weaning
      from cardiopulmonary bypass. The maximal potential flow through the composite
      graft was 2.3-fold (95% CI 1.6 to 3.2) greater than that after cardiopulmonary
      bypass. CONCLUSIONS: Total arterial revascularization, using a composite graft,
      provided a 2.3-fold reserve of blood flow to the coronary vascular bed through
      the grafts.

PMID- 10585031
TI  - Effect of skeletonization of the internal thoracic artery on vessel wall
      integrity.
AB  - BACKGROUND: This study was conceived to evaluate the effect of internal thoracic
      artery (ITA) skeletonization on vessel wall integrity. METHODS: Forty consecutive
      patients undergoing coronary artery bypass were randomized to receive a
      skeletonized (n = 22) or a pedicled (n = 18) ITA graft. ITA harvesting was
      performed by 2 experienced surgeons using the same instrumentation and technique.
      Specimens were examined by light and electron microscope in order to assess
      vascular wall integrity. A specific immunohistochemical staining and a
      computerized method were used to quantify the degree of endothelial integrity
      after surgical preparation. RESULTS: Morphologic analysis revealed 2 cases of
      limited subadventitial hemorrhage (one for each group) and no case of major
      arterial damage. Immunohistochemical staining demonstrated an extremely high
      degree of maintenance of the endothelial integrity in both groups (97.2% +/- 1.9%
      in the skeletonized and 96.8% +/- 2.1% in the pedicled one; p = 0.53).
      CONCLUSIONS: Skeletonization does not affect ITA wall integrity in humans
      submitted to coronary artery bypass procedures.

PMID- 10585032
TI  - Increased temperature reduces the protective effect of University of Wisconsin
      solution in the heart.
AB  - BACKGROUND: The protective effect of University of Wisconsin solution (UW) for
      hypothermic storage of donor hearts has been demonstrated in the laboratory.
      However, clinical usage is associated with occasional primary graft failures. We
      postulated that this could be related to adverse effects of UW on the coronary
      vasculature during cardiac implantation and rewarming. We therefore assessed
      recovery of contractile function and coronary flow in rat hearts after
      cardioplegic arrest using UW compared with St. Thomas' solution (ST) at 4 degrees
      C or 25 degrees C. METHODS: Cardioplegia was induced in isolated rat hearts using
      either UW or ST at 4 degrees C. Hearts were then maintained at 4 degrees C or 25
      degrees C. In some hearts, UW at 4 degrees C was used for inducing arrest
      followed by flushing with ST at 4 degrees C and then rewarming to 25 degrees C.
      After 40 minutes of arrest, recovery of function and coronary flow were measured.
      Nuclear track emulsion was used to assess microvascular competence. RESULTS:
      Compared with ST-treated hearts, UW-treated hearts showed significant reduction
      in recovery of function at 25 degrees C (76.2% +/- 4.0% versus 25.0% +/- 4.1%; p
      < 0.01) but not at 4 degrees C (88.0% +/- 1.6% versus 87.1% +/- 2.6%). Recovery
      of coronary flow in the UW-treated hearts at 25 degrees C was significantly lower
      than that in the ST-treated hearts at 25 degrees C (71.7% +/- 3.0% versus 94.5%
      +/- 6.3%; p < 0.01). At 25 degrees C, microvascular competence was reduced in the
      UW group compared with the ST group. At 25 degrees C, flushing out UW with ST
      resulted in greater recovery of function compared with UW throughout (73.4% +/-
      7.1% versus 25.0% +/- 4.1%; p < 0.01). CONCLUSIONS: University of Wisconsin
      solution provides effective donor heart protection under hypothermic conditions
      but can be deleterious at warmer temperatures.

PMID- 10585033
TI  - Angiographic anatomy of the grafted left internal mammary artery.
AB  - BACKGROUND: The hypothesis that persistence of undivided branches is a common
      finding after myocardial revascularization using the left internal mammary artery
      was explored. METHODS: Three hundred seven consecutive postoperative
      angiographies of the left internal mammary artery were considered. Seven were
      excluded because of occlusion or malfunction of the conduit or the anastomosis.
      Of the remaining 300, 150 were harvested through a left anterior small
      thoracotomy (group A) and 150 through a median sternotomy (group B). The
      persistence of undivided branches was recorded for each group. RESULTS: Common
      origin with other branches of the subclavian artery was present in 55 patients in
      group A and 54 in group B (p = not significant); the persistence of lateral
      costal branch was also equally distributed in both groups (15 and 17; p = not
      significant). The first intercostal artery was present in 5 patients in group A
      and in none in group B (p = not significant). Branches of 1 mm or more were more
      frequent in group A (34 versus 4, p < 0.001), as well as branches of less than 1
      mm (140 versus 67; p < 0.001). Only 2 patients in group A had no branches versus
      48 patients in group B (p < 0.001). CONCLUSIONS: Common origin with other
      branches of the subclavian artery and persistence of the lateral costal branch
      are common aspects in the angiographic anatomy of the grafted left internal
      mammary artery. Moreover, new branches, sometimes wider than 1 mm, develop with
      time. These findings are independent from the harvesting technique, the left
      anterior small thoracotomy, or the median sternotomy. If flow competition between
      the coronary and noncoronary territories was a reality, coronary artery grafting
      with the left internal mammary artery would be unsuccessful since the beginning.

PMID- 10585034
TI  - Blood product use in cardiac revascularization: comparison of on- and off-pump
      techniques.
AB  - BACKGROUND: Cardiac revascularization on a beating heart avoids the side effects
      of cardiopulmonary bypass (eg, neurologic injury, hemodilution, and
      coagulopathy). We examined perioperative bleeding and use of blood products
      during coronary artery bypass grafting using either on-pump or off-pump
      techniques. METHOD: The charts of 126 patients who had coronary artery bypass
      grafting were reviewed. Data from 66 patients revascularized off pump and 60
      patients with cardiopulmonary bypass (on pump) were analyzed using unpaired
      Student's t test. RESULTS: Average age was 62.5 years in either group. More
      patients received heparin preoperatively in the off-pump group that resulted in
      mild elevation of preoperative partial thromboplastin time and activated clotting
      time (40.4 +/- 2.9 seconds and 150.1 +/- 5.3 seconds, respectively). However, the
      off-pump group had less perioperative (intraoperative or postoperative) bleeding
      (2312 +/- 212 mL versus 3251 +/- 155 mL, p < 0.05) and required fewer blood
      products compared with the on-pump group. Hemoglobin and platelets decreased more
      in the conventional on-pump group. CONCLUSIONS: Avoiding cardiopulmonary bypass
      decreases perioperative bleeding and, consequently, reduces the use of blood
      products after coronary artery bypass grafting, which might result in fewer
      transfusion-related complications.

PMID- 10585035
TI  - Favorable impact of stents after emergent coronary artery bypass for failed
      angioplasty.
AB  - BACKGROUND: This study was undertaken to determine the impact of the use and
      availability of coronary stents on outcomes in patients requiring emergent
      coronary artery bypass graft (CABG) surgery following a failed percutaneous
      transluminal coronary angioplasty (PTCA). METHODS: Patients were divided into two
      groups based on the year of their CABG for a failed PTCA and the availability of
      stents: group 1, 1992 to 1994, stents not available (n = 34); and group 2, 1995
      to 1997, stents available (n = 26). RESULTS: CABG patients in the group where
      stents were not available were more likely to have had an abrupt coronary
      occlusion (26 of 34 versus 3 of 26; p < 0.0001) and less likely to have had a
      dissection (8 of 34 versus 23 of 26; p < 0.0001) as their indication for emergent
      CABG. Patients in the stent era had a lower incidence of perioperative myocardial
      infarction (5 of 26 versus 17 of 34; p < 0.01) and a decreased mortality rate (0
      of 26 versus 6 of 34; p < 0.03). In the 9 patients where stents were employed,
      patency of the lumen was restored in 8 patients and there was only 1 myocardial
      infarction. CONCLUSIONS: Stents have had a favorable impact on patients requiring
      an emergent CABG following a failed PTCA.

PMID- 10585036
TI  - Adjuvant treatment of deep sternal wound infection with collagenous gentamycin.
AB  - BACKGROUND: The treatment of deep sternal wound infections remains controversial.
      Currently advocated procedures carry the risk of reinfections. The significance
      of local antibiotic-releasing systems as an adjuvant therapy to avoid
      reinfections is the subject of the presented study. METHODS: Forty-two patients
      with deep sternal wound complication were treated with radical wound debridement,
      sternal refixation, retrosternal suction drainage, bilateral pectoralis major
      muscle flaps, and placement of collagenous drug carrier loaded with gentamycin
      (Sulmycin Implant) underneath, above, and between the sternal edges. RESULTS: No
      treatment failure and death were observed in our patients. Side effects after
      adjuvant treatment with collagenous gentamycin were not detected. CONCLUSIONS:
      The preliminary results of adjuvant therapy with collagenous gentamycin in
      combination with surgical debridement leads to excellent results in the treatment
      of early deep sternal wound infections with no death and no primary treatment
      failures. This technique is easy to perform, reliable, and safe. For final
      judgment controlled randomized trials are mandatory.

PMID- 10585037
TI  - Autologous blood donation with recombinant human erythropoietin in anemic
      patients.
AB  - BACKGROUND: Various blood management strategies can be used to reduce the need
      for allogeneic blood in cardiac surgery. In anemic patients, however, avoidance
      of allogeneic blood transfusion is difficult to achieve. This study was performed
      to assess the safety and effectiveness of preoperative blood collection using
      recombinant human erythropoietin (rHuEPO) for reducing the exposure to allogeneic
      blood in anemic patients. METHODS: Thirty-two anemic patients undergoing cardiac
      surgery at our hospital between January 1994 and October 1997 were divided into
      two groups according to preoperative strategies: 3-week treatment with rHuEPO and
      blood donation (group 1, n = 16) or iron supplementation alone (group 2, n = 16).
      RESULTS: There were no statistically significant differences between the two
      groups in patients' characteristics and surgical data. The number of
      reticulocytes was increased at just before surgery in group 1, whereas group 2
      showed no significant increase. The estimated hemoglobin increases in group 1
      were higher at 7 days and just before surgery. The mean number of required
      allogeneic blood for patients during surgery was 0.59 +/- 1.12 U in group 1 and
      5.01 +/- 2.63 U in group 2. In 75% of group 1 patients, allogeneic blood
      transfusion was successfully avoided, whereas all patients in group 2 received
      allogeneic blood. CONCLUSIONS: This study suggests that the combination of rHuEPO
      administration and autologous blood donation can reduce the need for allogeneic
      blood in anemic patients.

PMID- 10585038
TI  - Patient-prosthesis mismatch is negligible with modern small-size aortic valve
      prostheses.
AB  - BACKGROUND: Concern has been raised about residual significant gradients when
      small aortic prostheses are used, particularly in patients with large body
      surface areas. We studied the performance of six types of small aortic prostheses
      using dobutamine stress echocardiography. METHODS: Sixty-three patients (mean
      age, 67 +/- 7 years) who had undergone aortic valve replacement 17 +/- 6 months
      previously were studied. Two bileaflet mechanical prostheses (St. Jude Medical
      and CarboMedics: sizes, 19 mm and 21 mm) and two biological prostheses (Medtronic
      Intact and St. Jude BioImplant: size, 21 mm) were evaluated. A graded infusion of
      dobutamine was given and Doppler studies of valve performance were carried out.
      RESULTS: All prostheses except one biological valve had acceptable hemodynamic
      performance under stress. Using regression modeling, gradient at rest was the
      only variable found to predict gradient under stress (p < 0.001). Moreover, the
      most important predictor of gradient at rest was valve design, which accounted
      for 72% of the variance (p < 0.001). This relationship was independent of valve
      size (19 mm or 21 mm) or material (ie, mechanical or biological). Body surface
      area accounted for 4% of the variance in gradient only. CONCLUSIONS: The main
      predictor of transprosthetic gradient is the inherent characteristics of each
      particular prosthesis, with relatively insignificant contribution from variations
      in body surface area. Patient-prosthesis mismatch is not a problem of clinical
      significance when certain modern valve prostheses are used.

PMID- 10585039
TI  - Inhibitory effect of milrinone on cytokine production after cardiopulmonary
      bypass.
AB  - BACKGROUND: It has been suggested that cyclic adenosine monophosphate-elevating
      agents suppress cytokine production. To evaluate the effects of milrinone, a
      phosphodiesterase III inhibitor, on cytokine production after cardiopulmonary
      bypass, we conducted a prospective randomized study. METHODS: Twenty-four
      patients undergoing coronary artery bypass grafting were randomized to receive
      either milrinone treatment (milrinone, n = 12) or no milrinone treatment
      (control, n = 12). Administration of milrinone (0.5 microg x kg(-1) x min(-1))
      was started after induction of anesthesia and was continued for 24 hours. Blood
      samples for determination of plasma cyclic adenosine monophosphate, tumor
      necrosis factor-alpha, interleukin-1beta, interleukin-6, and interleukin-8 levels
      were collected perioperatively. RESULTS: No significant differences were observed
      in tumor necrosis factor-alpha and interleukin-8 levels between the groups.
      Interleukin-1beta and interleukin-6 levels after cardiopulmonary bypass were
      significantly (p < 0.05) lower in the milrinone group than in the control group.
      Plasma levels of cyclic adenosine monophosphate increased significantly (p <
      0.05) after the administration of milrinone and the levels correlated inversely
      (r = -0.55, p < 0.01) with interleukin-6 levels. CONCLUSIONS: The results
      indicate that milrinone suppresses cytokine production by elevating cyclic
      adenosine monophosphate levels in patients undergoing cardiopulmonary bypass.
      With its positive inotropic and vasodilator activities, milrinone may have
      antiinflammatory effects.

PMID- 10585040
TI  - Acute descending aortomyoplasty induces coronary blood flow augmentation.
AB  - BACKGROUND: Aortomyoplasty is a procedure aimed to improve cardiac output in
      patients suffering from heart failure. Stimulation of the latissimus dorsi muscle
      around the aorta produces hemodynamic effects similar to those of the intraaortic
      balloon pump. These may be maintained without the accompanying complications or
      the need for anticoagulation. The objective of this study was to test the acute
      effects of aortomyoplasty on coronary artery blood flow. METHODS: Eight mongrel
      dogs (18 to 30 kg) underwent acute descending aortomyoplasty. Several stimulation
      protocols were applied after wrapping of the latissimus dorsi muscle around the
      aorta in different surgical configurations. The left anterior descending coronary
      blood flow was measured using a transonic Doppler flow probe. Left ventricular
      and aortic pressures, proximal and distal to the aortomyoplasty site, were
      monitored continuously. RESULTS: Significant aortic diastolic pressure
      augmentation was expressed both as an increase in peak values, from 110 +/- 24 mm
      Hg to 120 +/- 24 mm Hg (p < 0.001) and as an increase in the diastolic integral,
      from 64 +/- 23 mm Hg x s to 84 +/- 37 mm Hg x s (p < 0.001). Concomitantly, peak
      left anterior descending coronary blood flow increased from 26 +/- 10 mL/min to
      32 +/- 12 mL/min (p < 0.001). This was associated with an increase in the
      diastolic flow integral from 11 +/- 4 mL to 14 +/- 6 mL (p < 0.001). CONCLUSIONS:
      Descending aortomyoplasty induces significant augmentation of coronary blood
      flow. Optimal timing of muscle stimulation is important in achieving the best
      assist. This procedure may prove beneficial for end-stage ischemic patients.

PMID- 10585041
TI  - Reoperations on the ascending aorta and aortic root: pitfalls and results in 134
      patients.
AB  - BACKGROUND: This analysis was performed to evaluate the results of reoperations
      on the ascending aorta and aortic root. METHODS: All reoperations (n = 134) on
      the aortic root and ascending aorta performed between February 1981 and April
      1998 were retrospectively analyzed. Indications for reintervention were a true or
      false aneurysm (35%), acute dissection (3.0%), aortic valve stenosis and/or
      insufficiency (23.1%), prosthetic valve endocarditis (32.8%), and combinations
      (4.5%). The principal reoperations performed were aortic root replacement
      (composite graft, freestyle, aortic allograft, or pulmonary autograft) in 116
      patients, ascending aortic replacement in 10 patients, and closure of a false
      aneurysm in 5 patients. Results were analyzed using univariate statistical
      methods. RESULTS: Hospital mortality was 6.6% (8 patients). Univariate predictors
      of hospital death were preoperative functional class III or IV (p = 0.02), an
      interval of less than 6 months between the primary and actual operation (p =
      0.02), preoperative creatinine level of more than 200 micromol/L (p = 0.001),
      acute aortic dissection (p = 0.001), intraoperative technical problems (p =
      0.001), and postoperative dialysis (p = 0.001). Freedom from repetitive
      reoperation was 99% at 1 year and 98% at 5 and 10 years. CONCLUSIONS:
      Reoperations on the aortic root and ascending aorta can be performed with an
      early mortality which is very acceptable.

PMID- 10585042
TI  - Antegrade/retrograde cardioplegia for valve replacement: a prospective study.
AB  - BACKGROUND: From 1994 to 1996, 75 patients undergoing valve replacement were
      randomized to antegrade (36 patients, group 1) or antegrade/retrograde (39
      patients, group 2) administration of cold blood cardioplegia. METHODS: Groups
      were comparable for age, sex, valve disease, and ventricular dysfunction. The
      aortic valve was replaced in 27 patients from group 1 and 24 patients from group
      2, the mitral valve in 8 and 15 patients, and 1 patient in group 1 underwent
      double valve replacement (p = not significant). RESULTS: Lengths of
      cardiopulmonary bypass and aortic cross-clamp averaged, respectively, 10 minutes
      (p = not significant) and 12 minutes (p = < 0.05) shorter in group 2. Total
      amount of cardioplegia solution infused averaged 1,279 +/- 406 mL and 1,341 +/-
      379 mL (p = not significant), respectively, in groups 1 and 2, and the period of
      infusion averaged 44% and 72% (p = < 0.01) of the total period of aortic cross
      clamping. No death occurred in group 1 compared to two in group 2 (p = not
      significant). The perioperative myocardial infarction and stroke rates were
      comparable in both groups. Peak enzyme release at 24 hours was similar both for
      creatine kinase-MB fraction (26 versus 37 IU/L) and for troponin T (2.1 versus
      2.5 IU/L). CONCLUSIONS: Our study shows no significant advantage of the
      antegrade/retrograde administration of cardioplegia over the antegrade route in
      routine valvular replacement, other than a slightly shorter aortic cross-clamping
      time.

PMID- 10585043
TI  - Partial tricuspid valve transfer for repair of mitral insufficiency due to
      ruptured chordae tendineae.
AB  - BACKGROUND: A new technique is suggested for the reconstructive surgical
      treatment of mitral regurgitation. It involves partial transfer of the tricuspid
      valve of the patient to the mitral valve, in order to provide chordae to correct
      anterior leaflet prolapse of the mitral valve, secondary to rupture of the
      chordae tendineae. METHODS: From January 1991 to May 1997, 20 patients with
      mitral insufficiency due to rupture of the chordae were operated on. The
      prevailing cause was myxomatous degeneration (70%). Patients were in New York
      Heart Association functional class III and IV. RESULTS: There were no hospital
      deaths. Two patients were reoperated on. Eighteen patients (90%) are alive with
      their own valves (class I and II). Doppler echocardiogram mean values were:
      ejection fraction, 0.65; left atrial diameter, 4.2 cm; mitral area, 2.4 cm2;
      mitral transvalvular gradient, 3.3 mm Hg. No regurgitation or mild regurgitation
      was observed in 16 (94.1%) of the 17 cases evaluated. Mean tricuspid valvular
      area was 3.3 cm2. In all cases, no tricuspid regurgitation was present or it was
      mild. CONCLUSIONS: Partial transfer of the tricuspid valve to the mitral valve is
      an effective procedure for the surgical treatment of mitral valve insufficiency
      secondary to ruptured chordae tendineae of the anterior leaflet.

PMID- 10585044
TI  - Long-term survival and functional follow-up in patients after the arterial switch
      operation.
AB  - BACKGROUND: For many years, the arterial switch operation (ASO) has been the
      therapy of choice for patients with transposition of the great arteries (TGA).
      Although excellent short- and mid-term results were reported, long-term results
      are rare. METHODS: Between May 1983 and September 1997, ASO was performed on 285
      patients with simple TGA (n = 171), TGA with ventricular septal defect (VSD) (n =
      85), and Taussig-Bing (TB) anomaly (n = 29). This retrospective study describes
      long-term morbidity and mortality over a 15-year period. RESULTS: Hospital
      mortality was 3.5% for simple TGA, 9.4% for TGA with VSD, and 13.8% for TB
      anomaly. Late death occured in 2 patients, 1 with simple TGA and 1 with TGA and
      VSD. The cumulative survival for all patients at 5 and 10 years is 93%, and at 15
      years is 86%. Reoperations were required in 31 patients and were most common for
      stenosis of the right ventricular outflow tract (RVOT). However, no correlation
      was found between technical variations on pulmonary artery reconstruction and
      this type of complication. Forty-six patients underwent follow-up angiography,
      which revealed five cases with coronary occlusion or stenosis. Follow-up is
      complete in 96% of the patients from 1 to 15.2 years. Sinus rhythm is present in
      97%; 88% of the patients show no limitations on exertion. CONCLUSIONS: The ASO
      can be performed with low early mortality, almost absent late mortality, and
      infrequent need for reoperation. The favorable long-term results demonstrate that
      the ASO can be considered as the optimal approach for patients with TGA and
      special forms of double-outlet right ventricle.

PMID- 10585045
TI  - Modified Fontan without use of cardiopulmonary bypass.
AB  - BACKGROUND: Direct cavopulmonary connection using an extracardiac conduit has a
      number of theoretical advantages in the staged management of children with single
      ventricular congenital heart defects. With appropriate planning, completion
      Fontan using an extracardiac connection may be accomplished without the use of
      cardiopulmonary bypass. METHODS: From January 1995 to October 1997, 32
      consecutive patients underwent completion Fontan using an extracardiac
      cavopulmonary connection. Twenty-one of these patients had completion Fontan
      without the use of cardiopulmonary bypass (No CPB group). Their postoperative
      outcome was retrospectively compared with a second group of 11 patients who
      underwent completion Fontan with an extracardiac conduit with the use of
      cardiopulmonary bypass. RESULTS: There was no operative or hospital mortality in
      either group. Early postoperative hemodynamics appear to be significantly
      improved in the No CPB group. Transfusion of cryoprecipitate and platelets was
      significantly less in the group without the use of cardiopulmonary bypass (p =
      0.026, p < 0.001, respectively). Review of the most recent 12 patients also
      demonstrated a substantially shorter extubation time and intensive care unit
      stay. The length of hospital stay was significantly shorter (p = 0.036).
      CONCLUSIONS: Completion Fontan without the use of cardiopulmonary bypass results
      in improved immediate postoperative hemodynamics, and decreased use of blood and
      blood products. The most recent group appears to demonstrate a more rapid
      recovery time and shorter hospital stay (p = 0.036).

PMID- 10585046
TI  - Significant intraoperative right ventricular outflow gradients after repair for
      tetralogy of Fallot: to revise or not to revise?
AB  - BACKGROUND: This study was performed to define alternative parameters for the
      management of intraoperative residual right ventricular outflow obstruction
      (RVOTO) after transatrial repair of tetralogy of Fallot (ToF) in order to
      differentiate those requiring immediate revision from those who do not. METHODS:
      Since October 1995, 166 patients of ToF underwent transatrial repair. Postbypass
      residual RVOTO was assessed by surgeon's subjective impression, direct
      intracardiac pressure measurements, and intraoperative echocardiography (IOE).
      RVOTO was labeled "significant" whenever it exceeded a gradient of 40 mm Hg on
      IOE or right ventricular to left ventricular pressure ratio (pRV/LV) exceeded
      0.85. Further, on IOE, significant RVOTO was defined "fixed", if there was no
      change in RVOT dimensions during the cardiac cycle, along with the presence of
      anatomic substrate for obstruction, and "dynamic" if RVOT dimensions increased
      appreciably in diastole. Postoperative course and follow-up echocardiograms of
      all patients were analyzed. RESULTS: Significant RVOTO was detected in 58 (35%)
      patients (mean gradient 54 mm Hg). Seven (12%) of them with fixed obstruction
      (mean 46 mm Hg) underwent immediate surgical revision, while the remaining 51
      patients with mean gradient of 78 mm Hg (including 10 patients with pRV/LV ratio
      of > or = 1.0) with dynamic obstruction did not undergo revision. There were six
      (3.6%) early deaths. Operative mortality and postoperative morbidity were not
      related to higher residual gradients, although the first 15 such patients had
      longer intensive care stay and inotropic support, in which this was done
      electively. On follow-up (mean 18.5 months), outflow gradients declined sharply
      (mean 16 mm Hg) irrespective of the severity of intraoperative gradients (p <
      0.001). There were no reoperations or late deaths. CONCLUSIONS: This study shows
      that: 1) existing parameters for immediate revision of residual RVOTO possibly
      need to be reviewed; 2) intraoperative echocardiography helps in differentiating
      "fixed" from "dynamic" obstruction and helps obviate needless revisions; and 3)
      dynamic RVOT gradients decline significantly irrespective of their severity after
      transatrial repair of ToF.

PMID- 10585048
TI  - Left ventricular outflow tract obstruction after partial atrioventricular septal
      defect repair.
AB  - BACKGROUND: Narrowing of the left ventricular outflow tract has been associated
      with partial atrioventricular septal defect (PAVSD) in about 3% of patients.
      Because of the predisposing anatomy, hemodynamically significant obstruction in
      the subaortic area may appear after repair of ostium primum atrial septal
      defects. METHODS: From 1984 to 1998, 40 patients underwent surgical correction of
      PAVSD by patch closure. The mean age at the initial repair was 5.8 years (range 3
      months to 22 years). RESULTS: Nine patients had 12 subsequent operations for
      hemodynamically significant subaortic obstruction. The mean age at PAVSD repair
      was 17 months (3 to 42 months) (p < 0.001 compared with others). Follow-up work
      up was obtained due to symptoms in 5 patients and an abnormal echocardiogram in 4
      asymptomatic patients. Subaortic stenosis developed at a mean of 5 years (range 4
      months to 10 years), and 6 or more years in 4 patients. The mean age at subaortic
      stenosis repair was 6 years (range 2 to 12 years). Nine patients underwent
      subaortic fibromuscular resection. Of these, 4 developed recurrent stenosis and 2
      have undergone additional operations. CONCLUSIONS: Left ventricular outflow tract
      obstruction after PAVSD repair may be more frequent than reported. Because of the
      progressive nature of the process, echocardiography should be utilized liberally
      on patients to uncover subclinical stenosis. Long-term follow-up is essential for
      diagnosis due to delayed appearance and lack of reliable clinical signs.

PMID- 10585047
TI  - Bosentan prevents hypoxia-reoxygenation-induced pulmonary hypertension and
      improves pulmonary function.
AB  - BACKGROUND: Acute hypoxia results in increased pulmonary vascular resistance.
      Despite reoxygenation, pulmonary vascular resistance remains elevated and
      pulmonary function is altered. Endothelin-1 might contribute to hypoxia
      reoxygenation-induced pulmonary hypertension and to reoxygenation injury by
      stimulating leukocytes. This study was carried out using an established model of
      hypoxia and reoxygenation to determine whether endothelin-1 blockade with
      Bosentan could prevent hypoxia-reoxygenation-induced pulmonary hypertension and
      reoxygenation injury. METHODS: Twenty neonatal piglets underwent 90 minutes of
      hypoxia, 60 minutes of reoxygenation on cardiopulmonary bypass, and 2 hours of
      recovery. Control animals (n = 12) received no drug treatment, whereas the
      treatment group (n = 8) received the endothelin-1 receptor antagonist, Bosentan,
      throughout hypoxia. RESULTS: In controls, pulmonary vascular resistance increased
      during hypoxia to 491% of baseline and remained elevated after reoxygenation;
      however in the Bosentan group, it increased to only 160% of baseline by end
      hypoxia, then decreased to 76% at end-recovery. Arterial endothelin-1 levels in
      controls increased to 591% of baseline after reoxygenation. Arterial nitrite
      levels decreased during hypoxia in controls but were maintained in the Bosentan
      group. Consequently, animals in the Bosentan group had better postreoxygenation
      pulmonary vascular resistance, A-a gradient, and airway resistance along with
      lower myeloperoxidase levels than controls. CONCLUSIONS: Acute hypoxia and
      postreoxygenation pulmonary hypertension was attenuated by Bosentan, which
      maintained nitric oxide levels during hypoxia, decreased leukocyte-mediated
      injury, and improved pulmonary function.

PMID- 10585049
TI  - Commissuroplasty: a method of valve repair for mitral and tricuspid endocarditis.
AB  - BACKGROUND: We describe our experience with a technique of cusp commissuroplasty
      to reconstruct atrioventricular valves damaged by endocarditis of the commissure
      and adjacent cusps. METHODS: We operated on 3 patients with mitral endocarditis
      and one patient with previous tricuspid endocarditis. Infected leaflet tissue was
      excised from each side of the commissure, leaving a defect between one quarter
      and one third of the valve area. Using the technique of valve commissuroplasty,
      leaflet remnants were reapposed at the cut edges to obliterate the commissure.
      The residual D-shaped defect between the apposed leaflets and annulus was either
      closed directly or patched with pericardium, depending on the size of the defect.
      RESULTS: Constructing unicommissural mitral and bicuspid tricuspid valves
      restored leaflet continuity. One patient was lost to follow-up. Postoperative
      echocardiography performed at a mean interval of 14.7 months showed competent and
      nonobstructed valves. There was no recurrent endocarditis at a mean follow-up
      time of 15.7 months. CONCLUSIONS: The technique of cusp commissuroplasty can be
      used to reconstruct atrioventricular valves that have been damaged by
      endocarditis of the commissure and adjacent cusps.

PMID- 10585050
TI  - Redirection of hepatic venous drainage after total cavopulmonary shunt in left
      isomerism.
AB  - BACKGROUND: Conversion from total cavopulmonary shunt (TCPS) to the Fontan
      circulation can improve cyanosis in patients with potential risks of development
      of pulmonary arteriovenous fistula (PAVF). METHODS: Inclusion of the hepatic
      veins in the pulmonary circulation was employed using an intra-atrial tube graft
      in 5 patients with left isomerism previously undergoing TCPS. Prior to the
      conversion, abnormal communication was identified between the azygos vein and
      either the hepatic or the portal vein in all. PAVF was seen in 3. RESULTS: All
      patients survived the procedure. Postoperative catheterization showed 13 +/- 2 mm
      Hg of superior caval venous pressure, and 2.3 +/- 0.4 L/min/m2 of cardiac index.
      Pulmonary arteriovenous fistula progressed markedly in the right lung even after
      the conversion in 2 patients, in whom the hepatic veins had been exclusively
      diverted to the left lung. Arterial oxygen saturation became below 65%, with
      exercise capacity reduced, in these 2 patients. The other patients remain
      asymptomatic. CONCLUSIONS: Total cavopulmonary shunt can be efficiently converted
      to the Fontan circulation by appropriately redirecting hepatic venous drainage to
      perfuse both lungs in a balanced fashion.

PMID- 10585051
TI  - Myocardial self-preservative effect of heat shock protein 70 on an immature lamb
      heart.
AB  - BACKGROUND: Heat shock proteins have been shown to enhance myocardial tolerance
      of ischemia-reperfusion injury and are induced in the myocardium of many animals
      by various stressors. METHODS: To assess the effects and time course of the
      inducible form of heat shock protein 70, we raised the rectal temperature of 15
      neonatal lambs to 43 degrees C for 15 minutes. At 15, 30, 60, and 120 minutes and
      24 hours after heat shock, hearts were subjected to immunoblot analysis for heat
      shock protein (hsp 72/73). Twenty-four hours after heat shock, neonatal lamb
      hearts (n = 8) were subjected to 2 hours of cold cardioplegic ischemia (HSP
      group). Eight neonatal lamb hearts without heat shock served as control. After 60
      minutes of reperfusion, left ventricular systolic and diastolic function,
      coronary blood flow (CBF), myocardial oxygen consumption (MVO2), and lactate
      levels were measured. Endothelial function was assessed by measuring in situ
      coronary vascular resistance response to acetylcholine and trinitroglycerine.
      RESULTS: The HSP group showed a significantly higher recovery of systolic
      function as well as MVO, and a lower lactate level compared to the control group
      at 60 minutes after reperfusion. Recovery of coronary endothelial function was
      also significantly better in the HSP group than in the control group. Inducible
      form of HSP 70 was expressed 15 minutes after heat shock and continued to be
      observed at 24 hours after the stress. CONCLUSIONS: Heat shock stress associated
      with the production of inducible heat shock proteins improved the recovery of
      ventricular function as well as endothelial function and aerobic metabolism after
      hypothermic cardioplegic ischemia. Induction of heat shock proteins by any means
      prior to planned hypothermic ischemia may lead to a new approach for myocardial
      protection.

PMID- 10585052
TI  - Minimally invasive surgery with cardioscopy for congenital heart defects.
AB  - BACKGROUND: Minimally invasive cardiac surgery remains a burgeoning discipline
      lacking adequate instrumentation and perfusion circuitry, particularly for the
      pediatric population. Cardioscopy, utilizing first generation imaging equipment
      with a variety of different angled lenses, provides a unique opportunity to
      expand the realm for the diagnosis and treatment of congenital heart disease.
      METHODS: Sixty-eight children with a mean weight of 23 +/- 11 kg (range 8-62 kg)
      who underwent repair of atrial septal defects (ASD) using a minimally invasive
      approach (MINI group) were compared to 25 consecutive children undergoing ASD
      repair via a full median sternotomy (CONT group). In addition, mini-sternotomy
      with or without cardioscopy allowed for the diagnosis and treatment of more
      complex congenital lesions in 24 children. RESULTS: The mean age in the MINI
      group was 7 +/- 3 years (range 1-15 years) compared to 4 +/- 4 years in the CONT
      group (p = 0.009). The mean body surface area of the MINI group (0.8 +/- 0.2 m2;
      range 0.4-1.6 m2) was larger than the CONT group (mean 0.6 +/- 0.3 m2; range 0.2
      1.6 m2; p = 0.04). Ischemic times and cardiopulmonary bypass times were similar
      in both groups. Postoperative hospital stay was shorter in the MINI group (3 +/-
      2 versus 4 +/- 1 days; p = 0.014). CONCLUSIONS: Minimally invasive cardiac
      surgery can be performed safely even in small children with congenital heart
      defects. In addition to improved cosmetic results, these techniques can reduce
      the utilization of hospital resources. Future advances in cardioscopic technology
      should permit minimally invasive repair of most complex congenital heart lesions
      and should obviate the need for full sternotomy in the majority of children
      undergoing cardiac surgery.

PMID- 10585053
TI  - Left atrioventricular valve repair technique in partial atrioventricular septal
      defects.
AB  - BACKGROUND: The aim of our study was to evaluate the effect of chordal transfer
      around the cleft on left atrioventricular valve competence in the late
      postoperative period. METHODS: Forty-four adult patients underwent surgical
      correction of partial atrioventricular septal defect between 1983 and 1997.
      Fenestration was found in 8 patients (18.2%) and cleft, in 35 (79.5%). There was
      no chordal support of the free edges of the left superior and left inferior
      leaflets around the cleft in 18 patients. Two chordae were mobilized from the
      left lateral leaflet and reimplanted into the tip of the left superior and left
      inferior leaflets around the cleft. RESULTS: At 5 years postoperatively, left
      atrioventricular valve insufficiency was severe in 5 patients and moderate in 11
      patients who had had cleft closure alone. In contrast, severe valvular
      insufficiency was present in only 1 patient in the group with chordal transfer (p
      < 0.05). Reoperation was done in 5 patients with isolated cleft closure. Left AV
      valve replacement was performed in 1 patient. CONCLUSIONS: Chordal transfer plus
      cleft closure with interrupted sutures significantly reduces early and late left
      atrioventricular valve incompetence and also decreases the rate of reoperation.

PMID- 10585054
TI  - IL-6 and IL-8 levels after cardiopulmonary bypass are not affected by surface
      coating.
AB  - BACKGROUND.:Contact of blood with the surfaces of the cardiopulmonary bypass
      (CPB) circuit has been implicated as a cause of the inflammatory response. We
      undertook a prospective randomized trial of 200 pediatric patients, all with a
      calculated total bypass flow of less than 2.3 L/min (< 0.96 L/m2/min). METHODS:
      Patients were randomly assigned to 1 of 4 CPB groups: (1) Nonheparin-bonded
      circuit with no albumin preprime; (2) Nonheparin-bonded circuit with albumin
      preprime; (3) Heparin-bonded circuit with no albumin preprime; (4) Heparin-bonded
      circuit with albumin preprime. Measurements of cytokines, (interleukin [IL]-6, IL
      8) and blood cell counts were made prebypass and 6 and 24 hours after institution
      of cardiopulmonary bypass. RESULTS: Analysis of variance showed no significant
      difference in any of the clinical or biochemical characteristics of the 4 groups.
      The interaction between heparin-bonded oxygenators and albumin preprime was not
      significant. No important differences in IL-6 or IL-8 concentrations were noted
      after CPB using either heparin or nonheparin-bonded oxygenators with albumin or
      albumin free preprime using two-way analysis of variance. CONCLUSIONS: Albumin
      preprime and heparin-bonding do not attenuate the inflammatory response component
      attributable to the concentration of these markers.

PMID- 10585056
TI  - Photodynamic therapy for esophageal lesions: selectivity depends on wavelength,
      power, and light dose.
AB  - BACKGROUND: Photodynamic therapy with 5-aminolevulinic acid-induced
      photosensitization could selectively eliminate esophageal epithelial lesions.
      This study aimed at optimizing laser parameters for 5-aminolevulinic acid
      photodynamic therapy of the normal rat esophagus. METHODS: Sixty rats received
      200 mg/kg 5-aminolevulinic acid orally and were illuminated 3 hours later with
      either 633 or 532 nm light (n = 30 for each group) through an endoesophageal
      balloon catheter. Rats received either 8.3 or 25 J/cm diffuser, applied with a
      33, 100, or 300 mW/cm diffuser. During illumination, tissue fluorescence
      measurements and light dosimetry were done. Rats were sacrificed at 48 hours
      after photodynamic therapy. RESULTS: During illumination, protoporphyrin IX
      fluorescence declined faster when a higher power output was used. Fluence rate at
      the esophageal surface was highest for 633-nm light. At 532 nm, light caused less
      damage to the epithelium and muscle than 633-nm light. Illumination with 33 mW
      resulted in selective epithelial ablation, whereas illumination with 300 mW
      caused muscle damage with minor epithelial damage. CONCLUSIONS: The assumed
      selective epithelial damage of 5-aminolevulinic acid photodynamic therapy in the
      esophagus largely depends on the combination of wavelength, power, and light dose
      applied. Most selective epithelial damage was found when low-power 633-nm light
      was used.

PMID- 10585055
TI  - Oncolytic therapy using a mutant type-1 herpes simplex virus and the role of the
      immune system.
AB  - BACKGROUND: Herpes simplex virus (HSV)-1716, a replication-restricted herpes
      simplex virus type 1, has shown efficacy as an oncolytic treatment for central
      nervous system tumors, breast cancer, ovarian cancer, and malignant mesothelioma.
      We evaluated the efficacy of HSV-1716 in a murine lung cancer model, Lewis lung
      carcinoma. METHODS: Lewis lung carcinoma cells were infected with HSV-1716 and
      implanted in the flanks of mice at varying ratios of infected to uninfected
      cells. Tumor burden was assessed by measurement of the weight of the tumor
      nodule. The role of the immune system was examined by performing experiments in
      both immunocompetent and SCID mice. Tumors were implanted in the opposite flank
      to evaluate the vaccine effect. RESULTS: In immunocompetent and SCID animals,
      ratio of 1:10 (infected-to-uninfected) cells completely prevented tumor formation
      and ratio of 1:100 suppressed tumor growth. Established tumors at a distant site
      in the groups receiving HSV-1716 infected cells showed no difference in size
      versus control, suggesting absence of a vaccine effect. CONCLUSIONS: We conclude
      that HSV-1716 may provide a oncolytic therapy for lung cancer even in the absence
      of immune system induction and a "carrier" cell could potentially deliver this
      vector.

PMID- 10585057
TI  - Reoperative pulmonary thromboendarterectomy.
AB  - BACKGROUND: Recurrent symptomatic pulmonary hypertension is uncommon after
      primary pulmonary thromboendarterectomy (PTE). We reviewed our experience with
      patients undergoing repeat PTE to determine the risk factors for recurrent
      disease, and the selection criteria, relative risks, and functional outcomes of
      reoperative PTE. METHODS: Since 1990, 13 of 870 (1.5%) patients underwent
      reoperative PTE at our institution. These 7 men and 6 women (mean age 38.6 years)
      were contrasted with the most recent 225 patients (111 men, 114 women, mean age
      52.7 years) who underwent primary PTE for whom complete hemodynamic data are
      available. The preoperative evaluation of all patients was similar. Pulmonary
      hemodynamic data and outcome measures were compared between groups. RESULTS: Of
      13 reoperated patients: 69% (9/13) had their primary operation at another
      institution, 54% (7/13) initially underwent unilateral PTE, 38% (5/13) had
      identifiable coagulation disorders, 38% (5/13) had ineffective caval filtration,
      31% (4/13) had suboptimal anticoagulation management, and 31% (4/13) had complete
      unilateral pulmonary artery obstruction. The mean interval to reoperation was 5.2
      years (range 0.7 to 10.9 years). All control patients underwent bilateral PTE
      using hypothermic circulatory arrest. Operative mortality was 7.7% (1/13) with
      reoperation vs 8.4% (19/225) in controls. No difference (p = NS) was observed
      between groups in the preoperative pulmonary artery pressure (PAP) or pulmonary
      vascular resistance; however, the control group had a significantly (p < 0.05)
      greater reduction in the postoperative PAP (46/19, mean 28 mm Hg vs 59/23, mean
      35 mm Hg) and PVR (271 +/- 172 vs 399 +/- 154 dynes/s/cm(-5)) compared with the
      redo group. No substantial difference in morbidity or functional outcomes was
      observed between groups. CONCLUSIONS: Reoperative PTE can be performed with a
      perioperative risk comparable with primary PTE, although the improvement in
      pulmonary hemodynamics is not as favorable. Bilateral primary operation,
      effective caval filtration, and vigilant anticoagulant management would prevent
      the need for most reoperative PTEs.

PMID- 10585058
TI  - A multidisciplinary surgical approach to superior sulcus tumors with vertebral
      invasion.
AB  - BACKGROUND: Vertebral body invasion by superior sulcus tumor has traditionally
      been considered a contraindication to surgical resection. Attempts at definitive
      radiation or chemoradiation have not been successful. Recent advances in spinal
      instrumentation have allowed more complete resection of vertebral body tumors.
      We, therefore, reviewed our recent experience with vertebral resection of
      superior sulcus tumors. METHODS: All patients (n = 17) undergoing resection of
      superior sulcus tumors with T4 involvement of the vertebrae from October 18, 1990
      to September 21, 1998 at the University of Texas M.D. Anderson Cancer Center
      (MDACC) were evaluated. Their clinical and pathologic data were reviewed and
      analyzed for short- and long-term outcomes. RESULTS: Total vertebrectomy was
      performed in 7 patients (42%), partial vertebrectomy in 7 (42%), and 3 (18%)
      underwent neural foramina or transverse process resection. The median hospital
      stay was 11 days. Postoperative complications occurred in 7 patients (42%) and
      included pneumonia (6, 36%), arrhythmia (2, 12%), cerebrospinal fluid leak (2,
      12%), wound breakdown (1, 6%), and reoperation for bleeding (1, 6%). Sixteen out
      of 17 patients received preoperative or postoperative radiation therapy. No
      perioperative mortality occurred. All patients remained ambulatory after spinal
      reconstruction. Overall actuarial survival at 2 years was 54%, with 11 patients
      still alive 2 to 50 months after resection. Locoregional tumor recurrence was
      noted in all 6 patients who had positive surgical margins, as opposed to 1 out of
      11 patients (9%) with negative margins (p < 0.006). Additionally, the 2-year
      actuarial survival of patients with negative microscopic margins was 80% versus
      0% for positive margins (p < 0.0006). CONCLUSIONS: An aggressive
      multidisciplinary approach to superior sulcus tumors with vertebral invasion can
      lead to long-term survival with acceptable morbidity if negative margins can be
      obtained. Vertebral body invasion should no longer be considered a
      contraindication for resection of superior sulcus tumors.

PMID- 10585059
TI  - Cognitive decline after major noncardiac operations: a preliminary prospective
      study.
AB  - BACKGROUND: Cardiac operations frequently are complicated by postoperative
      cognitive decline. Less common and less studied is postoperative cognitive
      decline after noncardiac surgery, so we determined its incidence, severity, and
      possible predictors. METHODS: Twenty-nine patients who had thoracic and vascular
      procedures were studied. A neurocognitive test battery was administered
      preoperatively and 6 to 12 weeks postoperatively. A change score (preoperative
      minus postoperative) was calculated for each measure in each individual.
      Cognitive deficit (a measure of incidence) was defined as a 20% decrement in 20%
      or more of the completed tests. The average scores of all tests and the average
      decline (a measure of severity) were determined. RESULTS: The incidence of
      cognitive deficit was 44.8%. Overall the severity of the decline was an average
      of 15% decline. In the 44.8% of patients who had cognitive deficit, the severity
      was 24.7%. Multivariable predictors of cognitive decline were age (for incidence
      and severity) and years of education (for severity). CONCLUSIONS: Cognitive
      decline after noncardiac operations is a frequent complication of surgical
      procedures. The severity could preclude successful return to a preoperative
      lifestyle.

PMID- 10585060
TI  - Two years' outcome of lung volume reduction surgery in different morphologic
      emphysema types.
AB  - BACKGROUND: Lung volume reduction surgery (LVRS) improves dyspnea, pulmonary
      function, and quality of life in selected patients with severe emphysema. We
      investigated the role of emphysema morphology in 37 patients as an outcome
      predictor for up to 2 years after operation. METHODS: Patients selected for
      bilateral thoracoscopic LVRS were divided, according to a simplified emphysema
      morphology classification, into three groups (homogeneous, moderately
      heterogeneous, and markedly heterogeneous) based on a preoperative chest computed
      tomogram. Pulmonary function, walking distance, and dyspnea were assessed.
      RESULTS: Functional improvement after LVRS was best in markedly heterogeneous
      emphysema with an increase from preoperative forced expiratory volume in 1 second
      of 31% +/- 2% (mean +/- standard error of the mean) to 52% +/- 4% of predicted
      postoperatively. It was significantly higher than in homogeneous emphysema (from
      26% +/- 1% to 38% +/- 2% predicted) and in intermediately heterogeneous emphysema
      (from 29% +/- 2% to 44% +/- 45% predicted). At 24 months postoperatively, forced
      expiratory volume in 1 second and dyspnea score continued to be significantly
      better than preoperative levels in all three morphologic groups. The survival
      rate was highest in patients with markedly heterogeneous emphysema. CONCLUSIONS:
      Functional and subjective improvements were maintained after LVRS for at least 24
      months in patients with heterogeneous or homogeneous emphysema type.

PMID- 10585061
TI  - Important prognostic factors in patients with malignant pleural mesothelioma,
      managed surgically.
AB  - BACKGROUND: The factors influencing outcome after resection of malignant pleural
      mesothelioma (MPM) are controversial. This analysis of a prospective surgical
      database identifies important prognostic factors. METHODS: Tumors were staged by
      the International Mesothelioma Interest Group staging system, and patients were
      followed until death. Prognostic factors were analyzed by log rank and Cox
      regression, and were considered significant if p was less than 0.05. RESULTS:
      From Oct 1983 to May 1998, 231 patients underwent thoracotomy, 115 had
      extrapleural pneumonectomy (EPP), and 59 pleurectomy/decortication (P/D). Among
      patients having EPP or P/D, 142 received adjuvant therapy. The median survival
      for stage I tumors was 29.9 months, for stage II 19 months, for stage III 10.4
      months, and for stage IV 8 months. By multivariate analysis, stage, histology,
      gender, adjuvant therapy, but not the type of surgical resection, were
      significant. CONCLUSIONS: The better survival previously reported for P/D
      compared with EPP is not seen in a large database with long follow-up. Stages I
      and II have better survival rates than generally assumed for MPM. Locally
      advanced T and N status, and nonepithelial histology, identify poor prognosis
      patients who should be considered for novel treatment regimens.

PMID- 10585062
TI  - Ex vivo transfection of pulmonary artery segments in lung isografts.
AB  - BACKGROUND: Gene transfer to lung grafts may be useful in ameliorating ischemia
      reperfusion injury and rejection. Proximal pulmonary artery endothelial
      transfection may provide beneficial downstream effects on the whole lung graft.
      We have already demonstrated the feasibility of in vivo and ex vivo transfection
      in proximal pulmonary artery segments of rat lung grafts. The aim of this study
      was to determine the optimal conditions for and duration of transfection.
      METHODS: Orthotopic left lung transplantation was performed in F344 rats after
      donor lung proximal pulmonary artery segments were isolated and injected with
      lipid 67/DOPE-chloramphenicol acetyl transferase (CAT) complementary
      deoxyribonucleic acid construct. Effect of exposure time was studied by exposing
      donor pulmonary artery segments to the construct for 0, 30, and 60 minutes prior
      to transplantation. In another series of experiments, pulmonary artery segments
      were exposed to the construct for 60 minutes prior to transplantation. Onset and
      duration of gene expression were determined after sacrificing animals at 3, 6,
      12, and 24 hours and 3 days as well as 1 week, 2, 4, and 8 weeks after
      transplantation. Effect of exposure temperature was studied by exposing pulmonary
      artery segments to the construct for 60 minutes at 4 degrees, 10 degrees, and 23
      degrees C. These recipients were sacrificed on postoperative day 3. Effect of
      exposure pressure was studied by using two volumes of the construct (0.01 and
      0.03 mL). These recipients were sacrificed on postoperative day 3. Transgene
      expression was assessed by chloramphenicol acetyl transferase activity assay.
      RESULTS: Transgene expression was similar after 30- and 60-minute exposure.
      Transgene expression was evident within 3 to 6 hours after operation and
      persisted at 8 weeks after operation. Expression was detected at all temperatures
      and was equivalent at both exposure pressures. CONCLUSIONS: Gene transfection
      into graft pulmonary artery segments is possible under a range of conditions
      applicable to clinical lung transplantation.

PMID- 10585063
TI  - Transfection of pulmonary artery segments in lung isografts during storage.
AB  - BACKGROUND: Proximal pulmonary artery segment (PPAS) endothelial transfection of
      lung grafts may be useful in ameliorating ischemia-reperfusion injury and
      rejection and may provide beneficial downstream effects on the whole lung graft.
      Transfection immediately after lung transplantation may be efficacious in
      ameliorating allograft dysfunction after transplantation. METHODS: In F344 rats,
      the PPAS was isolated and injected with 0.03 mL of GL-67/DOPE-chloramphenicol
      acetyl transferase (CAT) plasmid DNA. The PPASs were exposed for 60 minutes at
      several temperatures. The lung grafts were stored in saline solution (group 1, n
      = 24) or LPDG solution (group 2, n = 27) for 12 or 24 hours at 4 degrees to 37
      degrees C. In group 3 (n = 42), PPASs were stored in endothelial cell culture
      medium and incubated at 10 degrees or 37 degrees C in a carbon dioxide incubator
      for 3 to 72 hours. Group 4 (n = 18) served as transplanted controls; after 3 to
      24 hours' preservation at 4 degrees C in LPDG solution, lung grafts were
      transplanted. Transgene expression of PPASs was assessed with two CAT activity
      assays, thin-layer chromatography enzyme-linked immunosorbent assay and
      immediately after the preservation period (groups 1 to 3) or 24 hours after
      transplantation (group 4). RESULTS: In group 1, transgene expression did not
      appear. In groups 2 and 3, transgene expression was apparent after any storage
      duration at 37 degrees C. Transgene expression increased successively with longer
      storage periods. In group 4, transgene expression was detected after any storage
      duration. The enzyme-linked immunosorbent assay is able to quantify the
      expression of CAT activity, but thin-layer chromatography is more sensitive.
      CONCLUSIONS: Transgene expression did not occur during conventional cold storage.
      Transgene expression in rat PPASs during storage is possible with warm storage
      (37 degrees C) and appropriate storage solution.

PMID- 10585064
TI  - Fluoroscopy-aided thoracoscopic resection of pulmonary nodule localized with
      contrast media.
AB  - BACKGROUND: The pulmonary nodules have become the major indication of video
      assisted thoracic surgery (VATS). Recently, several preoperative or
      intraoperative techniques for identifying small or deeply seated pulmonary
      nodules have facilitated thoracoscopic resection. We describe the new technique
      for detecting difficult lesions. METHODS: Preoperatively, we marked the visceral
      pleura near the pulmonary nodules with dye, simultaneously injected contrast
      media (1 water-soluble Optiray [Mallinckrodt Medical Inc, Quebec, Canada], 18
      barium sulfate, 11 Lipiodol [Laboratoire Guerbet, Aulnay-sous-Bois, France]) into
      or around the nodule under computed tomography (CT) guidance. During VATS, we
      were able to easily and accurately detect and resect all the nodules localized
      with contrast media, of which the radiopacity was visualized on the portable
      fluoroscopic monitor. RESULTS: Between February 1996 and December 1998, we
      thoracoscopically resected 30 nodules in 28 patients (13 were women; age, 53 +/-
      14 years). The resected nodules were 17 +/- 7.6 mm (range; 4 to 32 mm) in size,
      and 8.9 +/- 8 mm (range, 2 to 34 mm) in depth. The pathologic diagnosis of the
      nodules was benign in 20 and malignant in 10 (six primary cancers of lung and
      four metastatic cancers). There were only minor complications related CT
      localization. CONCLUSIONS: This new technique can help the surgeons detect and
      resect the difficult lesions with safety and rapidity by VATS without
      thoracotomy.

PMID- 10585065
TI  - Postoperative adjuvant therapy for stage II non-small-cell lung cancer.
AB  - BACKGROUND: Stage II non-small-cell lung cancer is regarded as one of the early
      lung cancers. Although resection, including the mediastinal lymph nodes, is
      currently regarded as the standard treatment, the survival rate of this disease
      is not encouraging. It is well known that the most common causes of death are
      locoregional recurrences or distant metastases, or both. However, the best
      adjuvant treatment to improve survival is as controversial an issue as ever.
      METHODS: This study was designed as a randomized, blinded, two-armed study with
      operation and adjuvant radiotherapy in one arm, versus operation and adjuvant
      mitomycin C (10 mg/m2), vinblastine (6 mg/m2), and cisplatin (100 mg/m2) (MVP)
      chemotherapy in the other arm. We assigned 57 resected patients with pathologic
      proven stage II non-small cell lung cancer to the groups according to our
      eligibility criteria. RESULTS: The most common pattern of recurrence was distant
      metastases, and nearly all the recurrences (17 of 18 patients) in both groups
      were found within 2 years after operation. The rates of the locoregional and
      distant metastases were 3.6% and 46.4% in the adjuvant radiotherapy group and
      6.9% and 10.3% in the adjuvant chemotherapy group (p = 0.018). The 5-year disease
      free survival rates were 52.0% in the adjuvant radiotherapy group and 74.0% in
      the adjuvant chemotherapy group (p = 0.16, log-rank test). The 2-year, 5-year,
      and 6-year survival portions were 60.3%, 56.5%, and 28.3% in the adjuvant
      radiotherapy group, and 82.8%, 70.1%, and 60.1% in the adjuvant chemotherapy
      group (p = 0.01, p = 0.17, and p = 0.03, Z-test). The difference of the actuarial
      survival between these two groups was somewhat significant (p = 0.09, log-rank
      test). CONCLUSIONS: Our results suggest that the addition of adjuvant MVP
      chemotherapy may reduce the distant metastasis rates and prolong the survival of
      the surgically resected stage II non-small-cell lung cancer patients.

PMID- 10585066
TI  - Atrial fibrillation after operation for lung cancer: clinical and prognostic
      significance.
AB  - BACKGROUND: Atrial fibrillation is a common complication of early postoperative
      period in lung cancer thoracotomy. Its clinical incidence and short- and long
      term impact on overall mortality has never been definitely assessed; moreover, it
      is unclear whether the arrhythmia represents an independent cardiac risk factor.
      METHODS: We prospectively studied 233 consecutive patients undergoing operation
      for lung cancer (170 with non-small-cell lung cancer). Postoperative atrial
      fibrillation incidence was related to different clinical factors possibly
      involved in its occurrence and to both short- and long-term survival. RESULTS:
      Atrial fibrillation occurred in 28 patients (12%) (same percentage in non-small
      cell lung cancer); a strong relationship was observed between arrhythmia and age,
      history of hypertension and associated lymph node resection. The mean
      hospitalization time was 14 +/- 4 days in patients developing atrial fibrillation
      and 13 +/- 4 days in those who did not (p = not significant). No difference was
      observed between the two groups with regard to short- or long-term mortality or
      to long-term atrial fibrillation recurrences, also when considering the entire
      population and only non-small-cell lung cancer, separately. CONCLUSIONS: At our
      institution, early atrial fibrillation occurrence after operation for lung cancer
      does not show any negative impact on short- and long-term mortality or on
      recurrence rate.

PMID- 10585067
TI  - An adult case of Bland White Garland syndrome with huge right coronary aneurysm.
AB  - We report the case of a 62-year-old male patient with left main coronary artery
      originating from the pulmonary trunk, severe mitral insufficiency, and huge right
      coronary artery aneurysm. He is the oldest such patient among those reported in
      the literature, surviving to the sixth decade without any anginal symptoms. He is
      also the first such case with such a huge and calcified right coronary artery
      aneurysm and a prominent collateral from the noncoronary circulation.

PMID- 10585068
TI  - A review of aortopulmonary fistulas in aortic dissection.
AB  - Aortopulmonary fistula is an exceedingly rare complication of aortic dissection.
      Only 4 cases in acute dissection and 8 cases in the chronic one have been
      published previously. We report the thirteenth case and a review of the
      literature. A man underwent an operation for type A aortic dissection. At
      surgery, a fistula was discovered between the false lumen and the main pulmonary
      artery, although the preoperative investigations did not suggest such a
      complication.

PMID- 10585069
TI  - Nephrobronchial fistula secondary to xantogranulomatous pyelonephritis.
AB  - We report a case of staghorn nephrolithiasis that evolved into
      xanthogranulomatous pyelonephritis with perinephric abscess, nephrobronchial
      fistula, and lung abscess. The patient was an intravenous drug abuser who tested
      positive for human immunodeficiency virus, without evidence of acquired
      immunodeficiency syndrome. He presented with a 2-month history of untreated
      repeated episodes of left flank pain and hyperpyrexia. Treatment involved left
      nephrectomy, debridement of abscess, tube drainage, and intravenous antibiotics.
      The patient illustrates the need to consider untreated nephrolitiasis as a
      predisposing factor for pulmonary complications.

PMID- 10585070
TI  - Hemolytic anemia after atrioventricular septal defect repair without synthetic
      material.
AB  - We report a rare case of severe hemolytic anemia following repair of a congenital
      heart defect without the use of prosthetic material. A review of the literature,
      diagnosis, and management are described. Although this is an unusual complication
      following congenital heart surgery, a high index of suspicion must be maintained
      and a possible mechanical cause should be sought and corrected.

PMID- 10585071
TI  - Cardiac allograft valvulopathy: a case of donor-anorexigen-induced valvular
      disease.
AB  - We report on the transplantation of a cardiac allograft from a donor with
      prolonged exposure to anorexigens. This event allowed us to not only examine the
      early pathological alterations that characterize anorexigen-induced valvular
      damage, but to also study the posttransplantation outcome after the donor heart
      had been removed from the offending milieu. A donor history of anorexigen use
      should be sought, and if detected, careful evaluation for underlying valvular
      disease should be entertained. Early valvulopathy may appear clinically mild yet
      pathologically significant. Our single-case experience also suggests that
      anorexigen-induced valvulopathy may be a progressive disorder despite removal of
      the heart from the causative environment.

PMID- 10585072
TI  - Aneurysms complicating pulmonary autograft procedure for aortic valve
      replacement.
AB  - Aneurysm formation in the left ventricular outflow tract related to the proximal
      end of the pulmonary autograft after the Ross procedure was present in 2
      patients. Both occurred late after operation and were associated with prolapse of
      a leaflet of the autograft and significant regurgitation. Both were repaired with
      no immediate complications. There was no evidence of infection at time of
      operation. The probable mechanisms underlying this complication and the
      possibilities of avoiding it are discussed.

PMID- 10585074
TI  - The failing Fontan with atrial flutter: a successful surgical option.
AB  - Two successful cases of eliminated atrial flutter and improved clinical status
      for Fontan patients are presented. An operation combining introduction of an
      extracardiac conduit for the Fontan connection, to direct all systemic venous
      blood away from the atrium, and atrial pathway division and cryoablation, is a
      useful surgical option for failing Fontan patients.

PMID- 10585073
TI  - Intraatrial mitral valve insertion with native valve preservation in children.
AB  - Two patients underwent intraatrial mitral valve insertion for an unsuccessful
      valvotomy for severe mitral stenosis and left-sided atrioventricular valve
      insufficiency associated with corrected transposition utilizing a porcine valve
      from a valved conduit with preservation of the native valve. The valves were
      inserted using continuous suture distally at the mitral annulus and proximally at
      the pulled atrial wall distal to the pulmonary veins. Both patients had
      uneventful hospital course and are doing well at up to 6 months postoperatively.
      This approach provides a viable option for congenital mitral stenosis or
      insufficiency in children.

PMID- 10585075
TI  - Accelerated allograft degeneration after aortic valve endocarditis.
AB  - Early calcification of aortic allografts is usually seen in children less than 3
      years of age. We describe a case of a 22-year-old intravenous drug user who
      developed calcific aortic valve stenosis less than 3 years after an allograft
      root replacement for endocarditis.

PMID- 10585076
TI  - Common arterial trunk associated with double aortic arch.
AB  - The combination of common arterial trunk associated with double aortic arch is
      very rare. We are aware of only four cases ever reported in English literature.
      We add two cases of this entity and comment on the morphological aspects, the
      clinical impact of the combined lesions, and their diagnostic and therapeutic
      implications.

PMID- 10585077
TI  - Transthoracic fistula with erosion of the ascending aorta along an IMA-protecting
      graft.
AB  - Internal mammary artery (IMA) graft protection with nonbiodegradable material,
      such as polytetrafluorethylene (PTFE), is recognized as an effective means for
      preventing overexuberant adhesion development as well as injury of retrosternally
      crossing arterial grafts in the event of resternotomy and should enable better
      identification of the IMA graft. It is still uncertain whether the use of PTFE
      material is suitable for diabetic patients with complete arterial
      revascularization due to potential infectious complications. We report on a young
      diabetic patient after arterial T-grafting due to severe coronary disease and
      readmission with wound infection and retrosternal fistula formation 8 months
      after operation.

PMID- 10585078
TI  - Evolution toward dissection of an intramural hematoma of the ascending aorta.
AB  - Intramural hematoma of the aorta is a condition increasingly observed in clinical
      practice. Uncertainty exists whether such lesions represent a different pathology
      or simply the precursors of classic dissecting aneurysm. The patient was a 76
      year-old woman with intramural hematoma of the ascending aorta. Clinical course,
      progression of the lesion to type A aortic dissection, and surgical treatment are
      described. Although natural history of intramural hematoma of the ascending aorta
      is not clearly elucidated, the case presented confirms that the evolution toward
      intimal flap formation is possible and that we cannot foresee the stabilization
      of these lesions. We stress that intramural hematoma of the ascending aorta has
      to be managed as an aortic type A dissection and that aggressive treatment is
      advisable.

PMID- 10585079
TI  - Postoperative mediastinal chyloma.
AB  - Anterior mediastinal mass developed in a 69-year-old woman who had undergone
      right upper lobectomy and systematic lymph node dissection. The mass was
      diagnosed to be a mediastinal chyloma and surgical intervention was necessary to
      resolve the compression to the superior vena cava. Although posttraumatic
      mediastinal chyloma is not rare, postoperative mediastinal chyloma has not been
      reported in the literature. However, it should be noted as a differential
      diagnosis for a postoperative mediastinal mass.

PMID- 10585080
TI  - Stentless tricuspid valve replacement.
AB  - Stentless tricuspid valve replacement was performed in a 21-year-old patient with
      severe destructive tricuspid valve endocarditis resistant to medical therapy.
      Postoperative recovery was uneventful. Stentless atrioventricular valves are
      considered an additional treatment option besides stented valves or homograft
      implantations for severe right-sided endocarditis. Transvalvular hemodynamics are
      excellent, and right ventricular function can be preserved by suspending the
      valve at the papillary muscles.

PMID- 10585081
TI  - Enlargement of ulcer-like projections after repair of acute type A aortic
      dissection.
AB  - We treated two cases of enlargement of ulcer-like projections in the descending
      thoracic aorta, which were recognized after emergency graft replacement from the
      ascending aorta to the aortic arch for acute type A aortic dissection. The
      intimal tear, which was near the left subclavian artery, was resected during the
      initial operation. Graft replacement of the descending thoracic aorta was
      successful.

PMID- 10585082
TI  - Basaloid carcinoma of the thymus.
AB  - A 58-year-old man was found to have a basaloid carcinoma of the thymus, initially
      detected as an abnormal shadow on chest radiograph. The patient underwent
      resection followed by radiotherapy, and has survived 25 months without
      recurrence. Although this rare tumor may be related to multilocular thymic cyst,
      its pathogenesis is obscure. We discuss clinicopathologic features of our case
      and others.

PMID- 10585083
TI  - Images in cardiothoracic surgery. Biphasic pulse wave due to asynchronous heart
      contractions in heterotopic cardiac transplantation.

PMID- 10585084
TI  - A simple method of treating coronary air embolism after cardiopulmonary bypass.
AB  - Coronary air embolism is a potential complication of cardiac operations performed
      with cardiopulmonary bypass, especially open heart operations. There are many
      recommended methods described in the literature to treat the sequelae of coronary
      air embolism, none universally effective. We describe a simple and safe method to
      treat the condition, which we have found very effective in our practice.

PMID- 10585085
TI  - Left superior vena cava to the left atrium: do we have to change the traditional
      approach?
AB  - Left superior vena cava (LSVC) to the left atrium is a rare congenital cardiac
      complex, which may appear as an isolated anomaly, or as part of more complex
      cardiac anomalies. Traditionally, an intraatrial baffle was the preferred
      surgical technique. Although this technique has proved reliable and successful,
      acute ligation and extracardiac repair are simpler and easier solutions,
      requiring less myocardial ischemic time. We present 3 patients who underwent
      simple ligation and discuss the literature for other extracardiac options of
      surgical repair. Our patients had short transient congestion in the left upper
      part of their body that resolved completely after a few weeks, without further
      complications. We believe that either acute ligation or extracardiac repair is a
      much simpler yet effective solution to divert the left caval flow to the lesser
      circulation.

PMID- 10585086
TI  - A new patch for the Norwood procedure.
AB  - The problems related to the pediatric pulmonary homograft availability and the
      possible transmission of viral infection led us to design a new patch for aortic
      enlargement in the Norwood procedure for hypoplastic left heart syndrome. This
      sterile bovine pericardial patch is not expensive and can be tailor-made.

PMID- 10585087
TI  - A novel method to reduce device-related infections in patients supported with the
      HeartMate device.
AB  - Improved implantable left ventricular assist device technology has made survival
      to heart transplantation a near certainty. Nevertheless, infection remains a
      major risk to recipients of current percutaneous systems. We developed a modified
      implantation technique applied to the last 9 of 30 patients who received the
      HeartMate vented electric left ventricular assist system (LVAS). Covering the
      upper surface of the pump with a patch of knitted graft material was followed by
      a decline in the incidence of pocket infections from 33.3% to 11.1%. This
      modification compares favorably to that of a lengthened percutaneous driveline
      tunnel in reducing device-related infection.

PMID- 10585088
TI  - Direct aortic cannulation for port-access mitral or coronary artery bypass
      grafting.
AB  - A technique is described for direct aortic arterial cannulation during Port
      Access mitral valve or coronary artery bypass grafting. Femoral arterial
      cannulation is avoided, and endoaortic balloon occlusion is used for cardioplegic
      arrest. To date, excellent results have been obtained in 45 patients.

PMID- 10585089
TI  - Papillary fibroelastoma: increasing recognition of a surgical disease.
AB  - Papillary fibroelastomas are uncommon benign tumors usually involving the heart
      valves, which historically have been diagnosed at autopsy. With the advent of
      echocardiography, however, the number of patients diagnosed in life has
      increased. Papillary fibroelastomas represent a surgically treatable cause of
      cerebrovascular and cardiovascular ischemia and infarction making their
      identification clinically important. We report three unusual cases of papillary
      fibroelastoma; two patients presenting with symptoms of cerebrovascular ischemia
      and one presenting with myocardial infarction. We also present a comprehensive
      review of the literature and provide a compilation of all case reports to date.

PMID- 10585090
TI  - Postpneumonectomy bronchopleural fistula.

PMID- 10585091
TI  - Transmanubrial approach reproposed.

PMID- 10585092
TI  - Giant mediastinal bronchial artery aneurysm.

PMID- 10585093
TI  - Shunt control of ascending aortic bleeding.

PMID- 10585094
TI  - Operative excision of atrial septal fat.

PMID- 10585095
TI  - Multiple transmyocardial puncture revascularization.

PMID- 10585096
TI  - Reduction of wound healing problems after median sternotomy by use of retention
      sutures.

PMID- 10585097
TI  - Lung transplantation from a donor sustaining cardiac arrest while running a
      marathon.

PMID- 10585098
TI  - Repair of right ventricular rupture complicating mediastinitis.

PMID- 10585099
TI  - Transmyocardial laser revascularization: a historical perspective.

PMID- 10585100
TI  - Myocardial protection from surgical ischemic-reperfusion injury. Introduction.

PMID- 10585101
TI  - Mechanisms of postischemic contractile dysfunction.
AB  - Prolonged reversible postischemic contractile dysfunction that follows single or
      multiple brief periods of regional or global ischemia has been termed "stunned
      myocardium," and is thought to be the result of a decreased responsiveness of the
      cardiac myofilaments to calcium. A number of hypotheses have been proposed to
      explain the pathogenesis of stunned myocardium; however, the two major theories
      that are supported by the most experimental evidence suggest that the generation
      of oxygen-derived free radicals and a disturbance in calcium homeostasis are
      responsible for the postischemic contractile dysfunction observed. These
      mechanisms are not mutually exclusive, and data are available that support both
      theories. Evidence exists that indicates that one may pharmacologically enhance
      the recovery of stunned myocardium by use of oxygen radical scavengers, adenosine
      agonists, calcium channel blockers, and openers of the ATP-sensitive potassium
      channel, including the volatile anesthetic isoflurane. Ischemic preconditioning
      (IPC) has also been shown to produce delayed protection against myocardial
      stunning, and a novel pharmacological agent, monophosphoryl lipid A, has been
      shown to mimic the effect of IPC. Because stunning appears to occur in a number
      of clinical settings, it is important to understand the mechanisms involved and
      to develop pharmacological therapy that will result in an improved clinical
      outcome.

PMID- 10585102
TI  - Mechanisms of myocardial reperfusion injury.
AB  - Reperfusion of the ischemic myocardium results in irreversible tissue injury and
      cell necrosis, leading to decreased cardiac performance. While early reperfusion
      of the heart is essential in preventing further tissue damage due to ischemia,
      reintroduction of blood flow can expedite the death of vulnerable, but still
      viable, myocardial tissue, by initiating a series of events involving both
      intracellular and extracellular mechanisms. In the last decade, extensive efforts
      have focused on the role of cytotoxic reactive oxygen species, complement
      activation, neutrophil adhesion, and the interactions between complement and
      neutrophils during myocardial reperfusion injury. Without reperfusion, myocardial
      cell death evolves slowly over the course of hours. In contrast, reperfusion
      after an ischemic insult of sufficient duration initiates an inflammatory
      response, beginning with complement activation, followed by the recruitment and
      accumulation of neutrophils into the reperfused myocardium. Modulation of the
      inflammatory response, therefore, constitutes a potential pharmacological target
      to protect the heart from reperfusion injury. Recognition of the initiating
      factor(s) involved in myocardial reperfusion injury should aid in development of
      pharmacological interventions to selectively or collectively attenuate the
      sequence of events that mediate extension of tissue injury beyond that caused by
      the ischemic insult.

PMID- 10585103
TI  - Prime causes of rapid cardiomyocyte death during reperfusion.
AB  - In ischemic-reperfused myocardium, necrosis of cardiomyocytes may develop not
      only due to the ischemic conditions but also the specific circumstances of
      reperfusion. The existence of reperfusion injury becomes apparent when
      modifications of the conditions of reperfusion can prevent cell death otherwise
      occurring. Three prime causes of rapidly developing reperfusion injury are here
      discussed, ie, reenergization of cells at increased cytosolic Ca2+ contents,
      rapid normalization of tissue pH, and rapid normalization of tissue osmolality.
      All three causes lead to severe mechanical stress of cardiomyocytes which can
      cause their rapid deterioration. Propagation of cell injury among adjacent cells
      can cause a spreading of necrosis throughout myocardial tissue. The understanding
      of these initial causes of rapidly developing lethal reperfusion injury leads to
      new concepts for specific protection of reperfused myocardium.

PMID- 10585104
TI  - Role of the beta2-integrins and immunoglobulin superfamily members in myocardial
      ischemia-reperfusion.
AB  - Leukocytes play a key role in the inflammatory processes such as ischemia
      reperfusion of the coronary vasculature. Their interaction with the endothelium
      is closely regulated. The first step in the process is the rolling of leukocytes
      (eg, neutrophils) along the microvascular endothelium. This is regulated by the
      selectin family of cell adhesion molecules, primarily P-selectin. The next step
      in the inflammatory cascade is the firm adhesion of these neutrophils to the
      activated or dysfunctional endothelium. This process is governed by the beta2
      integrins on the leukocytes (eg, CD11/CD18) and by ICAM-1 on the activated
      endothelium. CD11/CD18 is a beta2-integrin, and ICAM-1 is a member of the
      immunoglobulin superfamily of adhesion glycoproteins. By their interaction,
      neutrophils flatten out and adhere to the vascular endothelium. Many of these
      adhered neutrophils are then able to transmigrate across the endothelium to the
      site of the inflammation (ie, the focus of the ischemia-reperfusion). This
      transmigration is primarily stimulated by PECAM-1, another member of the
      immunoglobulin superfamily. These processes are discussed in this brief review.

PMID- 10585105
TI  - Myocardial protection: is there a role for gene therapy?
AB  - Modification of gene expression within the heart could have a dramatic impact on
      both cardiac transplantation and routine cardiac surgery within the next decade.
      The advantage of gene therapy is that it would allow organ-selective local
      delivery of higher levels of cytokines, growth factors, vasodilators, or
      immunosuppressive drugs than could be safely achieved by systemic administration.
      Direct transfection or transduction of myocytes, endothelium, and/or vascular
      smooth muscle cells could increase the density of beta adrenergic receptors,
      inhibit endothelial adhesion molecule expression, or prevent neointimal formation
      in coronary bypass grafts. Cell transfer of neonatal or engineered adult myocytes
      might allow repopulation of infarct areas. The current limitations to effective
      clinical gene therapy are the variable transfection efficiencies of gene delivery
      systems, limited duration of gene expression, immune responses to viral vectors,
      and safety concerns. Ischemia-reperfusion injury will be one of the earliest
      applications for gene therapy since the short time course of injury and recovery
      would be amenable to therapeutic approaches with limited durations of action,
      achievable by currently available delivery vectors.

PMID- 10585106
TI  - Molecular targets of gene therapy.
AB  - Ischemic reperfused heart represents a potential target for gene therapy because
      gene transfer can represent an alternate pharmacological approach to protect the
      heart from cellular injury. Gene therapy may be particularly useful to deal with
      previously unapproachable problems. For myocardial preservation, gene therapy
      could replace those pharmacological interventions when drugs are delivered
      locally by sustained release with the help of mechanical device, eg, implants. In
      this review, attempts are made to define the molecular targets for gene therapy
      primarily applicable to myocardial preservation associated with ischemia and
      reperfusion. It has been emphasized that for successful gene transfer, not only
      characterization of proper targets and elimination of undesirable side effects
      are necessary, but also the therapy must be proven superior compared to other
      pharmacological interventions including surgery.

PMID- 10585108
TI  - Broad-spectrum cardioprotection with adenosine.
AB  - Ischemia-reperfusion results in contractile dysfunction, necrosis, and vascular
      injury. This postischemic injury is mediated in part by superoxide radical
      production, neutrophils, dysfunction to ionic pumps, and edema formation.
      Adenosine is an autacoid released tonically by myocytes, endothelium, and
      neutrophils; the release of adenosine from the myocyte compartment into the
      interstitium is increased during ischemia. The major effects of adenosine are
      mediated by specific receptors identified as A1, A2a, A2b, and A3. Each receptor
      subtype contributes to physiological responses that influence ischemia
      reperfusion injury. Adenosine has potent cardioprotective properties exerted
      during three major windows of opportunity: pretreatment, ischemia, and
      reperfusion. The cardioprotective effects exerted during pretreatment and
      ischemia may involve metabolic changes and hyperpolarization via K(ATP)-channel
      activation, mediated through A1 receptor mechanisms. The cardioprotective
      mechanisms exerted during reperfusion involve inhibition of neutrophils directly
      (superoxide anion generation, expression of adhesion molecules), and by
      inhibiting activation of the endothelium through A2 receptor-mediated mechanisms,
      thereby preventing neutrophil-endothelial cell interactions, which initiate the
      inflammatory-like component of reperfusion injury. Activation of the newly
      identified A3 receptor has been shown to be cardioprotective partially by
      inhibition of neutrophil adherence to endothelium and by neutrophil-independent
      mechanisms. These mechanisms of cardioprotection have been suggested to play
      major roles in the reduction of infarction and apoptosis after myocardial
      ischemia, cardioplegic arrest, and subsequent reperfusion. Adenosine has been
      used as an adjunct to both crystalloid and blood cardioplegia, but its potential
      as a cardioprotective agent has not been fully explored.

PMID- 10585107
TI  - Cellular and molecular therapeutic targets for treatment of contractile
      dysfunction after cardioplegic arrest.
AB  - Transient left ventricular (LV) dysfunction can occur after hypothermic
      hyperkalemic cardioplegic arrest. This laboratory has developed an isolated LV
      myocyte system of simulated cardioplegic arrest and rewarming in order to examine
      cellular and molecular events that may contribute to the LV dysfunction after
      cardioplegic arrest. Contractile function was examined using high-speed video
      microscopy after reperfusion and rewarming. After cardioplegic arrest and
      reperfusion, indices of myocyte contractility were reduced by over 40% from
      normothermic control values. The capacity of the myocyte to respond to an
      inotropic stimulus was examined through beta-adrenergic receptor stimulation with
      isoproterenol. After cardioplegic arrest, the contractile response to
      isoproterenol was reduced by over 50% from normothermic values. The next series
      of studies focused upon preventing these changes in myocyte contractile processes
      after cardioplegic arrest. First, the cardioplegic solutions were augmented with
      adenosine or an ATP-sensitive potassium channel opener, aprikalim. Both adenosine
      and aprikalim augmentation significantly improved myocyte function compared with
      cardioplegia alone values. A potential intracellular mechanism for the protective
      effects of either adenosine or the ATP-sensitive potassium channel is the
      activation of protein kinase C (PKC). A brief period of PKC activation before
      cardioplegic arrest provided protective effects on myocyte contractility with
      subsequent reperfusion and rewarming. In another set of studies, the potential
      protective effects of the active form of thyroid hormone (T3) were examined. In
      myocytes pretreated with T3, myocyte contractile function and beta-adrenergic
      responsiveness were significantly improved after hypothermic cardioplegic arrest
      and rewarming. Thus, endogenous means of providing improved myocardial protection
      during prolonged cardioplegic arrest can be achieved through a brief period of
      PKC activation or pretreatment with T3. Future studies, which more carefully
      deduce the basis for these pretreatment effects, will likely yield novel methods
      by which to protect myocyte contractile processes during cardioplegic arrest.

PMID- 10585109
TI  - Treating myocardial ischemia-reperfusion injury by targeting endothelial cell
      transcription.
AB  - Exacerbation of, rather than improvement in, a hypoxic injury after reperfusion
      of ischemic tissues is recognized as the specific clinicopathologic entity
      referred to as ischemia/reperfusion (I/R) injury. Arguably, one of the most
      common forms of I/R injury occurs during cardiac surgery, which has a mandatory
      period of myocardial ischemia required to allow surgery in a bloodless,
      motionless field, followed by coronary artery reperfusion after removal of the
      aortic cross-clamp. In this review, we examine the endothelial cell activation
      phenotype that initiates and propagates myocardial I/R injury. Emphasis is given
      to the biology of one transcription factor, NF-kappaB, that has the principal
      role in the regulation of many endothelial cell genes expressed in activated
      endothelium. NF-kappaB-dependent transcription of endothelial cell genes that are
      transcribed in response to I/R injury may be a favorable approach to preventing
      tissue injury in the setting of I/R. Elucidating safe and effective therapy to
      inhibit transcription of endothelial cell genes involved in promoting injury
      after I/R injury may have wide applicability to the patients with heart disease
      and other forms of I/R injury.

PMID- 10585110
TI  - Myocardial protection with monophosphoryl lipid-A against aortic cross clamping
      induced global stunning.
AB  - BACKGROUND: Monophosphoryl lipid-A (MLA) has a late window (24 hours) of
      cardioprotection against acute myocardial infarction. It is not known whether
      MLA, administered, 24 hours before surgery, attenuates intraoperative ventricular
      dysfunction "stunning" associated with aortic cross-clamping and reperfusion
      during elective cardiac surgery. We determined the dose-response relationship
      between MLA and ventricular function in a canine model of global myocardial
      stunning in the absence of necrosis. The role of expression of inducible heat
      shock protein 70 (HSP 70i) was also investigated. METHODS: Mongrel dogs (n = 32)
      were intravenously injected with either a vehicle solution or 3, 5, 10, 35 ug/kg
      MLA. Twenty four hours later, dogs were anesthetized and instrumented, in situ,
      to monitor the left ventricular performance (the slope of regression between
      stroke-work and end diastolic length). Tissue samples were obtained to determine
      HSP70i using immunoblot analysis. After a period of equilibration on
      cardiopulmonary bypass, the aortic cross-clamp was applied at normothermia for 30
      minutes followed by 60 minutes of reperfusion. ATP and catabolites were
      determined in transmural myocardial biopsies. Triphenyl-tetrazolium chloride
      (TTC) staining was used to determine myocardial necrosis. RESULTS: MLA treatment
      did not alter myocardial contractility or ATP metabolism. Global ischemia
      resulted in about 50% depletion of ATP and remained depressed during reperfusion
      in all groups. MLA-treated hearts had improved functional recovery in a dose
      dependent-manner. Significant recovery was observed at the highest dose (35
      ug/kg) compared to the control group. Immunoblot analysis demonstrated
      significant increase in HSP 70i in the MLA-treated hearts. CONCLUSIONS: MLA
      exhibits a delayed (24 hours) window of protection against myocardial stunning
      associated with aortic cross-clamping. HSP70i expression may play a role in MLA
      mediated cardioprotection.

PMID- 10585111
TI  - Developments in cardioprotection: "polarized" arrest as an alternative to
      "depolarized" arrest.
AB  - During cardiac surgery or cardiac transplantation, the heart is subjected to
      varying periods of global ischemia. The heart must be protected during this
      ischemic period to avoid additional injury, and techniques have been developed
      that delay ischemic injury and minimize reperfusion injury. Almost universally,
      this involves using a hyperkalemic cardioplegic solution and these solutions have
      become the gold standard for myocardial protection for more than 20 years.
      Despite the extensive and continued research aimed at improving these basic
      hyperkalemic cardioplegic solutions, patients undergoing surgery almost
      invariably experience some degree of postoperative dysfunction. It is likely that
      this relates to the depolarizing nature of hyperkalemic solutions, which results
      in ionic imbalance caused by continuing transmembrane fluxes and the consequent
      maintenance of high energy phosphate metabolism, even during hypothermic
      ischemia. A potentially beneficial alternative to hyperkalemic cardioplegia is to
      arrest the heart in a "hyperpolarized" or "polarized" state, which maintains the
      membrane potential of the arrested myocardium at or near to the resting membrane
      potential. At these potentials, transmembrane fluxes will be minimized and there
      should be little metabolic demand, resulting in improved myocardial protection.
      Recent studies have explored these alternative concepts for myocardial
      protection. The use of compounds such as adenosine or potassium channel openers,
      which are thought to induce hyperpolarized arrest, have demonstrated improved
      protection after normothermic, or short periods of hypothermic, ischemia when
      compared to hyperkalemic (depolarized) arrest. Similarly, studies from our own
      laboratory, in which the sodium channel blocker, tetrodotoxin, was used to induce
      polarized arrest (demonstrated by direct measurement of membrane potential during
      ischemia) was also shown to provide better recovery of function after 5 hours of
      long-term hypothermic (7.5 degrees C) storage. These promising initial studies
      need to be consolidated before experimental promise becomes clinical reality.

PMID- 10585112
TI  - Protection of acutely ischemic myocardium by controlled reperfusion.
AB  - The goal of revascularization after acute occlusion of a coronary artery is the
      return of contractile function and the reduction of mortality. Although
      reperfusion of ischemic myocardium is a prerequisite for return of function, it
      may, in itself, cause further injury. Controlled blood cardioplegic reperfusion
      reduces this "reperfusion injury" and provides maximal myocardial protection. In
      this article, we review recent advances in surgically controlled reperfusion and
      speculate on future prospects for myocardial protective techniques in patients
      with acute coronary artery occlusion.

PMID- 10585113
TI  - Protection in the failing heart.
AB  - Myocardial protection for surgical procedures on the failing heart can be broken
      down into three areas. The first area involves selection of the appropriate
      patient with enough myocardial viability and contractile reserve to permit a
      substantial cross-clamp time. Secondly, there should be adequate targets to
      revascularize or adequate tissue for reparative surgery. Thirdly, and most
      importantly, antegrade and retrograde blood cardioplegia given in sufficient
      amounts to satisfy myocardial oxygen needs is of prime importance.

PMID- 10585115
TI  - Control of the inflammatory response in extended myocardial preservation of the
      donor heart.
AB  - The damaging effects of inflammation after prolonged myocardial ischemia are
      typically manifest during the period of reperfusion. The imbalance between free
      radical generation and availability of natural free radical scavengers during
      postischemic reperfusion set the stage for free radical injury. Calcium overload
      may convert reversible ischemic damage to fatal myocyte contracture. Complement
      activation and neutrophil activation, adhesion, and diapedesis are central
      components of the damaging inflammatory response. Cytokines such as tumor
      necrosis factor and IL1 simulate IL8 synthesis which is also a potent
      chemoattractant for neutrophils. The endothelial contribution to ischemic
      reperfusion injury results from an imbalance between the production of naturally
      occurring vasodilators, such as prostacycline and nitric oxide, and
      vasoconstrictor products, such as endothelin, thromboxane A2, and angiotensin 2.
      Knowledge of these basic mechanisms has stimulated the formulation of
      preservation solutions and strategies to ameliorate the inflammatory response
      during reperfusion.

PMID- 10585114
TI  - Minimally invasive cardiac operation: adapting cardioprotective strategies.
AB  - BACKGROUND: Minimally invasive heart operation differs from traditional cardiac
      operations through the omission of a sternotomy, cardiopulmonary bypass, or both.
      Current concerns with minimally invasive operation include: operative safety,
      learning curve, operative times, arrest times, and adequacy of myocardial
      protection. While many of the protective strategies used for traditional
      procedures may be applied to minimally invasive cardiac operations, the safe
      applications of minimally invasive operations require unique techniques of
      myocardial protection. METHODS AND RESULTS: Omission of extracorporeal perfusion
      may benefit patients through attenuation of systemic inflammatory response,
      decrement in neurologic insults, and reduced bleeding complications. As a
      counterbalance, surgeons must consider long-term operative quality and level of
      myocardial protection provided during beating heart coronary operation. Current
      issues that must be addressed include: pharmacologic management, coronary
      collateralization and ischemic preconditioning, the utility of intraluminal
      coronary shunts, and technical adequacy of the anastomosis. Nonsternotomy
      cardiopulmonary bypass methods utilize alternative incisions and "port-access"
      technology, and may render more rapid patient recovery including: decreased pain,
      shortened hospital stay, and more rapid return to work. Altered strategies of
      myocardial protection in a closed chest environment must address: method of
      cannulation, technique of aortic occlusion, rapidity and maintenance of cardiac
      arrest, and cardiac de-airing techniques. CONCLUSIONS: Previous obstacles to
      minimally invasive cardiac operations included limitations in operative exposure,
      inadequate perfusion technology, and inability to provide myocardial protection.
      Recent advances in videoscopic visualization and evolving mechanisms of
      myocardial protection may justify the expanding application of minimally invasive
      techniques.

PMID- 10585116
TI  - Heart preservation for transplantation: principles and strategies.
AB  - While transplantation is a proven modality for the treatment of end stage organ
      disease, an important determinant of outcome is the adequacy of organ
      preservation. Currently, heart preservation is limited to 4 to 6 hours of cold
      ischemic storage, and the effectiveness depends to a great extent on the solution
      and its temperature. The formulation of the solution is based on three basic
      principles: (a) hypothermic arrest of metabolism, (b) provision of a physical and
      biochemical environment to maintain viability of the structural components of the
      tissue during hypothermic metabolic slowing, and (c) minimization of reperfusion
      injury. This review presents the physiologic principles underlying the use of
      hypothermia and the chemical components of preservation fluids, specifically
      pertaining to preservation of the heart for transplantation. New approaches
      designed to protect the heart from surgical ischemic-reperfusion injury are
      presented as well. The object is to survey current strategies and generate
      insight into new and promising solutions designed to optimize donor heart
      preservation.

PMID- 10585117
TI  - Preconditioning: can nature's shield be raised against surgical ischemic
      reperfusion injury?
AB  - Endogenous myocardial protection refers to the natural defense mechanisms
      available to the heart to withstand an ischemic injury. So far, these mechanisms
      have been shown to encompass two phenomena most likely interrelated: ischemic
      preconditioning and stress protein synthesis. Ischemic preconditioning can be
      defined as the adaptive mechanism induced by a brief period of reversible
      ischemia increasing the heart's resistance to a subsequent longer period of
      ischemia. The therapeutic exploitation of these natural adaptive mechanisms in
      cardiac surgery is an appealing prospect, as preconditioning could be used before
      aortic cross-clamping to enhance the current methods of myocardial protection.
      Two major conclusions emerge from the bulk of experimental data on
      preconditioning: First, the adaptive phenomenon reduces infarct size after
      regional ischemia in animal preparations across a wide variety of species but its
      effects on arrhythmias and on preservation of function after global ischemia are
      less consistent. This is relevant to cardiac surgery where postbypass pump
      failure is more often due to stunning than to discrete necrosis. Second,
      regardless of the various components of the intracellular signaling pathway
      elicited by the preconditioning stimulus, it seems that the major mechanisms by
      which this pathway leads to a cardioprotective effect are a slowing of adenosine
      triphosphate depletion and a limitation of acidosis during the protracted period
      of ischemia. If the latter is true, then it can reasonably be predicted that
      these energy-sparing and acidosis-limiting effects may become redundant to those
      of cardioplegia. From these observations, it can be inferred that preconditioning
      may find an elective indication in situations where the potential for suboptimal
      protection increases the risk of necrosis (extensive coronary artery disease,
      severe left ventricular hypertrophy, long ischemic time, and beating heart
      operations where occlusion of the target vessels leads to unprotected distal
      ischemia). Since an ischemic preconditioning stimulus could be clinically
      undesirable, it is critically important to identify the endogenous mediators of
      the phenomenon in order to use them therapeutically. One of the most important of
      these mediators seems to be the adenosine triphosphate-dependent potassium
      channel. Currently, however, the clinical application of these drugs is hampered
      by their poor cardioselectivity which could result in untoward systemic
      vasodilatory effects before cardioprotection becomes manifest. Thus, although the
      modalities of pharmacologically induced preconditioning still remain to be
      determined, the concept of therapeutic exploitation of the endogenous adaptive
      mechanisms of the heart could potentially represent an important adjunct to our
      current techniques of myocardial protection.

PMID- 10585118
TI  - Intraoperative myocardial protection: current trends and future perspectives.
AB  - BACKGROUND: The results of contemporary coronary artery bypass graft surgery
      (CABG) are excellent. However, recently changing trends in the population at risk
      have necessitated new measures to minimize perioperative morbidity and mortality.
      METHODS: We reviewed cardioplegic innovations developed, evaluated, and currently
      employed at the Toronto Hospital. In addition, we conducted an evaluation of
      novel cardioplegic formulations, with an eye towards future clinical
      applications. RESULTS: At the Toronto Hospital, we demonstrated that blood
      provided better protection than crystalloid cardioplegia. Subsequently, we found
      that a terminal infusion of warm blood cardioplegia repleted myocardial adenosine
      triphosphate (ATP) levels and improved postoperative ventricular function.
      Recently, we reported that tepid (29 degrees C) cardioplegia reduced lactate and
      acid production during cardioplegic arrest, and improved postoperative
      ventricular function. Combining antegrade and retrograde cardioplegic delivery
      reduced lactate production, preserved ATP stores, and improved metabolic recovery
      after cross-clamp release. Cardioplegic flows of at least 200 mL/min were
      required to washout detrimental metabolic end-products and improve ventricular
      function. To further optimize myocardial protection, attempts have been made to
      harness the beneficial effects of ischemic preconditioning using adenosine.
      Similarly, insulin cardioplegia has been employed in order to enhance ventricular
      performance by stimulating early postoperative aerobic metabolism. Finally L
      arginine, a nitric oxide donor has been demonstrated to be beneficial in
      experimental studies and may represent a further option for the enhancement of
      intraoperative myocardial protection. CONCLUSIONS: Despite continued improvements
      in cardioplegic techniques, low output syndrome following high-risk CABG remains
      an ongoing concern. The development of novel additives with various protective
      properties may provide added protection, allowing for a reduction morbidity and
      mortality following CABG.

PMID- 10585119
TI  - Hematospermia: an investigation of the bleeding site and underlying lesions.
AB  - BACKGROUND: The site of hemorrhage and causative lesions in patients with
      hematospermia were evaluated using the puncture technique for seminal vesicles
      and/or mullerian duct cysts under ultrasound guidance. METHODS: Twenty-one
      patients aged 26-75 years (mean, 49.8 years) underwent transperineal needle
      aspiration of the seminal vesicles and/or mullerian duct cysts guided by
      transrectal ultrasonography (TRUS). RESULTS: Dark reddish seminal vesicle fluid
      was aspirated and the site of bleeding was considered to be the seminal vesicles
      in 11 patients (52%) (group A). In group A, abnormalities of the seminal vesicles
      were noted in nine patients (82%). These consisted of dilated seminal vesicles in
      seven (bilateral in four, unilateral in three), a seminal vesicle cyst in one and
      seminal vesicle amyloidosis in one. A mullerian duct cyst was confirmed to be the
      bleeding site in two patients (10%; group B). The bleeding site was estimated to
      be organs rather than the seminal vesicles in four patients (group C), in all of
      whom ectopic prostatic tissue was observed in the prostatic urethra. In groups B
      and C, seminal vesicle abnormalities were not detected by TRUS. In the remaining
      four patients (group D), failure to aspirate seminal vesicle fluid means that it
      is unclear whether hemorrhage was from the seminal vesicle or from another
      source. In group D, ectopic prostatic tissue was demonstrated in the prostatic
      urethra of three patients and unilateral seminal vesicle dilation was detected by
      TRUS in one patient. CONCLUSION: Puncture of the seminal vesicles and/or
      mullerian duct cysts under ultrasonic guidance as well as cystourethroscopy is a
      useful and minimally invasive examination for determination of the bleeding site
      responsible for hematospermia.

PMID- 10585120
TI  - Why the flexible cystoscope has not yet been widely introduced?: A questionnaire
      to Japanese urologists.
AB  - BACKGROUND: The flexible cystoscope has not been as widely accepted in the field
      of urology as in other fields. The results of this investigation provided
      implications for determining the reasons for the under-use of flexible cystoscopy
      as well as for the drawbacks of the flexible cystoscope. METHODS: We performed an
      investigation by sending a questionnaire to urologists asking them to compare the
      flexible cystoscope with the rigid cystoscope in order to determine why use of
      the former lags behind that of the latter. RESULTS: We received answers from 420
      urologists. We classified the urologist into four groups according to their years
      of experience. We also classified patients, for whom flexible cystoscopy was
      carried out, into four groups. The majority of the urologists in all groups
      thought that the flexible cystoscope provided a small field of vision and rough
      images. Urologists thought that the flexible cystoscope was inferior to the rigid
      cystoscope in terms of manipulability in biopsy. However, doctors who examined
      many patients using flexible cystoscopy believed that it was advantageous in
      terms of decreasing the patients' pain and they have experienced no problem in
      clinical practice. CONCLUSIONS: Lack of experience in using the flexible
      cystoscope appears to be the main reason for the negative impression it
      generates. The flexible cystoscope can be routinely used in place of the rigid
      counterpart for urological investigations and it is recommended that it be used
      more widely for the benefit of the patients.

PMID- 10585121
TI  - A comparative study of endoscopic trigonoplasty for vesicoureteral reflux in
      children and in adults.
AB  - BACKGROUND: Endoscopic trigonoplasty is an experimental therapy for
      vesicoureteral reflux. We investigated differences in surgical results between
      children and adults. METHODS: Endoscopic trigonoplasty was performed on 51
      patients and 15 pediatric and 21 adult patients were included in this study. The
      children accounted for 27 cases of refluxing ureter (grade II, 8; III, 14; IV, 4;
      V, 1) and the adults for 28 cases (I, 4; II, 18; III, 4; IV, 2). There was a
      greater proportion of bilateral disease and a higher average degree of reflux in
      the children's group. RESULTS: We found no significant differences in operative
      time, complications, analgesics usage, the duration of the indwelling catheter
      and hospital stay. Our follow up at 3 months showed that the reflux had ceased in
      19 of 27 cases (70%) in the children's group and in 27 of 28 cases (96%) in the
      adults' group. The next follow up at 12 months showed that there was no reflux in
      16 of 27 cases (59%) in 15 children and in 17 of 23 adult cases (74%). Trigonal
      splitting caused recurrence of reflux greater than grade II, in two children
      (13%) affecting four ureters and in three adults (14%) affecting four ureters.
      CONCLUSIONS: Endoscopic trigonoplasty has proved to be equally less invasive in
      children and in adults, but vesicoureteral reflux was less often resolved in
      children. This suggests that the greater original distance between the ureteral
      orifices and the greater thickness of the detrusor muscle favor the adult
      patient. For children, a new surgical concept is needed to increase cessation
      rate of vesicoureteral reflux.

PMID- 10585122
TI  - Proteoglycan core protein in human urine and its possible role on calcium oxalate
      urolithiasis.
AB  - BACKGROUND: There are only a few papers reporting on the role of proteoglycan
      core protein in calcium oxalate stone formation. The present study was carried
      out to investigate the role of core protein of proteoglycan in human urine on
      calcium oxalate (CaOx) crystallization. METHODS: Proteoglycans were collected
      from whole human urine. The covalently bound glycosaminoglycans (GAG) of
      proteoglycans were then digested by GAG lyase. The inhibitory activity on CaOx
      crystal growth in vitro was measured before and after enzyme digestion of
      proteoglycans. Sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS
      PAGE) of the core protein of proteoglycans and the analysis of amino acid
      sequence were performed. RESULTS: The core protein showed significant inhibitory
      activity on CaOx crystal growth, which scarcely changed when compared with that
      of proteoglycans before enzyme digestion. The SDS-PAGE revealed that the core
      protein was a single unit with a molecular weight of 26 kDa and amino acid
      sequencing demonstrated high homology to interalpha-trypsin inhibitor (ITI) light
      chain (bikunin) with Kunitz inhibitor domain as a core protein. CONCLUSIONS: The
      results suggested that human urine contains proteoglycans and a major part of
      them is ITI light chain (bikunin). The Kunitz inhibitor domain, a core protein of
      bikunin, has significant inhibitory activity on CaOx crystallization without GAG
      bound covalently to the core protein.

PMID- 10585123
TI  - Expression of protein tyrosine phosphatase PTP-RL10 and its isoform in the mouse
      testis.
AB  - BACKGROUND: The cytoplasmic-type protein tyrosine phosphatase PTP
      RL10/PTPD1/PTP2E contains an ezrin-like domain and associates with the c-Src
      protein tyrosine kinase. Because tyrosine phosphorylation regulated by protein
      tyrosine kinases and phosphatases is involved in activation, migration,
      differentiation and proliferation of various cell types, the expression of PTP
      RL10 and c-src in the mouse testis was investigated. METHODS: Testes of wild-type
      mice and W/W(v) mutant mice that lack germ cells were analyzed by northern
      blotting, in situ hybridization histochemistry and reverse transcriptase
      polymerase chain reaction for the expression of PTP-RL10, its isoform PTP-RL10b
      and c-src. Expression in the Sertoli cell lines, TM4 and TAMA26 was also
      analyzed. RESULTS: PTP-RL10 transcripts of 5.7kb and 2.9kb in size were detected
      in the testis. In situ hybridization histochemistry demonstrated that the 5.7kb
      transcripts were expressed in pachytene spermatocytes and somatic cells including
      Sertoli cells, in which c-src transcripts were detected. The 2.9kb transcript
      encoded a novel isoform, PTP-RL10b, that has the catalytic domain but not the
      domains that associate with c-Src. PTP-RL10b was expressed mainly in the
      testicular somatic cells. TM4 and TAMA26 cells were found to co-express PTP-RL10,
      PTP-RL10b and c-src transcripts. CONCLUSION: PTP-RL10 and its isoform are
      expressed in the Sertoli cells and are suggested to play roles in spermatogenesis
      by interacting with c-Src and/or other protein(s).

PMID- 10585124
TI  - A case of urethral recurrence found 15 years after radical cystectomy.
AB  - PURPOSE: A case of a urethral recurrence found 15 years after radical cystectomy
      is reported. METHODS/RESULTS: A 78-year-old man, who had undergone radical
      cystectomy at age 63, presented with urethral bleeding and positive cytology in
      urethral washing. The urethra was surgically resected. Pathologic examination
      revealed transitional cell carcinoma located in the distal and mid portion of the
      penile urethra. CONCLUSION: Evidence suggested that urethral recurrence resulted
      from the implantation from the primary bladder tumor; in addition, the urethral
      neoplasm had scarcely grown in the penile urethra for 15 years.

PMID- 10585125
TI  - Intra-arterial infusion of 5-fluorouracil, leucovorin and cisplatin for primary
      adenocarcinoma of the urinary bladder.
AB  - BACKGROUND: Primary invasive adenocarcinoma of the urinary bladder was diagnosed
      in a 59-year-old man with a 6-month history of macrohematuria. METHODS: He was
      treated with intra-arterial infusion of 5-fluorouracil, leucovorin and cisplatin
      and underwent radical cystectomy and construction of ileal conduit. RESULTS: The
      pathologic examination of the specimen revealed no viable malignant cells.
      CONCLUSION: 5-Fluorouracil combined with leucovorin and/or cisplatin has been
      used in the treatment of gastrointestinal adenocarcinoma and may be useful in
      primary adenocarcinoma of the bladder.

PMID- 10585126
TI  - Retroperitoneal hemorrhage due to spontaneous rupture of adrenal myelolipoma.
AB  - BACKGROUND: A very rare case of retroperitoneal bleeding due to spontaneous
      rupture of a large adrenal myelolipoma in a 62-year-old woman is reported.
      METHODS/RESULTS: She consulted the emergency room of the Nagano Red Cross
      Hospital with a complaint of sudden left flank pain. A computerized tomography
      (CT) scan revealed a tumor with areas of fat density and hematoma in the left
      retroperitoneal space. After her general condition improved, an operation was
      performed. The tumor strongly adhered to the left kidney and a left nephrectomy
      with the tumor was curative. Histologic diagnosis was adrenal myelolipoma. No
      blood transfusion was required. CONCLUSIONS: A CT scan is very useful in the pre
      operative diagnosis of adrenal myelolipoma with retroperitoneal hemorrhage. Watch
      and wait treatments before operation and nephrectomy with adhered tumor are safe
      and curative.

PMID- 10585127
TI  - Metachronous bilateral torsion of the testicular appendices.
AB  - BACKGROUND: Torsion of the appendix testis is a common cause of scrotal pain in
      children and a common cause for surgical exploration of the pediatric scrotum.
      The first case of metachronous bilateral torsion of the testicular appendices
      managed by a non-operative approach is reported. METHODS/RESULTS: A case report
      and a computer-assisted review of the literature are presented. Physical findings
      of a tender, mobile mass over the anterior surface of the testis characterize the
      presentation. Doppler findings of normal blood flow to the testes with increased
      flow to the adjacent appendix testis can be utilized as an adjunct to diagnosis.
      Ultrasonographic findings of a pedunculated mass with a central hypoechoic area
      at the superior aspect of the testis support the diagnosis. Accurate non
      operative diagnosis of torsion of the appendix testis permits successful
      conservative management with non-steroidal anti-inflammatory agents. CONCLUSIONS:
      Improvements in ultrasonographic and Doppler imaging of torsion of the appendix
      testis have facilitated the diagnosis of this entity and decreased the need for
      surgical exploration of the scrotum.

PMID- 10585128
TI  - Recommendations for glucose control in diabetics on CAPD.

PMID- 10585129
TI  - Time and frequency of hemodialysis.

PMID- 10585130
TI  - Angiotensin-II, renal anemia and hyporesponsiveness to recombinant human
      erythropoietin.

PMID- 10585131
TI  - Saline-induced dilutional acidosis in a maintenance hemodialysis patient.
AB  - A patient with end-stage renal disease developed severe hyperchloremic acidosis
      (venous serum total CO2 level of 10 mmol/L) after treatment with 16 L of isotonic
      saline. Analysis of this case and published literature indicates that dilutional
      acidosis may result when very large volumes of isotonic saline are administered
      intravenously, especially in patients with impaired or absent renal function.

PMID- 10585132
TI  - Telemedicine technology and applications for home hemodialysis.
AB  - Home hemodialysis (HD) for the treatment of patients with end-stage renal disease
      (ESRD) was first put into practice about 30 years ago. In this paper we describe
      the application of telematics monitoring services (TMS) for supporting patients
      who need home or satellite HD (SHD). For the clinical trials two modified HD
      machines were located in the renal unit and a central control station (UNIX
      workstation with multimedia PC-terminal) was located in another room of the
      hospital. Bi-directional communication between modified HD machines and central
      control station was managed via ISDN (Integrated Services Digital Network) links.
      Using these HD-machines 150 HD sessions were performed in nine patients over a
      period of five months. This system enabled on-line remote supervision of the HD
      machine-related functions (air in the blood, leak of blood, low conductivity
      etc.) and the clinical condition of patients through measurement of blood
      pressure (BP), pulse rate, PO2 (pulse oxymetry) and electrocardiogram (ECG) from
      the central control station (CCS). The user checked the type of alarm/warning,
      its appearance on HD machines and multimedia terminal units (MTU), the action of
      the protective system and the appearance of consultative messages from CCS on the
      remote terminal unit RTU. According to the data collected, the disturbances of HD
      machine function were visible and audible in the CCS and the user messages were
      always observed on the RTU. No unusual dialysis-associated complications were
      observed, all data and alarms/warnings were transmitted correctly and patients
      had adequate HD treatment.

PMID- 10585133
TI  - Optimization of the pump driven venous return for minimally invasive open heart
      surgery.
AB  - Blood return into the cardiotomy reservoir is usually reduced when a
      cardiopulmonary bypass (CPB) is initiated through a peripheral access, even if
      the tip of the venous cannula is pushed into the right atrium. A centrifugal pump
      can be placed on the venous line to increase the negative pressure. Surgery
      involving the right atrium requires selective cannulation of both vena cavae.
      Because of the small diameter of the vena cava as compared to the right atrium,
      the benefit of the centrifugal pump may have limitations. We analyze the factors
      influencing the active venous return when the cannula is maintained into the vena
      cava. In 4 calves (83.0+/-14.9 Kg) a CPB was initiated through carotid and
      jugular access, with the tip of the venous cannula placed into the superior vena
      cava, before ventricular fibrillation was provoked. Venous drainage was
      progressively increased thanks to the centrifugal pump. Considering the negative
      pressure induced on the venous line, we analyzed the performance expressed in
      l/min of blood drained, of four one stage cannulae ("lighthouse" tip 24F, 28F or
      32F, and percutaneous 28F). The performance of all cannulae were highly dependent
      on the central venous pressure (CVP) with better drainage for higher CVP. The
      size and type of cannula also significantly affected blood drainage. Active
      drainage was best with the percutaneous 28F cannula. This cannula was specially
      attractive at low CVP conditions.

PMID- 10585134
TI  - Thrombosis of angiographic catheters in humans: experimental study.
AB  - One of the major problems in the use of catheters is their thrombogenicity since
      the embolization of clots near the central nervous system or the coronary
      arteries can cause permanent damage. Catheter thrombogenicity was evaluated in
      humans during angiographic procedures by their tendency to become occluded.
      Characterization of catheters was achieved using roughness measurements, FTIR
      with ATR, DSC and ESCA. The catheters were 5 commercially available catheters,
      made mainly of polyethylene, Pebax or polyamide sterilized and ready for clinical
      use. Thirty-one patients due to have an angiographic procedure and with normal
      blood and hemodynamic parameters were included in the study. The 50 cm catheter
      test sample was inserted through an introducer into the femoral artery at the
      beginning of an angiographic procedure. The outcoming blood flow rate (BFR) was
      continuously monitored by a special computerized device for 15 min or until the
      total amount of blood reached 30 ml. The angiographic procedure was then normally
      resumed. DSC and FTIR showed results consistent with the expected composition of
      catheters. ESCA results showed very high Si/C ratios and could not be explained
      in all instances. Occlusion of the catheters occurred in 44% of the cases and the
      average time to obtain occlusion was 8.5 min (3-15 min). Values of the decrease
      rate of BFR in ml/min2 allowed separation of the catheters into 3 groups of low,
      medium and high thrombogenicity. However, occlusion occurred at least one time
      for each type of catheter. Blood volume and BFR curves vs. time allowed the
      determination of 3 main types of thrombotic behavior: type I shows no significant
      reduction of BFR; type II shows a progressive decrease in flow rate; type III is
      much less frequent and shows an abrupt decrease of BFR either quickly followed by
      a compensatory increase and resuming of a steady flow or by abrupt occlusion. In
      type II curves the pattern of occlusion follows a classical diffusion model
      because the Peclet number is greater than 1 and then the classical Higbie
      solution for diffusion could be used. The most thrombogenic material was the
      smoothest. There was no correlation between surface chemical composition and
      thrombogenicity. However, catheters that were based on PE appeared less
      thrombogenic than PA catheters in this study.

PMID- 10585135
TI  - Significantly improved survival time in pigs with complete liver ischemia treated
      with a novel bioartificial liver.
AB  - Aim of the study was to evaluate treatment efficacy and safety of a scaled-up
      version of our porcine hepatocytes based BAL system in pigs with complete liver
      ischemia (LIS). Thirty-one pigs underwent total devascularization of the liver
      (LIS) by termino-lateral porta-caval shunts and sutures around the bile duct, the
      common hepatic and gastroduodenal arteries and their accessory branches. The
      hepato-duodenal ligament was completely transected. Four experimental groups were
      studied: the first control group (LIS Control, n = 10) received glucose infusion
      only, the second control group (LIS Plasmapheresis, n = 8) was connected to a
      centrifugal plasma-separator with a bottle representing the bioreactor volume,
      the third control group (LIS Empty-BAL, n = 5) received BAL treatment without
      cells, and the treated group (LIS Cell-BAL, n = 8) was connected for a maximum
      period of 24 hours to our scaled-up BAL seeded with around 14 billion viable
      primary porcine hepatocytes. BAL treatment significantly prolonged life in large
      animals (approximately 35 kg) with complete LIS (Controls, mean +/- SEM: 33.1 +/-
      3 h, Cell-BAL: 51.1 +/- 3.4 h; p = 0.001; longest survivor 63 h). In addition,
      blood ammonia and total bilirubin levels decreased significantly, indicating
      metabolic activity of porcine hepatocytes in the bioreactor. No significant
      differences were noticed among the three control groups, indicating that there
      was no device effect and that the plasmapheresis procedure was well tolerated. No
      important adverse effects were observed.

PMID- 10585136
TI  - Femoral catheters: safety and efficacy in peripheral blood stem cell collection.
AB  - Central venous access is necessary in patients candidate for peripheral blood
      stem cell (PBSC) collection. We report our experience with a dual lumen femoral
      catheter (Gamcath, 11 french), initially designed for hemodialysis. We studied
      147 patients and performed 488 collections after mobilization with either G-CSF
      alone or chemotherapy + G-CSF, when the white blood cell count exceeded 1 x
      10(9)/L, or when a measurable population of CD34+ cells (20/microL) was detected
      in peripheral blood. All patients received systemic anticoagulation with a low
      weight heparin and ultrasound examination was performed after the removal of the
      catheter. Seven patients developed thrombosis (4.7%), ten experienced hematomas
      at the site of catheter placement (6.8%) despite prophylactic platelet
      transfusions, while only one patient (0.6%) had a catheter-related infection. In
      conclusion, the short-term use of large bore femoral catheters in setting up PBSC
      collection seems to be associated with minimal risk of infection and low
      thrombotic incidence.

PMID- 10585137
TI  - Preliminary study on HA coating percutaneously implanted in bone.
AB  - A comparative investigation on the possibility of hydroxyapatite (HA) coating and
      pure Ti column to form biological sealing with skin tissue was completed in this
      study. HA coating and pure Ti column were percutaneously implanted in the tibia
      of rabbits. Compared with titanium (Ti) implant, HA coating forms epithelial
      sealing with skin tissue at 6 weeks postoperatively, while the Ti implant may
      loosen from the implanted site and be lost. The Ti column loosing rate at this
      time was 50%. However, once the Ti implant becomes fixed with the bone tissue, it
      can form epithelial sealing with skin tissue just like the HA coating, at 8 weeks
      postoperatively. At 8 weeks postoperatively, the epithelial sealing is not
      destroyed in spite of the fact that the HA coating is biodegraded. Our results
      show that the HA coating can become fixed with the bone faster than the Ti, which
      is beneficial for epithelial sealing formation. The main role of HA coating for
      epithelial sealing is beneficial for sealing at the initial period after it is
      implanted.

PMID- 10585138
TI  - Synthetic peptide vaccines effective in preventing virus infection.

PMID- 10585139
TI  - Cytokine secretion by stimulated monocytes depends on the growth phase and heat
      treatment of bacteria: a comparative study between lactic acid bacteria and
      invasive pathogens.
AB  - The consumption of food containing lactic acid bacteria (LAB) has been shown to
      exert immunomodulatory effects in humans. The specific cellular interaction of
      these bacteria with immuno-competent cells has not yet been fully understood.
      Since the TNF-alpha secretion of stimulated monocytes is an important initial
      response to a bacterial challenge, we investigated the potential of LAB
      originating from the human intestine or fermented food in comparison to the
      effect of invasive pathogens. The challenge of monocytes with three LAB strains,
      Listeria monocytogenes or enterohaemorrhagic Escherichia coli (EHEC) elicited a
      strain specific, dose-dependent biphasic TNF-alpha secretion. The concentration
      (EDmax) of bacteria or bacterial cell wall components necessary to induce maximal
      TNF-alpha secretion (TNFmax) by monocytes was mathematically approximated. It was
      shown for exponentially growing LAB strains that the maximal TNF-alpha secretion
      (TNFmax) was stronger (57 to 78%) upon stimulation with living bacteria than with
      heat killed cells. In contrast to log-phase bacteria, the maximal TNF-alpha
      secretion of monocytes (TNFmax) was higher (15 to 55%) after the stimulation with
      heat killed, stationary-phase bacteria when compared to that of live LAB. Thus,
      monocyte stimulation was clearly affected by the growth phase of bacteria.
      Purified cell walls of LAB strains revealed only a limited potential for monocyte
      stimulation. LPS exhibited a higher capacity to stimulate monocytes than purified
      gram positive cell walls or muramyldipeptide. In comparison to pathogenic
      bacteria, the maximal secretory TNF-alpha response (TNFmax) was up to 2 fold
      higher with LAB strains. In general, the amount of bacteria (EDmax) necessary to
      induce maximal TNF-alpha secretion (TNFmax) was approximately 1 to 3 log higher
      for heat killed bacteria when compared to live bacterial cells illustrating the
      significant lower potential of heat killed bacteria to activate monocytes.

PMID- 10585140
TI  - Characterization of an outer membrane protein gene, pgmA, and its gene product
      from Porphyromonas gingivalis.
AB  - A gene upstream from fimA, the gene encoding fimbrilin, on the chromosome of
      Porphyromonas gingivalis was sequenced and shown to be the gene encoding an outer
      membrane protein in this organism based on homology and biochemical analyses.
      Therefore, the gene (formerly ORF5) was designated pgmA, the P. gingivalis outer
      membrane protein A gene. The gene product, PgmA, was sensitive to protease, and
      was detected as a 60-kDa protein from wild-type strains with trichloroacetic acid
      treatment, which was carried out to destroy intrinsic proteases, and from
      protease-deficient mutants without this treatment prior to electrophoresis. PgmA
      was indeed present in the membrane fraction. Its nature was determined to be that
      of outer membrane proteins in gram-negative bacteria based on attempts at
      differential extraction of inner membrane proteins with detergents. No evidence
      has been found thus far from functional analyses that this protein is related to
      fimbrial morphogenesis and functions or to serum resistance of this organism.

PMID- 10585141
TI  - A Clostridium perfringens hem gene cluster contains a cysG(B) homologue that is
      involved in cobalamin biosynthesis.
AB  - The hem gene cluster, which consists of hemA, cysG(B), hemC, hemD, hemB, and hemL
      genes, and encodes enzymes involved in the biosynthetic pathway from glutamyl
      tRNA to uroporphyrinogen III, has been identified by the cloning and sequencing
      of two overlapping DNA fragments from Clostridium perfringens NCTC8237. The
      deduced amino acid sequence of the N-terminal region of C. perfringens HemD is
      homologous to those reported for the C-terminal region of Salmonella typhimurium
      CysG and Clostridium josui HemD. C. perfringens CysG(B) is a predicted 220
      residue protein which shows homology to the N-terminal region of S. typhimurium
      CysG. Disruption of the cysG(B) gene in C. perfringens strain 13 by homologous
      recombination reduced cobalamin (vitamin B12) levels by a factor of 200. When
      grown in vitamin B12-deficient medium, the mutant strain showed a four-fold
      increase in its doubling time compared with that of the wild-type strain, and
      this effect was counteracted by supplementing the medium with vitamin B12. These
      results suggest that C. perfringens CysG(B) is involved in the chelation of
      cobalt to precorrin II as suggested for the CysG(B) domain of S. typhimurium
      CysG, enabling the synthesis of cobalamin.

PMID- 10585142
TI  - Role of the cytomegalovirus (CMV)-antigenemia assay as a predictive and follow-up
      detection tool for CMV disease in AIDS patients.
AB  - Forty-two patients were evaluated to determine the value of the CMV antigenemia
      (CMV-Ag) test as a follow-up marker as well as a prediction marker of CMV
      disease. Twenty patients were positive for at least one positive CMV-Ag assay and
      9 of them developed CMV retinitis. With the threshold value (10 positive cells),
      sensitivity was 56% and specificity was 94%. The CMV-Ag assay, with the threshold
      value, produced high specificity, positive predictive value and negative
      predictive value but relatively poor sensitivity. Eight patients experienced CMV
      disease relapse a total of 16 times. At relapse, 8 of the 16 times showed
      negative for CMV-Ag assay; 7 underwent systemic maintenance while 1 underwent
      local maintenance. It is inferred that the CMV-Ag test is a poor follow-up marker
      to detect the relapse of CMV disease, particularly in patients undergoing
      systemic maintenance.

PMID- 10585143
TI  - Chemokine receptor-usage of clinical HIV-1 isolates obtained from patients with
      HIV-1 infection in late clinical stages using PHA-blast.
AB  - In the present sudy, chemokine receptor-usage of primary HIV-1 isolates was
      examined using U87-CD4 cells expressing chemokine receptors CCR3, CCR5 and CXCR4.
      HIV-1 was isolated from the peripheral blood mononuclear cells (PBMC) and/or
      plasma of eight HIV-1-infected individuals in late CDC-II and CDC-IV clinical
      stages using PHA-blast prepared from the PBMC of healthy blood donors. The
      primary HIV-1 isolates from patients in late CDC-II stage rarely infected
      monocyte-derived macrophages in the present study, whereas most isolates from
      patients in the CDC-IV stage infected the macrophages. In the experiments using
      U87-CD4 cells expressing chemokine receptors, the isolates from patients in the
      late CDC-II stage infected U87-CD4 cells expressing CXCR4, but not U87-CD4 cells
      expressing CCR5. In contrast, most isolates from patients in the CDC-IV stage
      infected both U87-CD4 cells expressing CXCR4 or CCR5. The isolates which infected
      both U87-CD4 cells were supposed to contain dual tropic HIV-1 or a mixture of
      CXCR4-tropic and CCR5-tropic HIV-1s. Analysis of the deduced amino acid sequence
      of the V3 region in proviral env gene showed that the V3 region in U87-CD4 cells
      infected with CXCR4-tropic HIV-1 isolates was largely different from that in the
      cells infected with CCR5-tropic isolates, but were highly similar to that in
      cells infected with dual tropic isolates. These results suggest that PHA-blasts
      may preferentially support the replication of the CXCR4-tropic and dual tropic
      HIV-1s, and that CXCR4-tropic and dual tropic HIV-1s are also present in
      peripheral blood from patients in the late stage of the asymptomatic phase.

PMID- 10585144
TI  - Decreased prevalence of Orientia tsutsugamushi in trombiculid mites and wild
      rodents in the Primorye region, Far East Russia.
AB  - The isolation of Orientia tsutsugamushi was attempted from 249 rodents and
      approximately 14,000 trombiculid mites captured in the Primorye region, Far East
      Russia in 1993 and 1994, where high infection rates were recorded in both rodents
      and mites in the 1960s. However, no rickettsia was isolated from the samples. Low
      antibody titers against O. tsutsugamushi were detected in 7.1% of the rodents.
      These results indicate that the prevalence of O. tsutsugamushi in the Primorye
      region has decreased considerably in the past 30 years.

PMID- 10585145
TI  - Isolation of Orientia tsutsugamushi from patients in Shikoku and finding of a
      strain which grows preferentially at low temperatures.
AB  - Three strains of Orientia tsutsugamushi were isolated from patients in Anan City,
      Tokushima Prefecture. The strains were identified as Karp type by analyses of
      reactivities with type-specific monoclonal antibodies. One strain, Okazaki, was
      isolated in L cells cultivated at 31 C, but not in cells at 36 C or in mice. This
      strain showed better growth at 31 C than 36 C. This is the first report of an O.
      tsutsugamushi strain which grows preferentially at low temperatures.

PMID- 10585146
TI  - Sequence analysis of the gene encoding a spotted fever group-specific
      intracytoplasmic protein PS120 of Rickettsia japonica.
AB  - The 3,438-nucleotide (nt) sequence containing a 3,054-nt open reading frame of
      the gene (rps120) encoding an antigenic, intracytoplasmic, spotted fever group
      specific and heat-stable 120-kilodalton protein (PS120) of Rickettsia japonica
      was determined. The nt and deduced 1,018 amino-acid (aa) sequences were compared
      to those of R. conorii since only those of this species had been determined among
      SFG rickettsiae. The homologies of these sequences between R. japonica and R.
      conorii were considerably high at 97 and 95%, respectively. These high homologies
      were comparable to those of beta-peptides encoded by the ompB genes among SFG
      rickettsiae. It was also found that the genome of R. prowazekii contained a nt
      sequence with 68% homology to that of the rps120 gene of R. japonica.

PMID- 10585147
TI  - Complete nucleotide sequence and the genome organization of tobacco leaf curl
      geminivirus from Japan.
AB  - The genomic DNA of tobacco leaf curl geminivirus (TLCV) from tomato plants with
      leaf curl disease in Japan has been sequenced. The single circular DNA molecule
      comprises 2,761 nucleotides. TLCV DNA contains six open reading frames (ORFs)
      capable of encoding proteins with a molecular weight greater than 10 K. In total
      nucleotide sequence comparisons with other geminiviruses, TLCV was most closely
      related to tomato leaf curl virus from Taiwan (TwToLCV) (76% identity), tomato
      leaf curl virus from Bangalore (ToLCV-Ba) (74%) and agerantum yellow vein virus
      (AYVV) (74%), all possessing a monopartite genome. The significant but relatively
      low sequence similarity in the genomic DNA between TLCV and other geminiviruses
      suggests it is a distinct geminivirus in genus Begomovirus.

PMID- 10585148
TI  - A literature review of cardiopulmonary bypass models for rats.
AB  - Cardiopulmonary bypass (CPB) has improved a great deal since its first
      applications in the early 1950s. If improvements are to be continued, a
      preclinical model of CPB for small animals is desirable, mainly because of
      convenience of equipment and low costs. We review the different models of CPB for
      rats that have been designed, discuss their characteristics and points where
      improvements may be made. We give suggestions and requirements for a new up-to
      date model that could be a useful tool in continued research on the
      pathophysiology and therapeutic strategies of CPB.

PMID- 10585149
TI  - Vacuum assisted venous drainage (VAVD).
AB  - Poor venous drainage is a common problem in cardiac surgery, causing trouble for
      the surgeon and adverse effects to the patient. Smaller incisions for minimally
      invasive cardiac surgery require smaller venous catheters. In this study the
      function, safety and possible benefits of a system for vacuum assisted venous
      drainage has been tested experimentally and applied clinically. A vacuum
      regulator ('The Hamlet box') and safety procedures were developed. The system was
      characterized in vitro in regard to the relationship between vacuum, catheter
      size, and blood temperature and flow. The clinical study included 54 adult
      patients, coronary artery bypass graft surgery and valve operations. Venous
      cannulation was bi-caval with two 24 Fr catheters. All the perfusions were
      essentially event free, and the system was easy to manage and regulate. Venous
      drainage was totally adequate, irrespective of the position of the heart, and
      less fluid was added during the perfusions (a median of 250 ml/patient compared
      to a median of 1000 ml/patient in the control group). There has been no evidence
      of increased haemolysis or other adverse effects. All patients were hospital
      survivors and had uneventful postoperative courses. Vacuum assisted venous
      drainage is now used routinely, and further studies are under way to develop the
      system and clarify the physiological effects.

PMID- 10585150
TI  - Oxygenator thrombosis: an international phenomenon.
AB  - Oxygenator thrombosis, despite adequate anticoagulation, has become a recent
      concern amongst perfusionists worldwide. The phenomenon is characterized by a
      transient increase in oxygenator inlet pressure of up to 900 mmHg about 10-15 min
      after the institution of cardiopulmonary bypass (CPB). Depending on the size and
      location of the thrombus, shunting may occur that compromises gas transfer to the
      extent where oxygenator change-out is necessary. This article presents various
      case reports and publications, both domestic and international, detailing this
      phenomenon. Research hypothesizes that it is the activation of platelets that
      subsequently may cause the deposition of fibrin, yielding thrombus formation;
      however, the primary etiology of this phenomenon remains unknown. Possible
      catalysts include bypass techniques, equipment selection, pharmacological agents,
      prime and the patient. This paper will review all of the above with an emphasis
      on the often overlooked factor--the patient, as there are certain variables in
      patient hematology that provoke a hypercoagulable state leading to thrombosis,
      including blood type, genetics, age, disease state, gender and heparin.

PMID- 10585151
TI  - Predictors for heparin resistance in patients undergoing coronary artery bypass
      grafting.
AB  - Heparin resistance (HR) is a common event in cardiac operations. At present, no
      clear recognition of the risk factors for HR has been reached. The aim of this
      study was to determine a predictive model for HR, based on the preoperative
      patient's profile. Two hundred consecutive patients scheduled for elective
      coronary artery bypass operations were enrolled in a prospective trial.
      Demographics, type of preoperative anticoagulation therapy and preoperative
      coagulation profile were collected and statistically analysed with respect to the
      evidence of a HR. Heparin resistance was defined as at least one activated
      clotting time < 400 s after heparinization and/or the need for purified
      antithrombin III (AT-III) administration. With a multivariate analysis we could
      identify five predictors for HR: AT-III < or = 60%; preoperative subcutaneous
      heparin therapy; intravenous heparin therapy; platelet count > or = 300000
      cells/mm3; age > or = 65 years. We conclude that HR is a predictable event. In
      the presence of all the risk factors, the likelihood of HR is 99%; in the absence
      of all of them, it is 10%. Predicting HR allows us to apply many possible
      therapeutic strategies.

PMID- 10585152
TI  - Tubing failure during prolonged roller pump use: a laboratory study.
AB  - Little is known about the mechanical forces acting on extracorporeal circuit
      tubing with prolonged roller pump use during extracorporeal membrane oxygenation
      (ECMO). We examined the time to tubing rupture of three different materials
      during actual roller pump use, mean and standard deviation (SD) (SD shown in
      parentheses): Tygon (control) 243.7 h (175.4); LVA 121 h (14.3); and SRT 6.6 h
      (2.1). Failure times for both LVA and SRT were significantly different from the
      control (paired t-test, p = 0.02 and p < 0.001, respectively). The minimum
      failure times for Tygon and LVA were 99 and 101 h, respectively. We then examined
      Tygon under conditions of pure compression, demonstrating that even after 3.67
      million compression cycles at full occlusion crack formation did not occur. If
      the tubing was over-occluded, cracks appeared within 24 h. Scanning electron
      microscopy of Tygon, which has been used during clinical ECMO, and the failure
      pattern during destruction testing demonstrate that shear stress and compression
      coexist during clinical ECMO. Use of under-occlusive pump settings could improve
      tubing life.

PMID- 10585153
TI  - A new bladder allows kinetic venous augmentation with a roller pump.
AB  - Augmented venous drainage improves venous return during minimally invasive
      cardiac surgery. Two systems to augment drainage are common: in one, a
      centrifugal pump draws blood from the venous site and pumps it into a venous
      reservoir. In the other, suction is applied directly to a hard-shell venous
      reservoir. Both systems overcome the high resistance of the venous cannula when
      gravity alone is insufficient to provide adequate drainage. Both systems also
      have shortcomings: in the first approach, the centrifugal pump head can entrap
      large bubbles, reducing flow and requiring pump stoppage to remove them. Air from
      the venous line also can be broken up by the centrifugal pump into small bubbles
      that can pass through the pump head. The direct suction system in the second
      approach cannot use a closed-bag reservoir, and has the potential to introduce
      air into the arterial line. We have developed a new venous augmentation system
      for a closed venous reservoir that provides excellent suction control without the
      potential to introduce air into the arterial line. Our system replaces the
      centrifugal pump of the first approach with a roller pump controlled by the
      Better-Bladder, a new device with FDA 510(k) clearance for long-term pumping. The
      Better-Bladder is a length of medical tubing, processed to form a thin-walled,
      enlarged bladder that is sealed within a clear rigid housing. It acts as an in
      line reservoir that provides compliance in the venous line and a noninvasive
      means to measure blood pressure at the pump inlet. The bladder housing can
      maintain a negative pressure set by the user that controls the degree of gravity
      drainage. Tests have shown that the Better-Bladder allows for safe, smooth pump
      control using a roller pump in the venous line.

PMID- 10585154
TI  - Outcome analysis of coronary artery bypass grafting: minimally invasive versus
      standard techniques.
AB  - Minimally invasive coronary artery bypass grafting (MIDCAB) procedures are
      purported to result in improvements in patient management over standard
      techniques. A comparative study was performed on risk-stratified patients treated
      with either technique. Following institutional review board approval, a
      retrospective random chart review was conducted on 27 MIDCAB and 37 standard
      coronary artery bypass grafting (CABG) patients who were operated on over a 12
      month period at the University of Nebraska Medical Center. Risk stratification
      was accomplished by dividing the two patient populations, MIDCAB and 'standard',
      into one of four subgroups based on a preoperative risk score. Risk
      stratification was achieved by dividing the patient populations into one of four
      subgroups: good, fair, poor and high risk. Both groups received similar
      operations and surgical interventions, except for the inclusion of
      cardiopulmonary bypass (CPB). Approximately 200 parameters were collected and
      analyzed in the following categories: anthropometric, operative and postoperative
      outcomes. The MIDCAB group had a significantly lower number of vessels bypassed
      (2.0+/-0.7 vs 3.4+/-0.9, p < 0.0001). Total postoperative blood product
      transfusions trended higher in the standard group (6.1+/-12.6 U) when compared to
      the MIDCAB patients (2.3+/-5.5 U, p < 0.15), although not statistically
      significant. Postoperative inotrope use was significantly less in the MIDCAB
      group (19% vs 59%, p < 0.002). Ventilator time in the MIDCAB group was 10.5+/-5.4
      h vs 15.0+/-12.3 h in the standard group (p < 0.07). The MIDCAB group had an
      overall greater length of stay, but was only statistically different within the
      poor-risk subgroup (12.2+/-10.7 vs 7.5+/-3.9, p < 0.04). The results of this
      study show that when CPB is not utilized in treating patients undergoing CABG
      procedures, the benefits in regards to patient outcomes are unclear. This
      necessitates the need for further work when comparing outcomes for risk
      stratified patients.

PMID- 10585155
TI  - Effect of Trillium Biopassive Surface coating of the oxygenator on platelet count
      drop during cardiopulmonary bypass.
AB  - The new Trillium Biopassive Surface is a coating designed to minimize the
      adsorption of protein and the attachment of cells. In previous studies, we were
      able to demonstrate that, by coating the bypass circuit with small amounts of
      albumin, the drop in circulating platelet count seen with the newer low-prime
      hollow-fiber membrane oxygenators is eliminated. A study was undertaken to
      compare the Avecor Affinity oxygenator with albumin in the prime with the
      Trillium-coated Affinity. Fifty-six patients undergoing nonemergency open-heart
      surgery were randomly divided into two groups. One group (Albumin) received the
      Affinity oxygenator with 10 ml of 25% albumin added to the pump prime. The other
      group (Trillium) received the Trillium-coated Affinity oxygenator. To normalize
      the data for the effects of hemodilution, the mean net platelet count drop on
      bypass was calculated for each group. The Albumin group had a net platelet count
      drop of 0.81+/-9.78%, while the Trillium group had a drop of 1.58+/-13.0%. There
      was no significant statistical difference between the two groups. From our
      investigation, we concluded that Trillium Biopassive Surface coating affords the
      Affinity oxygenator the same protective effects on circulating platelet counts as
      adding albumin to the prime.

PMID- 10585156
TI  - Ex vivo testing of the Quart arterial line filter.
AB  - Arterial line filters are now routinely used in cardiac surgery in order to
      decrease the microemboli load to the patient. The Quart filter (Jostra,
      Hirrlingen, Germany) with a new planar construction design, an easy de-airing
      system and an integrated bypass, was tested for air filtration capacity and
      resistance to blood path in a standardized setting with surviving animals. Three
      calves (mean body weight: 71+/-3.4 kg) were connected to a standard
      cardiopulmonary bypass (CPB) circuit by jugular venous and carotid arterial
      cannulation with a mean flow rate of 3.5 l/min. The arterial line filter was
      challenged with upstream injections of boluses of air of 5, 10 and 15 ml,
      respectively. A Doppler ultrasound was positioned downstream on the arterial line
      to measure bubble count and size. The pressure drop through the filter was
      monitored at flow rates of between 1 and 6 l/min. At the end of the procedure the
      animals were weaned from the CPB and, thereafter, from the ventilator. After 7
      days, the animals were sacrificed electively. This study shows that important
      quantities of air can be injected into the arterial line upstream of the filter
      with small volumes of small sized bubbles recorded downstream. With the 5 ml air
      bolus injection, mean values of 0.3+/-0.6 bubbles of 30 and 40 microm were
      detected, whereas with the 20 ml bolus, 32.6+/-8.7 bubbles of 10 microm, 3.7+/
      1.1 bubbles of 30 microm, 3.3+/-0.6 bubbles of 40 microm and 0.7+/-1.1 bubbles of
      50 microm were recorded. The blood path resistance at different blood flow rates
      was well within the acceptable range with a pressure drop of 20+/-0 and 26.6+/
      5.7 mmHg at flow rates of 4 and 5 l/min, respectively. With its planar concept,
      the Quart filter offers good air filtering capacity both in terms of bubble count
      and size after injection of large boluses of air, without any increase of
      resistance to the blood path. Moreover, it offers a venting function and an
      integrated bypass system.

PMID- 10585157
TI  - Extracorporeal lung support in a patient with traumatic brain injury: the benefit
      of heparin-bonded circuitry.

PMID- 10585158
TI  - Variation in hippocampal dynorphin b-immunoreactive mossy fiber terminal fields
      of apomorphine-(un)susceptible rats.
AB  - The size of distinct hippocampal sub-fields were measured in the apomorphine
      susceptible and apomorphine-unsusceptible rat lines. Mossy fiber terminal fields
      were delineated using dynorphin B immunoreactivity and area measurements were
      taken from (1) the supra-pyramidal mossy fiber terminal field; (2) the intra- and
      infra-pyramidal mossy fiber terminal field; (3) the hilus of the fascia dentata
      (4) the non dynorphin B immunoreactive area of the regio inferior and fascia
      dentata and (5) the total area of regio inferior and fascia dentata. The data
      indicate that statistically significant differences in the morphometry of the
      hippocampal subfields of the apomorphine susceptible and unsusceptible rats are
      confined to the intra- and infra terminal field: the relative size of the left
      and right intra- and infra terminal field of apomorphine unsusceptible rats are
      significantly larger than those of the apomorphine susceptible rats. These data
      explain at least in part the differential response of these rats to novelty.

PMID- 10585159
TI  - Mapping of cytoskeletal components in the hippocampal formation of the tree shrew
      (Tupaia belangeri).
AB  - The distribution of the major cytoskeletal components in frontal cryosections of
      the hippocampal formation of adult male tree shrews (Tupaia belangeri) was
      immunohistochemically investigated by using commercially available antibodies.
      Actin-immunolabeling was evident in all layers of the dentate gyrus as well as in
      the regio superior (CA1) and the regio inferior (CA3). Neurofilament 160 was
      detected only in the molecular layer of the dentate gyrus and in the axons of the
      granule cells (mossy fibers). For beta-tubulin, the microtubule associated
      proteins (MAPs) MAP2AB, MAP2ABC and Tau, immunoreactivity was evident within the
      granule cells and within the somatodendritic compartment of pyramidal neurons.
      Granule cells and the somata of the pyramidal neurons were intensely labeled for
      kinesin. Our findings show the elaborate expression of cytoskeletal proteins in
      the hippocampal formation of the tree shrew, relatively similar to what is seen
      in other species but with also some important differences, such as the
      immunonegativity of the axonal compartment for Tau in the tree shrew, which is
      contrary to what we see in the mouse (unpublished data). These findings provide
      useful insights regarding the organization of the hippocampal formation of the
      tree shrew and are fundamental for further research in this field.

PMID- 10585160
TI  - Chemical and anatomical changes in the striatum and substantia nigra following
      quinolinic acid lesions in the striatum of the rat: a detailed time course of the
      cellular and GABA(A) receptor changes.
AB  - The pattern and time-course of cellular, neurochemical and receptor changes in
      the striatum and substantia nigra were investigated following unilateral
      quinolinic acid lesions of the striatum in rats. The results showed that in the
      central region of the striatal lesion there was a major loss of Nissl staining of
      the small to medium sized cells within 2 h and a substantial loss of neuronal
      staining within 24 h after lesioning. Immunohistochemical studies showed a total
      loss of calbindin immunoreactivity, a known marker of GABAergic striatal
      projection neurons, throughout the full extent of the quinolinic acid lesion
      within 24 h. Similarly, within 24 h, there was a total loss of
      somatostatin/neuropeptide Y cells in the centre of the lesion but in the
      periphery of the lesion these cells remained unaltered at all survival times.
      Striatal GABA(A) receptors remained unchanged in the lesion for 7 days, and then
      declined in density over the remainder of the time course. Glial fibrillary
      acidic protein immunoreactive astrocytes were present in the periphery of the
      lesion at 7 days, occupied the full extent of the lesion by 4 weeks, and remained
      elevated for up to 2 months. In the substantia nigra, following placement of a
      striatal quinolinic acid lesion, there was: a loss of substance P
      immunoreactivity within 24 h; a marked astrocytosis evident from 1-4 weeks
      postlesion; and, a major increase in GABA(A) receptors in the substantia nigra
      which occurred within 2 h postlesion and was sustained for the remainder of the
      time course (15 months). This study shows that following quinolinic acid lesions
      of the striatum there is a major loss of calbindin and somatostatin/neuropeptide
      Y immunoreactive cells in the striatum within 24 h, and a marked increase in
      GABA(A) receptors in the substantia nigra within 2 h. These findings are similar
      to the changes in the basal ganglia in Huntington's disease and provide further
      evidence supporting the use of the quinolinic acid lesioned rat as an animal
      model of Huntington's disease.

PMID- 10585161
TI  - Localization of huntingtin-interacting protein-2 (Hip-2) mRNA in the developing
      mouse brain.
AB  - Huntingtin-interacting protein-2 (Hip-2) was identified as a human protein
      specifically associated with huntingtin in vitro, a gene product affected in
      patients with Huntington disease (HD). It is a ubiquitin-conjugating enzyme
      identical to the previously characterized bovine E2-25k. We identified the mouse
      Hip-2 homologue (mHip-2) and examined its distribution patterns in the developing
      mouse brain in order to gain an insight into the functional significance of the
      Hip-2 protein in the normal brain as well as in the pathogenesis of HD. As
      reported with huntingtin, the mHip-2 mRNA expression developed in parallel with
      neuronal maturation and became distributed widely in the postnatal mouse brain.
      This spatiotemporal pattern of mHip-2 mRNA expression resembled that of
      huntingtin. We further demonstrated that mHip-2 mRNA was colocalized with
      huntingtin-like immunoreactivity in a single neuron. These findings suggested
      that the Hip-2 interacted with huntingtin in vivo and played an important role in
      HD pathogenesis.

PMID- 10585163
TI  - Sport, leisure and ergonomics.

PMID- 10585162
TI  - NADPH-diaphorase and cytosolic urea cycle enzymes in the rat accessory olfactory
      bulb.
AB  - The nitric oxide cycle consists of nitric oxide synthase, argininosuccinate
      synthetase and argininosuccinate lyase to form nitric oxide. We have examined the
      colocalization of nitric oxide synthase and the cytosolic urea cycle enzymes
      (argininosuccinate synthetase, argininosuccinate lyase and arginase) in the
      accessory olfactory bulb of the rat by using a double labeling procedure
      combining reduced-nicotinamide-adenine-dinucleotide-phosphate-diaphorase (NADPH
      d) reaction with fluorescent immunocytochemistry. Each glomerulus showed a
      different NADPH-d activity, and those with the strongest NADPH-d activities were
      assembled in the caudomedial part of the accessory olfactory bulb.
      Argininosuccinate synthetase-like immunoreactive glomeruli were distributed in
      the caudomedial part of the accessory olfactory bulb, and most of them were also
      strongly NADPH-d positive. The mitral or tufted cells were argininosuccinate
      synthetase-, argininosuccinate lyase- and arginase-like immunoreactive, but were
      not NADPH-d positive. The granule cells were NADPH-d positive or
      argininosuccinate lyase-like immunoreactive, but were not argininosuccinate
      synthetase- or arginase-like immunoreactive. Some granule cells were both NADPH-d
      positive and argininosuccinate lyase-like immunoreactive. The results indicate
      the heterogeneity of glomeruli of the accessory olfactory bulb with respect to
      the distribution of these enzymes. The granule cells have nitric oxide synthase
      and argininosuccinate lyase, and thus may efficiently produce nitric oxide.

PMID- 10585164
TI  - The relationship between selected physiological variables of rowers and rowing
      performance as determined by a 2000 m ergometer test.
AB  - The aim of this study was to establish the relationship between selected
      physiological variables of rowers and rowing performance as determined by a 2000
      m time-trial on a Concept II Model B rowing ergometer. The participants were 13
      male club standard oarsmen. Their mean (+/- s) age, body mass and height were
      19.9+/-0.6 years, 73.1+/-6.6 kg and 180.5+/-4.6 cm respectively. The participants
      were tested on the rowing ergometer to determine their maximal oxygen uptake
      (VO2max), rowing economy, predicted velocity at VO2max, velocity and VO2 at the
      lactate threshold, and their velocity and VO2 at a blood lactate concentration of
      4 mmol x l(-1). Percent body fat was estimated using the skinfold method. The
      velocity for the 2000 m performance test and the predicted velocities at the
      lactate threshold, at a blood lactate concentration of 4 mmol x l(-1) and at
      VO2max were 4.7+/-0.2, 3.9+/-0.2, 4.2+/-0.2 and 4.6+/-0.2 m x s(-1) respectively.
      A repeated-measures analysis of variance showed that the three predicted
      velocities were all significantly different from each other (P<0.05). The VO2max
      and lean body mass showed the highest correlation with the velocity for the 2000
      m time-trial (r = 0.85). A stepwise multiple regression showed that VO2max was
      the best single predictor of the velocity for the 2000 m time-trial; a model
      incorporating VO2max explained 72% of the variability in 2000 m rowing
      performance. Our results suggest that rowers should devote time to the
      improvement of VO2max and lean body mass.

PMID- 10585165
TI  - The effect of longer-term creatine supplementation on elite swimming performance
      after an acute creatine loading.
AB  - We investigated the effect of an acute creatine loading (25 g per day for 4 days)
      and longer-term creatine supplementation (5 g of creatine or 5 g of placebo per
      day for 2 months) on the performance of 22 elite swimmers during maximal interval
      sessions. After the acute creatine loading, the mean of the average interval swim
      times for all swimmers (n = 22) improved (44.3+/-16.5 s before vs. 43.7+/-16.3 s
      after supplementation; P<0.01). Three of the 22 swimmers did not respond
      positively to supplementation. After 2 months of longer-term creatine
      supplementation or placebo, neither group showed a significant change in swimming
      performance (38.7+/-13.5 s before vs. 38.7+/-14.1 s after for the creatine group;
      48.7+/-18.0 s before vs. 48.7+/-18.1 s after for the placebo group). We conclude
      that, in elite swimmers, 4 days of acute creatine loading improves swimming
      performance significantly when assessed by maximal interval sessions. However,
      longer-term supplementation for 2 months (5 g of creatine per day) did not
      benefit significantly the creatine group compared with the placebo group.

PMID- 10585166
TI  - Development and validation of a mood measure for adolescents.
AB  - The aim of this study was to develop and validate a shortened version of the
      Profile of Mood States suitable for use with adolescents. The Profile of Mood
      States-Adolescents (POMS-A) was administered to 1693 participants from two
      populations: school children and young athletes. Confirmatory factor analysis
      supported the factorial validity of a 24-item six-factor model using both
      independent and multi-sample analyses. Correlations of POMS-A scores with
      previously validated inventories, which were consistent with theoretical
      predictions, provided evidence of criterion validity. It is proposed that the
      POMS-A is a valid instrument for the assessment of mood in adolescents.

PMID- 10585167
TI  - Does the individual zones of optimal functioning model discriminate between
      successful and less successful athletes? A meta-analysis.
AB  - According to the individual zones of optimal functioning (IZOF) model, an
      athlete's performance is successful when his or her pre-competition anxiety is
      within or near the individually optimal zone. When anxiety falls outside the
      optimal zone, performance deteriorates. The model also suggests that skilled
      athletes are aware of, and are able to accurately recall and anticipate, their
      pre-competition anxiety. A meta-analysis of 19 studies from 1978 to 1997 (146
      effect sizes based on 6387 participants) was conducted to examine the validity of
      the assumptions regarding the in-out of the zone notion and the accuracy of
      recalls and anticipatory measures of anxiety. The findings provide fairly good
      empirical support for the IZOF anxiety model, with an overall effect size (d) for
      the in-out of the zone notion of d = +0.44 (41 effect sizes, n = 3175). In other
      words, the performance of athletes who were within their individually optimal
      zones were almost one-half a standard deviation unit better than that of athletes
      who were outside their zones. Furthermore, both effect sizes (r(w)) for accuracy
      of precompetition anxiety measures, recall (r(w) = +0.71, 24 effect sizes, n =
      369) and anticipatory (r(w) = +0.69, 81 effect sizes, n = 2843), exceeded the
      'large effect' suggested for correlations by Cohen. The implications for future
      research extending the IZOF model to a wider range of positive and negative
      emotions are discussed.

PMID- 10585168
TI  - Energy substrate metabolism during dual work rate exercise: effects of order.
AB  - Changes in workload are evident during many physical activities. The aim of this
      study was to assess total substrate metabolism when the temporal placement of a
      period of higher-intensity work (75% VO2max) was varied within a low-intensity
      exercise session (50% VO2max). One experimental trial (higher intensity first)
      comprised 5 min low-intensity work, followed by 15 min high-intensity work,
      followed by 40 min low-intensity work. The other trial (low intensity first)
      comprised 40 min low-intensity work, followed by 15 min high-intensity work,
      followed by 5 min low-intensity work. The trials were designed to achieve an
      identical total energy expenditure. Energy expenditure, fat and carbohydrate
      utilization were estimated by expired gas analysis and compared between
      conditions. Mean total energy expenditure during the higher-intensity phase was
      1076 kJ and 1128 kJ in the high-intensity first and low-intensity first trials
      respectively (t6 = -3.76, P = 0.0047). Mean total energy expenditure for the
      whole trial was 3356 kJ and 3452 kJ in the high-intensity first and low-intensity
      first trials respectively (t6 = -3.48, P = 0.0065). Mean whole-trial fat
      utilization was 1753 kJ and 1857 kJ in the high-intensity first and low-intensity
      first trials respectively (t6 = -0.76, P = 0.24). Our findings suggest that
      changing the temporal placement of higher-intensity work within a low-intensity
      exercise session has a significant effect on total energy expenditure but not on
      the rate of fat oxidation.

PMID- 10585169
TI  - The influence of intermittent high-intensity shuttle running and fluid ingestion
      on the performance of a soccer skill.
AB  - The aim of this study was to examine the effect of intermittent high-intensity
      shuttle running and fluid ingestion on the performance of a soccer skill. Nine
      semi-professional soccer players volunteered to participate in the study. Their
      mean (+/- s(x)) age, body mass and maximal oxygen uptake were 20.2+/-0.4 years,
      73.2+/-1.8 kg and 59.1+/-1.3 ml x kg(-1) min(-1) respectively. The players were
      allocated to two randomly assigned trials: ingesting or abstaining from fluid
      intake during a 90 min intermittent exercise protocol (Loughborough Intermittent
      Shuttle Test: LIST). This test was designed to simulate the minimum physical
      demands faced by soccer players during a game. Before and immediately after
      performance of the test, the players completed a soccer skill test and a mental
      concentration test. Performance of the soccer skill test after the 'no-fluid'
      trial deteriorated by 5% (P<0.05), but was maintained during the fluid trial.
      Mean heart rate, perceived exertion, serum aldosterone, osmolality, sodium and
      cortisol responses during the test were higher (P<0.05) in the 'no-fluid' trial
      than in the fluid trial. The results of this study suggest that soccer players
      should consume fluid throughout a game to help prevent a deterioration in skill
      performance.

PMID- 10585170
TI  - Osteoporosis: prevention with estrogens in women over 60.

PMID- 10585171
TI  - Reproductive history and cardiovascular disease risk in postmenopausal women: a
      review of the literature.
AB  - OBJECTIVES: It is widely believed that oestrogen protects postmenopausal women
      from cardiovascular disease. It is unknown, however, whether reproductive
      history, which affects endogenous oestrogen levels during a woman's life, also
      influences cardiovascular disease risk in postmenopausal women. We present an
      overview of the studies which investigate the relationship between reproductive
      history and risk for cardiovascular disease in women. METHODS: We conducted a
      Medline search of literature pertaining to age at menarche, age at menopause,
      parity and gravidity, breast-feeding, and length and regularity of the menstrual
      cycle in relation to cardiovascular diseases. Data extraction and synthesis were
      performed by comparing odds ratios and relative risks presented or calculated.
      RESULTS: Age at menarche was not found to influence cardiovascular disease risk,
      while menstrual cycle irregularity was associated with this risk. The studies
      pertaining to parity presented conflicting results: protection against as well as
      an increase in the risk of cardiovascular disease were found in parous women.
      Pregnancy loss appeared to be related to cardiovascular disease risk. Age at
      menopause proved to be the reproductive factor most clearly related to
      cardiovascular disease risk. CONCLUSIONS: Only menstrual cycle irregularity,
      pregnancy losses, and age at menopause are possibly related to cardiovascular
      disease risk in postmenopausal women. All reproductive factors need to be studied
      together in order to assess reproductive history in a proper manner. Research of
      this kind will be essential if we are to further increase our knowledge regarding
      the nature of the effects of endogenous oestrogen on cardiovascular disease.

PMID- 10585172
TI  - Perception of future health risks in mid-aged women: estimates with and without
      behavioural changes and hormone replacement therapy.
AB  - Cardiovascular disease (CVD) and cancer are major causes of death for women, and
      osteoporosis negatively impacts upon the health and quality of life of many older
      women. There is evidence that risk of developing these diseases is partially
      determined by lifestyle factors, such as physical activity, diet and smoking, as
      well as being influenced by hormonal changes during the menopause. Participation
      in preventive strategies will be influenced by women's perceptions of the
      relative risks of developing these diseases, and beliefs about the effectiveness
      of the particular strategy. In this study, 103 mid-aged women were asked about
      their health and health behaviours and to estimate: (1) their future likelihood
      of developing CVD, osteoporosis and breast cancer; and (2) their future
      likelihood of developing diseases (a) if they improved their health behaviours,
      and (b) if they used hormone replacement therapy (HRT) for 5 years. Women
      believed that improving their health behaviours (diet, physical activity,
      smoking) would reduce their risks of CVD and osteoporosis, although modest
      reductions were expected. Breast cancer was not seen as significantly modifiable
      by lifestyle changes. They believed that taking HRT would significantly reduce
      their risk of osteoporosis, increase their risk of breast cancer, but not alter
      their risk of developing CVD. The findings are considered in the context of
      health psychology models of behaviour change and have implications for health
      promotion for mid-aged women.

PMID- 10585173
TI  - 17Beta-estradiol delivered by three different matrix patches 50 microg/day: a
      three way cross-over study in 21 postmenopausal women.
AB  - The aim of this study was to investigate the systemic bioavailability and plasma
      profiles of 17beta-estradiol (E2) after the application of three matrix patches
      for the transdermal delivery of E2: Menorest, Tradelia, and Estraderm MX claiming
      to deliver a dosage of 50 microg E2/day. All three patches were each worn
      randomly by 21 postmenopausal women volunteers over a 4-day period (i.e. 96 h).
      Each of the three treatment periods were separated by an at least 7 day wash out
      period according to a randomized, 3-way crossover design. Blood samples were
      taken from the antecubital vein before and 3, 6, 9, 12, 24, 28, 33, 48, 57, 72,
      81, and 96 h after application. E2 plasma values were determined by a specific
      direct radioimmunoassay method. The following pharmacokinetic parameters were
      evaluated: AUC0-96h, Cmax, Tmax, Cmin, C(average). The time to reach the maximal
      E2 value of 32 h was the only pharmacokinetic parameter which was identical for
      all three patches. Menorest produced the highest E2 bioavailability judged by the
      AUC0-96h = 3967.8 +/- 1651.8 pg/ml, C(average) = 41.3 +/- 21.3 pg/ml, Cmin = 36.8
      +/- 8.6 pg/ml. Tradelia showed statistically not significantly smaller C(average)
      = 38.9 +/- 17.0 pg/ml, AUC0-96h = 3737.9 +/- 1637.6 pg/ml x per h, and Cmin =
      33.8 +/- 26.7 than Menorest. Estraderm MX showed lowest E2 plasma profiles Cmax =
      38.9 +/- 25.1 pg/ml, C(average) = 33.2 +/- 17.1 pg/ml, AUC0-96 = 3192.1 +/-
      1646.0 pg/ml per x h. Menorest showed the smallest fluctuation over the entire
      test period, similar to Estraderm MX, while Tradelia showed the highest E2
      fluctuation (P < 0.01): Tradelia exhibited the highest Cmax = 48.0 +/- 20.3
      pg/ml. When E2 baseline levels, prior to patch application are subtracted
      individually from the produced E2 plasma level, Estraderm MX is not bioequivalent
      to Menorest (P < 0.05). A circadian curve pattern of the E2 plasma level was
      observed for all patches: in the evening higher E2 plasma level were always
      detected compared with the morning, however, less pronounced with Estraderm MX.
      Individual comparison of AUC0-96h of each patch exhibited a large interindividual
      variability of 2000-8000 pg/ml per h for all three patches but relatively small
      individual variability: women with high E2 bioavailability (high responders)
      maintained high bioavailability in all applied patches, women identified as low
      and medium responders remained the same regardless of the applied patch. Menorest
      produced in 2/3 of all postmenopausal women with the highest E2 bioavailability
      (AUC0-96h), Tradelia was found in less than 1/3 (28.6%), and Estraderm MX in only
      one postmenopausal woman. Menorest only produced the highest reduction in
      postmenopausal symptoms together with Tradelia. Estraderm MX produced a smaller
      reduction in postmenopausal symptoms compared to Menorest and Tradelia. The
      observed side-effects were approximately equal in all three patches, with a
      maximum value after 72 h. It can be concluded that the three patches for the
      transdermal delivery of E2 claiming to deliver 50 microg E2/day differed from
      each other in their pharmacokinetic performance, although statistically not
      significant: Menorest exhibited the highest C(average), AUC and Cmin, and the
      lowest fluctuation, followed by Tradelia and Estraderm MX.

PMID- 10585174
TI  - Bioavailability of norethisterone acetate alone and in combination with estradiol
      administered in single or multiple oral doses to postmenopausal women.
AB  - OBJECTIVES: Twenty-four postmenopausal women were randomly allocated to a cross
      over trial for an investigation of the pharmacokinetics of norethisterone acetate
      (NETA; 0.5 mg), administered alone or in combination with estradiol (E2; 1 mg),
      both after a single oral dose. In a second trial, the above combination of 0.5 mg
      NETA with 1 mg E2 was administered daily for 28 days. METHODS: Plasma levels of
      NET, E2, estrone (E1) and estrone sulphate fraction containing an admixture of
      estrone glucuronide (E1S/E1G) were measured by radioimmunoassay at various
      intervals up to 72 h in the first trial and at the same intervals after the 28th
      day in the second trial. RESULTS: In the first, single-dose trial,
      pharmacokinetic parameters of NET were similar for NETA administered alone and
      its combination with E2. There was no statistically significant difference in the
      area under curve values AUC0-24 and AUC0-infinity and no apparent major
      differences were observed for other pharmacokinetic parameters. No carry-over
      effects due to the cross-over design were seen. The multiple dosage in the second
      trial did not cause any major changes in the pharmacokinetic parameters of NET,
      except for the AUC0-24 and AUC0-infinity values which were significantly higher
      than those seen in the first trial. The levels of E2 exhibited, shortly after the
      intake of E2, a rapid burst. The levels gradually decreased to a nadir followed
      by an increase to the main peak and by the subsequent elimination phase. The
      difference between the peak and nadir levels was significant (P < 0.05) in the
      second, multiple-dose trial. This bimodal pattern was not observed in earlier
      studies. The main metabolite of E2 was E1S/E1G, followed by E1, as could be seen
      from the AUC0-infinity values. These were, in both trials, approximately 300 and
      7-times higher for the E1S/E1G and E1, respectively, than those for E2. For all
      analytes, the AUC0-24 values were significantly higher in the second trial than
      those found in the first trial, indicating accumulation upon repeated
      administration. Pharmacokinetics of all analytes remained linear in the second
      trial, as follows from the statistically established equality of AUC0-24 found in
      the second, multiple-dose trial with AUC0-infinity in the first, single-dose
      trial. The absorption half-life and t-max values of E1S/E1G appeared to be
      considerably shorter than those of E1 in both trials. CONCLUSIONS: The
      bioavailability of NET was not influenced by its combination with 1 mg E2. The
      most abundant metabolite of E2 was the E1S/E1G fraction, which may have served as
      the main source of E2 and other estrogens due to metabolic interconversions
      during the absorption and elimination phases.

PMID- 10585175
TI  - Changes with aging of steroidal levels in the cerebrospinal fluid of women.
AB  - OBJECTIVE: Age-related changes of steroid levels in the central nervous system
      (CNS) are not well understood. To investigate whether steroidal conditions in the
      CNS of women change with aging and menopause, steroid levels have been measured
      in serum and cerebrospinal fluid (CSF), and examined correlations with aging.
      METHODS: Serum and CSF concentrations of estradiol (E2), cortisol,
      dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS) and albumin were measured in
      80 female patients who underwent operations for benign gynecological diseases.
      They had no endocrinological or neurological disorders and were aged 17-71 years;
      62 patients were in premenopause and 18 were in postmenopause. RESULTS: Serum
      levels of E2 decreased markedly after menopause, while levels of DHEA and DHEAS
      decreased gradually with age. There was no significant change with age of serum
      cortisol levels. The CSF concentrations of E2 (0.2-3 pg/ml) decreased with age
      [correlation coefficient (r)= 0.31, P < 0.01]. The CSF DHEA levels (0.1-0.8
      ng/ml) did not change with age although not significantly, but CSF cortisol
      levels (0.1-0.6 microg/dl) increased with age (r = 0.35, P < 0.01). The CSF DHEAS
      concentrations were below the sensitivity of the radioimmunoassay (RIA) (1
      ng/ml). The CSF/serum ratios of cortisol increased with age (r = 0.30, P < 0.01),
      as did those of DHEA (r = 0.55, P < 0.01). Although serum albumin levels did not
      change throughout life, CSF albumin levels and CSF/serum albumin ratios increased
      gradually with age (r = 0.28, P = 0.052; r = 0.23, P = 0.114, respectively), but
      there was no significance. There were marked decreases of serum E2 and DHEA
      levels and CSF E2 levels in postmenopausal women (P < 0.05), but CSF cortisol
      levels increased (P < 0.05) and DHEA levels in CSF were maintained after
      menopause. CONCLUSION: These results indicate that steroids in CSF become
      cortisol dominated and deficient in estrogens with aging, especially after
      menopause.

PMID- 10585176
TI  - The acute effects of sublingual 17beta-estradiol on the cardiovascular system.
AB  - The beneficial effects of estrogen in postmenopausal women have been well
      documented. Cardioprotection by estrogen, which is probably the result of several
      metabolic alterations, appears after 2 or more years of constant use. However,
      acute administration of estrogen (intravenous or intracoronary) was found to
      improve cardiac hemodynamics and function through various non-genomic mechanisms.
      This article reviews data on the consequences of sublingual administration of
      estrogen, a non-invasive and simple dosing route which is associated with rapid
      absorption and prompt cardiovascular reactions. It appears that sublingual
      estradiol at 1 or 2 mg may improve ischemia and exercise performance in women
      with coronary artery disease, and augment the aortic and brachial blood flow as a
      result of vasodilation, whereas larger doses (4 mg) may lead to a decrease in
      myocardial contractility and aortic blood flow, and a slight drop in blood
      pressure. More data are needed to evaluate the actual clinical significance of
      sublingual estradiol in healthy women, in situations when endothelial dysfunction
      is anticipated (diabetes, hypertension) and in women with diagnosed coronary
      artery disease.

PMID- 10585177
TI  - The first clinical synthesis conference on hormone replacement therapy: new
      perspectives for HRT?

PMID- 10585178
TI  - Innovations in biomolecular electronics

PMID- 10585180
TI  - Optical CDMA system using bacteriorhodopsin for optical data storage
AB  - An optical CDMA (code division multiple access) system for the optical data
      storage using bacteriorhodopsin (BR) is reported as an application of the BR
      materials. The desired signal of multiple input can be recorded and reconstructed
      by use of orthogonal codes. An experimental setup is proposed and demonstrated.

PMID- 10585179
TI  - A biochemical logic gate using an enzyme and its inhibitor. 1. The inhibitor as
      switching element.
AB  - Molecular-scale logic systems will allow for further miniaturization of
      information processing assemblies and contribute to a better understanding of
      brain function. Of much interest are the pertinent biological systems, some of
      the basic components of which are biomolecular switching elements and enzyme
      based logic gates. In this series of accounts, results of investigations are
      presented on the implementation of an enzyme/inhibitor logic gate operating under
      the rules of Boolean algebra. In this report (part 1 of the series),
      consideration is given to the experimental conditions-particularly the
      irradiation mode-that affect the performance of proflavine as inhibitor of alpha
      chymotrypsin. Also, assessments are made on the reversibility of the process
      involved and the long-term stability of the system. Moreover, using a theoretical
      conformational analysis of proflavine and its reduction products, detailed
      features were established regarding their three-dimensional structure, partial
      charge distribution, and hydrophobicity. Accordingly, an understanding was
      reached as to the factors affecting the interaction between these compounds and
      the enzyme. In part 2 of this series, the actual implementation of an AND logic
      gate will be presented. This gate involves proflavine and a chemically
      derivatized alpha-chymotrypsin, and its operation relies on the conclusions
      reached in this report regarding the optimal mode for controlling the inhibitory
      activity of proflavine.

PMID- 10585181
TI  - Charge-transfer processes and redox reactions in planar lipid monolayers and
      bilayers.
AB  - Supported bilayer lipid membranes (BLMs) and lipid monolayers have been known for
      quite sometime and are attracting sustained interest since they open new research
      vista and offer practical approaches in biosensor development and molecular
      device applications. Central to these areas of interest are electric processes
      and redox reactions where the movement of ions and electrons plays a pivotal
      role. In this paper an overview of the major findings in this field is presented.
      Further, we summarize the work on planar lipid bilayers and monolayers that have
      been done in the past few years in a number of laboratories. Supported planar
      BLMs and their closely related systems provide the foundation for a variety of
      lipid bilayer-based molecular sensors that are sensitive, versatile, as well as
      potentially inexpensive (i.e., disposable), and open to all sorts of
      experimentation.

PMID- 10585182
TI  - Electronic transduction of photostimulated binding interactions at
      photoisomerizable monolayer electrodes: novel approaches for optobioelectronic
      systems and reversible immunosensor devices
AB  - Photoisomerizable monolayers assembled onto electrode supports act as "command
      interfaces" for controlling the binding interactions of biomaterials with the
      functionalized surfaces. The light-induced binding and dissociation of the
      biomaterials to and from the electrodes, respectively, are electronically
      transduced. Two systems, including the photostimulated binding and dissociation
      of cytochrome c (Cyt c) and of anti-DNP antibody to and from functionalized
      surfaces, are discussed. The application of the systems as optobioelectronic
      devices and reversible immunosensors is addressed. A mixed monolayer consisting
      of pyridine and nitrospiropyran (1a) photoisomerizable units assembled on a Au
      electrode acts as a command interface for the light-controlled association and
      dissociation of Cyt c to and from the monolayer. Cyt c binds to the pyridine/1a
      monolayer electrode, resulting in electrical contact between the redox protein
      and the electrode. Photoisomerization of the mixed monolayer to the
      pyridine/protonated merocyanine state (1b) results in the electrostatic repulsion
      of Cyt c and its dissociation from the electrode support. This blocks the
      electrical contact between Cyt c and the electrode. By the cyclic
      photoisomerization of the mixed monolayer between the 1a and 1b states,
      reversible "ON"-"OFF" amperometric transduction of the affinity interactions
      between the redox protein and the interface is accomplished. Coupling of the
      photostimulated electrical contact between Cyt c and the electrode surface to the
      Cyt c-mediated bioelectrocatalyzed reduction of O(2) by cytochrome oxidase
      provides a means to amplify the transduced electronic signal. A photoisomerizable
      thiolated dinitrospiropyran (2a) monolayer, assembled on solid supports, acts as
      a light-active antigen interface that enables the photocontrolled binding and
      dissociation of anti-dinitrophenyl antibody (DNP-Ab) to and from the interface.
      The dinitrospiropyran (2a) layer acts as an antigen for the DNP-Ab, whereas the
      protonated dinitromerocyanine (2b) lacks antigen features for the DNP-Ab. By
      reversible photoisomerization of the monolayer between the 2a and 2b states,
      cyclic binding and dissociation of DNP-Ab to and from the monolayer interface is
      accomplished. The association and dissociation of the DNP-Ab to and from the 2a-
      and 2b-monolayer states are electronically transduced, using amperometric,
      Faradaic impedance and microgravimetric, quartz crystal microbalance analyses.
      The photostimulated binding of an antibody to a photoisomerizable antigen
      monolayer provides a novel method to design reversible immunosensor devices.

PMID- 10585183
TI  - Membrane chromatography: preparation and applications to protein separation.
AB  - As a result of the convective flow of solutes through porous membranes, membrane
      chromatography has a higher capture efficiency and a higher productivity than
      column chromatography and shows most promising industrial applications for the
      recovery, isolation, and purification of proteins and enzymes. This paper
      presents a comprehensive review of the methods for preparation of adsorptive
      membranes (such as surface modification, in situ copolymerization, direct
      formation from hydrophilic materials, and functionalized particulate-entrapped
      membranes) and deals particularly with novel macroporous chitin and chitosan
      membranes for protein separations developed by the authors.

PMID- 10585184
TI  - Precursor and cofactor as a check valve for cephamycin biosynthesis in
      Streptomyces clavuligerus.
AB  - The biosynthesis of secondary metabolites is closely linked to primary metabolism
      via the supply of precursors, cofactors, and cellular energy. The availability of
      these precursors and cofactors can potentially be rate-limiting for secondary
      metabolism. A combined experimental and kinetic modeling approach was used to
      examine the regulation of flux in the cephamycin biosynthetic pathway in
      Streptomyces clavuligerus. The kinetic parameters of lysine 6-aminotransferase
      (LAT), the first enzyme leading to cephamycin biosynthesis and one which was
      previously identified as being a rate-limiting enzyme, were characterized. LAT
      converts lysine to alpha-aminoadipic acid using alpha-ketoglutarate as a
      cosubstrate. The K(m) values for lysine and alpha-ketoglutarate were
      substantially higher than those for their intracellular concentrations,
      suggesting that lysine and alpha-ketoglutarate may play a key role in regulating
      the flux of cephamycin biosynthesis. The important role of this
      precursor/cosubstrate was supported by simulated results using a kinetic model.
      When the intracellular concentrations and high K(m) values were taken into
      account, the predicted intermediate concentration was similar to the experimental
      measurements. The results demonstrate the controlling roles that precursors and
      cofactors may play in the biosynthesis of secondary metabolites.

PMID- 10585185
TI  - Kinetic effect of silkworm hemolymph on the delayed host cell death in an insect
      cell-baculovirus system
AB  - The kinetic effect of silkworm hemolymph on host cell viability during a
      baculovirus-induced insect cell death process was investigated. Host cell
      viability after viral infection is important for replication of the baculovirus
      DNA containing a recombinant gene and expression of the cloned gene. The
      baculovirus-induced insect cell death process can be divided into a delay phase
      and a first-order death phase, which are characterized by a delay time (t(d)) and
      a specific death rate (k(d)), respectively. For 0-10% silkworm hemolymph in the
      media, higher concentrations resulted in longer delay times and lower specific
      death rates. By adding 10% silkworm hemolymph, the delay time increased from 72
      to 164 h, and the specific death rate was reduced from 13.8 x 10(-)(3) to 6.0 x
      10(-)(3) h(-)(1). In addition, host cell viability correlated with DNA
      fragmentation, which is the biochemical hallmark of apoptosis. This indicates
      that the silkworm hemolymph inhibits the baculovirus-induced insect cell
      apoptosis. However, the silkworm hemolymph did not affect the number of
      hypothetical targets, which represents host cell susceptibility to the
      baculovirus. The concentration of fetal bovine serum (FBS) in the medium did not
      affect the delay time, while lower concentrations of silkworm hemolymph resulted
      in shorter delay times. This means that the substance which increases the
      longevity of the host cell is not in the FBS but in the silkworm hemolymph.

PMID- 10585186
TI  - Facilitating the formation of disulfide bonds in the Escherichia coli periplasm
      via coexpression of yeast protein disulfide isomerase.
AB  - Sacchromyces cerevisiae protein disulfide isomerase (yPDI) was expressed in the
      E. coli periplasm by using plasmids encoding the OmpA-yPDI-(His)(6) fusion gene
      under the control of the araBAD, trc, or T7 promoter. The expression levels of
      yeast PDI under these promoters were compared. Our results showed that yeast PDI
      expressed into the periplasm could catalyze the formation of disulfide bonds in
      alkaline phosphatase, restoring the phoA(+) phenotype in dsbA(-) mutants. The
      yeast PDI was purified from the Escherichia coli periplasm and shown to exhibit
      catalytic properties comparable to those of the rat enzyme with reduced RNase as
      substrate. In vivo, coexpression of the yeast PDI increased the yield of bovine
      pancreatic trypsin inhibitor (BPTI) in E. coli by 2-fold, similar to the effect
      seen previously with the coexpression of the rat enzyme. However yeast PDI was
      more effective than rat PDI in facilitating the expression of active tissue
      plasminogen activator (tPA). These results point to differences in the substrate
      specificity of various PDI enzymes, at least in the context of the E. coli
      periplasm.

PMID- 10585187
TI  - One-step production of D-p-hydroxyphenylglycine by recombinant Escherichia coli
      strains.
AB  - The gene encoding D-hydantoinase from Agrobacterium radiobacter NRRL B11291 was
      successfully cloned by use of polymerase chain reaction. A positive clone was
      scored, and its nucleotide sequence was further analyzed. The analysis by
      deleting various lengths of nucleotides from the amino terminus of the open
      reading frame revealed the putative regions for promoter and RBS site. By highly
      expressing both D-hydantoinase and carbamoylase, recombinant Escherichia coli
      strains were able to convert DL-hydroxyphenyl hydantoin (DL-HPH) to D-p
      hydroxyphenylglycine (D-HPG) with a conversion yield of 97%, accounting for
      productivity 5 times higher than that obtained by A. radiobacter NRRL B11291.
      Immobilizing the recombinant cells with kappa-carrageenan could also achieve a
      conversion of 93%, while A. radiobacter NRRL B11291 attained 20% within the same
      period of reaction time. These results illustrate the feasibility in employing
      recombinant E. coli to accomplish one-step conversion of DL-HPH to D-HPG. In the
      process of improving D-HPG production, D-hydantoinase activity was increased 2.57
      fold but carbamoylase activity remained constant, which resulted in only a 30%
      increase in the reaction rate. It suggests that carbamoylase is the step setting
      the pace of the reaction. Since the reaction substrate is highly insoluble,
      achieving sufficient agitation appears to be an important issue in this
      heterogeneous system. This view is further supported by the study on repeated use
      of cells, which shows that to reach a conversion of more than 90% free cells can
      be recycled six times, whereas immobilized cells can be used only twice. In
      conclusion, the poor reusability of immobilized cells is due to the fouling on
      the gel surface.

PMID- 10585188
TI  - Screening of transformed insect cell lines for recombinant protein production.
AB  - Nine insect cell lines were evaluated for their potential as host systems for
      recombinant protein production using a new expression vector permitting the
      continuous high-level expression of secreted glycoproteins by transformed insect
      cells (Farrell et al., 1998). As a means of preliminary screening, all nine
      insect cell lines were transfected with the green fluorescence protein. Growth in
      static and suspension culture was then examined as a further method of screening.
      On the basis of their transfection efficiencies and cell growth characteristics,
      five insect cell lines, Bm5, High Five, IPLB-LdFB, IZD-MB-0503, and Sf-21, were
      selected for stable transformation to produce granulocyte-macrophage colony
      stimulating factor (GM-CSF). These five cell lines were stably transformed using
      an antibiotic resistance scheme and evaluated as a polyclonal population.
      Increasing the antibiotic concentration was found to cause not only a decrease in
      the specific growth rate but also an increase in the specific protein production
      rate and final GM-CSF concentration. The transformed High Five cells exhibited by
      far the greatest specific protein production rate of 5.1 x 10(-)(6)
      microgram/(cell.h), resulting in the highest final GM-CSF concentration of 22.8
      mg/L when grown in static culture. One cloned High Five cell line produced a GM
      CSF concentration of 46 mg/L in static culture and 27 mg/L in suspension culture.

PMID- 10585190
TI  - Conceptual design of LED-based hydroponic photobioreactor for high-density plant
      cultivation
AB  - A novel hydroponic photobioreactor is proposed for high-density cultivation of
      plants. This cultivation can be achieved by growing plants on a floatable
      platform, allowing the roots to directly contact a continuously aerated nutrient
      solution. Plant growth of Mentha x piperita (peppermint) can be shown to strongly
      correlate with the light intensity at incident light intensities between 0 and
      650 &mgr;mol m(-)(2) s(-)(1). For a constant incident light intensity (I(0) = 420
      &mgr;mol m(-)(2) s(-)(1)), the overall specific growth rates of these plants are
      found to be strongly dependent on the plant density. They range from 0.023 to
      0.075 d(-)(1) for plants grown at a density range from 16 to 256 plants m(-)(2).
      A simple mathematical model is presented that allows one to predict these effects
      of light intensity and plant density on peppermint growth. Light delivery is
      derived from the modification of Beer-Lambert's law. From this, the relationship
      between the light extinction coefficient and plant density can be experimentally
      determined. The light transport can then be coupled with plant growth kinetics
      under light-limiting conditions. The predicted growth results agree reasonably
      well with most experimental results from a growth period of 17-20 days. On the
      basis of these simulation results, we suggest that a more efficient way of
      delivering light to this photobioreactor can be attained by supplying light from
      both the top and the bottom of the plant shoots. The proposed design takes
      advantage of the small size and low weight of light emitting diodes, which allow
      them to be mounted on platforms for delivering light closer to the plants.

PMID- 10585189
TI  - Peroxisomes as sites for synthesis of polyhydroxyalkanoates in transgenic plants.
AB  - Bacterial genes responsible for poly(3-hydroxybutyrate) (PHB) biosynthesis were
      targeted to plant peroxisomes by adding a carboxy-terminal targeting sequence.
      The enzymes evidently were transported into peroxisomes, retained their catalytic
      activity, and reacted with peroxisomally available precursors because PHB
      synthesis in transgenic plant cells was localized to peroxisomes. Up to 2 mg/g
      fresh weight PHB was produced in suspension cultures of Black Mexican Sweet maize
      cells after biolistic transformation with three peroxisomally targeted bacterial
      genes. An equilibrium effect is proposed to explain the unexpected existence of
      (R)-3-hydroxybutyryl-CoA in plant peroxisomes.

PMID- 10585191
TI  - Enhancing yield of infectious Bursal disease virus structural proteins in
      baculovirus expression systems: focus on media, protease inhibitors, and
      dissolved oxygen.
AB  - Structural proteins of the poultry pathogen, infectious bursal disease virus
      (IBDV), were expressed in the baculovirus/insect cell expression system. To date,
      several reports have indicated that animal virus structural proteins are
      expressed only at low yield in this system. In this article, several factors were
      examined to enhance yield. These include medium, dissolved oxygen level, and the
      addition (in vivo and in vitro) of protease inhibitors. Specifically, two media
      were compared, and SF-900 II was superior to Ex-Cell 401 for cell growth and IBDV
      protein expression. A cocktail of protease inhibitors including phenylmethyl
      sulfonyl fluoride (PMSF), leupeptin, and ethylenediamine tetraacetic acid (EDTA)
      minimized proteolysis in vitro. Also, aprotinin and pepstatin A deterred product
      degradation in vivo and increased the product yield nearly 2-fold. Finally, in 3
      L bioreactors, a dissolved oxygen tension of 50% DO (air saturation) was optimal.
      Results demonstrated that several relatively simple adjustments to the
      baculovirus system significantly improved the yield of IBD virus structural
      proteins.

PMID- 10585192
TI  - Kinetic studies of paclitaxel production by Taxus canadensis cultures in batch
      and semicontinuous with total cell recycle.
AB  - Suspension cultures of Taxus canadensis were elicited with methyl jasmonate (MJ)
      under defined headspace ethylene concentrations. Kinetic studies of growth,
      nutrient consumption, pH variation, and paclitaxel accumulation were conducted in
      batch cultures and semicontinuous culture with total cell recycle. A dramatic
      increase of paclitaxel was obtained when the cultures were elicited with 100
      microM MJ, but cell growth was thereby arrested. Supplementation of acetyl-CoA
      and MJ to the culture proved to be another way to improve paclitaxel yields.
      Using semicontinuous culture with total cell recycle, paclitaxel accumulation was
      increased by a factor of 4.0 relative to that in the batch culture during 35 days
      of cultivation.

PMID- 10585193
TI  - Affinity extraction of BSA with reversed micellar system composed of unbound
      Cibacron Blue.
AB  - Affinity Cibacron Blue 3GA (CB) dye in aqueous phase was directly transferred to
      the reversed micelles due to electrostatic interaction between anionic CB and
      cationic cetyltrimethylammonium bromide (CTAB). The bovine serum albumin (BSA)
      transfer to the reverse micelles increases significantly in a wide range of pH by
      the addition of a small amount of CB ( approximately 1.0-7.0% of the total
      surfactant concentration) to the aqueous phase. For pH < pI, the selectivity can
      be significantly improved with the presence of affinity CB because no BSA was
      extracted in the absence of CB. For backward extraction of BSA from the micellar
      phase with stripping aqueous solution, the addition of 2-propanol to the aqueous
      phase can recover almost all BSA (98.5%) extracted into the reverse micelles.

PMID- 10585194
TI  - Rice bran lipase: extraction, activity, and stability
AB  - A simple procedure for the extraction of the lipolytic activity from rice bran
      has been developed. Various conditions of extraction have been optimized so as to
      obtain maximum yield of the lipase. It was found that high enzyme activity could
      be obtained by first defatting the rice bran to remove the lipid component. This
      was followed by five cycles of aqueous extraction (potassium phosphate buffer, 50
      mM and pH 7, containing 0.5 mM of CaCl(2)). The stability of the rice bran lipase
      under storage and operative conditions was investigated. Further, the influence
      of glycerol as a stabilizer has been assessed. It was found that further
      purification using micro- and ultrafiltration yielded an enzyme preparation with
      higher activity and specific activity and better stability.

PMID- 10585195
TI  - Production of organic acids and amino acids from fish meat by sub-critical water
      hydrolysis
AB  - Fish meat was easily liquefied by hydrolysis under subcritical conditions without
      oxidants, and aqueous phase and water-insoluble phase containing oil and fat-like
      solid were formed. Lactic acid found in the raw fish meat (about 0.03 g/g-dry
      meat) was stable up to the reaction temperature 513 K (3.35 MPa). Pyroglutamic
      acid was produced with a yield of 0.095 kg/kg of dry meat by 30 min reaction at
      553 K (6.42 MPa). Amino acids such as cystine, alanine, glycine, and leucine were
      produced in the temperature range 513-623 K with a maximum peak at 543 K. Amounts
      of cystine, alanine, glycine, and leucine produced in 5 min at 543 K (5.51 MPa)
      were 0.024, 0.013, 0. 009, and 0.004 kg/kg of dry meat, respectively. The oil
      extracted with hexane contained useful fatty acids such as eicosapentanoic acid
      (EPA) and docosahexianoic acid (DHA). Thus, subcritical water hydrolysis would be
      an efficient process for recovering useful substances from organic waste such as
      fish waste discarded from fish market.

PMID- 10585196
TI  - An integrated process for biomolecule isolation and purification.
AB  - Biomolecule isolation and purification from a fermentation broth usually involve
      centrifugation, filtration, adsorption, and chromatography steps. Each step
      contributes to the product cost and product loss. In this research, a cyclic
      process integrating commercially available ultrafiltration membranes and
      chromatographic resin beads was developed to achieve the same goal in one device.
      The device consisted of ion exchange beads on the shell side of a hollow fiber
      ultrafiltration module. Loading of proteins on the stationary phase on the shell
      side was carried out for a period of 5-20 min from the permeate on the shell side
      produced from tube-side feed in ultrafiltration. The eluent was then introduced
      either from the shell-side inlet or tube-side inlet; the chromatographic
      fractions were collected from the shell-side outlet. The column was
      regenerated/washed next to start a new cycle. Systems studied in this cyclic
      process include the following binary mixtures: myoglobin and beta-lactoglobulin;
      hemoglobin and bovine serum albumin; and myoglobin and alpha-lactalbumin.
      Excellent resolutions of the proteins were obtained. A yeast-based cellular
      suspension containing a mixture of myoglobin and alpha-lactalbumin was also
      applied to this device. The target proteins were recovered and purified
      successfully. The cyclic process-based device integrates clarification,
      concentration, and chromatographic purification of biomolecules and is suitable
      for both extracellular and intracellular products.

PMID- 10585197
TI  - Measurements of multiply scattered light for on-line monitoring of changes in
      size distribution of cell debris suspension.
AB  - Dual wavelength frequency-domain measurements of photon migration (FDPM) are
      conducted on filtrate samples obtained from an industrial centrifugation process
      designed to separate Escherichia coli cell debris from the inclusion bodies. FDPM
      measurements consist of detecting phase delay of intensity-modulated light at 670
      and 820 (or 830) nm. Optical properties of isotropic scattering and absorption
      are obtained from the regression of phase delay data to the optical diffusion
      equation. We show that the corresponding intensity-based measurements alone
      cannot provide accurate and independent estimates for these optical properties.
      However, FDPM-derived scattering coefficients of filtrate solutions (primarily
      consisting of 0.1-0.2 micrometer E. coli cell debris) are sensitive to
      approximately 1 vol % of added inclusion bodies (of 1-2 micrometer size). The
      technique, theory, and future adaptation of FDPM as an on-line monitor to detect
      the loss of inclusion bodies in centrifugation following homogenization are
      presented and contrasted to conventional, intensity-based measurements.

PMID- 10585198
TI  - Selection of microbial mutants tolerant to extreme environmental stress using
      continuous culture-control design.
AB  - The design of controllers for a continuous selection technique (BOICS; Brown and
      Oliver, 1982) is considered. This technique is used to obtain microbial mutants
      that are tolerant to extreme environmental stress. Applications of BOICS have
      been hampered by the problem of controller design. In this paper, a modified
      implementation of BOICS is considered which has a number of practical advantages.
      A model-based approach to controller design is taken. The case in which the
      stress is due to an inhibitory substance in the growth environment is considered.
      The analysis is intended to be applicable to any reasonable combination of
      organism and inhibitor. Conventional linear and time-invariant controllers are
      considered. Guidelines for the selection of controller parameters' values are
      suggested. The application of these guidelines requires that certain process
      parameters' values be identified. Methods by which these parameters' values can
      be identified are suggested. Simulation results indicate that the resulting
      controllers perform satisfactorily. This is confirmed by experimental data from a
      model selection experiment. A recipe for the design of controllers is a necessary
      part of a protocol for BOICS. It is hoped that the solution to the controller
      design problem that is offered in this paper will encourage further applications
      for the technique.

PMID- 10585199
TI  - On-line fluorescence profile of aerobic sludge digestion
AB  - An online fluorometer designed for following intracellular NAD(P)H was used to
      monitor aerobic sludge digestion experiments. The fluorescence showed an initial
      rise to a high plateau, a sharp decline after staying at the plateau for 20-60 h,
      and a trailing very slow decrease. The characteristic fluorescence profile was
      shown to result mainly from the solids-associated fluorescence, after ruling out
      other factors such as pH, temperature, and supernatant fluorescence. The
      fluorescence profile was, however, not a mere result of the decreasing solids
      concentration. The varying sludge viability and population composition (e.g., the
      decay of heterotrophs and the increasing fraction of nitrifiers) played important
      roles. The fluorescence profile correlated well with the profile of the viable
      heterotrophic cell number concentration evaluated with TSB-agar plates. The
      initial increase of the number concentration was attributed to the growth of
      multiple small bacteria from the lysate of each large microorganism, which was
      demonstrated in the experiments with baker's yeast as the starting culture for
      digestion. The fluorescence profiles observed in the yeast experiments were
      similar to those in the sludge experiments. Responding to glucose additions and
      the switch from aerobic to anaerobic conditions, the yeast systems showed typical
      step increases of fluorescence as expected from the change of NAD(P)H level
      associated with heterotrophic metabolism. However, no such fluorescence responses
      were detectable in the sludge digestion systems. NAD(P)H were thus uncertain to
      be responsible for the online fluorescence observed. Nonetheless, the initial
      fluorescence plateau corresponded to the period of rapid digestion and, for the
      plant studied, the EPA regulation criteria of VSS reduction >38% and/or SOUR <1.5
      mg of O(2) (g of TS)(-)(1) h(-)(1) were satisfied at the end of the plateau. The
      online fluorescence provides an effective means of monitoring the aerobic sludge
      digestion process.

PMID- 10585200
TI  - Rapid calibration of near-infrared spectroscopic measurements of mammalian cell
      cultivations.
AB  - Near-infrared (NIR) spectroscopy is a flexible method that can be employed to
      noninvasively monitor the concentrations of multiple nutrients and wastes in
      mammalian cell bioreactors. Development of suitable calibrations can be a labor-
      and time-intensive process that must be repeated when process conditions are
      altered significantly. To address this difficulty, we have produced a new
      approach for generating NIR spectroscopic calibrations that requires
      significantly less time compared with standard calibration schemes. This method
      reduces development time from the present level of several weeks to several
      hours. A small number of experimentally collected spectra serve as inputs to a
      computational procedure that yields a large number of simulated spectra, each
      containing both analyte-specific and analyte-independent information. Such
      simulated spectra may be employed as a calibration set for quantifying analytes
      in experimentally collected spectra. Spectroscopic measurements of the
      concentrations of five components (ammonia, glucose, glutamate, glutamine, and
      lactate) can be accomplished with levels of error similar to those obtained with
      full experimental calibrations. A key to this process is the utilization of
      random numbers, which randomizes the influence of natural variations, present in
      each experimentally collected spectrum, on the resultant composite spectrum. This
      approach may increase the feasibility of employing NIR spectroscopy to monitor
      bioreactors and other biological processes subjected to varying operating
      conditions.

PMID- 10585201
TI  - A flexible policy concerning purity criteria for published target compounds.

PMID- 10585202
TI  - Inhibitors of efflux pumps in Pseudomonas aeruginosa potentiate the activity of
      the fluoroquinolone antibacterial levofloxacin.

PMID- 10585204
TI  - Designing libraries with CNS activity.
AB  - Library design is an important and difficult task. In this paper we describe one
      possible solution to designing a CNS-active library. CNS-actives and -inactives
      were selected from the CMC and the MDDR databases based on whether they were
      described as having some kind of CNS activity in the databases. This
      classification scheme results in over 15 000 actives and over 50 000 inactives.
      Each molecule is described by 7 1D descriptors (molecular weight, number of
      donors, number of acceptors, etc.) and 166 2D descriptors (presence/absence of
      functional groups such as NH(2)). A neural network trained using Bayesian methods
      can correctly predict about 75% of the actives and 65% of the inactives using the
      7 1D descriptors. The performance improves to a prediction accuracy on the active
      set of 83% and 79% on the inactives on adding the 2D descriptors. On a database
      with 275 compounds where the CNS activity is known (from the literature) for each
      compound, we achieve 92% and 71% accuracy on the actives and inactives,
      respectively. The models we construct can therefore be used as a "filter" to
      examine any set of proposed molecules in a chemical library. As an example of the
      utility of our method, we describe the generation of a small library of
      potentially CNS-active molecules that would be amenable to combinatorial
      chemistry. This was done by building and analyzing a large database of a million
      compounds constructed from frameworks and side chains frequently found in drug
      molecules.

PMID- 10585203
TI  - Structure-activity studies of cerulenin analogues as protein palmitoylation
      inhibitors.
AB  - Activation of ras oncogenes occurs in a high percentage of tumors, making the
      enzymes involved in the posttranslational processing of their encoded proteins
      (p21s) attractive targets for the development of new drugs. Although most effort
      has focused on farnesyl transferase, which catalyzes the first processing step,
      attachment of palmitate to p21 is required for optimal transformation by H-ras
      and N-ras. We have demonstrated that the natural product cerulenin ([2R,3S]-2,3
      epoxy-4-oxo-7,10-trans,trans-dodecadienamide) inhibits the palmitoylation of H
      ras- and N-ras-encoded p21s in parallel with inhibition of cell proliferation.
      More than 30 analogues of cerulenin, both aromatic and aliphatic, with various
      chain lengths and amide substitutions, have been synthesized for use in SAR
      studies. Studies on the inhibition of T24 cell proliferation indicate that the
      alpha-keto-epoxy moiety is critical for cytotoxicity, while alkyl chain length
      had only modest effects on potency. Several compounds inhibited the incorporation
      of [(3)H]palmitate into p21 in intact T24 cells, with the unsubstituted
      carboxamides being more active than N,N-dimethyl compounds. In contrast to the
      effects on palmitoylation, the only compounds which inhibited fatty acid synthase
      contained alkyl side chains of 12 carbons or fewer. Regression analyses indicated
      that inhibition of palmitoylation is more closely related to inhibition of
      proliferation than is inhibition of fatty acid synthase. Further characterization
      of the molecular pharmacology of these and analogous compounds may define a new
      class of drugs with antitumor activity.

PMID- 10585205
TI  - On the bioactive conformation of NAN-190 (1) and MP3022 (2), 5-HT(1A) receptor
      antagonists.
AB  - Structural modifications of 1, a postsynaptic 5-HT(1A) receptor antagonist,
      provided its flexible (8, 12) and rigid (7, 9, 11, 13) analogues. Compounds 7, 8,
      9, and 11 showed high 5-HT(1A) receptor affinity (K(i) = 4-72 nM). They acted as
      5-HT(1A) postsynaptic receptor antagonists, since, like 1, they inhibited the
      behavioral syndrome, i.e., flat body posture (FBP) and forepaw treading (FT), in
      reserpine-pretreated rats as well as the lower lip retraction (LLR) in rats, both
      induced by 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), a 5
      HT(1A) receptor agonist. Compound 12, which demonstrated high 5-HT(1A) receptor
      affinity (K(i) = 50 nM), revealed properties of a partial 5-HT(1A) receptor
      agonist: it induced LLR and, at the same time, inhibited FT in rats. Compound 13
      (K(i) = 1600 nM) was not tested in a behavioral study. Restriction of the
      conformational freedom in 2, a full 5-HT(1A) receptor antagonist, yielded
      compound 14 with high 5-HT(1A) receptor affinity (K(i) = 47 nM) and partial
      agonist properties at postsynaptic 5-HT(1A) receptors in the above tests in vivo;
      i.e., it induced LLR and inhibited FBP and FT in rats. New constrained analogues
      of 1 and 2 (compounds 7 and 14, respectively) were also synthesized to recognize
      a bioactive conformation of those 5-HT(1A) receptor antagonists. On the basis of
      in vitro and in vivo investigations, binding and functional properties of
      compound 7 were found to reflect those of 1 at 5-HT(1A) receptors. On the other
      hand, compound 14, a rigid analogue of 2, showed a different activity in vivo in
      comparison with the parent compound. PM3 and MM calculations revealed the
      existence of three low-energy conformers of 7 and six of 14, all of them
      belonging to the extended family of conformations. The optimized structures of
      both analogues had a different angle between aromatic planes of terminal
      fragments; moreover, the heteroaromatic system of those molecules occupied
      various space regions. Our present study provides support to the hypothesis that
      the bioactive conformation of 1, responsible for its postsynaptic 5-HT(1A)
      receptor antagonism, is an extended linear structure represented by 7.

PMID- 10585206
TI  - Structure-activity relationship studies of novel heteroretinoids: induction of
      apoptosis in the HL-60 cell line by a novel isoxazole-containing heteroretinoid.
AB  - In a search for retinoic acid receptor (RAR and RXR)-selective ligands, a series
      of isoxazole retinoids was synthesized and evaluated in vitro in transcriptional
      activation and competition binding assays for RARs and RXRs. In addition, these
      compounds were evaluated for their differentiating, cytotoxic, and apoptotic
      activities. In general, these derivatives showed scarcely any binding affinity
      and were not active in the transcriptional assay. However, among these isoxazole
      derivatives, the cis-isomer 14b was identified as a potent inducer of apoptosis,
      and its activity was found to be 6.5 and 4 times superior than that of 13-cis-
      and 9-cis-retinoic acids, respectively. On the other hand, compound 13b, which
      has the trans stereochemistry at the double bond, was found not to be active in
      the apoptotic assay, but it was endowed with appreciable differentiating
      activity. Therefore, it seems that the different stereochemistry of the double
      bond may be associated with a different biological activity: potent apoptotic
      activity for the cis-isomer but differentiating activity for the trans structure.
      This biological behavior was found, at least in part, for the 9-cis- and 13-cis
      retinoic acids with respect to the all-trans-retinoic acid. Thus, structure 14b
      could offer an interesting model for the design of new compounds endowed with
      apoptotic activity.

PMID- 10585207
TI  - Improving the nicotinic pharmacophore with a series of (Isoxazole)methylene-1
      azacyclic compounds: synthesis, structure-activity relationship, and molecular
      modeling.
AB  - A series of (isoxazole)methylene-1-azacyclic compounds was prepared. The
      compounds were tested for affinity to central nicotinic acetylcholine receptors
      (nAChRs) and central muscarinic receptors. The compounds covered a broad range of
      affinities for the nAChRs (IC(50) = 0.32 to >1000 nM), with selectivities for the
      nAChRs over the muscarinic receptors in the range of 3-183. The high-affinity
      compound (Z)-26 (3-(4-methyl-5-isoxazolyl)methylene-1-azabicyclo[2.2. 2]octane,
      IC(50) = 3.2 nM) having only one energy minimum was used as the reference
      structure in a computational study. This ligand has enabled definition of an
      important distance parameter, and the existence of this parameter was supported
      by showing that other potent nicotinic ligands (for example, nicotine and
      epibatidine) fit the model.

PMID- 10585208
TI  - 3-[3-(Piperidin-1-yl)propyl]indoles as highly selective h5-HT(1D) receptor
      agonists.
AB  - Several 5-HT(1D/1B) receptor agonists are now entering the marketplace as
      treatments for migraine. This paper describes the development of selective h5
      HT(1D) receptor agonists as potential antimigraine agents which may produce fewer
      side effects. A series of 3-[3-(piperidin-1-yl)propyl]indoles has been
      synthesized which has led to the identification of 80 (L-772,405), a high
      affinity h5-HT(1D) receptor full agonist having 170-fold selectivity for h5
      HT(1D) receptors over h5-HT(1B) receptors. L-772,405 also shows very good
      selectivity over a range of other serotonin and nonserotonin receptors and has
      excellent bioavailability following subcutaneous administration in rats. It
      therefore constitutes a valuable tool to delineate the role of h5-HT(1D)
      receptors in migraine. Molecular modeling and physical properties have been
      utilized to postulate the binding conformation of these compounds in the receptor
      cavity.

PMID- 10585209
TI  - Chemical syntheses and biological studies on dimeric chimeras of oxytocin and the
      V(2)-antagonist, d(CH(2))(5)[D-Ile(2), Ile(4)]arginine vasopressin.
AB  - Parallel and antiparallel heterodimers have been synthesized that combine into a
      single molecule the neurohypophyseal hormone oxytocin and the potent vasopressin
      V(2)-antagonist d(CH(2))(5)[D-Ile(2), Ile(4)]arginine vasopressin. Solid-phase
      synthesis with N(alpha)-9-fluorenylmethyloxycarbonyl (Fmoc) chemistry, featuring
      appropriate combinations of orthogonal protecting groups for the thiols [S-(N
      methyl-N-phenylcarbamoyl)sulfenyl (Snm); S-acetamidomethyl (Acm); S
      triphenylmethyl (Trt)], was used to assemble the required linear nonapeptide
      amide monomer intermediates, which were then brought together in defined ways by
      solution reactions to provide the two heterodimers. The first disulfide bridge
      was formed by a directed approach involving attack by the free thiol of the 1
      beta-mercapto-beta, beta-cyclopentamethylenepropionic acid (Pmp) residue of one
      monomer onto the Snm group of a cysteine residue on the other monomer; the
      inverse directed strategy failed due to steric hindrance. The second disulfide
      bridge was formed by iodine co-oxidation of Cys(Acm) residues on adjacent chains.
      Biological studies revealed that both the parallel and antiparallel chimeras lack
      pressor activity, have low uterotonic activity, and have diuretic activities
      comparable to that of the monomeric V(2)-antagonist. Sodium excretion depends on
      experimental conditions. Thus, with a 4% water load, both chimeras display
      effects similar to that of an equimolar mixture of oxytocin and V(2)-antagonist,
      i.e., lower sodium excretion than that resulting from administration of oxytocin
      alone but higher than that when V(2)-antagonist was administered alone. However,
      when no water load was used, the parallel chimera proved to be more effective in
      promoting sodium excretion than either oxytocin alone or an equimolar mixture of
      oxytocin and V(2)-antagonist.

PMID- 10585210
TI  - Further studies on the Dmt-Tic pharmacophore: hydrophobic substituents at the C
      terminus endow delta antagonists to manifest mu agonism or mu antagonism.
AB  - Twenty N- and/or C-modified Dmt-Tic analogues yielded similar K(i) values with
      either [(3)H]DPDPE (delta(1) agonist) or [(3)H]N, N(Me)(2)-Dmt-Tic-OH (delta
      antagonist). N-Methylation enhanced delta antagonism while N-piperidine-1-yl, N
      pyrrolidine-1-yl, and N-pyrrole-1-yl were detrimental. Dmt-Tic-X (X = -NHNH(2), 
      NHCH(3), -NH-1-adamantyl, -NH-tBu, -NH-5-tetrazolyl) had high delta affinities
      (K(i) = 0.16 to 1 nM) with variable mu affinities to yield nonselective or weakly
      mu-selective analogues. N, N-(Me)(2)Dmt-Tic-NH-1-adamantane exhibited dual delta
      and mu receptor affinities (K(i)delta = 0.16 nM and K(i)mu = 1.12 nM) and potent
      delta antagonism (pA(2) = 9.06) with mu agonism (IC(50) = 16 nM). H-Dmt-betaHTic
      OH (methylene bridge between C(alpha) of Tic and carboxylate function) yielded a
      biostable peptide with high delta affinity (K(i) = 0.85 nM) and delta antagonism
      (pA(2) = 8.85) without mu bioactivity. Dmt-Tic-Ala-X (X = -NHCH(3), -OCH(3), -NH
      1-adamantyl, -NHtBu) exhibited high delta affinities (K(i) = 0.06 to 0.2 nM) and
      elevated mu affinities (K(i) = 2.5 to 11 nM), but only H-Dmt-Tic-Ala-NH-1
      adamantane and H-Dmt-Tic-Ala-NHtBu yielded delta receptor antagonism (pA(2) =
      9.29 and 9.16, respectively). Thus, Dmt-Tic with hydrophobic C-terminal
      substituents enhanced mu affinity to provide delta antagonists with dual receptor
      affinities and bifunctional activity.

PMID- 10585211
TI  - Benzimidazole derivatives. 2. Synthesis and structure-activity relationships of
      new azabicyclic benzimidazole-4-carboxylic acid derivatives with affinity for
      serotoninergic 5-HT(3) receptors.
AB  - A new series of azabicyclic benzimidazole-4-carboxamides 2-21 and -carboxylates
      22-30 were synthesized and evaluated for binding affinity at serotoninergic 5
      HT(3) and 5-HT(4) receptors in the CNS. Most of the synthesized compounds
      exhibited high or very high affinity for the 5-HT(3) binding site and low to no
      significant affinity for the 5-HT(4) receptor. SAR observations indicated that a
      halogen atom at the 6-position and a nitro group at the 7-position of the
      benzimidazole ring is the best substitution pattern for 5-HT(3) affinity and 5
      HT(3)/5-HT(4) selectivity, as well as no substitution in this ring. (S)-(-)-N
      (Quinuclidin-3-yl)benzimidazole-4-carboxamides 2, 8, and 14 bound at central 5
      HT(3) sites with high affinity (K(i) = 2.6, 0. 13, and 1.7 nM, respectively) and
      excellent selectivity over serotonin 5-HT(4) and 5-HT(1A) receptors (K(i) > 1000
      10000 nM). Furthermore, these new 5-HT(3) receptor ligands were pharmacologically
      characterized as potent and selective 5-HT(3) antagonists in the isolated guinea
      pig ileum (pA(2) = 9.6, 9.9, and 9.1, respectively).

PMID- 10585212
TI  - Oxygenated analogues of 1-[2-(Diphenylmethoxy)ethyl]- and 1-[2-[Bis(4
      fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR
      12909) as potential extended-action cocaine-abuse therapeutic agents.
AB  - An investigation into the preparation of potential extended-release cocaine-abuse
      therapeutic agents afforded a series of compounds related to 1-[2
      (diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (1a) and 1-[2-[bis(4
      fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (1b) (GBR 12935 and GBR
      12909, respectively), which were designed, synthesized, and evaluated for their
      ability to bind to the dopamine transporter (DAT) and to inhibit the uptake of
      [(3)H]-labeled dopamine (DA). The addition of hydroxy and methoxy substituents to
      the benzene ring on the phenylpropyl moiety of 1a-1d resulted in a series of
      potent and selective ligands for the DAT (analogues 5-28). The hydroxyl groups
      were included to incorporate a medium-chain carboxylic acid ester into the
      molecules, to form oil-soluble prodrugs, amenable to "depot" injection
      techniques. The introduction of an oxygen-containing functionality to the propyl
      side chain provided ketones 29 and 30, which demonstrated greatly reduced
      affinity for the DAT and decreased potency in inhibiting the uptake of [(3)H]DA,
      and benzylic alcohols 31-36, which were highly potent and selective at binding to
      the DAT and inhibiting [(3)H]DA uptake. The enantiomers of 32 (34 and 36) were
      practically identical in biological testing. Compounds 1b, 32, 34, and 36 all
      demonstrated the ability to decrease cocaine-maintained responding in monkeys
      without affecting behaviors maintained by food, with 34 and 36 equipotent to each
      other and both more potent in behavioral tests than the parent compound 1b.
      Intramuscular injections of compound 41 (the decanoate ester of racemate 32)
      eliminated cocaine-maintained behavior for about a month following one single
      injection, without affecting food-maintained behavior. The identification of
      analogues 32, 34, and 36, thus, provides three potential candidates for
      esterification and formulation as extended-release cocaine-abuse therapeutic
      agents.

PMID- 10585213
TI  - Synthesis and in vitro evaluation of new 8-amino-1,4-benzoxazine derivatives as
      neuroprotective antioxidants.
AB  - A series of new 8-amino-1,4-benzoxazine derivatives 5a-o was synthesized and
      examined for their intrinsic cytotoxicity and their capacity to inhibit oxidative
      stress-mediated neuronal degeneration in neuronal cell cultures. In particular,
      substituent effects at the 3- and 8-positions of the 1,4-benzoxazine ring were
      investigated by in vitro evaluation. In this aim, 3-alkyl substituents seemed to
      be essential for efficient neuroprotective activity. Furthermore, within the
      subseries of substituted 3-alkyl benzoxazines, the most active derivatives were
      those bearing an 8-benzylamino substituent. From the combined results of both
      toxicity and neuroprotection expressed in terms of the safety index, 8
      benzylamino-substituted-3-alkyl-1,4-benzoxazines were identified as the most
      promising compounds, owing to their potent neuroprotective activity without the
      manifestation of intrinsic cytotoxicity.

PMID- 10585215
TI  - High-resolution NMR and computer modeling studies of the cannabimimetic
      aminoalkylindole prototype WIN-55212-2

PMID- 10585214
TI  - Bisphosphonate prodrugs: synthesis and in vitro evaluation of novel acyloxyalkyl
      esters of clodronic acid.
AB  - Novel tetra-, tri-, and P,P'-dipivaloyloxymethyl esters of clodronic acid were
      synthesized, and their properties as possible prodrugs of clodronate were
      evaluated in vitro. All pivaloyloxymethyl esters were significantly more
      lipophilic (log P(app) ranged from -2.1 to 7. 4) than clodronate (log P(app) < or
      = -5.4), which suggests that it may be possible to change the intestinal
      absorption mechanism of clodronate from a paracellular to a transcellular pathway
      by a prodrug approach. Pivaloyloxymethyl esters degraded rapidly in 10% rabbit
      liver homogenate, and half-lives of tri- and P,P'-diesters were 1.1 and 14 min,
      respectively. The intermediate degradation products were further degraded, and
      clodronic acid was released in quantitative amounts. In human serum, the
      stability of pivaloyloxymethyl esters was comparable to their stability in
      phosphate buffer (pH 7.4), which suggests that their degradation in human serum
      is mostly due to the chemical hydrolysis. Benzoyloxypropyl esters of clodronic
      acid were also synthesized, but they did not release clodronic acid due to the
      enzymatic and chemical stability of the formed 3-hydroxypropyl phosphonate esters
      and are, therefore, not prodrugs.

PMID- 10585216
TI  - Analytical ultracentrifugation in the pharmaceutical industry.

PMID- 10585217
TI  - A convenient assay method for the quality control of peptides and proteins.
AB  - The development of a convenient and very accurate procedure with which to
      discriminate among subsets of structurally similar peptides and proteins, and
      measure enantiomeric purities with very good accuracy, has been described in a
      series of recent articles. A factor preventing its general application to all
      peptide forms is that comparisons were originally limited to closed subsets of
      structurally similar types, e.g., dipeptides, tripeptides, and insulin drug
      forms. In the most recent of these articles, a modification to the method was
      described which did enable the comparisons to be extended between sets, in
      particular the di-and tripeptides. That same modification is extended even
      further in this article to include additional di- and tripeptides, glycylglycine
      oligomers, insulin drug forms, and neuropeptides. The same principal component
      analysis treatment used for data reduction and statistical comparisons in prior
      work enables the discrimination among 49 of the total of 51 analytes
      investigated.

PMID- 10585218
TI  - Clustering of CD spectral data as a prototype QSAR model for neuropeptides.
AB  - An analytical method that might eventually qualify as a general quality control
      assay procedure for polypeptide drug forms was described in the companion article
      to this paper. The detector is visible range circular dichroism spectroscopy.
      Multivariate data analysis reduced the spectral data to essentially four
      principal components (or factors) that are characteristic of each analyte. The
      level of analytical selectivity achieved among 51 analytes is very high. Using an
      alternative factor analysis algorithm, the selectivity is even more conveniently
      accomplished in the form of a 2-D cluster diagram presentation that has the
      potential of being a prototypical predictive in vitro model for correlating
      experimental data with structure-activity or structure-function relationships.
      Clustering of the analytes is a consequence not only of the chiral interactions
      associated with ligand exchange in the immediate primary coordination sphere of
      the host derivatizing reagent, but also of long-range intermolecular interactions
      between the coordination architecture of the host and the chiral polypeptides.

PMID- 10585219
TI  - Effect of cyclodextrins and polymers on triclosan availability and substantivity
      in toothpastes in vivo.
AB  - The aqueous solubility of triclosan is only about 10 microg/mL. This very low
      solubility can hamper its biological activity in the oral cavity, which could
      explain the mixed clinical results obtained from triclosan toothpaste trials.
      Triclosan availability in a silica-based toothpaste was improved through
      cyclodextrin solubilization. The triclosan in vivo availability was optimized
      through a series of phase-solubility studies and triclosan release studies. It
      was found that in toothpastes, natural beta-cyclodextrin (betaCD) was just as
      good a solubilizer as the more water-soluble betaCD derivatives. Furthermore, the
      amount of cyclodextrin could be reduced by as much as 60% through the addition of
      a small amount of carboxymethylcellulose (CMC), without affecting triclosan
      release from the toothpaste. Optimally, cyclodextrins resulted in an almost 3
      fold enhancement of triclosan availability compared to an identical toothpaste
      containing no cyclodextrin. In vivo studies in humans showed that replacing
      triclosan with triclosan/betaCD in the toothpaste resulted in only moderate
      improvement in triclosan substantivity. However, replacing triclosan with
      triclosan/betaCD/CMC complex resulted in significant improvement in triclosan
      substantivity. Furthermore, the in vivo studies showed that replacing free
      triclosan with triclosan/betaCD/CMC complex resulted in an almost 3-fold increase
      in initial triclosan concentration in saliva after brushing and about 2-fold
      increase in duration of activity.

PMID- 10585220
TI  - Diphenhydramine disposition in the sheep maternal-placental-fetal unit:
      determinants of plasma drug concentrations in the mother and the fetus.
AB  - The objective of this study was to identify the important factors that determine
      plasma concentrations of diphenhydramine (DPHM) in the mother and the fetus after
      maternal as well as fetal steady-state drug administration. Inter-relationships
      were evaluated between maternal and fetal placental and nonplacental clearances,
      plasma protein binding, and steady-state plasma concentrations of DPHM among data
      obtained from 18 pregnant sheep during late gestation. The major determinant of
      plasma DPHM concentrations in the mother after maternal as well as fetal
      administration appears to be maternal plasma protein binding and maternal
      nonplacental clearance. In contrast, the major determinant of fetal plasma DPHM
      concentrations after maternal drug administration was the extent of fetal first
      pass hepatic drug uptake from the umbilical vein. However, after fetal drug
      administration, the fetal plasma concentrations were related to the extent of
      fetal plasma protein binding and fetal placental and nonplacental clearances. The
      index of fetal-to-maternal placental drug transfer after fetal drug
      administration (steady-state maternal-to-fetal plasma concentration ratio) was
      related to steady-state fetal plasma unbound fraction and fetal placental and
      nonplacental clearance. However, this index was not related to the magnitude of
      the factors operating on the maternal side of the placenta such as maternal
      plasma protein binding and maternal nonplacental clearance. This might indicate a
      lack of complete equilibration of the unbound drug concentrations on the two
      sides of the placenta at the exchange site.

PMID- 10585222
TI  - Sulfathiazole polymorphism studied by magic-angle spinning NMR.
AB  - The literature on sulfathiazole polymorphs has many confusions and
      inconsistencies. These are largely resolved by the distinctive appearance of
      (13)C magic-angle spinning NMR spectra, which immediately show the number of
      molecules in the crystallographic asymmetric unit. The spectra presented include
      those of a newly-recognized form. The assignments of the spectra are established
      and discussed in relation to such factors as electronic structure of the aromatic
      ring, second-order quadrupolar effects originating from the nitrogen nuclei, and
      hydrogen bonding. The results are compared to literature information on the
      crystal structures. When the amino group acts as a hydrogen bond acceptor, there
      is a shielding effect on C-4 to the extent of ca. 8 ppm (which should be compared
      to a further shielding by ca. 10 ppm for sulfathiazole sulfate). The fact that
      the spectrum of form III is similar to the sum of those of forms IV and V is
      rationalized in relation to the crystal structures. Some surprising variability
      of spectra with temperature and with specific sample is reported.

PMID- 10585221
TI  - Cocaine and alcohol interactions in the rat: effect of cocaine and alcohol
      pretreatments on cocaine pharmacokinetics and pharmacodynamics.
AB  - This experiment was designed to investigate the effect of pretreatment with
      cocaine and alcohol on cocaine pharmacokinetics and pharmacodynamics. Four groups
      of rats (n = 8 per group) received one of the following pretreatments for two
      weeks: none, alcohol (10% v/v in drinking water), cocaine (15 mg/kg/day ip), and
      alcohol+cocaine (10% v/v in drinking water + 15 mg/kg/day ip). On the day of the
      experiment, cocaine was administered (30 mg/kg, ip) to each rat, either alone or
      in combination with alcohol (5 g/kg, po), in a balanced crossover experimental
      design. Plasma and brain ECF concentrations of cocaine and its three metabolites:
      benzoylecgonine, norcocaine, and cocaethylene were assayed by HPLC-UV. The
      percent change in brain dopamine concentration, mean arterial blood pressure, and
      heart rate were determined simultaneously. A sigmoid-E(max) model was used to
      describe the brain cocaine concentration-neurochemical effect (dopamine)
      relationship, and an indirect pharmacodynamic response model was used to describe
      the plasma cocaine concentration-cardiovascular effect relationships. Alcohol
      pretreatment led to significant increase in cocaine AUC(p), alpha(t1/2), and
      beta(t1/2). Cocaine pretreatment significantly increased cocaine bioavailability,
      absorption rate constant, TBC, and the formation clearance of cocaethylene. Acute
      alcohol coadministration with cocaine increased cocaine AUC(p) and
      bioavailability, reduced the fraction of cocaine dose converted to
      benzoylecgonine, and increased the formation of norcocaine. These results
      indicate that the pharmacokinetics of cocaine, either administered alone or in
      combination with alcohol, is significantly altered due to prior cocaine and/or
      alcohol use. Both cocaine and alcohol pretreatments increased the E(max) for
      dopamine, with no effect on the EC(50). Acute alcohol coadministration with
      cocaine significantly increased the E(max) for dopamine and reduced the EC(50).
      Cocaine pretreatment significantly decreased the I(max) for blood pressure,
      IC(50), and R(max). For the heart rate response, both alcohol and cocaine
      pretreatments significantly increased the IC(50), with no effect on I(max). These
      results indicate that both cocaine and alcohol pretreatments as well as acute
      alcohol coadministration lead to significant alterations in cocaine
      pharmacodynamics that are due, at least in part, to the changes in cocaine
      pharmacokinetics. If similar effects occur in humans, chronic cocaine and alcohol
      abusers may respond differently to cocaine administration compared to naive users
      and may be at higher risks of cocaine central nervous system toxicity.

PMID- 10585223
TI  - Physiologically based pharmacokinetics of digoxin in mdr1a knockout mice.
AB  - To determine the contribution of the mdr1a gene product to digoxin
      pharmacokinetics, we constructed a physiologically based pharmacokinetic model
      for digoxin in mdr1a (-/-) and mdr1a (+/+) mice. After intravenous
      administration, total body clearance and tissue-to-plasma concentration ratios
      for muscle and heart were decreased in mdr1a (-/-) mice as compared with mdr1a
      (+/+) mice, and in particular, the digoxin concentration in the brain was 68-fold
      higher than that in mdr1a (+/+) mice at 12 h. On the other hand, mdr1a gene
      disruption did not change the contributions of renal and bile clearances to total
      clearance, the plasma protein binding, or the blood-to-plasma partition
      coefficient. Brain concentration-time profiles in mdr1a (+/+) and mdr1a (-/-)
      mice showed a different pattern from those in plasma and other tissues,
      indicating digoxin accumulation in the brain tissue. Because there was no
      difference in the uptake or release of digoxin by brain tissue slices from the
      two types of mice, we assumed the brain tissue compartment to consist of two
      parts (a well-stirred part with influx and efflux clearance and an accumulative
      part). Simulation with this model gave excellent agreement with observation when
      active efflux clearance across the blood-brain barrier was assumed to be zero in
      mdr1a (-/-) mice. The observations in other tissues in both types of mice were
      also well simulated.

PMID- 10585224
TI  - Carrier-mediated transport of monocarboxylic acids in BeWo cell monolayers as a
      model of the human trophoblast.
AB  - The monolayer-forming, human choriocarcinoma cell line, BeWo, was used to study
      the mechanisms of monocarboxylic acid transport across the human trophoblast.
      Benzoic acid, acetic acid, and lactic acid were used as markers for
      monocarboxylic acid carrier-mediated transport. The uptake of benzoic acid by
      BeWo cells was saturable (K(t) = 0.6 +/- 0.3 mM) at higher concentrations and
      significantly inhibited by typical metabolic inhibitors, sodium azide and 2, 4
      dinitrophenol. A selection of different monocarboxylic acids, including a natural
      substrate lactic acid, also substantially inhibited the uptake of benzoic acid
      and acetic acid by BeWo cells, whereas dicarboxylic acids did not affect the
      uptake of either marker. Monocarboxylic acid uptake was pH-dependent and
      inhibited by carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), a
      protonophore. Kinetic analysis using Lineweaver-Burk plots revealed that
      monocarboxylic acids competitively inhibited the uptake of benzoic, lactic, and
      acetic acid by BeWo cells. In transport experiments, the permeation of benzoic
      acid from apical-to-basolateral side was greater than the permeation from the
      basolateral-to-apical side, and the transport of benzoic acid from apical-to
      basolateral side was inhibited by monocarboxylic acids. The findings obtained in
      the present study confirm the existence of an asymmetric, carrier-mediated
      transport system for monocarboxylic acids across the BeWo cell, a representative
      of the human trophoblast.

PMID- 10585225
TI  - Study of binding of 12(S)-hydroxy-5(Z),8(Z),10(E), 14(Z)-eicosatetraenoic acid to
      bovine serum albumin using dynamic surface tension measurements.
AB  - In a recent paper,(1) we demonstrated that molecular interactions between
      biopolymers and other smaller molecules can be detected by means of dynamic
      surface tension measurements. In the present paper, we demonstrate that the same
      methodology can be employed for investigating dose effects and specificity of
      molecular interactions. Three similar lipids were chosen for this study: 12(S)
      hydroxy-5(Z), 8(Z),10(E),14(Z)-eicosatetraenoic acid (12(S)-HETE-free acid),
      methyl 12(S)-hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoate (12(S)-HETE-methyl
      ester), and 5(Z),8(Z),11(Z), 14(Z)-eicosatetraenoic acid (arachidonic acid-free
      acid). These substances were added to a fatty acid free bovine serum albumin
      (BSA) aqueous solution at different lipid concentrations. The characteristic
      tension response indicates that molecular interactions between 12(S)-HETE-free
      acid and BSA exist. The detected interactions are concentration dependent: at a
      molecular ratio of lipid to protein of 1:1, the binding of 12(S)-HETE-free acid
      to BSA is hydrophobic in nature; at the molecular ratio of lipid to protein of
      10:1, a secondary binding occurs and is hydrophilic in nature. Similar molecular
      interactions were not detected between 12(S)-HETE-methyl ester or arachidonic
      acid-free acid and BSA, indicating that the interactions between 12(S)-HETE-free
      acid and BSA are specific. As an independent means, surface elasticity is used to
      probe the molecular interactions at the interface. In the case of 12(S)-HETE-free
      acid but not its methyl ester or arachidonic acid, distinct higher surface
      elasticities were observed at lipid concentrations in excess of a molecular ratio
      of lipid to protein of 1:1. This finding reinforces the above stipulations.

PMID- 10585226
TI  - Measurement and prediction of hydrophobicity parameters for highly lipophilic
      compounds: application of the HPLC column-switching technique to measurement of
      log P of diarylpyrazines.
AB  - In the preparatory stage of structure-activity relationship (QSAR) studies of
      anti-platelet aggregant pyrazine derivatives, log P values (P: 1-octanol/water
      partition coefficient) of diarylpyrazines were measured by a newly developed HPLC
      column-switching technique. The system consists of two processes: (1) adsorption
      of the sample at the top end of a short precolumn, and then (2) quantifying the
      enriched analyte by a conventional analytical column. By using the log P values
      thus obtained, the correction factor for the steric hindrance caused by the
      vicinal diphenyl groups was estimated. The log k values (k; retention factor)
      were also measured with methanol-buffer (pH 7.4) eluents and related to log P.
      The eluent of 50% methanol content (M50) gave a good linear relationship over a
      wide range of log P (-0.3< log P < 5.2), indicating that log k(M50) parameter is
      useful for predicting the log P value.

PMID- 10585227
TI  - Characterization of lipophilicity scales using vectors from solvation energy
      descriptors.
AB  - Lipophilicity scales were characterized by an approach using vectors provided
      from solvation energy descriptors (SED) of solutes such as an excess molar
      refraction, the dipolarity/polarizability, the hydrogen-bond acidity, the
      basicity, and the McGowan characteristic volume. The five components of the SED
      vector were obtained from the coefficients of the five SED terms of the linear
      solvation energy relationship (LSER) equation for the lipophilicity scales. The
      analogy between two lipophilicity scales was expressed as the angle between the
      two SED vectors, while the difference in the contribution of the five independent
      SEDs to these two lipophilicity scales was quantified by the difference of the
      unit vectors of the SED vectors. These approaches were applied to several
      lipophilicity scales measured using microemulsions, micelles, an immobilized
      artificial membrane column, and an octanol-water system. As a result, the
      quantitative classification of these scales was successfully carried out, and the
      difference in the scales was well characterized. In addition, this vector
      approach was extended to the estimation of the contribution of each constituent
      of the microemulsions to the lipophilicity scale. Furthermore, some biological
      parameters such as skin permeability and the distribution between blood and brain
      could be predicted by the summation of the SED vectors obtained from the
      chromatographic systems. These results suggest that complex biological systems
      can be expressed quantitatively by simple chemical models with their SED vectors.

PMID- 10585228
TI  - Evaluation of a novel, natural oligosaccharide gum as a sustained-release and
      mucoadhesive component of calcitonin buccal tablets.
AB  - The objective of this study was to evaluate the gum from Hakea gibbosa (hakea) as
      a sustained-release and mucoadhesive component in buccal tablets for a model
      peptide, namely, salmon calcitonin. Flat-faced core tablets containing either 12
      or 32 mg of hakea and 40 microg (200 IU) of salmon calcitonin (sCT) per tablet
      were formulated using a direct compression technique and were coated with Cutina
      on all but one face. The in vitro release profiles were sigmoidal in nature and
      according to a mathematical model indicated super Case II transport as the
      primary mechanism of release. The resulting plasma sCT and calcium concentrations
      were determined following both intravenous administration and buccal application
      of mucoadhesive tablets in rabbits. Following intravenous administration, the
      mean values determined for t(1/2) (alpha), t(1/2) (beta), V(d), and CL for sCT
      were 0.76 +/- 0.06 min, 67 +/- 18 min, 1484 +/- 454 mL/kg, and 19 +/- 2
      mL/min.kg, respectively. Following the application of the mucoadhesive buccal
      tablets which contained 40 microg of sCT and either 12 or 32 mg of hakea, the
      calculated apparent bioavailability (F) and clearance (CL) were 37 +/- 6% and 19
      +/- 3.3 mL/min.kg and 16 +/- 8% and 18 +/- 0.4 mL/min. kg, respectively. Serum
      calcium concentrations indicated that biologically active sCT was delivered
      across the rabbit buccal mucosa. The strength of mucoadhesion of the tablets was
      also quantitated in terms of the force of detachment as a function of time. The
      force of detachment for the mucoadhesive buccal tablets containing either 12 or
      32 mg of hakea and 40 microg of sCT increased from 4.47 +/- 0.68 to 8.41 +/- 1.0
      N and 8.23 +/- 1.62 to 14.98 +/- 1.63 N, respectively, from 5 to 90 min following
      application to excised rabbit intestinal mucosa. These results demonstrate that
      the novel, natural gum from Hakea gibbosa may be used to sustain the release of
      sCT from a unidirectional-release buccal tablet. The mechanism of in vitro
      release is likely to involve peptide diffusion/polymer dissolution. The
      mucoadhesive strength, as measured by the force of detachment, can be modulated
      by altering the amount of hakea in the tablet. The mucoadhesive buccal tablets
      described in this paper represent an improved transbuccal delivery system for
      therapeutic polypeptides.

PMID- 10585229
TI  - Protein behavior at the water/methylene chloride interface.
AB  - The objective of this study was to investigate the behaviors of proteins at the
      water/methylene chloride interface to better understand denaturing effects of
      emulsification upon proteins. Ribonuclease A (RNase) and human serum albumin
      (HSA) were used as model proteins throughout this study. Their behaviors at the
      interface were studied in terms of protein recovery after emulsification,
      interfacial protein aggregation, and dynamic interfacial tension. This study
      demonstrated that protein instability during emulsification was traced to
      consequences of the adsorption and conformational rearrangements of proteins at
      the water/methylene chloride interface. Compared to HSA, RNase was much more
      vulnerable to the interface-induced aggregation reactions that led to formation
      of water-insoluble aggregates upon emulsification. Even though HSA was almost
      completely recovered from the emulsified aqueous phase, the protein underwent
      dimerization and oligomerization reactions to some extent. The results also
      demonstrated that the extent of interfacial RNase aggregation was affected by its
      aqueous concentration and the presence of HSA. Interestingly, RNase stability
      during emulsification was almost achieved by dissolving an adequate quantity of
      HSA in the RNase solution. HSA seemed to compete for the interface site and to
      effectively keep RNase out the interface, minimizing the likelihood of the
      interface-induced RNase aggregation. These results indicated that competitive
      adsorption modes of proteins could be used to stabilize a protein of interest
      against the denaturing effects of emulsification.

PMID- 10585230
TI  - Skin penetration of nonsteroidal antiinflammatory drugs out of a lipophilic
      vehicle: influence of the viable epidermis.
AB  - The skin penetration of 10 nonsteroidal antiinflammatory drugs (NSAIDs) was
      investigated after application in the lipophilic vehicle light mineral oil. The
      skin permeabilities and maximum fluxes, which were calculated from the
      concentration decreases of the applied solutions in the steady state phases, were
      correlated with physicochemical parameters, mainly the vehicle solubilities and
      the partition coefficients of the model drugs according to the Fickian diffusion
      laws. The objective of the study was to characterize the barrier function of the
      stratum corneum and the viable epidermis and to predict their influences on the
      skin permeabilities and the maximum fluxes of the NSAIDs by model equations. The
      permeability of the human skin for NSAIDs applied in a lipophilic vehicle is a
      function of their hydrophilicity, while the maximum flux is primarily dependent
      on their vehicle solubilities. The viable epidermis was found to represent the
      decisive resistance to the drug transport.

PMID- 10585231
TI  - Oil-in-water liposomal emulsions: characterization and potential use in vaccine
      delivery.
AB  - Emulsification of mineral oil by phospholipids donated by liposomes composed of
      dimyristoyl phosphatidylcholine, dimyristoyl phosphatidylglycerol, cholesterol,
      and lipid A by extrusion resulted in the formation of oil-in-water liposomal
      emulsions containing a substantial number of intact liposomes. Increasing the
      proportion of liposomes from 25 mM to 150 mM phospholipid and increasing the oil
      content from 2.5% (v/v) to 42.5% (v/v) changed the flow characteristics of the
      emulsions from fluid liquid-like to viscous. Likewise, the degree of stability of
      the emulsions was liposomal phospholipid concentration-dependent, ranging from
      partial emulsification in the range 25-100 mM to complete stabilization in the
      range 125-150 mM. Despite some loss of liposome integrity, as evidenced by the
      release of liposomal trapped glucose, emulsification of liposomes containing
      encapsulated prostate-specific antigen (PSA) exhibited antigen-specific
      immunostimulation in mice. These results suggest that liposomes containing
      encapsulated antigen can serve as constituents for the formulation of oil-in
      water vaccines.

PMID- 10585232
TI  - In vitro transepithelial drug transport by on-line measurement: cellular control
      of paracellular and transcellular transport.
AB  - Studies on transcellular transport across epithelial cell layers are performed
      mostly by discontinuous sampling of the transported compound. This has several
      drawbacks, e.g., it gives disturbances in volume, it limits the time-resolution,
      and is often laborious. In this report we introduce a method to measure
      transepithelial transport of fluorescent compounds continuously. The time
      resolution is at the (sub)minute scale, allowing the measurement of the change in
      transport rate before and after transport modulation. We will describe how we
      used the method to measure transcellular and paracellular transport. For highly
      membrane-impermeable compounds, the paracellular transport and the regulation of
      the tight junctions was studied in wild-type and MDR1 cDNA transfected epithelial
      canine kidney cells (MDCKII). The effect of the multidrug transporter P
      glycoprotein (Pgp) on the transepithelial transport was studied. Addition of the
      Pgp inhibitor SDZ PSC 833 showed a modulation of the idarubicin (IDA) and
      daunorubicin (DNR) transport, which was larger during transport from the
      basolateral to the apical side than in the reverse direction. By modeling the
      transepithelial transport, we found that in these cells Pgp had more effect on
      the basolateral to apical transport than vice versa, which can be attributed to a
      relatively large passive permeation coefficient for the cellular basolateral
      plasma membrane.

PMID- 10585233
TI  - Diffuse reflectance near-infrared spectroscopy as a nondestructive analytical
      technique for polymer implants.
AB  - A near-infrared spectroscopic method to quantify drugs or excipients within
      polymeric matrixes is proposed. Cylindrical implants were fabricated by a melt
      mold technique containing various ratios of poly(epsilon-caprolactone) (PCL) and
      poly(ethylene glycol) (PEG) and various loadings of lomefloxacin HCl with a
      constant ratio (70:30 w/w) of PCL/PEG. Near-infrared (NIR) spectra were obtained
      on intact sections of larger implants using a Foss NIRSystems Model 5000
      monochrometer equipped with a Rapid Content Analyzer. Spectral data were treated
      with second derivative transformation followed by linear regression and PLS to
      obtain correlation with lomefloxacin or PEG content. Lomefloxacin content was
      separately determined by UV analysis (287 nm) using a validated extraction
      procedure. The NIR method was tested by comparing predicted loadings of test
      implants with either theoretical values based on weight (PEG) or with UV analysis
      results (lomefloxacin). Second derivative spectral values at particular
      wavelength ratios (PEG, 2064 nm/1698 nm; lomefloxacin, 2172 nm/2226 nm and 1824
      nm/1862 nm) yielded linear results for PEG or lomefloxacin content. PEG content
      determined by NIR spectroscopy was in excellent agreement with theoretical
      content. Lomefloxacin content determined by NIR spectroscopy was also in
      excellent agreement with UV analysis. NIR analysis is interpreted through the use
      of corresponding mid-infrared spectral data.

PMID- 10585234
TI  - Effects of buffer composition and processing conditions on aggregation of bovine
      IgG during freeze-drying.
AB  - The objective of this study was to identify critical formulation and processing
      variables affecting aggregation of bovine IgG during freeze-drying when no
      lyoprotective solute is used. Parameters examined were phosphate buffer
      concentration and counterion (Na versus K phosphate), added salts, cooling rate,
      IgG concentration, residual moisture level, and presence of a surfactant. No
      soluble aggregates were detected in any formulation after either freezing/thawing
      or freeze-drying. No insoluble aggregates were detected in any formulation after
      freezing, but insoluble aggregate levels were always detectable after freeze
      drying. The data are consistent with a mechanism of aggregate formation involving
      denaturation of IgG at the ice/freeze-concentrate interface which is reversible
      upon freeze-thawing, but becomes irreversible after freeze-drying and
      reconstitution. Rapid cooling (by quenching in liquid nitrogen) results in more
      and larger aggregates than slow cooling on the shelf of the freeze-dryer. This
      observation is consistent with surface area measurements and environmental
      electron microscopic data showing a higher surface area of freeze-dried solids
      after fast cooling. Annealing of rapidly cooled solutions results in
      significantly less aggregation in reconstituted freeze-dried solids than in
      nonannealed controls, with a corresponding decrease in specific surface area of
      the freeze-dried, annealed system. Increasing the concentration of IgG
      significantly improves the stability of IgG against freeze-drying-induced
      aggregation, which may be explained by a smaller percentage of the protein
      residing at the ice/freeze-concentrate interface as IgG concentration is
      increased. A sodium phosphate buffer system consistently results in more turbid
      reconstituted solids than a potassium phosphate buffer system at the same
      concentration, but this effect is not attributable to a pH shift during freezing.
      Added salts such as NaCl or KCl contribute markedly to insoluble aggregate
      formation. Both sodium and potassium chloride contribute more to turbidity of the
      reconstituted solid than either sodium or potassium phosphate buffers at similar
      ionic strength, with sodium chloride resulting in a substantially higher level of
      aggregates than potassium chloride. At a given cooling rate, the specific surface
      area of dried solids is approximately a factor of 2 higher for the formulation
      containing sodium chloride than the formulation containing potassium chloride.
      Turbidity is also influenced by the extent of secondary drying, which underscores
      the importance of minimizing secondary drying of this system. Including a
      surfactant such as polysorbate 80, either in the formulation or in the water used
      for reconstitution, decreased, but did not eliminate, insoluble aggregates. There
      was no correlation between pharmaceutically acceptability of the freeze-dried
      cake and insoluble aggregate levels in the reconstituted product.

PMID- 10585235
TI  - Notes on the inverse Gaussian distribution and choice of boundary conditions for
      the dispersion model in the analysis of local pharmacokinetics.
AB  - The dispersion model has been widely used to analyze local pharmacokinetics in
      the organs and the tissues since the 1980's. However, an ambiguity still remains
      in selecting the boundary conditions which are necessary to solve the basic
      equation of the model. In this note, theoretical considerations are given to this
      problem and we present here some deficiencies of the mixed boundary conditions.
      It seems that theoretical confusion exists in the literature for the mixed
      boundary conditions. It is well-known that the solution of the dispersion model
      with a bolus input is the inverse Gaussian distribution for the mixed boundary
      conditions. However, it is rarely recognized that the inverse Gaussian
      distribution requires an open boundary at either the inlet or the outlet. For the
      analysis of local pharmacokinetics, the use of the classical Danckwerts (or
      closed) boundary conditions is recommended.

PMID- 10585236
TI  - Development and evaluation of microbiocidal hydrogels containing monoglyceride as
      the active ingredient

PMID- 10585237
TI  - Sex differences in cognition: the role of testosterone and sexual orientation.
AB  - The performance of both heterosexual and homosexual males and females was
      compared on four cognitive tasks which have been shown to reveal evidence of
      sexual dimorphism. In one spatial and one verbal task, significant sex and
      orientation effects were found. Significant relationships were also found between
      salivary free-testosterone levels and performance on both spatial tasks, but no
      significant associations were found for performance on the two verbal tasks. The
      present study revealed both within- and between-sex differences in cognition and
      indicates that these differences may be partly accounted for by the activational
      effects of free testosterone.

PMID- 10585238
TI  - Sex differences in functional cerebral asymmetries in a repeated measures design.
AB  - The aim of the present study was to analyze whether task repetitions which are an
      inevitable part of repeated measures designs might induce performance alterations
      specific for gender and hemisphere. Male and female subjects conducted twice a
      lexical decision, a polygon recognition, and a face discrimination task as a
      visual half field paradigm with the two experimental sessions repeated by 2
      weeks. The results show that only in female subjects can a session effect for the
      lexical decision and the polygon recognition task be demonstrated which is
      hemisphere specific. Thus, repeated measures designs seem to have a gender- and
      hemisphere-specific effects of their own which could confound with other
      variables under study.

PMID- 10585239
TI  - Configural and local processing of faces in children with Williams syndrome.
AB  - Three experiments investigated face processing in children with Williams syndrome
      (WS). In Experiment 1, the ability to discriminate different aspects of faces was
      compared between WS subjects and a group of children individually matched for
      chronological age (CA-matches) and another group matched for mental age (MA
      matches). In Experiments 2 and 3, the ability to process the local and configural
      aspects of geometrical patterns and faces was assessed within the same groups of
      subjects. The results indicated that the WSs' overall performance on face
      recognition was below that of the CA-matches, but similar to that of the MA
      matches. This study revealed in addition that the CA- and MA-matches showed a
      bias toward a configural mode of face and geometrical shape processing, whereas
      children with WS did not show any bias. These findings suggest that face
      processing undergoes an abnormal developmental course in WS.

PMID- 10585240
TI  - Dopamine and the origins of human intelligence.
AB  - A general theory is proposed that attributes the origins of human intelligence to
      an expansion of dopaminergic systems in human cognition. Dopamine is postulated
      to be the key neurotransmitter regulating six predominantly left-hemispheric
      cognitive skills critical to human language and thought: motor planning, working
      memory, cognitive flexibility, abstract reasoning, temporal analysis/sequencing,
      and generativity. A dopaminergic expansion during early hominid evolution could
      have enabled successful chase-hunting in the savannas of sub-Saharan Africa,
      given the critical role of dopamine in counteracting hyperthermia during
      endurance activity. In turn, changes in physical activity and diet may have
      further increased cortical dopamine levels by augmenting tyrosine and its
      conversion to dopamine in the central nervous system (CNS). By means of the
      regulatory action of dopamine and other substances, the physiological and dietary
      changes may have contributed to the vertical elongation of the body, increased
      brain size, and increased cortical convolutedness that occurred during human
      evolution. Finally, emphasizing the role of dopamine in human intelligence may
      offer a new perspective on the advanced cognitive reasoning skills in nonprimate
      lineages such as cetaceans and avians, whose cortical anatomy differs radically
      from that of primates.

PMID- 10585241
TI  - The effect of midazolam on implicit memory tests.
AB  - Substantial empirical evidence exists suggesting that there are distinct forms of
      explicit and implicit memory. However, methodological problems have hampered
      attempts to identify the nature of the information processing underlying these
      forms of memory. These problems include the contamination of performance on
      implicit memory tests by explicit memory processes, as well as a host of
      difficulties inherent in correlational approaches that involve amnesiac subjects.
      In this paper we attempt to explore whether midazolam, a benzodiazepine used in
      surgical anesthesia, might be useful for studying implicit memory. Specifically,
      we attempt to determine whether midazolam produces selective effects on explicit,
      as opposed to implicit, memory. We focus on midazolam because of prior studies
      demonstrating that benzodiazepines do not affect implicit memory and because its
      rapid pharmacokinetics ensure that sedative effects are minimized when testing
      occurs at relatively short retention intervals. The results of an experiment
      using free recall, fragment completion and perceptual identification tests
      suggest that midazolam diminishes memory in implicit and explicit memory tests,
      although the diminution is proportionally larger in explicit memory. These
      results constrain the inferences that may be drawn when midazolam is used to
      explore implicit memory.

PMID- 10585242
TI  - Toward a cultural neuropsychology: An alternative view and a preliminary model.
AB  - Any integrated theory of mind and behavior must address the dynamic interaction
      between neurobiological and sociocultural systems as possible causes for human
      action. Newer findings within the behavioral neurosciences have pointed to the
      brain's exceptional plasticity and flexibility and suggest that one's
      surroundings, including one's cultural environment, may directly influence the
      way the human nervous system becomes organized. In this paper, a preliminary
      connectionist model of culture-brain interaction is proposed in an effort to
      illustrate the possible contribution of cultural factors to the development of
      the individual human brain.

PMID- 10585243
TI  - Visual field differences in spatial frequency discrimination.
AB  - Subjects discriminated between sine-wave gratings that differed by either +/
      0.125 octaves (small difference) or +/-1.0 octaves (large difference). Baseline
      stimuli consisted of either 1.0 or 4.0 cycles per degree gratings. A left visual
      field advantage was obtained for the small difference in frequency, with no
      visual field advantages for the large difference in frequency. Similarly,
      moderate support for right versus left visual field advantages in processing high
      versus low spatial frequencies was found, although these interactions were not
      statistically significant. The results are discussed in light of Kosslyn's (1987)
      categorical and coordinate framework.

PMID- 10585244
TI  - Individual differences in callosal efficiency: correlation with attention.
AB  - Previous studies of clinical populations and normal children have suggested that
      the efficiency of callosal transfer correlates with the ability to sustain
      attention. The purpose of the present study was to determine whether the same
      might be true for normal adults. Subjects were 42 right-handed adults. The
      efficiency of the transfer via the anterior callosum was assessed on a bimanual
      coordination task. The efficiency of the posterior callosum was measured on a
      tachistoscopic task that required subjects to compare two lines when both were
      presented either to the same visual field or to opposite visual fields. Sustained
      attention was measured on a vigilance task in which the time between target
      presentations (ISI) was varied. Performance on the bimanual task correlated with
      the ability to sustain attention over the entire 20 min of the vigilance task.
      The efficiency of the posterior callosum was related to the ability to detect
      targets that occurred after relatively long ISIs.

PMID- 10585246
TI  - Theoretical and experimental neuropsychology (TENNET XI)

PMID- 10585245
TI  - Inhibitory control differences following mild head injury.
AB  - Complex inhibitory control, defined as the ability to inhibit a planned or
      ongoing action, was assessed in a sample of individuals with a history of mild
      head injury, case-matched with normal control subjects for age and gender. This
      central act of control was assessed using a modification of the stop-signal
      paradigm. The group with mild head injury took longer to inhibit their on going
      action and reported more accidents than the normal control subjects. The group
      that reported having had a mild head injury did not differ in terms of their go
      reaction time, number of correct responses, handedness, education level, or
      reported learning disabilities. Limitations of this design and directions for
      future research are discussed.

PMID- 10585248
TI  - Hot hundred list

PMID- 10585247
TI  - Editorial

PMID- 10585249
TI  - Studies on the cellular basis of morphogenesis in the sea urchin embryo. Directed
      movements of primary mesenchyme cells in normal and vegetalized larvae.
AB  - A time-lapse study has been made of the movements of the primary mesenchyme cells
      in the developing sea urchin larva. It shows that these cells move by pseudopod
      formation and contraction, and that a transition takes place--within a few hours-
      from a more or less random cluster, in the early mesenchyme blastula, to a well
      organized, coherent pattern on the ectoderm of the gastrula. This organization is
      achieved by a striking random exploration of the wall of the larva by the
      pseudopods, followed by their contraction. The final pattern of the mesenchyme
      reflects those regions of the wall where the contacts between pseudopods and wall
      are most stable. The mechanism is thus one of selective fixation rather than of
      selective conduction. The pseudopodal contacts are seen to be continually made
      and broken, even when the final pattern is formed. The pseudopods of several
      cells may fuse to form a common pseudopod, these cells then migrating together.
      This is particularly evident in vegetalized larvae, but is also typical of the
      ventral side. Despite considerable variations in the way in which the final
      pattern is achieved, several main phases can be distinguished. The first is a
      radial displacement of the cells from the vegetal plate onto the presumptive
      ectoderm, followed by a phase of dispersion. The cells then gradually accumulate
      at a characteristic level, and form a ring. During this process, and when the
      ring is formed, the cells tend to accumulate in two clusters along the ring. The
      pseudopods of the cells in these clusters join into a cable, the end of which is
      highly branched; it explores the ectoderm, and extends the cell clusters to form
      branches from the ring. In vegetalized larvae, the pattern of distribution is
      simplified, but the same principles apply. It is suggested that the variations in
      the way in which the pattern is achieved are, in all probability, merely a
      reflexion of the lack of precision in the time sequence of changes in adhesive
      properties of the primary mesenchyme and blastocoel wall.

PMID- 10585250
TI  - The role of thin filopodia in motility and morphogenesis.

PMID- 10585251
TI  - Analysis of human metaphase chromosome set by aid of DNA-binding fluorescent
      agents.

PMID- 10585252
TI  - Technology and the evolution of human genetics.

PMID- 10585253
TI  - Chromosome segregation and cancer.

PMID- 10585254
TI  - Accumulating active p53 in the nucleus by inhibition of nuclear export: a novel
      strategy to promote the p53 tumor suppressor function.

PMID- 10585255
TI  - Natural and engineered cytotoxic ribonucleases: therapeutic potential.

PMID- 10585256
TI  - Molecular genetic studies of Wnt signaling in the mouse.

PMID- 10585257
TI  - The role of coactivators in steroid hormone action.

PMID- 10585258
TI  - Vertebrate bHLH genes and the determination of neuronal fates.

PMID- 10585259
TI  - Nuclear factor Y (NF-Y) and cellular senescence.
AB  - NF-Y, also termed CBF, is a major CCAAT-binding transcription factor that
      specifically recognizes the consensus sequence 5'-CTGATTGGYYRR-3 or 5'
      YYRRCCAATCAG-3' (Y = pyrimidines and R = purines) present in the promoter region
      of many constitutive, inducible, and cell-cycle-dependent eukaryotic genes. The
      functional NF-Y is a heterotrimeric protein, consisting of three different
      subunits, A, B, and C. Each of the three subunits contains two or three distinct
      protein-interacting domains for trimer formation and for interacting with other
      nuclear proteins. Only the trimeric NF-Y, and not the individual subunit, possess
      DNA-binding activity. The transcriptional activity of NF-Y can be regulated by
      differential expression, alternative splicing, protein-protein interactions, and
      cellular redox potential. The regulation of thymidine kinase (TK) and
      dihydrofolate reductase (DHFR) genes in human diploid fibroblasts serves as an
      example of how NF-Y may have a role in replicative senescence by regulating age
      dependent G1/S genes.

PMID- 10585260
TI  - The expression and activity of D-type cyclins in F9 embryonal carcinoma cells:
      modulation of growth by RXR-selective retinoids.
AB  - The growth rate of malignant F9 embryonal carcinoma cells slows considerably
      following all-trans-retinoic acid-induced differentiation into benign parietal
      endoderm. To determine the mechanism of this process, we examined the expression
      of cyclins D1, D2, and D3 and the activity of their associated kinases. Cyclin D1
      and D3 mRNA levels decreased during complete differentiation induced by all-trans
      retinoic acid and dibutyryl cAMP, while the levels of cyclin D2 and the cyclin
      dependent kinase (Cdk) inhibitor p27 mRNAs increased. Ultimately, terminally
      differentiated cells possessed 50% of the Cdk4-associated kinase activity
      observed in undifferentiated cells. Since numerous genes are differentially
      regulated during parietal endoderm differentiation, it is difficult to determine
      whether retinoic acid affects cell cycle gene expression directly or if these
      changes are caused by differentiation. We found that the retinoid X receptor
      (RXR)-selective agonists LG100153 and LG100268 significantly inhibited F9 cell
      growth without causing overt terminal differentiation as assessed by anchorage
      independent growth and differentiation-associated gene expression. As seen in
      cells induced to differentiate by the RAR agonist all-trans-retinoic acid, RXR
      activation led to an increase in the number of cells in G1 phase. RXR agonists
      also sharply induced the levels of the Cdk regulatory subunits, cyclin D2 and D3.
      However, Cdk4-dependent kinase activity was reduced by RXR-selective retinoid
      treatment. These observations suggest that some retinoids can directly inhibit
      proliferation and regulate Cdk4-dependent kinase activity without inducing
      terminal differentiation.

PMID- 10585261
TI  - Lineage-dependent collagen expression and assembly during osteogenic or
      chondrogenic differentiation of a mesoblastic cell line.
AB  - The mesoblastic clone, C1, behaves as a tripotential progenitor able to self
      renew and to differentiate toward osteogenesis, chondrogenesis, or adipogenesis
      in response to specific inducers. In this study, expression and deposition by the
      C1 cells of essential components of the extracellular matrix, collagens type I,
      II, III, V, XI, VI, IX, and X were followed along the osteogenic and chondrogenic
      pathways, through biochemical, immunochemical, and electron microscopy analyses.
      Implementation of each program involves profiles of collagen synthesis and matrix
      assembly close to those documented in vivo. Depending on the applied inducers,
      cells adopt a defined identity and, controls acting at transcriptional and
      posttranslational levels adapt the set of deposited collagens to one particular
      cell fate. Osteogenic C1 cells selectively build a type I collagen matrix also
      containing type III, V, and XI collagens but selectively exclude type II
      collagen. Chondrogenic C1 cells first elaborate a type II collagen network and
      then acquire hypertrophic chondrocyte properties while assembling a type X
      collagen matrix as in the growth plate. This study provides an example of how a
      mesoblastic cell line can develop, in vitro, each of its genetic programs up to
      terminal differentiation. Intrinsic factors and time-dependent cell-matrix
      interactions might, as in vivo, underline the implementation of an entire
      differentiation program.

PMID- 10585262
TI  - Role of P-glycoprotein in human natural killer-like cell line-mediated
      cytotoxicity.
AB  - Natural killer (NK) cells express the highest amount of P-glycoprotein (Pgp), a
      product of the multidrug resistance (MDR) 1 gene, among lymphoid cells, and our
      previous studies demonstrated that Pgp is required for NK cell-mediated
      cytotoxicity. In this study we examined the role of Pgp in NK cell-mediated
      cytotoxicity using a human NK-like cell line, i.e., YTN cells and two MDR
      reversing agents, nicardipine and its structural analog, AHC-93. These two agents
      inhibited the Pgp function (rhodamine-123 excretion) as well as cell-mediated
      cytotoxicity, confirming that Pgp is critical for NK cell-mediated cytotoxicity.
      As revealed by video-rate ultraviolet laser-scanning confocal microscopy, AHC-93
      did not inhibit the increase in the intracellular calcium concentration upon
      binding to target cells, whereas nicardipine did, as reported previously. These
      two reagents relocated acridine orange dye from lysosomes to the cytoplasm at
      concentrations similar to those required for the inhibition of cell-mediated
      cytotoxicity. These results suggest that Pgp is directly or indirectly involved
      in pH regulation in lysosomes, but not in calcium homeostasis.

PMID- 10585263
TI  - p21 promotes ceramide-induced apoptosis and antagonizes the antideath effect of
      Bcl-2 in human hepatocarcinoma cells.
AB  - p21, a potent cyclin-dependent kinase inhibitor, has been known to induce cell
      cycle arrest in response to DNA-damaging agents. Although p21 has been reported
      to play an important role in the regulation of apoptosis, the postulated role for
      p21 in apoptosis is still controversial. Previously, we reported that p21 was
      induced in a p53-independent manner during ceramide-induced apoptosis in human
      hepatocarcinoma cell lines. In the present study, we investigated the precise
      role of p21 in ceramide-induced apoptosis in human hepatocarcinoma cells by using
      a tetracycline-inducible expression system. Overexpression of p21 by itself did
      not induce apoptosis in p53-deficient Hep3B cells. However, Hep3B/p21 cells were
      more sensitive to ceramide-induced apoptosis. In these cells, p21 overexpression
      did not result in G1 arrest. The expression level of Bax was increased in
      Hep3B/p21 cells treated with ceramide and its expression was more accelerated
      under the p21-overexpressed condition compared to that of the p21-repressed
      condition. Overexpression of Bax induced apoptosis in Hep3B cells. On the other
      hand, the levels of p21 and Bax protein were increased by ceramide in another
      hepatocarcinoma cell line, SK-Hep-1, while the Bcl-2 protein level was not
      changed. Overexpression of Bcl-2 not only suppressed apoptosis but also
      completely prevented induction of p21 and Bax caused by ceramide in SK-Hep-1
      cells. Furthermore, overexpression of p21 antagonized the death-protective
      function of Bcl-2 and upregulated expression of Bax protein. These results
      suggest that p21 promotes ceramide-induced apoptosis by enhancing the expression
      of Bax, thereby modulating the molecular ratio of Bcl-2:Bax in human
      hepatocarcinoma cells.

PMID- 10585264
TI  - Activation of Xenopus eggs by the kinase inhibitor 6-DMAP suggests a differential
      regulation of cyclin B and p39(mos) proteolysis.
AB  - In Xenopus eggs, metaphase II arrest is due to the cytostatic factor that
      maintains a high level of MPF activity. Kinases are important in this phenomenon
      since p39(mos) and MAPK play a part in the cytostatic activity whereas p34(cdc2)
      is the catalytic subunit of MPF. Fertilization induces a rise in intracellular
      calcium leading to egg activation that can be mimicked by calcium-increasing
      agents such as calcium ionophore. We have performed on Xenopus eggs a biochemical
      comparison of the effects of the kinase inhibitor 6-DMAP and the calcium
      ionophore. Both drugs were able to induce pronucleus formation but the underlying
      molecular events were different. The inactivation of MAPK occurred earlier in
      eggs exposed to 6-DMAP. Cyclins B1 and B2 were stable and p39(mos) was
      proteolysed in 6-DMAP-treated eggs while the three proteins underwent degradation
      in A23187-treated ones. These results suggest a differential regulation of
      ubiquitin-dependent proteolysis of cyclin B and p39(mos).

PMID- 10585265
TI  - Integrin signaling at the M/G1 transition induces expression of cyclin E.
AB  - The activities of the mammalian G1 cyclins, cyclin D and cyclin E, during cell
      cycle progression (G1/S) are believed to be regulated by cell attachment and the
      presence of growth factors. In order to study the importance of cell attachment
      and concomitant integrin signaling on the expression of G1 cyclins during the
      natural adhesion process from mitosis to interphase, protein expression was
      monitored in cells that were synchronized by mitotic shake off. Here we show that
      in Chinese hamster ovary (CHO) and neuroblastoma (N2A) cells, expression of
      cyclin E at the M/G1 transition is regulated by both growth factors and cell
      attachment, while expression of cyclin D seems to be entirely dependent on the
      presence of serum. Expression of cyclin E appears to be correlated with the
      phosphorylation of the retinoblastoma protein, suggesting a link with the
      activity of the cyclin D/cdk4 complex. Expression of the cdk inhibitors
      p21(cip1/Waf1) and p27(Kip1) is not changed upon serum depletion or detachment of
      cells during early G1, suggesting no direct role for these CKIs in the regulation
      of cyclin activity. Although inhibition of cyclin E/cdk2 kinase activity has been
      reported previously, this is the first time that cyclin E expression is shown to
      be dependent on cell attachment.

PMID- 10585266
TI  - Accumulation of mutant p53(V143A) modulates the growth, clonogenicity, and
      radiochemosensitivity of malignant glioma cells independent of endogenous p53
      status.
AB  - Alterations of the p53 gene have been attributed a major role in the development
      and resistance to therapy of several human cancers. Accumulation of p53 in tumor
      cells may result from mutations associated with prolonged half-life or from
      stabilization of wild-type p53 by different mechanisms. To address the role of
      p53 accumulation in the response of malignant glioma cells to radiochemotherapy,
      we expressed the p53 mutant p53(V143A) in five human malignant glioma cell lines
      with different genetic and functional p53 status. Accumulation of p53(V143A)
      modulated proliferation in three and clonogenicity in four of five cell lines
      without a clear pattern with regard to their endogenous p53 status. p53(V143A)
      inhibited the camptothecin-induced accumulation of p21(WAF1/CIP1) in cell lines
      with p53 functional wild-type activity, but not in cell lines lacking p53
      activity, consistent with a transdominant-negative effect of p53(V143A).
      Irradiation induced a moderate G2/M arrest in all cell lines, irrespective of the
      p53 status, that was unaffected by p53(V143A). Radiosensitivity as well as
      sensitivity to BCNU, teniposide (VM26), topotecan, vincristine, Taxol, and
      cisplatin both in cytotoxic cell death and in clonogenic cell death was unchanged
      in p53(V143A)-transfected cells with few exceptions. These data do not support
      the hypothesis that accumulation of mutant p53 is a major determinant of the
      response to adjuvant radiochemotherapy in human malignant glioma cells.

PMID- 10585267
TI  - Ultrastructural and functional studies of the interaction between IL-12 and IL-2
      for the generation of lymphokine-activated killer cells.
AB  - IL-12 promotes generation of LAK activity in short-term-cultured NK cells, but
      information on the structure and function of IL-12-induced LAK cells is not yet
      available. The latter issues have been here investigated with emphasis on
      interactions between IL-12 and IL-2. Peripheral blood mononuclear cells (MNC)
      exposed to IL-12 for 5-7 days displayed a decrease in the amount and density of
      the matrix of large granular lymphocyte (LGL)-associated granules. In cells
      cultured with IL-12 and IL-2 for 5-7 days, empty vacuoles were predominant and
      the electron-dense matrix was scanty. In MNC incubated with IL-2 for 5-7 days,
      most granules were loaded with electron-dense matrix. IL-12 and IL-2 displayed an
      additive effect on LAK cell cytotoxicity until approximately 48 h in culture
      which was followed by a sharp decline. Immunocytochemical and biochemical studies
      demonstrated that MNC cultured for 5-7 days with IL-12 and IL-2 displayed
      downregulated perforin expression and upregulated granzyme B expression. Fas
      ligand expression was virtually undetectable in MNC cultured for 5-7 days with or
      without cytokines. It appears that perforin downregulation plays a major role in
      the reduced cytotoxicity of MNC cultured with IL-12 and IL-2 for 5-7 days.

PMID- 10585268
TI  - Changes in elemental content during apoptotic cell death studied by electron
      probe X-ray microanalysis.
AB  - Recent data suggest that changes in ionic content, primarily potassium, play a
      pivotal role in the progression of apoptosis. However, the changes in total
      element content, i.e., sodium (Na), magnesium (Mg), phosphorous (P), chlorine
      (Cl), potassium (K), and calcium (Ca), during apoptosis have not been evaluated.
      Electron probe X-ray microanalysis (EPXMA) was used to measure total element
      content in U937 cells before and after the induction of apoptosis. As an
      experimental model we used U937 cells irradiated with ultraviolet (UV) light.
      Apoptosis was evaluated with phase-contrast microscopy, with scanning and
      transmission electron microscopy, and with the fluorescent dye bisbenzimide
      (Hoechst 33342). Plasma membrane permeability as a measure of cell death was
      determined by trypan blue dye exclusion. To investigate element content with
      EPXMA, cells were cryoprepared, i.e., cryofixed and freeze-dried, and analyzed as
      whole cells using a scanning electron microscope. We found that the UV
      irradiation induced rapid (within 2 h) morphological changes associated with
      apoptosis, such as plasma membrane blebbing, condensation of the chromatin, and
      the formation of membrane-bound apoptotic bodies. At this time, 95% of the
      apoptotic cells excluded trypan blue dye. EPXMA results demonstrated that UV
      light-irradiated apoptotic cells (cells with membrane-bound apoptotic bodies) had
      a lower Cl content (P < 0.001) and K content (P < 0.001) and a higher Na content
      (P < 0.001) in comparison with nonirradiated control cells. Also, P and Ca
      content was higher in apoptotic cells than in control cells, but this difference
      did not reach statistical significance. No differences were found in Mg. These
      data indicated that morphological changes characteristic of apoptotic cell death
      are related with significant changes in sodium, chlorine, and potassium content.
      In addition, we demonstrated that these changes in elemental composition were not
      associated with loss of cell membrane integrity.

PMID- 10585269
TI  - The dual specificity protein kinase CLK3 is abundantly expressed in mature mouse
      spermatozoa.
AB  - CLK3, a member of the LAMMER family of dual-specificity protein kinases, is
      abundantly expressed in the reproductive system of male mice. Specifically, high
      levels of CLK3 protein expression are found in mature spermatozoa in the testis
      and epididymis. The majority of the CLK3 protein in the testis is a full-length
      kinase-containing form, and only a small amount of a catalytically inactive N
      terminally truncated splice variant protein product is observed. Within the
      mature spermatozoa CLK3 is localized to the acrosome and tail. CLK3 is expelled
      from the sperm following the acrosome reaction and inactivated, likely by
      degradation by the proteases released by the sperm during the acrosome reaction.
      The CLK family of kinases has previously been implicated in mRNA splicing;
      however, the bulk of the CLK3 protein in these cells is located in the cytoplasm,
      suggesting that CLK3 may have additional roles in the cell.

PMID- 10585270
TI  - Induction of human high K(M) 5'-nucleotidase in cultured 293 cells.
AB  - Human 293 cells were stably transfected with a plasmid introducing a receptor for
      the ecdysone analog muristerone. The cells were further stably transfected with
      muristerone-inducible expression vectors carrying either the cDNA for the human
      high K(M) 5'-nucleotidase or the coding sequence of the nucleotidase linked to
      the 5'-end of the sequence for the green fluorescent protein. Upon induction,
      both types of transfectants overproduced nucleotidase activity in a time- and
      dose-dependent manner. Western blots gave values close to the expected subunit
      molecular masses of 65 and 92 kDa, respectively, excluding processing of the
      induced proteins. Cells induced to overexpress the nucleotidase showed a
      decreased growth rate and contained smaller pools of each of the four common
      ribonucleoside triphosphates. They showed no increased resistance to the toxicity
      of 2-chlorodeoxyadenosine.

PMID- 10585271
TI  - A natural extracellular factor that induces Hsp72, inhibits apoptosis, and
      restores stress resistance in aged human cells.
AB  - Experiments with cultured cells showed that most cellular stress resistance
      components are specialized for certain types of damage. For example, superoxide
      dismutase protects from oxidative damage; DNA repair enzymes guard against
      mutagens and other DNA-damaging agents. On the other hand, the major inducible
      heat shock protein Hsp72 protects cells from a large variety of stresses and thus
      represents a generalized repair/stress resistance component. Hsp72 not only
      refolds damaged proteins but also interferes with programmed cell death signaling
      pathways, thus providing cells with time to repair the damage, hence its
      universality as a stress protector. In the present study we demonstrate the
      occurrence in murine and human ascites fluids (AF) of a natural nontoxic
      extracellular factor (ascites Hsp72-inducing factor, AHIF) capable of activating
      Hsp72 expression in different types of cells via a pathway distinct from the heat
      shock response pathway. AHIF is unique in that it is the first physiological
      factor capable of inducing synthesis of Hsp72 not only in young cells but,
      remarkably, also in aged human cells that largely have lost the ability to
      express Hsp72 in response to stresses, a manifestation at the cellular level of a
      progressive impairment in the ability to adapt to environmental changes which
      characterizes aging. Pretreatment of aged human cells with AF triggers Hsp72
      expression at levels seen in young stressed cells and protects cells from a
      variety of otherwise lethal stressful treatments such as heat shock, TNF, UV
      irradiation, etoposide, and menadione. Activation of Hsp72 expression is
      essential for antiapoptotic action of AHIF because specific inhibition of Hsp72
      expression by antisense RNA abolishes the cytoprotective effect of AF. In view of
      an important link between stress resistance and longevity in different organisms,
      the abilities of AHIF make it a unique candidate for the role of a systemic
      regulator of the aging process. While a cell-autonomous stress response
      diminishes with aging, aged cells retain the ability to respond to an
      extracellular factor which induces the expression of Hsp72. This finding opens up
      exciting possibilities for using AF factor to restore stress resistance to old
      cells and organisms and the possibility of interfering with the aging process.
      The ability to induce stress resistance in young cells and to restore it in aged
      cells could serve as a basis for developing effective antiapoptotic therapies.

PMID- 10585272
TI  - A new primary culture system representative of the human gastric epithelium.
AB  - The gastric pit-gland unit is a highly dynamic and compartimentalized structure
      which assumes important key functions such as acid secretion, digestion of
      dietary proteins and triglycerides, protection, and epithelial restitution
      following injury. However, in vitro models representative of the intact gastric
      epithelium are still lacking. The current study was undertaken to investigate the
      possibility of generating such primary cultures from human fetal stomach. The use
      of Matrisperse, a nonenzymatic solution, allowed complete dissociation of the
      epithelial layer and the maintenance for at least 7 days of all gastric
      epithelial cell types in primary culture on plastic. Indirect immunofluorescence
      and Western blot analyses confirmed the purity of epithelial cultures, composed
      of 60% mucus-secreting cells, 25% zymogenic chief cells, 5% parietal cells, and a
      small proportion of mitotic precursors. Their functionality was demonstrated by
      the presence of zonulae occludens and adherens at cell to cell contacts,
      [(3)H]thymidine incorporation, Periodic acid Schiff staining, and expression of
      growth factor receptors (EGF/TGFalpha, IGF1, HGF, KGF), gastric H(+)/K(+)-ATPase,
      pepsinogen (Pg5), and human gastric lipase (HGL). Chief cells were able to
      produce and secrete both Pg5 and HGL and to respond to EGF treatment. In
      conclusion, we developed a new primary culture system of human gastric epithelium
      characterized for the first time by the absence of added matrix and the
      maintenance of functional chief cells. It represents an experimental breakthrough
      that will serve applications in investigating the actions of hormones,
      mesenchymal growth factors, and basement membrane proteins on human gastric
      functions in vitro.

PMID- 10585273
TI  - Complex mechanisms underlying impaired activation of Cdk4 and Cdk2 in replicative
      senescence: roles of p16, p21, and cyclin D1.
AB  - Numerous changes in gene expression are known to occur during replicative
      senescence, including changes in genes involved in the cell cycle control. In the
      present study, we have found a severe impairment in the activation of Cdk2 and
      Cdk4 in response to mitogens in senescent human fibroblasts and determined the
      molecular basis for this. Although Cdk4 protein was constitutively expressed in
      senescent cells at the same level as in early-passage young cells, it was found
      to be complexed with a distinct set of Cdk inhibitors. Cdk4 derived from early
      passage quiescent cells was effectively activated by incubation with cyclin D1
      and Cdk-activating kinase (CAK) in vitro, whereas Cdk4 from senescent cells was
      not. Cdk2 protein was dramatically decreased in senescent cells and complexed
      primarily with cyclin D1 and p21. This cyclin D1-bound Cdk2 was not activated by
      CAK either in vivo or in vitro, implicating cyclin D1 as an inhibitor of Cdk2
      activation. Thus, one of the underlying molecular events involved in replicative
      senescence is the impaired activation of Cdk4 and Cdk2 due to increased binding
      of p16 to Cdk4 and increased association of Cdk2 with cyclin D1 and p21.

PMID- 10585274
TI  - Monocytically differentiating HL60 cells proliferate rapidly before they mature.
AB  - 1alpha,25-Dihydroxyvitamin D(3) (D(3)) provokes growth arrest and monocytic
      differentiation in myeloid cells. Although it is usually assumed that the
      cellular events leading to growth arrest start within one cell cycle of D(3)
      addition, there is also evidence that D(3) provokes the expression of
      proliferation-related genes and accelerates cell division. Herein we clarify the
      relationship between proliferation and maturation in differentiating HL60 cells.
      Cells were cultured singly, D(3) was added at various stages of the cell cycle,
      the progeny were counted, and the proportions of mature monocytes were
      determined. Initially, the D(3)-treated cells proliferated at an accelerated
      rate, and they matured only later. If cells encountered D(3) early in G1 they
      divided two to four times before maturing, and if they encountered D(3) later in
      the cell cycle they underwent an extra division. Indomethacin slows HL60 cell
      multiplication by prolonging G1, and when these slower-growing cells were exposed
      to D(3), they matured after the usual period but underwent one division less than
      indomethacin-free cells. Contrary to common assumptions, we conclude that
      promyeloid cells do not initiate growth arrest or monocytic maturation
      immediately after exposure to D(3). Instead, an encounter with D(3) early in G1
      sets in train a complex differentiation program. This consists of 2-3 days of
      rapid proliferation-probably employing cell cycles with a shortened G1 phase-that
      is followed by growth arrest and maturation. As a result, a single D(3)-treated
      promyeloid cell gives rise to 10 or more mature monocytes. These observations not
      only explain why "differentiating" cells express proliferation-related
      characteristics soon after D(3) addition, but they also show that the process of
      D(3)-induced monocytic differentiation is much more complex than has previously
      been realized.

PMID- 10585275
TI  - Differentiation between senescence (M1) and crisis (M2) in human fibroblast
      cultures.
AB  - Normal human fibroblasts undergo only a limited number of divisions in culture
      and eventually enter a nonreplicative state designated senescence or mortality
      stage 1 (M1). Expression of certain viral oncogenes, such as the SV40 large T
      antigen (SV40 T-Ag), can elicit a significant extension of replicative life span,
      but these cultures eventually also cease dividing. This proliferative decline has
      been designated crisis or mortality stage 2 (M2). BrdU incorporation assays are
      commonly used to distinguish between senescence (<5% labeling index) and crisis
      (>30% labeling index). It has not been possible, however, to ascertain whether
      the high labeling index, indicative of ongoing DNA replication, was caused by the
      presence of T-Ag. We used gene targeting to knock out both copies of the
      p21(CIP1/WAF1) gene in presenescent human fibroblasts. p21 -/- cells displayed an
      extended life span but eventually entered a nonproliferative state. In their
      terminally nonproliferative state both p21 +/+ and p21 -/- cultures were positive
      for the senescence-associated beta-galactosidase (SA-beta-gal) activity; in
      contrast, the labeling index of p21 +/+ cells was low (<5%) whereas the labeling
      index of p21 -/- cells was high (>30%). The observation that p21 -/- and SV40 T
      Ag-expressing cells behave identically with respect to life span extension as
      well as the high labeling index in the terminally nonproliferative state
      indicates that crisis is not a phenomenon induced solely by viral oncogenes, but
      a physiological state resulting from the bypass of normal senescence mechanisms.
      The widely used biomarker for senescence, SA-beta-gal, cannot distinguish between
      senescence and crisis. We propose that all SA-beta-gal-positive cultures should
      be further examined for their BrdU labeling index.

PMID- 10585276
TI  - Forced MyHCIIB expression following targeted genetic manipulation of
      conditionally immortalized muscle precursor cells.
AB  - The ability to carry out gene targeting in somatic stem cells while maintaining
      their stem cell characteristics would have important implications for gene
      therapy and for the analysis of gene function. Using mouse myoblasts, we have
      explored this possibility by attempting to alter the promoter of a myosin heavy
      chain gene (MyHCIIB) characteristic of physiologically "fast" muscle so as to
      force its unscheduled expression in physiologically "slow" muscle fibers.
      Conditionally immortalized muscle precursor cells were transfected with a gene
      targeting construct designed to replace the MyHCIIB promoter with that for the
      carbonic anhydrase III gene (CAIII), which is highly expressed in slow muscle. A
      potentially targeted clone was isolated and differentiated in culture to form
      myotubes which expressed MyHCIIB. Cells from the same clone were injected into
      both slow and fast muscle of host mice, where they contributed to fiber
      formation. In slow muscle, the fibers derived from this clone did not express
      MyHCIIB; this may reflect an instability of the targeted MyHCIIB locus and/or a
      failure of the hybrid promoter to function in slow fibers in vivo. Nonetheless,
      we have demonstrated that a "promoter knock-in" gene targeting procedure can be
      used to generate unique MyHCIIB-expressing myotubes in culture and that
      conditionally immortalized myoblasts can be subjected to extensive passaging and
      genetic manipulation without losing their ability to form fibers in culture and
      in vivo.

PMID- 10585277
TI  - Activated Rac1 selectively up-regulates the expression of integrin alpha6beta4
      and induces cell adhesion and membrane ruffles of nonadherent colon cancer
      Colo201 cells.
AB  - Functions of small GTPases in integrin expression were investigated when the
      interaction of nonadherent human colon carcinoma 201 cells with the extracellular
      matrix (ECM) was examined. By transfection of the constitutively active form of a
      small GTPase Rac1, Rac V12, adhesion of cells to the ECM increased with
      concomitant cell spreading and formation of membrane ruffles. Activated Cdc42 and
      Cdc42 V12, but not wild-type Rac1, Cdc42, or RhoA, also induced the adhesion and
      spreading of Colo201 cells. This adhesion is integrin beta4 dependent since an
      antibody for integrin beta4 inhibited the RacV12-dependent cell adhesion and
      numbers of adhesive cells on laminin-coated plates exceeded those on collagen-
      and fibronectin-coated plates. By immunofluorescence, in addition to clustering
      of integrin molecules, expression of integrin alpha6beta4 on the cell surface of
      Rac V12- and Cdc42 V12-expressing cells was selectively up-regulated without an
      increase in biosynthesis of alpha6beta4 integrin. Treatment of Rac V12-expressing
      cells with wortmannin or LY294002, specific inhibitors of phosphoinositide 3-OH
      kinase, decreased the up-regulated alpha6beta4 and cell adhesion. In light of
      this evidence, we propose that the regulation of integrin alpha6beta4 expression
      induced by Rac1 and Cdc42 may play an important role in cell adhesion and
      tumorigenesis of colon carcinoma cells.

PMID- 10585278
TI  - Apoptosis induced by DNA uptake limits transfection efficiency.
AB  - Electrotransfection is an effective method for transfecting lymphoid cells.
      However, the transfection efficiency of certain lymphoid cells is low. L1210
      subclones and NFS-70 pro-B cells, which are highly refractory to various
      transfection methods, were used to identify the limiting factors. Cells were
      electrotransfected with plasmids coding for green fluorescence protein or
      luciferase. The luciferase expression of L1210 subclone 3-3 was found to increase
      6-12 h after electroporation, but decreased significantly from 12 to 48 h. The
      lower level of luciferase activity at later time periods correlated with
      decreases in cell viability, which was shown to be due to apoptosis, as
      determined by propidium iodide/acrindine orange staining, DNA laddering, and
      prevention of cell death by addition of caspase inhibitors. Similar results were
      observed with NFS-70 pro-B cells and select L1210 subclones. In contrast, L1210
      parental and L1210 subclone 7-15.6 cells undergo only low levels of apoptosis (<
      or = 5%). Apoptosis occurred only when DNA (plasmids or salmon sperm DNA) was
      present during electroporation, but was not dependent on the conformation of the
      DNA used or the expression of transgenes. Cells pulsed in the presence of dextran
      sulfate (MW 500,000) did not apoptose. Similar results were observed when L1210
      subclone 3-3 was transfected using the cationic lipid 1, 2-dioleoyl-3
      trimethylammonium propane, although the transfection efficiency and corresponding
      rate of apoptosis were significantly lower. Applying the caspase inhibitor
      fluoromethyl ketone (Boc-ASP-FMK) dramatically improved cell viability and
      transgene expression of select L1210 subclones and NFS-70 pro-B cells.

PMID- 10585279
TI  - Endocytosis in skeletal muscle fibers.
AB  - Defining the organization of endocytic pathway in multinucleated skeletal
      myofibers is crucial to understand the routing of membrane proteins, such as
      receptors and glucose transporters, through this system. Here we analyzed the
      organization of the endocytic trafficking pathways in isolated rat myofibers. We
      found that sarcolemmal-coated pits and transferrin receptors were concentrated in
      the I band areas. Fluid phase markers were taken up into vesicles in the same
      areas along the whole length of the fibers and were then delivered into
      structures around and between the nuclei. These markers also accumulated beneath
      the neuromuscular and myotendinous junctions. The recycling compartment, labeled
      with transferrin, appeared as perinuclear and interfibrillar dots that partially
      colocalized with the GLUT4 compartment. Low-density lipoprotein, a marker of the
      lysosome-directed pathway, was transported into sparsely distributed perinuclear
      and interfibrillar dots that contacted microtubules. A majority of these dots did
      not colocalize with internalized transferrin, indicating that the recycling and
      the lysosome-directed pathways were distinct. In conclusion, the I band areas
      were active in endocytosis along the whole length of the multinucleated
      myofibers. The sorting endosomes distributed in a cross-striated fashion while
      the recycling and late endosomal compartments showed perinuclear and
      interfibrillar localizations and followed the course of microtubules.

PMID- 10585280
TI  - Activation of a cAMP pathway and induction of melanogenesis correlate with
      association of p16(INK4) and p27(KIP1) to CDKs, loss of E2F-binding activity, and
      premature senescence of human melanocytes.
AB  - There is strong evidence that the senescent phenotype, whether induced by
      telomere shortening, oxidative damage, or oncogenic stimuli, is an important
      tumor suppressive mechanism. The melanocyte is a cell of neural crest origin that
      produces the pigment melanin and can develop into malignant melanomas. To
      understand how malignant cells escape senescence, it is first crucial to define
      what genes control senescence in the normal cell. Prolonged exposure to high
      levels of cAMP results in accumulation of melanin and terminal differentiation of
      human melanocytes. Here we present evidence that activation of a cAMP pathway
      correlates with multiple cellular changes in these cells: (1) increased
      expression of the transcription factor microphthalmia; (2) increased
      melanogenesis; (3) increased association of the cyclin-dependent kinase
      inhibitors (CDK-Is) p27(KIP1) and p16(INK4) with CDK2 and CDK4, respectively; (4)
      failure to phosphorylate the retinoblastoma protein (pRB); (5) decreased
      expression of E2F1, E2F2, and E2F4 proteins; (6) loss of E2F DNA-binding
      activity; and (7) phenotypic changes characteristic of senescent cells. Senescent
      melanocytes have potent E2F inhibitory activity, because extracts from these
      cells completely abolished E2F DNA-binding activity that was present in extracts
      from the early proliferative phase. We propose that increased activity of the CDK
      Is p27 and p16 and loss of E2F activity in human melanocytes characterize a
      senescence program activated by the cAMP pathway. Disruption of cAMP-mediated and
      melanogenesis-induced senescence may cause immortalization of human melanocytes,
      an early step in the development of melanomas.

PMID- 10585281
TI  - The RRM protein NonA from Drosophila forms a complex with the RRM proteins Hrb87F
      and S5 and the Zn finger protein PEP on hnRNA.
AB  - The RRM protein NonA, an ubiquitous nuclear protein present in puffs on polytene
      chromosomes, has been immunopurified as a RNA-protein complex from Drosophila Kc
      cells. Three other proteins present in the complex have been identified: X4/PEP
      (protein on ecdysone puffs), a 100-kDa zinc finger RNA-binding protein; the 70
      kDa S5 protein, an as yet uncharacterized RNA-binding protein; and P11/Hrb87F, a
      38-kDa RRM protein homologous to hnRNP protein A1 from mammals. Monoclonal
      antibodies against any of the protein components coprecipitate all four proteins
      although at different ratios. NonA does not coprecipitate with the hrp40 hnRNP
      proteins and immunolocalizes in a pattern distinct of major hnRNP proteins. Like
      NonA, X4/PEP, S5, and P11/Hrb87F are present on active sites on polytene
      chromosomes. The precipitated NonA complex is enriched for certain protein
      encoding RNAs, notably, histone H3 and H4 RNA.

PMID- 10585282
TI  - Up-regulation of type XIX collagen in rhabdomyosarcoma cells accompanies myogenic
      differentiation.
AB  - Rhabdomyosarcomas are known to recapitulate some of the early events in skeletal
      muscle embryogenesis, and cultures derived from these tumors have been
      extensively used to elucidate processes associated with the differentiation of
      primitive mesenchymal cells. These neoplasms have also provided important systems
      for studying different collagen types. This aspect is particularly relevant to
      type XIX collagen, which was originally identified from rhabdomyosarcoma cDNA
      clones. Although this collagen has been localized in vivo to basement membrane
      zones in a wide variety of tissues, including skeletal muscle, the tumor cells
      appear to be a unique source of its expression in vitro. We have found that one
      particular cell line-derived from a peritesticular embryonal rhabdomyosarcoma
      produced relatively large amounts of type XIX collagen, especially in those rare
      instances in which these cells appear to spontaneously differentiate. To
      characterize this phenomenon, tumor cells were grown under conditions known to
      induce differentiation in normal myoblast cultures. In response to this
      treatment, the typical tumor cell morphology consistently and reproducibly
      switched from polygonal to round/spindle-shaped with the subsequent appearance of
      some structures resembling myotubes. Concurrently, the cultures commenced a
      dramatic up-regulation of type XIX collagen and skeletal muscle myosin heavy
      chain and alpha-actinin in a time-dependent fashion, whereas protein and mRNA
      levels of other matrix proteins were either decreased or unchanged. Moreover,
      immunocytochemical analysis revealed that only a subpopulation of the cells was
      responsible for the increased synthesis of type XIX collagen, alpha-actinin, and
      myosin, and that the same cells which stained positive for the collagen also
      stained positive for the muscle proteins. Taken together, the results suggested
      that type XIX collagen may be involved in the initial stages of skeletal muscle
      cell differentiation.

PMID- 10585283
TI  - Sorting of murine vascular smooth muscle cells during wound healing in the
      chicken chorioallantoic membrane.
AB  - The vascular wall is built up of a heterogeneous population of smooth muscle
      cells, which exhibit not only morphological distinctions but also important
      differences in the composition of their structural and contractile proteins.
      "Epithelioid" smooth muscle cells correspond to an intimal-like type and display
      features associated with immaturity, whereas "spindle-shaped" cells closely
      resemble the more typical medial smooth muscle population. We have investigated
      the integration of these two cell types into the vascular architecture of an in
      vivo wound-healing model. Stably transfected with the beta-galactosidase gene,
      intima- and media-like cells were injected intravenously into the chicken
      chorioallantoic membrane, within which superficial foci of granulation tissue had
      been created by thermal or chemical injury. At 24 to 72 h after injection, cells
      had honed in on the lesion sites and were observed in juxtaposition to the
      endothelial lining of the capillaries. They began to deposit laminin, thereby
      indicating an impending role in the formation of the vascular wall. Intima- and
      media-like smooth muscle cells did not differ in their capacity to associate with
      capillaries, and, in so doing, their biochemical lineage characteristics became
      indistinguishable from one another. However, intima-like cells also penetrated
      the adventitial and medial layers of arteries. These findings reveal vascular
      smooth muscle cells to possess an extraordinary degree of plasticity, being able
      to adapt flexibly to changes in functional demands.

PMID- 10585284
TI  - Tenascin-Y, a component of distinctive connective tissues, supports muscle cell
      growth.
AB  - Chicken tenascin-Y is an extracellular matrix protein most closely related to the
      mammalian tenascin-X. It is highly expressed in the connective tissue of skeletal
      muscle (C. Hagios, M. Koch, J. Spring, M. Chiquet, and R. Chiquet-Ehrismann,
      1996, J. Cell Biol. 134, 1499-1512). Here we demonstrate the presence of tenascin
      Y in specific areas of the connective tissues in developing lung, kidney, and
      skin. In skin tenascin-Y shows a complementary expression pattern to tenascin-C,
      whereas in the lung and kidney the sites of expression are partly overlapping.
      Tenascin-Y is also present in embryonic skeletal muscle where it is expressed in
      the developing connective tissue in between the muscle fibers. This connective
      tissue is also the major site of alpha5 integrin expression. We purified
      recombinantly expressed tenascin-Y and tested its effect on cell adhesion and its
      influence on muscle cell growth and differentiation. C2C12 myoblasts were able to
      adhere to tenascin-Y and showed extensive formation of actin-rich processes
      without generation of stress fibers. Furthermore, we found that tenascin-Y
      influenced cell morphology of chick embryo fibroblasts over prolonged times in
      culture and that it supports primary muscle cell growth and restricts muscle cell
      differentiation.

PMID- 10585285
TI  - IGF-II enhances trichostatin A-induced TGFbeta1 and p21(Waf1,Cip1, sdi1)
      expression in Hep3B cells.
AB  - Cell growth and division are controlled through the actions of cyclin-dependent
      kinases (CDKs) and cyclin dependent kinase inhibitors (CKIs). Treatment of cell
      lines with Trichostatin A leads to induction of one of these CKIs, p21, and
      growth arrest. Induction of p21 can also occur through the actions of TGFbeta1.
      Latent TGFbeta1 can be activated by the M6P/IGF2R. In the present study we have
      examined the effect of TSA on members of the IGF axis, the CKIs p21 and p27, and
      also TGFbeta1 in Hep3B cells. The only member of the IGF axis to be affected by
      treatments was IGF2. Expression of another gene from the same chromosomal
      location, H19, was also affected. TGFbeta1 expression was greatly enhanced by
      TSA. In addition, both CKIs, p21 and p27, were upregulated by TSA. Effects of
      adding IGF-II or TGFbeta1 to TSA-treated cells on p21 induction were examined.
      The results show that the induction of p21 by TSA can be modulated by additions
      of IGF-II whereas addition of TGFbeta1 affects its own expression but not p21. In
      conclusion, the results indicate that the induction of p21 and cell growth arrest
      caused by Trichostatin A may involve multiple signaling pathways.

PMID- 10585286
TI  - Tyrosine phosphorylation of caveolin-1 in the endothelium.
AB  - Caveolin-1, a scaffolding protein of caveolae, is known to be tyrosine
      phosphorylated by Src kinases. Recently we generated a specific antibody to
      caveolin-1 phosphorylated at tyrosine-14 (PY14) (R. Nomura and T. Fujimoto, 1999,
      Mol. Biol. Cell 10, 975-986). In the present study, by applying PY14 to sections
      of normal rat tissues, we found that tyrosine phosphorylation of caveolin-1
      occurred in limited locations, including the endothelium of the continuous
      capillaries and small venules. Cultured endothelial cells were not labeled by
      PY14 under a standard culture condition, but became positively labeled when
      exposed to oxidative stresses and/or tyrosine phosphatase inhibitors. The
      reaction was prohibited by pretreating the cells with herbimycin A or genistein.
      Vasoactive reagents or physical stimuli did not cause the phosphorylation.
      Concomitant with the tyrosine phosphorylation, the number of invaginated caveolae
      decreased drastically, and vesicles labeled intensely for caveolin-1 appeared in
      the cytoplasm; the average diameter of the vesicles was larger than that of
      caveolae. The result implies that tyrosine phosphorylation of caveolin-1 occurs
      at tyrosine-14 in the normal rat endothelium in vivo and may induce caveolar
      vesiculation and/or fusion.

PMID- 10585287
TI  - Transient overexpression of murine dishevelled genes results in apoptotic cell
      death.
AB  - The Dishevelled (Dvl) gene family encodes cytoplasmic proteins that are
      implicated in Wnt signal transduction. In mammals, the manner in which Wnt
      signals are transduced remains unclear. The biochemical and molecular mechanisms
      defining the Wnt-1 pathway are of great interest because of its important role in
      development and its activation in murine breast tumors. In order to elucidate
      Dvl's role in Wnt signaling, we attempted to overexpress Dvl in cells, but were
      unable to obtain stable cell lines. We show here that the overexpression of Dvl
      genes alters nuclear and cellular morphology of COS-1 and C57MG cells and causes
      cell death due to the induction of apoptosis. Deletion studies demonstrate that
      all three conserved domains of Dvl (DIX, PDZ, and DEP) are required for Dvl
      mediated cell death. Coexpression of protein phosphatase 2Calpha, a Dvl
      interacting protein identified in yeast two-hybrid studies, protects cells from
      the cell death observed in cells overexpressing Dvl alone. Furthermore, the
      adenomatous polyposis coli (APC) gene product appears to be required for Dvl
      mediated cell death. The relevance of these findings to Wnt signal transduction,
      as well as to developmental processes and disease, are discussed.

PMID- 10585288
TI  - alphaB-crystallin interacts with cytoplasmic intermediate filament bundles during
      mitosis.
AB  - The small heat-shock protein alphaB-crystallin interacts with intermediate
      filament proteins. Using cosedimentation assay, we showed previously that in
      vitro binding of alphaB-crystallin to peripherin and vimentin was temperature
      dependent. Furthermore, when NIH 3T3 cells were submitted to different stress
      conditions a dynamic reorganization of the intermediate filament network was
      observed concomitantly with the recruitment of alphaB-crystallins on the
      intermediate filament proteins. Thus, the intracellular state of alphaB
      crystallin correlated directly with the remodeling of the intermediate filament
      network in response to stress. Here, we show data suggesting that alphaB
      crystallin is implicated in remodeling of intermediate filaments during cell
      division. We investigated the intracellular distribution of alphaB-crystallin in
      naturally occurring mitotic NIH 3T3 cells and in neuroblastoma N2a and N1E115
      cells. In NIH 3T3 cells, alphaB-crystallin remained diffused throughout the cell
      cycle. Subcellular fractionation of alphaB-crystallin showed that alphaB
      crystallin remained in the cytosolic compartment during mitosis. Furthermore,
      alphaB-crystallin accumulated in mitotically arrested NIH 3T3 cells. This
      increased level of alphaB-crystallin protein was due to an increased level of
      alphaB-crystallin mRNA in mitotic NIH 3T3 cells. In the neuroblastoma cells, the
      intermediate filaments were rearranged into thick cable-like structures and
      alphaB-crystallin was recruited onto them. In neuroblastoma N2a cells the level
      of expression did not change during the cell cycle. However, a small fraction of
      alphaB-crystallin switched onto the insoluble fraction in mitotically arrested
      N2a cells. Our results suggested that depending on the state of rearrangement of
      the intermediate filament network during mitosis alphaB-crystallin was either
      recruited onto the intermediate filaments or upregulated in the cytosolic
      compartment.

PMID- 10585289
TI  - Role of PI 3-kinase in angiopoietin-1-mediated migration and attachment-dependent
      survival of endothelial cells.
AB  - Angiopoietin-1 is a unique growth factor which induces Tie2 receptor
      autophosphorylation and interaction with signal transduction molecules, GRB2 and
      p85 subunit of PI 3-kinase, but no detectable mitogenic response. Here we show
      that PI 3-kinase-dependent activation of Akt and attachment to extracellular
      matrix are required for angiopoietin-1-mediated endothelial cell survival.
      Apoptosis of growth factor-deprived cells grown in monolayer was decreased by
      angiopoietin-1 and correlated with Akt activation. In contrast, angiopoietin-1,
      bFGF or VEGF failed to protect cells in suspension culture. Ceramide, an
      intermediate of several apoptotic pathways, interferes with growth factor
      mediated Akt activation. Ceramide induced endothelial cell death and abolished
      angiopoietin-1-mediated activation of Akt and the effect on cell survival. In
      addition, we found that PI 3-kinase activity is necessary for migration of
      endothelial cells in response to Angiopoietin-1. A transient activation of
      MAPK/ERKs was also detected within 10 min after stimulation with angiopoietin-1.
      In contrast to VEGF-mediated biological effects, inhibition of MAPK/ERKs by
      PD98059 in endothelial cells did not affect angiopoietin-1 mediated survival or
      migration. These findings indicate significant differences in intracellular
      signaling between VEGF and angiopoietin-1 and that PI 3-kinase lipid products are
      key mediators of the biological effects of angiopoietin-1.

PMID- 10585290
TI  - Domain analysis of the actin-binding and actin-remodeling activities of drebrin.
AB  - Drebrin is an actin-binding protein which is expressed at highly levels in
      neurons. When introduced into fibroblasts, it has been known to bind to F-actin
      and to cause remodeling of F-actin. Here, we performed a domain analysis of the
      actin-binding and actin-remodeling activities of drebrin. Various fragments of
      drebrin cDNA were fused with green fluorescent protein cDNA and introduced into
      Chinese hamster ovary cells. Association of the fusion protein with F-actin and
      remodeling of the F-actin were examined. We found that the central 85-amino-acid
      sequence (residues 233-317) was sufficient for the binding to and remodeling of F
      actin. The binding activity of this fragment was relatively low compared with
      that of full-length drebrin, but all the types of abnormalities of F-actin that
      are observed with full-length drebrin were also observed with this fragment. When
      this sequence was further fragmented, the actin-binding activity was greatly
      reduced and the actin-remodeling activity disappeared. The actin-binding activity
      of the central region of drebrin was confirmed by a cosedimentation assay of
      chymotryptic fragments of drebrin with purified actin. These data indicate that
      the actin-binding domain and actin-remodeling domain are identical and that this
      domain is located at the central region of drebrin.

PMID- 10585291
TI  - Mammalian chondrocytes expanded in the presence of fibroblast growth factor 2
      maintain the ability to differentiate and regenerate three-dimensional
      cartilaginous tissue.
AB  - The differentiated phenotype of chondrocytes from hyaline cartilage is gradually
      lost during expansion in monolayers. Chondrocytes can reexpress their
      differentiated phenotype by transfer into an environment that prevents cell
      flattening, but serially passaged cells never completely recover their
      chondrogenic potential. We report that chondrocytes expanded (up to 2000-fold) in
      the presence of fibroblast growth factor 2 (FGF-2) dedifferentiated, but fully
      maintained their potential for redifferentiation in response to environmental
      changes. After seeding onto three-dimensional polymer scaffolds, chondrocytes
      expanded in the presence of FGF-2 formed cartilaginous tissue that was
      histologically and biochemically comparable to that obtained using primary
      chondrocytes, in contrast to chondrocytes expanded to the same degree but in the
      absence of FGF-2. The presence of FGF-2 inhibited the formation of thick F-actin
      structures, which otherwise formed during monolayer expansion, were maintained
      during tissue cultivation, and were associated with reduced ability of
      chondrocytes to reexpress their differentiated phenotype. This study provides
      evidence that FGF-2 maintains the chondrogenic potential during chondrocyte
      expansion in monolayers, possibly due to changes in the architecture of F-actin
      elements and allows more efficient utilization of harvested tissue for cartilage
      tissue engineering.

PMID- 10585292
TI  - Intracellular calcium puffs in osteoclasts.
AB  - We studied intracellular calcium ([Ca(2+)](i)) in acid-secreting bone-attached
      osteoclasts, which produce a high-calcium acidic extracellular compartment. Acid
      secretion and [Ca(2+)](i) were followed using H(+)-restricted dyes and fura-2 or
      fluo-3. Whole cell calcium of acid-secreting osteoclasts was approximately 100
      nM, similar to cells on inert substrate that do not secrete acid. However,
      measurements in restricted areas of the cell showed [Ca(2+)](i) transients to 500
      1000 nM consistent with calcium puffs, transient (millisecond) localized calcium
      elevations reported in other cells. Spot measurements at 50-ms intervals
      indicated that puffs were typically less than 400 ms. Transients did not
      propagate in waves across the cell in scanning confocal measurements. Calcium
      puffs occurred mainly over regions of acid secretion as determined using
      lysotracker red DND99 and occurred at irregular periods averaging 5-15 s in acid
      secreting cells, but were rare in lysotracker-negative nonsecretory cells. The
      calmodulin antagonist trifluoperazine, cell-surface calcium transport inhibitors
      lanthanum or barium, and the endoplasmic reticulum ATPase inhibitor thapsigargin
      had variable acute effects on the mean [Ca(2+)](i) and puff frequency. However,
      none of these agents prevented calcium puff activity, suggesting that the
      mechanism producing the puffs is independent of these processes. We conclude that
      [Ca(2+)](i) transients in osteoclasts are increased in acid-secreting
      osteoclasts, and that the puffs occur mainly near the acid-transporting membrane.
      Cell membrane acid transport requires calcium, suggesting that calcium puffs
      function to maintain acid secretion. However, membrane H(+)-ATPase activity was
      insensitive to calcium in the 100 nM-1 microM range. Thus, any effects of calcium
      puffs on osteoclastic acid transport must be indirect.

PMID- 10585293
TI  - Cytoplasmic domain is not essential for the cell adhesion activities of gicerin,
      an Ig-superfamily molecule.
AB  - Gicerin is a cell adhesion molecule in the immunoglobulin (Ig) superfamily and is
      expressed abundantly during development in the nervous system. It has homophilic
      cell adhesion activity and also has heterophilic binding activity with NOF
      (neurite outgrowth factor) and mediates neurite extension. There are two isoforms
      of gicerin, one with a short (s-gicerin) and the other with a longer cytoplasmic
      domain (l-gicerin). We have reported that s-gicerin possesses stronger activities
      than l-gicerin during cell aggregation, in NOF-binding, and in neurite extension.
      In this study, we established cell lines which expressed a mutant-gicerin whose
      cytoplasmic domain was deleted and we compared the above three biological
      activities of the mutant-gicerin with those of s- and l-gicerin. We found that
      the mutant-gicerin retained all these activities, but the activities were weaker
      than those of s-gicerin and almost the same as those of l-gicerin. We concluded
      that the cytoplasmic domain of gicerin is not essential for optimal adhesive
      activities of gicerin, but might be involved in the regulation of its activities.

PMID- 10585294
TI  - Phosphospecific antibodies reveal temporal regulation of platelet-derived growth
      factor beta receptor signaling.
AB  - The platelet-derived growth factor beta receptor (betaPDGFR) is a receptor
      tyrosine kinase involved in multiple aspects of cell growth and differentiation.
      Upon activation, betaPDGFR is phosphorylated at up to nine different tyrosine
      residues. Phosphorylation of the receptor results in at least two different
      outcomes: recruitment of signaling molecules and activation of intrinsic receptor
      kinase activity. In order to evaluate the phosphorylation state of the receptor,
      phosphospecific antibodies were generated against peptides encompassing betaPDGFR
      phospho-Y751, phospho-Y771, or phospho-Y857. When phosphorylated, these sites
      enable the receptor to recruit signaling molecules PI3K or RasGAP, or enhance the
      receptor's kinase activity, respectively. We found that receptors phosphorylated
      at Y751, Y771, and Y857 display distinct temporal and spatial distribution by
      immunofluorescence. Subsequent biochemical studies revealed that receptor
      function corresponding to each of the phosphorylated sites was regulated as a
      function of time. Within the first 10 min, PDGF enhanced the receptor's kinase
      activity and initiated recruitment of PI3K and RasGAP. After prolonged exposure
      to PDGF, PI3K binding persisted to approximately 85% of the amount bound at 10
      min, whereas binding of RasGAP and the exogenous kinase activity of the receptor
      diminished to less than 15% of the levels displayed at 10 min. We conclude that
      the phosphorylation state of the receptor, as well as its signaling capacity, is
      dynamic and changes as cells are continuously exposed to PDGF.

PMID- 10585295
TI  - Sequence requirements for plasmid nuclear import.
AB  - The nuclear envelope is a major barrier for nuclear uptake of plasmids and
      represents one of the most significant unsolved problems of nonviral gene
      delivery. We have previously shown that the nuclear entry of plasmid DNA is
      sequence-specific, requiring a 366-bp fragment containing the SV40 origin of
      replication and early promoter. In this report, we show that, although fragments
      throughout this region can support varying degrees of nuclear import, the 72-bp
      repeats of the SV40 enhancer facilitate maximal transport. The functions of the
      promoter and the origin of replication are not needed for nuclear localization of
      plasmid DNA. In contrast to the import activity of the SV40 enhancer, two other
      strong promoter and enhancer sequences, the human cytomegalovirus (CMV) immediate
      early promoter and the Rous sarcoma virus LTR, were unable to direct nuclear
      localization of plasmids. The inability of the CMV promoter to mediate plasmid
      nuclear import was confirmed by measurement of the CMV promoter-driven expression
      of green fluorescent protein (GFP) in microinjected cells. At times before cell
      division, as few as 3 to 10 copies per cell of cytoplasmically injected plasmids
      containing the SV40 enhancer gave significant GFP expression, while no expression
      was obtained with more than 1000 copies per cell of plasmids lacking the SV40
      sequence. However, the levels of expression were the same for both plasmids after
      cell division in cytoplasmically injected cells and at all times in nuclear
      injected cells. Thus, the inclusion this SV40 sequence in nonviral vectors may
      greatly increase their ability to be transported into the nucleus, especially in
      nondividing cells.

PMID- 10585296
TI  - Blood platelets contain and secrete laminin-8 (alpha4beta1gamma1) and adhere to
      laminin-8 via alpha6beta1 integrin.
AB  - Laminins, a family of heterotrimeric proteins with cell adhesive/signaling
      properties, are characteristic components of basement membranes of vasculature
      and tissues. In the present study, permeabilized platelets were found to react
      with a monoclonal antibody to laminin gamma1 chain by immunofluorescence. In
      Western blot analysis of platelet lysates, several monoclonal antibodies to
      gamma1 and beta1 laminin chains recognized 220- to 230-kDa polypeptides, under
      reducing conditions, and a structure with much slower electrophoretic mobility
      under nonreducing conditions. Immunoaffinity purification on a laminin beta1
      antibody-Sepharose column yielded polypeptides of 230, 220, 200, and 180 kDa from
      platelet lysates. In the purified material, mAbs to beta1 and gamma1 reacted with
      the two larger polypeptides, while affinity-purified rabbit antibodies to laminin
      alpha4 chain recognized the smallest polypeptide. Identity of the polypeptides
      was confirmed by microsequencing. One million platelets contained on average 1 ng
      of laminin (approximately 700 molecules per cell), of which 20-35% was secreted
      within minutes after stimulation with either thrombin or phorbol ester. Platelets
      adhered to plastic surfaces coated with the purified platelet laminin, and this
      process was largely inhibited by antibodies to beta1 and alpha6 integrin chains.
      We conclude that platelets contain and, following activation, secrete laminin-8
      (alpha4beta1gamma1) and that the cells adhere to the protein by using alpha6beta1
      integrin.

PMID- 10585297
TI  - Neural stem cells in the adult human brain.
AB  - New neurons are continuously generated in certain regions of the adult brain.
      Studies in rodents have shown that new neurons are generated from self-renewing
      multipotent neural stem cells. Here we demonstrate that both the lateral
      ventricle wall and the hippocampus of the adult human brain harbor self-renewing
      cells capable of generating neurons, astrocytes, and oligodendrocytes in vitro,
      i.e., bona fide neural stem cells.

PMID- 10585298
TI  - Fate of mesencephalic AHD2-expressing dopamine progenitor cells in NURR1 mutant
      mice.
AB  - The orphan nuclear receptor NURR1 was previously demonstrated to be required for
      the generation of mesencephalic dopamine (DA) cells. However, even in the absence
      of NURR1, which is normally expressed as cells become postmitotic, neuronal
      differentiation is induced and expression of several genes detected in developing
      dopamine cells appears normal during early stages of development. These include
      the homeobox transcription factors engrailed and Ptx-3 as well as aldehyde
      dehydrogenase 2, here defined as the earliest marker identified in developing DA
      cells, expressed already in mitotic DA progenitors. We have used the expression
      of these dopaminergic markers, retrograde axonal tracing, and apoptosis analyses
      to study the fate of the DA progenitor cells in the absence of NURR1. We conclude
      that NURR1 plays a critical role in the maturation, migration, striatal target
      area innervation, and survival of differentiating mesencephalic DA cells.

PMID- 10585299
TI  - Clinical efficacy of protease inhibitor based antiretroviral combination therapy-
      a prospective cohort study.
AB  - OBJECTIVES: To analyze virological and clinical efficacy of protease inhibitor
      based antiretroviral regimens in a cohort of unselected HIV-infected patients.
      METHODS: Prospective analysis of all HIV-infected patients started on protease
      inhibitor therapy until August 31, 1997 in two outpatient clinics. Partial viral
      suppression was defined as reduction of HIV-RNA at least 1log(10) below baseline
      and complete viral suppression as reduction below the limit of detection. Risk
      factors for clinical and virological failure were analyzed by a Cox proportional
      hazard model. RESULTS: 387 patients (median observation time 381 days) were
      analyzed. In 312 patients (81%) partial and in 265 (68%) complete viral
      suppression was observed. Secondary failure occurred in 75 patients and could be
      reversed in 11/75. The probability of virological failure at one year was 51% for
      complete and 47% for partial suppression. CD4-cells increased by a median of
      101/microl overall and 39/microl for patients without partial virologic
      suppression. 57 clinical events or deaths occurred in 44 pts. Risk factors for
      virological failure were AIDS at baseline (RR 1.6) and use of Saquinavir vs.
      Indinavir or Ritonavir (RR 1.7), for clinical failure AIDS at baseline (RR 4. 9),
      CD4-cell count (0.74 for increase of 50/microl), degree of viral suppression (RR
      0.1 for complete suppression) and PI used (Saquinavir vs. Indinavir or Ritonavir,
      RR 2.7). CONCLUSIONS: Virological failure of PI based combination therapy is
      common and associated with advanced HIV-infection. Clinical failure is associated
      with advanced HIV-infection and failure to suppress viral replication.

PMID- 10585300
TI  - Antiretroviral therapy (ART) from a neurological point of view. German Neuro-AIDS
      study group (DNAA).
AB  - Human Immunodeficiency virus can affect the peripheral (PNS) and central nervous
      system (CNS). In the ART / HAART era especially the CNS is said to be a virus
      reservoir so that neurologists have to be more and more integrated in therapy
      planning. Therefore the present paper describes neurological indications for ART,
      ART side effects involving the PNS and CNS and pharmacological interactions of
      ART with current neurological drug regimen.

PMID- 10585301
TI  - Response to inhaled nitric oxide (NO) is not associated with changes of plasma
      cGMP levels in patients with acute lung injury.
AB  - BACKGROUND: A clinically relevant increase of PaO subset2 or decrease of
      pulmonary vascular resistance (PVR) upon inhalation of NO (iNO) does occur in
      only 60 to 80% of patients with acute lung injury. The mechanisms for divergent
      responses of different patients have not yet been fully elucidated. Since NO
      mediates its pulmonary effects by stimulating soluble guanylate cyclase, thereby
      increasing levels of cyclic guanosinemonophosphate (cGMP), we hypothesized that
      pulmonary cGMP production upon iNO might be suppressed in patients not responding
      to iNO treatment. METHODS: After approval by the local ethical committee and
      after informed consent had been obtained, both arterial and mixed-venous cGMP
      levels were analyzed in 13 patients in whom iNO was administered to treat
      pulmonary hypertension and/or hypoxemia due to acute respiratory distress
      syndrome (n = 11) or reperfusion injury following lung transplantation (n = 2).
      Both cardiorespiratory variables and cGMP concentrations were documented
      simultaneously at baseline, 15 min after inhalation of 8 ppm of NO, and 15 min
      after withdrawal of NO, respectively. RESULTS: Inhaled NO resulted in a
      significant increase in PaO(2)/FiO(2) and a decrease in PVR. Arterial and mixed
      venous concentration of cGMP (median) also increased significantly upon iNO from
      2.5 to 6.5 nM (p <0.05) and from 3.0 to 5.7 nM (p <0.05), respectively. Theses
      effects were fully reversible after withdrawal of iNO. No gradients between
      arterial and mixed venous cGMP concentrations were detected (p = 0.12).
      Regression analysis showed no relationship between baseline arterial cGMP
      concentrations and changes of either PaO(2)/FiO(2) (p = 0. 62) or PVR (p = 0.91).
      Similarly, no relationship was found between the rise of arterial cGMP
      concentration subsequent to iNO and corresponding changes of PaO(2) (p = 0.40) or
      PVR (p = 0.74), respectively. CONCLUSION: Inhalation of NO significantly
      stimulates soluble guanylate cyclase within the lungs in patients with acute lung
      injury. However, neither baseline cGMP nor its rise during treatment with inhaled
      NO can predict the clinical efficacy of iNO in humans. Furthermore, the fact that
      increased cGMP concentrations were detected during administration of iNO in mixed
      venous blood (i.e. pulmonary inflow) strongly suggest that the pharmacological
      effects of iNO are not fully selective for the lungs, but may also affect
      extrapulmonary organs.

PMID- 10585302
TI  - Thyroid disorders in female patients with ankylosing spondylitis.
AB  - The association between rheumatological and thyroid disorders has long been
      known, the most common being the association of rheumatoid arthritis and
      autoimmune thyroiditis. Little is known as to possible thyroid involvement in
      ankylosing spondylitis (AS). In 22 female patients with AS and 22 healthy age
      matched control subjects parameters of thyroid gland function, rheumatic
      activity, as well as a subtle drug anamnesis of the rheumatic medication, and an
      ultrasonographic examination of the thyroid gland were determined. Thyroid
      function was tested by intravenous injection of 400 microg thyrotropin-releasing
      hormone (TRH). In parallel basal levels of reverse-T3 (rT3), calcium and anti
      thyroid antibodies were estimated. In the AS-group an enlarged thyroid volume was
      seen in 10 cases, basal FT4, FT3 and TT3 were significantly lower, TSH and TT4
      were found to be in the normal range and rT3 was significantly increased. The
      prevalence of anti-thyroid antibodies was significantly higher in the AS-group.
      The AS-patients responded as well as the controls with thyroid hormone secretion
      to TRH, within an observation period of 2 hours. No differences were observed in
      TSH response. Free serum calcium showed in both groups no significant difference.
      To summarize our results, female patients with AS showed a

PMID- 10585303
TI  - Determination of the extent of excessive copper concentrations in the tap-water
      of households with copper pipes and an assessment of possible health hazards for
      infants.
AB  - During the past 20 years there has been much discussion about copper in
      connection with a form of Early Childhood Liver Cirrhosis (ECLC) known as Non
      Indian Childhood Cirrhosis (NICC). NICC is similar to Indian Childhood Cirrhosis
      (ICC) which occurs in India, and has already been known for many years. ICC is
      attributed to the excessive intake of copper derived from milk or water stored in
      copper and brass vessels. To determine precisely a possible connection between
      the amount of copper in tap-water and the risk of early childhood liver disease,
      an attempt was first made, through an epidemiological survey, to determine the
      extent of excessive concentrations of copper in the tap-water of households with
      copper pipes. To achieve this, water samples from 956 households were tested for
      copper, and the state of health of the infants in these households was
      documented. Infants who had been fed using water with a copper concentration of
      0.8 mg/l or more received a paediatric examination with a blood check so as to
      rule out any possibility of liver damage. A copper level greater than 0.8 mg/l
      was found in only 2% of the households examined. Eight infants were examined by a
      paediatrician and received blood checks. (These infants had either been breast
      fed up until their 12th week or had received more than 200 ml of tap water per
      day during their first 12 months). None of the infants examined showed any signs
      of liver malfunction. From the results of the study, no indication of a hazard
      due to copper pipes connected to public water supplies could be found.

PMID- 10585304
TI  - Leiomyosarcoma of the thyroid gland with rapid growth and tracheal obstruction: A
      partial thyroidectomy and tracheostomy using an ultrasonically activated scalpel
      can be safely performed with less bleeding.
AB  - Primary leiomyosarcoma of the thyroid gland is rare, and to the best of our
      knowledge only nine well-documented cases have been previously reported in the
      world literature. We herein report a 90-year-old female patient with primary
      leiomyosarcoma of the thyroid gland who showed a rapid tumor growth and tracheal
      obstruction. The patient was successfully treated by a partial resection of the
      thyroid gland using an ultrasonically activated scalpel and emergency
      tracheostomy. Immunohistochemically, the tumor cells showed positive reactivity
      to smooth muscle actin and negative reactivity to thyroglobin. Palliative surgery
      successfully allowed the patient to recover from the symptoms of dyspnea related
      to this rare disease. The use of an ultrasonically activated scalpel and
      tracheostomy thus allowed us to safely perform a thyroidectomy with substantially
      less bleeding than normal.

PMID- 10585305
TI  - Meeting report - First international symposium on circulating nucleic acids in
      plasma/serum - Implications in cancer diagnostics, prognosis or follow up and in
      prenatal diagnosis - Menthon France, August 18-20, 1999.
AB  - The sessions were dedicated to the following topics: Detection of ras-gene
      mutations, Detection of other mutated oncogenes and tumor-suppressor genes,
      Alterations in microsatellite sequences (LOH and instability), Status of gene
      methylation of free circulating DNA, Detection of circulating tumor cells and RT
      PCR, Detection of fetal DNA in maternal plasma and Technical aspects.

PMID- 10585306
TI  - Microalbuminuria in essential hypertension: significance, pathophysiology, and
      therapeutic implications.
AB  - Some patients with essential hypertension manifest greater than normal urinary
      albumin excretion (UAE). The significance of this association, which is the
      object of this review, is not well established. Hypertensive patients with
      microalbuminuria manifest greater levels of blood pressure, particularly at
      night, and higher serum levels of cholesterol, triglycerides, and uric acid than
      patients with normal UAE. Levels of high-density lipoprotein cholesterol, on the
      other hand, were lower in patients with microalbuminuria than in those with
      normal UAE. Patients with microalbuminuria manifested greater incidence of
      insulin resistance and thicker carotid arteries than patients with normal UAE.
      After a follow-up of 7 years, we observed that 12 cardiovascular events occurred
      among 54 (21.3%) patients with microalbuminuria and only two such events among 87
      patients with normal UAE (P < 0.0002). Stepwise logistic regression analysis
      showed that UAE, cholesterol level, and diastolic blood pressure were independent
      predictors of the cardiovascular outcome. Rate of creatinine clearance from
      patients with microalbuminuria decreased more than that from those with normal
      UAE. In conclusion, these studies suggest that hypertensive individuals with
      microalbuminuria manifest a variety of biochemical and hormonal derangements with
      pathogenic potential, which results in hypertensive patients having a greater
      incidence of cardiovascular events and a greater decline in renal function than
      patients with normal UAE.

PMID- 10585307
TI  - Atherosclerosis profile and microalbuminuria in essential hypertension.
AB  - Whether microalbuminuria (MA) is the result of intrarenal hemodynamic changes
      induced by increased systemic blood pressure (BP) or a marker of capillary
      leakiness at the glomerular level that reflects more generalized atherosclerotic
      vascular damage is still debated. To address this question, 319 patients without
      diabetes, 154 men and 165 women aged 57 +/- 8.6 years (range, 37 to 73 years),
      but with essential hypertension (EH) never treated with drugs were enrolled onto
      the study. Using a multiple linear regression analysis, we analyzed the
      prevalence of MA and its relationship with BP level as well as with other risk
      factors for the development of atherosclerosis. MA was present in 40% of the
      population studied. A univariable analysis of ambulatory BP monitoring
      measurements showed that only 24-hour systolic BP (P = 0.04), daytime systolic BP
      (P = 0. 02), and 24-hour daytime and nighttime systolic BP load (P < 0.01)
      predicted the presence of MA, whereas all BP variability parameters significantly
      predicted it. Multivariable analysis showed that only a positive family history
      of hypertension (P < 0.001), BMI (P < 0. 001), glucose (P < 0.001), and 24-hour
      systolic BP coefficient of variation (P < 0.001) independently predicted MA. In
      summary, the prevalence of MA in our group of patients with EH was high,
      presumably as a consequence of the older mean age of the population and the
      selection criteria. Besides being a marker of concomitant cardiovascular damage,
      MA was associated with a worse pattern of atherosclerotic risk factors. Although
      its pathophysiological meaning remains to be completely clarified, MA seems to be
      more related to other atherosclerosis risk factors and presumably reflects a more
      diffuse vascular injury.

PMID- 10585308
TI  - Polymorphisms of angiotensin-converting enzyme and angiotensinogen genes in type
      2 diabetic sibships in relation to albumin excretion rate.
AB  - Familial clustering of altered albumin excretion and nephropathy risk has been
      described in both type 1 and type 2 diabetes; moreover, an association of micro
      macroalbuminuria and diabetic retinopathy has been recently reported in a large
      number of white families with type 2 diabetes. Conflicting reports, mainly
      comparing affected with unaffected unrelated subjects, have suggested a possible
      role of some genotypes of the renin-angiotensin system in conferring nephropathy
      risk in type 2 diabetes. To examine the role of genetic factors in influencing
      albuminuria in families, we studied the relation of angiotensin-converting
      enzymes (ACE) and angiotensinogen (AGN) genotypes with albumin excretion rate in
      a population of affected siblings of type 2 diabetic probands. We determined ACE
      insertion/deletion polymorphism and two polymorphisms of the AGN gene (T174M and
      M235T) in 160 families with at least one affected member. Defining proband as the
      patient with the longest known duration of diabetes, we compared the allelic
      distribution in diabetic probands with and without altered albumin excretion and
      in their siblings. Allelic distribution of these polymorphisms was similar in the
      two groups of probands, as well as in their siblings. Identity-by-State (IBS)
      analysis showed a link between AGN locus and arterial hypertension in these
      siblings, which was independent from the degree of renal involvement. Thus, our
      findings suggest that in white families with type 2 diabetes, there is no linkage
      between the degree of albumin excretion and ACE and AGN polymorphisms, whereas
      the latter is related to arterial hypertension, as previously found in patients
      without diabetes but with essential hypertension.

PMID- 10585309
TI  - Acute tubular necrosis in patients with diabetes mellitus.
AB  - We compared the clinical outcomes of patients with (n = 71) and without (n = 185)
      diabetes mellitus enrolled into the placebo arm of a large, multicenter clinical
      trial of patients with acute tubular necrosis (ATN). Compared with the
      nondiabetic patients, diabetic patients were older (65.5 +/- 12.9 versus 60.7 +/-
      18.0 years, P < 0. 05), had higher usual serum creatinine concentration (1.7 +/-
      0.6 versus 1.4 +/- 0.5 mg/dL, P < 0.001), and had a higher prevalence of
      underlying hypertension, coronary artery disease, and congestive heart failure
      (all P < 0.007). By day 21 after enrollment, neither mortality nor dialysis-free
      survival was different between the groups. Length of stay for surviving patients,
      in both the intensive care unit and the hospital, were significantly shorter for
      the diabetics. Among acute comorbidities predicting mortality or the need for
      dialysis, sepsis was more prevalent among the nondiabetic patients (18% versus
      35%, diabetics versus nondiabetics, P < 0.05). In conclusion, clinical outcomes
      for diabetic patients with ATN were no worse than for nondiabetic patients,
      despite their older age and worse underlying renal function. Patients with
      diabetes mellitus had more chronic cardiovascular disease but were less acutely
      ill. We speculate that cardiovascular disease is a risk factor for ATN in
      patients with diabetes mellitus. These results fail to implicate the increasing
      prevalence of diabetes mellitus in the persistently poor prognosis of patients
      with ATN.

PMID- 10585310
TI  - Course and outcome of tubulointerstitial nephritis and uveitis syndrome.
AB  - We report here the clinical features and outcomes of 10 patients, aged 11 to 21
      years (median, 13.0), with idiopathic tubulointerstitial nephritis (TIN) and
      uveitis syndrome (TINU syndrome). The initial symptoms were visual impairment in
      7 patients and prolonged fever, anemia, or asthenia in 4 patients. An increase in
      urinary beta(2)-microglobulin was noticed at the initial checkup in all patients,
      including 2 patients who showed the normal ranges of 24-hour protein excretion.
      Creatinine clearance was decreased in 8 patients. TIN was found simultaneously
      with ocular symptoms in 7 patients and preceded these symptoms in the remaining 3
      patients. Percutaneous renal biopsy indicated tubulointerstitial lesions in
      varying degrees. The histological grade of TIN was correlated with urinary
      beta(2)-microglobulin levels. Systemic steroid therapy was performed in 7
      patients because of the progression of uveitis. The 10 patients were followed-up
      for 16 to 94 months (median, 31.0 months). In all patients, creatinine clearance
      recovered to the normal ranges (>/=70 mL/min/1.73 m(2)) mostly within 1 year.
      Urinary beta(2)-microglobulin excretion gradually declined but was slightly
      elevated in 4 patients at the latest checkup. Uveitis recurred in all 10
      patients, which did not affect the renal status. Our findings indicate that early
      referral of patients from ophthalmologists and determination of beta(2)
      microglobulin in the urine is helpful for the early discovery of TINU syndrome.
      In children and adolescents with this syndrome, TIN spontaneously resolves and
      its long-term prognosis is good, but uveitis often relapses. Systemic steroids
      may be required for uveitis, but not for TIN.

PMID- 10585311
TI  - Differences between membranoproliferative glomerulonephritis types I and III in
      long-term response to an alternate-day prednisone regimen.
AB  - Membranoproliferative glomerulonephritis (MPGN) is classified as type I, II, or
      III based on ultrastructural alterations in the glomerular basement membrane.
      Whereas type II has long been recognized as clinically and pathologically unique,
      types I and III are often difficult to distinguish and have not been separated in
      most clinical studies. We compared the course and long-term outcome of patients
      with types I and III MPGN followed up at this institution since 1960. During this
      period, 21 patients with type I and 25 patients with type III were followed up
      for a minimum of 5 years. Patients with types I and III MPGN did not differ in
      age at apparent onset, age at diagnosis, or interval from apparent onset of
      symptoms to diagnosis (biopsy). They had similar initial serum C3 and serum
      albumin levels. Patients with type I had a significantly lower initial mean
      estimated glomerular filtration rate (GFR(est)) compared with those with type III
      (99.1 +/- 35.9 versus 131.6 +/- 36. 1 mL/min/1.73 m(2); P < 0.01). Type and
      duration of therapy, length of follow-up, and frequency of complications of
      therapy did not differ between groups. There was, however, a significant
      difference in duration of hypocomplementemia. After 1 year of an alternate-day
      prednisone regimen, 90% of the type I patients normalized their serum C3 levels
      compared with less than 50% of type III patients (P < 0.01). After 3 years of
      therapy, only 5% of type I patients were hypocomplementemic compared with 33% of
      type III patients (P < 0.02). In addition, disease relapse occurred in six type
      III patients (24%) compared with no type I patients. At last follow-up, type I
      patients had a slight improvement in mean GFR(est) (+6.3 +/- 48.4 mL/min/1.73
      m(2)), whereas type III patients had a 25% decrease in mean GFR(est) (-34.8 +/-
      47.6 mL/min/1.73 m(2); P < 0.01). Residual urinary abnormalities were
      significantly more frequent in patients with type III than type I MPGN. Hematuria
      persisted in 72% versus 38% (P < 0.05) and proteinuria in 28% versus 0% (P <
      0.01) of those with types III and I, respectively. These results give clear
      evidence of significant differences in the clinical progression of the two types
      and their response to the alternate-day prednisone regimen. Whereas the outcome
      of patients with type I MPGN treated with alternate-day prednisone was generally
      good, similarly treated patients with type III experienced significant reductions
      in renal function, slower improvement in serum C3 levels, more persistent urinary
      abnormalities, and more frequent relapses.

PMID- 10585312
TI  - Use of a state data bank to measure incidence and prevalence of a chronic
      disease: end-stage renal failure.
AB  - The Western Australian Health Services Research Linked Database was used to
      examine trends in the incidence rate and prevalence of end-stage renal failure
      and to describe treatment patterns in these patients. Linked hospital morbidity
      and mortality records from 1980 to 1994 were selected if a record had a principal
      diagnosis or procedure of chronic renal failure, dialysis, or renal
      transplantation. Patient records were grouped according to the stage of care
      (predialysis, dialysis, transplant, or death). A total of 1, 046 patients with a
      principal diagnosis or procedure that met our criteria for end-stage renal
      failure was admitted to the hospital from 1985 to 1994. Trends in the incidence
      rate and prevalence of end-stage renal failure by sex and race, patterns of care,
      indices of comorbidity, and waiting time to transplantation were calculated.
      Results showed that both the incidence rate and prevalence of end-stage renal
      failure increased from 1986 to 1994, most noticeably in the aboriginal
      population. Rates of renal failure in 1994 were 15 times greater in aborigines
      than in nonaborigines. Of the hospital patients, 73.5% received dialysis three
      times a week. Complications associated with dialysis treatment were the most
      common cause of comorbid hospitalization. The mean waiting time to
      transplantation was 503 days for those who had a transplant and 6.3 years for all
      patients. The escalating numbers of patients undergoing renal dialysis, the high
      cost of maintaining them on dialysis, and the additional use of hospital services
      for comorbid conditions highlight the need to develop programs to prevent the
      occurrence of renal failure, particularly in the aboriginal population.

PMID- 10585313
TI  - Antiphospholipid antibody syndrome in renal transplantation: occurrence of
      clinical events in 96 consecutive patients with systemic lupus erythematosus.
AB  - We report the results of a detailed examination of clinical events associated
      with the antiphospholipid antibody (aPL) syndrome in 96 consecutive patients with
      systemic lupus erythematosus (SLE) who underwent renal transplantation between
      January 1, 1984, and September 1, 1996. Because of the retrospective nature of
      our study, we developed strict definitions of clinical events considered to be
      associated with the aPL syndrome. We reviewed all available hospital, clinic, and
      outside records of the patients with SLE who underwent transplantation at our
      center during this time period and noted the results of three standard
      serological tests for aPLs, when available. Mean follow-up of the 96 patients was
      62.6 months. Eighty-five of the 96 patients (88.5%) had at least one test for
      aPLs performed, and 25 patients (29.4%) had at least one abnormal test result.
      Among these 25 patients, 15 patients (60%) had clinical events associated with
      aPL syndrome. Ten patients (10.4%) either died of the aPL syndrome or had an aPL
      associated clinical event within 3 months of transplantation. Other morbidity
      from the aPL syndrome in these 15 patients included: thrombotic arteriolar
      microangiopathy (2 patients), stroke (4 patients), ocular ischemia (7 patients),
      deep vein thrombosis or pulmonary embolism (6 patients), renal artery or vein
      thrombosis (4 patients), peripheral ischemia (1 patient), and fetal wastage (3
      patients). By comparison, among the 60 patients with normal aPL test results,
      only 5 patients had clinical events compatible with the aPL syndrome (P < 0.0001
      by chi-squared test). aPLs may be associated with significant morbidity and
      mortality in patients with SLE undergoing renal transplantation. This study is
      the first attempt to quantify the impact of aPLs on renal transplantation in a
      large population of patients with SLE. Further investigation of aPLs in SLE
      patients with end-stage renal disease is required to clarify the risks, benefits,
      and optimal clinical management of renal transplantation for these patients.

PMID- 10585314
TI  - Prediction and treatment of recurrent focal segmental glomerulosclerosis after
      renal transplantation in children.
AB  - The recurrence of focal segmental glomerulosclerosis (FSGS) after renal
      transplantation has a potentially detrimental course toward the loss of renal
      function. To identify prognostic markers for recurrence and efficacy of
      treatment, we evaluated the outcome of 32 renal allografts in 29 pediatric
      patients with FSGS who underwent transplantation from 1987 to 1998 in the North
      Italy Transplant program. Recurrence was observed in 15 of 29 patients (52%)
      after the first transplant and in 3 of 3 patients (100%) after the second graft.
      No significant differences in sex, age at FSGS onset, age at transplantation, or
      length of dialysis were noted between patients with recurrent and nonrecurrent
      FSGS. Those with recurrence originally developed end-stage renal failure faster
      (3.9 years) than those without recurrence (6.2 years). Pretransplantation serum
      samples from 25 patients were tested in an in vitro assay that evaluates
      glomerular permeability to albumin. FSGS recurred in 11 of 13 children who tested
      positive for the permeability factor and in 4 of 12 patients with a negative test
      result; the odds ratio for developing recurrence was 10.99 (95% confidence limit,
      1.6 to 75.47) in the former group. The immediate onset of proteinuria after
      transplantation was a negative prognostic factor for the outcome; 6 of 9 patients
      in whom proteinuria appeared within 2 days of transplantation returned to
      dialysis in less than 24 months. In 9 of 11 patients who were treated with
      plasmapheresis plus cyclophosphamide after recurrence, proteinuria was
      successfully reversed and persistent remission was obtained in 7 patients. These
      data show that the glomerular permeability test has a significant predictive
      value for the recurrence of proteinuria in children with FSGS who have received a
      renal allograft. Of the clinical parameters considered, only the duration of
      disease was significantly different in patients with recurrent versus
      nonrecurrent FSGS. Treatment with plasmapheresis plus cyclophosphamide can be
      effective in the control of FSGS relapse after renal transplantation.

PMID- 10585315
TI  - Independent effects of residual renal function and dialysis adequacy on
      nutritional status and patient outcome in continuous ambulatory peritoneal
      dialysis.
AB  - Dialysis adequacy has a major impact on outcome of continuous ambulatory
      peritoneal dialysis (CAPD) patients. However, there is a substantial confounding
      effect by residual renal function in most studies. We differentiated the effects
      of dialysis adequacy from those of residual renal function on nutritional status
      and outcome of CAPD patients. We identified 168 CAPD patients treated in our
      center between September 1995 and December 1996 and categorized them into three
      groups: 49 patients with an average total Kt/V of 1.93 +/- 0.18 and a median
      residual glomerular filtration rate (GFR) of 0. 07 mL/min/1.73 m(2) in the
      dialysis-dependent (DD) group; 48 patients with an average total Kt/V of 2.03 +/-
      0.25 and a residual GFR of 2. 33 mL/min/1.73 m(2) in the residual renal function
      (RRF) group; and 71 patients with an average total Kt/V of 1.38 +/- 0.22 and a
      residual GFR of 0.05 mL/min/1.73 m(2) in the control (CTL) group. They were
      followed-up for 1 year to compare baseline nutritional status and 1-year
      morbidity. Baseline normalized protein catabolic rates (NPCR) are 1.00 +/- 0.20
      and 0.96 +/- 0.19 (for RRF and DD, respectively) versus 0.89 +/- 0.16 g/kg/d for
      CTL (P < 0.01). Percentage lean body mass (%LBM) was 71.6 +/- 9.8 and 71.5 +/-
      10.0 (for RRF and DD, respectively) versus 65.2 +/- 8.5% for CTL (P < 0. 001). No
      difference was seen in the nutritional status between RRF and DD groups. Duration
      of hospitalization for 1 year was 6.9 +/- 11. 8 days in the RRF group versus 14.9
      +/- 25.1 in the DD and 10.6 +/- 11.6 days in the CTL groups (P < 0.05). The
      peritonitis rate was 44. 4 patient-months for the RRF group, versus 13.6 for the
      DD and 12.9 for the CTL groups (P < 0.05). There also was a trend toward superior
      1-year technique survival in the RRF group, but the number of observations was
      small. There was no difference in duration of hospitalization, peritonitis rate,
      and technique survival between the DD and CTL groups. Short-term morbidity in
      patients without residual renal function appears to be independent of total Kt/V,
      although Kt/V may have some effects on nutritional status. The assumption that
      renal and peritoneal clearances are equivalent must be carefully reexamined.
      Further studies on the effect of dialysis adequacy in patients without residual
      renal function are urgently needed.

PMID- 10585316
TI  - Mortality risks of peritoneal dialysis and hemodialysis.
AB  - Studies of outcomes associated with dialysis therapies have yielded conflicting
      results. Bloembergen et al showed that prevalent patients on continuous
      ambulatory peritoneal dialysis (CAPD) or continuous cycling peritoneal dialysis
      (CCPD) had a 19% higher mortality risk than hemodialysis patients, and Fenton et
      al, analyzing Canadian incident patients, found a 27% lower risk. Attempting to
      reconcile these differences, we evaluated incident Medicare patients (99,048 on
      hemodialysis, 18,110 on CAPD/CCPD) from 1994 through 1996, following up to June
      30, 1997. Patients were followed to transplantation, death, loss to follow-up, 60
      days after modality change, or end of the study period. For each 3-month survival
      period, we used an interval Poisson regression to compare death rates, adjusting
      for age, gender, race, and primary renal diagnosis. A Cox regression was used to
      evaluate cause-specific mortality, and proportionality was addressed in both
      regressions by separating diabetic and nondiabetic patients. The Poisson
      regressions showed CAPD/CCPD to have outcomes comparable with or significantly
      better than hemodialysis, although results varied over time. The Cox regression
      found a lower mortality risk in nondiabetic CAPD/CCPD patients (women younger
      than 55 years: risk ratio [RR] = 0. 61; Cl, 0.59 to 0.66; women age 55 years or
      older: RR = 0.87; Cl, 0. 84 to 0.91; men younger than 55 years: RR = 0.72; Cl,
      0.67 to 0.77; men age 55 years or older: RR = 0.87; Cl, 0.83 to 0.92) and in
      diabetic CAPD/CCPD patients younger than 55 (women: RR = 0.88; Cl, 0. 82 to 0.94;
      men: RR = 0.86; Cl, 0.81 to 0.92). The risk of all-cause death for female
      diabetics 55 years of age and older, in contrast, was 1.21 (Cl, 1.17 to 1.24) for
      CAPD/CCPD, and in cause-specific analyses, these patients had a significantly
      higher risk of infectious death. We conclude that, overall, within the first 2
      years of therapy, short-term CAPD/CCPD appears to be associated with superior
      outcomes compared with hemodialysis. It also appears that patients on the two
      therapies have different mortality patterns over time, a nonproportionality that
      makes survival analyses vulnerable to the length of follow-up. Further
      investigation is needed to evaluate both the potential explanations for these
      findings and the use of more advanced statistical methods in the analysis of
      mortality rates associated with these dialytic therapies.

PMID- 10585317
TI  - Can dialysis therapy be improved? A report from the ESRD Core Indicators Project.
AB  - We assessed the association between quality improvement interventions conducted
      during the End-Stage Renal Disease (ESRD) Core Indicators Project and changes in
      the adequacy of hemodialysis between 1993 and 1996. Improvement of hemodialysis
      adequacy was measured by baseline and annual urea reduction ratios (URRs) in
      representative samples of ESRD Network patients. Random samples of in-center
      hemodialysis patients aged 18 years and older who had received hemodialysis
      during the fourth quarters of 1993, 1994, 1995, and 1996 were used to calculate
      Network-specific outcomes. A mean URR was calculated for each patient using the
      first pretreatment and posttreatment blood urea nitrogen for October, November,
      and December of each study year. Both national and Network-specific interventions
      were used to provide feedback reports and technical assistance to treatment
      centers to foster improvement in hemodialysis adequacy. All Networks distributed
      reports on the patterns of treatment center URR levels and physician and patient
      educational materials to each center in the Network. Each Network selected an
      annual 10% sample of treatment centers in 1994 and 1995 and conducted quality
      improvement activities to assist the selected centers to improve dialysis
      adequacy. We defined Network-specific interventions by a survey of the 18
      Networks conducted during 1995 to determine the characteristics of Network
      specific activities used to improve adequacy of hemodialysis. The outcome of
      interest was the change over time in Network-specific URR value. Sustained
      improvement in the URR occurred within all 18 Networks between 1993 and 1996. The
      mean national URR increased from 62.7% in 1993 to 66. 8% in 1996. The proportion
      of patients with URR >/= 65% increased from 43% in 1993 to 68% in 1996. Networks
      reported implementing a variety of intervention strategies that included
      educational activities, continuous quality improvement workshops, on-site
      assistance, and supervision of selected treatment facilities until care improved.
      Network-specific interventions independently associated with an increased rate of
      improvement in URR included prolonged supervision of the selected facilities. We
      concluded that the sustained improvement in hemodialysis care that occurred after
      the inception of the ESRD Core Indicators Project was associated with specific
      ESRD Network interventions.

PMID- 10585318
TI  - High serum hyaluronan indicates poor survival in renal replacement therapy.
AB  - Atherosclerotic cardiovascular disease (CVD), malnutrition, and inflammation are
      common clinical features of chronic renal failure and are associated with
      increased mortality. Elevated levels of C-reactive protein (CRP) and cytokines
      are commonly observed in dialysis patients and have been shown to predict
      mortality. Serum hyaluronan previously has been used as a marker of an
      inflammatory reaction, irrespective of its cause. We have determined serum levels
      of albumin and hyaluronan, as well as the prevalence of malnutrition (subjective
      global assessment, 2 to 4), inflammation (CRP >/= 10 mg/L), and overt CVD in a
      cohort of 97 predialysis patients (52 +/- 13 years). Moreover, we determined the
      outcome of these patients 29 +/- 11 months after the basal measurement of
      hyaluronan. Serum levels of hyaluronan (median) were markedly elevated in
      predialysis patients with signs of malnutrition (127.1 v 50.5 ng/mL; P < 0.0001),
      inflammation (130.1 v 55.0 ng/mL; P < 0.0001) and CVD (118.8 v 56.0 ng/mL; P <
      0.001). The levels of log hyaluronan correlated significantly to log CRP (R =
      0.35; P < 0.001), serum albumin (R = -0.40; P < 0.0001), CVD (R = 0.36; P <
      0.001), and age (R = 0.40; P < 0.0001), respectively. Survival analysis by the
      Cox regression model showed that elevated hyaluronan levels were, independent of
      CVD, CRP, and age, significantly related to an increased mortality rate. The
      current study showed that markedly elevated serum hyaluronan levels are found in
      predialysis patients with malnutrition, inflammation, and CVD and that serum
      hyaluronan is a risk predictor of poor survival in dialysis.

PMID- 10585319
TI  - A preliminary study of the effects of correction of anemia with recombinant human
      erythropoietin therapy on sleep, sleep disorders, and daytime sleepiness in
      hemodialysis patients (The SLEEPO study).
AB  - End-stage renal disease (ESRD) is commonly associated with complaints of
      disturbed sleep and sleep disorders, frequently related to periodic limb
      movements in sleep (PLMS) or sleep apnea that may result in daytime sleepiness
      and other sequelae. Improvements in quality of life, including subjective sleep
      quality, have been reported in ESRD patients treated with recombinant human
      erythropoietin (rHuEPO). We investigated the objective effects of normalizing
      hematocrit on sleep disorders, sleep patterns, and daytime ability to remain
      awake in ESRD patients. Ten hemodialysis patients with sleep complaints while on
      rHuEPO therapy were studied by polysomnography while moderately anemic (mean
      hematocrit, 32.3%) and again when hematocrit was normalized (mean hematocrit,
      42.3%) by increased rHuEPO dosing. Sleep patterns and associated parameters were
      monitored. Delivered dialysis dose and iron storage factors were monitored.
      Maintenance of Wakefulness Testing (MWT) was performed to assess daytime
      alertness/sleepiness. All 10 subjects experienced highly statistically
      significant reductions in the total number of arousing PLMS (P = 0.002). Nine of
      10 subjects showed reductions in both the Arousing PLMS Index (P < 0.01) and the
      PLMS Index (P = 0.03) when hematocrit was normalized. Measures of sleep quality
      showed trends to improved quality of sleep. MWT demonstrated significant
      improvement in the length of time patients were able to remain awake (9.7 versus
      17.1 minutes; P = 0.04). RHuEPO therapy with full correction of anemia reduces
      PLMS, arousals from sleep, and sleep fragmentation while allowing for more
      restorative sleep and improved daytime alertness. These findings may explain one
      mechanism for the improved quality-of-life parameters reported in ESRD patients
      treated with rHuEPO.

PMID- 10585320
TI  - Hemodialysis causes severe orthostatic reduction in cerebral blood flow velocity
      in diabetic patients.
AB  - Orthostatic hypotension is a serious problem in patients with diabetes mellitus
      (DM) undergoing hemodialysis (HD). To evaluate cerebral circulation during
      orthostasis in patients with DM, we examined changes in mean blood flow velocity
      in the middle cerebral artery (VMCA) during 60 degrees head-up tilt for 5 minutes
      in patients with DM (six men, two women; age, 57 +/- 3 years [mean +/- SEM]; HD
      duration, 47 +/- 27 months) before and after bicarbonate HD by using transcranial
      Doppler sonography. The findings were compared with those in HD patients without
      diabetes (non-DM; 12 men, 5 women; age, 47 +/- 3 years; HD duration, 82 +/- 23
      months). Mean blood pressure (MBP) in the supine position, hematocrit (Hct),
      plasma fibrinogen, and volume of fluid removed by HD were not significantly
      different between the two groups (MBP, 106 +/- 6 versus 103 +/- 4 mm Hg; Hct, 26%
      +/- 1% versus 28% +/- 1%; fibrinogen, 355 +/- 37 versus 357 +/- 27 mg/dL; fluid,
      2.5 +/- 0.2 versus 2.3 +/- 0.2 L). Percentage of change in VMCA (% VMCA) during
      tilt was compared between the groups before and after HD. Before HD, MBP
      decreased significantly to 93 +/- 5 mm Hg during tilt only in patients with DM.
      The degree of MBP reduction was -13 +/- 2 mm Hg in DM and -2 +/- 2 mm Hg in non
      DM patients (P < 0.01). % VMCA equally decreased during tilt; DM, -12% +/- 3%,
      and non-DM, -12% +/- 2%. After HD; MBP decreased by 36 +/- 7 mm Hg in patients
      with DM, which was significantly greater than before HD. VMCA also decreased in
      both groups after HD, and % VMCA in DM (-32% +/- 5%) was significantly greater
      than before HD (P < 0.01) and in non-DM patients (-13% +/- 2%; P < 0.01). % VMCA
      positively correlated with the percentage of change ratio of MBP during tilt in
      both groups after HD (DM, r = 0. 87, P < 0.01; non-DM, r = 0.61, P < 0.01). Our
      results showed a significant decrease in cerebral blood flow velocity during tilt
      of equal magnitude in both groups before HD despite differences in the level of
      hypotension, whereas reduction in cerebral blood flow velocity and decrease in
      MBP were more marked in DM after HD. Orthostasis could thus cause hemodynamically
      mediated brain damage after HD, especially in patients with DM.

PMID- 10585321
TI  - Effect of hemodialysis on the signal-averaged electrocardiogram.
AB  - The presence of late potentials (LPs) on signal-averaged electrocardiography
      (SAECG) is predictive of ventricular tachycardia. The effect of hemodialysis (HD)
      on SAECG has not been well studied. SAECG was evaluated in 28 patients with
      chronic renal failure immediately before and after HD. In each SAECG, QRS
      duration, low-amplitude signal duration (LASd), and root-mean-square voltage of
      the terminal 40 milliseconds of the QRS (RMS40) were measured. To evaluate the
      effect of fluid removal on SAECG, the last 12 patients were studied during two
      different HD sessions, one with and one without fluid removal. Two-dimensional
      echocardiography was performed before and after HD on these 12 patients. At
      baseline, four patients met the criteria for LPs on SAECG. Only one patient met
      the criteria for LPs on SAECG after HD. After HD, the mean LASd decreased (28.3
      +/- 12.9 to 24.9 +/- 10.1 milliseconds; P = 0.041) and RMS40 increased (63.0 +/-
      56.9 to 79.0 +/- 59.2 microV; P = 0. 006). Among the 12 patients who underwent HD
      with and without fluid removal, left ventricular end-diastolic dimension
      decreased with (5. 4 +/- 0.6 to 5.1 +/- 0.6 cm; P = 0.024) but not without fluid
      removal (5.2 +/- 0.3 to 5.1 +/- 0.4 cm; P = not significant [NS]). RMS40 improved
      with (43.8 +/- 23.1 to 53.2 +/- 22.6 microV; P = 0. 03) but not without fluid
      removal (51.0 +/- 26.5 to 51.5 +/- 24.2 microV; P = NS). A significant negative
      correlation was found between change in body weight and change in RMS40 parameter
      (r = 0. 456; P = 0.0381). SAECG parameters are abnormal in a significant
      proportion of patients with chronic renal failure and improve with HD despite
      electrolyte and other proarrhythmic changes. Decreased left ventricular dimension
      because of fluid removal during HD is one possible explanation for this
      improvement.

PMID- 10585322
TI  - Bacteremia associated with tunneled, cuffed hemodialysis catheters.
AB  - Bacteremia is a frequent complication associated with tunneled, cuffed, permanent
      catheters (PCs). The incidence, spectrum of infecting organisms, and optimal
      treatment for catheter-associated bacteremia (CAB) have not been clearly
      established. In this study, 101 chronic hemodialysis (HD) patients with PCs for
      blood access were prospectively monitored for infection during a 24-month period.
      Data recorded for each patient included the number of catheter-days, episodes of
      suspected bacteremia, blood culture results, method of treatment, complications,
      and outcomes. All patients with CAB were treated with a 21-day course of
      intravenous antibiotics. The PC was removed if the patient had uncontrolled
      sepsis or if other vascular access was ready for use. Once the infection was
      controlled, catheter salvage was attempted, either by exchanging for a new
      catheter over a guidewire or treating with antibiotics only, leaving the original
      PC in place. Catheter exchange was the recommended approach in our program, but
      this was decided in each case by the treating nephrologist. During this study,
      there were 15,581 catheter-days, with 86 episodes of CAB, or 5.5 episodes/1,000
      catheter-days (95% confidence interval, 4.5 to 6.8/1,000 d). Forty-five
      infections (52.3%) were caused by gram-positive cocci only, including
      Staphylococcus aureus, coagulase-negative Staphylococcus, and Enterococcus
      species. Twenty-three infections (26.7%) were caused by gram-negative rods only,
      including a wide variety of enteric organisms. Eighteen infections (20.9%) were
      polymicrobial. Thirty-nine of 86 episodes (45.3%) included at least one gram
      negative organism. Five PCs were removed because of severe uncontrolled sepsis,
      and eight PCs were removed because they were no longer required. Of the remaining
      73 cases, attempted PC salvage was successful in 11 of 30 patients (36.7%)
      treated with antibiotics alone versus 35 of 43 patients (81.4%) who underwent PC
      exchange in addition to antibiotic therapy (P = 0.0005). The only important
      complication of CAB was endocarditis, occurring in 3 of 86 episodes (3.5%). We
      conclude that in our HD units, CAB is relatively common and frequently involves
      gram-negative bacteria. PC salvage is significantly improved when antibiotic
      treatment is combined with PC exchange over a guidewire.

PMID- 10585323
TI  - Acute vision loss in children with autosomal recessive polycystic kidney disease.
AB  - Patients with autosomal recessive polycystic kidney disease (ARPKD) often present
      with renal insufficiency and hypertension. We present two children with ARPKD and
      end-stage renal disease who developed anterior ischemic optic neuropathy and
      vision loss. Anterior ischemic optic neuropathy occurs rarely in children and has
      never been reported in children with ARPKD or end-stage renal disease. Both of
      our patients were chronically hypotensive and anemic, which are known risk
      factors for ischemic optic neuropathy.

PMID- 10585324
TI  - Acute renal failure in a neonate caused by the transplacental transfer of a
      nephrotoxic paraprotein: successful resolution by exchange transfusion.
AB  - Acute renal failure was diagnosed within 6 days of birth in a full-term neonate.
      The mother was known to have a monoclonal gammopathy, immunoglobulin G (IgG)
      lambda, discovered a year before pregnancy on being investigated for hematuria
      and proteinuria. Her renal function was intact. Maternal renal biopsy performed
      at the time showed a focal proliferative glomerulonephritis with nonfibrillary
      homogeneous mesangial and intramembranous electron-dense deposits.
      Immunoperoxidase staining was positive for IgG and lambda and kappa light chains
      along the glomerular and tubular basement membranes. Pregnancy was uneventful.
      Protein electrophoresis and immunofixation of the infant girl's serum and urine
      samples showed the presence of a paraprotein electrophoretically identical to
      that found in the mother. Exchange transfusion resulted in a rapid improvement of
      renal function in parallel to the disappearance of the monoclonal component.

PMID- 10585325
TI  - Parvovirus B19 infection causing red cell aplasia in renal transplantation on
      tacrolimus.
AB  - Parvovirus B19 infection is known to cause chronic anemia in immunocompromised
      hosts, including organ transplant recipients. Most reported cases of parvovirus
      B19-associated aplastic anemia in renal transplant recipients responded to
      intravenous immunoglobulin (IVIG) infusion. Tacrolimus is of special interest; it
      was proposed to be associated with pure red cell aplasia (PRCA) on its own
      because resolution of anemia on withdrawal of tacrolimus was previously observed.
      Interaction between parvovirus B19 infection and tacrolimus has not been
      reported. We report a case of parvovirus B19-associated PRCA in a renal
      transplant recipient treated with tacrolimus who failed to clear the virus
      despite repeated courses of IVIG. She showed complete recovery promptly after
      tacrolimus was switched to cyclosporine A. A well-documented concomitant decrease
      in serum parvovirus DNA polymerase chain reaction titer was also observed. This
      shows another mechanism by which tacrolimus can aggravate PRCA because of
      impaired clearance of parvovirus B19 infection in transplant recipients. For
      those patients receiving tacrolimus who have parvovirus B19 infection with
      refractory anemia and who fail to recover with IVIG, replacement of tacrolimus
      with cyclosporine A can be considered.

PMID- 10585326
TI  - Full-text articles, manuscript tracking, and automated literature search lead new
      array of AJKD online features.

PMID- 10585328
TI  - Relaxin may be the "elusive" renal vasodilatory agent of normal pregnancy.

PMID- 10585327
TI  - Should we screen for microalbuminuria in essential hypertension?

PMID- 10585329
TI  - Nephrotic syndrome in an adult: the ongoing saga of fibrils versus microtubules.

PMID- 10585330
TI  - Antithymocyte globulin-induced acute renal failure.

PMID- 10585331
TI  - First report of tropical myositis and crescentic glomerulonephritis in a renal
      transplant recipient.
AB  - We describe a renal transplant recipient who presented with tropical myositis and
      acute allograft dysfunction 2(1/2) years after transplantation. Graft biopsy
      showed immune-complex crescentic glomerulonephritis. He was receiving only 7.5
      mg/d of prednisolone for more than 2 months before presentation. Renal function
      did not improve despite treatment with antibiotics, methylprednisolone pulse
      therapy, and cyclophosphamide. He died of septicemia.

PMID- 10585332
TI  - Acute renal failure after immersion in seawater polluted by diesel oil.
AB  - Acute renal failure after exposure to toxic doses of hydrocarbon has been
      uniformly associated with multiorgan failure. We report a case of isolated acute
      renal failure in a patient after immersion in seawater polluted by diesel oil.
      The sites of absorption were likely to be skin, gastrointestinal tract, and lung.
      Investigations showed renal impairment as the only consequence from the exposure.
      The patient recovered uneventfully and did not require dialysis. This case
      highlighted the unusual consequence of isolated renal involvement resulting from
      hydrocarbon toxicity.

PMID- 10585333
TI  - Amyloidosis complicating idiopathic myelofibrosis.
AB  - An 84-year-old man presented with ankle edema, significant proteinuria, and mild
      impairment of renal function soon after treatment was started for idiopathic
      myelofibrosis. Renal amyloidosis was found on biopsy. The amyloid deposit was
      resistant to potassium permanganate treatment and showed no immunoreactivity to
      immunoglobulin light chains, beta-amyloid protein, or amyloid A component. A
      review of the literature showed that the occurrence of amyloidosis in idiopathic
      myelofibrosis is very rare, and the chemical nature of the amyloid involved
      remains unclear.

PMID- 10585334
TI  - Extrarenal manifestations of autosomal dominant polycystic kidney disease.

PMID- 10585335
TI  - Filter paper lead testing.

PMID- 10585336
TI  - Synthetic viral particles promise to be valuable in the standardization of
      molecular diagnostic assays for hepatitis C virus.

PMID- 10585337
TI  - Zinc protoporphyrin: A metabolite with a mission.
AB  - Zinc protoporphyrin (ZnPP) is a normal metabolite that is formed in trace amounts
      during heme biosynthesis. The final reaction in the biosynthetic pathway of heme
      is the chelation of iron with protoporphyrin. During periods of iron
      insufficiency or impaired iron utilization, zinc becomes an alternative metal
      substrate for ferrochelatase, leading to increased ZnPP formation. Evidence
      suggests that this metal substitution is one of the first biochemical responses
      to iron depletion, causing increased ZnPP to appear in circulating erythrocytes.
      Because this zinc-for-iron substitution occurs predominantly within the bone
      marrow, the ZnPP/heme ratio in erythrocytes reflects iron status in the bone
      marrow. In addition, ZnPP may regulate heme catabolism through competitive
      inhibition of heme oxygenase, the rate-limiting enzyme in the heme degradation
      pathway that produces bilirubin and carbon monoxide. Physiological roles,
      especially relating to carbon monoxide and possibly nitric oxide production, have
      been suggested for ZnPP. Clinically, ZnPP quantification is valuable as a
      sensitive and specific tool for evaluating iron nutrition and metabolism.
      Diagnostic determinations are applicable in a variety of clinical settings,
      including pediatrics, obstetrics, and blood banking. ZnPP analytical
      methodologies for clinical studies are discussed. In addition to diagnostic tests
      and metabolic studies, ZnPP has a potential therapeutic application in
      controlling bilirubin formation in neonates as a preventive measure for
      hyperbilirubinemia. Biochemical research techniques, both in vivo and in vitro,
      are described for further studies into the role of ZnPP in metabolism and
      physiology.

PMID- 10585338
TI  - Biochemical and molecular genetic characteristics of the severe form of tyrosine
      hydroxylase deficiency.
AB  - BACKGROUND: Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the
      biosynthesis of the catecholamines dopamine, norepinephrine, and epinephrine.
      Recently, mutations were identified in cases of autosomal recessive dopa
      responsive dystonia and infantile parkinsonism. We describe a patient with severe
      symptoms and a new missense mutation in TH. METHODS: Relevant metabolites in
      urine and cerebrospinal fluid were measured by HPLC with fluorometric and
      electrochemical detection. All exons of the TH gene were amplified by PCR and
      subjected to single-strand conformation polymorphism analysis. Amplimers
      displaying aberrant migration patterns were analyzed by DNA sequence analysis.
      RESULTS: The patient presented with severe axial hypotonia, hypokinesia, reduced
      facial mimicry, ptosis, and oculogyric crises from infancy. The major metabolite
      of dopamine, homovanillic acid, was undetectable in the patient's cerebrospinal
      fluid. A low dose of L-dopa produced substantial biochemical but limited clinical
      improvement. DNA sequencing revealed a homozygous 1076G-->T missense mutation in
      exon 10 of the TH gene. The mutation was confirmed with restriction enzyme
      analysis. It was not present in 100 control alleles. Secondary structure
      prediction based on Chou-Fasman calculations showed an abnormal secondary
      structure of the mutant protein. CONCLUSIONS: We describe a new missense mutation
      (1076G-->T, C359F) in the TH gene. The transversion is present in all known
      splice variants of the enzyme. It produces more severe clinical and biochemical
      manifestations than previously described in TH-deficient cases. Our findings
      extend the clinical and the biochemical phenotype of genetically demonstrated TH
      deficiency.

PMID- 10585339
TI  - Ribonuclease-resistant RNA controls (Armored RNA) for reverse transcription-PCR,
      branched DNA, and genotyping assays for hepatitis C virus.
AB  - BACKGROUND: Comparison and evaluation of molecular diagnostic assays for the
      detection and quantification of hepatitis C virus (HCV) RNA have been limited by
      the lack of RNA controls and calibrators. Armored RNA technology is a means for
      producing RNA that is completely protected from plasma ribonucleases. This method
      produces recombinant pseudoviral particles that are noninfectious and contain
      predefined RNA sequences. METHODS: A consensus 412-base sequence from the
      5'NCR/Core region of HCV subtype 2b was derived from 34 individually sequenced
      HCV genotype 2b variants. A DNA fragment encoding the consensus HCV-2b sequence
      was synthesized de novo, cloned, and expressed as an Armored RNA control. The
      resulting HCV-2b Armored RNA (AR-HCV-2b) contained the complete HCV-2b consensus
      RNA sequence encapsidated within a protective protein coat. RESULTS: AR-HCV-2b
      was fully recoverable from human plasma incubated at 4 degrees C for >300 days.
      The particles were tested in three clinical assay formats: Amplicor HCV Monitor
      1.0, Quantiplex HCV RNA 2.0, and INNO-LiPA HCV II. When added into seronegative,
      nonviremic plasma, AR-HCV-2b showed reproducible signals and linear dilutions in
      both the Amplicor and Quantiplex assays. AR-HCV-2b was correctly identified as
      subtype 2b in the INNO-LiPA line probe assay. CONCLUSION: The HCV-2b Armored RNA
      control is a versatile, durable, ribonuclease-resistant viral RNA control that is
      compatible in three different clinical assay formats.

PMID- 10585340
TI  - Application of a thermodynamic nearest-neighbor model to estimate nucleic acid
      stability and optimize probe design: prediction of melting points of multiple
      mutations of apolipoprotein B-3500 and factor V with a hybridization probe
      genotyping assay on the LightCycler.
AB  - BACKGROUND: PCR-based mutation detection is prone to methodological errors, e.g.,
      in restriction length fragment polymorphism (RFLP) and allele-specific
      amplification (ASA), false PCR results may occur because of technical faults or
      atypical new mutations. METHODS: We investigated the ability of a genotyping
      assay based on hybridization of labeled oligonucleotides to detect and
      discriminate known and as yet unknown mutations in the factor V and
      apolipoprotein B-100 genes. Expected melting points were calculated using a
      nearest-neighbor model for nucleic acid duplex stability and compared with
      experimental findings derived from LightCycler melting curves. A method for
      genotyping the apolipoprotein B-100 G10699A and C10698T mutations is presented.
      RESULTS: All mismatches tested for in the probed sequence could be detected with
      a single probe. The measured melting points were in good agreement with their
      values predicted using the nearest-neighbor model (r = 0.96; y = 0.98x + 1.18;
      S(y|x) = 0.96; n = 24). CONCLUSIONS: This procedure not only allows the
      identification of the mutation of interest but also enables the discrimination
      from other potential mutations in the vicinity of the former. The nearest
      neighbor model is valid for hybridization probe assays on the LightCycler and
      should be of general value in setting up such assays. We have shown for two
      clinically relevant genotyping examples that the LightCycler mutation detection
      system has superior discriminatory performance compared with conventional RFLP or
      ASA PCR-based methods for molecular diagnostic purposes. With this method, in
      every hybridization probe assay, all mutations under a properly designed probe
      should be detectable, but they will not necessarily be discriminated from each
      other in all cases.

PMID- 10585341
TI  - Single-step mutation scanning of the 6-pyruvoyltetrahydropterin synthase gene in
      patients with hyperphenylalaninemia.
AB  - BACKGROUND: Deficiency of 6-pyruvoyltetrahydropterin synthase (PTPS) is a
      recessively inherited disorder that leads to depletion of 5,6,7, 8
      tetrahydrobiopterin, the obligatory cofactor for hydroxylation of phenylalanine,
      tyrosine, and tryptophan. A marker for neonatal detection of PTPS deficiency is
      hyperphenylalaninemia (HPA). Molecular analysis would provide a simple and
      reliable means for distinguishing PTPS deficiency from other potential causes of
      HPA. METHODS: We developed a method based on PCR in combination with denaturing
      gradient gel electrophoresis (DGGE) that rapidly scans the six coding sequences
      and all splice sites of the PTPS gene (PTS) for mutations. This method was used
      to examine the status of the PTS gene in control samples with known PTS mutations
      and in five patients with PTPS deficiency. RESULTS: Two features of the PTS gene
      posed particular problems in relation to DGGE analysis: the very high GC content
      of exon 1, and a 15-bp poly(dT) stretch in the acceptor splice site of intron 1.
      Both problems were solved by special design of amplification primers. PCR and
      DGGE conditions were adjusted to allow simultaneous analysis of all six regions
      of the PTS gene. Using this one-step approach, all control mutations were readily
      resolved. Among the five PTPS patients, four mutations were identified, including
      IVS1-3C-->G, IVS2-7T-->A, V57del, and V97M (289G-->A). The IVS1-3C-->G mutation
      was shown by reverse transcription-PCR analysis to produce multiple splice
      variants. CONCLUSIONS: We have established a fast and reliable screening method
      for detection of mutations and small deletions/insertions in the PTS gene. This
      method should be useful for rapid diagnosis of PTPS deficiency in newborns with
      HPA.

PMID- 10585342
TI  - Hyperglycosylated human chorionic gonadotropin (invasive trophoblast antigen)
      immunoassay: A new basis for gestational Down syndrome screening.
AB  - BACKGROUND: Serum human chorionic gonadotropin (hCG) and hCG free beta-subunit
      tests are used in combination with unconjugated estriol and alpha-fetoprotein in
      the triple screen test, and with the addition of inhibin-A in the quadruple
      marker test for detecting Down syndrome in the second trimester of pregnancy.
      These tests have a limited detection rate for Down syndrome: approximately 40%
      for hCG or free beta-subunit alone, approximately 60% for the triple screen test,
      and approximately 70% for the quadruple marker test, all at 5%, or a relatively
      high, false-positive rate. New tests are needed with higher detection and lower
      false rates. Hyperglycosylated hCG (also known as invasive trophoblast antigen or
      ITA) is a new test. It specifically detects a unique oligosaccharide variant of
      hCG associated with Down syndrome pregnancies. We evaluated this new Down
      syndrome-directed test in prenatal diagnosis. METHODS: Hyperglycosylated hCG was
      measured in urine samples from women undergoing amniocentesis for advanced
      maternal age concerns at 14-22 weeks of gestation, 1448 with normal karyotype and
      39 with Down syndrome fetuses. RESULTS: The median hyperglycosylated hCG value
      was 9.5-fold higher in Down syndrome cases (9.5 multiples of the normal karyotype
      median). The single test detected 80% of Down syndrome cases at a 5% false
      positive rate. Urine hyperglycosylated hCG was combined with urine beta-core
      fragment (urine breakdown product of serum hCG free beta-subunit), serum alpha
      fetoprotein, and maternal age-related risk. This urine-serum combination detected
      96% of Down syndrome cases at a 5% false-positive rate, 94% of cases at a 3%
      false-positive rate, and 71% of cases at a 1% false-positive rate. These
      detection rates exceed those of any previously reported combination of
      biochemical markers. CONCLUSIONS: Hyperglycosylated hCG is a new base marker for
      Down syndrome screening in the second trimester of pregnancy. The measurement of
      hyperglycosylated hCG can fundamentally improve the performance of Down syndrome
      screening protocols.

PMID- 10585343
TI  - Rapid diagnosis of herpes simplex encephalitis using microchip electrophoresis of
      PCR products.
AB  - BACKGROUND: Herpes simplex virus (HSV) is the most common cause of acute sporadic
      encephalitis in the United States. PCR of DNA extracted from cerebrospinal fluid
      (CSF) allows for reliable diagnosis of herpes simplex encephalitis (HSE). A
      faster turnaround time for HSE testing would improve patient management and lead
      to better outcomes. The aims of this study, therefore, were to develop a
      microchip-based electrophoretic method for rapid detection of HSV PCR products,
      and to compare the performance characteristics of liquid hybridization/gel
      retardation as an established clinical PCR product detection method with the new
      microchip-based method. METHODS: The study examined archival DNA from 33 selected
      CSF specimens submitted for HSV PCR testing to the clinical laboratory. One
      aliquot of the HSV PCR product was analyzed by liquid hybridization/gel
      retardation analysis, and a second PCR aliquot was analyzed directly with a
      microchip capillary electrophoresis system using an instrument built in-house.
      PCR samples were introduced directly into the microchip without a desalting step
      by use of a novel fluidic interface. Channel surfaces on the glass microchip were
      silanized, followed by derivatization with polyvinylpyrrolidone. RESULTS: Of the
      33 CSF specimens tested by liquid hybridization analysis of HSV PCR products, 10
      tested positive for HSV DNA, 2 gave a weakly positive result, and 21 tested
      negative. Total analysis time for detection of HSV DNA by gel retardation assay
      was 18 h. Microchip electrophoresis provided identical results in <110 s/sample,
      achieving 100% sensitivity and specificity compared with the established method.
      CONCLUSIONS: Microchip-based electrophoresis can rapidly and accurately separate
      HSV PCR products, giving results identical to those obtained by liquid
      hybridization but with substantially decreased turnaround time. Clinical
      implementation of the new method will help to improve patient management and
      outcomes.

PMID- 10585344
TI  - RNA expression of cardiac troponin T isoforms in diseased human skeletal muscle.
AB  - BACKGROUND: The expression of multiple cardiac troponin T (cTnT) isoforms has
      been demonstrated in diseased human skeletal muscle. However, cardiac troponin I
      (cTnI) expression has been described only in heart muscle. The goal of this study
      was to determine whether mRNA for cTnT, slow skeletal troponin T (sTnT), or cTnI
      was expressed in skeletal muscle biopsies obtained from patients with end-stage
      renal disease (ESRD) and Duchenne muscular dystrophy (DMD). METHODS: Total mRNA
      was extracted from healthy human heart (n = 4), healthy human skeletal muscle (n
      = 5), and skeletal muscle from patients with ESRD (n = 7) and DMD (n = 5). Total
      RNA (1 microg) was reverse-transcribed using Moloney murine leukemia virus
      reverse transcriptase. The reverse-transcribed cDNAs were amplified by PCR using
      oligonucleotide primers specific for cTnT, sTnT, and cTnI sequences (GenBank
      accession numbers X74819, m19308, and X54163, respectively). RESULTS: In all
      heart specimens, a 150-bp cTnT amplicon was detected. Skeletal muscle from four
      of seven patients with ESRD and two of five patients with DMD showed expression
      of a 150-bp amplicon. Using DNA sequencing and a comparison program, the 150-bp
      amplicons found in heart and diseased skeletal muscle specimens were 100%
      identical and specific to the cTnT mRNA sequence. No cTnT mRNA expression was
      found in healthy skeletal muscle. No evidence of sTnT mRNA was found in heart
      muscle. A 200-bp sTnT amplicon specific to a human sTnT sequence was detected in
      all skeletal muscle specimens. A 250-bp cTnI amplicon specific to the cTnI
      sequence was detected in all heart specimens. However, no cTnI mRNA expression
      was found in healthy or diseased skeletal muscle specimens. cTnT mRNA expression
      in both heart and diseased skeletal muscles corresponded with cTnT isoform
      expression, respectively, as determined by Western blot analysis. CONCLUSION: Our
      findings demonstrate cTnT mRNA expression, but no cTnI mRNA expression, by
      reverse transcription-PCR in diseased human skeletal muscle that expresses cTnT
      isoforms.

PMID- 10585345
TI  - Clinical efficacy of an automated high-sensitivity C-reactive protein assay.
AB  - BACKGROUND: Prospective studies have shown that C-reactive protein (CRP) can be
      used to predict risk of future cardiovascular events. High-sensitivity methods
      for CRP (hs-CRP) measurement are needed for this purpose. METHODS: We compared
      the clinical efficacy of an automated and commercially available latex-enhanced
      assay (Latex) for hs-CRP (Dade Behring) to a validated in-house ELISA, previously
      shown to predict future peripheral arterial disease (PAD) in asymptomatic
      populations. Using a prospective, nested, case-control design, we measured
      baseline hs-CRP concentrations in 144 apparently healthy men who subsequently
      developed symptomatic PAD and 144 age- and smoking habit-matched controls who
      remained free of vascular disease over the follow-up period of 60 months.
      RESULTS: The two hs-CRP assays correlated highly (r = 0.95; P <0.001), and all
      but two participants were classified into concordant quartiles or varied by only
      one quartile. The median hs-CRP of the case group was significantly higher than
      that of controls when measured by either the ELISA (1.34 vs 0.99 mg/L; P = 0.034)
      or the Latex method (1.80 vs 1.20 mg/L; P = 0.042). Furthermore, for both ELISA
      and the Latex method, the calculated relative risks of developing PAD increased
      significantly with each increasing quartile of hs-CRP. The calculated
      interquartile increase in relative risk of PAD was 31% (95% confidence interval,
      5.2-62.2%; P = 0.01) for ELISA and 34% (95% confidence interval, 8.2-66.1%; P =
      0.007) for the Latex method. CONCLUSIONS: Our findings indicate that the Latex
      method is equally as efficacious as the validated ELISA in classifying patients
      into cutoff points established by prospective studies for risk stratification for
      coronary and cerebrovascular disease.

PMID- 10585346
TI  - Recombinant human tissue transglutaminase ELISA for the diagnosis of gluten
      sensitive enteropathy.
AB  - BACKGROUND: Tissue transglutaminase (TGc) has recently been identified as the
      major, if not the sole, autoantigen of gluten-sensitive enteropathy (GSE). We
      developed and validated an ELISA based on the human recombinant antigen and
      compared it to existing serological tests for GSE [guinea pig TGc ELISA and
      endomysium antibody (EMA) test]. METHODS: Human TGc was expressed in the human
      embryonic kidney cell line 293-EBNA as a C-terminal fusion protein with the eight
      amino acid Strep-tag II allowing one-step purification via streptavidin affinity
      chromatography. We carried out ELISA assays for IgA antibodies against TGc using
      calcium-activated human and guinea pig TGc. The sera were also tested on monkey
      esophagus sections by indirect immunofluorescence for IgA EMA. We examined 71
      serum samples from patients with GSE (38 with celiac disease, 33 with dermatitis
      herpetiformis), including 16 on therapy, and 53 controls. RESULTS: The human TGc
      could be expressed and purified as an active enzyme giving a single band on a
      Coomassie-stained gel. The mean intra- and interassay CVs for the human TGc ELISA
      were 3.2% and 9.2%, respectively. The area under the ROC curve was 0.999. The
      specificity and sensitivity were 98.1% (95% confidence interval, 95.7-100%) and
      98.2% (95.9-100%), respectively. CONCLUSIONS: The human TGc ELISA was somewhat
      superior to the guinea pig TGc ELISA, and was as specific and sensitive as the
      EMA test. The human TGc-based ELISA is the method of choice for easy and
      noninvasive screening and diagnosis of GSE.

PMID- 10585347
TI  - Clinical significance of immunoassays for type-5 tartrate-resistant acid
      phosphatase.
AB  - BACKGROUND: Tartrate-resistant acid phosphatase (TRAP; EC 3.1.3.2) is a product
      of osteoclasts and a biochemical marker of bone resorption rate. However,
      erythrocytes and platelets contribute to total TRAP activity in serum, reducing
      the specificity of direct biochemical assays in serum. Osteoclast TRAP is also
      known as type-5 TRAP and is antigenically unique. Immunoassays are sought to
      improve the specificity and sensitivity of TRAP as a bone marker. METHODS: We
      developed two colorimetric microplate assays for type-5 TRAP: an enzyme capture
      immunoassay to measure antibody-bound enzymatic activity, and a two-site
      immunoassay to measure bound enzyme protein. Both use the same monoclonal
      antibody (14G6) to capture type-5 TRAP, which permits determination of specific
      activity of serum TRAP in health and disease. RESULTS: Both TRAP assays were
      linear from one-tenth to fivefold the mean value in 18 healthy subjects. In these
      subjects, the mean (SD) TRAP activity was 3.2 (0.54) U/L for the enzyme capture
      assay and 37 (13) microg/L for the two-site assay. Mean TRAP activity was not
      significantly increased in 64 patients with endstage renal disease requiring
      hemodialysis (HD) or 99 unselected patients with rheumatic diseases. By contrast,
      TRAP protein was increased in both the HD and rheumatic disease groups. The
      specific activity of TRAP in the 17 of 64 HD sera that had increased TRAP
      activity (0.088 U/microg) was similar to that in healthy subjects (0.091
      U/microg). By contrast, the specific activity of TRAP in the 31 of 99 rheumatic
      sera with increased TRAP protein (0.035 U/microg) was significantly decreased.
      CONCLUSIONS: Wide sample distributions for TRAP activity in HD patients and TRAP
      protein in rheumatic disease patients suggest the presence of subpopulations of
      HD patients with increased TRAP activity and of rheumatic patients with increased
      TRAP protein. Each assay for TRAP activity and protein may have its own
      biological significance and clinical applications in specific groups of patients.

PMID- 10585348
TI  - Endpoint colorimetric method for assaying total cholesterol in serum with
      cholesterol dehydrogenase.
AB  - BACKGROUND: Various methods are available to measure serum cholesterol
      concentrations. Of these, the cholesterol ester hydrolase (CEH)-cholesterol
      oxidase-peroxidase chromogenic method is widely used. However, this method has
      the disadvantage of interference by reducing substances. We developed and
      evaluated an endpoint assay for serum cholesterol, based on a CEH-cholesterol
      dehydrogenase (CDH)-ultraviolet method. METHODS: Cholesterol esters are first
      hydrolyzed to free cholesterol by CEH. The free cholesterol is then reduced by
      CDH to cholest-4-ene-3-one with the simultaneous production of beta-NADH from
      beta-NAD(+). At equilibrium, the CDH reaction gives incomplete conversion of
      cholesterol to cholest-4-ene-3-one. To overcome this disadvantage, we added
      hydrazine monohydrate to the reaction mixture to remove cholest-4-ene-3-one,
      which allowed the reaction to proceed to completion and gave stoichiometric
      production of beta-NADH from the reaction of beta-NAD(+) with cholesterol.
      RESULTS: We tested whether the amount of cholesterol added was equivalent to the
      absorbance change of NADH at 340 nm with six aqueous samples. Recoveries were
      97.1-100.3%. The reaction was linear up to 20.28 mmol/L. The mean within-day (n =
      20) and between-day (n = 10) imprecision (CV) was 0. 29-0.43% and 0.22-0.61%,
      respectively. No interference by bilirubin, hemoglobin, ascorbic acid, and other
      reducing agents was observed. The equation obtained in comparison with the
      modified Abell-Levy-Brodie-Kendall method was: y = 0.992x - 0.0058 mmol/L; r =
      0.997; S(y|x) = 0.117 mmol/L; n = 50. CONCLUSION: This method is an accurate,
      reliable method for serum cholesterol analysis and is amenable to automation.

PMID- 10585349
TI  - Analysis of nicotine, 3-hydroxycotinine, cotinine, and caffeine in urine of
      passive smokers by HPLC-tandem mass spectrometry.
AB  - BACKGROUND: A method is described for the simultaneous analysis of nicotine and
      two of its major metabolites, cotinine and 3-hydroxycotinine, as well as for
      caffeine from urine samples. The method was developed to assess exposure of
      restaurant and hotel workers to environmental tobacco smoke. METHODS: The method
      includes sample pretreatment and reversed-phase HPLC separation with tandem mass
      spectrometric identification and quantification using electrospray ionization on
      a quadrupole ion trap mass analyzer. Sample pretreatment followed standard
      protocols, including addition of base before liquid-liquid partitioning against
      dichloromethane on a solid matrix, evaporation of the organic solvent using
      gaseous nitrogen, and transferring to HPLC vials using HPLC buffer. HPLC
      separation was run on-line with the electrospray ionization-tandem mass
      spectrometric detection. RESULTS: The detection limits of the procedure were in
      the 1 microg/L range, except for nicotine (10 microg/L of urine). Still lower
      detection limits can be achieved with larger sample volumes. Recoveries of the
      sample treatment varied from 99% (cotinine) to 78% (3-hydroxycotinine).
      CONCLUSIONS: The method described is straightforward and not labor-intensive and,
      therefore, permits a high throughput of samples with excellent prospects for
      automation. The applicability of the method was demonstrated in a small-scale
      study on restaurant employees.

PMID- 10585350
TI  - Efficient cleavage of conjugates of drugs or poisons by immobilized beta
      glucuronidase and arylsulfatase in columns.
AB  - BACKGROUND: Cleavage of conjugates is an important step in toxicological
      analysis, especially of urine samples. The aim of this study was to combine the
      advantages and to reduce the disadvantages of acid hydrolysis and conventional
      enzymatic hydrolysis procedures. METHODS: beta-Glucuronidase (GRD; EC 3.2.1.31)
      and arylsulfatase (ARS; EC 3.1.6.1) were purified and coimmobilized on an agarose
      gel matrix and packed into columns. RESULTS: In columns packed with GRD and ARS,
      the test conjugates 4-nitrophenyl glucuronide and 4-nitrophenyl sulfate added
      into urine could be completely cleaved within 25 min. Even the relatively stable
      morphine conjugates could be completely hydrolyzed within 60 min in authentic
      urine samples. Therefore, an incubation time of 1 h is recommended. Enzyme
      inhibition by matrix or by rather high concentrations of acetaminophen conjugates
      was tested and found to be up to 50%. However, a large excess of GRD and ARS was
      used. The immobilizate columns could be reused for at least 70 incubations and
      had a storage stability of at least 12 weeks. Carryover of analytes in reused
      columns could be avoided by rinsing with 200 mL/L methanol in acetate buffer.
      Thus, five drugs known to be contaminants added in very high concentrations into
      urine could be completely removed from the columns. A study on the applicability
      in systematic toxicological analysis showed that 120 different drugs and/or their
      metabolites could be detected in 35 different authentic urine samples.
      CONCLUSIONS: Use of immobilized and column-packed GRD and ARS is an efficient
      alternative for the cleavage of urinary conjugates in clinical toxicology.

PMID- 10585351
TI  - Preanalytical variables affecting the quantification of fatty acid ethyl esters
      in plasma and serum samples.
AB  - BACKGROUND: Fatty acid ethyl esters (FAEEs) are cytotoxic nonoxidative ethanol
      metabolites produced by esterification of fatty acids and ethanol. FAEEs are
      detectable in blood up to 24 h after ethanol consumption. The objective of this
      study was to assess the impact of gender, serum or plasma triglyceride
      concentration, time and temperature of specimen storage, type of alcoholic
      beverage ingested, and the rate of ethanol consumption on FAEE concentrations in
      plasma or serum. METHODS: For some studies, subject were recruited volunteers; in
      others, residual blood samples after ethanol quantification were used. FAEEs were
      isolated by solid-phase extraction and quantified by gas chromatography-mass
      spectrometry. RESULTS: For weight-adjusted amounts of ethanol intake, FAEE
      concentrations were twofold greater for men than women (P </=0.05). Accounting
      for triglycerides improved the correlation between blood ethanol concentrations
      and FAEE concentrations for both men (from r = 0.640 to r = 0.874) and women
      (from r = 0.619 to r = 0.673). FAEE concentrations did not change when samples
      were stored at or below 4 degrees C, but doubled when stored at room temperature
      for >/=24 h. The type of alcoholic beverage and rate of consumption did not
      affect FAEE concentrations. CONCLUSION: These studies advance plasma and serum
      FAEE measurements closer to implementation as a clinical test for ethanol intake.

PMID- 10585352
TI  - Increased serum transferrin saturation is associated with lower serum transferrin
      receptor concentration.
AB  - BACKGROUND: Serum transferrin receptor (sTfR) concentrations are increased in
      iron deficiency. We wished to examine whether they are decreased in the presence
      of potential iron-loading conditions, as reflected by increased transferrin
      saturation (TS) on a single occasion. METHODS: We compared sTfR concentrations
      between 570 controls with normal iron status and 189 cases with increased serum
      TS on a single occasion; these latter individuals may be potential cases of iron
      overload. Cases and controls were selected from adults who had been examined in
      the third National Health and Nutrition Examination Survey (1988-1994) and for
      whom excess sera were available to perform sTfR measurements after the survey's
      completion. Increased TS was defined as >60% for men and >55% for women; normal
      iron status was defined as having no evidence of iron deficiency, iron overload,
      or inflammation indicated by serum ferritin, TS, erythrocyte protoporphyrin, and
      C-reactive protein. RESULTS: Mean sTfR and mean log sTfR:ferritin were
      approximately 10% and 24% lower, respectively, in cases than in controls (P
      <0.002). Cases were significantly more likely to have an sTfR value <2.9 mg/L,
      the lower limit of the reference interval, than were controls (odds ratio = 1.8;
      95% confidence interval, 1.04-2.37). CONCLUSION: Our results support previous
      studies that suggested that sTfR may be useful for assessing high iron status in
      populations.

PMID- 10585353
TI  - Influence of repetitive finger puncturing on skin perfusion and capillary blood
      analysis in patients with diabetes mellitus.
AB  - BACKGROUND: Frequent puncturing of fingers to check blood glucose in patients
      with type 1 diabetes might alter skin perfusion and, hence, influence the
      representativeness of the blood sample. We investigated the influence of
      repetitive puncturing on skin microcirculatory perfusion using laser Doppler
      fluxmetry and on the preanalytical phase of capillary blood analysis for small
      molecules (glucose) and large particles (cholesterol). METHODS: In 49 patients
      with long-standing (mean, 21 years) type 1 diabetes, with a mean puncture
      frequency of three times daily for a mean duration of 13 years, laser Doppler
      skin perfusion was measured in a finger at a frequently punctured site and
      compared with a similar site of another finger of the same hand, which was never
      punctured. In the supine position with the hand level with the heart, resting
      flux (RF), peak flux (PF), and the microcirculatory reserve capacity (MRC; PF -
      RF) were assessed. Subsequently, blood samples for capillary whole blood glucose
      and cholesterol analyses were taken from the same sites. RESULTS: No significant
      differences were found between the puncture and control sites in mean RF (2.3 vs
      2.0 V; P = 0.14, paired-samples t-test), PF (3.3 vs 3.1 V; P = 0.24), MRC (1.0 vs
      1.0 V; P = 0.65), glucose (10.2 vs 10.2 mmol/L; P = 0.69), or cholesterol (5.1 vs
      5.2 mmol/L; P = 0.26). Power calculation for a RF of 2.0 V and the SD and n of
      this study indicate a power (beta) of 80% to detect a 25% change in RF at P
      <0.05. CONCLUSIONS: Repetitive finger puncturing in diabetics appears not to
      injure local skin microcirculatory perfusion nor to influence results of
      capillary blood analysis for glucose and cholesterol.

PMID- 10585354
TI  - Comparison of pituitary and recombinant human thyroid-stimulating hormone (rhTSH)
      in a multicenter collaborative study: establishment of the first World Health
      Organization reference reagent for rhTSH.
AB  - BACKGROUND: The increasing use of recombinant-DNA-derived materials in therapy
      and diagnosis poses a new challenge for biological standardization, that of
      developing reference preparations appropriate for both the native and recombinant
      products. Here we report the results of an international collaborative study that
      was carried out under the auspices of WHO to assess the suitability of a
      preparation of recombinant thyroid-stimulating hormone (rTSH; 94/674) to serve as
      a potential standard for the calibration of diagnostic immunoassays compared with
      the International Reference Preparation (IRP) for human TSH (80/558). METHODS:
      Coded samples were provided to the 33 laboratories in the study, and participants
      were asked to perform TSH assays currently in use in their laboratories. Twenty
      eight laboratories contributed 93 immunoassays in 41 different method-laboratory
      combinations, and an additional 5 laboratories contributed bioassay data. All
      data were analyzed centrally at the National Institute for Biological Standards
      and Control. RESULTS: The results obtained in different laboratories and with
      different assay systems revealed significant variability between estimates of
      rTSH relative to the IRP. These ranged from 5. 51 mIU (95% limits, 3.95-7.67 mIU)
      per ampoule by RIA to 7.15 mIU (95% limits, 6.7-7.63 mIU) per ampoule by
      immunofluorometric assay. However, the results showed that the assignment of a
      value of 6.70 mIU per ampoule of 94/674 would give reasonable continuity with the
      IRP in many assay systems. CONCLUSIONS: The preparation was established as the
      First WHO Reference Reagent for TSH, human, recombinant, to provide a means of
      validating assay performance and to maintain continuity with the IRP without
      compromising clinical data.

PMID- 10585355
TI  - Freedom from drug interference in new immunoassays for urinary catecholamines and
      metanephrines.
AB  - BACKGROUND: Determination of urinary free catecholamine and total (i. e., free
      plus conjugated) metanephrine excretion is considered the most clinically
      sensitive biochemical test for pheochromocytoma. In this study, we evaluated new
      immunoassay methods for the measurement of these analytes for potential drug
      based interference. METHODS: Urine samples collected from patients on a variety
      of medications were grouped by specific drug type. The significance of any
      difference in the free catecholamine or total metanephrine concentrations in the
      different groups was assessed by one-way ANOVA. A group of patients receiving no
      medication was included as a control (no analytical interference). Additionally,
      analytical accuracy, detection limit, and precision were determined. RESULTS: No
      significant differences were found in the concentrations of free catecholamines
      or total metanephrines in urine from patients taking the medications investigated
      and the control group: P = 0.649 (fE), 0.221 (fNE), 0.149 (tM), and 0.170 (tNM).
      For free catecholamines, intraassay CVs were 4.6-18%; interassay CVs were 10-25%.
      For total metanephrines, intraassay CVs were 9.6-27%; interassay CVs were 5. 8
      22%. Detection limits were 0.009 and 0.027 micromol/L for fE and fNE and 0.119
      and 0.346 micromol/L for tM and tNM, respectively. CONCLUSIONS: None of the drugs
      examined in this study interfered in the measurement of free catecholamines or
      total metanephrines by these immunoassays. The technique is easier to use,
      requires less equipment, and is more accessible than HPLC. In combination, these
      assays are suitable as initial screening tests for pheochromocytoma.

PMID- 10585356
TI  - New method for determining cystine in leukocytes and fibroblasts.
AB  - BACKGROUND: Cystinosis is a rare inborn error of cystine transport, leading to
      accumulation of cystine in the lysosomes. To diagnose cystinosis and monitor
      treatment with cysteamine, adequate measurements of cystine concentrations in
      leukocytes and cultured fibroblasts are required. METHODS: Cells were sonicated
      in the presence of excess N-ethylmaleimide to prevent oxidation of cysteine to
      cystine and disulfide exchange reactions of cystine with available sulfhydryl
      moieties. Cystine was measured as cysteine after reduction with sodium
      borohydride and derivatization with monobromobimane, followed by separation with
      automated HPLC and fluorescence detection. RESULTS: The assay was linear to 200
      micromol/L cysteine. Within-run and day-to-day (total) imprecision (CV) was <5%,
      and the detection limit was 0.3 micromol/L. Added cysteine, up to 200 micromol/L,
      was completely removed, and recovery of added cystine was 69-86%. Cystine was
      stable for at least 2 months in leukocytes frozen in liquid nitrogen and stored
      at -80 degrees C CONCLUSIONS: Oxidation of cysteine to cystine and disulfide
      exchange reactions of cystine with sulfhydryl moieties are prevented by N
      ethylmaleimide. The detection limit for the determination of cystine is adequate
      to measure cystine in leukocytes and cultured fibroblasts for diagnosis of
      cystinosis and monitoring treatment with cysteamine.

PMID- 10585357
TI  - Evaluation of filter paper blood lead methods: results of a pilot proficiency
      testing program.
AB  - BACKGROUND: Lead testing on dried filter paper (FP) blood spots is used routinely
      by some laboratories for lead poisoning screening. Proficiency testing (PT) as
      required under CLIA '88 laboratory regulations has not been available for these
      methods. METHODS: We describe a suitable PT scheme and evaluate FP laboratory
      performance based on program results. Monthly testing events consisting of five
      FP specimens were provided to six participating laboratories. Results were
      evaluated against target values determined by referee laboratories. RESULTS:
      Preliminary FP laboratory results showed poor agreement with specimen target
      values, exhibiting a mean absolute bias of 0.29 micromol/L (5.9 microg/dL). Five
      of six participating laboratories demonstrated significant improvement in later
      testing events, with bias decreasing to 0.12 micromol/L (2.5 microg/dL).
      Performance varied widely between the participating laboratories and appeared to
      be method dependent. When evaluated using CLIA blood lead acceptability criteria,
      the proportion of acceptable individual specimen results (n = 35) ranged from 54%
      to 100%. On a testing event basis (n = 7), the proportion of acceptable events
      ranged from 29% to 100%. CONCLUSIONS: A suitable FP PT program now exists to
      capably assist and monitor FP laboratories. Based on overt PT results, properly
      utilized FP testing methods can accurately measure blood lead concentration.

PMID- 10585358
TI  - Comparison of serum and plasma methylmalonic acid measurements in 13
      laboratories: An international study.
AB  - BACKGROUND: Detection of cobalamin deficiency is increasingly important, and
      methylmalonic acid (MMA) appears to be a useful marker. Information on
      interlaboratory variation and on methodological differences for MMA in serum and
      plasma is limited. METHODS: Using gas chromatography/mass spectrometry, 13
      laboratories participated in a 2-day analysis of 8 serum and 11 EDTA-plasma
      specimens. Results were analyzed for imprecision, recovery, and differences among
      laboratories and methods. RESULTS: The mean among-laboratory imprecision (CV) was
      19% and 21% for serum and plasma samples, respectively, and 9.3% and 7.8% for
      serum and plasma samples with added MMA, respectively. The mean within-laboratory
      (among-run) CV was 13% for both serum and plasma samples and 5.2% and 4.9% for
      serum and plasma samples with added MMA. Within-method imprecision was the same
      or higher than among-method imprecision. The mean among-laboratory recovery of
      MMA was 105% and 95% in serum and plasma, respectively. Most laboratories showed
      a proportional bias relative to the consensus mean of up to 15%. Two laboratories
      reported results that on average were almost 30% higher than the consensus mean.
      CONCLUSIONS: No method differences were found, but significant among-laboratory
      imprecision was found in the present study. Improvements are needed to reduce the
      analytical imprecision of most laboratories, and attention must be focused on
      calibration issues. Differences among laboratories can be improved by introducing
      high-quality reference materials and by instituting external quality assessment
      programs.

PMID- 10585359
TI  - Changes in plasma cystatin C after renal transplantation and acute rejection in
      adults.
AB  - BACKGROUND: Cystatin C has recently been proposed as an alternative marker of
      glomerular filtration rate. The diagnostic value of plasma cystatin C for the
      longitudinal assessment of kidney function after renal transplantation, however,
      has not been addressed. METHODS: Renal function was evaluated in 30 adults
      receiving renal transplants (46 +/- 9 years, mean +/- SD) and in 56 healthy
      controls (38 +/- 10 years) using cystatin C. Plasma cystatin C was determined
      daily starting the day of surgery and for 3 weeks after surgery by an
      immunonephelometric assay. RESULTS: Plasma concentration significantly decreased
      during the first week (-44% vs -29% for creatinine). Plasma cystatin C correlated
      with plasma creatinine (r = 0.741; P <0.0001) and the reciprocal of the
      creatinine clearance estimated by the Cockcroft-Gault formula (r = 0.882; P
      <0.001). In all three cases of acute renal impairment, the increase in plasma
      cystatin C values was more prominent than that of creatinine. CONCLUSIONS: Plasma
      cystatin C is an alternative and accurate marker of allograft function in adult
      transplant patients. Increased sensitivity compared with creatinine for the
      detection of acute reduction in glomerular filtration rate allows in some cases a
      more rapid diagnosis of acute rejection or treatment nephrotoxicity.

PMID- 10585360
TI  - Thyroid function during pregnancy.
AB  - BACKGROUND: This Case Conference reviews the normal changes in thyroid activity
      that occur during pregnancy and the proper use of laboratory tests for the
      diagnosis of thyroid dysfunction in the pregnant patient. CASE: A woman in the
      18th week of pregnancy presented with tachycardia, increased blood pressure,
      severe vomiting, increased total and free thyroid hormone concentrations, a
      thyroid-stimulating hormone (TSH) concentration within the reference interval,
      and an increased human chorionic gonadotropin (hCG) beta-subunit concentration.
      ISSUES: During pregnancy, normal thyroid activity undergoes significant changes,
      including a two- to threefold increase in thyroxine-binding globulin
      concentrations, a 30-100% increase in total triiodothyronine and thyroxine
      concentrations, increased serum thyroglobulin, and increased renal iodide
      clearance. Furthermore, hCG has mild thyroid stimulating activity. Pregnancy
      produces an overall increase in thyroid activity, which allows the healthy
      individual to remain in a net euthyroid state. However, both hyper- and
      hypothyroidism can occur in pregnant patients. In addition, two pregnancy
      specific conditions, hyperemesis gravidarum and gestational trophoblastic
      disease, can lead to clinical hyperthyroidism. The normal changes in thyroid
      activity and the association of pregnancy with conditions that can cause
      hyperthyroidism necessitates careful interpretation of thyroid function tests
      during pregnancy. CONCLUSION: Assessment of thyroid function during pregnancy
      should be done with a careful clinical evaluation of the patient's symptoms as
      well as measurement of TSH and free, not total, thyroid hormones. Measurement of
      thyroid autoantibodies may also be useful in selected cases to detect maternal
      Graves disease or Hashimoto thyroiditis and to assess risk of fetal or neonatal
      consequences of maternal thyroid dysfunction.

PMID- 10585361
TI  - Turner syndrome and multiple-marker screening.

PMID- 10585362
TI  - What happens to vitamin K(1) in serum after bone fracture?

PMID- 10585363
TI  - Molecular forms and ultrastructural localization of prostate-specific antigen in
      nipple aspirate fluids.

PMID- 10585364
TI  - Comparison of immunoreactivity of five human cardiac troponin I assays toward
      free and complexed forms of the antigen: implications for assay discordance.

PMID- 10585365
TI  - Glutamic acid decarboxylase antibodies in screening for autoimmune diabetes:
      influence of comorbidity, age, and sex on specificity and threshold values.

PMID- 10585366
TI  - Frequencies of defective CYP2C19 alleles in a Hong Kong Chinese population:
      detection of the rare allele CYP2C19*4.

PMID- 10585367
TI  - LightCycler PCR assay for simultaneous detection of the H63D and S65C mutations
      in the HFE hemochromatosis gene based on opposite melting temperature shifts.

PMID- 10585368
TI  - Analytical performance of microparticle enzyme immunoassay and HPLC-tandem mass
      spectrometry in the determination of sirolimus in whole blood.

PMID- 10585369
TI  - Enzymatic assay of calcium in serum with phospholipase D.

PMID- 10585370
TI  - Reference interval computation using robust vs parametric and nonparametric
      analyses.

PMID- 10585371
TI  - Measurement of thyroid-stimulating hormone receptor autoantibodies by ELISA.

PMID- 10585372
TI  - Evaluation of an automated enzyme inhibition assay for the detection of anti
      mitochondrial M2 autoantibodies.

PMID- 10585374
TI  - Interference of Luteinizing Hormone beta-Core Fragment in Urinary Gonadotropin
      Assays.

PMID- 10585373
TI  - Interference of luteinizing hormone beta-core fragment in urinary gonadotropin
      assays.

PMID- 10585375
TI  - Fetal urine cystatin C as a predictor of postnatal renal function in bilateral
      uropathies.

PMID- 10585376
TI  - Antibody selection for the Abbott AxSYM troponin I assay.

PMID- 10585377
TI  - Mesna and other free-sulfhydryl compounds produce false-positive results in a
      urine test strip method for ascorbic acid.

PMID- 10585378
TI  - Troponin I, troponin T, and creatine kinase-MB mass in patients with the
      carcinoid syndrome with and without heart failure.

PMID- 10585379
TI  - Getting past the statistical referee: moving away from P-values and towards
      interval estimation.

PMID- 10585380
TI  - What do mothers feed their children and why?
AB  - Health education interventions aimed at changing children's diets often target
      their mothers. However, little is known about what factors influence mothers'
      food choice for themselves and how this is related to their choice of food for
      their children. The present study aimed to examine the types of foods mothers eat
      themselves and their motivations for doing so in comparison with their choices
      for their primary school age children. In addition, the study aimed to assess
      whether the mother's dieting behaviour affected these differences. A
      questionnaire was completed by 218 (response rate 52%) mothers of children aged
      between 5 and 11 asking them about their behaviour and motivations for themselves
      and on behalf of their children. The results showed that mothers tend to feed
      their children in a less healthy way than they feed themselves. Specifically,
      they feed their children more sweet products, and more unhealthy breads and dairy
      products. However, whereas they are motivated more by practicality (e.g.
      availability, cost) and calories when choosing food for themselves, they state
      that health (e.g. nutritional value, long-term health) is more important when
      choosing for their children. In terms of the role of the mothers' dieting
      behaviour, dieters appeared to be more self-prioritizing than non-dieters in
      their differentiation between themselves and their children. The results are
      discussed in terms of the role of knowledge and cognitions in explaining the gaps
      between motivations and behaviour and the mothers' decisions for themselves and
      for their children. In addition, the implications for interventions are
      considered. In particular, it is suggested that changing a mother's own
      motivations and behaviour may not necessarily result in an improvement in their
      child's diet. Further, encouraging mothers to diet may be detrimental to their
      children's long-term health.

PMID- 10585381
TI  - Young people's understanding of mental illness.
AB  - Research exploring young people's perspectives on mental health is at an early
      stage of development and few studies have focused in detail on mental distress or
      illness. This paper reports findings from a qualitative study which used case
      vignettes in group and individual interviews to explore the ways in which the
      young people who took part constructed their understanding of what constitutes
      mental illness. In essence, they did so by drawing on their own experiences to
      distinguish between behaviours with which they could identify in some way and
      those with which they could not. An overview of previous relevant research is
      provided in the Introduction, followed by a description of the methods and
      sampling strategies used. The main findings of the study are then presented in
      relation to the ways in which young people defined unusual behaviour, their
      understanding of the behaviours associated with different mental health problems
      and their attitudes to the people concerned. Finally, some ways in which health
      promotion might build on the findings are identified and discussed.

PMID- 10585383
TI  - Attitudes toward anti-tobacco policy among California youth: associations with
      smoking status, psychosocial variables and advocacy actions.
AB  - To prevent smoking and exposure to environmental tobacco smoke, California has
      implemented anti-tobacco policies, including laws restricting youth access to
      tobacco, and smoking bans in workplaces, schools, restaurants and bars. Although
      studies have examined adults' attitudes toward anti-tobacco policies, little is
      known about adolescents' awareness of and support for these policies. This study
      examined attitudes toward anti-tobacco policies in a sample of 6887 10th grade
      California adolescents. Awareness of anti-tobacco policies was highest among
      current smokers and lowest among susceptible never-smokers. Support for anti
      tobacco policies was highest among non-susceptible never-smokers and lowest among
      current smokers. Policy awareness and support were significantly associated with
      psychosocial tobacco-related variables (e.g. perceived consequences of smoking,
      friends' smoking, perceived access to cigarettes, prevalence estimates of smoking
      among peers, cigarette offers and cigarette refusal self-efficacy). Policy
      awareness and support were associated with the probability of performing advocacy
      actions against tobacco use. Although these results cannot prove a causal
      association, they suggest that adolescents' attitudes toward anti-tobacco
      policies may play a role in their decisions about smoking. Tobacco control and
      education programs should include information about existing anti-tobacco
      policies, and should educate youth about the importance and benefits of anti
      tobacco policies.

PMID- 10585382
TI  - Exploring young people's difficulties in talking about contraception: how can we
      encourage more discussion between partners?
AB  - Interviews were conducted with 56 young men and women aged 16-19 within the
      Southampton Community Health NHS Trust to explore difficulties in talking about
      contraception. Concern about a partner's hostile or negative reaction to any
      discussion about contraception was central to explaining why some people found it
      so difficult to initiate such discussions. Admitting the intention to have
      intercourse, together with a perceived association between condom use and disease
      prevention, were the main concerns. There was some indication of gender
      differences in these findings. Furthermore, this negative reaction is perceived
      to be exacerbated according to the partner's reputation, the potential for
      harming one's own reputation and whether there is a desire for a longer-term
      relationship with this partner. The most important outcome of the interviews was
      that these concerns about a partner's negative reaction were largely unjustified,
      with the vast majority of participants showing only positive responses to
      scenarios of future partners initiating discussions with them about
      contraception. In addition to the need to improve communication skills, the data
      suggest that greater awareness about the positive reactions towards such
      discussions should be encouraged.

PMID- 10585384
TI  - Associations between parent awareness, monitoring, enforcement and adolescent
      involvement with alcohol.
AB  - In a statewide random telephone survey of 454 parents and their 14- to 19-year
      old adolescents, we examined the associations between various parenting
      strategies and self-reported teen drinking. Less teen drinking was associated
      with parents' reports of checking to see if other parents would be present at
      teen parties, particularly among White parents. Parents' monitoring of teens'
      activities was associated with feelings of competence at doing so. There was,
      however, no difference in drinking between teens with parents who did or did not
      report restricting their teens due to teen misbehavior. These findings suggest
      that a proactive parental monitoring approach may be associated with less
      adolescent drinking. Prospective research is needed to clarify the causal
      relationship between parental monitoring, efficacy and teen alcohol-related
      behavior.

PMID- 10585385
TI  - Communication strategies for dietary change in a worksite peer educator
      intervention.
AB  - At the heart of peer health education programs is the assumption that tapping
      social networks increases adoption of behavior change, yet the communication
      strategies used by peer educators have not been previously documented to assess
      the use of social networks in promotion of health messages. Our program in public
      worksites trained peer health educators to utilize their social networks along
      with individual persuasive strategies to promote the 5 a Day for Better Health
      message (i.e. eat five or more servings of fruits and vegetables every day).
      Communication strategies utilized by the peer health educators were tracked via
      monthly focus groups over a 9 month intervention in 40 social networks of labor
      and trades employees. Audiotapes were transcribed and content analyzed to
      identify 10 communication strategies used by peer educators. Strategies were
      rated as enacted in an individual or a group (collective) context. Peer health
      educators were more likely to implement 'creating context' and 'role modeling' as
      group context change strategies, and 'encouragement' and 'responding to employee
      needs' as individual change strategies. Strategies used most frequently by males
      were 'mock competition', 'giving materials' and 'encouragement', while females
      used 'creating context' and 'keeping 5 a Day visible' most frequently. Hispanic
      peer health educators were more likely to use individual change strategies than
      their non-Hispanic counterparts. Documentation of the creative approaches
      utilized by lay educators among their peers can inform public health
      professionals on (1) how to better train outreach workers within various
      cultural, gender and social contexts, and (2) how to maximize social network
      effects.

PMID- 10585386
TI  - Effectiveness of a social influence approach and boosters to smoking prevention.
AB  - This paper presents the short-term and long-term results of a randomized smoking
      prevention trial. The purpose was to evaluate two smoking prevention programs, a
      social influence (SI) program and a SI program with an additional decision-making
      component (SI(DM)). Moreover, the contribution of boosters was assessed as well.
      Fifty-two schools were randomly assigned to the SI program, the SI(DM) program or
      a control group. Half of the treatment schools were randomly assigned to the
      booster condition; the other half did not receive boosters. Both programs
      consisted of five lessons, each lasting 45 min, and were given in weekly sessions
      in grades 8 and 9 of high schools in the Netherlands. The most successful program
      was the SI program with boosters which resulted in a significantly lower increase
      in smoking rates (5.6 and 9.7%, respectively) compared to the control group (12.6
      and 14.9%, respectively) at both 12 and 18 months follow-up. The results suggest
      that boosters can be an effective tool for maintaining or increasing the
      effectiveness of smoking prevention programs. It is recommended that the SI
      program with the booster be implemented at the national level, since this
      intervention showed the greatest behavioral effects.

PMID- 10585387
TI  - The efficacy of accumulated short bouts versus single daily bouts of brisk
      walking in improving aerobic fitness and blood lipid profiles.
AB  - Fifty-six subjects (19 men and 37 woman) aged between 40 and 66 completed the
      study. They were allocated into three walking groups and a control group (C). The
      three walking groups performed the same total amount of walking for 18 weeks, but
      completed it in bouts of differing durations and frequencies. These were Long
      Walkers (LW; 20-40 min/bout), Intermediate Walkers (IW; 10-15 min/bout) and Short
      Walkers (SW; 5-10 min/bout); with the IW and SW performing more than one bout of
      walking a day. Following the 18 week walking programme, compared to the C group
      all walking groups showed similar improvements in fitness as determined by a
      reduction in blood lactate during a graded treadmill walking test (LW 1.0 mmol/l;
      IW 0. 8 mmol/l; SW 1.2 mmol/l; C 0.2 mmol/l; P = 0.003) and reduction in final
      heart rate (LW 8 beats/min; IW 6 beats/min; SW 10 beats/min; C 0 beats/min; P =
      0.056). Also compared to the C group, the LW and IW groups recorded statistically
      significant decreases in low-density lipoprotein cholesterol (LW 0.29 mmol/l; IW
      0.41 mmol/l; P = 0.024), whereas the control group showed a mean increase of 0.22
      mmol/l. The LW and IW groups also showed significant reductions in apolipoprotein
      (apo) A-II (LW 0.05 g/l; IW 0.02 g/l; SW 0.01 g/l; C 0.00 g/l; P = 0.012) with
      the LW recording a statistically significant increase in the ratio of apo A-I/A
      II (LW, 0.19, P = 0. 044). In conclusion, some health benefits were achieved from
      all walking programmes. However, whilst the changes in aerobic fitness were
      similar, the effects upon blood lipid profiles were not. The findings from this
      study suggest that the LW regimen was most effective in benefiting blood lipid
      profile, followed by the IW regimen, with the SW being least potent.
      Nevertheless, for the sedentary/low-active members of society, any improvement in
      health may be considered as important. Therefore accumulated bouts of moderate
      intensity exercise, which according to theories of exercise behaviour may be more
      easily incorporated into an individual's lifestyle than single prolonged bouts,
      may be advocated for health promotion but may not be as effective as the
      traditionally prescribed 20-40 min bouts.

PMID- 10585388
TI  - Effects of an educational programme on adolescents with premenstrual syndrome.
AB  - An education program was developed and evaluated to determine its efficacy in
      increasing knowledge and decreasing the severity of symptoms of premenstrual
      syndrome (PMS). Participants from a sample of 94 schoolgirls aged between 14 and
      18 years from four secondary schools in Hong Kong were assigned to either the
      experimental or control group. Immediately following the education program, the
      schoolgirls in the experimental group had significantly increased knowledge
      scores as measured by the Premenstrual Syndrome Knowledge Questionnaire. Three
      months following the education program, schoolgirls in the experimental group
      reported having a significant reduction in total PMS scores and three of the
      subscale scores as measured by a translated version of Abraham's Menstrual
      Symptom Questionnaire. In addition, no significant differences were found for the
      control group on pre-test and post-test PMS scores suggesting that the education
      program could have been the source of the reduction in PMS symptoms of the
      experimental group of young adolescents girls.

PMID- 10585389
TI  - Biogenesis of mitochondrial inner membrane proteins.

PMID- 10585390
TI  - Modifying human thymidylate kinase to potentiate azidothymidine activation.
AB  - Based on the knowledge of the crystal structures of yeast and Escherichia coli
      thymidylate kinases (TmpKs) and the observation that TmpK from E. coli can
      phosphorylate azidothymidine monophosphate (AZT-MP) much more efficiently than
      either the yeast or the highly homologous human enzyme, we have engineered yeast
      and human TmpKs to obtain enzymes that have dramatically improved AZT-MP
      phosphorylation properties. These modified enzymes have properties that make them
      attractive candidates for gene therapeutic approaches to potentiating the action
      of AZT as an inhibitor of human immunodeficiency virus (HIV) replication. In
      particular, insertion of the lid domain of the bacterial TmpK into the human
      enzyme results in a pronounced change of the acceptance of AZT-MP such that it is
      now phosphorylated even faster than TMP.

PMID- 10585391
TI  - Formation of peroxisomes from peroxisomal ghosts in a peroxisome-deficient
      mammalian cell mutant upon complementation by protein microinjection.
AB  - Most mammalian cell strains genetically deficient in peroxisome biogenesis have
      abnormal membrane structures called ghosts, containing integral peroxisomal
      membrane protein, PMP70, but lacking the peroxisomal matrix proteins. Upon
      genetic complementation, these mutants regain the ability of peroxisome
      biogenesis. It is postulated that, in this process, the ghosts act as the
      precursors of peroxisomes, but there has been no evidence to support this. In the
      present study, we investigated this issue by protein microinjection to a mutant
      Chinese hamster ovary cell line defective of PEX5, encoding a peroxisome
      targeting signal receptor. When recombinant Pex5p and green fluorescent protein
      (GFP) carrying a peroxisome-targeting signal were co-injected into the mutant
      cells, the GFP fluorescence gathered over time to particulate structures where
      PMP70 was co-localized. This process was dependent on both Pex5p and the
      targeting signal, and, most importantly, occurred even in the presence of
      cycloheximide, a protein synthesis inhibitor. These findings suggest that the
      ghosts act as acceptors of matrix proteins in the peroxisome recovery process at
      least in the PEX5 mutant, and support the view that peroxisomes can grow by
      incorporating newly synthesized matrix proteins.

PMID- 10585392
TI  - COP9 signalosome-directed c-Jun activation/stabilization is independent of JNK.
AB  - The basic region-leucine zipper transcription factor c-Jun regulates gene
      expression and cell function. It participates in the formation of homo- or
      heterodimeric complexes that specifically bind to DNA sequences called activating
      protein 1 (AP-1) sites. The stability and activity of c-Jun is regulated by
      phosphorylation within the N-terminal activation domain. Mitogen- and stress
      activated c-Jun N-terminal kinases (JNKs) were previously the only described
      enzymes phosphorylating c-Jun at the N terminus in vivo. In this report we
      demonstrate a JNK-independent activation of c-Jun in vivo directed by the
      constitutive photomorphogenesis (COP9) signalosome. The overexpression of
      signalosome subunit 2 (Sgn2), a subunit of the COP9 signalosome, leads to de novo
      assembly of the complex with a partial incorporation of the overexpressed
      subunit. The de novo formation of COP9 signalosome parallels an increase of c-Jun
      protein resulting in elevated AP-1 transcriptional activity. The c-Jun activation
      caused by Sgn2 overexpression is independent of JNK and mitogen-activated protein
      kinase kinase 4. The data demonstrate the existence of a novel COP9 signalosome
      directed c-Jun activation pathway.

PMID- 10585393
TI  - Dynamin is required for the activation of mitogen-activated protein (MAP) kinase
      by MAP kinase kinase.
AB  - Internalization of activated receptors from the plasma membrane has been
      implicated in the activation of mitogen-activated protein (MAP) kinase. However,
      the mechanism whereby membrane trafficking may regulate mitogenic signaling
      remains unclear. Here we report that dominant-negative dynamin (K44A), an
      inhibitor of endocytic vesicle formation, abrogates MAP kinase activation in
      response to epidermal growth factor, lysophosphatidic acid, and protein kinase C
      activating phorbol ester. In contrast, dynamin-K44A does not affect the
      activation of Ras, Raf, and MAP kinase kinase (MEK) by either agonist. Through
      immunofluorescence and subcellular fractionation studies, we find that activated
      MEK is present both at the plasma membrane and in intracellular vesicles but not
      in the cytosol. Our findings suggest that dynamin-regulated endocytosis of
      activated MEK, rather than activated receptors, is a critical event in the MAP
      kinase activation cascade.

PMID- 10585394
TI  - A G protein gamma subunit-specific peptide inhibits muscarinic receptor
      signaling.
AB  - Muscarinic acetylcholine receptors modulate the function of a variety of
      effectors through heterotrimeric G proteins. A prenylated peptide specific to the
      G protein gamma5 subunit type inhibits G protein activation by the M2 muscarinic
      receptor in a reconstitution assay. Scrambling the amino acid sequence of the
      peptide significantly reduces the efficacy of the peptide. The peptide does not
      disrupt the G protein heterotrimer. In cultured sympathetic neurons, the gamma5
      peptide inhibits modulation of Ca(2+) current by the M4 receptor. Peptide
      activity is specific, the scrambled peptide and peptides specific to two other
      members of the G protein gamma subunit family are significantly less effective.
      The gamma5 peptide has no effect on Ca(2+) current modulation by the alpha2
      adrenergic and somatostatin receptors. In addition, the gamma5 peptide inhibits
      muscarinic receptor signaling in spinal cord slices with specificity. These
      results support a specific role for G protein gamma subunit types in signal
      transduction, most likely at the receptor-G protein interface.

PMID- 10585395
TI  - Cullin 4A associates with the UV-damaged DNA-binding protein DDB.
AB  - The damaged DNA-binding protein (DDB) is believed to be involved in DNA repair,
      and it has been linked to the repair deficiency disease xeroderma pigmentosum.
      DDB also exhibits transcriptional activities. DDB binds to the activation domain
      of E2F1 and stimulates E2F1-activated transcription. Here we provide evidence
      that DDB or DDB-associated proteins are targets of cullin 4A (CUL-4A). CUL-4A is
      a member of the cullin family of proteins, which are believed to be ubiquitin
      protein isopeptide ligases (type E3). The CUL-4A gene has been shown to be
      amplified and up-regulated in breast carcinomas. In this study, we identify CUL
      4A as one of the DDB-associated proteins. CUL-4A co-immunoprecipitates with DDB,
      but not with a naturally occurring mutant of DDB. Moreover, CUL-4A in HeLa
      nuclear extracts co-purifies with DDB, suggesting they are parts of the same
      complex. The observation provides insights how CUL-4A, through an interaction
      with DDB, might be playing a role in the development of breast carcinomas.

PMID- 10585396
TI  - Molecular model, calcium sensitivity, and disease specificity of a conformational
      thyroperoxidase B-cell epitope.
AB  - While studying the humoral mechanisms involved in thyroid autoimmunity, we
      located a B-cell autoepitope in the extracellular C-terminal region of human
      thyroperoxidase. Structural modeling showed that this region encompasses both a
      Sushi-like and an epidermal growth factor-like domain, the flexible arrangement
      of which was putatively stabilized by calcium. The recombinant peptide was found
      to contain the previously identified conformational thyroperoxidase autoepitope.
      The occurrence of a calcium-induced conformational change was confirmed using a
      recombinant peptide monoclonal antibody, the decrease of which in binding to
      calcium-saturated thyroperoxidase was reversed by a chelating agent. The disease
      specificity of recombinant peptide, which was more frequently recognized by
      Hashimoto's than by Graves' patients, adds to its potential value as a diagnostic
      and preventive tool in the context of B-cell autoimmunity.

PMID- 10585397
TI  - Ca(2+) entry activated by S-nitrosylation. Relationship to store-operated ca(2+)
      entry.
AB  - The coupling between Ca(2+) pools and store-operated Ca(2+) entry channels (SOCs)
      remains an unresolved question. Recently, we revealed that Ca(2+) entry could be
      activated in response to S-nitrosylation and that this process was stimulated by
      Ca(2+) pool emptying (Favre, C. J., Ufret-Vincenty, C. A., Stone, M. R., Ma, H-T.
      , and Gill, D. L. (1998) J. Biol. Chem. 273, 30855-30858). In DDT(1)MF-2 smooth
      muscle cells and DC-3F fibroblasts, Ca(2+) entry activated by the lipophilic NO
      donor, GEA3162 (5-amino-3-(3, 4-dichlorophenyl)1,2,3,4-oxatriazolium), or the
      alkylator, N-ethylmaleimide, was observed to be strongly activated by transient
      external Ca(2+) removal, closely resembling activation of SOC activity in the
      same cells. The nonadditivity of SOC and NO donor-activated Ca(2+) entry
      suggested a single entry mechanism. Calyculin A-induced reorganization of the
      actin cytoskeleton prevented SOC but had no effect on GEA3162-induced Ca(2+)
      entry. However, a single entry mechanism could account for both SOC and NO donor
      activated entry if the latter reflected direct modification of the entry channel
      by S-nitrosylation, bypassing the normal coupling process between channels and
      pools. Small differences between SOC and GEA3162-activated Ba(2+) entry and
      sensitivity to blockade by La(3+) were observed, and in HEK293 cells SOC activity
      was observed without a response to thiol modification. It is concluded that in
      some cells, S-nitrosylation modifies an entry mechanism closely related to SOC
      and/or part of the regulatory machinery for SOC-mediated Ca(2+) entry.

PMID- 10585398
TI  - The adipocyte fatty acid-binding protein binds to membranes by electrostatic
      interactions.
AB  - The adipocyte fatty acid-binding protein (AFABP) is believed to transfer
      unesterified fatty acids (FA) to phospholipid membranes via a collisional
      mechanism that involves ionic interactions between lysine residues on the protein
      surface and phospholipid headgroups. This hypothesis is derived largely from
      kinetic analysis of FA transfer from AFABP to membranes. In this study, we
      examined directly the binding of AFABP to large unilamellar vesicles (LUV) of
      differing phospholipid compositions. AFABP bound LUV containing either
      cardiolipin or phosphatidic acid, and the amount of protein bound depended upon
      the mol % anionic phospholipid. The K(a) for CL or PA in LUV containing 25 mol %
      of these anionic phospholipids was approximately 2 x 10(3) M(-1). No detectable
      binding occurred when AFABP was mixed with zwitterionic membranes, nor when
      acetylated AFABP in which surface lysines had been chemically neutralized was
      mixed with anionic membranes. The binding of AFABP to acidic membranes depended
      upon the ionic strength of the incubation buffer: >/=200 mM NaCl reduced protein
      lipid complex formation in parallel with a decrease in the rate of FA transfer
      from AFABP to negatively charged membranes. It was further found that AFABP, but
      not acetylated AFABP, prevented cytochrome c, a well characterized peripheral
      membrane protein, from binding to membranes. These results directly demonstrate
      that AFABP binds to anionic phospholipid membranes and suggest that, although
      generally described as a cytosolic protein, AFABP may behave as a peripheral
      membrane protein to help target fatty acids to and/or from intracellular sites of
      utilization.

PMID- 10585399
TI  - STAT5b-deficient mice are growth hormone pulse-resistant. Role of STAT5b in sex
      specific liver p450 expression.
AB  - The signal transducer and transcriptional activator STAT5b is required to
      maintain the adult male pattern of liver gene expression and whole body pubertal
      growth rates, as demonstrated by the loss of these growth hormone (GH) pulse
      dependent responses in mice with a targeted disruption of the STAT5b gene. The
      present study investigates whether these phenotypes of STAT5b-deficient mice
      result from impaired intracellular GH signaling associated with a loss of GH
      pulse responsiveness, as contrasted with a feminization of the pituitary GH
      secretory profile leading to the observed feminization of body growth and liver
      gene expression. Pulsatile GH replacement in hypophysectomized mice stimulated
      body weight gain in wild-type but not in STAT5b-deficient mice. Expression of the
      male-specific liver P450 enzyme CYP2D9, which is reduced to female levels in
      hypophysectomized male mice, was restored to male levels by GH pulse replacement
      in wild-type but not in STAT5b-deficient mice. Similarly, a female-specific liver
      CYP2B P450 enzyme that was up-regulated to female levels following hypophysectomy
      of males was suppressed to normal basal male levels by GH pulses only in wild
      type hypophysectomized mice. Finally, urinary excretion of the male-specific, GH
      pulse-induced major urinary protein was restored to normal male levels following
      pulsatile GH treatment only in the case of wild-type hypophysectomized mice.
      STAT5b-deficient mice are thus GH pulse-resistant, supporting the proposed role
      of STAT5b as a key intracellular mediator of the stimulatory effects of plasma GH
      pulses on the male pattern of liver gene expression.

PMID- 10585400
TI  - Binding of nucleotides to guanylate kinase, p21(ras), and nucleoside-diphosphate
      kinase studied by nano-electrospray mass spectrometry.
AB  - The binding of nucleotides to three different nucleotide-binding proteins and to
      a control protein was studied by means of nano-electrospray mass spectrometry
      applied to aqueous nondenaturing solutions. The method leads to unambiguous
      identification of enzyme complexes with substrates and products but does not
      allow the determination of dissociation constants or even stoichiometries
      relevant to the binding in solution. For guanylate kinase (EC 2.7.4. 8), the
      transfer of HPO(3) between nucleotides was observed whenever a ternary complex
      with adenylate or guanylate nucleotides was formed. Guanosine 5'-tetraphosphate
      was generated after prolonged incubation with GDP or GTP. Mg(2+) binding was
      considerably enhanced in functional high affinity complexes, such as observed
      between guanylate kinase and its bisubstrate inhibitor P(1)-(5'-guanosyl)-P(5)
      (5'-adenosyl) pentaphosphate or with the tight nucleotide-binding protein
      p21(ras) and GDP. Nucleoside-diphosphate kinase (EC 2.7.4.6) itself was
      phosphorylated in accordance to its known ping-pong mechanism. All nucleotide
      binding proteins were shown to bind sulfate (SO(4)(2-)) with presumably high
      affinity and slow exchange rate. The binding of phosphate (PO(4)(3-)) could be
      inferred indirectly from competition with SO(4)(2-).

PMID- 10585401
TI  - Sphingosine 1-phosphate stimulates cell migration through a G(i)-coupled cell
      surface receptor. Potential involvement in angiogenesis.
AB  - Sphingosine 1-phosphate (SPP) has been shown to inhibit chemotaxis of a variety
      of cells, in some cases through intracellular actions, while in others through
      receptor-mediated effects. Surprisingly, we found that low concentrations of SPP
      (10-100 nM) increased chemotaxis of HEK293 cells overexpressing the G protein
      coupled SPP receptor EDG-1. In agreement with previous findings in human breast
      cancer cells (Wang, F., Nohara, K., Olivera, O., Thompson, E. W., and Spiegel, S.
      (1999) Exp. Cell Res. 247, 17-28), SPP, at micromolar concentrations, inhibited
      chemotaxis of both vector- and EDG-1-overexpressing HEK293 cells. Nanomolar
      concentrations of SPP also induced a marked increase in chemotaxis of human
      umbilical vein endothelial cells (HUVEC) and bovine aortic endothelial cells
      (BAEC), which express the SPP receptors EDG-1 and EDG-3, while higher
      concentrations of SPP were less effective. Treatment with pertussis toxin, which
      ADP-ribosylates and inactivates G(i)-coupled receptors, blocked SPP-induced
      chemotaxis. Checkerboard analysis indicated that SPP stimulates both chemotaxis
      and chemokinesis. Taken together, these data suggest that SPP stimulates cell
      migration by binding to EDG-1. Similar to SPP, sphinganine 1-phosphate (dihydro
      SPP), which also binds to this family of SPP receptors, enhanced chemotaxis;
      whereas, another structurally related lysophospholipid, lysophosphatidic acid,
      did not compete with SPP for binding nor did it have significant effects on
      chemotaxis of endothelial cells. Furthermore, SPP increased proliferation of
      HUVEC and BAEC in a pertussis toxin-sensitive manner. SPP and dihydro-SPP also
      stimulated tube formation of BAEC grown on collagen gels (in vitro angiogenesis),
      and potentiated tube formation induced by basic fibroblast growth factor.
      Pertussis toxin treatment blocked SPP-, but not bFGF-stimulated in vitro
      angiogenesis. Our results suggest that SPP may play a role in angiogenesis
      through binding to endothelial cell G(i)-coupled SPP receptors.

PMID- 10585402
TI  - Involvement of cysteine residues and domain interactions in the reversible
      unfolding of lipoxygenase-1.
AB  - Urea-induced unfolding of lipoxygenase-1 (LOX1) at pH 7.0 was followed by enzyme
      activity, spectroscopic measurements, and limited proteolysis experiments.
      Complete unfolding of LOX1 in 9 M urea in the presence of thiol reducing or thiol
      modifying reagents was observed. The aggregation and oxidative reactions
      prevented the reversible unfolding of the molecule. The loss of enzyme activity
      was much earlier than the structural loss of the molecule during the course of
      unfolding, with the midpoint concentrations being 4.5 and 7.0 M for activity and
      spectroscopic measurements, respectively. The equilibrium unfolding transition
      could be adequately fitted to a three-state, two-step model (N left arrow over
      right arrow I left arrow over right arrow U) and the intermediate fraction was
      maximally populated at 6.3 M urea. The free energy change (DeltaG(H(2)O)) for the
      unfolding of native (N) to intermediate (I) was 14.2 +/- 0.28 kcal/mol and for
      the intermediate to the unfolded state (U) was 11.9 +/- 0.12 kcal/mol. The ANS
      binding measurements as a function of urea concentration indicated that the
      maximum binding of ANS was in 6.3 M urea due to the exposure of hydrophobic
      groups; this intermediate showed significant amount of tertiary structure and
      retained nearly 60% of secondary structure. The limited proteolysis measurements
      showed that the initiation of unfolding was from the C-terminal domain. Thus, the
      stable intermediate observed could be the C-terminal domain unfolded with exposed
      hydrophobic domain-domain interface. Limited proteolysis experiments during
      refolding process suggested that the intermediate refolded prior to completely
      unfolded LOX1. These results confirmed the role of cysteine residues and domain
      domain interactions in the reversible unfolding of LOX1. This is the first report
      of the reversible unfolding of a very large monomeric, multi-domain protein,
      which also has a prosthetic group.

PMID- 10585403
TI  - gamma-cyclodextrins greatly enhance translocation of hydrophobic fluorescent
      phospholipids from vesicles to cells in culture. Importance of molecular
      hydrophobicity in phospholipid trafficking studies.
AB  - Short-chain, fluorescent derivatives are commonly used to investigate
      intracellular phospholipid trafficking. However, their use can yield misleading
      results because they, unlike the native species, can rapidly distribute between
      organelles due to their low hydrophobicity. On the other hand, hydrophobic
      derivatives are very difficult to introduce to cells and thus have hardly been
      used. Here we show that carboxyethylated gamma-cyclodextrin (CE-gamma-CD) greatly
      enhances transfer of a variety of hydrophobic fluorescent phospholipid
      derivatives from vesicles to cultured cells. Several lines of evidence indicate
      that CE-gamma-CD enhances transfer of lipid molecules by increasing their
      effective concentration in the aqueous phase, rather than by inducing membrane
      fusion or hemifusion. Incubation with CE-gamma-CD and donor lipid vesicles does
      not extract cholesterol or phospholipids from the cells or compromise plasma
      membrane intactness or long term cell viability. Using CE-gamma-CD-mediated
      transfer, we introduced hydrophobic pyrene-labeled phosphatidylserine to the
      plasma membrane of fibroblast cells and followed their distribution with time. In
      contrast to what has been previously observed for other, less hydrophobic
      species, transport of this lipid to the Golgi apparatus or mitochondria was not
      detected. Rather, much of this fluorescent PS remained in the plasma membrane or
      was incorporated to various endocytotic compartments. These findings indicate
      that the native, typically hydrophobic phosphatidylserine molecules efflux only
      very slowly via the cytoplasm to intracellular organelles. This helps to explain
      how cells can maintain a very high concentration of phosphatidylserine in the
      inner leaflet of their plasma membrane. Furthermore, the present results
      underline the importance of using hydrophobic analogues when studying
      intracellular trafficking of many phospholipid classes.

PMID- 10585404
TI  - The role of interfacial binding in the activation of Streptomyces chromofuscus
      phospholipase D by phosphatidic acid.
AB  - The Streptomyces chromofuscus phospholipase D (PLD) cleavage of
      phosphatidylcholine in bilayers can be enhanced by the addition of the product
      phosphatidic acid (PA). Other anionic lipids such as phosphatidylinositol, oleic
      acid, or phosphatidylmethanol do not activate this PLD. This allosteric
      activation by PA could involve a conformational change in the enzyme that alters
      PLD binding to phospholipid surfaces. To test this, the binding of intact PLD and
      proteolytically cleaved isoforms to styrene divinylbenzene beads coated with a
      phospholipid monolayer and to unilamellar vesicles was examined. The results
      indicate that intact PLD has a very high affinity for PA bilayers at pH >/= 7 in
      the presence of EGTA that is weakened as Ca(2+) or Ba(2+) are added to the
      system. Proteolytically clipped PLD also binds tightly to PA in the absence of
      metal ions. However, the isolated catalytic fragment has a considerably weaker
      affinity for PA surfaces. In contrast to PA surfaces, all PLD forms exhibited
      very low affinity for PC interfaces with an increased binding when Ba(2+) was
      added. All PLD forms also bound tightly to other anionic phospholipid surfaces
      (e.g. phosphatidylserine, phosphatidylinositol, and phosphatidylmethanol).
      However, this binding was not modulated in the same way by divalent cations.
      Chemical cross-linking studies suggested that a major effect of PLD binding to
      PA.Ca(2+) surfaces is aggregation of the enzyme. These results indicate that PLD
      partitioning to phospholipid surfaces and kinetic activation are two separate
      events and suggest that the Ca(2+) modulation of PA.PLD binding involves protein
      aggregation that may be the critical interaction for activation.

PMID- 10585405
TI  - Utrophin lacks the rod domain actin binding activity of dystrophin.
AB  - We previously identified a cluster of basic spectrin-like repeats in the
      dystrophin rod domain that binds F-actin through electrostatic interactions
      (Amann, K. J., Renley, B. A., and Ervasti, J. M. (1998) J. Biol. Chem. 273, 28419
      28423). Because of the importance of actin binding to the presumed physiological
      role of dystrophin, we sought to determine whether the autosomal homologue of
      dystrophin, utrophin, shared this rod domain actin binding activity. We therefore
      produced recombinant proteins representing the cluster of basic repeats of the
      dystrophin rod domain (DYSR11-17) or the homologous region of the utrophin rod
      domain (UTROR11-16). Although UTROR11-16 is 64% similar and 41% identical to
      DYSR11-17, UTROR11-16 (pI = 4. 86) lacks the basic character of the repeats found
      in DYSR11-17 (pI = 7.44). By circular dichroism, gel filtration, and
      sedimentation velocity analysis, we determined that each purified recombinant
      protein had adopted a stable, predominantly alpha-helical fold and existed as a
      highly soluble monomer. DYSR11-17 bound F-actin with an apparent K(d) of 7.3 +/-
      1.3 microM and a molar stoichiometry of 1:5. Significantly, UTROR11-16 failed to
      bind F-actin at concentrations as high as 100 microM. We present these findings
      as further support for the electrostatic nature of the interaction of the
      dystrophin rod domain with F-actin and suggest that utrophin interacts with the
      cytoskeleton in a manner distinct from dystrophin.

PMID- 10585406
TI  - The MEK pathway is required for stimulation of p21(WAF1/CIP1) by transforming
      growth factor-beta.
AB  - Transforming growth factor-beta (TGF-beta)can induce the cyclin-dependent kinase
      inhibitors p21 and p15 in a variety of cell types. We have shown previously that
      Smad3 is required for the growth inhibitory activity of TGF-beta, whereas
      overexpression of Smads is not sufficient to activate the expression of p21 in
      HaCaT cells. These data suggest that an additional signaling pathway may be
      involved in stimulating p21 in HaCaT cells. Given the recent finding that the
      mitogen-activated protein kinase (MAPK) pathway can cause p21 induction and
      arrest cells, we examined the involvement of this pathway for p21 and p15
      induction by TGF-beta. We found that TGF-beta can regulate the MAPK pathway,
      leading to the increased transactivation ability of transcription factor Elk.
      Constitutively active components in the MAPK pathway activate p21 expression, and
      inhibitors or dominant negative constructs for the MAPK pathway significantly
      decrease p21 induction by TGF-beta. Both constitutively active MEK and inhibitors
      for MEK have no effect on Smad activity, including DNA binding, localization, and
      interaction with coactivator p300/CBP. These findings suggest that the MAPK
      pathway may be an independent pathway that is involved in p21 and p15 induction
      by TGF-beta.

PMID- 10585407
TI  - Identification of residues in the drug-binding domain of human P-glycoprotein.
      Analysis of transmembrane segment 11 by cysteine-scanning mutagenesis and
      inhibition by dibromobimane.
AB  - The drug-binding domain of the human multidrug resistance P-glycoprotein (P-gp)
      probably consists of residues from multiple transmembrane (TM) segments. In this
      study, we tested whether the amino acids in TM11 participate in binding drug
      substrates. Each residue in TM11 was initially altered by site-directed
      mutagenesis and assayed for drug-stimulated ATPase activity in the presence of
      verapamil, vinblastine, or colchicine. Mutants G939V, F942A, T945A, Q946A, A947L,
      Y953A, A954L, and G955V had altered drug-stimulated ATPase activities. Direct
      evidence for binding of drug substrate was then determined by cysteine-scanning
      mutagenesis of the residues in TM11 and inhibition of drug-stimulated ATPase
      activity by dibromobimane, a thiol-reactive substrate. Dibromobimane inhibited
      the drug-stimulated ATPase activities of two mutants, F942C and T945C, by more
      than 75%. These results suggest that residues Phe(942) and Thr(945) in TM11,
      together with residues previously identified in TM6 (Leu(339) and Ala(342)) and
      TM12 (Leu(975), Val(982), and Ala(985)) (Loo, T. W., and Clarke, D. M. (1997) J.
      Biol. Chem. 272, 31945-31948) form part of the drug-binding domain of P-gp.

PMID- 10585408
TI  - Overexpression of phosphatidylinositol transfer protein alpha in NIH3T3 cells
      activates a phospholipase A.
AB  - In order to investigate the cellular function of the mammalian
      phosphatidylinositol transfer protein alpha (PI-TPalpha), NIH3T3 fibroblast cells
      were transfected with the cDNA encoding mouse PI-TPalpha. Two stable cell lines,
      i.e. SPI6 and SPI8, were isolated, which showed a 2- and 3-fold increase,
      respectively, in the level of PI-TPalpha. Overexpression of PI-TPalpha resulted
      in a decrease in the duration of the cell cycle from 21 h for the wild type
      (nontransfected) NIH3T3 (wtNIH3T3) cells and mock-transfected cells to 13-14 h
      for SPI6 and SPI8 cells. Analysis of exponentially growing cultures by
      fluorescence-activated cell sorting showed that a shorter G(1) phase is mainly
      responsible for this decrease. The saturation density of the cells increased from
      0.20 x 10(5) cells/cm(2) for wtNIH3T3 cells to 0.53 x 10(5) cells/cm(2) for SPI6
      and SPI8 cells. However, anchorage-dependent growth was maintained as shown by
      the inability of the cells to grow in soft agar. Upon equilibrium labeling of the
      cells with myo-[(3)H] inositol, the relative incorporation of radioactivity in
      the total inositol phosphate fraction was 2-3-fold increased in SPI6 and SPI8
      cells when compared with wtNIH3T3 cells. A detailed analysis of the inositol
      metabolites showed increased levels of glycerophosphoinositol, Ins(1)P, Ins(2)P,
      and lysophosphatidylinositol (lyso-PtdIns) in SPI8 cells, whereas the levels of
      phosphatidylinositol (PtdIns) and phosphatidylinositol 4, 5-bisphosphate were the
      same as those in control cells. The addition of PI-TPalpha to a total lysate of
      myo-[(3)H]inositol-labeled wtNIH3T3 cells stimulated the formation of lyso
      PtdIns. The addition of Ca(2+) further increased this formation. Based on these
      observations, we propose that PI-TPalpha is involved in the production of lyso
      PtdIns by activating a phospholipase A acting on PtdIns. The increased level of
      lyso-PtdIns that is produced in this reaction could be responsible for the
      increased growth rate and the partial loss of contact inhibition in SPI8 and SPI6
      cells. The addition of growth factors (platelet-derived growth factor, bombesin)
      to these overexpressers did not activate the phospholipase C-dependent
      degradation of phosphatidylinositol 4,5-bisphosphate.

PMID- 10585409
TI  - Identification of amino acid residues that determine pH dependence of ligand
      binding to the asialoglycoprotein receptor during endocytosis.
AB  - The rat hepatic asialoglycoprotein receptor mediates clearance of galactose- and
      N-acetylgalactosamine-terminated glycoproteins by endocytosis, binding ligands
      through a C-type, Ca(2+)-dependent carbohydrate-recognition domain (CRD) at
      extracellular pH and releasing them at lower pH in endosomes. At physiological
      Ca(2+) concentrations, the midpoint for ligand release from the CRD of the major
      subunit of the receptor is pH 7.1. In contrast, the midpoint is pH 5.0 for a
      galactose-binding derivative of the homologous C-type CRD of serum mannose
      binding protein, which would thus not efficiently release ligand at an endosomal
      pH of 5.4. Site-directed mutagenesis of the CRD from the major subunit of the
      asialoglycoprotein receptor has been used to identify residues that are essential
      for efficient release of ligand at endosomal pH. The effects of changes to
      residues His(256), Asp(266), and Arg(270) singly and in combination indicate that
      these residues reduce the affinity of the CRD for Ca(2+), so that ligands are
      released at physiological Ca(2+) concentrations. The proximity of these three
      residues to the ligand-binding site at Ca(2+) site 2 of the domain suggests that
      they form a pH-sensitive switch for Ca(2+) and ligand binding. Introduction of
      histidine and aspartic acid residues into the mannose-binding protein CRD at
      positions equivalent to His(256) and Asp(266) raises the pH for half-maximal
      binding of ligand to 6.1. The results, as well as sequence comparisons with other
      C-type CRDs, confirm the importance of these residues in conferring appropriate
      pH dependence in this family of domains.

PMID- 10585410
TI  - Biosynthesis of mannosylglycerate in the thermophilic bacterium Rhodothermus
      marinus. Biochemical and genetic characterization of a mannosylglycerate
      synthase.
AB  - The biosynthetic reaction scheme for the compatible solute mannosylglycerate in
      Rhodothermus marinus is proposed based on measurements of the relevant enzymatic
      activities in cell-free extracts and in vivo (13)C labeling experiments. The
      synthesis of mannosylglycerate proceeded via two alternative pathways; in one of
      them, GDP mannose was condensed with D-glycerate to produce mannosylglycerate in
      a single reaction catalyzed by mannosylglycerate synthase, in the other pathway,
      a mannosyl-3-phosphoglycerate synthase catalyzed the conversion of GDP mannose
      and D-3-phosphoglycerate into a phosphorylated intermediate, which was
      subsequently converted to mannosylglycerate by the action of a phosphatase. The
      enzyme activities committed to the synthesis of mannosylglycerate were not
      influenced by the NaCl concentration in the growth medium. However, the combined
      mannosyl-3-phosphoglycerate synthase/phosphatase system required the addition of
      NaCl or KCl to the assay mixture for optimal activity. The mannosylglycerate
      synthase enzyme was purified and characterized. Based on partial sequence
      information, the corresponding mgs gene was identified from a genomic library of
      R. marinus. In addition, the mgs gene was overexpressed in Escherichia coli with
      a high yield. The enzyme had a molecular mass of 46,125 Da, and was specific for
      GDP mannose and D-glycerate. This is the first report of the characterization of
      a mannosylglycerate synthase.

PMID- 10585411
TI  - Further biochemical and kinetic characterization of human eukaryotic initiation
      factor 4H.
AB  - A cDNA encoding human eukaryotic initiation factor (eIF) 4H was subcloned into a
      bacterial expression plasmid for purification of recombinant protein. Recombinant
      human eIF4H (heIF4H) was purified to greater than 95% homogeneity and shown to
      have similar physical characteristics to eIF4H purified from rabbit reticulocyte
      lysate as described previously. Functional studies have revealed that recombinant
      heIF4H functions identically to rabbit eIF4H in stimulating protein synthesis,
      and the ATP hydrolysis and helicase activities of eIF4A. More detailed enzymatic
      studies revealed that eIF4H increases the affinity of eIF4A for RNA by 2-fold,
      but has no effect on the binding of ATP by eIF4A. eIF4H stimulates the helicase
      activity of eIF4A at least 4-fold, and it is postulated that this stimulation
      occurs through increasing the processivity of eIF4A. Northern blot analysis shows
      that eIF4H is expressed ubiquitously in human tissues, and displays different
      levels of expression in given tissues relative to eIF4B. Secondary structure
      analysis of heIF4H by circular dichroism suggest that eIF4H has a mostly beta
      sheet structure, which appears similar to other RNA recognition motif-containing
      proteins. Finally, it is suggested that eIF4H functions in translation initiation
      through protein-protein interactions that possibly stabilize conformational
      changes that occur in eIF4A during RNA binding, ATP hydrolysis, and RNA duplex
      unwinding.

PMID- 10585413
TI  - Site-directed mutagenesis of diphosphoinositol polyphosphate phosphohydrolase, a
      dual specificity NUDT enzyme that attacks diadenosine polyphosphates and
      diphosphoinositol polyphosphates.
AB  - Diphosphoinositol polyphosphate phosphohydrolase (DIPP) hydrolyzes diadenosine
      5',5"'-P(1),P(6)-hexaphosphate (Ap(6)A), a Nudix (nucleoside diphosphate attached
      moiety "x") substrate, and two non-Nudix compounds: diphosphoinositol
      pentakisphosphate (PP-InsP(5)) and bis-diphosphoinositol tetrakisphosphate
      ((PP)(2)-InsP(4)). Guided by multiple sequence alignments, we used site-directed
      mutagenesis to obtain new information concerning catalytically essential amino
      acid residues in DIPP. Mutagenesis of either of two conserved glutamate residues
      (Glu(66) and Glu(70)) within the Nudt (Nudix-type) catalytic motif impaired
      hydrolysis of Ap(6)A, PP-InsP(5), and (PP)(2)-InsP(4) >95%; thus, all three
      substrates are hydrolyzed at the same active site. Two Gly-rich domains (glycine
      rich regions 1 and 2 (GR1 and GR2)) flank the Nudt motif with potential sites for
      cation coordination and substrate binding. GR1 comprises a GGG tripeptide, while
      GR2 is identified as a new functional motif (GX(2)GX(6)G) that is conserved in
      yeast homologues of DIPP. Mutagenesis of any of these Gly residues in GR1 and GR2
      reduced catalytic activity toward all three substrates by up to 95%. More distal
      to the Nudt motif, H91L and F84Y mutations substantially decreased the rate of
      Ap(6)A and (PP)(2)-InsP(4) metabolism (by 71 and 96%), yet PP-InsP(5) hydrolysis
      was only mildly reduced (by 30%); these results indicate substrate-specific roles
      for His(91) and Phe(84). This new information helps define DIPP's structural,
      functional, and evolutionary relationships to Nudix hydrolases.

PMID- 10585412
TI  - Holo-sterol carrier protein-2. (13)C NMR investigation of cholesterol and fatty
      acid binding sites.
AB  - Although sterol carrier protein-2 (SCP-2) stimulates sterol transfer in vitro,
      almost nothing is known regarding the identity of the putative cholesterol
      binding site. Furthermore, the interrelationship(s) between this SCP-2 ligand
      binding site and the recently reported SCP-2 long chain fatty acid (LCFA) and
      long chain fatty acyl-CoA (LCFA-CoA) binding site(s) remains to be established.
      In the present work, two SCP-2 ligand binding sites were identified. First, both
      [4-(13)C]cholesterol and 22-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl)amino)-23,24
      bisnor-5-cholen-3beta-ol (NBD-cholesterol) binding assays were consistent with a
      single cholesterol binding site in SCP-2. This ligand binding site had high
      affinity for NBD-cholesterol, K(d) = 4.15 +/- 0.71 nM. (13)C NMR-labeled ligand
      competition studies demonstrated that the SCP-2 high affinity cholesterol binding
      site also bound LCFA or LCFA-CoA. However, only the LCFA-CoA was able to
      effectively displace the SCP-2-bound [4-(13)C]cholesterol. Thus, the ligand
      affinities at this SCP-2 binding site were in the relative order cholesterol =
      LCFA-CoA > LCFA. Second, (13)C NMR studies demonstrated the presence of another
      ligand binding site on SCP-2 that bound either LCFA or LCFA-CoA but not
      cholesterol. Photon correlation spectroscopy was consistent with SCP-2 being
      monomeric in both liganded and unliganded states. In summary, both (13)C NMR and
      fluorescence techniques demonstrated for the first time that SCP-2 had a single
      high affinity binding site that bound cholesterol, LCFA, or LCFA-CoA.
      Furthermore, results with (13)C NMR supported the presence of a second SCP-2
      ligand binding site that bound either LCFA or LCFA-CoA but not cholesterol. These
      data contribute to our understanding of a role for SCP-2 in both cellular
      cholesterol and LCFA metabolism.

PMID- 10585414
TI  - Spin trapping and protein cross-linking of the lactoperoxidase protein radical.
AB  - Lactoperoxidase (LPO) reacts with H(2)O(2) to sequentially give two Compound I
      intermediates: the first with a ferryl (Fe(IV)=O) species and a porphyrin radical
      cation, and the second with the same ferryl species and a presumed protein
      radical. However, little actual evidence is available for the protein radical. We
      report here that LPO reacts with the spin trap 3,5-dibromo-4-nitroso
      benzenesulfonic acid to give a 1:1 protein-bound radical adduct. Furthermore, LPO
      undergoes the H(2)O(2)-dependent formation of dimeric and trimeric products.
      Proteolytic digestion and mass spectrometric analysis indicates that the dimer is
      held together by a dityrosine link between Tyr-289 in each of two LPO molecules.
      The dimer retains full catalytic activity and reacts to the same extent with the
      spin trap, indicating that the spin trap reacts with a radical center other than
      Tyr-289. The monomeric protein recovered from incubations of LPO with H(2)O(2) is
      fully active but no longer forms dimers when incubated with H(2)O(2), clear
      evidence that it has also been structurally modified. Myeloperoxidase, a
      naturally dimeric protein, and eosinophil peroxidase do not undergo H(2)O(2)
      dependent oligomerization. Analysis of the interface in the LPO dimers indicates
      that the same protein surface is involved in LPO dimerization as in the normal
      formation of myeloperoxidase dimers. Oligomerization of LPO alters its physical
      properties and may alter its ability to interact with macromolecular substrates.

PMID- 10585415
TI  - Regulation of Na(+) reabsorption by the aldosterone-induced small G protein K
      Ras2A.
AB  - Xenopus laevis A6 cells were used as model epithelia to test the hypothesis that
      K-Ras2A is an aldosterone-induced protein necessary for steroid-regulated Na(+)
      transport. The possibility that increased K-Ras2A alone is sufficient to mimic
      aldosterone action on Na(+) transport also was tested. Aldosterone treatment
      increased K-Ras2A protein expression 2.8-fold within 4 h. Active Ras is membrane
      associated. After aldosterone treatment, 75% of K-Ras was localized to the plasma
      membrane compared with 25% in the absence of steroid. Aldosterone also increased
      the amount of active (phosphorylated) mitogen-activated protein kinase kinase
      likely through K-Ras2A signaling. Steroid-induced K-Ras2A protein levels and
      Na(+) transport were decreased with antisense K-ras2A oligonucleotides, showing
      that K-Ras2A is necessary for the natriferic actions of aldosterone. Aldosterone
      induced Na(+) channel activity, was decreased from 0.40 to 0.09 by pretreatment
      with antisense ras oligonucleotide, implicating the luminal Na(+) channel as one
      final effector of Ras signaling. Overexpression of K-Ras2A increased Na(+)
      transport approximately 2.2-fold in the absence of aldosterone. These results
      suggest that aldosterone signals to the luminal Na(+) channel via multiple
      pathways and that K-Ras2A levels are limiting for a portion of the aldosterone
      sensitive Na(+) transport.

PMID- 10585416
TI  - Aberrant oxidation of the cholesterol side chain in bile acid synthesis of sterol
      carrier protein-2/sterol carrier protein-x knockout mice.
AB  - Peroxisomal beta-oxidation plays an important role in the metabolism of a wide
      range of substrates, including various fatty acids and the steroid side chain in
      bile acid synthesis. Two distinct thiolases have been implicated to function in
      peroxisomal beta-oxidation: the long known 41-kDa beta-ketothiolase identified by
      Hashimoto and co-workers (Hijikata, M., Ishii, N., Kagamiyama, H., Osumi, T., and
      Hashimoto, T. (1987) J. Biol. Chem. 262, 8151-8158) and the recently discovered
      60-kDa SCPx thiolase, that consists of an N-terminal domain with beta
      ketothiolase activity and a C-terminal moiety of sterol carrier protein-2 (SCP2,
      a lipid carrier or transfer protein). Recently, gene targeting of the SCP2/SCPx
      gene has shown in mice that the SCPx beta-ketothiolase is involved in peroxisomal
      beta-oxidation of 2-methyl-branched chain fatty acids like pristanic acid. In our
      present work we have investigated bile acid synthesis in the SCP2/SCPx knockout
      mice. Specific inhibition of beta-oxidation at the thiolytic cleavage step in
      bile acid synthesis is supported by our finding of pronounced accumulation in
      bile and serum from the knockout mice of 3alpha,7alpha, 12alpha-trihydroxy-27-nor
      5beta-cholestane-24-one (which is a known bile alcohol derivative of the cholic
      acid synthetic intermediate 3alpha,7alpha,12alpha-trihydroxy-24-keto-cholestano
      yl-coenzyme A). Moreover, these mice have elevated concentrations of bile acids
      with shortened side chains (i.e. 23-norcholic acid and 23-norchenodeoxycholic
      acid), which may be produced via alpha- rather than beta-oxidation. Our results
      demonstrate that the SCPx thiolase is critical for beta-oxidation of the steroid
      side chain in conversion of cholesterol into bile acids.

PMID- 10585417
TI  - Functional characterization of the intermediate isoform of the human prolactin
      receptor.
AB  - Prolactin-dependent signaling occurs as the result of ligand-induced dimerization
      of the prolactin receptor (PRLr). While three PRLr isoforms have been
      characterized in the rat, studies have suggested the existence of several human
      isoforms in breast carcinoma species and normal tissues. Reverse transcription
      polymerase chain reaction was performed on mRNA isolated from the breast
      carcinoma cell line T47D, revealing two predominant receptor isoforms: the
      previously described long PRLr and a novel human intermediate PRLr. The
      nucleotide sequence of the intermediate isoform was found to be identical to the
      long isoform except for a 573-base pair deletion occurring at a consensus splice
      site, resulting in a frameshift and truncated intracytoplasmic domain. Scatchard
      analysis of the intermediate PRLr revealed an affinity for PRL comparable with
      the long PRLr. While Ba/F3 transfectants expressing the long PRLr proliferated in
      response to PRL, intermediate PRLr transfectants exhibited modest incorporation
      of [(3)H]thymidine. Significantly, however, both the long and intermediate PRLr
      were equivalent in their inhibition of apoptosis of the Ba/F3 transfectants after
      PRL treatment. The activation of proximal signaling molecules also differed
      between isoforms. Upon ligand binding, Jak2 and Fyn were activated in CHO-K1
      cells transiently transfected with the long PRLr. In contrast, the intermediate
      PRLr transfectants showed equivalent levels of Jak2 activation but only minimal
      activation of Fyn. Last, Northern analysis revealed variable tissue expression of
      intermediate PRLr transcript that differed from that of the long PRLr. Taken
      together, differences in signaling and tissue expression suggest that the human
      intermediate PRLr differs from the long PRLr in physiological function.

PMID- 10585418
TI  - Constitutive G(i2)-dependent activation of adenylyl cyclase type II by the 5-HT1A
      receptor. Inhibition by anxiolytic partial agonists.
AB  - The 5-HT1A receptor is implicated in depression and anxiety. This receptor
      couples to G(i) proteins to inhibit adenylyl cyclase (AC) activity but can
      stimulate AC in tissues (e.g. hippocampus) that express ACII. The role of ACII in
      receptor-mediated stimulation of cAMP formation was examined in HEK-293 cells
      transfected with the 5-HT1A receptor, which mediated inhibition of basal and G(s)
      induced cAMP formation in the absence of ACII. In cells cotransfected with 5-HT1A
      receptor and ACII plasmids, 5-HT1A agonists induced a 1. 5-fold increase in cAMP
      level. Cotransfection of 5-HT1A receptor, ACII, and Galpha(i2), but not
      Galpha(i1), Galpha(i3), or Galpha(o), resulted in an agonist-independent 6-fold
      increase in the basal cAMP level, suggesting that G(i2) preferentially coupled
      the receptor to ACII. The 5-HT1B receptor also constitutively activated ACII.
      Constitutive activity of the 5-HT1A receptor was blocked by pertussis toxin and
      the Gbetagamma antagonist, betaCT, suggesting an important role for Gbetagamma
      mediated activation of ACII. The Thr-149 --> Ala mutation in the second
      intracellular domain of the 5-HT1A receptor disrupted Gbetagamma-selective
      activation of ACII. Spontaneous 5-HT1A receptor activity was partially attenuated
      by 5-HT1A receptor partial agonists with anxiolytic activity (e.g. buspirone and
      flesinoxan) but was not altered by full agonists or antagonists. Thus, anxiolytic
      activity may involve inhibition of spontaneous 5-HT1A receptor activity.

PMID- 10585419
TI  - Synergistic transcriptional activation by hGABP and select members of the
      activation transcription factor/cAMP response element-binding protein family.
AB  - The Ets-related DNA-binding protein human GA-binding protein (hGABP) alpha
      interacts with the four ankyrin-type repeats of hGABPbeta to form an hGABP
      tetrameric complex that stimulates transcription through the adenovirus early 4
      (E4) promoter. Using co-transfection assays, this study demonstrated that the
      hGABP complex mediated efficient activation of transcription from E4 promoter
      synergistically with activating transcription factor (ATF) 1 or cAMP response
      element-binding protein (CREB), but not ATF2/CRE-BP1. This synergy also partially
      occurred when hGABPalpha was used alone in place of the combination of hGABPalpha
      and hGABPbeta. hGABP activated an artificial promoter containing only ATF/CREB
      binding sites under coexistence of ATF1 or CREB. Consistent with these results,
      physical interactions of hGABPalpha with ATF1 or CREB were observed in vitro.
      Functional domain analyses of the physical interactions revealed that the amino
      terminal region of hGABPalpha bound to the DNA-binding domain of ATF1, which
      resulted in the formation of ternary complexes composed of ATF1, hGABPalpha, and
      hGABPbeta. In contrast to hGABPalpha, hGABPbeta did not significantly interact
      with ATF1 and CREB. Taken together, these results indicate that hGABP
      functionally interacts with selective members of the ATF/CREB family, and also
      suggest that synergy results from multiple interactions which mediate
      stabilization of large complexes within the regulatory elements of the promoter
      region, including DNA-binding and non-DNA-binding factors.

PMID- 10585420
TI  - The UDP-glucose:p-hydroxymandelonitrile-O-glucosyltransferase that catalyzes the
      last step in synthesis of the cyanogenic glucoside dhurrin in Sorghum bicolor.
      Isolation, cloning, heterologous expression, and substrate specificity.
AB  - The final step in the biosynthesis of the cyanogenic glucoside dhurrin in Sorghum
      bicolor is the transformation of the labile cyanohydrin into a stable storage
      form by O-glucosylation of (S)-p-hydroxymandelonitrile at the cyanohydrin
      function. The UDP-glucose:p-hydroxymandelonitrile-O-glucosyltransferase was
      isolated from etiolated seedlings of S. bicolor employing Reactive Yellow 3
      chromatography with UDP-glucose elution as the critical step. Amino acid
      sequencing allowed the cloning of a full-length cDNA encoding the
      glucosyltransferase. Among the few characterized glucosyltransferases, the
      deduced translation product showed highest overall identity to Zea mays flavonoid
      glucosyltransferase (Bz-Mc-2 allele). The substrate specificity of the enzyme was
      established using isolated recombinant protein. Compared with endogenous p
      hydroxymandelonitrile, mandelonitrile, benzyl alcohol, and benzoic acid were
      utilized at maximum rates of 78, 13, and 4%, respectively. Surprisingly, the
      monoterpenoid geraniol was glucosylated at a maximum rate of 11% compared with p
      hydroxymandelonitrile. The picture that is emerging regarding plant
      glucosyltransferase substrate specificity is one of limited but extended
      plasticity toward metabolites of related structure. This in turn ensures that a
      relatively high, but finite, number of glucosyltransferases can give rise to the
      large number of glucosides found in plants.

PMID- 10585421
TI  - Cross-talk between alpha(1B)-adrenergic receptor (alpha(1B)AR) and interleukin-6
      (IL-6) signaling pathways. Activation of alpha(1b)AR inhibits il-6-activated
      STAT3 in hepatic cells by a p42/44 mitogen-activated protein kinase-dependent
      mechanism.
AB  - Treatment of primary rat hepatocytes or tranfected HepG2 cells with the alpha(1B)
      adrenergic receptor (alpha(1B)AR) agonist phenylephrine (PE) significantly
      inhibited interleukin 6 (IL-6)-induced STAT3 binding, tyrosine phosphorylation,
      and IL-6-induced serum amyloid A mRNA expression. Western analyses and in vitro
      kinase assays indicate that this inhibition is not due to either down-regulation
      of STAT3 protein expression nor inactivation of upstream-located JAK1 and JAK2.
      Blocking the new RNA and protein syntheses antagonized the inhibitory effect of
      PE on IL-6-activated STAT3, suggesting synthesis of an inhibitory factor(s) is
      involved. The inhibitory effect of PE on IL-6 activation of STAT3 was also
      abolished by the tyrosine phosphatase inhibitor sodium vanadate, indicating
      involvement of protein tyrosine phosphatases. Furthermore, preincubation of the
      cells with the specific MEK1 inhibitor PD98059 or a dominant negative MEK1
      reversed the inhibitory effect of PE, and expression of constitutively activated
      MEK1 alone abolished IL-6-activated STAT3. Taken together, these data indicate
      that PE inhibits IL-6 activation of STAT3 in hepatic cells by a p42/44 mitogen
      activated protein kinase-dependent mechanism, and tyrosine phosphatases are
      involved. This inhibitory cross-talk between the alpha(1B)AR and IL-6 signaling
      pathways implicates the alpha(1B)AR involvement in regulating the IL-6-mediated
      inflammatory responses.

PMID- 10585422
TI  - Adenosine A(2A) receptor mRNA regulation by nerve growth factor is TrkA-, Src-,
      and Ras-dependent via extracellular regulated kinase and stress-activated protein
      kinase/c-Jun NH(2)-terminal kinase.
AB  - We have shown previously that nerve growth factor (NGF) down-regulates adenosine
      A(2A) receptor (A(2A)AR) mRNA in PC12 cells. To define cellular mechanisms that
      modulate A(2A)AR expression, A(2A)AR mRNA and protein levels were examined in
      three PC12 sublines: i) PC12nnr5 cells, which lack the high affinity NGF receptor
      TrkA, ii) srcDN2 cells, which overexpress kinase-defective Src, and iii) 17.26
      cells, which overexpress a dominant-inhibitory Ras. In the absence of functional
      TrkA, Src, or Ras, NGF-induced down-regulation of A(2A)AR mRNA and protein was
      significantly impaired. However, regulation of A(2A)AR expression was
      reconstituted in PC12nnr5 cells stably transfected with TrkA. Whereas NGF
      stimulated the mitogen-activated protein kinases p38, extracellular regulated
      kinase 1 and 2 (ERK1/ERK2), and stress-activated protein kinase/c-Jun NH(2)
      terminal kinase (SAPK/JNK) in PC12 cells, these kinases were activated only
      partially or not at all in srcDN2 and 17.26 cells. Inhibiting ERK1/ERK2 with
      PD98059 or inhibiting SAPK/JNK by transfecting cells with a dominant-negative
      SAPKbeta/JNK3 mutant partially blocked NGF-induced down-regulation of A(2A)AR
      expression in PC12 cells. In contrast, inhibiting p38 with SB203580 had no effect
      on the regulation of A(2A)AR mRNA and protein levels. Treating SAPKbeta/JNK3
      mutant-transfected PC12 cells with PD98059 completely abolished the NGF-induced
      decrease in A(2A)AR mRNA and protein levels. These results reveal a role for
      ERK1/ERK2 and SAPK/JNK in regulating A(2A)AR expression.

PMID- 10585423
TI  - 1,25-Dihydroxyvitamin D(3) stimulates activator protein-1-dependent Caco-2 cell
      differentiation.
AB  - 1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is a potential chemopreventive agent
      for human colon cancer. We have reported that 1,25(OH)(2)D(3) specifically
      activated protein kinase C-alpha (PKC-alpha) and also caused a reduction in
      proliferation while increasing apoptosis and differentiation in CaCo-2 cells, a
      cell line derived from a human colon cancer. The mechanisms by which this
      secosteroid influences these important cellular processes, however, remain
      unclear. The transcription factor, activator protein-1 (AP-1), regulates many
      genes involved in these processes. Therefore, we asked whether 1,25(OH)(2)D(3)
      activated AP-1 in CaCo-2 cells and, if so, by what mechanisms? 1,25(OH)(2)D(3)
      caused a time-dependent increase in AP-1 DNA binding activity and significantly
      enhanced the protein and mRNA abundance of c-Jun, a component of AP-1. 1,
      25(OH)(2)D(3) also induced a rapid and transient activation of ERK2 (where ERK is
      extracellular signal-regulated kinase) and a more persistent activation of JNK1
      (where JNK Jun N-terminal kinase). Transfection experiments revealed that
      1,25(OH)(2)D(3) also increased AP-1 gene-transactivating activity. This AP-1
      activation was completely blocked by PD 098059, a specific mitogen-activated
      protein kinase/ERK kinase inhibitor, as well as by a dominant negative JNK or a
      dominant negative Jun, indicating that the AP-1 activation induced by
      1,25(OH)(2)D(3) was mediated by ERK and JNK. Using a specific inhibitor of the
      Ca(2+)-dependent PKC isoforms, Go6976, and CaCo-2 cells stably transfected with
      antisense PKC-alpha cDNA, demonstrated that PKC-alpha mediated the AP-1
      activation induced by this secosteroid. Inhibition of JNK activation or c-Jun
      protein expression significantly reduced 1, 25(OH)(2)D(3)-induced alkaline
      phosphatase activity, a marker of CaCo-2 cell differentiation, in secosteroid
      treated cells. Taken together, the present study demonstrated that
      1,25(OH)(2)D(3) stimulated AP-1 activation in CaCo-2 cells by a PKC-alpha- and
      JNK-dependent mechanism leading to increases in cellular differentiation.

PMID- 10585424
TI  - Covalent flavinylation is essential for efficient redox catalysis in vanillyl
      alcohol oxidase.
AB  - By mutating the target residue of covalent flavinylation in vanillyl-alcohol
      oxidase, the functional role of the histidyl-FAD bond was studied. Three His(422)
      mutants (H422A, H422T, and H422C) were purified, which all contained tightly but
      noncovalently bound FAD. Steady state kinetics revealed that the mutants have
      retained enzyme activity, although the turnover rates have decreased by 1 order
      of magnitude. Stopped-flow analysis showed that the H422A mutant is still able to
      form a stable binary complex of reduced enzyme and a quinone methide product
      intermediate, a crucial step during vanillyl-alcohol oxidase-mediated catalysis.
      The only significant change in the catalytic cycle of the H422A mutant is a
      marked decrease in reduction rate. Redox potentials of both wild type and H422A
      vanillyl-alcohol oxidase have been determined. During reduction of H422A, a large
      portion of the neutral flavin semiquinone is observed. Using suitable reference
      dyes, the redox potentials for the two one-electron couples have been determined:
      -17 and -113 mV. Reduction of wild type enzyme did not result in any formation of
      flavin semiquinone and revealed a remarkably high redox potential of +55 mV. The
      marked decrease in redox potential caused by the missing covalent histidyl-FAD
      bond is reflected in the reduced rate of substrate-mediated flavin reduction
      limiting the turnover rate. Elucidation of the crystal structure of the H422A
      mutant established that deletion of the histidyl-FAD bond did not result in any
      significant structural changes. These results clearly indicate that covalent
      interaction of the isoalloxazine ring with the protein moiety can markedly
      increase the redox potential of the flavin cofactor, thereby facilitating redox
      catalysis. Thus, formation of a histidyl-FAD bond in specific flavoenzymes might
      have evolved as a way to contribute to the enhancement of their oxidative power.

PMID- 10585425
TI  - NMR structure and functional characteristics of the hydrophilic N terminus of the
      potassium channel beta-subunit Kvbeta1.1.
AB  - Rapid N-type inactivation of voltage-dependent potassium (Kv) channels controls
      membrane excitability and signal propagation in central neurons and is mediated
      by protein domains (inactivation gates) occluding the open channel pore from the
      cytoplasmic side. Inactivation domains (ID) are donated either by the pore
      forming alpha-subunit or certain auxiliary beta-subunits. Upon coexpression,
      Kvbeta1.1 was found to endow non-inactivating members of the Kv1alpha family with
      fast inactivation via its unique N terminus. Here we investigated structure and
      functional properties of the Kvbeta1.1 N terminus (amino acids 1-62, betaN-(1
      62)) using NMR spectroscopy and patch clamp recordings. betaN-(1-62) showed all
      hallmarks of N-type inactivation: it inactivated non-inactivating Kv1.1 channels
      when applied to the cytoplasmic side as a synthetic peptide, and its interaction
      with the alpha-subunit was competed with tetraethylammonium and displayed an
      affinity in the lower micromolar range. In aequous and physiological salt
      solution, betaN-(1-62) showed no well defined three-dimensional structure, it
      rather existed in a fast equilibrium of multiple weakly structured states. These
      structural and functional properties of betaN-(1-62) closely resemble those of
      the "unstructured" ID from Shaker B, but differ markedly from those of the
      compactly folded ID of the Kv3.4 alpha-subunit.

PMID- 10585426
TI  - Mechanism of mitogen-activated protein kinase phosphatase-3 activation by ERK2.
AB  - The mitogen-activated protein kinase phosphatase 3 (MKP3)-catalyzed hydrolysis of
      aryl phosphates in the absence and presence of extracellular signal-regulated
      kinase 2 (ERK2) was investigated in order to provide insights into the molecular
      basis of the ERK2-induced MKP3 activation. In the absence of ERK2, the MKP3
      catalyzed hydrolysis of simple aryl phosphates does not display any dependence on
      pH, viscosity, and the nature of the leaving group. Increased catalytic activity
      and enhanced affinity for oxyanions are observed for MKP3 in the presence of
      ERK2. In addition, normal bell-shaped pH dependence on the reaction catalyzed by
      MKP3 is restored in the presence of ERK2. Collectively, these results suggest
      that the rate-limiting step in the absence of ERK2 for the MKP3 reaction
      corresponds to a substrate-induced conformational change in MKP3 involving active
      site rearrangement and general acid loop closure. The binding of ERK2 to the N
      terminal domain of MKP3 facilitates the repositioning of active site residues and
      speeds up the loop closure in MKP3 such that chemistry becomes rate-limiting in
      the presence of ERK2. Remarkably, it is found that the extent of ERK2-induced
      MKP3 activation is substrate dependent, with smaller activation observed for
      bulkier substrates. Unlike simple aryl phosphates, the MKP3-catalyzed hydrolysis
      of bulky polycyclic substrates exhibits bell-shaped pH rate profiles in the
      absence of ERK2. Furthermore, it is found that glycerol can also activate the
      MKP3-catalyzed reaction, increase the affinity of MKP3 for oxyanion, and restore
      the bell-shaped pH rate profile for the MKP3-catalyzed reaction. Thus, the rate
      of repositioning of catalytic groups and the reorienting of the electrostatic
      environment in the MKP3 active site can be enhanced not only by ERK2 but also by
      high affinity substrates or by glycerol.

PMID- 10585427
TI  - p38-dependent activation of interferon regulatory factor 3 by lipopolysaccharide.
AB  - Interferon regulatory factor 3 (IRF3) is known to participate in the
      transcriptional induction of interferon (IFN) alpha and IFNbeta genes, as well as
      of a number of interferon-stimulated genes (ISGs), as a result of viral
      infection. In the present study we demonstrate the activation of IRF3 followed by
      ISG induction after exposure of cells to the bacterial cell wall component
      lipopolysaccharide. Engagement of Toll-like receptors by lipopolysaccharide
      triggered the nuclear translocation of IRF3, followed by its DNA binding and the
      subsequent induction of several interferon-regulated genes. Transcriptional
      activation of ISGs occurred in a protein synthesis independent manner, but was
      sensitive to inhibition of the stress-activated protein kinase, p38. The
      activation of IRF3 by viral particles or bacterial membrane components suggests
      that this signaling pathway might contribute to the evolutionary conserved innate
      immune response.

PMID- 10585428
TI  - Inhibition by calcium of mammalian adenylyl cyclases.
AB  - Ca(2+) regulates mammalian adenylyl cyclases in a type-specific manner.
      Stimulatory regulation is moderately well understood. By contrast, even the
      concentration range over which Ca(2+) inhibits adenylyl cyclases AC5 and AC6 is
      not unambiguously defined; even less so is the mechanism of inhibition. In the
      present study, we compared the regulation of Ca(2+)-stimulable and Ca(2+)
      inhibitable adenylyl cyclases expressed in Sf9 cells with tissues that
      predominantly express these activities in the mouse brain. Soluble forms of AC5
      containing either intact or truncated major cytosolic domains were also examined.
      All adenylyl cyclases, except AC2 and the soluble forms of AC5, displayed
      biphasic Ca(2+) responses, suggesting the presence of two Ca(2+) sites of high (
      approximately 0.2 microM) and low affinity ( approximately 0.1 mM). With a high
      affinity, Ca(2+) (i) stimulated AC1 and cerebellar adenylyl cyclases, (ii)
      inhibited AC6 and striatal adenylyl cyclase, and (iii) was without effect on AC2.
      With a low affinity, Ca(2+) inhibited all adenylyl cyclases, including AC1, AC2,
      AC6, and both soluble forms of AC5. The mechanism of both high and low affinity
      inhibition was revealed to be competition for a stimulatory Mg(2+) site(s). A
      remarkable selectivity for Ca(2+) was displayed by the high affinity site, with a
      K(i) value of approximately 0.2 microM, in the face of a 5000-fold excess of
      Mg(2+). The present results show that high and low affinity inhibition by Ca(2+)
      can be clearly distinguished and that the inhibition occurs type-specifically in
      discrete adenylyl cyclases. Distinction between these sites is essential, or
      quite spurious inferences may be drawn on the nature or location of high affinity
      binding sites in the Ca(2+)-inhibitable adenylyl cyclases.

PMID- 10585429
TI  - Role of transmembrane helix IV in G-protein specificity of the angiotensin II
      type 1 receptor.
AB  - G-protein activation by G-protein coupled receptors (GPCRs) is accomplished
      through proper interaction with the cytoplasmic loops rather than through
      sequence-specific interactions. However, the mechanism by which a specific G
      protein is selected by a GPCR is not known. In the current model of GPCR
      activation, agonist binding modulates helix-helix interactions, which is
      necessary for fully determining G-protein specificity and stimulation of GDP/GTP
      exchange. In this study, we report that a single-residue deletion in
      transmembrane helix IV leads the angiotensin II type 1 (AT(1)) receptor chimera
      CR17 to retain GTP-sensitive high affinity for the agonist angiotensin II but
      results in complete inactivation of intracellular inositol phosphate production.
      The agonist dissociation profile of CR17 in the presence of guanosine 5'-3-O
      (thio)triphosphate suggests that the activation-induced conformational changes of
      the chimeric receptor itself remain intact. Insertion of an alanine at position
      149 (CR17triangle down149A) in this chimera rescued the inactive phenotype,
      restoring intracellular inositol phosphate production by the chimera. This
      finding suggests that in the wild-type AT(1) receptor the orientation of
      transmembrane helix IV-residues following Cys(149) is a key determinant for
      effectively distinguishing among various structurally similar G-proteins. The
      results emphasize that the contacts within the membrane-embedded portion of
      transmembrane helix IV in the AT(1) receptor is important for specific G-protein
      selection.

PMID- 10585430
TI  - SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by
      multiple mechanisms.
AB  - The inhibition of growth hormone (GH) signaling by five members of the GH
      inducible suppressor of cytokine signaling (SOCS/CIS) family was investigated in
      transfected COS cells. Complete inhibition of GH activation of the signal
      transducer STAT5b and STAT5b-dependent transcriptional activity was observed upon
      expression of SOCS-1 or SOCS-3, while partial inhibition (CIS, SOCS-2) or no
      inhibition (SOCS-6) was seen with other SOCS/CIS family members. SOCS-1, SOCS-2,
      SOCS-3, and CIS each strongly inhibited the GH receptor (GHR)-dependent tyrosine
      phosphorylation of JAK2 seen at low levels of transfected JAK2; however, only
      SOCS-1 strongly inhibited the GHR-independent tyrosine phosphorylation of JAK2
      seen at higher JAK2 levels. To probe for interactions with GHR, in vitro binding
      assays were carried out using glutathione S-transferase-GHR fusion proteins
      containing variable lengths of GHR's COOH-terminal cytoplasmic domain. CIS and
      SOCS-2 bound to fusions containing as few as 80 COOH-terminal GHR residues,
      provided the fusion protein was tyrosine-phosphorylated. By contrast, SOCS-3
      binding required tyrosine-phosphorylated GHR membrane-proximal sequences, SOCS-1
      binding was tyrosine phosphorylation-independent, and SOCS-6 did not bind the GHR
      fusion proteins at all. Mutation of GHR's membrane-proximal tyrosine residues 333
      and 338 to phenylalanine suppressed the inhibition by SOCS-3, but not by CIS, of
      GH signaling to STAT5b. SOCS/CIS proteins can thus inhibit GH signaling to STAT5b
      by three distinct mechanisms, distinguished by their molecular targets within the
      GHR-JAK2 signaling complex, as exemplified by SOCS-1 (direct JAK2 kinase
      inhibition), SOCS-3 (inhibition of JAK2 signaling via membrane-proximal GHR
      tyrosines 333 and 338), and CIS and SOCS-2 (inhibition via membrane-distal
      tyrosine(s)).

PMID- 10585431
TI  - Inhibition of endothelial cell migration, intercellular communication, and
      vascular tube formation by thromboxane A(2).
AB  - The eicosanoid thromboxane A(2) (TXA(2)) is released by activated platelets,
      monocytes, and the vessel wall and interacts with high affinity receptors
      expressed in several tissues including endothelium. Whether TXA(2) might alter
      endothelial migration and tube formation, two determinants of angiogenesis, is
      unknown. Thus, we investigated the effect of the TXA(2) mimetic [1S-(1alpha,
      2beta(5Z),3alpha(1E,3R), 4alpha]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7
      o xab icyclo- [2.2.1]heptan-2-yl]-5'-heptenoic acid (IBOP) on human endothelial
      cell (HEC) migration and angiogenesis in vitro. IBOP stimulation inhibited HEC
      migration by 50% and in vitro capillary formation by 75%. These effects of IBOP
      were time- and concentration-dependent with an IC(50) of 25 nM. IBOP did not
      affect integrin expression or cytoskeletal morphology of HEC. Since gap junction
      mediated intercellular communication increases in migrating HEC, we determined
      whether IBOP might inhibit coupling or connexin expression in HEC. IBOP reduced
      the passage of microinjected dyes between HEC by 50%, and the effects of IBOP on
      migration and tube formation were mimicked by the gap junction inhibitor 18beta
      glycyrrhetinic acid (1 microM) with a similar time course and efficacy. IBOP (24
      h) did not affect the expression or phosphorylation of connexin 43 in whole HEC
      lysates. Immunohistologic examination of HEC suggested that IBOP may impair
      functional coupling by altering the cellular distribution of gap junctions,
      leading to increased connexin 43 internalization. Thus, this finding that TXA(2)
      mimetics can prevent HEC migration and tube formation, possibly by impairing
      intercellular communication, suggests that antagonizing TXA(2) signaling might
      enhance vascularization of ischemic tissue.

PMID- 10585432
TI  - Heterologous high level expression, purification, and enzymological properties of
      recombinant rat cobalamin-dependent methionine synthase.
AB  - Rat methionine synthase was expressed chiefly as apoenzyme in recombinant
      baculovirus-infected insect cells (Yamada, K., Tobimatsu, T., and Toraya, T.
      (1998) Biosci. Biotech. Biochem. 62, 2155-2160). The apoenzyme produced was very
      unstable, and therefore, after complexation with methylcobalamin, the functional
      holoenzyme was purified to homogeneity. The specific activity and apparent K(m)
      values for substrates were in good agreement with those obtained with purified
      rat liver enzyme. The electronic spectrum of the purified recombinant enzyme
      resembled that of cob(II)alamin and changed to a methylcobalamin-like one upon
      incubation of the enzyme with titanium(III) and S-adenosylmethionine. The rate of
      oxidative inactivation of the enzyme in the absence of S-adenosylmethionine was
      slower with a stronger reducing agent like titanium(III). The nucleotide moiety,
      especially the phosphodiester group, was shown to play an important role in the
      binding of the coenzyme to apoprotein and thus for catalysis. Upon incubation
      with the apoenzyme in the absence of a reducing agent, cyano- and aquacobalamin
      were not effective or were effective only slightly in reconstituting holoenzyme.
      Ethyl- and propylcobalamin formed inactive complexes with apoenzyme, which were
      converted to holoenzyme by photolytic activation. Adenosylcobalamin was not able
      to form a complex with apoenzyme, which was convertible to holoenzyme by
      photoirradiation.

PMID- 10585434
TI  - Self-association of the alpha subunit of phosphorylase kinase as determined by
      two-hybrid screening.
AB  - The structural organization of the (alphabetagammadelta)(4) phosphorylase kinase
      complex has been studied using the yeast two-hybrid screen for the purpose of
      elucidating regions of alpha subunit interactions. By screening a rabbit skeletal
      muscle cDNA library with residues 1-1059 of the alpha subunit of phosphorylase
      kinase, we have isolated 16 interacting, independent, yet overlapping transcripts
      of the alpha subunit containing its C-terminal region. Domain mapping of binary
      interactions between alpha constructs revealed two regions involved in the self
      association of the alpha subunit: residues 833-854, a previously unrecognized
      leucine zipper, and an unspecified region within residues 1015-1237. The cognate
      binding partner for the latter domain has been inferred to lie within the stretch
      from residues 864-1059. Indirect evidence from the literature suggests that the
      interacting domains contained within the latter two, overlapping regions may be
      further narrowed to the stretches from 1057 to 1237 and from 864 to 971. Cross
      linking of the nonactivated holoenzyme with N-(gamma
      maleimidobutyroxy)sulfosuccin-imide ester produced intramolecularly cross-linked
      alpha-alpha dimers, consistent with portions of two alpha subunits in the
      holoenyzme being in sufficient proximity to associate. This is the first report
      to identify potential areas of contact between the alpha subunits of
      phosphorylase kinase. Additionally, issues regarding the general utility of two
      hybrid screening as a method for studying homodimeric interactions are discussed.

PMID- 10585433
TI  - Evidence for triacylglycerol synthesis in the lumen of microsomes via a lipolysis
      esterification pathway involving carnitine acyltransferases.
AB  - In this study a pathway for the synthesis of triacylglycerol (TAG) within the
      lumen of the endoplasmic reticulum has been identified, using microsomes that had
      been preconditioned by depleting their endogenous substrates and then fusing them
      with biotinylated phosphatidylserine liposomes containing CoASH and Mg(2+).
      Incubating these fused microsomes with tri[(3)H] oleoylglycerol and [(14)C]oleoyl
      CoA yielded microsome-associated triacylglycerol, which resisted extensive
      washing and had a [(3)H]:[(14)C] ratio close to 2:1. The data suggest that the
      precursor tri[(3)H]oleoylglycerol was hydrolyzed by microsomal lipase to membrane
      bound di[(3)H]oleoylglycerol and subsequently re-esterified with luminal
      [(14)C]oleoyl-CoA. The accumulation of TAG within the microsomes, even when overt
      diacylglycerol acyltransferase (DGAT I) was inactive, is consistent with the
      existence of a latent diacylglycerol acyltransferase (DGAT II) within the
      microsomal lumen. Moreover, because luminal synthesis of TAG was carnitine
      dependent and markedly reduced by glybenclamide, a potent carnitine
      acyltransferase inhibitor, microsomal carnitine acyltransferase appears to be
      essential for trafficking the [(14)C]oleoyl-CoA into the microsomal lumen for
      subsequent incorporation into newly synthesized TAG. This study thus provides the
      first direct demonstration of an enzymatic process leading to the synthesis of
      luminal triacylglycerol, which is a major component of very low density
      lipoproteins.

PMID- 10585435
TI  - Involvement of 5'-flanking kappaB-like sites within bcl-x gene in silica-induced
      Bcl-x expression.
AB  - The present study investigated the involvement of the transcription factor NF
      kappaB in the expression of an anti-apoptotic gene, bcl-x, using a murine
      macrophage cell line and peritoneal macrophages from both wild type (p50(+/+))
      and NF-kappaB p50 gene knockout (p50(-/-)) mice. Increased expression of Bcl-x
      protein was observed in native and silica-exposed p50(-/-) macrophages in which
      the NF-kappaB p65-containing complex was predominantly induced. Co-transfection
      experiment using a bcl-x promoter reporter construct and an expression vector for
      NF-kappaB p50 or p65 indicates that p65, but not p50, up-regulates the promoter
      activity of the bcl-x gene. DNA sequence analysis revealed that there are several
      kappaB-like sites within the 5'-flanking region of the bcl-x gene.
      Electrophoretic mobility shift assay suggested differences in binding of the NF
      kappaB complexes to these putative NF-kappaB binding sites of the bcl-x gene.

PMID- 10585436
TI  - Reconstitution, identification, and purification of the rat liver golgi membrane
      GDP-fucose transporter.
AB  - Glycosylation of glycoproteins, proteoglycans, and glycolipids occurring in the
      Golgi apparatus requires the translocation of nucleotide sugars from the cytosol
      into the lumen of the Golgi. Translocation is mediated by specific nucleotide
      sugar transporters, integral Golgi membrane proteins that regulate the above
      glycosylation reactions. A defect in GDP-fucose transport into the lumen of the
      Golgi apparatus has been recently identified in a patient affected by leukocyte
      adhesion deficiency type II syndrome (Lubke, T., Marquardt, T., von Figura, K.,
      and Korner, C. (1999) J. Biol. Chem. 274, 25986-25989). We have now identified
      and purified the rat liver Golgi membrane GDP-fucose transporter, a protein with
      an apparent molecular mass of 39 kDa, by a combination of column chromatography,
      native functional size determination on a glycerol gradient, and photoaffinity
      labeling with 8-azidoguanosine-5'-[alpha-(32)P] triphosphate, an analog of GDP
      fucose. The purified transporter appears to exist as a homodimer within the Golgi
      membrane. When reconstituted into phosphatidylcholine liposomes, it was active in
      GDP-fucose transport and was specifically photolabeled with 8-azidoguanosine-5'
      [alpha-(32)P]triphosphate. Transport was also stimulated 2-3-fold after
      preloading proteoliposomes with GMP, the putative antiporter.

PMID- 10585437
TI  - Major anticodon-binding region missing from an archaebacterial tRNA synthetase.
AB  - The small size of the archaebacterial Methanococcus jannaschii tyrosyl-tRNA
      synthetase may give insights into the historical development of tRNAs and tRNA
      synthetases. The L-shaped tRNA has two major arms-the acceptor.TpsiC minihelix
      with the amino acid attachment site and the anticodon-containing arm. The
      structural organization of the tRNA synthetases parallels that of tRNAs. The more
      ancient synthetase domain contains the active site and insertions that interact
      with the minihelix portion of the tRNA. A second, presumably more recent, domain
      interacts with the anticodon-containing section of tRNA. The small size of the M.
      jannaschii enzyme is due to the absence of most of the second domain, including a
      segment thought to bind to the anticodon. Consistent with the absence of an
      anticodon-binding motif, a mutation of the central base of the anticodon had a
      relatively small effect on the aminoacylation efficiency of the M. jannaschii
      enzyme. In contrast, others showed earlier that the same mutation severely
      reduced charging by a normal-sized bacterial enzyme that has the aforementioned
      anticodon-binding motif. However, the M. jannaschii enzyme has a peptide
      insertion into its catalytic domain. This insertion is shared with all other
      tyrosyl-tRNA synthetases and is needed for a critical minihelix interaction. We
      show that the M. jannaschii enzyme is active on minihelix substrates over a wide
      temperature range and has preserved the same peptide-dependent minihelix
      specificity seen in other tyrosine enzymes. These findings are consistent with
      the concept that anticodon interactions of tRNA synthetases were later
      adaptations to the emerging synthetase-tRNA complex that was originally framed
      around the minihelix.

PMID- 10585438
TI  - NF-kappaB induces cAMP-response element-binding protein gene transcription in
      sertoli cells.
AB  - Spermatogenesis is dependent upon Sertoli cells, which relay hormonal signals and
      provide factors required for the differentiation and proliferation of germ cells.
      NF-kappaB transcription factors are constitutively expressed in the nuclei of
      Sertoli cells in rodent testis. Electrophoretic mobility shift assays
      demonstrated that Sertoli NF-kappaB proteins specifically bind to kappaB enhancer
      motifs within the promoter of the cAMP-response element-binding protein (CREB)
      gene, an important mediator of hormonal signals that control spermatogenesis.
      Overexpression of NF-kappaB proteins in primary Sertoli and NIH 3T3 fibroblast
      cells induced the CREB promoter in transient transfection assays. Stimulation of
      Sertoli cells with tumor necrosis factor-alpha, an NF-kappaB-activating cytokine
      produced by round spermatids located adjacent to Sertoli cells, stimulated the
      elimination of IkappaB, the translocation of additional NF-kappaB to the nucleus,
      and increased NF-kappaB binding to CREB promoter kappaB enhancer elements. Tumor
      necrosis factor-alpha also stimulated transcription from the CREB promoter. These
      data demonstrate that NF-kappaB contributes to the up-regulation of CREB
      expression in Sertoli cells and raises the possibility that NF-kappaB may induce
      other Sertoli genes required for spermatogenesis. Furthermore, the CREB promoter
      is also inducible by NF-kappaB in NIH 3T3 cells suggesting that NF-kappaB may be
      a general regulator of CREB in non-testis tissues.

PMID- 10585439
TI  - Structure and characterization of Ectothiorhodospira vacuolata cytochrome b(558),
      a prokaryotic homologue of cytochrome b(5).
AB  - A soluble cytochrome b(558) from the purple phototropic bacterium
      Ectothiorhodospira vacuolata was completely sequenced by a combination of
      automated Edman degradation and mass spectrometry. The protein, with a measured
      mass of 10,094.7 Da, contains 90 residues and binds a single protoheme.
      Unexpectedly, the sequence shows homology to eukaryotic cytochromes b(5). As no
      prokaryotic homologue had been reported so far, we developed a protocol for the
      expression, purification, and crystallization of recombinant cytochrome b(558).
      The structure was solved by molecular replacement to a resolution of 1.65 A. It
      shows that cytochrome b(558) is indeed the first bacterial cytochrome b(5) to be
      characterized and differs from its eukaryotic counterparts by the presence of a
      disulfide bridge and a four-residue insertion in front of the sixth ligand
      (histidine). Eukaryotes contain a variety of b(5) homologues, including soluble
      and membrane-bound multifunctional proteins as well as multidomain enzymes such
      as sulfite oxidase, fatty-acid desaturase, nitrate reductase, and lactate
      dehydrogenase. A search of the Mycobacterium tuberculosis genome showed that a
      previously unidentified gene encodes a fatty-acid desaturase with an N-terminal
      b(5) domain. Thus, it may provide another example of a bacterial b(5) homologue.

PMID- 10585441
TI  - Constitutively active mitogen-activated protein kinase kinase 6 (MKK6) or
      salicylate induces spontaneous 3T3-L1 adipogenesis.
AB  - Although much has been learned regarding the importance of p38 mitogen-activated
      protein kinase in inflammatory and stress responses, relatively little is known
      concerning its role in differentiation processes. Recently, we demonstrated that
      p38 mitogen-activated protein kinase activity is necessary for the
      differentiation of 3T3-L1 fibroblasts into adipocytes (Engelman, J. A., Lisanti,
      M. P., and Scherer, P. E. (1998) J. Biol. Chem. 273, 32111-32120). p38 activity
      is high during the initial stages of differentiation but decreases drastically as
      the fibroblasts undergo terminal differentiation into adipocytes. However, it
      remains unknown whether activation of p38 is sufficient to stimulate adipogenesis
      and whether the down-regulation of p38 activity in mature adipocytes is critical
      for maintaining adipocyte homeostasis. In this report, we have directly addressed
      these questions by analyzing 3T3-L1 cell lines harboring a specific upstream
      activator of p38 (a constitutively active mitogen-activated protein kinase kinase
      6 (MKK6) mutant, MKK6(Glu)) under the control of an inducible promoter. Induction
      of MKK6(Glu) in 3T3-L1 fibroblasts spurs adipocyte conversion in the absence of
      the hormonal mixture normally required for efficient differentiation of wild-type
      cells. However, activation of p38 in adipocytes leads to cell death. Furthermore,
      treatment of 3T3-L1 fibroblasts with salicylate, a potent stimulator of p38,
      produces adipocyte-specific changes consistent with those observed with induction
      of MKK6(Glu). Expression of MKK6(Glu) in NIH-3T3 fibroblasts (cells that do not
      differentiate into adipocytes under normal conditions) is capable of converting
      these fibroblasts into lipid-laden fat cells following hormonal stimulation.
      Thus, p38 activation has pro-adipogenic effects in multiple fibroblast cell
      lines.

PMID- 10585440
TI  - DFak56 is a novel Drosophila melanogaster focal adhesion kinase.
AB  - The mammalian focal adhesion kinase (FAK) family of nonreceptor protein-tyrosine
      kinases have been implicated in controlling a multitude of cellular responses to
      the engagement of cell surface integrins and G protein-coupled receptors. We
      describe here a Drosophila melanogaster FAK homologue, DFak56, which maps to band
      56D on the right arm of the second chromosome. Full-length DFak56 cDNA encodes a
      phosphoprotein of 140 kDa, which shares strong sequence similarity not only with
      mammalian p125(FAK) but also with the more recently described mammalian Pyk2
      (also known as CAKbeta, RAFTK, FAK2, and CADTK) FAK family member. DFak56 has
      intrinsic tyrosine kinase activity and is phosphorylated on tyrosine in vivo. As
      is the case for FAK, tyrosine phosphorylation of DFak56 is increased upon plating
      Drosophila embryo cells on extracellular matrix proteins. In situ hybridization
      and immunofluorescence staining analysis showed that DFak56 is ubiquitously
      expressed with particularly high levels within the developing central nervous
      system. We utilized the UAS-GAL4 expression system to express DFak56 and analyze
      its function in vivo. Overexpression of DFak56 in the wing imaginal disc results
      in wing blistering in adults, a phenotype also observed with both position
      specific integrin loss of function and position-specific integrin overexpression.
      Our results imply a role for DFak56 in adhesion-dependent signaling pathways in
      vivo during D. melanogaster development.

PMID- 10585442
TI  - Anatomy of a homeoprotein revealed by the analysis of human MODY3 mutations.
AB  - Hepatocyte nuclear factor 1alpha (HNF1alpha) is an atypical dimeric homeodomain
      containing protein that is expressed in liver, intestine, stomach, kidney, and
      pancreas. Mutations in the HNF1alpha gene are associated with an autosomal
      dominant form of non-insulin-dependent diabetes mellitus called maturity-onset
      diabetes of the young (MODY3). More than 80 different mutations have been
      identified so far, many of which involve highly conserved amino acid residues
      among vertebrate HNF1alpha. In the present work, we investigated the molecular
      mechanisms by which MODY3 mutations could affect HNF1alpha function. For this
      purpose, we analyzed the properties of 10 mutants resulting in amino acid
      substitutions or protein truncation. Some mutants have a reduced protein
      stability, whereas others are either defective in the DNA binding or impaired in
      their intrinsic trans-activation potential. Three mutants, characterized by a
      complete loss of trans-activation, behave as dominant negatives when transfected
      with the wild-type protein. These data define a clear causative relationship
      between MODY3 mutations and functional defects in HNF1alpha trans-activation. In
      addition, our analysis sheds new light on the structure of a homeoprotein playing
      a key role in pancreatic beta cell function.

PMID- 10585443
TI  - Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a
      cytosolic chaperone for hamartin.
AB  - Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by a
      broad phenotypic spectrum that includes seizures, mental retardation, renal
      dysfunction and dermatological abnormalities. Mutations to either the TSC1 or
      TSC2 gene are responsible for the disease. The TSC1 gene encodes hamartin, a 130
      kDa protein without significant homology to other known mammalian proteins.
      Analysis of the amino acid sequence of tuberin, the 200-kDa product of the TSC2
      gene, identified a region with limited homology to GTPase-activating proteins.
      Previously, we demonstrated direct binding between tuberin and hamartin. Here we
      investigate this interaction in more detail. We show that the complex is
      predominantly cytosolic and may contain additional, as yet uncharacterized
      components alongside tuberin and hamartin. Furthermore, because oligomerization
      of the hamartin carboxyl-terminal coiled coil domain was inhibited by the
      presence of tuberin, we propose that tuberin acts as a chaperone, preventing
      hamartin self-aggregation.

PMID- 10585445
TI  - Transcription factor YY1 is a vaccinia virus late promoter activator.
AB  - Vaccinia virus has a DNA genome, yet replicates in the cytoplasmic compartment of
      the cell. We previously described the identification of a cellular protein having
      high affinity for vaccinia virus late promoter DNA. Sequence substitutions in the
      vaccinia I1L promoter were used to define a 5-nucleotide block at the
      transcription initiation site as essential for interaction with the protein.
      Within this sequence is the recognition motif for the nuclear transcription
      factor YY1. This factor regulates a multitude of cellular promoters, as an
      activator of transcription, as a repressor, or as an initiator element-binding
      protein. Antibodies directed against YY1 were used to show that YY1 copurified
      with the vaccinia late promoter-binding protein and was present in late promoter
      protein complexes in gel supershift assays. Bacterially expressed YY1 also bound
      specifically to late promoter DNA. A dinucleotide replacement within the YY1
      recognition motif directly adjacent to the transcription start site severely
      reduced the affinity of YY1 for the I1L promoter in vitro and impaired I1L
      promoter-dependent transcription in vivo. The intracellular localization of YY1
      was shown by immunofluorescence microscopy to shift from primarily nuclear to the
      cytoplasm after vaccinia infection. These results indicate that YY1 has a
      positive role in the regulation of vaccinia virus late gene transcription and
      suggest that poxviruses have adapted cellular initiator elements as a means of
      regulating viral gene expression. This is the first identifiable cellular protein
      implicated in poxvirus transcription.

PMID- 10585444
TI  - Mapping the functional anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3. Clues to design
      analogs with enhanced selectivity.
AB  - BgK is a peptide from the sea anemone Bunodosoma granulifera, which blocks Kv1.1,
      Kv1.2, and Kv1.3 potassium channels. Using 25 analogs substituted at a single
      position by an alanine residue, we performed the complete mapping of the BgK
      binding sites for the three Kv1 channels. These binding sites included three
      common residues (Ser-23, Lys-25, and Tyr-26) and a variable set of additional
      residues depending on the particular channel. Shortening the side chain of Lys-25
      by taking out the four methylene groups dramatically decreased the BgK affinity
      to all Kv1 channels tested. However, the analog K25Orn displayed increased
      potency on Kv1.2, which makes this peptide a selective blocker for Kv1.2 (K(D) 50
      and 300-fold lower than for Kv1.1 and Kv1.3, respectively). BgK analogs with
      enhanced selectivity could also be made by substituting residues that are
      differentially involved in the binding to some of the three Kv1 channels. For
      example, the analog F6A was found to be >500-fold more potent for Kv1.1 than for
      Kv1.2 and Kv1.3. These results provide new information about the mechanisms by
      which a channel blocker distinguishes individual channels among closely related
      isoforms and give clues for designing analogs with enhanced selectivity.

PMID- 10585446
TI  - Dual roles for transcription factor IIF in promoter escape by RNA polymerase II.
AB  - Transcription factor (TF) IIF is a multifunctional RNA polymerase II
      transcription factor that has well established roles in both transcription
      initiation, where it functions as a component of the preinitiation complex and is
      required for formation of the open complex and synthesis of the first
      phosphodiester bond of nascent transcripts, and in transcription elongation,
      where it is capable of interacting directly with the ternary elongation complex
      and stimulating the rate of transcription. In this report, we present evidence
      that TFIIF is also required for efficient promoter escape by RNA polymerase II.
      Our findings argue that TFIIF performs dual roles in this process. We observe (i)
      that TFIIF suppresses the frequency of abortive transcription by very early RNA
      polymerase II elongation intermediates by increasing their processivity and (ii)
      that TFIIF cooperates with TFIIH to prevent premature arrest of early elongation
      intermediates. In addition, our findings argue that two TFIIF functional domains
      mediate TFIIF action in promoter escape. First, we observe that a TFIIF mutant
      selectively lacking elongation activity supports TFIIH action in promoter escape,
      but is defective in suppressing the frequency of abortive transcription by very
      early RNA polymerase II elongation intermediates. Second, a TFIIF mutant
      selectively lacking initiation activity is more active than wild type TFIIF in
      increasing the processivity of very early elongation intermediates, but is
      defective in supporting TFIIH action in promoter escape. Taken together, our
      findings bring to light a function for TFIIF in promoter escape and support a
      role for TFIIF elongation activity in this process.

PMID- 10585447
TI  - PHR1 encodes an abundant, pleckstrin homology domain-containing integral membrane
      protein in the photoreceptor outer segments.
AB  - We cloned human and murine cDNAs of a gene (designated PHR1), expressed
      preferentially in retina and brain. In both species, PHR1 utilizes two promoters
      and alternative splicing to produce four PHR1 transcripts, encoding isoforms of
      243, 224, 208, and 189 amino acids, each with a pleckstrin homology domain at
      their N terminus and a transmembrane domain at their C terminus. Transcript 1
      originates from a 5'-photoreceptor-specific promoter with at least three Crx
      elements ((C/T)TAATCC). Transcript 2 originates from the same promoter but lacks
      exon 7, which encodes 35 amino acids immediately C-terminal to the pleckstrin
      homology domain. Transcripts 3 and 4 originate from an internal promoter in
      intron 2 and either include or lack exon 7, respectively. In situ hybridization
      shows that PHR1 is highly expressed in photoreceptors, with lower expression in
      retinal ganglion cells. Immunohistochemistry localizes the PHR1 protein to
      photoreceptor outer segments where chemical extraction studies confirm it is an
      integral membrane protein. Using a series of PHR1 glutathione S-transferase
      fusion proteins to perform in vitro binding assays, we found PHR1 binds
      transducin betagamma subunits but not inositol phosphates. This activity and
      subcellular location suggests that PHR1 may function as a previously unrecognized
      modulator of the phototransduction pathway.

PMID- 10585448
TI  - The microtubule binding of Tau and high molecular weight Tau in apoptotic PC12
      cells is impaired because of altered phosphorylation.
AB  - Although the importance of the microtubule network throughout cell life is well
      established, the dynamics of microtubules during apoptosis, a regulated cell
      death process, is unclear. In a previous study (Davis, P. K., and Johnson, G. V.
      (1999) Biochem. J. 340, 51-58) we demonstrated that the phosphorylation of the
      microtubule-associated protein tau was increased during neuronal PC12 cell
      apoptosis. The purpose of this study was to determine whether the increased tau
      phosphorylation that occurred during apoptosis impaired the microtubule binding
      capacity of tau. This study is the first demonstration that microtubule-binding
      by tau and high molecular weight tau is significantly impaired as a result of
      altered phosphorylation during a naturally occurring process, apoptosis.
      Furthermore, co-immunofluorescence studies reveal for the first time that tau
      populations within an apoptotic neuronal PC12 cell exhibit differential
      phosphorylation. In control PC12 cells, Tau-1 staining (Tau-1 recognizes an
      unphosphorylated epitope) is evident throughout the entire cell body. In
      contrast, Tau-1 immunoreactivity in apoptotic PC12 cells is retained in the
      nuclear/perinuclear region but is significantly decreased in the cytoplasm up to
      the plasma membrane. The selective distribution of phosphorylated tau in
      apoptotic PC12 cells indicates that tau likely plays a significant role in the
      cytoskeletal changes that occur during apoptosis.

PMID- 10585449
TI  - Characterization of a plasma membrane calcium oscillator in rat pituitary
      somatotrophs.
AB  - In excitable cells, oscillations in intracellular free calcium concentrations
      ([Ca(2+)](i)) can arise from action-potential-driven Ca(2+) influx, and such
      signals can have either a localized or global form, depending on the coupling of
      voltage-gated Ca(2+) influx to intracellular Ca(2+) release pathway. Here we show
      that rat pituitary somatotrophs generate spontaneous [Ca(2+)](i) oscillations,
      which rise from fluctuations in the influx of external Ca(2+) and propagate
      within the cytoplasm and nucleus. The addition of caffeine and ryanodine,
      modulators of ryanodine-receptor channels, and the depletion of intracellular
      Ca(2+) stores by thapsigargin and ionomycin did not affect the global nature of
      spontaneous [Ca(2+)](i) signals. Bay K 8644, an L-type Ca(2+) channel agonist,
      initiated [Ca(2+)](i) signaling in quiescent cells, increased the amplitude of
      [Ca(2+)](i) spikes in spontaneously active cells, and stimulated growth hormone
      secretion in perifused pituitary cells. Nifedipine, a blocker of L-type Ca(2+)
      channels, decreased the amplitude of spikes and basal growth hormone secretion,
      whereas Ni(2+), a blocker of T-type Ca(2+) channels, abolished spontaneous
      [Ca(2+)](i) oscillations. Spiking was also abolished by the removal of
      extracellular Na(+) and by the addition of 10 mM Ca(2+), Mg(2+), or Sr(2+), the
      blockers of cyclic nucleotide-gated channels. Reverse transcriptase-polymerase
      chain reaction and Southern blot analyses indicated the expression of mRNAs for
      these channels in mixed pituitary cells and purified somatotrophs. Growth hormone
      releasing hormone, an agonist that stimulated cAMP and cGMP productions in a dose
      dependent manner, initiated spiking in quiescent cells and increased the
      frequency of spiking in spontaneously active cells. These results indicate that
      in somatotrophs a cyclic nucleotide-controlled plasma membrane Ca(2+) oscillator
      is capable of generating global Ca(2+) signals spontaneously and in response to
      agonist stimulation. The Ca(2+)-signaling activity of this oscillator is
      dependent on voltage-gated Ca(2+) influx but not on Ca(2+) release from
      intracellular stores.

PMID- 10585450
TI  - Separate cis-acting DNA elements control cell type- and tissue-specific
      expression of collagen binding molecular chaperone HSP47.
AB  - HSP47 is a collagen-binding heat shock protein and is assumed to act as a
      molecular chaperone in the biosynthesis and secretion of procollagen. As the
      synthesis of HSP47 is closely correlated with that of collagen in various cell
      lines and tissues, we performed a promoter/reporter assay using HSP47-producing
      and nonproducing cells. 280 base pairs (bp(s)) of upstream promoter were shown to
      be necessary for the basal expression but not to be enough for the cell type
      specific expression. When the first and the second introns were introduced
      downstream of this 280-bp region, marked up-regulation of the reporter activity
      was observed in HSP47-producing cells but not in nonproducing cells. This was
      confirmed in transgenic mice by staining the lacZ gene product under the control
      of the 280-bp upstream promoter and the introns. Staining was observed in skin,
      chondrocytes, precursor of bone, and other HSP47/collagen-producing tissues. A
      putative Sp1-binding site at -210 bp in the promoter, to which Sp3 and an
      unidentified protein bind, was shown to be responsible for this up-regulation
      when combined with the introns. However no difference in the binding to this
      probe was observed between HSP47-producing and nonproducing cells. The
      responsible region for cell type-specific up-regulation was found to be located
      in a 500-bp segment in the first intron. On electrophoresis mobility shift assay
      using this 500-bp probe, specific DNA-protein complexes were only observed in
      HSP47-producing cell extracts. These results suggest that two separate elements
      are necessary for the cell type-specific expression of the hsp47 gene; one is a
      putative Sp1-binding site at -210 bp necessary for basal expression, and the
      other is a 500-bp region within the first intron, required for cell type-specific
      expression.

PMID- 10585451
TI  - Apolipoprotein E participates in the regulation of very low density lipoprotein
      triglyceride secretion by the liver.
AB  - ApoE-deficient mice on low fat diet show hepatic triglyceride accumulation and a
      reduced very low density lipoprotein (VLDL) triglyceride production rate. To
      establish the role of apoE in the regulation of hepatic VLDL production, the
      human APOE3 gene was introduced into apoE-deficient mice by cross-breeding with
      APOE3 transgenics (APOE3/apoe-/- mice) or by adenoviral transduction. APOE3 was
      expressed in the liver and, to a lesser extent, in brain, spleen, and lung of
      transgenic APOE3/apoe-/- mice similar to endogenous apoe. Plasma cholesterol
      levels in APOE/apoe-/- mice (3.4 +/- 0.5 mM) were reduced when compared with apoe
      /- mice (12.6 +/- 1.4 mM) but still elevated when compared with wild type control
      values (1.9 +/- 0.1 mM). Hepatic triglyceride accumulation in apoE-deficient mice
      was completely reversed by introduction of the APOE3 transgene. The in vivo
      hepatic VLDL-triglyceride production rate was reduced to 36% of control values in
      apoE-deficient mice but normalized in APOE3/apoe-/- mice. Hepatic secretion of
      apoB was not affected in either of the strains. Secretion of (3)H-labeled
      triglycerides synthesized from [(3)H]glycerol by cultured hepatocytes from apoE
      deficient mice was four times lower than by APOE3/apoe-/- or control hepatocytes.
      The average size of secreted VLDL particles produced by cultured apoE-deficient
      hepatocytes was significantly reduced when compared with those of APOE3/apoe-/-
      and wild type mice. Hepatic expression of human APOE3 cDNA via adenovirus
      mediated gene transfer in apoE-deficient mice resulted in a reduction of plasma
      cholesterol depending on plasma apoE3 levels. The in vivo VLDL-triglyceride
      production rate in these mice was increased up to 500% compared with LacZ
      injected controls and correlated with the amount of apoE3 per particle. These
      findings indicate a regulatory role of apoE in hepatic VLDL-triglyceride
      secretion, independent from its role in lipoprotein clearance.

PMID- 10585452
TI  - Localization of endogenous Grb10 to the mitochondria and its interaction with the
      mitochondrial-associated Raf-1 pool.
AB  - Grb10 belongs to a small family of adapter proteins that are known to interact
      with a number of receptor tyrosine kinases and signaling molecules. We have
      recently demonstrated that the Grb10 SH2 domain interacts with both the Raf-1 and
      MEK1 kinases. Overexpression of Grb10 genes with mutations in their SH2 domains
      promotes apoptosis in cultured cells, a phenotype that is reversed by concomitant
      overexpression of the wild type gene. Using immunofluorescence microscopy and
      subcellular fractionation we now show that most of the Grb10 molecules are
      peripherally associated with mitochondria. Following insulin-like growth factor I
      or serum treatment, small pools of Grb10 can also be found at the plasma membrane
      and in actin-rich membrane ruffles, whereas overexpression of Grb10 leads to its
      mislocalization to the cytosol. Two-hybrid analysis shows that the Grb10-binding
      site on Raf-1 co-localizes with its Ras-binding domain. Finally, we show that the
      endogenous Grb10 and Raf-1 proteins can be co-immunoprecipitated from a partially
      purified mitochondrial extract, an interaction that is enhanced following the
      activation of Raf-1 by ultraviolet radiation. Thus, we infer that Grb10 may
      regulate signaling between plasma membrane receptors and the apoptosis-inducing
      machinery on the mitochondrial outer membrane by modulating the anti-apoptotic
      activity of mitochondrial Raf-1.

PMID- 10585453
TI  - Pit-1 binding sites at the somatotrope-specific DNase I hypersensitive sites I,
      II of the human growth hormone locus control region are essential for in vivo hGH
      N gene activation.
AB  - The human growth hormone gene cluster is composed of five closely related genes.
      The 5'-most gene in the cluster, hGH-N, is expressed exclusively in somatotropes
      and lactosomatotropes of the anterior pituitary. Although the hGH-N promoter
      contains functional binding sites for multiple transcription factors, including
      Sp1, Zn-15, and Pit-1, predictable and developmentally appropriate expression of
      hGH-N transgenes in the mouse pituitary requires the presence of a previously
      characterized locus control region (LCR) composed of multiple chromatin DNase I
      hypersensitive sites (HS). LCR determinant(s) necessary for hGH-N transgene
      activation are largely conferred by two closely spaced HS (HS I,II) located 14.5
      kilobase pairs upstream of the hGH-N gene. The region sufficient to mediate this
      activity has recently been sublocalized to a 404-base pair segment of HS I,II
      (F14 segment). In the present study, we identified multiple binding sites for the
      pituitary POU domain transcription factor Pit-1 within this segment. Using a
      transgenic founder assay, these sites were shown to be required for high level,
      position-independent, and somatotrope-specific expression of a linked hGH-N
      transgene. Because the Pit-1 sites in the hGH-N gene promoter are insufficient
      for such gene activation in vivo, these data suggested a unique chromatin
      mediated developmental role for Pit-1 in the hGH LCR.

PMID- 10585454
TI  - How an inhibitor of the HIV-I protease modulates proteasome activity.
AB  - The human immunodeficiency virus, type I protease inhibitor Ritonavir has been
      used successfully in AIDS therapy for 4 years. Clinical observations suggested
      that Ritonavir may exert a direct effect on the immune system unrelated to
      inhibition of the human immunodeficiency virus, type I protease. In fact,
      Ritonavir inhibited the major histocompatibility complex class I restricted
      presentation of several viral antigens at therapeutically relevant concentrations
      (5 microM). In search of a molecular target we found that Ritonavir inhibited the
      chymotrypsin-like activity of the proteasome whereas the tryptic activity was
      enhanced. In this study we kinetically analyzed how Ritonavir modulates
      proteasome activity and what consequences this has on cellular functions of the
      proteasome. Ritonavir is a reversible effector of proteasome activity that
      protected the subunits MB-1 (X) and/or LMP7 from covalent active site
      modification with the vinyl sulfone inhibitor(125)I-NLVS, suggesting that they
      are the prime targets for competitive inhibition by Ritonavir. At low
      concentrations of Ritonavir (5 microM) cells were more sensitive to canavanine
      but proliferated normally whereas at higher concentrations (50 microM) protein
      degradation was affected, and the cell cycle was arrested in the G(1)/S phase.
      Ritonavir thus modulates antigen processing at concentrations at which vital
      cellular functions of the proteasome are not yet severely impeded. Proteasome
      modulators may hence qualify as therapeutics for the control of the cytotoxic
      immune response.

PMID- 10585455
TI  - Molecular cloning of six novel Kruppel-like zinc finger genes from hematopoietic
      cells and identification of a novel transregulatory domain KRNB.
AB  - To clone zinc finger genes expressed in hematopoietic system, we designed primers
      based on conserved Cys(2)/His(2) zinc finger sequences to amplify corresponding
      domains from mRNA of normal bone marrow and leukemia cell line NB4. DNA fragments
      of novel zinc finger genes were chosen and used as probe pool to screen cDNA
      libraries or subject to rapid amplification of cDNA ends in order to obtain full
      length cDNA. Six cDNAs including whole open reading frame of zinc finger
      proteins, named as ZNF191, ZNF253 (BMZF-1), ZNF255 (BMZF-2), ZNF256 (BMZF-3),
      ZNF257 (BMZF-4), and ZNF254 (BMZF-5) were obtained. All six belong to the Kruppel
      like zinc finger gene family, and typical transcriptional regulatory motifs exist
      in the N-terminal moiety, such as the SCAN box in ZNF191, and the KRAB domains in
      ZNF253, ZNF254, ZNF256, and ZNF257. A previously undefined sequence nominated as
      Kruppel-related novel box, which may represent a new transregulatory motif, was
      revealed at the N terminus of ZNF255. The transregulatory function of non-zinc
      finger regions of ZNF191, ZNF253, and ZNF255 were addressed in yeast and
      mammalian cells. The results indicated that ZNF255 might be a conditional
      transactivator, whereas ZNF253 and ZNF191 displayed a suppressive effect on the
      transcription in yeast and/or mammalian systems.

PMID- 10585456
TI  - Functional analysis of a mutation occurring between the two in-frame AUG codons
      of human angiotensinogen.
AB  - Angiotensinogen (ANG) is the specific substrate of the renin-angiotensin system,
      a major participant in blood pressure control. We have identified a natural
      mutation at the -30 amino acid position of the angiotensinogen signal peptide, in
      which an arginine is replaced by a proline (R-30P). Heterozygous individuals with
      R-30P showed a tendency to lowered plasma angiotensinogen level (1563 ng of ANG
      I/ml (range 1129-1941)) compared with normal individuals in the family (1892 ng
      of ANG I/ml (range 1603-2072)). Human angiotensinogen mRNA has two in-phase
      translation initiation codons (AUG) starting upstream 39 and 66 nucleotides from
      the cap site. R-30P occurs in a cluster of basic residues adjacent to the first
      AUG codon that may affect intracellular sorting of the nascent protein. Pulse
      chase experiments in transiently transfected cultured cells revealed that the R
      30P mutation was associated with reduced amounts of both intra- and extracellular
      protein. In a cell-free system, we found that two forms of native angiotensinogen
      were generated by alternative initiation of translation at either AUG codon.
      Alteration of either the first or second AUG codons abolished the synthesis of
      the longer and the shorter form of native angiotensinogen, respectively.
      Furthermore, the rate of secretion of the shorter form was lower than that of the
      longer form. By transplanting angiotensinogen signal peptide onto green
      fluorescence protein, however, we found that both forms of the signal peptide
      could target green fluorescence protein, normally localized in the cytoplasm, to
      the secretory pathway. Although the R-30P mutation may not affect intracellular
      sorting of angiotensinogen in a qualitative manner, it leads to a quantitative
      reduction in the net secretion of mature angiotensinogen through decreased
      translocation or increased residence time in the endoplasmic reticulum.

PMID- 10585457
TI  - Expression and function of the gonadotropin-releasing hormone receptor are
      dependent on a conserved apolar amino acid in the third intracellular loop.
AB  - The coupling of agonist-activated heptahelical receptors to their cognate G
      proteins is often dependent on the amino-terminal region of the third
      intracellular loop. Like many G protein-coupled receptors, the gonadotropin
      releasing hormone (GnRH) receptor contains an apolar amino acid in this region at
      a constant distance from conserved Pro and Tyr/Asn residues in the fifth
      transmembrane domain (TM V). An analysis of the role of this conserved residue
      (Leu(237)) in GnRH receptor function revealed that the binding affinities of the
      L237I and L237V mutant receptors were unchanged, but their abilities to mediate
      GnRH-induced inositol phosphate signaling, G protein coupling, and agonist
      induced internalization were significantly impaired. Receptor expression at the
      cell surface was reduced by replacement of Leu(237) with Val, and abolished by
      replacement with Ala, Arg, or Asp residues. These results are consistent with
      molecular modeling of the TM V and VI regions of the GnRH receptor, which
      predicts that Leu(237) is caged by several apolar amino acids (Ile(233),
      Ile(234), and Val(240) in TM V, and Leu(262), Leu(265), and Val(269) in TM VI) to
      form a tight hydrophobic cluster. These findings indicate that the conserved
      apolar residue (Leu(237)) in the third intracellular loop is an important
      determinant of GnRH receptor expression and activation, and possibly that of
      other G protein-coupled receptors.

PMID- 10585458
TI  - The peroxynitrite reductase activity of cytochrome c oxidase involves a two
      electron redox reaction at the heme a(3)-Cu(B) site.
AB  - Fully and partially reduced forms of isolated bovine cytochrome c oxidase undergo
      a two-electron oxidation-reduction process with added peroxynitrite, leading to
      catalytic oxidation of ferrocytochrome c to ferricytochrome c. The other major
      reaction product is nitrite ion, 86% of the added peroxynitrite being measurably
      converted to this species. The reaction is inhibited in the presence of cyanide,
      implicating the heme a(3)-Cu(B) binuclear pair as the active site. Moreover,
      provided peroxynitrite is not added to excess, the reductase activity of the
      enzyme toward this oxidant efficiently protects other protein and detergent
      molecules in vitro from nitration of tyrosine residues and oxidative damage. If
      the enzyme is exposed to approximately 10(2)-fold excesses of peroxynitrite, then
      significant irreversible loss of electron transfer activity results, and the heme
      a(3)-Cu(B) binuclear pair no longer undergo a characteristic carbon monoxide
      driven reduction. The accompanying rather small changes in the observed
      electronic absorption spectrum are suggestive of a modification in the vicinity
      of one or both hemes but probably not to the cofactors themselves.

PMID- 10585459
TI  - The motif D loop of human immunodeficiency virus type 1 reverse transcriptase is
      critical for nucleoside 5'-triphosphate selectivity.
AB  - Human immunodeficiency virus type 1 reverse transcriptase (RT) has limited
      homology with DNA and RNA polymerases. The conserved Lys-220 of motif D is a
      signature of RNA-dependent polymerases. Motif D is located in the "palm" domain
      and forms a small loop from Thr-215 to Lys-223. This loop is absent from the
      polymerase I family of DNA-dependent polymerases. Analysis of RT structures in
      comparison with other polymerases reveals that the motif D loop has the potential
      to undergo a conformational change upon binding a nucleotide. We find that amino
      acid changes in motif D affect the interaction of RT with the incoming
      nucleotide. A chimeric RT in which the loop of motif D is substituted by the
      corresponding amino acid segment from Taq DNA polymerase lacking this loop has a
      decreased affinity for incoming nucleotides. We have also constructed a mutant RT
      where the conserved lysine at position 220 within the motif D is substituted with
      glutamine. Both RT(K220Q) and the chimeric RT are resistant in vitro to 3'-deoxy
      3'-azidothymidine 5'-triphosphate (AZTTP). These results suggest that motif D is
      interacting with the incoming nucleotide and a determinant of the sensitivity of
      reverse transcriptases to AZTTP. We do not observe any interaction of motif D
      with the template primer.

PMID- 10585460
TI  - Aspartate 142 is involved in both hydrolase and dehydrogenase catalytic centers
      of 10-formyltetrahydrofolate dehydrogenase.
AB  - The enzyme 10-formyltetrahydrofolate dehydrogenase (FDH) catalyzes conversion of
      10-formyltetrahydrofolate to tetrahydrofolate in either a dehydrogenase or
      hydrolase reaction. The hydrolase reaction occurs in a 310-residue amino-terminal
      domain of FDH (N(t)-FDH), whereas the dehydrogenase reaction requires the full
      length enzyme. N(t)-FDH shares some sequence identity with several 10
      formyltetrahydrofolate-utilizing enzymes. All these enzymes have a strictly
      conserved aspartate, which is Asp(142) in the case of N(t)-FDH. Replacement of
      the aspartate with alanine, asparagine, glutamate, or glutamine in N(t)-FDH
      resulted in complete loss of hydrolase activity. All the mutants, however, were
      able to bind folate, although with lower affinity than wild-type N(t)-FDH. Six
      other aspartate residues located near the conserved Asp(142) were substituted
      with an alanine, and these substitutions did not result in any significant
      changes in the hydrolase activity. The expressed D142A mutant of the full-length
      enzyme completely lost both hydrolase and dehydrogenase activities. This study
      shows that Asp(142) is an essential residue in the enzyme mechanism for both the
      hydrolase and dehydrogenase reactions of FDH, suggesting that either the two
      catalytic centers of FDH are overlapped or the dehydrogenase reaction occurs
      within the hydrolase catalytic center.

PMID- 10585461
TI  - Highly regulated cell type-restricted expression of human renin in mice
      containing 140- or 160-kilobase pair P1 phage artificial chromosome transgenes.
AB  - We generated transgenic mice with two P1 artificial chromosomes, each containing
      the human renin (HREN) gene and extending to -35 and -75 kilobase pairs,
      respectively. HREN protein production was restricted to juxtaglomerular cells of
      the kidney, and its expression was tightly regulated by angiotensin II and
      sodium. The magnitude of the up- and down-regulation in HREN mRNA caused by the
      stimuli tested was identical to the endogenous renin gene, suggesting tight
      physiological regulation. P1 artificial chromosome mice were mated with
      transgenic mice overexpressing human angiotensinogen to determine if there was a
      chronic compensatory down-regulation of the transgene. Despite a 3-fold down
      regulation of HREN mRNA, plasma angiotensin II and blood pressure was modestly
      elevated in the double transgenic mice. Nevertheless, this elevation was
      significantly less than a different double transgenic model containing a poorly
      regulated HREN transgene. The increase in blood pressure, despite the decrease in
      HREN mRNA, suggests that the HREN gene can partially, but not completely,
      compensate for excess circulating angiotensinogen. These data suggest the
      possibility that increases in circulating or tissue angiotensinogen may cause an
      increase in blood pressure in humans, even in the presence of a functionally
      active servo-mechanism to down-regulate HREN expression.

PMID- 10585462
TI  - Regulated trafficking of the human dopamine transporter. Clathrin-mediated
      internalization and lysosomal degradation in response to phorbol esters.
AB  - The dopamine transporter plays an essential role in the modulation of
      dopaminergic neurotransmission by mediating the reuptake of dopamine into
      presynaptic neurons. In cells expressing the dopamine transporter, activation of
      protein kinase C by phorbol esters results in a significant reduction in dopamine
      uptake. This phorbol ester-mediated inhibition of dopamine transport is
      associated with a decrease in V(max), although the apparent affinity of the
      transporter for dopamine remains unchanged. Using a green fluorescent protein
      tagged dopamine transporter stably expressed in Madin-Darby canine kidney cells,
      we show in live cells that the decrease in transporter activity is caused by the
      rapid internalization of carriers from the plasma membrane. This redistribution
      of the transporter is specific to phorbol ester activation and is unaffected by
      the presence of either substrates or inhibitors of the carrier. Upon the addition
      of phorbol esters, transporters at the cell surface are rapidly endocytosed
      through a clathrin-mediated and dynamin-dependent mechanism into early endosomes,
      where they colocalize with transferrin. The internalized carrier is targeted to
      the endosomal/lysosomal pathway and is completely degraded within 2 h of protein
      kinase C activation. Phorbol ester-mediated alterations in the trafficking of the
      dopamine transporter may serve as a mechanism for controlling extracellular
      dopamine levels in the central nervous system.

PMID- 10585463
TI  - Cloning, expression, and cellular localization of a human prenylcysteine lyase.
AB  - Prenylated proteins contain either a 15-carbon farnesyl or 20-carbon
      geranylgeranyl isoprenoid covalently attached to cysteine residues at or near
      their C terminus. These proteins constitute up to 2% of total cellular protein in
      eukaryotic cells. The degradation of prenylated proteins raises a metabolic
      challenge to the cell, because the thioether bond of the modified cysteine is
      quite stable. We recently identified and isolated an enzyme termed prenylcysteine
      lyase that cleaves the prenylcysteine to free cysteine and an isoprenoid product
      (Zhang, L., Tschantz, W. R., and Casey, P. J. (1997) J. Biol. Chem. 272, 23354
      23359). To facilitate the molecular characterization of this enzyme, its cloning
      was undertaken. Overlapping cDNA clones encoding the complete coding sequence of
      this enzyme were obtained from a human cDNA library. The open reading frame of
      the gene encoding prenylcysteine lyase is 1515 base pairs and has a nearly
      ubiquitous expression pattern with a message size of 6 kilobase pairs.
      Recombinant prenylcysteine lyase was produced in a baculovirus-Sf9 expression
      system. Analysis of both the recombinant and native enzyme revealed that the
      enzyme is glycosylated and contains a signal peptide that is cleaved during
      processing. Additionally, the subcellular localization of this enzyme was
      determined to be lysosomal. These findings strengthen the notion that
      prenylcysteine lyase plays an important role in the final step in the degradation
      of prenylated proteins and will allow further physiological and biochemical
      characterization of this enzyme.

PMID- 10585464
TI  - Thioredoxin-dependent redox regulation of p53-mediated p21 activation.
AB  - Thioredoxin (TRX) is a dithiol-reducing enzyme that is induced by various
      oxidative stresses. TRX regulates the activity of DNA-binding proteins, including
      Jun/Fos and nuclear factor-kappaB. TRX also interacts with an intranuclear
      reducing molecule redox factor 1 (Ref-1), which enhances the activity of Jun/Fos.
      Here, we have investigated the role of TRX in the regulation of p53 activity.
      Electrophoretic mobility shift assay showed that TRX augmented the DNA binding
      activity of p53 and also further potentiated Ref-1-enhanced p53 activity.
      Luciferase assay revealed that transfection of TRX enhanced p53-dependent
      expression of p21 and further intensified Ref-1-mediated p53 activation.
      Furthermore, Western blot analysis revealed that p53-dependent induction of p21
      protein was also facilitated by transfection with TRX. Overexpression of
      transdominant negative mutant TRX (mTRX) suppressed the effects of TRX or Ref-1,
      showing a functional interaction between TRX and Ref-1. cis
      Diamminedichloroplatinum (II) (CDDP) induced p53 activation and p21
      transactivation. The p53-dependent p21 transactivation induced by CDDP was
      inhibited by mTRX overexpression, suggesting that TRX-dependent redox regulation
      is physiologically involved in p53 regulation. CDDP also stimulated translocation
      of TRX from the cytosol into the nucleus. Hence, TRX-dependent redox regulation
      of p53 activity indicates coupling of the oxidative stress response and p53
      dependent repair mechanism.

PMID- 10585465
TI  - Functional characterization of mutations in melanocortin-4 receptor associated
      with human obesity.
AB  - Melanocortin-4 receptor (MC4R) is a G protein-coupled receptor implicated in the
      regulation of body weight. Genetic studies in humans have identified two
      frameshift mutations of MC4R associated with a dominantly inherited form of
      obesity. We have generated and expressed the corresponding MC4R mutants in 293T
      cells and found that cells transfected with the truncation mutants failed to
      exhibit agonist binding or responsiveness despite retention of structural motifs
      potentially sufficient for binding and signaling. Immunofluorescence studies
      showed that the mutant proteins were expressed and localized in the intracellular
      compartment but absent from the plasma membrane, suggesting that these mutations
      disrupted the proper cellular transport of MC4R. Further studies identified a
      sequence in the cytoplasmic tail of MC4R necessary for the cell surface
      targeting. We further investigated a possible dominant-negative activity of the
      mutants on wild-type receptor function. Co-transfection studies showed that the
      mutants affected neither signaling nor cell surface expression of wild-type MC4R.
      We also characterized three human sequence variants of MC4R, but these exhibited
      identical affinities for peptide ligands and identical agonist responsiveness.
      Thus, unlike the obesity-associated MC4R truncation mutants, the polymorphisms of
      MC4R are unlikely to be contributors to human obesity.

PMID- 10585466
TI  - The prespore vesicles of Dictyostelium discoideum. Purification,
      characterization, and developmental regulation.
AB  - The coordinate fusion of the prespore vesicles (PSVs) with the plasma membrane at
      the terminal stage of spore differentiation in Dictyostelium discoideum is an
      important example of developmentally regulated protein secretion. However, little
      is known about the composition of the vesicles, the molecular signals regulating
      secretion, or the mechanics of the membrane fusion. Taking a biochemical
      approach, we purified PSVs from different developmental stages. These
      preparations are highly enriched for their specific cargo of spore coat proteins
      while devoid of markers for other cellular compartments. Electron microscopic
      observations show that the PSV preparations are homogenous, with the soluble
      spore coat protein PsB/SP85 distributed throughout the lumen and the acid
      mucopolysaccharide localized in the central core. During development the PSVs
      increase in size and density concomitant with an increase in their protein cargo.
      The PSVs contain approximately 80 proteins, and we have identified a PSV-specific
      GTP-binding protein that may be involved in regulating vesicle fusion. The PSVs
      are not clathrin-coated and do not contain the SpiA spore coat protein. The PSV
      preparations are ideal for a global proteome analysis to identify proteins
      involved in signal reception, vesicle movement, docking, and fusion in this
      developmentally regulated organelle.

PMID- 10585467
TI  - Sterol regulatory element-binding protein-1 as a key transcription factor for
      nutritional induction of lipogenic enzyme genes.
AB  - To elucidate the physiological role of sterol regulatory element-binding protein
      1 (SREBP-1), the hepatic mRNA levels of genes encoding various lipogenic enzymes
      were estimated in SREBP-1 gene knockout mice after a fasting-refeeding treatment,
      which is an established dietary manipulation for the induction of lipogenic
      enzymes. In the fasted state, the mRNA levels of all lipogenic enzymes were
      consistently low in both wild-type and SREBP-1(-/-) mice. However, the absence of
      SREBP-1 severely impaired the marked induction of hepatic mRNAs of fatty acid
      synthetic genes, such as acetyl-CoA carboxylase, fatty acid synthase, and
      stearoyl-CoA desaturase, that was observed upon refeeding in the wild-type mice.
      Furthermore, the refeeding responses of other lipogenic enzymes, glycerol-3
      phosphate acyltransferase, ATP citrate lyase, malic enzyme, glucose-6-phosphate
      dehydrogenase, and S14 mRNAs, were completely abolished in SREBP-1(-/-) mice. In
      contrast, mRNA levels for cholesterol biosynthetic genes were elevated in the
      refed SREBP-1(-/-) livers accompanied by an increase in nuclear SREBP-2 protein.
      When fed a high carbohydrate diet for 14 days, the mRNA levels for these
      lipogenic enzymes were also strikingly lower in SREBP-1(-/-) mice than those in
      wild-type mice. These data demonstrate that SREBP-1 plays a crucial role in the
      induction of lipogenesis but not cholesterol biosynthesis in liver when excess
      energy by carbohydrates is consumed.

PMID- 10585469
TI  - Brain actin-associated protein phosphatase 1 holoenzymes containing spinophilin,
      neurabin, and selected catalytic subunit isoforms.
AB  - We previously characterized PP1bp134 and PP1bp175, two neuronal proteins that
      bind the protein phosphatase 1 catalytic subunit (PP1). Here we purify from rat
      brain actin-cytoskeletal extracts PP1(A) holoenzymes selectively enriched in
      PP1gamma(1) over PP1beta isoforms and also containing PP1bp134 and PP1bp175.
      PP1bp134 and PP1bp175 were identified as the synapse-localized F-actin-binding
      proteins spinophilin (Allen, P. B., Ouimet, C. C., and Greengard, P. (1997) Proc.
      Natl. Acad. Sci. U. S. A. 94, 9956-9561; Satoh, A., Nakanishi, H., Obaishi, H.,
      Wada, M., Takahashi, K., Satoh, K., Hirao, K., Nishioka, H., Hata, Y., Mizoguchi,
      A., and Takai, Y. (1998) J. Biol. Chem. 273, 3470-3475) and neurabin (Nakanishi,
      H., Obaishi, H., Satoh, A., Wada, M., Mandai, K., Satoh, K., Nishioka, H. ,
      Matsuura, Y., Mizoguchi, A., and Takai, Y. (1997) J. Cell Biol. 139, 951-961),
      respectively. Recombinant spinophilin and neurabin interacted with endogenous PP1
      and also with each other when co-expressed in HEK293 cells. Spinophilin residues
      427-470, or homologous neurabin residues 436-479, were sufficient to bind PP1 in
      gel overlay assays, and selectively bound PP1gamma(1) from a mixture of brain
      protein phosphatase catalytic subunits; additional N- and C-terminal sequences
      were required for potent inhibition of PP1. Immunoprecipitation of spinophilin or
      neurabin from crude brain extracts selectively coprecipitated PP1gamma(1) over
      PP1beta. Moreover, immunoprecipitation of PP1gamma(1) from brain extracts
      efficiently coprecipitated spinophilin and neurabin, whereas PP1beta
      immunoprecipitation did not. Thus, PP1(A) holoenzymes containing spinophilin
      and/or neurabin target specific neuronal PP1 isoforms, facilitating efficient
      regulation of synaptic phosphoproteins.

PMID- 10585468
TI  - A crucial role of sterol regulatory element-binding protein-1 in the regulation
      of lipogenic gene expression by polyunsaturated fatty acids.
AB  - Dietary polyunsaturated fatty acids (PUFA) are negative regulators of hepatic
      lipogenesis that exert their effects primarily at the level of transcription.
      Sterol regulatory element-binding proteins (SREBPs) are transcription factors
      responsible for the regulation of cholesterol, fatty acid, and triglyceride
      synthesis. In particular, SREBP-1 is known to play a crucial role in the
      regulation of lipogenic gene expression in the liver. To explore the possible
      involvement of SREBP-1 in the suppression of hepatic lipogenesis by PUFA, we
      challenged wild-type mice and transgenic mice overexpressing a mature form of
      SREBP-1 in the liver with dietary PUFA. In the liver of wild-type mice, dietary
      PUFA drastically decreased the mature, cleaved form of SREBP-1 protein in the
      nucleus, whereas the precursor, uncleaved form in the membranes was not
      suppressed. The decreases in mature SREBP-1 paralleled those in mRNAs for
      lipogenic enzymes such as fatty acid synthase and acetyl-CoA carboxylase. In the
      transgenic mice, dietary PUFA did not reduce the amount of transgenic SREBP-1
      protein, excluding the possibility that PUFA accelerated the degradation of
      mature SREBP-1. The resulting sustained expression of mature SREBP-1 almost
      completely canceled the suppression of lipogenic gene expression by PUFA in the
      SREBP-1 transgenic mice. These results demonstrate that the suppressive effect of
      PUFA on lipogenic enzyme genes in the liver is caused by a decrease in the mature
      form of SREBP-1 protein, which is presumably due to the reduced cleavage of SREBP
      1 precursor protein.

PMID- 10585470
TI  - SHP-1 regulation of p62(DOK) tyrosine phosphorylation in macrophages.
AB  - SHP-1 plays key roles in the modulation of hematopoietic cell signaling. To
      ascertain the impact of SHP-1 on colony-stimulating factor-1 (CSF-1)-mediated
      survival and proliferative signaling, we compared the CSF-1 responses of primary
      bone marrow macrophages (BMM) from wild-type and SHP-1-deficient motheaten
      (me/me) mice. CSF-1-induced protein tyrosine phosphorylation levels were similar
      in wild-type and me/me BMM, except for the constitutive hyperphosphorylation of a
      62-kDa phosphoprotein (pp62) in me/me macrophages. pp62 was identified as the
      RASGAP-associated p62(DOK) and was shown to be the major CSF-1R-associated
      tyrosine-phosphorylated protein in CSF-1-treated BMM. p62(DOK) was found to be
      constitutively associated with SHP-1 in BMM and in 293T cells, co-expressing
      p62(dok) and either wild-type or catalytically inert SHP-1 (SHP-1 C453S). In both
      cell types, the interaction of SHP-1 with p62(DOK) occurred independently of
      p62(DOK) tyrosine phosphorylation, but only the tyrosine-phosphorylated p62(DOK)
      was bound by SHP-1 C453S in a far Western analysis. These findings suggest a
      constitutive association of SHP-1 and p62(DOK) that is either conformation
      dependent or indirect as well as a direct, inducible association of the SHP-1
      catalytic domain with tyrosine-phosphorylated p62(DOK). p62(DOK)
      hyperphosphorylation is not associated with altered CSF-1-induced RAS signaling
      or proliferation. However, whereas wild-type macrophages undergo cell death
      following CSF-1 removal, me/me macrophages exhibit prolonged survival in the
      absence of growth factor. Thus, p62(DOK) is a major SHP-1 substrate whose
      tyrosine phosphorylation correlates with growth factor-independent survival in
      macrophages.

PMID- 10585471
TI  - The E249K mutator mutant of DNA polymerase beta extends mispaired termini.
AB  - The DNA polymerase beta mutant enzyme, which is altered from glutamic acid to
      lysine at position 249, exhibits a mutator phenotype in primer extension assays
      and in the herpes simplex virus-thymidine kinase (HSV-tk) forward mutation assay.
      The basis for this loss of accuracy was investigated by measurement of
      misincorporation fidelity in single turnover conditions. For the four
      misincorporation reactions investigated, the fidelity of the E249K mutant was not
      significantly different from wild type, implying that the mutator phenotype was
      not caused by a general inability to distinguish between correct and incorrect
      bases during the incorporation reaction. However, the discrimination between
      correct and incorrect substrates by the E249K enzyme occurred less during the
      conformational change and chemical steps and more during the initial binding
      step, compared with pol beta wild type. This implies that the E249K mutation
      alters the kinetic mechanism of nucleotide discrimination without reducing
      misincorporation fidelity. In a missing base primer extension assay, we observed
      that the mutant enzyme produced mispairs and extended them. This indicates that
      the altered fidelity of E249K could be due to loss of discrimination against
      mispaired primer termini. This was supported by the finding that the E249K enzyme
      extended a G:A mispair 8-fold more efficiently than wild type and a C:T mispair 4
      fold more efficiently. These results demonstrate that an enhanced ability to
      extend mispairs can produce a mutator phenotype and that the Glu-249 side chain
      of DNA polymerase beta is critical for mispair extension fidelity.

PMID- 10585472
TI  - Interaction in vivo and in vitro between the yeast fimbrin, SAC6P, and a
      polymerization-defective yeast actin (V266G and L267G).
AB  - A mutant yeast actin (GG) has decreased hydrophobicity in a subdomain 3/4
      hydrophobic plug believed to be involved in a hydrophobic cross-strand "plug
      pocket" interaction necessary for actin filament stability. This actin will not
      polymerize in vitro but is compatible with cell viability. We have assessed the
      ability of Sac6p, the yeast homologue of the actin filament stabilizing and
      bundling protein fimbrin, to restore polymerization in vitro and to facilitate GG
      actin function in vivo. Sac6p rescues GG-actin polymerization at 25 degrees C but
      not at 4 degrees C. The actin polymerizes into bundles at room temperature with a
      fimbrin:actin molar ratio of 1:4. At this ratio, every actin monomer contacts a
      Sac6p actin binding domain. Following cold-induced depolymerization, actin/Sac6p
      mixtures repolymerize beginning at 15 degrees C instead of the 25 degrees C
      required for de novo assembly, because of the presence of residual actin-Sac6p
      nuclei. Generation of haploid Deltasac6/GG-actin cells from either diploid or
      haploid cells was unsuccessful. The facile isolation of cells with either
      mutation alone indicates a synthetic lethal relationship between this actin
      allele and the SAC6 gene. Sac6p may allow GG-actin function in vivo by
      stabilizing the actin in bundles thereby helping maintain sufficient levels of an
      otherwise destabilized actin monomer within the cell.

PMID- 10585473
TI  - Peroxisome proliferator-activated receptor beta regulates acyl-CoA synthetase 2
      in reaggregated rat brain cell cultures.
AB  - Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors
      that regulate the expression of many genes involved in lipid metabolism. The
      biological roles of PPARalpha and PPARgamma are relatively well understood, but
      little is known about the function of PPARbeta. To address this question, and
      because PPARbeta is expressed to a high level in the developing brain, we used
      reaggregated brain cell cultures prepared from dissociated fetal rat
      telencephalon as experimental model. In these primary cultures, the fetal cells
      initially form random aggregates, which progressively acquire a tissue-specific
      pattern resembling that of the brain. PPARs are differentially expressed in these
      aggregates, with PPARbeta being the prevalent isotype. PPARalpha is present at a
      very low level, and PPARgamma is absent. Cell type-specific expression analyses
      revealed that PPARbeta is ubiquitous and most abundant in some neurons, whereas
      PPARalpha is predominantly astrocytic. We chose acyl-CoA synthetases (ACSs) 1, 2,
      and 3 as potential target genes of PPARbeta and first analyzed their temporal and
      cell type-specific pattern. This analysis indicated that ACS2 and PPARbeta mRNAs
      have overlapping expression patterns, thus designating the ACS2 gene as a
      putative target of PPARbeta. Using a selective PPARbeta activator, we found that
      the ACS2 gene is transcriptionally regulated by PPARbeta, demonstrating a role
      for PPARbeta in brain lipid metabolism.

PMID- 10585474
TI  - Interaction of bacteriophage T7 gene 4 primase with its template recognition
      site.
AB  - The primase fragment of the bacteriophage T7 63-kDa gene 4 helicase/primase
      protein contains the 271 N-terminal amino acid residues and lacks helicase
      activity. The primase fragment catalyzes the synthesis of oligoribonucleotides at
      rates similar to those catalyzed by the full-length protein in the presence of a
      5-nucleotide DNA template containing a primase recognition site (5'-GGGTC-3', 5'
      TGGTC-3', 5'-GTGTC-3', or 5'-TTGTC-3'). Although it is not copied into the
      oligoribonucleotides, the cytosine at the 3'-position is essential for synthesis
      and template binding. Two nucleotides flanking the 3'-end of the recognition site
      are required for tight DNA binding and rapid oligoribonucleotide synthesis.
      Nucleotides added to the 5'-end have no effect on the rate of oligoribonucleotide
      synthesis or the affinity of the primase for DNA. The binding of either ATP or
      CTP significantly increases the affinity of the primase for its DNA template. DNA
      lacking a primase recognition site does not inhibit oligoribonucleotide
      synthesis, suggesting that the primase binds DNA in a sequence-specific manner.
      The affinity of the primase for templates is weak, ranging from 10 to 150 microM.
      The tight DNA binding (<1 microM) observed with the 63-kDa gene 4 protein occurs
      via interactions between DNA templates and the helicase domain.

PMID- 10585475
TI  - Interaction of ribonucleoside triphosphates with the gene 4 primase of
      bacteriophage T7.
AB  - The primase fragment of bacteriophage T7 gene 4 protein catalyzes the synthesis
      of oligoribonucleotides in the presence of ATP, CTP, Mg(2+) (or Mn(2+)), and DNA
      containing a primase recognition site. During chain initiation, ATP binds with a
      K(m) of 0.32 mM, and CTP binds with a K(m) of 0.85 mM. Synthesis of the
      dinucleotides proceeds at a rate of 3.8/s. The dinucleotide either dissociates or
      is extended to a tetranucleotide. The primase preferentially inserts
      ribonucleotides forming Watson-Crick base pairs with the DNA template >200-fold
      more rapidly than other ribo- or deoxynucleotides. 3'-dCTP binds the primase with
      a similar affinity as CTP and is incorporated as a chain terminator at a rate
      (1)/(100) that of CTP. ATP analogues alpha,beta-methylene ATP, beta,gamma
      methylene ATP, and beta,gamma-imido ATP are incorporated by the primase fragment
      at the 5'-ends of the oligoribonucleotides but not at the 3'-ends. A model is
      presented in which the primase fragment utilizes two nucleotide-binding sites,
      one for the initiating ATP and one for the nucleoside triphosphate which
      elongates the primer on the 3'-end. The initiation site binds ATP or
      oligoribonucleotides, whereas the elongation site binds ATP or CTP as directed by
      the template.

PMID- 10585476
TI  - A requirement for ankyrin binding to clathrin during coated pit budding.
AB  - Recent studies suggest that the mobility of clathrin-coated pits at the cell
      surface are restricted by an actin cytoskeleton and that there is an obligate
      reduction in the amount of spectrin on membranes during coated pit budding. The
      spectrin-actin cytoskeleton associates with membranes primarily through ankyrins,
      which interact with the cytoplasmic region of numerous integral membrane
      proteins. We now report that the fourth repeat domain (D4) of ankyrin(R) binds to
      the N-terminal domain of clathrin heavy chain with high affinity. Addition of
      peptides containing the D4 region inhibited clathrin-coated pit budding in vitro.
      In addition, microinjection of D4 containing peptides blocked the endocytosis of
      fluorescent low density lipoprotein (LDL). Ankyrin(R) peptides that contained
      repeat domains other than D4 had no effect on either in vitro budding or
      internalization of LDL. Finally, immunofluorescence shows that ankyrin is
      uniformly associated with endosomes that contain fluorescent LDL. These results
      suggest that ankyrin plays a role in the budding of clathrin-coated pits during
      endocytosis.

PMID- 10585477
TI  - Identification of a U8 snoRNA-specific binding protein.
AB  - Eukaryotic nucleoli contain a large and diverse population of small nucleolar
      ribonucleoprotein particles (snoRNPs) that play diverse and essential roles in
      ribosome biogenesis. We previously demonstrated that U8 snoRNP is essential for
      processing of both 5.8 and 28 S rRNA. The RNA component of the U8 RNP particle is
      necessary but not sufficient for processing. Using an electrophoretic mobility
      sift assay, we enriched for U8-specific binding proteins from Xenopus ovary
      extracts. UV cross-linking reactions with partially purified fractions implicated
      a 29-kDa protein directly binding to U8 RNA. This protein interacted specifically
      and with high affinity with U8 snoRNA; it did not bind other snoRNAs and is
      probably not a common component of all snoRNPs. This is the first report of a
      protein component specific to an snoRNP essential for processing of the large
      ribosomal subunit in vertebrates.

PMID- 10585478
TI  - Functional analysis of a recombinant glycoprotein Ia/IIa (Integrin
      alpha(2)beta(1)) I domain that inhibits platelet adhesion to collagen and
      endothelial matrix under flow conditions.
AB  - The interaction of platelets with collagen plays an important role in primary
      hemostasis. Glycoprotein Ia/IIa (GPIa/IIa, integrin alpha(2)beta(1)) is a major
      platelet receptor for collagen. The binding site for collagen has been mapped to
      the I domain within the alpha(2) subunit (GPIa). In order to assess the role of
      the alpha(2)-I domain structure in GPIa/IIa binding to collagen, a recombinant I
      domain (amino acids 126-337) was expressed in Escherichia coli. The alpha(2)-I
      protein bound human types I and III collagen in a saturable and divalent cation
      dependent manner and was blocked by the alpha(2)beta(1) function blocking
      antibody 6F1. The alpha(2)-I protein inhibited collagen-induced platelet
      aggregation (IC(50) = 600 nM). Unexpectedly, 6F1, an antibody that fails to
      inhibit platelet aggregation in platelet-rich plasma, blocked the inhibitory
      effect of the alpha(2)-I protein. The alpha(2)-I protein was able to prevent
      platelet adhesion to a collagen surface exposed to flowing blood under low shear
      stress. Interestingly, it inhibited platelet adhesion to extracellular matrix at
      high shear stress. These results, taken together, provide firm evidence that
      GPIa/IIa directly mediates the first contact of platelets with collagen under
      both stirring and flow conditions.

PMID- 10585479
TI  - Quinolones inhibit DNA religation mediated by Staphylococcus aureus topoisomerase
      IV. Changes in drug mechanism across evolutionary boundaries.
AB  - Quinolones are the most active oral antibacterials in clinical use and act by
      increasing DNA cleavage mediated by prokaryotic type II topoisomerases. Although
      topoisomerase IV appears to be the primary cytotoxic target for most quinolones
      in Gram-positive bacteria, interactions between the enzyme and these drugs are
      poorly understood. Therefore, the effects of ciprofloxacin on the DNA cleavage
      and religation reactions of Staphylococcus aureus topoisomerase IV were
      characterized. Ciprofloxacin doubled DNA scission at 150 nM drug and increased
      cleavage approximately 9-fold at 5 microM. Furthermore, it dramatically inhibited
      rates of DNA religation mediated by S. aureus topoisomerase IV. This inhibition
      of religation is in marked contrast to the effects of antineoplastic quinolones
      on eukaryotic topoisomerase II, and suggests that the mechanistic basis for
      quinolone action against type II topoisomerases has not been maintained across
      evolutionary boundaries. The apparent change in quinolone mechanism was not
      caused by an overt difference in the drug interaction domain on topoisomerase IV.
      Therefore, we propose that the mechanistic basis for quinolone action is
      regulated by subtle changes in drug orientation within the enzyme.drug.DNA
      ternary complex rather than gross differences in the site of drug binding.

PMID- 10585480
TI  - Vinexin forms a signaling complex with Sos and modulates epidermal growth factor
      induced c-Jun N-terminal kinase/stress-activated protein kinase activities.
AB  - Vinexin, a novel protein that plays a key role in cell spreading and cytoskeletal
      organization, contains three SH3 domains and binds to vinculin through its first
      and second SH3 domains. We show here that the third SH3 domain binds to Sos, a
      guanine nucleotide exchange factor for Ras and Rac, both in vitro and in vivo.
      Point mutations in the third SH3 domain abolished the vinexin-Sos interaction.
      Stimulation of NIH/3T3 cells with serum, epidermal growth factor (EGF), or
      platelet-derived growth factor (PDGF) decreased the electrophoretic mobility of
      Sos and concomitantly inhibited formation of the vinexin-Sos complex. Phosphatase
      treatment of lysates restored the binding of Sos to vinexin, suggesting that
      signaling from serum, EGF, or PDGF regulates the vinexin-Sos complex through the
      Sos phosphorylation. To evaluate the function of vinexin downstream of growth
      factors, we examined the effects of wild-type and mutant vinexin expression on
      extracellular signal-regulated kinase (Erk) and c-Jun N-terminal kinase/stress
      activated protein kinase (JNK/SAPK) activation in response to EGF. Exogenous
      expression of vinexin beta in NIH/3T3 cells enhanced JNK/SAPK activation but did
      not affect Erk activation. Moreover mutations in the third SH3 domain abolished
      EGF activation of JNK/SAPK in a dominant-negative fashion, whereas they slightly
      stimulated Erk. Together these results suggest that vinexin can selectively
      modulate EGF-induced signal transduction pathways leading to JNK/SAPK kinase
      activation.

PMID- 10585481
TI  - In vitro reconstitution of the bacteriophage T4 clamp loader complex (gp44/62).
AB  - The clamp loader complex (CLC) of bacteriophage T4 is essential for viability and
      has analogs in both prokaryotes and eukaryotes. The gp44 and gp62 subunits of the
      T4 CLC, in a 4:1 ratio, tightly associate such that the two proteins co-purify.
      Using transformed Escherichia coli, we were able to demonstrate for the first
      time purification of the unique protein gp62 in the absence of gp44. We
      experimentally determined the isoelectric point for the individual subunits. An
      in vitro physical interaction could be observed between the native subunits,
      which resulted in a reconstituted CLC that displayed the signature pattern of the
      ATPase functions of native CLC. Thus we demonstrate that the CLC forms via a self
      assembly pathway rather than through a translational capture mechanism.

PMID- 10585482
TI  - Activation of FP prostanoid receptor isoforms leads to Rho-mediated changes in
      cell morphology and in the cell cytoskeleton.
AB  - Prostaglandin F(2alpha) (PGF(2alpha)) exerts its biological effects by binding to
      and activating FP prostanoid receptors. These receptors, which include two
      isoforms, the FP(A) and FP(B), have been cloned from a number of species and are
      members of the superfamily of G-protein-coupled receptors. Previous studies have
      shown that the activation of FP receptors leads to phosphatidylinositol
      hydrolysis, intracellular calcium release, and activation of protein kinase C.
      Here, we demonstrate that PGF(2alpha) treatment of 293-EBNA (Epstein-Barr nuclear
      antigen) cells that have been stably transfected with either the FP(A) or FP(B)
      receptor isoforms leads to changes in cell morphology and in the cell
      cytoskeleton. Specifically, cells treated with PGF(2alpha) show retraction of
      filopodia and become rounded, and actin stress fibers are formed. Pretreatment of
      the cells with bisindolylmaleimide I, a protein kinase C inhibitor, has no effect
      on the PGF(2alpha)-induced changes in cell morphology, although it does block the
      effects of phorbol myristate acetate on cell morphology. On the other hand, the
      PGF(2alpha)-induced changes in cell morphology and formation of actin stress
      fibers can be blocked by pretreatment of the cells with C3 exoenzyme, a specific
      inhibitor of the small G-protein, Rho. Consistent with FP receptor induced
      formation of actin stress fibers and focal adhesions, FP(A) receptor activation
      also leads to rapid (within two minutes) tyrosine phosphorylation of p125 focal
      adhesion kinase (FAK) which can be blocked by pretreating the cells with C3
      exoenzyme. Taken together, these results suggest that the FP receptor isoforms
      are coupled to at least two second messenger pathways, one pathway associated
      with protein kinase C activation, and the other with activation of Rho.

PMID- 10585483
TI  - Amplification of signaling activity of the arc two-component system of
      Escherichia coli by anaerobic metabolites. An in vitro study with different
      protein modules.
AB  - In Escherichia coli, changes in redox condition of growth are sensed and signaled
      by the Arc two-component system. This system consists of ArcB as the membrane
      associated sensor kinase and ArcA as the cytoplasmic response regulator. ArcB is
      a tripartite kinase, possessing a primary transmitter, a receiver, and a
      secondary transmitter domain that catalyzes the phosphorylation of ArcA via a His
      --> Asp --> His --> Asp phosphorelay, as well as the dephosphorylation of ArcA-P
      by a reverse phosphorelay. When ArcA and ArcB were incubated with ATP, the peak
      levels of phosphorylated proteins increased in the presence of the fermentation
      metabolites D-lactate, acetate, or pyruvate. In this study, we report that these
      effectors accelerate the autophosphorylation activity of ArcB and enhance the
      transphosphorylation of ArcA, but have no effect on the dephosphorylation of ArcA
      P. Moreover, the presence of the receiver domain of ArcB is essential for the
      effectors to influence the autophosphorylation rate of the primary transmitter
      domain of ArcB.

PMID- 10585484
TI  - Target and specificity of a nuclear gene product that participates in mRNA 3'-end
      formation in Chlamydomonas chloroplasts.
AB  - Chloroplast mRNA maturation is catalyzed by nucleus-encoded processing enzymes.
      We previously described a recessive nuclear mutation (crp3) that affects 3'-end
      formation of several chloroplast mRNAs in Chlamydomonas reinhardtii (Levy, H.,
      Kindle, K. L., and Stern, D. B. (1997) Plant Cell 9, 825-836). In the crp3
      background, atpB mRNA lacking a 3'-inverted repeat normally required for
      stability accumulates as a discrete transcript. The mutation also affects the
      atpA gene cluster; polycistronic mRNAs with psbI or cemA 3'-ends accumulate to a
      lower level in the crp3 background. Here, we demonstrate that the crp3 mutation
      also alters 3'-end formation of psbI mRNA and cemA-containing mRNAs. A novel 3'
      end is formed in monocistronic psbI transcripts, and this is the only terminus
      observed when the psbI 3'-untranslated region is fused to an aadA reporter gene.
      Accumulation of mRNAs with 3'-ends between cemA and atpH, which is immediately
      downstream, was reduced. However, this sequence was not recognized as a 3'-end
      formation element in chimeric genes. The crp3 mutation was able to confer
      stability to three different atpB 3'-stem-loop-disrupting mutations that lack
      sequence similarity, but are located at a similar distance from the translation
      termination codon. We propose that the wild-type CRP3 gene product is part of the
      general 3' --> 5' processing machinery.

PMID- 10585485
TI  - Distinct phosphatidylinositol 3-kinase lipid products accumulate upon oxidative
      and osmotic stress and lead to different cellular responses.
AB  - Signaling by phosphatidylinositol (PI) 3-kinases is mediated by 3
      phosphoinositides, which bind to Pleckstrin homology (PH) domains that are
      present in a wide spectrum of proteins. PH domains can be classified into three
      groups based on their different lipid binding specificities. Distinct 3
      phosphoinositides can accumulate upon PI 3-kinase activation in cells in response
      to different stimuli and mediate specific cellular responses. In Swiss 3T3 mouse
      fibroblasts, oxidative stress induced by 1 mM H(2)O(2) caused almost exclusive
      accumulation of phosphatidylinositol 3,4-bisphosphate (PtdIns(3, 4)P(2)), whereas
      osmotic stress increased both phosphatidylinositol 3,4,5-trisphosphate
      (PtdIns(3,4,5)P(3)) and PtdIns(3,4)P(2) levels. The increase in PtdIns(3,4)P(2)
      levels, caused by oxidative stress, correlated with the activation of protein
      kinase B, which has a promiscuous PH domain that binds both PtdIns(3,4,5)P(3) and
      PtdIns(3, 4)P(2). p70 S6 kinase, another signaling component downstream of PI 3
      kinase, however, was not activated by this oxidative stress-induced increase in
      PtdIns(3,4)P(2) levels. Increased PtdIns(3,4,5)P(3) and PtdIns(3,4)P(2) levels in
      response to osmotic stress did not correlate with protein kinase B activation,
      because of concomitant activation of an inhibitory pathway, but p70 S6 kinase was
      activated by osmotic stress. These results demonstrate that PtdIns(3,4)P(2) can
      accumulate independently of PtdIns(3,4, 5)P(3) and exerts a pattern of cellular
      responses that is distinct from that induced by accumulation of
      PtdIns(3,4,5)P(3).

PMID- 10585486
TI  - The coiled-coil domain of EspA is essential for the assembly of the type III
      secretion translocon on the surface of enteropathogenic Escherichia coli.
AB  - Enteropathogenic E. coli (EPEC) utilize a type III secretion system to deliver
      virulence-associated effector proteins to the host cell. Four proteins, EspA,
      EspB, EspD, and Tir, which are integral to the formation of characteristic
      "attaching and effacing" (A/E) intestinal lesions, are known to be exported via
      the EPEC type III secretion system. Recent work demonstrated that EspA is a major
      component of a filamentous structure, elaborated on the surface of EPEC, which is
      required for translocation of EspB and Tir. The carboxyl terminus of EspA is
      predicted to comprise an alpha-helical region, which demonstrates heptad
      periodicity whereby positions a and d in the heptad repeat unit abcdefg are
      occupied by hydrophobic residues, indicating a propensity for coiled-coil
      interactions. Here we demonstrate multimeric EspA isoforms in EPEC culture
      supernatants and EspA:EspA interaction on solid phase. Non-conservative amino
      acid substitution of specific EspA heptad residues generated EPEC mutants
      defective in filament assembly but which retained the ability to induce A/E
      lesions; additional mutation totally abolished EspA filament assembly and A/E
      lesion formation. These results demonstrate a similarity to flagellar
      biosynthesis and indicate that the coiled-coil domain of EspA is required for
      assembly of the EspA filament-associated type III secretion translocon.

PMID- 10585487
TI  - Induction by adozelesin and hydroxyurea of origin recognition complex-dependent
      DNA damage and DNA replication checkpoints in Saccharomyces cerevisiae.
AB  - DNA damaging agents induce a conserved intra-S-phase checkpoint that inhibits DNA
      replication in eukaryotic cells. To better understand this checkpoint and its
      role in determining the efficacy of antitumor drugs that damage DNA, we examined
      the effects of adozelesin, a DNA-alkylating antitumor agent that has a profound
      inhibitory effect on initiation of DNA replication in mammals, on the replication
      of Saccharomyces cerevisiae chromosomes. Adozelesin inhibited initiation of S.
      cerevisiae DNA replication by inducing an intra-S-phase DNA damage checkpoint.
      This inhibitory effect was abrogated in orc2-1 cells containing a temperature
      sensitive mutation in a component of the origin recognition complex (ORC) that
      also causes a defect in initiation. The orc2-1 mutation also caused a defect in a
      checkpoint that regulates the activation of origins in late S phase in cells
      treated with hydroxyurea. Defects in both initiation and checkpoint regulation in
      the orc2-1 strain were suppressed by deletion of a gene encoding a putative
      acetyltransferase, SAS2. Adozelesin also induced a cellular response that
      requires a function of ORC in G(1). A similar G(1)-specific response in mammals
      may contribute to the cytotoxic and antitumor properties of this and other DNA
      damaging drugs.

PMID- 10585488
TI  - Dimerization of the extracellular domain of the receptor for epidermal growth
      factor containing the membrane-spanning segment in response to treatment with
      epidermal growth factor.
AB  - A recombinant fragment of the human receptor for epidermal growth factor
      containing both its extracellular domain and its membrane-spanning segment, when
      dissolved with Triton X-100, was observed to dimerize in response to addition of
      epidermal growth factor (EGF) even at the lowest concentration of this fragment
      that could be assayed (4 nM). Consequently, the dissociation constant for the
      dimer of this fragment is at least 10,000-fold smaller than that for dimers of
      soluble, recombinant forms of the extracellular domain lacking the membrane
      spanning segment. The second-order rate constant for dimerization of the fragment
      containing the extracellular domain and the membrane-spanning segment was
      estimated to be greater than 0.3 nM(-1) min(-1), more than 10-fold that of the
      native enzyme under the same conditions. This result suggests that the
      cytoplasmic domain of the intact enzyme sterically hinders its dimerization. When
      EGF is removed from the dimer of the fragment, the rate constant for its
      dissociation is greater than 0.2 min(-1), more than 40-fold that of the native
      enzyme. This result suggests that interfaces between cytoplasmic domains of
      intact EGF receptor impart significant stabilization to the dimer of the enzyme.

PMID- 10585489
TI  - Translational regulation of ribonucleotide reductase by eukaryotic initiation
      factor 4E links protein synthesis to the control of DNA replication.
AB  - Ribonucleotide reductase synthesizes dNDPs, a specific and limiting step in DNA
      synthesis, and can participate in neoplastic transformation when overexpressed.
      The small subunit (ribonucleotide reductase 2 (RNR2)) was cloned as a major
      product in a subtraction library from eukaryotic initiation factor 4E (eIF4E)
      transformed cells (Chinese hamster ovary-4E (CHO-4E)). CHO-4E cells have 20-40
      fold elevated RNR2 protein, reflecting an increased distribution of RNR2 mRNA to
      the heavy polysomes. CHO-4E cells display an altered cell cycle with shortened S
      phase, similar to cells selected for RNR2 overexpression with hydroxyurea. The
      function of ribonucleotide reductase as a checkpoint component of S progression
      was studied in yeast in which elevated eIF4E rescued S-arrested rnr2-68(ts)
      cells, by increasing recruitment of its mRNA to polysomes. Crosses between rnr2
      68(ts) and mutant eIF4E (cdc33-1(ts)) engendered conditional synthetic lethality,
      with extreme sensitivity to hydroxyurea and the microtubule depolymerizing agent,
      benomyl. The double mutant (cdc33-1 rnr2-68) also identified a unique terminal
      phenotype, arrested with small bud and a randomly distributed single nucleus,
      which is distinct from those of both parental single mutants. This phenotype
      defines eIF4E and RNR2 as determinants in an important cell cycle checkpoint, in
      early/mid-S phase. These results also provide a link between protein and DNA
      synthesis and provide an explanation for cell cycle alterations induced by
      elevated eIF4E.

PMID- 10585490
TI  - Involvement of a cellular glycolytic enzyme, phosphoglycerate kinase, in Sendai
      virus transcription.
AB  - In vitro mRNA synthesis of Sendai virus is almost entirely dependent on the
      addition of cellular proteins (host factors). Previous studies indicated that the
      host factor activity from bovine brain was resolved into at least two
      complementary fractions, one of which may be tubulin. In this study, the host
      factor activity that stimulates the transcription in the presence of tubulin was
      further purified from bovine brain. This fraction was found to contain at least
      two complementary factors, and one of them was purified to a single polypeptide
      chain with an apparent M(r) of 46,000 (p46). From the amino acid sequence,
      biochemical, and immunological analyses, p46 was identified as a glycolytic
      enzyme, phosphoglycerate kinase (PGK). Purified native PGK from rabbit and yeast,
      and a recombinant human PGK substituted for p46. Although, as previously
      suggested, tubulin was involved in the transcription initiation complex formation
      by being integrated into the complex, p46 and its complementary factor had little
      effect on the complex formation. On the other hand, when p46 and the
      complementary factor were added to the RNA chain elongation reaction from the
      isolated initiation complex formed with tubulin, mRNA synthesis was dramatically
      stimulated. The enzymatic activity per se of PGK did not seem to be required for
      its activity. West-Western blot analysis showed that PGK could directly interact
      with tubulin. These data suggest that PGK stimulates Sendai virus mRNA synthesis
      at the elongation step, probably through its interaction with tubulin in the
      initiation complex.

PMID- 10585491
TI  - The assembly of the CAAT-box binding complex at a photosynthesis gene promoter is
      regulated by light, cytokinin, and the stage of the plastids.
AB  - A functionally important region in the promoter of the spinach photosynthesis
      gene AtpC, which encodes the subunit gamma of the chloroplast ATP synthase, is
      located immediately upstream of the CAAT-box. A single nucleotide exchange in
      this region (AAAATTCAAT --> AAGATCAAT) uncouples the expression of an AtpC
      promoter::uidA gene fusion from the regulation by light, cytokinin, and
      functional plastids and results in a high constitutive expression of the reporter
      gene. By screening an Arabidopsis thaliana expression library with a double
      stranded wild-type oligonucleotide from this promoter region, we have isolated
      cDNAs from Arabidopsis libraries that code for plant homologs of the CAAT-box
      binding factor (CBF)-C. Binding occurs only in the presence of nuclear extracts,
      consistent with reports from metazoa CBFs that the subunits A and B in addition
      to C are required for the formation of the CBF-DNA complex. At least eight genes
      with homologies to CBF-C are present in the Arabidopsis genome; one of them
      exhibits striking similarities to the gene for the human global transcriptional
      repressor Drap1. In gel mobility shift assays, low binding activity of CBF to the
      wild-type AtpC promoter sequence was observed with nuclear extracts from tissue
      with low AtpC expression levels, i.e. extracts from etiolated and photobleached
      seedlings, whereas high binding activity was detectable with extracts from
      tissues with high AtpC expression levels, i.e. extracts from light-grown
      seedlings and etiolated seedlings treated with cytokinin. Binding to the mutant
      sequence, which directs constitutive high level uidA expression in vivo, is
      significantly stronger than to the wild-type sequence. The data are consistent
      with the idea that the assembly of CBF at the AtpC promoter is regulated in
      response to light and cytokinin and that the low level of expression in etiolated
      and photobleached material is caused by an inhibitory effect. The
      structure/function relationships of the Arabidopsis CBFs are discussed in
      relation to their regulatory function in AtpC gene expression.

PMID- 10585492
TI  - Growth hormone-induced alteration in ErbB-2 phosphorylation status in 3T3-F442A
      fibroblasts.
AB  - The growth hormone receptor (GHR), a cytokine receptor superfamily member,
      requires the JAK2 tyrosine kinase for signaling. We now examine functional
      interactions between growth hormone (GH) and epidermal growth factor (EGF) in 3T3
      F442A fibroblasts. Although EGF enhanced ErbB-2 tyrosine phosphorylation, GH,
      while causing retardation of its migration on SDS-polyacrylamide gel
      electrophoresis, decreased ErbB-2's tyrosine phosphorylation. GH-induced
      retardation was reversed by treatment of anti-ErbB-2 precipitates with both
      alkaline phosphatase and protein phosphatase 2A, suggesting that GH induced
      serine/threonine phosphorylation of ErbB-2. Both GH-induced shift in ErbB-2
      migration and GH-induced MAP kinase activation were unaffected by a protein
      kinase C inhibitor but were blocked by the mitogen-activated protein
      kinase/extracellular signal-regulated kinase kinase 1 (MEK1) inhibitor, PD98059.
      Notably, leukemia inhibitory factor, but not interferon-gamma, also promoted ErbB
      2 shift and mitogen-activated protein kinase activation. Cotreatment with EGF and
      GH versus EGF alone resulted in a 35% decline in acute ErbB-2 tyrosine 1248
      autophosphorylation, a marked decline (approximately 50%) in DNA synthesis, and
      substantially decreased cyclin D1 expression. We conclude that in 3T3-F442A
      cells, 1) the GH-induced decrease in ErbB-2 tyrosine phosphorylation correlates
      with MEK1/mitogen-activated protein kinase activity and 2) GH antagonizes EGF
      induced DNA synthesis and cyclin D1 expression in a pattern consistent with its
      alteration in ErbB-2 phosphorylation status.

PMID- 10585493
TI  - The von Hippel-Lindau tumor suppressor gene product promotes, but is not
      essential for, NEDD8 conjugation to cullin-2.
AB  - We have previously shown that human cullin-2 (Cul-2) is covalently modified at
      Lys-689 by NEDD8 (Wada, H., Yeh, E. T. H., and Kamitani, T. (1999) Biochem.
      Biophys. Res. Commun. 257, 100-105). Cul-2 has also been reported to form a
      multiprotein complex, Cul-2.VBC, with the von Hippel-Lindau tumor suppressor gene
      product (pVHL) and elongins B and C. In this study, using an in vivo coexpression
      system in COS cells, we show that NEDD8 conjugation to Cul-2 is promoted by
      coexpression with wild-type pVHL and elongins B and C. Interestingly, tumorigenic
      mutants and deletion mutants of pVHL, which are unable to form a Cul-2.VBC
      complex, do not have the activity to promote NEDD8 conjugation to Cul-2. These
      results suggest that the complex formation is required for NEDD8 conjugation to
      Cul-2. Furthermore, we used a pVHL-deficient cell line, 786-0, to show that Cul-2
      is poorly but clearly conjugated by NEDD8, indicating that pVHL is not the only
      molecule that promotes NEDD8 conjugation to Cul-2. Taken together, the VBC
      complex appears to have ligase activity in the conjugation of NEDD8 to Cul-2.

PMID- 10585494
TI  - Homology modeling of the multicopper oxidase Fet3 gives new insights in the
      mechanism of iron transport in yeast.
AB  - Fet3, the multicopper oxidase of yeast, oxidizes extracellular ferrous iron which
      is then transported into the cell through the permease Ftr1. A three-dimensional
      model structure of Fet3 has been derived by homology modeling. Fet3 consists of
      three cupredoxin domains joined by a trinuclear copper cluster which is connected
      to the blue copper site located in the third domain. Close to this site, which is
      the primary electron acceptor from the substrate, residues for a potential iron
      binding site could be identified. The surface disposition of negatively charged
      residues suggests that Fet3 can translocate Fe(3+) to the permease Ftr1 through a
      pathway under electrostatic guidance.

PMID- 10585495
TI  - Protein threading by PROSPECT: a prediction experiment in CASP3.
AB  - We present an analysis of the protein fold recognition experiment using PROSPECT
      in The Third Community Wide Experiment on the Critical Assessment of Techniques
      for Protein Structure Prediction (CASP3). PROSPECT is a computer program we have
      recently developed for finding an optimal alignment between a protein sequence
      and a protein structural fold. Two unique features of PROSPECT are (a) that it
      guarantees to find the globally optimal sequence-structure alignment and does so
      in an efficient manner, when the alignment-scoring function consists of three
      additive terms: (i) a singleton fitness term, (ii) a pairwise contact preference
      term between residues that are spatially close (</=15 A between their beta
      carbons) and (iii) an alignment gap penalty; and (b) that it guarantees to find
      the globally-optimal alignment under various constraints on the unknown protein
      specified by the user. In the CASP3 experiment, PROSPECT correctly identified the
      most similar folds for 11 targets and predicted closely-similar folds for five
      other targets among the 23 targets which can be classified into the category of
      fold-recognition problems and also had their experimentally-determined structures
      available. Among the 11 correctly identified folds, PROSPECT obtained good
      sequence-structure alignments for nine of them. On three of the five ab initio
      prediction problems, PROSPECT successfully located partial structures from our
      template library, which align accurately with the corresponding targets.

PMID- 10585496
TI  - Use of a quantitative structure-property relationship to design larger model
      proteins that fold rapidly.
AB  - A quantitative structure-property relationship (QSPR) was used to design model
      protein sequences that fold repeatedly and relatively rapidly to stable target
      structures. The specific model was a 125-residue heteropolymer chain subject to
      Monte Carlo dynamics on a simple cubic lattice. The QSPR was derived from an
      analysis of a database of 200 sequences by a statistical method that uses a
      genetic algorithm to select the sequence attributes that are most important for
      folding and a neural network to determine the corresponding functional dependence
      of folding ability on the chosen attributes. The QSPR depends on the number of
      anti-parallel sheet contacts, the energy gap between the native state and quasi
      continuous part of the spectrum and the total energy of the contacts between
      surface residues. Two Monte Carlo procedures were used in series to optimize both
      the target structures and the sequences. We generated 20 fully optimized
      sequences and 60 partially optimized control sequences and tested each for its
      ability to fold in dynamic MC simulations. Although sequences in which either the
      number of anti-parallel sheet contacts or the energy of the surface residues is
      non-optimal are capable of folding almost as well as fully optimized ones,
      sequences in which only the energy gap is optimized fold markedly more slowly.
      Implications of the results for the design of proteins are discussed.

PMID- 10585497
TI  - Class-defining characteristics in the mouse heavy chains of variable domains.
AB  - Analysis of residue correlation in over 2700 mouse heavy chains of the V(H)
      domains was carried out on three hierarchical levels. At the 'position' level,
      statistical analysis revealed 45 positions that conserve similar residues in
      almost all chains. At the 'fragment' level, the focus of investigation shifted to
      the study of combinations of amino acids in strands and loops. It was found that
      no more than 10 patterns were sufficient for describing strands and loops in the
      chains. At the 'sequence' level, we determined all possible combinations of these
      patterns and classified the mouse heavy chains. Comparison of the sequences in
      the eight classes revealed residues at the class-determining positions that were
      unique to each class. Because a strong correlation of residues was found, one
      only needs several residues to classify a sequence. It follows that no all
      residue alignment procedure is necessary to divide sequences into classes. An
      important corollary of our approach is the possibility of predicting residues in
      an incomplete sequence from a small sequence fragment. On the basis of our
      analysis of mouse heavy chains we hypothesize about the presently unknown mouse
      V(H) germline repertoire.

PMID- 10585498
TI  - 3D modeling, ligand binding and activation studies of the cloned mouse delta, mu;
      and kappa opioid receptors.
AB  - Refined 3D models of the transmembrane domains of the cloned delta, mu and kappa
      opioid receptors belonging to the superfamily of G-protein coupled receptors
      (GPCRs) were constructed from a multiple sequence alignment using the alpha
      carbon template of rhodopsin recently reported. Other key steps in the procedure
      were relaxation of the 3D helix bundle by unconstrained energy optimization and
      assessment of the stability of the structure by performing unconstrained
      molecular dynamics simulations of the energy optimized structure. The results
      were stable ligand-free models of the TM domains of the three opioid receptors.
      The ligand-free delta receptor was then used to develop a systematic and reliable
      procedure to identify and assess putative binding sites that would be suitable
      for similar investigation of the other two receptors and GPCRs in general. To
      this end, a non-selective, 'universal' antagonist, naltrexone, and agonist,
      etorphine, were used as probes. These ligands were first docked in all sites of
      the model delta opioid receptor which were sterically accessible and to which the
      protonated amine of the ligands could be anchored to a complementary proton
      accepting residue. Using these criteria, nine ligand-receptor complexes with
      different binding pockets were identified and refined by energy minimization. The
      properties of all these possible ligand-substrate complexes were then examined
      for consistency with known experimental results of mutations in both opioid and
      other GPCRs. Using this procedure, the lowest energy agonist-receptor and
      antagonist-receptor complexes consistent with these experimental results were
      identified. These complexes were then used to probe the mechanism of receptor
      activation by identifying differences in receptor conformation between the
      agonist and the antagonist complex during unconstrained dynamics simulation. The
      results lent support to a possible activation mechanism of the mouse delta opioid
      receptor similar to that recently proposed for several other GPCRs. They also
      allowed the selection of candidate sites for future mutagenesis experiments.

PMID- 10585499
TI  - Analysis of heregulin symmetry by weighted evolutionary tracing.
AB  - Heregulins are members of the protein family of EGF-like growth and
      differentiation factors. The primary cell-surface targets of heregulins are
      heterodimers of the EGF-receptor homolog HER2 with either HER3 or HER4. We used a
      weighted evolutionary trace analysis to identify structural features that
      distinguish the EGF-like domain (hrg) of heregulins from other members of the EGF
      family. In this analysis, each amino acid sequence is weighted according to its
      uniqueness and the variability in each position is assigned by an amino acid
      substitution matrix. Conserved residues in heregulin that are variable in other
      EGF-like domains are considered possible specificity-conferring residues. This
      analysis identifies two clusters of residues at the foot of the boot-shaped hrg
      domain. The residues in one cluster are recruited from the N-terminus; those in
      the other are from the ohm-loop region and show a weak sequence similarity to the
      N-terminal residues at the opposite side of the boot. The remaining residues with
      high conservation scores distribute themselves into these two distinct surfaces
      on hrg. This pseudo-twofold symmetry and the presence of two distinct interfaces
      may reflect the preference of hrg for heterodimeric versus homodimeric HER
      complexes.

PMID- 10585500
TI  - Physicochemical factors for discriminating between soluble and membrane proteins:
      hydrophobicity of helical segments and protein length.
AB  - The average hydrophobicity of a polypeptide segment is considered to be the most
      important factor in the formation of transmembrane helices, and the partitioning
      of the most hydrophobic (MH) segment into the alternative nonpolar environment, a
      membrane or hydrophobic core of a globular protein may determine the type of
      protein produced. In order to elucidate the importance of the MH segment in
      determining which of the two types of protein results from a given amino acid
      sequence, we statistically studied the characteristics of MH helices, longer than
      19 residues in length, in 97 membrane proteins whose three-dimensional structure
      or topology is known, as well as 397 soluble proteins selected from the Protein
      Data Bank. The average hydrophobicity of MH helices in membrane proteins had a
      characteristic relationship with the length of the protein. All MH helices in
      membrane proteins that were longer than 500 residues had a hydrophobicity greater
      than 1.75 (Kyte and Doolittle scale), while the MH helices in membrane proteins
      smaller than 100 residues could be as hydrophilic as 0.1. The possibility of
      developing a method to discriminate membrane proteins from soluble ones, based on
      the effect of size on the type of protein produced, is discussed.

PMID- 10585501
TI  - Molecular modeling of the amyloid-beta-peptide using the homology to a fragment
      of triosephosphate isomerase that forms amyloid in vitro.
AB  - The main component of the amyloid senile plaques found in Alzheimer's brain is
      the amyloid-beta-peptide (A beta), a proteolytic product of a membrane precursor
      protein. Previous structural studies have found different conformations for the A
      beta peptide depending on the solvent and pH used. In general, they have
      suggested an alpha-helix conformation at the N-terminal domain and a beta-sheet
      conformation for the C-terminal domain. The structure of the complete A beta
      peptide (residues 1-40) solved by NMR has revealed that only helical structure is
      present in A beta. However, this result cannot explain the large beta-sheet A
      beta aggregates known to form amyloid under physiological conditions. Therefore,
      we investigated the structure of A beta by molecular modeling based on extensive
      homology using the Smith and Waterman algorithm implemented in the MPsrch program
      (Blitz server). The results showed a mean value of 23% identity with selected
      sequences. Since these values do not allow a clear homology to be established
      with a reference structure in order to perform molecular modeling studies, we
      searched for detailed homology. A 28% identity with an alpha/beta segment of a
      triosephosphate isomerase (TIM) from Culex tarralis with an unsolved three
      dimensional structure was obtained. Then, multiple sequence alignment was
      performed considering A beta, TIM from C.tarralis and another five TIM sequences
      with known three-dimensional structures. We found a TIM segment with secondary
      structure elements in agreement with previous experimental data for A beta.
      Moreover, when a synthetic peptide from this TIM segment was studied in vitro, it
      was able to aggregate and to form amyloid fibrils, as established by Congo red
      binding and electron microscopy. The A beta model obtained was optimized by
      molecular dynamics considering ionizable side chains in order to simulate A beta
      in a neutral pH environment. We report here the structural implications of this
      study.

PMID- 10585502
TI  - Conformation and stability of barley chymotrypsin inhibitor-2 (CI-2) mutants
      containing multiple lysine substitutions.
AB  - A major goal of agricultural biotechnology is to increase the nutritional value
      of maize seed through the expression of heterologous proteins enriched in lysine.
      One promising candidate is barley chymotrypsin inhibitor-2 (CI-2), a plant
      protein that has been extensively characterized with respect to structure and
      function. Based on the tertiary structure of wild-type (WT) CI-2, five mutants
      with lysine contents ranging from 20 to 25 mol percent were designed, expressed
      in Escherichia coli and purified by ion exchange and gel permeation
      chromatography. Inasmuch as previous transgenic experiments suggested that proper
      folding and stability may be essential for in vivo accumulation of the engineered
      proteins in plant cells, we first undertook an in vitro study of the conformation
      and thermodynamic stability of the CI-2 mutants in order to select an ideal
      candidate for plant expression. Mutant and WT CI-2 proteins had similar circular
      dichroism spectra, suggesting similar secondary structures. However, differences
      in the accessibility of the sole tryptophan residue, Trp24, indicated that the
      local conformation differed among the mutants. The thermodynamic stability of the
      mutants ranged from <2 to 4.9 kcal/mol compared with approximately 7 kcal/mol for
      the wild-type protein. In conjunction with proteolytic stability studies, we have
      identified one mutant that has the potential to be expressed in a stable manner
      in plant cells.

PMID- 10585503
TI  - Metal binding and activation of the ribonuclease H domain from moloney murine
      leukemia virus.
AB  - The RNase H family of enzymes degrades RNA in RNA.DNA hybrids in a divalent
      cation-dependent manner. RNases H from diverse sources such as Escherichia coli
      and human immunodeficiency virus (HIV) share homologous metal-binding active
      sites, and the activity of the RNase H domain of reverse transcriptase (RT) is
      required for retroviral replication. The isolated RNase H domain from HIV RT,
      however, is inactive. In contrast, the RNase H domain of Moloney murine leukemia
      virus (MMLV) is active, enabling functional studies. Unlike both E. coli RNase HI
      and HIV RT, the RNase H activity of MMLV RT shows greater activity in Mn(2+) than
      Mg(2+). We investigated the effect of mutations in five conserved active-site
      residues of the isolated MMLV RNase H domain. Mutations in two carboxylates
      eliminate metal binding while mutations in other active-site residues allow
      retention of metal ion affinity. Mutations that inactivate E.coli RNase HI in
      Mg(2+) have similar effects on the Mn(2+)-dependent activity of MMLV RNase H.
      These results suggest a similar one-metal catalytic mechanism for the Mn(2+)- and
      Mg(2+)-dependent activities of both prokaryotic and retroviral ribonucleases H.

PMID- 10585504
TI  - Elastase substrate specificity tailored through substrate-assisted catalysis and
      phage display.
AB  - The catalytic histidine of human neutrophil elastase was replaced with alanine
      (H57A) to determine if a substrate histidine could substitute for the missing
      catalytic group-'substrate-assisted catalysis'. H57A and wild-type elastase were
      recovered directly from Pichia pastoris following expression from a synthetic
      gene lacking the elastase pro sequence, thereby obviating the need for zymogen
      activation. Potential histidine-containing substrates for H57A elastase were
      identified from a phage library of randomized sequences. One such sequence,
      REHVVY, was cleaved by H57A elastase with a catalytic efficiency, k(cat)/K(M), of
      2800 s(-1) M(-1), that is within 160-fold of wild-type elastase. In contrast,
      wild-type but not H57A elastase cleaved the related non-histidine containing
      sequence, REAVVY. Ten different histidine-containing linkers were cleaved by H57A
      elastase. In addition to the requirement for a P2 histidine, significant
      preferences were observed at other subsites including valine or threonine at P1,
      and methionine or arginine at P4. A designed sequence, MEHVVY, containing the
      preferred residues identified at each subsite proved to be a more favorable
      substrate than any of the phage-derived sequences. Extension of substrate
      assisted catalysis to elastase suggests that this engineering strategy may be
      widely applicable to other serine proteases thereby creating a family of highly
      specific histidine-dependant proteases.

PMID- 10585505
TI  - Analysis of the reaction mechanism and substrate specificity of haloalkane
      dehalogenases by sequential and structural comparisons.
AB  - Haloalkane dehalogenases catalyse environmentally important dehalogenation
      reactions. These microbial enzymes represent objects of interest for protein
      engineering studies, attempting to improve their catalytic efficiency or broaden
      their substrate specificity towards environmental pollutants. This paper presents
      the results of a comparative study of haloalkane dehalogenases originating from
      different organisms. Protein sequences and the models of tertiary structures of
      haloalkane dehalogenases were compared to investigate the protein fold, reaction
      mechanism and substrate specificity of these enzymes. Haloalkane dehalogenases
      contain the structural motifs of alpha/beta-hydrolases and epoxidases within
      their sequences. They contain a catalytic triad with two different topological
      arrangements. The presence of a structurally conserved oxyanion hole suggests the
      two-step reaction mechanism previously described for haloalkane dehalogenase from
      Xanthobacter autotrophicus GJ10. The differences in substrate specificity of
      haloalkane dehalogenases originating from different species might be related to
      the size and geometry of an active site and its entrance and the efficiency of
      the transition state and halide ion stabilization by active site residues.
      Structurally conserved motifs identified within the sequences can be used for the
      design of specific primers for the experimental screening of haloalkane
      dehalogenases. Those amino acids which were predicted to be functionally
      important represent possible targets for future site-directed mutagenesis
      experiments.

PMID- 10585506
TI  - Role of Arg163 in the N-glycosidase activity of neo-trichosanthin.
AB  - Three mutant crystals of neo-trichosanthin (n-TCS), R163K, R163H and R163Q, were
      obtained by the hanging drop vapor diffusion method. Structure determination
      indicated that there are no significant differences between the mutants and n-TCS
      except in the active pocket. All of them were also soaked in sodium citrate
      buffer (pH 4. 5) containing 20% KCl and 10 mg/ml AMP. Structure determination
      suggests that in the active pocket of the crystals of R163K and R163H, parallel
      to the aromatic ring of Tyr70, each mutant possesses an adenine. The relationship
      between structure and function is discussed. Biochemical analysis reveals that
      the mutants R163K and R163H have N-glycosidase activity, while R163Q does not.
      This suggests that R163 is a crucial residue for the enzyme activity of n-TCS,
      and its role is providing proton.

PMID- 10585507
TI  - A loop-mimetic inhibitor of the HCV-NS3 protease derived from a minibody.
AB  - We have been interested for some time in establishing a strategy for deriving
      lead compounds from macromolecule ligands such as minibody variants. A minibody
      is a minimized antibody variable domain whose two loops are amenable to
      combinatorial mutagenesis. This approach can be especially useful when dealing
      with 'difficult' targets. One such target is the NS3 protease of hepatitis C
      virus (HCV), a human pathogen that is believed to infect about 100 million
      individuals worldwide and for which an effective therapy is not yet available.
      Based on known inhibitor specificity (residues P6-P1) of NS3 protease, we
      screened a number of minibodies from our collection and we were able to identify
      a competitive inhibitor of this enzyme. We thus validated an aspect of
      recognition by HCV NS3 protease, namely that an acid anchor is necessary for
      inhibitor activity. In addition, the characterization of the minibody inhibitor
      led to the synthesis of a constrained hexapeptide mimicking the bioactive loop of
      the parent macromolecule. The cyclic peptide is a lead compound prone to rapid
      optimization through solid phase combinatorial chemistry. We therefore confirmed
      that the potential of turning a protein ligand into a low molecular weight active
      compound for lead discovery is achievable and can complement more traditional
      drug discovery approaches.

PMID- 10585509
TI  - Editorial

PMID- 10585508
TI  - Inhibition of cell growth by a fused protein of human ribonuclease 1 and human
      basic fibroblast growth factor.
AB  - Pancreatic-type RNases are considered to have cytotoxic potential due to their
      ability to degrade RNA molecules when they enter the cytosol. However, most of
      these RNases show little cytotoxicity because cells have no active uptake
      mechanism for these RNases and because the ubiquitous cytoplasmic RNase inhibitor
      is considered to play a protective role against the endocytotic leak of RNases
      from the outside of cells. To study the cytotoxic potential of RNase toward
      malignant cells targeting growth factor receptors, the C-terminus of human RNase
      1 was fused to the N-terminus of human basic fibroblast growth factor (bFGF).
      This RNase-FGF fused protein effectively inhibited the growth of mouse melanoma
      cell line B16/BL6 with high levels of cell surface FGF receptor. This effect
      appeared to result from prolongation of the overall cell cycle rather than the
      killing of cells or specific arrest in a particular phase of the cell cycle.
      Thus, human RNase 1 fused to a ligand of cell surface molecules, such as the FGF
      receptor, is shown to be an effective candidate for a selective cell targeting
      agent with low toxic effects on normal cell types.

PMID- 10585510
TI  - Laboratory medicine in the United Kingdom: 1948-1998 and beyond.
AB  - The National Health Service in the United Kingdom was created in 1948,
      effectively becoming the main provider of healthcare and funded by the government
      from taxation. By the late 1970's, and despite many achievements, it was seen to
      be approaching a financial crisis. Radical reforms were introduced in the early
      1990's bringing in general management, a split between purchaser and provider,
      and competition. Whilst there has been a change of government more recently
      several of these initiatives have been retained, with the exception of
      competition (the internal market) which has been abandoned. There is now a much
      greater focus on the quality of care with increased clinical and financial
      accountability. Laboratory medicine (generally termed pathology in the United
      Kingdom) has evolved to meet the demands of more patients, reducing turnaround
      times, a greater repertoire of investigations and a continuing improvement in
      productivity. There is an increasing focus on improved dialogue between the
      laboratory and the clinician covering interpretation of results, audit of
      services and outcomes, research and development and continuous education in the
      pursuit of a high quality service. The major challenges for the future focus on
      alternative modes of delivery, on issues relating to staffing and on quality of
      service, in the face of an ever increasing demand.

PMID- 10585511
TI  - Health care system and laboratory medicine in Austria: present status and future
      perspectives.
AB  - In the recent past, the role of laboratory medicine has changed from merely
      supplier of analytical data to supplier of results together with clinical
      interpretation. In addition, the role of medical laboratories as important
      partners of health care management by providing data for management functions and
      decisions is rapidly growing. The article has the purpose of giving an overview
      of Austria's population, the governmental system and Austrian health politics in
      context with European health care. The existing health care system with its
      historical development, to-date status and recent changes due to socio-economic
      pressure are outlined. Special emphasis is given to the present situation of
      medical laboratories in Austria. Furthermore, hospital management strategies and
      some adjustment processes in the authors' clinical-medical laboratory to
      alleviate the ongoing economic pressure are described. As far as possible, an
      attempt of forecasting future scenarios is made.

PMID- 10585512
TI  - Laboratory medicine in Ontario: its downsizing and the consequences on quality.
AB  - Health care in Ontario consumes 35% of provincial government annual revenues.
      Fiscal constraint mandates restructuring of health services to maintain a fully,
      publicly-funded universally-accessible health system that is patient-focussed and
      health-outcome driven. Acute-care hospital restructuring under the authority of
      the Health Services Restructuring Commission and primary health-care reform
      characterise present government initiatives. Laboratory medicine services at
      about Can $1 billion annually account for about 5% of health expenditure. A
      Laboratory Services Restructuring Secretariat created by the Ministry of Health
      in 1995 has planned regionally-based integrated laboratory services systems
      bringing together public and private providers, designed a province-wide
      laboratory information system, developed a quality management program, reviewed
      the human resource needs for laboratory physicians, scientists and technologists,
      and recommended that the legislation be rewritten so as to be enabling - not
      controlling. Meanwhile both hospital and private laboratories have closed,
      leaving 296 in 1998 compared to 394 in 1991. Laboratory physician numbers at 39
      per million population falls far short of the recommended target of 52 and many
      are within 10 years of retirement. Renewal of laboratory physicians and
      scientists to meet the shortfall is not occurring. The numbers of registered
      laboratory technologists has fallen by 6. 8% over 2 years. Consolidation and
      downsizing of laboratories with the formation of core laboratories has resulted
      in multi-discipline and cross discipline tasking of specialist technologists.
      Senior and middle level management technologists have been declared redundant. As
      a consequence, quality control practices have been hard hit. Plans to address
      these deficiencies through regional integration and sharing of resources remain
      to be implemented.

PMID- 10585513
TI  - Laboratory restructuring in metropolitan Edmonton: a model for laboratory
      reorganization in Canada.
AB  - In 1994 the Alberta government acted to reduce to a decade-long deficit in the
      provincial budget with draconian reductions in the health, education and welfare
      expenditures. As a result, funding to Alberta clinical laboratories was to be
      reduced by approximately 40%. In response, the private and public laboratories in
      metropolitan Edmonton formed a unique alliance to provide laboratory testing in a
      more coordinated and efficient manner. Of the five metropolitan hospitals, only
      University of Alberta Hospital preserved its full service laboratory and its
      specialty reference testing. The other hospital laboratories were converted to
      rapid response laboratories with a merged private reference laboratory providing
      routine testing and support to the four hospitals, and far fewer outpatient
      collection facilities. This paper describes the steps in the laboratory
      restructuring from inception to execution.

PMID- 10585514
TI  - A new direction in automated laboratory testing in Japan: five years of
      experience with total laboratory automation system management.
AB  - The introduction of integrated laboratory systems has proceeded rapidly in Japan
      in these 15 years, but they require large initial investment for installation and
      do not always succeed in reducing laboratory cost. We also experienced three
      major events that taught us that total laboratory systems are not always
      effective: these were an earthquake, a nerve gas attack, and an outbreak of food
      poisoning. Political changes in the national health care system in Japan have
      forced the cutting of expenses for laboratory testing. In this context, cost
      effective laboratory testing has been considered, and many hospitals have
      replaced total laboratory systems with small laboratory systems. Our University
      Hospital introduced a mini-lab system consisting of compact instruments to
      increase laboratory efficiency, and we have begun point-of-care testing education
      for medical students. This combination enables rapid and convenient testing, and
      is responsive to the political changes in the Japanese health care system.

PMID- 10585515
TI  - High level processing scope in spoken sentence production.
AB  - Five experiments investigate the scope of conceptual and grammatical encoding
      during spoken sentence production. An online picture description task is employed
      in which participants generate a variety of sentences in response to an array of
      moving pictured objects. Experiment 1, demonstrates longer onset latencies for
      single clause sentences beginning with a complex phrase (e.g. The dog and the
      kite move above the house) than for matched single clause sentences beginning
      with a simple phrase (e.g. The dog moves above the kite and the house). This
      finding suggests that more time is dedicated to the processing of the first
      phrase of an utterance than the remainder prior to speech onset. Experiments 2
      and 3, compare the production of single and double clause sentences. The main
      effect of Experiment 1 is replicated. However, the data also suggest that some
      time is dedicated to the processing of elements within the second clause prior to
      speech onset. In Experiment 4, when participants are allowed to preview pictures
      prior to movement and timer onset the effect of initial phrase complexity is
      significantly reduced indicating that the latency effects observed previously
      primarily reflect lemma access. Finally, Experiment 5 demonstrates that this
      reduction is greater for nouns within the first phrase than for nouns beyond it.
      We conclude from these experiments that, prior to speech onset, lemma access is
      completed for the first phrase of an utterance and that high level processing is
      initiated but not completed for the remainder of a sentence beyond the first
      phrase.

PMID- 10585516
TI  - Incremental interpretation at verbs: restricting the domain of subsequent
      reference.
AB  - Participants' eye movements were recorded as they inspected a semi-realistic
      visual scene showing a boy, a cake, and various distractor objects. Whilst
      viewing this scene, they heard sentences such as 'the boy will move the cake' or
      'the boy will eat the cake'. The cake was the only edible object portrayed in the
      scene. In each of two experiments, the onset of saccadic eye movements to the
      target object (the cake) was significantly later in the move condition than in
      the eat condition; saccades to the target were launched after the onset of the
      spoken word cake in the move condition, but before its onset in the eat
      condition. The results suggest that information at the verb can be used to
      restrict the domain within the context to which subsequent reference will be made
      by the (as yet unencountered) post-verbal grammatical object. The data support a
      hypothesis in which sentence processing is driven by the predictive relationships
      between verbs, their syntactic arguments, and the real-world contexts in which
      they occur.

PMID- 10585517
TI  - Correlates of linguistic rhythm in the speech signal.
AB  - Spoken languages have been classified by linguists according to their rhythmic
      properties, and psycholinguists have relied on this classification to account for
      infants' capacity to discriminate languages. Although researchers have measured
      many speech signal properties, they have failed to identify reliable acoustic
      characteristics for language classes. This paper presents instrumental
      measurements based on a consonant/vowel segmentation for eight languages. The
      measurements suggest that intuitive rhythm types reflect specific phonological
      properties, which in turn are signaled by the acoustic/phonetic properties of
      speech. The data support the notion of rhythm classes and also allow the
      simulation of infant language discrimination, consistent with the hypothesis that
      newborns rely on a coarse segmentation of speech. A hypothesis is proposed
      regarding the role of rhythm perception in language acquisition.

PMID- 10585518
TI  - Language acquisition in the absence of explicit negative evidence: can simple
      recurrent networks obviate the need for domain-specific learning devices?

PMID- 10585519
TI  - Simple recurrent networks can distinguish non-occurring from ungrammatical
      sentences given appropriate task structure: reply to Marcus.

PMID- 10585520
TI  - Biological preparedness and evolutionary explanation.
AB  - It is commonly supposed that evolutionary explanations of cognitive phenomena
      involve the assumption that the capacities to be explained are both innate and
      modular. This is understandable: independent selection of a trait requires that
      it be both heritable and largely decoupled from other 'nearby' traits. Cognitive
      capacities realized as innate modules would certainly satisfy these contraints. A
      viable evolutionary cognitive psychology, however, requires neither extreme
      nativism nor modularity, though it is consistent with both. In this paper, we
      seek to show that rather weak assumptions about innateness and modularity are
      consistent with evolutionary explanations of cognitive capacities. Evolutionary
      pressures can affect the degree to which the development of a capacity is
      canalized by biasing acquisition/learning in ways that favor development of
      concepts and capacities that proved adaptive to an organism's ancestors.

PMID- 10585521
TI  - Temporal cortex activation during speech recognition: an optical topography
      study.
AB  - Cortical activity during speech recognition was examined using optical topography
      (OT), a recently developed non-invasive technique. To assess relative changes in
      hemoglobin oxygenation, local changes in near-infrared light absorption were
      measured simultaneously from 44 points in both hemispheres. A dichotic listening
      paradigm was used in this experiment, in which target stimuli and non-target
      stimuli were presented to different ears. Subjects were asked to track targets
      and to press a button when targets shifted from one ear to the other. We compared
      three tasks: (i) a control task, in which a tone was used as the target; (ii) a
      repeat task, in which the target was one repeated sentence; (iii) a story task,
      in which the targets were continuous sentences of a story. The activity for the
      story task, compared with the repeat task, was localized in the left superior
      temporal cortex. Relative to the control task, we observed in this region a
      larger increase in oxyhemoglobin concentration and a decrease in deoxyhemoglobin
      concentration in the story task than those in the repeat task. These results
      suggest that the activity in the left temporal association area reflects the load
      of auditory, memory, and language information processing.

PMID- 10585522
TI  - Spatial learning deficit in dopamine D(1) receptor knockout mice.
AB  - Dopamine D(1) receptors are expressed in the hippocampus and prefrontal cortex,
      suggesting a role in cognition. Dopamine D(1) receptor-deficient mice (D(1)-/-)
      were used to investigate the role of this receptor in spatial learning and
      memory. Using the Morris water maze, mice were trained to locate a hidden
      platform. Subsequently, the platform was removed from the maze and mice were
      scored for the percentage of time spent in the target quadrant and the number of
      crossings through the target position. D(1)-/- mice had significantly longer
      escape latencies compared to wild-type (D(1)+/+) and heterozygous (D(1)+/-)
      littermates and showed absence of spatial bias during the probe trials. In a
      visually cued task, D(1)-/- mice performed better than on the hidden platform
      trials, but maintained slightly higher escape latencies than D(1)+/+ and D(1)+/-
      mice. Naive D(1)-/- mice exposed only to the cued task eventually acquired
      identical escape latencies as the D(1)+/+ and D(1)+/- mice. Sensorimotor
      reflexes, locomotor activity, spontaneous alternation and contextual learning
      were not different among the groups. These results indicate that D(1)-/- mice
      have a deficit in spatial learning without visual or motor impairment, suggesting
      that dopamine D(1) receptors are involved in at least one form of the cognitive
      processes.

PMID- 10585523
TI  - Adenosine A(2) receptors inhibit morphine self-administration in rats.
AB  - In the present study, the effect of adenosine receptor agonists and antagonists
      on morphine self-administration was investigated. Intravenous administration of
      morphine (0.3-3 mg/kg/injection) induced dose-dependent self-administration. The
      adenosine receptor antagonists, theophylline (2.5, 5, 10 mg/kg) and 3, 7-Dimethyl
      1-propargylxanthine (DMPX; 0.25, 0.5, 1 mg/kg), when injected 1 h before the
      start of the test, reduced the number of self-administered morphine infusions.
      The adenosine receptor antagonists when administered in the training period (11
      days) greatly increased the number of morphine infusions, however, they did not
      induce any response by themselves. 5'-N-ethylcarboxamido-adenosine (NECA; 0.5, 1
      mg/kg) and 4-[2-[[6-Amino-9-(N-ethyl-beta-D-ribofuranuronamidosyl)-9H-purin-2 -yl
      ]amino] ethyl]benzenepropanoic acid (CGS21680; 0.001, 0.01, 0.025, 0. 05 mg/kg),
      given 1 h before the start of the test, increased morphine self-administration.
      Although the adenosine agonists, when injected during training period (11 days),
      reduced morphine self-administration. Furthermore, NECA, but not CGS21680,
      induced significant self-administration. The adenosine A(1) receptor agonist,
      N(6)-cyclohexyladenosine (CHA; 0.01, 0.1, 0.25, 0.5 and 1 mg/kg), and the
      adenosine A(1) receptor antagonist, 8-phenyletheophylline (2, 4, 6, 8 mg/kg),
      themselves neither altered morphine infusion nor induced any response. These
      results indicate a role for adenosine A(2) receptors in the expression and/or
      development of morphine self-administration.

PMID- 10585524
TI  - Antagonism of heroin and morphine self-administration in rats by the morphine
      6beta-glucuronide antagonist 3-O-methylnaltrexone.
AB  - In mice, 3-O-methylnaltrexone blocks the analgesic actions of morphine-6beta
      glucuronide and heroin at doses which are inactive against morphine. We found a
      similar selectivity in rats. 3-O-Methylnaltrexone antagonized the analgesic
      actions of 6-acetylmorphine in Sprague-Dawley rats and heroin in Wistar rats at
      doses that were inactive against morphine. Inclusion of a fixed dose of 3-O
      methylnaltrexone significantly shifted the analgesic dose-response curves for 6
      acetylmorphine and heroin without altering the morphine dose-response curves. In
      a self-administration model, 3-O-methylnaltrexone treatment significantly
      increased both heroin and morphine intake during the first hour, suggestive of an
      antagonist effect. This effect at doses of 3-O-methylnaltrexone which were
      inactive against morphine analgesia implied a role for the morphine-6beta
      glucuronide opioid receptor in the reinforcing properties of heroin and morphine.

PMID- 10585525
TI  - Dopamine D(1) receptor-mediated control of striatal acetylcholine release by
      endogenous dopamine.
AB  - The role of dopamine D(1) and D(2) receptors in the control of acetylcholine
      release in the dorsal striatum by endogenous dopamine was investigated by
      monitoring with microdialysis the effect of the separate or combined
      administration of the dopamine D(1) receptor antagonist, SCH 39166 ?(-)-trans
      6,7,7a,8,9, 13b-exahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo-[d]-nap hto-[2, 1b]
      azepine hydrochloride? (50 microg/kg subcutaneous (s.c.)), of the dopamine
      D(2)/D(3) receptor agonist, quinpirole (trans-(-)-4aR, 4a,5,6,7,8,8a,9-octahydro
      5-propyl-1H-pyrazolo-(3,4-g)-quinoline hydrochloride) (5 and 10 microg/kg s.c.),
      and of the D(3) receptor selective agonist, PD 128,907 [S(+)-(4aR,10bR)-3,4,4a,
      10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin -9-ol
      hydrochloride] (50 microg/kg s.c.), on in vivo dopamine and acetylcholine
      release. Microdialysis was performed with a Ringer containing low concentrations
      (0.01 microM) of the acetylcholinesterase inhibitor, neostigmine. Quinpirole (10
      microg/kg s.c.) decreased striatal dopamine and acetylcholine release.
      Administration of PD 128,907 (50 microg/kg) decreased dopamine but failed to
      affect acetylcholine release. SCH 39166 (50 microg/kg s.c.) stimulated dopamine
      release and reduced acetylcholine release. Pretreatment with quinpirole reduced
      (5 microg/kg s.c.) or completely prevented (10 microg/kg s.c.) the stimulation of
      dopamine release elicited by SCH 39166 (50 microg/kg s.c.); on the other hand,
      pretreatment with quinpirole (5 and 10 microg/kg) potentiated the reduction of
      striatal acetylcholine release induced by SCH 39166 (50 microg/kg s.c.).
      Similarly, pretreatment with PD 128,907 (50 microg/kg) which prevented the
      increase of dopamine release induced by SCH 39166 (50 microg/kg), potentiated the
      reduction of striatal acetylcholine transmission elicited by SCH 39166. Thus,
      pretreatment with low doses of quinpirole or PD 128,907 influences in opposite
      manner the effect of SCH 39166 on striatal dopamine and acetylcholine release,
      counteracting the increase of dopamine release and potentiating the decrease in
      acetylcholine release. These results provide further evidence for the existence
      of a tonic stimulatory input of endogenous dopamine on striatal acetylcholine
      transmission mediated by dopamine D(1) receptors.

PMID- 10585526
TI  - The role of nitric oxide in the development of morphine tolerance in rat
      hippocampal slices.
AB  - In the present study, we investigated the effects of a nitric oxide (NO)
      precursor, L-arginine, on the effect of different drugs, [trans-3, 4-dichloro-N
      methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamid e hydrochloride] (U
      50,488, a kappa-opioid receptor agonist); dPTyr(Me)AVP (a vasopressin receptor
      antagonist); dizocilpine (MK-801, a N-methyl-D-aspartate (NMDA) receptor
      antagonist), to block the development of morphine tolerance or NO release in
      Sprague-Dawley rat hippocampal slices (450 microm). Slices were continuously
      superfused with artificial cerebrospinal fluid (ACSF) or drugs at 1 ml/min.
      Nichrome wire electrodes were placed in the Schaffer-collateral pathway and used
      to deliver biphasic 0.2-ms pulses of 5-30 V (0.033 Hz). A glass microelectrode
      was placed in the CA1 area to record population spikes. The amount of NO released
      in the superfusate was measured as nitrite formation. When the slices were
      superfused with 10 microM morphine, the amplitude of population spikes increased
      200%-300% in 30-40 min. However, this effect of morphine decreased, i.e.,
      tolerance developed, after continuous superfusion of morphine for 2-6 h. On the
      other hand, the nitrite level was increased about 250% of the control level
      through 6 h of morphine superfusion. Co-superfusion of L-arginine with morphine
      could further increase the nitrite level and also facilitate the development of
      morphine tolerance. On the other hand, 3-Br-7-nitroindazole (a neuronal NO
      synthase inhibitor) decreased the nitrite level significantly and blocked the
      development of morphine tolerance. When either U-50,488 (200 nM) or dPTyr(Me)AVP
      (500 pM) or MK-801 (500 pM) was co-superfused with morphine (10 microM), the
      development of morphine tolerance was blocked significantly and the nitrite level
      decreased to 100%-150% of the control level. L-arginine (500 nM) significantly
      reversed the effect of these drugs to block the development of morphine tolerance
      or to decrease the nitrite level through 6 h of superfusion. These data suggest
      that NO may play a key role in the development of morphine tolerance. Drugs which
      suppress the synthesis or release of NO would be expected to block the
      development of morphine tolerance.

PMID- 10585527
TI  - Pharmacological re-evaluation of a GABA(B) receptor antagonist CGP 47332A in rat
      brain.
AB  - In rat neocortical slices maintained in Mg(2+)-free Krebs medium, the gamma
      aminobutyric acid (GABA(B)) receptor agonist baclofen concentration-dependently
      depressed the frequency of spontaneous discharges (EC(50)=12 microM). This was
      reversibly antagonised by (R, S)-3-amino-2-hydroxy-propyl-P-n-butyl-phosphinic
      acid (CGP 47332A) (25, 100, 300 microM) which produced rightwards shifts of the
      baclofen concentration-response curves (pA(2) value=4.8+/-0.1). In electrically
      stimulated slices preloaded with [3H]GABA, CGP 47332A increased its release
      (EC(150)=100 microM) through antagonism of GABA(B) autoreceptors. Although CGP
      47332A was some six times weaker on GABA(B) auto- than on heteroreceptors, yet
      its congener lacking the beta-hydroxy substituent displays equal potency in both
      binding (IC(50)=38 microM) and GABA(B) autoreceptor functional studies
      (EC(150)=38 microM) as previously reported [Froestl, W., Mickel, S.J. , Von
      Sprecher, G., Diel, P.J., Hall, R.G., Maier, L., Strub, D., Melillo, V., Baumann,
      P.A., Bernasconi, R., Gentsch, C., Hauser, K., Jaekel, J., Karlsson, G., Klebs,
      K., Maitre, L., Marescaux, C., Pozza, M.F., Schmutz, M., Steinmann, M.W., Van
      Riezen, H., Vassout, A., Mondadori, C., Olpe, H.R., Waldmeier, P.C., Bittiger,
      H., Phosphinic acid analogues of GABA: 2. Selective, orally active GABA(B)
      antagonists. J. Med. Chem. 38 (1995) 3313-3331.].

PMID- 10585528
TI  - Resistance to antagonism of atrial P(1) purinoceptor responses in the presence of
      K(+) channel blockade.
AB  - The rate of onset of the negative inotropic responses of guinea-pig isolated
      paced atria to the adenosine receptor agonist, N(6)-cyclopentyladenosine, was
      significantly slowed by the K(+) channel inhibitor, 4-aminopyridine (10 mM). The
      concentration-dependent inhibition of developed tension by N(6)
      cyclopentyladenosine, however, was unaffected by 4-aminopyridine (10 mM). Thus,
      K(+) efflux only governs the speed of onset of the negative inotropic response
      and does not appear to be a major component in the negative inotropy produced by
      the adenosine A(1) receptor agonist. The P(1) purinoceptor antagonist, 8(p
      sulfophenyl) theophylline (1 x 10(-5) M) significantly shifted the concentration
      response curve for N(6)-cyclopentyladenosine to the right (concentration-ratio,
      7.1+/-1.5). In the presence of 4-aminopyridine (10 mM), 8(p-sulfophenyl)
      theophylline caused a non-parallel rightwards shift of the curve. At the IC(35)
      there was no significant shift, whereas at the IC(75) there was a small
      significant displacement of the curve. The adenosine A(1)/A(3) receptor agonist,
      N(6)-2-(4-aminophenyl) ethyladenosine (APNEA) yielded a biphasic concentration
      response curve which was significantly shifted to the right by 8(p-sulfophenyl)
      theophylline (1 x 10(-5 ) M). In the presence 4-aminopyridine, however, there was
      no shift of the APNEA concentration-response curve by 8(p
      sulfophenyl)theophylline. These results show that when K(+) channels are blocked
      by 4-aminopyridine, the residual response is resistant to antagonism by the P(1)
      purinoceptor antagonist, 8(p-sulfophenyl)theophylline. This residual component
      may involve L-type Ca(2+) channels, the adenosine A(1) receptor being possibly
      coupled to the two transduction pathways for negative inotropism via the
      different components of the G protein (receptor-transducer promiscuity).

PMID- 10585529
TI  - Increase in the vasorelaxant potency of K(ATP) channel opening drugs by adenosine
      A(1) and A(2) receptors in the pig coronary artery.
AB  - Myograph recording from ring segments of pig small coronary arteries was used to
      investigate the effects of adenosine receptor activation on the vasorelaxant
      potency of ATP-sensitive K(+) channel opening drugs. Receptor activation with 2
      chloroadenosine (2-CA, 300 nM) increased the potency of both nicorandil and
      levcromakalim, shifting the pEC(50)s from 4.68+/-0.03 to 5.05+/-0.04 and from
      6.34+/-0.06 to 6.72+/-0.06, respectively (P<0.05 in each case). Experiments with
      selective adenosine receptor agonists (2-chloro-N(6)-cyclopentyladenosine (CCPA),
      2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride
      (CGS 21680)) and antagonists (8-cyclopentyl-1, 3-dipropylxanthine (DPCPX), 4-(2
      [7-amino-2-(2-furyl)[1,2, 4]triazolo[2,3-a] [1,3,5]triazin-5-ylamino]ethyl)phenol
      (ZM 241385)) suggest that both A(1) and A(2a) receptors can increase the potency
      of nicorandil, while that of levcromakalim is increased only by A(2) receptors.
      Adenosine receptor activation did not affect the potency of pinacidil. Thus,
      adenosine receptor activation can increase the potency of some K(+) channel
      opening drugs to relax coronary arteries, but the details of the interaction with
      adenosine receptors depend on the particular drug.

PMID- 10585530
TI  - Cerebroprotective properties of SM-20220, a potent Na(+)/H(+) exchange inhibitor,
      in transient cerebral ischemia in rats.
AB  - The aim of this study was to investigate the contribution of the Na(+)/H(+)
      exchanger to cerebral ischemia using SM-20220 (N-(aminoiminomethyl)-1-methyl-1H
      indole-2-carboxamide methanesulfonate), a newly synthesized compound. In in vitro
      experiments, we evaluated the inhibitory effect of SM-20220 on the Na(+)/H(+)
      exchanger in cultured neurons and glial cells. The IC(50) of SM-20220 in neurons
      and glial cells was 5 nM and 20 nM, respectively. To examine the in vivo effects
      of SM-20220 on brain injury, we used a transient middle cerebral artery occlusion
      model in rats. SM-20220 given intravenously 1 h after occlusion significantly
      reduced the extent of cerebral edema, Na(+) content and infarcted area in a dose
      dependent manner. The results of the present study suggest that the Na(+)/H(+)
      exchanger is involved in the aggravation of brain edema and infarction, and its
      inhibitor may exert protective effects on post-ischemic brain damage.

PMID- 10585531
TI  - Effects of K(+) channel inhibitors on relaxation induced by flufenamic and
      tolfenamic acids in guinea-pig trachea.
AB  - The effects of different K(+) channel inhibitors on flufenamic- and tolfenamic
      acids-induced relaxation were studied in prostaglandin F(2alpha) (1 microM)
      precontracted guinea-pig trachea. Flufenamic and tolfenamic acids (each 0.1-33
      microM) and lemakalim (0.01-33 microM), but not indomethacin (0.1-33 microM),
      caused relaxation. Iberiotoxin (33 and 100 nM) inhibited flufenamic- and
      tolfenamic-acids-, but not lemakalim-, induced relaxation. Iberiotoxin (100 nM)
      inhibited nifedipine (10 nM-10 microM)-induced relaxation. Nifedipine (0.1
      microM) inhibited the blockade of fenamate-induced relaxation by iberiotoxin.
      Apamin (0.1 and 1 microM) did not affect flufenamic- and tolfenamic-acids- and
      lemakalim-induced relaxation. Glibenclamide (10 and 33 microM) inhibited
      lemakalim-, but not flufenamic- and tolfenamic-acids-, induced relaxation. 4
      Aminopyridine (0.5 and 2 mM) inhibited flufenamic- and tolfenamic- acids- and
      lemakalim-induced relaxation. Flufenamic- and tolfenamic-acids-induced relaxation
      is likely to be activation of Ca(2+)-activated K(+) channels and differs from
      that of lemakalim.

PMID- 10585532
TI  - Dose-dependent attenuation of lipopolysaccharide-fever by inhibitors of inducible
      nitric oxide-synthase in guinea pigs.
AB  - Different doses of aminoguanidine or S-methylisothiourea, both predominantly
      inhibitors of the inducible form of nitric oxide (NO)-synthase, were injected
      into the arterial circulation of guinea pigs alone or along with 10 microg/kg
      bacterial lipopolysaccharide. Doses of 10 mg/kg, 50 mg/kg or 250 mg/kg
      aminoguanidine per se had no influence on abdominal temperature of guinea pigs.
      Only the highest dose of aminoguanidine (250 mg/kg) completely suppressed the
      first phase of the biphasic febrile response to lipopolysaccharide-injections.
      Lipopolysaccharide-fever was not modulated by administration of 10 mg/kg or 50
      mg/kg aminoguanidine, when compared to fever in response to injections of
      lipopolysaccharide along with solvent. Doses of 10 mg/kg or 50 mg/kg S
      methylisothiourea did not alter abdominal temperature while a dose of 250 mg/kg S
      methylisothiourea had a lethal effect in guinea pigs. The febrile response to
      lipopolysaccharide was unimpaired by administration of 10 mg/kg S
      methylisothiourea, while a dose of 50 mg/kg again attenuated fever predominantly
      by a suppression of the first fever phase. None of the applied doses of
      aminoguanidine or S-methylisothiourea resulted in a significant attenuation of
      the lipopolysaccharide-induced circulating cytokines tumor necrosis factor-alpha
      (TNF-alpha) and interleukin-6. The drugs themselves, without lipopolysaccharide
      injections, did not enhance or reduce circulating levels of the investigated
      cytokines. The results indicate that endogenous NO may participate in the
      induction of lipopolysaccharide-fever and that fever suppression by systemic
      administration of NO-synthase inhibitors occurs independently from the
      lipopolysaccharide-induced circulating cytokines.

PMID- 10585533
TI  - Effect of interleukin-16-blocking peptide on parameters of allergic asthma in a
      murine model.
AB  - In this study, we examined whether peptides based on the hydrophilic Cluster of
      Differentiation (CD) 4-binding part of the amino acid sequence of human
      interleukin-16 can block interleukin-16-induced chemotaxis of murine lymphocytes
      in vitro. Peptide 3 was capable of inhibiting interleukin-16-induced chemotaxis
      of murine splenocytes in vitro. Next, we compared the effects of intra-airway
      administration of peptide 3 with those of antibodies to interleukin-16 on antigen
      induced features in a murine model of allergic asthma. Intra-airway
      administration of peptide 3 largely inhibited the development of antigen-induced
      airway hyperresponsiveness while airway eosinophilia was not affected. Similar
      effects were observed after intranasal application of antibodies to interleukin
      16. These results indicate that treatment with peptide 3 causes the same effects
      as do antibodies to interleukin-16, possibly via the inhibition of interaction
      between interleukin-16 and its receptor CD4. Therefore, peptide 3 could be useful
      as a lead compound in attempting to limit airway hyperresponsiveness via binding
      to CD4.

PMID- 10585534
TI  - The effects of ZD6169 on the ATP-dependent K(+) current (I(K)(ATP)) in isolated
      cat ventricular myocytes.
AB  - The effect of the K(ATP) channel opener ZD6169 [(S)-N-(4-benzoyl-phenyl)-3,3, 3
      trifluoro-2-hydroxy-2-methyl-propionamide] currently under development for the
      treatment of urinary incontinence was explored in acutely isolated adult feline
      ventricular myocytes. ZD6169 activated a current over a wide range of
      concentrations (0.1-100 microM) that is completely blocked by 10 microM glyburide
      thereby identifying it as I(K(ATP)). The maximum activation of K(ATP) current was
      observed at 10 microM; higher concentrations decreased current activation. In
      contrast, the standard K(ATP) channel opener cromakalim showed a more usual
      concentration-response relationship, with increasing current for increased
      concentrations and no signs of saturation or reversal. The bell-shaped dose
      response relationship for ZD6169 activation of I(K(ATP)) has also been seen in
      bladder myocytes, albeit at a lower concentration, and it has been proposed to
      contribute to the reported lack of in vivo cardiovascular side effects. We
      compared the effects of ZD6169 to cromakalim and showed that both compounds
      dramatically shorten cardiac myocyte action potential duration and that ZD6169
      does so in spite of the bell-shaped concentration-response relationship for
      activation of K(ATP) current.

PMID- 10585535
TI  - Chronic ethanol enhances muscarinic receptor-mediated activator protein-1 (AP-1)
      DNA binding in cerebellar granule cells.
AB  - In this study we investigated effects of acute and chronic ethanol exposure on
      carbachol-induced activator protein-1 (AP-1) DNA binding in rat cerebellar
      granule cells. Acute ethanol application did not alter, whereas chronic ethanol
      exposure potentiated the carbachol-induced AP-1 DNA binding. The protein
      composition of the AP-1 transcription factor complex activated by carbachol
      stimulation of muscarinic receptors was analysed in control and chronic ethanol
      exposed cells using a supershift assay with specific antibodies against c-Fos,
      Fos B, c-Jun, Jun B and Jun D proteins. Supershift analysis revealed that the
      carbachol-induced AP-1 complex was composed predominantly of Jun D and c-Fos. The
      composition of the AP-1 complex activated by carbachol in chronic ethanol-exposed
      cells did not differ from control. These findings indicate that chronic ethanol
      treatment can modulate carbachol-induced AP-1 DNA binding activity in cerebellar
      granule cells.

PMID- 10585537
TI  - Electrophysiological characterization of BRL-32872 in canine Purkinje fiber and
      ventricular muscle. Effect on early after-depolarizations and repolarization
      dispersion.
AB  - Amongst the different pharmacological approaches to the treatment of cardiac
      arrhythmias, compounds with multiple electrophysiological activities appear to
      exhibit a reduced adverse effect profile. BRL-32872 (N-(3,4-dimethoxyphenyl)-N
      [3[[2-(3,4-dimethoxyphenyl) ethyl] propyl]-4-nitrobenzamide hydrochloride) is a
      typical example of an antiarrhythmic agent with combined K(+) and Ca(2+) blocking
      actions. In this study, we investigated the effects of BRL-32872 on early after
      depolarizations and on dispersion of repolarization. Action potentials were
      recorded either in canine cardiac Purkinje fibers alone or in preparations
      containing both ventricular muscle and the attached Purkinje fibers. In Purkinje
      fibers, BRL-32872 (0. 3-10 microM) induced a bell-shaped concentration-dependent
      increase in action potential duration. At 90% of repolarization, the action
      potential was prolonged at concentrations up to 1 microM and was shortened when
      the concentration of BRL-32872 was further increased. In all 17 experiments, BRL
      32872 did not cause early after-depolarizations in Purkinje fibers. On the
      contrary, BRL-32872 (3 microM) systematically suppressed early after
      depolarizations induced by clofilium (4-chloro-N, N-diethyl-N
      heptylbenzenebutanaminium tosylate, 1 microM), a selective inhibitor of the
      delayed rectifier K(+) current. A similar effect was observed once with 1 microM
      BRL-32872, a concentration able to prolong Purkinje fiber action potentials.
      Simultaneous recording of action potentials in ventricular and Purkinje
      preparations showed that increasing concentrations of BRL-32872 (0. 3-10 microM)
      induced a limited increase in the difference of repolarization time between the
      two tissues. The selective K(+) channel inhibitor E-4031 (N-(4-(1-[2-(6-methyl-2
      pyridyl) ethyl]-4-piperidyl)-carbonyl] phenyl) methanesulfonamide dihydrochloride
      dihydrate) exhibited a significant concentration-dependent increase in dispersion
      of repolarization. We conclude from the present results that the Ca(2+) blocking
      activity of BRL-32872 (i) prevents the occurrence of early after-depolarizations
      associated with action potential prolongation and (ii) limits an excessive
      increase in action potential duration heterogeneity. These electrophysiological
      features might represent the basis for antiarrhythmic compounds with reduced
      proarrhythmic profile.

PMID- 10585536
TI  - Mu-opioid receptor specific antagonist cyprodime: characterization by in vitro
      radioligand and [35S]GTPgammaS binding assays.
AB  - The use of compounds with high selectivity for each opioid receptor (mu, delta
      and kappa) is crucial for understanding the mechanisms of opioid actions. Until
      recently non-peptide mu-opioid receptor selective antagonists were not available.
      However, N-cyclopropylmethyl-4,14-dimethoxy-morphinan-6-one (cyprodime) has shown
      a very high selectivity for mu-opioid receptor in in vivo bioassays. This
      compound also exhibited a higher affinity for mu-opioid receptor than for delta-
      and kappa-opioid receptors in binding assays in brain membranes, although the
      degree of selectivity was lower than in in vitro bioassays. Cyprodime has
      recently been radiolabelled with tritium resulting in high specific radioactivity
      (36.1 Ci/mmol). We found in in vitro binding experiments that this radioligand
      bound with high affinity (K(d) 3. 8+/-0.18 nM) to membranes of rat brain
      affording a B(max) of 87. 1+/-4.83 fmol/mg. Competition studies using mu, delta
      and kappa tritiated specific ligands confirmed the selective labelling of
      cyprodime to a mu-opioid receptor population. The mu-opioid receptor selective
      agonist [D-Ala(2),N-MePhe(4),Gly(5)-ol]enkephalin (DAMGO) was readily displaced
      by cyprodime (K(i) values in the low nanomolar range) while the competition for
      delta- ([D-Pen(2), D-Pen(5)]enkephalin (DPDPE)) and kappa- (5alpha,7alpha, 8beta
      (-)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4, 5)dec-8-yl]-benzene-acetamide
      (U69,593)) opioid receptor selective compounds was several orders of magnitude
      less. We also found that cyprodime inhibits morphine-stimulated [35S]GTPgammaS
      binding. The EC(50) value of morphine increased about 500-fold in the presence of
      10 microM cyprodime. These findings clearly indicate that cyprodime is a useful
      selective antagonist for mu-opioid receptor characterization.

PMID- 10585538
TI  - Molecular pathogenesis of the cell surface proteins and lipids from Treponema
      denticola.
AB  - Treponema denticola, frequently isolated from the human oral cavity, is thought
      to be a major pathogen of human periodontal disease. Recent developments in
      molecular analysis have clarified the surface structure of this microorganism and
      the characteristics of its pathogenic factors. Structural analysis of the outer
      sheath showed T. denticola to have a new type of outer membrane lipid. Limited
      exposure of the major outer sheath protein is suggested by electron-microscopic
      analysis. A protease-deficient mutant has revealed the roles of the protease in
      the organization of the outer sheath material and in T. denticola pathogenicity.
      The surface features that contribute to the pathogenicity of T. denticola in
      periodontal disease are gradually being elucidated, and are reviewed.

PMID- 10585540
TI  - Presence of non-suppressive, M2-related dsRNAs molecules in Saccharomyces
      cerevisiae strains isolated from spontaneous fermentations.
AB  - Total dsRNA extractions in five killer K2 strains of Saccharomyces cerevisiae
      isolated from spontaneous fermentations revealed the presence of a novel dsRNA
      fragment (which we named NS dsRNA) of approximately 1.30 kb, together with L and
      M2 dsRNAs. NS dsRNA appeared to be encapsidated in the same kind of viral
      particles as L and M2 dsRNA. Northern blot hybridization experiments indicated
      that NS dsRNA was derived from M2 dsRNA, likely by deletion of the internal A+U
      rich region. However, unlike S dsRNAs (suppressive forms derived from M1 dsRNA in
      K1 killers), NS dsRNA did not induce exclusion of the parental M2 dsRNA when the
      host strain was maintained for up to 180 generations of growth.

PMID- 10585541
TI  - Construction and characterization of regulated L-arabinose-inducible broad host
      range expression vectors in Xanthomonas.
AB  - Several versions of broad host range (BHR), L-arabinose-inducible expression
      vectors were constructed. These expression vectors were based on a high copy
      number BHR pBBR1MCS-4 replicon that could replicate in both enteric and non
      enteric Gram-negative bacteria. Two versions of expression cassettes containing
      multiple cloning sites either with or without a ribosome binding site were placed
      under transcriptional control of the Escherichia coli BAD promoter and araC gene.
      Three versions of vectors containing ampicillin or kanamycin or tetracycline
      resistance genes as selectable markers were constructed. In all six new L
      arabinose-inducible BHR expression vectors containing many unique cloning sites,
      selectable markers were made to facilitate cloning and expression of genes in
      various Gram-negative bacteria. A Tn9 chloramphenicol acetyl transferase (cat)
      gene was cloned into an expression vector, resulting in pBBad18Acat that was used
      to establish optimal expression conditions (addition of 0.02% L-arabinose to mid
      exponential phase cells for at least 1 h) in a Xanthomonas campestris pv.
      phaseoli. Comparison of the Cat enzyme activities between uninduced and a 180-min
      L-arabinose-induced culture showed a greater than 150-fold increased Cat specific
      activity. In addition, L-arabinose induction of exponential phase cells harboring
      pBBad18Acat gave a higher amount of Cat than similarly treated stationary phase
      cells. The usefulness of the expression vector was also demonstrated in both
      enteric and non-enteric Gram-negative bacteria.

PMID- 10585539
TI  - Regulated expression of green fluorescent protein under the control of
      Aureobasidium pullulans xylanase gene xynA.
AB  - A mutant form of the jellyfish cDNA encoding green fluorescent protein (GFP) was
      fused to the promoter of the Aureobasidium pullulans xylanase gene xynA and the
      expression vector pxynEGFP was introduced into A. pullulans. In a manner
      consistent with regulation of the native xynA gene, gfp activity was induced by
      xylose and repressed by glucose. The marker may be useful for monitoring
      populations of A. pullulans in situ and for identifying transcriptional control
      elements of xynA.

PMID- 10585542
TI  - Isolation and transformation of uracil auxotrophs of the edible basidiomycete
      Pleurotus ostreatus.
AB  - Uracil auxotrophs of Pleurotus ostreatus were isolated using the selectable
      marker, resistance to 5'-fluoro-orotic acid (5'-FOA). Two of the nine uracil
      auxotrophs obtained were transformed to prototrophy using plasmid pTRura 3-2 that
      contains the orotidine monophosphate decarboxylase (ura3) gene from Trichoderma
      reesei. Southern blot analyses of the transformants showed that the transforming
      DNA had integrated into the genome of the protoplasts. Using 2 x 10(7)
      protoplasts, this system gave a transformation efficiency of about 30
      transformants per microg of DNA. Normal fruiting bodies were induced in the
      transformants by crossing them with wild-type monokaryons, and the basidiospores
      collected from these fruiting bodies showed a biased segregation rate to
      prototrophy. These results indicate the integrated DNA was stably inherited.

PMID- 10585543
TI  - Purification and characterization of cyanophycin and cyanophycin synthetase from
      the thermophilic Synechococcus sp. MA19.
AB  - The biosynthesis and accumulation of cyanophycin in the thermophilic
      cyanobacterium Synechococcus sp. MA19 were studied. By growing the cells in a 80
      l closed tubular photobioreactor under controlled conditions, the cells
      accumulated cyanophycin amounting up to 3.5% of the dry cell matter. The
      cyanophycin was purified and chemical analysis showed that it was composed of
      arginine and aspartic acid occurring at a molar ratio of 1:0.9. Sodium dodecyl
      sulfate-polyacrylamide gel electrophoresis revealed a broad distribution of the
      apparent molecular masses ranging from 20 to 130 kDa with a maximum at 50 kDa.
      During a three-step purification procedure involving ion exchange chromatography
      and gel filtration, the cyanophycin synthetase from strain MA19 was purified 144
      fold to electrophoretic homogeneity. It consisted of only one single type of
      subunit exhibiting an apparent molecular mass of 130 kDa. The enzyme catalyzed
      the polymerization of arginine and aspartate at elevated temperatures and was
      even active at 80 degrees C.

PMID- 10585544
TI  - Analysis of genetic diversity at the iron-containing superoxide dismutase locus
      in Plasmodium falciparum wild isolates.
AB  - In order to investigate the genetic diversity of iron-containing superoxide
      dismutase (FeSOD) from Plasmodium falciparum, a potential anti-malarial
      therapeutic target, we cloned and sequenced Plasmodium FeSOD from 26 blood
      samples from non-infected patients. Fifteen clones had the same nucleotide
      sequence as that of the FeSOD gene of the P. falciparum strain HB3 cultivated in
      vitro. The other 11 clones presented mutations responsible for punctual amino
      acid changes which did not modify key residues for the function or the structure
      of the enzyme. The high sequence conservation between FeSOD from the isolates
      confirms that this enzyme could represent a therapeutic target.

PMID- 10585545
TI  - Trophozoites of Giardia lamblia may have a Golgi-like structure.
AB  - Trophozoites of the primitive protozoan Giardia lamblia have been considered as
      cells which do not present the Golgi complex. Using C(6)-NBD ceramide, which has
      been shown to label the Golgi complex of mammalian cells, labelling of the
      perinuclear region of G. lamblia was observed by confocal laser scanning
      microscopy. Transmission electron microscopy of thin sections and of replicas of
      freeze-fractured cells revealed the presence of concentric perinuclear membranes
      resembling the Golgi complex.

PMID- 10585546
TI  - Cyanobacterial ycf27 gene products regulate energy transfer from phycobilisomes
      to photosystems I and II.
AB  - Two open reading frames (slr0115 and slr0947) in the genome of the cyanobacterium
      Synechocystis sp. PCC 6803 are shown to be involved in the regulation of the
      coupling of phycobilisomes to photosynthetic reaction centres. Homologues of
      these genes, called ycf27, have been found in a range of phycobilin-containing
      organisms. The slr0115 and slr0947 gene products are OmpR-type DNA-binding
      response regulator proteins. Deletion of slr0115 results in increased efficiency
      of energy transfer from phycobilisomes to photosystem II relative to photosystem
      I. Reduction of the copy number of slr0947 has the opposite phenotypic effect. We
      have given the slr0115 and slr0947 genes the designations rpaA and rpaB
      respectively.

PMID- 10585547
TI  - A small and compact genome in the marine cyanobacterium Prochlorococcus marinus
      CCMP 1375: lack of an intron in the gene for tRNA(Leu)(UAA) and a single copy of
      the rRNA operon.
AB  - Data obtained by pulsed field gel electrophoresis revealed for Prochlorococcus
      marinus CCMP 1375 a genome size of 1.81+/-0.04 Mbp. This value is significantly
      smaller than for all other cyanobacteria investigated so far. The absence of an
      intron in the gene for tRNA(Leu)(UAA), which otherwise is widespread among
      cyanobacteria, and the additional finding that the ribosomal operon exists as a
      single copy suggest that the deletion of non-essential sequences played a major
      role in the evolution of P. marinus. A small genome may have been advantageous in
      the adaptation to very oligotrophic marine conditions.

PMID- 10585549
TI  - Pythium periplocum, an aggressive mycoparasite of Botrytis cinerea causing the
      gray mould disease of grape-vine.
AB  - Pythium periplocum Dreschler has been found to be an aggressive mycoparasite of
      Botrytis cinerea, the causal agent of the gray mould disease of the grape-vine.
      When grown together, the former enters the latter's mycelium, branches freely
      within, coagulates its cytoplasm and finally tears its hyphae apart, bringing
      about widespread destruction of the grape-vine pathogen. Extensive coiling around
      the host, as reported in the case of other mycoparasites belonging to the genus
      Pythium, has not been observed here. The infected mycelium of B. cinerea fails to
      infect the grape-vine and does not induce the characteristic gray mould symptoms.
      Since P. periplocum is not a grape-vine parasite, it could be useful for the
      biological control of B. cinerea. A brief account of this mycoparasitism is
      discussed in this article.

PMID- 10585548
TI  - Adhesion and invasion of a mutant Shigella flexneri to an eukaryotic cell line in
      absence of the 220-kb virulence plasmid.
AB  - A Shigella flexneri strain, cured of the large 220-kb virulence plasmid,
      expresses adhering and invading ability in confluent monolayers of HeLa cells
      similar to its parent strain. Invasion by both the parent and the cured strains
      resulted in alteration of the monomeric actin (G) in the total actin pool of HeLa
      cells. Other indicators of invasive characteristics of virulent Shigella strains
      such as production of keratoconjunctivitis in guinea pig eye in vivo, Congo red
      binding and expression of contact hemolysin however, indicated loss of invasive
      properties in the plasmid cured strain. Further, pretreatment of bacterial cells
      with para-bromophenacyl bromide (p-BPB), a specific chemical inhibitor of
      phospholipase A, adversely affected adhesion to and invasion of HeLa cells in
      vitro, irrespective of the presence of the 220-kb plasmid indicating the possible
      involvement of the enzyme phospholipase A in the invasion process. Adherence of
      both the strains to guinea pig colonic epithelial cells (CECs) in vitro was
      reduced significantly on pretreatment of bacteria or CECs with p-BPB. Expression
      of exocellular enzymes viz. protease, elastase, phospholipase A and phospholipase
      C were not related to the large plasmid.

PMID- 10585550
TI  - Involvement of mitochondrial aldehyde dehydrogenase ALD5 in maintenance of the
      mitochondrial electron transport chain in Saccharomyces cerevisiae.
AB  - The physiological role of mitochondrial aldehyde dehydrogenase (ALD5) was
      investigated by analysis of the ald5 mutant (AKD321) in Saccharomyces cerevisiae.
      K(+)-activated ALDH activity of the ald5 mutant was about 80% of the wild-type in
      the mitochondrial fraction, while the respiratory activity of the ald5 mutant was
      greatly reduced. Cytochrome content was also reduced in the ald5 mutant.
      Enzymatic analysis revealed that the alcohol dehydrogenase activity of the ald5
      mutant was higher than that of the wild-type, while glycerol 3-phosphate
      dehydrogenase activity was the same in the two strains. Ethanol as a carbon
      source or addition of 1 M NaCl with glucose as the carbon source in the growth
      medium increased beta-galactosidase activity from an ALD5-lacZ fusion.
      Overexpression of another mitochondrial ALDH gene (ALD7) had no effect on
      increasing respiratory function of the ald5 mutant, but showed improved growth on
      ethanol. These observations show that mitochondrial ALD5 plays a role in
      regulation or biosynthesis of electron transport chain components.

PMID- 10585551
TI  - Cell density dependent acid sensitivity in stationary phase cultures of
      enterohemorrhagic Escherichia coli O157:H7.
AB  - Escherichia coli O157:H7, the causative agent of hemorrhagic colitis and
      hemolytic uremic syndrome, can survive in a highly acidic environment. The acid
      resistance of this organism, as measured by its ability to survive in low pH,
      depended on the density of the cells present during the assay. At low cell
      densities (</=2 x 10(7) ml(-1)), about 100% of the stationary phase cells
      survived in Luria broth pH 2.5 at 37 degrees C for at least 7 h. The same
      cultures at high cell densities (2-5 x 10(9) ml(-1)) were about 1000-fold more
      sensitive under identical conditions. Exponential phase cultures did not exhibit
      the cell density effect. The increased acid sensitivity at high cell densities
      was absent in the stationary phase cultures of a rpoS mutant (rpoS::pRR10) of an
      E. coli O157:H7 strain. Cell density dependent acid sensitivity of the stationary
      phase cultures was also observed in other enterohemorrhagic E. coli and Shigella
      strains. The increased acid sensitivity at high cell densities was absent in Gram
      positive organisms.

PMID- 10585552
TI  - Piriformospora indica: a new biological hardening tool for micropropagated
      plants.
AB  - Piriformospora indica is a novel plant growth promoting root endophyte.
      Regenerated plantlets of tobacco subjected to two different biological hardening
      techniques showed 88-94% survival when inoculated with P. indica as compared to
      62% survival of uninoculated controls under similar conditions. The tendency of
      the plantlet to overcome the stress in terms of revival capacity was maximal in
      the case of P. indica as compared to the control. The fungus has the potential to
      render protection to the micropropagated plantlets and help them escape the
      'transient transplant shock'.

PMID- 10585553
TI  - Ammonium (methylammonium) transport by heterocysts and vegetative cells of
      Anabaena variabilis.
AB  - Transport of the ammonium analogue [(14)C]methylammonium was similar in non
      growing, fully differentiated heterocysts as compared to vegetative, multiplying
      cells of the filamentous cyanobacterium Anabaena variabilis. NH(4)(+) inhibited
      uptake into the cells and released accumulated methylammonium from the cells.
      These observations suggest that the main function of ammonium transport in
      heterocysts may not be NH(4)(+) acquisition but cyclic retention of ammonia
      produced by nitrogenase.

PMID- 10585554
TI  - GcvA-mediated activation of gcvT-lacZ expression involves the carboxy-terminal
      domain of the alpha subunit of RNA polymerase.
AB  - Several LysR-type transcriptional regulators have been shown to require the
      carboxy-terminal domain of the alpha subunit (alphaCTD) of RNA polymerase to
      activate their target genes. We show here that GcvA, a LysR-type protein, also
      uses the alphaCTD to activate the Escherichia coli gcvTHP operon. Amino acid
      residues in the alphaCTD important for GcvA-dependent activation, however, have
      no effect on GcvA-mediated repression of the operon.

PMID- 10585555
TI  - Galactomannoglucans of lichenized fungi of Cladonia spp.: significance as
      chemotypes.
AB  - The chemical structures of the glucans, galactoglucomannans and
      galactomannoglucans of two species of the Cladonia, section Cocciferae, Cladonia
      miniata and Cladonia salmonea, were determined and compared. alpha-D-Glucans of
      the nigeran type were isolated from both species, in common with all Cladonia
      spp., along with galactoglucomannans containing (1-->6)-linked main-chains of
      alpha-D-Manp units substituted by structurally different and typical side-chains.
      Isolated were previously unreported galactomannoglucans, with (1-->3)-linked main
      chains of beta-D-Glcp units, substituted at O-2,6 by side-chains. These consisted
      of beta-D-Galf, 6-O-substituted beta-D-Galf and 2-O-, 4-O-, 6-O- and 2, 3-di-O
      substituted alpha-D-Manp units. According to (13)C NMR spectroscopy, a similar
      galactomannoglucan was isolated from the Cladonia spp. Cladonia signata, Cladonia
      crispatula, Cladonia penicillata, Cladonia imperialis, Cladonia clathrata,
      Cladonia connexa, Cladonia substellata and Cladonia ibitipocae. Its presence
      could also contribute to the classic taxonomy of lichenized fungi.

PMID- 10585556
TI  - Differential enhancement of Cry2A versus Cry11A yields in Bacillus thuringiensis
      by use of the cry3A STAB mRNA sequence.
AB  - Previously we demonstrated that the yield of Cry3A (70 kDa) can be increased as
      much as 10-fold when cry3A including its upstream STAB-SD mRNA stabilizing
      sequence is expressed in Bacillus thuringiensis under the control of cyt1A
      promoters. To determine whether the cyt1A promoters/STAB-SD combination
      (cyt1AP/STAB) has broader applicability, we used it to synthesize two other Cry
      endotoxins in the 70-kDa mass range, Cry2A and Cry11A. Combination of cyt1AP/STAB
      with orfs 2 and 3 of the cry2A operon yielded about 4. 4-fold the amount of Cry2A
      obtained with the wild-type cry2A operon. The yield of Cry11A obtained with a
      construct that contained the cyt1AP/STAB, cry11A and the 20-kDa protein gene was
      1.3-fold the amount obtained with a construct similar to the wild-type operon.
      These results demonstrate that the cyt1AP/STAB combination can enhance synthesis
      of different Cry proteins significantly, but that the level of enhancement varies
      with the specific protein synthesized.

PMID- 10585557
TI  - The hydA gene encoding the H(2)-evolving hydrogenase of Clostridium perfringens:
      molecular characterization and expression of the gene.
AB  - A putative hydrogenase (hydA) gene of Clostridium perfringens encodes a protein
      with strong identity to Clostridium pasteurianum hydrogenase I. Disruption of the
      hydA gene abolished H(2) productivity, confirming its function. A putative
      butyrate kinase gene (buk) is adjacent to the hydA gene. When cultures were grown
      in medium with glucose, 1.8-kb hydA and 2.1-kb buk transcripts and a 3. 9-kb
      transcript hybridized with both hydA and buk-probe were detectable in all the
      exponential growth phases. In medium without glucose, these transcripts were
      decreased rapidly after the mid-exponential phase. These results suggest that the
      transcription of these two genes is probably regulated by a similar mechanism in
      response to glucose availability.

PMID- 10585558
TI  - Gene trapping of two novel genes, Hzf and Hhl, expressed in hematopoietic cells.
AB  - Using an expression gene trapping strategy, we have identified and characterized
      two novel hematopoietic genes, Hzf and Hhl. Embryonic stem (ES) cells containing
      a gene trap vector insertion were cultured on OP9 stromal cells to induce
      hematopoietic differentiation and screened for lacZ reporter gene expression. Two
      ES clones displaying lacZ expression within hematopoietic cells in vitro were
      used to generate mice containing the gene trap integrations. Paralleling this in
      vitro expression pattern, both Hzf and Hhl were expressed in a tissue-specific
      manner during hematopoietic development in vivo. Hzf encodes a novel protein
      containing three C(2)H(2)-type zinc fingers predominantly expressed in
      megakaryocytes and CFU-GEMM. Hhl encodes a novel protein containing a putative
      phosphotyrosine binding (PTB) domain expressed in megakaryocytes, CFU-GEMM and
      BFU-E. These results demonstrate the utility of expression trapping to identify
      novel hematopoietic genes. Future studies of Hzf and Hhl should provide valuable
      information on the role these genes play during megakaryocytopoiesis.

PMID- 10585559
TI  - PC3 overexpression affects the pattern of cell division of rat cortical
      precursors.
AB  - The PC3 gene is transiently expressed during neurogenesis in precursor cells of
      the telencephalic ventricular/subventricular zone, and is rapidly downregulated
      before cell migration and differentiation. It is thought to have a role in
      controlling cell proliferation, but its precise function is not known. Here we
      present evidence that PC3, when overexpressed in vitro by retroviral-mediated
      gene transfer, acts by interfering with the normal pattern of cell division.
      Firstly, we report evidence that PC3 overexpression reduces the rate of cell
      proliferation in both NIH 3T3 cells and embryonic precursor cells from the rat
      cerebral cortex. Secondly, when studying the pattern of BrdU dilution in clones
      of cortical precursors, we observe that clones transduced with PC3 show an
      asymmetric pattern of BrdU dilution more frequently than clones transduced with a
      control vector. We discuss the hypothesis that the higher number of PC3
      transduced clones showing an asymmetric pattern of BrdU dilution may be due to an
      increase in asymmetric cell divisions.

PMID- 10585560
TI  - lacZ sequences prevent regulated expression of housekeeping genes.
AB  - In order to dissect the MHC class I H-2K gene regulatory sequences, we p
      reviously generated transgenic mice containing various H-2K/lacZ fusion genes.
      However contrary to transgenes where H-2K sequences were fused to other coding
      sequences, none of the lacZ fusion transgenes was widely ex pressed like H-2K
      gene. We now show that this silencing also occurs when lacZ is inserted into a
      larger H-2K genomic construct including promoter and other regulatory elements.
      Because the 5'H-2K region contains a CpG island, we suspected that the presence
      of lacZ coding sequences was inte rfering with the mechanism by which the H-2K
      promoter region is normally unmethylated and transcriptionally active. Indeed, we
      show that in high ( >10) copy number transgenic mice, insertion of lacZ sequences
      in the v icinity of the H-2K promoter results in partial or complete methylation
      of the H-2K CpG island. However, in low (1-3) copy number transgenic mic e no
      methylation was observed but the transgene was still silent, sugges ting that the
      silencing effect of lacZ does not only rely on abnormal CpG methylation.
      Intriguingly, when the H -2/lacZ construct was introduced via embryonic stem (ES)
      cells, regulate d transgene expression was observed in several chimaeric embryos
      derived from independent ES clones, but never in adult chimeras. Combined with t
      he fact that, despite much effort, it has been very difficult to generat e 'blue'
      mice, our results highlight the transcription-silencing effect of lacZ sequences
      when they are associated with regulatory sequences of ubiquitously expressed
      genes.

PMID- 10585561
TI  - Pitx2 isoforms: involvement of Pitx2c but not Pitx2a or Pitx2b in vertebrate left
      right asymmetry.
AB  - During vertebrate left-right development the homeobox gene Pitx2 serves as a
      mediator between transient nodal signaling in the left lateral plate mesoderm (l
      LPM) and asymmetric organ morphogenesis. Misexpression of Pitx2 in chick and frog
      led to alteration of organ situs. Here we report the presence of different Pitx2
      isoforms in mouse and frog. Pitx2c but not Pitx2a or Pitx2b was asymmetrically
      expressed in the l-LPM, heart and gut, and was specifically induced by nodal in
      Xenopus animal cap explant cultures and whole embryos. Pitx2c induced its own
      transcription, suggesting a maintenance mechanism following the down-regulation
      of nodal in the l-LPM. Pitx2c thus represents the left-specific isoform involved
      in vertebrate left-right asymmetry.

PMID- 10585562
TI  - Planar signalling is not sufficient to generate a specific anterior/posterior
      neural pattern in pseudoexogastrula explants from Xenopus and Triturus.
AB  - Early observations on the morphology of total exogastrulae from urodeles
      (Axolotl) had provided evidence for essential vertical signalling mechanisms in
      the process of neural induction. Conversely, more recent studies with anurans
      (Xenopus laevis) making use of molecular markers for neural-specific gene
      expression appear to support the idea of planar signalling as providing
      sufficient information for neural differentiation along the anterior-posterior
      axis. In an attempt to resolve this apparent contradiction, we report on the
      comparative analysis of morphology and gene expression characteristics with
      explants prepared from both urodeles (Triturus alpestris) and anurans (Xenopus
      laevis). For this purpose, we have made use of a refined experimental protocol
      for the preparation of exogastrulae that is intended to combine the advantages of
      the Holtfreter type exogastrula and the Keller sandwich techniques, and which we
      refer to as pseudoexogastrula explants. Analysis of histology and expression of
      several neural and ectodermal marker genes in such explants suggests that neural
      differentiation is induced in both species, but only within the intermediate zone
      between ectoderm and endomesoderm. Therefore, experiments with Xenopus and
      Triturus explants described in this communication argue against planar signalling
      events as being sufficient to generate a specific anterior/posterior neural
      pattern.

PMID- 10585563
TI  - Distinct promoter elements mediate endodermal and mesodermal expression of the
      HNF1alpha promoter in transgenic Xenopus.
AB  - The gene encoding the tissue specific transcription factor HNF1alpha is expressed
      in vertebrates in tissues of endodermal origin such as the liver and the gut as
      well as in the kidney, a mesoderm derived organ. Using a 6 kb HNF1alpha promoter
      fragment linked to GFP we observed green fluorescence in transgenic embryos
      restricted to the liver and gut as well as to the pronephros, the embryonic
      kidney. By deletion and mutation analysis of the HNF1alpha promoter we succeeded
      in dissecting the HNF1alpha promoter into two entities that are either active in
      the endoderm or the mesoderm. In conclusion, our data establish that the
      generation of transgenic Xenopus allows the functional dissection of promoters in
      the context of the entire organism.

PMID- 10585564
TI  - The Xvex-1 antimorph reveals the temporal competence for organizer formation and
      an early role for ventral homeobox genes.
AB  - The organizer in vertebrate embryos has been shown to play a central role in
      their development by antagonizing ventralizing signals and promoting dorsal
      development. The ventral homeobox gene, Xvex-1, is capable of fulfilling some of
      the functions of BMP-4. By fusion to activation and repression domains, Xvex-1
      was shown to function as a repressor of transcription. The activator version of
      Xvex-1, the antimorph, was made inducible by fusion to the ligand binding domain
      of the glucocorticoid receptor. The organizer genes, gsc and Otx-2, were
      identified as direct targets of Xvex-1. The XVEX-1 antimorph can induce the
      formation of secondary axes. Temporal analysis of secondary axis induction
      revealed that the competence to induce a secondary organizer ends with the onset
      of gastrulation. The same temporal competence window was exhibited by an
      inducible gsc construct. Partial loss of Xvex-1 activity was able to improve the
      efficiency of secondary axis induction by the dominant negative BMP receptor or
      Smad6. These observations together with the early widespread expression of Xvex-1
      throughout the embryo prior to gastrulation encoding a homeodomain repressor
      protein, suggest that elements of the ventral signaling pathway play an important
      role during late blastula in restricting the formation of Spemann's organizer.

PMID- 10585565
TI  - Characterization of the two zebrafish orthologues of the KAL-1 gene underlying X
      chromosome-linked Kallmann syndrome.
AB  - The gene underlying X chromosome-linked Kallmann syndrome, KAL-1, has been
      identified for several years, yet its role in development is still poorly
      understood. In order to take advantage of the zebrafish as a model in
      developmental genetics, we isolated the two KAL-1 orthologues, kal1.1 and kal1.2,
      in this species. Comparison of deduced protein sequences with the human one shows
      75.5 and 66.5% overall homology, respectively. The most conserved domains are the
      whey acidic protein-like domain and the first of four fibronectin-like type III
      repeats. However, kal1.2 putative protein lacks the basic C-terminal domain (20
      residues) found in kal1.1 and KAL-1. The expressions of kal1.1 and kal1.2 were
      studied in the embryo between 6 and 96 hours post fertilization using whole-mount
      in situ hybridization. Although a few structures express both genes, kal1.1 and
      kal1.2 expression patterns are largely non-overlapping. Taken together, these
      patterns match fairly well those previously reported for human KAL-1 and chicken
      kal1. As regards the olfactory system, kal1.1 is expressed, from 37 h.p.f.
      onward, in the presumptive olfactory bulbs, whereas kal1.2 transcript is only
      detected, from 48 h.p.f., in the epithelium of the nasal cavity. The relevance of
      the zebrafish as an animal model for studying both the function of KAL-1 in
      normal development and the developmental failure leading to the olfactory defect
      in Kallmann syndrome, is discussed.

PMID- 10585566
TI  - XYbp, a novel RING-finger protein, is a component of the XY body of spermatocytes
      and centrosomes.
AB  - RING-finger proteins participate in developmental processes, including
      gametogenesis. A fetal oocyte cDNA library was used to select genes expressed
      during male germ-cell differentiation. A novel RING-finger protein, XYbp (XY body
      protein), participating in mouse spermatogenesis has been identified. This novel
      gene generates a ubiquitously expressed transcript of 4.2 kb and a testis
      specific one of 2.8 kb, processed by an alternative polyadenylation mechanism
      from a non-canonical polyadenylation signal. Transcription of XYbp is regulated
      during spermatocyte differentiation. The antiserum raised against the XYbp
      peptide demonstrated that XYbp is localised mainly in the XY bivalent of
      spermatocytes (XY body) and in the centrosomes of somatic and germ cells in all
      phases of the cell cycle. These studies indicate that we have identified a new
      member of the RING-finger family of proteins associated with the XY meiotic
      bivalent during spermatogenesis development and with the centrosomes of all
      cells.

PMID- 10585567
TI  - Expression of FGFR1, FGFR2 and FGFR3 during early neural development in the chick
      embryo.
AB  - Studies involving chick embryos have implicated FGFs in neural induction and
      patterning as well as in other developmental events. Detailed analyses of FGF
      receptor expression at early stages of neural development have not been reported
      for the chick embryo and are incomplete for other vertebrate classes. Here we
      show the expression patterns of three FGF receptors, (FGFR1, FGFR2 and FGFR3) in
      embryonic stages between gastrulation and limb bud formation, focussing
      particularly on neural tissues. Between neural induction and neurulation, all
      three receptors are expressed in the neural plate albeit with distinct and
      overlapping distributions. During early neuromere formation FGFR1 transcripts are
      present throughout the neural tube, while transcripts for FGFR2 and FGFR3 become
      restricted to regions of the diencephalon and spinal cord. A little later, FGFR2
      and FGFR3 are additionally expressed in the anterior midbrain and within the
      hindbrain. During later neuromere development, FGFR1 transcripts become localised
      to the telencephalon, anterior dorsal diencephalon and throughout the midbrain
      and hindbrain, whereas FGFR2 mRNA is restricted to dorsal telencephalon,
      dorsoanterior midbrain and hindbrain. FGFR3 is also expressed in anterior
      midbrain and hindbrain during this developmental period, and is additionally
      expressed in the posterior telencephalon, in the pretectum, and at the zona
      limitans intrathalamica. The observed expression patterns of all three receptors
      within the hindbrain, including rhombomere boundaries, are complex and dynamic.
      Expression patterns within the somites, eye, head mesenchyme, branchial arches,
      limb buds, nephric kidney and pharynx are also described.

PMID- 10585568
TI  - Xotx1 maternal transcripts are vegetally localized in Xenopus laevis oocytes.
AB  - Xotx1 is a Xenopus homeobox gene related to the Drosophila gene orthodenticle
      (otd). We previously reported that Xotx1 transcripts are already present in
      unfertilized egg. Here we report that maternal Xotx1 mRNA is vegetally localized
      during oogenesis. In stage II oocytes Xotx1 transcripts are localized within the
      mitochondrial cloud, in a perinuclear position; later on, they are translocated
      to the vegetal cortex within the mitochondrial cloud. We also observed that in
      stage III oocytes the expression domain of Wnt11 is contained within the one of
      Xotx1 while, at stage IV, the Xotx1 expression domain is contained within the one
      of Vg1.

PMID- 10585569
TI  - Asymmetric expression of antivin/lefty1 in the early chick embryo.
AB  - Mammalian lefty and zebrafish antivin, highly related to lefty, are shown to be
      expressed asymmetrically and involved in the specification of the left body side
      of early embryos. We isolated a chick homologue of the antivin/lefty1 cDNA and
      studied its expression pattern during early chick development. We found that
      antivin/lefty1 is expressed asymmetrically on the left side of the prospective
      floorplate, notochord and lateral plate mesoderm of the chick embryo.

PMID- 10585570
TI  - Sequence and embryonic expression of deltaC in the zebrafish.
AB  - Four genes - deltaA, deltaB, deltaC and deltaD - coding for homologues of the
      Notch ligand Delta have been discovered in zebrafish (Haddon et al., 1998b). We
      report here the cDNA sequence and expression pattern of deltaC. Its closest
      relatives are deltaB and Xenopus X-Delta-2. Unlike deltaA, deltaB, and deltaD,
      deltaC is not expressed in the majority of nascent primary neurons; but it is
      strongly expressed in the early retina, where it precedes other delta genes. It
      is also expressed in cranial ganglia, in sensory epithelia including ear and
      lateral line, and in scattered epidermal cells. In the mesoderm, expression is
      visible by 50% epiboly; it is seen subsequently in the tail bud, in stripes in
      the presomitic mesoderm and in the posterior half of each somite. There is
      expression also in notochord, blood vessels and pronephros.

PMID- 10585571
TI  - [Small cell lung carcinoma].
AB  - Small cell lung carcinoma represents less than twenty five percent of all lung
      cancers. Nevertheless, a lot of studies permitted to better define this cancer
      and to propose specific therapeutic approaches. Clinical symptoms, results and
      roles of chemotherapy, radiation therapy and surgery are discussed in this
      review.

PMID- 10585572
TI  - [Epidemiology, prognostic factors, staging, and treatment of non-small cell lung
      cancer].
AB  - Non small cell lung cancer (NSCLC) is the leading cause of cancer death among the
      world. The incidence of adenocarcinoma is rising while squamous cell carcinoma
      decreases. The biology of NSCLC is characterized by a multistep carcinogenesis.
      During the last years, changing in the management of NSCLC have occurred. The
      lobectomy and mediastinal lymph node dissection are now the references.
      Postoperative radiotherapy has failed to improve survival, but hyperfractionated
      radiotherapy seems to be interesting for inoperable patients. The platin-based
      chemotherapy is now considered as standard treatment for stage IV. Gene therapy
      and angiogenesis inhibitors are currently under development.

PMID- 10585573
TI  - [Malignant pleural mesothelioma].
AB  - The malignant pleural mesothelioma is a rare tumor of the general population. The
      exposure of asbestos still remains the main factor of risk, found in 72 to 95 %
      of the patients. The diagnosis is difficult. The symptoms are poor, with most
      often chronic pleural effusion, with dyspnea, associated with localized chest
      pain. The histological diagnosis is made on thoracoscopic biopsy. Analysis of the
      histochemical profile (PAS-D, hyaluronidase, vimentine), the use of
      immunochemistry (CEA, keratines), and electron microscopy can facilitate the
      making of the diagnosis. There is 3 different entities of malignant mesothelioma:
      the epithelial type, mixed, and sarcomatous. The tagging is based on thoracic
      scanner, to determinate the extent of the tumor, her relation with the local
      structures, and the possible involvement of the mediastinal lymph nodes. There is
      several staging systems, the Butchart's staging classification, and most recently
      the IMIG (International Mesothelioma Interest Group) classification. The
      significant prognostic factors, in multivariate analysis are: the stage of the
      disease, the histologic type, and the performance status of the patient. The
      current therapeutic maneuvers (surgery, chemotherapy, radiotherapy) did not show
      significant improvement of the survival. The radical surgery, like
      pleuropneumonectomy, should be consider only for patients with an early stage of
      the disease. The chemotherapy, with single agent or in combination, still remains
      disappointing, with objective response rates between 20 and 30 %, in best cases.
      The curative radiotherapy is limited by the importance of the target-volume, and
      the proximity of critical organ (lung, heart). Only the preventive radiotherapy,
      on scars, niddle or surgical tracts is recommended. Immunotherapy, by systemic or
      intracavitary administration, remains limited because of the toxicity, especially
      infection. All of the therapeutic maneuvers should be proposed in clinical
      trials.

PMID- 10585574
TI  - Induction of apoptosis by abrogation of HSP70 expression in human oral cancer
      cells.
AB  - We have reported differential expression of 70-kDa heat shock protein (HSP70) in
      human oral tumorigenesis. The functional significance of elevated levels of HSP70
      protein in oral squamous cell carcinomas (SCC) remains to be elucidated. The
      present study was designed to investigate the role of HSP70 protein in the
      proliferation and survival of oral tumour cells. Abrogation of HSP70 expression
      by antisense HSP70 oligonucleotides treatment of human oral carcinoma cells
      isolated from primary tumours or HSC-2 cells triggered cell death with several
      characteristic features, including DNA laddering, chromatin condensation and
      fragmentation. Flow-cytometric analysis showed a hypodiploid DNA peak of
      propidium iodide-stained nuclei in the antisense oligomer-treated cells. This
      response was accompanied by a decrease in the percentage of cells in the S phase
      of the cell cycle, suggesting inhibition of cell proliferation. Treatment of oral
      cancer cells with HSP70 antisense oligomers resulted in decreased expression of
      anti-apoptotic signal protein bcl-2. Our results suggest that HSP70 antisense
      oligomer treatment abrogates the expression of HSP70 protein that may disrupt
      HSP70-bcl-2 interactions, in turn inhibiting cell proliferation and inducing
      apoptosis. Conversely, the data suggest that HSP70 is required for proliferation
      and survival of oral tumour cells.

PMID- 10585575
TI  - FHIT alterations in cancerous and non-cancerous cervical epithelium.
AB  - We have reported a significant frequency of an alteration of the fragile
      histidine triad (fhit) gene in squamous-cell carcinoma of the uterine cervix
      (series 1). To further define the role of fhit alteration in the development of
      cervical carcinoma, we surveyed 36 normal cervical epithelium, 22 cervical intra
      epithelial neoplasias (CINs) and 20 additional cases of invasive cervical
      carcinomas (series 2). fhit transcripts were analyzed using reverse-transcription
      polymerase-chain-reaction amplification and sequencing. Loss of expression of
      fhit was observed in 14 of 48 (29%) invasive carcinomas (8/28, series 1; 6/20,
      series 2) but not in any normal squamous epithelia or CINs analyzed. Abnormal
      fhit transcripts, including deletions and/or insertions, were observed in 12 of
      48 (25%) invasive carcinomas (9/28, series 1; 3/20, series 2), 6 of 22 (27%)
      CINs, and 10 of 40 (25%) normal squamous epithelia (0/4, series 1; 10/36, series
      2). Point mutation was detected in 9 of 48 (19%) cervical carcinomas (8/28,
      series 1; 1/20, series 2). Inactivation in both alleles was observed in 18 of 48
      cervical carcinomas (38%), but not in any of 22 CINs or 40 normal squamous
      epithelia. Loss or impaired expression of the fhit-gene product was detected in
      13 of 30 (43%) cervical carcinomas by immunohistochemistry, whereas all 6 normal
      cervical epithelia, or 22 CINs, expressed fhit protein. There was a strong
      association of impaired fhit protein expression with the disruption of normal
      fhit transcript in cervical carcinoma. No apparent correlation was observed
      between fhit inactivation and HPV infection. Our results suggest that fhit-gene
      inactivation occurs, not as an initiating event, but rather as a later event in
      cervical carcinogenesis, when the cervical tumor has acquired an invasive
      character.

PMID- 10585576
TI  - Role of MT-MMPs and MMP-2 in pancreatic cancer progression.
AB  - Activation of matrix metalloproteinase-2 (MMP-2) by the membrane-type matrix
      metalloproteinases (MT-MMPs) has been associated with tumor progression. In the
      present study, we examined the role of MMP-2 and its activators MT1-MMP, MT2-MMP
      and MT3-MMP in pancreatic tumor cell invasion and the development of the
      desmoplastic reaction characteristic of pancreatic cancer tissues. Northern blot
      analyses revealed that transcript levels of MT1-MMP and MT2-MMP, but not MT3-MMP,
      were enhanced in pancreatic cancer tissues (n = 18) compared with both chronic
      pancreatitis (n = 9) and healthy pancreas (n = 9). A good correlation was found
      between MT1-MMP and both MMP-2 expression (p < 0.01) and activity in pancreatic
      cancer tissues. In addition, expression and activation of MMP-2 were strongly
      associated with the extent of the desmoplastic reaction in pancreatic cancer
      tissues. Invasion assays showed a good correlation between MMP-2 expression and
      activity and the invasive potential of pancreatic cancer cell lines. In cell
      lines with high levels of MMP-2 expression and activity, the MMP inhibitor
      Batimastat led to significant reduction of the number of invading cells. Our
      results suggest that MT1-MMP is involved in the progression of pancreatic cancer
      via activation of MMP-2. MMP-2 itself plays an important role in tumor cell
      invasion and appears to be associated with the development of the characteristic
      desmoplastic reaction in pancreatic cancer.

PMID- 10585577
TI  - Analysis of repair of abasic sites in early onset breast cancer patients.
AB  - Defective DNA repair has been suggested as a possible predisposing factor for
      breast cancer. We have investigated the repair of the frequent endogenous lesions
      abasic sites in sporadic early onset breast cancer patients and matched control
      individuals. No significant difference was observed between the abasic site
      repair capacities of peripheral blood lymphocytes from cases and controls. Repair
      of abasic sites was also studied in tumor and surrounding normal tissues of the
      patients. The 2 tissues showed marked differences in histology and protein
      composition with a fibro-collagenous component varying from sample to sample but
      invariably higher in normal tissues as compared with the adjacent tumor. These
      differences involved the need to calculate the repair activities of tissues on
      the basis of cellular DNA content for comparison purposes. After doing so, tumor
      and normal tissues exhibited similar abasic site repair capacities, whereas
      lymphocytes showed a repair capacity significantly lower than tissues. We
      conclude that early onset sporadic breast cancer patients show no evident defect
      in repair of abasic sites at the level of both lymphocytes and tumor.

PMID- 10585578
TI  - Concomitant over-expression of vascular endothelial growth factor and its
      receptors in pancreatic cancer.
AB  - Vascular endothelial growth factor (VEGF) is a potent angiogenic polypeptide that
      activates 2 distinct high-affinity tyrosine kinase receptors, flk-1/KDR and flt
      1. In the present study, we characterized the expression of VEGF and its
      receptors flk-1/KDR and flt-1 in the normal human pancreas and in human
      pancreatic cancer tissues and cell lines. VEGF, flk-1/KDR and flt-1 mRNA levels
      were elevated in cancer tissues compared with normal pancreas. By immuno
      histochemistry, VEGF, flk-1/KDR and flt-1 immunoreactivity co-localized in many
      of the cancer cells within the tumor mass. Three (AsPC-1, Capan-1 and MIAPaCa-2)
      of 6 pancreatic cancer cell lines expressed flk-1/KDR mRNA and protein, and 4
      cell lines (AsPC-1, Capan-1, T3M4 and PANC-1) expressed flt-1 mRNA transcripts.
      Binding studies with (125)I-labeled VEGF165 indicated that only Capan-1 cells
      exhibited high levels of specific binding. Furthermore, VEGF enhanced the growth
      of Capan-1 cells but was without effect in the other cell lines. VEGF also
      enhanced mitogen-activated protein kinase (MAPK) phosphorylation and c-fos
      induction in Capan-1 cells, whereas the MAPK kinase inhibitor PD98059 abolished
      the growth-stimulatory effect of VEGF. These data indicate that human pancreatic
      cancers have the capacity to over-express VEGF and its receptors and suggest that
      in some instances VEGF may directly promote pancreatic cancer growth via the MAPK
      pathway.

PMID- 10585579
TI  - Chlamydia trachomatis infection as a risk factor for invasive cervical cancer.
AB  - Cervical carcinoma is a sexually transmitted disease most strongly linked with
      human-papillomavirus (HPV) infection. We conducted a prospective sero
      epidemiologic study to evaluate the role of Chlamydia trachomatis infection in
      the development of cervical carcinoma, with invasive cancer as an end point. A
      nested case-control study within a cohort of 530000 Nordic women was performed.
      Linking data files of 3 Nordic serum banks and the cancer registries of Finland,
      Norway and Sweden identified 182 women with invasive cervical carcinoma diagnosed
      during a mean follow-up of 5 years after serum sampling. The serum samples of the
      cases and matched cancer-free controls were analyzed for IgG antibodies to C.
      trachomatis, C. pneumoniae (a control microbe) and HPV types 16, 18 and 33, as
      well as for serum cotinine (an indicator of tobacco smoking). Serum antibodies to
      C. trachomatis were associated with an increased risk for cervical squamous-cell
      carcinoma (HPV- and smoking-adjusted OR, 2.2; 95% CI, 1.3-3.5). The association
      remained also after adjustment for smoking both in HPV16-seronegative and 
      seropositive cases (OR, 3.0; 95% CI, 1.8-5.1; OR, 2.3, 95% CI, 0. 8-7.0
      respectively). No such association was found for C. pneumoniae. Our prospective
      study provides sero-epidemiologic evidence that infection with C. trachomatis
      confers an increased risk for subsequent development of invasive squamous-cell
      carcinoma of the uterine cervix.

PMID- 10585580
TI  - Elevated levels of angiogenic cytokines in the plasma of cancer patients.
AB  - Although in the normal healthy organism angiogenesis is a tightly regulated
      process, under a variety of circumstances it may contribute to disease states.
      These include the growth of solid tumors, the hematogenous spread of tumor cells
      and the growth of metastasis. Our aim was to measure the levels of 5 angiogenic
      cytokines in the plasma of patients with a variety of cancers, to establish a
      plasmatic angiogenic profile. We prospectively obtained blood samples in citrated
      tubes from 40 healthy individuals and 75 patients with a variety of solid tumors.
      Patients who had received any form of treatment in the preceeding 6 months were
      excluded from the study. Plasma levels of the following 5 cytokines were
      determined by ELISA: vascular endothelial growth factor (VEGF), hepatocyte growth
      factor (HGF), basic fibroblast growth factor, transforming growth factor-beta and
      tumor necrosis factor-alpha. In some cases, additional samples were taken 4 and
      15 days after surgical removal of the tumor. Our findings demonstrate, that
      firstly, compared to the tumor group VEGF was almost always undetectable or
      present at very low levels in healthy individuals; secondly, a threshold value
      for HGF was found to exist between the 2 groups (healthy vs. tumor); and thirdly,
      there was a clear relationship between plasma levels of VEGF and HGF and
      extension of disease (i.e., without or with metastases). The timing of blood
      sampling in the post-operative period was found to be critical, particularly with
      regard to VEGF and HGF. The existence of a systemic angiogenic profile in the
      plasma of cancer patients may be useful as a diagnostic and prognostic tool and
      may help in the future to monitor the responses of individual patients to anti
      tumor and, particularly, anti-angiogenic therapy.

PMID- 10585581
TI  - Inherited polymorphism in the N-acetyltransferase 1 (NAT1) and 2 (NAT2) genes and
      susceptibility to gastric and colorectal adenocarcinoma.
AB  - The polymorphic arylamine N-acetyltransferases (NAT1 and NAT2) have been
      implicated in increased susceptibility to certain malignancies. We analyzed
      genetic polymorphisms in both the NAT1 and NAT2 genes among 140 gastric
      adenocarcinoma patients, 103 colorectal adenocarcinoma patients and 122 healthy
      controls from Japan. The frequency of the specific genotype NAT1*10 allele, which
      contains a variant polyadenylation signal, was higher among all gastric
      adenocarcinoma cases, but this increase did not reach statistical significance.
      After grouping according to tumor differentiation of gastric adenocarcinoma
      patients, NAT1 polymorphism was a risk factor among the well-differentiated type
      of tumors (OR = 3.03, 95% CI 1. 08-8.46). Stratifying by smoking status, we found
      that the OR for heavy smokers with the NAT1*10 allele was 2.97 (95% CI 1.23
      7.14). When the combined risk of NAT1*10 allele from smoking and tumor
      differentiation was calculated, we found that the risk of the NAT1*10 allele with
      heavy smoking was increased among the well - differentiated type of gastric
      adenocarcinoma (OR = 4.24, 95% CI 0. 87-20.6). The NAT1*10 genotype was not a
      significant risk factor in colorectal adenocarcinoma. No statistically
      significant differences were observed in the frequency of NAT2 rapid acetylation
      genotype in gastric (91.4%) or colorectal (95.2%) adenocarcinoma patients when
      compared with the control population (94.3%). Our results suggest the NAT1*10
      allele may be an important genetic determinant of the well-differentiated type of
      gastric adenocarcinoma, which may be induced by smoking.

PMID- 10585582
TI  - Methylation of the hMLH1 promoter in familial gastric cancer with microsatellite
      instability.
AB  - Microsatellite instability (MSI), which is recognized as an important mechanism
      in tumorigenesis, has been reported in familial gastric cancers (FGC). However,
      genetic defects responsible for this phenotype, that is, mutations in mismatch
      repair genes such as hMLH1 and hMSH2, have not been detected in most FGC cases.
      Earlier studies have shown that the promoter region of the hMLH1 gene was
      methylated in some sporadic colorectal and endometrial cancers. To determine how
      FGC acquire MSI, we examined the MSI status, hMLH1-protein expression and
      methylation status of the hMLH1-promoter region in FGC cases. Out of 9 cancers, 6
      from 8 FGC kindreds showed MSI at one or more loci; no germline mutations in the
      hMLH1 or hMSH2 genes were detected; 4 cancers exhibiting MSI displayed aberrant
      hMLH1 expression: complete loss in one, decreased level in another, and partially
      staining pattern in the remaining 2. Methylation in the hMLH1-promoter region was
      found in these 4 cases. In contrast, the cancers displaying hMLH1-protein
      expression were not methylated in the hMLH1-promoter region. Our data show a
      significant association between the absence of hMLH1 expression and methylation
      of its promoter in FGC cases with MSI. This suggests that the mechanism of
      inactivation of hMLH1 is epigenetic and that there are other genes responsible
      for FGC.

PMID- 10585583
TI  - Cancer incidence in the African population of Harare, Zimbabwe: second results
      from the cancer registry 1993-1995.
AB  - The data of the population-based cancer registry in Harare, Zimbabwe, for 1993
      1995 are presented and compared with those from 1990-1992. The most significant
      change in rates is the striking increase in the incidence of Kaposi's sarcoma
      (KS) in both men and women, compatible with the evolution of the AIDS epidemic in
      sub-Saharan Africa. The incidence of KS doubled in both sexes and now accounts
      for 31.1% of registered cancers. It has overtaken breast cancer to become the
      second most common tumour in African women, after cervical cancer, and is now one
      of the leading childhood tumours, accounting for 10. 3% of cancers recorded in
      children (ages 0-14). With the exception of KS, the incidence and pattern of
      occurrence of the other malignant neoplasms changed little during the observed 6
      years.

PMID- 10585584
TI  - International trends and patterns of prostate cancer incidence and mortality.
AB  - Prostate cancer is the most commonly diagnosed cancer in western men, and
      incidence is rising rapidly in most countries, including low-risk populations.
      Age-adjusted incidence and mortality rates from 15 and 13 countries between 1973
      77 and 1988-92, respectively, were compared to provide leads for future analytic
      studies. Large increases in both incidence and mortality rates of prostate cancer
      were seen for all countries. For incidence, increases were more pronounced in the
      United States, Canada, Australia, France and the Asian countries, while the
      increases in medium-risk countries were moderate. Increases in incidence ranged
      from 25%-114%, 24%-55% and 15%-104% in high-, medium- and low-risk countries,
      respectively. Mortality rates rose more rapidly in Asian countries than in high
      risk countries. Substantial differences in incidence and mortality across
      countries were evident, with U.S. blacks having rates that were 50-60 times
      higher than the rates in Shanghai, China. Increasing incidence rates in the
      United States and Canada are likely to be due in part to the widespread use of
      transurethral resection of the prostate and prostate-specific antigen testing,
      while increases in the Asian countries are probably related to westernization in
      these low-risk populations. The large disparities in incidence between high- and
      low-risk countries may be due to a combination of genetic and environmental
      factors. Future studies are needed to examine gene-gene and gene-environment
      interactions in various countries concurrently to shed light on the etiology of
      prostate cancer and to help elucidate reasons for the large differences in risk
      between populations.

PMID- 10585585
TI  - Determinants of O(6)-alkylguanine-DNA alkyltransferase activity in normal and
      tumour tissue from human colon and rectum.
AB  - O(6)-Alkylguanine-DNA-alkyltransferase (ATase) is an important modulator of
      alkylating agent-induced toxicity and carcinogenicity, but those factors which
      influence the expression of this repair protein in human tissues are poorly
      characterised. In this study, we have determined ATase levels in macroscopically
      normal and tumour tissues from 76 individuals with benign or malignant colorectal
      disease. All tissue samples had detectable ATase activity, with values ranging
      from 35 to 451 fmol/mg protein. ATase activity in normal rectal tissue was
      significantly higher than that in normal tissue from the sigmoid colon (148 +/-
      76 vs. 100 +/- 40 fmol/mg protein, p = 0.01), whereas ATase levels within
      different regions of the colon (proximal vs. sigmoid colon) were similar. In
      normal tissue, inter-individual variation in ATase activity was 4-fold in the
      colon and 6-fold in the rectum, whereas in tumour tissue the corresponding
      figures were approx. 13.0- and 7-fold, respectively. There was no detectable
      difference in normal tissue ATase activity between individuals with benign or
      malignant disease of the colon. Normal and tumour tissue ATase activities were
      strongly correlated in the sigmoid colon (r = 0.80) and rectum (r = 0.59) but not
      the caecum (r = -0.03). In a multivariate analysis, ATase activity in normal
      colon tissue increased with age (p = 0.01) and current smoking (p = 0.06),
      whereas tumour ATase activity increased only with use of anti-histamines (p =
      0.05). In rectal tumour tissue, activity decreased with age (p = 0.05) and use of
      anti-muscarinic medications (p = 0.01): in normal rectal tissue, no modulating
      factors were identified.

PMID- 10585586
TI  - A highly sensitive method for K-ras mutation detection is useful in diagnosis of
      gastrointestinal cancer.
AB  - Detection of molecular features such as K-ras mutations has been used to evaluate
      potential tumour markers in a wide variety of clinical samples. Here we have
      applied a recently developed highly sensitive method for detection of K-ras codon
      12 mutations to colorectal and pancreatic cancer diagnosis. We analysed 67 faecal
      samples from patients undergoing diagnostic colonoscopy under suspicion of
      colorectal cancer. PCR products were obtained in 62 of 67 (93%) faecal samples.
      Mutations were detected in exfoliated cells in 6 of 22 (27%) of the adenomas and
      in 6 of 11 (55%) of adenocarcinomas. No false positives were observed. Agreement
      between faecal samples and corresponding tissues was 100% for adenocarcinomas and
      65% for adenomas. Mutations were also analysed in 61 pancreatic fine-needle
      aspirates. Mutations were detected in 36 of 45 (80%) of the pancreatic aspirates
      diagnosed as pancreatic cancer without false positives. Our findings suggest
      that, when colorectal cancer is suspected, detection of K-ras codon 12 mutations
      in faecal samples using this new method is specific for colorectal tumours.
      Additionally, this technique is a good alternative for evaluation of pancreatic
      masses.

PMID- 10585587
TI  - Primary brain tumours as second primary: a novel association between meningioma
      and colorectal cancer.
AB  - In a previous study, a decreased risk for first degree relatives of patients with
      astrocytoma has been observed for breast and colorectal cancer. The aim of this
      study was to examine the associations between breast and colorectal cancer as
      first primary cancer and the risk of developing astrocytoma and meningioma as a
      second primary cancer. Two cohorts were constructed, one from all cases with
      breast cancer (1,036,466 person-years) and one from all cases of colorectal
      cancer (572,422 person-years) in Sweden during the period 1958-1994. The risk of
      developing astrocytoma and meningioma after breast or colorectal cancer was
      calculated. A significant increased risk for developing meningioma was seen after
      colorectal cancer, standardized incidence ratio (SIR) 1.60 confidence interval
      (CI; 1.32-1.94) and after breast cancer, SIR 1. 57 CI (1.36-1.81). The previously
      observed decreased risk for astrocytoma could not be verified in this study. A
      novel association between meningioma and colorectal cancer, particularly in
      females, was observed, which justifies further studies to evaluate common
      aetiological factors.

PMID- 10585588
TI  - Extensive ductal carcinoma In situ with small foci of invasive ductal carcinoma:
      evidence of genetic resemblance by CGH.
AB  - Although ductal carcinoma in situ (DCIS) of the breast is accepted as a potential
      precursor lesion for invasive ductal cancer (IDC), the critical genetic events
      associated with the tumor progression remain unknown. Since some extensive DCIS
      may show a small focus of IDC, these cases seem to be particularly suitable to
      investigate the primary abnormalities that determine the progression from in situ
      to early invasive cancer. We combined laser-microdissection with degenerative
      oligonucleotide-primed PCR (DOP-PCR) and comparative genomic hybridization (CGH)
      to detect copy number changes in 7 cases of extensive (>4 cm) DCIS with 1 small
      adjacent invasive focus. In 3 of the cases, single lymph node metastases (LN)
      were already present and were also investigated. Analysis of DCIS, IDC and LN
      components in the same patients revealed several consistent chromosomal changes
      present at all 3 sites: 1q, 7q, 8q, 16, 17, 19, 20q, 21q and 22q, the most
      frequent losses on 4q, 11q and 13q. DNA gain on 3p and 12q were more frequently
      found in IDC than in DCIS, suggesting the presence of proto-oncogenes activated
      during the progression to invasive cancer on these regions. Using paired
      analysis, resemblence of alterations found in DCIS and IDC could be quantified
      (odds ratio 7.0, p< or = 0.01). Gains on 6p, 10q, 14q and 15q and losses on 9p
      were identified in DCIS and IDC but not in LN, which may, therefore, represent
      early events in the carcinogenic process. Additional losses were found in the LNs
      on 2q, 3q, 5q, 6q, 12q and 16q. CGH results on chromosome 1 and 20 were confirmed
      by FISH and on chromosomal region 9p by microsatellite analyses. Our findings
      strongly underline the precursor status of high-grade DCIS, in which most of the
      chromosomal changes identified in IDC are already present. However, although the
      early stages of breast cancer, i.e., DCIS and the small foci of IDC were mainly
      characterized by DNA gains, the progression to metastatic tumor (LN) must have
      involved additional DNA losses on several regions.

PMID- 10585589
TI  - 105Ad7 cancer vaccine stimulates anti-tumour helper and cytotoxic T-cell
      responses in colorectal cancer patients but repeated immunisations are required
      to maintain these responses.
AB  - 105AD7 is a human anti-idiotypic antibody that recognises the binding site of the
      anti-tumour antibody 791T/36 and can thereby mimic the CD55 antigen. The
      molecular basis of 105AD7 mimicry has been identified with 3 CDR regions of
      105AD7 showing similarity to 3 regions of CD55. These regions have been analysed
      for potential T-cell epitopes, and sequences that are predicted to bind to
      HLA/A1, 3,24 and to HLA/DR1,3,7 have been identified within the CDRH3 region of
      105AD7. These epitopes should be stimulating CD8 and CD4 responses, respectively.
      This prediction was tested on 12 colorectal cancer patients receiving 105AD7
      therapy. There was good concordance in 10 of 11 patients between accumulation of
      CD8RO cells or tumour killing and expression of HLA/A1,3,24. The only patient who
      failed to respond had a non-permissive class II haplotype and failed to show a
      helper response. Again 10 of 11 patients showing accumulation of CD4RO cells, in
      vitro blastogenesis responses, enhanced IL-2 or enhanced NK activity expressed
      one or more of the HLA/DR1,3,7 haplotypes. Although there was a consistent
      accumulation of CD45RO cells following 14 of 18 immunisations, only one patient
      showed a sustained memory response. Our results suggest that 105AD7 can stimulate
      CD4 and CD8 responses in patients with the appropriate haplotype. However, it may
      be necessary to continue to immunise, since few patients produce a sustained
      memory response.

PMID- 10585590
TI  - Adenovirus-mediated wild-type-p53-gene expression sensitizes TNF-resistant tumor
      cells to TNF-induced cytotoxicity by altering the cellular redox state.
AB  - We have shown that the loss of p53 function contributed to resistance of tumor
      cells to TNF-induced cytotoxicity. In the present study, we evaluated the effect
      of wild-type p53 (wt-p53) expression on TNF sensitivity, by introducing wt-p53
      into MCF7/Adr cells in which p53 was deleted, via a recombinant adenovirus
      encoding p53 (Ad-p53). Our results indicate that infection with Ad-p53 (50-100
      viral particles per cell) resulted in pronounced cytotoxicity, whereas infection
      with 10 viral particles per cell, which was weakly toxic for the MCF7/Adr cells,
      sensitized these cells to TNF-induced cell death. Moreover, expression of wt-p53
      in MCF7/Adr cells induced the production of reactive oxygen intermediates (ROIs)
      and caused glutathione (GSH) depletion, indicating disturbances in the cellular
      redox state. Additional treatment of cells with the anti-oxidant and glutathione
      (GSH) precursor N-acetylcysteine (NAC) resulted in inhibition of p53-induced ROIs
      production and in partial restoration of intracellular GSH levels, which was
      associated with the ability of NAC to inhibit p53-modulated TNF-induced
      cytotoxicity. Interestingly, Ad-p53 was able to inhibit TNF-induced MnSOD mRNA
      expression in MCF7/Adr cells, which might contribute to the sensitization of
      cells to the cytotoxic action of TNF. Taken together, our data strongly suggest
      that wt-p53 expression sensitizes TNF-resistant MCF7 cells with p53 deletion to
      TNF-induced cell death by a pathway that is dependent on ROIs production.

PMID- 10585591
TI  - Activity of cisplatin and ICI 182,780 on estrogen receptor negative ovarian
      cancer cells: cell cycle and cell replication rate perturbation, chromatin
      texture alteration and apoptosis induction.
AB  - The activity of cisplatin (CP, range of concentrations 0.25-1 microg/ml), the
      pure steroidal antiestrogen compound ICI 182,780 (range of concentrations, 0.01
      10 microM) and various combinations of, was investigated on an estrogen receptor
      negative ovarian cancer cell line (A2780 WT) and its CP-resistant derivative
      subline (A2780 CP3). CP markedly reduced A2780 WT cell growth but marginally
      affected A2780 CP3, whereas ICI 182,780 was effective on both cell lines. CP but
      not ICI 182,780 provoked a significant blockade in late S/G(2) phase in both cell
      lines, particularly in the parental line. Measuring the number of rounds of cell
      replications showed that CP diminished the cell replication rate of both cell
      lines, particularly in A2780 WT. Conversely, ICI 182,780 reduced the cell
      replication rate of A2780 CP3 but not A2780 WT cells. Both drugs provoked
      apoptosis in A2780 WT cells, as assessed by the appearance of large (50-300 kbp)
      DNA fragmentation. However, laser scanning cytometry showed that only CP induced
      a measurable alteration of chromatin texture in A2780 WT but not in A2780 CP3
      cells. The combination CP and ICI 182,780 resulted in a synergistic inhibitory
      activity of cell growth with a CP potentiation up to 4 and 11-fold in A2780 WT
      and A2780 CP3 cells, respectively. This reflected an enhanced reduction of the
      cell replication rate and did not involve perturbations of the cell cycle other
      than those provoked by CP alone. Apoptosis induction and the level of CP-DNA
      adducts were not influenced by adding ICI 182,780 to CP in both cell lines.

PMID- 10585592
TI  - Synergistic cytotoxicity of iodine-131-anti-CD20 monoclonal antibodies and
      chemotherapy for treatment of B-cell lymphomas.
AB  - Preliminary clinical trials suggest that iodine-131 ((131)I)-labeled anti-CD20
      monoclonal antibodies (MAbs) are effective single agents for the treatment of
      relapsed non-Hodgkin's B-cell lymphomas. However, despite high initial response
      rates, most patients treated in this manner will eventually relapse. We
      hypothesized that regimens combining (131)I-anti-CD20 antibodies with standard
      chemotherapeutic agents may provide synergistic anti-tumor effects, and may
      improve the durability of responses in patients with lymphoma. To identify
      promising agents for clinical testing, we assessed the in vitro cytotoxicity of
      combinations of (131)I-anti-B1 (anti-CD20) antibody and 8 chemotherapeutic agents
      using 2 human CD20-expressing lymphoma cell lines and 2 corroborative assays, the
      thiazolyl tetrazolium bromide (MTT) and the Trypan blue dye exclusion assays.
      ID(50) isobolographic and dose modification factor (DMF) analyses were used to
      classify interactions between the (131)I-anti-B1 antibody and the
      chemotherapeutic agents as supra-additive (synergistic), additive or sub
      additive. Cytarabine and fludarabine were markedly supra-additive when combined
      with the radioimmunoconjugate, with the combination enhancing cytotoxicity 3. 5-
      to 5.2-fold over the level expected by simple addition of the 2 agents (DMFs 3.5
      5.2). Etoposide, doxorubicin and SN-38 were moderately supra-additive (DMFs 2.0
      2.8). Cisplatin and 4-hydroxycyclophosphamide exhibited merely additive
      cytotoxicity (DMFs 1.0-1.1). Thus, combination regimens containing (131)I-labeled
      anti-CD20 antibodies and nucleoside analogs or topoisomerase inhibitors appear
      particularly attractive for future clinical trials.

PMID- 10585593
TI  - Detection of amplification of a chromosomal fragment at 6p21 including the cyclin
      D3 gene in a glioblastoma cell line by arbitrarily primed polymerase chain
      reaction.
AB  - DNA from 10 human glioma cell lines was analyzed by arbitrarily primed polymerase
      chain reaction. By fingerprinting of the DNA fragments obtained, the presence of
      fragment Qx with an abnormal signal was detected in one of the glioblastoma cell
      lines, CCF-STTG1. The nucleotide sequence of this fragment of 387 base pairs
      showed no homology with any known sequences. Southern-blot analysis using Qx as a
      probe revealed that the abnormal signal was caused by amplification of DNA by
      about 50-fold. By analysis of radiation hybrid panels, the fragment was shown to
      be derived from a chromosomal region on 6p21. The cyclin D3 (ccnd3) gene and an
      EST locus, H40682, both of which were located in this region, were amplified by
      about 50-fold in this cell line. Two other loci, R75654 and M78872, flanking the
      Qx, CCND3 and H40682 loci, were not amplified, suggesting that the size of the
      amplicon was less than 62 cR. Since over-expression of the ccnd3 gene, but not
      the H40682 locus, was detected in the cell line CCF-STTG1, the increased amounts
      of cyclin D3 caused by gene amplification could be involved in the development
      and/or progression of this glioblastoma.

PMID- 10585594
TI  - Regulation of vascular endothelial growth factor expression by insulin-like
      growth factor-I in endometrial adenocarcinoma cells.
AB  - Angiogenesis is crucial for tumor growth and dissemination. Vascular endothelial
      growth factor (VEGF) is a potent angiogenic factor that promotes endothelial cell
      proliferation and chemotaxis. VEGF occurs as 5 isoforms, as a result of an
      alternatively spliced transcript that originates from one gene, of which the 2
      majors are the VEGF 121 and 165 isoforms. Our aim was firstly to determine the
      role of Insulin-like Growth Factor-I (IGF-I) in the regulation of VEGF expression
      in endometrial adenocarcinoma cells and then the mechanism by which this
      regulation occurs. IGF-I treatment of HEC-1A cells provoked an increase of VEGF
      mRNA expression that peaked at 48 hr with a 165 isoform mRNA more abundant than
      the 121 isoform. The IGF-I action was confirmed at the protein level, whose
      concentration was increased in the conditioned media. In experiments using
      transient transfection of VEGF promoter-luciferase constructs, the IGF-I failed
      to increase the activity of the VEGF promoter after a 24-hr period of IGF-I
      treatment, while the addition of Actinomycin D showed an increase of the VEGF
      mRNA half-life. Most interestingly, Northern blot analysis showed a different
      stability of the 2 major VEGF isoform mRNAs (VEGF 121 and 165), of which the 121
      isoform was more stable than the 165 isoform. The IGF-I treatment prolonged the
      half-life of both of the VEGF isoform mRNAs. Our results suggest that IGF-I
      regulates VEGF expression in endometrial adenocarcinoma cells at the post
      transcriptional level by enhancing the stabilization of the 2 major VEGF isoform
      mRNAs (VEGF(121) and VEGF(165)). In addition to its proliferative functions, IGF
      I induces VEGF expression and participates in the maintenance of an angiogenic
      phenotype.

PMID- 10585595
TI  - Expression of prolactin and prolactin receptors by non-Hodgkin's lymphoma cells.
AB  - Prolactin (PRL) interacts with lymphocyte-signaling molecules and cytokines.
      Previous work has shown independent and synergistic effects of PRL on the
      generation of IL-2-driven anti-tumor lymphokine activated killer (LAK) activity
      by peripheral blood mononuclear cells (PBMC). The potential importance of PRL as
      a biological immunomodifier, however, is challenged by its ability to influence
      normal lymphocyte mitogenesis and hence lymphoid tumor growth. Since non
      Hodgkin's lymphoma (NHL) cell lines were efficiently killed by LAK generated with
      native (n) or recombinant (r) human PRL combined with low, per se ineffective
      doses of IL-2, we have addressed here the question of whether PRL acts as a
      growth factor for LAK targets. NHL cells were analyzed for: 1. expression of the
      PRL receptor (PRL-R); 2. responsiveness to nPRL or rPRL; 3. constitutive
      expression and release of PRL; 4. existence of a PRL autocrine loop. PRL-R,
      defined by multiple antibodies, was detected in 3 of 12 NHL cell lines. However,
      nPRL or rPRL, in a wide range of concentrations (0.75-50 ng/ml), were not
      mitogenic for growth-arrested, PRL-R positive NHL cell lines. PRL mRNA was
      detected by RT-PCR in 10 of the 12 cell lines examined with a higher frequency
      among AIDS-related NHL cell lines. PRL protein in the immunoprecipitate of (35)S
      methionine-labeled cell lysates and supernatants paralleled mRNA expression, and
      Western blotting analysis showed the presence of the pituitary/lymphocyte non
      glycosylated (23.5 kDa) and glycosylated (25 kDa) isoforms. Experiments with
      blocking antibodies showed the independence from endogenous PRL for NHL cell
      growth.

PMID- 10585596
TI  - Increased intracellular drug accumulation and complete chemosensitization
      achieved in multidrug-resistant solid tumors by co-administering valspodar (PSC
      833) with sterically stabilized liposomal doxorubicin.
AB  - We have previously demonstrated that liposome encapsulation of doxorubicin (DOX)
      can alleviate adverse interactions with non-encapsulated DOX and the cyclosporine
      multidrug-resistant (MDR) modulator Valspodar. We have now investigated the
      behavior of different liposomal DOX formulations in MDA435LCC6/MDR-1 human breast
      cancer solid tumor xenograft models to identify liposome characteristics
      associated with enhanced therapeutic activity and the mechanism whereby increased
      chemosensitization is achieved. Toxicity studies incorporating conventional
      phosphatidylcholine (PC)/cholesterol (chol) and sterically stabilized
      (polyethylene glycol 2000 [PEG]-containing) formulations of DOX indicated that
      whereas PC/Chol DOX was approximately 3-fold more toxic in the presence of
      Valspodar, PEG containing distearoylglycerophosphocholine (DSPC)/Chol DOX was
      minimally affected. In mice bearing MDR tumors, co-administration of Valspodar
      and egg phosphocholine (EPC)/Chol DOX resulted in modest MDR modulation and
      efficacy, whereas the sterically stabilized formulation induced reductions in
      tumor growth equivalent to that achieved for drug-sensitive tumors treated with
      non-encapsulated DOX. Pharmacokinetic studies revealed a 2.5-fold increase in
      plasma DOX area under the curve (AUC) upon co-administration of Valspodar with
      EPC/Chol DOX whereas no such alterations were observed with the sterically
      stabilized liposomes. Compared to non-encapsulated DOX combined with Valspodar,
      improvements in efficacy and toxicity correlated with the extent to which
      liposomal DOX formulations were able to circumvent pharmacokinetic interactions.
      Confocal microscopy demonstrated that Valspodar increased cell-associated DOX
      which correlated with the level of anti-tumor efficacy.

PMID- 10585597
TI  - Role for alpha1,2-fucosyltransferase and histo-blood group antigen H type 2 in
      resistance of rat colon carcinoma cells to 5-fluorouracil.
AB  - 5-Fluorouracil (5-FU) is a drug of standard use in chemotherapy of colon
      carcinoma. However, its efficacy is limited by inherent and acquired cell
      resistance. Major changes in histo-blood group antigenic expression, at times
      associated with poor prognosis, occur on colon cancer cells. To assess whether
      these antigens might play a role in the resistance to 5-FU, a rat model of colon
      carcinoma was used. We observed that in vivo treatment of tumors with the drug
      increased expression of antigen H type 2. The increase was also observed after in
      vitro short-term exposure to 5-FU, as well as on a cell-resistant variant
      selected by continuous exposure to the drug, and was accompanied by an increase
      in alpha1,2-fucosyltransferase activity, the key enzyme involved in synthesis of
      H antigens. Transfection of cells devoid of this enzymatic activity by an alpha1,
      2-fucosyltransferase cDNA allowed expression of H type 2 antigen and increased
      resistance to 5-FU. Inversely, transfection of cells which possess enzymatic
      activity by a cDNA in anti-sense orientation reduced both H type 2 cell-surface
      antigen and resistance to the drug. These results demonstrate that, in this
      experimental model, alpha1,2-fucosyltransferase and H type 2 antigen are involved
      in cellular resistance to 5-FU.

PMID- 10585598
TI  - The impact of primary tumor volume on local control for oropharyngeal squamous
      cell carcinoma treated with radiotherapy.
AB  - BACKGROUND: A study was needed to determine the effect of primary tumor volume on
      local control of oropharyngeal carcinoma treated with radiation therapy, with or
      without induction chemotherapy. METHODS: Between July 1983 and April 1995, 114
      patients with T2-T4 squamous cell carcinoma of the oropharynx were treated for
      cure with radiation therapy, with or without induction chemotherapy, and had a
      pretreatment CT scan available for retrospective review. All scans were reviewed
      by a single radiologist (A. A. M.) to determine the tumor volume of the primary
      lesion. Volume was measured with a computer digitizer for each CT slice showing
      the primary lesion. RESULTS: A large variation in tumor volume within a given T
      stage was found. Multivariate analysis demonstrated T stage to be the most
      significant factor affecting local control. Tumor volume marginally influenced
      local control (p =.10). CONCLUSIONS: Primary tumor volume varies significantly
      within a given T stage and has a marginal impact on the likelihood of local
      control after radiotherapy.

PMID- 10585599
TI  - Assessing head and neck cancer patient outcome domains.
AB  - BACKGROUND: The purpose of this study was to assess the relative importance on
      patients' lives of multiple outcomes resulting from the management of head and
      neck cancer (HNC). METHODS: HNC patients filled out a disease-specific quality of
      life (QOL) survey covering 5 domains (speech, eating, aesthetics,
      pain/discomfort, and social/role functioning). Logistic regression was used to
      determine which of these domains best predicted the patients' response to a
      single, overall QOL assessment. RESULTS: In univariate analyses, all 5 domains
      were significantly correlated to QOL (p<.0001), with correlation coefficients
      ranging from.48 for eating to.64 for social/role functioning. Logistic regression
      indicated that speech and eating best predicted QOL (R(2) =.4647), with odds
      ratios of 2. 96 for speech and 2.49 for eating. CONCLUSIONS: These data
      demonstrated that, for this group of patients, speech has the most impact on well
      being, whereas eating has a substantial, unrelated influence. This is important
      information in counseling patients about treatment plans that have different
      levels of impairment.

PMID- 10585600
TI  - Survival and functional results of Pearson's near-total laryngectomy for larynx
      and pyriform sinus carcinoma.
AB  - BACKGROUND: Current treatment for most T3 and T4 transglottic and pyriform sinus
      carcinomas is total laryngectomy or total laryngectomy with partial
      pharyngectomy. Voice rehabilitation usually requires the use of a
      tracheoesophageal puncture (TEP). Pearson's near-total laryngectomy (NTL) is an
      option for voice preservation in selected cases with no invasion of the
      interarythenoid space and limited invasion of the subglottis. The purpose of this
      study is to report the functional and survival results of 42 consecutive patients
      who underwent NTL from 1988 to 1995. Patients and Methods The patients were 40
      men and two women, with a median age of 58 years. All patients had squamous cell
      carcinoma. There were 37 larynx and five pyriform sinus tumors. T3 stage tumor
      represented 85.7% of the cases. RESULTS: There were complications in 13 patients
      (28.9%). Vocal quality was considered good in 83.3% of the cases. To date, eight
      patients presented tumor recurrences: two local, two in the neck, and four
      distant. The 5-year actuarial overall survival rates were of 81.7% in larynx
      carcinoma and 66.6% in pyriform sinus carcinoma. CONCLUSIONS: In selected
      transglottic and pyriform sinus carcinomas, NTL can be carried out with
      acceptable morbidity and a high potential of voice preservation and tumor
      control.

PMID- 10585601
TI  - A modified classification for the maxillectomy defect.
AB  - BACKGROUND: At present no widely accepted classification exists for the
      maxillectomy defect suitable for surgeons and prosthodontists. An acceptable
      classification that describes the defect and indicates the likely functional and
      aesthetic outcome is needed. METHODS: The classification is made on the basis of
      the assessment of 45 consecutive maxillectomy patients derived prospectively from
      the database (September 1992) and retrospectively from 1989. RESULTS: The
      classification of the vertical component is as follows: Class 1, maxillectomy
      without an oro-antral fistula; Class 2, low maxillectomy (not including orbital
      floor or contents); Class 3, high maxillectomy (involving orbital contents); and
      Class 4, radical maxillectomy (includes orbital exenteration); Classes 2 to 4 are
      qualified by adding the letter a, b, or c. The horizontal or palatal component is
      classified as follows: a, unilateral alveolar maxillectomy; b, bilateral alveolar
      maxillectomy; and c, total alveolar maxillary resection. CONCLUSION: This
      practical classification attempts to relate the likely aesthetic and functional
      outcomes of a maxillectomy to the method of rehabilitation.

PMID- 10585602
TI  - Sentinel node biopsy for melanoma in the head and neck region.
AB  - BACKGROUND: Lymphatic drainage in the head and neck region is known to be
      particularly complex. This study explores the value of sentinel node biopsy for
      melanoma in the head and neck region. METHODS: Thirty consecutive patients with
      clinically localized cutaneous melanoma in the head and neck region were
      included. Sentinel node biopsy was performed with blue dye and a gamma probe
      after preoperative lymphoscintigraphy. Average follow-up was 23 months (range, 1
      48). RESULTS: In 27 of 30 patients, a sentinel node was identified (90%). Only
      53% of sentinel nodes were both blue and radioactive. A sentinel node was tumor
      positive in 8 patients. The sentinel node was false-negative in two cases.
      Sensitivity of the procedure was 80% (8 of 10). CONCLUSIONS: Sentinel node biopsy
      in the head and neck region is a technically demanding procedure. Although it may
      help determine whether a neck dissection is necessary in certain patients,
      further investigation is required before this technique can be recommended for
      the standard management of cutaneous head and neck melanoma.

PMID- 10585603
TI  - Salvage treatment for recurrent squamous cell carcinoma of the oral cavity.
AB  - BACKGROUND: Squamous cell carcinoma (SCCA) of the oral cavity recurs with a
      frequency of 25%-48%, a fact that usually portends a poor prognosis. Recent
      studies have reported salvage cure rates as high as 67%. Investigators have also
      claimed that restaging recurrent tumors provides useful prognostic information,
      although this has not been demonstrated with tumors of the oral cavity. The
      purposes of this study were: (1) to report the patterns of recurrent SCCA of the
      oral cavity; (2) to examine the benefit of restaging oral cavity tumors, and (3)
      to compare different treatment modalities in the management of recurrent SCCA of
      the oral cavity. Materials and Methods Thirty-eight patients who developed
      recurrent SCCA of the oral cavity were reviewed. Salvage treatment consisted of
      surgery, chemotherapy, radiation therapy, or a combination of these modalities.
      Survival analysis was based on the stage of the primary and recurrent tumors and
      the type of salvage treatment received. RESULTS: The overall recurrence rate was
      28%. Local recurrence was most common (58%) followed by locoregional (27%) and
      regional recurrence (16%). Patients who recurred more than 6 months after
      completion of their primary treatment had improved survival compared with those
      who recurred within 6 months of initial treatment. Individuals with stage I-II
      primary tumors had significantly improved salvage time and total survival time
      compared with those with stage III-IV primary tumors (p < 0.005 and p < 0.001).
      Conversely, the stage of the recurrent tumor was not predictive of either
      improved salvage time or total survival time. Patients who underwent salvage
      surgery had significantly improved salvage time and total survival time compared
      with those who received chemotherapy and/or radiation therapy (p < 0.001 and p <
      0.002). The overall salvage cure rate was 21%. Neither the stage of the primary
      or recurrent tumors nor the type of salvage treatment received significantly
      correlated with an improved cure rate. However, the group of patients who
      underwent salvage surgery approached a statistically significant improvement in
      cure rate (p = 0.08). CONCLUSIONS: Squamous cell carcinoma of the oral cavity is
      most likely to recur at the primary site. The stage of the primary tumor is
      significantly correlated with survival even after recurrence, but the stage of
      the recurrent tumor is not significantly correlated with survival. Patients most
      likely to benefit from retreatment are those who (1) have primary tumors stage I
      II, (2) recur greater than 6 months after their initial treatment, and (3)
      develop recurrences that are amenable to salvage surgery.

PMID- 10585604
TI  - Ear involvement in childhood Langerhans' cell histiocytosis.
AB  - BACKGROUND: Ear involvement (EI) in Langerhans' cell histiocytosis (LCH) occurs
      quite often. We reviewed the Italian pediatric population of 251 children with
      LCH diagnosed between 1982 and 1995, focusing on EI, to highlight the prevalence,
      the clinical presentation, the outcome during follow-up, and the prognostic
      impact of otologic LCH. METHODS: EI was defined by chronic otorrhea and/or
      mastoid infiltration, external auditory meatus lesions, and middle/internal EI.
      The age at diagnosis, sex, system involved, organ dysfunction, treatment, disease
      control, and outcome were recorded. RESULTS: EI was noted at presentation in 34
      children (13. 5%). They had a younger age at diagnosis (p=.0013) and near
      totality of multisystem disease (93.8% of patients with EI). Among patients with
      multisystem disease, children with EI seemed to have a higher risk of poor
      response and a higher percentage of second line treatment (p=.003). CONCLUSIONS:
      EI seems to identify patients with a particular disease behavior, which requires
      a more accurate evaluation at diagnosis, staging and treatment, and a strict
      follow-up, considering the possibility of an unfavorable outcome.

PMID- 10585605
TI  - alpha5 integrin distribution and TGFbeta1 gene expression in supraglottic
      carcinoma: their role in neoplastic local invasion and metastasis.
AB  - BACKGROUND: Head and neck carcinomas are characterized by tumor-infiltrating
      lymphocytes (TIL) producing cytokines. Adhesion molecules, extracellular matrix
      proteins (ECMPs), and cytokines regulate cell-cell and cell-ECMPs interactions.
      We investigated the distribution of these proteins to contribute to better
      understanding of their role in local tumor invasion and metastasis. METHODS:
      Distribution of integrins, laminin, type IV collagen, tenascin, and fibronectin
      was immunohistochemically evaluated in 13 supraglottis carcinomas. Cytokines gene
      expression was assessed by reverse-transcriptase-polymerase chain reaction (RT
      PCR). RESULTS: Neoplastic cells were alpha2beta1, alpha3beta1, alpha4beta1,
      alpha5beta1 and alpha6beta1 positive. Normal and metaplastic epithelium was
      alpha5beta1 negative; the stroma of primary and metastatic tumors was tenascin
      and fibronectin positive. TGFbeta1 and IFNgamma gene expression was observed in
      the majority of tumors. CONCLUSIONS: Because TGFbeta1 is known to down-modulate
      immune processes and to increase alpha2beta1, alpha5beta1, and tenascin
      distribution, we propose that their expression in neoplastic cells of
      supraglottis carcinoma might represent an immune-related process able to help
      tumor growth and progression.

PMID- 10585606
TI  - Interleukin-12 delivered by biodegradable microspheres promotes the antitumor
      activity of human peripheral blood lymphocytes in a human head and neck tumor
      xenograft/SCID mouse model.
AB  - BACKGROUND: The role of cytokines in tumor regression is now well established.
      The major limitation for the clinical use of cytokines is the lack of a simple
      and effective protocol for the local and sustained delivery of cytokines to the
      tumor milieu. This study reports suppression of human head and neck squamous cell
      carcinoma (HNSCC) by human peripheral blood lymphocytes (HuPBL) following local,
      sustained delivery of interleukin-12 (IL-12) to tumors with biodegradable
      microspheres in a human/SCID mouse chimeric model. Materials and Methods
      Nondisrupted biopsy pieces (120 mg) of primary HNSCC were implanted s.c. into
      severe combined immunodeficient (SCID) mice and were expanded by serial passage
      in mice. Tumors were then titrated with different doses of allogeneic HuPBL by
      coengraftment of tumor pieces and HuPBL into the subcutis of SCID mice to
      determine whether the HuPBL possessed antitumor activity (the SCID/Winn model).
      The lymphocyte subsets that were responsible for the suppression of tumor
      engraftment were identified by selective depletion of the CD4+, CD8+, and CD56+
      cells from the HuPBL prior to engraftment into mice. Attempts were then made to
      augment the antitumor activity of the HuPBL either by repeated intralesional
      bolus injections of recombinant human IL-12 (0.5 microg x 10 doses) or with a
      single dose of IL-12-loaded microspheres ( approximately 1.65 microg IL-12/mg
      microspheres, 2 mg microspheres/mouse). RESULTS: Successful engraftment of HNSCC
      was observed in 12 of 19 different patient samples. Normal histological
      architecture of tumor was maintained up to four serial passages in the SCID mice.
      After the first tumor engraftment, but not in subsequent passages, human
      immunoglobulin produced by plasma cells present in the tumor infiltrating
      lymphocyte population was detected in the mouse sera. Allogeneic human PBL
      displayed antitumor cytotoxic activity in a cell dose-dependent fashion when
      coengrafted with the tumors passaged in SCID mice. Lymphocyte subset depletion
      studies established that tumor suppression was dependent on both the CD8+ T
      lymphocytes and the CD56+ natural killer cells. Treatment of tumors with a single
      intralesional injection of IL-12-loaded microspheres was highly effective,
      resulting in the complete suppression of tumor engraftment in 50% of the mice. In
      contrast, treatment of tumors with repeated bolus IL-12 injections suppressed
      tumor engraftment only transiently and did not result in complete tumor rejection
      in any of the mice. CONCLUSION: The coengraftment of HNSCC and allogeneic
      lymphocytes into SCID mice provides a viable model with which to evaluate
      immunotherapeutic strategies for human cancer. The use of biodegradable
      microspheres for local sustained delivery of cytokines to augment lymphocyte
      mediated antitumor immunity within the tumor microenvironment provides a safer
      and simpler alternative to current cytokine immunotherapy protocols.

PMID- 10585607
TI  - Increased protein nitrosylation in head and neck squamous cell carcinogenesis.
AB  - BACKGROUND: Nitric oxide (NO.) and its metabolic byproducts are implicated in
      carcinogenesis. We examined a marker of NO.-species' pathologic protein
      nitrosylation, nitrotyrosine, during head and neck squamous cell carcinoma
      (HNSCCa) development. Materials and Methods Paraffin-embedded tissue samples of
      normal oral mucosa, squamous hyperplasia/dysplasia, and HNSCCa were
      immunohistochemically analyzed for staining intensity using an antinitrotyrosine
      monoclonal antibody, and correlated with retrospective clinical data. RESULTS:
      Significantly higher staining was noted in reactive, dysplastic and HNSCCa
      samples compared with samples of normal mucosa. Additionally, significant
      differences in staining were found between various primary sites of the upper
      aerodigestive tract. Lastly, individual inflammatory cells also stained
      intensely. CONCLUSIONS: Increasing amounts of nitrotyrosine staining were found
      in reactive/dysplastic and HNSCCa lesions compared to normal squamous mucosa.
      Inflammatory cell staining implicates NO. as a possible mediator of
      immunosuppression. Given these findings, the role of NO. in mutations leading to
      and the immunosuppression found in HNSCCa warrants further investigation.

PMID- 10585608
TI  - The yin and yang of nitric oxide: reflections on the physiology and
      pathophysiology of NO.
AB  - Nitric oxide (NO.) is an arginine-derived nitrogen-based radical that is rapidly
      becoming one of the most important molecular species to be discovered. Over the
      past decade, an explosion of evidence has revealed the extreme complexity of
      function of this seemingly simple inorganic molecule. It is now evident that NO.
      demonstrates a functional dualism, playing a pivotal role in numerous physiologic
      and pathophysiologic processes. Whether this molecule is beneficial or
      detrimental is dependent upon the tissue of generation, the level of production,
      the oxidative/reductive (redox) environment in which this radical is generated,
      and the presence or absence of NO. transduction elements. Nitric oxide is
      generated by three independent isoenzymes that resemble the p-450 enzyme
      superfamily in both form and function. It ultimately alters enzymatic function
      through covalent modification, redox interactions, and interactions with metallic
      functional centers. This radical is a key figure in a number of pathophysiologic
      processes by means of similar yet uncoordinated interactions. In consideration of
      the already broad spectrum of roles attributed to NO., it seems highly likely
      that this molecule will be implicated in an ever widening variety of functions
      relative to the practice of otolaryngology-head and neck surgery. This article
      reviews the enzymology, signal transduction mechanisms, physiology, and
      pathophysiology of NO. as it pertains to head and neck cancer.

PMID- 10585609
TI  - Primary cutaneous adenoid cystic carcinoma metastatic to cervical lymph nodes.
AB  - BACKGROUND: Adenoid cystic carcinoma (ACC) occurs not only as a neoplasm of
      salivary glands but also in the skin. Metastasis is rare, and metastasis to lymph
      nodes has not been reported in the English literature. Case Report A patient with
      a history of excisions of "cylindroma" of the scalp over the past 20 years was
      initially seen with 2 recurrent scalp nodules and a firm left neck mass. Both
      scalp lesions and multiple neck nodes were found to be ACC at resection. The
      patient underwent postoperative radiation therapy and is clinically free of
      disease at 4 years. CONCLUSIONS: We believe this represents the first reported
      case of nodal metastases from primary cutaneous ACC in the English literature.

PMID- 10585610
TI  - Malignant otitis externa caused by Malassezia sympodialis.
AB  - BACKGROUND: Malignant otitis externa caused by fungal infections is rare. A
      review of the literature showed only 9 cases, and the causative fungus in all
      cases was Aspergillus. This article reports an unusual case caused by Malassezia
      sympodialis. METHODS: A 53-year-old man with non-insulin dependent diabetes
      presented with malignant otitis externa. He deteriorated despite treatment with
      intravenous antipseudomonal therapy and surgical debridement. Microbiologic tests
      revealed M. sympodialis. He responded rapidly to intravenous amphotericin.
      RESULTS: Systemic human infections caused by M. sympodialis have not been
      reported. M. furfur systemic infection is rare and has been associated lipid
      hyperalimentation by means of a central catheter. Only 1 other case of M.
      fungemia without these associated risk factors has been reported. CONCLUSIONS:
      The first case of malignant otitis externa caused by M. sympodialis is presented.
      It highlights the difficulty of initial biologic diagnosis and the need for lipid
      enriched media to grow this fastidious organism.

PMID- 10585611
TI  - Surgical technique for reconstruction of the nasal septum: the pericranial flap.
AB  - BACKGROUND: We describe a new technique for the surgical reconstruction of large
      sized anterior septal perforations based on the pericranial flap. METHODS: The
      technique requires a standard open rhinoplasty combined with a pericranial flap
      harvested after a bicoronal approach and tunnelled to the nasal cavity. We
      present the case of a man with complete destruction of the nasal septum as a
      result of chronic cocaine abuse. RESULTS: Surgery resulted in a permanent and
      complete closure of the perforation. CONCLUSIONS: The main advantage of this
      technique is the use of well-vascularized autogenous tissue and the minimal donor
      site morbidity. This technique provides a new method to close large nasal
      perforations.

PMID- 10585612
TI  - The long-term outcome of the cartilage free graft to the tracheal defect.

PMID- 10585613
TI  - Population and sampling are important factors to consider in evaluation of a
      medical test.

PMID- 10585614
TI  - Letter to responder

PMID- 10585616
TI  - Circulating levels of free insulin-like growth factors in obese subjects: the
      impact of type 2 diabetes.
AB  - BACKGROUND: Obese subjects show major abnormalities in the growth hormone
      (GH)/insulin-like growth factor (IGF) system. Furthermore, they are prone to
      develop Type 2 diabetes, but the impact of diabetes plus obesity on the GH/IGF
      system remains unknown. METHODS: We compared overnight fasting serum levels of
      free and total (extractable) IGF-I and -II, IGF-binding protein (IGFBP) -1, -2
      and -3, and the high affinity GH-binding protein (GHBP) in matched groups of lean
      subjects (n=26) and obese subjects without (n=24) and with (n=29) Type 2
      diabetes. Two groups (n=7) of healthy and Type 1 diabetic subjects were also
      studied. RESULTS: Non-diabetic obese subjects had increased free IGF-I and -II,
      total IGF-II, IGFBP-3 and GHBP, reduced IGFBP-1 and -2 (p<0.05), but normal total
      IGF-I, when compared to lean subjects. In obese Type 2 diabetics free IGF-I was
      insignificantly reduced by 9% (p=0.3), when compared to non-diabetic obese
      subjects. However, the concentration was not significantly elevated when compared
      to that of lean controls (p=0.13). Also IGFBP-1 and total IGF-I were normal in
      obese Type 2 diabetics, whereas free and total IGF-II and IGFBP-3 remained
      elevated to a similar extent as in simple obesity (p<0.05). In contrast, GHBP was
      further increased and IGFBP-2 further reduced in obese Type 2 diabetics (p<0.05).
      In Type 1 diabetics total IGF-I and -II, and IGFBP-3 were normal. In contrast,
      free IGF-I and -II and GHBP were markedly reduced, whereas IGFBP-1 and -2 were
      increased (p<0.05). CONCLUSIONS: Simple obesity was associated with marked
      changes in the GH/IGF system. Many of these abnormalities were unaffected by the
      concomitant presence of Type 2 diabetes (total IGF-I, free and total IGF-II and
      IGFBP-3). However, some changes became accentuated (GHBP and IGFBP-2), while
      others (free IGF-I and IGFBP-1) were no longer present. Notably, the impact of
      Type 1 diabetes on the GH/IGF system was clearly different from that of Type 2
      diabetes.

PMID- 10585617
TI  - Gluten-free diet prevents diabetes in NOD mice.
AB  - BACKGROUND: Epidemiological as well as animal studies have shown that
      environmental factors such as nutrition contribute to the development of
      diabetes. In this study we investigated whether the early introduction of a
      gluten-free diet can influence the onset and/or incidence of diabetes, as well as
      insulitis and the number of gut mucosal lymphocytes, in non-obese diabetic (NOD)
      mice. METHODS: Gluten-free and standard Altromin diets (with the same milk
      protein and vitamin content) were given to breeding pairs of NOD mice as well as
      to the first generation of NOD female mice, which were then observed for 320
      days. RESULTS: A substantially lower diabetes incidence (chi(2)=15.8, p=0.00007)
      was observed in NOD mice on the gluten-free diet (15%, n=27) compared to mice on
      the standard diet (64%, n=28). In addition, mice on the gluten-free diet
      developed diabetes significantly later (244+/-24 days SEM) compared to those on
      the standard diet (197+/-8 days, p=0.03). No differences in the number of CD3(+),
      TCR-gammadelta(+), IgA(+), and IgM(+) cells in the small intestine were observed.
      CONCLUSION: We showed that gluten-free diet both delayed and to a large extent
      prevented diabetes in NOD mice that have never been exposed to gluten.

PMID- 10585618
TI  - Type 1 diabetes in the offspring does not increase the risk of parental type 2
      diabetes in South Indians.
AB  - OBJECTIVES: (a) To study whether there was an increased prevalence of glucose
      intolerance in the parents of probands with Type 1 diabetes and (b) to look for
      any possible link between the glucose intolerance in the parents with HLA-DQB1
      alleles transmitted in excess to the Type 1 diabetes offspring. Study Design and
      Methods From 215 families of South Indian Type 1 diabetes probands, 336 parents
      (170 fathers, age 30-70 years; 166 mothers, age 23-72 years) were studied by oral
      glucose tolerance test (GTT). Glucose intolerance in the parents was compared
      with the population data available. HLA-DQB1 alleles in 170 of the families were
      studied by the Olerup method (based on sequence specific primers) and the
      transmission disequilibrium test (TDT) was used to determine the Type 1 diabetes
      associated DQB1 alleles. RESULTS: Among the parents 11.2% had Type 2 diabetes
      which was similar to the population data of 11.6%. However there was a male
      predominence among the diabetic parents (chi(2)=7.0, p=0.008), while in the
      population there was a female predominence. Prevalence of IGT was significantly
      more among the parents (13.6%) compared with the population data (9.1%)
      (chi(2)=6.43, p=0.011). Both HLA-DQB1*0201 (p<0.0001) and DQB1*0302 (p=0.0001)
      were positively associated with Type 1 diabetes in the probands although 21% of
      the probands possessed neither DQB1*0201 or DQB1*0302. The distribution of
      glucose tolerance categories in the parents of the probands differed according to
      the presence of DQB1*0302 (p= 0.035) whilst no such differences existed for
      DQB1*0201. CONCLUSIONS: In summary, the presence of Type 1 diabetes in the South
      Indian offspring does not predict a higher occurrence of Type 2 diabetes in the
      parents. However, there is an increased occurrence of impaired glucose tolerance
      (IGT) among the parents. Family based studies demonstrate increased transmission
      of HLA-DQB1*0201 and HLA-DQB1*0302 with Type 1 diabetes similar to North American
      and European Caucasian subjects. Furthermore, HLA-DQB1*0302 may be a minor
      determinant of glucose tolerance in parents of offspring with Type 1 diabetes.

PMID- 10585619
TI  - Effects of long-term treatment with alpha-glucosidase inhibitor on the peripheral
      nerve function and structure in Goto-Kakizaki rats: a genetic model for type 2
      diabetes.
AB  - BACKGROUND: Continuous hyperglycemia is implicated in the pathogenesis of chronic
      diabetic complications. It is not well known, however, how and to what extent the
      development of neuropathy is inhibited by blood glucose control in subjects with
      Type 2 diabetes. We investigated therefore the effects of an alpha-glucosidase
      inhibitor (voglibose; Vg) on neuropathic changes in diabetic Goto-Kakizaki (GK)
      rats, a genetic model for Type 2 diabetes. METHODS: Twelve week-old male GK rats
      were given a diet containing Vg (50 ppm) for 24 weeks and monitored for blood
      glucose, glycated hemoglobin, motor nerve conduction velocity (MNCV). At the end
      of the administration period (Na(+), K(+))-ATPase activity and the structure of
      the peripheral nerves were examined. Age- and sex-matched normal Wistar rats were
      treated similarly and served as controls. RESULTS: GK rats showed fasting
      hyperglycemia after 8 weeks of age, and Vg treatment significantly lowered levels
      of blood glucose and glycated hemoglobin. Slowing of MNCV to 80% of normal
      control levels was detected in GK rats. Vg treatment inhibited this delay by 24%
      at 24 weeks and 57% at 36 weeks of age. Nerve (Na(+), K(+))-ATPase activity was
      reduced to 80% of normal control levels in GK rats and was restored by Vg
      treatment. Teased fiber studies revealed a higher incidence of fibers with
      paranodal, segmental demyelination and axonal degeneration in GK rats. Vg
      treatment significantly inhibited the development of these nerve-fiber
      abnormalities. CONCLUSIONS: Lowering of high blood glucose levels achieved by the
      use of Vg in GK rats improved MNCV and demyelinative nerve changes with
      restoration of (Na(+), K(+))-ATPase activity.

PMID- 10585620
TI  - Insulin pump therapy in type 1 pediatric patients: now and into the year 2000.
AB  - There are a number of medical conditions such as growth failure in children,
      pregnancy, lipid abnormalities, and early complications that are improved by the
      meticulous glycemic control that can be achieved with insulin pump therapy
      (CSII). By using an insulin pump, many patients with severe hypoglycemia, the
      dawn phenomenon, extremes of glycemic excursion, recurrent diabetic ketoacidosis
      (DKA) and hypoglycemia unawareness have amelioration of these problems. However,
      pump therapy involves problems such as weight gain, recurrent ketosis due to pump
      failure, infections, and risk of hypoglycemia. Owing to many developmental
      issues, young children may not be able to wear the pump without parental
      supervision. We have used the pump at night time only in these patients. This has
      allowed children of 7-10 years of age to benefit from improved nocturnal glycemia
      without the risk of pump therapy when they are without an adult to help. We have
      also used the pump in subjects with recurrent DKA and in our general patient
      population (mean age 13.6+/-3.9 years). In our pump cohort, CSII led to
      improvement in quality of life, knowledge, adherence, and responsibility. A
      reduction in hypoglycemia, DKA rate and mean HbA(1c) was associated with pump
      usage. For this to occur, however, pump education must be geared to the pediatric
      subject and his/her family. Education materials and tools help in learning how to
      use the pump and how to deal with the intricacies of basal and bolus dosing, and
      the effect of exercise, food and illness on diabetes management. The pump has
      improved since it was first introduced and these modifications have made it
      easier, more painless and less hazardous. With the development of continuous
      glucose sensors and implantable pumps, the next century will see pump therapy
      lead to the artificial pancreas.

PMID- 10585621
TI  - Gut and the induction of immune tolerance in type 1 diabetes.
AB  - The origin of beta-cell specific autoimmunity is not known in Type 1 diabetes.
      Several studies of this disease in animal models indicate that the manifestation
      of autoimmune diabetes can be modified by factors which influence the gut immune
      system. Some indirect evidence from studies in patients with Type 1 diabetes also
      suggests that aberrant function of the gut immune system may be involved in the
      development of this disease. These studies have encouraged the search for
      treatments interfering with mucosal immunity for the prevention of Type 1
      diabetes. Our understanding of the function of the gut immune system in humans
      is, however, limited and the use of drugs (e.g. oral antigens or immune
      adjuvants) which modify the function of the gut immune system may involve serious
      problems. In this review, the possible role of the gut immune system in the
      development of beta-cell autoimmunity and Type 1 diabetes is discussed with
      special reference to the putative therapeutic implications.

PMID- 10585622
TI  - The Greek contribution to diabetes research.
AB  - Interest in diabetes mellitus research has escalated in Greece during the last
      decade. This may be attributed to the realization that diabetes is becoming a
      major problem for the Greek population, the effect of the St Vincent Declaration
      in passing specific government legislation, and the founding of the National
      Hellenic Center for the Prevention and Treatment of Diabetes and its
      Complications. Research areas include epidemiology, etiopathogenesis, glucose
      metabolism, complications, prevention and treatment of the disease.

PMID- 10585624
TI  - Michel abu jamra (1916-1999)

PMID- 10585623
TI  - Treatment of severe proliferative retinopathy and diabetic maculopathy.
AB  - Strict blood glucose control, early detection and surveillance of diabetic
      retinopathy by means of validated screening programmes, and judicious use of
      laser photocoagulation can greatly reduce the risk of visual loss in diabetes.
      Some patients however, have aggressive neovascular disease resistant to laser
      treatment, or present at a late stage with advanced fibroproliferative disease,
      and may progress rapidly to blindness. In the elderly with Type 2 disease,
      diabetic maculopathy is more common and requires a different therapeutic
      approach. The present article describes two diabetic patients and discusses the
      management of patients with severe proliferative retinopathy or diabetic
      maculopathy.

PMID- 10585625
TI  - Training graduate students to be teachers.
AB  - Pedagogic education of graduate students, when and where it exists, is restricted
      to theoretical courses or to the participation of the students as teachers'
      assistants. This model is essentially reproductive and offers few opportunities
      for any significant curriculum innovation. To open an opportunity for novelty we
      have introduced a new approach in "Biochemistry Teaching", a course included in
      the Biochemistry Graduate Program of the Biochemistry Department (Universidade
      Estadual de Campinas and Universidade de Sao Paulo). The content of the course
      consists of a) choosing the theme, b) selecting and organizing the topics, c)
      preparing written material, d) establishing the methodological strategies, e)
      planning the evaluation tools and, finally, f) as teachers, conducting the course
      as an optional summer course for undergraduate students. During the first
      semester the graduate students establish general and specific educational
      objectives, select and organize contents, decide on the instructional strategies
      and plan evaluation tools. The contents are explored using a wide range of
      strategies, which include computer-aided instruction, laboratory classes, small
      group teaching, a few lectures and round table discussions. The graduate students
      also organize printed class notes to be used by the undergraduate students.
      Finally, as a group, they teach the summer course. In the three versions already
      developed, the themes chosen were Biochemistry of Exercise (UNICAMP),
      Biochemistry of Nutrition (UNICAMP) and Molecular Biology of Plants (USP). In all
      cases the number of registrations greatly exceeded the number of places and a
      selection had to be made. The evaluation of the experience by both graduate and
      undergraduate students was very positive. Graduate students considered this
      experience to be unique and recommended it to their schoolmates; the
      undergraduate students benefited from a more flexible curriculum (more options)
      and gave very high scores to both the courses and the teachers.

PMID- 10585626
TI  - Extralymphatic disease due to bancroftian filariasis.
AB  - Infection with Wuchereria bancrofti, Brugia malayi, or B. timori not only affects
      the structure and function of lymphatic vessels but is also associated with
      extralymphatic pathology and disease. Because it is now possible to detect living
      adult worms by ultrasonography, much emphasis is placed on lymphatic pathology.
      However, the finding of renal damage in asymptomatic microfilaremic carriers has
      led to increased recognition of the importance of extralymphatic clinical
      manifestation in bancroftian filariasis. The authors present a number of clinical
      syndromes that may be manifestations of extralymphatic filarial disease and
      discuss possible mechanisms that cause these conditions. The main purpose of this
      paper is to raise the awareness of students and physicians of the prevalence and
      the importance of extralymphatic disease in bancroftian filariasis so that it is
      diagnosed and treated properly and also to alert for the need of additional
      research in this area.

PMID- 10585627
TI  - The nucleolus: a paradigm for cell proliferation and aging.
AB  - The nucleolus is the cellular site of ribosome biosynthesis. At this site, active
      ribosomal DNA (rDNA) genes are rapidly transcribed by RNA polymerase I (pol I)
      molecules. Recent advances in our understanding of the pol I transcription system
      have indicated that regulation of ribosomal RNA (rRNA) synthesis is a critical
      factor in cell growth. Importantly, the same signaling networks that control cell
      growth and proliferation and are deregulated in cancer appear to control pol I
      transcription. Therefore, the study of the biochemical basis for growth
      regulation of pol I transcription can provide basic information about the nuclear
      signaling network. Hopefully, this information may facilitate the search for
      drugs that can inhibit the growth of tumor cells by blocking pol I activation. In
      addition to its function in ribosome biogenesis, recent studies have revealed the
      prominent role of the nucleolus in cell senescence. These findings have
      stimulated a new wave of research on the functional relationship between the
      nucleolus and aging. The aim of this review is to provide an overview of some
      current topics in the area of nucleolus biology, and it has been written for a
      general readership.

PMID- 10585628
TI  - Implications of ischemic penumbra for the diagnosis of brain death.
AB  - The data reviewed here suggest the possibility that a global reduction of blood
      supply to the whole brain or solely to the infratentorial structures down to the
      range of ischemic penumbra for several hours or a few days may lead to
      misdiagnosis of irreversible brain or brain stem damage in a subset of deeply
      comatose patients with cephalic areflexia. The following proposals are advanced:
      1) the lack of any set of clinically detectable brain functions does not provide
      a safe diagnosis of brain or brain stem death; 2) apnea testing may induce
      irreversible brain damage and should be abandoned; 3) moderate hypothermia,
      antipyresis, prevention of arterial hypotension, and occasionally intra-arterial
      thrombolysis may contribute to good recovery of a possibly large subset of cases
      of brain injury currently regarded as irreversible; 4) confirmatory tests for
      brain death should not replace or delay the administration of potentially
      effective therapeutic measures; 5) in order to validate confirmatory tests,
      further research is needed to relate their results to specific levels of blood
      supply to the brain. The current criteria for the diagnosis of brain death should
      be revised.

PMID- 10585629
TI  - Purification and partial characterization of Phaseolus vulgaris seed
      aminopeptidase.
AB  - The aminopeptidase activity of Phaseolus vulgaris seeds was measured using L-Leu
      p-nitroanilide and the L-aminoacyl-ss-naphthylamides of Leu, Ala, Arg and Met. A
      single peak of aminopeptidase activity on Leu-ss-naphthylamide was eluted at 750
      microS after gradient elution chromatography on DEAE-cellulose of the supernatant
      of a crude seed extract. The effluent containing enzyme activity was applied to a
      Superdex 200 column and only one peak of aminopeptidase activity was obtained.
      SDS-polyacrylamide gel electrophoresis (10%) presented only one protein band with
      molecular mass of 31 kDa under reducing and nonreducing conditions. The
      aminopeptidase has an optimum pH of 7.0 for activity on all substrates tested and
      the highest Vmax/K M ratio for L-Leu-ss-naphthylamide. The enzyme activity was
      increased 40% by 0.15 M NaCl, inhibited 94% by 2.0 mM Zn2+, inhibited 91% by
      sodium p-hydroxymercuribenzoate and inhibited 45% by 0.7 mM o-phenanthroline and
      30 microM EDTA. Mercaptoethanol (3.3 mM), dithioerythritol (1.7 mM), Ala, Arg,
      Leu and Met (70 microM), p-nitroaniline (0.25 mM) and ss-naphthylamine (0.53 mM)
      had no effect on enzyme activity when assayed with 0.56 mM of substrate. Bestatin
      (20 microM) inhibited 18% the enzyme activity. The aminopeptidase activity in the
      seeds decayed 50% after two months when stored at 4 degrees C and room
      temperature. The enzyme is leucyl aminopeptidase metal- and thiol group
      dependent.

PMID- 10585630
TI  - Application of isotope-selective non-dispersive infrared spectrometry for the
      evaluation of the 13C-urea breath test: comparison with three concordant methods.
AB  - The aim of this work was to compare the performance of isotope-selective non
      dispersive infrared spectrometry (IRIS) for the 13C-urea breath test with the
      combination of the 14C-urea breath test (14C-UBT), urease test and histologic
      examination for the diagnosis of H. pylori (HP) infection. Fifty-three duodenal
      ulcer patients were studied. All patients were submitted to gastroscopy to detect
      HP by the urease test, histologic examination and 14C-UBT. To be included in the
      study the results of the 3 tests had to be concordant. Within one month after
      admission to the study the patients were submitted to IRIS with breath samples
      collected before and 30 min after the ingestion of 75 mg 13C-urea dissolved in
      200 ml of orange juice. The samples were mailed and analyzed 11.5 (4-21) days
      after collection. Data were analyzed statistically by the chi-square and Mann
      Whitney test and by the Spearman correlation coefficient. Twenty-six patients
      were HP positive and 27 negative. There was 100% agreement between the IRIS
      results and the HP status determined by the other three methods. Using a cutoff
      value of delta-over-baseline (DOB) above 4.0 the IRIS showed a mean value of
      19.38 (minimum = 4.2, maximum = 41.3, SD = 10.9) for HP-positive patients and a
      mean value of 0.88 (minimum = 0.10, maximum = 2.5, SD = 0.71) for negative
      patients. Using a cutoff value corresponding to 0.800% CO2/weight (kg), the 14C
      UBT showed a mean value of 2.78 (minimum = 0.89, maximum = 5.22, SD = 1.18) in HP
      positive patients. HP-negative patients showed a mean value of 0.37 (minimum =
      0.13, maximum = 0.77, SD = 0.17). IRIS is a low-cost, easy to manage, highly
      sensitive and specific test for H. pylori detection. Storing and mailing the
      samples did not interfere with the performance of the test.

PMID- 10585631
TI  - Measurement of intestinal permeability using mannitol and lactulose in children
      with diarrheal diseases.
AB  - The excretion ratio of lactulose/mannitol in urine has been used to assess the
      extension of malabsorption and impairment of intestinal permeability. The
      recovery of lactulose and mannitol in urine was employed to evaluate intestinal
      permeability in children with and without diarrhea. Lactulose and mannitol probes
      were measured using high-performance liquid chromatography with pulsed
      amperometric detection (HPLC-PAD). Two groups of solutions containing 60 microM
      sugars were prepared. Group I consisted of glucosamine, mannitol, melibiose and
      lactulose, and group II of inositol, sorbitol, glucose and lactose. In the study
      of intra-experiment variation, a sample of 50 microl from each group was
      submitted to 4 successive determinations. The recovered amounts and retention
      times of each sugar showed a variation <2 and 1%, respectively. The estimated
      recovery was >97%. In the study of inter-experiment variation, we prepared 4
      independent samples from groups I and II at the following concentrations: 1.0,
      0.3, 0.1, 0.03 and 0.01 mM. The amounts of the sugars recovered varied by <10%,
      whereas the retention times showed an average variation <1%. The linear
      correlation coefficients were >99%. Retention (k'), selectivity (alpha) and
      efficiency (N) were used to assess the chromatographic conditions. All three
      parameters were in the normal range. Children with diarrhea presented a greater
      lactulose/mannitol ratio compared to children without diarrhea.

PMID- 10585632
TI  - Blockade of the action of nitric oxide in human septic shock increases systemic
      vascular resistance and has detrimental effects on pulmonary function after a
      short infusion of methylene blue.
AB  - To investigate the role of nitric oxide in human sepsis, ten patients with severe
      septic shock requiring vasoactive drug therapy and mechanical ventilation were
      enrolled in a prospective, open, non-randomized clinical trial to study the acute
      effects of methylene blue, an inhibitor of guanylate cyclase. Hemodynamic and
      metabolic variables were measured before and 20, 40, 60, and 120 min after the
      start of a 1-h intravenous infusion of 4 mg/kg of methylene blue. Methylene blue
      administration caused a progressive increase in mean arterial pressure (60 [55
      70] to 70 [65-100] mmHg, median [25-75th percentiles]; P<0.05), systemic vascular
      resistance index (649 [479-1084] to 1066 [585-1356] dyne s-1 cm-5 m-2; P<0.05)
      and the left ventricular stroke work index (35 [27-47] to 38 [32-56] g m-1 m-2;
      P<0.05) from baseline to 60 min. The pulmonary vascular resistance index
      increased from 150 [83-207] to 186 [121-367] dyne s-1 cm-5 m-2 after 20 min
      (P<0.05). Mixed venous saturation decreased from 65 [56-76] to 63 [55-69]%
      (P<0.05) after 60 min. The PaO2/FiO2 ratio decreased from 168 [131-215] to 132
      [109-156] mmHg (P<0.05) after 40 min. Arterial lactate concentration decreased
      from 5.1 +/- 2.9 to 4.5 +/- 2.1 mmol/l, mean +/- SD (P<0.05) after 60 min. Heart
      rate, cardiac filling pressures, cardiac output, oxygen delivery and consumption
      did not change. Methylene blue administration was safe and no adverse effect was
      observed. In severe human septic shock, a short infusion of methylene blue
      increases systemic vascular resistance and may improve myocardial function.
      Although there was a reduction in blood lactate concentration, this was not
      explained by an improvement in tissue oxygenation, since overall oxygen
      availability did not change. However, there was a significant increase in
      pulmonary vascular tone and a deterioration in gas exchange. Further studies are
      needed to demonstrate if nitric oxide blockade with methylene blue can be safe
      for patients with septic shock and, particularly, if it has an effect on
      pulmonary function.

PMID- 10585633
TI  - Monitoring human cytomegalovirus viral load in peripheral blood leukocytes of
      renal transplant recipients by a simple limiting dilution-PCR assay.
AB  - To assess the clinical relevance of a semi-quantitative measurement of human
      cytomegalovirus (HCMV) DNA in renal transplant recipients within the typical
      clinical context of a developing country where virtually 100% of both receptors
      and donors are seropositive for this virus, we have undertaken HCMV DNA
      quantification using a simple, semi-quantitative, limiting dilution polymerase
      chain reaction (PCR). We evaluated this assay prospectively in 52 renal
      transplant patients from whom a total of 495 serial blood samples were collected.
      The samples scored HCMV positive by qualitative PCR had the levels of HCMV DNA
      determined by end-point dilution-PCR. All patients were HCMV DNA positive during
      the monitoring period and a diagnosis of symptomatic infection was made for 4 of
      52 patients. In symptomatic patients the geometric mean of the highest level of
      HCMV DNAemia was 152,000 copies per 10(6) leukocytes, while for the asymptomatic
      group this value was 12,050. Symptomatic patients showed high, protracted HCMV
      DNA levels, whereas asymptomatic patients demonstrated intermittent low or
      moderate levels. Using a cut-off value of 100,000 copies per 10(6) leukocytes,
      the limiting dilution assay had sensitivity of 100%, specificity of 92%, a
      positive predictive value of 43% and a negative predictive value of 100% for HCMV
      disease. In this patient group, there was universal HCMV infection but relatively
      infrequent symptomatic HCMV disease. The two patient groups were readily
      distinguished by monitoring with the limiting dilution assay, an extremely simple
      technology immediately applicable in any clinical laboratory with PCR capability.

PMID- 10585634
TI  - Transforming growth factor beta activity in urine of patients with type 2
      diabetes and diabetic nephropathy.
AB  - Diabetic nephropathy (DN) is characterized structurally by progressive mesangial
      deposition of extracellular matrix (ECM). Transforming growth factor-ss (TGF-ss)
      is considered to be one of the major cytokines involved in the regulation of ECM
      synthesis and degradation. Several studies suggest that an increase in urinary
      TGF-ss levels may reflect an enhanced production of this polypeptide by the
      kidney cells. We evaluated TGF-ss in occasional urine samples from 14 normal
      individuals and 23 patients with type 2 diabetes (13 with persistent proteinuria
      >500 mg/24 h, DN, 6 with microalbuminuria, DMMA, and 4 with normal urinary
      albumin excretion, DMN) by enzyme immunoassay. An increase in the rate of urinary
      TGF-ss excretion (pg/mg U Creat.) was observed in patients with DN (296.07 +/-
      330.77) (P<0.001) compared to normal individuals (17.04 +/- 18.56) (Kruskal
      Wallis nonparametric analysis of variance); however, this increase was not
      observed in patients with DMMA (25.13 +/- 11.30) or in DMN (18.16 +/- 11.82).
      There was a positive correlation between the rate of urinary TGF-ss excretion and
      proteinuria (r = 0.70, alpha = 0.05) (Pearson's analysis), one of the parameters
      of disease progression.

PMID- 10585635
TI  - Anxiolytic effect of methylene blue microinjected into the dorsal periaqueductal
      gray matter.
AB  - The dorsal periaqueductal gray (DPAG) has been implicated in the behavioral and
      autonomic expression of defensive reactions. Several results suggest that, along
      with GABA, glutamate and serotonin, nitric oxide (NO) may play a role in defense
      reactions mediated by this region. To further investigate this possibility we
      microinjected methylene blue (MB; 10, 30 or 100 nmol/0.5 microl) into the DPAG of
      rats submitted to the elevated plus-maze test, an animal model of anxiety. MB has
      been used as an inhibitor of soluble guanylate cyclase (sGC) to demonstrate cGMP
      mediated processes, and there is evidence that NO may exert its biological
      effects by binding to the heme part of guanylate cyclase, causing an increase in
      cGMP levels. The results showed that MB (30 nmol) significantly increased the
      percent of time spent in the open arms (saline = 11.57 +/- 1.54, MB = 18.5 +/-
      2.45, P<0.05) and tended to do the same with the percentage of open arm entries
      (saline = 25.8 +/- 1.97, MB = 33. 77 +/- 3.07, P<0.10), but did not change the
      number of enclosed arm entries. The dose-response curve, however, had an inverted
      U shape. These results indicate that MB, within a limited dose range, has
      anxiolytic properties when microinjected into the DPAG.

PMID- 10585636
TI  - Defense reaction induced by a metabotropic glutamate receptor agonist
      microinjected into the dorsal periaqueductal gray of rats.
AB  - The behavioral effects of trans-(+/-)-1-amino-1, 3-cyclopentanedicarboxylic acid
      (t-ACPD), a metabotropic glutamate receptor (mGluR) agonist, or 0.9% (w/v)
      saline, injected into the dorsal periaqueductal gray (DPAG), was investigated.
      Male Wistar rats showed defense reactions characterized by jumps toward the top
      edges of the cages (saline = 0 vs t-ACPD = 6.0, medians P<0.05) and gallops
      (saline = 0 vs t-ACPD = 10.0, medians P<0.05) during the 60-s period after the
      beginning of the injection. In another experiment animals were placed inside an
      open arena for 5 min immediately after injection. Their behavior was recorded by
      a video camera and a computer program analyzed the videotapes. Eleven of fifteen
      rats injected with t-ACPD showed a short-lasting (about 1 min) flight reaction.
      No saline-treated animal showed this reaction (P<0.0005, chi-square test). The
      drug induced an increase in turning behavior (P = 0.002, MANOVA) and a decrease
      in the number of rearings (P<0.001, MANOVA) and grooming episodes (P<0.001,
      MANOVA). These results suggest that mGluRs play a role in the control of defense
      reactions in the DPAG.

PMID- 10585637
TI  - Changes in the behavioral and immunological parameters of the mollusk
      Biomphalaria tenagophila induced by disruption of the circadian cycle as a
      consequence of continuous illumination.
AB  - In the present investigation we studied some behavioral and immunological
      parameters of adult gastropod mollusk, Biomphalaria tenagophila, which have been
      reproducing for several generations under laboratory conditions. One group of
      gastropods was kept on a 14-h light/10-h dark cycle, corresponding to a regular
      circadian cycle, and another group was exposed to continuous light for 48 h.
      Animals were studied along (behavioral groups) or immediately after
      (immunological groups) 48 h of regular circadian cycle or continuous light
      conditions. Stopping/floating, dragging and sliding were the behavioral aspects
      considered (N = 20 for regular cycle; N = 20 for continuous illumination) and
      number of hemocytes/microl hemolymph was the immunological parameter studied (N =
      15 for regular cycle, N = 14 for continuous illumination). Animals under
      continuous illumination were more active (sliding = 33 episodes, dragging = 48
      episodes) and displayed a lower number of hemocytes (78.0 +/- 24. 27/microl) when
      compared with mollusks kept on a regular circadian cycle (sliding = 18 episodes,
      dragging = 27 episodes; hemocytes = 157.6 +/- 53.27/microl). The data are
      discussed in terms of neural circuits and neuroimmunological relations with the
      possible stressful effect of continuous illumination.

PMID- 10585638
TI  - Combined effects of diethylpropion and alcohol on locomotor activity of mice:
      participation of the dopaminergic and opioid systems.
AB  - The widespread consumption of anorectics and combined anorectic + alcohol misuse
      are problems in Brazil. In order to better understand the interactive effects of
      ethanol (EtOH) and diethylpropion (DEP) we examined the locomotion-activating
      effects of these drugs given alone or in combination in mice. We also determined
      whether this response was affected by dopamine (DA) or opioid receptor
      antagonists. A total of 160 male Swiss mice weighing approximately 30 g were
      divided into groups of 8 animals per group. The animals were treated daily for 7
      consecutive days with combined EtOH + DEP (1.2 g/kg and 5.0 mg/kg, ip), EtOH (1.2
      g/kg, ip), DEP (5.0 mg/kg, ip) or the control solution coadministered with the DA
      antagonist haloperidol (HAL, 0.075 mg/kg, ip), the opioid antagonist naloxone
      (NAL, 1.0 mg/kg, ip), or vehicle. On days 1, 7 and 10 after the injections, mice
      were assessed in activity cages at different times (15, 30, 45 and 60 min) for 5
      min. The acute combination of EtOH plus DEP induced a significantly higher
      increase in locomotor activity (day 1: 369.5 +/- 34.41) when compared to either
      drug alone (day 1: EtOH = 232.5 +/- 23.79 and DEP = 276.0 +/- 12.85) and to
      control solution (day 1: 153.12 +/- 7.64). However, the repeated administration
      of EtOH (day 7: 314.63 +/- 26.79 and day 10: 257.62 +/- 29.91) or DEP (day 7:
      309.5 +/- 31.65 and day 10: 321.12 +/- 39. 24) alone or in combination (day 7:
      459.75 +/- 41.28 and day 10: 427. 87 +/- 33.0) failed to induce a progressive
      increase in the locomotor response. These data demonstrate greater locomotion
      activating effects of the EtOH + DEP combination, probably involving DA and/or
      opioid receptor stimulation, since the daily pretreatment with HAL (day 1: EtOH +
      DEP = 395.62 +/- 11.92 and EtOH + DEP + HAL = 371.5 +/- 6.76; day 7: EtOH + DEP =
      502.5 +/- 42.27 and EtOH + DEP + HAL = 281.12 +/- 16.08; day 10: EtOH + DEP =
      445.75 +/- 16.64 and EtOH + DEP + HAL = 376.75 +/- 16.4) and NAL (day 1: EtOH +
      DEP = 553.62 +/- 38.15 and EtOH + DEP + NAL = 445.12 +/- 55.67; day 7: EtOH + DEP
      = 617.5 +/- 38.89 and EtOH + DEP + NAL = 418.25 +/- 61.18; day 10: EtOH + DEP =
      541.37 +/- 32.86 and EtOH + DEP + NAL = 427.12 +/- 51.6) reduced the locomotor
      response induced by combined administration of EtOH + DEP. These findings also
      suggest that a major determinant of combined anorectic-alcohol misuse may be the
      increased stimulating effects produced by the combination.

PMID- 10585639
TI  - Natural preference of zebrafish (Danio rerio) for a dark environment.
AB  - The zebrafish (Danio rerio) has been used as a model in neuroscience but
      knowledge about its behavior is limited. The aim of this study was to determine
      the preference of this fish species for a dark or light environment. Initially we
      used a place preference test and in a second experiment we applied an exit
      latency test. A two-chamber aquarium was used for the preference test. The
      aquarium consisted of a black chamber and a white chamber. In the first
      experiment the animal was placed in the aquarium and the time spent in the two
      compartments was recorded for 10 min. More time was spent in the black
      compartment (Wilcoxon matched-pairs signed-rank test, T = 7, N1 = N2 = 18, P =
      0.0001). In the second experiment the animal was placed in the black or white
      compartment and the time it took to go from the initial compartment to the
      opposite one was recorded. The test lasted a maximum of 10 min. The results
      showed that the animal spent more time to go from the black to the white
      compartment (Mann-Whitney rank sum test, T = 48, N1 = 9, N2 = 8, P<0.0230). These
      data suggest that this fish species has a natural preference for a dark
      environment and this characteristic can be very useful for the development of new
      behavioral paradigms for fish.

PMID- 10585640
TI  - Antidepressant-like effect of lead in adult mice.
AB  - It has been reported that lead can cause behavioral impairment by inhibiting the
      N-methyl-D-aspartate (NMDA) receptor complex. MK-801, a noncompetitive NMDA
      receptor antagonist, exhibits an antidepressant-like action in the forced
      swimming test. The purpose of the present study was to determine whether subacute
      lead exposure in adult male Swiss mice weighing 30-35 g causes an antidepressant
      like action in a forced swimming test. Mice were injected intraperitoneally (ip)
      with 10 mg/kg lead acetate or saline daily for 7 consecutive days. Twenty-four
      hours after the last treatment, the saline and lead-treated mice received an
      injection of MK-801 (0.01 mg/kg, ip) or saline and were tested in forced swimming
      and in open-field tests. Immobility time was similarly reduced in the saline-MK
      801, Pb-saline and Pb-MK-801 groups compared to the saline-saline group (mean +/-
      SEM; 197.3 +/- 18.5, 193.5 +/- 15.8, 191.3 +/- 12.3 and 264.0 +/- 14.4 s,
      respectively; N = 9). These data indicate that lead may exert its effect on the
      forced swimming test by directly or indirectly inhibiting the NMDA receptor
      complex. Lead treatment caused no deficit in memory of habituation and did not
      affect locomotor activity in an open-field (N = 14). However, mice that received
      MK-801 after lead exhibited a deficit in habituation (22% reduction in rearing
      responses between session 3 and 1; N = 14) as compared to control (41% reduction
      in rearing responses; N = 15), further suggesting that lead may have affected the
      NMDA receptor activity. Forced-swim immobility in a basin in two daily
      consecutive sessions was also significantly decreased by lead exposure (mean +/-
      SEM; day 1 = 10.6 +/- 3.2, day 2 = 19.6 +/- 3.6; N = 16) as compared to control
      (day 1 = 18.4 +/- 3.8, day 2 = 34.0 +/- 3.7; N = 17), whereas the number of
      crossings was not affected by lead treatment, further indicating a specific
      antidepressant-like action of lead.

PMID- 10585641
TI  - Chronic effect of antidopaminergic drugs or estrogen on male wistar rat
      lactotrophs and somatotrophs.
AB  - The aim of the present study was to evaluate the effect of antidopaminergic
      agents on the somatotrophs in the presence of hyperprolactinemia. Adult male
      Wistar rats were divided into 6 groups: a control group and five groups
      chronically treated (60 days) with haloperidol, fluphenazine, sulpiride,
      metoclopramide or estrogen. Somatotrophs and lactotrophs were identified by
      immunohistochemistry and the data are reported as percent of total anterior
      pituitary cells counted. The drugs significantly increased the percentage of
      lactotrophs: control (mean +/- SD) 21.3 +/- 4.4, haloperidol 27.8 +/- 2.2,
      fluphenazine 34.5 +/- 3.6, sulpiride 32.7 +/- 3.5, metoclopramide 33.4 +/- 5.5
      and estrogen 42.4 +/- 2.8. A significant reduction in somatotrophs was observed
      in animals treated with haloperidol (23.1 +/- 3.0), fluphenazine (22.1 +/- 1.1)
      and metoclopramide (24.2 +/- 3.0) compared to control (27.3 +/- 3.8), whereas no
      difference was observed in the groups treated with sulpiride (25.0 +/- 2.2) and
      estrogen (27.1 +/- 2.8). In the groups in which a reduction occurred, this may
      have simply been due to dilution, secondary to lactotroph hyperplasia. In view of
      the duplication of the percentage of prolactin-secreting cells, when estrogen was
      applied, the absence of a reduction in the percent of somatotrophs suggests a
      replication effect on this cell population. These data provide additional
      information about the direct or indirect effect of drugs which, in addition to
      interfering with the dopaminergic system, may act on other pituitary cells as
      well as on the lactotrophs.

PMID- 10585642
TI  - Binding sites and actions of Tx1, a neurotoxin from the venom of the spider
      Phoneutria nigriventer, in guinea pig ileum.
AB  - Tx1, a neurotoxin isolated from the venom of the South American spider Phoneutria
      nigriventer, produces tail elevation, behavioral excitation and spastic paralysis
      of the hind limbs after intracerebroventricular injection in mice. Since Tx1
      contracts isolated guinea pig ileum, we have investigated the effect of this
      toxin on acetylcholine release, as well as its binding to myenteric plexus
      longitudinal muscle membranes from the guinea pig ileum. [125I]-Tx1 binds
      specifically and with high affinity (Kd = 0.36 +/- 0.02 nM) to a single, non
      interacting (nH = 1.1), low capacity (Bmax 1.1 pmol/mg protein) binding site. In
      competition experiments using several compounds (including ion channel ligands),
      only PhTx2 and PhTx3 competed with [125I]-Tx1 for specific binding sites (K0.5
      apparent = 7.50 x 10(-4) g/l and 1.85 x 10(-5) g/l, respectively). PhTx2 and
      PhTx3, fractions from P. nigriventer venom, contain toxins acting on sodium and
      calcium channels, respectively. However, the neurotoxin PhTx2-6, one of the
      isoforms found in the PhTx2 pool, did not affect [125I]-Tx1 binding. Tx1 reduced
      the [3H]-ACh release evoked by the PhTx2 pool by 33%, but did not affect basal or
      KCl-induced [3H]-ACh release. Based on these results, as well as on the homology
      of Tx1 with toxins acting on calcium channels (omega-Aga IA and IB) and its
      competition with [125I]-omega-Cono GVIA in the central nervous system, we suggest
      that the target site for Tx1 may be calcium channels.

PMID- 10585643
TI  - Role of Anopheles (Kerteszia) bellator as malaria vector in southeastern Brazil
      (Diptera: Culicidae).
AB  - New research concerning Anopheles bellator in the southeast of the State of Sao
      Paulo, Brazil, are reported. Adult females of this mosquito showed remarkable
      endophily and endophagy which was even greater than An. cruzii. The
      epidemiological role of this anopheline as a malaria vector is discussed.

PMID- 10585644
TI  - Hepatitis C virus prevalence among an immigrant community to the southern Amazon,
      Brazil.
AB  - A community-based random survey was conducted in a southern Brazilian Amazonian
      county aiming to investigate hepatitis C virus (HCV) infection prevalence and the
      association of demographic variables and lifestyle behaviours. Seven hundred
      eighty individuals were serologically screened with a third generation enzyme
      linked immunosorbent assay to detect anti-HCV antibodies between 1994/1995.
      Positive samples were retested for confirmation with a line immunoassay (LIA,
      Inno-LIA HCV Ab III). Most of these subjects were low income and came from
      southern Brazilian states (65.8). Two point four percent (IC 95% 1.2%- 4.6%) of
      the subjects had LIA-confirmed anti-HCV antibodies reactivity. The age-specific
      prevalence of HCV antibodies slightly increased with age, with the highest
      prevalence after the age of 40 years. The results of multivariate analysis
      indicate a strong association between HCV antibodies and previous surgery and
      history of intravenous drug use. There were no apparent association with gender,
      hepatitis B virus markers, blood transfusion, and sexual activity. Mean time
      living in Amazon did not differ between confirmed and negative anti-HCV
      individuals. The present data point out an intermediate endemicity of HCV
      infection among this immigrant community to the Amazon region and that few HCV
      infected participants presented known risk factors.

PMID- 10585645
TI  - Helminths parasites of Eupsophus roseus (Anura: Leptodactylidae) from southern
      Chile.

PMID- 10585646
TI  - Notes on the bat flea Hormopsylla fosteri (Siphonaptera: Ischnopsyllidae)
      infesting Molossops abrasus (Chiroptera).

PMID- 10585647
TI  - The status of the Lutzomyia longipalpis species complex and possible implications
      for Leishmania transmission.
AB  - The sand fly Lutzomyia longipalpis sensu latu has been identified as the
      principal vector of American visceral leishmaniasis, a potentially fatal disease
      that primarily affects children in several countries of South and Central
      America. Over the past several years increases have occurred both in the number
      of reported cases and the population at risk: approximately 1.6 million people
      reside in highly endemic areas with 16,000 cases reported annually. Several
      studies have attempted to relate the epidemiology of this disease to variability
      in Lu. longipalpis that is now recognized to be a complex of at least three
      sibling species. Morphological variation in this species was first noted by
      Mangabeira (1969). Since then physiological and biochemical differences have been
      reported by several investigators. Recent reports in Costa Rica of the presence
      of Lu. longipalpis in a focus of cutaneous leishmaniasis caused by Leishmania
      chagasi may be an additional indication of variability in this species. While
      existing evidence indicates that the morphospecies Lu. longipalpis may represent
      a complex of sibling species, genetic, epidemiological and ecological
      distinctions have not been fully resolved. Thus, delimitation of systematic
      boundaries within the complex and corresponding to geographic distributions and
      roles in transmission remain unresolved. The purpose of this review is to
      summarize from the literature observations of polymorphism in this morphospecies
      and consider what significance this reported variability may have to the
      epidemiology of visceral leishmaniasis.

PMID- 10585648
TI  - Quantitative phenetics and taxonomy of some phlebotomine taxa.
AB  - Elucidating the evolution of Phlebotominae is important not only to revise their
      taxonomy, but also to help understand the origin of the genus Leishmania and its
      relationship with humans. Our study is a phenetic portrayal of this history based
      on the genetic relationships among some New Word and Old Word taxa. We used both
      multilocus enzyme electrophoresis and morphometry on 24 male specimens of the Old
      Word genus Phlebotomus (with three of its subgenera: Phlebotomus,
      Spelaeophlebotomus and Australophlebotomus), and on 67 male specimens of the
      three New World genera, Warileya, Brumptomyia and Lutzomyia, (with three
      subgenera of Lutzomyia: Lutzomyia, Oligodontomyia and Psychodopygus). Phenetic
      trees derived from both techniques were similar, but disclosed relationships that
      disagree with the present classification of sand flies. The need for a true
      evolutionary approach is stressed.

PMID- 10585649
TI  - Studies on Cercariae from Kuwait Bay. XI. Description and surface topography of
      Cercaria kuwaitae XI sp.n. (Digenea: Echinostomatidae).
AB  - A new echinostome cercaria, Cercaria kuwaitae XI sp.n., from the prosobranch
      gastropod Cerithidea cingulata (Gmelin) from Kuwait Bay is described. The new
      cercaria is characterized by 23 collar spines and primary excretory tubules with
      distinct diverticula. The cercaria encysts in the snail host and is similar to
      those of Acanthoparyphium sp. The surface topography of the redia, cercaria and
      metacercarial cyst wall is studied by scanning electron microscopy. This is the
      first echinostome cercaria to be recorded in a gastropod from the Arabian Gulf
      region.

PMID- 10585650
TI  - On two nematodes from Brazilian birds and description of a new species
      (Acuarioidea, Schistorophinae) parasitizing Laterallus viridis (Muller, 1776)
      (Gruiformes, Rallidae).
AB  - The present paper reports acuarioid nematodes recovered from avian hosts. A new
      species of the genus Schistorophus Railliet, 1916 is proposed based mainly on
      findings referring to ptilina, spicules and vagina. Ancyracanthopsis coronata
      (Molin, 1860) Chabaud & Petter, 1959 is referred again in Brazil since its
      proposition in 1860, from specimens recovered from a Brazilian bird. A revised
      key to the species of the genus Schistorophus is also presented.

PMID- 10585651
TI  - Description of Lutzomyia bianchigalatiae n. sp. A sand fly within the subgenus
      Pintomyia Costa Lima 1932 (Diptera; Psychodidae).
AB  - A new sand fly species is described based on males collected in Bananal,
      municipality of Mariana and the female from Sabara city, State of Minas Gerais,
      Brazil. Taxonomic remarks, geographic distribution and the description of new
      species are presented. The name Lutzomyia (Pintomyia) bianchigalatiae is in
      honour of Dr Eunice Aparecida Bianchi Galati, friend and researcher at the
      Faculdade de Saude Publica, Universidade de Sao Paulo.

PMID- 10585652
TI  - Extracellular serine-proteinases isolated from Streptomyces alboniger: partial
      characterization and effect of aprotinin on cellular structure.
AB  - Streptomyces alboniger ATCC 12461 grown in brain heart infusion (BHI) medium
      produced two extracellular serine-proteinases, denoted SP I and SP II, which were
      purified by ammonium sulfate precipitation and aprotinin-agarose affinity
      chromatography. SP I was purified 88,9-fold and SP II 66,7- fold, with 33.4% and
      10.4% yield, respectively. The optimum pH for the proteinases activity, using a-N
      p-tosyl-L-arginine-methyl ester (TAME) as substrate, was 9-10 and the optimum
      temperature was 37 degrees C. The proteolytic activity of SP I and SP II was
      inhibited by aprotinin and SP I was partially inhibited by leupeptin, both serine
      proteinase inhibitors. S. alboniger growth in BHI-liquid medium decreased when 5
      mg/ml, 10 mg/ml of aprotinin was used, being completely inhibited with 20 mg/ml
      and 40 mg/ml. At the ultrastructural level, aprotinin-treated S. alboniger cells
      showed swelling of the bacterial body and condensation of the genetic material,
      probably related to the inhibition of its growth.

PMID- 10585653
TI  - Metalloproteases in Trypanosoma rangeli-infected Rhodnius prolixus.
AB  - Protease activities in the haemolymph and fat body in a bloodsucking insect,
      Rhodnius prolixus, infected with Trypanosoma rangeli, were investigated. After
      SDS-polyacrylamide gel electrophoresis containing gelatin as substrate, analysis
      of zymograms performed on samples of different tissues of controls and insects
      inoculated or orally infected with short or long epimastigotes of T. rangeli,
      demonstrated distinct patterns of protease activities: (i) proteases were
      detected in the haemolymph of insects which were fed on, or inoculated with,
      short epimastigotes of T. rangeli (39 kDa and 33 kDa, respectively), but they
      were not observed in the fat body taken from these insects; (ii) protease was
      also presented in the fat bodies derived from naive insects or controls
      inoculated with sterile phosphate-saline buffer (49 kDa), but it was not detected
      in the haemolymph of these insects; (iii) no protease activity was observed in
      both haemolymph and fat bodies taken from insects inoculated with, or fed on,
      long epimastigotes of T. rangeli. Furthermore, in short epimastigotes of T.
      rangeli extracts, three bands of the protease activities with apparent molecular
      weights of 297, 198 and 95 kDa were detected while long epimastigotes preparation
      presented only two bands of protease activities with molecular weights of 297 and
      198 kDa. The proteases from the insect infected with T. rangeli and controls
      belong to the class of either metalloproteases or metal-activated enzymes since
      they are inhibited by 1,10-phenanthroline. The significance of these proteases in
      the insects infected with short epimastigotes of T. rangeli is discussed in
      relation to the success of the establishment of infection of these parasites in
      its vector, R. prolixus.

PMID- 10585654
TI  - Profile of organic acid concentrations in the digestive gland and hemolymph of
      Biomphalaria glabrata under estivation.
AB  - Using high performance liquid chromatography (HPLC) analysis it was possible to
      determine simultaneously the concentration of organic acids (pyruvate, lactate,
      succinate, fumarate, malate, acetate, propionate, acetoacetate, and ss
      hydroxybutyrate) in the digestive gland and the extracellular concentration of
      these same acids in the hemolymph of estivating Biomphalaria glabrata, the
      intermediate host of Schistosoma mansoni. After a 7 day period of estivation,
      there was a significant increase in the tissue levels of lactate, succinate,
      malate and acetate compared to non-estivating snails. After 14 days of
      estivation, the levels of lactate and acetate were also significantly elevated.
      The hemolymph concentrations of pyruvate and acetate increased significantly
      after 7 days and acetate concentrations continued to be significantly increased
      up to 14 days of estivation. The other organic acids studied, such as ketone body
      acetoacetate and ss-hydroxybutyrate or the volatile acid propionate, did not
      accumulate. Their tissue concentrations, however, increased on the 7th day of
      estivation and reached normal levels within two weeks of estivation for some of
      them. One should take into consideration how the reduction in metabolism can be
      handled under aerobic conditions, and what role anaerobic pathways may play in
      both energy formation and redox balance processes.

PMID- 10585655
TI  - Alkaline phosphatase isoenzymes in plasma of chagasic and healthy pregnant women.

PMID- 10585656
TI  - Predictive value of the acid fast smear for detection of Mycobacterium
      tuberculosis in respiratory specimens in a reference center of HIV/AIDS in Rio de
      Janeiro, Brazil.
AB  - In order to evaluate the predictive value of acid fast bacilii (AFB) smear for
      the diagnosis of Mycobacterium tuberculosis in respiratory specimens in a setting
      with a high prevalence of AIDS and an unknown prevalence of nontuberculous
      mycobacteria (NTM), we retrospectively examined specimens cultured for
      mycobacteria between 1 September 1993 and 30 September 1994 and medical records
      of patients with positive culture in a General Hospital, AIDS reference in Rio de
      Janeiro, Brazil. Seventy three per cent (1517/2077) of samples were respiratory
      specimens and mycobacteria were recovered from 20.6% (313/1517) of these. M.
      tuberculosis was identified in 94.2% (295/313) and NTM in 5.8% (18/313). The
      yield of positive AFB smear and of positive culture was 6.1% (93/1517) and 20.6%
      (313/1517), respectively. The positive predictive value (PPV) of AFB for M.
      tuberculosis was 98.4% in expectorated sputum and 96.4% in bronchoalveolar
      lavage. Forty four percent (130/295) of specimens with positive culture for M.
      tuberculosis and 66.7% (12/18) for NTM were from patients HIV positive. The
      conclusion was that in our study population, the PPV of AFB for M. tuberculosis
      in respiratory specimens was high and the prevalence of NTM was low despite the
      high prevalence of HIV positive.

PMID- 10585657
TI  - Studies on the effectiveness of diarylheptanoids derivatives against Leishmania
      amazonensis.
AB  - In a previous work we demonstrated that diarylheptanoids extracted from
      Centrolobium sclerophyllum are very active against Leishmania amazonensis
      promastigotes. In order to continue our studies with these class of compounds, we
      decided to evaluate the activity of several diarylheptanoids derived from
      curcumin (diferuloyl methane) against the extracellular form (promastigotes) of
      L. amazonensis. Furthermore, an experiment against the intracellular form of the
      parasite (amastigotes) was carried out, comparing the most active compound among
      the curcumin derivatives (the methylcurcumin) with des-O-methylcentrolobine, the
      most active diarylheptanoid derived from C. sclerophyllum.

PMID- 10585658
TI  - Evidences of gentamicin resistance amplification in Klebsiella pneumoniae
      isolated from faeces of hospitalized newborns.
AB  - The intestinal microbiota, a barrier to the establishment of pathogenic bacteria,
      is also an important reservoir of opportunistic pathogens. It plays a key role in
      the process of resistance-genes dissemination, commonly carried by specialized
      genetic elements, like plasmids, phages, and conjugative transposons. We obtained
      from strains of enterobacteria, isolated from faeces of newborns in a university
      hospital nursery, indication of phenotypical gentamicin resistance amplification
      (frequencies of 10(-3) to 10(-5), compatible with transposition frequencies).
      Southern blotting assays showed strong hybridization signals for both plasmidial
      and chromosomal regions in DNA extracted from variants selected at high
      gentamicin concentrations, using as a probe a labeled cloned insert containing
      aminoglycoside modifying enzyme (AME) gene sequence originated from a plasmid of
      a Klebsiella pneumoniae strain previously isolated in the same hospital. Further,
      we found indications of inactivation to other resistance genes in variants
      selected under similar conditions, as well as, indications of co-amplification of
      other AME markers (amikacin). Since the intestinal environment is a scenario of
      selective processes due to the therapeutic and prophylactic use of antimicrobial
      agents, the processes of amplification of low level antimicrobial resistance (not
      usually detected or sought by common methods used for antibiotic resistance
      surveillance) might compromise the effectiveness of antibiotic chemotherapy.

PMID- 10585659
TI  - Antimalarial drug susceptibility testing of Plasmodium falciparum in Brazil using
      a radioisotope method.
AB  - From March 1996 to August 1997, a study was carried out in a malaria endemic area
      of the Brazilian Amazon region. In vivo sensitivity evaluation to antimalarial
      drugs was performed in 129 patients. Blood samples (0.5 ml) were drawn from each
      patient and cryopreserved to proceed to in vitro studies. In vitro sensitivity
      evaluation performed using a radioisotope method was carried out with the
      cryopreserved samples from September to December 1997. Thirty-one samples were
      tested for chloroquine, mefloquine, halofantrine, quinine, arteether and
      atovaquone. Resistance was evidenced in 96.6% (29/30) of the samples tested for
      chloroquine, 3. 3% (1/30) for quinine, none (0/30) for mefloquine and none for
      halofantrine (0/30). Overall low sensitivity was evidenced in 10% of the samples
      tested for quinine, 22.5% tested for halofantrine and in 20% tested for
      mefloquine. Means of IC 50 values were 132.2 (SD: 46. 5) ng/ml for chloroquine,
      130.6 (SD: 49.6) ng/ml for quinine, 3.4 (SD: 1.3) ng/ml for mefloquine, 0.7 (SD:
      0.3) ng/ml for halofantrine, 1 (SD: 0.6) ng/ml for arteether and 0.4 (SD: 0.2)
      ng/ml for atovaquone. Means of chloroquine IC 50 of the tested samples were
      comparable to that of the chloroquine-resistant strain W2 (137.57 ng/ml) and
      nearly nine times higher than that of the chloroquine-sensitive strain D6 (15.09
      ng/ml). Means of quinine IC 50 of the tested samples were 1.7 times higher than
      that of the low sensitivity strain W2 (74.84 ng/ml) and nearly five times higher
      than that of the quinine-sensitive strain D6 (27.53 ng/ml). These results
      disclose in vitro high resistance levels to chloroquine, low sensitivity to
      quinine and evidence of decreasing sensitivity to mefloquine and halofantrine in
      the area under evaluation.

PMID- 10585660
TI  - Efficacy of a new schistosomicidal agent 2-[(methylpropyl)amino]-1
      octanethiosulfuric acid against an oxamniquine resistant Schistosoma mansoni
      isolate.

PMID- 10585661
TI  - Pathology of the spleen in hepatosplenic schistosomiasis. Morphometric evaluation
      and extracellular matrix changes.
AB  - Histological, ultrastructural, morphometric and immunohistochemical data obtained
      from the study of spleens removed by splenectomy from 34 patients with advanced
      hepatosplenic schistosomiasis revealed that the main alterations were congestive
      dilatation of the venous sinuses and diffuse thickening of the splenic cords.
      Splenic cord thickening was due to an increase of its matrix components,
      especially type IV collagen and laminin, with the conspicuous absence of
      interstitial collagens, either of type I or type III. Deposition of interstitial
      collagens (types I and III) occurred in scattered, small focal areas of the red
      pulp, but in the outside of the walls of the venous sinuses, in lymph follicles,
      marginal zone, in the vicinity of fibrous trabeculae and in sidero-sclerotic
      nodules. However, fibrosis was not a prominent change in schistosomal
      splenomegaly and thus the designation "fibro-congestive splenomegaly" seems
      inadequate. Lymph follicles exhibited variable degrees of atrophy, hyperplasia
      and fibrous replacement, sometimes all of them seen in different follicles of the
      same spleen and even in the same examined section. Changes in white pulp did not
      seem to greatly contribute to increasing spleen size and weight, when compared to
      the much more significant red pulp enlargement.

PMID- 10585662
TI  - Acute intestinal anisakiasis in Spain: a fourth-stage Anisakis simplex larva.
AB  - A case of acute intestinal anisakiasis has been reported; a nematode larva being
      found in the submucosa of the ileum of a woman in Jaen (Spain). The source of
      infection was the ingestion of raw Engraulis encrasicholus. On the basis of its
      morphology, the worm has been identified as a fourth-stage larva of Anisakis
      simplex. In Spain, this is the ninth report of human anisakiasis and also
      probably the first case of anisakiasis caused by a fourth-stage larva of A.
      simplex.

PMID- 10585663
TI  - Effects of the Digenea proctoeces lintoni (Fellodistomidae) in the proportion of
      hemolymphatic cells in Fissurella crassa (Mollusca: Archaeogastropoda).

PMID- 10585664
TI  - Quantitative morphological evidence for incipient species within Lutzomyia
      quinquefer (Diptera: Psychodidae).
AB  - Morphological variation among geographic populations of the New World sand fly
      Lutzomyia quinquefer (Diptera, Phlebotominae) was analyzed and patterns detected
      that are probably associated with species emergence. This was achieved by
      examining the relationships of size and shape components of morphological
      attributes, and their correlation with geographic parameters. Quantitative and
      qualitative morphological characters are described, showing in both sexes
      differences among local populations from four Departments of Bolivia. Four
      arguments are then developed to reject the hypothesis of environment as the
      unique source of morphological variation: (1) the persistence of differences
      after removing the allometric consequences of size variation, (2) the association
      of local metric properties with meristic and qualitative attributes, rather than
      with altitude, (3) the positive and significant correlation between metric and
      geographic distances, and (4) the absence of a significant correlation between
      altitude and general-size of the insects.

PMID- 10585665
TI  - Biology of Triatoma pallidipennis stal 1945 (Hemiptera: Reduviidae:Triatominae)
      under laboratory conditions.
AB  - Aspects related to hatching, life time, mortality, feeding behaviour and
      fecundity for each stage of Triatoma pallidipennis life-cycle were evaluated. The
      hatching rate observed for 200 eggs was 60% and the average time of hatching was
      18 days. Eighty nymphs (N) (40%) completed the cycle and the average time from NI
      to adult was 168. 7+/-11.7days. The average span in days for each stage was 18.0
      for NI, 18.5 for NII, 30.0 for NIII, 35.7 for NIV and 50.1 for NV. The number of
      bloodmeals at each nymphal stage varied from 1 to 5. The mortality rate was 9.17
      for NI, 5.5 for NII, 6.8 for NIII 4.17 for NIV and 13.04 for NV nymphs. The
      average number of eggs laid per female in a 9-month period was 498.6. The
      survival rates of adults were 357+/-217.9 and 262.53+/-167.7 for males and
      females respectively.

PMID- 10585666
TI  - Growth changes induced by gamma radiation on Biomphalaria straminea (Dunker,
      1848).
AB  - Doses of 60Co gamma radiation with 2.5; 5; 7.5; 10; 15; 20; 25; 30; 35; 40; 45;
      50; 55; 60; 80; 160; 320 and 640 Gy were applied to 1, 080 snails Biomphalaria
      straminea, an intermediate host of Schistosoma mansoni, divided in groups
      containing 30 mollusks. In addition, 60 non irradiated snails were kept as
      control. Fifty percent of the population was kept in colonies (allowing cross
      fertilization) while the other half was maintained in sexual isolation (allowing
      self fertilization) and during one month their growth was observed through the
      daily measurement of the shell diameter. Results showed that after 20 Gy doses
      the growth in shell diameter of irradiated snails was greater than that of the
      control group after 30 days. At this dose the snail size was the greatest, among
      all isolated groups. The 80 Gy doses also induced the final shell diameter of
      isolated snails to be greater then that observed in the control groups. As this
      effect was most evident among the isolated snails, a possible hormonal role may
      have been involved in the observed phenomena, which is under investigation with
      the objective of identifying any future applications that this could have to
      schistosomiasis control.

PMID- 10585667
TI  - A new larval diet for colonization of Phlebotominae sand flies.

PMID- 10585668
TI  - Larval preference of Psaroniocompsa incrustata (Lutz, 1910) (Diptera: Simuliidae)
      for different colors of artificial substrates in breeding grounds, at Pium River,
      State of Rio Grande do Norte, Brazil.

PMID- 10585669
TI  - [Influence of the temperature on the life cycle of Triatoma melanosoma Martinez,
      Olmedo & Carvavallo, 1987 (Hemiptera, Reduviidae)].

PMID- 10585671
TI  - Bad press and biotech.

PMID- 10585670
TI  - Capillary electrophoresis for detection of inherited disorders of purine and
      pyrimidine metabolism.
AB  - BACKGROUND: Measurement of purine and pyrimidine metabolites presents complex
      problems for separations currently performed by HPLC and thin-layer
      chromatography in clinical practice. We developed a novel capillary
      electrophoresis method for this purpose. METHODS: Separations were performed in
      60 mmol/L borate-2-amino-2-methyl-1-propanol-80 mmol/L sodium dodecyl sulfate (pH
      9.6) at 35 degrees C. RESULTS: The conditions reported allowed separation of all
      diagnostic metabolites from major urinary constituents in an analysis time of 3
      min and with a separation efficiency of 220 000 theoretical plates/m. The
      clinically important metabolites were detectable at concentrations of 0.85-4.28
      micromol/L. The method was linear over the range 5-500 micromol/L (r >0.99). The
      within-run and intra- and interday imprecision (CV) was <5%. Characteristic
      abnormalities were detected in the electropherograms of urine samples from
      patients with purine and pyrimidine enzyme deficiencies. We provide the
      electrophoretic and spectral characteristics of many intermediates in purine and
      pyrimidine metabolism and describe common artifacts from medication and
      ultraviolet-absorbing compounds. CONCLUSION: Capillary electrophoresis is a
      valuable screening tool in the detection of inborn errors of purine and
      pyrimidine metabolism.

PMID- 10585672
TI  - Ome is where the art is.

PMID- 10585673
TI  - From genomics to epigenomics: a loftier view of life.

PMID- 10585674
TI  - Forest biotechnology makes its position known.

PMID- 10585675
TI  - GFP movement between chloroplasts.

PMID- 10585678
TI  - US bill seeks GMO labeling

PMID- 10585676
TI  - Creativity and peer review.

PMID- 10585679
TI  - GMO roundup

PMID- 10585680
TI  - Leptin efficacy looks slim

PMID- 10585682
TI  - Biogen antibody may not be immune to side effects

PMID- 10585681
TI  - Fujitsu joins Japan's bionet

PMID- 10585684
TI  - $150M for stanford bio-X center

PMID- 10585683
TI  - Sequencing, patenting surge

PMID- 10585685
TI  - Agbiotech outreach boosted

PMID- 10585686
TI  - Japan patent directives

PMID- 10585688
TI  - Quenching biosensor

PMID- 10585687
TI  - Research collaborations

PMID- 10585689
TI  - BAC vaccine

PMID- 10585690
TI  - Germline transmission of artificial chromosome

PMID- 10585691
TI  - GFP chimeras monitor signal molecules

PMID- 10585692
TI  - beta-secretase identified

PMID- 10585693
TI  - Mapping protein interactions by phage display

PMID- 10585694
TI  - A new vector for fetal gene transfer

PMID- 10585695
TI  - Seeing red

PMID- 10585697
TI  - Cellular magnetism

PMID- 10585696
TI  - Mass analysis of receptor-DNA complexes

PMID- 10585698
TI  - Growing bigger pigs

PMID- 10585699
TI  - Genzyme acquires Cell Genesys.

PMID- 10585700
TI  - Millennium mergers bring pipeline.

PMID- 10585701
TI  - Gene therapy safety issues come to fore.

PMID- 10585702
TI  - GM corn poses little threat to monarch.

PMID- 10585703
TI  - Patent case unblocks antibody businesses.

PMID- 10585704
TI  - EC says 1% is acceptable GMO "contamination".

PMID- 10585705
TI  - Spanish R&D budget boosts biotechnology.

PMID- 10585706
TI  - Fashioning FGFs from phage?

PMID- 10585707
TI  - Shortcuts from gene sequence to function.

PMID- 10585708
TI  - "Itching" for new strategies in protein engineering.

PMID- 10585709
TI  - Enzyme beauty.

PMID- 10585710
TI  - Detecting estrogens in food and the environment.

PMID- 10585711
TI  - The new antibiotics.

PMID- 10585712
TI  - Prospects for the use of nuclear transfer in human transplantation.
AB  - The successful application of nuclear transfer techniques to a range of mammalian
      species has brought the possibility of human therapeutic cloning significantly
      closer. The objective of therapeutic cloning is to produce pluripotent stem cells
      that carry the nuclear genome of the patient and then induce them to
      differentiate into replacement cells, such as cardiomyocytes to replace damaged
      heart tissue or insulin-producing beta cells for patients with diabetes. Although
      cloning would eliminate the critical problem of immune incompatibility, there is
      also the task of reconstituting the cells into more complex tissues and organs in
      vitro. In the review, we discuss recent progress that has been made in this field
      as well as the inherent dangers and scientific challenges that remain before
      these techniques can be used to harness genetically matched cells and tissues for
      human transplantation.

PMID- 10585713
TI  - cobA, a red fluorescent transcriptional reporter for Escherichia coli, yeast, and
      mammalian cells.
AB  - We demonstrate the use of Propionibacterium freudenreichii uroporphyrinogen III
      methyltransferase (cobA) as a reporter of gene expression in Escherichia coli,
      fission yeast, and mammalian cells. Overexpression of cobA in cells resulted in
      bright red fluorescence that was visualized with standard fluorescence microscopy
      and fluorescence-activated cell sorting analysis at the single-cell level. As
      with green fluorescent protein (GFP), no addition of exogenous substrate was
      required. When expressed in Chinese hamster ovary cells from a bicistronic
      transcript, cobA and GFP gave rise to fluorescence signals of similar intensity.
      The bright red fluorescence generated by the cobA reporter promises a better
      signal-to-noise ratio than blue and green fluorescent reporter systems, as
      autofluorescence and light scattering of cells, media, and materials are reduced
      in the red wavelengths.

PMID- 10585714
TI  - Myogenic expression of an injectable protease-resistant growth hormone-releasing
      hormone augments long-term growth in pigs.
AB  - Ectopic expression of a new serum protease-resistant porcine growth hormone
      releasing hormone, directed by an injectable muscle-specific synthetic promoter
      plasmid vector (pSP-HV-GHRH), elicits growth in pigs. A single 10 mg
      intramuscular injection of pSP-HV-GHRH DNA followed by electroporation in three
      week-old piglets elevated serum GHRH levels by twofold to fourfold, enhanced
      growth hormone secretion, and increased serum insulin-like growth factor-I by
      threefold to sixfold over control pigs. After 65 days the average body weight of
      the pigs injected with pSP-HV-GHRH was approximately 37% greater than the placebo
      injected controls and resulted in a significant reduction in serum urea
      concentration, indicating a decrease in amino acid catabolism. Evaluation of body
      composition indicated a uniform increase in mass, with no organomegaly or
      associated pathology.

PMID- 10585715
TI  - Oligonucleotide-based inhibition of embryonic gene expression.
AB  - We describe a technique to define gene function using antisense oligonucleotide
      (AS-ODN) inhibition of gene expression in mice. A single intravenous injection of
      an AS-ODN targeting vascular endothelial growth factor (VEGF) into pregnant mice
      between E7.5-8.5 resulted in a lack of primary angiogenesis. This enabled us to
      define the critical window required to inhibit VEGF expression and recapitulate
      the primary loss of function phenotype observed in VEGF (-/-) embryos. This
      phenotype was sequence-specific and time- and dose-dependent. Injection of an AS
      ODN targeting a second gene, E-cadherin, into pregnant mice at E10 confirmed a
      hypothesized secondary phenotype. This is the first report of AS-ODN inhibition
      of gene expression in utero and provides a new strategy for target validation in
      functional genomics.

PMID- 10585716
TI  - Fetal gene transfer by transuterine injection of cationic liposome-DNA complexes.
AB  - In utero injection of cationic liposome-DNA complexes (CLDCs) containing
      chloramphenicol acetyltransferase, beta-galactosidase (beta-gal), or human
      granulocyte colony-stimulating factor (hG-CSF) expression plasmids produced high
      level gene expression in fetal rats. Tissues adjacent to the injection site
      exhibited the highest levels of gene expression. Chloramphenicol
      acetyltransferase expression persisted for at least 14 days and was reexpressed
      following postnatal reinjection of CLDCs. Intraperitoneal administration of the
      hG-CSF gene produced high serum hG-CSF levels. X-gal staining demonstrated
      widespread beta-gal expression in multiple fetal tissues and cell types. No toxic
      or inflammatory responses were observed, nor was there evidence of fetal-maternal
      or maternal-fetal gene transfer, suggesting that CLDCs may provide a useful
      alternative to viral vectors for in utero gene transfer.

PMID- 10585717
TI  - Mapping signal transduction pathways by phage display.
AB  - Rapid identification of proteins that interact with a novel gene product is an
      important element of functional genomics. Here we describe a phage display-based
      technique for interaction screening of complex cDNA libraries using proteins or
      synthetic peptides as baits. Starting with the epidermal growth factor receptor
      (EGFR) cytoplasmic tail, we identified known protein interactions that link EGFR
      to the Ras/MAP kinase signal transduction cascade and several novel interactions.
      This approach can be used as a rapid and efficient tool for elucidating protein
      networks and mapping intracellular signal transduction pathways.

PMID- 10585719
TI  - A combinatorial approach to hybrid enzymes independent of DNA homology.
AB  - We present a methodology, termed incremental truncation for the creation of
      hybrid enzymes (ITCHY), that creates combinatorial fusion libraries between genes
      in a manner that is independent of DNA homology. We compared the ability of ITCHY
      and DNA shuffling to create interspecies fusion libraries between fragments of
      the Escherichia coli and human glycinamide ribonucleotide transformylase genes,
      which have only 50% identity on the DNA level. Sequencing of several randomly
      selected positives from each library illustrated that ITCHY identified a more
      diverse set of active fusion points including those in regions of nonhomology and
      those with crossover points that diverged from the sequence alignment.
      Furthermore, some of the hybrids found by ITCHY that were fused at nonhomologous
      locations had activities that were greater than or equal to the activity of the
      hybrids found by DNA shuffling.

PMID- 10585718
TI  - Semirational design of a potent, artificial agonist of fibroblast growth factor
      receptors.
AB  - Fibroblast growth factors (FGFs) are being investigated in human clinical trials
      as treatments for angina, claudication, and stroke. We designed a molecule
      structurally unrelated to all FGFs, which potently mimicked basic FGF activity,
      by combining domains that (1) bind FGF receptors (2) bind heparin, and (3)
      mediate dimerization. A 26-residue peptide identified by phage display
      specifically bound FGF receptor (FGFR) 1c extracellular domain but had no
      homology with FGFs. When fused with the c-jun leucine zipper domain, which binds
      heparin and forms homodimers, the polypeptide specifically reproduced the
      mitogenic and morphogenic activities of basic FGF with similar potency (EC50 =
      240 pM). The polypeptide required interaction with heparin for activity,
      demonstrating the importance of heparin for FGFR activation even with designed
      ligands structurally unrelated to FGF. Our results demonstrate the feasibility of
      engineering potent artificial agonists for the receptor tyrosine kinases, and
      have important implications for the design of nonpeptidic ligands for FGF
      receptors. Furthermore, artificial FGFR agonists may be useful alternatives to
      FGF in the treatment of ischemic vascular disease.

PMID- 10585720
TI  - Optical tracking and detection of immunomagnetically selected and aligned cells.
AB  - We have developed a platform for cell analysis based on immunomagnetic selection
      and magnetic alignment of cells in combination with an epi-illumination tracking
      and detection system. Whole blood was labeled with ferromagnetic nanoparticles
      and fluorescent probes, and placed in a magnetic field in a chamber. Cells
      labeled with ferromagnetic nanoparticles moved upward and aligned along
      ferromagnetic lines deposited by lithographic techniques on an optically
      transparent surface of the chamber. An epi-illumination system using a 635 nm
      laser diode as a light source scanned the lines and measured signals obtained
      from the aligned cells. The cell counts per unit of blood volume obtained with
      the system correlated well with those obtained from the counts from a standard
      hematology analyzer and flow cytometer. The cell analysis platform is
      significantly less complex and more sensitive than current cell analysis
      equipment and provides additional functionality through its ability to subject
      the cells to repeated and varied analyses while they remain in a natural
      environment (i.e., whole blood).

PMID- 10585721
TI  - Analysis of transcription complexes and effects of ligands by microelectrospray
      ionization mass spectrometry.
AB  - The human vitamin D receptor (VDR) and retinoid X receptor-alpha (RXRalpha)
      modulate gene activity by forming homodimeric or heterodimeric complexes with
      specific DNA sequences and interaction with other elements of the transcriptional
      apparatus in the presence of their known endogenous ligands 1alpha,25
      dihydroxyvitamin D3 (1, 25-[OH]2D3) and 9-cis-retinoic acid (9-c-RA). We used
      rapid buffer exchange gel filtration in conjunction with microelectrospray
      ionization mass spectrometry (microESI-MS) to study the binding of these
      receptors to the osteopontin vitamin D response element (OP VDRE). In the absence
      of DNA, both VDR and RXRalpha existed primarily as monomers, but in the presence
      of OP VDRE, homodimeric RXRalpha and heterodimeric RXRalpha-VDR complexes were
      shown to bind OP VDRE. Addition of 9-c-RA increased RXRalpha homodimer-OP VDRE
      complexes, and addition of 1,25-(OH) 2D3 resulted in formation of 1, 25-(OH)2D 3
      VDR-RXRalpha-OP VDRE complexes. Addition of low-affinity binding ligands had no
      detectable effect on the VDR-RXRalpha-OP VDRE transcription complex. These
      results demonstrate the utility of microESI-MS in analyzing multimeric, high
      molecular-weight protein-protein and protein-DNA complexes, and the effects of
      ligands on these transcriptional complexes.

PMID- 10585722
TI  - A nonisotopic estrogen receptor-based assay to detect estrogenic compounds.
AB  - We have used the ligand binding domain of the recombinant human estrogen receptor
      (hER) to develop a nonisotopic assay for detection of estrogenic compounds. The
      assay is based on competition of the estrogenic ligand with 17beta-estradiol for
      binding to the receptor, which leaves 17beta-estradiol free to bind to an anti
      17beta-estradiol antibody. Unbound anti-17beta-estradiol antibody then binds to
      immobilized 17beta-estradiol-protein conjugate (to which hER is unable to bind
      for steric reasons), and is detected by an enzyme-labeled anti-rabbit IgG
      antibody. We used the assay to detect estrogenic compounds (mainly members of the
      flavonoid group of plant polyphenols) in a variety of commonly consumed plant
      foods.

PMID- 10585723
TI  - The use of cysteine proteinase inhibitors to engineer resistance against
      potyviruses in transgenic tobacco plants.
AB  - As the processing mechanism of all known potyviruses involves the activity of
      cysteine proteinases, we asked whether constitutive expression of a rice cysteine
      proteinase inhibitor gene could induce resistance against two important
      potyviruses, tobacco etch virus (TEV) and potato virus Y (PVY), in transgenic
      tobacco plants. Tobacco lines expressing the foreign gene at varying levels were
      examined for resistance against TEV and PVY infection. There was a clear, direct
      correlation between the level of oryzacystatin message, inhibition of papain (a
      cysteine proteinase), and resistance to TEV and PVY in all lines tested. The
      inhibitor was ineffective against tobacco mosaic virus (TMV) infection because
      processing of this virus does not involve cysteine proteinases. These results
      show that plant cystatins can be used against different potyviruses and
      potentially also against other viruses, whose replication involves cysteine
      proteinase activity.

PMID- 10585725
TI  - Using outsourcing to enhance core capabilities: winning strategy or dangerous
      manuever?

PMID- 10585726
TI  - Recent patents in angiogenesis research

PMID- 10585727
TI  - A yeast two-hybrid system for discerning differential interactions using multiple
      baits.

PMID- 10585728
TI  - Containerless vitrification of mammalian oocytes and embryos.

PMID- 10585729
TI  - People

PMID- 10585730
TI  - New products

PMID- 10585731
TI  - Biotechnology 2000.

PMID- 10585732
TI  - A synthetic FGF agonist

PMID- 10585733
TI  - Antisense scores a knockout

PMID- 10585734
TI  - Antiviral protease inhibitors

PMID- 10585735
TI  - Keeping tabs on estrogen

PMID- 10585736
TI  - Exploiting diversity

PMID- 10585737
TI  - The orientation of membrane proteins determined in situ by immunofluorescence
      staining.
AB  - Structural and functional characterization of membrane proteins includes the
      determination of their orientation within the membrane (integral proteins), or
      their exposure at either the cytosolic or extracytoplasmic surface of the
      membrane (peripheral proteins). We have developed an easily handled
      immunofluorescence-based method to investigate the exposure of antigenic epitopes
      at either surface of the membranes in situ. We present conditions for
      permeabilization of p-formaldehyde-fixed cells which allow the discrimination of
      epitopes exposed either at the cytosolic face of membranes, within the lumen of
      vesicles, or at the cell surface. The potential applications of this method
      include (1) the use of domain-specific antibodies as a tool to study integral
      membrane proteins with regard to the orientation of their carboxy-terminal and
      amino-terminal ends or the orientation of the loops of multispanning proteins,
      and (2) the assignment of the epitope of monoclonal antibodies to the cytosolic
      or luminal domain of integral membrane proteins with the established structure.

PMID- 10585738
TI  - Electrochemical assay of plasminogen activators in plasma using polyion-sensitive
      membrane electrode detection.
AB  - Two relatively simple electrochemical assay methods suitable for the measurement
      of plasminogen activators (including urokinase (u-PA), streptokinase (SK), and
      tissue plasminogen activator (t-PA)) in plasma samples are described. In one
      approach, the initial rate of decrease in the potentiometric response of a
      polycation-sensitive membrane electrode toward protamine is monitored after
      addition of a preincubated reaction mixture containing the sample and exogenous
      plasminogen. The plasmin formed from plasminogen by the activators catalyzes the
      decomposition of the arginine-rich protamine substrate, yielding smaller
      polycationic fragments that are not sensed by the electrode. Alternately, the
      sample, plasminogen, and protamine can be incubated together, and the remaining
      protamine in this reaction mixture can be measured at a fixed point in time by
      placing the electrode into the mixture and recording the electromotive force
      response. Working curves found with both methods for plasma samples spiked with
      varying levels of the activators cover the expected therapeutic activity ranges
      found in the plasma of patients treated with these "clot-busting" drugs.

PMID- 10585739
TI  - A method for distinguishing 1-acyl from 2-acyl lysophosphatidylcholines generated
      in biological systems.
AB  - Phospholipases A(1) and A(2) frequently coexist in biological systems. Generation
      of lysophosphatidylcholine (LPC) in such systems cannot be assigned to any of
      these types of enzymes unless the position of the fatty acid in the lysocompound
      can be unambiguously determined. We here present a simple method to achieve this
      purpose. It is based on the initial chemical acylation of the isolated LPC with a
      labeled fatty acid, followed by the enzymatic analysis of the resulting
      phosphatidylcholine (PC), using snake or bee venom phospholipase A(2). Thus, if
      treatment of the PC with this enzyme releases a labeled free fatty acid, it is
      demonstrated that the initial LPC was acylated at position sn-1, whereas if the
      product of hydrolysis yields labeled LPC, then the initial LPC was acylated at
      position sn-2. This is the first method devised to determine the source of LPC in
      the presence of mixtures of phospholipases A(1) and A(2) in complex biological
      systems.

PMID- 10585740
TI  - Usefulness of statistic experimental designs in enzymology: example with
      recombinant hCYP3A4 and 1A2.
AB  - First, the effects of 10 incubation factors were screened altogether on
      nifedipine dehydrogenase (NIF) and methoxyresorufin O-deethylase (MROD)
      activities catalyzed by recombinant human CYP3A4 and 1A2, respectively. Using a
      statistic experimental design, only 36 assays were needed to be exhaustive. Eight
      factors influenced CYP3A4-mediated NIF activity: buffer type, pH, temperature,
      Mg/EDTA, cytochrome b5, NADPH-P450 reductase, NADH, and solvent. Two factors had
      no significant effect: total ionic concentration and catalase/reduced
      glutathione. Six factors influenced CYP1A2-mediated MROD rates: buffer type, pH,
      temperature, Mg/EDTA, NADH, and glycerol. Four factors had no significant effect:
      total ionic concentration, cytochrome b5, reductase, and NAD+. Secondly, the
      combined effects of ionic strength and Mg concentration on NIF/CYP3A4 were
      studied and easily modeled using another statistic experimental design. The
      effect of Mg was strong at a constant ionic strength of 100 mM and negligible at
      a constant ionic strength of 500 mM. Thirdly, the effects of influencing factors
      and their interactions on MROD/CYP1A2 were modeled after 40 assays using a third
      statistic experimental design. Later experiments confirmed the predictivity of
      the models and the efficiency of optimized conditions. This approach can be
      applied to other biochemistry areas.

PMID- 10585741
TI  - Intramolecularly quenched BODIPY-labeled phospholipid analogs in phospholipase
      A(2) and platelet-activating factor acetylhydrolase assays and in vivo
      fluorescence imaging.
AB  - Phospholipase substrate analogs containing both a fluorescent BODIPY group and a
      quenching 2,4-dinitrophenyl (DNP) group were synthesized. They showed little
      fluorescence, but upon hydrolysis became fluorescent as the quenching group was
      removed. Two substrates were phosphatidylethanolamine analogs with a BODIPY
      pentanoyl group at the sn-2 position and DNP linked to the amino head group. The
      third was a phosphatidylcholine analog with a BODIPY-labeled alkyl ether at the
      sn-1 position and a N-(DNP)-8-amino-octanoyl group at the sn-2 position. These
      compounds were evaluated as substrates for cytosolic (85 kDa) phospholipase A(2)
      (cPLA(2)) and plasma platelet-activating factor acetylhydrolase (rPAF-AH). Two
      were good substrates for cPLA(2) (specific activities: 18 and 5 nmol min(-1) mg(
      1)) and all were good for rPAF-AH (specific activities: 17, 11, and 6 micro mol
      min(-1) mg(-1)). The minimal amount of enzyme detectable was 50 ng for cPLA(2)
      and 0.1 ng for rPAF-AH. These substrates were active in assays of PLA(2) in
      zebrafish embryo extracts and one was well suited for imaging of PLA(2) activity
      in living zebrafish embryos. Embryos were injected with substrate at the one- to
      four-cell stage and allowed to develop until early somitogenesis when endogenous
      PLA(2) activity increases dramatically; substrate persisted (12 h) and
      specifically labeled cells of the developing notochord.

PMID- 10585742
TI  - Kinetic analysis of antibody-antigen interactions at a supported lipid monolayer.
AB  - Modified phospholipids possessing carboxyl head groups synthesized from
      phosphatidylethanolamine were incorporated into supported lipid monolayers on top
      of a thin gold film. A monoclonal antibody was chemically coupled to the modified
      lipids in these monolayers and the kinetics of antigen binding were determined by
      surface plasmon resonance. The binding could be analyzed using a conventional 1:1
      binding algorithm and the derived kinetic and affinity constants were almost
      identical to those reported for the same interaction on a dextran hydrogel-based
      sensor chip. When an antigen was chemically coupled to a modified lipid
      monolayer, the binding of a monoclonal antibody to this surface was biphasic. A
      two-step algorithm describing the formation of a 1:2 antibody:antigen complex was
      developed which accurately described the data and enabled differentiation of the
      two binding steps. The binding was assayed varying both the concentration of
      antibody in solution and the density of antigen on the surface. The affinities
      determined by Scatchard analysis of equilibrium binding levels were similar to
      those values obtained from an ELISA.

PMID- 10585743
TI  - Separation of 17 DL-amino acids and chiral sequential analysis of peptides by
      reversed-phase liquid chromatography after labeling with R(-)-4- (3
      isothiocyanatopyrrolidin-1-yl)-7-(N, N-dimethylaminosulfonyl)-2,1,3
      benzoxadiazole.
AB  - Seventeen DL-amino acids labeled with a fluorescent chiral labeling reagent, R(-)
      4-(3-isothiocyanatopyrrolidin-1-yl)-7-(N, N-dimethylaminosulfonyl)-2,1,3
      benzoxadiazole (R(-)-DBD-PyNCS), were separated by reversed-phase chromatography
      and detected fluorometrically at 550 nm (excitation at 460 nm). The reagent
      reacted with amino functional group in dl-amino acids under basic medium. The
      thiocarbamoyl derivatives were converted to thiohydantoin via thiazolinone in
      trifluoroacetic acid (TFA) solution. The epimerization ratios during the reaction
      of the cyclization were less than 37% in all dl-amino acids tested. The resulting
      thiohydantoin derivatives of individual dl-amino acids were completely separated
      with isocratic elutions using acidic mobile phase involving 0.1% TFA. The
      separations of the thiohydantoins yielded from acidic, basic, neutral, hydroxyl,
      and aromatic amino acids were good enough for the identification of dl-amino
      acid. The method using the reagent was adopted to identification of dl-amino acid
      sequences in eight peptides. The separation and identification of the
      thiohydantoin derivatives liberated from the peptides labeled were performed by
      the isocratic elutions. The applicability of the proposed procedure to sequential
      analysis of peptide was demonstrated with [D-Ala(2)]-leucine enkephalin, [D
      Ala(2)]-deltorphin II, d-Phe-Met-Arg-Phe-amide, and Phe-D-Met-Arg-Phe-amide. D
      Ala, D-Phe, and D-Met in the peptides were positively identified with the
      proposed procedures. [L-Ala(2)]-leucine enkephalin, beta-lipotropin, Asp-Ser-Asp
      Pro-Arg, and Pro-Asp-Val-Asp-His-Val-Phe-Leu-Arg-Phe-amide were also analyzed as
      the references without D-amino acid.

PMID- 10585744
TI  - A quantitative fluorescence-based microplate assay for the determination of
      double-stranded DNA using SYBR Green I and a standard ultraviolet
      transilluminator gel imaging system.
AB  - Various assays are available for quantification of DNA in solution, but none has
      been described that is both sensitive and specific for double-stranded (ds) DNA
      and features practical properties such as low dye and equipment costs, speed, and
      highly parallel microplate formats. Here we show that quantitative and sensitive
      measurement of ds DNA in solution is achieved using a 96-well microplate SYBR
      Green I assay and a standard uv transillumination-based gel-imaging system for
      detection. Specific detection of ds DNA was obtained over a broad concentration
      range of 0.5-500 ng using a single low dye concentration of up to 1/6250.
      Measured SYBR Green I fluorescence was not significantly affected by pH variation
      (4-10), assay volume (50-250 microliter l), and time (4-15 min), and measurements
      were appreciably compatile with commonly encountered concentrations of
      contaminating salts, organics, detergents, and other substances. ds DNA yielded
      up to 13-fold higher fluorescence compared to single-stranded DNA or RNA, but
      this ratio was dependent somewhat on GC content and fragment size. Of note,
      linear ds DNA fluoresced significantly stronger than supercoiled plasmid DNA. Our
      method should be broadly applicable for sensitive, rapid, and inexpensive ds DNA
      quantification in the average molecular biology laboratory.

PMID- 10585745
TI  - Evaluation of lipid exposure of tryptophan residues in membrane peptides and
      proteins.
AB  - Fluorescence quenching is used to gain information on the exposure of tryptophan
      residues to lipid in membrane-bound proteins and peptides. A protocol is
      developed to calculate this exposure, based on a comparison of quenching
      efficiency and of a fluorescence lifetime (or quantum yield) measured for a
      protein and for a model tryptophan-containing compound. Various methods of
      analysis of depth-dependent quenching are compared and three universal measures
      of quenching profile are derived. One of the measures, related to the area under
      profile, is used to estimate quenching efficiency. The method is applied to
      single tryptophan mutants of a membrane-anchoring nonpolar peptide of cytochrome
      b(5) and of an outer membrane protein A. Analysis of quenching of the
      cytochrome's nonpolar peptide by a set of four brominated lipids reveals a
      temperature-controlled reversible conformational change, resulting in increased
      exposure of tryptophan to lipid and delocalization of its transverse position.
      Kinetic quenching profiles and fluorescence binding kinetics reported by
      Kleinschmidt et al. (Biochemistry (1999) 38, 5006-5016) were analyzed to extract
      information on the relative exposure of tryptophan residues during folding of an
      outer membrane protein A. Trp-102, which translocates across the bilayer, was
      found to be noticeably shielded from the lipid environment throughout the folding
      event compared to Trp-7, which remains on the cis side. The approach described
      here provides a new tool for studies of low-resolution structure and
      conformational transitions in membrane proteins and peptides.

PMID- 10585746
TI  - Fluorescent inhibitors for the qualitative and quantitative analysis of lipolytic
      enzymes.
AB  - We report on the determination of active enzyme components in pure and crude
      lipases, using fluorescent inhibitors for covalent modification and visualization
      of the enzymatically active proteins. Lipase-specific compounds are
      triacylglycerol analogs, namely 1,2(2, 3)-di-O-alkylglyceroalkylphosphonic acid-p
      nitrophenyl esters, containing a fluorescent substituent bound to the omega-end
      of an alkyl chain. Inhibitors derived from single-chain alcohols, such as p
      nitrophenyl esters of fluorescent alkyl phosphonates, react with lipases and
      esterases. The p-nitrophenyl ester bond is susceptible toward nucleophilic attack
      by the active serine of the lipolytic enzyme. This reaction is stoichiometric,
      specific, and irreversible. Stable lipid-protein complexes are formed which can
      be analyzed on the basis of their fluorescent signal. From fluorescence intensity
      the moles of active serine (enzyme) were accurately determined. A lipase-specific
      inhibitor was used for the analysis of a commercial lipase preparation from
      Rhizomucor miehei. After incubation of the enzyme with the fluorescent lipid, a
      single fluorescence band was observed after SDS-gel electrophoresis, indicating
      the presence of a single lipase in the crude enzyme material. A linear
      correlation was obtained between fluorescence intensity and the amount of enzyme.
      Using a combination of different inhibitors, we were able to discriminate between
      lipases and esterases.

PMID- 10585747
TI  - Simultaneous determination of alpha-fetoprotein and carcinoembryonic antigen in
      human serum by time-resolved fluoroimmunoassay.
AB  - A novel simultaneous measurement method for alpha-fetoprotein (AFP) and
      carcinoembryonic antigen (CEA) in human sera by time-resolved fluoroimmunoassay
      (TR-FIA) is described. The proposed approach combines the use of europium-labeled
      anti-AFP antibody for AFP TR-FIA and biotinylated anti-CEA antibody complexed to
      samarium-labeled streptavidin for CEA TR-FIA. A 96-well microtiter plate coated
      with a mixture of anti-AFP and anti-CEA monoclonal antibodies was used for the
      assay. After it was reacted with a solution containing AFP and CEA, a mixture of
      anti-AFP antibody labeled with BHHCT-Eu(3+) and biotinylated anti-CEA antibody
      was added. The AFP concentration was determined by measuring the solid-phase
      fluorescence of the europium-labeled anti-AFP antibody at 615 nm. Then a BHHCT
      Sm(3+)-labeled streptavidin-bovine serum albumin conjugate (SA-BSA) was added to
      react with the biotinylated anti-CEA antibody. After the reaction, the unreacted
      SA-BSA was washed out, and a 0.1 M NaOH solution containing 1.0 x 10(-5) M TOPO
      and 0.05% SDS was added to dissociate the samarium-labeled SA-BSA in the immune
      complex on the surface of the well into the solution. The CEA concentration was
      determined by measuring the solution fluorescence of 643 nm from the samarium
      labeled SA-BSA. The present method gives detection limits of 0.07 ng/ml for AFP
      and 0.3 ng/ml for CEA. The coefficient variations of the method are less than 7%,
      and the recoveries are in the range of 90-110% for serum samples. The AFP and CEA
      concentrations in 27 human serum samples were determined by the present method as
      well as by single assay for comparison. A good correlation was obtained with the
      correlation coefficients of 0.990 for AFP and 0.973 for CEA.

PMID- 10585748
TI  - Separation of the intracellular secretory compartment of rat liver and isolated
      rat hepatocytes in a single step using self-generating gradients of iodixanol.
AB  - A novel method is described for the separation on a single gradient of the major
      intracellular organelles of the secretory pathway, the Golgi, the smooth
      endoplasmic reticulum, and the rough endoplasmic reticulum. Total microsomes were
      prepared from rat liver by differential centrifugation and resuspended in 20%
      iodixanol. The microsomal suspension was then layered between a 30% iodixanol
      cushion and a layer of 15% iodixanol and centrifuged in a vertical rotor for 2 h.
      The microsomes distributed in four visible bands. The gradients were collected by
      upward displacement and were characterized (i) by determination of UDP galactose
      galactosyltransferase (Golgi marker) NADPH-cytochrome c reductase (endoplasmic
      reticulum marker) and RNA (rough endoplasmic reticulum marker); (ii) by
      immunoblotting for TGN38 (trans-Golgi marker) and GS28 (cis-Golgi marker) and for
      protein disulfide isomerase (endoplasmic reticulum lumenal marker); (iii) by
      determination of the lipid composition; and (iv) by electron microscopy. The
      results suggest that the top band (density 1.045-1. 090 g/ml), which contains 68%
      of the galactosyltransferase activity, consists of vesicles derived from the
      Golgi. The second broad band in the middle of the tube (density 1.130-1.160
      g/ml), which contains 54% of the NADPH-cytochrome c reductase activity, consists
      mainly of vesicles derived from the smooth endoplasmic reticulum, overlapped at
      the top by a small band of Golgi-derived lamellae. The two bands at the bottom of
      the tube (density 1.130-1.160 and density 1.180-1. 220 g/ml) appear to contain
      two subfractions of vesicles derived from the rough endoplasmic reticulum.

PMID- 10585749
TI  - A cellular reporter assay to monitor insulin receptor kinase activity based on
      STAT 5-dependent luciferase gene expression.
AB  - A highly sensitive method for determination of insulin receptor (IR) kinase
      activity in whole cells, which is based on a STAT5 (signal transducer and
      activator of transcription 5)-dependent reporter gene assay, has been developed.
      We show in Rat1 fibroblasts stably overexpressing the human IR (Rat1-HIR-cl5) an
      insulin-dependent direct association and phosphorylation of STAT5b by IR kinase.
      Rat1-HIR cells transfected with a luciferase gene reporter construct under
      control of a STAT5-inducible promoter showed insulin-mediated induction of STAT5
      dependent luciferase activity, with peak activities around 8 h of insulin
      treatment over a wide dose range. Transient STAT5b but not STAT5a cotransfection
      significantly enhanced reporter gene activity, yielding up to a fivefold
      induction. Addition of the IR kinase inhibitor tyrphostin AG1024 down-regulated
      luciferase induction in a dose-dependent manner. This is the first assay allowing
      determination of IR kinase activity in intact cells in a 24-well culture and a
      microtiter format. Kinetics of this cellular response, sensitivity range, and
      signal amplitude make it well suited for automation and offer the potential for
      establishing high-throughput screening systems for both insulin mimetic
      substances and IR kinase antagonists in a simple nonradioactive assay.

PMID- 10585750
TI  - Interaction between nuclear hormone receptors and coactivators analyzed using a
      nonradioactive "Pull-Down" assay.

PMID- 10585751
TI  - High-throughput nonradioisotopic determination of binding of platelet-derived
      growth factor to platelet-derived growth factor receptor beta-extracellular
      domain using biotinylated ligand with enzyme-linked immunosorbent assay.

PMID- 10585752
TI  - Three-component ligation efficiency analysis using prokaryotic green fluorescence
      protein expression vector.

PMID- 10585753
TI  - Splenic dendritic cells from the non-obese diabetic mouse induce a prolonged
      proliferation of syngeneic T cells. A role for an impaired apoptosis of NOD T
      cells?
AB  - In this study we have tried to detect abnormalities in the immunophenotype and/or
      function of dendritic cells from the non-obese diabetic mouse (NOD DC), that
      might be related to islet autoimmunity. The immunophenotype of NOD splenic DC did
      not show significant abnormalities as compared with the immunophenotype of
      splenic DC from C57BL/10 mice. Furthermore, NOD splenic and lymph node DC
      stimulated proliferation of syngeneic T cells as efficiently as DC from C57BL/10
      and BALB/c mice. The allogeneic response induced by NOD DC was similar to or only
      slightly lower than the response induced by C57BL/10 DC. Both a normal
      immunophenotype of NOD DC and efficient T cell stimulation were observed
      regardless of the stage of diabetes development. However, the syngeneic T cell
      proliferation induced by NOD splenic DC, but not by C57BL/10 splenic DC, was
      significantly prolonged, and it was accompanied by an increased proportion of
      activated/memory CD4(+)cells. We demonstrated that during the interaction of NOD
      cells fewer apoptotic cells were generated as compared with the interaction of
      C57BL/10 cells. Thus, the prolonged T cell response during the syngeneic
      interaction between NOD DC and T cells might be due to an impaired apoptosis
      induction. The impaired apoptosis might be of critical importance in the
      development of islet autoimmunity in the NOD mouse.

PMID- 10585754
TI  - Acceleration of autoimmune diabetes by cyclophosphamide is associated with an
      enhanced IFN-gamma secretion pathway.
AB  - Cyclophosphamide (CY), an alkylating cytostatic drug, is known for its ability to
      accelerate a number of experimental autoimmune diseases including spontaneous
      diabetes in NOD mice. The mechanism(s) by which CY renders autoreactive
      lymphocytes more pathogenic is largely unknown, but it has been postulated that
      the drug preferentially depletes regulatory (suppressor) T cells. It has been
      suggested that in cell-mediated autoimmune diseases, Th2-like lymphocytes
      secreting IL-4 and/or IL-10 provide protection, while Th1-like cells secreting
      IFN-gamma are pathogenic. In this study, we analysed the effects of CY on
      autoimmune diabetes and cytokines in two mouse models: the spontaneous diabetes
      of NOD mice and the diabetes induced in C57BL/KsJ mice by multiple injections of
      low dose streptozotocin (LD-STZ). In both models, CY induced severe lymphopenia
      and accelerated the progression to hyperglycemia. This was associated with
      changes in splenic cytokine patterns indicating a shift towards the IFN-gamma
      secreting phenotype. We provide here evidence that IFN-gamma producers are
      relatively resistant to depletion by CY and that Th0 clones can be shifted
      towards Th1. However, direct exposure of T lymphocytes to CY may not be a
      necessary condition for exacerbation of diabetes; NOD.scid mice treated with CY
      before adoptive transfer of NOD splenocytes developed diabetes at a higher rate
      than did controls. Thus, the acceleration of diabetes by CY seems to be a complex
      event, which includes the relatively high resistance of IFN-gamma producers to
      the drug, their rapid reconstitution, and a Th1 shift of surviving T cell clones.

PMID- 10585755
TI  - Abnormal thymic expression of epithelial cell adhesion molecule (EP-CAM) in New
      Zealand Black (NZB) mice.
AB  - New Zealand Black (NZB) mice have been well documented to have a variety of
      thymic epithelial cell microenvironmental abnormalities, including disruption of
      corticoepithelial cell networks and medullary cell clusters. These abnormalities
      of the thymic stromal network are particularly important because similar
      observations have been noted in other models of murine lupus. Thymic epithelial
      cells, a key component of the microenvironment, play an important role in
      selection of the mature T cell receptor repertoire. Recently, a homotypic calcium
      independent human and murine epithelial cell adhesion molecule, Ep-CAM, has been
      described which is located at the thymocyto-cortical cell junction. The function
      of Ep-CAM is still unclear but its unique location within the thymus suggests
      that it is critical in the process of providing maturation signals. Consequently,
      we examined the thymic expression of Ep-CAM in a series of autoimmune prone mice
      by thymic distribution of Ep-CAM in NZB, NZW, NZB/W, BXSB-Yaa, MRL- lpr/lpr, C3H-
      gld/gld and the control strains BALB/c, C57BL6, C3H and MRL(+/+), by
      immunohistology and flow cytometry. Interestingly, NZB mice are similar to
      control mice from day 4 to 2 weeks of age, having a very low expression of Ep-CAM
      at the thymocyto-cortical junction. In control strains, there is a marked
      increased in expression of Ep-CAM beginning at 5 weeks of age. In contrast, NZB
      mice fail to show significant expression of Ep-CAM even well into adulthood. This
      abnormality of NZB mice was also noted in NZB/W F1 and BXSB mice, but not MRL-
      lpr/lpr or C3H- gld/gld mice. Given the potential importance of Ep-CAM in thymic
      selection, this study provides important evidence that a defective stromal
      microenvironment is likely to be of etiological significance in the
      susceptibility of NZB to autoimmune disease.

PMID- 10585756
TI  - Suppression of systemic lupus erythematosus disease in mice by oral
      administration of kidney extract.
AB  - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the
      increased production of antibodies reactive with a variety of self and non-self
      antigens. A number of immunomodulatory therapies have been investigated for the
      disease process. Intragastric administration of low dose kidney extract (KE)
      three times weekly for 5 weeks and then weekly until 6 months of age in SLE mice,
      showed decreased anti-dsDNA antibody levels, less kidney damage and significantly
      prolonged survival compared with control phosphate buffered saline (PBS)-fed
      mice. The KE-fed mice also exhibited reduced T cell proliferative response to KE
      in comparison with PBS-fed controls. Serum isotype distribution of the anti-dsDNA
      antibodies revealed a marked reduction of IgG1 and IgG3 responses in the KE-fed
      mice. While the renal inflammatory cell infiltration and expression of
      interleukin-4 (IL-4) and IL-10 were markedly suppressed, no local enhancement of
      transforming growth factor-beta (TGF-beta) was detected. Oral administration of
      low dose KE, however, upregulated expression of IL-2, IFN-gamma and TNF-alpha in
      the kidneys and suppressed glomerulonephritis. These findings suggest that oral
      KE affects the disease process in SLE and raise the possibility that oral
      administration of KE or other potential autoantigens may provide a new approach
      for the treatment of SLE.

PMID- 10585757
TI  - Intracytoplasmic Th1 and Th2 cytokines in rheumatoid arthritis blood and synovial
      tissue.
AB  - In rheumatoid arthritis (RA), T cells have been proposed either as a main actor
      or as an epiphenomenon in such a primarily synoviocyte-driven disease. A major
      issue remains the remarkable paradox between the T cell infiltrate and the
      relative failure to detect definite markers of their activity. To determine the
      Th1/Th2 cytokine profile in RA synovium, we used a single cell flow cytometric
      assay for interleukin-2 (IL-2), interferon-gamma (IFN-gamma), IL-4 and IL-10 in
      paired peripheral blood (PB) and synovial tissue (ST) lymphocytes from RA and
      osteoarthritis (OA) patients and PB lymphocytes from healthy controls. Cytokines
      were undetectable in unstimulated PB and ST lymphocytes. More stimulated PB and
      ST CD4(+)lymphocytes produced IFN-gamma than IL-4, for all individuals tested. RA
      PB CD4(+)lymphocytes showed the same Th1 cytokine pattern as normal controls. No
      increase of such a Th1 profile was observed for ST lymphocytes. A specific
      recruitment of T CD4(+)lymphocytes in the rheumatoid inflamed synovium could not
      be concluded on the basis of these results.

PMID- 10585758
TI  - Heterogeneity of anti-dsDNA antibodies in their cross-reaction with ribosomal P
      protein.
AB  - We have investigated the possible cross-reaction of anti-dsDNA antibodies with
      ribosomal P peptide for several reasons. First, the antibodies frequently occur
      together, and secondly, they vary similarly with disease activity. Human
      polyclonal anti-dsDNA antibodies were affinity purified from eight patients and
      anti-ribosomal P antibodies from two patients with systemic Lupus erythematosus
      (SLE) who had high titers of anti-dsDNA as well as anti-ribosomal P antibodies.
      Nine of the 10 sera were totally specific in their reactivity with their cognate
      antigens. In only one patient did we find a subpopulation of antibodies which
      cross-reacted with both dsDNA and the carboxyl terminal 22 amino acid peptide.
      Our results indicate that anti-dsDNA antibodies are heterogeneous and usually do
      not cross-react with the carboxyl terminal P peptide, but on occasion (1/10) a
      patient will produce anti-dsDNA antibodies cross-reactive with the carboxyl
      terminal P peptide.

PMID- 10585759
TI  - Autoantibodies to La/SSB in patients with primary Sjogren's syndrome (pSS) are
      associated with upregulation of La/SSB mRNA in minor salivary gland biopsies
      (MSGs).
AB  - Recent studies have shown that minor salivary glands (MSGs) of patients with
      primary Sjogren's syndrome (pSS) are sites of anti-La/SSB autoantibody
      production. The aim of this study was to investigate the expression of La/SSB
      mRNA in MSGs of patients with pSS. La/SSB mRNA expression was studied by in situ
      hybridization in six biopsies of pSS patients with anti-La/SSB antibodies, nine
      pSS patients without anti-La/SSB and 10 patients with non-specific sialadenitis.
      Oligonucleotide probes corresponding to c-DNA encoding four linear epitopes of
      La/SSB (bp 423-471, bp 861-909, bp 903-954 and bp 1048-1092) were utilized. cDNA
      encoding linear epitopes of Ro52 (bp 786-837), Ro60 (bp 654-702) and the
      housekeeping genes of Sm and GAPDH were used as controls. The results were
      expressed as percent of positive cells by image analysis. Serum levels of anti
      La/SSB autoantibodies were correlated with the presence and the intensity of
      La/SSB mRNA labeling. All pSS patients with anti-La/SSB antibodies in their serum
      expressed mRNA transcripts of epitopes 301-318 aa and 349-364 aa (encoded by the
      cDNA probes bp 903-954 and bp 1048-1092 respectively), predominantly in acinar
      and mononuclear cells of MSGs. These epitopes are the major targets of anti
      La/SSB antibodies. Serum levels of anti-La/SSB antibodies were correlated with
      the number of positively stained cells in MSGs. Two of the nine pSS patients
      without anti-La/SSB autoantibodies and 2/10 non-pSS patients expressed the mRNA
      of the La/SSB molecule. The probes of RO52 and Ro60 epitopes did not react, while
      mRNA encoding the housekeeping genes of Sm and GAPDH was positive in all samples.
      In conclusion, pSS patients with anti-La/SSB antibodies showed upregulation of
      La/SSB mRNA in acinar and mononuclear cells of MSGs. Thus, active synthesis of
      La/SSB in MSGs of pSS seems to play an important role in the autoimmune response
      of the affected tissues.

PMID- 10585761
TI  - Volume contents and index

PMID- 10585760
TI  - Hu antigen specificities of ANNA-I autoantibodies in paraneoplastic neurological
      disease.
AB  - Despite a broad clinical spectrum, paraneoplastic enecephalomyelitis/sensory
      neuronopathy (PEM/SSN) is characterized by the presence of a common autoantibody,
      referred to as anti-Hu or type I anti-neuronal nuclear antibody (ANNA-1). The
      target of these antibodies is a family of four Hu antigens: three (Hel-N1, HuC,
      HuD) are neural-specific, while the fourth (HuR) is ubiquitous. Here, we have
      analysed by enzyme-linked immunosorbent assay (ELISA) the immunoreactivity of all
      four Hu antigens in serum from 75 patients with ANNA-1 autoantibodies and looked
      for clinical correlations. IgG in all the patients' sera bound to each of the
      four antigens, and the titers correlated with those of the ANNA-I
      immunofluorescence assay. Median titers for the neural-specific antigens (range:
      56, 892-90,051) were significantly higher than for HuR (36,799). Patients with
      gastrointestinal dysmotility or subacute sensory neuronopathy had the highest
      median titers to all four antigens, while patients with sensorineural deafness
      had the lowest titers. The results indicate a heterogeneous immune response to
      individual Hu antigens in patients with PEM/SSN, and that the titers to these
      antigens as a group, rather than individually, correlate with clinical profile.
      Furthermore, these results suggest that ELISA analysis of a single neural
      specific Hu antigen is sufficient for serological screening in PEM/SSN.

PMID- 10585762
TI  - Pseudoxanthoma elasticum maps to an 820-kb region of the p13.1 region of
      chromosome 16.
AB  - We have performed linkage analysis on 21 families with pseudoxanthoma elasticum
      (PXE) using 10 polymorphic markers located on chromosome 16p13.1. The gene
      responsible for the PXE phenotype was localized to an 8-cM region of 16p13.1
      between markers D16S500 and D16S3041 with a maximum lod score of 8.1 at a
      recombination fraction of 0.04 for marker D16S3017. The lack of any locus
      heterogeneity suggests that the major predisposing allele for the PXE phenotype
      is located in this region. Haplotype studies of a total of 36 PXE families
      identified several recombinations that further confined the PXE gene to a region
      (< 1 cM) between markers D16S3060 and D16S79. This PXE locus was identified
      within a single YAC clone and several overlapping BAC recombinants. From sequence
      analysis of these BAC recombinants, it is clear that the distance between markers
      D16S3060 and D16S79 is about 820 kb and contains a total of nine genes including
      three pseudogenes. We predict that mutations in one of the expressed genes in the
      locus will be responsible for the PXE phenotype in these families.

PMID- 10585763
TI  - Selection and mapping of replication origins from a 500-kb region of the human X
      chromosome and their relationship to gene expression.
AB  - In higher eukaryotes the mechanism controlling initiation of DNA replication
      remains largely unknown. New technologies are needed to shed light on how DNA
      replication initiates along the genome in specific regions. To identify the human
      DNA sequence requirements for initiation of replication, we developed a new
      method that allows selection of replication origins starting from large genomic
      regions of human DNA. We repeatedly isolated 15 new putative replication origins
      (PROs) from a human DNA region of 500 kb in which 17 genes have previously been
      characterized. Fine-mapping of these PROs showed that DNA replication can
      initiate at many specific points along actively transcribed DNA in the cell lines
      used for our selection. In conclusion, in this paper we describe a new method to
      identify PROs that suggests that the availability of initiation sites is
      dependent on the transcriptional state of the DNA.

PMID- 10585764
TI  - Genomic mapping of chromosomal region 2p15-p21 (D2S378-D2S391): integration of
      Genemap'98 within a framework of yeast and bacterial artificial chromosomes.
AB  - The region of chromosome 2 encompassed by the polymorphic markers D2S378
      (centromeric) and D2S391 (telomeric) spans an approximately 10-cM distance in
      cytogenetic bands 2p15-p21. This area is frequently involved in cytogenetic
      alterations in human cancers. It also harbors the genes for several genetic
      disorders, including Type I hereditary nonpolyposis colorectal cancer (HNPCC),
      familial male precocious puberty (FMPP), Carney complex (CNC), Doyne's honeycomb
      retinal dystrophy (DHRD), and one form of familial dyslexia (DYX-3). Only a
      handful of known genes have been mapped to 2p16. These include MSH2, which is
      responsible for HNPCC, FSHR, the gene responsible for FMPP, EFEMP-1, the gene
      mutated in DHRD, GTBP, a DNA repair gene, and SPTBN1, nonerythryocytic beta
      spectrin. The genes for CNC and DYX-3 remain unknown, due to lack of a contig of
      this region and its underrepresentation in the existing maps. This report
      presents a yeast- and bacterial-artificial chromosome (YAC and BAC, respectively)
      resource for the construction of a sequence-ready map of 2p15-p21 between the
      markers D2S378 and D2S391 at the centromeric and telomeric ends, respectively.
      The recently published Genemap'98 lists 146 expressed sequence tags (ESTs) in
      this region; we have used our YAC-BAC map to place each of these ESTs within a
      framework of 40 known and 3 newly cloned polymorphic markers and 37 new sequence
      tagged sites. This map provides an integration of genetic, radiation hybrid, and
      physical mapping information for the region corresponding to cytogenetic bands
      2p15-p21 and is expected to facilitate the identification of disease genes from
      the area.

PMID- 10585765
TI  - Mapping lipopolysaccharide response loci in mice using recombinant inbred and
      congenic strains.
AB  - Lipopolysaccharide (LPS) induces proliferation of splenic B-cells, and this
      response was found to be significantly lower in A/J than in C57BL/6J (B6) mice.
      Several strains and substrains mirrored the high and low responses of B6 and A/J.
      Assessment of 26 AXB/BXA recombinant inbred (RI) mouse strains identified 23
      strains with a low (A/J-like), high (B6-like), or intermediate response. The
      three remaining RI strains exhibited a novel hyperresponsive phenotype
      significantly different from that of either founder strain. RI analysis
      identified four suggestive loci contributing to the LPS response, two of which
      were confirmed by analysis of congenic strains containing the donor genomic
      segment from a high- or low-responder strain on the opposite background. The
      combination of A/J and B6 alleles fixed to homozygosity at the four suggestive
      loci would occur in only 1 of 256 intercross progeny, but occurred several times
      among the RI strains.

PMID- 10585766
TI  - Genomic organization, expression, and chromosome location of the human SNAIL gene
      (SNAI1) and a related processed pseudogene (SNAI1P).
AB  - Some of the zinc finger proteins of the snail family are essential in the
      formation of mesoderm during gastrulation and the development of neural crest and
      its derivatives. We have isolated the human SNAIL gene (HGMW-approved symbol
      SNAI1) and describe its genomic organization, having sequenced a region spanning
      more than 5882 bp. The human SNAIL gene contains three exons. The SNAIL
      transcript is 2. 0 kb and is found in placenta and adult heart, lung, brain,
      liver, and skeletal muscle. It codes for a protein of 264 amino acids and 29.1
      kDa. This protein contains three classic zinc fingers and one atypical zinc
      finger. The human SNAIL protein is 87.5, 58.7, 50.9, 50.7, 55.4, and 31.5%
      identical to mouse Snail, chicken snail-like, zebrafish snail1, zebrafish snail2,
      Xenopus snail, and Drosophila snail proteins, respectively. The zinc finger
      region is 95.5% identical between human and mouse Snail. Because Drosophila snail
      and twist are important regulators during mesoderm development and because human
      TWIST mutations have been implicated in craniosynostosis, a cohort of 59 patients
      with craniosynostosis syndromes were screened for SNAIL mutations. None were
      found. By somatic cell and radiation hybrid mapping panels, SNAIL was localized
      to human chromosome 20q13.2, between markers D20S886 and D20S109. A SNAIL
      related, putative processed pseudogene (HGMW-approved symbol SNAI1P) was also
      isolated and maps to human chromosome 2q33-q37.

PMID- 10585767
TI  - Structure and expression of the gene encoding mouse F-box protein, Fwd2.
AB  - A novel class of ubiquitin ligases, termed the SCF complex, consists of
      invariable components, Skp1 and Cullin, and variable components called F-box
      proteins, which have a primary role in determining substrate specificity. We have
      isolated a cDNA encoding the mouse F-box protein Fwd2 (also known as MD6) as a
      possible constituent of an SCF-type ubiquitin ligase. Fwd2 cDNA contains 1890 bp
      with a 1362-bp open reading frame and encodes an approximately 51.5-kDa protein.
      Fwd2 is expressed predominantly in liver and, to a lesser extent, in the testis,
      lung, heart, and skeletal muscle. Immunofluorescence staining for Fwd2 protein
      shows a pattern with the cytoplasm. A coimmunoprecipitation assay has revealed
      the in vivo interaction between Skp1 and Fwd2 through the F-box domain. Fwd2 also
      interacts with Cul1 through Skp1, suggesting that Skp1, Cul1, and the F-box
      protein Fwd2 form an SCF complex (SCF(Fwd2)). We have also isolated and
      determined the nucleotide sequence and genomic organization of the gene that
      encodes mouse Fwd2. This gene spans approximately 17 kb and consists of six exons
      and five introns. Our results suggest that Fwd2 is an F-box protein that
      constitutes an SCF ubiquitin ligase complex and that it plays a critical role in
      the ubiquitin-dependent degradation of proteins expressed in the liver.

PMID- 10585768
TI  - Human FRAG1 encodes a novel membrane-spanning protein that localizes to
      chromosome 11p15.5, a region of frequent loss of heterozygosity in cancer.
AB  - We have previously identified a chromosomal rearrangement between fibroblast
      growth factor receptor 2 (FGFR2) and a novel gene, FRAG1, in a rodent model of
      osteosarcoma. To assess the potential role of FRAG1 in disease further, we have
      isolated cDNA and genomic clones of human FRAG1. Sequence analysis of the cDNA
      revealed the presence of an insertion not contained in the original FRAG1
      sequence. This insertion in human FRAG1 encoded a region highly homologous to and
      immediately following the first 55 amino acids of the protein, indicating the
      presence of a repetitive domain within FRAG1, designated the FRAG1 homology (FH)
      domain. Analysis of FRAG1 gene structure revealed that the FH domains were
      encoded by tandem duplicated exons. Database searches identified several
      transmembrane proteins displaying homology to the FH domain of FRAG1. In
      addition, hydropathy analysis predicted FRAG1 to encode an integral membrane
      protein with multiple membrane-spanning segments. FRAG1 mRNA was ubiquitously
      expressed in human adult tissues and several tumor cell lines at varying levels
      of abundance. Human FRAG1 was mapped by fluorescence in situ hybridization and
      radiation hybrid analysis to chromosome 11 at band p15.5, a region implicated in
      Beckwith-Wiedemann syndrome and a region of frequent loss of heterozygosity in
      multiple tumor types. These results suggest that FRAG1 may be a useful candidate
      gene for genetic disorders associated with alterations at 11p15.5.

PMID- 10585769
TI  - Mutation in the betaA3/A1-crystallin encoding gene Cryba1 causes a dominant
      cataract in the mouse.
AB  - During the mouse ENU mutagenesis screen, mice were tested for the occurrence of
      dominant cataracts. One particular mutant was discovered as a progressive opacity
      (Po). Heterozygotes show opacification of a superficial layer of the fetal
      nucleus, which progresses and finally forms a nuclear opacity. Since the
      homozygotes have already developed the total cataract at eye opening, the mode of
      inheritance is semidominant. Linkage analysis was performed using a set of genome
      wide microsatellite markers. The mutation was mapped to chromosome 11 distal of
      the marker D11Mit242 (9.3 +/- 4.4 cM) and proximal to D11Mit36 (2.3 +/- 2.3 cM).
      This position makes the betaA3/A1-crystallin encoding gene Cryba1 an excellent
      candidate gene. Mouse Cryba1 was amplified from lens mRNA. Sequence analysis
      revealed a mutation of a T to an A at the second base of exon 6, leading to an
      exchange of Trp by Arg. Computer analysis predicts that the fourth Greek key
      motif of the affected betaA3/A1-crystallin will not be formed. Moreover, the
      mutation leads also to an additional splicing signal, to the skipping of the
      first 3 bp of exon 6, and finally to the deletion of the Trp residue. Both types
      of mRNA are present in the homozygous mutant lenses. The mutation will be
      referred to as Cryba1(po1). This particular mouse mutation provides an excellent
      animal model for a human congenital zonular cataract with suture opacities, which
      is caused by a mutation in the homologous gene.

PMID- 10585770
TI  - Multiple MSP pseudogenes in a local repeat cluster on 1p36.2: An expanding
      genomic graveyard?
AB  - Chromosomal region 1p36.2 harbors an intriguing gene cluster of about 1 Mb. In
      addition to normal high-copy-number repeats, this cluster consists entirely of
      locally repeated sequences among which there are tRNA and small nuclear RNA
      (snRNA) genes. In 23 PACs and YACs from the 1p36.2 cluster, we identified eight
      different copies of a sequence with about 97% homology to the macrophage
      stimulating protein (MSP) gene located on chromosomal band 3p21. These MSP-like
      (MSPL) sequences on 1p36.2 are scattered over the repeat region. Nucleotide
      substitutions and single nucleotide deletions in exons of all identified MSPL
      genes on 1p36.2 mark them as pseudogenes. We constructed a phylogenetic tree of
      these sequences with their most likely order of origin in evolution. MSP from
      3p21 could be identified as the ancestral sequence, a copy of which was captured
      into the cluster of tRNA and snRNA genes on 1p36.2 about 6 million years (MY)
      ago. MSP subsequently coamplified with the other sequences in the cluster.
      Analysis of the DNA of 18 individuals shows that the MSPL copy number is
      polymorphic, with a range of four to seven or more copies per haploid genome.
      Analysis of corresponding clusters in macaque chromosomes indicated an age for
      the tRNA/snRNA cluster of at least 30 MY. The MSPL sequence thus functions as a
      probe for the more recent primate evolution of this cluster and suggests a
      continuation of its unusual activity over the last 6 MY.

PMID- 10585771
TI  - ZNF74, a gene deleted in DiGeorge syndrome, is expressed in human neural crest
      derived tissues and foregut endoderm epithelia.
AB  - DiGeorge syndrome (DGS) is a developmental disorder associated with large
      hemizygous deletions on chromosome 22q11.2. ZNF74 zinc finger gene is a candidate
      from the commonly deleted region. To address the potential involvement of ZNF74
      in DGS, its human developmental expression pattern has been assessed. In situ
      hybridization on Carnegie Stage 18 embryos revealed that ZNF74 expression is
      limited to specific neural crest-derived tissues and neuroepithelium of the
      spinal cord as well as to foregut endoderm epithelia (esophagus and respiratory
      tract). Interestingly, ZNF74 expression was detected in the wall of the pulmonary
      artery and aorta and in the aortic valve, which are populated by neural crest
      derived cells. This finding is significant, considering that DGS is believed to
      result from defective neural crest contributions and that outflow tract and
      aorticopulmonary septation defects are typical features of the DGS phenotype.
      Thus, the restricted expression of ZNF74 in structures affected in DGS suggests a
      role for this putative regulator of gene expression in aspects of the DGS
      phenotype.

PMID- 10585772
TI  - Expression analysis of 21 transcripts physically anchored within the chromosomal
      region 10q24.
AB  - Chromosome band 10q24 harbors the critical regions for inherited neurological
      disorders such as partial epilepsy (EPT), urofacial syndrome, and a distinct form
      of spastic paraparesis. To facilitate the selection of candidate genes for these
      diseases, we determined the mRNA sizes and analyzed the expression patterns of 21
      brain transcripts defined by expressed sequence tags previously localized along a
      7.4-Mb interval of 10q24. In addition to a number of widely expressed transcribed
      sequences, we identified several transcripts exclusively or predominantly
      expressed in the brain, which represent potential candidates for the neurological
      diseases associated with this genomic region.

PMID- 10585773
TI  - Identification of a putative regulatory subunit of a calcium-activated potassium
      channel in the dup(3q) syndrome region and a related sequence on 22q11.2.
AB  - Duplication of a segment of the long arm of human chromosome 3 (3q26.3-q27)
      results in a syndrome characterized by multiple congenital abnormalities and
      neurological anomalies in some patients. We have identified a novel gene (KCNMB3)
      that maps to this region. KCNMB3 has significant sequence similarity to the
      regulatory subunit of the large-conductance calcium-activated potassium channel.
      Due to the significance of potassium channels in neuronal functions, the
      overexpression of this gene may play a role in the abnormal neurological
      functions seen in some of these patients. A related sequence corresponding to the
      second and third exons of this gene resides in the pericentromeric region of
      22q11, where a number of other unprocessed pseudogenes are known to map.

PMID- 10585774
TI  - Cloning and mapping of a novel human serum/glucocorticoid regulated kinase-like
      gene, SGKL, to chromosome 8q12.3-q13.1.
AB  - Serum/glucocorticoid regulated kinase (sgk) belongs to a newly emerging subfamily
      of the serine/threonine protein kinase family. Although human SGK shares 98%
      amino acid identity with rat sgk, their expression levels are regulated
      differently, which indicates the existence of other SGKs in humans. In this
      paper, we reported the cloning of human SGKL, which encodes a protein sharing 67
      and 66% amino acid identity with rat sgk and human SGK, respectively. A 4.4-kb
      transcript of human SGKL was detected in 16 human tissues examined and was found
      to be most abundant in lung. By radiation hybrid mapping, the SGKL gene was
      located to human chromosome 8q12. 1-q13.1 between markers D8S510 and D8S1797.

PMID- 10585775
TI  - Human peroxisome proliferator activated receptor gamma coactivator 1 (PPARGC1)
      gene: cDNA sequence, genomic organization, chromosomal localization, and tissue
      expression.
AB  - Brown adipose and muscle tissues can increase energy expenditure via adaptive
      thermogenesis, thereby protecting against obesity. Mouse peroxisome proliferator
      activated receptor gamma coactivator 1 (Pgc1) has been reported to enhance the
      expression of uncoupling protein-1, a key mediator of thermogenesis in brown
      adipose tissue (Puigserver et al., 1998, Cell 92, 829-839). We report here the
      characterization of the human PPARGC1 gene. PPARGC1 spans a genomic region of
      approximately 67 kb, is composed of 13 exons, and encodes a 91-kDa protein that
      exhibits 94% amino acid identity with the mouse ortholog. mRNA species,
      transcribed from the TATA-less promoter, are 6.4 and 5.3 kb in length due to
      utilization of two polyadenylation signals. Northern blotting revealed expression
      of both transcripts in heart, skeletal muscle, and kidney and to a lesser extent
      in liver, brain, and pancreas as well as in the perirenal adipose tissue of a
      pheochromocytoma patient. PPARGC1 was mapped to chromosome 4p15.1, a region that
      has been associated with basal insulin levels in Pima Indians. Hence, PPARGC1
      expression might influence insulin sensitivity as well as energy expenditure,
      thereby contributing to the development and pathophysiology of human obesity.

PMID- 10585776
TI  - Characterization of TNFRSF19, a novel member of the tumor necrosis factor
      receptor superfamily.
AB  - By searching the expressed sequence tag database, a novel murine tumor necrosis
      factor receptor designated TNFRSF19 was identified. TNFRSF19 cDNA encodes a
      putative membrane protein of 348 amino acids with one incomplete and two complete
      cysteine-rich motifs within its extracellular region and a large cytoplasmic
      domain. TNFRSF19 mRNA can be detected in most murine tissues examined,
      particularly in brain, reproductive organs, and late developmental stages of
      murine embryo, but not in tissues of the immune system. The cell surface
      expression of the ligand of TNFRSF19 is highly restricted. Of 22 human and murine
      cell lines examined by FACS analysis, only Raji (B cell lymphoma cell line),
      GM847 (fibroblast cell line), 293 (embryonic kidney cell line), and K562 (chronic
      myeloid leukemia) were positive. TNFRSF19 did not bind newly cloned TNF ligands,
      including TWEAK (HGMW-approved symbol TNFSF12), VEGI/TL1 (HGMW-approved symbol
      TNFSF15), TL6/endokine (HGMW-approved symbol TNFSF18), APRIL (HGMW-approved
      symbol TNFSF13), OPGL (HGMW-approved symbol TNFSF11), LIGHT (HGMW-approved symbol
      TNFSF14), or BAFF/THANK (HGMW-approved symbol TNFSF13B) by enzyme-linked
      immunosorbent assay and FACS analyses. Overexpression of TNFRSF19 transduced
      neither apoptotic signaling nor signals leading to NF-kappaB induction. Taken
      together with the data that the TNFRSF19 extracellular domain-immunoglobulin
      fusion protein did not affect the allogeneic mixed lymphocyte reaction, our data
      indicate that TNFRSF19 is not involved in the modulation of immune responses.

PMID- 10585777
TI  - The copper chaperone Atox1 in canine copper toxicosis in Bedlington terriers.
AB  - Copper toxicosis, resulting in liver disease, commonly occurs in Bedlington
      terriers. This recessively inherited disorder, similar in many respects to Wilson
      disease, is of particular interest because the canine Atp7b gene, homologous to
      ATP7B defective in Wilson disease, is not responsible for canine copper toxicosis
      as has been expected. Atox1, a copper chaperone delivering copper to Atp7b,
      therefore became a potential candidate. We cloned canine Atox1, which shows
      conserved motifs of the copper-binding domain (MTCXXC) and of the lysine-rich
      region (KTGK), and showed 88, 80, and 41% amino acid sequence identity with the
      orthologous mouse, human, and yeast proteins. No gross deletions of Atox1 could
      be identified in the affected Bedlington terriers by Southern blot analysis of
      genomic DNA. The canine Atox1 gene spans about 4 kb, with a 204-bp open reading
      frame cDNA contained within two exons. Sequence analysis of the coding regions,
      including intron/exon boundaries, showed no mutations in Atox1 from genomic DNA
      of an affected dog. We have also identified an apparently nontranscribed canine
      Atox1 pseudogene, with 12 sequence changes and no intron. Mapping of Atox1 and a
      marker closely linked to the canine copper toxicosis locus indicated lack of
      synteny. Atox1 is therefore excluded as a candidate gene for canine copper
      toxicosis, indicating that some other unidentified gene must be responsible for
      this copper storage disease in dogs and also suggesting the possibility of a
      similar gene responsible for a copper storage disease in humans.

PMID- 10585778
TI  - Identification of a novel homolog of the Drosophila staufen protein in the
      chromosome 8q13-q21.1 region.
AB  - We report the identification of a new transcript homologous to the Drosophila
      staufen protein. This transcript, named STAU2 (HGMW-approved gene symbol and
      name), maps to the chromosome 8q13-q21 region. The full-length STAU2 cDNA is 4058
      bp and contains an open reading frame of 479 amino acids. Analysis of the
      predicted protein product indicated the presence of three double-stranded RNA
      binding domains. Best-fit analysis revealed a 48.5% similarity to the Drosophila
      protein and a 59.9% similarity to the recently described mammalian homolog hStau,
      indicating that at least two different transcripts with homologies to the fly
      protein are present in mammals.

PMID- 10585779
TI  - Isolation, characterization, and mapping of a zinc finger gene, ZFP95, containing
      both a SCAN box and an alternatively spliced KRAB A domain.
AB  - A new zinc finger gene of the Kruppel family was identified by screening a human
      fetal cartilage cDNA library with degenerate oligonucleotides. Sequence analysis
      indicates that ZFP95 contains 12 highly conserved zinc finger motifs at the C
      terminus and a SCAN box as well as a KRAB A domain at the N-terminus of the
      protein. ZFP95 represents a member of a new subclass of Kruppel zinc finger
      proteins containing both a SCAN box and a KRAB domain. Sequence comparison
      revealed that ZFP95 is the human ortholog of murine Zfp95, which is
      differentially expressed during spermatogenesis. We demonstrate that ZFP95 is
      ubiquitously expressed in adult and fetal tissues with the strongest expression
      in testis. Two transcripts, 4. 2 and 4.6 kb, were detected in all tissues tested.
      In testis, a third transcript of 3.8 kb was present. RT-PCR analysis confirmed
      alternative splicing for the KRAB A domain and an upstream exon leading to three
      transcripts of ZFP95 with and without this transcriptional repressor domain.
      Finally, we show that ZFP95 maps on human chromosome 7q22 between the markers
      D7S651 and WI-5853.

PMID- 10585780
TI  - An integrated gene and SSLP BAC map framework of mouse chromosome 11.
AB  - Physical maps are important resources both in sequencing and in functional
      analyses of large genomes. Global contig-building approaches are regarded to be
      more efficient relative to the cumulative outcome of scattered and more localized
      physical mapping studies accompanying positional cloning. This work is part of an
      effort to assemble a complete physical map of mouse chromosome 11 in which
      selection of clones containing specific genetic markers from genomic libraries is
      the first step in the process. Using a previously developed strategy, we
      identified 361 bacterial artificial chromosomes (BACs) containing 88 gene
      markers. Since the linkage positions of markers chosen for these studies are
      known, the BAC framework obtained is anchored to the genetic map and represents
      about 13% of the length of the entire chromosome. Together with similar
      assignments of BACs generated previously using D11Mit markers (Cai et al., 1988,
      Genomics, 54: 387-397), 36-40% of the chromosome 11 is now assembled into
      contigs, and these contigs correlate through 51 clones carrying both gene and
      simple sequence length polymorphism markers.

PMID- 10585781
TI  - Anti-infective efficacy of silver-coated medical prostheses.

PMID- 10585782
TI  - Intestinal toxemia botulism in two young people, caused by Clostridium butyricum
      type E.
AB  - Two unconnected cases of type E botulism involving a 19-year-old woman and a 9
      year-old child are described. The hospital courses of their illness were similar
      and included initial acute abdominal pain accompanied by progressive neurological
      impairment. Both patients were suspected of having appendicitis and underwent
      laparotomy, during which voluminous Meckel's diverticula were resected. Unusual
      neurotoxigenic Clostridium butyricum strains that produced botulinum-like toxin
      type E were isolated from the feces of the patients. These isolates were
      genotypically and phenotypically identical to other neurotoxigenic C. butyricum
      strains discovered in Italy in 1985-1986. No cytotoxic activity of the strains
      that might explain the associated gastrointestinal symptoms was demonstrated. The
      clinical picture of the illness and the persistence of neurotoxigenic clostridia
      in the feces of these patients suggested a colonization of the large intestine,
      with in vivo toxin production. The possibility that Meckel's diverticulum may
      predispose to intestinal toxemia botulism may warrant further investigation.

PMID- 10585783
TI  - Commentary: where Marco Polo meets Meckel: type E botulism from Clostridium
      butyricum.

PMID- 10585784
TI  - Outpatient parenteral antimicrobial therapy for central nervous system
      infections.
AB  - Patients with central nervous system (CNS) infections are increasingly treated
      with intravenous antimicrobials outside the hospital, but the safety and problems
      associated with this therapy have not been well defined. To examine this issue,
      we reviewed 68 cases in which outpatient intravenous antimicrobial therapy (OPAT)
      was received through our physician office-based infusion clinic. All infections
      were cured, and no deaths occurred during therapy. Seizures occurred in 2
      patients but without significant injury and apparently were unrelated to
      antimicrobial therapy. Eleven patients (16%) were hospitalized after starting
      OPAT, 5 for procedures and 6 for medical reasons. The antimicrobial used was
      changed in 13 cases (19%) because of an adverse effect or clinical failure. OPAT
      can be safe and effective for patients with CNS infections, but patients must be
      carefully selected and monitored closely.

PMID- 10585785
TI  - Editorial response: direct involvement of physicians is vital to outpatient
      parenteral antimicrobial therapy for central nervous system infections.

PMID- 10585786
TI  - Clinical significance of nephrotoxicity in patients treated with amphotericin B
      for suspected or proven aspergillosis.
AB  - The records of 239 immunosuppressed patients receiving amphotericin B for
      suspected or proven aspergillosis were reviewed to determine rates of
      nephrotoxicity, dialysis, and fatality. The mean and median durations of
      treatment were 20.4 and 15.0 days, respectively. The creatinine level doubled in
      53% of patients and exceeded 2.5 mg/dL in 29%; 14.5% underwent dialysis; and 60%
      died. A multivariate Cox proportional hazards analysis showed that patients whose
      creatinine level exceeded 2.5 mg/dL (hazard ratio [HR], 42.02; P<.001),
      allogeneic bone marrow transplantation (BMT) patients (HR, 6.34; P<. 001), and
      autologous BMT patients (HR, 5.06; P=.024) were at greatest risk for requiring
      hemodialysis. Use of hemodialysis (HR, 3. 089; P<.001), duration of amphotericin
      B use (HR, 1.03 per day; P=. 015), and use of nephrotoxic agents (HR, 1.96;
      P=.017) were associated with greater risk of death, whereas patients undergoing
      solid organ transplantation were at lowest risk (HR, 0.46; P=.002). These data
      indicate that elevated creatinine levels during amphotericin B treatment are
      associated with a substantial risk for hemodialysis and a higher mortality rate,
      but the risks vary in different patient groups.

PMID- 10585787
TI  - Estimating the true cost of amphotericin B.

PMID- 10585788
TI  - Control of a prolonged outbreak of extended-spectrum beta-lactamase-producing
      enterobacteriaceae in a university hospital.
AB  - Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBLPE) were
      isolated from clinical specimens from 130 to 140 patients/year in 1989-1991 in
      our hospital. In February 1992, a control program was initiated: screening tests
      in 3 intensive care units (ICUs) and contact-isolation precautions in all units.
      The septic surgical unit served as an isolation ward for surgical patients from
      whom ESBLPE was isolated. In 1992, the incidence of ESBLPE acquisition failed to
      decrease, and most acquisitions occurred in 3 ICUs. Critical evaluation of
      implementation of isolation procedures in these ICUs prompted corrective measures
      for barrier precautions. The incidence of acquired cases subsequently decreased,
      and a second evaluation determined that these measures had been correctly
      applied. The incidence of acquired cases in the septic surgical unit was lower
      than those in the other units. Decreases were also found in the incidence of
      acquisition of other hand-transmitted multidrug-resistant organisms. Barrier
      precautions, screening tests for ICU patients, and grouping of cohorts after ICU
      discharge are effective in controlling the spread of multidrug-resistant
      microorganisms by cross-contamination. The outbreak was effectively controlled
      without restricting antimicrobial use.

PMID- 10585789
TI  - Extended-spectrum beta-lactamases: a call for improved detection and control.

PMID- 10585790
TI  - Clinical and immunologic response without decrease in virus load in patients with
      AIDS after 24 months of highly active antiretroviral therapy.
AB  - This study reports an analysis of clinical, virological, and immunologic outcomes
      in a cohort of 77 multidrug-experienced AIDS patients during 24 months of highly
      active antiretroviral therapy (HAART). Our results have shown a reduced risk of
      AIDS complications, prolonged survival, and immunologic benefit even in the
      absence of sustained virus suppression. The degree of immunodepression, the risk
      factors for HIV-1 infection, the use of 2 drugs instead of 3, and a change in
      protease inhibitor were independently correlated with virological failure. In the
      majority of studied patients, an increase in CD4+ T cells was observed after
      HAART. However, the increase was more pronounced in patients who showed a
      decrease in virus load than in those who did not. Moreover, we observed an
      absence of relapses among patients who permanently discontinued prophylaxis for
      Cytomegalovirus retinitis and atypical mycobacterial infections. Peripheral
      lipodystrophy developed in the majority of patients, regardless of treatment used
      and virological outcome.

PMID- 10585791
TI  - Discordance between virological, immunologic, and clinical outcomes of therapy
      with protease inhibitors among human immunodeficiency virus-infected patients.

PMID- 10585792
TI  - Tick paralysis: 33 human cases in Washington State, 1946-1996.
AB  - Tick paralysis is a preventable cause of illness and death that, when diagnosed
      promptly, requires simple, low-cost intervention (tick removal). We reviewed
      information on cases of tick paralysis that were reported to the Washington State
      Department of Health (Seattle) during 1946-1996. Thirty-three cases of tick
      paralysis were identified, including 2 in children who died. Most of the patients
      were female (76%), and most cases (82%) occurred in children aged <8 years.
      Nearly all cases with information on site of probable exposure indicated exposure
      east of the Cascade Mountains. Onset of illness occurred from March 14 to June
      22. Of the 28 patients for whom information regarding hospitalization was
      available, 54% were hospitalized. Dermacentor andersoni was consistently
      identified when information on the tick species was reported. This large series
      of cases of tick paralysis demonstrates the predictable epidemiology of this
      disease. Improving health care provider awareness of tick paralysis could help
      limit morbidity and mortality due to this disease.

PMID- 10585793
TI  - Brucellar spondylitis: review of 35 cases and literature survey.
AB  - Thirty-five patients aged 14-74 years (average, 54 years) who had brucellar
      spondylitis were treated between January 1991 and December 1997. The time from
      onset of symptoms to diagnosis of spondylitis ranged from 1 week to 8 months
      (median, 9 weeks). Back or neck pain (100% of patients), fever (66%), and
      constitutional symptoms (57%) were the most common symptoms. Cultures of blood
      specimens from 26 patients (74%) were positive for Brucella melitensis. The
      duration of antimicrobial therapy (median, 120 days; range, 45-535 days) varied
      according to clinical response and the presence of epidural and paravertebral
      masses. One of the 35 patients underwent surgical treatment of a spinal epidural
      abscess. Therapy failed for 9 patients (26%; 95% confidence interval [CI], 12%
      43%), and 5 (14%; 95% CI, 5%-30%) had a relapse. There were no deaths or severe
      sequelae in this study. Brucellar spondylitis causes considerable suffering and
      absenteeism from work, but long-term clinical responses are favorable.

PMID- 10585794
TI  - Septic arthritis due to Streptococcus pneumoniae in Nottingham, United Kingdom,
      1985-1998.
AB  - Pneumonia and meningitis are the 2 most frequent manifestations of Streptococcus
      neumoniae infection. Pneumococcal septic arthritis is considered to be relatively
      uncommon. Between 1985 and 1998, 32 (8. 2%) of 389 cases of septic arthritis seen
      in the 2 hospitals in Nottingham, United Kingdom, were due to S. pneumoniae. Six
      of 7 children with pneumococcal septic arthritis were aged <2 years. Of the 25
      adults, 20 (80%) were aged >60 years, 11 (44%) had concomitant pneumococcal
      infection elsewhere, and 23 (92%) had articular or nonarticular diseases and/or
      other risk factors. In the elderly, a lack of febrile response was striking. S.
      pneumoniae was isolated from blood and joint cultures in >70% of cases, and gram
      positive diplococci were seen in the joint fluids of 90% of patients. The mean
      duration of antimicrobial therapy for adults was twice as long as that for
      children. Eight (32%) of the adults died.

PMID- 10585795
TI  - Mycobacterium kansasii septic arthritis: French retrospective study of 5 years
      and review.
AB  - Septic arthritis due to Mycobacterium kansasii is rare; only 40 cases have been
      published. A French national inquiry revealed the occurrence of 10 new cases
      between 1992 and 1997 (8 men and 2 women: mean age, 37 years; range, 25-54
      years). Seven had an underlying condition: AIDS (n=4), chronic skin psoriasis and
      AIDS (n=2), or a renal transplant (n=1). Trauma to the joint, use of intra
      articular corticosteroid(s) 1 month to 2 years after the event, and chronic skin
      psoriasis were risk factors. The mean interval between appearance of the first
      symptoms of arthritis and the diagnosis was 5 months. Monarthritis was localized
      to the knee (n=4), wrist (n=3), finger (n=1), elbow (n=1), or ankle (n=1). The
      main diagnostic procedure was culture of a synovial biopsy specimen. In all
      cases, debridement was associated with antimycobacterial treatment. Three
      patients died of AIDS during treatment, and another is still undergoing
      treatment; the other 6 patients were cured. M. kansasii infection should be
      considered in all cases of indolent arthritis with any of the following risk
      factors: local trauma, local or systemic corticosteroid therapy, chronic skin
      psoriasis, and immunodepression, especially that due to human immunodeficiency
      virus infection.

PMID- 10585796
TI  - Comparison of high and low doses of trimethoprim-sulfamethoxazole for primary
      prevention of toxoplasmic encephalitis in human immunodeficiency virus-infected
      patients.
AB  - To evaluate the influence of the dose of co-trimoxazole prophylaxis on the risk
      of toxoplasmosis in human immunodeficiency virus (HIV)-infected patients, we
      performed a nested case-control study of 32 patients with toxoplasmosis (case
      patients) and 64 patients without toxoplasmosis (control patients) who were
      matched by CD4 cell count and Toxoplasma gondii serostatus; these patients were
      from a cohort of 521 HIV-infected patients who underwent a diagnostic
      neuroimaging study between March 1993 and January 1997. Twenty-seven (84.4%) of
      32 case patients and 33 (51.6%) of 64 control patients received low doses of co
      trimoxazole, a finding associated with an adjusted odds ratio (OR) of 9.36 (95%
      confidence interval [CI], 2.05-42.75) and indicating 89% protective efficacy for
      high doses. Fifteen (46.9%) of 32 case patients and 16 (25%) of 64 control
      patients were exposed to rifampin (adjusted OR, 3.38; 95% CI, 1.08-10.61). These
      results indicate that high doses of co-trimoxazole appear to be more effective
      than low doses for lowering the risk of toxoplasmosis in HIV-infected patients
      and that rifampin therapy may reduce the efficacy of co-trimoxazole.

PMID- 10585797
TI  - High rates of Pneumocystis carinii pneumonia in allogeneic blood and marrow
      transplant recipients receiving dapsone prophylaxis.
AB  - Chemoprophylaxis for Pneumocystis carinii pneumonia (PCP) is routinely given
      after allogeneic blood or marrow transplantation. We evaluated the effectiveness
      of dapsone prophylaxis (50 mg orally twice daily, 3 times per week) compared with
      twice-weekly trimethoprim-sulfamethoxazole (TMP-SMZ) in preventing PCP after
      allogeneic blood or marrow transplantation. Patients included all (n=646) who
      received allogeneic blood or marrow transplants between 1 September 1993 and 31
      December 1996 who survived at least 100 days after transplantation. A cohort of
      111 dapsone recipients was compared with the remaining 535 who received TMP-SMZ.
      Ten patients developed PCP; 8 were taking dapsone. PCP incidence in the TMP-SMZ
      cohort was 0.37% versus 7.2% for dapsone. The relative risk for PCP associated
      with dapsone use was 18.8 (P<.001) and was not accounted for by age, clinical
      extensive chronic graft-versus-host disease, donor source, or malignant relapse.
      Dapsone prophylaxis at this dosage is associated with significantly higher rates
      of PCP than is TMP-SMZ after allogeneic marrow transplantation. We advise caution
      in prescribing alternatives to TMP-SMZ prophylaxis in this setting.

PMID- 10585798
TI  - Clinical and epidemiological features of early Lyme disease and human
      granulocytic ehrlichiosis in Wisconsin.
AB  - To compare clinical features and assess risk factors for human granulocytic
      ehrlichiosis (HGE) and early Lyme disease, we enrolled patients in a case-control
      study during the 1996 and 1997 tick seasons. Clinical and demographic
      characteristics were assessed for patients with laboratory-confirmed cases of HGE
      or Lyme disease, and risk factors were compared with those of matched control
      subjects. We identified 83 persons with Lyme disease, 27 with HGE, and 11 with
      apparent coinfection. Unsuspected Ehrlichia infection was identified in 8 (13%)
      of 60 patients with Lyme disease. Patients with HGE were older and more likely to
      have fever, chills, or dyspnea than were those with Lyme disease only. Most
      patients with apparent coinfection did not have hematologic abnormalities. In the
      risk factor analysis, tickborne illness was independently associated with rural
      residence and camping. The clinical spectrum of HGE overlaps that of Lyme
      disease, and physicians in areas of endemicity should consider both diseases in
      treating patients with a compatible rash or febrile illness.

PMID- 10585799
TI  - Endocardial abscesses in children: case report and review of the literature.
AB  - The rarity of perivalvular abscesses arising as a complication of bacterial
      endocarditis in the pediatric population limits its recognition and awareness of
      its often malignant course. The diagnosis depends on a combination of clinical
      criteria, including persistent fever and bacteremia, the presence of an
      atrioventricular block and persistent embolic phenomenon, and transthoracic or
      transesophageal echocardiographic confirmation. Because of the infrequency of
      perivalvular abscesses in children, there is no consensus on a treatment
      strategy. Early detection and intervention with antibiotics and surgical
      debridement are recommended to decrease the morbidity and mortality associated
      with this disease. A case of a 14-year-old boy with an aortic root abscess is
      presented, along with review of other cases reported in the last 20 years in
      children in relation to risk factors, clinical features, diagnosis, therapy, and
      mortality.

PMID- 10585800
TI  - Cost-effectiveness of blood cultures for adult patients with cellulitis.
AB  - To assess the cost-effectiveness of blood cultures for patients with cellulitis,
      a retrospective review was conducted of clinical and microbiological data for all
      757 patients admitted to a medical center because of community-acquired
      cellulitis during a 41-month period. Blood cultures were performed for 553
      patients (73%); there were a total of 710 blood samples (i.e., a mean of 1.3
      cultures were performed per patient). In only 11 cases (2.0%) was a significant
      patient-specific microbial strain isolated, mainly beta-hemolytic streptococci (8
      patients [73%]). An organism that was considered a contaminant was isolated from
      an additional 20 culture bottles (3. 6%). The cost of laboratory workup of the
      710 culture sets was $36, 050. Isolation of streptococci led to a change from
      empirical treatment with cefazolin to penicillin therapy for 8 patients. All
      patients recovered. In conclusion, the yield of blood cultures is very low, has a
      marginal impact on clinical management, and does not appear to be cost-effective
      for most patients with cellulitis.

PMID- 10585801
TI  - Association of primary Pneumocystis carinii infection and sudden infant death
      syndrome.
AB  - To delineate clinical and histological features of the first Pneumocystis carinii
      infection affecting the immunocompetent host, P. carinii-specific histological
      stains were performed on autopsy lung specimens from 534 consecutive pediatric
      patients (those with AIDS and malignancies were excluded) in Santiago, Chile. P.
      carinii clusters were found in 4 (25%) of 16 infants who died of no apparent
      cause at arrival to the emergency department, and in 10 (2.9%) of 342 infants who
      died of multiple conditions at the hospital (P=.002, Fisher's exact test). This
      prompted us to analyze additional series of infants with sudden infant death
      syndrome (SIDS). In 161 additional SIDS cases, 47 (35.1%) of 134 infants from
      Chile and 4 (14.8%) of 27 infants from Oxford, United Kingdom, were found to have
      P. carinii clusters in the lungs. The quantity of P. carinii cysts was small
      compared with the numbers seen in immunocompromised hosts with P. carinii
      pneumonitis. This study provides histological evidence that primary P. carinii
      infection is associated with SIDS.

PMID- 10585802
TI  - Adenovirus infections in hematopoietic stem cell transplant recipients.
AB  - We report a 12% incidence of adenovirus infections among 532 recipients of
      hematopoietic stem cell transplant (HSCT) from January 1986 through March 1997.
      The median time from day of stem cell infusion to first positive culture was 41
      days. Recipients of allogeneic stem cells, as opposed to autologous stem cell
      recipients, were more likely to have a culture positive for adenovirus (16% vs.
      3%; P<.0001). Pediatric patients were also more likely than adults to have a
      positive culture (23% vs. 9%; P<.0001). Among stem cell recipients with partially
      matched related donors, pediatric recipients appear to be at significantly
      greater risk for infection than adult recipients (P<.001). Positive cultures were
      associated with evidence of invasion in 64% of cases (41 of 64). A multiple
      logistic regression analysis showed that isolating adenovirus from more than 1
      site correlated with greater risk for invasive infections (P=.002). Invasive
      infections were associated with poorer chance of survival.

PMID- 10585803
TI  - Primaquine as prophylaxis for malaria for nonimmune travelers: A comparison with
      mefloquine and doxycycline.
AB  - Malaria prophylaxis for travelers is a controversial issue. The commonly used
      regimens are associated with side effects, low compliance, or low efficacy, which
      have raised concern regarding their use. In addition, they are inefficient
      against the tissue stage of the parasite and thus do not prevent relapses of
      Plasmodium vivax infection. Primaquine is aimed at the pre-erythrocytic stage and
      thus may be a potential causal-prophylactic treatment that can abolish the need
      for long postexposure therapy. During 1995-1998, we followed retrospectively
      travelers who joined rafting trips to an area in Ethiopia where both P. vivax and
      Plasmodium falciparum are hyperendemic. Of the 106 travelers who received
      primaquine, 5.7% developed malaria; of the 19 doxycycline recipients, 53%
      developed malaria; and of the 25 mefloquine recipients, 52% developed P. vivax
      malaria (>/=3 months after return from the area of endemicity). Primaquine was
      well tolerated, and only 1 withdrawal from therapy (due to gastrointestinal
      symptoms) was reported. Primaquine was shown to be a safe and effective
      prophylactic drug against both P. falciparum malaria and P. vivax malaria in
      travelers.

PMID- 10585804
TI  - Four years of experience with silver-copper ionization for control of legionella
      in a german university hospital hot water plumbing system.
AB  - Silver-copper ionization was used for controlling Legionella distribution in a
      German university hospital hot water plumbing system for 4 years. In the
      beginning, silver concentrations were not allowed to exceed 10 microg/L because
      of drinking water regulation limits in Germany. Water samples were monitored for
      Legionella counts, temperature, and silver and copper concentrations. A
      significant (P<.001) 3.8-log reduction of Legionella counts, from 40, 000 cfu/L
      to 7 cfu/L, was found during the first year with silver-copper ionization.
      Nevertheless, the long-term efficacy of silver concentrations <10 ,++microg/L was
      not sufficient. Legionella counts increased to 10,000 cfu/L during the third
      year. During the fourth year, we studied the influence of higher silver
      concentrations on Legionella distribution. With an average silver level of 30
      microg/L, only a 1.3-log reduction in Legionella, to 500 cfu/L, was achieved. The
      effect was not significant (P=.071); therefore, it must be considered that
      Legionella developed a tolerance to silver ions.

PMID- 10585805
TI  - Unusual spread of a penicillin-susceptible methicillin-resistant Staphylococcus
      aureus clone in a geographic area of low incidence.
AB  - We describe the unusual spread of a penicillin-susceptible methicillin-resistant
      Staphylococcus aureus (MRSA) clone in hospitals in western Switzerland, where the
      incidence of MRSA is usually low. During a 2-year period, this clone had been
      responsible for several outbreaks and had been isolated from >156 persons in 21
      institutions. Molecular typing by pulsed-field gel electrophoresis (PFGE)
      demonstrated that all of these isolates belonged to the same clone. In 1 of the
      outbreaks, involving 30 cases, the clone was responsible for at least 17
      secondary cases. In contrast, during the period of the latter outbreak, 9 other
      patients harboring different MRSA strains, as assessed by PFGE, were hospitalized
      in the same wards, but no secondary cases occurred. These observations suggest
      that this clone, compared with other MRSA strains, had some intrinsic factor(s)
      that contributed to its ability to disseminate and could thus be considered
      epidemic.

PMID- 10585806
TI  - Pneumocystis carinii pneumonia in human immunodeficiency virus (HIV)-positive and
      HIV-negative immunocompromised patients.
AB  - For 89 human immunodeficiency virus (HIV)-positive and 32 HIV-negative
      immunocompromised patients who had 121 episodes of Pneumocystis carinii pneumonia
      (PCP), clinical features and changes over time were compared. HIV-infected
      patients characteristically had a longer duration of symptoms (23 vs. 13 days;
      P<.005); were younger (39 vs. 48 years; P<.001); had a higher frequency of
      sweating, weight loss, and thoracic pain; and had fewer admissions to the
      intensive care unit (16% vs. 31%; P<.05). In addition, they had significantly
      higher hemoglobin levels, lower thrombocyte counts, lower C-reactive protein
      values, and a higher proportion of eosinophils and lymphocytes in bronchoalveolar
      lavage fluid. After 1995, HIV-negative patients' mean length of stay dropped from
      34 days to 16 days (P<.005), and their hospital mortality rate dropped from 29%
      to 7% (P<.001). HIV-positive patients with PCP differed in several aspects from
      those without HIV infection. Knowledge gained from experience with treatment of
      opportunistic infections in patients with AIDS has improved the management of PCP
      in patients with other immunodeficiencies.

PMID- 10585807
TI  - Spectrum of opportunistic infections and malignancies in patients with human
      immunodeficiency virus infection in South Korea.
AB  - To determine the frequency and types of major opportunistic diseases in patients
      with HIV infection in South Korea, we reviewed the medical records of 173 HIV
      infected patients. The patients were seen from 1985 to 1998 at a referral
      hospital for AIDS in South Korea. Most patients (85%) were male, and 107 (62%)
      were infected by heterosexual contacts. CD4+ lymphocyte counts at presentation
      were <200/microL in 27% of the patients. Tuberculosis was the most frequent
      opportunistic infection (25% of patients), followed by candidiasis (21%), herpes
      zoster (20%), Pneumocystis carinii pneumonia (10%), cytomegalovirus disease
      (9.8%). There were no cases of toxoplasmosis. Kaposi's sarcoma developed in 3
      patients (1.7%), and non-Hodgkin's lymphoma, in 2 (1.2%). Eleven patients (6.4%)
      developed peripheral neuropathy, and 8 (4.6%) had HIV encephalopathy.
      Tuberculosis was the single most important HIV-related infection in South Korean
      patients.

PMID- 10585808
TI  - Life-threatening Mycoplasma hominis mediastinitis.
AB  - Mycoplasma hominis infections are easily missed because conventional methods for
      bacterial detection may fail. Here, 8 cases of septic mediastinitis due to M.
      hominis are reported and reviewed in the context of previously reported cases of
      mediastinitis, sternum wound infection, pleuritis, or pericarditis caused by M.
      hominis. All 8 patients had a predisposing initial condition related to poor
      cardiorespiratory function, aspiration, or complications related to coronary
      artery surgery or other thoracic surgeries. Mediastinitis was associated with
      purulent pleural effusion and acute septic symptoms requiring inotropic
      medication and ventilatory support. Later, the patients had a tendency for
      indolent chronic courses with pleuritis, pericarditis, or open sternal wounds
      that lasted for several months. M. hominis infections may also present as mild
      sternum wound infection or as chronic local pericarditis or pleuritis without
      septic mediastinitis. Treatment includes surgical drainage and debridement.
      Antibiotics effective against M. hominis should be considered when treating
      mediastinitis of unknown etiology.

PMID- 10585809
TI  - Hantavirus pulmonary syndrome in pregnancy.
AB  - This comprehensive case review of hantavirus pulmonary syndrome (HPS) during
      pregnancy in 5 women characterizes the effect of Sin Nombre virus infection on
      maternal and fetal outcomes. Histopathologic, serological, and clinical
      information were evaluated for evidence of vertical transmission. Maternal ages
      ranged from 20 to 34 years and gestational ages from 13 to 29 weeks. Symptoms,
      physical findings, and laboratory values other than those related to pregnancy
      were not noticeably different from those of nonpregnant patients with HPS,
      although fevers were somewhat lower. One maternal death and 2 fetal losses
      occurred. Gross, microscopic, and immunohistochemical examination for hantavirus
      antigen were done on 2 fetal autopsies and 3 placentas showing no evidence of
      transplacental hantavirus transmission. There was no serological evidence of
      conversion in the 3 surviving children. Maternal and fetal outcomes of HPS appear
      similar to those of nonpregnant HPS patients and of pregnant patients with other
      causes of acute respiratory distress syndrome. No evidence of vertical
      transmission of Sin Nombre virus was found.

PMID- 10585810
TI  - An outbreak of acute respiratory disease caused by Mycoplasma pneumoniae and
      adenovirus at a federal service training academy: new implications from an old
      scenario.
AB  - Outbreaks of Mycoplasma pneumoniae and adenovirus have been reported in military
      institutions for several decades. During a recent outbreak in a federal service
      training academy, we performed an epidemiological and laboratory investigation to
      better characterize and control the outbreak. Of 586 students responding to a
      questionnaire, 317 (54%) reported having a respiratory illness during the
      outbreak period. Among 42 students who underwent complete laboratory testing, 24
      (57%) had evidence of M. pneumoniae infection, 8 (19%) had evidence of adenovirus
      infection, and 4 (10%) had evidence of both. Polymerase chain reaction testing of
      oropharyngeal swabs revealed more acute M. pneumoniae infections (57% positive)
      than did serology or culture. Multivariate analysis revealed that visiting the
      campus health clinic >3 times for a nonrespiratory condition, such as injury, was
      a significant risk factor for illness among freshmen early in the course of the
      outbreak, whereas having an ill roommate was a risk factor throughout the
      duration of the outbreak.

PMID- 10585811
TI  - A pilot study of the management of uncomplicated candidemia with a standardized
      protocol of amphotericin B.
AB  - We evaluated an amphotericin treatment strategy on the basis of duration of
      candidemia and clinical findings. Patients without neutropenia who had
      uncomplicated candidemia received 200 mg of amphotericin B over 5-7 days if they
      had had </=1 day of documented positive blood cultures (SC group) or a total of
      500 mg of amphotericin B over 14-20 days if they had had >1 day of positive
      cultures (PC group). The clinical cure rate was 93% (95% confidence interval
      [CI], 77%-99%; n=29 episodes) in the SC group, with no relapses (median follow
      up, 272 days). The clinical cure rate was 83% (95% CI, 64%-94%; n=29 episodes) in
      the PC group, with 1 relapse (4.2%). The results of this pilot study suggest that
      patients with candidemia may be stratified into risk groups on the basis of the
      duration of positive blood cultures and other clinical findings. Decisions about
      the duration of therapy can be made 4-7 days after initiation of treatment.
      Carefully selected patients with transient uncomplicated candidemia may be safely
      treated with a short course of amphotericin B. Further prospective validation of
      this concept should be undertaken particularly to evaluate the impact on low
      frequency late complications (e.g., endophthalmitis).

PMID- 10585812
TI  - Old Testament biblical references to tuberculosis.
AB  - Two probable references to tuberculosis are found in Old Testament books of the
      Bible dating to a time when the Israelites lived in Egypt, which is known from
      archeological evidence to be an area where tuberculosis was then prevalent. Other
      putative biblical references to tuberculosis are less credible.

PMID- 10585813
TI  - Acute lung injury in leptospirosis: clinical and laboratory features, outcome,
      and factors associated with mortality.
AB  - Forty-two consecutive patients with leptospirosis and acute lung injury who were
      mechanically ventilated were analyzed in a prospective cohort study. Nineteen
      patients (45%) survived, and 23 (55%) died. Multivariate analysis revealed that 3
      variables were independently associated with mortality: hemodynamic disturbance
      (odds ratio [OR], 6.0; 95% confidence interval [CI], 0.9-38.8; P=. 047), serum
      creatinine level >265.2 micromol/L (OR, 10.6; 95% CI, 0. 9-123.7; P =.026), and
      serum potassium level >4.0 mmol/L (OR, 19.9; 95% CI, 1.2-342.8; P=.009). These
      observations can be used to identify factors associated with mortality early in
      the course of severe respiratory failure in leptospirosis.

PMID- 10585814
TI  - Amphotericin B lipid complex (ABLC)-associated hypertension: case report and
      review.
AB  - Amphotericin B (AmB) continues to be the mainstay of therapy for serious fungal
      infections, despite its relatively toxic side-effect profile. Lipid preparations
      of the medication have been marketed in the past few years in an attempt to
      reduce some of these side effects, especially nephrotoxicity. Although 6 cases of
      severe hypertension associated with the use of AmB deoxycholate have been
      reported in the literature, no cases of hypertension associated with a lipid
      containing preparation of the medication have been reported. We report here the
      first case of severe hypertension associated with the infusion of AmB lipid
      complex (ABLC) in a patient with multiple intraperitoneal and urinary fungal
      pathogens. We also provide a brief review of the previously reported cases of
      hypertension associated with the deoxycholate formulation of AmB.

PMID- 10585815
TI  - Seeking vancomycin resistant Staphylococcus aureus among patients with vancomycin
      resistant enterococci.
AB  - Clinical isolates of Staphylococcus aureus displaying intermediate resistance to
      vancomycin (VISA) have been identified. The objective of our study was to
      identify VISA colonization among patients known to be colonized or infected with
      vancomycin-resistant enterococci (VRE). Eight weekly point prevalence screening
      surveys for VRE and S. aureus were conducted on 5 hospital units. Of the 243
      patients screened, 31 (12.8%) were colonized with VRE. In addition, 18 inpatients
      were already known to be VRE-positive. Fourteen (28.6%) of the 49 VRE-positive
      patients were co-colonized with S. aureus. All 30 S. aureus isolates from these
      14 patients were methicillin-resistant (MRSA) but remained vancomycin-susceptible
      (minimal inhibitory concentration [MIC] range, 0.75-2 microg/mL). Population
      analysis profiling demonstrated no evidence of heteroresistant subpopulations
      that could grow on agar containing 3 microg/mL vancomycin for any of the MRSA
      isolates. Although 23 (77%) of 30 staphylococcal isolates had vancomycin MICs of
      1.5 or 2 microg/mL, no VISA strains (MICs, 8-16 microg/mL) were recovered.

PMID- 10585816
TI  - Distant cutaneous granulomas after bacille Calmette-Guerin immunotherapy for
      malignant melanoma: case for direct infection.

PMID- 10585817
TI  - Klebsiella pneumoniae liver abscess, endophthalmitis, and meningitis in a man
      with newly recognized diabetes mellitus.

PMID- 10585818
TI  - Bacteremia with CDC group IV c-2 in an immunocompetent infant.

PMID- 10585819
TI  - Ruptured mycotic aneurysm of the superior mesenteric artery that was due to
      cardiobacterium endocarditis.

PMID- 10585820
TI  - Cell-mediated immune responses and loss of hepatitis B e-antigen (HBeAg) during
      successful lamivudine and famciclovir combination therapy for chronic replicating
      hepatitis B virus infection.

PMID- 10585821
TI  - Absence of infection in a neonate after possible exposure to sin nombre
      hantavirus in breast milk.

PMID- 10585822
TI  - Temporary increase in incidence of invasive infection due to Streptococcus
      pneumoniae in The Netherlands.

PMID- 10585823
TI  - Cunninghamella bertholletiae infection mimicking myocardial infarction.

PMID- 10585824
TI  - Culture-negative spontaneous bacterial peritonitis: an ambiguous diagnosis
      without peritoneal biopsy.

PMID- 10585825
TI  - Community-acquired fungemia due to a multiple-azole-resistant strain of Candida
      tropicalis.

PMID- 10585827
TI  - Ritonavir enables combined therapy with rifampin and saquinavir.

PMID- 10585826
TI  - Detection of human herpesvirus 8 in cervical cells of Chinese women with abnormal
      papanicolaou smears.

PMID- 10585828
TI  - Vancomycin-resistant enterococci in Brooklyn, New York: a moment in time.

PMID- 10585829
TI  - Absence of interhuman transmission of hantavirus pulmonary syndrome in Minas
      Gerais, Brazil: evidence from a serological survey.

PMID- 10585830
TI  - Chronic prosthetic device infection with Francisella tularensis.

PMID- 10585831
TI  - Austrian syndrome caused by highly penicillin-resistant Streptococcus pneumoniae.

PMID- 10585832
TI  - Fluconazole-resistant Cryptococcus neoformans isolated from an immunocompetent
      patient without prior exposure to fluconazole.

PMID- 10585833
TI  - Brucella canis endocarditis: case report.

PMID- 10585834
TI  - Primary cutaneous Aspergillus nidulans infection associated with a Hickman
      catheter in a patient with neutropenia.

PMID- 10585835
TI  - Fusobacterium nucleatum empyema necessitans.

PMID- 10585836
TI  - Acute rhabdomyolysis during treatment with ofloxacin-a case report.

PMID- 10585837
TI  - Fatal meningitis due to levofloxacin-resistant Streptococcus pneumoniae.

PMID- 10585838
TI  - Perineal anatomy and urine-voiding characteristics of young women with and
      without recurrent urinary tract infections.

PMID- 10585839
TI  - Reply

PMID- 10585840
TI  - Shigella boydii as cause of malacoplakia in a human immunodeficiency virus
      infected patient.

PMID- 10585841
TI  - Thrombocytopenia and Borrelia burgdorferi: an association remains unproven.

PMID- 10585842
TI  - Differentiating relapse from same-strain reinfection in recurring gram-negative
      bacteremia.

PMID- 10585843
TI  - Reply

PMID- 10585844
TI  - Therapeutic failures with rabies vaccine and rabies immunoglobulin.

PMID- 10585845
TI  - Abdominal pain and fever-an unusual presentation of meningococcemia.

PMID- 10585846
TI  - Reply

PMID- 10585848
TI  - Neuropathy target esterase.
AB  - Neuropathy target esterase (NTE) is an integral membrane protein present in all
      neurons and in some non-neural-cell types of vertebrates. Recent data indicate
      that NTE is involved in a cell-signalling pathway controlling interactions
      between neurons and accessory glial cells in the developing nervous system. NTE
      has serine esterase activity and efficiently catalyses the hydrolysis of phenyl
      valerate (PV) in vitro, but its physiological substrate is unknown. By sequence
      analysis NTE has been found to be related neither to the major serine esterase
      family, which includes acetylcholinesterase, nor to any other known serine
      hydrolases. NTE comprises at least two functional domains: an N-terminal putative
      regulatory domain and a C-terminal effector domain which contains the esterase
      activity and is, in part, conserved in proteins found in bacteria, yeast,
      nematodes and insects. NTE's effector domain contains three predicted
      transmembrane segments, and the active-site serine residue lies at the centre of
      one of these segments. The isolated recombinant domain shows PV hydrolase
      activity only when incorporated into phospholipid liposomes. NTE's esterase
      activity appears to be largely redundant in adult vertebrates, but
      organophosphates which react with NTE in vivo initiate unknown events which lead,
      after a delay of 1-3 weeks, to a neuropathy with degeneration of long axons.
      These neuropathic organophosphates leave a negatively charged group covalently
      attached to the active-site serine residue, and it is suggested that this may
      cause a toxic gain of function in NTE.

PMID- 10585849
TI  - Polyamine transport in bacteria and yeast.
AB  - The polyamine content of cells is regulated by biosynthesis, degradation and
      transport. In Escherichia coli, the genes for three different polyamine transport
      systems have been cloned and characterized. Two uptake systems (putrescine
      specific and spermidine-preferential) were ABC transporters, each consisting of a
      periplasmic substrate-binding protein, two transmembrane proteins and a membrane
      associated ATPase. The crystal structures of the substrate-binding proteins (PotD
      and PotF) have been solved. They consist of two domains with an alternating beta
      alpha-beta topology, similar to other periplasmic binding proteins. The polyamine
      binding site is in a cleft between the two domains, as determined by
      crystallography and site-directed mutagenesis. Polyamines are mainly recognized
      by aspartic acid and glutamic acid residues, which interact with the NH(2)- (or
      NH-) groups, and by tryptophan and tyrosine residues that have hydrophobic
      interactions with the methylene groups of polyamines. The precursor of one of the
      substrate binding proteins, PotD, negatively regulates transcription of the
      operon for the spermidine-preferential uptake system, thus providing another
      level of regulation of cellular polyamines. The third transport system, catalysed
      by PotE, mediates both uptake and excretion of putrescine. Uptake of putrescine
      is dependent on membrane potential, whereas excretion involves an exchange
      reaction between putrescine and ornithine. In Saccharomyces cerevisiae, the gene
      for a polyamine transport protein (TPO1) was identified. The properties of this
      protein are similar to those of PotE, and TPO1 is located on the vacuolar
      membrane.

PMID- 10585850
TI  - The in vitro manipulation of carbohydrate metabolism: a new strategy for
      deciphering the cellular defence mechanisms against nitric oxide attack.
AB  - This study was aimed at examining the effects of manipulating the carbohydrate
      source of the culture medium on the cellular sensitivity of epithelial cells to
      an oxidative attack. Our rationale was that substituting galactose for glucose in
      culture media would remove the protection afforded by glucose utilization in two
      major metabolic pathways, i.e. anaerobic glycolysis and/or the pentose phosphate
      pathway (PPP), which builds up cellular reducing power. Indeed, we show that the
      polarized human colonic epithelial cell line HT29-Cl.16E was sensitive to the
      deleterious effects of the NO donor PAPANONOate [3-(2-hydroxy-2-nitroso-1
      propylhydrazino)-1-propanamine] only in galactose-containing medium. In such
      medium NO attack led to cytotoxic and apoptotic cell death, associated with
      formation of derivatives of NO auto-oxidation (collectively termed NOx) and
      peroxynitrite, leading to intracellular GSH depletion and nitrotyrosine
      formation. The addition of 2-deoxyglucose, a non-glycolytic substrate, to
      galactose-fed cells protected HT29-Cl. 16E cells from NO attack and maintained
      control GSH levels through its metabolic utilization in the PPP, as shown by
      (14)CO(2) production from 2-deoxy[1-(14)C]glucose. Therefore, increasing the
      availability of reducing equivalents without interfering with energy metabolism
      is able to prevent NO-induced cell injury. Finally, this background provides the
      conceptual framework for establishing nutritional manipulation of cellular
      metabolic pathways that could provide new means for (i) deciphering the
      mechanisms of cell injury by reactive nitrogen species and reactive oxygen
      species at the whole-cell level and (ii) establishing the hierarchy of
      intracellular defence mechanisms against these attacks.

PMID- 10585851
TI  - Stimulation of pancreatic beta-cell proliferation by growth hormone is glucose
      dependent: signal transduction via janus kinase 2 (JAK2)/signal transducer and
      activator of transcription 5 (STAT5) with no crosstalk to insulin receptor
      substrate-mediated mitogenic signalling.
AB  - Mitogenic signal-transduction pathways have not been well defined in pancreatic
      beta-cells. In the glucose-sensitive rat beta-cell line, INS-1, glucose (6-18 mM)
      increased INS-1 cell proliferation (>20-fold at 15 mM glucose). Rat growth
      hormone (rGH) also induced INS-1 cell proliferation, but this was glucose
      dependent in the physiologically relevant concentration range (6-18 mM glucose).
      The combination of rGH (10 nM) and glucose (15 mM) was synergistic, maximally
      increasing INS-1 cell proliferation by >50-fold. Moreover, glucose-dependent rGH
      induced INS-1 cell proliferation was increased further by addition of insulin
      like growth factor 1 (IGF-1; 10 nM) to >90-fold at 12 mM glucose. Glucose
      metabolism and phosphatidylinositol-3'-kinase (PI3'K) activation were necessary
      for both glucose- and rGH-stimulated INS-1 cell proliferation. Glucose (>3 mM)
      independently increased tyrosine-phosphorylation-mediated recruitment of growth
      factor-bound protein 2 (Grb2)/murine sons of sevenless-1 protein (mSOS) and PI3'K
      to insulin receptor substrate (IRS)-1 and IRS-2, as well as SH2-containing
      protein (Shc) association with Grb2/mSOS and downstream activation of mitogen
      activated protein kinase and 70 kDa S6 kinase. Glucose-induced IRS- and Shc
      mediated signal transduction was enhanced further by the addition of IGF-1, but
      not rGH. In contrast, rGH was able to activate Janus kinase 2 (JAK2)/signal
      transducer and activator of transcription 5 (STAT5) signal transduction at
      glucose concentrations above 3 mM, but neither glucose independently, nor glucose
      with added IGF-1, were able to activate the JAK2/STAT5 signalling pathway. Thus
      rGH-mediated proliferation of beta-cells is directly via the JAK2/STAT5 pathway
      without engaging the Shc or IRS signal-transduction pathways, although activation
      of PI3'K may play an important permissive role in the glucose-dependent aspect of
      rGH-induced beta-cell mitogensis. The additive effect of rGH and IGF-1 on glucose
      dependent beta-cell proliferation is therefore reflective of rGH and IGF-1
      activating distinctly different mitogenic signalling pathways in beta-cells with
      minimal crosstalk between them.

PMID- 10585852
TI  - Protein specific N-glycosylation of tyrosinase and tyrosinase-related protein-1
      in B16 mouse melanoma cells.
AB  - Tyrosinase and tyrosinase-related protein-1 (TRP-1) are two melanogenic enzymes
      that regulate melanin biosynthesis. Both are glycoproteins and belong to the TRP
      1 gene family. They share a significant level of sequence similarity in several
      regions, including the catalytic domain and the potential N-glycosylation sites.
      We have recently shown that inhibition of the early steps of N-glycan processing
      in B16F1 cells dramatically affects tyrosinase activity and melanin synthesis. We
      present here results on N-glycan processing of TRP-1 and tyrosinase and compare
      the maturation process and activity of both glycoproteins in the presence of
      inhibitors of the endoplasmic reticulum stages of N-glycosylation. N-glycan
      analysis reveals that each of these two glycoproteins contains a mixture of high
      mannose and sialylated complex N-glycans. However, in contrast to TRP-1,
      tyrosinase presents a homogeneous high-mannose glycoform, also. In the presence
      of alpha-glucosidases inhibitors, the maturation of tyrosinase N-glycans is
      completely inhibited, whereas TRP-1 is still able to acquire some complex
      glycans, indicating that endomannosidase acts preferentially on the later
      glycoprotein. In addition, the dopa-oxidase activity of tyrosinase is totally
      abolished, whereas for TRP-1 it is only partially affected. The results suggest
      that despite their structural similarity, tyrosinase is more sensitive than TRP-1
      to perturbations of early N-glycan processing, in terms of maturation and
      catalytical activity.

PMID- 10585853
TI  - Gene structure of mouse BIT/SHPS-1.
AB  - BIT/SHPS-1/SIRPalpha/P84 is a unique molecule with a high degree of homology with
      immune antigen recognition molecules (immunoglobulin, T-cell receptor and MHC),
      and is highly expressed in the brain. The extracellular region contains three
      immunoglobulin-like domains (V-type, C1-type and C1-type), and the intracellular
      region contains two signalling motifs that interact with SHP-2 protein tyrosine
      phosphatase. BIT-coated plates support cell-substrate adhesion and neurite
      extension of neurons, and BIT participates in neuronal signal transduction.
      Diversity of the V-type domain sequences of human BIT has been reported. In the
      present study we analysed the structure of the mouse BIT gene (Bit). The protein
      coding region consists of eight exons corresponding to a signal peptide, a V-type
      domain, a C1-type domain, a C1-type domain, a transmembrane region and three
      parts of one cytoplasmic region. The two signalling motifs are encoded in one
      exon. Four splicing forms of mouse BIT were revealed. We also found the sequence
      diversity in three mouse strains, namely BALB/c, 129/Sv and C57BL/6. The
      substitution patterns of amino acids and nucleotides indicate positive pressure
      to alter the amino acids in the V-type domain in evolution. Immunoblot analyses
      showed that mouse BIT and human BITalpha are predominantly expressed in the
      brain. On the bases of these findings we discuss the possibility that BIT
      contributes to the genetic individuality and diversity of the brain.

PMID- 10585854
TI  - Characterization of a novel transcript of prostaglandin endoperoxide H synthase 1
      with a tissue-specific profile of expression.
AB  - The enzyme prostaglandin endoperoxide H synthase (PGHS) has a pivotal role in the
      prostanoid biosynthetic pathway because it catalyses the formation of
      prostaglandin H(2) (PGH(2)), the common precursor of prostanoids. Two PGHS
      isoforms have been reported, PGHS-1 and PGHS-2, which have 61% identity (at the
      amino acid level) and 73% similarity (at the nucleotide level) between the two
      human enzymes. Transcription of the PGHS-1 gene leads to the formation of two
      transcripts (2.8 and 5.1 kb); two transcripts of 2.8 and 4.5 kb are produced from
      the PGHS-2 gene. By Northern blot analysis with the entire coding region of human
      PGHS-1, 2.8 and 5.1 kb transcripts as well as a novel 4.5 kb transcript were
      detected in the human megakaryoblastic cell line MEG-01. We designed a strategy
      to characterize the 4.5 kb PGHS transcript. Probes specific for each PGHS-1 and
      PGHS-2 were designed on the basis of the 3' untranslated region (3' UTR), where
      no similarity is present. The 4.5 kb transcript was detected only with the PGHS-1
      specific 3' UTR probes and not with the PGHS-2-specific 3' UTR probe. To
      investigate the origin of the 4.5 kb PGHS-1 transcript, the remaining 947 bp of
      the 5.1 kb PGHS-1 transcript was generated by 3' rapid amplification of cDNA ends
      (3' RACE) and sequenced. A non-canonical polyadenylation signal (AAGAAA) located
      upstream of a potential cleavage site (CA) was found and could generate the 4.5
      kb PGHS-1 transcript. Analysis of the sequence also produced several possible G/U
      rich elements downstream of the potential cleavage site. An RNA dot-blot with 50
      different human tissues was probed with the 4.5 and 5.1 kb PGHS-1-specific
      probes. A signal for the 4.5 kb PGHS-1 transcript was detected in the bladder and
      appendix. Signals of lower intensity were detected in the colon, bone marrow,
      small intestine, uterus, prostate, peripheral leucocyte, lymph node and stomach.
      In conclusion, our results suggest that the cell line MEG-01, the bladder and the
      appendix contain a new PGHS-1 transcript of 4.5 kb that can be produced from the
      PGHS-1 gene and we provide a better strategy for distinguishing PGHS-1
      transcripts from PGHS-2.

PMID- 10585855
TI  - Topology studies with biosynthetic fragments identify interacting transmembrane
      regions of the human red-cell anion exchanger (band 3; AE1).
AB  - The red-cell anion exchanger (band 3; AE1) is a multispanning membrane protein
      that traverses the bilayer up to 14 times and is N-glycosylated at Asn-642. We
      have shown that the integrity of six different loops are not essential for
      stilbene disulphonate-sensitive chloride uptake in Xenopus oocytes. We used an N
      glycosylation mutagenesis approach to examine the orientation of the N-terminus
      and the endogenous glycosylation site of each C-terminal fragment by cell-free
      translation. The fragments initiating in the loops preceding spans 2, 9 and 11
      did not insert into the membrane with the expected orientation. Furthermore, N
      glycosylation of Asn-642 might facilitate the membrane integration of span 7. The
      correct integration of spans 2-3 required the presence of the region containing
      span 4 and that the luminal exposure of the C-terminus of span 7 is increased in
      the presence of the region including span 6 or span 8. The results suggest the
      span 8 region is required for the correct folding of spans 9-10, at least in the
      presence of the span 11-12 region. Our results suggest that there are
      intramolecular interactions between the regions of transmembrane spans 1 and 2, 2
      and 4, 4 and 5, 7 and 8, 8 and 9-10, and 9-10 and 11-12. Spans 1, 4, 5, 6 and 8
      might act as a scaffold for the assembly of spans 2-3, 7 and 9-10. This approach
      might provide a general method for dissecting the interactions between membrane
      spanning regions of polytopic membrane proteins.

PMID- 10585856
TI  - Structural model for the organization of the transmembrane spans of the human red
      cell anion exchanger (band 3; AE1).
AB  - We have examined the functional co-assembly of non-complementary pairs of N- and
      C-terminal polypeptide fragments of the anion transport domain (b3mem) of human
      red-cell band 3. cDNA clones encoding non-contiguous pairs of fragments with one
      transmembrane (TM) region omitted, or overlapping pairs of fragments with between
      one and ten TM regions duplicated, were co-expressed in Xenopus oocytes and a
      cell-free translation system. Stilbene disulphonate-sensitive chloride uptake
      assays in oocytes revealed that the omission of any single TM region of b3mem
      except spans 6 and 7 caused a complete loss of functional expression. In
      contrast, co-expressed pairs of fragments overlapping a single TM region 5, 6, 7,
      8, 9-10 or 11-12 retained a high level of functionality, whereas fragments
      overlapping the clusters of TM regions 2-5, 4-5, 5-8 and 8-10 also mediated some
      stilbene disulphonate-sensitive uptake. The co-assembly of N- or C-terminal
      fragments with intact band 3, b3mem or other fragments was examined by co
      immunoprecipitation in non-denaturing detergent solutions by using monoclonal
      antibodies against the termini of b3mem. All the fragments, except for TM spans
      13-14, co-immunoprecipitated with b3mem. The medium-sized N-terminal fragments
      comprising spans 1-6, 1-7 or 1-8 co-immunoprecipitated particularly strongly with
      the C-terminal fragments containing spans 8-14 or 9-14. The fragments comprising
      spans 1-4 or 1-12 co-immunoprecipitated less extensively than the other N
      terminal fragments with either b3mem or C-terminal fragments. There is sufficient
      flexibility in the structure of b3mem to allow the inclusion of at least one
      duplicated TM span without a loss of function. We propose a working model for the
      organization of TM spans of dimeric band 3 based on current evidence.

PMID- 10585857
TI  - Identification of betacellulin as a major peptide growth factor in milk:
      purification, characterization and molecular cloning of bovine betacellulin.
AB  - Betacellulin (BTC), a member of the epidermal growth factor (EGF) family of
      peptide growth factors, was purified from a growth-factor-enriched whey fraction
      of bovine milk by a combination of ion-exchange chromatography, gel-filtration
      chromatography, affinity chromatography and reverse-phase HPLC. Bovine BTC (bBTC)
      had an apparent molecular mass of 21-22 kDa on SDS/PAGE and exists in a
      glycosylated form. The cDNA encoding bBTC was obtained by a combination of 5' and
      3' rapid amplification of cDNA ends ('RACE'). The primary translation product
      consists of 178 amino acid residues containing a putative signal sequence, a
      transmembrane domain, the mature BTC domain and a cytoplasmic domain containing a
      highly hydrophilic Arg-Lys-rich region similar to that of mouse BTC and human
      BTC. The amino acid sequence of the bBTC precursor was 88% identical with human
      BTC and 79% identical with mouse BTC. The bBTC gene was found to be expressed in
      a wide range of tissues, including the mammary gland. The identification of BTC
      in milk raises the possibility that it has a major role in the growth and
      development of the neonatal gastrointestinal tract.

PMID- 10585859
TI  - Biosynthesis of glycosylphosphatidylinositols of Plasmodium falciparum in a cell
      free incubation system: inositol acylation is needed for mannosylation of
      glycosylphosphatidylinositols.
AB  - The structures of glycosylphosphatidylinositols (GPIs) in Plasmodium have been
      described [Gerold, Schuppert and Schwarz (1994) J. Biol. Chem. 269, 2597-2606]. A
      detailed understanding of GPI synthesis in Plasmodium is a prerequisite for
      identifying differences present in biosynthetic pathways of parasites and host
      cells. A comparison of the biosynthetic pathway of GPIs has revealed differences
      between mammalian cells and parasitic protozoans. A cell-free incubation system
      prepared from asexual erythrocytic stages of Plasmodium falciparum, the causative
      agent of malaria in humans, is capable of synthesizing the same spectrum of GPIs
      as that found in metabolically labelled parasites. The formation of mannosylated
      GPIs in the cell-free system is shown to be inhibited by GTP and, unexpectedly,
      micromolar concentrations of GDP-Man. Lower concentrations of GDP-Man affect the
      spectrum of GPIs synthesized. The inositol ring of GPIs of P. falciparum is
      modified by an acyl group. The preferred donor of this fatty acid at the inositol
      ring is myristoyl-CoA. Inositol acylation has to precede the mannosylation of
      GPIs because, in the absence of acyl-CoA or CoA, mannosylated GPIs were not
      detected. Inositol myristoylation is a unique feature of plasmodial GPIs and thus
      might provide a potential target for drug therapy.

PMID- 10585858
TI  - Purification and characterization of heparan sulphate proteoglycan from bovine
      brain.
AB  - A heparan sulphate proteoglycan was purified from adult bovine brain tissues and
      its structure was characterized. The major heparan sulphate proteoglycan from
      whole bovine brain had a molecular mass of >200 kDa on denaturing SDS/PAGE and a
      core protein size of 66 kDa following the removal of glycosaminoglycan chains.
      Fractionation on DEAE-Sephacel showed that this proteoglycan consisted of three
      major forms having high, intermediate and low overall charge. All core proteins
      were identical in size and reacted with heparan sulphate proteoglycan-stub
      antibody and an antibody made to a synthetic peptide based on rat glypican. The
      three forms of proteoglycans had identical peptide maps and their amino acid
      compositional analysis did not match any of the known glypicans. The internal
      sequence of a major peptide showed only 37.5% sequence similarity with human
      glypican 5. The glycosaminoglycan chain sizes of the three forms of this
      proteoglycan, determined after beta-elimination by PAGE, were identical. The
      disaccharide compositional analysis on the heparan sulphate chains from the three
      forms of the proteoglycan, determined by treatment with a mixture of heparin
      lyases followed by high-resolution capillary electrophoresis, showed that they
      differed primarily by degree of sulphation. The most highly sulphated
      proteoglycan isolated had a disaccharide composition similar to heparan sulphate
      glycosaminoglycans found in brain tissue. Based on their sensitivity to low pH
      nitrous acid treatment, the N-sulphate groups in these proteoglycans were found
      to be primarily in the smaller glycosaminoglycan chains. The heparan sulphate
      proteoglycans were also heavily glycosylated with O-linked glycans and no
      glycosylphosphatidylinositol anchor could be detected.

PMID- 10585860
TI  - Biochemical and spectroscopic characterization of Escherichia coli aconitases
      (AcnA and AcnB).
AB  - Escherichia coli contains two major aconitases (Acns), AcnA and AcnB. They are
      distantly related monomeric Fe-S proteins that contain different arrangements of
      four structural domains. On the basis of the differential expression of the acnA
      and acnB genes, AcnA has been designated as an aerobic-stationary-phase enzyme
      that is specifically induced by iron and oxidative stress, whereas AcnB functions
      as the major citric-acid-cycle enzyme during exponential growth. The biochemical
      and kinetic properties of the purified enzymes have now shown that AcnA is more
      stable than AcnB, has a higher affinity for citrate, and operates optimally over
      a wider pH range, consistent with its role as a maintenance or survival enzyme
      during nutritional or oxidative stress. In contrast, the better performance at
      high substrate concentrations and greater instability of AcnB indicate that AcnB
      is specifically adapted to function as the main catabolic enzyme and, by
      inactivation, to rapidly modulate energy metabolism in response to oxidative or
      pH stress, either directly or indirectly by regulating post-transcriptional gene
      expression. EPR and magnetic-CD spectroscopy showed that the iron-sulphur
      clusters of the bacterial Acns (and their binding sites) strongly resemble those
      of the mammalian enzymes. The EPR and MCD spectra of the oxidized inactive form
      of AcnB confirmed the presence of a [3Fe-4S](1+) (S=1/2) cluster. Comparisons
      showed that the EPR spectrum of AcnB more closely resembled that of mammalian
      mitochondrial Acn (m-Acn), whereas the spectrum of AcnA more closely resembled
      that of the cytoplasmic enzyme (c-Acn). The MCD spectra revealed spectroscopic
      signatures similar to that of m-Acn. Reconstitution of the active [4Fe-4S](2+)
      forms followed by one-electron reduction gave rise to EPR spectra that are almost
      identical with those reported for the mammalian enzymes.

PMID- 10585861
TI  - Synthesis of 8-epi-prostaglandin F2alpha by human endothelial cells: role of
      prostaglandin H2 synthase.
AB  - The experiments described in this paper were designed to determine the mechanism
      underlying the increase in 8-isoprostaglandin F(2alpha) (8-epi-PGF(2alpha))
      production by cultured human endothelial cells during reoxygenation following
      hypoxia. Human umbilical artery endothelial cells were grown on microcarrier
      beads and exposed to sequential periods of normoxia, hypoxia, and reoxygenation.
      The amount of 8-epi-PGF(2alpha) in the medium was determined by ELISA. The
      production of 8-epi-PGF(2alpha) decreased by greater than 90% during hypoxia.
      Upon reoxygenation 8-epi-PGF(2alpha) production increased linearly for 90 min
      reaching nearly 3 times normoxic levels. When added to the medium during
      reoxygenation, neither superoxide dismutase nor Tiron, a cell-permeable
      superoxide scavenger, inhibited 8-epi-PGF(2alpha) production. However, 8-epi
      PGF(2alpha) production was inhibited by catalase. The production of 8-epi
      PGF(2alpha) was also inhibited by indomethacin and aspirin. Exogenous hydrogen
      peroxide stimulated 8-epi-PGF(2alpha) production by normoxic cells, and aspirin
      inhibited the hydrogen peroxide-mediated increase in 8-epi-PGF(2alpha)
      production. These results indicate that the reactive oxygen species responsible
      for 8-epi-PGF(2alpha) synthesis during reoxygenation is hydrogen peroxide and
      that in endothelial cells 8-epi-PGF(2alpha) synthesis is mediated by
      prostaglandin H(2) synthase (PGHS). To verify the role of PGHS in 8-epi
      PGF(2alpha) synthesis, human PGHS-1 was expressed in COS-7 cells, a PGHS negative
      cell line that does not synthesize 8-epi-PGF(2alpha). In the presence of
      exogenous arachidonic acid the COS-7 cells expressing human PGHS-1 produced
      substantial amounts of PGE(2) and 8-epi-PGF(2alpha). These data indicate that
      human PGHS-1 can support the synthesis of 8-epi-PGF(2alpha) and that 8-epi
      PGF(2alpha) synthesis by cultured human endothelial cells during reoxygenation is
      dependent on the activity of PGHS-1.

PMID- 10585863
TI  - Models for enzyme superactivity in aqueous solutions of surfactants.
AB  - Theoretical models are developed here for enzymic activity in the presence of
      direct micellar aggregates. An approach similar to that of Bru et al. [Bru,
      Sanchez-Ferrer and Garcia-Carmona (1989) Biochem. J. 259, 355-361] for reverse
      micelles has been adopted. The system is considered to consist of three pseudo
      phases: free water, bound water and surfactant tails. The substrate concentration
      in each pseudo-phase is related to the total substrate concentration in the
      reaction medium. In the absence of interactions between the enzyme and the
      micelles, the model predicts either monotonically increasing or monotonically
      decreasing trends in the calculated reaction rate as a function of surfactant
      concentration. With enzyme-micelle interactions included in the formulation (by
      introducing an equilibrium relation between the enzyme confined in the free water
      and in the bound water pseudo-phases, and by allowing for different catalytic
      behaviours for the two forms), the calculated reaction rate can exhibit a bell
      shaped dependence on surfactant concentration. The effect of the partition of
      enzyme and substrate is described, as is that of enzyme efficiency in the various
      pseudo-phases.

PMID- 10585862
TI  - Functional analysis of the promoter region of the human phosphotyrosine
      phosphatase activator gene: Yin Yang 1 is essential for core promoter activity.
AB  - The phosphotyrosine phosphatase activator (PTPA) has been isolated as an in vitro
      regulator of protein phosphatase 2A. Human PTPA is encoded by a single gene, the
      structure and chromosomal localization of which have been determined in our
      previous work. Here we describe the further isolation, sequencing and functional
      characterization of the PTPA promoter region. In agreement with its ubiquitous
      expression, the PTPA promoter displays several characteristics of housekeeping
      genes: it lacks both a TATA-box and a CAAT-box, it is very GC-rich and it
      contains an unmethylated CpG island surrounding the transcription initiation
      site. Transient transfection experiments in different cell types with several
      truncated chimaeric luciferase reporter gene plasmids revealed the importance of
      the region between positions -67 and -39 for basal promoter activity. This region
      coincides remarkably well with the determined CpG island. Further analysis of
      this region demonstrated the presence of a Yin Yang 1 (YY1) binding motif at
      positions -52 to -44. Binding of YY1 to this sequence is demonstrated in
      bandshift and DNase I footprinting experiments. Another YY1 binding motif is
      found in the 5' untranslated region, at positions +27 to +35. Mutations in either
      of these sites, abolishing YY1 binding in vitro, have differential effects on
      promoter activity. Point mutations in both sites completely abolish promoter
      activity. Moreover, induction of promoter activity by co-transfection with a YY1
      expression plasmid is fully dependent upon the presence of both intact YY1
      binding sites. Thus YY1 apparently mediates basal transcription of the human PTPA
      gene through two binding sites within its proximal promoter.

PMID- 10585864
TI  - Proteophosphoglycans of Leishmania mexicana. Identification, purification,
      structural and ultrastructural characterization of the secreted promastigote
      proteophosphoglycan pPPG2, a stage-specific glycoisoform of amastigote aPPG.
AB  - Protozoan parasites of the genus Leishmania secrete a range of
      proteophosphoglycans that appear to be important for successful colonization of
      the sandfly and for virulence in the mammalian host. A hallmark of these
      molecules is extensive phosphoglycosylation by phosphoglycan chains via the
      unusual linkage Manalpha1-PO(4)-Ser. In this study we have identified and
      purified to apparent homogeneity a novel proteophosphoglycan (pPPG2) which is
      secreted by Leishmania mexicana promastigotes (sandfly stage). Amino acid
      analysis and immunoblots using polypeptide-specific antisera suggest that pPPG2
      shares a common protein backbone with a proteophosphoglycan (aPPG) secreted by
      Leishmania mexicana amastigotes (mammalian stage). Both pPPG2 and aPPG show a
      similar degree of Ser phosphoglycosylation (50. 5 mol% vs. 44.6 mol%), but the
      structure of their phosphoglycan chains is developmentally regulated: in contrast
      to aPPG which displays unique, complex and highly branched glycan chains [Ilg,
      Craik, Currie, Multhaup, and Bacic (1998) J. Biol. Chem. 273, 13509-13523], pPPG2
      contains short unbranched structures consisting of >60 mol% neutral glycans, most
      likely (Manalpha1-2)(0-5)Man and Galbeta1-4Man, as well as about 40 mol%
      monophosphorylated glycans of the proposed structures PO(4)-6Galbeta1-4Man and
      PO(4)-6(Glcbeta1-3)Galbeta1-4Man. The major differences between pPPG2 and aPPG
      with respect to their apparent molecular mass, their ultrastructure and their
      proteinase sensitivity are most likely a consequence of this stage-specific
      glycosylation of their common protein backbone.

PMID- 10585865
TI  - Proteophosphoglycans of Leishmania mexicana. Molecular cloning and
      characterization of the Leishmania mexicana ppg2 gene encoding the
      proteophosphoglycans aPPG and pPPG2 that are secreted by amastigotes and
      promastigotes.
AB  - Intracellular amastigotes of the pathogenic protozoon Leishmania mexicana secrete
      an extensively phosphoglycosylated proteophosphoglycan (aPPG) into the
      phagolysosome of mammalian host macrophages, that appears to fulfil important
      functions for the parasites. Promastigotes (the sandfly vector forms) of the same
      species secrete a proteophosphoglycan with identical protein backbone but
      exhibiting stage-specific phosphoglycosylation patterns [Klein, Gopfert,
      Goehring, Stierhof and Ilg (1999) Biochem. J. 344, 775-786]. In this study we
      report the cloning of the novel repeat-containing proteophosphoglycan gene ppg2
      by antibody screening of a Leishmania mexicana amastigote cDNA expression
      library. ppg2 is equally expressed in promastigotes and amastigotes at the mRNA
      level. Targeted gene replacement of both alleles of the single copy gene ppg2
      results in the loss of pPPG2 expression in promastigotes. Antisera against
      Escherichia coli-expressed ppg2 recognize the deglycosylated forms of aPPG as
      well as pPPG2. These results confirm that ppg2 encodes the protein backbones of
      aPPG and pPPG2. An unusual finding is that ppg2 exhibits two stable allelic
      forms, ppg2a and ppg2b. Their main difference lies in the number of central 72 bp
      DNA repeats (7 versus 8). ppg2a and ppg2b encode polypeptide chains of 574 and
      598 amino acids, respectively, that show no homology to known proteins. The novel
      24 amino acid Ser-rich peptide repeats encoded by the 72 bp DNA repeats are
      targets for Ser phosphoglycosylation in Leishmania mexicana.

PMID- 10585866
TI  - Interferon-gamma-dependent stimulation of human involucrin gene expression: STAT1
      (signal transduction and activators of transcription 1) protein activates
      involucrin promoter activity.
AB  - Involucrin is one of the precursor proteins of the cornified cell envelope of
      keratinocytes, and is expressed during the later stages of keratinocyte
      differentiation. Interferon-gamma (IFN-gamma), a pleiotropic cytokine with anti
      proliferative and immunomodulatory activities, is also a potent inducer of
      squamous differentiation. Using cultured normal human keratinocytes (NHK cells)
      and simian virus 40-transformed human keratinocytes (SVHK cells), we investigated
      the effects of IFN-gamma on involucrin gene expression. Expression of involucrin
      was increased by about 3-fold after treating NHK cells with IFN-gamma (100
      units/ml). Northern blot analyses revealed that IFN-gamma increased the
      expression of involucrin mRNA. The fragment +42 to -2463 in the 5'-flanking
      region of the human involucrin gene was subcloned into a luciferase reporter
      vector and the construct (p2463Luc) was transfected into SVHK cells. p2463Luc
      produced a 3-fold increase in luciferase activity after IFN-gamma treatment.
      Sequence analysis detected two putative IFN-gamma-responsive regions [G1
      (positions -883 to -874) and G2 (-784 to -775)]. Deletion analyses of the
      p2463Luc vector revealed that the G1 region is critical for the IFN-gamma
      dependent up-regulation of the involucrin gene. Gel-shift analyses revealed that
      STAT1 (signal transduction and activators of transcription 1) protein bound to
      the G1 region and that involucrin promoter activity was augmented by transfection
      of a STAT1 expression vector in the presence of IFN-gamma. In contrast,
      transfection of a STAT1 dominant-negative expression vector suppressed the IFN
      gamma-dependent up-regulation of involucrin promoter activity. These results
      indicate that IFN-gamma stimulates expression of the human involucrin gene via
      the G1 (-883 to -874) region of the involucrin gene promoter.

PMID- 10585867
TI  - Immunosuppressants FK506 and rapamycin have different effects on the biosynthesis
      of cytoplasmic actin during the early period of T cell activation.
AB  - FK506 and rapamycin are immunosuppressants that interfere with T cell activation.
      FK506 inhibits early events of T cell activation such as the induction of
      cytokine transcription, whereas rapamycin inhibits later interleukin 2 signalling
      events. However, both reagents either directly or indirectly reduce protein
      synthesis. Therefore a kinetic study was conducted in human primary T lymphocytes
      examining increased synthesis of proteins stimulated by either ionomycin+phorbol
      myristate acetate (PMA) or PMA alone. Three patterns of protein expression were
      observed. Synthesis of one group of proteins had enhanced synthesis with FK506,
      but reduced synthesis with rapamycin. A second group had reduced synthesis with
      rapamycin and either no change or a slight reduction with FK506 and a third group
      had reduction with both FK506 and rapamycin. One major protein of the first
      group, p42, had a rapid increase in synthesis that decreased by 8 h. Its
      synthesis was strongly enhanced by FK506, but reduced by rapamycin after
      ionomycin+PMA stimulation. In contrast, this protein was strongly induced by PMA
      alone in these cells and not affected by FK506 treatment, but still reduced by
      rapamycin. p42 was identified as cytoplasmic actin. mRNA levels of both gamma-
      and beta-actin were found to be enhanced with FK506 treatment suggesting that
      regulation of actin was at a transcriptional or post-transcriptional level.
      Results with actinomycin D indicated that FK506 is regulating actin biosynthesis
      at the post-transcriptional level. Rapamycin, however, appeared to be operating
      at the level of translation.

PMID- 10585868
TI  - Insulin stimulates pancreatic-duodenal homoeobox factor-1 (PDX1) DNA-binding
      activity and insulin promoter activity in pancreatic beta cells.
AB  - Pancreatic-duodenal homoeobox factor-1 (PDX1) is a homoeodomain transcription
      factor that plays an important role in linking glucose metabolism in pancreatic
      beta cells to the regulation of insulin gene transcription. Our previous results
      indicated that glucose activates PDX1 DNA-binding activity and insulin promoter
      activity via a stress-activated signalling pathway involving phosphatidylinositol
      3-kinase (PtdIns 3-kinase) and stress-activated protein kinase 2 (SAPK2/p38). The
      present study was undertaken to determine the effects of other metabolizable and
      non-metabolizable nutrients. The results indicate that non-metabolizable
      nutrients, with the exception of 2-deoxyglucose, had no effect. Metabolizable
      nutrients that could stimulate calcium uptake and insulin release were shown to
      activate both PDX1 and the insulin promoter. The possible role of insulin acting
      via an autoregulatory loop was therefore examined. Insulin was shown to potently
      activate PDX1 DNA-binding activity and insulin promoter activity. The effects of
      insulin were inhibited by the PtdIns 3-kinase inhibitors wortmannin and LY294002
      and by the SAPK2 inhibitor SB203580, suggesting that its effects were mediated
      via activation of PtdIns 3-kinase and SAPK2. Further support for the insulin
      mediated activation of SAPK2 came from the observation that both glucose and
      insulin stimulated the phosphorylation of SAPK2. These results suggest that both
      glucose and insulin stimulate PDX1 DNA-binding activity and insulin promoter
      activity via a pathway involving PtdIns 3-kinase and SAPK2.

PMID- 10585869
TI  - Molecular cloning and characterization of a novel dual-specificity protein
      phosphatase possibly involved in spermatogenesis.
AB  - Dual-specificity protein phosphatases (DSPs) play roles in the regulation of
      mitogenic signal transduction for extracellular stimulation and the cell cycle.
      In the present study, we identified a novel DSP, termed TMDP (testis- and
      skeletal-muscle-specific DSP). Nucleotide sequence analysis of TMDP cDNA
      indicated that the open reading frame of 597 bp encodes a protein of 198 amino
      acid residues with a predicted molecular mass of 22.5 kDa. The deduced amino acid
      sequence contains a motif for a conserved catalytic domain of DSPs and shows
      highest similarity to human Vaccinia HI-related phosphatase (45.5% identity) but
      low homology to the mitogen-activated protein kinase phosphatase and CDC25
      subfamilies of DSPs. Recombinant TMDP protein exhibited intrinsic phosphatase
      activity towards both phospho-seryl/threonyl and -tyrosyl residues of myelin
      basic protein, with similar specific activities in vitro. Northern-blot analysis
      revealed that TMDP is most abundantly expressed in the testis. The expression in
      the testis is characterized as follows: (i) TMDP mRNA first appeared 3 weeks
      after birth, corresponding to the time that meiosis begins; (ii) TMDP mRNA was
      abundant in fractionated spermatocytes and round spermatids; and (iii)
      hybridization in situ showed that the TMDP mRNA is localized in spermatocytes
      and/or spermatids in seminiferous tubules. These data demonstrate that TMDP is a
      novel DSP abundantly expressed in the testis and suggest that TMDP may be
      involved in the regulation of meiosis and/or differentiation of testicular germ
      cells during spermatogenesis.

PMID- 10585870
TI  - Decorin endocytosis: structural features of heparin and heparan sulphate
      oligosaccharides interfering with receptor binding and endocytosis.
AB  - Receptor-mediated endocytosis of decorin depends on its core-protein-mediated
      interaction with a 51 kDa membrane protein, which, in addition to its core
      protein-binding site, carries a binding site for glycosaminoglycan chains.
      Membrane-associated heparan sulphate as well as heparin are known to have an
      inhibitory effect on decorin endocytosis by cultured skin fibroblasts. In this
      study, structural features of both glycosaminoglycans required for binding to the
      51 kDa protein and for inhibiting decorin endocytosis, were investigated. Upon
      digestion of [(3)H]glucosamine-labelled heparan sulphate with heparinase III,
      dodeca- and higher saccharides were able to interact with the receptor protein.
      In comparison with unbound fragments of the same size, bound fragments were
      enriched in N-sulphated disaccharides carrying one or two sulphate ester groups.
      Using heparinase III-generated fragments from [(35)S]sulphate-labelled heparan
      sulphate chains, binding of fragments as small as octasaccharides could be
      detected. Competition experiments between dermatan sulphate and chemically
      modified heparin revealed that N- and 6-O-sulphation of glucosamine residues are
      important structural elements for binding to the receptor, whereas iduronate-2-O
      sulphate groups contribute to binding only to a limited extent. However, with
      respect to the inhibition of decorin endocytosis, 2-O-desulphation had a
      quantitatively similar effect to 6-O-desulphation. Furthermore, for maximal
      inhibition of decorin endocytosis, longer fragments were required than for
      binding to the receptor. Thus, it appears that heparin/heparan sulphate has to
      interact with additional component(s) for effective inhibition of decorin uptake.

PMID- 10585872
TI  - Identification of an anti-mycobacterial domain in NK-lysin and granulysin.
AB  - NK-lysin and granulysin are homologous cationic anti-bacterial peptides produced
      by pig and human cytolytic lymphocytes, respectively. The solution structure of
      NK-lysin comprises five amphipathic alpha-helices. To investigate the properties
      of a helix-loop-helix region postulated to be a membrane-docking part of NK
      lysin, we synthesized 22- and 29-residue peptides reproducing this region for
      both NK-lysin and granulysin. CD spectroscopy of the synthetic peptides in a
      liposomal solution showed spectra typical of alpha-helical peptides. The peptides
      were active against Gram-positive and Gram-negative bacteria, with the two NK
      lysin peptides showing higher anti-bacterial activities than the two from
      granulysin. One NK-lysin peptide was active against Pseudomonas aeruginosa and
      Staphylococcus aureus, two organisms against which NK-lysin is inactive.
      Granulysin peptides were inactive against these bacteria, in contrast with
      granulysin, which is known to be active against them. Both NK-lysin and all
      synthetic analogues killed Mycobacterium tuberculosis and K562 tumour cells, but
      did not display haemolytic activity. These results identify a potent anti
      mycobacterial domain in NK-lysin and granulysin consisting of a 22-residue (helix
      3) sequence plus a disulphide-constrained loop.

PMID- 10585871
TI  - Glyoxalase I is a novel nitric-oxide-responsive protein.
AB  - To clarify the molecular mechanisms of nitric oxide (NO) signalling, we examined
      the NO-responsive proteins in cultured human endothelial cells by two-dimensional
      (2D) PAGE. Levels of two proteins [NO-responsive proteins (NORPs)] with different
      pI values responded to NO donors. One NORP (pI 5.2) appeared in response to NO,
      whereas another (pI 5.0) disappeared. These proteins were identified as a native
      form and a modified form of human glyoxalase I (Glox I; EC 4. 4.1.5) by peptide
      mapping, microsequencing and correlation between the activity and the isoelectric
      shift. Glox I lost activity in response to NO, and all NO donors tested inhibited
      its activity in a dose-dependent manner. Activity and normal electrophoretic
      mobility were restored by dithiothreitol and by the removal of sources of NO from
      the culture medium. Glox I was selectively inactivated by NO; compounds that
      induce oxidative stress (H(2)O(2), paraquat and arsenite) failed to inhibit this
      enzyme. Our results suggest that NO oxidatively modifies Glox I and reversibly
      inhibits the enzyme's activity. The inactivation of Glox I by NO was more
      effective than that of glyceraldehyde-3-phosphate dehydrogenase (G3PDH), another
      NO-sensitive enzyme. Thus Glox I seems to be a novel NO-responsive protein that
      is more sensitive to NO than G3PDH.

PMID- 10585873
TI  - cDNA cloning, bacterial expression, in vitro renaturation and affinity
      purification of the zinc endopeptidase astacin.
AB  - Astacin (EC 3.4.24.21) from the freshwater crayfish (Astacus astacus) is a
      prototype for the metzincin superfamily and for the astacin family of zinc
      peptidases, enzymes which are involved in hatching processes, embryonic
      patterning and tissue remodelling. Here we report on the cloning and
      overexpression in Escherichia coli of an astacin cDNA which was reverse
      transcribed from crayfish midgut-gland mRNA. A cDNA construct based on this clone
      was generated which comprised the nucleotide sequence encoding mature astacin
      devoid of the signal and propeptide. This construct was cloned into the pET3a
      vector and used to transform E. coli BL21(DE3) cells. Recombinant astacin was
      purified from inclusion bodies and dissolved under reducing conditions. For
      folding, the protein was diluted into neutral buffer containing l-arginine, GSH
      and EDTA. Eventually, Zn(2+) was added by dialysis and the fraction of active
      enzyme was affinity-purified on immobilized Pro-Leu-Gly hydroxamate. As shown by
      superimposition of the corresponding three-dimensional structures, this inhibitor
      binds to a region of the active-site cleft that is conserved in most metzincins.
      Therefore this principle behind this affinity technique, originally introduced
      for fibroblast collagenase by Moore and Spilburg [Biochemistry (1986) 25, 5189
      5195], is applicable throughout the metzincin superfamily of metalloproteases,
      despite their otherwise differing cleavage specificities. Recombinant astacin is
      active on gelatine zymograms and in a quenched fluorescence assay, yielding
      kinetic parameters comparable with those of wild-type astacin purified from
      crayfish stomach.

PMID- 10585874
TI  - Direct interaction between p47phox and protein kinase C: evidence for targeting
      of protein kinase C by p47phox in neutrophils.
AB  - p47(phox) is an essential component of the NADPH oxidase, and phosphorylation of
      p47(phox) is associated with activation of the enzyme. Here we have used
      p47(phox) affinity chromatography to extract a p47(phox) kinase from neutrophil
      cytosol. The kinase activity was purified by gel filtration and Mini Q
      chromatography and shown to be indistinguishable from the catalytic fragments of
      protein kinase C (PKC)-beta(I), -beta(II) and -delta. The C-terminus of p47(phox)
      represented the site of interaction with PKC. Co-immunoprecipitation experiments
      revealed that the interaction between PKC isotypes and p47(phox) takes place in
      intact cells. However PKC-beta and -delta showed different time courses of co
      immunoprecipitation, suggesting that the interactions may serve different
      functions for the various PKC isotypes. Using cells lacking p47(phox), we
      investigated the functional relevance of the interaction between PKC and
      p47(phox). Subcellular fractionation revealed an abnormal recruitment of PKC
      beta(I) and -beta(II), but not PKC-delta, to particulate fractions in p47(phox)
      deficient cells. Phosphorylation of cytosolic proteins was generally increased in
      stimulated p47(phox)-deficient neutrophils as compared with normal neutrophils.
      Furthermore, the cytoskeletal protein coronin was not phosphorylated upon
      stimulation of p47(phox)-deficient neutrophils. These findings were confirmed in
      an in vitro-reconstituted system using rat brain cytosol in which addition of
      p47(phox) affected phosphorylation by PKC/PKM (PKM is the catalytic fragment of
      PKC). These results indicate that p47(phox) can act as a regulator of PKC in
      neutrophils.

PMID- 10585875
TI  - Transcription from the P2 promoter of the growth hormone receptor gene involves
      members of the Sp transcription factor family.
AB  - The P2 promoter of the gene for growth hormone receptor is developmentally
      regulated and is differentially active in a number of tissues. Little is known
      about the identity of the transcription factors that participate to effect this
      pattern of transcription. Deletion analysis and transient transfection were used
      to localize a previously identified cis-acting element within the sheep P2
      promoter to between positions -99 and -87. Gel mobility-shift assays with nuclear
      extracts from Chinese hamster ovary (CHO-K1) fibroblasts revealed that this
      sequence encompasses an atypical binding site for both Sp1 and two isoforms of
      Sp3. A gel mobility-shift scan of promoter sequences between -88 and +21
      indicated the existence of three other binding sites for Sp1 and Sp3. One of
      these, designated site II and found by using a probe spanning -74 to -54,
      corresponds to a classical GC box consensus sequence. Site III (-63 to -41) and
      site IV (-27 to -5) harbour atypical Sp1/Sp3-binding sequences. Site-directed
      mutagenesis of site II or site IV decreased promoter activity by approx. 40%,
      whereas a promoter construct incorporating both mutations exhibited negligible
      (approx. 1%) activity. Co-transfection of expression plasmids encoding either Sp1
      or Sp3 significantly transactivated reporter gene activity from a P2 promoter
      construct carrying all four Sp1/Sp3-binding sites (8-fold compared with 7.1-fold
      induction respectively). Sp1 is known to interact with a variety of other
      transcription factors to regulate the transcription of a number of differentially
      expressed genes. The identification of four binding sites for Sp1 and Sp3 within
      the P2 promoter of the gene for growth hormone receptor might point to other
      factors that interact to regulate the activity of this promoter in different
      tissues during foetal and post-natal development.

PMID- 10585876
TI  - Functional antagonism between inhibitor of DNA binding (Id) and adipocyte
      determination and differentiation factor 1/sterol regulatory element-binding
      protein-1c (ADD1/SREBP-1c) trans-factors for the regulation of fatty acid
      synthase promoter in adipocytes.
AB  - We show that Id (inhibitor of DNA binding) 2 and Id3, dominant negative members
      of the helix-loop-helix (HLH) family, interact with the adipocyte determination
      and differentiation factor 1 (ADD1)/sterol regulatory element-binding protein
      (SREBP) 1c, a transcription factor of the basic HLH-leucine zipper family that
      controls the expression of several key genes of adipose metabolism. Gel mobility
      shift assays performed with in vitro-translated ADD1, Id2 or Id3 proteins and a
      fatty acid synthase (FAS) promoter oligonucleotide showed evidence for a marked
      inhibition of the formation of DNA-ADD1 complexes by Id2 or Id3 proteins. Co
      immunoprecipitation studies using in vitro-translated proteins demonstrated
      further the physical interaction of Id and ADD1/SREBP-1c proteins in the absence
      of DNA. Using the FAS gene as a model of an ADD1-regulated promoter in
      transiently transfected isolated rat adipocytes or mature 3T3-L1 adipocytes, a
      potent inhibition of the activity of the FAS-chloramphenicol acetyltransferase
      reporter gene was observed by overexpression of Id2 or Id3. Reciprocally, co
      transfection of Id3 antisense and ADD1 expression vectors in preadipocytes
      potentiated the ADD1/SREBP-1c effect on the FAS promoter activity. Finally, in
      the non adipogenic NIH-3T3 cell line, most of the ADD1-mediated trans-activation
      of the FAS promoter was counteracted by co-transfection of Id2 or Id3 expression
      vectors. Previous studies have indicated Id gene expression to be down-regulated
      during adipogenesis [Moldes, Lasnier, Feve, Pairault and Djian (1997) Mol. Cell.
      Biol. 17, 1796-1804]. We here demonstrated that there was a dramatic rise of Id2
      and Id3 mRNA levels when 3T3-L1 adipocytes or isolated rat fat cells were exposed
      to lipolytic and anti-lipogenic agents, forskolin and isoproterenol. Taken
      together, our data show that Id products are functionally involved in modulating
      ADD1/SREBP-1c transcriptional activity, and thus lipogenesis in adipocytes.

PMID- 10585877
TI  - [13C]Methionine NMR and metal-binding studies of recombinant human transferrin N
      lobe and five methionine mutants: conformational changes and increased
      sensitivity to chloride.
AB  - The N-lobe of human serum transferrin (hTF/2N) and single point mutants in which
      each of the five methionine residues was individually mutated have been produced
      in a mammalian tissue-culture expression system. Since the five methionine
      residues are well distributed in the transferrin N-lobe, (13)C NMR of the
      [epsilon-(13)C]methionine-labelled proteins has been used to monitor
      conformational changes of the protein during metal binding. All five methionine
      residues have been assigned [Beatty, Cox, Frenkiel, Tam, Mason, MacGillivray,
      Sadler and Woodworth (1996) Biochemistry 35, 7635-7642]. The tentative two
      dimensional NMR assignment for two of the five methionine residues, namely
      Met(26) and Met(109), has been corrected. A series of NMR spectra for the
      complexes of (13)C-Met-labelled hTF/2N with six different metal ions, Fe(III),
      Cu(II), Cr(III), Co(III), Ga(III) and In(III), demonstrate that the
      conformational change of the protein upon metal binding can be observed by means
      of the changes in the NMR chemical shifts associated with certain methionine
      residues, regardless of whether diamagnetic or paramagnetic metals are used.
      Changing any of the methionine residues should have minimal effects on
      transferrin function, since structural analysis shows that none of these residues
      contacts functional amino acids or has any obvious role in iron uptake or
      release. In fact, UV-visible spectra show little perturbation of the electronic
      spectra of any of the mutants. Nevertheless, the M109L mutant (Met(109)-->Leu)
      releases iron at half the rate of the wild-type N-lobe, and chloride shows a
      significantly greater retarding effect on the rate of iron release from all five
      mutants. All the methionine mutants (especially in the apo form) show a poor
      solubility in Hepes buffer lacking anions such as bicarbonate. These findings
      imply a more general effect of anion binding to surface residues than previously
      realized.

PMID- 10585878
TI  - Activation of tyrosine kinases by alpha1A-adrenergic and growth factor receptors
      in transfected PC12 cells.
AB  - We compared the role of tyrosine kinases in alpha(1A)-adrenergic receptor (AR)
      and growth factor receptor stimulation of mitogen-activated protein kinase
      pathways in PC12 cells. Norepinephrine (NE) (noradrenaline), epidermal growth
      factor (EGF) and nerve growth factor (NGF) caused different patterns of tyrosine
      phosphorylation in PC12 cells stably expressing alpha(1A)-ARs. NE increased
      tyrosine phosphorylation of focal adhesion-related kinase Pyk2 and a 70 kDa
      protein, probably paxillin, whereas EGF strongly stimulated tyrosine
      phosphorylation of the EGF receptor and cytokine-activated kinase Jak2. The EGF
      receptor inhibitor AG1478 inhibited activation of extracellular signal-regulated
      kinases (ERKs) by EGF but not by NE. EGF and NGF strongly activated tyrosine
      phosphorylation of Shc and caused association of Src-homology collagen (Shc) with
      growth-factor-receptor-bound protein 2 (Grb2); however, neither NE nor UTP caused
      substantial activation of the Shc/Grb2 pathway. NE, UTP, EGF and NGF all
      increased tyrosine phosphorylation of Src, and this was inhibited by the Src
      inhibitor PP2. However, PP2 inhibited ERK activation in response to NE and UTP,
      but not in response to EGF or NGF. PP2 also completely blocked NE-induced PC12
      cell differentiation, but had no measurable effect on NGF-induced
      differentiation. These studies show that activation of mitogen-activated protein
      kinase pathways by G-protein-coupled receptors and tyrosine kinase receptors
      proceed through distinct molecular pathways in PC12 cells, and support an
      obligatory role for Src activation in mitogenic responses to alpha(1A)-ARs in
      these cells.

PMID- 10585879
TI  - Role of janus kinase-2 in insulin-mediated phosphorylation and inactivation of
      protein phosphatase-2A and its impact on upstream insulin signalling components.
AB  - Our recent studies indicate that insulin rapidly inactivates serine/threonine
      protein phosphatase-2A (PP-2A) by increasing tyrosine phosphorylation on the
      catalytic subunit. The exact mechanism of PP-2A inactivation by insulin in vivo
      is unclear. The Janus kinase (JAK) family of non-receptor protein tyrosine
      kinases constitute a novel type of signal-transduction pathway which is activated
      in response to a wide variety of polypeptide ligands, including insulin. In this
      study we investigated the potential role of JAK-2 in insulin-mediated tyrosine
      phosphorylation and inactivation of PP-2A using the rat skeletal muscle cell line
      L6. Co-immunoprecipitation studies revealed that PP-2A is associated with JAK-2
      in the basal state. Insulin treatment did not alter JAK-2 association with PP-2A,
      but did increase JAK-2-mediated tyrosine phosphorylation of the PP-2A catalytic
      subunit and therefore inhibited PP-2A enzymic activity. Furthermore, PP-2A is
      associated with phosphoinositide 3-kinase (PI-3K) in the basal state and insulin
      treatment increases the catalytic activity of PI-3K bound to PP-2A. Pretreatment
      with AG-490, a specific JAK-2 inhibitor, and SpcAMP, a cAMP agonist, prevented
      the insulin-mediated increase in (i) JAK-2 kinase activity, (ii) PP-2A tyrosine
      phosphorylation, (iii) PP-2A inactivation and restored the enzyme activity to
      control levels, and (iv) PP-2A and JAK-2-associated PI-3K activity. These
      observations, together with the fact that insulin rapidly activates JAK-2 in L6
      cells, and that this is accompanied by an increase in tyrosine phosphorylation of
      PP-2A in JAK-2 immunoprecipitates, suggest that insulin controls the activation
      status of PP-2A by tyrosine phosphorylation via JAK-2. PP-2A inactivation may
      result in an amplification of insulin-generated signals at the level of PI-3K.

PMID- 10585880
TI  - Function of human mitochondrial 2,4-dienoyl-CoA reductase and rat monofunctional
      Delta3-Delta2-enoyl-CoA isomerase in beta-oxidation of unsaturated fatty acids.
AB  - Human 2,4-dienoyl-CoA reductase (2,4-reductase; DECR) and rat monofunctional
      Delta(3)-Delta(2)-enoyl-CoA isomerase (rat 3, 2-isomerase; ECI) are thought to be
      mitochondrial auxiliary enzymes involved in the beta-oxidation of unsaturated
      fatty acids. However, their function during this process has not been
      demonstrated. Although they lack obvious peroxisomal targeting signals (PTSs),
      both proteins have been suggested previously to also occur in the mammalian
      peroxisomal compartment. The putative function and peroxisomal location of the
      two mammalian proteins can be examined in yeast, since beta-oxidation of
      unsaturated fatty acids is a compartmentalized process in Saccharomyces
      cerevisiae requiring peroxisomal 2,4-dienoyl-CoA reductase (Sps19p) and
      peroxisomal 3, 2-isomerase (Eci1p). A yeast sps19Delta mutant expressing human 2,
      4-reductase ending with the native C-terminus could not grow on petroselinic acid
      [cis-C(18:1(6))] medium but could grow when the protein was extended with a PTS
      tripeptide, SKL (Ser-Lys-Leu). We therefore reason that the human protein is a
      physiological 2, 4-reductase but that it is probably not peroxisomal. Rat 3, 2
      isomerase expressed in a yeast eci1Delta strain was able to re-establish growth
      on oleic acid [cis-C(18:1(9))] medium irrespective of an SKL extension. Since we
      had shown that Delta(2,4) double bonds could not be metabolized extra
      peroxisomally to restore growth of the sps19Delta strain, we postulate that rat
      3,2-isomerase acted on the Delta(3) unsaturated metabolite of oleic acid by
      replacing the mutant's missing activity from within the peroxisomes.
      Immunoblotting of fractionated yeast cells expressing rat 3, 2-isomerase in
      combination with electron microscopy supported our proposal that the protein
      functioned in peroxisomes. The results presented here shed new light on the
      function and location of human mitochondrial 2,4-reductase and rat monofunctional
      3,2-isomerase.

PMID- 10585881
TI  - Metabolism, mitochondrial uptake and toxicity of 2', 3'-dideoxycytidine.
AB  - 2',3'-Dideoxycytidine (ddCyd) is a prescription anti-retroviral drug that causes
      mitochondrial toxicity and peripheral neuropathy. ddCyd is actively
      phosphorylated by cytosolic deoxycytidine kinase and nucleoside (di)phosphate
      kinase to the 5'-triphosphate derivative. However, 2',3'-dideoxycytidine 5'
      diphosphocholine (ddCDP-choline) was also found in human cells incubated with
      ddCyd. In this paper we show that ddCDP-choline is produced from dideoxyCTP
      (ddCTP) and phosphocholine by phosphocholine cytidylyltransferase. dCTP and CTP
      appear to activate this synthesis in a concentration-dependent manner. Although
      ddCTP and ddCDP-choline can both enter the mitochondria, ddCDP-choline uptake is
      more efficient than ddCTP uptake. These data suggest that ddCDP- choline is the
      ddCyd metabolite that is probably responsible for mitochondrial toxicity. The
      uptake of ddCTP and ddCDP-choline by mitochondria is inhibited by 3.0 mM l
      carnitine in the cell-free system investigated; when added to U937 cells grown in
      the presence of 0.25 microM ddCyd, 3.0 mM l-carnitine partially abrogated the
      mitochondrial toxicity of ddCyd.

PMID- 10585882
TI  - Different roles of protein kinase C alpha and delta isoforms in the regulation of
      neutral sphingomyelinase activity in HL-60 cells.
AB  - The signalling mechanisms responsible for the hydrolysis of sphingomyelin
      mediated by 1,25-dihydroxyvitamin D(3) [1, 25(OH)(2)D(3)] and interferon gamma
      (IFN-gamma) in HL-60 cells were investigated. IFN-gamma was found to increase
      selectively the activity of cytosolic, Mg(2+)-independent, neutral
      sphingomyelinase. The treatment of HL-60 cells with the combination of
      1,25(OH)(2)D(3) and IFN-gamma had an additive effect on sphingomyelin hydrolysis,
      ceramide release and the activity of cytosolic, Mg(2+)-independent, neutral
      sphingomyelinase. The pretreatment of HL-60 cells with staurosporine,
      chelerythrine chloride and bisindolylmaleimide abolished the activity of
      sphingomyelinase in response to 1,25(OH)(2)D(3) and IFN-gamma. Calphostin C,
      which acts on the regulatory site of protein kinase C (PKC), and Go 6976, a
      selective inhibitor of Ca(2+)-dependent PKC isoforms, inhibited the effect of
      1,25(OH)(2)D(3) but had no effect on the IFN-gamma-mediated increase in activity
      of sphingomyelinase. Isoform-specific antibodies were used to deplete different
      PKC isoforms from cytosol before the treatment of the cytosolic fraction with
      1,25(OH)(2)D(3), arachidonic acid (AA) and PMA. The depletion of PKC isoforms
      beta(1), beta(2), epsilon, eta, mu, zeta and lambda had no effect on the
      activation of sphingomyelinase induced by 1,25(OH)(2)D(3) or by AA. The depletion
      of PKC alpha from the cytosol completely abolished the effect of 1,25(OH)(2)D(3)
      on sphingomyelinase activity but had no effect on the AA-induced activity of
      sphingomyelinase. PMA had no effect on the activity of sphingomyelinase in either
      untreated or alpha-depleted cytosol but significantly increased the activity of
      sphingomyelinase when added to cytosol depleted of PKC delta. Moreover, PMA
      inhibited the effect of 1,25(OH)(2)D(3) on sphingomyelinase activation but the
      inhibitory effect was abolished by prior depletion of PKC delta from the cytosol.
      These studies demonstrate that 1,25(OH)(2)D(3)-induced activation of
      sphingomyelinase is mediated by PKC alpha. Furthermore, PKC delta had an
      inhibitory effect on sphingomyelinase, suggesting that the difference between the
      1,25(OH)(2)D(3)- and PMA-mediated effects on sphingomyelin turnover depends on
      the specific regulation of the PKC alpha and PKC delta isoforms.

PMID- 10585883
TI  - The pleckstrin homology domains of protein kinase B and GRP1 (general receptor
      for phosphoinositides-1) are sensitive and selective probes for the cellular
      detection of phosphatidylinositol 3,4-bisphosphate and/or phosphatidylinositol
      3,4,5-trisphosphate in vivo.
AB  - We have tested the binding specificities of the pleckstrin homology (PH) domains
      of protein kinase B (PKB) and GRP1 (general receptor for phosphoinositides-1),
      expressed as green fluorescent protein (GFP) fusion proteins [PH(PKB)GFP and
      PH(GRP1)GFP respectively] in HEK 293 cells and Swiss 3T3 cells, using confocal
      microscopy. Stimulation of HEK 293 cells with insulin caused a small, but
      sustained, increase in PtdIns(3,4,5)P(3) levels, detected using a radioligand
      displacement assay, which was mirrored by the translocation of PH(PKB)GFP and
      PH(GRP1)GFP from the cytosol to the plasma membrane of live, transfected cells.
      Similar results were obtained using Swiss 3T3 cells stimulated with platelet
      derived growth factor (PDGF) and expressing either PH(PKB)GFP or PH(GRP1)GFP.
      Biochemical analyses confirmed the accumulation of both PtdIns(3,4,5)P(3) and
      PtdIns(3,4)P(2) in response to PDGF, but only the latter was present at increased
      levels in Swiss 3T3 cells 30 min after an oxidative stress (1 mM H(2)O(2)).
      Concomitantly, only PH(PKB)GFP, and not PH(GRP1)GFP, was localized at plasma
      membranes after 30 min of treatment with H(2)O(2). The fusion proteins appear
      accurately to report the spatial and temporal distribution of PtdIns(3,4,5)P(3)
      and PtdIns(3,4)P(2) in intact cells. These results establish the lipid
      selectivity of these PH domains in vivo, and further emphasize the overlapping,
      but distinct, second messenger roles of PtdIns(3,4,5)P(3) and PtdIns(3,4)P(2).

PMID- 10585884
TI  - Expression of glypican-4 in haematopoietic-progenitor and bone-marrow-stromal
      cells.
AB  - Heparan sulphate proteoglycans and the extracellular matrix of bone-marrow
      stromal cells are important components of the microenvironment of haematopoietic
      tissues and are involved in the interaction of haematopoietic stem and stromal
      cells. Previous studies have emphasized the role of heparan sulphate proteoglycan
      synthesis by bone-marrow-stromal cells. In the present study we describe the
      expression of glypican-4 (GPC-4), belonging to the glypican family, in bone
      marrow-stromal cells and haematopoietic-progenitor cells of human and murine
      origin. Expression of GPC-4 was shown on the mRNA-level by reverse transcription
      PCR and Northern blot analysis. Amplification products were cloned and sequenced,
      to confirm these results. To analyze the expression of GPC-4 on the protein
      level, polyclonal antibodies against selected peptides were raised in rabbits.
      Western blot analysis showed expression of GPC-4 as a heparan sulphate
      proteoglycan in the human haematopoietic-progenitor cell line TF-1 and normal
      human bone marrow. These results were confirmed by FACS analysis of TF-1 cells.
      Furthermore, GPC-4-positive progenitor cells and stromal cells were enriched from
      normal human bone marrow by magnetic-cell sorting and analysed by confocal laser
      scanning microscopy.

PMID- 10585885
TI  - Acetylcholinesterase from Schistosoma mansoni: interaction of globular species
      with heparin.
AB  - In the cercarial and schistosomal stages of the life cycle of the trematode
      Schistosoma mansoni, acetylcholinesterase occurs as two principal molecular forms
      (both globular), present in approximately equal amounts, with sedimentation
      coefficients of 6.5 S and 8 S. The 6.5 S form is solubilized by bacterial
      phosphatidylinositol-specific phospholipase C from intact schistosomula. It is
      thus located on the outer surface of the schistosomal tegument and is most
      probably analogous to the glycosylphosphatidylinositol-anchored G(2) form of
      acetylcholinesterase found in the electric organ of Torpedo, on the surface of
      mammalian erythrocytes, and elsewhere. Both forms are fully solubilized by the
      non-ionic detergent Triton X-100. Upon passing such a detergent extract over a
      heparin-Sepharose column, only the 8 S form was retained on the column. The bound
      acetylcholinesterase could be progressively eluted by increasing the salt
      concentration, with approx. 0.5-0.6 M NaCl being needed for complete elution.
      Selective inhibition experiments carried out on live parasites using the covalent
      acetylcholinesterase inhibitor echothiophate (phospholine), which does not
      penetrate the tegument, selectively inhibited the 6.5 S form, but not the 8 S
      form, suggesting an internal location for the latter. Monoclonal antibodies
      raised against S. mansoni acetylcholinesterase also distinguished between the two
      forms. Thus monoclonal antibody SA7 bound the 6.5 S form selectively, whereas
      SA57 recognized the 8 S form. The selective binding of the 8 S form to heparin
      suggests that, within the parasite, this form may be associated with the
      extracellular matrix of the musculature.

PMID- 10585886
TI  - Organization and sequence of the gene for the human mitochondrial dicarboxylate
      carrier: evolution of the carrier family.
AB  - The dicarboxylate carrier (DIC) is a nuclear-encoded protein located in the
      mitochondrial inner membrane. It catalyses the transport of dicarboxylates such
      as malate and succinate across the mitochondrial membrane in exchange for
      phosphate, sulphate and thiosulphate. We have determined the sequences of the
      human cDNA and gene for the DIC. The gene sequence was established from
      overlapping genomic clones generated by PCRs by use of primers and probes based
      upon the human cDNA sequence. It is spread over 8.6 kb of human DNA and is
      divided into 11 exons. Five short interspersed repetitive Alu sequences are found
      in intron I. The protein encoded by the gene is 287 amino acids long. In common
      with the rat protein, it does not have a processed presequence to help to target
      it into mitochondria. It has been demonstrated by Northern- and Western-blot
      analyses that the DIC is present in high amounts in liver and kidney, and at
      lower levels in all the other tissues analysed. The positions of introns
      contribute towards an understanding of the processes involved in the evolution of
      human genes for carrier proteins.

PMID- 10585887
TI  - E-box motifs within the human vasopressin gene promoter contribute to a major
      enhancer in small-cell lung cancer.
AB  - [Arginine]vasopressin (AVP) is a neuropeptide physiologically synthesized in the
      hypothalamus but pathologically expressed by small-cell lung cancer (SCLC). A
      minimal 65 bp AVP promoter can restrict basal activity to SCLC in vitro, but a
      199 bp fragment directs 5-fold higher expression in SCLC [Coulson, Stanley and
      Woll (1999) Br. J. Cancer 80, 1935-1944]. Several predicted E-box motifs occur
      within the 199 bp fragment, and we now describe an enhancer which contributes to
      AVP promoter tumour-specificity in some cell lines. The deletion of two adjacent
      E-boxes (-157 to -131) resulted in an approx. 70% loss of reporter gene
      expression in a SCLC line (Lu-165) with high endogenous AVP production. Using a
      series of AVP promoter deletion constructs and site-directed mutagenesis, we show
      that both these E-box sites were required for enhancer function, whereas mutation
      of an adjacent AP-1 site had no effect on the promoter activity. Electrophoretic
      mobility-shift analysis indicated that, although both the predicted E-box motifs
      bound specific complexes, only one appeared to function as a strong E-box which
      binds basic helix-loop-helix (bHLH) factors. This motif formed a complex in lung
      tumour-cell extracts, which was particularly strongly bound in Lu-165, and was
      competed for by a characterized E-box motif from the preprotachykinin A promoter.
      Antibody supershifts indicate that this complex is a heterodimer of upstream
      stimulatory factor (USF)-1 and USF-2. Non-bHLH complexes weakly bound the second
      potential E-box motif in a SCLC-specific manner. These complexes were not
      recognized by the bHLH antibodies and remain unidentified; however, they were
      detected in seven of eight SCLC cell lines and not in four control lines. We
      postulate that there is a co-operative and complex interaction between an E-box
      and an adjacent site constituting a SCLC-specific enhancer within the AVP
      proximal promoter.

PMID- 10585888
TI  - Phosphorylation of P20 is associated with the actions of insulin in rat skeletal
      and smooth muscle.
AB  - Although a large number of protein kinases/phosphatases involved in insulin's
      actions have been characterized recently, relatively few of the downstream
      phosphoproteins have been identified. We have employed two-dimensional gel
      electrophoresis-based proteome analysis to investigate the insulin-evoked
      phosphorylation cascade in rat soleus muscle. Insulin reproducibly increased
      phosphorylation of a 20-kDa protein with a pI value of 6.0, which was identified
      subsequently as a phospho-isoform of P20, a small heat-shock-related protein. The
      adenylyl cyclase activator, forskolin, decreased phosphorylation of this P20
      isoform and increased phosphorylation of another two P20 isoforms, with pI values
      of 5.9 and 5.6. Two-dimensional peptide mapping revealed that the phospho
      peptides of these three P20 isoforms are different. In contrast to its action in
      soleus muscle, insulin decreased phosphorylation of the P20 isoform with pI 6.0
      and increased phosphorylation of the two isoforms with pI values of 5.9 and 5.6
      in vascular smooth muscle. This effect is similar to that induced by vasodilatory
      stimuli, suggesting that insulin could exert its vasodilatory action by affecting
      phosphorylation of P20. In summary, these results demonstrate that insulin
      differently modulates phosphorylation of P20 in skeletal and smooth muscle, and
      suggest that P20 could be a potential modulator of insulin's functions in these
      tissues.

PMID- 10585889
TI  - Androgen deprivation facilitates acetylcholine-induced relaxation by superoxide
      anion generation.
AB  - The aim of the present study was to assess the role of superoxide anions in the
      relaxation induced by acetylcholine (ACh) in aortic segments from male rats, and
      to investigate if their production is altered by sex hormone deprivation. In
      segments precontracted with 10 nmol/l noradrenaline, ACh (0.1 nmol/l-10
      micromol/l) induced concentration-dependent relaxation, which was greater in
      segments from castrated compared with control animals. ACh-induced relaxation was
      abolished in segments from control rats, and reduced in those from castrated
      rats, by 0.1 mmol/l N(G)-nitro-L-arginine methyl ester (L-NAME; a nitric oxide
      synthase inhibitor). Indomethacin (1 micromol/l; a cyclo-oxygenase blocker)
      decreased the ACh-induced relaxation in arteries from control males only.
      Incubation of segments with superoxide dismutase (SOD; 100 units/ml; a superoxide
      anion scavenger) enhanced and reduced relaxation in segments from control and
      castrated animals respectively. For arteries from castrated animals, the presence
      of SOD plus L-NAME abolished such responses. In these arteries, incubation with L
      NAME abolished the relaxation caused by ACh when the segments were precontracted
      with 30 mmol/l KCl. In segments obtained from castrated rats and pretreated with
      L-NAME, 1 mmol/l tetraethylammonium or 0.4 micromol/l charybdotoxin [blockers of
      Ca(2+)-sensitive and large-conductance Ca(2+)-sensitive (BK(Ca)) K(+) channels
      respectively] abolished the relaxation induced by ACh. These results suggest that
      ACh generates endothelial NO and superoxide anions from the arterial wall in both
      control and castrated animals; these agents negatively modulate ACh-induced
      relaxation in control rats by destruction of NO, and positively modulate ACh
      induced relaxation in castrated rats by activation of BK(Ca) channels.

PMID- 10585890
TI  - Small-intestinal mucosal protein synthesis and whole-body protein turnover in
      alcoholic liver disease.
AB  - We used stable-isotope-labelled amino acids to measure the effects of alcoholic
      liver disease (ALD) on whole-body protein turnover and small-intestinal mucosal
      protein synthesis. Groups comprising eight patients with ALD and eight healthy
      control subjects were studied. They received primed, continuous intravenous
      infusions of L-[1-(13)C]leucine after an overnight fast; after 4 h, duodenal
      biopsies were obtained via endoscopy. Protein synthesis was calculated from
      protein labelling relative to intracellular leucine enrichment. Rates of duodenal
      mucosal protein synthesis were 2. 58+/-0.32%.h(-1) (mean+/-S.D.) in the normal
      subjects and 2.04+/-0. 18%.h(-1) in the ALD patients (P<0.003), despite the fact
      that the protein synthetic capacity (microgram of RNA/mg of protein) was higher
      in ALD patients (160+/-14 compared with 137+/-6 microgram/mg; P<0.003). The
      mucosal cell size (protein/DNA ratio) was lower in ALD patients (9.23+/-0.91
      compared with 13+/-2.2 microgram/mg; P<0.002). Although the mean rates of whole
      body protein turnover were not significantly different between the two groups
      (204+/-18 and 196+/-44 micromol leucine.h(-1).kg(-1) for ALD and control subjects
      respectively), there was, in the ALD patients, an inverse relationship between
      the rate of small-intestinal mucosal protein synthesis and the severity of ALD;
      furthermore, there was a direct relationship between the rate of whole-body
      protein turnover and the severity of ALD. Thus there was an inverse relationship
      between the rate of small-intestinal mucosal protein synthesis and the rate of
      whole-body protein turnover in ALD patients, which was not seen in the normal
      subjects.

PMID- 10585891
TI  - Role of erythropoietin and nitric oxide in modulating the tone of human renal
      interlobular and subcutaneous arteries from uraemic subjects.
AB  - This study investigated potential reasons why erythropoietin (EPO) given
      therapeutically to patients with renal failure may increase peripheral, but not
      renal, vascular resistance. This was done by comparing the effects of EPO on
      resting tension in normal renal interlobular and subcutaneous vessels from
      uraemic patients. In human subcutaneous arteries from uraemic subjects,
      noradrenaline- and KCl-induced vasoconstrictions were enhanced when nitric oxide
      (NO) production was blocked with N(G)-nitro-L-arginine methyl ester (L-NAME), but
      were unaffected by EPO, while acetylcholine- and bradykinin-induced concentration
      dependent relaxations were markedly attenuated by L-NAME, but not by EPO. The
      noradrenaline- and KCl-induced vasoconstrictions of human renal interlobular
      arteries were unaffected by the presence of L-NAME, but were attenuated by EPO
      (20 units.ml(-1)) by some 33% (P<0.01); this effect was enhanced by the co
      administration of L-NAME. Acetylcholine and bradykinin caused comparable
      dilatations of the interlobular arteries; the response to the former was
      attenuated by L-NAME, but none of these responses were changed by EPO. EPO given
      alone, at a concentration of either 0.1 or 20 units.ml(-1), had no effect on
      basal resting tone. NO production mediated both acetylcholine- and bradykinin
      induced relaxation in this vessel type. In contrast, in the interlobular arteries
      there was no indication of NO modulating the level of vasoconstriction, and it
      only mediated acetylcholine-induced dilation. These acute responses to EPO only
      partially explain its differential effects on the vasculature in renal failure.

PMID- 10585892
TI  - Comparable vasorelaxant effects of 17alpha- and 17beta-oestradiol on rat
      mesenteric resistance arteries: an action independent of the oestrogen receptor.
AB  - 17beta-Oestradiol (17betaE(2)) has vasorelaxant properties that may contribute to
      its beneficial cardiovascular effects. The mechanism of vasorelaxation remains
      controversial, but does not appear to involve interaction of 17betaE(2) with its
      nuclear receptor. The present study examined the effects on resistance arteries
      of 17betaE(2) and its isomer, 17alpha-oestradiol (17alphaE(2)), which does not
      bind to the classical oestrogen receptor. In arteries precontracted with either
      noradrenaline or KCl, 17betaE(2) and 17alphaE(2) caused comparable relaxation in
      a concentration-dependent manner over the concentration range 0.1-10 micromol/l,
      with no significant difference in the maximal effect obtained. Pre-incubation of
      the arteries with 17betaE(2) or 17alphaE(2) for 15 min reduced the magnitude and
      duration of the force generated with both noradrenaline and KCl to a comparable
      degree. Vasorelaxation induced by either 17betaE(2) or 17alphaE(2) was not
      blocked by an inhibitor of NO synthase or by protein synthesis inhibitors,
      indicating that vasodilatation is not dependent upon either NO generation or
      protein synthesis. In the absence of extracellular calcium, both oestradiols
      still relaxed arteries precontracted with NA, suggesting that they inhibit
      intracellular calcium release. Both 17betaE(2) and 17alphaE(2) therefore have
      important and comparable vasorelaxant properties that do not require interaction
      with the nuclear oestrogen receptor. Direct interactions with the cell membrane
      or with ion-channel proteins may be responsible.

PMID- 10585893
TI  - Amino acid nutrition and immune function in tumour-bearing rats: a comparison of
      glutamine-, arginine- and ornithine 2-oxoglutarate-supplemented diets.
AB  - Dietary supplementation with glutamine (Gln), arginine (Arg) or ornithine 2
      oxoglutarate (alpha-ketoglutarate; OKG) has attracted recent attention for the
      potential to improve anti-cancer immune function. However, since these compounds
      have not been compared systematically in an internally controlled study, their
      relative efficacy is difficult to estimate. Buffalo rats were fed on
      nutritionally complete semi-purified diets supplemented with Gln, Arg or OKG for
      14 days after implantation of the Morris hepatoma 7777 (n>/=7 per diet). The
      control diet was made isonitrogenous and isoenergetic by addition of a mixture of
      non-essential amino acids. After 14 days, peritoneal macrophages and splenocytes
      were isolated to determine cell phenotypes, macrophage cytostatic activity and
      natural killer (NK) cell cytotoxicity, as well as nitric oxide (NO) and cytokine
      production. Diet had no effect on tumour weight (1.6+/-0.2 g; n=59). However,
      rats fed OKG had increased macrophage cytostatic activity and NK cell
      cytotoxicity (P<0.05). Although enhanced killing ability by NK cells was
      associated with higher splenocyte NO production (P<0.04), increased cytotoxicity
      was not inhibited by a specific inhibitor of inducible NO synthase. The
      proportion of interleukin-2-receptor-positive T cells after stimulation increased
      in rats fed OKG (P<0.05); however, cytokine production was not affected by diet.
      None of OKG, Gln or Arg altered tumour growth compared with a control mixture of
      non-essential amino acids. These results suggest no net advantage for anti-cancer
      immunity, but do not preclude benefits in immune responses to disease recurrence
      or metastasis, therapy or secondary infection.

PMID- 10585894
TI  - Structural and functional assessment of small arteries in patients with chronic
      heart failure.
AB  - The physiological response to a chronically failing heart is the implementation
      of compensatory mechanisms intended to support blood pressure. These mechanisms,
      which are not fully understood, increase peripheral vascular tone, thus
      increasing the strain on the weakened myocardium. This study investigated the
      structure and function of small arteries from heart failure patients and controls
      without heart failure in an attempt to identify abnormalities associated with
      heart failure which may be related to these mechanisms. Small arteries were
      dissected from gluteal biopsies and studied using wire myography. Arterial
      morphological parameters were measured and concentration-response curves
      constructed for a number of vasoconstrictor and vasodilator agonists. Plasma
      concentrations of neuroendocrine hormones were also measured. There were no
      morphological differences between small arteries from control subjects and those
      from patients with chronic heart failure. In heart failure patients,
      vasoconstrictor responses to endothelin-1 were significantly reduced, although
      plasma endothelin-1 levels were increased. Arteries from heart failure patients
      also showed evidence of an impaired neuronal uptake mechanism, since blockade by
      cocaine had no effect on noradrenaline-induced vasoconstriction in these vessels.
      These results suggest that small-artery structure is not altered in chronic heart
      failure and so cannot account for the heightened vascular resistance in this
      syndrome. However, abnormal neuronal uptake and impaired vasoconstriction in
      response to endothelin-1 may be associated with the complex compensatory
      phenomenon involved in heart failure.

PMID- 10585895
TI  - Renal effects of hyperinsulinaemia in subjects with two hypertensive parents.
AB  - The aim of this investigation was to study the effects of isoglycaemic
      hyperinsulinaemia on the renal metabolism of electrolytes and water in subjects
      with a strong genetic predisposition to essential hypertension, compared with
      that in non-predisposed subjects. We studied 25 normotensive subjects aged 18-35
      years whose parents both had essential hypertension, and 22 age- and sex-matched
      subjects whose parents were both normotensive. Diabetes or morbid obesity in any
      subject or parent excluded the family. The 24-h blood pressure was measured. The
      subjects received an isocaloric diet with a fixed content of sodium and potassium
      for 4 days before the study. An isoglycaemic, hyperinsulinaemic clamp with
      infusion of insulin (40 munits.min(-1).m(-2)) was performed. We measured the
      renal clearance of diethylenetriaminepenta-acetic acid, sodium, potassium and
      lithium both under basal conditions and during hyperinsulinaemia. In response to
      hyperinsulinaemia, renal sodium clearance decreased to a significantly greater
      extent in the hypertension-prone subjects [0.57 (0.74, 0.36) ml.min(-1).1.73 m(2)
      (median and quartiles)] than in the controls [0.34 (0.56, 0.18) ml. min(-1).1.73
      m(2)] (P=0.04). Compared with the controls, the subjects predisposed to
      hypertension had a higher 24-h diastolic blood pressure [78 (70, 82) mmHg,
      compared with 73 (68, 77) mmHg], but a similar insulin sensitivity index
      ?10(7)x[313 (225, 427)] compared with 10(7)x[354 (218, 435)] l(2).min(-1).pmol(
      1).kg(-1)?. Thus the sodium-retaining effect of insulin was more pronounced in
      subjects with a strong genetic predisposition to essential hypertension than in
      subjects with normotensive parents. This effect may contribute to the development
      of hypertension in subjects with a genetic predisposition to hypertension.

PMID- 10585896
TI  - Cardiac peptide stability, aprotinin and room temperature: importance for
      assessing cardiac function in clinical practice.
AB  - Brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and N-terminal
      ANP are good research indices of the severity of heart failure. The stability of
      these peptides at room temperature has become an important factor in assessing
      their use as indicators of cardiac function in routine clinical practice.
      Inhibitors such as aprotinin are routinely added in the blood collection process,
      but may provide no benefit in sample collection and routine clinical practice. We
      assessed the stability of BNP, ANP and N-terminal ANP in blood samples collected
      in either the presence or the absence of the protease inhibitor aprotinin. Blood,
      either with or without aprotinin, was processed immediately (initial; 0 h) and
      after blood samples had been left for 3 h, 2 days or 3 days at room temperature.
      These times were chosen to reflect processing in a hospital outpatient clinic (2
      3 h), or when posted from general practice (2-3 days). Initial plasma BNP, ANP
      and N-terminal ANP levels in the absence of aprotinin were 28.2+/-5.4, 44.2+/-7.9
      and 1997+/-608 pg/ml respectively, and were not significantly different from
      initial values in the presence of aprotinin (29.0+/-5.9, 45.2+/-8.0 and 2009+/
      579 pg/ml respectively). After 3 h at room temperature, there was a significant
      fall in ANP in the absence of aprotinin (36. 7+/-7.9 pg/ml; P<0.005), but not in
      the presence of aprotinin (41. 2+/-7.6 pg/ml). Both BNP and N-terminal ANP were
      unchanged in either the absence (BNP, 27.6+/-5.5 pg/ml; N-terminal ANP, 2099+/
      613 pg/ml) or the presence (BNP, 29.4+/-5.6 pg/ml; N-terminal ANP, 1988+/-600
      pg/ml) of aprotinin. After 2 days at room temperature, ANP had fallen
      significantly in both the absence (16.9+/-3.4 pg/ml) and the presence (24.0+/-5.0
      pg/ml) of aprotinin compared with initial values, and there was a significant
      difference in ANP levels in the absence and presence of aprotinin (P<0.001). ANP
      levels had decreased further after 3 days at room temperature, to 11.9+/-3.4
      pg/ml (no aprotinin) and 20.3+/-5.0 pg/ml (aprotinin added); these values were
      significantly different (P=0.002). In contrast, there was no change in the levels
      of BNP or N-terminal ANP after 2 or 3 days at room temperature, in either the
      absence or the presence of aprotinin. These studies indicate that aprotinin adds
      little benefit to the stability of cardiac peptides at room temperature. Blood
      samples for BNP and N-terminal ANP measurement used as a test of heart function
      in hospital clinics and by general practitioners in the community could be taken
      into blood tubes containing only EDTA as anticoagulant and without the additional
      step of adding the routinely used inhibitor aprotinin.

PMID- 10585897
TI  - Effects of lipoproteins from pre-eclamptic women on umbilical endothelial cell 6
      oxo-prostaglandin f1alpha and endothelin 1 synthesis, and nitric oxide synthase 3
      mRNA expression.
AB  - In order to evaluate whether lipid abnormalities may contribute to endothelial
      dysfunction in pre-eclampsia, the present study examined the in vitro effects of
      very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high
      density lipoprotein (HDL), isolated from women with pre-eclampsia and matched
      controls, on the endothelial synthesis of 6-oxo-prostaglandin F(1alpha) (6-oxo
      PGF(1alpha); a metabolite of prostacyclin) and endothelin 1, and on the
      expression of nitric oxide synthase 3 (NOS3) mRNA. VLDL, LDL and HDL cholesterol
      were isolated from 20 pre-eclamptic and 20 age- and gestation-matched normal
      pregnant women. The lipoproteins (50 microgram/ml) and lipoprotein-free control
      plasma were incubated for 1, 3 and 6 h at 37 degrees C with a human umbilical
      endothelial cell line. The synthesis of 6-oxo-PGF(1alpha) and endothelin 1, and
      NOS3 mRNA expression, were measured at each time point. VLDL from pre-eclamptic
      women stimulated endothelial cell 6-oxo-PGF(1alpha) synthesis to a lesser extent
      than that from normal pregnant women (P<0.05). LDL from women with pre-eclampsia
      also stimulated 6-oxo-PGF(1alpha) synthesis to a lesser extent than LDL from
      normal pregnant women, but the effect was less sustained. The effect of HDL from
      women with pre-eclampsia on 6-oxo-PGF(1alpha) synthesis was similar to that of
      HDL from normal pregnant women. The pre-incubation levels of lipid peroxides in
      VLDL and LDL were not different between the normal pregnant and pre-eclamptic
      women, and cannot account for the decrease in 6-oxo-PGF(1alpha) synthesis. VLDL,
      LDL and HDL from women with pre-eclampsia did not affect endothelial cell
      synthesis of endothelin 1 or expression of NOS3 mRNA differently from
      lipoproteins from normal pregnant women. This study suggests that VLDL, and to a
      lesser extent LDL, from women with pre-eclampsia could potentially contribute to
      the reduced systemic 6-oxo-PGF(1alpha) synthesis observed in the pre-eclamptic
      syndrome.

PMID- 10585898
TI  - Cytotoxic T lymphocytes and viral evolution in primary HIV-1 infection.
AB  - Efforts to develop immune-based therapies for HIV infection have been impeded by
      incomplete definition of the immunological correlates of protection. Despite many
      precedents demonstrating that CD8(+) cytotoxic T lymphocytes are key mediators of
      protective anti-viral immunity in non-human animal models, direct evidence that
      these effector cells control viral replication in HIV-1 infection has remained
      elusive. The first part of this paper describes a detailed immunological and
      genetic study founded on evolutionary considerations. Following infection with
      HIV-1, virus variants which escaped recognition by autologous cytotoxic T
      lymphocytes were shown to possess a selection advantage within the host
      environment. Cytotoxic T lymphocytes therefore exert anti-viral pressure in vivo.
      This observation provides compelling evidence that cytotoxic T lymphocytes
      comprise a significant element of anti-retroviral immunity. Subsequently, the
      quantification of peripheral cytotoxic T lymphocyte frequencies utilizing peptide
      (human leucocyte antigen class I) tetrameric complexes is described. Five
      patients with qualitatively similar immunodominant cytotoxic T lymphocyte
      responses during symptomatic primary HIV-1 infection were studied longitudinally.
      Expansions of virus-specific CD8(+) lymphocytes comprising up to 2% of the total
      CD8(+) T cell population were observed in the acute phase of infection. Antigenic
      load was identified as an important determinant of circulating HIV-1-specific
      CD8(+) lymphocyte levels; however, significant numbers of such cells were also
      found to persist following prolonged therapeutic suppression of plasma viraemia.
      In addition, an analysis of antigenic sequence variation with time in this case
      series suggests that the early administration of combination anti-retroviral
      therapy may limit HIV-1 mutational escape from host cytolytic specificities. The
      implications of these preliminary data are discussed. The data presented suggest
      that vaccination protocols should aim to elicit vigorous cytotoxic T lymphocyte
      responses to HIV-1. Attempts to stimulate polyvalent responses to mutationally
      intolerant epitopes are likely to be most effective. Optimal management of HIV-1
      infection requires an understanding of dynamic host-virus interactions, and may
      involve strategies designed to enhance cytotoxic T lymphocyte activity following
      periods of anti-retroviral drug therapy.

PMID- 10585899
TI  - Chemical and biological weapons: new questions, new answers.
AB  - The words "chemical and biological weapons" (CBW) send a shiver down most spines
      these days. With the end of the Cold War, the possibility of a massive nuclear
      confrontation appears remote, so today many popular doomsday scenarios center on
      the aggressive use of chemical or biological warfare by rogue nations or
      terrorist groups. As exaggerated as some of the accounts are, with CBW cast as
      the latest unseen, unstoppable enemy, the threat posed by these weapons is all
      too real, and growing.

PMID- 10585901
TI  - Biological warfare agents as threats to potable water.
AB  - Nearly all known biological warfare agents are intended for aerosol application.
      Although less effective as potable water threats, many are potentially capable of
      inflicting heavy casualties when ingested. Significant loss of mission capability
      can be anticipated even when complete recovery is possible. Properly maintained
      field army water purification equipment can counter this threat, but personnel
      responsible for the operation and maintenance of the equipment may be most at
      risk of exposure. Municipal water treatment facilities would be measurably less
      effective. Some replicating (infectious) agents and a few biotoxins are
      inactivated by chlorine disinfection; for others chlorine is ineffective or of
      unknown efficacy. This report assesses the state of our knowledge of agents as
      potable water threats and contemplates the consequences of intentional or
      collateral contamination of potable water supplies by 18 replicating agents and 9
      biotoxins known or likely to be weaponized or otherwise used as threats.

PMID- 10585900
TI  - The sources, fate, and toxicity of chemical warfare agent degradation products.
AB  - We include in this review an assessment of the formation, environmental fate, and
      mammalian and ecotoxicity of CW agent degradation products relevant to
      environmental and occupational health. These parent CW agents include several
      vesicants: sulfur mustards [undistilled sulfur mustard (H), sulfur mustard (HD),
      and an HD/agent T mixture (HT)]; nitrogen mustards [ethylbis(2-chloroethyl)amine
      (HN1), methylbis(2-chloroethyl)amine (HN2), tris(2-chloroethyl)amine (HN3)], and
      Lewisite; four nerve agents (O-ethyl S-[2-(diisopropylamino)ethyl]
      methylphosphonothioate (VX), tabun (GA), sarin (GB), and soman (GD)); and the
      blood agent cyanogen chloride. The degradation processes considered here include
      hydrolysis, microbial degradation, oxidation, and photolysis. We also briefly
      address decontamination but not combustion processes. Because CW agents are
      generally not considered very persistent, certain degradation products of
      significant persistence, even those that are not particularly toxic, may indicate
      previous CW agent presence or that degradation has occurred. Of those products
      for which there are data on both environmental fate and toxicity, only a few are
      both environmentally persistent and highly toxic. Major degradation products
      estimated to be of significant persistence (weeks to years) include thiodiglycol
      for HD; Lewisite oxide for Lewisite; and ethyl methyl phosphonic acid, methyl
      phosphonic acid, and possibly S-(2-diisopropylaminoethyl) methylphosphonothioic
      acid (EA 2192) for VX. Methyl phosphonic acid is also the ultimate hydrolysis
      product of both GB and GD. The GB product, isopropyl methylphosphonic acid, and a
      closely related contaminant of GB, diisopropyl methylphosphonate, are also
      persistent. Of all of these compounds, only Lewisite oxide and EA 2192 possess
      high mammalian toxicity. Unlike other CW agents, sulfur mustard agents (e.g., HD)
      are somewhat persistent; therefore, sites or conditions involving potential HD
      contamination should include an evaluation of both the agent and thiodiglycol.

PMID- 10585902
TI  - Hazards of chemical weapons release during war: new perspectives.
AB  - The two major threat classes of chemical weapons are mustard gas and the nerve
      agents, and this has not changed in over 50 years. Both types are commonly called
      gases, but they are actually liquids that are not remarkably volatile. These
      agents were designed specifically to harm people by any route of exposure and to
      be effective at low doses. Mustard gas was used in World War I, and the nerve
      agents were developed shortly before, during, and after World War II. Our
      perception of the potency of chemical weapons has changed, as well as our concern
      over potential effects of prolonged exposures to low doses and potential target
      populations that include women and children. Many of the toxicologic studies and
      human toxicity estimates for both mustard and nerve agents were designed for the
      purpose of quickly developing maximal casualties in the least sensitive male
      soldier. The "toxicity" of the chemical weapons has not changed, but our
      perception of "toxicity" has.

PMID- 10585903
TI  - Association of prenatal maternal or postnatal child environmental tobacco smoke
      exposure and neurodevelopmental and behavioral problems in children.
AB  - We review the potential neurodevelopmental and behavioral effects of children's
      prenatal and/or postnatal exposure to environmental tobacco smoke (ETS).
      Children's exposure to ETS has been assessed in epidemiologic studies as a risk
      factor for a variety of behavioral and neurodevelopmental problems including
      reduced general intellectual ability, skills in language and auditory tasks, and
      academic achievement, and behavioral problems such as hyperactivity and decreased
      attention spans. We review 17 epidemiologic studies that have attempted to
      separate the effects of maternal active smoking during pregnancy from passive ETS
      smoke exposure by the pregnant mother or the child. Based on the available data,
      we found that ETS exposure could cause subtle changes in children's
      neurodevelopment and behavior. However, studies to date are difficult to
      interpret because of the unknown influence of uncontrolled confounding factors,
      imprecision in measurements of smoking exposure, and collinearity of pre- and
      postnatal maternal smoking. Although some evidence suggests that maternal smoking
      during pregnancy may be associated with deficits in intellectual ability and
      behavioral problems in children, the impact of prenatal or postnatal ETS exposure
      remains less clear.

PMID- 10585905
TI  - The precautionary principle and scientific research are not antithetical.
AB  - The Precautionary Principle is intended to protect human health and the
      environment. To serve these goals effectively, precautionary action must be
      coupled with concurrent research to decide whether the action taken is in fact
      protective.

PMID- 10585906
TI  - Comments on "Comparative hazards of chrysotile asbestos and its substitutes: a
      European perspective".

PMID- 10585904
TI  - Climate, traffic-related air pollutants, and asthma prevalence in middle-school
      children in taiwan.
AB  - This study compared the prevalence of asthma with climate and air pollutant data
      to determine the relationship between asthma prevalence and these factors. We
      conducted a nationwide survey of respiratory illness and symptoms in middle
      school students in Taiwan. Lifetime prevalences of physician-diagnosed asthma and
      of typical symptoms of asthma were compared to air monitoring station data for
      temperature, relative humidity, sulfur dioxide, nitrogen oxides, ozone, carbon
      monoxide, and particulate matter with aerodynamic diameter [less than/equal to]
      10 microm (PM(10)). A total of 331,686 nonsmoking children attended schools
      located within 2 km of 55 stations. Asthma prevalence rates adjusted for age,
      history of atopic eczema, and parental education were associated with nonsummer
      (June-August) temperature, winter (January-March) humidity, and traffic-related
      air pollution, especially carbon monoxide and nitrogen oxides, for both girls and
      boys. Nonsummer temperature, winter humidity, and traffic-related air pollution,
      especially carbon monoxide and nitrogen oxides, were positively associated with
      the prevalence of asthma in middle-school students in Taiwan.

PMID- 10585907
TI  - Comments on "A critical review of epidemiologic studies of radiofrequency
      exposure and human cancers".
AB  - Comments on Elwood's article: A critical review of epidemiologic studies of
      radiofrequency exposure and human cancers. Environ Health Perspect 107(suppl
      1):155-168 (1999).

PMID- 10585908
TI  - Comments on "What is a tumor promoter?".
AB  - Comments on Tennant's article: What is a tumor promoter? [Editorial]. Environ
      Health Perspect 107:A390-A391 (1999).

PMID- 10585909
TI  - Medicinal herbs: NTP extracts the facts.
AB  - The National Toxicology Program (NTP) has announced that it will design and
      initiate studies to identify and characterize possible adverse health effects
      that may be associated with prolonged use or higher doses of some of the most
      popular medicinal herbs, including Ginkgo biloba, Echinacea angustifolia, and
      Panax quinquefolius (American ginseng). The NTP studies a large variety of
      substances to which the population may be exposed in the environment,
      occupationally, in the food supply, or elsewhere.

PMID- 10585911
TI  - Closer to a compromise on the direction of environmental research.
AB  - The Committee for the National Institute for the Environment (CNIE) was created
      in 1990 "to improve the scientific basis for making decisions on environmental
      issues," possibly through the establishment of a separate institute devoted to
      the environmental sciences. But while the goals proposed for the National
      Institute for the Environment were universally applauded, Congress was averse to
      adding a new agency to the federal bureaucracy. Recently, a compromise plan has
      been proposed that could expand the science base without having to create a new
      agency. On 29 July 1999, the National Science Board approved an interim report
      recommending an expanded program of environmental research and research planning,
      education, and scientific assessment with a funding target of an additional $1
      billion over five years. The report stresses the importance of environmental
      research in formulating environmental protection programs and contains 12
      recommendations intended to enhance and complement existing research activities
      in environmental sciences and engineering. If the National Science Foundation
      implements the recommendations in the report and if Congress appropriates funds
      for that purpose, the need for additional funding for new science activities
      identified by the CNIE should be satisfied.

PMID- 10585912
TI  - Update on asthma and air pollution research in inner cities
AB  - The health impact of current ambient levels of particulate matter (PM) and ozone
      (O(3)) remains controversial. Exposure to both ambient O(3) and airborne PM has
      been shown to be related to short-term lung function deficits in children, a
      correlation that is greater among children with symptoms of asthma than among
      asymptomatic children. Day-to-day fluctuations in airborne PM also appear to be
      related to mortality and hospitalizations among the elderly. Despite these and
      other data suggesting that current ambient levels of O(3) and PM are associated
      with adverse health effects, there is an ongoing debate about the magnitude and
      clinical importance of the health effects of exposure to these pollutants.

PMID- 10585913
TI  - Sequencing and the single channel.

PMID- 10585914
TI  - Novel size-independent modeling of the dilute solution conformation of the
      immunoglobulin IgG Fab' domain using SOLPRO and ELLIPS.
AB  - The proliferation of hydrodynamic modeling strategies to represent the shape of
      quasirigid macromolecules in solution has been hampered by ambiguities caused by
      size. Universal shape parameters, independent of size, developed originally for
      ellipsoid modeling, are now available for modeling using the bead-shell
      approximation via the algorithm SOLPRO. This paper validates such a "size
      independent" bead-shell approach by comparison with the exact hydrodynamics of 1)
      an ellipsoid of revolution and 2) a general triaxial ellipsoid (semiaxial ratios
      a/b, b/c) based on a fit using the routine ELLIPSE (. J. Mol. Graph. 1:30-38) to
      the chimeric (human/mouse) IgG Fab' B72.3; a similar fit is obtained for other
      Fabs. Size-independent application of the bead-shell approximation yields errors
      of only approximately 1% in frictional ratio based shape functions and
      approximately 3% in the radius of gyration. With the viscosity increment, errors
      have been reduced to approximately 3%, representing a significant improvement on
      earlier procedures. Combination of the Perrin frictional ratio function with the
      experimentally measured sedimentation coefficient for the same Fab' from B72.3
      yields an estimate for the molecular hydration of the Fab' fragment of
      approximately (0.43 +/- 0.07) g/g. This value is compared to values obtained in a
      similar way for deoxyhemoglobin (0.44) and ribonuclease (0.27). The application
      of SOLPRO to the shape analysis of more complex macromolecules is indicated, and
      we encourage such size-independent strategies. The utility of modern
      sedimentation data analysis software such as SVEDBERG, DCDT, LAMM, and MSTAR is
      also clearly demonstrated.

PMID- 10585915
TI  - Annealing accounts for the length of actin filaments formed by spontaneous
      polymerization.
AB  - We measured the lengths of actin filaments formed by spontaneous polymerization
      of highly purified actin monomers by fluorescence microscopy after labeling with
      rhodamine-phalloidin. The length distributions are exponential with a mean of
      approximately 7 microm (2600 subunits). This length is independent of the initial
      concentration of actin monomer, an observation inconsistent with a simple
      nucleation-elongation mechanism. However, with the addition of physically
      reasonable rates of filament annealing and fragmenting, a nucleation-elongation
      mechanism can reproduce the observed average length of filaments in two types of
      experiments: 1) filaments formed from a wide range of highly purified actin
      monomer concentrations, and 2) filaments formed from 24 microM actin over a range
      of CapZ concentrations.

PMID- 10585916
TI  - Protein-assisted pericyclic reactions: an alternate hypothesis for the action of
      quantal receptors.
AB  - The rules for allowable pericyclic reactions indicate that the
      photoisomerizations of retinals in rhodopsins can be formally analogous to
      thermally promoted Diels-Alder condensations of monoenes with retinols. With
      little change in the seven-transmembrane helical environment these latter
      reactions could mimic the retinal isomerization while providing highly sensitive
      chemical reception. In this way archaic progenitors of G-protein-coupled chemical
      quantal receptors such as those for pheromones might have been evolutionarily
      plagiarized from the photon quantal receptor, rhodopsin, or vice versa. We
      investigated whether the known structure of bacteriorhodopsin exhibited any
      similarity in its active site with those of the two known antibody catalysts of
      Diels-Alder reactions and that of the photoactive yellow protein. A remarkable
      three-dimensional motif of aromatic side chains emerged in all four proteins
      despite the drastic differences in backbone structure. Molecular orbital
      calculations supported the possibility of transient pericyclic reactions as part
      of the isomerization-signal transduction mechanisms in both bacteriorhodopsin and
      the photoactive yellow protein. It appears that reactions in all four of the
      proteins investigated may be biological analogs of the organic chemists' chiral
      auxiliary-aided Diels-Alder reactions. Thus the light receptor and the chemical
      receptor subfamilies of the heptahelical receptor family may have been unified at
      one time by underlying pericyclic chemistry.

PMID- 10585917
TI  - Intracellular Ca(2+) dynamics and the stability of ventricular tachycardia.
AB  - Ventricular fibrillation (VF), the major cause of sudden cardiac death, is
      typically preceded by ventricular tachycardia (VT), but the mechanisms underlying
      the transition from VT to VF are poorly understood. Intracellular Ca(2+) overload
      occurs during rapid heart rates typical of VT and is also known to promote
      arrhythmias. We therefore studied the role of intracellular Ca(2+) dynamics in
      the transition from VT to VF, using a combined experimental and mathematical
      modeling approach. Our results show that 1) rapid pacing of rabbit ventricular
      myocytes at 35 degrees C led to increased intracellular Ca(2+) levels and complex
      patterns of action potential (AP) configuration and the intracellular Ca(2+)
      transients; 2) the complex patterns of the Ca(2+) transient arose directly from
      the dynamics of intracellular Ca(2+) cycling, and were not merely passive
      responses to beat-to-beat alterations in AP; 3) the complex Ca(2+) dynamics were
      simulated in a modified version of the Luo-Rudy (LR) ventricular action potential
      with improved intracellular Ca(2+) dynamics, and showed good agreement with the
      experimental findings in isolated myocytes; and 4) when incorporated into
      simulated two-dimensional cardiac tissue, this action potential model produced a
      form of spiral wave breakup from VT to a VF-like state in which intracellular
      Ca(2+) dynamics played a key role through its influence on Ca(2+)-sensitive
      membrane currents such as I(Ca), I(NaCa), and I(ns(Ca)). To the extent that
      spiral wave breakup is useful as a model for the transition from VT to VF, these
      findings suggest that intracellular Ca(2+) dynamics may play an important role in
      the destabilization of VT and its degeneration into VF.

PMID- 10585918
TI  - Dynamics and thermodynamics of beta-hairpin assembly: insights from various
      simulation techniques.
AB  - Small peptides that might have some features of globular proteins can provide
      important insights into the protein folding problem. Two simulation methods,
      Monte Carlo Dynamics (MCD), based on the Metropolis sampling scheme, and Entropy
      Sampling Monte Carlo (ESMC), were applied in a study of a high-resolution lattice
      model of the C-terminal fragment of the B1 domain of protein G. The results
      provide a detailed description of folding dynamics and thermodynamics and agree
      with recent experimental findings (. Nature. 390:196-197). In particular, it was
      found that the folding is cooperative and has features of an all-or-none
      transition. Hairpin assembly is usually initiated by turn formation; however,
      hydrophobic collapse, followed by the system rearrangement, was also observed.
      The denatured state exhibits a substantial amount of fluctuating helical
      conformations, despite the strong beta-type secondary structure propensities
      encoded in the sequence.

PMID- 10585919
TI  - Involvement of the carboxy-terminus region of the dihydropyridine receptor beta1a
      subunit in excitation-contraction coupling of skeletal muscle.
AB  - Skeletal muscle knockout cells lacking the beta subunit of the dihydropyridine
      receptor (DHPR) are devoid of slow L-type Ca(2+) current, charge movements, and
      excitation-contraction coupling, despite having a normal Ca(2+) storage capacity
      and Ca(2+) spark activity. In this study we identified a specific region of the
      missing beta1a subunit critical for the recovery of excitation-contraction.
      Experiments were performed in beta1-null myotubes expressing deletion mutants of
      the skeletal muscle-specific beta1a, the cardiac/brain-specific beta2a, or
      beta2a/beta1a chimeras. Immunostaining was used to determine that all beta
      constructs were expressed in these cells. We examined the Ca(2+) conductance,
      charge movements, and Ca(2+) transients measured by confocal fluo-3 fluorescence
      of transfected myotubes under whole-cell voltage-clamp. All constructs recovered
      an L-type Ca(2+) current with a density, voltage-dependence, and kinetics of
      activation similar to that recovered by full-length beta1a. In addition, all
      constructs except beta2a mutants recovered charge movements with a density
      similar to full-length beta1a. Thus, all beta constructs became integrated into a
      skeletal-type DHPR and, except for beta2a mutants, all restored functional DHPRs
      to the cell surface at a high density. The maximum amplitude of the Ca(2+)
      transient was not affected by separate deletions of the N-terminus of beta1a or
      the central linker region of beta1a connecting two highly conserved domains.
      Also, replacement of the N-terminus half of beta1a with that of beta2a had no
      effect. However, deletion of 35 residues of beta1a at the C-terminus produced a
      fivefold reduction in the maximum amplitude of the Ca(2+) transients. A similar
      observation was made by deletion of the C-terminus of a chimera in which the C
      terminus half was from beta1a. The identified domain at the C-terminus of beta1a
      may be responsible for colocalization of DHPRs and ryanodine receptors (RyRs), or
      may be required for the signal that opens the RyRs during excitation-contraction
      coupling. This new role of DHPR beta in excitation-contraction coupling
      represents a cell-specific function that could not be predicted on the basis of
      functional expression studies in heterologous cells.

PMID- 10585920
TI  - Different ionic selectivities for connexins 26 and 32 produce rectifying gap
      junction channels.
AB  - The functional diversity of gap junction intercellular channels arising from the
      large number of connexin isoforms is significantly increased by heterotypic
      interactions between members of this family. This is particularly evident in the
      rectifying behavior of Cx26/Cx32 heterotypic channels (. Proc. Natl. Acad. Sci.
      USA. 88:8410-8414). The channel properties responsible for producing the
      rectifying current observed for Cx26/Cx32 heterotypic gap junction channels were
      determined in transfected mouse neuroblastoma 2A (N2A) cells. Transfectants
      revealed maximum unitary conductances (gamma(j)) of 135 pS for Cx26 and 53 pS for
      Cx32 homotypic channels in 120 mM KCl. Anionic substitution of glutamate for Cl
      indicated that Cx26 channels favored cations by 2.6:1, whereas Cx32 channels were
      relatively nonselective with respect to charge. In Cx26/Cx32 heterotypic cell
      pairs, the macroscopic fast rectification of the current-voltage relationship was
      fully explained at the single-channel level by a rectifying gamma(j) that
      increased by a factor of 2.9 as the transjunctional voltage (V(j)) changed from 
      100 to +100 mV with the Cx26 cell as the positive pole. A model of
      electrodiffusion of ions through the gap junction pore based on Nernst-Planck
      equations for ion concentrations and the Poisson equation for the electrical
      potential within the junction is developed. Selectivity characteristics are
      ascribed to each hemichannel based on either pore features (treated as uniform
      along the length of the hemichannel) or entrance effects unique to each connexin.
      Both analytical GHK approximations and full numerical solutions predict
      rectifying characteristics for Cx32/Cx26 heterotypic channels, although not to
      the full extent seen empirically. The model predicts that asymmetries in the
      conductance/permeability properties of the hemichannels (also cast as Donnan
      potentials) will produce either an accumulation or a depletion of ions within the
      channel, depending on voltage polarity, that will result in rectification.

PMID- 10585921
TI  - Barium inhibition of the collapse of the Shaker K(+) conductance in zero K(+).
AB  - In the absence of K(+) on both sides of the membrane, delivery of standard
      activating pulses collapses the Shaker B K(+) conductance. Prolonged
      depolarizations restore the ability to conduct K(+). It has been proposed that
      the collapse of the conductance results from the dwelling of the channels in a
      stable closed (noninactivated) state (, J. Physiol. (Lond.). 499:3-15). Here it
      is shown that 1) Ba(2+) impedes the collapse of the K(+) conductance, protecting
      it from both sides of the membrane; 2) external Ba(2+) protection (K(d) = 63
      microM at -80 mV) decreases slightly as the holding potential (HP) is made more
      negative; 3) external Ba(2+) cannot restore the previously collapsed conductance;
      on the other hand, 4) internal Ba(2+) (and K(+)) protection markedly decreases
      with hyperpolarized HPs (-80 to -120 mV), and it is not dependent on the pulse
      potential (0 to +60 mV). Ba(2+) is an effective K(+) substitute, inhibiting the
      passage of the channels into the stable nonconducting (noninactivated) mode of
      gating.

PMID- 10585922
TI  - Effects of channel cytoplasmic regions on the activation mechanisms of cardiac
      versus skeletal muscle Na(+) channels.
AB  - Functional comparison of skeletal muscle (rSkM1) and cardiac (hH1) voltage-gated
      sodium channel isoforms expressed in Chinese hamster ovary cells showed rSkM1
      half-activation (V(a)) and inactivation (V(i)) voltages 7 and 10 mV more
      depolarized than hH1 V(a) and V(i), respectively. Internal papain perfusion
      removed fast inactivation from each isoform and caused a 20-mV hyperpolarizing
      shift in hH1 V(a), with an insignificant change in rSkM1 V(a). Activation voltage
      of the inactivation-deficient hH1 mutant, hH1Q3, was nearly identical to wild
      type hH1 V(a), both before and after papain treatment, with hH1Q3 V(a) also
      shifted by nearly 20 mV after internal papain perfusion. These data indicate that
      while papain removes both hH1 and rSkM1 inactivation, it has a second effect only
      on hH1 that causes a shift in activation voltage. Internal treatment with an
      antibody directed against the III-IV linker essentially mimicked papain treatment
      by removing some inactivation from each isoform and causing a 12-mV shift in hH1
      V(a), while rSkM1 V(a) remained constant. This suggests that some channel segment
      within, near, or interacting with the III-IV linker is involved in establishing
      hH1 activation voltage. Together the data show that rSkM1 and hH1 activation
      mechanisms are different and are the first to suggest a role for a cytoplasmic
      structure in the voltage-dependent activation of cardiac sodium channels.

PMID- 10585923
TI  - Oxidation and reduction of pig skeletal muscle ryanodine receptors.
AB  - Time-dependent effects of cysteine modification were compared in skeletal
      ryanodine receptors (RyRs) from normal pigs and RyR(MH) (Arg(615) to Cys(615))
      from pigs susceptible to malignant hyperthermia, using the oxidizing reagents
      4,4'-dithiodipyridine (4, 4'-DTDP) and 5,5'-dithio-bis(2-nitrobenzoic acid)
      (DTNB) or the reducing agent dithiothreitol (DTT). Normal and RyR(MH) channels
      responded similarly to all reagents. DTNB (1 mM), either cytoplasmic (cis) or
      luminal (trans), or 1 mM 4,4'-DTDP (cis) activated RyRs, introducing an
      additional long open time constant. 4,4'-DTDP (cis), but not DTNB, inhibited
      channels after >5 min. Activation and inhibition were relieved by DTT (1-10 mM).
      DTT (10 mM, cytoplasmic or luminal), without oxidants, activated RyRs, and
      activation reversed with 1 mM DTNB. Control RyR activity was maintained with 1 mM
      DTNB and 10 mM DTT present on the same or opposite sides of the bilayer. We
      suggest that 1) 4,4'-DTDP and DTNB covalently modify RyRs by oxidizing activating
      or inhibiting thiol groups; 2) a modified thiol depresses mammalian skeletal RyR
      activity under control conditions; 3) both the activating thiols and the modified
      thiols, accessible from either cytoplasm or lumen, reside in the transmembrane
      region; 4) some cardiac sulfhydryls are unavailable in skeletal RyRs; and 5)
      Cys(615) in RyR(MH) is functionally unimportant in redox cycling.

PMID- 10585924
TI  - Polymeric nonelectrolytes to probe pore geometry: application to the alpha-toxin
      transmembrane channel.
AB  - Asymmetrical (one-sided) application of penetrating water-soluble polymers,
      polyethylene glycols (PEGs), to a well-defined channel formed by Staphylococcus
      aureus alpha-toxin is shown to probe channel pore geometry in more detail than
      their symmetrical (two-sided) application. Polymers added to the cis side of the
      planar lipid membrane (the side of protein addition) affect channel conductance
      differently than polymers added to the trans side. Because a satisfactory theory
      quantitatively describing PEG partitioning into a channel pore does not exist, we
      apply the simple empirical rules proposed previously (, J. Membr. Biol. 161:83
      92) to gauge the size of pore openings as well as the size and position of
      constrictions along the pore axis. We estimate the radii of the two openings of
      the channel to be practically identical and equal to 1. 2-1.3 nm. Two apparent
      constrictions with radii of approximately 0. 9 nm and approximately 0.6-0.7 nm
      are inferred to be present in the channel lumen, the larger one being closer to
      the cis side. These structural findings agree well with crystallographic data on
      the channel structure (, Science. 274:1859-1866) and verify the practicality of
      polymer probing. The general features of PEG partitioning are examined using
      available theoretical considerations, assuming there is no attraction between PEG
      and the channel lumen. It is shown that the sharp dependence of the partition
      coefficient on polymer molecular weight found under both symmetrical and
      asymmetrical polymer application can be rationalized within a "hard sphere
      nonideal solution model." This finding is rather surprising because PEG forms
      highly flexible coils in water with a Kuhn length of only several Angstroms.

PMID- 10585925
TI  - Nickel block of three cloned T-type calcium channels: low concentrations
      selectively block alpha1H.
AB  - Nickel has been proposed to be a selective blocker of low-voltage-activated, T
      type calcium channels. However, studies on cloned high-voltage-activated Ca(2+)
      channels indicated that some subtypes, such as alpha1E, are also blocked by low
      micromolar concentrations of NiCl(2). There are considerable differences in the
      sensitivity to Ni(2+) among native T-type currents, leading to the hypothesis
      that there may be more than one T-type channel. We confirmed part of this
      hypothesis by cloning three novel Ca(2+) channels, alpha1G, H, and I, whose
      currents are nearly identical to the biophysical properties of native T-type
      channels. In this study we examined the nickel block of these cloned T-type
      channels expressed in both Xenopus oocytes and HEK-293 cells (10 mM Ba(2+)). Only
      alpha1H currents were sensitive to low micromolar concentrations (IC(50) = 13
      microM). Much higher concentrations were required to half-block alpha1I (216
      microM) and alpha1G currents (250 microM). Nickel block varied with the test
      potential, with less block at potentials above -30 mV. Outward currents through
      the T channels were blocked even less. We show that depolarizations can unblock
      the channel and that this can occur in the absence of permeating ions. We
      conclude that Ni(2+) is only a selective blocker of alpha1H currents and that the
      concentrations required to block alpha1G and alpha1I will also affect high
      voltage-activated calcium currents.

PMID- 10585926
TI  - Inhibition of alphabeta epithelial sodium channels by external protons indicates
      that the second hydrophobic domain contains structural elements for closing the
      pore.
AB  - We have examined the effect of extracellular protons on the activity of
      epithelial sodium channels (ENaCs). We found that alphabeta channels, but not
      alphabetagamma or alphagamma channels, are inhibited by low extracellular pH.
      External protons induced short and long closed states that markedly decreased the
      open probability of alphabeta channels. External protons did not change the
      single-channel conductance or amiloride binding. Analysis of the proton-induced
      changes on the kinetics of single channels indicates that at least two protons
      sequentially bind to the extracellular domain at sites that are not in the ion
      pathway. Conformational changes induced by protonation of those sites are
      transmitted to the second hydrophobic domain (M2) of the subunits to induce
      closure of the pore. The results suggest that elements located in the carboxy
      terminal half of M2 participate in the gating mechanism of ENaCs.

PMID- 10585927
TI  - Cluster organization and pore structure of ion channels formed by beticolin 3, a
      nonpeptidic fungal toxin.
AB  - Beticolin 3 (B3) belongs to a family of nonpeptidic phytotoxins produced by the
      fungus Cercospora beticola, which present a broad spectrum of cytotoxic effects.
      We report here that, at cytotoxic concentration (10 microM), B3 formed voltage
      independent, weakly selective ion channels with multiple conductance levels in
      planar lipid bilayers. In symmetrical standard solutions, conductance values of
      the first levels were, respectively, 16 +/- 1 pS, 32 +/- 2 pS, and 57 +/- 2 pS (n
      = 4) and so on, any conductance level being roughly twice the lower one. Whether
      a cluster organization of elementary channels or different channel structures
      underlies this particular property was addressed by investigating the ionic
      selectivity and the pore size corresponding to the first three conductance
      levels. Both selectivity and pore size were found to be almost independent of the
      conductance level. This indicated that multiple conductance behavior resulted
      from a cluster organization of "B3 elementary channels." According to the
      estimated pore size and analyses of x-ray diffraction of B3 microcrystals, a
      structural model for "B3 elementary channels" is proposed. The ability to form
      channels is likely to be involved in the biological activity of beticolins.

PMID- 10585928
TI  - K(+)-dependent composite gating of the yeast K(+) channel, Tok1.
AB  - TOK1 encodes an outwardly rectifying K(+) channel in the plasma membrane of the
      budding yeast Saccharomyces cerevisiae. It is capable of dwelling in two
      kinetically distinct impermeable states, a near-instantaneously activating R
      state and a set of related delayed activating C states (formerly called C(2) and
      C(1), respectively). Dwell in the R state is dependent on membrane potential and
      both internal and external K(+) in a manner consistent with the K(+)
      electrochemical potential being its determinant, where dwell in the C states is
      dependent on voltage and only external K(+). Whereas activation from the C states
      showed high temperature dependencies, typical of gating transitions in other
      Shaker-like channels, activation from the R state had a temperature dependence
      nearly as low as that of simple ionic diffusion. These findings lead us to
      conclude that although the C states reflect the activity of an internally
      oriented channel gate, the R state results from an intrinsic gating property of
      the channel filter region.

PMID- 10585929
TI  - Tryptophan octyl ester in detergent micelles of dodecylmaltoside: fluorescence
      properties and quenching by brominated detergent analogs.
AB  - The fluorescence properties of tryptophan octyl ester (TOE), a hydrophobic model
      of Trp in proteins, were investigated in various mixed micelles of
      dodecylmaltoside (DM) and 7,8-dibromododecyl beta-maltoside (BrDM) or 10,11
      dibromoundecanoyl beta-maltoside (BrUM). This study focuses on the mechanism via
      which these brominated detergents quench the fluorescence of TOE in a micellar
      system. The experiments were performed at a pH at which TOE is uncharged and
      almost completely bound to detergent micelles. TOE binding was monitored by its
      enhanced fluorescence in pure DM micelles or its quenched fluorescence in pure
      BrUM or BrDM micelles. In DM/BrUM and DM/BrDM mixed micelles, the fluorescence
      intensity of TOE decreased, as a nonlinear function of the molar fraction of
      brominated detergent, to almost zero in pure brominated detergent. The indole
      moiety of TOE is therefore highly accessible to the bromine atoms located on the
      detergent alkyl chain because quenching by bromines occurs by direct contact with
      the fluorophore. TOE is simultaneously poorly accessible to iodide (I(-)), a
      water-soluble collisional quencher. TOE time-resolved fluorescence intensity
      decay is heterogeneous in pure DM micelles, with four lifetimes (from 0.2 to 4.4
      ns) at the maximum emission wavelength. Such heterogeneity may arise from dipolar
      relaxation processes in a motionally restricted medium, as suggested by the time
      dependent (nanoseconds) red shift (11 nm) of the TOE emission spectrum, and from
      the existence of various TOE conformations. Time-resolved quenching experiments
      for TOE in mixed micelles showed that the excited-state lifetime values decreased
      only slightly with increases in the proportion of BrDM or BrUM. In contrast, the
      relative amplitude of the component with the longest lifetime decreased
      significantly relative to that of the short-lived species. This is consistent
      with a mainly static mechanism for the quenching of TOE by brominated detergents.
      Molecular modeling of TOE (in vacuum and in water) suggested that the indole ring
      was stabilized by folding back upon the octyl chain, forming a hairpin
      conformation. Within micelles, the presence of such folded conformations, making
      it possible for the entire molecule to be located in the hydrophobic part of the
      micelle, is consistent with the results of fluorescence quenching experiments.
      TOE rotational correlation time values, in the nanosecond range, were consistent
      with a hindered rotation of the indole moiety and a rotation of the complete TOE
      molecule in the pure DM or mixed detergent micelles. These results, obtained with
      a simple micellar model system, provide a basis for the interpretation of
      fluorescence quenching by brominated detergents in more complex systems such as
      protein- or peptide-detergent complexes.

PMID- 10585931
TI  - The deformation of spherical vesicles with permeable, constant-area membranes:
      application to the red blood cell.
AB  - The deformation of an initially spherical vesicle of radius a with a permeable
      membrane under extensive forces applied at its poles is calculated as a function
      of the in-plane shear modulus, H, and the out-of-plane bending modulus, B, using
      an axisymmetric theory that is valid for large deformations. Suitably
      nondimensionalized, the results depend upon a single nondimensional parameter, C
      identical with a(2)H/B. For small deformations, the calculated force-polar strain
      curves are linear and, under these conditions, the slope of the curve determines
      only C, not the values of H and B separately. Independent determination of H and
      B from experimental measurements require deformations that are large enough to
      produce nonlinear behavior. Simple approximations for large and small C are
      given, which are applied to experimental measurements on red blood cell ghosts
      that have been made permeable by treatment with saponin.

PMID- 10585930
TI  - Elasticity of the red cell membrane and its relation to hemolytic disorders: an
      optical tweezers study.
AB  - We have used optical tweezers to study the elasticity of red cell membranes;
      force was applied to a bead attached to a permeabilized spherical ghost and the
      force-extension relation was obtained from the response of a second bead bound at
      a diametrically opposite position. Interruption of the skeletal network by
      dissociation of spectrin tetramers or extraction of the actin junctions
      engendered a fourfold reduction in stiffness at low applied force, but only a
      twofold change at larger extensions. Proteolytic scission of the ankyrin, which
      links the membrane skeleton to the integral membrane protein, band 3, induced a
      similar effect. The modified, unlike the native membranes, showed plastic
      relaxation under a prolonged stretch. Flaccid giant liposomes showed no
      measurable elasticity. Our observations indicate that the elastic character is at
      least as much a consequence of the attachment of spectrin as of a continuous
      membrane-bound network, and they offer a rationale for formation of elliptocytes
      in genetic conditions associated with membrane-skeletal perturbations. The theory
      of Parker and Winlove for elastic deformation of axisymmetric shells
      (accompanying paper) allows us to determine the function BH(2) for the spherical
      saponin-permeabilized ghost membranes (where B is the bending modulus and H the
      shear modulus); taking the literature value of 2 x 10(-19) Nm for B, H then
      emerges as 2 x 10(-6) Nm(-1). This is an order of magnitude higher than the value
      reported for intact cells from micropipette aspiration. Reasons for the
      difference are discussed.

PMID- 10585932
TI  - Fluorescence studies of dehydroergosterol in
      phosphatidylethanolamine/phosphatidylcholine bilayers.
AB  - Our previous fluorescence study has provided indirect evidence that lipid
      headgroup components tend to adopt regular, superlattice-like lateral
      distribution in fluid phosphatidylethanolamine/phosphatidylcholine (PE/PC)
      bilayers (, Biophys. J. 73:1967-1976). Here we have further studied this
      intriguing phenomenon by making use of the fluorescence properties of a sterol
      probe, dehydroergosterol (DHE). Fluorescence emission spectra, fluorescence
      anisotropy (r), and time-resolved fluorescence intensity decays of DHE in 1
      palmitoyl-2-oleoyl-PC (POPC)/1-palmitoyl-2-oleoyl-PE (POPE) mixtures were
      measured as a function of POPE mole fraction (X(PE)) at 23 degrees C. Deviations,
      including dips or kinks, in the ratio of fluorescence peak intensity at 375
      nm/fluorescence peak intensity at 390 nm (I(375)/I(390)), fluorescence decay
      lifetime (tau), or rotational correlation time (rho) of DHE versus PE composition
      plots were found at X(PE) approximately 0.10, 0.25, 0.33, 0.65, 0.75, and 0.88.
      The critical values at X(PE) approximately 0.33 and 0.65 were consistently
      observed for all measured parameters. In addition, the locations, but not the
      depth, of the dips for X(PE) < 0.50 did not vary significantly over 10 days of
      annealing at 23 degrees C. The observed critical values of X(PE) coincide (within
      +/-0.03) with some of the critical mole fractions predicted by a headgroup
      superlattice model proposing that the PE and PC headgroups tend to be regularly
      distributed in the plane of the bilayer. These results agree favorably with those
      obtained in our previous fluorescence study using dipyrenylPC and Laurdan probes
      and thus support the proposition that 1) regular arrangement within a domain
      exists in fluid PE/PC bilayers, and 2) superlattice formation may play a
      significant role in controlling the lipid composition of cellular membranes (,
      Proc. Natl. Acad. Sci. USA. 95:4964-4969). The present data provide new
      information on the physical properties of such superlattice domains, i.e., the
      dielectric environment and rotational motion of membrane sterols appear to change
      abruptly as the lipid headgroups exhibit regular superlattice-like distributions
      in fluid bilayers.

PMID- 10585933
TI  - Membrane lysis by the antibacterial peptides cecropins B1 and B3: A spin-label
      electron spin resonance study on phospholipid bilayers.
AB  - Custom antibacterial peptides, cecropins B1 (CB1) and B3 (CB3), were synthesized.
      These peptides have particular sequence characteristics, with CB1 having two
      amphipathic alpha-helical segments and CB3 having two hydrophobic alpha-helical
      segments. These differences were exploited for a study of their efficacy in
      breaking up liposomes, which had different combinations of phosphatidic acid (PA)
      and phosphatidylcholine (PC), and a study of their lipid binding ability. Binding
      and nonbinding lysis actions of CB1 and CB3 on liposomes were examined further by
      electron spin resonance (ESR). The spin-labeled lipids 5'SL-PC, 7'SL-PC, 10'SL
      PC, 12'SL-PC, and 16'SL-PC were used as probes. The ESR spectra revealed larger
      outer hyperfine splittings (2A(max)) for CB1 when the interactions of CB1 and CB3
      with liposomes were compared. These observations indicate a larger restriction of
      the motion of the spin-labeled chains in the presence of CB1. Plots of the
      effective order parameter at the various probe positions (chain flexibility
      gradient) versus the peptide-lipid ratio further suggested that the lysis action
      of CB1 is related to its capacity to bind to the lipid bilayers. In contrast,
      there is no evidence of binding for CB3. To augment these findings, four spin
      labeled peptides, C8SL-CB1, C32SL-CB1, C5SL-CB3, and C30SL-CB3, were also
      examined for their binding to and their state of aggregation within the lipid
      bilayers. Association isotherms of the peptides were measured for liposomes
      containing two molar fractions of PA (0.25 and 0.75). The membrane binding of the
      CB1 peptides exhibited a cooperative behavior, whereas the association isotherm
      of CB3 revealed binding to the lipid only for beta = 0.75 liposomes. To further
      identify the location of CB1 in the lipid bilayers, measurements of the collision
      rate with chromium oxalate in solution were conducted. Results from ESR power
      saturation measurements suggested that the NH(2)-terminal alpha-helix of CB1 is
      located on the surface of the lipid bilayers, whereas the COOH-terminal alpha
      helix of CB1 is embedded below the surface of the lipid bilayers. These
      conclusions were further supported by the observed relationship between the
      partition distribution of peptides bound to liposomes at different PA/PC ratios
      and the amounts of free peptides. Based on the above observations, possible
      mechanisms of the bilayer lysis induced by CB1 and CB3 on liposomes of different
      composition are discussed.

PMID- 10585934
TI  - Persistence of phase coexistence in disaturated phosphatidylcholine monolayers at
      high surface pressures.
AB  - Prior reports that the coexistence of the liquid-expanded (LE) and liquid
      condensed (LC) phases in phospholipid monolayers terminates in a critical point
      have been compromised by experimental difficulties with Langmuir troughs at high
      surface pressures and temperatures. The studies reported here used the continuous
      interface of a captive bubble to minimize these problems during measurements of
      the phase behavior for monolayers containing the phosphatidylcholines with the
      four different possible combinations of palmitoyl and/or myristoyl acyl residues.
      Isothermal compression produced surface pressure-area curves for dipalmitoyl
      phosphatidylcholine (DPPC) that were indistinguishable from previously published
      data obtained with Langmuir troughs. During isobaric heating, a steep increase in
      molecular area corresponding to the main LC-LE phase transition persisted for all
      four compounds to 45 mN/m, at which collapse of the LE phase first occurred. No
      other discontinuities to suggest other phase transitions were apparent. Isobars
      for DPPC at higher pressures were complicated by collapse of the monolayer, but
      continued to show evidence up to 65 mN/m for at least the onset of the LC-LE
      transition. The persistence of the main phase transition to high surface
      pressures suggests that a critical point for these monolayers of disaturated
      phospholipids is either nonexistent or inaccessible at an air-water interface.

PMID- 10585935
TI  - Hemifusion between cells expressing hemagglutinin of influenza virus and planar
      membranes can precede the formation of fusion pores that subsequently fully
      enlarge.
AB  - The chronological relation between the establishment of lipid continuity and
      fusion pore formation has been investigated for fusion of cells expressing
      hemagglutinin (HA) of influenza virus to planar bilayer membranes. Self-quenching
      concentrations of lipid dye were placed in the planar membrane to monitor lipid
      mixing, and time-resolved admittance measurements were used to measure fusion
      pores. For rhodamine-PE, fusion pores always occurred before a detectable amount
      of dye moved into an HA-expressing cell. However, with DiI in the planar
      membrane, the relationship was reversed: the spread of dye preceded formation of
      small pores. In other words, by using DiI as probe, hemifusion was clearly
      observed to occur before pore formation. For hemifused cells, a small pore could
      form and subsequently fully enlarge. In contrast, for cells that express a
      glycosylphosphatidylinositol-anchored ectodomain of HA, hemifusion occurred, but
      no fully enlarged pores were observed. Therefore, the transmembrane domain of HA
      is required for the formation of fully enlarging pores. Thus, with the planar
      bilayer membranes as target, hemifusion can precede pore formation, and the
      occurrence of lipid dye spread does not preclude formation of pores that can
      enlarge fully.

PMID- 10585936
TI  - Orientation of cecropin A helices in phospholipid bilayers determined by solid
      state NMR spectroscopy.
AB  - The orientation of the insect antibiotic peptide cecropin A (CecA) in the
      phospholipid bilayer membrane was determined using (15)N solid-state NMR
      spectroscopy. Two peptide samples, each specifically labeled with (15)N at
      Val(11) or Ala(27), were synthesized by solid phase techniques. The peptides were
      incorporated into phospholipid bilayers, prepared from a mixture of
      dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol, and oriented
      on glass slides. The (15)N chemical shift solid-state NMR spectra from these
      uniaxially oriented samples display a single (15)N chemical shift frequency for
      each labeled residue. Both frequencies are near the upfield end of the (15)N
      chemical shift powder pattern, as expected for an alpha-helix with its long axis
      in the plane of the membrane and the NH bonds perpendicular to the direction of
      the magnetic field. These results support a mechanism of action in which CecA
      binds to and covers the membrane surface, thereby causing a general
      destabilization and leakiness of the lipid bilayer membrane. The data are
      discussed in relation to a proposed mechanism of membrane lysis and bacterial
      killing via an ion channel activity of CecA.

PMID- 10585937
TI  - The mechanism of inactivation of a 50-pS envelope anion channel during
      chloroplast protein import.
AB  - The mechanism of import-competent precursor protein-induced inactivation of a 50
      pS anion channel of the chloroplast envelope is investigated using single-channel
      recordings. The inactivation by precursor protein is the result of the induction
      of a long-lived closed state of the channel. The mean duration of this state does
      not depend on precursor concentration. From this it can be concluded that the
      protein import related anion channel enters the inactive state less frequently
      when the precursor concentration is lowered, but that the time spent in this
      state remains the same. Furthermore, it was found that the presence of precursor
      protein also decreases the mean durations of preexisting open and closed states
      of the channel. This decrease is found to be dependent on the precursor
      concentration. From this it is concluded that there is a direct interaction
      between the precursor protein and a protein complex of which the channel is a
      constituent. The mean duration of the precursor-induced long-lived closed state
      does not depend on the length of the translocation-competent precursor. This
      suggests that the duration of import is independent of precursor length.

PMID- 10585938
TI  - A model for membrane patchiness: lateral diffusion in the presence of barriers
      and vesicle traffic.
AB  - Patches (lateral heterogeneities) of cell surface membrane proteins and lipids
      have been imaged by a number of different microscopy techniques. This patchiness
      has been taken as evidence for the organization of membranes into domains whose
      composition differs from the average for the entire membrane. However, the
      mechanism and specificity of patch formation are not understood. Here we show how
      vesicle traffic to and from a cell surface membrane can create patches of
      molecules of the size observed experimentally. Our computer model takes into
      account lateral diffusion, barriers to lateral diffusion, and vesicle traffic to
      and from the plasma membrane. Neither barriers nor vesicle traffic alone create
      and maintain patches. Only the combination of these produces a dynamic but
      persistent patchiness of membrane proteins and lipids.

PMID- 10585939
TI  - Electrostatic properties of membranes containing acidic lipids and adsorbed basic
      peptides: theory and experiment.
AB  - The interaction of heptalysine with vesicles formed from mixtures of the acidic
      lipid phosphatidylserine (PS) and the zwitterionic lipid phosphatidylcholine (PC)
      was examined experimentally and theoretically. Three types of experiments showed
      that smeared charge theories (e.g., Gouy-Chapman-Stern) underestimate the
      membrane association when the peptide concentration is high. First, the zeta
      potential of PC/PS vesicles in 100 mM KCl solution increased more rapidly with
      heptalysine concentration (14.5 mV per decade) than predicted by a smeared charge
      theory (6.0 mV per decade). Second, changing the net surface charge density of
      vesicles by the same amount in two distinct ways produced dramatically different
      effects: the molar partition coefficient decreased 1000-fold when the mole
      percentage of PS was decreased from 17% to 4%, but decreased only 10-fold when
      the peptide concentration was increased to 1 microM. Third, high concentrations
      of basic peptides reversed the charge on PS and PC/PS vesicles. Calculations
      based on finite difference solutions to the Poisson-Boltzmann equation applied to
      atomic models of heptalysine and PC/PS membranes provide a molecular explanation
      for the observations: a peptide adsorbing to the membrane in the presence of
      other surface-adsorbed peptides senses a local potential more negative than the
      average potential. The biological implications of these "discreteness-of-charge"
      effects are discussed.

PMID- 10585941
TI  - Extensibility and symmetry of actin filaments in contracting muscles.
AB  - When isometrically contracting muscles are subjected to a quick release followed
      by a shortening ramp of appropriate speed (V(o)), tension decays from its value
      at the isometric plateau (P(o)) to <0. 05 P(o) with the same time course as the
      quick part of the release; thereafter, tension remains at a negligible level for
      the duration of the shortening ramp. X-ray diffraction data obtained under these
      conditions provide evidence that 1) at V(o) very few heads form an actomyosin
      complex, while the number of heads doing so at P(o) is significant; 2) relative
      to rest the actin filament at V(o) is approximately 0.12% shorter and more
      twisted, while it is approximately 0.3% longer and less twisted at P(o); and 3)
      the myosin heads attaching to actin during force development do so against a thin
      filament compliance of at least 0.646 +/- 0.046% nm per P(o).

PMID- 10585940
TI  - Molecular dissection of N2B cardiac titin's extensibility.
AB  - Titin is a giant filamentous polypeptide of multidomain construction spanning
      between the Z- and M-lines of the cardiac muscle sarcomere. Extension of the I
      band segment of titin gives rise to a force that underlies part of the diastolic
      force of cardiac muscle. Titin's force arises from its extensible I-band region,
      which consists of two main segment types: serially linked immunoglobulin-like
      domains (tandem Ig segments) interrupted with a proline (P)-, glutamate (E)-,
      valine (V)-, and lysine (K)-rich segment called PEVK segment. In addition to
      these segments, the extensible region of cardiac titin also contains a unique 572
      residue sequence that is part of the cardiac-specific N2B element. In this work,
      immunoelectron microscopy was used to study the molecular origin of the in vivo
      extensibility of the I-band region of cardiac titin. The extensibility of the
      tandem Ig segments, the PEVK segment, and that of the unique N2B sequence were
      studied, using novel antibodies against Ig domains that flank these segments.
      Results show that only the tandem Igs extend at sarcomere lengths (SLs) below
      approximately 2.0 microm, and that, at longer SLs, the PEVK and the unique
      sequence extend as well. At the longest SLs that may be reached under
      physiological conditions ( approximately 2.3 microm), the PEVK segment length is
      approximately 50 nm whereas the unique N2B sequence is approximately 80 nm long.
      Thus, the unique sequence provides additional extensibility to cardiac titins and
      this may eliminate the necessity for unfolding of Ig domains under physiological
      conditions. In summary, this work provides direct evidence that the three main
      molecular subdomains of N2B titin are all extensible and that their contribution
      to extensibility decreases in the order of tandem Igs, unique N2B sequence, and
      PEVK segment.

PMID- 10585942
TI  - Calponin interaction with alpha-actinin-actin: evidence for a structural role for
      calponin.
AB  - The purpose of this study was to address the paradox of calponin localization
      with alpha-actinin and filamin, two proteins with tandem calponin homology (CH)
      domains, by determining the effect of these proteins on the binding of calponin
      to actin. The results show that actin can accommodate near-saturating
      concentrations of either calponin and alpha-actinin or calponin and filamin with
      little change or no change in ligand affinity. Little direct interaction occurred
      between alpha-actinin and calponin in the absence of actin, so this effect is not
      likely to explain the co-distribution of these proteins. Calponin, like alpha
      actinin, induced elastic gel formation when added to actin. When alpha-actinin
      was added to newly formed calponin/actin gels, no change was seen in the
      mechanical properties of the gel compared to calponin and actin alone. However,
      when calponin was added to newly formed alpha-actinin/actin gels, the resulting
      gel was much stronger than the gels formed by either ligand alone. Furthermore,
      gels formed by the addition of calponin to alpha-actinin/actin exhibited a
      phenomenon known as strain hardening, a characteristic of mechanically resilient
      gels. These results add weight to the concept that one of the functions of
      calponin is to stabilize the actin cytoskeleton.

PMID- 10585943
TI  - Abasic sites in duplex DNA: molecular modeling of sequence-dependent effects on
      conformation.
AB  - Molecular modeling calculations using JUnction Minimization of Nucleic Acids
      (JUMNA) have been used to study sequence effects on the conformation of abasic
      sites within duplex DNA. We have considered lesions leading to all possible
      unpaired bases (X), adenine, guanine, cytosine, or thymine contained within two
      distinct sequence contexts, CXC and GXG. Calculations were carried out on DNA 11
      mers using extensive conformational search techniques to locate the most stable
      abasic conformations and using Poisson-Boltzmann corrected electrostatics to
      account for solvation effects. The results, which are in very good agreement with
      available experimental data, point to strong sequence effects on both the
      position of the unpaired base (intra or extrahelical) and on the overall
      curvature induced by the abasic lesion. For CXC, unpaired purines are found to
      lie within the helix, while unpaired pyrimidines are either extrahelical or in
      equilibrium between the intra and extrahelical forms. For GXG, all unpaired bases
      lead to intrahelical forms, but with marked, sequence-dependent differences in
      induced curvature.

PMID- 10585944
TI  - Microsecond time-scale discrimination among polycytidylic acid, polyadenylic
      acid, and polyuridylic acid as homopolymers or as segments within single RNA
      molecules.
AB  - Single molecules of DNA or RNA can be detected as they are driven through an
      alpha-hemolysin channel by an applied electric field. During translocation,
      nucleotides within the polynucleotide must pass through the channel pore in
      sequential, single-file order because the limiting diameter of the pore can
      accommodate only one strand of DNA or RNA at a time. Here we demonstrate that
      this nanopore behaves as a detector that can rapidly discriminate between
      pyrimidine and purine segments along an RNA molecule. Nanopore detection and
      characterization of single molecules represent a new method for directly reading
      information encoded in linear polymers, and are critical first steps toward
      direct sequencing of individual DNA and RNA molecules.

PMID- 10585945
TI  - Crowding effects on EcoRV kinetics and binding.
AB  - The cytosol of the cell contains high concentrations of small and large
      macromolecules, but experimental data are often obtained in dilute solutions that
      do not reflect in vivo conditions. We have studied the crowding effect that large
      macromolecules have on EcoRV cleavage by adding high-molecular-weight Ficoll 70
      to reaction solutions. Results indicate that Ficoll has surprisingly little
      effect on overall EcoRV reaction velocity because of offsetting increases in
      V(max) and K(m), and stronger nonspecific binding. The changes in measured
      parameters can largely be attributed to the excluded volume effects on reactant
      activities and the slowing of protein diffusion. Covolume reduction upon binding
      appears to reinforce nonspecific binding strength, and k(cat) appears to be
      slowed by stronger nonspecific binding, which slows product release. The data
      also suggest that effective Ficoll particle volume decreases as its concentration
      increases above a few weight percent, which may be due to Ficoll interpenetration
      or compression.

PMID- 10585946
TI  - Heat capacity effects on the melting of DNA. 1. General aspects.
AB  - In this paper we analyze published data on DeltaH and DeltaS values for the DNA
      melting transition under various conditions. We show that there is a significant
      heat capacity increase DeltaC(p) associated with DNA melting, in the range of 40
      100 cal/mol K per base pair. This is larger than the transition entropy per base
      pair, DeltaS(0) approximately 25 cal/mol K. The ratio of DeltaC(p)/DeltaS(0)
      determines the importance of heat capacity effects on melting. For DNA this ratio
      is 2-4, larger than for many proteins. We discuss how DeltaC(p) values can be
      extracted from experimental data on the dependence of DeltaH and DeltaS on the
      melting temperature T(m). We consider studies of DNA melting as a function of
      ionic strength and show that while polyelectrolyte theory provides a good
      description of the dependence of T(m) on salt, electrostatics alone cannot
      explain the accompanying strong variation of DeltaH and DeltaS. While T(m) is
      only weakly affected by DeltaC(p), its dependence on one parameter (e.g., salt)
      as a function of another (e.g., DNA composition) is determined by DeltaC(p). We
      show how this accounts for the stronger stabilization of AT relative to GC base
      pairs with increasing ionic strength. We analyze the source of discrepancies in
      DeltaH as determined by calorimetry and van't Hoff analysis and discuss ways of
      analyzing data that yield valid van't Hoff DeltaH. Finally, we define a standard
      state for DNA melting, the temperature at which thermal contributions to DeltaH
      and DeltaS vanish, by analyzing experimental data over a broad range of
      stabilities.

PMID- 10585947
TI  - Heat capacity effects on the melting of DNA. 2. Analysis of nearest-neighbor base
      pair effects.
AB  - The stability of a DNA double helix of any particular sequence is conventionally
      estimated as the average of the stabilities of the 10 different nearest-neighbor
      (NN) base pair doublets that it contains. Therefore, much effort has been devoted
      to the experimental characterization and tabulation of the enthalpy, entropy, and
      free energy of melting for each of the NN doublets. Although data from different
      research groups generally agree for the NN free energies and melting
      temperatures, there are major disagreements for the enthalpies and entropies. The
      largest differences are between the parameters obtained on oligomeric relative to
      polymeric DNA. This disagreement interferes with the practical application of NN
      thermodynamic parameters. It also raises doubts regarding several fundamental
      assumptions about DNA melting, such as the absence of longer range interactions,
      the length dependence of DNA melting parameters per base pair, the applicability
      of polyelectrolyte theory to the description of salt effects on oligomers, and
      the purely enthalpic difference between NN doublets. Here we show that if one
      takes into account the significant heat capacity increase associated with DNA
      melting, all of the above assumptions are self-consistently reconciled with
      experiment.

PMID- 10585948
TI  - Flexibility of duplex DNA on the submicrosecond timescale.
AB  - Using a site-specific, Electron Paramagnetic Resonance (EPR)-active spin probe
      that is more rigidly locked to the DNA than any previously reported, the internal
      dynamics of duplex DNAs in solution were studied. EPR spectra of linear duplex
      DNAs containing 14-100 base pairs were acquired and simulated by the stochastic
      Liouville equation for anisotropic rotational diffusion using the diffusion
      tensor for a right circular cylinder. Internal motions have previously been
      assumed to be on a rapid enough time scale that they caused an averaging of the
      spin interactions. This assumption, however, was found to be inconsistent with
      the experimental data. The weakly bending rod model is modified to take into
      account the finite relaxation times of the internal modes and applied to analyze
      the EPR spectra. With this modification, the dependence of the oscillation
      amplitude of the probe on position along the DNA was in good agreement with the
      predictions of the weakly bending rod theory. From the length and position
      dependence of the internal flexibility of the DNA, a submicrosecond dynamic
      bending persistence length of around 1500 to 1700 A was found. Schellman and
      Harvey (Biophys. Chem. 55:95-114, 1995) have estimated that, out of the total
      persistence length of duplex DNA, believed to be about 500 A, approximately 1500
      A is accounted for by static bends and 750 A by fluctuating bends. A measured
      dynamic persistence length of around 1500 A leads to the suggestion that there
      are additional conformations of the DNA that relax on a longer time scale than
      that accessible by linear CW-EPR. These measurements are the first direct
      determination of the dynamic flexibility of duplex DNA in 0.1 M salt.

PMID- 10585949
TI  - Time-resolved absorption and photothermal measurements with recombinant sensory
      rhodopsin II from Natronobacterium pharaonis.
AB  - Purified wild-type sensory rhodopsin II from Natronobacterium pharaonis (pSRII
      WT) and its histidine-tagged analog (pSRII-His) were studied by laser-induced
      optoacoustic spectroscopy (LIOAS) and flash photolysis with optical detection.
      The samples were either dissolved in detergent or reconstituted into polar lipids
      from purple membrane (PML). The quantum yield for the formation of the long-lived
      state M(400) was determined as Phi(M) = 0.5 +/- 0.06 for both proteins. The
      structural volume change accompanying the production of K(510) as determined with
      LIOAS was DeltaV(R,1) </= 10 ml for both proteins, assuming Phi(K) >/= Phi(M),
      indicating that the His tag does not influence this early step of the photocycle.
      The medium has no influence on DeltaV(R,1), which is the largest so far measured
      for a retinal protein in this time range (<10 ns). This confirms the occurrence
      of conformational movements in pSRII for this step, as previously suggested by
      Fourier transform infrared spectroscopy. On the contrary, the decay of K(510) is
      an expansion in the detergent-dissolved sample and a contraction in PML. Assuming
      an efficiency of 1.0, DeltaV(R,2) = -3 ml/mol for pSRII-WT and -4.6 ml/mol for
      pSRII-His were calculated in PML, indicative of a small structural difference
      between the two proteins. The energy content of K(510) is also affected by the
      tag. It is E(K) = (88 +/- 13) for pSRII-WT and (134 +/- 11) kJ/mol for pSRII-His.
      A slight difference in the activation parameters for K(510) decay confirms an
      influence of the C-terminal His on this step. At variance with DeltaV(R,1), the
      opposite sign of DeltaV(R,2) in detergent and PML suggests the occurrence of
      solvation effects on the decay of K(510), which are probably due to a different
      interaction of the active site with the two dissolving media.

PMID- 10585950
TI  - Ab initio study of the role of lysine 16 for the molecular switching mechanism of
      Ras protein p21.
AB  - Quantum chemical computations using the ab initio molecular orbital (MO) method
      have been performed to investigate the molecular switching mechanism of Ras
      protein p21, which has an important role in intracellular signal cascades.
      Lys(16) was demonstrated to be crucial to the function of Ras p21, and the
      hydrolysis of GTP to GDP was found to be an one-step reaction. The potential
      energy barrier of this hydrolysis reaction from GTP to (GDP + P) was calculated
      to be approximately 42 kcal/mol. The role of GAP (GTPase-activating protein) was
      also discussed in terms of the delivery of the water molecules required for the
      hydrolysis.

PMID- 10585951
TI  - Sampling field heterogeneity at the heme of c-type cytochromes by spectral hole
      burning spectroscopy and electrostatic calculations.
AB  - We report on a comparative investigation of the heme pocket fields of two Zn
      substituted c-type cytochromes-namely yeast and horse heart cytochromes c-using a
      combination of hole burning Stark spectroscopy and electrostatic calculations.
      The spectral hole burning experiments are consistent with different pocket fields
      experienced at the hemes of the respective cytochromes. In the case of horse
      heart Zn-cytochrome c, two distinguishable electronic origins with different
      electrostatic properties are observed. The yeast species, on the other hand,
      displays a single electronic origin. Electrostatic calculations and graphics
      modeling using the linearized finite-difference Poisson-Boltzmann equation
      performed at selected time intervals on nanosecond-molecular dynamics
      trajectories show that the hemes of the respective cytochromes sample different
      potentials as they explore conformational space. The electrostatic potentials
      generated by the protein matrix at the heme show different patterns in both
      cytochromes, and we suggest that the cytochromes differ by the number of
      "electrostatic substates" that they can sample, thus accounting for the different
      spectral populations observed in the two cytochromes.

PMID- 10585952
TI  - Amyloid-beta-sheet formation at the air-water interface.
AB  - An amyloid(1-40) solution rich in coil, turn, and alpha-helix, but poor in beta
      sheet, develops monolayers with a high beta-sheet content when spread at the air
      water interface. These monolayers are resistant to repeated compression
      dilatation cycles and interaction with trifluoroethanol. The secondary structure
      motifs were detected by circular dichroism (CD) in solution and with infrared
      reflection-absorption spectroscopy (IRRAS) at the interface. Hydrophobic
      influences are discussed for the structure conversion in an effort to understand
      the completely unknown reason for the natural change of the normal prion protein
      cellular (PrP(C)) into the abnormal prion protein scrapie (PrP(Sc)).

PMID- 10585953
TI  - Role of hydration water in protein unfolding.
AB  - In this paper, following our work on the two-state outer neighbor mixed bonding
      model of water, it is proposed that polar groups promote the formation of the low
      density ice Ih-type bonding in their neighborhood, whereas nonpolar groups tend
      to promote the higher density ice II-type structure. In a protein, because of the
      large numbers of exposed polar and nonpolar groups, large changes in the
      neighboring water structure can occur. These changes, of course, depend on
      whether the protein is in its native or its unfolded state and will be shown here
      to have a direct impact on the thermodynamics of protein unfolding at both high
      and low temperatures. For example, it is known that the polar hydration entropies
      become rapidly more negative with increasing temperature. This very unusual
      behavior can be directly related to the promotion in the outer bulk liquid of the
      more stable Ih-type bonding at the expense of II-type bonding by polar groups of
      the protein. In contrast, nonpolar groups have an opposite effect on the
      thermodynamics. It is the delicate balance created by these outer hydration
      contributions, mixed with ordinary thermodynamic contributions from the inner
      hydration shell and those from hydrogen-bond and van der Waals forces within the
      protein molecule itself that is responsible for both heat and cold denaturation
      of proteins.

PMID- 10585954
TI  - Energetics of Na(+)-Ca(2+) exchange in resting cardiac muscle.
AB  - The energetic effect of extracellular Na(+) removal and readmission (in a
      nominally Ca(2+)-free perfusate) in Langendorff-perfused ventricles of transgenic
      mice (TM), which overexpress the sarcolemmal Na(+)-Ca(2+) exchanger; normal mice
      (NM); young (7-12 days old) rats (YR); and older (13-20 days old) rats (OR) was
      studied. In all heart muscles, extracellular Na(+) removal induced an increase in
      heat production (H(1)). Na(+) readmission further increased heat production to a
      peak value (H(2)) followed by a decrease toward initial values. These effects
      were more marked in the YR and TM as compared with the OR and NM groups,
      respectively. Caffeine (1 mM), ryanodine (0.2 microM), and verapamil (1 microM)
      decreased H(1) and H(2) in both rat groups. EGTA (1 mM) decreased H(1) and H(2)
      in the YR but not in the OR group. Thapsigargin (1 microM) decreased H(1) and
      H(2) in all four hearts preparations. A possible interpretation is that Na(+)
      Ca(2+) exchange acts as an energy-saving mechanism to prevent Ca(2+) accumulation
      at the junctional sarcoplasmic reticulum zone (JSR) and thus prevents further
      release of Ca(2+). Extracellular Na(+) removal lead to Ca(2+) accumulation in the
      JSR inducing further SR-Ca(2+) release and increased energy release. Na(+)
      readmission removes the accumulated Ca(2+) at the JSR (cleft) zone by exchanging
      Ca(2+) with Na(+) producing a transitory increase in energy release due to Na(+)
      K pump activation.

PMID- 10585955
TI  - Spectroscopic properties of the CP43 core antenna protein of photosystem II.
AB  - CP43 is a chlorophyll-protein complex that funnels excitation energy from the
      main light-harvesting system of photosystem II to the photochemical reaction
      center. We purified CP43 from spinach photosystem II membranes in the presence of
      the nonionic detergent n-dodecyl-beta,D-maltoside and recorded its spectroscopic
      properties at various temperatures between 4 and 293 K by a number of polarized
      absorption and fluorescence techniques, fluorescence line narrowing, and Stark
      spectroscopy. The results indicate two "red" states in the Q(y) absorption region
      of the chlorophylls. The first peaks at 682.5 nm at 4 K, has an extremely narrow
      bandwidth with a full width at half-maximum of approximately 2.7 nm (58 cm(-1))
      at 4 K, and has the oscillator strength of a single chlorophyll. The second peaks
      at approximately 679 nm, has a much broader bandshape, is caused by several
      excitonically interacting chlorophylls, and is responsible for all 4 K absorption
      at wavelengths longer than 685 nm. The Stark spectrum of CP43 resembles the first
      derivative of the absorption spectrum and has an exceptionally small overall
      size, which we attribute to opposing orientations of the monomer dipole moments
      of the excitonically coupled pigments.

PMID- 10585956
TI  - High-resolution nonlinear optical imaging of live cells by second harmonic
      generation.
AB  - By adapting a laser scanning microscope with a titanium sapphire femtosecond
      pulsed laser and transmission optics, we are able to produce live cell images
      based on the nonlinear optical phenomenon of second harmonic generation (SHG).
      Second harmonic imaging (SHIM) is an ideal method for probing membranes of living
      cells because it offers the high resolution of nonlinear optical microscopy with
      the potential for near-total avoidance of photobleaching and phototoxicity. The
      technique has been implemented on three cell lines labeled with membrane-staining
      dyes that have large nonlinear optical coefficients. The images can be obtained
      within physiologically relevant time scales. Both achiral and chiral dyes were
      used to compare image formation for the case of single- and double-leaflet
      staining, and it was found that chirality plays a significant role in the
      mechanism of contrast generation. It is also shown that SHIM is highly sensitive
      to membrane potential, with a depolarization of 25 mV resulting in an
      approximately twofold loss of signal intensity.

PMID- 10585957
TI  - Second harmonic generation of glucose oxidase at the air/water interface.
AB  - We present a study of the adsorption of the glucose oxidase enzyme (GOx) at the
      air/water interface, using the nonlinear optical technique of surface second
      harmonic generation (SSHG). Resonant SSHG experiments were achieved by probing
      the pi-pi* transition of the flavin adenine dinucleotide (FAD) chromophores
      embedded in the GOx protein. Because of the subsequent resonance enhancement of
      the signal, the second harmonic (SH) wave arising from the GOx entities adsorbed
      at the interface was detectable for protein bulk aqueous concentrations as low as
      70 nM. The protein adsorption was followed, and, at high GOx coverage, a change
      in the orientation of the FAD chromophore was observed, indicating either a
      rearrangement or a reorientation of the protein at the interface. Inasmuch as GOx
      is negatively charged at the biological pH of 7, its interactions with charged
      surfactants were also investigated. As expected, spreading positively charged
      surfactants onto a partial protein monolayer was found to increase the GOx
      surface concentration, whereas in the case of negatively charged surfactants, the
      GOx surface concentration decreased until the SH signal went back to the pure
      buffer solution response level. With the increasing GOx surface concentration,
      the rearrangement or reorientation of the protein was also observed.

PMID- 10585958
TI  - Torocyte membrane endovesicles induced by octaethyleneglycol dodecylether in
      human erythrocytes.
AB  - Endovesicles induced in human erythrocytes by octaethyleneglycol dodecylether
      (C12E8) were studied by confocal laser scanning microscopy, using fluorescein
      isothiocyanate dextran as a nonspecific fluid marker. The endovesicles appeared
      to consist mainly of a ring-formed toroidal part joined with a central flat
      membrane segment. The torocyte contour length was several microm. There was
      usually one torocyte endovesicle per cell. The endovesicles seemed to be located
      near the cell surface. In sections of C12E8-treated erythrocytes transmission
      electron microscopy revealed the frequent occurrence of flat membrane structures
      with a bulby periphery, which apparently are cross sections of torocyte
      endovesicles. The possible physical mechanisms leading to the observed torocyte
      endovesicle shape are discussed. The torocyte endovesicles seem to be formed in a
      process in which an initially stomatocytic invagination loses volume while
      maintaining a large surface area. Because intercalation of C12E8 in the
      erythrocyte membrane induces inward membrane bending (stomatocytosis) we assume
      that C12E8 is preferentially located in the inner lipid layer of the erythrocyte
      membrane, i.e., in the outer lipid layer of the endovesicle membrane. It is
      suggested that local disturbances of the lipid molecules in the vicinity of the
      C12E8 molecules in the outer lipid layer of the endovesicle membrane form
      membrane inclusions with the effective shape of an inverted truncated cone. If
      the interaction between the inclusion and the membrane is weak, the membrane of
      such an endovesicle can be characterized by its negative spontaneous curvature,
      which may lead to a torocyte endovesicle shape with a small relative volume.
      Effects of a possible strong interaction between the C12E8-induced membrane
      inclusions and the membrane on the stability of the torocyte endovesicles are
      also indicated.

PMID- 10585959
TI  - Membrane tether formation from blebbing cells.
AB  - Membrane tension has been proposed to be important in regulating cell functions
      such as endocytosis and cell motility. The apparent membrane tension has been
      calculated from tether forces measured with laser tweezers. Both membrane
      cytoskeleton adhesion and membrane tension contribute to the tether force.
      Separation of the plasma membrane from the cytoskeleton occurs in membrane blebs,
      which could remove the membrane-cytoskeleton adhesion term. In renal epithelial
      cells, tether forces are significantly lower on blebs than on membranes that are
      supported by cytoskeleton. Furthermore, the tether forces are equal on apical and
      basolateral blebs. In contrast, tether forces from membranes supported by the
      cytoskeleton are greater in apical than in basolateral regions, which is
      consistent with the greater apparent cytoskeletal density in the apical region.
      We suggest that the tether force on blebs primarily contains only the membrane
      tension term and that the membrane tension may be uniform over the cell surface.
      Additional support for this hypothesis comes from observations of melanoma cells
      that spontaneously bleb. In melanoma cells, tether forces on blebs are
      proportional to the radius of the bleb, and as large blebs form, there are spikes
      in the tether force in other cell regions. We suggest that an internal osmotic
      pressure inflates the blebs, and the pressure calculated from the Law of Laplace
      is similar to independent measurements of intracellular pressures. When the
      membrane tension term is subtracted from the apparent membrane tension over the
      cytoskeleton, the membrane-cytoskeleton adhesion term can be estimated. In both
      cell systems, membrane-cytoskeleton adhesion was the major factor in generating
      the tether force.

PMID- 10585960
TI  - A direct comparison of selectin-mediated transient, adhesive events using high
      temporal resolution.
AB  - Leukocyte capture and rolling on the vascular endothelium is mediated principally
      by the selectin family of cell adhesion receptors. In a parallel plate flow
      chamber, neutrophil rolling on purified selectins or a selectin-ligand substrate
      was resolved by high speed videomicroscopy as a series of ratchet-like steps with
      a characteristic time constant (Kaplanski, G., C. Farnarier, O. Tissot, A.
      Pierres, A.-M. Benoliel, M. C. Alessi, S. Kaplanski, and P. Bongrand. 1993.
      Biophys. J. 64:1922-1933; Alon, R., D. A. Hammer, and T. A. Springer. 1995.
      Nature (Lond.). 374:539-542). Under shear, neutrophil arrests due to bond
      formation events were as brief as 4 ms. Pause time distributions for neutrophils
      tethering on P-, E-, L-selectin, or peripheral node addressin (PNAd) were
      compared at estimated single bond forces ranging from 37 to 250 pN. Distributions
      of selectin mediated pause times were fit to a first order exponential, resulting
      in a molecular dissociation constant (k(off)) for the respective selectin as a
      function of force. At estimated single bond forces of 125 pN and below, all three
      selectin dissociation constants fit the Bell and Hookean spring models of force
      driven bond breakage equivalently. Unstressed k(off) values based on the Bell
      model were 2.4, 2.6, 2.8, 3.8 s(-1) for P-selectin, E-selectin, L-selectin, and
      PNAd, respectively. Bond separation distances (reactive compliance) were 0.39,
      0.18, 1.11, 0.59 A for P-selectin, E-selectin, L-selectin, and PNAd,
      respectively. Dissociation constants for L-selectin and P-selectin at single bond
      forces above 125 pN were considerably lower than either Bell or Hookean spring
      model predictions, suggesting the existence of two regimes of reactive
      compliance. Additionally, interactions between L-selectin and its leukocyte
      ligand(s) were more labile in the presence of flow than the L-selectin
      endothelial ligand, PNAd, suggesting that L-selectin ligands may have different
      molecular and mechanical properties. Both types of L-selectin bonds had a higher
      reactive compliance than P-selectin or E-selectin bonds.

PMID- 10585961
TI  - Magnesium binding to DM-nitrophen and its effect on the photorelease of calcium.
AB  - The effect of Mg(2+) on the process of Ca(2+) release from the caged Ca(2+)
      compound DM-nitrophen (NP) was studied in vitro by steady light UV photolysis of
      NP in the presence of Ca(2+) and Mg(2+). Ca(2+) release during photolysis and its
      relaxation/recovery after photolysis were monitored with the Ca(2+)-sensitive dye
      fura-2. Mg(2+) speeds the photorelease of Ca(2+) during photolysis and slows the
      relaxation of Ca(2+) to new steady-state levels after photolysis. Within the
      context of a model describing NP photolysis, we determined the on and off rates
      of Mg(2+) binding to unphotolyzed NP (k(on) = 6.0 x 10(4) M(-1) s(-1); k(off) =
      1.5 x 10(-1) s(-1)). Furthermore, to fully account for the slow postphotolysis
      kinetics of Ca(2+) in the presence of Mg(2+) we were forced to add an additional
      photoproduct to the standard model of NP photolysis. The additional photoproduct
      is calculated to have a Ca(2+) affinity of 13.3 microM and is hypothesized to be
      produced by the photolysis of free or Mg(2+)-bound NP; photolysis of Ca(2+)-bound
      NP produces the previously documented 3 mM Ca(2+) affinity photoproduct.

PMID- 10585962
TI  - Analysis of competition binding between soluble and membrane-bound ligands for
      cell surface receptors.
AB  - Binding of the Fc portion of IgG coated on targets to Fcgamma receptors (e.g.,
      CD16) expressed on leukocytes (i.e., 2D binding) is an initiating step for immune
      responses such as phagocytosis or antibody-dependent cellular cytotoxicity. In
      vivo, circulating leukocytes are exposed to plasma IgG. The competition from
      soluble IgG (i.e., 3D binding) may affect the 2D binding. Many cell surface
      receptors, CD16 included, have soluble counterparts. While their physiological
      significance is not clear, receptor-based competitive inhibition therapy, in
      which soluble receptors, ligands, and their analogs are employed to compete with
      surface-bound receptors and ligands to prevent unwanted adhesion, is widely used
      to treat various diseases. To provide a quantitative basis for design of these
      therapeutic approaches, we developed a mathematical model for 2D and 3D
      competition binding. The model relates cell-surface adhesion (in the presence and
      absence of dislodging forces) to the concentration of the soluble competitor, the
      densities of the surface-bound receptors and ligands, as well as the binding
      affinities of the 2D and 3D interactions. Binding of CD16-expressing cells to an
      IgG-coated surface in the presence of a soluble competitor (IgG or anti-CD16
      antibody) was quantified by a centrifugation assay. The agreement between
      experiment and theory supports the validity of the model, which could be useful
      in predicting the efficacy of the competitor.

PMID- 10585963
TI  - An analysis of actin delivery in the acrosomal process of thyone.
AB  - The acrosomal process of the sea cucumber Thyone briareus can extend 90 microm in
      10 s, but an epithelial goldfish keratocyte can only glide a few microns in the
      same time. Both speeds reflect the rate of extension of an actin network. The
      difference is in the delivery of actin monomers to the polymerization region.
      Diffusion supplies monomers fast enough to support the observed speed of goldfish
      keratocytes, but previous models have indicated that the acrosomal process of
      Thyone extends too rapidly for diffusion to keep up. Here we reexamine the
      assumptions made in earlier models and present a new model, the Actin
      Reconcentration Model, that includes more biological detail. Salt and water
      fluxes during the acrosomal reaction and the nonideality of the cytoplasm are
      particularly significant for actin delivery. We find that the variability of the
      acrosomal growth curve can be explained by the salt and water fluxes, and that
      nonideality magnifies the effect of actin concentration changes. We calculate the
      speed of process growth using biologically relevant parameters from the
      literature and find that the predictions of the model fall among the experimental
      data.

PMID- 10585964
TI  - Alkaliphiles: some applications of their products for biotechnology.
AB  - The term "alkaliphile" is used for microorganisms that grow optimally or very
      well at pH values above 9 but cannot grow or grow only slowly at the near-neutral
      pH value of 6.5. Alkaliphiles include prokaryotes, eukaryotes, and archaea. Many
      different taxa are represented among the alkaliphiles, and some of these have
      been proposed as new taxa. Alkaliphiles can be isolated from normal environments
      such as garden soil, although viable counts of alkaliphiles are higher in samples
      from alkaline environments. The cell surface may play a key role in keeping the
      intracellular pH value in the range between 7 and 8.5, allowing alkaliphiles to
      thrive in alkaline environments, although adaptation mechanisms have not yet been
      clarified. Alkaliphiles have made a great impact in industrial applications.
      Biological detergents contain alkaline enzymes, such as alkaline cellulases
      and/or alkaline proteases, that have been produced from alkaliphiles. The current
      proportion of total world enzyme production destined for the laundry detergent
      market exceeds 60%. Another important application is the industrial production of
      cyclodextrin by alkaline cyclomaltodextrin glucanotransferase. This enzyme has
      reduced the production cost and paved the way for cyclodextrin use in large
      quantities in foodstuffs, chemicals, and pharmaceuticals. It has also been
      reported that alkali-treated wood pulp could be biologically bleached by
      xylanases produced by alkaliphiles. Other applications of various aspects of
      alkaliphiles are also discussed.

PMID- 10585966
TI  - Pathology and epizootiology of Entomophaga maimaiga infections in forest
      Lepidoptera.
AB  - The insect-pathogenic fungal pathogen Entomophaga maimaiga is endemic to
      northeastern Asia and was first found in North America in 1989. Due to repeated
      epizootics and spread within populations of the major forest defoliator in
      northeastern North America, the gypsy moth (Lymantria dispar), this pathogen has
      gained much notoriety. Although this pathogen was purposely introduced to North
      America for biological control of L. dispar in 1910 to 1911, it is questionable
      whether it became established at the time of release and then remained at
      innocuous levels until relatively recently. Alternatively, the fungal strain
      present in North America today could be a more recent accidental introduction.
      DNA analysis demonstrates that this pathogen differs significantly from North
      American members of the same species complex (the Lepidoptera-specific
      Entomophaga aulicae species complex), and, to date, isolates of this introduced
      pathogen display little heterogeneity in North America. Nonsusceptible
      lepidopteran larvae have been identified, and either E. maimaiga is unable to
      penetrate the cuticle or the fungus cannot survive within the hemocoel. In the
      latter case, although E. maimaiga grows as protoplasts lacking cell walls in the
      host hemolymph, glycoproteins on plasma membranes of the protoplasts could lead
      to host recognition. Epizootiological studies demonstrate a clear association
      between fungal activity and environmental moisture but little association with
      host density under hypothesized conditions of high fungal density. Prediction of
      the occurrence of epizootics is not yet possible. E. maimaiga is easily
      established in new areas by releasing azygospores, but the ability to use this
      pathogen further for biological control will depend, in large part, on the
      development of mass production systems.

PMID- 10585967
TI  - Retroviral DNA integration.
AB  - DNA integration is a unique enzymatic process shared by all retroviruses and
      retrotransposons. During integration, double-stranded linear viral DNA is
      inserted into the host genome in a process catalyzed by the virus-encoded
      integrase (IN). The mechanism involves a series of nucleophilic attacks, the
      first of which removes the terminal 2 bases from the 3' ends of the long terminal
      repeats and of the second which inserts the viral DNA into the host genome. IN
      specifically recognizes the DNA sequences at the termini of the viral DNA,
      juxtaposing both ends in an enzyme complex that inserts the viral DNA into a
      single site in a concerted manner. Small duplications of the host DNA,
      characteristic of the viral IN, are found at the sites of insertion. At least two
      host proteins, HMG-I(Y) and BAF, have been shown to increase the efficiency of
      the integration reaction.

PMID- 10585968
TI  - Prions in Saccharomyces and Podospora spp.: protein-based inheritance.
AB  - Genetic evidence showed two non-Mendelian genetic elements of Saccharomyces
      cerevisiae, called [URE3] and [PSI], to be prions of Ure2p and Sup35p,
      respectively. [URE3] makes cells derepressed for nitrogen catabolism, while [PSI]
      elevates the efficiency of weak suppressor tRNAs. The same approach led to
      identification of the non-Mendelian element [Het-s] of the filamentous fungus
      Podospora anserina, as a prion of the het-s protein. The prion form of the het-s
      protein is required for heterokaryon incompatibility, a normal fungal function,
      suggesting that other normal cellular functions may be controlled by prions.
      [URE3] and [PSI] involve a self-propagating aggregation of Ure2p and Sup35p,
      respectively. In vitro, Ure2p and Sup35p form amyloid, a filamentous protein
      structure, high in beta-sheet with a characteristic green birefringent staining
      by the dye Congo Red. Amyloid deposits are a cardinal feature of Alzheimer's
      disease, non-insulin-dependent diabetes mellitus, the transmissible spongiform
      encephalopathies, and many other diseases. The prion domain of Ure2p consists of
      Asn-rich residues 1 to 80, but two nonoverlapping fragments of the molecule can,
      when overproduced, induce the de nova appearance of [URE3]. The prion domain of
      Sup35 consists of residues 1 to 114, also rich in Asn and Gln residues. While
      runs of Asn and Gln are important for [URE3] and [PSI], no such structures are
      found in PrP or the Het-s protein. Either elevated or depressed levels of the
      chaperone Hsp104 interfere with propagation of [PSI]. Both [URE3] and [PSI] are
      cured by growth of cells in millimolar guanidine HCl. [URE3] is also cured by
      overexpression of fragments of Ure2p or fusion proteins including parts of Ure2p.

PMID- 10585971
TI  - Rhizobium-legume symbiosis and nitrogen fixation under severe conditions and in
      an arid climate.
AB  - Biological N(2) fixation represents the major source of N input in agricultural
      soils including those in arid regions. The major N(2)-fixing systems are the
      symbiotic systems, which can play a significant role in improving the fertility
      and productivity of low-N soils. The Rhizobium-legume symbioses have received
      most attention and have been examined extensively. The behavior of some N(2)
      fixing systems under severe environmental conditions such as salt stress, drought
      stress, acidity, alkalinity, nutrient deficiency, fertilizers, heavy metals, and
      pesticides is reviewed. These major stress factors suppress the growth and
      symbiotic characteristics of most rhizobia; however, several strains, distributed
      among various species of rhizobia, are tolerant to stress effects. Some strains
      of rhizobia form effective (N(2)-fixing) symbioses with their host legumes under
      salt, heat, and acid stresses, and can sometimes do so under the effect of heavy
      metals. Reclamation and improvement of the fertility of arid lands by application
      of organic (manure and sewage sludge) and inorganic (synthetic) fertilizers are
      expensive and can be a source of pollution. The Rhizobium-legume (herb or tree)
      symbiosis is suggested to be the ideal solution to the improvement of soil
      fertility and the rehabilitation of arid lands and is an important direction for
      future research.

PMID- 10585972
TI  - Annual summary of vital statistics--1998.
AB  - Most vital statistics indicators of the health of Americans were stable or showed
      modest improvements between 1997 and 1998. The preliminary birth rate in 1998 was
      14.6 births per 1000 population, up slightly from the record low reported for
      1997 (14.5). The fertility rate, births per 1000 women aged 15 to 44 years,
      increased 1% to 65.6 in 1998, compared with 65.0 in 1997. The 1998 increases,
      although modest, were the first since 1990, halting the steady decline in the
      number of births and birth and fertility rates in the 1990s. Fertility rates for
      total white, non-Hispanic white, and Native American women each increased from 1%
      to 2% in 1998. The fertility rate for black women declined 19% from 1990 to 1996,
      but has changed little since 1996. The rate for Hispanic women, which dropped 2%,
      was lower than in any year for which national data have been available. Birth
      rates for women 30 years or older continued to increase. The proportion of births
      to unmarried women remained about the same at one third. The birth rate for teen
      mothers declined again for the seventh consecutive year, and the use of timely
      prenatal care (82.8%) improved for the ninth consecutive year, especially for
      black (73.3%) and Hispanic (74.3%) mothers. The number and rate of multiple
      births continued their dramatic rise; the number of triplet and higher-order
      multiple births jumped 16% between 1996 and 1997, accounting, in part, for the
      slight increase in the percentage of low birth weight (LBW) births. LBW continued
      to increase from 1997 to 1998 to 7.6%. The infant mortality rate (IMR) was
      unchanged from 1997 to 1998 (7.2 per 1000 live births). The ratio of the IMR
      among black infants to that for white infants (2.4) remained the same in 1998 as
      in 1997. Racial differences in infant mortality remain a major public health
      concern. In 1997, 65% of all infant deaths occurred to the 7.5% of infants born
      LBW. Among all of the states, Maine, Massachusetts, and New Hampshire had the
      lowest IMRs. State-by-state differences in IMR reflect racial composition, the
      percentage LBW, and birth weight-specific neonatal mortality rate for each state.
      The United States continues to rank poorly in international comparisons of infant
      mortality. Expectation of life at birth increased slightly to 76.7 years for all
      gender and race groups combined. Death rates in the United States continue to
      decline, including a drop in mortality from human immunodeficiency virus. The age
      adjusted death rate for suicide declined 6% in 1998; homicide declined 14%. Death
      rates for children from all major causes declined again in 1998. A large
      proportion of childhood deaths, however, continue to occur as a result of
      preventable injuries.

PMID- 10585973
TI  - The effect of passenger airbags on child seating behavior in motor vehicles.
AB  - Objective. The purpose of this study was to determine the effect of the presence
      of passenger airbags on places where children sit when traveling in motor
      vehicles. Methodology. An observational and driver interview survey of 503
      passenger vehicles was conducted in five New England states at randomly selected
      long- and short-distance travel sites during the summer of 1998. Each vehicle was
      occupied by at least 1 child <13 years of age. Seating position, vehicle
      information, and driver and passenger characteristics were collected. Logistic
      regression analysis was used to identify the association between the presence of
      passenger airbags in vehicles and the seating positions of children. Results.
      Controlling for the effects of the driver and vehicle characteristics, children
      <13 years of age were less likely to be observed riding in the front right seat
      when a passenger airbag was present in the vehicle (odds ratio:.34; 95%
      confidence interval:.19-.61). Of the vehicles carrying children, 23% had at least
      1 child riding in the front seat. Children rode in the front seat in 17% of
      vehicles with a passenger airbag, and in 30% of those without a passenger airbag.
      Half of all vehicles without a teenage or adult passenger carried a child in the
      front seat. In 91% of vehicles with a child riding in the front seat, there was
      at least one available seat in the rear. Driver safety belt use, younger child
      age, and the presence of an adult passenger in the vehicle were all associated
      with children being seated in the rear. Conclusions. Some New England drivers are
      protecting children from the risks of passenger airbags by seating them in the
      rear. There remains, however, a substantial number of children who are being
      exposed to the risk of passenger airbag deployment.

PMID- 10585969
TI  - Adding the third dimension to virus life cycles: three-dimensional reconstruction
      of icosahedral viruses from cryo-electron micrographs.
AB  - Viruses are cellular parasites. The linkage between viral and host functions
      makes the study of a viral life cycle an important key to cellular functions. A
      deeper understanding of many aspects of viral life cycles has emerged from
      coordinated molecular and structural studies carried out with a wide range of
      viral pathogens. Structural studies of viruses by means of cryo-electron
      microscopy and three-dimensional image reconstruction methods have grown
      explosively in the last decade. Here we review the use of cryo-electron
      microscopy for the determination of the structures of a number of icosahedral
      viruses. These studies span more than 20 virus families. Representative examples
      illustrate the use of moderate- to low-resolution (7- to 35-A) structural
      analyses to illuminate functional aspects of viral life cycles including host
      recognition, viral attachment, entry, genome release, viral transcription,
      translation, proassembly, maturation, release, and transmission, as well as
      mechanisms of host defense. The success of cryo-electron microscopy in
      combination with three-dimensional image reconstruction for icosahedral viruses
      provides a firm foundation for future explorations of more-complex viral
      pathogens, including the vast number that are nonspherical or nonsymmetrical.

PMID- 10585974
TI  - Antimicrobial use for pediatric upper respiratory infections: reported practice,
      actual practice, and parent beliefs.
AB  - BACKGROUND: In response to the dramatic emergence of resistant pneumococci, more
      judicious use of antibiotics has been advocated. Physician beliefs, their
      prescribing practices, and the attitudes of patients have been evaluated
      previously in separate studies. METHODS: This 3-part study included a statewide
      mailed survey, office chart reviews, and parent telephone interviews. We compared
      survey responses of 366 licensed pediatricians and family physicians in Georgia
      to recently published recommendations on diagnosis and treatment of upper
      respiratory infections (URIs). We further evaluated 25 randomly selected
      pediatricians from 119 surveyed in the Atlanta metropolitan area. For each,
      charts from the first 30 patients between the ages of 12 and 72 months seen on a
      randomly selected date were reviewed for encounters during the preceding year. A
      sample of parents from each practice were interviewed by telephone. RESULTS: In
      the survey, physicians agreed that overuse of antibiotics is a major factor
      contributing to the development of antibiotic resistance (97%), and that they
      should consider selective pressure for resistance in their decisions on providing
      antibiotic treatment for URIs in children in their practices (83%). However, many
      reported practices do not conform to the recently published principles for
      judicious antibiotic use. For example, 69% of physicians considered purulent
      rhinitis a diagnostic finding for sinusitis; 86% prescribed antibiotics for
      bronchitis regardless of the duration of cough; and 42% prescribed antibiotics
      for the common cold. Reported practices by family physicians were more often at
      odds with the published principles: they were significantly more likely than
      pediatricians to omit pneumatic otoscopy (46% vs 25%); to omit the requirement
      for prolonged symptoms to diagnose sinusitis (median 4 vs 10 days); and to omit
      laboratory testing for pharyngitis (27% vs 14%). Of the 7531 encounters analyzed
      in the chart review, 43% resulted in an antibiotic prescription, including 11% of
      checkups, 18% of telephone calls, and 72% of visits for URIs. There was wide
      variability in the overall antibiotic use rates among the 25 physicians (1-10
      courses per child per year). There was an even wider variability in some
      diagnosis-specific rates; bronchitis and sinusitis in particular. Those with the
      highest antibiotic prescribing rates had up to 30% more return office visits.
      Physicians who prescribed antibiotics for purulent rhinitis were more likely to
      see parents who believed that their children should be evaluated for cold
      symptoms. CONCLUSIONS: Physicians recognize the problem of antibiotic resistance
      but their reported practices are not in line with recently published
      recommendations for most pediatric URIs. The actual prescribing practices of
      pediatricians are often considerably different from their close colleagues.
      Patient beliefs are correlated with their own physician's practices.

PMID- 10585975
TI  - Prophylaxis against early adrenal insufficiency to prevent chronic lung disease
      in premature infants.
AB  - BACKGROUND. Many extremely low birth weight infants (<1000 g) show biochemical
      evidence of adrenal insufficiency in the first week of life, correlating with
      subsequent development of chronic lung disease (CLD). METHODS: We conducted a
      randomized, double-masked, placebo-controlled pilot study to test whether early
      treatment with low-dose hydrocortisone for 12 days (1 mg/kg/day for 9 days
      followed by.5 mg/kg/day for 3 days), begun before 48 hours of life, would
      increase the likelihood of survival without CLD. RESULTS: Forty patients were
      enrolled at two centers. Birth weight and gestation were similar for treatment
      and placebo groups: 732 +/- 135 g versus 770 +/- 135 g and 25.2 +/- 1.3 weeks
      versus 25.4 +/- 1.5 weeks. More infants treated with hydrocortisone achieved
      study success, defined as survival without supplemental oxygen at 36 weeks'
      postconception (12/20 [60%] vs 7/20 [35%]). Lower birth weight, histologic
      chorioamnionitis, and preeclampsia were significant risk factors, whereas study
      center, prenatal steroids, sex, and ethnicity were not significant.
      Hydrocortisone treatment decreased days on >40% oxygen, days on >25% oxygen, days
      on ventilator, and oxygen at discharge. Among infants exposed to
      chorioamnionitis, hydrocortisone treatment also was associated with increased
      enteral intake during the first month of life and with increased weight at 36
      weeks' postconception. Five treated infants and 6 placebo infants developed
      sepsis; 3 in each group died. CONCLUSIONS: First, early treatment with low-dose
      hydrocortisone in this population of extremely low birth weight infants increased
      the likelihood of survival without CLD. Second, the benefit was particularly
      apparent in infants with chorioamnionitis. Third, a larger multicenter trial is
      needed to verify the primary outcome and to better evaluate risks and benefits.

PMID- 10585976
TI  - Parental stress and parent-rated child behavior in relation to otitis media in
      the first three years of life.
AB  - OBJECTIVE: As part of a long-term study of possible effects of early-life otitis
      media on speech, language, cognitive, and psychosocial development, we tested
      relationships between parents' ratings of parent-child stress at ages 1, 2, and 3
      years, and of their children's behavior problems at ages 2 and 3 years, and the
      children's cumulative duration of middle-ear effusion (MEE) in their first 3
      years of life. METHODS: We enrolled healthy infants by age 2 months who presented
      for primary care at 1 of 2 urban hospitals or 1 of 2 small-town/rural and 4
      suburban private pediatric practices. We obtained standardized baseline measures
      of parental stress; we intensively monitored the children's middle-ear status by
      pneumatic otoscopy, supplemented by tympanometry, throughout their first 3 years
      of life; we monitored the validity of the otoscopic observations on an ongoing
      basis; and we treated children for otitis media according to specified
      guidelines. We obtained parent ratings of parental stress using the Parenting
      Stress Index/Short Form when the children reached ages 1, 2, and 3 years, and
      parent ratings of children's behavior using the Child Behavior Checklist when the
      children reached ages 2 and 3 years. RESULTS: In 2278 children we found no
      substantial relationships between parents' ratings of parent-child stress when
      the children reached ages 1, 2, and 3 years, or of their children's behavior
      problems at ages 2 and 3 years, and the cumulative duration of the children's MEE
      during antecedent periods. On the other hand, ratings both of parent-child stress
      and of behavior problems were consistently highest among the most
      socioeconomically disadvantaged children and lowest among the most
      socioeconomically advantaged children. Ratings also tended to be highest among
      children whose parents' baseline stress scores were highest. CONCLUSIONS: Parent
      child stress and children's behavior problems in the first 3 years of life, as
      rated by parents, bear little or no relationship to the children's previous
      cumulative duration of MEE.

PMID- 10585965
TI  - Recombinational repair of DNA damage in Escherichia coli and bacteriophage
      lambda.
AB  - Although homologous recombination and DNA repair phenomena in bacteria were
      initially extensively studied without regard to any relationship between the two,
      it is now appreciated that DNA repair and homologous recombination are related
      through DNA replication. In Escherichia coli, two-strand DNA damage, generated
      mostly during replication on a template DNA containing one-strand damage, is
      repaired by recombination with a homologous intact duplex, usually the sister
      chromosome. The two major types of two-strand DNA lesions are channeled into two
      distinct pathways of recombinational repair: daughter-strand gaps are closed by
      the RecF pathway, while disintegrated replication forks are reestablished by the
      RecBCD pathway. The phage lambda recombination system is simpler in that its
      major reaction is to link two double-stranded DNA ends by using overlapping
      homologous sequences. The remarkable progress in understanding the mechanisms of
      recombinational repair in E. coli over the last decade is due to the in vitro
      characterization of the activities of individual recombination proteins. Putting
      our knowledge about recombinational repair in the broader context of DNA
      replication will guide future experimentation.

PMID- 10585970
TI  - Stress genes and proteins in the archaea.
AB  - The field covered in this review is new; the first sequence of a gene encoding
      the molecular chaperone Hsp70 and the first description of a chaperonin in the
      archaea were reported in 1991. These findings boosted research in other areas
      beyond the archaea that were directly relevant to bacteria and eukaryotes, for
      example, stress gene regulation, the structure-function relationship of the
      chaperonin complex, protein-based molecular phylogeny of organisms and eukaryotic
      cell organelles, molecular biology and biochemistry of life in extreme
      environments, and stress tolerance at the cellular and molecular levels. In the
      last 8 years, archaeal stress genes and proteins belonging to the families Hsp70,
      Hsp60 (chaperonins), Hsp40(DnaJ), and small heat-shock proteins (sHsp) have been
      studied. The hsp70(dnaK), hsp40(dnaJ), and grpE genes (the chaperone machine)
      have been sequenced in seven, four, and two species, respectively, but their
      expression has been examined in detail only in the mesophilic methanogen
      Methanosarcina mazei S-6. The proteins possess markers typical of bacterial
      homologs but none of the signatures distinctive of eukaryotes. In contrast, gene
      expression and transcription initiation signals and factors are of the eucaryal
      type, which suggests a hybrid archaeal-bacterial complexion for the Hsp70 system.
      Another remarkable feature is that several archaeal species in different
      phylogenetic branches do not have the gene hsp70(dnaK), an evolutionary puzzle
      that raises the important question of what replaces the product of this gene,
      Hsp70(DnaK), in protein biogenesis and refolding and for stress resistance.
      Although archaea are prokaryotes like bacteria, their Hsp60 (chaperonin) family
      is of type (group) II, similar to that of the eukaryotic cytosol; however, unlike
      the latter, which has several different members, the archaeal chaperonin system
      usually includes only two (in some species one and in others possibly three)
      related subunits of approximately 60 kDa. These form, in various combinations
      depending on the species, a large structure or chaperonin complex sometimes
      called the thermosome. This multimolecular assembly is similar to the bacterial
      chaperonin complex GroEL/S, but it is made of only the large, double-ring
      oligomers each with eight (or nine) subunits instead of seven as in the bacterial
      complex. Like Hsp70(DnaK), the archaeal chaperonin subunits are remarkable for
      their evolution, but for a different reason. Ubiquitous among archaea, the
      chaperonins show a pattern of recurrent gene duplication-hetero-oligomeric
      chaperonin complexes appear to have evolved several times independently. The
      stress response and stress tolerance in the archaea involve chaperones,
      chaperonins, other heat shock (stress) proteins including sHsp,
      thermoprotectants, the proteasome, as yet incompletely understood thermoresistant
      features of many molecules, and formation of multicellular structures. The latter
      structures include single- and mixed-species (bacterial-archaeal) types. Many
      questions remain unanswered, and the field offers extraordinary opportunities
      owing to the diversity, genetic makeup, and phylogenetic position of archaea and
      the variety of ecosystems they inhabit. Specific aspects that deserve
      investigation are elucidation of the mechanism of action of the chaperonin
      complex at different temperatures, identification of the partners and substitutes
      for the Hsp70 chaperone machine, analysis of protein folding and refolding in
      hyperthermophiles, and determination of the molecular mechanisms involved in
      stress gene regulation in archaeal species that thrive under widely different
      conditions (temperature, pH, osmolarity, and barometric pressure). These studies
      are now possible with uni- and multicellular archaeal models and are relevant to
      various areas of basic and applied research, including exploration and conquest
      of ecosystems inhospitable to humans and many mammals and plants.

PMID- 10585977
TI  - The relationship between psychosocial factors and asthma morbidity in inner-city
      children with asthma.
AB  - OBJECTIVE: Children living in the inner city are affected disproportionately by
      asthma morbidity and mortality. Previous research has shown that behavioral and
      psychosocial factors affect asthma morbidity in children. The National
      Cooperative Inner-City Asthma Study investigated the factors that contribute to
      asthma morbidity among inner-city children. This article examines the
      relationship between psychosocial factors and asthma morbidity in this
      population. METHODS: A total of 1528 English- and Spanish-speaking children 4 to
      9 years of age with asthma and their primary caretakers were recruited from 8
      research centers in 7 metropolitan inner-city areas in the United States.
      Psychosocial variables were assessed at baseline and included measures of child
      and caretaker mental health, caretaker's problems with alcohol, life stress,
      social support, and parenting style. Morbidity measures were evaluated at
      baseline and at 3-, 6-, and 9-month follow-up intervals. These included number of
      hospitalizations and unscheduled visits for asthma in the past 3 months and
      number of days of wheeze and functional status in the previous 2-week period.
      RESULTS: Of the psychosocial variables assessed, mental health had the strongest
      relationship to children's asthma morbidity. Children whose caretakers had
      clinically significant levels of mental health problems were hospitalized for
      asthma at almost twice the rate as children whose caretakers did not have
      significant mental health problems. Children with clinically significant behavior
      problems had significantly more days of wheeze and poorer functional status in
      the follow-up period. CONCLUSION: Psychosocial factors, particularly the mental
      health of children and caretakers, are significant factors in predicting asthma
      morbidity. They may need to be included in intervention programs aimed at
      decreasing asthma morbidity in inner-city children with asthma in order for these
      programs to be successful.

PMID- 10585978
TI  - Repeated school-based screening for sexually transmitted diseases: a feasible
      strategy for reaching adolescents.
AB  - OBJECTIVES: To determine whether repeated school-based screening and treatment
      for chlamydia and gonorrhea will decrease the prevalence of infection among
      students. DESIGN: At three high schools serving over 2000 students, all 9th
      through 12th grade students were given the opportunity to be tested during three
      consecutive school years for chlamydia and gonorrhea, using urine ligase chain
      reaction tests. Five comparable schools with 5063 students enrolled served as
      wait-listed controls. SETTING: Eight urban public high schools in Louisiana.
      PARTICIPANTS: Annually, 52% to 65% of all enrolled students participated; among
      those enrolled in schools for > or = 2 years, 83.4% of students were tested at
      least once. INTERVENTION: Education of all students; counseling and treatment of
      infected students with oral single-dose antibiotic therapy. MAIN OUTCOME MEASURE:
      Prevalence of Chlamydia trachomatis and gonorrhea infection. RESULTS: At first
      test, 286 (11.5%) of 2497 girls and 143 (6.2%) of 2308 boys were infected with
      chlamydia, and 48 (2.5%) of 1883 girls and 19 (1.2%) of 1628 boys had gonorrhea.
      Over 90% of infections were asymptomatic. With repeated testing, chlamydia
      prevalence among boys dropped to half the rate of comparison schools (3.2% vs
      6.4%). Among girls chlamydia prevalence declined only slightly (10.3% vs 11. 9%
      in comparison schools). CONCLUSION: There are high rates of asymptomatic sexually
      transmitted diseases (STDs) in the general urban school population. Repeated
      screening and treatment are associated with declines in chlamydia prevalence
      among boys. Expansion of STD screening and treatment programs to school settings
      is likely to be a critical component of a national strategy to control bacterial
      STDs.

PMID- 10585979
TI  - Gender differences in risk behaviors among adolescents who experience date
      fighting.
AB  - OBJECTIVE: Although dating violence frequently begins during adolescence, few
      studies have focused on date fighting in middle and high school students. Fewer
      studies have studied gender differences in date violence. This study examines
      whether gender-specific patterns of risk behaviors exist among adolescents who
      report date fighting. DESIGN: The study was conducted on data collected from 21
      297 students in grades 8 through 12 participating in the Vermont 1995 Youth Risk
      Behavior Survey. Data were analyzed on 20 724 students (females = 50.1%) who
      reported: 1) never having been involved in a physical fight (n = 8737); 2) that
      their last physical fight was with a girlfriend, boyfriend, or other dating
      partner (n = 432); and 3) that their last fight was with someone other than a
      dating partner (n = 11 555). Indicators of violence (weapon carrying, being
      threatened, and fighting), suicide attempts, substance use, sexual behavior, and
      pregnancy were analyzed with chi(2) tests. Significant variables were analyzed
      with stepwise logistic regression. RESULTS: Of the males, 1.8% and of the
      females, 4.2% reported that their last fight was with a boyfriend, girlfriend, or
      dating partner. Risk behaviors significantly associated among females who only
      experienced date fighting included the number of male sexual partners in the past
      3 months (adjusted odds ratio: 1. 48; 95% confidence interval: 1.26-1.74), number
      of suicide attempts in the past 12 months (1.55; 1.30-1.85), riding in a car with
      a drinking driver (1.23; 1.10-1.37), injection of illegal drugs (2.87; 1.10
      7.50), use of alcohol before last sexual encounter (1.53; 1. 27-1.86), number of
      pregnancies (1.66; 1.26-2.21), forced sex (2.92; 2.18-3.91), and inhalant use
      (1.19; 1.06-1.34). Risk behaviors significantly associated among males who
      experienced only date fighting were sexual activity (4.11; 2.24-7.53), number of
      male partners in the past 3 months (1.40; 1.12-1.75), number of times of getting
      someone pregnant (1.68; 1.17-2.40), experiencing forced sex (2.38; 1.11-5.13),
      and the number of times threatened with physical violence in past 12 months
      (1.82; 1.53-2.17). When compared with adolescents who reported fighting with
      someone other than a date, risk factors significantly associated with date
      fighting among females were the number of male sexual partners in the past 3
      months (1.21; 1.10-1.34), older age (1.21; 1.10-1.34), carrying a weapon in the
      past 30 days (.77;.66-.90), experiencing forced sex (1.70; 1. 30-2.22), condom
      non-use (1.96; 1.60-2.41), and number of times of being threatened with physical
      violence in past 12 months (1.11; 1. 01-1.22). The risk factors among males were
      the number of male sexual partners in the past 3 months (1.43; 1.28-1.60),
      experiencing forced sex (1.91; 1.02-3.60), and older age (1.34; 1.14-1.57).
      CONCLUSIONS: The patterns of risk behaviors differed among male and female
      adolescents reporting dating violence. Females who reported date fighting were
      more likely than were nonfighters to have attempted suicide, to engage in sexual
      and human immunodeficiency virus risk behaviors (use of injectable drugs), to
      have been pregnant, experienced forced sex, and to have ridden in a car with a
      drinking driver. Sexual behaviors, including same-gender sexual partners, forced
      sex, and having been threatened with physical violence, were associated with date
      fighting among males. These findings are important in screening adolescents at
      risk for date violence.date fighting, adolescence, risk behaviors, gender.

PMID- 10585980
TI  - Looking beyond the physical injury: posttraumatic stress disorder in children and
      parents after pediatric traffic injury.
AB  - BACKGROUND: Traffic crashes are the leading health threat to children in the
      United States, resulting in nearly 1 million injuries annually. The psychological
      consequences of these injuries are primarily unknown. The aims of this study were
      to estimate the prevalence of posttraumatic stress disorder (PTSD) in traffic
      injured children and their parents and to identify risk factors for PTSD
      development. METHODS: A prospective cohort study of traffic-injured children
      between 3 and 18 years of age was conducted at a level 1 Pediatric Trauma Center.
      The children were enrolled as part of an ongoing surveillance system of traffic
      related injuries. Presence and severity of PTSD were determined in the children
      and their parents through a validated diagnostic questionnaire 7 to 12 months
      after child injury. RESULTS: Twenty-five percent of the children and 15% of the
      parents suffered diagnostic PTSD, but only 46% of the parents of affected
      children sought help of any form (including from friends) for their child and
      only 20% of affected parents sought help for themselves. Child PTSD was
      associated with older child age and parent PTSD. Parent PTSD was associated with
      younger child age, child PTSD, and parent witnessing the event. Injury severity
      was not predictive of PTSD. CONCLUSIONS: PTSD in children and their parents is a
      common, yet overlooked, consequence of pediatric traffic-related injury with
      prevalence rates similar to those found in children exposed to violence.
      Physicians managing the pediatric trauma patient, regardless of injury severity
      or whether the injury was intentional, should screen for PTSD and refer for
      treatment where appropriate.

PMID- 10585981
TI  - A comparison of morning-only and morning/late afternoon Adderall to morning-only,
      twice-daily, and three times-daily methylphenidate in children with attention
      deficit/hyperactivity disorder.
AB  - OBJECTIVE: 1) To compare standard twice-daily methylphenidate (MPH) dosing with a
      single morning dose of MPH and of Adderall during a typical school-day time
      period, and 2) to conduct a dose-response study of the effects of a late
      afternoon (3:30 PM) dose of MPH and Adderall on evening behavior and side
      effects. DESIGN: Within-subject, placebo-controlled, crossover design. SETTING:
      Intensive summer treatment program with a comprehensive behavioral approach.
      STUDY PARTICIPANTS: Twenty-one children with attention-deficit/hyperactivity
      disorder (19 boys and 2 girls), between the ages of 6 and 12 years.
      INTERVENTIONS: Children received, in random order with daily crossovers, each of
      the following conditions: 1) placebo, 2) 0.3 mg/kg of MPH received 3 times, 3)
      0.3 mg/kg of MPH received twice (7:30 AM and 11:30 AM) with 0.15 mg/kg received
      at 3:30 PM, 4) 0.3 mg/kg of MPH received once in the morning only, 5) 0.3 mg/kg
      of Adderall received at 7:30 AM and at 3:30 PM, 6) 0.3 mg/kg of Adderall once in
      the morning with 0.15 mg/kg received at 3:30 PM, 7) 0.3 mg/kg of Adderall
      received in the morning only. OUTCOME MEASURES: Daily rates of behaviors in
      social and academic settings, and standardized ratings from counselors and
      teachers, were assessed for the hours between 8:00 AM and 3:30 PM (a typical
      school-day). Relative sizes of the medication effects were compared hourly
      between first daily ingestion (7:30 AM) and 4:45 PM to assess the time course of
      the 2 drugs. Effects of the 3:30 PM doses on functioning in the evenings at home
      were evaluated using parent ratings of behavioral and side effects. RESULTS: A
      single morning dose of Adderall produced equivalent behavioral effects to those
      of MPH received twice-daily and behavioral effects of that single morning dose
      lasted throughout the school-day period. One morning dose of MPH was less
      effective than either 2 daily doses of MPH or 1 dose of Adderall, and seemed to
      wear off in the early to mid-afternoon. For some children a single morning dose
      of MPH maintained their behavior for an entire school day in the context of the
      summer treatment program. On parent ratings of evening behavior, 0.3 mg/kg of MPH
      at 3:30 PM was superior to 0.15 mg/kg at 3:30 PM, but there was no difference
      between the 2 doses of Adderall. Compared with placebo at 3:30 PM, only the 0.3
      mg/kg dose of MPH caused significant improvement in parent ratings. In placebo
      versus Adderall comparisons, all doses, even the condition that consisted of
      Adderall in the morning and placebo at 3:30 PM, produced a significant change in
      evening behavior. CONCLUSIONS: The results show that, at least in the context of
      an intensive behavioral intervention, a single morning dose of Adderall had
      behavioral effects throughout an entire school day period that were equivalent to
      standard twice-daily MPH dosing. These results indicate that Adderall may be used
      as a long-acting stimulant for children for whom midday dosing is a problem.
      Further study including dose-response comparisons, effects in regular school
      settings, and direct comparisons with comparable doses of MPH and d-amphetamine
      will help to clarify the time course and relative advantages of Adderall.

PMID- 10585982
TI  - Short-term health and economic benefits of smoking cessation: low birth weight.
AB  - OBJECTIVES: To estimate excess direct medical costs of low birth weight from
      maternal smoking and short-term cost savings from smoking cessation programs
      before or during the first trimester of pregnancy. METHODS: Simulations using
      data on neonatal costs per live birth. Outcome measures are mean US excess direct
      medical cost per live birth, total excess direct medical cost, reductions in low
      birth weight, and savings in medical costs from an annual 1 percentage point drop
      in smoking prevalence among pregnant women. RESULTS: Mean average excess direct
      medical cost per live birth for each pregnant smoker (in 1995 dollars) was $511;
      total cost was $263 million. An annual drop of 1 percentage point in smoking
      prevalence would prevent 1300 low birth weight live births and save $21 million
      in direct medical costs in the first year of the program; it would prevent 57,200
      low birth weight infants and save $572 million in direct medical costs in 7
      years. CONCLUSIONS: Smoking cessation before the end of the first trimester
      produces significant cost savings from the prevention of low birth weight.

PMID- 10585983
TI  - Tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 levels in
      febrile, young children with and without occult bacteremia.
AB  - OBJECTIVE: To determine the utility of plasma levels of tumor necrosis factor
      alpha (TNF), interleukin 1 beta (IL-1), and interleukin 6 (IL-6) in the
      prediction of occult bacteremia in febrile, young children. STUDY DESIGN:
      Prospective, case-control study conducted in a large, urban, children's hospital
      emergency department. Eligibility criteria were: 0 to 36 months of age, febrile,
      nontoxic appearing, immunocompetent, no apparent bacterial source for fever on
      physical examination, and blood culture obtained. Additional blood, procured at
      the time of the blood culture, was analyzed by enzyme-linked immunosorbent assay
      for TNF, IL-1, and IL-6. Children with positive blood cultures for pathogenic
      bacteria served as cases. Two age-matched controls for each case were selected
      from the children with negative cultures. RESULTS: Out of 1329 enrollees, 33
      cases and 66 controls were evaluated. IL-6 levels were significantly higher for
      the cases than controls but with moderate overlap in their ranges. TNF and IL-1
      levels were not significantly different between cases and controls. Height of
      fever, duration of fever, acute illness observation score, absolute band count,
      and white blood cell count were all much less predictive of bacteremia than
      either IL-6 or absolute neutrophil count (ANC). The optimum IL-6 threshold value
      had a sensitivity of 88%, a specificity of 70%, a positive predictive value (PPV)
      of 7.0%, a negative predictive value (NPV) of 99.6%, and an odds ratio (OR) of
      16.7 (95% confidence interval [CI], 4.8-71.6). The optimum ANC threshold value
      had a sensitivity of 82%, a specificity of 74%, a PPV of 7.5%, a NPV of 99.4%,
      and an OR of 12.8 (95% CI, 3.2-59.7). The best predictor was a combination of IL
      6 and ANC. It had a sensitivity of 100%, a specificity of 78%, a PPV of 10.4%, a
      NPV of 100%, and an OR which is undefined because of the 100% sensitivity (95%
      CI, 33.0-infinity). For comparison, a WBC >15 x 10(9) cells/L had a sensitivity
      of 48%, a specificity of 79%, a PPV of 5.5%, a NPV of 98.3%, and an OR of 3. 5
      (95% CI, 1.1-10.7). CONCLUSIONS: In febrile children 0 to 36 months of age, IL-6
      levels may be helpful in the prediction of occult bacteremia, but TNF and IL-1
      levels are not. IL-6 levels alone or notably when combined with an ANC were more
      predictive of occult bacteremia than traditional tests and clinical criteria. The
      wide range in the IL-6 values for cases and controls detracts from the precision
      of the findings. The lack of rapid processing and clinical availability of IL-6
      assays hampers its present application. However, despite these drawbacks and
      given the poor ability of traditional clinical and laboratory criteria to predict
      occult bacteremia, these results suggest a possible future role for IL-6 in
      predicting occult bacteremia when rapid assays become available.

PMID- 10585984
TI  - Impaired innate immunity in the newborn: newborn neutrophils are deficient in
      bactericidal/permeability-increasing protein.
AB  - OBJECTIVE: The mechanisms by which newborns are at increased risk for invasive
      bacterial infections have been incompletely defined. A central element of innate
      immunity to bacterial infection is the neutrophil-a cell that contains
      cytoplasmic granules replete with antibiotic proteins and peptides. The activity
      of adult neutrophils against gram-negative bacteria is believed to depend to a
      significant degree on the presence in neutrophil primary (azurophilic) granules
      of the 55-kDa bactericidal/permeability-increasing protein (BPI), which binds
      with high affinity to bacterial lipopolysaccharides and kills gram-negative
      bacteria. In light of the importance of BPI to antibacterial host defense and to
      investigate possible factors underlying the risk of neonatal bacterial
      infections, we determined the relative content of BPI in the neutrophils of
      adults and newborns. DESIGN: The cellular content of BPI was determined by
      Western blotting of neutrophils derived from full-term newborn cord blood (n =
      21; mean gestational age: 38.6 weeks) and from adult peripheral blood (n = 22;
      mean age: 29 years). Extracellular levels of BPI in adult and newborn plasma were
      assessed by enzyme-linked immunosorbent assay. Neutrophil content of other
      azurophil granule markers also was assessed: myeloperoxidase by Western blotting
      and defensin peptides by acid-urea polyacrylamide gel electrophoresis and
      Coomassie staining. Acid extracts of newborn and adult neutrophils were analyzed
      for antibacterial activity against serum-resistant encapsulated isolate
      Escherichia coli K1/r. RESULTS: The neutrophils of newborns contain at least
      threefold to fourfold less BPI per cell than adult neutrophils (67 +/- 13 ng per
      10(6) cells vs 234 +/- 27 ng per 10(6) cells). The relative BPI-deficiency of
      newborn neutrophils apparently was not attributable to perinatal stress-related
      degranulation of intracellular BPI stores because: 1) newborn and adult
      neutrophils contained nearly identical amounts of 2 microbicidal constituents
      derived from the same primary (azurophil) granule compartment as BPI (the enzyme
      myeloperoxidase as well as defensin peptides), and 2) levels of extracellular BPI
      in newborn plasma, measured by enzyme-linked immunosorbent assay, represent only
      approximately 2% of cellular BPI content. As predicted by their lower BPI
      content, newborn neutrophil acid extracts demonstrated significantly lower
      antibacterial activity against E coli K1/r than did adult neutrophil acid
      extracts. CONCLUSION: These data suggest that the neutrophils of newborns are
      selectively deficient in BPI, a central effector of antibacterial activity
      against gram-negative bacteria. BPI deficiency correlates with decreased
      antibacterial activity of newborn neutrophil extracts against serum-resistant E
      coli and could contribute to the increased incidence of gram-negative sepsis
      among newborns relative to healthy adults.neonatal sepsis, gram-negative
      bacteria, endotoxin, neutrophil, polymorphonuclear leukocyte, innate immunity,
      bactericidal/permeability-increasing protein, defensin, myeloperoxidase.

PMID- 10585985
TI  - Evaluation of an evidence-based guideline for bronchiolitis.
AB  - OBJECTIVE: To describe the effect of implementing an evidence-based clinical
      practice guideline for the inpatient care of infants with bronchiolitis at the
      Children's Hospital Medical Center in Cincinnati, Ohio. METHODOLOGY: A
      multidisciplinary team generated the guideline for infants < or = 1 year old who
      were admitted to the hospital with a first-time episode of typical bronchiolitis.
      The guideline was implemented January 15, 1997, and data on all patients admitted
      with bronchiolitis from that date through March 27, 1997, were compared with data
      on similar patients admitted in the same periods in the years 1993 through 1996.
      Data were extracted from hospital charts and clinical and financial databases.
      They included LOS and use and costs of resources ancillary to bed occupancy.
      RESULTS: After implementation of the guideline, admissions decreased 29% and mean
      LOS decreased 17%. Nasopharyngeal washings for respiratory syncytial virus were
      obtained in 52% fewer patients. Twenty percent fewer chest radiographs were
      ordered. There were significant reductions in the use of all respiratory
      therapies, with a 30% decrease in the use of at least 1 beta-agonist inhalation
      therapy. In addition, 51% fewer repeated inhalations were administered. Mean
      costs for all resources ancillary to bed occupancy decreased 37%. Mean costs for
      respiratory care services decreased 77%. CONCLUSIONS: An evidence-based clinical
      practice guideline for managing bronchiolitis was highly successful in modifying
      care during its first year of implementation.guideline, bronchiolitis, evidence
      based medicine, pediatrics, outcome research.

PMID- 10585986
TI  - Wood's lamp utility in the identification of semen.
AB  - BACKGROUND: The accurate detection of semen is critical to forensic, medical, and
      legal personnel. The Wood's lamp (WL) emits ultraviolet light (UVL) and has been
      identified as useful in rape evaluations because it is purported to cause semen
      to fluoresce. This study was intended to determine if semen can be distinguished
      from other products by WL analysis. METHODS: Investigators reviewed the previous
      training and frequency of use of the WL by emergency medicine and pediatric
      emergency medicine physicians at 2 medical centers. The participants were asked
      to use a WL to distinguish between a semen sample (<6 hours old) and 13 commonly
      used products. Next, 29 semen samples were collected and evaluated under high
      power microscopy and under UVL. RESULTS: A total of 41 physicians participated in
      the study (68% male). The number of years practicing in an emergency setting
      spanned from.3 to 25 years with a mean of 7. 1 years. A total of 51% of
      participants trained in emergency medicine, 23% in pediatrics and pediatric
      emergency medicine. A total of 22% reported formal training in the collection of
      forensic evidence. A total of 62% of the physicians believed they have identified
      semen in the past; one third felt they could differentiate semen from other
      products under UVL. None of the 41 physicians were able to differentiate semen
      from other products using a WL. Moreover, the semen samples used for the study
      did not fluoresce under WL analysis. None of the 29 semen samples fluoresced
      whether wet or dry. The medicaments most commonly mistaken for semen were A&D
      ointment (Cardinal Health, Inc, Dublin, OH), Surgilube (Division of Atlanta, Inc,
      Melville, NY), Barrier cream (Carrington Laboratories, Inc, Irving, TX), and
      bacitracin (Division of Atlanta, Inc, Melville, NY). CONCLUSIONS: Participating
      physicians were unable to distinguish between semen and other common products,
      using the WL. Although the WL has been purported to be a useful tool as a
      screening device for the detection of seminal stains, the investigators have
      found it to be unreliable. Semen, previously reported to fluoresce under WL
      analysis, does not appear to do so. The correct identification of semen may be
      complicated by the presence of previously existing ointments and creams, some of
      which may be iatrogenically introduced (ie, Surgilube).

PMID- 10585987
TI  - Risk factors for chronic lung disease in the surfactant era: a North Carolina
      population-based study of very low birth weight infants. North Carolina
      Neonatologists Association.
AB  - OBJECTIVE: To identify risk factors for chronic lung disease (CLD) in a
      population-based cohort of very low birth weight infants, born in an era of
      surfactant usage. We specifically investigated the effects of antenatal steroids,
      nosocomial infection, patent ductus arteriosus (PDA), fluid management, and
      ventilator support strategies. METHODS: Data were prospectively collected on 1244
      infants born in North Carolina in 1994 with birth weights 500 to 1500 g, and
      treated at 1 of the 13 intensive care nurseries across the state. The outcome of
      interest was CLD, defined as dependency on supplemental oxygen at 36 weeks'
      postmenstrual age. Multivariate odds ratios (OR) and 95% confidence intervals
      (CI) were estimated with logistic regression models. RESULTS: Among 865 survivors
      to 36 weeks' postmenstrual age, 224 (26%) had CLD. Nosocomial infection (OR: 2.0;
      95% CI: 1.4-3.3), fluid intake on day 2 (OR: 1.06 per 10 mL increase; 95% CI:
      1.01-1.11), and the need for ventilation at 48 hours of life (OR: 2.2; 95% CI:
      1.3-3.7) were associated with an increased risk of CLD. Among infants ventilated
      at 48 hours, nosocomial infection (OR: 1.64; 95% CI: 1.02-2.62) and PDA (OR: 1.9;
      95% CI: 1.2-3.1) were associated with an increased risk. No association was found
      with antenatal steroid receipt or increased levels of ventilator support.
      CONCLUSION: This analysis suggests that with widespread use of surfactant,
      nosocomial infection, PDA, and water balance persist as risk factors for CLD.

PMID- 10585988
TI  - Persistence of dyslexia: the Connecticut Longitudinal Study at adolescence.
AB  - OBJECTIVE: The outcome in adolescence of children diagnosed as dyslexic during
      the early years of school was examined in children prospectively identified in
      childhood and continuously followed to young adulthood. This sample offers a
      unique opportunity to investigate a prospectively identified sample of
      adolescents for whom there is no question of the childhood diagnosis and in whom
      highly analytic measures of reading and language can be administered in
      adolescence. DESIGN: Children were recruited from the Connecticut Longitudinal
      Study, a cohort of 445 children representative of those children entering public
      kindergarten in Connecticut in 1983. Two groups were selected when the children
      were in grade 9: children who met criteria for persistent reading disability in
      grades 2 through 6 (persistently poor readers [PPR]; n = 21) and a comparison
      group of nondisabled children, subdivided into average readers (n = 35) and
      superior readers (n = 39). In grade 9, each child received a comprehensive
      assessment of academic, language, and other cognitive skills. RESULTS: Measures
      of phonological awareness (but not orthographic awareness) were most significant
      in differentiating the 3 reading groups, with smaller contributions from measures
      of word finding and digit-span. Academic measures that best separated good from
      poor readers were decoding and spelling, whereas measures of math and reading
      comprehension did not. Measures of phonological awareness, followed next by
      teacher rating of academic skills were the best predictors of decoding, reading
      rate, and reading accuracy. In contrast, the best predictor of reading
      comprehension was word finding, with digit span and socioeconomic status also
      contributing significantly. Using a growth curve model (quadratic model of growth
      to a plateau) all 3 groups demonstrated similar patterns of growth over time,
      with the superior group outperforming the average group, and the average group
      outperforming the PPR group. There was no evidence that the children in the PPR
      group catch up in their reading skills. CONCLUSIONS: Deficits in phonological
      coding continue to characterize dyslexic readers even in adolescence; performance
      on phonological processing measures contributes most to discriminating dyslexic
      and average readers, and average and superior readers as well. These data support
      and extend the findings of previous investigators indicating the continuing
      contribution of phonological processing to decoding words, reading rate, and
      accuracy and spelling. Children with dyslexia neither spontaneously remit nor do
      they demonstrate a lag mechanism for catching up in the development of reading
      skills. In adolescents, the rate of reading as well as facility with spelling may
      be most useful clinically in differentiating average from poor readers.

PMID- 10585990
TI  - Vitamin A supplementation in very low birth weight neonates: rationale and
      evidence.

PMID- 10585989
TI  - Workshop summary: nutrition of the extremely low birth weight infant.

PMID- 10585991
TI  - The science and fiction of pertussis vaccines.

PMID- 10585992
TI  - Understanding antibiotic overuse for respiratory tract infections in children.

PMID- 10585994
TI  - Subacute sclerosing panencephalitis in an identical twin.

PMID- 10585993
TI  - Previously healthy infants may have increased risk of aspiration during
      respiratory syncytial viral bronchiolitis.
AB  - OBJECTIVE: Respiratory illnesses may cause feeding difficulties in infants. We
      studied the safety of oral feeding during respiratory syncytial viral (RSV)
      bronchiolitis in previously healthy infants. METHODS: Twelve previously healthy
      infants (3-12 months) with RSV bronchiolitis underwent barium swallow studies
      during the acute phase of illness. Those with abnormal studies underwent repeat
      studies 2 to 4 weeks later. RESULTS: The initial barium studies revealed
      aspiration in 3 infants. All repeat studies, performed 2 to 4 weeks later, were
      normal. CONCLUSIONS: Even previously healthy infants may be at risk of aspiration
      during RSV bronchiolitis.

PMID- 10585996
TI  - The prevention of unintentional injury among American Indian and Alaska Native
      children: a subject review. Committee on Native American Child Health and
      Committee on Injury and Poison Prevention. American Academy of Pediatrics.
AB  - Among ethnic groups in the United States, American Indian and Alaska Native
      (AI/AN) children experience the highest rates of injury mortality and morbidity.
      Injury mortality rates for AI/AN children have decreased during the past quarter
      century, but remain almost double the rate for all children in the United States.
      The Indian Health Service (IHS), the federal agency with the primary
      responsibility for the health care of AI/AN people, has sponsored an
      internationally recognized injury prevention program designed to reduce the risk
      of injury death by addressing community-specific risk factors. Model programs
      developed by the IHS and tribal governments have led to successful outcomes in
      motor vehicle occupant safety, drowning prevention, and fire safety. Injury
      prevention programs in tribal communities require special attention to the
      sovereignty of tribal governments and the unique cultural aspects of health care
      and communication. Pediatricians working with AI/AN children on reservations or
      in urban environments are strongly urged to collaborate with tribes and the IHS
      to create community-based coalitions and develop programs to address highly
      preventable injury-related mortality and morbidity. Strong advocacy also is
      needed to promote childhood injury prevention as an important priority for
      federal agencies and tribes.

PMID- 10585997
TI  - Human immunodeficiency virus and other blood-borne viral pathogens in the
      athletic setting. Committee on Sports Medicine and Fitness. American Academy of
      Pediatrics.
AB  - Because athletes and the staff of athletic programs can be exposed to blood
      during athletic activity, they have a very small risk of becoming infected with
      human immunodeficiency virus, hepatitis B virus, or hepatitis C virus. This
      statement, which updates a previous position statement of the American Academy of
      Pediatrics, (1) discusses sports participation for athletes infected with these
      pathogens and the precautions needed to reduce the risk of infection to others in
      the athletic setting. Each of the recommendations in this statement is dependent
      upon and intended to be considered with reference to the other recommendations in
      this statement and not in isolation.

PMID- 10585995
TI  - Resolution of HIV-associated nephrotic syndrome with highly active antiretroviral
      therapy delivered by gastrostomy tube.
AB  - There is no consensus regarding the specific management of HIV-associated
      nephrotic syndrome. We report a child whose first manifestation of human
      immunodeficiency virus type 1 (HIV-1) infection was nephropathy and wasting
      syndrome associated with profound immunodeficiency. The patient had a dramatic
      clinical and immunologic response to triple antiretroviral therapy delivered
      through a gastrostomy tube, with complete resolution of nephrotic syndrome. A
      51/2-year-old African-American girl presented with a 2-week history of cough,
      chest pain, vomiting, loose stools, abdominal distention, anorexia, and fever. In
      addition, she had recurrent oral thrush. Her weight and height were below the 5th
      percentile. She was chronically ill, appearing with oropharyngeal thrush and
      pitting edema in lower extremities. She had scattered rhonchi and decreased
      breath sounds on both lung bases. Her abdomen was distended and diffusely tender.
      A chest radiograph showed consolidation of the right upper and left lower lobes
      with bilateral pleural effusion. Admission laboratories were consistent with
      nephrotic syndrome. Streptococcus pneumoniae grew from the blood culture and the
      child responded well to treatment with intravenous ceftriaxone. She was found to
      be HIV-infected, her CD4(+) cell count was 3 cells/mcL and her plasma HIV-1 RNA
      was >750 000 copies/mL. A percutaneous gastrostomy tube was placed for
      supplemental nutrition. She was treated with stavudine, lamivudine, and
      nelfinavir via gastrostomy tube with good clinical response. Twenty-one months
      after instituting antiretroviral therapy, her weight and height had increased to
      the 50th and 10th percentile respectively, and she had complete resolution of her
      nephrotic syndrome. Her CD4(+) cell count increased to 1116 cells/mcL and her
      viral load has remained undetectable. HIV-1 associated nephrotic syndrome has
      been described in children with profound immunodeficiency. The course of
      untreated HIV-associated nephrotic syndrome is rapid progression to renal failure
      in up to 40% of the children. Regardless of the presence of renal insufficiency,
      if untreated, it is uniformly fatal. A modest improvement of HIV-1 associated
      nephrotic syndrome has been observed in patients treated with zidovudine. Steroid
      and cyclosporine treatment have resulted in improved renal function but long-term
      use of immunosuppressive therapy has raised concerns about safety. We have
      described, to our knowledge, the first child with HIV-associated nephrotic
      syndrome who had a remarkable clinical, immunologic, and virologic response to
      triple-drug combination therapy given by gastrostomy tube, with complete
      resolution of proteinuria and normalization of the serum albumin. She also had a
      striking improvement in weight, height, and quality-of-life. Whether the presence
      of a gastrostomy tube contributed to the excellent response because of improved
      compliance is unknown, but warrants systematic evaluation.

PMID- 10585998
TI  - Prevention of poliomyelitis: recommendations for use of only inactivated
      poliovirus vaccine for routine immunization. Committee on Infectious Diseases.
      American Academy of Pediatrics.
AB  - Since 1997, when the American Academy of Pediatrics (AAP) initially recommended
      expanded use of inactivated poliovirus vaccine (IPV) for routine childhood
      immunization against poliovirus infection, the occurrence of vaccine-associated
      paralytic poliomyelitis (VAPP) has decreased in the United States. However, VAPP
      will not be eliminated until oral poliovirus vaccine (OPV) no longer is given. As
      a result of continuing progress toward global eradication of poliomyelitis, the
      risk of imported infection has continued to decrease. Concomitantly, the use of
      IPV has increased substantially with the corresponding decrease in the use of
      OPV, indicating widespread acceptance by health care professionals and parents of
      the sequential or all-IPV immunization schedule previously recommended by the
      AAP. In addition, availability of OPV will be substantially diminished beginning
      in early 2000. To eliminate VAPP in the context of decreasing risk of wild-type
      poliovirus importation, the AAP recommends an all-IPV schedule for routine
      childhood immunization beginning in early 2000. The AAP further recommends that,
      effective immediately, OPV no longer should be purchased for routine use.
      Guidelines are given for utilization of remaining supplies of OPV during the
      transition in early 2000 to the all-IPV schedule.

PMID- 10585999
TI  - The management of minor closed head injury in children. Committee on Quality
      Improvement, American Academy of Pediatrics. Commission on Clinical Policies and
      Research, American Academy of Family Physicians.
AB  - The American Academy of Pediatrics (AAP) and its Committee on Quality Improvement
      in collaboration with the American Academy of Family Physicians (AAFP) and its
      Commission on Clinical Policies and Research, and in conjunction with experts in
      neurology, emergency medicine and critical care, research methodologists, and
      practicing physicians have developed this practice parameter. This parameter
      provides recommendations for the management of a previously neurologically
      healthy child with a minor closed head injury who, at the time of injury, may
      have experienced temporary loss of consciousness, experienced an impact seizure,
      vomited, or experienced other signs and symptoms. These recommendations derive
      from a thorough review of the literature and expert consensus. The methods and
      results of the literature review and data analyses including evidence tables can
      be found in the technical report. This practice parameter is not intended as a
      sole source of guidance for the management of children with minor closed head
      injuries. Rather, it is designed to assist physicians by providing an analytic
      framework for the evaluation and management of this condition. It is not intended
      to replace clinical judgment or establish a protocol for all patients with a
      minor head injury, and rarely will provide the only appropriate approach to the
      problem.

PMID- 10586000
TI  - Dose-dependent effect of folic acid on the prevention of orofacial clefts.
AB  - OBJECTIVE: In 1982, Tolarova(4) found a reduction in the recurrence rate of
      isolated cleft lip (CL) with or without cleft palate (CP; CL +/- CP) after
      periconceptional supplementation with a multivitamin including a very high dose
      (10 mg) of folic acid. The Hungarian randomized, double-blind, controlled trial
      of periconceptional supplementation with a multivitamin including a physiologic
      dose (.8 mg) of folic acid did not show any preventive effect on the first
      occurrence of isolated CL +/- CP and CP. However, the general evaluation of
      congenital abnormalities in the Hungarian Case-Control Surveillance of Congenital
      Abnormalities indicated, among others, a reduction of isolated CL +/- CP and CP
      after the use of high doses of folic acid in the critical period for the
      development of these congenital abnormalities in the 12-year dataset between 1980
      and 1991. We hypothesized that the prevention of orofacial clefts by folic acid
      has a dose-dependent effect, and this hypothesis was tested in 2 recent Hungarian
      datasets. DESIGN: In a prospective cohort study, the occurrence of isolated CL +/
      CP and CP was studied in the newborn infants born to mothers with or without
      periconceptional folic acid-containing (.8 mg) multivitamin supplementation.
      Supplemented women with confirmed pregnancy were recruited from the participants
      of the periconceptional service. Unsupplemented women were invited to take part
      in the study after the first visit between the 8th and 12th week of gestation in
      the antenatal care. Supplemented and unsupplemented women were matched based on
      age, socioeconomic status, and residence. In contrast, the occurrence of high
      dose (in general daily 6 mg) folic acid supplementation was evaluated in the case
      control pairs of CL +/- CP and CP, particularly during the critical period of
      these 2 types of orofacial clefts in the 17 years dataset of the Case-Control
      Surveillance of Congenital Abnormalities, between 1980 and 1996. Cases were
      selected from the population-based Hungarian Congenital Abnormality Registry,
      whereas population controls without congenital abnormality were ascertained from
      the national birth registry. Two population controls were matched to every case
      according to sex, week of birth, and district of parental residence. The drug
      uses, including pregnancy supplements as folic acid, were evaluated based on
      retrospective self-reported maternal questionnaire and prospective medically
      documented data of antenatal care logbook. RESULTS: In the prospective cohort
      study, of 3019 informative offspring (termination of pregnancies in the second
      and third trimesters because of fetal defect, stillborn fetuses, and liveborn
      infants) in the supplemented group, 3 had CL +/- CP and 1 was affected with CP,
      whereas of 3432 informative offspring in the unsupplemented group, 2 had CL +/-
      CP and 1 had CP. The lack of preventive effect was in agreement with the result
      of the previous Hungarian randomized double-blind controlled trial; thus, these 2
      datasets were combined. The preventive effect of a folic acid containing
      multivitamin used in the periconceptional period for the first occurrence of
      isolated CL +/- CP and CP was estimated by the Mantel-Haenszel test. Of 5488
      supplemented women, 6 had CL +/- CP, and of 5821 unsupplemented women, 4 had CL
      +/- CP. Of 5489 supplemented women, 1 had CP, and of 5823 unsupplemented pregnant
      women, 3 had CP. The Hungarian Case-Control Surveillance of Congenital
      Abnormalities, 1980-1996, included 38 151 population controls (1.8% of the
      Hungarian births) and 22 865 cases with congenital abnormalities. Within the
      latter group, 1368 had isolated CL +/- CP, and 596 had CP. A significantly more
      frequent use of high-dose folic acid (in general daily 6 mg) supplementation was
      found in controls than in cases of 1246 case-control pairs of CL +/- CP group and
      of 537 case-control pairs of CP group, respectively. (ABSTRACT TRUNCATED)

PMID- 10586001
TI  - Development of guidelines for treatment of children with phenylketonuria: report
      of a meeting at the National Institute of Child Health and Human Development held
      August 15, 1995, National Institutes of Health, Bethesda, Maryland.
AB  - OBJECTIVE: To convene a small group of experts in diagnosis and management of PKU
      to discuss the following issues: the Subject Review of PKU management being
      performed by the American Academy of Pediatrics (AAP) Committee on Genetics
      (COG), the published British guidelines on PKU management, and the feasibility,
      suitability, and mechanism of developing PKU management guidelines for the United
      States. METHODS: A 1-day meeting was held at the National Institutes of Health
      under the auspices of National Institute of Child Health and Human Development,
      convening experts in PKU diagnosis and management and members of the AAP/COG.
      RESULTS: The group reviewed the published reports of outcomes of treatment of PKU
      and the British guidelines that were developed based on those data. It also
      reviewed the results of surveys of directors of clinics that manage PKU, parents
      of children with PKU, and young adults with PKU. CONCLUSION: The group supported
      the efforts of the AAP/COG to perform this review of PKU management. The group
      concluded that significant issues need to be resolved to provide sufficient
      information to establish US guidelines for PKU management. The establishment of
      such guidelines is an important next step in PKU management in the United States.

PMID- 10586002
TI  - Management of phenylketonuria for optimal outcome: a review of guidelines for
      phenylketonuria management and a report of surveys of parents, patients, and
      clinic directors.
AB  - OBJECTIVE: The development of guidelines for phenylketonuria (PKU) management in
      the United Kingdom has resulted in much discussion in the community of parents
      and PKU clinics and parents have asked why the United States does not have such
      guidelines. The objective of this report is to discuss PKU management in the
      United States, the British guidelines on PKU management, and the feasibility,
      suitability, and mechanism of developing PKU management guidelines in the United
      States. METHODS: Members of the American Academy of Pediatrics (AAP) Committee on
      Genetics (COG) reviewed the literature and conducted surveys of parents of
      children with PKU, young adults with PKU, and directors of PKU clinics in the
      United States. A meeting was held at the National Institute of Child Health and
      Human Development to review the AAP/COG efforts at reviewing the status of PKU
      management and guideline development in the United States. RESULTS: The British
      guidelines are more stringent than the PKU management practices in many parts of
      the United States. Evidence exists that stricter management improves
      developmental outcome. The parents who responded to the surveys indicated
      willingness to comply with more stringent dietary management if that would
      improve outcome. They also identified problems that make such management
      difficult. The clinic directors supported the timeliness of the review. Some had
      begun a trend toward more stringent control of blood phenylalanine
      concentrations, at least in the first 4 years of life. CONCLUSION: The AAP
      Committee on Genetics will complete its subject review of the management of PKU.
      Guidelines for care of PKU in the United States probably would look quite similar
      to the existing guidelines in other countries. The parents surveyed supported
      more stringent PKU management, but information from a broader distribution of
      parents would provide a more representative view. The status of the US health
      care system creates problems for improved PKU management in the United States
      that do not exist in the countries already following stricter guidelines.

PMID- 10586003
TI  - Immunization outreach in an inner-city housing development: reminder-recall on
      foot.
AB  - OBJECTIVE: To determine rates of immunization coverage among children 3 to 72
      months of age in a large public housing development, to develop a community-based
      outreach program to increase coverage, and to evaluate the effect of the program.
      DESIGN: A door-to-door canvass of the development by specially trained emergency
      medical technicians to enroll families, to determine immunization status from
      written records, and to follow-up to encourage immunizations and well-child care.
      The program was evaluated, comparing rates of immunization by age with an
      expectation based on the immunization histories before enrollment. SETTING: A
      Chicago public housing development, October 1993 through December 1996. OUTCOME
      VARIABLES: Antigen-specific and series-specific coverage based on written
      records. RESULTS: Of the caregivers, 92% were able to identify a primary care
      provider. At the time of enrollment, 37% of 1075 children were up-to-date, but
      that proportion varied by age with 27% of children 19 to 35 months of age being
      up-to-date. The program increased rates of immunization compared with the
      expectation from the preenrollment rates. At their final assessment, 50% of the
      children were up-to-date. For individual vaccines, there was a positive program
      effect. For example, before enrollment, 22% of children 15 months of age had
      received measles, mumps, and rubella vaccine. However, 39% of children who were
      enrolled in the program before they were 12 months of age had received their
      first immunizations by 15 months of age. CONCLUSIONS: Children in the housing
      development had very low rates of immunization before enrollment. An in-person
      intervention was effective in reaching families and determining immunization
      status. In the 3-year enrollment and observation period, rates of immunization
      increased.

PMID- 10586004
TI  - Acellular vaccines containing reduced quantities of pertussis antigens as a
      booster in adolescents.
AB  - OBJECTIVE: To evaluate the immunogenicity and reactogenicity of an acellular
      pertussis vaccine (pa) either formulated with diphtheria and tetanus toxoids
      (dTpa) or administered consecutively with a licensed tetanus and diphtheria
      vaccine (Td) as a 5th dose in adolescents. METHODS: A total of 510 healthy
      children 10 to 13 years of age were assigned randomly, using a single-blind
      design, to receive either the dTpa vaccine or the Td vaccine with the pa vaccine
      1 month later. The quantities of 3 pertussis antigens (pertussis toxin,
      filamentous hemagglutinin, and pertactin) in the dTpa and the pa vaccines were
      one third of those of the Infanrix vaccine (SmithKline Beecham Biologicals,
      Rixensart, Beligium) licensed for use in infants. For enzyme-linked immunosorbent
      assay measurement of serum immunoglobulin G antibodies and proliferation assay of
      peripheral blood mononuclear cells, blood samples were obtained before and 1
      month after immunization. Local and systemic reactions were recorded on diary
      cards for 15 days after immunization. RESULTS: After immunization with dTpa or
      pa, significant and comparable rises in geometric mean values of antibodies (12-
      to 46-fold) and proliferations (8- to 18-fold) to each of the pertussis antigens
      were noted. After immunization with dTpa or Td, significant rises in geometric
      mean values of antidiphtheria and antitetanus antibodies (35- to 76-fold) were
      noted, and all subjects had values of these antibodies >/=.1 international
      units/mL. The dTpa and pa vaccines were at least as well tolerated as the
      licensed Td vaccine. CONCLUSIONS: Booster immunization of adolescents with an
      acellular vaccine containing reduced quantities of pertussis antigens in addition
      to diphtheria and tetanus toxoids induces good responses in both arms of the
      immune system without an increase in adverse reactions.

PMID- 10586005
TI  - Reliability and validity of the Children's Health Survey for Asthma.
AB  - OBJECTIVE: Describe the psychometric properties of the Children's Health Survey
      for Asthma (CHSA)- a condition-specific, self-report, functional health measure
      for parents of children 5 to 12 years of age with chronic asthma. METHOD: Data
      from two cross-sectional and one longitudinal study were used to assess internal
      consistency reliability, test-retest reliability, and validity of the CHSA. Over
      275 parents and guardians of children with asthma completed the CHSA in one of
      three studies. The combined samples included a heterogenous mix of respondents by
      child age and race/ethnicity and parental marital and socioeconomic status. Five
      domain scores were computed: physical health, activity (child), activity
      (family), emotional health (child), and emotional health (family). Raw scale
      scores were transformed from 0 to 100 with higher scores indicating better or
      more positive outcomes. RESULTS: Across the three samples, mean scale scores
      ranged from a low of 61.5 (emotional health of the child) to a high of 86.1
      (activity [family]). Internal consistency reliability for each of the scales was
      high (Cronbach's alpha =.81-. 92), and test-retest reliability (correlation
      between forms) ranged from.62 to.86. Significant differences in mean scores for
      four of five scales were noted between those with low versus moderate to high
      recent symptom activity. CONCLUSION: In three tests, the CHSA displays strong
      reliability and validity. Descriptive statistics demonstrate a range of scale
      scores. Internal consistency is good to excellent and short-term test-retest
      reliability is good for each of the five scales. Construct validity is
      demonstrated by the ability of CHSA to distinguish levels of disease severity,
      defined by symptom activity.

PMID- 10586006
TI  - Neisseria gonorrhea infections in girls younger than 12 years of age evaluated
      for vaginitis.
AB  - OBJECTIVE: This study examined the prevalence of gonorrhea in girls <12 years of
      age who presented with vaginitis and in whom sexual abuse was not suspected.
      DESIGN: A prospective, consecutive patient series was performed in a pediatric
      emergency department with 90 000 visits per year and in 2 affiliated pediatric
      continuity clinics. All girls (Tanner I or II) between the ages of 12 months and
      12 years, presenting with a chief complaint of vaginal discharge, burning, pain,
      or itching, were enrolled (n = 93). Patients were excluded (n = 6) if there was a
      history of sexual abuse. The presence or absence of vaginal discharge, vaginal
      erythema, or trauma was recorded. Physicians were instructed to collect cultures
      for Neisseria gonorrhea (GC), Chlamydia trachomatis, and bacteria/yeast. Wet
      prep, urinalysis, urine culture, serum rapid plasma reagin, and fungal culture
      were obtained at the physician's discretion. RESULTS: Of the girls, 43 had a
      vaginal discharge on examination. Of these girls, 4 (9%) had GC, 9 (26%) had
      group A, B, or F streptococcus and 1 had Staphylococcus aureus. Of the girls, 44
      had no discharge on examination. In this group, 3 had streptococcus infection and
      2 had Candida albicans. Both children with C albicans had been treated recently
      with systemic antibiotics. Those girls with a vaginal discharge on examination
      had a microbial etiology significantly more often than did those without
      discharge. All of the girls with infection were Tanner I on genital examination.
      CONCLUSIONS: The prevalence of unsuspected GC infection was high and emphasizes
      the importance of culturing Tanner I girls for GC when they have a vaginal
      discharge along with routine bacterial cultures. Testing and/or treating for C
      albicans should be considered when there has been recent antibiotic use. Girls
      with vaginal complaints but without vaginal discharge may have a bacterial
      infection, but such diagnoses occur less frequently than with girls who have a
      discharge.

PMID- 10586007
TI  - Evaluation of the effects of oxandrolone on malnourished HIV-positive pediatric
      patients.
AB  - OBJECTIVE: To determine the safety and efficacy of anabolic therapy to prevent or
      reverse wasting and malnutrition in human immunodeficiency virus (HIV)-infected
      pediatric patients. The anabolic steroid, oxandrolone, was evaluated because of
      its safe and effective use in other pediatric conditions. METHODS: Nine HIV
      positive children who were malnourished or at risk for malnutrition (4 females, 5
      males; 4-14 years of age) took oxandrolone for 3 months (.1 mg/kg/day orally).
      Quantitative HIV ribonucleic acid polymerase chain reaction and CD4(+) T-cell
      levels, complete blood cell count (CBC) and chemistry profile, endocrinologic
      studies, resting energy expenditure, respiratory quotient, nutritional measures,
      body composition assessment with quantitative computed tomography, and skinfold
      body composition measurements were determined before treatment, during treatment
      (3 months), and for 3 months after treatment. Statistical analyses were completed
      using the Friedman two-way analysis of variance and Spearman correlation tests.
      RESULTS: No adverse clinical or laboratory events or changes in Tanner staging or
      virilization occurred. Quantitative HIV ribonucleic acid polymerase chain
      reaction and CD4(+) T-cell levels did not change significantly. Insulin-like
      growth factor 1 increased, suggesting an anabolic effect of treatment. The rate
      of weight gain increased during treatment and was maintained after treatment.
      Linear growth continued and was maintained throughout treatment, whereas bone age
      did not increase significantly. Anthropometric assessments indicated an increase
      in muscle mass and a decrease in fat while patients were on treatment, and a mild
      decrease of muscle and increased fat posttreatment. Likewise, computed tomography
      scan results demonstrated similar changes in muscle mass. Resting energy
      expenditure and respiratory quotient remained stable throughout treatment and
      follow-up. No significant changes were seen in the quality of life questionnaire.
      CONCLUSIONS: Treatment with oxandrolone for 3 months in HIV-infected children was
      well-tolerated, safe, and associated with markers of anabolism. The latter effect
      was maintained partially for 3 months after discontinuation of a 3-month course
      of therapy. Additional studies are needed to assess the potential benefits and
      risks of a longer course of therapy or a higher dose of oxandrolone in HIV
      infected children.

PMID- 10586009
TI  - Codeine intoxication in the neonate.
AB  - Although opiates can provide patients with relief from pain and the discomfort of
      cough, the routine prescription of these drugs for infants demands caution and
      concern. Infants, particularly neonates, are not merely small adults requiring
      smaller dosages, but rather uniquely different patients. Neonates present with an
      immature physiology and biochemistry with respect to drug metabolism. We report a
      case of codeine intoxication in the neonate, in which the drug was prescribed for
      cough control during an emergency department visit.

PMID- 10586008
TI  - The impact of low birth weight, perinatal conditions, and sociodemographic
      factors on educational outcome in kindergarten.
AB  - OBJECTIVE: To assess the relative effects and the impact of perinatal and
      sociodemographic risk factors on long-term morbidity within a total birth
      population in Florida. METHODS: School records for 339 171 children entering
      kindergarten in Florida public schools in the 1992-1993, 1993-1994, or 1994-1995
      academic years were matched with Florida birth records from 1985 to 1990. Effects
      on long-term morbidity were assessed through a multivariate analysis of an
      educational outcome variable, defined as placement into 9 mutually exclusive
      categories in kindergarten. Of those categories, 7 were special education (SE)
      classifications determined by statewide standardized eligibility criteria, 1 was
      academic problems, and the reference category was regular classroom. Generalized
      logistic regression was used to simultaneously estimate the odds of placement in
      SE and academic problems. The impact of all risk factors was assessed via
      estimated attributable excess/deficit numbers, based on the multivariate
      analysis. RESULTS: Educational outcome was significantly influenced by both
      perinatal and sociodemographic factors. Perinatal factors had greater adverse
      effects on the most severe SE types, with birth weight <1000 g having the
      greatest effect. Sociodemographic predictors had greater effects on the mild
      educational disabilities. Because of their greater prevalence, the impact
      attributable to each of the factors (poverty, male gender, low maternal
      education, or non-white race) was between 5 and 10 times greater than that of low
      birth weight and >10 times greater than that of very low birth weight, presence
      of a congenital anomaly, or prenatal care. CONCLUSIONS: Results are consistent
      with the hypothesis that adverse perinatal conditions result in severe
      educational disabilities, whereas less severe outcomes are influenced by
      sociodemographic factors. Overall, sociodemographic factors have a greater total
      impact on adverse educational outcomes than perinatal factors.

PMID- 10586010
TI  - Plasma creatinine rises dramatically in the first 48 hours of life in preterm
      infants.
AB  - OBJECTIVE: Published data show that plasma creatinine falls steadily during the
      first 28 days of life and that creatinine levels in the neonatal period are
      higher in more premature infants. However, the best reference data commence on
      day 2 of life. The objective of this study was to document how plasma creatinine
      changes in the first 48 hours of life and to examine the reason for the
      apparently high levels of creatinine in preterm infants, compared with maternal
      levels. DESIGN: A prospective observational study on a regional neonatal
      intensive care unit. PATIENTS: A total of 42 preterm infants, mean gestational
      age of 29.4 weeks (range: 23-35), mean birth weight of 1.42 kg (.55-2.77),
      divided into 4 gestation groups: 23 to 26 weeks (n = 9), 27 to 29 weeks (n = 13),
      30 to 32 weeks (n = 12), and 33 to 35 weeks (n = 8). INTERVENTIONS: Measurement
      of plasma creatinine and urea concentration in cord blood and in serial samples
      taken for routine arterial blood gas analysis. OUTCOME MEASUREMENTS: Changes in
      creatinine concentration with time and relationship to gestational age, birth
      weight, and illness severity. RESULTS: Mean creatinine at birth was 73 micromol/L
      (95% confidence interval [CI]: 68-79 micromol/L). Plasma creatinine rose
      significantly over the first 48 hours. Mean peak creatinine in the most preterm
      infants (23-26 weeks) was 221 micromol/L (CI: 195-247 micromol/L). Peak plasma
      creatinine was inversely related to gestation (Spearman's coefficient: -.73) and
      birth weight (Spearman's coefficient: -.76). Significant differences in
      creatinine concentration were seen among different gestational groups at 24 and
      48 hours of life. Peak creatinine correlated with a high Clinical Risk Index for
      Babies score (Spearman's coefficient:. 64). The fall in creatinine began later in
      more premature infants. All 38 surviving infants had normal renal function; their
      mean plasma creatinine at discharge was 52 micromol/L (CI: 46-58 micromol/L).
      CONCLUSIONS: Rather than falling steadily from birth, creatinine rises
      dramatically in the first 48 hours of life, especially in infants of <30 weeks'
      gestation. Even large rises in creatinine in the first 48 hours may be expected
      and should not be used in isolation to diagnose renal failure.

PMID- 10586011
TI  - Prednisolone treatment of respiratory syncytial virus infection: a randomized
      controlled trial of 147 infants.
AB  - OBJECTIVE: To evaluate the effect of systemic prednisolone as an adjunct to
      conventional treatment with beta2-agonist, respiratory support, and fluid
      replacement in hospitalized infants <24 months of age with respiratory syncytial
      virus (RSV) infection. METHODS: The study was randomized, double-blind, and
      placebo-controlled. During the winter of 1995-1996, 147 infants <2 years of age,
      hospitalized with RSV infection, were allocated to treatment with either systemic
      prednisolone mixture 2 mg/kg daily or placebo for 5 days. MAIN OUTCOME MEASURES:
      The acute effect variables were duration of stay in hospital, use of medicine,
      and supportive measures while in hospital. At follow-up 1 month after discharge,
      the acute effect variables were duration of illness, start in day care center,
      morbidity, and use of medicine. At follow-up 1 year after discharge, the acute
      effect variables were morbidity, use of medicine, and skin prick tests with
      allergens. RESULTS: Prednisolone treatment had no effect on any of the outcome
      measures. CONCLUSIONS: Our randomized prospective study in infants hospitalized
      with acute RSV infection showed no effect of systemic prednisolone treatment
      either in the acute state of RSV infection, nor in the follow-up 1 month and 1
      year after admission to hospital. We find our results in agreement with the
      largest studies reported earlier; therefore, corticosteroid, whether by the
      systemic route or by inhalation, should not be prescribed to infants with RSV
      infection.

PMID- 10586012
TI  - Technical report: minor head injury in children.
AB  - Minor head trauma affecting children is a common reason for medical consultation
      and evaluation. In order to provide evidence on which to base a clinical practice
      guideline for the American Academy of Pediatrics, we undertook a systematic
      review of the literature on minor head trauma in children. METHODS: Medline and
      Health databases were searched for articles published between 1966 and 1993 on
      head trauma or head injury, limited to infants, children, and adolescents.
      Abstracts were reviewed for relevance to mild head trauma consistent with the
      index case defined by the AAP subcommittee. Relevant articles were identified,
      reviewed, and abstracted. Additional citations were identified by review of
      references and expert suggestions. Unpublished data were also identified through
      contact with authors highlighting child-specific information. Abstracted data
      were summarized in evidence tables. The process was repeated in 1998, updating
      the review for articles published between 1993 and 1997. RESULTS: A total of 108
      articles were abstracted from 1033 abstracts and articles identified through the
      various search strategies. Variation in definitions precluded any pooling of data
      from different studies. Prevalence of intracranial injury in children with mild
      head trauma varied from 0% to 7%. Children with no clinical risk characteristics
      are at lower risk than are children with such characteristics; the magnitude of
      increased risk was inconsistent across studies. Computed tomography scan is most
      sensitive and specific for detection of intracranial abnormalities; sensitivity
      and specificity of skull radiographs ranged from 21% to 100% and 53% to 97%,
      respectively. No high quality studies tested alternative strategies for
      management of such children. Outcome studies are inconclusive as to the impact of
      minor head trauma on long-term cognitive function. CONCLUSIONS: The literature on
      mild head trauma does not provide a sufficient scientific basis for evidence
      based recommendations about most of the key issues in clinical management. More
      consistent definitions and multisite assessments are needed to clarify this
      field.

PMID- 10586013
TI  - High-resolution endoluminal sonography in gastroenterology.
AB  - Endosonography is an imaging method where a high frequency ultrasound probe is
      inserted blindly or under endoscopic control into a lumen. Examination of the
      gastrointestinal tract is performed using dedicated echoendoscopes or
      transendoscopic miniprobes. The gastrointestinal wall, mediastinum, pancreas,
      bile ducts, retroperitoneum, and other structures surrounding the
      gastrointestinal tract are target organs for endosonography. A detailed image of
      pathological processes can thus be obtained. The method can be used both for
      primary diagnosis of lesions and in follow-up of gastrointestinal diseases. It is
      accurate in local staging of cancer and in detecting small lesions, which cannot
      be seen with other imaging modalities. There are some limitations for optimal
      examination like stenoses or other factors prohibiting a precise position of the
      ultrasound transducer. The clinical importance of endosonographic examinations
      must be continuously evaluated on the basis of new technical modalities and
      changes in therapeutic procedures.

PMID- 10586014
TI  - The role of gastrointestinal endosonography in diagnostic and therapeutic
      interventional procedures.
AB  - Over the past 15 years endoscopic ultrasonography (EUS) has become an integrated
      part of gastrointestinal imaging. The more recent development of echoendoscopes
      and needles for EUS guided fine needle aspiration has stimulated the interest in
      interventional EUS procedures, both for diagnostic and therapeutic purposes. This
      paper describes the technique and experience with some of the interventional EUS
      procedures based on the present literature. Many of the techniques must still be
      considered experimental and will need substantial clinical testing in larger
      series before any final conclusions can be made. However, the present level of
      interventional EUS seems to indicate, that some of these techniques could be cost
      effective alternatives in specific clinical situations, and in some cases even
      the only possible theraputic action. Future research in interventional EUS should
      be concentrated in experienced endosonography centers under careful monitoring of
      complications and clinical outcome.

PMID- 10586015
TI  - Intraductal ultrasonography (IDUS) of the pancreato-biliary duct system. Personal
      experience and review of literature.
AB  - Endoscopic ultrasonography (EUS) represents a major advance in endoscopic
      imaging. Usefulness and effectiveness of EUS have been established during the
      past few years. However, endosonography using dedicated echoendoscopes (7.5/12
      MHz) has some serious drawbacks: (1) combining endoscopy and ultrasonography in
      one instrument increases the diameter of such echoendoscopes (13 mm); (2) as a
      result of the large diameter insertion into the pancreato-biliary duct system is
      not feasible at all; (3) image quality and resolution for small lesions is not
      always satisfactory; and (4) conventional endosonography needs a second
      examination separate from the previous routine endoscopy. Recently developed
      ultrasonographic miniprobes (diameters about 2 mm; frequencies 12-20 MHz) can be
      passed through the working channel of standard endoscopes to provide high
      frequency ultrasound images. These miniprobes might overcome some of the above
      mentioned drawbacks and contribute to patients' security and convenience.
      Moreover, in various diseases of the pancreato-biliary duct system diagnostic
      accuracy of miniprobe ultrasonography has been shown to be superior to that of
      EUS. In summary, miniprobe ultrasonography appears to be a promising addition to
      the armamentarium of gastroenterologic diagnostics.

PMID- 10586016
TI  - The role of endosonography in the diagnosis of choledocholithiasis.
AB  - Biliary endoscopic ultrasonography (EUS), even if complex and difficult to
      interpret, can depict with great accuracy the normal anatomy and abnormalities of
      this region. In case of choledocholithiasis, EUS has the unique ability to
      directly visualize the cause of biliary obstruction and to evaluate and integrate
      ductal abnormalities. For these tasks EUS is superior to conventional
      ultrasonography (US), computed tomography (CT) and also to new imaging techniques
      such as magnetic resonance cholangiography. The aim of this review is to provide
      an overview of the most significant EUS findings in choledocholithiasis together
      with the results of EUS in terms of diagnostic accuracy and cost-effectiveness.
      The role of EUS in the diagnosis of bile duct stones is therefore highlighted.

PMID- 10586017
TI  - Endoscopic ultrasonography in patients with gastro-esophageal cancer.
AB  - For patients with gastro-esophageal cancer ultrasonography (EUS) is superior to
      any other imaging modality in the assessment of local tumor infiltration and
      local lymph nodes status. EUS is especially important in the preoperative staging
      of patients with esophageal cancer and patients with proximal gastric cancer.
      Here it allows for the identification of those patients with advanced disease who
      are unlikely to benefit from surgery and in whom a conservative palliative
      treatment is indicated. In advanced gastric cancer the clinical implications of
      EUS less clear. Still preoperative EUS is indicated in every patient with cancer
      of the proximal stomach to assess tumor infiltration in the esophagus. Relatively
      new is the use of EUS in staging early cancers in order to select patients for
      local endoscopic treatment. High-frequency miniprobes are the instruments of
      choice for imaging these lesions. Strict criteria should be applied in the
      selection of patients for local endoscopic treatment of early gastro-esophageal
      cancers. EUS guided fine needle aspiration (EUS-FNA) is currently only indicated
      in patients with esophageal cancer and suspicious celiac lymph nodes. It may
      become more important if new treatment protocols demand more objective and
      reliable assessment of lymph node status.

PMID- 10586018
TI  - Endosonography in decision making and management of gastrointestinal endocrine
      tumors.
AB  - OBJECTIVE: gastroenteropancreatic (GEP) neuroendocrine tumors, suspected on
      clinical basis, are often difficult to localize. We report our experience with
      endoscopic ultrasonography (EUS) in the preoperative localization of pancreatic
      endocrine tumors (PETs), compared to other imaging modalities, and in staging and
      following up carcinoid tumors (CTs) of the gastrointestinal (GI) wall. METHODS:
      50 patients (20 males; mean age 54 years), 39 with suspected PETs and 11 with GI
      CTs underwent EUS (Olympus GF-UM2 or GF-UM3). EUS data could be compared with
      resected specimens in 25 out of the 39 PETs and five out of the 11 CTs. RESULTS:
      in the PETs group 42 tumors (35<20 mm) were removed: 23 in the pancreas, eight in
      the duodenum, and 11 in the lymph nodes. EUS correctly localized 20 out of the 23
      (87%) pancreatic tumors, included 11 out of the 12 (91.6%) insulinomas, three out
      of the eight (37.5%) duodenal gastrinomas, and ten out of the 11 (90.9%)
      metastatic lymph nodes. Furthermore EUS accurately evaluated the depth of
      parietal invasion of CTs in three out of four patients (75%) (two after and one
      prior to endoscopic resection). In three patients EUS was confirmed as normal on
      resected specimens (two pancreas and one stomach). In the PETs group, a correct
      localization was obtained by ultrasonography (US) only in 17.4% of cases, by
      computed tomography (CT) in 30.4%, by magnetic resonance imaging (MRI) in 25%, by
      angiography in 26.6%, and by somatostatin receptor scintigraphy in 15.4%.
      CONCLUSION: EUS must be considered the first-intention method in localizing PETs
      and is helpful in decision making and management of GEP endocrine tumors.

PMID- 10586019
TI  - EUS-guided fine needle biopsy: minimally invasive access to metastatic or
      recurrent cancer.
AB  - OBJECTIVE: Endoscopic ultrasound (EUS) is a sensitive technique for preoperative
      staging of gastrointestinal tumors. However, the value of this technique in the
      diagnosis of metastatic or recurrent disease is limited by the inability to
      differentiate malignant and benign lesions. We have prospectively investigated
      the role of EUS-guided biopsy in the evaluation of peri-intestinal tumors.
      METHODS: EUS-guided biopsy was performed in 167 patients with thoracic, intra
      abdominal or pelvic lesions. The upper gastrointestinal tract was examined with a
      flexible echoendoscope equipped with a 7.5 MHz curved array transducer. For
      transrectal EUS a rigid endoprobe with a bifocal multiplane transducer (10 MHz)
      was used. Both instruments allowed to observe the biopsy procedure exactly in the
      longitudinal scan plane. RESULTS: Real time ultrasonography guidance of the
      biopsy needle enabled precise tissue sampling even of small lesions with a
      diameter of 1 cm. Overall EUS-guided fine needle biopsy yielded tissue samples
      for histopathologic or cytologic analysis in of 151 of 167 patients. Histology
      demonstrated benign lesions in 71 of 74 patients and malignant tumors in 68 of 93
      patients. EUS-guided fine needle biopsy failed to provide the correct diagnosis
      in 28 cases. The overall sensitivity and specificity of EUS-guided biopsy in the
      diagnosis of malignancy were 73 and 96%, respectively. The histopathological
      results changed the clinical and endosonographic diagnosis in 49 patients. No
      complications were observed related to the biopsy. CONCLUSIONS: EUS-guided needle
      biopsy is a safe and efficient method for tissue sampling of peri-intestinal
      lesions. This minimally invasive technique provides adequate biopsies and
      improves the diagnostic value of endoscopic ultrasonography considerably.

PMID- 10586020
TI  - Laparoscopic ultrasound (LUS) in gastrointestinal surgery.
AB  - Intraoperative ultrasonography during abdominal surgery became widespread by
      availability of high-frequency, high-resolution transducers. It's usefulness has
      particularly been proven in biliar and gastrointestinal surgery. Our objective
      was to examine the method in laparoscopic cholecystectomy and in laparoscopic
      staging of malignancies of the upper gastrointestinal tract as well. Lapaoscopic
      ultrasound (LUS) examination was performed in 567 patients operated on because of
      biliary stones and in 12 patients with carcinoma in the upper part of the
      gastrointestinal tract. In accordance to the known criteria endoscopic retrograde
      cholangiopancreatography (ERCP) was performed in 89 patients, and additionally,
      ERCP was performed in 58 patients because of dilated common bile duct.
      Choledochal stones were demonstrated in 72 of the 147 patients. Laparoscopic
      ultrasonography demonstrated preoperatively undetected bile duct stones in 18 of
      these patients (12%). In 294 other patients without any criteria of bile duct
      stones, laparoscopic ultrasonography demonstrated bile duct stones in 11 patients
      (4%). Laparoscopic ultrasonography in 12 patients with proximal gastrointestinal
      malignancies demonstrated inoperability in all of the patients. Laparotomy could
      thereby be avoided. LUS examination is an ideal operative tool as it is safe,
      reproducible and requires no special patient preparation or positioning. The
      method of imaging is therefore justified for patients undergoing laparoscopic
      surgery because of biliary stones and gastrointestinal surgery.

PMID- 10586022
TI  - Standardized terminology in endoscopic ultrasound.
AB  - Standardized terminology is a prerequisite for meaningful collaboration and
      communication. This issue has been addressed for regular gastrointestinal
      endoscopy, through the OMED terminology and minimal standard terminology (MST)
      for endoscopic reporting. However, no similar initiative was taken for endoscopic
      ultrasound, although the need for a specific reporting language may be even
      greater for ultrasound investigations. This report describes the process and
      results of 'The International Working Group for Minimal Standard Terminology in
      Gastrointestinal Endosonography'. The resulting 'Minimal standard terminology in
      gastrointestinal endosonography' is presently available in a 1.0 version, and
      will now be subjected to clinical testing to further improve the selection and
      definition of core terms. It is reasonable to expect a fusion of this Endoscopic
      ultrasound (EUS) terminology with the general endoscopy MST terminology in the
      near future, to supply software developers with a joint standardized terminology.

PMID- 10586021
TI  - 3D-endosonography in gastroenterology: methodology and clinical applications.
AB  - Endoluminal ultrasonography allows detailed imaging of the gastrointestinal wall
      and adjacent structures. Three-dimensional (3D) imaging may improve visualisation
      of topographic relations and the nature of pathologic lesions. The objective of
      this report is to summarise current status of 3D-endosonography and to discuss
      the possible clinical impact of this new modality. 3D ultrasonographic images are
      usually generated from a series of digitised two-dimensional ultrasound pictures
      acquired in a manner that enables registration of their relative spatial
      position. Such acquisition can be accomplished with different ultrasound probes,
      but in most cases of endosonography, a controlled pullback of radial-scanning
      probes has been applied. Digital ultrasound images are obtained by frame grabbing
      of analogue video recordings or by direct transmission from digital scanners.
      Dedicated software programs have been developed for 3D reconstruction and
      visualisation, allowing interactive display and measurements. 3D endosonography
      provides new possibilities for clinical imaging, but the impact on therapeutic
      strategies and clinical outcome has yet to be established.

PMID- 10586023
TI  - Cutting edge: absence of expression of RAG1 in peritoneal B-1 cells detected by
      knocking into RAG1 locus with green fluorescent protein gene.
AB  - It has been proposed that Ig gene rearrangement in the peritoneal cavity (Pc) B-1
      cells might be involved in autoantibody generation. To study possible secondary B
      cell maturation, we prepared mice carrying a target integration of gfp gene into
      a rag1 locus (rag1/gfp mice). The GFP+ cells express rag1 mRNA and are undergoing
      Ig gene rearrangement. RAG1 expression was studied in Pc B-1 cells to detect
      cells during the stage of Ig gene rearrangement. In contrast to previous reports,
      Pc B-1 cells did not show RAG1 expression in adolescent or elderly mice. RAG1
      expression was not induced in Pc B-1 cells in vivo after stimulation by oral or
      i.p. administration of LPS. Our results suggest that RAG1 expression in Pc B-1
      cells is inhibited for a long period under normal condition and that this
      suppression is an essential state which maintains allelic exclusion of Ig genes.

PMID- 10586024
TI  - Cutting edge: the HLA-A*0101-restricted HY minor histocompatibility antigen
      originates from DFFRY and contains a cysteinylated cysteine residue as identified
      by a novel mass spectrometric technique.
AB  - In this report, we describe the use of novel mass spectrometry instrumentation to
      identify a male-specific minor histocompatibility Ag restricted by HLA-A*0101 (A1
      HY). This Ag has the sequence IVDC*LTEMY, where C* represents a cysteine
      disulfide bonded to a second cysteine residue. The core peptide sequence is found
      in the protein product of DFFRY, a Y chromosome gene not previously identified as
      the source of an HY Ag. The male-specific form of the peptide differs from its X
      chromosomal counterpart by the substitution of serine for the C* residue. Both
      peptides are expressed on the cell surface at 30 or fewer copies per cell.
      However, A1-HY-specific CTL recognize the DFFRY-derived peptide at a 1500-fold
      lower dose than the female homologue. Thus, these studies have identified a new
      source of HY epitopes and provide additional information about the influence of
      posttranslational modifications of class I-associated peptides on T cell
      recognition.

PMID- 10586025
TI  - Targeting of human dendritic cells by autologous NK cells.
AB  - NK cells have the capacity to spontaneously kill tumor cell lines, in particular
      cell lines of hemopoietic origin. In contrast, they do not generally kill
      nontransformed autologous cells. However, here we demonstrate that short-term
      activated polyclonal human NK cells, as well as human NK cell lines, efficiently
      lyse autologous dendritic cells (DC) derived from peripheral blood monocytes as
      well as Langerhans-like cells derived from CD34+ stem cells isolated from
      umbilical cord blood. Lysis of autologous DC by short-term activated NK cells and
      NK cell lines was dependent on granule exocytosis, since total abrogation of
      lysis was observed in the presence of EGTA. Induction of DC maturation by LPS,
      monocyte conditioned media (MCM), or stimulation through CD40 ligand (CD40L)
      rendered the DC less susceptible to lysis by NK cells. Infection of DC with
      influenza virus was likewise associated with a reduced susceptibility to lysis by
      NK cells. Thus, susceptibility to lysis by autologous NK cells is a particular
      property of immature DC. The present results are discussed in relation to the
      ability of DC to interact with NK cells and to the ability of NK cells to
      regulate development of specific immunity.

PMID- 10586026
TI  - Characterization of paired Ig-like receptors in rats.
AB  - To explore the phylogenetic history of the murine paired Ig-like receptors of
      activating (PIR-A) and inhibitory (PIR-B) types, we isolated PIR homologues from
      a rat splenocyte cDNA library. The rat (ra) PIR-A and raPIR-B cDNA sequences
      predict transmembrane proteins with six highly conserved extracellular Ig-like
      domains and distinctive membrane proximal, transmembrane, and cytoplasmic
      regions. The raPIR-B cytoplasmic region contains prototypic inhibitory motifs,
      whereas raPIR-A features a charged transmembrane region and a short cytoplasmic
      tail. Southern blot analysis predicts the presence of multiple Pira genes and a
      single Pirb gene in the rat genome. Although raPIR-A and raPIR-B are coordinately
      expressed by myeloid cells, analysis of mRNA detected unpaired expression of
      raPIR-A by B cells and raPIR-B by NK cells. Collectively, these findings indicate
      that the structural hallmarks of the Pir gene family are conserved in rats and
      mice, yet suggest divergence of PIR regulatory elements during rodent speciation.

PMID- 10586027
TI  - IL-2 plasmid therapy of murine ovarian carcinoma inhibits the growth of tumor
      ascites and alters its cytokine profile.
AB  - We have evaluated whether i.p. murine ovarian tumors could be treated with an IL
      2 plasmid DNA complexed with the cationic lipid, (+/-)-N-(2-hydroxyethyl)-N,N
      dimethyl-2, 3-bis(tetradecyloxy)-1-propanaminium
      bromide/dioleoylphosphatidylethanolamine (DMRIE/DOPE). Reporter gene studies were
      initially conducted in which mice bearing i.p. murine ovarian teratocarcinoma
      (MOT) were injected i.p. with reporter gene plasmid DNA (pDNA):DMRIE/DOPE.
      Histochemical analyses revealed that transfection occurred primarily in the tumor
      cells of the ascites, with only a minority of other ascitic cells or surrounding
      tissues transfected. IL-2 levels in the MOT ascites were determined after i. p.
      injection of either IL-2 pDNA:DMRIE/DOPE or recombinant IL-2 protein. IL-2 was
      detected in tumor ascites for up to 10 days after a single i.p. injection of IL-2
      pDNA:DMRIE/DOPE, but was undetectable 24 h after a single i.p. injection of IL-2
      protein. In an antitumor efficacy study, MOT tumor-bearing mice injected i.p.
      with IL-2 pDNA:DMRIE/DOPE on days 5, 8, and 11 after tumor cell implant had a
      significant inhibition of tumor ascites (p = 0.001) as well as a significant
      increase in survival (p = 0.008). A cytokine profile of the MOT tumor ascites
      revealed that mice treated with IL-2 pDNA:DMRIE/DOPE had an IL-2-specific
      increase in the levels of IFN-gamma and GM-CSF. Taken together, these findings
      indicate that i. p. treatment of ovarian tumors with IL-2 pDNA:DMRIE/DOPE can
      lead to an increase in local IL-2 levels, a change in the cytokine profile of the
      tumor ascites, and a significant antitumor effect.

PMID- 10586028
TI  - T suppressor lymphocytes inhibit NF-kappa B-mediated transcription of CD86 gene
      in APC.
AB  - CD8+CD28- human T suppressor cells (Ts) act on APC, inhibiting their ability to
      elicit Th activation and proliferation. This effect is due to inhibition of the
      CD40 pathway which normally leads to CD80 and CD86 up-regulation. To determine
      whether Ts inhibit expression of B7 molecules by blocking transcription, we
      cloned and characterized the CD86 promoter. Mutational analysis revealed that Ts
      inhibit transcription driven by the CD86 promoter. The NF-kappa B binding site,
      at -612 of the CD86 promoter, is essential for Th-induced transcription. In
      cultures containing Th and Ts, Ts inhibit Th-induced NF-kappa B activation in
      APC. Together, these findings indicate that Ts inhibition of NF-kappa B
      activation in APC is a means by which they regulate the activation and
      proliferation of Th.

PMID- 10586029
TI  - Th1 and Th2 deviation of myelin-autoreactive T cells by altered peptide ligands
      is associated with reciprocal regulation of Lck, Fyn, and ZAP-70.
AB  - Th0 clones recognizing an immunodominant peptide of myelin basic protein
      (residues 83-99) were derived from patients with multiple sclerosis. We
      demonstrate that analogue peptides with alanine substitution at Val86 and His88
      had a unique partial agonistic property in inducing Th0 -->Th1 and Th0 -->Th2
      deviation of the myelin basic protein-reactive T cell clones, respectively. Th0
      to Th1 deviation induced by peptide 86V-->A correlated with up-regulation of Fyn
      and ZAP-70 kinase activities. Conversely, Th0 to Th2 deviation induced by peptide
      88H-->A was associated with complete failure to activate Fyn and ZAP-70 kinases.
      The observed Th1 and Th2 shift also correlated, to a lesser extent, with Lck
      kinase activity that was down-regulated with Th1 deviation and increased with Th2
      deviation in some T cell clones. We demonstrated that the Th1 and Th2 shift
      induced by the analogue peptides was a reversible process, as the T cell clones
      previously exposed to either 86V-->A or 88H-->A peptide could revert to an
      opposite phenotype when rechallenged reciprocally with a different analogue
      peptide. The study has important implications in our understanding of regulation
      of TCR-associated tyrosine kinases by altered peptide ligands and its role in
      cytokine regulation of autoreactive T cells.

PMID- 10586030
TI  - Extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP)
      kinases differentially regulate the lipopolysaccharide-mediated induction of
      inducible nitric oxide synthase and IL-12 in macrophages: Leishmania
      phosphoglycans subvert macrophage IL-12 production by targeting ERK MAP kinase.
AB  - Macrophage activation by cytokines or microbial products such as LPS results in
      the induction and release of several key immune effector molecules including NO
      and IL-12. These have been shown to play crucial roles in the development of
      immunity to intracellular pathogens such as Leishmania. The molecular mechanisms
      underlying the induction of these effector molecules are not fully understood. We
      now show that the extracellular signal-related kinase (ERK) and p38 mitogen
      activated protein (MAP) kinases play differential roles in the regulation of LPS
      stimulated inducible NO synthase and IL-12 gene expression. In macrophages, LPS
      stimulates the simultaneous activation of all three classes of MAP kinases, ERK,
      c-jun N-terminal kinase, and p38, albeit with differential activation kinetics.
      However, studies using inhibitors selective for ERK (PD98059) and p38 (SB203580)
      show that while p38 plays an essential role in the induction of inducible NO
      synthase, ERK MAP kinases play only a minor role in promoting NO generation. In
      contrast, while p38 promotes induction of IL-12 (p40) mRNA, ERK activation
      suppresses LPS-mediated IL-12 transcription. The biological relevance of these
      regulatory signals is demonstrated by our finding that Leishmania
      lipophosphoglycans, which promote parasite survival, act by stimulating ERK MAP
      kinase to inhibit macrophage IL-12 production. Thus, as ERK and p38 MAP kinases
      differentially regulate the induction of the macrophage effector molecules,
      inducible NO synthase and IL-12, these kinases are potential targets not only for
      the development of novel strategies to combat intracellular pathogens but also
      for therapeutic immunomodulation.

PMID- 10586031
TI  - Role of APC in the selection of immunodominant T cell epitopes.
AB  - Following antigenic challenge, MHC-restricted T cell responses are directed
      against a few dominant antigenic epitopes. Here, evidence is provided
      demonstrating the importance of APC in modulating the hierarchy of MHC class II
      restricted T cell responses. Biochemical analysis of class II:peptide complexes
      in B cells revealed the presentation of a hierarchy of peptides derived from the
      Ig self Ag. Functional studies of kappa peptide:class II complexes from these
      cells indicated that nearly 20-fold more of an immunodominant epitope derived
      from kappa L chains was bound to class II DR4 compared with a subdominant epitope
      from this same Ag. In vivo, T cell responses were preferentially directed against
      the dominant kappa epitope as shown using Ig-primed DR4 transgenic mice. The bias
      in kappa epitope presentation was not linked to differences in class II:kappa
      peptide-binding affinity or epitope editing by HLA-DM. Rather, changes in native
      Ag structure were found to disrupt presentation of the immunodominant but not the
      subdominant kappa epitope; Ag refolding restored kappa epitope presentation.
      Thus, Ag tertiary conformation along with processing reactions within APC
      contribute to the selective presentation of a hierarchy of epitopes by MHC class
      II molecules.

PMID- 10586032
TI  - Immunogenicity. I. Use of peptide libraries to identify epitopes that activate
      clonotypic CD4+ T cells and induce T cell responses to native peptide ligands.
AB  - Recent studies have demonstrated the utility of synthetic combinatorial libraries
      for the rapid identification of peptide ligands that stimulate clonotypic
      populations of T cells. Here we screen a decapeptide combinatorial library
      arranged in a positional scanning format with two different clonotypic
      populations of CD4+ T cells to identify peptide epitopes that stimulate
      proliferative responses by these T cells in vitro. An extensive collection of
      mimic peptide sequences was synthesized and used to explore the fine specificity
      of TCR/peptide/MHC interactions. We also demonstrate that many of these deduced
      ligands are not only effective immunogens in vivo, but are capable of inducing T
      cell responses to the original native ligands used to generate the clones. These
      results have significant implications for considerations of T cell specificity
      and the design of peptide vaccines for infectious disease and cancer using
      clinically relevant T cell clones of unknown specificity.

PMID- 10586033
TI  - Regulated association between the tyrosine kinase Emt/Itk/Tsk and phospholipase-C
      gamma 1 in human T lymphocytes.
AB  - The Emt/Itk/Tsk tyrosine kinase is involved in intracellular signaling events
      induced by several lymphocyte surface receptors. Modulation of TCR/CD3-induced
      phospholipase-C gamma 1 (PLC gamma 1) activity by the tyrosine kinase Emt/Itk/Tsk
      has been demonstrated based on studies of Itk-deficient murine T lymphocytes.
      Here we report a TCR/CD3-regulated association between Emt and PLC gamma 1 in
      both normal and leukemic T cells. In addition, this association was enhanced
      following independent ligation of the CD2, CD4, or CD28 costimulatory molecules,
      but not of CD5 or CD6 surface receptors, correlating to the induced tyrosine
      phosphorylation of Emt. Before Ab-induced T cell activation, we found that the
      Emt-SH3 domain was crucial for the constitutive Emt/PLC gamma 1 association;
      however, upon TCR/CD3 engagement, the Emt-SH2 domain was more efficient in
      mediating the enhanced Emt/PLC gamma 1 interaction. Furthermore, the PLC gamma 1
      SH3 domain, but not the two PLC gamma 1-SH2 domains, contributed to formation of
      the protein complex. Thus, we describe a regulated interaction between Emt and
      PLC gamma 1, and based on our studies with individual Emt and PLC gamma 1 SH2/SH3
      domains, we propose a mechanism for this association.

PMID- 10586034
TI  - Follicular dendritic cells protect malignant B cells from apoptosis induced by
      anti-Fas and antineoplastic agents.
AB  - The observation that follicular dendritic cells (FDC) reduce apoptosis in B cells
      prompted the hypothesis that FDC might enhance tumor cell survival by protecting
      malignant B cells from apoptotic death. To test this notion, apoptosis was
      induced in B cell lymphomas by anti-Fas or various antineoplastic agents in the
      presence and absence of FDC. Apoptosis was detected and quantified by TUNEL
      analysis. Induction of apoptosis with anti-Fas, etoposide, cyclophosphamide, and
      busulfan was markedly antagonized by FDC at FDC to B cell ratios of >/=1:16. For
      example, treatment with 10 ng/ml anti-Fas caused 60-90% of A20 cells to undergo
      apoptosis in 6 h, whereas addition of FDC reduced apoptosis to background levels
      (3-15%). Similarly, treatment with busulfan induced apoptosis in 55-80% of A20
      cells, whereas addition of FDC reduced B cell death to </=15%; moreover,
      depletion of FDC abrogated the protective actions. In contrast, the apoptosis
      inducing effect of Adriamycin was not reversed by FDC. The ability to block
      apoptosis induced by anti-Fas or busulfan was not limited to A20 but was observed
      in four other malignant pre-B cell or B cell lines. The mechanism by which FDC
      spare malignant B cells from apoptosis did not involve alterations in levels of
      Bcl-2, Bcl-XL, or Bax. Collectively, these data raise the possibility that FDC
      may enhance tumor cell survival by protecting malignant B cells against apoptosis
      induced by anti-Fas and some but not all chemotherapeutic agents.

PMID- 10586035
TI  - Aluminium hydroxide adjuvant initiates strong antigen-specific Th2 responses in
      the absence of IL-4- or IL-13-mediated signaling.
AB  - Previous studies demonstrate that aluminium hydroxide adjuvant (alum) produces
      increased Th1 responses in IL-4-deficient mice compared with wild-type animals,
      although the continued production of IL-5 by spleen cells from these mice also
      indicates that Th2 responses are induced. In the present study, we demonstrate
      that alum can induce Th2-associated IL-4 and IL-5 production in the absence of IL
      4 signaling in mice deficient in either IL-4Ralpha or Stat6. The Th2 responses
      observed could not be due to IL-13 as IL-13 responses are also impaired in IL
      4Ralpha- and Stat6-deficient mice. We also detected higher levels of IL-4 in IL
      4Ralpha gene-deficient, though not Stat6-deficient, mice compared with their wild
      type counterparts. The increased levels of IL-4 could be explained by the IL-4R
      being unavailable to neutralize this cytokine in IL-4Ralpha-deficient mice. While
      levels of IL-5 production in IL-4Ralpha- or Stat6-deficient mice were similar to
      IL-4-deficient and wild-type mice, other type 2-associated responses, which are
      largely or wholly IL-4 dependent, such as the production of IgG1 or IgE Abs, were
      either reduced or absent. We conclude that alum adjuvants can induce IL-4
      production and Th2 responses independently of IL-4 or IL-13, negating the
      requirement for an early source of IL-4 in the Th2 response induced by this
      adjuvant.

PMID- 10586036
TI  - Antigen-induced unresponsiveness results in altered T cell signaling.
AB  - Pretransplant exposure to allogeneic lymphocytes can result in donor-specific
      unresponsiveness and prolonged allograft survival. Intracellular signaling events
      have been described in anergic T cell clones, but the biochemical events
      underlying in vivo induced unresponsiveness have not been studied in detail. We
      employed a TCR transgenic mouse, bearing the 2C TCR, providing adequate numbers
      of homogenous peripheral T cells to study biochemical aspects of T cell
      unresponsiveness in vivo. 2C mice exposed to semiallogeneic lymphocytes (H-2b x H
      2d) experienced prolonged H-2d cardiac allograft survival, and cells from these
      mice did not proliferate or make IL-2 in response to alloantigen (H-2d).
      Importantly, there were marked differences in TCR-associated tyrosine
      phosphorylation activation patterns. The targets for the unresponsive state
      appear to be diminished Lck activation and absent ZAP-70 and LAT (linker for
      activation of T cells) phosphorylation. Our study demonstrates that Ag-induced
      tolerance in vivo is accompanied by altered early TCR-mediated signaling events.

PMID- 10586037
TI  - The in vivo fate of APCs displaying minor H antigen and/or MHC differences is
      regulated by CTLs specific for immunodominant class I-associated epitopes.
AB  - The goal of this work was to evaluate the fate of APCs following interactions
      with T cells in unprimed mice with a normal T cell repertoire. We elaborated a
      model in which male adherent peritoneal mononuclear cells were injected into the
      foreleg footpads of naive female recipients mismatched for either minor or major
      histocompatibility Ags. At various times after injection, APC numbers in the
      draining (axillary and brachial) lymph nodes were assessed using a Ube1y gene
      specific PCR assay. Our experimental model was designed so that the number of
      APCs expressing the priming epitope was similar to what is observed under real
      life conditions. Thus, early after injection, the frequency of afferent lymph
      derived APCs expressing the priming epitope was in the range of 101-102/106 lymph
      node cells. We found that APCs presenting some, but not all, nonself epitopes
      were killed rapidly after entrance into the lymph nodes. Rapid elimination of
      APCs occurred following interactions with MHC class I-restricted, but not class
      II-restricted, T cells and was observed when APCs presented an immunodominant
      (B6dom1/H7a), but not a nondominant (HY), epitope. Killing of APCs was mediated
      partly, but not exclusively, by perforin-dependent process. We propose that
      killing of APCs by CTLs specific for immunodominant MHC class I-restricted
      epitopes may be instrumental in regulating the intensity, duration, and diversity
      of T cell responses.

PMID- 10586038
TI  - Protein-protein and DNA-protein interactions affect the activity of lymphoid
      specific IFN regulatory factors.
AB  - IFN regulatory factors (IRFs) constitute a family of transcription factors that
      are involved in IFN signaling and the development and differentiation of the
      immune system. Targeted gene disruption studies in mice assigned their primary
      role to the immune system. Two lymphoid-specific IRF members, IFN consensus
      sequence binding protein (ICSBP) and IRF-4, bind target DNA with greater
      efficiency following interaction with two transcription factors, PU.1 and E47,
      leading to transcriptional synergy. PU.1 and E47 are essential for proper
      differentiation and maturation of lymphoid cells. In addition, ICSBP interacts
      with two IRF members, IRF-1 and IRF-2, which also have central roles in the
      regulation of cell-mediated immunity. Previously, we identified a region in
      ICSBP, termed the IRF association domain (IAD), that is conserved in all IRFs
      (excluding IRF-1 and IRF-2) and is essential for its interactions with other IRF
      proteins. Here we show that the IAD is an independent module used by ICSBP and
      IRF-4 for protein-protein interactions. In addition, an IAD of IRF-2 (IAD2),
      necessary for interaction with ICSBP, was identified and found to be conserved in
      IRF-1. The IAD2 shares similar characteristics with the PEST domain that is
      essential for the interaction of PU.1 with IRF-4. We also show that the ICSBP DNA
      binding domain is indispensable for the formation of DNA binding heterocomplexes
      and transcriptional activity. Therefore, our results shed light on the molecular
      mechanisms that affect IRF activities in the immune system via discrete
      functional domains.

PMID- 10586039
TI  - Role of immunoregulatory donor T cells in suppression of graft-versus-host
      disease following donor leukocyte infusion therapy.
AB  - In murine models of allogeneic bone marrow transplantation (BMT), MHC-mismatched
      recipients given a delayed infusion of donor leukocytes (DLI) at 21 days
      posttransplant develop significant GVHD whereas MHC-matched recipients do not.
      The current study was initially designed to test the hypothesis that small
      numbers of T cells in the MHC-mismatched donor bone marrow (BM) graft exacerbated
      graft-vs-host disease (GVHD) when DLI was administered at 21 days after BMT. Ex
      vivo depletion of Thy1+ cells from the donor BM had no impact on the severity of
      GVHD after DLI. However, depletion of donor T cells in vivo with a Thy1 allele
      specific mAb given after BMT resulted in significantly more severe GVHD after
      DLI. Similar results were obtained in a MHC-matched model of allogeneic BMT,
      indicating that this was a general phenomenon and not model dependent. These
      results indicated that a population of donor-derived Thy1+ cells suppressed graft
      vs-host reactivity after DLI. Results of experiments with thymectomized
      recipients demonstrated that an intact thymus was required for generation of the
      immunoregulatory donor cells. Experiments using TCR beta-chain knockout mice as
      BM donors indicated that the immunosuppressive Thy1+ cells coexpressed
      alphabetaTCR heterodimers. Similar experiments with CD4 and CD8 knockout donor BM
      suggested that the immunoregulatory Thy1+alphabetaTCR+ cells consisted of two
      subpopulations: a CD4+CD8- subpopulation and a CD4-CD8- subpopulation. Together,
      these results show that thymus-derived, Thy1+alphabetaTCR+ donor cells generated
      early after allogeneic BMT suppress the graft-vs-host reactivity of T cells given
      as DLI. These cells may mediate dominant peripheral tolerance after allogeneic
      BMT.

PMID- 10586040
TI  - IFN-gamma production and cytotoxicity of IL-2-activated murine NK cells are
      differentially regulated by MHC class I molecules.
AB  - Activation of NK cells by target cells leads to cytotoxicity as well as
      production of various cytokines including IFN-gamma. MHC class I molecules on
      target cells regulate NK cytotoxicity. However, little is known about the
      regulation of IFN-gamma production by NK cells. We examined the production of IFN
      gamma in individual murine NK cells stimulated with tumor cell lines by flow
      cytometric analysis of intracellular IFN-gamma. Among several tumor lines tested,
      the rat basophilic leukemia line RBL-1 induced particularly high level of IFN
      gamma production in IL-2-activated NK cells, whereas other lines, including the
      prototypic NK target YAC-1, induced very low or no IFN-gamma production.
      Transfection of murine classical MHC class I molecules into RBL-1 cells
      substantially inhibited IFN-gamma production. This inhibition of IFN-gamma
      production by MHC class I was independent of Ly-49 or CD94/NKG2A expression on NK
      cells. These results indicate that some target cells directly stimulate IL-2
      activated NK cells and induce IFN-gamma production, but the requirements for the
      induction of IFN-gamma production seem different from those for NK cytotoxicity.
      Furthermore, similar to NK cytotoxicity, induction of IFN-gamma production is
      inhibited by MHC class I on stimulating cells. However, the MHC class I-specific
      receptors inhibiting IFN-gamma production are different from those for NK
      cytotoxicity.

PMID- 10586041
TI  - Negative regulation of CD4 lineage development and responses by CD5.
AB  - CD5 deficiency results in a hyper-responsive phenotype to Ag receptor
      stimulation. Here we show that the development and responses of CD4 lineage T
      cells are regulated by the function of CD5. Thymocytes expressing the I-Ad
      restricted DO11.10 TCR undergo abnormal selection without CD5. In H-2d mice, the
      absence of CD5 causes deletion of double-positive thymocytes, but allows for
      efficient selection of cells expressing high levels of the DO11.10 clonotype. By
      contrast, there is enhanced negative selection against the DO11.10 clonotype in
      the presence of I-Ab. T cell hybridomas and DO11.10 T cells are more responsive
      to TCR stimulation in the absence of CD5. Such hypersensitivity can be eliminated
      by expression of wild-type CD5, but not by a form of CD5 that lacks the
      cytoplasmic tail. Finally, CD5 deficiency partially suppresses the block of CD4
      lineage development in CD4-deficient mice. Taken together, the data support a
      general role for CD5 as a negative regulator of Ag receptor signaling in the
      development and immune responses of CD4 lineage T cells.

PMID- 10586042
TI  - MHC class I-restricted cytotoxic lymphocyte responses induced by enterotoxin
      based mucosal adjuvants.
AB  - The ability of enterotoxin-based mucosal adjuvants to induce CD8+ MHC class I
      restricted CTL responses to a codelivered bystander Ag was examined. Escherichia
      coli heat-labile toxin (LT), or derivatives of LT carrying mutations in the A
      subunit (LTR72, LTK63), were tested in parallel with cholera toxin (CT) or a
      fusion protein consisting of the A1 subunit of CT fused to the Ig binding domain
      of Staphylococcus aureus protein A (called CTA1-DD). Intranasal (i.n.)
      immunization of C57BL/6 mice with CT, CTA1-DD, LT, LTR72, LTK63, but not rLT-B,
      elicited MHC class I-restricted CD8+ T cell responses to coadministered OVA or
      the OVA CTL peptide SIINFEKL (OVA257-264). CT, LT, and LTR72 also induced CTL
      responses to OVA after s.c. or oral coimmunization whereas LTK63 only activated
      responses after s.c. coimmunization. rLT-B was unable to adjuvant CTL responses
      to OVA or OVA257-264 administered by any route. Mice treated with an anti-CD4 mAb
      to deplete CD4+ T cells mounted significant OVA-specific CTL responses after i.n.
      coadministration of LT with OVA or OVA257-264. Both 51Cr release assays and IFN
      gamma enzyme-linked immunospot assays indicated that IFN-gamma-/- and IL-12 p40-/
      gene knockout mice developed CTL responses equivalent to those detected in
      normal C57BL/6 mice. The results highlight the versatility of toxin-based
      adjuvants and suggest that LT potentiates CTL responses independently of IL-12
      and IFN-gamma and probably by a mechanism unrelated to cross-priming.

PMID- 10586043
TI  - Tolerance to maternal immunoglobulins: resilience of the specific T cell
      repertoire in spite of long-lasting perturbations.
AB  - T cell tolerance is established and maintained through various mechanisms, the
      critical component being the persistence of the specific Ag. However, at the
      molecular level, the nature of the recovering TCR repertoire following breakdown
      of tolerance is unknown. We address this important question by following kappa
      light chain constant region (C kappa)-specific CD4+ T cells of kappa light chain
      knock-out (kappa-/-) mice born to kappa+/- mothers. These cells, which were in
      contact with maternal kappa+ Igs from early ontogeny until weaning, were strongly
      tolerized. Tolerance was reversible and waned with the disappearance of peptide C
      kappa 134-148 presentation in lymphoid organs, including the thymus. Whereas
      three specific V beta-J beta rearrangements emerged in the peptide C kappa 134
      148-specific CD4+ T cell response of all regular kappa-/- mice, soon after
      breakdown of tolerance only one of these rearrangements was detected. The two
      others displayed a significant delay in reappearance and were still rare at 26 wk
      of age, while the control proliferative response had already recovered 3 mo
      earlier. At 52 wk of age, a complete recovery of the three canonical V beta-J
      beta rearrangements was observed. Thus, although profoundly perturbed for several
      months, the T cell repertoire returns to equilibrium, highlighting the resilient
      nature of this system.

PMID- 10586044
TI  - Robust B cell immunity but impaired T cell proliferation in the absence of CD134
      (OX40).
AB  - CD134 (OX40) is a member of the TNF receptor family that is expressed on
      activated T lymphocytes. T cells from mice that lack expression of CD134 made
      strong responses to a range of challenges, but they showed impaired proliferation
      in response to direct stimulation through the TCR with monoclonal anti-CD3epsilon
      Ab. CD134-deficient mice controlled infection with Leishmania major,
      Nippostrongylus brasiliensis, and Theiler's murine encephalomyelitis virus, and
      they made overtly normal Ab responses to a variety of antigens. Thus, CD134 is
      not essential for many T cell responses in vivo, nor is it required for the
      provision of help to B cells. Nonetheless, a subtle role in the regulation of T
      cell reactivity is suggested by the effect of CD134 deficiency on in vitro T cell
      responses.

PMID- 10586045
TI  - Increased p27Kip1 cyclin-dependent kinase inhibitor gene expression following
      anti-IgM treatment promotes apoptosis of WEHI 231 B cells.
AB  - Engagement of the B cell receptor of WEHI 231 immature B cells leads sequentially
      to a drop in c-Myc, to induction of the cyclin-dependent kinase inhibitor
      p27Kip1, and finally to apoptosis. Recently we demonstrated that the drop in c
      Myc expression promotes cell death, whereas the induction of p27 has been shown
      to lead to growth arrest. In this paper, we demonstrate that increased p27
      expression also promotes apoptosis of WEHI 231 B cells. The rescue of WEHI 231
      cells by CD40 ligand engagement of its receptor prevented the increase in p27
      induction. Inhibition of p27-ablated apoptosis induced upon expression of
      antisense c-myc RNA. Furthermore, specific induction of p27 gene expression
      resulted in apoptosis of WEHI 231 cells. Lastly, inhibition of expression of c
      Myc, upon induction of an antisense c-myc RNA vector, was sufficient to induce
      increased p27 levels and apoptosis. Thus, these findings define a signaling
      pathway during B cell receptor engagement in which the drop in c-Myc levels leads
      to an increase in p27 levels that promotes apoptosis.

PMID- 10586046
TI  - Stat6-dependent and -independent pathways for IL-4 production.
AB  - Stat6 has been shown to have a crucial role in the IL-4-dependent differentiation
      of Th2 cells. In this report, we explore whether in vitro Th2 differentiation
      driven by altered costimulatory signals or Ag dose is Stat6 dependent. We find
      that blocking B7-1 signaling in vitro promotes the differentiation of IL-4
      secreting Th2 cells in wild-type but not Stat6-deficient T cell cultures.
      Additionally, stimulation with peptide Ag doses that normally result in the
      production of Th2 cells in vitro fails to do so in cultures of Stat6-deficient
      cells. We also demonstrate that Stat6 is required for the in vitro
      differentiation of CD8+ T cells into IL-4-secreting cytotoxic T cell type 2
      cells. However, IL-4 expression is not absolutely dependent on Stat6. We
      demonstrate that populations of T cells that do not require IL-4 for their
      development, such as NK T cells, are still competent to secrete IL-4 in the
      absence of Stat6. These results demonstrate that Stat6 is required for the
      differentiation program leading to the generation of Th2 and cytotoxic T cell
      type 2 cells but not for IL-4 expression in cells that do not undergo
      differentiation in response to IL-4.

PMID- 10586047
TI  - Bacterial/CpG DNA down-modulates colony stimulating factor-1 receptor surface
      expression on murine bone marrow-derived macrophages with concomitant growth
      arrest and factor-independent survival.
AB  - Unmethylated CpG motifs within bacterial DNA constitute a pathogen-associated
      molecular pattern recognized by the innate immune system. Many of the
      immunomodulatory functions of bacterial DNA can be ascribed to the ability to
      activate macrophages and dendritic cells. Here we show stimulatory DNA, like LPS,
      caused growth arrest of murine bone marrow-derived macrophages proliferating in
      CSF-1. Stimulatory DNA caused selective down-modulation of CSF-1 receptor surface
      expression. Flow cytometric analysis of CSF-1-deprived bone marrow-derived
      macrophages revealed that in contrast to the synchronous reduction of CSF-1
      receptor upon CSF-1 addition, activating DNA (both bacterial DNA and CpG
      containing oligonucleotide) caused rapid removal of receptor from individual
      cells leading to a bimodal distribution of surface expression at intermediate
      times or submaximal doses of stimulus. Despite causing growth arrest, both
      stimulatory DNA and LPS promoted factor-independent survival of bone marrow
      derived macrophages, which was associated with phosphorylation of the mitogen
      activated protein kinase family members, extracellular-regulated kinase 1 and 2.
      CSF-1 receptor down-modulation may polarize the professional APC compartment to
      the more immunostimulatory dendritic cell-like phenotype by suppressing terminal
      macrophage differentiation mediated by CSF-1.

PMID- 10586048
TI  - Central nervous system-targeted expression of the complement inhibitor sCrry
      prevents experimental allergic encephalomyelitis.
AB  - Although generally thought of as a T cell-driven autoimmune disease, recent
      studies in experimental allergic encephalomyelitis (EAE), the animal model of
      multiple sclerosis, suggest a significant role for innate immune mechanisms. To
      address the possibility that the complement system plays a central role in these
      diseases, we developed a transgenic mouse with astrocyte-targeted production of a
      soluble inhibitor of complement activation, complement receptor-related protein y
      (sCrry). Here, we show that sCrry transgenic mice are either fully protected
      against EAE or develop significantly delayed clinical signs. These results
      indicate that complement activation may have an essential role in the
      pathogenesis of the disease and that complement-mediated events may occur early
      during the effector phase of EAE. Furthermore, this work underscores the
      importance of humoral immunity in amplifying a T cell-initiated pathogenic
      process.

PMID- 10586049
TI  - Ability of a nondepleting anti-CD4 antibody to inhibit Th2 responses and allergic
      lung inflammation is independent of coreceptor function.
AB  - Nondepleting anti-CD4 Abs have been used in vivo to induce Ag-specific
      immunological tolerance in Th1 responses, including tissue allograft rejection
      and autoimmune diabetes. To examine whether this Ab (YTS177.9) acts by provoking
      a Th2 shift, we tested the effect in a mouse model of allergic lung inflammation.
      Interestingly, nondepleting anti-CD4 treatment induces tolerance to allergens as
      well, especially when given during initial priming. In vitro studies indicate
      that the effect of the Ab is independent of CD4 coreceptor function, as Ab
      treatment also inhibits proliferation and induces a persistent anergy in naive
      CD4 T cells stimulated by anti-CD3/CD28. Moreover, the Ab stimulated a distinct
      pattern of tyrosine phosphorylation in T cells even in the absence of TCR
      triggering, suggesting that signaling through CD4 alone induces significant
      physiological changes in T cell function. These results show that tolerance
      induced by anti-CD4 triggering is not a simple shift in Th1/Th2 effector function
      or depletion of Ag-specific cells, but may instead induce a persistent clonal
      anergy capable of blocking subsequent immunity.

PMID- 10586050
TI  - Selective pharmacologic inhibition of murine and human IL-12-dependent Th1
      differentiation and IL-12 signaling.
AB  - We have previously shown that lisofylline (LSF) inhibits murine Th1-mediated
      disease in vivo by blocking IL-12-induced differentiation of Th1 cells. The
      cellular and molecular mechanisms underlying this inhibition were further
      explored by testing LSF in several IL-12-responsive model systems in vitro. IL-12
      dependent Th1 differentiation was abrogated by LSF and yielded effector T cells
      that were deficient in proinflammatory cytokine secretion, including IFN-gamma,
      IL-2, and TNF-alpha. The diminished Th1 phenotype resulted from both a lower
      frequency of IL-12-derived Th1 clones and a reduced capacity of individual clones
      to secrete IFN-gamma due to lower levels of IFN-gamma mRNA. The arrest in Th1
      development resulted from a blockade of IL-12 signaling that preceded the Th0 to
      Th1 transition. Thus, LSF blocked IL-12-enhanced IFN-gamma production in anti-CD3
      stimulated T cells and prevented IL-12-mediated repression of the transcription
      factor GATA-3. Lisofylline also inhibited IL-12-induced increases in STAT4
      tyrosine phosphorylation, but did not block TCR signaling or inhibit acquisition
      of IL-12 responsiveness. These findings were extended to show that LSF also
      inhibits IL-12-dependent responses in human T cells. LSF, which has one
      asymmetric chiral center, was selectively inhibitory for IL-12 signaling compared
      with its S-enantiomer (1501-S) and the oxidized side chain analog,
      pentoxifylline. The results suggest that LSF may be useful as a modulator of Th1
      mediated disease in humans.

PMID- 10586051
TI  - TNF and lymphotoxin beta cooperate in the maintenance of secondary lymphoid
      tissue microarchitecture but not in the development of lymph nodes.
AB  - Inactivation of genes encoding members of TNF and TNF receptor families reveal
      their divergent roles in the formation and function of secondary lymphoid organs.
      Most lymphotoxin alpha (ltalpha)- and all lymphotoxin beta receptor (ltbetar)
      deficient mice are completely devoid of lymph nodes (LNs); however, most
      lymphotoxin beta (ltbeta)-deficient mice develop mesenteric LNs. Tnf- and tnfrp55
      deficient mice develop a complete set of LNs, while ltbeta/tnfrp55 double
      deficient mice lack all LNs, demonstrating cooperation between LTbeta and TNFRp55
      in LN development. Now we report that ltbeta/tnf double-deficient mice develop
      the same set of mucosal LNs as do ltbeta-deficient mice, suggesting that ligands
      other than TNF signal through TNFRp55 during LN development. These LNs retain
      distinct T and B cells areas; however, they lack follicular dendritic cell
      networks. Structures resembling germinal centers can be found in the LNs from
      immunized ltbeta-deficient mice but not in ltbeta/tnf double-deficient mice.
      Additionally, stromal components of the spleen and LNs appear to be more severely
      disturbed in ltbeta/tnf double-deficient mice as compared with ltbeta-deficient
      mice. We conclude that LTbeta and TNF cooperate in the establishment of the
      correct microarchitecture of lymphoid organs.

PMID- 10586052
TI  - Distinct activities of p52/NF-kappa B required for proper secondary lymphoid
      organ microarchitecture: functions enhanced by Bcl-3.
AB  - Mice rendered deficient in p52, a subunit of NF-kappa B, or in Bcl-3, an I kappa
      B-related regulator that associates with p52 homodimers, share defects in the
      microarchitecture of secondary lymphoid organs. The mutant mice are impaired in
      formation of B cell follicles and are unable to form proper follicular dendritic
      cell (FDC) networks upon antigenic challenge. The defects in formation of B cell
      follicles may be attributed, at least in part, to impaired production of the B
      lymphocyte chemoattractant (BLC) chemokine, possibly a result of defective FDCs.
      The p52- and Bcl-3-deficient mice exhibit additional defects within the splenic
      marginal zone, including reduced numbers of metallophilic macrophages, reduced
      deposition of the laminin-beta 2 chain and impaired expression of a mucosal
      addressin marker on sinus-lining cells. Whereas p52-deficient mice are severely
      defective in all of these aspects, Bcl-3-deficient mice are only partially
      defective. We determined that FDCs or other non-hemopoietic cells that underlie
      FDCs are intrinsically impaired in p52-deficient mice. Adoptive transfers of wild
      type bone marrow into p52-deficient mice failed to restore FDC networks or
      follicles. The transfers did restore metallophilic macrophages to the marginal
      zone, however. Together, the results suggest that p52 carries out functions
      essential for a proper splenic microarchitecture in both hemopoietic and non
      hemopoietic cells and that Bcl-3 is important in enhancing these essential
      activities of p52.

PMID- 10586053
TI  - Distinct subcellular localization and substrate specificity of extracellular
      signal-regulated kinase in B cells upon stimulation with IgM and CD40.
AB  - We and others previously observed that IgM and CD40 stimulation in murine B cells
      resulted in activation of extracellular signal-regulated kinase (ERK), a
      subfamily of mitogen-activated protein kinase. The present study demonstrated
      that ERK was rapidly phosphorylated and translocated to the nucleus in murine B
      cells upon stimulation with CD40, whereas it was preferentially localized within
      the cytosol after stimulation with IgM, suggesting that signaling through CD40
      and IgM differentially regulates ERK subcellular localization. Costimulation with
      CD40 and IgM (CD40/IgM) resulted in subcellular localization of ERK within the
      cytosol, supporting the notion that stimulation with IgM delivers the signal
      responsible for inhibition of ERK nuclear transport. Consistent with these
      observations, IgM and CD40/IgM stimulation resulted in activation of ribosomal S6
      kinase, which is a cytoplasmic substrate for ERK, whereas CD40 stimulation had
      little effect on its activity. Disruption of the microtubule by colchicine in
      WEHI231 cells resulted in reduction of ERK activity in IgM signaling, but not in
      CD40 signaling, compatible with the notion that the microtubule network may hold
      cytoplasmic ERK activity mediated by IgM stimulation. These results support the
      notion that ERK could mediate different effector functions in B cells upon
      stimulation with IgM and CD40.

PMID- 10586054
TI  - Commitment to the CD4 lineage mediated by extracellular signal-related kinase
      mitogen-activated protein kinase and lck signaling.
AB  - The development of T cells results in a concordance between the specificity of
      the TCR for MHC class I and class II molecules and the expression of CD8 and CD4
      coreceptors. Based on analogy to simple metazoan models of organ development and
      lineage commitment, we sought to determine whether extracellular signal-related
      kinase (Erk) mitogen-activated protein (MAP) kinase pathway signaling acts as an
      inductive signal for the CD4 lineage. Here, we show that, by altering the
      intracellular signaling involving the Erk/MAP kinase pathway, T cells with
      specificity for MHC class I can be diverted to express CD4, and, conversely, T
      cells with specificity for MHC class II can be diverted to express CD8.
      Furthermore, we find that activation of the src-family tyrosine kinase, p56lck is
      an upstream mediator of lineage commitment. These results suggest a simple
      mechanism for lineage commitment in T cell development.

PMID- 10586055
TI  - Negative regulation of macrophage activation in response to IFN-gamma and
      lipopolysaccharide by the STK/RON receptor tyrosine kinase.
AB  - IFN-gamma primes macrophages for antimicrobial activity, increased killing of
      intracellular pathogens, and Ag processing and presentation to lymphocytes by
      cooperating with a second signal (provided by LPS or endogenous TNF-alpha) to
      promote increased proinflammatory cytokine production, NO production, and MHC
      class II expression. Macrophage-stimulating protein (MSP) suppresses NO
      production by activated peritoneal macrophages in vitro. Furthermore, targeted
      deletion of the receptor for MSP, stem cell-derived tyrosine kinase receptor
      (STK/RON), resulted in increased production of NO by activated macrophages both
      in vitro and in vivo. Here we demonstrate that expression of STK in RAW264.7
      cells resulted in suppression of NO production following IFN-gamma+/- LPS
      stimulation in the presence of MSP, reflecting a decrease in the levels of
      inducible NO synthase (iNOS) mRNA and protein, which was confirmed by decreased
      trans-activation of an iNOS reporter. The iNOS expression is regulated by the
      coordinate activity of the inducible transcription factors STAT-1, IFN response
      factor-1, and NF-kappaB. The presence of the STK receptor did not significantly
      alter the expression of the IFN-gamma receptor, STAT1 phosphorylation, or the up
      regulation of IFN response factor-1 expression following IFN-gamma stimulation.
      However, nuclear translocation of NF-kappaB following stimulation of RAW cells
      with IFN-gamma and LPS was reduced in the presence of the MSP/STK signaling
      pathway. These results suggest that the negative regulation of macrophage
      responses by MSP/STK occurs at least in part via inhibition of costimulatory
      signals, resulting in NF-kappaB activation, that cooperate with IFN-gamma to
      promote activation.

PMID- 10586056
TI  - Ligation of microglial CD40 results in p44/42 mitogen-activated protein kinase
      dependent TNF-alpha production that is opposed by TGF-beta 1 and IL-10.
AB  - Recently, it has been demonstrated that the CD40 receptor is constitutively
      expressed on cultured microglia at low levels. Ligation of CD40 by CD40 ligand on
      these cells results in microglial activation, as measured by TNF-alpha production
      and neuronal injury. However, the intracellular events mediating this effect have
      yet to be investigated. We report that ligation of microglial CD40 triggers
      activation of p44/42 mitogen-activated protein kinase (MAPK). This effect is
      evident 30 min posttreatment, and progressively declines thereafter (from 30 to
      240 min). Phosphorylated p38 MAPK is not observed in response to ligation of
      microglial CD40 across the time course examined. Inhibition of the upstream
      activator of p44/42 MAPK, mitogen-activated protein/extracellular signal-related
      kinase kinase 1/2, with PD98059, decreases phosphorylation of p44/42 MAPK and
      significantly reduces TNF-alpha release following ligation of microglial CD40.
      Furthermore, cotreatment of microglial cells with CD40 ligand and TGF-beta1 or IL
      10, or both, inhibits CD40-mediated activation of p44/42 MAPK and production of
      TNF-alpha in a statistically interactive manner. Taken together, these data show
      that ligation of microglial CD40 triggers TNF-alpha release through the p44/42
      MAPK pathway, an effect that can be opposed by TGF-beta1 and IL-10.

PMID- 10586057
TI  - Analysis of the defect in IFN-gamma induction of MHC class II genes in G1B cells:
      identification of a novel and functionally critical leucine-rich motif (62
      LYLYLQL-68) in the regulatory factor X 5 transcription factor.
AB  - MHC class II deficiency found in bare lymphocyte syndrome patients results from
      the absence or dysfunction of MHC class II transcriptional regulators, such as
      regulatory factor X (RFX) and class II transactivator (CIITA). Understanding the
      roles of these factors has been greatly facilitated by the study of genetic
      defects in cell lines of bare lymphocyte syndrome patients, as well as in cell
      lines that have been generated by chemical mutagenesis in vitro. The latter group
      includes MHC class II-deficient lines that are no longer responsive to induction
      by IFN-gamma. Here, we show that the defect in G1B, one such cell line, is
      attributed to the lack of functional RFX5, the largest subunit of RFX. The RFX5
      gene isolated from G1B cells contains two separate single-base pair mutations.
      One alteration does not exhibit a phenotype, whereas a leucine-to-histidine
      mutation eliminates DNA-binding and transactivating functions. This mutation lies
      outside of previously defined functional domains of RFX5 but within an unusual,
      leucine-rich region (62-LYLYLQL-68). To further investigate the significance of
      the leucine-rich region, we targeted all neighboring leucine residues for
      mutagenesis. These mutants were also unable to transactivate a MHC class II
      reporter gene, confirming that these leucine residues play an essential role in
      RFX activity and characterize a novel leucine-rich motif.

PMID- 10586058
TI  - The -180 site of the IL-2 promoter is the target of CREB/CREM binding in T cell
      anergy.
AB  - Anergic T cells display a marked decrease in their ability to produce IL-2 even
      in the presence of optimal TCR and costimulatory signals. Using IL-2
      enhancer/promoter-driven reporter constructs, we have previously identified a
      region that appears to be a target for cis transcriptional repression in anergy.
      This region of the promoter, which shares partial homology with a consensus AP-1
      binding sequence, is located about -180 bp from the transcriptional start site.
      In the present study, we demonstrate that cAMP response element-binding
      protein/cAMP response element modulator (CREB/CREM), activating transcription
      factor-2/c-Jun, and Jun-Jun/Oct complexes bind to this site. However, the
      induction of anergy by prolonged stimulation through the TCR led to an increase
      in binding of only the CREB/CREM complex. Furthermore, the level of binding of
      this complex appeared to be up-regulated in both resting and restimulated anergic
      T cells. Finally, an IL-2 promoter-driven reporter construct that contained a
      mutation that specifically reduced the binding of the CREB/CREM complex displayed
      a decreased ability to be affected by anergy, while a construct that contained a
      mutation that decreased the binding of the Jun-Jun/Oct complex was still
      susceptible to anergy. These findings suggest that the -180 region of the IL-2
      promoter is the target of a CREB/CREM transcriptional inhibitor that contributes
      to the repression of IL-2 production in T cell anergy.

PMID- 10586059
TI  - T cell activation up-regulates the expression of the focal adhesion kinase Pyk2:
      opposing roles for the activation of protein kinase C and the increase in
      intracellular Ca2+.
AB  - T cell activation initiates signals that control gene expression of molecules
      important for T cell function. The focal adhesion kinase Pyk2 has been implicated
      in T cell signaling. To further analyze the involvement of Pyk2 in T cell
      processes, we examined the effect of T cell stimulation on the expression of
      Pyk2. We found that TCR ligation or PMA increased Pyk2 expression in Jurkat T
      cells and in normal T cells. In contrast, TCR ligation and PMA failed to induce
      any detectable increase in the expression of the other member of the focal
      adhesion kinase family, Fak, in Jurkat T cells and induced only a weak increase
      in Fak expression in normal T cells. The serine/threonine kinases, protein kinase
      C and mitogen-activated protein/extracellular signal-related kinase kinase (MEK),
      regulated Pyk2 expression, as inhibitors of these kinases blocked stimulus
      induced Pyk2 expression. Cyclosporin A, FK506, and KN-62 did not block Pyk2
      expression; thus, calcineurin and Ca2+/calmodulin-activated kinases are not
      critical for augmenting Pyk2 expression. TCR ligation increased Pyk2 mRNA, and
      the transcriptional inhibitor actinomycin D blocked Pyk2 expression. Strikingly,
      Ca2+ ionophores, at concentrations that in combination with other stimuli induced
      IL-2 expression, blocked TCR- and PMA-induced up-regulation of Pyk2 expression.
      Thus, the increase in Ca2+ has opposing effects on IL-2 and Pyk2 expression.
      Cyclosporin A and FK506, but not KN-62, blocked Ca2+ ionophore-mediated
      inhibition of Pyk2 expression, implicating calcineurin in down-regulating Pyk2
      expression. These results show that TCR-triggered intracellular signals increase
      Pyk2 expression and shed light on the molecular mechanisms that regulate Pyk2
      expression in T cells.

PMID- 10586060
TI  - Contributions of leukemia inhibitory factor receptor and oncostatin M receptor to
      signal transduction in heterodimeric complexes with glycoprotein 130.
AB  - Leukemia inhibitory factor (LIF), cardiotrophin-1, ciliary neurotrophic factor,
      and oncostatin M (OSM) lead to heterodimerization of LIF receptor (LIFR) or the
      OSM-specific receptor (OSMR) with glycoprotein (gp) 130, the common receptor
      subunit for IL-6-type cytokines. Thereby intracellular signaling via Janus
      kinases (Jaks) and STAT transcription factors is initiated. We investigated the
      contributions of LIFR and OSMR to signal transduction in the context of
      heterodimers with gp130. Chimeric receptors based on the extracellular parts of
      the IL-5R alpha- and beta-chains were generated, allowing the induced
      heterodimerization of two different cytoplasmic tails. Our studies demonstrate
      that upon heterodimerization with the gp130 cytoplasmic region, the cytoplasmic
      parts of both LIFR and OSMR were critical for activation of an acute phase
      protein promoter in HepG2 hepatoma cells. The membrane-proximal region of LIFR or
      OSMR was crucial for the ability of such receptor complexes to induce DNA binding
      of STAT1 and STAT3 in COS-7 cells. Membrane-distal regions of LIFR and OSMR
      contributed to STAT activation even in the absence of gp130 STAT recruitment
      sites. We further show that the Janus kinases Jak1 and Jak2 constitutively
      associated with receptor constructs containing the cytoplasmic part of LIFR,
      OSMR, or gp130, respectively. Homodimers of the LIFR or OSMR cytoplasmic regions
      did not elicit responses in COS-7 cells but did in HepG2 cells and in MCF-7
      breast carcinoma cells. Thus, in spite of extensive functional similarities,
      differential signaling abilities of gp130, LIFR, and OSMR may become evident in a
      cell-type-specific manner.

PMID- 10586061
TI  - Activation and targeting of immunoglobulin switch recombination by activities
      induced by EBV infection.
AB  - EBV is strongly associated with Burkitt's lymphoma, a B cell malignancy. In
      certain types of Burkitt's lymphoma, the c-myc gene has undergone translocation
      to the S regions associated with heavy chain switch recombination. It has not
      been established whether EBV infection induces recombination activities, which in
      turn promote translocation of c-myc, or whether translocation precedes viral
      infection and provides a growth advantage that is further enhanced by factors
      encoded or induced by the virus. To distinguish between these possibilities, we
      have compared the level of switch recombination activities in the EBV-negative
      lymphoma, BJAB, and in its EBV-infected derivative, BJAB-B1, in experiments that
      assayed recombination of an extrachromosomal switch substrate during transient
      transfection. We have found that BJAB-B1 and other EBV-positive B cell lines
      supported high levels of recombination of switch substrates, to produce junctions
      like those found in products of chromosomal switch recombination. In contrast,
      BJAB did not support comparable levels of switch substrate recombination. In EBV
      positive B cell lines, the ability to support switch substrate recombination
      correlated with levels of LR1, a B cell-specific factor which is a
      transcriptional regulator of c-myc and which also appears to function in switch
      recombination. Our observations support the hypothesis that EBV infection can
      induce activities that affect switch recombination and thus contribute to the
      translocations of c-myc to the S regions that characterize certain classes of
      lymphomas.

PMID- 10586062
TI  - Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for
      its role in susceptibility to spondyloarthropathies.
AB  - The MHC class I protein HLA-B27 is strongly associated with susceptibility to
      spondyloarthropathies and can cause arthritis when expressed in rats and mice,
      implying a direct role in disease pathogenesis. A prominent hypothesis to explain
      this role suggests that the unique peptide binding specificity of HLA-B27 confers
      an ability to present arthritogenic peptides. The B pocket, a region of the
      peptide binding groove that is an important determinant of allele-specific
      peptide binding, is thought to be critical for arthritogenicity. However, this
      hypothesis remains unproven. We show that in addition to its role in peptide
      selection, the B pocket causes a portion of the pool of assembling HLA-B27 heavy
      chains in the endoplasmic reticulum to misfold, resulting in their degradation in
      the cytosol. The misfolding phenotype is corrected by replacing the HLA-B27 B
      pocket with one from HLA-A2. Our results suggest an alternative to the
      arthritogenic peptide hypothesis. Misfolding and its consequences, rather than
      allele-specific peptide presentation, may underlie the strong link between the
      HLA-B27 B pocket and susceptibility to spondyloarthropathies.

PMID- 10586063
TI  - Microphthalmic mice display a B cell deficiency similar to that seen for mast and
      NK cells.
AB  - The microphthalmic mouse (mi) possesses a 3-bp deletion of the Mi gene that
      alters the DNA binding site of the transcription factor gene product. This animal
      has diminished numbers of NK and mast cells (MC) and is osteopetrotic due to a
      lack of the normal complement of functional osteoclasts. The reduction of MC has
      been proposed to be due to the lack of adequate c-Kit expression that is required
      for MC differentiation. However, data from other labs has questioned this
      interpretation. In this report, we present data suggesting bone marrow-derived
      deficiencies of the mi mouse are not due to a lack of c-Kit expression and
      function, but instead due to an inhospitable environment within the bone marrow
      itself. Specifically, we have found that such animals also lack virtually all B
      cell precursors within the marrow and rely upon other lymphatic sites, such as
      the spleen, for B cell development and maturation. Although the animal has
      depressed numbers of NK cells, B cells, and MC, it still possesses a normal
      thymus and peripheral T cells. Therefore, the block in cellular differentiation
      must be within the marrow environment, which is essential for maturing B cells,
      NK cells, and MC but not T cells.

PMID- 10586064
TI  - Membrane topology and dimerization of the two subunits of the transporter
      associated with antigen processing reveal a three-domain structure.
AB  - Presentation of peptides derived from cytosolic and nuclear proteins by MHC class
      I molecules requires their translocation across the membrane of the endoplasmic
      reticulum (ER) by a specialized ABC (ATP-binding cassette) transporter, TAP. To
      investigate the topology of the heterodimeric TAP complex, we constructed a set
      of C-terminal deletions for the TAP1 and TAP2 subunits. We identified eight and
      seven transmembrane (TM) segments for TAP1 and TAP2, respectively. TAP1 has both
      its N and C terminus in the cytoplasm, whereas TAP2 has its N terminus in the
      lumen of the ER. A putative TM pore consists of TM1-6 of TAP1 and, by analogy,
      TM1-5 of TAP2. Multiple ER-retention signals are present within this region, of
      which we positively identified TM1 of both TAP subunits. The N-terminal domain
      containing TM1-6 of TAP1 is sufficient for dimerization with TAP2. A second,
      independent dimerization domain, located between the putative pore and the
      nucleotide-binding cassette, lies within the cytoplasmic peptide-binding domains,
      which are anchored to the membrane via TM doublets 7/8 and 6/7 of TAP1 and TAP2,
      respectively. We present a model in which TAP is composed of three subdomains: a
      TM pore, a cytoplasmic peptide-binding pocket, and a nucleotide-binding domain.

PMID- 10586065
TI  - Staphylococcal enterotoxin H displays unique MHC class II-binding properties.
AB  - Staphylococcal enterotoxin H (SEH) has been described as a superantigen by
      sequence homology with the SEA subfamily and briefly characterized for its in
      vivo activity. In this study, we demonstrate that SEH is a potent T cell mitogen
      and inducer of T cell cytotoxicity that possesses unique MHC class II-binding
      properties. The apparent affinity of SEH for MHC class II molecules is the
      highest affinity ever measured for a staphylococcal enterotoxin (Bmax1/2
      approximately 0.5 nM for MHC class II expressed on Raji cells). An excess of SEA
      or SEAF47A, which has reduced binding to the MHC class II alpha-chain, is able to
      compete for binding of SEH to MHC class II, indicating an overlap in the binding
      sites at the MHC class II beta-chain. The binding of SEH to MHC class II is like
      SEA, SED, and SEE dependent on the presence of zinc ions. However, SEH, in
      contrast to SEA, binds to the alanine-substituted DR1 molecule, betaH81A,
      believed to have impaired zinc-bridging capacity. Furthermore, alanine
      substitution of residues D167, D203, and D208 in SEH decreases the affinity for
      MHC class II as well as its in vitro potency. Together, this indicates an MHC
      class II binding site on SEH with a different topology as compared with SEA.
      These unique binding properties will be beneficial for SEH to overcome MHC class
      II isotype variability and polymorphism as well as to allow an effective
      presentation on APCs also at low MHC class II surface expression.

PMID- 10586066
TI  - Mutational analysis of avidity and fine specificity of anti-levan antibodies.
AB  - Using the polyfructose, bacterial levan, as a model polysaccharide, we analyzed
      how V regions affect binding in anti-polysaccharide mAbs. Previously, panels of
      mAb were constructed from bacterial levan-immunized BALB/c and CBA/Ca mice. The
      BALB/c mAb were mostly germline VHJ606:Vkappa11, and a subset contained presumed
      somatic mutations in the complementarity-determining regions (CDRs) that
      correlated with increases in avidity for the beta(2-->1) inulin linkage of levan.
      The CBA/Ca mAb were more heterogeneous in V gene usage, but a subset of inulin
      nonreactive mAb were VHJ606:Vlambda and had VH sequence differences in the CDRs
      from the VHJ606 regions of the BALB/c mAb. In this report, VHJ606 Abs containing
      various combinations of specifically mutated H and L chains were produced by
      engineered transfectants and tested for inulin avidity and levan binding. Two
      presumed somatic mutations seen in CDRs of the BALB/c hybridomas were shown to
      directly cause marked increases in avidity for inulin (VH N53H, 9-fold; VL N53I,
      20-fold; together, 46-fold) but not for beta(2-->6) levan. Exchange of either
      positions 50 or 53 in VH or the H3 loop between the BALB/c and CBA/Ca mAb
      resulted in either fine specificity shift or total loss of bacterial levan
      binding. Three-dimensional models of the V regions suggested that residues that
      affect binding to inulin alone are near the edge of the CDR surface, while
      residues involved with binding both forms of levan and affecting fine specificity
      are in the VH:VL junctional area.

PMID- 10586067
TI  - Kupffer cells from Schistosoma mansoni-infected mice participate in the prompt
      type 2 differentiation of hepatic T cells in response to worm antigens.
AB  - Infection with Schistosoma mansoni, a portal vein-residing helminth, is well
      known to generate life cycle-dependent, systemic immune responses in the host,
      type 1 deviation during the prepatent period, and type 2 polarization after
      oviposition. Here we investigated local immunological changes in the liver after
      infection. Unlike splenocytes, hepatic lymphocytes from infected mice during the
      prepatent period already produced a higher amount of IL-4 and a lesser amount of
      IFN-gamma than those from uninfected mice. Hepatic lymphocytes, particularly
      conventional T cells, but not NK1.1+ T cells, promptly produced IL-4 in response
      to worm products, soluble worm Ag preparation (SWAP), whenever presented by
      Kupffer cells from infected mice. The hepatic lymphocytes that had been
      stimulated with SWAP presented by infected mice-derived Kupffer cells produced a
      huge amount of IL-4, IL-13, and IL-5 as well as little IFN-gamma in response to
      immobilized anti-CD3 mAb. Kupffer cells from uninfected mice produced IL-6 and IL
      10, but not IL-12 or IL-18, in response to SWAP stimulation and gained the
      potential to additionally produce IL-4 and IL-13 after the infection. These
      results suggested that prompt type 2 deviation in the liver after the infection
      might be due to the alteration of Kupffer cells that induces SWAP-mediated type 2
      development of hepatic T cells.

PMID- 10586068
TI  - Induction of Th2 responses and IgE is largely due to carbohydrates functioning as
      adjuvants on Schistosoma mansoni egg antigens.
AB  - Infection with the helminth parasite Schistosoma mansoni induces a pronounced Th2
      type response that is associated with significant IgE production. To better
      understand how the parasite drives these responses, we investigated the relative
      roles of proteins and carbohydrates in driving Th2-type and/or IgE responses
      using a murine model of intranasal sensitization with soluble egg Ags (SEA) of
      Schistosoma mansoni. We found that repeated intranasal sensitization with soluble
      egg Ags led to the induction of both total and specific IgE production and nasal
      eosinophilia. By comparing the responses of mice sensitized with SEA or
      metaperiodate-treated SEA we were able to demonstrate that carbohydrates on SEA
      are the major inducers of IgE production and nasal recruitment of eosinophils.
      Mice sensitized with periodate-treated SEA displayed a significant decrease in
      both total and specific IgE levels in comparison to mice sensitized with native
      SEA. Furthermore, sensitization of mice with periodate-treated SEA significantly
      reduced levels of Ag-specific IgG1, but had no effect on IgG2a production. Nasal
      lymphocytes from mice sensitized with native SEA, but not with periodate-treated
      SEA, produced IL-4, IL-5, and IL-10 when restimulated with native SEA in vitro.
      On the other hand, lymphocytes from mice sensitized with periodate-treated SEA
      did not produce any of these same cytokines following in vitro restimulation,
      suggesting that carbohydrates were required for in vivo induction of Th2 response
      and for that of associated cytokine responses in this model. Lastly, competitive
      inhibition ELISA showed that although carbohydrates are required for SEA-specific
      IgE induction, they are not targets of the induced IgE response.

PMID- 10586069
TI  - Expression and regulation of the human beta-defensins hBD-1 and hBD-2 in
      intestinal epithelium.
AB  - The intestinal epithelium forms a physical barrier to limit access of enteric
      microbes to the host and contributes to innate host defense by producing effector
      molecules against luminal microbes. To further define the role of the intestinal
      epithelium in antimicrobial host defense, we analyzed the expression, regulation,
      and production of two antimicrobial peptides, human defensins hBD-1 and hBD-2, by
      human intestinal epithelial cells in vitro and in vivo. The human colon
      epithelial cell lines HT-29 and Caco-2 constitutively express hBD-1 mRNA and
      protein but not hBD-2. However, hBD-2 expression is rapidly induced by IL-1alpha
      stimulation or infection of those cells with enteroinvasive bacteria. Moreover,
      hBD-2 functions as a NF-kappaB target gene in the intestinal epithelium as
      blocking NF-kappaB activation inhibits the up-regulated expression of hBD-2 in
      response to IL-1alpha stimulation or bacterial infection. Caco-2 cells produce
      two hBD-1 isoforms and a hBD-2 peptide larger in size than previously described
      hBD-2 isoforms. Paralleling the in vitro findings, human fetal intestinal
      xenografts constitutively express hBD-1, but not hBD-2, and hBD-2 expression, but
      not hBD-1, is up-regulated in xenografts infected intraluminally with Salmonella.
      hBD-1 is expressed by the epithelium of normal human colon and small intestine,
      with a similar pattern of expression in inflamed colon. In contrast, there is
      little hBD-2 expression by the epithelium of normal colon, but abundant hBD-2
      expression by the epithelium of inflamed colon. hBD-1 and hBD-2 may be integral
      components of epithelial innate immunity in the intestine, with each occupying a
      distinct functional niche in intestinal mucosal defense.

PMID- 10586070
TI  - Reduced ultraviolet-induced carcinogenesis in mice with a functional disruption
      in B7-mediated costimulation.
AB  - Immunosuppression by UV light contributes significantly to the induction of skin
      cancer by suppressing the cell-mediated immune responses which control the
      development of carcinogenesis. The B7/CD28-CTLA-4 signaling pathway provides
      costimulatory signals essential for Ag-specific T cell activation. To investigate
      the role of this pathway in photocarcinogenesis, we utilized transgenic (Tg) mice
      which constitutively express CTLA-4Ig, a high-affinity CD28/CTLA-4 antagonist
      that binds to both B7-1 and B7-2. The transgene is driven by a skin-specific
      promoter yielding high levels of CTLA-4Ig in the skin and serum. Chronic UV
      exposure of CTLA-4Ig Tg mice resulted in significantly reduced numbers of skin
      tumors, when compared to control mice. In addition, Tg mice were resistant to UV
      induced suppression of delayed-type hypersensitivity responses to alloantigens.
      Most importantly, upon stimulation with mitogens and alloantigens, T cells
      isolated from CTLA-4Ig Tg mice produced significantly less IL-4 but more IFN
      gamma compared to control T cells, suggesting an impaired Th2 response and a
      relative increase of Th1-type immunity. Together, these data show that overall B7
      engagement directs immune responses toward the Th2 pathway. Moreover, they point
      out the crucial role of Th1 immune reactions in the protection against
      photocarcinogenesis.

PMID- 10586071
TI  - NADPH oxidase activation and assembly during phagocytosis.
AB  - Generation of superoxide (O2-) by the NADPH-dependent oxidase of
      polymorphonuclear leukocytes is an essential component of the innate immune
      response to invading microorganisms. To examine NADPH oxidase function during
      phagocytosis, we evaluated its activation and assembly following ingestion of
      serum-opsonized Neisseria meningitidis, serogroup B (NMB), and compared it with
      that elicited by serum-opsonized zymosan (OPZ). Opsonized N. meningitidis- and
      OPZ-dependent generation of reactive oxygen species by polymorphonuclear
      leukocytes peaked early and then terminated. Phosphorylation of p47phox coincided
      with peak generation of reactive oxygen species by either stimulus, consistent
      with a role for p47phox phosphorylation during NADPH oxidase activation, and
      correlated with phagosomal colocalization of flavocytochrome b558
      (flavocytochrome b) and p47phox and p67phox (p47/67phox). Termination of
      respiratory burst activity did not reflect dephosphorylation of plasma membrane-
      and/or phagosome-associated p47phox; in contrast, the specific activity of
      phosphorylated p47phox at the phagosomal membrane increased. Most significantly,
      termination of oxidase activity paralleled the loss of p47/67phox from both NMB
      and OPZ phagosomes despite the continued presence of flavocytochrome b. These
      data suggest that 1) the onset of respiratory burst activity during phagocytosis
      is linked to the phosphorylation of p47phox and its translocation to the
      phagosome; and 2) termination of oxidase activity correlates with loss of
      p47/67phox from flavocytochrome b-enriched phagosomes and additional
      phosphorylation of membrane-associated p47phox.

PMID- 10586072
TI  - The adjacent flanking region plays a critical role in facilitating the
      presentation of the Listeria monocytogenes product lemA to H2 M3wt-restricted,
      peptide-specific murine CD8 cells.
AB  - Mice infected with Listeria monocytogenes (LM) generate CD8 effectors specific
      for f-MIGWII, the amino terminus of the bacterial product lemA presented by the
      class Ib MHC molecule H2 M3wt. lemA has several distinctive properties: 1) it is
      readily presented as an exogenous Ag in the absence of bacterial infection; 2) it
      is processed by a TAP-independent pathway, which is sensitive to chloroquine,
      pepstatin, and brefeldin; and 3) the immunogenic portion of the molecule is
      extremely resistant to proteolytic degradation even by proteinase K. To assess
      the structural basis for these findings, we expressed a truncated variant (t
      lemA) containing the amino-terminal hexapeptide and the subsequent 27 amino acids
      linked to a histidine tail in Escherichia coli, and purified the product by
      affinity chromatography. Purified t-lemA could be presented to f-MIGWII-specific
      effectors by macrophages and fibroblasts at 1-10 nM. Unlike f-MIGWII, which binds
      directly to H2 M3wt, t-lemA required processing by a chloroquine-, pepstatin-,
      and brefeldin-sensitive pathway. Brefeldin sensitivity often implies endogenous
      processing in the cytoplasm, but several lines of evidence suggest translocation
      to the cytoplasm and proteosomal degradation are not critical for t-lemA
      presentation. Unlike f-MIGWII, t-lemA was profoundly resistant to proteinase K,
      and, using 35S-labeled t-lemA, we could identify the region from position 1 to
      approximately 30 as the protease-resistant element. Thus, the hydrophobic peptide
      sequence following f-MIGWII can account for the unusual properties of lemA noted
      above. Analogous modification could be used to alter the properties of other
      peptide Ags presented by class I MHC products.

PMID- 10586073
TI  - The CD14 ligands lipoarabinomannan and lipopolysaccharide differ in their
      requirement for Toll-like receptors.
AB  - Mammalian Toll-like receptor (TLR) proteins are new members of the IL-1 receptor
      family that participate in activation of cells by bacteria and bacterial
      products. Several recent reports indicate that TLR proteins mediate cellular
      activation by bacterial LPS via a signaling pathway that is largely shared by the
      type I IL-1 receptor. We previously showed that Chinese hamster ovary (CHO)
      fibroblasts engineered to express CD14 (CHO/CD14) were responsive to LPS, but not
      to a distinct CD14 ligand, mycobacterial lipoarabinomannan (LAM). These CHO/CD14
      cells were subsequently found to possess a frame-shift mutation within the TLR2
      gene which resulted in their inability to express functional TLR2 protein. Thus,
      we hypothesized that TLR2, but not TLR4, was necessary for LAM signaling. In this
      paper we show that CHO/CD14 cells engineered to express functional TLR2 protein
      acquired the ability to be activated by LAM. Similarly, overexpression of TLR2 in
      murine macrophages conferred enhanced LAM responsiveness. Together, our data
      demonstrate that the distinct CD14 ligands LAM and LPS utilize different TLR
      proteins to initiate intracellular signals. These findings suggest a novel
      receptor signaling paradigm in which the binding of distinct ligands is mediated
      by a common receptor chain, but cellular activation is initiated via distinct
      signal-transducing chains that confer ligand specificity. This paradigm contrasts
      with many cytokine receptor complexes in which receptor specificity is conferred
      by a unique ligand-binding chain but cellular activation is initiated via shared
      signal-transducing chains.

PMID- 10586074
TI  - A DNA immunization model study with constructs expressing the tick-borne
      encephalitis virus envelope protein E in different physical forms.
AB  - We have conducted a DNA immunization study to evaluate how the immune response is
      influenced by the physical structure and secretion of the expressed Ag. For this
      purpose, we used a series of plasmid constructs encoding different forms of the
      envelope glycoprotein E of the flavivirus tick-borne encephalitis virus. These
      included a secreted recombinant subviral particle, a secreted carboxyl-terminally
      truncated soluble homodimer, a nonsecreted full-length form, and an inefficiently
      secreted truncated form. Mice were immunized using both i.m. injection and Gene
      Gun-mediated application of plasmids. The functional immune response was
      evaluated by determining specific neutralizing and hemagglutination-inhibiting Ab
      activities and by challenging the mice with a lethal dose of the virus. As a
      measure for the induction of a Th1 and/or Th2 response, we determined specific
      IgG subclasses and examined IFN-gamma, Il-4, and Il-5 induction. The plasmid
      construct encoding a secreted subviral particle, which carries multiple copies of
      the protective Ag on its surface, was superior to the other constructs in terms
      of extent and functionality of the Ab response as well as protection against
      virus challenge. As expected, the type of Th response was largely dependent on
      the mode of application (i.m. vs Gene Gun), but our data show that it was also
      strongly influenced by the properties of the Ag. Most significantly, the plasmid
      encoding the particulate form was able to partially overcome the Th2 bias imposed
      by the Gene Gun, resulting in a balanced Th1/Th2 response.

PMID- 10586075
TI  - Vaccinia virus inhibits the maturation of human dendritic cells: a novel
      mechanism of immune evasion.
AB  - Vaccinia virus employs multiple mechanisms to evade the immune system, yet is
      highly immunogenic. We studied the interaction between vaccinia and human
      dendritic cells (DCs), potent APCs. DCs develop from precursor cells in two
      stages: an immature stage in which Ag uptake and processing occur, and a mature
      stage in which there is up-regulation of costimulatory and HLA molecules and
      efficient T cell activation. Vaccinia virus undergoes an abortive replication in
      both stages of DCs and induces apoptotic cell death. Furthermore, maturation of
      immature DCs and consequently T cell activation are inhibited. Obstruction of DC
      maturation may constitute a novel mechanism by which vaccinia attempts to evade
      the immune response.

PMID- 10586076
TI  - Critical role of CD28 in protective immunity against Salmonella typhimurium.
AB  - Efficient T cell activation requires both TCR signals and costimulatory signals.
      CD28 is one of the molecules that provide costimulatory signals for T cells. We
      used mice deficient in CD28 expression (CD28-/- mice) to analyze the role of CD28
      in the immune response against the intracellular bacterium Salmonella
      typhimurium, the causative agent of murine typhoid fever. CD28-/- mice were
      highly susceptible to infection with wild-type S. typhimurium and even failed to
      control infection with attenuated aroA- S. typhimurium. More detailed analysis
      revealed that CD28-/- animals did not mount a T-dependent Ab response and were
      highly impaired in the production of IFN-gamma. Thus, CD28 cosignaling is crucial
      for immunity against S. typhimurium. To our knowledge, this is the first report
      describing an essential role for CD28 in protective immunity against an
      intracellular microbial pathogen.

PMID- 10586077
TI  - Utilization of two seven-transmembrane, G protein-coupled receptors, formyl
      peptide receptor-like 1 and formyl peptide receptor, by the synthetic hexapeptide
      WKYMVm for human phagocyte activation.
AB  - Trp-Lys-Tyr-Val-D-Met (WKYMVm) is a synthetic leukocyte-activating peptide
      postulated to use seven-transmembrane, G protein-coupled receptor(s). In the
      study to characterize the receptor(s) for WKYMVm, we found that this peptide
      induced marked chemotaxis and calcium flux in human phagocytes. The signaling
      induced by WKYMVm in phagocytes was attenuated by high concentrations of the
      bacterial chemotactic peptide fMLP, suggesting that WKYMVm might use receptor(s)
      for fMLP. This hypothesis was tested by using cells over expressing genes
      encoding two seven-transmembrane receptors, formyl peptide receptor (FPR) and
      formyl peptide receptor-like 1 (FPRL1), which are with high and low affinity for
      fMLP, respectively. Both FPR- and FPRL1-expressing cells mobilized calcium in
      response to picomolar concentrations of WKYMVm. While FPRL1-expressing cells
      migrated to picomolar concentrations of WKYMVm, nanomolar concentrations of the
      peptide were required to induce migration of FPR-expressing cells. In contrast,
      fMLP elicited both calcium flux and chemotaxis only in FPR-expressing cells with
      an efficacy comparable with WKYMVm. Thus, WKYMVm uses both FPR and FPRL1 to
      stimulate phagocytes with a markedly higher efficacy for FPRL1. Our study
      suggests that FPR and FPRL1 in phagocytes react to a broad spectrum of agonists
      and WKYMVm as a remarkably potent agonist provides a valuable tool for studying
      leukocyte signaling via these receptors.

PMID- 10586078
TI  - Syk activation initiates downstream signaling events during human
      polymorphonuclear leukocyte phagocytosis.
AB  - We investigated the requirement for Syk activation to initiate downstream
      signaling events during polymorphonuclear leukocyte (PMN) phagocytosis of Ab
      coated erythrocytes (EIgG). When PMN were challenged with EIgG, Syk
      phosphorylation increased in a time-dependent manner, paralleling the response of
      PMN phagocytosis. Pretreatment of PMN with piceatannol, a Syk-selective
      inhibitor, blocked EIgG phagocytosis and Syk phosphorylation. We found that
      piceatannol inhibited protein kinase Cdelta (PKCdelta) and Raf-1 translocation
      from cytosol to plasma membrane by >90%. Extracellular signal-regulated protein
      kinase-1 and -2 (ERK1 and ERK2) phosphorylation was similarly blocked. We also
      investigated phosphatidylinositide 3-kinase (PI 3-kinase) activity and Syk
      phosphorylation using piceatannol, wortmannin, and LY294002, inhibitors of PI 3
      kinase. The phosphorylation of Syk preceded the activation of PI 3-kinase. Both
      wortmannin and piceatannol inhibited PI 3-kinase, but only piceatannol inhibited
      Syk. In contrast to piceatannol, wortmannin did not inhibit PKCdelta and Raf-1
      translocation. To elucidate signaling downstream of Syk activation, we assessed
      whether the cell-permeable diacylglycerol analogue didecanoylglycerol could
      normalize PMN phagocytosis, PKCdelta and Raf-1 translocation, and ERK1 and ERK2
      phosphorylation inhibited by piceatannol. The addition of didecanoylglycerol to
      the Syk-inhibited phagocytosing PMN normalized all three without a concomitant
      effect on PI 3-kinase activity and Syk phosphorylation. We conclude that Syk
      activation following Fcgamma receptor engagement initiates downstream signaling
      events leading to mitogen-activated protein kinase activation independent of PI 3
      kinase activation.

PMID- 10586079
TI  - Blockade of T cell costimulation by CTLA4-Ig inhibits lung inflammation in murine
      hypersensitivity pneumonitis.
AB  - Hypersensitivity pneumonitis (HP) is characterized by an influx of activated T
      cells in the lungs. The CD28/B7 system provides costimulatory signals essential
      for complete T cell activation and differentiation. We have previously
      demonstrated that alveolar macrophages from patients with HP have an up-regulated
      expression of B7 molecules. In the present study, we investigated the effect of
      i. p. administration of CTLA4-Ig, a CD28/B7 antagonist, on the lung inflammation
      of mice inoculated with Saccharoplyspora rectivirgula (SR), a major causative
      agent of HP. Five groups of C57BL/6 mice were intranasally instilled with SR or
      saline for 3 consecutive days per wk during 3 wk. CTLA4-Ig was administered
      starting either after 1 wk of SR challenge or 6 h before the first antigenic
      exposure and continued during the whole period of sensitization. A control-IgG
      was given similarly during the 3 wk of SR exposure. The groups included: 1,
      saline; 2, SR; 3, SR + control-Ig; 4, SR + CTLA4-Ig for the last 2 wk; and 5, SR
      + CTLA4-Ig for 3 wk. CTLA4-Ig treatment markedly decreased lung inflammation as
      shown by significantly fewer inflammatory cells in the bronchoalveolar lavage and
      in lung tissue and reduced SR-specific serum and bronchoalveolar lavage Ig
      levels. Production of IL-4, IL-10, and IFN-gamma by IL-2-stimulated pulmonary T
      cells was also decreased by CTLA4-Ig. Administration of CTLA4-Ig did not affect
      the SR-induced up-regulation of B7-2 expression. These results show that blockade
      of CD28/B7 interactions by CTLA4-Ig inhibits SR-induced lung inflammation and
      immune response to SR Ag in mice and may provide a novel approach in the
      treatment of HP.

PMID- 10586080
TI  - Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal
      kinase, and apoptosis.
AB  - Silymarin is a polyphenolic flavonoid derived from milk thistle (Silybum
      marianum) that has anti-inflammatory, cytoprotective, and anticarcinogenic
      effects. How silymarin produces these effects is not understood, but it may
      involve suppression of NF-kappa B, a nuclear transcription factor, which
      regulates the expression of various genes involved in inflammation,
      cytoprotection, and carcinogenesis. In this report, we investigated the effect of
      silymarin on NF-kappa B activation induced by various inflammatory agents.
      Silymarin blocked TNF-induced activation of NF-kappa B in a dose- and time
      dependent manner. This effect was mediated through inhibition of phosphorylation
      and degradation of Iota kappa B alpha, an inhibitor of NF-kappa B. Silymarin
      blocked the translocation of p65 to the nucleus without affecting its ability to
      bind to the DNA. NF-kappa B-dependent reporter gene transcription was also
      suppressed by silymarin. Silymarin also blocked NF-kappa B activation induced by
      phorbol ester, LPS, okadaic acid, and ceramide, whereas H2O2-induced NF-kappa B
      activation was not significantly affected. The effects of silymarin on NF-kappa B
      activation were specific, as AP-1 activation was unaffected. Silymarin also
      inhibited the TNF-induced activation of mitogen-activated protein kinase kinase
      and c-Jun N-terminal kinase and abrogated TNF-induced cytotoxicity and caspase
      activation. Silymarin suppressed the TNF-induced production of reactive oxygen
      intermediates and lipid peroxidation. Overall, the inhibition of activation of NF
      kappa B and the kinases may provide in part the molecular basis for the
      anticarcinogenic and anti-inflammatory effects of silymarin, and its effects on
      caspases may explain its role in cytoprotection.

PMID- 10586081
TI  - Determination of the contribution of cysteinyl leukotrienes and leukotriene B4 in
      acute inflammatory responses using 5-lipoxygenase- and leukotriene A4 hydrolase
      deficient mice.
AB  - Arachidonic acid metabolism by 5-lipoxygenase leads to production of the potent
      inflammatory mediators, leukotriene (LT) B4 and the cysteinyl LT. Relative
      synthesis of these subclasses of LT, each with different proinflammatory
      properties, depends on the expression and subsequent activity of LTA4 hydrolase
      and LTC4 synthase, respectively. LTA4 hydrolase differs from other proteins
      required for LT synthesis because it is expressed ubiquitously. Also, in vitro
      studies indicate that it possesses an aminopeptidase activity. Introduction of
      cysteinyl LT and LTB4 into animals has shown LTB4 is a potent chemoattractant,
      while the cysteinyl LT alter vascular permeability and smooth muscle tone. It has
      been impossible to determine the relative contributions of these two classes of
      LT to inflammatory responses in vivo or to define possible synergy resulting from
      the synthesis of both classes of mediators. To address this question, we have
      generated LTA4 hydrolase-deficient mice. These mice develop normally and are
      healthy. Using these animals, we show that LTA4 hydrolase is required for the
      production of LTB4 in an in vivo inflammatory response. We show that LTB4 is
      responsible for the characteristic influx of neutrophils accompanying topical
      arachidonic acid and that it contributes to the vascular changes seen in this
      model. In contrast, LTB4 influences only the cellular component of zymosan A
      induced peritonitis. Furthermore, LTA4 hydrolase-deficient mice are resistant to
      platelet-activating factor, identifying LTB4 as one mediator of the physiological
      changes seen in systemic shock. We do not identify an in vivo role for the
      aminopeptidase activity of LTA4 hydrolase.

PMID- 10586082
TI  - Protection against the mortality associated with disease models mediated by TNF
      and IFN-gamma in mice lacking IFN regulatory factor-1.
AB  - Mortality and cytokine production associated with disease models mediated by TNF-
      and IFN-gamma were studied in mice lacking IFN regulatory factor-1 (IRF-1). IRF-1
      knockout (KO) mice showed no mortality after the injection of a dose of LPS
      lethal in intact control mice (LD95). KO mice showed lower circulating levels of
      TNF and IFN-gamma than controls. KO mice also showed lower TNF and IFN-gamma mRNA
      in the spleen or liver than controls. KO mice had smaller spleens than controls,
      which contained similar percentage but lower absolute count of macrophages and
      lower percentage and absolute count of NK cells. IRF-1 KO mice survived longer
      than controls after the coinjection of LPS and galactosamine. IRF-1 KO mice also
      showed less mortality than controls after the injection of Con A and in a model
      of cerebral malaria. After the injection of a lethal dose of TNF (LD88),
      mortality was similar between KO and intact mice. Mortality was also similar
      after the coinjection of two nonlethal doses of TNF and IFN-gamma, a lethal
      combination (LD100). This study shows that the lack of IRF-1 protects against the
      mortality associated with disease models mediated by TNF and IFN-gamma but has no
      effect on the mortality directly induced by TNF and IFN-gamma. The lack of IRF-1
      appears to result in impaired production of TNF and IFN-gamma, reflecting a down
      regulation of gene expression in the liver and spleen as well as a reduction in
      the number of splenic cells.

PMID- 10586083
TI  - NF-kappa B/Rel transcription factors: c-Rel promotes airway hyperresponsiveness
      and allergic pulmonary inflammation.
AB  - The NF-kappa B/Rel family of transcription factors induces many genes involved in
      immune and inflammatory responses. Mice with germline deletions of individual NF
      kappa B/Rel subunits have different phenotypes, suggesting that the NF-kappa
      B/Rel transcription factors have different functions. We tested whether c-Rel
      promotes allergic asthma using a murine model of allergen-induced pulmonary
      inflammation and airway hyperresponsiveness. Our investigation focused on c-Rel,
      which is expressed in lymphoid cells and is important for lymphocyte activation.
      In response to allergen sensitization and challenge, c-Rel-deficient mice did not
      develop increases in pulmonary inflammation, bronchoalveolar lavage fluid
      eosinophilia, or total serum IgE. c-Rel deficiency also prevented the induction
      of airway hyperresponsiveness. Allergen-treated wild-type mice had increased DNA
      binding to an NF-kappa B consensus site. Chemokine expression was altered in
      allergen-treated c-Rel-deficient mice. Monocyte chemoattractant protein-1, which
      is regulated by NF-kappa B, was decreased in allergen-treated c-Rel-deficient
      mice relative to wild-type controls. The increase in NF-kappa B/Rel transcription
      factors after allergen challenge in wild-type mice and the decrease in allergen
      reactivity found in c-Rel-deficient mice indicate that c-Rel promotes allergic
      inflammation. Alteration of pulmonary chemokine expression in c-Rel-deficient
      mice may inhibit allergen-induced pulmonary inflammation and airway
      hyperresponsiveness.

PMID- 10586084
TI  - Development of adenovirus vectors encoding rat complement regulators for use in
      therapy in rodent models of inflammatory diseases.
AB  - C activation has been implicated in the pathogenesis of numerous inflammatory
      human diseases and disease models. A therapy based on C inhibition might
      therefore be of benefit to reduce inflammation and ameliorate disease. C
      inhibition in vivo can be accomplished by the delivery of soluble recombinant C
      regulators either systemically or directly to a target site, but effects are
      transitory. We have developed a strategy for the efficient delivery of the
      membrane-bound rat C inhibitors, CD59, Crry, and decay-accelerating factor (DAF),
      using replication-deficient adenovirus vectors with the intention of treating rat
      models of disease in which C is implicated. The adenovirus recombinants(RAd),
      RAdCD59, RAdCrry, and RAdDAF, respectively, have been tested for expression and
      function of the transgene in vitro. Infection of human fetal foreskin fibroblasts
      resulted in high levels of expression of each of the rat inhibitors. The
      constructs were also tested for inhibition of rat C-mediated cell lysis and C3b
      deposition. In a cell lysis assay, each inhibited to varying degrees of
      efficiency in the order RAdCD59 = RAdDAF > RAdCrry. In a C3b deposition assay,
      RAdDAF caused a greater reduction in C3b deposition than RAdCrry and RAdCD59 was
      ineffective. These agents, individually or in combination, provide the tools for
      testing the effects of prolonged inhibition of C at a target site on the progress
      of experimental models of disease.

PMID- 10586085
TI  - Nitric oxide plays a critical role in the recovery of Lewis rats from
      experimental autoimmune encephalomyelitis and the maintenance of resistance to
      reinduction.
AB  - Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune
      disease of the CNS and an animal model for the human demyelinating disease,
      multiple sclerosis. In the Lewis rat, myelin basic protein (MBP)-CFA-induced EAE
      is an acute monophasic disease from which animals recover fully, do not relapse,
      and develop a robust long-term resistance to further active reinduction of
      disease. In this paper, we report that rats recovering from MBP-CFA-induced EAE
      have significantly increased serum levels of reactive nitrogen intermediates
      indicative of increased NO production. These levels remain elevated after the
      recovery period and increase even further early after a rechallenge with MBP-CFA,
      and all animals are totally refractory to a second episode of disease. Oral
      treatment of rats with N-methyl-l -arginine acetate (l -NMA), beginning at peak
      disease on day 11 postimmunization, results in significant prolongation of
      disease and an alteration in the presentation of clinical symptoms from that of
      solely hind limb paresis/paralysis to severe fore limb involvement as well.
      Treatment of fully recovered rats with l -NMA 24 h before a rechallenge with MBP
      CFA leads to decreased serum reactive nitrogen intermediate levels and results in
      a second episode of EAE in 100% of animals. Furthermore, l -NMA treatment of
      fully recovered rats in the absence of a rechallenge immunization leads to
      spontaneous relapse of disease.

PMID- 10586086
TI  - The rat and mouse homologues of MASP-2 and MAp19, components of the lectin
      activation pathway of complement.
AB  - Recently, we described two novel constituents of the multimolecular initiation
      complex of the mannan-binding lectin (MBL) pathway of complement activation, a
      serine protease of 76 kDa, termed MASP-2, and a MASP-2 related plasma protein of
      19 kDa, termed MAp19. Upon activation of the MBL/MASPs/MAp19 complex, MASP-2
      cleaves the fourth complement component C4, while the role of MAp19 within the
      MBL/MASP-1/MASP-2/MAp19 complex remains to be clarified. In humans, the mRNA
      species encoding MASP-2 (2.6 kb) and MAp19 (1.0 kb) arise by an alternative
      polyadenylation/splicing mechanism from a single structural MASP-2 gene. Here, we
      report the complete primary structures of the rat homologue of MASP-2 and of rat
      and mouse MAp19. We show that both MASP-2 and MAp19 are part of the rat MBL
      pathway activation complex and demonstrate their exclusively hepatic
      biosynthesis. Southern blot and PCR analyses of rat genomic DNA indicate that as
      in humans, rat MASP-2 and MAp19 are encoded by a single structural gene.

PMID- 10586087
TI  - Endothelial cell E- and P-selectin up-regulation in murine contact sensitivity is
      prolonged by distinct mechanisms occurring in sequence.
AB  - The selectins are adhesion molecules that mediate the tethering and rolling of
      leukocytes on vascular endothelium. Although E-selectin and P-selectin are known
      to be expressed by endothelial cells (EC) in response to proinflammatory stimuli,
      their pattern and mechanisms of expression in immune-mediated inflammation remain
      poorly understood. By quantifying luminal endothelial selectin expression via
      i.v. administration of radiolabeled mAb, we detected constitutive expression of P
      selectin, but not E-selectin, in mouse skin. Both selectins were transiently up
      regulated after intradermal TNF-alpha, IL-1alpha, or IL-1beta. In contrast,
      during a contact sensitivity response to oxazolone, expression of both selectins
      was prolonged, with distinct peaks at 6 and 48 h. Experiments with P-selectin
      gene-targeted mice showed that the P-selectin measured was exclusively expressed
      by EC rather than platelets. The early and late phases of selectin expression in
      contact sensitivity were differentiated in terms of their requirement for prior
      sensitization, and the action of IL-1. Whereas the early phase was a nonspecific
      'irritant' response to oxazolone, the late phase was Ag specific and was
      partially IL-1 dependent. Therefore, persistence of both E- and P-selectin
      expression in vivo can occur as a result of sequential and distinct EC activation
      processes that appear to be at least partially different from those previously
      reported as stimulating ICAM-1 and VCAM-1 expression. The further elucidation of
      mechanisms of EC activation in this model may help determine the relative roles
      of selectins and ligands for leukocyte integrins in the sequential recruitment of
      T cells and other leukocyte subsets during ongoing immune-mediated inflammatory
      responses.

PMID- 10586088
TI  - Functional analysis of antigen-specific T lymphocytes by serial measurement of
      gene expression in peripheral blood mononuclear cells and tumor specimens.
AB  - The cloning of cancer Ags recognized by T cells has provided potentially new
      tools to enhance immunity against metastatic cancer. The biological monitoring of
      effective immunization has, however, remained a dilemma. We describe here a
      sensitive molecular quantitation methodology that allows analysis of in vivo
      immune response to vaccination. Metastatic melanoma patients were immunized with
      a synthetically modified peptide epitope (209-2M) from the melanoma self-Ag
      gp100. Using serial gene expression analysis, we report functional evidence of
      vaccine-induced CTL reactivity in fresh cells obtained directly from the
      peripheral blood of postimmunized patients. Further, we demonstrate in vivo
      localization of vaccine-induced immune response within the tumor
      microenvironment. The results of these molecular assays provide direct evidence
      that peptide immunization in humans can result in tumor-specific CTL that
      localize to metastatic sites.

PMID- 10586089
TI  - Activation of eotaxin gene transcription by NF-kappa B and STAT6 in human airway
      epithelial cells.
AB  - The C-C chemokine eotaxin is a potent chemoattractant for eosinophils and
      probably plays an important role in the pathogenesis of asthma, although the
      mechanisms of its regulation are not well known. Airway epithelial cells express
      eotaxin mRNA and protein after stimulation with a variety of cytokines. We
      focused on the molecular mechanisms of eotaxin gene regulation by TNF-alpha and
      IL-4 in the airway epithelial cell line, BEAS-2B. Cells were transfected with
      luciferase reporter plasmids, which contained up to 1363 bp of the eotaxin
      promoter. Eotaxin promoter activity was increased by TNF-alpha (2.5-fold) and IL
      4 (1.5-fold), respectively. The combination of TNF-alpha and IL-4 produced 3.6
      fold activation of the eotaxin promoter. The eotaxin promoter contains
      overlapping consensus binding sites for transcription factors, NF-kappa B and
      STAT6, which are known to mediate responses to TNF-alpha and IL-4, respectively.
      Electrophoretic mobility shift assays revealed NF-kappa B binding after TNF-alpha
      stimulation and STAT6 binding after IL-4 stimulation using a DNA probe derived
      from the eotaxin promoter. Mutant plasmids were generated to define the roles of
      these transcription factors in eotaxin promoter activity. TNF-alpha stimulation,
      but not IL-4 stimulation, was lost in plasmids mutated at the NF-kappa B binding
      site, whereas IL-4 stimulation, but not TNF-alpha stimulation, was lost in
      plasmids mutated at the STAT6 binding site. When both sites were mutated, all
      transcriptional activation was lost. These results imply that TNF-alpha and IL-4
      stimulate expression of the eotaxin gene by activating NF-kappa B and STAT6.

PMID- 10586090
TI  - IL-12 drives IFN-gamma-dependent autoimmune kidney disease in MRL-Fas(lpr) mice.
AB  - IL-12 is secreted by kidney tubular epithelial cells in autoimmune MRL-Fas(lpr)
      mice before renal injury and increases with advancing disease. Because IL-12 is a
      potent inducer of IFN-gamma, the purpose of this study was to determine whether
      local provision of IL-12 elicits IFN-gamma-secreting T cells within the kidney,
      which, in turn, incites injury in MRL-Fas(lpr) mice. We used an ex vivo
      retroviral gene transfer strategy to construct IL-12-secreting MRL-Fas(lpr)
      tubular epithelial cells (IL-12 "carrier cells"), which were implanted under the
      kidney capsule of MRL-Fas(lpr) mice before renal disease for a sustained period
      (28 days). IL-12 "carrier cells" generated intrarenal and systemic IL-12. IL-12
      fostered a marked, well-demarcated accumulation of CD4, CD8, and double negative
      (CD4-CD8- B220+) T cells adjacent to the implant site. We detected more IFN-gamma
      producing T cells (CD4 > CD8 > CD4-CD8- B220+) at 28 days (73 +/- 14%) as
      compared with 7 days (20 +/- 8%) after implanting the IL-12 "carrier cells;" the
      majority of these cells were proliferating (60-70%). By comparison, an increase
      in systemic IL-12 resulted in a diffuse acceleration of pathology in the
      contralateral (unimplanted) kidney. IFN-gamma was required for IL-12-incited
      renal injury, because IL-12 "carrier cells" failed to elicit injury in MRL
      Fas(lpr) kidneys genetically deficient in IFN-gamma receptors. Furthermore, IFN
      gamma "carrier cells" elicited kidney injury in wild-type MRL-Fas(lpr) mice.
      Taken together, IL-12 elicits autoimmune injury by fostering the accumulation of
      IFN-gamma-secreting CD4, CD8, and CD4-CD8- B220+ T cells within the kidney,
      which, in turn, promote a cascade of events culminating in autoimmune kidney
      disease in MRL-Fas(lpr) mice.

PMID- 10586091
TI  - In vivo administration of recombinant IL-2 to individuals infected by HIV down
      modulates the binding and expression of the transcription factors ying-yang-1 and
      leader binding protein-1/late simian virus 40 factor.
AB  - Leader binding protein-1 (LBP-1)/late SV40 factor (LSF) and ying yang-1 (YY1)
      transcription factors are involved in the regulation of HIV expression. In
      particular, YY1 and LBP-1 have been shown to cooperate in repressing HIV-1-long
      terminal repeat reporter gene expression by in vitro cotransfection experiments.
      However, no information is available on the levels of expression and activation
      of these transcription factors in PBMC of HIV-infected individuals. Therefore, we
      have evaluated the expression and DNA binding activity of YY1 and LBP-1 (LSF) in
      PBMC of HIV-infected individuals before, during, and after administration of IL-2
      in association with antiretroviral therapy (ART), a regimen under consideration
      for broad clinical use in this disease based on its ability to stably raise the
      absolute number of circulating CD4+ T lymphocytes. Both YY1- and LBP-1 (LSF)-DNA
      binding were profoundly down-modulated during administration of IL-2/ART, and a
      proteolytic activity probably responsible for the reduced expression of the two
      cellular transcription factors was found activated in PBMC of individuals
      receiving the immunotherapeutic regimen. This study is the first evidence of
      modulation of cellular transcription factors following IL-2/ART administration
      and provides a potential correlate of the transient raises in plasma viremia
      early reported in patients receiving IL-2 in the absence of ART, thus
      underscoring the importance of always administering this cytokine to HIV-infected
      individuals together with potent antiretrovirals.

PMID- 10586092
TI  - Antibody repertoires of four- and five-feature translocus mice carrying human
      immunoglobulin heavy chain and kappa and lambda light chain yeast artificial
      chromosomes.
AB  - We have produced mice that carry the human Ig heavy (IgH) and both kappa and
      lambda light chain transloci in a background in which the endogenous IgH and
      kappa loci have been inactivated. The B lymphocyte population in these translocus
      mice is restored to about one-third of normal levels, with preferential (3:1)
      expression of human lambda over human kappa. Human IgM is found in the serum at
      levels between 50 and 400 microg/ml and is elevated following immunization. This
      primary human Ab repertoire is sufficient to yield diverse Ag-specific responses
      as judged by analysis of mAbs. The use of DH and J segments is similar to that
      seen in human B cells, with an analogous pattern of N nucleotide insertion.
      Maturation of the response is accompanied by somatic hypermutation, which is
      particularly effective in the light chain transloci. These mice therefore allow
      the production of Ag-specific repertoires of both IgM,kappa and IgM,lambda Abs
      and should prove useful for the production of human mAbs for clinical use.

PMID- 10586093
TI  - Production of soluble granulocyte colony-stimulating factor receptors from
      myelomonocytic cells.
AB  - It has been speculated that a soluble form of G-CSFR might be physiologically
      present in humans, since G-CSFR mRNA that lacks a transmembrane domain has been
      identified from a human myelomonocytic cell line. Here, we demonstrate human
      soluble G-CSFR (sG-CSFR) of two different molecular sizes (80 and 85 kDa) on an
      immunoblot analysis using Abs generated against the amino-terminal, extracellular
      domain of the full-length G-CSFR. Both isoforms of sG-CSFR were able to bind
      recombinant human G-CSF (rhG-CSF). RT-PCR analysis with primers targeted outside
      of the transmenbrane region revealed that membrane-anchored G-CSFR is expressed
      at all maturation stages of purified myeloid cells, including CD34+CD13+ cells
      (blasts), CD11b-CD15+ cells (promyelocytes or myelocytes), CD11b+CD15+ cells
      (metamyelocytes and mature neutrophils), and CD14+ cells (monocytes). On the
      other hand, sG-CSFR mRNA was detectable in CD11b-CD15+, CD11b+CD15+, and CD14+
      cells, but not in the CD34+CD13+ blast population. The serum concentration of
      both isoforms of sG-CSFR appeared to be correlated with the numbers of
      neutrophils/monocytes before and after rhG-CSF treatment in normal individuals.
      Thus, two isoforms of sG-CSFR are physiologically secreted from relatively mature
      myeloid cells and might play an important role in myelopoiesis through their
      binding to serum G-CSF.

PMID- 10586094
TI  - Differential loss of T cell signaling molecules in metastatic melanoma patients'
      T lymphocyte subsets expressing distinct TCR variable regions.
AB  - In this study we tested the hypothesis that loss of T cell signaling molecules in
      metastatic melanoma patients' T cells may affect differently T cell subsets
      characterized by distinct TCR variable regions. By a two-color immunofluorescence
      technique, expression of zeta-chain, lck, and ZAP-70 was evaluated in CD3+ T
      cells and in three representative T cell subsets expressing TCRAV2, TCRBV2, or
      TCRBV18. Partial loss of lck and ZAP-70 was found in CD3+ T cells from PBL of
      most melanoma patients, but not of healthy donors. The extent of zeta-chain, lck,
      and ZAP-70 loss depended on the TCRV region expressed by the T cells, and this
      association was maintained or increased during progression of disease. Coculture
      of patients' or donors' T cell with melanoma cells, or with their supernatants,
      but not with normal fibroblasts or their supernatants, down-modulated expression
      of zeta-chain, lck, and ZAP-70 in a TCRV region-dependent way. Immunodepletion of
      soluble HLA class I molecules present in tumor supernatants, but not of soluble
      ICAM-1, blocked the suppressive effect on T cell signaling molecule expression. T
      cell activation with mAbs to a single TCRV region and to CD28 led to significant
      and TCRV region-specific re-induction of zeta-chain expression. These findings
      indicate that extent of TCR signaling molecules loss in T lymphocytes from
      metastatic melanoma patients depends on the TCRV region and suggest that tumor
      derived HLA class I molecules may contribute to induce such alterations.

PMID- 10586095
TI  - Monomeric complement-activating IgG paraproteins.
AB  - Three patients presented a unique syndrome of recurrent panniculitis with an
      IgGkappa paraprotein and depletion of the early components of the classical
      pathway of complement. The IgGkappa paraproteins were monomers with a normal
      structure, and with no evidence for aggregation, as assessed by electron
      microscopy and ultracentrifugation. Both heavy and light chains were of normal
      molecular size (SDS-PAGE), and the paraproteins were not heavily glycosylated.
      However, the paraproteins from all three patients had unusual features that
      included abnormal behavior on gel filtration chromatography and a heavy chain of
      high pI. When analyzed by fast protein liquid chromatography (Superdex 200),
      elution of the paraproteins was retarded, particularly when the ionic strength
      was increased. This retardation was partially reversed in 20% alcohol, and fully
      reversed in 6 M guanidine-HCl. Neither anti-C1 inhibitor nor anti-C1q
      autoantibodies were found in any of the patients' sera. However, the paraproteins
      bound to the globular heads of C1q at normal ionic strength. They activated C4 in
      normal human serum, but not in C1q-deficient serum. Activation led to the
      formation of C1s-C1 inhibitor complexes. Taken together, the data suggest that
      the unusual paraproteins have the capacity to bind C1q, which then leads to
      activation of C1. The ability of these paraproteins to activate C1, in spite of
      their being soluble monomers, is likely to be related to their unique
      physicochemical features.

PMID- 10586097
TI  - Polymer substrate topography actively regulates the multicellular organization
      and liver-specific functions of cultured hepatocytes.
AB  - This study examines the role of topography of porous synthetic polymer substrates
      in regulating the tissue-specific morphogenesis of cultured hepatocytes. Porous
      foams of amorphous 50/50 poly(D,L glycolic-co-lactic acid) (PGLA) with a wide
      range of controlled pore-size distributions ( approximately 1 to 100 microm) were
      used as culture model surfaces. We found that the induction of microporosity in
      PGLA substrates significantly improved cell attachment and viability in
      comparison to those observed on non-porous PGLA films. A detailed evaluation of
      cellular morphogenesis on the microporous matrices showed that hepatocellular
      organization was sensitively dependent on the topographical feature size of the
      foam surfaces. Foams with subcellular size voids ( approximately 3 microm)
      induced kinetics of two-dimensional hepatocyte reorganization, yet limited the
      extent of three-dimensional aggregation. In contrast, foams with supercellular
      size voids ( approximately 67-microm) restricted hepatocyte motility, thereby
      promoting the kinetics of 3D aggregation. At intermediate void sizes (
      approximately 17 microm), both 2D and 3D reorganization kinetics were promoted.
      Albumin secretory kinetics progressively increased on all void size
      configurations, the most rapid and sustained kinetics observed in supercellular
      sized voids, which may serve to minimize cell-polymer contacts and maximize cell
      cell contacts in 3D. Overall, these studies demonstrate that void topography of
      porous polymer substrates is a critical textural feature to induce short-term
      cell adhesion and viability, and to also selectively regulate the kinetics and
      extent of multicellular spreading versus 3D aggregation. By virtue of its effects
      on cell adhesion and morphogenesis, the void topography of nonphysiological
      polymer scaffolds also is a powerful variable to microengineer hepatospecific
      activity of tissue analogs.

PMID- 10586096
TI  - Persistent T cell anergy in human type 1 diabetes.
AB  - An anergic phenotype has been observed in nonobese diabetic (NOD) mice and some
      autoreactive T cells from patients with type I diabetes. To better understand
      this phenomenon, we measured T cell proliferative responses to 10 diabetes
      associated and up to 9 control Ags/peptides in 148 new diabetic children, 51 age-
      and MHC (DQ)-matched siblings (sibs), 31 patients with longstanding diabetes, and
      40 healthy controls. Most (78-91%) patient and sib responses to glutamate
      decarboxylase of 65 kDa (GAD65), islet cell cytoplasmic autoantibody (ICA) 69,
      diabetes-associated T cell epitopes in ICA69 (Tep69), and heat shock protein
      (Hsp) 60 involved anergic T cells that required exogenous IL-2 to proliferate.
      Responses to proinsulin, IA-2 (and tetanus toxoid) required no IL-2 and generated
      sufficient cytokine to rescue anergic T cell responses. Most new patients (85%)
      had autoreactive T cells, three quarters targeting more than half of the diabetes
      Ags. Only 7.8% of the sibs and none of the controls had such multiple T cell
      autoreactivities, which thus characterize overt disease. Multiple anergic and
      nonanergic T cell autoreactivities were sustained during 2 yr follow-up after
      onset and in patients with longstanding (3-26 yr) diabetes. Activated patient T
      cells survived severe IL-2 deprivation, requiring 20-100 times less IL-2 than
      normal T cells to escape apoptosis. Diabetic T cell anergy thus persists for
      decades and is Ag and host specific but not related to disease course. Rescue by
      IL-2 from bystander T cells and high resistance to apoptosis may contribute to
      this persistence. These data explain some of the difficulties in the routine
      detection of disease-associated T cells, and they emphasize challenges for
      immunotherapy and islet transplantation.

PMID- 10586098
TI  - Effect of osteoblastic culture conditions on the structure of poly(DL-lactic-co
      glycolic acid) foam scaffolds.
AB  - Poly(DL-lactic-co-glycolic acid) (PLGA) foams are an osteoconductive support that
      holds promise for the development of bone tissue in vitro and implantation into
      orthopedic defects. Because it is desirable that foams maintain their shape and
      size, we examined a variety of foams cultured in vitro with osteoblastic cells.
      Foams were prepared with different porosities and pore sizes by the method of
      solvent casting/porogen leaching using 80, 85, and 90 wt% NaCl sieved with
      particle sizes of 150-300 and 300-500 microm and characterized by mercury
      intrusion porosimetry. Foams seeded with cells were found to have volumes after 7
      days in static culture that decreased with increasing porosity: the least porous
      exhibited no change in volume while the most porous foams decreased by 39 +/-
      10%. In addition, a correlation was observed between decreasing foam volume after
      7 days in culture and decreasing internal surface area of the foams prior to
      seeding. Furthermore, foams prepared with the 300-500 microm porogen had lower
      porosities, greater mean wall thicknesses between adjacent pores, and larger
      volumes after 7 days in culture than those prepared with the smaller porogen. Two
      culture conditions for maintaining cells, static and agitated (in a rotary
      vessel), were found to have similar influences on foam size, cell density, and
      osteoblastic function for 7 and 14 days in culture. Finally, we examined unseeded
      foams in aqueous solutions of pH 3.0, 5.0, and 7.4 and found no significant
      decrease in foam size with degradation. This study demonstrates that adherent
      osteoblastic cells may collapse very porous PLGA foams prepared by solvent
      casting/particulate leaching: a potentially undesirable property for repair of
      orthopedic defects.

PMID- 10586099
TI  - Direct-, fibroblast- and myoblast-mediated gene transfer to the anterior cruciate
      ligament.
AB  - The anterior cruciate ligament (ACL) has poor capabilities of healing. Maturation
      or "ligamentization" of the ACL following autograft or allograft reconstruction
      has been found slow and remains under investigation. In vitro and in vivo studies
      have shown that platelet-derived growth factor (PDGF), transforming growth factor
      beta (TGF-beta), and epidermal growth factor (EGF) have the potential to improve
      ligament healing. Gene therapy approaches may represent a new alternative in
      delivering these specific growth factors to the ACL. The aim of this study was to
      investigate the feasibility of three different gene therapy approaches (direct-,
      fibroblast-, and myoblast-mediated gene transfer) to the ACL. Rabbit myoblasts
      and ACL-fibroblasts were transduced with 5 x 10(7) recombinant adenoviral
      particles carrying the LacZ reporter gene (MOI = 50). Myoblasts and fibroblasts
      (1 x 10(6)) were each injected into the right ACL of 10 adult rabbits; direct
      injection of 5 x 10(7) adenoviral particles was performed in 10 other rabbits.
      The left side was used as sham. The beta-galactosidase production was revealed
      using the LacZ histochemical technique. The transduced fibroblasts and myoblasts
      were found in the ligament tissue and in the synovial tissue surrounding the ACL
      at 4, 7, 14, and 21 days postinjection. The myoblasts fused and formed myotubes
      in the ligament. The direct approach also allowed the transfer of the marker gene
      in the ligament at 4, 7, 21, and 42 days postinjection. X-gal staining revealed
      no expression of beta-galactosidase in the sham ligament. The presence of cells
      expressing the marker gene in the ACL opens up the possibility of delivering
      proteins (i.e., PDGF, TGF-beta, and EGF) capable of improving ACL healing and
      graft maturation. Furthermore, engineered myoblasts may mediate and accelerate
      the intraligament neovascularization. This new technology based on gene therapy
      and tissue engineering may allow a persistent expression of selected growth
      factors to enhance ACL healing following injury.

PMID- 10586100
TI  - Ligament tissue engineering using synthetic biodegradable fiber scaffolds.
AB  - Tissue engineering offers the possibility of replacing damaged human ligaments
      with engineered ligament tissues. Hence, we attempted to culture in vitro
      ligament tissues by seeding human anterior cruciate ligament (ACL) and medial
      collateral ligament (MCL) cells onto synthetic biodegradable polymer fiber
      scaffolds. The ACL and MCL cells readily attached to the scaffold fibers. These
      cells and their secreted matrix soon surrounded the scaffold fibers and bridged
      the gaps in between. Beginning at 2 weeks, portions of the scaffolds were
      completely filled with tissue matrix. By 5 weeks, the scaffolds became single
      bundles of tissue. Thus the cell/fiber system appears to be a viable system for
      culturing ligament tissues. Additionally, cell proliferation under mechanical and
      biochemical stimuli was studied for up to 4 days. Whereas mechanical stimulus and
      transforming growth factor enhanced proliferation, inflammatory agents
      (lipopolysaccharide and complement C5a) had a negative effect. This work can thus
      contribute to a sound strategy for culturing replacement ligament tissues in
      vitro.

PMID- 10586101
TI  - Dose control with cell lines used for encapsulated cell therapy.
AB  - Cell therapy-use of cells to deliver active factors-is an emerging technique in
      treatment of neurodegenerative disease. Successful devices maintain cell
      viability and functionality over extended implant periods. Use of dividing cell
      lines to deliver therapeutic factors has been studied extensively. One emerging
      issue is the tendency of cells to continue proliferation within the intracapsular
      environment-potentially outstripping nutrient supply. This work presents a method
      of controlling proliferation and delivering therapeutic molecules within a dose
      range. The method entails encapsulation into a hollow fiber device of discrete
      numbers of cell-containing microcarriers. Proliferation control is attained by
      embedding cell-containing microcarriers in nonmitogenic hydrogels. PC-12 cells
      secreting L-dopa and dopamine was the model cell line tested. Feasibility of the
      method in controlling growth of normally rapidly dividing cells in the
      intracapsular environment was demonstrated in vitro and in vivo. Control
      nonmicrocarrier PC-12 cell devices had approximately fourfold greater expansion
      in cell number compared to experimental microcarrier-containing devices over 4
      weeks in vitro and in vivo after implant into rat striatum. Ability to control
      dose released over a several-fold range was demonstrated with encapsulated PC-12
      cells delivering neurotransmitters and C2C12 mouse myoblast cells delivering
      neurotrophic factors (CNTF).

PMID- 10586102
TI  - Neural tissue formation within porous hydrogels implanted in brain and spinal
      cord lesions: ultrastructural, immunohistochemical, and diffusion studies.
AB  - A biocompatible heterogeneous hydrogel of poly [N-(2-hydroxypropyl)
      methacrylamide] (PHPMA), was evaluated for its ability to promote tissue repair
      and enhance axonal regrowth across lesion cavities in the brain and spinal cord
      in adult and juvenile (P17 P21) rats. Incorporation of PHPMA hydrogels into
      surrounding host tissue was examined at the ultrastructural level and using
      immunohistochemical techniques. In addition, and in parallel to these studies,
      diffusion parameters (volume fraction and tortuosity of the gel network) of the
      PHPMA hydrogels were evaluated pre- to postimplantation using an in vivo real
      time iontophoretic method. The polymer hydrogels were able to bridge tissue
      defects created in the brain or spinal cord, and supported cellular ingrowth,
      angiogenesis, and axonogenesis within the structure of the polymer network. As a
      result, a reparative tissue grew within the porous structure of the gel, composed
      of glial cells, blood vessels, axons and dendrites, and extracellular biological
      matrices, such as laminin and/or collagen. Consistent with matrix deposition and
      tissue formation within the porous structure of the PHPMA hydrogels, there were
      measurable changes in the diffusion characteristics of the polymers.
      Extracellular space volume decreased and tortuosity increased within implanted
      hydrogels, attaining values similar to that seen in developing neural tissue.
      PHPMA polymer hydrogel matrices thus show neuroinductive and neuroconductive
      properties. They have the potential to repair tissue defects in the central
      nervous system by replacing lost tissue and by promoting the formation of a
      histotypic tissue matrix that facilitates and supports regenerative axonal
      growth. () ()

PMID- 10586103
TI  - Tissue engineering of a trileaflet heart valve-early in vitro experiences with a
      combined polymer.

PMID- 10586104
TI  - Japan's new patent law.

PMID- 10586105
TI  - [Dolastatins].

PMID- 10586106
TI  - [Cellular signaling in response to TGFbeta: the paradox of a factor that blocks
      cell proliferation and enhances metastasis].
AB  - The growth factor TGFbeta (transforming growth factor beta) was initially
      characterized as a repressor of cellular proliferation. However, studies over the
      last few years have highlighted another striking property of TGFbeta, which is
      its capacity to enhance development of the extracellular matrix and formation of
      metastases from primary tumors. Our understanding of TGFbeta signaling mechanisms
      has advanced substantially with the identification of the SMAD proteins that
      transduce TGFbeta signals from the cell membrane to the nucleus where they
      regulate transcription. Activation of these inducible SMADs occurs through a
      series of serine phosphorylations mediated by TGFbeta receptors. Other members of
      the SMAD family act antagonistically downstream of TGFbeta and participate in
      feedback regulation loops. The fact that members of the TGFbeta family are
      involved in biological processes as diverse as development, cell proliferation
      and the immune response can be explained by the intricate regulation of TGFbeta
      signaling, which involves tissue specificity as well as synergy with distinct
      signaling pathways. The dual role of TGFbeta as regulator of cellular
      proliferation and metastasis inducer opens novel possibilities for the use of
      TGFbeta signaling as a target for cancer therapy.

PMID- 10586107
TI  - [Interferon signaling pathways].
AB  - Interferons (IFNs) encode a large family of multifonctional secreted proteins
      that are involved in antiviral defense, the regulation of cell growth and
      modulation of the immune response. They are subdivided into two types that
      activate transduction pathways via different cell surface receptors. Binding of
      both IFN type I and II results in the differential activation of JAK (Janus
      kinases) that phosphorylate latent cytoplasmic transcription factors termed STATs
      (signal transducer and activator of transcription). Phosphorylated STATs
      translocate to the nucleus, bind specific DNA elements and direct transcription.
      Type I IFN induces the phosphorylation of STAT1 and STAT2 proteins by tyrosine
      phosphorylation involving the type I IFN receptor-associated tyrosine kinases
      TYK2 and JAK1. Following phosphorylation, STAT1 and STAT2 form the
      transcriptionally active IFN-stimulated gene factor 3 (ISGF3) by association with
      a protein of the IFN regulatory factor (IRF) family, p48. The specificity of the
      transcriptional activation by ISGF3 is mediated by specific elements termed IFN
      stimulatory response element (ISRE) located in the promoter region of IFN
      inducible genes. ISREs drive the expression of most IFN type I-regulated genes
      and a few IFN type II-regulated genes. Gene induction by type II IFN involves the
      phosphorylation of only STAT1 by JAK1 and Jak2 kinases. This phosphorylation
      generates a homodimer of STAT1 which is able to bind the IFNgamma-activated site
      (GAS) to activate transcription. This signaling is rapid and direct. Molecules
      involved in the IFN signaling pathways have been shown to be used by other
      polypeptide ligands in their own signal transduction pathways. Pathways other
      than JAK/STAT are also involved in IFN signaling, but their mechanisms are less
      clear. The best documented are the mitogen-activated protein kinase (MAPK)
      cascade, the components of the TCR (T cell receptor) signaling cascade and the
      Pi3 kinase pathway.

PMID- 10586108
TI  - [Genetics of uterine leiomyomata].
AB  - Uterine leiomyomata, or fibroids, represent the most common tumor in women of
      reproductive age. Although benign, leiomyomata constitute a major health problem,
      and are the most frequent indication for hysterectomy. The pathobiology of these
      tumors is still poorly understood. Cytogenetic and genetic studies have, in
      recent years, advanced our understanding of the etiology of these tumors.
      Specifically, cytogenetic aberrations involving chromosomes 6, 7, 12 and 14 have
      been shown to constitute the major chromosomal abnormalities seen in leiomyomata
      and have led to the discovery that HMGIC and HMGIY, two members of the non
      histone high mobility group of genes, are involved in fibroid development. HMGIC
      and HMGIY map to 12q15 and 6p21, and their disruption or dysregulation has been
      shown to contribute to leiomyomata formation. Given the observation of several
      additional, but consistent, chromosomal aberrations, it is likely that other
      genes with fundamental roles in the pathobiology of uterine leiomyomata await
      identification. Furthermore, twin studies and the discovery of both ethnic and
      familial predispositions have suggested a genetic liability to develop uterine
      leiomyomata.

PMID- 10586109
TI  - [Leukemias induced by anticancer chemotherapies].
AB  - The frequency of leukemia and myelodysplasia following treatment with cytotoxic
      agents is increasing. Theses treatment-related leukemias raise both theoretical
      and practical concerns. On a theoretical basis, cytogenetic and molecular
      abnormalities described constitute useful models to study leukemogenesis. On a
      practical basis, prognosis of treatment related-leukemia is somehow unfavorable
      and implies to take in account this risk in the development of combination
      therapy for solid tumors or hematological malignancies. There are two distinctive
      types of treatment-induced leukemia: those secondary after alkylating agents and
      those secondary after topoisomerase-II- inhibitors. These two types of leukemia
      after regarding their clinical and their hematological characteristics, but also
      regarding their prognosis and their associated molecular abnormalities. Leukemias
      induced by alkylating agents occur generally 5 or 6 years after the beginning of
      the chemotherapy and are preceded by a more or less long phase of pancytopenia or
      myelodysplasia and according to their cytologic aspects are difficult to be
      classified within FAB classification. Their prognosis is pejorative. The most
      commonly found cytogenetic abnormalities associated with these types of induced
      leukemia are losses or deletions of chromosomes 5 and 7. Leukemias induced by
      topoisomerase-II-inhibitors occur shortly after the treatment (12 to 30 months),
      they begin generally suddenly without preleukemia prodom and their more frequent
      cytological aspects are M4 and M5 type. The prognosis is less severe than
      alkylating agent related forms with higher response rates and is dependant of
      discovered cytogenetic abnormalities. The more frequent molecular abnormalities
      are not chromosome deletions but balanced translocations. They affect
      particularly the MLL gene located at band 11q23. Other translocations have been
      described in this type of leukemia and are comparable to the one found in the de
      novo leukemia (t8;21, t15;17) for example. The evaluation of the risk of
      treatment-related leukemia for a given chemotherapeutic agent is difficult as for
      as current treatment use the combination of several agents potentially
      leukemogenic (chemotherapy and radiotherapy, combination chemotherapy). It is
      necessary to set up an up-dated data register in order to centralize all therapy
      related myelodysplasia and leukemia within the treatment of a given type of
      cancer.

PMID- 10586110
TI  - [Subareolar injection of 99m-Tc sulfur colloid for sentinel nodes identification
      in multifocal invasive breast cancer].
AB  - The objective were to study the relevance of the subareolar injection for
      sentinel node [SN] detection in multiple foci breast cancer. Seventy-nine
      patients with infiltrative breast carcinoma (diagnosed pre-operatively by core
      biopsy) and a mean age of 55 (31-78) years were enrolled. All patients were free
      of previous homolateral surgery, chemotherapy, locoregional radiotherapy or
      prevalent axillary lymph node. Using four 0.1 ml injections of 1.8 MBq, the
      technetium-99m 100 nm filtered sulfur colloid was injected by subareolar way
      (group I) in 16 cases of radiologically cancer with multiple invasive foci and 31
      cases of radiologically unifocal cancer, and by peritumoral way (group II) in 32
      cases of radiologically unifocal cancer. Scintigrams were obtained 2 to 4 hours
      after the injections and radioactive nodes were detected peroperatively 18 hours
      after the injection by intraoperative detection probe. Individual removal of all
      radioactive nodes was followed by axillary dissection at levels I and II of Berg
      including Rotter area control. All sentinel nodes were submitted to standard
      histopathological analysis on serial sections at 500 mu intervals completed by
      immunohistochemistry for cytokeratin on negative SN. SN were detected by
      scintigrams in 85% and 88% of the cases of group I and group II respectively, but
      in 98% and 97% of the cases of respectively both groups by intraoperative probe.
      Group I was composed of 69% ductal, 22% lobular and 9% tubular carcinomas, and
      group II of 87% ductal, 10% lobular and 3% tubular carcinomas. Seven and 5
      radiologically unifocal tumors were in fact with multiple invasive foci at
      histology in groups I and II respectively. The complete scintigraphic procedure
      permitted the detection of a mean number of 2.7 (1-7) SN in group I and 2.3 (1-4)
      in group II (NS). In group I, the SN were metastatic in 22 patients (48%), 15 of
      them with the metastases being restricted to the SN, whereas in group II, the SN
      were metastatic in 9 patients (28%), 5 of them with the positivity restricted to
      the SN. No false negative result (SN negative and other axillary nodes positive)
      was observed in group I and only one false negative result in group II which was
      related to a cancer with histological multiple invasive foci. Sensitivities were
      100% and 90%, and negative predictive values were 100% and 95%, for groups I and
      II respectively. Subareolar injection of radiocolloid allows identification of SN
      in cases of unifocal and multiple cancer. The mean number of SN detected by the
      subareolar method is not significantly different, although higher, to that
      detected by peritumoral injection.

PMID- 10586111
TI  - [Stability of 5-fluorouracil-folinic acid mixture: influence of concentrations,
      container and form of folinic acid].
AB  - Since the discovery of the superiority of the combination 5-fluorouracil (5FU)
      folinic acid (FA) in comparison to 5FU alone in the treatment of gastrointestinal
      cancers, the interest of this association has been demonstrated in many other
      tumors. In the treatment of advanced colorectal carcinoma, FA is usually
      administered in 1 or 2 h infusion before 5FU. In treatment of other cancers, the
      two drugs are generally mixed together in the same container and administered as
      a continuous intravenous infusion over several days. Many studies have
      demonstrated the stability of 5FU alone in different vials, but results about
      compatibility of 5FU with AF in racemate (d,l) or levogyre (l) forms are
      conflicting. The aim of our study was to determine the influence of the
      container, the concentrations of the two drugs and the form of folinic acid (d, l
      or l) on the stability of the 5 FU-FA admixtures. Based on drug concentrations
      corresponding to current 5FU-FA chemotherapeutic protocols, 5FU was used at 50
      mg/ml and 6.5 mg/ml in association with equitherapeutic and equimolar doses of FA
      respectively. Each association has been studied in three types of containers. For
      all combinations with 5FU 50 mg/ml, flocculation was noted, whatever form or
      concentration of FA which associated. No influence of the type of containers was
      noted. No precipitate was observed with the combinations 5FU 6.5 mg/ml. The
      evolution of the concentrations of 5FU and FA with time have been compared with a
      regression straight corresponding to a loss of product of 10% in 96 h. The
      mixtures 5FU 6.5 mg/ml with FA (d,l) 4 mg/ml and FA (l) 2 and 4 mg/ml remained
      stable in the three types of container. When a precipitate was noted (with 5FU 50
      mg/ml), the concentration of 5FU decreased with time, whereas FA was stable in
      racemate and levogyre forms. Analysis of the precipitate showed that principally
      5FU and equal parts of FA and calcium constituted it. Our results allowed to
      conclude that 5FU mixed with FA (d,l or l) 2 mg/ml and 4 mg/ml remained stable
      during 96 h in glass vials, PVC infusion bags and cassettes for portable pump in
      normal conditions of temperature and light. A precipitate of 5FU appears
      systematically with the concentration 50 mg/ml. These findings do not confirm
      those obtained in previously published studies. It seems that the precipitation
      is more a result of the decline of 5FU solubility at high concentrations than the
      form of folinic acid associated.

PMID- 10586112
TI  - The CIS/SOCS proteins: a family of cytokine-inducible regulators of signaling.
AB  - This review describes the main properties of a new family of cytokine-inducible
      proteins which interfere with the Jak/Stat transduction pathway and negatively
      regulate the duration of cytokine-induced signal activation. These proteins act
      not only as negative feedback regulators but also inhibit response to cytokines
      different from those used to induce their expression. These proteins are
      potentially important regulators of inflammatory and immune responses of
      hematopoiesis and hormone response.

PMID- 10586113
TI  - Cytokines in the muscle tissue of idiopathic inflammatory myopathies:
      implications for immunopathogenesis and therapy.
AB  - The inflammatory myopathies (IM), dermatomyositis (DM), polymyositis (PM) and
      idiopathic inclusion body myositis (IBM) are acquired immune-mediated myopathies.
      About their pathogenesis and etiology no definitive insights are available yet.
      Here we present a review of cytokine studies in IM. Combined with cellular
      immunohistochemical findings a model is presented describing a common mechanism
      of immune activation in IM. This model is based on a "hit" triggering local
      cytokine production with dominance of pro-inflammatory cytokines, like IFN-gamma
      and Th1-mediated activities. The altered Th1-Th2 balance necessitates detection
      of the anti-inflammatory arm of immune activation, which includes Th2-derived IL
      4, IL-1, and Th3/Tr1 derived IL-10 and TGF-beta. Redirection of the ratio
      provides targets for novel immunotherapy by direct inhibition of the IFN-gamma
      mediated Th1 response, stimulation of Th3/Tr1, or IL-4-secreting Th2-cells,
      negative feedback inhibition with IFN-beta and IFN-gamma and inactivation of MHC
      molecules.

PMID- 10586114
TI  - Differential effects of interleukin-3 and interleukin-1 on the proliferation and
      interleukin-6 protein secretion of acute myeloid leukemic cells; the involvement
      of ERK, p38 and STAT5.
AB  - In the present study we examined whether the p38 and extracellular signal
      regulated kinase (ERK) signal transduction pathways are involved in the
      interleukin-3 (IL-3)- or interleukin-1 (IL-1)-mediated proliferation and cytokine
      production of acute myeloid leukemic (AML) cells. The IL-3- and IL-1-mediated
      proliferation were both inhibited by the specific p38 and MEK1 inhibitors
      SB203580 and PD98059, respectively. Specificity of these inhibitors was
      demonstrated by in vitro kinase assays. Furthermore, we examined whether STAT5
      (signal transducer and activator of transcription) activity is modulated by the
      p38 and ERK signal transduction pathways, since STAT5 activation has been linked
      to proliferation. We provide evidence that the p38 kinase pathway, but not the
      ERK pathway, is to a certain degree involved in the modulation of STAT5
      transactivation since SB203580 and overexpression of an inactive MKK3 mutant
      inhibited the IL-3-induced STAT5 reporter transactivation. In addition, the p38
      and ERK pathways are also involved in cytokine production. The IL-1-enhanced IL-6
      protein secretion was strongly reduced by SB203580 and PD98059. Despite the fact
      that IL-3 did induce p38 and ERK kinase activity, it was not able to enhance IL-6
      protein secretion, which coincided with the inability of IL-3 to induce NFkappaB
      (nuclear factor kappaB) activation and IkappaB (inhibitory protein kappaB)
      degradation. This study demonstrates that the p38 and ERK pathways play a
      functional role in cell proliferation and IL-6 secretion of AML cells which are
      dependent on the activated cytokine receptors.

PMID- 10586115
TI  - Expression of PKCeta in NIH-3T3 cells promotes production of the pro-inflammatory
      cytokine interleukin-6.
AB  - Protein kinase C encodes a family of enzymes implicated in cellular
      differentiation, growth control and tumor promotion. The generation and
      characterization of NIH-3T3 cells which stably overexpress the PKCeta isoform has
      been previously described by us. In these cells, overexpression of PKCeta altered
      the expression of specific cell cycle regulators and promoted differentiation
      [20]. Since PKC has been implicated in the regulation of gene expression,
      including that of various cytokines, we examined the production of several
      cytokines in these cells. We report here that out of the major pro-inflammatory
      cytokines examined, IL-1alpha, IL-1beta, TNF-alpha and IL-6, only IL-6 was
      generated and secreted in PKCeta -expressing cells without any additional inducer
      in serum-supplemented cultures (10% FCS). IL-6 was not detected in the control
      cell line, transfected with the same vector, but lacking the cDNA coding for
      PKCeta. Moreover, the production of IL-6 on serum stimulation correlated with the
      levels of PKCeta expressed in these cells. This implies that factors in the serum
      activate PKCeta and induce IL-6 production. We have examined several growth
      factors and cytokines for their ability to induce IL-6 production in our PKCeta
      expressing cells. Among the growth factors tested (EGF, PDGF, FGF, insulin, IGF-1
      and IL-1), PDGF and FGF were the most potent IL-6 inducers. The effects of FGF
      and PDGF on IL-6 production were blocked in the presence of PKC inhibitors. We
      also examined the signaling pathways that mediate production of IL-6 in PKCeta
      expressing cells. Using specific inhibitors of the MAPK pathway, we have shown a
      role for ERK and p38 MAPK in FGF- and serum-stimulated IL-6 production, but only
      for p38 MAPK in PDGF-stimulated IL-6 production. Our studies provide evidence
      that PDGF and FGF can serve as upstream regulators of PKCeta and that PKCeta is
      involved in the expression of IL-6. This suggests that inhibition of PKC may
      provide a basis for the development of drugs for the treatment of disorders in
      which IL-6 is pathologically involved.

PMID- 10586116
TI  - Human interleukin-6 is in vivo an autocrine growth factor for human herpesvirus-8
      infected malignant B lymphocytes.
AB  - Human interleukin-6 (hIL-6) acts as a growth factor in several human B lymphoid
      cancers. As human herpesvirus-8 (HHV-8) encodes for a viral IL-6 (vIL-6), the
      viral cytokine may be responsible for several manifestations of HHV-8-related
      disorders. Using an anti-hIL-6 mAb (B-E8) which does not recognize vIL-6, we
      investigated the involvement of the human cytokine in the proliferation of HHV-8
      positive primary effusion lymphoma (PEL) cells. In vitro, 5/5 PEL cell lines
      produced hIL-6 (4 to 1,200 pg/ml). The EBV- HHV-8+ cell line (BCBL-1) was adapted
      to grow in SCID mice. hIL-6 was detected in the serum of mice with grafts, as
      well as human soluble CD138 (sCD138) and human IL-10 (hIL-10). The serum level of
      these mediators increased with tumor progression. The effect of treatment with
      the B-E8 mAb on the tumor progression and survival was evaluated. This treatment
      significantly slowed down the tumor development: on day 54, there were more mice
      with low levels of sCD138 and hIL-10 in the treated group than in controls (p =
      0.03 and 0.02, respectively); treatment also delayed death (median date of death
      was day 65 for control mice and day 84 for anti-hIL-6 mAb-treated mice; p <
      0.02). Thus, hIL-6 is expressed in addition to vIL-6 in HHV-8-positive malignant
      B lymphocytes, and the viral cytokine does not totally substitute for human IL-6
      in promoting tumor progression.

PMID- 10586117
TI  - FCgammaRII (CD32)-dependent induction of interferon-alpha by serum from patients
      with lupus erythematosus.
AB  - Interferon-alpha (IFN-alpha) is detected in the serum of 70-80% of patients with
      systemic lupus erythematosus (SLE). Furthermore, soluble factors in SLE serum can
      induce peripheral blood mononuclear cells (PBMC) to produce IFN-alpha. The
      purpose of this work was to investigate the mechanism of this IFN-alpha
      induction. In eleven of fifteen SLE serum samples, an IFN-alpha inducing activity
      was detected, whereas serum from healthy controls, patients with other autoimmune
      disease and patients with viral infections were ineffective under the same
      conditions. After gel filtration of the serum, the inducing activity was found in
      the same fraction as IgG. The IFN-alpha inducing activity was inhibited by native
      monoclonal antibodies to the receptors for the Fc portion of IgG: FcgammaRIIA/C
      and FcgammaRIIB subclasses (CD32) and by their F(ab)'2 fragments. Purified Fc
      fragments of human IgG were also effective in abolishing the IFN-alpha-inducing
      activity. Since no anti-CD32 autoantibodies were found in SLE serum, this IFN
      alpha-inducing activity may be due to immune complex antibodies. Such results may
      allow better understand the origin of endogenous IFN-alpha, which has a
      deleterious effect on the course of this autoimmune disease. The inhibition of
      this function by the CD32 antibody could lead to new therapeutic approach in SLE.

PMID- 10586118
TI  - Primary immune response in skin and skin-associated lymphoid tissue of
      interleukin-4 transgenic mice.
AB  - The interleukin-4 transgenic mice investigated here exhibit a ubiquitous
      expression of interleukin-4 in all organs, including the skin. In this study, the
      induction phase of oxazolone-induced local primary contact hypersensitivity and
      croton oil-induced irritant contact dermatitis in transgenic and wild-type mice
      was analysed. Compared to wild-type mice, the transgenic mice showed a decreased
      activation of the skin-draining lymph nodes but a strong hyperreactivity in the
      skin after topical sensitisation. In contrast to this, both the transgenic and
      the wild-type mice developed a strong and comparable inflammatory skin reaction
      after topical irritation. A striking increased expression level of tumour
      necrosis factor-alpha and macrophage inflammatory protein-2 genes were found in
      the skin of the transgenic mice during primary local contact hypersensitivity,
      while both the transgenic and the wild-type mice developed comparable expression
      levels of these cytokines during irritant contact dermatitis. Compared to wild
      type mice, a strongly enhanced expression level of interleukin-6 transcripts
      derived from epidermal antigen presenting cells were detected in the skin of IL-4
      transgenic mice, whereas in the skin-draining lymph nodes of transgenic mice
      significantly lower levels were detected. We conclude that the migration of
      epidermal antigen-presenting cells towards the skin-draining lymph nodes is
      reduced in transgenic mice, which could be due to the different cytokine balance
      in these mice strains. The atypical irritant-like reaction observed in transgenic
      mice after topical sensitisation is a phenomenon comparable to atopic diseases
      and therefore this transgenic strain might be a helpful model for investigating
      the immunopathophysiological features of these diseases.

PMID- 10586119
TI  - Granulocyte interactions with GM-CSF and G-CSF secretion by endothelial cells and
      monocytes.
AB  - We have, in previous studies, characterized the cytokine and cellular regulation
      of GM-CSF and G-CSF production by monocytes and endothelial cells. In this study,
      we investigated the regulatory role of granulocytes. The addition of granulocytes
      to endotoxin-stimulated monocytes dose-dependently decreased both GM-CSF and G
      CSF concentrations, presumably by absorbing the cytokines. A similar dose
      dependent decrease in GM-CSF concentration was found when granulocytes were added
      to IL-1-stimulated endothelial cells. In contrast, G-CSF secretion by endothelial
      cells responded to granulocytes in a biphasic fashion. At low granulocyte
      concentrations, endothelial cells responded with an increased G-CSF secretion,
      but at high concentrations of granulocytes G-CSF secretion was down modulated.
      Our results suggest that there exist two loops between granulocytes and
      endothelial cells for regulating G-CSF activity. Granulocytes can stimulate G-CSF
      secretion by activated endothelial cells but can also decrease the biological
      activity by absorbing the cytokine. These mechanisms might be involved in the
      regulation of the local and systemic levels of granulocytes.

PMID- 10586120
TI  - Tumor necrosis factor is required for the priming of peritoneal macrophages by
      trehalose dimycolate.
AB  - Trehalose dimycolate (TDM), a glycolipid present in the cell wall of
      Mycobacterium spp., is a powerful immunostimulant. We have developed an original
      model of macrophage activation where TDM is injected in vivo to prime peritoneal
      macrophages. These primed macrophages do not express inducible NO synthase (NOS
      II), however, they can be fully activated, i.e. induced to express NOS II and to
      develop a NOS II-dependent antiproliferative activity, following in vitro
      exposure to low concentrations of LPS. In a previous paper, we have shown that
      TDM-priming of mouse peritoneal macrophages is mediated by the sequential
      production of IL-12 and IFN-gamma. In the present paper, we investigated the role
      of TNF in the priming of macrophages by TDM. By semi-quantitative RT-PCR, we have
      shown that TDM injection induced transcription of TNF-alpha in peritoneal cells.
      TNF-mRNA levels peaked 5 hours after TDM injection and remained elevated for at
      least 32 hours. TNF expression was absolutely necessary for macrophage priming,
      as injection of an anti-TNF monoclonal antibody, 4 h before and 20 hours after
      TDM injection, prevented LPS-dependent activation of macrophages in vitro. This
      result was confirmed by the inability of TDM to prime macrophages from LT
      alpha/TNF-alpha knockout (LT/TNFKO) mice. In addition, analysis of LT/TNFKO mice
      treated with TDM revealed that induction of the IL-12 transcript in their
      peritoneal cells and expression of a functional NADPH oxidase in macrophages are
      TNF-independent events.

PMID- 10586121
TI  - Interleukin-12 activates NK cells for IFN-gamma-dependent and NKT cells for IFN
      gamma-independent antimetastatic activity.
AB  - Mechanisms involved in the antimetastatic effect of IL-12 were analyzed in a
      mouse model of experimental metastasis with either syngeneic fibrosarcoma cells
      colonizing the lungs or syngeneic B cell lymphoma cells colonizing the liver. IL
      12 pretreatment effectively reduced the number of tumor colonies in both systems.
      This effect was already manifest 24 hours after tumor cell injection, indicating
      a T and B cell-independent mechanism. Therefore, the involvement of NK and
      alphabetaNKT cells was investigated using mice with defective NK and alphabetaNKT
      cell functions. Mice with impaired NK functions due to NK cell depletion, were
      less responsive to the antimetastatic IL-12 effect. IL-12 treatment failed to
      inhibit metastasis in beta2-microglobulin-deficient mice which lack alphabetaNKT
      cells in addition to having impaired NK cell activity, thus, demonstrating the
      functional importance of IL-12-activated NK and alphabetaNKT cells. While the IL
      12-induced antimetastatic effect of NK cells was dependent on IFN-gamma action,
      IL-12 activation of alphabetaNKT cells did not involve IFN-gamma. The
      neutralization of IFN-gamma or the use of IFN-gamma receptor-deficient mice did
      not alter the IL-12-induced effect in the absence of NK cells. Activation of
      effector cells of the innate immune system, such as NK and alphabetaNKT cells,
      seems to be the main mechanism for the antimetastatic effect of IL-12.

PMID- 10586122
TI  - Analysis of Tyr to Phe and fa/fa leptin receptor mutations in the PC12 cell line.
AB  - Weight regulation through body-fat content and energy homeostasis, is regulated
      mainly through the actions of leptin. Herein, we analyse the effect of mutations
      in the mouse leptin receptor using the PC12 pheochromocytoma cell line as a model
      system. Both the induction of pancreatitis associated protein 1 and
      metallothionein-II, two leptin regulated genes in PC12, was evaluated. Tyr to Phe
      mutations in the cytoplasmic tail of the mouse leptin receptor confirmed the
      critical role of Tyr1138 (a YxxQ motif) and STAT-3 activation for induction of
      leptin-induced genes in PC12. In addition, the Tyr985Phe mutation showed enhanced
      responsiveness to leptin, which was even more pronounced in combination with
      Tyr1077Phe. The short isoform of the leptin receptor showed complete loss of
      stimulation of both genes. In contrast, a leptin receptor devoid of all Tyr
      residues in its cytoplasmic tail was still capable of a limited induction of the
      PAP 1 gene. A mutant mouse leptin receptor containing the fa/fa mutation showed
      constitutive signalling and impaired responsiveness to leptin. Treatment with the
      adenylate cyclase activator forskolin alone, in the absence of leptin was
      sufficient to obtain full induction of both genes.

PMID- 10586123
TI  - Effects of immunosuppressive therapy on murine Leishmania infantum visceral
      leishmaniosis.
AB  - We evaluated the effect of immunosuppressive therapy on the course of infection,
      the spleen cell immunophenotype and cytokine production during murine Leishmania
      infantum visceral leishmaniosis (VL). Rousseau et al. [1] recently reported that
      prolonged administration of dexamethasone induces limited reactivation of chronic
      murine visceral leishmaniosis, with no clear Th1-Th2 cytokine patterns. We found
      that another glucocorticoid, hydrocortisone acetate, had similar effects during
      acute visceral leishmaniosis, i.e. an increase in parasite burden in the spleen,
      but not the liver, of infected mice. A significant increase in parasite burden in
      both the liver and the spleen was only achieved when mice were treated with
      combined dexamethasone + pentoxifylline immunotherapy; increases in parasite
      burden were never associated with a specific spleen cell immunophenotype or a Th1
      Th2 cytokine secretion profile.

PMID- 10586124
TI  - Physiopathology of urticaria.
AB  - Urticaria is a common disorder that affects as many of 20% of all people at
      sometime during their lives. It is a cutaneous reaction pattern for which there
      are multiple potential causes. Its physiopathology is poorly defined. The
      vascular changes observed in urticarial lesions can be attributed to the release
      of mediators: histamine plays an essential role but others mediators, such as
      serotonin, eicosanoids, kinins, neuropeptides. may also be involved. These
      mediators are synthetized by mast cells which are the major effector cell type.
      However, other cells, basophils, mononuclear cells, platelets, endothelial cells
      have also been implicated. During immediate hypersensitivity reaction, mast cells
      and basophils are activated by allergens through cross linking of cell-surface
      bound IgE. However, more often than not, these cells are stimulated by non
      immunological mechanisms. At present, some data are better understood: in
      urticaria, there is a late phase reaction which involves cytokines and cell
      adhesion molecules. Recent work has also demonstrated the role of circulating
      functional histamine - releasing auto antibodies that bind to the high affinity
      IgE receptor (FcepsilonRI) or, less commonly, to IgE. As the pathophysiological
      mechanisms responsible for urticaria are better defined, therapeutic agents other
      than H1 histamines, should be available.

PMID- 10586125
TI  - Current management of androgenetic alopecia in men.
AB  - Androgenetic alopecia (AGA) is a common dermatological condition affecting both
      men and women. Until recently there has been little interest in AGA as a clinical
      condition, largely due to the lack of any genuinely effective treatment for it. A
      number of "remedies" exist, such as vitamin supplements, which are not generally
      harmful but which have no proven efficacy in promoting hair growth or preventing
      further hair loss. Hair systems and surgery provide camouflage for the symptoms
      but do not effect a cure. By far the most promising approaches to the treatment
      of AGA are drug therapies, such as minoxidil and finasteride. Finasteride, an
      inhibitor of the type II 5alpha-reductase that converts testosterone to
      dihydrotestosterone, has been shown to prevent further hair loss, and promotes
      new hair growth in the majority of the men taking part in clinical trials.
      Tailored drug approaches like this offer the greatest hope for the successful
      future treatment of AGA.

PMID- 10586126
TI  - Etretinate therapy for papuloerythroderma.
AB  - Papuloerythroderma, first reported by Ofuji et al. (1984), is a rare cutaneous
      disorder whose pathogenesis remains unknown. Owing to the small number of cases,
      there is no recommended choice of treatment. This is the first report on the
      efficacy of etretinate for papuloerythroderma. Seven male cases ranging in age
      from 65 to 84 years were treated with moderate doses (0.2-0.6 mg/kg/day) of
      etretinate. All but one case showed quick and excellent responses and the chronic
      recalcitrant erythrodermatous lesions disappeared within 2-5 weeks. Eventually
      all the seven cases could be brought into remission. Once remission was achieved,
      etretinate was tapered by 0.1-0.2 mg/kg/day over a period of 2-4 weeks. One case
      remained in complete remission after cessation of etretinate without any
      treatment for 16 months. Another case could stop etretinate treatment and the
      subsequent recurrence of papular eruption could be managed by topical steroids.
      In the other five cases remission could be maintained by daily doses of 0.16-0.36
      mg/kg etretinate. None of the patients developed severe side effects. Our
      observation suggests that etretinate is a safe and effective agent for
      papuloerythroderma.

PMID- 10586127
TI  - Short-term cyclosporin monotherapy for chronic severe plaque-type psoriasis.
AB  - Cyclosporin is an effective treatment for psoriasis but its efficacy is only
      palliative. The aim of this study was to evaluate the percentage of patients in
      whom a short term therapy may be used without relapse after discontinuation of
      cyclosporin. In this multicenter, open, non-controlled study fifty-eight patients
      were included who had severe and extensive chronic plaque-type psoriasis.
      Treatment duration was 28 weeks. The absence of relapse was defined as the
      requirement to resume systemic treatment at 16 weeks after discontinuation of
      Sandimmun . The overall efficacy of Sandimmun at W20 was 72%. No relapse or
      premature withdrawal occurred in 18 cases out of 39 (47%). In these cases local
      treatment was sufficient following discontinuation. Thus we show the potential
      value of a single 5 month course of cyclosporin treatment. In this study tapering
      of cyclosporin was not useful. In 50% of cases short-term cyclosporin treatment
      was not followed by resumption of systemic treatment and constitutes an
      improvement in qualify of life.

PMID- 10586128
TI  - Focal dermal hypoplasia (Goltz-Gorlin syndrome) associated with obstructive
      papillomatosis of the larynx and hypopharynx.
AB  - A 14-year-old girl with focal dermal hypoplasia (Goltz-Gorlin-syndrome) presented
      with dysphagia, hoarseness, inspiratory stridor, intermittent dry cough and a 10%
      weight loss. Endoscopy showed that these symptoms were caused by papillomatosis
      of the hypopharynx and the larynx. The papillomatous masses were resected
      subtotally by endoscopic laser treatment. Residual papillomas were left in the
      subglottic space but tracheotomy could be avoided. Complete clinical recovery
      with adequate weight gain as well as, resolution of dyspnoe and dysphagia
      resulted after the intervention. Histological examination did not show
      morphological signs of human papilloma virus as an etiological agent.

PMID- 10586129
TI  - Familial nevoid sebaceous gland hyperplasia affecting three generations of a
      family.
AB  - Familial sebaceous gland hyperplasia is a benign entity with onset at puberty and
      a tendency to worsen with age. It is characterized by a nevoid symmetric pattern
      in the sebaceous areas of the face sparing the orbital, perinasal, preauricular
      and perioral areas showing prominent follicular openings and interfollicular
      dermal yellowish or white prominent skin. Usually, the face is affected, with the
      neck, column and thorax affected in a milder pattern. We describe a family with
      familial nevoid sebaceous gland hyperplasia in three consecutive generations. All
      the patients were successfully treated with oral isotretinoin. The pedigree
      suggests autosomal dominant inheritance with incomplete penetrance.

PMID- 10586131
TI  - Enhanced expression of SCF in the dermis is a prognostic factor for the
      regression of urticaria pigmentosa.
AB  - Urticaria pigmentosa (UP) is a disorder of mast cell proliferation that occurs in
      cutaneous tissue. Most patients whose skin manifestations appear in infancy or
      childhood, experience a resolution of the disease by adolescence. In order to
      elucidate the relationship between mast cell character and UP prognosis, we used
      an immunohistochemical approach to examine the expression of stem cell factor
      (SCF) and c-Kit in the skin of patients with UP. The results revealed
      intercellular SCF expression throughout the dermis in improving cases. On the
      other hand, in cases with a tendency to worsen, dermal SCF was recognized only
      partially or not at all. Regardless of the clinical course, intracellular SCF
      immunoreactivity of the entire epidermis increased in cases of child onset UP.
      The c-Kit expression of mast cells in all UP patients showed no relation to
      clinical features. These findings suggest that SCF in the dermis promotes the
      differentiation of mast cells infiltrating in UP, and might be an attractive
      candidate to induce the remission of UP.

PMID- 10586130
TI  - Partial amino acid sequence of an amyloid fibril protein from unusual cutaneous
      cystic lesions in myeloma-associated amyloidosis.
AB  - Although common cutaneous lesions in myeloma-associated systemic amyloidosis are
      petechiae, purpura, ecchymoses, plaques, waxy, translucent or purpuric papules or
      nodules, we encountered an unusual case of myeloma-associated amyloidosis with
      multiple cystic nodules. We isolated amyloid substance from the cutaneous cystic
      nodules of this patient and characterized it ultrastructurally, immunologically,
      and biochemically. Electron microscopy demonstrated that amyloid substances
      isolated by distilled water were principally straight and non-branching fibrils
      with a diameter of 8 to 10 nm, which was morphologically similar to amyloid
      fibrils. SDS-PAGE showed that these fibrils consisted of the 20 kDa and 29 kDa
      peptides, which reacted with the antibody to kappa light chain of immunoglobulin
      by immunoblot study. Partial amino acid sequence of N-terminal residues of this
      20 kDa peptide showed a homology to kappa immunoglobulin light chain of variable
      subgroup I. These results suggest that amyloid fibrils in this unusual case with
      cutaneous cystic nodules may be derived from kappa I light chain of
      immunoglobulin.

PMID- 10586132
TI  - Onychomycosis: predisposed populations and some predictors of suboptimal response
      to oral antifungal agents.
AB  - The population groups predisposed to onychomycosis and factors associated with a
      poor response to antifungal therapy may be subdivided into (a) genetic, (b)
      environmental, (c) systemic conditions, (d) local nail characteristics, and (e)
      other miscellaneous items. By paying attention to the scenarios that may lead to
      a suboptimal response to the therapy and a higher probability of relapse of the
      onychomycosis, it may be possible to improve the overall cost-effectiveness of
      treatments for onychomycosis. Besides attempting to achieve a cure when treating
      onychomycosis it is important to take steps to prevent reinfection with fungal
      organisms.

PMID- 10586133
TI  - Treatment of Ota's nevus by Q-switched alexandrite laser : therapeutic outcome in
      relation to clinical and histopathological findings.
AB  - Ota's nevus is a dermal melanocytic disease which causes serious cosmetic
      problems for affected individuals. Recently Q-switched lasers with a pulse
      duration of 100 nsec or less became available for patient treatment. We evaluated
      the clinical efficacy of the Q-switched alexandrite laser (755 nm, 100 nsec) in
      relation to the histopathological findings. Fifty-five Korean patients with Ota's
      nevus were treated with a Q-switched alexandrite laser for three sessions (7.5
      J/cm2) at three month intervals. Skin biopsies were taken in all of the patients
      before treatment and immediately after treatment in five patients. Clinical
      effectiveness and side effects were evaluated by direct observation and
      photographs. Pigment clearing was excellent in 27 patients (49%), good in 17
      patients (31%), fair in 7 patients (13%) and poor in 4 (7%) patients.
      Postinflammatory hyperpigmentation developed in 30 patients (55%) which resolved
      within four months. But there were no serious complications including scarring or
      textural change. The therapeutic outcome was not affected by color but by depth
      of the nevus. Nevi of Ota with depth of 1 mm or less were associated with
      excellent or good results. Q-switched alexandrite laser is a very effective and
      safe tool for treating Ota's nevus. Depth of 1 mm or less of dermal melanocytes
      was a good prognostic marker.

PMID- 10586134
TI  - Subcorneal pustular dermatosis and IgA lambda myeloma: a uncommon association but
      probably not coincidental.
AB  - The present report deals with a case of subcorneal pustular dermatosis (SCPD)
      associated with IgAlambda myeloma and reviews the literature for similar cases.
      Three relevant points arise from this case: the association of the dermatosis
      with an IgAlambda myeloma that, as far as we know, has been described only three
      times previously; the longest period of time between the onset of the dermatosis
      and that of the myelopathy observed up to now; the good therapeutic response to
      etretinate, useful in the management of severe recalcitrant forms of SCPD.

PMID- 10586135
TI  - Papular elastolytic giant cell granuloma: a clinical variant of annular
      elastolytic giant cell granuloma or generalized granuloma annulare?
AB  - A 71-year-old man with asymptomatic red papules on the trunk and upper arms was
      reported as a case of papular elastolytic giant cell granuloma. A skin biopsy
      specimen from a papule on the back showed similar findings to those of annular
      elastolytic giant cell granuloma. However, centrifugal annular lesions were not
      clinically observed. He was successfully treated with tranilast and topical
      steroids.

PMID- 10586136
TI  - Cutaneous manifestation of left atrial myxoma.
AB  - A 53-year-old woman had a left hemiplegia with suspicion of cerebral metastases.
      Thoracic and abdominal computed tomography revealed renal and splenic infarction
      features and she presented violaceous papulosis on her fingers corresponding to
      thrombosis of dermal vessels. Echocardiography showed a left atrial tumor evoking
      myxoma. The clinical features of left atrial myxomas are intracardiac
      obstruction, extracardiac embolism and general symptoms. Cutaneous manifestations
      are frequently reported and can correspond to cutaneous manifestations of emboli,
      symptoms related to auto-immune disorders and specific cutaneous findings that
      suggest atrial myxoma as part of more complex syndromes.

PMID- 10586137
TI  - Tongue necrosis provoked by ergotamine tartrate and disclosing a giant cell
      arteritis.
AB  - A case of tongue necrosis induced by ergotamine tartrate is reported in a patient
      who was suffering from an unknown giant cell arteritis (GCA). The role of
      ergotamine in provoking tongue necrosis in temporal arteritis has only
      infrequently been considered. The hypothesis concerning ergotamine-induced
      vasospasm potentially being able to trigger a tongue necrosis in GCA is supported
      by the present case. This unusual complication warns us against uncritical
      prescription of this drug for elderly people suffering from migraine without
      considering GCA.

PMID- 10586138
TI  - Drug-induced urticaria and angioedema caused by non-IgE mediated pathomechanisms.
AB  - Urticaria and angioedema may be elicited by a considerable number of drugs,
      particularly nonsteroidal antiinflammatory drugs, angiotensin converting enzyme
      inhibitors, radiocontrast media and antibiotics. Pathogenic mechanisms involved
      include pseudoallergy, idiosyncrasy and IgE-mediated hypersensitivity,
      occasionally also IgG antibodies. In this survey the common problems which still
      lack established diagnostic in vitro tests such as pseudoallergic reactions to
      analgesic drugs and idiosyncratic side effects to angiotensin-converting-enzyme
      inhibitors are presented. In addition some examples of drugs are given where, due
      to progress in research, instead of a pseudoallergic mechanism an immunological
      pathogenesis could be demonstrated.

PMID- 10586139
TI  - Stefanie jablonska, the iron lady of warsaw
AB  - Among the founders of immuno-dermatology, a prominent place is occupied by
      Stefanie Jablonska, Professor of Dermatology in Warsaw. Despite all the
      difficulties which her country has known, she has been able to work, train many
      students, travel the whole world over and survive all the crises. She is always
      on the go and the years have left no mark on her. From the time of my nomination
      as Professor of Dermatology I had occasion to see her at the Hopital St-Louis
      where the monthly meetings united many French and foreign dermatologists. From
      our first contact we got on well. She attended certain of my lectures, criticized
      with interest and supported the beginnings of my career. She believed that
      dermatology could no longer be content with clinical description, which was where
      the French reputation in dermatology lay. It was now necessary to give a larger
      role to biological research. And this is what I tried to do in adding a research
      laboratory to the clinical service I directed.

PMID- 10586140
TI  - Home hygiene: a reemerging issue for the new millennium.

PMID- 10586141
TI  - Impact of changing societal trends on the spread of infections in American and
      Canadian homes.
AB  - Infectious diseases continue to exert a heavy toll on human health even in
      industrialized countries. Recent data from the World Health Organization suggests
      that infectious diseases are the leading cause of death in the world. Many
      changing trends in our society have a known or potential impact on infectious
      disease spread and may have an impact on the normal routine of home hygiene.
      Important amongst these societal trends are increasing population and life
      expectancy, changes in urbanization, grouping of susceptibles, increased
      ambulatory and home care, increased immunosuppression, increased and faster
      travel, changes in technology, increasing antibiotic resistance as a result of
      misuse of antibiotics, changes in food and water consumption, and changes in
      personal cleaning, washing, and laundry practices. This review will highlight
      these factors and their impact on home hygiene and steps that may be needed to
      reduce the risk from infections.

PMID- 10586142
TI  - Hygiene issues in the home.
AB  - There is a growing recognition of the involvement of the home in several public
      health and hygiene issues and of the need to promote effective hygiene practices
      for the home. Hygiene practice in the home includes the categories of personal
      hygiene, food hygiene, environmental or surface hygiene, and home health care.
      This article reviews some of the hygiene risks in the home, including the role of
      cross-contamination via inanimate surfaces and outlines hygiene strategies and
      guidelines for the home as a means of breaking the chain of cross-contamination.

PMID- 10586143
TI  - A risk assessment framework for the evaluation of skin infections and the
      potential impact of antibacterial soap washing.
AB  - Antibacterial soaps may have an important role in the control of skin infection.
      However, quantitative estimation of their benefit is difficult because of the
      problems associated with conducting epidemiologic studies. An alternative benefit
      estimation approach, quantitative microbial risk assessment, has application to
      this problem. This article sets forth the quantitative microbial risk assessment
      method and applies it specifically to the estimation of the reduction in risk of
      dermal infection from Staphylococcus aureus resulting from use of antibacterial
      soaps. A dose-response model was formulated by using available information on
      growth kinetics of the organism on the skin and dose data based on the
      inoculation of the forearm skin in volunteers. A predictive relationship for
      microbial growth on the skin was developed. These data were limited, and clearly
      more studies are needed on inoculation at more than one site and growth leading
      to infection on the skin with and without the use of germicidal soaps.However, by
      using relationships based on extant data sets, it was estimated that the use of
      germicidal soap could result in a substantial reduction in the risk of infection
      by S aureus. The estimated risk reduction was in general concordance with
      published results from epidemiologic studies conducted on military cadets. The
      methodology of quantitative microbial risk assessment has thus been shown to be
      applicable to this problem and may have broader applicability in other personal
      hygiene contexts.

PMID- 10586144
TI  - Use of quantitative microbial risk assessment for evaluation of the benefits of
      laundry sanitation.
AB  - The goal of this study was to evaluate the risk assessment process for
      quantifying the contribution of contamination in the home to microbial
      infections. Whereas risks of enteric pathogens spread through food has been
      assessed, the spread of fecal-oral pathogens through surfaces likely at low rates
      would be difficult to address through epidemiologic studies. An alternative is
      quantitative risk assessment. The 4-step process of hazard identification, dose
      response, exposure assessment, and risk characterization can be used; however,
      exposure assessment may follow a complicated pathway consisting of survival and
      transference. Microbial hazards in the home have focused primarily on enteric
      bacteria. Dose-response data are available; however, the transfer from the hands
      to the dose is uncertain. Through day care studies, Shigella has been shown to be
      transferred in this manner, and a dose-response model is available. By using
      these data and information on the transference of bacteria between clothing and
      hands, risk estimates were made for contaminated laundry. Risks were calculated
      as high as 10 per million population to much lower levels associated with lower
      excretion rates of the bacteria in the feces. Approximately a 90% and 99%
      reduction in the probability of disease through laundering and use of a
      sanitizing detergent, respectively, were suggested by the models. Better data are
      needed on incidence of disease in the population, excretion rates over the course
      of an infection, amount of feces spread in the home, distribution of bacteria,
      survival, and the transfer of the bacteria from surfaces to the hands and to the
      mouth.

PMID- 10586145
TI  - Bioterrorism: media hype or real potential nightmare?

PMID- 10586146
TI  - Centers for disease control and prevention bioterrorism preparedness and
      response.

PMID- 10586147
TI  - An ounce of prevention is worth a pound of cure-shoring up the public health
      infrastructure to respond to bioterrorist attacks.
AB  - US public health departments must be prepared for the possibility of a biological
      terrorist event. Readiness means not only making sure our national security
      systems are adequate and vigilant, but that public health has the ability and
      resources to rapidly identify, investigate, and control the consequences of a
      terrorist event. Preparing for a bioterrorist attack will also improve public
      health's ability to address infectious disease outbreaks, food safety concerns,
      and environmental hazards.

PMID- 10586148
TI  - Overview of bioterrorism readiness plan: a template for health care facilities.

PMID- 10586149
TI  - Risks of publicity about bioterrorism: anthrax hoaxes and hype.

PMID- 10586150
TI  - Methodologies used in surveillance of surgical wound infections and bacteremia in
      Australian hospitals.
AB  - BACKGROUND: The prevalence of nosocomial infection in Australian hospitals is
      estimated to be between 5.5% and 6.3%. Since 1989, infection control
      professionals (ICPs) in hospitals accredited by the Australian Council on Health
      Care Standards (ACHS) have been encouraged to collect nosocomial infection data
      according to ACHS methodology. METHOD: In 1996, we surveyed members of the
      Australian Infection Control Association to examine the time spent on
      surveillance, the practice of surveillance of all hospital infections (hospital
      wide surveillance), case-finding methods, case definitions, and reporting
      routinely used by ICPs in acute care hospitals. We also examined the ICPs'
      education and experience in infection control (IC). RESULTS: The survey was
      completed and returned by 65% (644 of 993) of Australian Infection Control
      Association members. Of the ICPs who completed the survey, 47.8% (308 of 644; 95%
      CI, 43.9%-51.7%) met the criteria for inclusion, because they coordinated an IC
      program in an acute care or surgical hospital and performed surveillance for
      either surgical wound infection, intravascular device-related bacteremia, or non
      device-related bacteremia. Of the ICPs who reported their facility's
      accreditation status, 93.5% participated in ACHS system. Most (97.6%) ICPs had
      completed hospital-based general registered nurse training. Only 1.9% (6 of 308)
      of ICPs reported completion of continuing education relating to hospital
      epidemiology. The number of years of IC experience ranged from zero to 35 years,
      with a median of 4 years. ICPs spent a substantial proportion of their total
      weekly IC time on surveillance irrespective of ACHS accreditation; 19.5 hours in
      ACHS hospitals and 15.6 hours in non-ACHS hospitals (P =.33). More than three
      quarters (76.0%) of ICPs performed hospital-wide surveillance. The case-finding
      methods, definitions of infections, and reporting formats varied greatly. The
      definition most commonly applied by ICPs (6.8%; 95% CI, 4.1%-10.4%) to define
      surgical wound infection was infection within 30 days after the operative
      procedure, plus purulent drainage, plus isolation of organisms from a culture
      from the incision site, plus diagnosis by a medical officer. A 5-item definition
      of a patient being asymptomatic, plus afebrile on admission, plus infection
      occurring at least 48 hours after admission, plus the patient having a fever of
      >38 degrees C, plus a recognized culture from one or more bottles was used by
      15.7% (95% CI, 11.3%-21.0%) of ICPs to define a case of bacteremia. CONCLUSION:
      Surveillance is the core business of Australian ICPs and consumes a substantial
      proportion of their time. The importance of surveillance, the epidemiologic
      limitations of the current ACHS system, and the nonstandard methods we report
      indicate that improved methodology is required for case finding and reporting of
      nosocomial infections. Australian ICPs should complete training in the principles
      of surveillance and epidemiology. With this training, ICPs can work
      collaboratively with other health care professionals to develop epidemiologically
      sound, local, nosocomial surveillance systems and lobby for a voluntary,
      national, standardized, risk-adjusted system of targeted nosocomial surveillance.

PMID- 10586151
TI  - Vancomycin use in pediatric neurosurgery patients.
AB  - OBJECTIVE: The objective of this article is to describe a pediatric neurosurgery
      patient population receiving vancomycin and examine the indications for and
      appropriateness of vancomycin use. METHODS: A cross-sectional study was performed
      on the pediatric neurosurgery patients at Egleston Children's Hospital who
      received vancomycin from January 1 through December 31, 1996. Vancomycin use was
      compared with the Centers for Disease Control and Prevention Hospital Infection
      Control Practices Advisory Committee recommendations for vancomycin use. RESULTS:
      Thirty patients received 115 doses of vancomycin. The median patient age was 8.0
      years, and 17 (56.7%) were male. Vancomycin was used for prophylaxis in 28
      (93.3%) patients and empiric therapy in 3 (10.0%) patients; one patient received
      vancomycin for surgical prophylaxis followed by empiric therapy for suspected
      meningitis. Vancomycin prophylaxis was initiated after the incision in 6 (21.4%)
      patients and was continued as prophylaxis for more than one dose in 26 (92.9%)
      patients. CONCLUSIONS: Vancomycin was used primarily as surgical prophylaxis in
      pediatric neurosurgery patients, and use was not consistent with the Hospital
      Infection Control Practices Advisory Committee recommendations. These data
      suggest that for certain subpopulations, such as pediatric neurosurgery patients,
      there is a need for more specialized recommendations. Furthermore, prudent
      vancomycin use is warranted to successfully decrease the risk of further
      emergence of vancomycin resistance. Because vancomycin use may be prevalent in
      this population, assessment of vancomycin use in pediatric neurosurgery patients
      followed by establishment of vancomycin clinical guidelines may help improve the
      appropriateness of vancomycin use in this population.

PMID- 10586152
TI  - A prospective, randomized, controlled trial comparing transparent polyurethane
      and hydrocolloid dressings for central venous catheters.
AB  - BACKGROUND: This study was undertaken to determine the frequency of skin
      colonization, hub colonization, and central venous catheter colonization in
      transparent hydrocolloid versus standard polyurethane dressings. METHODS: Adult
      patients requiring the insertion of a multilumen central venous catheter in an
      intensive care unit were randomized to receive either a standard polyurethane
      dressing or a transparent hydrocolloid dressing. Cultures were obtained from 125
      skin insertion sites, 141 catheter hubs, 128 catheter tips, and blood samples
      from 132 patients. Extensive data on patient and catheter characteristics were
      collected. RESULTS: Skin and hub cultures revealed no significant difference in
      degree of colonization. However, the hydrocolloid group had a significantly
      higher level of catheter colonization than the polyurethane group (P =.048).
      Conversely, there was a significantly higher frequency of positive blood cultures
      in the polyurethane group (P =.03), although the majority were considered to be
      potential contaminants. There were only 6 cases in which the same species was
      simultaneously isolated from a positive blood culture and a colonized catheter, 5
      from the hydrocolloid group and 1 from the polyurethane group. CONCLUSIONS: The
      results of this study suggest that an increased risk of catheter colonization is
      associated with the use of hydrocolloid dressings, despite previous research
      suggesting that they significantly reduce microbial growth compared with standard
      polyurethane. The clinical significance of increased numbers of positive blood
      cultures in the polyurethane group requires further examination, although
      distinguishing between contamination and true infection in intensive care
      settings continues to be methodologically challenging. Further studies are
      required to determine whether these findings are generalizable across different
      study settings and whether similar outcomes are obtained when different brands of
      hydrocolloid dressing are used.

PMID- 10586153
TI  - Emerging infectious diseases and professional integrity: thoughts for the new
      millennium.
AB  - The challenges of infection control can put the professional in conflict with
      political, legal, or administrative authorities. What is likely to be effective
      infection control policy may not be popular institutional policy. Economic
      implications of an outbreak investigation or infection control strategy may
      dominate a debate that should be informed by the greatest good for the public.
      Privacy concerns, legal liability fears, economic disincentives, and failures to
      confront issues that are embarrassing for the institution inhibit public health
      professionals whose helpful insights can protect the public health only when
      accompanied by policy change. We discuss key issues that can inhibit effective
      infection control responses, highlighting that personal and professional
      integrity is as vital a feature of disease control in the new millennium as it
      has been throughout the history of infection prevention and control.

PMID- 10586154
TI  - Interdisciplinary group advises the National Institute of Nursing Research on
      research opportunities for controlling emerging infections.

PMID- 10586155
TI  - Global consensus conference: final recommendations.

PMID- 10586156
TI  - Certification in infection control and epidemiology-a celebration of 15 years!
AB  - Certification in infection control has been available since 1983. In this, the
      15th anniversary of the Certified in Infection Control examination, it seems
      appropriate to examine how the program was developed, how it has evolved, and
      future opportunities for Certification in Infection Control and Epidemiology.
      This article was written to provide a brief history and an update on the current
      status of the Certified in Infection Control program.

PMID- 10586157
TI  - National Nosocomial Infections Surveillance (NNIS) System Report, Data Summary
      from January 1990-May 1999, issued June 1999. A report from the NNIS System.

PMID- 10586158
TI  - Chryseobacterium meningosepticum bacteremia secondary to central intravenous line
      related infection.

PMID- 10586159
TI  - Pathophysiology of surgical site infection in total hip arthroplasty.
AB  - This article is a case report of a 69-year-old man who underwent a right total
      hip replacement procedure and developed a surgical site infection. Areas of
      concern in prevention and treatment of hip arthroplasty infection are presented,
      focusing on the pathophysiologic process involved. A review of the patient risk
      factors and the pathophysiologic action potentiating risk for infection include
      host immunity, nutritional status, diabetes, age, use of steroids or
      immunosuppressive drugs, rheumatoid arthritis, and urinary tract or other
      infections. The case report identifies the patient's age, multiple
      instrumentation of the bladder resulting in bacteriuria and the reinfusion of 400
      cc of autologous shed blood via cell saver, a controversial risk subject, as the
      primary risk factors for surgical site infection in this patient. Readmission to
      the hospital on day 16 after the operation was completed on identification of 2
      pathogenic organisms, methicillin-resistant Staphylococcus aureus and
      Acinetobacter calcoaceticus bio anitratus. The infection was successfully treated
      with oral ciprofloxacin and intravenous administration of tobramycin, preventing
      progression from superficial to deep infection and preserving the prosthesis.

PMID- 10586160
TI  - Bacillus cereus infections among oncology patients at a children's hospital.
AB  - BACKGROUND: Bacillus cereus can cause severe infections in immunocompromised
      persons. METHODS: We report 3 cases of bacteremia/septicemia (1 fatal) among
      oncology patients in a children's hospital. Because all cases occurred during a
      10-day period, a common source outbreak was suspected. An epidemiologic
      investigation was performed. Molecular comparison of patient and environmental
      isolates was performed by using pulsed-field gel electrophoresis. RESULTS: After
      an extensive investigation, no common hospital source could be found. Pulsed
      field gel electrophoresis proved that the isolates were not related. CONCLUSION:
      Sporadic infections in immunocompromised persons do occur and can be associated
      with significant morbidity.

PMID- 10586161
TI  - Nosocomial infections in the intensive care units at a university hospital in a
      developing country: comparison with National Nosocomial Infections Surveillance
      intensive care unit rates.
AB  - OBJECTIVE: As a measure of the quality of care provided to patients in the
      intensive care unit, comparison of nosocomial infection rates with those of the
      National Nosocomial Infection surveillance was completed during a 3-year
      observation period. DESIGN: The study design was a prospective study during 3
      years between 1993 and 1995. During that period, patients at the medical/surgical
      and neurosurgical intensive care units and the high-risk nursery were surveyed
      for nosocomial infections. Device use, bloodstream infection, urinary tract
      infection, and ventilator-associated pneumonia nosocomial infection rates were
      calculated and compared with the National Nosocomial Infection Surveillance
      published rates for the same period. SETTING: The study setting was the
      medical/surgical intensive care unit, the neurosurgical intensive care unit, and
      the high-risk nursery at the Jordan University Hospital. RESULTS: Overall
      infection rates were 17.2 per 100 patients in the medical/surgical intensive care
      unit, 14.2 to 18.5 per 100 patients in the neurosurgical intensive care unit, and
      13.4 to 73.5 per 100 patients in the high-risk nursery. When compared with the
      weight of the infants, these rates were 61.9 to 94 per 100 in infants weighing
      <1500 g, 26 to 30.8 per 100 patients in infants weighing >1500 g to 2500 g, and
      11.7 to 14.4 per 100 in infants weighing >2500 g. Whereas device use was
      moderate, bloodstream infection and ventilator-associated pneumonia rates were
      >90th percentile for National Nosocomial Infection Surveillance in the high-risk
      nursery, and urinary tract infection was >90th percentile in the medical/surgical
      and neurosurgical intensive care units. Nosocomial infections at the intensive
      care units in developing countries need further investigation and control.

PMID- 10586162
TI  - Highly active antiretroviral therapy: progress and pitfalls.

PMID- 10586163
TI  - Respiratory syncytial virus and subsequent lower respiratory tract infections in
      developing countries: A new twist to an old virus.

PMID- 10586164
TI  - Zinc, diarrhea, and pneumonia.

PMID- 10586165
TI  - Quality research meets urinary tract infection.

PMID- 10586166
TI  - Noonan syndrome revisited.

PMID- 10586167
TI  - Issues related to subspecialty education: weasel words in action.

PMID- 10586168
TI  - Clinical and immuno-virologic characterization of the efficacy of stavudine,
      lamivudine, and indinavir in human immunodeficiency virus infection.
AB  - Clinical, virologic, and immunologic outcomes were analyzed in children with
      vertically transmitted human immunodeficiency virus (HIV) infection (n = 25) and
      clinical symptoms and evidence of immunosuppression to establish the efficacy of
      18 months' treatment with stavudine, lamivudine, and indinavir. Children were
      naive for treatment with protease inhibitors and lamivudine and had minimal
      exposure to stavudine. At 1, 6, 12, and 18 months, the proportions of patients
      with HIV-RNA <400 copies/mL were 79%, 100%, 94%, 87% in Centers for Disease
      Control and Prevention (CDC) immunologic class 2 and 50%, 67%, 67%, 72% in CDC
      immunologic class 3. At 12 months, the median CD4(+) count and percent increased
      significantly in both CDC immunologic class groups, but to a greater extent in
      the class 3 group. In the 12- to 18-month period, there were no significant
      changes within the groups. In both groups there was a steady increase in the
      proportion and number of children with positive skin test responses. Children in
      class 2 were more likely to have a positive delayed-type hypersensitivity
      response and a greater number of positive responses. Lymphocyte proliferative
      response to recall antigens improved significantly in all patients. The rate of
      increase in positive test results was faster in children in class 2 than in those
      in class 3. Only minor clinical events occurred during 18 months of therapy.
      Potent antiretroviral therapy achieves a sustained benefit in HIV-infected
      children, but immune reconstitution is more likely achieved in children with less
      advanced disease.

PMID- 10586169
TI  - Respiratory illness after severe respiratory syncytial virus disease in infancy
      in The Gambia.
AB  - OBJECTIVE: To determine the frequency of later respiratory tract morbidity after
      respiratory syncytial virus (RSV) disease in infancy. DESIGN: Cohort study with
      passive, clinic-based surveillance. SETTING: Outpatient department in The Gambia.
      SUBJECTS: One hundred five children admitted to the hospital with severe RSV
      disease (case cohort), 105 control children matched for age not admitted to the
      hospital during the previous RSV season (control cohort 1), and 102 control
      children born after the RSV season (control cohort 2). MAIN OUTCOME MEASURES:
      Frequencies of pneumonia, wheezing, and hospital admission with acute lower
      respiratory tract infection. RESULTS: Pneumonia was more common in case children
      than in both control groups (adjusted incidence rate ratio [IRR, 95% CI]: 3.80
      [2.73, 6. 10]), as was wheezing (IRR 7.33 [3.10,17.54]), pneumonia or wheezing
      (IRR 3.96 [2.60, 6.04]), and admission with pneumonia or wheezing (IRR 3.40
      [1.87, 6.15]). The incidence rate per 100 child-years for pneumonia in the dry
      season for 12-month-old children was 27 for case patients, 8.1 for control cohort
      1, and 6.51 for control cohort 2. By 3 years of age, the rates had fallen to low
      levels in all groups. CONCLUSIONS: Pneumonia and wheezing are significantly more
      common in children after RSV-associated lower respiratory tract disease than in
      control subjects, but the incidence declines rapidly with increasing age.

PMID- 10586170
TI  - Prevention of diarrhea and pneumonia by zinc supplementation in children in
      developing countries: pooled analysis of randomized controlled trials. Zinc
      Investigators' Collaborative Group.
AB  - OBJECTIVES: This study assessed the effects of zinc supplementation in the
      prevention of diarrhea and pneumonia with the use of a pooled analysis of
      randomized controlled trials in children in developing countries. STUDY DESIGN:
      Trials included were those that provided oral supplements containing at least one
      half of the United States Recommended Daily Allowance (RDA) of zinc in children
      <5 years old and evaluated the prevention of serious infectious morbidity through
      household visits. Analysis included 7 "continuous" trials providing 1 to 2 RDA of
      elemental zinc 5 to 7 times per week throughout the period of morbidity
      surveillance and 3 "short-course" trials providing 2 to 4 RDA daily for 2 weeks
      followed by 2 to 3 months of morbidity surveillance. The effects on diarrhea and
      pneumonia were analyzed overall and in subgroups defined by age, baseline plasma
      zinc concentration, nutritional status, and sex. The analysis used random effects
      hierarchical models to calculate odds ratios (OR) and 95% CIs. RESULTS: For the
      zinc-supplemented children compared with the control group in the continuous
      trials, the pooled ORs for diarrheal incidence and prevalence were 0.82 (95% CI
      0.72 to 0.93) and 0.75 (95% CI 0.63 to 0.88), respectively. Zinc-supplemented
      children had an OR of 0.59 (95% CI 0.41 to 0.83) for pneumonia. No significant
      differences were seen in the effects of the zinc supplement between the subgroups
      examined for either diarrhea or pneumonia. In the short-course trials the OR for
      the effects of zinc on diarrheal incidence (OR 0.89, 95% CI 0.62 to 1.28) and
      prevalence (OR 0.66, 95% CI 0.52 to 0.83) and pneumonia incidence (OR 0.74, 95%
      CI 0.40 to 1.37) were similar to those in the continuous trials. CONCLUSIONS:
      Zinc supplementation in children in developing countries is associated with
      substantial reductions in the rates of diarrhea and pneumonia, the 2 leading
      causes of death in these settings.

PMID- 10586171
TI  - Effect of cranberry juice on bacteriuria in children with neurogenic bladder
      receiving intermittent catheterization.
AB  - OBJECTIVE: To determine the effect of cranberry prophylaxis on rates of
      bacteriuria and symptomatic urinary tract infection in children with neurogenic
      bladder receiving clean intermittent catheterization. DESIGN: Double-blind,
      placebo-controlled, crossover study of 15 children receiving cranberry
      concentrate or placebo concentrate for 6 months (3 months receiving one
      concentrate, followed by 3 months of the other). Weekly home visits were made.
      During each visit, a sample of bladder urine was obtained by intermittent
      catheterization. Signs and symptoms of urinary tract infection and all
      medications were recorded, and juice containers were counted. RESULTS: During
      consumption of cranberry concentrate, the frequency of bacteriuria remained high.
      Cultures of 75% (114 of 151) of the 151 samples obtained during consumption of
      placebo were positive for a pathogen (>/=10(4) colony-forming units/mL) compared
      with 75% (120 of 160) of the 160 samples obtained during consumption of cranberry
      concentrate. Escherichia coli remained the most common pathogen during placebo
      and cranberry periods. Three symptomatic infections each occurred during the
      placebo and cranberry periods. No significant difference was observed in the
      acidification of urine in the placebo group versus the cranberry group (median,
      5.5 and 6.0, respectively). CONCLUSION: The frequency of bacteriuria in patients
      with neurogenic bladder receiving intermittent catheterization is 70%; cranberry
      concentrate had no effect on bacteriuria in this population.

PMID- 10586172
TI  - Congenital heart diseases in children with Noonan syndrome: An expanded cardiac
      spectrum with high prevalence of atrioventricular canal.
AB  - OBJECTIVE: To report the relative prevalence of various forms of congenital heart
      disease (CHD) in children with Noonan syndrome (NS) and to describe anatomic
      characteristics of the subgroup of patients with atrioventricular canal (AVC).
      STUDY DESIGN: Phenotypic and cardiologic examinations were performed in 136
      patients with NS and CHD evaluated at our hospital from January 1986 to December
      1998. Cardiac evaluation included chest x-ray film, electrocardiogram, 2
      dimensional and color Doppler echocardiography, cardiac catheterization with
      angiocardiography, and cardiac surgery. RESULTS: The CHDs classically reported in
      NS, including pulmonary stenosis (39%), hypertrophic cardiomyopathy (10%), atrial
      septal defect (8%), and tetralogy of Fallot (4%), are well represented in our
      series; however, aortic coarctation (9%) and anomalies of the mitral valve (6%)
      may also occur in this syndrome. Moreover, AVC was diagnosed in 21 patients,
      representing 15% of all CHDs in our series. All patients showed a partial form of
      AVC, and an associated subaortic stenosis caused by additional anomalies of the
      mitral valve was detected in 5 of 21 (23.8%) of those patients. CONCLUSION: Left
      sided lesions, such as aortic coarctation and anomalies of the mitral valve, are
      not rare in patients with NS and CHD. Moreover, in this syndrome AVC is quite
      frequent, the partial form is prevalent, and subaortic stenosis caused by
      additional anomalies of the mitral valve may be present. This information should
      be taken into consideration during the cardiologic evaluation of children with
      NS.

PMID- 10586173
TI  - Patterns of cognitive functioning in school-aged children with Noonan syndrome
      associated with variability in phenotypic expression.
AB  - OBJECTIVE: To evaluate the cognitive profiles of children with Noonan syndrome
      (NS) and to relate these profiles to measures of overall clinical severity. STUDY
      DESIGN: Thirty-five children with NS between the ages of 7 and 18 years were
      tested on their intellectual, psychosocial, and academic functioning. The
      diagnosis of NS was established on the presence of a typical face, the
      characteristic heart defect, thorax deformity, short stature, affected first
      degree relative(s), and cryptorchidism in male subjects. RESULTS: The total group
      of children with NS (n = 35) achieved significantly lower mean full-scale IQ,
      verbal IQ (VIQ), and performance IQ (PIQ) scores (between 85.9 and 89.3) than
      expected based on normative data. The individual full-scale IQ scores varied
      between 48 and 130. Because of this wide range of individual scores, the mean
      group values are not extremely informative. The mean full-scale IQ for the group
      with moderate NS (n = 19) is 90.8; for the children with severe NS (n = 16) the
      mean full-scale IQ is 80.6. The patterns of discrepancies between VIQ and PIQ
      are: (1) an extreme discrepancy between VIQ and PIQ is most likely to emerge in
      children with severe NS with (low) average intellectual abilities; (2) children
      with moderate NS are more likely to attain similarities in VIQ and PIQ scores;
      and (3) children with moderate NS demonstrate a particular pattern of discrepancy
      between VIQ and PIQ (ie, VIQ > PIQ). CONCLUSION: For children with NS, the
      findings on physical examination are indicative of the pattern of cognitive
      abilities. NS is not associated with substantial deficits in the level of
      intellectual functioning or with a single/unitary cognitive pattern. Severe NS
      expression, however, predicts in part a specific pattern of deficits and
      capacities in cognitive functioning.

PMID- 10586174
TI  - Diagnosis of congenital toxoplasmosis in the neonatal period: A multicenter
      evaluation.
AB  - OBJECTIVE: To evaluate different laboratory tests used to diagnose congenital
      toxoplasmosis in the neonatal period. STUDY DESIGN: A retrospective multicenter
      study of 294 pregnant women who experienced seroconversion for Toxoplasma gondii
      and subsequently delivered live-born infants. Fetal infection was assessed via
      specific IgM and IgA antibodies (cord and neonatal blood) and detection of T
      gondii in placenta and cord blood by mouse inoculation. RESULTS: Ninety-three
      (32%) of the 294 infants were congenitally infected. The sensitivity of IgA in
      cord blood and in neonatal blood was 64% and 66%; the sensitivity of IgM was 41%
      and 42%, respectively. Mouse inoculation of the placenta and cord blood had
      sensitivities of 45% and 16%. Positive results of the serologic tests in
      congenitally infected children correlated significantly with the gestational age
      at the time of maternal infection but was not significantly influenced by the
      administration of specific antiparasitic treatment during pregnancy. CONCLUSION:
      Specific T gondii IgA antibody is a more sensitive test than IgM for detecting
      congenital toxoplasmosis in the neonatal period. The overall specificity is
      better for serologic tests performed on neonatal blood than for those on cord
      blood. Neonatal screening with IgM or IgA antibodies will not detect the majority
      of children with congenital toxoplasmosis when the maternal infection occurred
      before the 20th week of pregnancy.

PMID- 10586175
TI  - Cow's milk and intestinal blood loss in late infancy.
AB  - OBJECTIVES: Young infants commonly show occult intestinal blood loss when fed
      cow's milk, but in older infants blood loss may be less common. This study
      examined intestinal blood loss in response to cow's milk feeding in normal 7(1/2)
      month-old and 12-month-old infants. STUDY DESIGN: Infants (n = 62) were fed
      formula for 1 month and then pasteurized cow's milk for 2 months. Stools were
      collected for quantitative determination of hemoglobin. Iron nutritional status
      was assessed. RESULTS: Infants fed cow's milk from 7(1/2) months of age showed a
      significant increase in guaiac-positive stools and in stool hemoglobin
      concentration. These effects were largely limited to those infants who had been
      breast fed early in life. Infants fed cow's milk from 12 months of age at
      baseline had greater stool hemoglobin concentrations than 7(1/2)-month-old
      infants, but cow's milk produced no significant increase. In neither age group
      did cow's milk affect iron nutritional status. CONCLUSION: The response to cow's
      milk is attenuated in infants aged 7(1/2) months compared with younger infants.
      By 12 months of age, the response has disappeared entirely. We conclude that the
      gastrointestinal tract of healthy infants gradually loses its responsiveness to
      cow's milk.

PMID- 10586176
TI  - Colonoscopy and technetium-99m white cell scan in children with suspected
      inflammatory bowel disease.
AB  - OBJECTIVES: To determine the utility of the technetium-labeled autologous white
      cell scintigraphy (Tc-WCS) for detecting intestinal inflammation in children with
      suspected inflammatory bowel disease (IBD). Tc-WCS was compared with colonoscopy
      and histologic examination. STUDY DESIGN: Forty-eight children (26 boys; median
      age, 10 years; range, 2-17 years) with symptoms and signs suggesting IBD had
      colonoscopy with exploration of terminal ileum and mucosal biopsies. The scans
      were judged to be abnormal if activity was seen in the gut within the first hour.
      RESULTS: Twenty-one patients had a diagnosis of IBD (Crohn's disease, 13;
      ulcerative colitis, 5; indeterminate colitis, 3); results of scintigraphy were
      positive in 16 and negative in 5 (sensitivity, 76.2%); the latter had a moderate
      degree of intestinal inflammation. In 27 patients, IBD was ruled out. Results of
      scintigraphy were negative in children with non-specific colitis and in those
      with lymphoid hyperplasia of the terminal ileum, whereas results were positive in
      6 of 12 patients with spondyloarthropathy. In children with IBD, there was a
      significant correlation between results of scintigraphy and endoscopy for the
      intensity of inflammation (r = 0.70); however, there was a poor correlation
      regarding the number of involved segments (r = 0.30) because in 16 patients,
      endoscopy revealed additional diseased segments as compared with scintigraphy.
      CONCLUSIONS: A positive Tc-WCS result indicates the presence of an inflammatory
      process of the gut, whereas a negative test result does not rule out intestinal
      inflammation, especially when the latter is of moderate degree. Colonoscopy and
      biopsy are the investigations of choice to establish the diagnosis of IBD and are
      superior to Tc-WCS in assessing topographic extension of IBD.

PMID- 10586177
TI  - Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in
      preterm infants with patent ductus arteriosus.
AB  - OBJECTIVE: To evaluate the effect of intravenous ibuprofen and indomethacin for
      treatment of patent ductus arteriosus (PDA) on mesenteric and renal blood flow
      velocity in preterm infants. STUDY DESIGN: Seventeen mechanically ventilated
      preterm infants (<33 weeks' gestation) with PDA received either 0.2 mg/kg
      indomethacin (n = 8) or 10 mg/kg ibuprofen (n = 9), infused over 15 minutes.
      Mesenteric and renal blood flow velocity were measured by using Doppler
      ultrasonography. RESULTS: Indomethacin caused a significant reduction in
      mesenteric and renal blood flow velocity 30 minutes after drug administration;
      mesenteric and renal blood flow velocity did not return to the pretreatment
      values by 120 minutes. Ibuprofen did not alter blood flow 30 minutes after
      treatment, and blood flow increased 120 minutes after treatment. Mesenteric and
      renal blood flow velocity changes were significantly different between the 2
      treatment groups. CONCLUSIONS: Compared with indomethacin, ibuprofen did not
      significantly reduce mesenteric and renal blood flow velocity.

PMID- 10586178
TI  - Lung symptoms in pseudohypoaldosteronism type 1 are associated with deficiency of
      the alpha-subunit of the epithelial sodium channel.
AB  - OBJECTIVE: To study patients with autosomal recessive pseudohypoaldosteronism
      type 1 and to relate pulmonary disease to gene mutations of the epithelial sodium
      channel (ENaC). STUDY DESIGN: Clinical and laboratory data were collected from 4
      Swedish patients with pseudohypoaldosteronism type 1. The genes for ENaC and
      cystic fibrosis transmembrane conductance regulator were analyzed for mutations
      with methods including DNA sequencing. RESULTS: Three novel mutations were found
      in the alpha-gene of ENaC, 2 frameshifts (1449delC and 729delA) and 1 missense
      mutation resulting in the substitution of leucine for serine 562 in the alpha
      chain (S562L). The 1449delC mutation was found in all patients in either
      homozygous or heterozygous form and seems to be the predominant cause of
      pseudohypoaldosteronism in Sweden. The allele coding for S562L also contained a
      transition converting tryptophan 493 to arginine (W493R), which seems to be a
      rare polymorphism. All patients had pulmonary symptoms to various degrees. The
      bacterial findings resembled, to some extent, those in cystic fibrosis, but
      development of chronic lung disease and progressive decline in lung function were
      not observed. CONCLUSIONS: Genetic deficiencies of the alpha subunit of the ENaC
      are associated with prominent lung symptoms, which are, however, clearly
      different from those in cystic fibrosis.

PMID- 10586179
TI  - Primary hyperoxaluria in infants: medical, ethical, and economic issues.
AB  - OBJECTIVES: Survey on the current medical approach to and the economic issues
      affecting infants with primary hyperoxaluria type 1. METHODS: Questionnaire to
      specialized centers worldwide. RESULTS: Seventy-eight infants were identified:
      44% were of Muslim origin and 56% were not. The consanguinity rate was 76% and
      0%, respectively. Thirty-three percent were treated in developing countries
      (group 1) and 67% in developed countries (group 2). Initial presentation (4.9 +/-
      2.8 months) consisted of failure to thrive (22%), urinary tract infection (21%),
      and uremia (14%). Radiologic findings included nephrocalcinosis (91%),
      urolithiasis (44%), or both (22%). The diagnosis was based on family history,
      tissue biopsy, and urine oxalate level in most patients from group 1 and on urine
      oxalate and glycolate levels, alanine:glyoxalate aminotransferase activity, and
      DNA analysis in patients from group 2. Therapeutic withdrawal was the final
      option for 40% of children; financial reasons were given for 10 of 17 patients
      from group 1 and 0 of 9 from group 2. End-stage renal disease started at 3.2 +/-
      6.4 years of age and was present in half of the patients at the time of
      diagnosis. Fifty-two percent of the patients died: 82% in group 1 versus 33% in
      group 2; 33% of patients who underwent transplantation died versus 71% of those
      who did not. CONCLUSION: The management of primary hyperoxaluria type 1 in
      infants is a major example of the ethical, epidemiologic, technical, and
      financial challenges that are raised by recessive inherited diseases with early
      life-threatening onset. In certain circumstances, oxalosis can be regarded as a
      condition for which therapeutic withdrawal may be an acceptable option.

PMID- 10586180
TI  - Serum anion gap in the differential diagnosis of metabolic acidosis in critically
      ill newborns.
AB  - OBJECTIVES: To determine in critically ill newborn infants (1) the range of the
      serum anion gap without metabolic acidosis and (2) whether the serum anion gap
      can be used to distinguish newborns with lactic acidosis from those with
      hyperchloremic metabolic acidosis. STUDY DESIGN: Umbilical arterial blood gases
      and serum electrolyte and lactate concentrations were measured simultaneously in
      210 samples from 63 infants over the first week of life. Metabolic acidosis was
      defined as a blood base deficit (BD) >4 mmol/L. The anion gap was calculated as
      [Na(+)] - [C1(-)] - [TCO (2)]. Lactic acidosis was defined as a serum lactate
      concentration >2 SD above the mean serum lactate concentration in samples without
      metabolic acidosis. RESULTS: In 89 blood samples with BD <4 mmol/L, serum lactate
      concentration decreased with postnatal age (r = 0.51). The upper limit of serum
      lactate concentration was 3.8 mmol/L at less than 48 hours, 2.4 mmol/L between 48
      and 96 hours, and 1.5 mmol/L for infants greater than 96 hours of age. The mean
      serum anion gap +/- 2 SD in 174 samples without lactic acidosis was 8 +/- 4
      mmol/L; in 36 samples with lactic acidosis it was 16 +/- 9 mmol/L (P <.0001).
      Serum anion gap and lactate concentration were poorly correlated for samples
      without lactic acidosis (r = 0.04) but highly correlated in those with lactic
      acidosis (r = 0.81, P <.0001). None of the 85 samples with metabolic acidosis but
      without lactic acidosis had an anion gap >16 mmol/L; only 4 of 36 samples with
      lactic acidosis had an anion gap <8 meq/L. However, 25 of 36 samples with lactic
      acidosis had serum anion gaps of 8 to 16 mmol/L. CONCLUSION: In the presence of
      metabolic acidosis, a serum anion gap >16 mmol/L is highly predictive of lactic
      acidosis; a serum anion gap <8 is highly predictive of the absence of lactic
      acidosis; an anion gap = 8 - 16 mmol/L has no use in the differential diagnosis
      of metabolic acidosis in the critically ill newborn.

PMID- 10586181
TI  - Risk for later school problems in preterm children who do not cooperate for
      preschool developmental testing.
AB  - OBJECTIVE: To determine whether preterm children born at </=32 weeks' gestation
      who did not cooperate for developmental testing at 3(1/2) to 4(1/2) years old
      were more likely to have school problems at 7 to 10 years old than preterm
      children who completed developmental testing. STUDY DESIGN: The McCarthy Scales
      of Children's Abilities were administered to a cohort of 118 preterm children at
      3(1/2) to 4(1/2) years old when they were seen in the neonatal follow-up clinic.
      When these children were 7 to 10 years old, their parents completed the Child
      Behavior Checklist, and the child's teacher completed the Teacher's Report Form.
      RESULTS: Parents returned questionnaires on 105 (89%) children. On the Teacher's
      Report Form, children who were untestable had more somatic complications and more
      attention problems and scored higher on the Total Problems Scale and the
      Internalizing Scale than children who had completed testing. Children who were
      untestable were twice as likely to receive help in school than were children who
      completed developmental testing. CONCLUSIONS: Preterm children born at </=32
      weeks' gestation who do not cooperate for developmental testing at 3(1/2) to
      4(1/2) years old should be examined at school age for evidence of school and
      behavior problems.

PMID- 10586182
TI  - Occurrence and outcome of epilepsy in children younger than 2 years.
AB  - OBJECTIVE: To analyze the occurrence of epilepsy between the ages of 28 days and
      2 years and the outcome of children with the onset of epilepsy at that age. STUDY
      DESIGN: The study included all children who were born between January 1, 1976,
      and December 31, 1986, in an area with a mean annual live birth rate of 5027 and
      who were treated for epilepsy at that age. Follow-up data were gathered from
      medical records and/or with a questionnaire. RESULTS: By age 2 years, 72 children
      had epilepsy, giving a cumulative incidence rate of 1.3 cases per 1000 children
      (95% CI, 1.0-1.6). Thirty-two (97.0%) of the 33 children with cryptogenic
      epilepsy were without medication at the time of the last visit and had been in
      remission for a mean period of 13.0 years (range, 7.4-19.7 years), in contrast to
      only 5 (15.6%) of the 32 children with symptomatic epilepsy (difference, 81.3%;
      95% CI of the difference, 63.0%-91.3%; P <.0001). In the logistic regression
      model, the type of the epilepsy (symptomatic/cryptogenic) was the only variable
      that explained the persistence of epilepsy during the follow-up (P <.05). Thirty
      one (93.9%) of the 33 children with cryptogenic epilepsy were mentally normal, as
      opposed to only 3 (9.4%) of the 32 children with symptomatic epilepsy (difference
      84. 6%; 95% CI of the difference, 66.3%-93.4%; P <.0001). CONCLUSION: The outcome
      of children whose epilepsy starts between the ages of 28 days and 2 years is
      determined by the underlying brain disease, and the outcome is good in
      cryptogenic cases.

PMID- 10586183
TI  - Accuracy of clean-catch urine collection in infancy.
AB  - OBJECTIVE: To compare the accuracy of cultures of urine obtained by clean-catch
      urine (CCU) collection and suprapubic aspiration (SPA) in infants. DESIGN:
      Prospective case series undertaken in a pediatric teaching hospital and
      associated neonatal unit. Fifty-eight paired urine cultures (CCU collection and
      SPA) were obtained from 49 infants with suspected urinary tract infection. The
      primary outcome measure was the presence or absence of significant bacteriuria on
      both CCU collection and SPA; secondary outcome measures were the success of SPA
      with ultrasound guidance compared with aspiration without ultrasound guidance.
      Statistical analysis was done by using a chi(2) test. RESULTS: A false-positive
      rate of 5% and a false-negative rate of 12% were recorded. Sensitivity was 88.9%
      (95% CI 65.3-98.6), and specificity was 95.0% (95 CI% 83.1-99. 4). Ultrasound
      assisted SPA was successful in 26 of 28 patients (93%) and in 13 of 21 patients
      (62%) when SPA was performed without ultrasound (chi(2) = 7.08, P =.008).
      CONCLUSIONS: We conclude that there is a good association in results of culture
      of urine obtained by CCU collection and SPA and would encourage the use of the
      CCU technique.

PMID- 10586184
TI  - Failure of pre-diarrheal antibiotics to prevent hemolytic uremic syndrome in
      serologically proven Escherichia coli O157:H7 gastrointestinal infection.
AB  - A girl had hemolytic uremic syndrome after Escherichia coli O157:H7 infection,
      despite pre-diarrheal administration of an antibiotic that prevented detectable
      intestinal colonization. This report casts doubt on the advisability of
      antibiotic therapy for E coli O157:H7 infections and has implications for our
      understanding of the mechanism of this disorder.

PMID- 10586185
TI  - Decreased levels of nitrosothiols in the lower airways of patients with cystic
      fibrosis and normal pulmonary function.
AB  - Airway S-nitrosothiols (SNOs) are naturally occurring bronchodilators. SNOs,
      nitrate, and nitrite were measured in bronchoalveolar lavage fluid of 23 patients
      with cystic fibrosis (CF) and mild pulmonary disease (aged 6-16 years) and 13
      healthy children (aged 8-15 years). Concentrations of SNOs were decreased in the
      lower airways of patients with CF and mild pulmonary disease (median, range: 0, 0
      320 nmol/L vs 80, 0-970 nmol/L) despite normal levels of the inert nitric oxide
      metabolites nitrate and nitrite (mean +/- SEM: 3.7 +/- 0.5 micromol/L vs 4.8 +/-
      0.9 micromol/L). S-nitrosolation- mediated bioreactivities may be impaired by
      depletion of the CF airway SNO reservoir.

PMID- 10586186
TI  - Congenital heart defects and maternal derangement of homocysteine metabolism.
AB  - Methionine loading tests and folate, vitamin B(6), and vitamin B(12) analyses
      were performed in 27 mothers of children with congenital heart defects. Median
      fasting plasma homocysteine concentrations were significantly higher in the study
      group as compared with 56 control subjects (P =.0001). Maternal
      hyperhomocysteinemia may be a risk factor for congenital heart defects.

PMID- 10586187
TI  - Severe hypoglycemia as a presenting symptom of carbohydrate-deficient
      glycoprotein syndrome.
AB  - We describe clinical, biochemical, and molecular findings in a 2(1/2)-year-old
      girl with a phosphomannose isomerase deficiency who presented with severe and
      persistent hypoglycemia and subsequently developed protein-losing enteropathy,
      liver disease, and coagulopathy. Six months of therapy with mannose
      supplementation resulted in clinical improvement and partial correction of
      biochemical abnormalities.

PMID- 10586188
TI  - Toxicity profile of interferon alfa-2b in children: A prospective evaluation.
AB  - The toxicity of interferon (IFN) alfa-2b therapy was prospectively evaluated in
      53 children treated from 1991 to 1996 in 2 successive studies of IFN alfa therapy
      for severe hemangiomas at Sainte-Justine Hospital. Toxicity was generally mild
      and transient, with grade 1 toxicity occurring in 100% of patients, grade 2
      toxicity in 89%, grade 3 toxicity in 58%, and grade 4 toxicity in 17%. Ten of 43
      patients available for evaluation had an abnormal neurologic examination. Severe
      neurotoxicity in the form of spastic diplegia occurred in one patient. In
      conclusion, IFN alfa therapy is generally well tolerated in children. However, it
      may rarely be associated with severe toxicity and must be used with caution.

PMID- 10586189
TI  - Absence of amiloride-sensitive sodium absorption in the airway of an infant with
      pseudohypoaldosteronism.
AB  - We report the measurement of transepithelial voltage across the nasal epithelium
      in a neonate with pseudohypoaldosteronism (PHA) type 1. A 5-day-old infant was
      seen with hyponatremia, hyperkalemia, and elevated plasma renin and aldosterone
      levels. Sweat Cl(-) concentration was also increased. Measurements of voltage
      showed a basal value of zero and the absence of an amiloride-sensitive voltage.
      However, voltage changed as expected for normal cyclic adenosine monophosphate
      stimulated Cl(-) transport. These data demonstrate the absence of amiloride
      sensitive Na(+) transport across airway epithelia in a neonate with PHA. The
      findings suggest that measurements of voltage could be of value in the diagnosis
      of PHA.

PMID- 10586190
TI  - Intravenous immunoglobulin in neonatal myasthenia gravis.

PMID- 10586191
TI  - Recent advances in experimental microsurgery: the 4th congress of the
      international society for experimental microsurgery (ISEM)

PMID- 10586192
TI  - Evaluation of the longitudinal musculature of segments of the distal colon
      interposed following extended jejunum-ileum resection.
AB  - Several morbid conditions may necessitate extensive intestinal resection, leading
      to short-bowel syndrome. When clinical treatment becomes inefficient, a surgical
      approach is necessary. Distal colon interposition is one of the viable
      techniques. The interposition of colon segments between remnants of the small
      bowel improved lifestyle, increased transit time, and diminished diarrhea. The
      aim of this study is to observe the longitudinal muscular contractions after
      distal colon interposition. Sixteen male Wistar rats (EPM-1) were submitted to an
      80% small bowel resection associated with a partial colectomy of the distal colon
      immediately after the bifurcation of the middle colic artery followed by a 3-cm
      isoperistaltic distal colon interposition. After 70 days, the animals were
      submitted to euthanasia and segments of the jejunum, ileum, remnant colon, and
      interposed colon were prepared for pharmacological tests. The isometric
      contractions were measured by a polygraph. After 30 minutes, the dose/effect
      curves were obtained for both metacholine and barium chloride stimulation through
      the extraluminal surface (serosa). After this period, we observed a significant
      increase in the length, diameter, and thickness of the intestinal wall. Regarding
      the sensibility (pD(2)), no difference was found (interposed colon = 7.21 +/-
      0.2; remnant colon = 7.65 +/- 0.1; remnant jejunum 7.46 +/- 0.1; and remnant
      ileum 7.57 +/- 0.1), even though the animals were submitted to different
      procedures. In relation to the maximal effect (E(max)), the longitudinal muscle
      contraction responses (interposed colon = 11.79 +/- 0.1; remnant jejunum = 15.42
      +/- 0.2; and remnant ileum = 11.48 +/- 0.2) were lower than those of the remnant
      colon (E(max) = 22.42 +/- 0.1). This means that there was a possible adaptation
      of colonic segments to their new location.

PMID- 10586193
TI  - Interleukin-2 receptoralpha gene expression in intestinal allograft rejection.
AB  - This study was undertaken to determine whether the interleukin-2 receptor alpha
      (IL-2Ralpha) coding gene could serve as a genetic marker of intestinal allograft
      rejection. The small bowel graft from Jinbai mice was heterotopically
      transplanted to BALB/c mice. Naive BALB/c mice and BALB/c mice with intestinal
      isografts were used as controls. The mRNA transcription level of the spleen cells
      harvested from the recipients and controls was measured with quantitative reverse
      transcription polymerase chain reaction (Q-RT-PCR) on postoperative day (POD) 3
      and routine pathology was studied in these grafts. The IL-2Ralpha mRNA
      transcription level in untreated allografts was significantly higher than that of
      controls on POD 3, when intestinal allograft rejection was not detected. These
      data suggest that the IL-2Ralpha mRNA transcription level may reflect the early
      cellular immune response and this genetic marker may be of value in monitoring
      intestinal allograft rejection.

PMID- 10586194
TI  - Prolongation of rat heart allograft survival with K(+)ATP-dependent channel
      modulators.
AB  - Controversies exist regarding the immunoregulatory properties of K(+) ATP channel
      modulators. We investigated the effects of aprikalim, a K(+) ATP-dependent
      channels activator, and glibenclamide and gliclazide, two inhibitors of K(+) ATP
      dependent channels, on the prolongation of heart allograft survival in the rat.
      Nine groups (n >/= 5) were involved in this study with the Brown-Norway to Lewis
      rat combination treated with aprikalim, glibenclamide, gliclazide, and/or
      cyclosporine. The results indicate that modulators of K(+) ATP-dependent channels
      can improve the survival of rat heart allograft without interfering with the
      immunosuppressive properties of cyclosporine.

PMID- 10586195
TI  - Outcome of different models of multiorgan transplantation in rats.
AB  - In the PVG (RT1(c)) to DA(RT1(a)) rat combination, liver allografts are
      spontaneously accepted across a complete MHC barrier while cardiac and renal
      allografts are rejected. We postulated that this spontaneous liver acceptance was
      associated with the large quantity of antigen in the transplanted liver. In order
      to test this hypothesis, we have developed three different models of multiorgan
      transplantation: model I, triple heart transplantation; model II, triple kidney
      transplantation; and model III, double heart and double kidney transplantation.
      The results showed that prolongation of heart and kidney allografts was achieved
      with the increasing number of organs transplanted. The models proved reliable and
      useful in transplant immunological studies.

PMID- 10586196
TI  - Feasibility of a porto-intracaval shunt for liver total vascular exclusion in the
      rabbit: preliminary report.
AB  - The animals do not tolerate prolonged caval and/or portal clamping which induces
      negative pathophysiological events such as release of kinins, damage of the
      intestinal mucosa, and bacterial translocation. In human liver surgery, these
      problems have been solved by bio-pump for veno-venous bypass. In order to find a
      simple method to reproduce a veno-venous bypass, we developed the porto
      intracaval shunt and used it in six adult rabbits. The shunt tested was a self
      constructed 7-french polyurethane shunt modeled as an inverted Y. The inferior
      vena cava vein below the diaphragm and below the liver and the portal vein were
      gently dissected. The two longer branches of the shunt were inserted in the cava
      vein, while the remaining branch of the Y shunt was inserted in the portal vein.
      After clamping the hepatic artery, the liver was partially resected in three
      animals and after 60 min the shunt was removed. The insertion of the shunt was
      always easy and the animals tolerated well the procedure and the anhepatic phase.
      Our study has been performed in order to test especially the technical
      feasibility of this shunt in an effort to reduce portal and caval stasis during
      the anhepatic phase of the surgical procedures that require caval and portal
      clamping. The technical feasibility has been obtained but we believe that the
      materials and dimensions of the shunt have to be perfected and adapted depending
      on the size of the cava and portal veins.

PMID- 10586197
TI  - A new vascularized skin transplant model in rats.
AB  - The aim of this work was to develop a vascularized skin transplantation model in
      the rat to allow comparison of the immunological events with those of classic
      free skin grafts and vascularized organ grafts. Seventy-nine syngeneic
      transplants were performed using inbred Wistar and PVG rats to develop the model.
      Epigastric skin flaps were taken with a vascular pedicle of common femoral artery
      and vein and implanted on the back of the neck. The graft vessels were
      anastomosed end-to-end and end-to-side to the recipient common carotid artery and
      external jugular vein with interrupted 10-0 nylon sutures under an operating
      microscope. A high success rate (11 of 11) was achieved in the final method
      developed, with light microscopy confirming normal skin structure in the flaps
      following transplantation. The advantages of the model include comparable skin
      size to that commonly used for nonvascularized skin grafts, while the physiology
      in terms of blood supply is similar to that of vascularized organ grafts; the
      grafts are visible with free access for biopsy; and the size of the graft can
      easily be varied to allow studies concerning antigen load.

PMID- 10586198
TI  - Heterotopic sternum transplant in rats: A new model of a vascularized bone marrow
      transplantation.
AB  - We introduced the heterotopic vascularized sternum transplant as a more simple
      and pure alternative to allogeneic hind limb transplantation for the study of
      bone marrow transplantation. We report the clinical and histopathological
      manifestations after transplantation of syngeneic and allogeneic sternal grafts
      with and without immunosuppression with FK-506. Syngeneic grafts maintained
      normal histology, whereas allografts showed rejection, which was prevented by FK
      506. FK-506-treated allografts developed chimerism that was present throughout
      the observation period. Transplantation of the sternum may be a valuable model to
      study vascularized bone marrow transplantation and its effects on repopulation of
      bone marrow of the host, chimerism, and tolerance.

PMID- 10586199
TI  - Improved techniques for kidney transplantation in the monkey.
AB  - Improved microsurgical techniques for kidney transplantation in the monkey are
      described. The left graft kidney is transplanted to the lower part of abdomen
      with end-to-side anastomoses of renal artery to aorta without a patch of aorta,
      renal vein to inferior vena cava, and end-to-end anastomosis of donor and
      recipient ureter with 8-0 nylon sutures in a bilateral nephrectomized recipient
      monkey. We recently performed 60 kidney transplantations in Vervet monkeys. None
      died of surgery or surgical complications. This reproducible model provides a
      useful tool to test new immunosuppressants and to investigate the mechanism of
      drug-induced tolerance and xenotransplantation in primates as a support to
      clinical trial.

PMID- 10586200
TI  - Significant role of intragraft lymphoid tissues in preventing insulin-dependent
      diabetes mellitus recurrence in whole pancreaticoduodenal transplantation.
AB  - Graft recurrence of insulin-dependent diabetes mellitus (IDDM) was examined.
      Islet transplantation or pancreas-alone transplantation excluding the duodenum
      and peripancreatic lymph nodes was compared with whole pancreaticoduodenal
      transplantation. A Wistar Furth (WF; RT1(u), RT6.2) to major histocompatibility
      complex (MHC)-compatible diabetes-prone (DP; RT1(u), RT6.1 gene carrier)
      biobreeding (BB) rat transplantation model was used. Only DP recipients that had
      been transplanted with whole pancreaticoduodenal grafts were free from IDDM
      recurrence (>60 days postgrafting) when treated with anti-intercellular adhesion
      moluecule-1 (ICAM)-1/leukocyte function-associated antigen-1 (LFA-1) monoclonal
      antibodies (mAbs). In the spleen cells of the DP rats that had accepted
      pancreatic grafts (60 days postgrafting), flow cytometric analysis showed that
      NKR-P1(+)TCRalphabeta(+) (NKT) cells had proliferated markedly, with the
      proportion of 12.8 +/- 1.7% in the total splenic T cells, most of which (86.2%)
      were derived from the donor (RT6.2(+)). By enzyme-linked immunonosorbent assay
      (ELISA), serum interferon gamma (IFN-gamma) was not detected (<13 pg/ml) in all
      rats. However, interleukin-4 (IL-4) was detected as 158.8 +/- 28.0 pg/ml in the
      nonrecurrent DP recipients. These data suggested that to prevent IDDM recurrence
      in the pancreatic graft, the lymphocytes in the pancreaticoduodenal grafts are
      necessary. Also, the donor-derived NKT cells might have some immunoregulatory
      functions with a Th2 deviation.

PMID- 10586201
TI  - Synergistic effect of rapamycin and cyclosporine in prevention of acute kidney
      allograft rejection in the mouse.
AB  - The effect of rapamycin (RAPA) and cyclosporine A (CsA) monotherapy and
      combination therapy was examined in prevention of kidney allograft rejection in
      the mouse. Both drugs were administered orally for up to 14 days in BALB/c (H
      2(d)) to C57BL/6 (H-2(b)) mice strong combination. Six groups were treated with
      RAPA and/or CsA. This study shows that concomitant therapy of RAPA and CsA
      produces strong synergistic interaction in prolonging renal allograft survival in
      mice when compared with monotherapy of RAPA or CsA.

PMID- 10586202
TI  - Intragraft CD45 RO gene expression is an early marker to detect small bowel
      allograft rejection in rats.
AB  - Wistar Furth (WF) intestinal allografts were transplanted into Sprague-Dawley
      (SD) rats. Recipients were randomly allocated into the following groups: (1) no
      treatment; (2) cyclosporine (CsA) 6 mg/kg/day, daily, subcutaneously (s.c.; full
      dose therapy); (3) CsA 3 mg/kg/day, daily, s.c. (half-dose therapy); and (4) CsA
      3 mg/kg/day, daily, s.c. + Tripterygium Wilfordii Hook. WF (TW) 3 mg/kg/day,
      daily, s.c. WF rats with intestinal autografts were used as controls. CD45RO
      intragraft expression and its index (CD45RO/CD45), measured by reverse
      transcription polymerase chain reaction (RT-PCR), were significantly elevated in
      untreated and half-dose CsA-treated allografts as early as postoperative day
      (POD) 4, when rejection of intestinal allografts was not detected by routine
      pathology. Intestinal permeability measured by Tc-DTPA radioassay was
      significantly elevated in untreated allografts on POD 6. Histology showed that
      there was severe rejection in untreated intestinal allografts and mild rejection
      in allografts treated with a half dose of CsA on POD 6. There was a normal CD45RO
      expression, permeability, and histology in intestinal allografts treated with
      either a full dose of CsA or a half dose of CsA + TW. These data indicate that
      CD45RO intragraft gene expression is an early marker to detect intestinal
      allograft rejection in rats.

PMID- 10586203
TI  - Optimizing the management of thrombosis in the antiphospholipid-antibody
      syndrome.

PMID- 10586204
TI  - Combined use of erythropoietin and G-CSF in the treatment of myelodysplastic
      syndromes.

PMID- 10586205
TI  - Erythropoietin plus granulocyte colony-stimulating factor in the treatment of
      myelodysplastic syndromes. Identification of a subgroup of responders. The
      Spanish Erythropathology Group.
AB  - BACKGROUND AND OBJECTIVE: Anemia leading to transfusion is probably the most
      important problem in patients with myelodysplastic syndromes (MDS). Human
      recombinant erythropoietin (rHuEpo) and granulocyte colony-stimulating factor (G
      CSF) have been used to treat patients with anemia of MDS, but fewer than 50%
      respond. The aim of this work was to evaluate the benefit of rHuEpo +/- G-CSF
      treatment and to isolate the response predictive variables in a group of selected
      patients with MDS. DESIGN AND METHODS: A non-randomized multicenter trial was
      carried out in 32 patients with MDS. The inclusion criteria were age >= 18 years,
      refractory anemia (RA) or refractory anemia with ringed sideroblasts, Hb <= 100
      g/L or receiving transfusions and serum erythropoietin <= 250 U/L. These patients
      were treated with subcutaneous rHuEpo (300 U/kg) three times a week for 8 weeks.
      In the case of partial response (PR) or no response (NR) subcutaneosly
      administered G-CSF (1 microg/kg) three times a week was added to the rHuEpo for 8
      more weeks. If the patient achieved complete response (CR) or PR in the second
      phase, he was included in a follow-up phase of 24 weeks in which the dose of
      growth factors was tapered down. Several variables, including the score published
      by the Scandinavian-American group, were used as possible predictive variables.
      RESULTS: An erythroid response was observed in 16 patients (50%); in 12 it was a
      CR and in 4 it was a PR. During the period of rHuEpo administration, 7 CR and 4
      PR (34.4%) were documented. Of the 14 patients in whom G-CSF was added to rHuEpo,
      7 (50%) responded (3 CR and 4 PR). No major side-effects associated with growth
      factors were observed. The multivariate analysis showed that of the different
      variables evaluated only the Scandinavian-American response score was significant
      with a relative probability of response of 11.8 (95% confident intervals: 2.5-53)
      when this score was > +1 (77% of cases responded). In contrast, when this score
      was <= 1 only 15 % of the cases responded. INTERPRETATION AND CONCLUSIONS: Use of
      the Scandinavian-American response score is to be recommended in a patient
      oriented approach to treating MDS cases with the Epo and G-CSF. Treatment with
      rHuEpo and G-CSF is safe, its main drawback being its cost. However, a long-term
      study evaluating the regimen's cost-benefit ratio is warranted.

PMID- 10586206
TI  - Interference of lupus anticoagulants in prothrombin time assays: implications for
      selection of adequate methods to optimize the management of thrombosis in the
      antiphospholipid-antibody syndrome.
AB  - BACKGROUND AND OBJECTIVE: Prolonged anticoagulation aiming at International
      Normalized Ratio (INR) values > 3.0 has been recommended for patients with
      thrombosis and the antiphospholipid-antibody syndrome. We evaluated the influence
      of anticoagulant antibodies in two different prothrombin time (PT) assays carried
      out on plasma from lupus anticoagulant patients on oral anticoagulation. DESIGN
      AND METHODS: INR values obtained with a combined (final test plasma dilution
      1:20) and a recombinant (final test plasma dilution 1:3) thromboplastin were
      compared in 17 patients with persistent lupus anticoagulants (LA) receiving oral
      anticoagulant treatment and monitored for 69.8 patient-years. Doses of
      anticoagulant drugs were always assigned based on the results obtained with the
      combined thromboplastin, aiming at a target INR of 2.5 or 3.0 for patients with
      venous or arterial thromboembolic disease. Paired determinations with both
      reagents were also obtained throughout the study period in 150 patients on stable
      oral anticoagulation but free of antiphospholipid antibodies. Total IgG fractions
      were purified from selected patients to evaluate effect in the two PT assay
      systems. RESULTS: No patient experienced recurrence of thrombosis or major
      bleeding complications (95% confidence interval: 0.1-6.5 per 100 patient-years).
      INR values with the recombinant reagent were significantly higher than with the
      combined reagent in 8 LA patients (mean DINR ranging from 0.17 to 0.54) of the
      degree of anticoagulation was overestimated in all but one LA patients with the
      recombinant reagent when compared to the DINR observed in non-LA patients (-0.64
      +/- 0.42). The anti-cardiolipin IgG titer (r(2) = 0.43, p = 0.004) and the anti
      b(2)GPI IgG titer (r(2) = 0.30, p = 0.023) were positively associated with the
      mean deltaINR observed in LA patients. When added to plasmas with different
      levels of vitamin K-dependent factors, total IgG fractions from 6 LA patients
      with significant overestimation of the INR with the recombinant reagent (mean
      DINR ranging from 0.17 to 0.54, group 1) and from 7 LA patients with mean
      deltaINR < or = 0.0 (ranging from -0.25 to 0.04, group 2) reproduced the effects
      observed ex vivo in the two assay systems. However, when total IgG fractions were
      tested at the same final concentration in the two PT assay systems, there was no
      difference in the clotting times determined with total IgG fractions from group 1
      and group 2 LA patients. Addition of negatively charged liposomes (0.4 and 0.8
      mg/mL final concentrations) to platelet free plasma from LA-free patients on
      stable oral anticoagulation caused a 20% to 48% prolongation of the prothrombin
      time determined with the recombinant reagent. In contrast, no significant
      prolongation of the prothrombin time determined with the recombinant reagent was
      observed upon addition of negatively charged liposomes to plasma from group 1 LA
      patients. INTERPRETATION AND CONCLUSIONS: These results confirm previous
      suggestions of assay-dependency of INR values in LA patients on oral
      anticoagulation. For these patients, accurate INR values may be obtained using
      combined thromboplastin reagents that permit testing at high plasma dilution.

PMID- 10586207
TI  - p190 bcr-abl rearrangement: a secondary cytogenetic event in some chronic myeloid
      disorders?
AB  - BACKGROUND AND OBJECTIVE: A small number of chronic myeloproliferative disorders
      with hematologic features of chronic myelomonocytic leukemia (CMML) or atypical
      chronic myeloid leukemia and Ph1 chromosome with m-BCR rearrangement have been
      reported (p190 CMPD). We report here 3 new cases of p190 CMPD that had unusual
      features. In 2 of the cases the m-BCR rearrangement appeared to be a secondary
      event. DESIGN AND METHODS: Patients were studied by cytogenetic, FISH, and
      molecular biology analyses and followed-up clinically. RESULTS: The first patient
      initially had typical 5q- syndrome, without m-BCR rearrangement. Five years
      later, she developed hematologic features of CMML, with t(9;22) translocation, m
      BCR rearrangement and high levels of p190 BCR-ABL transcript. The second patient
      initially had hematologic characteristics of chronic myeloid leukemia (CML) with
      t(9;22) translocation and m-BCR rearrangement but also other complex cytogenetic
      findings including 17p rearrangement. Monocytosis developed during the course of
      the disease. The third patient initially had agnogenic myeloid metaplasia (AMM).
      Five years later, while the hematologic characteristics were still those of AMM,
      a first karyotype showed a t(9;22) translocation and molecular analysis showed a
      very low level of p190 BCR-ABL transcript. Four years later, the patient
      developed hematologic features of atypical CML with blood monocytosis, t(9;22)
      and much greater (100 fold) p190 BCR-ABL transcript levels. INTERPRETATION AND
      CONCLUSIONS: Our 3 cases and review of the previously published cases show the
      variability of clinical features of p190 positive CMPD. Our results also suggest
      that, at least in some cases, p190 BCR-ABL rearrangement could be a secondary
      event in the course of a myeloid disorder.

PMID- 10586208
TI  - Identification of the Hb Lepore phenotype by HPLC.
AB  - BACKGROUND AND OBJECTIVE: Hb Lepore is a structurally abnormal hemoglobin in
      which the abnormal globin chain is a hybrid or fused globin chain (db). Three
      different Lepore hemoglobins have been identified, differing from each other in
      the point at which the db fusion occurs; Hb Lepore Hollandia (d22/b50), Hb Lepore
      Baltimore (d59/b86) and Hb Lepore Boston (d87/b116). In Spain only Hb Lepore
      Boston and Hb Lepore Baltimore have been identified. Hb Lepore is easily detected
      by electrophoretic and chromatographic studies, whereas the type of Hb Lepore is
      distinguished by chromatography of tryptic peptides of abnormal db chain. In this
      work, we show an easier chromatography technique for identifying the Hb Lepore
      phenotype. DESIGN AND METHODS: Thirteen different unrelated families (23
      patients) from different parts of Spain were studied. The existence of Hb Lepore
      was diagnosed by standard methodology and quantified by ionic exchange HPLC. The
      globin chains were studied by reversed phase HPLC, which showed us the phenotype
      of Hb Lepore; this phenotype was corroborated by a gold standard test using
      molecular biology techniques. The statistical analysis was designed to determine
      the behavior of the quantitative (hematologic) variables using the independent
      variable (Hb Lepore Baltimore or Hb Lepore Boston) categorized by Student's t
      test for independent groups. The distribution of the variable was established
      using theoretical models and the variance homogeneity hypothesis was tested. The
      validity of the hematologic data was estimated by creating a receiver operating
      characteristic (ROC) curve. RESULTS: In the study of globin chains by reversed
      phase HPLC, in 14 patients (8 families) three peaks were eluted; they
      corresponded to a, b and db globin chains. In these cases when DNA was studied by
      PCR followed by digestion with the restriction enzyme Pvu II, the phenotype of Hb
      Lepore was identified as being the Boston variant, whereas in the rest of
      patients (9 in total), the peak identified with hybrid chain globin (db) was not
      present and the molecular study showed that these patients were heterozygotes for
      Hb Lepore Baltimore. INTERPRETATION AND CONCLUSIONS: The study of globin chains
      by reversed phase HPLC is sufficient to know the phenotype of Hb Lepore and thus
      tedious techniques such as chromatography of tryptic digestion product of db
      abnormal chains are not essential, a particularly important consideration in
      those laboratories that do not have the possibility of carrying out molecular
      biology studies. Neverteheless, we should continue to use a gold standard
      molecular biology test in cases of prenatal diagnosis because this technique is
      the most exact and reproducible that we have.

PMID- 10586209
TI  - Allogeneic bone marrow transplantation for secondary leukemia or myelodysplasia.
AB  - BACKGROUND AND OBJECTIVE: Marrow transplantation results in disease-free survival
      for less than one-third of patients treated for secondary leukemia. The objective
      of this report is to review results following allogeneic marrow transplantation
      for treatment of secondary leukemia or myelodysplasia at a single tertiary
      referral center to determine the patient characteristics which lead to better
      survival and lower relapse. DESIGN AND METHODS: The medical records of 99
      patients with secondary leukemia or myelodysplasia transplanted consecutively at
      the Fred Hutchinson Cancer Research Center between 1971 and 1997 were reviewed.
      Prior to development of secondary leukemia or myelodysplasia, the patients'
      original diagnoses were hematopoietic malignancies, solid tumors, aplastic
      anemia, or miscellaneous individual disorders previously treated by chemotherapy
      alone, radiation alone, chemoradiotherapy, or immunosuppressive therapy. At the
      time of transplantation, at each stage of myelodysplasia the numbers of patients
      were 52 with acute myelogenous leukemia (AML), 15 with refractory anemia with
      excess blasts in transition (RAEB-T), 18 with refractory anemia with excess
      blasts (RAEB), 11 with refractory anemia (RA), 1 with refractory anemia with
      ringed sideroblasts (RARS), and 2 with hypoplastic unclassifiable hematologic
      disorders. Sixty-five patients received marrow from an HLA identical or partially
      identical family member, and 34 received marrow from an HLA identical unrelated
      donor after conditioning with chemotherapy and total body irradiation or
      chemotherapy alone. RESULTS: The Kaplan-Meier probability of survival after
      transplantation for all patients was 13%, and by stage of disease was 33% for
      RA/RARS, 20% for RAEB, and 8% for RAEB-T/AML. The probability of relapse for all
      patients was 47%, was 34% for RAEB, and 58% for RAEB-T/AML. None of the patients
      with RA/RARS has relapsed. The overall probability of non-relapse mortality was
      78%, divided equally among infection or organ failure-related causes of death.
      INTERPRETATION AND CONCLUSIONS: The main impediments to long-term survival after
      transplantation for secondary leukemia or myelodysplasia are relapse and
      mortality from infections or organ failure. The survival is better when
      transplantation is done during the early stages of myelodysplasia because it is
      then associated with a lower relapse rate. These data suggest that patients at
      risk of secondary myelodysplasia should be followed prospectively to detect the
      early stages of myelodysplasia, and be considered for transplantation at that
      time.

PMID- 10586210
TI  - Fractionated cyclophosphamide added to the IVAP regimen (idarubicin-vincristine-L
      asparaginase-prednisone) could lower the risk of primary refractory disease in T
      lineage but not B-lineage acute lymphoblastic leukemia: first results from a
      phase II clinical study.
AB  - BACKGROUND AND OBJECTIVE: In a prior study, primary resistant acute lymphoblastic
      leukemia (RES-ALL) was observed in 11 of 176 (6%) adult patients treated with a
      four drug regimen (IVAP), its incidence being higher in T-cell or Philadelphia
      (Ph) chromosome/BCR-ABL rearrangement positive ALL cases with a blast cell count
      >25x10(9)/L (RES-ALL rate 19%, p=0.04). Aiming to minimize this percentage of
      resistant disease, fractionated cyclophosphamide (f-CY) was then added to the
      IVAP regimen. DESIGN AND METHODS: Study 08-96 was a prospective, collaborative
      phase II trial carried out at eight general hospital centers specialized in the
      care of hematologic malignancies. Historical IVAP-treated patients served as a
      retrospective control group. All consecutive, untreated patients (>15 years) with
      a diagnosis of ALL or advanced-stage lymphoblastic lymphoma (LBL) were eligible.
      RES-ALL was defined as the persistence of >5% ALL cells in the bone marrow 28-40
      days after the start of the IVAP regimen (idarubicin 10 mg/m(2)/d on days 1 and
      2; vincristine 2 mg on days 1, 8 and 15; L-asparaginase 6,000 U/m(2) on alternate
      days 3 6 from day 8; prednisone 60 mg/m(2)/d on days 1-21). In the new study, two
      f-CY schedules were sequentially adopted: CY 150 or 75 mg/m(2)/bd, given for 4
      consecutive days before IVAP (f-CY 1200 or 600, expressing total CY dose in
      mg/m(2)). RESULTS: Eighty-eight patients were evaluable (age range 15-74 years,
      blast count 0-240x10(9)/L, 14 T-lineage, 74 B-lineage, 13 Ph/BCR-ABL+). The first
      39 patients received the f-CY 1200 schedule, 22 patients received f-CY 600, and
      the last 27 patients were not given any f-CY. These changes were dictated by the
      results of interim analyses of the f-CY groups (RES-ALL rate not reduced,
      myelotoxicity increased). Altogether, compared with the historical IVAP and no f
      CY groups, the incidence of RES-ALL was not decreased by the addition of f-CY
      1200/600 in B-lineage ALL, regardless of Ph/BCR-ABL expression and blast count.
      However, none of 14 T-ALL cases in the new study had RES-ALL (8 in f-CY groups, 5
      of whom with >25x10(9)/L blast cells), compared to 5/39 (13%, overall) or 4/21
      (19%, with >25x10(9)/L blast cells) among the control cases. Owing to small
      sample size, this difference was not statistically significant. INTERPRETATION
      AND CONCLUSIONS: This preliminary experience suggests that T-ALL may be more
      sensitive than B-lineage ALL to an early therapy including f-CY. The hypothesis
      could be tested in a larger clinical trial.

PMID- 10586211
TI  - Natural history of early chronic lymphocytic leukemia. A single institution study
      with emphasis on the impact of disease-progression on overall survival.
AB  - BACKGROUND AND OBJECTIVE: Criteria for identifying patients with early chronic
      lymphocytic leukemia (CLL) who are likely to progress to a more advanced clinical
      stage rely on results of prospective clinical trials. Is not clear whether these
      same criteria apply to patients followed-up in the setting of clinical practice.
      With the aim of addressing this issue we investigated the clinical outcome of a
      series of patients with Binet stage A CLL. DESIGN AND METHODS: Two hundred and
      four Binet stage A CLL patients observed at a single institution over an 18-year
      period form the basis of this study. Different proposals for subclassifying Binet
      stage A were validated by using our patients as test-set cases. RESULTS: The
      survival of patients with early CLL (i.e., Binet stage A and Rai stage 0) was
      significantly different from that of an age- and sex-matched population. Three of
      4 different criteria for subclassifying stage A (Rai substaging, Montserrat
      criteria, French Group proposal), when applied to our patients, gave similar
      results in terms of sample size, death rate and disease progression (DP) risk.
      The French Group proposal, based exclusively on blood counts and hemoglobin
      levels, was not effective in predicting the risk of DP. Forty-nine (23.5%)
      patients progressed to a more advanced clinical stage (30 to stage B and 19 to
      stage C); the risk of DP was 32.8% at 5 years and 49.6% at 10 years. When
      analyzed as a time-dependent variable (Mantel-Byar method), DP had a clear cut
      impact on overall survival (p < 0.0001). Finally, outlook for survival of
      patients who experienced a change of clinical stage was similar to that of
      patients in that stage at the time of diagnosis. INTERPRETATION AND CONCLUSIONS:
      As many patients are now being diagnosed while asymptomatic and at a younger age
      than previously, an accurate evaluation of prognosis is mandatory in early CLL.
      How prognostic information translates into a policy of early or delayed therapy
      is still unclear. Our results further support a conservative approach for CLL in
      early stage; patients who progress into a more advanced stage have similar
      survival to those in that stage at diagnosis.

PMID- 10586212
TI  - Long-term immune recovery after CD34+ immunoselected and unselected peripheral
      blood progenitor cell transplantation: a case-control study.
AB  - BACKGROUND AND OBJECTIVE: CD34+ stem cell selection induces extensive T-cell
      depletion as a consequence of ex vivo manipulation. The impact of T-cell
      depletion on long-term immunologic recovery after autologous CD34+ peripheral
      blood progenitor cell transplantation (CD34+ PBPCT) is not well characterized. We
      compared the long term immunologic recovery in two groups of patients submitted
      to CD34+ PBPCT or unselected autologous peripheral blood progenitor cell
      transplantation (uPBPCT). DESIGN AND METHODS: Eight patients in both groups were
      closely matched for diagnosis, age, disease status at transplantation and
      conditioning regimen and lymphocyte phenotype was prospectively evaluated during
      long-term post-transplantation follow-up. RESULTS: At a median of 18 months after
      transplantation, CD3+ lymphocyte subset remained below the normal range in both
      groups. CD19+ B lymphocytes subset after CD34+ PBPCT was within the normal range
      in both groups. CD4+ lymphocytes were depressed while the CD8+ lymphocyte subset
      was increased in group A and in the normal range in group B. As a result,
      inversion of CD4/CD8 ratio was documented in both groups. T-activated lymphocytes
      (CD3DR+) and natural killer (CD16/56+) cells were increased in both groups.
      INTERPRETATION AND CONCLUSIONS: Long-term immune recovery appears to be
      unaffected by extensive ex vivo manipulation in this adult population when
      compared to recovery after unmanipulated PBPCT. CD34+ selection, although causes
      an extensive depletion of T lymphocytes in the graft does not represent a risk
      factor for delayed CD4+ recovery late after transplantation. Elevated numbers of
      NK cells and activated T-cells, which have antineoplastic activity, are
      maintained late after autologous CD34+ transplantation.

PMID- 10586213
TI  - Evaluation of the hemostatic function of stored platelet concentrates using the
      platelet function analyzer (PFA-100 ).
AB  - BACKGROUND AND OBJECTIVE: Progressive functional impairment is known to occur in
      platelet concentrates through the storage period. Standardized methods providing
      direct measurement of residual platelet function in stored platelets are lacking.
      The purpose of this study was to determine whether a new platelet function
      analyzer (PFA-100 ) could provide standardized methods for assessing the
      hemostatic capacity of stored platelets. DESIGN AND METHODS: The PFA-100 was used
      to evaluate platelet function in stored platelets. The instrument can process
      citrated whole blood but it is unable to process platelet suspensions.
      Accordingly, the function of platelet concentrates should be measured following
      reconstitution of pseudo-whole blood. The analysis of the results included the
      closure time (sec) and a predictive index, an arithmetical index computed on the
      basis of the instrument's output data: the flow rate, the flow volume, the
      closure time. RESULTS: A final hematocrit of 58+/-2 and a final platelet
      concentration of 230+/-20x10(9)/L were used as standardized operative conditions
      to measure the function of stored platelet concentrates. The closure time (PFA
      CT) and the predictive index (PFA-PI) both resulted to be capable of
      discriminating platelet concentrates with maintained or impaired function. PFA-PI
      was more informative than PFA-CT in terms of description of the residual platelet
      function. Of the two agonists used, epinephrine (EPI) resulted to be particularly
      sensitive for the detection of initial platelet hyporeactivity, whereas adenosine
      5'-diphosphate (ADP) was particularly useful for measuring the residual platelet
      reactivity. INTERPRETATION AND CONCLUSIONS: PFA-CT and PFA-PI can be
      standardized; they provide new information about the hemostatic function of
      stored platelet concentrates and can be used to assess the quality of platelet
      concentrates.

PMID- 10586214
TI  - Cell therapy: achievements and perspectives.
AB  - BACKGROUND AND OBJECTIVE: Cell therapy can be considered as a strategy aimed at
      replacing, repairing, or enhancing the biological function of a damaged tissue or
      system by means of autologous or allogeneic cells. There have been major advances
      in this field in the last few years. This has prompted the Working Group on
      Hematopoietic Cells to examine the current utilization of this therapy in
      clinical hematology. EVIDENCE AND INFORMATION SOURCES: The method employed for
      preparing this review was that of informal consensus development. Members of the
      Working Group met three times, and the participants at these meetings examined a
      list of problems previously prepared by the chairman. They discussed the single
      points in order to reach an agreement on different opinions and eventually
      approved the final manuscript. Some of the authors of the present review have
      been working in the field of cell therapy and have contributed original papers in
      peer-reviewed journals. In addition, the material examined in the present review
      includes articles and abstracts published in journals covered by the Science
      Citation Index and Medline. STATE OF THE ART: Lymphokine-activated killer (LAK)
      and tumor-infiltrating lymphocytes (TIL) have been used since the '70s mainly in
      end-stage patients with solid tumors, but the clinical benefits of these
      treatments has not been clearly documented. TIL are more specific and potent
      cytotoxic effectors than LAK, but only in few patients (mainly in those with
      solid tumors such as melanoma and glioblastoma) can their clinical use be
      considered potentially useful. Adoptive immunotherapy with donor lymphocyte
      infusions has proved to be effective, particularly in patients with chronic
      myeloid leukemia, in restoring a state of hematologic remission after leukemia
      relapse occurring following an allograft. The infusion of donor T-cells can also
      have a role in the treatment of patients with Epstein-Barr virus (EBV)-induced
      post-transplant lymphoproliferative disorders. However, in this regard,
      generation and infusion of donor-derived, virus specific T-cell lines or clones
      represents a more sophisticated and safer approach for treatment of viral
      complications occurring in immunocompromised patients. Whereas too few clinical
      trials have been performed so far to draw any firm conclusion, based on animal
      studies dendritic cell-based immunotherapy holds promises of exerting an
      effective anti-tumor activity. Despite leukemic cells not being immunogenic,
      induction on their surface of co-stimulatory molecules or generation of leukemic
      dendritic cells may induce antileukemic cytotoxic T-cell responses. Tumor cells
      express a variety of antigens and can be genetically manipulated to become
      immunogenic. The main in vitro and in vivo functional characteristics of marrow
      mesenchymal stem cells (MSCs) with particular emphasis on their hematopoietic
      regulatory role are reviewed. In addition, prerequisites for clinical
      applications using culture-expanded mesenchymal cells are discussed PERSPECTIVES:
      The opportuneness of using LAK cells or activated natural killer (NK) cells in
      hematologic patients with low tumor burden (e.g. after stem cell transplantation)
      should be further explored. Moreover the role of new cytokines in enhancing the
      antineoplastic activity of NK cells and the infusion of selected NK in
      alternative to CTL for graft versus leukemia (GVL) disease (avoiding graft versus
      host disease (GvHD) seems very promising. Separation of GVL from GvHD through
      generation and infusion of leukemia-specific T-cell clones or lines is one of the
      most intriguing and promising fields of investigations for the future. Likewise,
      strategies devised to improve immune-reconstitution and restore specific anti
      infectious functions through either induction of unresponsiveness to recipient
      alloantigens or removal of alloreactive donor T-cells might increase the
      applicability and success of hematopoietic stem cell transplantation. (ABSTRACT
      TRUNCATED)

PMID- 10586215
TI  - Invasive pulmonary aspergillosis in a patient with acute myeloid leukemia.

PMID- 10586216
TI  - Liposome encapsulated daunorubicin doubles anthracycline toxicity in cell lines
      showing a non-PGP related multidrug resistance.

PMID- 10586217
TI  - Chronic myeloid leukemia in chronic phase with a partial trisomy 9 mosaicism.

PMID- 10586218
TI  - Refractory pure red-cell aplasia associated with B chronic lymphocytic leukemia
      successfully treated by fludarabine.

PMID- 10586219
TI  - Inappropriate secretion of antidiuretic hormone as the initial sign of central
      nervous system progression of nocardiosis in a patient with chronic lymphocytic
      leukemia.

PMID- 10586220
TI  - Graft-versus-lymphoma effect in a patient with a refractory low-grade lymphoma.

PMID- 10586221
TI  - Rituximab for the treatment of type II mixed cryoglobulinemia.

PMID- 10586222
TI  - Introduction to the Third International Symposium on Charcot-Marie-Tooth
      disorders.

PMID- 10586223
TI  - Overview of Charcot-Marie-Tooth disease type 1A.
AB  - Type 1A CMT disease is most commonly due to a segmental duplication on chromosome
      17p11.2, leading to the presence of an extra copy of the gene for peripheral
      myelin protein 22 (PMP22). Inheritance is autosomal dominant in pattern. Analysis
      of nerve biopsies suggests that the disorder is caused by increased gene dosage.
      Occasionally CMTIA results from point mutations in the PMP22 gene. Onset of
      symptoms in cases with a duplication is usually in the first decade of life;
      slowing of nerve conduction velocity is evident from the age of 2 years. Active
      demyelination is restricted to childhood. It leads to hypertrophic "onion bulb"
      changes and is accompanied and followed by progressive axonal loss. The commonest
      clinical phenotype is the CMT syndrome with distal muscle wasting and weakness,
      tendon areflexia, usually mild sensory loss, and foot deformity. Other phenotypes
      include the Roussy-Levy syndrome, in which postural tremor and ataxia are
      associated, and cases with severe distal sensory loss and acrodystrophic changes.

PMID- 10586224
TI  - Historical perspective of defining Charcot-Marie-Tooth type 1B.
AB  - A single family (1521) with CMT has been followed for 36 years (1962-1998) at
      Children's Hospital and the University of Washington in Seattle. The family was
      initially called peroneal muscular atrophy with severely slowed motor nerve
      conduction velocities (5-15 m/sec). In the late 1970s the family was part of
      several genetic studies of CMT and in 1980 represented linkage of CMT to the
      Duffy (Fy) locus on chromosome 1q. This finding was confirmed in an Indiana CMT
      family by Stebbins and Conneally (1982). This subtype of CMT was designated 1B.
      These investigations represented some of the last successful linkage studies in
      the now seemingly "ancient" pre-DNA marker era. In 1993 Hayasaka and colleagues
      found a point mutation in the myelin P0 gene (Asp 90 Glu) in this family, giving
      CMT1B a molecular basis. The historical development of this "defining" of a
      neurogenetic disorder reveals interesting insights into the workings of clinical
      genetics over the past 3 decades.

PMID- 10586225
TI  - Overview of hereditary neuropathy with liability to pressure palsies.
AB  - Hereditary neuropathy with liability to recurrent pressure-sensitive palsies
      (HNPP; also called tomaculous neuropathy) is an autosomal dominant disorder that
      produces an episodic, recurrent demyelinating neuropathy. HNPP generally develops
      during adolescence, and may cause attacks of numbness, muscular weakness, and
      atrophy. Peroneal palsies, carpal-tunnel syndrome, and other entrapment
      neuropathies are frequent manifestations of this disorder. Motor and sensory
      nerve conduction velocities may be reduced in clinically affected patients, as
      well as in asymptomatic gene carriers. Pathological changes observed in
      peripheral nerves of HNPP patients include segmental demyelination and tomaculous
      or "sausage-like" formations. Because of mild overlap of clinical features with
      CMT1, HNPP patients may be misdiagnosed as having CMT1. HNPP and CMT1 are both
      demyelinating neuropathies; however, their clinical, pathological, and
      electrophysiological features are quite distinct. The HNPP locus maps to
      chromosome 17p11.2-12 and is associated with a 1.5-Mb deletion. DNA markers known
      to map to the region in 17p11.2-12 associated with the CMT1A duplication,
      including the PMP22 gene, are deleted in HNPP. The deletion breakpoints in HNPP
      map to the same intervals in which the CMT1A duplication breakpoints map. In one
      pedigree, de novo deletion of paternal origin was detected as a basis for
      sporadic HNPP. HNPP results from deletion of the PMP22 gene and underexpression
      of this locus, which is reflected in reduced mRNA and protein levels in sural
      nerve biopsy samples from HNPP patients. Further support for this hypothesis was
      provided by the identification of a nondeleted HNPP kindred in which a two base
      pair deletion and early termination codon within exon 1 of PMP22 was present. The
      possibility of genetic heterogeneity in HNPP was raised by the identification of
      an HNPP pedigree that did not demonstrate linkage to the region of 17p11.2-12.
      Hereditary neuralgic amyotrophy (familial brachial plexus neuropathy) is an
      autosomal dominant disorder causing painful, recurrent brachial plexopathies and
      maps to chromosome 17q25.

PMID- 10586226
TI  - Molecular mechanisms for CMT1A duplication and HNPP deletion.
AB  - As the best characterized human genomic disorders, CMT1A and HNPP illustrate
      several common mechanistic features of genomic rearrangements. These features
      include the following: (1) Recombination occurs between homologous sequences
      flanking the duplicated/deleted genomic segment. (2) The evolution of the
      mammalian genome may result in an architecture consisting of region-specific low
      copy repeats that predispose to rearrangement secondary to providing homologous
      regions as substrate for recombination. (3) Strand exchange occurs preferentially
      in a region of perfect sequence identity within the flanking repeat sequences.
      (4) Double-strand breaks likely initiate recombination between the flanking
      repeats. (5) The mechanism and rate of homologous recombination resulting in DNA
      rearrangement may differ for male and female gametogenesis. (6) Homologous
      recombination resulting in DNA rearrangement occurs with high frequency in the
      human genome. (7) Genomic disorders result from structural features of the human
      genome and not population specific alleles or founder effects; therefore, genomic
      disorders appear to occur with equal frequencies in different world populations.

PMID- 10586227
TI  - X-linked Charcot-Marie-Tooth disease and connexin32.
AB  - X-linked Charcot-Marie-Tooth disease is caused by mutations in the gene for the
      gap junction protein connexin32. This protein is expressed in peripheral nerve
      and present in noncompacted myelin, where it likely forms channels around and
      across the myelin sheath. Studies in cell culture and in transgenic mice show
      that connexin32 mutations can cause a loss of channel function or a gain of toxic
      effects on myelinating Schwann cells or both, with resulting peripheral nerve
      degeneration.

PMID- 10586228
TI  - Charcot-Marie-Tooth disease type 2.
AB  - No unique genes have yet been found for CMT2, but both Cx32 and P0 appear to
      contribute to the phenotype. Not surprisingly, CMT2 is likely to display much
      more genetic heterogeneity than CMT1. However, it is also likely continue to
      challenge previous concepts on classification and relationship of traditional
      inherited phenotypes in neurology. Future work on CMT2 should produce insight not
      only into the cellular interactions of the peripheral nerve especially Schwann
      cell and axon relationships, but also into idiopathic neuropathy.

PMID- 10586229
TI  - Autosomal recessive hereditary motor and sensory neuropathy with focally folded
      myelin sheaths (CMT4B).
AB  - Hereditary motor and sensory neuropathy with focally folded myelin sheaths, or
      Charcot-Marie-Tooth neuropathy type 4B (CMT4B), is a distinct clinical and
      genetic entity belonging to the heterogeneous group of autosomal recessive
      demyelinating neuropathies. We first described a large inbred pedigree with 10
      patients affected by CMT4B, which enabled us to uncover the genetic findings,
      clinical spectrum, and natural history of such a disorder. The clinical picture
      was characterized by infantile onset with progressive symmetric distal and
      proximal muscular weakness. Using homozygosity mapping and haplotype sharing
      analysis, we found evidence of linkage of chromosome 11q23. We then identified a
      second unrelated family in which two individuals were affected with CMT4B.
      Although the clinical findings were similar to those previously reported, we
      excluded the disease locus segregating in this smaller pedigree from the 11q23
      region. We thus provided evidence for a second locus causing the CMT4B phenotype.
      All these findings indicate that CMT4B seems to be phenotypically quite
      homogeneous, but is genetically heterogeneous.

PMID- 10586230
TI  - The autosomal recessive form of CMT disease linked to 5q31-q33.

PMID- 10586231
TI  - Distal hereditary motor neuropathy type II (distal HMN type II): phenotype and
      molecular genetics.
AB  - The distal hereditary motor neuropathies (distal HMN) are clinically and
      genetically heterogeneous and are subdivided in seven subtypes according to the
      mode of inheritance, age at onset and clinical evolution. We studied a
      multigenerational Belgian pedigree with autosomal dominant distal HMN type II.
      The clinical phenotype closely resembles classical Charcot-Marie-Tooth (CMT)
      disease with an age at onset between 15 and 25 years. Linkage studies have shown
      that distal HMN II is not linked to the known CMT1 and CMT2 loci. A genome-wide
      search was performed and significant linkage was obtained between markers D12S86
      and D12S340, suggesting that a gene causing distal HMN II is located on
      chromosome 12q24.3. The gene encoding the human pancreatic phospholipase A2
      (PLA2A), which is expressed in peripheral nerves during degeneration, is a
      positional candidate gene. Because no disease-specific mutations were detected in
      the coding region, however, PLA2A is most likely not the disease causing gene. A
      yeast artificial chromosome (YAC) contig map spanning the candidate region has
      been constructed to isolate the gene responsible for distal HMN II. Positional
      and functional candidate genes are currently being screened for the presence of
      mutations in distal HMN II patients.

PMID- 10586232
TI  - Distal hereditary motor neuronopathy of the Jerash type.
AB  - A novel form of autosomal recessive distal hereditary motor neuronopathy (distal
      HMN) is reported. The presence of pyramidal signs within the early stages of the
      disease with persistence of knee hyperreflexia form distinctive clinical
      features. We have mapped the HMN-J gene to chromosome 9p21.1-p12, within an
      estimated interval of 1.2-Mb.

PMID- 10586233
TI  - A clinical review of Charcot-Marie-Tooth.
AB  - CMT polyneuropathy is a complex genetically and clinically heterogeneous group of
      disorders. The rapid advances in our understanding of the molecular basis of
      these groups of neuropathies have helped to resolve some of the controversial
      issues regarding the clinical and genetic classification. However, there is still
      confusion and chaos in the terminology employed by different groups of
      researchers. A reclassification based on the molecular mechanisms of these
      neuropathies will help in the future to unify and simplify the diagnosis of these
      complex disorders. The understanding of the molecular mechanisms will also help
      in the future to find a way to control or treat these hereditary neuropathies.

PMID- 10586234
TI  - Schwann cell-axon interactions in Charcot-Marie-Tooth disease.
AB  - The consequences of the molecular defects in myelin genes are manifest from the
      time of birth in most patients, as assessed either electrodiagnostically or
      pathologically. Reduction in nerve conduction velocity is present from the first
      weeks of life, but the clinical manifestations have been recognized as
      predominantly distal and dominated by distal muscle atrophy. The recent advances
      in understanding the molecular defects involved present a paradox: the molecular
      abnormalities are found in intrinsic Schwann cell proteins, not in distal axons.
      Thus, the interactions between Schwann cells and axons have been the focus of
      much attention. Here, we present findings on the effects of Schwann cell
      phenotype on the exon and how abnormalities in myelin alter the axonal
      cytoskeleton. The clinical importance of Schwann cell-axon interactions extends
      beyond Charcot-Marie-Tooth disorders. The same principles may apply in the CNS,
      for example, in multiple sclerosis.

PMID- 10586235
TI  - Regulation of myelin-specific gene expression. Relevance to CMT1.
AB  - Schwann cells, the myelinating cells of the peripheral nervous system, are
      derived from the neural crest. Once neural crest cells are committed to the
      Schwann cell fate, they can take on one of two phenotypes to become myelinating
      or nonmyelinating Schwann cells, a decision that is determined by interactions
      with axons. The critical step in the differentiation of myelinating Schwann cells
      is the establishment of a one-to-one relationship with axons, the so-called
      "promyelinating" stage of Schwann cell development. The transition from the
      promyelinating to the myelinating stage of development is then accompanied by a
      number of significant changes in the pattern of gene expression, including the
      activation of a set of genes encoding myelin structural proteins and lipid
      biosynthetic enzymes, and the inactivation of a set of genes expressed only in
      immature or nonmyelinating Schwann cells. These changes are regulated mainly at
      the transcriptional level and also require continuous interaction between Schwann
      cells and their axons. Two transcription factors, Krox 20 (EGR2) and Oct 6
      (SCIP/Tst1), are necessary for the transition from the promyelinating to the
      myelinating stage of Schwann cell development. Krox 20, expressed in myelinating
      but not promyelinating Schwann cells, is absolutely required for this transition,
      and myelination cannot occur in its absence. Oct 6, expressed mainly in
      promyelinating Schwann cells and then down-regulated before myelination, is
      necessary for the correct timing of this transition, since myelination is delayed
      in its absence. Neither Krox 20 nor Oct 6, however, is required for the initial
      activation of myelin gene expression. Although the mechanisms of Krox 20 and Oct
      6 action during myelination are not known, mutation in Krox 20 has been shown to
      cause CMT1, further implicating this protein in the pathogenesis of this disease.
      Identifying the molecular mechanisms of Krox 20 and Oct 6 action will thus be
      important both for understanding myelination and for designing future treatments
      for CMT1. Point mutlations in the genes encoding the myelin proteins PMP22 and P0
      cause CMT1A without a gene duplication and CMT1B, respectively. Although the
      clinical and pathological phenotypes of CMT1A and CMT1B are similar, their
      molecular pathogenesis is quite different. Point mutations in PMP22 alter the
      trafficking of the protein, so that it accumulates in the endoplasmic reticulum
      (ER) and intermediate compartment (IC). Mutant PMP22 also sequesters its normal
      counterpart in the ER, further reducing the amount of PMP22 available for myelin
      synthesis at the membrane, and accounting, at least in part, for its severe
      effect on myelination. Mutant PMP22 probably also activates an ER-to-nucleus
      signal transduction pathway associated with misfolded proteins, which may account
      for the decrease of myelin gene expression in Schwann cells in Trembler mutant
      mice. In contrast, absence of expression of the homotypic adhesion molecule, P0,
      in mice in which the gene has been inactivated, produces a unique pattern of
      Schwann cell gene expression, demonstrating that P0 plays a regulatory as well as
      a structural role in myelination. Whether this role is direct, through a P0
      mediated adhesion pathway, or indirect, through adhesion pathways mediated by
      cadherins or integrins, however, remains to be determined. The molecular
      mechanisms underlying dysmyelination in CMT1 are thus complex, with pleitropic
      effects on Schwann cell physiology that are determined both by the type of
      mutation and the protein mutated. Identifying these molecular mechanisms,
      however, are important both for understanding myelination and for designing
      future treatments for CMT1. Although demyelination is the hallmark of CMT1, the
      clinical signs and symptoms of this disease are probably produced by axonal
      degeneration, not demyelination. (ABSTRACT TRUNCATED)

PMID- 10586236
TI  - Why do Schwann cells survive in the absence of axons?
AB  - Schwann cell precursors in embryonic nerves rely for survival on signals from the
      axons they associate with. A major component of this signal is beta neuregulin.
      While it can be argued that such paracrine axonal regulation makes biological
      sense in embryonic nerves, such an arrangement would be problematic postnatally,
      since nerve damage would then lead to Schwann cell death with adverse
      consequences for regeneration; in fact, transection of older nerves is not
      accompanied by a detectable increase in Schwann cell death. Our evidence
      indicates that this is, at least in part, due to the ability of Schwann cells to
      support their own survival by autocrine circuits. These circuits are not present
      in Schwann cell precursors. We have identified insulin-like growth factor,
      neurotrophin-3 and platelet-derived growth factor-BB as components of the
      autocrine Schwann cell survival signal.

PMID- 10586237
TI  - P0-Cre transgenic mice for inactivation of adhesion molecules in Schwann cells.
AB  - Normal peripheral nerve myelination depends on Schwann cell-basal lamina
      interactions. An important component of Schwann cell basal lamina is laminin-
      predominantly laminins 2 and 4. Mutations in the alpha 2 chain common to these
      two isoforms are associated with dysmyelination in mouse (dy) and man (congenital
      muscular dystrophy). Thus, laminin 2 and 4 receptors are also likely to be
      important for myelin formation. Several laminin 2/4 receptors are detected at the
      basal lamina surface of myelin-forming Schwann cells, namely, alpha 6 beta 4 and
      alpha 6 beta 1 integrins and dystroglycan. The evidence linking these receptors
      to myelination is suggestive, but not conclusive. Genetic studies have not yet
      confirmed a role for these molecules in myelin formation. Natural or targeted
      inactivation of alpha 6, beta 4, and beta 1 integrins and of dystroglycan have
      profound effects on other tissues causing embryonic or perinatal death before
      myelination. Therefore, to conditionally inactivate these receptors specifically
      in myelin-forming Schwann cells, we have constructed and initially characterized
      a P0-Cre transgene that activates Cre-mediated recombination of loxP-containing
      genes in peripheral nerve.

PMID- 10586238
TI  - IGF-I promotes peripheral nervous system myelination.
AB  - Insulin-like growth factor-I (IGF-I) promotes the proliferation and
      differentiation of Schwann cells (SC). We use SC/dorsal root ganglion neuron
      (DRG) cocultures to examine the effects of IGF-I on the interaction between axons
      and SC. As SC extend processes toward the axon in the presence of IGF-I, these
      processes attach to and ensheath axons. Continued IGF-I exposure leads to
      enhanced P0 expression and long-term myelination. No myelination occurs in the
      absence of IGF-I. These data imply that IGF-I is critical not only for SC
      attachment and ensheathment of axons but also for long-term myelination.

PMID- 10586239
TI  - Nodes, paranodes, and incisures: from form to function.
AB  - The exquisite molecular architecture of myelinated fibers is the basis for
      saltatory conduction. The nodal axolemma contains high concentrations of voltage
      dependent sodium channels as well as the cell adhesion molecules neurofascin and
      Nr-CAM, all of which are probably linked to the axonal cytoskeleton by ankyrin.
      At paranodes, the axonal membrane contains paranodin/Caspr, which may be a Ca(2+)
      dependent cell adhesion molecule with a heterophilic partner on the apposed glial
      cell membrane. The juxtaparanodal axonal membrane contains the potassium channels
      Kv1.1 and Kv1.2, as well as the associated beta 2 subunit, which together may
      function to dampen re-entrant excitation. The paranodes and incisures of the
      Schwann cell myelin sheath contain "reflexive" adherens junctions and gap
      junctions. The adherens junctions are composed of E-cadherin as well as alpha-
      and beta-catenin, which together probably join the adjacent layers of noncompact
      myelin together. Reflexive gap junctions, comprising connexin32 and at least one
      other connexin protein, form a radial pathway for the diffusion of ions and small
      molecules directly across the myelin sheath.

PMID- 10586240
TI  - The anatomy and cell biology of peripheral myelin protein-22.
AB  - The gain of function phenotypes exhibited by the heterozygous Tr, Tr-J, and CMT1A
      mutations indicate that these mutations interfere with more than the function of
      a single PMP22 allele. The identification of proteins that interact with PMP22
      and that are sensitive both to stoichiometry and the effects of the mutations
      could provide important leads to a unified hypothesis to explain the riddle of
      the PMP22-related neuropathies.

PMID- 10586241
TI  - New vistas on the pathomechanism of Charcot-Marie-Tooth and related peripheral
      neuropathies.
AB  - A gene-dosage mechanism in CMT1A and HNPP has been postulated previously. Here,
      recent findings are discussed concerning (i) the functional consequences of
      altered PMP22 expression on Schwann cell growth regulation and on the capacity of
      genetically modified Schwann cells to myelinate peripheral axons, (ii) the cell
      physiological effects caused by the expression of certain disease-related
      missense mutations of PMP22 that are known to alter the Schwann cell phenotype
      and impair myelination in vivo, and (iii) the pathomechanism of CMT1 in light of
      findings on a novel association between PMP22 and P0 in PNS myelin.

PMID- 10586242
TI  - Characterization of the effect on adhesion of different mutations in myelin P0
      protein.
AB  - Table 1 summarizes the results obtained from expressing in CHO cells C21A P0 and
      N93A P0 alone, and each with wild-type P0. As can be seen, each of these mutated
      proteins reach the cell surface when expressed alone, but neither is adhesive.
      Finally, when each of these mutated P0 molecules is expressed with the wild-type
      P0, wild-type P0 is no longer adhesive. Therefore, both C21A Po and N93A P0 each
      have a dominant negative effect on adhesion of wild-type P0. This approach to
      address the functional consequences of mutations in P0 can now be used to assess
      the effects of different mutations associated with CMT1B.

PMID- 10586243
TI  - Connexin32 in the peripheral nervous system. Functional analysis of mutations
      associated with X-linked Charcot-Marie-Tooth syndrome and implications for the
      pathophysiology of the disease.

PMID- 10586244
TI  - Ultrastructural immunocytochemical abnormalities of peripheral myelin proteins in
      hereditary sensory-motor neuropathies: 12 cases.
AB  - Hereditary sensorimotor neuropathies form a heterogeneous group of genetically
      determined diseases, of which Charcot-Marie-Tooth (CMT) disease is the most
      common. In order to establish relations between genotype and the expression of
      peripheral myelin proteins, we carried out a quantitative study by
      ultrastructural immunocytochemistry of several myelin proteins (PMP22, P0, MBP)
      on sural nerve biopsy samples from 12 unrelated CMT patients. The diagnosis of
      CMT was based on the clinical, electrophysiological, and histological findings
      along with those of molecular biological studies. CMT X diagnoses were not
      included in this study. The expression of myelin proteins was well correlated
      with the molecular biological findings in these patients. The results also
      provided evidence for interference between different myelin proteins. Our
      findings are in line with the results from animal studies (trembler and knock-out
      mice), which may provide insights into the pathogenesis of these human
      conditions.

PMID- 10586245
TI  - Schwann cell-derived desert hedgehog signals nerve sheath formation.
AB  - Reciprocal signaling between axons and Schwann cells during development is well
      established. The contribution of Schwann cells to the formation and maintenance
      of the protective nerve sheaths (endo-, peri-, and epineurium) has been less
      studied. Although mesenchymal cells contribute to all these structures, only
      perineurial cells contribute to the diffusion barrier between nerves and
      surrounding tissues. During development, prospective perineurial cells shift from
      a mesenchymal to epithelial phenotype, forming concentric layers of cells around
      the nerve fascicles that collectively form a barrier against unwanted molecules
      and cellular infiltration. We have studied the role of Schwann cells in the
      formation and maintenance of this barrier. The signaling molecule Desert hedgehog
      is expressed in Schwann cell precursors, and in Schwann cells until at least
      postnatal day 10, while its receptor patched is seen in mesenchymal cells
      surrounding the developing nerve at embryo day 15. In Desert hedgehog knockout
      mice, the connective tissue sheaths in adult nerves appear highly abnormal by
      electron microscopy. There is almost no epineurium, and the perineurium is thin
      and highly abnormal. In addition, perineurial-like cells invade the endoneurial
      space, forming mini-fascicles around small bundles of nerve fibers similar to
      those seen in regenerating nerves. Functional tests reveal that the diffusion and
      cellular infiltration barrier is compromised, demonstrating that Desert hedgehog
      signaling from Schwann cells to the mesenchyme is involved in the formation of a
      morphologically and functionally normal perineurium.

PMID- 10586246
TI  - Neurofibromin, the neurofibromatosis type 1 Ras-GAP, is required for appropriate
      P0 expression and myelination.
AB  - The neurofibromatosis type 1 (NF1) gene product, neurofibromin, regulates
      activation of the Ras intracellular signaling pathway in Schwann cells. Schwann
      cells purified from mouse embryos with null mutations in the Nf1 gene increase
      expression of the major myelin glycoprotein P0. v-Ras expression in cultured
      Schwann cells partially mimics loss of Nf1, suggesting a role for Ras in
      upregulation of P0 expression in Nf1-deficient cells. We tested whether loss of
      Nf1 alters the ability of Schwann cells to form myelin. No significant changes in
      myelin formation resulted when Nf1-deficient or v-Ras-expressing Schwann cells
      were cultured with normal neurons. Yet, in organotypic cultures of neurons,
      Schwann cells, and fibroblasts without neurofibromin, myelination was
      dramatically reduced. We suggest that Nf1-dependent signaling cascades in neurons
      and/or fibroblasts, as well as Schwann cells, are required for normal
      myelination.

PMID- 10586247
TI  - The biology of chronically denervated Schwann cells.
AB  - This paper is divided into two sections, both concerned with the effects of
      chronic denervation on Schwann cells. The first group of experiments explore the
      proposal that lengthy denervation produces changes in Schwann cells in vivo that
      compromise axonal regeneration. The second group of experiments compare the
      molecular phenotypes of acutely and chronically denervated Schwann cells in
      vitro, and examine their responses to an exogenously applied neuregulin.

PMID- 10586248
TI  - Distinct phenotypes associated with increasing dosage of the PLP gene:
      implications for CMT1A due to PMP22 gene duplication.
AB  - Increased dosage of the proteolipid protein (Plp) gene causes CNS disease
      (Pelizaeus-Merzbacher disease [PMD]), which has many similarities to disorders of
      the PNS associated with duplication of the peripheral myelin protein-22 (PMP22)
      gene locus. Transgenic mice carrying extra copies of the wild-type Plp gene
      provide a valid model of PMD. Variations in gene dosage can cause a wide range of
      phenotypes from severe, lethal dysmyelination through late-onset demyelination. A
      predilection for different fiber diameters may occur within the various
      phenotypes with dysmyelination being more obvious in large fibers and late-onset
      degeneration predominantly affecting small fibers. Although the frequency of
      apoptotic oligodendrocytes is increased with high gene dosage, the number of
      mature oligodendrocytes appears adequate. Oligodendrocytes in the dysmyelinated
      CNS express a range of genes typical of mature cells, yet are unable to assemble
      sufficient myelin. Oligodendrocytes contain abnormal vacuoles and stain intensely
      for PLP and other proteins such as MAG. The findings suggest that with high gene
      dosage much of the PLP, and possibly other proteins, is missorted and degraded in
      the lysosomal system.

PMID- 10586249
TI  - Transgenic mouse models of CMT1A and HNPP.
AB  - We have generated several PMP22 animal mutants with altered PMP22 gene dosage. A
      moderate increase in the number of PMP22 genes led to hypomyelination comparable
      to CMT1A, whereas high copy numbers of transgenic PMP22 resulted in phenotypes
      resembling more severe forms of hereditary motor and sensory neuropathies. In
      contrast, eliminating one of the two normal PMP22 genes by gene targeting caused
      unstable focal hypermyelination (tomacula) similar to the pathology in HNPP. A
      related but more severe phenotype was observed in mice that lack PMP22
      completely. Detailed analysis of the different PMP22 mutants revealed, in
      addition to the obvious myelinopathy, distal axonopathy as a characteristic
      feature. We conclude that the maintenance of axons might be a promising target
      for therapeutic interventions in these demyelinating hereditary neuropathies.
      Furthermore, our results strongly support the concept that PMP22-related
      neuropathies (and most likely also other forms of inherited motor and sensory
      neuropathies) should be viewed as the consequence of impaired neuron-Schwann cell
      interactions that are likely already to be operative during development. Such
      considerations should be taken into account in the design of potential novel
      treatment strategies.

PMID- 10586250
TI  - The "CMT rat": peripheral neuropathy and dysmyelination caused by transgenic
      overexpression of PMP22.
AB  - We have generated a transgenic rat model of Charcot-Marie-Tooth disease type 1A
      (CMT1A) providing formal proof that this neuropathy can be caused by increased
      expression of peripheral myelin protein-22 (PMP22). Heterozygous PMP22-transgenic
      rats develop muscle weakness and gait abnormalities as well as reduced nerve
      conduction velocities and EMG abnormalities, which closely resemble recordings in
      patients with CMT1A. Dys- and demyelination, Schwann cell hypertrophy, and "onion
      bulb" formation are also similar to findings in humans. When bred to
      homozygosity, transgenic rats completely fail to elaborate myelin, but all myelin
      forming Schwann cells segregate with axons in the normal one-to-one ratio.
      Although arrested at this "promyelin" stage, differentiation proceeds in
      homozygous rats at the molecular level, as demonstrated by high-level expression
      of myelin structural genes. Intracellular trafficking of the wild-type protein is
      not visibly impaired, even when strongly overexpressed, suggesting that PMP22
      blocks myelin assembly in a late Golgi/cell membrane compartment of the affected
      Schwann cell.

PMID- 10586251
TI  - Trembler as a mouse model of CMT1A?
AB  - The Trembler mouse suffers from a dominantly inherited autosomal mutation that
      results in an abnormal myelination of the peripheral nervous system. Biochemical
      studies have shown that dysmyelination is the primary event, demyelination being
      a late-occurring process. The expression of myelin protein genes has been
      studied. The steady-state levels for PMP22 mRNA represent 10 and 5% of normal
      values in the nerves of heterozygous and homozygous Trembler, respectively. This
      is due to a reduced expression of the specific transcript driven by the promoter
      1 of the PMP22 gene. Collective results indicate that Trembler dysmyelination is
      not necessarily the consequence of a large accumulation of the mutated PMP22
      protein. Moreover, it appears that the situation in the Trembler is different
      from that encountered in most CMT1A patients, where an increased PMP22 gene
      dosage is responsible for the disease. Therefore, the Trembler mutant is perhaps
      not an ideal model for this human neuropathy.

PMID- 10586252
TI  - P0-deficient knockout mice as tools to understand pathomechanisms in Charcot
      Marie-Tooth 1B and P0-related Dejerine-Sottas syndrome.
AB  - P0 (mylin protein zero, MPZ) is one of the four identified culprit genes for
      hereditary peripheral neuropathies. Homo- or heterozygous null mutants for P0
      share pathological features with some patients suffering from P0-related Dejerine
      Sottas-Syndrome (DSS) or Charcot-Marie-Tooth (CMT) neuropathy, type 1B,
      respectively, and can thus be considered as appropriate animal models for the
      corresponding diseases. This article focuses on distinct histopathological
      features in these mice. Such features include dysregulation of Schwann cell genes
      and axonal loss in homozygous mutants and significant infiltration of T
      lymphocytes and macrophages in heterozygous mutants. These histological
      characteristics are instrumental in understanding the pathogenesis of the disease
      and may help in developing treatments.

PMID- 10586253
TI  - The absence of myelin P0 protein produces a novel molecular phenotype in Schwann
      cells.
AB  - In order to better understand the pathogenesis of demyelination in P0 knockout
      (P0-/-) mice, we analyzed the myelin gene expression and the localization of
      myelin proteins in P0 null mouse sciatic nerve. We have demonstrated that the
      severe demyelinating neuropathy of P0-knockout mouse is associated with changes
      in the program of myelin gene expression. Some changes in myelin gene expression
      occur early, others occur during adulthood. We also provide evidence that the
      absence of P0 is associated with changes in the localization of specific
      paranodal proteins in the peripheral nerve. These data suggest that P0 plays an
      important role, either directly or indirectly, in the program of Schwann cell
      gene expression and in the specific distribution of peripheral myelin proteins.
      Furthermore, myelin gene dysregulation and improper localization of paranodal
      proteins may account, in part, for the pathogenesis of demyelination in P0
      knockout mice, as well as in human demyelinating peripheral neuropathy associated
      with mutations in the P0 gene.

PMID- 10586254
TI  - Peripheral nerve dysmyelination due to P0 glycoprotein overexpression is dose
      dependent.
AB  - We have previously shown that increased dosage of the mouse protein zero gene
      (Mpz) causes a dysmyelinating neuropathy in transgenic (Tg80) mice. To ask
      whether the dysmyelination is dose dependent, we inbred one of the Tg80 lines and
      compared the resulting phenotype in homozygous and heterozygous mice. Whereas
      heterozygous mice (30% overexpression) have only transient peripheral nerve
      hypomyelination at two weeks after birth and normal myelin at four weeks after
      birth, homozygous mice demonstrated more severely hypomyelinated nerves. In the
      latter, many Schwann cells had achieved a one-to-one relationship with large
      axons but formed no myelin at four weeks after birth. Expression analysis
      confirmed a doubling of Mpz overexpression in the sciatic nerves of the
      homozygous mice. Thus, a threshold exists for Mpz overexpression, above which
      dysmyelination results. These data have important implications for replacement
      therapy in Charcot-Marie-Tooth 1B neuropathies due to loss of P0 function.

PMID- 10586255
TI  - Characterization of targeted connexin32-deficient mice: a model for the human
      Charcot-Marie-Tooth (X-type) inherited disease.

PMID- 10586256
TI  - Nerve conduction abnormalities and neuromyotonia in genetically engineered mouse
      models of human hereditary neuropathies.
AB  - We performed electrophysiological studies in myelin protein mutant mice in order
      to characterize nerve conduction changes. We performed neurographic studies on
      the facial and sciatic nerves and needle electromyography (EMG). Mice
      homozygously deficient for the peripheral myelin protein 22 gene (Pmp22-/-)
      exhibited increased motor latencies, reduced nerve conduction velocities, and
      polyphasia of the M-response, which are the typical electrophysiological signs of
      dysmyelination. PMP22 +/- mice developed only mild conduction slowing at an old
      age and a mild reduction of the M-amplitude, which indicates mild axonal
      dysfunction. Mice overexpressing Pmp22 developed severe electrophysiological
      signs of dysmyelination. In myelin protein zero-deficient mice (P0 -/-), we found
      alterations similar to those found in Pmp22 -/- mice, whereas P0 +/- mice
      developed mildly increased sciatic nerve F-wave latencies only late in life,
      which indicates only mild dysmyelination. Connexin 32-deficient mice showed
      electrophysiological evidence of mild axonal damage. By EMG, we found the
      clinical and electrophysiological signs of neuromyotonia, that is, continuous
      spontaneous motor unit discharges, often in rhythmic patterns (myokymia), in P0 
      /-, Pmp22 -/-, Trembler, Trembler-J, and Pmp22-overexpressing mice. This
      indicates abnormal impulse generation in these dysmyelinated nerves. In summary,
      our studies demonstrate nerve conduction changes in mice with myelin protein gene
      defects that are similar to those found in patients with Charcot-Marie-Tooth
      disorders. In addition, we identified new mouse models of hereditary
      neuromyotonia.

PMID- 10586257
TI  - Electrophysiologic features of inherited demyelinating neuropathies: a
      reappraisal.
AB  - The observation that inherited demyelinating neuropathies tend to have uniform
      conduction slowing and acquired disorders (CIDP and variants) have nonuniform or
      multifocal slowing was made before the identification of genetic defects of
      specific myelin constituents that cause the different forms of Charcot-Marie
      Tooth and other inherited disorders involving peripheral nerve myelin. It is
      becoming clear that the electrophysiologic aspects of these disorders are more
      complex than previously realized. We review the current information available on
      the electrophysiologic features of the inherited demyelinating neuropathies in
      hopes of clarifying the clinical electrodiagnostic features of these disorders as
      well as to shed light on the physiologic consequences of the different genetic
      mutations.

PMID- 10586258
TI  - Human nerve pathology caused by different mutational mechanisms of the PMP22
      gene.
AB  - The study of the morphological phenotypes in patients with different mutations of
      the PMP22 gene gives additional insights into the role of the protein in myelin
      function. The pathology in young patients is in some aspects different from the
      pathology in older patients, providing essential and additional information about
      the early disease processes in humans induced by different PMP22 mutational
      mechanisms. Duplication of chromosome 17p11.2, causing an overexpression of the
      PMP22 gene, results in early hypermyelination. This suggests that PMP22 has a
      function in establishing the proper myelin thickness, probably in response to an
      axonal signal. Demyelination and remyelination with gradual formation of onion
      bulbs occur apparently as secondary processes, but these processes subside at the
      end of the first decade. PMP22 missense mutations usually result in a more severe
      phenotype showing an early hypomyelination and onion bulb formation, likely
      disturbing normal myelin formation and maintenance. The morphological differences
      with duplication cases underline the essential difference in pathogenesis between
      duplication and missense mutations despite the large overlap in clinical and
      electrophysiological phenotypes. The reciprocal deletion of chromosome 17p11.2,
      resulting in an underexpression of the PMP22 gene, is responsible for the
      clinical phenotype of HNPP. As the nerve abnormalities in HNPP show a marked
      resemblance to the changes in experimental and genuine human entrapment
      neuropathies, it is postulated that PMP22 has a function in adhesion of myelin
      lamellae, preventing mutual longitudinal sliding. Deletion of one PMP22 copy
      results in increased susceptibility for mechanical forces through which already
      minor nerve injuries might induce a longitudinal displacement of myelin lamellae.
      The frame shift mutation Gly94(insG) combines a loss of function like in the
      common deletion HNPP with a mild CMT1 phenotype, likely inducing a (mild) toxic
      gain of function by disturbing myelin formation and maintenance, comparable to
      the effect in missense mutations.

PMID- 10586259
TI  - Variability of presentation in hereditary neuropathy with liability to pressure
      palsy results in underrecognition.
AB  - The genetic defect responsible for hereditary neuropathy with liability to
      pressure palsy (HNPP) is located in the same segment that is duplicated in
      Charcot-Marie-Tooth type 1A (CMT1A). HNPP had been presumed to be rare until an
      epidemiological study found a much higher incidence than was expected; the
      researchers suggested that HNPP was underrecognized because many affected persons
      have mild symptoms. We believe that another reason for underdiagnosis of HNPP is
      the marked phenotypic variability of the disease. We recommend, therefore, that
      DNA analysis for the 17p11.2 deletion be considered in patients with unexplained
      demyelinating neuropathy regardless of family history.

PMID- 10586260
TI  - Peripheral neuropathy caused by proteolipid protein gene mutations.
AB  - Pelizaeus-Merzbacher disease (PMD) is a dysmyelinating disorder of the central
      nervous system typically caused by duplications or missense mutations of the
      proteolipid protein (PLP) gene. Most investigators have found that peripheral
      nerve function and structure is normal in PMD patients. We have found that null
      mutations of the PLP gene cause demyelinating peripheral neuropathy, whereas
      duplications and a proline 14 to leucine mutation do not affect nerve function. A
      family with a nonsense mutation at position 144, which affects only PLP but not
      the alternatively spliced gene product DM20, has a very mild syndrome, including
      normal peripheral nerve function. Our findings suggest that DM20 alone is
      sufficient to maintain normal nerve function and that there may be domains of
      PLP/DM20 that have a relatively more active role in the peripheral nervous system
      compared with that in the central nervous system.

PMID- 10586261
TI  - Genotype/phenotype correlations in X-linked dominant Charcot-Marie-Tooth disease.
AB  - We have studied the relationship between genotype, clinical phenotype, and
      pathology in 13 families with dominant X-linked Charcot-Marie-Tooth (CMT)
      neuropathy. Connexin32 (Cx32) gene mutations were spread throughout the coding
      region and included eight missense mutations, one 8-bp deletion/4-bp insertion
      frame shifting mutation, two nonsense mutations, and one deletion of the entire
      coding sequence. One hundred sixteen affected CMTX patients (53 males and 63
      females) and 63 unaffected, at-risk individuals were compared by neurological and
      electrophysiological examinations and analyzed by gender; nerve biopsies were
      available from seven index cases. It was found that mutations within all regions
      of the Cx32 gene coding sequence caused an identical clinical phenotype. Male
      CMTX patients were affected more severely and showed an age-dependent progression
      of clinical signs and of the pathology; there was, however, variability in the
      severity of disease expression, irrespective of age, among males within families
      of defined genotype. All but 10% of female CMTX patients had only mild signs.
      Motor nerve conduction velocities were moderately slowed (median nerve MNCV:
      males 34.5 +/- 6.2 m/sec; females 45.8 +/- 7.3 m/sec), and motor and sensory
      nerve amplitudes were reduced (median nerve CMAP: males 3.7 +/- 3.7 mV; females
      7.8 +/- 3.4 mV), with electromyographic evidence of chronic denervation.
      Differences were significant between gender and between affected and unaffected
      individuals. In agreement with the electrophysiological observations,
      pathological studies showed evidence of paranodal demyelination and of a length
      related axonal degeneration in motor and sensory nerve fibers. Correlations
      between genotype and clinical phenotype suggested that missense mutations located
      within the second transmembrane domain and/or cytoplasmic loop might be
      associated with milder clinical phenotype, and therefore might be less disruptive
      of connexin32 gap junction function. Missense, chain-terminating, or deletion
      mutations in all other locations of the connexin32 protein caused severe forms of
      CMTX and disease onset in the first decade. Observed variability of disease
      severity among males within kinships suggests the influence of other modifying
      factors.

PMID- 10586262
TI  - Mutation testing in Charcot-Marie-Tooth neuropathy.
AB  - In order to determine the optimal approach for mutation testing in the form of
      Charcot-Marie-Tooth (CMT) neuropathy, consecutive patients with a CMT phenotype,
      available family history information on at least first-degree relatives, and
      median motor conduction velocities of less than 50 m/sec were tested for the
      CMT1A duplication and for connexin32, peripheral myelin protein 22 (PMP22) and
      myelin protein zero (P0) point mutations. A cutoff value for median motor
      conduction velocity of less than 50 m/sec was adopted to include all CMTX
      families. All of the connexin32 mutations, except for one sporadic case, were
      found by first selecting families with no male-to-male inheritance of CMT and
      neurophysiological indicators of CMTX. All PMP22 and P0 mutations were found by
      selecting Dejerine-Sottas cases or dominantly inherited CMT1 with a very severe
      phenotype. It is concluded that "blind" testing of CMT1 families for connexin32,
      P0, and PMP22 mutations is of limited value.

PMID- 10586263
TI  - Molecular diagnostic testing in Charcot-Marie-Tooth disease and related
      disorders. Approaches and results.
AB  - The inherited neuropathies of the peripheral nervous system are clinically and
      genetically a heterogeneous group of disorders. Molecular genetic studies have
      made major breakthroughs in unraveling the underlying gene defects, and DNA
      diagnosis can now be offered to a large number of families with distinct forms of
      hereditary peripheral neuropathies. With the currently available technology,
      however, molecular genetic diagnosis still remains a labor-intensive and costly
      procedure. We have developed an algorithm for mutation screening based on
      clinical phenotype, electrophysiological findings, and the relative frequencies
      of mutations in the distinct peripheral myelin genes.

PMID- 10586264
TI  - Overcoming cellular immunity to prolong adenoviral-mediated gene expression in
      sciatic nerve.
AB  - In a previous report, we demonstrated that a first generation (E1- and E3
      deleted) recombinant adenovirus can transduce expression of the E. coli lacZ gene
      into Schwann cells, both in vitro and in vivo, suggesting that this method might
      be useful for future therapy of peripheral neuropathy, including CMT1. Adenoviral
      mediated gene transfer was limited, however, by demyelination and Wallerian
      degeneration at the site of virus injection, as well as by attenuation of viral
      gene expression over time. In our current work we have optimized adenoviral
      mediated gene expression after intraneural injection into sciatic nerve. Using an
      improved injection protocol, peak expression of lacZ occurs between 10 and 14
      days after injection of 2-week-old animals, decreases thereafter, and there is
      minimal associated tissue injury. In contrast, very few adenoviral-infected
      Schwann cells are found in nerves of adult animals 10 days after injection,
      probably due to immune clearance of viral-infected cells. Consistent with this
      notion, high levels of lacZ are found in sciatic nerve 30 days after injection of
      adult SCOD mice, which have a genetic defect in both cellular and humoral
      immunity, of adult beta 2 microglobulin-deficient mice (beta 2 M-/-), which have
      a genetic defect in cellular immunity, or of adult mice treated with the
      immunosuppressing agent FK506. In addition, adenoviral-infected Schwann cells co
      cultured with axons in vitro, in the absence of a host immune response, ensheath
      axons and express lacZ for at least 8 weeks. These data thus demonstrate that
      expression of first generation recombinant adenovirus in sciatic nerve in adult
      mice, as in other tissues, is limited mainly by the host cellular immune response
      to the virus, which can be overcome by attenuation of host cell-mediated
      immunity. Adenoviral vectors might thus be used to modulate Schwann cell gene
      expression in patients with peripheral neuropathy after appropriate
      immunosuppression.

PMID- 10586265
TI  - Abnormal Schwann cell-axon interactions in CMT neuropathies. The effects of
      mutant Schwann cells on the axonal cytoskeleton and regeneration-associated
      myelination.
AB  - Preferential distal axonal loss is a common feature of Charcot-Marie-Tooth (CMT)
      hereditary neuropathies. The general hypothesis tested here is that the axonal
      loss in these disorders is due to perturbed Schwann cell-axon interactions
      resulting from primary Schwann genetic defects. The nerve xenograft model was
      used to study the local influence of mutant Schwann cells derived from patients
      on axonal properties and the regeneration-associated myelination process. Sural
      nerve segments from individuals with PMP22 duplications or deletions and point
      mutations, as well as Cx32 point mutations were grafted into cut ends of the
      sciatic nerve of nude mice and studied at different time intervals after
      grafting. CMT1A and CMTX xenografts examined at 16 weeks show that the nude mouse
      axons within the proximal part of grafts demonstrate a significant increase in
      axonal area with an increase in the neurofilament and membranous organelle
      density compared to distal graft and distal host segments. A preferential distal
      axonal loss associated with a perpetual axonal atrophy, degeneration, and axonal
      sprouting was observed over time with increasing frequency at 8 to 16 weeks. A
      distal summation of the pathology, as evidenced by a greater amount of fiber loss
      in the distal graft segments, was present similar to that observed in patients.
      These alterations were seen to a lesser extent in PMP22 deletion or point
      mutation xenografts and were not observed in controls. Collectively, these
      findings show that Schwann cells bearing the PMP22 or Cx32 genetic defects cause
      major perturbations in Schwann cell-axon interactions emphasizing the role of
      axonal component in the pathogenesis of hereditary neuropathies.

PMID- 10586266
TI  - Trophic factors in neuron-Schwann cell interactions.

PMID- 10586267
TI  - Distal hereditary motor neuronopathy of the Jerash type.

PMID- 10586268
TI  - Hereditary neuralgic amyotrophy: mutation analysis of candidate genes.

PMID- 10586269
TI  - A second family with autosomal dominant burning feet syndrome.

PMID- 10586270
TI  - Hereditary motor and sensory neuropathy with proximal dominant involvement:
      clinical, pathological, and genetic features.

PMID- 10586271
TI  - The autosomal recessive form of CMT disease linked to 5q31-q33.

PMID- 10586272
TI  - Prenatal diagnosis of Charcot-Marie-Tooth disease type 1A.
AB  - Charcot-Marie-Tooth disease (CMT) is the most common cause of peripheral
      neuropathy, with an incidence of 1: 2500 persons affected. CMT1A is caused by a
      submicroscopic duplication in 17p12. Several methods exist for determining a
      diagnosis in an individual. Many of these methods are not suitable for prenatal
      diagnosis. Previously, we reported the use of fluorescence in situ hybridization
      (FISH) to detect the common duplication found in more than 98% of individuals
      with CMT1A. We also have reported the validation of the FISH assay for amniotic
      fluid specimens and chorionic villus samples. Herein, we report our experience
      with testing for CMT1A in prenatal specimens.

PMID- 10586273
TI  - Preimplantation diagnosis for Charcot-Marie-Tooth type 1A.

PMID- 10586274
TI  - Construction of a PAC contig within the distal hereditary motor neuropathy type
      II candidate region at 12q24.

PMID- 10586275
TI  - A family with Friedreich ataxia and onion-bulb formations at sural nerve biopsy.

PMID- 10586276
TI  - Proximal Charcot-Marie-Tooth syndrome with duplication on chromosome 17p11.2.

PMID- 10586277
TI  - Modification of CMT1 phenotypes by the independent coexisting neurogenetic
      disorders, McArdle disease and chromosome 5p trisomy.

PMID- 10586278
TI  - Heterozygous null mutation in the P0 gene associated with mild Charcot-Marie
      Tooth disease.

PMID- 10586279
TI  - A unique mutation in connexin32 associated with severe, early onset CMTX in a
      heterozygous female.

PMID- 10586280
TI  - Charcot-Marie-Tooth 1A: heterozygous T118M mutation over a CMT1A duplication has
      no influence on the phenotype.

PMID- 10586281
TI  - Correlation between weakness and axonal loss in patients with CMT1A.
AB  - We have developed a protocol to measure the progression of disability in patients
      with Charcot Marie Tooth (CMT) disease, particularly CMT1 over a several year
      period. Because CMT1 is a chronic disease, the natural history of changes
      occurring in such a brief period are not well understood, making clinical trials
      for CMT1 patients difficult to evaluate. We hypothesize that weakness in CMT1
      correlates with axonal loss secondary to the abnormalities in Schwann cell myelin
      gene expression, which cause the disease. To test this hypothesis, we elected to
      carefully evaluate CMT patients by various modalities to measure strength,
      sensory loss, and axonal loss and demyelination and to compare these modalities
      to determine whether they correlated with findings on clinical examination. As
      suspected, patient weakness correlates more with secondary axonal loss than with
      demyelination, even though the primary abnormality in CMT1 is demyelination.

PMID- 10586282
TI  - Mutation screening of Charcot-Marie-Tooth patients in Poland.

PMID- 10586283
TI  - Phenotypic manifestations in French-Canadian populations with Charcot-Marie-Tooth
      disease type 1A associated with 17p11.2 duplication.

PMID- 10586284
TI  - HMSN and HNPP. Laboratory service provision in the south west of England--two
      years' experience.

PMID- 10586285
TI  - Electrodiagnostic findings in CMTX: a disorder of the Schwann cell and peripheral
      nerve myelin.

PMID- 10586286
TI  - Alterations in nodes of Ranvier and Schmidt-Lanterman incisures in Charcot-Marie
      Tooth neuropathies.

PMID- 10586287
TI  - Induction of myelin gene expression in murine Schwann cells in primary culture
      and in a Schwann cell line.

PMID- 10586288
TI  - Schwann cell apoptosis during cell-mediated demyelination.

PMID- 10586289
TI  - Human schwann cell proliferation and IL-6 production following TNF-alpha
      stimulation in vitro.

PMID- 10586290
TI  - Tumor necrosis factor-alpha induces monocyte chemoattractant protein-1 mRNA in a
      Schwann cell line.

PMID- 10586292
TI  - Altered protein synthesis in sciatic nerve by transgenic overexpression of PMP22
      in the CMT rat.

PMID- 10586291
TI  - Altered assembly of gap junction channels caused by COOH-terminal connexin32
      mutants of CMTX.

PMID- 10586293
TI  - Characteristics of gap junction channels in Schwann cells from wild-type and
      connexin-null mice.

PMID- 10586294
TI  - MBP-lacZ transgene expression in juvenile and adult Trembler-J mice.

PMID- 10586295
TI  - Dissociative identity disorder: recent developments.

PMID- 10586296
TI  - An overview of the psychotherapy of dissociative identity disorder.
AB  - Dissociative Identity Disorder (DID) is identified and studied with increasing
      frequency. However, the controversy that often surrounds DID can make it
      difficult to approach its treatment in a circumspect manner. This paper will
      provide an overview of DID treatment as it is practiced by those experienced and
      skilled in the treatment of this group of patients. The treatment of DID
      resembles the treatment of other traumatized populations in that it is stage
      oriented, beginning with supportive and strengthening work. Various stances
      toward the treatment of DID are reviewed, and specific issues that arise in the
      psychotherapy of DID are addressed, such as pragmatic arrangements, informed
      consent, work with alters, and the use of specific techniques, such as hypnosis.
      The employment of therapeutic modalities and ancillary therapies is discussed.
      The heterogeneity of DID patients is reviewed, and the characteristics of three
      general groups of DID patients, high, intermediate, and low in both function and
      prognosis, are explored. Considerations in the matching of DID patients to either
      exploratory or supportive treatments are discussed, and observations are made
      about both trauma work and the supportive psychotherapy of DID.

PMID- 10586297
TI  - Dissociative identity disorder and pseudo-hysteria.
AB  - The diagnostic validity of dissociative identity disorder (DID) continues to
      inspire controversy, with some commentators claiming that DID is a modern variant
      of "hysteria"; that is, attention-seeking behavior. The author asserts that DID
      is indeed a valid psychiatric disorder, and believes that this skeptical reaction
      can largely be attributed to a specific set of transference/countertransference
      interactions that these patients tend to inspire. The paper delineates several
      clinical features of DID that can easily be mistaken for hysterical phenomena,
      and attempts to find the roots of this confusion in the DID patients' experience
      of interpersonal powerlessness, which leads them to present their symptoms in an
      unconvincing, "hysterical" manner. Confusion between the vertical split seen in
      the dissociative disorders and the horizontal split characteristic of the classic
      hysterical personality is discussed, as is the powerful effect of observer bias
      in creating hysterical-appearing phenomena. The term "pseudo-hysteria" is used to
      denote a situation in which a genuine psychiatric disorder, DID, is perceived as
      an hysterical production.

PMID- 10586298
TI  - Deconstructing DID.
AB  - The author contends that a psychoanalytically informed approach to the patient
      with dissociative identity disorder (DID) can be very useful. However, there are
      difficulties in conceptualizing this condition without extending existing theory
      or applying in new ways what is already known. It is also difficult to put DID in
      a proper context relative to all the other disorders known to occur in the human
      mind. Depending on one's clinical experience, level of skepticism, and
      appreciation of history, DID may be seen as either: a) the psychological "missing
      link" that realizes Freud's goal of uniting the psychology of dreams with
      psychopathology, or b) a fraudulent condition that is wittingly or unwittingly
      manufactured in the therapist's office or c) a population of disturbed and
      disturbing patients, once the subject of great scientific interest, which, exiled
      like a "Lost Tribe," is now back in the fold of legitimacy. The author has had
      extensive clinical experience with psychic trauma, and bases his own views of DID
      on three assumptions: 1. that dissociation may be seen as a complex defense; 2.
      that DID may be thought of as a "lower level dissociative character"; and 3. that
      there is a unique psychic structure, the "dissociative self" whose function is to
      create "alter personalities" out of disowned affects, memories, fantasies, and
      drives. This "dissociative self" must be dissolved in order for integration of
      "alter personalities" to occur. A clinical vignette is offered to illustrate how
      he addresses some of the challenges of developing a therapeutic alliance at this
      end of the dissociative-character-pathology continuum, and how he grapples with
      the difficulty of integrating clinical phenomena, such as the appearance of
      "alters," with the psychoanalytic model of the mind.

PMID- 10586299
TI  - The tactical-integration model for the treatment of dissociative identity
      disorder and allied dissociative disorders.
AB  - The ebb and flow of the diagnosis of Dissociative Identity Disorder (DID) and
      other dissociative conditions has led to the evolution of theories and treatment
      modalities to resolve the fluctuating and ephemerous symptoms of these
      conditions. This paper summarizes the structured cognitive-behavioral-based
      treatment of dissociative disorders that will foster not only symptom relief but
      also an integration of the personalities and/or ego states into one mainstream of
      consciousness. This model of DID therapy is called the tactical integration
      model; it promotes proficiency over posttraumatic and dissociative symptoms, is
      collaborative and exploratory, and conveys a consistent message of empowerment to
      the patient.

PMID- 10586300
TI  - Successful treatment of refractory obsessive-compulsive disorder.
AB  - A case study is presented of a 40-year-old man with obsessive-compulsive disorder
      (OCD). He had been treated with long-term institutional placement,
      electroconvulsive therapy, exhaustive pharmacotherapy, and psychodynamic and
      cognitive-behavioral psychotherapy. Nothing had relieved his excessive hand
      washing and door checking. Records from previous treatment revealed a diagnosis
      of dissociative identity disorder (DID). This information led to
      reconceptualization of the OCD symptoms as manifestations of the patient's ego
      fragmentation. When his fragments were catalogued and addressed, all overt OCD
      symptoms abated within weeks. It is believed that the patient's most anxious ego
      fragment communicated dread from the background of the patient's psyche, the
      executive component only being aware of the anxiety and not the triggering
      stimulus. The patient was taught to address this fragment verbally to elicit its
      cooperation, whereupon the fragment stopped sounding alarm, creating anxiety and
      driving the patient to check and recheck, wash and rewash. Symptoms have returned
      only when the patient has suspended his announcing behavior and have abated when
      this was resumed. Connections between OCD and DID are addressed. CONCLUSION:
      Patients exhibiting refractory OCD symptoms should be assessed for dissociative
      symptomatology.

PMID- 10586301
TI  - The "adualistic" representation of trauma: on malignant internalization.
AB  - This paper suggests that traumatic memories are represented in a way that is
      qualitatively different from nontraumatic memories. The argument depends upon a
      concept of self, derived from Hughlings Jackson and William James, which is
      double, involving not only mental life but reflection upon it. Trauma is seen as
      causing an uncoupling, or dedoubling, of consciousness. The traumatic
      diminishment of the subject-object distinction in psychic life has several main
      effects. First, there is a change in the form of consciousness to a state which
      is focussed on the present and on immediate stimuli. Secondly, the memory system
      in which the traumatic events are recorded is nonepisodic, lacking the reflective
      component. In this way, it is unconscious. Thirdly, the traumatized-traumatizer
      dyad is represented not as two persons in relation but more nearly as a fused
      monad. This representation is not integrated into the system of self as the
      stream of consciousness but remains relatively sequestered. This sequestration is
      "unstable," determining rapidly oscillating, and opposite, forms of relatedness,
      termed "reversals." Finally, in an "uncoupled" state, the interpretation of the
      "meaning" of the traumatic event is impaired. Its construction is determined by
      affect.

PMID- 10586302
TI  - Edgar Allan Poe's "Ligeia": an object-relational interpretation.
AB  - This paper argues that Poe's short story "Ligeia," in which the narrator
      experiences the death of his adored first wife (Ligeia), a second marriage to the
      despised Rowena, and ultimately the death of Rowena and the revivification of
      Ligeia, is not a supernatural tale, but rather a psychological one. According to
      this reading, the poisoning of Rowena and the revivification of Ligeia are
      hallucinated by the narrator in the course of an opium-induced psychotic break.
      The antecedents to this break are explored in light of object relations theory,
      with particular emphasis placed on the way in which the two women function as
      part objects. Ligeia represents the narrator's romantic and spiritual side and is
      associated with the good mother, while Rowena, who represents his more mundane
      and materialistic side, is associated with the rejecting mother. It is argued
      that the narrator, functioning primarily in the schizoid position and employing
      such defense mechanisms as splitting and projection--which already require a high
      degree of fantasy--is not an unlikely candidate for such a break.

PMID- 10586303
TI  - Dialectical behavior therapy: a new treatment approach for suicidal adolescents.

PMID- 10586304
TI  - [Hydroxyethyl starch. HES in volume substitution].

PMID- 10586305
TI  - The clinical role of clinical biochemists.
AB  - Project EVETSIN investigated the training of clinical biochemists and other
      professional groups in the UK National Health Service. One of the most
      significant professional changes (with a training implication) identified was the
      increasing importance of the clinical role of clinical biochemists. The skills
      involved and the processes by which trainee clinical biochemists learn them had
      not been described or analysed to a significant extent. Factors that influence
      this changing role, the nature of the skills, how they are acquired and
      maintained, and the associated knowledge base are presented and discussed in the
      context of the training of clinical biochemists in the UK.

PMID- 10586306
TI  - Microalbuminuria: yet another cardiovascular risk factor?

PMID- 10586307
TI  - Interference in immunoassay.

PMID- 10586308
TI  - Cytochrome P450 enzyme system: genetic polymorphisms and impact on clinical
      pharmacology.
AB  - The cytochrome P450 (CYP) enzyme system is involved in the metabolism and
      elimination of numerous widely used drugs. The capacity of this system varies
      from one person to another, leading to variable drug excretion rates and
      intersubject differences in the final serum drug concentrations. For this reason,
      therapeutic response and side-effects vary widely between patients treated with
      the same dose of drug. The intersubject variability in metabolic rate is largely
      determined by genetic factors. Some CYP enzymes, including CYP2D6 and CYP2C19,
      are genetically polymorphic. Several mutant alleles have been described,
      Environmental factors such as smoking, diet and co-administration of medications
      might also influence the CYP enzyme activity. By the use of genotyping or
      phenotyping methods every individual can be classified as either a poor, an
      intermediate, an extensive or an ultrarapid metabolizer. If this could be
      performed prior to drug therapy, the knowledge could be applied to drug selection
      and dose adjustment in order to reach therapeutic serum drug levels.

PMID- 10586309
TI  - Precision, accuracy and linearity of radiometer EML 105 whole blood metabolite
      biosensors.
AB  - The analytical performance of a new, whole blood glucose and lactate electrode
      system (EML 105 analyser. Radiometer Medical A/S. Copenhagen, Denmark) was
      evaluated. Between-day coefficients of variation were < or = 1.9% and < or = 3.1%
      for glucose and lactate, respectively. Recoveries of glucose were 100 +/- 10%
      using either aqueous or protein-based standards. Recoveries of lactate depended
      on the matrix, being underestimated in aqueous standards (approximately -10%) and
      95-100% in standards containing 40 g/L albumin at lactate concentrations of 15
      and 30 mmol/L. However, recoveries were high (up to 180%) at low lactate
      concentrations in protein-based standards. Carry-over, investigated according to
      National Clinical Chemistry Laboratory Standards EP10-T2, was negligible (alpha =
      0.01). Glucose and lactate biosensors equipped with new membranes were linear up
      to 60 and 30 mmol/L, respectively. However, linearity fell upon daily use with
      increasing membrane lifetime. We conclude that the Radiometer metabolite
      biosensor results are reproducible and do not suffer from specimen-related carry
      over. However, lactate recovery depends on the protein content and the lactate
      concentration.

PMID- 10586310
TI  - Faecal elastase 1: a marker of exocrine pancreatic insufficiency in cystic
      fibrosis.
AB  - Pancreatic elastase 1 (E1), a digestive protease, is synthesized by the acinar
      cells of the pancreas. Using an enzyme-linked immunosorbent assay, we evaluated
      stool E1 levels in the following groups of patients. (a) Specimens submitted for
      occult blood examination from 20 adults, over 3 consecutive days, to assess the
      inter-day variability in E1 excretion. There were no symptoms suggestive of
      pancreatic insufficiency in this group. The mean E1 concentration over all
      samples was 457 micrograms E1/g stool (range 124-1683). The intra-assay variation
      was 6.4% (n = 14) and the inter-assay variation was 8.8% (n = 12). The mean intra
      patient variation was 17%. (b) Cystic fibrosis (CF) patients. Eight patients had
      E1 levels in the reference range (> 200 micrograms E1/g stool). The remaining 25
      patients had undetectable E1 levels. (c) A control group of children presenting
      with unexplained bronchiectasis and/or recurrent respiratory infections and no
      symptoms of pancreatic dysfunction. The mean E1 concentration in the group was
      519 micrograms E1/g stool (range 139-1941). There was no significant difference
      in E1 concentrations between the two non-CF groups, nor between the pancreatic
      sufficient CF patients when compared with both non-CF groups. There was a
      significant difference between the pancreatic-sufficient and -insufficient CF
      groups (P < 0.001) using the Mann Whitney U test. All fifteen CF patients who
      were delta F508 homozygotes had undetectable E1. It may be possible to relate CF
      genotype to the presence or absence of E1 and to the degree of pancreatic
      insufficiency. Measurement of faecal E1 in children with CF appears to
      differentiate them into a group of children with normal pancreatic function and a
      larger group with severe insufficiency.

PMID- 10586311
TI  - An unusual alkaline phosphatase isoenzyme associated with gastric carcinoma.
AB  - We describe a 50-year-old man with a diagnosis of gastric carcinoma made on
      gastroscopy after X-rays of the thoracolumbar spine had revealed multiple lytic
      metastases. A bone marrow aspirate showed adenocarcinoma cells. Polyacrylamide
      gel electrophoresis incorporating wheat germ lectin was used to separate the
      serum alkaline phosphatase isoenzymes. Isoenzyme separation showed a markedly
      increased amount of bone isoenzyme, a normal amount of liver isoenzyme and a
      considerable amount of an intestinal-like isoenzyme running cathodic to the bone
      isoenzyme. There was also some immunoglobulin-complexed alkaline phosphatase,
      which, when digested, showed more of the intestinal-like isoenzyme. This was a
      variant alkaline phosphatase isoenzyme found in a patient with a gastric
      carcinoma with a super bone scan. There have been two previous reports of
      patients with a variant alkaline phosphatase isoenzyme and a super bone-scan.

PMID- 10586312
TI  - Serum concentration and renal handling of 1,5-anhydro-D-glucitol in patients with
      chronic renal failure.
AB  - We measured serum and urinary 1,5-anhydro-D-glucitol (1,5-AG) during a glucose
      tolerance test (GTT) in patients with chronic renal failure (CRF) and compared
      the fractional excretion of 1,5-AG (FEAG) with that of diabetes mellitus (DM)
      patients and healthy controls. The mean serum 1,5-AG in CRF patients [60 +/-
      23(SE) mumol/L] was significantly lower than in controls (155 +/- 7 mumol/L) in
      spite of a normal glycaemia. The levels in the CRF group were similar to those in
      the DM group. During GTT, the blood glucose profile in the CRF group was not
      significantly different from that of the control group, and urinary glucose
      excretion was negligible. However, FEAG was significantly higher in CRF patients
      than in controls. These data suggest that serum 1,5-AG in patients with CRF
      decreases due to a decrease in 1,5-AG reabsorption, independently of glucose
      excretion, and that serum and/or urinary 1,5-AG can be a useful marker for renal
      tubular dysfunction because the 1,5-AG reabsorption system is more vulnerable
      than the glucose reabsorption system.

PMID- 10586313
TI  - A simple, rapid and sensitive semimicro method for the measurement of cyanide in
      blood.
AB  - Conventional methods do not meet the clinical need for rapid cyanide
      measurements. We report a procedure which can provide a result in 10 min. It
      should be of particular interest to laboratories serving cardiac or renal units
      which use the hypotensive agent sodium nitroprusside, and burns units to which
      fire victims may be admitted suffering the effects of HCN from inhaled smoke. A
      sample of blood (100 microL) is mixed with H3PO4, containing a surfactant, and
      the HCN is trapped in an alkaline mixture of 1,2-dinitrobenzene and 4
      nitrobenzaldehyde in 2-methoxyethanol. The catalytic action of cyanide, which
      produces purple 2-nitrophenylhydroxylamine, is stopped with acetone after 6 min.
      The absorbance measured at 560 nm shows a linear relationship with the cyanide
      concentration, but the slope varies with the ambient temperature. Since KCN added
      to both 50 mmol/L NaOH and blood gives similar assay results, any inaccuracy
      arising from changes in temperature can be avoided by running standards at the
      same time as the blood sample.

PMID- 10586314
TI  - Experience with assessing the quality of comments on clinical biochemistry
      reports.
AB  - We assess a previously described scoring system for the appropriateness of
      interpretative comments on clinical biochemistry reports over 21 distributed
      cases and over a group of 41 UK-based participants. The distributed cases covered
      a range of clinical scenarios and included pre- and post-analytical problems. The
      UK-based participants had all registered an interest in using this case
      participation for their continuing professional development; all had higher
      professional qualifications in clinical biochemistry, and the group included
      participants based in teaching hospitals and district general hospitals as well
      as those with a medical or a scientific background. Although the present scoring
      system favours participants who mention more than one possible outcome and who
      include several ideas for further investigation, its advantages seem to outweigh
      its disadvantages. The scored cases are currently unique, and are seen to be of
      major educational value not only by active participants but also by those who are
      using them for teaching or in discussion groups.

PMID- 10586315
TI  - Knowing the serum C-reactive protein concentration is not helpful when
      interpreting thyroid function tests.

PMID- 10586316
TI  - Can isoelectric focusing reduce the number of samples requiring immunofixation?

PMID- 10586317
TI  - Increased serum thymidine kinase following chemotherapy.

PMID- 10586318
TI  - Quantitative determination of methaemoglobin and carboxyhaemoglobin by co
      oximetry, and effect of anticoagulants.

PMID- 10586319
TI  - Measurement of S-100 protein using the automated chemiluminescence system Lia-mat
      300.

PMID- 10586320
TI  - Nephrogenic diabetes insipidus due to a new mutation of the arginine vasopressin
      V2 receptor gene in a girl presenting with non-accidental injury.

PMID- 10586321
TI  - Alcoholic ketoacidosis as the cause of repeated episodes of severe metabolic
      acidosis.

PMID- 10586322
TI  - New antiepileptic drugs.

PMID- 10586323
TI  - Hepatitis C virus in calibrators and quality assurance samples made from pooled
      human serum.

PMID- 10586324
TI  - Hyphens.

PMID- 10586325
TI  - Influence of acetate and bicarbonate dialysate on acyl carnitine in
      pyelonephritis.

PMID- 10586326
TI  - Atorvastatin and low-density lipoprotein subfractions profile in mixed
      hyperlipidaemia: a contributory effect of reduced hepatic lipase activity?

PMID- 10586327
TI  - Are cotinine assays of value in predicting adverse pregnancy outcome?

PMID- 10586328
TI  - An update on thymidylate synthase inhibitors.

PMID- 10586329
TI  - How to interpret the radiological abnormalities that persist after treatment in
      non-Hodgkin's lymphoma patients?

PMID- 10586330
TI  - High-dose chemotherapy: is it standard management for any common solid tumor?
AB  - High-dose chemotherapy with stem-cell support had as its basis the observation of
      dose-response relationships for many chemotherapeutic agents in laboratory
      models. The rationale to explore high-dose treatment in the clinic was further
      enhanced by several retrospective reviews in the 1980s which suggested delivered
      dose intensity of treatment was an important determinant of patient outcome. The
      availability of hematopoietic growth factors and technologic advances in the
      efficiency of stem-cell collection and administration have made the evaluation of
      exploring high-dose therapy safe and feasible. However, real questions remain
      regarding the apparently superior results of this treatment in the management of
      solid tumors. This paper reviews the results of high-dose chemotherapy in breast,
      ovarian and small cell lung cancers. Firstly the evidence for a dose-response
      relationship to chemotherapeutic agents in the 'standard' dosage range is
      examined. Secondly results of non-randomized and, where available, randomized
      trials of high-dose chemotherapy (HDCT) with stem-cell support are summarized and
      finally conclusions regarding the weight of the evidence for use of HDCT as
      'standard' treatment are given. In none of these tumors is there sufficient
      evidence from randomized trials to consider HDCT a standard to be offered to all
      patients with a given stage of disease. The apparent benefit of HDCT seen in
      phase II trials could well be explained by such phenomena as stage shifts and
      patient selection. Many randomized trials in ovary and breast cancer are either
      ongoing or presented only as abstracts so final results must be awaited to
      quantify the benefit, if any of HDCT. It is acknowledged, however, that some
      practitioners already utilize this treatment. We speculate about the differences
      in philosophical approaches to cancer treatment which might contribute to early
      acceptance of novel therapies in the absence of adequate randomized data.

PMID- 10586331
TI  - The influence of familial and hereditary factors on the prognosis of breast
      cancer.
AB  - BACKGROUND: Family history is a well recognized risk factor for breast cancer,
      but its impact in terms of breast cancer survival is uncertain. The recent
      identification of breast cancer predisposing genes has provided new clinical
      insights in this field. DESIGN: English literature identified through Medline
      between 1976 and February 1999 was reviewed including search terms: breast
      cancer, survival, prognosis, family history, genetics, BRCA1, BRCA2, and related
      articles. RESULTS: Publications were divided into three categories. Family
      history-based studies: eighteen articles were reviewed. Four studies showed a
      statistically significant better survival in patients with a family history of
      breast cancer, and two studies demonstrated a significantly worse prognosis in
      this context. The remaining articles showed no significant difference. LINKAGE
      STUDIES: Two studies based on linkage to BRCA1 found that overall survival was
      better in linked families. A third one concluded to a worse outcome in BRCA2
      linked tumors. MUTATION-BASED STUDIES: 10 studies looking at the association
      between germ-line mutations in BRCA1/BRCA2 and clinical outcomes were reviewed.
      Eight articles reported no significant difference in outcome, whereas two studies
      showed a worse outcome in patients with mutations. CONCLUSIONS: Conflicting data
      exist as to whether the prognosis of familial or hereditary breast cancer differs
      from that of sporadic cases. Some of the discrepancies may be explained by
      methodological differences or biases. However, no studies showed a survival
      advantage for BRCA1 mutation carriers. This seems to indicate that BRCA1-related
      breast cancer is not associated with a survival advantage, and that in fact,
      certain BRCA1 germline mutations confer a worse prognosis. However, to adequately
      answer this question, more efficient molecular tools to identify all the genetic
      changes responsible for breast cancer predisposition, and large cohort studies to
      evaluate their clinical consequences, are needed.

PMID- 10586332
TI  - Paclitaxel, ifosfamide and cisplatin (TIP) chemotherapy for recurrent or
      persistent squamous-cell cervical cancer.
AB  - PURPOSE: The results of salvage chemotherapy for recurrent or persistent squamous
      cell cervical cancer are unsatisfactory. Cisplatin and Ifosfamide are effective
      compounds in cervical cancer. Paclitaxel has recently been tested with promising
      results. The aim of this study was to assess the efficacy of a combination of
      paclitaxel, ifosfamide and cisplatin (TIP) for persistent/recurrent squamous-cell
      cervical carcinoma in a phase II trial. PATIENTS AND METHODS: Forty-five women
      were treated with the TIP regimen. Thirty-one had received prior irradiation.
      Paclitaxel was given at a dose of 175 mg/m2, ifosfamide at a dose of 5 g/m2, and
      cisplatin at a dose of 75 mg/m2 (50 mg/m2 in irradiated patients) at three-week
      intervals. RESULTS: We observed 15 clinical complete responses, 15 partial
      responses, 9 stable diseases and 6 progressions. The objective response rate was
      67% (95% confidence interval: 51%-81%). Ten complete responders underwent
      subsequent surgery and seven had pathology-defined complete responses (two in
      irradiated areas). The response rate was 52% in irradiated and 75% in non
      irradiated areas. The median survival for non-responders is 6 months, 9+ month
      for partial responders and 13+ for complete responders. The most relevant side
      effect was myelotoxicity, with 91% of patients experiencing grade 3-4. One woman
      had life-threatening toxic effects. CONCLUSIONS: This combination is highly
      effective for salvage treatment in non-irradiated patients. For irradiated women
      the response rate is higher than that observed with other regimens but further
      investigation is warranted. The toxicity is relevant but adequate hydration and
      prolonged infusion of ifosfamide make it acceptable.

PMID- 10586333
TI  - Phase II study of first-line LY231514 (multi-targeted antifolate) in patients
      with locally advanced or metastatic colorectal cancer: an NCIC Clinical Trials
      Group study.
AB  - BACKGROUND: Metastatic colon cancer is difficult to treat with treatment being
      palliative and with little effect on survival. This trial has evaluated the
      effects of LY231514 (Multitargeted antifolate (MTA)) given to previously
      untreated patients with recurrent or metastatic colorectal carcinoma. PATIENTS
      AND METHODS: All patients were required to have a histological diagnosis of
      colorectal adenocarcinoma with measurable disease and no prior chemotherapy for
      metastatic disease. Patients had to have had performance status of 0-2,
      pretreatment absolute granulocyte count of > or = 1.5 x 10(9)/l and a platelet
      count of > or = 150 x 10(9)l. Patients received MTA at a dose of 600 mg/m2 by 10
      minute infusion on day 1 repeated every 21 days. After the first 9 patients, this
      dose was reduced down to 500 mg/m2 every 21 days because of toxicity. Doses of
      MTA were modified depending on nadir counts. RESULTS: Thirty-two eligible
      patients were enrolled and twenty-nine were evaluable for response. Three
      patients did not have repeat radiological testing to determine response because
      they went off study after only one cycle of treatment due to toxicity. In the 29
      evaluable patients, there was 1 complete response, 4 partial responses and 14
      patients with stable disease. Response rate was 17.2% (95% confidence intervals:
      5.8%-35.8%). All responses occurred in the patients receiving a starting dose of
      MTA 500 mg/m2. Median time to progression for all eligible patients was 3.3
      months. The most common toxicities experienced were mild to moderate fever,
      lethargy, anorexia, nausea, vomiting, stomatitis, abdominal pain, diarrhea, and
      skin rash. There was one death due to sepsis. CONCLUSION: Single-agent MTA at 500
      mg/m2 given every three weeks has modest activity in metastatic colorectal
      carcinoma.

PMID- 10586334
TI  - The role of positron emission tomography (PET) in the management of lymphoma
      patients.
AB  - BACKGROUND: Treatment of both Hodgkin's disease (HD) and aggressive non-Hodgkin's
      lymphoma (NHL) with abdominal presentation at the time of diagnosis is often
      followed by detection of residual masses by computed tomography (CT). However, CT
      is usually unable to discriminate between residual tumor and fibrosis/necrosis.
      We investigated the ability of fluorine-18 fluorodeoxyglucose positron emission
      tomography (PET) to differentiate between residual active tumor tissue and
      fibrosis. PATIENTS AND METHODS: Forty-four patients with HD or aggressive NHL
      presenting abdominal involvement (41% with bulky mass) were studied with CT and
      PET at the end of chemotherapy +/- radiation therapy. RESULTS: After treatment,
      seven patients had negative PET and CT, and none of them relapsed. The remaining
      37 patients all had positive CT (abnormalities < or = 10%). All of the 13 who
      also had positive PET relapsed (100%). By contrast, there was only 1 (4%) relapse
      among the 24 patients who were positive at CT but negative at PET. The two-year
      actuarial relapse-free survival rate was 95% for those with negative PET compared
      with 0% for positive PET patients (P < 0.000000). CONCLUSIONS: In lymphoma
      patients with abdominal masses who present CT positivity at restaging, PET should
      be considered the noninvasive imaging modality of choice for differentiating
      early recurrences or residual disease from fibrosis.

PMID- 10586335
TI  - Positron emission tomography with fluorine-18-2-fluoro-2-deoxy-D-glucose (F18
      FDG) does not visualize extranodal B-cell lymphoma of the mucosa-associated
      lymphoid tissue (MALT)-type.
AB  - BACKGROUND: On the basis of promising data on the use of fluorine-18-2-fluoro-2
      deoxy-D-glucose (F18-FDG) whole body positron emission tomography (WB-FDG-PET) in
      the staging of patients with lymphoma, we initiated a pilot series to evaluate
      the role of WB-FDG-PET in the staging of extranodal B-cell lymphoma of the mucosa
      associated lymphoid tissue (MALT) type. PATIENTS AND METHODS: We examined ten
      consecutive patients with histologically-verified MALT-type lymphomas of various
      origin before initiation of therapy. Nine patients had low-grade lymphomas (five
      cases of gastric lymphoma, two patients with lymphoma arising in the lung, one
      parotid and one lacrimal gland lymphoma), while one patient had a high-grade
      gastric lymphoma arising from a low-grade background. Two patients had stage EI,
      seven had stage EII disease, and one presented with stage EIII. WB-FDG-PET scans
      were performed 40 min following the injection of 300-380 MBq of F18-FDG. The PET
      scans were correlated with extensive conventional staging including
      ophthalmologic investigation, otolaryngologic examination, gastroscopy,
      endosonography, enteroclysis, colonoscopy, CT of thorax and abdomen, and bone
      marrow biopsy. RESULTS: WB-FDG-PET documented no lymphoma in any of the 10
      patients studied, as no focal tracer uptake was demonstrated in either gastric or
      extragastric lesions or in involved lymph nodes, irrespective of histologic
      grading. In three patients the scan showed a false negative result with respect
      to the MALT lesions but showed focal tracer uptake indicating tumor spread,
      which, however, was ruled out by further follow-up and biopsy, respectively, and
      was thus rated false positive. Due to these results, the study was discontinued
      prematurely after the first ten patients. CONCLUSIONS: These discouraging results
      indicated that WB-FDG-PET is not useful for staging and follow-up of MALT-type
      lymphoma, and should therefore not be included in the clinical decision making
      process.

PMID- 10586336
TI  - Fludarabine alone compared to CHVP plus interferon in elderly patients with
      follicular lymphoma and adverse prognostic parameters: a GELA study. Groupe
      d'Etudes des Lymphomes de l'Adulte.
AB  - BACKGROUND: Fludarabine was associated with a good response and was well
      tolerated in patients with follicular lymphoma in phase II trials and this
      treatment may be associated with less adverse events than treatment with CHVP
      plus interferon in elderly patients. PATIENTS AND METHODS: One hundred thirty-one
      patients older than 59 years with a follicular lymphoma and poor prognosis were
      randomized between the association of CHVP (12 cycles in 18 months) plus
      interferon (5 MU TIW for 18 months) or fludarabine alone (25 mg/m2/d x 5 days for
      6 cycles, then 20 mg/m2/day for 6 further cycles for 18 months). Poor prognosis
      was defined by the presence of a large tumor mass, poor performance status, the
      presence of B symptoms, above normal LDH level, or > or = 3 mg/l beta
      microglobulin level. RESULTS: Patients treated with CHVP plus interferon had a
      higher response to treatment, a longer time to progression and a longer survival
      than those treated with fludarabine alone (P < 0.05 for all analyses). With a
      median follow-up of 29 months, the 2-year failure-free survival was 63% for the
      CHVP-plus-interferon arm compared to 49% for the fludarabine arm and the two-year
      survival was 77% and 62%, respectively. This benefit was confirmed in a
      multivariate analysis including initial prognostic parameters. Fludarabine alone
      was associated with less neutropenia than CHVP plus interferon. Interferon was
      decreased or stopped in 39% of the patients because of severe fatigue.
      CONCLUSIONS: CHVP plus interferon over 18 months was associated with a better
      outcome, even though the combination of interferon plus chemotherapy was less
      well tolerated than fludarabine.

PMID- 10586337
TI  - Comparison of the long-term mortality in Hodgkin's disease patients with that of
      the general population.
AB  - BACKGROUND: Although Hodgkin's disease can be treated successfully, its long-term
      survival rate has yet to be definitely established. We compared the long-term
      mortality rate of patients diagnosed as having Hodgkin's disease with that of the
      general population. PATIENTS AND METHODS: We studied a retrospective cohort of
      477 patients who received pathology-confirmed diagnoses of Hodgkin's disease
      between 1967 and 1993 and were treated with combined chemotherapy or radiotherapy
      with follow-up from the day of diagnosis. Standardised mortality ratios were
      computed with reference rates taken from the Spanish population. RESULTS: The
      follow-up was complete for 427 (89.5%) of the patients. The median follow-up time
      was 8 years, 133 patients (28%) died and the median survival time was 21 years.
      The overall survival rates were 80% at 5 years, 70% at 10 years, and 64% at 15
      years after diagnosis. The standardised mortality ratios were 10.8 (95%
      confidence interval: 9.0-12.8, P < 0.0001) overall, 5.5 in patients in favourable
      stages (IA, IIA), and 15.2 in those with unfavourable stages (IB, IIB, III, IV).
      There was a decreasing trend in mortality by calendar period (standardised
      mortality ratios for 1967-1975, 1976-1974 and 1985-1993: 16.8, 10.3 and 5.1,
      respectively). Higher mortality was observed in all periods of follow-up after
      diagnosis, even after 20 years. CONCLUSIONS: Despite the improvements in
      treatment, mortality in Hodgkin's disease remains higher than in the general
      population in all disease stages, even 20 years after diagnosis.

PMID- 10586338
TI  - Treatment of multicentric Castleman's disease complicated by the development of
      non-Hodgkin's lymphoma with high-dose chemotherapy and autologous peripheral stem
      cell support.
AB  - BACKGROUND: Castleman's disease or angiofollicular lymph node hyperplasia is a
      rare entity with a localized/unicentric or a generalized/multicentric
      presentation. While surgery is curable for most localized presentations, there is
      limited information regarding the optimal management of the multicentric type.
      The latter type is associated with a poor prognoses and can be associated with
      the development of lymphoma and infections. PATIENTS AND METHODS: In this report
      we describe a case of multicentric Castleman's disease who failed steroids and
      chemotherapy and developed a follicular mixed lymphoma. He was treated with high
      dose chemotherapy with autologous stem-cell support and remains disease at four
      years of follow-up. CONCLUSIONS: A long-term durable remission may be possible
      with high dose chemotherapy with stem-cell support. This treatment modality
      should be considered an option in the management of multicentric Castleman's
      disease.

PMID- 10586339
TI  - A phase II study of cisplatin, ifosfamide and doxorubicin in operable primary,
      axial skeletal and metastatic osteosarcoma. European Osteosarcoma Intergroup
      (EOI).
AB  - BACKGROUND: Despite advances in the treatment of primary limb osteosarcoma, the
      outcome of patients with primary metastatic and axial skeletal disease remains
      poor. The European Osteosarcoma Intergroup have assessed a combination
      chemotherapy regimen consisting of ifosfamide (IFOS) 3 g/m2/dl-2, doxorubicin
      (DOX) 25 mg/m2/dl-3 i.v. bolus and cisplatin (CDDP) 100 mg/m2/dl. PATIENTS AND
      METHODS: One hundred nine previously untreated patients with primary osteosarcoma
      were registered. Eligibility was confirmed in 103. At presentation, 45 eligible
      patients had metastatic disease, 15 axial skeletal primary tumours and 43 non
      metastatic limb tumours. RESULTS: The major toxicities were myelosuppression
      (90%, grade 3 or 4) and nausea and vomiting (74%, grade 3 or 4). Overall mean
      relative dose intensity (RDI) was 80% (88% CDDP, 75% IFOS, 81% DOX). Clinical
      response as measured by reduction in tumour volume occurred in 36% (95%
      confidence interval (95% CI): 27%-47%) of primary tumours. Response of pulmonary
      metastases to chemotherapy was seen in 33% (95% CI: 19%-49%). Good histological
      response (> or = 90% necrosis of the tumour) occurred in 33% (95% CI: 22%-45%) of
      resected tumours. Five-year survival was 62% in limb-non-metastatic, 41% in axial
      skeletal and 16% in limb metastatic patients. CONCLUSIONS: This regimen is active
      in osteosarcoma but does not appear to be more active than the two-drug CDDP-DOX
      regimen currently recommended by EOI.

PMID- 10586340
TI  - A randomized, open, parallel-group trial to compare the endocrine effects of oral
      anastrozole (Arimidex) with intramuscular formestane in postmenopausal women with
      advanced breast cancer.
AB  - BACKGROUND: This study provides a direct randomized comparison of a new
      generation, non-steroidal aromatase inhibitor, anastrozole (Arimidex), with a
      steroidal aromatase inhibitor (formestane) with respect to oestrogen (oestradiol,
      oestrone, and oestrone sulphate) suppression and tolerability. PATIENTS AND
      METHODS: Sixty postmenopausal women with advanced breast cancer were randomized
      to receive either anastrozole 1 mg once daily orally (n = 29), or formestane 250
      mg once every two weeks by intramuscular injection (n = 31). Treatment was
      continued until progression of disease or withdrawal from the study. The primary
      endpoints of this study were oestradiol suppression and tolerability. The
      secondary endpoints included oestrone and oestrone sulphate suppression. All
      laboratory analyses were conducted 'blind' of the randomized drug treatment.
      RESULTS: Anastrozole produced a greater and more consistent suppression of
      oestradiol levels compared with formestane. Based on two- and four-week
      measurements, the mean fall from baseline (pre-dose) in oestradiol level was 79%
      and 58% in the anastrozole and formestane groups, respectively (P = 0.0001).
      After four weeks of treatment, oestrone and oestrone sulphate levels were also
      suppressed to a greater extent by anastrozole compared with formestane (oestrone:
      85% versus 67%, respectively, P = 0.0043; oestrone sulphate: 92% versus 67%,
      respectively, P = 0.0007). No statistical differences were seen between the two
      drugs in the incidence of adverse events. CONCLUSIONS: Anastrozole provides a
      more consistent and significantly more effective suppression of oestradiol
      compared with formestane. Similar results were observed for oestrone and oestrone
      sulphate. The clinical significance of these differences in total oestrogen
      suppression remains to be established.

PMID- 10586341
TI  - Tumors of the papilla of Vater--inadequate diagnostic impact of endoscopic
      forceps biopsies taken prior to and following sphincterotomy.
AB  - BACKGROUND: It has been proposed that adenomas of the papilla of Vater are
      precursors of adenocarcinomas. Duodenoscopy with ERCP and forceps biopsies have
      substantially improved the morphologic exploration of the major duodenal papilla.
      Yet there is little and contradictory information as to the diagnostic accuracy
      of endoscopic biopsies in tumors of the papilla. Moreover, after endoscopic
      sphincterotomy data on the diagnostic impact of endoscopic biopsies from the
      papilla are scarce and, in most cases, retrospectively obtained. Thus, the aim of
      the present prospective and histopathologically controlled study was to assess
      the diagnostic accuracy of endoscopic biopsies taken from tumors of the papilla
      before and after sphincterotomy. PATIENTS AND METHODS: Forty patients with tumors
      of the papilla of Vater were included in the study. In each case, a comparison
      was made between endoscopic forceps biopsy diagnoses prior to and following
      sphincterotomy and the definitive histological diagnosis after surgical tumor
      resection. RESULTS: Resected tumors were diagnosed histomorphologically as
      follows: 19 adenocarcinomas (47%), 6 tubular adenomas (15%), 7 villous adenomas
      (17%), 7 inflammatory non-neoplastic lesions (pseudotumors) (17%), and one
      adenomyoma (2%). Overall accuracy for preoperative histopathological diagnosis
      was 62% (25 of 40, 95% CI: 47%-76%) prior to sphincterotomy while it was 70% (28
      of 40, 95% CI: 55%-81%) following the procedure. Regarding adenocarcinomas,
      sensitivity was found to be 21% (4 of 19, 95% CI: 8%-43%) prior to and 37% (7 of
      19, 95% CI: 19%-58%) after sphincterotomy while specificity was 100% at both
      times. CONCLUSIONS: Endoscopic forceps biopsies do not allow for reliable
      preoperative diagnosis of tumors of the papilla of Vater.

PMID- 10586342
TI  - High antitumour activity of ET743 against human tumour xenografts from melanoma,
      non-small-cell lung and ovarian cancer.
AB  - BACKGROUND: Ecteinascidin-743 (ET743) is a novel antitumour agent originating
      from the Caribbean tunicate Ecteinascidia turbinata. It has potent cytotoxic and
      antitumour activity and a potential new mechanism of action. The aim of the
      present study was to further explore the antitumour activity of ET743 in human
      tumour xenografts from melanoma, non-small-cell lung and ovarian cancer. DESIGN:
      As the antitumour profile of ET743 was largely unknown a chemo-sensitive and a
      marginal chemo-resistant human tumour xenograft were selected for each tumour
      type. ET743 was administered intravenously using two administration schedules
      (days 0, 4, 8 and 0-2, 13-15). RESULTS: ET743 was very active at the maximum
      tolerated dose (MTD) in the chemo-sensitive xenograft melanoma MEXF 989, non
      small-cell lung cancer LXFL 529, and ovarian cancers HOC22 and (marginally
      resistant to cisplatin) HOC18. Activity was also seen at 1/2 MTD. Apart from
      HOC18, ET743 caused complete remissions in the responding xenografts. The
      compound was inactive in the chemo-resistant xenograft melanoma MEXF 514 and non
      small-cell lung cancer LXFA 629. In terms of antitumour activity the days 0, 4, 8
      schedule had advantages over the days 0-2, 13-15 schedule. CONCLUSIONS: ET743 is
      a very effective agent in chemo-sensitive and marginal chemo-resistant
      xenografts, but inactive in chemo-resistant tumour xenografts. The activity of
      ET743 in the marginally cisplatin-resistant ovarian cancer HOC18 might indicate
      absence or incomplete cross-resistance against cisplatin. It is recommended to
      include melanoma, non-small-cell lung cancer, and ovarian cancer in phase II
      clinical trials and to use an intermittent schedule.

PMID- 10586343
TI  - Cowden disease and Lhermitte Duclos disease, markers of breast carcinoma: report
      of two patients.

PMID- 10586344
TI  - Bilateral facial nerve palsy secondary to the administration of high-dose
      paclitaxel.
AB  - Bilateral facial nerve palsy is an uncommon occurrence. We describe a case of
      bilateral facial nerve palsy secondary to a single cycle of high-dose paclitaxel
      therapy (825 mg/m2), in a woman with breast cancer. Prior to her high-dose
      therapy, she had a residual grade 2 peripheral neuropathy following treatment
      with ten cycles of standard-dose paclitaxel (total dose 3200 mg). The features of
      the peripheral neuropathy due to standard-dose paclitaxel, which can be both
      motor and sensory, are well described. Cumulative paclitaxel dose is considered a
      risk factor for development of the neuropathy. Although facial nerve palsy
      secondary to paclitaxel is not previously reported, other cranial nerve toxicity
      has been described. Consistent with reports of the reversibility of paclitaxel
      induced peripheral neuropathy, the facial nerve palsies in our patient resolved
      over 23 months. Ongoing studies of high-dose paclitaxel warrant close attention
      to its cumulative neurotoxic effects, particularly in patients previously treated
      with neurotoxic chemotherapy.

PMID- 10586345
TI  - Accelerated progression of multiple myeloma during anti-CD20 (Rituximab) therapy.

PMID- 10586346
TI  - Substantial activity of budesonide in patients with irinotecan (CPT-11) and 5
      fluorouracil induced diarrhea and failure of loperamide treatment.
AB  - BACKGROUND: Diarrhea is one of the most disturbing effects of chemotherapy,
      affecting quality of life on the one hand and limiting applicable doses on the
      other. Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are associated with an
      elevated risk of developing severe diarrhea. Standard therapy consists of high
      dose loperamide, but is associated with frequent failure. Other therapeutic
      regimens are still experimental. Endoscopic examination of a patient with severe
      loperamide-resistant diarrhea after CPT-11 chemotherapy revealed an inflammation
      of the ileo-coecal region. Oral therapy with the topical corticosteroid
      budesonide was immediately effective. This led to a phase I study of budesonide
      in CPT-11- and 5-FU-induced and loperamide-refractory diarrhea. PATIENTS AND
      METHODS: Fourteen patients with CPT-11- and seven patients with 5-FU-induced
      grade 3-4 (NCI/WHO) diarrhea and loperamide failure were enrolled in this study.
      All patients had metastatic colorectal cancer. RESULTS: In 86% of the CPT-11- and
      57% of the 5-FU-treated patients with grade 3-4 diarrhea and loperamide failure,
      treatment with budesonide resulted in a reduction of diarrhea severity by at
      least two grades. CONCLUSIONS: The orally administered topical active steroid
      budesonide is highly effective in the therapy of loperamide-refractory
      chemotherapy (CPT-11 or 5-FU)-induced diarrhea.

PMID- 10586347
TI  - A randomized controlled trial of local injections of hyaluronidase versus placebo
      in cancer patients receiving subcutaneous hydration.
AB  - BACKGROUND: Most cancer patients develop reduced oral intake or dehydration
      before death. Subcutaneous hydration (SCH) can be safe and effective. SCH is
      frequently administered using hyaluronidase to improve fluid absorption. The
      objective of this study was to determine the effects of hyaluronidase on patient
      comfort during bolus SCH. PATIENTS AND METHODS: Twenty-one cancer patients
      requiring parenteral hydration were administered a 500 cc bolus of two-thirds
      dextrose (5%) and one-third normal saline solution subcutaneously at 08:00 and
      16:00 hours during day 1 and day 2. On day 1 patients were randomized on a double
      blind basis to receive 150 units of hyaluronidase versus placebo as a bolus into
      the site of infusion immediately before starting each one-hour infusion. During
      day 2 patients were crossed over to receive the alternate treatment at a new
      infusion site. Visual analogue scales (0 = best, 100 = worst) for pain and
      swelling at the infusion site were completed by each patient. In addition,
      investigators blindly assessed the site of infusion for the presence of edema,
      rash, and leakage. RESULTS: No significant differences were observed for pain,
      swelling, edema, rash or leakage between the placebo and the hyaluronidase
      scores. After completion of the two days of the study, patients blindly chose
      hyaluronidase in 1 (5%) case, placebo in 5 (24%) cases, and no preference in 15
      (71%) cases (P < 0.01). There was no treatment or interaction effect for pain,
      except for a period effect (P = 0.045) for the morning bolus administration.
      There were no treatment, period, or interaction effects for any of the other
      variables. CONCLUSIONS: Our results suggest that hyaluronidase is not necessary
      for routine bolus SCH. It may still be useful for a minority of patients who are
      not able to tolerate infusion well due to swelling or pain.

PMID- 10586348
TI  - Analysis of BCL-10 gene mutations in ovarian cancer cell lines.

PMID- 10586350
TI  - Advances in the primary treatment of rectal cancer: a European surgeons view.

PMID- 10586349
TI  - Weekly paclitaxel plus Herceptin in metastatic breast cancer patients who relapse
      after stem-cell transplant.

PMID- 10586351
TI  - Recent advances in the treatment of rectal carcinoma.

PMID- 10586352
TI  - Primary treatment of rectal cancer: present and future.

PMID- 10586353
TI  - Aging, DNA methylation and cancer.

PMID- 10586354
TI  - Lung cancer radiation treatment in the elderly.

PMID- 10586355
TI  - Up date in the management of advanced ovarian carcinoma.

PMID- 10586356
TI  - Idarubicin including regimens in acute myelogenous leukemia in elderly patients.

PMID- 10586357
TI  - [Noninvasive screening for pheochromocytoma in patients with an incidentally
      discovered adrenal mass: usefulness of provocative test with metoclopramide and
      131I-metaiodobenzylguanidine scintigraphy].
AB  - Pheochromocytoma accounts for approximately 25% of incidentally discovered
      adrenal masses. Certain diagnostic procedures (e.g., adrenal arteriography,
      needle biopsy of an adrenal mass), anesthesia and abdominal surgery may cause a
      sudden release of catecholamines from a pheochromocytoma and induce paroxysmal
      attacks of hypertension. In addition, pheochromocytoma is well known to cause
      unsuspected operating room deaths. Therefore, we must carefully separate this
      functioning neoplasm from other types of adrenal masses. In this study, we
      compared the results of noninvasive tests including (1) assay of urinary
      catecholamines and their metabolites, (2) a provocative pharmacologic test using
      metoclopramide (MCP test), and (3) 131I-metaiodobenzylguanidine (MIBG)
      scintigraphy to screen for pheochromocytoma in 10 consecutive patients with an
      incidentally discovered adrenal mass (6 pheochromocytomas and 4 non-functioning
      adrenocortical adenomas). We measured the 24-hour urinary excretion of
      catecholamines, metanephrines and vanillyl mandelic acid in all 10 patients; 5
      were positive, 4 were negative and 1 was false-negative (sensitivity = 83%,
      specificity = 100%). The MCP test was performed in 7 patients; 3 were positive, 3
      were negative and 1 was false-negative (sensitivity = 75%, specificity = 100%).
      MIBG scintigraphy was performed in 7 patients; 4 were positive, 1 was negative
      and 2 were false-negative (sensitivity = 67%, specificity = 100%). According to
      these results, all patients with an incidentally discovered adrenal mass should
      undergo a determination of the 24-hour urinary excretion of catecholamines and
      their metabolites, including metanephrines. If this urine assay is negative,
      other noninvasive tests including the MCP test and MIBG scintigraphy should be
      considered in selected patients with radiographic characteristics of
      pheochromocytoma.

PMID- 10586358
TI  - [Serum alkaline phosphatase flare in prostate cancer accompanied by bone
      metastases and treated with hormonal therapy. TEKK Study Group].
AB  - To clarify the roles of alkaline phosphatase (ALP) flare in prostate cancer
      accompanied by bone metastases and treated with hormonal therapy, we evaluated
      the clinicopathological character, treatment efficacy and outcome for patients
      with and without ALP flare. We evaluated 60 patients with newly diagnosed
      prostate cancer accompanied by bone metastases and treated with hormonal therapy,
      whose response in terms of serum prostate specific antigen (PSA) levels showed a
      partial response (PR) or better response. The patients were classified into two
      groups, an ALP flare group (13 cases) and a non-ALP flare group (47 cases). The
      former showed serum ALP elevation of more than double, and the latter less than
      double that of pretreatment levels following hormonal therapy. Patient
      characteristics, PSA response and outcome were compared between the two groups.
      Extent of disease (EOD) as grade of bone metastasis was significantly higher in
      the ALP flare group than in the non-flare group (p = 0.0352). Pre-treatment serum
      PSA levels were also significantly higher in the ALP flare group (p = 0.0010).
      However, there were no significant differences in pretreatment serum ALP levels.
      Serum PSA levels were normalized in 37 of the 47 patients (78.7%) in the non-ALP
      flare group compared with 6 of the 13 (46.2%) in the ALP flare group (p =
      0.0211). Moreover, the period until biochemical failure was significantly shorter
      for the ALP flare than the non-flare group (p = 0.0027). These results suggest
      that prostate cancer patients with bone metastases in whom ALP flare is observed
      in response to hormonal therapy tend to have more extensive bone metastases, high
      pretreatment PSA levels, to be resistant to PSA normalization and more likely to
      experience biochemical failure.

PMID- 10586359
TI  - [Clinical study of carcinoma of the penis].
AB  - We reviewed six cases of carcinoma of the penis seen at our department during the
      last 12 years. The mean age and mean followup period were 56 +/- 11 years and 53
      +/- 42 months, respectively. Inguinal lymphadenopathy was evident in all
      patients, one of whom was diagnosed as having nodal metastasis because of the
      persistence of adenopathy after antimicrobial therapy. Four patients, had Jackson
      Stage 1, 1 Stage 2 and 1 Stage 3 cancer. The patient with Stage 3 cancer
      underwent total penectomy and bilateral inguinal lymphadenectomy. He died of
      cancer 2 years after the operation. The 5 patients with stage 1 or 2 underwent
      partial penectomy without lymphadenectomy. Pathological examination showed
      moderately differentiated squamous cell carcinoma (SCC) in 2 patients with stage
      2 and 3 cancer, well differentiated SCC in 3 and verrucous carcinoma in the other
      patient with stage 1 cancer. Prophylactic external radiation therapy to the groin
      was performed in 3 of the 4 patients with invasion to corpus spongiosum (pT2).
      Two of the 3 patients developed mild radiation dermatitis, and no major
      complications were observed. The 5 patients with clinically negative nodes showed
      no evidence of recurrence after surgery. As reported by others, inguinal node
      metastasis appears to worsen the prognosis of patients with carcinoma of the
      penis.

PMID- 10586360
TI  - [Laparoscopic resection of retroperitoneal tumors: report of two cases].
AB  - Here we report two rare cases of retroperitoneal tumors which were found
      incidentally and resected laparoscopically. Case 1; A 43-year-old woman presented
      with general fatigue and revealed liver dysfunction. Although the initial
      diagnosis with computed tomography (CT) was left non-functioning adrenal tumor,
      it was proven as a retroperitoneal tumor adjacent to the left adrenal gland by
      laparoscopic examination. The tumor was resected laparoscopically and diagnosed
      histopathologically as a solitary retroperitoneal neurofibroma. Case 2; A 68-year
      old man was being followed for a renal stone and a perirenal tumor was found by
      CT. It was resected laparoscopically and diagnosed as a mature retroperitoneal
      teratoma by histopathological examination. We conclude that laparoscopic
      resection is useful for the retroperitoneal tumors as well as for adrenal tumors.

PMID- 10586361
TI  - [Bilateral synchronous renal cell carcinoma: report of three cases].
AB  - We report here three cases of bilateral synchronous renal cell carcinoma. One of
      the 3 patients underwent bilateral partial nephrectomy, while the other 2
      underwent combined partial nephrectomy and radical nephrectomy. All patients
      received adjuvant therapy of interferon-alpha and tegafur uracil. In the
      management of synchronous bilateral renal cell carcinoma, we discussed the
      selection of surgical procedure for primary lesions, i.e., based on the renal
      function of both sides, and the necessity of adjuvant therapy in such cases.

PMID- 10586362
TI  - [Renal angiomyolipoma with marked extrarenal development: a case report].
AB  - A 28-year-old female complained of minimal fever elevation. Computed tomography
      (CT) revealed a left renal tumor of 10 cm in diameter. Ultrasonogram and CT,
      magnetic resonance imaging and angiography suggested a renal angiomyolipoma (AML)
      with marked extrarenal development. Partial nephrectomy was performed using a
      microwave tissue coagulater without clamping of the renal artery. The tumor
      weight was 800 g and the pathological diagnosis was AML. The management of large
      AML is reviewed in the literature. Nephron sparing surgery should be performed
      even in patients who have a larger tumor with extrarenal development.

PMID- 10586363
TI  - [A case of renal capsular leiomyoma].
AB  - A 50-year-old woman was admitted for the treatment of retroperitoneal tumor.
      Enhanced comtuted tomography showed a low density mass between the left kidney
      and psoas muscle. Magnetic resonance imaging revealed a high intensity and
      homogeneous mass on T1-weighted sequence, and a low intensity and heterogeneous
      mass on T2-weighted sequence. Surgical exploration revealed that the tumor was
      adherent to the left kidney and en bloc excision of the tumor and the left kidney
      was performed. Histopathological diagnosis was leiomyoma originating from the
      renal capsule.

PMID- 10586364
TI  - [A case of transitional cell carcinoma presenting as rupture of a renal
      arteriovenous malformation].
AB  - A 76-year-old man was seen at this hospital for the treatment of asymptomatic
      gross hematuria. Retrograde pyelography revealed a filling defect in the left
      lower calyx. The diagnosis was left renal pelvic carcinoma by urinary cytology.
      The patient underwent left nephrouretectomy with partial cystectomy. Hemosiderin
      accumulation on histological examination demonstrated an arteriovenous
      malformation in the left lower calyx. Transitional cell carcinoma was confirmed
      apart from the arteriovenous malformation, and no relation between the two was
      seen. These findings suggest the coexistence of a renal arteriovenous
      malformation with a renal pelvic and ureteral carcinoma. Hematuria was due
      probably to rupture of the renal arteriovenous malformation.

PMID- 10586365
TI  - [A case of transitional cell carcinoma of the bladder in a juvenile patient].
AB  - A case of transitional cell carcinoma of the bladder in a 18-year-old female is
      presented. Cystoscopic examination revealed a papillary tumor on the left lateral
      wall. Histopathology of the excised tumor showed transitional cell carcinoma, G1
      > 2, pT1a. Recurrence has not been observed for about 1 year, after intravesical
      pirarubicin therapy.

PMID- 10586366
TI  - [A case of urothelial carcinoma associated with penile metastasis].
AB  - A 71-year-old man, who had been treated with continuous ambulatory peritoneal
      dialysis due to chronic renal failure for 5 months, visited our hospital with a
      complaint of penile induration in April, 1998. He underwent wedge biopsy of the
      penis. On the day after the biopsy, he had an episode of gross hematuria.
      Cystoscopy revealed a papillary tumor that seemed to have arisen from the right
      ureteral orifice and another in the trigone. Computed tomographic scan revealed
      the bladder tumors and swelling of the internal iliac lymph nodes. The bladder
      tumors were resected transurethrally. The pathological diagnosis of the specimen
      from the penile induration was metastatic transitional cell carcinoma.

PMID- 10586367
TI  - [A case of primary malignant lymphoma of the bladder].
AB  - A case of primary malignant lymphoma of the bladder is reported. A 61-year-old
      female visited our outpatient clinic with the chief complaints of asymptomatic
      grosshematuria and was recognized as having a bladder tumor by abdominal
      ultrasonography. On cystoscopic examination, the tumor was non-papillary and dome
      like in shape. Computed tomography revealed that the bladder tumor was invading
      into the bladder wall. The histopathological study of endoscopic biopsy specimen
      revealed malignant lymphoma. After further examinations, it was diagnosed as
      primary malignant lymphoma of bladder, stage IE (Ann Arbor classification). Four
      courses of CHOP regimen (cyclophosphamide, vincristine, doxorubicin,
      predonisolone) was performed and no lymphoma cell was found by re-biopsy at the
      primary site. No local or distant recurrence was found during the 15 months'
      follow up.

PMID- 10586368
TI  - [Pheochromocytoma of the urinary bladder: a case report].
AB  - A 49-year-old man was hospitalized with the chief complaint of coagulation in
      urine. The patient was not hypertensive. Cystoscopic examination showed a
      submucosal tumor in the left lateral wall of the bladder. A transurethral
      sonogram revealed a low echoic nodule. Transurethral resection of the tumor in
      the urinary bladder was performed. The histopathological diagnosis indicated
      pheochromocytoma. Blood pressure was stable. After operation, the patient's
      course was uneventful, and there has been no recurrence for one year after
      surgery. This patient is the 52nd patient with pheochromocytoma of the urinary
      bladder reported in the Japanese literature.

PMID- 10586369
TI  - [Extragonadal seminoma with testicular microlithiasis: a case report].
AB  - A 43-year-old men presented with left supraclavicular growing mass.
      Ultrasonography revealed a 31 x 21 mm solid mass with a homogeneous echoic
      pattern. Lymph node metastasis of some malignant neoplasms was highly suspected.
      However, whole body evaluation with computed tomographic scan revealed no
      findings in the primary region. In addition, tumor markers including alpha
      fetoprotein, human chorionic gonadotropin and carcinoembryonic antigen were
      within normal limits. Then, extirpation of supraclavicular mass was performed and
      pathological diagnosis was made as pure seminoma. Evaluation of testicle by
      ultrasonography revealed a diffuse calcification. However, histological
      examination of biopsy specimen of testicle revealed no malignancy. The mass was
      finally diagnosed as extragonadal or "burned-out" pure seminoma. The patient
      received two courses of Peplomycin, vinblastine and cisplatin (PVP) therapy, and
      there has been no evidence of recurrence for 34 months.

PMID- 10586370
TI  - [Three cases of gastric cancer (Borrmann type IV) presenting with right back pain
      caused by right hydronephrosis as the first symptom].
AB  - We experienced three cases of right hydronephrosis, which were later diagnosed to
      have been caused by gastric cancer (Borrmann type IV). The patients were 25-, 38
      , and 50-year-old women who complained of right back pain. Ultrasound sonography
      revealed right hydronephrosis in all three cases. We conducted drip infusion
      pyelography, computed tomographic scan and retrograde pyelography, but there were
      no signs of urinary stones or tumors, except for the presence of right ureteral
      stenosis. Since the patients had upper abdominal discomfort, they underwent
      gastrofiberscopy, which revealed scirrhous gastric cancer. We suspected that the
      right ureteral stenosis was caused by metastasis of gastric cancer. After a
      double J catheter was indwelt at the right ureter, combination chemotherapy of
      methetrexate + 5-fluorouracil was conducted. The right hydronephrosis diminished
      and all three patients became catheter-free.

PMID- 10586371
TI  - Inhibitory effect of electroacupuncture on murine collagen arthritis and its
      possible mechanisms.
AB  - The influence of electroacupuncture (EA), a traditional Chinese medical
      treatment, on type II collagen-induced arthritis (CIA) was examined in DBA/IJ
      mice in vivo. Mice were immunized intradermally twice at a 3-week interval with
      bovine type II collagen (C II). EA stimulation, begun on day 21 simultaneously
      with the second immunization, was applied at the acupoint equivalent to GV4 three
      times a week for 3 weeks. The results showed that EA delayed the onset,
      attenuated the severity of arthritis, and reduced the anti-collagen antibody
      level. Furthermore, we investigated the impact of EA on the productions of
      endogenous interleukin-1 beta (IL-1 beta) and prostaglandin E2 (PGE2), and the
      levels of IL-1 beta mRNA in splenocytes and synovial tissues from C II immunized
      mice on day 45 and cyclooxygenase-2 (COX-2) mRNA in lipopolysaccharide (LPS)
      stimulated macrophages of normal mice by using reverse transcriptase-polymerase
      chain reaction (RT-PCR). EA stimulation significantly inhibited the
      concentrations of splenic endogenous IL-1 beta and serum PGE2. The expression of
      IL-1 beta mRNA in spleen cells was obviously down-regulated and that in synovial
      tissues was modestly affected by EA. COX-2 mRNA was highly expressed in cultured
      peritoneal macrophages when stimulated with LPS. Previous treatment with EA also
      reduced LPS-stimulated induction of COX-2 mRNA. These data suggest that EA has an
      inhibitory effect on murine CIA, and the partial mechanism of its therapeutic
      result may be attributed to inhibiting the productions of IL-1 beta and PGE2 by
      suppressing the IL-beta and COX-2 gene activations.

PMID- 10586372
TI  - Improvement of an impaired chemiluminescence response to formyl-methionyl-leucyl
      phenylalanine in neutrophils from patients with non insulin dependent diabetes
      mellitus by recombinant human granulocyte-colony stimulating factor.
AB  - To explore the possibility that b type recombinant human granulocyte-colony
      stimulating factor (rhG-CSF) is a useful drug to prevent the morbidity and
      mortality caused by infections in diabetic patients, we have studied effects of
      rhG-CSF on chemiluminescence amplified by a luciferin analog (CLA-DCL) and
      luminol (L-DCL) in response to formyl-Methionyl-Leucyl-Phenylalanine (fMLP) in
      neutrophils from patients with non insulin dependent diabetes mellitus (NIDDM)
      (diabetic neutrophils) and healthy subjects (control neutrophils). Both CLA-DCL
      and L-DCL in diabetic neutrophils were significantly reduced, and L-DCL was more
      sensitive to this suppression than CLA-DCL. RhG-CSF did not change the basal
      chemiluminescence in control and diabetic neutrophils, but it primed CLA-DCL and
      L-DCL. Although, in diabetic neutrophils, the priming effect of rhG-GSF on both
      CLA-DCL and L-DCL was less compared to that in control neutrophils, L-DCL was
      more sensitive to this priming effect than CLA-DCL. Because bacterial infection
      is still an important cause of the morbidity and mortality in diabetic patients,
      these data suggest that rhG-CSF is a useful drug to prevent the aggravation of
      bacterial infection in patients with NIDDM.

PMID- 10586373
TI  - Direct action by doxycycline against canine osteosarcoma cell proliferation and
      collagenase (MMP-1) activity in vitro.
AB  - BACKGROUND: Matrix metalloproteinases (MMPs) produced by tumor cells disrupt the
      integrity of the extracellular matrix (ECM). Inhibiting MMPs activity could
      significantly reduce tumor invasion and metastasis. MATERIALS AND METHODS: Canine
      osteosarcoma (OSA) cells were exposed to doxycycline in vitro to determine
      whether this chemically modified tetracycline had antiproliferative and
      anticollagenolytic activity. RESULTS: Doxycycline significantly reduced cell
      proliferation in a dose dependent manner. Doxycycline at the doses of 5 and 10
      micrograms/ml suppressed cell number 50% and 72%, respectively. Furthermore,
      doxycycline significantly reduced collagenase activity at the doses of 10 and 20
      micrograms/ml by 35% and 50%, respectively. OSA cells did not produce any
      endogenous collagenase in the culture medium. CONCLUSIONS: This study has shown
      that doxycycline at doses greater than 5 micrograms/ml in vitro significantly
      decreases cell proliferation and collagenase (MMP-1) activity. Prospective
      studies should be conducted to determine if doxycycline, a chemically modified
      tetracycline with low systemic toxicity, has specific anti-collagenase activity
      in vivo. Our studies indicate that canine osteosarcoma represents a suitable
      model for additional in vitro and in vivo studies.

PMID- 10586374
TI  - Anti-pressor effect of a Chinese-Japanese herbal medicine, saiko-ka-ryukotsu
      borei-to on hemodynamics in rabbits.
AB  - Saiko-ka-ryukotsu-borei-to (TJ-12) is a traditional Chinese-Japanese medicinal
      mixture clinically used for the treatment of hypertension and/or atherosclerosis
      concurrent with neurotic disorders. Study on the effect of TJ-12 on the
      vasoconstriction of cutaneous arterioles induced by nor-adrenaline (NA) was
      carried out using a rabbit ear chamber (REC) under conscious conditions. Before
      and after oral administration of TJ-12 everyday for 2 weeks, the same position of
      an arteriole within a REC was analyzed using an image shearing monitor every
      minute up to 15 min after varying doses (0.3, 1.0, 3.0 and 10.0 micrograms/kg
      i.v.) of NA. The changes of mean arteriolar diameter and vasomotion amplitude,
      before and after feeding of TJ-12 (1% w/w) supplemented diet were compared in the
      same position. Consequently, the pretreatment with TJ-12 significantly attenuated
      the changes of mean diameter of NA-induced vasoconstriction and also shortened
      its duration. In addition, concurrent with its cutaneous microcirculatory
      response, the pretreatment with TJ-12 systemically suppressed the increase of
      blood pressure under NA-induced vasoconstriction. These results suggest that the
      anti-pressor effect of TJ-12 might be apparently attributable to the inhibition
      of NA-induced vasoconstriction.

PMID- 10586375
TI  - Analysis of immune cells in a patient with post-transfusion hepatitis caused by
      human cytomegalovirus.
AB  - Cellular immune responses are associated with the pathogenesis of human
      cytomegalovirus (HCMV) hepatitis. We investigated a patient with post-transfusion
      HCMV hepatitis. A 9 year-old girl was involved in a traffic accident and suffered
      from traumatic damage to the left kidney and diaphragm and received a pelvic bone
      fracture. At emergency surgery she was transfused with 1200 ml of fresh whole
      donor blood. Abnormal liver function was observed in the 10 days after surgery.
      Titers of serum anti-HCMV IgG and IgM antibodies were elevated at 11, 17 and 25
      weeks after operation. We analyzed the surface markers of peripheral blood
      mononuclear cells obtained 21 weeks after surgery. The CD4/CD8 ratio and the
      number of CD16 + CD56 decreased. We detected HCMV immediate early (IE) DNA in the
      fractionated peripheral blood cells (polymorphonuclear leukocytes, CD2+, CD4+ and
      CD8+ T lymphocytes) by polymerase chain reaction. The histology of liver biopsy
      at 23 weeks after operation showed the findings of acute hepatitis and the
      absence of HCMV IE antigen. It was considered that the immunosuppressive
      condition associated with the trauma, operation or transfusion itself induced the
      reactivation of HCMV or that transfused blood cells infected with HCMV caused
      reinfection. It was also speculated that HCMV hepatitis was not only due to the
      direct damage of hepatic cells by HCMV, but also due to the cellular immune
      responses associated with HCMV infection.

PMID- 10586377
TI  - Presarcomatous lesions of experimentally induced sarcomas in rats: morphologic,
      histochemical, and immunohistochemical features.
AB  - Morphological studies have been performed mainly on manifest sarcomas, leading to
      divergent views of its histogenesis. However, histogenesis requires understanding
      of the tumor precursor cells and cannot be resolved by static morphologic
      studies. Defining presarcomatous lesions is made more difficult because they do
      not possess a basement membrane that serves as biologic and nosologic boundary
      like in epithelial cancers. The present study, therefore, investigated the early
      phases of experimentally induced rat sarcoma, which closely resembles human
      malignant fibrous histiocytoma (MFH). Histological, enzyme- and
      immunohistochemical methods were used to define the sequential events involved in
      tumorigenesis. A benzo[a]pyrene-oil mixture was injected intramuscularly into the
      thighs of rats, producing MFH 120 days later. Groups of animals were sacrificed
      every 10 days. The injections produced soft tissue lesions characterized by three
      distinct phases that overlapped or existed simultaneously in one animal: an
      initial acute inflammatory reaction characterized by an infiltration of
      lymphocytes, monocytes and macrophages, a second mesenchymal fibromatous phase
      characterized by the predominance of spindle-shaped, focally atypical fibroblast
      like cells and collagen, and a third premalignant neovascularization phase
      characterized by dominant capillary proliferations. Overt MFH developed 120 days
      after injection and consisted of spindle-shaped fibroblast- and histiocyte-like
      cells containing atypical mitoses and arranged in a storiform pattern. Control
      animals injected with olive oil revealed acute inflammatory reactions after 30
      days and no signs of chronic inflammation or malignancy after 60 and 120 days. We
      concluded that these experimentally-induced rat sarcomas develop in a triphasic
      pattern that resembles non-healing granulation tissue, with neovascularization
      preceding the occurrence of overt MFH.

PMID- 10586376
TI  - Detection of hypoxia by measurement of DNA damage and repair in human lymphocytes
      (comet assay): a predictive variable for tumor response during chemotherapy in
      patients with head and neck squamous cell carcinoma.
AB  - BACKGROUND: Only few studies have tried to identify parameters at the time of
      diagnosis or during treatment that can assist the clinician in predicting the
      response to Cisplatin, 5-Fluorouracil +/- Folinic acid therapy in patients with
      head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: The
      alkaline comet assay was used to measure both cellular hypoxia and DNA single
      strand break (ssb) kinetics in individual lymphocytes of HNSCC patients
      undergoing combined therapy. The intracellular level of FdUMP, dUMP and mTHF were
      also measured during treatment. RESULTS: Two distinct types of cell populations
      were detected, from the less damaged population representing the hypoxic cells to
      the most damaged cells population representing the aerobic cells. We also
      described a direct relationship between DNA damage and repair and drug metabolism
      in lymphocytes and treatment efficacy. CONCLUSION: The response of tumors to
      chemotherapy is thought to be a function of the drug's pharmacological properties
      (the intracellular level of FdUMP and mTHF). In addition, a relationship between
      platinum DNA adduct levels in lymphocytes DNA (comet assay) and tumor response
      has been observed, suggesting that clinical resistance to platinum drugs is
      attributable to DNA repair functions of the host, and thus the degree of
      cytotoxicity is similar across all cell types.

PMID- 10586378
TI  - Fas (Apo-1, CD95) receptor expression in childhood astrocytomas. Is it a marker
      of the major apoptotic pathway or a signaling receptor for immune escape of
      neoplastic cells?
AB  - Apoptosis is a physiological process wherein the cell initiates a sequence of
      events culminating in the fragmentation of its DNA, nuclear collapse, and finally
      disintegration of the cell into small, membrane-bound apoptotic bodies.
      Expression of Fas (APO-1, CD95) Receptor (FasR) and programmed or active cell
      (PCD) death was studied in childhood astrocytomas (ASTRs) with varying stages of
      malignancy, including pilocytic ASTR, low grade ASTR, anaplastic ASTR, and
      glioblastoma multiforme (GBM). The great majority of childhood glial tumors,
      particularly ASTRs express FasR whereas normal cells in the central nervous
      system (CNS) do not. FasR represents a transmembrane glycoprotein which belongs
      to the nerve growth factor/tumor necrosis factor (NGF/TNF) receptor superfamily.
      Apoptosis within ASTRs is triggered by the binding of FasR to its natural ligand
      (FasL) or by cross-linking with antibodies developed against FasR. Presence of
      FasL was also detected in childhood glial tumors. The expression of both FasR and
      FasL was also observed within the same ASTRs. Therefore, spontaneous, IP
      regulatory, intratumoral apoptotic cell death (autocrine suicide) is possible in
      childhood glial tumors. During a systematic, immunocytochemical screening of 42
      childhood ASTRs tissues divided according to WHO classification: 6 WHO grade I or
      pilocytic ASTRs; 14 WHO grade II or low grade ASTRs; 16 WHO grade III or
      anaplastic ASTRs and 6 WHO grade IV or glioblastoma multiforme (GBM), we detected
      strong expression (intensity of staining: "A"--the highest possible; number of
      stained cells: +2 to +4, between 20% to 90%) of FasR, employing 4 microns thick,
      formalin fixed, paraffin-wax embedded tissue slides. FasR was present on 70% to
      90% of tumor cells in pilocytic ASTRs, in 50% to 60% of the tumor cells in low
      grade ASTRs, in between 30% and 40% of the tumor cells in anaplastic ASTRs, and
      in between 20% to 35% of GBM cells. The panel of normal tissues employed as
      positive and negative tissue controls demonstrated presence of FasR in the
      prenatal thymus, mature tonsils and colonic epithelium. The use of a sensitive,
      indirect, six step immunoperoxidase or alkaline phosphatase conjugated
      streptavidin-biotin antigen detection technique provided excellent
      immunocytochemical results. A broad spectrum of neoplastic cells have been
      identified to express FasR: 1) carcinomas of epithelial origin, such as breast
      (ductal invasive, lobular invasive, mucinous), renal cell, gastric, colorectal,
      endometrial, prostate, pancreas, hepatocellular and large cell and squamous cell
      lung carcinomas: 2) non-epithelial neoplasms such as B cell mediastinal B cell
      and nodal non-Hodgkin's lymphomas large granular lymphocytic leukemia of T or NK
      cell origin malignant fibrous histiocytoma, malignant mesothelioma,
      leiomyosarcoma, epitheloid sarcoma and alveolar soft part sarcoma, as well as
      melanomas. Flow cytometry studies have also detected FasR expression on cells of
      adult T cell, and hairy cell leukemias, as well as in chronic B cell lymphocytic
      leukemia (BCLL). The coexpression of both FasR and FasL on several malignant cell
      types may represent an effective mechanism of tumor escape from the cellular
      immunological response of the host. It has been well established that brain
      tumors and melanomas produce their autocrine FasL, and even become capable of
      switching the signal transduction associated with FasL-FasR coupling from the PCD
      pathway to a tumor growth, proliferative pathway. It seems that the therapeutical
      use of FasR-FasL (main apoptotic pathway) may represent a new and exciting type
      of immunotherapy in the treatment of primary childhood glial tumors.

PMID- 10586379
TI  - Smoking and drinking behavior in patients with head and neck cancer: effects of
      behavioral self-blame and perceived control.
AB  - Patients who continue to use tobacco or alcohol following treatment for head and
      neck cancers are at greater risk for cancer recurrence and mortality. The present
      study examined the effects of behavioral self-blame and perceived control over
      health on smoking and alcohol use in a sample of 55 patients with cancers of the
      head and neck. Measures of self-blame, perceived control, and depression were
      administered and an assessment of past and current smoking and drinking behavior
      was obtained. As anticipated, continued smoking after completion of oncologic
      treatment was predicted by the interaction of behavior specific self-blame and
      perceived control. Patients who attributed the cause of their cancer to their
      past substance use exhibited a lower likelihood of smoking only if they also held
      the expectancy that their future cancer-related health was contingent on their
      own behavior. Among patients not holding the belief that cancer recurrence was
      contingent on their own actions, self-blame was associated with a higher
      probability of continued smoking. Self-blame and perceived control had no effect
      on continued alcohol use.

PMID- 10586380
TI  - The role of cultural variables in breast self-examination and cervical cancer
      screening behavior in young Asian women living in the United States.
AB  - This study examined cultural factors as predictors of breast self-examination
      (BSE) and participation in cervical cancer screening in young Asian and Caucasian
      women in the United States. Comparisons between Asian and Caucasian samples
      revealed significant differences in ever performing BSE and obtaining a pap test;
      the Caucasian women reported higher participation in both behaviors. Factor
      analysis of cultural barriers to screening revealed four factors: communication
      with mother, openness around sexuality, prevention orientation, and utilization
      of Western medicine. Logistic regression predicting BSE performance from
      demographics, acculturation, and cultural barriers revealed openness around
      sexuality to be a significant predictor. Pap test participation was predicted by
      year in college, ever having engaged in sexual intercourse, prevention
      orientation, and global acculturation. Cultural factors should be considered in
      programs to enhance participation in cancer screening.

PMID- 10586381
TI  - Antecedents, concomitants, and consequences of pediatric headache: confirmatory
      construct validation of two parent-report scales.
AB  - The aim of the study presented is to examine the psychometric properties of two
      parent-report scales for the assessment of environmental factors in pediatric
      headache, namely, the Children's Headache Assessment Scale (CHAS) and the Illness
      Behavior Encouragement Scale (IBES). Data were gathered in a sample of 160
      parents of children suffering from headaches regularly. The internal structure of
      both scales is investigated by means of confirmatory factor analysis. The
      internal consistency of the resulting subscales is explored and data on the
      convergent validity and on the relationship with demographics are presented. Both
      the CHAS and the IBES appear to be promising assessment tools in a behavioral
      approach to pediatric headache.

PMID- 10586382
TI  - Event-specific versus unitary causal accounts of optimism bias.
AB  - Optimism bias is often assumed to have a unitary cause regardless of the event,
      however, factors causing it may actually be event-specific. In Experiment 1 (N =
      23), subjects rated the importance of various causes for individual events. The
      results identified consistent differences in perceptions of causal factors across
      events. Experiment 2 (N = 190) employed the possible causal factors absent/exempt
      error and degree of motivation to investigate an event-specific theory of
      optimism bias in a manipulation design. Participants were encouraged to view one
      causal factor (absent/exempt or motivation) as either important or unimportant to
      future risk when they estimated their risk of absent/exempt-related, motivation
      related and unrelated events (as determined in Experiment 1). A hanging control
      group received no manipulation. The event-specific theory's prediction that these
      manipulations would affect particular events and not others were not supported.
      However, discouraging the absent/exempt error reduced optimism bias across
      events, generally. Hence, a unitary and not an event-specific theory of optimism
      bias was supported. Furthermore, for the first time, the possible role of and
      confounding of cognitive manipulations of optimism bias by mood were evaluated,
      and not supported.

PMID- 10586383
TI  - Examination of cognitive variables relevant to sunscreen use.
AB  - The present study is an examination of the underlying psychological variables
      relevant to a sun-damage preventive behavior, sunscreen use. The focus of the
      research was to examine cognitive predictors of sunscreen use, utilizing a
      decision theoretic framework. Two hundred thirty subjects were recruited from
      psychology classes and administered questionnaires assessing sunscreen behavioral
      tendencies, attitudes toward sunscreen use, and internal- and external-based
      cognitions relevant toward sunscreen use. In contrast to previous work that had
      examined only one or two of these predictor variables in isolation, the present
      study evaluated the relative impact of these variables on sunscreen use
      tendencies. The findings revealed evidence of a multivariate model (using
      structural equation modeling; LISREL VIII) relating perceived need for, perceived
      efficacy of, perceived consequences of, and social normative influences on
      sunscreen use. The findings are discussed with respect to improving the
      effectiveness of short-term education efforts to increase sunscreen use.

PMID- 10586384
TI  - Teaching health-care providers coping: results of a two-year study.
AB  - This study examined coping strategies and occupational burnout in a sample of 118
      health-care providers. Subjects who participated in a 6-week program designed to
      improve coping reported significant short-term decreases in emotional exhaustion
      and lack of personal accomplishment, two dimensions of burnout. Subjects who
      received 1-hr coping "refresher" sessions at 5, 11, and 17 months showed
      consistent decreases in burnout throughout the 2-year period. However, those who
      did not receive the refresher sessions following the 6-week course showed only
      temporary improvement. Results indicate that health-care providers can be taught
      to employ adaptive coping strategies that improve levels of burnout, but long
      term changes are achieved only through long-term coping training.

PMID- 10586385
TI  - The contribution of P-glycoprotein to pharmacokinetic drug-drug interactions.
AB  - P-glycoprotein (PGP) is well known because of its contribution to multiple-drug
      resistance during anticancer treatment. More recent work indicates that PGP
      mediates the transcellular transport of many drugs in addition to anticancer
      compounds. Because of this reason, its potential role in clinically significant
      drug-drug interactions has just begun to be realized. This article provides an
      overview of published in vitro, in situ, and in vivo drug-drug interaction
      results that are related to PGP transport so that the awareness of the scientific
      community can be heightened. In addition, several recommendations are made to
      take full advantage of the recently published data.

PMID- 10586386
TI  - Concurrent administration of the erythromycin breath test (EBT) and oral
      midazolam as in vivo probes for CYP3A activity.
AB  - Given the prominent role of CYP3A in the metabolism of drugs, it is important to
      identify whether new chemical entities will affect this enzyme system and produce
      clinically relevant drug interactions. This study evaluated concomitant
      administration of intravenous [14C N-methyl] erythromycin (3 microCi)
      (erythromycin breath test; EBT) and 2 mg oral midazolam as probes of systemic and
      of systemic plus presystemic CYP3A activity, respectively. Twelve males received
      the probes in a two-period crossover fashion: one period included the probes on
      two occasions, 5 days apart; in the second period, 200 mg ketoconazole was given
      orally 2 hours prior to the probes. The within-subject CV for EBT (%14CO2/h) and
      midazolam AUC0-last was 4.9% and 16.9%, respectively. Ketoconazole reduced
      %14CO2/h by 43% and increased midazolam AUC0-last by approximately fivefold. In a
      nonrandomized third period (N = 5), ketoconazole was given simultaneously with
      midazolam (no EBT); midazolam AUC0-last was similar whether ketoconazole was
      given 2 hours prior to or simultaneously with the midazolam. The low midazolam
      dose was generally well tolerated; mild sedation was occasionally seen.
      Concurrent administration of the EBT and oral midazolam is a sensitive and
      reproducible tool to screen new chemical entities for potentially important CYP3A
      interactions.

PMID- 10586388
TI  - Limits of confidence in tracer compounds as a means of measuring patient
      compliance with medication.
AB  - Chemical tracers are thought to be a desirable means of measuring patient
      compliance with medication. However, no compound has emerged as a standard. To
      explain this observation, the authors explored the mathematics of simulated
      tracers with half-lives 5 to 140 days over a month of daily dosing. To model
      assay variability, they added random "noise" to calculated tracer serum levels.
      They then fitted those altered levels to the dosing pattern most likely to have
      produced them, given known kinetics of the tracers. The large number of possible
      dosing patterns over a month (268,435,456) magnified uncertainty in interpreting
      noise-altered levels. At best, with an assay variability of 5%, compliance could
      be estimated only within 4 to 8 doses per month. The tracer with a half-life of
      30 days performed best. Pairing tracers did not improve uncertainty. The authors
      found that even a model neglecting many real-world variables suggests a limited
      role for tracers in measuring compliance.

PMID- 10586387
TI  - The frequency of caffeine withdrawal in a population-based survey and in a
      controlled, blinded pilot experiment.
AB  - Reports of symptoms when regular caffeine consumption is stopped have appeared in
      the medical literature, but the frequency and significance of this phenomenon
      have remained controversial. The objective of this study was to collect
      information on the prevalence and severity of caffeine withdrawal in the general
      population and determine the incidence and type of symptoms reported on blind
      abrupt and gradual caffeine cessation among coffee drinkers reporting past
      episodes of caffeine-withdrawal symptoms. A community-based telephone survey was
      followed by a stratified, randomized, double-blind controlled study. Participants
      included 11,112 persons spontaneously calling to inquire about studies not
      related to caffeine and 57 regular caffeine users selected from among the callers
      because of self-reported caffeine-withdrawal symptoms. Gradual or abrupt
      withdrawal from caffeine was compared to continuation of the same caffeine level.
      In a survey of 11,112 persons, 61% reported daily caffeine consumption, and 11%
      of the caffeine consumers reported symptoms upon stopping caffeine. Among the
      regular caffeine users, only 0.9% of males and 5.5% of females reported symptoms
      significant enough to interfere with normal activities when they abruptly stopped
      caffeine. A group of those reporting withdrawal symptoms were randomly assigned
      to three subsamples. In the group subjected to abrupt withdrawal (N = 18), 6
      (33.3%) reported symptoms (e.g., headaches and tiredness). Including decreases in
      functional ratings, a total of 7 of the 18 (38.8%) could be considered to have
      experienced caffeine withdrawal. The gradual withdrawal group (N = 20) reported
      minimal if any caffeine withdrawal symptoms. A third group (N = 18) was kept on a
      level dose of caffeine for comparison. When participants are unaware of the
      caffeine-withdrawal focus of the study, these results suggest that both the
      frequency and severity of caffeine-withdrawal symptoms are much lower than found
      in some previous reports and that clinically significant symptoms may be uncommon
      events among the general population.

PMID- 10586389
TI  - The pharmacokinetics of oral ranitidine in children and adolescents with cystic
      fibrosis.
AB  - The pharmacokinetics of oral ranitidine were studied in 9 patients (ages 9.9 to
      19.6 years) with cystic fibrosis (CF). Patients were evaluated at steady-state
      conditions, and the mean maximum serum concentration (Cmax) was 845.7 +/- 448.1
      ng/mL. To adjust for the variable drug dosing used among study patients, both
      Cmax and area under the concentration curve (AUC) were standardized to dose
      (CmaxST and AUCST, respectively) and were 217.9 +/- 87.9 ng/mL and 1038.0 +/-
      242.2 ng/mL.h. The elimination half-life (t1/2) was 2.7 +/- 1.4 hours, and the
      apparent steady-state volume of distribution (Vdss) was 4.6 +/- 1.7 L/kg. The
      plasma clearance was 1.022 +/- 0.290 L/kg/h. The Vdss in this study was greater
      than that previously reported in children with peptic ulcer disease.
      Statistically significant relationships between pharmacokinetic parameters and
      measures of disease severity were not observed in the study population. The
      pharmacokinetics of ranitidine in children and adolescents with CF may differ
      from those in children and adolescents without CF.

PMID- 10586390
TI  - Clinical pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor
      B43-Genistein in patients with B-lineage lymphoid malignancies.
AB  - The authors examined the pharmacokinetics of the CD19 receptor-directed tyrosine
      kinase inhibitor B43-Genistein in 17 patients (4 children, 13 adults) with B
      lineage lymphoid malignancies, including 12 patients with acute lymphoblastic
      leukemia (ALL) and 5 patients with non-Hodgkin's lymphoma (NHL). The
      immunoconjugate was administered intravenously as a 1-hour continuous infusion at
      a dose level of either 0.1 mg/kg (N = 12) or 0.18 mg/kg (N = 5), and the plasma
      concentration-time data were modeled by using the WinNonlin program to estimate
      the pharmacokinetic parameters. Pharmacokinetic analyses revealed a plasma half
      life of 19 +/- 4 hours, mean residence time of 22 +/- 4 hours, and a systemic
      clearance of 18 +/- 2 mL/h/kg. The average (mean +/- SEM) values for the maximum
      plasma concentration Cmax, volume of distribution at steady state (Vss), and area
      under curve (AUC) were 1092 +/- 225 ng/ml, 291 +/- 37 mL/kg, and 9987 +/- 2021
      micrograms x h/L, respectively. The AUC values were higher at the 0.18 mg/kg dose
      level than at the 0.1 mg/kg dose level (16,848 +/- 5118 micrograms x h/L vs. 7128
      +/- 1156 micrograms x h/L, p = 0.009). Patients with ALL had a significantly
      larger volume of distribution at steady state (332 +/- 47 mL/kg vs. 191 +/- 12
      mL/kg, p = 0.04), faster clearance (21 +/- 3 mL/h/kg vs. 11 +/- 2 mL/h/kg, p =
      0.03), and lower dose-corrected AUC than patients with NHL (6010 +/- 836
      micrograms x h/L vs. 12,044 +/- 2707 micrograms x h/L, p = 0.006). There was a
      trend toward faster clearance rates (23 +/- 4 mL/h/kg vs. 16 +/- 3 mL/h/kg, p =
      0.1), shorter elimination half-lives (5.7 +/- 3.6 hours vs. 13 +/- 8.8 hours, p =
      0.1), and shorter mean residence times (11 +/- 3 hours vs. 25 +/- 5 hours, p =
      0.08) for non-Caucasian patients as compared to Caucasian patients. When compared
      to adult patients, pediatric patients showed a significantly larger volume of
      distribution at steady state (418 +/- 82 mL/kg vs. 252 +/- 34 mL/kg, p = 0.02)
      and a longer elimination half-lives (18.4 +/- 13.6 hours vs. 8.7 +/- 6.7 hours, p
      = 0.04). The pharmacokinetics of B43-Genistein was not affected by the gender of
      the patients or by bone marrow transplantation in past medical history. Overall,
      B43-Genistein showed favorable pharmacokinetics in this heavily pretreated
      leukemia/lymphoma patient population, which is reminiscent of its recently
      reported favorable pharmacokinetics in cynomolgus monkeys. To our knowledge, this
      is the first clinical pharmacokinetics study of a tyrosine kinase inhibitor
      containing immunoconjugate.

PMID- 10586391
TI  - Pharmacokinetic changes of theophylline and amikacin through the menstrual cycle
      in healthy women.
AB  - The objective of this open-label, single-dose study was to clarify the influence
      of the menstrual cycle on the pharmacokinetics of theophylline (n = 10) and
      amikacin (n = 8) in young healthy Japanese women with regular menstrual cycles.
      Each subject received an intravenous infusion of theophylline or amikacin sulfate
      at four different phases--mid-follicular (phase I), peri-ovulatory (phase II),
      mid-luteal (phase III), and premenstrual days (phase IV). In the theophylline
      study, there were no significant differences in the pharmacokinetic parameters
      among the four phases studied. In the amikacin study, CLtot was 15% higher in
      phase III than in phase I (p < 0.01). Vd beta was 35% higher in phase III than in
      phase I (p < 0.05). The other pharmacokinetic parameters of amikacin were not
      significantly altered during the menstrual cycle. Evidence suggests that the
      phase of the menstrual cycle may be a factor in determining the pharmacokinetics
      of amikacin.

PMID- 10586392
TI  - Pharmacokinetics and pharmacodynamics following intravenous doses of azimilide
      dihydrochloride.
AB  - Azimilide pharmacokinetics and pharmacodynamics were characterized in a safety
      and tolerance study of intravenously administered azimilide dihydrochloride. This
      was a parallel-group design (seven treatments), and 68 healthy volunteers
      received the drug. Single intravenous infusion doses (4.5 to 9 mg/kg) were
      administered over 60 minutes, and single 4.5 mg/kg intravenous infusion doses
      were also given over 15 or 30 minutes. Blood and urine specimens were collected
      and analyzed for azimilide and metabolites. QTc was measured as a marker of class
      III antiarrhythmic activity. Azimilide pharmacokinetics were dose proportional
      and did not differ among infusion rates. Azimilide pharmacodynamics did not
      differ among treatments. Mean Emax ranged from 23 to 28% delta QTc, with mean
      EC50 of 509 to 566 ng/mL. Peak circadian variation in QTc was equivalent to 14%
      of Emax. Rapid equilibration occurred between blood and the biophase.
      Unconfounded pharmacodynamic estimates required inclusion of circadian QTc
      variation in the pharmacodynamic model.

PMID- 10586393
TI  - Azimilide pharmacokinetics following intravenous and oral administration of a
      solution and capsule formulation.
AB  - Azimilide dihydrochloride (NE-10064) is a novel class III anti-arrhythmic agent
      that blocks both the slowly and rapidly acting components of the delayed
      rectifier potassium current of human atrial and ventricular myocytes. In clinical
      studies, azimilide reduced the frequency of symptomatic episodes of atrial
      fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia. This
      study was conducted to characterize azimilide pharmacokinetics following single
      dose administration of a 1 mg/kg intravenous infusion (18 min), 2 mg/kg oral
      solution, and a 150 mg orally administered capsule. This was a three-period,
      randomized, crossover study in 27 healthy, drug-free (including caffeine and
      alcohol), non-smoking male volunteers (mean [SD]; age, 25.9 [1.0] years; weight
      74.3 [0.7] kg; 23 Caucasians and 4 Hispanics). Blood and urine samples were
      collected for 27 days and analyzed for azimilide using HPLC with UV detection.
      Subjects were monitored for adverse events and abnormalities in clinical
      laboratory tests, vital signs, and electrocardiography (including Holter
      monitoring). Mean (%CV) azimilide parameters were total clearance = 0.143 L/h/kg
      (38%), renal clearance = 0.014 L/h/kg (35%), steady-state volume of distribution
      = 13.2 L/kg (23%), and terminal exponential half-life = 78.8 h (44%). Similar
      parameter estimates were obtained following oral administration. Both the oral
      solution and capsule formulations were completely absorbed. In addition, the rate
      (Cmax) and extent of absorption (AUC) following oral administration of the
      capsule dosage form were bioequivalent to the oral solution with means for times
      of maximum blood concentration of 7.08 and 7.18 hours for the oral solution and
      capsule, respectively. Azimilide dihydrochloride was generally well tolerated in
      all subjects.

PMID- 10586394
TI  - A pharmacokinetic evaluation of concomitant administration of linezolid and
      aztreonam.
AB  - Linezolid, a new oxazolidinone antimicrobial agent, has a spectrum of activity
      encompassing a wide variety of Grampositive bacteria. The purpose of this study
      was to evaluate the pharmacokinetics of linezolid and aztreonam, an antimicrobial
      agent with selective activity against Gram-negative bacteria, when given alone
      and in combination. Healthy subjects were randomized to receive single, 30-minute
      intravenous infusions of (1) linezolid 375 mg, (2) aztreonam 1000 mg, and (3)
      linezolid 375 mg plus aztreonam 1000 mg in an open-label, crossover manner. The
      only statistically significant differences observed with combination treatment
      relative to each drug alone were an increase in the maximum plasma concentration
      of linezolid (approximately 18%) and an approximate 7% decrease in the apparent
      elimination rate of aztreonam, neither of which are expected to be clinically
      significant. In healthy subjects, the combination of linezolid and aztreonam was
      safe and well tolerated compared with each agent used alone. Pharmacokinetic data
      demonstrate that coadministration of linezolid and aztreonam does not alter the
      disposition of either agent under single-dose conditions. Therefore, it is not
      expected that a dose alteration of either agent will be necessary in a clinical
      setting.

PMID- 10586396
TI  - Severe life-threatening hyponatremia during paroxetine therapy.
AB  - Hyponatremia secondary to the syndrome of inappropriate secretion of antiduretic
      hormone (SIADH) is an uncommon complication of treatment with the antidepressants
      the selective serotonin reuptake inhibitors (SSRIs). These effective anti
      depressant agents are becoming widely used because of their favorable side effect
      profile and their safety in overdose. Although most reports have implicated
      fluoxetine in causing hyponatremia, there have also been a few reports of
      hyponatremia associated with paroxetine. We describe an elderly patient with
      severe life-threatening hyponatremia in association with paroxetine therapy. The
      present case and the others previously reported emphasize the need for greater
      awareness of the development of this serious and potentially fatal complication,
      and suggest that serum sodium concentration should be measured periodically in
      elderly patients soon after they start taking any agent of the SSRIs, especially
      during the first 2 to 4 weeks of treatment.

PMID- 10586395
TI  - Lack of pharmacokinetic interaction between lansoprazole and intravenously
      administered phenytoin.
AB  - The objective of this randomized, double-blind, two-period crossover study was to
      investigate whether concomitant steady-state lansoprazole influences the
      pharmacokinetics of CYP2C9 substrates using single intravenously dosed phenytoin
      as a model substrate. In addition, the safety of concomitant administration of
      these two drugs was evaluated. Twelve healthy, nonsmoking, adult male subjects
      received 60 mg lansoprazole or placebo once daily for 9 days during each study
      period. On the morning of day 7, each subject received a single 250 mg
      intravenous phenytoin dose. There were no statistically significant differences
      between the two regimens for mean phenytoin Cmax or tmax. There was a minor (<
      3%) but statistically significant difference between the two regimens for
      phenytoin AUC resulting from a very low intrasubject coefficient of variation
      (2.3%). The treatment and control mean plasma concentration phenytoin profiles
      were virtually super-imposable. In conclusion, concomitant multidose lansoprazole
      administration is unlikely to have any clinically significant effect on the
      pharmacokinetics of CYP2C9 substrates in general or intravenous phenytoin
      specifically.

PMID- 10586397
TI  - How to preserve psychoanalysis: introduction to Gunderson and Gabbard.

PMID- 10586398
TI  - Making the case for psychoanalytic therapies in the current psychiatric
      environment.
AB  - A variety of political, economic, and scientific forces have caused
      psychoanalytic therapies to become marginalized in psychiatry. These therapies
      are given short shrift in recently developed treatment guidelines, which are
      based largely on notions of empirical validation narrowly construed. Questions
      about the efficacy of psychoanalytic therapy can be meaningfully addressed by
      systematic assessment of available knowledge and potential data bases and by
      explicit efforts to locate the role of psychoanalytic therapies alongside other
      modalities. Several steps that might lend the psychoanalytic therapies greater
      credibility are proposed: (1) define the distinguishing features; (2) identify
      clear indications and contraindications; (3) systematically collect case
      histories of successfully treated mentally ill (diagnosable) patients; (4)
      increase vigilance (together with the patient) toward assessing progress in
      treatment.

PMID- 10586399
TI  - The effectiveness of psychoanalytic psychotherapy: the role of treatment
      duration, frequency of sessions, and the therapeutic relationship.
AB  - This is an effectiveness study of treatment outcome that relies on patients'
      perception of their mental health during and after psychoanalytic psychotherapy.
      Ninety-nine outpatients attending the IPTAR Clinical Center (ICC) responded to
      the Effectiveness Questionnaire (EQ) adapted from that developed by Consumer
      Reports. Effectiveness is studied from various perspectives. Findings indicated
      (1) an incremental gain in effectiveness scores from six to over twenty-four
      months of therapy; (2) an incremental gain with greater session frequency from
      one to two or three weekly sessions; (3) facilitation of effectiveness by the
      experience of a positive relationship with the therapist; (4) an interplay
      between clinical syndrome and treatment conditions. A method giving clinical
      validity to the quantitative findings is described. Brief summaries of two
      recorded interviews reveal differential reconstruction of events that had
      occurred during treatment. The findings are discussed from the vantage point of
      two hypotheses: cognitive dissonance and internalization of therapeutic
      experience.

PMID- 10586400
TI  - Oedipal dynamics in panic disorder.
AB  - Both research and clinical work have revealed factors that can lead to the onset
      and persistence of panic disorder. Preoedipal conflicts intensify the danger of
      oedipal longings for panic patients. Competition with the same-sex parent is
      linked with angry preoedipal fantasies and associated fears of disruption in
      attachments. Fantasies or actual successes can thus trigger panic episodes.
      Regression to a helpless, dependent state such as panic defends against the
      danger of aggressive, competitive fantasies and actual achievements. However, the
      regressive state can also be experienced as dangerous, and can be linked with
      frightening homosexual fantasies. A reactive aggressive oedipal stance can
      sometimes result, triggering escalating turmoil. The panic episode serves a
      series of compromise formations in dealing with these conflicted wishes.

PMID- 10586401
TI  - Three perspectives on addiction.
AB  - Three perspectives on addiction promulgated during the 1990s are reviewed, along
      with many earlier contributions to the understanding of addictive illness. It is
      suggested that these distinct yet overlapping formulations of the dynamics of
      addiction form a hierarchy for each patient suffering from an addiction.
      Assessment of a patient's ego strength, and of the relative importance of
      addictive behaviors in overall character structure, allows referral to various
      types of treatment, including psychoanalytic therapy. Case examples are
      presented, including material from the psychoanalysis of a woman addicted to
      heroin, methadone, cocaine, amphetamines, nicotine, alcohol, and shopping.

PMID- 10586402
TI  - Anxiety, signal anxiety, and unconscious anticipation: neuroscientific evidence
      for an unconscious signal function in humans.
AB  - A central tenet of psychoanalysis, and arguably of any comprehensive theory of
      mind, is the existence of a psychological unconscious. Years of clinical
      investigation into the nature of unconscious processes have facilitated the
      development of psychoanalysis as a clinical method. Empirical investigations of
      unconscious mental processes, however, have lagged behind clinical inquiry. With
      few exceptions, attempts to understand unconscious processes using rigorous
      experimental controls have remained sequestered in scientific domains other than
      psychoanalysis, where they have proliferated recently. In view of this recent
      upsurge of research on unconscious processes outside of psychoanalysis, efforts
      to integrate such knowledge into general theories of psychopathology and clinical
      investigation are critical. In this paper, an interdisciplinary approach is taken
      to the study of one aspect of unconscious mental functioning--what Freud
      originally termed signal anxiety. Signal anxiety is examined using information
      from cognitive psychology and learning theory, psychophysiology, behavioral
      neuroscience, and psychoanalytic theory. Though the original concept of signal
      anxiety is supported by recent research, it is concluded that signal anxiety is
      probably best thought of not as the affect of anxiety but as a subset of
      unconscious mental processes that have a signal function of anticipating danger.
      Such unconscious anticipatory processes are a general feature of the mind that
      includes responses to both real and imagined (neurotic) appraisals of a
      situation. The neurophysiological structures and processes associated with
      unconscious anticipation in humans are just beginning to be understood.

PMID- 10586403
TI  - Modern ego psychology.
AB  - This paper reviews the history of ego psychology, describing problems in the
      theory that have perhaps contributed to subsequent theory development and
      theoretical splintering. The present status of ego psychology is then described,
      with a focus on broadly accepted general principles. A proposal/prediction is
      then made regarding efforts to integrate the main schools and splinter groups. It
      is argued that the ego's method of synthesizing aspects of experience will help
      integrate divergent metapsychological viewpoints.

PMID- 10586404
TI  - Citation disorder.

PMID- 10586405
TI  - Compromise formation.

PMID- 10586406
TI  - Psychoanalytic training in eastern Europe.

PMID- 10586407
TI  - [Clinical utility and possibility of MR spectroscopy].

PMID- 10586408
TI  - [Use of fluid-attenuated inversion recovery (FLAIR) images in brain check-up].
AB  - Fluid-attenuated inversion recovery (FLAIR) images are magnetic resonance (MR)
      images obtained with an inversion recovery sequence having a long inversion time
      (T 1) and a long echo time (TE). The purpose of this study was to evaluate the
      utility of FLAIR images in brain check-up. 320 healthy adults (229 males, 91
      females) were examined with FLAIR sequences of several types having repetitive
      time (TR) of 7000 msec, inversion times of 1700 msec and echo times (TE) of 110
      msec. All studies were performed on a SHIMAZU MAGNEX 100 HP 1.0 T imaging system.
      FLAIR images were useful in detecting cortical and subcortical lesions near the
      brain surface, which were unclear in the conventional T 2 weighted images. FLAIR
      images were useful in evaluation of periventricular hyperintensity area (PVH).
      Frequency and degree of PVH were increased in aging. FLAIR images were useful in
      the differential diagnosis of lacuna and perivascular space. In conclusion, FLAIR
      images were very sensitive for the detection of brain lesions in brain check-up.

PMID- 10586409
TI  - [Schizencephaly: clinical and MRI features].
AB  - We report the clinical and neuroimaging features of 4 cases with schizencephaly.
      Case 1 had bilateral schizencephaly with open-lip on the right and closed-lip on
      the left. Case 2 had unilateral schizencephaly with closed-lip on the left and
      subcortical heterotopia on the right. Case 3 had unilateral schizencephaly with
      closed-lip on the left. Case 4 had bilateral closed-lip schizencephaly. Although
      all cases except for Case 3 had bilateral lesions, neurodevelopmental outcome was
      generally good; Case 1 and 3 had mild hemiparesis. All patient have epilepsy
      which are well-controlled with antiepileptic drugs. Thus, the clinical
      presentation of schizencephaly, even if bilateral lesions, are quite variable.

PMID- 10586410
TI  - [Is hippocampal atrophy a specific change for Alzheimer's disease?].
AB  - Although detection of hippocampal atrophy has been proposed for the diagnosis of
      Alzheimer's disease (AD), atrophic changes in MRI can be found in other dementia
      diseases. This study was undertaken to determine whether hippocampal atrophy was
      a specific change for AD. Coronal T 1-weighted images were performed in 36
      patients with AD, 40 patients with non-AD including vascular dementia,
      frontemporal dementia, Parkinson's disease with dementia, dementia with Lewy
      bodies, progressive supranuclear palsy, and normal pressure hydrocephalus, 9
      patients with age-associated memory impairment (AAMI), and 24 control subjects.
      Hippocampal atrophy was graded subjectively on a 5-point scale. Scores of
      hippocampal atrophy for AD (2.11 +/- 0.95) and non-AD (1.80 +/- 0.91) were
      significantly higher than those for controls (0.79 +/- 0.72). Scores for AD were
      also significantly higher than those for AAMI (1.11 +/- 0.160), but no difference
      was found between AD and non-AD. These results suggest that hippocampal atrophy
      is not a specific marker for AD and appears to be a common phenomenon in dementia
      syndromes.

PMID- 10586411
TI  - [Computed assisted area measurement using CT scans: clinical application for
      craniosynostosis in children].
AB  - This paper describes a method for obtaining intracranial area measurements using
      CT scans with a software for quantitative analysis of tracing data. A Toshiba CT
      1010 scanner was used (120 kv, 10 mm slice thickness) to examine 13 children
      before and after cranioplastic surgery for craniosynostosis. Using Scion Image
      (Scion Corporation) with Intuos tablet system (WACOM), the intracranial space was
      measured at approximately same scanning level. Our findings show that the reverse
      pi and bilateral canthal advancement procedures usually carried out are
      associated with increased intracranial area, 4.5 +/- 2.1% and 12.0 +/- 8.3%,
      respectively. This measurement method should be further modified to intracranial
      volume gain by several surgical procedures.

PMID- 10586412
TI  - [Ultrasonogram of carotid artery in endoarterectomy patients].
AB  - Ultrasonograms of the carotid artery were compared with the intraoperative
      finding of atheroma plaque in terms of stenosis, fragility, ulceration and
      calcification. Soft type, intermediate type and these mixed type plaques were
      fragile plaques in almost all cases. All hard type plaques were tough plaques.
      The detection of stenosis and calcification was satisfactory, however that of
      ulceration was not sufficient. The stenotic lesions frequently existed in
      bilateral carotid arteries and the intima was easy to become thick even after the
      endoarterectomy. The ultrasonogram was thought to be the essential study for the
      carotid artery lesions.

PMID- 10586413
TI  - [An autopsy case of motoneuron disease with dementia of long duration].
AB  - An autopsy case of MND with dementia, 67 years old, man, was reported. The
      behavioral disturbance appeared at 61 years old, and was followed by the upper
      limb weakness and respiratory failure. He had remained on a respirator for 56
      months. The total duration of the disease was 74 months, which was far longer
      than mean duration of the cases previously reported, 25-30 months. The
      pathological findings were about essentially identical to those mentioned before,
      such as cortical alterations in temporal and frontal lobes, neuronal loss with
      gliosis in amygdaloid body and substantia nigra, and loss of lower motoneurons in
      anterior horn of spinal cord and in the several motor cranial nerve nuclei. There
      were several Bunina bodies in the remnant lower motoneurons, but no changes in
      the pyramidal tracts or loss of Betz cells in the precentral gyrus.
      Intracytoplasmic ubiquitin-immunopositive inclusions in the granule cells of
      hippocampal dentate gyrus were also encountered, but the number of which did not
      increased, compared to the preceding data. There may be frequently little
      correlation between the disease duration and the number of such inclusions. The
      regional alteration in the intermediate zone between subiculum and entorhinal
      cortex was revealed also at the level of the splenium of corpus callosum. It has
      been reported that such parahippocampal lesion may initiate at the anterior part
      of temporal lobe and become undiscernible at more posterior level than the
      lateral geniculate body. The formation of such parahippocampal lesion may be
      concerning with the length of disease duration. In addition, there were numerous
      senile plaques, diffuse or neuritic type only in the parietal lobe cortex without
      any other changes.

PMID- 10586414
TI  - [An autopsied case of subacute progressive dementia with flactuated disturbance
      of consciousness, myoclonus and periodic synchronous discharges on EEGs].
AB  - We present an autopsied case which developed progressive dementia at the age of
      45. EEGs showed periodic synchronous discharges (PSD) when he showed fluctuated
      cloudy consciousness with myoclonus. Cerebrospinal fluid examination showed mild
      to moderate increase in protein and monocytes for duration of illness, but
      antivirotics and antibiotics were not effective. He was not apallic even at the
      terminal stage when computed tomography (CT) revealed marked cerebral atrophy,
      and died of pneumonia 27 months after onset. He was clinically diagnosed as
      having Creutzfeldt-Jakob disease (CJD) because of subacute progressive dementia,
      myoclonus and PSD. Neuropathological examination revealed marked brain atrophy
      with severe neuronal loss and gliosis in the cerebral cortex and subcortical
      nuclei, although no spongiform degeneration was found. Senile plaques,
      neurofibrillaly tangles, argyrophilic glial inclusions and glial nodules were not
      detected. Prion protein immunoreactivity was negative. Therefore, this case can
      not be neuropathologically diagnosed as having CJD, Alzheimer's disease, non
      Alzheimer-type degenerative dementias or any encephalitis. This case might have
      suffered from an unknown new disease.

PMID- 10586415
TI  - [A family of hereditary motor and sensory neuropathy with spastic paraplegia
      (HMSN type V) presenting with phenotypic uniformity including onset in early
      childhood].
AB  - The proband was a 38 year old mother, who had begun to walk abnormally at one
      year old. She developed weakness and wasting in the intrinsic hand muscles in the
      third decades. On neurological examinations, she showed weakness with atrophy in
      the distal muscles of the upper and lower limbs, mild impairment of deep
      sensation in the feet, and severe spastic gait with scissoring. Deep tendon
      reflexes were hypoactive in the arms and at the ankles, and brisk at the knees.
      Babinski sign was present bilaterally. Nerve conduction studies revealed mild
      slowing of conduction velocities and reduction of muscle and sensory action
      potential amplitudes. Sural nerve biopsy showed a prominent decrease in
      myelinated fiber density, especially in the large fibers. Neither demyelination
      nor typical onion-bulb was found. Results of gene analysis of PMP-22 was
      negative. Her two daughters, 14- and 11-year-old, respectively, also presented
      with gait disturbance from the beginning of walking at one year old and had
      almost the same clinical manifestations as their mother, indicating autosomal
      dominant inheritance. This family of the hereditary motor and sensory neuropathy
      with spastic paraplegia (HMSN type V) was distinctive in having phenotypic
      uniformity including onset in early childhood.

PMID- 10586416
TI  - [An autopsy case of pericallosal lipoma with mental retardation].
AB  - The patient was a 69-year-old male who had visited our psychological department
      due to mental retardation. Pericallosal lipoma was indicated by MRI taken during
      treatment. On December 30, 1998, the patient fell from steps and struck his
      forehead hard, and then limb palsy occurred. He was emergently brought to our
      hospital. Under the suspected diagnosis of traumatic cervical spinal cord injury,
      preventive therapy was performed to observe the clinical course in which
      paralysis gradually improved. On January 22, 1999, however, he died of
      cardiopulmonary arrest due to sudden suffocation. In general, the connection of
      choroid plexus lipoma and pericallosal lipoma is bilateral in most cases. In our
      patients, MRI suggested that a connection with cerebral ventricles through
      choroidal fissure existed with no right and left difference, however, autopsy
      findings revealed that the lipoma existed along the left cerebral arch with
      obvious connection only with the left choroid plexus. The present case seemed to
      be a very rare case.

PMID- 10586417
TI  - [Episodic and semantic memory after traumatic brain injury in a child].
AB  - In an early-life, a memory disturbance affects the learning and school record
      directly. Furthermore, it may cause the problem of maltreatment or adaptation
      difficulty for school life. We report a child amnesia caused by a traumatic brain
      injury when she was 9 years old. We examined her episodic and semantic memory. We
      developed 3-steps tasks of recognition and recall for the post-accident episodic
      memory. First, the examiner presented the patient with four words orally
      including a label of her episode, and asked her to choose one that she felt
      familiar with (the recognition of the episodic label). Second, if the word she
      selected was correct, she was required to recall the episode related to the word
      (the recall of the episode). Third, if she could not recall the episode herself
      correctly, she was required to choose a correct sentence about the episode (the
      recognition of the episode). She could not recall episodes correctly, but
      produced confabulation instead. She showed, however, good recognition of each
      episode. Furthermore, we performed recognition tests of time, person, and place
      about the same post-accident episodes, which were poor especially for time. In
      semantic memory tasks, we examined about kanji characters (ideogram) learned from
      the first grade to the sixth grade and mathematical knowledge learned from the
      second grade to the sixth grade at elementary school ("What centimeters is equal
      to one meter?" or "Tell me the formula of the size of a circle." etc). We found
      that she showed a retrograde impairment for about one year. For both episodic and
      semantic memory, she showed an anterograde impairment. Because of the anterograde
      amnesia she could not acquire new facts, and also showed para-amnesia or
      confabulation. In a child with brain damage, neuropsychological assessment is
      important in predicting effect of rehabilitation and recovery of school
      performance.

PMID- 10586418
TI  - [Superficial siderosis accompanied with massive degeneration of cerebellar
      vermis].

PMID- 10586419
TI  - [Cortical laminar necrosis in a patient with possible catastrophic
      antiphospholipid syndrome].

PMID- 10586420
TI  - [A 54-year-old man with action myoclonus, parkinsonism and epilepsy].
AB  - We describe 3-year clinical course of a 54-year-old Japanese man who presented
      with action myoclonus, parkinsonism and epilepsy. There was no family history or
      consanguinity. The patient was well until the age of 51 years (in 1986), when he
      noted slow movements, memory disturbance and left hand tremor. He was treated
      with anti-Parkinson drugs without any improvements. Soon thereafter, he developed
      a gait disturbance and generalized tonic clonic seizures. He was admitted to our
      service at the age of 53 years. General physical examination revealed no
      hepatosplenomegaly. Neurological examination showed mild dementia. Neither
      retinal pigmentation nor cherry red spot was noted. He was unable to walk due to
      marked frozen gait. His upward gaze was limited and saccadic eye movement was
      slow. He had action myoclonus in both upper extremities and resting tremor on the
      left side. He showed mild left hemiparesis. Deep tendon reflex was hyperactive in
      both side with extensor plantar responses. MRI demonstrated cortical atrophy,
      especially marked at the bilateral temporal lobes with a right side predominance.
      Leukocyte lysosomal enzyme activities of beta-hexosaminidase, beta-galactosidase
      and sialidase were within normal limits. The patient died of pneumonia on April
      25, 1989. At the time of a neurological CPC, neurologists reached the clinical
      diagnosis of adult-type neuronal ceroid-lipofuscinosis. Postmortem examination
      revealed bilateral bronchopneumonia. The brain weighed 1,219 g and showed atrophy
      of the temporal lobes. Histological examination showed neuronal cells with
      swollen cytoplasm and lipofuscin-like granules throughout the CNS, including the
      cerebral cortex, thalamus, substantia nigra, motor nuclei of the brain stem,
      dentate nuclei, inferior olivary nuclei. Clarke's nuclei and anterior horn cells.
      Marked neuronal loss was noted in the right temporal lobe and substantia nigra.
      Electron micrographs of the frontal cortex revealed "fingerprint profiles" in the
      cytoplasm of neuronal and glial cells. Pathological findings were consistent with
      the diagnosis of adult-type neuronal ceroid-lipofuscinosis (Kufs' disease).

PMID- 10586421
TI  - Antioxidants in the prevention of renal disease.
AB  - In view of the role of oxidative processes in inflicting damage that leads to
      glomerulosclerosis and renal medullary interstitial fibrosis, more attention
      could be paid to the use of antioxidant food constituents and the usage of drugs
      with recognized antioxidant potential. In any case atherosclerosis is an
      important component of chronic renal diseases. There is a wide choice of foods
      and drugs that could confer benefit. Supplementation with vitamins E and C, use
      of soy protein diets and drinking green tea could be sufficient to confer
      remarkable improvements.

PMID- 10586422
TI  - Protection against cis-diamminedichloroplatinum-induced nephrotoxicity by 2,3
      dimercaptosuccinic acid in rats.
AB  - The present study was designed to examine the usefulness of 2,3
      dimercaptosuccinic acid (DMSA) for the purpose of reducing cis
      diamminedichloroplatinum (DDP)-induced nephrotoxicity and effective clinical use
      of DDP and safe. The effectiveness of DMSA on the DDP-excretion in rat kidney was
      observed by measuring the platinum concentration using Atomic Absorption
      Instrument. Co-administration of DMSA (1.0 or 2.0 mmol/kg) 1 hour after DDP
      injection (20 mumol/kg) showed more decrease in the platinum concentration than
      that immediately after DDP injection. The alleviating effect of DMSA on DDP
      toxicity was evaluated by lipid peroxidation, enzymatic antioxidants, and
      glutathione levels. The administration of DDP alone caused a significant increase
      in lipid peroxidation and significant decreases in enzymatic antioxidants and
      glutathione levels in the kidney. Co-administration of DMSA (2.0 mmol/kg) 1 hour
      after DDP injection showed the most effective reduction of these enzymatic
      damages caused by DDP. These findings suggested that the co-administration of
      DMSA (2.0 mmol/kg) 1 hour after DDP injection leads DDP to effective excrete from
      renal tissue and suppresses the lipid peroxide reaction and results in reduction
      of nephrotoxicity.

PMID- 10586423
TI  - Importance of early and continuous use of protein restriction on the progression
      of adriamycin nephropathy.
AB  - Three experimental protocols were carried out with the aim of evaluating the role
      of protein restriction on the progression of the established adriamycin-induced
      nephropathy, and whether the protective effect of the diet persists after the
      diet is discontinued. The effect of a low protein diet (LPD) was studied for 6
      weeks in protocol 1, 16 weeks in protocol 2 and for 28 weeks in protocol 3. In
      protocol 3, one group (LL) received LPD and another (NN) was given a normal
      protein diet (NPD). A third group (LN) received LPD for 16 weeks and then NPD for
      12 weeks and a fourth group (NL) was fed NPD for 16 weeks and then LPD for 12
      weeks. In protocol 1 the tubulo-interstitial index (TILI) of rats on LPD (Md = 2,
      P25 = 0.0; P75 = 3.5) after six weeks, was smaller than that of the animals on
      NPD (Md = 6.0; P25 = 3.0; P75 = 8.0; p < 0.05). In protocol 2, the group taking
      LPD presented an area of interstitial fibrosis (IF) (Md = 0.5%, P25 0.2%; P75 =
      1.9%) smaller than that of the NPD group (Md = 6.8%; P25 = 5.2%; P75 = 7.1%; p <
      0.05). No significant difference in the area of glomerulosclerosis (GSA) was
      observed between the animals on LPD (Md = 0.0%; P25 = 0.0%, P75 = 0.0%) and NPD
      (Md = 0.37%; P25 = 02%, P75 = 1.25%; p > 0.05). In protocol 3, the group LL
      showed GSA (Md = 1.3%; P25 0.6%, P75 = 2.5%) and IF (Md = 3.6%; P25 = 1.6%; P75 =
      5.9%) smaller that those of LN (GSA Md = 10.1%; P25 = 6.6%; P75 = 14.8%; IF: Md =
      17.3%; P25 = 14.1%; P75 = 24.5%), NL (GSA: Md = 9.1%; P25 = 5.8%; P75 = 11.7%;
      IF: Md = 25.0%; P25 = 20.4%; P75 = 30%), and NN (GSA: Md = 6.75%; P25 = 4.9%; P75
      = 11.7%; IF: Md = 20.9%; P25 = 16.2%; P75 = 32.4%). In conclusion, in order to be
      effective, LPD must be introduced early and maintained for a long period of tune.

PMID- 10586424
TI  - Colony-promoting activity in mice kidneys with phenylhydrazine hemolytic anemia.
AB  - Aqueous anemic mice kidney extracts (MKE) were assessed colony-promoting activity
      (CPA) of hematopoietic progenitor cells in serum-free cultures stimulated by
      interleukin-3 and erythropoietin (Epo). Mice with hemolytic anemia followed by
      phenylhydorazine (PHZ) injection for 3 days showed a decrease in the hematocrit
      (25.4%) and an increase in serum Epo by 14-fold of the control on day 3 after the
      treatment. At 3 days, the total number of hematopoietic progenitor cells in the
      bone marrow of PHZ mice decreased by 67% of the control, while these cells in the
      spleen increased to 22-fold of the control on day 3 and 55-fold on day 6. A
      significant increase in CPA was observed in MKE prepared from PHZ mice kidneys.
      Additionally, bone marrow suppressive anemia induced by 5-fluorouracil resulted
      in enhanced CPA the same as for PHZ mice, but in contrast, anemia with
      suppression of Epo-production due to nephrotoxicity induced by cisplatin caused a
      decrease in CPA. These results suggest that CPA in MKE correlates with
      hematopoietic conditions, and may have a definite role in hematopoiesis through
      the function of the kidney.

PMID- 10586425
TI  - Protective effect of a bioflavonoid proanthocyanidin-BP1 in glycerol-induced
      acute renal failure in the rat: renal stereological study.
AB  - Renal ischemia as well as oxygen metabolites play an important role in renal
      injury during myoglobinuric acute renal failure (ARF). On the other hand,
      flavonoids, a diverse group of constituents naturally occurring in plants, have a
      strong antioxidative activity, and have been implicated in vascular relaxation.
      In this study the protective effect of a new bioflavonoid proanthocyanidin-BP1
      (BP1), extracted from seeds of grapes, was evaluated in glycerol-induced ARF in
      rats. Stereological methods were used to quantify changes in renal morphology
      associated with ARF. Volume density of tubular lumen and intratubular cast
      formations, nuclear parameters (area, diameter, volume) of epithelial cells in
      the cortical proximal tubules, and glomerular parameters (surface area, diameter,
      volume, perimeter) were estimated on kidney sections of rats treated either with
      50% glycerol (8 mL/kg i.m.) alone. BP1 (20 mg/kg i.p.) in addition to glycerol,
      or BP1 alone. It was noted that the volume density of tubular lumen and cast
      formations were significantly lower (p < 0.001) in kidneys of the rats treated
      with BP1 in addition to glycerol, compared with those treated with glycerol
      alone. There were no significant differences in glomerular and nuclear parameters
      between glycerol treated, and BP1 in addition to glycerol treated rats. Renal
      function was significantly improved in rats treated with BP1 in addition to
      glycerol. The results suggest that BP1 is a protective agent in glycerol model of
      ARF. This effect is probably due to the antioxidative activity of BP1 and reduced
      toxicity of myoglobin in renal tissue. Moreover, it is possible that the ability
      of BP1 to protect the kidney is dependent upon renal vascular relaxation. The
      potential beneficial effects of bioflavonoid-BP1 demonstrated in experimental ARF
      could be considered in therapy of myoglobinuric ARF.

PMID- 10586427
TI  - Effect of anticoagulation on renal function and protein excretion in experimental
      acute ischemic renal failure.
AB  - Female Sprague-Dawley rats underwent right nephrectomy and 40 min left renal
      artery occlusion (RAO). After 15 min of reflow, polyethylene glycol 1000
      (PEG1000) was infused to induce osmotic diuresis and to enable glomerular
      filtration rate (GFR) measurements. Urine was collected during a 90 min period,
      and the concentrations of PEG1000, albumin, IgG, IgM and fibrin(ogen)/degradation
      products (FIB) were assessed both in plasma and urine by radial immuno diffusion
      technique Groups of rats were subjected to saline + RAO, warfarin + RAO or sham
      operation. GFR as measured by PEG1000 clearance averaged 0.61, 0.036 and 0.094
      mL/min/100g BW/kidney in sham-operated, saline + RAO and warfarin + RAO rats,
      respectively. Urinary excretion of albumin and IgG increased substantially in
      both ischemic groups. IgM was not detected in any of the urine samples. FIB
      excretion was lowest in the saline + RAO group, possibly due to retention of FIB
      containing obstructions in the tubules. Rats subjected to warfarin + RAO had
      significantly higher excretion of FIB. This result suggests that warfarin does
      not prevent the glomerular sieving of macromolecules in the glomerular filter,
      but reduces tubular obstruction by preventing fibrin formation, which may explain
      its positive effect on GFR.

PMID- 10586426
TI  - Co-administration of co-trimoxazole does not augment tacrolimus-induced
      impairment in kidney function in rats.
AB  - Co-trimoxazole is an antibiotic that is frequently used in organ transplant
      patients. Our objective was to determine the effect of co-trimoxazole on
      tacrolimus-mediated functional impairment of the kidney in rats. Sprague Dawley
      rats were divided into three groups. Group 1 (dextrose) received 5% dextrose and
      Group 2 (tacrolimus) received tacrolimus (1 mg/kg/day) as a continuous
      intravenous infusion for seven days. Group 3 (combination) received tacrolimus as
      above and co-trimoxazole (30 mg/kg/day trimethoprim and 150 mg/kg/day
      sulfamethoxazole) intraperitoneally for six or seven days. Biochemical and
      functional parameters were measured pre- and post-drug infusion. On day 7,
      glomerular filtration rate (GFR) was evaluated using 3H-inulin while the
      effective renal plasma flow (ERPF)/cationic tubular secretion was assessed using
      14C-tetraethylammoniumbromide(TEA). GFR (mL/min/kg) as measured by inulin
      clearance was higher (p < or = 0.05) in the dextrose (12.0 +/- 1.4) group as
      compared to tacrolimus group (6.0 +/- 1.3) and combination group (6.4 +/- 1.6),
      but there was no difference between the tacrolimus and combination group.
      ERPF/cationic tubular secretion (mL/min/kg) was also significantly higher in the
      dextrose group (62.6 +/- 10.3) as compared to the other two groups. ERPF/cationic
      tubular secretion was not different between the combination (33.3 +/- 5.9) and
      the tacrolimus (35.1 +/- 6.7) groups when there was no co-trimoxazole in the
      body. However, in the presence of co-trimoxazole ERPF/cationic tubular secretion
      was significantly reduced in the combination (23.1 +/- 3.5) group as compared to
      the tacrolimus group (35.1 +/- 6.7). These results indicate that co-trimoxazole
      does not further potentiate tacrolimus induced impairment in kidney function but
      is likely to further inhibit cationic tubular secretion in patients on tacrolimus
      therapy.

PMID- 10586428
TI  - Lack of association between the heparan sulfate proteoglycan gene polymorphism
      and diabetic nephropathy in Japanese NIDDM with proliferative diabetic
      retinopathy.
AB  - The development of diabetic nephropathy shows remarkable variation among
      individuals. Therefore, not only hyperglycemia but also genetic factors may
      contribute to the development of diabetic nephropathy Heparan sulfate
      proteoglycan (HSPG) is thought to play an important role as a component of the
      charge selectivity barrier in the glomerular basement membrane. Recently, a BamHI
      restriction fragment length polymorphism (RFLP) in the HSPG gene (HSPG2) was
      reported to be associated with diabetic nephropathy in Caucasian insulin
      dependent diabetes mellitus (IDDM). The aim of the present study was to examine
      the contribution of the BamHI HSPG2 polymorphism to the development of diabetic
      nephropathy in Japanese non-insulin-dependent diabetes mellitus (NIDDM). For this
      purpose, we recruited 102 patients with diabetic nephropathy and 64 age-matched
      patients without diabetic nephropathy from Japanese NIDDM patients. Since all the
      subjects had proliferative diabetic retinopathy, it seems likely that they would
      be exposed to hyperglycemia for a long time. In the present study, the BamHI
      HSPG2 genotype and allele frequencies were not significantly different between
      the patients with nephropathy and the patients without nephropathy. Therefore, we
      conclude that the BamHI HSPG2 polymorphism is not associated with the development
      of diabetic nephropathy in Japanese NIDDM.

PMID- 10586429
TI  - Low dose desferrioxamine can improve erythropoiesis in iron-overload hemodialysis
      patients without side effects.
AB  - OBJECTIVE: Multiple blood transfusions were often required to treat anemia in
      uremia patients before the era of recombinant human erythropoietin (r-HuEPO).
      Iron overload thus frequently occurred in chronic hemodialysis patients.
      Desferrioxamine (DFO) is an effective chelating agent, which can remove excessive
      iron and can enhance erythropoiesis. Large dose DFO treatment is a therapy
      associated with the development of severe complications. In this study, a low
      dose DFO regime was used to treat iron overloaded hemodialysis patients. The
      efficacy and side effects of this regiment were evaluated. MATERIALS AND METHODS:
      Eight iron overloaded chronic hemodialysis patients were enrolled in this study.
      All patients received DFO 500 mg intravenously twice-a-week for eight months.
      Serum aluminum, transferrin saturation (TFS) and r-HuEPO requirement were
      recorded before and after DFO treatment. Serum ferritin and hematocrit (Hct) were
      measured before, during, and after the DFO withdrawal period. All patients were
      evaluated and followed closely during treatment. RESULTS: Changes in aluminum,
      TFS and r-HuEPO dosage were unremarkable (p > 0.05). Hct increased significantly
      after eight months of DFO treatment (from 25.3% to 27.0%, p < 0.05). Ferritin
      level was reduced by 43.2% at the end of treatment and an evident decline of
      ferritin was achieved after four months of treatment (2102 ng/mL to 1166 ng/mL, p
      < 0.05). All patients tolerated the treatment well and no complications were
      found. CONCLUSION: Low dose DFO can chelate iron effectively in chronic
      hemodialysis patients. This treatment can enhance erythropoiesis without adverse
      effects.

PMID- 10586430
TI  - Rhabdomyolysis and acute renal failure in intensive care unit.
AB  - Rhabdomyolysis is common clinical and laboratory syndrome resulting from skeletal
      muscle injury and acute renal failure is the most important complication. Acute
      renal failure is common in critically ill medical patients. The aim of our study
      was to determine the prevalence of rhabdomyolysis induced acute renal failure in
      these patients and to established the prognosis of critically ill patients with
      acute renal failure and rhabdomyolysis. In the study were included 1557 patients
      treated in our medical intensive care unit. Seventy-three patients had criteria
      for acute renal failure. Twelve of them (16.4%) had rhabdomyolysis, eight were
      women and four were men (average age was 71 years). Sixty-one patients (83.6%)
      had acute renal failure without rhabdomyolysis, 33 were women and 28 were men
      (average age was 69 years). We found no difference in age and sex between
      patients with acute renal failure with or without rhabdomyolysis. Ten patients
      (83.3%) with rhabdomyolysis and 39 patients (63.9%) without rhabdomyolysis had
      multiorgan failure syndrome. In patients with rhabdomyolysis, the number of
      failing organs were statistically significantly higher (p < 0.027). Nine patients
      (75%) with rhabdomyolysis and 27 patients (44.3%) without rhabdomyolysis died.
      Mortality was statistically significantly higher (p < 0.05) in patients with
      rhabdomyolysis. Rhabdomyolysis with acute renal failure was frequently observed
      in patients treated in our medical intensive care unit. Multiorgan failure
      syndrome was common in these patients and mortality was higher compared to
      patients without rhabdomyolysis.

PMID- 10586431
TI  - Transcriptional regulation of PDGF-A and TGF-beta by +KTS WT1 deletion mutants
      and a mutant mimicking Denys-Drash syndrome.
AB  - Denys-Drash syndrome (DDS) and Frasier syndrome (FS) are rare diseases caused by
      the mutations of Wilms tumor gene, WT1. The common denominator in these syndromes
      is a nephropathy which is manifested by early-onset proteinuria, nephrotic
      syndrome and end stage renal failure. Although these syndromes are genetic models
      of nephropathy and the mutations of WT1 gene are characterized in these patients
      the mechanism how mutations of WT1 gene affect the embryonic kidney adversely has
      not been elucidated. Recently, there was a report that FS is caused by mutations
      in the donor splice site of WT1. These mutations predicted loss of +KTS isoform,
      which is one of the four splicing variants of WT1. In this study, two +KTS
      deletion mutants of WT1 were made as well as a WT1 mutant mimicking a mutation
      found in a patient who had diffuse mesangial sclerosis, end stage renal failure
      and Wilms tumor. Mutant embryonic kidney cell lines were established by
      transfection of 293 embryonic kidney cells with WT1 mutants. We investigated the
      transcription regulation of mutant WT1 among these cell lines using the reporter
      vectors containing PDGF-A and TGF-beta promoter sequence. Our results showed that
      the promoter activity of PDGF-A and TGF-beta, which are related to the
      progression of glomerular diseases, was modestly increased in the mutant cell
      mimicking the patent, while those activities were markedly increased in other two
      deletion mutant cell lines. This study demonstrated that +KTS WT1 mutation found
      in DDS affected the cytokine expression adversely in vitro. From these results,
      we suggest that the alteration of +KTS WT1 expression be responsible for the
      rapid progression of renal diseases in DDS and FS.

PMID- 10586432
TI  - Unrecognized renal damage in critically ill patients.
AB  - INTRODUCTION: The objective of this study was to evaluate the percentage of
      unrecognized renal damage in patients with normal creatinine and urea in serum
      and normal creatinine clearance and to evaluate the usefulness of various
      proteins and enzymes as supplementary procedures for the investigation of renal
      function. MATERIAL AND METHODS: Forty critically ill male patients (APACHE II
      score > 20, injury severity score > 15) were daily screened for a period of five
      days. In the 1st group there were 30 patients with normal creatinine and urea in
      serum and with normal creatinine clearances. In the second group there were ten
      patients with increased values of these parameters. The base-line condition of
      all patients and any changes in hemodynamic, nutrition and ventilation were
      noted. Clearances of inulin, para-aminohippuric acid, and creatinine were
      measured and the Cockcroft-Gault equation was calculated daily for a period of
      five days. Excretion of alpha-1-microglobulin. Tamm-Horsfall-protein, alanine
      aminopeptidase, angiotensinase A, albumin and immunoglobulin G were also measured
      daily. RESULTS: 21 Patients of group 1 and all patients of group 2 showed the
      expected correlation between the routine parameters of creatinine and urea in
      serum and the level of protein and enzyme excretion. Nine patients of group 1
      (30%) showed normal glomerular filtration rates but pathological excretion
      fractions of all proteins and enzymes. CONCLUSIONS: Although all routine
      parameters of renal function (creatinine and urea in serum, creatinine clearance
      both by 24-h collection period and from the Cockcroft-Gault equation), and
      additionally inulin and para-aminohippuric acid clearance were measured, no
      references on tubular and glomerular damage were found in 30% of the investigated
      patients.

PMID- 10586433
TI  - Acute renal failure in epidemic dropsy.
AB  - Acute renal failure (ARF) complicating epidemic dropsy is reported in three
      patients. In this study, ARF resolved in two patients over a period of 4-6 weeks
      with conservative and dialytic support. One patient died of refractory heart
      failure. To the best of our knowledge ARF in association with epidemic dropsy has
      not been reported before in the literature from India.

PMID- 10586434
TI  - [The 17th Congress of the International Society on Thrombosis and Hemostasis
      (ISTH). Washington, D.C., 14-21 August 1999].

PMID- 10586435
TI  - [The Internet and medicine].

PMID- 10586436
TI  - [A comparative study of body temperature using rectal and tympanic measurement].
AB  - INTRODUCTION: Tympanic temperature measuring is more and more used currently. We
      wanted to test this method's accuracy in an internal medicine service. METHODS:
      First, we compared rectal and tympanic temperatures in 37 consecutive patients.
      Tympanic temperature was assessed by two examiners. Secondly, we compared, in 32
      other patients, the readings given by tympanic thermometer used in the first
      part, with those given by nine other tympanic thermometers used in other hospital
      departments. RESULTS: We did not find any difference between right and left
      auricular temperature, nor between the temperatures assessed by the two
      examiners. However, there was a difference between the average tympanic and
      rectal temperatures (36.88 degrees C +/- 0.63 vs 37.36 degrees C +/- 0.57; P <
      0.001). The correlation coefficient between tympanic and rectal temperature was
      only 0.77. If a threshold of temperature of > or = 38 degrees C were given for
      fever, only 29% of febrile patients would have been detected with a tympanic
      thermometer (Kappa coefficient = 0.406 [0.326-0.485]). Fever was especially
      underestimated for high temperatures. The comparison of different tympanic
      thermometers gives different averages for these ten thermometers between 36.5
      degrees C and 37.2 degrees C. CONCLUSION: Though tympanic temperature measure is
      an easy method, it is not sensitive enough to detect fever.

PMID- 10586437
TI  - [Primary pleural lymphoma after collapse therapy: modern aspects of an historic
      disease].
AB  - INTRODUCTION: Pleural lymphomas after long standing pyothorax due to pulmonary
      tuberculosis are now well identified. Most cases have been described by Japanese
      investigators and it seems rare or unrecognised in Western countries. We report
      the study of six cases observed in a single institution. PATIENTS AND METHODS:
      Six pyothorax-associated pleural lymphomas, among 1,038 lymphoma (0.6%) collected
      during a period from 1989 to 1998, are described. Diagnosis was established by
      two pathologists with the usual histologic and immunohistochemical methods,
      according to the working formulation. The in situ hybridization method for
      Epstein-Barr virus was performed. RESULTS: The average age of the patient was 73
      years. Presenting symptoms combined chest pain and constitutional symptoms more
      than 45 years after artificial pneumothorax or tuberculous pleuritis.
      Computerized tomography revealed a pleural mass which involved the adjacent chest
      wall. Open biopsy by thoracotomy show a diffuse B-cell non-Hodgkin-lymphoma in
      all cases. Though the lymphoma was initially localized, many poor prognostic
      factors (age, performance status, LDH, histology) explain the pejorative
      evolution (average survival of five months). Patients died from an uncontrolled
      tumoral proliferation or by infectious complications. In situ hybridization
      confirms the presence of Epstein-Barr virus in tumoral cells. CONCLUSION: Pleural
      lymphoma is an established complication of artificial pneumothorax. Even if the
      Epstein-Barr virus plays a crucial role in the pathogenesis, and despite the
      number of artificial pneumothorax operations that have been widely performed,
      this lymphoma remains rare, suggesting additional oncogenic factors.

PMID- 10586438
TI  - [Neoplastic disorders and organ transplantation].
AB  - INTRODUCTION: Organ transplantation is associated with an increased risk of
      neoplasia, which seems to be caused by the total effect of immunosuppression,
      i.e., the combination of factors involved, rather than by the use of a specific
      class of immunosuppressants. The presence and proliferation of viral oncogenes is
      frequently observed during this immunosuppressive state. The neoplasia in
      immunosuppressed patients therefore has particular histological, clinical,
      evolutive, and therapeutical characteristics. CURRENT KNOWLEDGE AND KEY POINTS:
      The oncogenic mechanisms in immunosuppressed patients have been progressively
      clarified. A viral infection is associated with each type of neoplasia: thus, B
      lymphoma are generally associated with Epstein-Barr viral infection. Skin and
      uterine cervical carcinomas frequently appear after viral dysplasia due to
      papillomavirus. The significant increase in the incidence of Kaposi sarcoma shows
      the role of the immune system in the control of the infection by the human herpes
      virus 8, which has been recently discovered. Liver cancer is associated with a
      history of hepatitis B or C chronic infection. FUTURE PROSPECTS AND PROJECTS:
      Post-transplantation neoplasia constitutes a major problem in patient follow-up,
      as the number of transplant patients has increased and their survival rate has
      improved. In addition, there is an increasingly powerful new generation of
      immunosuppressive drugs. A precise knowledge of the immune system's control
      mechanisms regarding neoplasic cells and viral infection is an important step in
      the prevention and efficient treatment of these forms of cancer. Further research
      into the relationship between the immune system and viral oncogenesis should
      therefore be considered a major aim.

PMID- 10586439
TI  - [Pulmonary involvement in systemic scleroderma. Part I. Chronic fibrosing
      interstitial lung disease].
AB  - INTRODUCTION: Chronic pulmonary interstitial fibrosis is the most frequent
      respiratory manifestation in systemic sclerosis, occurring in 80% of cases. It
      remains a severe complication of the disease and is the primary cause of
      mortality related to respiratory insufficiency in 20 to 60% of cases. CURRENT
      KNOWLEDGE AND KEY POINTS: The date of onset of interstitial lung disease remains
      undetermined, and only in rare cases does it reveal the presence of systemic
      sclerosis. The clinical signs are only observable at a later stage, when at least
      50% of the lung parenchyma is affected. The methods of choice adopted for early
      diagnosis of this disease are high resolution computed tomography and pulmonary
      functional investigations; they should be carried out during the preliminary
      investigation and at follow-up once a year. Moreover, high resolution computed
      tomography also provides prognostic data, for there is a correlation between the
      type of lesion and its severity as determined by high resolution computed
      tomography and by histological findings. The value of other methods of
      investigation, in particular bronchoalveolar lavage, has not yet been clearly
      established. The association of cyclophosphamide and corticoids is currently
      being evaluated (indications, administration modalities, duration), and this
      combination may be the most effective treatment. FUTURE PROSPECTS AND PROJECTS:
      Interstitial lung disease is one of the major causes of morbidity and mortality
      in systemic sclerosis. Early diagnosis and management of this disease is
      therefore of utmost importance.

PMID- 10586441
TI  - [Pancoast-Tobias syndrome disclosing a primary pulmonary non-Hodgkin lymphoma].
AB  - INTRODUCTION: Pancoast's syndrome is generally due to superior sulcus tumors,
      generally bronchial cancer. In rare cases, other causes are found, but these are
      potentially curable. CASE-REPORT: A 78-year old woman with a long history of
      tobacco intake presented with Pancoast's syndrome in the form of a locally
      invasive left apical lung mass. Despite her advanced age and the diagnosis of the
      high probability of lung cancer, a transparietal biopsy procedure was
      nevertheless performed, with the subsequent diagnosis of primary malignant
      pulmonary lymphoma. The patient was satisfactorily treated by combined
      chemotherapy. CONCLUSION: The present study has shown that malignant non-Hodgkin
      lymphomas should be considered in the etiology of the disease, and as a rare but
      potentially treatable cause of Pancoast's syndrome.

PMID- 10586440
TI  - [Pulmonary involvement in systemic scleroderma. Part II. Isolated pulmonary
      arterial hypertension, bronchopulmonary cancer, alveolar hemorrhage].
AB  - INTRODUCTION: Pulmonary interstitial fibrosis is the most frequent cause of lung
      disease in systemic sclerosis. However, other pulmonary complications exist,
      including lung cancer, alveolar hemorrhage, and in particular isolated pulmonary
      arterial hypertension, which is still considered the bete noire as regards this
      disease. CURRENT KNOWLEDGE AND KEY POINTS: The prevalence of pulmonary arterial
      hypertension has been reported to range from 5 to 60% in cases of systemic
      sclerosis; isolated pulmonary arterial hypertension has been principally observed
      in subjects with a ten-year history of limited forms of the disease. As the
      patient remains asymptomatic for a long period, with nonspecific respiratory
      clinical manifestations, the diagnosis is made at a much later stage in the
      course of the disease. The diagnostic method of choice is echocardiography
      doppler, which should be performed during the preliminary investigation, and at
      follow-up. The prognosis is poor, and patient survival rate at 2 years after
      onset of symptoms amounts to 40%. To date, no curative therapy for pulmonary
      arterial hypertension has yet been found. FUTURE PROSPECTS AND PROJECTS: A
      knowledge of the mechanisms involved in the development of isolated pulmonary
      arterial hypertension is essential to the determination of new and relevant
      therapeutic strategies. Vasodilatory treatment, notably calcium channel blockers,
      prostacyclin and analogs such as iloprost, may be effective at an early stage of
      the disease before the appearance of permanent vascular damage.

PMID- 10586442
TI  - [Normal pressure hydrocephalus in an elderly patient].
AB  - INTRODUCTION: Idiopathic normal pressure hydrocephalus is a disease that most
      frequently concerns subjects of an advanced age. It is not easy to establish a
      definitive diagnosis, and the practitioner frequently encounters decision-making
      problems regarding the following question: should a shunt be performed, or not?
      Opinions remain contradictory, even though the available scientific data is
      increasingly precise. The aim of this review is to analyze the physiopathogenic,
      clinical, paraclinical and therapeutic data associated with this type of
      hydrocephalus. CURRENT KNOWLEDGE AND KEY POINTS: If the clinical triad is
      determinant, no other investigation is in fact necessary to confirm the
      diagnosis, although it should always be questioned in the case of ventricular
      enlargement determined by tomodensitometry. The decision to perform the only
      efficient procedure, i.e., a ventricular shunt operation, depends upon a number
      of established arguments in favor of that procedure. Clinical improvement, which
      is often spectacular, can then confirm the diagnosis. FUTURE PROSPECTS AND
      PROJECTS: The efficacy of surgical treatment has been confirmed by clinical
      studies, and there is a reduced tendency as regards post-operative complications.
      However, each case should be considered individually and with the cooperation of
      and coordination between the family, the physician and the neurosurgeon.

PMID- 10586443
TI  - [Pseudotumoral adenopathies, an unusual means of detecting systemic amyloidosis].
AB  - INTRODUCTION: It is uncommon that lymph node enlargement is diagnostic of
      systemic amyloidosis as found in the case reported in this study. EXEGESIS: This
      study examined the case of a 49-year old male with chronic bronchitis in whom in
      1990 the presence had been detected of an isolated cervical lymphadenopathy, 2 cm
      in diameter, and which had previously remained unnoticed. In 1993, a significant
      number of other peripheral adenopathies also appeared in various locations, i.e.,
      cervical, axillary, inguinal. Chest and abdominal CT-scans revealed several
      mediastinal and abdominal lymphadenopathies. The histological study with Congo
      red stain of a cervical lymph node biopsy determined the diagnosis of
      amyloidosis. The patient was at that time asymptomatic. In September 1997, upon
      physical examination the following were found: lower limb edema, superior vena
      cava syndrome, and several cervical lymphadenopathies. Abdominal ultrasonography
      showed enlarged kidneys, and homogeneous splenomegaly. Biological examination
      determined the existence of a nephrotic syndrome with renal failure and
      creatinemia of 350 mumol/L. Due to superior vena cava syndrome worsening,
      cervical lymph node removal was performed. However, the patient died after rapid
      renal failure. CONCLUSION: Although it is a rare occurrence, amyloidosis should
      be taken into consideration in the differential diagnosis of isolated
      lymphadenopathy. Congo red stain amongst others, and an immunohistochemical study
      should be performed in cases of uncertain diagnosis.

PMID- 10586444
TI  - [A disquieting hip].

PMID- 10586445
TI  - [Miliary tuberculosis with neurologic involvement: apropos of a case].

PMID- 10586446
TI  - [False Moskowitz disease, true Biermer disease].

PMID- 10586447
TI  - [Peritoneal mesothelioma, a new complication of pica syndrome: apropos of a
      case].

PMID- 10586448
TI  - [Dissection of the internal carotid artery in antiphospholipid syndrome].

PMID- 10586449
TI  - [Nodular sarcoidosis of the spleen. A new case].

PMID- 10586450
TI  - [Intracellular signal transduction and inflammation: variations of an
      intracellular symphony. 2nd movement].

PMID- 10586451
TI  - Sensory innervation of the dorsal portion of the lumbar intervertebral disc in
      rats.
AB  - STUDY DESIGN: The vertebral levels of dorsal root ganglia innervating the dorsal
      portion of the L5-L6 intervertebral disc were investigated in rats using a
      retrograde transport method. The pathways and functions of nerve fibers supplying
      the dorsal portion of the disc were determined by denervation and
      immunohistochemistry. OBJECTIVES: The dorsal portion of the lumbar intervertebral
      disc has been reported to be innervated segmentally, but anesthetic block of the
      paravertebral sympathetic trunks and the L2 spinal nerve can relieve discogenic
      low back pain. In the current study, the sensory innervation of the dorsal
      portion of the L5-L6 intervertebral disc was investigated, because the disc
      anatomically corresponds to the L4-L5 disc in humans, and the dorsal portion of
      the human L4-L5 disc is frequently subject to injury that causes low back pain.
      METHODS: A retrograde transport of Fluoro-Gold (F-G; Fluorochrome, Denver, CO)
      was used. Subjects included nontreated control (n = 32) and sympathectomized rats
      in which paravertebral sympathetic trunks were removed from L2 to L3 (n = 9). In
      a ventral approach, Fluoro-Gold crystals were placed on the dorsal portion of the
      L5-L6 disc, and labeled neurons in the bilateral dorsal root ganglia from T10 to
      L6 were counted. RESULTS: Fluoro-Gold crystals did not leak from the dorsal
      portion of the L5-L6 disc in 14 of the 32 nontreated rats and in 5 of the 9
      sympathectomized rats. These rats were used for analysis. Fluro-Gold-labeled
      neurons were found in dorsal root ganglia from T13 to L6 in the 14 control rats
      but only from L2 to L6 in the 5 sympathectomized rats. CONCLUSION: The dorsal
      portion of the L5-L6 disc of rats was shown to be multisegmentally innervated by
      the T13 to L6 dorsal root ganglia. The sensory fibers from T13, L1, and L2 dorsal
      root ganglia were shown to innervate the dorsal portion of the L5-L6 disc through
      the paravertebral sympathetic trunks. In contrast, those from the L3-L6 dorsal
      root ganglia may innervate the dorsal portion of the L5-L6 disc through the
      sinuvertebral nerves.

PMID- 10586452
TI  - Augmentation of an anterior solid rod construct with threaded cortical bone
      dowels. A biomechanical study.
AB  - STUDY DESIGN: This static, nondestructive, in vitro biomechanical study examines
      anterior solid rod construct stiffness following the addition of multilevel,
      threaded cortical bone dowels in a bovine model. A comparison is made with a
      clinically relevant posterior construct with and without an anterior release.
      OBJECTIVES: To determine if the addition of solid, multilevel disc space implants
      will increase construct rigidity, while maintaining or enhancing anterior column
      length. SUMMARY OF BACKGROUND DATA: Anterior instrumentation for thoracolumbar
      and lumbar scoliosis has achieved greater correction and preserved distal motion
      segments; however, kyphosis over the instrumented segments and nonunion have been
      observed more frequently than with posterior segmental spinal instrumentation.
      METHOD: Fifteen calf spines underwent mechanical testing. Group A (n = 7)
      included anterior constructs: 1) intact, 2) anterior release/rod/rib graft (L2
      L5), and 3) anterior release/rod/dowels (L2-L5). Group B (n = 8) included
      posterior constructs: 1) intact, 2) posterior rod without anterior release (T13
      L5), 3) posterior rod (T13-L5)/anterior release/rib graft (L2-L5). The protocol
      included axial compression (-600 N), axial rotation (+7 Nm), flexion/extension
      (+7.5 Nm), and lateral bending (+7.5 Nm). An anterior extensometer measured
      segmental displacements to calculate construct stiffness. Lateral radiographs
      evaluated alignment for the anterior constructs. Statistical analysis involved a
      one way analysis of variance (ANOVA) and a Student-Newman-Keuls post hoc test.
      RESULTS: All reconstructions restored stiffness to intact values with the
      exception of the dowels alone in axial rotation. The rod/dowel construct was
      stiffer than all other groups in axial compression, flexion/extension, and
      lateral bending, with the exception of the posterior rod without discectomy,
      which was superior in flexion and statistically similar in extension, lateral
      bending, and axial rotation. The anterior construct with rib graft was equivalent
      to the posterior construct with rib graft in all modes of testing. The dowels
      created greater lordosis than the bicortical rib grafts. CONCLUSIONS: Disc space
      augmentation increased stiffness except in axial rotation, in which values were
      restored to the intact level. Stiffness was superior to a clinically relevant
      posterior instrumentation comparison group following anterior release, and was
      equivalent to a posterior construct without anterior release except in anterior
      flexion. In addition, the implants enhanced lordosis. Increased rigidity should
      improve rates of arthrodesis, while maintenance of sagittal alignment may prevent
      pathologic compensatory curves in adjacent spinal segments. Further research is
      required to determine the optimal method of achieving structural interspace
      support.

PMID- 10586453
TI  - Operative results of canal-expansive laminoplasty for cervical spondylotic
      myelopathy in elderly patients.
AB  - STUDY DESIGN: The study involved elderly patients (age > or = 65), who underwent
      treatment for cervical spondylotic myelopathy by canal-expansive laminoplasty.
      OBJECTIVES: To determine the factors that influence the operative results of
      canal-expansive laminoplasty for treatment of cervical spondylotic myelopathy in
      elderly patients. SUMMARY OF BACKGROUND DATA: Although there have been previous
      reports of many operative procedures, to the authors' knowledge there are no
      reports on the results of surgical treatment for cervical spondylotic myelopathy
      in elderly patients, treated by a unified surgical procedure. To date, no
      attempts have been made to predict the results of these procedures. METHODS:
      Forty-seven patients (age > or = 65) who underwent canal-expansive laminoplasty
      were reviewed in this study. The severity of the clinical picture and the quality
      of operative results were graded according to the Japanese Orthopaedic
      Association scoring system. RESULTS: Of the 13 patients whose period of
      disability persisted for less than 3 months before the operation, 12 were able to
      walk after surgery. The operative results of patients more than 80 years of age
      were not significantly different from those of patients aged between 65 and 79
      years. Results of multiple regression analysis indicate that the predictive
      probability of the postoperative motor function score of the lower extremities
      was 70%. CONCLUSIONS: The severity of the clinical picture and the duration of
      symptoms influenced the outcome of the operation. Despite the advanced age of
      some patients (> 80), the operation increased the chance of recovery from the
      disease.

PMID- 10586454
TI  - Seven- to 20-year outcome of lumbar discectomy.
AB  - STUDY DESIGN: A retrospective, follow-up study. OBJECTIVES: To assess the effects
      of conventional surgery for lumbar disc herniation over an extended period of
      time and to examine factors that might correlate with unsatisfactory results.
      SUMMARY OF BACKGROUND DATA: Although the short-term results of lumbar discectomy
      are excellent when there is a proper patient selection, the reported success
      rates in the long-term follow-up studies vary, and few factors have been
      implicated for an unsatisfactory outcome. METHODS: One hundred-nine patients with
      surgically documented herniated lumbar disc were analyzed, retrospectively, by an
      independent observer. Long-term follow-up (mean 12.2 years) was done by a mailed,
      self-report questionnaire that included items about pain relief in the back and
      leg, satisfaction with the results, need for analgesics, level of activity,
      working capacity, and reoperations. Subjective disability was measured by the
      Oswestry questionnaire. Radiographic review was carried out in 66% of patients.
      End results were assessed using the modified Stauffer-Coventry's evaluating
      criteria. Several variables were examined to assess their influence to the
      outcome. RESULTS: The late results were satisfactory in 64% of patients. The mean
      Oswestry disability score was 18.9. Of the 101 patients who had primary
      procedures, 28% still complained of significant back or leg pain. Sixty-five
      percent of patients were very satisfied with their results, 29% satisfied, and 6%
      dissatisfied. The reoperation rate was 7.3% (8 patients), about one-third of
      which was due to recurrent disc herniation. Sociodemographic factors predisposing
      to unsatisfactory outcome, including female gender, low vocational education, and
      jobs requiring significant physical strenuousness. Disc space narrowing was
      common at the level of discectomy, but was without prognostic significance.
      CONCLUSIONS: The long-term results of standard lumbar discectomy are not very
      satisfying. More than one-third of the patients had unsatisfactory results and
      more than one quarter complained of significant residual pain. Heavy manual work,
      particularly agricultural work, and low educational level were negative
      predictors of a good outcome. These indicators should be used preoperatively to
      identify patients who are at high risk for an unfavorable long-term result.

PMID- 10586455
TI  - Ten-year follow-up evaluation of a school screening program for scoliosis. Is the
      forward-bending test an accurate diagnostic criterion for the screening of
      scoliosis?
AB  - STUDY DESIGN: A 10-year follow-up evaluation of the effectiveness of school
      screening for scoliosis performed in a closed island population. OBJECTIVES: To
      evaluate the diagnostic accuracy of methods used for screening scoliosis and to
      re-examine the long-term effectiveness of the school scoliosis screening program.
      SUMMARY OF BACKGROUND DATA: The diagnostic accuracy of the forward-bending test
      and the long-term efficacy of the screening programs have not been clearly
      established. METHODS: In 1987, 2700 pupils aged 8 to 16 years from the island of
      Samos were screened for scoliosis. The Adams forward-bending test, Moire
      topography, the scoliometer, and the humpometer were used. Radiologic evaluation
      of the spine was available for each pupil and the number of false-negative and
      false-positive results of the screening methods was calculated. Subsequently,
      sensitivity, specificity, and positive and negative predictive values were
      estimated for each screening technique. Pupils found positive for spinal
      deformity were then followed up regularly at yearly intervals. In 1997, all
      positive subjects attended a 10-year clinical and radiologic follow-up, and the
      remaining subjects were re-evaluated by a postal questionnaire and were
      clinically examined if necessary. RESULTS: Spinal deformity was found in 153
      (5.66%) pupils. Scoliosis (defined as a spinal curvature > or = 10 degrees) was
      found in 32 pupils, for a prevalence of 1.18%. For scoliosis, the Adams forward
      bending test showed a number of false-negative results (in five cases), for a
      sensitivity of 84.37% and specificity of 93.44%. The sensitivities of Moire
      topography, the humpometer, and the scoliometer were 100%, 93.75%, and 90.62%,
      respectively, and specificity was 85.38%, 78.11%, and 79.76% respectively. The
      negative predictive value of the forward-bending test was inferior to those of
      the other methods. During this scoliosis screening program, if cutoff limits for
      referral had been used, such as the asymmetry of two Moire fringes, a humpogram
      deformity of (D + H) = 10 mm, and 8 degrees of scoliometer angle, it would have
      been possible to reduce radiologic examination by 89.4%. Three (0.11%) pupils
      aged between 12 and 14 years with scoliotic deformities greater than 20 degrees
      underwent satisfactory nonoperative treatment with Boston braces. One pupil with
      a 40 degrees thoracic curvature, underwent satisfactory surgical treatment
      because of progression 1 year later. Of the 121 spinal deformities with an
      initial Cobb angle less than 10 degrees, 44 (35.8%), and of the 29 scoliotic
      deformities with an initial Cobb angle between 10 degrees and 20 degrees, 14
      (48.3%) progressed (a Cobb angle difference of at least 5 degrees in more than
      one examination). Observation and physiotherapy were the only treatments applied
      to all except one of the pupils in these groups. CONCLUSIONS: The Adams forward
      bending test cannot be considered a safe diagnostic criterion for the early
      detection of scoliosis (especially when it is used as the only screening tool)
      because it results in an unacceptable number of false-negative findings. For the
      early detection of scoliosis, a combination of back-shape analysis methods can be
      safely used with the introduction of cutoff limits for referral being a useful
      procedure. The incidence of significant scoliosis is low, and its natural history
      seems to be independent of early detection. The wide-spread use of school
      scoliosis screening with the use of the forward-bending test must be questioned.

PMID- 10586456
TI  - The spine in diastrophic dysplasia. The surgical arthrodesis of thoracic and
      lumbar deformities in 21 patients.
AB  - STUDY DESIGN: Retrospective chart and radiographic film review. OBJECTIVES: To
      discern the deformity problems in diastrophic dysplasia and to report our results
      in surgical treatment. SUMMARY OF BACKGROUND DATA: Due to the rarity of the
      problem, the literature is very scanty as to the indications for surgery or the
      best technique. METHODS: Analysis of radiographic film for scoliosis, kyphosis,
      lordosis, and decompensation before surgery, after surgery, and at follow-up.
      Analysis of charts for complications and problems. RESULTS: The most common
      deformity pattern was a double thoracic kyphosis (79 degrees/97 degrees) with a
      true kyphosis at the junction of the two scolioses (101 degrees). Combined
      anterior-posterior arthrodesis gave the best results. CONCLUSIONS: Very severe
      deformity can occur in children with diastrophic dysplasia, even at a young age.
      Prompt anterior-posterior arthrodesis can prevent catastrophic deformity.

PMID- 10586457
TI  - Physiological response to submaximal isometric contractions of the paravertebral
      muscles.
AB  - STUDY DESIGN: Brief (30-second) isometric trunk extensions at 5%, 20%, 40%, 60%,
      and 80% of maximal voluntary contraction (MVC) and 3 minutes of prolonged trunk
      extension (20% MVC) in erect position were studied in nine healthy male subjects.
      OBJECTIVES: To investigate the intercorrelation between intramuscular pressure
      and tissue oxygenation of the paravertebral muscles during submaximal isometric
      contractions and further, to evaluate paravertebral electromyogram and
      intramuscular pressure as indicators of force development. SUMMARY OF BACKGROUND
      DATA: Local physiologic responses to muscle contraction are incompletely
      understood. METHODS: Relative oxygenation was monitored with noninvasive near
      infrared spectroscopy, intramuscular pressure was measured with a transducer
      tipped catheter, and surface electromyogram was monitored at three recording
      sites. RESULTS: The root mean square amplitudes of the paravertebral
      electromyogram (L4, left and right; T12, right) and intramuscular pressure
      measured in the lumbar multifidus muscle at L4 increased with greater force
      development in a curvilinear manner. A significant decrease in the oxygenation of
      the lumbar paravertebral muscle in response to muscle contraction was found at an
      initial contraction level of 20% MVC. This corresponded to a paravertebral
      intramuscular pressure of 30-40 mm Hg. However, during prolonged trunk extension,
      no further decrease in tissue oxygenation was found compared with the tissue
      oxygenation level at the end of the brief contractions, indicating that
      homeostatic adjustments (mean blood pressure and heart rate) over time were
      sufficient to maintain paravertebral muscle oxygen levels. CONCLUSION: At a
      threshold intramuscular pressure of 30-40 mm Hg during muscle contraction,
      oxygenation in the paravertebral muscles is significantly reduced. The effect of
      further increase in intramuscular pressure on tissue oxygenation over time may be
      compensated for by an increase in blood pressure and heart rate. Surface
      electromyogram amplitudes and intramuscular pressure can be used as indicators of
      paravertebral muscle force.

PMID- 10586458
TI  - A comparison of pain, functional limitations, and work status indices as outcome
      measures in back pain research.
AB  - STUDY DESIGN: We conducted a prospective study with a 2-year follow-up.
      OBJECTIVE: To compare pain, functional limitations, and work status indices as
      measures of outcome among back pain patients. SUMMARY OF BACKGROUND DATA: Work
      status, pain, and functional limitations indices are often considered as
      interchangeable outcome measures in back pain research. This perspective has been
      criticized by several authors, who argue that each of these outcome measures
      reflects a different construct that may vary independently of the others.
      METHODS: The study was conducted on 720 patients, who sought care for back pain
      in primary care settings of a large health maintenance organization in 1989-90,
      and were interviewed one month and two years later. X2 analyses and receiver
      operating characteristic curves were used to compare the accuracy of a pain
      rating and a modified 16-item Roland-Morris score in classifying patients on work
      status and on the change in work status over time. RESULTS: Moderate agreement
      between the pain and functional limitations measures and work status was
      observed. Pain and functional limitations change scores agreed moderately with
      improvement in work status, but were poorly associated with decline in work
      status. CONCLUSIONS: Although the pain, functional limitations, and work status
      indices examined in this study are related, they are not equivalent and should
      not be regarded as interchangeable. These results argue for a clearer distinction
      of outcome measures in back pain research.

PMID- 10586459
TI  - Activity restrictions after posterior lumbar discectomy. A prospective study of
      outcomes in 152 cases with no postoperative restrictions.
AB  - STUDY DESIGN: A prospective clinical trial was conducted. OBJECTIVES: To
      determine the feasibility of removing activity restrictions after surgery and
      encouraging early return to work; to ascertain the clinical and behavioral
      response to such a strategy; and to identify factors predictive of early return
      to work, preparatory to possible randomized clinical trials. SUMMARY OF
      BACKGROUND INFORMATION: Current practice usually entails several weeks to several
      months of restricted activities after lumbar discectomy to avoid disc "reinjury."
      Earlier work has suggested these restrictions may not be necessary. METHODS: One
      hundred fifty-two consecutive working patients undergoing limited open discectomy
      for herniated lumbar intervertebral disc were treated postoperatively with no
      activity restrictions. Patients were encouraged to return to full activities as
      soon as possible. The patients were followed for a minimum of 2 years (average
      follow-up time = 4.8 years). At follow-up, an independent examiner evaluated each
      patient and collected further postoperative data. RESULTS: One hundred forty-nine
      of the 152 patients (98%) returned to work. The average work loss was 1.2 weeks
      and 148 of 149 patients had returned to full duty by 8 weeks. Approximately one
      third of the group returned to work within 1 week of surgery (32%), many the next
      day. Statistical analysis demonstrated very early return to work did not
      correlate with either recurrent sciatica, reoperation for reherniation, or
      ultimate clinical outcome. Seventeen patients (11.2%) had possible reherniations
      (recurrent sciatica) and eight underwent reoperation (5.3%). CONCLUSION: Lifting
      of postoperative activity restrictions after limited discectomy allowed shortened
      time to return to work relative to the 4 to 16 weeks commonly recommended.
      Complication rates appear comparable to those reported in the literature for
      patients under postoperative restrictions. Postoperative restrictions may not be
      necessary in most patients.

PMID- 10586460
TI  - Treatment of unstable thoracolumbar and lumbar spine injuries using Cotrel
      Dubousset instrumentation.
AB  - STUDY DESIGN: In this prospective study, the results of treating unstable
      thoracolumbar and lumbar injuries with Cotrel-Dubousset instrumentation were
      investigated. OBJECTIVE: To determine the pain and work status of the patients,
      to evaluate neurologic status, and to assess the efficacy of instrumentation in
      the short term. SUMMARY OF BACKGROUND DATA: Short-segment pedicle screw construct
      is the method of choice for reduction and stabilization of unstable thoracolumbar
      spinal injuries. Many investigators have recently reported a high rate of
      instrument failure. In this study, the use of segmental transpedicular fixation
      two levels above the kyphosis decreased instrument failure and sagittal collapse.
      METHODS: Thirty patients, who had unstable thoracolumbar and lumbar spinal
      injuries, underwent application from a posterior approach of Cotrel-Dubousset
      instrumentation two levels above and one below at the thoracolumbar junction and
      short segment fixation in the lumbar area. Radiologic parameters were evaluated
      before and after surgery. RESULTS: The mean follow up was 31 months (range, 25
      49) months. There were statistically significant differences between the pre- and
      postoperative values in all radiologic parameters. Neurologic status improved in
      70% of the patients, with a mean Frankel grade of 1.3 grades. CONCLUSIONS: Cotrel
      Dubousset instrumentation provided spinal stability in unstable injuries, forming
      a rigid construct and restoring physiologic thoracolumbar and lumbar postural
      contours because of its highly corrective effect in the sagittal profile with no
      loss of correction.

PMID- 10586461
TI  - Galen: a pioneer of spine research.
AB  - Galen of Pergamum AD (2nd century), the most eminent Greek physician after
      Hippocrates, marked the history of medicine for more than 14 centuries. His
      doctrines, expressed in his voluminous work, combined the medical heritage of the
      Hippocratic, the Alexandrian, and some of the most important medical schools of
      antiquity. The strong influence of the Hippocratic tradition can
      characteristically be traced in orthopaedics and particularly in Galen's
      presentation of the spine. Based on his observations, derived from dissection and
      vivisection of animals, Galen established a pioneer model for the study of human
      spine. His research ended in an accurate description of the vertebral column and
      the spinal cord. He also described the course and the distribution of the nerves
      emerging from the spine. In addition, he dealt with the diseases affecting these
      structures focusing on spinal tuberculosis and the injuries of the spine and the
      spinal marrow. Galen was the first physician to demonstrate the neurological
      implications following transection of the spinal cord at several levels. The
      predominant feature in Galen's reference to spine is its teleological
      perspective; the great physician tended to attribute the prodigious structure of
      the spine to nature's providence. Despite the inevitable anatomical errors,
      Galen's inspired experiments remained the only thorough approach of spinal
      anatomy and pathology until the recent centuries, when the evolution of
      sophisticated technical aids opened new pathways to spine research.

PMID- 10586462
TI  - 1998 cervical spine research society presidential address. Collegiality in the
      Cervical Spine Research Society.

PMID- 10586463
TI  - The in vitro effects of instrumentation on multilevel cervical strut-graft
      mechanics.
AB  - STUDY DESIGN: Biomechanical study using a programmable testing apparatus that
      replicated physiologic flexion-extension cervical spine motion, and loading
      mechanics. OBJECTIVES: To determine the influence of anterior, posterior, or
      combined plating on multilevel cervical strut-graft mechanics in vitro. SUMMARY
      OF BACKGROUND DATA: The addition of instrumentation does not prevent construct
      failure in multilevel (more than two levels) cervical corpectomy. METHODS: Six
      fresh human cadaveric cervical spines (C2-T1) were tested in six sequential
      conditions that included harvested (H), C4-6 corpectomy, strut grafted, strut
      grafted with an anterior cervical plate (SGAP), strut grafted with posterior
      plates (SGPP), and strut grafted with combined anterior and posterior plates
      (SGAPP). A customized force-sensing strut graft (FSSG) was used to measure axial
      compression-tension, flexion-extension and lateral bending moments, and axial
      torsion. Parameters of stiffness, segmental vertebral motion, and strut-graft
      loads were compared, to determine differences among the spine conditions.
      RESULTS: Flexion of the strut-grafted spine loaded the FSSG, and extension motion
      unloaded the FSSG. With the anterior plate, flexion of the SGAP spine
      significantly unloaded the FSSG; extension loaded the FSSG more than flexion of
      the unplated spine (P = 0.03). The opposite occurred with the posterior plates
      (SGPP), where flexion of the spine significantly loaded the FSSG (more than the
      strut grafted spine) and extension unloaded the FSSG (P < 0.03). The combined
      construct (SGAPP) counteracted the tension band effect of the individual plates
      and demonstrated significantly less overall FSSG load change than either plate
      alone (P = 0.03). CONCLUSIONS: Multilevel cervical instrumentation effectively
      increases stiffness after corpectomy. However, anterior or posterior plating
      alone excessively loads the graft with small degrees of motion, which may promote
      pistoning and failure of multilevel constructs.

PMID- 10586464
TI  - Biomechanical evaluation of five different occipito-atlanto-axial fixation
      techniques.
AB  - STUDY DESIGN: The stabilizing effects of five different occipitocervical
      fixations were compared. OBJECTIVES: To evaluate the construct stability provided
      by five different occipito-atlanto-axial fixation techniques. SUMMARY OF
      BACKGROUND DATA: Few studies have addressed occipitocervical reconstruction
      stability and no studies to data have investigated anterior-posterior
      translational stiffness. METHODS: A total of 21 human cadaveric spines were used.
      After testing intact spines (CO-C2), a type II dens fracture was created and five
      different reconstructions were performed: 1) occipital and sublaminar
      wiring/rectangular rod, 2) occipital screws and C2 lamina claw hooks/rod, 3)
      occipital screws, foramen magnum screws, and C1-C2 transarticular screws/rod, 4)
      occipital screws and C1-C2 transarticular screws/Y-plate, and 5) occipital screws
      and C2 pedicle screws/rod. Biomechanical testing parameters included axial
      rotation, flexion/extension, lateral bending, and anterior-posterior translation.
      RESULTS: Pedicle screw fixation demonstrated the highest stiffness among the five
      reconstructions (P < 0.05). The two types of transarticular screw methods
      provided greater stability than hook or wiring reconstructions (P < 0.05). The C2
      claw hook technique resulted in greater stability than sublaminar wiring fixation
      in anterior-posterior translation (P < 0.05). However, the wiring procedure did
      not significantly increase the stiffness levels beyond the intact condition under
      anterior-posterior translation and lateral bending (P > 0.05). DISCUSSION: C2
      transpedicular and C1-C2 transarticular screws significantly increased the
      stabilizing effect compared to sublaminar wiring and lamina hooks. The improved
      stability afforded by C2 pedicular and C1-C2 transarticular screws offer many
      potential advantages including a high rate of bony union, early ambulation, and
      easy nursing care. CONCLUSION: Occipitocervical reconstruction techniques using
      C1-C2 transarticular screws or C2 pedicle screws offer biomechanical advantages
      compared to sublaminar wiring or lamina hooks. Pedicle screw fixation exhibited
      the highest construct stiffness among the five reconstructions.

PMID- 10586465
TI  - Loosening at the screw-vertebra junction in multilevel anterior cervical plate
      constructs.
AB  - STUDY DESIGN: An in vitro biomechanical study of one-level and three-level
      corpectomy and anterior cervical plate models. OBJECTIVE: To investigate the
      failure of the screw-vertebra interfaces in one- and three-level corpectomy
      models. SUMMARY AND BACKGROUND DATA: Although there are several biomechanical
      studies of strength and stability of anterior cervical plating, there has been no
      investigation into clinically observed failures. METHODS: One- and three-level
      models (corpectomy, strut graft, and anterior plate) were constructed from eight
      cadaveric specimens (C2-T1). Multidirectional flexibility tests (1.0 Nm moments)
      performed before and after fatigue (1000 cycles, 1.0 Nm flexion-extension, 0.14
      Hz) documented the screw-vertebra motions at upper and lower ends. Ranges of
      motion and neutral zones were determined. Analysis of variance was used to
      evaluate significant differences between the upper and lower ends of the plates
      and changes caused by fatigue loading (P < 0.05). RESULTS: Extension motion at
      the lower ends was more than at the upper ends in both models. Fatigue increased
      three-level model ranges of motion at the lower end by 171% in flexion, 164% in
      extension, 153% in lateral bending, and 115% in axial rotation. Similar increases
      were observed in neutral zones. Fatigue loading produced no significant changes
      in one-level models. CONCLUSION: There was excessive screw-vertebra motion caused
      by fatigue at the lower end of the three-level corpectomy model. These findings
      of loosening may explain clinically observed failures at the caudal end of long
      anterior cervical plate constructs. Longer screws, larger diameter screws, and
      supplemental posterior fixation may decrease screw-vertebra loosening.

PMID- 10586466
TI  - Correction of cervical kyphosis using pedicle screw fixation systems.
AB  - STUDY DESIGN: This retrospective study was conducted to analyze the clinical
      results in 30 patients with cervical kyphosis that had been treated using
      cervical pedicle screw fixation systems. OBJECTIVES: To evaluate the
      effectiveness of a pedicle screw fixation procedure in correction of cervical
      kyphosis. SUMMARY OF BACKGROUND DATA: Correction of cervical kyphosis is a
      challenging problem in the field of spinal surgery. There have been several
      reports regarding surgical correction of cervical kyphosis; however, there have
      been no detailed reports on correction of cervical kyphosis using a pedicle screw
      fixation procedure. METHODS: Thirty patients with cervical kyphosis underwent
      correction and fusion using cervical pedicle screw fixation. Seventeen of 30
      patients with flexible kyphosis (Group I) were managed by a posterior procedure
      alone. The remaining 13 patients with rigid or fixed kyphosis (Group II) had a
      combined anterior and posterior procedure. RESULTS: The average preoperative
      cervical kyphosis of 29.4 degrees improved to 2.3 degrees after surgery and was
      2.8 degrees at the final follow-up. In Group I patients, preoperative kyphosis of
      28.4 degrees improved to 5.1 degrees at the final follow-up. In contrast,
      preoperative kyphosis of 30.8 degrees in Group II patients improved to 0.5 degree
      at the final follow-up. Solid fusion was achieved in all patients. There were two
      patients with transient nerve root complications related to pedicle screw
      instrumentation. CONCLUSION: Cervical kyphosis in 30 patients was effectively
      corrected using a pedicle screw fixation procedure with no serious complications.
      Flexible kyphosis with segmental motion can be satisfactorily corrected by a
      single posterior procedure using pedicle screw fixation. However, circumferential
      osteotomies combined with a posterior shortening procedure involving a pedicle
      screw system are required to achieve the best correction of fixed kyphosis by
      bony union. Cervical pedicle screw fixation is the most advantageous
      instrumentation in the correction of cervical kyphosis.

PMID- 10586467
TI  - Characteristics of unicortical and bicortical lateral mass screws in the cervical
      spine.
AB  - STUDY DESIGN: A biomechanical study evaluating the safety and efficacy of
      unicortical versus bicortical lateral mass screws in the cervical spine.
      OBJECTIVES: To analyze the safety, pullout strength and radiographic
      characteristics of unicortical and bicortical screws placed in cadaveric spines
      and to evaluate the influence of level of training on the positioning of these
      screws. SUMMARY OF BACKGROUND DATA: Lateral mass plating for posterior cervical
      spine fusion is an effective method for the treatment of traumatic and
      degenerative instability. The initial description of the technique included
      bicortical screw purchase. The added benefit of bicortical purchase must be
      weighed against the increased risk of injury to nerve roots and the vertebral
      artery. METHODS: In 21 cadaveric spines (mean age 78.9 years), 3.5-mm anterior
      oblique lateral mass screws were placed bilaterally from C3 to C6 (n = 168) using
      a modification of the Magerl technique. In the right side (unicortical) only 14
      mm screws (effective length of 11 mm) were used, whereas on the left side,
      bicortical purchase was obtained. All screws were evaluated clinically and
      radiographically for safety and zone placement. Pullout force was determined for
      all screws. RESULTS: Most screws (92.8%) were rated satisfactory. There were no
      injuries to the spinal cord. On the right side (14 mm) 98.9% of the screws were
      satisfactory, and on the left side (bicortical) 68.1% were satisfactory. There
      was a 5.8% incidence of direct artery injury (compression of vessel wall) and a
      17.4% incidence of direct nerve root injury by the bicortical screws. There were
      no direct injuries with the unicortical screws. Most of the direct-injury
      bicortical screws were placed by the surgeon with the least experience. The mean
      pullout force for all screws was 542.9 +/- 296.6 N. There was no statistically
      significant difference between the pullout force for unicortical (519.9 +/- 286.9
      N) and bicortical (565.2 +/- 306 N) screws (P < 0.05). There were no significant
      differences in pullout strengths in association with zone placement. CONCLUSIONS:
      Fourteen-millimeter lateral mass screws (effective length, 11 mm) placed in a
      superolateral trajectory in the adult cervical spine provide an equivalent
      strength with a much lower risk of injury than the longer bicortical screws
      placed in a similar orientation.

PMID- 10586468
TI  - Complications of buttress plate stabilization of cervical corpectomy.
AB  - STUDY DESIGN: A retrospective analysis of 14 patients treated with cervical
      corpectomy and buttress plate fixation. OBJECTIVES: To determine the
      complications of buttress plate fixation following multilevel cervical
      corpectomies. SUMMARY OF BACKGROUND DATA: Buttress plate fixation of multilevel
      cervical corpectomy has recently been reported. Biomechanical data suggests that
      it is preferable to long plates spanning the entire corpectomy site. There are no
      clinical studies that have specifically addressed the complications of this type
      of plate fixation. METHODS: The records and radiographs of all patients who had
      undergone cervical buttress plate fixation following anterior cervical corpectomy
      for myelopathy were independently reviewed. Twelve of the patients had three
      level corpectomies and two had two-level corpectomies. All patients had placement
      of a short plate at the inferior end of the construct with sufficient overhang to
      act as a buttress against graft extrusion. Three patients underwent posterior
      cervical fusion in addition to the anterior procedure. RESULTS: Graft extrusion.
      One patient had complete graft extrusion on the third post-operative night. A
      second patient who had undergone circumferential fusion had minimal plate
      dislodgement secondary to graft settling. Pseudarthrosis. Three patients had
      pseudarthroses. Two of these required revision posterior surgery. Neurologic.
      None of the patients suffered neurologic complications. With the exception of the
      one patient who died, the rest of the patients all improved by at least one
      Nurick grade. CONCLUSION: The most catastrophic complication in the present
      series was plate dislodgement causing airway compromise and eventually resulting
      in death. Surgeons who utilize these types of buttress plates without additional
      posterior instrumentation should be aware of the potential complications of
      buttress plate fixation.

PMID- 10586469
TI  - Re: A study of the diagnostic accuracy and reliability of the scoliometer and
      Adam's forward bend test (Spine 1999;23;796-802)

PMID- 10586470
TI  - Hangman's fracture.

PMID- 10586471
TI  - Prenatal screening of congenital heart disease between ethics and cost
      effectiveness. Time for a change in current prenatal ultrasound screening
      policies?

PMID- 10586472
TI  - Further attempts to refine our diagnostic capabilities in potential ectopic
      pregnancies.

PMID- 10586473
TI  - The expectant management of women with early pregnancy of unknown location.
AB  - OBJECTIVE: To assess the results of expectant management in women with pregnancy
      of unknown location and to identify diagnostic parameters that are predictive of
      spontaneous pregnancy resolution. DESIGN: Prospective, observational study.
      SUBJECTS: Women with a positive pregnancy test and suspected early pregnancy
      complications who were referred for ultrasound assessment. METHODS: Women were
      first examined by transvaginal ultrasound to establish the location and viability
      of pregnancy. All women with pregnancies that could not be located on the scan
      had a blood sample taken to quantify the serum human chorionic gonadotropin (hCG)
      and progesterone levels. Management was expectant until the pregnancy was
      identified, the condition resolved spontaneously or an intervention was required
      because clinical symptoms deteriorated or hCG levels did not decline. For each
      woman, age, clinical symptoms (pain and bleeding), menstrual dates, past
      gynecological history, endometrial thickness and levels of serum hCG and
      progesterone were recorded. All parameters were tested by univariate analysis and
      then analyzed in a stepwise procedure to form a logistic regression model for
      predicting spontaneous resolution of pregnancy. RESULTS: A total of 1625 women
      were included in the study. In 135 cases (8%) the location of pregnancy was
      unknown. Complete data sets were obtained in 127 cases. These included 34 (27%)
      normal intrauterine pregnancies, 11 (9%) miscarriages and 18 (14%) ectopic
      pregnancies. A total of 64 (50%) pregnancies resolved spontaneously. Stepwise
      analysis showed that four diagnostic parameters--vaginal bleeding, endometrial
      thickness, serum hCG level and progesterone level--contributed significantly to
      the predictive power of the logistic model. With the use of this model,
      spontaneous pregnancy resolution could be predicted at the initial visit with a
      sensitivity and specificity of 92%. CONCLUSIONS: The majority of pregnancies of
      unknown location are abnormal: many resolve spontaneously when managed
      expectantly. A logistic model may be used at the initial visit to identify those
      cases in which the pregnancy is likely to resolve without the need for
      intervention.

PMID- 10586474
TI  - Central arterial hemodynamics in small-for-gestational-age fetuses before and
      during maternal hyperoxygenation: a Doppler velocimetric study with particular
      attention to the aortic isthmus.
AB  - OBJECTIVE: Hemodynamic changes indicating a normalization of fetal blood flow
      redistribution during maternal oxygen administration have been suggested to be of
      positive prognostic value in growth-restricted fetuses. The aortic isthmus has
      been suggested as a site for early detection of blood flow redistribution as well
      as for verification of a response to maternal hyperoxygenation. The present study
      was performed to investigate whether this concept could be confirmed in a study
      involving fetuses assumed to have only a moderate disturbance in fetoplacental
      hemodynamics. DESIGN AND SUBJECTS: Twenty-five singleton fetuses with an
      estimated weight less than -2 SD below the gestational age-related mean and
      without any malformation or chromosomal aberration were studied between 27 and 38
      (median 34) weeks of gestation. METHODS: Velocity waveforms from the mitral
      valve, aortic valve, middle cerebral artery, aortic isthmus and umbilical artery
      were recorded before and during maternal breathing of 100% oxygen. RESULTS: Nine
      fetuses demonstrated absent or reversed end-diastolic velocity (ARED) in the
      aortic isthmus while forward flow was present in the umbilical artery. The
      cerebral artery pulsatility index (PI) increased with oxygen administration and
      there was a decrease in the aortic isthmus PI. Variables obtained from the other
      recording sites did not change with maternal hyperoxygenation. CONCLUSIONS: ARED
      in the aortic isthmus appears to be an early sign of blood flow redistribution in
      this group of fetuses. Maternal oxygenation results in velocity waveform changes
      that suggest an increase of cerebral vascular resistance and a redistribution of
      blood from the brain to the vascular beds supplied by the descending aorta. The
      aortic isthmus is a suitable site to verify this response.

PMID- 10586475
TI  - Do heart rate and velocity variability derived from umbilical artery velocity
      waveforms change prior to clinical pregnancy-induced hypertension?
AB  - OBJECTIVE: To investigate the hypothesis that alterations in heart rate
      variability, peak systolic velocity variability and time-averaged velocity
      variability in the human umbilical artery may predict early signs of
      dysfunctional fetal-placental coupling in pregnancies that later develop
      pregnancy-induced hypertension. METHODS: Doppler flow velocity recordings from
      the umbilical artery were performed at 10-20 weeks of gestation in 12 nulliparous
      women who subsequently developed pregnancy-induced hypertension. From umbilical
      artery velocity waveforms of at least 12 s in duration we determined absolute
      values and beat-to-beat variability in fetal heart rate, peak systolic and time
      averaged velocity and compared these findings with those in normal nulliparous
      pregnant women matched for gestational age. RESULTS: Absolute values for fetal
      heart rate, peak systolic and time-averaged velocity as well as beat-to-beat
      variability in fetal heart rate did not differ significantly between women later
      developing pregnancy-induced hypertension and normal controls. However,
      variability in peak systolic velocity and time-averaged velocity were decreased
      in women who subsequently developed pregnancy-induced hypertension. CONCLUSIONS:
      Whereas fetal heart rate variability was similar, umbilical artery flow velocity
      variability was reduced in women developing pregnancy-induced hypertension
      compared with controls. It is proposed from this study that variability of the
      umbilical artery flow velocity is associated with mechanical changes in the
      vascular bed of women who later develop pregnancy-induced hypertension.

PMID- 10586476
TI  - Assessment of umbilical arterial and venous flow using color Doppler.
AB  - OBJECTIVE: To estimate the umbilical artery and vein blood volume flow using B
      mode and Doppler ultrasound in the second and third trimesters of pregnancy.
      DESIGN: This was a cross-sectional study of 129 singleton, healthy pregnancies at
      23-33 weeks' gestation. The umbilical artery and vein cross-sectional area, time
      averaged velocity and pulsatility index were measured in a free loop of cord, and
      the fetal weight was estimated. Ranges for each parameter were obtained; from
      these the blood flow for the vein and artery was calculated, and the average flow
      corrected for fetal weight was derived. RESULTS: The median time for examination
      was 6 min. The mean cross-sectional area and time-averaged velocity for both the
      vein and artery increased linearly with gestation. The umbilical artery flow
      correlated closely with the average vein flow (r = 0.9, p < 0.001). There was a
      significant, though poor, inverse correlation between the umbilical artery
      pulsatility index and the average umbilical flow (r = -0.25, p < 0.05). The
      average umbilical flow (calculated from the mean of arterial and venous flow),
      corrected for estimated fetal weight, decreased from 189.2 ml/kg per min at 23
      weeks to 176.2 ml/kg per min at 33 weeks' gestation. CONCLUSION: The estimates of
      fetal umbilical flow obtained by this Doppler method are consistent with
      previously published data. Averaging the arterial and venous flow is
      theoretically advantageous in reducing the inherent errors in estimating either
      the arterial or the venous flow. This method of measuring umbilical flow may have
      clinical potential in assessing fetal health and disease processes.

PMID- 10586477
TI  - Simultaneous multigate spectral Doppler imaging of the umbilical artery and
      placental vessels: novel ultrasound technology.
AB  - OBJECTIVE: To establish gestational age-specific nomograms of pulsatility indices
      in the umbilical artery and chorionic and intraplacental vessels, using novel
      ultrasound technology. STUDY DESIGN: A prospective, cross-sectional study of 160
      healthy singleton pregnancies between 18 and 33 weeks of gestation. MEASUREMENTS:
      Using simultaneous multigate spectral Doppler imaging specialized hardware and
      software, we measured the flow velocity waveforms of the umbilical artery,
      chorionic and intraplacental vessels. Computerized automatic mapping calculated
      the pulsatility indices in regions of interest. RESULTS: Data were adequately
      obtained for 160 fetuses. The pulsatility index values in the three sites
      measured decreased with advancing gestational age; the correlation coefficients r
      = -0.74, r = -0.67 and r = -0.68 for the umbilical artery, chorionic and
      intraplacental vessels, respectively, were found to be highly statistically
      significant (p < 0.0001). CONCLUSION: Simultaneous multigate spectral Doppler
      imaging provides simultaneous measurements of the velocity waveforms in the
      umbilical artery, chorionic and intraplacental vessels, and is a feasible and
      reproducible method of obtaining these data. The normal data presented may
      facilitate early detection of flow disturbances in the fetoplacental circulation.

PMID- 10586478
TI  - Placental blood flow measured by simultaneous multigate spectral Doppler imaging
      in pregnancies complicated by placental vascular abnormalities.
AB  - OBJECTIVE: To evaluate the role of placental blood flow measurements by
      simultaneous multigate spectral Doppler imaging in pregnancies complicated by
      intrauterine growth restriction (IUGR), and for early detection of placental
      vascular abnormalities in high- and low-risk pregnancies. METHODS: To assess the
      sensitivity and specificity of abnormal placental blood flow in detecting IUGR,
      we followed 22 women whose pregnancies were complicated by IUGR at 28-34 weeks'
      gestation, and compared the findings with those obtained in 22 matched controls.
      We defined placental blood flow impedance as abnormal when 10% of placental
      pulsatility index (PI) measurements were greater than, or equal to, the mean
      umbilical artery PI (placental PI/umbilical PI > or = 1). To determine the
      predictive value of abnormal placental blood flow measurement for identifying
      developing uteroplacental insufficiency, we examined an unselected group of 100
      low- and high-risk patients at 20-22 weeks' gestation. We correlated the Doppler
      findings with the development of pre-eclampsia, IUGR, placental abruption,
      oligohydramnios and the presence of persistent late decelerations during labor.
      RESULTS: Placental blood flow determination was more sensitive than umbilical
      artery blood flow in detecting abnormal umbilical-placental flow impedances as
      manifested by the presence of IUGR. Of the 100 mixed high- and low-risk patients
      examined at 20-22 weeks, 32 had abnormal placental blood flow. Of these, 19
      (59.4%) subsequently developed pathologies associated with placental vascular
      disease. Of the 68 patients with normal placental blood flow, only six (8.8%)
      developed such pathologies. The sensitivity was 76% (19/25), with positive
      predictive value 59.4% (19/32); the specificity was 82.7% (62/75), with negative
      predictive value 91.2% (62/68). CONCLUSIONS: Abnormal intraplacental blood flow
      at 28-34 weeks' gestation is strongly associated with IUGR. In addition, it has
      moderate positive and negative predictive values for identifying subsequent
      development of uteroplacental vascular abnormalities.

PMID- 10586479
TI  - Women's knowledge, concerns and psychological reactions before undergoing an
      invasive procedure for prenatal karyotyping.
AB  - OBJECTIVES: To evaluate women's reasons for having an invasive procedure, their
      knowledge, how information was obtained, their satisfaction with this
      information, their concerns about complications and psychological reactions and
      distress evoked by the procedure. METHODS: Ninety-four pregnant women undergoing
      early amniocentesis or chorionic villus sampling (CVS) at 10-13 weeks' gestation
      participated in a questionnaire study. The women could choose between early
      amniocentesis (n = 38) and CVS (n = 31), or to be randomized to either of them (n
      = 25). RESULTS: Apart from two items, no differences were found between the
      groups. Age was the main reason for testing, and anxiety was stated as a reason
      by 38.3%. The women knew more about methods for fetal karyotyping, what the tests
      can reveal and how they are performed, than about the risks and reliability of
      the tests. The main source of information had been doctors and midwives at the
      antenatal care center. For a majority of women (64.9%) the decision to have the
      test was made together with their partner. The women's concerns were focused on
      worry about fetal injury, miscarriage and waiting for the result. The test did
      not have a major psychological impact on the women in general, but a substantial
      minority reacted with anxiety and distress. CONCLUSIONS: Knowledge of factors
      important to women and their concerns is essential for professionals working with
      genetic counselling and performance of invasive procedures.

PMID- 10586480
TI  - Prospective cross-validation of Doppler ultrasound examination and gray-scale
      ultrasound imaging for discrimination of benign and malignant pelvic masses.
AB  - OBJECTIVE: To cross-validate, prospectively, the diagnostic performance of
      established ultrasound methods for discrimination of benign and malignant pelvic
      masses. METHODS: A total of 173 consecutive women with a pelvic mass judged
      clinically to be of adnexal origin underwent preoperative ultrasound examination
      including color and spectral Doppler techniques. A total of 149 tumors were
      benign, and 24 were malignant. The sensitivity and false-positive rate with
      regard to malignancy were calculated for the following methods, using cut-off
      values recommended in previous publications: Lerner score; ultrasound morphology,
      i.e. tumors without solid components being classified as benign and tumors with
      solid components as malignant; tumor color score; pulsatility index; resistance
      index; time-averaged maximum velocity; peak systolic velocity; the combined use
      of ultrasound morphology and tumor color score and the combined use of ultrasound
      morphology and peak systolic velocity. Sensitivity and false-positive rate were
      also calculated for subjective evaluation of the gray-scale ultrasound image and
      for subjective evaluation of the gray-scale ultrasound image supplemented with
      subjective evaluation of color Doppler ultrasound examination. The confidence
      with which the diagnosis was made, based on subjective evaluation, was rated on a
      visual analog scale. RESULTS: Subjective evaluation of the gray-scale ultrasound
      image was by far the best method for distinguishing benign from malignant tumors
      (sensitivity 88%, false-positive rate 4%), followed in descending order by
      subjective evaluation of the gray-scale ultrasound image supplemented with color
      Doppler examination, the Lerner score and the time-averaged maximum velocity.
      Adding Doppler examination to subjective evaluation of the gray-scale image did
      not increase the number of correct diagnoses, but it increased the confidence
      with which a correct diagnosis was made in 14% of tumors. In 11 tumors (6% of the
      series as a whole), the addition of Doppler examination changed the diagnosis
      based on subjective evaluation of the gray-scale ultrasound image from an
      incorrect (n = 1) or uncertain (n = 10) diagnosis to a correct and confident
      diagnosis. CONCLUSION: In experienced hands, subjective evaluation of the gray
      scale ultrasound image is the best ultrasound method for discriminating between
      benign and malignant adnexal masses. The main advantage of adding Doppler
      examination to subjective evaluation of the gray-scale image is an increase in
      the confidence with which a correct diagnosis is made.

PMID- 10586481
TI  - Cervical pregnancy: assessment with three-dimensional power Doppler imaging and
      successful management with selective uterine artery embolization.
AB  - Cervical pregnancy is frequently associated with extensive hemorrhage which, in
      severe cases, may be stopped only by hysterectomy. We report a case of an
      anembryonic cervical pregnancy diagnosed at 10 weeks, and associated with a large
      arteriovenous malformation. The patient was conservatively managed with simple
      selective uterine artery embolization. After embolization, her vaginal bleeding
      ceased and the level of serum beta-human chorionic gonadotropin decreased
      rapidly. No additional treatment was given. The patient's postoperative course
      was uneventful and the cervical mass had disappeared at the follow-up 4 months
      later. To the best of our knowledge, this is the first report of conservative
      management of cervical pregnancy simply by uterine artery embolization. The role
      of three-dimensional power Doppler ultrasonography in the assessment of cervical
      pregnancy and in monitoring the therapeutic response is discussed.

PMID- 10586483
TI  - In vitro demonstration of the radiation pressure effect caused by obstetric
      Doppler.

PMID- 10586482
TI  - A case of achondrogenesis type II associated with huge cystic hygroma: prenatal
      diagnosis by ultrasonography.

PMID- 10586484
TI  - The year 2000 software bug.

PMID- 10586485
TI  - Three-dimensional ultrasound diagnosis of interstitial pregnancy.

PMID- 10586486
TI  - [Botulinum toxin therapy: from dreaded biological toxin to standard
      pharmaceutical].

PMID- 10586487
TI  - [High altitude headache: epidemiology, pathophysiology, therapy and prophylaxis].
AB  - Headache is known to be the predominant symptom in acute mountain sickness which
      is also frequently accompanied by nausea, vomiting and insomnia. Nowadays, every
      year millions of skiers and mountaineers are attracted to mountains all over the
      world. At altitudes between 2500 m and 5000 m about 20% to 90% of those who are
      not adapted to high altitude will experience high altitude headache (HAH). It is
      well documented that HAH can be best prevented by observance of the golden rule:
      not to go too high too fast. Although many mountaineers are aware of this rule,
      its observance is complicated by unknown individual susceptibility, the location
      of mountain huts, the use of cable cars, limited holiday time, unfavorable
      weather or avalanche conditions. Therefore, there is a widespread use of drugs
      for the treatment and prevention of HAH. In the past, the increase in cerebral
      blood flow during acute hypoxia was thought to be the main cause of HAH. More
      recent findings, however, have caused this hypothesis to be reduced in importance
      and have supported the pathogenetic consequence of sensitization of intracranial
      pain-sensitive structures. The effectiveness of cyclooxygenase inhibition for the
      treatment and prevention of HAH suggests that especially prostaglandins may be an
      important mediator between hypoxia and HAH. Besides oxygen, acetazolamide,
      dexamethasone and especially inhibitors of prostaglandin synthesis such as
      ibuprofen and naproxen are approved for the treatment of HAH. Acetazolamide,
      dexamethasone, and aspirin were also found to prevent HAH. The most beneficial
      effects however, may be achieved by the combined application of acetazolamide and
      aspirin. This combination increases oxygenation and reduces prostaglandin
      synthesis.

PMID- 10586488
TI  - [Safety and tolerance of single-dose botulinum toxin Type A treatment in 204
      patients with spasticity and localized associated symptoms. Austrian and German
      botulinum toxin A spasticity study group].
AB  - High dose oral anti-spastic medication is effective in the treatment of
      spasticity but has the disadvantage of frequent systemic side effects such as
      drowsiness and general weakness. Therefore, neurolytic and chemodenervation
      procedures are further therapeutic options, especially in cases of local
      spasticity. Apart from phenol blocks with the risk of persisting painful
      dysesthesia, botulinum toxin type A (BtxA) appears to be a safe and effective
      treatment. In 204 patients (mean age, 41.5 years [range 3-91 years]) with acute
      (n = 29, mean duration of disease 2.9 months [range, 1-6 months]) and chronic (n
      = 175, mean duration of disease 111 months [range, 7-500 months]) spasticity due
      to stroke, traumatic brain and spinal injury and other lesions of the upper motor
      neuron, the effects of single-dose BtxA treatment were studied. An overall dose
      of 181.2 units [range, 15-600 units] of BtxA (Botox) was injected in a mean of
      3.3 [1-14] muscles per patient. Results were assessed using a modified Rating of
      Response to BtxA (RRB, Brin et al. 1995). The RRB includes a pre- and post BtxA
      assessment of the severity of spasticity-associated problems (patient's self
      assessment), a rating of the current percentage of normal function in the region
      of the body selected for BtxA and a global rating of changes induced by BtxA. 191
      (93.6%) patients demonstrated improvement over a mean of 7.7 weeks [1-36]; no
      deterioration was observed. Mean overall severity and function improved
      significantly (p < 0.001). No systemic or severe side effects were registered.
      Only in 5.9% of the patients were mild (n = 10) or moderate (n = 2) reversible
      adverse events reported. We conclude that BtxA injections are safe and effective
      in the treatment of local spasticity.

PMID- 10586489
TI  - [Clinical phase II-evaluation of neoadjuvant, cytostatic combination chemotherapy
      with docetaxel and epidoxorubicin in female breast cancer patients (T1-4, N0-2,
      M0)].
AB  - BACKGROUND: Preoperative (neo-adjuvant) chemotherapy is very effective in
      downstaging primary tumors and moreover is able to prevent advancing metastatic
      growth early in the course of the disease. METHODS: We report on 38 patients with
      a median age of 54 years (range, 33-70 years) suffering from biopsy-proven breast
      cancer (T1-T4). Mastectomy had been considered the treatment of choice in all
      cases. The patients received 194 cycles of chemotherapy with docetaxel (75 mg/m2)
      and epidoxorubicin (75 mg/m2) on day 1, every 21 days, together with 30 million
      IU of G-CSF from days 3 to 10. Three to 8 cycles (median 5 cycles) of the
      treatment were administered until best response was achieved on mammography and
      clinical assessment. RESULTS: The neo-adjuvant chemotherapy was well tolerated
      and all patients completed the treatment regimen on an out-patient basis. During
      194 cycles we observed leukopenia WHO grade IV only at one occasion (0.5%). WHO
      grade III toxicity consisted of leukopenia (0.5%), diarrhoea (2%), and stomatitis
      (0.5%). Response to treatment was present in 85%, with 4 patients (11%)
      experiencing a pathological complete response (pCR) of the invasive tumor (T0: n
      = 2, DCIS: n = 2) and 28 patients (74%) showing a partial pathological response.
      In 21 patients (52%) a breast-conserving surgical procedure was possible.
      SUMMARY: We conclude that neo-adjuvant treatment of primary breast cancer with
      docetaxel and epidoxorubicin is safe and effective. By applying more chemotherapy
      cycles preoperatively it might even be possible to raise the rate of pCR and
      prolong survival.

PMID- 10586490
TI  - [Epidemiologic data for tetanus prophylaxis. Assessment of the need for
      vaccination].
AB  - OBJECTIVE: In spite of the low morbidity secondary to tetanus, the high fatality
      rate (about 50%) requires effective and extensive protection of the population by
      vaccination. Since documentation is often lacking, booster tetanus vaccination is
      frequently applied in cases of minor injury. This leads to vaccination associated
      complications such as hyperergic reactions. The more intense the vaccination
      associated side effects are, the less revaccination is possible. We investigated
      the tetanus immune status of a selected Austrian population. MATERIALS AND
      METHODS: Tetanus antitoxin antibodies were measured with ELISA (Immunozym
      Tetanus, Immuno AG) in serum samples from 218 subjects who were hospitalised in a
      dermatology unit. In addition, patient history and data concerning vaccination
      were collected. RESULTS: Based on the assumption that an antitoxin level of 0.1
      IU/ml provides sufficient protection, 63% of the subjects were found to be
      adequately protected. 56% showed high antibody concentrations above 0.5 IU/ml.
      However, the data also revealed no protection by vaccination in 37% of the
      subjects. Data obtained by case history or vaccination certificates could not
      serve as a discrimination factor for applying revaccination or not. CONCLUSION:
      We strongly recommend better documentation of tetanus vaccination. In some cases,
      a search for tetanus antibodies before applying booster tetanus vaccination might
      be necessary.

PMID- 10586491
TI  - Primary aldosteronism caused by aldosterone-producing adenoma in pregnancy-
      complicated by EPH gestosis.
AB  - Pregnancy in conjunction with primary aldosteronism is an unusual occurrence. We
      report a 28-year-old woman who presented with mild hypertension and hypokalemia
      as manifestations of primary aldosteronism caused by an aldosterone-producing
      adenoma in the left adrenal gland during pregnancy. Although the diagnosis was
      straightforward, the patient refused to undergo the proposed operation during the
      second trimester of her pregnancy. She was not admitted to hospital until she
      developed EPH gestosis in the 27th week of gestation, which had an unfavourable
      outcome for the infant who died nine days after delivery. The patient underwent a
      laparoscopic adrenalectomy which resulted in normalization of blood pressure and
      blood potassium levels. In cases of aldosterone-producing adenoma, surgery in the
      second trimester is the most appropriate option to avoid a poor obstetric
      outcome.

PMID- 10586492
TI  - [Goncharov's novel Oblomow as an example of the story of impeded convalescence].
AB  - After the termination of an illness involving a long period of being bedridden
      and in need of care, not every patients is willing to immediately terminate the
      state of being ill. Some patients show a more or less concealed resistance to
      return into their customary social lives, which can hinder the progress of
      convalescence and rehabilitation. Two of the possible bases for such behaviour
      were described in depth in medical, but above all in non-medical literature: for
      one in Goncarov's novel Oblomov, published in 1859, and for another in numerous
      reports concerning the possible consequences of boredom. To recognize a patient's
      proneness to such behaviour at an early stage and to be able to implement
      appropriate countermeasures, extensive knowledge of the person of Oblomov, so
      called oblomovism, and boredom with its various sequelae is required.

PMID- 10586493
TI  - [Azimilide: Search for an effective and well-tolerated anti-arrhythmia agent].

PMID- 10586494
TI  - Molecular analysis of prenyl chain elongating enzymes.
AB  - Multiple alignments of primary structures of many kinds of prenyltransferases
      that participate in the most fundamental prenyl-chain backbone synthesizing
      process in isoprenoid biosynthesis showed seven conserved regions in the primary
      structures of (E)-prenyl diphosphate synthases. However, no information has been
      available about the structures of (Z)-prenyl diphosphate synthases until our
      recent isolation of the gene for the undecaprenyl diphosphate synthase of
      Micrococcus luteus B-P 26. The amino acid sequence of the (Z)-prenyl diphosphate
      synthase is totally different from those of (E)-prenyl chain elongating enzymes.
      Protein data base searches for sequences similar to that of the undecaprenyl
      diphosphate synthase yielded many unknown proteins which have not yet been
      characterized. Two of the proteins have recently been identified as the
      undecaprenyl diphosphate synthase of Escherichia coli and the dehydrodolichyl
      diphosphate synthase of Saccharomyces cerevisiae, indicating that there are three
      highly conserved regions in the primary structure of (Z)-prenyl chain elongating
      enzymes.

PMID- 10586495
TI  - Enzymatic synthesis of N-acetylglucosaminyl-cyclodextrin by the reverse reaction
      of N-acetylhexosaminidase from jack bean.
AB  - Novel heterobranched cyclodextrins (CDs), N-acetylglucosaminyl-cyclodextrins
      (GlcNAc-CD), were synthesized from a mixture of GlcNAc and alpha, beta, or gamma
      CD by the reverse reaction of N-acetylhexosaminidase from jack bean. Optimum pH
      and temperature for the production of GlcNAc-alpha CD by N-acetylhexosaminidase
      were pH 4.9 and 50-70 degrees C, respectively. The maximum yield of GlcNAc-alpha
      CD was 17.5% (mol/mol) at the concentration of 1 M GlcNAc and 0.25 M alpha CD.
      The reverse reaction product, GlcNAc-alpha CD, was separated into two peaks by
      HPLC analysis on the ODS column. Their structures were identified as 6-O-beta-D-N
      acetylglucosaminyl-alpha CD and 2-O-beta-D-N-acetylglucosaminyl-alpha CD by FAB
      MS and NMR spectroscopies. N-Acetylhexosaminidase from jack bean also synthesized
      N-acetylgalactosaminyl-alpha CD from N-acetylgalactosamine and alpha CD.

PMID- 10586496
TI  - Structure-activity relationships of RGD mimetics as fibrinogen-receptor
      antagonists.
AB  - The activities of a series of RGD mimetics, which contained a variety of cationic
      structures, for the inhibition of platelet aggregation and fibrinogen-receptor
      binding were measured. The stability of the coulombic ion-pairing complex of the
      model compounds with the acetate anion as a model for the receptor was calculated
      in terms of the ionic interaction energy. The results suggest that stability is
      one of the significant factors which govern the inhibitory potency of fibrinogen
      receptor binding. The distance between cationic and anionic groups might also
      affect the potency. A compound which contained an amidinophenyl structure as the
      cationic moiety showed exceptionally high inhibitory activity, suggesting that
      some other factors, in addition to coulombic interaction and the distance, affect
      the potency.

PMID- 10586497
TI  - Dietary effect of tocopherols and tocotrienols on the immune function of spleen
      and mesenteric lymph node lymphocytes in Brown Norway rats.
AB  - The immunoregulatory effects of dietary alpha-tocopherol (Toc) and tocotrienols
      (T-3) on humoral and cell-mediated immunity and cytokine productions were
      examined in Brown Norway rats. We found that the IgA and IgG productivity of
      spleen and mesenteric lymph node (MLN) lymphocytes was significantly enhanced in
      the rats fed on Toc or T-3, irrespective of concanavalin A (Con A) stimulation of
      the lymphocytes. On the contrary, the IgE productivity of lymphocytes from the
      rats fed on Toc or T-3 was less without Con A stimulation, but was greater in the
      presence of Con A, especially in the T-3 group. Toc or T-3 feeding significantly
      decreased the proportion of CD4+ T cells and the ratio of CD4+/CD8+ in both
      spleen and MLN lymphocytes of the rats fed on Toc or T-3. The interferon-gamma
      productivity of MLN lymphocytes was higher in the rats fed on Toc or T-3 than in
      those fed on a control diet in the presence of Con A, while that of spleen
      lymphocytes was lower in the rats fed on Toc or T-3. In addition, T-3 feeding
      decreased the productivity of tumor necrosis factor-alpha of spleen lymphocytes,
      while it enhanced the productivity of MLN lymphocytes. These results suggest that
      oral administration of Toc and T-3 affects the proliferation and function of
      spleen and MLN lymphocytes.

PMID- 10586498
TI  - Site-directed mutagenesis of restriction endonuclease HindIII.
AB  - Site-directed mutagenesis by inverse PCR was done on the HindIII gene. Target
      residues to be mutated were chosen according to (i) the fact that a mutant
      obtained by sodium nitrite treatment showed almost no HindIII activity, where Asp
      123 was replaced with Asn, and (ii) the model proposed by Stahl et al. (Stahl,
      F., Wende, W., Jeltsch, A. and Pingoud, A. Biol. Chem. 379, 467-473 (1998)).
      Seven kinds of mutants were obtained by the PCR, and their enzymatic and
      biochemical properties were examined. Three mutants, P50S, D108L, and D123N,
      showed fairly low HindIII activity. On the other hand, the other four, P84Q,
      E86K, V106E, and K125N, retained the activity. In particular, E86K showed higher
      activity than the wild enzyme. This fact was confirmed when activities of the
      purified wild and E86K enzymes were assayed. These results coincided fairly well
      with data using E. coli strains that carry the respective mutant plasmids, on
      their resistance to phage T7 and on growth rate. We conclude that the PE motif at
      residues 50 and 51, and DXK motif at residues 108-110, are responsible for the
      enzymic reaction of HindIII.

PMID- 10586499
TI  - Purification and characterization of an esterase involved in cellulose acetate
      degradation by Neisseria sicca SB.
AB  - An esterase catalyzing the hydrolysis of acetyl ester moieties in cellulose
      acetate was purified 1,110-fold to electrophoretic homogeneity from the culture
      supernatant of Neisseria sicca SB, which can assimilate cellulose acetate as the
      sole carbon and energy source. The purified enzyme was a monomeric protein with a
      molecular mass of 40 kDa and the isoelectric point was 5.3. The pH and
      temperature optima of the enzyme were 8.0-8.5 and 45 degrees C. The enzyme
      catalyzed the hydrolysis of acetyl saccharides, p-nitrophenyl esters of short
      chain fatty acids, and was slightly active toward aliphatic and aromatic esters.
      The K(m) and Vmax for cellulose acetate (degree of substitution, 0.88) and p
      nitrophenyl acetate were 0.0162% (716 microM as acetyl content in the polymer)
      and 36.0 microM, and 66.8 and 39.1 mumol/min/mg, respectively. The enzyme was
      strongly inhibited by phenylmethylsulfonyl fluoride and diisopropyl
      fluorophosphate, which indicated that the enzyme was a serine esterase.

PMID- 10586500
TI  - Heterologous expression and characterization of endoglucanase I (EGI) from
      Trichoderma viride HK-75.
AB  - Endoglucanase I (EGI) secreted from Trichoderma viride HK-75 has a unique
      transglycosylation activity. The genomic and cDNA clones encoding EGI (egl1) of
      T. viride HK-75 were isolated and characterized. The coding region of egl1,
      composed of 1392 bp, was found to encode a polypeptide of 464 amino acids that
      has extensive similarity (93.8%) with EGI of T. reesei. Expression of the egl1
      gene in E. coli as a fusion protein (with N-terminal thioredoxin and C-terminal
      histidine tag) led to a large production of a nonglycosylated protein of 62.5
      kDa. However, it formed an insoluble inclusion body. Upon denaturation with 8 M
      urea followed by dialysis and successive purification, the enzymatically active
      recombinant EGI (rEGI) was obtained at a level as high as 18.3 mg/l of 1,000 ml
      of culture. The rEGI had 67.8% activity for carboxymethyl cellulose (CMC),
      compared to native EGI (nEGI). The optimum pH and optimum temperature of rEGI
      were lower than those of nEGI by 0.5 and 5 degrees C, respectively. The rEGI also
      had narrower CMCase ranges than nEGI in pH and temperature stabilities. However,
      the catalytic and transglycosylation abilities against cellotriose of rEGI were
      comparable to those of nEGI. These results suggest that the glycosylation is
      important for the stabilities of EGI but not critical for the essential enzymatic
      capacity.

PMID- 10586501
TI  - NAD(+)-dependent (S)-specific secondary alcohol dehydrogenase involved in
      stereoinversion of 3-pentyn-2-ol catalyzed by Nocardia fusca AKU 2123.
AB  - An NAD(+)-dependent alcohol dehydrogenase was purified to homogeneity from
      Nocardia fusca AKU 2123. The enzyme catalyzed (S)-specific oxidation of 3-pentyn
      2-ol (PYOH), i.e., part of the stereoinversion reaction for the production of (R)
      PYOH, which is a valuable chiral building block for pharmaceuticals, from the
      racemate. The enzyme used a broad variety of secondary alcohols including alkyl
      alcohols, alkenyl alcohols, acetylenic alcohols, and aromatic alcohols as
      substrates. The oxidation was (S)-isomer specific in every case. The K(m) and
      Vmax for (S)-PYOH and (S)-2-hexanol oxidation were 1.6 mM and 53 mumol/min/mg,
      and 0.33 mM and 130 mumol/min/mg, respectively. The enzyme also catalyzed
      stereoselective reduction of carbonyl compounds. (S)-2-Hexanol and ethyl (R)-4
      chloro-3-hydroxybutanoate in high optical purity were produced from 2-hexanone
      and ethyl 4-chloro-3-oxobutanoate by the purified enzyme, respectively. The K(m)
      and Vmax for 2-hexanone reduction were 2.5 mM and 260 mumol/min/mg. The enzyme
      has a relative molecular mass of 150,000 and consists of four identical subunits.
      The NH2-terminal amino acid sequence of the enzyme shows similarity with those of
      the carbonyl reductase from Rhodococcus erythropolis and phenylacetaldehyde
      reductase from Corynebacterium sp.

PMID- 10586502
TI  - Three domains comprised in thermostable molecular weight 54,000 pullulanase of
      type I from Bacillus flavocaldarius KP1228.
AB  - The gene that coded for a cellular pullulanase of type I (alpha-dextrin 6
      glucanohydrolase, EC 3.2.1.41) in Bacillus flavocaldarius KP1228 (FERM-P9542)
      cells growing at 51 to 82 degrees C was expressed in Escherichia coli MV1184. The
      enzyme had a half-life of 10 min at 107 degrees C. Purification of the enzyme and
      its characterization showed that the enzyme was identical with the native one.
      Its primary structure of 475 residues with a molecular weight of 53,856 deduced
      from the gene was 15-21% and 43% identical to the corresponding C-terminal
      regions in the sequences of 2 plant and 6 bacterial pullulanases of type I, and
      of Bacillus stearothermophilus TRS40 neoplullulanase, respectively. Sequence
      analysis showed that B. flavocaldarius pullulanase comprised 3 domains, i.e., one
      catalytic (beta/alpha)8-barrel domain, one domain made of the region protruding
      from the barrel between the third beta-strand and the third alpha-helix, and one
      beta-stranded domain attached to the C-end of the barrel domain, but that the
      pullulanase lacked the beta-stranded domain commonly found in addition to the 3
      domains in the neopullulanase and all other pullulanases, and attached to the N
      end of the barrel domain.

PMID- 10586503
TI  - High fat feeding of lactating mice causing a drastic reduction in fat and energy
      content in milk without affecting the apparent growth of their pups and the
      production of major milk fat globule membrane components MFG-E8 and butyrophilin.
AB  - Lactating mice were fed either a low fat or a high fat diet. Milk samples were
      collected and the composition was examined. Triglyceride and free fatty acid
      contents were greatly reduced in the milks of high fat diet group, while protein
      and lactose contents were almost the same between both diet groups. Although the
      energy content of each component was also lower in milk of high fat diet group,
      there was apparently no significant difference in the growth of the pups raised
      by either diet group. This discrepancy might be in part explained by a hypothesis
      that the pups might monitor calorie content in milk and keep suckling until the
      energy intake reaches their satisfaction. Moreover, nearly the same amounts of
      major milk fat globule membrane proteins MFG-E8 and butyrophilin were shown to be
      present in the milks from both diet groups and gene expression of both proteins
      in the mammary glands were also indistinguishable, suggesting that production of
      major MFGM components is not simply related to fat production and secretion.

PMID- 10586504
TI  - Structures and expression patterns of two tropinone reductase genes from
      Hyoscyamus niger.
AB  - In the biosynthesis of tropane alkaloids, two tropinone reductases (TRs) catalyze
      reduction of tropinone to different stereoisomers, tropine and pseudotropine. Two
      TRs from Hyoscyamus niger have 64% of identical amino acids and hence a common
      evolutionary origin. In this study, genomic clones of TRs were isolated from H.
      niger. Their sequence comparison showed that although they have the same
      exon/intron organization, sequence similarity was restricted to the coding
      regions. In H. niger transgenic hairy roots, both TR promoters activated
      transcription of the reporter genes in endodermis and pericycle of the roots. A
      quantitative reporter assay and a nuclear run-on experiment indicated that the
      two genes are transcribed at a similar rate. The results indicate that although
      different activity levels have been observed for the TR enzymes in the H. niger
      root, the TR genes per se conserve similar tissue-specific expression pattern and
      transcriptional rate.

PMID- 10586505
TI  - Purification and characterization of the overexpressed Aspergillus oryzae
      xylanase, XynF1.
AB  - The Aspergillus oryzae xynF1 gene coding for a xylanase, XynF1, was successfully
      overexpressed under the strong A. oryzae TEF1 gene promoter. The high-XynF1
      producing transformant secreted about 180 mg/l of XynF1 in the glucose-containing
      medium. The overexpressed XynF1 was purified by only one chromatographic step.
      The purified XynF1 had a molecular mass of 35.0 kDa, a pH optimum of 5.0, and a
      temperature optimum of 60 degrees C.

PMID- 10586506
TI  - Stimulative effect of dietary protein on the phosphorylation of p70 S6 kinase in
      the skeletal muscle and liver of food-deprived rats.
AB  - The effect of dietary protein on p70S6k phosphorylation was examined in rats
      starved for 18 h and then fed either a 20% casein diet (20C) or a protein-free
      diet (0C). Refeeding the 20C diet, but not the 0C diet, increased p70S6k
      phosphorylation in both the skeletal muscle and liver. The plasma insulin
      concentrations were the same after refeeding the 20C or 0C diet, suggesting that
      a combination of dietary protein and insulin may be required to stimulate p70S6k
      phosphorylation.

PMID- 10586507
TI  - Molecular analysis of the Corynebacterium glutamicum transketolase gene.
AB  - Transketolase is important in production of the aromatic amino acids in
      Corynebacterium glutamicum. The complete nucleotide sequence of the C. glutamicum
      transketolase gene has been identified. The DNA-derived protein sequence is
      highly similar to the transketolase of Mycobacterium tuberculosis, taxonomically
      related to C. glutamicum. The alignment of the N-terminus regions between both
      transketolases showed TTG to be the most probable start codon. Potential
      ribosomal binding and promoter regions were situated upstream from the TTG. The
      deduced amino acid sequence consists of 700 residues with a calculated molecular
      mass of 75 kDa, and contains all amino acid residues involved in cofactor and
      substrate binding in the well-characterized yeast transketolase sequence.

PMID- 10586508
TI  - Identification of zerumbone in Zingiber zerumbet Smith as a potent inhibitor of
      12-O-tetradecanoylphorbol-13-acetate-induced Epstein-Barr virus activation.
AB  - Zerumbone was isolated from the rhizomes of Zingiber zerumbet Smith as a potent
      inhibitor of tumor promoter 12-O-tetradecanoylphorbol-13-acetate-induced Epstein
      Barr virus activation. The IC50 value of zerumbone (0.14 microM) is noticeably
      lower than those of the anti-tumor promoters we have hitherto obtained.
      Interestingly, alpha-humulene lacking the carbonyl group at the 8-position in
      zerumbone was inactive (IC50 > 100 microM), while 8-hydroxy-alpha-humulune was
      markedly active (IC50 = 0.95 microM).

PMID- 10586509
TI  - A 20-kDa protein with the GTP-binding and trypsin inhibitory activities from
      Glycine max.
AB  - A 20-kDa protein (p20) with a GTP binding activity was purified from the cultured
      cells of Glycine max (soybean). The amino acid sequence of p20 showed 65%
      identity in a 23 amino acid overlap against the Kunitz-type trypsin inhibitor of
      soybean reported. Furthermore, it was found that a Kunitz-type soybean trypsin
      inhibitor of commercial origin also binds GTP.

PMID- 10586510
TI  - Insight into the molecular evolution of two tropinone reductases.
AB  - In tropane alkaloid biosynthesis, two tropinone reductases produce different
      stereoisomers from a common substrate, tropinone. The two enzymes share 64% of
      identical amino acids, and highly homologous proteins with variable substrate
      binding residues have also been found in tropane alkaloid non-producing species.
      This exemplifies a simple evolutionary process that plants have taken to acquire
      a new secondary metabolic pathway.

PMID- 10586511
TI  - Transcriptional regulation of tyrosine phenol-lyase gene mediated through TyrR
      and cAMP receptor protein.
AB  - Using a lac reporter system in Escherichia coli, we showed that the expression of
      E. herbicola tpl was regulated through TyrR and cAMP receptor protein. Three TyrR
      boxes upstream of tpl were essential for full expression. The results suggested
      that the tyrosine-mediated TyrR hexamerization was an important process. The DNA
      bending between two TyrR boxes, which is triggered by the binding of cAMP
      receptor protein, may facilitate the conformational change of TyrRs.

PMID- 10586512
TI  - Construction of a LukS-PV mutant of a staphylococcal Panton-Valentine leukocidin
      component having a high LukS-like function.
AB  - A 2-residue (D12I13) segment of LukS of a staphylococcal leukocidin component is
      an essential region for the hemolytic function of LukS towards rabbit
      erythrocytes in the presence of LukF. Here, we report that insertion of D, I, or
      AA residue(s) between A11 and E12 residues of LukS-PV, in which the 2-residue
      D12I13 segment in LukS was absent, confers the full LukS function on LukS-PV,
      which has only 4% hemolytic activity of that of LukS towards rabbit erythrocytes.

PMID- 10586513
TI  - Consumption of a buckwheat protein extract retards 7,12
      dimethylbenz[alpha]anthracene-induced mammary carcinogenesis in rats.
AB  - Female rats were examined for the effects of feeding buckwheat protein extract
      (BWPE) on the development of mammary tumor caused by administration of 7,12
      dimethylbenz[alpha]anthracene. The percentage of rats with palpable mammary
      tumors and serum estradiol were lower in the BWPE-fed animals than the casein-fed
      ones, implying that BWPE intake retarded the mammary carcinogenesis by lowering
      serum estradiol.

PMID- 10586514
TI  - Identification of the amino acid residues conferring substrate specificity upon
      Selenomonas ruminantium lysine decarboxylase.
AB  - Lysine decarboxylase (LDC, EC 4.1.1.18) from Selenomonas ruminantium has
      decarboxylating activities towards both L-lysine and L-ornithine with similar
      K(m) and Vmax. Here, we identified four amino acid residues that confer substrate
      specificity upon S. ruminantium LDC and that are located in its catalytic domain.
      We have succeeded in converting S. ruminantium LDC to an enzyme with a preference
      in decarboxylating activity for L-ornithine when the four-residue of LDC were
      replaced by the corresponding residues of mouse ornithine decarboxylase (EC
      4.1.1.17).

PMID- 10586515
TI  - Stereoselective serum protein binding of ketoprofen in liver diseases.
AB  - The stereoselective binding of ketoprofen (KP) to human serum was studied in
      patients with liver diseases and was compared with that of normal volunteers. The
      serum protein binding of racemic KP was found to be decreased in hepatic patients
      whereas, interestingly, the stereoselectivity of KP was increased. The ratio of
      unbound concentrations of the KP enantiomers (FR/FS) showed positive linear
      correlation with albumin concentrations. Inhibition of KP binding to human serum
      albumin (HSA) induced by lithocholate, lithocholate sulfate and bilirubin was
      studied. The data presented in this paper strongly suggest that the variation of
      stereoselective binding of KP in patients suffering from liver diseases was
      mainly caused by the decrease of HSA levels and secondly by the stereoselective
      inhibition induced by the increased concentrations of bile acid and its
      metabolite.

PMID- 10586516
TI  - Identification of cDNA encoding cytochrome c oxidase subunit 5c (COX5c) from
      rice: comparison of its expression with nuclear-encoded and mitochondrial-encoded
      COX genes.
AB  - Little is presently known about the nuclear-encoded genes for cytochrome c
      oxidase (COX) in higher plants. In rice, only the nuclear-encoded COX5b gene has
      been reported. To understand the relationship between the expression of nuclear
      encoded and mitochondrial-encoded COX genes in rice, we first characterized a
      cDNA encoding one of the other nuclear COX genes, COX5c, which encodes 63 amino
      acids. The deduced amino acid sequence of COX5c from rice was highly homologous
      to that from sweet potato. Genomic Southern hybridization indicated that the rice
      COX5c subunit is encoded by a single copy of the COX5c gene. Furthermore, we
      compared the expression patterns of the nuclear-encoded COX5c and COX5b genes
      with the expression pattern of the mitochondrial-encoded COX1 gene among several
      organs by Northern blot analysis. The results suggested that regulatory systems
      of expression between the nuclear-encoded and the mitochondrial-encoded COX genes
      are different among different organs in rice.

PMID- 10586517
TI  - RIRE2, a novel gypsy-type retrotransposon from rice.
AB  - The 441-bp DNA segment in a PCR-amplified fragment from Oryza sativa cv. IR36 was
      found to have a sequence with features characteristic of LTRs of retroelements,
      which was named RIRE2 (Rice retroelement #2) and further analyzed. Cloning and
      sequencing analyses of the DNA segments connected to LTR-like sequence showed
      that RIRE2 has a long internal region almost 10 kb long that is flanked by LTR
      like sequences. This internal region carries a primer binding site (PBS) and
      polypurine tract (PPT) which are necessary for cDNA synthesis of retroelements.
      The PBS sequence is complementary to the 3' end region of tRNA(Arg). The internal
      region has an rt gene homologous to that of gypsy-type retrotransposons, evidence
      that RIRE2 is indeed a retrotransposon related to gypsy from Drosophila. RIRE2
      has an extra sequence more than 4 kb long in the region downstream of gag-pol.
      Phylogenetic analysis of the putative amino-acid sequences of the rt gene as well
      as the int gene showed that RIRE2 is related to a group of gypsy-type
      retrotransposons of a large size that include Grande1-4 of teosinte, Tat4-1 and
      Athila1-1 of Arabidopsis thaliana, and Cyclops-2 of pea, but distantly related to
      any other group of gypsy-type retrotransposons, including RIRE3 and RIRE8 of
      rice. RIRE2 and Grande1-4 had the highest homology in the gag-pol region, but the
      nucleotide sequences of the LTR regions differed. Both elements had significant
      homology in the middle area of the extra regions downstream of gag-pol, in which
      they had an open reading frame encoding a protein with no known function on the
      opposite strand from that coding for gag-pol.

PMID- 10586518
TI  - Genes controlling prolamin biosynthesis, Pro1 and Pro2, in foxtail millet,
      Setaria italica (L.) Beauv.
AB  - Variation and genetic control of seed protein in foxtail millet (Setaria italica)
      were studied using SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Variation
      in the electrophoregram of the total seed protein were detected in the range
      between 20 and 30 kDa which is derived from the polymorphism of five prolamin
      bands. The segregation for each of the bands in F2 seeds showed that these bands
      are governed by seven alleles at two loci, Pro1 and Pro2, which are not linked to
      one another. Among 271 local cultivars examined, eight out of ten possible
      genotypes were observed. With its level of diversity comparable to that of
      isozymes, the alleles conferring prolamin polymorphism are useful genetic
      markers.

PMID- 10586519
TI  - Structure and transcriptional control of the flagellar master operon of
      Salmonella typhimurium.
AB  - The flhD and flhC genes constitute the flagellar master operon whose products are
      required for expression of all the remaining flagellar operons in Salmonella
      typhimurium. Here we report the molecular structure and in vivo and in vitro
      expression of the flhD operon. Nucleotide sequence analysis revealed that the
      upstream region of this operon contains the consensus sequence for the cAMP-CRP
      binding site. Primer extension analysis demonstrated six possible transcription
      start sites for this operon. They include CRP-dependent and CRP-repressible
      transcription start sites. The CRP-dependent transcription start site is located
      203 bp upstream of the initiation codon of the flhD gene and preceded by the
      consensus sequences of the -10 and -35 regions of the sigma 70-dependent
      promoter. The putative cAMP-CRP binding site is located centered 70 bp upstream
      of this start site. The CRP-repressible transcription start site is located
      within this putative cAMP-CRP binding site. These two start sites were confirmed
      by in vitro transcription experiments using sigma 70-RNA polymerase with or
      without cAMP-CRP.

PMID- 10586520
TI  - Reevaluation of the promoter structure of the class 3 flagellar operons of
      Escherichia coli and Salmonella.
AB  - Flagellar class 3 operons of Escherichia coli and Salmonella are transcribed by
      RNA polymerase containing sigma 28. The consensus sequence of the sigma 28
      dependent promoters was believed to be TAAA N15 GCCGATAA. In this study, we found
      that the E. coli genome contains a large number of sequences homologous to this
      consensus. However, we showed that they do not always exert a sigma 28-dependent
      promoter activity. We compare more carefully the sequences of the class 3
      flagellar promoters and propose a revised structure of the sigma 28-dependent
      promoters as TAAAGTTT N11 GCCGATAA.

PMID- 10586521
TI  - K5 rather than K4 for diastolic blood pressure measurement in pregnancy.

PMID- 10586522
TI  - Serum levels of alpha-tocopherol in hypertensive pregnancies.
AB  - OBJECTIVE: Assess alpha-tocopherol serum levels in a population of pregnant women
      affected by different hypertensive disorders. METHODS: Alpha-tocopherol serum
      levels were determined by high-pressure liquid chromatography in 177 third
      trimester pregnant women: 63 affected by gestational hypertension, 69 by
      preeclampsia, 26 by chronic hypertension, and 19 normotensive controls. In 39 out
      of the 158 hypertensive patients, pregnancy was complicated by intrauterine
      growth retardation (IUGR). RESULTS: Alpha-tocopherol serum levels did not show
      any significant difference among gestational hypertensive, preeclamptic, chronic
      hypertensive patients, and controls. A significant reduction of alpha-tocopherol
      levels was observed when we compared patients with IUGR and patients with a
      normally grown fetus. Such significant reduction was maintained when we analyzed
      the different classes of hypertension. CONCLUSIONS: The reduction of antioxidant
      nutrients and, in particular, of alpha-tocopherol is not a feature of
      preeclampsia and seems better correlated with the presence of placental
      insufficiency, rather than maternal disease.

PMID- 10586523
TI  - Preeclampsia in twin pregnancies: incidence and outcome.
AB  - OBJECTIVES: To confirm the increased incidence of preeclampsia in twin pregnancy
      and to determine the relationship to zygosity and placentation; to consider the
      perinatal outcome of twin pregnancies in this condition. METHODS: Retrospective
      study of all twin pregnancies (n = 2473) identified from the Aberdeen Maternity
      and Neonatal Databank to women resident in the Grampian Region of Scotland for
      the period 1950-1995. RESULTS: The increased relative risk for gestational
      hypertension, preeclampsia, and eclampsia in twin pregnancies compared to
      singleton pregnancies has been confirmed as significant both in primiparas and
      multiparas with little variation in rates over the time period under review.
      Neither the sex of the offspring nor zygosity influences the incidence of
      hypertensive disease, whereas preeclampsia is more common in association with
      monochorionic placentation. As the birth weight was lower and placental weight
      greater in MzMc twins compared to either MzDc or DzDc, there was a higher
      placental index in such cases. No difference in the birth weights of individual
      twins, the difference in birth weights between the twins, placental weight, or
      placental index were found in relation to hypertensive disease. Gestation at
      delivery was earlier in normotensive twin pregnancies than in those women who
      developed a hypertensive problem. This leads to a higher perinatal death rate and
      lower survival rate for the babies in normotensive women with a twin pregnancy.
      CONCLUSION: Although gestational hypertension, preeclampsia, and eclampsia all
      occur more commonly in twin pregnancy, this does not lead to significant growth
      retardation nor discordant fetal growth and a poor outcome for the twins.
      Although the incidence of preeclampsia is higher in twin pregnancies with
      monochorionic placentation, this does not seem to be mediated by deficiencies in
      placental development as assessed in this study.

PMID- 10586524
TI  - Urinary protein/creatinine ratio in hypertensive pregnant women.
AB  - OBJECTIVES: To determine the correlation between the protein/creatinine ratio and
      24-h proteinuria; to estimate the sensitivity and specificity of this ratio for
      the diagnosis of significant proteinuria; to establish its cutoff point with the
      best predictive value for the diagnosis of significant proteinuria in patients
      with systemic arterial hypertension. STUDY DESIGN: A cross-sectional study of 47
      hypertensive patients who had been pregnant for 20 weeks or more seen at the
      Maternity of the University Hospital of Porto Alegre. The studied factor was the
      protein/creatinine ratio measured in a single random urine sample and the outcome
      was protein determination in 24-h urine. The level of significance was set at
      0.05. RESULTS: The correlation coefficient between the protein/creatinine ratio
      and 24-h proteinuria was 0.94 when urine was properly collected. A receiver
      operator characteristic curve was constructed to determine the sensitivity and
      specificity of the ratio for the diagnosis of significant proteinuria (> or = 300
      mg in 24 h). Specificity and predictive positive value were 100% for a ratio > or
      = 0.8. The best values for sensitivity, specificity, positive predictive value,
      and negative predictive value in the diagnosis of proteinuria > or = 300 mg in 24
      h were obtained when the protein/creatinine ratio was 0.5 (0.96, 0.96, 0.96, and
      0.96, respectively). CONCLUSION: The protein/creatinine ratio measured in a
      single urine sample taken at random from hypertensive pregnant women showed good
      sensitivity and specificity for the diagnosis of 24-h proteinuria > or = 300 mg
      and was strongly correlated with 24-h proteinuria. A ratio of 0.5 mg/mg is
      predictive of significant proteinuria and can be used for the diagnosis and
      follow-up of hypertensive pregnant women.

PMID- 10586525
TI  - In vitro human decidual endothelial cell thromboxane secretion in preeclampsia is
      not abnormal.
AB  - OBJECTIVES: The aims of this study were to describe levels of thromboxane
      secretion by decidual endothelial cells from normal pregnancies and to determine
      whether decidual endothelial cell secretion of thromboxane, implicated in the
      causation of the hypertension and vasoconstriction of preeclampsia, is increased
      in this disorder. METHODS: We measured thromboxane generation by cultured
      decidual endothelial cells from 13 normal pregnancies (NDEC) and 13 pregnancies
      complicated by preeclampsia (PEDEC), compared with a control population of 6
      normal human umbilical vein endothelial cells (HUVEC). Responses to stimulation
      by bacterial lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha),
      and interleukin-1 beta (IL-1 beta) were examined. MAIN OUTCOME MEASURES:
      Thromboxane B2 levels in supernatants of cultured endothelial cells. RESULTS: The
      level of secretion over 24 h in culture by NDEC [14 (7-26) pg/10(6) cells] was
      approximately 25% that of HUVEC [63 (49-70) pg/10(6) cells]. Levels achieved in
      response to all stimuli examined were consistently lower in NDEC than in HUVEC (p
      < 0.01). Proportional stimulation by LPS and TNF-alpha was comparable in HUVEC
      and NDEC, whereas NDEC displayed a greater increase (25-fold) than HUVEC (10
      fold) in response to IL-1 beta (p < 0.01). There were no significant differences
      between decidual endothelial cells from normotensive and preeclamptic women in
      basal secretion of thromboxane or in responses to the stimuli examined.
      CONCLUSIONS: In vitro thromboxane secretion by decidual endothelial cells is
      lower than that of HUVEC, and responsiveness to specific stimuli may be
      quantitatively different. These findings emphasize the importance of examining
      endothelial cells from the involved maternal vascular bed if intrauterine
      vascular pathophysiological events are to be clarified. No significant
      differences were noted in decidual endothelial cell thromboxane secretion between
      normal and preeclamptic subjects.

PMID- 10586526
TI  - Implication of apolipoprotein E and the L-arginine-nitric oxide system in
      preeclampsia.
AB  - OBJECTIVE: During pregnancy, Apolipoprotein (Apo) E is synthesized in the
      placenta to facilitate the uptake of maternal lipoproteins. Preeclampsia is
      associated with an abnormal lipid profile. Apo E levels may affect the production
      of nitric oxide. We investigated whether Apo E variations could be related to the
      high lipid levels and nitric oxide secretion in preeclamptic women. METHODS:
      Blood samples from 15 normotensive women and 12 mild and 23 severe cases of
      preeclampsia were assayed for standard lipid profile, Apo E, and nitrate. Urine
      samples were analyzed for nitrate and cyclic GMP. RESULTS: In women with mild
      preeclampsia, the triglyceride concentration was significantly higher (p < 0.05)
      than in normotensive women (3.30 +/- 1.38 versus 2.31 +/- 0.92 g/L) and
      associated with a higher (p < 0.01) triglyceride/Apo E ratio (0.71; range = 0.40
      1.70). In women with severe preeclampsia, the triglyceride/Apo E ratio was
      similar to normotensive women [0.39 (range = 0.18-1.19) versus 0.41 (range = 0.18
      0.79)] associated with a normal triglyceride level and a twofold higher serum
      nitrate level [36 (range = 1-63 mumol/L) versus 14 (range = 1-37 mumol/L)].
      CONCLUSION: The triglyceride/Apo E ratio is significantly higher in mild
      preeclampsia. In the severe form, this ratio is similar to that of normotensive
      pregnant women, probably due to a better uptake of triglyceride. Moreover, in the
      severe form, it is associated with a twofold normal serum nitrate level. Thus,
      Apo E and the nitric oxide status may be implicated in preeclampsia.

PMID- 10586527
TI  - Effects of two antihypertensive agents, labetalol and metoprolol, on the
      production of reactive oxygen species by normal polymorphonuclear leukocytes in
      vitro.
AB  - OBJECTIVE: Increased lipid peroxidation is a putative causal factor for
      preeclampsia. Because oxygen free radicals are involved in inducing the lipid
      oxidation chain reaction, we evaluated two beta adrenoreceptor blockers,
      labetalol and metoprolol, currently used for treating hypertension with regard to
      their ability to inhibit the formation of reactive oxygen species during
      respiratory burst of human normal polymorphonuclear leukocytes in vitro. METHODS:
      We determined whether labetalol or metoprolol have antioxidative activity in a
      model of polymorphonuclear leukocytes stimulated in vitro with phorbol-12
      myristate-13-acetate (PMA) and N-formyl-methionin-leucin-phenylalanin (fMLP). We
      also studied the scavenging properties of these two drugs using acellular
      systems. RESULTS: Labetalol inhibits O2-. production by neutrophils activated by
      fMLP (IC50 = 17.5 mg/L) and weakly by PMA (43.6% inhibition at 100 mg/L). It also
      possesses a significant activity on OH. production (IC50 = 65 mg/L) that may
      depend in part on its ability to interfere with iron in the Fenton reaction. The
      same assays performed with metoprolol did not show any inhibitory effect on O2.-
      generation. It decreased weak OH. production by neutrophils, as a result of
      cellular and scavenging effects. CONCLUSION: Labetalol shows important
      antioxidative properties in vitro with regard to normal leukocyte oxidative
      metabolism.

PMID- 10586528
TI  - Induction of eclampticlike changes by stimulation of the celiac ganglion in rats.
AB  - OBJECTIVE: To examine the relation between the stimulation of the abdominal
      sympathetic nervous system and vasospasm of the brain in eclamptic seizures, we
      analyzed brain blood flow after stimulation of the celiac ganglion by
      lipopolysaccharide (LPS, 5, 50, or 500 mg/mL) or normal saline before and after
      denovation of sympathetic trunk in pregnant and nonpregnant rats. METHODS: The
      brain blood flow was measured after stimulation of the celiac ganglion with 50
      microL (5 mg/mL) LPS in group I, 50 microL (50 mg/mL) LPS in group II, 50 microL
      saline in group III, and 50 microL (500 mg/mL) LPS (after denovation of the
      sympathetic trunk) in group IV. A sham control experiment was also done by
      stimulation of the abdominal peritoneum with 50 microL (500 mg/mL) LPS in group
      V. Changes in water content and histological findings in the brain were also
      studied in this protocol. RESULTS: A significant reduction in brain blood flow
      was observed in pregnant rats in groups I and II on stimulation of the celiac
      ganglion with LPS (p < 0.0001, p < 0.001) compared with before stimulation.
      Celiac ganglion stimulation with saline (group III) and LPS (group IV, after
      denovation of the sympathetic trunk) did not affect brain blood flow. Stimulation
      of the abdominal peritoneum with LPS (group V) could not induce any changes in
      brain blood flow. Repeated seizures occurred in 60% of pregnant rats and a
      remarkable increase in water content was observed after LPS stimulation of the
      celiac ganglion in groups I and II (p < 0.0001, p < 0.001). Histologically, we
      found that stimulation of the celiac ganglion with LPS caused widening of
      perivascular spaces with compression of the vessels leading to ischemic changes
      in brain tissues. There were no such findings observed in other groups. However,
      a lesser extent effect was noticed in nonpregnant than seen in pregnant rats.
      CONCLUSION: Stimulation of the abdominal sympathetic ganglions could induce
      vasoconstriction of the brain vessels, thus decreasing brain blood flow, which
      results in eclampsialike changes in rats.

PMID- 10586529
TI  - Is angiotensinogen gene polymorphism associated with hypertension in pregnancy?
AB  - OBJECTIVE: To determine whether a state of hypertension in pregnancy in the
      Japanese can be predicted in the early period based on detection of the M235T
      variant of the angiotensinogen gene, alone or with other factors. METHODS: A
      total of 313 Japanese pregnant women were divided into 3 groups on the basis of
      their angiotensinogen genotype: TT, MT, and MM. Hypertension in pregnancy was
      diagnosed for 33 patients in all. For each group, we sought to determine what
      factors increased the risk of the disease. MAIN OUTCOME MEASURES: The
      angiotensinogen M235T variant, mean arterial pressure (MAP) before the 12th
      gestational week, body mass index (BMI) before pregnancy, age at delivery,
      parity, a familial history of hypertension, and development of preeclampsia or
      gestational hypertension were considered. RESULTS: The frequencies of the allele
      T were the same among preeclampsia, gestational hypertension, and normal
      subjects. In TT subjects, a high incidence of gestational hypertension was found
      for women with MAP > or = 90 mm Hg, high or low BMI before pregnancy > or = 22.0
      or < 18.0, and maternal history of hypertension. In MT subjects, women who showed
      MAP > or = 90 mm Hg or who were above 36 years old at delivery had a high
      incidence of gestational hypertension. Preeclampsia could not be predicted in
      either group. CONCLUSIONS: Hypertension in pregnancy cannot be predicted on the
      basis of the M235T variant of angiotensinogen gene alone. However, gestational
      hypertension is associated with combinations of other factors. In contrast, it is
      virtually impossible to predict the development of preeclampsia.

PMID- 10586530
TI  - Antepartum middle mean cerebral blood flow velocity correlation with maternal
      hemodynamics.
AB  - OBJECTIVE: To determine the correlation between simultaneous assessment of
      maternal middle cerebral blood flow velocity with the other maternal hemodynamic
      factors of cardiac output and mean arterial pressure. STUDY DESIGN: Eight
      normotensive patients were assessed. Maternal cerebral blood flow velocity was
      assessed using transcranial Doppler. Cardiac output was assessed noninvasively
      using the thoracic electrical bioimpedance technique over four cycles.
      Transcranial assessment of cerebral blood flow velocity was done over four
      cycles. Statistical analysis was then done using the Pearson correlation
      coefficient and linear regression analysis with stepwise regression. A p-value of
      < 0.05 was considered significant. RESULTS: The value of the hemodynamic
      parameters were cardiac output 8.6 +/- 2.6 L/min, mean arterial pressure 82 +/-
      9.7 mm Hg, and mean maternal cerebral blood flow velocity 59.6 +/- 11 cm/s. The
      pulsatility index was 0.85 +/- 0.15. The mean blood pressure could only explain
      42% of the variation in systolic maternal cerebral blood flow velocity and 32% of
      the variation in mean maternal cerebral blood flow velocity. The mean middle
      cerebral blood flow velocity did not correlate with cardiac output. CONCLUSIONS:
      Middle cerebral artery velocity correlates moderately with mean arterial pressure
      but not with cardiac output. The control of mean arterial pressure cannot be used
      as the only indicator of appropriate reduction in cerebral blood flow velocity.

PMID- 10586531
TI  - Optimism in the treatment of Alzheimer's disease.

PMID- 10586532
TI  - The 22nd annual meeting of the Canadian College of Neuropsychopharmacology.
      Halifax, Canada, June 12-15, 1999.

PMID- 10586535
TI  - American ginseng extract reduces scopolamine-induced amnesia in a spatial
      learning task.
AB  - OBJECTIVE: To determine if HT-1001, an extract of American ginseng, affects
      scopolamine-induced memory and performance deficits in a spatial learning task,
      alters brain concentrations of aminergic neurotransmitters, and alters choline
      uptake in synaptosome preparations. DESIGN: Animal study. ANIMALS: 48 Sprague
      Dawley rats. INTERVENTIONS: Long-term oral administration of a test material or
      control solution. Intraperitoneal administration of scopolamine (2 mg/kg) 30
      minutes before testing. OUTCOME MEASURES: Performance on Morris water maze task,
      choline uptake, aminergic neurotransmitter analysis, in vitro monoamine oxidase
      analysis (of compounds). RESULTS: HT-1001 protected against scopolamine-induced
      amnesia and increased choline uptake in synaptosomal preparations. HT-1001 did
      not alter brain concentrations of norepinephrine, dopamine, 5-HT (serotonin), 3,4
      dihydroxyphenylacetic acid or 5-hydroxyindoleactic acid. HT-1001 had a very weak
      ability to inhibit monoamine oxidase activity in vitro. CONCLUSIONS: HT-1001
      demonstrates a capacity to protect against scopolamine-induced memory deficits.

PMID- 10586533
TI  - The prediction and prevention of Alzheimer's disease--towards a research agenda.
AB  - This paper sets a research agenda for the prediction and prevention of future
      onset of Alzheimer's disease (AD). From a MEDLINE review of the literature, the
      authors found age to be a predictor of AD. The literature also indicates that
      memory and attentional impairments predict AD, although the relative risk is
      relatively low. Late-onset depression may also predict AD, but these data are
      limited by a lack of cohort studies. Studying cognitively impaired subjects with
      late-onset depression may identify a high-risk group, facilitating prevention
      trials. Characteristics of an "ideal" preventive agent are suggested. There is a
      biologic rationale, and preliminary evidence, that non-steroidal anti
      inflammatory drugs (including ASA), estrogen and vitamin E may play a preventive
      role in AD. Other compounds (such as acetylcholinesterase inhibitors) are also
      promising, but costs, side effects, and lack of other health benefits may
      preclude their use in all but very high-risk groups.

PMID- 10586534
TI  - Conventional versus novel antipsychotics: changing concepts and clinical
      implications.
AB  - Novel antipsychotics represent a significant advance in the treatment of
      schizophrenia after many years of few developments. The conventional
      antipsychotics are potent D2 antagonists, but fail to achieve a response in about
      30% of cases. They are also associated with a high rate of extrapyramidal side
      effects. The greater and broader spectrum of efficacy combined with the reduced
      short- and long-term side effects of the new drugs such as quetiapine,
      risperidone, olanzapine and ziprasidone, contribute to a fresh optimism for the
      pharmacotherapy of schizophrenia. These novel agents are now driving further
      advances in schizophrenia research through a growing understanding of their
      pharmacological and clinical profiles. Clozapine, the first novel antipsychotic,
      has relatively low activity at D2 receptors, a high affinity for D4 receptors and
      a greater 5-HT2 (serotonin) than D2 antagonism. Hence, clozapine and other novel
      antipsychotics can be classified as such by this latter characteristic. However,
      some of these drugs have D2 occupancy greater than 60% (the clinical response
      threshold), while others have a lower D2 occupancy. The novel antipsychotics
      according have also been classified according to their activity on different
      neurotransmitter systems. While more effective, novel antipsychotics are not a
      panacea; they have limitations and side effects. In clinical practice, the
      American Psychiatric Association recommends either a conventional or novel
      antipsychotic for initial treatment of schizophrenia, whereas Canadian guidelines
      recommend novel agents. These agents should also be considered for treatment of
      refractory schizophrenia. Patients whose schizophrenia does not respond to one of
      these agents may respond to another. Future research should involve longer
      clinical trials, given the long periods needed to establish efficacy, and should
      address many remaining questions about the novel agents.

PMID- 10586536
TI  - The effects of clozapine on levels of total cholesterol and related lipids in
      serum of patients with schizophrenia: a prospective study.
AB  - OBJECTIVE: To investigate the effects of 12 weeks of clozapine treatment on
      levels of cholesterol and related lipids in patients with schizophrenia. DESIGN:
      Prospective study. SETTING: University department associated with a teaching
      hospital. PARTICIPANTS: Eight patients (6 women and 2 men) with a clinical
      diagnosis of schizophrenia consistent with DSM-IV criteria. The patients were
      classified as treatment-resistant and had not responded to treatment with at
      least 2 conventional antipsychotics. INTERVENTIONS: Current antipsychotic
      medications were tapered and treatment with clozapine was initiated. OUTCOME
      MEASURES: Cholesterol and serum lipid levels, as well as Brief Psychiatric Rating
      Scale (BPRS) scores were measured before and after 12 weeks of treatment with
      clozapine. RESULTS: Clozapine treatment significantly improved the BPRS scores
      but did not significantly alter serum lipid levels, except triglyceride levels,
      which increased. CONCLUSION: The previously reported lower levels of cholesterol
      in treatment-resistant patients with schizophrenia cannot be attributed to the
      effects of clozapine administration. Further research is required to support and
      clarify the effects of antipsychotic drugs on lipid levels.

PMID- 10586537
TI  - Refractory symptomatic schizophrenia resulting from frontal lobe lesion: response
      to clozapine.
AB  - A 34-year-old man with a 10-year history of persistent auditory hallucinations
      and passivity delusions had failed to respond to a variety of conventional
      antipsychotic medications. He had a history of head trauma 8 years before the
      onset of psychiatric symptoms. Recent investigations revealed a post-traumatic
      infarct, situated in the left frontal lobe, on a magnetic resonance imaging scan.
      Treatment with clozapine for more than 2 years resulted in a marked improvement
      in his psychotic symptoms. The localization of the brain lesion may be related to
      the etiology of his symptoms and to the clinical response to clozapine.

PMID- 10586539
TI  - Mania associated with donepezil.

PMID- 10586538
TI  - Smooth pursuit and saccadic eye movement performance in a prefrontal leukotomy
      patient.
AB  - The authors wished to examine the role of the prefrontal cortex in oculomotor
      performance. They assessed smooth pursuit and saccadic performance in a patient
      with schizophrenia who had undergone a bilateral prefrontal leukotomy. Her
      performance on neuropsychological test measures sensitive to frontal lobe
      functioning were also examined. Against a background of intact intellectual and
      neurological functioning, the patient displayed a dissociation in premotor and
      prefrontal functioning. Smooth pursuit performance was within normal limits, as
      were the patient's finger tapping scores. In contrast, the patient performed
      poorly on the Wisconsin Card Sorting Test, and verbal and design fluency tasks.
      Similarly, her performance on the antisaccade task was markedly deviant. Despite
      advanced age and a frontal leukotomy, this patient with schizophrenia displayed
      intact smooth pursuit, indicating that the frontal cortex is not necessary for
      normal smooth pursuit performance.

PMID- 10586540
TI  - [Estimation of integral of input function for quantification of cerebral blood
      flow with N-isopropyl-p-[123I]iodoamphetamine using one-point venous blood
      sampling].
AB  - The present study was designed to investigate a possibility of substitution of
      the venous blood radioactivity counts sampled 26 min post injection for the
      octanol-extracted arterial blood radioactivity counts obtained at 5 min after the
      injection of N-isopropyl-p-[123I]iodoamphetamine (123I-IMP). Furthermore, we
      investigated whether the integral of input function can be estimated from the
      venous blood radioactivity counts sampled 26 min post injection and the whole
      brain time-activity curves early after 123I-IMP injection. There was a good
      correlation between the arterial blood radioactivity counts sampled 5 min post
      injection (y) and those obtained at 26 min (r = 0.902; n = 91; y = 2.348x -
      867.063). There was also a good correlation between the arterial (x) and venous
      blood radioactivity counts (y) sampled 26 min post injection (r = 0.954; n = 14;
      y = 0.761x + 924.336). The venous blood radioactivity counts sampled at 26 min
      (x) correlated well with the octanol-extracted arterial blood radioactivity
      counts sampled at 5 min (y) (r = 0.964; n = 32; y = 0.173x - 21.598). There was a
      good correlation between the integrals of input function obtained from the
      regression equation obtained above and the whole-brain time-activity curves
      acquired during 7 min post injection (y) and those obtained by 5-min continuous
      arterial blood sampling (x) (r = 0.965; n = 41; y = 0.957x + 2665.208). These
      results indicate that this noninvasive and simple method can estimate the
      integral of input function for quantification of cerebral blood flow using 123I
      IMP.

PMID- 10586541
TI  - [Application of measuring 99mTc-MAG3 plasma clearance based on one-compartment
      model (MPC method) to renal transplantation].
AB  - Measurement of 99mTc-MAG3 plasma clearance (CLmag) based on one-compartment model
      (MPC method) was applied to renal transplantation and evaluated for the factors
      which might affect the calculated results, especially concerning renal depth.
      Correlation coefficient of CLmag between MPC method using real renal depth and
      Russell or Bubeck single sampling method was good (r = 0.852 or 0.876,
      respectively). Regression equation between MPC method and Russell method was y =
      1.044x - 3.0 and was more closer to y = x than that between MPC method and Bubeck
      method. CLmag of MPC method calculated by estimated renal depth from the
      abdominal thickness was also similar to that by real renal depth. Even if the
      fixed renal depth, 4 cm, was applied, the coefficient and regression equation
      between MPC method and Russell method were r = 0.884 and y = 1.004x - 10.2. In
      conclusion, MPC method is applicable to the evaluation of renal transplants.
      Though measuring renal depth is best, calculation with fixed renal depth of 4 cm
      might be practically acceptable.

PMID- 10586542
TI  - [Detection of culprit lesion in patients with unstable angina pectoris by using
      ATP thallium-201 myocardial SPECT].
AB  - The purpose of this study is to determine the diagnostic accuracy for detection
      of culprit lesions in patients with unstable angina. Both ATP 201Tl SPECT and
      coronary angiography were performed in 51 patients with unstable angina pectoris
      within a week since the last attack. SPECT images were divided into 17 segments
      and the regional uptakes were scored semiquantitatively (0 = normal to 3 = no
      activity) and compared with the coronary angiographic findings. ATP 201Tl SPECT
      revealed decreased uptakes in 54 of 56 culprit lesions. The sensitivity,
      specificity and accuracy for detection of culprit lesions were 96.4%, 89.5% and
      92.4%, respectively. Although adverse effects during ATP administration were
      complicated in 28 (54.9%) patients, all the complications were mild and resolved
      within two minutes. ATP 201Tl SPECT is sensitive and reliable method for
      detecting culprit lesions and can be performed safely even at acute phase in
      patients with unstable angina pectoris.

PMID- 10586543
TI  - [Iodine-123-MIBG scintigraphy in neuroblastoma; relationship between the
      intensity of uptake and tumor characteristics].
AB  - Iodine-123-MIBG (123I-MIBG) scintigraphy were performed for 23 patients with
      neuroblastoma at diagnosis. The intensity of MIBG activity in the primary tumor
      was evaluated visually (grade 3; intense uptake-grade 0; no definite uptake), and
      its relationship to the size, degree of tumor spread, urinary catecholamine
      metabolites (VMA, HVA), and histological types were investigated. The results of
      123I-MIBG uptake grade were as follows: grade 3; 44% (10/23), grade 2; 30%
      (7/23), grade 1; 17% (4/23), grade 0; 9% (2/23). The grade was not associated
      with the tumor size, or the degree of tumor extension to the distant lesion,
      either. The more catecholamine metabolites were excreted in the urine, the tumor
      tended to have more intense uptake. The tumors of neuroblastoma rosette
      fibrillary type, and ganglioneuroblastoma poorly differentiated type had more
      intense uptake than neuroblastoma round cell type and ganglioneuroblastoma well
      differentiated type. The case of ganglioneuroma did not have definite MIBG
      uptake. The intensity of MIBG uptake is not relevant to the pathological grade of
      neuroblastoma, but considering the electromicroscopical features of neuroblastoma
      reported previously, it is thought to reflect the histological type.

PMID- 10586544
TI  - [A case of massive bloody stool caused by Meckel diverticulum in which 99mTc-HSA
      DTPA SPECT was useful].
AB  - A 15-year-old boy was admitted to our hospital because of massive bloody stool.
      At the age of 11 years, he had two episodes of massive bloody stool, and 99mTcO4-
      Meckel scintigraphy failed to contribute to the diagnosis. On this admission,
      99mTc-HSA-DTPA scintigraphy, especially coronal SPECT clearly showed bleeding
      site. Operation revealed Meckel diverticulum. We showed the usefulness of coronal
      SPECT in the evaluation of gastrointestinal bleeding.

PMID- 10586545
TI  - [A simple method for regional cerebral blood flow measurement by one-point
      arterial blood sampling and 123I-IMP microsphere model (Part 2): A study of time
      correction of one-point blood sample count].
AB  - In our previous paper regarding determination of the regional cerebral blood flow
      (rCBF) using the 123I-IMP microsphere model, we reported that the accuracy of
      determination of the integrated value of the input function from one-point
      arterial blood sampling can be increased by performing correction using the 5
      min: 29 min ratio for the whole-brain count. However, failure to carry out the
      arterial blood collection at exactly 5 minutes after 123I-IMP injection causes
      errors with this method, and there is thus a time limitation. We have now revised
      our method so that the one-point arterial blood sampling can be performed at any
      time during the interval between 5 minutes and 20 minutes after 123I-IMP
      injection, with addition of a correction step for the sampling time. This revised
      method permits more accurate estimation of the integral of the input functions.
      This method was then applied to 174 experimental subjects: one-point blood
      samples collected at random times between 5 and 20 minutes, and the estimated
      values for the continuous arterial octanol extraction count (COC) were
      determined. The mean error rate between the COC and the actual measured
      continuous arterial octanol extraction count (OC) was 3.6%, and the standard
      deviation was 12.7%. Accordingly, in 70% of the cases, the rCBF was able to be
      estimated within an error rate of 13%, while estimation was possible in 95% of
      the cases within an error rate of 25%. This improved method is a simple technique
      for determination of the rCBF by 123I-IMP microsphere model and one-point
      arterial blood sampling which no longer shows a time limitation and does not
      require any octanol extraction step.

PMID- 10586547
TI  - [Collection conditions of ECG-gated myocardial SPECT].
AB  - In ECG-gated myocardial SPECT, we evaluated the effects of data acquisition and
      imaging conditions on the parameters of left ventricular cardiac function by a
      phantom experiments and in patients (n = 50) and normal controls (n = 15). Data
      acquisition was performed under the following conditions: (1) matrix size, 64 x
      64 or 128 x 128; R-R interval, 8 or 6 frames; (3) presence or absence of
      attenuation and scatter corrections; and (4) changes in the accumulation rate of
      the radioactive tracer (information content) in the myocardium. When the matrix
      size was 64 x 64 and an R-R interval was divided into 8 frames, end-diastolic
      volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) were 98.30 +/
      13.74 ml, 44.20 +/- 7.45 ml, and 54.91 +/- 2.84%, respectively, for normal
      controls. These values were slightly lower than those under other conditions.
      When attenuation and scatter corrections were not performed, the values of the
      above parameters were even lower. In patients with high accumulation of the
      radioactive tracer in the liver affecting the myocardial area, the cardiac
      function parameters were markedly decreased. In phantom experiments in which a
      decreased accumulation of the radioactive tracer was assumed, the left
      ventricular volume increased.

PMID- 10586546
TI  - [Phase 2 clinical study of 123I-IBF, a dopamine D2 receptor imaging agent, to
      evaluate clinical efficacy and safety in Parkinson's disease and Parkinson
      syndromes].
AB  - A Phase 2 multicenter trial of 123I-IBF, (S)-5-iodo-7-N-[(1-ethyl-2-
      pyrrolidinyl)methyl]carboxamido-2,3-dihydrobenzofuran, was conducted to evaluate
      its clinical efficacy and safety in 158 patients with Parkinson's disease (PD) or
      Parkinson syndromes (PS). SPECT data were acquired at two hours (2H-SPECT), after
      intravenous injection of 123I-IBF (167 MBq). Additional SPECT scan at three hours
      (3H-SPECT) and dynamic SPECT scan at most until one hour were performed when
      possible. No severe side effects due to 123I-IBF injection were observed. The
      sensitivity, specificity and accuracy for discriminating PS from PD using the
      striatal specific binding count-to-frontal cortex count ratio (St/Fc-1) in 3H
      SPECT were 72.7%, 81.0% and 78.1% in 64 clinically definite cases (i.e., typical
      cases), respectively. The putamen-to-caudate ratios were significantly lower in
      striatonigral degeneration compared with those in PD. The contralateral-to
      ipsilateral ratios against the symptomatic side of tremor and/or rigidity in the
      patients with PD (Hoehn & Yahr I) were significantly higher than the left-to
      right ratios in the normal controls. St/Fc-1 in 3H-SPECT was significantly lower
      in the patients showing a poor response to levodopa than in those showing a good
      response. The dopamine D2 receptor binding potential (k3/k4), obtained by dynamic
      SPECT based on compartment model analysis, correlated well with the striatal
      specific binding count-to-occipital cortex count ratio. These results suggest
      that 123I-IBF is a promising agent for differential diagnosis and
      pathophysiological evaluation of PD and PS.

PMID- 10586548
TI  - [Synthesis of 18F-FDG with FDG MicroLab system: basic studies for clinical
      application].
AB  - We synthesized 18F-FDG by using an automated synthetic apparatus "FDG MicroLab"
      (GE Medical Systems) which produces 18F-FDG by a solid phase 18F-fluorination.
      Its quality and reproducibility were evaluated in order to assess feasibility of
      the apparatus for routine clinical production of 18F-FDG. For 5 consecutive 18F
      FDG synthesis, target irradiation was carried out at 15 microA for 60 min. 18F
      FDG was obtained in 50 min after EOB with an end-of-synthesis yield of 9.34 +/-
      1.06 GBq. Radiochemical yield and radiochemical purity were 47 +/- 3% (decay
      corrected) and 98.0 +/- 0.5%, respectively. Other several quality control
      parameters tested conformed with "Standards of Compounds Labeled with Positron
      Nuclides" (RADIOISOTOPES, 44, 1995). Thus, the automated synthetic apparatus "FDG
      MicroLab" has proven to stably produce 18F-FDG with high yield and high purity.
      The apparatus is feasible for routine clinical production of 18F-FDG.

PMID- 10586549
TI  - [Validation and optimization of the use of standardized arterial input function
      in N-isopropyl-p[123I]iodoamphetamine cerebral blood flow SPECT].
AB  - Use of a standardized arterial input function and calibrating it by a single
      blood sample has been proposed to assess quantitatively cerebral blood flow using
      N-isopropyl-p[123I]iodoamphetamine (IMP) and single-photon emission computed
      tomography. This study was intended to validate this approach using a larger
      number of measured arterial radioactivity curves in the clinical setting. METHOD:
      Arterial input function was measured for 50 patients at rest following the i.v.
      IMP, and its inter-subject variation was assessed. Difference between smokers and
      non-smokers in addition to effects of acetazolamide administration were
      particularly investigated. We also evaluated the accuracy of the calibration
      procedures by means of either a single blood sample or a continuous arterial
      blood withdrawal sampling for an early period. RESULTS: Inter-subject variation
      of the observed arterial input function appeared not to show large variations
      among the 50 patients, thus suggesting the validity of using the standardized
      arterial input function for the IMP SPECT study. There was a significant
      difference in the shape of the arterial input function between the smokers and
      non-smokers, but the calibration at an optimized sampling time provided the area
      under-the curve (AUC) that was not significantly different between the two
      groups. The arterial input function after the acetazolamide showed no significant
      difference as compared with the shape at rest. The calibration of the
      standardized input function by means of the early integration of individual curve
      did not show better accuracy except for a short period of AUC (i.e., < 20 min)
      for longer integration period > 10 min. CONCLUSION: Thus, use of the standardized
      arterial input function has been validated for the IMP SPECT study. The single
      blood sampling procedure for calibrating the standardized input function has also
      been validated, and has been shown to provide better accuracy compared with the
      continuous withdrawal procedure.

PMID- 10586550
TI  - [Antimicrobial peptides/proteins--application to the therapy of sepsis].
AB  - Many antimicrobial peptides and proteins were discovered recently in various
      animals. Cecropins are insect-derived antimicrobial peptides which contain 35-39
      amino acid residues. Magainins are amphibian-derived antimicrobial peptides with
      21-27 amino acid residues. In mammals, defensins, 29-35 amino acid peptides, were
      identified in the granules of neutrophils and various epithelial cells. In
      addition, the granules of neutrophils in the mammal have been shown to have
      several antimicrobial proteins. Among them, bactericidal/permeability increasing
      protein (BPI) and cationic antimicrobial peptide-18 (CAP 18) have been found to
      have potent bactericidal activity against gram-negative bacteria and strong
      lipopolysaccharide-neutralizing function. The recombinant BPIs (recombinant BPI,
      23-kDa N-terminal fragment of BPI, and lipopolysaccharide-binding protein-BPI
      fusion protein) and synthetic peptides derived from C-terminal of CAP 18 are now
      under investigation for the application to the therapy of sepsis or septic shock.

PMID- 10586551
TI  - [Measurements of extracellular water volume by bioelectrical impedance analysis
      during perioperative period of esophageal resection].
AB  - Segmental bioelectrical impedance analysis (BIA) was conducted in five patients
      who underwent esophageal resections. Resistance values fitted at zero frequency
      (R0) in each body segment (arm, trunk and leg) were determined before the
      induction of anesthesia, at the end of surgery and on the second or third
      postoperative day. Extracellular water volume (ECW) in each body segment was
      estimated using the equation derived from the cell suspension theory. ECW in
      whole body was obtained from the sum of each body segment. R0 in trunk and leg
      significantly decreased at the end of surgery compared to the values before the
      induction of anesthesia (P < 0.05). The change ratio of R0 in trunk before the
      induction of anesthesia was significantly lower at the end of surgery than that
      in arm (P < 0.05), resulting from the most striking fluid accumulation in the
      trunk. Postoperatively, R0 in all body segments, however, appeared to decrease
      similarly compared to the values before the induction of anesthesia, suggesting
      the redistribution phenomena of extracellular water among body segments. The
      correlation (r = 0.90, P < 0.001) and good agreement [bias = 0.01 (L)] between
      net fluid balances and estimates of ECW changes in whole body suggest that BIA
      allows close monitoring of tissue hydration during perioperative period by
      providing estimates of ECW in body segments.

PMID- 10586552
TI  - [Inorganic fluoride concentrations and their sequential changes in the five
      layers of the kidney in rabbits after sevoflurane or methoxyflurane anesthesia].
AB  - In this study, intrarenal inorganic fluoride concentrations (IR-F) in rabbits
      were measured after sevoflurane or methoxyflurane anesthesia (SA or MA) to
      investigate the mechanism of methoxy-flurane nephrotoxicity and to confirm the
      safety of SA in fluoride nephrotoxicity. At the end of SA of MA, IR-F was 1.5 to
      5 times greater in the cortex to papilla region than serum fluoride
      concentrations (S-F). When S-F were nearly equal, IR-F after MA was not greater
      than IR-F after SA. IR-F after SA declined rapidly. In contrast, IR-F after MA
      was maintained at high levels for a protracted period due to the greater
      solubility of methoxyflurane in fatty tissue. The present study suggests that the
      most important factor in methoxyflurane nephrotoxicity is the high IR-F of long
      duration established by urine formation, and that sevoflurane, although it is not
      associated with fluoride nephrotoxicity under normal conditions, may not be safe
      when it is used for an extremely long period and at high concentrations.

PMID- 10586553
TI  - [Apneic anesthesia for microsurgery of the larynx under propofol anesthesia].
AB  - Apneic anesthesia with intermittent ventilation (AAIV) under inhalational
      anesthesia has been reported to improve visualization of the larynx with lack of
      vocal cord motion in laryngeal microsurgery. In this study, we evaluated AAIV
      using total intravenous anesthesia with propofol and fentanyl instead of
      inhalational anesthesia in 11 patients undergoing microsurgery of the larynx, and
      examined the effects of AAIV on respiration and circulation. Anesthesia was
      maintained with infusion of propofol 4-10 mg.kg-1.h-1 and intermittent
      administration of fentanyl and vecuronium intravenously. The lungs were
      ventilated with 100% oxygen, and the endotracheal tube was removed during the
      apneic period. AAIV provided the otorhinolaryngologist sufficient room in which
      to operate and an immobile field without complications in any of the patients.
      The number of periods of apnea (mean +/- SD) was 3.3 +/- 1.3, and the duration of
      apnea was 292 +/- 23 seconds. Neither blood pressure nor heart rate changed
      during the apneic periods. Arterial oxygen saturation measured using pulse
      oxymetry (Spo2) changed in none of the patients except an obese patient whose
      Spo2 declined to 90%. End-tidal carbon dioxide level increased for 14.9 mmHg
      immediately after apneic periods. Propofol vielded stable and adequate levels of
      anesthesia during apneic periods. We conclude that AAIV using constant monitoring
      of Spo2 is a useful and safe technique, and that propofol is a suitable
      anesthetic agent for AAIV.

PMID- 10586554
TI  - [The effects of propofol anesthesia with or without the use of nitrous oxide on
      the intraoperative involuntary movement, the postoperative awareness and
      vomiting].
AB  - The authors investigated the effect of anesthesia with nitrous oxide and propofol
      on intraoperative involuntary movement, muscle relaxant usage, postoperative
      nausea and vomiting, the total amount of propofol used, and recovery time from
      anesthesia. Eighty-eight patients for gynecological surgery were randomly divided
      into group PE: propofol/epidural (n = 44), and group PEG:
      propofol/epidural/nitrous oxide (n = 44). The frequency of postoperative nausea
      and vomiting were assessed at 24-h postoperatively by blinded observers. There
      were significant decreases of the mean amounts of propofol and muscle relaxant
      used between group PEG and group PE. The authors found no correlation between the
      use of nitrous oxide and intraoperative involuntary movement, subsequent
      development of postoperative quality of awareness, recovery time, nausea and
      vomiting. We recommend PEG method for gynecological surgery rather than PE from
      an economical viewpoint because it is associated with the reduction of mean
      propofol and muscle relaxant used.

PMID- 10586555
TI  - [General anesthesia for a patient with primary aldosteronism complicated with
      hypertrophic nonobstructive cardiomyopathy].
AB  - We report a patient with primary aldosteronism (PA) complicated with hypertrophic
      nonobstructive cardiomyopathy (HNCM) who underwent resection of a left adrenal
      tumor. Amrinone was administered to improve the features of congestive heart
      failure induced by retention of body fluid. Maintaining adequate preload and
      afterload and preventing excessive increases in contractility are important in
      the anesthetic management of patients with hypertrophic obstructive
      cardiomyopathy (HOCM). Although the preoperative diagnosis may be HNCM, stenosis
      of the left ventricular outflow tract may occur due to hemodynamic changes during
      surgery. Therefore amrinone is not often used for patients with HNCM. We inserted
      a pulmonary arterial catheter (Swan-Ganz CCO Thermodilution Catheter) and
      measured the cardiac output continuously to monitor hemodynamic changes. The
      symptoms of pulmonary edema were diminished one month after the surgery. These
      findings suggest that the increased blood volume induced by PA is a main factor
      aggravating preoperative congestive heart failure with HNCM.

PMID- 10586556
TI  - [Anesthetic management for transtracheal placement of a catheter for intracavity
      infusion of an antifungal drug in patients with pulmonary fungus ball of
      aspergillosis].
AB  - A catheter was inserted through the cricothyroid membrane under general
      anesthesia using a laryngeal mask airway in two patients with pulmonary fungus
      ball of aspergillosis to administer an antimycotic into the fungus ball.
      Anesthesia was induced with fentanyl and propofol in both patients. The laryngeal
      mask airway was inserted using intravenous injection of vecuronium. Anesthesia
      was maintained with continuous infusion of propofol. The catheter was inserted
      through the cricothyroid membrane and placed in the pulmonary fungus ball using
      bronchoscope. Perioperative and postoperative courses were uneventful in both
      patients. It was concluded that the laryngeal mask airway is useful for airway
      management when a catheter is inserted into a pulmonary fungus ball through the
      cricothyroid membrane.

PMID- 10586557
TI  - [Epidural anesthesia for cesarean section in a patient with dilated
      cardiomyopathy (DCM)].
AB  - A 23-year-old patient with dilated cardio myopathy (DCM) was scheduled for a
      cesarean section. We inserted an epidural catheter at the L 2/3 interspace and
      injected 1.5% lidocaine 6 ml with epinephrine 30 micro g and fentanyl 50 micro g.
      The analgesic level 15 minutes after injection was achieved up to the eighth
      thoracic dermatome. Dopamin 5 micro g.kg-1.min-1 was infused simultaneously.
      Analgesia was sufficient for the surgery, and heart rate and blood pressure were
      stable throughout the operation. The infant's apgar scores were 9 and 10.
      Epidural anesthesia is one of the options for cesarean section in pregnant women
      with DCM.

PMID- 10586559
TI  - [Anesthetic management for urgent endoscopy in a child with heterotopic liver
      transplant].
AB  - A 6-year-old boy with heterotopic liver transplant underwent urgent endoscopy
      under general anesthesia because of bloody stool. He was taking cyclosporin as an
      immunosuppressant. His hepatic function was normal and no side effects of
      cyclosporin were observed. Preoperative blood transfusion was performed because
      of severe anemia. Anesthesia was induced with midazolam 2 mg, ketamine 20 mg and
      fentanyl 0.05 mg, and maintained with addition of midazolam and ketamine. We did
      not use any inhalation anesthetics to avoid postoperative hepatic dysfunction.
      The endoscopy was successfully performed and the postoperative course was
      uneventful. We conclude that preanesthetic evaluation of immunosuppressant state
      and the hepatic function of transplanted liver is important for anesthetic
      management of a patient with heterotopic liver transplant.

PMID- 10586558
TI  - [Anesthetic management of a patient with dilated cardiomyopathy under total
      intravenous anesthesia with propofol and ketamine combined with continuous
      epidural analgesia].
AB  - We report our experience with total intravenous anesthesia (TIVA) with propofol
      and ketamine combined with continuous epidural analgesia in a 72-year-old-male
      patient with dilated cardiomyopathy scheduled for a total prostatectomy. After
      premedication with atropine 0.5 mg and pethidine 35 mg, anesthesia was induced
      with ketamine 50 mg, fentanyl 0.1 mg and using a step down method of propofol (6-
      >4-->2 mg.kg-1.hr-1). After hemodynamic parameters had been stabilized, the
      trachea was intubated. Then, 1.5% lidocaine 6 ml was injected through an epidural
      catheter, placed at the L 1-2 intervertebral space. Anesthesia was maintained
      with continuous infusion of propofol 1 mg.kg-1.hr-1 and ketamine 1 mg.kg-1.hr-1,
      and continuous epidural analgesia with 1.5% lidocaine 2 ml.hr-1. Hemodynamics
      remained stable throughout the operative procedure. No postoperative
      complications occurred. TIVA with propofol and ketamine in combination with
      epidural analgesia is useful for patients with dilated cardiomyopathy in order to
      maintain stable hemodynamics during anesthesia.

PMID- 10586560
TI  - [Bronchospasm during crush induction with propofol under the Sellick maneuver in
      a patient for emergency laparotomy].
AB  - A 61-year-old man was scheduled for an emergency laparotomy due to ileus. He had
      a history of asthma, but it was well controlled without medication. Anesthesia
      was induced with propofol and ketamine under the Sellick maneuver. Following
      administration of vecuronium, endotracheal intubation was performed. However, he
      could not be ventilated. We thought that the tube had been inserted into the
      esophagus, and re-intubation was performed. However he could not be ventilated as
      in the first trial. At that time, we suspected that bronchospasm had occurred.
      Bronchospasm improved rapidly using hyperventilation with 100% oxygen and 3-5%
      sevoflurane, and intravenous aminophylline. Because he had a history of asthma,
      propofol was relatively indicated from the point of smooth muscle relaxant
      effects. However we should consider the risk of bronchospasm in a patient with a
      history of asthma, even if we use propofol.

PMID- 10586561
TI  - [Perioperative management of vagotomy for treatment of frequent syncope].
AB  - A 66-year-old man was admitted to our hospital because of frequent chest pain and
      loss of consciousness. He had a 6-year history of angina and has taken
      nitroglycerin. He had received total laryngo-pharyngoectomy with the graft by
      jejunum for pharyngeal cancer seven months ago. The tumor, however, recurred at
      the neck lymphnodes. Against the increased episodes of severe bradycardia and
      loss of consciousness, he was scheduled to undergo subemergent vagotomy at
      proximal and distal side of the cancer since the cancer surrounded the nutrition
      vessels of the graft. Atropine 0.25 mg i.m. and 0.25 mg i.v. were administered to
      treat bradycardia and hypotension in the morning of operation. As a premedication
      atropine 0.5 mg p.o. was given. Anesthesia was induced with midazolam 3 mg,
      sevoflurane 5%, nitrous oxide 8 l.min-1 in oxygen 4 l.min-1. Intubation through
      tracheostomy was facilitated with fentanyl 100 micrograms. When the operator
      touched the neck, heart rate and blood pressure decreased suddenly to 35
      beats.min-1 and 62 mmHg/20 mmHg, respectively. Atropine 1 mg i.v. and ephedrine 8
      mg i.v. were effective. This was the only episode during surgery. After surgery
      all bradycardiac episodes have gone away without atropine or any other treatment.
      His frequent attack of bradycardia and hypotension with syncope was due to vagal
      reflex by the recurrent tumor.

PMID- 10586562
TI  - [PGE1 and dopamine administration in a pediatric patient during hepatectomy].
AB  - A 2-year-old male underwent medial inferior hepatectomy for the treatment of
      metastatic tumors. Due to congenital hepatoblastoma, at 6-months of age, right
      lobectomy of his liver had been performed. To protect liver functions, PGE1 and
      dopamine were administered during the surgery. Although half of his circulating
      blood volume was lost, his perioperative hemodynamics was stable, with no
      development of postoperative liver dysfunction. PGE1 and dopamine may thus be
      beneficial in pediatric hepatectomy.

PMID- 10586563
TI  - [Spinal myoclonus possibly caused by epidural anesthesia].
AB  - We report a patient who developed a rare neurological complication of spinal
      myoclonus possibly caused by an epidural catheter. A 24-yr-old female received
      laparoscopy and intrauterine curettage under general combined with epidural
      anesthesia. Spinal myoclonus started about 4 hours after the last epidural drug
      injection and disappeared 2 hours following removal of the epidural catheter. The
      patient was discharged without any untoward neurological sequelae.

PMID- 10586564
TI  - [Usefulness of tracheal tube with N2O gas-barrier cuff].
AB  - We evaluated three different tracheal tubes, Portex Profile Soft-Seal Cuff
      (PSSC), Portex Profile Cuff (PC) and Mallincrodt Lo-Contour (LC), when they are
      used in the artificial trachea and in anesthetized patients. When a cuff was
      inflated in the artificial trachea, PSSC with a cuff of high N2O gas-barrier
      property, and PC could achieve air-tight sealing with a smaller amount of
      injected air, compared with LC. This finding suggests that the inflated cuff
      shape and cuff-fold formation are important to block the airway leakage with
      small volume of air. Either of three tubes was used randomly in thirty adult
      patients for general anesthesia using nitrous oxide 65%. Intracuff pressures were
      increased significantly with the passage of time. In PSSC group, however,
      intracuff pressure was 25 +/- 6 mmHg (mean +/- SD) at two hours, and in other two
      groups it was between 32 and 48 mmHg. The use of a tracheal tube with gas-barrier
      cuff is recommended to prevent a high tracheal wall pressure.

PMID- 10586565
TI  - [Blind orotracheal intubation using Trachilight in a pediatric patient with
      Arnold-Chiari malformation].
AB  - We used Trachilight for orotracheal intubation in an 11-year-old boy with severe
      cervical abnormality caused by Arnold-Chiari malformation. Anesthesia was induced
      with intravenous propofol, fentanyl and ketamine, and tracheal intubation was
      successfully performed with this device using intravenous vecuronium. The patient
      underwent suboccipital decompression, C-1 laminectomy and duraplasty in the prone
      position under general anesthesia. The peroperative course was uneventful. We
      conclude that Trachilight is useful for orotracheal intubation in a patient with
      Arnold-Chiari malformation.

PMID- 10586566
TI  - [Corneal abrasion after general anesthesia despite application of eye patches].
AB  - A 37-year-old man with exophthalmos underwent resection of the left apical
      peridontal cyst under general anesthesia. Eye patches (Opticlude) without
      adherence to epibulbar area were used during anesthesia and surgery. At the end
      of the surgery, his left eyelid was noted to be incompletely closed. His left
      bulbar conjunctiva showed marked conjestion with severe pain. Staining with
      fluorescein dye demonstrated corneal abrasion in the lower third of the left eye.
      The corneal abrasion healed in two days after topical treatment.

PMID- 10586567
TI  - [A patient uninformed about his illness became aware of his lung cancer when an
      anesthesiologist visited him for pain control].
AB  - Much has been said about the importance of informed consent in Japan, but
      informing cancer to the patient has not been popular so far. We, as
      anesthesiologists, often treat pain in cancer patients, who occasionally, are not
      informed about the cancer. And we sometimes have patients with whom cautious
      consulting is necessary. This report presents our experience with a patient
      uninformed about the cancer but suspicious of his lung cancer. We met him as
      anesthesiologists, and this made the patient convinced that he had a cancer and
      was about to die soon.

PMID- 10586568
TI  - [S-tube; a new device for the simulation of mechanical ventilation].
AB  - We introduce a new device which can be used to simulate the situation of
      mechanical ventilation. A Suzuki Snorkel-shaped Spirosimulation Tube (S-tube)
      consists of a truncated snorkel and an L-connector/slipjoint. The mouthpiece is
      placed in the subject's mouth and the rubber tip is held firmly between the teeth
      in order to form a secure connection between the mouth and the tube. The other
      end of the tube is connected to a ventilator. A nose clip is used to minimize the
      leakage of air from the subject's nostrils. The upper airway is thus connected to
      the S-tube with minimal leakage of air. The ventilatory pattern can be easily
      changed by altering the mode of the ventilator. Using this device, the subject
      can be placed under a variety of ventilatory patterns easily. Thus, this device
      can allow a trainee medical staff to better understand the different types of
      mechanical ventilation. This simple, non-invasive device is a useful educational
      tool for a medical staff.

PMID- 10586569
TI  - [Patil-Syracuse mask for fiberoptic intubation].
AB  - Patil-Syracuse mask, recently introduced in Japan, has a port for fiberscopy. A
      fiberoptic bronchoscope and an endotracheal tube can be passed through the port
      with little air leakage. Positive pressure ventilation can be continuously
      maintained using this mask during fiberoptic intubation. This mask is
      particularly useful when a patient can be easily ventilated through a face mask
      but the trachea is unexpectedly difficult to intubate. With a modified endoscopy
      mask technique, the mean expiratory tidal volume of 10 ml.kg-1 could be obtained
      during fiberoptic orotracheal intubation. We describe a fiberoptic intubation
      technique using this mask, and discuss the complications and limitations of this
      method.

PMID- 10586570
TI  - Can Bartlett's repeated reproduction experiments be replicated?
AB  - Surprisingly, Bartlett's (1932) famous repeated reproduction experiments, in
      which he found systematically increasing errors in recall from the same people
      tested over time, have never been successfully replicated. Several studies have
      attempted partial replications, which were unsuccessful, and their authors
      concluded that the original observations might not be replicable. We conducted a
      study modeled closely after Bartlett's procedures: Subjects studied "The War of
      the Ghosts," took an initial test 15 min later, and then took a delayed test
      after 1 week. A follow-up test was conducted 6 months later on as many subjects
      as could be obtained. We did replicate Bartlett's results, in that (1) subjects
      forgot the story over delays but (2) introduced rationalization and distortion
      into their accounts of the story, with increases in the proportion of material
      distorted as retention interval increased. Subjects also imported new
      propositions at long delays, further confirming Bartlett's empirical observations
      and conclusions. Bartlett's repeated reproduction results can be replicated.

PMID- 10586571
TI  - Music, emotion, and autobiographical memory: they're playing your song.
AB  - Very long-term memory for popular music was investigated. Older and younger
      adults listened to 20-sec excerpts of popular songs drawn from across the 20th
      century. The subjects gave emotionality and preference ratings and tried to name
      the title, artist, and year of popularity for each excerpt. They also performed a
      cued memory test for the lyrics. The older adults' emotionality ratings were
      highest for songs from their youth; they remembered more about these songs, as
      well. However, the stimuli failed to cue many autobiographical memories of
      specific events. Further analyses revealed that the older adults were less likely
      than the younger adults to retrieve multiple attributes of a song together (i.e.,
      title and artist) and that there was a significant positive correlation between
      emotion and memory, especially for the older adults. These results have
      implications for research on long-term memory, as well as on the relationship
      between emotion and memory.

PMID- 10586572
TI  - Priming in a free association task as a function of association directionality.
AB  - Two experiments investigated priming in free association, a conceptual implicit
      memory task. The stimuli consisted of bidirectionally associated word pairs
      (e.g., BEACH-SAND) and unidirectionally associated word pairs that have no
      association from the target response back to the stimulus cue (e.g., BONE-DOG).
      In the study phase, target words (e.g., SAND, DOG) were presented in an
      incidental learning task. In the test phase, participants generated an associate
      to the stimulus cues (e.g., BEACH, BONE). In both experiments, priming was
      obtained for targets (e.g., SAND) that had an association back to the cue, but
      not for targets (e.g., DOG) for which such a backward association was absent.
      These results are problematic for theoretical accounts that attribute priming in
      free association to the strengthening of target responses. It is argued that
      priming in free association depends on the strengthening of cue-target
      associations.

PMID- 10586573
TI  - Recognition memory for sentences from spatial descriptions: a test of the
      episodic construction trace hypothesis.
AB  - Many researchers believe that when people read spatial descriptions, they
      construct mental models of the configurations described. Payne (1993) proposed
      that reading a spatial description produces a memory of the operations used to
      construct a mental model, an episodic construction trace. The episodic
      construction trace hypothesis predicts that memory for a spatial description will
      be influenced by the degree of overlap between the construction processes
      required by the original description and the construction processes prompted by
      an item in a recognition test. The two experiments reported here show that
      readers of spatial descriptions are more likely to accept sentences in a
      recognition test that are consistent with the operations used to construct a
      mental model than to accept sentences that are inconsistent. Consistency with the
      episodic construction trace leads to both correct recognition of verbatim
      sentences from the original description and false recognition of sentences that
      were not present in the original descriptions.

PMID- 10586574
TI  - The role of movement in the recognition of famous faces.
AB  - The effects of movement on the recognition of famous faces shown in difficult
      conditions were investigated. Images were presented as negatives, upside down
      (inverted), and thresholded. Results indicate that, under all these conditions,
      moving faces were recognized significantly better than static ones. One possible
      explanation of this effect could be that a moving sequence contains more static
      information about the different views and expressions of the face than does a
      single static image. However, even when the amount of static information was
      equated (Experiments 3 and 4), there was still an advantage for moving sequences
      that contained their original dynamic properties. The results suggest that the
      dynamics of the motion provide additional information, helping to access an
      established familiar face representation. Both the theoretical and the practical
      implications for these findings are discussed.

PMID- 10586575
TI  - Deconstructing Marilyn: robust effects of face contexts on stimulus-response
      compatibility.
AB  - Hommel and Lippa (1995) found a left-right spatial compatibility effect with
      respect to a background context of Marilyn Monroe's face, rotated 90 degrees
      clockwise or counterclockwise from upright, when subjects responded to up or down
      stimuli by pressing a left or a right key. They interpreted their results as
      providing evidence for object-based coding of stimulus location. We conducted
      four experiments in order to evaluate the reliability of this face context
      effect, to control for possible artifacts and evaluate alternative explanations,
      and to establish generalizability to other face contexts. This was accomplished
      by using not only the original photograph, but also a mirror-reversed image,
      chimeric faces composed from the left or the right sides of the original
      photograph, an outline drawing face, and a circle with markings for facial
      features. Our results were much stronger than those of Hommel and Lippa, and the
      face context effect was found for all of the face variations. Our experiments
      also provided evidence to suggest that asymmetric coding of the up and down
      locations contributes to performance in the face context as well.

PMID- 10586576
TI  - View dependence in scene recognition after active learning.
AB  - Human spatial encoding of three-dimensional navigable space was studied, using a
      virtual environment simulation. This allowed subjects to become familiar with a
      realistic scene by making simulated rotational and translational movements during
      training. Subsequent tests determined whether subjects could generalize their
      recognition ability by identifying novel-perspective views and topographic floor
      plans of the scene. Results from picture recognition tests showed that familiar
      direction views were most easily recognized, although significant generalization
      to novel views was observed. Topographic floor plans were also easily identified.
      In further experiments, novel-view performance diminished when active training
      was replaced by passive viewing of static images of the scene. However, the
      ability to make self-initiated movements, as opposed to watching dynamic movie
      sequences, had no effect on performance. These results suggest that
      representation of navigable space is view dependent and highlight the importance
      of spatial-temporal continuity during learning.

PMID- 10586577
TI  - Effect of causal structure on category construction.
AB  - In four experiments, the question of how the causal structure of features affects
      the creation of new categories was examined. Features of exemplars to be sorted
      were related in a single causal chain (causal chain), were caused by the same
      factor (common cause), or caused the same effect (common effect). The results
      showed that people are more likely to rely on common-cause or common-effect
      background knowledge than on causal-chain background knowledge in category
      construction. Such preferences suggest that the common-cause or the common-effect
      structures are considered more natural conceptual structures.

PMID- 10586578
TI  - Induction with cross-classified categories.
AB  - One of the main functions of categories is to allow inferences about new objects.
      However, most objects are cross-classified, and it is not known whether and how
      people combine information from these different categories in making inferences.
      In six experiments, food categories, which are strongly cross-classified (e.g., a
      bagel is both a bread and a breakfast food), were studied. For each food, the
      subjects were told fictitious facts (e.g., 75% of breads are subject to spoilage
      from Aspergillus molds) about two of the categories to which it belonged and then
      were asked to make an inference about the food (e.g., how likely is a bagel to be
      subject to spoilage from Aspergillus molds?). We found no more use of multiple
      categories in these cases of cross-classification than in ambiguous
      classification, in which it is uncertain to which category an item belongs.
      However, some procedural manipulations did markedly increase the use of both
      categories in inferences, primarily those that focused the subjects' attention on
      the critical feature in both categories.

PMID- 10586579
TI  - The effect of memory load on negative priming: an individual differences
      investigation.
AB  - The effect of a verbal (Experiment 1) and a nonverbal (Experiment 2) memory load
      on negative priming was investigated by employing a concurrent memory task with a
      letter naming task. Across both experiments, negative priming was reliable only
      under conditions of zero memory load, suggesting that the processes that
      contribute to negative priming are resource demanding and dependent on a domain
      free resource pool. Individual differences in negative priming were observed,
      such that high working memory capacity subjects showed reliable negative priming
      whereas low working memory capacity subjects did not. The results suggest that
      the negative priming effect results from allocation of controlled attention and
      that individual differences in working memory capacity correspond to the ability
      to efficiently handle irrelevant information.

PMID- 10586580
TI  - Cross-language positive priming disappears, negative priming does not: evidence
      for two sources of selective inhibition.
AB  - The authors used a unilingual and bilingual primed lexical decision task to
      investigate priming effects produced by attended and ignored words. In the
      unilingual experiment, accelerated lexical decisions to probe target words
      resulted when the word matched the preceding target word, whereas slowed lexical
      decisions to probe target words resulted when the word matched the preceding
      ignored nontarget word. In the bilingual (English-Spanish) experiment, between
      language, rather than within-language, priming manipulations were used. Although
      the ignored repetition negative priming effect replicated across languages, cross
      language attended repetition positive priming did not. This dissociation of
      priming effects in the inter- versus intralanguage priming conditions contradicts
      episodic retrieval accounts of negative priming that deny the existence of
      selective inhibitory processes. On the other hand, these results support an
      extension of inhibition-based accounts of negative priming, because they indicate
      that inhibition can operate at two levels of abstraction--local word and global
      language--simultaneously.

PMID- 10586581
TI  - Visual distraction, working memory, and aging.
AB  - In two experiments, the effects of taxing selective attention processes on the
      efficiency of working memory processes were considered in relation to normal
      aging. In both experiments, the presence of task-irrelevant information disrupted
      the efficiency of working memory processes, and the effect was generally greater
      for older than for younger adults. The presence of distracting information
      increased the frequency of intrusion errors in both younger and older adults and
      of memory-based errors in older adults. These findings suggest that distraction
      disrupts both the ability to maintain a coherent stream of goal-directed thought
      and action in younger and older adults and the encoding and retention of relevant
      information in older adults.

PMID- 10586582
TI  - Bars and lines: a study of graphic communication.
AB  - Interpretations of graphs seem to be rooted in principles of cognitive
      naturalness and information processing rather than arbitrary correspondences.
      These predict that people should more readily associate bars with discrete
      comparisons between data points because bars are discrete entities and facilitate
      point estimates. They should more readily associate lines with trends because
      lines connect discrete entities and directly represent slope. The predictions
      were supported in three experiments--two examining comprehension and one
      production. The correspondence does not seem to depend on explicit knowledge of
      rules. Instead, it may reflect the influence of the communicative situation as
      well as the perceptual properties of graphs.

PMID- 10586583
TI  - Reasoning about conventional time as a function of conventional time systems.
AB  - This study investigated how reasoning about conventional time information varied
      as a function of conventional time systems by using the Chinese month and Jieqi
      systems. Twenty Chinese students were asked to answer month-related questions and
      another 20 were asked to answer Jieqi-related questions. Reaction time and
      accuracy were the dependent measures. A cross-boundary effect was observed in
      processing months, and distance and direction effects were obtained when
      participants judged the interval of Jieqi. These results suggested that
      arithmetic operations were used in Chinese reasoning about months and verbal
      articulatory processes were used for the Jieqi. The effects of mode of language
      representation on cognition and the strategies for cross-linguistic study are
      discussed.

PMID- 10586584
TI  - Mental multiplication: nothing but the facts?
AB  - Current models of adult arithmetic performance assume that representation
      includes only facts and procedures. However, other kinds of representations such
      as an analog scale or sets of number multiples might be useful in a variety of
      multiplication-related tasks. Introducing the practice transfer paradigm, we
      demonstrate that associations between distinct representational structures can be
      detected via cross-task transfer, provided that initial performance is retrieval
      based. Results support the predictions of the integrated-structures model of
      multiplication knowledge. Implications for well-established item differences such
      as the problem-size effect are addressed, and the question of how integration
      occurs is considered.

PMID- 10586585
TI  - Individual solution processes while solving addition and multiplication math
      facts in adults.
AB  - Contrary to predictions of current solution process models, adults used a variety
      of procedures other than retrieval to solve addition and multiplication math
      facts. Predictors assumed to capture retrieval processes posited by such models
      did account for a substantial proportion of variance in averaged retrieval
      solution times. But most of the variance in individual participants' retrieval
      times remained unaccounted for. Cross-operation associations in patterns of
      strategy use and retrieval latencies were obtained. Adults with stronger higher
      level math achievement were more likely to use retrieval, solved math facts
      faster and less variably, and executed retrieval processes posited by current
      solution process models faster than participants with less math attainment. The
      results are explained within the context of the adaptive strategy choice model.

PMID- 10586586
TI  - [Body surface ultrasonography-guided bronchofiberscopy].
AB  - Transbronchial lung biopsies and cytologic studies under ultrasonographic
      guidance from the body surface were conducted in 39 patients whose lesions were
      adjacent to the thoracic wall. In 26 patients, biopsy, curettage, or brushing
      forceps were visualized in the mass or infiltrative lesion by thoracic echogram.
      Positive findings were obtained in 23 patients, for a conclusive diagnostic rate
      of 88.5%. Of the 13 patients in whom forceps could not be visualized by echogram,
      10 had positive findings, for a diagnostic rate of 76.9%. For visualization by
      thoracic echogram, abnormal lung lesions must be in direct contact with the
      thoracic wall. Occasionally, diagnostic procedures may be impeded by anatomical
      structures such as shoulder joints or scapula. Despite these disadvantages, the
      ultrasonography-guided bronchofiberscope is quite useful because it facilitates
      real-time confirmation of the positioning of the forceps relative to the lesions.
      It is also useful in cases when the peripheral lesions are too small or vague to
      be demonstrated by fluoroscopy alone, because the echo probe can be the target of
      the forceps instead of the missing shadows. The diagnostic rate should be higher
      when the forceps are visualized in the lesions ultrasonographically.

PMID- 10586587
TI  - [Compensatory increases in residual lobar volume following lung resection].
AB  - To investigate compensatory increases in residual lobar volume after lobectomy
      and pneumonectomy, we measured lung lobar volumes on the basis of pre- and
      postoperative computed tomographic (CT) images obtained on 40 patients (11 right
      upper, 7 right lower, 10 left upper, 8 left lower lobectomies and 4 left
      pneumonectomies). A personal computer image processing program was utilized to
      calculate lung lobar volumes from sequential CT images. Decreases in whole lung
      volume after lung resection averaged from 7.4% to 9.5% of preoperative whole lung
      volume in the lobectomy patients, and 30% in the patients who underwent left
      pneumonectomy. Those values were much smaller than the volumes of resected lobe,
      as measured on the basis of preoperative CT images. Increased residual lobar
      volume after lung resection averaged from 11% to 15% of preoperative whole lung
      volume in both the lobectomy and left pneumonectomy patient groups. Residual
      lobes compensated for approximately 60% of the resected lobar volume in the
      lobectomy patients, but only about 30% of resected lung volume in the left
      pneumonectomy patients. Increases in residual lobar volume tended to be larger in
      patients who underwent upper lobectomies, and on the operative side in patients
      other than those who underwent left lower lobectomies. We concluded that
      compensatory increases in residual lobar volume should be taken into full
      consideration when making predictions about postoperative pulmonary function.

PMID- 10586588
TI  - [An analysis of nutritional status and pulmonary hypertension in patients with
      sequela of pulmonary tuberculosis and chronic obstructive pulmonary disease].
AB  - The prognostic value of hypercapnia and/or pulmonary hypertension differs in
      patients with sequela of pulmonary tuberculosis (TBseq) and those with chronic
      obstructive pulmonary disease (COPD) who are receiving home oxygen therapy (HOT).
      In an attempt to identify the factors, if any, that might explain this
      difference, we first compared nutritional status, respiratory function test
      results, dyspnea indexes, and other data for hypercapnic patients (PaCO2 > or =
      45 Torr) and normocapnic patients (PaCO2 < 45 Torr) receiving HOT. Second, we
      examined the relationship between the degree of pulmonary hypertension and
      several respiratory function parameters for patients in each disease category. In
      44 patients with TBseq, nutritional status estimated by body mass index and serum
      albumin was significantly better in the hypercapnic patients than in the
      normocapnic patients. However, this difference was not observed in 37 patients
      with COPD. In 30 patients with TBseq, the degree of pulmonary hypertension
      correlated significantly only with PaO2; in 32 patients with COPD, however,
      significant correlations were observed not only with PaO2 but also with PaCO2,
      %VC, and FEV1. These differences distinguishing groups of patients with the 2
      diseases may provide an explanatory basis for the difference in prognostic value
      of hypercapnia and/or pulmonary hypertension in patients receiving HOT.

PMID- 10586589
TI  - [Eosinophilic pneumonia without eosinophilia in BALF or peripheral blood and
      diagnosed by open lung biopsy].
AB  - A 47-year-old woman was referred to our hospital because of cough and an abnormal
      shadow in the left lung field. The infiltrate reduced without therapy and another
      infiltrate appeared in the right lung field. Bronchiolitis obliterans organizing
      pneumonia was clinically suspected due to the absence of signs of eosinophilia in
      peripheral blood and bronchoalveolar lavage fluid (BALF). Open lung biopsy
      specimens disclosed alveolitis with mononuclear cell infiltration and
      organization within the air spaces of bronchioli and alveolar ducts. The
      observation of pronounced eosinophil infiltration in the alveolar spaces of some
      specimens yielded a diagnosis of eosinophilic pneumonia. After steroid therapy,
      the abnormal shadows disappeared. BALF lymphocyte surface marker analysis
      detected no decrease in the CD4/CD8 ratio; activated CD4 and CD8 lymphocytes were
      notably higher than the corresponding levels in peripheral blood. IL-5, IL-3, and
      GM-CSF values in BALF were not significantly elevated. This was a case of
      borderline eosinophilic pneumonia that was difficult to diagnose on the basis of
      clinical parameters alone.

PMID- 10586590
TI  - [Primary Sjogren's syndrome with lymphocytic interstitial pneumonia and pulmonary
      multiple cystic lesions].
AB  - We report a case of primary Sjogren's syndrome with lymphocytic interstitial
      pneumonia and multiple cystic lesions. The patient was a 64-year-old woman.
      Abnormal chest shadows were detected by x-ray and computed tomographic (CT)
      examinations. The patient had no family history of disease and had never smoked.
      She had complained of dryness in the eyes and mouth for about 10 years.
      Laboratory tests were positive for anti-nuclear antigen, anti-SS-A antigen, and
      anti-SS-B antigen. Sialography revealed marked destruction of the salivary
      glands, yielding a diagnosis of Sjogren's syndrome. Chest X-ray films and CT
      scans showed multiple cystic lesions in both lungs, measuring from a few mm to 3
      cm in diameter, as well as fine centrilobular nodules. Slight anemia and hyper
      gamma globlinemia were also detected. Pulmonary function tests showed mild
      obstructive disturbance. Bronchoalveolar lavage analysis disclosed an elevated
      lymphocytic fraction (28.6%), but transbronchial lung biopsy provided no adequate
      specimens for diagnosis. Thoracoscopic lung biopsy specimens demonstrated marked
      infiltration of lymphocytes and histiocytes through the interstitium of alveolar
      walls and peri-bronchovascular sheath, with some lymphoid follicles. The overall
      appearance was compatible with lymphocytic interstitial pneumonia. The cysts
      themselves were nonspecific, and no cellular infiltration was noted in the cyst
      walls. Because of the predominantly peribronchial distribution of the lesions, we
      suspected that the cysts were formed by the check valve mechanism. However, no
      definitive evidence was obtained.

PMID- 10586591
TI  - [An autopsy case of MPO-ANCA-positive microscopic polyangiitis with
      manifestations of pulmonary hemorrhage and diffuse alveolar damage].
AB  - A 68-year-old woman was admitted to our hospital because of fever of unknown
      origin and pain in the lower extremities. Six weeks after onset, diffuse
      infiltrative shadows were observed on chest X-ray films, and marked hypoxemia and
      progressive renal dysfunction suddenly developed. Corticosteroid therapy (2
      courses of pulse therapy, each consisting of methylprednisolone at 500 mg/day for
      3 days) was not effective, and the patient died 9 weeks after onset because of
      respiratory failure. Serologic tests were positive for MPO-ANCA. Histopathologic
      findings at autopsy disclosed arteriolar fibrinoid necrosis in tissues of the
      liver, spleen, lungs, and kidneys, thus yielding a diagnosis of microscopic
      polyangiitis. Lung specimens also demonstrated massive alveolar hemorrhaging in
      the mid-lung fields and diffuse alveolar damage (DAD) in all lobes. Pulmonary
      hemorrhage coexistent with DAD worsens the prognosis for microscopic polyangiitis
      in patients positive for MPO-ANCA.

PMID- 10586592
TI  - [Idiopathic pulmonary fibrosis of the upper lobe: a case report].
AB  - A 26-year-old man was admitted to our hospital complaining of exertional dyspnea.
      Chest x-ray films disclosed reticulonodular shadows predominantly in the upper
      fields of both lungs, but no apical cap. Lung biopsy specimens obtained from the
      upper lobe by video-assisted thoracoscopy revealed subpleural elasto-fibrosis.
      Also, specimens obtained from the lower lobes disclosed micro-honeycombing due to
      peri-lobular fibrosis resembling usual interstitial pneumonia. Although
      pneumothorax occurred repeatedly, the lungs reinflated on each occasion without
      artificial intervention. Similar radiographic findings had been obtained on the
      patient's father, who died of idiopathic pulmonary fibrosis at the age of 56.
      Idiopathic pulmonary upper lobe fibrosis was conclusively diagnosed because the
      patient exhibited most of the features originally described by Amitani et al.

PMID- 10586593
TI  - [Churg-Strauss syndrome with pulmonary eosinophilia and intrapulmonary lymph
      nodes 2 years before the onset of vasculitis].
AB  - We report a case of a 55-year-old man who had been treated for bronchial asthma
      diagnosed at the age of 51. One year following diagnosis, chest X-ray films
      disclosed nodular shadows. Biopsy specimens obtained by video-assisted
      thoracoscopic surgery were histopathologically identified as intrapulmonary lymph
      nodes. Three years after the initial diagnosis, the patient experienced sensory
      disturbance of the lower extremities, low-grade fever, and weight loss. At this
      point he was admitted to our hospital. On admission, physical examination and
      clinical investigations showed peripheral eosinophilia and signs of vasculitis.
      Specimens obtained by transbronchial lung biopsy and bronchoalveolar lavage
      showed strong evidence of tissue damage with infiltration of eosinophils but no
      evidence of necrotizing vasculitis or extra-vascular granuloma. Churg-Strauss
      syndrome (CSS) was diagnosed, and treatment was initiated with prednisolone at a
      dose of 60 mg/day. Except for the sensory disturbances in the lower extremities,
      after a few days of treatment the patient's symptoms subsided and his clinical
      data improved. This case was clinically important because pulmonary eosinophilic
      infiltration into vessel walls was confirmed a year after the diagnosis of
      bronchial asthma, and 2 years before the patient demonstrated signs of
      vasculitis. Further, it was a very rare case of CSS in which intrapulmonary lymph
      nodes had developed beneath the visceral pleura despite the absence of a history
      of heavy smoking, thus suggesting continuous stimulation by some as yet unknown
      antigen.

PMID- 10586594
TI  - [Diffuse idiopathic skeletal hyperostosis with fibrobullous change in upper lung
      lobes and dyspnea due to limitation of thoracic cage].
AB  - A 48-year-old man was admitted to our hospital because of shortness of breath and
      abnormal shadows on chest roentgenograms. Although he had been given a diagnosis
      of ankylosing spondylitis (AS) at the onset of his symptoms, a diagnosis of
      diffuse idiopathic skeletal hyperostosis (DISH) was made by our orthopedics
      department on the basis of bone X-ray findings. Spirograms demonstrated a
      restrictive pattern and residual volume was increased. Total lung capacity and
      respiratory muscle function were normal, suggesting that the abnormal spirogram
      findings were due to decreased thoracic cage compliance. Chest roentgenograms and
      computed tomographic scans showed apical fibrobullous changes in both lungs,
      similar to those observed in AS. To our knowledge, this is the first case of DISH
      with pulmonary involvement to be reported to date. The pulmonary manifestations
      were similar to those of AS, and it was speculated that they were due to
      limitation of the thoracic cage.

PMID- 10586595
TI  - [Multiple intrapulmonary rheumatoid nodules].
AB  - A 66-year-old woman who had been treated at a nearby hospital since 1977 for
      rheumatoid arthritis complained of cough. Chest X-ray films disclosed multiple
      nodular shadows with cavitation in the fields of both lungs. The patient was
      admitted to our hospital and a thoracoscopic lung biopsy was performed.
      Histologically, the nodule consisted of necrotizing granuloma, indicating a
      necrobiotic nodule. Rheumatoid nodule was diagnosed because the patient exhibited
      rheumatoid arthritis. The chest X-ray shadow disappeared without medication.
      Rheumatoid nodules without coniosis are uncommon, but should be considered in the
      differential diagnosis of lung nodular lesions in patients with rheumatoid
      arthritis.

PMID- 10586596
TI  - [Solitary fibrous tumor of the pleura with elevated high-molecular-weight insulin
      like growth factor II and hypoglycemia].
AB  - Recurrent hypoglycemia occurred in a 58-year-old woman with a solitary fibrous
      tumor of the pleura and exhibiting CD34 immunopositivity. During episodes of
      hypoglycemia, serum high-molecular-weight insulin-like growth factor II (big IGF
      II) was elevated. After removal of the tumor containing IGF-II, the hypoglycemia
      and serum big IGF-II disappeared. This was followed by an increase in normal IGF
      II. We speculate that the primary cause of hypoglycemia in this patient was the
      presence of big IGF-II produced by the solitary fibrous tumor of the pleura. To
      our knowledge, the presence of this type of IGF-II in CD34+ solitary fibrous
      tumors of the pleura has not been described to date in the literature.

PMID- 10586597
TI  - [Multiple pulmonary nodules due to ticlopidine-induced pneumonitis].
AB  - A 54-year-old man had been treated with Ticlopidine for antithrombotic therapy
      after a myocardial infarction. Six months after the start of Ticlopidine,
      pruritic skin rash developed. After 8 months, chest X-ray films revealed multiple
      nodules, and the patient was admitted to our hospital. Laboratory data indicated
      liver dysfunction and sputum eosinophilia. Transbronchial biopsy specimens
      disclosed intraluminal organization and alveolar septal thickening with
      lymphocyte infiltration. After cessation of Ticlopidine, the cutaneous lesions
      quickly improved, and multiple nodules completely resolved within 4 months. These
      findings resulted in a diagnosis of Ticlopidine-induced pneumonitis. The
      radiographic pattern of multiple pulmonary nodules was very rare. Sputum
      eosinophilia may be helpful in the diagnosis of drug-induced pneumonitis. To our
      knowledge, there have been no previous reports of Ticlopidine-induced pneumonitis
      in Japan.

PMID- 10586598
TI  - [Increased neuron-specific enolase levels in patients with long-standing
      pyothorax-associated lymphoma].
AB  - A 78-year-old man was admitted for the evaluation of chest pain and a
      subcutaneous giant mass in the left chest, which had been growing for 3 months. A
      computed tomogram of the chest revealed a giant tumor attached to the parietal
      pleura with calcification of long-standing pyothorax. Pathological findings of a
      specimen obtained from this tumor showed diffuse proliferation of large atypical
      lymphocytes with 1-2 nucleoli and abundant cytoplasm. In immunohistochemical
      studies, tumor cells stained positive for CD20 but not for CD45 RO. The diagnosis
      was long-standing pyothorax-associated lymphoma (diffuse large-cell lymphoma, B
      cell type). The patient's serum neuron-specific enolase (NSE) level was 101 ng/ml
      on admission, and declined in tandem with a chemotherapy-induced decrease in
      tumor size. In addition, immunohistochemical studies showed staining of tumor
      cells by anti-NSE polyclonal antibody. Although rarely observed in patients with
      malignant lymphoma, increased serum NSE levels may serve as an index of
      chemotherapeutic effectiveness.

PMID- 10586599
TI  - [Bronchocutaneous fistula after treatment for breast cancer: a case report].
AB  - We describe a case of bronchocutaneous fistula that developed after surgery and
      radiotherapy for breast cancer. A 69-year-old woman presented with fever and the
      leakage, on expiration, of bubbles from a site on the left chest wall where a
      Halsted mastectomy and radiotherapy (60 Gy) had been performed 19 years earlier.
      Computed tomography and magnetic resonance imaging revealed a fistula bridging a
      bronchus and the skin. Repeated biopsies of the fistula failed to disclose any
      malignancy. The fistula closed after treatment with antibiotics, and has remained
      closed for 9 months, as disclosed by identical tomographic images. The paucity of
      literature describing the diagnostic imaging of bronchocutaneous fistula prompted
      this report.

PMID- 10586600
TI  - [Extrahepatic manifestation associated with HCV infection].

PMID- 10586601
TI  - [A model of quality of life in the patients with Crohn's disease].
AB  - PURPOSE: To identify the integrated impact of psychological, social, and clinical
      factors onto the quality of life (QOL) in the patients with Crohn's disease.
      SUBJECTS AND METHODS: Two hundred twenty two out-patients participated in a cross
      sectional questionnaire survey in which health-related QOL (SF36), disease
      specific symptoms, psychological adaptation and social support were measured.
      Multi-variable regression models were used to test the impact of clinical,
      psychological, and social factors on the patient's QOL and symptom reports.
      RESULTS: The patient's symptoms and health-related QOL were significantly
      associated not only with disease activities, but also with the patient's
      psychological adaptation and the quality of social support. CONCLUSION: The
      results strongly suggest that a psychoeducational intervention may be useful in
      combination with a clinical intervention to improve the patient's QOL.

PMID- 10586602
TI  - [A case of phlegmonous gastritis].

PMID- 10586603
TI  - [A case of acute appendicitis perforating to the sigmoid colon].

PMID- 10586604
TI  - [A case of intestinal malrotation with bleeding of the jejunal diverticula].

PMID- 10586605
TI  - [A case of Weber-Christian disease associated with abdominal pain caused by
      mesenteric panniculitis].

PMID- 10586606
TI  - [A case of intramural gastric metastasis from ascending colon cancer].

PMID- 10586607
TI  - [Intravenous cyclosporine therapy for ulcerative colitis refractory to steroid
      therapy].

PMID- 10586608
TI  - [A case report of multiple hepatic angiosarcoma].

PMID- 10586609
TI  - [A case of liver metastasis of the non-functioning islet cell tumor of the
      pancreas treated by percutaneous ethanol injection therapy].

PMID- 10586610
TI  - [A case of duodenal aberrant pancreas causing massive upper gastrointestinal
      hemorrhage].

PMID- 10586611
TI  - [Obesity and quality of life].
AB  - The health status from the patient's own perspective is being given more
      importance every day, both with regard to his or her physical aspect and the
      mental and social aspects, this is the so-called Health Related Quality of Life.
      In order to evaluate this, tools are being developed that permit a quantification
      of this qualitative concept, using generic and specific tools which, if
      adequately validated, will lead to an understanding of the impact of the obesity
      on the individual, its change over time, enable comparisons with other
      individuals, with the quality of life of other diseases, with that of a healthy
      population, or with the general population. They will also allow the patients to
      be grouped and they will facilitate the study of the mechanisms that have led to
      the patient being obese and the consequences thereof. The QoL tests will serve to
      select the treatments and to monitor the efficacy thereof. Although there is no
      evidence of major psychiatric disease in obese patients considered globally,
      those with a greater degree of obesity, are more prone to suffering from these.
      The latter also show an alteration in most of the dimensions explored by the QoL
      tests and if they subject to a radical weight loss, these improve from the first
      months on, but it has yet to be determined whether these improvements are
      maintained over time and whether they are equally manifest in patients with
      moderate weight losses, and as yet the frustration that the frequent relapses of
      this disease imply, have not been properly quantified. The rapid development of
      valid tools to assess the Health Related Quality of Life in obesity, require
      their use as yet another part of the clinical evaluation of any obese individual.

PMID- 10586612
TI  - [Effect of the diet on the nutritional status of ballerinas: immunologic
      markers].
AB  - Athletes have special nutritional needs that will vary with sex, age, body
      composition and most importantly by the type, intensity, frequency and duration
      of the physical exercise. However the diet of certain groups of athletes such as
      ballet dancers is inadequate due to overly restrictive habits as a consequence of
      their obsession with losing or maintaining a low body weight that reflects an
      aesthetic preference for thinness. Physical exercise implies energy expenditure
      and thus, an increase in the energy intake is required to avoid possible
      situations of malnutrition. Both a negative energy balance and physical exertion
      have been shown to induce immunological changes which have been implicated as a
      possible explanation for increased susceptibility to illness and infections.
      OBJECTIVE: To find out the influence of a restricted energy intake on the immune
      system of 14 ballet dancers (20-25 h/w) in comparison with a control sedentary
      group (n = 23) by evaluating dietetic, anthropometric and some immunological
      parameters. RESULTS: Ballet dancers consumed a hypocaloric diet (mean: 1555
      kcal), the energy intake being significantly lower than in the control group.
      None of both groups showed a similar calorie profile to the recommended intake
      for Spanish population, especially fat percentage was higher than it should.
      Regarding weight, ideal body weight and BMI values, no significant differences
      were shown between both groups. However, all the skinfolds thickness and the sum
      of skinfolds were significantly lower in ballet dancers than in controls.
      Leukocytes, lymphocytes and all lymphocyte subset counts were lower in ballet
      dancers in comparison with controls. CONCLUSIONS: In view of these results,
      ballet dancers may suffer from an impaired nutritional status, determined by a
      depletion of anthropometric and immunological parameters. The nutritional
      requirements for this population should be increased in order to compensate their
      high-energy expenditure, avoid a negative energy balance and lessen the
      nutritional damage.

PMID- 10586613
TI  - [Postoperative gastric emptying following heart surgery].
AB  - We analyzed the lag in the gastric emptying immediately after of cardiac surgery,
      in fourteen patients by means of administration of amniophem. Plasmatic levels
      (area under the curve) and time in reaching he highest ones were measured. The
      main objective was to detect any difference between measurements in our patients
      and healthy adults (control group). A secondary objective was to find any
      relationship between our results and other factors, such as pre and post-surgical
      conditions and demographic features. We found a significant reduction in the area
      under the area under he curve and in time to obtain the highest plasmatic levels
      with respect to group. In addition, we observed a significant correlation between
      our results and other issues: age and fentanyl doses during surgical proceedings.

PMID- 10586614
TI  - [Effect of Ispaghula husks on postprandial glycemia in healthy female
      volunteers].
AB  - OBJECTIVES: To evaluate the influence of Ispaghula husk in the postprandial
      glucose concentrations in serum in healthy volunteers. MATERIAL AND METHODS: This
      study is divided in two assays and 7 healthy women with ages ranging from 35 to
      45 years participated in both assays. Assay 1. Administration of 50 g of glucose
      dissolved in 125 ml of water (followed by other 150 ml of water). Assay 2. It was
      carried out one week later in the same women and conditions as assay 1 but adding
      10.5 g of Ispaghula husk to the dissolution. In both assays, blood samples were
      obtained at 0, 10, 20, 30, 45, 60, 75, 90 and 120 minutes after administration
      and glucose concentration was determined in serum. RESULTS: The value of the area
      under the mean glucose concentration-time curve obtained in assay 2 (in the
      presence of fiber) was a 13.6% lower than that obtained in assay 1 (significant
      difference, p < or = 0.05). Individual concentration-time curves obtained in
      assay 1 can be considered as normal in 4 of the 7 volunteers. Abnormalities
      observed in the other 3 curves were due to: her history of prediabetic in one of
      them (glucose concentration values over 180 mg/100 ml); diabetic patients in her
      family in other of them (2 values over 180 mg/100 ml) and hypoglycaemia in two of
      the volunteers. When we administered glucose with fiber in assay 2, in all cases,
      the maximum concentration reached was lower, the variations in glycaemia values
      were also lower along the different sampling times (peaks disappear or are less
      marked) and no hypoglycaemia appeared.

PMID- 10586615
TI  - [Evaluation of a high protein diet in critical care patients].
AB  - OBJECTIVE: To verify the hypothesis that a high nitrogen intake leads to better
      nutritional results in critical patients. REFERENCE POPULATION: Patients
      hospitalized in the critical care unit between 1995 and 1998 with nutritional
      support for 14 days, excluding patients with liver and/or kidney failure.
      INTERVENTIONS: The calculation of the requirements was made using a computerized
      program for determining the eliminated nitrogen, depending on the degree of
      stress. At the end of the second year the formulae for calculating the
      requirements were changed, thus we had two groups of patients with a different
      protein intake. The nutritional biochemical parameters are usually analyzed on
      days 1, 4, and 14, as were the characteristics of the nutrition used during the
      first and second week of treatment in both periods. RESULTS: 32 patients were
      included in the first period, and 50 in the second. It was seen that there were
      no significant differences between them. The characteristics of the administered
      nutrition showed a greater caloric supply in the first week of the first period
      (35.14 +/- 4.4 vs. 30.04 +/- 6.1 cal/kg), with there not being any difference in
      the protein intake (0.26 +/- 0.04 vs. 0.24 +/- 0.09 grams of nitrogen/kg) and a
      greater protein intake in the second week of the second period (0.34 +/- 0.06 vs.
      0.28 +/- 0.04 grams of nitrogen/kg), with there not being any differences in the
      caloric intake (34.08 +/- 5.6 vs. 34.13 +/- 3.1 cal/kg). The analyzed parameters
      did not present any significant differences between the periods. The evolution of
      these was similar for each period, although in the second period the transferrin
      improved with respect to the first period, and the decrease in the height
      creatinine index was stopped in the second week. The nitrogen balance could not
      be improved. CONCLUSIONS: The increase in the protein intake above certain limits
      only very slightly improves some of the nutritional biochemical parameters,
      without improving the nitrogen balance as a result of an increased elimination
      thereof.

PMID- 10586616
TI  - [Helicobacter pylori infection and cancer of the stomach].
AB  - Although the incidence of gastric cancer has declined in the past few decades in
      developed countries, it has remained one of the most frequent malignomas with
      high mortality. Epidemiological, clinical and basic research studies confirm the
      role of Helicobacter pylori in the pathogenesis of the tumors of the distal
      stomach and low-grade MALT lymphomas. On the contrary more and more data suggest
      a possible protective role of the infection in the gastro-oesophageal reflux
      disease, tumors of the cardia and adenocarcinoma of the distal oesophagus. The
      intensive research being done in the past few years prove our previous concept,
      that the pathogenesis of gastric cancer is a multifactorial process, which is
      affected by Helicobacter pylori ("a major environmental factor") together with
      distinct environmental, social and genetic factors. The interaction of these
      factors and the importance of them urge further investigations, which may differ
      in different populations.

PMID- 10586617
TI  - [Current questions concerning nutrition during pregnancy].
AB  - Maternal nutrition during pregnancy is known to influence the health state of the
      offspring during the whole lifetime. The paper discusses in details the sequelae
      of the imbalanced energy intake and the role of fats. Out of the micronutrients
      the effects of retinol, vitamins of the B-group, calcium, iron, iodine and
      magnesium are discussed and attention is called to the action of the high sodium
      intake. Finally, the principles of the nutritional recommendations in pregnancy
      are presented.

PMID- 10586618
TI  - [Acute effect of maternal smoking on fetal blood circulation].
AB  - The authors examined the acute effects of cigarette smoking on maternal and fetal
      cardiovascular system in 22 healthy voluntary pregnant smoker women. All examined
      patients were chronic cigarette smokers who smoked more than 5 cigarettes per day
      before and during pregnancy. All of the pregnancies subsequently had normal
      outcomes. Maternal heart rate, and blood pressure, fetal heart rate, resistance
      indices of fetal descending aorta, those of umbilical artery, middle cerebral
      artery and uterine artery were measured immediately before and after cigarette
      smoking. It was found that smoking was associated with increase in maternal and
      fetal heart rate and an increase in umbilical artery resistance indices was also
      observed. These changes might be considered as a reaction improving fetal oxygen
      supply.

PMID- 10586619
TI  - [A new method of molecular testing in the differential diagnosis of hereditary
      hemochromatosis].
AB  - Hereditary hemochromatosis is an autosomal, recessive disorder of the iron
      metabolism. The hemochromatosis gene (HFE) was previously located on chromosome 6
      and recently identified by positional cloning. A point mutation, C282Y, was found
      to be present in the HFE gene in homozygous form in 64 to 100% of patients with
      established hemochromatosis. The relationship of a second polymorphic variant of
      the HFE gene, H63D to the formation of iron overload is debated. Although
      hemochromatosis is one of the most common inherited disorders among Caucasians,
      in the absence of specific signs it is rarely diagnosed. In order to obtain
      comparable epidemiological data for Hungary, we tested 1271 and 277 randomly
      selected, unrelated, healthy subjects for C282Y and H63D respectively. In
      addition C282Y testing was carried out in 58 patients suffering from liver
      cirrhosis, and in 191 individuals with suspected hemochromatosis. For C282Y and
      H63D mutation analyses polymerase chain reaction technique followed by Rsa I and
      Bcl I restriction enzyme digestion was used. We developed an alternative method
      for the detection of C282Y based on an amplification-generated Kpn I restriction
      site. The allele frequencies were 3.8% and 12.3% for C282Y and H63D respectively
      in the normal Hungarian population. There was no significant difference in C282Y
      allele frequencies between liver disease patients (1.7%) and the normal
      population. We identified 15 homozygous and 25 heterozygous individuals among 191
      individuals with suspected hemochromatosis. The C282Y and the H63D allele
      frequencies in the normal Hungarian population were found to be similar to the
      allele frequencies observed in other European populations, indicating that there
      is a large number of individuals susceptible for iron overload in Hungary
      (1:700). Mutation analysis is a novel, non-invasive method in the diagnostics of
      hereditary hemochromatosis, which increasingly becomes part of the routine
      clinical work.

PMID- 10586620
TI  - [Diagnostic possibilities in gastric leiomyoma in relation to two of our cases].
AB  - Two cases of rare, benignant gastric tumors are reported. The suggest that while
      in the diagnosis of tumors with a mucous membrane involvement endoscopy has
      doubtless a leading role, tumors not infiltrating the mucous membrane are usually
      better recognizable by radiological (ultrasonography, computer tomography and
      double contrast x-ray) methods. An appropriate diagnosis followed by surgical
      removal of the tumor might result in a complete healing of the patient.

PMID- 10586621
TI  - [A clinical trial of acetazolamide for SCA6].
AB  - Spinocerebellar ataxia type 6 (SCA 6) is an allelic disorder of episodic ataxia
      type 2 (EA 2) and is caused by a small CAG repeat expansion in the gene encoding
      the alpha 1A-voltage-dependent-Ca channel subunit (CACNA 1 A) on chromosome
      19p13.1. The disorder starts at adulthood with progressive cerebellar ataxia, and
      the symptoms often fluctuate at early stage. These clinical features overlap with
      those of EA 2, which has been known as acetazolamide-responsive ataxia. On this
      background, we studied the clinical effectiveness of acetazolamide for SCA 6 in 9
      consecutive patients. Their clinical severity was serially evaluated by ARS
      (ataxia rating scale) and gravimetric test, over 32 weeks of oral administration
      of acetazolamide (250-500 mg/day). Consequently, a significant improvement was
      observed in ARS and postural sway. Our results indicate that acetazolamide is
      temporally effective for ameliorating the symptoms of SCA 6. However, its effects
      for the disease progression need to be examined in more large scales in number
      and duration.

PMID- 10586622
TI  - [Clinicopathological characteristics of Creutzfeldt-Jakob disease with a PrP
      V180I mutation and M129V polymorphism on different alleles].
AB  - We report an 80-year-old Japanese man with histologically-diagnosed Creutzfeldt
      Jakob disease (CJD). The patient was admitted to our neurological unit because of
      sudden onset motor aphasia-like symptoms and right hemiparesis. His medical and
      family histories were unremarkable, and he had taken no medications. Urine, blood
      counts and blood chemistry were all within normal limits. Cerebrospinal fluid was
      normal except for elevation of neuron specific enolase (29.9 ng/ml). High-signal
      intensity was demonstrated in the cortex of the left temporal lobe on T2-weighted
      MRI images, and the lesion swelled during the initial stage of the disease. There
      was no enhancement with Gd-DTPA. Serial MRI showed that the high-signal lesion
      had spread into the bilateral cerebral cortex. The patient developed myoclonus
      followed by akinetic mutism within 6 months of onset. Consecutive EEGs revealed
      no periodic synchronous discharge (PSD). He died of pneumonia 21 months after of
      admission. Autopsy revealed spongiform changes in the cerebral cortex with Kuru
      plaques, confirming the diagnosis of CJD. The Cerebellar cortex was well
      preserved. The high-signal lesions corresponded to the spongiform changes in the
      cerebral cortex. Immunohistochemical analysis showed weak synaptic prion
      staining. Prion protein (PrP) gene analysis of genomic DNA isolated from the
      autopsied brain by polymerase chain reaction, the restriction fragment length
      polymorphisms, and direct sequencing revealed a point mutation (Val-->Ile) at
      codon 180 and a polymorphism (Met/Val) at codon 129 on different alleles. A few
      CJD patients with point mutations in codon 180 of the PrP gene have been
      reported. Combination of the codon 180 point mutation and codon 129 polymorphism
      may yield an atypical clinicopathological form of CJD that includes late onset,
      negative PSD, and atypical MRI findings, with preservation of the cerebellar
      cortex.

PMID- 10586623
TI  - [A study of clinical symptoms, muscle pathology, therapeutic response, and
      prognosis of myositis in patients with HTLV-1 associated myelopathy (HAM)].
AB  - Myositis is one of well-known complications of HTLV-1 associated myelopathy
      (HAM). On twelve HAM patients, 10 women and 2 men complicated with myositis, we
      examined their clinical symptoms, muscle pathology, and therapeutic response.
      Clinical examination revealed gait disturbance in 10, weakness of upper limbs in
      6, muscle atrophy in 4, and myalgia in 3 patients. Blood test disclosed elevated
      serum CK level in 6 patients. Muscle biopsy showed marked inflammatory changes
      with many necrotic and degenerating fibers in 7 patients, and the rest showed
      only focal invasion of inflammatory cells. Eight patients received corticosteroid
      or immunosuppressant therapy. The neurological symptoms were improved in 5 of 8
      patients 3 months after the treatment. And only one out of 5 patients whom we
      followed up 3 years after the treatment showed improvement.

PMID- 10586624
TI  - [Orthostatic transient unresponsiveness in an elderly patient with severe
      cerebral arteriosclerosis under antihypertensive medication].
AB  - An 80-year-old man who had was administered antihypertensive medication showed
      repeated transient unresponsiveness during standing and/or walking. Neurological
      examination showed no focal neurological signs except mild dementia. Head-up
      tilting examination induced unresponsiveness and a decrease of systolic blood
      pressure from 111 mmHg to 86 mmHg. This unresponsiveness disappeared 3 minutes
      later when the blood pressure recovered to 102/64 mmHg. Cerebral angiography
      demonstrated occlusion in the right internal carotid artery and the right
      vertebral artery. Severe stenosis was observed at the left internal carotid
      artery and the left vertebral artery. Discontinuance of the antihypertensive
      medication reduced the frequency of orthostatic transient unresponsiveness.
      Elastic stockings in the lower extremities completely prevented the attack; head
      up tilting did not induce hypotension with elastic stockings. The transient
      unresponsiveness in the present case was probably correlated to hemodynamic
      failure under the condition of severe cerebral arteriosclerosis.

PMID- 10586625
TI  - [A case of radiculomyelitis following chickenpox in adulthood].
AB  - A 34-year-old woman presented with numbness in both lower limbs and weakness of
      right lower limb twenty six days after a primary varicella infection (chickenpox)
      associated with fever and rash. Neurological examination revealed numbness of
      both lower limbs, more severe on the right side, mild paresis of the right lower
      limb, particularly in the tibialis anterior muscle, and absent ankle jerk on the
      right. After admission, hyperalgesia appeared at the thoracic 10-12 levels. The
      T2-weighted MRI of the spinal cord revealed a high signal intensity lesion at the
      Th 9 level and gadolinium enhancement was seen in that lesion as well as in the
      bilateral posterior radicles and the left anterior radix at the Th 9 level. On
      needle electromyography, fasciculation was found in the right tibialis anterior
      and gastrocnemius muscles. The temporal dispersion of F-wave was seen in the
      right peroneal nerve. We diagnosed the patient suffered from radiculomyelitis
      following the primary varicella infection. The secondary immunological mechanism
      rather than direct viral invasion is most likely in our patient, because (1)
      neither VZV DNA, nor anti-VZV antibody was positive in the CSF, and (2) the
      duration was relatively long between the development of skin rash and that of
      neurological symptoms.

PMID- 10586626
TI  - [An early-onset case of acute disseminated encephalomyelitis with bilateral
      thalamic lesions on MRI].
AB  - We report the case of 5-year-old girl with acute disseminated encephalomyelitis
      (ADEM), whose MRI showed bilateral thalamic lesions. She suffered from left optic
      neuritis and generalized convulsion. Examination of cerebrospinal fluid revealed
      elevation of mononuclear cells and myelin basic protein (MBP). MRI showed the
      swelling of left optic nerve and high intensity areas of bilateral thalamus.
      After methylprednisolone pulse therapy, her visual acuity was dramatically
      improved and bilateral thalamic lesions were decreased. In childhood, bilateral
      thalamic lesions were observed in several diseases, such as viral encephalitis.
      Reye syndrome, Leigh syndrome and acute necrotizing encephalopathy. Demyelinating
      diseases involving the grey matter were very rare, but we must consider the
      presence of symmetrical thalamic involvement in patients with ADEM.

PMID- 10586627
TI  - [A case of post-irradiation lumbosacral radiculopathy successfully treated with
      corticosteroid and warfarin].
AB  - A 33-year-old man underwent post-operative radiation therapy for the left
      testicular anaplastic seminoma. One year later, the patient developed muscle
      weakness and sensory disturbance in the left lower extremity, and muscle weakness
      in the right lower extremity. MRI demonstrated linear and focal gadolinium (Gd)
      enhancement of the anterior portion of the lumbosacral roots within the cauda
      equina. The neurological symptoms improved after administration of corticosteroid
      and warfarin. Radiation myelopathy of this type was classified as "selective
      anterior horn cell injury or amyotrophy" by Reagan, and the site of the lesion
      was considered to be the lower motor neurons. However, based on the clinical and
      MRI findings, we proposed that the disease process was injury to the spinal nerve
      roots rather than the lower motor neurons. Recent neuropathological studies of
      this syndrome have demonstrated degeneration of the proximal spinal nerve roots.
      We consider that primary lesions of this syndrome occur in spinal nerve roots
      rather than in lower motor neurons, and "lumbosacral radiculopathy" is a more
      appropriate term for this condition.

PMID- 10586628
TI  - [A case of various neurological deficits caused by multi-vitamin deficiency
      associated with malabsorption syndrome after pancreatomy and small bowel
      resection].
AB  - A 34-year-old woman presented with walking difficulty and pain in the legs 3
      years after several abdominal operations for pancreatic cancer and intestinal
      obstruction thereafter. Corneal erosion, loss of deep sensation in the legs,
      polyneuropathy, myopathy, and memory disturbance were recognized. Deficiency of
      multiple vitamins (A, B1, B6, D, E, K) was found. The diagnoses were vitamin A
      deficient corneal erosion, vitamin K-deficient bleeding abnormality
      (asymptomatic), and the neurological deficits caused by vitamin E, B1, B6 and D
      deficiency. Although the vitamin supplement started 2 years after the onset of
      the neurological disease, both clinical and electrophysiological recovery was
      seen. She was unable to walk on admission, but became able to walk after vitamin
      E supplement. To our knowledge, this is the first report showing multi-vitamin
      deficiency causing extensive neurological, ophthalmological, and hematological
      deficits. Recognition of this condition would prevent the progression of
      potentially irreversible neurological disorders in patients with malabsorption
      syndrome after extensive abdominal surgery.

PMID- 10586629
TI  - [A case of cervical myelopathy due to dural arteriovenous fistula at the
      craniocervical junction].
AB  - A 70-year-old woman noted paresthesia ascending from both legs to her thighs 27
      months previously. She also suffered from urinary urgency and incontinence.
      Thereafter, weakness in both legs developed and gradually became worse. At the
      time of admission, a neurological examination revealed diffuse atrophy and mild
      spasticity in all four extremities, bilateral mild weakness in both upper
      extremities, and severe weakness in both lower extremities. Her superficial
      sensation was moderately impaired below the Th 3 level on her right side, and
      below the Th 4 level on her left side along with a mildly decreased sense of
      vibration in her left leg. Marked hyperreflexia in all four extremities and
      bilateral pathological reflexes were also observed. Pollakisurea, urinary
      incontinence and constipation were also present. Cervical MRI showed a swelling
      of the spinal cord at the C3 to C7 levels. Inside the spinal cord, low signal
      intensity lesions were seen on the T1-weighted MRI, and high signal intensity
      lesions were observed on the T2-weighted MRI, and the rim of the cervical cord
      was also enhanced by gadolinium-DTPA. MR angiography revealed enlarged and
      tortuous vessels at the craniocervical junction, thus suggesting the presence of
      a dural arteriovenous fistula (AVF). Vertebral arteriography demonstrated
      abnormal vessels at the spinomedullary junction supplied by the right vertebral
      artery, which drained into the anterior and posterior spinal veins. After
      surgically treating the dural AVF, the swelling of the spinal cord, the abnormal
      signals on MRI, and the clinical symptoms all markedly improved. Although most of
      the spinal dural AVF were located at the thoracic and lumbar levels, the present
      case was considered to be a very rare case of dural AVF, since it was located at
      the craniocervical junction and thus led to the development of cervical
      myelopathy.

PMID- 10586630
TI  - [Neovascular glaucoma following cataract surgery--a case report].
AB  - A 75-year-old man suffered from right neovascular glaucoma following ipsilateral
      cataract surgery. Cerebral angiogram showed occlusion of the right internal
      carotid artery and the steal phenomenon of right ophthalmic artery. Chronic
      ocular ischemia caused by carotid occlusion and ophthalmic artery steal
      phenomenon is one of the decisive risk factors for secondary glaucoma after
      cataract surgery.

PMID- 10586631
TI  - [A case of brain infarction of lateral geniculate body showing strange formed
      scotomas].
AB  - A 58-year-old woman suddenly noticed that soccer players disappeared and emerged
      in right inferior portion of her vision while she was watching soccer game on TV.
      She was admitted in our hospital on the day 9. Goldman perimeter revealed strange
      formed hemianopic soctomas which located at right side of her both visual fields.
      Brain MRI scan showed a tiny infarction in left lateral geniculate body. No
      abnormalities were found on cerebral angiography and 24 hours holter ECG study.
      Transesophageal echocardiography and transcranial Doppler study showed the
      presence of intracardiac right-to-left shunting via atrial septum defect.
      Paradoxical embolism was considered and oral anticoagulation therapy was started.
      Her visual defect disappeared by the day 79. Strange formed homonymous hemianopic
      scotomas were attributable to highly localized small lesion in left anterior
      choroidal artery territory of lateral geniculate body.

PMID- 10586632
TI  - [Habitual mandibular dislocation in two patients with Parkinson's disease].
AB  - There have been few case reports of mandibular dislocation in Parkinson's disease
      (PD) so far. We experienced habitual mandibular dislocation in two PD patients.
      They were a 74-year-old woman and a 56-year-old man, who were both graded V by
      Hoehn and Yahr's staging and had a 13- and 14-year history of PD, respectively.
      Remarkable retroflexion and rigidity of the neck was observed in both patients.
      Anterior dislocation of the jaw occurred without any special cause. Once the jaw
      was dislocated, it required unexpected power to reduce the dislocation against
      the rigidity. In a case of postencephalitic parkinsonism, continuous parkinsonian
      tremors of the mandible over a long period was indicated as a cause of the
      recurrent dislocation seen in the patient. No mandibular tremor, however, was
      observed in the present cases. The common feature of our two patients was
      retroflexion of the neck, which was assumed to make the suprahyoid muscles
      stretched and the mouth opened widely, causing the recurrent mandibular
      dislocation. Since the recurrence was prevented by chin cap, early chin cap
      therapy for the mandibular dislocation in parkinsonian patients is recommended.

PMID- 10586633
TI  - [A case of HTLV-I associated myelopathy presenting with cerebellar signs as
      initial and principal manifestations].
AB  - We reported a 75-year-old woman with HTLV-I associated myelopathy (HAM)
      presenting with cerebellar signs. She was admitted to our hospital because of
      walking unsteadiness, which initially appeared 3 years previously with gradual
      worsening. Neurological examination revealed limb and truncal ataxia, cerebellar
      type dysfunction of eye movement, pyramidal sign, diminished vibration sense and
      neurogenic bladder. Anti HTLV-I antibody titers in serum and CSF were markedly
      elevated. MRI revealed abnormal signals in cerebral white matter, mild cerebellar
      atrophy and thoracic cord atrophy. Cerebellar signs and symptoms were initial and
      main neurological manifestations in this patient, which were improved by steroid
      therapy. We considered this case was unique among HAM, because cerebellum was
      considered her main lesions.

PMID- 10586634
TI  - [A case of Behcet's disease presenting cerebral infarction due to occlusions of
      the bilateral internal carotid arteries].
AB  - This is a case report of a 41-year-old man with Behcet's disease who suffered
      from cerebral infarction due to complete occlusions of the bilateral internal
      carotid arteries. His illness began at age 23 with blurred vision of the right
      eye. The last few years he complained of recurrent painful ulcers on the mucosa
      or skin of the mouth and the external genitalia. In August 1998, he was admitted
      to our hospital in an acute confusional state with right hemiplegia. Head CT
      scans and MRIs revealed acute and subacute ischemic lesions in the left frontal
      lobe and some other regions of the bilateral hemispheres. Carotid angiography
      showed complete occlusions of the bilateral internal carotid arteries just
      rostral to the bifurcations. He did not have any histories of hypertension nor
      other risks for cerebrovascular diseases. Although direct evidence for the cause
      of carotid occlusions was not obtained, we speculated that his cervical lesions
      came from the arterial changes attributable to vasculo-Behcet's disease. Vascular
      involvements are not infrequent in Behcet's disease, but we believe such
      occlusive lesions in the bilateral internal carotid arteries as seen in our case
      are extremely rare. As a construction worker he had undergone a lot of mechanical
      stress on his neck, which might be a trigger for the carotid lesions.

PMID- 10586635
TI  - [A case of Bickerstaff's brainstem encephalitis which started with Wallenberg's
      syndrome].
AB  - A 54-year-old female developed dysarthria, left limb ataxia, and crossed
      dissociated sensory impairment, followed by external ophthalmoplegia, severe
      bulbar palsy and bilateral pyramidal tract involvement. A high titer of anti-GQ1b
      IgG antibody was detected in her serum. Brain MRI (T2 weighted image, diffusion
      weighted image) and peripheral nerve conduction study were normal. We diagnosed
      her as having Bickerstaff's brainstem encephalitis. In the past literature, we
      could not find any case of Bickerstaff's brainstem encephalitis showing crossed
      dissociated sensory impairment.

PMID- 10586636
TI  - [The pathophysiological mechanism of paroxysmal kinesigenic choreoathetosis].

PMID- 10586638
TI  - [In Process Citation]

PMID- 10586637
TI  - Neuroendocrine studies and antidepressant drug development.

PMID- 10586639
TI  - [Trends of commitment in the large cities. Developments and criteria of the
      emergency commitment].

PMID- 10586640
TI  - [In Process Citation]

PMID- 10586641
TI  - [In Process Citation]

PMID- 10586642
TI  - [In Process Citation]

PMID- 10586644
TI  - Progress on a potentially lethal disease.

PMID- 10586643
TI  - [Possibility of discharge and need for rehabilitation of psychiatric patients
      hospitalized for one year or more in Japan: a preliminary report. Committee on
      Rehabilitation Affairs, Subcommittee of Survey on Rehabilitation Need].
AB  - A total of 19,342 psychiatric patients staying in a total of 143 hospitals in
      Japan for one year or more entered in this study in order to determine the
      possibility of discharge (POD) and the need for rehabilitation. Those who were
      assessed by the psychiatrist in charge to have POD provided community support was
      assured accounted for 32.5%. As for the levels of daily life functions measured
      with the GAF score, those assessed to have POD showed the maximum frequency
      between scores 51 and 60, while the others, who were not considered suitable for
      discharge, showed the maximum frequency between scores 21 and 30. On the other
      hand, the control group, consisting of subjects with psychiatric disabilities and
      living in the community while using day care or rehabilitation facilities, showed
      the maximum frequency of GAF scores between 51 and 60. Two-thirds of the study
      subjects were older than fifty, while in the control group those aged between 30
      and 49 accounted for 49.0%, thus indicating that the residents of mental
      hospitals tend to be older. More than 60% of the study subjects had been staying
      in hospital for five years or more. Those without their own home accounted for
      about 60%.

PMID- 10586645
TI  - Child abuse reporting in South Dakota and the non-primary care provider.

PMID- 10586646
TI  - Get off the fence--vaccinate against varicella.

PMID- 10586647
TI  - An illustrative example of infant and child death review in South Dakota: "the
      1998 annual report of the Regional Infant and Child Mortality Review Committee".
AB  - Local, regional, or state infant and child death review teams provide an
      excellent mechanism for identifying risk factors for infant and childhood deaths
      along with establishing a conduit for effecting preventive measures to reduce the
      number of deaths in these particularly vulnerable age groups. In 1997, a
      predecessor of the current Regional Infant and Child Mortality Review Committee
      was established in Minnehaha County as South Dakota's first non-Indian review
      committee for infant and childhood deaths. The 1998 Review Committee's annual
      report to the public is presented in this paper as an illustration of what can be
      expected from such a committee along with the specific public health concerns
      identified and their potential remedies. Especially noted in the committee's 1998
      report is an alarming increase in Sudden Infant Death Syndrome (SIDS) death in
      the region and the educational role the Back to Sleep Campaign can play in the
      prevention of SIDS. The annual report serves as an example to illustrate how
      local review mechanisms can identify community strategies that may promote the
      health and well being of infants and children in their review areas.

PMID- 10586648
TI  - [Study on mechanism of environmental adaptation and tolerance in plants].

PMID- 10586649
TI  - [Acclimative response to temperature stress: overview].

PMID- 10586650
TI  - [Transduction of low-temperature signals in plants].

PMID- 10586651
TI  - [Low-temperature stress and biosynthesis of plant lipids].

PMID- 10586652
TI  - [Genetically engineered enhancement of cold tolerance in plants].

PMID- 10586653
TI  - [Regulatory mechanisms of the heat-shock response in plants].

PMID- 10586654
TI  - [Small heat shock proteins in cyanobacteria].

PMID- 10586655
TI  - [Plant response to drought and salt stress: overview].

PMID- 10586656
TI  - [Roles of drought-inducible genes in stress tolerance and signal transduction].

PMID- 10586657
TI  - [Drought-responsive gene expression and stress tolerance in plants].

PMID- 10586658
TI  - [Osmotic response of the yeast Saccharomyces cerevisiae].

PMID- 10586659
TI  - [Salinity tolerance and functions of compatible solubles].

PMID- 10586660
TI  - [Gene engineering of salt tolerance in higher plants].

PMID- 10586661
TI  - [Responses to active oxygens, strong and weak lights, an overview].

PMID- 10586662
TI  - [Gene regulation of active oxygen scavenging system and stress tolerance in
      plants].

PMID- 10586663
TI  - [Molecular mechanisms of the water-water cycle and other systems to circumvent
      photooxidative stress in plants].

PMID- 10586664
TI  - [Molecular engineering of plants with tolerance to photooxidative damage].

PMID- 10586665
TI  - [Molecular mechanisms of damage caused by air pollutants and protection against
      it].

PMID- 10586666
TI  - [Phytochrome and plant responses to low fluence light].

PMID- 10586667
TI  - [Environmental adaptation of nutritional metabolisms in plants: overview].

PMID- 10586668
TI  - [Molecular mechanisms of gene regulation by nitrogen availability in plants].

PMID- 10586669
TI  - [Functions of phosphate-responsible genes in plants].

PMID- 10586670
TI  - [Mechanisms of gene regulation by sulfur nutrition in higher plants].

PMID- 10586671
TI  - [Molecular regulation and engineering of sulfur transport and assimilation].

PMID- 10586672
TI  - [Gene expression induced by the deficiency of essential micro nutrients].

PMID- 10586673
TI  - [Perception of pathogen signals and gene-for-gene hypothesis].

PMID- 10586674
TI  - [Plant pathogens and mechanisms of defense responses].

PMID- 10586675
TI  - [Induction of hypersensitive cell death and defense gene expression by elicitors
      in higher plants].

PMID- 10586676
TI  - [Receptors for the microbial elicitors of plant defense responses].

PMID- 10586677
TI  - [Molecular mechanisms of plant disease resistance].

PMID- 10586678
TI  - [How do disease resistance genes function?].

PMID- 10586679
TI  - [Wound response in plants: overview].

PMID- 10586680
TI  - [Signal transduction of wound responses in plants].

PMID- 10586681
TI  - [Control of wound-responsive gene expression].

PMID- 10586682
TI  - [Wound-responsive protein kinases in plant].

PMID- 10586683
TI  - [Present status and future aspects on study of molecular mechanisms of animal
      physiological adaptation to the environment].

PMID- 10586684
TI  - [Transcriptional regulation of detoxication enzyme genes: overview].

PMID- 10586685
TI  - [Transcriptional regulation of the phase II drug detoxifying enzyme genes].

PMID- 10586686
TI  - [Regulatory mechanism of phase I drug-metabolizing enzymes].

PMID- 10586687
TI  - [Mechanisms of dioxin toxicity].

PMID- 10586688
TI  - [Electrophile counter-attack response].

PMID- 10586689
TI  - [Control of gene expression in response to stress by a transcription factor
      Pap1].

PMID- 10586690
TI  - [Oxy-stress response and its control mechanism: overview].

PMID- 10586691
TI  - [Biological response to oxidative stress and the signal transduction pathway of
      NF-kappa B].

PMID- 10586692
TI  - [Reactive oxygen intermediates, thioredoxin, and Ref-1 as effector molecules in
      cellular signal transduction].

PMID- 10586693
TI  - [Signal transduction pathways for activation of Src family protein tyrosine
      kinases in stress responses].

PMID- 10586694
TI  - [Transcriptional control of AP-1 by oxidative stress].

PMID- 10586695
TI  - [Regulatory mechanism of stress responses: overview].

PMID- 10586696
TI  - [Signalling pathways of heat shock response in higher eukaryotes].

PMID- 10586697
TI  - [Cellular response to endoplasmic reticulum stress mediated by unfolded protein
      response pathway].

PMID- 10586698
TI  - [Stress proteins in infections].

PMID- 10586699
TI  - [Molecular mechanisms of thermoregulation].

PMID- 10586700
TI  - [The regulation of cellular functions by molecular chaperones].

PMID- 10586701
TI  - [Overview: hypoxia].

PMID- 10586702
TI  - [Molecular mechanism of hypoxic response in animals].

PMID- 10586703
TI  - [Erythropoietin and hypoxia responsive system].

PMID- 10586704
TI  - [Cellular stress response to ischemia].

PMID- 10586705
TI  - [Response to environment and the failure leading to diseases: overview].

PMID- 10586706
TI  - [Endocrine disrupters].

PMID- 10586707
TI  - [Cell cycle and environmental factors].

PMID- 10586708
TI  - [The activation and function of p53 in cellular response to environmental
      stress].

PMID- 10586709
TI  - [Role of MAP kinases in stress response and diseases].

PMID- 10586710
TI  - [Ultraviolet radiation-mediated cellular response].

PMID- 10586711
TI  - [Establishment of antigen-specific IgE transgenic mice].

PMID- 10586712
TI  - [Chemical sensitivity].

PMID- 10586713
TI  - Osteoporosis: not for women only.

PMID- 10586714
TI  - Setting a steady course for benign essential tremor.

PMID- 10586715
TI  - Staying active despite chronic lung disease.

PMID- 10586716
TI  - When chest pain isn't a sign of a heart attack.

PMID- 10586718
TI  - Why do fingernails split at the tips and what can be done to correct it?

PMID- 10586717
TI  - Puzzling postmenopausal bleeding.

PMID- 10586719
TI  - Are there ways to minimize the sexual side effects of antidepressants?

PMID- 10586720
TI  - Controlling a whooping cough outbreak.
AB  - Data gathered during a whooping cough (or pertussis) outbreak in the northern
      Coromandel in 1995 highlights some distinct characteristics about how the disease
      manifests itself in a defined geographical area.

PMID- 10586721
TI  - Integrating services to improve health.

PMID- 10586722
TI  - Realising a nursing dream.
AB  - Establishing a community nursing service for Pacific Island families in
      Christchurch has not been without problems. But the project has been an undoubted
      success.

PMID- 10586723
TI  - Practice nurses need to adapt.
AB  - Nurses working in union and community health clinics have pioneered the
      development of the independent nurse practitioner role. One of those pioneers
      offers her views on future directions for practice nurses.

PMID- 10586724
TI  - Primary care: differences and similarities.
AB  - A group of health professionals from the United Kingdom visited New Zealand
      earlier this year. A nurse in the group shares her impressions.

PMID- 10586725
TI  - The virtues of nursing.
AB  - Nursing is a practice of caring. But what and who is nursing for and what type of
      virtues characterise the practice of nursing? The parable of the-Good Samaritan
      provides some answers.

PMID- 10586726
TI  - Practice nurse accreditation pilot completed.
AB  - After a three-year pilot project and some minor changes, the new practice nurse
      accreditation model has been endorsed as the model for all NZNO sections.

PMID- 10586727
TI  - In the forefront of change. Interview by Anne Manchester.

PMID- 10586728
TI  - Coping with night shift.
AB  - Working night shifts can adversely affect the performance and health of nurses,
      both in the short and long term. The key to improving conditions for workers lies
      with management.

PMID- 10586729
TI  - Two hospitals report: the pros and cons of 12-hour shifts.
AB  - Earlier last year, paediatric nurses and delivery suite midwives at two North
      Island hospitals took part in six-month trials working 12-hour shifts. In both
      cases the trials were successful and have resulted in a decision by staff to
      continue working longer hours. Staff at both hospitals report on the trials and
      the introduction of 12-hour shifts in their areas.

PMID- 10586730
TI  - Sharing the Canadian experience. Interview by Anne Manchester.

PMID- 10586731
TI  - On the road with an organiser. Interview by Anne Manchester.

PMID- 10586732
TI  - High dropout rate a concern.

PMID- 10586733
TI  - From student to registered nurse.

PMID- 10586734
TI  - Bullying--a problem for nurses?

PMID- 10586735
TI  - Coping with horizontal violence.

PMID- 10586736
TI  - Getting politically active.

PMID- 10586737
TI  - Community nursing under the spotlight.

PMID- 10586738
TI  - Super clinics offer new culture of care.

PMID- 10586739
TI  - Combating meningococcal disease.
AB  - A thorough knowledge of the community and its networks are essential tools for a
      public health nurse following up contacts of someone infected with meningococcal
      disease.

PMID- 10586740
TI  - Oxygen therapy: challenges for nurses.
AB  - Long-term oxygen therapy can be effective for people suffering chronic
      obstructive pulmonary disease. How can nurses best meet the physical and
      psychological needs of those needing this therapy?

PMID- 10586741
TI  - Partners in the community.
AB  - TO MARK this year's International Nurses' Day and the theme chosen by the
      International Council of Nurses (ICN)--Partnership for Community Health--Kai
      Tiaki Nursing New Zealand profiles ten nurses who work hand-in-hand with their
      communities. Our search for suitable people took us from Auckland to Queenstown,
      from small rural settings to large metropolitan areas. Our final selection
      presents two Plunket nurses, a district nurse, a diabetes nurse specialist, a
      community midwife, an oncology nurse specialist, a caregiver, a practice nurse, a
      mental health nurse and a rural emergency nurse practitioner.

PMID- 10586742
TI  - Working with communities for health.
AB  - Nurses must continue to build links with communities to enable communities to
      control their own health outcomes.

PMID- 10586743
TI  - Closing the health gap.

PMID- 10586744
TI  - Getting the formula right.
AB  - One of the oldest and largest iwi health providers in the country, Te Oranganui
      Iwi Health Authority seeks to empower people to take responsibility for their own
      health.

PMID- 10586745
TI  - Many factors affect children's health.
AB  - A health strategy for children which concentrates only on the health sector will
      not serve our children well.

PMID- 10586746
TI  - Family-centred care in practice.
AB  - Helping parents and carers participate in the care of their child in hospital is
      the aim of a new model of family-centred care at Dunedin Hospital.

PMID- 10586747
TI  - Nurses' role in Maori health.
AB  - Maori nurses have a pivotal role to play in improving Maori health and the Health
      Funding Authority wants to make sure they're in a position to do so.

PMID- 10586748
TI  - Report of major significance for nurses.

PMID- 10586749
TI  - Nurses have rights too.
AB  - Nurses in their professional role are proud to serve others. But they have rights
      which should be respected.

PMID- 10586750
TI  - Breaking down barriers to knowledge.
AB  - While the Ministry of Health accepts that both health providers and consumers
      need good health information, no-one seems to be taking responsibility for
      ensuring nurses have fair and easy access to information services.

PMID- 10586751
TI  - Clarity needed on standing orders.

PMID- 10586752
TI  - Nurses gain right to prescribe.

PMID- 10586753
TI  - Finding the way to nursing knowledge.

PMID- 10586754
TI  - Proving the competence of nurses.
AB  - Registration in itself is no guarantee that a nurse is competent to practise. A
      system of competence-based pracitising certificates linked with registration
      would raise the professionalism of nursing and assure the public it was receiving
      competent, safe nursing care.

PMID- 10586755
TI  - Preparing students for a nursing career.
AB  - Undergraduate education of nursing students has often been the target of
      criticism. One polytechnic nursing tutor shares the challenges of her working
      life.

PMID- 10586756
TI  - Where to for nursing education and practice?

PMID- 10586757
TI  - An education dream realised.

PMID- 10586758
TI  - Advancing the skills of rural nurses.

PMID- 10586759
TI  - Working with unregulated caregivers.

PMID- 10586760
TI  - Knowing how to care for the dying.

PMID- 10586761
TI  - Caring for the dying.
AB  - To provide the best possible care to dying patients, nurses must attend to their
      physical, emotional and spiritual needs. Nurses must also be aware of their own
      feelings towards death and dying.

PMID- 10586762
TI  - Taking i.v. therapy into the community.

PMID- 10586763
TI  - Meeting Len's spiritual need.

PMID- 10586764
TI  - Examining holistic health care.

PMID- 10586765
TI  - The right to die: a case for reform.
AB  - The debate over patients' right to die is a complex one. Here one nurse looks at
      the statutory requirements and ethical considerations and makes a case for the
      development of living wills.

PMID- 10586766
TI  - Caring after miscarriage.

PMID- 10586767
TI  - Preparing for the professional future.

PMID- 10586768
TI  - Important decision for workers.

PMID- 10586769
TI  - Positive changes proposed in the field of resuscitation provision and training.

PMID- 10586770
TI  - Bringing education and practice closer.

PMID- 10586771
TI  - Improving pulmonary disease outcomes.

PMID- 10586772
TI  - Developing a new model of integrated care.
AB  - A proposed model of nursing care attempts to break out of the straitjacket of
      providing health care within current service structures. A family nursing
      practitioner would play a key role in integrating health care for families across
      traditional health service boundaries.

PMID- 10586773
TI  - How an integrative nursing practice model might work.

PMID- 10586774
TI  - Defining the advanced nurse practitioner.

PMID- 10586775
TI  - Contracting out nursing services.

PMID- 10586776
TI  - Ensuring consent is informed.

PMID- 10586777
TI  - Helping nurses overcome addiction.

PMID- 10586778
TI  - The challenges of phantom pain.

PMID- 10586779
TI  - Removing the toll bridge to compulsory treatment.
AB  - The Mental Health Act 1992 requires that an application for compulsory assessment
      is accompanied by a medical certificate. This requirement has placed nurses and
      proposed patients at risk.

PMID- 10586780
TI  - Government promotes health care rationing.

PMID- 10586781
TI  - Protecting members and promoting safety.
AB  - NZNO has been involved in some major investigations into public health services
      over the last three years. There have been many lessons for the organisation and
      its members.

PMID- 10586782
TI  - The pitfalls of verbal medication orders.

PMID- 10586783
TI  - Challenging the idealogy of the new right.

PMID- 10586784
TI  - Reducing professional liability.

PMID- 10586785
TI  - Supporting nurses with disabilities.

PMID- 10586786
TI  - Deciding who is a competent midwife.

PMID- 10586787
TI  - Nursing under pressure.

PMID- 10586788
TI  - Coping with stress on the job.

PMID- 10586789
TI  - Nursing care in leech therapy.

PMID- 10586790
TI  - Caring for a patient having leech therapy.

PMID- 10586791
TI  - A question of aging.

PMID- 10586792
TI  - What's ahead for nursing?

PMID- 10586793
TI  - Taking time to reflect.

PMID- 10586794
TI  - Delegates to look at poverty and health.

PMID- 10586795
TI  - Establishing a neonatal outreach service.

PMID- 10586796
TI  - Reaching out to babies and their families.

PMID- 10586797
TI  - Has nursing education lost its way?

PMID- 10586798
TI  - Clinical career pathways: where are we at?

PMID- 10586799
TI  - Nursing in poverty-stricken China.

PMID- 10586801
TI  - Coping with 'critical incidents'.

PMID- 10586800
TI  - Making a difference in Afghanistan.

PMID- 10586802
TI  - Nursing education to be reviewed.

PMID- 10586803
TI  - Rising costs place pressure on students.

PMID- 10586804
TI  - Bridging the theory-practice gap.
AB  - In New Zealand, there is a festering debate over a "theory-practice gap" in
      nursing. Joint appointments may be a potential solution to this issue. Joint
      appointments refer to a variety of arrangements whereby concurrent employment
      occurs within an educational institution and a clinical setting. Advantages for
      the appointees include job satisfaction and professional growth. Clinical
      credibility for nurse educators enables improved facilitation of student
      learning. In clinical areas, benefits in patient care are associated with the
      marrying of academic rigour with clinical practice. Some appointees assist with
      staff development, act as consultants on nursing issues and undertake research.
      Disadvantages in the concept focus on role conflict, i.e. incongruity between the
      roles and role ambiguity, i.e. lack of clarity concerning expectations. Success
      depends upon the personal attributes of appointees; realistic expectations;
      flexibility to allow the concept to evolve; and support from colleagues and
      management. This research describes a case study of a joint appointment between a
      nurse lecturer and a staff nurse in an acute forensic psychiatry unit.
      Advantages, disadvantages and reasons for success are discussed in relation to
      the literature findings. (See p15-15) The discussion focuses on the need to
      develop research methodology to further clarify potential benefits and
      advantages.

PMID- 10586805
TI  - Case study of a joint appointment.

PMID- 10586806
TI  - A new threat to nurse staffing levels?

PMID- 10586807
TI  - Valuing gerontology nursing.
AB  - It is time the specialist skills required in gerontology nursing were recognised:
      they have been underrated and undervalued for too long. This and the following
      article mark 1999 as the International Year of Older Persons.

PMID- 10586808
TI  - Choosing gerontology as a career.

PMID- 10586809
TI  - Whither nursing in the 21st century?
AB  - There is no doubt that the role of the nurse in New Zealand will continue to
      evolve. Developments in the US where clinical nurse specialists and advanced
      nurse practitioners are taking on roles and responsibilities that in New Zealand
      are undertaken by other health professionals, mainly medical, will ultimately
      permeate the New Zealand health care system. Today the nurse practitioner has a
      greater degree of professional independence than at any time in the history of
      the profession, and, if the recommendations of the taskforce are accepted and
      nurse prescribing eventuates, the nurse will have even greater independence and
      autonomy. With this increased professional independence comes a greater emphasis
      on the responsibilities of the nurse and professional accountability. The
      acceptance of greater responsibility will inevitably result in a proliferation of
      nurse "specialists". Postgraduate programmes must be established with carefully
      planned curricula to accommodate the requirements of these nurse specialists.
      Planning, content and design of these programmes must come from nurses in
      consultation with the Nursing Council, the Ministries of Health and Education,
      and health agencies. The functioning of the human species within their
      environment, in both wellness and illness, can only be adequately explained or
      explored with a sound knowledge of biological systems. It is for this reason that
      the study of biological sciences must be undertaken by nursing students to
      prepare them for the advanced role they are likely to play in the health care
      system of the 21st century.

PMID- 10586810
TI  - Setting professional goals.

PMID- 10586811
TI  - Making sure best practice guidelines are used.

PMID- 10586812
TI  - Enhancing patient care through computers.

PMID- 10586813
TI  - New act heralds radical change.

PMID- 10586814
TI  - Celebrating nursing history.

PMID- 10586815
TI  - Are you prepared to leave the 20th century?

PMID- 10586816
TI  - Modelling partnership in midwifery practice.

PMID- 10586817
TI  - A case for nurse prescribing.

PMID- 10586818
TI  - Advancing nursing practice.

PMID- 10586819
TI  - Sharing skills in the Pacific. Interview by Anne Manchester.

PMID- 10586820
TI  - Creating new nursing models.

PMID- 10586821
TI  - When is nursing care not nursing care?

PMID- 10586822
TI  - Making family-centred care a reality.
AB  - The role of families in caring for their sick children has evolved over the last
      century. Where once they were banned from hospitals, families now play an
      integral part in the care of their children, whether in hospital or at home.

PMID- 10586823
TI  - Nursing council's proposals under fire.

PMID- 10586824
TI  - Meeting student health needs.

PMID- 10586825
TI  - Choosing NZNO's indemnity cover.
AB  - NZNO's professional indemnity insurance ensures members get comprehensive cover
      to defend accusations or claims made against them about their practice. These
      pages contain valuable information and can be removed for display on workplace
      noticeboards.

PMID- 10586826
TI  - Dealing with the police.

PMID- 10586827
TI  - Funding essential health services.

PMID- 10586828
TI  - Magnesium for the next millennium.
AB  - BACKGROUND: Magnesium is a trace mineral in several hundred chemical reactions in
      the body. It has therapeutic potential in many medical conditions. In this
      review, we attempted to clarify the current information on the role of magnesium
      as a therapeutic agent. METHODS: A MEDLINE search from 1966 through March 1999
      was conducted, using PubMed and "Magnesium" and "Therapeutic Usage" as the two
      initial key headings. Important articles were also identified from the
      bibliographies of the initial articles. RESULTS: A total of 51 articles were
      included in this review. Articles were excluded if they were based on animal
      study or were in a language other than English. CONCLUSION: Magnesium has long
      been used as an ingredient in laxatives and antacids. It seems clear that
      intravenous magnesium also is effective for the suppression of ventricular ectopy
      in the hospital setting and is a first-line agent for torsades de pointes. It is
      less clear whether it is useful in patients with congestive heart failure or
      acute myocardial infarction (MI). Although effective for treatment of
      preeclampsia/eclampsia, its use in the termination of preterm labor has recently
      been questioned. In asthma and chronic lung disease, intravenous magnesium may be
      useful when conventional treatment has failed. Finally, magnesium may have a role
      in the prevention and treatment of vascular headaches.

PMID- 10586829
TI  - Employee Retirement Income Security Act and managed care: current issues and
      their impact on medical practice.
AB  - BACKGROUND: Managed care organizations (MCOs) routinely make decisions regarding
      utilization of health services, with an expectation of protection from liability
      through the Employee Retirement Income Security Act of 1974 (ERISA). An MCO
      decision to deny services to a patient may expose the physician to liability,
      while ERISA often shields the MCO from liability. A recent United States Supreme
      Court decision, New York State Conference of Blue Cross and Blue Shield Plans v
      Travelers, as well as legislation on the state and federal levels, may resolve
      this area of friction between physicians and MCOs. METHODS: We reviewed federal
      and state laws, as well as relevant case law and legal commentaries. RESULTS: The
      Travelers decision raised the threshold for ERISA preemption, decreasing the
      protection once afforded to MCOs. The American Medical Association, many state
      legislatures, and some members of Congress have recognized ERISA preemption and
      its protection of MCOs as a source of potential risk to patient care and
      increased liability for physicians. CONCLUSION: The problems created by the
      interaction of ERISA and managed care appear headed for a legislative resolution
      on the federal and state levels. This will significantly affect the interaction
      of MCOs with patients and physicians.

PMID- 10586830
TI  - Changing role of radiotherapy in the management of cancer of the esophagus.
AB  - BACKGROUND: Cancer of the esophagus remains a highly lethal disease, but new
      treatment approaches that build onto traditional surgical and radiotherapeutic
      methods are making an impact on organ preservation while offering hope for
      improved survival. METHODS: Reviewed here are recent data from trials on the use
      of new radiotherapeutic approaches. RESULTS: There is clinical trial evidence for
      improved treatment results with radiotherapy and concurrent systemic
      chemotherapy. For some patients with responsive cancers, the use of
      chemoradiation results in about 25% being cured-a marked departure from the
      results of treatment with radiotherapy alone in the preceding decades. This idea
      is being explored further with new trials using advanced radiotherapy treatment
      planning systems called "conformal therapy," in which the high irradiation dose
      envelope is designed to fit tightly around the cancer. CONCLUSIONS: Cancer of the
      esophagus can now be treated aggressively with chemoradiation to offer a choice
      for local symptom control, organ preservation, and cure.

PMID- 10586831
TI  - Physician participation and nonparticipation in Medicaid managed care: the
      TennCare experience.
AB  - BACKGROUND: TennCare is a significant state health reform effort, channeling all
      Medicaid recipients into managed care. We examined physician attitudes about
      TennCare. METHODS: In 1997, we surveyed a stratified random sample of Tennessee
      physicians using predominantly Likert-type scale questions. All physicians
      surveyed were involved in patient care and were selected from seven specialties:
      general practice, family practice, general internal medicine,
      obstetrics/gynecology, neurosurgery, general surgery, and pediatrics. We asked
      about participation, satisfaction, perceptions of quality, and appropriateness of
      care. RESULTS: Major reasons for nonparticipation included bureaucracy and low
      compensation. Overall, dissatisfaction with TennCare was high (72% not at all or
      not very satisfied), relating to reimbursement issues and constraints on
      obtaining services, particularly pharmaceuticals. More physicians (45.9%) thought
      quality had declined under TennCare than believed it improved (12.6%).
      CONCLUSIONS: Despite strong negative opinions about TennCare, physician
      participation is high (85.6%) because of a sense of professional responsibility.

PMID- 10586832
TI  - Moraxella catarrhalis bacteremia: a 10-year experience.
AB  - BACKGROUND: Moraxella catarrhalis commonly inhabits the upper respiratory tract
      and is a cause of acute otitis media and sinusitis in children. It is an
      infrequent cause of invasive disease. METHODS: We reviewed records of all
      patients with positive blood cultures for M catarrhalis admitted to our hospital
      during the 10-year period (1988 through 1997). RESULTS: Eleven cases were
      identified. Age range was 11 to 32 months. Four (44%) had risk factors for
      infection, including sickle cell disease (2), acquired immunodeficiency syndrome
      (AIDS) (1), and leukopenia (1). Upper respiratory symptoms and fever were present
      in all patients. Ten had acute otitis media, five had sinusitis, and three had
      pneumonia. All isolates were beta-lactamase producers. Treatment included
      intravenous cefuroxime (8), cefotaxime (2), and ceftazidime (1), followed by oral
      amoxicillin/clavulanate or cefuroxime axetil. CONCLUSION: Moraxella catarrhalis
      bacteremia should be considered in febrile young children with upper respiratory
      infections and/or acute otitis media especially in those with underlying immune
      dysfunction.

PMID- 10586833
TI  - Epidural analgesia provided during labor by obstetricians: outcome analysis.
AB  - BACKGROUND: Epidural analgesic has been given during labor by attending
      obstetricians at Minden Medical Center since 1976. This outcome analysis was done
      to determine the frequency, effectiveness, and complications of epidural
      analgesia from January 1, 1993 through December 31, 1995. METHODS: Each of the
      1,851 obstetric patient charts for the 3-year period was reviewed
      retrospectively. RESULTS: Among the 1,704 patients who had labor, 1,565 (91.8%)
      received epidural analgesia. Epidural analgesia was effective for adequate pain
      relief in 1,484 patients (94.8%). Hypotension was treated by ephedrine in 24
      patients (1.53%). Subarachnoid puncture necessitating a blood patch for treatment
      of postural headache occurred in 4 patients (0.26%), and unexpected spinal
      anesthesia occurred in 3 patients (0.19%). A high level of analgesia, above the
      T5 dermatome, occurred in 16 patients (1.02%). CONCLUSION: Obstetricians at this
      hospital provided epidural analgesia for a high percentage (91.8%) of patients in
      labor. Adequate pain relief was obtained in 94.8% of the patients who received
      epidural analgesia. No serious complications occurred.

PMID- 10586834
TI  - Posttransplantation lymphoproliferative disease in children: otolaryngologic
      manifestations and management.
AB  - BACKGROUND: Posttransplantation lymphoproliferative disease (PTLD) is associated
      with Epstein-Barr virus (EBV) infection after solid organ and bone marrow
      transplantation. METHODS: We did a retrospective analysis of cases with a
      diagnosis of PTLD at Children's Hospital of Wisconsin. RESULTS: Ten patients were
      identified. Seven of 10 cases (70%) were associated with bone marrow
      transplantation and 3 with solid organ transplantation. Three patients (30%) died
      of PTLD. The average time to development of PTLD after transplantation was 120
      days. CONCLUSIONS: Otolaryngologic symptoms and findings are often the first
      manifestations of PTLD. Associated findings in this series included tonsillar
      necrosis, tonsillitis, airway obstruction, lymphadenitis, sinusitis, and otitis
      media. Diagnosis generally requires pathologic evaluation of tonsillar or adenoid
      tissue. Surgical intervention may also be important for relief of airway
      obstruction when present. Prompt recognition, diagnosis, and intervention with
      reduction in immunosuppression and antiviral therapy are essential to reduce the
      mortality of PTLD.

PMID- 10586835
TI  - Firearm ownership among female physicians in the United States.
AB  - BACKGROUND: Physicians have been called upon to counsel patients about firearm
      safety, but the personal prevalence of firearm ownership among physicians is
      poorly established. METHODS: We examined responses to the question "Do you keep a
      gun/firearm in your home?" from the Women Physicians' Health Study, a nationally
      representative survey of US female physicians (n = 4,501). RESULTS: Among female
      physicians, 16.5% reported having a firearm in their homes. Those who were older,
      married, practicing in a rural region, and residing in the South Central or
      Mountain states were more likely to report having a firearm in the home.
      Emergency medicine specialists, Protestants, physicians reporting a history of
      depression, and those on call more than six times per month were also more likely
      to report keeping a firearm in their home. Female physicians residing on the East
      Coast, Hindus, and Jews were least likely to report keeping a firearm in the
      home. CONCLUSIONS: In the United States, the proportion of female physicians who
      report having a firearm in the home was about half that reported by other women
      and one third that reported by men. This observation may have important
      implications for encouraging female physicians to counsel their patients about
      firearm ownership and storage.

PMID- 10586836
TI  - Is 24-hour observation necessary after elective laparoscopic cholecystectomy?
AB  - BACKGROUND: Laparoscopic cholecystectomy is now the procedure of choice for
      symptomatic gallbladder disease. The procedure can be done safely and cost
      effectively on an outpatient basis, either as same-day surgery or with 24-hour
      observation. METHODS: This report represents a retrospective chart review of 60
      patients having elective laparoscopic cholecystectomy. A comparison was made
      between same-day surgery and 24-hour observation. RESULTS: Of the 60 elective
      cases, 33 were done as a same-day procedure, and 27 were followed by 24-hour
      observation. There were no major complications and no return visits to the
      emergency room (ER) or hospital in either group. The average cost of same-day
      surgery was $4,940, and the average cost for 24-hour observation was $6,118.
      CONCLUSIONS: We found no advantage to routinely keeping patients for 24-hour
      observation. Elective laparoscopic cholecystectomy as same-day surgery is safe
      and cost effective.

PMID- 10586837
TI  - Acute renal insufficiency due to oral acyclovir in a man with sickle cell trait.
AB  - Several published reports have suggested that oral acyclovir can cause renal
      insufficiency, but baseline renal function was either abnormal or unclear in
      those reports. We describe a patient with oral acyclovir-induced acute renal
      failure and a normal serum creatinine level documented just before exposure to
      the drug. Conceivably, competition with a cephalosporin for renal tubular
      elimination predisposed our patient to nephrotoxic serum levels of acyclovir. In
      addition, the patient had sickle cell trait, which might have contributed to a
      disproportionate degree of hyperkalemia and acidosis seen early in the patient's
      clinical course.

PMID- 10586838
TI  - Acute hepatitis after ingestion of herbs.
AB  - Herbal preparations are marketed as natural and safe alternatives to conventional
      medicines for the prevention and treatment of a variety of ailments. However,
      consumers may not be fully aware of their potential side effects. We report two
      cases of acute hepatitis after the ingestion of herbal preparations. One of the
      mixtures included chaparral and bee pollen; the other was pure bee pollen.
      Chaparral has been reported to have similar effects in other patients, but we
      found no reports of acute hepatitis from bee pollen. We discuss chaparral and
      several other hepatotoxic herbs and review the literature. Our case reports
      remind primary care physicians to ask their patients about herbal use and discuss
      their potential toxicities.

PMID- 10586839
TI  - Bivalve polymicrobial infective endocarditis.
AB  - Polymicrobial infective endocarditis is uncommon, particularly vancomycin
      resistant endocarditis and fugal endocarditis. The incidence of these infections
      is likely to. increase with advances in mediCAl technology and widespread use of
      central venous catheters. We report a case of bivalve endocarditis in which four
      organisms were identified, including vancomycin-resistant Enteroocausfaecium and
      Torulopsis glabrata.

PMID- 10586840
TI  - Hydrochlorothiazide-induced pulmonary edema.
AB  - A 46-year-old woman had features of acute pulmonary edema soon after taking
      hydrochlorothiazide (HCTZ) for the first time. Although 31 cases of HCTZ-induced
      pulmonary edema have been reported in the world literature since it was first
      described in 1968, little is known about this clinical entity. Because its
      presence may be underestimated or underreported, it must be considered in the
      differential diagnosis in any case of pulmonary edema in a patient taking HCTZ.
      It is important to review the pathophysiology and management of this rare but
      potentially life-threatening idiosyncratic reaction to a commonly prescribed
      drug.

PMID- 10586841
TI  - CA-125 tumor-associated antigen in a patient with tuberculous peritonitis.
AB  - A 64-year-old woman with a history of chronic hepatitis B had abdominal pain and
      ascites, a serum albumin ascitic gradient (SAAG) of 0.8, and an elevated serum CA
      125 value. Exploratory laparotomy revealed ascites and obliteration of the
      abdominal cavity by advanced adhesive disease consistent with carcinomatosis.
      Surgical biopsy revealed noncaseating granulomas. She responded well to
      antituberculous therapy and is presently asymptomatic.

PMID- 10586842
TI  - Neurologic disease presenting as chronic pelvic pain.
AB  - Neurologic disease as a cause of chronic pelvic pain may be more common than
      previously reported. We report three cases wherein patients with complaints of
      pelvic pain were subsequently found to have neurologic disease involving the
      lumbosacral spine. In all three cases, the presenting features were complaints of
      cyclic or noncyclic lower abdominal pain attributed to endometriosis, pelvic
      inflammatory disease, or uterine fibroids. When conventional therapies failed to
      resolve the pain, magnetic resonance imaging (MRI) of the lumbosacral spine
      showed a neoplasm in one patient and disk herniation in two patients. Evolving
      lumbar disk disease or intradural neoplasms in the upper lumbar area can produce
      symptoms interpreted as pelvic pain. Symptoms consistent with radiculopathy
      occurred late in the course of each of the three cases reported.

PMID- 10586843
TI  - Chest wall ectopic synovial bursa cyst.
AB  - We report an unusual case of chest wall tumor in a 27-year-old patient. A
      complete resection was accomplished, and the patient had an excellent
      postoperative course. Histologically, the mass was confirmed to be an ectopic
      synovial bursa cyst. Although rare, synovial cysts should be considered in any
      case of a fluctuating chest wall mass. We also discuss the etiology and
      diagnostic approach of cystic masses of the chest wall.

PMID- 10586844
TI  - Patient management algorithm.

PMID- 10586845
TI  - Alendronate.

PMID- 10586846
TI  - Raloxifene.

PMID- 10586847
TI  - Hormonal replacement therapy.

PMID- 10586848
TI  - Calcitonin, vitamin D, and calcium.

PMID- 10586849
TI  - Iatrogenic osteoporosis.

PMID- 10586850
TI  - Seedless in Seattle?

PMID- 10586851
TI  - A bioethics dilemma for Germany.

PMID- 10586852
TI  - German bioethics inquiry 'could hold up essential rule changes'.

PMID- 10586853
TI  - 'It's a G': the one-billionth nucleotide.

PMID- 10586855
TI  - Science lobby 'ecstatic' after triumph in NIH budget battle.

PMID- 10586854
TI  - Concern at cheap AIDS drug fears.

PMID- 10586856
TI  - Hughes institute unveils top team.

PMID- 10586857
TI  - Genentech pays $200m over growth hormone 'theft'.

PMID- 10586858
TI  - Access issues may determine whether agri-biotech will help the world's poor.

PMID- 10586859
TI  - India intends to reap the full commercial benefits.

PMID- 10586860
TI  - Smugglers aim to circumvent GM court ban in Brazil.

PMID- 10586861
TI  - Academies link to map scientific priorities for meeting real needs.

PMID- 10586862
TI  - Promoting a standard nomenclature for genes and proteins.

PMID- 10586863
TI  - Sequencing challenge.

PMID- 10586864
TI  - What's in a name?

PMID- 10586865
TI  - Precautionary approach to risk assessment.

PMID- 10586866
TI  - Two millennia of animal spirits.

PMID- 10586867
TI  - The family tree flowers.

PMID- 10586868
TI  - Clouds from near and far.

PMID- 10586869
TI  - What do yeast proteins do?

PMID- 10586870
TI  - Phylogenomics. Ancestral primate viewed.

PMID- 10586871
TI  - Charles M. Steinberg (1932-99)

PMID- 10586872
TI  - A universal marker for transgenic insects.

PMID- 10586873
TI  - Ubiquitin tag for sperm mitochondria.

PMID- 10586874
TI  - Active site-directed protein regulation.
AB  - Regulation of protein function is vital for the control of cellular processes.
      Proteins are often regulated by allosteric mechanisms, in which effectors bind to
      regulatory sites distinct from the active sites and alter protein function.
      Intrasteric regulation, directed at the active site and thus the counterpart of
      allosteric control, is now emerging as an important regulatory mechanism.

PMID- 10586875
TI  - Structure of fumarate reductase from Wolinella succinogenes at 2.2 A resolution.
AB  - Fumarate reductase couples the reduction of fumarate to succinate to the
      oxidation of quinol to quinone, in a reaction opposite to that catalysed by the
      related complex II of the respiratory chain (succinate dehydrogenase). Here we
      describe the crystal structure at 2.2 A resolution of the three protein subunits
      containing fumarate reductase from the anaerobic bacterium Wolinella
      succinogenes. Subunit A contains the site of fumarate reduction and a covalently
      bound flavin adenine dinucleotide prosthetic group. Subunit B contains three iron
      sulphur centres. The menaquinol-oxidizing subunit C consists of five membrane
      spanning, primarily helical segments and binds two haem b molecules. On the basis
      of the structure, we propose a pathway of electron transfer from the dihaem
      cytochrome b to the site of fumarate reduction and a mechanism of fumarate
      reduction. The relative orientations of the soluble and membrane-embedded
      subunits of succinate:quinone oxidoreductases appear to be unique.

PMID- 10586876
TI  - Discovery of molecular hydrogen in a high-velocity cloud of the Galactic halo.
AB  - The Milky Way's halo contains clouds of neutral hydrogen with high radial
      velocities which do not follow the general rotational motion of the Galaxy. Few
      distances to these high-velocity clouds are known, so even gross properties such
      as total mass are hard to determine. As a consequence, there is no generally
      accepted theory regarding their origin. One idea is that they result from gas
      that has cooled after being ejected from the Galaxy through fountain-like flows
      powered by supernovae; another is that they are composed of gas, poor in heavy
      elements, which is falling onto the disk of the Milky Way from intergalactic
      space. The presence of molecular hydrogen, whose formation generally requires the
      presence of dust (and therefore gas, enriched in heavy elements), could help to
      distinguish between these possibilities. Here we report the discovery of
      molecular hydrogen absorption in a high-velocity cloud along the line of sight to
      the Large Magellanic Cloud. We also derive for the same cloud an iron abundance
      which is half of the solar value. From these data, we conclude that gas in this
      cloud originated in the disk of the Milky Way.

PMID- 10586877
TI  - Accretion of low-metallicity gas by the Milky Way.
AB  - Models of the chemical evolution of the Milky Way suggest that the observed
      abundances of elements heavier than helium ('metals') require a continuous infall
      of gas with metallicity (metal abundance) about 0.1 times the solar value. An
      infall rate integrated over the entire disk of the Milky Way of approximately 1
      solar mass per year can solve the 'G-dwarf problem'--the observational fact that
      the metallicities of most long-lived stars near the Sun lie in a relatively
      narrow range. This infall dilutes the enrichment arising from the production of
      heavy elements in stars, and thereby prevents the metallicity of the interstellar
      medium from increasing steadily with time. However, in other spiral galaxies, the
      low-metallicity gas needed to provide this infall has been observed only in
      associated dwarf galaxies and in the extreme outer disk of the Milky Way. In the
      distant Universe, low-metallicity hydrogen clouds (known as 'damped Ly alpha
      absorbers') are sometimes seen near galaxies. Here we report a metallicity of
      0.09 times solar for a massive cloud that is falling into the disk of the Milky
      Way. The mass flow associated with this cloud represents an infall per unit area
      of about the theoretically expected rate, and approximately 0.1-0.2 times the
      amount required for the whole Galaxy.

PMID- 10586878
TI  - Angiosperm phylogeny inferred from multiple genes as a tool for comparative
      biology.
AB  - Comparative biology requires a firm phylogenetic foundation to uncover and
      understand patterns of diversification and evaluate hypotheses of the processes
      responsible for these patterns. In the angiosperms, studies of diversification in
      floral form, stamen organization, reproductive biology, photosynthetic pathway,
      nitrogen-fixing symbioses and life histories have relied on either explicit or
      implied phylogenetic trees. Furthermore, to understand the evolution of specific
      genes and gene families, evaluate the extent of conservation of plant genomes and
      make proper sense of the huge volume of molecular genetic data available for
      model organisms such as Arabidopsis, Antirrhinum, maize, rice and wheat, a
      phylogenetic perspective is necessary. Here we report the results of parsimony
      analyses of DNA sequences of the plastid genes rbcL and atpB and the nuclear 18S
      rDNA for 560 species of angiosperms and seven non-flowering seed plants and show
      a well-resolved and well-supported phylogenetic tree for the angiosperms for use
      in comparative biology.

PMID- 10586879
TI  - The earliest angiosperms: evidence from mitochondrial, plastid and nuclear
      genomes.
AB  - Angiosperms have dominated the Earth's vegetation since the mid-Cretaceous (90
      million years ago), providing much of our food, fibre, medicine and timber, yet
      their origin and early evolution have remained enigmatic for over a century. One
      part of the enigma lies in the difficulty of identifying the earliest
      angiosperms; the other involves the uncertainty regarding the sister group of
      angiosperms among extant and fossil gymnosperms. Here we report a phylogenetic
      analysis of DNA sequences of five mitochondrial, plastid and nuclear genes (total
      aligned length 8,733 base pairs), from all basal angiosperm and gymnosperm
      lineages (105 species, 103 genera and 63 families). Our study demonstrates that
      Amborella, Nymphaeales and Illiciales-Trimeniaceae-Austrobaileya represent the
      first stage of angiosperm evolution, with Amborella being sister to all other
      angiosperms. We also show that Gnetales are related to the conifers and are not
      sister to the angiosperms, thus refuting the Anthophyte Hypothesis. These results
      have far-reaching implications for our understanding of diversification,
      adaptation, genome evolution and development of the angiosperms.

PMID- 10586880
TI  - The dynamics of chromosome evolution in birds and mammals.
AB  - Comparative mapping, which compares the location of homologous genes in different
      species, is a powerful tool for studying genome evolution. Comparative maps
      suggest that rates of chromosomal change in mammals can vary from one to ten
      rearrangements per million years. On the basis of these rates we would expect 84
      to 600 conserved segments in a chicken comparison with human or mouse. Here we
      build comparative maps between these species and estimate that numbers of
      conserved segments are in the lower part of this range. We conclude that the
      organization of the human genome is closer to that of the chicken than the mouse
      and by adding comparative mapping results from a range of vertebrates, we
      identify three possible phases of chromosome evolution. The relative stability of
      genomes such as those of the chicken and human will enable the reconstruction of
      maps of ancestral vertebrates.

PMID- 10586881
TI  - Large-scale analysis of the yeast genome by transposon tagging and gene
      disruption.
AB  - Economical methods by which gene function may be analysed on a genomic scale are
      relatively scarce. To fill this need, we have developed a transposon-tagging
      strategy for the genome-wide analysis of disruption phenotypes, gene expression
      and protein localization, and have applied this method to the large-scale
      analysis of gene function in the budding yeast Saccharomyces cerevisiae. Here we
      present the largest collection of defined yeast mutants ever generated within a
      single genetic background--a collection of over 11,000 strains, each carrying a
      transposon inserted within a region of the genome expressed during vegetative
      growth and/or sporulation. These insertions affect nearly 2,000 annotated genes,
      representing about one-third of the 6,200 predicted genes in the yeast genome. We
      have used this collection to determine disruption phenotypes for nearly 8,000
      strains using 20 different growth conditions; the resulting data sets were
      clustered to identify groups of functionally related genes. We have also
      identified over 300 previously non-annotated open reading frames and analysed by
      indirect immunofluorescence over 1,300 transposon-tagged proteins. In total, our
      study encompasses over 260,000 data points, constituting the largest functional
      analysis of the yeast genome ever undertaken.

PMID- 10586882
TI  - Chromosomal landscape of nucleosome-dependent gene expression and silencing in
      yeast.
AB  - Eukaryotic genomes are packaged into nucleosomes, which are thought to repress
      gene expression generally. Repression is particularly evident at yeast telomeres,
      where genes within the telomeric heterochromatin appear to be silenced by the
      histone-binding silent information regulator (SIR) complex (Sir2, Sir3, Sir4) and
      Rap1 (refs 4-10). Here, to investigate how nucleosomes and silencing factors
      influence global gene expression, we use high-density arrays to study the effects
      of depleting nucleosomal histones and silencing factors in yeast. Reducing
      nucleosome content by depleting histone H4 caused increased expression of 15% of
      genes and reduced expression of 10% of genes, but it had little effect on
      expression of the majority (75%) of yeast genes. Telomere-proximal genes were
      found to be de-repressed over regions extending 20 kilobases from the telomeres,
      well beyond the extent of Sir protein binding and the effects of loss of Sir
      function. These results indicate that histones make Sir-independent contributions
      to telomeric silencing, and that the role of histones located elsewhere in
      chromosomes is gene specific rather than generally repressive.

PMID- 10586883
TI  - LTP promotes formation of multiple spine synapses between a single axon terminal
      and a dendrite.
AB  - Structural remodelling of synapses and formation of new synaptic contacts has
      been postulated as a possible mechanism underlying the late phase of long-term
      potentiation (LTP), a form of plasticity which is involved in learning and
      memory. Here we use electron microscopy to analyse the morphology of synapses
      activated by high-frequency stimulation and identified by accumulated calcium in
      dendritic spines. LTP induction resulted in a sequence of morphological changes
      consisting of a transient remodelling of the postsynaptic membrane followed by a
      marked increase in the proportion of axon terminals contacting two or more
      dendritic spines. Three-dimensional reconstruction revealed that these spines
      arose from the same dendrite. As pharmacological blockade of LTP prevented these
      morphological changes, we conclude that LTP is associated with the formation of
      new, mature and probably functional synapses contacting the same presynaptic
      terminal and thereby duplicating activated synapses.

PMID- 10586884
TI  - Conserved regulation of proximodistal limb axis development by Meis1/Hth.
AB  - Vertebrate limbs grow out from the flanks of embryos, with their main axis
      extending proximodistally from the trunk. Distinct limb domains, each with
      specific traits, are generated in a proximal-to-distal sequence during
      development. Diffusible factors expressed from signalling centres promote the
      outgrowth of limbs and specify their dorsoventral and anteroposterior axes.
      However, the molecular mechanism by which limb cells acquire their proximodistal
      (P-D) identity is unknown. Here we describe the role of the homeobox genes
      Meis1/2 and Pbx1 in the development of mouse, chicken and Drosophila limbs. We
      find that Meis1/2 expression is restricted to a proximal domain, coincident with
      the previously reported domain in which Pbx1 is localized to the nucleus, and
      resembling the distribution of the Drosophila homologues homothorax (hth) and
      extradenticle (exd); that Meis1 regulates Pbx1 activity by promoting nuclear
      import of the Pbx1 protein; and that ectopic expression of Meis1 in chicken and
      hth in Drosophila disrupts distal limb development and induces distal-to-proximal
      transformations. We suggest that restriction of Meis1/Hth to proximal regions of
      the vertebrate and insect limb is essential to specify cell fates and
      differentiation patterns along the P-D axis of the limb.

PMID- 10586885
TI  - CtBP/BARS induces fission of Golgi membranes by acylating lysophosphatidic acid.
AB  - Membrane fission is essential in intracellular transport. Acyl-coenzyme As (acyl
      CoAs) are important in lipid remodelling and are required for fission of COPI
      coated vesicles. Here we show that CtBP/BARS, a protein that functions in the
      dynamics of Golgi tubules, is an essential component of the fission machinery
      operating at Golgi tubular networks, including Golgi compartments involved in
      protein transport and sorting. CtBP/BARS-induced fission was preceded by the
      formation of constricted sites in Golgi tubules, whose extreme curvature is
      likely to involve local changes in the membrane lipid composition. We find that
      CtBP/BARS uses acyl-CoA to selectively catalyse the acylation of lysophosphatidic
      acid to phosphatidic acid both in pure lipidic systems and in Golgi membranes,
      and that this reaction is essential for fission. Our results indicate a key role
      for lipid metabolic pathways in membrane fission.

PMID- 10586886
TI  - Crystal structures of the membrane-binding C2 domain of human coagulation factor
      V.
AB  - Rapid and controlled clot formation is achieved through sequential activation of
      circulating serine proteinase precursors on phosphatidylserine-rich procoagulant
      membranes of activated platelets and endothelial cells. The homologous complexes
      Xase and prothrombinase, each consisting of an active proteinase and a non
      enzymatic cofactor, perform critical steps within this coagulation cascade. The
      activated cofactors VIIIa and Va, highly specific for their cognate proteinases,
      are each derived from precursors with the same A1-A2-B-A3-C1-C2 architecture.
      Membrane binding is mediated by the C2 domains of both cofactors. Here we report
      two crystal structures of the C2 domain of human factor Va. The conserved beta
      barrel framework provides a scaffold for three protruding loops, one of which
      adopts markedly different conformations in the two crystal forms. We propose a
      mechanism of calcium-independent, stereospecific binding of factors Va and VIIIa
      to phospholipid membranes, on the basis of (1) immersion of hydrophobic residues
      at the apices of these loops in the apolar membrane core; (2) specific
      interactions with phosphatidylserine head groups in the groove enclosed by these
      loops; and (3) favourable electrostatic contacts of basic side chains with
      negatively charged membrane phosphate groups.

PMID- 10586887
TI  - Structure of the C2 domain of human factor VIII at 1.5 A resolution.
AB  - Human factor VIII is a plasma glycoprotein that has a critical role in blood
      coagulation. Factor VIII circulates as a complex with von Willebrand factor.
      After cleavage by thrombin, factor VIIIa associates with factor IXa at the
      surface of activated platelets or endothelial cells. This complex activates
      factor X (refs 6, 7), which in turn converts prothrombin to thrombin in the
      presence of factor Va (refs 8, 9). The carboxyl-terminal C2 domain of factor VIII
      contains sites that are essential for its binding to von Willebrand factor and to
      negatively charged phospholipid surfaces. Here we report the structure of human
      factor VIII C2 domain at 1.5 A resolution. The structure reveals a beta-sandwich
      core, from which two beta-turns and a loop display a group of solvent-exposed
      hydrophobic residues. Behind the hydrophobic surface lies a ring of positively
      charged residues. This motif suggests a mechanism for membrane binding involving
      both hydrophobic and electrostatic interactions. The structure explains, in part,
      mutations in the C2 region of factor VIII that lead to bleeding disorders in
      haemophilia A.

PMID- 10586888
TI  - The epidemic of allergy and asthma.
AB  - Allergic diseases, such as asthma, rhinitis, eczema and food allergies, are
      reaching epidemic proportions in both the developed and developing world. Key
      factors driving these rising trends are increased exposure to sensitizing
      allergens and reduced stimulation of the immune system during critical periods of
      development. In allergic disease, there is a polarization of T-lymphocyte
      responses, and enhanced secretion of cytokines involved in regulation of
      immunoglobulin E, mast cells, basophils and eosinophils, ultimately leading to
      inflammation and disease. A clear understanding of the cellular and molecular
      mechanisms of allergic disease and the complex interplay between genetic and
      environmental factors will undoubtedly create new opportunities for public health
      and therapeutic interventions.

PMID- 10586889
TI  - The alliance of genes and environment in asthma and allergy.
AB  - The diseases of asthma, eczema and hay fever are typified by reactions to common
      allergens, which are mediated by immunoglobulin E. These allergic diseases are
      increasing in prevalence, and are now a major source of disability throughout the
      developed world. They are the result of complex interactions between largely
      unknown genetic and environmental mechanisms. The identification of the
      environmental factors offers the real possibility of prevention of disease, and
      unravelling the genetics of allergic illnesses is likely to change their
      classification and treatment. Early life seems particularly important, when the
      initiation of allergic disease may result from genetic and environmental
      modification of the immune interaction between mother and child.

PMID- 10586890
TI  - The role of allergy in the development of asthma.
AB  - Recent studies have shown that initial sensitization to airborne environmental
      allergens occurs typically in early childhood, but subsequent progression to
      persistent atopic asthma, which may not manifest for several years, is restricted
      to only a subset of atopics. The key to establishing the link between atopy and
      asthma lies in the development of persistent inflammation in the airway wall,
      resulting in structural and functional changes in local tissues which are
      responsible for the symptoms of the disease. This review summarizes recent
      findings on the nature of the cellular and molecular mechanisms underlying this
      process, and addresses the issue of why the intensity and duration of these
      tissue-damaging responses in the airway wall apparently exceeds the critical
      threshold required for development of persistent asthma in only a minority of
      allergy sufferers.

PMID- 10586891
TI  - Induction and regulation of the IgE response.
AB  - Immunoglobulin E (IgE) is believed to be one of the major mediators of immediate
      hypersensitivity reactions that underlie atopic conditions such as urticaria,
      seasonal allergy, asthma and anaphylaxis. Factors that control IgE production are
      therefore essential to the pathogenesis of these important afflictions. But a
      complete understanding of this topic is lacking, while new data have raised
      questions regarding the precise role of IgE in atopic disease. Evolving concepts
      of IgE production and elimination are likely to clarify the importance of IgE in
      health and disease.

PMID- 10586892
TI  - Signalling through the high-affinity IgE receptor Fc epsilonRI.
AB  - The Fc epsilonRI complex forms a high-affinity cell-surface receptor for the Fc
      region of antigen-specific immunoglobulin E (IgE) molecules. Fc epsilonRI is
      multimeric and is a member of a family of related antigen/Fc receptors which have
      conserved structural features and similar roles in initiating intracellular
      signalling cascades. In humans, Fc epsilonRI controls the activation of mast
      cells and basophils, and participates in IgE-mediated antigen presentation.
      Multivalent antigens bind and crosslink IgE molecules held at the cell surface by
      Fc epsilonRI. Receptor aggregation induces multiple signalling pathways that
      control diverse effector responses. These include the secretion of allergic
      mediators and induction of cytokine gene transcription, resulting in secretion of
      molecules such as interleukin-4, interleukin-6, tumour-necrosis factor-alpha and
      granulocyte-macrophage colony-stimulating factor. Fc epsilonRI is therefore
      central to the induction and maintenance of an allergic response and may confer
      physiological protection in parasitic infections.

PMID- 10586893
TI  - Therapeutic strategies for allergic diseases.
AB  - Many drugs are now in development for the treatment of atopic diseases, including
      asthma, allergic rhinitis and atopic dermatitis. These treatments are based on
      improvements in existing therapies or on a better understanding of the cellular
      and molecular mechanisms involved in atopic diseases. Although most attention has
      been focused on asthma, treatments that inhibit the atopic disease process would
      have application to all atopic diseases, as they often coincide. Most of the many
      new therapies in development are aimed at inhibiting components of the allergic
      inflammatory response, but in the future there are real possibilities for the
      development of preventative and even curative treatments.

PMID- 10586894
TI  - The American Society of Tropical Medicine and Hygiene initiative to stimulate
      educational programs to enhance medical expertise in tropical diseases.
AB  - More than a decade ago, at a time when current and emerging tropical diseases
      posed growing threats to the United States, expert panels convened by the
      Institute of Medicine of the U.S. National Academy of Sciences concluded that
      medical expertise within the United States competent to address diseases of the
      tropics had declined. Recognizing a national need to encourage and enhance such,
      The American Society of Tropical Medicine and Hygiene developed a program to
      stimulate new postgraduate medical education in diseases of the tropics. The
      Society formally requested academic institutions within the United States and
      Canada to propose new postgraduate programs. To assure the quality of these new
      curricular offerings, the Society developed an outline of key areas of competency
      and agreed to offer an examination that would grant physicians a Certificate of
      Knowledge in Clinical Tropical Medicine and Travelers Health. The certifying
      examination was to be an integral component of a program to stimulate academic
      institutions to provide instructional programs in tropical diseases and to
      encourage physicians to become trained, evaluated, and recognized for their
      knowledge of clinical tropical diseases and travelers' health. The Society's
      initiative to stimulate educational programs in tropical medicine is reviewed.

PMID- 10586895
TI  - Mycobacterium ulcerans infection (Buruli ulcer): first reported case in a
      traveler.
AB  - A chronic, painless sore developed over a 2-month period on the left calf of a
      Canadian man traveling for 8 months in Africa. A presumptive diagnosis of a
      Mycobacterium spp. infection was made despite initially negative biopsy and
      culture results, after failure of several courses of anti-bacterial antibiotics.
      Mycobacterium ulcerans was eventually isolated and the lesion progressed despite
      treatment with multiple anti-mycobacterial agents. The lesion finally responded
      to wide and repeated excision, aggressive treatment with anti-mycobacterial
      antibiotics, and split-thickness skin grafting. The isolation and treatment of
      this unusual organism are discussed.

PMID- 10586896
TI  - Transmission of Mycobacterium ulcerans to the nine-banded armadillo.
AB  - Animal models for Mycobacterium ulcerans infections (Buruli ulcer) include guinea
      pigs, rats, and mice, but each has limitations in replicating the spectrum of
      human disease. Here, 19 adult nine-banded armadillos were inoculated
      intradermally with M. ulcerans. Injection sites were examined and skin samples
      obtained for histologic and microbiology studies. Necropsies were conducted to
      assess systemic involvement. In group 1 (n = 4), 2 animals developed progressive
      skin ulcers with undermined borders at the injection sites within 6-10 weeks.
      Biopsies showed features similar to human disease including extensive necrosis in
      the deep dermis and subcutaneous fat, mixed cellular infiltrates, and acid-fast
      bacilli (AFB). In group 2 (n = 15), 5 animals developed progressive skin ulcers,
      3 had evanescent papulo-nodules, 3 died shortly after inoculation of unknown
      causes, and 4 showed no signs of infection. Lesion samples from 3 animals with
      progressive ulcers were culture positive for AFB. Our findings indicate that nine
      banded armadillos are susceptible to M. ulcerans and may develop cutaneous
      lesions that closely mimic Buruli ulcer.

PMID- 10586897
TI  - Histologic and functional renal alterations caused by Bothrops moojeni snake
      venom in rats.
AB  - Acute renal failure (ARF) is the main cause of death following snake bites by
      Bothrops species. In this study, we investigated the morphologic and functional
      renal disturbances caused by Bothrops moojeni venom in rats. Renal function was
      assessed based on creatinine and lithium clearances and on histologic examination
      of renal tissue 5 hr after the intravenous administration of 0.2 mg of venom/kg
      and 5 hr, 16 hr, and 48 hr after 0.4 mg of venom/ kg. A venom dose of 0.4 mg/kg
      produced renal tubule disturbances, including acute impairment of proximal and
      post-proximal tubule sodium handling associated with acute tubule necrosis. The
      glomerular filtration rate (GFR) decreased significantly and was accompanied by
      severe morphologic disturbances in the renal glomeruli. These functional and
      morphologic findings were observed in the absence of any change in mean arterial
      blood pressure. The decrease in GFR was not related to the presence of fibrin
      deposits in the glomerular capillary loops. These results suggest an early
      nephrotoxic action of B. moojeni venom involving significant morphologic and
      functional changes similar to those observed in snakebite-induced ARF in humans.

PMID- 10586898
TI  - Association of early childhood diarrhea and cryptosporidiosis with impaired
      physical fitness and cognitive function four-seven years later in a poor urban
      community in northeast Brazil.
AB  - To determine potential, long-term deficits associated with early childhood
      diarrhea and parasitic infections, we studied the physical fitness (by the
      Harvard Step Test) and cognitive function (by standardized tests noted below) of
      26 children who had complete surveillance for diarrhea in their first 2 years of
      life and who had continued surveillance until 6-9 years of age in a poor urban
      community (favela) in Fortaleza in northeast Brazil. Early childhood diarrhea at
      0-2 years of age correlated with reduced fitness by the Harvard Step Test at 6-9
      years of age (P = 0.03) even after controlling for anthropometric and muscle area
      effects, anemia, intestinal helminths, Giardia infections, respiratory illnesses,
      and socioeconomic variables. Early childhood cryptosporidial infections (6 with
      diarrhea and 3 without diarrhea) were also associated with reduced fitness at 6-9
      year of age, even when controlling for current nutritional status. Early diarrhea
      did not correlate with activity scores (P = 0.697), and early diarrhea remained
      significantly correlated with fitness scores (P = 0.035) after controlling for
      activity scores. Early diarrhea burdens also correlated in pilot studies with
      impaired cognitive function using a McCarthy Draw-A-Design (P = 0.01; P = 0.017
      when controlling for early helminth infections), Wechsler Intelligence Scale for
      Children coding tasks (P = 0.031), and backward digit span tests (P = 0.045).
      These findings document for the first time a potentially substantial impact of
      early childhood diarrhea and cryptosporidial infections on subsequent functional
      status. If confirmed, these findings have major implications for calculations of
      global disability adjusted life years and for the importance and potential cost
      effectiveness of targeted interventions for early childhood diarrhea.

PMID- 10586899
TI  - Hydatid disease of the breast: a case report and literature review.
AB  - Hydatid disease of the breast is rare. However, it might constitute a potentially
      serious differential diagnosis of a breast lump in areas endemic for this
      disease. Fine-needle aspiration cytology provides a safe preoperative diagnosis.
      A case of an isolated breast involvement that was diagnosed during surgery is
      presented and is followed by a brief discussion on the topic.

PMID- 10586900
TI  - Replication of hepatitis B virus in first-degree relatives of patients with
      hepatocellular carcinoma.
AB  - Hepatocellular carcinoma (HCC) may occur in family clusters. No genetic mechanism
      has been identified as responsible for this familial tendency. We suspected that
      a longer hepatitis B virus (HBV) replication phase might be the reason for a
      higher risk of HCC in families with this disease. We performed liver biochemical
      tests, test for viral hepatitis markers and hepatitis B e antigen (HBeAg), and
      liver ultrasonography in relatives of patients with HCC. A total of 1,885 first
      degree relatives from 688 families participated in this study. Seven hundred
      fifty-two relatives were found to be carriers of hepatitis B surface antigen
      (HBsAg) and 675 of them were tested for HBeAg. The prevalence of HBeAg was 27.4%
      in relatives of those with HCC and 20% in asymptomatic HBsAg carriers. The HBeAg
      prevalence rate was higher in relatives of those with HCC > or = 40 years old
      than in asymptomatic HBsAg carriers. Moreover, HBeAg was more likely to persist
      in men than in women > or = 40 years old. We conclude that families with HCC
      showed a prolonged HBV replication phase that may be one of the cofactors for a
      familial tendency for HCC.

PMID- 10586901
TI  - Detection of dengue virus RNA by reverse transcription-polymerase chain reaction
      in the liver and lymphoid organs but not in the brain in fatal human infection.
AB  - Autopsy tissues from 18 children believed to have died of dengue hemorrhagic
      fever were tested for the presence of dengue virus RNA by reverse transcription
      polymerase chain reaction (RT-PCR). Such RNA was found in 14 of 18 liver
      specimens, 13 of 18 spleen specimens and 7 of 16 mesenteric lymph node specimens.
      No dengue virus RNA was detected in 44 samples of brain tissue from 15
      individuals, 1 or more of whose other tissues yielded such RNA. All tissues had
      been tested previously for dengue virus by mosquito inoculation. In those tests,
      virus was recovered from 5 of 18 liver and 2 of 18 spleen specimens. Thus, the RT
      PCR is more sensitive than the most sensitive virus isolation technique for
      detecting dengue virus or its components in human tissue. Failure to isolate
      virus from most of spleen and all mesenteric lymph node specimens may indicate
      that those tissues contained primarily degraded virus undergoing inactivation.

PMID- 10586902
TI  - Common occurrence of concurrent infections by multiple dengue virus serotypes.
AB  - The co-circulation of all 4 dengue virus serotypes in the same community, common
      since the 1950s in Southeast Asia, has now become a frequent occurrence in many
      Caribbean Islands, Mexico, and Central and South America in the past 20 years. As
      a consequence, the frequency of concurrent infections would be expected to
      increase in these areas. To assess this, using state of the art technology, we
      screened viremic serum samples and mosquitoes inoculated with serum samples
      collected during epidemics involving multiple dengue virus serotypes in
      Indonesia, Mexico, and Puerto Rico for virus isolation. Of 292 samples tested, 16
      (5.5%) were found to contain 2 or more dengue viruses by an indirect
      immunofluorescence test and/or the reverse transcriptase-polymerase chain
      reaction.

PMID- 10586903
TI  - Assessment of the efficacy of an IgM-elisa and microscopic agglutination test
      (MAT) in the diagnosis of acute leptospirosis.
AB  - In a prospective study in Barbados between 1979 and 1989, 321 cases were
      diagnosed in 638 patients presenting at a hospital with symptoms of
      leptospirosis. Initial diagnosis was based on patient history and characteristic
      signs and symptoms. In 92 cases (29%), diagnosis was confirmed by isolation of
      organisms from the blood, urine, or dialysate fluid; in the remaining 229 cases
      (71%) diagnosis was confirmed by serology alone. Results of an IgM-ELISA and
      microscopic agglutination test (MAT) in cases with isolates and in non
      leptospirosis cases were used to assess the sensitivity and specificity of the
      tests. The sensitivity of IgM detection by ELISA was 52% in the first acute-phase
      specimen, increasing to 89% and 93% in the second acute-phase and convalescent
      specimens, respectively. The specificity of the IgM-ELISA was high (> or = 94%)
      in all specimens. The sensitivity of the MAT was low (30%) in the first acute
      phase specimen, increasing to 63% in the second acute-phase specimen and 76% in
      the convalescent specimen. The specificity of the MAT was > or = 97% in all
      specimens.

PMID- 10586904
TI  - Short report: evaluation of a monoclonal antibody-based latex agglutination test
      for rapid diagnosis of septicemic melioidosis.
AB  - A monoclonal antibody (MAb)-based latex agglutination (MAb-LA) test was developed
      to rapidly identify Burkholderia pseudomallei in hemoculture of patients with
      septicemic melioidosis. The method was evaluated in a clinical situation on 396
      hemocultures positive for bacterial growth, of which 75 cultures were positive
      for B. pseudomallei by conventional biochemical tests. The sensitivity and
      specificity of the MAb-LA test were 95% and 100%, respectively. The positive and
      negative predictive values were 100% and 99%. The method is highly reliable and
      suitable for rapid diagnosis of septicemic melioidosis, reducing the time
      normally required from a minimum of 3-4 days by conventional methods to less than
      30 hr. Most of these 30 hr are involved in growing up enough bacteria to perform
      the MAb-LA test, which itself takes only 1 min.

PMID- 10586905
TI  - Parasite-specific antibody profile in human fascioliasis: application for
      immunodiagnosis of infection.
AB  - The antibody isotype response to an adult Fasciola worm antigen preparation
      (FWAP) was examined in sera from 60 Egyptians with parasitologically confirmed
      fascioliasis by an ELISA. The FWAP-specific IgG1 and IgG4 antibodies were found
      in 97-100% of the patients. The ratio of the mean absorbance values between
      infected patients and healthy controls was 9.7 and 29.7 for IgG1 and IgG4
      antibodies, respectively. The IgM, IgA, IgG2, and IgG3 antibodies were less
      dominant. In contrast to IgG1 antibodies, which were often detected in sera from
      patients infected with Schistosoma, Echinococcus granulosus, Ascaris
      lumbricoides, Ancylostoma duodenale, or Hymenolepis nana, FWAP-specific IgG4
      antibodies were detected exclusively in the sera of patients with fascioliasis.
      The data thus support the conclusion that an IgG4/ELISA with crude FWAP as
      antigen may be used for sensitive and accurate immunodiagnosis of human
      fascioliasis.

PMID- 10586906
TI  - Development and evaluation of LIPODEET, a new long-acting formulation of N, N
      diethyl-m-toluamide (DEET) for the prevention of schistosomiasis.
AB  - N, N-diethyl-m-toluamide (DEET) is a common and fairly safe active ingredient in
      many insect repellents. Our recent studies showed that when applied to the skin,
      DEET has a potent anti-parasitic effect against Schistosoma mansoni. However, the
      beneficial effects of DEET lasted only for a few minutes, presumably due to its
      rapid absorption through the skin. In this study, we evaluated different carrier
      formulations that prolong the activity of DEET in the skin. Among the various
      formulations analyzed, DEET incorporated into liposomes (LIPODEET) appeared to
      prolong the activity of DEET for more than 48 hr after a single application.
      Furthermore, LIPODEET was found to be minimally absorbed through the skin and
      loss due to washing off was limited. These findings thus suggest LIPODEET is a
      safe and long-acting formulation of DEET that is quite effective against
      schistosomiasis.

PMID- 10586907
TI  - Impact of the crayfish Procambarus clarkii on Schistosoma haematobium
      transmission in Kenya.
AB  - The Louisiana red swamp crayfish, Procambarus clarkii, which was introduced into
      east Africa in the 1950s or 1960s, has since widely dispersed. Previous work by
      our group has shown that P. clarkii can reduce populations of the molluscan
      intermediate hosts of human schistosomes through predatory and competitive
      interactions. Here, we investigate whether crayfish can reduce populations of
      Bulinus africanus and consequently, Schistosoma haematobium prevalence in school
      children. Children from 6 primary schools in the Machakos and Kitui Districts of
      Kenya were selected for study. Schools were divided into 3 experimental-control
      pairs. At experimental schools, crayfish were introduced into nearby aquatic
      habitats harboring Bulinus africanus snails and serving as S. haematobium
      transmission sites. Snail habitats near control schools did not receive crayfish.
      Six months after crayfish introduction, all infected children were treated with
      praziquantel. Children were then monitored quarterly for 2 years, at which time
      infection and reinfection rates were compared statistically between the paired
      schools. In one such pair, crayfish failed to establish, resulting in neither
      snail control nor a reduction in transmission. At the second pair of schools, the
      numbers of snails were decreased by the presence of crayfish, but a clear
      difference in infection rates in children could not be detected, primarily
      because drought conditions kept overall transmission rates low. At the third
      school pair, crayfish established well in experimental habitats, snail numbers
      decreased precipitously, and children at the experimental school were
      significantly less likely to acquire S. haematobium infections than children at
      the control school. Our results indicate that under certain environmental
      circumstances, P. clarkii exerts a significant impact on the transmission of
      human schistosomiasis in Kenya. Important questions remain regarding the impact
      of P. clarkii on Kenyan freshwater ecosystems, not the least of which is its
      potential to significantly influence the epidemiology of schistosomiasis in east
      Africa.

PMID- 10586908
TI  - The contribution of host-related factors to low cure rates of praziquantel for
      the treatment of Schistosoma mansoni in Senegal.
AB  - Surprisingly low cure rates were repeatedly observed after treatment with a
      standard dosage of praziquantel in a recently established Schistosoma mansoni
      focus in northern Senegal. In 4 discrete cohorts from the same population, cure
      rates were 18-36% and egg count reduction rates were 77-88%. Data and material of
      920 compliant subjects from all 4 cohorts were further analyzed to identify
      possible host-related factors associated with low cure rates. The lowest cure
      rates were found in the highest egg count groups. However, in low and moderate
      egg count groups, drug efficacy was also below normal values. Cure rates were
      similar in males and females, showed no seasonal variation, and were independent
      of previous praziquantel treatment. They were significantly higher in adults than
      in children, also after allowing for intensity of infection. Individual water
      contact behavior and specific humoral immune responses were examined in 2 extreme
      subgroups, either without significant egg count reduction or showing complete
      parasitologic cure. There was no significant difference in frequency and duration
      of water contact between those individuals with complete cure and those that
      showed little effect of praziquantel treatment. Levels of IgG, IgG1, IgG3, IgG4,
      IgM, and IgE against adult worm antigen were not different between the 2
      subgroups. Thus, the abnormally frequent failure of treatment observed in this
      focus could not be associated with any host-related factor, other than age and
      pretreatment egg counts.

PMID- 10586909
TI  - High frequency of serious side effects from meglumine antimoniate given without
      an upper limit dose for the treatment of visceral leishmaniasis in human
      immunodeficiency virus type-1-infected patients.
AB  - Organic pentavalent antimonials are one of the mainstays of treatment for
      visceral leishmaniasis (VL). Few data are available on the toxicity and efficacy
      of these drugs at the dosing schedule recommended by the Centers for Disease
      Control and Prevention (CDC) (Atlanta, GA). We analyzed 25 VL episodes in human
      immunodeficiency virus (HIV)-infected patients who were treated with meglumine
      antimoniate (MA) at the CDC-recommended dose in southern Spain. Adverse effects
      were observed in 14 (56%) VL episodes. In 7 (28%), treatment with MA was
      permanently discontinued due to serious adverse effects that included acute
      pancreatitis, acute renal failure, and leukopenia. Three (12%) patients died
      during therapy due to severe acute pancreatitis attributable to MA. The dosing
      regimen of MA currently recommended for treating VL is associated with a high
      rate of serious side effects in HIV-1-infected patients.

PMID- 10586910
TI  - Anti-malarial drug use among preschool children in an area of seasonal malaria
      transmission in Kenya.
AB  - The aims of this study were to estimate the proportion of asymptomatic Kenyan
      preschool children using anti-malarial drugs, to identify factors associated with
      chloroquine use, and to assess the validity of frequency of febrile episodes and
      drug use reported by mothers or carers. Of 318 children studied, 38% (95%
      confidence interval [CI] = 30-47%]) tested positive for chloroquine or
      sulfadoxine. Of chloroquine-positive children, 15% had concentrations exceeding
      the estimated minimum therapeutically effective values. Among those testing
      negative for sulfadoxine, chloroquine-positive children were more frequently
      parasitemic (odds ratio = 2.6, 95% CI = 1.3-5.2), and had lower mean hemoglobin
      concentrations (6.1 g/L, 95% CI = 2.1-10.1) than chloroquine-negative children.
      Mothers over-reported the frequency of malaria or fever episodes as usually
      defined in medical studies, and underreported anti-malarial drug use. We conclude
      that anti-malarials are frequently given for treatment of malaria or malaria
      associated illness, rather than prophylactically or for symptoms unrelated to
      malaria. Questionnaire surveys cannot replace biochemical markers to obtain
      information on anti-malarial drug use.

PMID- 10586911
TI  - Association of the ICAM-1Kilifi mutation with protection against severe malaria
      in Lambarene, Gabon.
AB  - The intercellular adhesion molecule-1 (ICAM-1) is thought to be a receptor that
      mediates binding of Plasmodium falciparum-infected erythrocytes. Especially in
      vital organs, the binding of parasitized cells to the endothelium via ICAM-1 may
      lead to severe disease and death. Recently, a mutation in the coding region of
      ICAM-1, termed ICAM-1Kilifi, was described, causing a change from Lys to Met in
      the loop that interacts with rhinoviruses, lymphocytes, and parasitized red blood
      cells. Surprisingly, this mutation was shown to increase susceptibility of Kenyan
      children to severe malaria in one study. When we compared the distribution of
      ICAM-1Kilifi in two groups of Gabonese children enrolled in a case-control,
      matched-pair study who presented with either mild or severe malaria, we found
      that 55% of the patients with mild malaria were carriers whereas only 39% of
      those with severe malaria were carriers. The difference in the distribution of
      ICAM-1Kilifi homozygous pairs between the groups, as well as the distribution of
      ICAM-1Kilifi carriers, was statistically highly significant (P = 0.027 and P =
      0.012, by the McNemar test). In a group of healthy school children from the same
      region, a distribution of 52% ICAM-1Kilifi carriers to 48% wild-type individuals
      was found. In a survey for the ICAM-1Kilifi in other malaria-endemic regions,
      this allele was also found in Nigeria and Papua New Guinea, but not in Thailand.

PMID- 10586912
TI  - Analysis of mefloquine resistance and amplification of pfmdr1 in multidrug
      resistant Plasmodium falciparum isolates from Thailand.
AB  - Resistance to quinoline-containing compound has been associated with the
      Plasmodium falciparum multidrug resistance 1 (pfmdr1) gene. We analyzed wild P.
      falciparum isolates with high levels of chloroquine and mefloquine resistance for
      their macrorestriction maps of chromosome 5 and sequence of pfmdr1. Two types of
      chromosome 5 amplification were found. Eleven of 62 resistant isolates displayed
      Bgl 1 fragments larger than 100 kb. Twenty-nine isolates possessed multiple
      copies of the fragments. We failed to detect any amplification of this region on
      chromosome 5 in 22 mefloquine-resistant isolates, suggesting that other
      mechanisms can mediate the mefloquine-resistant phenotype. There was no direct
      association between pfmdr1 mutations and chloroquine sensitivity. Resistant lines
      could have Asn-86 and Tyr-184 or Phe-184, the predicted sequence of those
      chloroquine-sensitive isolates. No mutation at Asn-1042 and Asp-1246 was detected
      among these chloroquine-resistant isolates. Therefore, a few base substitutions
      in the pfmdr1 gene may not be sufficient to account for all chloroquine-resistant
      phenotypes.

PMID- 10586913
TI  - Temporal and spatial patterns of malaria reinfection in northeastern Venezuela.
AB  - We stratified the risk of malaria transmission (Plasmodium vivax) in 35 villages
      along a coastal range in northeastern Venezuela (51 km2) where the main vector is
      the mosquito Anopheles aquasalis. After 20 years without local malaria
      transmission, reinfection of the entire area occurred from May to December 1985
      by local (continuous) and jump (discontinuous) dispersal. Epidemiologic,
      environmental, and vector variables were investigated with the aid of a
      Geographic Information System. Risk factors for malaria transmission were human
      population density, proximity to pre-adult mosquito habitats (< 500 m), and the
      number of pre-adult habitats nearby. Most inhabitants, immature mosquito
      habitats, and malaria cases were located at low elevations and on gentle slopes.
      High prevalence of malaria during the dry seasons was associated with the
      presence of permanent bodies of water containing An. aquasalis. Occurrence of a
      La Nina event in 1988 (wet and cool phase of the El Nino Southern Oscillation)
      triggered malaria transmission to unusually high levels, consolidating infection
      in the area, and rendering traditional control efforts useless. We recommend
      tracking malaria persistence per village and associated risk factors as methods
      to reduce the cost of malaria control programs.

PMID- 10586914
TI  - Parasite density and malaria morbidity in the Pakistani Punjab.
AB  - The relationship between quantitative Plasmodiumfalciparum or P. vivax
      parasitemia and clinical illness has not been defined in Pakistan or in other
      areas where malaria transmission is not highly endemic. Standardized
      questionnaires were given to and physical examinations and parasitologic tests
      were performed in 8,941 subjects seen in outpatient clinics in 4 villages for 13
      consecutive months in the Punjab region of Pakistan. The results, based on
      multivariable analysis, showed that a clinical diagnosis of malaria, a history of
      fever, rigors, headache, myalgia, elevated temperature, and a palpable spleen
      among children were all strongly associated with the presence and density of P.
      falciparum or P. vivax malaria in a monotonic dose-response fashion. The malaria
      attributable fraction of a clinical diagnosis of malaria, and the same symptoms
      and signs also increased with increasing P. falciparum and, to a lesser extent,
      P. vivax, parasitemia. Unlike in sub-Saharan Africa, clinical illness due to
      malaria often occurs in the Punjab among adolescents and adults and in patients
      with parasite densities less than 1,000/microl. Clinical guidelines based upon
      parasitemia and symptomatology must be adjusted according to the intensity of
      transmission and be specific for each geographic area.

PMID- 10586915
TI  - Molecular epidemiology of malaria in Yaounde, Cameroon IV. Evolution of
      pyrimethamine resistance between 1994 and 1998.
AB  - Pyrimethamine, in combination with sulfadoxine, is currently one of the major
      alternative drugs used for the treatment of chloroquine-resistant Plasmodium
      falciparum malaria infections in Africa. The mechanism of pyrimethamine
      resistance has been strongly associated with a single, key point mutation in the
      dihydrofolate reductase-thymidylate synthase gene, resulting in the substitution
      of the wild-type allele Ser-108 by either Asn-108 or Thr-108. The pyrimethamine
      resistant phenotype and/or genotype were determined in 273 Cameroonian clinical
      isolates obtained in Yaounde by in vitro assays and polymerase chain reaction
      restriction fragment length polymorphism over a 5-year period. The in vitro
      assays showed that 42% (18 of 43) and 63% (69 of 110) of the isolates obtained in
      1994-1995 and 1997-1998, respectively, were resistant to pyrimethamine (50%
      inhibitory concentration [IC50] > 100 nM). The polymerase chain reaction showed
      that 43% (55 of 127) and 59% (50 of 85) of the isolates in 1994-1995 and 1997
      1998, respectively, had the mutant Asn-108 allele. The pyrimethamine-resistant
      genotype (Asn-108) corresponded with the pyrimethamine-resistant phenotype (IC50
      > or = 100 nM) in a large majority (> 95%) of the isolates. The results of our
      study suggest an increasing prevalence of pyrimethamine resistance in Yaounde.
      Our study further suggests that pyrimethamine resistance can be monitored by a
      technique that can be adopted by malaria research centers in Africa.

PMID- 10586917
TI  - Incidence of plague associated with increased winter-spring precipitation in New
      Mexico.
AB  - Plague occurs episodically in many parts of the world, and some outbreaks appear
      to be related to increased abundance of rodents and other mammals that serve as
      hosts for vector fleas. Climate dynamics may influence the abundance of both
      fleas and mammals, thereby having an indirect effect on human plague incidence.
      An understanding of the relationship between climate and plague could be useful
      in predicting periods of increased risk of plague transmission. In this study, we
      used correlation analyses of 215 human cases of plague in relation to
      precipitation records from 1948 to 1996 in areas of New Mexico with history of
      human plague cases (38 cities, towns, and villages). We conducted analyses using
      3 spatial scales: global (El Nino-Southern Oscillation Indices [SOI]); regional
      (pooled state-wide precipitation averages); and local (precipitation data from
      weather stations near plague case sites). We found that human plague cases in New
      Mexico occurred more frequently following winter-spring periods (October to May)
      with above-average precipitation (mean plague years = 113% of normal rain/
      snowfall), resulting in 60% more cases of plague in humans following wet versus
      dry winter-spring periods. However, we obtained significant results at local
      level only; regional state-wide precipitation averages and SOI values exhibited
      no significant correlations to incidence of human plague cases. These results are
      consistent with our hypothesis of a trophic cascade in which increased winter
      spring precipitation enhances small mammal food resource productivity (plants and
      insects), leading to an increase in the abundance of plague hosts. In addition,
      moister climate conditions may act to promote flea survival and reproduction,
      also enhancing plague transmission. Finally, the result that the number of human
      plague cases in New Mexico was positively associated with higher than normal
      winter-spring precipitation at a local scale can be used by physicians and public
      health personnel to identify and predict periods of increased risk of plague
      transmission to humans.

PMID- 10586916
TI  - Molecular epidemiology of malaria in Yaounde, Cameroon V. analysis of the omega
      repetitive region of the plasmodium falciparum CG2 gene and chloroquine
      resistance.
AB  - A novel Plasmodium falciparum gene, denoted cg2 gene, has been recently
      discovered, and a distinct genotype, characterized by 12 point mutations and 3
      size polymorphisms, has been shown to be associated with chloroquine resistance
      in laboratory-adapted parasite strains. One of the polymorphic regions, denoted
      the omega region, consists of 16 tandem repeat units in chloroquine-resistant
      strains, while the chloroquine-sensitive strains have either < or = 15 or > or =
      17 repeat units. In this study, the in vivo and in vitro responses were compared
      with the number of repeat units in the omega region of the cg2 gene for 75
      Cameroonian isolates determined either by DNA sequencing or agarose gel
      electrophoresis. The 16-repeat units that characterize the resistant strains were
      found in 10 chloroquine-sensitive isolates (50% inhibitory concentration [IC50] <
      100 nM) and 30 chloroquine-resistant isolates (IC50 > or = 100 nM). Thirty-five
      isolates (28 chloroquine-sensitive isolates and 7 chloroquine-resistant isolates)
      displayed < or = 15 or > or = 17 repeat units. Of the 18 patients responding with
      treatment failure, 15 were infected with parasites carrying 16 repeat units.
      Twenty-eight patients (11 with isolates carrying 16 repeat units and 17 with
      isolates carrying < or = 15 or > or = 17 repeat units) showed an adequate
      clinical response. The sensitivity, specificity, and predictive value were 81%
      (83%), 74% (61%), and 75% (58%), respectively compared with in vitro (or in vivo)
      responses. Neither the level of IC50 nor the key P. falciparum multidrug
      resistance gene 1 (pfmdr 1) allele at position 86 was associated with the number
      of omega repeat units. Although in vitro and in vivo resistance to chloroquine
      was statistically associated with the presence of 16 repeat units in the omega
      region (P < 0.05), the number of omega repeat units did not adequately
      discriminate patients infected with chloroquine-resistant parasites from those
      infected with chloroquine-sensitive parasites. Further studies on the cg2 gene
      are needed to determine whether cg2 gene is a reliable genetic marker for
      chloroquine resistance.

PMID- 10586918
TI  - Hepatitis E seroconversion in United States travelers abroad.
AB  - Sporadic cases of symptomatic hepatitis E virus (HEV) infection have been
      reported in United States travelers to developing countries, including Mexico and
      Pakistan. To evaluate the risk of exposure in United States travelers, 356
      patients seen in our Travel Clinics were tested for antibodies to HEV before and
      6 weeks after traveling. Samples obtained 6 months after traveling were available
      for 211 travelers. IgG and IgM antibodies to HEV were assayed with HEV ELISA
      diagnostic kits containing 3 recombinant antigens expressed in Escherichia coli
      representing immunodominant epitopes within open reading frames 2 and 3 of HEV.
      Nine patients were IgG seropositive in specimens obtained before travel. Four
      individuals seroconverted. In all 4 patients, IgG seroconversion was demonstrated
      in samples obtained at least 6 months after return. Samples obtained 6 weeks
      after return were seronegative for HEV in all 3 patients for whom such samples
      were available. Travel destinations were diverse: Thailand, China, Russia, and
      Peru. These data are consistent with an infection acquired while traveling. None
      of the seropositive subjects reported any symptoms of hepatitis before or after
      travel. In the absence of overt disease, these results imply that exposure to HEV
      resulted in subclinical infections.

PMID- 10586919
TI  - Hepatitis A in Latin America: a changing epidemiologic pattern.
AB  - In a multicenter study, hepatitis A virus (HAV) seroprevalence was surveyed in
      six countries in Latin America in which in 12,000 subjects were stratified for
      age. The highest rates of seroprevalence were recorded in the Dominican Republic
      (89.0%) and Mexico (81.0%), with lower rates in Brazil (64.7%), Chile (58.1%),
      Venezuela (55.7%), and Argentina (55.0%). The seroprevalence of HAV in children
      between 1 and 5 years of age was less than 50%, except in the Dominican Republic.
      In the 5-10-year-old age group, seroprevalence rates have also decreased compared
      with previous reports. This suggests that the epidemiology is shifting from high
      to intermediate endemicity, with the population susceptible to HAV infection
      shifting from children to adolescents and adults. Furthermore, data from Brazil,
      Argentina, and Mexico show that HAV seroprevalence is significantly lower in
      people living in medium and high socioeconomic conditions. This study suggests
      the need for appropriate vaccination programs to be implemented targeting
      children, adolescents, and adults, particularly in higher socioeconomic groups.

PMID- 10586920
TI  - Mansonella ozzardi infection in Bolivia: prevalence and clinical associations in
      the Chaco region.
AB  - A cross-sectional survey carried out in the Chaco region of Bolivia showed that
      26% (77 of 296) and 0.7% (2 of 298) of the rural population of the Camiri and
      Villa Montes areas, respectively, harbored Mansonella ozzardi microfilariae (mf).
      No significant differences were observed between sexes. The lowest prevalence
      (9%) was in the 0-14-year-old age group, with no children <11 months of age
      infected. The prevalence increased sharply in the 25-34-year-old age group (32%),
      and continued increasing in the older age classes. Microfilaremia, ranging from 1
      to 305 mf/20 microl of blood, was lowest in 0-14-year-old children (geometric
      mean concentration = 1.1 mf/20 microl), and increased with age (>100 mf/20 microl
      in people >44 years old). An expected increasing sensitivity with the blood
      volume examined was observed. No significant association between clinical
      symptoms (fever, skin rash, pruritus, headache, lymphedema, elephantiasis, and
      articular pain) and microfilaremia was observed.

PMID- 10586921
TI  - Human trichinellosis in Sourthern Spain: serologic and epidemiologic study.
AB  - An outbreak of trichinellosis caused by wild boar meat occurred in the Iruela
      (Jaen) in southern Spain in February 1996. Thirty-five people were diagnosed on
      the basis of epidemiologic data, but only 24 patients agreed to participate in
      this study. Twenty-three (96%) had symptoms suggestive of trichinellosis.
      Immunofluorescent and Western blot test results for trichinellosis were positive
      in 18 persons, and 15 had circulating Trichinella spiralis antigens. These
      findings suggest that results of tests for circulating antigens in conjunction
      with clinical presentation are useful for the diagnosis of trichinellosis.

PMID- 10586922
TI  - Genetic analysis of leishmania parasites in Ecuador: are Leishmania (Viannia)
      panamensis and Leishmania (V.) Guyanensis distinct taxa?
AB  - In the course of an epidemiologic survey in Ecuador, the following collection of
      Leishmania stocks was isolated: 28 from patients with clinical signs of
      leishmaniasis, 2 from sloths, 1 from a dog, and 4 from sand flies. For genetic
      characterization of these stocks, multilocus enzyme electrophoresis (MLEE) and
      random amplified polymorphic DNA (RAPD) were used. Twenty six of the 35 stocks
      were identified as either Leishmania (V.) panamensis or L. (V.) guyanensis, 2
      stocks were identified as L. (V.) braziliensis, the 2 stocks from sloths showed
      specific genotypes, and 5 stocks were characterized as hybrids between L. (V.)
      braziliensis and L. (V.) guyanensis. These data show that genetic diversity of
      Leishmania in Ecuador is high and that L. (V.) panamensis/guyanensis is the
      dominant group in this country. The genetic analysis questioned the distinctness
      between the two species L.(V.) panamensis and L. (V.) guyanensis, since MLEE and
      RAPD data did not indicate that L. (V.) panamensis and L. (V.) guyanensis
      correspond to distinct monophyletic lines. Population genetic analysis performed
      on the L. (V.) panamensis/guyanensis group favors the hypothesis of a basically
      clonal population structure.

PMID- 10586923
TI  - Lutzomyia nuneztovari anglesi (Le pont & Desjeux, 1984) as a vector of Leishmania
      amazonensis in a sub-Andean leishmaniasis focus of Bolivia.
AB  - Recently, a new Leishmania amazonensis focus was described in a sub-Andean region
      (1,450-2,100 meters above sea level) of Bolivia. In this area, three
      anthropophilic sandfly species were identified: Lutzomyia nuneztovari anglesi Le
      Pont & Desjeux, 1984, which represented 86-99% of the captures, Lu. galatiae Le
      Pont et al., 1998, and Lu. shannoni Dyar 1929. Only Lu. nuneztovari anglesi was
      found naturally infected by flagellates (16 of 1,715 females). Three Leishmania
      stocks were isolated and analyzed by isoenzyme electrophoresis at 11 loci. No
      significant isoenzymatic differences were demonstrated between them and 7 stocks
      isolated from patients from the same area, and previously characterized as L.
      amazonensis. Moreover, in a simplified protocol, the experimental infection of
      Lu. nuneztovari anglesi by L. amazonensis was successful in 92% of the surviving
      specimens. These data are discussed in relation to the Killick-Kendrick criteria.
      These results strongly suggest that Lu. nuneztovari anglesi is the vector of L
      amazonensis at Cajuata, Inquisivi, La Paz, Bolivia.

PMID- 10586925
TI  - The implications of rod-dependent cone survival for basic and clinical research.

PMID- 10586924
TI  - Anti-arthropod saliva antibodies among residents of a community at high risk for
      Lyme disease in California.
AB  - The role of the western black-legged tick (Ixodes pacificus) versus that of other
      potential arthropod vectors in the epidemiology of Lyme disease was evaluated by
      determining the prevalence of anti-arthropod saliva antibodies (AASA) among
      residents (n = 104) of a community at high-risk (CHR). Salivary gland extracts
      prepared from I. pacificus, the Pacific Coast tick (Dermacentor occidentalis),
      the western cone-nose bug (Triatoma protracta), and the western tree-hole
      mosquito (Aedes sierrensis) were used as antigens in an ELISA. Sera from 50
      residents of the San Francisco Bay region in northern California and 51 residents
      of Imperial County in southern California served as comparison groups. The
      prevalence of AASA ranged from 2% for A. sierrensis to 79% for I. pacificus in
      study subjects, 0% for D. occidentalis to 36% for I. pacificus among residents of
      the San Francisco Bay region, and 6% for I. pacificus to 24% for A. sierrensis in
      residents of Imperial County. The associations between AASA and demographic
      factors, potential risk factors, probable Lyme disease, and seropositivity for
      Borrelia burgdorferi were assessed for 85 members of the CHR. Seropositivity for
      I. pacificus and B. burgdorferi were significantly correlated, the relative risk
      of seropositivity to B. burgdorferi was about 5 (31% versus 6%) for subjects who
      were seroreactive to I. pacificus, nearly every individual who was seropositive
      for B. burgdorferi had elevated levels of antibodies to I. pacificus, and the
      mean titer for antibodies to I. pacificus was significantly higher for subjects
      seropositive versus those seronegative for B. burgdorferi. Together, these
      findings support the widely held belief that I. pacificus is the primary vector
      of B. burgdorferi for humans in northern California, and they demonstrate the
      utility of the AASA method as an epidemiologic tool for studying emerging tick
      borne infections.

PMID- 10586926
TI  - Which factors stimulate lens fiber cell differentiation in vivo?

PMID- 10586927
TI  - Light-induced apoptosis in the neonatal mouse retina and superior colliculus.
AB  - PURPOSE. Apoptosis occurs naturally in the rodent retina and superior colliculus
      (SC) during the neonatal period. The authors used mice to demonstrate the
      dependency of this apoptosis on the light stimulation and the developmental
      period. METHODS: A number of apoptotic cells were counted in the retina and SC
      from a group of newborn mice reared in constant darkness (DD group), a group
      reared in normal light and dark conditions (LD group), and a group reared in
      constant darkness up to P7 and then transferred to normal condition (DD-to-LD
      group). Terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick end
      labeling (TUNEL) was used for visualization of the apoptotic cells. RESULTS: In
      the LD group, apoptotic cells significantly increased in the retinal nuclear
      layers, including both the outer and inner nuclear layers, the retinal ganglion
      cell layer, and SC at postnatal day 1 (P1) and postnatal day 2 (P2). The number
      of apoptotic cells in the ganglion cell layer and SC reached the maximum level at
      P1. In contrast, in the DD group, an increase in the number of apoptotic cells
      was not observed. At P9, no significant increase in the number of apoptotic cells
      was observed in the outer nuclear layer, ganglion cell layer, and SC either in
      the LD, DD, or DD-to-LD groups, but the LD and DD-to-LD groups showed a
      significant increase in the inner nuclear layer compared to the DD group.
      CONCLUSIONS: Apoptosis during the neonatal period in the mouse visual system is
      induced by a light stimulus. This apoptosis was not induced after P7 in the
      retinal ganglion cell layer and SC, even if excessive cells survived.

PMID- 10586928
TI  - Optic nerve and peripapillary choroidal microvasculature of the rat eye.
AB  - PURPOSE: To investigate the three-dimensional microvascular anatomy of the optic
      nerve and peripapillary choroid in the rat eye. METHODS: Gross vascular anatomy
      of the posterior eye segment of Wistar rats was studied in serial microsections
      with a light microscope. The optic nerve and peripapillary choroidal vessels were
      sequentially microdissected, using methylmethacrylate corrosion microvascular
      castings, and were examined with a scanning electron microscope to determine the
      three-dimensional relationships of the vessels. RESULTS: The posterior ciliary
      artery traveled along the inferior side of the optic nerve sheath, directly
      entered the optic nerve head, and divided into three branches: the central
      retinal artery and medial and lateral long posterior ciliary arteries, which
      provided several short branches to the choroid. The optic nerve head vasculature
      was consistently nourished by a recurrent arteriole from the central retinal
      artery and an arteriole from the choroidal artery at the peripapillary choroid.
      The central retinal vein flowed into a venous anastomosis along the optic disc
      border of the peripapillary choroid. Capillaries within the optic nerve drained
      into the central retinal vein, the marginal venous anastomosis of the
      peripapillary choroid, and the pial veins, all of which flowed into the posterior
      ciliary veins along the optic nerve sheath. CONCLUSIONS: The findings illustrate
      vascular anatomic differences in optic nerve and peripapillary choroidal
      microcirculation between rat and human. In rats, the peripapillary choroid plays
      a significant role in both blood supply and venous drainage of the optic nerve
      head. The central retinal artery also contributes to the optic nerve head
      circulation.

PMID- 10586929
TI  - Gelatinase A and TIMP-2 expression in the fibrous sclera of myopic and recovering
      chick eyes.
AB  - PURPOSE: Myopia, or nearsightedness, is characterized by excessive lengthening of
      the ocular globe and is associated with extracellular matrix remodeling in the
      posterior sclera. The activity of gelatinase A, a member of the matrix
      metalloproteinase family, has been shown to increase in the posterior sclera
      during the development of induced myopia in several species. In the present
      study, the distribution and relative expression of gelatinase A and its
      associated inhibitor, tissue inhibitor of metalloproteinases (TIMP)-2, were
      measured within the fibrous scleras of experimentally myopic (form-deprived)
      eyes, control eyes, and eyes recovering from form deprivation to better
      understand the mechanisms that regulate scleral remodeling and the rate of ocular
      elongation. METHODS: Total RNA was extracted from the posterior scleras of form
      deprived chick eyes, eyes recovering from deprivation myopia, and paired
      contralateral control eyes, and subjected to northern blot analysis analyses
      using cDNA probes to chicken gelatinase A and TIMP-2. The distribution of
      gelatinase A and TIMP-2 mRNAs was evaluated by in situ hybridization on frozen
      sections of chick scleras using 33P-labeled RNA probes. Gelatinase A activity
      within the fibrous scleras of form-deprived eyes and paired contralateral
      recovering eyes was evaluated by gelatin zymography. RESULTS: Northern blot
      analysis indicated that the relative expression of gelatinase A was increased by
      128% in deprived eyes (P = 0.009), whereas after 1 day of recovery, levels were
      decreased by 80% in scleras from recovering eyes (P = 0.005). In contrast, TIMP-2
      expression was significantly decreased (-53%, P = 0.027) in the posterior scleras
      of form-deprived eyes. No significant differences were detected in levels of TIMP
      2 expression between recovering eyes and paired control eyes. In situ
      hybridization indicated that most of the gelatinase A transcripts were present in
      the fibrous layer of the posterior scleras from form-deprived and recovering
      eyes. CONCLUSIONS: Changes in the steady state levels of gelatinase A and TIMP-2
      mRNA lead to changes in gelatinase activity within the fibrous sclera and
      mediate, at least in part, the process of visually regulated ocular growth and
      scleral remodeling.

PMID- 10586930
TI  - Tear lipocalins: potential lipid scavengers for the corneal surface.
AB  - PURPOSE: To investigate the dynamic effect of tear lipocalins (TLs), the major
      lipid-binding protein in tears, at aqueous-cornea and lipid-aqueous interfaces,
      and their potential contribution to surface tension in the tear film. METHODS:
      Human apo- and holo-TLs were applied to the aqueous subphase in a Langmuir
      trough, and changes in surface pressure were measured. Changes in the contact
      angle of tear components were observed on Teflon and ferric-stearate-treated
      surfaces. A nitroxide-labeled derivative of lauric acid and a fluorescence
      labeled derivative of palmitic acid were used to monitor the dynamic interaction
      of lipid removed from a hydrophobic surface by the major tear components in
      solution. RESULTS: TLs increase the surface pressure at the aqueous-air interface
      by penetrating, spreading, and rearranging on the surface. Apo-TLs show a longer
      diffusion-dependent induction time than holo-TLs due to more extensive
      oligomerization of the apoprotein. Kinetic analysis of relaxation time suggests
      that apo-TLs have more rapid surface penetration and rearrangement than holo-TLs,
      indicative of a more flexible structure in apo-TLs. TLs reduce the contact angle
      of solutions on lipid films, a property that is greater with TLs than other tear
      proteins. TLs, unlike lysozyme and lactoferrin, remove labeled lipids from
      hydrophobic surfaces and deliver them into solution. CONCLUSIONS: TLs are potent
      lipid-binding proteins that increase the surface pressure of aqueous solutions
      while scavenging lipids from hydrophobic surfaces and delivering them to the
      aqueous phase of tears. These data suggest important functional roles for TLs in
      maintaining the integrity of the tear film.

PMID- 10586931
TI  - Analysis of gene expression in human bullous keratopathy corneas containing
      limiting amounts of RNA.
AB  - PURPOSE: To validate the use of polymerase chain reaction (PCR)-amplified full
      length cDNA as a substitute for mRNA in nucleic acid array and gene expression
      analysis. METHODS: Total RNA was isolated from age-matched normal autopsy corneas
      and pseudophakic bullous keratopathy (PBK) corneas. Full-length cDNA was
      generated and PCR amplified using the Smart cDNA synthesis technology. Southern
      blot analysis of this cDNA was compared with Northern blot analysis of the RNA.
      Amplified cDNA was used to probe a commercial gene array. By
      immunohistochemistry, the expression pattern of several adhesion molecules
      represented on the array was assessed. RESULTS: The cDNA produced by the Smart
      cDNA system gave results very similar to those of northern blot analysis when
      examined for beta2-microglobulin, Rab geranylgeranyl transferase, and tenascin-C.
      This cDNA obtained from normal or PBK corneas was labeled and used to probe a 588
      gene array (Clontech). Among other differences, beta6 integrin was detected only
      with the PBK probe, beta-catenin was markedly elevated in PBK, and beta4 integrin
      appeared to be reduced in PBK. Immunohistochemical patterns of these proteins
      were consistent with the hybridization signals on the gene array. CONCLUSIONS:
      Smart cDNA synthesis and nucleic acid arrays were combined and validated for the
      first time to identify differential gene expression in normal and diseased
      corneas. These techniques require very little RNA such as that equivalent to a
      half of a single cornea, which is useful when the amount of tissue is limiting.
      Altered expression of adhesive proteins beta6 integrin and beta-catenin may be
      related to the formation of epithelial bullae and microcystic changes in PBK
      patients.

PMID- 10586932
TI  - Sympathetic swelling response of the control eye to soft lenses in the other eye.
AB  - PURPOSE: To compare central corneal swelling and light scatter after 8 hours of
      sleep in eyes wearing high- and low-Dk hydrogel lenses and to the contralateral
      control eyes. METHODS: Twenty neophyte subjects wore a Lotrafilcon A (Dk, 140;
      Ciba Vision, Duluth GA) silicone hydrogel lens and an Etafilcon A (Dk, 18;
      Acuvue; Vistakon, Jacksonville, FL) 58% water content hydrogel lens of similar
      center thickness in random order in the right eye only, for overnight 8-hour
      periods. The contralateral nonwearing left eyes served as controls. Central
      corneal thickness was measured using an optical pachometer and light scatter
      using a Van den Berg stray-light meter before lens insertion, after lens removal
      on waking, and every 20 minutes for the next 3 hours. RESULTS: Central corneal
      swelling induced by the Etafilcon A lens on eye opening was significantly higher
      than with the Lotrafilcon A lens (8.66%+/-2.84% versus 2.71%+/-1.91%; P<0.00001).
      Light scatter induced by the Etafilcon A lens on eye opening was significantly
      higher than with the Lotrafilcon A lens (46.09+/-5.62 versus 42.78+/-6.07 Van den
      Berg units, P = 0.0078). The swelling of the control eyes paired with the
      Etafilcon A lens-wearing eyes was also slightly but significantly higher than
      that of the control eyes paired with the Lotrafilcon A lens-wearing eyes (2.34%+/
      1.26% versus 1.44%+/-0.91%; P = 0.0002). Light-scatter measurements were not
      significantly different between control sets of eyes but showed the same trend.
      CONCLUSIONS: In neophyte subjects, corneal swelling of the contralateral control
      eyes appears to be influenced by the swelling of the fellow lens-wearing eyes
      that is, the swelling of the contralateral control eye was significantly lower
      when there was less swelling of the fellow eye wearing the high-Dk lens. Although
      there was no statistically significant difference in light-scatter measurements
      between the control sets of eyes, a trend similar to the corneal swelling results
      was observed, which could be used to support the suggestion that this may be a
      sympathetic physiological response rather than an unusual sampling coincidence.

PMID- 10586933
TI  - Failure to activate transcription factor NF-kappaB in corneal stromal cells
      (keratocytes).
AB  - PURPOSE: Freshly isolated cultures of corneal stromal cells (keratocytes) are
      incompetent to synthesize the tissue remodeling proteinase, collagenase, in
      response to agents such as cytochalasin B (CB) or phorbol myristate acetate
      (PMA), which are strong stimulators of collagenase expression in subcultured
      fibroblasts of all types, including those from corneal stroma. Incompetence is
      due to failure to activate an autocrine interleukin (IL)1alpha feedback loop
      required to mediate cell response. The goal of the present study was to
      investigate the mechanism for this failure. METHODS: A cell culture model of
      freshly isolated corneal stromal cells and subcultured stromal fibroblasts from
      rabbits was used for these studies. RESULTS: Competence to synthesize collagenase
      in response to CB was acquired as a differentiation property by corneal stromal
      cells placed in culture, and did not require subculture. Competence acquisition
      correlated with transition to a fibroblastic spindle shape, assembly of actin
      stress fibers, and the acquired capacity to collapse in response to CB. It was
      demonstrated that competence could be more precisely defined as the capacity to
      express IL-1alpha in response to IL-1, making possible activation of the feedback
      loop. Investigation into the signaling pathway for IL-1alpha expression in
      response to IL-1 revealed a requirement for reactive oxygen species and activity
      of the transcription factor nuclear factor (NF)kappaB. Importantly, freshly
      isolated stromal cells were found to be relatively incompetent to activate NF
      kappaB in comparison to subcultured stromal fibroblasts. CONCLUSIONS: Failure to
      activate NF-kappaB explains incompetence for expression of IL-1alpha in corneal
      stromal cells. Because NF-kappaB regulates many cell functions with potential to
      disturb corneal structure, including expression of inflammatory, stress, and
      degradative proteinase genes; protection against apoptosis; and cell replication;
      this seems likely to be an important mechanism protecting corneal stasis and
      preserving function.

PMID- 10586934
TI  - Photodynamic tissue adhesion with chlorin(e6) protein conjugates.
AB  - PURPOSE: To test the hypothesis that a photodynamic laser-activated tissue solder
      would perform better in sealing scleral incisions when the photosensitizer was
      covalently linked to the protein than when it was noncovalently mixed. METHODS:
      Conjugates and mixtures were prepared between the photosensitizer chlorin(e6) and
      various proteins (albumin, fibrinogen, and gelatin) in different ratios and used
      to weld penetrating scleral incisions made in human cadaveric eyes. A blue-green
      (488-514 nm) argon laser activated the adhesive, and the strength of the closure
      was measured by increasing the intraocular pressure until the wound showed
      leakage. RESULTS: Both covalent conjugates and noncovalent mixtures showed a
      light dose-dependent increase in leaking pressure. A preparation of albumin
      chlorin(e6) conjugate with additional albumin added (2.5 protein to chlorin(e6)
      molar ratio) showed significantly higher weld strength than other protein
      conjugates and mixtures. CONCLUSIONS: This is the first report of dye-protein
      conjugates as tissue solders. These conjugates may have applications in
      ophthalmology.

PMID- 10586935
TI  - Mucocutaneous junction as the major source of replacement palpebral conjunctival
      epithelial cells.
AB  - PURPOSE: The conjunctival epithelium performs an important role in the
      homeostasis and integrity of the eye. To protect the integrity of the ocular
      surface, these cells must be replaced from locally concentrated or randomly
      distributed foci of stem cells. These slow-cycling stem cells produce transient
      amplifying cells that undergo further divisions before becoming mature
      conjunctival epithelial cells. In the current study, the source of palpebral
      conjunctival cells was determined. METHODS: Adult rabbits were injected
      intraperitoneally with bromodeoxyuridine (BrdU) at a dose of 50 mg/kg body weight
      and killed after 1, 3, 5, and 7 days and 2 months. The orbital contents and
      eyelids were exenterated en bloc, frozen to maintain the orientation between the
      eyelids and globe, and sectioned in a parasagittal plane. Random midglobe
      sections were stained for the presence of proliferating cell nuclear antigen
      (PCNA). Additional sections were immunostained to detect BrdU-labeled
      conjunctival epithelial cells. BrdU-positive cells were counted in a series of
      0.4-mm zones from the mucocutaneous junction of the eyelid, through the fornix
      and bulbar conjunctiva. A second set of rabbits received daily injections of BrdU
      for 2 or 4 weeks followed by a 2-month BrdU-free period before death and
      processing. RESULTS: In all eyelid sections examined, there was a focus of PCNA
      positive cells in the mucocutaneous junction and a few scattered PCNA-positive
      cells along the length of the palpebral conjunctiva toward the fornix. In both
      the upper and lower eyelids, the peak concentration of BrdU-labeled cells/0.4-mm
      zone was located at progressively greater distances from the mucocutaneous
      junction in the animals killed at 1, 3, and 5 days respectively and was
      unidentifiable by 7 days. A focus of BrdU-labeled conjunctival cells remained
      within 1 to 2 mm of the mucocutaneous junction at all postinjection intervals.
      These were always found within one cell height of the basement membrane in the
      basal layer of the epithelium. In the long-term studies, BrdU-labeled nuclei were
      retained at the mucocutaneous junction. CONCLUSIONS: The mucocutaneous junction
      of the conjunctival epithelium is a source of actively dividing transient
      amplifying cells that migrate toward the fornix at a rate of approximately 1.7
      mm/d with a transit time of approximately 6 days. Long-term retention of label at
      the mucocutaneous junction indicates that slow-cycling stem cells are present at
      this location. It appears that most palpebral conjunctival epithelial stem cells
      are located near the mucocutaneous junction. These results are not necessarily at
      variance with previous studies, but they diminish the relative importance of the
      forniceal region in palpebral conjunctival homeostasis. The mucocutaneous
      junction may provide a therapeutically significant source of replacement
      conjunctival cells.

PMID- 10586936
TI  - Diffuse loss of sensitivity in early glaucoma.
AB  - PURPOSE: To establish whether there is significant diffuse loss of sensitivity in
      a population of patients with early glaucoma. METHODS: The differential light
      sensitivities at the 10 most sensitive locations from within the central 24
      degrees of program 30-2 of the Humphrey Field Analyzer (Humphrey Instruments, San
      Leandro, CA) were compared in 38 pairs of age-matched subjects, one of each pair
      with early primary open-angle glaucoma (POAG) and the other with normal eyes. All
      subjects had had experience with automated perimetry and had clear media, visual
      acuity of 20/25 or better, and one or fewer false-positive or false-negative
      responses to catch trials. RESULTS: The mean difference in age between the
      subjects with glaucoma and normal subjects was 29 days (P = 0.44, maximum 1.42
      years). The mean paired difference in pupil size was 0.16 mm (P = 0.26), and
      visual acuity was higher in the glaucoma-affected subjects (P = 0.044). The 10
      highest sensitivity measurements in the POAG-affected subjects were found to be
      lower by a median of between 1.0 and 2.0 dB than those in the normal pair members
      (0.0001<P<0.012, sign test). In 60% of the pairs the sensitivity at the seventh
      most sensitive location was 2 dB or more lower in the POAG-affected eyes.
      CONCLUSIONS: Early glaucomatous visual field loss frequently involves a diffuse
      component that includes the 10 most sensitive locations. These findings suggest
      that purely localized visual field loss in glaucoma is rare. These observations
      could not be explained by factors of pupil size and media opacity.

PMID- 10586937
TI  - Apoptosis induced by a corneal-endothelium-derived cytokine.
AB  - PURPOSE: The purpose of this study was to isolate and characterize cDNA clones
      encoding target proteins for autoantibodies in patients at high risk for
      transplant rejection. METHODS: A pool of 10 sera from patients at high risk for
      rejection who had undergone corneal transplantation was used for immunoscreening
      of an endothelial cDNA library, and the cDNA fragments were subcloned into
      prokaryotic expression vectors to generate recombinant fusion proteins.
      Cytotoxicity of recombinant protein was determined by a modified 51Cr-release
      assay. Apoptosis induced by recombinant protein was determined by fluorescent dye
      chromatin fragmentation assay and by TdT-dUTP terminal nick-end labeling (TUNEL)
      assay. An enzyme-linked immunosorbent assay was used to detect the presence of
      antibodies to recombinant protein in the sera of high-risk patients undergoing
      corneal transplantation and of control subjects. RESULTS: Screening of 500,000
      plaques identified six positive clones, one of which demonstrated extensive
      homology with a novel tumor-derived cytokine termed endothelial monocyte
      activating polypeptide (EMAP). EMAP was synthesized as a 39-kDa precursor that
      was proteolytically cleaved to generate an active 22-kDa cytokine. The mature
      peptide of EMAP alone was capable of inducing the death of cultured endothelial
      cells, whereas the propeptide was inactive. The protein synthesis inhibitor
      cycloheximide potentiated EMAP-induced apoptosis in endothelial cells. Cell death
      by apoptosis was evidenced by DNA fragmentation, extensive surface bleb
      formation, and chromatin condensation. A statistically significant difference was
      found in the level of antibodies specific to EMAP between patients at high risk
      for corneal transplant rejection and control subjects (P<0.001). The antibody
      levels were elevated in patients with severe graft reaction when compared with
      patients with no graft reaction (P<0.001). CONCLUSIONS: These studies
      demonstrated that EMAP is a novel protein in corneal endothelial cells that is
      capable of inducing programmed cell death. Overexpression of this cytokine could
      initiate endothelial cell damage leading to stromal edema and corneal
      decompensation.

PMID- 10586938
TI  - Cancer-associated retinopathy induced by both anti-recoverin and anti-hsc70
      antibodies in vivo.
AB  - PURPOSE: In a previous study, both recoverin and heat shock cognate protein 70
      (hsc 70) were found as autoantigens recognized by sera from four patients with
      cancer-associated retinopathy (CAR). This observation suggested that autoimmune
      reactions against recoverin and hsc 70 might be involved together in the
      pathogenesis of CAR. The purpose of the present study is to investigate the
      effects of these autoantibodies on retinas in vivo. METHODS: Functional and
      morphologic properties of the retinas were evaluated after anti-recoverin and/or
      anti-hsc 70 antibodies were intravitreously injected into Lewis rats' eyes.
      RESULTS: Responses in electroretinogram (ERG) of eyes penetrated with anti-hsc 70
      antibody were comparable with the control, but those with anti-recoverin antibody
      were remarkably reduced during the 3-week period after the injection. Such anti
      recoverin antibody-induced reduction was significantly enhanced by copenetration
      with anti-hsc 70 antibody. Immunofluorescence microscopy demonstrated that after
      intravitreal injection, anti-recoverin antibody penetrated toward the outer
      nuclear layer (ONL) and outer segments within 12 to 24 hours, and the presence of
      the antibody in the retina diminished during the next few days. Histopathology
      revealed significant thinning of the ONL and inner nuclear layer (INL) in the
      affected retina in comparison with the control. Throughout the ONL and INL,
      apoptotic cells were recognized by TdT-dUTP terminal nick-end labeling. The
      antibody-induced retinal dysfunction was effectively treated by administrations
      of either corticosteroid or cyclosporin A. CONCLUSIONS: These observations
      suggest that anti-recoverin- and anti-hsc 70 antibody-induced retinal dysfunction
      in Lewis rat is a good model to study the pathophysiology of CAR.

PMID- 10586939
TI  - Evidence for TIMP-1 protection against P. aeruginosa-induced corneal ulceration
      and perforation.
AB  - PURPOSE: To determine the biological significance of individual endogenous tissue
      inhibitors of metalloproteinases (TIMPs) in protection against tissue destruction
      using a Pseudomonas aeruginosa-induced model of corneal ulceration. METHODS:
      Corneal TIMP-1, -2, and -3 mRNA levels were compared between young adult
      (resistant) and aged (susceptible) mice challenged with P. aeruginosa. Resistant
      mice that demonstrated greater amounts of an individual TIMP were treated with
      polyclonal antibody (pAb) to that TIMP. To determine whether TIMP neutralization
      exacerbated P. aeruginosa-induced corneal disease, TIMP pAb- and normal rabbit
      serum (NRS)- (control) treated mice were examined macroscopically and
      histopathologically after infection. Corneal neutrophil (PMN) myeloperoxidase
      (MPO) levels also were examined in these mice. RESULTS: Greater amounts of TIMP-1
      mRNA only were found in corneas of resistant versus suscep tible mice after P.
      aeruginosa challenge. Systemic treatment of resistant mice with TIMP-1 pAb
      resulted in corneal perforation by 5 to 7 days after infection (PI).
      Histopathologic evaluation of corneal tissues from TIMP-1 pAb- versus NRS-treated
      mice confirmed that TIMP-1 pAb treatment resulted in extensive stromal
      dissolution. This treatment also was associated with loss of epithelium within
      the central cornea. Both the histopathology and PMN MPO enzyme assays also showed
      an increase in corneal PMN number following TIMP-1 pAb treatment. CONCLUSIONS:
      These studies provide evidence that, after P. aeruginosa infection, adequate
      endogenous expression of TIMP-1 in cornea protects against extensive corneal
      tissue destruction. The protective effects of TIMP-1 may be multifactorial. In
      addition to directly protecting extracellular matrix components from active
      matrix metalloproteinases, TIMP-1 may either directly or indirectly influence
      recruitment of PMNs into infected cornea. Finally, TIMP-1 also may affect wound
      healing and resurfacing of the corneal epithelium.

PMID- 10586940
TI  - Macrophages and dendritic cells in IRBP-induced experimental autoimmune
      uveoretinitis in B10RIII mice.
AB  - PURPOSE: To investigate the characteristics of the mononuclear cell infiltrate in
      murine experimental autoimmune uveoretinitis (EAU). METHODS: EAU was induced by
      immunization with bovine interphotoreceptor retinal binding protein (IRBP) in
      Freund's complete adjuvant (subcutaneous injection) and pertussis toxin
      (intraperitoneal injection) in B10RIII mouse. Then animals were killed on days 7,
      9, 12, 15, 20, 26, and 39 after immunization. Eyes were processed for hematoxylin
      and eosin staining to characterize the disease and to assess the severity and
      extent of the EAU. Single and dual immunohistochemical staining in various
      combinations with monoclonal antibodies against CD45, CD4, CD8, major
      histocompatibility complex (MHC) class II, CD11c, NLDC-145, and a variety of
      macrophage markers was performed. RESULTS: The authors' results showed that
      vitritis, vasculitis and perivasculitis, retinal detachment, and granuloma
      formation in retina and choroid were the predominant features of IRBP-induced
      B10RIII mice EAU. Immunohistologic results showed that CD4+ T cells and
      macrophages were the main infiltrating cells in retina and choroid throughout the
      entire course of the disease. MHC class II negative macrophages expressing
      antigens reacting with MOMA-2, F4/80, sialoadhesin, and CD11b were prominent
      during the peak phase of tissue damage in the retina and choroid. Dendritic cells
      (DCs) characterized by dual positivity for MHC class II and CD11c and negative
      for sialoadhesin appeared at time of disease onset and continued to be recruited
      during the inflammatory process. DCs at the site of inflammation were NLDC-145
      weak and CD8 negative, indicating that they were of the myeloid rather than the
      lymphoid lineage. CONCLUSIONS: The results suggest that EAU in B10RIII mice is
      initiated by local-infiltrating, dendritic antigen-presenting cells, whereas
      tissue damage is associated with sialoadhesin-positive, phagocytic nonantigen
      presenting macrophages during the effector stage.

PMID- 10586941
TI  - Retinal microglia differentially express phenotypic markers of antigen-presenting
      cells in vitro.
AB  - PURPOSE: Retinal microglial cells of newborn Lewis rats were isolated and
      cultured, and the effect of macrophage colony-stimulating factor (M-CSF),
      granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma
      (IFN-gamma) on microglial expression of the accessory molecules required for
      antigen presentation were studied. METHODS: Retinal microglia were isolated from
      newborn Lewis rats and cultured in media supplemented with either M-CSF or GM
      CSF. Immunohistochemical tests using anti-macrophage complement receptor 3 (OX42)
      or anti-monocyte-macrophage (ED1) and DiI-ac-low-density lipoprotein (LDL) uptake
      were used to identify microglia. The effect on accessory molecule expression of
      microglial cells cultured under varying conditions (M-CSF, GM-CSF, and M-CSF plus
      IFN-gamma) was analyzed by fluorescence-activated cell sorter, using one of the
      following antibodies: anti-OX3, anti-OX6, anti-rat intercellular adhesion
      molecule (ICAM)-1, anti-rat B7-1, or anti-rat B7-2. RESULTS: The cultured retinal
      microglia were positive for macrophage-related antigens (ED1 and OX42) and also
      showed uptake of LDL. Furthermore, ICAM-1 and B7-2 were expressed constitutively
      on these cells, and MHC class II and B7-1 were also expressed after IFN-gamma
      stimulation. CONCLUSIONS: In vitro, the retinal microglia express the molecules
      required for effective antigen presentation to CD4-positive T cells. These
      findings suggest that microglia may play a role in local antigen presentation,
      especially when they are exposed to IFN-gamma.

PMID- 10586942
TI  - Changes in cytokine mRNA levels in experimental corneal allografts after local
      clodronate-liposome treatment.
AB  - PURPOSE: Corneal allograft rejection in rats can be prevented by subconjunctival
      injections of liposomes containing dichloromethylene diphosphonate (clodronate
      LIP), which selectively eliminate macrophages. In this study, the effect of
      clodronate-LIP treatment on cytokine mRNA levels in corneal allografts was
      examined. METHODS: AO rats received corneal grafts of PVG rats. Rats were either
      not treated or injected subconjunctivally with clodronate-LIP on the day of
      transplantation and on postoperative days (PODs) 2, 4, 6, and 8. RNA was isolated
      from the graft and rim of corneas at different times after transplantation and
      from normal controls. Interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1RA),
      IL-2, IL-4, IL-6, IL-10, IL-12p40, tumor necrosis factor (TNF)-alpha, TNF
      beta/lymphotoxin (LT), interferon (IFN)-gamma, monocyte chemotactic protein 1
      (MCP-1), and macrophage inflammatory protein 2 (MIP-2) mRNA levels were analyzed
      by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR).
      RESULTS: Corneal rejection, observed in all untreated rats by POD 12, was
      associated with increased mRNA levels of all cytokines investigated in grafts and
      rims. Clodronate-LIP treatment prevented allograft rejection and strongly
      decreased the levels of IL-1beta, IL-1RA, IL-2, IL-4, IL-6, IL-10, IFN-gamma, TNF
      beta/LT, MCP-1, and MIP-2 mRNA in grafts and IL-1 beta, IL-2, IL-4, IL-6, and IFN
      gamma mRNA in rims. Interleukin-12p40 mRNA levels were unaltered in clodronate
      treated rats, except for a transient increase in grafts at POD 3. TNF-alpha mRNA
      levels were increased by clodronate-LIP in grafts and rims early after
      transplantation (PODs 3 and 7). Despite a normal appearance, long-term accepted
      corneal grafts (POD 100) contained mRNA for IL-10, IL-12p40, TNF-alpha, MCP-1,
      and MIP-2. CONCLUSIONS: Clodronate-liposome treatment markedly altered the mRNA
      levels of all cytokines investigated in corneal allografts. These results may
      explain in part the mechanism by which clodronate-LIP treatment prevents corneal
      allograft rejection.

PMID- 10586943
TI  - Immune privilege is extended, then withdrawn, from allogeneic tumor cell grafts
      placed in the subretinal space.
AB  - PURPOSE: To determine whether the subretinal space can extend immune privilege to
      allogeneic tumor cell grafts that do not possess their own inherent immune
      privilege. METHODS: P815 tumor cells were injected into the anterior chamber
      (AC), the subretinal (SR) space, or subconjunctivally in eyes of BALB/c
      (allogeneic), SCID (immune incompetent), normal DBA/2 (syngeneic), or DBA/2 mice
      presensitized with P815 cells transfected with interleukin-12 and B7.1. Tumor
      growth was observed clinically and histologically for up to 50 days. BALB/c
      recipients were tested for suppression of DBA/2-specific delayed hypersensitivity
      and concomitant immunity. The SR space of tumor-containing eyes was assessed for
      its capacity to support ovalbumin (OVA)-specific anterior chamber associated
      immune deviation (ACAID). RESULTS: P815 cells injected into the SR space of
      presensitized and normal DBA/2 and SCID mice grew progressively, resulting
      eventually in recipient death. Tumor cells injected into the SR space of eyes of
      BALB/c mice grew progressively until day 14, followed by tumor regression
      resulting in phthisis bulbi (14/35) or tumor elimination (19/35) with preserved
      ocular anatomy by day 35. Despite elimination of tumors from the SR space, BALB/c
      recipients exhibited DBA/2-specific ACAID and concomitant immunity. In addition,
      OVA injected into the SR space of eyes from which tumor has been eliminated
      induced ACAID. CONCLUSIONS: Various parameters of immune privilege, originally
      described for the AC, are characteristic of immune privilege within the SR space.
      However, because P815 cells placed in the AC prove lethal for BALB/c recipients,
      but P815 cells placed in the SR space resolve without jeopardizing the host's
      life, immune privilege in the SR space can be distinguished from immune privilege
      in the AC, and this may have implications for grafts of retinal tissue placed
      within the SR space.

PMID- 10586944
TI  - Loss of anterior chamber-associated immune deviation (ACAID) in aged retinal
      degeneration (rd) mice.
AB  - PURPOSE: To determine whether the capacity to induce ACAID by antigen injection
      into the anterior chamber is altered in animals with genetically determined
      retinal degeneration and increased age. METHODS: Anterior chamber-associated
      immune deviation (ACAID) induced by injection of ovalbumin into the anterior
      chamber of the eye was studied in three rodent strains with different forms of
      hereditary retinal degeneration (Royal College of Surgeon [RCS] rats, retinal
      degeneration [rd] mice, and Norrie-Disease [ND] mice) and in different age groups
      (age range, 1-23 months). The data were compared with those of age-matched
      controls. Aqueous humors of rd mice, RCS rats, and age-matched congenic controls
      were investigated for concentrations of transforming growth factor-beta2 (TGF
      beta2) using enzyme-linked immunosorbent assay. RESULTS: ACAID was readily
      induced in RCS rats and ND mice irrespective of amount of retinal degeneration or
      aging. In rd mice ACAID could be induced in young animals but not in animals more
      than 12 months of age. In old rd mice, loss of ACAID was accompanied by a marked
      reduction in total TGF-beta2 levels in aqueous humor. CONCLUSIONS: Rd mice more
      than 1 year of age lose the capacity of the anterior chamber to support the
      induction of ACAID by intracameral injection of soluble protein antigen. Because
      loss of ACAID correlated with a decrease in TGF-beta2 concentration in aqueous
      humor, it is proposed that eyes of rd mice are unable to maintain an
      immunosuppressive microenvironment necessary for ACAID.

PMID- 10586945
TI  - Stimulation of macrophages by retinal proteins: production of reactive nitrogen
      and oxygen metabolites.
AB  - PURPOSE: In previous work, it has been shown that in experimental autoimmune
      uveitis, the peroxynitrite-mediated protein nitration product nitrotyrosine was
      localized in the degenerating photoreceptors. Subsequently, phagocyte-generated
      inducible nitric oxide synthase (iNOS) was also found to localize, primarily in
      the outer retina and to a lesser extent in the anterior segments. This study was
      intended to determine whether retinal soluble proteins such as S-antigen and
      interphotoreceptor retinoid-binding protein (IRBP) play a role in the induction
      of *NO and superoxide by a macrophage cell line and by rat and rabbit peritoneal
      macrophages. METHODS: Cells from the murine macrophage cell line RAW 264.7 and
      rat and rabbit peritoneal macrophages were incubated in the presence of retinal
      soluble proteins. The nitrite level in the cultured supernatant was evaluated for
      *NO production using the Griess reaction. Activation of nuclear transcription
      factor kappaB (NF-kappaB) was determined by electrophoretic mobility shift assay.
      Superoxide production was measured by superoxide dismutase-inhibitable reduction
      of cytochrome C. RESULTS: Both S-antigen and IRBP induced significant, dose
      dependent nitrite production in RAW 264.7 and rat peritoneal macrophages.
      Induction of iNOS by retinal proteins was inhibited by the iNOS-specific
      inhibitor aminoguanidine and the tyrosine kinase inhibitor genistein. This iNOS
      induction was accompanied by the activation of NF-kappaB. S-antigen also induced
      superoxide production in rabbit peritoneal macrophages, but not in RAW 264.7.
      CONCLUSIONS: These results show that soluble retinal proteins significantly
      induce *NO and superoxide production by macrophages. Increased production of
      reactive oxygen species by macrophages in the presence of these soluble retinal
      proteins in vivo may accelerate photoreceptor degeneration in uveitis.

PMID- 10586946
TI  - Differential expression of facilitative glucose transporters GLUT1 and GLUT3 in
      the lens.
AB  - PURPOSE: To determine the expression patterns for members of the facilitative
      glucose transporter family (GLUT1-4) in the rat lens. METHODS: An initial
      molecular profiling of GLUT expression in lens fiber cells was achieved using
      reverse transcription-polymerase chain reaction (RT-PCR). The presence of isoform
      specific transcript detected by RT-PCR was then confirmed using northern blot
      analysis and in situ hybridization. The presence of transporter protein was
      verified by western blot analysis and immunocytochemistry. RESULTS: Transcripts
      for GLUT1 and GLUT3, but not for GLUT2 and GLUT4, were detected by RT-PCR of
      fiber cell mRNA. Transcript for GLUT3, but not for GLUT1, was detected by
      northern blot analysis of fiber cell total RNA, indicating that GLUT3 was the
      predominant isoform in the fiber cells. In situ hybridization and
      immunolocalization in rat lens sections confirmed this result at the transcript
      and protein levels, respectively. In contrast, GLUT1 was predominantly expressed
      in the lens epithelium and only to a limited extent in the equatorial fiber
      cells. CONCLUSIONS: GLUT1 and GLUT3 are differentially expressed in the rat lens.
      The presence of the high-affinity transporter GLUT3 in fiber cells indicates that
      these cells have the capacity to take up glucose independently from the
      epithelium.

PMID- 10586947
TI  - Intravitreal injection of TGFbeta induces cataract in rats.
AB  - PURPOSE: In a previous study, it was determined that TGFbeta induces cataractous
      changes in the rat lens in vitro. The purpose of the present study was to
      determine whether the introduction of biologically active TGFbeta into the
      vitreous stimulates cataractous changes in the rat lens in situ. METHODS: TGFbeta
      was injected into the vitreous of the left eye of anesthetized adult male Wistar
      rats. The right eye received sterile vehicle as a control. Three to four months
      after injection, animals were killed, and lenses were enucleated and examined for
      cataractous changes. RESULTS: All lenses from control eyes remained transparent
      and maintained normal cellular architecture throughout. In contrast, lenses from
      TGFbeta-injected eyes displayed cloudiness in the cortex. In some lenses,
      distinct opacities were also apparent at the equator and extending some distance
      toward the anterior and posterior poles. Histologically, the opacities
      corresponded to subcapsular plaques containing aberrant cells and accumulations
      of extracellular matrix. In addition, cortical fibers in the anterior and
      posterior of all lenses displayed variable degrees of swelling, and many retained
      their nuclei. In some regions, the fiber cells appeared to have degenerated to
      form large homogeneous areas. The cellular architecture of the equator of these
      lenses was also disrupted and, in the most severe case, no bow zone was apparent
      with nucleated cells extending to the posterior pole. CONCLUSION: The
      introduction of active TGFbeta into the vitreous induced lenses to undergo
      cataractous changes. In addition to the TGFbeta-induced changes in the epithelium
      that were reported previously, cataractous changes observed in this study also
      involved the lens fiber cells and resembled changes observed in human posterior
      subcapsular and cortical cataracts.

PMID- 10586948
TI  - UV filter compounds in human lenses: the origin of 4-(2-amino-3-hydroxyphenyl)-4
      oxobutanoic acid O-beta-D-glucoside.
AB  - PURPOSE: To investigate UV filter synthesis in the human lens, in particular the
      biosynthetic origin of the second most abundant UV filter compound, 4-(2-amino-3
      hydroxyphenyl)-4-oxobutanoic acid O-beta-D-glucoside. METHODS: Human lenses were
      analyzed by high-performance liquid chromatography (HPLC) after separate
      incubation with 3H-tryptophan (3H-Trp), beta-benzoylacrylic acid, D,L-alpha-amino
      beta-benzoylpropionic acid, or D,L-3-hydroxykynurenine O-beta-D-glucoside. The
      effect of pH on the model compound D,L-alpha-amino-beta-benzoylpropionic acid and
      D,L-3-hydroxykynurenine O-beta-D-glucoside was also investigated. RESULTS: UV
      filters were not detected in fetal lenses, despite a 5-month postnatal lens
      displaying measurable levels of UV filters. In adults no radiolabel was
      incorporated into 4-(2-amino-3-hydroxyphenyl)-4-oxobutanoic acid O-beta-D
      glucoside after 3H-Trp incubations. Beta-benzoylacrylic acid was readily reduced
      in lenses. D,L-alpha-amino-beta-benzoylpropionic acid and D,L-3-hydroxykynurenine
      O-beta-D-glucoside slowly deaminated at physiological pH and were converted to
      beta-benzoylpropionic acid and 4-(2-amino-3-hydroxyphenyl)-4-oxobutanoic acid O
      beta-D-glucoside, respectively, after lens incubations. CONCLUSIONS: UV filter
      biosynthesis appears to be activated at or near birth. Compounds containing the
      kynurenine side chain slowly deaminate, and in the lens, the newly formed double
      bond is rapidly reduced. These findings suggest that 4-(2-amino-3-hydroxyphenyl)
      4-oxobutanoic acid O-beta-D-glucoside is derived from L-3-hydroxykynurenine O
      beta-D-glucoside through this deamination-reduction process. The slowness of the
      deamination presumably accounts for the absence of incorporation of radiolabel
      from 3H-Trp into 4(2-amino-3-hydroxyphenyl)4-oxobutanoic acid O-beta-D-glucoside.

PMID- 10586949
TI  - Effects of adrenomedullin on cyclic AMP formation and on relaxation in iris
      sphincter smooth muscle.
AB  - PURPOSE: To determine whether iris sphincter and other tissues of the iris
      ciliary body secrete adrenomedullin (ADM), a novel hypotensive peptide that is
      classified into the calcitonin gene-related peptide (CGRP) family and to
      determine the binding sites for ADM and compare the effects of ADM and CGRP in
      the absence and presence of their receptor antagonists on cAMP formation and
      relaxation in the iris sphincter. METHODS: Sphincter muscle was incubated in
      Krebs-Ringer bicarbonate buffer in the absence and presence of ADM for 10
      minutes. Accumulation of cAMP in the tissue extract was determined by
      radioimmunoassay (RIA). The binding of [125I]ADM to iris sphincter membranes was
      carried out by rapid filtration. Distribution of ADM in the ocular tissues was
      determined by RIA. Changes in muscle tension were recorded isometrically.
      RESULTS: Immunoreactive ADM was present in all tissues of the cat iris-ciliary
      body. In the isolated cat iris sphincter, ADM increased cAMP accumulation in a
      time- (t1/2 = 2.2 minutes) and concentration- (EC50 = 13 nM) dependent manner,
      and this effect was sixfold more efficacious than CGRP. ADM, CGRP, vasoactive
      intestinal peptide, prostaglandin E2, isoproterenol, and forskolin increased cAMP
      formation in cat sphincter by 12.5-, 2-, 2.2-, 1-, 2.6-, and 2.4-fold,
      respectively. The rank of the effects of ADM on cAMP formation in iris sphincter
      isolated from different animal species was in the following order: cat > dog >
      bovine > human > rabbit. In the cat iris sphincter, the CGRP antagonist, CGRP(8
      to 37), was more effective than the ADM antagonist, ADM (26 to 52), in inhibiting
      both ADM- and CGRP-induced cAMP formation. ADM and CGRP inhibited carbachol
      induced contraction in a concentration-dependent manner with IC50 values of 10
      and 90 nM, respectively. Both ADM and CGRP displaced the binding of [125I]ADM to
      sphincter membranes effectively, with IC50 values of 0.81 and 1.15 nM,
      respectively. CONCLUSIONS: In iris sphincter isolated from cat and other
      mammalian species including human, ADM is a much more efficacious activator of
      adenylate cyclase and a much more effective relaxant than CGRP. Its biological
      effects may be due to direct involvement of ADM receptors, but also to activation
      of CGRP receptors. Activation of ADM receptors by the peptide leads to
      concentration-dependent increases in cAMP accumulation and subsequent inhibition
      (relaxation) of smooth muscle contraction. These findings suggest a role for ADM
      as a local modulator of smooth muscle tone. A possible function for this potent
      hypotensive peptide in the regulation of intraocular pressure remains to be
      investigated.

PMID- 10586950
TI  - The effects of protein kinase C on trabecular meshwork and ciliary muscle
      contractility.
AB  - PURPOSE: The possible role of protein kinase C (PKC) inhibitors in novel pressure
      lowering drugs is currently under investigation. To gain further insight into
      regulation of contractility by PKC in trabecular meshwork (TM) and ciliary muscle
      (CM), the effects of various PKC inhibitors and activators were tested. METHODS:
      Isometric tension measurements of bovine TM and CM strips were performed. PKC was
      stimulated by phorbol ester and by the diacylglycerol analogue diC8. PKC blockade
      was accomplished using H7 and myristoilated PKC substrate (mPKC). Western blot
      analysis was used to identify specific PKC isoforms in human trabecular meshwork
      (HTM), human ciliary muscle (HCM), and bovine TM and CM. RESULTS: In tissues
      precontracted by carbachol PKC antagonist H7 led to a relaxation of TM (25+/-7.2
      versus 100%; n = 8) with no effect on CM. mPKC substrate selectively blocks PKC.
      This substance led to relaxation of TM (32.8+/-7.4 versus 100%, n = 7), whereas
      CM was not affected. PMA at concentrations of 10(-6) M led to a slow contraction
      of both tissues that was more marked in TM. DiC8 and 4alpha-phorbol had no effect
      on contractility. Western blot analysis revealed expression of calcium-dependent
      PKC-alpha and calcium-independent PKC-epsilon isoforms in HTM and HCM. PKC
      epsilon expression was more pronounced in HTM than in HCM. Similar PKC isoform
      expression was found in native bovine tissue. CONCLUSIONS: PKC isoforms show
      different tissue distributions in human and bovine TM and CM. Contractility
      differences exist in both tissues in response to PKC antagonists and agonists.
      The data indicate that PKC may be involved in regulation of aqueous humor outflow
      by the TM. Thus, inhibition of PKC may represent a new way of influencing outflow
      facility through isolated relaxation of TM.

PMID- 10586952
TI  - Comet assay of UV-induced DNA damage in retinal pigment epithelial cells.
AB  - PURPOSE: The molecular mechanisms mediating photic injury to the retinal pigment
      epithelial (RPE) cell are not clearly understood. This study examined qualitative
      and quantitative aspects of DNA damage caused by broadband UVA and UVB radiation
      in RPE cells. METHODS: Cultured bovine RPE cells were exposed to doses of between
      0 and 0.9 J/cm2 UVA or 0 and 0.09 J/cm2 UVB, as either a suspension or as an
      attached monolayer. The damage to DNA resulting in single-strand breaks was
      assessed by means of the comet assay in which the damaged DNA migrates out of the
      nucleus forming a tail, and this was quantified using image analysis. Two
      measurements were taken: the mean percentage of tail DNA, which reflects the
      overall level of DNA damage in the group of cells, and the Olive tail moment,
      which represents the extent of migration and thus the pattern of DNA damage in
      individual cells. Cells were processed by the comet assay immediately after UV
      exposure in acute experiments. To study the occurrence of DNA repair, RPE cells
      were first exposed to UVB and then incubated at 37 degrees C for either 1 or 24
      hours before processing for the comet assay. RESULTS: UVA- and UVB-exposed cells
      showed a mean percentage of tail DNA that was significantly greater than in
      unexposed cells. Olive tail moment was higher in cells exposed to larger doses of
      UVB. This parameter also showed a bimodal distribution when assessed 24 hours
      after exposure to UVB indicating the presence of two distinct subpopulations of
      cells with small and large tail moments. Cells with very large tail moments were
      not seen with doses below 0.045 J/cm2. CONCLUSIONS: Relatively low doses of UVA
      and UVB induce the formation of DNA strand breaks in cultured RPE. The tail
      moment profiles for cells incubated for 24 hours after UVB irradiation are
      consistent with the occurrence of DNA repair in most cells exposed to low doses
      and apoptosis in a subpopulation of the cells exposed to high doses.

PMID- 10586951
TI  - A point mutation (W70A) in the rod PDE-gamma gene desensitizing and delaying
      murine rod photoreceptors.
AB  - PURPOSE: To examine the corneal electroretinogram (ERG) of transgenic mice (W70A
      mice) carrying a point mutation (W70A) in the gene encoding for the gamma-subunit
      of rod cGMP phosphodiesterase (PDEgamma). METHODS: The ERG of W70A mice was
      compared with that of normal mice. Cone responses were separated from rod
      responses by light adaptation, whereas rod sensitivity was assessed by threshold
      stimulation with dim light. Spectral sensitivity curves of the ERG were obtained
      using a constant response criterion. RESULTS: The ERG of the W70A mouse has a
      desensitized, delayed rod b-wave at threshold, and a prolonged rod b-wave at
      higher flash intensities. The a-wave is absent even at maximal stimulation. The
      cone ERG of the W70A mouse is indistinguishable from that of normal mice. The
      spectral sensitivity of the W70A mouse is maximal in the UV spectrum, in contrast
      to the normal mouse, which is most sensitive in the green region of the spectrum.
      This supports the interpretation of the results as normal cone and abnormal rod
      function in the W70A mouse. CONCLUSIONS: The W70A mouse represents new model of
      stationary nyctalopia that can be recognized by its unusual ERG features.

PMID- 10586953
TI  - Fluorescent photoreceptors of transgenic Xenopus laevis imaged in vivo by two
      microscopy techniques.
AB  - PURPOSE: To develop a method for imaging individual photoreceptors in an intact
      transgenic Xenopus eye, thus allowing in vivo observation of the effects of
      various transgenes on photoreceptor development, degeneration, or both. METHODS:
      Albino and pigmented transgenic Xenopus laevis that express enhanced green
      fluorescent protein (GFP) in the major ("red") rods were generated. The
      distribution of GFP throughout the retina and within the rods was evaluated by
      confocal microscopy of frozen sections and immunoelectron microscopy. In vivo
      images of photoreceptors were obtained using conventional fluorescence
      microscopes to image through the lens of the eye or a laser scanning confocal
      microscope to image through the hypopigmented iris of albino eyes. RESULTS:
      Confocal and immunoelectron microscopy of tissue sections showed that GFP was
      predominantly localized to the inner segments of the major rods; a smaller amount
      was in the outer segments. In a number of animals, not all the major rods
      expressed GFP. It was possible to identify these animals by obtaining
      fluorescence images of the retinas of intact, living tadpoles with conventional
      fluorescence microscopes, using the lens of the tadpole as part of the optical
      path. Confocal images of living animals could be used to visualize the
      distribution of GFP within the photoreceptors. CONCLUSIONS: The ability to
      observe individual photoreceptors noninvasively allows in vivo longitudinal
      microscopic analysis of photoreceptor development in transgenic Xenopus tadpoles.

PMID- 10586955
TI  - Induction of vascular endothelial growth factor after application of mechanical
      stress to retinal pigment epithelium of the rat in vitro.
AB  - PURPOSE: To investigate the response to mechanical stress of vascular endothelial
      growth factor (VEGF) production by cultured retinal pigment epithelial (RPE)
      cells. METHODS: A pulsatile stretch device was used in vitro. RPE cells of the
      second passage were seeded onto flexible-bottomed culture plates; then, at
      subconfluent culture, the plates were subjected to pulsatile stretch. Culture
      plates prepared in the same way but not subjected to stretch were used as
      controls. After stretching for 1 hour or 24 hours, conditioned medium for
      measurement of VEGF production by RPE cells was collected using a mouse VEGF
      immunoassay. To study the expression of VEGF in RPE cells, passaged-cultured RPE
      cells were exposed to pulsatile stretch for 0, 1, 3, or 14 hours. Total
      cytoplasmic RNA was then prepared from the RPE cells. Northern blot analysis was
      performed for VEGF, with G3PDH used as an internal control. RESULTS: The
      expression and secretion of VEGF in RPE cells were increased by pulsatile
      stretching. CONCLUSIONS: Results indicate that stretching of the RPE could result
      in increased production of VEGF, with associated risk for neovascularization and
      changes in the blood-retinal barrier.

PMID- 10586954
TI  - Insulin-induced vascular endothelial growth factor expression in retina.
AB  - PURPOSE: Clinical studies have demonstrated that intensive insulin therapy causes
      a transient worsening of retinopathy. The mechanisms underlying the initial
      insulin-induced deterioration of retinal status in patients with diabetes remain
      unknown. Vascular endothelial growth factor (VEGF) is known to be operative in
      the pathogenesis of diabetic retinopathy. The current study was conducted to
      characterize the effect of insulin on retinal VEGF gene expression in vitro and
      in vivo. METHODS: The effect of insulin on VEGF expression in vivo was examined
      by in situ hybridization studies of rat retinal VEGF transcripts. To examine the
      mechanisms by which insulin regulates VEGF expression, human retinal pigment
      epithelial (RPE) cells were exposed to insulin, and VEGF mRNA levels were
      quantified with RNase protection assays (RPAs). Conditioned media from insulin
      treated RPE cells were assayed for VEGF protein and capillary endothelial cell
      proliferation. The capacity of insulin to stimulate the VEGF promoter linked to a
      luciferase reporter gene was characterized in transient transfection assays.
      RESULTS: Insulin increased VEGF mRNA levels in the ganglion, inner nuclear, and
      RPE cell layers. In vitro, insulin increased VEGF mRNA levels in human RPE cells
      and enhanced VEGF promoter activity without affecting transcript stability.
      Insulin treatment also increased VEGF protein levels in conditioned RPE cell
      media in a dose-dependent manner with a median effective concentration of 5 nM.
      The insulin-conditioned RPE cell media stimulated capillary endothelial cell
      proliferation, an effect that was completely blocked by anti-VEGF neutralizing
      antibody. CONCLUSIONS: Insulin increases VEGF mRNA and secreted protein levels in
      RPE cells through enhanced transcription of the VEGF gene. Intensive insulin
      therapy may cause a transient worsening of retinopathy in patients with diabetes
      through increased retinal VEGF gene expression.

PMID- 10586956
TI  - Retinal pathology of canine X-linked progressive retinal atrophy, the locus
      homologue of RP3.
AB  - PURPOSE: To describe the course of photoreceptor disease in canine X-linked
      retinal degeneration. METHODS: Retinas from 55 dogs (44 males, 8 carrier females,
      3 homozygous females) were obtained by enucleation under general anesthesia.
      After fixation and dehydration, tissues were embedded in epoxy resin, sectioned
      at 1 microm for light microscopy and stained with azure II/methylene blue and a
      paraphenylenediamine counterstain. For electron microscopy, regions identified by
      light microscopy were selected and cut at 60 nm. Sections were stained with
      uranyl acetate-lead citrate. Electroretinography from an additional group of
      normal males, affected males, and carrier females was performed and the rod and
      cone responses evaluated. RESULTS: The earliest lesion detectable by electron
      microscopy was vesiculation of rod discs, followed by disruption of outer
      segments and death of rods. Loss of cones and progressive atrophy of inner
      retinal layers followed. Lesions were most severe in the peripheral retina and
      advanced toward the optic disc with disease progression. Significant variation in
      disease severity was present in males despite the presence of the same disease
      allele in all affected dogs. Carrier females displayed generalized reduction in
      photoreceptor density as well as multifocal areas of complete rod loss. The
      electroretinogram (ERG) findings were compatible with the histopathologic
      abnormalities. Homozygous females had lesions similar to those seen in affected
      males. CONCLUSIONS: X-linked retinal degeneration is characterized by initial
      degeneration of rod photoreceptors, followed by loss of cones and progressive
      atrophy of the inner retina. Carrier females display a phenotype consistent with
      random X-chromosome inactivation. Variation in genetic background may alter
      expression of the disease allele in affected animals, thus accounting for
      variation in phenotypic expression of the disease.

PMID- 10586957
TI  - Vitronectin gene expression in the adult human retina.
AB  - PURPOSE: To determine whether vitronectin (Vn), a plasma protein and
      extracellular matrix molecule that is also a prominent constituent of drusen, is
      synthesized by cells in the adult human retina. METHODS: The distribution of Vn
      in the normal adult human retina was examined using antibodies to circulating
      plasma Vn and to the multimeric, heparin-binding form that is most prevalent in
      extravascular tissues. Evidence of Vn transcription by retinal cells was analyzed
      by in situ hybridization and also by reverse transcription of total RNA derived
      from dissociated human or mouse photoreceptors followed by amplification using
      polymerase chain reaction (RT-PCR). RESULTS: Cytoplasmic immunoreactivity for
      plasma Vn or multimeric Vn was detected in photoreceptors, in a subpopulation of
      neurons situated in the inner retina, and in vitreous hyalocytes. Extracellular
      labeling was limited primarily to Bruch's membrane and the retinal vasculature.
      At the transcriptional level, Vn mRNA was localized to both photoreceptors and
      ganglion cells by in situ hybridization. The in situ findings were corroborated
      by RT-PCR using total RNA from dissociated mouse or human photoreceptor cells.
      CONCLUSIONS: The results constitute the first evidence for Vn gene expression by
      adult neurons in the mammalian central nervous system. The identification of the
      photoreceptors as a cellular source of Vn suggests that these cells have the
      potential to make a biosynthetic contribution to the Vn that is found in drusen.

PMID- 10586958
TI  - Human Muller glial cells: altered potassium channel activity in proliferative
      vitreoretinopathy.
AB  - PURPOSE: To determine differences of K+ channel activity between Muller glial
      cells obtained from retinas of healthy human donors and of patients with retinal
      detachment and proliferative vitreoretinopathy. METHODS: Muller cells were
      enzymatically isolated from retinas of healthy donors and from excised retinal
      pieces of patients. The whole-cell and the cell-attached configurations of the
      patch-clamp technique were used to characterize the current densities of
      different K+ channel types and the activity of single Ca2+ -activated K+ channels
      of big conductance (BK). RESULTS: Cells from patients displayed a less negative
      mean membrane potential (-52.8 mV) than cells from healthy donors (-80.6 mV).
      However, the membrane potentials in cells from patients scattered largely between
      -6 and -99 mV. The inwardly rectifying K+ permeability in cells from patients was
      strongly reduced (0.3 pA/pF) when compared with cells from healthy donors (6.0
      pA/pF). At the resting membrane potential, single BK channels displayed a higher
      mean activity (open probability, Po, and channel current amplitude) in cells from
      patients (Po, 0.30) than in cells from healthy donors (Po: 0.03). The variations
      of BK current amplitudes were correlated with the variations of the membrane
      potential. CONCLUSIONS: The dominant expression of inwardly rectifying channels
      in cells from healthy donors is thought to support important glial cell functions
      such as the spatial buffering of extracellular K+. The downregulation of these
      channels and the less negative mean membrane potential in cells from patients
      should impair spatial buffering currents and neurotransmitter clearance. The
      increased activity of BK channels may support the proliferative activity of
      gliotic cells via feedback regulation of Ca2+ entry and membrane potential.

PMID- 10586959
TI  - Development of rivalry and dichoptic masking in human infants.
AB  - PURPOSE: To examine the development of rivalry, dichoptic masking, and binocular
      interactions in infants more than 5 months of age using the visual evoked
      potential (VEP). METHODS: VEPs were recorded in 35 infants between 5 and 15
      months of age and 23 adults between 13 and 59 years of age. Counterphasing,
      sinusoidal, 1 cycle/deg gratings were presented dichoptically. Responses from
      each eye were isolated by "tagging" each half-image with a different temporal
      frequency (5 or 7.5 Hz). Observers were presented with fixed 80% contrast
      gratings in each eye in experiment 1. Rivalry was detected on the basis of a
      negative correlation between the simultaneously measured response amplitudes at
      the second harmonics of the two eye-tagging frequencies. In a second analysis of
      the same data, response amplitudes recorded under dichoptic viewing conditions
      were compared to those obtained in a monocular control condition (dichoptic
      masking). In experiment 2, a 40% fixed-contrast grating was presented to one eye,
      whereas the other eye viewed a grating that was swept in contrast from 1% to 67%.
      Dichoptic masking was measured as the reduction in the fixed-grating response
      caused by the variable contrast grating. RESULTS: Experiment 1: although adults
      showed evidence of VEP amplitude alternations between the eyes for cross-oriented
      half-images (physiological rivalry), infants did not. This immature response to
      rivalrous stimuli occurred despite the presence of responses at nonlinear
      combination frequencies recorded with gratings of the same orientation in each
      eye, a definitive indication of binocular interaction. In addition, both iso- and
      cross-oriented half-images produced less dichoptic masking in infants than in
      adults in this experiment. Experiment 2: dichoptic masking in the infants was
      equivalent to that seen in adults with parallel gratings in the two eyes;
      however, masking with cross-oriented configurations was approximately five times
      weaker in the infants relative to the adults. CONCLUSIONS: The authors have
      identified a set of stimulus conditions under which infants between 5 and 15
      months of age fail to demonstrate physiological rivalry despite the presence of
      binocular interactions. The observed lack of binocular rivalry may be the result
      of a specific immaturity in dichoptic, cross-orientation suppression.

PMID- 10586960
TI  - Vasoactive intestinal polypeptide produces depolarization and facilitation of C
      fibre evoked synaptic responses in superficial dorsal horn neurones (laminae I
      IV) of the rat lumbar spinal cord in vitro.
AB  - The actions of vasoactive intestinal polypeptide (VIP) were investigated on
      superficial dorsal horn (LI-IV) neurones in longitudinal slices of the rat lumbar
      spinal cord in vitro. Bath application of VIP (1-2 mM) cause depolarizations
      which were accompanied by a lowering of the threshold for excitation of the
      neurone by current injection in the majority of cells studied. In some cases
      these depolarizations were very large and caused depolarization block and
      prolonged desensitization. An increase in spontaneous excitatory postsynaptic
      potential (EPSP) frequency and amplitude was also produced by VIP. Synaptic
      responses evoked by peripheral nerve stimuli at intensities which recruited C
      fibres were also facilitated by VIP. The principle action was on the later
      components of these responses which are dependent on C-fibre activation. EPSP
      summation evoked by trains of peripheral nerve stimulation (wind-up) was also
      facilitated by VIP and the duration of these responses was clearly increased.
      These observations are discussed briefly in the context of the possible role of
      VIP in neuropathic pain.

PMID- 10586961
TI  - Hippocampal theta waves as an electrocardiogram rhythm timer in paradoxical
      sleep.
AB  - Episodes of heart arrhythmia are present during paradoxical sleep, a known non
      homeostatic--'open loop'--physiological state, while wakefulness and slow wave
      sleep exhibit 'closed-loop' control. A brain-stem autonomic oscillator, a
      hypothalamic and a corticofrontal center, entrained by baroreceptor input, has
      been proposed as the main heart rhythm control system. We are postulating another
      neural timer, i.e. the hippocampal theta rhythm. Cross-correlation between the R
      wave of the electrocardiogram and the hippocampal theta revealed phase-locking
      during behavioral periods under 'open-loop' operations as paradoxical sleep
      indicative of a participation of such a rhythm in autonomic heart rate timing, in
      coordination with hypothalamic neuronal activities.

PMID- 10586962
TI  - Macrowell cultures identify a subpopulation of neonatal rat dorsal root
      ganglionic neurons displaying nerve growth factor independent survival.
AB  - Dorsal root ganglionic (DRG) neurons of the newborn rat in vitro die by apoptosis
      within 24-48 h unless nerve growth factor (NGF) is added. Using a novel cell
      culture system (macrowell), we identified a neuronal subpopulation displaying NGF
      independent survival in vitro. Neurons were grown on glass coverslips at standard
      cell density in different volumes of defined medium (standard: 500 microl;
      macrowell: 10 ml). In standard culture, 40% of neurons survived in the presence
      of NGF whereas there was no survival under control conditions. In macrowell
      culture, however, about 15% of neurons survived even in the absence of NGF.
      Addition of NGF to these cultures increased survival up to 65%. Neurons surviving
      independent of NGF in macrowell culture were heterogeneous in size and were
      lacking the low-affinity NGF receptor.

PMID- 10586963
TI  - Outwardly rectifying K+ channels display clustering in guinea pig retinal Muller
      cells.
AB  - The cell-attached configuration of the patch-clamp technique was used to
      characterize the outward currents in acutely isolated Muller cells from the
      guinea pig retina. Sixty-five of 353 patches displayed macroscopic, outwardly
      rectifying currents due to depolarizing voltage steps. Single channel transitions
      were found in only two patches. The remaining patches did not reveal any voltage
      dependent currents. Tail current analysis revealed a reversal potential close to
      the resting membrane potential. The currents disappeared if internal K+ was
      replaced by Cs+ in inside-out patches. From these results we conclude that guinea
      pig Muller cells possess voltage-dependent K+ channels that are distributed in
      clusters.

PMID- 10586964
TI  - Functional coupling in rat central olfactory pathways: a coherence analysis.
AB  - This experiment determined the importance of functional coupling between
      structures of central olfactory pathways: the olfactory bulb (OB), anterior
      (APC), posterior (PPC) parts of the piriform cortex and lateral entorhinal cortex
      (EC). From local field potential signals obtained in awake rats, coupling during
      spontaneous activity was estimated with variables reflecting level of coherence
      computed with a dynamical method. Results revealed a clear hierarchy in the
      strength of coupling between structures with dissociation within the piriform
      cortex: PPC was more tightly coupled with the EC than with APC. Systemic
      injection of a cholinergic antagonist, scopolamine, suggested that tonic coupling
      is strongly mediated by cortico-cortical connections and not by an external
      synchronizer, except between OB and APC.

PMID- 10586965
TI  - Extracellular adenosine 5'-triphosphate plus activation of glutamatergic
      receptors induces long-term potentiation in CA1 neurons of guinea pig hippocampal
      slices.
AB  - The mechanism of adenosine 5'-triphosphate (ATP)-induced long-term potentiation
      (LTP) was studied pharmacologically using guinea pig hippocampal slices.
      Application of 10 microM ATP for 10 min transiently depressed, then slowly
      augmented, synaptic transmission in CA1 neurons, leading to LTP. This ATP-induced
      LTP was blocked by addition of an N-methyl-D-aspartate (NMDA) glutamate receptor
      antagonist. Furthermore, co-application of 10 microM ATP and 100 microM L
      glutamate for 10 min also induced LTP, and this effect was blocked by the use of
      Ca2+-free solution during drug application. These results suggest that, in CA1
      neurons, a co-operative effect involving extracellular ATP and the activation of
      NMDA receptors, which increases intracellular Ca2+ levels, is required to trigger
      the intracellular biological process involved in ATP-induced LTP.

PMID- 10586966
TI  - The effect of lumbar puncture stress on dopamine and serotonin metabolites in
      human cerebrospinal fluid.
AB  - In order to examine concentrations of cerebrospinal fluid (CSF) neurochemicals,
      the technique of lumbar puncture is typically used. However, the effect of the
      intrinsic stress of undergoing a lumbar puncture on CSF monoamine concentrations
      in humans has not yet been established. We used lumbar puncture followed 3 h
      later by continuous CSF sampling to examine the effect of lumbar puncture on
      levels of the dopamine and serotonin metabolites homovanillic acid (HVA) and 5
      hydroxyindoleacetic acid (5-HIAA), respectively. Additionally, we examined the
      effect of lumbar puncture on the CSF HVA to 5-HIAA ratio. Immediately post lumbar
      puncture, CSF concentrations of HVA and 5-HIAA were, respectively, only 51 and
      54% of the mean levels detected hours later. However, the HVA to 5-HIAA ratio
      remained stable during lumbar puncture. While HVA and 5-HIAA levels in CSF
      obtained via lumbar puncture reflect highly variable responses to the stress of
      the procedure, the ratio of these metabolites is unaffected.

PMID- 10586967
TI  - Guanosine 5',3'-cyclic monophosphate enhances lipopolysaccharide-induced nitric
      oxide synthase expression in mixed glial cell cultures of rat.
AB  - Primary mixed glial cell cultures treated with lipopolysaccharide (LPS; 1.0
      microg/ml) showed biphasic increases of inducible nitric oxide synthase (iNOS)
      mRNA expression 6 h and 24-36 h after LPS treatment. Dibutyryl-guanosine 5',3'
      cyclic monophosphate (db-cGMP; 1.0 mM) enhanced the second phase of the LPS
      induced iNOS expression 24 and 30 h after LPS stimulation. KT5823 (1.0 microM), a
      protein kinase G (PKG) inhibitor, inhibited the LPS-induced iNOS expressions at
      24 and 30 h and their enhancements caused by db-cGMP. In astrocyte-enriched
      cultures with reduced microglial contamination, the LPS-induced iNOS expression
      was decreased, though slightly enhanced by db-cGMP. These results suggest that
      cGMP/PKG signaling may be involved in the second phase of the LPS-induced glial
      iNOS expression and its upregulation, which are apparent in the presence of
      microglial cells.

PMID- 10586968
TI  - Somatostatin reduces the meningeal arterial blood flow in the rat.
AB  - The effect of somatostatin (SOM) on neurogenic increases in meningeal blood flow
      was examined in barbiturate anaesthetized rats. The parietal skull was trepanized
      and the blood flow in the medial meningeal artery was monitored using a laser
      Doppler flowmeter with needle probes. Electrical stimulation (pulses of 8-10 V at
      5-10 Hz for 30 s) close to the superior sagittal sinus evoked reproducible
      increases in blood flow. These increases were reduced by topical applications of
      SOM at concentrations of 10(-5)-10(-3) M in a dose-dependent manner. The effect
      was most pronounced within 10 min after application of SOM followed by a recovery
      of the flow responses. We conclude that stimulus-evoked increases in dural
      arterial flow, which are most likely caused by afferent activation and can be
      regarded as an element of neurogenic inflammation, are reduced by anti
      inflammatory peptides such as SOM.

PMID- 10586969
TI  - Cerebellar morphological alterations in rats induced by prenatal ozone exposure.
AB  - The present study analyzes the morphological aspects of the cerebellum of rats
      with prenatal exposure to ozone. A double blind histological and planimetric
      analysis was performed studying sagittal sections of the anterior cerebellar lobe
      at postnatal days 0, 12 and 60. Ozone exposed rats showed cerebellar necrotic
      signs at age 0, diminished area of the molecular layer with Purkinje cells with
      pale nucleoli and perinucleolar bodies at age 12, and Purkinje cells showing
      nuclei with unusual clumps of chromatin in the periphery at age 60. We conclude
      that exposure to high concentrations of ozone during gestation induces permanent
      cerebellar damage in rats.

PMID- 10586970
TI  - Pre-attentive processing of auditory patterns in dyslexic human subjects.
AB  - It has been hypothesized that auditory temporal processing plays a major role in
      the aetiology of dyslexia. Event-related brain potentials (mismatch negativity,
      MMN) of auditory temporal processing were assessed in 15 dyslectic adults and 20
      controls. A complex tonal pattern was used where the difference between standard
      and deviant stimuli was the temporal, not the frequency structure. Dyslexics had
      a significantly smaller MMN in the time window of 225-600 ms. This result shows
      that dyslexics have a significant pre-attentive deficit in processing of rapid
      temporal patterns suggesting that it may be the temporal information embedded in
      speech sounds, rather than phonetic information per se, that resulted in the
      attenuated MMN found in dyslexics in previous studies. MMN scalp topographies
      were similar for both groups, showing a maximum over fronto-central leads.

PMID- 10586971
TI  - The role of the posterior parietal cortex in human object recognition: a
      functional magnetic resonance imaging study.
AB  - The mechanisms involved in visual object recognition from non-canonical
      viewpoints were investigated using functional magnetic resonance imaging (fMRI).
      We used a passive observation task and found three areas activated more strongly
      in the non-canonical viewing condition compared with the canonical viewing
      condition. First, it was found that the fusiform gyrus and posterior part of the
      inferior temporal cortex were involved in the processing of shape information.
      Next, it was found that the posterior parietal cortex, mainly the superior
      parietal lobule and the ventral part of premotor area were involved in
      visuospatial processing and accessing sensorimotor knowledge. These results may
      indicate that recognition from non-canonical viewpoints is supported by using
      functional properties of the object, which require more real-time processing for
      object manipulation.

PMID- 10586972
TI  - Nitric oxide synthase inhibitor aminoguanidine potentiates iminodipropionitrile
      induced neurotoxicity in rats.
AB  - This investigation was undertaken to study the effect of nitric oxide synthase
      inhibitor, aminoguanidine on iminodipropionitrile (IDPN)-induced neurobehavioral
      and vestibular toxicity in rats. The dyskinetic syndrome was produced in male
      Wistar rats by i.p. injections of IDPN (100 mg/kg) for 6 days. Aminoguanidine was
      administered orally in the doses of 50, 150 and 300 mg/kg, 60 min before IDPN in
      three different groups. Control rats received vehicle only, whereas another group
      was treated with 300 mg/kg of aminoguanidine alone (without IDPN). Our results
      showed that aminoguanidine significantly and dose dependently exacerbated the
      incidence and intensity of IDPN-induced dyskinetic head movements. Aminoguanidine
      potentiated IDPN-induced loss of air righting reflex. The histopathological
      examination of inner ear showed aggravation of IDPN-induced degeneration of
      sensory hair cells in the crista ampullaris by aminoguanidine. These results
      suggest the role of nitric oxide in IDPN-induced neurobehavioral and vestibular
      toxicity.

PMID- 10586973
TI  - Activation of adenylate cyclase results in down-regulation of c-jun mRNA
      expression in rat C6 glioma cells.
AB  - To investigate the possible mechanisms involved in forskolin-induced c-jun mRNA
      decrease in rat C6 glioma cells, we examined effects of a PKA inhibitor (H-89), a
      L-type Ca2+ channel blocker (nimodipine), a calmodulin activation inhibitor
      (calmidazolium chloride) and a Ca2+/calmodulin-dependent protein kinase II
      inhibitor (KN-62) on forskolin-induced c-jun mRNA down-regulation. H-89 caused a
      reversal of forskolin-induced c-jun mRNA decrease. Furthermore, nimodipine, KN-62
      and calmidazolium chloride partially blocked forskolin-induced c-jun mRNA down
      regulation. Our results suggest that activation of adenylate cyclase appears to
      be involved in a down-regulation of c-jun mRNA expression through a PKA pathway.
      In addition, L-type calcium channels, calmodulin and Ca2+/calmodulin-dependent
      protein kinase II may be partially involved in c-jun mRNA down-regulation induced
      by forskolin.

PMID- 10586974
TI  - Hippocampal auditory gating in the hyperactive mocha mouse.
AB  - The mouse mutants mocha (mh) and mocha2J (mh2J) result from separate mutations in
      the same gene (AP-3 delta) that arose independently on different backgrounds of
      inbred strains. They exhibit a neurological phenotype that includes
      hyperactivity, an epileptiform EEG and changes in the basic function of the
      hippocampus. Depth electrode recordings of hippocampal auditory evoked potentials
      revealed that the response to the first of two paired tones was significantly
      enhanced in mocha and mocha2J, as compared with littermate controls. The
      pronounced theta rhythm characteristic of unanesthetized mocha mice was not
      observed in these chloral-hydrate anesthetized mice, whereas spike discharge
      activity was frequently present in the recordings.

PMID- 10586975
TI  - The effect of corticosteroids on amyloid beta precursor protein/amyloid precursor
      like protein expression and processing in vivo.
AB  - In this study, we have investigated the effect of altered corticosteroid levels
      on the expression and processing of the amyloid beta precursor protein (A betaPP)
      and its amyloid precursor-like protein (APLP) homologue in rat brain. Four groups
      of animals were used in the study: sham operated, adrenalectomised, and
      adrenalectomised treated with either dexamethasone or aldosterone, with the A
      betaPP/APLP expression being determined by western blot analysis. While there
      were no changes in the levels of A betaPP/APLP following adrenalectomy, treatment
      with dexamethasone, but not aldosterone, resulted in a marked increase in protein
      expression levels with the level of increase varying between the brain regions
      examined. Corticosteroids had a more marked effect on the particulate rather than
      the soluble form of the protein, thus suggesting that elevated glucocorticoids
      may also be adversely influencing A betaPP/APLP processing.

PMID- 10586976
TI  - Frequency-dependent modulation of inhibition in the rat olfactory bulb.
AB  - Active sniffing in rodents at theta frequency during exploratory behavior has
      been hypothesized to enhance odorant access to the receptor sheet and to evoke
      activity patterns in olfactory and limbic structures which facilitate induction
      of synaptic plasticity. The present results demonstrate a third potential
      consequence of theta frequency sniffing -- reversible enhancement of
      lateral/feedback inhibition in the rat olfactory bulb. Suppression of
      mitral/tufted cell single-unit spontaneous activity evoked by single lateral
      olfactory tract (LOT) shocks was examined during LOT stimulation at either 1 or 5
      Hz (theta frequency). Theta frequency stimulation rapidly and reversibly enhanced
      LOT-evoked suppression compared with 1 Hz stimulation. This enhancement was not
      stimulus intensity dependent. Sniffing-induced modification of lateral/feedback
      inhibition may enhance odor processing during exploration.

PMID- 10586977
TI  - Regional distribution of parkinsonism-preventing endogenous
      tetrahydroisoquinoline derivatives and an endogenous parkinsonism-preventing
      substance-synthesizing enzyme in monkey brain.
AB  - 1,2,3,4-Tetrahydroisoquinoline (TIQ) and 1-benzyl-1,2,3,4-tetrahydroisoquinoline
      (1BnTIQ), which exist in the brain of several mammalian species, are parkinsonism
      inducing substances, and 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), which
      is enzymatically synthesized in rat brain, is a parkinsonism-preventing
      substance. In this study, we examined the regional distribution of contents of
      TIQ, 1MeTIQ, and 1BnTIQ, and activity of 1MeTIQ-synthesizing enzyme in monkey
      brain. The TIQ and 1BnTIQ contents in cerebrum and substantia nigra, and the
      1MeTIQ contents in striatum and substantia nigra were higher than those in other
      brain regions, and 1MeTIQ-synthetic activity was high in cerebrum and thalamus.
      We speculate that 1MeTIQ-synthesizing enzyme may play an important role in
      idiopathic Parkinson's disease.

PMID- 10586978
TI  - Twin-to-twin transfusion syndrome with hydrops: a retrospective analysis of ten
      cases.
AB  - We retrospectively studied 10 cases of twin-to-twin transfusion syndrome (TTTS)
      with fetal hydrops. TTTS was diagnosed sonographically between the 17-31 weeks of
      gestation. All twins were delivered by emergency cesarean section because of
      cardiac decompensation of one or both fetuses. The mean (+/-SD) age at diagnosis
      was 26.1 +/- 4.5 and the mean age at delivery was 28.8 +/- 2.0 weeks. Gestational
      age at birth was similar in survivors and nonsurvivors. However, surviving
      infants were diagnosed later in gestation (23.6 +/- 4.8 vs. 28.7 +/- 1.9 weeks; p
      < 0.01); and gestational age at appearance of hydrops were later in survivors
      (26.1 +/- 3.2 vs. 29.2 +/- 2.4 weeks; p < 0.05). Overall survival rate was 50%
      (10 of 20 infants). All survivors were delivered within 3 days after the
      appearance of fetal hydropic changes. Extrauterine treatment in earlier stages of
      TTTS might improve the outcome. Nevertheless, more aggressive intrauterine
      treatment should be considered in the most severe cases of TTTS developing before
      24-25 weeks' gestation.

PMID- 10586979
TI  - Treatment of women with an abnormal glucose challenge test (but a normal oral
      glucose tolerance test) decreases the prevalence of macrosomia.
AB  - Infant macrosomia is a serious medical concern. Pregnant women who do not meet
      the specific diagnosis for gestational diabetes may still have glucose-mediated
      macrosomia. In Santa Barbara County all pregnant women are screened for
      gestational diabetes at 24-28 weeks with a 50-g, 1-hr glucose challenge test
      (GCT). All patients who fail this test are placed on a standard euglycemic diet
      (40% carbohydrate, 20% protein, 40% fat) and perform home glucose monitoring of
      fasting and postprandial glucose levels. The objective of this study was to
      examine the effectiveness of this treatment program in decreasing infant
      macrosomia, maternal and infant morbidity, maternal complications, and operative
      delivery. We studied 103 women who had a positive GCT, but a negative 100-g, 3-hr
      oral glucose tolerance test (OGTT). The women were randomly assigned to either
      experimental or control groups with experimental women receiving dietary
      counseling and home glucose monitoring instruction (HBGM). HBGM diaries were
      reviewed weekly by clinic nurses. All women had hemoglobin A1c (HbA1c) tests at
      28 and 32 weeks. Maternal and fetal charts were reviewed to determine delivery
      type and complications, indications for cesarean section (C-section), and infant
      gestational age, gender, Apgar scores, birth weight, morbidities, and congenital
      anomalies. Of the 103 women, 5 women required insulin treatment, 1 woman had an
      abortion, and 14 women were indeterminate regarding compliance or were control
      women who received diet counseling and HBGM. The results are based on 83 women-
      48 control and 35 experimental. There were no significant differences between the
      groups for age, parity, or weight at 28-30 weeks or 37 weeks to delivery, or
      HbA1c at 28 weeks. HbA1c was significantly higher in control women at 32 weeks.
      Birth weight expressed in grams or as a percentile specific for gender,
      ethnicity, and gestational age was significantly higher in control infants. Birth
      weight was significantly correlated with maternal intake weight, weight at 28-30
      weeks, and weight at delivery and with HbA1c at 32 weeks' gestation. There were
      no significant differences between groups for maternal complications. Groups were
      significantly different for mode of delivery with experimental women having more
      induced vaginal deliveries but fewer repeat C-sections than control women. Groups
      were not different for primary C-sections. Women who fail the GCT, but not the
      OGTT and thus do not receive the diagnosis of GDM are still at risk for
      delivering a macrosomic infant and operative delivery. Our program of treatment
      for all women who fail the GCT improves outcome by reducing infant birth weight
      and the number of cesarean sections.

PMID- 10586980
TI  - Use of a PCR-based assay for fetal Cw antigen genotyping in a patient with a
      history of moderately severe hemolytic disease of the newborn due to anti-Cw.
AB  - Anti-Cw is an uncommon cause of clinically significant hemolytic disease of the
      newborn (HDN). We report an unusually severe case of HDN due to anti-Cw that
      required phototherapy and exchange transfusion. We also describe a novel PCR-RFLP
      method for Cw typing of fetal genomic DNA that was used for prenatal diagnosis in
      a subsequent pregnancy. Following PCR amplification of a 163 bp segment of the
      RHCE gene containing the nucleotide 122 G to A substitution that corresponds to
      the Cw allele, Cw types were distinguished by TaqI digestion. PCR-RFLP analysis
      confirmed that the father and previously affected child were Cw-positive. The
      fetus was Cw-negative, thus excluding HDN in the current pregnancy and obviating
      the need for further invasive or noninvasive diagnostic procedures for the
      remainder of the pregnancy. This case illustrates the utility of PCR-based fetal
      genotype determination in pregnancies at risk of HDN due to uncommon red cell
      antibodies such as anti-Cw.

PMID- 10586981
TI  - Influenza vaccination in pregnancy.
AB  - The objective of this paper is to determine the acceptance rate of and incidence
      of adverse reactions to the influenza vaccine in pregnant women, and to determine
      the immunized patients' attitudes toward future vaccination. A total of 448
      eligible pregnant women were offered the influenza vaccine at routine prenatal
      visits. Vaccinated women were interviewed at their subsequent visit regarding
      adverse effects and attitudes toward future vaccination. Of the 448 women
      studied, 319 (71.2%) accepted the vaccine. There was no difference in acceptance
      rates between English- and Spanish-speaking women. Mild adverse reactions were
      experienced by 5.3%. Women who reported adverse reactions were less likely to
      agree to future vaccination as compared with unaffected women (64.7 vs. 94.0% p <
      0.001). The influenza vaccine is readily accepted by pregnant women, and is
      infrequently associated with mild side effects. Women who experience side effects
      are less likely to accept the vaccine in the future.

PMID- 10586982
TI  - Cystatin C in healthy women at term pregnancy and in their infant newborns:
      relationship between maternal and neonatal serum levels and reference values.
AB  - Human cystatin C, a basic low molecular mass protein with 120 amino acid
      residues, is freely filtered by the glomerulus and almost completely reabsorbed
      and catabolized by the proximal tubular cells. Cystatin C has been recently
      proposed as a new sensitive endogenous serum marker for the early assessment of
      changes in the glomerular filtration rate. To define a reference basis for future
      clinical investigations in the perinatal period, we investigated the relationship
      between maternal and neonatal serum cystatin C in comparison with that of
      creatinine. We also defined reference values in healthy women at full-term
      pregnancy and in full-term newborns over the first 5 days of life. Seventy-eight
      women with uncomplicated pregnancy, aged between 19 and 40 years, and their
      infant newborns (43 males, 35 females) were enrolled in the study. The
      gestational age ranged from 37 to 43 weeks, and the birth weight from 2.50 to
      4.15 kg. Blood samples were taken from all the women immediately before delivery
      and from their newborns at birth, 72 and 96 h after birth. Maternal and neonatal
      renal function was evaluated by standards parameters and by calculating
      creatinine clearance. In all serum samples, we measured cystatin C, creatinine,
      and urea. At term gestation, serum cystatin C ranged from 0.64 to 2.30 mg/L. At
      birth, serum cystatin C values ranged from 1.17 to 3.06 mg/L, significantly
      decreasing after 3 and 5 days of life. No correlation was found between maternal
      and neonatal serum cystatin C values (r = 0.09). As cystatin C serum levels in
      newborns are not significantly correlated with the respective maternal levels,
      neonatal serum cystatin C may originate almost exclusively in the neonate.

PMID- 10586983
TI  - Glanzmann's thrombasthenia in pregnancy: a case and review of the literature.
AB  - Glanzmann's thrombasthenia is a rare autosomal recessive bleeding disorder
      resulting from a deficiency of glycoprotein IIb-IIIa complex in platelets. The
      deficient complex normally mediates platelet aggregation by binding adhesive
      proteins, which form bridges between activated cells. Despite normal platelet
      counts, morphology, prothrombin, and activated thromboplastin times, Glanzmann's
      thrombasthenia is characterized by a prolonged bleeding time and a severe
      hemorrhagic mucocutaneous diasthesis. Pregnancy and delivery are rare in these
      patients and have been associated with a high risk of severe hemorrhage. We
      present an unusual case in which a primi-gravida patient with Glanzmann's
      thrombasthenia underwent an uneventful pregnancy and spontaneous vaginal
      delivery, following intrapartum intravenous administration of single-donor
      platelets. Subsequent late postpartum hemorrhage required intravenous transfusion
      of an additional unit of single-donor platelets. In addition, we review the
      literature pertaining to pregnancy and Glanzmann's thrombasthenia with an
      emphasis on intrapartum prophylactic management.

PMID- 10586984
TI  - Utilization of real-time ultrasound on labor and delivery in an active academic
      teaching hospital.
AB  - OBJECTIVE: Ultrasound (US) is currently available on most if not all Labor and
      Delivery (L+D) services. Our objective was to survey utilization of real-time US
      on L+D in an active academic teaching hospital. STUDY DESIGN: Between April 1,
      and July 31, 1998, all US examinations performed for clinical purposes on
      patients presenting to L+D, were documented. Data collected included: gestational
      age, whether or not the patient was in labor, number of fetuses, and indication
      for US. All US examinations were performed by OB/GYN housestaff at the PGY 2-3
      level, and fellows in Maternal-Fetal Medicine. Statistical analysis included
      Student's t-test and chi2 when appropriate, with p < 0.05 considered significant
      throughout. RESULTS: During the 4-month study period, 1316 patients delivered and
      1363 were discharged from L+D, not in labor. Of 630 US examinations 31.64% (192
      of 630) and 67.69% (418 of 630) were performed in laboring versus nonlaboring
      patients, respectively. Of all patients delivered during the study period, 14.5%
      (192 of 1316) underwent intrapartum US, and of all nonlaboring patients, 30.66%
      (418 of 1363) underwent US on L+D. The mean gestational age at the time of
      assessment was 37.32 +/- 4.23 weeks' versus 35.74 +/- 5.76 weeks' gestation, in
      laboring versus nonlaboring patients respectively, p < 0.05. Main indications for
      US in patients in labor were; fetal presentation in patients with spontaneous
      rupture of membranes (SROM) 34.4% (n = 66), confirmation of vertex presentation
      20.3% (n = 39), preterm labor 12% (n = 23), multiple gestation 7.3% (n = 14), and
      malpresentation 7.3% (n = 14). Main indications for patients not in labor were;
      amniotic fluid index 15.8% (n = 66), SROM 15.6% (n = 65), postdates 9.8% (n = 41)
      placental location 9.6% (n = 40), and decreased fetal movement 9.3% (n = 39).
      Ultrasound-guided interventions included: all deliveries of multiple gestations
      (n = 9), version in nonlaboring patients (n = 10), and postpartum curettage for
      retained placental tissue in conjuction with severe early postpartum hemorrhage
      (n = 2). The incidences of each separate indication for US were significantly
      different between laboring versus nonlaboring patients, p < 0.05, respectively.
      CONCLUSION: US examination is performed in 15% of patients in labor and 31% of
      patients not in labor assessed on L+D, constituting a widely applied diagnostic
      tool in this environment.

PMID- 10586985
TI  - Necrotizing enterocolitis in infants born to women with severe early preeclampsia
      and absent end-diastolic umbilical artery doppler flow velocity waveforms.
AB  - The aim of this study was to determine the prevalence of necrotizing
      enterocolitis (NEC) in infants born to a homogeneous group of women with severe
      preeclampsia before 34 weeks' gestation and who had absent end-diastolic
      umbilical artery Doppler flow (AEDF) or normal umbilical Doppler flow velocities
      (NUFV). A total of 242 infants were entered into the study. The mean birth weight
      was 1260.5 g (SD = 339) and the mean gestational age 30.5 weeks (SD = 2.0). Sixty
      eight (28%) infants had AEDF, 43 (18%) had umbilical artery Doppler flow
      velocities between the 95th and 99th percentile, and 131 (54%) had NUFV. Forty
      one (18%) infants developed NEC, of whom 20 (8%) developed definite and advanced
      NEC (grade 2 and 3). Of these, 16(80%) had grade 2 and 4(20%) had grade 3. Twenty
      one (8%) infants developed suspected NEC (grade 1). The mean onset of grade 1 NEC
      (7.2 days) occurred significantly earlier than in those with grades 2 and 3 NEC
      (18.7 and 23.3 days, respectively). Of the 21 infants with grade 1 NEC, 10 (48%)
      had AEDF and 9 (43%) had NUFV. None of the infants with grades 2 or 3 NEC had
      AEDF. We conclude that although chronically hypoxemic fetuses born to women with
      severe early onset preeclampsia and AEDF respond by redistributing blood flow to
      vital organs and away from the gut; the intestinal compromise is of insufficient
      magnitude to induce intestinal necrosis or NEC. Enteral feeding, however, should
      be introduced cautiously in infants with AEDF, as so-called suspected NEC
      developed significantly more often in these infants.

PMID- 10586986
TI  - Incidence and clinical significance of echogenic vasculature in the basal ganglia
      of newborns.
AB  - Cranial sonography has become the main modality of the investigation and
      diagnosis of a wide variety of neonatal intracranial abnormalities. Occasionally,
      cranial sonograms reveal basal ganglia and thalami bright echoes. It is believed
      that these lesions are indicative of vasculitis due to intrauterine infections,
      in particular with cytomegalovirus (CMV). We hypothesized that the incidence of
      proven neonatal intrauterine TORCH infection is low and that screening of all
      asymptomatic infants with bright lenticulostriate echodensities would not be cost
      effective. We reviewed brain sonograms of 3700 infants, performed over a period
      of 3 1/2 years. Echogenic basal ganglia vasculature were observed in 75 patients
      (2%). Chart review performed for clinical presentation and TORCH studies showed
      that only one infant had confirmed intrauterine congenital infection, which was
      by CMV. This infant had no signs or symptoms of CMV. In addition, there were 4
      patients with chromosomal anomalies among the 75 patients (5%), of these one had
      trisomy 13 and another-trisomy 21. Our results indicate that echogenic basal
      ganglia blood vessels are not an exceptional finding on cranial sonograms, and
      are seldom associated with intrauterine infection. We conclude that it is not
      cost-effective to screen infants with echogenic basal ganglia blood vessels for
      intrauterine infection, unless clinical suspicion exists.

PMID- 10586987
TI  - The backpropagation algorithm in J, a fast prototyping tool for researching
      neural networks.
AB  - This paper illustrates the use of a powerful language, called J, that is ideal
      for simulating neural networks. The use of J is demonstrated by its application
      to a gradient descent method for training a multilayer perceptron. It is also
      shown how the back-propagation algorithm can be easily generalized to multilayer
      networks without any increase in complexity and that the algorithm can be
      completely expressed in an array notation which is directly executable through J.
      J is a general purpose language, which means that its user is given a flexibility
      not available in neural network simulators or in software packages such as
      MATLAB. Yet, because of its numerous operators, J allows a very succinct code to
      be used, leading to a tremendous decrease in development time.

PMID- 10586988
TI  - Successive learning in hetero-associative memory using chaotic neural networks.
AB  - In this paper, we propose a successive learning method in hetero-associative
      memories, such as Bidirectional Associative Memories and Multidirectional
      Associative Memories, using chaotic neural networks. It can distinguish unknown
      data from the stored known data and can learn the unknown data successively. The
      proposed model makes use of the difference in the response to the input data in
      order to distinguish unknown data from the stored known data. When input data is
      regarded as unknown data, it is memorized. Furthermore, the proposed model can
      estimate and learn correct data from noisy unknown data or incomplete unknown
      data by considering the temporal summation of the continuous data input. In
      addition, similarity to the physiological facts in the olfactory bulb of a rabbit
      found by Freeman are observed in the behavior of the proposed model. A series of
      computer simulations shows the effectiveness of the proposed model.

PMID- 10586989
TI  - Human learning characteristics in the tracking tasks of iterative nature.
AB  - In this paper, human learning characteristics in the tracking tasks of iterative
      nature are investigated. Various linear and nonlinear systems are used as plant,
      and a human operator has to generate the proper control inputs to force these
      systems in tracking the desired trajectory. The learning behaviour of the human
      operator in modifying his control actions is studied and it is observed that the
      human operator can improve his performance quite efficiently despite the
      unavailability of any information about the system or the desired trajectories.
      It is concluded from the experiments that the human operator not only use the
      information that is directly available to him (error in this case), but also
      extracts some useful information (e.g. error rate) that he feels is necessary to
      generate a good control action. The limitation of the human performance is
      studied in frequency domain, and the performance of the human operator against
      the frequency bandwidth of error and error rate signals are highlighted. Analysis
      of the results revealed that a human operator gives more importance to the error
      rate in generating his control actions and, accordingly, it is observed that his
      limitation in term of performance is more sensitive to the frequency bandwidth of
      the error rate as compared to the error. The human operator cannot improve his
      performance once the frequency components of the error or error rates shift to
      the higher frequencies, say above 1.0 Hz.

PMID- 10586990
TI  - A space-time delay neural network for motion recognition and its application to
      lipreading.
AB  - Motion recognition has received increasing attention in recent years owing to
      heightened demand for computer vision in many domains, including the surveillance
      system, multimodal human computer interface, and traffic control system. Most
      conventional approaches classify the motion recognition task into partial feature
      extraction and time-domain recognition subtasks. However, the information of
      motion resides in the space-time domain instead of the time domain or space
      domain independently, implying that fusing the feature extraction and
      classification in the space and time domains into a single framework is
      preferred. Based on this notion, this work presents a novel Space-Time Delay
      Neural Network (STDNN) capable of handling the space-time dynamic information for
      motion recognition. The STDNN is unified structure, in which the low-level
      spatiotemporal feature extraction and high-level space-time-domain recognition
      are fused. The proposed network possesses the spatiotemporal shift-invariant
      recognition ability that is inherited from the time delay neural network (TDNN)
      and space displacement neural network (SDNN), where TDNN and SDNN are good at
      temporal and spatial shift-invariant recognition, respectively. In contrast to
      multilayer perceptron (MLP), TDNN, and SDNN, STDNN is constructed by vector-type
      nodes and matrix-type links such that the spatiotemporal information can be
      accurately represented in a neural network. Also evaluated herein is the
      performance of the proposed STDNN via two experiments. The moving Arabic numerals
      (MAN) experiment simulates the object's free movement in the space-time domain on
      image sequences. According to these results, STDNN possesses a good
      generalization ability with respect to the spatiotemporal shift-invariant
      recognition. In the lipreading experiment, STDNN recognizes the lip motions based
      on the inputs of real image sequences. This observation confirms that STDNN
      yields a better performance than the existing TDNN-based system, particularly in
      terms of the generalization ability. In addition to the lipreading application,
      the STDNN can be applied to other problems since no domain-dependent knowledge is
      used in the experiment.

PMID- 10586991
TI  - Growing of a Fuzzy Recurrent Artificial Neural Network (FRANN) for pattern
      classification.
AB  - This paper describes a method for growing a recurrent neural network of fuzzy
      threshold units for the classification of feature vectors. Fuzzy networks seem
      natural for performing classification, since classification is concerned with set
      membership and objects generally belonging to sets of various degrees. A fuzzy
      unit in the architecture proposed here determines the degree to which the input
      vector lies in the fuzzy set associated with the fuzzy unit. This is in contrast
      to perceptrons that determine the correlation between input vector and a
      weighting vector. The resulting membership value, in the case of the fuzzy unit,
      is compared with a threshold, which is interpreted as a membership value.
      Training of a fuzzy unit is based on an algorithm for linear inequalities similar
      to Ho-Kashyap recording. These fuzzy threshold units are fully connected in a
      recurrent network. The network grows as it is trained. The advantages of the
      network and its training method are: (1) Allowing the network to grow to the
      required size which is generally much smaller than the size of the network which
      would be obtained otherwise, implying better generalization, smaller storage
      requirements and fewer calculations during classification; (2) The training time
      is extremely short; (3) Recurrent networks such as this one are generally readily
      implemented in hardware; (4) Classification accuracy obtained on several standard
      data sets is better than that obtained by the majority of other standard methods;
      and (5) The use of fuzzy logic is very intuitive since class membership is
      generally fuzzy.

PMID- 10586992
TI  - A new neural network architecture with associative memory, pruning and order
      sensitive learning.
AB  - A new paradigm of neural network architecture is proposed that works as
      associative memory along with capabilities of pruning and order-sensitive
      learning. The network has a composite structure wherein each node of the network
      is a Hopfield network by itself. The Hopfield network employs an order-sensitive
      learning technique and converges to user-specified stable states without having
      any spurious states. This is based on geometrical structure of the network and of
      the energy function. The network is so designed that it allows pruning in binary
      order as it progressively carries out associative memory retrieval. The capacity
      of the network is 2n, where n is the number of basic nodes in the network. The
      capabilities of the network are demonstrated by experimenting on three different
      application areas, namely a Library Database, a Protein Structure Database and
      Natural Language Understanding.

PMID- 10586993
TI  - Electronystagmographic analysis of optokinetic nystagmus for the evaluation of
      ocular symptoms in myasthenia gravis.
AB  - Ocular symptoms of 17 myasthenia gravis (MG) patients were examined by
      electronystagmographic registration of optokinetic nystagmus. The aim of this
      study was to replace the subjective methods used previously with a more reliable
      quantitative technique and thus assess ophthalmoplegia and diplopia, important
      initial symptoms in MG. Slow phase angular speed values of foveolar type
      optokinetic nystagmus in the horizontal plane at 10, 20 and 30 degrees/s target
      speed were determined. Measurements were performed before and after
      administration of Mestinon, a reversible cholinesterase inhibitor. Twelve healthy
      volunteers were examined as controls under standard conditions. Results showed
      significant differences between MG patients and control group. Slow-phase angular
      speed was significantly larger after Mestinon administration (p < 0.001). It is
      concluded, that the exhaustion of external ocular muscles in MG can be well
      characterized by the determination of the slow phase angular speed values of
      optokinetic nystagmus (OKN). The examination of OKN was also recommended for the
      evaluation of ocular symptoms in other neurological disorders.

PMID- 10586994
TI  - Vestibular-evoked myogenic potentials in patients with dehiscence of the superior
      semicircular canal.
AB  - Recently Minor and co-workers described patients with sound- and pressure-induced
      vertigo due to dehiscence of bone overlying the superior semicircular canal.
      Identifying patients with this "new" vestibular entity is important, not only
      because the symptoms can be very incapacitating, but also because they are
      surgically treatable. We present symptoms and findings for three such patients.
      On exposure to sounds, especially in the frequency range 0.5-1 kHz, they showed
      vertical/torsional eye movements analogous to a stimulation of the superior
      semicircular canal. They also showed abnormally large sound-induced vestibular
      evoked myogenic potentials (VEMP), i.e. the short latency sternomastoid muscle
      response considered to be of saccular origin. The VEMP also had a low threshold,
      especially in the frequency range 0.5-1 kHz. However, in response to saccular
      stimulation by skull taps, i.e. when the middle ear route was bypassed, the VEMP
      were not enlarged. This suggests that the relation between the sound-induced and
      the skull tap-induced responses can differentiate a large but normal VEMP from an
      abnormally large response due to dehiscence of bone overlying the labyrinth,
      because only the latter would produce large sound-induced VEMP compared to those
      induced by skull taps.

PMID- 10586995
TI  - Vestibular disturbance in patients with large vestibular aqueduct syndrome
      (LVAS).
AB  - Large vestibular aqueduct syndrome (LVAS) is a common inner ear anomaly
      responsible for some unusual vestibular and audiological symptoms. The gross
      appearance of CT scan of the inner ear is generally normal. However, precise
      measurement of the inner ear components reveals abnormal dimensions, which may
      account for accompanying auditory or vestibular dysfunction. It has been reported
      that sudden increase in cerebrospinal fluid pressure can cause further
      deterioration of hearing due to transmission of pressure to the inner ear through
      the enlarged vestibular aqueduct. However, vestibular function is not often
      studied. In this report, audiovestibular function of 10 patients with large
      vestibular aqueducts was analysed and compared with the severity of the
      radiological deformity. The literature was reviewed and typical findings were
      discussed to emphasize varying aspects of audiovestibular function. It was found
      that some patients with LVAS have some spontaneous or provoked vestibular
      disturbance such as vertigo after watching revolving objects. The mean value of
      electronystagmographic abnormality in patients with hearing loss is greater than
      in patients with normal hearing. However, there is no statistical correlation
      between the level of hearing loss, electronystagmographic abnormality and
      severity of radiological deformity.

PMID- 10586996
TI  - Bell's palsy and tinnitus during pregnancy: predictors of pre-eclampsia? Three
      cases and a detailed review of the literature.
AB  - We present two cases of Bell's palsy, and another with tinnitus, all in
      association with pre-eclampsia in the third trimester of pregnancy. We also
      systematically reviewed the published literature on both Bell's palsy and
      tinnitus in pregnancy and the puerperium using Medline from January 1966 to
      October 1998, and searched through the references from review articles and
      original research publications for further studies. Studies were limited to those
      published in the English language. We then pooled the rates of occurrence for
      Bell's palsy according to trimester of pregnancy, and postpartum, as well as the
      associated prevalence of pre-eclampsia or gestational hypertension. We found that
      the majority of cases of Bell's palsy arose during the third trimester (pooled
      event rate 71.1%, 95% confidence interval (CI) 64.1-77.2), while almost none
      arose in the first trimester. During the postpartum period, the distribution of
      Bell's palsy was 21.3% (95% CI 15.7-28.1) of all cases, with the majority arising
      within days of delivery. Gestational hypertension or pre-eclampsia was present in
      22.2% of cases (95% CI 12.5-36.4), well above the 5% rate in the general
      population. Only one paper provided data on tinnitus in pregnancy, with the
      distribution equal across all three trimesters. When compared to non-pregnant
      controls, the odds ratio for the development of tinnitus during pregnancy was 2.8
      (95% CI 1.0-8.1). In conclusion, Bell's palsy, and perhaps, tinnitus, occur more
      frequently during the third trimester of pregnancy. Both may be presenting
      prodromal signs of underlying early pre-eclampsia. The pathophysiologic mechanism
      relating these two entities to pre-eclampsia is also discussed.

PMID- 10586997
TI  - Distortion product oto-acoustic emissions in Andean children and adults with
      chronic lead intoxication.
AB  - Neuroauditory disorders and sensory-neural hearing loss have been suggested as
      possible etiologic factors in the neurodevelopmental learning disabilities
      attributed to lead (Pb) intoxication. However, studies relating hearing loss to
      Pb poisoning have presented disparate results, suggesting that auditory
      sensitivity may not be a reliable marker of Pb intoxication. Oto-acoustic
      emissions, sounds that can be recorded non-invasively from the ear canal and are
      preneural responses of the outer hair cells of the inner ear, have been found to
      be diminished in ears exposed to some toxic agents. In the current study,
      distortion product oto-acoustic emissions (DPOAEs) were obtained from 28 ears of
      14 children and 10 ears of 5 adults living in a highly Pb-contaminated
      environment in remote villages in the Andes Mountains of Ecuador. Blood lead
      (PbB) levels for the children (ages: 5-14 years) ranged from 33.4 to 118.2
      microg/dl (mean: 51.5; SD: 22.9 microg/dl), or 3-12 times higher than the U.S.
      Centers for Disease Control and Prevention's toxic level of 10 microg/dl. The PbB
      levels for the adults ranged from 19.2 to 55.7 microg/dl. Despite the high PbB
      levels, the children had normal hearing thresholds, and DPOAEs were present for
      the children at the following f2 frequencies: 1187, 1500, 1906, 2406, 3031, 3812,
      4812 and 6031 Hz. Although there was a tendency for the children to have
      diminished DPOAEs, no consistent correlation of DPOAEs with PbB level was found.
      The adults had diminished DPOAEs that were consistent with their observed,
      probably noise-related hearing loss. Contrary to some reports in the literature,
      the current results show no unequivocal clinical or subclinical evidence that
      high PbB levels have a toxic effect on the cochlea.

PMID- 10586998
TI  - Performance of compressed analogue (CA) and continuous interleaved sampling (CIS)
      coding strategies for cochlear implants in quiet and noise.
AB  - Speech understanding with compressed analogue (CA) and continuous interleaved
      sampling (CIS) coding strategies for cochlear implants was compared in quiet and
      in noise at signal-to-noise ratios (SNRs) of 15, 10 and 5 dB. The speech
      recognition of three experienced users of the Ineraid cochlear implant (CA coding
      strategy) was assessed using a set of sentence, vowel and consonant tests. Three
      weeks after the fitting of a CIS processor, the tests were repeated with the new
      device. Speech recognition scores for the sentence and consonant tests tended to
      be higher with the CIS processor in no or little noise, but lower in the test
      situations with less favourable SNRs, when compared to the CA processor (average
      score differences for the consonant test: +7.8% correct at 15 dB SNR; -6.8%
      correct at 5 dB SNR; p = 0.05). Results for the vowel test were slightly lower on
      average for the CIS processing strategy at all SNRs. A possible explanation for
      the differences in performance between CIS and CA in the consonant and sentence
      tests at different SNRs is the generally higher free-field threshold associated
      with the CA coding strategy, which may act as a single-channel noise suppression.

PMID- 10586999
TI  - Experimental autoimmune labyrinthitis induced by cell-mediated immune reaction.
AB  - This study was designed to establish an experimental cell-mediated autoimmune
      labyrinthitis model in C57BL/6 mice, which could exhibit high reproducibility and
      be adopted for precise immunological analysis. Inner ear antigen (IEA) was
      prepared from bovine membranous labyrinth. Following pretreatment with
      cyclophosphamide (CP) and primary sensitization with IEA/FCA, many inflammatory
      cells infiltrated transiently into the perilymphatic and endolymphatic regions of
      the cochlea, vestibule and the endolymphatic sac, but not into the kidney, lung,
      brain or liver. This reaction occurred from day 7 and peaked on day 12 in all
      animals, and then rapidly reduced. This reaction occurred in all experimental
      mice during day 10 to day 12. The control mice showed no cellular reaction in the
      inner ear. These results suggest that the inner ear may possess cross-species
      organ-specific antigen and that a cell-mediated immune reaction may play an
      important role in the induction of autoimmune labyrinthitis.

PMID- 10587000
TI  - Cystine protects cochlear outer hair cells against glutamate toxicity.
AB  - We previously reported that long-term exposure to glutamate (Glu) induced death
      of cochlear outer hair cells (OHCs). However, the mechanisms of OHC death induced
      by Glu were unclear. In the central nervous system, Glu is known to interfere
      with a cystine-Glu antiporter, leading to a decrease in cystine uptake and
      reducing the intracellular glutathione level. We therefore investigated the
      effect of cystine supplementation on degeneration of OHCs caused by long-term
      exposure to Glu. Supplementation of cystine significantly decreased the number of
      dying OHCs. These findings suggest that a cystine-Glu interaction may be involved
      in the mechanism of OHC degeneration caused by Glu.

PMID- 10587001
TI  - Chronic electrical stimulation of the auditory nerve using non-charge-balanced
      stimuli.
AB  - This study was designed to evaluate the pathophysiological response of the
      cochlea following long-term intracochlear electrical stimulation using a poorly
      charge-balanced stimulus regime, leading to direct current (DC) levels >0.1
      microA. Four normal-hearing adult cats were bilaterally implanted with scala
      tympani electrode arrays and unilaterally stimulated for periods up to 2200 h.
      Stimuli consisted of 50 micros monophasic current pulses presented at 2000 pulses
      per second (pps) per channel, and resulted in DC levels of 0.4-2.8 microA. Both
      acoustic and electrical (EABR) evoked potentials were periodically recorded
      during the stimulation program. Frequency-specific stimuli indicated that an
      extensive and widespread hearing loss occurred over the 4-24 KHz region in all
      stimulated cochleae, although the 2 KHz region exhibited thresholds close to
      normal in some animals, despite long-term implantation and chronic stimulation.
      Longitudinal EABRs showed a statistically significant increase in threshold for
      three of the four animals. Histopathological evaluation of the cochleae revealed
      a highly significant reduction in ganglion cell density in stimulated cochleae
      compared with their controls. Spiral ganglion cell loss was significantly
      correlated with the degree of inflammation, duration of electrical stimulation,
      and the level of DC. In conclusion, the present study highlights the potential
      for neural damage following stimulation using poorly charge-balanced stimuli.

PMID- 10587002
TI  - Single ototopical application of mesna has no ototoxic effects on guinea pig
      cochlear hair cells: a morphological study.
AB  - Mesna (Mistabron) is a mucolytic substance that is also used for chemically
      assisted dissection during cholesteatoma surgery. The present animal study aims
      to evaluate its possible ototoxic side effects. To this end, the right tympanic
      cavity of 9 guinea pigs was filled with either 20% mesna or 10% neomycin (serving
      as a positive control), while the left tympanic cavity was filled with saline
      (serving as a negative control). One week after administration, the inner ears
      were dissected out and further processed for morphological evaluation by means of
      either interference contrast microscopy or scanning electron microscopy. No
      macroscopic signs of middle ear inflammation were observed in any of the ears
      treated. Whereas damage was obvious in all neomycin-treated specimens, the
      morphology of both saline- and mesna-treated inner ears was unaffected. These
      findings led us to conclude that, at least on a morphological basis, no
      indications are at hand to assume ototoxic effects of this mucolytic substance
      due to a single application during cholesteatoma surgery.

PMID- 10587003
TI  - Autoimmune deafness is not related to hyperreactivity to type II collagen.
AB  - The pathogenic role of anti-type II collagen was analysed in a variety of hearing
      losses, in age-matched controls and in different autoimmune diseases. The immune
      reactivity of peripheral blood lymphocytes to type II collagen was studied by the
      degree of proliferation measured as the incorporation of bromodeoxyuridine in
      cultured lymphocytes. The anti-type II collagen antibodies showed a very low
      incidence in the hearing loss group. Lymphocytes of otosclerosis, Meniere's
      disease and other sensorineural deafness patients proliferated in response to
      concanavalin A and to type II collagen to a lower extent than peripheral blood
      lymphocytes from healthy controls. Nonetheless, these differences were not
      statistically significant. The immune hyperreactivity to type II collagen cannot
      explain the autoimmune mechanism of hearing losses. Humoral and cellular
      hyperreactivities to inner ear proteins different from type II collagen, could
      explain the autoimmune mechanism of deafness.

PMID- 10587004
TI  - Mucosal surface area determines the middle ear pressure response following
      establishment of sniff-induced underpressures.
AB  - INTRODUCTION: Miura and colleagues presented data that they interpreted as
      evidencing a pressure-regulating function of the mastoid mucosa. Specifically,
      they reported different responses after sniff-induced middle ear (ME)
      underpressure for ears with and without a history of otitis media with effusion
      (OME). To understand the mechanism underlying that effect, a previously developed
      mathematical model was adapted to their experiment and used to simulate the
      expected pressure-time functions under different conditions. METHODS: A simple,
      two-compartment model of passive, gradient-driven, trans-mucosal gas exchange was
      used to simulate ME pressure behaviour. Initial conditions for the free
      parameters of the model were taken from published data for humans and monkeys.
      Functions relating surface area to volume for geometric representations of the ME
      were constructed and used as model parameters. The effect of sniffing on ME gas
      partial pressure was modelled as a fractional reduction proportional to gas
      representation in the ME. RESULTS: The model accurately simulated the time course
      and magnitude of the post-sniffing pressure change reported for both normal and
      abnormal MEs. The post-sniffing pressure increase is driven by sniff-induced
      blood-ME partial pressure gradients for CO2, O2, and H2O, which cause passive
      counter-diffusion of those gases. The effect of disease on the rate of pressure
      increase is attributable to the reduced surface area for exchange caused by
      underdevelopment of the mastoid in ears with a history of OME. CONCLUSIONS: These
      results do not support a pressure-regulating role for the mastoid mucosa.
      Contrary to currently held beliefs, the model simulation suggests that small, not
      large mastoid volumes buffer ME pressure from rapid change due to trans-mucosal
      gas transfers.

PMID- 10587005
TI  - Antibody responses to the outer membrane protein P6 of non-typeable Haemophilus
      influenzae and pneumococcal capsular polysaccharides in otitis-prone children.
AB  - Acute otitis media (AOM) is a common infectious disease in children. Some
      children experience recurrent episodes of AOM. Recent investigations demonstrate
      antigen-specific immunological deficiencies in children prone to AOM. In the
      present study, the immune responses to non-typeable Haemophilus influenzae (NTHi)
      and Streptococcus pneumoniae (S. pneumoniae) were further investigated in otitis
      prone children and normal children. Forty-eight percent of otitis-prone children
      exhibited reduced IgG2 levels to S. pneumoniae and 55% exhibited reduced IgG
      levels to NTHi. These data suggest that otitis proneness appears to be related to
      numerous immunological derangements. Pathogen-specific antibodies are a reliable
      measure of otitis proneness.

PMID- 10587007
TI  - Structure of the human uvula.
AB  - Eleven uvular biopsies were investigated for their morphology, the presence of
      mast cells and the distribution of hyaluronan and its major ligand CD44. Three
      microanatomical sites--surface epithelium, subepithelial area and area of glands-
      were examined. The oral side of the uvula was covered by a 15-20 cell thick layer
      of keratinized/parakeratinized surface epithelium, firmly anchored to the
      underlying connective tissue by connective tissue papillae. The width of the
      intercellular spaces in the epithelium increased toward the basal lamina, a
      location that exhibited intense hyaluronan and anti-CD44 staining. Most mast
      cells were located in the vicinity of blood vessels, at which sites there was
      high staining intensity of hyaluronan. Tissue mast cells could also be observed
      in the connective tissue septa enclosing the acini. Glands and muscle fibres
      became more sparse from the proximal part of the uvula to the distal end, while
      the amount of connective tissue increased. The localization and architecture of
      connective tissue elements and mast cells are consistent with the ability of the
      uvula to resist mechanical stresses and to develop oedema and fibrosis,
      respectively.

PMID- 10587006
TI  - Expression of endothelin A- and B-receptors in human nasal mucosa.
AB  - Several studies have suggested an important role for the endothelin (ET) family
      of peptides in the vascular regulation of the nose. In addition, there is
      increasing evidence that ETs play a role in allergic airway inflammation.
      Endothelin is produced locally in the nose and mediates its effects via two
      distinct receptor subtypes, termed ET(A) and ET(B). Using reverse transcriptase
      polymerase chain reaction, mRNAs encoding ET(A)- and ET(B)-receptors were
      detected in the human lower turbinate and sinus mucosa. The possibility of local
      release of ETs in connection with specific target receptors suggests a role for
      endothelin in the regulation of vascular tone, glandular secretion and epithelial
      functions.

PMID- 10587008
TI  - SIgA- and IgG-coated Streptococcus pyogenes on the tonsillar surfaces during
      acute tonsillitis.
AB  - Bacterial swabs were collected from the tonsillar surfaces of eight patients with
      current acute tonsillitis, culture-positive for Streptococcus pyogenes. Using
      gold-labelled antiserum to S. pyogenes, these micro-organisms could be localized
      in the samples by transmission electron microscopy. S. pyogenes pathogens were
      further characterized with gold-labelled antiserum to human IgG and SIgA
      antibodies. Roughly 90% of the pathogens were found coated with IgG antibodies,
      irrespective of the duration of the disease, whereas the proportion of SIgA
      coated pathogens increased with disease duration. Insufficient IgA coating of
      pathogens might well be a contributory cause of the induction of tonsillar
      infection, probably due to inadequate prevention of the attachment of the S.
      pyogenes bacteria to the tonsillar surface epithelium.

PMID- 10587009
TI  - Quantitative voice analysis in the assessment of bulbar involvement in
      amyotrophic lateral sclerosis.
AB  - Bulbar and pseudobulbar symptoms are diagnostic criteria of amyotrophic lateral
      sclerosis (ALS). One of the earliest symptoms of bulbar involvement is voice
      deterioration. Until now voice assessment in ALS patients has been done mainly by
      perceptual analysis. The objective parameters, including acoustic measures, one
      aerodynamic measure and the maximal phonation time, have been measured only in a
      few small series of patients. The first purpose of this prospective study was to
      determine which vocal parameters discriminate ALS patients with bulbar
      involvement from control patients. The second was to identify sensitive
      parameters for early detection of voice deterioration due to bulbar involvement
      in pre-symptomatic ALS patients. The voices of 63 female ALS patients, including
      40 with bulbar symptoms (sALS patients) and 23 without bulbar symptoms (aALS
      patients), were studied using an objective voice analysis system that allows
      simultaneous analysis of acoustic and aerodynamic parameters. Measurements were
      compared with those obtained in 40 normal female subjects (control patients).
      Five of eight acoustic parameters were significantly different among the three
      groups: jitter, coefficient of variation for frequency, shimmer, number of
      harmonics, and maximum phonatory frequency range. Three aerodynamic parameters,
      phonatory airflow, cycle-to-cycle variation for phonatory airflow, and
      coefficient of variation for phonatory airflow were significantly different
      between sALS patients and control patients. No aerodynamic parameter allowed
      discrimination between aALS patients and control patients. This study shows that
      acoustic parameters are more sensitive than aerodynamic parameters for early
      detection of bulbar involvement. Nevertheless, the measurements used can predict
      bulbar involvement in 73% of those in the sALS group, but only in 52% of those in
      the aALS group.

PMID- 10587010
TI  - Vascular endothelial growth factor (VEGF) and microvessel density in squamous
      cell carcinomas of the larynx: an immunohistochemical study.
AB  - The distribution of vascular endothelial growth factor (VEGF), one of the most
      important angiogenic factors, and microvessel density (MVD) were assessed in
      laryngeal carcinomas by means of immunohistochemistry. Correlation of VEGF with
      MVD and clinical parameters (T stage, N stage, histological grading, survival,
      recurrence-free interval) was also examined. VEGF expression was evaluated semi
      quantitatively and was observed in varying intensity (i) in tumour cells, (ii) in
      the stromal department as diffuse, sometimes strong reactivity, especially in
      close proximity to tumour masses and (iii) in macrophages and endothelial cells.
      Normal epithelium presented no VEGF reactivity except in the immediate vicinity
      of tumour transformation. Forty percent of our specimens exhibited substantial
      VEGF reactivity, whereas 20% showed no staining in tumour cells and stroma. These
      results could be positively correlated with MVD. Moreover, high-graded carcinomas
      revealed higher VEGF expression, but there was no association of tumour stage or
      lymph node status with VEGF or MVD. There was a trend in the survival and
      recurrence analysis towards a higher risk of disease relapse and shorter survival
      time for patients with enhanced VEGF expression. Apart from tumour cells,
      macrophages seem to be a substantial source of VEGF in carcinomas. This
      observation supports the concept of a pivotal role of these cells in tumour
      defence--in our case, promoting tumour formation by contributing to
      neovascularization. VEGF was also found in the connective tissue, where it seems
      to be bound on collagens and probably builds a reservoir for rapid enzymatic
      mobilization.

PMID- 10587011
TI  - Relationship of intra-abdominal adiposity and peripheral fat distribution to
      lipid metabolism in an island population in western Japan: gender differences and
      effect of menopause.
AB  - Intra-abdominal adiposity is associated with unfavorable serum lipid profiles
      (high total cholesterol or triacylglycerol, and low high-density lipoprotein
      cholesterol) in obese people. However, the relation in mainly nonobese Japanese
      population is not well known. We examined the relationship between intra
      abdominal adiposity measured by ultrasonography and body fat distribution with
      serum lipids in Japanese people living in an island in western Japan. Mainly
      nonobese healthy individuals (98 men, 72 premenopausal and 182 postmenopausal
      women) aged between 33 and 69 years were examined. Accumulation of intra
      abdominal fat (Pmax) and abdominal subcutaneous fat (Smin) was measured by
      ultrasonography. We also measured triceps and subscapular skinfold thicknesses,
      and the concentrations of total cholesterol, triacylglycerol and high-density
      lipoprotein (HDL) cholesterol. In men and postmenopausal women, Pmax correlated
      significantly with the majority of serum lipids after adjusting for age, body
      mass index and smoking habit. In premenopausal women, Pmax correlated
      significantly with only total cholesterol, but marginally with triacylglycerol
      and HDL/total cholesterol ratio after adjustment. Our findings suggest that intra
      abdominal adiposity is related to unfavorable lipid profile in both genders among
      mainly nonobese Japanese population.

PMID- 10587012
TI  - L-DOPS-Accelerated recovery of locomotor function in rats subjected to
      sensorimotor cortex ablation injury: pharmacobehavioral studies.
AB  - Central norepinephrine (NE) has been shown to play a beneficial role in
      amphetamine-facilitated recovery of behavior. To give insight into understanding
      the mechanism, the present studies were conducted to examine (a) the effects of L
      threo-3,4-dihydroxyphenylserine (L-DOPS) combined with benserazide (BSZ; a
      peripheral aromatic amino acid decarboxylase inhibitor) and L-3,4
      dihydroxyphenylalanine (L-DOPA), precursors of NE and dopamine (DA),
      respectively, on the recovery from beam-walking performance deficits in rats
      subjected to unilateral sensorimotor cortex ablation injury, and (b) the
      relationships between the behavioral recovery and the frequency of postoperative
      training and the size of ablation injury. It was found that the combined
      treatments with L-DOPS and BSZ promoted the recovery of locomotor function as
      early as 24 hours after injury. L-DOPA alone, however, did not facilitate
      behavioral recovery. The results of assay for the tissue levels of NE and its
      major metabolite (3-methoxy-4-hydoxyphenylethylene glycol; MHPG) in the brain
      using high-pressure liquid chromotography showed MHPG, but not NE, significantly
      increased in the cerebellum and the hippocampus. The behavioral recovery was also
      significantly correlated with the frequency of training subsequent to injury, but
      inversely with the size of cortex ablation. These results suggest that NE is
      likely to modulate functional recovery in this rodent model.

PMID- 10587013
TI  - Trace element levels in drinking water and the incidence of colorectal cancer.
AB  - We determined the levels of 15 elements in drinking water from 34 water treatment
      plants in Aomori Prefecture and studied how element levels relate to colorectal
      cancer incidence by district. Colorectal cancer incidence was calculated from the
      data of Aomori Colorectal Cancer Registry. Multiple regression analysis was
      performed by using age-adjusted incidences of rectal cancer and colon cancer by
      gender as object variables and each element level as an explanatory variable. The
      standardized partial regression coefficient was significant in gold (p < 0.01),
      magnesium (p < 0.01), selenium (p < 0.01) and tin (p < 0.05) for age-adjusted
      rectal cancer incidence in men as objective variable; in gold (p < 0.05), calcium
      (p < 0.01) and phosphorus (p < 0.01) with age-adjusted colon cancer incidence in
      men as the objective variable; and in sodium (p < 0.05), phosphorus (p < 0.05),
      tin (p < 0.05) and strontium (p < 0.01) with age-adjusted colon cancer incidence
      in women as the objective variable. These results confirm the need to further
      study trace elements in drinking water and food, and relationship to colorectal
      carcinogenesis.

PMID- 10587014
TI  - Comparative study of effects of impact tone and steady state tone exposure: EP
      and concentration of K+ ion and Na+ ion.
AB  - To test the adequacy of equal energy principle (EEP), guinea pigs were exposed to
      impact tone. The changes in electrophysiological data, namely endocochlear
      potential (EP) and the change in K+ ion and Na+ ion concentrations in the
      endolymph were investigated. The frequency of impact tone was 1 pulse/second or 1
      pulse/3 seconds. The steady state tone had Leq24h = 100, 95, 90 or 85 dB, and
      impact tone had Leq24h = 95, 90 or 85 dB. The results are the following. Both
      steady state and impact tone exposure cause changes of electrophysiological data.
      The effects on the absolute value of negative EP induced by impact tone exposures
      were smaller than that of steady state tone of the same Leq. The rate of pulses
      was also an important factor for impact tone exposure. Impact tone exposure of 1
      pulse/second caused smaller absolute value of negative EP than that of 1 pulse/3
      seconds. The K+ ion concentration time course in the endolymph remained similar
      to the control (Exp. 1) only in Exp. 8 (85 dB; the lowest steady state noise
      exposure in our experiments), but no decrease in the K+ ion concentration was
      detected in the other experiments, suggesting an alteration in the K+ ion flow.
      The Na+ ion concentration time course was also influenced showing no increase in
      Na+ ion concentration compared to the control (Exp. 1c) and the lowest steady
      state exposure experiment (Exp. 8c). Our experimental results suggest that both
      the K+ ion and Na+ ion movement are altered by tone exposure. We found also that
      the different types of noise exposure with the same Leq value does not exhibit
      the same changes. Leq24h is not an accurate damage risk criteria.

PMID- 10587015
TI  - Deletion and nonsense mutations of the connexin 32 gene associated with Charcot
      Marie-Tooth disease.
AB  - Two patients with a mild to moderate phenotype of Charcot-Marie-Tooth disease
      were identified to carry the mutations of the connexin (Cx) 32 gene. One of the
      patient had a novel nonsense mutation of tryptophan at amino acid 132 and the
      other had a deletion of the Cx 32 gene. Our study indicated that a loss of Cx 32
      function contributes to a major pathogenesis of X-linked Charcot-Marie-Tooth
      disease.

PMID- 10587016
TI  - Ganglion-cell tumor of the filum terminale: immunohistochemical characterization.
AB  - A case of an unusual spinal neuronal tumor is described in a 36-year-old woman
      presenting with a buttock pain. The spinal tumor was fully characterized by
      neuroradiological means, and in particular MRI was of significant value in
      delineating the extension of the tumor within the spinal canal and its exophitic
      growth pattern. Pathologically, a well circumscribed tumor originating from the
      intradural filum terminale characteristically comprised both large and small
      cells, resembling mature and immature neuronal cells, respectively. In addition,
      two neuronal markers, i.e., chromogranin A (CGA) and neuron-specific enolase
      (NSE), and other markers such as glial fibrilary acidic protein (GFAP), S-100
      protein, HNK-1, tyrosine hydroxylase and beta 2-microgloblin were investigated
      immunohistochemically. We found that both neuronal cells expressed
      immunoreactivity for CGA and NSE, and small neuronal cells showed more intense
      CGA immunoreactivity, indicating an earlier stage of neuronal differentiation.
      Weakly positive immunoreactivity for HNK-1 was also demonstrated in small
      neuronal cells, consistent with evidence of maturation along a neuronal
      differentiation. From these findings a pathological diagnosis of ganglioneuroma
      was made. This unique group of ganglion-cell spinal tumors is reviewed in the
      literature and differential diagnosis and immunohistochemical features are
      discussed.

PMID- 10587017
TI  - Analysis of liver single photon emission computed tomography in a case of
      fulminant hepatic failure.
AB  - Fulminant hepatic failure is associated with a high mortality rate. Thus,
      accurate assessment of hepatic functional reserve and hepatic regeneration is
      important. We describe a 67-year-old woman who survived subacute hepatic failure.
      We had an opportunity to monitor the clinical course of the patient using single
      photon emission computed tomography (SPECT) with 99mTc-galactosyl-human serum
      albumin (99mTc-GSA) and frequent hematological examinations. On admission,
      prothrombin time was remarkably prolonged (23.1% of control). The liver uptake of
      99mTc-GSA was also considerably low. She responded well to treatment. Four weeks
      after admission, SPECT analysis showed a dramatic increase in liver uptake of
      99mTc-GSA, suggesting promotion of hepatic regeneration. Moreover, functional
      liver volume calculated from the SPECT data showed a marked increase at 4 weeks
      after admission, whereas CT scan showed no change at that point. This indicated
      that SPECT with 99mTc-GSA reflected functional hepatocytes more accurately than
      liver volume determined by CT scan, which cannot exclude nonfunctional
      hepatocytes. The patient's condition improved in parallel with the improvements
      in the indices measured by SPECT and hematological examinations. SPECT analysis
      is practically useful for the prompt assessment of improvement in patients with
      fulminant hepatic failure.

PMID- 10587018
TI  - Emergency abdominal surgery for small bowel perforation secondary to metastatic
      lung cancer.
AB  - Emergency surgery for bowel perforation caused by metastases from lung cancer is
      rare. Two cases of small bowel perforation due to metastasizing lung cancer are
      reported. Both patients were admitted as a surgical emergency case. One of the
      two patients presented herein survived and was discharged from the hospital.
      Perforated small bowel due to metastatic lung cancer is a highly fatal event that
      occurs in the late phases of the disease. Despite the poor prognosis, early and
      appropriate therapy will occasionally yield successful surgical palliation.
      Patients with known lung cancer who develop abdominal complaints should be
      examined thoroughly and treated quickly.

PMID- 10587019
TI  - Usefulness of procalcitonin in Pseudomonas burn wound sepsis model.
AB  - Procalcitonin (PCT), a precursor of calcitonin, and endotoxin were determined in
      the burn wound sepsis model in which 21 Sprague-Dawley rats were scalded
      approximately 30% on their back. On day 2 post burn, the wounds were inoculated 1
      x 10(8) colony-forming units of Pseudomonas aeruginosa. On day 5 post burn P.
      aeruginosa was detected by blood culture in 10 of the 21 rats (47.6%). The
      mortality rate 7 days after burn was 90.5%. Significant correlations were
      observed between serum endotoxin levels and serum PCT levels on day 5 post burn
      (r = 0.860, p<0.001). It was suggested that endotoxin may induce the release of
      PCT and that measuring the levels of PCT may be useful in diagnosing burn wound
      sepsis.

PMID- 10587020
TI  - A phase I-II trial of high-dose ifosfamide in patients with ovarian cancer
      refractory or resistant to platinum and/or paclitaxel-containing chemotherapy.
AB  - AIMS AND BACKGROUND: To evaluate the toxicity of high-dose ifosfamide in ovarian
      cancer patients refractory or resistant to platinum and/or paclitaxel-containing
      chemotherapy. METHODS: This was an open, non-randomized phase I-II trial of high
      dose ifosfamide. Eligibility criteria were: patients aged 18-75 years affected by
      ovarian cancer with refractory or resistant disease or early relapse after first
      line treatment including platinum or paclitaxel. Three patients were given
      escalating ifosfamide doses; if no severe adverse events occurred, the ifosfamide
      dose was increased. The starting dose of ifosfamide was 10 g/m2 i.v. and the dose
      increase was 1 g/m2 every four weeks for a total of five courses; 12 g/m2 was the
      maximum ifosfamide dose to be administered. The trial then progressed to a phase
      II trial, in which ifosfamide was given at the maximum tolerated dose reached
      during the escalating dose phase. RESULTS: A total of 36 patients entered the
      trial. Nine patients were involved in phase I of the study; 3 received 10 g/m2
      ifosfamide, 3 11 g/m2 and 3 12 g/m2. Of the 32 evaluable patients 6 (18.8%)
      achieved a complete response and three (9.4%) a partial response, giving an
      overall response rate of 28.1% (95% CI, 15-61% based on Poisson's approximation).
      The median number of ifosfamide courses was five. G1, G2 and G3 neurotoxicity was
      reported in 3 (8%), 2 (5%) and 2 (5%) patients, respectively. CONCLUSION: This
      phase I-II trial indicates that high-dose ifosfamide has some activity but also a
      relevant degree of toxicity in resistant or refractory platinum and paclitaxel
      pretreated ovarian cancer.

PMID- 10587021
TI  - Locally advanced breast cancer treated with primary chemotherapy: comparison
      between magnetic resonance imaging and pathologic evaluation of residual disease.
AB  - AIMS AND BACKGROUND: We evaluated the response of locally advanced breast cancer
      to induction chemotherapy using MRI techniques. The size and vitality of any
      residual pathologic tissue was quantified by means of morphologic and dynamic
      analysis. A curve derived from the dynamic parameters shows the uptake intensity
      with respect to the time elapsed since administration, which is related to
      vascularization and therefore indirectly reflects the angiogenesis of malignant
      tissue. METHODS AND STUDY DESIGN: A group of 30 patients were examined with MRI
      for staging purposes before undergoing treatment and subsequently to assess the
      response to treatment. Alterations in size and dynamic parameters were closely
      monitored. RESULTS: The overall accuracy was 90%, the sensitivity 96%, the
      specificity 75%, the positive predictive value 92.5% and the negative predictive
      value 66%. Interestingly, analysis of the dynamic curves made it possible to
      obtain additional information regarding the angiogenetic activity of the residual
      tumor. CONCLUSIONS: Evaluation of the response to treatment by means of
      conventional imaging and clinical examination can be particularly difficult
      because of the fibrosis induced by cytotoxic drugs or the small volume of
      residual disease. The additional information supplied by MRI could therefore
      allow a more conservative surgical approach in selected cases of optimal response
      to treatment, as well as a much more accurate follow-up. Furthermore, the
      variation in dynamic parameters according to the vitality of residual disease
      could in the future become a useful tool for monitoring the effectiveness of anti
      angiogenetic drugs.

PMID- 10587023
TI  - High doses of 5-fluorouracil and epirubicin with or without cisplatin in advanced
      gastric cancer: a randomized study.
AB  - BACKGROUND: A prospective randomized clinical study was performed in patients
      with locally advanced or metastatic gastric cancer. The purpose of the study was
      to determine the activity of high doses of 5-fluorouracil and epirubicin (FE) vs.
      the same combination + cisplatin (FEP), and particularly the value of cisplatin
      in the combination. PATIENTS AND METHODS: A total of 122 patients was included in
      the study; 110 of them were assessable. In the FE arm, the treatment involved
      1000 mg/m2 in a 6-hr infusion of 5-fluorouracil on days 1, 2, 3, 4 and 5 and 120
      mg/m2 of epirubicin i.v. on day 1. In the FEP arm, the same combination of
      cytostatics + cisplatin (30 mg/m2) was administered on days 2 and 4. The cycles
      were repeated after 4 weeks. Altogether, 468 cycles of chemotherapy were given
      (FE, 240; FEP, 228). RESULTS: In the FE arm, 56 patients were assessable, with 2
      complete and 14 partial remissions (28.6%); in the FEP arm, 4 complete and 19
      partial remissions (42.6%) were observed in 54 assessable patients. Median
      survival in the FE group was 7.1 months and in the FEP group 9.6 months. The
      survival difference was statistically significant (Cox's test, P<0.05). The most
      frequent side effects included grade 2 and 3 alopecia (FE, 93%; FEP, 94%) and
      grade 2 and 3 vomiting (FE, 20%; FEP, 35%). Grade 3 and 4 leukopenia was observed
      in 9% of patients in the FE group and in 13% of patients in the FEP group, with 6
      cases of febrile neutropenia (FE, 4%; FEP, 7%). Stenocardia was registered in 1
      patient in the FE group and in 2 patients in the FEP group. No treatment-related
      death was registered. CONCLUSIONS: The addition of cisplatin to high doses of 5
      fluorouracil and epirubicin resulted in a statistically significant better
      survival of treated patients.

PMID- 10587022
TI  - Increasing dose of continuous infusion ifosfamide and fixed dose of bolus
      epirubicin in soft tissue sarcomas. A study of the Italian group on rare tumors.
AB  - PURPOSE: To evaluate the maximum tolerated doses (MTD) of ifosfamide when given
      as a continuous infusion and in combination with fixed doses of bolus 4'
      epidoxorubicin in advanced previously untreated adult soft tissue sarcoma
      patients. METHODS: Treatment consisted of epidoxorubicin, 60 mg/m2 days one and
      two, and ifosfamide, 1.5 g/m2 every 12 hrs as a 72-hr infusion, at the first
      level. Further levels of ifosfamide were defined as increments of 12 hrs of the
      same infusion program. G-CSF 300 microg/die was administered from days +7 to +14.
      Dose-limiting toxicity (DLT) was defined as: G4 leukopenia or thrombocytopenia of
      > or =5 days; any G3 neuro or nephrotoxicity; G4 toxicity of any kind. Patients
      had to complete at least 2 consecutive cycles, and MTD was defined as the level
      in which 20% of patients developed a DLT; 10-15 patients were entered in each
      level. RESULTS: First level: overall, 13 patients entered, 3 were not assessable
      for MTD, and only one developed a DLT. Second level: 18 patients entered, 3 were
      not assessable for MTD. Hematologic DLT was observed in 3/15 assessable patients.
      Therefore, the MTD was found at the ifosfamide level of 10.5 g/m2 given in 84
      hrs. Eight patients of 29 assessable for response achieved an objective response:
      1 complete and 7 partial. The overall response rate was 28% (95% CI: 13-47%).
      CONCLUSIONS: If we accept 4-day G4 leukopenia as a reliable cutoff for safety,
      ifosfamide intensification cannot be substantially exploited over already
      available schedules with the combination of ifosfamide and anthracyclines.

PMID- 10587024
TI  - Treatment of inoperable non-small cell lung carcinoma stage IIIb and IV with
      cisplatin, epidoxorubicin, vindesine and lonidamine: a phase II study.
AB  - AIMS AND BACKGROUND: The polychemotherapeutic regimen PEV (cisplatin,
      epidoxorubicin and vindesine) + lonidamine proved to be valid in terms of
      activity and efficacy in the treatment of patients with advanced, previously
      untreated non-small cell lung carcinoma. The goal of the study was to verify
      whether a different dose of lonidamine, together with an increase in cisplatin
      and epidoxorubicin compared to the standard regimen, is able to improve the
      activity and efficacy of PEV without increasing toxicity. PATIENTS AND METHODS:
      Thirty-one patients were treated with cisplatin (80 mg/m2/i.v.), epidoxorubicin
      (70 mg/m2/i.v.) and vindesine (3 mg/m2/i.v.) every 28 days for 6 courses in
      combination with lonidamine (600 mg/day on days 1 and 2 of each course followed
      by 450 mg/day until progression of disease or intolerance). All the patients were
      monitored for clinical response, median duration of response and survival and for
      toxicity. RESULTS: The clinical response in the 29 assessable patients was: 41.4%
      partial remission, 48.3% stable disease, and 10.3% progression of disease. The
      median duration of response was 8.5 months (range, 4-26+) and median survival was
      12 months (range, 4-26+). Survival was above the median in 15 stage IIIb
      patients, and 2 patients were long survivors at 26+ months. The toxicity of PEV +
      lonidamine was mild; there were no toxic deaths nor acute toxicity of grade 4
      according to the WHO scoring system. CONCLUSIONS: Our polychemotherapeutic
      regimen proved to be valid in terms of activity and efficacy, and a further dose
      increase in single chemotherapeutic agents as well as lonidamine could therefore
      be justified.

PMID- 10587025
TI  - Cold knife conization and loop excision for cervical intraepithelial neoplasia.
AB  - AIMS AND BACKGROUND: Our aim was to investigate whether loop excision is an
      acceptable alternative to traditional cold knife conization of the cervix.
      PATIENTS AND METHODS: 240 with cervical intraepithelial neoplasia (CIN) were
      randomly assigned to loop excision (n = 120) or cold knife conization (n = 120).
      Success and complication rates of both methods were analysed. RESULTS: 100% of
      cold knife conization and 98% of loop excision surgical specimens were positive
      for dysplasia. The rate of complete resection was 91% in the cold knife and 82%
      in the loop excision group, but histologic confirmation of residual CIN was
      obtained in only 2 (1.7%) women after cold knife conization and in 5 (4.2%) after
      loop excision. Loop excision cones were significantly shallower than those
      obtained by a cold knife. Secondary surgical procedures due to early hemorrhage
      were performed in 9 (7.5%) patients treated with cold knife conization and in 8
      (6.7%) treated with loop excision. Elevated temperature postoperatively was
      observed in 16.4% of patients after cold knife conization and in 13.9% after loop
      excision. There were no other postoperative complications. CONCLUSIONS: The
      results suggest that cold knife conization and loop excision are comparable and
      equally effective diagnostic and therapeutic procedures for CIN.

PMID- 10587026
TI  - Hyperthyroidism and concurrent thyroid cancer.
AB  - AIMS AND BACKGROUND: The aim of this study was to analyze the frequency of
      coexisting hyperthyroidism and thyroid malignancy in endemic goiter areas and
      review the current literature on the subject. METHODS: During the period January
      1984 to June 1998, 1853 patients were examined for hyperthyroidism at the Spedali
      Civili Hospital of Brescia, Italy; 512 (27.6%) subjects underwent surgery. Of
      these patients 108 (21%) had Graves' disease, 251 (49%) multinodular toxic goiter
      (MTG) and 153 (30%) uninodular toxic goiter (UTG). RESULTS: Malignancy was found
      in 24 (4.7%) patients: 19 females and 5 males with a mean age of 52.2 years
      (range, 21-76 years). The frequency of cancer in Graves' disease was 6.4%, 5
      females and 2 males; in MTG 3.9%, 2 females and 8 males, and in UTG 4.4%, 7
      females and 1 male. CONCLUSIONS: Our data confirm previous reports on the
      frequency of thyroid cancer in hyperthyroidism. This association is more relevant
      than previously suspected. The frequent coexistence of hyperthyroidism and
      neoplasia, demonstrated by our study and the most recent literature, underlines
      the importance of studying and excluding the possibility of neoplastic
      degeneration by means of a systematic approach.

PMID- 10587027
TI  - Clinical relevance of tumor ploidy and micronucleus formation for oral cavity
      cancer.
AB  - AIMS AND BACKGROUND: To study the clinical relevance of tumor ploidy and
      micronucleus formation as prognostic factors. METHODS AND STUDY DESIGN: Twenty
      eight patients with squamous cell carcinoma of the oral cavity were treated with
      primary radiochemotherapy consisting of irradiation up to 70 Gy in combination
      with cisplatin. Cell cycle distribution, micronucleus formation and ploidy were
      evaluated by flow cytometry of biopsies taken before treatment and after
      irradiation to 10 Gy (5x2 Gy). Sexteen out of 28 patients relapsed after a
      minimum follow-up period of two years. RESULTS: Flow cytometry of the recurrence
      biopsy showed hyperpentaploid (5c exceeding) cells in 13/16 (81%) of the relapsed
      patients. In 7 patients the hyperploid clone was not present in the flow
      cytometry of the primary tumors. Ploidy could retrospectively be determined also
      by image cytometry in archival tumor material of the pretreatment specimens.
      Patients with a level below 100 5c cells per 10,000 cell nuclei were shown to
      have a significantly better prognosis than patients with more than 100
      hyperpentaploid tumor cells. The micronucleus formation was 2-5 times higher in
      tumors showing a good response to treatment than in carcinomas relapsing within
      two years. CONCLUSIONS: The 5c-exceeding ratio measured by image cytometry and
      micronucleus formation proved to be good prognostic parameters for the clinical
      outcome of patients with locally advanced head and neck carcinomas.

PMID- 10587028
TI  - Retroperitoneal soft tissue sarcoma: effect of hyperthermic total abdominal
      perfusion.
AB  - AIMS AND BACKGROUND: Soft tissue sarcomas (STS) of the retroperitoneum are rare
      tumors. Surgery remains the principal modality of therapy in the management of
      primary and recurrent retroperitoneal STS. However, little is known about the
      effect of regional chemotherapy using hyperthermic total abdominal perfusion
      (HTAP). We analyzed independent prognostic variables in 33 patients with STS in
      the retroperitoneum admitted from November 1990 through December 1996. METHODS
      AND STUDY DESIGN: Data regarding patients' age, gender, tumor size, histological
      tumor type, tumor location, type of operation (primary or secondary surgery),
      extent of surgical management (marginal or extended), use of HTAP, tumor grade,
      and tumor stage according to the TNM classification were examined by univariate
      and multivariate analyses. RESULTS: All 33 patients underwent complete resections
      (marginal or extended). Eleven of them received locoregional chemotherapy by
      HTAP. The overall cumulative 5-year survival rates in patients with stage IIA and
      advanced disease were 82% and 22%, respectively (log-rank test, P<0.01). Using
      Cox's proportional hazard model, tumor stage, use of HTAP and type of operation
      were found to have significant influence on overall survival (P<0.05).
      CONCLUSIONS: Our results showed that complete resection along with HTAP
      chemotherapy may improve survival in patients with retroperitoneal STS. These
      phase II data could be used to support the initiation of a phase III trial to
      test HTAP in patients submitted to complete resection of retroperitoneal STS.

PMID- 10587029
TI  - Endoscopic treatment of carpet-like adenomas of the rectum.
AB  - BACKGROUND: Transanal microsurgery, endoscopic laser photocoagulation and snare
      resection have all been used to treat large sessile adenomas of the rectum
      alternatively to a surgical approach. However, such modalities are often
      defective due to the carpet-like shape and the frequently large extension of the
      lesions. METHODS: Ten patients with carpet-like adenoma were submitted to
      transanal endoscopic resection by urological resectoscope. RESULTS: Complete
      eradication was obtained in all lesions. The mean number of treatment sessions
      was 3 (range, 1-5). The mean time between the first treatment and the complete
      eradication was 6 months (range, 1-18). The only complications were an
      intraoperative and an early postoperative bleeding. There was no early or late
      mortality related to the procedure. CONCLUSIONS: Transanal endoscopic resection
      by urological resectoscope appears to be a suitable therapeutic approach for
      sessile and carpet-like adenomas of the rectum or for pTI cancer in patients who
      refuse major surgery.

PMID- 10587030
TI  - Management of malignant mucinous adenomas.
AB  - BACKGROUND: Malignant polyps are defined as adenoma with cancerous tissue
      penetrating into or through the muscolaris mucosae in the submucosa, and
      endoscopic removal is the most common treatment for such polyps. In the presence
      of malignant mucinous adenoma, defined as a malignant adenoma in which a
      significant amount of mucus is present in the stroma, the therapeutic approach is
      controversial and authors have performed surgical resection in all cases. The
      purpose of the study was to demonstrate that malignant mucinous adenoma is not a
      condition suggesting by itself a bowel resection. METHODS: Ten patients with
      malignant mucinous adenoma were enrolled in the study: endoscopic treatment alone
      was performed in 4 cases, and polypectomy was followed by surgical resection in 6
      cases. RESULTS: At a median follow-up of 74.2 months no distant metastases had
      occurred in any of the patients treated with endoscopic polypectomy alone; during
      the follow-up, 1 patient had a local recurrence and surgical resection was
      performed. Only one case of residual disease was found at histology among the
      patients in which endoscopic polypectomy was followed by surgical resection. No
      complications occurred after endoscopic treatment in any case. CONCLUSIONS: In
      the absence of unfavorable histologic parameters, malignant mucinous adenomas
      should be managed with the same criteria of other malignant adenomas, and
      endoscopic polypectomy is considered as a safe and effective treatment when
      radicality criteria are fulfilled.

PMID- 10587031
TI  - Improving the quality of life for children with cancer. European School of
      Oncology Advisory Group.
AB  - There are now more than one million new cases of cancer every year in the
      European Community (EC) including the children to whom particular needs should be
      addressed. Besides the disease-free survival other outcomes reflecting the impact
      of treatment on the patient and their families must also be assessed and include
      their physical, psychological and social functioning throughout their care:
      during therapy, after completion of treatment or, for some, in the terminal phase
      of their illness. To provide optimal care and thus improve the quality of life
      for these children needs: a) an appropriately structured Paediatric Cancer Unit;
      b) well trained and permanent staff members: comprising doctors, nurses,
      psychologists, social workers and other health care professionals; c) facilities
      such as a specific out-patient clinic, a hospital school, a residence for
      parents; d) a well defined programme for the terminally ill children; e) a well
      defined programme for controlling the late effects of therapy.

PMID- 10587032
TI  - Efficacy of total androgen blockade in metastatic prostatic carcinoma with
      transient hypogonadotropic hypogonadism: a case report.
AB  - A patient affected by metastatic prostatic carcinoma and hypogonadotropic
      hypogonadism (HH) was treated with flutamide 750 mg/day plus an LH-RH analog.
      After confirmation of basal castration during treatment, he continued with
      antiandrogens alone. Following the normalization of gonadic function and
      subjective mild bone flare-up, the patient resumed the initial treatment and
      obtained a partial response. When flutamide was interrupted because of liver
      toxicity, the patient showed progressive disease in the bone, which was
      unresponsive to both flutamide resumption and salvage hormone therapy
      (bicalutamide). The patient is currently receiving chemotherapy with VP16 and
      estramustine phosphate and is showing both serologic (PSA) and symptomatic
      response. The interest of this case lies in the incidental detection of HH during
      therapy and in the responsiveness to treatment.

PMID- 10587033
TI  - A case of primary small cell carcinoma of the cervical esophagus with long-term
      survival following concurrent chemoradiotherapy: case report and review of the
      literature.
AB  - The authors describe a case of small cell carcinoma of the esophagus that was
      treated by concurrent chemoradiotherapy. Both the esophageal tumor and the
      regional lymph node metastases disappeared after this treatment. The patient is
      alive and disease free after more than five years. Primary small cell carcinoma
      of the esophagus is a rare and aggressive neoplasm with a very poor prognosis,
      and the treatment modality is controversial. This case illustrates the
      possibility of treating this tumor type with concurrent chemoradiotherapy.

PMID- 10587034
TI  - Fludarabine phosphate as an active and well tolerated salvage therapy in an
      elderly heavily pretreated Hodgkin's disease patient: a case report.
AB  - Up to two thirds of all patients affected by advanced Hodgkin's disease will be
      cured by chemotherapy alone or by combined chemoradiation modalities. High-dose
      chemotherapy with autologous stem cell rescue may be potentially curative for
      patients progressing under frontline chemotherapy or developing early relapse of
      disease. In spite of this, an unacceptably high percentage of these high-risk
      patients will relapse after salvage treatments and die of their disease.
      Fludarabine phosphate is an adenosine nucleoside analog highly active in chronic
      lymphocytic leukemia and low-grade non-Hodgkin's lymphomas. There are only few
      data in the literature concerning its use in the management of Hodgkin's disease.
      We report the case of an elderly, heavily pretreated Hodgkin's disease patient in
      progression under third-line chemotherapy who experienced good palliation of her
      B symptoms and a major clinical response of her refractory bone lesions with the
      administration of fludarabine as monotherapy. The treatment was well tolerated,
      without grade 4 hematological toxicity or opportunistic infections. The duration
      of clinical remission and systemic symptom palliation was 9 and 11 months,
      respectively. Further evaluation of fludarabine phosphate as salvage therapy in
      relapsed/refractory elderly Hodgkin's disease patients is needed.

PMID- 10587035
TI  - Spontaneous hemorrhage of a liver metastasis from squamous cell cervical
      carcinoma: case report and review of the literature.
AB  - Liver metastases are an uncommon cause of spontaneous bleeding compared with
      primary benign/malignant liver lesions. Since metastatic lesions tend to maintain
      the vascular characteristics of the primary tumor, some metastases have a greater
      proclivity for hemorrhage into the host organ than others. We describe the
      clinical and computed tomography (CT) features of a patient previously treated
      for nonkeratinizing small cell squamous carcinoma of the cervix uteri. As the
      metastatic rupture was diagnosed while still intraparenchymal and subcapsular,
      with minimal peritoneal reaction, the patient's outcome was favorable.

PMID- 10587036
TI  - Choroidal metastasis from carcinoma of the hypopharynx: a case report.
AB  - Choroidal metastasis from primaries other than breast or lung cancer is a rare
      event. There is no documented case in the literature of choroidal metastases in
      patients with hypopharynx carcinoma. Early treatment with radiation therapy
      provides effective palliation by preserving visual function and preventing the
      need for enucleation. Chemotherapy alone does not seem to be as effective as
      radiation therapy for patients with choroidal metastases. In this paper a case of
      choroidal metastasis arising from a primary hypopharynx carcinoma is presented.

PMID- 10587037
TI  - Hypersensitivity reaction to carboplatin during treatment for ovarian cancer:
      successful resolution by replacement with cisplatin.
AB  - Development of hypersensitivity reactions to carboplatin (CP) during cancer
      treatment makes optimal chemotherapy difficult to achieve. Many approaches have
      previously been used following the development of reactions to CP. We report on a
      patient with ovarian cancer who developed a hypersensitivity reaction to CP. The
      patient was successfully treated following replacement of carboplatin with
      cisplatin.

PMID- 10587038
TI  - Accrual issues for chemoprevention trials: the example of the 4-HPR study for the
      prevention of contralateral breast cancer.
AB  - This paper describes the accrual of the controlled clinical trial with
      fenretinide for the prevention of contralateral breast cancer. Accrual screened
      4,030 potentially eligible patients of whom 1,815 were randomized. Two strategies
      of recruitment were used, i.e. retrospective and prospective. In the
      retrospective accrual, the medical staff reviewed the records of breast cancer
      patients who had received curative surgery to select those who fulfilled the
      eligibility criteria of the study. For the prospective recruitment operated,
      patients were contacted after the beginning of the trial. The study started in
      March 1987 and accrual closed on July 31, 1993. The planned accrual period was
      extended by 19 months. The yearly accrual tended to decrease with time. This was
      mainly due to the end of the retrospective recruitment and to the introduction of
      adjuvant chemotherapy, a reason for exclusion from the trial, also for patients
      with negative axillary nodes. The known accrual difficulties of chemoprevention
      studies proved also to be true for the high-risk population of this trial.

PMID- 10587039
TI  - Terminology to benefit children.

PMID- 10587040
TI  - Brain perfusion SPECT and MRI in foetal alcohol syndrome.
AB  - Six boys and five girls with a mean age of 8.6 (range 3 to 13) years with foetal
      alcohol syndrome (FAS) were studied by MRI and single photon emission computed
      tomography (SPECT) to find specific areas of vulnerability. Morphological
      anomalies shown in six of 11 patients by MRI were situated both cortically and
      subcortically: cortical atrophy (N = 2), dilated ventricle (N = 1), corpus
      callosum hypoplasia (N = 1), cerebellar atrophy (N = 2), one of the latter with
      Arnold-Chiari malformation (N = 1). Delayed myelination of the white matter was
      seen in two patients. Volumetric studies of the hippocampus showed morphological
      left-right asymmetry in five of eight patients. However, SPECT showed mild
      hypoperfusion of the left hemisphere in all 10 subjects. The negative left-right
      index was located especially in the left parietooccipital region, i.e. in the
      brain areas implicated in arithmetical and logical-grammatical functions, which
      are known to be affected in FAS. Normal left-right dominance was also lacking in
      the frontal area, i.e. the brain area affected in attention-deficit-hyperactivity
      disorder (ADHD). Detection of these abnormalities, although they are not unique
      to FAS, may be helpful in the diagnosis and any attempts at rehabilitation.
      Diverse morphological and functional abnormalities are more frequent than has
      usually been believed even in less impaired children with FAS.

PMID- 10587041
TI  - Cognitive deficits after cryptogenic infantile spasms with benign seizure
      evolution.
AB  - Between 1989 and 1994, 18 children with cryptogenic infantile spasms-defined by
      normal development before onset of spasms, symmetrical hypsarrhythmia or
      multifocal spikes, and typical spasms on presentation, and no abnormal findings
      on aetiological studies including neuroradiology-were diagnosed and treated. To
      assess the risk of cognitive impairment later in life, 15 of these 18 children
      whose spasms completely resolved within the first year of life were studied. Age
      at onset of spasms varied between 4.4 and 9.8 months (mean 6.5 months). Children
      were effectively treated with adrenocorticotrophic hormone (10 children),
      pyridoxine (three), vigabatrin (one), or sodium valproate (one). Spasms lasted
      between 11 and 138 days (mean 50 days) and stopped between the age of 6.3 and
      10.2 months(mean 8.1 months). EEGs normalized between the age of 7.1 and 13.2
      months (mean 9.4 months). Early development was assessed on presentation and
      within a few months after spasms had stopped. A detailed neuropsychological
      assessment was performed between the age of 4.0 and 5.9 years. Twelve children
      had normal intelligence; specific cognitive deficits were found in five. Three
      children had mild learning disability. Abnormal developmental status at age 8 to
      15 months after complete resolution of spasms and EEG abnormalities was
      associated with cognitive deficits at age 4 to 6 years.

PMID- 10587042
TI  - Cognitive predictors of young children's readiness for powered mobility.
AB  - Independent mobility in early childhood has been associated with the development
      of various cognitive and psychosocial skills. However, children with physical
      disabilities are not always able to move independently and may be at risk for
      delays in these areas. Early provision of powered mobility can offer young
      children an opportunity for independent mobility. Despite this, there is little
      information to help determine when a young child has the cognitive skills
      necessary to operate a powered wheelchair safely. This current research aims to
      identify these skills. A cognitive assessment battery and a wheelchair mobility
      training and assessment program were developed. Twenty-six children with physical
      disabilities between the ages of 20 and 36 months were evaluated on the cognitive
      assessment and participated in the wheelchair training and assessment program. A
      stepwise regression analysis was used to determine which of the cognitive skills
      predicted wheelchair mobility performance. The cognitive domains of spatial
      relations and problem solving were found to be significant and accounted for 57%
      of the variance in wheelchair skills. Developmental cut-off points on these
      scales as they relate to wheelchair skills are presented and clinical
      applications are discussed.

PMID- 10587043
TI  - Sexual and reproductive health in young people with spina bifida.
AB  - This study aimed to identify the sexual and reproductive health knowledge,
      attitudes, and behaviour of young people, aged between 14 and 23 years, with
      spina bifida who had attended the Spina Bifida Clinic at a tertiary centre in
      Melbourne, Australia within the past 10 years. Subjects participated in a
      structured interview and their parents completed a written questionnaire. Fifty
      one (55%) of 93 eligible young people and 69 of 97 parents (71%) participated.
      Most young people were satisfied with the amount of general sex education they
      had received. However, 95% stated they had inadequate knowledge about sexual and
      reproductive health relating to spina bifida and 59% of parents considered they
      had inadequate knowledge. Thirty-nine percent of young people and 30% of parents
      had discussed sexuality issues with a doctor. However, 93% of young people and
      100% of parents said that they would definitely talk about these issues if the
      discussions were initiated by their doctor. A significant degree of sexual
      intimacy was reported, with 60% reporting an intimate relationship, and 25% (10
      females, three males) reporting sexual intercourse. Thirty-seven percent of
      females had experienced unwanted sexual attention, and 30% reported unwanted
      sexual touching. This study suggests that health professionals should pay greater
      attention to sexual and reproductive health issues in young people with spina
      bifida.

PMID- 10587044
TI  - High- or low- technology measurements of energy expenditure in clinical gait
      analysis?
AB  - The repeatability of energy-expenditure measurements were studied in five
      children and four adults without disabilities using the Cosmed K4 (high
      technology). The ability to detect change in measurements was compared between
      this instrument and the Physiological Cost Index (PCI; low technology). The
      results of repeatability (95% range) for oxygen cost were 13.1% in children and
      13% in adults. In contrast, the SD of PCI was 6 to 72% of the mean in adults and
      wider in children (91%; 95% range). The validity of PCI as an outcome measure was
      questioned. In addition, 177 children with motor disability were prospectively
      studied using the Cosmed K4. Previous experience with the Cosmed K2 (intermediate
      technology) helped to develop a practical and repeatable protocol for testing
      children with disability using the Cosmed K4. The protocol commenced with 5
      minutes of rest to achieve baseline values of heart rate and oxygen consumption,
      followed by 10 minutes of continuous walking at a self-selected speed on a 10
      metre level oval walking track. The test concluded with 5 minutes of rest to
      monitor the return to baseline values. Ninety-one percent of the children with
      disability quickly reached a steady-state of oxygen consumption and carbon
      dioxide production. The carbon-dioxide sensor in the Cosmed K4 has enabled a new
      group of severely involved children with cerebral palsy (9%) to be defined. These
      children have been termed 'physiologically marginal ambulators'.

PMID- 10587045
TI  - Medical aspects of school-aged children with Down syndrome.
AB  - Current and comprehensive information about the medical issues affecting children
      with Down syndrome (DS) is of value in counselling parents who are considering
      prenatal diagnosis and in planning services for people with DS as they age,
      especially given the continued improvements in their survival. Parents of school
      aged children (mean age 11.37 years, 57.3% male, 42.7% female) with DS were
      identified by linking registers from the Disability Services Commission and the
      Birth Defects Registry. Less than half the children had cardiac and bowel
      conditions. More than half had ear conditions and more than three quarters had
      eye conditions. Ear, nose, and throat professionals were the specialists seen
      most often and the rate of tympanostomy tube insertion was nearly 17 times that
      of the general childhood population. Children with DS were over five times more
      likely to wear glasses than other children. These findings suggest that chronic,
      non life-threatening conditions impose a burden on families but do not threaten
      quality of life.

PMID- 10587046
TI  - Outcome at 1 year of neonatal encephalopathy in Kathmandu, Nepal.
AB  - To determine the outcome at 1 year of neonatal encephalopathy (NE) and to
      estimate the possible contribution of birth asphyxia to childhood disability in a
      low-income South Asian country, a prospective cohort study was undertaken in the
      principal maternity hospital of Kathmandu, where over 50% of local women give
      birth. From a total population cohort of 21609 live births, 131 term infants with
      NE (after exclusion of cases associated with neonatal sepsis, congenital
      malformations, or primary hypoglycaemia) and 208 term control infants were
      recruited. Of these, 102 (78%) infants with NE and 106 (51%) control infants were
      followed-up to 1 year of age. Outcome measures were death or neurodevelopmental
      impairment, graded as major, minor or none. Of the 131 term infants with NE, 83
      were graded with moderate or severe NE according to conventional definition. By 1
      year of age, 45 (44%) of the infants with NE had died, 18 (18%) had severe
      impairments, and two (2%) had minor impairments; four (4%) of the control
      subjects had died and two (2%) had minor impairments. Most deaths in subjects
      with NE occurred in the early neonatal period; NE carried no excess risk of death
      beyond the neonatal period. Of the 18 children with major impairment, 14 (78%)
      had spastic tetraplegic cerebral palsy and eight (44%) had multiple impairments.
      Compared with the control group the relative risk of death by 1 year was 5 (95%
      CI 1.4 to 15) for mild NE, 8 (95% CI 3 to 23) for moderate, and 26 (95% CI 10 to
      67) for severe. Twenty-seven of 38 (71%) infants with moderate NE either died or
      survived with major impairment. An upper estimate for the prevalence of major
      neuroimpairment at 1 year attributable to birth asphyxia is 1 per 1000 live
      births in this population.

PMID- 10587047
TI  - Cutaneous flexion reflex in human neonates: a quantitative study of threshold and
      stimulus-response characteristics after single and repeated stimuli.
AB  - The cutaneous flexion reflex has been used to study spinal sensory processing in
      68 infants (37 female, 31 male) aged between 28 and 42 weeks postconceptional age
      (PCA). Mechanical and electrical stimuli were singularly and repeatedly applied
      to the foot, and single-surface EMG responses were recorded from the biceps
      femoris muscle. A clear correlation was demonstrated between the mechanical
      stimulus intensity and latency and the amplitude of the reflex. Mechanical
      threshold normally increased with age, but the flexion-reflex threshold was
      lowered by local limb-tissue damage in the contralateral limb. The incidence of
      response to repeated mechanical stimulation at 2.8 x threshold decreased
      significantly with increasing age. Repeated mechanical stimulation at 2.8 x
      threshold caused a build-up in the size of the response followed by a diminution.
      The flexion reflex can, therefore, be used to investigate sensory processing in
      the neonate, and the effects of tissue damage. The importance of using natural
      rather than electrical stimulation is highlighted.

PMID- 10587048
TI  - Painful seizures with allodynia in an 11-year-old boy.
AB  - An 11-year-old boy's epileptic seizures started with a feeling of impending
      crisis, dizziness, headache, and a bad taste in the mouth. This was followed by
      swallowing and a burning sensation in the left hand. At the same time, other
      parts of the body experienced allodynia. MRI and CT scans showed a right
      anteromesial temporal lesion which proved at neuropathology to be a
      ganglioglioma. Lesionectomy resulted in complete cessation of seizures. Seizures
      were absent at an 18-month follow-up. Allodynia is discussed in relation to the
      locality of the lesion.

PMID- 10587049
TI  - Supraspinal pathways and the development of muscle-tone dysregulation.

PMID- 10587050
TI  - Test-retest reliability of the energy expenditure index in adolescents with
      cerebral palsy'.

PMID- 10587051
TI  - Antimicrobial resistance--can we, should we do anything about it?

PMID- 10587052
TI  - Bibliometric analysis of HRC-supported biomedical publications, 1990 to 1994.
AB  - AIM: To document changes in the rate and impact of publications resulting from
      Health Research Council of New Zealand (HRC) biomedical grants since its
      inception and to relate the number of publications to Health Priority Areas,
      fields of research and specific types of grant. METHODS: All original papers or
      reviews and editorials published by HRC-supported investigators in peer-refereed
      journals, from 1990 to 1994, were entered into a bibliographic database. RESULTS:
      In this five-year period, researchers receiving HRC biomedical grants published a
      total of 2094 articles in 623 peer-reviewed journals, of which 1190 (57%) derived
      from HRC support. Of the publications, 90.2% were original papers; the remainder
      were reviews or editorials. From 1990 to 1994, there was an increase in the
      number of HRC-supported publications (p<0.04) but not of those deriving from
      other support. There was no change in the quality of publications over this
      period, as reflected by the impact factor (a measure of the number of times that
      publications in a journal are cited). The majority (62.6%) of publications
      derived from project grants, however, the average cost per publication was 8.4%
      higher for project than for programme (multi-investigator) grants. Finally,
      nearly 40% of HRC publications directly addressed designated health priority
      areas. CONCLUSIONS: The present study has examined one aspect of the value for
      money obtained from the public investment in biomedical research. As the HRC is
      the major provider of contestable biomedical research funding in New Zealand,
      bibliometric analysis may be of ongoing value to monitor the effects of changes
      to the organisation of biomedical research funding in New Zealand.

PMID- 10587053
TI  - The epidemiology of breast cancer in Pacific women in New Zealand.
AB  - AIM: To describe the epidemiology of breast cancer in Pacific women in New
      Zealand and determine whether ethnic disparities exist. METHODS: Analysis of data
      obtained from the New Zealand Cancer Registry for breast cancer notifications
      from 1987-94 inclusive. Statistical analysis compared the age-specific incidence,
      tumour stage at presentation and pathological tumour type of Pacific, Maori and
      Other women. RESULTS: Notification data were analysed for 12,914 breast cancer
      cases including 688 Maori and 227 Pacific women. The age-standardised incidence
      rate per 100,000 person years for Pacific women (104.5) was statistically
      significantly (p<0.05) lower than that for Other (139.1) and Maori (148.6) women.
      Pacific and Maori women presented with significantly less localised tumours
      (31.4% and 41.3% respectively) than Other women (47.2%). CONCLUSION: Ethnic
      disparities in breast cancer epidemiology exist in New Zealand. Pacific women may
      have decreased incidence rates of breast cancer but they and Maori women present
      with a more advanced stage of breast cancer than Other women. The latter is a
      modifiable factor which could be targeted by improved participation in screening
      programmes.

PMID- 10587054
TI  - Primary antiphospholipid syndrome associated with pernicious anaemia.
AB  - AIM: To determine whether there is an association between pernicious anaemia and
      antiphospholipid antibody syndrome. METHODS: Fifteen patients with pernicious
      anaemia and 11 patients with iron deficiency anaemia (controls) were evaluated
      for clinical parameters of thrombosis and/or the presence of antiphospholipid
      antibodies, antinuclear antibodies or lupus anticoagulant. RESULTS: One
      asymptomatic patient with pernicious anaemia had laboratory features suggestive
      of the antiphospholipid syndrome. An additional three patients in each group had
      slightly elevated antiphospholipid antibody concentrations, within one standard
      deviation of the normal range. CONCLUSION: The association between pernicious
      anaemia and antiphospholipid antibody syndrome is rare and evaluation should be
      guided by clinical indications.

PMID- 10587055
TI  - Screening for a prothrombotic diathesis in patients attending family planning
      clinics.
AB  - AIMS: 1. To determine the frequency of prothrombotic markers in young women
      seeking a new or a repeat prescription of the oral contraceptive pill and
      perceived to be at high risk of thrombosis. 2. To assess cost-effectiveness of
      thrombophilia testing within this population. 3. To determine the frequency of
      acquired activated protein C (APC) resistance. METHODS: Results of thrombophilia
      testing were retrospectively reviewed on 220 consecutively referred patients'
      plasmas. Women tested were clients attending local family planning clinics for a
      new or repeat contraceptive prescription. Samples for testing were collected by
      the Community Laboratory Service. Investigations included: antithrombin III (AT
      III), protein C, protein S, APC resistance, factor V Leiden mutation analysis and
      anti-cardiolipin antibodies. RESULTS: Abnormalities were detected in 35 (15.9%)
      of the 220 women tested. No patient had all tests performed. The most frequently
      detected abnormality was an increased APC resistance in 6.8% of the women tested.
      Three of the 13 patients with an abnormal APC resistance had a discrepancy
      between the low APC ratio and a negative mutation analysis result for factor V
      Leiden, suggesting acquired APC resistance. Deficiency of protein C was found in
      1.2% (of 162), protein S in 2.0% (of 140), antithrombin III in 0.6% (of 159). Low
      titre anti-cardiolipin antibodies were detected in 13.9% of this group (115
      tested). CONCLUSIONS: The frequency of abnormal thrombophilia markers detected in
      this cohort of young women is not significantly different from that seen in a
      control population. This low incidence suggests that testing has been applied on
      a population screening basis, rather than preselecting a high-risk group.
      Thrombophilia screening in this patient group cannot be justified when the
      clinically relevant end-point is death from pulmonary embolism. The cost of
      preventing one fatal pulmonary embolism arising as a consequence of screening for
      activated protein C resistance due to the commonly occurring factor V Leiden is a
      minimum $25,000,000. This compares very unfavourably with the estimated cost per
      life saved in the National Breast Screening Programme.

PMID- 10587056
TI  - Community networking as a means for identifying people with diabetes in a rural,
      predominantly bicultural community in New Zealand.
AB  - AIMS: To assess the use of community networking to estimate the prevalence of
      diabetes in a predominantly New Zealand Maori and European community. METHODS: A
      cross-sectional survey of people with known diabetes identified either through
      general practice or community networks (others with diabetes, public notices or
      public meetings) was undertaken. Ascertainment was compared using capture
      recapture methods for two independent samples. RESULTS: Overall ascertainment by
      community networking was greater for Maori than Europeans (40 +/- 3% vs 15 +/-
      2%, p < 0.001). Ascertainment using general practice registers was comparable in
      the two ethnic groups (48 +/- 4% vs 55 +/- 5%, respectively). Women were more
      likely than men to be contacted through community networking (odds ratio 1.47,
      1.05-2.06). CONCLUSION: In closely knit communities, community networking
      provides an independent source for estimating the prevalence of diabetes.

PMID- 10587057
TI  - Tuberculosis in immigrants and visitors.
AB  - Immigrants and visitors are a significant factor in the epidemiology of
      tuberculosis (TB) in New Zealand, accounting for an increasing proportion of
      notifications in recent years. At present screening of immigrants from countries
      with a high incidence of TB is inadequate. There are deficiencies in procedures,
      inadequate screening coverage, ineffectual coordination between the Ministry of
      Health and New Zealand Immigration Service, incomplete follow-up on those at risk
      of TB, confusion over financial responsibility, inadequate data to describe the
      problems and monitor interventions, and a lack of commitment to assistance with
      TB control in neighbouring countries from which some of our TB arises. We make
      recommendations in all of these areas. Timely screening of high-risk immigrants
      should be seen as health protection for ethnic minorities.

PMID- 10587058
TI  - Measuring health-related quality of life.

PMID- 10587059
TI  - Unravelling the tapestry of meningococcal disease.

PMID- 10587060
TI  - Travel health advice for animal bites and rabies.

PMID- 10587061
TI  - Foil packaging of pills.

PMID- 10587062
TI  - Genes by biology or culture?

PMID- 10587063
TI  - Antibiotic resistance and otitis media with effusion in Dunedin.

PMID- 10587064
TI  - General practitioner found guilty of misconduct

PMID- 10587065
TI  - Rationing health care: how should the HFA proceed?

PMID- 10587066
TI  - How well do we monitor patient satisfaction? Problems with the nation-wide
      patient survey.
AB  - AIM: To outline and assess the accuracy and usefulness of the quarterly nation
      wide patient survey of all New Zealand hospitals. METHOD: Data generated by an
      improved patient survey at South Auckland Health (SAH) was used to examine some
      of the problems and issues pertaining to this survey: i.e. the format of the
      questionnaire; unintended consequences of the specific methodology employed and
      the usefulness of the obtained information. RESULTS: Evidence is provided to show
      that the inpatient sample is not representative of the SAH patient population and
      that patients across different socio-demographic groups have different
      satisfaction rates. Additional research projects undertaken by the authors at SAH
      suggest that different methods of completing the questionnaire can significantly
      influence the results. CONCLUSION: The nation-wide patient survey is in need of
      revision, if it is to be used as an effective management tool within hospitals
      and for the sector as a whole.

PMID- 10587067
TI  - The acutely painful scrotum in children: how to avoid the traps in diagnosis.
AB  - The acutely painful scrotum is one of the more common surgical emergencies in the
      prepubertal boy. It is almost always caused by torsion of a testicular appendage
      or torsion of the testis. It may be difficult to distinguish the two conditions
      clinically with certainty. Where torsion of the testis has occurred, delay in
      diagnosis and treatment increases the likelihood that the testis will be found
      dead at the time of surgical exploration. This review identifies the main causes
      of diagnostic error and describes how the various traps in clinical assessment
      can be avoided.

PMID- 10587068
TI  - Analgesia in soft-tissue injury: current practice in Auckland is not supported by
      the available evidence.
AB  - AIMS: To document current prescribing habits and attitudes of doctors in the
      Auckland region towards analgesic medication for soft-tissue injury and determine
      whether the available evidence supports this practice. METHOD: A survey of 573
      doctors in the Auckland region was conducted. There was a 71.4% response rate.
      The clinical and experimental evidence concerning non-steroidal, anti
      inflammatory (NSAID) use in soft-tissue injury was reviewed. The side-effect
      profiles of NSAIDs were reviewed, with emphasis on the incidence of
      gastrointestinal side-effects when NSAIDs are prescribed for short periods and
      evidence implicating adverse renal effects on healthy exercising adults. RESULTS:
      Most doctors ranked NSAIDs more effective than paracetamol (70.4%, p<0.01).
      NSAIDs were the most prescribed single analgesic agents (47.8%, p<0.0001).
      Diclofenac was the NSAID of choice for 69.8% of doctors, who used NSAIDs
      (p<0.001). The incidence of gastrointestinal side-effects for short-term use of
      NSAIDs in acute soft tissue was 11%. CONCLUSION: The available evidence does not
      support the belief by the doctors surveyed that NSAIDs are more effective than
      paracetamol in soft-tissue injury. NSAIDs delay, but do not prevent the
      inflammatory response in injured tissue and may expose athletes to an increased
      risk of re-injury by delaying healing. Significant adverse effects do occur in
      previously healthy patients who receive NSAIDs.

PMID- 10587069
TI  - Changes in cigarette purchasing by fourth form students in New Zealand 1992-1997.
AB  - AIM: To determine recent changes in cigarette purchasing behaviour of 14- and 15
      year-old students in New Zealand. METHOD: Nationwide cross-sectional surveys of
      fourth form students in 85 schools in New Zealand by means of an anonymous self
      administered questionnaire collected in November 1992 and in November 1997.
      RESULTS: Analyses were restricted to 4198 out of 11 824 total students in 1992,
      and 4526 out of a total of 11 350 in 1997, who were current smokers aged 14 and
      15 years. Self-purchasing of cigarettes decreased by 37% (95% CI: -40, -34) from
      1992 to 1997, adjusting for age, sex and ethnicity, while acquiring cigarettes
      from other people increased. There was decreased purchasing from dairies (-6%;
      95% CI: -8, -4) and supermarkets (-9%; 95% CI: -16, -1) but increases from other
      sources such as take-away shops, tobacconists and vending machines. From 1992 to
      1997, weekly buying increased by 23% (95% CI 16, 32), students who were refused a
      sale increased by 153% (95% CI 139, 169) and students who had difficulty in
      buying increased by 324% (95% CI 276, 379). The latter were less likely to buy
      weekly than students who did not have difficulty (31.1% vs 41.4%). Students who
      smoked < or =5 cigarettes per week were 32% (95% CI 13, 53) more likely to have
      difficulty in buying than students smoking >20 per week. CONCLUSION: These
      results indicate major changes in cigarette purchasing behaviour between 1992 and
      1997, when there was increased enforcement against underage sales of tobacco.

PMID- 10587070
TI  - The personal costs of diabetes: a significant barrier to care in South Auckland.
AB  - AIM: To estimate the out-of-pocket expenses associated with diabetes care and
      their impact on self-care activities in inner urban South Auckland. METHODS:
      Follow-up, cross-sectional household survey among 1629 residents with known
      diabetes. A brief questionnaire was completed during either two consecutive mail
      surveys or a subsequent household visit to diabetic patients identified in a
      previous household survey. RESULTS: Responses were obtained from 802 (75%) of the
      1075 subjects remaining resident in the area. Median annual costs of scripts,
      shoes, clinic and general practice visits ranged between $191-$329 depending on
      ethnic group. Costs were higher among males, those requiring insulin therapy and
      those aged under 60 years. A significant proportion of subjects reported that
      these costs prevented regular self-blood-glucose monitoring (18-49%), self
      medication (11-47%) and regular insulin therapy among insulin-treated patients (8
      52%). CONCLUSIONS: The out-of-pocket expenses associated with diabetes remain a
      substantial portion of disposable income and a barrier to the prevention of
      diabetes-related complications. These data support the provision of preventive
      diabetes care at no cost to the patient at the point of care.

PMID- 10587071
TI  - The cost of research: an analysis of Auckland Healthcare's research activity.
AB  - AIM: Research informs clinical practice. It may also increase the cost of health
      service delivery, especially in an academic medical centre, where there is a
      greater concentration of research activity. Data on the cost of research in New
      Zealand Hospital and Health Services, particularly those providing teaching and
      other academic opportunities, are scarce. This article describes a method for
      collecting and analysing data related to research activities at Auckland
      Healthcare, New Zealand's largest Hospital and Health Service and, in association
      with the Auckland School of Medicine, the largest clinical research facility.
      METHOD: During the 1996/1997 financial year, 190 research projects received
      Auckland Healthcare management approval. The nature, purposes, and budget for
      each project were recorded on a dedicated database. The financial data excluded
      the University-funded components of research. RESULTS: Data presented for the
      1996/1997 financial year reveal the volume, nature and cost of research for
      Auckland Healthcare. The budgeted external revenue was $1.6M, with 52% coming
      from commercial sponsors. Interestingly, 8% of the research projects during this
      period were budgeted to generate savings to the cost of standard clinical care.
      This was achieved primarily through the sponsorship of pharmaceuticals in
      commercial clinical trials. When these revenues and savings are deducted, the net
      budgeted cost of research at Auckland Healthcare in the 1996/1997 financial year
      was $86 572, or only 0.02% of total cost. CONCLUSION: The Ministry of Health and
      the Health Funding Authority are voicing concern over the diversion of clinical
      care funding for research in Hospital and Health Services. While these concerns
      might be philosophically challenged on the grounds that sound research informs
      best clinical practice, it is also clear from these results that the net cost of
      research at Auckland Healthcare is indeed very small.

PMID- 10587072
TI  - Alternative therapies--how to make an informed choice?

PMID- 10587073
TI  - Iron deficiency anaemia in New Zealand infants.

PMID- 10587074
TI  - Ethics of ACC.

PMID- 10587075
TI  - Netilmicin and staphylococci.

PMID- 10587076
TI  - Iodine supplementation programme in Nepal.

PMID- 10587078
TI  - Radiologist guilty of professional misconduct

PMID- 10587077
TI  - Screening for diabetes mellitus.

PMID- 10587079
TI  - Ligands for the isolation of GABA(B) receptors [corrected] .
AB  - Since the discovery that the most abundant inhibitory neurotransmitter in the
      mammalian brain, GABA (gamma-aminobutyric acid), interacts not only with
      ionotropic GABA(A) receptors, but also with metabotropic GABA(B) receptors
      (Bowery et al., 1980) much work has been devoted to the elucidation of the
      structure of GABA(B) receptors by either affinity chromatography purification or
      by expression cloning. In 1997 Kaupmann et al. succeeded in cloning two splice
      variants designated GABA(B) R1a (960 amino acids) and GABA(B) R1b (844 amino
      acids). Although the amino acid sequences are now known, precise information on
      the three-dimensional environment of the GABA(B) R1 binding site is still
      lacking. Recent experiments demonstrated that the amino acids of the seven
      transmembrane helices are not essential for ligand binding as a soluble GABA(B)
      receptor fragment is still able to bind antagonists (Malitschek et al., 1999).
      For the isolation and purification of the soluble N-terminal extracellular domain
      (NTED) of GABA(B) receptors potent ligands for affinity chromatography were
      synthesised with the aim of obtaining a crystalline receptor fragment-ligand
      complex for X-ray structure determination. The most promising ligand
      [125I]CGP84963 (K(D) = 2 nM) combines, in one molecule, a GABA(B) receptor
      binding part, an azidosalicylic acid as a photoaffinity moiety separated by a
      spacer consisting of three GABA molecules from 2-iminobiotin, which binds to
      avidin in a reversible, pH-dependent fashion.

PMID- 10587080
TI  - Calcium sensing properties of the GABA(B) receptor.
AB  - The GABA(B) receptor has been shown to consist of a heterodimer of two related 7
      transmembrane receptors GABAB-R1 and GABA(B)-R2. These receptors share close
      homology to the Ca2+-sensing receptor and also to the metabotropic glutamate
      receptors, which have also been shown to respond to extracellular calcium. We
      show here that the GABA(B) receptor also has Ca2+ sensing properties. Ca2+ (0.001
      1 mM) potentiated the GABA stimulation of [35S]GTPgammaS binding in membranes
      prepared from CHO cells stably expressing the GABA(B)-R1/R2 heterodimer. The GABA
      EC50 was reduced from 72 to 7.7 microM by addition of 1 mM Ca2+, with no change
      in the maximum response. A similar effect was observed in membranes from rat
      brain cortex. Ca2+ also potentiated GABA inhibition of forskolin-stimulated cAMP
      levels in the CHO cells and enhanced coupling to GIRK K+ channels in Xenopus
      oocytes. Other divalent cations were ineffective. The effects of Ca2+ were found
      to be agonist dependent with baclofen having a reduced sensitivity compared to
      GABA. Calcium appears to act allosterically to enhance GABA responses at the
      GABA(B) receptor, however, unlike the Ca2+-sensing receptor and some of the mGluR
      family, Ca2+ does not act as a ligand in its own right.

PMID- 10587081
TI  - The heteromeric GABA-B receptor recognizes G-protein alpha subunit C-termini.
AB  - The recently cloned GABA-B receptors are related to the metabotropic glutamate
      receptors (mGlu receptors), the Ca2+-sensing receptor and one group of
      vomeronasal receptors. The GABA-B receptors likely function in a heterodimeric
      form, constituted of GABA-BR1 and GABA-BR2. This novel feature in the G-protein
      coupled receptors (GPCRs) structure raises questions as to the mechanism of
      recognition of G-proteins by such receptors. In the present study we show that
      the GABA-BR1 and BR2 subunits form a functional receptor that recognizes the
      extreme C-termini of the G alpha i and G alpha o proteins when expressed in
      HEK293 cells. Indeed, heteromeric GABA-BR1/BR2 receptors do not activate PLC when
      co-expressed with G alpha q, but do so when co-expressed with the chimeric G
      alpha qi5 or G alpha qo5 subunits, the G alpha q subunit in which the 5 C
      terminal residues are those of G alpha i or G alpha o, respectively.
      Interestingly, the heteromeric GABA-B receptor did not activate the chimeric G
      alpha qz5 subunit that contains the 5 C-terminal residues of G alpha z. Among the
      three residues that are distinct between G alpha qo5 and G alpha qz5 (at position
      -5, -4 and -1), the amino acid residue at position -4 of G alpha o proteins is
      critical for specifying the coupling selectivity with the receptor and residue -5
      influences the coupling efficacy. Interestingly, these findings correspond to
      data obtained with the mGluR2 receptor, a distant relative of GABA-B proteins.
      This shows that the same molecular determinants of the G-protein alpha-subunits
      are involved in the specific recognition of both the heteromeric GABA-B receptors
      and the other GPCRs.

PMID- 10587082
TI  - Gamma-hydroxybutyrate is a weak agonist at recombinant GABA(B) receptors.
AB  - Gamma-hydroxybutyrate (GHB) is a neuromodulator with high affinity binding sites
      in the mammalian brain. However, the receptor for GHB has not yet been
      identified. There are indications that GHB and gamma-aminobutyric acid (GABA)
      mediate their effects via the same receptor. We tested this hypothesis using
      GABA(B)R1/R2 receptors co-expressed with Kir3 channels in Xenopus oocytes. GHB
      activated these receptors with an EC50 of approximately 5 mM and a maximal
      stimulation of 69% when compared to the GABA(B) receptor agonist L-baclofen. GHB
      and L-baclofen did not amplify each others effect nor did they stimulate the
      GABA(B) receptor in a linearly additive manner. CGP54626A, 2-OH saclofen and
      CGP35348, three competitive GABA(B) receptor antagonists, inhibited the GHB
      induced response completely. A concentration of 30 mM GHB displaced
      [125I]CGP64213 binding at GABA(B)R1 expressed in COS cells by 21%. These results
      indicate that GHB is a weak partial agonist at the GABA binding site of
      GABA(B)R1/R2.

PMID- 10587083
TI  - Distribution of GABA(B) binding sites in the thalamus and basal ganglia of the
      rhesus monkey (Macaca mulatta).
AB  - The regional distribution of GABA(B) receptor binding sites in the thalamus and
      basal ganglia of rhesus monkey has been determined by receptor autoradiography
      using the agonist ligand, [3H]-GABA. Whilst binding sites were evident throughout
      the thalamus, the internuclear differences in the Bmax were up to 10-fold. In the
      basal ganglia the binding density was on average lower than in the thalamus. The
      highest number of binding sites was in striatum followed closely by substantia
      nigra. In both the thalamus and basal ganglia, the binding density was higher
      than previously described in the rat. Although our results do not allow us to
      differentiate between presynaptic and postsynaptic locations of GABA(B) sites we
      conclude that with a few exceptions the distribution pattern of GABA(B) binding
      sites in the monkey thalamus appears to correlate with the known innervation from
      the NRT.

PMID- 10587084
TI  - Functional characterization and expression of thalamic GABA(B) receptors in a
      rodent model of Parkinson's disease.
AB  - Increased GABAergic neurotransmission of the basal ganglia output nuclei
      projecting to the motor thalamus is thought to contribute to the pathophysiology
      of Parkinson's disease. We investigated the functional role of thalamic GABA(B)
      receptors in a rodent model of Parkinson's disease. First, we examined the
      effects of blockade of GABA(B) receptors in the ventromedial thalamic nucleus of
      rats with a unilateral 6-OHDA lesion of the substantia nigra on locomotor
      activity. In addition we studied the expression of GABA(B) receptor mRNA in the
      basal ganglia and thalamus using in situ hybridisation. Unilateral
      microinjections of the GABA(B) receptor antagonist 2-hydroxysaclofen into the
      ventromedial thalamic nucleus ipsilateral to the nigrostriatal lesion induced
      contralateral rotations in a dose-dependent manner. However, microinjection of
      antagonists with higher affinity for the GABA(B) receptor SCH 50911, CGP 56433
      and CGP 55845 did not result in rotational behaviour, but did induce convulsions
      at higher doses. GABA(B) receptor mRNA expression was found throughout the basal
      ganglia and thalamus, including the ventromedial thalamic nucleus. No
      statistically significant differences in GABA(B) mRNA expression were observed in
      the ventromedial thalamic nucleus following a unilateral 6-OHDA lesion of the
      substantia nigra. These results make it improbable that thalamocortical GABA(B)
      receptors play an important role in the pathophysiology of parkinsonism.
      Therefore, GABA(B) receptors do not appear to be a promising target for novel
      antiparkinsonian drugs.

PMID- 10587085
TI  - Pertussis toxin decreases absence seizures and GABA(B) receptor binding in
      thalamus of a genetically prone rat (GAERS).
AB  - Postsynaptic GABA(B) receptor-mediated events have previously been shown to be
      reduced by prior treatment with pertussis toxin in rat brain. In the present
      study genetic absence epilepsy rats from Strasbourg (GAERS) were given single
      bilateral injections of pertussis toxin (PTx 0.4 microg), denatured-PTx or
      vehicle saline into the relay nuclei of the thalamus under anaesthesia. After
      recovery the spike and wave discharge duration (SWD) was monitored for up to 6
      days following which the brains were removed and GABA(B) or GABA(A) receptor
      autoradiography performed on 10 microm transverse sections. By 6 days the SWD of
      the rats treated with PTx was suppressed by 96% compared with vehicle-injected
      rats with a significant (62%) reduction even after 1 day. Denatured toxin had no
      effect at any time. After 6 days GABA(B), but not GABA(A), receptor binding was
      significantly reduced by 70-80% in the ventrolateral and ventral posteriolateral
      thalamic nuclei. No changes in other brain regions were detected and denatured
      toxin failed to alter GABA(A) or GABA(B) receptor binding in any brain region.
      These data implicate G-protein mechanisms in the generation of SWD in GAERS and
      support the role of GABA(B) receptors in their induction within the thalamus.

PMID- 10587086
TI  - On the putative contribution of GABA(B) receptors to the electrical events
      occurring during spontaneous spike and wave discharges.
AB  - Cortical and thalamic neurones play a major role in the generation/expression of
      spike and wave discharges (SWDs), the main electroencephalographic (EEG) feature
      of absence seizures. The detailed mechanisms leading to this paroxysmal EEG
      activity, however, are still poorly understood. We have now made in vivo
      intracellular recordings from layer V cortical neurones of the facial motor
      cortex and from thalamocortical (TC) neurones of the ventroposteromedial and
      ventroposterolateral nuclei in a well established model of this disease: the
      Genetic Absence Epilepsy Rats from Strasbourg (GAERS). The main feature of the
      intracellularly recorded activity of TC neurones during spontaneous SWDs was the
      presence of rhythmic sequences of synaptic potentials consisting of an EPSP
      closely followed by 2-6 IPSPs. These rhythmic sequences were superimposed on a
      small tonic hyperpolarization that lasted for the whole duration of the SWD and
      was still present at potentials close to -85 mV. The rhythmic IPSPs, on the other
      hand, had a reversal potential of -68 mV, and always appeared as depolarizing
      events when recording with KCl-filled electrodes at -55 mV. Low frequency
      electrical stimulation of the corresponding cortical area evoked in TC neurones a
      short and a long lasting IPSP, whose waveforms were reminiscent of a GABA(A) and
      a GABA(B) IPSP, respectively. The main feature of the intracellular activity
      recorded in cortical neurones during spontaneous SWDs was the presence of
      rhythmic depolarizations. Their frequency was similar to the one of SWDs in the
      EEG, and was not affected by DC injection. The amplitude of the rhythmic
      depolarizations, however, increased following steady hyperpolarization of the
      neurone by DC injection. An increase in the apparent input resistance of cortical
      neurones was observed during SWDs compared to the inter-SWDs periods. Low
      frequency electrical stimulation of the contralateral striatum evoked in cortical
      neurones a short and a long lasting IPSP, whose waveforms were reminiscent of a
      GABA(A) and a GABA(B) IPSP, respectively. Our data indicate that there are no
      rhythmic GABA(B) IPSPs and low threshold Ca2+ potentials in GAERS TC neurones
      during SWDs, but rhythmic sequences of EPSP/IPSPs superimposed on a tonic
      hyperpolarization that might represent a long lasting GABA(B) IPSP. Further
      experiments are required to clarify the nature of the voltage waveform and the
      increase in input resistance observed in cortical neurones during spontaneous
      SWDs in GAERS.

PMID- 10587087
TI  - Localization of GABA(B) (R1) receptors in the rat hippocampus by
      immunocytochemistry and high resolution autoradiography, with specific reference
      to its localization in identified hippocampal interneuron subpopulations.
AB  - Immunocytochemical and autoradiographic methods were used to localize the GABA(B)
      receptor in the normal rat hippocampus. GABA(B) receptor 1-like immunoreactivity
      (GBR1-LI) was most intense in presumed GABAergic interneurons of all hippocampal
      subregions. It was also present throughout the hippocampal neuropil, where it was
      most intense in the dendritic strata of the dentate gyrus, which are innervated
      by the perforant pathway and inhibitory dentate hilar cells, and in strata oriens
      and radiatum of area CA3. The dendritic regions of area CA1 exhibited less GBR1
      LI than area CA3. GBR1-LI was detectable in the somata of CA1 pyramidal cells,
      but was minimal or undetectable within the somata of dentate granule cells and
      CA3 pyramidal cells. GBR1-LI was similarly minimal in the dentate hilar neuropil,
      and in stratum lucidum, the two regions that contain granule cell axons and
      terminals. Nor was GBR1-LI detectable in the inhibitory basket cell fiber systems
      that surround hippocampal principal cell somata. Fluorescence co-localization
      studies indicated that significant proportions of interneurons expressing
      somatostatin, neuropeptide Y, cholecystokinin, calbindin, or calretinin also
      expressed GBR1-LI constitutively. Conversely, parvalbumin-positive GABAergic
      basket cells of the dentate gyrus and hippocampus, which form GABA(A) receptor
      mediated inhibitory axo-somatic synapses, rarely contained detectable GBR1-LI.
      High resolution autoradiography with the GABA(B) receptor antagonist CGP 62349
      revealed a close correspondence between receptor ligand binding and GBR1-LI, with
      several notable exceptions. Ligand binding closely matched GBR1-LI throughout the
      hippocampal, cortical, thalamic, and cerebellar neuropil. However, the
      hippocampal interneuron somata and dendrites that exhibited the most intense GBR1
      LI, and the GBR1-positive somata of CA1 pyramidal cells, did not exhibit a
      similar density of [3H]-CGP 62349 binding. These data clarify the relationship
      between immunocytochemically identified receptor protein and potentially
      functional receptors, indicating that GBR1-LI reflects both non-functional
      cytoplasmic GBR1 and the ligand-bindable form of the protein, both before
      dimerization with GBR2 and after translocation to functional sites within cells.
      The staining and binding patterns further suggest that GBR1 is constitutively
      expressed in specific neuronal populations, and may exist in higher concentration
      in the axons of inhibitory hippocampal pathways that innervate dendritic zones,
      than in axo-somatic inhibitory terminals. Whether GBR1 is inducible in cells that
      contain GBR1 mRNA, but no detectable constitutive protein, remains to be
      determined in experimental studies.

PMID- 10587088
TI  - Regulation of depolarizing GABA(A) receptor-mediated synaptic potentials by
      synaptic activation of GABA(B) autoreceptors in the rat hippocampus.
AB  - The role of GABA(B) autoreceptors in the regulation of GABA(A) and GABA(B)
      receptor-mediated inhibitory post-synaptic potentials (IPSPs) during repetitive
      synaptic activation has been established. In the present study the role of these
      receptors in the regulation of depolarising GABA(A) receptor-mediated synaptic
      potentials (DPSP(A)s) in the CA1 region of the hippocampus is documented.
      Following blockade of AMPA and NMDA receptor-mediated synaptic excitation,
      DPSP(A)s could be evoked by a single stimulus. The size of this response was
      enhanced by increasing the stimulus number (1-10 shocks) or stimulus frequency
      (10-100 Hz). Conversely, the amplitude of the DPSP(A) was dramatically reduced by
      a priming pulse (single shock) or priming burst (four shocks) delivered 200 ms
      beforehand. This activity-dependent depression was eliminated by the GABA(B)
      receptor antagonist CGP 35348 (1 mM). As such, GABA(B) autoreceptor-mediated
      regulation of DPSP(A)s prevented a pronounced, potentially epileptogenic, DPSP(A)
      from occurring during theta burst stimulation. Thus, during repetitive
      stimulation, activation of GABA(B) autoreceptors not only enables a transient
      reduction in GABA(A) receptor-mediated synaptic inhibition sufficient to enable
      NMDA receptor-dependent synaptic plasticity [Davies, C.H., Collingridge, G.L.,
      1996. J. Physiol. 496.2, 451-470] but also prevents the development of a
      potentially pathogenic depolarising GABA-mediated synaptic potential.

PMID- 10587089
TI  - Late maturation of GABA(B) synaptic transmission in area CA1 of the rat
      hippocampus.
AB  - Whole cell voltage clamp recordings were used to investigate the postnatal
      development of GABA(B) synaptic transmission in CA1 pyramidal cells of rat
      hippocampal slices. In the presence of antagonists of glutamate and GABA(A)
      ionotropic receptors, electrical stimulation evoked slow IPSCs in pyramidal cells
      from mature animals (35-45 days postnatal, P35-45). Brief trains of stimulation
      evoked slow IPSCs of greater magnitude. I-V relations of slow IPSCs were inwardly
      rectifying, with a mean equilibrium potential near -75 to -80 mV. Slow IPSCs were
      completely antagonized by the GABA(B) antagonist CGP55845A (0.5 microM). In cells
      from young animals (P12-14), similar stimulation evoked either no or very small
      slow IPSCs (mean conductance approximately 10% of adult). In cells from animals
      of intermediate age (P22-24), slow IPSCs were more frequent and their mean
      conductance was approximately 60-80% of adult values. Bath application of 20
      microM baclofen evoked outward currents in cells of animals P35-45. I-V relations
      of baclofen currents showed inward rectification and reversed near -80 mV.
      Baclofen currents were absent or minimal in animals P12-14, and of intermediate
      magnitude in animals P22-24. These results indicate that baclofen and GABA(B)
      postsynaptic currents are virtually absent 2 weeks postnatally, and appear
      gradually until 35-45 days postnatal. Thus, GABA(B) synaptic transmission appears
      to mature late in area CA1 of the rat hippocampus.

PMID- 10587090
TI  - GABA(B) receptor-mediated presynaptic inhibition of glutamatergic and GABAergic
      transmission in the basolateral amygdala.
AB  - The information processing at central synapses is mediated not only by
      homosynaptic transmission with direct synaptic connections but also by
      heterosynaptic interactions between distinct synaptic inputs. Using rat brain
      slices and whole-cell recordings this study aimed to examine the roles of GABA(B)
      receptors in synaptic interactions in the basolateral amygdala (BLA), a critical
      brain structure related to fear and anxiety. Stimulation in the BLA produced non
      NMDA type glutamate receptor antagonist-sensitive excitatory postsynaptic
      currents (EPSCs) and bicuculline-sensitive inhibitory postsynaptic currents
      (IPSCs) in the BLA neurons. The GABA(B) receptor agonist baclofen markedly
      inhibited both EPSCs and IPSCs in a concentration-dependent manner, and the
      baclofen-induced inhibition was selectively abolished by the GABA(B) receptor
      antagonist CGP55845A. The paired-pulse ratio of EPSC and IPSC amplitude was
      increased by baclofen. The effect of baclofen was mimicked by lowering the
      external Ca2+ concentration but not by glutamate- and GABA(A)-receptor
      antagonists. The frequency but not the mean amplitude of miniature EPSCs and
      IPSCs was decreased by baclofen. The findings suggest that activation of GABA(B)
      receptors by baclofen reduces the strength of excitatory and inhibitory
      transmission in the BLA by a presynaptic mechanism. Repetitive conditioning
      stimulation applied to GABAergic synaptic inputs exerted an inhibitory action on
      glutamatergic excitatory transmission, and the stimulation-induced inhibition was
      abolished by CGP55845A. Furthermore, the paired-pulse ratio of EPSCs was
      increased during the stimulation-induced inhibition. The results in this study
      provide evidence that synaptic activation of GABA(B) heteroreceptors elicits
      presynaptic inhibition of glutamatergic excitatory transmission in the BLA.

PMID- 10587091
TI  - GABA(B) receptor-mediated effects in human and rat neocortical neurones in vitro.
AB  - GABA(B) receptor-mediated responses were investigated in human and rat
      neocortical neurones in vitro by using intracellular recording. Human
      epileptogenic tissue and cortex from rats were compared for differences related
      to the cellular mechanisms of hyperexcitability. In both tissues, single stimuli
      of various intensities were used to compare basic properties of excitatory and
      inhibitory postsynaptic potentials (EPSP, IPSP). Paired stimuli, causing a
      decrease of a second IPSP, were used as an index of presynaptic activation of
      GABA(B) receptors. In neocortical neurones of rats, increasing intensities of
      stimulation elicited at low intensities (6-8 V) a fairly pure EPSP which was
      curtailed at higher stimulus intensities (10-14 V) by a GABA(A) receptor mediated
      IPSP (IPSP(A)). In all rat neocortical neurones the IPSP(A) was followed by a
      late inhibitory component (IPSP(B), time to peak about 150 ms) which was
      eliminated by the GABA(B) receptor antagonists CGP 35348 or CGP 55845A. On
      average, paired stimuli reduced the amplitude of a second IPSP(A) to 57% of the
      first (in the presence of 10 microM CNQX and 20 microM D-APV). Paired-pulse
      depression was only antagonized by CGP 55845A, but not by CGP 35348. The
      magnitude and time course of paired-pulse depression was markedly enhanced at
      lower temperatures. In human cortical neurones obtained following epilepsy
      surgery only low intensity stimuli (4 V) elicited EPSPs. Intermediate to higher
      stimulus intensities (8-10 V) elicited often all-or-none depolarization shifts or
      prolonged and increased EPSPs. Few neurones exhibited a sequence of EPSP and
      IPSPs comparable to that observed in rat neurones. Application of CGP 55845A
      caused little change in excitability near 150 ms, indicating that the IPSP(B) is
      weak. Paired-pulse depression of inhibition was small in most neurones, the
      second IPSPA was reduced to 82.8% of the first at a 500 ms interval (n = 6). Only
      two neurones exhibited a paired-pulse depression comparable to rat neurones. The
      consequences of GABA receptor-mediated paired-pulse depression on neuronal
      synchronisation are discussed towards the different cellular mechanisms of focal
      and bilateral synchronous epilepsies.

PMID- 10587092
TI  - Nociceptive regulation of GABA(B) receptor gene expression in rat spinal cord.
AB  - Activation of gamma-aminobutyric acid (GABA) neurotransmission evokes
      antinociceptive responses in laboratory animals. The recent cloning of GABA(B)
      receptor gene products makes it possible to examine the regulation of this
      receptor system as it relates to the mediation of pain-related sensory
      information. Inasmuch as acute and chronic pain alter the expression of a number
      of nociception-related receptors, and because such changes are important
      components in the regulation of pain, the present study was undertaken to
      determine whether GABA(B) receptor gene expression is altered in sensory systems
      following a peripheral nociceptive stimulus. Solution hybridization-nuclease
      protection assays conducted 24 h after formalin injection into the right hindpaw
      of the rat revealed a significant bilateral increase in GABA(B) R1 and R2
      receptor expression in the dorsal lumbar spinal cord, and a significant increase
      in GABA(B) R1 receptor mRNA in the ipsilateral lumbar dorsal root ganglion. These
      findings indicate an activity-dependent, differential regulation of GABA(B) R1
      and R2 receptor gene expression in spinal sensory systems in response to
      chemogenic nociceptive activation, suggesting that GABA(B) receptor plasticity
      may play an important role in regulating the mediation, and perception, of
      chronic pain.

PMID- 10587093
TI  - Baclofen and midazolam alter c-fos induction by peripheral noxious or innocuous
      stimulation in the spinal cord of normal and monoarthritic rats.
AB  - In order to further clarify the role of gamma-aminobutyric acid (GABA) receptors
      in spinal sensory processing we have studied the effects of baclofen, a GABA(B)
      agonist, and midazolam, a benzodiazepine agonist, on the activation of spinal
      neurones by peripheral innocuous or noxious stimulation, in normal or
      monoarthritic rats, as signalled by the induction of the proto-oncogene c-fos.
      Baclofen (10 mg/kg, i.v.) caused a significant reduction in the number of Fos
      positive neurones following noxious stimulation of both normal and monoarthritic
      animals, which was prevented by the GABA(B) antagonist CGP 35348 (200 mg/kg,
      i.v.). The latter caused an increase of c-fos expression in normal animals
      subject to noxious stimulation, suggesting an endogenous tonic activation of
      GABA(B) receptors. This effect was not observed in monoarthritic animals.
      Baclofen also reduced the number of Fos-positive neurones in monoarthritic
      animals subject to innocuous stimulation. Midazolam (5 mg/kg, i.v.) had no effect
      in normal animals, but caused an increase in c-fos expression induced by noxious
      stimulation in monoarthritic animals. Flumazenil (1 mg/kg, i.v.), a
      benzodiazepine antagonist, prevented the effect of midazolam, and if given alone
      evoked a decrease in Fos-positive neurones. It can be concluded that although
      GABA(B) receptors modulate sensory input at the spinal level, high doses of
      systemic baclofen are required to inhibit nociceptive-induced c-fos expression.
      The paradoxical facilitation of c-fos expression by midazolam in monoarthritic
      animals, may be due to the reported increase in spinal GABA levels found in those
      animals.

PMID- 10587094
TI  - Selective block of rat and human neocortex GABA(B) receptors regulating
      somatostatin release by a GABA(B) antagonist endowed with cognition enhancing
      activity.
AB  - Previously, we have shown that presynaptic GABA(B) receptors regulating the
      release of various transmitters from CNS terminals can be differentially blocked
      by GABA(B) antagonists suggesting the existence of pharmacologically distinct
      GABA(B) receptor subtypes. We here examined the ability of CGP 36742 [(3
      aminopropyl)n-butylphosphinic acid], a selective GABA(B) antagonist endowed with
      cognition enhancing activity, to block release-regulating GABA(B) receptors. In
      particular, CGP 36742 was tested against the inhibition of the depolarization
      evoked release of GABA, glutamate, cholecystokinin and somatostatin produced by (
      )baclofen in rat and human neocortex axon terminals. CGP 36742 potently
      antagonized (IC50 = 0.14 microM) the inhibition by (-)baclofen of somatostatin
      release from superfused rat neocortex synaptosomes. In contrast, the effects of (
      )baclofen on GABA, glutamate and cholecystokinin release were insensitive to CGP
      36742, at concentrations of up to 100 microM. In human neocortex synaptosomes CGP
      36742 exhibited a pattern of selectivity identical to that in rat synaptosomes,
      although the antagonist was at least 10-fold less potent in human than in rat
      brain. CGP 36742 is the first compound displaying great selectivity for the
      GABA(B) presynaptic receptors regulating somatostatin release. Considering the
      proposed implication of the neuropeptide in cognitive processes, disinhibition of
      somatostatin release merits consideration as one of the mechanisms possibly
      involved in the behavioral activity of CGP 36742.

PMID- 10587095
TI  - The GABA(B) agonist CGP 44532 decreases cocaine self-administration in rats:
      demonstration using a progressive ratio and a discrete trials procedure.
AB  - Previous self-administration experiments have shown that baclofen, the
      prototypical GABA(B) agonist, produces an apparent attenuation in the reinforcing
      effects of cocaine in rats. The present experiments examined the effects of CPG
      44532, a novel and highly specific GABA(B) agonist, on cocaine self
      administration using two distinctly different procedures. CGP 44532 (0.063-0.5
      mg/kg) produced a dose dependent decrease in break point on a progressive-ratio
      (PR) schedule. A low dose of CGP 44532 (0.125 mg/kg) produced an apparent shift
      of the cocaine dose-response curve to the right. In contrast there was
      comparatively little effect on food-reinforced responding on the same PR
      schedule. Using a discrete-trials procedure that engendered a circadian pattern
      of self-administration, CPG 44532 (0.063-0.5 mg/kg) produced a dose-dependent
      suppression of cocaine intake in the 4 h period following treatment. When a
      concurrently available food reinforced lever was added to the discrete trials
      paradigm CGP 44532 failed to disrupt responding for food at any of the doses
      tested. Data from the PR and discrete-trials procedures taken together indicate
      that CGP 44532 produced a specific decrease in the motivation to self-administer
      cocaine.

PMID- 10587096
TI  - GABA(B) auto- versus hetero-receptor sensitivity: implications for novel
      pharmacotherapy.
AB  - After uncoupling G-protein dependent post-synaptic GABA(B) receptors--without
      altering GABA(B) nerve terminal receptors--we demonstrate that the GABA(B)
      agonist, CGP44533, exhibits less efficacy and potency at GABA(B) auto- versus
      hetero-receptors. CGP44533 (1 and 10 microM) depressed monosynaptic GABA(A)
      mediated transmission by 2 and 35%, but depressed glutamate mediated transmission
      by 41 and 78%, respectively. These data suggest a differential pharmacological
      sensitivity for CGP44533 at glutamate versus GABA releasing neurons.

PMID- 10587097
TI  - Characterization of radioactive metabolites of 5-HT2A receptor PET ligand
      [18F]altanserin in human and rodent.
AB  - This study was performed to identify and characterize the radiometabolites of the
      serotonin 5-HT2A receptor ligand [18F]altanserin in supporting quantification of
      the target receptors by positron emission tomography. In analogy to its analog
      ketanserin, we postulated 4-(4-fluorobenzoyl)piperidine (FBP) and altanserinol
      for the previously observed two polar radiometabolites, corresponding to
      dealkylation at the piperidine nitrogen and reduction at the ketone,
      respectively. To test this hypothesis and characterize the in vivo and in vitro
      behavior of the radiometabolites, we synthesized nonradioactive authentic
      compounds altanserinol, 1-(4-fluorophenyl)-1-(piperidin-4-yl)methanol (FBPOH),
      and isolated nonradioactive FBP metabolite from monkey plasma. [18F]Altanserinol
      was obtained by NaBH4 reduction of [18F]altanserin, followed by acid hydrolysis.
      Identification of radiometabolites was carried out by high performance liquid
      chromatography and thin layer chromatography comparison of the radioactive plasma
      after injection of tracers with five authentic compounds. Human studies revealed
      that at least four radiometabolites, one identified as [18F]altanserinol,
      resulted from reduction of the ketone functionality. The N-dealkylation product
      [18F]FBP was not detectable; however, a radiometabolite of FBP was present in
      plasma after administration of [18F]altanserin. Monkey studies showed
      nonradioactive FBP was converted rapidly to a less polar metabolite. In rat,
      altanserin and altanserinol were converted to each other in vivo, and all the
      radiometabolites likely penetrated the blood-brain barrier and entered the brain.
      Displacement binding of altanserin to cloned serotonin 5-HT2A, 5-HT2C, 5-HT6, and
      5-HT7 receptors showed Ki values of 0.3, 6.0, 1,756, and 15 nM; the binding of
      FBP and altanserinol to these four 5-HT subtypes was negligible. We conclude from
      these studies that the radiometabolites of [18F]altanserin from N-dealkylation
      and ketone reduction should not interfere with specific receptor quantification
      in an equilibrium paradigm.

PMID- 10587098
TI  - N-(3-Iodophenyl)trozamicol (IPHT) and related inhibitors of vesicular
      acetylcholine transport: synthesis and preliminary biological characterization.
AB  - Four isomeric N-(halophenyl)trozamicol analogues (6a-d) were synthesized and
      evaluated as potential vesicular acetylcholine transporter (VAChT) ligands. Of
      the four compounds, N-(3-bromophenyl) trozamicol (6b) and N-(3
      iodophenyl)trozamicol (6d) displayed the highest affinity for the VAChT in vitro,
      whereas the para-substituted compound 6c showed the lowest affinity for this
      transporter. Tissue distribution studies of N-(3-[125I]iodophenyl)trozamicol
      ([125I]6d, [125I)IPHT) suggest that the central distribution of the latter is
      consistent with cholinergic innervation. However, only moderate target-to
      background ratios were obtained, suggesting little improvement over the N
      (halobenzyl)trozamicols described previously.

PMID- 10587099
TI  - Development of N-[3-(2',4'-dichlorophenoxy)-2-18F-fluoropropyl]-N
      methylpropargylamine (18F-fluoroclorgyline) as a potential PET radiotracer for
      monoamine oxidase-A.
AB  - We have synthesized N-[3-(2',4'-dichlorophenoxy)-2-18F-fluoropropyl]-N
      methylpropar gylamine (18F-fluoroclorgyline) as a potential positron emission
      tomography (PET) radiotracer for monoamine oxidase A (MAO-A). The radiosynthesis
      was carried out by a 18F-fluoride-for-mesylate substitution reaction in
      approximately 20% radiochemical yield in specific activities of 1-2 Ci/micromol.
      Selectivity for MAO-A was demonstrated by the high affinity of clorgyline (IC50 =
      39 nM) and lower affinity of (R)-deprenyl (IC50 > or = 100 microM) for the
      inhibition of 18F-fluoroclorgyline binding in vitro in rat brain membranes. The
      uptake of 18F-fluoroclorgyline in the rat brains was high (> 1.0% injected
      dose/g). The binding of 18F-fluoroclorgyline in the rat brain correlated with the
      distribution of MAO-A and was inhibited by preadministration of MAO-A inhibitors,
      clorgyline, and Ro 41-1049, whereas (R)-deprenyl, a MAO-B blocker, had no
      inhibitory effect. These results suggest that 18F-fluoroclorgyline is a potential
      PET radiotracer for MAO-A.

PMID- 10587100
TI  - In vivo binding of [11C]nemonapride to sigma receptors in the cortex and
      cerebellum.
AB  - Radiolabeled nemonapride (NEM, YM-09151-2) is widely used as a representative
      dopamine D2-like receptor ligand in pharmacological and neurological studies, and
      11C-labeled analog ([11C]NEM) has been developed for positron emission tomography
      (PET) studies. The aim of this study was to evaluate whether [11C]NEM binds in
      vivo to sigma receptors. [11C]NEM and one of six dopamine D2-like receptor
      ligands or seven sigma receptor ligands were co-injected into mice, and the
      regional brain uptake of [11C]NEM was measured by a tissue dissection method. The
      striatal uptake of [11C]NEM was reduced by D2-like receptor ligands, NEM,
      haloperidol, (+)-butaclamol, raclopride, and sulpiride, but not by a D4 receptor
      ligand clozapine. In the cortex and cerebellum the uptake was also reduced by D2
      like receptor ligands with affinity for sigma receptors, but not by raclopride.
      Although none of seven sigma receptor ligands, SA6298, N,N-dipropyl-2-[4-methoxy
      3-(2-phenylethoxy)phenyl]ethylamine hydrochloride (NE-100), (+)-pentazocine, R(-)
      N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane hydrochloride ([-]-PPAP), (-)
      pentazocine, R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride ([+]-3
      PPP), and (+)-N-allylnormetazocine hydrochloride ([+]-SKF 10047), blocked the
      striatal uptake, five of them with relatively higher affinity significantly
      reduced the [11C]NEM uptake by the cortex, and four of them reduced that by the
      cerebellum. We concluded that [11C]NEM binds in vivo not only to dopamine D2-like
      receptors in the striatum but also to sigma receptors in other regions such as
      cortex and cerebellum.

PMID- 10587101
TI  - In vivo positron emission tomography studies on the novel nicotinic receptor
      agonist [11C]MPA compared with [11C]ABT-418 and (S)(-)[11C]nicotine in rhesus
      monkeys.
AB  - The novel 11C-labeled nicotinic agonist (R,S)-1-[11C]methyl-2(3-pyridyl)azetidine
      ([11C]MPA) was evaluated as a positron emission tomography (PET) ligand for in
      vivo characterization of nicotinic acetylcholine receptors in the brain of Rhesus
      monkeys in comparison with the nicotinic ligands (S)-3-methyl-5-(1-[11C]methyl-2
      pyrrolidinyl)isoxazol ([11C]ABT-418) and (S)(-)[11C]nicotine. The nicotinic
      receptor agonist [11C]MPA demonstrated rapid uptake into the brain to a similar
      extent as (S)(-) [11C]nicotine and [11C]ABT-418. When unlabeled (S)(-)nicotine
      (0.02 mg/kg) was administered 5 min before the radioactive tracers, the uptake of
      [11C]MPA was decreased by 25% in the thalamus, 19% in the temporal cortex, and
      11% in the cerebellum, whereas an increase was found for the uptake of (S)(
      )[11C]nicotine and [11C]ABT-418. This finding indicates specific binding of
      [11C]MPA to nicotinic receptors in the brain in a simple classical displacement
      study. [11C]MPA seems to be a more promising radiotracer than (S)(-)[11C]nicotine
      or [11C]ABT-418 for PET studies to characterize nicotinic receptors in the brain.

PMID- 10587102
TI  - Synthesis and evaluation of [123I]labelled analogues of the partial inverse
      agonist Ro 15-4513 for the study of diazepam-insensitive benzodiazepine
      receptors.
AB  - The imidazobenzodiazepines ethyl 8-iodo-5,6 dihydro-5-methyl-6-oxo-4H
      imidazo[1,5a][1,4] benzodiazepine-3-carboxylate 1 and tert-butyl 8-iodo-5,6
      dihydro-5-methyl-6-oxo-4H-imidazo [1,5a][1,4] benzodiazepine-3-carboxylate 2 were
      prepared to study the diazepam-insensitive (DI) benzodiazepine receptor (BZR)
      subtype. The [123I] analogues were prepared via iododestannylation reactions in
      radiochemical yields of 70-80% and a specific activity >2,500 Ci/mmol. The tert
      butyl analogue [123I]-2 exhibited nanomolar affinity for BZRs in homogenate
      membranes of rat cerebellum with Kd values for the diazepam-sensitive (DS) and DI
      receptors of 3.18 +/- 0.58 and 13.55 +/- 2.72 nM, respectively. The Bmax for
      cerebellar DS and DI receptors were 1,276 +/- 195 and 518 +/- 26 fmol/mg protein,
      respectively.

PMID- 10587103
TI  - Radiosynthesis and biodistribution of 123I-labeled antagonists of the histamine
      H3 receptor as potential SPECT ligands.
AB  - We have synthesized three 123I-labeled histamine H3 receptor ligands, i.e.,
      [123I]GR 190028, [123I]FUB 271, and [123I]iodoproxyfan, in moderate to good
      radiochemical yields via a Cu+-assisted I-for-123I exchange method.
      Biodistribution in the rat of these compounds revealed high hepatic and pulmonary
      uptake. Brain uptake was moderate, but for [123I]iodoproxyfan, brain uptake was
      high enough for a pilot single photon emission computed tomography (SPECT) study
      in the rabbit. However, for this compound, the cerebral uptake could not be
      blocked by a pretreatment with [R]-alpha-methylhistamine, a selective, high
      affinity histamine H3 receptor agonist, both in the SPECT study in the rabbit and
      in the biodistribution study in the rat. Apparently, [123I]iodoproxyfan is
      binding to a non-H3 receptor binding site. None of the three investigated
      compounds is suitable for use as a SPECT ligand for the H3 receptor in the brain.

PMID- 10587104
TI  - Synthesis of [123I]IBZM: a reliable procedure for routine clinical studies.
AB  - The single photon emission computed tomography (SPECT) D2/D3 receptor radiotracer
      [123I]IBZM, is prepared by electrophilic radioiodination of the precursor BZM
      with high-purity sodium [123I]iodide in the presence of diluted peracetic acid.
      However, in our hands, the most commonly used procedure for this radiosynthesis
      produced variable and inconsistent labeling yields, to such extent that it became
      inappropriate for routine clinical studies. Our goal was to modify the labeling
      procedure, to obtain consistently better labeling and radiochemical yields. The
      best conditions found for the radioiodination were as follows: 50 microg
      precursor in 50 microL EtOH mixed with buffer pH 2; Na[123I]I in 0.1 M NaOH (<
      180 microL), 50 microL peracetic acid diluted solution, heating at 65 degrees C
      for 14 min. Purification was achieved by solid phase extraction (SPE) and reverse
      phase high performance liquid chromatography (HPLC). Under these conditions,
      labeling yield average was 76 +/- 4% (n = 31); radiochemical yield was 69 +/- 4%
      and radiochemical purity was 98 +/- 1%. With larger volumes of the Na[123I]I
      solution the yields were consistent but lower. For example, for volumes between
      417 and 523 microL the labeling yield was 61 +/- 5% (n = 21), radiochemical yield
      was 56 +/- 5% and radiochemical purity was 98 +/- 1%.

PMID- 10587105
TI  - Radiolabelled 5'-iodo-2'-deoxyuridine: a promising alternative to [18F]-2-fluoro
      2-deoxy-D-glucose for PET studies of early response to anticancer treatment.
AB  - We investigated the potential of radiolabelled 5-iodo-2'-deoxyuridine (IUdR) as a
      pharmacodynamic probe for use with positron emission tomography (PET) in studies
      of early proliferative response to anticancer treatment. Using the hormone
      responsive rat mammary carcinoma OES.HR1, we used a multiple radiotracer method
      to examine treatment-induced changes in 24 h tumour retention of [131I]IUdR,
      uptake of [3H]2-deoxy-D-glucose ([3H]DG) together with
      [99mTc]hexylmethylpropylene amineoxine ([99mTc]HMPAO) uptake as a measure of
      blood flow. Radiotracer data were compared with macroscopic changes in tumour
      growth, and cell proliferation as determined by DNA histogram flow cytometry.
      From 4 days after tumour growth arrest induced by oestrogen ablation, a sustained
      fall in tumour cell proliferation was demonstrated, which was associated with
      reduced tumour uptake of each tracer. Whereas reduced levels of tumour [3H]DG
      could be accounted for by changes in blood flow, this was not the case for
      [131I]IUdR, which was found to be closely related to percentage S-phase cells
      within tumour (r = 0.73, p < 0.002). It was also estimated that residual levels
      of radioiodide may contribute significantly, to the low levels of retained
      radioactivity associated with responding tumours at 24 h following IUdR
      administration, suggesting that metabolite correction methods should be
      implemented as part of IUdR PET imaging protocols. We conclude that [124I]IUdR is
      a promising alternative to [18F]fluorodeoxyglucose ([18F]FDG) for the early
      assessment by PET of tumour response to treatments directed at targets associated
      with cell proliferation.

PMID- 10587106
TI  - [76Br]Bromodeoxyuridine, a potential tracer for the measurement of cell
      proliferation by positron emission tomography, in vitro and in vivo studies in
      mice.
AB  - 5-Bromo-2'-deoxyuridine (BrUdR) labeled with 77Br and 76Br was compared with 5
      iodo-2'-deoxyuridine (IUdR) labeled with 125I or 131I, first in vitro then in in
      vivo experiments in mice. The results showed a significantly higher incorporation
      of BrUdR into DNA than IUdR, which can be explained by the greater similarity
      (size and surface hydrophilicity of the molecules) of BrUdR to thymidine. Both
      tracers are dehalogenated quickly in vivo but not in vitro. Free bromide is
      excreted more slowly than iodide, resulting in a higher background activity level
      after the application of [76Br]BrUdR and compensates for the favorable DNA
      incorporation. 76Br has more favorable properties than 124I for imaging purposes
      with positron emission tomography (PET) because of a very convenient half-life
      (16 h vs. 4.15 days) and about double the positron yield per decay. However, the
      more favorable physical properties are balanced by the slower excretion and thus
      the estimated radiation dose is higher in the case of 76Br than 124I. Thus, both
      tracers, [124I]IUdR and [76Br]BrUdR are potentially suitable but not optimal to
      measure cell proliferation in vivo. The difference between the two tracers is
      small and the extrapolation from mice to human difficult, and thus it cannot be
      concluded if one of the tracers would be better than the other for imaging of
      cancer patients.

PMID- 10587107
TI  - 99mTc-monoclonal antibody radiolabeled via hydrazino nicotinamide derivative for
      imaging disialoganglioside G(D2)-positive tumors.
AB  - 3F8 is a murine IgG3 monoclonal antibody (MAb) selective for the ganglioside
      G(D2). Previous studies using 131I-3F8 have shown great potential in the imaging
      of neuroectodermal tumors and the therapy of human neuroblastoma. 131I is
      commonly used in radioimmunodiagnosis, but its relatively long half-life (8 days)
      and its high energy gamma-emission (364 KeV) are suboptimal for imaging purposes
      when compared with 99mTc (6 h and 140 KeV, respectively). To label 3F8 with
      99mTc, the antibody was first coupled with a heterobifunctional linker,
      succinimidyl-6-hydrazinonicotinate hydrochloride (SHNH), obtaining a
      hydrazinonicotinamide-antibody conjugate. Using 99mTc-Tricine as the precursor
      complex, 3F8-SHNH was coupled efficiently to 99mTc, resulting in >90% radiometal
      incorporation, with a specific activity >10 mCi/mg and retaining full
      immunoreactivity. Immunoscintigraphy at 6, 22, and 46 h after intravenous
      injection of 1 mCi of 99mTc-3F8 showed selective neuroblastoma localization in
      xenografted nude mice, comparable to that obtained with the injection of 100
      microCi of 131I-3F8. Biodistribution studies of 131I-3F8 and 99mTc-3F8 in mice
      demonstrated comparable %ID/g uptake in tumor (with a T/B ratio: approximately
      2.5 at 24 h and approximately 3.5 at 48 h) and normal organs, including blood,
      except for spleen and liver which had about a three times higher uptake of the
      99mTc conjugate. In conclusion, 99mTc can be coupled conveniently at high
      specific activity to 3F8 without compromising immunoreactivity. SHNH appears to
      be a useful linker for 99mTc in tumor diagnostic imaging and may have potential
      utility in coupling other radioisotopes (e.g., 94mTc) for positron imaging and
      therapy.

PMID- 10587108
TI  - In vivo evaluation of 99mTc/188Re-labeled linear alpha-melanocyte stimulating
      hormone analogs for specific melanoma targeting.
AB  - Radiolabeled alpha-melanocyte stimulating hormone (alpha-MSH) analogs were
      examined in melanoma-bearing mice to determine the effects of peptide length,
      structure, and radiometal chelation chemistry on tumor targeting and in vivo
      biodistribution. The linear alpha-MSH analogs [Nle4,D-Phe7]alpha-MSH (NDPMSH) and
      [D-Phe7]alpha-MSH(5-10) (DPMSH) were radiolabeled with 99mTc and 188Re via the
      addition of tetrafluorophenyl mercapto-acetylglycylglycyl-gamma-aminobutyrate
      (MAG2) or tetrapeptide Ac-Cys-Gly-Cys-Gly (CGCG) chelation moieties. 125I-Tyr2
      NDPMSH was obtained by direct iodination of the Tyr2 residue. Tumor uptake of
      99mTc-labeled CGCG- and MAG2-NDPMSH analogs at 30 min postinjection were 6.52 +/-
      1.11 %ID/g and 4.17 +/- 1.34 %ID/g, respectively, resulting in a significantly
      higher tumor-to-blood uptake ratio than that of 125I-NDPMSH or a shorter alpha
      MSH analog, 99mTc-CGCG-DPMSH. The combination of radiolabeling efficacy and in
      vivo tumor uptake highlights the potential of 99mTc-CGCG-NDPMSH as a melanoma
      imaging agent.

PMID- 10587109
TI  - Tc-99m erythromycin lactobionate inhalation scintigraphy in parenchymal lung
      diseases.
AB  - We have investigated Technetium 99m erythromycin lactobionate (Tc 99m EL)
      clearance from the lungs after inhalation, in the presence of an alveolitis.
      Eighteen patients (6 sarcoidosis, 7 idiopathic fibrosis, and 5 miliary
      tuberculosis) were imaged after the patients inhaled 1,110 MBq of Tc 99m EL.
      Clearance half time for the first 45 min, for 24 h, and retention at 24 h
      correlated with percentage of lymphocytes in bronchoalveolar lavage fluid (BAL)
      (r = .729, r = .883, and r = .826, respectively). There was a positive
      correlation between peripheral penetration (PP) and forced expiratory volume in 1
      s (FEV1) (r = .806) and forced vital capacity (FVC) (r = .781). Retention was
      more marked in sarcoidosis compared with tuberculosis (0.025 < p < or = 0.05).
      Radioaerosol lung imaging may reflect the pulmonary function impairment in
      parenchymal lung diseases. Retention of Tc 99m EL may be related to number of BAL
      cells or presence of a lymphocytic alveolitis. Long residency time of Tc 99m EL
      in the lungs implies that erythromycin can also be administered by inhalation for
      therapeutic purposes.

PMID- 10587110
TI  - Effect of arteriovenous difference in measuring renal function by single
      injection plasma clearance: role of bolus.
AB  - Error estimates for arteriovenous difference were calculated by two models, a lag
      time model and a compartmental model, using Tc99m-diethylenetriaminepentaacetic
      acid (DTPA) plasma clearance curves from 40 subjects and Tc99m-MAG3
      (mercaptoacetyltriglycine) curves from 18 subjects. It was found that correcting
      for the effect of the initial bolus largely cancelled the conventional
      arteriovenous difference, so that the net error was negligible.

PMID- 10587111
TI  - Characterisation of 67Ga3+ complexes of triaza macrocyclic ligands:
      biodistribution and clearance studies.
AB  - The 67Ga3+ complexes of three triazamacrocycles, 1,4,7-triazacyclononane-N,N',N''
      triacetic acid (NOTA), its phosphonate analog 1,4,7-triazacyclononane-N,N',N''
      tris(methylenephosphonic) acid (NOTP), and the monoethyl ester of NOTP, 1,4,7
      triazacyclononane-N,N',N''-tris (methylenephosphonate-monoethylester) (NOTPME)
      were studied for possible use as radiopharmaceuticals. Biodistribution studies
      and gamma imaging were performed in Wistar rats. The present results demonstrated
      that all the macrocyclic complexes studied display renal clearance and are almost
      completely eliminated within 24 h. The [67Ga](NOTP)3- chelate, with a large
      negative charge, has a considerably slower uptake and elimination by the kidneys
      than the neutral [67Ga](NOTA) and [67Ga](NOTPME) chelates. We have thus
      demonstrated a charge-clearance relationship for a series of stable and well
      characterized complexes. The high stability and rapid renal excretion properties
      displayed by the NOTA and NOTPME chelates support their possible application as
      imaging agents for kidney structural and functional studies.

PMID- 10587112
TI  - In vitro and in vivo evaluation of bidentate, water-soluble phosphine ligands as
      anchor groups for the organometallic fac-[99mTc(CO)3]+-core.
AB  - The organometallic precursor fac-[99mTc(OH2)3(CO)3]+, 1a, was reacted with the
      bidentate, water-soluble phosphine ligands bis(bis(hydroxymethyl)phosphino)ethane
      (HMPE) and bis(bis(hydroxymethyl)phosphino)benzene (HMPB) in 0.9% saline to
      produce complexes in >95% yields. High performance liquid chromatography analyses
      indicate the initial formation of the complexes fac-[99mTcCl(CO)3L] (L = HMPE 2a,
      HMPB 3a). The neutral complexes ultimately lose the coordinated chloride to
      produce the cationic species fac-[99mTc(OH2)(CO)3L]+ 2b/3b. In vitro studies
      showed a high stability of 2b/3b over a wide pH range for >24 h. No decomposition
      or alteration of the complexes was observed even in the presence of excess
      histidine, cysteine, or human serum albumin. Experiments performed in normal mice
      demonstrated a fast clearance of the cationic compounds 2b/3b from the blood pool
      and clearance through the hepatobiliary and the urinary pathways.

PMID- 10587113
TI  - Freeze-dried formulation for direct 99mTc-labeling ior-egf/r3 MAb: additives,
      biodistribution, and stability.
AB  - Monoclonal antibodies (MAbs) have been useful for immunoscintigraphic
      applications in clinical diagnosis since they were introduced in nuclear medicine
      practice. The MAb ior egf/r3 developed at the Center of Molecular Immunology
      (Havana, Cuba) is a murine antibody that recognizes the human epidermal growth
      factor receptor (EGF-R) and has been used widely in the radioimmunodiagnosis of
      tumors of epithelial origin. Based on the direct Schwarz method, the present
      report describes the preparation of a freeze-dried formulation for radiolabeling
      the MAb ior egf/r3 with 99mTc for immunoscintigraphic applications. Radiolabeling
      efficiency, effects on immunoreactivity, biodistribution, pharmacokinetic, and
      stability of the formulation are reported. The study demonstrated that the freeze
      dried formulation can be labeled with 99mTc at high yield. The resulting 99mTc
      labeled ior egf/r3 MAb can be used to visualize in vivo human tumors of
      epithelial origin by immunoscintigraphy studies. The kit does not need any other
      addition or purification at the time of tagging other than the requisite amount
      of pertechnetate (40-50 mCi). Because the contents of the kit are lyophilized, no
      special storage or transportation is required.

PMID- 10587114
TI  - The "win-win" of research.

PMID- 10587115
TI  - Malpractice issues in radiology. Admitting mistakes.

PMID- 10587116
TI  - Hiring of diagnostic radiologists in 1997.
AB  - OBJECTIVE: We sought to determine the hiring activities of physician groups with
      respect to diagnostic radiologists. MATERIALS AND METHODS: A survey was mailed to
      a stratified, random sample of 589 groups of physicians in the autumn of 1997;
      76% responded. Responses were weighted to represent all practices in the United
      States that have more than one radiologist. Findings were compared with results
      of similar, previous surveys. RESULTS: In the 12 months before the survey, groups
      sought to hire 1909 (+/-111[SE]) diagnostic radiologists; 888 (+/-77) of these
      jobs were new positions, the rest were replacements for radiologists who left
      groups. Groups did not seek to refill another 366 (+/-57) positions that had been
      vacated during these 12 months. Groups succeeded in hiring 1488 (+/-92)
      diagnostic radiologists. Generally, the percentage of available positions that
      groups succeeded in filling did not differ among subspecialty fields. A greater
      perceived effect of managed care on a group was associated with fewer expansion
      positions and less likelihood that positions were offered on a partnership-track
      basis but otherwise was unrelated to hiring activity. Eighty-one percent of
      available positions were in groups that preferred recently trained radiologists
      to those with 10-20 years' experience; 28% of full-time positions in private
      nonacademic groups were not partnership-track. CONCLUSION: The decline in hiring
      evident during 1991-1995 has reversed. In the year ending in the autumn of 1997,
      for the first time in recent years, positions available exceeded radiologists to
      fill them; the excess was approximately 278 positions.

PMID- 10587117
TI  - A World Wide Web Internet engine for collaborative entry and peer review of
      radiologic teaching files.
AB  - OBJECTIVE: Radiologists can now use the Internet as a dissemination medium for
      radiologic teaching files. This has greatly increased the availability of
      radiologic information to a larger number of people. However, the creation of the
      teaching files themselves remains a static and labor-intensive process. As a
      partial solution to this problem, we set out to create a World Wide Web-based
      Internet engine for the collaborative entry and peer review of radiologic
      teaching files. CONCLUSION: We created a system that facilitates, simplifies, and
      improves the generation of radiologic teaching files. We used the Internet to
      help promote the creation of teaching files in a more timely, efficient, and
      effective manner.

PMID- 10587118
TI  - Blunt abdominal trauma: the role of emergent sonography and a review of the
      literature.

PMID- 10587119
TI  - Sonography in a clinical algorithm for early evaluation of 1671 patients with
      blunt abdominal trauma.
AB  - OBJECTIVE: The purpose of this study was to evaluate the efficacy of sonography
      in our algorithm when differentiating patients with blunt abdominal trauma who
      need immediate surgery from patients who would benefit from further diagnostic
      workup or who need no treatment. SUBJECTS AND METHODS: We performed abdominal
      sonography as the primary screening tool in 1671 consecutive patients in our
      prospective study. Radiologists performed sonography in the trauma room within
      minutes of the arrival of each patient. Hemodynamic instability in conjunction
      with positive sonographic findings led to emergency laparotomy. Otherwise,
      positive sonographic findings warranted additional diagnostic tests. Observing
      free fluid or organ injury caused us to categorize sonographic findings as
      positive. RESULTS: Sonography correctly identified all patients requiring
      emergency laparotomy. No inconclusive laparotomies were performed in this group.
      The sensitivity of sonography for revealing intraabdominal injury was 88%, the
      specificity was 100%, and the accuracy was 99%. In 132 patients (8%), abdominal
      CT was performed. CT revealed relevant posttraumatic abnormalities in 61% of all
      patients. Four hundred seventy patients with negative sonographic findings were
      discharged approximately 12 hr after admission; two of these patients (0.4%) were
      mistakenly discharged. Trauma scores did not influence the efficacy of
      sonography. CONCLUSION: Our algorithm that uses sonography as the primary
      diagnostic tool provides accurate, fast, cost-effective, and noninvasive initial
      management of patients with blunt abdominal trauma. Our test characteristics were
      excellent indicators of the need for emergency laparotomy. Sonography also
      achieves high values in revealing relevant injury. Our algorithm produced
      medically satisfactory and economically prudent management of patients with blunt
      abdominal trauma.

PMID- 10587120
TI  - Endoluminal CT colonography after an incomplete endoscopic colonoscopy.
AB  - OBJECTIVE: We evaluated the clinical usefulness of endoluminal CT colonography
      after an incomplete colonoscopy. SUBJECTS AND METHODS: We prospectively studied
      40 patients in whom the cecum could not be reached endoscopically despite
      adequate bowel preparation. Endoluminal CT colonography (120 kVp, 120 mA, 3-mm
      collimation, pitch of 2, 1.5-mm interval reconstruction) was performed within 2
      hr of incomplete colonoscopy. Two-dimensional multiplanar reformatted images and
      three-dimensional endoluminal images were analyzed. Twenty-six patients (65%)
      underwent barium enema immediately after endoluminal CT colonography. We analyzed
      colonic distention; duration of endoluminal CT colonography; patient tolerance;
      number of colonic segments seen at colonoscopy, endoluminal CT colonography, and
      barium enema; and reasons for incomplete colonoscopy as well as colonic and
      extracolonic findings. RESULTS: Duration of endoluminal CT colonography was 14.2
      +/- 4.6 min (mean +/- SD). Endoluminal CT colonography was better tolerated than
      colonoscopy or barium enema (p < .001). Probable causes for incomplete
      colonoscopy were identified at endoluminal CT colonography in 74% of 40 patients.
      Baseline colonic distention in the region of the transverse and right colon was
      considered adequate before additional air insufflation; however, the addition of
      air significantly enhanced colonic distention throughout the entire colon (p <
      .001). Endoluminal CT colonography adequately revealed 96% of all colonic
      segments; in comparison, barium enema adequately revealed 91% of all segments (p
      < .05). CONCLUSION: In patients with incomplete colonoscopy, endoluminal CT
      colonography successfully showed the previously unrevealed colon in more than 90%
      of patients. Endoluminal CT colonography is a rapid, well-tolerated technique
      that provides clinically useful colonic and extracolonic information and should
      be considered for all patients who undergo incomplete colonoscopy.

PMID- 10587121
TI  - Colonic wall thickening in patients with cirrhosis: CT findings and clinical
      implications.
AB  - OBJECTIVE: The purpose of this study was to determine the prevalence and spectrum
      of colonic wall changes in patients with cirrhosis and to determine the
      association between these colonic wall changes and portal hypertension. MATERIALS
      AND METHODS: Abdominal CT examinations of 57 patients with cirrhosis were
      evaluated for colonic abnormalities including bowel wall thickening and
      pneumatosis. The degree and extent of colonic involvement, other CT features of
      cirrhosis including ascites and portal hypertension, and clinical symptoms were
      recorded. A correlation was made with available colonoscopy, exploratory
      laparotomy, and pathologic results. RESULTS: Colonic wall abnormalities were seen
      in 37% (21/57) of the patients with cirrhosis, 25% (14/57) of whom had isolated
      or predominantly right-sided colonic changes. Abnormal bowel wall thickening
      (ranging from 6 mm to 3 cm in thickness) was present in 35% of the patients.
      Pneumatosis was found in 4% of the patients. Of the 18 liver transplant
      recipients who had CT examinations before and after liver transplantation,
      colonic changes were seen in 44% preoperatively but in only 6% postoperatively.
      Isolated right-sided colonic changes and diffuse colonic changes were associated
      with varices in 93% and 100% of the patients, respectively; with ascites in 93%
      and 100%, respectively; and with splenomegaly in 83% and 86%, respectively.
      Specific or focal bowel symptoms were present in only 29% of the patients with
      colonic changes, whether the changes were diffuse or isolated to the right side.
      CONCLUSION: Thirty-five percent of the patients with severe cirrhosis who
      underwent CT were shown to have colonic wall thickening; two thirds of these
      patients had thickening limited predominantly to the right colon. We postulated
      that predominantly right-sided colonic wall thickening may be related to changes
      in blood flow and hydrostatic pressures caused by portal hypertension. Many
      patients with isolated or predominately right-sided colonic wall thickening did
      not have specific or focal bowel symptoms, and in most patients, the colonic wall
      thickening resolved after successful liver transplantation, requiring no further
      testing. On the other hand, we found that pneumatosis or severe diffuse colonic
      wall thickening may indicate a more serious colonic problem such as ischemia or
      infection with Clostridium difficile and should prompt further investigation.

PMID- 10587122
TI  - Pancreaticoduodenal arcades and dorsal pancreatic artery: comparison of CT
      angiography with three-dimensional volume rendering, maximum intensity
      projection, and shaded-surface display.
AB  - OBJECTIVE: The objective of this study was to compare the ability of CT
      angiography to depict the pancreaticoduodenal arcades and the dorsal pancreatic
      artery using the techniques of three-dimensional (3D) volume rendering, maximum
      intensity projection (MIP), and shaded-surface display (SSD). SUBJECTS AND
      METHODS: Twenty-seven patients were selected at random from a group of 42
      patients undergoing arterial-phase helical CT angiography before liver
      transplantation. CT angiograms were constructed from identical data sets using 3D
      volume rendering, MIP, and SSD. RESULTS: Seventy-two vessels were evaluated in 27
      patients. Three-dimensional volume rendering depicted 24 anterior and 22
      posterior arcades and 26 dorsal pancreatic arteries; combined MIP and SSD
      depicted 14 anterior and 13 posterior arcades and 19 dorsal pancreatic arteries.
      Thirty vessels with diameters of between 2 and 3 mm were well seen with 3D volume
      rendering but were incompletely depicted with MIP and SSD. Sixteen vessels with
      diameters of greater than 3 mm were well seen using all three techniques. Twenty
      six vessels with diameters of less than 2 mm were faintly seen with 3D volume
      rendering but were unidentifiable with MIP and SSD. CONCLUSION: Three-dimensional
      volume rendering is superior to MIP and SSD in the depiction of
      pancreaticoduodenal arcades and dorsal pancreatic arteries. Unlike the other
      rendering techniques, 3D volume rendering can also show relationships between
      these vessels and pancreatic parenchyma and adjacent structures.

PMID- 10587123
TI  - Imaging-guided percutaneous biopsy of focal splenic lesions: update on safety and
      effectiveness.
AB  - OBJECTIVE: The purpose of this study is to determine the safety and effectiveness
      of percutaneous imaging-guided biopsy in the diagnosis of focal splenic lesions.
      MATERIALS AND METHODS: From May 1995 to November 1997, 20 imaging-guided biopsies
      of focal splenic lesions were performed in 18 patients, including seven patients
      with a prior diagnosis of extrasplenic malignancy (breast cancer, n = 3;
      lymphoma, n = 2; ovarian cancer, n = 1; and osteogenic sarcoma, n = 1), three
      immunosuppressed patients (cause of immunosuppression: AIDS, n = 1; liver
      transplantation, n = 1; and bone marrow transplantation, n = 1), two patients
      with anemia, one patient with a recent history of IV drug abuse, and five
      patients with incidentally discovered splenic lesions. Biopsies were performed
      with an 18-gauge (n = 1), a 20-gauge (n = 8), or a 22-gauge (n = 14) self
      aspirating needle or an 18-gauge cutting needle (n = 1). Biopsies were considered
      successful if a specific diagnosis of benign or malignant disease was made.
      RESULTS: A specific diagnosis was made in 16 (88.9%) of 18 patients, and no
      complications occurred. Malignancy was diagnosed in six patients including three
      patients with lymphoma. Benign conditions were diagnosed in 10 patients: a cyst
      in two patients; hamartoma in one; lipogranuloma in one; infarct in one; and
      infection in four, including one case each of Candida albicans, Pneumocystis
      carinii, Mycobacterium tuberculosis, and mixed flora. The tenth benign diagnosis
      was a pseudotumor of the spleen related to a bulbous tail of the pancreas that
      was inseparable from the splenic hilum. Biopsy did not establish a diagnosis in
      one patient with lymphoma and in one patient with presumed splenic candidiasis. A
      mean of 1.5 needle passes was made per biopsy. CONCLUSION: Imaging-guided splenic
      biopsy is a safe technique that provides a specific diagnosis in most patients
      with focal splenic lesions.

PMID- 10587124
TI  - Cytomegalovirus duodenitis in an AIDS patient.

PMID- 10587125
TI  - Endoscopic banding of esophageal varices: radiographic findings.

PMID- 10587126
TI  - Choledocholithiasis: diagnosis with oral-contrast-enhanced CT cholangiography.
AB  - OBJECTIVE: The objective of this investigation was to assess the performance of
      helical CT cholangiography after administration of an oral biliary contrast agent
      for the diagnosis of choledocholithiasis. SUBJECTS AND METHODS: Helical CT
      cholangiography was performed on 31 patients referred for endoscopic retrograde
      cholangiography of suspected choledocholithiasis. Iopanoic acid (6 g) was
      administered orally 8-12 hr before acquisition of helical CT cholangiograms.
      Three-dimensional and two-dimensional reformations were generated from a set of
      axial source images. Two radiologists independently interpreted the helical CT
      cholangiograms. Sensitivity and specificity were calculated using findings on
      retrograde cholangiography as the standard of reference. In addition,
      interobserver agreement was determined using kappa statistics. RESULTS: Our
      patients had no adverse reactions to iopanoic acid. The degree of biliary
      opacification was sufficient to perform three-dimensional and two-dimensional
      reconstructions in 29 patients (93.5%). Two patients were excluded from
      statistical analysis because cannulation of the common bile duct during
      retrograde cholangiography failed. Findings on endoscopic retrograde
      cholangiography in the remaining 29 patients were the following:
      choledocholithiasis (n = 14), common bile duct dilatation with no stones (n =
      11), and normal bile ducts (n = 4). Sensitivity and specificity of oral-contrast
      enhanced CT cholangiography for detection of choledocholithiasis were 92.9% (95%
      confidence interval [CI], 66.1-99.8%) and 100% (95% CI, 78.2-100%), respectively,
      for observer 1 and 85.7% (95% CI, 57.2-98.2%) and 100% (95% CI, 78.2-100%),
      respectively, for observer 2. Interobserver agreement was .92 (excellent).
      CONCLUSION: Helical CT cholangiography performed after oral administration of
      iopanoic acid appears promising for diagnosis of choledocholithiasis.

PMID- 10587127
TI  - Xanthogranulomatous cholecystitis: radiologic findings with histologic
      correlation that focuses on intramural nodules.
AB  - OBJECTIVE: The purpose of this study was to histologically classify intramural
      nodules associated with xanthogranulomatous cholecystitis and to evaluate the
      radiologic findings for each type of nodule. MATERIALS AND METHODS: Pathologic
      slides and radiologic studies including 14 sonographic and 16 CT examinations in
      19 patients (12 men, seven women; mean age, 61 years) with xanthogranulomatous
      cholecystitis were reviewed. Radiologic findings were correlated with the
      histologic type of intramural nodule: abscess, xanthogranuloma, or a combination
      of the two. The duration of symptoms for each type of intramural nodule was also
      evaluated. RESULTS: Histologically, all patients had intramural nodules that were
      either abscesses (n = 11), xanthogranulomas (n = 5), or a combination of the two
      (n = 3). Radiologic studies revealed nodules in 10 patients (52.6%; four
      abscesses, four xanthogranulomas, and two combinations). For abscesses, the mean
      interval from onset of symptoms to surgery was 25 days; for xanthogranulomas, 70
      days (p = .0057). Abscesses were associated with more complications of
      xanthogranulomatous cholecystitis. CONCLUSION: Intramural nodules in patients
      with xanthogranulomatous cholecystitis were found to represent abscesses or
      xanthogranulomas at histology. Xanthogranulomas were more often revealed
      radiologically than were abscesses. Abscesses caused more clinical complications.
      Because symptoms lasted longer for xanthogranulomas, we hypothesized that
      abscesses may become xanthogranulomas.

PMID- 10587128
TI  - Injury to aberrant bile ducts during cholecystectomy: a common cause of
      diagnostic error and treatment delay.
AB  - OBJECTIVE: The purpose of this study was to determine the prevalence of injured
      aberrant bile ducts in a population with complications after cholecystectomy and
      to determine whether such injury resulted in significant delay in the diagnosis
      and treatment of bile duct injuries. MATERIALS AND METHODS: The cholangiograms of
      82 patients who sustained bile duct injury during cholecystectomy were reviewed.
      Prevalence of aberrant bile duct anatomy in the injured ducts was noted. The time
      periods from injury to diagnosis and treatment of bile duct leaks in patients
      with aberrant bile duct anatomy were compared with those in patients with normal
      anatomy. RESULTS: Seventeen percent (14/82) of the patients were found to have
      aberrant bile duct anatomy. Fifteen percent (12/82) were found to have had an
      aberrant bile duct involved in the injury. Eleven of the patients had an aberrant
      bile duct leak, and one patient had an aberrant bile duct clipping injury. The
      time period required for diagnosis and treatment of a leaking aberrant bile duct
      was significantly longer (p < .005) than that required for a bile leak in an
      anatomically normal bile duct. CONCLUSION: Aberrant bile ducts are present in a
      significant number of patients who sustain bile duct injuries during
      cholecystectomy. Diagnosis of an aberrant bile duct leak may be delayed because
      of nonfilling of the bile duct during standard cholangiographic techniques.
      Careful examination of cholangiograms for nonfilling segments and contrast
      material injection of biloma drains and T tubes may shorten the time to
      definitive treatment for this group of patients.

PMID- 10587129
TI  - Comparison of unenhanced, hepatic arterial-dominant, and portal venous-dominant
      phase helical CT for the detection of liver metastases in women with breast
      carcinoma.
AB  - OBJECTIVE: The purpose of this study was to evaluate triple-phase helical CT for
      detection of hepatic metastases from breast carcinoma. SUBJECTS AND METHODS:
      Breast cancer patients were studied prospectively with triple-phase helical CT in
      300 consecutive examinations. Hepatic arterial-dominant and portal venous
      dominant phase scans were initiated at 20 and 65 sec, respectively, after IV
      injection of 175 ml of iopamidol (30 mg/ml) at 5 ml/sec. Three independent
      observers each reviewed 200 cases of the portal venous-dominant phase for lesion
      number, conspicuity, and attenuation. Subsequently, portal venous-dominant phase
      images were reevaluated in conjunction with hepatic arterial-dominant phase or
      unenhanced images. RESULTS: Hepatic metastases were identified in 79 (26%) of 300
      cases. Lesions detected on portal venous-dominant, hepatic arterial-dominant, and
      unenhanced images were as follows: observer 1, n = 198, 164, and 171; observer 2,
      n = 254, 233, and 233; and observer 3, n = 291, 270, and 276 (p > .05). The mean
      total lesion count was 387, with more lesions detected on portal venous-dominant
      phase than on either hepatic arterial-dominant phase or unenhanced images (p <
      .001 and p < .0001, respectively). For individual observers, 10-26% of lesions
      were hypervascular on hepatic arterial-dominant phase images. Two to 4% of
      lesions were identified only on hepatic arterial-dominant phase or unenhanced
      images. However, in these few cases, the lesions either were false-positives or
      were seen in conjunction with additional metastases on portal venous-dominant
      images. CONCLUSION: Routine use of triple-phase CT in patients with breast
      carcinoma may not be warranted: Addition of the hepatic arterial-dominant phase
      or unenhanced images revealed few additional lesions in our group of 300
      patients.

PMID- 10587130
TI  - Correlation between the blood supply and grade of malignancy of hepatocellular
      nodules associated with liver cirrhosis: evaluation by CT during intraarterial
      injection of contrast medium.
AB  - OBJECTIVE: The purpose of this study is to evaluate the correlation between the
      intranodular blood supply revealed by CT during intraarterial injection of
      contrast medium, mainly using helical CT, and the grade of malignancy of
      hepatocellular nodules associated with liver cirrhosis as classified by the
      International Working Party of the World Congress of Gastroenterology. SUBJECTS
      AND METHODS: We studied 201 histologically proven nodules (101 resected and 100
      biopsied nodules), including 47 low-grade dysplastic nodules (low-DNs), 56 high
      grade dysplastic nodules (high-DNs), 24 well-differentiated hepatocellular
      carcinomas (wd-HCCs), and 74 moderately or poorly differentiated HCCs (mp-HCCs),
      in 139 cirrhotic patients. Findings on CT during arterial portography (n = 201)
      and CT during hepatic arteriography (n = 74) were reviewed and compared with the
      histologic diagnosis. RESULTS: CT findings were classified into four types
      relative to the surrounding liver: type A (isodense), type B (slightly
      hypodense), type C (partially hypodense), and type D (markedly hypodense) on CT
      during arterial portography and type I (isodense), type II (hypodense), type III
      (partially hyperdense), and type IV (hyperdense) on CT during hepatic
      arteriography. On CT during arterial portography, the distributions of each type
      were low-DN (n = 47 [A, n = 36; B, n = 8; C, n = 3]), high-DN (n = 56 [A, n = 18;
      B, n = 20; C, n = 10; D, n = 8]), wd-HCC (n = 24; [B, n = 4; C, n = 13; D, n =
      7]), and mp-HCC (n = 74 [D, n = 74]). On CT during hepatic arteriography, the
      distributions were low-DN (n = 26 [I, n = 18; II, n = 7; III, n = 1]), high-DN (n
      = 19 [I, n = 6; II, n = 7; III, n = 4; IV, n = 2]), wd-HCC (n = 15 [I, n = 1;
      III, n = 8; IV, n = 6]), and mp-HCC (n = 14 [IV, n = 14]). We found a
      statistically significant correlation between the four types and the grade of
      malignancy of these nodules. CONCLUSION: Findings on CT during arterial
      portography and CT during hepatic arteriography correlated positively with
      histologic grading when overlap in appearance between dysplastic nodules and HCCs
      occurred. The concept revealed in this study can apply to diagnoses made on the
      basis of Doppler sonography, dynamic CT, and MR imaging.

PMID- 10587131
TI  - The value of prone scanning to distinguish ureterovesical junction stones from
      ureteral stones that have passed into the bladder: leave no stone unturned.
AB  - OBJECTIVE: When a stone is located in the region of the ureterovesical junction
      on CT studies, it is important to determine if the stone is impacted at the
      ureterovesical junction or has already passed into the bladder. The purpose of
      this study was to determine if CT findings can be used to distinguish stones
      impacted at the ureterovesical junction from stones that have already passed into
      the bladder. SUBJECTS AND METHODS: From February 1, 1997, to January 31, 1998, 37
      patients with acute flank pain underwent unenhanced CT studies in the supine
      position that showed stones in the region of the ureterovesical junction. To
      determine stone location, limited rescans were obtained with the patients in the
      prone position. The supine images were reviewed retrospectively by one of the
      authors, who was unaware of the findings of the prone scans. Forty-one stones
      were classified as being impacted at the ureterovesical junction or as having
      passed into the bladder. RESULTS: On CT, 23 stones were correctly classified as
      being impacted at the ureterovesical junction; nine stones were correctly
      classified as having passed into the bladder; and nine stones were incorrectly
      classified as being within the bladder. We calculated a sensitivity of 72%, a
      specificity of 100%, a positive predictive value of 100%, a negative predictive
      value of 50%, and an accuracy of 78% for CT in revealing stones impacted at the
      ureterovesical junction. CONCLUSION: If patients are imaged in the supine
      position only, unenhanced helical CT cannot reliably distinguish stones impacted
      at the ureterovesical junction from stones that have already passed into the
      bladder. A prone scan can be used to make this distinction.

PMID- 10587132
TI  - Sonography during early pregnancy: dependence of threshold and discriminatory
      values on transvaginal transducer frequency.
AB  - OBJECTIVE: Our goal was to determine if normal and abnormal pregnancies could be
      distinguished at smaller sac sizes with a higher frequency transvaginal
      transducer than with a 5-MHz transducer. SUBJECTS AND MATERIALS: Thirty-nine
      patients with potentially abnormal pregnancies identified with a 5-MHz
      transvaginal transducer were immediately reimaged with a 9-5-MHz transducer. We
      compared our ability to visualize the yolk sac, embryo, and cardiac activity
      relative to mean sac diameter on imaging at both frequencies in women with normal
      and abnormal pregnancies. RESULTS: Of the 39 pregnancies, 22 (56%) were normal or
      probably normal. Using the 5-MHz transducer, a yolk sac was first seen in a 6.4
      mm gestational sac but was not definitively seen in 12 gestational sacs measuring
      5-13 mm. Using the 9-5-MHz transducer, yolk sacs were identified in all
      gestational sacs measuring 4.6-13 mm, and live embryos were seen in five of eight
      sacs measuring 8.1-13 mm. The largest normal gestational sac without a live
      embryo measured 11 mm. When we compared these pregnancies with 17 (44%) abnormal
      pregnancies, we found that all pregnancies that had no yolk sac by the time the
      gestational sac measured 5.0 mm or no live embryo by 13 mm had abnormal findings
      on higher frequency imaging. CONCLUSION: The ability to visualize the yolk sac
      and embryo in early pregnancy is critically dependent on transvaginal transducer
      frequency. Threshold values and discriminatory sizes used to distinguish normal
      and abnormal pregnancies are smaller on higher frequency than on lower frequency
      imaging and, therefore, should be redetermined for specific transducer
      frequencies.

PMID- 10587133
TI  - Arterial anatomy of the female genital tract: variations and relevance to
      transcatheter embolization of the uterus.

PMID- 10587134
TI  - Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman Disease): a rare
      cause of bilateral renal masses.

PMID- 10587135
TI  - CT appearance of the adrenal glands in adrenocorticotrophic hormone-dependent
      Cushing's syndrome.
AB  - OBJECTIVE: The purpose of this study was to describe the size and appearance of
      the adrenal glands on CT in patients with adrenocorticotrophic hormone (ACTH)
      dependent Cushing's syndrome and to correlate gland dimensions with circulating
      cortisol and ACTH levels. MATERIALS AND METHODS: We retrospectively analyzed
      clinical, biochemical, and imaging data for 53 patients referred for CT of the
      adrenals as part of an investigation for ACTH-dependent Cushing's syndrome at our
      institution between 1988 and 1997. Two observers, who were unaware of the
      endocrine data, measured the body and limb widths of the adrenal glands using an
      electronic cursor. RESULTS: Of the 53 patients, 37 (70%) were shown to have
      enlarged adrenal glands on CT. The mean width of the adrenal limbs positively
      correlated with the circulating cortisol and ACTH levels. The adrenals were
      larger in patients with ectopic ACTH syndrome than in patients with Cushing's
      disease (p < .02). Ten patients (19%) had nodules that were 10 mm or greater in
      diameter. CONCLUSION: The adrenal glands were often enlarged in patients with
      ACTH-dependent Cushing's syndrome, and the enlargement could be quantified on CT.
      However, having normalsized adrenals (observed in 30% the patients in our study)
      did not preclude such a diagnosis. We found that adrenal limb width positively
      correlates with ACTH and cortisol levels.

PMID- 10587136
TI  - Testicular adrenal rest tissue in congenital adrenal hyperplasia: comparison of
      MR imaging and sonographic findings.
AB  - OBJECTIVE: The purpose of our study was to describe the MR features of testicular
      adrenal rest tissue in patients with congenital adrenal hyperplasia and to
      compare the usefulness of MR imaging with that of sonography for the detection of
      testicular adrenal rest tissue. SUBJECTS AND METHODS: Nineteen patients with
      congenital adrenal hyperplasia underwent MR imaging and gray-scale and color
      Doppler sonography of the testicles during the same visit to our institution.
      Findings were compared. RESULTS: MR features of testicular adrenal rest tissue
      included the following: isointensity (71% of the masses) and slight
      hyperintensity (29% of the masses) relative to normal testicular tissue on T1
      weighted images; hypointensity relative to normal testicular tissue on T2
      weighted images (100% of the masses); and diffuse enhancement on contrast
      enhanced T1-weighted images (85% of the masses). MR imaging and sonography
      revealed the testicular lesions equally well. Eleven (58%) of 19 patients had
      normal findings on MR imaging and sonography. Eight (42%) of 19 patients had 14
      intratesticular masses detected by both imaging techniques. CONCLUSION: MR
      imaging and sonography are equally useful in the detection of testicular adrenal
      rest tissue. Because sonography is more accessible to most institutions and is
      less expensive, it is the imaging technique of choice for the detection of
      testicular adrenal rest tissue.

PMID- 10587137
TI  - Optimizing contrast-enhanced abdominal CT in infants and children using bolus
      tracking.
AB  - OBJECTIVE: Manual administration of IV contrast material results in unpredictable
      injection rates. Our purpose was to determine the effect of bolus tracking on
      overall abdominal helical CT scan quality, particularly on hepatic enhancement,
      in children with manually administered contrast media. MATERIALS AND METHODS: We
      compared 33 abdominal helical CT scans of 29 children in whom bolus tracking was
      used with 22 CT scans of a control group of 21 children in whom bolus tracking
      was not used. All contrast material was administered by manual injection.
      Qualitative assessment was made of organ and vessel enhancement and overall scan
      appearance. Quantitative assessment using region-of-interest cursors was
      performed at three anatomic levels, and the results for the two groups of
      children were compared. RESULTS: Qualitative comparison of enhancement parameters
      between the bolus tracking group (number given first) and the control group
      (number given second) yielded the following: splenic artifact in 9% versus 23% (p
      = .24); inferior vena cava flow artifact in 3% versus 27% (p = .01); scanning
      during the nephrographic phase in 89% versus 59% (p = .02); and good quality
      grade in 79% versus 64% (p = .23). Significantly greater hepatic enhancement (as
      measured in mean Hounsfield units) was achieved in the bolus tracking group than
      in the control group at the superior (48.5 versus 28.6; p < .001), middle (47.9
      versus 32.3; p < .001), and inferior (48.2 versus 36.5; p = .01) levels. Hepatic
      enhancement increased significantly from the superior to the inferior level in
      the control group (p < .02), whereas enhancement was homogeneous in the bolus
      tracking group (p > .50). CONCLUSION: Bolus tracking provides improved contrast
      enhancement, including significantly greater hepatic enhancement, during
      abdominal helical CT in children in whom the rate of injection of contrast
      material is unpredictable.

PMID- 10587138
TI  - Prevalence and distribution of extraperitoneal hemorrhage associated with splenic
      injury in infants and children.
AB  - OBJECTIVE: The purpose of this study was to evaluate the prevalence and
      distribution of associated extraperitoneal hemorrhage in infants and children
      with splenic injury. CONCLUSION: Splenic injury occasionally resulted in
      extraperitoneal hemorrhage that tracked into the anterior pararenal space.
      Extraperitoneal hemorrhage always occurred in association with intraperitoneal
      hemorrhage. In addition, blood tracking into the anterior pararenal space after
      splenic injury dissected the splenic vein and pancreas in two (25%) of eight
      patients.

PMID- 10587139
TI  - Pediatric body applications of FDG PET.

PMID- 10587140
TI  - Fluoroscopically guided biopsies of the stomach and duodenum through a 10-French
      feeding tube in pigs: potential for use in pediatric patients.

PMID- 10587141
TI  - Direct versus indirect signs of traumatic aortic injury revealed by helical CT:
      performance characteristics and interobserver agreement.
AB  - OBJECTIVE: The purpose of this study was to evaluate the relative value of and
      interobserver agreement on direct versus indirect (hematoma) signs of traumatic
      aortic injury using helical CT. MATERIALS AND METHODS: From April 1994 through
      January 1997, 40 patients who were suspected to have traumatic aortic injury and
      who underwent contrast-enhanced helical CT had subsequent proof or exclusion of
      aortic injury. All available CT scans of these patients were combined with CT
      scans of 13 randomly chosen patients that had been initially interpreted as
      negative, and clinical follow-up showed no evidence of aortic injury. Two
      emergency radiologists and a nonemergency radiologist who were unaware of
      clinical outcome performed independent review of these cases to evaluate for
      mediastinal hematoma, periaortic hematoma, and direct signs of aortic injury.
      RESULTS: Direct signs of injury were seen on helical CT by both emergency
      radiologists in all 17 cases of aortic injury with no false-positive
      interpretations. The nonemergency radiologist failed to observe subtle direct
      signs in two cases of aortic injury, but patient management would not have been
      adversely affected. All observers had more false-negative interpretations for
      both mediastinal hematoma and periaortic hematoma than for direct signs.
      Interobserver agreement was higher for direct signs (kappa = .93) than for either
      mediastinal hematoma (kappa = .65) or periaortic hematoma (kappa = .71).
      CONCLUSION: In this study, helical CT revealed direct signs of traumatic aortic
      injury that were more accurate and more often observed than were indirect signs.
      Emphasis on direct signs should improve confidence in using helical CT to
      evaluate traumatic aortic injury.

PMID- 10587142
TI  - Traumatic lung herniation.

PMID- 10587143
TI  - Focal air trapping in patients with HIV infection: CT evaluation and correlation
      with pulmonary function test results.
AB  - OBJECTIVE: HIV-positive individuals commonly have symptoms of airway disease. We
      evaluated thin-section CT scans of HIV-infected individuals during inspiration
      and expiration for evidence of focal air trapping. We also correlated imaging
      findings with pulmonary function test results. SUBJECTS AND METHODS: Fifty-nine
      subjects, 48 of whom were HIV-positive and 11 of whom were HIV-negative,
      underwent thin-section CT of the thorax during inspiration and expiration. All
      subjects also underwent pulmonary function tests. Two radiologists, who were
      unaware of the subjects' HIV status and smoking history and of the results of
      pulmonary function tests, evaluated the CT scans for the presence and severity of
      focal air trapping. RESULTS: Expiratory CT revealed focal air trapping in 33
      subjects: 30 were HIV-positive and three were HIV-negative (p = .0338). The mean
      values of forced expiratory volume in 1 sec (FEV1), forced mid expiratory flow,
      and diffusion capacity (DL(CO)) were significantly lower for subjects with focal
      air trapping (mean = 88.85, 84.52, and 80.80, respectively) than for those with
      normal findings on CT (mean = 100.84, 99.24, and 95.82, respectively; p = .001, p
      = .021, and p = .003, respectively). We found no significant differences in
      smoking history between HIV-positive and HIV-negative subjects. Severe air
      trapping on expiratory CT scans was seen in three subjects: All three had HIV
      infection, low CD4 counts, and abnormally decreased FEV1 and DL(CO) values.
      CONCLUSION: Focal air trapping was a common finding on thoracic CT scans obtained
      during expiration in HIV-positive subjects. In addition, focal air trapping was
      associated with significantly lower FEV1, forced mid expiratory flow, and DL(CO)
      values than those found for subjects in whom CT revealed no focal air trapping.
      These results suggest that small airways disease may accompany a decline in
      pulmonary function in HIV-positive individuals.

PMID- 10587144
TI  - Staging of malignant pleural mesothelioma: comparison of CT and MR imaging.
AB  - OBJECTIVE: This article compares the accuracy of CT with that of MR imaging in
      staging of malignant pleural mesothelioma. SUBJECTS AND METHODS: Ninety-five
      patients were enrolled in a prospective staging protocol based on the
      International Mesothelioma Interest Group staging system. Sixty-five patients
      underwent CT and MR imaging and a surgical procedure (excluding percutaneous
      needle biopsy) to stage and resect the tumor. Receiver operating characteristic
      analyses were performed. CT and MR scans were interpreted independently by
      observers who were unaware of the results of the other imaging study; these
      imaging findings were compared with the results of surgery and pathologic
      examination. RESULTS: The areas under the receiver operating characteristic
      curves for eight of 10 features revealed by imaging showed no statistically
      significant differences between CT and MR imaging. However, MR imaging was
      superior to CT in revealing invasion of the diaphragm (A(z) = .55 for CT versus
      .82 for MR imaging) and in revealing invasion of endothoracic fascia or solitary
      resectable foci of chest wall invasion (A(z) = .46 for CT; A(z) = .69 for MR
      imaging). Several anatomic regions could not be evaluated because positive
      findings at surgery were rare. CONCLUSION: CT and MR imaging are of nearly
      equivalent diagnostic accuracy in staging malignant pleural mesothelioma. MR
      imaging is superior to CT in revealing solitary foci of chest wall invasion and
      endothoracic fascia involvement and in showing diaphragmatic muscle invasion;
      however, this advantage does not affect surgical treatment. For cost reasons, CT
      should be considered the standard diagnostic study before therapy.

PMID- 10587145
TI  - Pneumothoraces and chest tube placement after CT-guided transthoracic lung biopsy
      using a coaxial technique: incidence and risk factors.
AB  - OBJECTIVE: This study investigates factors influencing the risk of pneumothorax
      and chest tube placement in patients undergoing CT-guided transthoracic lung
      biopsy for pulmonary lesions using a coaxial technique. SUBJECTS AND METHODS: The
      study included 307 patients with pulmonary lesions biopsied under CT guidance.
      Patient-related parameters considered were age, sex, presence of emphysema or
      bullae, and lung function data. Lesion-related variables were size, location,
      cavitary appearance on CT, pleural contact, and depth of the lesion. Procedure
      variables were duration, type of needle, and experience of the operator. All
      variables were analyzed as single and multiple dependent variables for occurrence
      of pneumothorax. RESULTS: Pneumothorax occurred in 61 (19.9%) of the 307
      patients, and chest tube placement was required in six patients (2.0%).
      Univariate analysis showed that lesion size, lesion location, lesion depth, and
      difficulty of the procedure were significantly associated with a higher rate of
      pneumothorax. Using multivariate logistic regression analysis, we found that
      lesion depth from the pleural entry point was the sole variable that was
      significantly associated with an increased risk of pneumothorax. This risk
      increased with the depth of the lesion. Chest tube placement was required more
      frequently in patients with severe emphysema, obstructive lung disease, or
      hyperinflation. CONCLUSION: Lesion depth is the predominant risk factor for
      pneumothorax in patients undergoing CT-guided transthoracic lung biopsy. Chest
      tube placement is necessary more frequently in patients with severe emphysema,
      obstructive lung disease, or hyperinflation.

PMID- 10587146
TI  - Noninvasive evaluation of coronary artery bypass graft patency using three
      dimensional angiography obtained with contrast-enhanced electron beam CT.
AB  - OBJECTIVE: The purpose of this study was to determine the accuracy of three
      dimensional coronary angiography obtained with electron beam CT in the assessment
      of the patency of coronary artery bypass grafts. SUBJECTS AND METHODS: Twenty
      five patients who had undergone coronary artery bypass graft surgery were
      included. All patients underwent electron beam CT and conventional coronary
      angiography for the evaluation of the status of their bypass grafts. Three
      dimensional reconstructions of the heart and bypass grafts were compared with
      selective angiographic images of the bypass grafts. RESULTS: Fifty-seven
      saphenous vein grafts and 22 left internal mammary artery grafts were evaluated
      for occlusion or patency. Sensitivity and specificity of electron beam CT in
      revealing left internal mammary artery patency were 80% and 82.4%, respectively.
      Sensitivity and specificity of electron beam CT in revealing saphenous vein graft
      patency were 91.7% and 91.1%, respectively. Sensitivity and specificity of
      electron beam CT for evaluating saphenous vein grafts according to coronary area
      were as follows: saphenous vein grafts to left anterior descending artery, 100%
      and 100%, respectively; to diagonal branch, 100% and 100%; to left circumflex
      artery, 100% and 88.9%; and to right coronary artery, 75% and 85.7%. CONCLUSION:
      Three-dimensional coronary angiography obtained with electron beam CT is a
      promising, useful, and relatively accurate diagnostic imaging technique for the
      evaluation of graft patency in patients who have undergone coronary artery bypass
      graft surgery.

PMID- 10587147
TI  - Relationship between motion of coronary arteries and diaphragm during free
      breathing: lessons from real-time MR imaging.
AB  - OBJECTIVE: Diaphragmatic navigators are frequently used in free-breathing
      coronary MR angiography, either to gate or prospectively correct slice position
      or both. For such approaches, a constant relationship between coronary and
      diaphragmatic displacement throughout the respiratory cycle is assumed. The
      purpose of this study was to evaluate the relationship between diaphragmatic and
      coronary artery motion during free breathing. SUBJECTS AND METHODS: A real-time
      echoplanar MR imaging sequence was used in 12 healthy volunteers to obtain 30
      successive images each (one per cardiac cycle) that included the left main
      coronary artery and the domes of both hemidiaphragms. The coronary artery and
      diaphragm positions (relative to isocenter) were determined and analyzed for
      effective diaphragmatic gating windows of 3, 5, and 7 mm (diaphragmatic
      excursions of 0-3, 0-5, and 0-7 mm from the end-expiratory position,
      respectively). RESULTS: Although the mean slope correlating the displacement of
      the right diaphragm and the left main coronary artery was approximately 0.6 for
      all diaphragmatic gating windows, we also found great variability among
      individual volunteers. Linear regression slopes varied from 0.17 to 0.93, and r2
      values varied from .04 to .87. CONCLUSION: Wide individual variability exists in
      the relationship between coronary and diaphragmatic respiratory motion during
      free breathing. Accordingly, coronary MR angiographic approaches that use
      diaphragmatic navigator position for prospective slice correction may benefit
      from patient-specific correction factors. Alternatively, coronary MR angiography
      may benefit from a more direct assessment of the respiratory displacement of the
      heart and coronary arteries, using left ventricular navigators.

PMID- 10587148
TI  - Single coronary artery: evaluation of conventional two-dimensional and gadolinium
      enhanced three-dimensional MR coronary angiography.

PMID- 10587149
TI  - External validation of the Ottawa knee rules in an urban trauma center in the
      United States.
AB  - OBJECTIVE: We evaluated the Ottawa knee rules in a high-volume teaching hospital
      in the United States to determine whether the rules could be safely used to
      decide whether patients with acute blunt knee trauma should undergo radiography.
      SUBJECTS AND METHODS: During a 13-month period, 378 patients with acute blunt
      knee trauma were prospectively examined using the Ottawa knee rules. Data
      collected included the presence or absence of fracture predictors and the results
      of radiography. RESULTS: A fracture was seen in 43 (11%) of the 378 patients who
      met inclusion criteria. The knee rules predicted 42 of the 43 fractures;
      sensitivity was 98%, and specificity was 19%. Radiography of 65 patients (17%)
      who had no predictors for fracture could have been avoided if the knee rules had
      been used to screen for radiography. CONCLUSION: The Ottawa knee rules are highly
      sensitive for fracture in this setting and may safely be used to decide whether
      patients with acute blunt knee trauma should undergo radiography.

PMID- 10587150
TI  - Accuracy of T2-weighted fast spin-echo MR imaging with fat saturation in
      detecting cartilage defects in the knee: comparison with arthroscopy in 130
      patients.
AB  - OBJECTIVE: The purpose of this study was to assess the accuracy of routine T2
      weighted MR imaging in detecting and grading articular cartilage lesions in the
      knee compared with arthroscopy. SUBJECTS AND METHODS: We examined 130 consecutive
      patients who underwent MR imaging and arthroscopy of the knee for suspected
      internal derangement. MR imaging consisted of axial and coronal T2-weighted fast
      spin-echo sequences with fat saturation and sagittal T2-weighted spin-echo
      sequences. Each single plane was evaluated and graded for the presence and
      appearance of articular cartilage defects using a standard arthroscopic grading
      scheme adapted to MR imaging. RESULTS: Of the 86 arthroscopically proven
      abnormalities, 81 were detected on MR imaging. Sensitivity of the T2-weighted
      fast spin-echo sequence with fat saturation was 61% for the coronal plane alone
      and 59% for the axial plane alone. Specificity for each plane was 99%.
      Sensitivity for the sagittal T2-weighted spin-echo sequence was 40%, and
      specificity was 100%. Sensitivity of the combination of axial and coronal T2
      weighted fast spin-echo sequences with fat saturation and sagittal T2-weighted
      spin-echo sequence compared with arthroscopy for revealing cartilage lesions was
      94%, specificity was 99%, and accuracy was 98%. Sensitivity of coronal and axial
      T2-weighted fast spin-echo sequences with fat saturation was 93%, and specificity
      was 99%. Fifty-five lesions (64%) were identically graded on MR imaging and
      arthroscopy. Seventy-eight lesions (90%) were within one grade using MR imaging
      and arthroscopy, and 84 lesions (97%) were within two grades using MR imaging and
      arthroscopy. CONCLUSION: T2-weighted fast spin-echo MR imaging with fat
      saturation is an accurate and fast technique for detecting and grading articular
      cartilage defects in the knee. The combination of the axial and coronal planes
      offers sufficient coverage of articular surfaces to provide a high sensitivity
      and specificity for chondral defects.

PMID- 10587151
TI  - Three-dimensional analysis of the width of the subacromial space in healthy
      subjects and patients with impingement syndrome.
AB  - OBJECTIVE: The aim of this study was to per form a three-dimensional analysis of
      the width of the subacromial space during passive and active arm abduction in
      healthy volunteers and patients with impingement syndrome. SUBJECTS AND METHODS:
      The shoulders of 10 healthy subjects and 10 patients with impingement syndrome
      were imaged with an open MR system during abduction, with and without activation
      of the shoulder muscles. An apparatus was designed for applying an adduction
      force of 10 N to the distal humerus during image acquisition, and the minimal
      acromiohumeral distance was measured after three-dimensional reconstruction.
      RESULTS: In the 10 healthy volunteers, muscle activity led to a significant
      decrease (-32%; p < .05) of the acromiohumeral distance at 60 degrees of
      abduction, whereas at 120 degrees of abduction the distance was significantly
      increased (+44%; p < .05). In these volunteers, muscle activation caused no
      significant effect at 90 degrees of abduction. However, in the 10 patients with
      impingement syndrome, muscle activity led to a significant decrease in the width
      of the subacromial space compared with that of the healthy contralateral side (
      68%; p < .05). CONCLUSION: Muscle activity and arm position were found to cause
      systematic changes in the width of the subacromial space. However, functional
      deficits of the supraspinous muscle in patients with early-stage impingement
      syndrome were not apparent during muscle relaxation.

PMID- 10587152
TI  - Pigmented villonodular synovitis and giant cell tumors of the tendon sheath:
      radiologic and pathologic features.

PMID- 10587153
TI  - Giant cell tumor of the fourth metacarpal.

PMID- 10587154
TI  - A new vacuum device for extremity immobilization.

PMID- 10587155
TI  - Changes in cross-sectional measurements of the spinal canal and intervertebral
      foramina as a function of body position: in vivo studies on an open-configuration
      MR system.
AB  - OBJECTIVE: The purpose of this study was to evaluate physiologic changes of the
      cross-sectional area of the spinal canal and neural foramina in young
      asymptomatic volunteers. SUBJECTS AND METHODS: Twelve asymptomatic volunteers
      were examined in a 0.5-T open-configuration MR system. T2-weighted fast spin-echo
      sequences were obtained in upright neutral, upright flexed, upright extended, and
      supine extended positions. The cross-sectional area of the spinal canal and the
      thickness of the ligamentum flavum were measured on angled axial images at the L4
      L5 level. The anteroposterior diameter of the spinal canal and cross-sectional
      areas of the neural foramina were measured on sagittal images from L1 to S1.
      RESULTS: At disk level, the cross-sectional area of the spinal canal varied
      significantly between body positions, most notably between the upright flexed
      (mean, 268 mm2) and the upright extended (mean, 224 mm2) positions (p < .0001).
      The maximum thickness of the ligamenta flava increased in the extended positions
      (p < .0001). The cross-sectional area of the neural foramina underwent position
      dependent variations of as much as 44.4%. The smallest cross-sectional areas were
      found in the extended positions. CONCLUSION: In asymptomatic volunteers, MR
      imaging is able to show position-dependent changes in the cross-sectional areas
      of the spinal canal and the intervertebral foramina. The extended positions best
      reveal important findings.

PMID- 10587156
TI  - Gangliogliomas: characterization by registered positron emission tomography-MR
      images.
AB  - OBJECTIVE: The purpose of this study was to correlate 18F-fluorodeoxyglucose
      positron emission tomography (PET) and MR imaging features of cerebral
      gangliogliomas before and after PET-MR image registration. CONCLUSION: After
      registration of PET and MR images, all six gangliogliomas in our series were
      shown to have heterogeneous metabolic activity. Areas of hypermetabolic activity
      were seen in all lesions. In five of the six cases, PET-MR image registration
      provided information regarding tumor metabolism that was not available on
      nonregistered hard-copy examinations.

PMID- 10587157
TI  - Hyperintense basal ganglia on T1-weighted MR imaging.

PMID- 10587158
TI  - Neuroimaging in posttransplantation lymphoproliferative disorder.

PMID- 10587159
TI  - Doppler sonographic parameters for detection of carotid stenosis: is there an
      optimum method for their selection?
AB  - OBJECTIVE: A wide range of Doppler threshold values for carotid stenosis is found
      in the literature. We undertook this study to compare methods of derivation and
      to determine if an optimum strategy of threshold selection exists for a high-risk
      population. MATERIALS AND METHODS: From the sonograms of all patent internal
      carotid arteries, peak systolic velocity in the internal carotid artery
      (ICA(PSV)) and the ratio of peak systolic velocity in the internal carotid artery
      to that of the common carotid artery (ICA(PSV)/ CCA(PSV)) were compared with the
      percentage of angiographically determined stenosis. Receiver operating
      characteristic curves were generated for levels of stenosis > or =60% and > or
      =70%. Doppler thresholds were chosen on the basis of maximum accuracy and on the
      basis of > or =90% sensitivity and specificity. Patients were then segregated
      into symptomatic and asymptomatic cohorts, and the above process was repeated. An
      effectiveness analysis was also conducted using various Doppler thresholds.
      Thresholds derived using these three methods were compared and optimal values
      chosen. RESULTS. Of 333 carotid arteries that fit inclusion criteria, 132 were
      found in asymptomatic patients and 201 in symptomatic patients. Maximum accuracy,
      > or =90% sensitivity and specificity, and effectiveness analysis each produced
      different ranges of thresholds. We chose final thresholds that maintained patient
      outcome profiles. For asymptomatic patients at the > or =60% stenosis level,
      thresholds were ICA(PSV) = 200 cm/sec and ICA(PSV)/CCA(PSV) = 3.0. For
      symptomatic patients with stenosis > or =70%, thresholds were ICA(PSV) = 175
      cm/sec and ICA(PSV)/CCA(PSV) = 2.5. CONCLUSION: Considerable latitude exists in
      the choice of carotid Doppler thresholds. We propose a rational strategy for
      threshold selection based on a combination of three commonly used methods. Our
      observations indicate that it appears advisable to consider symptomatic and
      asymptomatic patients separately and to apply appropriately derived thresholds.

PMID- 10587160
TI  - Migration of a foreign body from the pharynx to the soft tissues of the neck:
      delayed presentation with Horner's syndrome.

PMID- 10587161
TI  - Memorial. Harry William Fischer, 1921-1998.

PMID- 10587162
TI  - What role, if any, does peripheral (forearm) densitometry play in the evaluation
      of osteoporosis?

PMID- 10587163
TI  - With proper imaging technique, is it still necessary to obtain images of the
      liver before administering contrast material in patients with known tumors who
      can have hypervascular liver metastases?

PMID- 10587164
TI  - Are there any indications for routine breast cancer screening of asymptomatic
      women who are less than 40 years old?

PMID- 10587165
TI  - Osteosarcoma of the abdominal wall with lung metastases.

PMID- 10587166
TI  - Origin of syphilis.

PMID- 10587167
TI  - MR imaging of perianal fistulas using body and endoanal coils.

PMID- 10587168
TI  - Occult fractures.

PMID- 10587169
TI  - Cardiac arrest caused by IV gadopentetate dimeglumine.

PMID- 10587170
TI  - Hepatic iron overload: quantification with MR imaging at 1.5 T.

PMID- 10587171
TI  - Interpretation of radiographs and sonograms by nonradiologists.

PMID- 10587172
TI  - Mycobacterium genavense enteritis in a patient with AIDS: radiologic features.

PMID- 10587173
TI  - Contained hematoma (pseudoaneurysm) of the inferior vena cava associated with
      blunt abdominal trauma.

PMID- 10587174
TI  - MR imaging of an extrauterine lipoleiomyoma.

PMID- 10587175
TI  - Lung herniation occurring after video-assisted thoracic surgery.

PMID- 10587176
TI  - Pedunculated hepatic adenoma: sonographic and MR imaging features.

PMID- 10587177
TI  - Characteristic radiologic findings for cavernous hemangioma of the uterus.

PMID- 10587178
TI  - Imaging features of liposarcoma of the pectoral muscle.

PMID- 10587180
TI  - Review of current literature

PMID- 10587179
TI  - Desmoid tumor of the chest wall.

PMID- 10587181
TI  - Infected aortic aneurysm.

PMID- 10587182
TI  - An aggressive resectional approach to cystic neoplasms of the pancreas.
AB  - BACKGROUND: Prognosis is good after curative resection for serous and mucinous
      cystic neoplasms of the pancreas. There has been a recent trend to resect all
      cystic neoplasms, without attempts to preoperatively determine the exact
      histologic subtype. Our purpose is to report on the results of such an aggressive
      surgical approach to all cystic neoplasms of the pancreas. METHODS: This is a
      retrospective cohort analysis of 25 patients with cystic neoplasms of the
      pancreas treated between July 1991 and July 1998. Data include patient
      demographics, presenting symptom, operative procedure, pathologic diagnosis,
      periop morbidity and mortality, survival, and symptomatic follow-up data.
      RESULTS: Twenty-one patients were women, with a mean age of 60 for the entire
      cohort. Mean follow-up was 24 months (range 6 months to 4.3 years) with complete
      follow-up possible in 92%. Twenty-three patients had curative resections and 2
      had palliative resections. One patient with an uncinate mass had a partial
      pancreatectomy; 4 patients underwent distal pancreatectomy and 9 had distal
      pancreatectomy with splenectomy; 11 patients required a pancreatoduodenectomy,
      and of these, 4 had tumors involving the portal vein, necessitating a portal vein
      resection. Pathologic analysis revealed 12 serous cystadenomas, 4 mucinous
      cystadenomas, 3 mucinous cystadenocarcinomas, 5 intraductal papillary cystic
      neoplasms, and 1 serous cystadenocarcinoma. The overall perioperative
      complication rate was 40% with 5 major and 5 minor complications. In the 11
      pancreatoduodenectomy patients alone, there were 1 major and 4 minor
      complications. There were no pancreatic fistulas or portal vein thromboses and no
      operative mortalities. Two patients, both with mucinous cystadenocarcinomas, died
      of their disease at 6 and 16 months postoperatively. All 11 pancreatoduodenectomy
      patients have only mild pancreatic insufficiency relieved by daily enzyme
      replacement. CONCLUSIONS: The good outcomes in this study support an aggressive
      surgical approach to all patients diagnosed with a cystic neoplasm of the
      pancreas, if medically fit to tolerate surgery. This approach is justified for
      the following reasons: (1) preoperative differentiation of a benign versus
      malignant tumor is unreliable and routine testing for this purpose is of
      questionable utility; (2) potential adverse consequences of nonresectional
      therapy are significant; (3) perioperative morbidity and mortality of pancreatic
      surgery is low; and (4) prognosis with curative resection is good.

PMID- 10587183
TI  - Repeat liver resection for recurrent colorectal liver metastases.
AB  - BACKGROUND: This study aimed to delineate the role of surgery for recurrent
      colorectal cancer in the liver and to identify prognosticators for better patient
      selection and outcome. METHODS: Data from 90 repeat hepatectomies (second = 75;
      third = 12; fourth = 3) for recurrent colorectal cancer were collected. RESULTS:
      After the second hepatectomy, the 3-and 5-year survival rates were 48% and 31%,
      respectively. Twenty-seven percent (20 of 75) of patients are alive without
      recurrence after a median follow-up of 27 months, and 9 survived more than 5
      years. Four or more tumors, positive regional lymph node metastases, concomitant
      extrahepatic disease, and residual tumor were independent poor prognostic factors
      after the second hepatectomy. CONCLUSIONS: Repeat hepatectomy should be applied
      for recurrent colorectal cancer, when curative removal of the tumor is possible,
      although the benefit from treatment was limited in a patient with regional lymph
      node metastases, 4 or more metastases, or extrahepatic disease.

PMID- 10587184
TI  - Utility of 18F-FDG positron emission tomography scanning on selection of patients
      for resection of hepatic colorectal metastases.
AB  - BACKGROUND: Hepatectomy represents a standard and potentially curative therapy
      for hepatic colorectal metastases. However, up to two thirds of patients explored
      for resection are found to have unsuspected disease, which precludes resection.
      METHODS: In order to determine if 18F-FDG positron emission tomography (PET)
      scanning may prevent unnecessary surgery, a group of 40 patients being considered
      for hepatic resection but at high risk for unresectable disease by clinical
      criteria were subjected to whole body 18F-FDG-PET scanning. Effect on clinical
      outcome was evaluated. In addition, PET findings in the 25 patients who underwent
      resection of hepatic metastases were directly compared with the resected specimen
      to determine the sensitivity of 18F-FDG PET scanning in the liver. RESULTS:
      Findings on 18F-FDG-PET scanning influenced the clinical management in 16
      patients (40%) and directly altered management in 9 cases (23%). Six patients
      were spared laparotomy, and 3 others had PET-directed surgery that found
      extrahepatic tumor and spared the patient unwarranted liver resection. In 3 cases
      PET missed peritoneal metastases found on laparotomy. In these cases all missed
      tumors were less than 1 cm in size. Out of 52 resected hepatic lesions, 18F-FDG
      PET detected 37. Within the liver, sensitivity of detection was also related to
      size. Only 25% of hepatic lesions smaller than 1 cm were detected by PET, while
      85% of lesions larger than 1 cm were detected. CONCLUSIONS: FDG-PET is best for
      detecting extrahepatic disease. There are few false positives, and surgeons
      should carefully evaluate and biopsy extrahepatic positive sites. This test
      should be used for patients at high risk for extrahepatic disease and should be
      evaluated prospectively for all patients under consideration for liver resection.

PMID- 10587185
TI  - Selective defects of T lymphocyte function in patients with lethal intraabdominal
      infection.
AB  - BACKGROUND: In recent models, compensatory antiinflammatory immune reactions
      triggered in response to systemic inflammation were considered important for the
      outcome of sepsis. The present study investigated T-cell functions in patients
      with postoperative sepsis due to intra-abdominal infection. METHODS: Peripheral T
      cells were purified from 32 sepsis patients and 41 healthy controls.
      Proliferation and production of interferon (IFN)-gamma, interleukin (IL)-2, IL-4,
      tumor necrosis factor (TNF), and IL-10 were stimulated by cross-linking of CD3
      and CD28. RESULTS: T-cell proliferation and production of IL-2 and TNF were
      severely suppressed in patients with lethal intraabdominal infection as compared
      with survivors and healthy controls. Sepsis survivors showed normal T-cell
      proliferation and IL-2 release, whereas secretion of TNF was reduced. However,
      TNF suppression in survivors was less severe than in nonsurviving patients.
      Defective T-cell functions were observed at the onset of sepsis and persisted
      throughout the entire observation period. T-cell production of IL-4 and IL-10 was
      not affected by postoperative intraabdominal infection. CONCLUSIONS: Defective T
      cell proliferation and secretion of IL-2 and TNF correlate with sepsis mortality,
      thus indicating an important role of T 'cells for the immune defense against
      postoperative infection. Immune defects were evident at the onset of sepsis,
      suggesting that immunosuppression may develop as a primary response to sepsis
      without preceding immune hyperactivity.

PMID- 10587186
TI  - Effect of persistently elevated intraabdominal pressure on healing of colonic
      anastomoses.
AB  - BACKGROUND: The adverse effects of elevated intraabdominal pressure (IAP) on
      abdominal organs are realized, but its influence on anastomotic healing has not
      been studied. The aim of this study was to evaluate the effect of elevated IAP on
      healing of colonic anastomoses. METHODS: Thirty rats, which all had right colonic
      anastomoses, were divided into five groups. Group 1 was the control group, and
      group 2 had fecal peritonitis. IAP was maintained between 4 to 6 mm Hg in group
      3, 8 to 12 mm Hg in group 4, and 14 to 18 mm Hg in group 5 until all rats were
      sacrificed on day 4. Bursting pressures and tissue hydroxyproline concentrations
      of anastomoses were then analyzed and compared. RESULTS: Mean +/- SEM of bursting
      pressures were 143+/-2.9 mm Hg in group 1, 72+/-14.4 mm Hg in group 2, 77.3+/-7.9
      mm Hg in group 3, 57.5+/-11.2 mm Hg in group 4, and 40.1+/-9.6 mm Hg in group 5
      (P<0.0001, one-way analysis of variance [ANOVA]). Mean +/- SEM of tissue
      hydroxyproline concentrations were 5.3+/-0.3 microg/mg in group 1, 4.7+/-0.5
      microg/mg in group 2, 4.6+/-0.6 microg/mg in group 3, 3.6+/-0.5 microg/mg in
      group 4, and 2.4+/-0.2 microg/mg in group 5 (P = 0.0026, one-way ANOVA). The
      bursting pressure and hydroxyproline concentrations had good correlation
      (P<0.001, r = 0.76). CONCLUSIONS: Elevated IAP delays healing of colonic
      anastomoses and 4 to 6 mm Hg IAP delays healing as much as fecal peritonitis.
      More elevated IAP delays healing more than fecal peritonitis. These events may be
      clinically important and may result from local-systemic effects of IAP.

PMID- 10587187
TI  - Minimally invasive, nonlaparoscopic, preperitoneal, and sutureless, inguinal
      herniorrhaphy.
AB  - BACKGROUND: Recent efforts at development of an ideal method for herniorrhaphy
      have resulted in a number of tremendous advances. The keen interest in hernia
      surgery and newer methods of repair, however, suggests that most surgeons are not
      fully satisfied with the methods currently available. METHODS: This repair
      involves a preperitoneal approach accomplished under regional or local
      anesthesia, with limited instrumentation and expense. It is performed in both a
      tension-free and sutureless fashion through a very small incision. It is
      effective in the treatment of primary and recurrent direct and indirect hernias
      as well as femoral hernias using the same approach in each case. RESULTS: With
      808 hernia repairs performed over a 54-month period of time there have been only
      five recurrences identified. There were only two wound infections. No specific
      restrictions with regard to activity were placed on these patients after surgery.
      In almost all cases the patients were able to return to regular activities,
      including work, within a few days after surgery. CONCLUSIONS: The results with
      this procedure suggest that it may be a more effective method of hernia repair
      when cost, ease of performance, and rapid recovery are important considerations.

PMID- 10587188
TI  - The impact of patient delay and physician delay on the outcome of laparoscopic
      cholecystectomy for acute cholecystitis.
AB  - BACKGROUND: Laparoscopic cholecystectomy is now used in the management of acute
      cholecystitis. Under these circumstances unfavorable conditions may result in
      conversion and complications. Information about these conditions may help in
      planning the laparoscopic approach or in proceeding directly to open
      cholecystectomy. This study was initiated to evaluate perioperative factors
      associated with conversion and complications of laparoscopic cholecystectomy in
      acute cholecystitis. Special attention was paid to the duration of complaints
      until surgery, to the delay on the part of the patient, and to the delay on the
      part of the physician. METHODS: Between January 1994 and December 1997, we
      attempted to perform laparoscopic cholecystectomy on 348 patients with acute
      cholecystitis. All perioperative data were collected on standardized forms.
      RESULTS: There were 182 cases (52%) of acute uncomplicated cholecystitis, 90
      (26%) of gangrenous cholecystitis, 33 of hydrops (9.5%), and 43 of empyema of the
      gallbladder (12.5%). Seventy six patients (22%) needed conversion to open
      cholecystectomy and complications occurred in 57 cases. Advanced cholecystitis
      was associated with significant patient delay (P = 0.01), and it had a
      significantly higher conversion rate (39%) compared with early cholecystitis
      (14.5%); (P <0.00001). Conversion rates were also associated with male gender (P
      = 0.0017), a history of biliary disease (P = 0.0085), and a patient delay of >48
      hours (P = 0.028). The total and infectious complication rates were associated
      with an age older than 60 years (P = 0.023 and 0.007, respectively) and male
      gender (P = 0.026 and 0.014, respectively). CONCLUSIONS: In acute cholecystitis,
      patient delay is associated with a high conversion rate. Early timing of
      laparoscopic cholecystectomy tends to reduce the conversion rate, as well as the
      total and the infectious complication rates. Male gender, a history of biliary
      disease, and advanced cholecystitis are associated with conversion. Male and
      older patients are associated with a high total and infectious complication
      rates.

PMID- 10587189
TI  - Laparoscopic direct supragastric left adrenalectomy.
AB  - BACKGROUND: In this paper a novel laparoscopic approach to the left adrenal gland
      by the transabdominal anterior route is presented. This approach avoids an
      extensive viscera dissection to gain access to the left adrenal gland. METHODS:
      The first step of the procedure is the division of the gastrophrenic ligament and
      the section of 1 or 2 short gastric vessels in order to mobilize the gastric
      fundus. The gastric fundus is then pulled down, allowing a wide exposure of the
      left crus of the diaphragm, the perirenal fat, and the superior edge of the
      pancreatic body. The diaphragmatic-adrenal channel runs on the left crus, crosses
      the middle adrenal artery, and, usually, joins the left adrenal vein before its
      junction with the left renal vein. By pulling on the diaphragmatic vein, exposure
      of the adrenal vein is facilitated. The adrenal vein is then isolated and divided
      between clips. Using the monopolar electrocautery to control arteries and small
      veins, the mobilization of the gland is then completed. The adrenal gland is then
      placed in a plastic bag to prevent cell spillage and removed through an enlarged
      umbilical incision. RESULTS: During a 20-month period, 6 consecutive patients
      with left adrenal gland neoplasms have been operated on with the above mentioned
      original approach. The diameter of the adrenal mass ranged from 3 cm to 6 cm. No
      conversion to open surgery or complications have been registered. The mean
      operative time was 126 minutes. The mean length of hospitalization was 4.1 days
      (range 3 to 6). CONCLUSIONS: This approach offers a complete visualization of the
      left adrenal gland, avoiding mobilization of the spleen, pancreatic tail, and
      left flexure of the colon, and allows an early and easy control of the left
      adrenal vein so adrenalectomy can be safely performed.

PMID- 10587190
TI  - Edema volume, not timing, is the key to success in lymphedema treatment.
AB  - BACKGROUND: There are currently between 1 and 2 million breast cancer survivors
      in the United States. Is the advocated, early intervention the key to successful
      treatment, or are there other, more important factors? METHODS: Responses to
      combined decongestive therapy (CDT) for 69 women were analyzed with regard to
      duration of lymphedema, differences in arm circumference, percent differences in
      arm volumes, volume of edema, reduction of edema volumes, and duration of
      treatment. RESULTS: Two- and three-dimensional (2D and 3D) analyses showed little
      correlation between duration and volume of edema or between duration and response
      and treatment. However, they did show a correlation between initial volumes of
      fluid in the tissues and responses. Patients with initial volumes of 250 mL or
      less had a mean reduction of 78% with CDT, whereas those with initial volumes
      between 250 and 500 mL had a mean reduction of 56%. CONCLUSION: The key to
      predicting successful lymphedema treatment is the initial volume of edema in the
      tissues regardless of whether the intervention is early or late.

PMID- 10587191
TI  - Reconstruction of the pharynx and cervical esophagus using ileocolic free
      autograft.
AB  - BACKGROUND: Advanced stage hypopharyngeal cancer is commonly treated by surgery
      and radiotherapy. This report presents a technique using ileocolic free autograft
      as a single-stage procedure for voice and swallowing rehabilitation after
      pharyngolaryngoesophagectomy. METHODS: Digestive tract restoration is obtained by
      using the cecum and ascending colon, while the last ileal loop, protected by the
      ileocecal valve for food and liquid inhalation, is anastomized to the cervical
      trachea. After abdominal harvesting, the ileocolic complex is transected,
      transposed, and then revascularized in the cervical field. RESULTS: Six patients
      underwent this operation successfully with recovery of swallowing function and
      vocal performance within a short period of time, varying from 18 to 38 days.
      CONCLUSION: On the basis of achieved results, the ileocolic free autograft can be
      considered a good option for pharyngoesophageal reconstruction, offering as it
      does an immediate restoration of swallowing and voice function.

PMID- 10587192
TI  - Irradiation-induced extracranial carotid stenosis in patients with head and neck
      malignancies.
AB  - BACKGROUND: Carotid stenosis is a recognized complication of external irradiation
      to the head and neck for malignancy. This study aim to investigate the pattern
      and prevalence of radiation induced carotid disease, and to identify risk factors
      associated with significant stenosis. METHODS: In a comparative cross-sectional
      study, carotid arteries color flow duplex scan was performed on 240 patients who
      had received external irradiation to the head and neck area, with a mean interval
      of 72 months from radiotherapy. They consisted of 181 men and 59 women, with a
      mean age of 59 years. Fifteen patients had a history of cerebrovascular symptoms.
      RESULTS: Internal carotid artery (ICA) stenosis of 70% or greater was detected in
      29 arteries in 24 patients. Common carotid artery (CCA) disease of > or =70% was
      present in 13 arteries in 12 patients. Overall 28 patients had significant ICA/
      CCA disease (11.7%). Patients with nasopharyngeal and laryngeal carcinoma had
      more cerebrovascular symptoms, and more frequent CCA stenosis. Significant
      ICA/CCA stenosis was associated with age, smoking, coronary heart disease,
      stroke, no head and neck surgery, time interval from radiotherapy, and the site
      of primary tumor. On logistic regression analysis age (>60 years),
      cerebrovascular symptoms, interval from irradiation (>5 years), and nasopharynx
      and larynx cancer were found to be independent significant (P<0.05) predictors of
      70% or greater ICA/CCA stenosis. CONCLUSIONS: Patients who had received
      radiotherapy to the head and neck have a high risk of developing significant
      carotid stenosis. Routine duplex ultrasound screening in these patients is
      indicated.

PMID- 10587193
TI  - The effect of skin transplantation on tumor growth in mice.
AB  - BACKGROUND: Skin allograft is an immunostimulant. Skin allograft activates
      effector arms of the immune system including the cytotoxic T lymphocytes,
      activated macrophages, and natural killer cells. These cells may be involved in
      the destruction of tumor cells. METHODS: Balb/c mice were divided into the study
      (n = 10) and control (n = 10) groups. Alloskin grafts 1 cm in diameter from the
      backs of Swiss albino mice were placed on the backs of balb/c mice (study group).
      The same size autoskin grafts from the backs of other balb/c mice were used for
      the control group. Fourteen days after grafting, we inoculated 1,000 Ehrlich
      ascites tumor cells intraperitoneally into both groups. Two days after tumor
      inoculation, we used secondary allografts and autografts (which were about 2 to 3
      mm in diameter) for the same groups. We followed up graft survival and animal
      survival in both groups. RESULTS: All 10 of the autografted mice died between the
      18th and 25th days owing to malignancy. In the allografted group, 2 mice died (1
      on day 17 and the other on day 23). Allograft rejection had not occurred in these
      2 mice at the time of their death. The other 8 mice in the same group rejected
      allograft, on average within 9 days (9+/-3, median 8). These 8 mice were alive
      and without apparent health problems during the 4 months of follow-up.
      CONCLUSION: Allo-skin graft rejection may help rejection of tumor cells and may
      be of use in immunotherapy of cancer.

PMID- 10587194
TI  - Effects of a parathyroidectomy on the immune system and nutritional condition in
      chronic dialysis patients with secondary hyperparathyroidism.
AB  - BACKGROUND: Parathyroid hormone (PTH) has an adverse effect on the immune system
      and may cause immunologic disorders in patients with chronic renal failure. The
      in vivo effects of a parathyroidectomy on the immunologic parameters was
      examined. METHODS: Thirty-four patients under dialysis therapy received a
      parathyroidectomy (PTx) for secondary hyperparathyroidism (HPT). They were
      prospectively studied regarding serum immunoglobulins, complements, CD markers,
      and serum soluble IL-2 receptor (sIL-2R) until 12 months after PTx. RESULTS: The
      serum levels of IgG, IgA and IgM showed significant increase until 12 months
      after PTx (P<0.001, respectively). C3, C4, and CH50 also indicated significant
      increase at 12 months after PTx. In cellular immunity, only serum sIL-2R showed
      significant increase 2 weeks after PTx (P = 0.028). The hematocrit and serum
      albumin also improved significantly at 12 months. CONCLUSIONS: PTx showed
      beneficial effects on humoral immunological markers. The effects are probably due
      to the remarkable PTH reduction and partly improved nutritional state after PTx.

PMID- 10587195
TI  - Endoanal advancement flap repair for complex anorectal fistulas.
AB  - BACKGROUND: Most anorectal fistulas may be safely and reliably treated by
      fistulotomy. However, certain complex fistulas (e.g., rectovaginal fistulas, high
      transsphincteric tracts, Crohn's disease) are not well suited to this technique.
      Few satisfactory alternatives exist. The aim of this study was to assess the
      utility of endoanal advancement flap repair for these difficult fistulas.
      METHODS: Thirty-three consecutive patients underwent endoanal advancement flap
      repair of a complex anorectal fistula. Patients were followed up via a
      prospective database. Demographic information, the presence of previous fistula
      surgery, and surgical complications were noted. Patients were closely followed up
      until healing of the fistula or treatment failure was noted. RESULTS: The overall
      initial healing rate was 81% (27 of 33). However, 3 patients with perianal
      Crohn's disease ultimately developed a recurrent fistula. There were no major
      complications and two minor urinary complications. No patient required hospital
      readmission, and there were no new problems with fecal incontinence. No patient
      required a colostomy. CONCLUSION: Endoanal advancement flap repair is effective
      in a variety of difficult, complicated anorectal fistulas. Since the morbidity is
      quite low, it should be attempted prior to fecal diversion, when possible, in
      these settings.

PMID- 10587196
TI  - A new technical aspect of ultrasound-guided liver surgery.
AB  - Nowadays, resective hepatic surgery should be considered an echo-guided surgical
      procedure to guarantee that effective anatomical resection is accomplished. We
      describe a simple and original technique guided by intraoperative ultrasonography
      (IOUS), called the hooking technique, that enables the ligation sites of the
      intrahepatic vessels during systematic segmentectomy to be chosen precisely.
      Together with other IOUS-guided techniques described previously, the hooking
      technique provides a further guarantee for the successful execution of anatomical
      and radical liver resection.

PMID- 10587197
TI  - Intraductal papillary mucinous tumors of the pancreas.
AB  - BACKGROUND: An increasing number of intraductal papillary mucinous tumors of the
      pancreas have been reported in recent years. The indolent character and favorable
      prognosis of this neoplasm have been described. METHODS: Intraductal papillary
      mucinous tumors were classified into main duct type (n = 8) and branch type (n =
      28) according to the dominant location of the tumor. This single-institute study
      examined the clinicopathological features and outcome after surgical resection in
      patients with intraductal papillary mucinous tumors. RESULTS: The gender, age,
      tumor size, and prognosis were quite similar for the main duct type and branch
      type groups. Branch type tumors were more frequently located in the head of the
      pancreas than were main duct type tumors. Histological examination revealed that
      88% of main duct type tumors were adenocarcinomas; however, only 46% of branch
      type tumors were adenocarcinomas. Five-year survival rates for the patients with
      all main duct type tumors (n = 8), main duct type adenocarcinoma (n = 7), all
      branch type tumors (n = 28), and branch duct adenocarcinoma (n = 13) were 100%,
      100%, 90.6%, and 90.9%, respectively. CONCLUSIONS: Intraductal papillary mucinous
      tumors had a favorable prognosis after surgical treatment. A curative
      pancreatectomy should be indicated for this localized malignant tumor.

PMID- 10587198
TI  - Comparison of the first 100 coronary bypass patients of a supervised resident
      with his first 100 as an attending surgeon at the same institution.
AB  - BACKGROUND: Although coronary artery bypass grafting (CABG) has been analyzed
      intensely for 30 years, little information is available on the characteristics
      and outcome of CABG patients operated upon by resident trainees or first-year
      attending surgeons in a public teaching hospital. METHODS: The first 100 CABG
      patients operated upon by a supervised resident were compared with the first 100
      CABG patients under the care of the same person as an attending surgeon at the
      same institution. In the first group, the resident was directly supervised by one
      of three different staff surgeons. In the second group, the same person, as an
      attending, performed 60 operations and directly supervised one of two trainees in
      40. RESULTS: Comparing the resident group versus the attending group, mean age
      (62 versus 61 years), percentage of females (37 and 37), tobacco use (74 versus
      77), obesity (43 versus 55), insulin-dependent diabetes mellitus (20 versus 17),
      ejection fraction < or =0.5 (29 versus 35), and previous myocardial infarction
      (56 versus 54) were similar. Three or more coronary anastomoses were performed in
      83 patients in the first group and in 74 in the second group. Early mortality (in
      hospital and/or < or =30 days) occurred in 2 patients in the resident group and 3
      in the attending group; each patient had a low ejection fraction and severe
      narrowing of all three major epicardial coronary arteries. Morbidity in the two
      groups was similar. CONCLUSION: If properly supervised by experienced staff
      surgeons, a resident trainee can achieve satisfactory results in CABG in a
      heterogeneous group of patients. Furthermore, the transition to attending surgeon
      can be achieved with a good outcome for the patients.

PMID- 10587199
TI  - Assessing medical students' competence in obtaining informed consent.
AB  - BACKGROUND: Medical schools increasingly place emphasis on preparing students to
      perform routine, ethically important clinical activities with sensitivity and
      acumen. A method for evaluating students' skills in obtaining informed consent
      that was created at our institution is described. METHODS: Formal assessment of
      medical students' professional attitudes, values, and ethics skills occurs in the
      context of three required and developmentally attuned comprehensive examinations.
      A videotaped station tested senior medical students' ability to obtain informed
      consent from a standardized patient who expresses concern about undergoing
      cardiac catheterization. Two checklists were completed by the patient. Videotapes
      were reviewed by a faculty member, and students' reactions to the assessment
      experience were documented. RESULTS: Seventy-one senior students participated,
      and all performed well. Mean scores of 6.3 out of 7 (range 5 to 7, SD = 0.5) on
      the informed consent checklist and 8.7 out of 9 (range 6 to 9, SD = 0.5) on the
      communication skills checklist were obtained. Students endorsed the importance of
      the skills tested. CONCLUSIONS: This method of examining medical students'
      abilities to obtain informed consent has several positive features and holds
      promise as an ethics competence assessment tool.

PMID- 10587200
TI  - Superior survival of young women with malignant melanoma.

PMID- 10587201
TI  - Medical physicists should seek patent protection for new ideas before publishing
      articles about them.

PMID- 10587202
TI  - Performance evaluation of a multi-slice CT system.
AB  - Our purpose in this study was to characterize the performance of a recently
      introduced multi-slice CT scanner (LightSpeed QX/i, Version 1.0, General Electric
      Medical Systems) in comparison to a single-slice scanner from the same
      manufacturer (HiSpeed CT/i, Version 4.0). To facilitate this comparison, a
      refined definition of pitch is introduced which accommodates multi-slice CT
      systems, yet maintains the existing relationships between pitch, patient dose,
      and image quality. The following performance parameters were assessed: radiation
      and slice sensitivity profiles, low-contrast and limiting spatial resolution,
      image uniformity and noise, CT number and geometric accuracy, and dose. The multi
      slice system was tested in axial (1, 2, or 4 images per gantry rotation) and HQ
      (Pitch = 0.75) and HS (Pitch = 1.5) helical modes. Axial and helical acquisition
      speed and limiting spatial resolution (0.8-s exposure) were improved on the multi
      slice system. Slice sensitivity profiles, image noise, CT number accuracy and
      uniformity, and low-contrast resolution were similar. In some HS-helical modes,
      helical artifacts and geometric distortion were more pronounced with a different
      appearance. Radiation slice profiles and doses were larger on the multi-slice
      system at all scan widths. For a typical abdomen and pelvis exam, the central and
      surface body doses for 5-mm helical scans were higher on the multi-slice system
      by approximately 50%. The increase in surface CTDI values (with respect to the
      single-slice system) was greatest for the 4 x 1.25-mm detector configuration
      (190% for head, 240% for body) and least for the 4 x 5-mm configuration (53% for
      head, 76% for body). Preliminary testing of version 1.1 software demonstrated
      reduced doses on the multi-slice scanner, where the increase in body surface CTDI
      values (with respect to the single-slice system) was 105% for the 4 x 1.25-mm
      detector configuration and 10% for the 4 x 5-mm configuration. In summary, the
      axial and HQ-helical modes of the multi-slice system provided excellent image
      quality and a substantial reduction in exam time and tube loading, although at
      varying degrees of increased dose relative to the single-slice scanner.

PMID- 10587203
TI  - A simple theorem relating noise and patient dose in computed tomography.
AB  - Presented is a simple model describing the dependence of image noise in computed
      tomography on the x-ray beam profile. The model is used to derive the x-ray
      profile which minimizes total image noise at constant integral patient dose. The
      profile may be produced with a bow-tie-type beam shaping filter. Results of the
      analysis are validated using a computer simulation of computed tomography (CT)
      acquisition and reconstruction.

PMID- 10587204
TI  - Dose reduction in CT by anatomically adapted tube current modulation. I.
      Simulation studies.
AB  - Tube current modulation governed by x-ray attenuation during CT (computed
      tomography) acquisition can lead to noise reduction which in turn can be used to
      achieve patient dose reduction without loss in image quality. The potential of
      this technique was investigated in simulation studies calculating both noise
      amplitude levels and noise distribution in CT images. The dependence of noise on
      the inodulation function, amplitude of modulation, shape and size of the object,
      and possible phase shift between attenuation and modulation function were
      examined. Both sinusoidal and attenuation-based control functions were used to
      modulate tube current. Noise reduction was calculated for both ideal systems and
      for real systems with limited modulation amplitude. Dose reductions up to 50% can
      be achieved depending on the phantom geometry and tube current modulation
      function. Attenuation-based tube current modulation yields substantially higher
      reduction than fixed-shape modulation functions. Optimal results are obtained
      when the current is modulated as a function of the square root of attenuation. A
      modulation amplitude of at least 90% should be available to exploit the potential
      of these techniques.

PMID- 10587205
TI  - Dose reduction in CT by anatomically adapted tube current modulation. II. Phantom
      measurements.
AB  - Theoretical considerations and simulation studies have led to the expectation
      that patient dose in CT (computed tomography) can be reduced significantly
      without a concomitant loss in image quality if tube current is modulated
      according to rotation angle-dependent x-ray attenuation. In this study, the
      simulation results presented in Part I were validated with phantoms. We used one
      cylindrical, two oval, and one elliptical phantom, available both as mathematical
      descriptions and in physical form, to mimic different parts of the human anatomy.
      Prototype hardware was available to control tube current on a commercial clinical
      CT scanner. The potential for dose reduction was evaluated for sinusoidal and
      attenuation-based current modulation for variable modulation amplitudes.
      Agreement between simulations and measured results was better than within 10%.
      Dose reduction values of 8%-56% were found depending on the phantom geometry and
      tube current modulation function. Attenuation-based tube current modulation
      consistently yielded higher reduction than fixed-shape sinusoidal modulation
      functions. For the shoulder phantom and 70% modulation amplitude, 44.6% dose
      reduction was measured as compared to 34.1% for sinusoidal modulation. A maximum
      of 56% was measured for the shoulder phantom including inserts. Specifying mAs
      reduction as an estimate for dose reduction proved to be a valid and conservative
      estimate; measured dose is reduced more strongly than the total mAs product both
      centrally and on average. First patient studies confirm the results of simulation
      and phantom studies. We conclude that attenuation-based online tube current
      control has great potential for reducing patient dose in CT and that it should be
      made generally available for clinical use.

PMID- 10587206
TI  - On the statistical nature of mammograms.
AB  - We show that digitized mammograms can be considered as evolving from a simple
      process. A given image results from passing a random input field through a linear
      filtering operation, where the filter transfer function has a self-similar
      characteristic. By estimating the functional form of the filter and solving the
      corresponding filtering equation, the analysis shows that the input field gray
      value distribution and spectral content can be approximated with parametric
      methods. The work gives a simple explanation for the variegated image appearance
      and multimodal character of the gray value distribution common to mammograms.
      Using the image analysis as a guide, a simulated mammogram is generated that has
      many statistical characteristics of real mammograms. Additional benefits may
      follow from understanding the functional form of the filter in conjunction with
      the input field characteristics that include the approximate parametric
      description of mammograms, showing the distinction between homogeneously dense
      and nondense images, and the development of mass analysis methods.

PMID- 10587207
TI  - Effect of display luminance on the feature detection rates of masses in
      mammograms.
AB  - Our purpose in this study was to determine the importance of the luminance range
      of the display system for the detection of simulated masses in mammograms.
      Simulated masses were embedded in selected portions (512 x 512 pixels) of
      mammograms digitized at 50 micro pixels, 12 bits deep. The masses were embedded
      in one of four quadrants in the image. An observer experiment was conducted in
      which the observer's task was to determine in which quadrant the mass is located.
      The key variables involved in each trial included the position of the mass, the
      contrast level of the mass, and the luminance of the display. The contrast of the
      mass with respect to the background was fixed to one of four selected contrast
      levels. The digital images were printed to film, and displayed on a mammography
      lightbox. The display luminance was controlled by placing neutral density films
      between the laser printed films of mammographic backgrounds and the lightbox. The
      resulting maximum luminances examined in this study ranged from 34 cd/m2 to 2056
      cd/m2. Twenty observers viewed 80 different images (20 observations at each of 4
      different mass contrast levels) under each of the 5 luminance conditions for a
      total of 800 independent observations per observer. An analysis of variance
      yielded no statistically significant correlation between the luminance range of
      the display and the feature detection rate of the simulated masses in mammograms.
      However, the performance of the lower luminance display systems (less than 300
      cd/m2), may be reduced due to the high levels of ambient light found in many
      reading environments.

PMID- 10587208
TI  - Analysis of the detective quantum efficiency of a developmental detector for
      digital mammography.
AB  - We are developing a modular detector for applications in full field digital
      mammography and for diagnostic breast imaging. The detector is based on a design
      that has been refined over the past decade for applications in x-ray
      crystallography [Kalata et al., Proc. SPIE 1345, 270-279 (1990); Phillips et al.
      ibid. 2009, 133-138 (1993), Phillips et al., Nucl. Instrum. Methods Phys. Rev. A
      334, 621-630 (1993)]. The full field mammographic detector, currently undergoing
      clinical evaluation, is formed from a 19 cm x 28 cm phosphor screen, read out by
      a 2 x 3 array of butted charge-coupled device (CCD) modules. Each 2k x 2k CCD is
      optically coupled to the phosphor via a fiber optic taper with dimensions of 9.4
      cm x 9.4cm at the phosphor. This paper describes the imaging performance of a two
      module prototype, built using a similar design. In this paper we use cascaded
      linear systems analysis to develop a model for calculating the spatial frequency
      dependent noise power spectrum (NPS) and detective quantum efficiency (DQE) of
      the detector using the measured modulation transfer function (MTF). We compare
      results of the calculation with the measured NPS and DQE of the prototype.
      Calculated and measured DQEs are compared over a range of clinically relevant x
      ray exposures and kVps. We find that for x-ray photon energies between 10 and 28
      keV, the detector gain ranges between 2.5 and 3.7 CCD electrons per incident x
      ray, or approximately 5-8 electrons per absorbed x ray. Using a Mo/Mo beam and
      acrylic phantom, over a detector entrance exposure range of approximately 10 to
      80 mR, the volume under the measured 2-d NPS of the prototype detector is
      proportional to the x-ray exposure, indicating quantum limited performance.
      Substantial agreement between the calculated and measured values was obtained for
      the frequency and exposure dependent NPS and DQE over a range of tube voltage
      from 25 to 30 kVp.

PMID- 10587209
TI  - Use of a slit camera for MTF measurements.
AB  - The slit camera was analyzed in order to establish its utility and limitations as
      an MTF measurement tool for characterizing radiographic imaging systems.
      Commercial slit cameras are attractive for MTF measurements because the beveled
      edges significantly reduce their alignment sensitivity as compared to the
      conventional parallel jaw slit. Radiation passing through the beveled edges
      increases the effective width of the slit camera so that a correction based on
      the nominal slit width would leave residual error in the MTF measurement.
      Experimental and Monte Carlo simulated MTF measurements were made on a slit
      camera (10 microm nominal slit width) in order to estimate its sensitivity in
      alignment, quantify the error in MTF due to transmission through the beveled
      jaws, and provide a correction factor. The alignment tolerances of the slit
      camera were found to be about 12 times larger than for the parallel jaw slit at
      small HVLs (approximately 1.3 mm Al) of the incident beam and 9 times larger at
      higher HVLs (approximately 7 mm Al). The magnitude of the residual error in MTF
      was dependent on the quality of the incident spectrum. For incident spectra with
      high kVp and HVL (> or = 120 kVp, > or =5 mm Al HVL), transmission through the
      beveled edges produced errors in MTF up to 15% at 5 cycles/mm and 30% at 10
      cycles/mm. By assuming a rectangular slit profile with an effective width based
      on the kVp, HVL, and filtration material of the incident beam, an MTF correction
      factor was determined. Application of this correction factor reduced the errors
      to less than 4% up to 10 cycles/mm. At low beam energies and spatial frequencies,
      the correction is less critical. Ease of alignment and greater availability make
      a commercial slit camera useful for MTF measurements. Accurate MTF measurements
      can be made if appropriate correction factors are applied.

PMID- 10587210
TI  - Computerized radiographic texture measures for characterizing bone strength: a
      simulated clinical setup using femoral neck specimens.
AB  - We are investigating computerized methods to ultimately characterize bone
      trabecular pattern from clinical skeletal radiographs. In this paper, we present
      a "phantom" for potential use in the development and evaluation of computerized
      methods for characterizing radiographic trabecular patterns and ultimately bone
      strength. Femoral neck specimens were excised during total hip arthroplasties
      from subjects exhibiting a range of diseases. To mimic the femoral neck in vivo,
      a "simulated clinical" setup was implemented in which specimens were exposed
      under conditions that yielded radiographs similar in appearance to standard
      pelvis radiographs. Fourier-based and fractal-based texture measures were used in
      the computer analysis; including RMS variation, first moment of the power
      spectrum, angular-dependent forms of these measures, and fractal dimension. The
      texture measures obtained from the "simulated clinical" specimen films correlated
      modestly with those from direct exposure "verification" films of the specimens
      (r= 0.59-0.69; p<0.0001). From our study, we conclude that the femoral neck
      specimen "phantoms" may be useful in the development and evaluation of
      computerized methods for analyzing bone trabecular patterns from skeletal
      radiographs. The use of a phantom that simulates the clinical radiographic
      examination allows for repeat exposures without the concern of excessive
      radiation exposure to a patient.

PMID- 10587211
TI  - Scatter and veiling glare estimation based on sampled primary intensity.
AB  - Scatter and veiling glare are predominant sources of error in videodensitometric
      iodine quantification. Standard beam stop techniques such as lead strips or an
      array of lead discs, placed before the patients, have previously been used to
      measure scatter and veiling glare in digital radiographic images. However, these
      techniques significantly increase patient x-ray exposure. In order to overcome
      this limitation, a scatter measurement technique based on sampled primary
      intensity has been investigated. This technique uses an array of apertures in a
      lead sheet to sample the primary x-ray intensity. The scatter-glare intensity in
      these locations is calculated by subtracting the sampled primary intensity from
      an open field image which contains both primary and scatter-glare. The calculated
      scatter-glare values can be interpolated or combined with digital filtration to
      estimate the scatter-glare intensity on a pixel by pixel basis. The technique was
      evaluated using a Lucite step phantom and an anthropomorphic chest phantom. The
      average rms percentage errors of scatter and veiling glare estimation using bi
      cubic interpolation and digital filtration techniques were 8.02% and 7.53%,
      respectively. The average rms percentage errors of primary intensity estimation
      using bi-cubic interpolation and digital filtration techniques were 10.01% and
      8.91%, respectively. The x-ray exposure-area product (EAP) from the aperture
      array was only 4.38% of the EAP from the open field. These results indicate that
      the scatter-glare intensity can be accurately estimated with minimal x-ray
      exposure using sampled primary intensity.

PMID- 10587212
TI  - Estimation of the depth-dependent component of the point spread function of
      SPECT.
AB  - The point spread function (PSF) of a gamma camera describes the photon count
      density distribution at the detector surface when a point source is imaged.
      Knowledge of the PSF is important for computer simulation and accurate image
      reconstruction of single photon emission computed tomography (SPECT) images. To
      reduce the number of measurements required for PSF characterization and the
      amount of computer memory to store PSF tables, and to enable generalization of
      the PSF to different collimator-to-source distances, the PSF may be modeled as
      the two-dimensional (2D) convolution of the depth-dependent component which is
      free of detector blurring (PSF(ideal)) and the distance-dependent detector
      response. Owing to limitations imposed by the radioactive strength of point
      sources, extended sources have to be used for measurements. Therefore, if
      PSF(ideal) is estimated from measured responses, corrections have to be made for
      both the detector blurring and for the extent of the source. In this paper, an
      approach based on maximum likelihood expectation-maximization (ML-EM) is used to
      estimate PSF(ideal). In addition, a practical measurement procedure which avoids
      problems associated with commonly used line-source measurements is proposed. To
      decrease noise and to prevent nonphysical solutions, shape constraints are
      applied during the estimation of PSF(ideal). The estimates are generalized to
      depths other than those which have been measured and are incorporated in a SPECT
      simulator. The method is validated for Tc-99m and T1-201 by means of measurements
      on physical phantoms. The corrected responses have the desired shapes and
      simulated responses closely resemble measured responses. The proposed methodology
      may, consequently, serve as a basis for accurate three-dimensional (3D) SPECT
      reconstruction.

PMID- 10587213
TI  - A mathematical model of motion of the heart for use in generating source and
      attenuation maps for simulating emission imaging.
AB  - This manuscript documents the alteration of the heart model of the three
      dimensional (3D) mathematical cardiac torso (MCAT) phantom to represent cardiac
      motion. The objective of the inclusion of motion was to develop a digital
      simulation of the heart such that the impact of cardiac motion on single-photon
      emission computed tomography (SPECT) imaging could be assessed and methods of
      quantitating cardiac function could be investigated. The motion of the gated 3D
      MCAT's (gMCAT) heart is modeled using 128 separate and evenly spaced time samples
      from a blood volume curve approximating an average heart cycle. Sets of adjacent
      time samples can be grouped together to represent a single time interval within
      the heart cycle. Maximum and minimum chamber volumes were selected to be similar
      to those of a normal healthy person while the total heart volume stayed constant
      during the cardiac cycle. Myocardial mass was conserved during the cardiac cycle
      and the bases of the ventricles were modeled as moving towards the static apex.
      The orientation of the 3D MCAT heart was changed during contraction to rotate
      back and forth around the long axis through the center of the left ventricle (LV)
      using the end systolic time interval as the time point at which to reverse
      direction. Simple respiratory motion was also introduced by changing the
      orientation of the long axis of the heart to represent its variation with
      respiration. Heart models for 24 such orientations spanning the range of motion
      during the respiratory cycle were averaged together for each time sample to
      represent the blurring of the heart during the acquisition of multiple cardiac
      cycles. Finally, an option to model apical thinning of the myocardium was
      included. As an illustration of the application of the gMCAT phantom, the gated
      heart model was evaluated by measuring myocardial wall thickening. A linear
      relationship was obtained between maximum myocardial counts and myocardial
      thickness, similar to published results. Similar results were obtained for full
      width at half maximum (FWHM) measurements. With the presence of apical thinning,
      an apparent increase in counts in the apical region compared to the other heart
      walls in the absence of attenuation compensation turns into an apparent decrease
      in counts with attenuation compensation. The apical decrease was more prominent
      in end systole (ES) than end diastole (ED) due to the change in the partial
      volume effect. These observations agree with clinical trends. It is concluded
      that the gMCAT phantom can be used to study the influence of various physical
      parameters on radionuclide perfusion imaging.

PMID- 10587214
TI  - Differential attenuation method for simultaneous estimation of activity and
      attenuation in multiemission single photon emission computed tomography.
AB  - A penalized weighted least squares reconstruction algorithm is described that
      simultaneously estimates activity and attenuation distributions from emission
      sinogram data alone. This estimation technique is based on differential
      attenuation information and is applicable to any single photon emission computed
      tomography imaging isotope with emissions at two or more distinct energies, after
      accurate compensation for Compton scatter. A rotation-based forward projector is
      used to efficiently model photon attenuation at multiple emission energies, as
      well as distance-dependent spatial resolution. The algorithm was tested using
      simulated scatter-free 201T1 projection data from a single-slice numerical
      cardiac phantom with and without cold myocardial defects. Poisson noise was added
      to the projection data to mimic clinically realistic count densities. The
      activity estimates resulting from the proposed method had fewer artifacts and
      were substantially more accurate than images reconstructed with filtered
      backprojection without compensation for attenuation. Several techniques were
      employed to reduce the time required for the iterative routine to converge and to
      reduce the sensitivity of the solution to noise in the projection data. These
      included: (1) a preconditioning image variable transformation; (2) a coarse-to
      fine grid initialization schedule; and (3) a convex hull image mask determined
      directly from the data. The combined effect of these techniques substantially
      reduced the compute time required for the reconstruction.

PMID- 10587215
TI  - An automated iterative algorithm for water and fat decomposition in three-point
      Dixon magnetic resonance imaging.
AB  - An iterative, outlier exclusion, second-order surface fitting algorithm has been
      developed to solve the well-known phase wraparound problem associated with in
      vivo applications of the three-point Dixon magnetic resonance imaging method. The
      technique was optimized for speed by reducing the problem to a pair of planar
      fits. The spatial misalignment between water and fat components due to the
      chemical shift was handled on a subpixel level by invoking the shift theorem of
      Fourier transformation. From the chemical shift corrected water and fat images,
      high quality recombined MR images were generated. The algorithm was validated in
      both phantom and patient studies. In vivo breast images and pelvic images are
      provided as a demonstration of the method.

PMID- 10587216
TI  - Estimation theory and model parameter selection for therapeutic treatment plan
      optimization.
AB  - Treatment optimization is usually formulated as an inverse problem, which starts
      with a prescribed dose distribution and obtains an optimized solution under the
      guidance of an objective function. The solution is a compromise between the
      conflicting requirements of the target and sensitive structures. In this paper,
      the treatment plan optimization is formulated as an estimation problem of a
      discrete and possibly nonconvex system. The concept of preference function is
      introduced. Instead of prescribing a dose to a structure (or a set of voxels),
      the approach prioritizes the doses with different preference levels and reduces
      the problem into selecting a solution with a suitable estimator. The preference
      function provides a foundation for statistical analysis of the system and allows
      us to apply various techniques developed in statistical analysis to plan
      optimization. It is shown that an optimization based on a quadratic objective
      function is a special case of the formalism. A general two-step method for using
      a computer to determine the values of the model parameters is proposed. The
      approach provides an efficient way to include prior knowledge into the
      optimization process. The method is illustrated using a simplified two-pixel
      system as well as two clinical cases. The generality of the approach, coupled
      with promising demonstrations, indicates that the method has broad implications
      for radiotherapy treatment plan optimization.

PMID- 10587217
TI  - Application of constrained optimization to radiotherapy planning.
AB  - Essential for the calculation of photon fluence distributions for intensity
      modulated radiotherapy (IMRT) is the use of a suitable objective function. The
      objective function should reflect the clinical aims of tumor control and low side
      effect probability. Individual radiobiological parameters for patient organs are
      not yet available with sufficient accuracy. Some of the major drawbacks of some
      current optimization methods include an inability to converge to a solution for
      arbitrary input parameters, and/or a need for intensive user input in order to
      guide the optimization. In this work, a constrained optimization method was
      implemented and tested. It is closely related to the demanded clinical aims,
      avoiding the drawbacks mentioned above. In a prototype treatment planning system
      for IMRT, tumor control was guaranteed by setting a lower boundary for target
      dose. The aim of low complication is fulfilled by minimizing the dose to organs
      at risk. If only one type of tissue is involved, there is no absolute need for
      radiobiological parameters. For different organs, threshold dose, relative
      seriality of the organs or an upper dose limit could be set. All parameters,
      however, were optional, and could be omitted. Dose-volume constraints were not
      used, avoiding the possibility of local minima in the objective function. The
      approach was benchmarked through the simulation of both a head and neck and a
      lung case. A cylinder phantom with precalculated dose distributions of individual
      pencil beams was used. The dose to regions at risk could be significantly reduced
      using at least seven ports of beam incidence. Increasing the number of ports
      beyond seven produced only minor further gain. The relative seriality of organs
      was modeled through the use of an added exponent to the dose. This approach
      however increased calculation time significantly. The alternative of setting an
      upper limit is much faster and allows direct control of the maximum dose.
      Constrained optimization guarantees high tumor control probability, it is
      computationally more efficient than adding penalty terms to the objective
      function, and the input parameters are dose limits known in clinical practice.

PMID- 10587218
TI  - The development of target-eye-view maps for selection of coplanar or noncoplanar
      beams in conformal radiotherapy treatment planning.
AB  - Three-dimensional conformal radiotherapy allows the use of tightly conformed,
      multiple coplanar or noncoplanar beams. However, visualizing the spatial
      relationships between the target volume and adjacent critical structures is not
      always obvious or intuitive. Tools such as beam's eye view (BEV) have aided in
      this process and been very useful. In this study, a target-eye-view (TEV) map is
      developed as a functional extension of BEVs. The TEV map for a critical structure
      is created by checking the BEVs for all gantries and table rotations. For each
      possible BEV, the amount of overlap between the planning target volume (PTV) and
      the organ at risk (OAR) is determined. This information is presented in a
      Mercator spherical map, where the color tone indicates the amount of overlap
      between the PTV and the OAR. A composite TEV map is then created by summing the
      TEV grading scores for all OARs. The composite map shows beam orientations with
      the most overlap being light and the least overlap being dark, thus simplifying
      the selection of appropriate beam angles. The accuracy of the TEV maps has been
      confirmed separately with corresponding BEVs generated by a three-dimensional
      treatment planning system.

PMID- 10587219
TI  - Dosimetric verification of intensity modulated beams produced with dynamic
      multileaf collimation using an electronic portal imaging device.
AB  - Dose distributions can often be significantly improved by modulating the two
      dimensional intensity profile of the individual x-ray beams. One technique for
      delivering intensity modulated beams is dynamic multileaf collimation (DMLC).
      However, DMLC is complex and requires extensive quality assurance. In this paper
      a new method is presented for a pretreatment dosimetric verification of these
      intensity modulated beams utilizing a charge-coupled device camera based
      fluoroscopic electronic portal imaging device (EPID). In the absence of the
      patient, EPID images are acquired for all beams produced with DMLC. These images
      are then converted into two-dimensional dose distributions and compared with the
      calculated dose distributions. The calculations are performed with a pencil beam
      algorithm as implemented in a commercially available treatment planning system
      using the same absolute beam fluence profiles as used for calculation of the
      patient dose distribution. The method allows an overall verification of (i) the
      leaf trajectory calculation (including the models to incorporate collimator
      scatter and leaf transmission), (ii) the correct transfer of the leaf sequencing
      file to the treatment machine, and (iii) the mechanical and dosimetrical
      performance of the treatment unit. The method was tested for intensity modulated
      10 and 25 MV photon beams; both model cases and real clinical cases were studied.
      Dose profiles measured with the EPID were also compared with ionization chamber
      measurements. In all cases both predictions and EPID measurements and EPID and
      ionization chamber measurements agreed within 2% (1 sigma). The study has
      demonstrated that the proposed method allows fast and accurate pretreatment
      verification of DMLC.

PMID- 10587220
TI  - Matching photon and electron fields with dynamic intensity modulation.
AB  - A technique was developed to reduce the size and magnitude of the hot and cold
      spots in the abutting regions of photon and electron fields. The photon and
      electron fields were set up such that the photon field extended approximately 2
      cm into the electron field in the abutting region. The region of the photon beam
      that overlapped the electron field was modulated using a multileaf collimator,
      effectively broadening the photon penumbra to make it complimentary to the
      electron penumbra. The computer calculations were verified using film
      measurements for abutting a 6 MV photon beam with a 9 MeV electron beam. A
      uniform dose was achieved at a prespecified depth of 2 cm, and dose uniformity
      was improved at the specified depth and beyond compared with unmodulated photon
      beams. A slight increase in dose inhomogeneity was seen at shallower depths. The
      overall areas of the hot and cold spots were significantly reduced. The technique
      also reduced the sensitivity of dose homogeneity to setup errors such that the
      magnitudes of the hot and cold spots were about half of those produced with
      unmodulated photon beam when an overlap or gap of 4 mm was introduced. The
      technique was applied to the treatment of a head and neck cancer and a lymphoma
      involving the right pleura with markedly reduced dose inhomogeneity in the
      abutting regions.

PMID- 10587221
TI  - A practical method for the calculation of multileaf collimator shaped fields
      output factors.
AB  - Output factors of multileaf-collimator (MLC) shaped radiation fields were
      measured for a commercial linear accelerator whose MLC leaves form parts of the
      upper collimator system. The approach of taking into account the reduced phantom
      scatter due to the MLC shaping on the output factor has previously been shown to
      be inadequate for this type of machine because of the effect of the MLC leaves on
      the collimator factor [Palta et al., Med. Phys. 23, 1219-1224(1996)]. In this
      article, we present two forms of the collimator factor that give satisfactory
      agreement with measured values of the output factors of MLC-shaped fields. The
      present method should be directly applicable to other linacs of similar MLC
      configuration. For clinical treatment planning, we believe the method is
      practical and accurate enough to be satisfactory. The equation for calculating
      the output factor requires only peak scatter and output factors of the machine.
      These are normally measured during machine commissioning.

PMID- 10587222
TI  - Comparison of algorithms for multileaf collimator field segmentation.
AB  - In the "stop and shoot" method of intensity modulated radiation therapy, it is
      desirable to use an efficient multileaf collimator (MLC) field segmentation
      algorithm in the sense that it translates beam intensity maps into the least
      number of MLC field segments. In this work, we compare the performance of eight
      different algorithms, including the ones by Bortfeld et al., Galvin et al., Xia
      and Verhey, the Siemens IMFAST algorithm, and four other algorithms which have
      not been studied before. We find that the algorithm of Xia and Verhey is most
      frequently the algorithm that needs the least MLC field segments. However, no
      single algorithm is the most efficient for all clinical cases or intensity maps.
      This suggests that it is desirable to have multiple algorithms available in a
      clinical treatment planning system which will search through all algorithms
      automatically and find the most efficient delivery sequence for a given
      treatment. Each intensity map in a treatment could be delivered by a different
      algorithm, whichever is the most efficient for that map. It is pointed out that
      when the background intensity level is not zero, it is not always efficient to
      deliver a segment to bring the background level down to zero.

PMID- 10587223
TI  - Quantization of setup uncertainties in 3-D dose calculations.
AB  - Random setup errors can lead to erroneous prediction of the dose distribution
      calculated for a patient using a static computed tomography (CT) model. Multiple
      recomputations of the dose distribution covering the range of expected patient
      positions provides a way to estimate a course of treatment. However, due to the
      statistical nature of the setup uncertainties, many courses of treatment must be
      simulated to calculate a distribution of average dose values delivered to a
      patient. Thus, direct simulation methods can be time consuming and may be
      impractical for routine clinical treatment planning applications. Methods have
      been proposed to efficiently calculate the distribution of average dose values
      via a convolution of the dose distribution (calculated on a static CT model) with
      a probability distribution function (generally Gaussian) that describes the
      nature of the uncertainty. In this paper, we extend the convolution-based
      calculation to calculate the standard deviation of potential outcomes
      sigmaD(x,y,z) about the distribution of average dose values, and we characterize
      the statistical significance of this quantity using the central limit theorem.
      For an example treatment plan based on a treatment protocol in use at our
      institution, we found that there is a 68% probability that the actual dose
      delivered to any point (x,y,z) will be within 3% of the average dose value at
      that point. The standard deviation also yields confidence limits on the dose
      distribution, and these may be used to evaluate treatment plan stability.

PMID- 10587224
TI  - Portal dosimetry using x-ray film: an experimental and computational study.
AB  - To evaluate the accuracy and precision of relative portal dosimetry using x-ray
      film, we compared the radiation doses measured by x-ray film and by an ion
      chamber at various portal planes that were 0 to 50 cm behind an 18 cm thick
      phantom. In addition, we calculated photon spectra at the measurement planes by
      using the Monte Carlo particle transport technique. The experiments showed that
      the film usually measured relative doses to within 5% of the measurements by the
      ion chamber and that the errors were associated with the changes in the spectra
      of photon energy fluence at portal planes. The relative magnitude of low-energy
      fluence in the photon fluence spectrum and its variance across the portal plane
      caused the film response to differ from the ion-chamber response especially with
      lead screen on top of film in the film cassette. Relative film dosimetry may be
      improved to accuracy of better than 2% by using solid water or other tissue
      equivalent cassettes.

PMID- 10587225
TI  - Potential and role of a prototype amorphous silicon array electronic portal
      imaging device in breathing synchronized radiotherapy.
AB  - Current electronic portal imaging devices (EPID) are limited in their ability to
      provide direct and quick verification and monitoring of patients during both
      setup and treatment of breathing synchronized radiotherapy (BSRT, including
      breathing gated, voluntary and forced breath-hold radiotherapy treatment.) These
      limitations are largely due to their slow image capture rate and poor image
      quality. An amorphous silicon array flat panel electronic portal imaging device
      (si-EPID) is emerging to meet the challenge. The purpose of this study is
      threefold: (1) to characterize the performance of a prototype si-EPID; (2) to
      compare image quality against that of digitized films; and (3) to evaluate the
      device in terms of verification of patient setup and monitoring during BSRT. In
      this study a Varian prototype si-EPID detector array and Clinic accelerator at
      the University of California Davis Cancer Center were used for imaging. Three
      quality assurance phantoms: a Lutz PVC phantom, a modified "Las Vegas" phantom,
      and a RMI model 1151 phantom, were used to characterize the imaging system. A
      Rando head phantom was used for anthropomorphic imaging tests. Images were
      obtained with the si-EPID and a Fuji RX film in a Kodak X-Omatic cassette. To
      investigate the clinical application, two sets of si-EPID images were collected
      from a lung cancer patient during a 22 s breath-hold and normal breathing. The
      quality of images obtained with the fast mode was found to be comparable to that
      obtained with the digitized films. The images with the standard mode were found
      to be better than the digitized film images. With this prototype si-EPID, it is
      possible to collect the images at the beginning, middle, and end of each breath
      hold for those patients who can hold their breath for longer than 15 s. The si
      EPID images can provide a quick verification of the initial patient setup and
      subsequent treatment position throughout the daily fractionation.

PMID- 10587226
TI  - Treatment field shape verification using elliptic Fourier transform.
AB  - An automated field shape correlation technique based on elliptic Fourier
      transform (EFT) is developed to verify the radiation treatment field in digital
      portal images. In this method, the edge of the treatment field is initially
      extracted from the portal image and is then approximated by a polygon. The
      polygon is further represented with elliptic Fourier coefficients. The invariants
      to shift, rotation, and scale are computed from the elliptic Fourier coefficients
      to characterize the genuine shape feature and are used to match the reference
      treatment field. Invariants calculated from both test and reference field shapes
      are compared to determine the similarity between two treatment fields. The
      proposed procedure uses the first approved field shape as the reference for
      automated comparison with subsequent portal images. This technique not only
      verifies the shape of each portal field but also provides information about
      relative shift, rotation, and scale. A set of generic shapes is simulated to test
      the robustness of the algorithm and to determine the parameters used in the
      decision procedure. Experimental results on the simulated shapes show that this
      method can detect shape distortions of 2% in area and the standard deviations are
      0 for shifting, 0.24 degrees for rotation, and 0.0031 for scaling. Preliminary
      tests on clinical portal images indicated that this technique is potentially
      useful for automated real-time portal verification.

PMID- 10587227
TI  - Three-dimensional anatomy setup verification by correlation of orthogonal portal
      images and digitally reconstructed radiographs.
AB  - A method for three-dimensional verification of anatomy setup that uses the
      correlation of portal images and reference megavoltage digitally reconstructed
      radiographs (MDRRs) is presented. Prior to a treatment, an orthogonal pair of
      portal images is acquired from which subimages containing anatomical features are
      selected. These subimages are consequently matched to MDRRs that represent
      different rotations of the anatomy around axes going through the treatment
      isocenter. The Pearson correlation coefficient is employed for the matching since
      it is invariant with respect to global scaling and shifting of the image
      intensities. Furthermore, it does not require feature extraction or point-pair
      identification. The greatest value of the correlation coefficient corresponds to
      the proper rotational alignment of the anatomy and the location of the
      correlation maximum in each view indicates the translational shifts of the
      anatomy. The mean accuracy of translation and rotation registrations tests were a
      fraction of a millimeter and a fraction of a degree, respectively, for MDRR-to
      MDRR matching. For portal-to-MDRR matching, the mean translation registration
      error is on the order of 1 mm and the mean error in radial displacement is of the
      order of 2.7 mm.

PMID- 10587228
TI  - Verification of the alignment of a therapeutic radiation beam relative to its
      patient positioner.
AB  - An easily-used system has been developed for routine measurements of the
      alignment of beams used for radiation therapy. The position of a beam of circular
      cross section is measured with respect to a steel sphere fixed to the patient
      positioning table and which should coincide with the isocenter. Since
      measurements can be done at all gantry angles (if one is available) and with all
      possible orientations of the patient table, the system is particularly suited for
      rapid and accurate measurements of gantry and/or couch isocentricity. Because it
      directly measures beam-to-positioner offset, the system provides an inclusive
      alignment verification of the total treatment system. The system has been
      developed for use with proton beams, but it could equally be used for alignment
      checks of an x-ray beam from a linear accelerator or other source. The measuring
      instrument consists of a scintillation screen viewed by a CCD camera, mounted on
      the gantry downstream of the sphere. The steel sphere is not large enough to stop
      protons of all energies of interest; however, it will always modify the energy
      and direction of protons which intersect it, creating a region of lower intensity
      (a "shadow") in the light spot created by the proton beam hitting the screen. The
      position of the shadow with respect to the light spot is a measure of the
      alignment of the system. An image-analysis algorithm has been developed for an
      automatic determination of the position of the shadow with respect to the light
      spot. The specifications and theoretical analysis of the system have been derived
      from Monte Carlo simulations, which are validated by measurements. We have
      demonstrated that the device detects beam misalignments with an accuracy (1 s.d.)
      of 0.05 mm, which is in agreement with the expected performance. This accuracy is
      more than sufficient to detect the maximum allowed misalignment of +/-0.5 mm.

PMID- 10587229
TI  - A parallel plate chamber for calibration of 192Ir LDR and HDR sources.
AB  - A good program of quality assurance requires the user to check the calibration of
      brachytherapy sources. Conventional well-type ionization chambers have
      restrictions on the length of the source which can be used due to the variation
      in the relative ionization with distance from the position of maximum
      sensitivity. We have fabricated a parallel plate chamber, which can be used for
      both LDR and HDR sources of 192Ir placed centrally inside. The electrodes are
      made from printed circuit boards. Sources of lengths up to 15 cm can be
      calibrated with this chamber. It has a good linear response and stability. It
      costs little and can be used with any electrometer. The chamber, which has a
      volume of about 40 cm3, has a response of 820 nCmin(-1) per cGy m2 h(-1).

PMID- 10587230
TI  - Spectra and air-kerma strength for encapsulated 192Ir sources.
AB  - The photon spectra in vacuum around four types of 192Ir HDR brachytherapy sources
      are calculated using the Monte Carlo code EGS4 and the most recent spectral
      information on 192Ir decay. The air-kerma strengths per unit activity are
      calculated based on the photon fluence around a bare 192Ir source and around each
      of four types of encapsulated sources using recent mass energy-absorption
      coefficients. For the full spectrum the bare vs encapsulated difference is up to
      23% due to the large air-kerma contribution from the unfiltered low-energy
      photons. For the penetrating part of the photon spectrum (> 11.3 keV), the air
      kerma strength per unit source activity on the transverse axis for a bare source
      is 2-15% higher than for the encapsulated sources due to the attenuation and
      absorption in the core and the encapsulating material. The contribution to the
      air-kerma strength from photons scattered in the capsule and from bremsstrahlung
      are calculated to increase the air-kerma strength by 2-4% and 0.2-0.3%,
      respectively. Air-kerma strengths for a variety of sources agree well with
      previously reported results for sources from Nucletron International, Best
      Industries, Inc., and Alpha-Omega Services, Inc. In addition we present air-kerma
      strengths for the present model of the HDR source from Nucletron International
      and the source from Varian Associates, Inc.

PMID- 10587231
TI  - Refinements to the geometry factor used in the AAPM Task Group Report No. 43
      necessary for brachytherapy dosimetry calculations. American Association of
      Physicists in Medicine.
AB  - Determination of the geometry factor is necessary for brachytherapy dosimetry
      calculations as recommended by the AAPM Task Group No. 43 (TG-43). The
      equivalence and errors associated with use of a point source approximation for an
      extended line segment source are examined. For all angles, the error using the
      point source approximation is less than 2% for distances in which the ratio of
      radius to active source length, (r/L), exceed about 3.6. A novel approach to
      determining the geometry factor using Monte Carlo methods is discussed in which
      the particle flux emanates from the active source and streams with no
      interactions occurring within the source or phantom. This method was performed
      for determining the geometry factor along the transverse axis for six
      brachytherapy sources. Differences in the geometry factor exceeding 2% between
      the point source approximation and that obtained using Monte Carlo methods
      occurred at distances ranging from 0.5 to 5 mm from the source center along the
      transverse plane. The merits of the Monte Carlo approach for solving the geometry
      factor are discussed in light of using a point or line source approximation for
      calculating additional brachytherapy dosimetry parameters.

PMID- 10587232
TI  - Dose model for a beta-emitting stent in a realistic artery consisting of soft
      tissue and plaque.
AB  - A model for the description of the near-field dose deposition from a 32p
      impregnated stent in an arterial system consisting of soft tissue and dense
      plaque is presented. The model is based on the scaling property of the dose-point
      kernel (DPK) function which is extended to a heterogeneous medium consisting of a
      series of layers of different materials. It is shown that, for each point source
      originating from the stent surface, the DPK function for water can be scaled
      consistently along the path through the different layers of material to predict
      the dose at a given point in the heterogeneous medium. Radiochromic film
      dosimetry on actual 32p stents is used to test the new model. The experimental
      setup consists of a water-equivalent phantom in which a stent is deployed and on
      which a thin layer of polytetrafluoroethylene (PTFE) is deposited to simulate the
      presence of plaque. Layers of radiochromic films stacked over the phantom are
      used to measure the dose at distances varying from approximately 0.1 mm to
      approximately 3 mm from the stent surface with and without PTFE. It is shown that
      the proposed new DPK model for a heterogeneous medium agrees very well with the
      experimental data and that it compares favorably to the usual homogeneous DPK
      model. These results indicate that the new model can be used with confidence to
      predict the dose in a realistic artery in the presence of plaque.

PMID- 10587233
TI  - Radiochromic film dosimetry of a high dose rate beta source for intravascular
      brachytherapy.
AB  - Good clinical physics practice requires that dose rates of brachytherapy sources
      be checked by the institution using them, as recommended by American Association
      of Physicists in Medicine Task Group 56 and The American College of Radiology.
      For intravascular brachytherapy with catheter-based systems, AAPM Task Group 60
      recommends that the dose rate be measured at a reference point located at a
      radial distance of 2 mm from the center of the catheter axis. AAPM Task Group 60
      also recommends that the dose rate along the catheter axis at a radial distance
      of 2 mm should be uniform to within +/- 10% in the center two-thirds of the
      treated length, and the relative dose rate in the plane perpendicular to the
      catheter axis through the center of the source should be measured at distances
      from 0.5 mm to R90 (the distance from a point source within which 90% of the
      energy is deposited) at intervals of 0.5 mm. Radiochromic film dosimetry has been
      used to measure the dose distribution in a plane parallel to and at a radial
      distance of 2 mm from the axis of a novel, catheter-based, beta source for
      intravascular brachytherapy. The dose rate was averaged along a line parallel to
      the catheter axis at a radial distance of 2 mm, in the centered 24.5 mm of the
      treated length. This average dose rate agreed with the dose rate measured with a
      well ionization chamber by the replacement method using source trains calibrated
      with an extrapolation chamber at the National Institute of Standards and
      Technology. All of the dose rates in the centered 24.5 mm of a line parallel to
      the axis at a distance of 2 mm were within +/-10% of the average.

PMID- 10587234
TI  - Dosimetric characterization of a new design 103 palladium brachytherapy source.
AB  - Low-energy gamma emitting isotopes encapsulated for permanent implant are in
      routine use in the treatment of prostate cancer. New source designs require full
      dosimetric analysis and calibration standardization before responsible clinical
      application. The results of one such experimental measurement and analysis are
      here reported for a new design of 103palladium source, model MED3633 (North
      American Scientific, Inc.). By AAMP Task Group #43 recommendations, the reference
      material for brachytherapy dosimetry is liquid water. The dose measurements were
      made using standard methods employing thermoluminescent dosimeters in a water
      equivalent plastic phantom. Precision machined bores in the phantom located
      dosimeters and source(s) in a reproducible fixed geometry providing for
      transverse-axis and angular dose profiles over a range of distances from 0.17 to
      7 cm. The data were analyzed in terms of parameters recommended by AAPM TG43. The
      dose-rate constant, lambda, was evaluated with reference to a 60 cobalt standard,
      accounting for response variation with isotope energy spectrum. The radial dose
      function, g(r), the anisotropy function, F(r, theta), the anisotropy factor,
      phi,un(r), and the point-source approximation anisotropy constant, phi(un), were
      derived from one- and two-dimensional dose distribution data measured in the
      phantom, accounting for finite dosimeter volume and with attention to interchip
      effects. The results are compared to TG43 and other existing data for 103Pd
      sources. The new source is comparable to the model 200 103Pd source design,
      demonstrating equivalent radial dose function, g(r). The dose surrounding a
      MED3633 source may be slightly more isotropic than for the model 200 source. The
      air-kerma strength of the MED3633 source used in this study was provided by the
      manufacturer and is traceable to the NIST 1999 standard. The evaluated dose-rate
      constant, lambda, with NIST traceable strength calibration is lower than that of
      the model 200 source, with that manufacturer's strength calibration.

PMID- 10587235
TI  - Assessment of the strength of individual 192Ir seeds in ribbons.
AB  - Assessing the strength of individual seed-type sources in ribbon assembles
      remains a challenge in brachytherapy quality assurance. Geometries to measure a
      single source in the ribbon usually fail because of low signals if using very
      thick shielding to block the radiation from the other sources, or contributions
      from all the other sources if they are not shielded well. A normal well-type
      chamber with partial lead shielding forming a small slot provides a differential
      response along the chamber axis that, through a deconvolution/simultaneous
      equations technique, sorts the contributions from each source, allowing the
      derivation of each source's strength.

PMID- 10587236
TI  - Fluorescence 125I eye applicator.
AB  - A new approach to optimize curative eye plaque brachytherapy is presented. The
      application of ophthalmic plaques is a common therapy modality for small and
      medium sized intraocular tumors. At Essen University Hospital eye applicators
      with photon emitting 125I seeds are used for the treatment of tumors with a
      thickness from 5 to 10 mm. Our clinical experiences indicate that the dose
      distributions of these applicators-used so far worldwide-are not optimal. A
      steeper dose falloff would meet the radiobiological requirements better, to
      provide the eradication of all tumor cells as well as sufficient occlusion of
      tumor supplying blood vessels. Our investigations for eye plaque optimization are
      based both on measurements and Monte Carlo simulation. For fast dosimetric
      measurements we have built a computer controlled device which allows reading out,
      directly and simultaneously, 16 1 mm3 scintillators. For the numerical
      simulations of the dose distribution of 125I eye plaques we have adapted a Monte
      Carlo program originally developed to calculate the synchrotron radiation in
      particle physics. We have investigated the influence of geometrical as well as
      physical eye plaque parameters on the dose distribution: Shielding of the primary
      radiation, penumbra modification, and energy conversion by exploiting
      fluorescence x-radiation have been considered. New types of fluorescence eye
      applicators have been designed which are more suitable for the prevention of
      radiopathic effects on structures at risk.

PMID- 10587237
TI  - Paired Mg and Mg(B) ionization chambers for the measurement of boron neutron
      capture dose in neutron beams.
AB  - The use of the boron neutron capture (BNC) reaction to provide a dose enhancement
      in fast neutron therapy is currently under investigation at the Gershenson
      Radiation Oncology Center of Harper Hospital in Detroit, MI. The implementation
      of this treatment modality presents unique challenges in dosimetry. In addition
      to the measurement of photon and neutron doses in the mixed field, a measure of
      the thermal neutron flux and the associated boron neutron capture dose throughout
      the treatment volume is desired. A pair of small-volume magnesium ionization
      chambers has been constructed with the aim of providing this information. One of
      the chambers, denoted the Mg(B) chamber, is lined with a boron-loaded foil. The
      ionization response of this chamber has been calibrated in terms of BNC dose per
      ppm loading of 10B. These paired chambers can be used to map the local BNC
      response in neutron beams. From this data and an estimation of the boron
      concentration in the tumor and normal tissue, the boron neutron capture
      enhancement may be evaluated.

PMID- 10587238
TI  - Boron self-shielding effects on dose delivery of neutron capture therapy using
      epithermal beam and boronophenylalanine.
AB  - Previous dosimetry studies for boron neutron capture therapy have often neglected
      the thermal neutron self-shielding effects caused by the 10B accumulation in the
      brain and the tumor. The neglect of thermal neutron flux depression, therefore,
      results in an overestimation of the actual dose delivery. The relevant errors are
      expected to be more pronounced when boronophenylalanine is used in conjunction
      with an epithermal neutron beam. In this paper, the boron self-shielding effects
      are calculated in terms of the thermal neutron flux depression across the brain
      and the dose delivered to the tumors. The degree of boron self-shielding is
      indicated by the difference between the thermal neutron fluxes calculated with
      and without considering a 10B concentration as part of the head phantom
      composition. The boron self-shielding effect is found to increase with increasing
      10B concentrations and penetration depths from the skin. The calculated
      differences for 10B concentrations of 7.5-30 ppm are 2.3%-8.3% at 2.3 cm depth
      (depth of the maximum brain dose) and 4.6%-17% at 7.3 cm depth (the center of the
      brain). The additional self-shielding effects by the 10B concentration in a bulky
      tumor are investigated for a 3-cm-diam spherical tumor located either near the
      surface (3.3 cm depth) or at the center of the brain (7.3 cm depth) along the
      beam centerline. For 45 ppm of 10B in the tumor and 15 ppm of 10B in the brain,
      the dose delivered to the tumors is approximately 10% lower at 3.3 cm depth and
      20% lower at the center of the brain, compared to the dose neglecting the boron
      self-shielding in transport calculations.

PMID- 10587239
TI  - Monte Carlo simulation of a typical 60Co therapy source.
AB  - The BEAM Monte Carlo code is used to simulate the 60Co beam from an Eldorado 6
      radiotherapy unit and to calculate the relative air-kerma output factors as a
      function of field size. The unit is realistically modeled, including source
      capsule, housing and collimator assembly. The calculated relative air-kerma
      output factors at SSD=80.5 cm agree to within 0.1% with measured values. It is
      shown that the variation of the output factor is almost entirely due to scattered
      photons from the fixed and adjustable collimators and there is no effect of
      shadowing primary photons. The influence of the geometry of the collimation
      system on the photon spectra on-axis is shown to be small but finite. The
      calculated buildup region of a depth-dose curve in a water phantom irradiated by
      a narrow and a broad 60Co beam is shown to agree with experimental data at the 2%
      to 3% level. Unlike previous calculations, the results accurately predict the
      effects of electron contamination from the surface to dose maximum. The variation
      of electron contamination with field size is also presented, as are spectra as a
      function of field size.

PMID- 10587240
TI  - A Monte Carlo comparison of the response of the PTW-diamond and the TL-diamond
      detectors in megavoltage photon beams.
AB  - A detailed Monte Carlo study of the PTW-diamond solid state detector response in
      megavoltage photon beams (60Co gamma rays to 25 MV x rays) has been performed
      with the EGS4 Monte Carlo Code. The sensitive volume of the diamond detector is a
      disk of diameter 4.4 mm and thickness 0.40 mm. The phantom material was water and
      the irradiation depth was usually 3 cm but additional simulations were performed
      at six other depths for the 10 and 25 MV x rays. Results show that the PTW
      diamond detector response per unit of absorbed dose is constant within 1% for
      photon beam energies ranging from 60Co gamma rays to 25 MV x rays. Accurate depth
      dose curves for 10 and 25 MV x-ray beams may be measured with the diamond
      detector since the response per unit of absorbed dose at different depths in a
      water phantom is also constant to within 1% for depths ranging from 3 to 25 cm
      and field sizes ranging from 2.5 cm by 2.5 cm to 10 cm by 10 cm. An examination
      of the difference between the PTW-diamond detector and the wall-less form of the
      detector (e.g., TLDs) revealed that there is no significant difference in their
      response in megavoltage photon beams. This implies that the encapsulation of the
      diamond dosimeter causes less than a 1.3% change in its response for these
      megavoltage photon beams. Analysis of the total dose deposited in the sensitive
      volume of the detector shows that the PTW-diamond detector behaves as an
      intermediate-sized cavity, not a simple Bragg-Gray cavity, since the dose
      contribution from photon interactions within the cavity (alpha(c)) to the total
      cavity dose is 8% for 25 MV x rays and increases to 42% for 60Co gamma rays.

PMID- 10587241
TI  - CCD imaging for optical tomography of gel radiation dosimeters.
AB  - Several investigations have been carried out by a number of researchers over the
      past few years to evaluate the utility of imaging gel dosimeters for the three
      dimensional measurement of radiation fields. These have been proposed to be of
      particular value in mapping radiation dose distributions associated with emerging
      and complex approaches to cancer treatment such as conformal (CRT), intensity
      modulated (IMRT), "gamma knife," and pencil beam radiotherapies. Imaging of the
      gels has been successfully accomplished with clinical MRI units and via laser
      based optical scanning. However, neither of these methods is generally accessible
      to all potential users, limiting the broader study and implementation of this
      valuable tool. We report here the design, methodology, and results of a
      preliminary study carried out to evaluate the utility of a new, inexpensive, and
      simplified approach to tomographic imaging of gel radiation dosimeters. For the
      purpose of this initial investigation, an array of liquid scintillation vials was
      prepared, containing a ferrous sulphate xylenol orange (FSX) gelatin formulation.
      The FSX formulation undergoes a change in optical absorption characteristics
      following irradiation, and the resulting color change can be observed visually.
      The vials were irradiated individually to different doses. Three-dimensional
      imaging was accomplished by tomographic reconstruction from two-dimensional
      optical images acquired using a diffuse, fluorescent light source, a digital
      charge-coupled device camera, single-photon-emission-computed tomography
      software, and other simple components designed by the authors. The resulting
      transverse images were evaluated through a region-of-interest (ROI) analysis to
      obtain the average change in image density in each vial as a function of
      radiation dose. These measured ROI values were subjected to a linear regression
      analysis to fit them to a straight line, and to determine the goodness of fit.
      Results from multiple imaging trials are compared. The correlation coefficients
      obtained are typically on the order of 0.98, and the p value from analysis of
      variance is approximately 0.05, indicating a linear and reproducible response for
      the dosimeter formulation and imaging system.

PMID- 10587242
TI  - Comment on "Dosimetry of interstitial brachytherapy sources: recommendations of
      the AAPM Radiation Therapy Committee Task Group 43" [Med. Phys. 22, 209-234
      (1995)]. American Association of Physicists in Medicine.

PMID- 10587243
TI  - Comment on "Intensity-modulated conformal radiation therapy and 3-dimensional
      treatment planning will significantly reduce the need for therapeutic approaches
      with particles such as protons" [Med. Phys. 26, 1185-1187 (1999)].

PMID- 10587244
TI  - A randomized clinical trial of intra-articular sodium hyaluronate in patients
      with osteoarthritis of the knee: a summary.

PMID- 10587245
TI  - Intra-articular hyaluronic acid: duration of effect and results of repeated
      treatment cycles.
AB  - An open-label, multicenter study was designed to evaluate the effects of intra
      articular (IA) hyaluronic acid in patients given a diagnosis of osteoarthritis of
      the knee. Patients (n = 108) received five weekly IA injections of hyaluronic
      acid 20 mg (Hyalgan) under sterile conditions, and were observed for up to 12
      months after the last injection. Some patients received a second series of
      injections after 4 to 8 months. For the 59 patients who were observed for 12
      months after the first treatment cycle, evaluation of pain according to a visual
      analog scale showed significant improvements lasting 12 months, with pain during
      load, pain at rest, and duration of walking ability compared with a baseline
      evaluation. Patients who required a second treatment cycle showed a further
      amelioration. Significant improvements were also seen in knee function and in
      global evaluations by both patient and investigators. Relief of symptoms of
      osteoarthritis of the knee was seen as early as 4 weeks after treatment in 68% of
      patients receiving IA hyaluronic acid. In 55% of these patients, relief was
      maintained until the end of the 12-month follow-up.

PMID- 10587246
TI  - Pathogenesis of osteoarthritis--approaches to specific therapy.
AB  - Although osteoarthritis is the most prevalent rheumatic disorder affecting the
      musculoskeletal system, the details of its causes are still unknown. Primary
      osteoarthritis is thought to be an active process featuring enhanced metabolic
      activity of the joint. Studies suggest there is a positive influence of
      hyaluronic acid (hyaluronan) on physiologic joint function that exceeds the well
      known effects on cartilage repair. Research on joint metabolism and chondrocyte
      function suggests that intra-articular drug delivery of chondroprotective drugs
      represents a very rational approach. This review of osteoarthritis concentrates
      on epidemiology, etiology, pathogenetic factors, and therapeutic approaches to
      osteoarthritis.

PMID- 10587247
TI  - Sodium hyaluronate--application in a community practice.
AB  - This office tracked the clinical results of 73 patients who received sodium
      hyaluronate for their knees, as well as two ankle patients and one elbow patient.
      A questionnaire designed to evaluate six areas of function-relief of pain,
      stiffness, walking tolerance, pain while negotiating stairs, swelling, night
      symptoms--was mailed to patients who had received the series of five sodium
      hyaluronate injections. Ninety-five percent of the questionnaires were completed
      and returned. We found that injectible sodium hyaluronate is a viable treatment
      option for properly selected patients, namely those with mild to moderate
      osteoarthritis of the knee. We found that it relieved pain and stiffness in most
      patients. The majority of patients were willing to repeat the treatment if
      necessary. Sodium hyaluronate allows the physician to relieve patient pain in
      early stages of the disease and to manage the patient comfortably until surgery
      is a viable option. With the appropriate precertification and billing protocol,
      reimbursement should not be an obstacle in using this product.

PMID- 10587248
TI  - Man bites dog: Helicobacter in the new millennium.

PMID- 10587249
TI  - Gastric function in dogs with naturally acquired gastric Helicobacter spp.
      infection.
AB  - The association of Helicobacter pylori with gastritis, peptic ulcers, and gastric
      neoplasia has led to fundamental changes in the understanding of gastric disease
      in humans. The relationship of Helicobacter spp. infection to gastric disease in
      dogs is unclear. The objective of this study was to determine if Helicobacter
      infection affects the gastric secretory axis of dogs. Eight Beagle dogs with
      naturally acquired Helicobacter spp. infection were studied before and after (4
      and 29 days) the attempted eradication of Helicobacter spp. with a combination of
      amoxicillin, metronidazole, and famotidine (AMF). Six specific-pathogen-free,
      Helicobacter-free Beagle dogs served as controls. The electron microscopic
      appearance of spiral organisms in infected dogs indicated coinfection with
      Helicobacter felis- and H bizzozeronii-like organisms. Unstimulated gastric pH
      and fasting, postprandial, and bombesin-stimulated plasma gastrin were similar in
      both infected and uninfected dogs, although a trend (P = .09) toward higher meal
      stimulated gastrin was observed in infected dogs at 60 minutes. Pentagastrin
      stimulated maximal acid output (mmol HCI/kg0.75/hour) and titratable acidity
      (mmol HCl/mL) were similar in both infected and uninfected dogs, but gastric pH
      during maximal acid output was lower (P < .01) in uninfected dogs. Mild gastric
      inflammation was present in both infected and uninfected dogs. Gastric spiral
      organisms were undetectable in 6/8 infected dogs 4 days after AMF but had
      recurred in 8/8 dogs 29 days after AMF. Analysis of gastric DNA with Helicobacter
      specific primers indicated persistence of Helicobacter DNA at 4 and 29 days after
      antibiotic therapy. Acid secretion, plasma gastrin, and mucosal inflammation were
      not affected by the transient suppression of Helicobacter spp. by AMF. These
      findings suggest that gastric secretory function in dogs is not markedly
      perturbed by naturally acquired Helicobacter spp. infection and that treatment
      with amoxicillin, metronidazole, and famotidine causes suppression rather than
      eradication of gastric Helicobacter spp. in dogs.

PMID- 10587250
TI  - Progression of chronic renal disease in the dog.
AB  - Progressive loss of nephron function may be caused by persistence of factors that
      initiated renal disease. However, newer studies suggest that nephron damage is
      self-perpetuating once renal mass is reduced to some critical level. Original
      theories on mechanisms of self-perpetuated nephron injury focused on
      intraglomerular hypertension and glomerular hypertrophy, but several other
      factors have now been incriminated, including tubulointerstitial responses,
      proteinuria, and oxidative stress. Studies of dogs with surgically reduced renal
      mass (remnant kidney model of chronic renal disease) have allowed investigation
      of the self-progression theory in this species. Use of this model eliminates pre
      existing renal disease as a confounding factor. Data from these studies indicate
      that self-perpetuated renal injury is initiated when mild azotemia is induced
      (plasma creatinine concentration = 2 to 4 mg/dL). Thus, with naturally occurring
      renal disease(s), it is likely that self-perpetuated nephron damage is occurring
      before or at the time when most cases of chronic renal disease are diagnosed. In
      dogs with remnant kidneys, loss of renal function often occurs at a linear rate
      over time, but non-linear patterns are common as well. The reciprocal of plasma
      creatinine concentration, which has been used to monitor rate of progression, is
      only a fair marker of renal function when compared to GFR. Thus, clinical results
      from creatinine measurements on cases of naturally occurring disease should not
      be interpreted too stringently. In remnant kidney dogs, the magnitude of
      proteinuria (UPC ratio) was not predictive of the rate in decline of GFR, casting
      doubt on importance of proteinuria in causing progression of renal disease.
      However, progressive increases in UPC may be a marker of an accelerated rate of
      renal injury. Self-perpetuation of renal injury in dogs could be the sole
      mechanism by which naturally occurring renal diseases progress. When more
      information is available on the rate of progression of naturally occurring
      diseases, it may become apparent whether factors initially inciting renal damage
      have an additive effect on rate of progression.

PMID- 10587251
TI  - Thoracoscopic partial pericardiectomy in 13 dogs.
AB  - Thirteen dogs with cardiac tamponade resulting from pericardial effusion were
      prospectively evaluated to determine feasibility and outcome of thoracoscopic
      partial pericardiectomy. A lateral thoracoscopic approach allowed adequate
      exposure to remove a 4- to 5-cm-diameter section of pericardium in all dogs.
      Complete resolution of cardiac tamponade occurred in all dogs for which there was
      follow-up (11 dogs). Ten of 13 dogs (76.9%) had neoplastic pericardial effusion.
      One of these dogs remains alive at 220 days postoperatively and is asymptomatic.
      The mean survival of the remaining 9 patents with neoplastic effusion was 128
      days (range, 14-544 days; median, 38 days). Three of 13 patients (23.1%) had
      idiopathic pericardial effusion. Two of these dogs remain alive at 585 and 1,250
      days postoperatively. One dog with idiopathic pericardial effusion developed
      cardiomyopathy and was euthanized 18 days after the procedure. Results indicate
      that the procedure was technically successful in all dogs. No anesthetic
      complications occurred. Procedural complications included phrenic nerve
      transection (1 dog), lung laceration (1 dog), and moderate intraoperative
      bleeding (1 dog). No adverse clinical manifestations of the complications were
      apparent. We conclude that thoracoscopic partial pericardiectomy is technically
      feasible and offers several advantages over conventional open thoracic surgical
      pericardiectomy.

PMID- 10587252
TI  - Detection and effects on platelet function of anti-platelet antibody in mule
      foals with experimentally induced neonatal alloimmune thrombocytopenia.
AB  - Horse mares carrying mule foals were immunized during the last trimester of
      pregnancy with whole acid-citrate-dextrose-anticoagulated donkey blood to
      experimentally induce neonatal alloimmune thrombocytopenia. Thrombocytopenia
      occurred in the neonatal mule foals born to immunized horse mares within 24 hours
      after ingestion of their dams' colostrum. Mule foals born to mares not immunized
      with donkey blood did not develop thrombocytopenia. These findings suggest that
      antibodies may have been directed against a donkey platelet antigen present in
      the mule foals but not present in their dams. The objectives of this study were
      to determine whether anti-platelet antibody could be detected in mule foals with
      experimentally induced neonatal alloimmune thrombocytopenia, to identify any
      platelet proteins recognized by serum antibody in these foals, and to determine
      if platelet function was altered by sera from these mule foals. An indirect
      enzyme-linked immunosorbent assay demonstrated significantly higher absorption at
      1:200 of platelet-bindable immunoglobulin G in serum from thrombocytopenic mule
      foals, compared with nonthrombocytopenic mule foals. Sera from thrombocytopenic
      and nonthrombocytopenic mule foals produced similar binding patterns in western
      immunoblots with donkey platelet proteins separated on sodium dodecyl sulfate
      polyacrylamide gels. Maximal platelet aggregation and relative slope of
      aggregation in response to collagen were significantly inhibited after incubation
      with sera from thrombocytopenic mule foals. These results suggest that mule foals
      with induced alloimmune thrombocytopenia have serum antibodies that bind to
      platelets and may compete with collagen binding sites to impair platelet
      aggregation.

PMID- 10587253
TI  - Coccygeal muscle injury in English Pointers (limber tail).
AB  - A condition colloquially referred to as "limber tail" and "cold tail" is familiar
      to people working with hunting dogs, primarily Pointers and Labrador Retrievers.
      The typical case consists of an adult dog that suddenly develops a flaccid tail.
      The tail either hangs down from the tail base or is held out horizontally for
      several inches from the tail base and then hangs straight down or at some degree
      below horizontal. Initially, the hair on the dorsal aspect of the proximal tail
      may be raised and dogs may resent palpation of the area 3-4 inches (8-10 cm) from
      the tail base. Most dogs recover spontaneously within a few days to weeks.
      Anecdotal reports suggest that anti-inflammatory drugs administered within 24
      hours after onset hasten recovery. Less than one half of affected dogs experience
      a recurrence. Affected Pointers almost always have a history of prolonged cage
      transport, a hard workout the previous day, or exposure to cold or wet weather
      Most owners and trainers familiar with the condition do not seek veterinary
      assistance. In cases where people are not familiar with this disease, other
      conditions such as a fracture, spinal cord disease, impacted anal glands, or
      prostatic disease have been incorrectly diagnosed. We examined 4 affected
      Pointers and found evidence of coccygeal muscle damage, which included mild
      elevation of creatine kinase early after onset of clinical signs, needle
      electromyographic examination showing abnormal spontaneous discharges restricted
      to the coccygeal muscles several days after onset, and histopathologic evidence
      of muscle fiber damage. Specific muscle groups, namely the laterally positioned
      intertransversarius ventralis caudalis muscles, were affected most severely.
      Abnormal findings on thermography and scintigraphy further supported the
      diagnosis.

PMID- 10587254
TI  - Acute insulin response to intravenous arginine in nonobese healthy cats.
AB  - The purpose of this study was to document and characterize insulin response to
      intravenous administration of arginine, a nonglucose secretagogue, and compare it
      to insulin response during intravenous glucose tolerance tests (IVGTTs) in
      clinically healthy nonobese cats. In addition, we examined the influence of
      plasma glucose level on insulin response to arginine in cats. Five dosages of 10%
      L-arginine hydrochloride (0.015, 0.025, 0.05, 0.1, and 0.2 g/kg of body weight)
      were administered to 5 cats. All doses of arginine elicited an abrupt insulin
      response that peaked at 2-4 minutes and returned to basal concentrations within
      30 minutes. Mean insulin peak response (IPR) and mean area under the curve of
      plasma insulin concentration evaluated for the initial 10 minutes after
      administration (AUC10) increased with each progressive increase in arginine
      dosage. An asymptotic maximal response estimated by mean insulin AUC10 reached
      plateau at 0.1-0.2 g arginine/kg. Arginine at 0.2 g/kg induced hypersalivation in
      2 of 4 cats. No adverse effects were evident at lower doses. Mean insulin AUC10
      produced by equimolar amount of glucose (0.086 g/kg) was only 42% of that seen in
      response to 0.1 g arginine/kg, and mean IPR was much lower (18 +/- 7 versus 61 +/
      17 microU/mL). Mild hyperglycemia (211 +/- 6 mg/dL) induced by variable infusion
      rate of glucose resulted in a significant (P < .05) potentiation of insulin
      response to arginine; mean insulin AUC10 increased 287 +/- 26 to 551 +/- 167
      microU/mL/10 minutes. These findings indicate that the arginine challenge is a
      more meaningful tool than is the IVGTT for evaluating the insulin secretory
      capacity in cats.

PMID- 10587255
TI  - Retrospective evaluation of urinary tract infection in 42 dogs with
      hyperadrenocorticism or diabetes mellitus or both.
AB  - A retrospective study was performed to determine the proportion of dogs with
      hyperadrenocorticism or diabetes mellitus or both that had urinary tract
      infection (UTI) and to describe clinical and laboratory findings. Dogs with these
      endocrine disorders were included if results of quantitative urine culture were
      available and dogs were not receiving antimicrobials. Dogs with positive urine
      cultures were considered to have UTI and dogs with negative urine cultures were
      used as controls. Information including history, clinical signs, physical
      examination findings, and results of laboratory tests and urine culture was
      extracted from all records. Findings in dogs with UTI were compared with control
      dogs. There were 101 dogs with hyperadrenocorticism or diabetes mellitus or both
      that met inclusion criteria; 42 (41.6%) had UTI and 59 (58.4%) did not. UTI was
      present in 46% of dogs with hyperadrenocorticism, 37% of dogs with diabetes
      mellitus, and 50% of dogs with both endocrine disorders. There was no association
      between endocrine group and occurrence of UTI. Escherichia coli was the most
      common bacteria isolated, and cultures from 29 dogs (69%) showed growth of this
      organism. Of dogs with UTI, <5% had stranguria, pollakiuria, or discolored urine,
      whereas 60% had pyuria and 69% had bacteriuria. We conclude that UTIs are common
      in dogs with hyperadrenocorticism, diabetes mellitus, or both diseases. Clinical
      signs of UTI, however, are uncommon and results of urinalysis may be normal.
      Therefore, it is appropriate to recommend urine culture as part of the evaluation
      of dogs with these endocrine disorders.

PMID- 10587256
TI  - Evaluation of the effect of pleural effusion on central venous pressure in cats.
AB  - This study was undertaken to determine if pleural effusion (PEF) increases
      central venous pressure (CVP) in cats, to define any relationship between volume
      of PEF and CVP and to ascertain the significance of CVP alterations in cats
      having PEF and suspected right heart failure (RHF). CVP was measured from a
      jugular vein before (CVPpre) and after (CVPpost) bilateral thoracentesis in 9
      cats with naturally occurring PEF and under experimental conditions in 3
      spontaneously breathing anesthetized cats receiving graded intrathoracic infusion
      of saline. Volumes of introduced and recovered fluid were recorded. A significant
      decrease occurred in CVP after thoracentesis in cats with naturally occurring PEF
      (mean difference, 4.5 cm H2O; range, 0-7.0 cm H2O, P < .005). The magnitude of
      change in CVP was constant (r = 0.36, P > .05) over the range of volumes
      recovered (range, 95-450 mL or 16.4-90 mL/kg). Five cats had CVPpre suggestive of
      RHF (range, 8.16-20.4 cm H2O). After thoracentesis, RHF was ruled out in 1 cat
      (CVPpost, 4.08 cm H2O) and the CVP declined but remained abnormally high (9.52 cm
      H2O) in 1 cat with a mediastinal mass. In 2 cats with confirmed RHF (CVPpre, 20.4
      and 16.3 cm H2O), CVP decreased after thoracentesis but remained abnormally high
      (CVPpost, 14.96 and 10.88 cm H2O). In 1 cat with noncardiogenic PEF and
      inadequate removal of fluid, CVPpost (8.16 cm H2O) did not decrease.
      Experimentally, a positive linear relationship was observed between CVP and
      volume of PEF. The threshold volume required to increase CVP (17 mL/kg)
      approximated that suggested by clinical observation (22 mL/kg). PEF increases CVP
      and can cause abnormally high CVP in the absence of RHF.

PMID- 10587257
TI  - Sry-negative XX sex reversal in a family of Norwegian Elkhounds.
AB  - Two related female Norwegian Elkhounds were evaluated at 6 and 8 months of age
      for enlarged clitori. Both had a 78 XX karyotype. Histology of their internal
      reproductive tracts demonstrated 1 to be an XX true hermaphrodite with bilateral
      ovotestes and the other to be an XX male with bilateral aspermatogenic testes.
      Polymerase chain reaction-based tests of genomic DNA showed that both dogs lacked
      Sry, the testis-determining gene. Pedigree analysis was consistent with an
      autosomal recessive mode of inheritance, as has been reported in the American
      Cocker Spaniel and the German Shorthaired Pointer. This is the 1st reported case
      of familial Sry-negative XX sex reversal in the Norwegian Elkhound. A summary of
      34 previously unreported cases of dogs with masculinized external genitalia and a
      normal 78 XX karyotype seen from 1980 to 1997 is given.

PMID- 10587258
TI  - Analysis of blood clotting factor activities in canine Legg-Calve-Perthes'
      disease.
AB  - Legg-Calve-Perthes' (LCP) disease is a noninflammatory aseptic necrosis of the
      femoral head and neck in small-breed dogs. The etiology of the disease is not
      known, but ischemia resulting from vascular compression or occlusion has been
      proposed. A latent ischemic phase during development of the femoral epiphysis
      seems to be responsible for the onset of the typical clinical features of LCP
      disease. Ischemia might result from insufficient oxygen supply either caused by a
      reduced number of afferent arterial vessels or an occlusion of the efferent
      venous vessels by thrombosis. In humans, LCP disease has been linked to
      hypercoagulability and hypofibrinolysis caused by deficiencies of protein C,
      protein S, or resistance to activated protein C. To determine whether canine LCP
      disease is caused by similar deficiencies, we determined protein C, protein S,
      activated protein C, factor II, factor V, factor VIII:C, and AT III activities in
      plasma samples of 18 dogs with clinically and histopathologically verified LCP
      disease. All dogs had normal plasma activities of these factors, indicating that
      in these dogs LCP disease was not caused by deficiencies of the analyzed blood
      clotting factors.

PMID- 10587259
TI  - Platelet function in dogs treated for lymphoma and hemangiosarcoma and
      supplemented with dietary n-3 fatty acids.
AB  - A prospective randomized, double-blind clinical trial was performed to test the
      hypothesis that dogs with malignancies that are supplemented with n-3 fatty acids
      do not have clinical or laboratory evidence of coagulation disorders or altered
      platelet function when compared with unsupplemented dogs with similar
      malignancies. Thirteen dogs with hemangiosarcoma and 66 dogs with lymphoma were
      evaluated. Coagulation status of the dogs with lymphoma and hemangiosarcoma was
      evaluated with prothrombin time, partial thromboplastin time, platelet count, and
      in vitro platelet aggregometry using the whole-blood method. These tests were
      performed at 5 time points: before beginning the diet (week 0), at weeks 3, 15,
      and 21, and at 1 year or when progressive disease was evident. Alterations in
      platelet function in dogs receiving a diet supplemented with dietary n-3 fatty
      acids were not identified when compared to dogs fed a control diet. Dietary n-3
      fatty acid supplementation using this dosage and ratio in dogs with lymphoma or
      hemangiosarcoma did not induce clinically significant hemorrhage in these
      animals. Therefore, supplementation with n-3 fatty acids did not result in
      clinical or laboratory evidence relating to uncontrolled hemorrhage in these
      dogs.

PMID- 10587260
TI  - Plasma granulocyte colony-stimulating factor concentrations in neutropenic,
      parvoviral enteritis-infected puppies.
AB  - We evaluated the temporal relationship between neutrophil numbers and plasma
      granulocyte colony-stimulating factor (G-CSF) concentrations in dogs infected
      with canine parvovirus, a common infectious cause of neutropenia. G-CSF is
      produced in response to neutropenia, infection, or inflammation, and results in
      the production and release of neutrophils from the bone marrow. Adequate numbers
      of functional neutrophils are necessary for protection from infection, and the
      timely production of G-CSF is a crucial response to certain diseases. The
      relationship between peripheral neutrophil numbers and plasma G-CSF
      concentrations during the course of an infectious disease characterized by
      neutropenia has not been described previously in dogs. Eight mixed-breed puppies
      were given an oronasal challenge with canine parvovirus, and peripheral
      neutrophil numbers as well as plasma G-CSF concentrations were measured daily. G
      CSF was not detectable in plasma of any dog before the onset of neutropenia, but
      G-CSF became detectable just after the onset of neutropenia in the 7 dogs that
      developed clinical illness. Neutropenia persisted or worsened for at least 2 days
      after plasma G-CSF became detectable in all 7 dogs. Neutrophil nadir, the highest
      plasma G-CSF concentrations, and the most severe clinical illness occurred
      concurrently in most dogs. Although 1 dog died while still neutropenic, plasma G
      CSF concentrations declined before resolution of neutropenia in the other 6 dogs,
      and were again below the limits of detection in 5 of the 6 dogs at the time of
      resolution.

PMID- 10587261
TI  - The relationship between some plasma clearance methods for estimation of
      glomerular filtration rate in dogs with pyometra.
AB  - The purpose of the present study was to compare different pharmacokinetic models
      for estimation of glomerular filtration rate (GFR) in 50 dogs with pyometra. GFR
      was estimated by plasma clearance (CLplasma) of iohexol by four 1-compartment
      methods (CL1c), a 2-compartment method (CL2c), and the trapezoidal method (CLtr).
      Regression analysis was performed to establish correction formulas for prediction
      of CLtr from the CL1c values and to find optimal times of sampling.
      Standardization of clearance values to body weight (kg), body surface area (m2)
      and extracellular fluid volume (ECFV) was compared by ranking of values. CLtr and
      CL2c values were similar, whereas CL1c overestimated CLtr. CLtr could be
      predicted from 2 samples at 2 and 3 hours after injection, using the formula CLtr
      = 4.52 + 0.84CL1c - 0.00080(CL1c)2 (R2 = .97). Similar relationships were found
      when sampling at 2 and 4 hours or at 2, 3 and 4 hours after injection, whereas
      predictions from the 3- and 4-hour estimates were not optimal (R2 = .79). The 2
      sample methods for calculating GFR/ECFV generally produced unreliable predictions
      of the complete curve GFR/ECFV values. For some dogs, the choice of
      standardization procedure substantially changed the apparent level of renal
      function relative to other dogs in the study. We conclude that by applying an
      appropriate correction formula, GFR may be estimated using 2 blood samples at 2
      and 3, or 2 and 4 hours after injection of iohexol when renal function is normal
      or moderately reduced. The method of standardizing the analysis with respect to
      body size may influence interpretation of the results substantially.

PMID- 10587262
TI  - Accuracy of a portable blood gas analyzer incorporating optodes for canine blood.
AB  - The accuracy of a portable blood gas analyzer (OPTI 1) was evaluated using canine
      blood and aqueous control solutions. Sixty-four arterial blood samples were
      collected from 11 anesthetized dogs and were analyzed for pH, partial pressure of
      carbon dioxide (PCO2) partial pressure of oxygen (PO2), and bicarbonate
      concentration ([HCO3-]) values by the OPTI 1 and a conventional blood gas
      analyzer (GASTAT 3). The conventional analyzer was considered as a standard
      against which the OPTI 1 was evaluated. Comparison of OPTI 1 results with those
      of GASTAT 3 by linear regression analysis revealed a high degree of correlation
      with the GASTAT 3 (r = .90-.91). The mean +/- SD of the differences between OPTI
      1 and GASTAT 3 values was -0.008 +/- 0.017 for pH, -0.88 +/- 3.33 mm Hg for PCO2,
      3.71 +/- 6.98 mm Hg for PO2, and -0.34 +/- 1.45 mEq/L for [HCO3-]. No
      statistically significant difference was found between the OPTI 1 and the GASTAT
      3. Agreement between these 2 methods is within clinically acceptable ranges for
      pH, PCO2, PO2, and [HCO3-]. The coefficients of variation for measured pH, PCO2,
      and PO2 values of 3 aqueous control solutions (acidic, normal, and alkalotic)
      analyzed by the OPTI 1 ranged from 0.047 to 0.072% for pH, 0.78 to 1.81% for
      PCO2, and 0.73 to 2.77% for PO2. The OPTI 1 is concluded to provide canine blood
      gas analysis with an accuracy that is comparable with that of conventional
      benchtop blood gas analyzers.

PMID- 10587263
TI  - Treatment of canine mast cell tumors with CCNU (lomustine).
AB  - The efficacy and toxicity of CCNU (1-[2-chloroethyl]3-cyclohexyl-1-nitrosourea)
      were evaluated in 23 dogs with measurable mast cell tumors (MCT). Twenty-two dogs
      had cutaneous MCT and 1 dog had an intranasal MCT Nineteen (83%) dogs had biopsy
      of their original mass performed and 4 (17%) had aspiration cytology of masses.
      Of the 19 tumors histologically graded, 1 (5%) neoplasm was classified as grade
      I, 10 (53%) were grade II, and the remaining 8 (42%) were grade III. Dogs were
      treated with CCNU at a dosage of 90 mg/m2 body surface area every 3 weeks.
      Response could be evaluated in 19 dogs. Eight of the 19 dogs (42%) had a
      measurable response to CCNU. One dog had a durable complete response for 440
      days. Seven dogs (37%) had a partial response for a median and mean duration of
      77 days and 109 days, respectively (range, 21-254 days). Treatment with CCNU
      resulted in stable disease in 6 dogs (32%) for a median and mean duration of 78
      days and 122 days, respectively (range, 42-347 days). The acute dose-limiting
      toxicity was neutropenia 7 days after administration of CCNU. The median and mean
      neutrophil counts 7 days after CCNU were 1,452 cells/microL and 1,683
      cells/microL, respectively (n = 17). Other toxicoses were uncommon. CCNU should
      be considered an active agent in the treatment of MCT in dogs.

PMID- 10587264
TI  - Injection site eosinophilic granulomas and collagenolysis in 3 horses.
AB  - Three horses were presented with a history of having developed raised cutaneous
      nodules, within 24-48 hours, in areas of previous injections using standard
      silicone-coated hypodermic needles. Skin biopsies were taken from a selected
      cutaneous nodule from all horses for histopathologic evaluation. Histologically,
      the nodules were consistent with a diagnosis of equine eosinophilic granuloma. A
      hypersensitivity reaction to the silicone, or another component of the coating
      formulation, was hypothesized to be responsible for these lesions. Two horses
      were experimentally injected using both coated and noncoated stainless steel
      hypodermic needles and skin biopsies were obtained 14 days after injection. The
      sites of the coated needle injections were characterized by severe eosinophilic
      granulomatous inflammation with and without collagenolysis. The eosinophilic
      granulomas with and without collagenolysis observed in these horses are proposed
      to represent a complex immunologic response to the silicone-based coating of most
      hypodermic needles.

PMID- 10587265
TI  - Black widow spider envenomation in a cat.

PMID- 10587266
TI  - Balloon dilation of cor triatriatum dexter in a dog.

PMID- 10587267
TI  - B-cell lymphoma in a horse with associated Sezary-like cells in the peripheral
      blood.

PMID- 10587268
TI  - Odontogenic tumors. Introduction.

PMID- 10587269
TI  - Benign epithelial odontogenic tumors.
AB  - Teeth are formed from a complex interaction of primitive ectoderm and
      ectomesenchymal tissues. Because humans develop 2 sets of teeth (deciduous and
      permanent), odontogenesis is a prolonged biologic process. Residues of
      odontogenic tissues are present in most humans- both during and after
      odontogenesis. These elements may be found in either bone or soft tissue of the
      jaws and may contribute to the formation of odontogenic tumors in these sites.
      Further, the mixture of epithelium and mesenchyme necessary for tooth formation
      allows for the development of tumors composed of either element or for mixed
      neoplasms. This article discusses 4 of the 5 benign odontogenic neoplasms that
      are of epithelial origin and offers an agreed on classification scheme, which
      includes important clinicopathological subtypes. Specifically discussed are
      ameloblastoma, calcifying epithelial odontogenic tumor (Pindborg tumor),
      adenomatoid odontogenic tumor, and squamous odontogenic tumor. A brief history of
      each tumor is given along with a discussion of demographic data, clinical
      findings, radiographic features, and gross features where useful. A thorough
      discussion is presented of diagnostic histopathology including histologic
      variants. Generally accepted modes of therapy and follow-up recommendations are
      discussed.

PMID- 10587270
TI  - Odontogenic ghost cell tumor.
AB  - Odontogenic ghost cell tumor is a rare epithelial odontogenic tumor that is the
      neoplastic counterpart of the calcifying odontogenic cyst. There is confusion and
      controversy in the literature regarding the integration or segregation of these 2
      lesions. It shows many histologic features with ameloblastoma but in addition has
      characteristic ghost cells and dentinoid. It occurs within the maxillary and
      mandibular bones (central) and in the gingival soft tissues (peripheral).
      Peripheral tumors are treated with simple excision. Although central tumors are
      often amenable to curettage or simple excision, some tumors have been more
      aggressive and require partial resection of the jaw. Malignant tumors with
      similar features have been reported. This is a US government work. There are no
      restrictions on its use.

PMID- 10587271
TI  - Odontogenic fibroma.
AB  - The odontogenic fibroma is a rare tumor that has generated controversy, perhaps
      disproportionately to its importance in the family of odontogenic tumors. The
      clinical and radiographic features are well documented but the histologic aspects
      have generated controversy. The behavior is benign, and published accounts
      indicate a low recurrence rate following treatment by curettage. The tumor
      recognized by the World Health Organization (WHO) is the legitimate odontogenic
      fibroma. Histologic variants include the granular cell type and the hybrid
      odontogenic fibroma giant cell-like tumor. Although the extraosseous "peripheral"
      odontogenic fibroma presents as a gingival enlargement clinically
      indistinguishable from other gingival lesions, its histomorphology is similar to
      the central tumor. A normal dental follicle around the crown of an unerupted
      tooth may histologically mimic the odontogenic fibroma and other odontogenic
      tumors.

PMID- 10587272
TI  - Odontogenic myxoma.
AB  - The odontogenic myxoma is an uncommon tumor that has the potential for extensive
      bony destruction, extension into surrounding structures, and a relatively high
      recurrence rate. Treatment often requires bone resection. The bland histologic
      features of a monotonous proliferation of a loose, mesenchymal fibrous tissue
      that lacks atypia may easily lead to a misdiagnosis. The primitive dental pulp,
      the dental papilla, and the tooth follicle are histologically similar to myxoma.
      These soft tissue fragments often separate from extracted developing teeth that
      are submitted to the pathologist and may easily be misinterpreted as an
      odontogenic myxoma. The pathologist must have good clinical and radiographic
      correlation to avoid a misdiagnosis and to prevent unnecessary additional
      surgery.

PMID- 10587273
TI  - Cemento-ossifying fibroma and benign cementoblastoma.
AB  - Cementum is a calcified dental tissue that covers the roots of teeth and is part
      of the periodontium. Its function is to help anchor the teeth in their sockets
      within the alveolar bone of the jaws. Two benign mesenchymal odontogenic tumors
      are uniquely distinguished by elaboration of cementum or cementum-like material:
      cemento-ossifying fibroma and benign cementoblastoma (true cementoma). Cemento
      ossifying fibroma, which is also termed periodontoma, is characterized by
      production of cementum and bone in a fibrous stroma. It is a painless, slow
      growing tumor usually detected in the third and fourth decade of life and is more
      common in women. The mandible is its site of predilection. Benign cementoblastoma
      is intimately associated with the roots of teeth, most commonly mandibular
      molars. It affects young patients, usually under the age of 20 years. Pain is a
      common symptom in addition to bone expansion. Benign cementoblastoma bears
      considerable histologic resemblance to osteoblastoma.

PMID- 10587274
TI  - Benign mixed odontogenic tumors.
AB  - As a group, the mixed odontogenic tumors histologically resemble various stages
      of tooth formation (odontogenesis). Because of this, confusion arises in
      diagnosis and nomenclature unless one is familiar with normal tooth development
      and its subsequent resemblance to the neoplasms and hamartomas which arise from
      the tooth-forming tissues of the jaws. This article reviews odontogenesis and
      relates it to the formation of the mixed odontogenic tumors-the ameloblastic
      fibroma, ameloblastic fibro-odontoma, and the odontomas. Correlation of clinical
      and radiographic features with the histologic features will generally result in
      correct diagnosis and proper treatment.

PMID- 10587275
TI  - Malignant epithelial odontogenic tumors.
AB  - Malignant epithelial odontogenic tumors are very rare. They may arise from the
      epithelial components of the odontogenic apparatus. The rests of Malassez, the
      reduced enamel epithelium surrounding the crown of an impacted tooth, the rests
      of Serres in the gingiva, and the linings of odontogenic cysts represent the
      precursor cells for malignant transformation. Because metastatic carcinoma is the
      most common malignancy of the jaws, the diagnosis of a primary intraosseous
      carcinoma must always be made to the exclusion of metastatic disease. Odontogenic
      carcinomas include malignant (metastasizing) ameloblastoma, ameloblastic
      carcinoma, primary intraosseous squamous cell carcinoma, clear cell odontogenic
      carcinoma, and malignant epithelial ghost cell tumor. There are specific
      histopathologic features that support the diagnosis of a primary carcinoma of
      odontogenic epithelium which are presented in this article. Immunohistochemical
      (IHC) staining is important for distinguishing clear cell odontogenic carcinoma
      from metastatic renal cell tumors, yet IHC stains are not particularly helpful
      for other lesions in this group-all of which exhibit low molecular weight
      cytokeratin positivity. Aggressive growth and nodal and distant metastases occur
      with all of these entities.

PMID- 10587276
TI  - Odontogenic sarcoma and carcinosarcoma.
AB  - Odontogenic sarcoma is a gnathic malignant connective tissue tumor containing
      epithelium similar to that seen in an ameloblastoma or ameloblastic fibroma. It
      is a mixed odontogenic tumor in which the epithelial component is benign and the
      proliferative mesenchymal component is malignant. With each recurrence, the
      ameloblastic fibrosarcoma demonstrates increasing evidence of stromal cellularity
      and mitotic activity but diminishing evidence of odontogenic epithelium. If an
      ameloblastic fibrosarcoma exhibits dysplastic dentin, it can be called an
      ameloblastic fibrodentinosarcoma, and if it additionally shows focal deposits of
      dysplastic enamel proteins, it can be designated an ameloblastic fibro
      odontosarcoma. A jaw tumor displaying both a carcinomatous and a malignant
      spindle cell component can be termed an odontogenic carcinosarcoma if it reveals
      an ameloblastic fibroma-like pattern. If it lacks this pattern, the appellations
      "spindle-cell ameloblastic carcinoma" or "biphasic ameloblastic sarcomatoid
      carcinoma" might be preferable. This is a US government work. There are no
      restrictions on its use.

PMID- 10587277
TI  - Dispelling myths about benzodiazepines.

PMID- 10587278
TI  - Effectiveness and safety of benzodiazepines.
AB  - Benzodiazepines have been used to treat a wide variety of disorders, including
      generalized anxiety disorder, panic disorder, sleep disorders, somatopsychic
      disorders, and depression. Concerns regarding physiologic dependence, withdrawal,
      and abuse potential with benzodiazepines prompted the development of strict
      guidelines for the use of these agents. Studies have shown that the risk of
      physiologic dependence increases with factors such as the dose of the
      benzodiazepine used and the duration of treatment. Restrictions involving
      benzodiazepines have led to the substitution of alternative medicines that may
      have decreased efficacy and greater safety concerns. There is a need for a more
      balanced assessment of the benefits and risks associated with benzodiazepine use
      to ensure that patients who would truly benefit from these agents are not denied
      appropriate treatment.

PMID- 10587279
TI  - Pharmacologic strategies for discontinuing benzodiazepine treatment.
AB  - Benzodiazepines have been shown to have broad-spectrum activity, rapid onset of
      action, and a wide therapeutic window compared with other anxiolytic medications.
      Yet the use of benzodiazepines has been limited by concern regarding dependence,
      withdrawal, and abuse. Agents such as antidepressants, serotonergic anxiolytics,
      anticonvulsants, and beta-blockers have been used with varying degrees of success
      to help facilitate the tapering of benzodiazepines. Carbamazepine, imipramine,
      valproate, and trazodone have been beneficial in the management of benzodiazepine
      discontinuation, but not in decreasing the severity of benzodiazepine withdrawal.
      A stepwise approach to discontinuing benzodiazepines is offered.

PMID- 10587280
TI  - Psychological strategies for discontinuing benzodiazepine treatment.
AB  - Successful discontinuation of therapeutic drugs requires patients to negotiate
      two potentially difficult phases. First, they must complete the drug
      discontinuation procedure itself, which may entail coping with rebound and
      withdrawal symptoms as well as anxiety due to stopping a treatment on which they
      depend psychologically. Second, they must maintain drug abstinence over time,
      despite possible exacerbations or recurrences of the disorder that the drug was
      treating. For optimal success, interventions aimed at assisting patients to
      discontinue drug use must address both of those tasks. Patients' ability to
      discontinue benzodiazepines seems to be strongly influenced by cognitive
      appraisals of the threat represented by symptoms and of their own competence to
      cope with it without medication. For problems of that kind, cognitive and
      behavioral techniques such as those developed for the treatment of panic disorder
      may be especially well-suited. Currently, the most successful approaches to
      benzodiazepine discontinuation include the following components: (1) assisting
      with initial drug discontinuation, educating patients about benzodiazepine
      dependence and withdrawal, and about the kinds of symptoms that can emerge as the
      drug dose is decreased, combined with a flexible drug taper conducted in
      supportive collaboration with the patient; and (2) dealing with exacerbations of
      the illness, and providing disorder-specific cognitive-behavioral treatment as an
      alternative to the resumption of pharmacotherapy. It seems to be crucial that the
      drug taper be completed before psychological treatment concludes.

PMID- 10587281
TI  - International study of expert judgment on therapeutic use of benzodiazepines and
      other psychotherapeutic medications: IV. Therapeutic dose dependence and abuse
      liability of benzodiazepines in the long-term treatment of anxiety disorders.
AB  - Despite decades of relevant basic and clinical research, active debate continues
      about the appropriate extent and duration of benzodiazepine use in the treatment
      of anxiety and related disorders. The primary basis of the controversy seems to
      be concern among clinicians, regulators, and the public about the dependence
      potential and the abuse liability of benzodiazepines. This article reports
      systematically elicited judgments on these issues by a representative panel of 73
      internationally recognized experts in the pharmacotherapy of anxiety and
      depressive disorders, a panel which was constituted by a multistage process of
      peer nomination. The criterion for inclusion at each stage was the nomination by
      at least two peers as one of the "professionally most respected physicians of the
      world with extensive experience and knowledge in the pharmacotherapy of anxiety
      and depressive disorders." Sixty-six respondents (90%) completed a comprehensive
      questionnaire covering a wide range of topics relevant to the therapeutic use of
      benzodiazepines and other medications that might be used for the same purposes.
      Overall, the expert panel judged that benzodiazepines pose a higher risk of
      dependence and abuse than most potential substitutes but a lower risk than older
      sedatives and recognized drugs of abuse. There was little consensus about the
      relative risk of dependence and abuse among the benzodiazepines. Differences
      between benzodiazepines with shorter and longer half-lives in inducing withdrawal
      symptoms are much less clear during tapered than during abrupt discontinuation.
      There was little agreement about the most important factors contributing to
      withdrawal symptoms and failure to discontinue benzodiazepines. The pharmacologic
      properties of the medication may be the most important contributors to withdrawal
      symptoms. In contrast, the clinical characteristics of the patient may be the
      most important contributors to failure to discontinue medication. The experts'
      judgment seems to support the widespread use of benzodiazepines for the treatment
      of bona fide anxiety disorders, even over long periods. The experts generally
      viewed dependence and abuse liability as clinical issues amenable to appropriate
      management, as for other adverse events related to therapy. However, more
      definitive clinical research on the remaining controversial issues is urgently
      needed to promote optimal patient care.

PMID- 10587282
TI  - Human cytochromes mediating sertraline biotransformation: seeking attribution.

PMID- 10587283
TI  - Pharmacokinetic interaction of fluvoxamine and thioridazine in schizophrenic
      patients.
AB  - This study investigated to what extent fluvoxamine affects the pharmacokinetics
      of thioridazine (THD) in schizophrenic patients under steady-state conditions.
      Concentrations of THD, mesoridazine, and sulforidazine were measured in plasma
      samples obtained from 10 male inpatients, aged 36 to 78 years, at three different
      time points: A, during habitual monotherapy with THD at 88 +/-54 mg/day; B, after
      addition of a low dosage of fluvoxamine (25 mg twice a day) for 1 week; and C, 2
      weeks after fluvoxamine discontinuation. After the addition of fluvoxamine, THD
      concentrations relative to time point A significantly increased approximately
      threefold from 0.40 to 1.21 micromol/L (225%) (p < 0.002), mesoridazine
      concentrations increased from 0.65 to 2.0 micromol/L (219%) (p < 0.004), and
      sulforidazine levels increased from 0.21 to 0.56 micromol/L (258%) (p < 0.004).
      The THD-mesoridazine and THD-sulforidazine ratios remained unchanged during the
      study. Mean plasma THD, mesoridazine, and sulforidazine levels decreased at time
      point C, but despite fluvoxamine discontinuation for 2 weeks, three patients
      continued to exhibit elevated concentrations of THD and its metabolites. In
      conclusion, fluvoxamine markedly interferes with the metabolism of THD, probably
      at the CYP2C19 and/or CYP1A2 enzyme level. Therefore, clinicians should be aware
      of the potential for a clinical drug interaction between both compounds, and
      careful monitoring of THD levels is valuable to prevent the accumulation of the
      drug and resulting toxicity.

PMID- 10587284
TI  - Acute mania: haloperidol dose and augmentation with lithium or lorazepam.
AB  - Antipsychotic dosing for acute mania has not been well studied. Combined
      treatment with lithium and an antipsychotic is the most common treatment, but
      additional antimanic efficacy of a lithium-antipsychotic combination beyond that
      of an antipsychotic alone has not been well demonstrated. Furthermore, the
      possibility that lithium could affect antipsychotic dose requirement is believed
      to have never been studied. In this study, 63 acutely psychotic bipolar manic
      inpatients were randomly assigned to receive double-blind treatment with 1 of 2
      haloperidol doses, 25 mg/day or 5 mg/day, for 21 days. In addition to
      haloperidol, subjects were randomly assigned to receive concomitant treatment
      with placebo, standard lithium, or lorazepam 4 mg/day. The high haloperidol dose
      produced greater improvement and more side effects than did the low dose. Lithium
      added to the low dose produced a markedly greater clinical response than did the
      low dose alone. Lorazepam did not improve the outcome for the patients receiving
      low-dose haloperidol. The clinical response produced by high-dose haloperidol was
      not enhanced by adding either lithium or lorazepam. All treatment effects emerged
      by the fourth day of treatment and persisted. Used alone, a haloperidol dose of 5
      mg/day is too low for most manic patients, but concomitant lithium produces a
      dose-dependent enhancement of haloperidol response. Lorazepam 4 mg/day was
      insufficient to produce an advantage when added to low-dose haloperidol.

PMID- 10587285
TI  - Beneficial effects of glycine (bioglycin) on memory and attention in young and
      middle-aged adults.
AB  - The N-methyl D-aspartate receptor complex is involved in the mechanism of long
      term potentiation, which is thought to be the biological basis of learning and
      memory. This complex can be manipulated in a number of ways, one of which is
      through the strychnine-insensitive glycine receptor coagonist site. The effects
      of Bioglycin(Konapharma, Pratteln, Switzerland), a biologically active form of
      the amino acid glycine, were therefore studied in healthy students (mean age,
      20.7 years) and middle-aged men (mean age, 58.9 years) with tests that measured
      attention, memory and mood, using a double-blind, randomized, crossover design.
      Compared with the young group, the middle-aged group had significantly poorer
      verbal episodic memory, focused, divided, and sustained attention; they also
      differed in their subjective responses at the end of testing. Bioglycin
      significantly improved retrieval from episodic memory in both the young and the
      middle-aged groups, but it did not affect focused or divided attention. However,
      the middle-aged men significantly benefited from Bioglycin in the sustained
      attention task. The effects of Bioglycin differed from those of other cognitive
      enhancers in that it was without stimulant properties or significant effects on
      mood, and it primarily improved memory rather than attention. It is likely to be
      of benefit in young or older people in situations where high retrieval of
      information is needed or when performance is impaired by jet lag, shift work, or
      disrupted sleep. It may also benefit the impaired retrieval shown in patients
      with schizophrenia, Parkinson's disease, and Huntington's disease.

PMID- 10587286
TI  - Preferential cerebrospinal fluid acetylcholinesterase inhibition by rivastigmine
      in humans.
AB  - This study sought to examine the feasibility of prolonged assessment of
      acetylcholinesterase (AChE) activity in the cerebrospinal fluid (CSF) of
      volunteers and to test the hypothesis that rivastigmine (ENA-713; Exelon,
      Novartis Pharma AG, Basel, Switzerland) selectively inhibits AChE in CSF in
      humans at a dose producing minimal inhibition of the peripheral enzyme. Lumbar
      CSF samples were collected continuously (0.1 mL x min(-1)) for 49 hours from
      eight healthy volunteers who took either placebo or a single oral dose of
      rivastigmine (3 mg). CSF specimens and samples of blood cells and blood plasma
      were analyzed at intervals for rivastigmine and its metabolite NAP 226-90 ([-] [3
      ([1-dimethylaminolethyl)-phenol]), erythrocyte AChE activity, CSF AChE activity,
      and plasma and CSF butyrylcholinesterase (BuChE) activity. Safety evaluations
      were performed 23 hours after drug dosing and at the end of the study. Evaluable
      data were obtained from six subjects. The mean time to maximal rivastigmine
      plasma concentration (tmax) was 0.83 +/- 0.26 hours, the mean maximal plasma
      concentration (Cmax) was 4.88 +/- 3.82 ng x mL(-1), the mean plasma area under
      the concentration versus time curve (AUC0-infinity) was 7.43 +/- 4.74 ng x hr x
      mL(-1), and the mean plasma t1/2 was 0.85 +/- 0.115 hours. The concentration of
      rivastigmine in CSF was lower than the quantification limit for assay (0.65 ng x
      mL(-1)), but NAP 226-90 reached a mean Cmax of 3.14 +/- 0.57 ng x mL(-1). Only
      minimal inhibition of erythrocyte AChE activity (approximately 3%) was observed.
      Inhibition of AChE in the CSF after rivastigmine administration was significantly
      greater than after placebo for up to 8.4 hours after the dose and was maximal
      (40%) at 2.4 hours. Plasma BuChE activity was significantly lower after
      rivastigmine than after placebo, but this was not clinically relevant. BuChE
      activity in CSF was significantly lower after rivastigmine than after placebo for
      up to 3.6 hours after dosing, but this difference was not sustained. This study
      confirms the feasibility of using continuous measurement of AChE activity in CSF
      over prolonged periods, that rivastigmine markedly inhibits CSF AChE after a
      single oral dose of 3 mg, and that the inhibition of central AChE is
      substantially greater than that of peripheral AChE or BuChE.

PMID- 10587287
TI  - Deprenyl augmentation for treating negative symptoms of schizophrenia: a double
      blind, controlled study.
AB  - Augmentation of dopaminergic neurotransmission has been suggested as a treatment
      strategy for negative symptoms of schizophrenia. On the basis of open studies
      that reported the potential benefit of deprenyl (selegiline) as augmentation to
      antipsychotic treatment, this double-blind, controlled study was designed to
      further address this question. Sixteen schizophrenic patients with predominately
      negative symptoms, manifesting clinical stability on maintenance antipsychotic
      treatment, were randomly assigned to receive either deprenyl 15 mg/day or placebo
      in addition to their antipsychotic treatment for 8 weeks. Clinical follow-up and
      ratings were done during this period and for 8 more weeks after deprenyl
      discontinuation. Both groups showed a statistically significant but clinically
      marginal improvement over the 8 weeks of deprenyl or placebo treatment. This
      improvement was abolished during the postdiscontinuation follow-up period.
      Deprenyl at a dose of 15 mg/day did not offer therapeutic benefit in our
      patients. A significant placebo effect was observed, which may be the result of
      increased patient-doctor contact during the study.

PMID- 10587288
TI  - Which is the optimal antiandrogen for use in combined androgen blockade of
      advanced prostate cancer? The transition from a first- to second-generation
      antiandrogen.
AB  - Many physicians use combined androgen blockade in the form of a luteinizing
      hormone-releasing hormone analog or bilateral orchiectomy in combination with a
      non-steroidal antiandrogen to offer patients a potentially more effective
      treatment than castration alone. Three non-steroidal anti-androgens are available
      in the US, i.e. flutamide (Eulexin), bicalutamide (Casodex) and nilutamide
      (Nilandron). Nilutamide offers patients no benefit over flutamide or bicalutamide
      and has the least favorable safety profile. Because of its short half-life,
      flutamide must be administered 3 times a day. Furthermore, flutamide therapy is
      associated with a relatively high incidence of diarrhea, often intolerable for
      some patients. Bicalutamide is available in a convenient one tablet, once-a-day
      dosing regimen, is at least as effective as flutamide and is better tolerated in
      terms of diarrhea. Therefore, bicalutamide would seem to represent an appropriate
      first choice in patients who are suitable candidates for combined androgen
      blockade.

PMID- 10587289
TI  - In vitro chemosensitivity testing of hematological cancers: immunohistochemical
      detection of ornithine decarboxylase.
AB  - A new method for in vitro chemosensitivity testing of human lymphoma and leukemia
      patients has been developed. The method is based on the use of ornithine
      decarboxylase (ODC), a universal marker of proliferation, which is expressed
      early during the cell cycle and has a short half-life. This marker was detected
      by a quantitative immunohistochemical analysis, using an ODC antibody and a FITC
      linked second antibody. The in vitro chemosensitivity of lymphocytes from four
      normal individuals was tested by the immunohistochemical method. Lymphocytes from
      25 cancer patients were also examined. In drug-sensitive cells, the intensity of
      the marker declined in the presence of the drug, whereas resistance to the drug
      was demonstrated by the presence of the marker. A good correlation was found
      between the predicted chemosensitivity and the outcome of the therapy. It has
      been suggested that this approach could be used for in vitro chemosensitivity
      testing of hematological cancers and most likely also for other malignancies.

PMID- 10587290
TI  - Population pharmacokinetic approach to compare oral and i.v. administration of
      etoposide.
AB  - The antitumor effect of etoposide (ETO) may be related to duration of exposure to
      a relatively low serum level while myelosuppression may be dependent on peak ETO
      serum levels. With regard to such therapeutic ranges, duration of exposure to
      predefined plasma ETO concentration ranges and the related AUC (expressed as
      percent of total AUC, pAUC) were used to compare pharmacokinetic profiles after
      oral and short time i.v. (1 h infusion) administration of identical ETO doses
      (100 mg/m2). Patients included in this study received i.v. (18 patients, short
      term infusions) or oral (16 patients) ETO on different treatment schedules.
      Plasma ETO concentrations were determined by HPLC and population pharmacokinetic
      parameters were calculated (P-Pharm 1.4). Despite an 'apparent bioavailability'
      of 59%, oral administration of ETO was associated with the same time of exposure
      to a predefined 'therapeutic range' of 0.5-3 mg/l and a significantly higher pAUC
      compared to i.v. administration. By contrast, time of exposure to the probably
      more myelotoxic concentration range above 3 mg/l was significantly shorter and
      the related pAUC was highly significantly lower after oral than after i.v.
      administration. These findings demonstrate that oral ETO therapy is at least
      equivalent to short time i.v. therapy in terms of achieving specific target
      concentration ranges and avoiding peak concentrations.

PMID- 10587291
TI  - Pharmacokinetic interaction between etoposide and tamoxifen in patients with
      hepatocellular carcinoma.
AB  - The effect of tamoxifen (TAM) on the pharmacokinetics of oral administration of
      etoposide (VP-16) in patients with nonoperable hepatocellular carcinoma was
      investigated. The pharmacokinetics of VP-16 was studied by using a validated
      limited sampling strategy. The pharmacokinetic parameters of VP-16, such as area
      under curve (AUC), free AUC and protein binding, were determined from drug plasma
      concentrations at 1 and 4 h after VP-16 administration on the first day (day -1)
      and at the end of the chemotherapy cycle (day -21) for VP-16 alone and VP-16+TAM,
      respectively. When VP-16 was administered in association with TAM, the median
      total systemic exposure was not significantly (p = NS) different from that
      observed when VP-16 was administered alone [33.74 (range 11.19-56.58) versus
      32.97 (range 20.23-119.28) mg/l/h]. Moreover, TAM did not affect significantly (p
      = NS) the levels of protein binding of VP-16 [median 94.6 (range 87.7-98.2)
      versus median 94.9 (range 91.6-98.0)% for VP-16+TAM and VP-16 alone,
      respectively] and the systemic exposure of the free drug (free AUC) [1.86 (range
      0.21-4.57) versus median 1.78 (range 0.59-3.73) mg/l/h for VP-16+TAM and VP = 16
      alone, respectively]. These results indicate a lack of pharmacokinetic
      interaction between VP-16 and TAM, and suggest that the increased hematological
      toxicity observed when TAM is given in combination with VP-16 could be related to
      pharmacodynamic interactions.

PMID- 10587292
TI  - Phase I and pharmacologic study of BMS-181174 given as a 6 h infusion every 4
      weeks to patients with advanced solid tumors.
AB  - BMS-181174, a new mitomycin C (MMC) analog, showed more activity than the parent
      compound in tumor xenografts. In a phase I study with a 5-30 min slow bolus
      administration, hematologic and vascular toxicity were observed as major side
      effects. A prolonged infusion was suggested to circumvent the vascular toxicity.
      In this phase I study BMS-181174 was administered as a 6 h infusion every 4
      weeks; the doses studied were 3.2, 6.4, 11.5, 19.0, 32.0, 50.0, 75.0 and 100
      mg/m2. Twenty-eight patients were enrolled in the study, the majority with
      colorectal cancer. Hematologic side effects consisted of thrombocytopenia, and
      mild leuko- and granulocytopenia. The most distressing non-hematologic side
      effect was vascular toxicity consisting of phlebosclerosis and phlebitis,
      becoming dose limiting at 100 mg/m2. One patient developed a hemolytic uremic
      syndrome at a cumulative dose of 350 mg/m2. Pharmacokinetic data are available
      for 24 patients. The AUC ranged from 3.35 to 41.49 (microg x h/ml) and was highly
      correlated with the dose administered (r = 0.83). The kinetics appeared to be
      linear. One patient with metastatic colon cancer had a partial response of liver
      metastases. BMS-181174 is a MMC analog with a toxicity profile comparable to that
      of the parent compound. As doses above 50 mg/m2 are complicated by vascular
      toxicity precluding multiple administrations, further exploration of BMS-181174
      will not be performed.

PMID- 10587293
TI  - Antitumor activity of KF22678, a novel thioester derivative of leinamycin.
AB  - KF22678, a novel thioester derivative of leinamycin with the 1-oxo-1,2-dithiolane
      3-one moiety, was examined for anti-tumor activity, toxicity in mice and
      activation mechanism. KF22678 showed a broad antitumor spectrum against human
      carcinoma xenografts (lung, colon, ovary and prostate). The efficacy of KF22678
      was significantly higher than that of cisplatin. KF22678 exhibited low cross
      resistance against various drug-resistant cell lines of MDR1 or MRP
      overexpressing human tumors, and, in addition, exhibited more potent antitumor
      activity in vivo than ADM against A2780/ADM and KB/MRP xenograft. DL-Buthionine
      sulfoximine (BSO) pretreatment significantly reduced intracellular glutathione
      (GSH) level in human lung carcinoma A549 cells, leading to decrease in the
      cytotoxicity of KF22678, whereas the cytotoxicity of melphalan was augmented by
      BSO pretreatment. DNA single-strand breaks (SSB) were observed in A549 cells
      treated with KF22678 and bleomycin. DNA SSB induced by KF22678 was greatly
      reduced in the presence of BSO in the cells, whereas DNA SSB induced by bleomycin
      was not. In addition, the antitumor activity of KF22678 against BSO-pretreated
      human lung carcinoma PC-9 tumor was significantly decreased. These results
      suggest that the activation of KF22678 by intracellular GSH might be important
      for DNA SSB and antitumor activity in vitro and in vivo.

PMID- 10587294
TI  - Antitumor activity of MGI 114 (6-hydroxymethylacylfulvene, HMAF), a semisynthetic
      derivative of illudin S, against adult and pediatric human tumor colony-forming
      units.
AB  - MGI 114 (6-hydroxymethylacylfulvene, HMAF) is a novel semisynthetic antitumor
      compound derived from the sesquiterpene mushroom toxin illudin S. Although
      illudins did not demonstrate significant activity as antiproliferative agents in
      tumor-bearing animals, several properties including its potent inhibition of DNA
      synthesis and a unique interaction with DNA led to a structure-activity-based
      synthetic effort to obtain analogs with improved therapeutic potential. MGI 114
      was selected for further development based on its antitumor activity in numerous
      preclinical tests. MGI 114 was evaluated against adult and pediatric human tumors
      taken directly from cancer patients and cultured in a human tumor colony-forming
      assay (HTCFA) to assess the antitumor spectra, concentration-response
      relationship, schedule dependence and activity of this agent against tumors
      considered resistant to conventional anticancer drugs. Human tumor colony-forming
      units were treated with HMAF at concentrations of 0.001, 0.01, 0.1 and 1
      microg/ml, both as a 1 h exposure and as a continuous 14 day exposure. A response
      was scored if there was 50% or less colony survival. In vitro response rates in
      the range of 50-80% were observed against tumor colony-forming units originating
      from carcinomas of the colon, kidney, breast, lung cancer, ovary and melanoma.
      MGI 114 also demonstrated antitumor activity against neuroblastoma colony-forming
      units. Antitumor activity was not influenced by exposure time as demonstrated by
      the similar responses rates obtained with the 1 h and continuous exposure at all
      concentrations tested. However, there was a significant positive concentration
      response relationship to both exposure duration with responses increasing from
      below 10% at the lowest concentration to over 70% at the highest concentration,
      except for the pediatric tumors on the 1 h exposure for which this relationship
      was less apparent. At the higher concentration tested, MGI 114 displayed
      substantial antiproliferative effects in the range of 70% against tumor specimens
      resistant to classic cytotoxic agents including irinotecan, paclitaxel, 5
      fluorouracil, cisplatin, doxorubicin and cyclophosphamide. These results
      demonstrate that MGI 114 exhibits a broad spectrum of antitumor activity against
      both adult and pediatric primary tumor colony-forming units in a concentration
      dependent manner both at short and prolonged exposure duration. The substantial
      in vitro activity of MGI 114 at concentrations achievable in clinical trials,
      together with its activity against tumors resistant to classic standard cytotoxic
      drugs, justifies the further clinical evaluation of this unique agent.

PMID- 10587295
TI  - Induction of apoptosis by gallic acid in lung cancer cells.
AB  - The apoptosis-inducing effect of gallic acid (3,4,5-trihydroxybenzoic acid) was
      investigated in four human lung cancer cell lines, SBC-3 (small cell carcinoma),
      EBC-1 (squamous cell carcinoma), A549 (adenocarcinoma) and SBC-3/CDDP (cisplatin
      resistant subclone of SBC-3). Gallic acid induced apoptosis in a dose-dependent
      manner as evidenced by analyses of DNA fragmentation, changes in cell morphology
      and loss of viability. Fifty percent inhibitory concentration (IC50) values of
      gallic acid on the cell viability of SBC-3, EBC-1 and A549 were around 10, 20 and
      60 microg/ml, respectively. The IC50 value for SBC-3/CDDP cells was almost the
      same as that of SBC-3, suggesting that susceptibility of cells to gallic acid
      induced apoptosis is not altered by the acquisition of cisplatin resistance. The
      apoptotic process was effectively triggered by 30 min exposure to gallic acid. A
      caspase inhibitor and alpha-tocopherol effectively prevented the gallic acid
      induced apoptosis, indicating the involvememt of caspase activation and oxidative
      processes during the course of apoptosis in gallic acid-treated cancer cells.
      These findings suggest the possible applicability of gallic acid in lung cancer
      therapy, especially to circumvent resistance to anti-cancer drugs.

PMID- 10587296
TI  - Diazene JK-279: potential anticancer drug.
AB  - The aim of this study was to examine the cytotoxic effect of 10 newly synthesized
      diazenecarboxamides (diazenes). Using a modified colorimetric MTT assay, their
      cytotoxicity was determined on 10 human cell lines: cervical carcinoma parental
      and cisplatin-resistant cells, laryngeal carcinoma parental and cisplatin- and
      vincristine-resistant cells, glioblastoma parental and cisplatin-resistant cells,
      breast adenocarcinoma parental and doxorubicin-resistant cells, and mammary
      carcinoma cells. Results show that diazene JK-279 was most effective, reducing
      significantly the cell survival of all 10 cell lines examined, including five
      drug-resistant cell lines. A cytotoxic effect was observed also on nine from 10
      cell lines for diazene JK-835. A small reduction in cell survival was obtained
      (mainly for highest drug concentrations) for diazenes LV-57 and MG-19 on two cell
      lines, and JK-429 and JK-913 on one cell line. Other diazenes did not demonstrate
      any cytotoxic activity. The results encourage further research on diazene JK-279
      as a potential anticancer drug.

PMID- 10587297
TI  - Bm86 antigen induces a protective immune response against Boophilus microplus
      following DNA and protein vaccination in sheep.
AB  - Vaccination of sheep with a plasmid bearing the full length gene for the tick
      antigen Bm86 either alone or co-administered with plasmid carrying the ovine
      genes for the cytokines, granulocyte and macrophage colony stimulating factor (GM
      CSF) or interleukin (IL)-1beta induced a relatively low level of protection
      against subsequent tick infestation. This tick damage reached statistical
      significance only for the groups which were vaccinated with plasmid encoding for
      Bm86, co-administered with plasmid encoding for ovine GM-CSF. Antibody titres
      measured against Bm86 were also low in all groups injected with the Bm86 DNA
      vaccine. Antibody production and anti-tick effect were significantly less than
      that achieved by two vaccinations with recombinant Bm86 protein. In all cases
      only a low level of antigen-specific stimulation of peripheral blood lymphocytes
      was recorded, as measured either by the incorporation of tritiated thymidine or
      the release of IFN-gamma. Injection of DNA encoding for Bm86, either alone or
      with co-administered cytokine genes, did however prime for a strong subsequent
      antibody response following a single injection of recombinant Bm86 protein in
      adjuvant. Antibody production nevertheless appeared to be slightly less effective
      than following two vaccinations with recombinant protein. The persistence of
      antibody following vaccination was the same regardless of the method of primary
      sensitization. In all cases the half-life of the antibody response was
      approximately 40-50 days indicating that, in contrast to results reported in
      mice, DNA vaccination in sheep did not result in sustained antibody production.

PMID- 10587298
TI  - Natural cytotoxic activity of gilthead seabream (Sparus aurata L.) leucocytes.
      Assessment by flow cytometry and microscopy.
AB  - This paper describes an easy and sensitive flow cytometric assay for assessing
      the non-specific cytotoxic activity of gilthead seabream (Sparus aurata L.) head
      kidney leucocytes against tumor target cells. Concomitantly, the cytotoxic
      process and the cell types involved were microscopically studied. The assay was
      based on the consecutive use of two fluorochromes. The targets were preincubated
      with 3,3'-dioctadecyloxacarbocyanine perchlorate (DiO) and then mixed with
      effectors. At the end of incubation time propidium iodide (PI) was added. While
      live effectors were non-fluorescent, live and dead targets retained the DiO
      (green) fluorescence and non-viable targets and effectors showed PI (red)
      fluorescence staining. The kinetics of the cytotoxic activity was studied from 10
      to 240 min. Lymphocytes, monocyte-macrophages and granulocytes showed non
      specific cytotoxic activity, as demonstrated by light and electron microscopy. In
      conclusion, the technique presented validates the effectiveness of a dual-color
      flow cytometric assay for assessing the activity of non-specific cytotoxic cells
      in fish.

PMID- 10587299
TI  - A DNA fragment of Leptospira interrogans encodes a protein which shares epitopes
      with equine cornea.
AB  - Horses infected with Leptospira interrogans present several clinical disorders,
      one of them being recurrent uveitis. An antigenic relationship between this
      bacterium and equine cornea has been described in previous studies. With the aim
      to make progress on defining the molecular basis and pathogenesis of equine
      recurrent uveitis, here we describe the cloning of one DNA fragment from a
      Leptospira interrogans serovar pomona genomic lambda gt11 library. Although there
      are references of transcription of leptospiral genes in E. coli from their own
      leptospiral promoters, in this recombinant construction the leptospiral DNA was
      located under the control of lacZ promoter since no expression could be detected
      in the absence of IPTG. This clone, isolated by expression screening with
      polyclonal serum raised against equine corneal proteins, encodes a 90 kDa protein
      of L. interrogans which crossreacts with equine cornea as proved Western
      blotting. Antibodies directed against this leptospiral protein strongly
      recognised a 66 kDa equine corneal protein, one of those recognised by an anti
      equine cornea serum. Our findings suggest that an immune response to 90 kDa
      protein participates in pathogenesis of equine uveitis.

PMID- 10587300
TI  - The immune response and PBMC subsets in canine visceral leishmaniasis before, and
      after, chemotherapy.
AB  - Peripheral blood mononuclear cell subsets, in vitro lymphoproliferative response
      to leishmanial antigen, and Leishmania-specific serum antibody levels were
      examined in 11 dogs, naturally infected with L. infantum, and 9 healthy control
      dogs. A decrease in the percentage of CD4+ T-cells and an increase in the
      proportion of gammadelta T-cells and sIgG+ B-cells were observed during canine
      visceral leishmaniasis (CVL). These changes may be responsible for the marked
      humoral response and the absence of in vitro lymphoproliferation to mitogen and
      specific parasite antigens. This possibility was supported by the analysis of
      these subsets after treatment with amphotericin B. One month after therapy, a
      significant increase in the percentage of CD4+ T-cells and a decrease of
      gammadelta T-cells and sIgG+ B-cells were observed. At the same time, the
      lymphocyte blastogenesis assay with leishmanial antigen was positive and the
      levels of specific antibodies to Leishmania were significantly lower than before
      the treatment. Five months after therapy, lymphocyte proliferative response to
      LSA disappeared, antibody and lymphocyte subsets levels returned to those
      observed during CVL. Therapeutic failure in CVL is associated with the inability
      of antileishmanial drugs to completely revert the profound immunodepression
      induced by the infection and prevent relapse.

PMID- 10587301
TI  - Functional characterization of equine dendritic cells propagated ex vivo using
      recombinant human GM-CSF and recombinant equine IL-4.
AB  - Naive T cells can be activated both in vivo and in vitro by specialized antigen
      presenting cells, dendritic cells (DC), with potent antigen-specific,
      immunostimulatory activity. Indeed, DC can provide an extremely powerful and
      important immunological tool by which to potentiate the immune response for
      specific recognition of foreign antigens. Until recently, the direct isolation of
      DC from PBMC required laborious procedures with extremely poor yields (<0.1%).
      Methods have been developed for the human, lower primate, and murine model
      systems to propagate large numbers of DC from PBMC or bone marrow ex vivo with
      various cytokines. However, all other model systems, including equine, still
      require the laborious isolation procedures to obtain DC. In this study, we have
      adapted the methods developed for the human system to generate large numbers of
      equine DC from PBMC precursors using recombinant human GM-CSF and recombinant
      equine IL-4. Our report is the first documentation of ex vivo generated DC from
      PBMC in a domesticated animal model system. Equine DC derived from PBMC were
      rigorously characterized by analyzing morphological, phenotypic, and functional
      properties and were determined to have similar attributes as DC generated from
      human PBMC. Equine DC appeared stellate with large projectiles and veils and had
      cell surface antigens at similar levels as those defined on human and murine DC.
      Furthermore, functional attributes of the DC included rapidly capturing antigens
      by pinocytosis, receptor-mediated endocytosis, and phagocytosis, activating naive
      T cells in a mixed leukocyte reaction to a much greater extent than macrophage or
      lymphoblasts, presenting soluble and particulate antigen 10-100 fold more
      effectively to T cells on a per cell basis than macrophage or lymphoblasts, and
      presenting soluble and particulate antigen to both CD4+ and CD8+ T cells. Taken
      together, our study provides a framework by which equine DC can now be readily
      produced from PBMC precursors and presents an impetus for and model by which DC
      can be simply generated in other animal model systems.

PMID- 10587302
TI  - Depletion of bovine CD8+ T cells with chCC63, a chimaeric mouse-bovine antibody.
AB  - In order to investigate the role of T cells in immune responses to infectious
      pathogens, depletion of individual T cell subsets using monoclonal antibodies
      (mAbs) is commonly undertaken. Since most mAbs are of murine origin, such
      depletion studies in cattle are restricted by the bovine anti-mouse antibody
      (BAMA) response to the mouse mAbs used for the depletions. In this study, we
      describe the use of antibody engineering to overcome the BAMA response. The
      variable region cDNA from CC63, a monoclonal mouse anti-bovine CD8 antibody, has
      been expressed in conjunction with bovine constant region genes to produce a
      mouse-bovine chimaeric antibody (chCC63). Characterisation of chCC63 showed that
      the antibody contained a bovine constant region and specifically bound bovine
      CD8+ T cells. Furthermore, chCC63 blocked the binding of the original mouse
      antibody, CC63, and mediated complement-dependent lysis of bovine CD8+ cells in
      vitro. In vivo, chCC63 depleted calves of CD8+ T cells as effectively as CC63 and
      provoked a BAMA response that was about one-tenth of that seen with the mouse
      antibody.

PMID- 10587303
TI  - Immune response of neonatal specific pathogen-free cats to experimental infection
      with Bartonella henselae.
AB  - The purpose of this study was to determine whether neonatal cats develop and
      maintain a persistent bacteremia for longer than do adult cats with a normal
      mature immune system, and whether neonatal cats are susceptible to infection with
      Bartonella henselae by oral inoculation. Neonatal specific pathogen-free (SPF)
      cats were inoculated with B. henselae intradermally (n = 4) or orally (n = 5) or
      with 0.9% NaCl (n = 2). Blood was collected periodically through 16 weeks post
      inoculation (PI) for serology, bacteriology and complete blood count. Cats
      inoculated orally or intradermally at 3-5 days of age were bacteremic through 12
      16 weeks PI, similar to what is documented for adult cats inoculated
      intradermally or intravenously. One cat inoculated at age 2 weeks was bacteremic
      through 10 weeks PI; the other was not bacteremic. Intradermally inoculated
      neonatal cats produced serum IgG antibodies to B. henselae but orally inoculated
      neonatal cats did not. Infected cats with and without serum IgG antibodies to B.
      henselae became blood-culture negative simultaneously, suggesting that IgG is not
      required to clear bacteremia.

PMID- 10587304
TI  - cDNA cloning and gene expression of the type 1 bovine interleukin-1 receptor.
AB  - Regulation of interleukin-1 (IL-1) mediated biological responses is complicated
      by the multiple ligands and receptors of the IL-1 family. Most studies of IL-1
      receptors have used human or rodent cells. Here, we report that the coding region
      of the bovine type 1 interleukin-1 receptor (type 1 IL-1R) cDNA extends 1719 bp
      in length. Northern analysis of specific bovine cell and tissue RNA demonstrated
      a 4.5 kb transcript. Overall, the bovine type 1 IL-1R coding region exhibits
      approximately 81 and 76% similarity with the human type 1 IL-1R at the nucleotide
      and amino acid level, respectively, and somewhat less similarity with the mouse
      and rat sequences. Type 1 IL-1R transcripts were confirmed by RT-PCR in several
      bovine cell types, including peripheral blood mononuclear cells (PBMCs),
      neutrophils (PMNs), and fibroblast, peritoneal macrophage, and arterial
      endothelial cell lines. It is expected that molecular clones for the bovine type
      1 and 2 IL-1 receptors will provide us with the tools needed to decipher species
      and cell-specific regulation of IL-1 action in the bovine.

PMID- 10587305
TI  - Changes in macrophage and lymphocyte subpopulations of lymphoid tissues from pigs
      infected with the porcine reproductive and respiratory syndrome virus (PRRSV).
AB  - We used an immunohistochemical method to investigate changes in macrophage and
      lymphocyte subpopulations in various lymphoid tissues of pigs in the acute phase
      of porcine reproductive and respiratory syndrome virus (PRRSV) infection. The
      numbers of CD8+ cells and B-cells varied among lymphoid tissues after PRRSV
      infection. In the infected pigs, numbers of CD8+ cells increased in systemic
      lymphoid tissues whereas numbers of B-cells increased in mucosa-associated
      lymphoid tissues. There was no difference in the distribution of virus-infected
      cells and macrophages between lymphoid tissues of the infected pigs. These
      changes may be associated with the establishment of virus persistence or the
      emergence of concurrent infection in mucosal organs.

PMID- 10587306
TI  - Changes in local IFN-gamma and TGF-beta4 mRNA expression and intraepithelial
      lymphocytes following Eimeria acervulina infection.
AB  - Inbred chickens SC (B2B2) and TK (B15B21) display different levels of
      susceptibility to Eimeria acervulina infection. Following primary and secondary
      infections, SC chickens showed significantly lower oocyst production compared to
      TK chickens. Both strains produce significantly fewer oocysts during secondary
      infection (si) indicating that a protective host immune response had developed
      subsequent to primary infection (pi). To elucidate the immunologic differences
      between SC and TK chickens that may account for their different levels of disease
      susceptibility, cellular and molecular parameters of intestinal immunity were
      compared. CD4 T-lymphocytes increased significantly and more rapidly post-pi and
      si in SC relative to TK chickens during the later stages of infections. However,
      later during the infections, CD4 cells were higher in TK compared to SC chickens.
      Although the percentage of CD8 lymphocytes increased in both strains after pi,
      following si the percentage of these cells continued to increase in SC chickens
      but showed a marked decrease in TK chickens. Contrary to the effects on CD4
      cells, the percentage of TCR1 cells was higher in TK chickens early after pi
      while the same cell subset was higher in SC chickens later following infection.
      The percentages of TCR2 cells were significantly higher in both strains following
      pi. At the molecular level, IFN-gamma mRNA expression in caecal tonsils and
      splenic lymphocytes was generally higher in SC compared to TK chickens following
      E. acervulina infection, while intraepithelial lymphocytes from the duodenum
      demonstrated reduced levels of this cytokine in both the strains, particularly
      following pi. TGF-beta4 mRNA levels generally increased in lymphocytes from the
      caecal tonsils, spleen and duodenum from both the strains. These differences in
      lymphocyte subpopulations and cytokine mRNA expression between SC and TK chickens
      following E. acervulina infection indicate a complex genetic control of the
      native immune response to coccidiosis.

PMID- 10587307
TI  - V(D)J recombinational signal sequence DNA binding activities expressed by fetal
      bovine thymus.
AB  - V(D)J recombination, or immunoglobulin gene rearrangement is a developmentally
      regulated, cell type specific, site directed recombination event that brings
      either immunoglobulin or T-cell receptor gene segments together to form mature,
      expressible Ig or TCT genes. This DNA recombination is directed by the
      recombinational signal sequences or RSS elements present adjacent to Ig and TCR
      gene segments. The RSS element is composed of a conserved nonamer element and a
      conserved heptamer element separated by a conserved length spacer region. In this
      report, we examine the expression of DNA binding proteins that interact with the
      RSS element in the bovine fetal thymus using EMSA assays. Our data indicates that
      the nonamer portion of the RSS element is the primary site of recognition for RSS
      binding proteins expressed in the bovine fetal thymus. We also show that these
      proteins are expressed from early stages of bovine fetal development through to
      full term development.

PMID- 10587308
TI  - Quantitative real-time PCR for the measurement of feline cytokine mRNA.
AB  - We have developed real-time PCR systems to quantitate feline cytokine gene
      expression. The method is based on the cleavage of fluorescent dye-labelled
      probes by the 5'-3' exonuclease activity of the Taq DNA polymerase during PCR and
      measurement of fluorescence intensity by a Sequence Detection System. The feline
      specific TaqMan probes were designed to encompass an intron, thus allowing
      differentiation of complementary DNA versus genomic DNA amplification products.
      Quantitative analysis of cytokine cDNA concentrations was performed in comparison
      to feline GAPDH. Messenger RNA (mRNA) from the universally expressed housekeeping
      gene GAPDH proved to be useful as an amplification control and allowed for
      correction of variations in the efficiencies of RNA extraction and reverse
      transcription. GAPDH mRNAs were readily detectable in cDNAs prepared from
      unstimulated feline peripheral blood mononuclear cells (PBMCs) and from frozen
      cell pellets, while cytokines (Interleukin (IL)-4, IL-10, IL-12 p35, IL-12 p40,
      IFNgamma, IL-16) were expressed at variable amounts. IFNgamma transcription was
      found to be upregulated in stimulated PBMCs and feline cell lines. The synthesis
      of cDNA and the performance of the PCR in separate tubes proved to be of superior
      sensitivity compared to a single-tube based system. The assays described are
      highly reproducible, require no post-PCR manipulation of the amplicons and permit
      the analysis of several hundred PCR reactions per day. With this method it is
      possible to detect and quantify cytokine mRNA expression reliably in small
      amounts of cells even after storage of samples for at least 5 years.

PMID- 10587309
TI  - Sulfidoleukotriene generation from peripheral blood leukocytes of horses affected
      with insect bite dermal hypersensitivity.
AB  - Sulfidoleukotrienes (sLT) generated in vitro after incubation of equine
      peripheral blood leukocytes (PBL) with different inducing agents were determined
      in 18 healthy and 16 insect bite dermal hypersensitivity (IDH)-affected horses.
      PBL from these 32 horses were stimulated with Concanavalin A, Parascaris equorum,
      Culicoides nubeculosus and Simulium extracts, and with a six-Grass mix. The cells
      of all but four horses generated sLT after incubation with Concanavalin A; these
      four horses did also not produce sLT with the other inducing agents. Of the 28
      remaining horses (12 affected with IDH and 16 healthy), all but three generated
      sLT with the P. equorum extract. The six-Grass mix did not induce sLT production
      in any of the tested horses. sLT generation with Concanavalin A and Parascaris
      was statistically not different between IDH-affected and healthy horses. PBL of
      the diseased horses, however, produced significantly more sLT with the Culicoides
      (p < 0.01) and Simulium (p < 0.05) extracts than those of the healthy animals.
      Additionally, sLT generation with the Culicoides extract was measured at
      different times of the year in one IDH-affected animal and remained high even in
      winter, when the horse was asymptomatic. sLT and histamine release were
      determined in 10 horses in parallel. Positive correlations of 0.81 and 0.82 for
      Concanavalin A and Parascaris (p < 0.01 and p < 0.05, respectively), and of 0.95
      and 0.94 for Culicoides and Simulium (p < 0.01) were found between sLT and
      histamine release. These results indicate that, alike in humans, sLT are released
      in vitro from equine basophils along with histamine in response to various
      stimuli and that immediate type hypersensitivity reactions to Culicoides and
      Simulium are often involved in the pathogenesis of IDH. Thus, sLT generation from
      equine basophils offers an in vitro diagnostic tool for IDH even in sensitised
      but asymptomatic horses.

PMID- 10587310
TI  - The detection of CD2+, CD4+, CD8+, and WC1+ T lymphocytes, B cells and
      macrophages in fixed and paraffin embedded bovine tissue using a range of antigen
      recovery and signal amplification techniques.
AB  - In order to develop procedures to label the main bovine leucocyte populations in
      paraffin embedded sections, the immunoreactivity of 25 monoclonal antibodies
      (mAbs) to different leucocyte antigens was assessed with formal dichromate (FD5)
      and 10% formalin fixation, a battery of antigen retrieval (AR) methods, and the
      biotin-tyramide amplification system. All the leucocyte populations investigated
      (CD2+, CD4+, CD8+, WC1+ T lymphocytes, B cells and macrophages) were strongly and
      specifically detectable under an appropriate combination of mAb, AR method and
      signal amplification system. CD4 and CD8 required the most stringent conditions
      and could only be demonstrated in FD5 fixed sections. For detection of CD2, WC1+
      T lymphocytes, B cells and macrophages, all the mAbs produced immunoreactivity in
      FD5 or formalin fixed tissues. The need to check a range of different AR methods
      is stressed, as the method of choice varied for each individual mAb. The
      incorporation of the signal amplification system was necessary to observe a
      strong signal and the complete distribution of CD4, CD8 and B cells. Fixation by
      FD5 proved to be better than formalin for the preservation of surface antigens
      but it was inferior for the detection of markers which were found to show
      cytoplasmic immunoreactivity, such as the macrophage marker MAC387 or the B cell
      markers BAQ155 or IL-A59.

PMID- 10587311
TI  - A short guide to abbreviations and their use in peptide science.

PMID- 10587312
TI  - Synthesis and structure-activity investigation of novel vasopressin hypotensive
      peptide agonists.
AB  - We report the solid phase synthesis and vasodepressor potencies of the novel
      hypotensive peptide [1(-beta-mercapto-beta,beta-pentamethylene propionic acid)-2
      O-ethyl-D-tyrosine, 3-arginine, 4-valine] arginine vasopressin, d(CH2)5[D
      Tyr(Et)2, Arg3, Val4]AVP (A), its related Lys3 (B), Tyr-NH(9)2 (C), [Lys3, Tyr
      NH(9)2 (D) analogs and in a preliminary structure-activity study of positions 2-4
      and 7-9, 24 analogs (1-24) of A-C. Peptides 1-6, 9-14 have the following single
      substituents at positions 2, 3, 4, 8 and 9 in (A): 1, D-Tyr(Me)2; 2, L-Tyr(Et)2;
      3, Orn3; 4, N-Me-Arg3; 5, Glu3; 6, Arg4; 9, D-Arg8; 10, Eda9; 11, Arg-NH(9)2; 12,
      Ala-NH(9)2; 13, desGly9; 14, desGly-NH(9)2. Peptides 15 and 16 are analogs of B
      which possess the following single modifications: 15, Arg-NH(9)2; 16, desGly9.
      Peptides 7 and 8 are analogs of (C) with the following single modification: 7,
      Gln4; 8, Lys8. Peptides 17-24 are analogs of A possessing the following multiple
      modifications: 17, [Sar7, Eda9]; 18, [Arg7, Eda9]; 19, [Arg7, Eda9<--Tyr10]; 20,
      [Arg4, Arg-NH(9)2]; 21, [Ile4, desGly9]; 22, [Arg4, desGly9]l; 23, [Arg7,
      desGly9]; 24, [Arg7, Lys8, desGly9]. All 24 new peptides were evaluated for
      agonistic and antagonistic activities in in vivo antidiuretic (V2-receptor),
      vasopressor (V1a-receptor) and in in vitro (no Mg2+) oxytocic (OT-receptor)
      assays and like the parent peptides (A-D) (Chan et al. Br. J. Pharmacol. 1998;
      125: 803-811) were found to exhibit no or negligible activities in these assays.
      Vasodepressor potencies were determined in anesthetized male rats with baseline
      mean arterial blood pressure maintained at 110-120 mmHg. The effective dose (ED),
      in microg 100 g(-1) i.v., required to produce a vasodepressor response of 5 cm2,
      area under the vasodepressor response curve (AUC) during the 5-min period
      following the injection of the test peptide, was determined. Therefore, the EDs
      measure the relative vasodepressor potencies of the hypotensive peptides. The
      following ED values were obtained for A-D and for peptides 1-24: A, 4.66; B,
      5.75; C, 10.56; D, 11.60; 1, approximately 20; 2, approximately 30; 3, 6.78; 4,
      non-detectable (ND); 5, ND; 6, approximately 32; 7, ND; 8, 8.67; 9, ND; 10, 2.43;
      11, 3.54; 12, 10.57; 13, 4.81; 14, ND; 15, 4.47; 16, 9.78; 17, 5.72; 18, 1.10;
      19, 1.05; 20, 10.41; 21, 9.13; 22, approximately 33; 23, 3.01; 24, 1.71. A is
      clearly the most potent of the four original hypotensive peptides A-D. These data
      provide insights to which modification of A enhance, retain or abolish
      hypotensive potencies. Six of the new hypotensive peptides are significantly more
      potent than A. These are peptides 10, 11, 18, 19, 23 and 24. Peptide 19, a
      radioiodinatable ligand, is ten times more potent than C or D. The Gln4
      modification of C and the N-Me-Arg3, Glu3, D-Arg8 and desGly-NH(9)2 modifications
      of A abolished hypotensive potency. By contrast, the Eda9, Arg-NH(9)2, [Sar7,
      Eda9], [Arg7, Eda9<- -Tyr10], [Arg7, desGly9], [Arg7, Lys8, desGly9]
      modifications of A all led to enhancements of hypotensive potency. This initial
      structure-activity exploration provides useful clues to the design of (a) more
      potent vasodepressor peptides and (b) high affinity radioiodinatable ligands for
      the putative AVP vasodilating receptor. Some of the peptides here may be of value
      as pharmacological tools for studies on the complex cardiovascular actions of AVP
      and may lead to the development of a new class of anti-hypertensive agents.

PMID- 10587313
TI  - Conformations and pharmacophores of cyclic RGD containing peptides which
      selectively bind integrin alpha(v)beta3.
AB  - This paper reports a detailed conformational characterization in solution by 1H
      NMR in H2O and DMSO-d6 and molecular modeling simulations of cyclic peptides
      containing the RGDDV pharmacophore and the RGDY(Me)R pharmacophore. These two
      pentapeptide sequences when properly constrained in cyclic peptides are low to
      sub-nanomolar inhibitors of integrin alpha(v)beta3. The peptides containing the
      RGDDY(Me)R sequence bind potently to integrin alphaIIb3 as well. The
      conformations found in H2O and in DMSO-d6 solutions are valuable for the design
      of peptidomimetics of these two pharmacophores. The structure-activity
      relationships of the RGDDV and RGDY(Me)R pharmacophores within cyclic peptides
      are discussed. Specifically, the orientation of surface-accessible chemical
      features on the ligand, such as hydrophobic, positive and negative ionizable
      groups, which are considered to be responsible for the desired biological
      activity, is focused on.

PMID- 10587314
TI  - Structure investigation of amphiphilic cyclopeptides in isotropic and anisotropic
      environments-A model study simulating peptide-membrane interactions.
AB  - It has been proposed that the membrane allows a much more efficient binding of
      certain small or medium-sized amphiphilic messenger molecules to their receptor,
      not only by accumulation of the drug, but also by induction of orientations and
      conformations that are much more favorable for receptor docking than structures
      adopted in isotropic phases. A series of eight amphiphilic cyclic peptides
      containing lipophilic (L-alpha-aminodecanoic acid = Ada, L-alpha
      aminohexadecanoic acid = Ahd, Nhdg = N-hexadecylglycine) and hydrophilic (Lys,
      Asp) amino acids were synthesized and examined by means of NMR spectroscopy and
      molecular dynamics (MD) simulations in isotropic (CDCl3) and membrane-mimicking
      anisotropic (SDS/H2O) solvents to study the influence of the environment on their
      individual conformations. NMR data of cyclo(-Gly1-D-Asp2-Ahd3-Ahd4-Asp5-Gly6+ ++
      ) (C4), cyclo(-Lys1-D-Pro2-Lys3-Ada4-Pro5-Ada6-) (C5) and cyclo(-Lys1-Pro2-Lys3
      Ada4-D-Pro5-Ada6-) (C6) clearly indicate that those compounds are too rigid to
      perform a conformational change upon transition from an isotropic to an
      anisotropic environment. On the other hand, the experimental data of cyclo (-Gly1
      Asp2-Ahd3-Ahd4-Asp5-Gly6-) (C1), cyclo(-Asp1-Ala2-Nhdg3-Ala4-D-Asp5-) (C7), and
      cyclo(-D-Asp1-Ala2-Nhdg3-Ala4-Asp5-) (C8) suggest highly flexible unstructured
      molecules in both environments. However, for cyclo(-Asp1-Asp2-Gly3-Ahd4-Ahd5-Gly6
      ) (C2) we observed a structure inducing effect of a membrane-like environment.
      The compound populates three different conformations in SDS/H2O, whereas in CDCI3
      no preferred conformation can be detected. cyclo(-D-Asp1-Asp2-Gly3-Ahd4-Ahd5-Gly6
      ) (C3) clearly exhibits two different conformations with a shifted beta,beta-turn
      motif in CDCI3 and SDS/H2O solutions. The conformational change could be
      reproduced in a restraint-free MD simulation using the biphasic membrane mimetic
      CCl4/H2O. Our results give clear evidence that membrane interactions may not only
      lead to structure inductions, but can also induce major conformational changes in
      compounds already exhibiting a defined structure in isotropic solution.

PMID- 10587315
TI  - Photomodulation of conformational states. Synthesis of cyclic peptides with
      backbone-azobenzene moieties.
AB  - The search for photoresponsive conformational transitions accompanied by changes
      in physicochemical and biological properties led us to the design of small cyclic
      peptides containing azobenzene moieties in the backbone. For this purpose, (4
      aminomethyl)phenylazobenzoic acid (H-AMPB-OH) and (4-amino)phenylazobenzoic acid
      (H-APB-OH) were synthesized and used to cyclize a bis-cysteinyl-octapeptide
      giving monocyclic derivatives in which additional conformational restriction
      could be introduced by conversion to bicyclic structures with a disulphide
      bridge. While synthesis with H-AMPB-OH proceeded smoothly on a chlorotrityl-resin
      with Fmoc/tBu chemistry, the poor nucleophilicity of the arylamino group of H-APB
      OH required special chemistry for satisfactory incorporation into the peptide
      chain. Additional difficulties were encountered in the reductive cleavage of the
      S-tert-butylthio group from the cysteine residues since concomitant reduction of
      the azobenzene moiety took place at competing rates. This difficulty was
      eventually bypassed by using the S-trityl protection. Side-chain cyclization of
      the APB-peptide proved to be difficult, suggesting that restricted conformational
      freedom was already present in the monocyclic form, a fact that was fully
      confirmed by NMR structural analysis. Conversely, the methylene spacer in the
      AMPB moiety introduced sufficient flexibility for facile and quantitative side
      chain cyclization to the bicyclic form. Both of the monocyclic peptides and both
      of the bicyclic peptides are photoresponsive molecules which undergo cis/trans
      isomerization reversibly.

PMID- 10587316
TI  - Tuberculosis in the 21st century: DOTS and SPOTS. Plenary lecture given at the
      29th World Conference of the International Union Against Tuberculosis and Lung
      Disease, Bangkok, Thailand, 23-26 November 1998. Directly observed therapy.
AB  - Surveys of the global burden of disease have established that formidable health
      problems loom as the new millennium approaches. In both industrialized and
      developing countries lung disease is particularly problematic. Tuberculosis
      provides a concrete example of the ability of existing interventions such as
      directly observed therapy (DOT) to save millions of lives in the immediate future
      and the potential for new knowledge and tools to eventually eliminate the
      disease. Molecular epidemiology shows the potential of new technology to
      supplement established approaches in answering questions central to public
      health. Our knowledge of the complete genomic sequence of Mycobacterium
      tuberculosis now has us poised on the brink of a new era. Emerging technologies
      such as microscopic arrays comprised of thousands of spots of DNA will provide
      knowledge that will fundamentally alter our approach to disease control. The
      synergy of a balanced portfolio incorporating a globalized public health
      commitment and creative basic research will provide us with the infrastructure
      and tools needed to eliminate tuberculosis before the close of the 21st century.

PMID- 10587317
TI  - Infant BCG vaccination study in Lithuania.
AB  - SETTING: Infants identified in maternity hospitals in Vilnius, Lithuania.
      OBJECTIVES: To test the capacity of the BCG vaccine, Danish strain 1331 (Danish
      vaccine), to induce tuberculin reactivity and scar formation in neonates compared
      to the WHO International Reference Preparation of BCG (IRP vaccine), and to study
      the effect of dose and of age at vaccination. DESIGN: A randomized four-armed
      study: 1) normal dose, 0.05 ml Danish vaccine given to neonates at birth, 2) half
      the normal dose of Danish vaccine given at birth, 3) IRP vaccine given at birth
      at normal infant dose, and 4) the normal infant dose of Danish vaccine given at 3
      months of age. RESULTS: Larger tuberculin reactions, as well as an increased
      frequency and larger scars, were seen when Danish vaccine was given at 3 months
      of age in comparison to neonatal vaccination. Halving the dose resulted in
      smaller reactions, but the difference was not significant. The IRP vaccine
      resulted in borderline significantly larger reactions in comparison to the Danish
      vaccine. The number of infants receiving very early vaccination (0-2 days) was
      not evenly distributed in all groups, however, which is believed to explain the
      observed difference.

PMID- 10587318
TI  - Tuberculin sensitivity: conversions and reversions in a rural African population.
AB  - SETTING: Karonga District, northern Malawi, 1980-1989. OBJECTIVE: To measure and
      interpret incidence and prevalence of tuberculin sensitivity. DESIGN: Tuberculin
      testing carried out within two total population surveys. Tuberculin 'positivity'
      and 'conversion' were defined using criteria recommended by the Tuberculosis
      Surveillance Research Unit and the American Thoracic Society, respectively.
      RESULTS: Data on 64,225 tests were available for analysis, including paired
      results on 6991 individuals tested in both surveys. Frequency distributions of
      induration varied by age, sex, BCG scar status and zone within the district. The
      prevalence of 'positivity' was similar in males and females until age 15, then
      higher among males, and was consistently higher among individuals with than among
      those without a BCG scar. Tuberculin 'conversion' rates estimated from cross
      sectional data ranged from 0.34 to 1.15 per cent per annum. Conversion rates
      derived from longitudinal data were found to increase linearly with age, and the
      reversion rates declined rapidly with age among younger individuals. Such trends,
      which have been reported in other populations, are shown here to arise as an
      artefact of test instability. Prospective follow-up of observed converters showed
      greatly increased risks of tuberculosis, in particular during the two years
      following the second ('converted') test (relative risk > 10). CONCLUSION:
      Estimation of a convincing 'true' annual risk of infection from tuberculin survey
      data is not possible from either cross-sectional or longitudinal data, due to
      misclassifications and the instability of delayed type hypersensitivity over
      time. An apparent increase in infection risk with age can arise as an artefact of
      test instability. BCG-induced tuberculin sensitivity declines rapidly in this
      population in most individuals. It is necessary to consider tuberculin
      reversions, whether real or apparent, when interpreting tuberculin data on
      individuals or populations.

PMID- 10587319
TI  - Treatment costs of directly observed therapy and traditional therapy for
      Mycobacterium tuberculosis: a comparative analysis.
AB  - OBJECTIVE: Treatment of tuberculosis is a time-consuming and expensive process,
      often complicated by patient non-adherence. Directly observed therapy (DOT), an
      out-patient management strategy designed to ensure adherence, is not widely used
      because it is perceived to be too expensive. This study compared costs of
      tuberculosis treatment in DOT to the same factors in traditional therapy. DESIGN:
      A retrospective economic evaluation of 659 tuberculosis cases was reported to a
      major metropolitan county public health department between 1980 and 1994. Out
      patient costs, in-patient costs and the cost impact of relapse and acquired
      resistance were estimated in 1995 dollars. RESULTS: Treatment costs were lower
      with DOT: $15,670 per case for in-patient care and $700 per case for out-patient
      care (P < 0.001). These cost differences resulted from shorter therapy duration
      (334 vs 550 days), fewer patient hospitalizations (58 vs 75%) and shorter
      hospital stays (26 vs 55 days per hospitalized patient). Relapse or acquired
      resistance occurred in 10.9% of patients and accounted for 35.7% of cost with
      traditional therapy, as compared to 1.2% of patients and 6.0% of cost with
      observed therapy. CONCLUSIONS: Directly observed therapy is less costly than
      traditional therapy.

PMID- 10587320
TI  - Hospital admission policy for tuberculosis in pulmonary centres in Italy: a
      national survey. AIPO Tuberculosis Study Group. Italian Association of Hospital
      Pulmonologists.
AB  - SETTING: A national survey including 203 pulmonary centres (PCs) (144 hospital
      PCs with beds dedicated to TB patients and 59 out-patient PCs) managing
      tuberculosis cases in Italy during 1995. OBJECTIVES: To evaluate: 1)
      hospitalisation practices (criteria for admission/discharge; duration of
      hospitalisation) as primary end-points; and 2) as secondary end-points the
      availability of beds, the preventive measures adopted to reduce the spread of
      infection, the sources of referral for hospitalisation and the procedures adopted
      to follow up TB patients after discharge. DESIGN: A 26-point questionnaire mailed
      to 203 PCs. RESULTS: Of 167 PCs that responded to the questionnaire (82.3%), 159
      questionnaires were considered valid for the analysis (110 from hospitals PCs and
      49 from out-patient PCs). The criteria adopted by PCs to admit TB patients were:
      all TB cases 47%, only smear-positive pulmonary TB 14%, TB cases with clinical
      problems 39%. Hospital PCs hospitalised significantly more cases of smear
      negative, extra-pulmonary TB. On average 71.6% of all cases were hospitalised
      (88.2% by hospital and 28% by out-patient PCs). The median hospital stay was 34
      days for sputum smear-positive, 20 for sputum smear-negative and 21.5 for extra
      pulmonary TB cases. Sputum conversion was considered the mandatory criterion to
      allow discharge from 61% of hospital PCs. CONCLUSION: A switch from the present
      policy (majority of cases hospitalised for a long period) to an outpatient
      oriented policy needs the co-ordinated educational effort of scientific societies
      and health authorities.

PMID- 10587321
TI  - Delay and discontinuity--a survey of TB patients' search of a diagnosis in a
      diversified health care system.
AB  - SETTING: Ho Chi Minh City (HCMC), Vietnam. OBJECTIVES: To describe delay to
      diagnosis; to compare diagnostic procedures and referral routines used by private
      and public health care providers; and to examine associations between contact
      with various types of providers and risk of delay to TB diagnosis. DESIGN: Cross
      sectional survey of new patients in the National Tuberculosis Programme (NTP).
      Retrospective assessment of health seeking and diagnostic procedures used by
      previously contacted health care providers. RESULTS: Four weeks after first
      symptom, 81% of patients had sought help outside the household. Four weeks after
      first health care contact, 47% had been diagnosed with TB. Private physicians
      used X-rays, sputum smears, and referrals significantly less often than public
      health care providers. Patients who had turned first to a private pharmacy, a
      private physician or a public hospital were significantly more likely to have a
      long provider delay than those who turned first to the NTP. CONCLUSION: Delay to
      diagnosis of TB in HCMC is due more to inability among health care providers to
      detect TB than to under-utilisation of health care services. Diagnostic
      procedures need to be improved and referral chains need to be strengthened in
      HCMC, particularly among private providers.

PMID- 10587322
TI  - Tuberculosis among homeless people in London: an effective model of screening and
      treatment.
AB  - SETTING: Hostels and day centres for homeless people in south London. OBJECTIVE:
      To develop an appropriate and effective method of screening for pulmonary
      tuberculosis (TB) among the homeless. DESIGN: Observational study evaluated for
      acceptability, yield of cases and completion of treatment. The screening included
      a symptom questionnaire, a Heaf test and a chest X-ray, developed and read on
      site. RESULTS: Ten clients (0.5%) were identified as having active pulmonary TB;
      seven of these were white men over the age of 50. The symptom questionnaire was
      seldom helpful. Nine of the cases were initially identified by chest X-ray,
      however only three of the 10 had a Heaf test performed. Eight of the 10 clients
      with active TB completed therapy; five additional clients were started on
      chemoprophylaxis. All of these had strongly positive Heaf reactions and normal
      chest X-rays. CONCLUSIONS: Chest X-ray screening is the most useful screening
      method and is effective if it is targeted. The use of incentives seems to
      increase the uptake of screening. Heaf testing is useful for the identification
      of those clients needing prophylactic treatment or BCG immunisation. Good
      compliance can be achieved provided clients are case managed appropriately.

PMID- 10587323
TI  - Sputum examination for acid-fast bacilli in private laboratories, Kathmandu
      Valley, Nepal.
AB  - OBJECTIVE: To investigate the characteristics of private laboratories and the
      process of sputum examination for acid-fast bacilli (AFB). DESIGN: A door-to-door
      survey of private laboratories in an urban municipality of Kathmandu valley was
      conducted during the first quarter of 1998. Semi-structured interviews were
      conducted with staff of 14/20 (70%) identified laboratories. RESULTS: All 14
      private laboratories conducted sputum examination for AFB. The majority (71%) of
      staff lacked special training for AFB examinations. Monocular microscopes were
      commonly used (36%). Reagents were prepared irregularly, without quality control,
      and kept for as long as they lasted, often up to 4-6 months (43%). Laboratory
      registers were usually present (86%), but lacked information on patient's address
      and the purpose of the test. A median of 12.5 slides per laboratory had been
      examined during the previous month (range 0-70). A total of 235 AFB slides were
      examined, of which 18 (7.7%) were reported as positive. CONCLUSION: AFB
      examinations were widely available. Lack of training and quality control suggest
      a variable standard of AFB test results. It is recommended that the National
      Tuberculosis Programme (NTP) provide support and quality control to two to three
      (i.e., one for every 10) private laboratories in the area to secure private
      doctors' confidence in sputum testing.

PMID- 10587324
TI  - Biodegradable implants from poly-(alpha-hydroxy acid) polymers for isoniazid
      delivery.
AB  - SETTING: In vitro and in vivo study of an isoniazid (INH) drug delivery system.
      OBJECTIVE: To develop a system for the treatment of tuberculosis using a
      subcutaneous polymer implant with a large drug load released slowly over a long
      period. INH delivery by biodegradable poly-(alpha-hydroxy acid) polymers was
      evaluated using ground polymer and compression molded implants. DESIGN: Rate of
      drug release and structural stability of the implant in an aqueous environment
      were measured, as were in vivo evaluations of the duration of measurable levels
      of INH in serum and urine. RESULTS: Factors that influenced the suitability of an
      implant in an in vitro system included polymer molecular weight and
      crystallinity, polymer and drug particle size, drug loading dose, and press
      temperature and pressure. The implant characteristics that most closely
      approached optimal conditions include a polymer of 100% L-lactide with low
      intrinsic viscosity, polymer particle size <75 micron, and INH particle = 126-180
      micron, INH loading dose not to exceed 46%, and press conditions of 70 degrees C
      and 345000 kPa. Studies of subcutaneous implants in rabbits and baboons show that
      INH is released from the implant for 15 to 26 weeks. CONCLUSIONS: An INH
      containing polymer was developed that was structurally stable in an aqueous
      environment and that released INH over a period of at least 15 weeks. Studies
      with infected animals will be necessary to determine the dose required for
      prophylaxis and treatment of active disease.

PMID- 10587325
TI  - Partial protection against oral challenge with Mycobacterium bovis in ferrets
      (Mustela furo) following oral vaccination with BCG.
AB  - SETTING: Ferrets (Mustela furo) are important wildlife vectors of bovine
      tuberculosis (TB) in New Zealand. Protective vaccination of ferrets may limit the
      potential of transmission to livestock. OBJECTIVE: To determine whether orally
      delivered Mycobacterium bovis BCG can confer protection against oral challenge
      with virulent M. bovis. DESIGN: Ten ferrets were vaccinated by feeding measured
      doses of live BCG, and subsequently challenged with virulent M. bovis via the
      oral route. Ten non-vaccinated (control) ferrets were similarly challenged. Live
      body weights and lymphocyte reactivity were monitored longitudinally, and ferrets
      were killed 20 weeks following challenge. Necropsy, histological examination and
      bacterial culture of alimentary tract lymphatic tissues were undertaken. RESULTS:
      There was a significant reduction in the incidence of gross tuberculous lesions
      among vaccinated ferrets compared to control animals, and fewer vaccinated
      ferrets had histologically-detectable acid-fast organisms in mesenteric lymph
      node (LN) tissues. There were significantly fewer vaccinated ferrets with culture
      positive retropharyngeal LNs, and the mean bacterial burden was significantly
      lower for retropharyngeal LNs isolated from vaccinated animals than from
      controls. CONCLUSION: These results demonstrate that oral BCG vaccination of
      ferrets can confer partial protection against M. bovis, and suggest that systemic
      immune responses may be less important in mediating this degree of protection
      than local immunity.

PMID- 10587326
TI  - Prevalence rates of respiratory symptoms and diseases in general population
      samples of North and Central Italy.
AB  - SETTING: Four cross-sectional general population surveys in Italy: northern rural
      Po Delta area (1980-1982, n = 3284; 1988-1991, n = 2841), and central urban Pisa
      area (1985-1988, n = 3865; 1991-1993, n = 2841). OBJECTIVE: To analyse changes in
      prevalence rates of respiratory symptoms and diseases. DESIGN: Prospective
      epidemiological studies by standardised interviewer-administered questionnaire.
      RESULTS: Prevalence rates of respiratory symptoms and diseases tended to be
      higher in males (except for dyspnea and pleuritis), in the urban area (more
      polluted), and in the second surveys; moreover, they increased with age. Asthma
      peaked in those aged under 25 years and over 64 years. The highest prevalence
      rates were shown by current smokers of both sexes for all respiratory symptoms
      and by ex-smoker males for all respiratory diseases, while female current smokers
      reported chronic bronchitis, emphysema and asthma more frequently. The most clear
      cut trend towards increase between the two surveys within each area was exhibited
      by wheeze and asthma. CONCLUSIONS: These findings highlight the relevance of sex,
      age and smoking habit, as well as the possible effects of air pollution, in
      relation to respiratory symptoms. They also indicate a trend towards an increase
      in asthma symptoms in Italian general population samples in the 1990s, and an
      under-estimate of medically diagnosed chronic respiratory diseases.

PMID- 10587327
TI  - Tolerability of twice-weekly rifabutin-isoniazid combinations versus daily
      isoniazid for latent tuberculosis in HIV-infected subjects: a pilot study.
AB  - The tolerability of and adherence to intermittent short-term rifabutin-isoniazid
      preventive treatment was assessed in subjects dually infected with Mycobacterium
      tuberculosis and the human immunodeficiency virus (HIV). In a randomised, open
      label, phase II pilot study, 44 subjects received either rifabutin 300 mg and
      isoniazid 750 mg twice weekly for 3 months (group A, n = 16) or the same regimen
      with rifabutin at 600 mg (group B, n = 14), or isoniazid 300 mg/day for 6 months
      (group C, n = 14). Three, two and four subjects in groups A, B, and C,
      respectively, did not complete their treatment (one case of flu-like syndrome in
      group B; one methadone withdrawal syndrome in group A; and patient decision in
      two cases in group A and four in group C). Overall, adverse events were reported
      by four, nine, and seven subjects in groups A, B and C, respectively.
      Intermittent combined rifabutin + isoniazid for 3 months had lower default rates
      than daily standard isoniazid for 6 months. The regimen with rifabutin at 300 mg
      dose compared favourably to standard isoniazid, and warrants larger efficacy
      studies to assess its role for the prevention of latent tuberculosis in HIV
      infected subjects.

PMID- 10587328
TI  - Sputum smear status at two months and subsequent treatment outcome in new
      patients with smear-positive pulmonary tuberculosis.

PMID- 10587329
TI  - Lung health in developing countries.

PMID- 10587330
TI  - The study of the determinants of non adherence to anti-tuberculosis treatment:
      are we using appropriate research methodology?

PMID- 10587331
TI  - Molecular inotropy: a future approach to the treatment of heart failure?

PMID- 10587332
TI  - Bradykinin in the heart: friend or foe?

PMID- 10587334
TI  - Comparative effects of low and high doses of the angiotensin-converting enzyme
      inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS
      Study Group.
AB  - BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors are generally
      prescribed by physicians in doses lower than the large doses that have been shown
      to reduce morbidity and mortality in patients with heart failure. It is unclear,
      however, if low doses and high doses of ACE inhibitors have similar benefits.
      METHODS AND RESULTS: We randomly assigned 3164 patients with New York Heart
      Association class II to IV heart failure and an ejection fraction < or = 30% to
      double-blind treatment with either low doses (2.5 to 5.0 mg daily, n=1596) or
      high doses (32.5 to 35 mg daily, n=1568) of the ACE inhibitor, lisinopril, for 39
      to 58 months, while background therapy for heart failure was continued. When
      compared with the low-dose group, patients in the high-dose group had a
      nonsignificant 8% lower risk of death (P=0.128) but a significant 12% lower risk
      of death or hospitalization for any reason (P=0.002) and 24% fewer
      hospitalizations for heart failure (P=0.002). Dizziness and renal insufficiency
      was observed more frequently in the high-dose group, but the 2 groups were
      similar in the number of patients requiring discontinuation of the study
      medication. Conclusions-These findings indicate that patients with heart failure
      should not generally be maintained on very low doses of an ACE inhibitor (unless
      these are the only doses that can be tolerated) and suggest that the difference
      in efficacy between intermediate and high doses of an ACE inhibitor (if any) is
      likely to be very small.

PMID- 10587333
TI  - Restoration of contractile function in isolated cardiomyocytes from failing human
      hearts by gene transfer of SERCA2a.
AB  - BACKGROUND: Failing human myocardium is characterized by abnormal relaxation, a
      deficient sarcoplasmic reticulum (SR) Ca(2+) uptake, and a negative frequency
      response, which have all been related to a deficiency in the SR Ca(2+) ATPase
      (SERCA2a) pump. METHODS AND RESULTS: To test the hypothesis that an increase in
      SERCA2a could improve contractile function in cardiomyocytes, we overexpressed
      SERCA2a in human ventricular myocytes from 10 patients with end-stage heart
      failure and examined intracellular Ca(2+) handling and contractile function.
      Overexpression of SERCA2a resulted in an increase in both protein expression and
      pump activity and induced a faster contraction velocity (26.7+/-6.7% versus
      16.6+/-2.7% shortening per second, P<0.005) and enhanced relaxation velocity (32.
      0+/-10.1% versus 15.1+/-2.4%, P<0.005). Diastolic Ca(2+) was decreased in failing
      cardiomyocytes overexpressing SERCA2a (270+/-26 versus 347+/-30 nmol/L, P<0.005),
      whereas systolic Ca(2+) was increased (601+/-38 versus 508+/-25 nmol/L, P<0.05).
      In addition, the frequency response was normalized in cardiomyocytes
      overexpressing SERCA2a. CONCLUSIONS: These results support the premise that gene
      based therapies and targeting of specific pathways in human heart failure may
      offer a new modality for the treatment of this disease.

PMID- 10587335
TI  - Estrogen and progesterone reduce lipid accumulation in human monocyte-derived
      macrophages: a sex-specific effect.
AB  - BACKGROUND: Males have an earlier onset and greater prevalence of clinical
      atherosclerosis than age-matched females, which is consistent with an
      atheroprotective effect of the female sex steroids, estrogen and progesterone. We
      therefore examined the effects of estrogen and progesterone on human foam cell
      formation, a key early event in atherogenesis. METHODS AND RESULTS: Monocytes
      from healthy female and male donors were obtained from white cell concentrates
      and allowed to differentiate into macrophages over 10 days. These human monocyte
      derived macrophages (MDMs) were exposed to either control (0.1% vol/vol ethanol)
      or estrogen or progesterone treatment on days 3 through 10. Lipid loading was
      achieved on days 8 through 10 by incubation with acetylated LDL. Lipid from the
      MDMs was then extracted for analysis of cholesteryl ester (CE) content. 17beta
      Estradiol at both physiological (2 nmol/L) and supraphysiological (20 and 200
      nmol/L) concentrations produced a significant reduction in macrophage CE content
      (88+/-3%, 88+/-2%, and 85+/-4%, respectively; P<0.02 compared with control).
      Physiological and supraphysiological levels of progesterone (2, 10, and 200
      nmol/L) produced an even more dramatic reduction in CE content (74+/-9%, 56+/
      10%, and 65+/-8%, respectively; P<0.002 compared with control). This effect could
      be abrogated by coincubation with the progesterone receptor antagonist RU486.
      Neither estrogen nor progesterone produced a reduction in lipid loading in male
      donor-derived MDMs. Detailed lipid trafficking studies demonstrated that both
      estrogen and progesterone altered macrophage uptake and/or processing of modified
      LDL. CONCLUSIONS: Physiological levels of estrogen and progesterone are
      associated with a female-sex-specific reduction in human macrophage lipid
      loading, which is consistent with an atheroprotective effect.

PMID- 10587336
TI  - Infection with Helicobacter pylori is not a major independent risk factor for
      stable coronary heart disease: lack of a role of cytotoxin-associated protein A
      positive strains and absence of a systemic inflammatory response.
AB  - BACKGROUND: There is controversy about the association between Helicobacter
      pylori infection and manifestations of coronary heart disease (CHD), the
      potential role of the more virulent H pylori strains, and whether or not a
      positive serostatus is related to increased levels of markers of systemic
      inflammation. METHODS AND RESULTS: We assessed the prevalence of an infection
      with H pylori and in particular the anti-cytotoxin-associated protein A (CagA)
      antibody response of the more virulent strains expressing CagA in 312 patients
      with stable CHD and in 479 control subjects. Serological prevalence of H pylori
      infection (IgG titer) was significantly higher in patients than in control
      subjects after adjustment for age and sex (44.2% versus 31.3%, P<0.001). After
      adjustment for various covariates in multiple logistic regression, the odds ratio
      (OR) for CHD was 1.3 (95% CI, 0.9 to 1.9) given a positive IgG serostatus. The
      prevalence of CagA-positive strains was 27.9% in patients and 21.7% in control
      subjects (P=0.076 adjusted for age and sex). The OR for CHD in the fully adjusted
      model was 1.1 (95% CI, 0.7 to 1.7). None of the inflammatory markers (C-reactive
      protein, fibrinogen, plasma viscosity, or leukocytes) was significantly different
      according to serostatus. CONCLUSIONS: In this large case-control study, the
      association of H pylori infection with stable CHD was strongly reduced and was no
      longer statistically significant after controlling for potential confounders. We
      also found no independent association between the more virulent strains and CHD.
      In addition, a positive serostatus was not associated with a systemic
      inflammatory response. Thus, these data do not support the hypothesis that
      infection with H pylori might be a major risk factor for stable CHD.

PMID- 10587337
TI  - Nocturnal continuous positive airway pressure decreases daytime sympathetic
      traffic in obstructive sleep apnea.
AB  - BACKGROUND: Patients with obstructive sleep apnea (OSA) have high levels of
      muscle sympathetic nerve activity (MSNA). We tested the hypothesis that long-term
      continuous positive airway pressure (CPAP) treatment will decrease MSNA in OSA
      patients. METHODS AND RESULTS: We measured blood pressure, heart rate, and MSNA
      in 11 normotensive, otherwise healthy patients with OSA who were treated with
      CPAP. The measurements were obtained at baseline and after 1 month, 6 months, and
      1 year of CPAP treatment. These measurements were compared with those recorded in
      9 otherwise healthy OSA patients who were not treated with CPAP for 1 year. In
      both untreated and treated patients, blood pressure and heart rate did not change
      over time. MSNA was similar during repeated measurements in the untreated group.
      By contrast, MSNA decreased significantly over time in patients treated with
      CPAP. This decrease was evident after both 6 months and 1 year of CPAP treatment
      (P=0.02 for both). CONCLUSIONS: CPAP treatment decreases muscle sympathetic
      traffic in patients with OSA. This effect of CPAP is evident only after an
      extended duration of therapy.

PMID- 10587338
TI  - Subtype specific regulation of human vascular alpha(1)-adrenergic receptors by
      vessel bed and age.
AB  - BACKGROUND: alpha(1)-adrenergic receptors (alpha(1)ARs) regulate blood pressure,
      regional vascular resistance, and venous capacitance; the exact subtype
      (alpha(1a), alpha(1b), alpha(1 d)) mediating these effects is unknown and varies
      with species studied. In order to understand mechanisms underlying cardiovascular
      responses to acute stress and chronic catecholamine exposure (as seen with
      aging), we tested two hypotheses: (1) human alpha(1)AR subtype expression differs
      with vascular bed, and (2) age influences human vascular alpha(1)AR subtype
      expression. METHODS AND RESULTS: Five hundred vessels from 384 patients were
      examined for alpha(1)AR subtype distribution at mRNA and protein levels (RNase
      protection assays, ligand binding, contraction assays). Overall vessel alpha(1)AR
      density is 16+/-2.3fmol/mg total protein. alpha(1a)AR predominates in arteries at
      mRNA (P<0.001) and protein (P<0.05) levels; all 3 subtypes are present in veins.
      Furthermore, alpha(1)AR mRNA subtype expression varies with vessel bed (alpha(1a)
      higher in splanchnic versus central arteries, P<0.05); competition analysis
      (selected vessels) and functional assays demonstrate alpha(1a) and alpha(1b)
      mediated mammary artery contraction. Overall alpha(1)AR expression doubles with
      age (<55 versus > or = 65 years) in mammary artery (no change in saphenous vein),
      accompanied by increased alpha(1b)>alpha(1a) expression (P< = 0.001).
      CONCLUSIONS: Human vascular alpha(1)AR subtype distribution differs from animal
      models, varies with vessel bed, correlates with contraction in mammary artery,
      and is modulated by aging. These findings provide potential novel targets for
      therapeutic intervention in many clinical settings.

PMID- 10587339
TI  - Risks of spontaneous injury and extraction of an active fixation pacemaker lead:
      report of the Accufix Multicenter Clinical Study and Worldwide Registry.
AB  - BACKGROUND: The Telectronics Accufix pacing leads were recalled in November 1994
      after 2 deaths and 2 nonfatal injuries were reported. This multicenter clinical
      study (MCS) of patients with Accufix leads was designed to determine the rate of
      spontaneous injury related to the J retention wire and results of lead
      extraction. METHODS AND RESULTS: The MCS included 2589 patients with Accufix
      atrial pacing leads that were implanted at or who were followed up at 12 medical
      centers. Patients underwent cinefluoroscopic imaging of their lead every 6
      months. The risk of J retention wire fracture was approximately 5.6%/y at 5 years
      and 4.7%/y at 10 years after implantation. The annual risk of protrusion was
      1.5%. A total of 40 spontaneous injuries were reported to a worldwide registry
      (WWR) that included data from 34 672 patients (34 892 Accufix leads), including
      pericardial tamponade (n=19), pericardial effusion (n=5), atrial perforation
      (n=3), J retention wire embolization (n=4), and death (n=6). The risk of injury
      was 0.02%/y (95% CI, 0.0025 to 0. 072) in the MCS and 0.048%/y (95% CI, 0.035 to
      0.067) in the WWR. A total of 5299 leads (13%) have been extracted worldwide.
      After recall in the WWR, fatal extraction complications occurred in 0.4% of
      intravascular procedures (16 of 4023), with life-threatening complications in
      0.5% (n=21). Extraction complications increased with implant duration, female
      sex, and J retention wire protrusion. CONCLUSIONS: Accufix pacing leads pose a
      low, ongoing risk of injury. Extraction is associated with substantially higher
      risks, and a conservative management approach is indicated for most patients.

PMID- 10587340
TI  - Frequency of early occlusion and stenosis in a left internal mammary artery to
      left anterior descending artery bypass graft after surgery through a median
      sternotomy on conventional bypass: benchmark for minimally invasive direct
      coronary artery bypass.
AB  - BACKGROUND: Uncertainty exists regarding the frequency of early occlusion when
      the left internal mammary artery (LIMA) is anastomosed to the left anterior
      descending artery (LAD) through a sternotomy with conventional coronary artery
      bypass grafting (CABG). The issue has gained importance for comparison with less
      invasive surgical approaches in which operative exposure may be limited and graft
      anastomosis more difficult. METHODS AND RESULTS: Data were analyzed from the
      International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial in
      which 617 patients underwent conventional CABG of the LAD with a LIMA between
      April 1993 and May 1995. Coronary angiography was performed a mean of 10.8 days
      postoperatively. Patients were randomized to receive intraoperative aprotinin, an
      inhibitor of several serine proteinases, or placebo. Because no differences
      existed in patency rates of LIMA grafts between patients who received aprotinin
      and placebo, both groups were analyzed collectively. On coronary angiography, the
      LIMA was widely patent (<50% stenosis) in 561 patients (91%), had > or = 50% and
      <99% stenosis in 48 patients (7.8%), and was occluded in 8 patients (1.3%).
      Therefore, the LIMA was patent in 609 patients (98.7%). Conclusions-In the IMAGE
      trial, the largest and most contemporary early angiographic analysis of CABG
      available, early patency of the LIMA was >98% when anastomosed to the LAD. These
      data provide an important benchmark for less invasive surgical approaches in
      which the LIMA is anastomosed to the LAD.

PMID- 10587341
TI  - Dilated and failing cardiomyopathy in bradykinin B(2) receptor knockout mice.
AB  - BACKGROUND: The activation of B(2) receptors by kinins could exert
      cardioprotective effects in myocardial ischemia and heart failure. METHODS AND
      RESULTS: To test whether the absence of bradykinin B(2) receptors may affect
      cardiac structure and function, we examined the developmental changes in blood
      pressure (BP), heart rate, and heart morphology of bradykinin B(2) receptor gene
      knockout (B(2)(-/-)), heterozygous (B(2)(+/-)), and wild-type (B(2)(+/+)) mice.
      The BP of B(2)(-/-) mice, which was still normal at 50 days of age, gradually
      increased, reaching a plateau at 6 months (136+/-3 versus 109+/-1 mm Hg in
      B(2)(+/+), P<0.01). In B(2)(+/-) mice, BP elevation was delayed. At 40 days, the
      heart rate was higher (P<0.01) in B(2)(-/-) and B(2)(+/-) than in B(2)(+/+) mice,
      whereas the left ventricular (LV) weight and chamber volume were similar among
      groups. Thereafter, the LV growth rate of B(2)(-/-) and B(2)(+/-) mice was
      accelerated, leading at 360 days to a LV weight-to-body weight ratio that was 9%
      and 17% higher, respectively, than that of B(2)(+/+) mice. In B(2)(-/-) mice,
      hypertrophy was associated with a marked chamber dilatation (42% larger than that
      of B(2)(+/+) mice), an elevation in LV end-diastolic pressure (25+/-3 versus 5+/
      1 mm Hg in B(2)(+/+) mice, P<0.01), and reparative fibrosis. CONCLUSIONS: The
      disruption of the bradykinin B(2) receptor leads to hypertension, LV remodeling,
      and functional impairment, implying that kinins are essential for the functional
      and structural preservation of the heart.

PMID- 10587342
TI  - Long-term coronary vascular response to (32)P beta-particle-emitting stents in a
      canine model.
AB  - BACKGROUND: The arterial placement of (32)P beta-particle-emitting stents in
      various experimental animal models results in discordant effects on neointimal
      formation. We studied the vascular effects of beta-particle-emitting stents in
      normal canine coronary arteries because compared with pigs and rabbits, the
      canine model may more closely mimic the vascular response of humans. METHODS AND
      RESULTS: Thirty stents (control nonradioactive, n=10; low-activity (32)P, 3.5 to
      6.0 microCi, n=11; high-activity (32)P, 6.5 to 14.4 microCi, n=8) were implanted
      in normal canine coronary arteries through the use of a single balloon inflation
      at nominal pressure. Histological analysis after 15 weeks included the
      measurement of neointimal and adventitial area and thickness. Neointimal fibrin
      area was measured with the use of computer-assisted color segmentation on Movat
      pentachrome sections. Luminal stenosis was significantly increased in (32)P
      stents compared with control stents (44.6+/-16.8% versus 32.7+/-10.8%; P=0.05)
      and was highest in the high-activity group (45.5+/-24.3%). No evidence of an
      "edge effect" was seen in adjacent, nonstented coronary segments. All (32)P
      stents showed incomplete vascular healing as indicated by a dose-dependent
      increase in fibrin area with increasing stent activity. Arterial radiation
      resulted in a decrease in adventitial size, which was maximal for high-activity
      (32)P stents, indicating an inhibitory effect on the adventitial response to
      injury. CONCLUSIONS: (32)P beta-particle-emitting stents have adverse vascular
      effects at 15 weeks in the canine normal coronary artery model. Vascular
      brachytherapy with this device causes increased neointimal formation and
      prominent, dose-dependent lack of healing.

PMID- 10587343
TI  - Adenoviral gene transfer of activated phosphatidylinositol 3'-kinase and Akt
      inhibits apoptosis of hypoxic cardiomyocytes in vitro.
AB  - BACKGROUND: The intracellular signaling pathways that control cardiomyocyte
      apoptosis have not been fully defined. Because insulin-like growth factor-1 (IGF
      1) prevents cardiomyocyte apoptosis, we examined the role of its downstream
      signaling molecules in an in vitro model of hypoxia-induced cardiomyocyte
      apoptosis. METHODS AND RESULTS: Treatment of rat neonatal cardiomyocytes with IGF
      1 increased activity of both phosphatidylinositol 3' (PI 3)-kinase and its
      downstream target, Akt (also known as protein kinase B or PKB). Cardiomyocytes
      were subjected to hypoxia for 24 hours, and apoptosis was assessed by DNA
      laddering, TUNEL staining, and ELISA for histone-associated DNA fragments. IGF-1
      treatment (100 nmol/L) reduced cardiomyocyte apoptosis, and this effect was
      inhibited by simultaneous treatment with a PI 3-kinase inhibitor. Cardiomyocytes
      were infected with either a control adenovirus (Ad.EGFP) or adenoviruses carrying
      constitutively active forms of PI 3-kinase (Ad.BD110) or Akt (Ad. myr-Akt-HA).
      Ad.BD110 significantly inhibited apoptosis of hypoxic cardiomyocytes compared
      with Ad.EGFP (61.0+/-4.6% less DNA fragmentation than in Ad.EGFP-infected cells,
      P<0.0001). Ad. myr-Akt-HA even more dramatically inhibited apoptosis of hypoxic
      cardiomyocytes (90.9+/-1.4% less DNA fragmentation than in controls, P<0.0001).
      CONCLUSIONS: IGF-1 activates PI 3-kinase and Akt in cardiomyocytes. Activated PI
      3-kinase and Akt are each sufficient to protect hypoxic cardiomyocytes against
      apoptosis in vitro. Adenoviral gene transfer provides a useful tool for
      investigating the role of these signaling pathways in cardiomyocyte apoptosis.

PMID- 10587344
TI  - Profound apoptosis-mediated regional myocyte loss and compensatory hypertrophy in
      pigs with hibernating myocardium.
AB  - BACKGROUND: Myocyte apoptosis is seen in ischemic heart disease, but whether it
      can occur after reversible ischemia or independent of necrosis and replacement
      fibrosis is unknown. METHODS AND RESULTS: Pigs were instrumented with a stenosis
      of the left anterior descending coronary artery to chronically reduce coronary
      flow reserve over a period of 3 months. At this time, there was viable
      dysfunctional myocardium having the physiological features of hibernating
      myocardium. Resting subendocardial perfusion was reduced to 0.65+/-0.08 (mean+/
      SEM) mL. min(-1). g(-1) in hibernating myocardium of instrumented pigs compared
      with 0.98+/-0.14 mL. min(-1). g(-1) in myocardium of sham-operated pigs (P<0.05).
      There was a critical limitation in subendocardial flow during vasodilation to
      0.78+/-0.20 mL. min(-1). g(-1) in instrumented pigs versus 3. 24+/-0.50 mL. min(
      1). g(-1) in sham-operated pigs (P<0.001). Histology revealed a regional
      reduction in myocyte nuclear density to 995+/-100 nuclei/mm(2) in hibernating
      myocardium from the instrumented group versus 1534+/-65 nuclei/mm(2) in
      myocardium from the sham-operated group (P<0.05), regional myocyte hypertrophy
      (myocyte volume per nucleus, 14 183+/-2594 in the instrumented group versus
      9130+/-1301 microm(3) in the sham group; P<0.05), and minimal increases in
      connective tissue (5.8+/-0.9% in the instrumented group versus 3.0+/-0.2% in the
      sham group, P<0.05). Necrosis was not identified, but apoptosis was increased
      from 30+/-9 myocytes per 10(6) myocyte nuclei in myocardium from the sham group
      to 220+/-77 myocytes per 10(6) myocyte nuclei in hibernating myocardium (P<0.05).
      CONCLUSIONS: These findings indicate that reversible ischemia in an area of
      chronically reduced coronary flow reserve induces regional myocyte loss via an
      apoptotic mechanism. This may contribute to the progression of chronic coronary
      disease to heart failure and explain the lack of complete functional recovery
      after revascularization in hibernating myocardium.

PMID- 10587345
TI  - Somatostatin-receptor scintigraphy identifies a cardiac pheochromocytoma.

PMID- 10587346
TI  - A role for lipid rafts in B cell antigen receptor signaling and antigen
      targeting.
AB  - The B cell antigen receptor (BCR) serves both to initiate signal transduction
      cascades and to target antigen for processing and presentation by MHC class II
      molecules. How these two BCR functions are coordinated is not known. Recently,
      sphingolipid- and cholesterol-rich plasma membrane lipid microdomains, termed
      lipid rafts, have been identified and proposed to function as platforms for both
      receptor signaling and membrane trafficking. Here we show that upon cross
      linking, the BCR rapidly translocates into ganglioside G(M1)-enriched lipid rafts
      that contain the Src family kinase Lyn and exclude the phosphatase CD45R. Both
      Igalpha and Lyn in the lipid rafts become phosphorylated, and subsequently the
      BCR and a portion of G(M1) are targeted to the class II peptide loading
      compartment. Entry into lipid rafts, however, is not sufficient for targeting to
      the antigen processing compartments, as a mutant surface Ig containing a deletion
      of the cytoplasmic domain is constitutively present in rafts but when cross
      linked does not internalize to the antigen processing compartment. Taken
      together, these results provide evidence for a role for lipid rafts in the
      initial steps of BCR signaling and antigen targeting.

PMID- 10587347
TI  - Normal regulatory alpha/beta T cells effectively eliminate abnormally activated T
      cells lacking the interleukin 2 receptor beta in vivo.
AB  - Although interleukin 2 (IL-2) has been thought to be the most important cytokine
      for T cell growth, animals lacking IL-2 or a component of its receptor molecules
      have more expanded T cells with activated memory phenotype, indicating an
      indispensable role for the IL-2/IL-2 receptor system in regulating the size and
      activity of the T cell population. In this study, we investigated the possible
      mechanism of abnormal expansion of activated T cells in IL-2 receptor beta chain
      (IL-2Rbeta)(-/-) mice using the systems of bone marrow transplantation and T cell
      transfer. Here, we show that IL-2Rbeta(2/-) T cells in mice reconstituted with a
      mixture of IL-2Rbeta(2/-) and IL-2Rbeta(1/+) bone marrow cells did not develop
      into an abnormally activated stage, and that already activated IL-2Rbeta(2/-) T
      cells were effectively eliminated by IL-2Rbeta(1/+) T cells when both cells were
      cotransferred to T cell-deficient host mice. This regulation and/or elimination
      was dependent on T cells bearing alpha/beta type T cell receptor, especially on
      CD8(+) T cells and independent of the Fas-Fas ligand (FasL) system. IL
      2Rbeta(1/+) T cells that eliminated activated IL-2Rbeta(2/-) T cells expressed
      FasL, perforin, granzyme B, and tumor necrosis factor alpha/beta. These results
      indicate a novel function of IL-2Rbeta that is necessary for the induction of
      regulatory T cells acting to eliminate activated T cells.

PMID- 10587348
TI  - Impairment of natural killer cytotoxic activity and interferon gamma production
      in CCAAT/enhancer binding protein gamma-deficient mice.
AB  - We have investigated in vivo roles of CCAAT/enhancer binding protein gamma
      (C/EBPgamma) by gene targeting. C/EBPgamma-deficient (C/EBPgamma(2/-)) mice
      showed a high mortality rate within 48 h after birth. To analyze the roles of
      C/EBPgamma in lymphoid lineage cells, bone marrow chimeras were established.
      C/EBPgamma(2/-) chimeras showed normal T and B cell development. However,
      cytolytic functions of their splenic natural killer (NK) cells after stimulation
      with cytokines such as interleukin (IL)-12, IL-18, and IL-2 were significantly
      reduced as compared with those of control chimera NK cells. In addition, the
      ability of C/EBPgamma(-/-) chimera splenocytes to produce interferon (IFN)-gamma
      in response to IL-12 and/or IL-18 was markedly impaired. NK cells could be
      generated in vitro with normal surface marker expression in the presence of IL-15
      from C/EBPgamma(2/-) newborn spleen cells. However, they also showed lower
      cytotoxic activity and IFN-gamma production when stimulated with IL-12 plus IL-18
      than control NK cells, as observed in C/EBPgamma(2/-) chimera splenocytes. In
      conclusion, our study reveals that C/EBPgamma is a critical transcription factor
      involved in the functional maturation of NK cells.

PMID- 10587349
TI  - 1alpha,25-dihydroxyvitamin D(3)-induced myeloid cell differentiation is regulated
      by a vitamin D receptor-phosphatidylinositol 3-kinase signaling complex.
AB  - 1alpha,25-dihydroxyvitamin D(3) (D(3)) promotes the maturation of myeloid cells
      and surface expressions of CD14 and CD11b, markers of cell differentiation in
      response to D(3). To examine how these responses are regulated, THP-1 cells were
      grown in serum-free medium and incubated with D(3). This was associated with
      rapid and transient increases in phosphatidylinositol 3-kinase (PI 3-kinase)
      activity. Furthermore, induction of CD14 expression in response to D(3) was
      abrogated by (a) the PI 3-kinase inhibitors LY294002 and wortmannin; (b)
      antisense oligonucleotides to mRNA for the p110 catalytic subunit of PI 3-kinase;
      and (c) a dominant negative mutant of PI 3-kinase. In THP-1 cells, induction of
      CD11b expression by D(3) was also abrogated by LY294002 and wortmannin.
      Similarly, LY294002 and wortmannin inhibited D(3)-induced expression of both CD14
      and CD11b in peripheral blood monocytes. In contrast to CD14 and CD11b, hormone
      induced expression of the Cdk inhibitor p21 in THP-1 cells was unaffected by
      either wortmannin or LY294002. These findings suggest that PI 3-kinase
      selectively regulates D(3)-induced monocyte differentiation, independent of any
      effects on p21.

PMID- 10587350
TI  - Methylation-dependent gene silencing induced by interleukin 1beta via nitric
      oxide production.
AB  - Interleukin (IL)-1beta is a pleiotropic cytokine implicated in a variety of
      activities, including damage of insulin-producing cells, brain injury, or
      neuromodulatory responses. Many of these effects are mediated by nitric oxide
      (NO) produced by the induction of NO synthase (iNOS) expression. We report here
      that IL-1beta provokes a marked repression of genes, such as fragile X mental
      retardation 1 (FMR1) and hypoxanthine phosphoribosyltransferase (HPRT), having a
      CpG island in their promoter region. This effect can be fully prevented by iNOS
      inhibitors and is dependent on DNA methylation. NO donors also cause FMR1 and
      HPRT gene silencing. NO-induced methylation of FMR1 CpG island can be reverted by
      demethylating agents which, in turn, produce the recovery of gene expression. The
      effects of IL-1beta and NO appear to be exerted through activation of DNA
      methyltransferase (DNA MeTase). Although exposure of the cells to NO does not
      increase DNA MeTase gene expression, the activity of the enzyme selectively
      increases when NO is applied directly on a nuclear protein extract. These
      findings reveal a previously unknown effect of IL-1beta and NO on gene
      expression, and demonstrate a novel pathway for gene silencing based on
      activation of DNA MeTase by NO and acute modification of CpG island methylation.

PMID- 10587351
TI  - Thymocyte maturation is regulated by the activity of the helix-loop-helix
      protein, E47.
AB  - The E2A proteins, E12 and E47, are required for progression through multiple
      developmental pathways, including early B and T lymphopoiesis. Here, we provide
      in vitro and in vivo evidence demonstrating that E47 activity regulates double
      positive thymocyte maturation. In the absence of E47 activity, positive selection
      of both major histocompatibility complex (MHC) class I- and class II-restricted T
      cell receptors (TCRs) is perturbed. Additionally, development of CD8 lineage T
      cells in an MHC class I-restricted TCR transgenic background is sensitive to the
      dosage of E47. Mice deficient for E47 display an increase in production of mature
      CD4 and CD8 lineage T cells. Furthermore, ectopic expression of an E2A inhibitor
      helix-loop-helix protein, Id3, promotes the in vitro differentiation of an
      immature T cell line. These results demonstrate that E2A functions as a regulator
      of thymocyte positive selection.

PMID- 10587352
TI  - Commitment of common T/Natural killer (NK) progenitors to unipotent T and NK
      progenitors in the murine fetal thymus revealed by a single progenitor assay.
AB  - We have established a new clonal assay system that can evenly support the
      development of T and natural killer (NK) cells. With this system, we show that
      all T cell progenitors in the earliest CD44(+)CD25(-)FcgammaRII/III(-) fetal
      thymus (FT) cell population retain NK potential, and that the NK lineage
      committed progenitors (p-NK) also exist in this population. T cell lineage
      committed progenitors (p-T), which are unable to generate NK cells, first appear
      at the CD44(+)CD25(-) FcgammaRII/III(+) stage in day 12 FT. The proportion of p-T
      markedly increases during the transition from the CD44(+)CD25(-) stage to the
      CD44(+)CD25(+) stage in day 14 FT. On the other hand, p-NK preferentially
      increase in number at the CD44(+)CD25(-) stage between days 12 and 14 of
      gestation. The production of p-NK continues up to the CD44(+)CD25(+) stage, but
      ceases before the rearrangement of T cell receptor beta chain genes. It was
      further shown that the CD44(+)CD25(-) CD122(+) population of day 14 FT
      exclusively contains p-NK. These results indicate that the earliest T cell
      progenitor migrating into the FT is T/NK bipotent, and strongly suggest that the
      bipotent progenitor continuously produces p-NK and p-T until the CD44(+)CD25(+)
      stage.

PMID- 10587353
TI  - Partially phosphorylated T cell receptor zeta molecules can inhibit T cell
      activation.
AB  - The T cell receptor complex (TCR) zeta chain is constitutively tyrosine
      phosphorylated specifically at two of the six zeta immunoreceptor tyrosine-based
      activation motif (ITAM) tyrosine residues in resting peripheral T cells. Further
      phosphorylation of zeta is induced by both agonist and antagonist ligands of the
      TCR, with agonists inducing complete phosphorylation of the zeta ITAM tyrosines.
      After antagonist stimulation, zeta phosphorylation is incomplete and generates
      discrete forms of partially phosphorylated ITAMs. Here, we mutate specific
      tyrosines in chimeric human CD8-zeta molecules to reflect phosphorylation in
      resting T cells as well as phosphorylation induced by agonist and antagonist
      ligands. We demonstrate that such partially phosphorylated TCR-zeta species can
      inhibit IL-2 production in T cell hybridomas and proliferation in T cell clones.
      This reveals a previously unrecognized, inhibitory function of partially
      phosphorylated ITAMs. These findings support the concept that TCR antagonism can
      arise through the generation of an inhibitory signal within the TCR complex and
      that constitutive zeta phosphorylation in resting T cells is an inhibitory
      signaling environment.

PMID- 10587354
TI  - In vivo role of complement-interacting domains of herpes simplex virus type 1
      glycoprotein gC.
AB  - Immune evasion is critical for survival of viruses that establish persistent or
      recurrent infections. However, at the molecular level, little is known about how
      viruses evade immune attack in vivo. Herpes simplex virus (HSV)-1 glycoprotein gC
      has two domains that are involved in modulating complement activation; one binds
      C3, and the other is required for blocking C5 and properdin (P) binding to C3. To
      evaluate the importance of these regions in vivo, HSV-1 gC mutant viruses were
      constructed that lacked one or both gC domains and studied in a murine model of
      infection. Each gC region of complement regulation contributed to virulence;
      however, the C3 binding domain was far more important, as virus lacking this
      domain was much less virulent than virus lacking the C5/P inhibitory domain and
      was as attenuated as virus lacking both domains. Studies in C3 knockout mice and
      mice reconstituted with C3 confirmed that the gC domains are inhibitors of
      complement activation, accounting for a 50-fold difference in virulence between
      mutant and wild-type viruses. We conclude that the C3 binding domain on gC is a
      major contributor to immune evasion and that this site explains at a molecular
      level why wild-type virus resists complement attack.

PMID- 10587355
TI  - Extracellular signal-regulated kinase (ERK) activation by the pre-T cell receptor
      in developing thymocytes in vivo.
AB  - The first checkpoint in T cell development occurs between the CD4(-)CD8(-) and
      CD4(+)CD8(+) stages and is associated with formation of the pre-T cell receptor
      (TCR). The signaling mechanisms that drive this progression remain largely
      unknown. Here, we show that extracellular signal-regulated kinases (ERKs)-1/2 are
      activated upon engagement of the pre-TCR. Using a novel experimental system, we
      demonstrate that expression of the pre-TCR by developing thymocytes induces ERK
      1/2 activation within the thymus. In addition, the activation of this pre-TCR
      signaling cascade is mediated through Lck. These findings directly link pre-TCR
      complex formation with specific downstream signaling components in vivo.

PMID- 10587356
TI  - RIBP, a novel Rlk/Txk- and itk-binding adaptor protein that regulates T cell
      activation.
AB  - A novel T cell-specific adaptor protein, RIBP, was identified based on its
      ability to bind Rlk/Txk in a yeast two-hybrid screen of a mouse T cell lymphoma
      library. RIBP was also found to interact with a related member of the Tec family
      of tyrosine kinases, Itk. Expression of RIBP is restricted to T and natural
      killer cells and is upregulated substantially after T cell activation. RIBP
      disrupted knockout mice displayed apparently normal T cell development. However,
      proliferation of RIBP-deficient T cells in response to T cell receptor (TCR)
      mediated activation was significantly impaired. Furthermore, these activated T
      cells were defective in the production of interleukin (IL)-2 and interferon
      gamma, but not IL-4. These data suggest that RIBP plays an important role in TCR
      mediated signal transduction pathways and that its binding to Itk and Rlk/Txk may
      regulate T cell differentiation.

PMID- 10587357
TI  - Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells
      expands specific cytotoxic T cells and induces regression of some metastases in
      advanced stage IV melanoma.
AB  - Dendritic cells (DCs) are considered to be promising adjuvants for inducing
      immunity to cancer. We used mature, monocyte-derived DCs to elicit resistance to
      malignant melanoma. The DCs were pulsed with Mage-3A1 tumor peptide and a recall
      antigen, tetanus toxoid or tuberculin. 11 far advanced stage IV melanoma
      patients, who were progressive despite standard chemotherapy, received five DC
      vaccinations at 14-d intervals. The first three vaccinations were administered
      into the skin, 3 x 10(6) DCs each subcutaneously and intradermally, followed by
      two intravenous injections of 6 x 10(6) and 12 x 10(6) DCs, respectively. Only
      minor (less than or equal to grade II) side effects were observed. Immunity to
      the recall antigen was boosted. Significant expansions of Mage-3A1-specific
      CD8(+) cytotoxic T lymphocyte (CTL) precursors were induced in 8/11 patients.
      Curiously, these immune responses often declined after the intravenous
      vaccinations. Regressions of individual metastases (skin, lymph node, lung, and
      liver) were evident in 6/11 patients. Resolution of skin metastases in two of the
      patients was accompanied by erythema and CD8(+) T cell infiltration, whereas
      nonregressing lesions lacked CD8(+) T cells as well as Mage-3 mRNA expression.
      This study proves the principle that DC "vaccines" can frequently expand tumor
      specific CTLs and elicit regressions even in advanced cancer and, in addition,
      provides evidence for an active CD8(+) CTL-tumor cell interaction in situ as well
      as escape by lack of tumor antigen expression.

PMID- 10587358
TI  - FLICE-inhibitory protein expression during macrophage differentiation confers
      resistance to fas-mediated apoptosis.
AB  - Macrophages differentiated from circulating peripheral blood monocytes are
      essential for host immune responses and have been implicated in the pathogenesis
      of rheumatoid arthritis and atherosclerosis. In contrast to monocytes,
      macrophages are resistant to Fas-induced cell death by an unknown mechanism.
      FLICE (Fas-associated death domain-like interleukin 1beta-converting enzyme)
      inhibitory protein (Flip), a naturally occurring caspase-inhibitory protein that
      lacks the critical cysteine domain necessary for catalytic activity, is a
      negative regulator of Fas-induced apoptosis. Here, we show that monocyte
      differentiation into macrophages was associated with upregulation of Flip and a
      decrease in Fas-mediated apoptosis. Overexpression of Flip protected monocytes
      from Fas-mediated apoptosis, whereas acute Flip inhibition in macrophages induced
      apoptosis. Addition of an antagonistic Fas ligand antibody to Flip antisense
      treated macrophages rescued cultures from apoptosis, demonstrating that
      endogenous Flip blocked Fas-induced cell death. Thus, the expression of Flip in
      macrophages conferred resistance to Fas-mediated apoptosis, which may contribute
      to the development of inflammatory disease.

PMID- 10587359
TI  - High pathogenic potential of low-affinity autoantibodies in experimental
      autoimmune hemolytic anemia.
AB  - To assess the potency of low-affinity anti-red blood cell (RBC) autoantibodies in
      the induction of anemia, we generated an immunoglobulin (Ig)G2a class-switch
      variant of a 4C8 IgM anti-mouse RBC autoantibody, and compared its pathogenic
      potential with that of its IgM isotype and a high-affinity 34-3C IgG2a
      autoantibody. The RBC-binding activity of the 4C8 IgG2a variant was barely
      detectable, at least 1,000 times lower than that of its IgM isotype, having a
      high-binding avidity, and that of the 34-3C IgG2a monoclonal antibody (mAb). This
      low-affinity feature of the 4C8 mAb was consistent with the lack of detection of
      opsonized RBCs in the circulating blood from the 4C8 IgG2a-injected mice.
      However, the 4C8 IgG2a variant was highly pathogenic, as potent as its IgM
      isotype and the 34-3C IgG2a mAb, due to its capacity to interact with Fc
      receptors involved in erythrophagocytosis. In addition, our results indicated
      that the pentameric form of the low-affinity IgM isotype, by promoting the
      binding and agglutination of RBCs, is critical for its pathogenic activity.
      Demonstration of the remarkably high pathogenic potency of low-affinity
      autoantibodies, if combined with appropriate heavy chain effector functions,
      highlights the critical role of the Ig heavy chain constant regions, but the
      relatively minor role of autoantigen-binding affinities, in autoimmune hemolytic
      anemia.

PMID- 10587360
TI  - Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune
      manifestations.
AB  - The cause of many autoimmune and inflammatory diseases is unresolved, although
      dysregulated production of tumor necrosis factor (TNF) family members appears to
      be important in many cases. BAFF, a new member of the TNF family, binds to B
      cells and costimulates their growth in vitro. Mice transgenic for BAFF have
      vastly increased numbers of mature B and effector T cells, and develop autoimmune
      like manifestations such as the presence of high levels of rheumatoid factors,
      circulating immune complexes, anti-DNA autoantibodies, and immunoglobulin
      deposition in the kidneys. This phenotype is reminiscent of certain human
      autoimmune disorders and suggests that dysregulation of BAFF expression may be a
      critical element in the chain of events leading to autoimmunity.

PMID- 10587361
TI  - Targeted disruption of the plasmodium berghei CTRP gene reveals its essential
      role in malaria infection of the vector mosquito.
AB  - CTRP (circumsporozoite protein and thrombospondin-related adhesive protein [TRAP]
      related protein) of the rodent malaria parasite Plasmodium berghei (PbCTRP) makes
      up a protein family together with other apicomplexan proteins that are
      specifically expressed in the host-invasive stage 1. PbCTRP is produced in the
      mosquito-invasive, or ookinete, stage and is a protein candidate for a role in
      ookinete adhesion and invasion of the mosquito midgut epithelium. To demonstrate
      involvement of PbCTRP in the infection of the vector, we performed targeting
      disruption experiments with this gene. PbCTRP disruptants showed normal
      exflagellation rates and development into ookinetes. However, no oocyst formation
      was observed in the midgut after ingestion of these parasites, suggesting
      complete loss of their invasion ability. On the other hand, when ingested
      together with wild-type parasites, disruptants were able to infect mosquitoes,
      indicating that the PbCTRP gene of the wild-type parasite rescued infectivity of
      disruptants when they heterologously mated in the mosquito midgut lumen. Our
      results show that PbCTRP plays a crucial role in malaria infection of the
      mosquito midgut and suggest that similar molecular mechanisms are used by malaria
      parasites to invade cells in the insect vector and the mammalian host.

PMID- 10587362
TI  - Coupling and uncoupling of tumor immunity and autoimmunity.
AB  - Self-antigens, in the form of differentiation antigens, are commonly recognized
      by the immune system on melanoma and other cancers. We have shown previously that
      active immunization of mice against the melanocyte differentiation antigen, a
      tyrosinase-related protein (TRP) gp75(TRP-1) (the brown locus protein) expressed
      by melanomas, could induce tumor immunity and autoimmunity manifested as
      depigmentation. In this system, tumor immunity and autoimmunity were mediated by
      autoantibodies. Here, we characterize immunity against another tyrosinase family
      glycoprotein TRP-2 (the slaty locus protein), using the same mouse model and
      method of immunization. As observed previously for gp75(TRP-1), immunity was
      induced by DNA immunization against a xenogeneic form of TRP-2, but not against
      the syngeneic gene, and depended on CD4(+) cells. Immunization against TRP-2
      induced autoantibodies and autoreactive cytotoxic T cells. In contrast to
      immunization against gp75(TRP-1), both tumor immunity and autoimmunity required
      CD8(+) T cells, but not antibodies. Only autoimmunity required perforin, whereas
      tumor immunity proceeded in the absence of perforin. Thus, immunity induced
      against two closely related autoantigens that are highly conserved throughout
      vertebrate evolution involved qualitatively different mechanisms, i.e., antibody
      versus CD8(+) T cell. However, both pathways led to tumor immunity and identical
      phenotypic manifestations of autoimmunity.

PMID- 10587363
TI  - Human placental GnRH-like factors: parallel displacement in GnRH immuno- and
      receptor-binding assays can be caused by degradation of radiolabelled GnRH
      tracers.
AB  - Human term placental cytosol fractions decreased the specific binding of
      gonadotrophin-releasing hormone (GnRH) isoform tracers to placental membranes
      (and to rat pituitary GnRH receptors and anti-GnRH antibodies) in a dose
      dependent manner, and in parallel to GnRH standard curves. However, cytosol
      fractions had little or no effect on the binding of two GnRH superagonist
      tracers. The specificity of placental binding sites for a range of GnRH-like and
      unrelated peptides was shown to be similar with GnRH isoforms or GnRH agonists as
      binding ligands, suggesting that isoforms and agonists did not bind to different
      forms of the GnRH-receptor. Inclusion of a cocktail of protease inhibitors during
      the preparation of placental cytosol significantly reduced immuno- and receptor
      binding activity. Moreover, incubation of radiolabelled chicken GnRH II with
      placental cytosol led to marked inactivation of tracer, as assessed by
      radioreceptor and radioimmunoassays for GnRH, high resolution liquid
      chromatography, thin layer chromatography and adsorption to dextran-coated
      charcoal and other matrices. There was a good negative correlation between tracer
      degradation and apparent GnRH immuno- and receptor-binding activities. These
      results emphasize the important effects which proteases in un-denatured tissue
      extracts can have on radioreceptor and radioimmunoassays due to inactivation of
      peptide tracers, and suggest that previous measurements of receptor- and immuno
      active GnRH-like factors may have been over-estimated due to peptidase action
      during the GnRH assay.

PMID- 10587364
TI  - Transferrin in the developing ovarian follicle: evidence for de-novo expression
      by granulosa cells.
AB  - Transferrin is produced primarily by the liver and is best known as a carrier of
      iron in the circulation. Transferrin is also produced extra-hepatically where it
      may serve to suppress the generation of reactive oxygen species and act as a
      growth factor, in addition to its role in the endocytosis of iron. There is
      evidence that transferrin and its cognate receptor are important for successful
      development of follicles but little is known about their precise roles in this
      context. To learn more about their modus operandi, we undertook
      immunocytochemical studies which revealed that transferrin and its receptor are
      distributed heterogeneously in human granulosa cells, with more pronounced
      expression in more mature follicles. Expression within the oocyte itself was not
      prominent until the antral stage of development. Using nested reverse
      trancription-polymerase chain reaction (RT-PCR), transferrin mRNA expression was
      demonstrated in granulosa cells of the human and mouse ovary but not in the
      oocyte. Hence it appears that local production of transferrin is possible in
      addition to the likely uptake of circulating protein into the follicle by
      endocytosis. Values of transferrin in the follicular fluid were found to be
      highly correlated with those in serum, suggesting that the small contribution
      made by its localized synthesis in the granulosa cell may be important for some
      as yet unknown mechanism in follicle maturation.

PMID- 10587365
TI  - Vascular endothelial growth factor (VEGF) and angiopoietin regulation by
      gonadotrophin and steroids in macaque granulosa cells during the peri-ovulatory
      interval.
AB  - The role of endothelial cell-specific growth factors in the vascularization of
      the primate peri-ovulatory follicle was examined. Experiments were designed
      firstly to detect expression of vascular endothelial growth factor (VEGF),
      angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) in granulosa cells and
      secondly, to determine whether gonadotrophins and/or steroids regulate their
      expression during the peri-ovulatory interval. Granulosa cells and follicular
      fluid were collected from rhesus macaques undergoing ovarian stimulation before
      (0 h), 12, or 36 h after a bolus of ovulatory human chorionic gonadotrophin
      (HCG), with or without steroid ablation and progestin replacement. VEGF, Ang-1
      and Ang-2 mRNA were all detected prior to the ovulatory stimulus. Whereas
      follicular fluid VEGF concentrations increased 6-fold (P < 0.05) between 0 and 12
      h, VEGF mRNA values were unchanged and were unaffected by steroid ablation. Ang-1
      mRNA decreased from 0 to 12 h (P < 0.05), followed by a 30-fold increase (P <
      0.05) at 36 h, while Ang-2 mRNA values were unchanged between 0, 12 and 36 h.
      Steroid ablation decreased (P < 0.05) Ang-1 mRNA at 36 h, and Ang-2 mRNA at 12 h,
      while only Ang-1 was restored by progestin replacement. These data suggest a
      dynamic expression of vascular-specific growth factors in a gonadotrophin
      dependent, steroid-independent (VEGF) or steroid-dependent (Ang-1) manner in
      granulosa cells of peri-ovulatory follicles of primates.

PMID- 10587366
TI  - Specific expression of heat shock protein HspA2 in human male germ cells.
AB  - In the mouse, the heat shock protein 70-2 (Hsp70-2) has been found to play a
      critical role in spermatogenesis. The HspA2 gene is the human homologue of the
      murine Hsp70-2 gene with 91.7% identity in the nucleotide coding sequence. We
      examined the expression of HspA2 in human tissues. To detect HspA2 expression,
      antiserum 2A that was raised against mouse Hsp70-2 and that cross-reacted with
      human HspA2 protein expressed in Escherichia coli was used. The results of
      Western blotting indicate that significant HspA2 expression occurs in testes with
      normal spermatogenesis, whereas only a low amount of HspA2 was expressed in
      testis with Sertoli cell-only syndrome. Only a small amount of HspA2 was detected
      in breast, stomach, prostate, colon, liver, ovary, and epididymis.
      Immunoreactivity to HspA2 was present in spermatocytes and spermatids in the
      testes with normal spermatogenesis, while immunoreactivity to HspA2 in testis
      with Sertoli cell-only syndrome was remarkably decreased or inconspicuous over
      the entire cell. These results demonstrate that the HspA2 protein is highly
      expressed in human male specific germ cells, suggesting that HspA2 protein may
      play a specific role during meiosis in human testes as found in the murine model.

PMID- 10587367
TI  - Identification, sequence analysis and expression of transcripts encoding a
      putative metalloproteinase, eMDC II, in human and macaque epididymis.
AB  - The metalloproteinase-like, disintegrin-like, cysteine-rich (MDC) family is a
      large group of sequence-related proteins, first characterized in the male
      reproductive tract, but subsequently also identified in non-reproductive tissues.
      Their primary translation products are of approximately 90 kDa and each can be
      divided into distinct domains which show remarkable homology to reprolysins;
      snake venom haemorrhagic components possessing metalloproteinase and/or
      disintegrin domains. Several MDC proteins are abundantly-expressed in the male
      reproductive tract, suggesting functions in fertility. We now describe the
      cloning, sequence determination and characterization of transcripts encoding the
      human and macaque (Macaca fascicularis) orthologues of a novel member of the MDC
      family (eMDC II) which is abundantly-expressed in the epididymis. Unlike many MDC
      proteins expressed in the reproductive tract, eMDC II possesses the extended
      'catalytic centre' consensus sequence characteristic of a reprolysin-like
      metalloproteinase. This suggests that eMDC II has proteolytic activity.

PMID- 10587368
TI  - Interleukin-8 expression in endometrial stromal cells is regulated by integrin
      dependent cell adhesion.
AB  - Concentrations of interleukin (IL)-8, a potent chemotactic factor produced by
      many cell types, are elevated in the peritoneal fluid of women with
      endometriosis. We investigated whether endometrial stromal cell (ESC) adhesion
      induces the expression of IL-8 and if this process is integrin-mediated. ESCs
      were plated onto culture dishes coated with various extracellular matrix (ECM)
      substrates, such as fibronectin, laminin, collagen IV, and poly-L-lysine, or
      mouse anti-human integrin beta(1,) and beta(2) monoclonal antibodies. IL-8
      expression was induced by adherence of ESCs to fibronectin or collagen IV, but
      not to poly-L-lysine, a non-integrin-dependent adhesion matrix. Engagement of
      beta(1)-containing integrins was associated with ESC adhesion and resulted in up
      regulation of IL-8 mRNA expression and protein secretion. Disruption of the actin
      cytoskeleton by treating ESC with cytochalasin D completely blocked the increase
      of IL-8 that was induced in response to integrin activation. These findings
      indicate a novel mechanism of IL-8 regulation; cell adhesion to ECM is an
      important event that leads to stimulation of IL-8 expression, and this process is
      mediated by integrins.

PMID- 10587369
TI  - Regulation of TNF-alpha mRNA expression in endometrial cells by TNF-alpha and by
      oestrogen withdrawal.
AB  - During each menstrual cycle, the human endometrium undergoes a series of
      orchestrated and well controlled changes in anticipation of the arrival of the
      blastocyst. In the absence of implantation, the endometrium is shed. The
      underlying basis of the menstrual bleeding is not clear, however, it seems to be
      related to steroid hormone withdrawal. We showed that tumour necrosis factor
      alpha (TNF-alpha) is released by human endometrium and that endometrial
      epithelial cells are a major source of TNF-alpha mRNA and protein. We show here
      that TNF-alpha mRNA shows a specific menstrual cycle-dependent expression. The
      expression of TNF-alpha is mostly minimal throughout the proliferative, early and
      mid-secretory phases. Expression of TNF-alpha mRNA, however, is increased in the
      human endometrium in the late secretory phase and during endometrial bleeding.
      Such a menstrual cycle-dependent expression suggests that specific signals
      regulate the expression of TNF-alpha mRNA in the human endometrium. In vitro, the
      expression of TNF-alpha mRNA in endometrial epithelial cells could be regulated
      by exogenous TNF-alpha. This induced expression was both time- and dose
      dependent. In vitro, the TNF-alpha mRNA expression was not altered by oestrogen,
      progesterone, or both, in the endometrial epithelial cells under conditions that
      maintain the steroid hormone receptors. However, in vivo, oestrogen withdrawal
      led to an enhanced expression of TNF-alpha in endometrial epithelial cells. These
      findings suggest that the up-regulation of TNF-alpha in human endometrium in the
      late secretory phase may be related to the falling serum oestrogen concentration
      at the end of the menstrual cycle as well as the potentiating effect of released
      TNF-alpha on its own mRNA expression.

PMID- 10587370
TI  - Chromosomal translocations affecting 12q14-15 but not deletions of the long arm
      of chromosome 7 associated with a growth advantage of uterine smooth muscle
      cells.
AB  - Cytogenetically, uterine leiomyomata are the best investigated human tumours. The
      most frequent clonal abnormalities are structural rearrangements involving 12q14
      15 and deletions of part of the long arm of chromosome 7. The present study
      investigated a possible growth advantage conferred by these abnormalities, when
      compared with myomata having an apparently normal karyotype. A total of 155
      myomata were included in the study. All samples were obtained after hysterectomy
      enabling karyotype analysis of all detectable tumours. Myomata with clonal
      chromosome abnormalities were significantly larger than those with a normal
      karyotype (6.8 +/- 5.3 versus 3.4 +/- 2.1 cm; P < 0.001). However, when
      differentiating between the two main aberrations, this was found to be true for
      the myomata with 12q14-15 changes affecting the high mobility group protein IC
      (HMGIC) gene (8.9 +/- 5.6 cm), but not for the group of tumours characterized by
      deletions of chromosome 7 (3.5 +/- 2.0 cm). The results are compatible with the
      hypothesis that myomata develop due to an unknown event, whereas the chromosomal
      abnormalities act as secondary changes, with those affecting the HMGIC gene
      increasing the growth potential of the corresponding tumours.

PMID- 10587371
TI  - Expression of uteroglobin in the human endometrium.
AB  - Uteroglobin is a progesterone binding protein, a member of the antiflammin gene
      family and possibly a novel cytokine. Initially, uteroglobin was identified as
      the major protein of rabbit uterine secretion during the phase of
      preimplantation. Counterparts of the rabbit uteroglobin or its gene are described
      in rat, mouse, hamster, hare, pig, horse and human. While uteroglobin appears as
      one of the most extensively studied proteins, particularly its physico-chemical
      properties, including its crystal structure and its gene, the true physiological
      role of this protein still remains to be unravelled. Essential to understanding
      the significance of human uteroglobin in reproductive organs, particularly in the
      endometrium, is a knowledge of the spatial and chronological expression of this
      secretory protein. Our studies on 115 volunteers combined reverse transcription
      polymerase chain reaction (RT-PCR), immunohistochemistry and quantitative
      assessment by an enzyme-linked immunosorbent assay for uteroglobin. The
      expression, localization and release of uteroglobulin in the human endometrium
      are presented. Secretory uteroglobin is found in endometrial tissue homogenates
      in highest levels of expression during the early luteal phase (days 15-19, 340
      pg/mg total protein). In turn, uteroglobin is released into the uterine lumen in
      peak amounts during the receptive phase of the menstrual cycle (mid-luteal phase,
      days 20-23, secretion level 833.4 pg/mg total protein). Our immunohistochemical
      studies match with these results, as uteroglobin is located during the early and
      mid-luteal phase in the apical compartments of endometrial gland cells. These
      observations strongly suggest an involvement of uteroglobin in endometrial
      preparations for implantation.

PMID- 10587372
TI  - Approximately half of the erythroblasts in maternal blood are of fetal origin.
AB  - The enrichment of fetal erythroblasts from the peripheral blood of pregnant women
      is currently actively pursued for the development of a non-invasive means of
      prenatal diagnosis. Since erythroblasts in maternal blood are not all of fetal
      origin, and currently no reliable method exists to distinguish between the
      maternal and fetal erythroblasts, their use for prenatal diagnosis is not without
      uncertainty. The purpose of this study was to determine the percentage of fetal
      erythroblasts in maternal blood at the single cell level and to what extent such
      cells can reproducibly be used for polymerase chain reaction (PCR)-based prenatal
      diagnostic analyses. Erythroblasts were enriched from the peripheral blood of
      rhesus negative pregnant women using magnetic cell sorting (MACS). Single
      erythroblasts identified morphologically were individually micromanipulated and
      analysed by a multiplex PCR reaction for the fetal SRY and rhesus D genes. As a
      control for the PCR reaction the beta-globin gene was used. The PCR results were
      validated by the results obtained by invasive procedures. In all instances where
      single erythroblasts were examined, the correct fetal genotype for the two fetal
      specific loci was detected. Furthermore, our results indicate that approximately
      50% of the enriched erythroblasts are of fetal origin.

PMID- 10587373
TI  - Assessment of multiplex fluorescent PCR for screening single cells for trisomy 21
      and single gene defects.
AB  - A great majority of patients seeking preimplantation genetic diagnosis (PGD) are
      women >35 years of age. In addition to being carriers for single gene defects,
      these women also have a higher risk of having children with Down's syndrome
      (trisomy 21). For these patients, it would be advantageous if a diagnostic test
      for trisomy 21 was developed, which could be used in conjunction with tests for
      single gene defects. Here, we assessed the feasibility of developing an accurate
      genetic test for diagnosing trisomy 21 and the mutation causing spinal muscular
      atrophy (SMA) in single cells using multiplex fluorescence polymerase chain
      reaction (PCR). Single- and two-round PCR were developed using a combination of
      primers for the survival motor neuron (SMN) gene exons 7 and 8 and two chromosome
      21 short tandem repeats (STRs), D21S226 and D21S11. After only 36 cycles, 88 and
      68% of normal single cells were screened for SMA mutations and trisomy 21
      respectively. In multiplex PCR using only two primers (SMN exon 7 and D21S11)
      instead of four, the efficiency of SMA diagnosis was increased to 93%. In the
      same reactions, the D21S11 alleles were detected in 83% of the normal single
      cells. Clinical applications of this assay should enable detection of those
      embryos that have inherited three heterozygous alleles and, therefore, benefit
      many PGD patients who are at an increased risk of Down's syndrome.

PMID- 10587375
TI  - Caenorhabditis elegans as a model for parasitic nematodes: beginning to scratch
      the surface.

PMID- 10587374
TI  - Rapid prenatal diagnosis of aneuploidy by quantitative fluorescent PCR on fetal
      samples from mothers at high risk for chromosome disorders.
AB  - We report the results of a prospective study using quantitative fluorescent
      polymerase chain reaction (QF-PCR) and small tandem repeat markers (STR) for the
      rapid prenatal detection of aneuploidies in a group of pregnant women at
      increased risk of having fetuses with numerical chromosome disorders. Amniotic
      fluid samples (n = 52) were collected from mothers undergoing prenatal invasive
      testing for fetal abnormalities on ultrasonographic examination or abnormal
      maternal serum aneuploidy screening results. All samples were tested by
      cytogenetic analysis, but rapid diagnoses of aneuploidies were offered and
      performed using QF-PCR analysis with several STRs specific for chromosomes 21,
      18, 13 and X. All cases with numerical chromosome aberrations involving
      chromosomes 21, 18 and 13 (n = 8) were correctly diagnosed. Three gonosomal
      aneuplodies (one 47,XXY and two 45,X) were not detected because they were
      uninformative for the X markers. Another sample with a deletion (46,XX,7q-), that
      the present assay was not designed to detect, was not identified. One sample was
      heavily contaminated with maternal blood and the results of the QF-PCR assays
      were uninformative. The remaining samples from normal fetuses provided QF-PCR
      patterns disomic for chromosomes 21, 18, 13 and X. Our study demonstrates that QF
      PCR is a rapid method for the detection of common numerical chromosome disorders
      and it may play an important role in prenatal diagnosis for women at high risk
      for fetal aneuploidy.

PMID- 10587376
TI  - Caenorhabditis elegans as a biomonitor for immunological stress in nematodes.
AB  - An experimental system has been developed using Caenorhabditis elegans
      (Secernentea: Rhabditida), to monitor immunological stress in nematodes. The
      transgenic C. elegans strain PC72 carries a lacZ reporter gene fused to a C.
      elegans hsp16-1 gene, which is inducible for beta-galactosidase activity at the
      heat stress temperature of 26 degrees C. The investigate the possibility of using
      PC72 to monitor immunological stress, its surface coat was targeted, to mimic
      immune attack, by raising immune sera against surface coat components selectively
      removed by the cationic detergent cetyltrimethylammoniunm bromide. Initially, a
      highly significant induction of beta-galactosidase activity was seen in PC72
      incubated in either surface-reactive or naive rabbit serum. Complement (C3) was
      detected over the entire surface of adult PC72 and was thought to be responsible
      for stress-induction with naive sera. When the immunoglobulin (Ig)G fraction of
      naive sera was used in isolation, no stress-induction was seen. In contrast, a
      two-fold increase in beta-galactosidase activity was seen in the presence of
      surface-reactive IgG (SR-IgG) which recognised surface components of between 6
      and 40 kDa in western blot. The belief that surface reactive IgG could induce a
      stress response was reinforced by analysis of hsp-16 protein expression.
      Cationised ferritin was then used to assess whether stress-induction was truly a
      surface reactive event; binding of cationised ferritin to the nematode surface
      also resulted in two-fold induction of beta-galactosidase activity. To
      investigate the downstream biological effects of stress induction, worm growth
      and fecundity were measured in the presence of IgG preparations. A significant
      reduction was seen in both worm length and fecundity only when larvae were
      incubated in surface-reactive IgG, compared to both naive IgG and K-medium
      controls. In conclusion, it would appear that C. elegans is a suitable model to
      monitor the induction of immunological stress at the level of the nematode
      surface coat. Given the ability of nematode surface antigens to protect the
      vaccinated host in animal model systems, and the close phylogenetic relationships
      which exist between C. elegans and nematodes of medical and veterinary
      importance, it is conceivable that the immunological targets in or on the surface
      of C. elegans warrant rapid identification.

PMID- 10587377
TI  - Nasal immunization of mice with Cryptosporidium parvum DNA induces systemic and
      intestinal immune responses.
AB  - DNA immunization offers a novel approach to inducing humoral and cellular
      immunity against infectious pathogens. We examined whether such an approach could
      be used against cryptosporiodiosis, an intestinal disease caused by the protozoan
      parasite Cryptosporidium parvum. This infection is a major problem for young
      ruminants and immunosuppressed individuals in whom cryptosporidiosis causes life
      threatening symptoms. The life cycle of C. parvum takes place in the enterocytes
      of the intestinal epithelium. We therefore focused our attention on a route of
      immunization that might induce a mucosal immunoglobulin (Ig)A response. Eight
      week-old BALB/c mice were immunized intranasally with DNA encoding a 15-kDa C.
      parvum sporozoite antigen (CP15-DNA) cloned onto the plasmid pcDNA3. CP15-DNA
      immunized mice developed specific and longlasting production of anti-CP15 Ig A in
      intestinal secretions and specific IgG in sera 3 months and 1 year after the
      first DNA inoculation. CP15-DNA-immunized mice also developed an antigen-specific
      T lymphocyte proliferative response in both spleen and mesenteric lymph nodes.
      Control mice that received the pcDNA3 plasmid alone did not develop specific
      humoral and cellular responses. These results indicate that plasmid DNA may
      provide a powerful means of eliciting intestinal humoral and cellular responses
      to C. parvum infections in mammals.

PMID- 10587378
TI  - L3 antigen-specific antibody isotype responses in human strongyloidiasis:
      correlations with larval output.
AB  - Autoinfective strongyloidiasis is potentially fatal, yet the majority of infected
      individuals harbour asymptomatic and chronic infections. The role of humoral
      responses in modulating autoinfection was assessed by examining antibody isotype
      responses to filariform larval antigens amongst chronically infected ex-Far East
      Prisoners of War (exFEPOWs) with longstanding (> 30 years) infection. Serum
      immunoglobulin (Ig)G1, IgG4, IgE and IgA responses to whole Strongyloides
      stercoralis L3 extracts and their constituent antigenic components were
      characterized by ELISA and quantitative immunoblotting. Comparison of two groups
      of S. stercoralis infected exFEPOWs with and without detectable larvae in stool
      demonstrated novel trends. Significantly enhanced recognition of six
      immunodominant antigenic components by IgA was associated with undetectable
      larval output, as was enhanced IgE recognition of several components.
      Additionally, IgE and IgG4 exhibited parallel antigen recognition patterns. These
      findings are consistent with roles for IgA in modulating larval output, for IgE
      in regulating autoinfection, and for IgG4 in blocking IgE-mediated responses in
      human strongyloidiasis.

PMID- 10587379
TI  - Presidential address: education and brotherhood.

PMID- 10587380
TI  - The incidence, natural history, and outcome of secondary intervention for
      persistent collateral flow in the excluded abdominal aortic aneurysm.
AB  - OBJECTIVE: The goal of abdominal aortic aneurysm (AAA) repair is the prevention
      of rupture. Exclusion of the infrarenal AAA by means of operation or endovascular
      graft placement is an alternative therapy to achieve this goal. However,
      thrombosis of the excluded aneurysm sac does not always occur and further
      intervention may be needed. This study examines the efficacy of available
      screening methods to detect the persistence of aneurysm sac flow and the outcome
      of secondary procedures to treat this problem. METHODS: During the past 14 years,
      1218 patients have undergone operative retroperitoneal exclusion of AAA. To date,
      48 patients have been found to have persistent flow in the excluded AAA sac with
      duplex scanning. Twenty-seven patients underwent surgical intervention, and seven
      of these procedures were performed for rupture. Six patients have undergone
      treatment with interventional techniques (four successfully). The patients were
      evaluated for preoperative angiographic, anatomic, and comorbid factors that may
      have predisposed them to failed exclusion. Also, perioperative morbidity and
      mortality, estimated blood loss, and survival were assessed in the patients who
      required surgical treatment. RESULTS: There were no perioperative parameters that
      correlated with postoperative persistent flow in the excluded AAA sac. The mean
      time to secondary intervention was 51 months (range, 2 to 113 months). Two
      patients had false-negative computed tomographic angiogram results, eight
      patients had false-negative angiogram results, and six patients had duplex scan
      examinations that had initially negative results that were then positive for flow
      in sac. Reoperation had a 7.4% mortality rate (two deaths) and a median blood
      loss of 2600 mL, as compared with 500 mL for primary procedures. CONCLUSION:
      Secondary operations for patent excluded aortic aneurysm sacs have higher
      mortality and intraoperative blood loss rates than do primary procedures for AAA
      repair. The localization of branch leaks with computerized tomographic
      angiography, angiography, and duplex scanning were imprecise, and better methods
      are needed to adequately diagnose patent sacs. Expansion of AAA sac may be the
      only reliable factor.

PMID- 10587381
TI  - Minimal incision abdominal aortic aneurysm repair.
AB  - PURPOSE: The use of a limited incision for abdominal aortic aneurysm (AAA) repair
      was evaluated, and its outcome was analyzed in comparison to laparoscopic
      assisted and standard open repair. METHODS: Eleven patients who had an AAA that
      required a tube graft underwent minimal incision (MINI) repair. The procedure
      consisted of a standard endoaneurysmorrhaphy performed through an 8- to 10-cm
      minilaparotomy. Clinical characteristics, in-hospital outcomes, and total in
      hospital charges for this procedure were then compared with those of comparative
      groups of patients who had undergone repair of AAA by means of a laparoscopic
      assisted (LAP) approach or a standard open (OPEN) technique. RESULTS: MINI repair
      was successfully completed in all 11 patients. Patients in the three groups were
      comparable for age, sex, risk factors, and aortic dimensions. The mean values for
      operative time, blood loss, length of hospital stay, and total hospital charges
      for the three comparison groups were: 129. 7 minutes (MINI) vs. 244.8 minutes
      (LAP)*, 209.9 minutes (OPEN)*; 522.7 mL (MINI) vs. 1214.7 mL (LAP), 1795.8 mL
      (OPEN)*; 5.18 days (MINI) vs. 18.7 days (LAP), 17.4 days (OPEN); $22,692 (MINI)
      vs. $59, 922 (LAP)*, $62,324 (OPEN)* (*P <.05). Local complications occurred in
      18.2% of patients who underwent MINI repair, 23.5% of patients who underwent LAP
      repair, and 29.7% of patients who underwent OPEN repair (P = not significant).
      Patients undergoing minilaparotomy demonstrated decreased compromise of
      gastrointestinal function, with a decreased need for postoperative fluid
      resuscitation (6799.7 mL [MINI], 7781.8 mL [LAP] vs. 11061.1 mL [OPEN]*) and
      shortened nasogastric tube decompression (1.6 days [MINI], 1.5 days [LAP] vs. 4.1
      days [OPEN]*; *P <.05). CONCLUSION: MINI repair is a technically feasible
      technique that combines the benefits of minimally invasive surgery with those of
      conventional open repair with few, if any disadvantages. Facility of the
      procedure, combined with the potential cost benefits, encourages further study
      for consideration of this technique as a viable alternative for the management of
      AAAs.

PMID- 10587382
TI  - Results of elective abdominal aortic aneurysm repair in the 1990s: A population
      based analysis of 2335 cases.
AB  - OBJECTIVE: The safety and efficacy of conventional abdominal aortic aneurysm
      (AAA) repair are undergoing increased examination in parallel with the
      development of less invasive repair methods. Because most published studies of
      elective AAA repair report operations performed in tertiary referral institutions
      and thus may not reflect the outcome in the surgical community at large, the
      current population-based study was undertaken to document the results obtained
      across a broad spectrum of clinical practice in a defined geographic area and to
      examine the factors that influence the outcomes. METHODS: The Maryland Health
      Services Cost Review Commission database was used to identify all the elective
      AAA repairs that were performed in all the nonfederal acute care hospitals in the
      state from 1990 to 1995. RESULTS: Elective AAA repair was performed on 2335
      patients (mean age, 70.4 years) in 46 of the 52 (88%) nonfederal acute care
      hospitals in the state, including seven high-volume (>100 cases), nine moderate
      volume (50 to 99 cases), and 30 low-volume (<50 cases) institutions. The in
      hospital mortality rate was 3.5% and increased significantly with advancing age:
      less than 65 years, 2.2%; 65 to 69 years, 2.5%; 70 to 79 years, 3.5%; and more
      than 80 years, 7.3% (P =.002). Mortality rates were higher for women (4.5% vs
      3.2%; P =.17), for blacks (6.7% vs 3.2%; P =.046), and for patients with renal
      failure (11.8% vs 3. 4%; P =.11) but not for patients with hypertension,
      diabetes, heart disease, and pulmonary disease. The operative mortality rate was
      inversely correlated with hospital volume (4.3% in low-volume hospitals, 4.2% in
      moderate-volume hospitals, and 2.5% in high-volume hospitals; P =.08), although
      no differences were noted in the mean ages or comorbidity levels of patients who
      underwent operations in these three hospital populations. The operative mortality
      rate was inversely correlated with the experience of the individual surgeon: one
      case, 9.9%; two to nine cases, 4.9%; 10 to 49 cases, 2.8%; 50 to 99 cases, 2.9%;
      and more than 100 cases, 3.8% (P =.01). Multivariate analysis results identified
      patient age (P =. 002), low hospital volume (P =.039), and very low surgeon
      volume (P =.01) as independent predictors of operative mortality. The mean length
      of stay and mean hospital charges were 10.6 days and $17,589 and decreased with
      increasing surgeon volume: one case, 22.7 days/$32,800; two to nine cases, 10.6
      days/$18,509; 10 to 49 cases, 10.0 days/$16,611; 50 to 99 cases, 10.9
      days/$17,843; and more than 100 cases, 9.6 days/$16,682 (P <.0001/P <.0001).
      CONCLUSION: Elective AAA repair is a safe procedure in contemporary practice in
      Maryland. Operative risk is increased among the elderly and when operations are
      performed by surgeons with very low volumes or in low-volume hospitals. Hospital
      lengths of stay were shorter and charges were lower when elective AAA repair was
      performed by surgeons with higher volumes.

PMID- 10587383
TI  - Emergency repair of thoracoabdominal aortic aneurysms with immediate
      presentation.
AB  - OBJECTIVE: The objective of this report was the study of the clinical outcome of
      emergently repaired thoracoabdominal aortic aneurysms (TAAAs). METHODS: We
      retrospectively reviewed our experience with TAAA repairs from 1990 to 1998.
      During this interval, 110 TAAA procedures were performed, 33 (30%) of which were
      for immediate presentations. The chi(2) test and regression analysis were used
      for the analysis of mortality, paraplegia, and renal failure (hemodialysis) rates
      and of factors that predict these complications, respectively. RESULTS: There
      were no significant differences between the elective and immediate presentations
      with respect to the use of adjunctive procedures (lumbar drain, hypothermia, and
      bypass grafting). The overall mortality rate was 13%. There were no statistically
      significant differences between the 30-day mortality rates or the complication
      rates in elective versus immediate presentations. Subgroup analysis results
      showed a significantly higher in-hospital mortality rate in type II TAAA with
      immediate presentation and free rupture presentation as compared with the overall
      mortality rate (50% vs 13%, P <.05, and 67% vs 13%, P <.01, respectively).
      Multiple regression analysis results identified the use of bypass grafting
      (atrial-femoral or cardiopulmonary) and lumbar drain and shorter bypass grafting
      time as significant predictors of decreased overall mortality (P <.05). The
      mortality rates were not significantly different among aneurysm types and were
      not significantly decreased with the use of hypothermia. Paraplegia (5%) and
      renal failure (9%) rates were not predicted with aneurysm type, immediate versus
      elective presentation, or the adjunctive use of hypothermia, lumbar drain, or
      bypass grafting. CONCLUSION: The emergency repair of TAAA with immediate
      presentation can be performed with mortality and morbidity rates that approach
      those of elective presentations, except in the setting of free rupture or
      symptomatic type II TAAA. Adjunctive circulatory management techniques and lumbar
      drains may reduce mortality in TAAA repair.

PMID- 10587384
TI  - Arterial reconstruction with deep leg veins for the treatment of mycotic
      aneurysms.
AB  - PURPOSE: Mycotic pseudoaneurysms (MPA) remain challenging clinical problems.
      Primary surgical management includes control of hemorrhage and debridement of the
      infected arterial wall. Because critical ischemia may develop after arterial
      resection, revascularization has been a secondary goal of treatment. Standard
      anatomic graft placement or prosthetic bypass grafting has been compromised by a
      high rate of recurrent infection. Extra-anatomic reconstruction is preferred,
      with the basic goals being threefold: (1) the use of autogenous graft material to
      reduce the risk of reinfection; (2) the avoidance of significant size mismatches;
      and (3) graft placement that is anatomically inaccessible, because drug abuse
      causes many of these lesions. This study reviews a recent series of MPAs applying
      these treatment goals. METHODS: In a 2-year period, the superficial femoral and
      proximal popliteal veins were used in the repair of eight MPAs of the common
      femoral (5), common iliac (1), and brachial (1) arteries, and the infrarenal
      aorta (1). Most patients (5 of 7) were known intravenous drug users, who had a
      painful pulsatile mass in an injection area. Two patients had systemic sepsis,
      one patient with an infected common iliac pseudoaneurysm and one patient with an
      MPA of the infrarenal aorta. The diagnosis of MPA was made by means of
      duplex/computed tomography scanning and confirmed by means of arteriography in
      all cases. RESULTS: Obturator bypass grafting was performed by using a reversed
      deep leg vein in the five femoral MPAs. An ilioiliac, cross-pelvic bypass
      grafting procedure with a deep vein was used to repair an MPA of the common iliac
      artery. A deep vein was also used as a "pantaloon" aortobiiliac graft and for a
      brachial artery repair. Staphylococcus aureus was revealed by means of cultures
      in nearly all cases. Distal arterial perfusion was normal after reconstruction.
      Patients had no significant postoperative leg swelling. No new venous thrombosis
      below the level of deep vein harvest was revealed by means of duplex scanning.
      There were no septic complications. CONCLUSION: The superficial femoral/popliteal
      veins may be particularly useful for limb revascularization in patients with
      MPAs. This autogenous conduit provides an excellent size-match and a suitable
      length for reconstruction, because peripheral, axial arteries are generally
      affected. No clinically significant limb morbidity was related to deep vein
      removal. Late follow-up is challenging in such cases, but will be required to
      accurately determine the durability of this strategy.

PMID- 10587385
TI  - Endovascular versus surgical treatment for thrombosed hemodialysis grafts: A
      prospective, randomized study.
AB  - PURPOSE: The objective of this study was to compare clinical outcome and costs
      for two widely used treatment strategies for hemodialysis graft thrombosis.
      METHODS: During a 4-year period, 80 patients with thrombosed dialysis grafts were
      randomly assigned to surgical thrombectomy with or without graft revision (SURG)
      or thrombolytic therapy with urokinase with the pulse-spray technique (ENDO),
      with adjunctive percutaneous transluminal angioplasty as indicated. All the
      procedures were performed in an endovascular operating suite with fistulography.
      The clinical and cost data were tabulated, and the outcome was analyzed with the
      life-table method. RESULTS: Fifty-six women and 24 men ranged in age from 33 to
      90 years (mean, 63.7 years). The patients had undergone a mean of 2.8 prior
      access procedures in the ipsilateral extremity. All the grafts were upper
      extremity expanded polytetrafluoroethylene grafts. Lesions that were presumed to
      be the primary cause of graft thrombosis were identified in 73 of 80 grafts, and
      60 of these were at the venous anastomosis. The procedure time averaged 99
      minutes for the patients in the SURG group and 113 minutes for the patients in
      the ENDO group (P =.12). Eleven patients in the ENDO group crossed over to
      surgical revision as compared with two patients in the SURG group who required
      adjunctive percutaneous transluminal angioplasty (P =.005). The mean cost of
      treatment (including room and supply costs but not professional fees) was
      significantly higher for the ENDO group than for the SURG group ($2945 vs $1512;
      P <.001). There were no procedure-related complications in either group. At a
      median follow-up time of 24 months, there was no difference in primary or
      assisted primary patency between groups, which averaged 6 and 7 months,
      respectively. CONCLUSION: Although thrombolytic therapy combined with
      endovascular treatment can extend the life of dialysis grafts with results
      similar to surgical revision, there is a high rate of technical failure
      necessitating surgery and a substantially higher cost for thrombolysis.

PMID- 10587386
TI  - Is carotid endarterectomy cost-effective in symptomatic patients with moderate
      (50% to 69%) stenosis?
AB  - OBJECTIVE: Recently published data from the North American Carotid Endarterectomy
      Trial revealed a benefit for carotid endarterectomy (CEA) in symptomatic patients
      with moderate (50% to 69%) carotid stenosis. This benefit was significant but
      small (absolute stroke risk reduction at 5 years, 6.5%; 22.2% vs 15.7%), and
      thus, the authors of this study were tentative in the recommendation of operation
      for these patients. To better elucidate whether CEA in symptomatic patients with
      moderate carotid stenosis is a proper allocation of societal resources, we
      examined the cost-effectiveness of this intervention. METHODS: A decision
      analytic Markov process model was constructed to determine the cost-effectiveness
      of CEA versus medical treatment for a hypothetical cohort of 66-year-old patients
      with moderate carotid stenosis. This model allowed the comparison of not only the
      immediate hospitalization but also the lifetime costs and benefits of these two
      strategies. Our measure of outcome was the cost-effectiveness ratio (CER),
      defined as the incremental lifetime cost per quality-adjusted life year saved. We
      assumed an operative stroke and death rate of 6.6% and a declining risk of
      ipsilateral stroke after the ischemic event with medical treatment (first year,
      9.3%; second year, 4%; subsequent years, 3%). The hospitalization cost of CEA
      ($6,420) and the annual costs of major stroke ($26,880), minor stroke ($798), and
      aspirin therapy ($63) were estimated from a hospital cost accounting system and
      the literature. RESULTS: CEA for moderate carotid stenosis increased the survival
      rate by 0.13 quality-adjusted life years as compared with medical treatment at an
      additional lifetime cost of $580. Thus, CEA was cost-effective with a CER of
      $4,462. Society is usually willing to pay for interventions with CERs of less
      than $60,000 (eg, CERs for coronary artery bypass grafting at $9,100 and for
      dialysis at $53,000). CEA was not cost-effective if the perioperative risk was
      greater than 11.3%, if the ipsilateral stroke rate associated with medical
      treatment at 1 year was reduced to 4.3%, if the age of the patient exceeded 83
      years, or if the cost of CEA exceeded $13,200. CONCLUSION: CEA in patients with
      symptomatic moderate carotid stenosis of 50% to 69% is cost-effective.
      Perioperative risk of stroke or death, medical and surgical stroke risk, cost of
      CEA, and age are important determinants of the cost-effectiveness of this
      intervention.

PMID- 10587387
TI  - Efficacy of a filter device in the prevention of embolic events during carotid
      angioplasty and stenting: An ex vivo analysis.
AB  - OBJECTIVE: Although percutaneous angioplasty and stenting (PTAS) of carotid
      bifurcation lesions is feasible and appropriate for surgically inaccessible
      lesions, its general role and comparative value remain unclarified. Moreover, the
      acceptance of carotid PTAS has been limited by its potential for producing
      embolic debris. This study used an ex vivo model to evaluate the efficacy of a
      novel filter device to entrap emboli during PTAS of human carotid plaques.
      METHODS: Eight carotid bifurcation plaques were obtained from patients who
      underwent carotid endarterectomy for high-grade atherosclerotic stenosis (>90%).
      The mean age of the patients was 63 years, and six patients were symptomatic.
      Each plaque was encased with polytetrafluoroethylene material to simulate
      adventitia and was connected to a perfusion circuit, which provided continuous
      flow through the plaque. The filter device consisted of an expandable polymeric
      membrane with multiple micro pores that was attached to the distal end of a 0.014
      in wire with a shapeable tip. This filter was encased in a delivery catheter.
      With fluoroscopic guidance, the filter wire was passed through the stenosis and
      the delivery catheter was then retracted to open the filter to capture particles
      released into the distal internal carotid artery. PTAS with a self-expandable
      stent then was carried out over the filter wire. The particles released during
      the initial filter passage, those captured in the filter, and those that flowed
      through or around the filter (missed) were collected and analyzed with light
      microscopy. RESULTS: Filter deployment, PTAS, and filter retrieval were achieved
      successfully with each lesion. Because the filter has a low crossing profile, it
      passed through the stenoses smoothly and only produced occasional small
      particles. PTAS improved the angiographic stenosis from 96.2% +/- 3.7% to 1.3% +/
      1.6%. The mean number and the maximum size of the particles that were released
      during initial filter passage, missed, and captured by the filter device were 3.1
      and 500 microm, 2.8 and 360 microm, 20.1 and 1100 microm, respectively. Most of
      the particles and those of large size were released during PTAS. The filter
      captured 88% of these particles. CONCLUSION: These study results show that this
      filter device, at least in this model, did not add complexity to the
      interventional procedure itself. Furthermore, the filter may markedly decrease
      embolic events during carotid PTAS and expand the indications for this procedure.

PMID- 10587388
TI  - Accelerated carotid artery disease after high-dose head and neck radiotherapy: is
      there a role for routine carotid duplex surveillance?
AB  - PURPOSE: High-dose external radiotherapy used in the treatment of head and neck
      carcinoma has been implicated as a risk factor for accelerated atherosclerotic
      disease of the carotid arteries. However, how radiotherapy affects
      atherosclerotic disease is controversial, and little data exist to demonstrate a
      strong relationship between radiotherapy and progressive carotid disease.
      METHODS: We performed a retrospective chart review of 69 patients (all men) who
      underwent duplex ultrasound scanning examinations for carotid disease between
      1993 and 1998. Twenty-three patients had received high-dose radiotherapy for the
      treatment of head and neck carcinoma within the past 12 years (group 1; mean age,
      67.8 years), and 46 patients were randomly selected as age-matched control
      subjects (group 2; mean age, 68.3 years). The mean radiation dose was 6060 +/-
      182 rads, and the average interval between radiotherapy and ultrasound scanning
      was 6. 5 +/- 1.8 years. There was no significant difference between the two
      groups in the presence of these comorbidities: diabetes mellitus, coronary artery
      disease, hypertension, tobacco use, hypercholesterolemia, peripheral vascular
      disease, or stroke. Similarly, there was no difference in the indications for the
      duplex scanning studies. RESULTS: Five of the 23 patients in group 1 (21. 7%)
      were found to have advanced carotid disease (70% to 99% stenosis); four patients
      were symptomatic, three patients went on to endarterectomy, and one patient was
      awaiting surgery. Two of the 46 patients in the control group (4%) had advanced
      carotid disease. One patient was symptomatic, and both patients underwent
      endarterectomy. A significant difference in the prevalence of advanced disease
      between the two groups was noted (P =.037). Sixteen patients who survived
      irradiation underwent a second duplex scanning study and had evidence of
      progressive disease with significant increases in peak systolic velocities.
      CONCLUSION: High-dose radiotherapy to the head and neck region may be a
      significant risk factor for accelerated carotid atherosclerotic disease. Routine
      carotid duplex surveillance may be warranted in this high-risk patient
      population.

PMID- 10587389
TI  - Thrombin injection versus compression of femoral artery pseudoaneurysms.
AB  - OBJECTIVE: The compression of femoral artery pseudoaneurysms is a time consuming,
      painful, and sometimes unsuccessful procedure. Thrombin injection has been
      advocated as a superior alternative. In this study, we compare our experiences
      with both techniques. METHODS: All the records of femoral artery false aneurysms
      that were treated in the vascular laboratory from January 1996 to April 1999 were
      retrospectively reviewed. Treatment with ultrasound scan-guided compression was
      compared with treatment with dilute thrombin injection (100 U/mL). RESULTS: Both
      groups had similar demographics and aneurysm sizes (P >.2). Of the
      pseudoaneursyms, 88% were caused by cardiac catheterization and the others were
      the results of femoral artery access for cardiac surgery (6%), arteriography
      (5%), and renal dialysis (1%). Compression was successful in 25 of 40 patients
      (63%). Nine persistent aneurysms necessitated operation, and six were treated
      successfully with thrombin injection. Primary thrombin injection successfully
      obliterated 21 pseudoaneurysms in 23 patients. Overall, 27 of 29 pseudoaneurysms
      were treated successfully with thrombin injection (93%). Thrombosis occurred
      within seconds of the thrombin injection and required, on average, 300 units of
      thrombin (100 to 600 units). The patients who underwent successful compression
      required an average of 37 minutes of compression (range, 5 to 70 minutes) and
      required analgesia on several occasions. No patients in the thrombin group
      required analgesia or sedation. Neither group had complications. A cost analysis
      shows that thrombin treatment results in considerable savings in vascular
      laboratory resource use but not in overall hospital expenditures. CONCLUSION:
      Ultrasound scan-guided thrombin injection is a safe, fast, and painless procedure
      that completely obliterates femoral artery pseudoaneurysms. The shift from
      compressive therapy to thrombin injection reduces vascular laboratory use and is
      less expensive, although it does not significantly impact hospital costs.

PMID- 10587390
TI  - A volumetric index for the quantification of deep venous thrombosis.
AB  - PURPOSE: The evaluation of treatment strategies for deep venous thrombosis (DVT)
      is assessed through the use of a reliable method of quantifying the extent of the
      thrombotic process. Previous indices of thrombus burden have suffered from
      various limitations, including lack of clinical relevance, poor correlation with
      actual thrombus mass, and failure to include important venous segments in the
      methodology. The use of a novel scheme of quantifying venous thrombus was
      evaluated as an alternative method that would avoid some of the drawbacks of
      existing indices. METHODS: The volumes of 14 venous segments (infrarenal inferior
      vena cava, common iliac, hypogastric, external iliac, common femoral, profunda,
      superficial femoral, and popliteal and six tibial veins) were calculated from
      computed tomography (pelvic vein diameter), duplex ultrasound scan (infrainguinal
      vein diameter), and contrast venography (length of all segments) measurements. A
      venous volumetric index (VVI) was assigned with the normalization of the values
      to the volume of a single calf vein. The VVI was validated with the assessment of
      the ability to discriminate between asymptomatic and symptomatic DVT and between
      those DVT that were associated with pulmonary emboli and those that were not.
      RESULTS: With the imaging data, the VVI ranged from 1 for a single calf vein
      thrombus to 26 for the infrarenal inferior vena cava. Each VVI unit represented
      2.3 mL of thrombus, with a maximum possible score of 63 representing a thrombus
      burden of 145 mL for a single extremity, including the infrarenal inferior vena
      cava. In 885 patients with DVT, the VVI ranged from 1 to 56, averaging 3.9 +/-
      0.2 in patients who were asymptomatic and 8.7 +/- 0.3 in patients who were
      symptomatic (P <.001). The VVI was similar in the patients with pulmonary emboli
      as compared with those without (9.6 +/- 1.2 vs 7.7 +/- 0.2, respectively). In
      comparison with the three existing methods of quantifying venous thrombus burden,
      the receiver operating characteristic curve analysis results suggested that the
      VVI and the Venous Registry index were better than the other two indices in the
      discrimination of patients with symptomatic and asymptomatic DVT (P <.001).
      CONCLUSION: A novel index of venous thrombus burden, on the basis of actual
      venous volume measurements, was more accurate than present indices in the
      differentiation between clinical categories of patients with DVT. As such, it
      offers an acceptable alternative to current scoring systems.

PMID- 10587391
TI  - Photoplethysmography and calf muscle pump function after subfascial endoscopic
      perforator ligation.
AB  - OBJECTIVE: Subfascial endoscopic perforator surgery (SEPS) results in acceptable
      healing and recurrence rates. The role of hemodynamic venous testing in this
      situation, however, is poorly understood and inconsistently used. Our ongoing
      experience was reviewed to explore how SEPS affects the photoplethysmographic
      assessment of the leg. METHODS: Preoperative and postoperative venous refill
      times (VRTs) were measured with photoplethysmography in 30 limbs in 28 patients
      who underwent SEPS and superficial ablation, when indicated, with complete
      clearing of the anterolateral surface of the tibia, thus opening the deep
      posterior compartment from mid calf to close to the malleolus. Postoperative
      healing and duplex scanning were used to assess clinical and anatomic success,
      respectively. The VRTs were classified as "interpretable" if the leg emptied or
      "uninterpretable" if the calf could not empty. The "interpretable" study results
      were further classified as "normal" if the refill took 20 seconds or more or
      "abnormal" if less. RESULTS: Before the patients underwent SEPS, six study
      results (20%) showed inability of the calf to empty and thus were judged
      uninterpretable. After the patients underwent SEPS, 12 study results (40%) were
      uninterpretable (NS; P =.09 with the chi(2) test). Of the 24 preoperative
      interpretable study results, two (8%) were normal, and of the 18 postoperative
      interpretable study results, seven (39%) were normal (P <.03). With the
      consideration of only interpretable study results, the mean VRT increased
      slightly from 12.0 +/- 5.1 seconds (mean +/- standard deviation) to 14.3 +/- 8.1
      seconds (NS). Seventeen of 19 ulcers (89%) had healed at a mean follow-up period
      of 8.6 +/- 4.8 months. CONCLUSION: Although VRT is unpredictably affected by
      SEPS, the most consistent finding is the inability of the calf to empty, which
      invalidates the remainder of the test. In addition, most ulcers heal, even with
      uninterpretable or abnormal postoperative VRTs. This suggests that
      photoplethysmography is a poor method of assessment of venous reflux after SEPS.

PMID- 10587392
TI  - Comparative evaluation of externally supported Dacron and polytetrafluoroethylene
      prosthetic bypasses for femorofemoral and axillofemoral arterial reconstructions.
      Veterans Affairs Cooperative Study #141.
AB  - PURPOSE: Currently, the choice of a vascular prosthesis for an extra-anatomic
      arterial bypass graft is left to the surgeon's preference because well-designed
      comparative evaluations have not been performed. The Department of Veterans
      Affairs Cooperative Study 141 was organized to identify whether there is improved
      patency with different prosthetic grafts for patients with femorofemoral or
      axillofemoral bypass grafts. METHODS: Between June 1983 and June 1988, patients
      at 20 Veterans Affairs Medical Centers who had aortoiliac occlusive disease but
      were not considered suitable candidates for aortic bypass surgery were randomized
      to receive either an externally supported polytetrafluoroethylene or Dacron
      bypass graft for an extra anatomic bypass. Doppler-derived ankle brachial indices
      (ABIs) were determined before the operation and serially after the operation.
      Patients were seen in follow-up every 3 months for the first year and every 6
      months thereafter. All patients were instructed to take 650 mg of aspirin each
      day for the duration of the study. A bypass graft was considered to be patent if
      the Doppler-derived postoperative ABI remained significantly improved (0.15 units
      above the preoperative value), and additional clinical information (such as
      subsequent ABIs, angiograms, or operations) did not contradict these
      observations. RESULTS: Three hundred forty patients with femorofemoral bypass
      grafts and 79 patients with axillofemoral or axillofemorofemoral bypass grafts
      were randomized. The indication for the bypass operation was limb salvage in 72%
      of the patients. The assisted primary patency rate for a Dacron bypass grafting
      was 79% at 1 year, 63% at 3 years, and 50% at 5 years; for
      polytetrafluoroethylene bypass grafting, the patency was 77% at 1 year, 62% at 3
      years, and 47% at 5 years. CONCLUSION: The overall results of this prospective
      randomized study suggest that the current choices of prosthetic bypass grafting
      have similar long-term patency in patients who undergo femorofemoral or
      axillofemoral vascular reconstruction.

PMID- 10587393
TI  - Mural aortic thrombi: An important cause of peripheral embolization.
AB  - PURPOSE: Arterial thromboembolism in patients with an unknown source of
      embolization is still associated with significant morbidity and mortality. The
      advent of transesophageal echocardiography (TEE) and magnetic resonance imaging
      (MRI) and the more frequent use of computed tomography (CT) have led to the
      identification of mural aortic thrombi (MAT) as a source of distal embolization
      in a much higher proportion of patients than previously appreciated. The
      incidence, diagnosis, and treatment of patients with MAT is reported. METHODS: In
      a prospective study, from January 1996 to December 1998, 89 patients with acute
      embolic events underwent an extensive diagnostic workup, consisting of TEE, CT,
      or MRI, to detect the source of embolization. Patients in whom the heart (n =
      51), occlusive aortoiliac disease (n = 16), or aortic aneurysms (n = 12) was
      identified as the source of embolization were excluded. RESULTS: Five female and
      three male patients, with a median age of 63 years (range, 35 to 76 years), with
      bilateral or repetitive embolic events resulting from MAT were identified,
      representing 9% of all patients with arterial thrombembolism. All patients had
      several risk factors for atherosclerosis, but only one young patient had a single
      risk factor that promoted thrombosis. Successful percutaneous catheter aspiration
      embolectomy was performed in six patients. The remaining two patients underwent
      surgical thromboembolectomy. A below-knee amputation had to be performed in two
      patients, thus representing a morbidity of the primary treatment of 25%. MAT of
      equal value were detected in the ascending (n = 1) and thoracic aorta (n = 3) by
      means of TEE, CT, or MRI. MAT in the abdominal aorta (n = 4) were identified by
      means of CT and MRI. Surgical removal of MAT was performed in seven patients by
      means of graft replacement of the ascending aorta (n = 1), open thrombectomy of
      the descending aorta (n = 2), and thrombendarterectomy of the abdominal aorta (n
      = 4), without intraoperative or postoperative complications. No recurrence of MAT
      occurred during a median follow-up period of 13 months (range, 4 to 24 months).
      CONCLUSION: MAT represent an important source of arterial thrombembolism. A
      diagnostic workup of the aorta, preferably by means of CT or MRI, should be
      performed in all patients in whom other sources of embolization have been ruled
      out. The ideal therapeutic approach to these patients still awaits prospective
      evaluation. However, based on our experience, MAT can be successfully treated
      with a definitive surgical procedure in selected patients, with low mortality and
      morbidity.

PMID- 10587394
TI  - Inflammatory abdominal aortic aneurysm: A postoperative course of retroperitoneal
      fibrosis.
AB  - PURPOSE: The long-term outcome and the development of retroperitoneal fibrosis
      after surgery on an inflammatory aortic aneurysm was studied. METHODS: Between
      1989 and 1997, 1035 patients underwent surgery for an abdominal aneurysm, 42 of
      whom (4.1%) had typical signs of inflammation. All patients underwent computed
      tomography (CT) scans before operation, and 26 patients were followed up with a
      CT scan after a median of 36 months (range, 10 to 91 months). RESULTS: The
      inflammatory layer resolved completely in only 23% of the patients. One patient
      had marked progression, 35% of patients showed improvement, and the remaining
      patients had no change, compared with the preoperative findings. Although
      clinical symptoms subsided in 90% of patients, in five cases an involvement of
      the ureter or intestine that did not exist at the time of operation developed.
      Although ureteral involvement to the inflammation tends to subside after surgery,
      persisting fibrosis was associated with ureteral entrapment in 30% of these cases
      and resulted in renal compromise in 49%. Hydronephrosis that was not present at
      the time of operation was found in 19% of patients, despite improving or stable
      inflammatory lesions. CONCLUSION: This case-control study supports the findings
      that retroperitoneal fibrosis persists longer than previously thought, and
      progression might even occur. Formerly uninvolved organs might become included in
      the process despite regression of the layer, leading to considerable problems if
      the condition is not treated in institutions familiar with this complex disease.
      We advocate a moderated follow-up scheme, as in the case of ordinary abdominal
      aortic aneurysm, and the need for long-term surveillance of inflammatory
      aneurysms.

PMID- 10587395
TI  - The association between cigarette smoking and abdominal aortic aneurysms.
AB  - PURPOSE: The purpose of this study was to investigate the precise effect of
      smoking, duration of smoking, and cessation of smoking on the risk of the
      development of an abdominal aortic aneurysm (AAA). METHODS: A nested case control
      study was carried out in a population-based screening program for men over the
      age of 50 years. Smoking data were collected by questionnaire, and serum levels
      of cotinine were used as an objective measure of nicotine exposure. RESULTS: Data
      of 210 cases and 237 control individuals were analyzed. Current smokers were 7.6
      times more likely to have an AAA than nonsmokers (95% confidence interval, 3.3%
      17.8%). Exsmokers were 3.0 times more likely to have an AAA than nonsmokers (95%
      confidence interval, 1.4%-6.4%). Duration of smoking was significantly associated
      with an increased risk of AAA, and there was a clear linear dose response
      relationship with the duration of smoking; each year of smoking increased the
      relative risk of AAA by 4% (95% confidence interval, 2%-5%). In contrast, the
      effect of the amount smoked disappeared when an adjustment was made for the
      duration of smoking. After the cessation of smoking, there was a very slow
      decline in the risk of the occurrence of an AAA. Smoking was associated with a
      higher relative risk of a small aneurysm than a large aneurysm. Serum cotinine
      levels were higher in men with a small aneurysm than in men with a large
      aneurysm. Cotinine levels were similar in expanding aneurysms and stable
      aneurysms. CONCLUSION: The duration of exposure rather than the level of exposure
      appears to determine the risk of the development of an AAA in men older than 50
      years. The slow decline of risk after the cessation of smoking and the higher
      relative risk for small compared with large aneurysms suggest that smoking is an
      initiating event for the condition.

PMID- 10587396
TI  - Axillary-to-carotid artery bypass grafting for symptomatic severe common carotid
      artery occlusive disease.
AB  - PURPOSE: Revascularization of the internal or external carotid arteries is
      occasionally indicated for symptomatic atherosclerotic common carotid artery
      occlusion or long-segment high-grade stenosis beginning at its origin. I report
      the outcome of axillary artery-based bypass grafts to the distal common,
      internal, or external carotid arteries. METHODS: Between 1981 and 1997, 29
      axillary-to-carotid bypass grafting procedures were performed on 28 patients, 15
      men and 13 women, with a mean age of 68 years. Indications were transient
      ischemia in nine patients, amaurosis fugax in four patients, completed stroke in
      six patients, and nonlateralizing global ischemia in nine patients. Twenty-three
      common carotid arteries were totally occluded, and six had long-segment stenosis
      of 90% or greater beginning at the origin. Saphenous vein grafts were used in 25
      procedures, and synthetic grafts were used in four. Grafts were placed to 13
      internal, eight distal common, and eight external carotid arteries. RESULTS:
      There were no perioperative deaths; one stroke occurred (3.4%). No lymphatic or
      peripheral nerve complications occurred. In a 1- to 11-year follow-up period
      (mean, 4.5 years), there were no graft occlusions, one restenosis of 50% or
      greater, and two restenoses of 70% or greater. The 1-year stenosis-free rate for
      50% or greater stenosis was 93%, and the 5- and 10-year rates were 87%. No late
      ipsilateral strokes occurred. The 5- and 10-year survival rates were 64% and 28%,
      respectively. Coronary artery disease was the major cause of late mortality.
      CONCLUSION: Axillary-to-carotid bypass grafting for severe symptomatic common
      carotid occlusive disease is safe, well tolerated, durable, and effective in
      stroke prevention. There is a high late mortality rate because of coronary artery
      disease in patients with severe proximal common carotid occlusive disease.

PMID- 10587397
TI  - An unexpectedly high rate of pulmonary embolism in patients with superficial
      thrombophlebitis of the thigh.
AB  - PURPOSE: The rate of objectively proven pulmonary embolism in patients with
      thrombophlebitis of the greater saphenous vein was studied. METHODS: Consecutive
      ambulant patients with thrombophlebitis of the greater saphenous vein, involving
      the above-knee segment, underwent a complete venous echo color Doppler
      examination of the lower limbs, perfusion lung scanning, and chest radiography. A
      high probability of pulmonary embolism was defined as the presence of two or more
      large segmental defects, one large and two or more moderate perfusion defects, or
      four or more moderate perfusion defects, with no corresponding abnormality found
      by means of chest radiography. RESULTS: Of the 21 patients included in the study,
      findings compatible with a high probability of pulmonary embolism were detected
      in seven patients (33.3%; 95% CI, 14.6 to 57. 0), although clinical symptoms of
      pulmonary embolism were present only in one patient. No association was found
      between the presence of thrombosis at the saphenofemoral junction and the risk
      for pulmonary embolism. CONCLUSION: The rate of pulmonary embolism in patients
      with thrombophlebitis of the greater saphenous vein is unexpectedly high. This
      risk is similarly high in patients with thrombosis at the saphenofemoral junction
      and in patients without thrombosis at the saphenofemoral junction. Our results
      are consistent with those of other recent investigations and suggest that
      superficial thrombophlebitis of the thigh is not as benign a disease entity as
      previously described.

PMID- 10587398
TI  - Mandibular subluxation for distal internal carotid exposure: technical
      considerations.
AB  - PURPOSE: Carotid endarterectomy (CEA) has become one of the most commonly
      performed vascular procedures, because of the beneficial outcome it has when
      compared with medical therapy alone and because of the anatomic accessibility of
      the artery. In cases of distal carotid occlusive disease, high cervical carotid
      bifurcation, and some reoperative cases, access to the distal internal carotid
      artery may limit surgical exposure and increase the incidence of cranial nerve
      palsies. Mandibular subluxation (MS) is recommended to provide additional space
      in a critically small operative field. We report our experience to determine and
      illustrate a preferred method of MS. METHODS: Techniques for MS were selected
      based on the presence or absence of adequate dental stability and periodontal
      disease. All patients received general anesthesia with nasotracheal intubation
      before subluxation. Illustrations are provided to emphasize technical
      considerations in performing MS in 10 patients (nine men and one woman) who
      required MS as an adjunct to CEA (less than 1% of primary CEAs). Patients were
      symptomatic (n = 7) or asymptomatic (n = 3) and had high-grade stenoses
      demonstrated by means of preoperative arteriography. RESULTS: Subluxation was
      performed and stabilization was maintained by means of: Ivy loop/circumdental
      wiring of mandibular and maxillary bicuspids/cuspids (n = 7); Steinmann pins with
      wiring (n = 1); mandibular/maxillary arch bar wiring (n = 1); and superior
      circumdental to circummandibular wires (n = 1). MS was not associated with
      mandibular dislocation in any patient. No postoperative cranial nerve palsies
      were observed. Three patients experienced transient temporomandibular joint
      discomfort, which improved spontaneously within 2 weeks. CONCLUSION: Surgical
      exposure of the distal internal carotid artery is enhanced with MS and
      nasotracheal intubation. We recommend Ivy loop/circumdental wiring as the
      preferred method for MS. Alternative methods are used when poor dental health is
      observed.

PMID- 10587399
TI  - Folic acid inhibits homocysteine-induced proliferation of human arterial smooth
      muscle cells.
AB  - PURPOSE: An elevated plasma homocysteine level has been identified as an
      independent risk factor for atherosclerosis. Whether this represents a marker for
      vascular disease or a direct effect on the vasculature remains unclear. Because
      vascular smooth muscle cells (VSMCs) play an integral role in the atherosclerotic
      process, we studied the effect of homocysteine on human infragenicular VSMC
      proliferation and the role of folic acid in reversing the homocysteine effect.
      METHODS: Human infragenicular VSMCs harvested from amputation specimens were
      studied. Various cell groups were exposed to physiologic (6.25 micromol/L and
      12.5 micromol/L) and pathologic (25 micromol/L to 500 micromol/L) concentrations
      of homocysteine. Similar groups were simultaneously exposed to 20 nmol/L of folic
      acid. Cell counts and DNA synthesis, as reflected by [methyl-(3)H]-thymidine
      incorporation, were performed at 6 days and 24 hours, respectively. Additional
      groups were exposed to various combinations of folic acid (20 nmol/L), vitamin
      B(6) (145 nmol/L), and vitamin B(12) (0.45 nmol/L) in the presence of
      homocysteine (25, 50, and 250 micromol/L). RESULTS: Homocysteine resulted in a
      dose-dependent increase in DNA synthesis and cell proliferation. Cell counts
      increased significantly at homocysteine concentrations ranging from 25 micromol/L
      to 500 micromol/L (P <.05), with a maximal increase of 98% at 500 micromol/L of
      homocysteine. The addition of 20 nmol/L folic acid resulted in significant
      inhibition of cell proliferation at all homocysteine concentrations studied (P
      <.001). Maximal inhibition of 70% occurred in the cells exposed to 50 micromol/L
      of homocysteine. The increases in [methyl-(3)H]-thymidine incorporation ranged
      from 36% at 6 micromol/L homocysteine to a maximum of 247% at 500 micromol/L
      homocysteine. All increases were statistically significant (P <.05). The addition
      of 20 nmol/L folic acid resulted in significant inhibition of DNA synthesis (P
      <.002). Vitamins B(6) and B(12) did not demonstrate significant antiproliferative
      properties. CONCLUSION: A possible role of homocysteine in the formation of
      atherosclerotic lesions is through a direct proliferative effect on VSMCs in a
      dose-dependent fashion. Folic acid intake at levels available in dietary
      supplements may prove protective in hyperhomocysteinemia-induced atherosclerosis.
      Vitamins B(6) and B(12) alone do not appear to exhibit a substantial inhibitory
      effect in the setting of elevated homocysteine levels.

PMID- 10587400
TI  - Dermal tissue fibrosis in patients with chronic venous insufficiency is
      associated with increased transforming growth factor-beta1 gene expression and
      protein production.
AB  - PURPOSE: Pathologic dermal degeneration in patients with chronic venous
      insufficiency (CVI) is characterized by aberrant tissue remodeling that results
      in stasis dermatitis, tissue fibrosis, and ulcer formation. The cytochemical
      processes that regulate these events are unclear. Because transforming growth
      factor-beta(1) (TGF-beta(1)) is a known fibrogenic cytokine, we hypothesized that
      the increased production of TGF-beta(1) would be associated with CVI disease
      progression. METHODS: Seventy-eight punch biopsy specimens of the lower calf (LC)
      and the lower thigh (LT) of 52 patients were snap frozen in liquid nitrogen and
      stratified into four groups according to the Society for Vascular
      Surgery/International Society for Cardiovascular Surgery CEAP classification (C,
      clinical; E, etiologic; A, anatomic distribution; and P, pathophysiology). One
      set of LC biopsy specimens were analyzed for TGF-beta(1) gene expression with
      quantitative reverse transcriptase-polymerase chain reaction: healthy skin, n =
      6; class 4, n = 6; class 5, n = 5; and class 6, n = 7. A second set of biopsy
      specimens from the LC and LT were analyzed for the amount of bioactive TGF
      beta(1) with a certified cell line 64 mink lung epithelial bioassay: healthy
      skin, n = 8; class 4, n = 23; class 5, n = 13; and class 6, n = 10. The location
      of TGF-beta(1) was determined at the light and electron microscopy level with
      immunocytochemistry and immunogold (IMG) labeling. Multiple comparisons were
      analyzed with a one-way analysis of variance and the Student-Newman-Keuls post
      hoc tests. The LC and LT comparisons were analyzed with a two-tailed unpaired t
      test. RESULTS: The TGF-beta(1) gene transcripts for control subjects and patients
      in classes 4, 5, and 6 were 7.02 +/- 7.33, 43.33 +/- 9.0, 16.13 +/- 7.67, and
      7.22 +/- 0.56 x 10(-14) mol/microg total RNA, respectively. The transcripts were
      significantly elevated in class 4 patients only (P </=.05). The amount of active
      TGF-beta(1) in picograms/gram of tissue from LC and LT biopsy specimens as
      compared with healthy skin biopsy specimens were as follows: healthy skin, <1. 0
      pc/g; class 4: LC, 5061 +/- 1827 pc/g; LT, 317.3 +/- 277 pc/g; class 5: LC, 8327
      +/- 3690 pc/g; LT, 193 +/- 164 pc/g; and class 6: LC, 5392 +/- 1800 pc/g; LT, 117
      +/- 61 pc/g. Differences between healthy skin and the skin of the patients in
      classes 4 and 6 were significant (P </=.05 and P </=.01, respectively).
      Differences between the LC and LT biopsy specimens within each CVI group were
      also significant: class 4, P </=.003; class 5, P </=.008; and class 6, P </=.02.
      Immunocytochemistry results of healthy skin showed TGF-beta(1) staining of
      epidermal basal cells only. CVI dermal biopsy results demonstrated positive
      staining in epidermal basal cells, fibroblasts, and leukocytes. Many leukocytes
      had positive staining of intracellular granules, which appeared morphologically
      similar to mast cells. IMG labeling results demonstrated gold particles in the
      leukocytes and collagen fibrils of the extracellular matrix. CONCLUSION: Our
      study indicated that activated leukocytes traverse perivascular cuffs and release
      active TGF-beta(1). Positive TGF-beta(1) staining results of dermal fibroblasts
      were observed and suggest that fibroblasts are the targets of activated
      interstitial leukocytes. Increased protein production, despite normal levels of
      gene transcripts in patients in classes 5 and 6, suggests that alternate
      mechanisms other than gene transcription regulate protein production. A potential
      mechanism for quick access and release is storage of TGF-beta(1) in the
      extracellular matrix. IMG labeling to collagen fibrils support this possibility.
      Furthermore, TGF-beta(1) was exclusively elevated in areas of clinically active
      disease, indicating a regionalized response to injury. These data suggest that
      alterations in tissue remodeling occur in patients with CVI and that dermal
      tissue fibrosis in CVI is regulated by TGF-beta(1).

PMID- 10587401
TI  - Endovascular management of ureteroarterial fistula.
AB  - Ureteroarterial fistulas, although rare, appear to be increasing in frequency.
      Because open surgical repair may be difficult and associated with significant
      risk for complications, endovascular intervention may provide an attractive
      treatment alternative. We review the diagnosis and management of a
      ureteroarterial fistula and iliac pseudoaneurysm that presented with massive
      hematuria during ureteral stent removal. The patient was treated by means of the
      percutaneous embolization of the right hypogastric artery and placement of an
      expanded polytetrafluoroethylene stent-graft. Endovascular stent-graft placement
      may serve as a safe and practical alternative in the treatment of these patients,
      whose cases are challenging.

PMID- 10587402
TI  - Aortoesophageal fistula caused by aneurysm of the thoracic aorta: successful
      surgical treatment, case report, and literature review.
AB  - Aortoesophageal fistula induced by atherosclerotic thoracic aortic aneurysm is
      rare, but is usually a fatal disorder, with few survivors reported. We report the
      case of a 72-year-old man with aortoesophageal fistula successfully treated in a
      two-stage operation. In the first stage, we performed resection and replacement
      of the aortic aneurysm with a prosthetic graft in situ, esophagectomy, cervical
      esophagostomy, and jejunostomy. After the patient recovered well postoperatively,
      a transmediastinal retrosternal interposition of the stomach was performed, with
      esophagogastroanastomosis in the cervical area, to re-establish the
      gastrointestinal tract. We include a discussion of the causes, diagnostic
      approach, management of the aorta and esophagus, and review of the literature.

PMID- 10587403
TI  - Hyperbaric oxygenation treatment of acute paraplegia after resection of a
      thoracoabdominal aortic aneurysm.
AB  - Acute spinal cord ischemic injury after resection of thoracoabdominal aneurysm
      remains a relatively common and potentially devastating complication. The
      complete resolution of postoperative paraplegia after resection of a type II
      thoracoabdominal aneurysm, after treatment with hyperbaric oxygenation, is
      reported.

PMID- 10587406
TI  - Reply

PMID- 10587404
TI  - EuroQol values for economic modeling quality of life after infrainguinal bypass
      grafting surgery: a rectification.

PMID- 10587405
TI  - Regarding "A prospective study to assess changes in proximal aortic neck
      dimensions after endovascular repair of abdominal aortic aneurysms".

PMID- 10587407
TI  - Maternal and fetal toxicity of N-methylmorpholine by oral administration in rats.
AB  - N-methylmorpholine, which is used as a catalyst in polyurethane foams producing,
      in solvents, stabilizing agents, and corrosion inhibitors, was administered to
      female rats by gavage at 100, 200, 600, and 900 mg/kg during organogenesis. It
      did not exhibit selective toxicity toward the developing conceptus. This compound
      administered to pregnant females was fetotoxic and teratogenic in the presence of
      maternal toxicity. N-methylmorpholine induced anophthalmia, internal
      hydrocephalus, and hydronephrosis but only at one dose which was also
      maternotoxic. Teratogenesis Carcinog. Mutagen. 19:369-376, 1999.

PMID- 10587408
TI  - Investigation of genotoxic activity of trans-dehydrocrotonin, a clerodane
      diterpene from Croton cajucara.
AB  - The genotoxic action of three doses of trans-dehydrocrotonin (t-DCTN), an active
      ingredient obtained from the bark extracts of an Amazon native plant, Croton
      cajucara, were examined in Swiss mouse bone marrow cells in vivo, submitted to
      acute intraperitoneal treatment, by micronucleus (MN) and chromosomal aberration
      (CA) tests. The statistical tests (Anova and Tukey) made to compare the results
      obtained in each of the three doses of t-DCTN with the negative-control group
      showed that the frequencies of MN and mitotic index were equal to the negative
      control and that the frequencies of CA were lower than that observed in the
      negative-control. Therefore, based on our results it can be said that t-DCTN is
      not genotoxic nor cytotoxic to mouse bone marrow cells, submitted to acute
      intraperitoneal treatment in vivo. Teratogenesis Carcinog. Mutagen. 19:377-384,
      1999.

PMID- 10587409
TI  - An integrated pharmacokinetic and pharmacodynamic study of arsenite action. 1.
      Heme oxygenase induction in rats.
AB  - Rat heme oxygenase (HO) activity was used as a specific (among forms of arsenic)
      and sensitive biomarker of effect for orally administered sodium arsenite in
      rats. Time course studies showed that HO was induced in rat liver from 2 to 48 h
      in both rat liver and kidney. Hepatic and renal inorganic arsenic (iAs)
      concentrations were high at times preceding a high degree of HO induction. At
      times following pronounced HO induction, tissue dimethylarsinic acid
      concentrations were high. Dose-response studies of arsenite showed substantial HO
      induction in liver at doses of 30 micromol/kg and higher and in the kidney at
      doses of 100 micromol/kg and higher. Doses of 10 (in liver) and of 30 micromol/kg
      (in kidney) sodium arsenite given by gavage did not significantly induce rat HO
      activity. Speciation of tissue total arsenic into iAs, methylarsonic acid (MMA),
      and dimethylarsinic acid (DMA) permits us to link tissue iAs and HO enzyme
      induction. There was a linear relationship between tissue inorganic arsenic (iAs)
      concentration and tissue HO in individual rats (r(2) = 0.780 in liver and r(2) =
      0.797 in kidney). Nonlinear relationships were observed between administered
      arsenite dose and either liver or kidney iAs concentration. Overall, there was a
      sublinear relationship between administered arsenite and biological effect in
      rats. Teratogenesis Carcinog. Mutagen. 19:385-402, 1999. Published 1999 Wiley
      Liss, Inc.

PMID- 10587410
TI  - Inhibitory effect of propolis and bee venom on the mutagenicity of some direct-
      and indirect-acting mutagens.
AB  - The antimutagenic effect of ethanolic extract of propolis (EEP) and honeybee
      (Apis mellifera) venom, both collected in the State of Sao Paulo, Brazil, was
      assessed by the Salmonella/microsome assay upon direct- and indirect-acting
      mutagens. EEP had inhibitory effect (in an ascending order) on the mutagenicity
      power of daunomycin (TA102), benzo(a)pyrene (TA100), and aflatoxin B(1)(TA98) and
      the venom acted against the mutagenicity of 4-nitro-o-phenylenediamine (TA98) and
      daunomycin (TA102). Teratogenesis Carcinog. Mutagen. 19:403-413, 1999.

PMID- 10587411
TI  - Cautious enthusiasm.

PMID- 10587412
TI  - Race, socioeconomic factors, and area of residence are associated with asthma
      prevalence.
AB  - Asthma prevalence in the United States has been reported to be higher in minority
      groups such as Blacks and Hispanics. Because a disproportionate number of
      individuals from such minority groups are of low socioeconomic status (SES), it
      is unclear how much of the racial/ethnic differences in asthma prevalence is
      related to low SES. We investigated the effect of SES on the relationship between
      race/ethnicity and asthma prevalence in a cohort of families with a history of
      asthma or allergies from the Boston, Massachusetts area. From 499 families, a
      cohort of 998 parents and 307 children was identified. We used total yearly
      family income (<$50,000 vs. > or = $50, 000), highest level of education (< or =
      high school vs. > or = college), and residence in high-poverty areas vs. low
      poverty areas as measures of SES. Yearly family income <$50,000, < or = high
      school education, and residence in high poverty areas were all associated with
      increased risks for asthma in both cohorts. In the parental cohort, Blacks and
      Hispanics (OR = 2.1, 95% CI = 1.5, 2.8; and OR = 2.2, 95% CI = 1.5, 3.2,
      respectively) were at greater risk for asthma than Whites. In the cohort of
      children, Black and Hispanic children (OR = 2.9, 95% CI = 1.0, 8.0; and OR = 5.3,
      95% CI = 1.6, 17.5, respectively) were also at increased risk for asthma. When
      the three measures of SES were included in the multivariable models, the risks
      associated with Blacks and Hispanics decreased in both cohorts: OR = 1.4, 95% CI
      = 0.9, 2.0; and OR = 1.6, 95% CI = 1.0, 2. 6, respectively, for the parents; and
      OR = 0.8, 95% CI = 0.2, 3.0; and 2.5, 95% CI = 0.5, 11.7, respectively, for the
      children. We conclude that a large proportion of the racial/ethnic differences in
      asthma prevalence in our study is explained by factors related to income, area of
      residence, and level of education.

PMID- 10587413
TI  - Exhaled nitric oxide before and after montelukast sodium therapy in school-age
      children with chronic asthma: a preliminary study.
AB  - Exhaled nitric oxide (ENO) is a surrogate marker of airway inflammation in
      asthma. In 12 children aged 6-11 years with mild to moderate persistent asthma,
      ENO concentrations were measured before and after 4 weeks of treatment with
      montelukast sodium, a leukotriene receptor antagonist, and 2 weeks after
      withdrawal of therapy. Baseline ENO levels (mean and 95% confidence interval)
      were significantly elevated in patients with asthma compared to age-matched
      nonasthmatic control subjects, with levels of 83 (42-123) vs. 13 (11-15) ppb (P <
      0.001). After treatment with montelukast sodium, there was a significant (P <
      0.01) reduction in ENO to 58 (27-89) ppb which again rose to 69 (38-99) ppb 2
      weeks after treatment was withdrawn. During treatment, the fall in ENO was
      accompanied by nonsignificant improvements in prebronchodilator forced expiratory
      volume in 1 s (FEV(1)) from 81-85% predicted or reductions in use of albuterol
      from a mean of 2.5 to 1.6 puffs/day. Individual ENO measurements and change in
      ENO concentrations with treatment did not correlate with either pulmonary
      function changes or use of bronchodilator. These data show that ENO is elevated
      in children with relatively mild asthma treated with bronchodilator alone, and
      that treatment with montelukast sodium for 4 weeks results in a significant
      reduction in ENO concentrations, even in the absence of significant changes in
      pulmonary function. These findings suggest an anti-inflammatory role for
      leukotriene D(4) receptor antagonism in the treatment of children with mild to
      moderate asthma.

PMID- 10587414
TI  - Determinants of bronchial responsiveness at school age in prematurely born
      children.
AB  - The bronchial challenge test using isocapnic hyperventilation of cold air (IHCA)
      was used to evaluate bronchial responsiveness in 63 offspring of multiple
      pregnancies when they were 8-15 years old. At birth, 27 (43%) children had had
      intrauterine growth retardation (IUGR, birth weight <-2 SD, or birth weight
      difference between twin pairs >1.3 SD). The median birth weight was 2,050 g
      (range, 800-3, 150), and the median gestational age was 35 weeks (range, 28-38).
      None of the children had asthma or suffered from asthma-like symptoms. In the
      interpretation of the IHCA test, a fall of 9% or more in the forced expiratory
      volume in 1 sec (FEV(1)) was considered as abnormal, and these children were
      classified as "cold air responders." The number of responders was 16 (25%); their
      baseline FEV(1)/forced vital capacity ratio (FEV(1)/FVC) and forced expiratory
      flow between 25-75% FVC (FEF(25-75)), but not FEV(1) were significantly lower
      than the corresponding values in nonresponders. No differences were found in
      perinatal or neonatal factors between responders or nonresponders. Eight (30%) of
      the 27 IUGR and 8 (22%) of the 36 appropriate for gestational age (AGA) children
      were IHCA responders. In particular, IUGR was not correlated with maximal FEV(1)
      falls following the IHCA test. Respiratory infections after the neonatal period
      were equally common in IUGR and AGA children; but infections were associated with
      subsequent IHCA responsiveness. Adenoidectomy, tonsillectomy, and/or myringotomy
      had been performed significantly more often in the responders than in the
      nonresponders. At least one of the above invasive procedures had been performed
      in 20 (32%) of the children; this group was termed the "ENT (ear, nose, throat)
      surgery group." Fifty-six percent of the responders, but only 26% of the
      nonresponders, belonged to the ENT surgery group (P = 0.02). We conclude that
      intrauterine growth retardation or prematurity is not associated with abnormal
      cold air responsiveness in the IHCA test.

PMID- 10587415
TI  - Pulmonary function in children of school age is related to the number of siblings
      in their family.
AB  - It has been suggested that the number of siblings in a family is a surrogate
      variable for exposure to early infections. Since there may be an association
      between early respiratory infections and impaired lung function in later life,
      the aim of this study was to elucidate the relationship between the number of
      siblings and pulmonary function. We analyzed pulmonary function data from 677
      schoolchildren living in 431 nuclear families. Our results show that forced vital
      capacity (FVC) and forced expiratory volume in 1 second (FEV(1)) expressed as a
      percentage of deviation from the predicted values (FVC%, FEV(1)%) increase
      significantly in line with the number of siblings in a family (FVC%: no sibling =
      reference, 1 sibling = +1.3%, 2 siblings = +1.9%, 3 siblings = +4.0%, 4 or more
      siblings = +5.1%; P-value for trend = 0.01; FEV(1)%: no sibling = reference, 1
      sibling = +1.6%, 2 siblings = +2.0%, 3 siblings = +4.3%, 4 or more siblings =
      +6.5%; P-value for trend = 0.007). Pulmonary function values were no more
      strongly related to the number of older siblings than to the number of younger
      siblings (difference between the trend for older and younger siblings for FCV%: P
      = 0.7; FEV(1)%: P = 0.9). The association between pulmonary function and number
      of siblings can be explained neither by the child's atopic status, prevalence of
      asthma, or history of pneumonia, nor by former or current cigarette smoke
      exposure. This suggests that pulmonary function status of the child appears to be
      related to the number of siblings, and is unlikely to be explained solely by
      exposure to infections early in life. Our data therefore adds strength to the
      hypothesis that factors which cause the size of a sibship to influence a child's
      respiratory health have not yet been adequately explained.

PMID- 10587416
TI  - Mechanisms of nocturnal oxyhemoglobin desaturation in children and adolescents
      with sickle cell disease.
AB  - Oxyhemoglobin desaturation in patients with sickle cell disease has been proposed
      as a possible mechanism in the initiaton of vasco-occlusive pain crises.
      Nocturnal oxyhemoglobin desaturation (NOD) has been described with a prevalence
      of up to 40% in children and adolescents with sickle cell disease. The objective
      of this study was to evaluate the mechanisms of nocturnal oxyhemoglobin
      desaturation in sickle cell disease and determine the role of obstructive sleep
      apnea. We performed 16-channel polysomnograms and pulmonary function testing in
      20 patients with sickle cell disease (ages 7-21 years) who had documented
      desaturation on home oximetry studies. The median saturation awake was 94%
      (quartile range, 88-95). Median saturation during REM sleep was 93.5% (88-95) and
      during non-REM sleep 93.5% (87.5-95). The median respiratory disturbance index
      was low (1.35 quartile range, 0.25-2.85). Twelve patients had no obstructive
      apnea recorded, while 3 patients had a total of 9 or 10 episodes during the
      entire study. The median snoring time was 5. 65% of total sleep time (quartile
      range, 1.35-22.65). There was no correlation between number of obstructive apneas
      and mean sleeping saturation (r = 0.012, p = 0.95). There was no correlation
      between pulmonary function data and prevalence of NOD. There was a strong,
      positive correlation between sleeping and awake saturation (r = 0.96, p < 0.001).
      We conclude that while nocturnal oxyhemoglobin desaturation may be common in
      children and adolescents with sickle cell disease, upper airway obstruction does
      not appear to play an important role in its genesis.

PMID- 10587417
TI  - Measurement of hemoglobin saturation by oxygen in children and adolescents with
      sickle cell disease.
AB  - Pulse oximetry is a noninvasive method of measuring oxyhemoglobin saturation. The
      validity of pulse oximetry in sickle cell disease (SCD) has been questioned. We
      evaluated pulse oximetry, arterial blood gas analysis, and co-oximetry in
      patients with SCD, and we assessed the effect of dyshemoglobin and altered blood
      oxygen affinity on their accuracy. Sixteen patients with SCD aged 7-21 years had
      arterial and venous blood drawn and transcutaneous pulse oximetry performed.
      Oxyhemoglobin dissociation curves were plotted from the venous blood of 15
      patients. Oxyhemoglobin saturation estimated by arterial blood gas analysis
      (SaO(2)) and measured by pulse oximetry (SpO(2)) were both higher than the
      saturation by co-oximetry (FO(2)Hb) (mean +/- SD = 96.3 +/- 1.6%, 94 +/- 3.1%,
      and 89.1 +/- 3.8%, respectively). There was a significant, positive correlation
      between SpO(2) and FO(2)Hb (r = 0.7, P = 0.002). The patients had elevated levels
      of methemoglobin (MetHb) and carboxyhemoglobin (COHb) (2.3 +/- 1.4% and 4.7 +/-
      1.3%, respectively). The oxyhemoglobin dissociation curves were frequently
      shifted to the right with oxygen tensions elevated when hemoglobin was 50%
      saturated with oxygen (P(50)) (32.5 +/- 4.5 mm Hg). There was a strong
      correlation between the amounts of dyshemoglobin (MetHb + COHb) and the
      difference between SaO(2) and FO(2)Hb (r = 0.7, P = 0.002). There was no
      correlation between the difference between SaO(2) and FO(2)Hb and the P(50) (r =
      0.27, P = 0.33) There was also a strong positive correlation between SaO(2)
      SpO(2) and dyshemoglobin fraction (r = 0.77, P = 0.001). We conclude that pulse
      oximetry and arterial blood gas analysis overestimate oxygen saturation when
      compared to co-oximetry, but that SpO(2) is consistently closer than SaO(2) to
      FO(2)Hb. SpO(2) is partially affected by MetHb and COHb. The discrepancy between
      SaO(2) and FO(2)Hb is due to the presence of dyshemoglobin and a shifted
      oxyhemoglobin dissociation curve, but the effect from dyshemoglobin predominates.

PMID- 10587418
TI  - Reproducibility of forced expiratory flow and volume measurements in infants with
      bronchiolitis.
AB  - The end-tidal rapid thoracoabdominal compression (ETRTC) technique is an
      established method for lung function testing in infancy. Previous work in healthy
      infants, however, has shown that measurements with the newly developed raised
      volume rapid thoracoabdominal compression (RVRTC) technique are more reproducible
      than those with the ETRTC technique. So far, reproducibility of the two
      techniques has not been compared in infants with acute airway disease. Twenty
      three infants with acute viral bronchiolitis underwent lung function assessment
      with both the ETRTC and the RVRTC technique. A series of 8-10 measurements with
      each technique was done in randomized order. Forced expired volumes at 0.5, 0.75,
      and 1 sec after chest compression (FEV(0.5), FEV(0.75), and FEV(1.0)) were
      measured with the RVRTC technique; maximum expiratory flow at functional residual
      capacity (V'(maxFRC)) was measured with the ETRTC technique. Group mean
      intrasubject coefficients of variation (CV) were 4.84% for FEV(0.5), 5.01% for
      FEV(0.75), 5.43% for FEV(1. 0), and 13.79% for V'(maxFRC), respectively.
      Differences between FEV parameters were statistically insignificant, whereas the
      difference between each FEV parameter and V'(maxFRC) was highly significant (P <
      0.001). In infants with acute viral bronchiolitis, RVRTC measurements have
      significantly less intraindividual variability than flow rates assessed with the
      conventional ETRTC technique. This finding provides the basis for assessing
      disease course and effects of therapeutic interventions on an individual basis.

PMID- 10587420
TI  - Cystic fibrosis lung disease: the role of nitric oxide.
AB  - This review summarizes current knowledge about the role of nitric oxide (NO) in
      cystic fibrosis (CF) lung disease. NO is endogenously produced by a group of
      enzymes, the NO synthases (NOSs). There are three isoforms of NOS, each encoded
      by different genes: neuronal (nNOS), immune or inducible (iNOS), and endothelial
      (eNOS) nitric oxide synthase.(1) They all form NO and L-citrulline by enzymatic
      oxidation of L-arginine. This reaction requires a number of cosubstrates,
      including molecular oxygen and tetrahydrobiopterin. It is now known whether all
      three isoenzymes are constitutively expressed in cells of the respiratory tract
      and that their gene expression is inducible.(2,3) NO production by iNOS, the
      "high-output" NOS, is stimulated by bacterial lipopolysaccharide (LPS) as well as
      proinflammatory cytokines such as interleukin (IL)-1gamma, IL-2, interferon (IFN)
      gamma, and tumor necrosis factor (TNF). In contrast to nNOS and eNOS, activation
      of iNOS does not require an increase in intracellular Ca(2+) concentration.

PMID- 10587419
TI  - Tidal breathing parameters in young children: comparison of measurement by
      respiratory inductance plethysmography to a facemask pneumotachograph system.
AB  - The ratio of expiratory time at tidal peak flow to total expiratory time
      (t(ptef)/t(e)) correlates with conventional measures of airway obstruction. It is
      usually assessed using a facemask and pneumotachograph system which may be poorly
      tolerated in young children and hence limits the usefulness of this technique. We
      therefore determined in young asthmatic children the accuracy of t(ptef)/t(e),
      using an uncalibrated respiratory inductance plethysmograph (RIP), and compared
      the results with those from a facemask-pneumotachograph system. We also assessed
      whether age influenced the agreement between measurements using the two devices.
      Forty-seven children aged between 1 month and 12 years were recruited: 39 were
      inpatients recovering from an acute wheezy episode, and 8 were recruited from the
      asthma clinic. All were receiving bronchodilators. Tidal breathing parameters
      t(ptef)/t(e), the duty cycle (t(i)/t(tot)), and respiratory rate were initially
      measured using the Respitrace alone and then simultaneously with both the
      Respitrace and the facemask-pneumotachograph system. Eight children did not
      tolerate the facemask, and in two others it was impossible to analyze the
      Respitrace trace due to artefacts. In the remaining 37 children, the reliability
      coefficients and coefficients of variation of the two techniques were similar.
      Similar values of t(i)/t(tot) and respiratory rate were obtained using the two
      devices. The mean t(ptef)/t(e) obtained using the Respitrace was lower than with
      the facemask-pneumotachograph system (P < 0.01), although this was age group
      dependent (P < 0.05), as the difference was less apparent in the 1 to 2-year-old
      children than in other age groups. Application of the facemask-pneumotachograph
      system did not significantly influence the results obtained using the Respitrace.
      We conclude that uncalibrated respiratory inductance plethysmography can measure
      tidal breathing parameters as reliably as a facemask-pneumotachograph system in
      young asthmatic children, and is better tolerated than the pneumotachograph
      system. The results obtained using the two devices are not interchangeable.

PMID- 10587421
TI  - If you can't stand the rash, get out of the kitchen: an unusual adverse reaction
      to ciprofloxacin.
AB  - Ciprofloxacin, a quinolone antibiotic, is used to treat a wide variety of
      infections including Pseudomonas aeruginosa in patients with cystic fibrosis
      (CF). Photosensitivity is a well-known complication of treatment with this group
      of antibiotics, and it is more common in patients with CF. We report on a case of
      photosensitivity induced by indoor fluorescent strip-lighting (spectral range,
      295-760 nm) in a 12-year-old girl with CF treated with ciprofloxacin. This type
      of lighting emits UVA rays (320-400 nm) which cause skin damage in the presence
      of sensitizing agents. Patients taking ciprofloxacin are usually advised to
      protect their skin from direct sunlight. We suggest that more attention should be
      paid to indoor sources of UV light.

PMID- 10587422
TI  - Treatment of severe status asthmaticus with nitric oxide.
AB  - The paper reports on a 13-year-old girl with chronic asthma who presented in
      acute respiratory failure following an exacerbation of her disease. Nitric oxide
      was added to the ventilator circuit at 7 ppm and then 15 ppm after the patient
      failed to respond to bronchodilators and steroids. This was followed by rapid
      improvement in respiratory mechanics and blood gases with no adverse effects.
      Nitric oxide appears to have a direct relaxing effect on the bronchial smooth
      muscle.

PMID- 10587423
TI  - Selected abstracts

PMID- 10587424
TI  - Eighteenth annual conference on sleep disorders in infancy and childhood
      annenberg center for health sciences rancho mirage, california, january 20-22,
      2000

PMID- 10587425
TI  - Structural basis for the guanosine requirement of the hairpin ribozyme.
AB  - To form a catalytically active complex, the essential nucleotides of the hairpin
      ribozyme, embedded within the internal loops of the two domains, must interact
      with one another. Little is known about the nature of these essential interdomain
      interactions. In the work presented here, we have used recent topographical
      constraints and other biochemical data in conjunction with molecular modeling
      (constraint-satisfaction program MC-SYM) to generate testable models of
      interdomain interactions. Visual analysis of the generated models has revealed a
      potential interdomain base pair between the conserved guanosine immediately
      downstream of the reactive phosphodiester (G(+1)) and C(25) within the large
      domain. We have tested this former model through activity assays, using all 16
      combinations of bases at positions +1 and 25. When the standard ribozyme was
      used, catalytic activity was severely suppressed with substrates containing
      U(+1), C(+1), or A(+1). Similarly, mutations of the putative pairing partner
      (C(25) to A(25) or G(25)) reduce activity by several orders of magnitude. The
      U(25) substitution retains a significant level of activity, consistent with the
      possible formation of a G.U wobble pair. Strikingly, when combinations of Watson
      Crick (or wobble) base pairs were introduced in these positions, catalytic
      activity was restored, strongly suggesting the existence of the proposed
      interaction. These results provide a structural basis for the guanosine
      requirement of this ribozyme and indicate that the hairpin ribozyme can now be
      engineered to cleave a wider range of RNA sequences.

PMID- 10587426
TI  - NMR observation of selected segments in a larger protein: central-segment isotope
      labeling through intein-mediated ligation.
AB  - Peptide segments in a protein, which can include an active site of interest or be
      a series of parts constituting the entire structure, are now selectively observed
      by nuclear magnetic resonance (NMR) spectroscopy using samples prepared by the
      intein-mediated ligation method. Two separate inteins were used to ligate NMR
      transparent segments to both the ends of an NMR-visible segment, producing a
      partly visible intact protein molecule. The (15)N-(1)H correlation spectrum of a
      370-residue maltose binding protein labeled with (15)N at a continuous segment
      comprising residues Gly(101)-Ser(238) showed the essential elimination of signal
      overlapping, the signals being at the same positions as for the uniformly labeled
      sample. This method will allow structural analysis by NMR of over 50-kDa proteins
      in combination with contemporary NMR techniques suppressing the signal decays of
      larger proteins.

PMID- 10587427
TI  - Intercalation of the (1S,2R,3S,4R)-N6-[1-(1,2,3,4-tetrahydro-2,3, 4
      trihydroxybenz[a]anthracenyl)]-2'-deoxyadenosyl adduct in an oligodeoxynucleotide
      containing the human N-ras codon 61 sequence.
AB  - The (1S,2R,3S,4R)-N(6)-[1-(1,2,3,4-tetrahydro-2,3, 4
      trihydroxybenz[a]anthracenyl)]-2'-deoxyadenosyl adduct at X6 of 5'-d(CGGACXAGAAG)
      3'.5'-d(CTTCTTGTCCG)-3', incorporating codons 60, 61 (underlined), and 62 of the
      human N-ras protooncogene, results from trans opening of (1R,2S,3S,4R)-1,2-epoxy
      1,2,3, 4-tetrahydrobenz[a]anthracenyl-3,4-diol by the exocyclic N6 of adenine.
      Two conformations of this adduct exist, in slow exchange on the NMR time scale. A
      structure for the major conformation, which represents approximately 80% of the
      population, is presented. In this conformation, an anti glycosidic torsion angle
      is observed for all nucleotides, including S,R,S,RA6. The refined structure is a
      right-handed duplex, with the benz[a]anthracene moiety intercalated on the 3'
      face of the modified base pair, from the major groove. It is located between
      S,R,S,RA6.T17 and A7.T16. Intercalation is on the opposite face of the modified
      S,R,S,RA6.T17 base pair as compared to the (1R,2S,3R,4S)-N6-[1-(1,2,3,4
      tetrahydro-2, 3,4-trihydroxybenz[a]anthracenyl)]-2'-deoxyadenosyl adduct, which
      intercalated 5' to the modified R,S,R,SA6.T17 base pair [Li, Z. , Mao, H., Kim,
      H.-Y., Tamura, P. J., Harris, C. M., Harris, T. M., and Stone, M. P. (1999)
      Biochemistry 38, 2969-2981]. The spectroscopic data do not allow refinement of
      the minor conformation, but suggest that the adenyl moiety in the modified
      nucleoti111S,R, S,RA6 adopts a syn glycosidic torsion angle. Thus, the minor
      conformation may create greater distortion of the DNA duplex. The results are
      discussed in the context of site-specific mutagenesis studies which reveal that
      the S,R,S,RA6 lesion is less mutagenic than the R,S,R,SA6 lesion.

PMID- 10587428
TI  - Structure and stability of the consecutive stereoregulated chiral
      phosphorothioate DNA duplex.
AB  - The duplex structures of the stereoregulated phosphorothioate DNAs, [R(p),R(p)]-
      and [S(p),S(p)]-[d(GC(ps)T(ps)ACG)] (ps, phosphorothioate; PS-DNA), with their
      complementary RNA have been investigated by combined use of (1)H NMR and
      restrained molecular dynamics calculation. Compared to those obtained for the
      unmodified duplex structures (PO-DNA.RNA), the NOE cross-peak intensities are
      virtually identical for the PS-DNA.RNA hybrid duplexes. The structural analysis
      on the basis of the NOE restraints reveals that all of the three DNA.RNA duplexes
      take a A-form conformation and that there is no significant difference in the
      base stacking for the DNA.RNA hybrid duplexes. On the other hand, the NOE cross
      peak intensities of the protons around the central T(ps)A step of the PS-DNA.DNA
      duplexes are apparently different from those of PO-DNA. DNA. The chemical shifts
      of H8/6 and H1' at the T(ps)A step are also largely different among PS-DNA.DNAs
      and PO-DNA.DNA, suggesting that the DNA.DNA structure is readily changed by the
      introduction of the phosphorothioate groups to the central T(p)A step. The
      structure calculations indicate that all of these DNA.DNA duplexes are B-form
      although there exist some small differences in helical parameters between the
      [R(p),R(p)]- and [S(p),S(p)]PS-DNA.DNA duplexes. The melting temperatures (T(m))
      were determined for all of the duplexes by plotting the chemical shift change of
      isolated peaks as a function of temperature. For the PS-DNA.RNA hybrid duplexes,
      the [S(p),S(p)] isomer is less stable than the [R(p),R(p)] isomer while this
      trend is reversed for the PS-DNA.DNA duplexes. Consequently, although the PS
      DNA.RNA duplexes take the similar A-form structure, the duplex stability is
      different between PS-DNA.RNA duplexes. The stability of the DNA.RNA duplexes may
      not be governed by the A-form structure itself but by some other factors such as
      the hydration around the phosphorothioate backbone, although the T(m) difference
      of the DNA.DNA duplexes could be explained by the structural factor.

PMID- 10587430
TI  - Prediction of inhibitor binding free energies by quantum neural networks.
      Nucleoside analogues binding to trypanosomal nucleoside hydrolase.
AB  - A computational method has been developed to predict inhibitor binding energy for
      untested inhibitor molecules. A neural network is trained from the electrostatic
      potential surfaces of known inhibitors and their binding energies. The algorithm
      is then able to predict, with high accuracy, the binding energy of unknown
      inhibitors. IU-nucleoside hydrolase from Crithidia fasciculata and the inhibitor
      molecules described previously [Miles, R. W. Tyler, P. C. Evans, G. Furneaux R.
      H., Parkin, D. W., and Schramm, V. L. (1999) Biochemistry 38, xxxx-xxxx] are used
      as the test system. Discrete points on the molecular electrostatic potential
      surface of inhibitor molecules are input to neural networks to identify the
      quantum mechanical features that contribute to binding. Feed-forward neural
      networks with back-propagation of error are trained to recognize the quantum
      mechanical electrostatic potential and geometry at the entire van der Waals
      surface of a group of training molecules and to predict the strength of
      interactions between the enzyme and novel inhibitors. The binding energies of
      unknown inhibitors were predicted, followed by experimental determination of
      K(i)() values. Predictions of K(i)() values using this theory are compared to
      other methods and are more robust in estimating inhibitory strength. The average
      deviation in estimating K(i)() values for 18 unknown inhibitor molecules, with 21
      training molecules, is a factor of 5 x K(i)() over a range of 660 000 in K(i)()
      values for all molecules. The a posteriori accuracy of the predictions suggests
      the method will be effective as a guide for experimental inhibitor design.

PMID- 10587429
TI  - Sequence and structural selectivity of nucleic acid binding ligands.
AB  - The sequence and structural selectivity of 15 different DNA binding agents was
      explored using a novel, thermodynamically rigorous, competition dialysis
      procedure. In the competition dialysis method, 13 different nucleic acid
      structures were dialyzed against a common ligand solution. More ligand
      accumulated in the dialysis tube containing the structural form with the highest
      ligand binding affinity. DNA structural forms included in the assay ranged from
      single-stranded forms, through a variety of duplex forms, to multistranded
      triplex and tetraplex forms. Left-handed Z-DNA, RNA, and a DNA-RNA hybrid were
      also represented. Standard intercalators (ethidium, daunorubicin, and actinomycin
      D) served as control compounds and were found to show structural binding
      preferences fully consistent with their previously published behavior. Standard
      groove binding agents (DAPI, distamycin, and netropsin) showed a strong
      preference for AT-rich duplex DNA forms, along with apparently strong binding to
      the poly(dA)-[poly(dT)](2) triplex. Thermal denaturation studies revealed the
      apparent triplex binding to be complex, and perhaps to result from displacement
      of the third strand. Putative triplex (BePI, coralyne, and berberine) and
      tetraplex [H(2)TmPyP, 5,10,15, 20-tetrakis[4-(trimethylammonio)phenyl]-21H,23H
      porphine, and N-methyl mesoporphyrin IX] selective agents showed in many cases
      less dramatic binding selectivity than anticipated from published reports that
      compared their binding to only a few structural forms. Coralyne was found to bind
      strongly to single-stranded poly(dA), a novel and previously unreported
      interaction. Finally, three compounds (berenil, chromomycin A, and
      pyrenemethylamine) whose structural preferences are largely unknown were
      examined. Pyrenemethylamine exhibited an unexpected and unprecedented preference
      for duplex poly(dAdT).

PMID- 10587431
TI  - Dimers generated from tetrameric phosphorylating glyceraldehyde-3-phosphate
      dehydrogenase from Bacillus stearothermophilus are inactive but exhibit
      cooperativity in NAD binding.
AB  - Tetrameric phosphorylating glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from
      Bacillus stearothermophilus has been described as a "dimer of dimers" with three
      nonequivalent interfaces, P-axis (between subunits O and P and between subunits Q
      and R), Q-axis (between subunits O and Q and between subunits P and R), and R
      axis interface (between subunits O and R and between subunits P and Q). O-P
      dimers, the most stable and the easiest to generate, have been created by
      selective disruption of hydrogen bonds across the R- and Q-axis interfaces by
      site-directed mutagenesis. Asp-186 and Ser-48, and Glu-276 and Tyr-46, which are
      hydrogen bond partners across the R- and Q-axis interfaces, respectively, have
      been replaced with glycine residues. All mutated residues are highly conserved
      among GAPDHs from different species and are located in loops. Both double mutants
      D186G/E276G and Y46G/S48G were dimeric, while all single mutants remained
      tetrameric. As previously described [Clermont, S., Corbier, C., Mely, Y., Gerard,
      D., Wonacott, A., and Branlant, G. (1993) Biochemistry 32, 10178-10184], NAD
      binding to wild type GAPDH (wtGAPDH) was interpreted according to the induced-fit
      model and exhibited negative cooperativity. However, NAD binding to wtGAPDH can
      be adequately described in terms of two independent dimers with two interacting
      binding sites in each dimer. Single mutants D186G, E276G, and Y46G exhibited
      behavior in NAD binding similar to that of the wild type, while both dimeric
      mutants D186G/E276G and Y46G/S48G exhibited positive cooperativity in binding the
      coenzyme NAD. The fact that O-P dimer mutants retained cooperative behavior shows
      that (1) the P-axis interface is important in transmitting the information
      induced upon NAD binding inside the O-P dimer from one subunit to the other and
      (2) the S-loop of the R-axis-related subunit is not directly involved in
      cooperative binding of NAD in the O-P dimer. In both O-P dimer mutants, the
      absorption band of the binary enzyme-NAD complex had a highly decreased intensity
      compared to that of the wild type and, in addition, totally disappeared in the
      presence of G3P or 1,3-dPG. However, no enzymatic activity was detected,
      indicating that the formed ternary enzyme-NAD-G3P or -1, 3-dPG complex was not
      catalytically efficient. In the O-P dimers, the interaction with the S-loop of
      the R-axis-related subunit is disrupted, and therefore, the S-loop should be less
      structured. This resulted in increased accessibility of the active site to the
      solvent, particularly for the adenosine-binding site of NAD. Thus, together, this
      is likely to explain both the lowered affinity of the dimeric enzyme for NAD and
      the absence of activity.

PMID- 10587432
TI  - Protein-carbohydrate interactions defining substrate specificity in Bacillus 1,3
      1,4-beta-D-glucan 4-glucanohydrolases as dissected by mutational analysis.
AB  - The carbohydrate-binding site of Bacillus macerans 1,3-1, 4-beta-D-glucan 4
      glucanohydrolase has been analyzed through a mutational analysis to probe the
      role of protein-carbohydrate interactions defining substrate specificity. Amino
      acid residues involved in substrate binding were proposed on the basis of a
      modeled enzyme-substrate complex [Hahn, M., Keitel, T., and Heinemann, U. (1995)
      Eur. J. Biochem. 232, 849-859]. The effects of the mutations at 15 selected
      residues on catalysis and binding were determined by steady-state kinetics using
      a series of chromogenic substrates of different degree of polymerization to
      assign the individual H-bond and hydrophobic contributions to individual subsites
      in the binding site cleft. The glucopyranose rings at subsites -III and -II are
      tightly bound by a number of H-bond interactions to Glu61, Asn24, Tyr92, and
      Asn180. From k(cat)/K(M) values, single H-bonds account for 1.8-2.2 kcal mol(
      )(1) transition-state (TS) stabilization, and a charged H-bond contributes up to
      3.5 kcal mol(-)(1). Glu61 forms a bidentated H-bond in subsites -III and -II, and
      provides up to 6.5 kcal mol(-)(1) TS stabilization. With a disaccharide substrate
      that fills subsites -I and -II, activation kinetics were observed for the wild
      type and mutant enzymes except for mutations on Glu61, pointing to an important
      role of the bidentate interaction of Glu61 in two subsites. Whereas removal of
      the hydroxyl group of Tyr121, initially proposed to hydrogen-bond with the 2OH of
      Glcp-I, has essentially no effect (Y121F mutant), side-chain removal (Y121A
      mutant) gave a 100-fold reduction in k(cat)/K(M) and a 10-fold lower K(I) value
      with a competitive inhibitor. In subsite -IV, only a stacking interaction with
      Tyr22 (0.7 kcal mol(-)(1) TS stabilization) is observed.

PMID- 10587433
TI  - Haloalkane dehalogenases: structure of a Rhodococcus enzyme.
AB  - The hydrolytic haloalkane dehalogenases are promising bioremediation and
      biocatalytic agents. Two general classes of dehalogenases have been reported from
      Xanthobacter and Rhodococcus. While these enzymes share 30% amino acid sequence
      identity, they have significantly different substrate specificities and halide
      binding properties. We report the 1.5 A resolution crystal structure of the
      Rhodococcus dehalogenase at pH 5.5, pH 7.0, and pH 5.5 in the presence of NaI.
      The Rhodococcus and Xanthobacter enzymes have significant structural homology in
      the alpha/beta hydrolase core, but differ considerably in the cap domain.
      Consistent with its broad specificity for primary, secondary, and cyclic
      haloalkanes, the Rhodococcus enzyme has a substantially larger active site
      cavity. Significantly, the Rhodococcus dehalogenase has a different catalytic
      triad topology than the Xanthobacter enzyme. In the Xanthobacter dehalogenase,
      the third carboxylate functionality in the triad is provided by D260, which is
      positioned on the loop between beta7 and the penultimate helix. The carboxylate
      functionality in the Rhodococcus catalytic triad is donated from E141. A model of
      the enzyme cocrystallized with sodium iodide shows two iodide binding sites; one
      that defines the normal substrate and product-binding site and a second within
      the active site region. In the substrate and product complexes, the halogen binds
      to the Xanthobacter enzyme via hydrogen bonds with the N(eta)H of both W125 and
      W175. The Rhodococcusenzyme does not have a tryptophan analogous to W175.
      Instead, bound halide is stabilized with hydrogen bonds to the N(eta)H of W118
      and to N(delta)H of N52. It appears that when cocrystallized with NaI the
      Rhodococcus enzyme has a rare stable S-I covalent bond to S(gamma) of C187.

PMID- 10587434
TI  - Structural correlates for enhanced stability in the E2 DNA-binding domain from
      bovine papillomavirus.
AB  - Papillomaviral E2 proteins participate in viral DNA replication and
      transcriptional regulation. We have solved the solution structure of the DNA
      binding domain of the E2 protein from bovine papillomavirus (BPV-1). The
      structure calculation used 2222 distance and 158 dihedral angle restraints for
      the homodimer (202 residues in total), which were derived from homonuclear and
      heteronuclear multidimensional nuclear magnetic resonance (NMR) spectroscopic
      data. The root-mean-square deviation for structured regions of the monomer when
      superimposed to the average is 0.73 +/- 0.10 A for backbone atoms and 1.42 +/-
      0.16 A for heavy atoms. The 101 residue construct used in this study (residues
      310-410) is about 4.5 kcal/mol more stable than a minimal domain comprising the C
      terminal 85 amino acid residues (residues 326-410). The structure of the core
      domain contained within BPV-1 E2 is similar to the corresponding regions of other
      papilloma viral E2 proteins. Here, however, the extra N-terminal 16 residues form
      a flap that covers a cavity at the dimer interface and play a role in DNA
      binding. Interactions between residues in the N-terminal extension and the core
      domain correlate with the greater stability of the longer form of the protein
      relative to the minimal domain.

PMID- 10587435
TI  - The three-dimensional structures of nicotinate mononucleotide:5,6-
      dimethylbenzimidazole phosphoribosyltransferase (CobT) from Salmonella
      typhimurium complexed with 5,6-dimethybenzimidazole and its reaction products
      determined to 1.9 A resolution.
AB  - Nicotinate mononucleotide:5,6-dimethylbenzimidazole phosphoribosyltransferase
      (CobT) from Salmonella typhimurium plays a central role in the synthesis of alpha
      ribazole, which is a key component of the lower ligand of cobalamin. Two X-ray
      structures of CobT are reported here at 1.9 A resolution. First, a complex of
      CobT with 5,6-dimethylbenzimidazole, and second, a complex of CobT with its
      reaction products, nicotinate and alpha-ribazole-5'-phosphate. CobT was
      cocrystallized with 5,6-dimethylbenzimidazole (DMB) in the space group P2(1)2(1)2
      with unit cell dimensions of a = 72.1 A, b = 90.2 A, and c = 47.5 A and one
      protomer per asymmetric unit. Subsequently, the crystals containing DMB were
      soaked in nicotinate mononucleotide whereupon the physiological reaction occurred
      in the crystal lattice to yield nicotinate and alpha-ribazole-5'-phosphate. These
      studies show that CobT is a dimer where each subunit consists of two domains. The
      large domain is dominated by a parallel six-stranded beta-sheet with connecting
      alpha-helices that exhibit the topology of a Rossmann fold. The small domain is
      made from components of the N- and C-terminal sections of the polypeptide chain
      and contains a three-helix bundle. The fold of CobT is unrelated to the type I
      and II phosphoribosylpyrophosphate dependent transferases and does not appear to
      be related to any other protein whose structure is known. The enzyme active site
      is located in a large cavity formed by the loops at the C-terminal ends of the
      beta-strands and the small domain of the neighboring subunit. DMB binds in a
      hydrophobic pocket created in part by the neighboring small domain. This is
      consistent with the broad specificity of this enzyme for aromatic substrates
      [Trzebiatowski, J. R., Escalante-Semerena (1997) J. Biol. Chem. 272, 17662
      17667]. The binding site for DMB suggests that Glu317 is the catalytic base
      required for the reaction. The remainder of the cavity binds the nicotinate and
      ribose-5'-phosphate moieties, which are nestled within the loops at the ends of
      the beta-strands. Interestingly, the orientation of the substrate and products
      are opposite from that expected for a Rossmann fold.

PMID- 10587436
TI  - Folding, stability, and physical properties of the alpha subunit of bacterial
      luciferase.
AB  - Bacterial luciferase is a heterodimeric (alphabeta) enzyme composed of homologous
      subunits. When the Vibrio harveyi luxA gene is expressed in Escherichia coli, the
      alpha subunit accumulates to high levels. The alpha subunit has a well-defined
      near-UV circular dichroism spectrum and a higher intrinsic fluorescence than the
      heterodimer, demonstrating fluorescence quenching in the enzyme which is reduced
      in the free subunit [Sinclair, J. F., Waddle, J. J., Waddill, W. F., and Baldwin,
      T. O. (1993) Biochemistry 32, 5036-5044]. Analytical ultracentrifugation of the
      alpha subunit has revealed a reversible monomer to dimer equilibrium with a
      dissociation constant of 14.9 +/- 4.0 microM at 18 degrees C in 50 mM phosphate
      and 100 mM NaCl, pH 7.0. The alpha subunit unfolded and refolded reversibly in
      urea-containing buffers by a three-state mechanism. The first transition occurred
      over the range of 0-2 M urea with an associated free-energy change of 2.24 +/-
      0.25 kcal/mol at 18 degrees C in 50 mM phosphate buffer, pH 7.0. The second,
      occurring between 2.5 and 3.5 M urea, comprised a cooperative transition with a
      free-energy change of 6.50 +/- 0.75 kcal/mol. The intermediate species, populated
      maximally at ca. 2 M urea, has defined near-UV circular dichroism spectral
      properties distinct from either the native or the denatured states. The intrinsic
      fluorescence of the intermediate suggested that, although the quantum yield had
      decreased, the tryptophanyl residues remained largely buried. The far-UV circular
      dichroism spectrum of the intermediate indicated that it had lost ca. 40% of its
      native secondary structure. N-Terminal sequencing of the products of limited
      proteolysis of the intermediate showed that the C-terminal region of the alpha
      subunit became protease labile over the urea concentration range at which the
      intermediate was maximally populated. These observations have led us to propose
      an unfolding model in which the first transition is the unfolding of a C-terminal
      subdomain and the second transition represents the unfolding of a more stable N
      terminal subdomain. Comparison of the structural properties of the unfolding
      intermediate using spectroscopic probes and limited proteolysis of the alpha
      subunit with those of the alphabeta heterodimer suggested that the unfolding
      pathway of the alpha subunit is the same, whether it is in the form of the free
      subunit or in the heterodimer.

PMID- 10587437
TI  - Three-dimensional structure of Escherichia coli asparagine synthetase B: a short
      journey from substrate to product.
AB  - Asparagine synthetase B catalyzes the assembly of asparagine from aspartate,
      Mg(2+)ATP, and glutamine. Here, we describe the three-dimensional structure of
      the enzyme from Escherichia colidetermined and refined to 2.0 A resolution.
      Protein employed for this study was that of a site-directed mutant protein,
      Cys1Ala. Large crystals were grown in the presence of both glutamine and AMP.
      Each subunit of the dimeric protein folds into two distinct domains. The N
      terminal region contains two layers of antiparallel beta-sheet with each layer
      containing six strands. Wedged between these layers of sheet is the active site
      responsible for the hydrolysis of glutamine. Key side chains employed for
      positioning the glutamine substrate within the binding pocket include Arg 49, Asn
      74, Glu 76, and Asp 98. The C-terminal domain, responsible for the binding of
      both Mg(2+)ATP and aspartate, is dominated by a five-stranded parallel beta-sheet
      flanked on either side by alpha-helices. The AMP moiety is anchored to the
      protein via hydrogen bonds with O(gamma) of Ser 346 and the backbone carbonyl and
      amide groups of Val 272, Leu 232, and Gly 347. As observed for other
      amidotransferases, the two active sites are connected by a tunnel lined primarily
      with backbone atoms and hydrophobic and nonpolar amino acid residues. Strikingly,
      the three-dimensional architecture of the N-terminal domain of asparagine
      synthetase B is similar to that observed for glutamine
      phosphoribosylpyrophosphate amidotransferase while the molecular motif of the C
      domain is reminiscent to that observed for GMP synthetase.

PMID- 10587438
TI  - The small subunit of carbamoyl phosphate synthetase: snapshots along the reaction
      pathway.
AB  - Carbamoyl phosphate synthetase (CPS) plays a key role in both arginine and
      pyrimidine biosynthesis by catalyzing the production of carbamoyl phosphate. The
      enzyme from Escherichi coli consists of two polypeptide chains referred to as the
      small and large subunits. On the basis of both amino acid sequence analyses and X
      ray structural studies, it is known that the small subunit belongs to the Triad
      or Type I class of amidotransferases, all of which contain a cysteine-histidine
      (Cys269 and His353) couple required for activity. The hydrolysis of glutamine by
      the small subunit has been proposed to occur via two tetrahedral intermediates
      and a glutamyl-thioester moiety. Here, we describe the three-dimensional
      structures of the C269S/glutamine and CPS/glutamate gamma-semialdehyde complexes,
      which serve as mimics for the Michaelis complex and the tetrahedral
      intermediates, respectively. In conjunction with the previously solved glutamyl
      thioester intermediate complex, the stereochemical course of glutamine hydrolysis
      in CPS has been outlined. Specifically, attack by the thiolate of Cys269 occurs
      at the Si face of the carboxamide group of the glutamine substrate leading to a
      tetrahedral intermediate with an S-configuration. Both the backbone amide groups
      of Gly241 and Leu270, and O(gamma) of Ser47 play key roles in stabilizing the
      developing oxyanion. Collapse of the tetrahedral intermediate leads to formation
      of the glutamyl-thioester intermediate, which is subsequently attacked at the Si
      face by an activated water molecule positioned near His353. The results described
      here serve as a paradigm for other members of the Triad class of
      amidotranferases.

PMID- 10587439
TI  - Identification of surface residues of the monocyte chemotactic protein 1 that
      affect signaling through the receptor CCR2.
AB  - The CC chemokine, monocyte chemotactic protein, 1 (MCP-1) functions as a major
      chemoattractant for T-cells and monocytes by interacting with the seven
      transmembrane G protein-coupled receptor CCR2. To identify which residues of MCP
      1 contribute to signaling though CCR2, we mutated all the surface-exposed
      residues to alanine and other amino acids and made some selective large changes
      at the amino terminus. We then characterized the impact of these mutations on
      three postreceptor pathways involving inhibition of cAMP synthesis, stimulation
      of cytosolic calcium influx, and chemotaxis. The results highlight several
      important features of the signaling process and the correlation between binding
      and signaling: The amino terminus of MCP-1 is essential as truncation of residues
      2-8 ([1+9-76]hMCP-1) results in a protein that cannot stimulate chemotaxis.
      However, the exact peptide sequence may be unimportant as individual alanine
      mutations or simultaneous replacement of residues 3-6 with alanine had little
      effect. Y13 is also important and must be a large nonpolar residue for chemotaxis
      to occur. Interestingly, both Y13 and [1+9-76]hMCP-1 are high-affinity binders
      and thus affinity of these mutants is not correlated with ability to promote
      chemotaxis. For the other surface residues there is a strong correlation between
      binding affinity and agonist potency in all three signaling pathways. Perhaps the
      most interesting observation is that although Y13A and [1+9-76]hMCP are
      antagonists of chemotaxis, they are agonists of pathways involving inhibition of
      cAMP synthesis and, in the case of Y13A, calcium influx. These results
      demonstrate that these two well-known signaling events are not sufficient to
      drive chemotaxis. Furthermore, it suggests that specific molecular features of
      MCP-1 induce different conformations in CCR2 that are coupled to separate
      postreceptor pathways. Therefore, by judicious design of antagonists, it should
      be possible to trap CCR2 in conformational states that are unable to stimulate
      all of the pathways required for chemotaxis.

PMID- 10587440
TI  - Chemical mechanism of DNA cleavage by the homing endonuclease I-PpoI.
AB  - Homing endonucleases are distinguished by their ability to catalyze the cleavage
      of double-stranded DNA with extremely high specificity. I-PpoI endonuclease, a
      homing endonuclease from the slime mold Physarum polycephalum, is a small enzyme
      (2 x 20 kDa) of known three-dimensional structure that catalyzes the cleavage of
      a long target DNA sequence (15 base pairs). Here, a detailed chemical mechanism
      for catalysis of DNA cleavage by I-PpoI endonuclease is proposed and tested by
      creating six variants in which active-site residues are replaced with alanine.
      The side chains of three residues (Arg61, His98, and Asn119) are found to be
      important for efficient catalysis of DNA cleavage. This finding is consistent
      with the proposed mechanism in which His98 abstracts a proton from an attacking
      water molecule bound by an adjacent phosphoryl oxygen, Arg61 and Asn119 stabilize
      the pentavalent transition state, and Asn119 also binds to the essential divalent
      metal cation (e.g., Mg(2+) ion), which interacts with the 3'-oxygen leaving
      group. Because Mg(2+) is required for cleavage of a substrate with a good leaving
      group (p-nitrophenolate), Mg(2+) likely stabilizes the pentavalent transition
      state. The pH-dependence of k(cat) for catalysis by I-PpoI reveals a macroscopic
      pK(a) of 8.4 for titratable groups that modulate product release. I-PpoI appears
      to be unique among known restriction endonucleases and homing endonucleases in
      its use of a histidine residue to activate the attacking water molecule for in
      line displacement of the 3'-leaving group.

PMID- 10587441
TI  - An asparagine-phenylalanine substitution accounts for catalytic differences
      between hGSTM3-3 and other human class mu glutathione S-transferases.
AB  - The hGSTM3 subunit, which is preferentially expressed in germ-line cells, has the
      greatest sequence divergence among the human mu class glutathione S-transferases.
      To determine a structural basis for the catalytic differences between hGSTM3-3
      and other mu class enzymes, chimeric proteins were designed by modular
      interchange of the divergent C-terminal domains of hGSTM3 and hGSTM5 subunits.
      Replacement of 24 residues of the C-terminal segment of either subunit produced
      chimeric enzymes with catalytic properties that reflected those of the wild-type
      enzyme from which the C-terminus had been derived. Deletion of the tripeptide C
      terminal extension found only in the hGSTM3 subunit had no effect on catalysis.
      The crystal structure determined for a ligand-free hGSTM3 subunit indicates that
      an Asn212 residue of the C-terminal domain is near a hydrophobic cluster of side
      chains formed in part by Ile13, Leu16, Leu114, Ile115, Tyr119, Ile211, and
      Trp218. Accordingly, a series of point mutations were introduced into the hGSTM3
      subunit, and it was indeed determined that a Y119F mutation considerably enhanced
      the turnover rate of the enzyme for nucleophilic aromatic substitution reactions.
      A more striking effect was observed for a double mutant (Y119F/N212F) which had a
      k(cat)/K(m)(CDNB) value of 7.6 x 10(5) s(-)(1) M(-)(1) as compared to 4.9 x 10(3)
      s(-)(1) M(-)(1) for the wild-type hGSTM3-3 enzyme. The presence of a polar Asn212
      in place of a Phe residue found in the cognate position of other mu class
      glutathione S-transferases, therefore, has a marked influence on catalysis by
      hGSTM3-3.

PMID- 10587442
TI  - Metabolic effects of mislocalized mitochondrial and peroxisomal citrate synthases
      in yeast Saccharomyces cerevisiae.
AB  - Genes CIT1 and CIT2 from Saccharomyces cerevisiae encode mitochondrial and
      peroxisomal citrate synthases involved in the Krebs tricarboxylic acid (TCA)
      cycle and glyoxylate pathway, respectively. A Deltacit1 mutant does not grow on
      acetate, despite the presence of Cit2p that could, in principle, bypass the
      resulting block in the TCA cycle. To elucidate this absence of cross
      complementation, we have examined the ability of Cit1p to function in the
      cytosol, and that of Cit2p to function in mitochondria. A cytosolically localized
      form of Cit1p was also incompetent for restoration of growth of a Deltacit1
      strain on acetate, suggesting that mitochondrial localization of Cit1p is
      essential for its function in the TCA cycle. Cit2p was able, when mislocalized in
      mitochondria, to restore a wild-type phenotype in a strain lacking Cit1p. We have
      purified these two isoenzymes as well as mitochondrial malate dehydrogenase,
      Mdh1p, and have shown that Cit2p was also able to mimic Cit1p in its in vitro
      interaction with Mdh1p. Models of Cit1p and Cit2p structures generated on the
      basis of that of pig citrate synthase indicate very high structural and
      electrostatic surface potential similarities between the two yeast isozymes.
      Altogether, these data indicate that metabolic functions may require structural
      as well as catalytic roles for the enzymes.

PMID- 10587443
TI  - Exchange of pigment-binding amino acids in light-harvesting chlorophyll a/b
      protein.
AB  - Four amino acids in the major light-harvesting chlorophyll (Chl) a/b complex
      (LHCII) that are thought to coordinate Chl molecules have been exchanged with
      amino acids that presumably cannot bind Chl. Amino acids H68, Q131, Q197, and
      H212 are positioned in helixes B, C, A, and D, respectively, and, according to
      the LHCII crystal structure [Kuhlbrandt, W., et al. (1994) Nature 367, 614-621],
      coordinate the Chl molecules named a(5), b(6), a(3), and b(3). Moreover, a double
      mutant was analyzed carrying exchanges at positions E65 and H68, presumably
      affecting Chls a(4) and a(5). All mutant proteins could be reconstituted in vitro
      with pigments, although the thermal stability of the resulting mutant versions of
      recombinant LHCII varied significantly. All complexes reconstituted with the
      mutant proteins contained fewer chlorophyll molecules per two lutein molecules
      than complexes reconstituted with the wild-type protein. However, the chlorophyll
      binding amino acids could not be unambiguously assigned to binding either
      chlorophyll a or b, as in most cases more than one chlorophyll molecule was lost
      due to the mutation. The changes in Chl stoichiometries suggest that in LHCII
      some chlorophyll positions can be filled with either Chl a or b. Only some of the
      point mutations in LHCII affected the ability of the apoprotein to assemble into
      trimeric LHCII upon insertion into isolated thylakoid membranes. Among these were
      exchanges of H68 with either F or L, suggesting that the stability of the LHCII
      trimer significantly depends on this amino acid or the Chl molecule named a(5)
      that is attached to it and is located close to the center of the trimeric
      complex. The ion pair bridge between E65 and R185 in LHCII does not appear to be
      essential for the proper folding of the protein.

PMID- 10587444
TI  - Mutant trimers of light-harvesting complex II exhibit altered pigment content and
      spectroscopic features.
AB  - Mutants of plant light-harvesting complex II (LHC-II) were produced by refolding
      the complex in vitro from bacterially expressed apoprotein and purified pigments
      by a method which yields native-like LHC-II in a single step. Amino acid residues
      known from the structure of the complex [Kuhlbrandt, W., et al. (1994) Nature
      367, 614-621] to bind chlorophyll (Chl) were replaced with nonbinding residues by
      site-directed mutagenesis. Recombinant monomeric and trimeric pigment-protein
      complexes were separated by density gradient centrifugation, and their pigment
      composition was determined. Six out of nine mutants formed trimers with Chl a:Chl
      b ratios and Chl contents which suggested they were lacking one Chl a or b per
      polypeptide. In this way, the identities of Chls a1, a2, a3, b5, and b6 were
      confirmed as Chl a or b, respectively, whereas Chl b3 in the structure was found
      to be a Chl a. Absorption and fluorescence emission spectra of the mutant lacking
      Chl a2 indicated a central role for this Chl in energy transfer to the reaction
      center.

PMID- 10587445
TI  - Redox and spectral properties of cytochrome b559 in different preparations of
      photosystem II.
AB  - A detailed analysis of the properties of cytochrome b(559) (Cyt b(559)) in
      photosystem II (PS II) preparations with different degrees of structural
      complexity is presented. It reveals that (i) D1-D2-Cyt b(559) complexes either in
      solubilized form or incorporated into liposomes contain only one type of Cyt
      b(559) with E(m) values of 60 +/- 5 and 100 +/- 10 mV, respectively, at pH 6.8;
      (ii) in oxygen-evolving solubilized PS II core complexes Cyt b(559) exists
      predominantly (>85%) as an LP form with an E(m,7) of 125 +/- 10 mV and a minor
      fraction with an E(m,7) of -150 +/- 15 mV; (iii) in oxygen-evolving PS II
      membrane fragments three different redox forms are discernible with E(m) values
      of 390 +/- 15 mV (HP form), 230 +/- 20 mV (IP form), and 105 +/- 25 mV (LP form)
      and relative amplitudes of 58, 24, and 18%, respectively, at pH 7.3; (iv) the
      E(m) values are almost pH-independent between pH 6 and 9.5 in all sample types
      except D1-D2-Cyt b(559) complexes incorporated into liposomes with a slope of -29
      mV/pH unit, when the pH increases from 6 to 9.5 (IP and LP form in PS II membrane
      fragments possibly within a restricted range from pH 6.5 to 8); (v) at pH >8 the
      HP Cyt b(559) progressively converts to the IP form with increasing pH; (vi) the
      reduced-minus-oxidized optical difference spectra of Cyt b(559) are very similar
      in the lambda range of 360-700 nm for all types except for the HP form which
      exhibits pronounced differences in the Soret band; and (vii) PS II membrane
      fragments and core complexes are inferred to contain about two Cyt b(559) hemes
      per PS II. Possible implications of conformational changes near the heme group
      and spin state transitions of the iron are discussed.

PMID- 10587447
TI  - Sequencing and preliminary characterization of the Na+-translocating
      NADH:ubiquinone oxidoreductase from Vibrio harveyi.
AB  - The Na(+)-translocating NADH: ubiquinone oxidoreductase (Na(+)-NQR) generates an
      electrochemical Na(+) potential driven by aerobic respiration. Previous studies
      on the enzyme from Vibrio alginolyticus have shown that the Na(+)-NQR has six
      subunits, and it is known to contain FAD and an FeS center as redox cofactors. In
      the current work, the enzyme from the marine bacterium Vibrio harveyi has been
      purified and characterized. In addition to FAD, a second flavin, tentatively
      identified as FMN, was discovered to be covalently attached to the NqrC subunit.
      The purified V. harveyi Na(+)-NQR was reconstituted into proteoliposomes. The
      generation of a transmembrane electric potential by the enzyme upon NADH:Q(1)
      oxidoreduction was strictly dependent on Na(+), resistant to the protonophore
      CCCP, and sensitive to the sodium ionophore ETH-157, showing that the enzyme
      operates as a primary electrogenic sodium pump. Interior alkalinization of the
      inside-out proteoliposomes due to the operation of the Na(+)-NQR was accelerated
      by CCCP, inhibited by valinomycin, and completely arrested by ETH-157. Hence, the
      protons required for ubiquinol formation must be taken up from the outside of the
      liposomes, which corresponds to the bacterial cytoplasm. The Na(+)-NQR operon
      from this bacterium was sequenced, and the sequence shows strong homology to the
      previously reported Na(+)-NQR operons from V. alginolyticus and Haemophilus
      influenzae. Homology studies show that a number of other bacteria, including a
      number of pathogenic species, also have an Na(+)-NQR operon.

PMID- 10587446
TI  - Suicide inactivation of cytochrome c oxidase: catalytic turnover in the absence
      of subunit III alters the active site.
AB  - The catalytic core of cytochrome c oxidase is composed of three subunits: I, II,
      and III. Subunit III is a highly hydrophobic membrane protein that contains no
      redox centers; its role in cytochrome oxidase function is not obvious. Here,
      subunit III has been removed from the three-subunit mitochondrial-like oxidase of
      Rhodobacter sphaeroides by detergent washing. The resulting two-subunit oxidase,
      subunit III (-), is highly active. Ligand-binding analyses and resonance Raman
      spectroscopy show that its heme a(3)-Cu(B) active site is normal. However,
      subunit III (-) spontaneously and irreversibly inactivates during O(2) reduction.
      At pH 7.5, its catalytic lifetime is only 2% that of the normal oxidase. This
      suicide inactivation event primarily alters the active site. Its ability to form
      specific O(2) reduction intermediates is lost, and CO binding experiments suggest
      that the access of O(2) to reduced heme a(3) is inhibited. Reduced heme a
      accumulates in response to a decrease in the redox potential of heme a(3);
      electron transfer between the hemes is inhibited. Ligand-binding experiments and
      resonance Raman analysis show that increased flexibility in the structure of the
      active site accompanies inactivation. Cu(B) is partially lost. It is proposed
      that suicide inactivation results from the dissociation of a ligand of Cu(B) and
      that subunit III functions to prevent suicide inactivation by maintaining the
      structural integrity of the Cu(B) center via long-range interactions.

PMID- 10587448
TI  - Changes in secondary structure and salt links of cytochrome P-450cam induced by
      photoreduction: a Fourier transform infrared spectroscopic study.
AB  - Tris(2,2'-bipyridyl)ruthenium(II) was used as a light-induced artificial electron
      donor for the transfer of the first electron to cytochrome P-450(cam) bound with
      (1R)-camphor and camphane substrates, and in the substrate-free form. Fourier
      transform infrared spectroscopy was used to detect changes of the amide I' band
      and the CO ligand stretch vibration of heme-bound carbon monoxide associated with
      the heme redox transition. The reduced-minus-oxidized difference spectra show
      that not only the heme group but also the protein backbone and individual amino
      acid side chains were affected by the redox transition. Observed secondary
      structure changes were almost identical for (1R)-camphor-bound and camphane-bound
      cytochrome P-450(cam), with a remarkable negative signal at 1724.3 cm(-)(1) and a
      positive signal at 1716.0 cm(-)(1). These signals were not observed in substrate
      free P-450(cam). On the basis of known crystallographic data, we assign these
      signals to a change of hydrogen bonds of a salt link between Arg112, His355, and
      the heme 6-propionic group.

PMID- 10587449
TI  - Overexpression of the Escherichia coli nuo-operon and isolation of the
      overproduced NADH:ubiquinone oxidoreductase (complex I).
AB  - The proton-pumping NADH:ubiquinone oxidoreductase (complex I) of Escherichia coli
      is composed of 13 different subunits. The corresponding genes are organized in
      the nuo-operon (from NADH:ubiquinone oxidoreductase) at min 51 of the E. coli
      chromosome. To study the structure and function of this complex enzyme, a
      suitable purification protocol yielding sufficient amount of a stable protein is
      needed. Here, we report the overproduction of complex I in E. coli and a novel
      isolation procedure of the complex. Overexpression of the nuo-operon on the
      chromosome was achieved by replacing its 5'-promotor region with the phage-T7 RNA
      polymerase promotor and by expressing the genes with the T7 RNA polymerase coded
      on an inducible plasmid. It is shown by means of enzymatic activity and EPR
      spectroscopy of cytoplasmic membranes that complex I is overproduced 4-fold after
      induction. Complex I was isolated by chromatographic steps performed in the
      presence of dodecyl maltoside. The preparation comprises all subunits and known
      cofactors and exhibits a high enzymatic activity and inhibitor sensitivity. Due
      to its stability over a wide pH range and at very high salt concentrations, this
      preparation is well suited for structural investigations.

PMID- 10587450
TI  - The C-terminal region of human glutathione transferase A1-1 affects the rate of
      glutathione binding and the ionization of the active-site Tyr9.
AB  - In human glutathione transferase (GST) A1-1, the C-terminal region covers the
      active site and contributes to substrate binding. This region is flexible, but
      upon binding of an active-site ligand, it is stabilized as an amphipatic alpha
      helix. The stabilization has implications for the catalytic activity of the
      enzyme. In the present study, residue M208 in GST A1-1 has been mutated to Lys
      and Glu, and residue F220 to Ala and Thr. These mutations are likely to
      destabilize the C-terminal region due to loss of hydrophobic interactions with
      the rest of the hydrophobic binding site. The rate constant for binding of
      glutathione to wild-type GST A1-1 is 450 mM(-)(1) s(-)(1) at 5 degrees C and pH
      7.0, which is less than for an association limited by diffusion. However, the
      M208 and the F220 mutations increase the apparent on-rate constant for
      glutathione binding to 640-1170 mM(-)(1) s(-)(1). The binding data can be
      explained by a rapid reversible transition between different enzyme conformations
      occurring prior to glutathione binding, and restriction of the access to the
      active site by the C-terminal region. The effect of the mutations appears to be
      promotion of a less closed conformation, thereby facilitating the association of
      glutathione and enzyme. Both the M208 and F220 mutants display a lowered pK(a)
      value ( approximately 0.3 log unit) of the catalytically important Tyr9. Residue
      208 does not interact directly with Tyr9 in the active site, and the shift in
      pK(a) value is therefore ascribed to the proposed dislocation of the C-terminal
      region caused by the mutation.

PMID- 10587451
TI  - The chaperone-like properties of mammalian inhibitor-2 are conserved in a
      Drosophila homologue.
AB  - Phosphatase inhibitor-2 (I-2) is a mammalian phosphoprotein that binds to the
      catalytic subunit of type 1 serine/threonine phosphoprotein phosphatase (PP1c)
      and inhibits its activity in vitro. Recombinant PP1c differs from native PP1c in
      several biochemical criteria, including the requirement for Mn(2+), sensitivity
      to vanadate, and p-nitrophenyl phosphate (pNPP) phosphatase activity. I-2 can
      convert recombinant PP1c into a native-like activity in vitro. It has therefore
      been suggested that I-2 may act as a molecular chaperone for PP1 in vivo. We have
      identified a Drosophila homologue (I-2Dm) in a two-hybrid screen for PP1c-binding
      proteins. The sequence of I-2Dm is 35% identical with that of I-2, whereas the
      catalytic subunits themselves are >85% identical in flies and humans; however, we
      show that many biochemical properties of I-2 are conserved. Like I-2, I-2Dm can
      convert recombinant PP1c to a native-like activity. This strongly suggests that
      this ability is an essential, conserved role of I-2 and I-2Dm.

PMID- 10587452
TI  - Influence of steric bulk and electrostatics on the hydroxylation regiospecificity
      of tryptophan hydroxylase: characterization of methyltryptophans and
      azatryptophans as substrates.
AB  - Tryptophan hydroxylase is a pterin-dependent amino acid hydroxylase that
      catalyzes the incorporation of one atom of molecular oxygen into tryptophan to
      form 5-hydroxytryptophan. The substrate specificity and hydroxylation
      regiospecificity of tryptophan hydroxylase have been investigated using
      tryptophan analogues that have methyl substituents or nitrogens incorporated into
      the indole ring. The products of the reactions show that the regiospecificity of
      tryptophan hydroxylase is stringent. Hydroxylation does not occur at the 4 or 6
      carbon in response to changes in substrate topology or atomic charge. 5
      Hydroxymethyltryptophan and 5-hydroxy-4-methyltryptophan are the products from 5
      methyltryptophan. These products establish that the hydroxylating intermediate is
      sufficiently potent to hydroxylate benzylic carbons and that the direction of the
      NIH shift in tryptophan hydroxylase is from carbon 5 to carbon 4. The effects on
      the V/K values for the amino acids indicate that the enzyme is most sensitive to
      changes at position 5 of the indole ring. The V(max) values for amino acid
      hydroxylation differ at most by a factor of 3 from that observed for tryptophan,
      while the efficiencies of hydroxylation with respect to tetrahydropterin
      consumption vary 6-fold, consistent with oxygen transfer to the amino acid being
      partially or fully rate limiting in productive catalysis.

PMID- 10587453
TI  - Roles of aromatic residues in high interfacial activity of Naja naja atra
      phospholipase A2.
AB  - Acidic phospholipase A2 (PLA2) from the venom of Chinese cobra (Naja naja atra)
      has high activity on zwitterionic membranes and contains six aromatic residues,
      including Tyr-3, Trp-18, Trp-19, Trp-61, Phe-64, and Tyr-110, on its putative
      interfacial binding surface. To assess the roles of these aromatic residues in
      the interfacial catalysis of N. n. atra PLA2, we mutated them to Ala and measured
      the effects on its interfacial catalysis. Enzymatic activities of the mutants
      toward various vesicle substrates and human neutrophils indicate that all but Trp
      18 make significant contributions to interfacial catalysis. Among these aromatic
      residues, Trp-19, Trp-61, and Phe-64 play the most important roles. Binding
      affinities of the mutants for phospholipid-coated beads and their monolayer
      penetration indicate that Trp-19, Trp-61, and Phe-64 are critically involved in
      interfacial binding of N. n. atra PLA2 and penetrate into the membrane during the
      interfacial catalysis of N. n. atra PLA2. Further thermodynamic analysis suggests
      that the side chain of Phe-64 is fully inserted into the hydrophobic core of
      membrane whereas those of Trp-19 and Trp-61 are located in the membrane-water
      interface. Together, these results show that all three types of aromatic residues
      can play important roles in interfacial binding of PLA2 depending on their
      location and side-chain orientation. They also indicate that these aromatic side
      chains interact with membranes in distinct modes because of their different
      intrinsic preference for different parts of membranes.

PMID- 10587454
TI  - The purified and functionally reconstituted multidrug transporter LmrA of
      Lactococcus lactis mediates the transbilayer movement of specific fluorescent
      phospholipids.
AB  - Lactococcus lactis possesses an ATP-binding cassette transporter, LmrA, which is
      a homolog of the mammalian multidrug resistance (MDR) P-glycoprotein, and is able
      to transport a broad range of structurally unrelated amphiphilic drugs. A
      histidine tag was introduced at the N-terminus of LmrA to facilitate purification
      by nickel affinity chromatography. The histidine-tagged protein was overexpressed
      in L. lactis using a novel protein expression system for cytotoxic proteins based
      on the tightly regulated, nisin-inducible nisA promoter. This system allowed us
      to get functional overexpression of LmrA up to a level of 30% of total membrane
      protein. For reconstitution, LmrA was solubilized with dodecylmaltoside, purified
      by nickel-chelate affinity chromatography, and reconstituted in dodecylmaltoside
      destabilized, preformed liposomes prepared from L. lactis phospholipids. The
      detergent was removed by adsorption onto polystyrene beads. The LmrA protein was
      reconstituted in a functional form, and mediated the ATP-dependent transport of
      the fluorescent substrate Hoechst-33342 into the proteoliposomes. Interestingly,
      reconstituted LmrA also catalyzed the ATP-dependent transport of fluorescent
      phosphatidylethanolamine, but not of fluorescent phosphatidylcholine. These data
      demonstrate that LmrA activity is independent of accessory proteins and support
      the notion that LmrA may be involved in the transport of specific lipids or lipid
      linked precursors in L. lactis.

PMID- 10587455
TI  - Cell cholesterol efflux to reconstituted high-density lipoproteins containing the
      apolipoprotein A-IMilano dimer.
AB  - The apolipoprotein A-IMilano (apoA-IM) is a molecular variant of apoA-I
      characterized by the Arg(173)-->Cys substitution, resulting in the formation of
      homodimers A-IM/A-IM. The introduction of the interchain disulfide bridge in the
      A-IM dimer limits the apolipoprotein conformational flexibility and restricts HDL
      particle size heterogeneity, thus possibly affecting HDL function in lipid
      metabolism and atherosclerosis protection. To investigate whether the structural
      changes in A-IM/A-IM affect apoA-I capacity for cell cholesterol uptake, we
      tested the ability of four reconstituted HDL (rHDL), that contained either apoA-I
      or A-IM/A-IM, to remove cholesterol from Fu5AH hepatoma cells and cholesterol
      loaded murine primary macrophages (MPM). As the HDL particle size is known to
      affect the rHDL capacity for cell cholesterol uptake, the reconstitution
      conditions were carefully selected to produce two sets of rHDL particles of small
      and large size (7.8 and 12.5 nm in diameter). The small A-IM/A-IM rHDL were more
      efficient than the corresponding apoA-I particles as acceptors of membrane
      cholesterol from Fu5AH cells and MPM, and as inhibitors of cholesterol
      esterification in MPM. The large rHDL and the lipid-free apolipoproteins
      displayed instead similar capacities for cell cholesterol efflux. These results
      suggest that cell cholesterol efflux to rHDL particles of different size occurs
      through different mechanisms. Large HDL accommodate and retain the cholesterol
      molecules that have desorbed from the cell membrane into the extracellular fluid,
      in a process that is less sensitive to protein conformation. Small HDL accelerate
      the desorption of cholesterol from the cell membrane, in a process that is
      influenced by the conformation of the proteins on the surface of the acceptor
      particle. The enhanced efficiency of small A-IM/A-IM rHDL seems related to the
      peculiar structure of the protein on the rHDL surface, with a hydrophobic C
      terminal domain extending out of the rHDL particle, available for anchoring the
      acceptor to the plasma membrane.

PMID- 10587456
TI  - Apolipoprotein AI efficiently binds to and mediates cholesterol and phospholipid
      efflux from human but not rat aortic smooth muscle cells.
AB  - Aortic smooth muscle cells (SMC) from several animal species have been reported
      to resist depletion of cellular cholesterol by the major apolipoprotein of HDL,
      apoAI. Resistance of SMC to this protective action of apoAI, if present in
      humans, could contribute to the overaccumulation of arterial wall cholesterol
      seen in atherosclerosis. We investigated the ability of human aortic medial SMC
      to bind and be depleted of cholesterol and phospholipids by apoAI. In contrast to
      rat aortic SMC, but similar to human fibroblasts, human SMC were readily depleted
      of cholesterol by apoAI, measured by a marked depletion of intracellular
      cholesterol available for esterification, and an increase in cholesterol efflux
      to the medium. Human SMC were also actively depleted of the phospholipids
      phosphatidylcholine and sphingomyelin by apoAI. In contrast, rat SMC released
      only a small fraction of these cellular phospholipids to apoAI-containing medium.
      (125)I-labeled apoAI bound with high affinity and specificity to human SMC, but
      failed to bind to rat SMC. Similar levels of expression of class B, type I
      scavenger receptor (SR-BI) and caveolin in human and rat SMC suggested these
      proteins do not account for the differences in apoAI binding or lipid efflux seen
      in these cells. An enhancer of apolipoprotein-mediated cholesterol efflux,
      tyrosyl radical-oxidized HDL, markedly amplified the depletion of cholesterol
      available for esterification in human SMC compared to HDL, but had no enhanced
      effect in rat SMC. These results show that human SMC bind and are readily
      depleted of cellular lipids by apoAI, and suggest that apoAI-mediated cholesterol
      efflux from arterial SMC may contribute significantly to the circulating pool of
      HDL cholesterol in vivo. The marked difference in apoAI binding to human and rat
      arterial SMC provides an excellent model to study the nature of the apoAI-cell
      binding interaction.

PMID- 10587457
TI  - Evidence of intramolecular regulation of the Dictyostelium discoideum 34 000 Da F
      actin-bundling protein.
AB  - Intramolecular interaction within the Ca(2+)-regulated 34 kDa actin-bundling
      protein from Dictyostelium discoideum was found to contribute to the regulation
      of its actin-binding activity. Recombinant N-terminally truncated proteins aa77
      295, 124-295, and 139-295 bound actin at > or = 2:1 stoichiometry, which is 5
      fold greater than the intact protein aa1-295 as assessed by cosedimentation with
      F-actin. These proteins also have enhanced cross-linking activity as assessed by
      viscometry and electron microscopy. All truncated 34 kDa proteins failed to bind
      (45)Ca(2+) on blots and displayed Ca(2+)-insensitive binding with actin, although
      most proteins possessed intact putative EF-hand Ca(2+)-binding motifs. An
      intramolecular interaction within the 34 kDa protein was inferred from direct
      demonstrations of domain-domain interaction among the truncated 34 kDa proteins
      both in the presence and absence of actin. The intramolecular interaction between
      interaction zone 1 (aa71-123) and interaction zone 2 (aa193-254) is proposed to
      maintain the N-terminal inhibitory region (aa1-76) in close proximity with the
      strong actin-binding site (aa193-254) in order to modulate the interaction of the
      intact protein with actin filaments.

PMID- 10587458
TI  - Interactions between lipid-anchored and transmembrane proteins. Spin-label ESR
      studies on avidin-biotinyl phosphatidylethanolamine in membrane recombinants with
      myelin proteolipid proteins.
AB  - Interactions between lipid-anchored and transmembrane proteins are relevant to
      the intracellular membrane sorting of glycosyl phosphatidylinositol-linked
      proteins. We have studied the interaction of a spin-labeled biotinyl diacyl
      phospholipid, with and without specifically bound avidin, with the myelin
      proteolipid protein (or the DM-20 isoform) reconstituted in
      dimyristoylphosphatidylcholine. Tetrameric avidin bound to the N-biotinyl lipid
      headgroup is a surface-anchored protein, and the myelin proteolipid is an
      integral protein containing four transmembrane helices. The electron spin
      resonance (ESR) spectrum of N-biotinyl phosphatidylethanolamine spin-labeled at
      the C-14 position of the sn-2 chain consists of two components in fluid-phase
      membranes of dimyristoylphosphatidylcholine containing the proteolipid. In the
      absence of avidin, this is characteristic of lipid-protein interactions with
      integral transmembrane proteins. The more motionally restricted component
      represents the lipid population in direct contact with the intramembranous
      surface of the integral protein, and the more mobile component corresponds to the
      bulk fluid lipid environment of the bilayer. In the presence of avidin, the
      biotin-lipid chains have reduced mobility because of the binding to avidin, even
      in the absence of the proteolipid [Swamy, M. J., and Marsh, D. (1997)
      Biochemistry 36, 7403-7407]. In the presence of the proteolipid, the major
      fraction of the avidin-anchored chains is further restricted in its mobility by
      interaction with the transmembrane protein. At a biotin-lipid concentration of 1
      mol %, approximately 80% of the avidin-linked chains are restricted in membranes
      with a phosphatidylcholine:proteolipid molar ratio of 37:1. This relatively high
      stoichiometry of interaction can be explained when allowance is made for the
      closest interaction distance between the lipid-anchored avidin tetramer and the
      transmembrane proteolipid hexamer, without any specific interaction between the
      two types of membrane-associated proteins. The interaction is essentially one of
      steric exclusion, but the lipid chains are rendered more sensitive to interaction
      with the integral protein by being linked to avidin, even though they are removed
      from the immediate intramembrane protein-lipid interface. This could have
      implications for the tendency of lipid-anchored chains to associate with membrane
      domains with reduced lipid mobility.

PMID- 10587459
TI  - Transmembrane helix 5 is critical for the high water permeability of aquaporin.
AB  - Aquaporin-2 (AQP2), a vasopressin-regulated water channel, plays a major role in
      urinary concentration. AQP2 and the major intrinsic protein (MIP) of lens fiber
      are highly homologous (58% amino acid identity) and share a topology of six
      transmembrane helices connected by five loops (loops A-E). Despite the
      similarities of these proteins, however, the water channel activity of AQP2 is
      much higher than that of MIP. To determine the site responsible for this gain of
      activity in AQP2, several parts of MIP were replaced with the corresponding parts
      of AQP2. When expressed in Xenopus oocytes, the osmotic water permeability (P(f))
      of MIP and AQP2 was 48 and 245 x 10(-)(4) cm/s, respectively. Substitutions in
      loops B-D failed to increase P(f), whereas substitution of loop E significantly
      increased P(f) 1.5-fold. A similar increase in P(f) was observed with the
      substitution of the front half of loop E. P(f) measurements taken in a yeast
      vesicle expression system also confirmed that loop E had a complementary effect,
      whereas loops B-D did not. However, P(f) values of the loop E chimeras were only
      approximately 30% of that of AQP2. Simultaneous exchanges of loop E and a distal
      half of transmembrane helix 5 just proximal to loop E increased P(f) to the level
      of that of AQP2. Replacement of helix 5 alone stimulated P(f) 2.7-fold.
      Conversely, P(f) was decreased by 73% when helix 5 of AQP2 was replaced with that
      of MIP. Moreover, P(f) was stimulated 2.6- and 3.3-fold after helix 5 of AQP1 and
      AQP4 was spliced into MIP, respectively. Our findings suggested that the distal
      half of helix 5 is necessary for maximum water channel activity in AQP. We
      speculate that this portion contributes to the formation of the aqueous pore and
      the determination of the flux rate.

PMID- 10587460
TI  - Characterization of unique DNA-binding and transcriptional-activation functions
      in the carboxyl-terminal extension of the zinc finger region in the human vitamin
      D receptor.
AB  - The vitamin D receptor (VDR) binds 1,25-dihydroxyvitamin D(3) and mediates its
      actions on gene transcription by heterodimerizing with retinoid X receptors
      (RXRs) on direct repeat (DR+3) vitamin D responsive elements (VDREs) located in
      target genes. The VDRE binding function of VDR has been primarily ascribed to the
      zinc finger region (residues 24-87). To define the minimal VDRE binding domain
      for human VDR (hVDR), a series of C-terminally truncated hVDR mutants (Delta134,
      Delta113, Delta102, Delta90, Delta84, Delta80, and Delta60) was generated and
      expressed in bacteria. Only the Delta134 and Delta113 mutants bound the VDRE
      (predominantly as monomers), suggesting that, in addition to the conserved zinc
      finger region of hVDR, as many as 25 amino acids in a C-terminal extension (CTE)
      participate in DNA binding. Site-directed mutagenesis of conserved charged
      residues in full-length hVDR was then performed to dissect the functional
      significance of the CTE (residues 88-112) in the context of the complete hVDR-RXR
      VDRE interaction. Functional assays revealed that E98K/E99K, R102A/K103A/R104A,
      and K109A/R110A/K111A mutant hVDRs possessed dramatically reduced DNA binding and
      transcriptional activities, whereas distinct point mutants, such as K103A, bound
      to DNA normally but lacked transcriptional activity. Therefore, the boundary for
      the minimal DNA-binding domain in hVDR extends C-terminal of the zinc fingers to
      Lys-111, with clusters of highly conserved charged amino acids playing a crucial
      role in binding to the DR+3 element. Further, individual residues in this region
      (e.g., Lys-103) may lie on the opposing face of a DNA-binding alpha-helix, where
      they could contact transcriptional coactivators or basal transcription factors.

PMID- 10587461
TI  - Evidence for breaking domain-domain functional communication in a synthetase-tRNA
      complex.
AB  - We report here evidence for mutations that break domain-domain functional
      communication in a synthetase-tRNA complex. Each synthetase is roughly divided
      into two major domains that are paralleled by the two arms of the L-shaped tRNA
      structure. The active-site-containing domain interacts with the acceptor arm of
      the tRNA. The second domain frequently interacts with the anticodon-containing
      arm. By an induced-fit mechanism, contacts with the anticodon can activate
      formation of a robust transition state at a site over 70 A away. This induced-fit
      based activation is thought to occur through domain-domain signaling and is seen
      by the enhancement of aminoacylation of the anticodon-containing full tRNA versus
      a substrate based on the acceptor arm alone. Here we describe a rationally
      designed mutant methionyl-tRNA synthetase containing two point substitutions at
      sites that potentially link an anticodon-binding motif to the catalytic domain.
      The double mutation had no effect on interactions with either the isolated
      acceptor arm or the anticodon stem-loop. In contrast to interactions with the
      separate pieces, the mutant enzyme was severely impaired for binding the native
      tRNA and lost much of its ability to enhance the rate of charging of the full
      tRNA over that of a substrate based on the acceptor arm alone. We propose that
      these residues are part of a network for facilitating domain-domain communication
      for formation of an active synthetase-tRNA complex by induced fit.

PMID- 10587462
TI  - Purification and characterization of a tungsten-containing formate dehydrogenase
      from Desulfovibrio gigas.
AB  - An air-stable formate dehydrogenase (FDH), an enzyme that catalyzes the oxidation
      of formate to carbon dioxide, was purified from the sulfate reducing organism
      Desulfovibrio gigas (D. gigas) NCIB 9332. D. gigas FDH is a heterodimeric protein
      [alpha (92 kDa) and beta (29 kDa) subunits] and contains 7 +/- 1 Fe/protein and
      0.9 +/- 0.1 W/protein. Selenium was not detected. The UV/visible absorption
      spectrum of D. gigas FDH is typical of an iron-sulfur protein. Analysis of pterin
      nucleotides yielded a content of 1.3 +/- 0.1 guanine monophosphate/mol of enzyme,
      which suggests a tungsten coordination with two molybdopterin guanine
      dinucleotide cofactors. Both Mossbauer spectroscopy performed on D. gigas FDH
      grown in a medium enriched with (57)Fe and EPR studies performed in the native
      and fully reduced state of the protein confirmed the presence of two [4Fe-4S]
      clusters. Variable-temperature EPR studies showed the presence of two signals
      compatible with an atom in a d(1) configuration albeit with an unusual relaxation
      behavior as compared to the one generally observed for W(V) ions.

PMID- 10587463
TI  - Reconstitutive refolding of diacylglycerol kinase, an integral membrane protein.
AB  - While the formation of kinetically trapped misfolded structural states by
      membrane proteins is related to a number of diseases, relatively few studies of
      misfolded membrane proteins in their purified state have been carried out and few
      methods for refolding such proteins have been reported. In this paper, misfolding
      of the trimeric integral membrane protein diacylglycerol kinase (DAGK) is
      documented and a method for refolding the protein is presented; 65 single
      cysteine mutants of DAGK were examined. A majority were found to have lower-than
      expected activities when purified into micellar solutions, with additional losses
      in activity often being observed following membrane reconstitution. A variety of
      evidence indicates that the low activities observed for most of these mutants
      results from kinetically based misfolding of the protein, with misfolding often
      being manifested by the formation of aberrant oligomeric states. A method
      referred to as "reconstitutive refolding" for correcting misfolded DAGK is
      presented. This method is based upon reconstituting DAGK into multilamellar POPC
      vesicles by dialyzing the detergent dodecylphosphocholine out of mixed micellar
      mixtures. For 55 of the 65 mutants tested, there was a gain of DAGK activity
      during reconstitutive refolding. In 33 of these cases, the gain in activity was
      greater than 2-fold. The refolding results for cysteine replacement mutants at
      DAGK sites known to be highly conserved provide teleological insight into whether
      sites are conserved, because they are critical for catalysis, for maintenance of
      the proper folding pathway, or for some other reason.

PMID- 10587464
TI  - Determination of protein secondary structure and solvent accessibility using site
      directed fluorescence labeling. Studies of T4 lysozyme using the fluorescent
      probe monobromobimane.
AB  - We report an investigation of how much protein structural information could be
      obtained using a site-directed fluorescence labeling (SDFL) strategy. In our
      experiments, we used 21 consecutive single-cysteine substitution mutants in T4
      lysozyme (residues T115-K135), located in a helix-turn-helix motif. The mutants
      were labeled with the fluorescent probe monobromobimane and subjected to an array
      of fluorescence measurements. Thermal stability measurements show that
      introduction of the label is substantially perturbing only when it is located at
      buried residue sites. At buried sites (solvent surface accessibility of <40
      A(2)), the destabilizations are between 3 and 5.5 kcal/mol, whereas at more
      exposed sites, DeltaDeltaG values of < or = 1.5 kcal/mol are obtained. Of all the
      fluorescence parameters that were explored (excitation lambda(max), emission
      lambda(max), fluorescence lifetime, quantum yield, and steady-state anisotropy),
      the emission lambda(max) and the steady-state anisotropy values most accurately
      reflect the solvent surface accessibility at each site as calculated from the
      crystal structure of cysteine-less T4 lysozyme. The parameters we identify allow
      the classification of each site as buried, partially buried, or exposed. We find
      that the variations in these parameters as a function of residue number reflect
      the sequence-specific secondary structure, the determination of which is a key
      step for modeling a protein of unknown structure.

PMID- 10587465
TI  - Kinetic study of the activation of the neutrophil NADPH oxidase by arachidonic
      acid. Antagonistic effects of arachidonic acid and phenylarsine oxide.
AB  - The O(2)(-) generating NADPH oxidase complex of neutrophils comprises two sets of
      components, namely a membrane-bound heterodimeric flavocytochrome b which
      contains the redox centers of the oxidase and water-soluble proteins of cytosolic
      origin which act as activating factors of the flavocytochrome. The NADPH oxidase
      can be activated in a cell-free system consisting of plasma membranes and cytosol
      from resting neutrophils in the presence of GTPgammaS and arachidonic acid. NADPH
      oxidase activation is inhibited by phenylarsine oxide (PAO), a sulfhydryl reagent
      for vicinal or proximal thiol groups. The site of action of PAO was localized by
      photolabeling in the beta-subunit of flavocytochrome b [Doussiere, J., Poinas, A,
      Blais, C., and Vignais, P. V. (1998) Eur. J. Biochem. 251, 649-658]. Moreover,
      the spin state of heme b is controlled by interaction of arachidonic acid with
      the flavocytochrome b [Doussiere, J., Gaillard, J., and Vignais, P. V. (1996)
      Biochemistry 35, 13400-13410]. Here we report that the promoting effect of
      arachidonic acid on the activation of NADPH oxidase is due to specific binding of
      arachidonic acid to flavocytochrome b. Elicitation of NADPH oxidase activity by
      arachidonic acid is in part associated with an increased affinity of
      flavocytochrome b for O(2), an effect that was counteracted by the methyl ester
      of arachidonic acid. On the other hand, the affinity for NADPH was not affected
      by arachidonic acid. We further demonstrate that PAO antagonizes the effect of
      arachidonic acid on oxidase activation by decreasing the affinity of the oxidase
      for O(2), but not for NADPH. PAO induced a change in the spin state of heme b, as
      arachidonic acid does, with, however, some differences in the constraints imposed
      to the heme. It is concluded that the opposite effects of arachidonic acid and
      PAO are exerted on the beta-subunit of flavocytochrome b at two different
      interacting sites.

PMID- 10587467
TI  - Dynamic models for nonstationary signal segmentation.
AB  - This paper investigates Hidden Markov Models (HMMs) in which the observations are
      generated from an autoregressive (AR) model. The overall model performs
      nonstationary spectral analysis and automatically segments a time series into
      discrete dynamic regimes. Because learning in HMMs is sensitive to initial
      conditions, we initialize the HMM model with parameters derived from a cluster
      analysis of Kalman filter coefficients. An important aspect of the Kalman filter
      implementation is that the state noise is estimated on-line. This allows for an
      initial estimation of AR parameters for each of the different dynamic regimes.
      These estimates are then fine-tuned with the HMM model. The method is
      demonstrated on a number of synthetic problems and on electroencephalogram data.

PMID- 10587466
TI  - Identification of allosteric sites in rabbit phosphofructo-1-kinase.
AB  - Earlier studies indicated an evolutionary relationship between bacterial and
      mammalian phosphofructo-1-kinases (PFKs) that suggests duplication, tandem
      fusion, and divergence of catalytic and effector binding sites of a prokaryotic
      ancestor to yield in eukaryotes a total of six organic ligand binding sites. The
      identities of residues involved in the four binding sites for allosteric ligands
      in mammalian PFK have been inferred from this assumed relationship. In the
      current study of the C isozyme of rabbit PFK, two arginine residues that can be
      aligned with important residues in the catalytic and allosteric binding sites of
      bacterial PFK and that are conserved in all eukaryotic PFKs were mutated. Arg-48
      was suggested previously to be part of either the ATP inhibitory or the adenine
      nucleotide activating site. However, the mutant enzyme showed only slightly less
      sensitivity to ATP inhibition and was fully activatable by adenine nucleotides.
      On the other hand, sensitivity to citrate and 3-phosphoglycerate inhibition was
      lost, indicating an important role for Arg-48 in the binding of these allosteric
      effectors. Mutation of Arg-481, homologous to an active site residue in bacterial
      PFK, prevented binding and allosteric activation by fructose 2,6-bisphosphate. A
      new relationship between the allosteric sites of mammalian PFK and bacterial PFK
      is proposed.

PMID- 10587468
TI  - A fuzzy logic approach to identifying brain structures in MRI using expert
      anatomic knowledge.
AB  - We report a novel computer method for automatic labeling of structures in 3D MRI
      data sets using expert anatomical knowledge that is coded in fuzzy sets and fuzzy
      rules. The method first identifies major structures and then uses spatial
      relationships to these landmarks to recognize other structures. This labeling
      process simulates the iterative process that we ourselves use to locate
      structures in images. We demonstrate its application in three data sets, labeling
      brain MRI by locating the longitudinal and lateral fissures and the central sulci
      and then determining boundaries for the frontal lobes. Our method is adaptable to
      the identification of other anatomical structures.

PMID- 10587469
TI  - Familial associations between cancer sites.
AB  - The Utah Population Database links together genealogical records, the Utah Cancer
      Registry, and Utah death certificates and allows identification of cancer
      clusters. Groups of individuals with cancers of some types tend to fall into
      related clusters within the genealogy. We examine the apparent tendency of cases
      of two types of cancer to cluster together and distinguish real clusters from
      chance occurrences. Some established associations are found, whereas some are
      surprisingly absent. Some new associations are also suggested.

PMID- 10587470
TI  - Evaluation of measures of technical image quality for intracranial magnetic
      resonance angiography.
AB  - We evaluate three measures of technical image quality for intracranial magnetic
      resonance angiography (MRA): (1) a two-alternative forced choice (2AFC)
      evaluation of vessel visibility, (2) vessel-to-background signal-difference-to
      noise ratio (SDNR), and (3) observer ranking of the fidelity of vessel morphology
      compared to that in a gold standard image. The gold standard used for both the
      2AFC and ranking measures is intraarterial catheter angiography. These measures
      are applied to healthy arterial segments. The 2AFC and SDNR measures directly
      evaluate the visibility of artery segments for which the existence is known from
      the gold standard images. We argue that (1) 2AFC evaluates the carrier signals on
      which any vascular disease process is modulated and provides an upper bound on
      the detectibility of vascular lesions, (2) SDNR is a predictor of 2AFC, and (3)
      ranking may be used to predict the relative performance of techniques in the
      detection of vascular lesions.

PMID- 10587471
TI  - Mechanisms of hyphal tip growth: tube dwelling amebae revisited.
AB  - Over 100 years ago, Reinhardt suggested that hyphal tip growth is comparable to
      ameboid movement inside a tube; the apical cytoplasm being protruded like a
      pseudopodium with the wall assembled on its surface. There are increasing data
      from hyphae which are explicable by this model. Fungi produce pseudopodia-like
      structures and their cytoplasm contains all of the major components implicated in
      pseudopodium production in animal cells. Most of these components are
      concentrated in hyphal tips and tip growth involves actin, a major component of
      pseudopodia. Together these data indicate that the essence of the ameboid model
      is still tenable. However, detailed mechanisms of tip growth remain too poorly
      known to provide definitive proof of the model and the behavior of the trailing
      cytoplasm indicates differences which are probably a response to the walled
      lifestyle.

PMID- 10587472
TI  - Initial assessment of gene diversity for the oomycete pathogen Phytophthora
      infestans based on expressed sequences.
AB  - A total of 1000 expressed sequence tags (ESTs) corresponding to 760 unique
      sequence sets were identified using random sequencing of clones from a cDNA
      library constructed from mycelial RNA of Phytophthora infestans. A number of
      software programs, represented by a relational database and an analysis pipeline,
      were developed for the automated analysis and storage of the EST sequence data. A
      set of 419 nonredundant sequences, which correspond to a total of 632 ESTs
      (63.2%), were identified as showing significant matches to sequences deposited in
      public databases. A putative cellular identity and role was assigned to all 419
      sequences. All major functional categories were represented by at least several
      ESTs. Four novel cDNAs containing sequences related to elicitins, a family of
      structurally related proteins that induce the hypersensitive response and
      condition avirulence of P. infestans on Nicotiana plants, were among the most
      notable genes identified. Two of these elicitin-like cDNAs were among the most
      abundant cDNAs examined. The set also contained several ESTs with high sequence
      similarity to unique plant genes.

PMID- 10587473
TI  - Genetic structure of typical and atypical populations of Candida albicans from
      Africa.
AB  - Atypical isolates of the pathogenic yeast Candida albicans have been reported
      with increasing frequency. To investigate the origin of a set of atypical
      isolates and their relationship to typical isolates, we employed a combination of
      molecular phylogenetic and population genetic analyses using rDNA sequencing, PCR
      fingerprinting, and analysis of co-dominant DNA nucleotide polymorphisms to
      characterize the population structure of one typical and two atypical populations
      of C. albicans from Angola and Madagascar. The extent of clonality and
      recombination was assessed in each population. The analyses revealed that the
      structure of all three populations of C. albicans was predominantly clonal but,
      as in previous studies, there was also evidence for recombination. Allele
      frequencies differed significantly between the typical and the atypical
      populations, suggesting very low levels of gene flow between them. However,
      allele frequencies were quite similar in the two atypical C. albicans
      populations, suggesting that they are closely related. Phylogenetic analysis of
      partial sequences encoding the nuclear 26S rDNA demonstrated that all three
      populations belong to a single monophyletic group, which includes the type strain
      of C. albicans.

PMID- 10587475
TI  - Measurement of exhaled nitric oxide in humans and animals.

PMID- 10587474
TI  - Disruption of the cyanide hydratase gene in Gloeocercospora sorghi increases its
      sensitivity to the phytoanticipin cyanide but does not affect its pathogenicity
      on the cyanogenic plant sorghum.
AB  - The release of hydrogen cyanide (HCN) from preformed cyanogenic compounds in
      plants such as sorghum is thought to provide a protective barrier against
      infection by microorganisms. Gloeocercospora sorghi, a fungal pathogen of
      sorghum, produces the enzyme cyanide hydratase (CHT) which converts HCN to the
      less toxic compound formamide. There is considerable prior evidence indicating
      that this mechanism for detoxifying HCN plays an important role in the
      pathogenicity of G. sorghi on sorghum. In the present study, the CHT gene was
      made nonfunctional in G. sorghi through transformation-mediated gene disruption.
      The transformant lacked CHT activity and no reacting polypeptides were detected
      with CHT-specific antibodies. This CHT mutant was highly sensitive to HCN,
      confirming that CHT is an HCN detoxifying mechanism, but it retained virulence on
      sorghum, causing lesions indistinguishable from those caused by the wild-type
      strain. This result indicates that G. sorghi does not require CHT for
      pathogenicity on cyanogenic lines of sorghum and suggests that cyanogenic
      compounds in plants may serve functions other than providing a mechanism of
      disease resistance.

PMID- 10587476
TI  - Pharmacokinetics and pharmacodynamics of cumulative single doses of inhaled
      salbutamol enantiomers in asthmatic subjects.
AB  - Objectives of this study were to compare the pharmacokinetics, pharmacodynamics
      and safety of single cumulative doses of active (R)-salbutamol given either as
      the single enantiomer or racemic mixture by inhalation to subjects with mild to
      moderate asthma. This was a double-blind, crossover, cumulative-dose, randomized
      study where all subjects received either four doses of 1.25 mg of (R)-salbutamol
      or 2.5 mg of racemic (RS-) salbutamol by nebulization. The pharmacokinetic
      parameters were determined by noncompartmental analysis and model-fitting.
      Changes in FEV(1), plasma potassium, plasma glucose, heart rate, and QTc interval
      were measured. The potassium and glucose data were fitted to indirect response
      pharmacodynamic models. The heart rate and QTc data were evaluated using data
      descriptors. No significant differences in pharmacokinetics of (R)-salbutamol
      given as either (R)- or (RS)-salbutamol were found with AUC values of 11.90 +/-
      4.37 and 11. 47 +/- 2.88 ng.h/ml. The t(max)of about 2 h reflected serial dosing
      rather than delayed absorption. The t(1/2)averaged about 3.5 h. The (S)
      salbutamol showed AUC of 48.46 +/- 12.11 ng.h/ml with a t(1/2)of about 5 h. The
      changes in FEV(1)reached a plateau after an initial increase and did not return
      to pre-drug values for 10 h. All pharmacodynamic parameters were similar whether
      (R)- or (RS)-salbutamol was given. The exposure to (R)-salbutamol was identical
      after inhalation of (R) -and (RS)-salbutamol by subjects with asthma. Several
      pharmacological responses including FEV(1)were also similar and there were no
      unique safety concerns with either treatment.

PMID- 10587477
TI  - Effect of fenspiride, a non-steroidal antiinflammatory agent, on neurogenic mucus
      secretion in ferret trachea in vitro.
AB  - Neural mechanisms contribute to control of mucus secretion in the airways.
      Fenspiride is a non-steroidal antiinflammatory agent which has a variety of
      actions, including inhibition of neurogenic bronchoconstriction. The effect of
      fenspiride on neurally-mediated mucus secretion was investigated in vitro in
      electrically-stimulated ferret trachea, using(35)SO(4)as a mucus marker.
      Cholinergic secretory responses were isolated using adrenoceptor and tachykinin
      receptor antagonists. Tachykinin responses were isolated using cholinoceptor and
      adrenoceptor antagonists. Electrical stimulation increased cholinergic secretion
      by;90% and tachykininergic secretion by;40%. Fenspiride (1 microM-1 mM) tended to
      inhibit cholinergic secretion in a concentration-dependent manner, although only
      at 1 mM was inhibition (by 87%) significant. Inhibition by fenspiride of
      tachykininergic secretion was not concentration-dependent, and again significant
      inhibition (by 85%) was only at 1 mM. Inhibition was not due to loss of tissue
      viability, as assessed by restitution of secretory response after washout.
      Fenspiride also inhibited secretion induced by acetylcholine, but did not inhibit
      substance P-induced secretion. Histamine receptor antagonists increased basal
      secretion by 164%, whereas fenspiride did not affect basal secretion. We conclude
      that, in ferret trachea in vitro, fenspiride inhibits neurally-mediated mucus
      secretion, with antimuscarinic action the most plausible mechanism of action, but
      not necessarily the only mechanism.

PMID- 10587478
TI  - N-acetylcysteine and ambroxol inhibit endotoxin-induced phagocyte accumulation in
      rat lungs.
AB  - We have investigated whether pretreatment with N-acetylcysteine (NAC) and/or
      ambroxol (Amb), drugs known as reactive oxygen species (ROS) scavengers, would
      minimize lipopolysaccharide (LPS)-induced leucocyte accumulation in rat lung
      microvasculature and protect lungs from damage and the effect of these drugs on
      chemotactic peptide (fMLP)-induced chemiluminescence of human polymorphonuclear
      leukocytes (PMNs). Animals were injected ip with NAC (27.6 mg/kg, n=8), ambroxol
      (70 mg/kg, n=8), combination NAC+ambroxol (n=8), or 1 ml buffer alone (n=8), once
      a day for 3 consecutive days. Then animals were injected with LPS (17 mg/kg), and
      killed 3 h later. In each of another four groups eight rats were used as a
      control, and received the same drug treatment but LPS was replaced with 0.9%
      NaCl. PMNs and macrophages (Ms) were counted in histologic slides of lung tissue.
      Using computer image analysis we measured the area of alveolar profiles. Luminol
      enhanced chemiluminescence was measured in PMNs suspensions obtained from healthy
      volunteers. Chemiluminescence intensity was measured in resting and fMLP
      stimulated cells, and compared between cells incubated with Amb, NAC or distilled
      water. We observed significant differences in the number of PMNs and Ms, alveolar
      profile area between control and LPS-treated animals (P<0.01). PMNs and Ms were
      numerous in lungs of LPS-administered animals (PMNs: Median (M)=137.5 per 6 high
      power fields range (r)=54.0; Ms: M=123.0 r=11.0), less numerous in ambroxol
      treated group (PMNs: M=101.5 r=32.0 and Ms:53.5 r=36.0), not abundant in NAC
      (PMNs:M=56.0 r=28.0 and Ms:M=20.5 r=13.0) and in NAC+ambroxol treated rats
      (PMNs:M=53.5 r=21.0 and Ms:M=29.0 r=9.0), and rare in LPS+drugs-untreated control
      group (PMNs:M=40.5 r=19.0 and Ms:M=18.5 r=15.0). Chemiluminescence assay revealed
      that 100 micro;M ambroxol stimulated fMLP-induced PMNs chemiluminescence and NAC
      of the same concentration had no significant effect. CONCLUSION: In our
      experiment we showed that pretreatment with NAC and ambroxol may inhibit
      phagocyte influx to rat lung and may protect it from damage. We also revealed
      that NAC at dose 27.6 mg/kg has stronger protective properties than ambroxol at
      dose 70 mg/kg and this may result from enhancing effect of ambroxol on fMLP
      provoked PMNs chemiluminescence.

PMID- 10587480
TI  - Volume contents and index

PMID- 10587479
TI  - Characterization of the phosphodiesterase (PDE) pattern of in vitro-generated
      human dendritic cells (DC) and the influence of PDE inhibitors on DC function.
AB  - During differentiation of human monocytes (CD14(+)/CD1a(-)) to CD14(
      )/CD1a(+)dendritic cells (DC), a drastic decrease in PDE4 activity was observed,
      while activities of PDE1 and PDE3 substantially increased. DC released tumour
      necrosis factor-alpha (TNF) in response to lipopolysaccharide (LPS) challenge,
      which was abolished both by dexamethasone and the cyclic AMP-elevating drugs db
      cAMP and PGE(2). In addition, rolipram, at PDE4-selective concentrations, blocked
      TNF release by 37 +/- 5% (P<0.05 vs. control). The PDE3 inhibitor motapizone only
      marginally influenced TNF synthesis, but a synergistic inhibitory effect was
      noted in combination with rolipram. Qualitatively, similar inhibitory effects
      were observed in DC-stimulated T cell responses. Motapizone, lacking efficacy
      when used alone, increased the effect of rolipram in blocking CD4(+)T lymphocyte
      proliferation in response to antigen (Ag) (tetanus toxoid, TT; keyhole limpet
      hemocyanin, KLH) presented by DC and in allogeneic mixed leukocyte reactions
      (MLR). However, in these coculture systems the T cells rather than the DC seem to
      be the major target cells of PDE-inhibitor action. In summary, PDE inhibitors can
      affect DC function directly as demonstrated by blocking TNF release and their
      efficacy reflects the changes in the PDE activity profile during differentiation
      from their monocyte precursors. These results together with the known efficacy of
      PDE3/4 inhibitors in T cells support the concept of combined PDE3/4 inhibitors
      for asthma therapy.

PMID- 10587481
TI  - Soft X-Ray Absorption by High-Redshift Intergalactic Helium.
AB  - The Lyalpha absorption from intergalactic, once-ionized helium (He ii) has been
      measured with the Hubble Space Telescope in four quasars over the last few years
      in the redshift range 2.4<z<3.2. These observations have indicated that the He ii
      reionization may not have been completed until z approximately 2.8 and that large
      fluctuations in the intensity of the He ii-ionizing background were present
      before this epoch. The detailed history of He ii reionization at higher redshifts
      is, however, model-dependent and difficult to determine from these observations,
      since the intergalactic medium (IGM) can be completely optically thick to Lyalpha
      photons when only a small fraction of the helium remains as He ii. In addition,
      finding quasars in which the He ii Lyalpha absorption can be observed becomes
      increasingly difficult at higher redshift owing to the large abundance of
      hydrogen Lyman limit systems. It is pointed out here that He ii in the IGM should
      also cause detectable continuum absorption in the soft X-rays. The spectrum of a
      high-redshift source seen behind the IGM when most of the helium was He ii should
      recover from the He ii Lyman continuum absorption at an observed energy of
      approximately 0.1 keV. Galactic absorption will generally be stronger, but not by
      a large factor; the intergalactic He ii absorption can be detected as an excess
      over the expected Galactic absorption from the 21 cm H i column density. In
      principle, this method allows a direct determination of the fraction of helium
      that was singly ionized as a function of redshift if the measurement is done on a
      large sample of high-redshift sources over a range of redshifts.

PMID- 10587482
TI  - The Two-Component Virial Theorem and the Physical Properties of Stellar Systems.
AB  - Motivated by present indirect evidence that galaxies are surrounded by dark
      matter halos, we investigate whether their physical properties can be described
      by a formulation of the virial theorem that explicitly takes into account the
      gravitational potential term representing the interaction of the dark halo with
      the baryonic or luminous component. Our analysis shows that the application of
      such a "two-component virial theorem" not only accounts for the scaling relations
      displayed by, in particular, elliptical galaxies, but also for the observed
      properties of all virialized stellar systems, ranging from globular clusters to
      galaxy clusters.

PMID- 10587483
TI  - Clump Giant Distance to the Magellanic Clouds and Anomalous Colors in the
      Galactic Bulge.
AB  - I demonstrate that the two unexpected results in the local universe-(1) anomalous
      intrinsic (V-I&parr0;0 colors of the clump giants and RR Lyrae stars in the
      Galactic center, and (2) very short distances to the Magellanic Clouds (LMC, SMC)
      as inferred from clump giants-are connected with each other. The (V-I&parr0;0
      anomaly is partially resolved by using the photometry from phase II of the
      Optical Gravitational Lensing Experiment (OGLE) rather than phase I. The need for
      V- or I-magnitude-based change in the bulge (V-I&parr0;0 is one option to explain
      the remaining color discrepancy. Such a change may originate in a coefficient of
      selective extinction AV&solm0;E&parl0;V-I&parr0; smaller than typically assumed.
      Application of the (V-I&parr0;0 correction (independent of its source) doubles
      the slope of the absolute magnitude-metallicity relation for clump giants, so
      that MI&parl0;RC&parr0;=-0.23+0.19 [Fe/H]. Consequently, the estimates of the
      clump distances to the LMC and SMC are affected. Udalski's distance modulus of
      uLMC=18.18+/-0.06 increases to 18.27+/-0.07. The distance modulus to the SMC
      increases by 0.12 to uSMC=18.77+/-0.08. I argue that a more comprehensive
      assessment of the metallicity effect on MI&parl0;RC&parr0; is needed.

PMID- 10587484
TI  - Viewing the Shadow of the Black Hole at the Galactic Center.
AB  - In recent years, evidence for the existence of an ultracompact concentration of
      dark mass associated with the radio source Sagittarius A* in the Galactic center
      has become very strong. However, unambiguous proof that this object is indeed a
      black hole is still lacking. A defining characteristic of a black hole is the
      event horizon. To a distant observer, the event horizon casts a relatively large
      "shadow" with an apparent diameter of approximately 10 gravitational radii that
      is due to the bending of light by the black hole, and this shadow is nearly
      independent of the black hole spin or orientation. The predicted size (
      approximately 30 uas) of this shadow for Sgr A* approaches the resolution of
      current radio interferometers. If the black hole is maximally spinning and viewed
      edge-on, then the shadow will be offset by approximately 8 uas from the center of
      mass and will be slightly flattened on one side. Taking into account the scatter
      broadening of the image in the interstellar medium and the finite achievable
      telescope resolution, we show that the shadow of Sgr A* may be observable with
      very long baseline interferometry at submillimeter wavelengths, assuming that the
      accretion flow is optically thin in this region of the spectrum. Hence, there
      exists a realistic expectation of imaging the event horizon of a black hole
      within the next few years.

PMID- 10587485
TI  - Black Hole Mergers in the Universe.
AB  - Mergers of black hole binaries are expected to release large amounts of energy in
      the form of gravitational radiation. However, binary evolution models predict
      merger rates that are too low to be of observational interest. In this Letter, we
      explore the possibility that black holes become members of close binaries via
      dynamical interactions with other stars in dense stellar systems. In star
      clusters, black holes become the most massive objects within a few tens of
      millions of years; dynamical relaxation then causes them to sink to the cluster
      core, where they form binaries. These black hole binaries become more tightly
      bound by superelastic encounters with other cluster members and are ultimately
      ejected from the cluster. The majority of escaping black hole binaries have
      orbital periods short enough and eccentricities high enough that the emission of
      gravitational radiation causes them to coalesce within a few billion years. We
      predict a black hole merger rate of about 1.6x10-7 yr-1 Mpc-3, implying gravity
      wave detection rates substantially greater than the corresponding rates from
      neutron star mergers. For the first-generation Laser Interferometer Gravitational
      Wave Observatory (LIGO-I), we expect about one detection during the first 2 years
      of operation. For its successor LIGO-II, the rate rises to roughly one detection
      per day. The uncertainties in these numbers are large. Event rates may drop by
      about an order of magnitude if the most massive clusters eject their black hole
      binaries early in their evolution.

PMID- 10587486
TI  - ASCA Observation of the Quiescent X-Ray Counterpart to SGR 1627-41.
AB  - We present a 2-10 keV ASCA observation of the field around the soft gamma
      repeater SGR 1627-41. A quiescent X-ray source, whose position is consistent both
      with that of a recently discovered BeppoSAX X-ray source and with the
      Interplanetary Network localization for this soft gamma repeater, was detected in
      this observation. In 2-10 keV X-rays, the spectrum of the X-ray source may be fit
      equally well by a power-law, blackbody, or bremsstrahlung function, with
      unabsorbed flux approximately 5x10-12 ergs cm-2 s-1. We do not confirm a
      continuation of a fading trend in the flux, and we find no evidence for
      periodicity, both of which were noted in the earlier BeppoSAX observations.

PMID- 10587487
TI  - Detection of 33.8 Millisecond X-Ray Pulsations in SAX J0635+0533.
AB  - We revisited the BeppoSAX observation of SAX J0635+0533, which was suggested as a
      possible counterpart to the gamma-ray source 2EG J0635+0521. We have discovered a
      33.8 ms pulsation from the source and derived an improved position, consistent
      with the location of the Be star proposed as a binary companion. We interpret the
      periodicity as the spin period of a neutron star in a binary system with a Be
      companion.

PMID- 10587488
TI  - On the Maximum Mass of Differentially Rotating Neutron Stars.
AB  - We construct relativistic equilibrium models of differentially rotating neutron
      stars and show that they can support significantly more mass than their
      nonrotating or uniformly rotating counterparts. We dynamically evolve such
      "hypermassive" models in full general relativity and show that there do exist
      configurations that are dynamically stable against radial collapse and bar
      formation. Our results suggest that the remnant of binary neutron star
      coalescence may be temporarily stabilized by differential rotation, leading to
      delayed collapse and a delayed gravitational wave burst.

PMID- 10587489
TI  - Identification of SH Deltav=1 Ro-vibrational Lines in R Andromedae.
AB  - We report the identification of SH Deltav=1 ro-vibrational lines in the published
      high-resolution infrared spectrum of the S-type star R Andromedae. This is the
      first astronomical detection of this molecule. The lines show inverse P Cygni
      profiles, indicating infall motion of the molecular layer due to stellar
      pulsation. A simple spherical shell model with a constant infall velocity is
      adopted to determine the condition of the layer. It is found that a single
      excitation temperature of 2200 K reproduces the observed line intensities
      satisfactorily. SH is located in a layer from 1.0 to approximately 1.1 stellar
      radii, which is moving inward with a velocity of 9 km s-1. These results are
      consistent with the previous measurements of CO Deltav=3 transitions. The
      estimated molecular abundance SH/H is 1x10-7, consistent with a thermal
      equilibrium calculation.

PMID- 10587490
TI  - A Submillimeter HCN Laser in IRC +10216.
AB  - We report the detection of a strong submillimeter-wavelength HCN laser line at a
      frequency near 805 GHz toward the carbon star IRC +10216. This line, the J=9-8
      rotational transition within the (0400) vibrationally excited state, is one of a
      series of HCN laser lines that were first detected in the laboratory in the early
      days of laser spectroscopy. Since its lower energy level is 4200 K above the
      ground state, the laser emission must arise from the innermost part of IRC
      +10216's circumstellar envelope. To better characterize this environment, we
      observed other, thermally emitting, vibrationally excited HCN lines and found
      that they, like the laser line, arise in a region of temperature approximately
      1000 K that is located within the dust formation radius; this conclusion is
      supported by the line width of the laser. The (0400), J=9-8 laser might be
      chemically pumped and may be the only known laser (or maser) that is excited both
      in the laboratory and in space by a similar mechanism.

PMID- 10587491
TI  - The Evolution of the Angular Momentum Distribution during Star Formation.
AB  - If the angular momentum of the molecular cloud core were conserved during the
      star formation process, a newborn star would rotate much faster than its fission
      speed. This constitutes the angular momentum problem of newborn stars. In this
      Letter, the angular momentum transfer in the contraction of a rotating magnetized
      cloud is studied with axisymmetric MHD simulations. Because of the large dynamic
      range covered by the nested-grid method, the structure of the cloud in the range
      from 10 AU to 0.1 pc is explored. First, the cloud experiences a runaway
      collapse, and a disk forms perpendicularly to the magnetic field, in which the
      central density increases greatly in a finite timescale. In this phase, the
      specific angular momentum j of the disk decreases to about one-third of the
      initial cloud. After the central density of the disk exceeds approximately 1010
      cm-3, the infall on to the central object develops. In this accretion stage, the
      rotation motion and thus the toroidal magnetic field drive the outflow. The
      angular momentum of the central object is transferred efficiently by the outflow
      as well as by the effect of the magnetic stress. In 7000 yr from the core
      formation, the specific angular momentum of the central 0.17 M middle dot in
      circle decreases a factor of 10-4 from the initial value (i.e., from 1020 to 1016
      cm2 s-1).

PMID- 10587492
TI  - TRACE-derived Temperature and Emission Measure Profiles along Long-lived Coronal
      Loops: The Role of Filamentation.
AB  - In a recent Letter, Lenz et al. have shown evidence of uniform temperature along
      steady long coronal loops observed by TRACE in two different passbands (171 and
      195 A filters). We propose that such a piece of evidence can be explained by the
      subarcsecond structuring of the loops across the magnetic field lines. In this
      perspective, we present a model of a bundle of six thin parallel hydrostatic
      filaments with temperature stratification dictated by detailed energy balance and
      with temperatures at their apex ranging between 0.8 and 5 MK. If analyzed as a
      single loop, the bundle would appear isothermal along most of its length.

PMID- 10587493
TI  - Development of Coronal Mass Ejections: Radio Shock Signatures.
AB  - We present observational imaging evidence for the existence of metric radio
      bursts closely associated with the front edge of coronal mass ejections (CMEs).
      These radio bursts drift in frequency similarly to type II bursts. They are weak
      and usually go undetected on spectrograph data. We find the same measured
      projected velocity for the displacement of, respectively, the radio source (when
      observed at two or more frequencies) and the CME leading edge. The position of
      the emitting source coincides with the CME leading edge. Among the events
      analyzed, the fastest of them, with a velocity over 1400 km s-1, was associated
      with interplanetary type II bursts.

PMID- 10587494
TI  - Random-Lag Singular Cross-Spectrum Analysis.
AB  - In a previous paper (Varadi et al.), random-lag singular spectrum analysis was
      introduced for finding oscillations in very noisy and long time series. This work
      presents a generalization of the technique to search for common oscillations in
      two or more time series.

PMID- 10587495
TI  - Confusing tastes and smells: how odours can influence the perception of sweet and
      sour tastes.
AB  - This study investigated the relationship between perception of an odour when
      smelled and the taste of a solution to which the odour is added as a flavorant.
      In Experiment 1 (E1) sweetness, sourness, liking and intensity ratings were
      obtained for 20 odours. Taste ratings were then obtained for sucrose solutions to
      which the odours had been added as flavorants. Certain odours were found to
      enhance tasted sweetness while others suppressed it. The degree to which an odour
      smelled sweet was the best predictor of the taste ratings. These findings were
      extended in Experiment 2 (E2), which included a second tastant, citric acid, and
      employed four odours from E1. The most sweet smelling odour, caramel, was found
      to suppress the sourness of citric acid and, as in E1, to enhance the sweetness
      of sucrose. Again, odours with low sweetness suppressed the sweetness of tasted
      sucrose. The study demonstrated that the effects of odours on taste perception
      are not limited to sweetness enhancement and apply to sour as well as sweet
      tastes. The overall pattern of results is consistent with an explanation of the
      taste properties of odours in terms of prior flavour-taste associations.

PMID- 10587496
TI  - Performance of mice in an automated olfactometer: odor detection, discrimination
      and odor memory.
AB  - Mice were trained on a variety of odor detection and discrimination tasks in 100-
      or 200-trial sessions using a go, no-go discrete trials operant conditioning
      procedure. Odors, presented for 1 s on each trial, were generated by an air
      dilution olfactometer (for threshold tests) and an easily constructed eight
      channel liquid dilution unit (for two- and multiple-odor discrimination tasks).
      Mice rapidly acquired the operant task and demonstrated excellent stimulus
      control by odor vapors. Their absolute detection threshold for ethyl acetate was
      similar to that obtained with rats using similar methods. They readily acquired
      four separate two-odor discrimination tasks and continued to perform well when
      all eight odors were presented in random order in the same session and when
      reinforcement probability for correct responding was decreased from 1 to 0.5.
      Memory for these eight odors, assessed under extinction after a 32 day rest
      period, was essentially perfect. Time spent sampling the odor on S+ and S- trials
      was highly correlated with response accuracy. When accuracy was at chance levels
      (e.g. initial trials on a novel task), stimulus sampling time on both S+ and S-
      trials was approximately 0.5-0.7 s. As response accuracy increased, sampling time
      on S+ trials tended to increase and remain higher than sampling time on S-
      trials.

PMID- 10587497
TI  - Ammonia as an attractive component of host odour for the yellow fever mosquito,
      Aedes aegypti.
AB  - Behavioural responses of Aedes aegypti mosquitoes to ammonia were investigated in
      a modified Y-tube olfactometer. Ammonia was attractive in concentrations from 17
      ppb to 17 ppm in air when presented together with lactic acid. Aqueous solutions
      of ammonia salts in concentrations comparable to those found in human sweat also
      increased the attractiveness of lactic acid. The role of lactic acid as an
      essential synergist for ammonia became further apparent by the fact that ammonia
      alone or in combination with carbon dioxide was not effective, even though the
      synergistic effect of carbon dioxide and lactic acid was corroborated. An extract
      from human skin residues, which attracts approximately 80% of the tested
      mosquitoes, contains both lactic acid and ammonia. The combination of these
      compounds, however, attracts no more than 45%, indicating that other components
      on human skin also play a role in host finding. Preparative liquid chromatography
      of the skin extract yielded three behaviourally active fractions which work
      together synergistically. Fraction III contains lactic acid as the effective
      principle; the compositions of the other two have not been clarified yet. The
      attractiveness of fraction I was augmented considerably when ammonia was added,
      whereas the effect of fraction II was not influenced by ammonia. These results
      suggests that ammonia is part of the effective principle of fraction II and
      contributes to the attractive effect of host odours.

PMID- 10587498
TI  - Intramedullary projections of the rostral nucleus of the solitary tract in the
      rat: gustatory influences on autonomic output.
AB  - The efferent connections of the rostral nucleus of the solitary tract (NTS) in
      the rat were studied by anterograde transport of Phaseolus vulgaris
      leucoagglutinin. Rostral to the injection site, fibers travel through the rostral
      parvocellular reticular formation and deflect medially or laterally around the
      motor trigeminal nucleus, giving off few terminals in these nuclei and terminate
      in the parabrachial nucleus. Moderate projections to the peritrigeminal zone,
      including the intertrigeminal nucleus and the dorsal subcoeruleus nucleus, were
      observed. Caudally to the injection site, dense innervations from the rostral
      nucleus of the solitary tract were detected in the parvocellular reticular
      formation ventral and caudal to the injection site and in the intermediate and
      ventral medullary reticular formation. The rostral central and ventral
      subdivisions of the NTS up to the level where the nucleus of the solitary tract
      abuts the fourth ventricle and the hypoglossal nucleus, receive moderate input
      from the rostral nucleus of the solitary tract. In general, the projections from
      the rostral nucleus of the solitary tract were bilateral with an ipsilateral
      predominance. The caudal part of the nucleus of the solitary tract, the dorsal
      motor nucleus of the vagus and the facial nucleus were not labeled. It is
      concluded that medullary rNTS projections participate in oral motor behavior and
      autonomic control of abdominal organs.

PMID- 10587499
TI  - Odorants presented to the rat nasal cavity increase cortical blood flow.
AB  - Complaints about unpleasant environmental odorants, both outdoor and indoor, are
      increasingly being reported. The main complaints of health symptoms from
      environmental odorants are eye, nose and throat irritation, headache and
      drowsiness. Complaints may arise from the stimulation of olfactory receptors or
      trigeminal chemoreceptors. Stimulation of cerebrovascular nociceptors originating
      from a branch of the trigeminal nerve may be associated with an increase in
      cortical blood flow which is thought to be related to headache. Since odorants
      are reported to elicit headaches, the possibility that odorants may increase
      cortical blood flow was examined. Cortical blood flow was monitored in rats using
      a laser-Doppler flowmeter. The flowmeter probe was placed over the left frontal
      cortex while propionic acid, cyclohexanone, amyl acetate or butanol was delivered
      to the nasal cavity via an olfactometer. Cortical blood flow increased as the
      concentration increased for three of the odorants tested. The greatest increase
      in blood flow occurred to the presentation of propionic acid, followed by
      cyclohexanone and amyl acetate. There was no response to butanol. These data
      demonstrate that odorants can alter cerebrovascular blood flow, which may
      account, in part, for one of the health symptoms reported for odorants.

PMID- 10587500
TI  - Measurement of sensitivity to olfactory flavor: application in a study of aging
      and dentures.
AB  - Olfaction involves a dual sensory process for perceiving odors orthonasally
      (through the nostrils) and retronasally (through the mouth). This investigation
      entailed developing a measure of sensitivity to an odor delivered in an orally
      sampled food (orange flavoring in a sucrose-sweetened gelatin) and examining
      sensitivity in the elderly. In experiment 1, olfactory flavor sensitivity was 49
      times lower in elderly (n = 21) than in young (n = 28) subjects. In experiment 2,
      with 73 elderly women, higher olfactory flavor sensitivity correlated
      significantly with higher orthonasal perception (Connecticut Chemosensory
      Clinical Research Center test). Some women, however, exhibited low olfactory
      flavor sensitivity despite high orthonasal perception; none had high olfactory
      flavor sensitivity and low orthonasal perception. Those who wore complete or
      palatal covering dentures had lower olfactory flavor sensitivity than those who
      were dentate or wore dentures that did not cover the palate. Through multiple
      regression analysis, orthonasal perception and denture status were found to be
      independent contributors to predicting olfactory flavor sensitivity. In summary,
      elderly subjects showed depressed olfactory flavor sensitivity (i.e. retronasal
      sensitivity) that related to poor orthonasal olfactory perception and denture
      characteristic. Thus, while good orthonasal olfaction may be necessary for good
      olfactory flavor sensitivity, it is not sufficient. Other factors, some
      associated with oral conditions, may impede release and retronasal transport of
      odors from the mouth to the olfactory receptors.

PMID- 10587501
TI  - A functional map in rat olfactory epithelium.
AB  - Multiple (four or eight) electrode arrays were placed for simultaneous electro
      olfactogram (EOG) recordings of responses to a series of odors applied directly
      to the olfactory epithelium. Three different surfaces of the epithelium were
      exposed in rats immediately after death by anesthetic overdose. We tested three
      terpene compounds (carvone, limonene and 1,8-cineole) across the epithelium along
      the medial surface of the endoturbinate bones. Carvone, a ketone, evoked larger
      responses dorsally on the epithelium. The largest responses to 1,8-cineole (an
      ether) were seen in an intermediate-ventral region. The responses to limonene (a
      hydrocarbon) did not vary greatly across the regions, although they were often
      larger ventrally. The response distributions deviated from this simple pattern on
      the caudal part of endoturbinate IV, where the carvone responses were small and
      the limonene responses were larger. These differences were evident across a
      substantial concentration range. Similar distributions were seen for these three
      odors in tests along the dorsal-to-ventral direction across the nasal septum and
      in the medial-to-lateral direction across the dorsal aspect of one of the
      endoturbinate bones reaching out into the lateral recess. We argue that the
      spatial distributions of responses are correlated with the olfactory receptor
      gene expression zones.

PMID- 10587502
TI  - Hemispheric lateralization in the processing of odor pleasantness versus odor
      names.
AB  - It is well established that for most people linguistic processing is primarily a
      left hemisphere activity, whereas recent evidence has shown that basic odor
      perception is more lateralized to the right hemisphere. Importantly, under
      certain conditions, emotional responding also shows right hemisphere laterality.
      Hedonic (pleasantness) assessments constitute basic level emotional responses.
      Given that olfaction is predominantly ipsilateral in function, it was
      hypothesized that odor pleasantness evaluations may be accentuated by right
      nostril perception and that odor naming would be superior with left nostril
      perception. To test this prediction we presented eight familiar neutral-mildly
      pleasant odors for subjects to sniff through the left and right nostrils.
      Subjects smelled each odor twice (once through each nostril) at two different
      sessions, separated by 1 week. At each session subjects provided pleasantness,
      arousal and naming responses to each odorant. Results revealed that odors were
      rated as more pleasant when sniffed through the right nostril and named more
      correctly when sniffed through the left. No effects for arousal were obtained.
      These findings are consistent with previously demonstrated neural laterality in
      the processing of olfaction, emotion and language, and suggest that a local and
      functional convergence may exist between olfaction and emotional processing.

PMID- 10587503
TI  - What a tangled web we weave: discriminating between malingering and anosmia.
AB  - Two groups of normosmic subjects were instructed to feign a total olfactory loss
      when tested with the Olfactory Confusion Matrix (OCM). One of the groups was
      given specific instructions as to the number of odorants and trials in the test,
      as well as the number of items that might be expected to be correctly identified
      by chance. The responses of both groups of malingerers were compared with
      responses gathered from a group of anosmic patients. The groups did not differ in
      terms of performance level (percent correct). In spite of the similarity in terms
      of accuracy level, an analysis of the pattern of OCM responses to an irritant
      allowed the anosmic patients to be distinguished from subjects attempting to
      feign a loss. Subjects were given explicit details about the test performed at
      the same level as those simply told to feign a loss. These results suggest that
      the OCM is an effective tool in separating malingering from anosmia.

PMID- 10587504
TI  - Simulation analysis of effects of adrenaline on spike generation in olfactory
      receptor cells.
AB  - Adrenaline is known to affect action potentials induced by the step current
      injection in an olfactory receptor cell (ORC). It is unclear, however, whether it
      also modulates action potentials induced by odor stimuli. In the present study,
      the effects of adrenaline on action potentials in ORCs were investigated
      quantitatively using a computer simulation. Adrenaline suppressed simulated
      action potentials induced by step current injection near threshold, and increased
      spike frequency to strong stimuli by 8-25%. Similar effects were obtained by
      applying a pseudo-transduction current to a model cell. Surprisingly, adrenaline
      markedly increased spike frequency to strong stimuli by 30-140%, and increased
      the slope of the stimulus-response relation compared with that of the step
      current injection. This suggests that adrenaline enhances odorant contrast in
      olfactory perception by modulating signal encoding of ORCs.

PMID- 10587505
TI  - Assessing the impact of anosmia: review of a questionnaire's findings.
AB  - The inability to detect odours, anosmia, can cause profound psychological effects
      resulting in feelings of physical and social vulnerability and victimization. In
      addition, there may be unhappiness related to the loss of the ability to detect
      pleasurable food smells and, as a consequence, anosmics may develop problems
      relating to eating. These profound effects arise from a condition which can have
      a rapid onset and a very poor prognosis for recovery, and are largely treated
      with a lack of sympathy and indifference by people with normal olfactory ability.
      In an attempt to educate, inform and help sufferers, a questionnaire was
      developed in the early 1980s and sent to those who contacted the Warwick
      Olfaction Research Group. The responses from this questionnaire form the basis of
      this review. Feelings of personal isolation, lack of interest in eating and
      emotional blunting were common responses from these sufferers and it seems that
      we still have some way to go before an adequate recognition of problems
      associated with anosmia is gained by the general population and, more
      importantly, within the medical profession.

PMID- 10587506
TI  - Odor and affect: individual differences in the impact of odor on liking for
      places, things and people.
AB  - This paper provides evidence of substantial individual differences in the
      affective importance of odors, and offers initial validation for an eight-item
      scale of the impact of odor (AIO) on liking for people, places, foods and
      cosmetic/health products. In study 1, 116 American college students and 336
      Flemish Belgian college students completed the AIO along with other measures of
      reactions to odors and to commercial products designed to mask body odors. There
      were substantial individual differences in AIO scores, but means were similar for
      males and females, and for US and Belgian respondents. Higher AIO scores were
      associated with more odor-mediated memory, more attention to odors and more
      liking or disliking for odors as a function of their association with liked and
      disliked persons. AIO scores were not related to preference for toiletries with
      artificial scents, to use of products to mask natural body odors, or to disgust
      sensitivity. In study 2, AIO scores were strongly related to a measure of
      evaluative conditioning (a form of Pavlovian associative learning) in the
      laboratory, using liked and disliked odors as unconditioned stimuli and pictures
      of faces as conditioned stimuli.

PMID- 10587507
TI  - Single allele mutations at the heart of congenital disease.

PMID- 10587508
TI  - Heme oxygenase-1: a redoubtable response that limits reperfusion injury in the
      transplanted adipose liver.

PMID- 10587509
TI  - Selecting culprits in type 1 diabetes beta-cell killing.

PMID- 10587510
TI  - Bad for cats, good for humans? Modified feline immunodeficiency virus for gene
      therapy.

PMID- 10587511
TI  - Taking aim at novel molecular targets in cancer therapy.

PMID- 10587512
TI  - Anticancer drug targets: approaching angiogenesis.

PMID- 10587513
TI  - Choosing anticancer drug targets in the postgenomic era.

PMID- 10587514
TI  - Resistance of young gelatinase B-deficient mice to experimental autoimmune
      encephalomyelitis and necrotizing tail lesions.
AB  - Regulated expression of matrix metalloproteinases (MMPs) and their inhibitors
      (TIMPs) plays a role in various physiological processes. To determine in vivo how
      unbalanced expression of these factors can promote or affect the course of
      pathologies, we knocked out the mouse gelatinase B gene by replacing the
      catalytic and zinc-binding domains with an antisense-oriented neomycin resistance
      gene. Adult gelatinase B-deficient mice and wild-type controls could be induced
      to develop experimental autoimmune encephalomyelitis (EAE) with similar scores
      for neurologic disease, blood-brain barrier permeability, and central nervous
      system histopathology. However, whereas diseased control animals showed
      necrotizing tail lesions with hyperplasia of osteocartilaginous tissue, adult
      gelatinase B-deficient mice were resistant to this tail pathology. Gelatinase B
      deficient mice younger than 4 weeks of age were significantly less susceptible to
      the development of EAE than were age matched controls and, even as they aged,
      they remained resistant to tail lesions. These data illustrate that gelatinase B
      expression plays a role in the development of the immune system and that, in
      ontogenesis, the propensity to develop autoimmunity is altered by the absence of
      this MMP.

PMID- 10587515
TI  - Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both
      chondrogenesis and osteogenesis.
AB  - Missense mutations in fibroblast growth factor receptor 3 (FGFR3) result in
      several human skeletal dysplasias, including the most common form of dwarfism,
      achondroplasia. Here we show that a glycine-to-cysteine substitution at position
      375 (Gly375Cys) in human FGFR3 causes ligand-independent dimerization and
      phosphorylation of FGFR3 and that the equivalent substitution at position 369
      (Gly369Cys) in mouse FGFR3 causes dwarfism with features mimicking human
      achondroplasia. Accordingly, homozygous mice were more severely affected than
      heterozygotes. The resulting mutant mice exhibited macrocephaly and shortened
      limbs due to retarded endochondral bone growth and premature closure of cranial
      base synchondroses. Compared with their wild-type littermates, mutant mice growth
      plates shared an expanded resting zone and narrowed proliferating and
      hypertrophic zones, which is correlated with the activation of Stat proteins and
      upregulation of cell-cycle inhibitors. Reduced bone density is accompanied by
      increased activity of osteoclasts and upregulation of genes that are related to
      osteoblast differentiation, including osteopontin, osteonectin, and osteocalcin.
      These data reveal an essential role for FGF/FGFR3 signals in both chondrogenesis
      and osteogenesis during endochondral ossification.

PMID- 10587516
TI  - Interleukin-11 therapy selectively downregulates type I cytokine proinflammatory
      pathways in psoriasis lesions.
AB  - Psoriasis is a chronic inflammatory skin disease in which epidermal hyperplasia
      results from skin infiltration by type I T lymphocytes and release of associated
      cytokines. A multifunctional cytokine, rhIL-11, modulates macrophage and type I T
      lymphocyte function in cell culture and shows anti-inflammatory activity in
      animal models. We are testing subcutaneous delivery of rhIL-11 to patients with
      psoriasis in a phase 1 open-label dose-escalation clinical trial. Tissue was
      obtained from lesional and uninvolved skin before and during treatment with rhIL
      11 and was examined by histology/immunohistochemistry and quantitative RT-PCR.
      Expression of over 35 genes was examined in all patients, and multiple genetic
      markers of psoriasis were identified. Expression of numerous proinflammatory
      genes was elevated in psoriatic tissue compared with nonlesional skin. Seven of
      12 patients responded well to rhIL-11 treatment. Amelioration of disease by rhIL
      11, as shown by reduced keratinocyte proliferation and cutaneous inflammation,
      was associated with decreased expression of products of disease-related genes,
      including K16, iNOS, IFN-gamma, IL-8, IL-12, TNF-alpha, IL-1beta, and CD8, and
      with increased expression of endogenous IL-11. We believe that this is the first
      study in humans to indicate that type I cytokines can be selectively suppressed
      by an exogenous immune-modifying therapy. The study highlights the utility of
      pharmacogenomic monitoring to track patient responsiveness and to elucidate anti
      inflammatory mechanisms.

PMID- 10587517
TI  - A paradoxical reduction in susceptibility to colonic injury upon targeted
      transgenic ablation of goblet cells.
AB  - Goblet cells are the major mucus-producing cells of the intestine and are
      presumed to play an important role in mucosal protection. However, their
      functional role has not been directly assessed in vivo. In initial studies, a 5'
      flanking sequence of the murine intestinal trefoil factor (ITF) gene was found to
      confer goblet cell-specific expression of a transgene. To assess the role of
      goblet cells in the intestine, we generated transgenic mice in which
      approximately 60% of goblet cells were ablated by the expression of an attenuated
      diphtheria toxin (DT) gene driven by the ITF promoter; other cell lineages were
      unaffected. We administered 2 exogenous agents, dextran sodium sulfate (DSS) and
      acetic acid, to assess the susceptibility of mITF/DT-A transgenic mice to colonic
      injury. After oral administration of DSS, 55% of control mice died, whereas DT
      transgenic mice retained their body weight and less than 5% died. Similarly, 30%
      of the wild-type mice died after mucosal administration of acetic acid, compared
      with 3.2% of the transgenic mice. Despite the reduction in goblet-cell number,
      the total amount of ITF was increased in the mITF/DT-A transgenic mice,
      indicating inducible compensatory mechanisms. These results suggest that goblet
      cells contribute to mucosal protection and repair predominantly through
      production of trefoil peptides.

PMID- 10587518
TI  - Lack of chemokine receptor CCR1 enhances Th1 responses and glomerular injury
      during nephrotoxic nephritis.
AB  - During the development of nephrotoxic nephritis (NTN) in the mouse, we find that
      a variety of chemokines and chemokine receptors are induced: CCR1 (RANTES, MIP
      1alpha), CCR2 (MCP-1), CCR5 (RANTES, MIP-1alpha, MIP-1beta), CXCR2 (MIP-2), and
      CXCR3 (IP-10). Their timing of expression indicated that CXCR2 and CCR1 are
      probably important in the neutrophil-dependent heterologous phase of the disease,
      whereas CCR1, CCR2, CCR5, and CXCR3 accompany the subsequent mononuclear cell
      infiltration characteristic of autologous disease. We therefore assessed the role
      of CCR1 in NTN using CCR1(-/-) mice. We found that neutrophil accumulation in
      CCR1(-/-) mice was comparable to that in wild-type animals but that renal
      recruitment of CD4(+) and CD8(+) T cells and macrophages increased significantly.
      Moreover, CCR1(-/-) mice developed more severe glomerulonephritis than did
      controls, with greater proteinuria and blood urea nitrogen, as well as a higher
      frequency of crescent formation. In addition, CCR1(-/-) mice showed enhanced Th1
      immune responses, including titers of antigen-specific IgG2a antibody, delayed
      type hypersensitivity responses, and production of IFN-gamma and TNF-alpha.
      Lastly, using recombinant proteins and transfected cells that overexpressed CCR1,
      we demonstrated that MIP-1alpha, but not RANTES, bound CCR1 and induced cell
      chemotaxis. Thus, rather than simply promoting leukocyte recruitment during NTN,
      CCR1 expression profoundly alters the effector phase of glomerulonephritis.
      Therapeutic targeting of chemokine receptors may, on occasion, exacerbate
      underlying disease.

PMID- 10587519
TI  - Nephritogenic mAb 5-1-6 is directed at the extracellular domain of rat nephrin.
AB  - mAb 5-1-6 identifies an antigen on rat podocyte slit-diaphragms and induces
      severe proteinuria when injected into rats. Nephrin, an Ig-like transmembrane
      protein that is mutated in congenital nephrotic syndrome of the Finnish type, has
      been localized to the slit-diaphragm on human podocytes. Here we document that
      the mAb 5-1-6 antigen is rat nephrin. After incubation of rat glomeruli with this
      mAb, the antibody/antigen complex was chemically cross-linked, extracted, and
      immunoprecipitated, prior to Western analysis. By mass spectrometry and 2D gel
      electrophoresis, we identified several peptides with complete identity to human
      nephrin. In addition, the 185-kDa protein immunoprecipitated by mAb 5-1-6 from
      rat glomerular extracts reacts with a rabbit anti-mouse nephrin antibody.
      Finally, nephrin and the mAb 5-1-6 antigen have identical glomerular localization
      patterns on immunofluorescence of rat kidney. These results demonstrate that the
      nephritogenic mAb 5-1-6 identifies the extracellular domain of nephrin, thereby
      documenting the importance of the slit-diaphragm and its component, nephrin, in
      the regulation of glomerular permselectivity.

PMID- 10587520
TI  - Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac
      developmental pathways.
AB  - Heterozygous mutations in NKX2.5, a homeobox transcription factor, were reported
      to cause secundum atrial septal defects and result in atrioventricular (AV)
      conduction block during postnatal life. To further characterize the role of
      NKX2.5 in cardiac morphogenesis, we sought additional mutations in groups of
      probands with cardiac anomalies and first-degree AV block, idiopathic AV block,
      or tetralogy of Fallot. We identified 7 novel mutations by sequence analysis of
      the NKX2.5-coding region in 26 individuals. Associated phenotypes included AV
      block, which was the primary manifestation of cardiac disease in nearly a quarter
      of affected individuals, as well as atrial septal defect and ventricular septal
      defect. Ventricular septal defect was associated with tetralogy of Fallot or
      double-outlet right ventricle in 3 individuals. Ebstein's anomaly and other
      tricuspid valve abnormalities were also present. Mutations in human NKX2.5 cause
      a variety of cardiac anomalies and may account for a clinically significant
      portion of tetralogy of Fallot and idiopathic AV block. The coinheritance of
      NKX2.5 mutations with various congenital heart defects suggests that this
      transcription factor contributes to diverse cardiac developmental pathways.

PMID- 10587521
TI  - A nemaline myopathy mutation in alpha-tropomyosin causes defective regulation of
      striated muscle force production.
AB  - Nemaline myopathy (NM) is a rare autosomal dominant skeletal muscle myopathy
      characterized by severe muscle weakness and the subsequent appearance of nemaline
      rods within the muscle fibers. Recently, a missense mutation inTPM3, which
      encodes the slow skeletal alpha-tropomyosin (alphaTm), was linked to NM in a
      large kindred with an autosomal-dominant, childhood-onset form of the disease. We
      used adenoviral gene transfer to fully differentiated rat adult myocytes in vitro
      to determine the effects of NM mutant human alphaTm expression on striated muscle
      sarcomeric structure and contractile function. The mutant alphaTm was expressed
      and incorporated correctly into sarcomeres of adult muscle cells. The primary
      defect caused by expression of the mutant alphaTm was a decrease in the
      sensitivity of contraction to activating Ca(2+), which could help explain the
      hypotonia seen in NM. Interestingly, NM mutant alphaTm expression did not
      directly result in nemaline rod formation, which suggests that rod formation is
      secondary to contractile dysfunction and that load-dependent processes are likely
      involved in nemaline rod formation in vivo.

PMID- 10587522
TI  - Synthetic peptides define critical contacts between elongin C, elongin B, and the
      von Hippel-Lindau protein.
AB  - The von Hippel-Lindau tumor suppressor protein (pVHL) negatively regulates
      hypoxia-inducible mRNAs such as the mRNA encoding vascular endothelial growth
      factor (VEGF). This activity has been linked to its ability to form multimeric
      complexes that contain elongin C, elongin B, and Cul2. To understand this process
      in greater detail, we performed a series of in vitro binding assays using pVHL,
      elongin B, and elongin C variants as well as synthetic peptide competitors
      derived from pVHL or elongin C. A subdomain of elongin C (residues 17-50) was
      necessary and sufficient for detectable binding to elongin B. In contrast,
      elongin B residues required for binding to elongin C were not confined to a
      discrete colinear domain. We found that the pVHL (residues 157-171) is necessary
      and sufficient for binding to elongin C in vitro and is frequently mutated in
      families with VHL disease. These mutations preferentially involve residues that
      directly bind to elongin C and/or alter the conformation of pVHL such that
      binding to elongin C is at least partially diminished. These results are
      consistent with the view that diminished binding of pVHL to the elongins plays a
      causal role in VHL disease.

PMID- 10587523
TI  - Hyposmolality stimulates apical membrane Na(+)/H(+) exchange and HCO(3)(-)
      absorption in renal thick ascending limb.
AB  - The regulation of epithelial Na(+)/H(+) exchangers (NHEs) by hyposmolality is
      poorly understood. In the renal medullary thick ascending limb (MTAL),
      transepithelial bicarbonate (HCO(3)(-)) absorption is mediated by apical membrane
      Na(+)/H(+) exchange, attributable to NHE3. In the present study we examined the
      effects of hyposmolality on apical Na(+)/H(+) exchange activity and HCO(3)(-)
      absorption in the MTAL of the rat. In MTAL perfused in vitro with 25 mM HCO(3)(-)
      solutions, decreasing osmolality in the lumen and bath by removal of either
      mannitol or sodium chloride significantly increased HCO(3)(-) absorption. The
      responses to lumen addition of the inhibitors ethylisopropyl amiloride,
      amiloride, or HOE 694 are consistent with hyposmotic stimulation of apical NHE3
      activity and provide no evidence for a role for apical NHE2 in HCO(3)(-)
      absorption. Hyposmolality increased apical Na(+)/H(+) exchange activity over the
      pH(i) range 6.5-7.5 due to an increase in V(max). Pretreatment with either
      tyrosine kinase inhibitors or with the tyrosine phosphatase inhibitor molybdate
      completely blocked stimulation of HCO(3)(-) absorption by hyposmolality. These
      results demonstrate that hyposmolality increases HCO(3)(-) absorption in the MTAL
      through a novel stimulation of apical membrane Na(+)/H(+) exchange and provide
      the first evidence that NHE3 is regulated by hyposmotic stress. Stimulation of
      apical Na(+)/H(+) exchange activity in renal cells by a decrease in osmolality
      may contribute to such pathophysiological processes as urine acidification by
      diuretics, diuretic resistance, and renal sodium retention in edematous states.

PMID- 10587524
TI  - Mechanical strain activates BNP gene transcription through a p38/NF-kappaB
      dependent mechanism.
AB  - Application of mechanical strain to neonatal rat ventricular myocytes in culture
      evokes changes in gene expression reminiscent of those that occur with
      hypertrophy in vivo, such as stimulation of brain natriuretic peptide (BNP) gene
      expression. Here, we show that a major component of strain-dependent BNP promoter
      activation results from stimulation of p38 mitogen-activated protein kinase
      (MAPK) in the cardiac myocyte. Strain increased p38 activity in a time-dependent
      fashion. The p38 inhibitor SB203580 led to a reduction of approximately 60% in
      strain-activated human BNP (hBNP) promoter activity. Cotransfection of wild-type
      p38 increased both basal and strain-dependent promoter activity, while
      cotransfection with MKK6AL, a dominant-negative inhibitor of p38 MAPK kinase,
      resulted in partial inhibition of either p38- or strain-activated hBNP promoter
      activity. p38 MAPK increased hBNP promoter activity through activation of the
      transcription factor NF-kappaB. Activation of the hBNP promoter by either p38 or
      strain was mediated by DNA elements present in the 5' flanking sequence of the
      gene. Mechanical strain promoted assembly of NF-kappaB components on these DNA
      elements in vitro. Thus, induction of the hBNP promoter by mechanical strain
      depends, at least in part, on stimulation of p38 and subsequent activation of NF
      kappaB. This activation may play an important role in signaling the increased BNP
      gene expression that accompanies hemodynamic overload and cardiac hypertrophy in
      vivo.

PMID- 10587525
TI  - VEGF antagonism reduces edema formation and tissue damage after
      ischemia/reperfusion injury in the mouse brain.
AB  - VEGF is mitogenic, angiogenic, and a potent mediator of vascular permeability.
      VEGF causes extravasation of plasma protein in skin bioassays and increases
      hydraulic conductivity in isolated perfused microvessels. Reduced tissue oxygen
      tension triggers VEGF expression, and increased protein and mRNA levels for VEGF
      and its receptors (Flt-1, Flk-1/KDR) occur in the ischemic rat brain. Brain
      edema, provoked in part by enhanced cerebrovascular permeability, is a major
      complication in central nervous system pathologies, including head trauma and
      stroke. The role of VEGF in this pathology has remained elusive because of the
      lack of a suitable experimental antagonist. We used a novel fusion protein,
      mFlt(1-3)-IgG, which sequesters murine VEGF, to treat mice exposed to transient
      cortical ischemia followed by reperfusion. Using high-resolution magnetic
      resonance imaging, we found a significant reduction in volume of the edematous
      tissue 1 day after onset of ischemia in mice that received mFlt(1-3)-IgG. 8-12
      weeks after treatment, measurements of the resultant infarct size revealed a
      significant sparing of cortical tissue. Regional cerebral blood flow was
      unaffected by the administration of mFlt(1-3)-IgG. These results demonstrate that
      antagonism of VEGF reduces ischemia/reperfusion-related brain edema and injury,
      implicating VEGF in the pathogenesis of stroke and related disorders.

PMID- 10587526
TI  - Overexpression of monocarboxylate transporter and lactate dehydrogenase alters
      insulin secretory responses to pyruvate and lactate in beta cells.
AB  - Previous investigations revealed low activities of lactate dehydrogenase (LDH)
      and plasma membrane monocarboxylate transporters (MCT) in the pancreatic beta
      cell. In this study the significance of these characteristics was explored by
      overexpressing type A LDH (LDH-A) and/or type 1 MCT (MCT-1) in the clonal INS-1
      beta cells and isolated rat islets. Inducible overexpression of LDH-A resulted in
      an 87-fold increase in LDH activity in INS-1 cells. Adenovirus-mediated
      overexpression of MCT-1 increased lactate transport activity 3.7-fold in INS-1
      cells. Although overexpression of LDH-A, and/or MCT-1 did not affect glucose
      stimulated insulin secretion, LDH-A overexpression resulted in stimulation of
      insulin secretion even at a low lactate concentration with a concomitant increase
      in its oxidation in INS-1 cells regardless of MCT-1 co-overexpression. Adenovirus
      mediated overexpression of MCT-1 caused an increase in pyruvate oxidation and
      conferred pyruvate-stimulated insulin release to isolated rat islets. Although
      lactate did not stimulate insulin secretion from control or MCT-1-overexpressing
      islets, co-overexpression of LDH-A and MCT-1 evoked lactate-stimulated insulin
      secretion with a concomitant increase in lactate oxidation in rat islets. These
      results suggest that low expression of MCT and LDH is requisite to the
      specificity of glucose in insulin secretion, protecting the organism from
      undesired hypoglycemic actions of pyruvate and lactate during exercise and other
      catabolic states.

PMID- 10587527
TI  - Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from
      ischemia/reperfusion injury.
AB  - We examined the effects of upregulation of heme oxygenase-1 (HO-1) in steatotic
      rat liver models of ex vivo cold ischemia/reperfusion (I/R) injury. In the model
      of ischemia/isolated perfusion, treatment of genetically obese Zucker rats with
      the HO-1 inducer cobalt protoporphyrin (CoPP) or with adenoviral HO-1 (Ad-HO-1)
      significantly improved portal venous blood flow, increased bile production, and
      decreased hepatocyte injury. Unlike in untreated rats or those pretreated with
      the HO-1 inhibitor zinc protoporphyrin (ZnPP), upregulation of HO-1 by Western
      blots correlated with amelioration of histologic features of I/R injury.
      Adjunctive infusion of ZnPP abrogated the beneficial effects of Ad-HO-1 gene
      transfer, documenting the direct involvement of HO-1 in protection against I/R
      injury. Following cold ischemia/isotransplantation, HO-1 overexpression extended
      animal survival from 40% in untreated controls to about 80% after CoPP or Ad-HO-1
      therapy. This effect correlated with preserved hepatic architecture, improved
      liver function, and depressed infiltration by T cells and macrophages. Hence,
      CoPP- or gene therapy-induced HO-1 prevented I/R injury in steatotic rat livers.
      These findings provide the rationale for refined new treatments that should
      increase the supply of usable donor livers and ultimately improve the overall
      success of liver transplantation.

PMID- 10587529
TI  - The Internet for pediatricians.

PMID- 10587530
TI  - Eating disorders in adolescents and older children.

PMID- 10587528
TI  - Feline immunodeficiency virus vectors persistently transduce nondividing airway
      epithelia and correct the cystic fibrosis defect.
AB  - Several problems limit the application of gene transfer to correct the cystic
      fibrosis (CF) Cl(-) transport defect in airway epithelia. These include
      inefficient transduction with vectors applied to the apical surface, a low rate
      of division by airway epithelial cells, failure of transgene expression to
      persist, and immune responses to vectors or vector-encoded proteins. To address
      these issues, we used a feline immunodeficiency virus-based (FIV-based) vector.
      FIV vector formulated with a calcium chelator transduced fully differentiated,
      nondividing human airway epithelia when applied to the apical surface. FIV-based
      vector encoding the cystic fibrosis transmembrane conductance regulator cDNA
      corrected the Cl(-) transport defect in differentiated CF airway epithelia for
      the life of the culture (>3 months). When this approach was applied in vivo, FIV
      vector expressing beta-galactosidase transduced 1-14% of adult rabbit airway
      epithelia. Transduced cells were present in the conducting airways, bronchioles,
      and alveoli. Importantly, gene expression persisted, and cells with progenitor
      capacity were targeted. FIV-based lentiviral vectors may be useful for the
      treatment of genetic lung diseases such as CF. This article may have been
      published online in advance of the print edition.

PMID- 10587532
TI  - Spontaneous subarachnoid hemorrhage in children.

PMID- 10587533
TI  - Index of suspicion. Case 1. Diagnosis: acute vertebral osteomyelitis.

PMID- 10587534
TI  - Question from the clinician. Use of topical hydrocortisone.

PMID- 10587535
TI  - The maintenance need for sodium in parenteral fluid therapy.

PMID- 10587537
TI  - Conventional mechanical ventilation: traditional and new strategies.

PMID- 10587538
TI  - High-frequency ventilation: current status.

PMID- 10587539
TI  - Liquid ventilation: current status.

PMID- 10587540
TI  - Behcet's syndrome.

PMID- 10587541
TI  - Primary care rheumatology-leading the way?

PMID- 10587542
TI  - The role of apoptosis in systemic lupus erythematosus.

PMID- 10587543
TI  - Pain amongst ethnic minority groups of South Asian origin in the United Kingdom:
      a review.

PMID- 10587544
TI  - Eosinophilic arthritis.
AB  - OBJECTIVE: To report the clinical picture, laboratory findings and management of
      10 patients presenting with acute polyarthritis and hypereosinophilia of unknown
      causation. METHODS: Patients presenting with acute arthritis and elevated
      eosinophil counts (>0.7x10(9) cells/l) or percentage (>11%) were studied during
      the period 1990-1997. Exhaustive investigations were carried out to exclude
      allergy, parasitic and infectious diseases, autoimmune disorders and malignancy.
      They were managed by standard treatment with oral non-steroidal anti-inflammatory
      drugs (NSAIDs), failing which, some were given oral corticosteroids. Those
      resistant to corticosteroids were treated empirically with diethylcarbamazine
      citrate or levamisole. All were closely monitored. RESULTS: Nine females and one
      male were found to have acute polyarthritis of 1-6 weeks duration. Most affected
      were the large joints: knees, ankles, elbows and shoulders. Except for localized
      urticarial rash, none had constitutional symptoms or extra-articular
      manifestations. Mild to moderate eosinophilia (absolute count 0.7-7.08x10(9)
      cells or 11-63%) was detected at the disease onset, but other laboratory findings
      were generally non-contributory. Treatment with oral NSAIDs did not relieve the
      joint symptoms nor reduce the hypereosinophilia, but oral prednisolone brought
      rapid recovery to five out of eight patients. Three of the corticosteroid
      resistant patients were treated with an oral diethylcarbamazine, an anti-filarial
      drug. Complete resolution of arthritis and normalization of eosinophil count were
      observed after 2-3 weeks. Similar success was obtained in one patient after a
      single dose of levamisole. No side-effects or relapse were encountered. It was
      also observed that there was a good correlation between joint activity and the
      eosinophilic count, indicating the joint as the possible target end organ of
      these cells. CONCLUSION: Ten patients were found to have an acute polyarthritis
      without systemic involvement, but with marked hypereosinophilia of unknown
      aetiology. They had clinical and laboratory findings which differed from other
      diseases with eosinophilia, especially the idiopathic hypereosinophilic syndrome
      (HES) and parasitic or infectious conditions. The response to NSAIDs,
      corticosteroids and, most interestingly, to anthelmintic drugs, like
      diethylcarbamazine citrate and levamisole, was noteworthy, although the basic
      mechanism remains unknown. The term eosinophilic arthritis (EA) is used here to
      describe this group of arthritides which has a benign course and is most likely a
      reaction to some occult allergen or agent.

PMID- 10587545
TI  - Autocrine induction of gliostatin/platelet-derived endothelial cell growth factor
      (GLS/PD-ECGF) and GLS-induced expression of matrix metalloproteinases in
      rheumatoid arthritis synoviocytes.
AB  - OBJECTIVE: The purpose of this study was to examine how gliostatin/platelet
      derived endothelial cell growth factor (GLS/PD-ECGF) is involved in the molecular
      mechanism of cartilage degradation in rheumatoid arthritis (RA) with special
      reference to the GLS-induced gene expression and protein synthesis of matrix
      metalloproteinase (MMP)-1 (collagenase-1) and MMP-3 (stromelysin-1). METHODS:
      Fibroblast-like synoviocytes (FLSs) obtained from RA patients were cultured and
      stimulated by GLS. Changes in the expression levels of GLS, MMP-1 and MMP-3 were
      assessed by Northern blot analysis and reverse transcription-polymerase chain
      reaction (RT-PCR) for GLS, and by RT-PCR and enzyme-linked immunosorbent assay
      for MMPs and tissue inhibitor of metalloproteinase 1. RESULTS: GLS demonstrated a
      self-induction of mRNA in cultured RA FLSs. GLS evoked a dose-dependent induction
      of MMP-1 and MMP-3 mRNAs, and subsequently their extracellular secretion.
      CONCLUSION: These findings suggest that GLS is a plausible pathogenic factor
      causing the extensive joint destruction in RA mediated via MMPs.

PMID- 10587546
TI  - The relative proportions of secreted interleukin-2 and interleukin-10 determine
      the magnitude of rheumatoid arthritis T-cell proliferation to the recall antigen
      tuberculin purified protein derivative.
AB  - OBJECTIVE: To investigate the mechanisms of the deficient proliferative responses
      by rheumatoid arthritis (RA) peripheral blood T cells to the recall antigen
      tuberculin purified protein derivative (PPD). METHODS: The concomitant production
      of interleukin (IL)-2, IL-10 and lymphocyte proliferation were studied by enzyme
      linked immunosorbent assay and [(3)H]thymidine uptake, respectively, in 12 normal
      controls and eight RA patients. RESULTS: An inverse correlation was found between
      IL-10 production and proliferation to PPD. The proliferative response was shown
      to be critically affected by the IL-2:IL-10 ratio so that absolute levels of
      secreted IL-2 or IL-10 correlated non-significantly with lymphocyte
      proliferation. CONCLUSION: The deficient T-cell proliferation in RA peripheral
      blood mononuclear cells is related to the relative proportions of IL-2:IL-10
      rather than the absolute amounts secreted.

PMID- 10587547
TI  - The epidemiology of biopsy-positive giant cell arteritis: special reference to
      cyclic fluctuations.
AB  - OBJECTIVE: The aim of this work was to study changes in the incidence of biopsy
      proven giant cell arteritis (GCA) over a period of 20 yr in Goteborg, Sweden.
      METHODS: All cases of biopsy-verified GCA between 1976 and 1995 were included in
      the study. The annual incidence was calculated for the whole material, for women
      and men separately, and its fluctuations were tested statistically. In addition,
      the monthly variation during the last 9 yr could be statistically analysed for
      the whole material. RESULTS: In total, 665 patients were diagnosed with biopsy
      verified GCA during the 20 yr period. The average annual incidence was
      22.2/100000 inhabitants over 50 yr of age (women 29.8, men 12.5). The annual
      incidence increased significantly with time (P<0.001) for both men and women.
      Statistical analysis did not reveal any cyclic fluctuation in the annual
      incidence (P=0.26), while the monthly number of positive biopsies showed
      significant fluctuation with peaks in late winter and autumn (P=0.041).
      CONCLUSIONS: The annual incidence of biopsy-positive GCA increased during the
      years 1976 through 1995. The significant seasonal variation, as well as
      considerable variation in annual incidence, might be due to the influence of
      exogenous triggering factors, such as infections. Further support for an
      exogenous aetiology, in terms of a statistically significant cyclic fluctuation
      of the annual incidence, was not found, however.

PMID- 10587548
TI  - Reading radiographs in chronological order, in pairs or as single films has
      important implications for the discriminative power of rheumatoid arthritis
      clinical trials.
AB  - OBJECTIVE: To determine the influence of reading series of films in chronological
      order, in pairs with unknown time sequence, or as single films, on precision and
      sensitivity to change. METHODS: Two studies were performed with 10 and 12
      patients fulfilling the American College of Rheumatology criteria. In Study 1,
      two sets of films with a 1 yr interval were scored in chronological order, in
      pairs, and as single films. In Study 2, four sets of films, with a 1 yr interval
      each, were scored in chronological order, as single films and as single-pair
      (right and left together). All films were scored with the Sharp/van der Heijde
      method by two independent observers. Data were analysed with a repeated measures
      ANOVA using a full mixed effects model. Two generalizability (G) coefficients
      were constructed for reliability and for change. RESULTS: Study 1: the
      interobserver reliability was similar for the three methods (G(reliability)
      chronological 0.94, paired 0.88, single 0.93); progression was a mean increase
      (averaged over patients, observers and methods) from 26 to 37 (P=0.046). The
      sensitivity for change was greater for the chronological than for the paired and
      single scoring (G(change) 0.39, 0.22 and 0.24, respectively). Study 2: the
      interobserver reliability was 0.86 for chronological, 0.76 for single-pair and
      0.91 for single readings. Significantly more progression was measured with the
      chronological compared with the single-paired and single methods (15.9 vs 8.5 and
      8.3; P=0.0001). A constant progression was suggested by chronological reading, in
      contrast to a stabilization in the other two methods after 1 yr. CONCLUSION:
      Reading films in chronological order is most sensitive to change in a time period
      up to 3 yr follow-up; this was already present after 1 yr, but even more
      pronounced with longer follow-up.

PMID- 10587549
TI  - The influence of HLA-DRB1 alleles encoding the DERAA amino acid motif on
      radiological outcome in rheumatoid arthritis.
AB  - OBJECTIVES: To investigate the influence of HLA-DRB1 alleles encoding the QK/RRAA
      shared epitope (SE) on radiological outcome in rheumatoid arthritis (RA), and to
      determine whether it is modulated by alleles carrying the putative rheumatoid
      arthritis-protective (RAP) sequence DERAA. Patients and methods. The association
      between erosive damage and HLA-DRB1 status was examined in 315 RA patients with a
      disease duration of 5-30 yr. Radiological outcome was measured by scoring X-rays
      of the hands and feet using the standard radiographs of Larsen (Larsen score).
      HLA-DRB1 typing was carried out using polymerase chain reaction methodology.
      RESULTS: Patients with two alleles encoding the QK/RRAA SE had significantly
      higher Larsen scores than SE-negative patients (96.9 vs 83.3; P=0.04, after
      correction for multiple testing), with DRB1*0401/*0401 homozygotes demonstrating
      the greatest radiological damage (99.9). The lowest Larsen score (65.6) was
      observed in patients carrying the DERAA motif without an accompanying SE allele
      (RAP+/SE-). This was significantly lower than in patients with RAP+/SE+ (105.6;
      P=0.04), RAP-/SE- (88.2; P=0.05) and RAP-/SE+ (95.8; P=0.009), after correction
      for multiple testing. There was no evidence that the RAP sequence was modulating
      the effect of the SE since radiological outcome in RAP+/SE+ patients was not
      significantly different to that in RAP-/SE+ individuals. CONCLUSIONS: Our data
      support a possible role for DRB1 alleles encoding the DERAA motif in protection
      against severe erosive damage in patients lacking the QK/RRAA SE, but not in
      patients heterozygous for the SE. This suggests that DRB1 alleles encoding the SE
      have a dominant influence over 'protective alleles' and are not merely 'non
      protective'.

PMID- 10587550
TI  - Recurrent pregnancy loss and autoantibody profile in autoimmune diseases.
AB  - OBJECTIVE: To explore the association of non-organ-specific autoimmune responses
      against three distinct Ro antigen-related reactivities (Ro52, Ro60, p57) with a
      history of pregnancy loss in women with autoimmune disorders. Materials and
      methods. Seventy unselected anti-Ro/SSA-positive women were studied in a
      retrospective cohort study. Forty anti-Ro/SSA-positive women were age matched to
      an equal number of women with autoimmune disorders who were anti-Ro/SSA negative
      in a case-control study. The association of reactivities against three distinct
      antigen specificities (Ro52, Ro60, p57) with recurrent pregnancy loss was
      investigated. Independence and modification of these associations from the effect
      of antithyroglobulin, antithyroid peroxidase and anticardiolipin antibodies were
      also examined. RESULTS: In the cohort study, reactivity against each of the three
      antigen specificities (Ro52, Ro60, p57) was independently associated with a
      history of recurrent pregnancy loss. In the case-control study, the effects were
      still independent and were not modified when other autoantibodies were
      considered. In particular, the number of reactivities against Ro52, Ro60 and p57
      peptides, and the presence of antithyroglobulin antibodies, were independent
      predictors of recurrent pregnancy loss (odds ratios 3.35 per each additional
      reactivity and 5.54 in the presence of antithyroglobulin; P=0.002 and 0.025,
      respectively). CONCLUSIONS: In women with autoimmune disorders, a history of
      recurrent pregnancy loss is independently associated with reactivity against each
      of the three antigen specificities (Ro52, Ro60, p57) and also with the presence
      of antithyroglobulin antibodies, suggesting that cumulative autoimmune responses
      against these non-organ-specific and organ-specific antigens correlate with the
      risk of stillbirth and spontaneous abortion.

PMID- 10587551
TI  - Spontaneous ambulatory activity as a quantifiable outcome measure for rheumatoid
      arthritis.
AB  - OBJECTIVE: To validate the objective monitoring of ambulatory activity as an
      outcome measure for rheumatoid arthritis (RA). METHODS: We have compared
      ambulatory activity to a range of currently favoured outcome measures, ranging
      from subjective opinions to X-ray damage, in a population of 93 RA sufferers.
      RESULTS: Correlations were stronger with measures of joint damage and disability,
      and less strong with measures of disease activity. Sensitivity to change was
      good. Three different interventions were compared for the quantity of the
      response, and the results agree with clinical experience, with steroid injection
      of the knee and use of non-steroidal anti-inflammatory drugs (NSAIDs) having a
      similar response and the provision of surgical shoes producing a more modest
      increase in ambulation. CONCLUSION: The measurement of ambulatory activity has
      validity for RA assessment. It provides different but related data to the
      currently used measures. It is objective, relevant, quantifiable and of unlimited
      scale. It could be used to quantify interventions aimed at increasing ambulation,
      in carefully constructed studies.

PMID- 10587552
TI  - Osteopenia in young hypogonadal women with systemic lupus erythematosus receiving
      chronic steroid therapy: a randomized controlled trial comparing calcitriol and
      hormonal replacement therapy.
AB  - OBJECTIVE: To evaluate the efficacy of calcitriol and hormonal replacement
      therapy (HRT) in the treatment of steroid-induced osteoporosis in hypogonadal
      women. METHODS: We studied 28 young patients (aged 37 +/- 6 yr) with systemic
      lupus erythematosus (SLE) on chronic steroid therapy for 130 +/- 22 months and
      requiring more than 10 mg/day prednisone. They were amenorrhoeic for more than 2
      yr with proven ovarian failure. All had osteopenia with a T score at L2-4 of less
      than -1. They were randomized to receive HRT (conjugated oestrogen 0.625 mg daily
      from day 1 to day 21 plus medroxyprogesterone acetate 5 mg daily days 10-21) or
      calcitriol 0.5 microg daily. All received calcium carbonate 1 g/day. RESULTS:
      There were no differences in the baseline demographic, bone mineral density (BMD)
      and biochemical data between the two groups. Lumbar spine BMD increased by 2.0 +/
      0.4% after 2 yr with HRT (P<0.05), but reduced by 1.74 +/- 0.4% (P<0.05) with
      calcitriol treatment. No change was seen at the distal one-third radius with HRT
      treatment but significant bone loss (2.3 +/- 1.4%, P<0.02) was observed with
      calcitriol therapy. BMD at the hip did not change in both groups. Comparing both
      treatment groups, significant differences in the BMD at the spine (P<0.03) and
      radius (P<0.05) were seen at the end of 2 yr. The changes in urinary n
      telopeptide excretion but not serum osteocalcin at 6 months and 12 months were
      inversely correlated with the changes in lumbar spine BMD at 24 months. HRT did
      not cause an adverse effect on SLE disease activity. CONCLUSION: HRT but not
      calcitriol could prevent bone loss in young hypogonadal women on chronic steroid
      therapy.

PMID- 10587553
TI  - Peripheral ulcerative keratitis 'corneal melt' and rheumatoid arthritis: a case
      series.
AB  - OBJECTIVES: (1) To review the visual and systemic outcomes of patients who
      developed rheumatoid arthritis (RA)-associated peripheral ulcerative keratitis
      (PUK). (2) To describe the clinical and serological characteristics of the
      patients' arthropathy at the time of presentation of this rare condition. (3) To
      review the aetiology and management of RA-associated PUK. Patients and methods. A
      case series is given of all nine patients within our unit who have developed RA
      associated PUK since 1996. Details of the patients' arthropathy and the
      serological characteristics of the RA at presentation of PUK were noted. The
      patients' visual outcomes and the development of any significant systemic
      complications were recorded. RESULTS: All patients had long-standing
      seropositive, erosive RA. PUK was associated with a poor visual outcome in most
      patients, five requiring emergency corneal surgery to prevent perforation of the
      globe. Two patients developed systemic vasculitis within 1 month of PUK onset,
      one of whom died. CONCLUSION: RA-associated PUK often has a poor visual outcome
      and its appearance may herald the transformation of a patient's RA into the
      systemic vasculitic phase. RA-associated PUK should be managed with aggressive
      immunosuppression if the associated morbidity and mortality are to be avoided.
      Cell-mediated mechanisms appear to be important in the aetiopathogenesis of PUK
      and a combination of corticosteroids and cyclosporin is therefore probably the
      regimen of choice.

PMID- 10587554
TI  - Serum lysozyme: a potential marker of monocyte/macrophage activity in rheumatoid
      arthritis.
AB  - OBJECTIVE: Estimate the contribution of monocytes/macrophages to the disease
      process in rheumatoid arthritis (RA), by measuring the serum levels of the
      leucocyte-derived granular proteins: lysozyme, myeloperoxidase (MPO), lactoferrin
      and human neutrophil lipocalin (HNL). METHODS: Serum levels of these granular
      proteins were measured in patients with RA (n=23) and in healthy controls (n=27),
      and in 10 patients with RA after treatment with low-dose prednisolone. The serum
      levels of the granular proteins were also measured before and after treatment
      with metyrapone, a substance that inhibits the synthesis of cortisol in the
      adrenals. RESULTS: The serum levels of lysozyme and MPO were elevated in patients
      with RA, while the concentrations of lactoferrin and HNL were similar in both
      groups. Prednisolone treatment decreased the serum concentration of lysozyme and
      MPO. Metyrapone did not influence the level of the granular proteins measured.
      CONCLUSIONS: The increased serum levels of lysozyme and MPO, but not of HNL and
      lactoferrin in RA could indicate a stimulated secretory activity of mononuclear
      phagocytes. The measurement of serum lysozyme, as an indicator of
      monocyte/macrophage activity, might be used to study disease activity in RA.

PMID- 10587555
TI  - A randomized, double-blind, placebo-controlled trial of sclerosing injections in
      patients with chronic low back pain.
AB  - OBJECTIVE: To determine the clinical efficacy of sclerosing injections in
      patients with chronic low back pain. METHODS: Randomized, double-blind, placebo
      controlled trial of three, once weekly injections of dextrose-glycerine-phenol
      with lignocaine vs saline plus lignocaine in patients with mechanical back pain
      of more than 6 months' duration. All patient assessments were performed blind by
      an experienced physiotherapist. The injections to the ligaments of the L4-5 and
      L5-S1 lumbar motion segments were given by an orthopaedic physician experienced
      in the technique, blinded to the nature of the injection solution according to a
      standard protocol. Demographic and clinical data, the short-form McGill Pain
      Questionnaire, the modified Somatic Pain Questionnaire, the Zung Depression
      Inventory, Oswestry Disability Scale and the modified Schober method of measuring
      spinal flexion were undertaken at 0, 1, 3 and 6 months. RESULTS: Seventy-four
      patients [mean (S.D.) age 45(11) yr, female:male ratio 1:1, median pain duration
      >10 yr] were recruited and there were no drop-outs over the study period. There
      were no statistically significant differences in patient characteristics between
      the placebo and treatment groups at baseline or for any measure at follow-up.
      CONCLUSIONS: Three, weekly sclerosant injections alone may not be effective
      treatment in many patients with undifferentiated chronic back pain. Patient
      selection and combination with other treatment modalities may be factors in
      determining treatment success.

PMID- 10587556
TI  - A preliminary study determining the feasibility of electromagnetic tracking for
      kinematics at the ankle joint complex.
AB  - OBJECTIVE: To determine the feasibility of using electromagnetic tracking (EMT)
      for quantifying three-dimensional kinematics at the ankle joint complex (AJC).
      METHODS: AJC kinematics were recorded in 10 normal healthy adults, and 10
      rheumatoid arthritis patients presenting with AJC instability and deformity who
      were undergoing footwear and orthotic intervention. RESULTS: Kinematics in normal
      subjects had strong face validity, curve shape showing moderate (n=9), good (n=8)
      or excellent (n=4) agreement with data from seven published studies. The range of
      motion about the x-axis (15.2 degrees ) was similar to reference values (17.0
      degrees ), but our technique underestimated rotations about the y- (8.1 degrees
      vs 14.0 degrees ) and z-axes (7.7 degrees vs 12.2 degrees ). In the rheumatoid
      arthritis pronated foot group, eversion and internal rotation during the stance
      phase of gait were between 2 and 5 times greater than for normal subjects. The
      use of a corrective foot orthosis in this group restored normal kinematics,
      reducing maximum eversion and internal rotation by 57 and 68%, respectively.
      CONCLUSION: A new technique for measuring kinematics at the AJC is described.
      Based upon the findings of this pilot study, EMT may be useful for diagnosing AJC
      dysfunction and quantifying the mechanical efficacy of footwear and orthosis
      interventions.

PMID- 10587557
TI  - Ultrasonic measurement of the thickness of human articular cartilage in situ.
AB  - OBJECTIVE: The objective of the present study was to explore the possibility of
      using the ultrasonic pulse-echo technique for the non-invasive measurement of
      cartilage thickness in situ during a joint arthroscopic examination. The accuracy
      of the ultrasonic measurement was assessed in vitro against that of an
      established needling technique which is destructive. METHODS: The velocity of
      sound in articular cartilage was measured in an in vitro study of one set of
      ipsilateral human ankle and hip joints at 69 test sites. Its variability was
      determined. RESULTS: The velocity of sound in human articular cartilage measured
      in situ varied widely (1419-2428 m/s; mean: 1892 m/s; S.D. 183 m/s) and therefore
      the error in the thickness of cartilage obtained from ultrasonic measurement
      based upon a constant velocity of sound could be as large as 33.6% (mean 7. 38%;
      S.D. 6.25%). CONCLUSIONS: The ultrasonic pulse-echo technique is not accurate for
      the measurement of the thickness of cartilage in situ. An alternative (albeit
      minimally invasive) would be the needling technique. This requires the
      development of a specialized probe.

PMID- 10587558
TI  - Frequency of sepsis after local corticosteroid injection (an inquiry on 1160000
      injections in rheumatological private practice in France).
AB  - OBJECTIVES: The principal aims of this study were to determine the frequency of
      sepsis after local corticosteroid injection (SALCSI), to compare the results with
      those of the literature and to determine the main factors leading to a decrease
      in the frequency of SALCSI. METHODS: A retrospective study was conducted among 69
      rheumatologists in private practice. Sixteen items were studied and are reported.
      RESULTS: The mean number of years of private practice in rheumatology was 20.9.
      The total number of CS injections (CSI) was 1160000 for an average of 809 CSI per
      year and per therapist. The mean number of CSI performed by one rheumatologist
      was 16 800. Fifteen SALCSI had occurred, which corresponds to a frequency of
      1/77300 CSI. The rate of SALCSI for the older rheumatologists was lower than that
      of their younger colleagues. The frequency of use of corticosteroid packaged in a
      sterile syringe (CSPSS) was approximately 85%. Nine out of the 15 cases of sepsis
      had occurred after the use of CS not packaged in a sterile syringe and six after
      the use of CSPSS. Thus, the frequency of SALCSI was 1/162000 after the use of
      CSPSS and 1/21000 after the use of CS not packaged in a sterile syringe.
      CONCLUSIONS: The mean frequency of SALCSI in Paris and the surrounding area was
      1/77300 during the last 21 yr, a decrease since the 1960s and 1970s. This
      decreased incidence is in part due to the greater experience of the
      rheumatologist, but even more to the use of CSPSS.

PMID- 10587559
TI  - Comparison of the concentrations of pentosidine in the synovial fluid, serum and
      urine of patients with rheumatoid arthritis and osteoarthritis.
AB  - OBJECTIVE: Pentosidine, an advanced glycation end product (AGE), has recently
      been observed to be elevated in rheumatoid arthritis (RA). The aim was to
      elucidate which pentosidine levels, i.e. in serum, synovial fluid or urine, are
      more related to the disease status of RA. METHODS: We measured levels of
      pentosidine in serum, synovial fluid or urine in RA compared with osteoarthritis
      (OA), and examined the relationship between pentosidine and RA disease activity.
      Subjects were 20 patients with RA and 22 patients with OA. RESULTS: In total RA
      and OA patients combined, there was a significant correlation between pentosidine
      in serum, synovial fluid and urine. Pentosidine in serum and synovial fluid was
      significantly higher in RA than in OA. In RA, there were significant correlations
      between pentosidine in serum and synovial fluid and C-reactive protein, Lansbury
      index (LI) and erythrocyte sedimentation rate. CONCLUSIONS: These results
      demonstrate that pentosidine levels in body fluids correlated with each other,
      and pentosidine in serum and in synovial fluid is associated with the systemic
      inflammatory activity of RA. Higher or similar concentrations of pentosidine in
      serum compared with synovial fluids indicate that the elevated pentosidine levels
      in serum in RA are not derived from the synovial fluid, but from an increase in
      the formation of pentosidine in the whole body in RA. Among body fluids, serum
      pentosidine was the superior indicator for RA disease status.

PMID- 10587560
TI  - Prevalences of hepatitis A, B, C and E viruses in Behcet's disease.
AB  - OBJECTIVE: To determine whether Behcet's disease (BD), being a systemic
      vasculitis of unknown aetiology, is associated with hepatitis viruses (HAV, HBV,
      HCV and HEV). METHODS: In addition to 124 patients [male:female (M/F): 73/51],
      all fulfilling the diagnostic criteria of the International Study Group for BD
      (1991), 14 patients with systemic necrotizing vasculitis (M/F: 7/7), 47 patients
      with ankylosing spondylitis (M/F: 36/11) and 51 healthy controls (M/F: 22/29)
      were also included in this study. Serological markers of four different types of
      hepatitis (anti-HAV IgM, total anti-HAV, HBsAg, anti-HBs, total anti-HBc, anti
      HBc IgM, anti-HCV and anti-HEV) were studied in all cases. RESULTS: There was no
      difference between the groups with respect to HAV, HCV and HEV serologies. Anti
      HBs positivity was observed less frequently in BD compared with healthy controls
      and systemic vasculitis (P<0.05). CONCLUSION: Serological evidence of previous
      HAV, HCV and HEV infections was not significantly different between Behcet's
      patients and other groups. However, previous HBV infection was found in a
      significantly lower number of BD patients as compared with healthy controls and
      systemic vasculitic patients.

PMID- 10587561
TI  - Soluble CD30 in early rheumatoid arthritis as a predictor of good response to
      second-line therapy.
AB  - OBJECTIVE: To evaluate whether serum levels of the soluble form of CD30 (sCD30)
      correlate with disease activity in early rheumatoid arthritis (RA) and may have
      prognostic value in predicting the response to disease-modifying anti-rheumatic
      drugs (DMARDs). METHODS: The levels of sCD30 and C-reactive protein (CRP) were
      measured in the serum of 14 untreated subjects with early RA, before and during
      treatment with hydroxychloroquine, for a follow-up period of 8 months. At the end
      of the study, patients were also evaluated for their response to DMARDs. RESULTS:
      An inverse correlation between sCD30 and CRP serum values was demonstrated at
      baseline, but not during the follow-up. Patients who responded to DMARD therapy
      had higher sCD30 basal levels than non-responders. CONCLUSIONS: The evaluation of
      sCD30 serum levels in early RA may reflect the attempt by CD30+ T cells to
      downmodulate inflammation and may be a useful marker to predict a good response
      to DMARDs.

PMID- 10587562
TI  - Organizing pneumonia associated with pulmonary artery aneurysms in Behcet's
      disease.

PMID- 10587563
TI  - Postgraduate degrees for rheumatology trainees: an options appraisal of MD, PhD
      and MSc degrees. On behalf of the BSR Research and Training Committee.

PMID- 10587564
TI  - A comparison between primary care-led rheumatology services and secondary care
      provision.

PMID- 10587565
TI  - Recurrent focal myositis.

PMID- 10587566
TI  - Two ultraviolet radiation-induced episodes of optic neuritis in a patient with
      antinuclear antibody.

PMID- 10587567
TI  - Procoagulant mutations and venous thrombosis in Behcet's disease.

PMID- 10587568
TI  - Coronary dissection associated with hepatitis C virus-related cryoglobulinaemia.

PMID- 10587569
TI  - Nitric oxide synthesis in peripheral blood mononuclear and polymorphonuclear
      cells from patients with systemic sclerosis.

PMID- 10587570
TI  - Familial hypersensitivity to allopurinol with subsequent desensitization.

PMID- 10587571
TI  - Oral low-dose glucocorticosteroids as compared with intravenous
      methylprednisolone pulses in the treatment of rheumatoid arthritis.

PMID- 10587572
TI  - Oral methotrexate: hazard of different tablet strengths.

PMID- 10587573
TI  - Primary renal hypoplasia in humans and mice with PAX2 mutations: evidence of
      increased apoptosis in fetal kidneys of Pax2(1Neu) +/- mutant mice.
AB  - PAX2 mutations cause renal-coloboma syndrome (RCS), a rare multi-system
      developmental abnormality involving optic nerve colobomas and renal
      abnormalities. End-stage renal failure is common in RCS, but the mechanism by
      which PAX2 mutations lead to renal failure is unknown. PAX2 is a member of a
      family of developmental genes containing a highly conserved 'paired box' DNA
      binding domain, and encodes a transcription factor expressed primarily during
      fetal development in the central nervous system, eye, ear and urogenital tract.
      Presently, the role of PAX2 during kidney development is poorly understood. To
      gain insight into the cause of renal abnormalities in patients with PAX2
      mutations, kidney anomalies were analyzed in patients with RCS, including a large
      Brazilian kindred in whom a new PAX2 mutation was identified. In a total of 29
      patients, renal hypoplasia was the most common congenital renal abnormality. To
      determine the direct effects of PAX2 mutations on kidney development fetal
      kidneys of mice carrying a Pax2 (1Neu)mutation were examined. At E15,
      heterozygous mutant kidneys were approximately 60% of the size of wild-type
      littermates, and the number of nephrons was strikingly reduced. Heterozygous 1Neu
      mice showed increased apoptotic cell death during fetal kidney development, but
      the increased apoptosis was not associated with random stochastic inactivation of
      Pax2 expression in mutant kidneys; Pax2 was shown to be biallelically expressed
      during kidney development. These findings support the notion that heterozygous
      mutations of PAX2 are associated with increased apoptosis and reduced branching
      of the ureteric bud, due to reduced PAX2 dosage during a critical window in
      kidney development.

PMID- 10587574
TI  - Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause
      neurodegeneration in Drosophila.
AB  - Several dominant, late-onset neurodegenerative diseases (e.g. Huntington's
      disease) are caused by expansion of polyglutamine (polyQ) repeats within specific
      proteins. The diverse, yet overlapping, pathology of these diseases could be due
      to novel deleterious functions unique to each protein or to a common
      pathophysiology mediated by the long polyQ chains themselves. By engineering
      Drosophila to express different polyQ peptides, we find that expanded polyQ
      chains alone are intrinsically cytotoxic and cause neuronal degeneration and
      early adult death. We further find that this intrinsic toxicity is dependent on
      cell type and polyQ length and that the inclusion of other amino acids modifies
      and reduces toxicity. This is the first in vivo evidence that polyQs, when
      removed from their disease gene context, cause neurotoxicity. These studies
      provide a basis for understanding the diverse clinical presentations in terms of
      the intrinsic cytotoxic effect of polyQ peptides being modulated by protein
      context. Parallel experiments in which cytotoxic polyQ expansions were engineered
      into Dishevelled, a Drosophila protein containing a naturally occurring polyQ
      tract, strongly suggest that the effect of a toxic polyQ peptide can be
      neutralized by protein context. This animal model provides a simple and effective
      means of screening for therapeutics that relieves the polyQ-induced lethality,
      independent of any particular disease gene. By quantifying the degree of
      lethality in several transgenic lines, we have identified a number of genetically
      modified strains that are suitable for eventual testing of compounds or genes
      that ameliorate the pathology of polyQ peptides.

PMID- 10587575
TI  - A frameshift mutation in prominin (mouse)-like 1 causes human retinal
      degeneration.
AB  - The disks of vertebrate photoreceptors are produced by outgrowths of the plasma
      membrane. Hence genes that encode retinal proteins targeted to plasma membrane
      protrusions represent candidates for inherited retinal degenerations. One such
      candidate is the gene encoding human prominin (mouse)-like 1 (PROML1, previously
      known as AC133 antigen) which belongs to the prominin family of 5-transmembrane
      domain proteins. Murine prominin (prom) shows a strong preference for plasma
      membrane protrusions in a variety of epithelial cells whereas PROML1 is expressed
      in retinoblastoma cell lines and adult retina. In the present study, molecular
      genetic analyses of a pedigree segregating for autosomal recessive retinal
      degeneration indicated that the affected individuals were homozygous for a
      nucleotide 1878 deletion in PROML1. This alteration is predicted to result in a
      frameshift at codon 614 with premature termination of translation. Expression of
      a similar prom deletion mutant in CHO cells indicated that the truncated protein
      does not reach the cell surface. Immunocytochemistry revealed that prom is
      concentrated in the plasma membrane evaginations at the base of the outer
      segments of rod photoreceptors. These findings suggest that loss of prominin
      causes retinal degeneration, possibly because of impaired generation of the
      evaginations and/or impaired conversion of the evaginations to disks.

PMID- 10587576
TI  - NF1 microdeletion breakpoints are clustered at flanking repetitive sequences.
AB  - Neurofibromatosis type 1 patients with a submicroscopic deletion spanning the NF1
      tumor suppressor gene are remarkable for an early age at onset of cutaneous
      neurofibromas, suggesting the deletion of an additional locus that potentiates
      neurofibromagenesis. Construction of a 3.5 Mb BAC/PAC/YAC contig at chromosome
      17q11.2 and analysis of somatic cell hybrids from microdeletion patients showed
      that 14 of 17 cases had deletions of 1.5 Mb in length. The deletions encompassed
      the entire 350 kb NF1 gene, three additional genes, one pseudogene and 16
      expressed sequence tags (ESTs). In these cases, both proximal and distal
      breakpoints mapped at chromosomal regions of high identity, termed NF1REPs. These
      REPs, or clusters of paralogous loci, are 15-100 kb and harbor at least four ESTs
      and an expressed SH3GL pseudogene. The remaining three patients had at least one
      breakpoint outside an NF1REP element; one had a smaller deletion thereby
      narrowing the critical region harboring the putative locus that exacerbates
      neurofibroma development to 1 Mb. These data show that the likely mechanism of
      NF1 microdeletion is homologous recombination between NF1REPs on sister
      chromatids. NF1 microdeletion is the first REP-mediated rearrangement identified
      that results in loss of a tumor suppressor gene. Therefore, in addition to the
      germline rearrangements reported here, NF1REP-mediated somatic recombination
      could be an important mechanism for the loss of heterozygosity at NF1 in tumors
      of NF1 patients.

PMID- 10587577
TI  - Subcellular localization and axonal transport of the survival motor neuron (SMN)
      protein in the developing rat spinal cord.
AB  - The subcellular localization of the survival motor neuron (SMN) protein, encoded
      by the spinal muscular atrophy determining gene, was investigated in motor
      neurons of the developing and adult rat spinal cord by light and electron
      microscopy immunocytochemistry. The experiments were carried out with a panel of
      anti-SMN antibodies, all recognizing an SMN-specific protein band at 39 kDa in
      HeLa cells and rat spinal cord protein extracts. SMN protein expression decreased
      during postnatal spinal cord development, but it remained unchanged in
      distribution and intensity in motor neurons at all ages examined. SMN protein was
      mainly organized in immunoreactive aggregates sparse in the nucleoplasm and
      cytoplasm of both mature and developing motor neurons, and it was more rarely
      localized within the endoplasmic reticulum and in apposition to the external
      mitochondrial membrane. Most strikingly, the SMN protein was found in association
      with cytoskeletal elements in spinal dendrites and axons, where it was
      particularly evident during postnatal development. The present findings suggest
      that SMN protein may be transported via axoplasmic flow in maturing neurons.
      Given the RNA-binding activity of SMN, the SMN protein could be involved in the
      transport of specific mRNAs in axons and dendrites of motor neurons. The reduced
      transport of specific mRNAs within motor neurons during development could play a
      role in the motoneuronal degeneration and impaired axonal sprouting observed in
      spinal muscular atrophy.

PMID- 10587578
TI  - Independent association of an APOE gene promoter polymorphism with increased risk
      of myocardial infarction and decreased APOE plasma concentrations-the ECTIM
      study.
AB  - Apolipoprotein E (APOE) is a major protein in lipid metabolism existing in three
      common isoforms: APOE2, -3 and -4. The varepsilon4 allele of the APOE gene ( APOE
      ) coding for the APOE4 isoform is associated with an increased risk of myocardial
      infarction (MI) and of Alzheimer's disease (AD). Recently, several polymorphisms
      in the APOE regulatory region have been reported. Some of these have been
      associated with AD and modified APOE allelic mRNA expression in AD brains. Here,
      we have investigated whether three of these promoter polymorphisms (-491AT, 
      427CT and -219GT) can also modify cardiovascular risk. The hypothesis was tested
      in a large multicentre case-control study of MI, the ECTIM Study, on 567 cases
      and 678 controls. Among the three APOE promoter polymorphisms tested, only the
      219T allele was associated with a significantly increased risk of MI (OR = 1.29,
      95% CI: 1.09-1.52, P < 0.003) and the effect was shown to be independent of the
      presence of the other mutations, including the APOE epsilon2/epsilon3/epsilon4
      polymorphism. Moreover, the-219T allele greatly decreased the APOE plasma
      concentrations in a dose-dependent manner ( P < 0.008). These data indicate that
      the-219GT polymorphism of the APOE regulatory region emerges as a new genetic
      susceptibility risk factor for MI and constitutes another common risk factor for
      both neurodegenerative and cardiovascular diseases.

PMID- 10587579
TI  - Mutations in connexin31 underlie recessive as well as dominant non-syndromic
      hearing loss.
AB  - Mutations in the GJB3 gene encoding connexin31 (Cx31) can cause a dominant non
      syndromic form of hearing loss (DFNA2). To determine whether mutations at this
      locus can also cause recessive non-syndromic deafness, we screened 25 Chinese
      families with recessive deafness and identified in two families affected
      individuals who were compound heterozygotes for Cx31 mutations. The three
      affected individuals in the two families were born to non-consanguineous parents
      and had an early onset bilateral sensorineural hearing loss. In both families,
      differing SSCP patterns were observed in affected and unaffected individuals.
      Sequence analysis in both families demonstrated an in-frame 3 bp deletion (423
      425delATT) in one allele, which leads to the loss of an isoleucine residue at
      codon 141, and a 423A-->G transversion in the other allele, which creates an Ile-
      >Val substitution at codon 141 (I141V). Neither of these two mutations was
      detected in DNA from 100 unrelated control subjects. The altered isoleucine
      residue lies within the third conserved alpha-helical transmembrane domain (M3),
      which is critical for the formation of the wall of the gap junction pore. Both
      the deletion of the isoleucine residue 141 and its substitution to valine in the
      two families could alter the structure of M3, and impair the function of the gap
      junction. The present data demonstrate that, like mutations in connexin26,
      mutations in Cx31 can lead to both recessive and dominant forms of non-syndromic
      deafness.

PMID- 10587580
TI  - Cell cycle arrest enhances the in vitro cellular toxicity of the truncated
      Machado-Joseph disease gene product with an expanded polyglutamine stretch.
AB  - Machado-Joseph disease (MJD) is an inherited neurodegenerative disorder caused by
      the expansion of the polyglutamine stretch in the MJD gene-encoded protein,
      ataxin-3. Using a series of deletion constructs expressing ataxin-3 fragments
      with expanded polyglutamine stretches, we observed aggregate formation and cell
      death in cultured BHK-21 cells. The cytotoxic effect of N-terminal-truncated
      ataxin-3 with the expanded polyglutamine tract was enhanced under serum
      starvation culture, in which cells were arrested in the G(0)/G(1)phase.
      Coexpression of p21 (waf1/cip1/sdi1), a cyclin-Cdk inhibitor that induced cell
      cycle arrest in the G(1)phase, also increased the cell death susceptibility
      produced by the mutant ataxin-3 fragment in BHK-21 cells. The elevated
      susceptibility to cell death in the G(0)/G(1)phase was confirmed in nerve growth
      factor-treated, postmitotic neuronal PC12 cells compared with undifferentiated
      proliferating PC12 cells. These results strongly suggest that the cellular
      toxicity of truncated ataxin-3 with an expanded polyglutamine stretch is enhanced
      by cell cycle arrest in the G(0)/G(1)phase. Mutant ataxin-3 may confer a higher
      susceptibility to cell death on cells in the G(0)/G(1)phase.

PMID- 10587581
TI  - The sex-linked fidget mutation abolishes Brn4/Pou3f4 gene expression in the
      embryonic inner ear.
AB  - We have demonstrated that the phenotype of the mouse mutant sex-linked fidget (
      slf ) is caused by developmental malformations of the inner ear that result in
      hearing loss and vestibular dysfunction. Recently, pilot mapping experiments
      suggested that the mouse Brn4 / Pou3f4 gene co-segregated with the slf locus on
      the mouse X chromosome. These mapping data, in conjunction with the observation
      that the vertical head-shaking phenotype of slf mutants is identical to that
      observed in mice with a targeted deletion of the Brn4 gene, suggested that slf is
      a mutant allele of the Brn4 gene. In this paper, we have identified the nature of
      the slf mutation, and demonstrated that it is an X chromosomal inversion with one
      breakpoint close to Brn4. This inversion selectively eliminates the expression of
      the Brn4 gene in the developing inner ear, but not the neural tube. Finally,
      these results demonstrate that the slf mutation is a good mouse model for the
      most prevalent form of X-linked congenital deafness in man, which is associated
      with mutations in the human Brn4 ortholog, POU3F4.

PMID- 10587582
TI  - Significant evidence for linkage of febrile seizures to chromosome 5q14-q15.
AB  - Febrile seizures (FSs) represent the most common form of childhood seizure. In
      the Japanese population, the incidence rate is as high as 7%. It has been
      recognized that there is a significant genetic component for susceptibility to
      this type of seizure. Two putative FS loci, FEB1 (chromosome 8q13-q21) and FEB2
      (chromosome 19p), have been mapped. Furthermore, a mutation in the voltage-gated
      sodium (Na(+))-channel beta1 subunit gene ( SCN1B ) at chromosome 19q13.1 was
      identified in a family with a clinical subset, termed generalized epilepsy with
      febrile seizures plus (GEFS(+)). These loci are linked to some large families. In
      this study, we conducted a genome-wide linkage search for FS in one large family
      with subsequent linkage confirmation in 39 nuclear families. Significant linkage
      was found at D5S644 by multipoint non-parametric analysis using GENEHUNTER ( P =
      5.4 x 10(-6)). Estimated lambda(s)at D5S644 was 2.5 according to maximum
      likelihood analysis. Significant linkage disequilibria with FS were observed at
      the markers D5S644, D5S652 and D5S2079 in 47 families by transmission
      disequilibrium tests. These findings indicate that there is a gene on chromosome
      5q14-q15 that confers susceptibility to FSs and we call this gene FEB4.

PMID- 10587583
TI  - CGG/CCG repeats exhibit orientation-dependent instability and orientation
      independent fragility in Saccharomyces cerevisiae.
AB  - An expansion to >200 CGG/CCG repeats (hereafter called CGG) in the 5' region of
      the FMR1 gene causes fragile X syndrome, and this locus becomes a folate
      sensitive fragile site. We used Saccharomyces cerevisiae as a model system to
      study the stability and fragility of CGG repeats. Tracts of (CGG)(81)and
      (CGG)(160)were integrated onto a yeast chromosome in both orientations relative
      to the nearest replication origin. Tracts of this length are pre-mutation alleles
      in humans, with a high probability of expansion in future generations. The CGG
      tracts in yeast colonies showed a length-dependent instability with longer tracts
      being more prone to contraction than shorter tracts. In addition, there was an
      orientation bias for tract stability with tracts having fewer contractions when
      the CCG strand was the template for lagging strand synthesis. Expansions of the
      CGG tracts also occurred in an orientation-dependent manner, although at a lower
      frequency than contractions. To determine whether CGG tracts are fragile sites in
      yeast, the CGG tracts were flanked by direct repeats, and the rate of
      recombination between the repeats determined. Strains carrying the
      (CGG)(160)tract in either orientation had a large increase in their rate of
      recombination compared with a no-tract control strain. Because this increase was
      dependent on genes involved in double-strand break repair, recombination was
      likely to be initiated by CGG tract-induced breakage between the direct repeats.
      The observation of orientation-dependent instability and orientation-independent
      fragility suggests that at least some aspects of their underlying mechanisms are
      different.

PMID- 10587584
TI  - Profound obesity associated with a balanced translocation that disrupts the SIM1
      gene.
AB  - Studies of mice and humans have revealed a number of genes that when mutated
      result in severe obesity. We have studied a unique girl with early-onset obesity
      and a de novo balanced translocation between chromosomes 1p22.1 and 6q16.2. Her
      weight gain is most likely due to excessive food intake, since measured energy
      expenditure was normal. We cloned and sequenced both translocation breakpoints.
      The translocation does not appear to affect any transcription unit on 1p, but it
      disrupts the SIM1 gene on 6q. SIM1 encodes a human homolog of Drosophila Sim
      (Single-minded), a transcription factor involved in midline neurogenesis, and is
      a prototypical member of the bHLH-PAS (basic helix-loop-helix + period, aryl
      hydrocarbon receptor, Single-minded) gene family. Our subject's trans- location
      separates the 5' promoter region and bHLH domain from the 3' PAS and putative
      transcriptional regulation domains. The transcriptional targets of SIM1 are not
      known. Mouse Sim1 is expressed in the developing kidney and central nervous
      system, and is essential for formation of the supraoptic and paraventricular
      (PVN) nuclei of the hypothalamus. Previous neuroanatomical and pharmacological
      studies have implicated the PVN in the regulation of body weight: PVN neurons
      express the melanocortin 4 receptor and appear to be physiological targets of
      alpha-melanocyte-stimulating hormone, which inhibits food intake. We hypothesize
      that haploinsufficiency of SIM1, possibly acting upstream or downstream of the
      melanocortin 4 receptor in the PVN, is responsible for severe obesity in our
      subject.

PMID- 10587585
TI  - Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial
      partial lipodystrophy.
AB  - Patients with Dunnigan-type familial partial lipodystrophy (FPLD) are born with
      normal fat distribution, but after puberty experience regional and progressive
      adipocyte degeneration, often associated with profound insulin resistance and
      diabetes. Recently, the FPLD gene was mapped to chromosome 1q21-22, which
      harbours the LMNA gene encoding nuclear lamins A and C. Mutations in LMNA were
      shown to underlie autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD-AD),
      which is characterized by regional and progressive skeletal muscle wasting and
      cardiac effects. We hypothesized that the analogy between the regional muscle
      wasting in EDMD-AD and the regional adipocyte degeneration in FPLD, in addition
      to its chromosomal localization, made LMNA a good candidate gene for FPLD. DNA
      sequencing of LMNA in five Canadian FPLD probands indicated that each had a novel
      missense mutation, R482Q, which co-segregated with the FPLD phenotype and was
      absent from 2000 normal alleles ( P = 1.1 x 10(-13)). This is the first report of
      a mutation underlying a degenerative disorder of adipose tissue and suggests that
      LMNA mutations could underlie other diseases characterized by tissue type- and
      anatomical site-specific cellular degeneration.

PMID- 10587586
TI  - Molecular structure and evolution of an alpha satellite/non-alpha satellite
      junction at 16p11.
AB  - We have determined the detailed molecular structure and evolution of an alpha
      satellite junction from human chromosome 16p11. The analysis reveals that the
      alpha satellite sequence bordering the transition lacks higher-order structure
      and that the non-alpha satellite portion consists of a mosaic of duplicated
      segments of complex evolutionary origin. The 16p11 junction was formed recently
      (5-10 million years ago) by the duplication and transposition of genomic segments
      from Xq28 and 4q24. Once this mosaic structure was formed, a larger complex was
      spread among multiple pericentromeric regions. This resulted in the formation of
      large (>62 kb) paralogous segments that share a high degree ( approximately 97%)
      of sequence similarity. Both phylogenetic and comparative analyses indicate that
      these pericentromeric-directed duplications occurred around the time of the
      divergence of the human, gorilla and chimpanzee lineages, resulting in the subtle
      restructuring of the primate genome among these species. The available data
      suggest that such chimeric structures are a general property of several different
      human chromosomes near their alpha satellite junctions.

PMID- 10587587
TI  - Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a
      phosphorylation site with functional significance.
AB  - MITF (microphthalmia-associated transcription factor) is a basic-helix-loop-helix
      leucine zipper (bHLHZip) factor which regulates expression of tyrosinase and
      other melanocytic genes via a CATGTG promoter sequence, and is involved in
      melanocyte differentiation. Mutations of MITF in mice or humans with Waardenburg
      syndrome type 2 (WS2) often severely disrupt the bHLHZip domain, suggesting the
      importance of this structure. Here, we show that Ser298, which locates downstream
      of the bHLHZip and was previously found to be mutated in individuals with WS2,
      plays an important role in MITF function. Glycogen synthase kinase 3 (GSK3) was
      found to phosphorylate Ser298 in vitro, thereby enhancing the binding of MITF to
      the tyrosinase promoter. The same serine was found to be phosphorylated in vivo,
      and expression of dominant-negative GSK3beta selectively suppressed the ability
      of MITF to transactivate the tyrosinase promoter. Moreover, mutation of Ser298,
      as found in a WS2 family, disabled phos-phorylation of MITF by GSK3beta and
      impaired MITF function. These findings suggest that the Ser298 is important for
      MITF function and is phosphorylated probably by GSK3beta.

PMID- 10587589
TI  - Discretion is the name of the game.

PMID- 10587588
TI  - Motoneuronal cell death is not correlated with aggregate formation of androgen
      receptors containing an elongated polyglutamine tract.
AB  - Spinal and bulbar muscular atrophy (SBMA) is associated with an abnormal
      expansion of the (CAG)(n)repeat in the androgen receptor (AR) gene. Similar
      mutations have been reported in other proteins that cause neurodegenerative
      disorders. The CAG-coded elongated polyglutamine (polyGln) tracts induce the
      formation of neuronal intracellular aggregates. We have produced a model to study
      the effects of potentially 'neurotoxic' aggregates in SBMA using immortalized
      motoneuronal cells (NSC34) transfected with AR containing polyGln repeats of
      different sizes [(AR.Q(n = 0, 23 or 46)]. Using chimeras of AR.Q(n) and the green
      fluorescent protein (GFP), we have shown that aggregate formation occurs when the
      polyGln tract is elongated and AR is activated by androgens. In NSC34 cells co
      expressing the AR with the polyGln of pathological length (AR.Q46) and the GFP we
      have noted the presence of several dystrophic neurites. Cell viability analyses
      have shown a reduced growth/survival rate in NSC34 expressing the AR.Q46, whereas
      testosterone treatment partially counteracted both cell death and the formation
      of dystrophic neurites. These observations indicate the lack of correlation
      between aggregate formation and cell survival, and suggest that neuronal
      degeneration in SBMA might be secondary to axonal/dendritic insults.

PMID- 10587590
TI  - The Herbst appliance and the incidence of recidivism.

PMID- 10587592
TI  - Treatment effects produced by the twin-block appliance and the FR-2 appliance of
      Frankel compared with an untreated Class II sample.
AB  - This retrospective cephalometric study compares the treatment effects produced in
      40 patients treated with the Twin-block appliance to those seen in a matched
      sample of 40 children treated with the FR-2 appliance of Frankel and to changes
      undergone in 40 untreated Class II controls from The University of Michigan
      Elementary and Secondary School Growth Study. The average starting ages for the
      Twin-block, Frankel, and control groups were 10 years 5 months, 10 years 2
      months, and 9 years 11 months, respectively. The T(2) to T(1) observation period
      was adjusted to an average of 16 months for all groups. Significant decreases in
      overbite and overjet were observed at the end of treatment in the Twin-block and
      Frankel groups. Compared with the untreated subjects, statistically significant
      increases in mandibular length were observed in both treated groups. The Twin
      block patients achieved an additional 3.0 mm of mandibular length, whereas the
      Frankel group increased 1.9 mm more than did the controls. No significant
      restriction of midfacial growth was observed in either functional appliance group
      relative to controls. A significant increase in lower anterior facial height was
      evident in both treatment groups. Vertical increase in the Twin-block patients
      was significantly greater than in the FR-2 group. In general, more extensive
      dentoalveolar adaptation was observed with the tooth-borne Twin-block appliance
      than with the more tissue-borne FR-2 of Frankel. The Twin-block and FR-2 samples
      both showed significant retroclination and extrusion (eruption) of the maxillary
      incisors. The Twin-block patients also exhibited distal movement of the upper
      molars; however, there was no extrusion. Slight lower incisor proclination was
      noted in both treatment groups, and lower molar extrusion was found to be
      significantly greater in the Twin-block group compared with the other 2 samples.
      No horizontal differences were detected in the lower molars among groups. The
      present study suggests, therefore, that Class II correction with the Twin-block
      appliance is achieved through normal growth in addition to mandibular skeletal
      and dentoalveolar changes. Class II correction with the FR-2 is more skeletal in
      nature, with less dentoalveolar changes noted.

PMID- 10587593
TI  - Long-term application of chincup force alters the morphology of the dolichofacial
      Class III mandible.
AB  - The conventional orthopedic Milwaukee brace exerts a large and continuous force
      that induces malocclusion and a significant deformation of the mandible. Our
      previous chincup study examined its use in moderately severe mandibular
      prognathism without retrusion of the maxilla. The orthopedic force was
      approximately 500 g at the center of chin and was applied during sleep for 6 to
      24 months. For mandibular prognathism subjects (means, 1.0 degrees and -1.3
      degrees of ANB angle in the prepubertal and pubertal subjects), the resultant
      changes were maintained after retention. However, research reported that the
      changes obtained during chincup treatment (average, 4 (1/2) years' use) were
      often not maintained in severe skeletal Class III malocclusion. The aim of this
      clinical study was to investigate the immediate and long-term effects of
      prolonged use (mean, 7 years 2 months) of chincup appliances in subjects with
      dolichofacial Class III mandibles. Thirty-six female subjects with severe
      skeletal Class III malocclusions, associated with large gonial angles, were
      selected from the dental records of a private clinic. At posttreatment (T1, 65
      months' duration) and postretention (T2, 56 months after T1), Ar-Me and Wits
      appraisal cephalometric parameters were significantly different (P <.01) between
      patients and control subjects (n = 230). Furthermore, the Go-Me parameter in
      treated subjects was longer than that of the controls at T0 but became
      significantly shorter at T2 (P <.01). Treatment was associated with a finding
      that the Ar-Go parameter increased less than the controls at T2. Our results
      indicate that long-term use of the chincup appliance (>5 years) is effective in
      subjects with severe skeletal Class III abnormality.

PMID- 10587594
TI  - Effect of time on the shear bond strength of glass ionomer and composite
      orthodontic adhesives.
AB  - The purpose of this study was to compare the effects of time on the shear bond
      strength of a resin-reinforced glass ionomer and a composite adhesive system
      specifically (1) within half an hour after bonding the bracket to the tooth and
      (2) at least 24 hours from the time of bonding when the adhesive has achieved
      most of its bond strength. Ninety-one freshly extracted human molars were
      collected and stored in a solution of 0.1% (weight/volume) thymol. The teeth were
      cleaned and polished. The teeth were randomly separated into four groups: Group
      I, glass ionomer adhesive debonded within 30 minutes from initial bonding; Group
      II, glass ionomer adhesive debonded after 24 hours immersion in deionized water
      at 37 degrees C; Group III, composite adhesive debonded within 30 minutes from
      initial bonding; Group IV, composite adhesive debonded after 24 hours immersion
      in deionized water at 37 degrees C. The results of the analysis of variance
      comparing the 4 experimental groups (F = 59. 3) indicated the presence of
      significant differences between the 4 groups (P =.0001). In general, the shear
      bond strengths were significantly greater in the 2 groups debonded after 24
      hours. This was true for both the resin-modified glass ionomer (x = 8.8 +/- 3.6
      MPa) and the composite (x = 10.4 +/- 2.8 MPa) adhesives. On the other hand, the
      shear bond strengths were significantly lower in the 2 groups debonded within 30
      minutes of their initial bonding. The bond strength of the resin-modified glass
      ionomer adhesive (x = 0.4 +/- 1.0 MPa) was significantly lower than that for the
      composite (x = 5.2 +/- 2.9 MPa) adhesive. The present findings indicated that the
      resin reinforced glass ionomer adhesive has a significantly lower initial bond
      strength but increased more than 20-fold within 24 hours. In comparison, the
      composite adhesive has a significantly larger initial bond strength that doubled
      within 24 hours. The clinician needs to take these properties into consideration
      when ligating the initial arch wires.

PMID- 10587595
TI  - Does 2 years' nocturnal treatment with a mandibular advancement splint in adult
      patients with snoring and OSAS cause a change in the posture of the mandible?
AB  - The aim of this pilot study was to investigate the effects of 2 years' nocturnal
      treatment with a mandibular advancement splint in adult patients with snoring and
      obstructive sleep apnea syndrome with respect to possible development of a
      forward position of the mandible or other dentofacial changes. Thirty snoring and
      sleep apnea patients, mean age 55.3 years (SD, 8.61; range, 46.5 to 79.8 years),
      referred from the Ear, Nose, and Throat Department, were treated with an acrylic
      splint with full tooth coverage that advanced the mandible 5 to 8 mm (70% of
      maximal protrusion) and used 5 mm opening vertically. The splint was used 6 to 8
      hours per night and 5 to 7 nights per week. Two lateral head radiographs were
      taken in centric occlusion, 1 before and 1 after 2 years of treatment. A small
      but statistically significant forward and downward change in mandibular position
      was found after treatment; mean was 0.4 mm (SD, 0.53; range, 0.0 to 2.0 mm; P
      <.001) and 0.3 mm (SD, 0.43; range, 0. 0 to 1.5 mm; P <.001), respectively. The
      forward and downward movement of the mandible was accomplished by a statistically
      significant increase in mandibular length-mean was 0.4 mm (SD, 0.62; range, 0.0
      to 2.5 mm; P <.01)-and a significant decrease in overjet (P <.001) and overbite
      (P <.05). However, none of the patients reported any permanent sense of altered
      occlusion, and the anteroposterior distance between habitual occlusion
      (intercuspal position) and centric relation (retruded position) did not exceed 1.
      0 mm in any of the patients either before or after the treatment. The change in
      mandibular position might be a result of a condylar and/or glenoid fossa
      remodeling or condylar position changes within the fossa as a compensatory
      reaction to the advancement of the mandible (bite jumping). However, to visualize
      and analyze such possible changes in detail, additional studies using lateral
      tomography of the temporomandibular joints or magnetic resonance imaging are
      required. Furthermore, because the treatment of snoring and OSAS patients is
      considered to be lifelong, long-term studies are needed to analyze if the small
      change in mandibular position will continue with further treatment.

PMID- 10587596
TI  - Effectiveness of a fluoride-releasing sealant in reducing decalcification during
      orthodontic treatment.
AB  - Decalcification and caries during orthodontic treatment still remains a problem.
      A method to protect the susceptible area beneath and adjacent to bonded
      attachments, independent of patient compliance, would be extremely beneficial. A
      clinical trial was performed using a dual-cured lightly filled BIS-GMA fluoride
      releasing sealant. The barrier effect of this material on white spot formation,
      gingival irritation, and plaque accumulation during fixed orthodontic therapy was
      examined. Twenty patients with a total of 225 metal brackets placed on anterior
      teeth participated in this study. Brackets were placed in both arches in a
      conventional manner with a chemically cured, unfilled bonding resin; 112 teeth
      (every other tooth) received the barrier material after bracket placement, while
      the remaining 113 teeth served as controls. Intraoral photographic slides were
      taken before and after treatment and were evaluated blindly by 7 observers for
      white spot formation. Gingival and plaque indexes were recorded initially and
      consecutively every 6 months. Observation time ranged from 5 to 18 months. The
      results of this prospective clinical study indicated that there was no
      significant difference (P >.05) between the decalcification rates of the
      treatment or control groups. Likewise there was no added benefit with respect to
      plaque accumulation or gingival irritation.

PMID- 10587597
TI  - An in vitro evaluation of a metal reinforced orthodontic ceramic bracket.
AB  - The objectives of the present study were to measure and compare the bond strength
      and failure sites of a currently available ceramic bracket (Transcend 3M-Unitek)
      with the new metal reinforced ceramic bracket (Clarity 3M-Unitek) and to evaluate
      the amount of composite left on the tooth using the Adhesive Remnant Index in the
      teeth that were debonded with pliers recommended for this purpose. In addition,
      the presence or absence of enamel damage after debonding was also assessed. One
      hundred and twenty extracted premolar teeth were divided into 4 groups of 30
      each. Two groups of 30 teeth had Transcend 6000 brackets bonded, and the other 2
      groups had Clarity brackets bonded. Shear bond strength was carried out on 30
      Transcend 6000 brackets and 30 Clarity brackets, whereas the other 2 groups of 30
      teeth bonded with Transcend 6000 and Clarity brackets were debonded with
      debonding pliers recommended by the manufacturer of both ceramic brackets. The
      mean shear bond strength of the Clarity brackets was 13.27 MPa, whereas that of
      the Transcend 6000 was 21.19 MPa. Both brackets failed mostly at the bracket
      adhesive interface (75%), indicating a possible reduction of the chances of
      enamel damage. Six of the premolars, bonded with Transcend 6000 brackets and
      debonded with the plier, showed an increase in the number or length of enamel
      cracks as evaluated by an optical microscope (Micro-Vu); one premolar, bonded
      with Clarity brackets and debonded with the pliers, showed an increased enamel
      crack length. Gross enamel damage, assessed by enamel dislodgment, was not
      evident in any specimen. Results of this study suggest that the new metal
      reinforced ceramic bracket (Clarity) may be recommended for clinical use because
      of its acceptable shear bond strength and possible reduced chances of enamel
      damage during bracket removal.

PMID- 10587598
TI  - Effect of repeated orthodontic treatment on the dental and periodontal tissues of
      the rat incisor.
AB  - This study evaluated the response of treated teeth to renewed orthodontic force.
      Thirty female rats (201 +/- 2.7 g) were divided into groups A and B.
      Linguointrusive loads (20.58 +/- 1.88 g) generated by springs were applied to the
      lower left incisor for 2 weeks and then removed to allow recovery during 27 weeks
      (group A). Identical loading was then repeated in group A and applied as primary
      treatment in group B. Five animals from each group were killed with the springs
      in situ (A-1 and B-1), while the remaining 20 animals were killed after a 3-month
      recovery (A-2, B-2). The decalcified incisors were cross-sectioned serially (2
      microm), and the distance of each section from the apex was computed. Dental and
      periodontal injuries were evaluated by light microscopy and plotted according to
      their location on the tooth axis. The intrusion of the teeth in group A-1 was
      significantly greater, whereas recovery of the normal eruption rate in group A-2
      was significantly slower compared with groups B-1 and B-2. The histopathologic
      lesions in groups A-1 and B-1 did not differ. However, group A-2 showed a higher
      frequency of injured enamel organ, tissue infiltration by inflammatory cells,
      necrotic areas, and dentin resorption than group B-2. Initial orthodontic loading
      had a detrimental effect on the ability of the periodontal and dental tissues to
      cope with, and to recover from, repeated stress, probably because of a decrease
      in the number of periodontal fibroblasts and damage to the dentin-protecting
      cementoblastic layer.

PMID- 10587599
TI  - Eruption disturbances of the first and second permanent molars: results of
      treatment in 43 cases.
AB  - Impaction or retention of first and second permanent molars is an uncommon
      condition with diverse therapeutic approaches. To ascertain the success rate of
      different treatment possibilities, a retrospective study was made of 25 patients
      with a total of 43 permanent molars with eruption disturbances. In most cases,
      the nonerupted teeth were mandibular second molars (65%), followed by maxillary
      second molars (21%). Their position, degree of impaction (inclusion), clinical
      features, repercussion on the neighboring teeth, type of treatment, and outcome
      were evaluated. Infraocclusion was often associated with malposition of
      neighboring teeth, as well as extrusion and infraocclusion of opposing teeth. Due
      mostly to a delay in the diagnosis of the condition, an acceptable final position
      of the nonerupted molar was obtained in only 8 of 13 conservatively treated
      second molars. In order to prevent this situation, radiographic examination
      (ideally during the early mixed dentition period) and early diagnosis of eruption
      disturbances of permanent first and second molars are recommended, particularly
      when considering that these anomalies are associated with a high rate of occlusal
      disturbances that may require orthodontic correction.

PMID- 10587600
TI  - Total quality management in orthodontic practice.
AB  - Quality is the buzz word for the new Millennium. Patients demand it, and we must
      serve it. Yet one must identify it. Quality is not imaging or public relations;
      it is a business process. This short article presents quality as a balance of
      three critical notions: core clinical competence, perceived values that our
      patients seek and want, and the cost of quality. Customer satisfaction is a
      variable that must be identified for each practice. In my practice, patients
      perceive quality as communication and time, be it treatment or waiting time. Time
      is a value and cost that must be managed effectively. Total quality management is
      a business function; it involves diagnosis, design, implementation, and
      measurement of the process, the people, and the service. Kazien is a function
      that reduces value services, eliminates waste, and manages time and cost in the
      process. Total quality management is a total commitment for continuous
      improvement.

PMID- 10587601
TI  - Treatment of a Class III malocclusion with a missing mandibular incisor and
      severe crowding.

PMID- 10587602
TI  - Idiopathic condylar resorption: diagnosis, treatment protocol, and outcomes.
AB  - Idiopathic condylar resorption is a poorly understood progressive disease that
      affects the TMJ and that can result in malocclusion, facial disfigurement, TMJ
      dysfunction, and pain. This article presents the diagnostic criteria for
      idiopathic condylar resorption and a new treatment protocol for management of
      this pathologic condition. Idiopathic condylar resorption most often occurs in
      teenage girls but can occur at any age, although rarely over the age of 40 years.
      These patients have a common facial morphology including: (1) high occlusal and
      mandibular plane angles, (2) progressively retruding mandible, and (3) Class II
      occlusion with or without open bite. Imaging usually demonstrates small resorbing
      condyles and TMJ articular disk dislocations. A specific treatment protocol has
      been developed to treat this condition that includes: (1) removal of hyperplastic
      synovial and bilaminar tissue; (2) disk repositioning and ligament repair; and
      (3) indicated orthognathic surgery to correct the functional and esthetic facial
      deformity. Patients with this condition respond well to the treatment protocol
      presented herein with elimination of the disease process. Two cases are presented
      to demonstrate this treatment protocol and outcomes that can be achieved.
      Idiopathic condylar resorption is a progressive disease that can be eliminated
      with the appropriate treatment protocol.

PMID- 10587603
TI  - Palatal implant anchorage reinforcement of posterior teeth: A prospective study.
AB  - A new orthodontic implant anchor system (Orthosystem) has been developed. This 1
      piece device made from titanium consists of a screw-type endosseous section
      (lengths of 4 and 6 mm), a cylindrical transmucosal neck, and an abutment. Clamp
      caps with slots provide for attachment of square orthodontic wires (transpalatal
      bars) to the implant. The aim of the present prospective study was to evaluate
      the anchorage capacity of palatally inserted Orthosystem implants for anchorage
      reinforcement of posterior teeth. The sample consisted of 9 dental Class II
      patients (age 15 to 35 years) whose treatment plan included extraction of the
      maxillary first premolars. Each of the patients received 1 implant inserted into
      the center of the anterior palate. After a mean unloaded implant healing period
      of 3 months, transpalatal bars were inserted to connect the posterior teeth to
      the implant. Retraction of the canines and incisors was accomplished without the
      use of compliance-dependent headgear or Class II elastics. The degree of
      anchorage loss as well as the amount of canine and incisor retraction were
      evaluated by measurements of the casts and lateral cephalograms. The mean
      anchorage loss was 0.7 mm on the right side and 1.1 mm on the left (P <.05). The
      right and left canines were retracted 6.6 and 6.4 mm, respectively, and the mean
      overjet reduction was 6.2 mm. Because clinical assessment and postremoval
      histologic assessment both revealed stability of the short implant, the small
      anchorage loss was most likely from the deformation of the transpalatal bars by
      the orthodontic forces. Nevertheless, the treatment goal was achieved in all
      patients without the use of compliance-dependent auxiliaries. The clinical
      experience during and after implant insertion, active orthodontic treatment,
      retrieval of the implant, and subsequent wound healing are described.

PMID- 10587604
TI  - Investigation of bacteremia after orthodontic banding.
AB  - The aim of this study was to assess the incidence of bacteremia after orthodontic
      banding. The study was conducted on 40 healthy orthodontic patients with good
      oral hygiene. Venous blood samples were obtained with a strict aseptic technique
      before and after fitting of a molar band in each patient. Microbiologic
      evaluation of the samples revealed a postoperative bacteremia incidence of 7.5%.

PMID- 10587605
TI  - Effect of serial extraction alone on crowding: relationships between tooth width,
      arch length, and crowding.
AB  - In this study, we examined the effect of serial extraction alone on crowding. We
      also investigated the relationships between tooth width, arch length, and
      irregularity index. Maxillary dental casts from 32 subjects who had undergone
      only serial extraction were analyzed at 3 stages: before deciduous canines
      extraction, after first premolars extraction, and at the end of the observation
      period. The mean of the irregularity index decreased significantly as serial
      extraction proceeded and further decreased during the observation period. In
      cases where the width of the incisor was more than 2 standard deviations above
      the means for the control subjects, there was a significant correlation between
      tooth width of the lateral incisors and irregularity index before extraction as
      well as a significant correlation between the summation of tooth widths of the
      central and lateral incisors and irregularity index at that time. There was a
      significant negative correlation between arch length discrepancy and irregularity
      index before extraction and also a significant correlation between arch length
      discrepancy and correction of the irregularity index from before deciduous
      canines extraction to after first premolars extraction. These results suggest
      that tooth width and arch length discrepancy might preferentially affect the
      degree of anterior crowding in cases of severe crowding. There was no aggravation
      of the average crowding level during the observation period in the present study.
      The present study quantitatively suggested that serial extraction was useful for
      the purpose of correcting crowding in most cases.

PMID- 10587606
TI  - AAO continuing education

PMID- 10587607
TI  - Computer survey.

PMID- 10587608
TI  - Litigation, legislation, and ethics. Statute of limitations declared
      unconstitutional.

PMID- 10587609
TI  - Cholesterol inhibits glutamine metabolism in LLC WRC256 tumour cells but does not
      affect it in lymphocytes: possible implications for tumour cell proliferation.
AB  - The effect of cholesterol on proliferation and glutamine metabolism of
      lymphocytes and tumour cells was investigated. The addition of cholesterol to the
      culture medium did not cause a significant effect on [2-(14)C]-thymidine
      incorporation in lymphocytes. In the presence of concanavalin A, lymphocyte
      proliferation was increased by cholesterol (from 0.013 up to 1.3 microm). At high
      concentrations (234 and 468 microm), however, a marked inhibition of lymphocyte
      proliferation occurred. The same inhibitory effect was observed in the presence
      of lipopolysaccharides. Cholesterol also caused a marked decrease of LLC WRC256
      tumour cell growth at 117 and 234 microm. The same findings were obtained by the
      measurement of [2-(14)C]-thymidine incorporation in these cells. The effect of
      cholesterol on phosphate-dependent glutaminase activity was then tested in
      cultured lymphocytes and LLC WRC256 tumour cells. Cholesterol at concentrations
      of 117 and 234 microm did not alter this enzyme activity in lymphocytes. However,
      this sterol, already at 26 microm, caused a 44 per cent reduction in glutaminase
      activity. Similar to the changes observed for glutaminase, cholesterol reduced
      glutamine oxidation in LLC WRC256 tumour cells, whereas no effect was observed on
      lymphocytes. Therefore, cholesterol might control lymphocyte and tumour cells
      proliferation by different mechanisms. The significance of these findings for the
      immune function in tumour-bearing patients remains to be investigated.

PMID- 10587610
TI  - Modulation of gastrin-releasing peptide (GRP) receptors in insulin secreting
      cells.
AB  - Gastrin-releasing peptide (GRP) receptors are present in pancreatic islets,
      though their regulation is unknown except for homologous desensitization. The
      modulation of binding of GRP to mouse pancreatic islets and INS-1 cells was
      studied. At 60 min (steady-state), total binding of [(125)I-Tyr(15)] GRP was 1.62
      per cent of total radioactivity per 50 islets; non-specific binding (presence of
      1 mM unlabelled GRP(1-27)) was 0.05 to 0.61 per cent of total radioactivity. A
      preincubation with 1000 nM cholecystokinin (CCK(8)) or with 1000 nM glucose
      dependent insulinotropic peptide (GIP) augmented the number of GRP binding sites
      but not their affinity. [(125)I-Tyr(15)]GRP binding to INS-1 cells was saturable
      (90 min) and specific with respect to compounds that are not chemically related
      to GRP (e.g. calcitonin gene-regulated peptide-CGRP and atrial natriuretic
      peptide-ANP). Displacement studies showed one binding site with a K(d) of 0.39 nM
      and a B(max) of 13.2 fmoles mg(-1) protein. When the cells were pretreated for 24
      h with 10 nM GIP or CCK(8), only GIP but not CCK(8) increased the B(max) of the
      GRP binding site. The affinity (K(d)) was not changed by either compound. This
      effect of GIP pretreatment was not affected by downregulating PKC by TPA (phorbol
      ester; long-term pretreatment). These data indicate that: (1) specific binding
      sites for GRP are present in mouse pancreatic islets and INS-1 cells; (2) the GRP
      binding is upregulated by GIP in both islets and INS-1 cells and additionally by
      CCK(8 ), albeit only in islets; and (3) PKC does not seem to be involved in the
      up-regulation process. Thus a positive interplay between both the incretins GIP
      and CCK(8) and the neurotransmitter GRP is obvious.

PMID- 10587611
TI  - Derivatives of 1,4-dihydropyridines as modulators of ascorbate-induced lipid
      peroxidation and high-amplitude swelling of mitochondria, caused by ascorbate,
      sodium linoleate and sodium pyrophosphate.
AB  - A group of 26 2,6-dimethyl-3,5-disubstituted and 2,6-dimethyl-3,4, 5
      trisubstituted-1,4-dihydropyridines (1,4-H(2)Py=1,4-DHPs) and five related
      pyridines were studied as inhibitors of rat liver mitochondrial swelling and O(2)
      uptake by ascorbic acid-dependent lipid peroxidation (LP) and as modulators of
      mitochondrial swelling induced by Na(+)-linoleate or Na(+)-pyrophosphate. 1,4
      DHPs studied include 4-unsubstituted and 4-methyl- and 4-phenyl-substituted 3, 5
      dialkoxycarbonylderivatives of 2,6-dimethyl-1,4-DHP with variations in alkoxy
      chain length and composition, 4-unsubstituted and 4-methyl-, 4-aryl- and 4
      pyridyl-substituted 3, 5-dianilidocarbonylderivatives, and a structurally related
      group of 3,5-dipyridylamidocarbonylderivatives. Many 1,4-DHPs possess marked
      antioxidant (AO) and membrane stabilizing activity, expressed as the
      mitochondrial swelling (deltaA(520)/t) and/or O(2) uptake rate decrease (V(0)/V)
      as well as prolongation of the induction period (tau/tau(0)) of mitochondrial
      swelling and/or O(2) uptake at ascorbic acid-dependent LP of rat liver
      mitochondria. 4-Unsubstituted 3,5-dialkoxycarbonyl-2,6-dimethyl-1,4-DHPs, as well
      as 4-unsubstituted or those possessing lipophylic 4-aryl- groups 3, 5-diamido-2,6
      dimethyl-1,4-DHPs, reveal marked AO and membrane stabilizing properties. Oxidized
      (heteroaromatized) derivatives have minimal activity. Perhaps 1,4-DHPs preferably
      act as antioxidants on stages of initiation and prolongation of LP chain
      reactions at low concentrations: IC(50) (when V(0)/V or tau/tau(0)=2) are 0.1
      microM to 100 microM. At 100 microM 3,5-di-p-hydroxyphenoxycarbonyl- and 3, 5-di
      p-tolyloxycarbonyl-2,6-dimethyl-1,4-DHPs, as well as 3, 5-diethoxycarbonyl-2,6
      dimethylpyridine (oxidized form of Hantzsch ester) and 3,5-diamyloxycarbonyl-2,6
      dimethylpyridine, alter the mitochondrial swelling rate in the presence of
      natural protonophore Na(+)-linoleate (0.063 mM and 0.125 mM). 3,5-Di-n
      butyloxycarbonyl-2, 6-dimethyl-1,4-DHP at 100 microM completely stops
      mitochondrial swelling in the presence of 0.8 mM Na(+)-pyrophosphate. In the
      presence of many of the 1,4-DHPs, the lipid peroxidation process was inhibited.
      However, the swelling process could be prolonged, promoted, accelerated or
      inhibited-depending on 1,4-DHPs structure, concentration, the type of initiators
      of the swelling process and the medium composition.

PMID- 10587612
TI  - Protective effects of vitamin E on carbon tetrachloride-induced liver damage in
      rats.
AB  - In this study we investigated whether the increase of hepatic vitamin E content
      by intraperitoneal administration, influences chronic liver damage induced by
      carbon tetrachloride (CCl(4)) in rats. Thirty adult male Wistar rats were divided
      into three groups. The first group was used as a control and the rats in the
      second group were administered CCl(4) in olive oil subcutaneously. Rats in the
      third group were administered intraperitoneally vitamin E (dl-alpha-tocopherol
      acetate, 100 mg kg(-1)). This administration was performed three times per week
      for five weeks. Liver samples were used for the determination of vitamin E
      levels, glutathione peroxidase (GSHPx) activities and histological examination.
      Serum levels of alanine aminotransferase, lactate dehydrogenase, alkaline
      phosphatase, aspartate aminotransferase, gamma-glutamyltranspeptidase, total and
      conjugated bilirubin were significantly (p<0.05, p<0.01, p<0.001) higher in
      animals treated with CCl(4) than in the controls and had returned to normal
      values by the administration of vitamin E + CCl(4 ). Liver vitamin E levels were
      significantly (p<0.05) lower in the CCl(4) group than in the control group.
      However, the liver vitamin E content was significantly (p<0.01, p<0.001)
      increased in the vitamin E + CCl(4) injected group. On the other hand, liver
      GSHPx activity was not statistically different among the groups. On histological
      examination, vitamin E administered animals showed incomplete, but significant,
      prevention of liver necrosis and cirrhosis induced by CCl(4 ). these data
      indicate that intraperitoneally administered vitamin E has protective effects
      against CCl(4)-induced chronic liver damage and cirrhosis as evidenced by
      biochemical data and conventional histological examination.

PMID- 10587613
TI  - Molecular cloning and expression of nitric oxide synthase gene in chick embryonic
      muscle cells.
AB  - The chick skeletal muscle nitric oxide synthase (NOS) gene was cloned in order to
      further define the involvement of NOS in the differentiation of skeletal muscle
      cells. The respective cDNA had an open reading frame of 1136 amino acid residues,
      predicting a protein of 129,709.85 Da, and recognition sites for FAD, FMN, NADPH,
      and a calmodulin-binding site like those of other mammalian NOS's. Alignment of
      the deduced amino acid sequence revealed high homology with mammalian inducible
      NOS (iNOS), but not other NOS isoforms, suggesting chick skeletal muscle NOS may
      be an iNOS isoform. Immunoblots showed that NOS expression was highly restricted
      in embryonic muscle, but not in adult skeletal muscle: NOS expression markedly
      increased from embryonic day 9, reached a maximum by embryonic day 13, and then
      gradually declined until it was no longer detectable on embryonic day 19. When
      muscle cells obtained on embryonic day 12 were cultured, NOS expression increased
      transiently prior to the onset of differentiation and decreased thereafter.
      Inhibition of NOS expression by PDTC completely prevented muscle cell
      differentiation, as indicated by the inhibition of expression of myosin heavy
      chain and creatine kinase. The inhibitory effect of PDTC was completely reversed
      by addition of sodium nitroprusside, a compound that produces NO. These results
      clearly indicate that NOS is significantly involved in the differentiation of
      chick skeletal muscle cells.

PMID- 10587615
TI  - Iron metabolism and HIV infection: reciprocal interactions with potentially
      harmful consequences?
AB  - Humans with advanced human immunodeficiency virus (HIV) infection present some
      evidence suggestive of iron accumulation. Ferritin concentrations increase with
      HIV disease progression, and iron accumulates in several tissues. Iron excess may
      exert negative effects in individuals with HIV. Indeed, iron accumulation seems
      to be associated with shorter survival, and a number of investigations point to
      an iron-mediated oxidative stress in subjects with HIV infection. The
      observations on humans infected with HIV are in part supported by in-vitro
      findings. Indeed, in-vitro HIV infection is associated with changes in iron
      metabolism, and an iron-mediated oxidative stress is likely to contribute to
      viral cytopathogenicity. Furthermore, it is interesting to point out that the
      interaction between iron and HIV may be reciprocal, since viruses with a life
      cycle involving a DNA phase require chelatable iron for optimum replication. This
      combined evidence suggests that iron metabolism is an important area for
      virus/host interaction. These observations may be relevant to both laboratory
      monitoring and clinical treatment of individuals with HIV.

PMID- 10587614
TI  - Gluconeogenesis in the liver of arthritic rats.
AB  - The gluconeogenic response in the liver from rats with chronic arthritis to
      various substrates and the effects of glucagon were investigated. The
      experimental technique used was the isolated liver perfusion. Hepatic
      gluconeogenesis in arthritic rats was generally lower than in normal rats. The
      difference between normal and arthritic rats depended on the gluconeogenic
      substrate. In the absence of glucagon the following sequence of decreasing
      differences was found: alanine (-71.8 per cent) reverse similarglutamine (-71.7
      per cent)>pyruvate (-60 per cent)>lactate+pyruvate (-44.9 per cent)>xylitol
      (n.s.=non-significant) reverse similarglycerol (n.s.). For most substrates
      glucagon increased hepatic gluconeogenesis in both normal and arthritic rats. The
      difference between normal and arthritic rats, however, tended to diminish, as
      revealed by the data of the following sequence: alanine (-48.9 per cent) reverse
      similarpyruvate (-47.6 per cent)>glutamine (-33.8 per cent)>glycerol (n.s.)
      reverse similarlactate+pyruvate (n.s.) reverse similarxylitol (n.s.). The causes
      for the reduced hepatic gluconeogenesis in arthritic rats are probably related
      to: (a) lower activities of key enzymes catalyzing most probably steps preceding
      phosphoenolpyruvate (e.g. phosphoenolpyruvate carboxykinase, pyruvate
      carboxylase, etc. ); (b) a reduced availability of reducing equivalents in the
      cytosol; (c) specific differences in the situations induced by hormones or by the
      individual substrates. Since glycaemia is almost normal in chronically arthritic
      rats, it seems that lower gluconeogenesis is actually adapted to the specific
      needs of these animals.

PMID- 10587616
TI  - Simulation of ion trajectories in a quadrupole ion trap: a comparison of three
      simulation programs
AB  - An attempt has been made to compare the performance, design and operation of
      three simulators, ISIS, ITSIM and SIMION-3D, when applied to the calculation of
      ion trajectories in a quadrupole ion trap. For the simulation of the trajectory
      of a single ion in a collision-free system, the calculated spatial trajectory
      components, kinetic energies and secular frequencies from the three simulators
      were virtually identical. It is concluded that, despite the various approaches to
      electrode design, calculation of fields, integration methods and ion generation
      tactics, there is a remarkable degree of consistency among the products of the
      simulators when dealing with collision-free conditions. The results of the ion
      injection simulations under collisional conditions were indicative of the
      complexity that can be introduced into the simulations with little effort. Random
      effects such as collisions of ions with He buffer gas and accumulated calculation
      errors together with the different collision model settings and the different
      approaches to field calculation are thought to have contributed to the somewhat
      minor differences in trapping efficiency. SIMION is the simulator of choice for
      the simulation of ion trajectories in hybrid instruments and in custom-designed
      assemblies of electrodes; and ITSIM would appear to be the best choice on the
      basis of computational speed for running multiparticle simulations and user
      friendliness. Both ISIS and ITSIM are adept at providing detailed information of
      collision events. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10587617
TI  - Mass spectrometry of 3,5- and 4,5-dicaffeoylquinic acids and selected derivatives
AB  - The mass spectral properties of 3,5- and 4,5-dicaffeoylquinic acids (DCQAs) and
      selected derivatives were examined using electron ionization (EI), fast atom
      bombardment (FAB) and electrospray ionization (ESI). EI analysis of the
      trimethylsilyl derivatives provides molecular mass (M(r)) information, but the
      spectrum is dominated by fragment ions of the caffeic acid group; isomers cannot
      be differentiated using EI. FAB analysis, in both the positive and negative ion
      detection modes, provides M(r) information on the free compounds, but little
      fragmentation is observed using normal scan conditions. The FAB mass-analyzed ion
      kinetic energy spectroscopic analysis of the free compounds does, however, permit
      differentiation of the isomers, with 3,5-DCQA showing selective loss of water, a
      process not observed with the 4,5-isomer. Both EI and FAB provide M(r) and some
      structural information when applied to the peracetate derivatives of the DCQAs.
      ESI of the DCQAs provides considerably more structural information, especially in
      the negative ion detection mode, and is the recommended method of analysis of the
      quinic acid esters. M(r) information, identity of the ester groups and
      differentiation of isomers are possible using ESI. Copyright 1999 John Wiley &
      Sons, Ltd.

PMID- 10587618
TI  - Fragmentation reactions of alkylphenylammonium ions
AB  - The fragmentation reactions of a variety of alkylphenylammonium ions,
      C(6)H(5)NH(3 -n)R(n)(+) (n >/= 1, R = CH(3), C(2)H(5), i-C(3)H(7), n-C(4)H(9))
      were studied by energy-resolved mass spectrometry. Ionization was by fast atom
      bombardment (FAB) or electrospray ionization. Energy-resolved fragmentation data
      were obtained by low-energy collision-induced dissociation (CID) in the
      quadrupole cell of a hybrid sector/quadrupole instrument following FAB ionization
      and by cone-voltage CID in the interface region of the electrospray/quadrupole
      instrument. A comparison of the two methods of obtaining energy-resolved data
      showed that very similar results are obtained by the two methods. The
      fragmentation reactions of the alkylphenylammonium ions are rationalized in terms
      of competitive formation of an [R(+)-NC(6)H(5)H(3-n)R(n-1)] complex or a
      [C(6)H(5)H(3-n)R(n-1)N(+.)-(.)R] complex. The former complex fragments by
      internal proton transfer to yield C(6)H(5)H(3 -n)R(n -1)NH(+) and [R -H] whereas
      the latter complex fragments to form C(6)H(5)H(3 -n)R(n -1)N(+) and an alkyl
      radical. Alkane elimination, which is very prominent for tetraalkylammonium ions,
      most likely involves sequential elimination of an alkyl radical and either an H
      atom or an alkyl radical for the phenyl-substituted ammonium ions. Copyright 1999
      John Wiley & Sons, Ltd.

PMID- 10587619
TI  - Ion-molecule reactions of dimethyl ether cations with polycyclic aromatic
      hydrocarbons in a quadrupole ion trap mass spectrometer
AB  - The reaction chemistry between dimethyl ether (DME) cations and polycyclic
      aromatic hydrocarbons (PAHs) was elucidated by isolating three different types of
      DME ions using a quadrupole ion trap and reacting them individually with neutral
      PAH molecules eluting from a gas chromatographic column. The results obtained
      show that the CH(2)OCH(3)(+) ion (m/z 45) reacts via adduct formation followed by
      elimination of CH(3)OH, the (CH(3))(2)OH(+) (m/z 47) ion serves as proton donor
      and the (CH(3))(3)O(+) ion (m/z 61) does not yield any reaction products.
      Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10587620
TI  - Effect of charge derivatization in the determination of phosphorylation sites in
      peptides by electrospray ionization collision-activated dissociation tandem mass
      spectrometry

PMID- 10587621
TI  - Determination of the sensitivity of an external source ion trap tandem mass
      spectrometer using dimethyl ether chemical ionization

PMID- 10587622
TI  - Meeting report-The 17th informal meeting on mass spectrometry

PMID- 10587623
TI  - Unfolding dynamics of a beta-sheet protein studied by mass spectrometry.
AB  - The unfolding dynamics of cellular retinoic acid-binding protein I (CRABP I), an
      18 kDa predominantly beta-sheet protein, were studied by monitoring the hydrogen
      deuterium (H-D) exchange reaction under various solution conditions. A bimodal
      charge state distribution was observed when a denaturing agent was added to the
      protein aqueous solution. These two populations exhibit different kinetics of H-D
      exchange, with the high charge state ions undergoing very rapid isotope exchange,
      while the low charge state protein ions exchange cooperatively but at much slower
      rates. Transiently populated intermediate states were detected indirectly using
      hydrogen exchange measurement in aqueous solution at various pHs. At pH 2.5 and
      room temperature, three distinct populations of CRABP I ions exist over an
      extended period of time, each corresponding to a specific degree of backbone
      amide hydrogen atom protection. Mass spectral data are complementary to hydrogen
      exchange measurements by NMR, since the former samples a much faster time-scale
      of dynamic events in solution.

PMID- 10587624
TI  - Gas-phase ion-molecule reactions in organophosphorus esters
AB  - Self-condensation ion-molecule reactions of trimethyl phosphite, triethyl
      phosphite, dimethyl phosphonate, trimethyl phosphate and 2, 2-dichlorovinyl
      dimethyl phosphate (dichlorvos) were investigated by ion trap mass spectrometry
      and Fourier transform ion cyclotron resonance mass spectrometry. Reaction paths
      for the main processes observed were elucidated by parent ion selection and for
      reaction times up to 500 ms. In parallel, high-resolution measurements were
      performed in order to determine the composition of the principal ions. Among the
      compounds under examination, trimethyl phosphite and triethyl phosphite mainly
      give [M + H](+) and [M + (RO)(2)P](+) (R = CH(3), C(2)H(5)) adduct ions, whereas
      trimethyl phosphate and dimethyl phosphonate display [2M + H](+) ions, as the
      only abundant products, formed by reaction of [M + H](+) and M. 2,2-Dichlorovinyl
      dimethyl phosphate mostly shows fragmentation processes. The reaction patterns of
      the compounds examined were related to their different structural features. Gas
      phase basicities of the phosphoryl compounds were also determined or re-examined.
      Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10587625
TI  - Low-temperature fast atom bombardment mass spectra of frozen nitric acid-water
      solution
AB  - Positive ion low-temperature fast atom bombardment mass spectra of the frozen
      nitric acid-water system with an initial components ratio which provides
      preferential formation of the crystalline hydrate of the nitric acid trihydrate,
      HNO(3).3H(2)O, are reported. A complicated spectral pattern is created by a
      number of cluster sets which, on the basis of discussion, were attributed to
      (H(2)O)(n). NO(+) (n = 1-3), (H(2)O)(n).NO(2)(+) (n = 1, 2), (HNO(3))(m).
      (H(2)O)(n).H(+) (m = 1-5 and n variable) and (H(2)O)(n).H(+) (n = 1-9).
      Similarities between the size-dependent behavior of hydrate clusters of nitrogen
      oxides and nitric acid obtained with sputtering from the solid in the present low
      temperature experiments and under gas-phase conditions (reported earlier in the
      literature) were revealed. A suggestion as to possibility of the yield of the
      cluster ions sputtered due to energetic particle collision with the frozen grains
      of water ice and nitric acid trihydrate, present in the atmosphere, to the total
      ionic population of the atmosphere is discussed. Copyright 1999 John Wiley &
      Sons, Ltd.

PMID- 10587626
TI  - Identification of factor C protein from Streptomyces griseus by microelectrospray
      mass spectrometry.
AB  - Factor C, an extracellular signal protein of cellular differentiation, was
      studied and significant homology was found to several zinc finger-type regulatory
      proteins. The complete amino acid sequence, deduced from the gene, that encodes
      the protein, did not support the hypothesis that this protein might be a zinc
      finger-type regulatory protein. However, a theoretical single nucleotide
      insertion in the gene can result in another similarly sized protein containing
      about 20 His residues, which would be responsible for the high zinc affinity of
      factor C. The protein sample was reduced, alkylated and then in-gel digested with
      trypsin. The peptide fragments were then separated by capillary chromatography
      and identified by microelectrospray mass spectrometry. Peaks of higher intensity
      were sequenced by tandem mass spectrometry. The identified peptide fragments and
      the measured molecular mass of factor C protein also confirmed the original
      sequence of protein, as there was no shift in the open reading frame.

PMID- 10587627
TI  - Electrospray mass spectrometry of phosphoramidites, a group of acid-labile
      compounds
AB  - In contemporary solid-phase synthesis of oligonucleotides, phosphoramidites
      containing O-beta-cyanoethyl and N,N -diisopropyl groups are the most widespread
      monomer units. The N,N -diisopropyl phosphoramidite group can be activated by
      mild acidic treatment and then it easily reacts with nucleophiles (alcohols,
      water, etc.) to furnish the required phosphodiester linkage efficiently and
      cleanly. Owing to these properties, these compounds cannot be investigated using
      classical electrospray ionization. Their mass spectometric analysis is further
      hampered by the fact that they are often transiently protected with acid
      sensitive groups (4, 4'-dimethoxytrityl, 4-monomethoxytrityl or trityl), which
      give intense signals in the spectra. Nanoelectrospray measurements from non
      aqueous solvents (e.g. acetonitrile, methanol, tetrahydrofuran) were carried out
      in order to eliminate the nucleophilic water. Different types of alkali metal
      salts were used to form adduct ions. Among these salts, lithium chloride was
      found to be the most suitable for the analysis of amidites. Fairly abundant
      [M+Li](+) and [M+Cl](-) ions are formed in the positive and negative ion mode,
      respectively. These ions represent the base peaks in most cases whereas the
      intensities of the peaks corresponding to the protecting group are reduced by
      approximately 20%. This method is a powerful tool for the mass spectrometric
      identification of phosphoramidites. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10587628
TI  - Electron ionization mass spectra of acetals of beta-D-glycopyranosylnitromethanes
AB  - O-Isopropylidene and O-benzylidene acetals of common 2, 6-anhydro-1-deoxy-1
      nitroalditols (beta-D-glyco- pyranosylnitromethanes) derived from D-glucose, D
      galactose and D-mannose were studied by electron ionization (EI) mass
      spectrometry. Fragment pathways of the title compounds were studied using
      accurate mass measurements, collision-induced dissociation, B/E and B2/E
      measurements of selected ions and mass spectra of O-deuterium-labelled compound.
      The fragmentation pathways and some differences found among the mass spectra of
      stereoisomers are discussed. Noteworthy is the splitting off of the (.)NO(2)
      radical and elimination of acetone from the molecular ions of 4, 6-O-benzylidene
      2, 3-O-isopropylidene-beta-D-galactopyranosylnitromethane. This fragmentation
      route of relatively high abundance was not observed in the case of D-gluco and D
      manno analogues. The differences in the EI mass spectra of stereoisomers may help
      to provide some information serving for the estimation of the stereochemical
      arrangement of compounds of this type. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10587629
TI  - Interaction between antitumor drugs and a double-stranded oligonucleotide studied
      by electrospray ionization mass spectrometry.
AB  - Electrospray ionization mass spectrometry was used to investigate the complex
      formation between a double-stranded oligonucleotide and various antitumor drugs
      belonging to two categories: intercalators (ethidium bromide, amsacrine and
      ascididemin) and minor groove binders (Hoechst 33258, netropsin, distamycin A,
      berenil and DAPI). The goal of this study was to determine whether the relative
      intensities in the mass spectra reflect the relative abundances of the species in
      the solution phase. The full-scan mass spectra suggest non-specific binding for
      the intercalators and specific binding for the minor groove binders. The
      preferential stoichiometries adopted by each minor groove binder were determined
      by studying the influence of the drug concentration on the spectra. We obtained
      2:1 > 1:1 for distamycin, 1:1 > 2:1 for Hoechst 33258 and DAPI and only the 1 : 1
      complex for netropsin and berenil. These features reflect their known behavior in
      solution. The compared tandem mass spectra of the 1 : 1 complexes with Hoechst
      33258 and netropsin, when correlated with published crystallographic data,
      suggest the possibility of inferring some structural information. The relative
      binding affinities of the drug for the considered duplex were deduced with two by
      two competition experiments, assuming that the relative intensities reflect the
      composition of the solution phase. The obtained affinity scale is netropsin >
      distamycin A > DAPI > Hoechst 33258 > berenil. These examples show some of the
      potential uses of mass spectrometry as a useful tool for the characterization of
      specific drug binding to DNA, and possibly a rapid drug screening method
      requiring small amounts of materials.

PMID- 10587630
TI  - Matrix-assisted laser desorption/ionization mass spectrometry for monitoring
      bacterial protein digestion in yogurt production
AB  - Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry was
      employed to determine the changes in milk protein profile due to the action of
      Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus, the
      strains usually employed in yogurt production. Whereas the fermentation with the
      former shows the digestion of high molecular mass casein with the production of a
      low molecular mass peptide (3850 Da), the latter does not seem to exhibit any
      proteolytic activity. Proteolysis becomes relevant when milk is treated with a
      mixture of the two bacteria, reasonably due to symbiotic phenomena. The analysis
      of yogurt samples coming from industrial plants indicates increased activity of
      the two bacteria in the presence of ingredients containing sugars. Copyright 1999
      John Wiley & Sons, Ltd.

PMID- 10587631
TI  - Positive chemical ionization and tandem mass spectrometric fragmentation for the
      gas chromatographic analysis of beta-agonists using the ion trap technique.
AB  - A procedure is described for the determination of three characteristic beta
      agonists (clenbuterol, terbutalin and salbutamol) based on the formation of the
      corresponding protonated molecules and related collisional experiments.
      Quantification was carried out on selected collisional fragments and the
      reproducibility of the relative abundances of these fragments was estimated. The
      performance of the method was tested on bovine urine samples spiked at the lowest
      level of 0.2 ng ml(-1) in each of the chosen compounds.

PMID- 10587632
TI  - Reactions of ionic species from acetonitrile with long-chain saturated and
      unsaturated alcohols
AB  - Ten long-chain saturated and unsaturated alcohols were reacted with the ionic
      species [C(2) H(2) N](+) and [C(3) H(4) N](+) generated by ionization of
      acetonitrile into an ion trap. The mass spectra of the compounds under
      investigation show the formation of [M -H](+), [M + C(2) H(2) N](+) and [M + C(2)
      H(4) N](+) ions in the case of saturated alcohols, whereas for monounsaturated
      and polyunsaturated derivatives additional peaks corresponding to [M + H](+) and
      [M + H -H(2) O](+) are observed. The reaction mechanisms were investigated by
      means of D- and (13)C-labelled acetonitrile. Collisional experiments were
      performed on the [M + C(3) H(4) N](+) species from the polyunsaturated alcohols
      in order to identify any possibly diagnostic fragments for the identification of
      the double bond positions. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10587633
TI  - Liquid chromatography/electrospray mass spectrometry of bioactive terpenoids in
      Ginkgo biloba L.
AB  - Standardized extracts of Ginkgo biloba leaves are mainly used in the treatment of
      peripheral and celebral circulation disorders, and also as a remedy against
      asthma, coughs, bladder inflammation, blenorrhagia and alcohol abuse. The leaf
      extracts contain biflavones, flavonol glycosides and terpene lactones. This paper
      reports a method based on liquid chromatography coupled with electrospray mass
      spectrometry for the analysis of terpenoids in G. biloba extracts. This method
      allows the rapid isocratic separation of underivatized ginkgolides (GA, GB, GC
      and GJ) and bilobalide at very low levels (10 pg on the column) and their
      quantitative detection by external standardization with relative standard
      deviations of 3 and 5% for intra- and inter-day analyses, respectively.

PMID- 10587634
TI  - Miniaturized time-of-flight mass spectrometer for peptide and oligonucleotide
      analysis.
AB  - A matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass
      spectrometer was developed which uses a novel reflectron composed of a grounded
      cylinder and an adjustable endcap electrode to provide high-order kinetic energy
      focusing for a miniaturized mass analyzer. The nearly quadratic potential form of
      the reflecting field focuses ions desorbed from a source of very small dimensions
      formed by placing the sample probe within the centered hole of the coaxial dual
      channel plate detector. At the same time, the depth of the reflectron can be
      adjusted to accommodate a short drift length between the source/detector and the
      reflectron. For larger drift lengths, in particular to allow the addition of an
      XY stage for the analysis of sample arrays, endcap reflectron focusing can be
      combined with time-delayed ion extraction to achieve good mass resolution. The
      instrument has been used for the analysis of peptides digested with trypsin or
      carboxypeptidase, and also small DNA oligomers.

PMID- 10587635
TI  - Thermal energy distribution observed in electrospray ionization
AB  - A new method was developed which fits a thermal internal energy distribution to
      ions formed by electrospray ionization. The molecular ion survival yield was
      measured and determined by RRKM calculations as a function of temperature. The
      ('characteristic') temperature was determined when the calculated and measured
      molecular ion survival yields were equal. The 'characteristic' temperatures were
      very similar (average RSD errors were 8%) for a set of analogous compounds
      (benzylpyridine salts), and the resulting thermal internal energy distributions
      were close to those determined by De Pauw's method. The validity of the method
      was also checked performing blackbody infrared radiation and on-resonance
      excitation experiments on a Fourier transform ion cyclotron resonance instrument
      with benzylpyridine salts and leucine enkephalin. The results strongly suggest
      that internal energy distributions in electrospray ionization are very close to
      thermal distributions. It was found that the characteristic temperature increases
      linearly with the cone voltage. It is suggested that the characteristic
      temperature can be used as a quantitative measure to control and standardize
      conditions in electrospray ionization. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10587636
TI  - Electrospray ionization in the study of polycondensation of Si(OEt)(4)

PMID- 10587637
TI  - Determination by solid-phase microextraction/gas chromatography/mass spectrometry
      of polycyclic aromatic hydrocarbons in bitumen fumes during road paving

PMID- 10587638
TI  - Qualitative characterization of bacterial strains employed in the production of
      yogurt by matrix-assisted laser desorption/ionization mass spectrometry

PMID- 10587639
TI  - Wide band ion isolation in an ion trap for the analysis of polychlorobiphenyls

PMID- 10587640
TI  - Pleiotropic cell-division defects and apoptosis induced by interference with
      survivin function.
AB  - Here we investigate the role of the control of apoptosis in normal cell division.
      We show that interference with the expression or function of the apoptosis
      inhibitor survivin causes caspase-dependent cell death in the G2/M phase of the
      cell cycle, and a cell-division defect characterized by centrosome dysregulation,
      multipolar mitotic spindles and multinucleated, polyploid cells. Use of a
      dominant-negative survivin mutant or antisense survivin complementary DNA
      disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin
      dependent-kinase inhibitor p21Waf1/Cip1 within centrosomes, and results in
      caspase-dependent cleavage of p21. Polyploidy induced by survivin antagonists is
      accentuated in p21-deficient cells, and corrected by exogenous expression of p21.
      These findings show that control of apoptosis and preservation of p21 integrity
      within centrosomes by survivin are required for normal mitotic progression.

PMID- 10587641
TI  - Coordination of calcium signalling by endothelial-derived nitric oxide in the
      intact liver.
AB  - Calcium ions (Ca2+) and nitric oxide (NO) are key signalling molecules that are
      implicated in the regulation of numerous cellular processes. Here we show that,
      in the intact liver, stimulation of endothelial cells by bradykinin coordinates
      the propagation of vasopressin-dependent intercellular Ca2+ waves across hepatic
      plates, and markedly increases the frequency of Ca2+ oscillations in individual
      hepatocytes. Modulation of Ca2+ oscillations by bradykinin is lost following
      isolation of hepatocytes, but restored in co-cultures of hepatocytes and
      endothelial cells. The sensitizing effects of bradykinin are mimicked by NO
      donors and abrogated by NO inhibitors. Thus, crosstalk between NO and Ca2+
      signalling pathways through the microvasculature is probably an important
      mechanism for the coordination of liver function and may have a function in other
      organs.

PMID- 10587642
TI  - Ubiquitin-dependent degradation of TGF-beta-activated smad2.
AB  - SMAD proteins are phosphorylated by transforming growth factor-beta (TGF-beta)
      receptors and translocate to the nucleus, where they control transcription. Here
      we investigate the fate of activated Smad2. We show that receptor-mediated
      activation leads to multi-ubiquitination and subsequent degradation of Smad2 by
      the proteasome. Ubiquitination of Smad2 is a consequence of its accumulation in
      the nucleus. If degradation is averted, the phosphorylated Smad2 remains in the
      nucleus in an active state. By targeting Smad2 for destruction, TGF-beta ensures
      the irreversible termination of its own signalling function.

PMID- 10587643
TI  - Presenilin-1 mutations downregulate the signalling pathway of the unfolded
      protein response.
AB  - Missense mutations in the human presenilin-1 (PS1) gene, which is found on
      chromosome 14, cause early-onset familial Alzheimer's disease (FAD). FAD-linked
      PS1 variants alter proteolytic processing of the amyloid precursor protein and
      cause an increase in vulnerability to apoptosis induced by various cell stresses.
      However, the mechanisms responsible for these phenomena are not clear. Here we
      report that mutations in PS1 affect the unfolded-protein response (UPR), which
      responds to the increased amount of unfolded proteins that accumulate in the
      endoplasmic reticulum (ER) under conditions that cause ER stress. PS1 mutations
      also lead to decreased expression of GRP78/Bip, a molecular chaperone, present in
      the ER, that can enable protein folding. Interestingly, GRP78 levels are reduced
      in the brains of Alzheimer's disease patients. The downregulation of UPR
      signalling by PS1 mutations is caused by disturbed function of IRE1, which is the
      proximal sensor of conditions in the ER lumen. Overexpression of GRP78 in
      neuroblastoma cells bearing PS1 mutants almost completely restores resistance to
      ER stress to the level of cells expressing wild-type PS1. These results show that
      mutations in PS1 may increase vulnerability to ER stress by altering the UPR
      signalling pathway.

PMID- 10587644
TI  - CUL-2 is required for the G1-to-S-phase transition and mitotic chromosome
      condensation in Caenorhabditis elegans.
AB  - The human cullin protein CUL-2 functions in a ubiquitin-ligase complex with the
      von Hippel-Lindau (VHL) tumour suppressor protein. Here we show that, in
      Caenorhabditis elegans, cul-2 is expressed in proliferating cells and is required
      at two distinct points in the cell cycle, the G1-to-S-phase transition and
      mitosis. cul-2 mutant germ cells undergo a G1-phase arrest that correlates with
      accumulation of CKI-1, a member of the CIP/KIP family of cyclin-dependent-kinase
      inhibitors. In cul-2 mutant embryos, mitotic chromosomes are unable to condense,
      leading to unequal DNA segregation, chromosome bridging and the formation of
      multiple nuclei.

PMID- 10587645
TI  - Cooperative symmetry-breaking by actin polymerization in a model for cell
      motility.
AB  - Polymerizing networks of actin filaments are capable of exerting significant
      mechanical forces, used by eukaryotic cells and their prokaryotic pathogens to
      change shape or to move. Here we show that small beads coated uniformly with a
      protein that catalyses actin polymerization are initially surrounded by
      symmetrical clouds of actin filaments. This symmetry is broken spontaneously,
      after which the beads undergo directional motion. We have developed a stochastic
      theory, in which each actin filament is modelled as an elastic brownian ratchet,
      that quantitatively accounts for the observed emergent symmetry-breaking
      behaviour. Symmetry-breaking can only occur for polymers that have a significant
      subunit off-rate, such as the biopolymers actin and tubulin.

PMID- 10587646
TI  - Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB.
AB  - Organismal size is determined by a tightly regulated mechanism that coordinates
      cell growth, cell proliferation and cell death. The Drosophila insulin
      receptor/Chico/Dp110 pathway regulates cell and organismal size. Here we show
      that genetic manipulation of the phosphoinositide-3-OH-kinase-dependent
      serine/threonine protein kinase Akt (protein kinase B) during development of the
      Drosophila imaginal disc affects cell and organ size in an autonomous manner.
      Ectopic expression of Akt does not affect cell-fate determination, apoptosis or
      proliferation rates in imaginal discs. Thus, Akt appears to stimulate
      intracellular pathways that specifically regulate cell and compartment size
      independently of cell proliferation in vivo.

PMID- 10587647
TI  - Melanoma chondroitin sulphate proteoglycan regulates cell spreading through
      Cdc42, Ack-1 and p130cas.
AB  - Melanoma chondroitin sulphate proteoglycan (MCSP) is a cell-surface antigen that
      has been implicated in the growth and invasion of melanoma tumours. Although this
      antigen is expressed early in melanoma progression, its biological function is
      unknown. MCSP can stimulate the integrin-alpha4 beta1-mediated adhesion and
      spreading of melanoma cells. Here we show that stimulated MCSP recruits tyrosine
      phosphorylated p130 cas, an adaptor protein important in tumour cell motility and
      invasion. MCSP stimulation also results in a pronounced activation and
      recruitment of the Rho-family GTPase Cdc42. MCSP-induced spreading of melanoma
      cells is dependent upon active Cdc42, a Cdc42-associated tyrosine kinase (Ack-1)
      and tyrosine phosphorylation of p130cas. Furthermore, vectors inhibiting Ack-1 or
      Cdc42 expression and/or function abrogate MCSP-induced tyrosine phosphorylation
      and recruitment of p130cas. Our findings indicate that MCSP may modify tumour
      growth or invasion by a unique signal-transduction pathway that links Cdc42
      activation to downstream tyrosine phosphorylation and subsequent cytoskeletal
      reorganization.

PMID- 10587648
TI  - Components of the spindle-assembly checkpoint are essential in Caenorhabditis
      elegans.
AB  - The spindle-assembly checkpoint ensures that, during mitosis and meiosis,
      chromosomes do not segregate until they are properly attached to the microtubules
      of the spindle. Here we show that mdf-1 and mdf-2 are components of the spindle
      assembly checkpoint in Caenorhabditis elegans, and are essential for the long
      term survival and fertility of this organism. Loss of function of either of these
      genes leads to the accumulation of a variety of defects, including chromosome
      abnormalities, X-chromosome non-disjunction or loss, problems in gonad
      development, and embryonic lethality. Antibodies that recognize the MDF-2 protein
      localize to nuclei of the cleaving embryo in a cell-cycle-dependent manner. mdf
      1, a gene encoding a product that interacts with MDF-2, is required for cell
      cycle arrest and proper chromosome segregation in premeiotic germ cells treated
      with nocodazole, a microtubule-depolymerizing agent. In the absence of mdf gene
      products, errors in chromosome segregation arise and accumulate, ultimately
      leading to genetic lethality.

PMID- 10587649
TI  - The yeast phosphatidylinositol-4-OH kinase pik1 regulates secretion at the Golgi.

PMID- 10587650
TI  - Ten years of intercontinental research funding

PMID- 10587651
TI  - From small flies come big discoveries about size control.

PMID- 10587652
TI  - Lipids: defining the shape of things to come.

PMID- 10587653
TI  - Nitric oxide pumps up calcium signalling.

PMID- 10587654
TI  - SMAD destruction turns off signalling.

PMID- 10587655
TI  - Breaking through an actin cloud.

PMID- 10587656
TI  - Survivin' cell-separation anxiety.

PMID- 10587657
TI  - A new piece in the telomere jigsaw.

PMID- 10587658
TI  - One hundred years of membrane permeability: does Overton still rule?
AB  - The Overton Rule states that entry of any molecule into a cell is governed by its
      lipid solubility. Overton's studies led to the hypothesis that cell membranes are
      composed of lipid domains, which mediate transport of lipophilic molecules, and
      protein 'pores', which transport hydrophilic molecules. Recent studies, however,
      have shown that hydrophobic molecules are also transported by families of
      transporter proteins.

PMID- 10587659
TI  - 'Shocking' developments in chick embryology: electroporation and in ovo gene
      expression.
AB  - Efficient gene transfer by electroporation of chick embryos in ovo has allowed
      the development of new approaches to the analysis of gene regulation, function
      and expression, creating an exciting opportunity to build upon the classical
      manipulative advantages of the chick embryonic system. This method is applicable
      to other vertebrate embryos and is an important tool with which to address cell
      and developmental biology questions. Here we describe the technical aspects of in
      ovo electroporation, its different applications and future perspectives.

PMID- 10587660
TI  - Bcl-2 proteins: regulators of apoptosis or of mitochondrial homeostasis?
AB  - Programmed cell death (apoptosis) is used by multicellular organisms during
      development and to maintain homeostasis within mature tissues. One of the first
      genes shown to regulate apoptosis was bcl-2. Subsequently, a number of Bcl-2
      related proteins have been identified. Despite overwhelming evidence that Bcl-2
      proteins are evolutionarily conserved regulators of apoptosis, their precise
      biochemical function remains controversial. Three biochemical properties of Bcl-2
      proteins have been identified: their ability to localize constitutively and/or
      inducibly to the outer mitochondrial, outer nuclear and endoplasmic reticular
      membranes, their ability to form heterodimers with proteins bearing an
      amphipathic helical BH3 domain, and their ability to form ion-conducting channels
      in synthetic membranes. The discovery that mitochondria can play a key part in
      the induction of apoptosis has focused attention on the role that Bcl-2 proteins
      may have in regulating either mitochondrial physiology or mitochondria-dependent
      caspase activation. Here we attempt to synthesize our current understanding of
      the part played by mitochondria in apoptosis with a consideration of how Bcl-2
      proteins might control cell death through an ability to regulate mitochondrial
      physiology.

PMID- 10587670
TI  - The Internet--don't teach without it.

PMID- 10587671
TI  - Learning disabilities: compromising undergraduate GPAs.

PMID- 10587672
TI  - Departmental chairs' perspectives on faculty development.

PMID- 10587673
TI  - Risks and benefits of early clinical exposure.

PMID- 10587674
TI  - Mini-med school at a community teaching hospital.

PMID- 10587675
TI  - Getting residents involved in research: a challenge in the era of managed care.
AB  - The changing climate of health care, with the associated increasing financial
      constraints, challenges faculty and residents to find time for mentoring and
      pursuing research. Departments and institutions can encourage residents to
      conduct research by assuring them that they have a supportive infrastructure.
      Only when the institution and faculty value research will residents do the same.
      More than half of academic surgeons spend less than 20% of their effort in
      research; how can residency programs expect residents to enthusiastically pursue
      research when members of the teaching faculty are themselves not writing and
      publishing? If the ACGME is serious about asking residents to devote their time
      and energy to becoming more active in research activities, we must be prepared to
      decrease service commitments, and we must provide clinically active mentors and
      visible career models.

PMID- 10587676
TI  - Overcoming barriers to creating a tobacco-use curriculum.

PMID- 10587677
TI  - Understanding health behavior and speaking out on the uninsured: two leadership
      opportunities.
AB  - The author reviews the growth of managed care and its transforming effect on
      academic medical centers. He then maintains that in this time of fundamental
      changes and stress, academic medical centers should not only attend to the
      organization and financing of the clinical enterprise and the enhancement of
      biomedical research capacity, but also ask how academic medicine can live up to
      the unique opportunities and responsibilities it has been entrusted with to
      improve the health of the public, particularly in two neglected areas. First, if
      the nation does not expand the research agenda to include social and behavioral
      factors involved in preventable causes of morbidity and mortality, it will fail
      to maximize the dividends from the generous public investment in research and
      fail to learn how to promote healthy personal behavior. Academic medicine can
      promote such behavior by increasing the science base of prevention and
      translating into action what is already known, including how to market that
      knowledge so the public will respond. Second, the number of the medically
      uninsured is increasing; the largest percentage are the working poor. It is
      becoming more difficult for teaching hospitals to continue providing a third of
      the nation's uncompensated care. The author shares a variety of statistics about
      the uninsured and their care, and maintains that academic medicine, which has
      been entrusted with the health of the public, can declare that the high number of
      the uninsured is not acceptable and is a dangerous side effect of the U.S. health
      care system that must be treated. Doing so will also set an example to medical
      students and trainees that medicine's responsibility is to all Americans.

PMID- 10587678
TI  - Students are not customers: a better model for medical education.
AB  - The author argues that the student-as-customer model of medical education has
      many failings that result in interactions that are educationally dysfunctional.
      Ten "pathologies" resulting from the adoption of this model are presented (e.g.,
      "The student-customer model seduces students into believing that they know what
      is best for them"). Part of the reason for the unprofessional conduct often
      demonstrated by students and faculty alike may be a result of the influence of
      this model on medical education and the consequent inappropriate empowerment of
      students in the role of customers, the diminishment of faculty in the role of
      workers who provide instruction, and the view that instruction is the service or
      product of medical education. The author proposes a new model of medical
      education in which faculty are managers of instruction, students are learning
      workers, the product is successful learning, and the customers are faculty,
      residency supervisors, patients, managed care organizations, and society. The
      implications of this new model are profound and are described in terms of
      Deming's 14 principles for achieving quality in business. The author maintains
      that the proposed model is the critical first step in clarifying and identifying
      the proper roles of all those involved in the medical education process, which in
      turn will diminish or eliminate the pathologies that currently plague medical
      education and lead to the achievement of real quality.

PMID- 10587679
TI  - In defense of expert opinion.
AB  - Evidence-based medicine, centered on the incorporation of evidence from clinical
      trials and systematic reviews into the teaching and practice of clinical
      medicine, explicitly attempts to supplant expert opinion, which is viewed as an
      antiquated and unreliable form of medical authority. The epistemology of evidence
      based medicine categorizes expert opinion as the lowest form of medical evidence,
      superseded even by methodologically flawed clinical research. When derived from
      direct clinical experience, however, expert opinion represents an alternative
      form of medical knowledge, one that may be complementary to empirical evidence.
      Input from clinical experts is vital to informing the context of clinical
      research and an appeal to alternate forms of medical knowledge, including expert
      opinion, is necessary to overcome the intrinsic gap between clinical research and
      the care of individual patients. Even when the quality and quantity of empirical
      medical evidence are ideal, expert opinion will remain an integral part of the
      multifaceted knowledge required for the optimal practice of clinical medicine.

PMID- 10587680
TI  - Needs and challenges for health services research at academic health centers.
AB  - What are the institutional strategies used by academic health centers and other
      academic institutions to support and maintain the infrastructure that promotes
      health services research? Using the findings from interviews conducted in late
      1998 with health services researchers at ten health services research centers of
      several types and from several geographic areas, and with the directors of ten
      health services research training centers, the authors address this key issue by
      examining four central infrastructure needs and challenges for health services
      research: (1) organizing core institutional resources (most centers received some
      level of core financial support from their parent organizations); (2) supporting
      career development of individual researchers (the more competitive health care
      system may diminish the ability of academic health centers and other institutions
      to give such support, but certain opportunities were noted); (3) supporting and
      enhancing training in health services research (such support comes from many
      different disciplines and organizations; the typical career path is in academic
      settings); and (4) establishing and supporting research partnerships (there are
      growing opportunities for such alliances). The authors reach a number of
      conclusions from their study, including the fact that there are a wide variety of
      models of successful health services research centers, with very different
      missions, organizational and interdisciplinary configurations, research and
      policy objectives, and collaborative relationships. Additional studies are needed
      to further specify those infrastructure elements that foster effective and
      productive health services research in academic health centers and other
      university settings.

PMID- 10587681
TI  - A new vocabulary and other innovations for improving descriptive in-training
      evaluations.
AB  - Progress in improving the credibility of teachers' descriptive evaluations of
      students and residents has not kept pace with the progress made in improving the
      credibility of more quantified methods, such as multiple-choice examinations and
      standardized patient examinations of clinical skills. This article addresses
      innovative approaches to making the ongoing in-training evaluation (ITEv) of
      trainees during their clinical experiences more reliable and valid. The
      innovations include the development of a standard vocabulary for describing the
      progress of trainees from "reporter" to "interpreter" to "manager" and "educator"
      (RIME), the use of formal evaluation sessions, and closer consideration of the
      unit of clinical evaluation (the case, the rotation, or the year). The author
      also discusses initial results of studies assessing the reliability and validity
      of descriptive methods, as well as the use of quantified methods to complement
      descriptive methods. Applying basic principles--the use of a taxonomy of
      professional development and statistical principles of reliability and validity-
      may foster research into more credible descriptive evaluation of clinical skills.

PMID- 10587682
TI  - Electronic research administration: managing a valuable resource.
AB  - Millions of dollars are spent each year to support research activities in
      academic health centers (AHCs). Managed care and the Balanced Budget Act have
      made it even more critical that these dollars be carefully managed. Information
      technology provides the essential tool for overseeing the grant administration
      and procurement process. To achieve greater fiscal responsibility and better
      management of research funds. AHCs must use this technology to develop
      comprehensive electronic research administration (ERA) systems. The author
      describes the essential steps involved in creating an ERA system. She also
      discusses systems already in place at AHCs and the various approaches their
      developers have taken to design and implement them.

PMID- 10587683
TI  - Empathy, humanism, and the professionalization process of medical education.
AB  - This study sought to identify the common stages in the development of capacities
      contributing to humanistic medical care in young physicians, as revealed by their
      dreams about medical school and training. Using a databank of approximately 400
      dreams dreamt by non-patient students and housestaff at a major academic medical
      center, the author traces the development of the two components of humanistic
      medicine: empathy and humanistic attitudes. The "critical episodes" of medical
      education produce in young physicians emotional and psychological defenses
      affecting their ability to interact with patients in an empathic and altruistic
      manner. Medical educators need to reevaluate the traditional curricular
      milestones and pedagogic style to help foster the development of medical
      humanism.

PMID- 10587684
TI  - The plight of premedical education: myths and misperceptions--Part II: science
      "versus" the liberal arts.
AB  - For decades it has been known that students who major in non-science fields
      perform as well as science majors who go to medical school. Yet the overwhelming
      majority of future medical students still major in biology or chemistry, and
      organic chemistry has come to be the defining premedical science course. This
      article traces the history of the liberal arts tradition, discusses its
      importance for medicine, and urges that readers think about the medical college
      in the age of the university. The author believes that the medical faculties
      should take a lead in helping to reshape the premedical as well as the medical
      education of future doctors.

PMID- 10587685
TI  - Academic medicine can transform health care through clinical research.

PMID- 10587686
TI  - Still seeking gender equity in health care.

PMID- 10587687
TI  - Leadership behaviors for successful university--community collaborations to
      change curricula.
AB  - PURPOSE: What constitutes effective leadership in a collaborative effort to
      achieve enduring curricular and student career changes? This question was
      investigated as part of a larger evaluation of the W. K. Kellogg Foundation's
      Community Partnership Health Professions Education, a five-year initiative
      involving projects at seven sites. The goal was to produce more primary care
      health providers by making enduring curricular change. METHOD: Data were
      collected from participants with respect to predictors of project success and
      leaders' use of 16 behaviors via telephone interviews, mailed surveys, and focus
      groups. Focus groups also gathered project leaders' views of skills and knowledge
      necessary for effective leadership. RESULTS: Leadership strategies associated
      with positive outcomes were: consistent leader; use of multiple cognitive frames,
      especially a human resource frame; use of a broad range of leadership behaviors,
      particularly participative governance and cultural influence; and a majority of
      community representatives on the partnership board. The primary leader, compared
      with a leadership team, is most influential in achieving positive outcomes.
      CONCLUSION: Effective leaders use a broad array of behaviors, but particularly
      emphasize the use of participative governance and culture/value-influencing
      behaviors. In addition, the more frequent use of these behaviors compared with
      the use of organizational power behaviors is important. It is helpful to perceive
      the project from a human-relations frame and at least one other frame. Using a
      leadership team can be helpful, especially in building coalitions, but the
      importance of the primary leader's behaviors to project outcomes is striking.

PMID- 10587688
TI  - Early clinical experience enhances third-year pediatrics clerkship performance.
AB  - PURPOSE: To determine whether clinical experiences in the preclinical years
      improve medical students' performances in a third-year clerkship. METHOD: A
      cohort study reviewed the pediatrics clerkship performances of 400 Eastern
      Virginia Medical School students in the graduating classes of 1996 through 1999.
      The first two classes completed a traditional preclinical curriculum with limited
      clinical experience. The final two classes participated in a mentorship program
      that provided 18 months of early clinical experience, consisting of one-on-one
      half-day sessions every other week with a generalist community faculty. The
      authors compared the clinical clerkship performances of the groups using clinical
      skills (CS) scores, history and physical examination (H&P) scores, and scores on
      the NBME pediatrics shelf examination. They also looked at the mean MCAT and
      USMLE scores for each group. The authors also looked at the scores within each
      class, comparing students who completed one of the first two pediatrics clerkship
      rotations with their classmates who completed clerkships later in the academic
      year. RESULTS: The students' NBME scores rose significantly (p < .05, r2 = 0.95)
      over the four-year study, paralleling a significant rise in MCAT scores (p < .03,
      r2 = 0.73). The CS and H&P scores did not rise. Students who had the traditional
      preclinical curriculum and who completed their clerkships early in the year had
      significantly lower CS and H&P scores than did their classmates. In contrast, the
      scores of students who had the early clinical experiences did not differ
      significantly according to the timing of their rotation. CONCLUSION: Students who
      had participated in a mentorship program that provided early clinical experience
      demonstrated significantly improved clinical skills in the pediatrics clerkship
      early in the academic year.

PMID- 10587689
TI  - Teaching self-awareness enhances learning about patient-centered interviewing.
AB  - PURPOSE: To evaluate the effect of intensive attitudinal training on residents'
      learning the patient-centered interviewing skills required to establish a healthy
      provider-patient relationship and to communicate effectively. METHOD: While
      teaching 53 residents patient-centered interviewing skills, the authors also
      trained them to recognize previously unrecognized, negative attitudes that
      interfered with learning the skills. The authors, using an iterative, consensus
      building process based on the residents' performances and personality data,
      identified a spectrum of responses to the educational intervention. Barriers to
      and facilitators of mastery of skills were analyzed and this information was used
      to help residents overcome skill deficits. RESULTS: To varying degrees, 44
      residents became aware of previously unrecognized attitudes to the extent that
      they improved their patient-centered interviewing skills. Six residents failed to
      develop awareness of negative attitudes and showed little learning and clinical
      use of the interviewing skills being taught. Three residents who rapidly
      developed superb interviewing skills showed no negative attitude towards using
      them. CONCLUSIONS: Pending a confirmatory hypothesis-testing study, the authors
      believe that, as residents learn how to conduct patient-centered interviews,
      training in awareness of interfering attitudes should accompany training in
      skills.

PMID- 10587690
TI  - Adult medicine training experiences in a small-town family practice residency.
AB  - PURPOSE: To document the adult medicine experiences of family practice residents
      training in a small rural hospital. METHOD: The authors tracked all inpatient
      admissions and consults for the first year of a newly accredited family practice
      residency program, located in a small-town, 80-bed hospital. They analyzed the
      data for volume of admissions, sources of admissions, diagnoses, lengths of stay,
      and ICU experience. RESULTS: The residents saw a significant volume of patients,
      encountered a wide variety of diagnoses, and had ample opportunities for
      learning, in spite of the small number of occupied beds. CONCLUSION: Family
      practice residents in small hospitals can have sufficient inpatient training
      experiences in adult medicine. The authors believe that the Accreditation Council
      for Graduate Medical Education should encourage the development of residency
      programs in rural communities by simplifying the accreditation documentation
      requirements for smaller hospitals.

PMID- 10587691
TI  - Faculty training in general internal medicine: a survey of graduates from a
      research-intensive fellowship program.
AB  - PURPOSE: To determine the fellowship experiences and career activities of the
      graduates of a research-intensive general internal medicine fellowship program.
      METHOD: In 1997, the authors surveyed all graduates of the Harvard General
      Internal Medicine Fellowship Program, a research-intensive fellowship begun in
      1979. RESULTS: Of 105 surveys delivered to graduates, 103 (98%) were returned.
      During the fellowship, 82 graduates (80%) presented research findings at regional
      or national meetings, 89 (86%) published peer-reviewed articles based on their
      fellowship work, 75 (73%) precepted residents or medical students in the
      ambulatory setting, and 67 (65%) taught medical students in the preclinical
      years. At the time of the survey, 100 graduates (97%) held academic appointments:
      48 as clinician-investigators, 23 as clinician-administrators, 15 as clinician
      educators, and 15 as clinicians. CONCLUSION: Graduates of this research-intensive
      fellowship pursued academic careers with research, teaching, administration, and
      clinical activities. Directors of similar fellowship programs should prepare
      their graduates for all these activities.

PMID- 10587692
TI  - Should students in problem-based learning sessions be graded by the facilitator?

PMID- 10587693
TI  - Communication apprehension among third-year medical students.

PMID- 10587694
TI  - Cardiac troponin. How specific is specific?

PMID- 10587695
TI  - Analytic and clinical evaluation of the Abbott AxSYM cardiac troponin I assay.
AB  - We evaluated the AxSYM immunoassay for the quantification of cardiac troponin I
      (cTnI). Total assay imprecision, expressed as coefficient of variation, ranged
      between 5.6% and 8.3% for commercial control serum samples and between 4.2% and
      13.9% for pooled patient samples. Linearity was verified up to 42 micrograms/L.
      Triglycerides (up to 1,000 mg/dL) did not interfere with the assay, but minor
      hemolysis and clinically relevant hyperbilirubinemia caused a negative bias. In
      186 patient samples, AxSYM cTnI levels correlated significantly with data
      obtained with the Stratus II cTnI fluorometric enzyme immunoassay but were 3 to 4
      times higher on AxSYM than on Stratus II. In 111 healthy blood donors, the
      reference range for cTnI levels on AxSYM was 0.0 to 0.4 microgram/L. After
      eccentric isokinetic exercise, healthy volunteers showed a rise in creatine
      kinase MB mass (AxSYM) but not in cTnI. On AxSYM and Stratus II, cTnI levels
      increased above the manufacturer's cutoff for acute myocardial infarction in all
      17 patients followed up after onset of infarction-related chest pain but in only
      1 of 91 control subjects. The AxSYM cTnI assay is a valid alternative for the
      detection of myocardial injury with diagnostic performance comparable to the
      established Stratus cTnI assay.

PMID- 10587696
TI  - False-positive troponin I in the MEIA due to the presence of rheumatoid factors
      in serum. Elimination of this interference by using a polyclonal antisera against
      rheumatoid factors.
AB  - We report false-positive cardiac troponin (cTn) I results in the microparticle
      enzyme immunoassay (MEIA) using the AxSYM analyzer. We studied serum samples from
      12 patients with positive rheumatoid factor but with no indication of myocardial
      infarction (MI); 2 also had positive antinuclear antibody (ANA) titers. Serum
      samples from 7 patients with positive ANA titers and negative rheumatoid factors
      also were studied. Total creatine kinase (CK) was run using a Hitachi 747
      analyzer, cTnT using an Elecsys 2010 analyzer, and cTnI and CK-MB using an AxSYM
      analyzer. We observed no measurable cTnI and cTnT concentrations in 12 control
      samples or in specimens with positive ANA titers and negative rheumatoid factors.
      In contrast, samples from 7 of 12 patients containing rheumatoid factors had
      measurable cTnI concentrations. Four specimens showed cTnI concentrations more
      than 2.0 micrograms/L, the suggested diagnostic cutoff for MI. None of the
      specimens showed detectable cTnT. The concentrations of total CK and CK-MB were
      within normal ranges in all specimens. False-positive results were observed only
      with the MEIA for cTnI. This interference can be eliminated by using a polyclonal
      antisera against rheumatoid factor. The chemiluminescent assay for cTnI showed no
      detectable cTnI concentration in any specimen.

PMID- 10587697
TI  - Validation of an immunoassay for measurement of plasma total homocysteine.
AB  - Hyperhomocysteinemia is an evolving cardiovascular risk factor. It is imperative
      that a simple, precise, and accurate assay be available in the clinical
      laboratory. The aim of this study was to evaluate an automated fluorescence
      polarization immunoassay for homocysteine. The assay had excellent precision at
      normal and high levels (intra-assay and interassay coefficients of variation <
      5%). The method was linear from 0.24 to 50 mumol/L and displayed good correlation
      with a high-performance liquid chromatography (HPLC) method. There was no
      significant interference detectable in icteric and hyperlipidemic samples, but
      hemolysis resulted in a significant negative bias. While homocysteine levels were
      not increased in smokers, patients with renal failure had significantly higher
      levels compared with control subjects. This automated assay requires no sample
      preparation, displays excellent precision, shows good correlation with HPLC, and,
      thus, is favored over HPLC for use in the clinical laboratory. The main
      indications for measuring plasma homocysteine levels will be in the early
      diagnosis of cobalamin deficiency, patients with cardiovascular disease and few
      or no established risk factors, and patients with unexplained venous
      thromboembolic disease.

PMID- 10587698
TI  - LSIL biopsies after HSIL smears. Correlation with high-risk HPV and greater risk
      of HSIL on follow-up.
AB  - Can the risk associated with a high-grade cervical smear be disregarded when
      followed by a low-grade biopsy? We examined the distribution of human
      papillomavirus (HPV) types in such cases to see whether they segregated
      preferentially with low-risk or high-risk viruses and compared the distribution
      with that reported in the literature for women with high-grade squamous
      intraepithelial lesions (HSILs) and low-grade squamous intraepithelial lesions
      (LSILs). We identified 48 cases of HSIL smears with corresponding LSIL biopsy
      specimens. Biopsy specimens were tested and typed for HPV by polymerase chain
      reaction amplification with consensus primers followed by restriction fragment
      length polymorphism analysis, and HPVs were scored as low-risk or high-risk
      types. Thirty-seven cases scored positive for HPV DNA: 2 for low-risk HPV types,
      17 for high-risk types, and 18 for types of unknown oncogenicity. The prevalence
      of high-risk HPV was significantly higher than that of low-risk HPV. There was a
      higher rate of high-risk HPV than that seen in historic unselected LSIL cases.
      Cases of HSIL cytology/LSIL histology represent a group distinct from unselected
      LSILs by virtue of their higher prevalence of high-risk HPV types and, therefore,
      warrant closer clinical follow-up.

PMID- 10587699
TI  - Do proficiency test results correlate with the work performance of screeners who
      screen Papanicolaou smears?
AB  - We rescreened Papanicolaou smear slides from 40,245 women, which had been
      examined by 81 cytology screeners, scored the screeners' work performance, and
      compared these scores with the results of the screeners' performance on glass
      slide and computer-based proficiency tests. All diagnoses (i.e., from the
      proficiency tests, the original slides, and the rescreened slides) were
      classified in the 4 diagnostic categories specified in the Clinical Laboratory
      Improvement Amendments. The rescreening scores were standardized to account for
      different distributions of abnormalities in the proficiency tests and rescreened
      slides. We compared a standardized score with the proficiency test scores. Of the
      cases, 91% were categorized as normal, benign, or reactive changes when
      rescreened, and 98% of these agreed with the original diagnosis. Sixteen percent
      of low-grade and 15% of high-grade intraepithelial lesions were classified as
      normal. The rank correlation between the rescreening scores and both proficiency
      tests was 0.24 using a scoring scheme for cytotechnologists. The correlation
      between the rescreening and proficiency testing scores indicates that performance
      on a 10-slide test gives some indication of the true performance of screeners.
      The computer-based test shows promise as an alternative to the glass slide test
      but needs further development and validation.

PMID- 10587700
TI  - The diagnosis and significance of visceral pleural invasion in lung carcinoma.
      Histologic predictors and the role of elastic stains.
AB  - Invasion of the visceral pleura is an important component of lung carcinoma
      staging, and in some studies is an independent prognostic indicator. Evaluation
      of invasion by H&E may be indeterminate. Elastic stains can be helpful but are
      performed rarely. We reviewed all lung carcinoma resections from 1993 for 13
      histologic features potentially predictive of pleural invasion. Of 57 resections,
      20 were indeterminate by H&E. Verhoeff-Van Gieson (VVG) stain revealed invasion
      in 8 cases, increasing the pathologic stage in 1. VVG stain was negative in 12
      cases, 2 of which had been falsely reported as positive, decreasing the stage in
      1. Angiolymphatic invasion and single-cell spread were significant predictors of
      invasion. Absence of both or the presence of intervening aerated parenchyma
      predicted lack of involvement in all cases. Elastic stains can provide
      prognostically important information, changing the pathologic stage in 4% of lung
      carcinoma resections overall and in 10% of cases indeterminate by H&E for pleural
      invasion.

PMID- 10587701
TI  - Grading of spindle cell sarcomas in fine-needle aspiration biopsy specimens.
AB  - We studied whether histologic criteria for grading sarcomas could be applied to
      fine-needle aspiration biopsy (FNAB) specimens of adult spindle cell sarcomas,
      without knowledge of the sarcoma subtype, by reviewing 36 specimens. Grade 1 was
      assigned for minimal nuclear atypia and overlap, no necrosis, and rare mitotic
      figures, and grade 2 for moderate nuclear atypia, at least moderate nuclear
      overlap, appreciable mitotic figures, and necrosis. Severe nuclear atypia
      distinguished grade 3 from grade 2. A major noncorrelation between FNAB and
      histologic grades was defined as a misclassification of grade 1 vs grade 2 or 3.
      FNAB grades assigned were grade 1, 1; grade 2, 25; and grade 3, 10. There was 1
      major noncorrelation due to a probable FNAB interpretation error. In 15 of 16
      FNAB specimens of grade 2 or 3 sarcomas lacking mitotic figures, necrosis, or
      both, the nuclear atypia reflected the grade. In the remaining case, the degree
      of nuclear overlap and necrosis determined the grade. The histologic grading of
      sarcomas can be applied accurately to most FNAB specimens of spindle cell
      sarcomas without knowledge of the sarcoma subtype.

PMID- 10587702
TI  - A reappraisal of the histopathologic criteria for the diagnosis of cutaneous
      allogeneic acute graft-vs-host disease.
AB  - To determine the validity of the Lerner grading system and review the
      histopathologic findings of cutaneous acute graft-vs-host disease (aGVHD), 78
      skin biopsy specimens from 49 bone marrow transplant recipients were evaluated.
      Histopathologic sections were independently reviewed twice by 3 pathologists and
      classified (Lerner system), without knowledge of the patients' clinical
      evolution. Intraobserver agreement in grading aGVHD was substantial to almost
      perfect. Interobserver agreement between pairs of observers was moderate to
      substantial on first review and substantial on second review. Overall, we found
      an almost perfect agreement in diagnosing Lerner grade III, whereas areas of
      disagreement occurred with Lerner grades 0, I, and II. Histopathologically,
      specimens of patients who developed aGVHD (aGVHD-positive) showed significantly
      higher frequency of epidermal atrophy, spongiosis, diffuse basal vacuolization,
      more than 3 single necrotic keratinocytes per high-power field, satellitosis,
      inflammatory infiltrate, with a predominantly lichenoid pattern, lymphocytic
      exocytosis, and dermal melanophages. When considering skin samples classified as
      grade I and II, we found statistically significant differences between aGVHD
      positive and aGVHD-negative cases only for the presence of inflammatory
      infiltrate, lymphocytic exocytosis, and satellitosis. Lerner grading is
      reproducible, although lesser agreement occurred when evaluating grades I and II,
      and the Lerner grading system should be revised by including the estimate of the
      inflammatory infiltrate as an additional criterion for grade II.

PMID- 10587704
TI  - Thymoma-associated autoimmune enteropathy. A report of two cases.
AB  - Autoimmune enteropathy is an increasingly recognized cause of severe protracted
      diarrhea, usually affecting infants and children predisposed to autoimmune
      phenomena. Although this may be a common cause of diarrheal illness, it is
      scarcely recognized in the American literature. In association with thymoma, a
      case of so-called graft-vs-host-like colitis and 2 cases of chronic diarrhea
      associated with thymoma were reported, but, to our knowledge, no cases of
      autoimmune enteropathy have been reported as such. We describe 2 adults with
      autoimmune enteropathy found in association with a thymoma.

PMID- 10587703
TI  - Detection of p16, RB, CDK4, and p53 gene deletion and amplification by
      fluorescence in situ hybridization in 96 gliomas.
AB  - Inactivation of the p53 gene is a common early event of astrocytoma
      tumorigenesis. Alternatively, since the p16, retinoblastoma (RB), and CDK4 genes
      have been implicated in malignant progression, detection of losses or
      amplifications of these genes in gliomas could be diagnostically, prognostically,
      and therapeutically important. We obtained smear preparations from 96 diffuse
      gliomas and 10 nonneoplastic specimens. Dual-color fluorescence in situ
      hybridizations using paired probes for CEN9/p16, CEN8/RB, CEN17/p53, and
      CEN12/CDK4 were performed and revealed expected frequencies of abnormalities,
      except for p53 losses, which were low (7%). The latter supports the concept that
      p53 inactivation usually occurs by mitotic recombination. Detected abnormalities
      of the p16/RB/CDK4 pathway were highly associated with astrocytic differentiation
      and were univariately associated with decreased patient survival. However, only
      patient age and histologic classification retained statistical significance on
      multivariate analysis. We conclude that in diffuse gliomas, p16/RB/CDK4
      abnormalities are markers of astrocytic phenotype. Thus, their detection by
      fluorescence in situ hybridization may have diagnostic usefulness in cases with
      equivocal morphologic features. Although our numbers are small, we find no
      additional prognostic significance to these genetic abnormalities one age, grade,
      and oligodendroglial histology are taken into account.

PMID- 10587705
TI  - Evidence for early hematopoietic progenitor cell involvement in acute
      promyelocytic leukemia.
AB  - Acute promyelocytic leukemia (APL) represents a subtype of acute myeloid leukemia
      with characteristic morphologic, molecular, and immunophenotypic features.
      Previous immunophenotypic analyses have shown that leukemic cells in APL
      typically express the myeloid markers CD33 and CD13 but lack expression of the
      early hematopoietic progenitor cell antigens CD34 and HLA-DR. We analyzed
      selected immunophenotypic features of APL by flow cytometry and showed that 7
      (41%) of 17 cases contained significant subsets of CD34+ leukemic cells: CD34+
      myeloid cells predominated in 2 APL cases. By using a fluorescence-activated cell
      sorter-fluorescence in situ hybridization approach, we confirmed that the CD34+
      cells harbored the t(15;17) translocation characteristic of APL. By using the
      same experimental approach, CD34+ populations were stratified into primitive
      CD34+ CD38- and committed CD34+ CD38+ progenitor cell subpopulations; cells in
      both subsets contained the t(15;17) translocation. The knowledge that APL may be
      partly or largely CD34+ is important for proper diagnosis. Furthermore,
      identification of the t(15;17) translocation in CD34+ CD38- blasts indicates
      that, in at least some cases, the leukemogenic mutation in APL occurs within
      primitive hematopoietic progenitor cells.

PMID- 10587706
TI  - De novo CD5+ Burkitt lymphoma/leukemia.
AB  - CD5 is a T-cell marker aberrantly expressed in B-cell chronic lymphocytic
      leukemia and mantle cell lymphoma. Other B-cell neoplasms, including Burkitt
      lymphoma, are usually CD5-. We report 4 cases of de novo CD5+ Burkitt
      lymphoma/leukemia in elderly patients, all of whom were in a leukemic phase and
      had variable lymph node and splenic involvement. The blasts were typically medium
      sized, with folded nuclei, distinct but not prominent nucleoli, and moderate
      amounts of somewhat vacuolated basophilic cytoplasm; they were terminal
      deoxynucleotidyl transferase--negative and surface immunoglobulin--positive. All
      4 cases demonstrated c-myc rearrangement, but none had t(14;18), t(11;14), or
      cyclin D1 overexpression or rearrangement. Only 1 patient achieved complete
      remission after hyper-CVAD (hyperfractionated cyclophosphamide, vincristine,
      doxorubicin, dexamethasone) therapy. One patient responded poorly to hyper-CVAD,
      and 2 patients died during induction chemotherapy. These rare cases of aggressive
      lymphoid malignancy with CD5 positivity and molecular features associated with
      Burkitt lymphoma/leukemia are best classified as Burkitt leukemia. However, the
      morphologic and immunophenotypic similarity to the blastoid variant of mantle
      cell lymphoma are diagnostically challenging. The diseases can be distinguished
      at the genetic level, since Burkitt lymphoma involves the rearrangement of c-myc,
      and mantle cell lymphoma usually the overexpression or rearrangement of cyclin
      D1.

PMID- 10587707
TI  - Precursor B lymphoblastic lymphoma presenting as lytic bone lesions.
AB  - Precursor B lymphoblastic lymphoma is an aggressive but potentially curable
      disease. This lymphoma most often manifests in the skin and lymph nodes and, less
      commonly, as lytic bone lesions. In the bone, this lymphoma must be
      differentiated from small round blue cell tumors, diffuse large B-cell lymphoma,
      and acute myelogenous leukemia. We describe the morphologic and immunophenotypic
      features in 4 patients, 2 children, 1 teenager, and 1 adult, who initially
      presented with bone pain and osteolytic lesions but without peripheral blood or
      iliac bone marrow involvement. Positive immunohistochemical staining of the
      neoplastic cells was observed for anti-CD10 (3/4), CD20 (3/4), CD34 (1/4), CD43
      (4/4), CD45/CD45RB (2/4), CD79a (4/4), CD99 (MIC2) (2/4), and terminal
      deoxynucleotidyl transferase (4/4). CD3 was absent in all cases.
      Immunophenotyping these neoplasms is essential to establish the correct diagnosis
      of precursor B lymphoblastic lymphoma, and a panel of antibodies is required
      because of the immunophenotypic heterogeneity.

PMID- 10587708
TI  - Lymphoid aggregates in bone marrow mimic residual lymphoma after rituximab
      therapy for non-Hodgkin lymphoma.
AB  - Rituximab is a novel anti-CD20 monoclonal antibody used in the treatment of
      relapsed low-grade non-Hodgkin lymphoma. To determine the impact of this therapy
      on the interpretation of posttherapy specimens, we reviewed the pretherapy and
      posttherapy bone marrow and peripheral blood morphologic and flow cytometric
      findings for 20 patients who received rituximab. Nine patients had a total of 13
      posttherapy bone marrow specimens; all were positive for lymphoma before therapy.
      After therapy, 11 of 13 posttherapy bone marrow specimens were interpreted as
      positive or suggestive of lymphoma based on routine H&E-stained sections.
      However, immunohistochemical and/or flow cytometric immunophenotyping showed that
      6 of the 11 cases were negative for lymphoma; the lymphoid infiltrates were
      composed entirely of T cells without B cells. We report that posttherapy bone
      marrow specimens from patients treated with rituximab may mimic residual lymphoma
      if examined by morphologic features alone. Familiarity with this finding and the
      use of ancillary immunophenotypic studies will aid in the accurate interpretation
      of posttherapy specimens.

PMID- 10587709
TI  - More biopsies per block.

PMID- 10587710
TI  - Epstein-Barr virus and primary brain lymphomas.

PMID- 10587711
TI  - [Postoperative heparin-induced thrombocytopenia. Recent insights for clinical
      management].

PMID- 10587712
TI  - [Primary stent implantation in the internal carotid artery].
AB  - BACKGROUND AND OBJECTIVE: Advances in interventional catheter technology have
      made it possible to dilate stenoses also in the internal carotid artery (ICA).
      This may cause cerebral emboli, but primary stent implantation may fixate
      atherosclerotic material on the vessel wall and thus prevent embolization.
      PATIENTS AND METHODS: Marked stenosis in the ICA was treated by balloon
      dilatation in 71 consecutive patients aged between 40 and 85 years (mean 69 +/- 9
      years). If possible, a stent was implanted before the first balloon dilatation.
      RESULTS: A stent was placed before dilatation in 53 of 76 procedures. Dilatation
      with a small balloon to allow stent placement was necessary in 23. Thus stent
      implantation before definitive dilatation was successful in all instances. The
      degree of stenosis was reduced from 79 +/- 11 to 9 +/- 14%. In all procedures the
      stenosis was reduced to less than 50%. One patient had a severe and two had a
      mild stroke. One patient died of a myocardial infarction 2 days after the
      procedure. Thus the neurological complication rate was 3.9% and the death rate
      1.3%. Follow-up examination revealed an asymptomatic occlusion of the ICA after
      two weeks in one patient, a recurrent stenosis after 6 months in two of 46
      patients. In all other patients the degree of stenosis was less than 50% at 6
      months. CONCLUSION: Primary stent placement before balloon dilatation in ICA
      stenosis was possible in the majority of patients. This procedure would thus seem
      to reduce the risk of thromboembolic complications.

PMID- 10587713
TI  - [Heparin-induced thrombocytopenia type II: reexposure to heparin].
AB  - HISTORY AND ADMISSION FINDINGS: At the age of 55 years a now 70-year-old man had
      his aortic valve replaced by a prosthetic (Bjork-Shiley) valve, and 11 years
      later a VDD pacemaker had been implanted. 18 months before the latest admission
      he had been hospitalized for treatment of staphylococcal endocarditis involving
      the aortic prothesis. At that time thrombocytopenia developed during heparin
      administration, diagnosed clinically and with the heparin-induced platelet
      activity (HIPA) test as type II heparin induced thrombocytopenia. His latest
      admission was for the diagnosis and treatment of peripheral arterial disease of
      the right leg (Fontaine stage IIb). INVESTIGATIONS: Right popliteal and pedal
      pulses were not palpable. He was able to walk pain-free for only 70 m. Doppler
      sonography demonstrated an arm-leg index on the right of 0.7. Angiography
      revealed marked stenosis in the right superficial femoral artery and a filiform
      stenosis in the right popliteal artery. TREATMENT AND COURSE: Both stenoses were
      relieved by percutaneous transluminal balloon angioplasty, in the course of which
      5000 IU heparin were administered as a bolus intraarterially. Postoperative
      anticoagulation was maintained for 2 days with recombinant hirudin. There was no
      evidence of platelet reduction or heparin-induced antibodies despite the renewed
      infusion of heparin. CONCLUSION: Single re-administration of heparin in a patient
      who had developed a type II heparin-induced thrombocytopenia several years before
      does not necessarily lead to a booster of antibodies and thus to a reduction of
      platelets in the peripheral blood. It is a moot point whether the course in this
      case was an exception or the rule.

PMID- 10587714
TI  - [Late onset of heparin-induced thrombocytopenia with recurrent arterial
      thromboses and amputation].
AB  - HISTORY: An 80-year-old woman had been hospitalized in a psychiatric clinic
      where, on the 22nd day, she sustained a fracture of the neck of the left femur,
      which was treated by internal screw fixation. The postoperative course was at
      first without complication. But 9 days postoperatively her platelet count had
      fallen to 59,000/microliter. As heparin induced type II thrombocytopenia (HIT II)
      was suspected, the thrombosis prophylaxis with low-molecular heparin was replaced
      by sodium danaparoid (twice 750 units subcutaneously). Despite this, ischaemia of
      the right lower leg developed and required amputation. On the following day the
      left lower leg and foot also became ischemic, where upon she was admitted to the
      author's hospital (37 days after her admission to the psychiatric clinic).
      ADMISSION FINDINGS: The patient was in a reduced general condition (body-mass
      index 19.5 kg/m2). She was disoriented as to place and time. Her blood pressure
      was 140/80 mmHg, her pulse irregular with a ventricular rate of 100/min. The skin
      below the middle of the left lower leg was cold and livid and the pedal pulses
      were not palpable. LABORATORY TESTS: Haemoglobin content was 9.7 g/dl, the white
      cell count 9,200/microliter, and platelet count 54,000/microliter. Electrolytes
      and creatinine were within normal limits. TREATMENT AND COURSE:
      Thrombendarterectomy was performed once via the left groin under danaparoid
      anticoagulation. There was no re-occlusion and the patient was able to walk
      again.--It was ascertained subsequently, she had already been given ordinary
      heparin in the psychiatric clinic for 20 days. Her platelet count of around
      70,000/microliter returned to normal even though heparin administration was
      continued. CONCLUSION: A reduction in platelet count by more than half during
      heparin treatment suggests heparin-induced thrombocytopenia, in which case
      heparin should be discontinued at once. In high-risk patients adequate treatment
      should be initiated with other anticoagulants even before the occurrence of
      thromboembolism.

PMID- 10587715
TI  - [Diagnosis and therapy of migraine].

PMID- 10587716
TI  - [The value of echocardiography for the assessment of chronic mitral valve
      insufficiency].

PMID- 10587717
TI  - [A 63-year-old patient with deterioration of general health, bone
      demineralization, hypocalcemia and parathyroid hormone excess].

PMID- 10587718
TI  - [Pregnancy (5-6 weeks)].

PMID- 10587719
TI  - [Treatment of periocular carcinoma by interstitial iridium curietherapy. 77
      patients].
AB  - OBJECTIVES: We used a pluridisciplinary approach with the participation of
      ophthalmologists, dermatologists and oncologists-radiotherapists to assess
      therapeutic results after interstitial indium 192 curietherapy for carcinomas
      located in the periocular region. PATIENTS AND METHODS: A retrospective study
      included 77 patients with stage T1T2 carcinoma treated from 1997 to 1988. Median
      survival was 42 months. RESULTS: Disease control was obtained in 100% of the
      cases. Functional and esthetic results were evaluated using 4 criteria. Esthetic
      results were excellent in 71.4% of cases with no functional disorders in 88.3%.
      CONCLUSION: Interstitial curietherapy is a good indication for the treatment of
      small tumors of the periocular region. The esthetic result is excellent with few
      minor complications which have little effect on patientsi quality of life.

PMID- 10587720
TI  - [Acute hepatitis in the course of cyclosporine therapy of Crohn's disease].
AB  - BACKGROUND: Cyclosporin is used for the treatment of corticosteroid-resistant
      inflammatory bowel disease. Secondary liver disease is a risk. CASE REPORT: Acute
      hepatitis with predominant major transaminase elevation occurred in a patient
      treated with cyclosporin for corticosteroid-resistant Crohns disease. No viral,
      alcoholic, autoimmune or metabolic cause could be incriminated. Complete cure was
      achieved after withdrawal of cyclosporin. DISCUSSION: Only one case of
      cholestatic hepatitis has been reported in chronic inflammatory bowel disease.
      Cyclosporin was the probable cause in our case as other causes of acute hepatitis
      were ruled out and withdrawal led to cure. Cyclosporin can induce abnormal liver
      tests in 25% of cases. If reducing dose does not lead to improvement, it may be
      necessary to discontinue cyclosporin. Regular liver tests would thus be required
      for patients given cyclosporin for chronic inflammatory bowel disease.

PMID- 10587721
TI  - [A history of diseases: apropos of idiopathic capillary hyperpermeability
      syndrome].
AB  - BACKGROUND: Idiopathic capillary hyperpermeability syndrome is expressed by
      episodes of hypovolemic shock with normal consciousness. CASE REPORT: A 61-year
      old man had a history of recurrent shock. During the shock episodes, blood
      pressure was non-measurable and laboratory tests showed polycythemia, low serum
      protein and monoclonal immunoglobulinemia. The patient also developed
      pneumocystosis and had an infra-His block. DISCUSSION: The final diagnosis was
      idiopathic capillary hyperpermeability syndrome. This rare syndrome associates
      recurrent shock with IgG monoclonal immunoglobulinemia and, at the time of the
      shock episodes, increased hematocrit with paradoxical fall in serum protein.

PMID- 10587722
TI  - [Unique bone metastasis in the foot revealing recurrence of cancer of the
      rectum].

PMID- 10587723
TI  - [Deep venous thrombosis during pregnancy: long-term treatment with low molecular
      weight heparin].

PMID- 10587724
TI  - [Effect of breast cancer screening on mortality].

PMID- 10587725
TI  - [The G virus: the orphan virus].
AB  - The GB-C/hepatitis G virus (GBV-C/HGV) was discovered in 1995. Its prevalence in
      the general population of industrialized countries is relatively high. The GBV
      C/HGV virus is transmitted by blood and blood-product transfusion, intravenous
      drug abuse, sexual transmission and mother-fetus transmission. To date, this
      virus has not been associated with acute or chronic hepatitis and as such
      hepatitis G virus is a misnomer. This orphelin virus is thus still looking for
      the right name and perhaps an induced pathology.

PMID- 10587726
TI  - [Cellular telephones and their relay stations: a health risk?].
AB  - Portable cellular phones and their relay stations emit ultra-high frequency waves
      (microwaves) with amplitude modulation and extremely low frequency pulsation. The
      user is absorbed by the head and reaches the nervous structures leading to
      increased brain temperature. The general population is exposed to a distant field
      with an electromagnetic intensity which depends on the distance from the emitting
      antennas, the presence of "passive re-emitters", and the number of communications
      processed by the relay station. Among the main biological effects, "radio
      frequency disease", electroencephalogram disturbances, and blood pressure
      disorders as well as risk of cancer have been observed in humans and animals.

PMID- 10587727
TI  - [Therapeutic aspects in the management of hairy cell leukemia].
AB  - CHRONIC B CELL PROLIFERATION: An estimated 80 to 120 new cases of hairy cell
      leukemia are diagnosed annually in France. Median survival is 5 years for
      untreated patients who develop a series of infectious complications. For many
      years, interferon alpha was the standard therapy but the therapeutic strategy has
      changed with the arrival of purine analogs, deoxycoformicine and 2-CdA.
      THERAPEUTIC OPTIONS: We searched Medline, Pascal, and Current Contents for
      literature on the treatment of hairy cell leukemia over the last 10 years and
      discuss here available data on response rate, mechanism of action and adverse
      effects of different therapeutic options. BY TREATMENT: Interferon generally
      induces partial response and most patients relapse after treatment withdrawal.
      The purine analogs, desoxycoformycine and 2-chlorodeoxyadenosine, are more active
      than interferon inducing response in approximately 90% of the cases, even after
      interferon failure, complete response is achieved in 50% to 70% of patients.
      Relapse rate at 5 years appears to be limited to 10% n 15%. Besides infections,
      the main adverse effect is the constant deep and persistent decline in CD4 counts
      but with no special risk of opportunistic infection. The increased rate of
      secondary cancers in long-term survivors and its possible relationship with
      treatments remains a controversial topic.

PMID- 10587728
TI  - [Type 1 diabetes mellitus].
AB  - POSITIVE DIAGNOSIS: Among the various diseases leading to chronic hyperglycemia,
      type 1 diabetes mellitus is distinctive by the presence of specific
      autoantibodies. The common from of type 1 diabetes mellitus is insulin-dependant
      diabetes, but type 1 diabetes may also present as non-insulin-dependent. In order
      to predict insulin-dependence and screen for associated autoimmune diseases,
      search for autoantibodies is required in all patients with diabetes, whatever the
      clinical presentation. COMPLEX PATHOPHYSIOLOGY: Diabetes mellitus is a
      multifactorial disease implicating of environmental and genetic factors leading
      to breakdown immune tolerance. LONG PRECLINICAL PHASE: Chronic hyperglycemia is
      preceded by a long preclinical phase during which the only observable anomalies
      result from activation of the immune system. With the development of simplified
      techniques for detecting autoantibodies, it would be reasonable to foresee large
      scale screening. ONGOING SECONDARY PREVENTION TRIALS: The goal is to prevent the
      development of chronic hyperglycemia by intervening early, during the
      infraclinical phase, in patients with signs of immune activation. AT THE TIME OF
      DIAGNOSIS: When diabetes is discovered, intensive insulin therapy helps preserve
      residual insulin secretion and guarantees better long-term metabolic control.

PMID- 10587729
TI  - [Autoimmune deafness].
AB  - A REAL ENTITY: Deafness resulting from an autoimmune mechanism is suggested by a
      growing number of clinical and experimental arguments. The audio-vestibular
      system is known to be involved in a certain number of systemic diseases,
      particularly Cogan's disease. In other cases, the inner ear alone is involved;
      deafness may be the first manifestation of a systemic disease or result from a
      possible immunological mechanism. CLINICAL ASPECTS: Autoimmune deafness is very
      invalidating. Bilateral perception deafness is observed in 80% of the cases and
      vestibular involvement is found in 70% DIAGNOSIS: No one simple reliable test is
      known which can establish the diagnosis of autoimmune deafness. Other causes must
      be ruled out by appropriate clinical and complementary explorations. For humoral
      immunity, the western blot method has given promising results suggesting a
      possible role of the heat shock protein in the underlying immunological
      mechanism. TREATMENT: Immediate care is needed but no standard treatment has been
      defined. High-dose corticosteroids can provide symptom relief, particularly in
      case of abnormal immunological tests. The role of immunosuppressive therapy,
      sometimes proposed in case of corticosteroid resistance, remains to be defined.

PMID- 10587730
TI  - [Contribution of immunotherapy to the treatment of T-cell lymphoma of the skin].
AB  - DEFINITION: T-cell lymphomas localized predominantly or primarily in skin
      comprise a heterogeneous group of tumors. The most frequent is fungoid mycosis. T
      CELL TUMORS AND GROWTH FACTORS: When growth factors of T-cell tumors,
      particularly IL-7 and IL-5, were identified, it became possible to grow T-cell
      tumoral clones in long-term in vitro cultures used to evidence anti-tumoral
      cellular immune reactions in T-cell skin cancers. Reactional T-cell clones with
      specific anti-tumoral reactions can be expaned ex vivo. This advance has made it
      possible to identify tumoral antigens and better understand the mechanisms
      leading to tumoral escape from anti-tumoral defense systems. THERAPEUTIC
      PERSPECTIVES: It is now possible to develop immunotherapy strategies based on
      reinjection of T lymphocytes with specific cytotoxic activity after ex vivo
      expansion. Injections of immunogenic peptides associated or not with dendritic
      cells or injection of DNA coding for these tumor antigens are other
      possibilities.

PMID- 10587731
TI  - Eyewitness memory and suggestibility in children with mental retardation.
AB  - We examined how well children with mental retardation were able to recall a live
      staged event one day later compared to CA- and MA-comparable peers. Children with
      mental retardation performed very well on many measures of eyewitness memory
      performance, reaching the level of the CA-comparable group for free recall,
      general questions, open-ended questions, and correctly leading questions. They
      were, however, more suggestible in response to closed misleading questions than
      were children in the CA-comparable group, although they were not more suggestible
      than those in the MA-comparable group. Some relationships were found between a
      standardized measure of suggestibility and performance on the eyewitness memory
      task, but most of these relationships were not the same within each of our study
      groups.

PMID- 10587732
TI  - Teaching participants with developmental disabilities to comply with self
      instructions.
AB  - Four adults with mild mental retardation were taught to sort based on what two
      pictures had in common and to name each object and common features of two pairs
      as well as to comply with a series of instructions to sort the pictures
      selectively. The criterion task was to inspect a sample pair, sort through a deck
      of 15 pictures to find those showing what the sample pair had in common, and to
      repeat a series of pairs. They failed this task and continued to fail even after
      a supposedly relevant self-instruction. After being taught to act on what they
      told themselves, they self-instructed correctly and sorted accordingly. Imperfect
      generalization by 2 participants was remediated by revoking self-instructions.
      They were taught to act on what they told themselves; thereafter, they self
      instructed correctly and sorted accordingly. Imperfect generalization by 2
      participants was remediated by re-evoking the relevant self-instructions.

PMID- 10587733
TI  - Second-order belief attribution in Williams syndrome: intact or impaired?
AB  - Second-order mental state attribution in a group of children with Williams
      syndrome was investigated. The children were compared to age, IQ, and language
      matched groups of children with Prader-Willi syndrome or nonspecific mental
      retardation. Participants were given two trials of a second-order reasoning task.
      No significant differences between the Williams syndrome and Prader-Willi or
      mentally retarded groups on any of the test questions were found. Results
      contrast with the view that individuals with Williams syndrome have an intact
      theory of mind and suggest that in their attributions of second-order mental
      states, children with Williams syndrome perform no better than do other groups of
      children with mental retardation.

PMID- 10587734
TI  - Social interactions of high school students with mental retardation and their
      general education peers.
AB  - The informal social interaction behavior that is typical of a high school
      lunchroom in which general and special education students are physically included
      was described. Using systematic observation and social comparison methods, we
      compared the performance of two groups of students (12 general education students
      and 12 students with mental retardation). Both similarities and differences were
      found in the interactions of students with mental retardation and their general
      education peers with respect to social behaviors, conversational topics, and
      context within which interactions occurred. However, despite being in proximity,
      students with mental retardation rarely interacted with any of approximately 500
      general education students present in the lunchroom. Implications are discussed
      for increasing social interaction among high school students.

PMID- 10587735
TI  - Differences in coping effectiveness and well-being among aging mothers and
      fathers of adults with mental retardation.
AB  - In this longitudinal study, we examined stress and coping processes among 133
      married mothers (age 59 to 83) and fathers (age 56 to 84) of adults with mental
      retardation (age 19 to 53). There were no differences between mothers and fathers
      with respect to their frequency of use of emotion-focused coping, but mothers
      used significantly more problem-focused coping strategies than did their
      husbands. For mothers, greater use of problem-focused coping strategies and lower
      use of emotion-focused coping buffered the impacts of caregiving stress on their
      psychological well-being. However, for fathers, no buffering effects of coping
      were detected. The implications of gender differences in coping effects were
      examined in the context of the impact of lifelong caregiving.

PMID- 10587736
TI  - [Siblings of children with chronic disease].

PMID- 10587737
TI  - [Pediatricians and the "morning-after pill": Should they discuss this with
      adolescents?].

PMID- 10587738
TI  - [Efficacy and limits of rescue high-frequency oscillatory ventilation in the
      treatment of hyaline membrane disease in preterm newborns].
AB  - Conflicting reports of high-frequency oscillatory ventilation (HFOV) use as an
      alternative to conventional mechanical ventilation have been published. This
      retrospective study has evaluated the efficacy and safety of rescue HFOV in
      preterm infants with severe hyaline membrane disease (HMD) after the failure of
      conventional mechanical ventilation (CMV). POPULATION AND METHODS: All newborns
      hospitalized in our neonatal intensive care unit (NICU) from 10.1.1993 to
      15.4.1995 with CMV failure, defined as the need for more than 55% FiO2 without
      any improvement for at least six hours, have been retrospectively studied. The
      infants were shared according to the absence (Gr I) or the presence (Gr II) of
      persistent pulmonary hypertension of neonate (PPHN) in addition to HMD before
      HFOV. RESULTS: Gestational age (GA) was 29.2 +/- 3.7 weeks (mean +/- SD) in Gr I
      and 30.3 +/- 2.8 in Gr II. Birth weight was 1379 +/- 750 g and 1471 +/- 612 g,
      respectively. As soon as three hours after the onset of HFOV in both groups, a
      dramatic improvement was observed with a FiO2 drop from 82 +/- 20% to 64.8 +/-
      25.5% (P < 0.01). Among the infants, 62% survived without any major disability
      and 28% died (46% in Gr II vs 12% in Gr I, P < 0.01). A trend towards a worsening
      of pre-existing brain lesions has been noticed. An increased risk of mortality
      was observed when a secondary worsening in O2 requirements occurred 24 hours
      after the onset of HFOV, despite an initial significant improvement. SGA was also
      associated with a poor prognosis (46% of the deaths vs 29% for AGA infants, P <
      0.05). CONCLUSION: HFOV has been successfully used in premature infants with
      severe respiratory disease and failure of CMV. Criteria of poor prognosis were
      PPHN and SGA, or a secondary worsening in oxygen requirements after initial
      improvement. A trend towards aggravation of pre-existing brain lesions has been
      noticed after HFOV. This aggravation is more frequent when PPHN is associated
      with HMD. This observation suggests caution for HFOV use when these conditions
      are present in premature infants.

PMID- 10587739
TI  - [Medical and psychological status of one-year-old premature babies without severe
      disability. Case-control prospective study].
AB  - BACKGROUND: This case-control prospective study was conducted to determine
      whether and how medical, psychological and affective development differs from
      premature to full-term newborns without severe disability. POPULATION AND
      METHODS: Newborns under or at 33 weeks gestation (W) were included from December
      1992 to January 1994 and were matched with two controls. The same examiners
      evaluated each infant at the effective postnatal age of nine to ten months.
      RESULTS: Fifty premature babies (average gestational age [GA] = 30.7 W) were
      compared to 100 controls. The main problems were bronchopulmonary (P = 0.03) and
      sleep (P = 0.027) disorders. Motor disability was suspected in 9% of the cases
      and none control (P = 0.00003, OR = 3.44). By multivariate analysis, cases
      differed from the controls by infant-mother relation disturbances (OR = 13.3),
      motherhood anxiety (OR = 13.3), poor expressiveness (OR = 5.6), peripheral tonus
      anomalies (OR = 39.5) and sleep troubles (OR = 5.8). CONCLUSION: Premature
      newborns had risks for the child-mother relation but not for psychoaffective
      development disturbances.

PMID- 10587740
TI  - [Evaluation of the ability of asthmatic children to use a breath-actuated
      pressurized inhaler].
AB  - BACKGROUND: Poor inhaler technique in asthmatics is well documented. The
      objective of this study was to evaluate the influence of reading the instruction
      leaflet and the consultant's explanations on the use of the new breath-actuated
      inhaler (Autohaler 3M). METHODS: In this study were participating 379 asthmatic
      children and adolescents, aged from four to 17 years (mean age: 10; 64% boys),
      recruited by 80 pediatricians. The use of the Autohaler device was considered to
      be correct if the shaking, lip position, deep inhalation and apnea were all
      properly performed. RESULTS: The Autohaler was used correctly by 42% of the
      subjects simply after reading the instruction leaflet (phase I), and by 75% of
      the subjects who, having failed phase I, received the consultant's explanations
      (phase II). At the end of phases I and II, the device was correctly used by 84%
      of the subjects. In multivariate analysis, those under the age of nine years and
      those with no prior use of inhaler systems accounted for a significant amount of
      the incorrect use of the Autohaler during phase I. In phase II, only the fact of
      being less than nine years old was significantly related to incorrect use.
      CONCLUSION: More than four-fifths of the asthmatic children and adolescents
      properly used the Autohaler after merely reading the instructions and after
      receiving additional explanation from the consultant. The marked improvement
      obtained after medical explanations underlines the essential educative role of
      the physician when prescribing. Young children require specific training and
      particularly careful attention.

PMID- 10587741
TI  - [Buprenorphine and pregnancy. Analysis of 24 cases].
AB  - BACKGROUND: Maintenance therapy of drug-addict mothers with medical and
      psychosocial support may reduce complications (prematurity, growth retardation,
      fetal distress and fetal death). Methadone has been widely used during pregnancy
      with beneficial effects. Buprenorphine (BUP) is used more and more and shows the
      same beneficial effects. PATIENTS AND METHOD: Twenty-four pregnant women received
      BUP and their infants were enrolled in the study. Thirteen retrospective (GI) and
      11 prospective (GII) cases were studied. In the GII, the women were treated and
      followed up in an interdisciplinary manner. RESULTS: Complications in GII were
      less frequent than in GI: 9 vs 30% of prematurity, 9 vs 46% of fetal growth
      retardation and 0 vs 23% of acute fetal distress. However, the frequency of
      withdrawal syndrome was the same in both groups, 63 vs 69%, though improvements
      came more rapidly in GII. CONCLUSION: This study shows that the use of BUP during
      pregnancy, combined with medical and psychosocial support, may reduce addiction
      complications. This support has to be maintained after the birth.

PMID- 10587742
TI  - [Moyamoya disease: advantage of early diagnosis and survival treatment. Review of
      three cases].
AB  - A diagnosis of moyamoya disease was made in three children aged five, eight and
      13 years (including two Turkish sisters). Clinical presentation was recurrent
      episodes of cerebral ischemia and stroke. CT scans and MRI showed infarcts in
      various distributions. Angiography revealed anterior bilateral stenosis of the
      circle of Willis and development of Moyamoya collateral pathways. In one case
      there was coagulopathy with protein C deficiency. To increase transdural
      collateral flow, revascularisation with encephalo-duro-arterio-synangiosis was
      attempted in all three children. Outcome was clinically and angiographically
      satisfactory and none of the children developed further neurological
      complications. The current state of study on Moyamoya disease is also presented.

PMID- 10587743
TI  - [Hypertransaminasemia in an adolescent].
AB  - CASE REPORT: An adolescent admitted to hospital because of an obvious convulsion
      seizure presented with a high level of serum macroaspartate aminotransferase.
      This macroaspartate aminotransferase was discovered by chance when blood tests
      were made. DISCUSSION: Macroaspartate aminotransferase is a persistent, benign
      phenomenon, probably not congenital, discovered either in healthy patients, or in
      adults suffering from malignancies or autoimmune diseases. Macroenzymes have been
      identified as a cause of benign increase in a number of serum enzymes, like
      macroamylase serum levels. The macroenzyme is often an immunoglobulin G-complexed
      enzyme. CONCLUSION: It is important for clinicians to be aware of their existence
      in order to avoid unnecessary procedures. It is important that the patient is
      informed of the macroaspartate aminotransferase and that the same is stated in
      his health record.

PMID- 10587744
TI  - [Association of aplasia cutis congenita with coarctation of the aorta: a
      coincidence?].
AB  - The association of aplasia cutis congenita and aortic coarctation could be a
      coincidence. CASE REPORT: A neonate was born with an aplasia cutis congenita in
      the midline of the scalp. When she was two months old, an aortie coarctation was
      detected and surgically resected. Spontaneously, the scalp gradually cicatrized.
      CONCLUSION: A search for a candidate gene in this second reported case is
      mandated.

PMID- 10587746
TI  - [The biochemical and hematological assessment of iron metabolism].
AB  - Despite the progress in the knowledge of iron metabolism, its precise assessment
      remains uneasy. Serum ferritin assesses the extent of storage iron. Serum iron
      and the percentage of transferrin saturation evaluate the tissues' iron supply.
      But these parameters are indirect measurements and they do not reflect marrow
      iron supply. Serum transferrin receptors, red cell ferritin and red cell zinc
      protoporphyrin are good indicators of this iron supply to the erythroid marrow
      for erythropoiesis. Since the introduction of recombinant human erythropoietin,
      it has become apparent that an adequate iron supply to the bone marrow is
      essential for a satisfactory hematopoietic response. In some cases, despite a
      high baseline ferritin, iron may not be sufficiently released from reserves in
      the bone marrow, resulting in a functional iron deficiency. The percentage of
      hypochromic red cells and reticulocyte haemoglobin content tends to reflect
      direct marrow iron status.

PMID- 10587745
TI  - [Acute Corynebacterium diphtheriae aortic endocarditis with negative blood
      cultures].
AB  - Acute endocarditis with negative blood culture is a challenge requiring close
      cooperation between several specialists. CASE REPORT: A 15-year-old boy presented
      with an acute aortic endocarditis due to Corynebacterium diphtheriae. Blood
      cultures were negative due to an empiric anti-infective therapy. Valvular
      replacement with a mechanical prosthesis failed to cure the sepsis, which
      resolved after a cryopreserved allograft implantation. CONCLUSION: This case
      underlines the efficiency of the highly specialized bacteriological centers and
      the advantages of using a cryopreserved allograft during the septic state.

PMID- 10587747
TI  - [Enterovirus infections in children under three months of age].
AB  - Enterovirus infections in childhood (echoviruses, coxsackie viruses A and B,
      unclassified enteroviruses) are varied, nonspecific and benign (except for
      poliovirus infections). However, in infants, they may lead to severe neurological
      or cardiac lesions. In neonates, enterovirus infections are difficult to
      distinguish from late-onset bacterial infection. Maternal-fetal or postnatal
      transmission can induce early spontaneous abortions or severe neonatal
      infections. Diagnosis is usually based on viral cultures and, in recent years, on
      PCR techniques. At the present time, no potential effective drug is available:
      intravenous immunoglobulins, immunization or anti-proteases may be of interest.

PMID- 10587748
TI  - [Radiologic case of the month].

PMID- 10587749
TI  - [Anorexia nervosa in children and adolescent: new therapeutic approaches].
AB  - Classical therapeutic recommendations requires that girls with anorexia nervosa
      be separated from their parents. Refeeding, and later individual psychodynamic
      approaches were also emphasized. These guidelines are now broadened towards
      psychotherapeutic approaches (psychodynamic, familial, cognitive-behavioral)
      associated with psychoeducational and dietetic strategies. In the Child and
      Adolescent Psychopathology Unit of Robert-Debre Hospital in Paris, individual
      therapeutic programs are applied to young anorectic girls and their families.
      These programs are implemented within an inpatient (full-time, part-time) or
      outpatient (consultations, weekly day-therapeutic program) framework. In order to
      forge a therapeutic alliance with parents and restore "parental competences"
      feelings, we do not separate any longer anorectic girls from their parents during
      hospitalization, and we have developed an alternative therapeutic model to full
      time hospitalization.

PMID- 10587750
TI  - [Management of chronic constipation in the infant].
AB  - Constipation is a common symptom of various pathologies with dysfunction of the
      intestinal motricity which largely differ in their expression and severity.
      However chronic idiopathic constipation is by far the most frequent condition.
      Only constipations associated with symptoms such as poor nutritional status,
      failure to thrive, signs of upper intestinal tract obstruction (gross abdominal
      distention), or showing resistance to the usual therapeutic approach, justify
      investigations looking for an organic disease, mainly Hirschsprung disease.
      Treatment of chronic idiopathic constipation requires, first to evacuate the
      fecal mass, then to prevent its reconstitution mainly by dietetic measures,
      regular large hydration, stool modifying therapy, daily bowel habit, and regular
      physical activities; in addition it is important that clear and reassuring
      explanations be given to the parents.

PMID- 10587751
TI  - [Accidental ingestion of button battery].
AB  - Button batteries are easily swallowed by children and may produce severe
      digestive injuries through two different mechanisms: electrochemical burns when
      in contact with the digestive mucosa, release of caustic substances when
      fragmented. Esophageal lesions are especially dangerous, as they can lead to
      perforation, fistula or secondary stenosis. The risk of mercury intoxication is
      less worrying since the assimilated fraction of the metal is unlikely to produce
      clinical effect. Although the large majority of the reported cases of button
      battery ingestion remained asymptomatic, the potentially lethal outcome justifies
      a precise diagnostic procedure: any button battery ingestion must be documented
      with a radiography of the digestive tract. Any battery lodged in the esophagus
      must be urgently removed by endoscopy. Other locations do not need any removal
      attempt unless complications: nonetheless a follow-up is necessary to confirm the
      spontaneous elimination of the battery. Manufacturers, physicians and parents
      share responsibility for preventing such accidents.

PMID- 10587752
TI  - [Dengue shock syndrome in two brothers].

PMID- 10587753
TI  - [Sudden infant death in infants previously hospitalized during the neonatal
      period (1986-1996). 1994: a pivotal year?].

PMID- 10587754
TI  - Family medicine and psychiatry. Opportunities for sharing mental health care.

PMID- 10587755
TI  - Ethical considerations in sharing personal information on computer data sets.

PMID- 10587756
TI  - Managing hyperbilirubinemia in term newborn infants.

PMID- 10587757
TI  - What a challenge!

PMID- 10587758
TI  - Facing the challenge.

PMID- 10587759
TI  - No special treatment given.

PMID- 10587760
TI  - South African saga continues.

PMID- 10587761
TI  - Is reimmunization necessary?

PMID- 10587762
TI  - Infertility is a family medicine issue.

PMID- 10587763
TI  - Roy Henry Vickers inspires National ASA in Victoria. Interview by Barbara Kermode
      Scott.

PMID- 10587764
TI  - Folic acid and neural tube defects. Good news at last!
AB  - QUESTION: I read last year that Canada has followed the United States in
      fortifying flour with folic acid to prevent neural tube defects. Do we know yet
      whether this strategy is working? ANSWER: In Canada, flour is fortified with
      folic acid to a level of 0.15 mg/100 g. Although a mandatory date was set for
      November 1, 1998, most if not all companies implemented the change on or before
      January 1, 1998. Recent figures from the United States, where the deadline for
      fortification was January 1998, show that by March 1999, mean folate levels in
      flour doubled, substantially decreasing the risk for neural tube defects.

PMID- 10587766
TI  - Dermacase. Pseudoxanthoma elasticum

PMID- 10587765
TI  - Ophthaproblem. Vitelliform macular dystrophy (Best's disease).

PMID- 10587767
TI  - Locum accepting new patients.

PMID- 10587768
TI  - Reminders for preventive services.

PMID- 10587769
TI  - What's old is new again. Spironolactone and heart failure.

PMID- 10587770
TI  - Valsartan. Just a second-line antihypertensive drug.
AB  - Valsartan (Diovan) is an antihypertensive drug belonging to the family of
      angiotensin II receptor antagonists. At a dose of 40 mg/d, its antihypertensive
      effect is inconsistent. At 80 mg/d its effect on blood pressure, its adverse
      effects, and its contraindications (mainly pregnancy and renal artery stenosis)
      are similar to those of angiotensin-converting enzyme (ACE) inhibitors, except
      that coughing is rarer with valsartan than with ACE inhibitors. Valsartan has no
      demonstrated advantage over losartan, another angiotensin II antagonist.
      Valsartan has not been shown to prevent complications of arterial hypertension,
      and its use is, therefore, less well validated than that of diuretics and beta
      blockers.

PMID- 10587771
TI  - No psychiatry? Assessment of family medicine residents' training in mental health
      issues.
AB  - OBJECTIVE: To assess whether the mental health component of the family medicine
      residency program at Memorial University of Newfoundland, which contains no
      formal mental health training with psychiatrists, adequately prepares residents
      for practice, and to assess which aspects of their training enhanced their mental
      health skills most. DESIGN: Cross-sectional mailed survey. SETTING: A 2-year
      family practice residency program with a focus on training for rural practice
      offering integrated and eclectic multidisciplinary mental health training rather
      than formal psychiatry experience. PARTICIPANTS: Graduates of the family practice
      residency program, 1990 to 1995. Completed questionnaires were returned by 62 of
      116 physicians. MAIN OUTCOME MEASURE: Confidence of respondents in dealing with
      23 mental health problems. RESULTS: Respondents felt prepared to address most of
      the mental health needs of their patients. Higher levels of confidence were
      associated with lower referral rates. There was no significant relationship
      between time spent in practice and confidence in dealing with mental health
      problems. Graduates' confidence correlated with areas in the program identified
      as strong. CONCLUSIONS: The program appears to train family doctors effectively
      to meet the mental health needs of their patients.

PMID- 10587772
TI  - Common colds. Reported patterns of self-care and health care use.
AB  - OBJECTIVE: To describe the self-reported prevalence and patterns of self-care and
      health care use for colds and flu. DESIGN: Using the expert panel method, a
      questionnaire was developed to explore self-care practices, attitudes,
      pharmaceutical use, and health care use for a range of cold and flu symptoms.
      SETTING: London and Windsor, Ont. PARTICIPANTS: Using a random-digit-dialing
      survey method, 210 residents were interviewed between November and December 1993.
      Of 1484 telephone numbers called, 1179 calls were ineligible. Two hundred ten
      questionnaires were completed for 305 eligible respondents. MAIN OUTCOME
      MEASURES: Demographic data, typical self-care practices, actual practice during
      respondents' last cold, opinions on appropriate practices, and knowledge of how
      to treat colds. RESULTS: Self-care was respondents' treatment of choice, and most
      respondents use over-the-counter drugs. Prescription drug use was low. Only 1%
      reported seeing a physician for their last cold. As the number of symptoms
      increased, however, reported use of over-the-counter drugs and calls or visits to
      doctors increased. CONCLUSIONS: Results are congruent with other studies showing
      that the health care practices of most respondents are consistent with low use of
      the health care system and high levels of self-care for colds and flu.

PMID- 10587773
TI  - Preventing recurrent suicidal behaviour.
AB  - OBJECTIVE: To highlight recent empirical evidence for effective interventions
      that can guide family physicians in managing patients after suicide attempts.
      QUALITY OF EVIDENCE: Randomized control trials of psychosocial interventions for
      people after suicide attempts have provided some evidence for effective
      interventions. MAIN MESSAGE: Suicide attempts are more common than suicides; the
      number of attempts seen in a family practice is estimated to be 10 to 15 yearly.
      Up to two thirds of patients who take their lives by suicide have seen a family
      physician in the month before their death. Principles of care after a suicide
      attempt include actively engaging the patient, involving the family, restricting
      access to means of suicide, and developing intervention plans to deal with the
      psychopathology that has placed the patient at risk. CONCLUSIONS: Family
      physicians have a crucial role in preventing suicide through aftercare and
      ongoing monitoring of patients who have attempted suicide.

PMID- 10587774
TI  - Pharmacological treatment of depression. Consulting with Dr Oscar.
AB  - OBJECTIVE: To review the pharmacological treatment of depression and to evaluate
      current strategies for treatment to maximize the benefits of antidepressant
      medications. QUALITY OF EVIDENCE: MEDLINE was searched to January 1999, using the
      headings depression, combination, augmentation, lithium, triiodothyronine,
      pindolol, buspirone, methylphenidate, and electroconvulsive therapy, for
      randomized controlled trials, systematic overviews, and consensus reports. Recent
      high-quality reviews were often found. References from papers retrieved were
      scrutinized for other relevant reports. Preference was given to more recent
      articles and well-designed studies. Recommendations from academic groups were
      analyzed. MAIN MESSAGE: Optimization of antidepressant therapy is the cornerstone
      of pharmacological treatment of depression. When symptoms persist despite
      optimization, further strategies include substitution, combination, augmentation,
      and reviewing and sometimes referring. Decisions are based on the evidence
      supporting the various strategies. CONCLUSIONS: Antidepressants will work only if
      prescribed correctly. Awareness of the strategies for using antidepressants and
      evaluating their effectiveness improves primary care physicians' ability to treat
      this common disorder.

PMID- 10587775
TI  - Anxiety disorders in late life.
AB  - OBJECTIVE: To review the epidemiology, clinical characteristics, and treatment of
      anxiety disorders in late life. QUALITY OF EVIDENCE: Epidemiologic and
      comorbidity data are derived from well designed random-sample community surveys.
      There are virtually no controlled data specific to treatment of anxiety in the
      elderly. Guidelines for treating anxiety disorders in late life, therefore, must
      be extrapolated from results of randomized controlled trials conducted in younger
      patients. MAIN MESSAGE: Generalized anxiety disorder and agoraphobia account for
      most cases of anxiety disorder in late life. Late-onset generalized anxiety is
      usually associated with depressive illness and, in this situation, the primary
      pharmacologic treatment is antidepressant medication. Most elderly people with
      agoraphobia do not give a history of panic attacks; exposure therapy is the
      preferred treatment for agoraphobia without panic. CONCLUSIONS: Physicians need
      to make more use of antidepressant medication and behavioural therapy and less
      use of benzodiazepines in treating anxiety disorders in late life.

PMID- 10587776
TI  - Case report: adverse effects of taking tricyclic antidepressants and smoking
      marijuana.

PMID- 10587777
TI  - Hyperbilirubinemia in term newborn infants. The Canadian Paediatric Society.

PMID- 10587778
TI  - Jaundice in newborns. Information for patients.

PMID- 10587779
TI  - Postgraduate education for rural family practice. Vision and recommendations for
      the new millenium. Working Group on Postgraduate Education for Rural Family
      Practice.

PMID- 10587780
TI  - Residents' page.

PMID- 10587781
TI  - Frequency and predictors of medically attended injuries in HIV-infected children.
AB  - The extent to which medically attended injuries complicate the clinical course of
      HIV-infected (HIV+) children is unknown. In a cohort of HIV+ children delivered
      from 1985 to 1990 and aged less than 60 months, we determined medically attended
      injuries per 100 child-years, Injury Severity Scores (ISS), and predictors of
      medically attended injuries by using New York State Medicaid claims from 1986 to
      1992 linked to birth certificates. Injury rates and ISS were compared to those of
      a population of black, inner city children aged less than 60 months from
      emergency room records. HIV+ children had slightly more injuries (19.3 vs.
      16.8/100 child-years) but similar ISS (2.4 vs. 2.3). Predictors of injuries in
      HIV+ children included younger maternal age (24/100 child-years, p = 0.008) and
      delivery outside of New York City (29/100 child-years, p = 0.02). Illicit drug
      use and alcohol use were associated with greater ISS while cocaine use was
      associated with a higher rate of possibly intentional injuries. Medically
      attended injuries affected one in five HIV+ children in our cohort annually,
      slightly more than the comparison population. Specific maternal and birth
      characteristics such as substance abuse and younger age at delivery may help
      target at-risk children.

PMID- 10587782
TI  - Observer variability in interpretation of abdominal radiographs of infants with
      suspected necrotizing enterocolitis.
AB  - We examined (1) the observer variability (both interobserver and intraobserver)
      in interpretation of abdominal radiographs of infants with suspected necrotizing
      enterocolitis (NEC), (2) the interobserver variability for individual radiologic
      signs used to diagnose NEC, and (3) the influence of experience in determining
      the extent of observer variability. Our hypotheses were (1) there would be
      considerable observer variability in interpretation of abdominal radiographs of
      infants with suspected NEC; (2) the extent of observer variability would differ
      for individual radiologic signs of NEC; and (3) the extent of observer
      variability would be determined by the observer's experience. The participants
      included 12 observers: two pediatric radiologists, four attending neonatologists,
      three neonatal fellows, and three pediatric residents. The participating
      observers under similar interpretation conditions, twice independently,
      interpreted the same 40 pairs of abdominal radiographs from infants with
      suspected NEC. The interval between the two interpretations was 3 to 6 months.
      Intraobserver and interobserver variability was assessed by applying the Kappa
      statistic to the radiologic signs of NEC for the two separate interpretations.
      The observers were blinded to patient's identity and the clinical course. Each
      observer recorded the absence, suspicion, or presence of (1) intestinal
      distention, (2) air fluid levels, (3) bowel wall thickening, (4) pneumatosis
      intestinalis, (5) portal venous gas, (6) pneumoperitoneum, and (7) NEC. We found
      low intraobserver and interobserver agreements. There was considerable variation
      in observer variability for individual radiologic signs. Trained observers
      performed better than intraining observers. We conclude that the radiologic signs
      in isolation should not be considered reliable. We recommend studies to formulate
      more objective criteria for many of the radiographic features of NEC.
      Standardization and periodic enforcement of these criteria among observers could
      reduce observer variability. We suggest that, to decrease both false-negative and
      false-positive interpretation, an experienced observer should always review the
      radiographs of infants with suspected NEC.

PMID- 10587783
TI  - Design and reliability of pediatric HealthQuiz: preliminary report of a
      comprehensive, computerized, self-administered child health assessment.
AB  - The time available for pediatric ambulatory visits is rarely sufficient to permit
      a truly comprehensive health assessment. We hypothesized that a reliable,
      computerized, self-administered questionnaire could be designed to screen for a
      full range of pediatric health issues and provide a comprehensive health database
      for pediatric patients. An age- and gender-specific pediatric questionnaire of
      478 questions was formatted to elicit only a "Yes," "No," or "Not Sure" response
      and structured in a branched, decision-tree format. The initial draft was
      reviewed for content by pediatric experts in Canada and the United States and
      revised in accordance with their suggestions. The questionnaire was divided into
      two modules, Medical Peds, covering biomedical issues and Prevent Peds, covering
      prevention, psychosocial, educational, and safety topics. Cognitive interviews
      were carried out with 132 parents in pediatric ambulatory care centers in Chicago
      and Halifax, with use of scripted and nonscripted probe questions, to ensure
      comprehensibility among patients with widely varying educational levels and
      health knowledge. Reliability was tested in 100 parents of children aged 1 month
      to 12 years, through use of five different test-retest sequences. Respondents'
      impressions were surveyed on completion of the procedure. Following content
      reviews, and cognitive and reliability testing, the total bank of questions was
      reduced to 375. As a result of the use of branching logic, individual parents
      answered an average of 111 Prevent Peds and 144 Medical Peds questions. Average
      time required to complete the entire questionnaire was 13 minutes for Prevent
      Peds and 19 minutes for Med Peds. Retesting within 36 hours showed an overall 97%
      concordance of response pairs in the Medical Peds and Prevent Peds
      questionnaires. There were no statistically significant differences in test
      retest reliability between different sequence formats used, (e.g., HealthQuiz
      followed by personal interview, or HealthQuiz vs. HealthQuiz). A few questions
      that frequently elicited "Not Sure" responses were eliminated. As a result, the
      majority of questions elicited either a "Yes" or "No" response. Pediatric
      HealthQuiz identified a wide spectrum of child health problems that are often
      overlooked in routine health visits. Parents completing Pediatric HealthQuiz
      indicated a high degree of satisfaction with the procedure. Most reported that
      they believed the information would improve their child's health care.

PMID- 10587784
TI  - Lead screening among low-income children in Galveston, Texas.
AB  - The objective of this study was to report results of a lead-screening program for
      low-income children living in Galveston, Texas. We obtained blood lead by
      graphite furnace spectrophotometry on 1,571 children aged 6 months to 8 years.
      Nineteen percent of children had blood lead levels > or = 10 mcg/dL. Risk factors
      included African-American ethnicity, young age, and residence in old housing.
      Follow-up was accomplished in only 50% of children with low-level toxicity. Lead
      screening is an important public health measure in communities with old houses.
      For screening to be successful, caregivers need to devote additional effort to
      follow-up.

PMID- 10587785
TI  - Genital herpes and diabetic ketoacidosis: a patient report.

PMID- 10587786
TI  - Jaclyn's story.

PMID- 10587787
TI  - Inflammatory bowel disease presenting as Salmonella colitis: the importance of
      early histologic examination in recognition and management.

PMID- 10587788
TI  - Atlantoaxial subluxation related to pharyngitis: Grisel's syndrome.

PMID- 10587789
TI  - Hand and eye preference in normal preschool children.

PMID- 10587790
TI  - Valproate-induced hyperandrogenism during pubertal maturation in girls with
      epilepsy.

PMID- 10587791
TI  - Plastibell complications? Use Mogen.

PMID- 10587792
TI  - Lung carcinoma.
AB  - Lung cancer is the leading cause of cancer mortality in the United States.
      Imaging is helpful in the diagnosis of peripheral lung cancers and in the staging
      of lung neoplasms. CT may establish the benign nature of a solitary pulmonary
      nodule by detecting either benign types of calcification or fat. Contrast
      enhancement is a new and innovative method that can be used to distinguish benign
      from malignant peripheral lung lesions. Both CT and MR play important roles in
      the preoperative staging of lung carcinoma. Both have significant limitations,
      however, and surgical staging is often required.

PMID- 10587793
TI  - Positron emission tomography imaging in the thorax.
AB  - Positron emission tomography imaging has proven valuable in the evaluation and
      management of thoracic abnormalities. It is more accurate than CT or MR imaging
      in characterizing indeterminate focal abnormal pulmonary opacities, staging lung
      cancer, and assessing the therapeutic response. PET imaging in lung cancer also
      appears to be cost-effective, particularly with whole-body studies. The metabolic
      and physiologic abnormalities used in FDG-PET imaging, rather than conventional
      anatomic or morphologic characteristics, provide an invaluable model for the
      future of tumor imaging.

PMID- 10587794
TI  - Virtual bronchoscopy.
AB  - The sophistication of three-dimensional (3-D) radiographic imaging from CT data
      has accelerated with the development and ongoing advances of helical CT. Virtual
      bronchoscopy (VB), the ability to create 3-D models of the airways and navigate
      through the tracheobronchial tree lumen in realtime simulated bronchoscopy, has
      gained popularity over the past 3 years. The ability of VB to image the airway
      and mediastinal structures simultaneously and in a 3-D format has helped
      revolutionize CT imaging. Unlike conventional bronchoscopy, VB can display the
      extent of narrowing caused by an airway lesion, the presence of patentcy beyond a
      stenosis, and the relationship between an airway lesion and the adjacent
      mediastinal structures.

PMID- 10587795
TI  - Spiral computed tomography in the evaluation of pulmonary embolism.
AB  - Determining the presence or absence of thromboembolic disease can often be
      problematic. Traditional diagnostic algorithms are reviewed and discussed. Spiral
      CT technology allows a relatively noninvasive visualization of the pulmonary
      vasculature and is a promising new diagnostic modality for acute and chronic
      thromboembolic disease. Its potential roles are discussed, and a new diagnostic
      algorithm is proposed.

PMID- 10587796
TI  - High-resolution computed tomography in the evaluation of fibrosing alveolitis.
AB  - High-resolution computed tomography (HRCT) is now widely used in the
      investigation of patients with suspected or known diffuse lung disease. This
      article reviews some of the technical aspects of HRCT and the pathologic
      considerations that should be appreciated in the context of diagnosing fibrosing
      alveolitis. The precise quantitation of disease extent and characterization of
      disease pattern on HRCT has been used to provide new insights about the prognosis
      and pathophysiology of fibrosing lung disease.

PMID- 10587797
TI  - Imaging the airways. Hemoptysis, bronchiectasis, and small airways disease.
AB  - Advances in technology have increased the contribution of radiology in
      understanding and evaluating diseases of the airways. In patients with
      hemoptysis, CT is now established as a complementary technique to bronchoscopy,
      or as an alternative to bronchoscopy in selected cases. The introduction of high
      resolution CT has improved the detection and assessment of bronchiectasis and
      small airways disease, allowed better correlation between pathologic changes and
      radiologic appearances, and provided new insights into possible links between
      small airways disease and bronchial disease.

PMID- 10587798
TI  - Magnetic resonance imaging of the thorax. Past, present, and future.
AB  - Magnetic resonance is a valuable modality of extreme flexibility for specific
      problem-solving capability in the thorax. This article reviews MR applications in
      the imaging of great vessels, which are currently the most important applications
      in the thorax; other established applications in the thorax; and pulmonary
      functional MR imaging.

PMID- 10587799
TI  - Interventional techniques in the thorax.
AB  - Transthoracic needle biopsy (TNB) has become the diagnostic procedure of choice
      in evaluation of focal chest lesions. Both advances in cross-sectional image
      guidance and cytopathologic techniques allow TNB to accurately diagnose
      malignancy and characterize a spectrum of benign conditions. Image-guided
      percutaneous drainage of intrathoracic collections has developed as an extension
      of similar procedures in the abdomen and pelvis. The ability of CT and ultrasound
      to accurately detect and characterize parenchymal and pleural collections, and
      advances in interventional techniques and catheter design, have made percutaneous
      catheter drainage the treatment of choice for a variety of intrathoracic
      collections. This article provides an updated review of the spectrum of image
      guided diagnostic and therapeutic procedures in the thorax.

PMID- 10587800
TI  - Imaging of lung transplantation.
AB  - Lung transplantation is an accepted treatment for a large number of end-stage
      pulmonary diseases. There are several complications that pertain specifically to
      lung transplant recipients, including airway ischemia, reperfusion edema,
      infections, acute rejection, obliterative bronchiolitis, and other postoperative
      problems relating to surgical technique and immuno-suppressive therapy. Imaging
      procedures play an important role in the diagnosis and management of these
      problems.

PMID- 10587801
TI  - Radiologic evaluation of emphysema for lung volume reduction surgery.
AB  - Lung volume reduction surgery has created an opportunity for the advanced imaging
      of emphysema. Patients with CT or perfusion scintigraphy demonstrating an upper-
      or lower-lobe-predominant pattern of emphysema have better patient outcomes after
      LVRS than patients with emphysema diffusely or homogeneously distributed
      throughout the lungs. Some patients with diffuse or homogeneous emphysema may
      demonstrate improvement in function or dyspnea after surgery, but the magnitude
      of the improvement seen is less than in patients with heterogeneous emphysema,
      and the duration of benefit is not known. An ongoing, multicenter National Heart,
      Lung, and Blood Institute (NHLBI)/Health Care Financing Association (HCFA)
      sponsored trial of LVRS aims to determine whether LVRS together with maximal
      medical therapy and pulmonary rehabilitation improves patient outcomes compared
      with maximal medical therapy and pulmonary rehabilitation alone. This study will
      address the duration of clinical benefit and the cost-effectiveness of LVRS.

PMID- 10587802
TI  - Experts in ethics.

PMID- 10587803
TI  - Medical professionalism and politics.

PMID- 10587804
TI  - Mediation in the medical field. Is neutral intervention possible?
AB  - Neutrality is held to be the touchstone of good mediation. True neutrality is
      elusive, however, and probably not even desirable, at least when applied to
      patient-provider disputes over medical care. In this context, mediators should
      not posture as "neutrals"; they should strive instead to protect their clients'
      autonomy.

PMID- 10587805
TI  - The physician as a health care proxy.
AB  - Many states prohibit patients from appointing their physicians as health care
      proxies, fearing paternalism and conflict of interest. But the potential for
      conflict is not unique to physicians, and patients may have compelling reasons to
      prefer that their doctor make decisions on their behalf. Managing potential
      conflicts serves patients better than denying them the right to choose who will
      make health care decisions for them when they are no longer competent.

PMID- 10587806
TI  - Baby Aaron and the elders.

PMID- 10587807
TI  - Job in court.

PMID- 10587808
TI  - Questioning bioethics. AIDS, sexual ethics, and the duty to warn.
AB  - Bioethicists have virtually assumed that Tarasoff generated a duty to warn the
      sexual partners of an HIV-positive man that they risked infection. Yet given the
      views of sex and of AIDS that have evolved in the gay community, in many cases
      the parallels to Tarasoff do not hold. Bioethicists should at the least attend to
      the community's views, and indeed should go beyond doing mere "professional
      ethics" to participate in the moral self-exploration in which these views are
      located.

PMID- 10587809
TI  - The disability rights critique of prenatal genetic testing. Reflections and
      Recommendations.

PMID- 10587810
TI  - Religion, spirituality, and medicine: a rebuttal to skeptics.

PMID- 10587811
TI  - Mental, physical and functional status in primary care attenders.
AB  - OBJECTIVE: The purpose of the present study was to analyze the association, in
      primary care attenders, between psychiatric disorders, medical comorbidity, and
      impairment in mental and physical function status. METHODS: The study had a two
      stage design. The GHQ-12 was used to screen 1647 patients, and 323 of them were
      then interviewed using the CIDI-PHC to obtain ICD-10 diagnoses. Severity of
      mental illness was assessed using the Hamilton scales for anxiety and depression.
      The DUSOI was used to evaluate the severity of physical illness. The MOS SF-36
      was used to assess health related quality of life. RESULTS: The estimated
      prevalence of ICD-10 psychiatric disorders and subthreshold disorders was 12.4
      percent and 18 percent respectively. The most common psychiatric disorders were
      generalized anxiety, major depression, and neurasthenia. The severity of physical
      illness did not vary across diagnostic status categories. Significant impairment,
      both in physical and mental functioning was seen in patients suffering from ICD
      10 full-fledged and subthreshold disorders. Severity of impairment increased from
      sub-threshold cases to full-fledged cases, and among the latter according to the
      severity of depressive and anxious symptoms, assessed using Hamilton scales. The
      most frequent psychiatric disorders were associated with significant worsening in
      health related quality of life, with relevant differences between psychiatric
      diagnoses regarding the domains affected. Impairment associated with mental
      disorders was greater than that associated with physical illness. CONCLUSIONS:
      The results of the present study confirm that ICD-10 psychiatric disorders are
      common in general practice and are associated with relevant impairment in
      physical and mental functional status. Psychiatric morbidity is not related to
      severity of physical illness rated by general practitioner.

PMID- 10587812
TI  - Physical illness and parasuicide: evidence from the European Parasuicide Study
      Interview Schedule (EPSIS/WHO-EURO).
AB  - OBJECTIVE: The aim of this research was to identify psychosocial characteristics
      which might predict future suicidal behavior in parasuicidal subjects in Europe.
      METHOD: The interview utilized for the survey (European Parasuicide Study
      Interview Schedule--EPSIS) was administered to 1269 parasuicides aged fifteen
      years and over, within one week of hospital admission after a suicide attempt,
      and is part of a longitudinal multicenter study. EPSIS included a brief medical
      questionnaire, scales rating depression, hopelessness, self-esteem, suicide
      intention, questions on sociodemographic characteristics, an interview on life
      events and social support, a description of the parasuicidal act, and an
      evaluation of factors precipitating the index parasuicide. RESULTS: Physical
      illness proved to be very frequent among suicide attempters. One in two subjects
      suffered from an acute, chronic, or chronic disorder in relapse at the time of
      the parasuicide. Subjects with a physical illness were significantly more
      depressed, particularly subjects from the intermediate age band and ones affected
      by a chronic physical disease in relapse. Forty-two percent of patients with
      physical illness rated their somatic problem as a factor precipitating the
      attempt and 22 percent judged it to be major one. Furthermore, subjects with
      physical illnesses considered psychiatric symptoms and disorders to be relevant
      factors in triggering suicidal behavior, to a greater extent than non-sufferers.
      The importance of physical illness in contributing to suicidal behavior increased
      with advancing age. CONCLUSIONS: More careful attention to somatic conditions and
      their subjective implications would probably augment chances of effectively
      preventing suicide.

PMID- 10587813
TI  - The psychiatric profile of patients with chronic diseases who do not receive
      regular medical care.
AB  - OBJECTIVE: To assess the relationship between psychiatric disorders and lack of
      regular medical care in individuals with chronic medical diseases. METHODS: Nine
      hundred sixty-three respondents to the household-based Baltimore Epidemiologic
      Catchment Area (ECA) Follow-Up Study were interviewed in 1981, 1982, and 1993
      1996. The main outcome measures were: 1) not receiving regular care from a health
      professional for an active chronic medical condition in 1981, 2) persistent lack
      of regular medical care, and 3) leaving regular medical care. RESULTS: In cross
      sectional analyses, having a psychiatric disorder (OR 1.70, 95% CI 1.17-2.48) was
      associated with not receiving regular medical care. This was mostly due to
      individuals with phobic disorder (OR 1.57, 95% CI 1.02-2.43). In prospective
      analyses, depression (RR 2.4, p < 0.04) and alcohol abuse (RR 2.9, p < 0.001)
      predicted leaving regular medical care one year later. Phobic disorder (RR 2.8, p
      < 0.001) predicted leaving care thirteen years later. CONCLUSIONS: Psychiatric
      disorders appear to place an individual at risk for irregular medical care.
      Studies of the quality and continuity of care for patients with chronic medical
      conditions should include measures of common psychiatric conditions.

PMID- 10587814
TI  - Mental disorders and help seeking in a rural impoverished population.
AB  - OBJECTIVE: This study examined the impact of an in-home screening and educational
      intervention on help seeking among rural impoverished individuals with untreated
      mental disorders. The effect of including a significant other in the intervention
      and reasons for not seeking help were explored. METHOD: The sample was randomly
      selected from households in nine rural counties in Virginia. The short form of
      the CIDI was used to screen 646 adult residents. Respondents who screened
      positive were randomly assigned to one of three groups: 1) no intervention, 2) an
      educational intervention, or 3) the educational intervention with a significant
      other. A list of local sources of health and mental health care was distributed.
      At one-month post interview, respondents were telephoned to inquire about help
      seeking. RESULTS: Almost one-third (32.4%) of these respondents screened positive
      for at least one disorder. Five hundred and sixty-six (87.6%) were successfully
      followed up, and thirty-three of the 566 (5.8%) reported that they had sought
      professional help since the interview. Eighty-four subjects who screened positive
      and received the educational intervention reported in follow up that they had
      discussed the interview with a friend or family member, but only eleven (13.1%)
      received encouragement to seek treatment. The predominant reason endorsed for not
      seeking help was "felt there was no need," even among respondents who were
      informed that they had a disorder. CONCLUSIONS: A significant proportion of this
      rural impoverished sample screened positive for a mental disorder. Few
      individuals sought professional help and significant others did not encourage
      them to seek treatment. The implication of these results for investigators and
      service providers is that motivating individuals to seek mental health services
      is a complex process; more attention must be devoted to the development of
      culturally relevant methods for facilitating help seeking.

PMID- 10587815
TI  - Gender and minor psychiatric morbidity: results of a case-control study in a
      developing country.
AB  - OBJECTIVE: Women suffer from minor psychiatric disorders (MPM) more frequently
      than men. Most of the studies were conducted in England and in the United States
      and some reported the higher occurrence of MPM among women to be modified by
      marital status and others by sociodemographic variables. The present study
      intends to address this question in a developing country. METHOD: A population
      based case-control study was conducted in three important urban centers in
      Brazil. Two hundred seventy-six individuals diagnosed as new cases of MPM and 261
      controls were selected to investigate the role of a set of sociodemographic
      variables in the association between gender and MPM using logistic regression
      models. RESULTS: Univariate analysis showed that women were more likely than men
      to suffer from MPM (OR = 3.34; 2.27-4.91). After controlling for other
      sociodemographic variables, female gender was still positively associated with
      MPM, but not in a homogeneous way. A multiplicative interaction of gender with
      age group was found (LRT = 6.01; 2 df; p = 0.05) suggesting an increment in the
      magnitude of the association among those older than thirty years. Odds-ratios
      were 2.33 (1.19-4.55), 6.85 (2.86-16.41), and 7.47 (2.90-19.22) for age groups of
      fourteen to twenty-nine; thirty to forty-four; forty-five or more, respectively.
      There was no evidence of interaction of gender with marital status or other
      sociodemographic variables. CONCLUSIONS: The findings are consistent with the
      modification of the association between gender and MPM being mediated by social
      factors.

PMID- 10587816
TI  - Characteristics and treatment of women with antenatal and postpartum depression.
AB  - OBJECTIVE: Investigations of the efficacy of treatment for non-psychotic
      pregnancy-related mood disorders are scarce. Thus, a prospective, longitudinal
      study of six months duration, involving ninety-six index cases and forty-five
      healthy women as a reference group, was implemented to determine the response of
      mood, parenting stress and dyadic adjustment to an eclectic management. METHOD:
      In this naturalistic study, the index cases were offered treatment consistent
      with their symptoms, context, and level of compliance. All women received
      individual psychotherapy combining strategies from Interpersonal and Cognitive
      Behavioral Psychotherapy and/or Marital Interventions and Pharmacology. Rating
      scales (Dyadic Adjustment Scale, Hamilton Rating Scale for Depression, Edinburgh
      Postnatal Depression Scale, Child Stress Inventory) scored monthly, were used to
      measure the response to treatment over time. RESULTS: Depressive symptoms are
      generally alleviated by the second to third month of treatment. Dyadic discord
      accentuated by traditional sex role expectations and child care stress
      exacerbated by low self-esteem persisted throughout the trial at levels
      significantly different from the untreated reference group. CONCLUSIONS: Short
      term interventions are cost-effective for the relief of mood disorders. However,
      creative solutions, during an era of economic restraints, are required to extend
      treatment sufficiently to address couple conflicts and facilitate the transition
      to parenthood for index cases.

PMID- 10587817
TI  - Parameters of grieving in spontaneous abortion.
AB  - OBJECTIVE: The study's objective was to determine the quality and severity of
      grief after spontaneous abortion and to statistically determine the effect of
      significant demographics and social variables such as age, number of previous
      losses and the effect of perceived family support on the grief experienced.
      METHODS: Two hundred and ninety-four women who had experienced a miscarriage
      within the last year were the participants. One hundred and seventy-five had
      miscarried three months prior to participation in the study; one hundred and
      nineteen had miscarried one year previously. Ninety-five percent of women
      approached consented to participate. Standardized psychometric tests and Likert
      Scales measured elements of grief such as depression, self-esteem, perceived
      guilt and stress at two time periods in the first year after loss. RESULTS: Women
      in both time periods after miscarriage had mean depression scores in the
      "clinical risk for depression" or "in need of treatment" range, i.e.,
      pharmacotherapy or psychotherapy. A majority of women showed negative emotions
      like self blame and stress. Younger women with multiple miscarriages showed more
      depression in the early time period after miscarriage than older women (p < .05).
      However, at one year younger women had the least depression. Marital and family
      conflict correlated positively with depressive symptomatology (p < .05).
      CONCLUSIONS: Women assessed in the first year after spontaneous abortion show
      grief characterized by perceived stress and high levels of depressive symptoms
      including self-blame. Marital or family problems increase emotional risk to a
      woman after miscarriage.

PMID- 10587818
TI  - Coping mechanisms in patients presenting for in-vitro-fertilization.
AB  - OBJECTIVES: The purpose of this study was to assess the coping mechanisms in
      patients presenting for in-vitro fertilization (IVF). METHODS: We evaluated
      thirty consecutive couples presenting for in-vitro-fertilization. All couples
      were interviewed individually at first, and then together, using a semi
      structured interview technique. Psychiatric diagnoses were made using the
      Diagnostic and Statistical Manual-IV (DSM-IV) criteria. Coping mechanisms used by
      the individuals were assessed using the Mechanisms of Coping Scale (MOCS). Other
      instruments used were Hamilton Depression Rating Scale (HAM-D-17), Hamilton
      Anxiety Rating Scale (HAM-A), Brief Psychiatric Rating Scale (BPRS), Self-Rating
      Symptom Scale (SRSS), and Eysenck Personality Inventory (EPI). RESULTS: The mean
      age of the sixty patients was 32.3 +/- 5.2 years. Fatalism was the commonest
      factor on the mechanisms of coping scale. Analysis of variance (ANOVA) across all
      factors of the MOCS for demographic factors showed that men used problem-solving
      mechanisms significantly more often than women (F = 3.0, df = 1, 58, p < 0.05).
      ANOVA across coping factors on stressors with post-hoc tests of significance
      revealed that individuals facing social stress used fatalism significantly more
      often than other coping mechanisms, while those facing career stress used problem
      solving significantly more often than other coping mechanisms (F = 5.6, df = 1,
      58, p < 0.05 and F = 3.04, df = 1, 58, p < 0.01 respectively). ANOVA across
      coping factors on HAM-D-17 scores revealed that individuals who used fatalism had
      significantly higher HAM-D-17 scores compared to those who did not (F = 4.4, df =
      1, 58, p < 0.05). ANOVA across coping factors on HAM-A scores revealed that
      individuals who used escape-avoidance had significantly lower HAM-A scores than
      those who did not (F = 4.3, df = 1, 58, p < 0.05). ANOVA across coping factors on
      SRSS scores revealed that individuals who used passivity or fatalistic coping
      mechanisms had significantly higher scores on SRSS than who did not (F = 4.6, df
      = 1, 58, p < 0.05 and F = 3.5, df = 1, 58, p < 0.05). CONCLUSIONS: Differential
      patterns of coping were found among the sixty individuals presenting for IVF and
      were associated with a variety of factors including gender, education, stressors,
      and levels of depression, anxiety, and overall psychopathology. Efforts to
      recognize and recruit the coping mechanisms of infertile individuals are likely
      to enhance their ability to participate effectively in treatment.

PMID- 10587819
TI  - Inflammation and diabetic vascular complications.

PMID- 10587820
TI  - The short-term impact of a continuing medical education program on providers'
      attitudes toward treating diabetes.
AB  - OBJECTIVE: The objective of this study was to evaluate the short-term impact of a
      7-h type 2 diabetes continuing medical education (CME) program. Outcomes included
      a measure of health care providers' diabetes knowledge and the Diabetes Attitude
      Scale (DAS), a validated measure of attitudes toward diabetes. RESEARCH DESIGN
      AND METHODS: A CME program on type 2 diabetes was presented by an expert panel in
      Chicago during November 1998. A before-after trial with pre- and postintervention
      measurements of diabetes knowledge and attitudes toward diabetes was administered
      as part of the program. A convenience sample of the 129 health care providers in
      attendance resulted in 91 (71%) completed pre- and postintervention surveys.
      RESULTS: Within-subjects analysis revealed increases in knowledge and more
      favorable attitudes toward diabetes after the program. Between-subjects analysis
      revealed that attitude changes differed for physicians as compared with allied
      health care providers. CONCLUSIONS: A CME program was associated with an increase
      in knowledge of diabetes and more favorable attitudes toward diabetes as measured
      by the DAS. The DAS changes were subtly different for the physician group as
      compared with the allied health care provider group. These results suggest that
      the DAS can be a useful instrument for measuring the short-term impact of
      educational interventions.

PMID- 10587821
TI  - Failure to maintain the benefits of home-based intervention in adolescents with
      poorly controlled type 1 diabetes.
AB  - OBJECTIVE: To determine whether a 6-month home-based intervention program in
      adolescents with poorly controlled diabetes improves metabolic control and
      whether benefits are maintained after the intervention. RESEARCH DESIGN AND
      METHODS: Adolescents with a mean HbA1c of > 9.0% over the preceding 12 months
      received either routine care in a diabetes clinic and an ambulatory intervention
      for 6 months (n = 37) or routine care only (n = 32). A diabetes educator provided
      monthly home visits and weekly phone contact to educate and support the
      adolescents in setting goals for insulin adjustment, blood glucose monitoring,
      and target blood glucose range. There was no systematic change in the frequency
      of insulin injections. After the intervention, there was a 12-month follow-up
      when the intervention and control groups both received only routine care. Outcome
      measures were HbA1c and Diabetes Knowledge Assessment (DKN). RESULTS: During the
      intervention, mean HbA1c fell (baseline: 11.1 +/- 1.3%, 6 months: 9.7 +/- 1.6%; P
      = 0.0001) and mean knowledge scores increased (P = 0.0001) in the intervention
      group but not in control subjects. However, this improvement in HbA1c and
      increase in knowledge was not maintained in the intervention group at 12- and 18
      month follow-up assessments. Parents' knowledge scores also improved
      significantly from baseline levels in the intervention group at 6 and 12 months
      (P = 0.001, P = 0.005, respectively). CONCLUSIONS: An ambulatory program improves
      metabolic control and knowledge in adolescents with poorly controlled type 1
      diabetes; however, it is effective only while the intervention is maintained.

PMID- 10587822
TI  - Discriminating glucose tolerance status by regions of interest of dual-energy X
      ray absorptiometry. Clinical implications of body fat distribution.
AB  - OBJECTIVE: To determine whether measuring body fat distribution by dual-energy X
      ray absorptiometry (DEXA) can be used to discriminate glucose tolerance status.
      RESEARCH DESIGN AND METHODS: Using a 75-g oral glucose tolerance test, a total of
      1,015 Chinese subjects (559 men and 456 women) were categorized as having normal
      glucose tolerance (NGT), impaired glucose tolerance (IGT), or diabetes. Blood
      pressure and lipid profiles of these subjects were measured. Waist-to-hip ratio
      (WHR) and DEXA were used to evaluate the varying patterns of body fat
      distribution among the groups. RESULTS: Body fat distribution, as reflected by
      WHR and the centrality index, showed significant partial correlation coefficients
      with glycosylated hemoglobin, blood pressure, and lipid profiles in all subjects.
      After adjusting for age and BMI, there were significant differences among the
      three glycemic groups for all the cardiovascular risk factors except for total
      cholesterol level. The diabetic group had a significantly higher WHR and
      centrality index, but lower femoral fat percentage than the NGT and IGT groups.
      The diabetic group also showed higher abdominal fat percentage than the NGT
      group. Moreover, the IGT group had a higher centrality index than the NGT group.
      However, no significant differences were found in the percentage of lean tissue
      mass among the three groups. Using multiple stepwise logistic regression models,
      the centrality index remained a significant factor for discriminating different
      glucose tolerance status independent of the percentage total body fat.
      CONCLUSIONS: Central obesity has shown significant correlation with
      cardiovascular risk factors among the three different glycemic groups. Centrality
      index measured by DEXA appears to be the better predictor of glucose intolerance,
      compared with WHR, abdominal fat, and general obesity (reflected by percentage
      total body fat or BMI) in a large cohort of the Chinese population.

PMID- 10587823
TI  - Progression of retinopathy after improved metabolic control in type 2 diabetic
      patients. Relation to IGF-1 and hemostatic variables.
AB  - OBJECTIVE: To determine the impact of improved glycemic control on the
      development and progression of retinopathy after the institution of insulin
      therapy in patients with type 2 diabetes and to assess the relation to IGF-1 and
      hemostatic variables. RESEARCH DESIGN AND METHODS: In a prospective observational
      study, 45 type 2 diabetic patients were examined at baseline and 1, 3, 6, 12, and
      24 months after change to insulin therapy. Retinopathy was graded on fundus
      photographs using the Wisconsin scale; HbA1c, IGF-1, and hemostatic variables
      were measured. RESULTS: During the observation period of 2 years, 23 patients
      progressed in the retinopathy scale; 8 progressed > or = 3 levels. After 2 years
      of insulin treatment, HbA1c and IGF-1 were significantly lower than at baseline,
      whereas the hemostatic variables had not changed significantly. Progression of
      retinopathy > or = 3 levels was related to the degree of HbA1c reduction, the
      duration of diabetes, a higher prothrombin fragment 1 + 2 levels (F1 + 2), but
      not to other hemostatic variables or IGF-1. The relative risk for progression >
      or = 3 levels was 2.6 when HbA1c had been reduced > or = 3 percent units (95% CI
      1.1-6.1). CONCLUSIONS: The magnitude of improvement of HbA1c by the institution
      of insulin treatment over a 2-year period may be associated with progression of
      retinopathy in patients with type 2 diabetes.

PMID- 10587824
TI  - Clinical, autoimmune, and genetic characteristics of very young children with
      type 1 diabetes. Childhood Diabetes in Finland (DiMe) Study Group.
AB  - OBJECTIVE: To study the characteristics of type 1 diabetes in very young
      children. RESEARCH DESIGN AND METHODS: Clinical outcome, islet cell antibodies
      (ICA), insulin autoantibodies (IAA), antibodies against GAD (GADA), IA-2
      antibodies (IA-2A), and HLA-DQB1-defined genetic risk were analyzed in 35
      children diagnosed with type 1 diabetes before 2 years of age and compared with
      those in 146 children who were diagnosed between 2.0 and 4.9 years of age and
      with those in 620 children diagnosed between 5.0 and 14.9 years of age. RESULTS:
      The youngest age-group had severer metabolic decompensation at clinical onset,
      and their serum C-peptide levels, compared with those of older children, were
      lower at the time of diagnosis and during the first 2 years after the diagnosis.
      The levels of ICA and IAA were highest in children < 2 years of age, but there
      were no differences in GADA levels among the three age-groups. The youngest age
      group had the lowest IA-2A levels. The HLA DQB1*02/*0302 genotype associated with
      strong genetic susceptibility was more frequent in children diagnosed < 5 years
      of age, whereas the proportion of children carrying a genotype, which includes
      protective alleles, was higher among those diagnosed at > or = 5 years of age.
      CONCLUSIONS: The clinical presentation of type 1 diabetes at a very young age is
      associated with severe metabolic decompensation, poorly preserved residual beta
      cell function, strong humoral autoimmunity against islet cells and insulin, and
      strong HLA-defined disease susceptibility.

PMID- 10587825
TI  - Eating habits, body weight, and insulin misuse. A longitudinal study of teenagers
      and young adults with type 1 diabetes.
AB  - OBJECTIVE: To examine disordered eating, insulin misuse, weight change, and their
      relationships with glycemic control and diabetic complications in adolescents
      with type 1 diabetes followed up over eight years. RESEARCH DESIGN AND METHODS:
      Of 76 adolescents (43 male, 33 female) with type 1 diabetes aged 11-18 years at
      the first assessment, 65 were interviewed as young adults (aged 20-28 years).
      Eating habits were assessed using a standardized Eating Disorder Examination.
      Height and weight were determined and BMI calculated. Three consecutive urine
      specimens were collected for measurement of albumin/creatinine ratio and other
      significant diabetic complications were recorded. Glycemic control was assessed
      by glycated hemoglobin. RESULTS: Weight and BMI increased from adolescence to
      young adulthood. Females were overweight as adolescents and both sexes were
      overweight as young adults. Concern over weight and shape increased significantly
      for both sexes from adolescence to young adulthood. This increase in concern was
      reflected in increased levels of dietary restraint. Features of disordered eating
      were apparent in females at both assessments, but no patients met the criteria
      for anorexia nervosa or bulimia nervosa at either assessment. A total of 10 (30%)
      females, but none of the males admitted underusing insulin to control weight.
      Five (45%) females with microvascular complications had intentionally misused
      insulin to prevent weight gain. CONCLUSIONS: An increase in BMI from adolescence
      to adulthood was associated with higher levels of concern over shape and weight
      and more intense dietary restraint, especially among females. Overt eating
      disorders were no more prevalent in these patients than in the general
      population, but milder forms of disordered eating were common and had
      implications for diabetes management. Insulin omission for weight control was
      frequent among females and may contribute to poor glycemic control and to risk of
      complications.

PMID- 10587826
TI  - Infant feeding, early weight gain, and risk of type 1 diabetes. Childhood
      Diabetes in Finland (DiMe) Study Group.
AB  - OBJECTIVE: To evaluate whether the increased risk of type 1 diabetes conferred by
      an early introduction of cow's milk supplements can be mediated by accelerated
      growth in formula-fed infants. RESEARCH DESIGN AND METHODS: All children < or =
      14 years of age who were diagnosed with type 1 diabetes from September 1986 to
      April 1989 were invited to participate in the study. Birth date- and sex-matched
      control children were randomly selected from the Finnish Population Registry. At
      least three weight measurements from the first year of life were obtained for 435
      full-term diabetic subjects and 386 control subjects from well-baby clinics and
      school health care units. RESULTS: Increase in body weight was greater in the
      diabetic girls than in the control girls, and the difference increased from 111 g
      (95% CI 0-218, P = 0.04) at 1 month of age to 286 g (95% CI 123-450, P = 0.0006)
      at 7 months. For boys, the difference in weight between the diabetic subjects and
      the control subjects remained stable during infancy (difference 95 g, 95% CI-2
      205, P = 0.09). Increased weight was associated on average with a 1.5-fold risk
      of type 1 diabetes. Early introduction of formula feeding (< 3 vs. > or = 3
      months) was also associated with an increased risk of type 1 diabetes after
      adjustment for the individual weight gain curve (adjusted odds ratio 1.53, 95% CI
      1.1-2.2). No evidence for interaction was observed. CONCLUSIONS: These
      observations indicate that an early exposure to cow's milk formula-feeding and
      rapid growth in infancy are independent risk factors of childhood type 1
      diabetes.

PMID- 10587827
TI  - Plantar pressures are elevated in the neuroischemic and the neuropathic diabetic
      foot.
AB  - OBJECTIVE: Clinical observation has noted that diabetic neuropathic ulcers occur
      frequently on the plantar surface, whereas neuroischemic ulcers seem to occur
      often on the foot margins. The reason for this difference in the site of
      ulceration is unknown, but it may be related to differences in pressure loading.
      The aim of the study was to compare vertical in-shoe foot pressures measured
      during walking (using the F-SCAN system) in four groups of patients whose degree
      of neuropathy was measured by vibration perception threshold (VPT). RESEARCH
      DESIGN AND METHODS: Subjects included 14 neuroischemic diabetic patients (VPT
      29.3 +/- 13.5 V) with history of ulceration on the margins of the foot, 18
      patients with neuropathy alone (VPT 38.7 +/- 12.7 V) and previous history of
      ulceration on the plantar surface, 10 diabetic control patients (VPT 9.9 +/- 2.7
      V), and 15 nondiabetic control subjects (VPT 7.0 +/- 0.5 V). RESULTS: When
      compared with the other three groups, neuroischemic patients had higher foot
      pressures when measured as mean peak pressures and highest peak pressures under
      four areas of the foot: medial and lateral forefoot, hallux, and heel.
      Furthermore, when measuring the maximum pressures developed at any point under
      the plantar surface, the neuroischemic patients also had the most elevated
      pressures (757.6 +/- 135.9 kPa), significantly higher than those found in the
      neuropathic group (482.8 +/- 68.6 kPa, P = 0.04) and in both diabetic control
      patients (310.2 +/- 34.7 kPa, P = 0.008) and nondiabetic controls subjects (365.1
      +/- 49.8 kPa, P = 0.007). CONCLUSIONS: Despite having increased plantar pressures
      and a comparable degree of neuropatny, the neuroischemic patients did not have a
      history of ulceration on the plantar surface. These observations may have
      relevance to different mechanisms of ulcer formation in the neuroischemic and
      neuropathic foot.

PMID- 10587828
TI  - Body mass index, diabetes, and C-reactive protein among U.S. adults.
AB  - OBJECTIVE: The author examined the relationship between C-reactive protein and
      BMI and diabetes status among 16,573 participants aged > or = 20 years of the
      Third National Health and Nutrition Examination Survey (1988-1994). RESEARCH
      DESIGN AND METHODS: The study had a cross-sectional design. RESULTS: Geometric
      mean concentrations of C-reactive protein were lowest among individuals with a
      BMI < 18.5 kg/m2 and increased with increasing BMI categories. Restricting the
      analysis to participants without various medical conditions did not change the
      relation. After adjusting for age, sex, race or ethnicity, and education, using
      logistic regression analysis, odds ratios for an elevated C-reactive protein
      concentration (> or = 85th percentile of the sex-specific C-reactive protein
      concentration distribution) among participants with a BMI of 25 to < 30, 30 to <
      35, 35 to < 40, and > or = 40 kg/m2 were 1.51 (95% CI 1.23-1.86), 3.19 (2.60
      3.91), 6.11 (4.67-7.98), and 9.30 (6.43-13.46), respectively, compared with
      participants with a BMI < 25 kg/m2. C-reactive protein concentrations were lowest
      among those individuals without diabetes or with impaired fasting glucose and
      highest among those with newly or previously diagnosed diabetes. Compared with
      participants with a normal fasting glucose, participants with impaired fasting
      glucose, newly diagnosed diabetes, and previously diagnosed diabetes had 0.99
      (0.72-1.37), 1.84 (1.25-2.71), and 1.59 (1.25-2.01) odds of having an elevated C
      reactive protein concentration after adjustment for age, sex, race or ethnicity,
      education, and BMI. CONCLUSIONS: These results confirm cross-sectional findings
      from previous studies that show elevated C-reactive protein concentrations among
      individuals who are obese or have diabetes. The implications of these findings,
      however, remain unclear.

PMID- 10587829
TI  - Diabetes and serum ferritin concentration among U.S. adults.
AB  - OBJECTIVE: We examined the association between serum ferritin concentration and
      the risk of diabetes. RESEARCH DESIGN AND METHODS: We examined the cross
      sectional associations among ferritin concentration, glucose tolerance status,
      and concentrations of insulin, glucose, and glycosylated hemoglobin in 9,486 U.S.
      adults aged > or = 20 years from the Third National Health and Nutrition
      Examination Survey (1988-1994). RESULTS: After adjusting for age, sex, ethnicity,
      education, BMI, alcohol consumption, alanine aminotransferase concentration, C
      reactive protein concentration, and examination session attended, and after
      dichotomizing ferritin concentration into < 300 and > or = 300 micrograms/l for
      men and < 150 and > or = 150 micrograms/l for women, the odds ratios for newly
      diagnosed diabetes were 4.94 (95% CI 3.05-8.01) for men and 3.61 (2.01-6.48) for
      women. The increased risk of newly diagnosed diabetes was concentrated among
      participants with transferrin saturations < 45%. All multiple linear regression
      coefficients between ferritin concentration and concentrations of insulin,
      glucose, and glycosylated hemoglobin were positive and significant for both men
      and women. CONCLUSIONS: Elevated serum ferritin concentration was associated with
      an increased risk of diabetes. We were unable to eliminate conclusively the
      possibility that the observed association reflected inflammation rather than
      excess body iron stores.

PMID- 10587830
TI  - Exogenous estrogen exposures and changes in diabetic retinopathy. The Wisconsin
      Epidemiologic Study of Diabetic Retinopathy.
AB  - OBJECTIVE: To investigate whether the use of exogenous estrogen is associated
      with changes in the severity of diabetic retinopathy and the incidence of macular
      edema. RESEARCH DESIGN AND METHODS: The study design involved observation of two
      well-defined cohorts of women with diabetes. One group was diagnosed with
      diabetes at < 30 years of age and used insulin (younger-onset group), and the
      other group was diagnosed at > or = 30 years of age with no criteria regarding
      therapy (older-onset group). Subjects received standard examinations, medical
      interviews, and retinal photography in 1980-1982. Specific questions about
      exogenous hormone exposure were added to the study questionnaire at the first
      follow-up examination 4 years after the baseline examination. Change in the
      severity of retinopathy 6 and 10 years after the 4-year follow-up examination
      were examined regarding the use of oral contraceptives at the first follow-up
      examination in the younger-onset group and at 6 years after the first follow-up
      examination regarding hormone replacement therapy in the older-onset group.
      RESULTS: Changes in the severity of retinopathy and incidence of macular edema
      were unrelated to either type of estrogen exposure in univariable and
      multivariable analyses. CONCLUSIONS: These data are compatible with the
      hypothesis that the medications used by our population do not affect the severity
      of diabetic retinopathy or macular edema.

PMID- 10587831
TI  - Screening for impaired glucose tolerance. Results from a population-based study
      in 21,057 individuals.
AB  - OBJECTIVE: To study the distribution of fasting plasma glucose and impaired
      glucose tolerance (IGT) in a large general population and explore their possible
      implications for large-scale screening. The study focuses especially on the
      relation to age, obesity, and heredity background of diabetes. RESEARCH DESIGN
      AND METHODS: A total of 21,057 men and women aged 30-60 years were used for this
      cross-sectional study. Individuals with known diabetes and individuals with a
      fasting plasma glucose > or = 7 mmol/l were excluded. A physical examination,
      including blood sampling and an oral glucose tolerance test, was conducted.
      RESULTS: The relative risk for IGT increased more than fourfold among obese
      subjects compared with normal-weight subjects, yet only 25% of IGT subjects were
      obese. Similarly, IGT subjects more frequently reported having first-degree
      relatives with diabetes than did subjects with normal glucose tolerance.
      Nonetheless, > 70% of IGT subjects reported no heredity background of diabetes.
      Subjects with IGT showed higher mean values of BMI, blood pressure, and
      triglycerides. Only 13% of the men and 19% of the women having impaired fasting
      glucose (IFG) fulfilled the criteria of IGT. CONCLUSIONS: The present study shows
      that a high-risk screening strategy for IGT targeted solely toward subjects with
      obesity and/or heredity background of diabetes will fail to detect the majority
      of subjects with IGT in the general population. The new concept of IFG may not
      replace the concept of IGT as a risk marker for worsening to diabetes.

PMID- 10587832
TI  - Diabetes incidence in an Australian aboriginal population. An 8-year follow-up
      study.
AB  - OBJECTIVE: To examine prospectively the association between age, BMI, and
      subsequent incidence of type 2 diabetes in Australian aboriginal people. RESEARCH
      DESIGN AND METHODS: We performed a stratified analysis of incidence data from a
      community-based longitudinal study. Measures included fasting and 2-h postload
      glucose concentrations, and BMI, stratified into four categories. Subjects were
      882 male and female participants in diabetes screening initiatives in two remote
      Australian aboriginal communities, free from diabetes at baseline, ages 15-77
      years. RESULTS: There were 46 incident cases of diabetes over 2,808 person-years
      of follow-up. BMI modified strongly the sex- and community-adjusted association
      between age and diabetes incidence (P < 0.001). Adjusted for age, sex, and
      community, the population diabetes incidence rate was 20.3 cases/1,000 person
      years, with BMI-specific rates of 10.7-47.2 cases/1,000 person-years, and
      relative risks (95% CI) for BMI strata beyond the reference category (< 25 kg/m2)
      of 3.3 (1.5-7.0), 2.7 (1.1-6.8), and 4.4 (1.7-11.6), respectively. The
      population's attributable risk (95% CI) associated with BMI beyond the reference
      category was 70.1% (58.1-82.4). CONCLUSIONS: BMI-specific diabetes incidence
      rates in Australian aboriginal people are among the highest in the world.
      Diabetes incidence in the lowest BMI category (10.7 cases/1,000 person-years) is
      two to five times greater than corresponding rates for non-aboriginal
      populations. An urgent need exists to prevent weight gain associated with
      diabetes. Further study is required to determine for aboriginal people an optimal
      range of BMI, likely lower than that suggested for non-aboriginal populations.

PMID- 10587833
TI  - Education and the metabolic syndrome in women.
AB  - OBJECTIVE: The main objective was to examine the association between the
      metabolic syndrome and socioeconomic position (as indicated by education) among
      women. RESEARCH DESIGN AND METHODS: The study sample comprised healthy women
      (aged 30-65 years) in Sweden who were representative of the general population in
      a metropolitan area. Socioeconomic position was measured by educational level
      (mandatory [< or = 9 years], high school, or college/university). The metabolic
      syndrome was defined as the presence of two or more of the following components:
      1) fasting plasma glucose level > or = 7.0 mmol/l; 2) arterial blood pressure >
      or = 160/90 mmHg; 3) fasting plasma triglycerides > or = 1.7 mmol/l and/or HDL
      cholesterol < 1.0 mmol/l; and 4) central obesity (waist-to-hip ratio > 0.85
      and/or BMI > 30 kg/m2). RESULTS: After adjustment for age, the risk ratio for the
      presence of the metabolic syndrome comparing the lowest (< or = 9 years) with the
      highest (college/university) education was 2.7 (95% CI 1.1-6.8). This association
      persisted after controlling for menopausal status, family history of diabetes,
      and behavioral risk factors. CONCLUSIONS: Low education is associated with
      increased risk for metabolic syndrome in middle-aged women. These findings show
      that not only are women with low socioeconomic position at increased risk for
      individual risk factors that are associated with cardiovascular disease and type
      2 diabetes, they are also at increased risk for the metabolic clustering of risk
      factors.

PMID- 10587834
TI  - The 12-item well-being questionnaire. An evaluation of its validity and
      reliability in Dutch people with diabetes.
AB  - OBJECTIVE: The objective of this study was to investigate the validity and
      reliability of the short-form 12-Item Well-Being Questionnaire (W-BQ12). The 12
      items were used to construct the three 4-item subscales Negative Well-Being
      (NWB), Energy (ENE), and Positive Well-Being (PWB), and the 12-item overall scale
      General Well-Being (GWB). RESEARCH DESIGN AND METHODS: A total of 1,472 patients
      with diabetes completed the W-BQ12, the Hospital Anxiety and Depression scale,
      and the State Trait Anxiety Inventory. Statistics covered Cronbach's alpha,
      Pearson's correlation, t tests, and logistic regression. Test-retest reliability
      was studied in a sample of 202 patients who twice completed the W-BQ12, which was
      supplemented with the Center for Epidemiological Studies Depression scale and the
      Short Form (SF)-36 Health Survey. RESULTS: Of the tested subjects, 739 were
      defined as having type 1 diabetes and 701 as having type 2 diabetes. Cronbach's
      alpha proved to be high and stable across sex and type of diabetes for all W-BQ12
      scales. Test-retest reliability ranged from 0.66 (PWB) to 0.83 (GWB), with a mean
      interval of 66 +/- 14 days. Convergent validity of the W-BQ12 scales was
      supported by high correlations with other measures of affect. Of all scales of
      the first measurement, ENE proved to have the strongest association with self
      reported chronic fatigue. NWB and trait anxiety both had the strongest
      associations with self-reported depression and current treatment by a
      psychologist/psychiatrist. CONCLUSIONS: The W-BQ12 appeared to be a reliable and
      valid measure of psychological well-being. This short instrument is easy to
      administer and may be considered a useful tool for both clinicians and
      researchers to assess the psychological well-being of patients with diabetes.

PMID- 10587835
TI  - Diabetes management in a health maintenance organization. Efficacy of care
      management using cluster visits.
AB  - OBJECTIVE: To evaluate the effectiveness of a cluster visit model led by a
      diabetes nurse educator for delivering outpatient care management to adult
      patients with poorly controlled diabetes. RESEARCH DESIGN AND METHODS: This study
      involved a randomized controlled trial among patients of Kaiser Permanente's
      Pleasanton, CA, center who were aged 16-75 years and had either poor glycemic
      control (HbA1c > 8.5%) or no HbA1c test performed during the previous year.
      Intervention subjects received multidisciplinary outpatient diabetes care
      management delivered by a diabetes nurse educator, a psychologist, a
      nutritionist, and a pharmacist in cluster visit settings of 10-18 patients/month
      for 6 months. Outcomes included change (from baseline) in HbA1c levels; self
      reported changes in self-care practices, self-efficacy, and satisfaction; and
      utilization of inpatient and outpatient health care. RESULTS: After the
      intervention, HbA1c levels declined by 1.3% in the intervention subjects versus
      0.2% in the control subjects (P < 0.0001). Several self-care practices and
      several measures of self-efficacy improved significantly in the intervention
      group. Satisfaction with the program was high. Both hospital (P = 0.04) and
      outpatient (P < 0.01) utilization were significantly lower for intervention
      subjects after the program. CONCLUSIONS: A 6-month cluster visit group model of
      care for adults with diabetes improved glycemic control, self-efficacy, and
      patient satisfaction and resulted in a reduction in health care utilization after
      the program.

PMID- 10587836
TI  - Biopsychobehavioral model of severe hypoglycemia. II. Understanding the risk of
      severe hypoglycemia.
AB  - OBJECTIVE: To evaluate the clinical/research utility of the biopsycho-behavioral
      model of severe hypoglycemia in differentiating patients with and without a
      history of severe hypoglycemia and in predicting occurrence of future severe
      hypoglycemia. RESEARCH DESIGN AND METHODS: A total of 93 adults with type 1
      diabetes (mean age 35.8 years, duration of diabetes 16 +/- 10 years, HbA1 8.6 +/-
      1.8%), 42 of whom had a recent history of recurrent severe hypoglycemia (SH) and
      51 who did not (NoSH), used a handheld computer for 70 trials during 1 month
      recording cognitive-motor functioning, symptoms, blood glucose (BG) estimates,
      judgments concerning self-treatment of BG, actual BG readings, and actual
      treatment of low BG. For the next 6 months, patients recorded occurrence of
      severe hypoglycemia. RESULTS: SH patients demonstrated significantly more
      frequent and extreme low BG readings (low BG index), greater cognitive-motor
      impairments during hypoglycemia, fewer perceived symptoms of hypoglycemia, and
      poorer detection of hypoglycemia. SH patients were also less likely to treat
      their hypoglycemia with glucose and more likely to treat with general foods. Low
      BG index, magnitude of hypoglycemia-impaired ability to do mental subtraction,
      and awareness of neuroglycopenia, neurogenic symptoms, and hypoglycemia
      correlated separately with number of SH episodes in the subsequent 6 months.
      However, only low BG index, hypoglycemia-impaired ability to do mental
      subtraction, and awareness of hypoglycemia entered into a regression model
      predicting future severe hypoglycemia (R2 = 0.25, P < 0.001). CONCLUSIONS:
      Patients with a history of severe hypoglycemia differed on five of the seven
      steps of the biopsychobehavioral model of severe hypoglycemia. Helping patients
      with a recent history of severe hypoglycemia to reduce the frequency of their low
      BG events, become more sensitive to early signs of neuroglycopenia and neurogenic
      symptoms, better recognize occurrence of low BG, and use fast-acting glucose more
      frequently in the treatment of low BG, may reduce occurrence of future severe
      hypoglycemia.

PMID- 10587837
TI  - Transcutaneous glucose measurement using near-infrared spectroscopy during
      hypoglycemia.
AB  - OBJECTIVE: To analyze a transcutaneous near-infrared spectroscopy system as a
      technique for in vivo noninvasive blood glucose monitoring during euglycemia and
      hypoglycemia. RESEARCH DESIGN AND METHODS: Ten nondiabetic subjects and two
      patients with type 1 diabetes were examined in a total of 27 studies. In each
      study, the subject's plasma glucose was lowered to a hypoglycemia level
      (approximately 55 mg/dl) followed by recovery to a glycemic level of
      approximately 115 mg/dl using an intravenous infusion of insulin and 20%
      dextrose. Plasma glucose levels were determined at 5-min intervals by standard
      glucose oxidase method and simultaneously by a near-infrared spectroscopic
      system. The plasma glucose measured by the standard method was used to create a
      calibration model that could predict glucose levels from the near-infrared
      spectral data. The two data sets were correlated during the decline and recovery
      in plasma glucose, within 10 mg/dl plasma glucose ranges, and were examined using
      the Clarke Error Grid Analysis. RESULTS: Two sets of 1,704 plasma glucose
      determinations were examined. The near-infrared predictions during the fall and
      recovery in plasma glucose were highly correlated (r = 0.96 and 0.95,
      respectively). When analyzed during 10 mg/dl plasma glucose segments, the mean
      absolute difference between the near-infrared spectroscopy method and the
      chemometric reference ranged from 3.3 to 4.4 mg/dl in the nondiabetic subjects
      and from 2.6 to 3.8 mg/dl in the patients with type 1 diabetes. Using the Error
      Grid Analysis, 97.7% of all the near-infrared predictions were assigned to the A
      zone. CONCLUSIONS: Our findings suggest that the near-infrared spectroscopy
      method can accurately predict plasma glucose levels during euglycemia and
      hypoglycemia in humans.

PMID- 10587838
TI  - Renal disease as a determinant of increased lipoprotein(a) concentrations in
      diabetic patients.
AB  - OBJECTIVE: This study examined the hypothesis that kidney function is an
      independent determinant of lipoprotein(a) [Lp(a)] concentrations in people with
      diabetes. RESEARCH DESIGN AND METHODS: Lp(a) concentrations were measured in
      plasma samples from 273 type 2 and 223 type 1 diabetic patients recruited from a
      diabetes clinic. Kidney function was categorized as normal or pathological
      according to plasma creatinine levels and creatinine clearance rates. RESULTS:
      Macroalbuminuria was uniformly associated with significantly raised plasma
      concentrations of Lp(a) regardless of the marker used to identify kidney
      dysfunction. In contrast, in patients with microalbuminuria, significantly raised
      plasma Lp(a) levels were observed only when creatinine clearance rates or plasma
      creatinine levels indicated pathological kidney function. These conclusions were
      independent of diabetes type. CONCLUSIONS: In microalbuminuria and apparently in
      normoalbuminuria, altered kidney function determined by creatinine clearance
      rates or creatinine levels appears to be a major determinant of raised Lp(a)
      levels in both type 1 and type 2 diabetic patients. In contrast, Lp(a)
      concentrations were uniformly raised in patients with macroalbuminuria.

PMID- 10587839
TI  - Low-dose ethanol predisposes elderly fasted patients with type 2 diabetes to
      sulfonylurea-induced low blood glucose.
AB  - OBJECTIVE: It has previously been demonstrated that the risk of hypoglycemia is
      low among otherwise healthy elderly fasted patients with type 2 diabetes taking
      oral sulfonylurea medications. Nevertheless, these agents do cause hypoglycemia
      in clinical practice, suggesting that accompanying factors must typically be
      present for hypoglycemia to occur. Ethanol is one putative risk factor that has
      not been evaluated as a mechanism for low blood glucose among sulfonylurea users.
      We hypothesized that low concentrations of ethanol would reduce blood glucose
      concentrations in elderly type 2 diabetic patients receiving sulfonylureas during
      a short-term fast. RESEARCH DESIGN AND METHODS: A total of 10 type 2 diabetic
      patients, aged 68 +/- 3 years and receiving 20 mg glyburide daily, participated
      in a prospective double-blind placebo-controlled in-patient study consisting of
      two 24-h fasts at least 1 week apart. During hours 14 and 15 of the fasting
      studies, subjects received intravenous infusions of either 4.35 mmol.kg-1.h-1
      ethanol (equivalent to one or two alcoholic beverages) or saline placebo in
      random order. Ethanol, plasma glucose, insulin, and counterregulatory hormones
      were assessed very 30-60 min during the final 10 h of the fast. RESULTS: Blood
      ethanol levels peaked at 17 +/- 2 mmol/l (the lower legal limit of intoxication
      in New Mexico) during the ethanol study. Plasma glucose concentrations did not
      differ at baseline (placebo 8.5 +/- 1.8 vs. ethanol 8.7 +/- 1.7 mmol/l; P =
      0.50), but nadir plasma glucose was lower after the ethanol infusion compared
      with placebo (4.4 +/- 1.2 vs. 5.0 +/- 1.4 mmol/l; P = 0.01), and the absolute
      decline in plasma glucose was also greater during the ethanol study than the
      placebo study (4.7 +/- 0.9 vs. 3.6 +/- 1.2 mmol/l; P = 0.01). Counterregulatory
      hormone levels were increased during the ethanol study and nonesterified fatty
      acid concentrations were suppressed compared with the placebo study. CONCLUSIONS:
      Low doses of ethanol predispose fasted elderly type 2 diabetic patients to low
      blood glucose during a short-term fast. This may be one of several mechanisms by
      which sulfonylurea-induced hypoglycemia occurs in elderly patients.

PMID- 10587840
TI  - Soluble L-selectin level is a marker for coronary artery disease in type 2
      diabetic patients.
AB  - OBJECTIVE: To investigate whether the fall in soluble L-selectin (sL-selectin)
      level constitutes a marker for myocardial ischemia. RESEARCH DESIGN AND METHODS:
      The levels of soluble forms of adhesion molecules, i.e., intercellular adhesion
      molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE
      selectin), P-selectin (sP-selectin), and L-selectin (sL-selectin), were compared
      in type 2 diabetic patients without inflammatory syndrome but with symptomatic
      coronary artery disease (CAD) (group 1, n = 11), with silent ischemic disorders
      and proven coronary stenoses (group 2, n = 11), with silent myocardial ischemia
      (SMI) and normal coronary angiography (group 3, n = 10), and without proven SMI
      (group 4, n = 13). These levels were compared with those of 22 control subjects.
      RESULTS: The sL-selectin level was significantly lower in groups 1, 2, or 3 with
      symptomatic CAD or with SMI as compared with the control group (P = 0.0004).
      Group 4 without myocardial ischemia did not significantly differ from the control
      subjects (P = 0.6). In type 2 diabetic patients, after controlling for HbA1c, a
      partial correlation between sL-selectin and the CAD status was significant (P =
      0.001). sICAM-1 and sP- or sE-selectin did not differ significantly between type
      2 diabetic patients and control subjects or among the different groups of
      patients. The sVCAM-1 level in type 2 diabetic patients was significantly higher
      than in the control subjects (P = 0.001), but there were no significant
      intergroup differences (P = 0.4). CONCLUSIONS: In type 2 diabetic patients, sVCAM
      1 is increased with regard to glycemic control, whatever the CAD status. In type
      2 diabetic patients with symptomatic CAD or SMI associated with coronary
      stenoses, sL-selectin is significantly decreased. A marked fall in sL-selectin
      might constitute a marker for silent CAD in type 2 diabetic patients.

PMID- 10587841
TI  - Progression to diabetes in relatives with islet autoantibodies. Is it inevitable?
AB  - OBJECTIVE: A large cohort of family members with islet cell antibodies (ICA) > or
      = 20 Juvenile Diabetes Foundation units (JDF U) was examined to determine whether
      there was a subgroup at low risk of progression to diabetes; whether risk of
      progression changed over time; and whether rate of progression to diabetes varied
      according to age, islet autoantibodies, and genetic markers of susceptibility.
      RESEARCH DESIGN AND METHODS: Individuals with ICA > or = 20 JDF U were identified
      from 4,423 family members recruited to prospective family studies in the U.K.
      Subjects were followed for up to 18 years. Antibodies to insulin, GAD, and IA-2
      were measured in the first sample, and HLA class II typing was performed.
      RESULTS: Of 147 family members with ICA > or = 20 JDF U on at least one occasion,
      29 developed type 1 diabetes after a median of 3.2 years (maximum 18.1). The
      cumulative risk of developing diabetes within 15 years was 47% (95% CI 28-67) for
      all family members with ICA > or = 20 JDF U, 2.8% (0-8.2) for those with ICA
      alone, and 66% (44-87) for those with at least one additional autoantibody
      marker. There were no differences in age, HLA class II type, or levels of ICA,
      insulin autoantibodies, or IA-2 antibodies between those who developed diabetes
      within 5 years of testing and those who developed diabetes after this time. GAD
      antibody levels we ..., however, higher in those who progressed more slowly.
      CONCLUSIONS: Family members with ICA alone are at low risk of progression to
      diabetes. Rapid development of disease after ICA detection could not be
      distinguished from delayed development on the basis of autoantibodies or markers
      of genetic susceptibility, and those with multiple antibodies remained at high
      risk throughout long-term follow-up. This suggests that all family members with
      multiple islet autoantibodies are destined to develop autoimmune diabetes.

PMID- 10587842
TI  - In vivo endothelial dysfunction characterizes patients with impaired fasting
      glucose.
AB  - OBJECTIVE: The American Diabetes Association has recently defined a new category
      of abnormal glucose homeostasis called "impaired fasting glucose" (IFG), where
      glucose levels do not meet the criteria of diabetes but are too high to be
      considered normal. We determined whether endothelial dysfunction is a
      characteristic of subjects with IFG. RESEARCH DESIGN AND METHODS: In vivo
      vasodilatory responses to intra-arterial infusions of endothelium-dependent
      (acetylcholine [ACh]) and -independent (sodium nitroprusside [SNP]) vasoactive
      agents were determined in 17 IFG subjects (age 63 +/- 1 years, BMI 26.5 +/- 0.8
      kg/m2, serum LDL cholesterol 3.5 +/- 0.2 mmol/l) with fasting plasma glucose
      levels of 117 +/- 1 mg/dl and in 12 subjects with normal fasting plasma glucose
      concentrations. RESULTS: The blood-flow response to the low dose of ACh was 46%
      (5.9 +/- 0.7 vs. 10.9 +/- 1.3 ml.dl-1.min-1, IFG vs. normal, P < 0.01) and to the
      high dose was 31% (9.1 +/- 1.2 vs. 13.2 +/- 1.5 ml.dl-1.min-1, P < 0.05,
      respectively) lower in the IFG than in the normal subjects. In contrast, blood
      flow responses to both low (7.8 +/- 0.5 vs. 9.0 +/- 0.9 ml.dl-1.min-1, IFG vs.
      normal, NS) and high (11.6 +/- 1.2 vs. 12.3 +/- 1.3 ml.dl-1.min-1, NS,
      respectively) doses of SNP were comparable. The ratio of endothelium-dependent to
      -independent blood flow was 40% lower in the IFG (0.75 +/- 0.1) than in the
      normal (1.24 +/- 0.1, P < 0.001) subjects. Both fasting plasma glucose (r = 
      0.48, P < 0.01) and glycosylated hemoglobin (r = -0.42, P < 0.05) were inversely
      correlated with endothelium-dependent vasodilation but not with other parameters,
      such as weight, blood pressure, or lipids. CONCLUSIONS: We conclude that vascular
      dysfunction is associated with abnormal, although nondiabetic, glucose
      homeostasis.

PMID- 10587843
TI  - Relationship of endothelial function to birth weight in humans.
AB  - OBJECTIVE: Low birth weight has been associated with hyperlipidemia,
      hypertension, diabetes, and coronary heart disease in adult life, but the precise
      mechanism is debated. The endothelium is thought to play a pivotal role in each
      of the above conditions with abnormalities being detectable before the
      development of overt disease. To investigate the possibility that endothelium has
      a role in mediating the excessive risk of adult vascular disease associated with
      low birth weight, endothelial function was assessed in young healthy adults who
      were either of low or normal birth weight at term. RESEARCH DESIGN AND METHODS:
      Twelve low birth weight (2.2 +/- 0.05 kg, mean +/- SEM) subjects (six men/six
      women; age 28 +/- 0.2 years) and twelve age- and sex-matched normal birth weight
      (3.3 +/- 0.07 kg) control subjects were studied. The L-arginine-nitric oxide
      pathway was assessed in the forearm vascular bed by using venous occlusion
      plethysmography during intra-arterial brachial infusion of acetylcholine, sodium
      nitroprusside, norepinephrine, and NG-monomethyl-L-arginine (L-NMMA). Von
      Willebrand factor, a noninvasive marker of endothelial dysfunction, was also
      measured. Comparisons were made using Student's t test. RESULTS: Von Willebrand
      factor was significantly elevated in low birth weight compared with normal birth
      weight subjects (136.9 +/- 12.7 vs. 95.6 +/- 9.5%; P = 0.016). The groups did not
      differ in the responses to acetylcholine (P = 0.76), sodium nitroprusside (P =
      0.84), norepinephrine (P = 0.21), or L-NMMA (P = 0.35). CONCLUSIONS: The finding
      of elevated von Willebrand factor in low birth weight subjects is suggestive of
      endothelial cell injury but does not appear to be associated with dysfunction of
      the L-arginine-nitric oxide pathway.

PMID- 10587844
TI  - Frequency of liver disease in type 2 diabetic patients treated with oral
      antidiabetic agents.
AB  - OBJECTIVE: We evaluated liver disease in conventionally treated type 2 diabetic
      patients to provide a reference against which reports of liver disease related to
      novel oral antidiabetic treatments could be compared. RESEARCH DESIGN AND
      METHODS: In this follow-up study, patients with type 2 diabetes who were treated
      with oral antidiabetic agents were identified from the U.K.-based General
      Practice Research Database and were followed to determine whether they developed
      liver disease. The specific types and etiologies of liver disorders were
      determined. Incidence rates were calculated based on the accumulated exposure
      time to oral antidiabetic agents. RESULTS: Among 44,406 type 2 diabetic patients,
      605 had a computer diagnosis of liver disease with an incidence rate of
      53.2/10,000 person-years (95% CI 49.2-57.6). Of the 605 subjects, 186 had
      nonsymptomatic, mild, and transient liver disorders; 249 had a predisposing
      condition; and 113 had another cause for the disease. A total of 57 cases were
      possibly drug induced with an incidence rate of 5.0/10,000 person-years (3.9
      6.5). Of the cases, 11 were attributed to other drugs, 8 were attributed to fatty
      liver disease of diabetes, and the remaining cases were attributed to uncertain
      causes. Oral antidiabetic agents were continued in 51 of these 57 cases, and we
      could not rule out oral antidiabetic agents as a cause of liver disease in 2
      cases with an incidence rate of 0.2/10,000 person-years (< 0.1-0.6). CONCLUSIONS:
      In this population, the background incidence of liver disease was high. Most
      cases involved other systemic diseases that may cause liver disease.

PMID- 10587845
TI  - Impaired diurnal cardiac autonomic function in subjects with type 2 diabetes.
AB  - OBJECTIVE: To assess diurnal cardiac sympathetic and parasympathetic nerve
      functions in diabetic subjects with variable diabetic neuropathy. RESEARCH DESIGN
      AND METHODS: Frequency domain analysis of 24-h Holter ECG was done for 132
      diabetic subjects (84 without any symptomatic neuropathy; 37 with only
      symptomatic peripheral neuropathy; 11 with symptomatic autonomic neuropathy) and
      57 normal volunteers to calculate the low frequency (LF) component representing
      the beta-adrenoceptor function and the high frequency (HF) component representing
      the cardiac parasympathetic nerve function. RESULTS: Cardiac LF and HF components
      in diabetic subjects without peripheral neuropathy showed values comparable to
      those of normal volunteers and a similar circadian rhythm. Diabetic subjects with
      peripheral neuropathy or autonomic neuropathy showed significantly depressed LF
      and HF components and loss of the circadian rhythm of LF and HF components
      compared with diabetic subjects without neuropathy. Impairment of the LF
      component in the afternoon could be accounted for by the duration of diabetes and
      elevated HbA1c level. Impairment of the HF component at night could be accounted
      for by the duration of diabetes but not an elevated HbA1c level. CONCLUSIONS:
      These data indicated that diabetic subjects with peripheral neuropathy and
      diabetic subjects with symptomatic autonomic neuropathy, but not diabetic
      subjects without neuropathy, showed a marked decrease in cardiac sympathetic and
      parasympathetic nerve functions and loss of circadian rhythm.

PMID- 10587846
TI  - American Diabetes Association Annual Meeting, 1999. New approaches to insulin
      treatment and glucose monitoring.

PMID- 10587847
TI  - Lack of effect on LDL oxidation and antioxidant status after improvement of
      metabolic control in type 2 diabetes.

PMID- 10587848
TI  - Meal-generated oxidative stress in diabetes. The protective effect of red wine.

PMID- 10587849
TI  - Red blood cell autoantibodies with a shortened erythrocyte life span as a cause
      of lack of relation between glycosylated hemoglobin and mean blood glucose levels
      in a woman with type 1 diabetes.

PMID- 10587850
TI  - Enterovirus antibodies in relation to islet cell antibodies in two populations
      with high and low incidence of type 1 diabetes.

PMID- 10587851
TI  - Troglitazone efficacy in a subject with glucocorticoid-induced diabetes.

PMID- 10587852
TI  - Safety of human insulin in poor-sighted elderly diabetic patients.

PMID- 10587853
TI  - Assessment of in vivo stability of a new insulin preparation for implantable
      insulin pumps. A randomized multicenter prospective trial. EVADIAC Group.
      Evaluation Dans le diabete du Traitement par Implants Actifs.

PMID- 10587854
TI  - In diabetes care, moving from compliance to adherence is not enough. Something
      entirely different is needed.

PMID- 10587855
TI  - Prevalence of patients reaching the targets of good control in normal clinical
      practice. A cohort-based study in type 2 diabetes.

PMID- 10587856
TI  - Neonatal anthropometric measurements and risk of childhood-onset type 1 diabetes.
      DiMe Study Group.

PMID- 10587857
TI  - All patients with Werner's syndrome are insulin resistant, but only those who
      also have impaired insulin secretion develop overt diabetes.

PMID- 10587858
TI  - Youth-onset type 2 diabetes (Y2DM) associated with HNF1A S319 in aboriginal
      Canadians.

PMID- 10587859
TI  - Two-hour post-glucose loading plasma glucose is the main determinant for the
      progression from impaired glucose tolerance to diabetes in Hong Kong Chinese.

PMID- 10587860
TI  - Total plasma homocysteine and insulin levels in type 2 diabetic patients with
      secondary failure to oral agents.

PMID- 10587861
TI  - Benzodiazepine interruption. Does it cause hypoglycemia?

PMID- 10587862
TI  - American Orthopaedic Foot and Ankle Society diabetic shoe survey.

PMID- 10587863
TI  - Insulin-sensitive and insulin-resistant variants in nonobese Japanese type 2
      diabetic patients. The role of triglycerides in insulin resistance.

PMID- 10587864
TI  - Insulin lispro, pregnancy, and retinopathy.

PMID- 10587865
TI  - Impaired fasting glucose is not a risk factor for cardiovascular mortality.

PMID- 10587867
TI  - Response to Lin and Ito. Effect of troglitazone on atorvastatin pharmacokinetics
      and pharmacodynamics

PMID- 10587866
TI  - A drug interaction between troglitazone and simvastatin.

PMID- 10587868
TI  - Breath-hold 3D MR angiography of the renal vasculature using a contrast-enhanced
      multiecho gradient-echo technique.
AB  - OBJECTIVE: Significant evolution of contrast-enhanced MR angiography for
      evaluating vascular diseases in the abdomen has occurred during the past several
      years. The state-of-the-art gradient-echo imaging technique employs a short echo
      time (TE) and a short repetition time (TR) for rapid vascular imaging with
      contrast-enhanced MR angiography. However, because of the short TR (< or = 3-8
      msec), the background stationary tissue becomes saturated, with resultant poor
      contrast resolution of visceral organs. The authors present a new approach to
      vascular imaging using a multiecho gradient-echo technique with a TR sufficiently
      long (41 msec) to image the renal vasculature and parenchyma without background
      tissue suppression. METHODS: Twenty-four partitions (3D slab thickness = 72 mm)
      with an in-plane resolution of 224 x 256 were obtained in 21 seconds. Three
      measurements were performed with an interscan delay of 8 seconds. In the pulse
      sequence, the partition loop is defined as the innermost loop, in which Kz views
      are acquired centrically for a fixed Ky, followed by Ky views in a conventional
      linear or sequential order. The partition encodings are segmented to permit
      multiple encodings in which two TR loops were used to span a total of 24 echoes
      with 12 along the positive and 12 along the negative direction in k space. A
      large bandwidth of 650 Hz/pixel was used to keep the echo train length short,
      with an echo spacing of 1.86 msec. A frequency-selective fat saturation pulse was
      placed before slab-selective excitation. The other parameters in the pulse
      sequence were TR/TE/flip = 41/2.2/45; the field of view was 360 to 390 mm.
      Maximum intensity projections of each 3D contrast-enhanced measurement were
      performed. The vascular-to-background contrast, bowel-related magnetic
      susceptibility artifact, and background stationary signals were subjectively
      graded. The authors examined the utility of this technique in 16 randomly
      selected patients (3 normal, 13 abnormal) with varied renal vasculature and
      parenchymal abnormalities. Results were confirmed with conventional x-ray
      angiography, surgery, or clinical follow-up. RESULTS: Vascular-to-background
      contrast was graded as very good (grade III/III) in all cases. The bowel-related
      magnetic susceptibility artifacts were not considered significant. Background
      visceral organ soft tissue contrast was not suppressed and was graded as good
      (grade III/III) in all cases. Eight hemodynamically significant (> 50% diameter)
      stenoses in seven patients were accurately assessed (one with fibromuscular
      dysplasia). Three patients with renal masses (two with renal cell carcinoma and
      one with renal lymphoma) were accurately assessed for arterial anatomy and venous
      extension. Other renal venous abnormalities seen were retroaortic renal vein (n =
      1), chronic occlusion (n = 1), and accessories (total of five) (n = 1).
      CONCLUSIONS: Rapid breath-hold contrast-enhanced MR angiography of the renal
      vasculature with a multiecho gradient-echo using a long TR depicted the renal
      vasculature with high vessel-to-background contrast without significant bowel
      related susceptibility artifact and without background visceral organ tissue
      signal suppression, resulting in high background soft tissue contrast resolution.

PMID- 10587869
TI  - Detection of groin hernia with physical examination, ultrasound, and MRI compared
      with laparoscopic findings.
AB  - OBJECTIVE: To determine the diagnostic accuracy of physical examination,
      ultrasound, and dynamic MRI in patients with inguinal hernia. METHODS: In 41
      patients with clinically evident herniations, 82 groins were evaluated using a
      standard ultrasound and MRI protocol, the latter including T1- and T2-weighted
      sequences as well as two dynamic sequences. All ultrasound examinations and MRI
      scans were reviewed without knowledge of clinical findings. In all cases,
      correlation with findings at laparoscopic surgery was made. RESULTS: At surgery,
      55 inguinal herniations were found. Physical examination revealed 42 herniations
      (one false-positive finding), whereas ultrasound made the diagnosis of a hernia
      in 56 cases (five false-positive and four false-negative findings). MRI diagnosed
      53 herniations (one false-positive and three false-negative findings). Thus,
      sensitivity and specificity figures were 74.5% and 96.3% for physical
      examination, 92.7% and 81.5% for ultrasound, and 94.5% and 96.3% for MRI.
      CONCLUSIONS: In patients with clinically uncertain herniations, MRI is a valid
      diagnostic tool with a high positive predictive value.

PMID- 10587870
TI  - Optimal injection protocol for CT evaluation during hepatic arterial infusion
      chemotherapy.
AB  - OBJECTIVE: As an imaging modality for follow-up during continuous or repeated
      hepatic arterial infusion chemotherapy using a hepatic intra-arterial indwelling
      catheter, the usefulness of CT while infusing contrast through the indwelling
      catheter (reservoir port) was examined. METHODS: Using reservoir ports implanted
      in eight patients with hepatic metastasis from colon cancer, radioisotope
      perfusion scintigraphy (RI), CT (three rates of infusion of contrast were used),
      and digital subtraction angiography (AG) were performed to compare the
      modalities' ability to visualize the intrahepatic and abnormal extrahepatic
      distributions. RESULTS: CT (infusion rate 0.1 mL/sec) was superior to AG and RI
      in terms of the ability to visualize intrahepatic distribution, particularly in
      small areas, and facilitated 3D delineation of the distribution. In evaluating
      extrahepatic distribution, CT also outperformed the other modalities.
      CONCLUSIONS: For imaging study follow-up during hepatic arterial infusion
      chemotherapy, CT proved to be more useful than conventional RI and AG.

PMID- 10587871
TI  - Effective contrast use in CT angiography and dual-phase hepatic CT performed with
      a subsecond scanner.
AB  - OBJECTIVE: To deduce an optimal injection protocol for CT angiography and fast
      dual-phase hepatic CT. METHODS: Fifty-two patients underwent fast dual-phase
      hepatic CT using one of three different injection protocols: A (0.9 g/sec iodine
      injection rate, 36 g dose); B (1.35 g/sec, 30 g); C (1.6 g/sec, 40 g). Aortic
      attenuation time curves as well as aorta-to-liver contrast and hepatic
      enhancement time curves obtained by region of interest measurements along the
      helical axis were analyzed. RESULTS: Protocol C revealed a significantly higher
      peak in aortic attenuation and hepatic enhancement than the other protocols.
      Approximately 50 seconds after the bolus injection, hepatic enhancement declined
      to a plateau similar to that seen with the other protocols. In terms of the areas
      under the curves of the aorta-to-liver contrast and hepatic enhancement dynamics,
      protocol C was significantly superior to the other protocols. CONCLUSIONS: A high
      iodine injection rate realized by a high iodine concentration in conjunction with
      fast dual-phase scanning (total scan time < 50 seconds) promises to enhance CT
      angiography and contrast of liver lesions.

PMID- 10587872
TI  - Pelvic imaging with a selenium-based detector (Thoravision). Comparison with
      screen-film radiography in 75 patients.
AB  - OBJECTIVE: To evaluate whether the selenium detector (Thoravision) provides
      sufficient diagnostic confidence in digital pelvic imaging compared with a
      conventional screen-film combination. METHODS: In 75 patients, pelvic imaging
      with conventional screen-film and isodose selenium radiography using a dedicated
      postprocessing mode was compared independently by three radiologists. The
      depiction of cortical and cancellous bone was evaluated in the iliac wings,
      sacral and pubic bones, acetabulum, femoral head, and trochanter. Demarcation of
      soft tissue was assessed in the iliac and trochanteric region. RESULTS:
      Visualization of cortical bone and soft tissue in the iliac area as well as soft
      tissue and cortical and cancellous bone in the trochanteric region was
      significantly superior with the selenium detector. However, conventional imaging
      was better in the trabecular bone of the sacral region, where results with the
      selenium system were particularly poor. CONCLUSIONS: The selenium detector
      (Thoravision) is advantageous in imaging soft tissue adjacent to the iliac wings
      and the trochanter, but results for the cancellous sacral bone are poor. Further
      modifications of postprocessing modes may lead to improved depiction of this
      critical pelvic area.

PMID- 10587873
TI  - Comparison of two different software systems for electron-beam CT-derived
      quantification of coronary calcification.
AB  - OBJECTIVE: The growing interest in coronary calcium quantification by electron
      beam CT (EBCT) has led to the development of various software systems for the
      analysis of EBCT raw data, but it is unknown whether these software systems yield
      comparable results. METHODS: Two sets of EBCT scans were obtained in 73
      asymptomatic patients less than 15 minutes apart. Both scans of each patient were
      analyzed using two different software systems, the Mayo Clinic software and the
      AccuImage Scoring System. The authors compared the calcium quantities yielded by
      the two different software systems, analyzed the interscan variability, and
      calculated the interobserver variability. Finally, they investigated the
      influence of the CT density factor inherent in the widely used Agatston score for
      the quantification of coronary calcium on reproducibility. RESULTS: The mean
      score determined by the Mayo Clinic software was 14% greater than that determined
      by the AccuImage system. The mean difference between the two systems was 14% +/-
      25%, and the median difference was 3%. The relative mean and the median
      difference between the two scans of one patient were 15.3% and 6% determined by
      the AccuImage system and 17% and 6.5% determined by the Mayo Clinic software. The
      interobserver reliability calculated by the Mayo Clinic software was better than
      that of the AccuImage system. There was a trend for better reproducibility using
      calcium area rather than the Agatson score. CONCLUSIONS: Two different scoring
      systems do not necessarily yield the same result. Calcium quantities were
      systematically determined to be greater by one system than the other, and there
      were significant differences with regard to interobserver reliability. Hence,
      software should be tested with regard to reproducibility data, and the
      interpretation of calcium quantities should acknowledge which type of software
      was used.

PMID- 10587874
TI  - Neurogenic hypertension. A new MRI protocol for the evaluation of neurovascular
      compression of the cranial nerves IX and X root-entry zone.
AB  - OBJECTIVE: Neurovascular compression of the rostral ventrolateral medulla (RVLM)
      has been implicated in the pathogenesis of essential hypertension. Although MRI
      has been widely used to evaluate the morphologic relation of structures in this
      region, spatial resolution of the previously used techniques was limited. This
      article describes the use of a new MRI protocol that combines two sequences with
      improved spatial resolution and complementary image information as well as a set
      of defined criteria for image analysis. METHODS: MRI of the brain stem was
      performed in 60 hypertensive and 50 normotensive subjects using a 3D-CISS and a
      3D-FISP-MRA sequence. Neurovascular contact in the RVLM was independently
      assessed by four readers using predefined criteria and compared with a consensus
      finding. Agreement was expressed by kappa statistics on a 0 to 1 scale. RESULTS:
      Left-sided neurovascular contact within the RVLM was found in 13 (22%)
      hypertensive and 6 (12%) control subjects. The inter-reader agreement for
      positive and negative findings ranged from 0.47 to 0.79; agreement to the
      consensus finding ranged from 0.65 to 0.90. CONCLUSIONS: The combination of 3D
      CISS and arterial flow-sensitive 3D-FISP, together with the evaluation criteria
      defined in this study, can be used for describing the finer anatomic features of
      the brain stem, and in particular for investigation of neurovascular contact of
      the IX/X cranial nerve root-entry zone. The high quality of images and the
      substantial or almost perfect reader-consensus agreement should make this
      protocol useful for future investigations of the neurovascular compression
      syndrome in patients with essential hypertension and possibly in other
      neurovascular compression syndromes, such as trigeminal neuralgia and hemifacial
      spasm.

PMID- 10587875
TI  - Influence of instrument settings on flow signal and background noise in power
      Doppler US. An experimental study using a flow phantom with hyperechoic
      background.
AB  - OBJECTIVE: To determine the influence of various power Doppler instrument
      settings on intensities of flow signal and background noise in flow with a tissue
      equivalent phantom. METHODS: Power Doppler images were obtained with changing
      wall filter level (low, medium, high, and maximum), pulse repetition frequency
      (PRF; 500, 700, 1000, 1500, 3000, and 6000 Hz), and Doppler gain (60%, 70%, 80%,
      90%, and 100%) at different flow velocities (13.3, 26.5, and 49.8 cm/sec). To
      make a quantitative comparison of different settings, the authors measured the
      intensities of flow signal and background noise in obtained power Doppler images
      using the scanner and a computer program, calculated signal-to-noise difference
      (SND; intensity of flow signal--intensity of background noise), and evaluated the
      relation between SND and power Doppler settings. RESULTS: The intensities of flow
      signal and background noise were proportional to flow velocity and power Doppler
      gain but were inversely proportional to PRF and wall filter level. At constant
      wall filter level (medium), changes of PRF and Doppler gain to the same
      directions resulted in a high SND. At constant PRF (1000 Hz), changes of wall
      filter and Doppler gain to the same directions also resulted in a high SND.
      However, at constant Doppler gain (80%), a high SND was obtained with changing
      wall filter level and PRF to the opposite directions. CONCLUSIONS: Three Doppler
      instrument settings--wall filter level, pulse repetition frequency, and Doppler
      gain--have reciprocal influences on SND.

PMID- 10587876
TI  - Contrast media research.
AB  - This selective review highlights research in contrast media development and
      application in the field of diagnostic radiology in 1998 and 1999. The focus is
      on research published in Investigative Radiology, supplemented with work from
      other publications in the few areas not extensively covered by the journal.
      Studies continue to be performed, although at a low level, examining safety
      issues. Most preclinical investigations have focused on MR and ultrasound agents.
      In MR, the research effort is concentrated on the development of targeted agents;
      in ultrasound, work is focused on the characterization of basic contrast
      mechanisms. The demonstration of clinical applications is still dominated by work
      with MR, both in disease models and human investigations. The use of
      extracellular gadolinium chelates to enhance visualization of blood vessels (the
      field of contrast-enhanced MR angiography) is the largest single new clinical
      application of contrast media to emerge in several years. New clinical
      applications continue to be pursued with contrast media in CT, ultrasound, and x
      ray angiography. As intravenously injected ultrasound contrast agents come to
      market, trials demonstrating clinical applications and subsequent scientific
      publications will increase in number.

PMID- 10587877
TI  - [Necessity and usefulness of detection by PCR of mecA and aac(6')/aph(2") genes
      for identification of arbekacin-resistant MRSA].
AB  - Arbekacin (ABK)-resistant bacteria (43 strains) isolated as MRSA by regular
      clinical procedures in Japanese clinics in 1998 were characterized in terms of
      taxonomic properties, aminoglycoside resistance, and mecA and aac(6')/aph(2")
      genes linking with ABK-resistant MRSA. Taxonomically the 43 strains fell into
      Staphylococcus aureus (33 strains) and Enterococcus (10 strains). As to ABK
      resistance, the 13 strains of MRSA clinically reported as high ABK resistance
      (128 micrograms/ml or higher) did not show clear high ABK resistance except for 2
      strains when their ABK resistance was tested using 0.5% NaCl containing nutrient
      agar. We designed and established the primers and conditions for PCR to detect
      the above two resistance genes. PCR analysis of DNAs from the 43 strains clearly
      indicated that only 33 strains identified taxonomically as S. aureus possessed
      mecA indicating MRSA and 23 out of them possessed aac(6')/aph(2"). The other 10
      strains of MRSA lacking aac(6')/aph(2") were ABK-sensitive. Thus, there were a
      good correlation between ABK resistance and aac(6')/aph(2") existence. Based on
      these, it was conclusive that the appropriate ABK resistance test as well as the
      detection of mecA and aac(6')/aph(2") genes by PCR are necessary and useful to
      avoid false ABK-resistant MRSA strains.

PMID- 10587878
TI  - [In vitro and in vivo activities of cefpodoxime proxetil against penicillin
      resistant Streptococcus pneumoniae].
AB  - We evaluated in vitro and in vivo activities of cefpodoxime proxetil (CPDX-PR) in
      comparison with other oral beta-lactams, cefdinir (CFDN), cefditoren pivoxil
      (CDTR-PI), and faropenem (FRPM), against penicillin-susceptible and -resistant
      Streptococcus pneumoniae. In vitro activities (MICs) of CPDX, CFDN, CDTR, and
      FRPM against clinical isolates, penicillin-susceptible S. pneumoniae (PSSP: MIC
      of penicillin G, < or = 0.063 microgram/ml), penicillin-intermediate S.
      pneumoniae (PISP: MIC of penicillin G, 0.125-1 microgram/ml), and penicillin
      resistant S. pneumoniae (PRSP: MIC of penicillin G, > or = 2 micrograms/ml), were
      tested by an agar dilution method. The MIC80s of CPDX against 27 PSSP strains, 23
      PISP strains, and 23 PRSP strains were 0.032, 1, and 8 micrograms/ml,
      respectively, which were superior to or equal to those of CFDN (0.063, 4, and 8
      micrograms/ml) and were inferior to those of CDTR (0.016, 0.5, and 1
      microgram/ml) and FRPM (< or = 0.008, 0.25, and 1 microgram/ml). Infection was
      induced in mice by inoculating with a PRSP clinical isolate, 9605 or 9601
      (serotype 6), or 10692 (serotype 19), through the nares of male ddY mice into the
      lungs. The mice were treated with drugs with doses of 2-50 mg/kg at 18, 26, 42,
      and 50 hours after the infection. Viable cell numbers in the lungs and blood were
      assayed at 66 hours after the infection. The efficacy of each drug was dose
      dependent. CPDX-PR showed the most potent in vivo efficacy among the drugs tested
      against the infections caused by the PRSP strains. MICs of the drugs against PRSP
      9605, 9601, and 10692 were as follows: CPDX, 4, 4 and 2 micrograms/ml; CFDN, 16,
      16, and 4 micrograms/ml; CDTR, 1, 1, and 0.5 microgram/ml; and FRPM, 1, 0.5, and
      0.5 microgram/ml, respectively. Thus, CPDX-PR showed a stronger in vivo activity
      than that expected from the MICs of CPDX. This was probably caused by the
      pharmacokinetic advantage of CPDX over the other drugs used in this study.

PMID- 10587879
TI  - [In vitro antibacterial activity of faropenem, a novel oral penem antibiotic,
      against enterohemorrhagic Escherichia coli O157 strains].
AB  - Against enterohemorrhagic Escherichia coli (EHEC) O157 clinically isolated, the
      effects of faropenem (FRPM), a novel oral penem antibiotic, on the MICs,
      bactericidal activity, verotoxin (VT)-release, and lipopolysaccharide (LPS)
      release were investigated in vitro and compared with those of other types of
      antibacterial agents. The MICs of FRPM in aerobic and anaerobic culture
      condition, were 0.78 and 0.39 microgram/ml, respectively. In aerobic condition,
      FRPM was more active than ampicillin, amoxicillin (AMPC), fosfomycin (FOM),
      kanamycin (KM), minocycline (MINO), and clarithromycin (CAM), but was slightly
      less active than cefdinir (CFDN), cefditoren (CDTR), and norfloxacin (NFLX)
      against O157 clinical isolates. In anaerobic condition, however, FRPM showed as
      strong activity as CFDN, CDTR, and NFLX. FOM, NFLX, and KM as well as the beta
      lactams including FRPM indicated the powerful bactericidal activity against one
      strain of O157 clinical isolates. The effects of MINO and CAM were
      bacteriostatic. FOM and the beta-lactams including FRPM promoted verotoxin type 1
      (VT1)-release, but rather suppressed verotoxin type 2 (VT2)-release from the same
      isolate. NFLX, however, promoted VT1-release and vast amount of VT2-release. In
      the case of KM, MINO, and CAM, the release suppression of both VT1 and VT2 was
      observed. FRPM, AMPC, and FOM had very weak activity on LPS-release, while CFDN,
      CDTR, and NFLX released a large amount of LPS from the strain. KM, MINO, and CAM
      had relatively weak activity. In these in vitro experiments, FRPM demonstrated
      the effective profile to the treatment for EHEC infection, except for the effect
      on VT1-release. These results suggest the possibility that FRPM shows good
      clinical efficacy for EHEC infection.

PMID- 10587880
TI  - [Neuromuscular blocking properties of arbekacin, astromicin, isepamicin and
      netilmicin in the rabbit].
AB  - The neuromuscular blocking properties of aminoglycoside group of antibiotics
      arbekacin sulfate (ABK), astromicin sulfate (ASTM), isepamicin sulfate (ISP),
      netilmicin sulfate (NTL) and d-tubocurarine were studied in 30 rabbits
      anesthetized with pentobarbital. The left gastrocnemius tendon was cut and
      secured to a force-displacement transducer. The left tibial nerve was directly
      stimulated by electrodes with supramaximal square waves of 0.1 msec duration at a
      frequency of 0.1 Hz. The resultant force of twitch tension was recorded. The
      intravenous administration of ABK 60-100 mg/kg, ASTM 160-320 mg/kg, ISP 320-480
      mg/kg or NTL 20-40 mg/kg resulted in dose-dependent decreases in twitch tensions.
      The ED50 values of 4 antibiotics were NTL = 30.2 mg/kg (4.2 x 10(-2) mmol/kg) <
      ABK = 78.3 mg/kg (1.4 x 10(-1) mmol/kg) < ASTM = 215.2 mg/kg (3.6 x 10(-1)
      mmol/kg) < ISP = 359.7 mg/kg (6.3 x 10(-1) mmol/kg), respectively. These
      antibiotics-induced blockades were antagonized by calcium or by neostigmine.
      Although the relative neuromuscular blocking potencies of 4 antibiotics
      equipotent to d-tubocurarine on the basis of therapeutic doses in man were below
      0.6 mg, it may be concluded that the potential clinical hazard lies in the
      sequence of administration of the aminoglycoside group of antibiotics.

PMID- 10587882
TI  - Recall readiness in children with autism.
AB  - When people are asked to learn information they need to judge when they have
      encoded the information accurately and will be able to retrieve it correctly.
      Making such a judgment is an aspect of metacognitive ability, and is referred to
      as "recall readiness." Previous researchers have not considered recall readiness
      in children with autism, therefore we asked matched groups of children with
      autism, children with mental retardation, and normally developing children (mean
      mental age: 7 years) to study several pictures of objects until they felt ready
      to recall all the objects without error. Their recall was then tested. The
      children with autism and the children with mental retardation had impaired recall
      readiness compared to the normally developing children. We discuss this result
      with reference to other research into the metacognitive abilities of children
      with autism.

PMID- 10587881
TI  - Autism and hearing loss.
AB  - A group of 199 children and adolescents (153 boys, 46 girls) with autistic
      disorder was audiologically evaluated. Mild to moderate hearing loss was
      diagnosed in 7.9% and unilateral hearing loss in 1.6% of those who could be
      tested appropriately. Pronounced to profound bilateral hearing loss or deafness
      was diagnosed in 3.5% of all cases, representing a prevalence considerably above
      that in the general population and comparable to the prevalence found in
      populations with mental retardation. Hearing deficits in autism occurred at
      similar rates at all levels of intellectual functioning, so it does not appear
      that the covariation with intellectual impairment per se can account for all of
      the variance of hearing deficit in autism. Hyperacusis was common, affecting
      18.0% of the autism group and 0% in an age-matched nonautism comparison group. In
      addition, the rate of serous otitis media (23.5%) and related conductive hearing
      loss (18.3%) appeared to be increased in autistic disorder. The study emphasizes
      the need for auditory evaluation of individuals with autism in order to refer
      those with pronounced to profound hearing loss for aural habilitation and to
      follow those with mild to moderate hearing loss because of the risk of
      deterioration.

PMID- 10587883
TI  - Children with autism experience problems with both objects and people.
AB  - Kanner (1943), in his classic account, described autism as a specific impairment
      in interpersonal relations which leaves the child's uses of objects relatively
      unaffected. This combination of the difficulties in relating to people and the
      supposedly "excellent" relations to objects figures centrally within many of the
      current theories of autism, which have had relatively little to say on the
      question of object use. This paper draws attention to evidence of widespread
      impairments in relating to objects, not only in interpersonal aspects of object
      use but also in early sensorimotor exploration and the functional and
      conventional uses of objects. In stressing these problems with objects, our
      purpose is not to downplay the social dimension of autism, but rather to
      highlight the reciprocal nature of the interactions between the child, other
      people, and objects. Given the evidence that other people play an important role
      in introducing objects to children, we propose that an impairment in
      interpersonal relations should itself lead us to expect corresponding disruption
      in the autistic child's use of objects. Conversely, an unusual use of objects is
      likely to manifest itself in disturbances in relating to other people, given the
      importance of a shared understanding and use of objects in facilitating
      interaction.

PMID- 10587884
TI  - Vineland Adaptive Behavior Scale scores as a function of age and initial IQ in
      210 autistic children.
AB  - Human growth modeling statistics were utilized to examine how Vineland Adaptive
      Behavior Scale (VABS) scores changed in individuals with autistic disorder as a
      function of both age and initial IQ. Results revealed that subjects improved with
      age in all domains. The rate of growth in Communication and Daily Living Skills
      was related to initial IQ while rate of growth in Social Skills was not. Results
      should provide hope for parents and further support for the importance of
      functional social-communication skills in the treatment of autism.

PMID- 10587885
TI  - Season of birth in autism: a fiction revisited.
AB  - Variations of season of birth among autistic individuals were studied. The
      replicability of previously reported increases in birth rates in the months of
      March and August were examined in groups of individuals with autism or mental
      retardation (the comparison group). The sample was obtained from the Yale Child
      Study Center Developmental Disabilities Clinic and from the DSM-IV Autism/PDD
      field trial. Data were analyzed by applying the Jonckheere test of ordinal trend
      and the chi-square test, with Yates correction factor. With respect to March and
      August births, and with calculations based on the beginning and middle of the
      month, no significant seasonal effect was observed. Samples were subcategorized
      into verbal and mute groups, and again results failed to support the seasonality
      hypothesis.

PMID- 10587886
TI  - The Strange Stories Test: a replication with high-functioning adults with autism
      or Asperger syndrome.
AB  - Two groups of individuals, one with high-functioning autism and the other with
      Asperger syndrome were tested using Happe's Strange Stories Test of a more
      advanced theory of mind (Happe, 1994). This assesses the ability to interpret a
      nonliteral statement. Relative to normal controls who were IQ and age-matched,
      individuals with autism or Asperger syndrome performed less well on the task,
      while performing normally on a non-mentalistic control task. Individuals with
      autism or Asperger syndrome could provide mental state answers, but had
      difficulty in providing contextually appropriate mental state answers. Rather,
      their answers tended to concentrate on the utterance in isolation. This
      replicates Happe's result. Although the majority of both clinical groups provided
      context-inappropriate interpretations, the autism group had the greater
      difficulty. Results are discussed in relation to both weak central coherence and
      theory of mind.

PMID- 10587887
TI  - Recognition of faux pas by normally developing children and children with
      Asperger syndrome or high-functioning autism.
AB  - Most theory of mind (ToM) tests are designed for subjects with a mental age of 4
      6 years. There are very few ToM tests for subjects who are older or more able
      than this. We report a new test of ToM, designed for children 7-11 years old. The
      task involves recognizing faux pas. Study 1 tested 7-9, and 11-year-old normal
      children. Results showed that the ability to detect faux pas developed with age
      and that there was a differential developmental profile between the two sexes
      (female superiority). Study 2 tested children with Asperger syndrome (AS) or high
      functioning autism (HFA), selected for being able to pass traditional 4- to 6
      year level (first- and second-order) false belief tests. Results showed that
      whereas normal 9- to 11-year-old children were skilled at detecting faux pas,
      children with AS or HFA were impaired on this task. Study 3 reports a refinement
      in the test, employing control stimuli. This replicated the results from Study 2.
      Some patients with AS or HFA were able to recognize faux pas but still produced
      them. Future research should assess faux pas production.

PMID- 10587888
TI  - Brief report: delusional disorder in a male adolescent with high-functioning
      PDDNOS.

PMID- 10587889
TI  - Home-based behavioral treatment.

PMID- 10587890
TI  - Auditory dysfunction in autism: a submicroscopic form of Wernicke's
      encephalopathy?

PMID- 10587891
TI  - Are children with autism better off in an autism classroom or a multidisability
      classroom?

PMID- 10587892
TI  - Incorporating a developmental perspective in doctoral training: survey of
      clinical child psychology training programs and introduction to the special
      section.
AB  - Examined the degree to which clinical child programs incorporate and integrate
      developmental theory into their training, and introduced the contributions of 6
      leaders in the field to this special section. Fifty-one clinical child doctoral
      programs responded to the survey. Results indicate that 3 types of training
      programs are operating: (a) child emphasis (n = 7), which do not have a formal
      clinical child training program but do have a faculty member who has child
      research interests; (b) clinical child (n = 37), which have a group of faculty
      members with specific child research and clinical interests and a formalized
      program of study; and (c) developmental-clinical programs (n = 7), which are
      similar to clinical child programs but require a substantive amount of
      developmental psychology course work and endorse a developmental psychopathology
      perspective. Findings reveal that clinical child programs have become
      increasingly differentiated and specialized over the past 20 years, but, with the
      exception of developmental-clinical programs, most programs are still neglecting
      to incorporate developmental theory into training. This issue, as well as
      concerns about the future direction of clinical child doctoral training is
      addressed in this special section on the Importance of Incorporating
      Developmental Theory Into Clinical Child Training.

PMID- 10587893
TI  - United we stand, divided we fall: the education and training needs of clinical
      child psychologists.
AB  - Reviews efforts to delineate training needs for psychologists who are providing
      clinical services to children, adolescents, and families. In particular, this
      article (a) describes efforts of clinical child and other psychologists who work
      with children, adolescents, and families to develop education and training
      guidelines; (b) discusses the overlap among various child and adolescent
      providers within psychology; and (c) highlights several key competencies that
      have been identified as important for all psychologists in practice roles with
      children and adolescents. In particular, we emphasize the need for greater
      collaboration and integration among various psychological specialties that focus
      on children, adolescents, and families and for greater system-wide discussion of
      training needs and priorities.

PMID- 10587894
TI  - Importance of developmental theory and investigation to research in clinical
      child psychology.
AB  - Focuses on the developmental periods of infancy, childhood, and adolescence to
      offer illustrations of the advantages of using developmental theory and research
      to establish targets for research on intervention, assessment and treatment
      planning, and evaluation of effective strategies for prevention of childhood and
      later adult disorders. The importance for training clinical graduate students in
      developmental approaches to research is stressed, and hopes for a future of
      mutual contributions of developmental and clinical psychology are expressed in
      light of the fact that, after a troubled history of isolation from one another
      and even active denigration of one another's goals and methods, developmental and
      clinical psychology are exhibiting joint recognition of the advantages of
      collaborative research.

PMID- 10587895
TI  - Developmental theory and the practice of clinical child psychology.
AB  - Examined developmental theory and its relevance for the practice of clinical
      child psychology. Following a brief review of basic principles of developmental
      psychology and developmental psychopathology, implications of a developmental
      perspective are explored for the diagnosis, assessment, and treatment of
      childhood disorders. Although it is obvious that many developmental issues
      confront the clinical child psychologist and that we have learned much about
      translating developmental theory into clinical practice, we conclude we have a
      long way to go before we can assert that a true developmental-clinical child
      interface has been realized.

PMID- 10587896
TI  - Closing the gaps: developmental psychopathology as a training model for clinical
      child psychology.
AB  - Espouses developmental psychopathology as a framework for training our future
      leaders due to its emphasis on an ecological, transactional lifespan perspective,
      as well as interdisciplinary bridging and policy focus. This perspective, used as
      a framework for questioning and thinking about the complex interplay of
      psychological and social phenomena, provides a method for closing the gaps in
      training future psychologists as it allows for the development of niche expertise
      under an umbrella of the broader, ecological perspective. In an increasingly
      complex world of shrinking mental health dollars and growing severity of mental
      health problems for families and youth, clinical psychologists are needed more
      than ever to solve social problems. The current training paradigms in clinical
      child psychology programs need redirection and clarification for future
      psychologists to contribute meaningfully to science, practice, and policy. This
      article provides background in the history and influence of the developmental
      psychopathology perspective, as well as future implications for doctoral training
      programs in clinical psychology.

PMID- 10587897
TI  - Clinical child and developmental-clinical programs: perhaps necessary but not
      sufficient?
AB  - Takes the position that, when considering the science component of clinical
      psychology, both clinical child and developmental-clinical approaches to training
      may be too narrow or limiting and that perhaps we should consider broader
      alternatives, such as an ecological training model. However, I also propose that
      the type of training program selected is not the only factor to consider, as the
      working relationship between the individual faculty member and graduate student
      exerts considerable influence on what a student learns in a graduate program.

PMID- 10587898
TI  - Training in clinical child psychology: doing it right.
AB  - Discusses (a) what roles the specialty of clinical child psychology fulfills and
      how societal and professional changes have enhanced the need for the specialty,
      (b) how the field defines itself, (c) how models of training are conceptualized
      for the specialty, and (d) how some training programs implement specialty
      training with broad, interdisciplinary components. Clinical child psychology is a
      professional field of research and practice that, when adequate training is
      provided, properly deserves a places as a specialty. The dangers of
      overspecialization and narrowness are more likely present in traditional clinical
      (adult) psychology than in clinical child psychology, especially when the
      clinical child training is done in a broadly comprehensive and integrated manner.

PMID- 10587899
TI  - Role of theory in child psychosocial intervention and research: introductory
      comments.

PMID- 10587900
TI  - Child-focused behavioral assessment and modification.
AB  - Argues that behavioral principles have been translated into practice with
      children too literally and that a more integrative framework is required to guide
      assessment and treatment. The framework advocated is Staats's (1996)
      psychological behaviorism. This is a consistently behavioristic, positivist
      paradigm, using multilevel theory to emphasize the integration of social
      learning, developmental, and personality principles. Psychological behaviorism
      thus allows for a much more expansive approach than has typically been the case
      within child behavior therapy. Given the complexity of this perspective, I
      selected four broad tenets of the theory and suggested their implications for
      clinical contexts. The further translation from clinical models to specific
      clinical practices is quite difficult but may yield more flexible and
      substitutable practices than do unidimensional treatment outcome studies. Of
      special importance, the principles demonstrate how children themselves can retain
      the central focus of child behavioral assessment and modification. Specific
      practices still need to be constructed according to an understanding of the
      multiple sources of influence on children as well as the culture of childhood
      itself.

PMID- 10587901
TI  - Model building in developmental psychopathology: a pragmatic approach to
      understanding and intervention.
AB  - Proposes model building as a pragmatic and integrative approach to developmental
      psychopathology. The model-building process is iterative within a program of
      research, cycling through the following phases of research: theory, field
      observation, construct definition, measurement development, construct analysis,
      model testing, experimental field trials, and model revision. Research on the
      development of and interventions for antisocial behavior is discussed as a tool
      for reflecting on the model-building process. The ecological framework is offered
      as a science-based heuristic that integrates various levels of analysis and
      theoretical perspectives.

PMID- 10587902
TI  - Relation of theory and practice in psychodynamic therapy.
AB  - Explores the role of theory in psychodynamic practice. This article attempts to
      show that clinicians commonly labor under the illusion that practice is governed
      by the logic of theory, by deduction rather than by induction. With
      psychoanalytic theory and practice as an example, theory is shown to be logically
      independent of practice and technique. It is suggested that maintaining the
      illusion of a logical relation between the two can cause a petrification of
      practice and ultimately the downfall of a theoretical orientation. Further, the
      inductive use of clinical experience can generate an excessive number of
      irreconcilable theoretical ideas, which in turn explains the tendency of
      psychodynamic clinicians to eschew operationalization and rigorous theory
      building. The abandonment of the pretense of a logical relation, by contrast,
      could lead to a renewed excitement about the development of technique.

PMID- 10587903
TI  - Theory development in a family-based therapy for adolescent drug abuse.
AB  - Family-based treatments for adolescent drug abuse and related behavior problems
      have been developed and evaluated with success. Empirical support exists for the
      efficacy of family-based treatments, and process studies have begun to identify
      mechanisms by which these treatments may achieve their effects. This article
      discusses theory and related clinical refinements in a contemporary family-based
      intervention, multidimensional family therapy. Expansions in the theoretical
      basis of the model are discussed. I highlight 2 aspects of the theory evolution
      process, resulting in a sharper clinical focus on intrapersonal development and
      on adolescents' and families' functioning vis-a-vis influential extrafamilial
      ecologies of development.

PMID- 10587904
TI  - Current (lack of) status of theory in child and adolescent psychotherapy
      research.
AB  - Considers fundamental issues raised by current child and adolescent psychotherapy
      research, including the neglect of theory in psychotherapy research, the
      distinction between theories of onset of dysfunction and therapeutic change, and
      the progression of knowledge from description to explanation and from risk
      factors to causal agents. The complex relations of proposed influences and
      clinical outcomes and constraints of current statistical models illustrate key
      challenges for understanding the nature of clinical disorders and therapeutic
      change. Much more attention to understanding how treatment achieves therapeutic
      change is needed, not only to address conspicuous lacunae in the knowledge base
      but also to optimize the effects of treatment in clinical work.

PMID- 10587905
TI  - Role of theoretical bias in therapeutic interventions: to see or not to see?
AB  - Considering the role of theory in child psychosocial treatment, it is important
      to acknowledge some of its associated problems. Among the shortcomings of theory
      discussed in this article are its potential for biasing what we see and do
      clinically, the arbitrary nature of some theoretical explanations, and the way
      that theory-based jargon can interfere with communication. A bottom-up approach
      to the development of clinical principles is advocated instead, especially when
      these principles are derived from the convergence of clinical observation and
      research findings.

PMID- 10587906
TI  - Does theory have value in clinical child psychology?
AB  - Examines the value and importance of theory in child psychology, particularly
      with respect to clinical practice. Although it is readily apparent that theory is
      not an essential element of treatment, the role of theory is to provide a
      coherent framework for clinical intervention. Theory provides a foundation for
      understanding the presenting pathology, the factors that affect it, the patient's
      and therapist's roles within the context of treatment, and the specific
      intervention strategies to be utilized. Therapeutic commonalities are considered
      as they may affect treatment outcome, but they are not viewed as the essential
      factors in efficacy. The value and meaning of eclecticism are also discussed.

PMID- 10587907
TI  - Postempiricism and psychological theory.
AB  - Discusses postempiricism as a view of scientific knowledge and of knowledge in
      general. It gives a prominent role to theory in relation to experience,
      experiment, and action and emphasizes the contextual nature of knowledge. The
      articles by Dishion and Patterson (this issue), Evans (this issue), and Liddle
      (this issue) are all positioned clearly in this contemporary epistemology.
      Fonagy's (this issue) analysis of the apparent restriction of psychoanalytic
      methods of change is discussed.

PMID- 10587908
TI  - Links among theory, research, and practice: cornerstones of clinical scientific
      progress.
AB  - Discusses how explicit links among clinical theory, research, and practice are
      necessary if a clinical discipline is to survive in the managed care marketplace
      of today. Robust links among theory, research, and practice enable the
      elaboration of a systematic body of clinical knowledge that is practical in its
      deployment, effective in its methods, and compelling in its rationale. Moreover,
      theoretical advances are increasingly necessary, in that they allow scientists to
      categorize and prioritize the growing amount of empirically derived information,
      determine how pieces of multilevel data fit together, identify knowledge gaps,
      and set priorities for future studies. As shown by some of the articles in this
      special section, evolving theories of behavior have several characteristics in
      common; namely that they are developmental, transactional, contextual,
      adaptational, multilevel, and multidetermined. Concerns may be raised, however,
      as to whether current research methods are fully adequate to test these newer,
      more complex, multilevel theories or the clinical phenomena they seek to
      characterize. To address these difficulties, as well as to increase the pace of
      scientific advances that may result from propitious links among theory, research,
      and practice, I offer several recommendations to clinical psychology in general
      and to clinical child psychological research in particular.

PMID- 10587909
TI  - Emerging views of the role of theory.
AB  - Offers a few broadly evaluative observations about what we have learned from the
      articles and commentaries contained in this special section. We discuss how-
      although the contributions contained in this special section might be viewed on
      one level as suggesting a lack of consensus concerning the role of theory--on a
      metalevel the contributions are suggestive of movement toward consensus. The
      emerging consensus seems to be that not only is theory alive and well but it is
      unlikely that we will ever be able to do without theory. However, our ways of
      thinking and talking about theory appear to be undergoing change; that is, the
      trend is in the emergence of theory as a guide for action or action-based
      epistemology. We conclude with ideas about future directions, including the call
      for methodological pluralism, theoretical pluralism, and metatheoretical
      development.

PMID- 10587910
TI  - Characterization of monochrome CRT display systems in the field.
AB  - This article presents a review of image quality assessment methods for monochrome
      CRTs in the field as opposed to the laboratory. The review includes image quality
      programs at the University of Washington, the University of Texas at Houston, the
      University of Michigan, and the University of Arizona. CRT manufacturers and
      display-board suppliers also are concerned with image quality, particularly with
      respect to the life time of the CRT. The programs show that the need for image
      quality assessment for CRTs in the clinic is recognized. Although several
      experimental programs are in place, there is no universally accepted program. In
      fact, the clinical consequences of degraded monitor performance are not even well
      known and must be established. The existing programs mainly are based on the most
      comprehensive test pattern, the SMPTE pattern. The programs permit assessment of
      maximum luminance, display function, dynamic range, and contrast. They do not
      permit assessment of spatial resolution. There is no easy method to determine the
      spatial resolution in the field as precisely as desired simply because there are
      no visual aids (test patterns) to reliably determine loss of spatial resolution
      and signal-to-noise ratio using human observers. This report also presents
      initial and encouraging data obtained at the University of Arizona with a CCD
      camera. This CCD camera has the potential to be developed into an important tool
      for practical CRT evaluation for the clinic.

PMID- 10587911
TI  - Comparison of the quality of temporal subtraction images obtained with manual and
      automated methods of digital chest radiography.
AB  - The authors have been developing a fully automated temporal subtraction scheme to
      assist radiologists in the detection of interval changes in digital chest
      radiographs. The temporal subtraction image is obtained by subtraction of a
      previous image from a current image. The authors' automated method includes not
      only image shift and rotation techniques but also a nonlinear geometric warping
      technique for reduction of misregistration artifacts in the subtraction image.
      However, a manual subtraction method that can be carried out only with image
      shift and rotation has been employed as a common clinical technique in
      angiography, and it might be clinically acceptable for detection of interval
      changes on chest radiographs as well. Therefore, the authors applied both the
      manual and automated temporal subtraction techniques to 181 digital chest
      radiographs, and compared the quality of the subtraction images obtained with the
      two methods. The numbers of clinically acceptable subtraction images were 147
      (81.2%) and 176 (97.2%) for the manual and automated subtraction methods,
      respectively. The image quality of 148 (81.8%) subtraction images was improved by
      use of the automated method in comparison with the subtraction images obtained
      with the manual method. These results indicate that the automated method with the
      nonlinear warping technique can significantly reduce misregistration artifacts in
      comparison with the manual method. Therefore, the authors believe that the
      automated subtraction method is more useful for the detection of interval changes
      in digital chest radiographs.

PMID- 10587912
TI  - Interslice coding for medical three-dimensional images using an adaptive mode
      selection technique in wavelet transform domain.
AB  - In this article the authors propose a novel interslice coding algorithm
      especially appropriate for medical 3-dimensional (3D) images. The proposed
      algorithm is based on a video coding algorithm using motion
      estimation/compensation and transform coding. In the algorithm, warping is
      adopted for motion compensation. Then, by using adaptive mode selection, an MC
      residual image and original image are mixed up in the wavelet transform domain
      for improvement in coding performance. The mixed image is then compressed by the
      zerotree coding method. It is proven that the adaptive mode selection technique
      in the wavelet transform domain is very useful for medical 3D image coding.
      Simulation results show that the proposed scheme provides good performance,
      regardless of interslice distance, and is prospective for medical 3D image
      compression.

PMID- 10587913
TI  - A fast way to visualize the brain surface with volume rendering of MRI data.
AB  - The preprocessing of 3-dimensional (3D) MRI data constitutes a bottleneck in the
      process of visualizing the brain surface with volume rendering. As a fast way to
      achieve this preprocessing, the authors propose a simple pipeline based on an
      algorithm of seed-growing type, for approximate segmentation of the intradural
      space in T1-weighted 3D MRI data. Except for the setting of a seed and four
      parameters, this pipeline proceeds in an unsupervised manner; no interactive
      intermediate step is involved. It was tested with 15 datasets from normal adults.
      The result was reproducible in that as long as the seed was located within the
      cerebral white matter, identical segmentation was achieved for each dataset.
      Although the pipeline ran with gross segmentation error along the floor of the
      cranial cavity, it performed well along the cranial vault so that subsequent
      volume rendering permitted the observation of the sulco-gyral pattern over
      cerebral convexities. Use of this pipeline followed by volume rendering is a
      handy approach to the visualization of the brain surface from 3D MRI data.

PMID- 10587914
TI  - Quality-of-service improvements from coupling a digital chest unit with
      integrated speech recognition, information, and picture archiving and
      communications systems.
AB  - Speech recognition reporting for chest examinations was introduced and tightly
      integrated with a Radiology Information System (RIS) and a Picture Archiving and
      Communications System (PACS). A feature of this integration was the unique one-to
      one coupling of the workstation displayed case and the reporting via speech
      recognition for that and only that particular examination and patient. The
      utility of the resulting, wholly integrated electronic environment was then
      compared with that of the previous analog chest unit and dedicated wet processor,
      with reporting of hard copy examinations by direct dictation to a typist.
      Improvements in quality of service in comparison to the previous work environment
      include (1) immediate release of the patient, (2) decreased rate of repeat
      radiographs, (3) improved image quality, (4) decreased time for the examination
      to be available for interpretation, (5) automatic hanging of current and previous
      images, (6) ad-hoc availability of images, (7) capability of the radiologist to
      immediately review and correct the transcribed report, (8) decreased time for
      clinicians to view results, and (9) increased capacity of examinations per room.

PMID- 10587915
TI  - Evaluating the outcome of two teaching methods of breath actuated inhaler in an
      inner city asthma clinic.
AB  - OBJECTIVES: Our objective was to compare two different teaching methods used to
      educate patients in the use of a breath actuated inhaler (BAI) and to assess the
      impact of its continued use on their metered-dose inhaler (MDI) technique.
      DESIGN: Prospective, randomized, controlled trial. SETTING: Adult
      Pulmonary/Asthma clinic of Cook County Hospital, Chicago, IL. PATIENTS:
      Diagnosed, stable asthmatics. INTERVENTION: The patients were randomized into two
      groups. The experimental group received verbal instructions and demonstration on
      breath actuated inhaler technique while the control group received written
      instructions only on BAI use. The metered dose inhaler technique of both groups
      of patients was also evaluated. MEASURES: A checklist evaluating the key aspects
      of proper BAI and MDI inhalation techniques was used to assess the use of both
      types of inhalers at entry into the study and upon postintervention follow-up at
      8 to 20 weeks. RESULTS: At baseline, 97% of patients in the experimental group
      and 83% of patients in the control group were initially able to demonstrate BAI
      inhalation technique correctly. Upon follow-up, 82% of the control group and 68%
      of the experimental group were able to use the BAI correctly, which was a
      statistically significant deterioration in the experimental group. In both of
      these groups, there was a statistically significant improvement in MDI technique.
      CONCLUSIONS: Written instructions alone may be an adequate teaching tool for
      proper inhalation technique of BAI. Continued BAI use appears not to impact
      adversely on proper MDI technique.

PMID- 10587916
TI  - A Pascal-based decision support system model for diagnosis and treatment
      processes in urology.
AB  - This program is designed for a urologist as a Decision Support System to
      facilitate the pre-diagnosis and identify the definite diagnosis as quickly as
      possible with the help of symptoms and physical examination by taking into
      consideration all the possible diseases with cross-questioning. The aim is to
      enable the physician to display on the monitor all the possible diseases causing
      the arising symptoms by entering the symptoms and the physician's observations
      into the database with "yes" or "no" type answers.

PMID- 10587917
TI  - Consumer opinions with ancillary hospital services: improving service delivery in
      Turkish hospitals.
AB  - This article reports the results of 2,045 consumer interviews conducted after
      discharge from seven major public and private hospitals in the country of Turkey.
      The direct measurement of consumer-satisfaction and utilization of this
      information to improve service delivery is a relatively new phenomena for this
      country. Based on postdischarge consumer interviews information on satisfaction
      of several ancillary hospital service variables was identified and inclusion for
      achieving overall consumer satisfaction is emphasized. Two critical areas were
      examined: ancillary staff and consumer relations and overall impressions of the
      comfort of the facility. Relationships and percentages within and among these
      variables are reported. Overall, the majority of the complaints noted by
      consumers were not related to direct treatment rather they focused on
      interactions with the hospital's staff and other services provided by the
      facility (e.g., comfort, cleanliness, parking, etc.). When comparing the
      different hospitals across these variables significant differences were noted at
      the .05 level between the seven different hospitals examined. Findings and
      recommendations from this study are presented to assist in providing a basis for
      the development of improved consumer satisfaction.

PMID- 10587918
TI  - New approach to the medical information system for quality management in patient
      care: development of Problem Mapping System.
AB  - A new type of medical information system named Problem Mapping System (P-Map) has
      been developed, which aids physicians with solving patients' problems. With this
      system, physicians can define the problems of in-patients, monitor their progress
      clearly, and share information efficiently. In P-map, a list of problems, such as
      disease names, can be set for each inpatient easily. The progress of each problem
      is clearly shown using progress lines on a time axis. Physicians can save the
      Subjective Objective Assessment Plan (SOAP) notes which are linked to each
      problem. At the final stage of patient care, a discharge summary can be made
      easily. With the aid of this system, the quality of patient care is improved due
      to the following: (1) physicians can make the best decision; (2) medical staff in
      the same team can provide the best medical treatment; (3) evaluation of each
      medical treatment is easy; (4) saved data can be used effectively for education
      and research; (5) the system can improve cooperation with other medical
      institutes by providing discharge summary information which can be distributed
      using e-mail; and (6) the system can improve patients' understanding for the
      purpose of informed consent by providing clear and well organized information to
      patients.

PMID- 10587919
TI  - Histopathologic variants of basal cell carcinoma correlation with sex, age and
      localization.
AB  - During the 6-year period (January 1, 1993 to December 31, 1998) in the Laboratory
      for Dermatopathology of Department of Dermatovenereology in Clinical Hospital
      Split, 1616 basal cell carcinomas (BCC) of a total of 323 investigated specimens
      were diagnosed. The incident rate varies from 92 to 114 BCC per 100,000
      inhabitants in the Split region. The sex ratio in material is 1.2:1 in favor of
      males. The frequence of BCC increases with the advanced age in both sexes with
      the peak in the age group from 70 to 79 years. The most frequent location in both
      sexes is the nose followed by cheeks and trunk. Statistic analysis showed a
      significantly higher occurrence of BCC in temporal region in the males and
      perioral region in the females; respectively. The solid variant is the most
      frequent followed by superficial multicentric and solid-adenoid. Pure variants
      are found in 83.1% specimens, and mixed variants in 16.9%. Solid and adenoid
      variants are the most frequent on the nose and cheeks. According to statistics
      cystic variant is significantly higher on the forehead, and morpheic variant on
      the nose. Superficial multicentric variant is statistically more frequent on the
      trunk than on other locations. All specimens were reexamined and histopathologic
      variants were obtained. Over 2000 data are comprised which is a sufficient
      examination sample. In programs such as SPSS, and Graph master ver 1.12, Win95,
      MO'97 (Word, Excel, Access) on Pentium II 200 MHz, floppy, 64 MB RAM, HDD 2.1 GB,
      CD x24, HP LJet 6L, a comprehensive analysis has been performed.

PMID- 10587920
TI  - The public health care planning problem: a case study using geographic
      information systems.
AB  - We address the problem of designing new networks for the delivery of public
      health care services in the United States. The paper is based on a case study
      design conducted with the Fulton County Health Department (Atlanta, GA). The
      research contribution this paper makes is twofold. First, it presents a planning
      methodology to deliver health care services through a mix of fixed health
      centers, satellite facilities, and mobile facilities. Second, it gives insights
      on how to use geographic information systems to design new health care service
      networks.

PMID- 10587921
TI  - Are electronic emergency department data predictive of heat-related mortality?

PMID- 10587922
TI  - What is your diagnosis? Rodenticide poisoning.

PMID- 10587923
TI  - Management of cervical spondylopathy-associated intervertebral, disc protrusions
      using metal washers in 78 dogs.
AB  - Intervertebral 7.5 mm (n = 75) and 6.0 mm (n = 22) metal washers were used to
      distract intervertebral spaces in 78 consecutive cases of canine cervical
      spondylopathy-associated disc protrusions, where myelography had demonstrated
      traction-responsive spinal cord compression. Nineteen dogs had compressive
      lesions at two sites. Fifty lesions were evaluated myelographically on immediate
      postoperative radiographs; of these, 32 compressions had been eliminated and 18
      had been reduced. Euthanasia was performed in nine dogs within six months of
      surgery and 15 dogs had varying degrees of neck pain during this period. Long
      term follow-up information was available on 65 dogs nine to 70 months following
      surgery (median 32 months). Sixty-three of these dogs improved postoperatively.
      Neurological function subsequently deteriorated in 17 dogs 10 to 59 months
      following surgery (median 34 months). Eight of these 17 cases had further
      myelographic investigations and all had additional disc protrusions with no
      evidence of cord compression at the previous sites of surgery. The remaining nine
      cases had a deterioration in hindlimb function but were not investigated further.

PMID- 10587924
TI  - Aetiology and diagnosis of persistent nasal disease in the dog: a retrospective
      study of 42 cases.
AB  - Forty-two dogs with a history of persistent nasal disease were evaluated by a
      combination of clinical examination, thoracic and nasal radiography, retroflexed
      endoscopy and biopsy, and anterograde rhinoscopy and blind nasal biopsy. A
      definitive diagnosis was made in 91 per cent of cases. Neoplasia was the most
      common diagnosis (33 per cent of cases), followed by inflammatory rhinitis (24
      per cent). Other diagnoses included periodontal disease (10 per cent),
      aspergillosis (7 per cent) and foreign bodies (7 per cent). Adenocarcinoma was
      the most common tumour diagnosed. The clinical findings were found to be too
      variable to be used as specific diagnostic criteria. Anterograde rhinoscopy and
      retroflexed endoscopy had higher specificity and sensitivity than radiology for
      the diagnosis of neoplasia, inflammatory rhinitis, aspergillosis and foreign
      bodies. With a systematic approach to the investigation of persistent nasal
      disease, a definitive diagnosis can be successfully obtained in the vast majority
      of cases.

PMID- 10587925
TI  - Survey of canine and feline follicular tumours and tumour-like lesions in central
      Italy.
AB  - Between January 1985 and June 1997, a total of 4005 skin biopsies were received
      from dogs and 898 from cats. Follicular tumours and tumour-like lesions together
      represented 10.4 per cent and 8.1 per cent of all skin tumours in the dog and
      cat, respectively. The prevalence of tumour-like lesions, such as follicular and
      dermoid cysts, dilated pore and focal adnexal dysplasia, was highest,
      representing 41.2 per cent and 68 per cent of all follicular lesions in dogs and
      cats, respectively. In the dog, follicular tumours were distributed as follows:
      trichoblastoma (25.6 per cent of all tumours and tumour-like lesions),
      infundibular keratinising acanthoma, (14 per cent), pilomatricoma (13 per cent),
      trichoepithelioma (3.9 per cent) and tricholemmoma (2.3 per cent). In the cat,
      the distribution was 26 per cent for trichoblastoma, 4 per cent for
      trichoepithelioma and 2 per cent for pilomatricoma. Tumour-like lesions and
      infundibular keratinising acanthoma in the dog were mostly located on the trunk,
      trichoblastoma and tricholemmoma on the head, and pilomatricoma on the neck. In
      the cat, both tumour-like lesions and trichoblastoma were frequently present on
      the neck and head.

PMID- 10587926
TI  - Stifle joint luxation in the cat: treatment using transarticular external
      skeletal fixation.
AB  - Extra-articular suturing techniques and transarticular external skeletal fixators
      were used to repair traumatic luxation of the stifle joint in four cats. Rupture
      of the cranial cruciate, caudal cruciate and medial collateral ligaments,
      together with injury to one or both menisci, were the most common injuries
      observed. The method of stifle repair was successful in all cases, but serious
      complications occurred when cats with transarticular external fixators were not
      kept confined indoors. Complications consisted of pin loosening and disruption of
      the fixator, or fractures through proximal or distal pins. Transarticular
      external skeletal fixation was considered to be a simple and effective method of
      maintaining short-term joint stability to allow healing of injured soft tissue
      structures. The apparatus facilitated early weightbearing and, on removal,
      allowed for the return of near-normal stifle function. Careful pin insertion and
      owner compliance in enforcing confinement are essential in minimising
      complications associated with immobilising the stifle joint using transarticular
      external skeletal fixation.

PMID- 10587927
TI  - Synovial myxoma: magnetic resonance imaging in the assessment of an unusual
      canine soft tissue tumour.
AB  - Magnetic resonance imaging (MRI) of the hindlimb of a 10-year-old Labrador
      retriever was performed preoperatively to define the limits and invasive nature
      of a synovial myxoma. This unusual tumour in dogs has also only rarely been
      reported in humans, although the use of advanced imaging techniques has been more
      widely reported in the assessment of soft tissue tumours in people. MRI was an
      invaluable aid in the delineation of the extensive pathological changes
      associated with this tumour and consequently its surgical treatment. Amputation
      was performed and the dog remained disease-free 18 months after surgery.

PMID- 10587928
TI  - Skin lesions caused by orthopoxvirus infection in a dog.
AB  - A seven-year-old male dobermann was presented for examination of a non-pruritic
      ulcerated lesion occurring at the site of a suspected rat bite on the muzzle.
      Biopsy revealed focal ulcerative dermatitis, with cells in the epidermis,
      follicular infundibula and interposed sebaceous glands undergoing ballooning
      degeneration and containing large acidophilic intracytoplasmic structures
      resembling poxvirus inclusion bodies. The diagnosis of orthopoxvirus infection
      was confirmed by transmission electron microscopy and immunohistochemistry. The
      biopsy site healed uneventfully, without evidence of recurrence or development of
      further cutaneous or internal lesions, and a serum sample collected eight weeks
      after first presentation had a low titre of poxvirus antibodies. This report
      demonstrates that orthopoxvirus infection should be considered as a cause of
      ulcerative skin lesions in dogs, particularly if there has been recent contact
      with rodents or other small mammals.

PMID- 10587929
TI  - Atraumatic bilateral avulsion of the origins of the gastrocnemius muscle.
AB  - A golden retriever was presented with a prolonged history of a persistent
      lameness of the hindlimbs and the recent development of a plantigrade stance.
      Radiography showed bilateral chronic changes associated with the origins of both
      the lateral and medial heads of the gastrocnemius muscles. Surgical correction
      was carried out sequentially, with good results three months postsurgically and
      after a three-year follow-up.

PMID- 10587930
TI  - The heuristic system. Precision and creativity in addiction treatment.
AB  - The Heuristic System (HS) is a method of developing case formulations for use in
      addiction treatment. Pertinent guidelines, models, or rules of thumb (heuristics)
      are applied in a stepwise process in order to generate at least two competing or
      complementary hypotheses concerning the clinical dynamics of the case. These
      hypothesis are then integrated and/or their relative utility for use in treatment
      is appraised. Key elements of HS include (a) a model of addiction based on cycles
      of self-experience, (b) a structured method for arriving at clinical problem
      formulations, (c) a schematic of the recovery process, (d) a menu of fundamental
      principles of substance abuse treatment, and (e) a format for providing updatable
      guidance to the patient for use in treatment. A case developed from the HS
      approach is presented. This article concludes with a discussion of the
      implications of HS theory and methods for program design and research.

PMID- 10587931
TI  - Case management and behavioral contracting. Components of rural substance abuse
      treatment.
AB  - This article presents a model of case management with rural clients entering drug
      and alcohol treatment. As part of a larger treatment protocol called Structured
      Behavioral Outpatient Rural Therapy, behavioral contracting is combined with
      strengths perspective case management to help rural clients motivate themselves
      to engage and complete drug and alcohol treatment. This combined approach is
      designed to continually communicate and teach an "A-B-C" cognitive-behavioral
      approach to problem-solving and change. While not a panacea for addressing the
      myriad problems facing clients with drug use problems, such an approach promises
      to improve "treatment as usual" formats, which often ignore the formidable
      obstacles to human change experienced by rural clients and clinicians.

PMID- 10587932
TI  - The value of acupuncture detoxification programs in a substance abuse treatment
      system.
AB  - Our purpose is to compare baseline characteristics and detoxification readmission
      rates of clients treated at outpatient acupuncture programs and at short-term
      residential programs, two options available to persons seeking substance abuse
      detoxification. This was a retrospective cohort study using data on clients
      discharged from publicly funded detoxification programs in Boston between January
      1993 and September 1994. Multivariate models were used to examine the effect on 6
      month detoxification readmission rates of treatment at residential detoxification
      programs (used by 6,907 clients) versus at outpatient acupuncture programs (used
      by 1,104 clients) after adjusting for baseline differences. Acupuncture clients
      were less likely to be readmitted for detoxification within 6 months (odds ratio
      [OR] 0.71, 95% confidence interval [CI] 0.53-0.95). Similar results were found
      when the analysis was performed on a subsample of clients that were relatively
      similar in terms of baseline characteristics (OR 0.61, 95% CI 0.39-0.94). We
      determined that acupuncture detoxification programs are a useful component of a
      substance abuse treatment system.

PMID- 10587933
TI  - Prior treatment history and its impact on criminal recidivism.
AB  - This study examines the hypothesis that treatment is a cumulative process; that
      is, treatment success is best viewed in terms of the patient's entire treatment
      history, rather than the index treatment episode. Three-hundred and eight
      patients with a primary heroin addiction were studied for 2 years posttreatment.
      Using posttreatment arrests as the dependent variable, the effects of prior
      treatment were assessed. Those with six or more prior treatment episodes and who
      had been in treatment for 12 or more months during the most recent episode
      averaged only 0.2 arrests in the 2 years posttreatment, while those with no prior
      treatment, but 12 or more months in the recent treatment averaged 0.88 arrests.
      Logistic analysis found that each prior treatment reduced the probability of a
      posttreatment arrest by 25%. Based on a linear regression, patients with six or
      more treatments prior treatments averaged half the number of posttreatment
      arrests as someone with no treatments before the index episode.

PMID- 10587934
TI  - Node-link mapping and psychological problems. Perceptions of a residential drug
      abuse treatment program for probationers.
AB  - The current study examined program perceptions of 367 probationers admitted to a
      4-month residential drug abuse treatment facility that focuses on group
      counseling. Prior research has shown that many individuals within the criminal
      justice system have both psychological and drug abuse problems, and that they
      often have limited success in drug abuse treatment programs. The current study
      examined whether the benefits of node-link mapping, a visual representation
      counseling technique that is especially beneficial in group counseling
      environments, would extend to individuals with psychological problems.
      Probationers were randomly assigned to mapping-enhanced or standard counseling.
      Those residents who had higher levels of psychological problems (based on a
      global indicator of psychological problems), and who received mapping-enhanced
      counseling, had more favorable perceptions of their counselors and fellow
      community members over time than their counterparts who received standard
      counseling.

PMID- 10587935
TI  - The Swiss heroin trials. Scientifically sound?
AB  - The objective of this article is to critique a study conducted by the Swiss
      Federal Office of Public Health to evaluate Switzerland's heroin maintenance
      project. Heroin abusers (N = 1,146) were enrolled in 18 research clinics.
      Subjects were recruited into three study arms--heroin, morphine, or methadone
      maintenance, but randomization was unsuccessful, and all received heroin.
      Medications were self-administered by injection on site. Patients were
      interviewed at intake and 6-month intervals up to 18 months. A review of the
      study revealed design weaknesses, including the absence of control groups, lack
      of corroboration of self-reports, failure to control for the influence of social
      services on outcome, and the absence of follow-up on those who left the trial
      prematurely. The program's ability to avert human immunodeficiency virus (HIV)
      transmission could not be fully evaluated because patients did not consistently
      submit to HIV testing. The Swiss trials of supervised heroin prescription trials
      do not withstand scientific scrutiny.

PMID- 10587936
TI  - Comparing the impact of standard and abbreviated treatment in a therapeutic
      community. Findings from the district of Columbia treatment initiative
      experiment.
AB  - This study examines the efficacy of providing Enhanced Abbreviated or Standard
      Inpatient treatment and Outpatient treatment to drug-abusing clients. The
      experiment randomly assigned 412 clients to two therapeutic community programs,
      which differed primarily in planned duration. This study addressed limitations of
      prior research, as it used random assignment of clients to treatment programs,
      achieved high follow-up rates and used objective measures of drug use and
      criminal history. Self-reports and objective measures of criminal activity and
      substance abuse were collected at pre- and posttreatment interviews. Completing
      the entire 12-month program (inpatient and outpatient) was more important than
      duration of inpatient program attended. Regardless of program, completers had
      substantial reductions in posttreatment drug abuse and arrests. A 12-month course
      of treatment including at least 6 months in a therapeutic community followed by
      outpatient treatment can produce marked reductions in drug abuse and crime among
      persons who complete both phases.

PMID- 10587937
TI  - Genetics and "race" in the Merchant of Venice.

PMID- 10587938
TI  - "I'll cry myself sick": illness in Wuthering Heights.

PMID- 10587939
TI  - Troubled teen or troubled system?: TV interprets the Zion malpractice case.

PMID- 10587940
TI  - The ethics of metaphor and the infant body in pain.

PMID- 10587941
TI  - The difficulty of being anti-NICU.

PMID- 10587942
TI  - Wolbachia: why these bacteria are important to genome research.

PMID- 10587943
TI  - The Wolbachia Genome Consortium.

PMID- 10587944
TI  - SST versus EST in gene recognition.
AB  - The expressed sequence tag (EST) data provide a powerful tool for identification
      of transcribed DNA sequences. However, as EST are relatively short, many exons
      are poorly covered by EST, thus reducing the utility of EST data. Recently,
      signature sequence tag (SST) fingerprints were proposed as an alternative to EST
      fingerprints. Given a fingerprint set of probes, SST of a clone is a subset of
      probes from the fingerprint set that hybridize with the clone. We demonstrate
      that besides being a powerful technique for screening cDNA libraries, SST
      technology provides for very accurate gene predictions. Even with a small
      fingerprint set (600-800 probes), SST-based gene recognition outperforms many
      conventional and EST-based methods. The increase in the size of the fingerprint
      set to 1500 probes provides almost perfect gene recognition. Even more
      importantly, SST-based gene predictions miss very few exons and, therefore,
      provide an opportunity to bypass the cDNA sequencing step on the way from
      finished genomic sequence to mutation detection in gene-hunting projects. Because
      SST data can be obtained in a highly parallel and inexpensive way, SST technology
      has a potential of complementing EST technology for gene hunting.

PMID- 10587945
TI  - Phylogenetic analyses of proton-translocating transhydrogenases.
AB  - The proton-translocating nicotinamide nucleotide transhydrogenases (TH) provide a
      simple model for understanding chemically coupled transmembrane proton
      translocation. To further our understanding of TH structure-function
      relationships, we have identified all sequenced homologous of these vectorial
      enzymes and have conducted sequence comparison studies. The NAD-binding domains
      of TH are homologous to bacterial alanine dehydrogenases (ADH) and eukaryotic
      saccharopine dehydrogenases (SDH) as well as N5(carboxyethyl)-L-ornithine
      synthase of Lactococcus lactis and dipicolinate synthase of Bacillus subtilis. A
      multiple alignment, a phylogenetic tree, and two signature sequences for this
      family, designated the TH-ADH-SDH or TAS superfamily, have been derived.
      Additionally, the TH family has been characterized. Phylogenetic analyses
      suggested that these proteins have evolved without inter-system shuffling.
      However, interdomain splicing-fusion events have occurred during the evolution of
      several of these systems. Analyses of the multiple alignment for the TH family
      revealed that domain conservation occurs in the order: NADP-binding domain
      (domain III) > NAD-binding domain (domain I) > proton-translocating transmembrane
      domain (domain II). A topologic model for the proton-translocating transmembrane
      domain consistent with published data is presented, and a possible involvement of
      specific transmembrane alpha-helical segments in channel formation is suggested.

PMID- 10587946
TI  - Computational analysis of the polymorphic membrane protein superfamily of
      Chlamydia trachomatis and Chlamydia pneumoniae.
AB  - Whole sequence genome analysis is invaluable in providing complete profiles of
      related proteins and gene families. The genome sequences of the obligate
      intracellular bacteria Chlamydia trachomatis and Chlamydia pneumoniae both encode
      proteins with similarity to several 90-kDa Chlamydia psittaci proteins. These
      proteins are members of a large superfamily, C. trachomatis with 9 members and C.
      pneumoniae with 21 members. All polymorphic membrane protein (Pmp) are
      heterogeneous, both in amino acid sequence and in predicted size. Most proteins
      have apparent signal peptide leader sequences and hence are predicted to be
      localized to the outer membrane. The unifying features of all proteins are the
      conserved amino acid motifs GGAI and FXXN repeated in the N-terminal half of each
      protein. In both genomes, the pmp genes are clustered at various locations on the
      chromosome. Phylogenetic analysis suggests six related families, each with at
      least one C. trachomatis and one C. pneumoniae orthologue. One of these families
      has seen prolific expansion in C. pneumoniae, resulting in 13 protein paralogues.
      The maintenance of orthologues from each species suggests specific functions for
      the proteins in chlamydial biology.

PMID- 10587947
TI  - Physical map and gene survey of the Ochrobactrum anthropi genome using bacterial
      artificial chromosome contigs.
AB  - Bacterial artificial chromosome (BAC) clones are effective mapping and sequencing
      reagents for use with a wide variety of small and large genomes. This report
      describes research aimed at determining the genome structure of Ochrobactrum
      anthropi, an opportunistic human pathogen that has potential applications in
      biodegradation of hazardous organic compounds. A BAC library for O. anthropi was
      constructed that provides a 70-fold genome coverage based on an estimated genome
      size of 4.8 Mb. The library contains 3072 clones with an average insert size of
      112 kb. High-density colony filters of the library were made, and a physical map
      of the genome was constructed using a hybridization without replacement strategy.
      In addition, 1536 BAC clones were fingerprinted with HindIII and analyzed using
      IMAGE and Fingerprint Contig software (FPC, Sanger Centre, U.K.). The FPC results
      supported the hybridization data, resulting in the formation of two major contigs
      representing the two major replicons of the O. anthropi genome. After determining
      a reduced tiling path, 138 BAC ends from the reduced tile were sequenced for a
      preliminary gene survey. A search of the public databases with the BLASTX
      algorithm resulted in 77 strong hits (E-value < 0.001), of which 89% showed
      similarity to a wide variety of prokaryotic genes. These results provide a contig
      based physical map to assist the cloning of important genomic regions and the
      potential sequencing of the O. anthropi genome.

PMID- 10587948
TI  - [Antoine Remond January 15, 1917-July 5, 1998].

PMID- 10587949
TI  - [Neurophysiological bases of the counterirritation phenomenon:diffuse control
      inhibitors induced by nociceptive stimulation].
AB  - To define the counterirritation phenomenon, we might refer to the Hippocratic
      aphorism: 'If two sufferings take place at the same time, but at different
      points, the stronger one makes the weaker silent'. On the basis of this
      clinically common observation, often used advantageously by the patients
      themselves, a number of therapeutic methods have been developed which are grouped
      under the terms counterirritation or counterstimulation. This phenomenon has not
      been scientifically analysed until recent years. Experimental results gathered
      during the last decade have shown that counterirritation phenomena have a well
      defined neural substrate both in animals and in man. In particular, they have
      proved not to rely on segmental mechanisms, but rather imply spino-bulbo-spinal
      loops involving ascending pathways in the anterolateral spinal columns,
      integration in the lower brain stem, and descending influences reaching dorsal
      horn neurons via the dorsolateral quadrant. The results also suggest that the
      study of counterirritation is essential for accessing the physiology of
      nociception and pain control. The very existence of the counterirritation
      phenomenon is the easiest demonstrable index of a specific system for pain
      modulation in man. Besides its scientific interest, the elucidation of its
      neurophysiological bases has clinical importance, in as much as it may ameliorate
      our understanding of certain pain syndromes and contribute to the development of
      new investigative and therapeutic procedures.

PMID- 10587950
TI  - [Operculo-insular responses to nociceptive skin stimulation in humans. A review
      of the literature].
AB  - CO2 laser stimulation selectively activates the endings of small myelinated A
      delta fibers, involved with non-myelinated C fibers in the processing of
      nociceptive information. Thus, potentials evoked by CO2 laser stimulation reflect
      the activation of cortical areas receiving inputs from the spinothalamic tract.
      In this article we review data on the early pain-related CO2 laser evoked
      potentials recorded on the scalp, or by intracortical electrodes, during
      presurgical assessment of patients with drug-resistant epilepsy. A combination of
      surface and depth recordings allows the description of early cortical pain
      responses in terms of latency, polarity and scalp topography. Such a technique
      also allows the localization of the anatomical generators of these early
      responses using dipolar source modeling of scalp-recorded evoked potentials, or
      intracortical recordings, in stereotactical conditions. The earliest response
      recorded on the scalp to CO2 laser stimulation was an N1-P1 dipolar potential
      field at a latency of 140-200 ms. The N1 and P1 maximal voltages are recorded in
      the temporal region contralateral to stimulation and mid-frontal region,
      respectively. Intracerebral electrodes record an activation of a dipolar cortical
      source in the same latency range located in the upper bank of the sylvian
      fissure, corresponding to the second somatosensory (SII) area ipsi- and
      contralateral to the stimulation and insular cortex. The SII-insular responses
      ipsilateral to stimulation are likely to be triggered via transcallosal fibers
      coming from the opposite SII area. The operculo-insular cortex contralateral to
      stimulation, activated through direct thalamocortical projections, is likely to
      represent the first step in the cortical processing of peripheral A delta fiber
      pain inputs.

PMID- 10587951
TI  - Determination of nerve conduction velocity of C-fibres in humans from thermal
      thresholds to contact heat (thermode) and from evoked brain potentials to radiant
      heat (CO2 laser).
AB  - This study was designed to estimate and compare nerve conduction velocity (NCV)
      of cutaneous heat-sensitive C-fibres obtained using two methods. The first is a
      method based on reaction times to different rates of temperature change produced
      by a large contact thermode (Thermotest). The second is a novel method based on
      ultra-late-evoked brain potentials to CO2 laser stimuli with tiny beam sections
      (< 0.25 mm2), allowing selective and direct activation of very slow conducting
      afferents. Both methods were applied on three sites of the right leg (foot, knee
      and thigh) of ten healthy subjects. When based on the reaction times to contact
      heat, NCV estimations were 0.4 +/- 0.22 m/s for the proximal segment (knee-thigh)
      and 0.6 +/- 0.23 m/s for the distal segment (foot-knee). When based on the
      difference in latency of the ultra-late positivity of laser-evoked brain
      potentials, NCV estimations were respectively 1.4 +/- 0.77 m/s and 1.2 +/- 0.55
      m/s. For both methods, the difference in NCV between proximal and distal limb
      segments was not significant. Although both methods give NCV estimations within
      the range of C-fibres, the systematic difference between NCV obtained from each
      method may result from the activation of subpopulations of C-fibres with
      different NCV depending on the method of stimulation (low-threshold thermal
      receptors by the thermode and thermal nociceptors by the CO2 laser). Considering
      the difficulty of investigating peripheral fibres with slow conduction velocities
      (C-fibres) in humans, the methods used in the present study may be useful tools
      in both experimental and clinical situations.

PMID- 10587952
TI  - The pain-related negative difference potential: a direct measure of central pain
      pathway activity or of interactions between the innocuous somatosensory and pain
      pathways?
AB  - Negative difference potential (NDP) is a sural nerve-evoked scalp potential
      derived by subtracting potentials elicited at the pain threshold level from those
      elicited at supra-pain threshold levels. Our recent work examined the possibility
      that the NDP reflects a pain-related inhibition of neurons in the innocuous
      somatosensory pathways. Although failing to find any evidence for this
      inhibition, these studies do present the possibility that the NDP reflects an
      attention- and/or task-related decrease in the innocuous somatosensory activity
      that is elicited by the noxious electrical stimulus. To test this hypothesis, 35
      healthy subjects were given three attention/task relevance conditions presented
      in counterbalanced order: rate the subjective magnitude of the painful aspects of
      the noxious electrical stimulus; rate the subjective magnitude of the non-painful
      aspects of the noxious electrical stimulus; and, ignore the stimulus. Neither
      changes in attention nor the task relevance of the non-painful aspects of the
      stimulus had any effect on NDP amplitude. These data demonstrate that the NDP
      does not reflect an attention- or task-related modulation of innocuous
      somatosensory activity. Rather, our evidence to date suggests that the NDP is
      generated by activity in the central pain pathways.

PMID- 10587953
TI  - [From cathodic tube to digitalized electromyography: a brief story of
      electromyography in France].
AB  - This article covers the stages of the development of electromyography in France,
      since the founding works of Lerique [4], the first publications of the "Societe
      d'EEG et des sciences connexes de langue francaise" (1948), the first
      international meeting (Strasbourg, 1960), the French-speaking meeting on
      electromyography which is now being held every other year. It also deals with the
      difficulties of registering and interpreting the first recordings and the
      considerable help brought by the improvement in electronics and computer
      sciences.

PMID- 10587954
TI  - Nonstress testing and contraction stress testing.
AB  - Antepartum fetal heart rate (FHR) testing, including the nonstress test and
      contraction stress test, has evolved in clinical usage over the past 3 decades.
      Although the nonstress test has become a standard of care in high-risk pregnancy,
      it has been modified by the use of fetal stimulation (vibroacoustic stimulation)
      and the addition of automated fetal movement recording (actocardiotocography). In
      all of its formats, antepartum FHR testing has been associated with reduction of
      preventable fetal loss. More recently, there have been attempts to improve test
      efficacy by computer-enhanced approaches.

PMID- 10587955
TI  - Fetal biophysical profile.
AB  - This article begins with an outline of the theoretic basis of the fetal
      biophysical profile, the method for the biophysical profile score (BPS), and the
      timing and frequency of testing. The article further discusses the clinical
      management based on test scores; modified methods of the BPS; and clinical
      application, predictive accuracy, and impact on outcome of BPS. The authors
      specifically examine the relationship between BPS and cerebral palsy. They
      conclude with a discussion of adult sequelae and fetal adaptation to asphyxia.

PMID- 10587956
TI  - Amniotic fluid volume assessment in singleton and twin pregnancies.
AB  - The best method of ultrasonic mensuration to identify abnormal AFV reliably in
      singletons and the individual sacs of diamniotic twins remains elusive. With
      respect to twins, localization of the dividing membrane seems to be necessary for
      AFV assessments of each amniotic cavity. The relationship of ultrasonic
      estimates, actual AFV, and pregnancy outcome remains undetermined. In the
      authors' opinion, the subjective assessment in twin gestation may be as accurate
      as semiquantitative ultrasonic estimates of AFV, similar to the situation in
      singleton pregnancies. The authors propose that further prospective research
      address the following questions: (1) What is the appropriate threshold for
      intervention when AFI decreases to lower ranges? (2) What other factors (e.g.,
      cervical examination, fetal heart rate patterns, underlying obstetric conditions,
      fetal growth pattern) are important when the AFI falls to low values in making
      clinical decisions?

PMID- 10587957
TI  - Vascular Doppler techniques.
AB  - Doppler ultrasound used for the assessment of the fetal umbilical circulation in
      the human pregnancy has been reported in the scientific literature since the
      early 1980s and has been rigorously evaluated by randomized, controlled trials.
      The consensus of the reviewers of these trials is that there do appear to be
      grounds for including umbilical artery Doppler ultrasound studies in the
      management of high-risk pregnancies. There is no apparent benefit for low-risk
      pregnancies or later gestation. Other fetal vascular beds are currently
      undergoing prospective studies and some limited randomized, controlled trials
      have been reported; but to date they are not at a point of development to be
      considered part of clinical management.

PMID- 10587958
TI  - Fetal movement counts.
AB  - Monitoring fetal movement serves as an indirect measure of central nervous system
      integrity and function. The coordination of whole body movement in the fetus,
      which requires complex neurologic control, is similar to the coordination of
      movement in the preterm newborn infant. Short-term observations of the fetus are
      best performed using real-time ultrasound imaging or Doppler ultrasound. Daily
      fetal kick counting by the compliant gravida is a worthwhile adjunct in
      determining the need for fetal surveillance tests in the office and in predicting
      abnormal FHR patterns and perhaps impending stillbirth. Monitoring has its
      greatest value when placental insufficiency is long-standing; its routine role in
      low-risk pregnancies requires further clinical investigation. The presence of a
      vigorous fetus is reassuring. Perceived inactivity requires a reassessment of any
      underlying antepartum complication and a more precise evaluation by FHR testing
      or real-time ultrasonography before delivery is considered.

PMID- 10587959
TI  - Intrapartum fetal heart rate monitoring.
AB  - Intrapartum fetal heart rate monitoring is commonly used to evaluate fetal status
      in labor, despite a lack of convincing randomized studies to support its use. The
      National Institutes of Health have helped standardize fetal heart rate monitoring
      terminology with their 1997 task force report, which will aid clinicians and
      scientists in their goal of providing quality care and research. The American
      College of Obstetricians and Gynecologists has recommended the term nonreassuring
      fetal status for electronic fetal monitor patterns that are not normal; however,
      Vanderbilt continues to use the terms fetal stress and fetal distress, using
      specific criteria for each. The approximately 30% of fetal heart rate tracings
      labeled as fetal stress (or nonreassuring fetal status) can be evaluated further
      by the use of fetal pulse oximetry, a new technology currently under evaluation
      in this country.

PMID- 10587960
TI  - Scalp blood gas analysis.
AB  - The use of fetal blood sampling has been advocated widely to improve the
      specificity of fetal heart rate monitoring, but it remains a clinically unpopular
      procedure. This article considers its physiologic rationale and evidence base. It
      includes descriptions of the technique with suggestions for improved clinical
      interpretation and discusses the efficacy of fetal blood sampling with some
      consideration of possible alternatives.

PMID- 10587961
TI  - Vibroacoustic and scalp stimulation.
AB  - Both VAS and scalp stimulation are useful in the evaluation of fetal compromise
      by decreasing the number of falsely abnormal FHR tests and limiting the number of
      unnecessary interventions, thus improving the efficiency of antepartum and
      intrapartum FHR monitoring. As is true for all types of fetal assessment using
      FHR monitoring, VAS and scalp stimulation have limitations, and a lack of
      response to these methodologies does not necessarily indicate fetal acidemia.
      When either VAS or scalp stimulation is employed, one must take into
      consideration their respective predictive values (see Table 1). Fetal VAS or
      scalp stimulation should be considered as one facet of comprehensive fetal
      evaluation. When these techniques are used in this manner, the clinician
      evaluating the fetus in the antepartum or intrapartum period may prevent
      unnecessary intervention and improve maternal and neonatal outcome.

PMID- 10587962
TI  - Continuous intrapartum pH, pO2, pCO2, and SpO2 monitoring.
AB  - The goal of intrapartum surveillance and its further development is better
      patient care for both the fetus and the gravida. A normal FHR pattern is usually
      associated with the delivery of a normal well-oxygenated infant; however, a
      nonreassuring FHR is not always associated with the delivery of a compromised
      infant. This situation has led to an increase in unnecessary obstetric
      interventions in the form of a rising cesarean section rate. Fetal scalp sampling
      was developed in an attempt to improve the predictive value of electronic FHR
      monitoring, but because this technique is not widely used, management decisions
      are frequently made using FHR patterns alone. Much research has been performed in
      the search for a continuous biochemical measurement of fetal status, including
      continuous pH, pO2, or pCO2 and various combinations of these methodologies. None
      of these measurements are used in current clinical practice, mainly owing to
      technical problems and difficulties associated with the continuous direct
      measurement of these parameters in fetal blood throughout labor. The promising
      new field of fetal pulse oximetry has the potential to provide reliable,
      meaningful, and reproducible data as shown in early cross-sectional studies and
      more recent longitudinal studies. By identifying developing hypoxia, this
      technology may reduce the uncertainty associated with electronic FHR monitoring.
      Fetal pulse oximetry may also provide critical information relating to the
      detection and management of the hypoxic fetus. Any new method of intrapartum
      fetal monitoring requires careful evaluation to assess its potential value before
      its introduction into clinical practice. The use of fetal SpO2 monitoring in the
      presence of a nonreassuring FHR pattern is being examined in a multicenter
      randomized controlled trial. This study will address the question of whether
      supplementary monitoring of fetal SpO2 levels can lead to a reduction in the
      cesarean section rate for fetal distress. The available data on fetal noninvasive
      pulse oximetry have been obtained from a combination of well-designed cohort
      studies (level II-2 evidence) or from earlier multiple time series (level II-3
      evidence). The results from the US Multicenter Trial (level I evidence) should
      provide a significant addition to current evidence. A continuous fetal
      noninvasive monitor measuring fetal oxygenation directly could lead to an
      improvement in the sensitivity and specificity of fetal surveillance. This
      improvement could ultimately result in a reduction in unnecessary interventions
      by differentiating hypoxic fetuses from nonhypoxic fetuses and, more importantly,
      may lead to earlier intervention for fetuses in danger of serious compromise.

PMID- 10587963
TI  - Umbilical cord blood gas analysis.
AB  - Umbilical cord blood gas and pH values should always be obtained in the high-risk
      delivery and whenever newborn depression occurs. This practice is important
      because umbilical cord blood gas analysis may assist with clinical management and
      excludes the diagnosis of birth asphyxia in approximately 80% of depressed
      newborns at term. The most useful umbilical cord blood parameter is arterial pH.
      Sampling umbilical venous blood alone is not recommended because arterial blood
      is more representative of the fetal metabolic condition and because arterial
      acidemia may occur with a normal venous pH. A complete blood gas analysis may
      provide important information regarding the type and cause of acidemia and
      sampling the artery and vein may provide a more clear assessment. The sampling
      technique is simple and easily mastered by any treatment person in the delivery
      room. Preheparinized syringes ensure a consistent dose and amount of heparin.
      Depending on how normality is defined and on the population studied, normal
      ranges for umbilical cord blood gas values vary (see Table 1). In general, the
      lower range for normal arterial pH extends to at least 7.10 and that for venous
      pH to at least 7.20. Many different factors during pregnancy, labor, and delivery
      can affect cord blood gases. Umbilical blood sampling for acid-base status at all
      deliveries cannot be universally recommended because many facilities do not have
      the capabilities to support such a practice and in doing so may impose an
      excessive financial burden. Considering the costs, the accumulated published
      data, and the nonspecificity of electronic fetal monitoring in the evaluation of
      fetal oxygenation, it may be more rational to implement universal cord blood gas
      analysis. Care providers and institutions with the logistical capabilities in
      place should consider the cost efficacy of routine cord blood gas analysis
      because it is the gold standard assessment of uteroplacental function and fetal
      oxygenation/acid-base status at birth.

PMID- 10587964
TI  - Proceedings of the Conference on Marrow Transplantation in Children. Palm Beach,
      Florida, USA. 25-27 June 1998.

PMID- 10587965
TI  - Fixing the intestinal mucosa in the bone marrow transplant patient: lessons from
      other intestinal immunodeficiencies and inflammatory disorders.
AB  - Gastrointestinal inflammation is common following bone marrow transplantation.
      Key pathogenetic events, such as major histocompatibility complex (MHC)
      expression on intestinal epithelial cells and local production of cytokines in
      the gastrointestinal mucosa, are common features of many gastrointestinal
      inflammatory disorders. Drawing from clinical experience of the treatment of
      other disorders associated with gastrointestinal inflammation, such as ulcerative
      colitis and Crohn's disease, a number of therapeutic alternatives may be relevant
      for the bone marrow transplant patient with significant graft-vs.-host disease
      (GvHD). Options to consider include therapeutics that alter inflammatory cell
      migration, anti-inflammatory cytokines, direct neutralization of proinflammatory
      cytokines, and cytokines that promote epithelial restitution in the
      gastrointestinal mucosa. In addition, a variety of nutritional and other novel
      treatments are available, which may improve epithelial function or which have
      anti-inflammatory actions. Prospective studies of combined nutrient and cytokine
      modulating treatments for the bone marrow transplant patient are warranted.

PMID- 10587966
TI  - Immunological recovery post-hematopoietic stem cell transplantation: role of
      prophylactic prevention of infection in post-transplant period.
AB  - Immunological recovery post-hematopoietic stem cell transplantation is variable.
      This depends upon the type of transplantation, source of hematopoietic stem cells
      for transplantation, prophylactic treatment for graft-versus-host disease and
      ongoing therapy for the treatment of graft-versus-host disease with
      immunosuppressive agents. Periodic numerical and functional assessment of
      recovery of the immune system after transplantation can identify the patients
      with inadequate immune system who are at risk for development of infectious
      complications. These patients should receive prophylactic therapy to decrease
      infection-related morbidity and mortality associated with transplantation
      procedures.

PMID- 10587967
TI  - Leukocyte-reduction to prevent transfusion-transmitted cytomegalovirus
      infections.
AB  - Certain infectious organisms, including cytomegalovirus, are associated
      'exclusively' with blood leukocytes (WBC), and their transmission by transfusion
      is strikingly diminished by marked WBC-reduction of cellular blood components.
      Based on several reports of WBC-reduction, it is clear that the risk of CMV is
      nearly eliminated by consistently removing WBC to a level < 1-5 x 10(6) WBCs/unit
      (< or = 1 x 10(6) preferred in Europe; < or = 5 x 10(6) in the United States).
      Alternatively, the rate of CMV infections is reduced by transfusing blood
      components collected from donors negative for CMV antibody. However, neither
      technique is perfect, with a failure rate of 1-4%. Although WBC-reduction is
      favored by many experts, practitioners must choose the method that they believe
      to be most efficacious--being mindful that data do not exist to establish
      additive protection by combining WBC-reduction and transfusion of blood
      components collected from antibody negative donors.

PMID- 10587968
TI  - Stem-cell transplant preparative regimens.
AB  - Owing to the relatively high probability of recurrent disease in patients
      receiving hematopoietic stem-cell transplantation (HSCT) for malignancies,
      further development of new preparative regimens is warranted. Based on the data
      presented, one can predict that it will continue to be difficult to identify HSCT
      regimens that are more effective. Incremental improvements are expected to be
      small, difficult to measure, and will require inclusion of very large numbers of
      patients. Controlled trials to evaluate the effectiveness of specific treatment
      regimens for specific groups of patients will require only centers with large
      numbers of patients or co-operative groups to successfully conduct these studies.
      Development of HSCT regimens with low mortality and a minimum of morbidity
      without compromising efficacy are needed. This may be accomplished through the
      use of agents to protect normal, non-hematopoietic tissues from regimen-related
      toxicity (RRT), further exploration and expansion of applications of targeted
      radiolabeled antibody approaches and mixed chimerism approaches. The future holds
      much work, but great promise, in the development of new HSCT regimens.

PMID- 10587969
TI  - Allogeneic hematopoietic stem-cell engraftment and graft failure.
AB  - Two immunologically mediated reactions, the graft-versus-host (GvH) and host
      versus-graft (HvG) responses, form primary and opposing barriers to successful
      transplantation of allogeneic hematopoietic stem-cells (HSC). The HvG barrier is
      set by the strength of the allogeneic immune response, which is determined by
      antigenic stimulation provided by donor cells, owing to differences in
      histocompatibility antigens, and the capacity of host immune cells to generate a
      response. Risk of graft failure must be viewed as the interplay of multiple
      factors, including degree of human leukocyte antigen and minor histocompatibility
      antigen disparity, capacity of host immune response, and the capacity of donor
      hematopoietic and immunologic cells for overcoming residual host immunity.

PMID- 10587970
TI  - Hepatic veno-occlusive disease.
AB  - Hepatic veno-occlusive disease (VOD) after stem cell transplantation is a toxic
      manifestation of the conditioning regimen most probably emphasized by the
      allogeneic reaction. Its overall mortality rate is < 4% in adults as well as in
      children. Recent progress has been achieved in the diagnosis of this
      complication. However, better methods of both prophylaxis and treatment are
      needed.

PMID- 10587971
TI  - Can we make some general recommendations regarding immune recovery after
      hematopoietic reconstitution preceded by ablative therapy?
AB  - Children undergoing marrow transplantation have compromised immune systems for
      variable periods of time after transplant. A number of methods have been utilized
      to assess recovery of the immune system. Four recommendations are made in regards
      to the testing that should be done, when the testing should be done, when
      immunizations should be provided and when antibiotic and other infection
      prophylaxis can be reduced.

PMID- 10587972
TI  - Graft-vs.-malignancy with allogeneic blood stem cell transplantation: a potential
      primary treatment modality.
AB  - The high-dose chemotherapy and radiation typically used as the preparative
      regimen for bone marrow transplantation produces considerable morbidity and
      mortality. An alternative strategy is to utilize a low-dose, non-myeloablative,
      preparative regimen designed not to eradicate the malignancy, but to provide
      sufficient immunosuppression to achieve engraftment of an allogeneic
      hematopoietic graft and allow subsequent development of a graft-vs.-malignancy
      effect. We studied this approach in patients who were ineligible for standard
      myeloablative preparative regimens because of advanced age or comorbidities and
      demonstrated that purine analog (fludarabine or 2-CDA) containing non
      myeloablative chemotherapy allows engraftment of HLA-compatible hematopoietic
      progenitor cells, and extended remissions were observed in approximately half of
      chemosensitive patients with recurrent AML or CML. Patients with CLL or lymphoma
      have been effectively treated using a non-myeloablative regimen of
      fludarabine/cyclophosphamide of fludarabine, cytarabine, cisplatin. This
      chemotherapy is known to be non-myeloablative and mixed chimerism was
      anticipated. All patients with engraftment have responded and 67% have achieved
      complete remission. Maximal responses are slow to develop and occur gradually
      over a period of several months to one year. Long-term efficacy must still be
      determined and controlled trials are necessary comparing this approach with
      alternative therapies as well as standard transplantation regimens.

PMID- 10587973
TI  - T-cell recovery following marrow transplant: experience with delayed lymphocyte
      infusions to accelerate immune recovery or treat infectious problems.
AB  - All forms of hematopoietic stem-cell transplantation are complicated by delayed
      immune reconstitution, which results in an increased risk of infectious
      complications and relapse of disease. Donor lymphocyte infusions have been used
      in an attempt to enhance immune recovery and for the prevention and treatment of
      specific infections following transplantation. While there is little data to
      support the use of donor lymphocytes for the enhancement of general immune
      function post-transplant, unselected and virus-specific donor T cells may have
      efficacy for the prophylaxis and treatment of infections and disease caused by
      Epstein-Barr virus (EBV) and cytomegalovirus (CMV). While donor lymphocyte
      infusions may cause significant morbidity and mortality, they are a novel and
      potentially powerful approach for the treatment of frequently fatal post
      transplant infectious complications.

PMID- 10587974
TI  - Mobilization/harvest and transplantation with blood stem cells, manipulated or
      unmanipulated.
AB  - Collection of peripheral blood stem cells (PBSC) is very feasible without the
      risk of anesthesia or invasive multiple bone marrow aspirations, because it can
      be accomplished by modification to the standard apheresis techniques that are
      routinely used at blood centers for the collection of single donor platelets. Use
      of PBSC results in rapid and durable trilineage hematopoietic recovery after
      myeloablative chemotherapy. There has been increasing development in technology
      for cell processing ('graft engineering'), moving from the experimental to the
      clinical settings. Although peripheral blood stem cell transplantation (PBSCT)
      makes 'cell component therapy' far more effective than bone marrow
      transplantation, its advantages/disadvantages still need to be clarified in
      children. The following paper presents our pediatric experience of PBSCT.

PMID- 10587975
TI  - Intensification of therapy using hematopoietic stem-cell support for high-risk
      neuroblastoma.
AB  - The use of new strategies for dose intensification using peripheral blood stem
      cell or autologous purged bone marrow rescue has raised expectations for cure in
      advanced neuroblastoma, although conflicting reports exist regarding the efficacy
      of these approaches. Using risk groups based on both biological and clinical
      staging, the Children's Cancer Group and the Pediatric Oncology Group have agreed
      upon common prognostic criteria for treatment stratification. We summarize below
      the prognostic classification and treatment approaches that have improved the
      overall outcome for children with advanced neuroblastoma. Intensive induction
      therapy, myeloablative therapy, hematopoietic stem cell purging, and post
      transplant therapy for minimal residual disease all have an important role in the
      treatment. Possible future improvements may incorporate more tumor-specific
      therapy with targeted radiotherapy, monoclonal antibodies, tumor vaccines, and
      differentiating agents.

PMID- 10587976
TI  - High-dose therapy with stem cell rescue for pediatric solid tumors: rationale and
      results.
AB  - Metastatic and recurrent pediatric solid tumors usually respond to chemotherapy
      but are likely to recur. Because of steep dose-response relationships, HDT
      requiring hematopoietic rescue may improve outcome. This strategy has recently
      been shown to be effective for metastatic neuroblastoma. Metastatic Ewing's
      sarcoma appears to be a closely analogous situation, and promising phase II
      studies suggest that a definitive trial of efficacy would be appropriate. Phase I
      or II trials remain appropriate and are needed to define further the efficacy of
      HDT for most other poor prognosis pediatric solid tumors.

PMID- 10587977
TI  - The role of high-dose chemotherapy and stem cell rescue in the treatment of
      malignant brain tumors: a reappraisal.
AB  - The outcome for children with malignant brain tumors has improved modestly in
      recent years. Notable is the improved 5-yr disease-free survival for those
      children with 'standard-risk' medulloblastoma and other primitive neuro
      ectodermal tumors (PNET) (i.e. tumors without neuraxis dissemination at
      presentation). For other children with newly diagnosed malignant brain tumors,
      especially in the absence of radical surgical resection, the outcome remains poor
      despite surgery, irradiation and conventional chemotherapy. Patients whose tumors
      recur despite initial therapy continue to experience a dismal outlook with these
      conventional strategies of treatment. In an attempt to improve the outlook for
      such brain tumor patients with poor prognoses, strategies utilizing high-dose
      (potentially myeloablative) chemotherapy with autologous stem cell rescue have
      been developed. These studies, conducted initially in patients with recurrent
      tumors, were then extended to patients with newly diagnosed malignant gliomas and
      brain-stem tumors, as well as to young children with various malignant brain
      tumors at diagnosis in an attempt to avoid irradiation to the brain. The results
      of several of these studies are summarized, updating information reviewed in an
      earlier summary in 1996, demonstrating durable disease-free survival for a
      proportion of patients with recurrent malignant gliomas and
      medulloblastomas/PNET, as well as encouraging data in some of those patients with
      newly diagnosed brain tumors.

PMID- 10587978
TI  - Post-transplant immunotherapy designed to prevent cancer recurrence.
AB  - Most stem cell transplants are performed to treat neoplasms. Yet many patients
      survive the transplant but die from cancer recurrence post-transplant. The
      incorporation of post-transplant immunotherapy offers the potential for enhanced
      antitumor efficacy.

PMID- 10587979
TI  - Human malignant osteopetrosis: pathophysiology, management and the role of bone
      marrow transplantation.
AB  - Osteopetrosis is a heterogeneous group of diseases characterized by lack of
      osteoclast function. Osteopetrosis is found spontaneously in most mammalian
      species and many transgenic animals have been created, but so far no animal model
      has been found that genetically corresponds to human malignant autosomal
      recessive osteopetrosis. The only curative treatment for malignant osteopetrosis
      is bone marrow transplantation. A review of the literature and preliminary data
      from IBMTR shows that infants transplanted with marrow from an HLA-identical
      sibling or unrelated volunteer donor have an actuarian five-year survival with a
      functioning graft of 50-70%, while those transplanted with a T-cell-depleted
      mismatched marrow have a very poor survival of only about 10%.

PMID- 10587980
TI  - Acute lymphoblastic leukaemia: whom and when should we transplant?
AB  - To date, the evidence upon which a decision is made to transplant a child with
      acute lymphoblastic leukaemia either in first or subsequent remission has rarely
      been based on randomized trial data. Modern era management of infection and graft
      versus-host disease lessens risks but procedure-related deaths still remain
      higher than with chemotherapy alone. However, disease control appears superior
      with successful bone marrow transplantation (BMT). The critical need is for
      international consensus on who is at such great risk of recurrent disease that
      BMT is required (from no matter what donor source) and conversely those for whom
      transplantation is not needed to achieve long-term cure.

PMID- 10587981
TI  - Gene therapy of genetic diseases and cancer.
AB  - The scope of gene transfer applications in human therapy has expanded enormously
      over the last 15 years to include not only several types of genetic diseases but
      also a variety of genetic approaches to the treatment of cancer. Hematopoietic
      stem cells have been considered excellent targets for therapeutic gene transfer
      because of their capacity for self-renewal and for differentiation into multiple
      cellular lineages. Retrovirus-mediated gene transfer has been tested for
      treatment of diseases that specifically affect the hematopoietic system, such as
      adenosine deaminase deficiency and chronic granulomatous disease. Storage
      disorders such as Gaucher disease, Hurler syndrome and Hunter syndrome, genetic
      deficiencies that affect a broad range of tissue types, may also be amenable to
      treatment by gene transfer into hematopoietic cells, owing to the release of
      enzyme expressed in transduced cells with subsequent uptake by untransduced cells
      ("metabolic cross-correction"). Hematopoietic stem cells may also be targeted for
      introduction of drug-resistance genes for the purpose of protecting normal
      tissues from the toxic side-effects of cancer chemotherapeutic agents, thus
      allowing more effective antitumor chemotherapy. The danger of introducing drug
      resistance function into tumor cells may be dealt with by including sequences
      specifically designed to reduce expression of oncogenes or to restore expression
      of tumor suppressor genes. Current limitations on the efficiency of gene transfer
      into hematopoietic stem cells may be alleviated by the development of new vector
      systems such as adeno-associated virus or lentivirus vectors, or by advances in
      cell processing that render hematopoietic cells more susceptible to transduction.
      Drug-resistance genes may also be applied for in vivo selection to expand the
      representation of a small proportion of transduced hematopoietic cells. These
      approaches toward increasing the frequency of hematopoietic cell transduction
      contribute to the anticipated feasibility of gene therapy for genetic diseases
      and cancer.

PMID- 10587982
TI  - Long-term follow-up in hematopoietic stem-cell transplant patients.
AB  - Hematopoietic stem-cell transplantation (HSCT) has increasingly become an
      accepted treatment for many childhood diseases and disorders. Potential HSCT
      recipients can be children with hematological malignancies or solid tumors, as
      well as congenital and acquired disorders. In the past decade, the use of HSCT in
      the treatment of pediatric disorders has grown exponentially while advances in
      supportive care have improved survival rate, contributing to a rapidly growing
      population of transplant survivors. Although numerous similarities can be found
      between pediatric and adult long-term HSCT survivors, this article provides a
      brief overview of the pediatric patients, emphasizing the aspects of surveillance
      and late effects. Understanding the long-term complications that can occur after
      HSCT is important in determining the appropriate evaluations and medical
      treatment for the patient involved. The goal of this article is to assist
      caregivers in providing optimal care for long-term survivors of HSCT. The initial
      section of this work comprises the three major causes of late effects in HSCT. It
      will then encompass a system review of the different potential complications that
      are seen with HSCT.

PMID- 10587983
TI  - Improving treatment for persons with schizophrenia.
AB  - The time has come for the development of standards to ensure quality and cost
      effective care for the treatment of persons with schizophrenia. Advances in
      understanding the efficacy of treatments for schizophrenia, the promise of new
      treatment advances derived from a rapidly evolving neuroscience, pressures to
      contain health care costs while maintaining or increasing quality, and the growth
      of advocacy on behalf of persons with schizophrenia are driving this need. The
      evidence for the efficacy of pharmacotherapies, psychological interventions,
      family interventions, vocational rehabilitation, and case management and
      assertive community treatment is substantial, yet many patients do not receive
      treatments consistent with this evidence. Service systems must do much more to
      ensure that efficacious treatments are available, that both effectiveness and
      costs are considered in the allocation of resources, and that evaluative systems
      are in place to promote on-going quality improvement to provide the best care.

PMID- 10587984
TI  - Symptom assessment in schizophrenic prodromal states.
AB  - Individuals who develop schizophrenia often suffer long standing deficits. All
      too often available treatments remain palliative and do not improve the long-term
      course of illness. The neurobiological deficits associated with the onset of
      schizophrenia may be most active and damaging in the early stages of this life
      long illness, a fact which has shifted the focus of research and clinical work
      toward the early or prodromal stages of this disorder. Results from limited
      studies suggest that early intervention may lead to a better prognosis. Early
      interventions that could delay or prevent the onset of psychotic illnesses have
      obvious public health implications and rely on being able to identify true
      prodromal patients. The Structured Interview for Prodromal Symptoms and the Scale
      of Prodromal Symptoms are assessment instruments developed for operationally
      defining diagnosis and for quantitatively rating symptom severity for patients
      prodromal for psychosis.

PMID- 10587985
TI  - Research on the individual placement and support model of supported employment.
AB  - This paper reviews research on the Individual Placement and Support (IPS) model
      of supported employment for people with severe mental illness. Current evidence
      indicates that IPS supported employment is a more effective approach for helping
      people with psychiatric disabilities to find and maintain competitive employment
      than rehabilitative day programs or than traditional, stepwise approaches to
      vocational rehabilitation. There is no evidence that the rapid-job-search, high
      expectations approach of IPS produces untoward side effects. IPS positively
      affects satisfaction with finances and vocational services, but probably has
      minimal impact on clinical adjustment. The cost of IPS is similar to the costs of
      other vocational services, and cost reductions may occur when IPS displaces
      traditional day treatment programs. Future research should be directed at efforts
      to enhance job tenure and long-term vocational careers.

PMID- 10587986
TI  - Competency to consent to treatment.
AB  - Competency to consent to treatment is an especially critical determination to
      make in the field of psychiatry. Psychiatric patients are often capable, despite
      their illness, of self-advocacy. Careful assessments are required to
      differentiate competent patients from incompetent patients. Moreover, the
      character of their illness, from psychosis to organic brain disease, has been
      found to correlate with a lack of competency. The presence of auditory
      hallucinations or delusions, however, are not pathognomonic of incompetency.
      Currently, there exists no standardized method to establish competency, either in
      psychiatric or in medical patients. This is a review of the several instruments
      developed by various researchers attempting to create one. It finds promise in
      several questionnaires that have good inter-rater reliability and validity.

PMID- 10587987
TI  - Body dysmorphic disorder and depression: theoretical considerations and treatment
      strategies.
AB  - Body dysmorphic disorder (BDD), also known as dysmorphophobia, consists of a
      distressing and impairing preoccupation with an imagined or slight defect in
      appearance. BDD is an underrecognized and relatively common disorder that is
      associated with high rates of occupational and social impairment,
      hospitalization, and suicide attempts. BDD is unlikely to simply be a symptom of
      depression, although it often coexists with depression and may be related to
      depression. It is important to recognize BDD in depressed patients, because
      missing the diagnosis can result in refractory BDD and depressive symptoms.
      Available data indicate that BDD may not respond to all treatments for depression
      and may instead respond preferentially to serotonin-reuptake inhibitors. In
      addition, lengthier treatment trials than those required for depression may be
      needed to successfully treat BDD and comorbid depression. It can be difficult and
      challenging to diagnose BDD in depressed patients because the symptoms are often
      concealed due to embarrassment and shame. This paper discusses the relationship
      between BDD and depression and discusses practical strategies for recognizing and
      treating BDD and depressive symptoms in patients with depression.

PMID- 10587989
TI  - [A new approach to addictive behavior].

PMID- 10587988
TI  - When are psychotherapy and pharmacotherapy combinations the treatment of choice
      for major depressive disorder?
AB  - Treating major depressive disorder with the combination of psychotherapy and
      pharmacotherapy is highly valued by both psychiatrists and their patients.
      However, results of most systematic research studies suggest that this approach
      may be overvalued: evidence of additive benefits (in relation to the respective
      component therapies, alone) is meager. In this paper it is argued that the
      advantage of combined treatment may be limited to treatment of patients with more
      complex depressive disorders, including characteristics such as comorbidity,
      chronicity, treatment resistance, episodicity, and severity. Said another way,
      milder acute depressions, especially initial or sporadic episodes, probably do
      not warrant the routine use of psychotherapy and pharmacotherapy. By focusing
      attention on the patient subgroups most likely to show a true additive response
      to combined treatment, it may be possible to obtain maximum benefits from
      dwindling resources.

PMID- 10587990
TI  - [Incidence and management of male urethritis in the district of Tunis].
AB  - BACKGROUND: The aim of the study was to evaluate the incidence of male urethritis
      and the relative frequency of the different etiological agents in order to adapt
      standard case management. METHODS: The incidence of urethritis has been estimated
      with a postal study made on a sample of druggists (1/10) of the area. The total
      observation period was four weeks. The relative frequency of the etiological
      agents and the positive predictive value (PPV) of the therapeutic approach based
      on antibiotic treatment of gonorrhoea and Chlamydia trachomatis was achieved on
      92 cases of male urethritis attending general physicians in two polyclinics.
      RESULTS: The annual incidence of male urethritis was estimated at 680 per
      100,000. The relative frequency of etiological agents was as 34.7% for Neisseria
      gonorrhoea, 7.6% for Chlamydia trachomatis and was found at 3.3% for Trichomonas
      vaginalis; the PPV was only 43% because of the high proportion of negative
      results reported by the laboratory. CONCLUSION: Gonococcal urethritis incidence
      tends to decrease regarding non gonococcal urethritis and the therapeutic
      approach appears to be warranted.

PMID- 10587991
TI  - [Study of the incidence of giardiasis in Quebec (Canada) and association with
      drinking water source and quality].
AB  - BACKGROUND: We analyzed data from the notifiable diseases data base in Quebec to
      document the incidence of giardiasis. The objectives were to perform a
      descriptive analysis of the cases of giardiasis and to verify the relation
      between their incidence and the quality of drinking water. METHODS: The Quebec
      notifiable diseases data-base contained 4273 cases of giardiasis declared between
      January 1st, 1990 and December 31st, 1995. Incidence rates were adjusted for age
      and calculated monthly. The sources and kinds of treatment of drinking water
      permitted to elaborate a vulnerability scale for classifying contamination by
      Giardia sp. into four categories. Incidence of giardiasis was examined in
      relation with this vulnerability scale. Other socioeconomic indicators possibly
      associated with the incidence of giardiasis were also analyzed. RESULTS: Analysis
      showed that there were few annual variations in the incidence of giardiasis and
      that there were no epidemic peaks during the study period. According to age, the
      incidence follows a bimodal pattern with a peak for young children and young
      adults. The incidence rates showed an increase of the cases at the end of summer
      and at the beginning of fall, with a higher relative risk for males. Even if no
      relation was found between the incidence of giardiasis and the vulnerability of
      the drinking water source, incidence rates were lower for people living in
      communities that use the St. Lawrence River as a drinking water source than for
      those using other sources of surface water. CONCLUSION: This study allowed us to
      obtain a good description of the cases of giardiasis declared in Quebec and to
      formulate hypothesis about their causes. The lower incidence of giardiasis in
      communities that use the St. Lawrence river as their drinking water source is
      possibly related to a lower contamination of this source. However, considering
      the limits of this work, case-control studies should be considered to understand
      variables, which influence the incidence of giardiasis in Quebec.

PMID- 10587992
TI  - [Geographic differences of bronchopulmonary cancer mortality in France and
      spatial scales of analysis: significance of scale change in health geography].
AB  - BACKGROUND: It is important to choose a valid spatial scale to study health
      differences in a geographical perspective. Many scales can be valid and a
      combination is required to understand the spatial distribution of a given health
      problem. Geographic distribution of lung cancer was studied in France using
      different scales to illustrate the importance of changing scales in health
      geography. METHODS: Standardized rates (direct method) for lung cancer were
      calculated for the period 1988-92 and mapped at different scales. RESULTS:
      Original spatial structure was observed for each scale. This proved that
      different interactions occur at each scale between environmental and social
      factors. Changing the scale allowed a better understanding of variations in the
      spatial distribution of lung cancer. CONCLUSIONS: The validity of a regional
      scale to study health geographical distributions is questioned. Changing the
      scale would allow proposing action to improve health promotion.

PMID- 10587993
TI  - [Regional differences in the compensation of pleural mesothelioma as occupational
      disease in France (1986-1993)].
AB  - BACKGROUND: Occupational exposure to asbestos is responsible for 80% at least of
      all mesothelioma in developed countries. In France there are important regional
      differences in the rate of mesothelioma compensated as occupational diseases,
      without knowing if these differences could be explained by a real difference of
      risk. The objective here is to quantify these regional differences in relation
      with the differences of level of risk. METHODS: The analysis compares, for each
      of the 16 regions of the national social security system, mortality for both
      genders and among men by pleural cancer (ICD 163) in the general population and
      mesothelioma compensated as occupational diseases during the 1986-1993 period. We
      computed for each region the number of expected compensated mesothelioma under
      the hypothesis where the regional distributions of compensated mesothelioma and
      mesothelioma deaths are the same; as well as the percentage of compensated
      mesothelioma compared to the deaths, and the variation from the national mean
      under two hypotheses, high and low; and the probability that a mesothelioma is
      compensated as an occupational disease taking as a reference the "best" region.
      RESULTS: The compensation rate differed significantly among regions (p < 0.05)
      and for men, the rate between observed and expected numbers of compensated
      mesothelioma varied from 0.15 (region of Montpellier) to 2.29 (region of Nantes),
      a ratio over 15. For all of France, the compensation rate was 25% under the best
      hypothesis. The region of Nantes compensated 61.5% of the male mesothelioma as
      occupational diseases, while the region of Montpellier and Clermont-Ferrand only
      around 5%. The probability for a mesothelioma to be compensated, compared to the
      region of Nantes, was 2.5 times less in national average, and about 10 times less
      in Montpellier and Clermont-Ferrand regions. CONCLUSION: In spite of limits
      linked to the imprecision of the available data, important regional differences
      in term of compensation of mesothelioma as occupational diseases clearly exist.
      Indications lead to think that their origin lies essentially in differences
      between physicians when considering the occupational etiology of mesothelioma,
      but differences within the system of compensation of occupational diseases can
      not be excluded. An improvement of the national statistical system concerning
      occupational diseases is highly recommendable.

PMID- 10587994
TI  - [Epidemiologic study of lead contamination of children of occupationally exposed
      parents].
AB  - BACKGROUND: As part of the screening of infantile saturnism in France, a cross
      sectional study has been conducted among 125 children with professionally lead
      exposed parents, working in two plants, both located at the edge of a rural
      village. The aim of this study was to seek a lead contamination of these children
      by their own parents, who may bring back home after work lead particles on their
      clothes, hair or skin. METHODS: These children were compared for blood lead
      levels by logistic regression to a reference group made of forty seven nursery
      school children, in these villages, without any lead exposed parents. Blood lead
      levels (< or > or = 70 micrograms/l) were performed for both children group and
      compared by logistic regression. Moreover parent's blood lead levels (< or = or >
      400 micrograms/l) and lead air concentrations measured at their own working
      places (< or = or > 100 micrograms/m3, available from occupational health
      services) were also compared to their children blood lead levels. RESULTS: Blood
      lead levels in the "exposed group" were significantly higher than in the control
      group (OR = 9.9 [3.6-27.3]), all the more so as there were several exposed people
      in children home. In the exposed group, children blood lead levels were both
      correlated with parents blood lead levels (OR = 8.3 [2.9-24.0]) and lead air
      concentration measured at their working places (OR = 4.2 [1.6-10.9]).
      CONCLUSIONS: These results suggest a lead contamination of children by their
      exposed parents, which made it necessary to strengthen individual and collective
      lead prevention measures in both plants.

PMID- 10587995
TI  - [Patterns of health care delivery and breast cancer in the department of Isere in
      1955].
AB  - BACKGROUND: Caring for cancer patients is expensive, warranting verification that
      health care organization works in a satisfactory way. A first step of this
      evaluation deals with the description of the pathway followed in the health care
      system by the patient. METHODS: 671 breast cancer cases were diagnosed in Isere
      in 1995. According to the place where each treatment (surgery, chemotherapy,
      radiotherapy) was performed, we described pathways for the patient, either
      entirely private, public or mixed. Characteristics of the patient (age, place of
      residence), of the disease (extent of disease, way of discovery) and of the
      physician (general practitioner, specialist) might have influenced the choice of
      this pathway. We described and tested the distribution of these characteristics
      within the 3 groups using univariate analysis. Relative risk of being affected to
      the private pathway compared to the public one was computed, after adjusting for
      age, type of physician, extent of disease, way of discovery and sanitary area,
      using a multivariate analysis (logistic regression). RESULTS: In the department
      of Isere, the private pathway cared for 55% of breast cancers, the public one 23%
      and the mixed one 19%. There was no preferential recruitment according to age,
      physician type, presence of metastasis or of the rural or urban residence. In
      sanitary area number 5, characterized by an important attraction of the patients
      by the nearby department of Rhone, 41% of the patients were cared for the private
      pathway, compared to 63% in sanitary area 4, where most patients were treated in
      the main town of Isere: Grenoble. After early breast cancer detection with
      mammography instead of breast cancer screening, probability of being cared for in
      the private pathway was 2-fold higher (OR = 2) than in the public one.
      CONCLUSION: In Isere department, early breast cancer detection with mammography
      is in favor of the private pathway. This is not true for physician type, neither
      for characteristics of the patient or extent of the disease. Finally, the
      distance to next department of oncology or radiotherapy plays a major role.

PMID- 10587996
TI  - [Use of a structured diagnostic interview to identify depressive episodes in an
      epidemiologic study: a posteriori internal validation].
AB  - BACKGROUND: During these last years, many structured and standardized diagnostic
      interviews have been developed in order to identify psychiatric disorders in a
      standardized way. These tools enable a systematic investigation of these
      disorders according to international classifications. Their main drawback is to
      be long. To assess the care of depression, we used a shorter and more simple
      tool: the Mini International Neuropsychiatric Interview (MINI) to identify
      depressive subjects. METHOD: The study was conducted in the Gazel cohort from the
      French National Electricity and Gas Company. A stratified sample of 2394 civil
      servants selected in order to over-represent depressive subjects was asked to
      answer to the MINI interview through a phone interview. An epidemiological and
      statistical analysis was performed to test the MINI internal validity: prevalence
      of depressive disorders using different threshold of diagnosis (number of
      symptoms required to identify someone as depressive), frequency of different
      symptoms, variability between investigators and potential biases. RESULTS:
      Respondents to the phone interview (1108 civil servants) had more often presented
      depression markers for the last 5 years. Prevalence of depressive episodes
      changed little when we varied the threshold of diagnosis and did not stress any
      threshold problem. The variability between investigators was important, but the
      estimation of prevalence remained stable when we excluded extreme rates of
      prevalence. The choice of a classification system affected the prevalence
      estimation. Using the Diagnostic and Statistical Manual of Mental Disorders (DSM
      IV) from the American Psychiatric Association, the prevalence of depressive
      episodes was lower and closer to the estimations shown in the literature than
      using the International Classification of Disease (ICD 10). Moreover, the
      stratification assigned very unbalanced weights to the stratification strata. By
      excluding depressive episodes observed in the stratum "control" (no depression
      "marker" from 1989 to 1994 in the database), the prevalence was very lower,
      whatever the classification was. Finally, factors which appeared linked to care
      of depression with the ICD definition remained the same when the DSM diagnosis
      definition was used, and relative risks were quite similar. CONCLUSION: The MINI
      appears to be a short and simple tool, suited to the epidemiological studies.
      This analysis does not highlight any failure in the internal consistency of the
      MINI. The remaining question is what the MINI really measures, particularly
      comparing to a psychiatrist's diagnosis.

PMID- 10587997
TI  - [Tobacco taxation: economic and public health issues].
AB  - Cigarette smoking is a major public health issue. An increase of cigarette tax
      might be a way for promoting tobacco control. This article reviews the
      economist's perspective of tobacco control. It shows that a crucial economic
      criteria for supporting an increase of cigarette tax--the cost of externalities-
      is not fulfilled, since smokers may well have been paying their own financial
      externalities. However, the theory of rationale addiction cannot fully explain
      smoking behavior because of risk perception bias. The nicotine dependence and the
      onset of nicotine addiction occurring mostly during childhood and adolescence
      explain why consumption decision cannot be assumed to be the product of informed,
      rational choice by mature individuals. Children and teenagers fail to appreciate
      the risks associated with behavior and heavily discount the future. Protecting
      children and teenagers constitutes the strongest argument favoring increased
      taxation of cigarettes.

PMID- 10587998
TI  - [Causal research epistemology and epidemiology of complex systems].
AB  - Epidemiology now meets with the crisis of its most fundamental paradigm. The
      biomedical paradigm of the search for individual-level disease risk factors
      opposes the public-health paradigm of the search for contextual-level disease
      risk factors. The public-health paradigm exacerbates the causal research of
      disease risk factors in that it must now count on a hierarchy of scales of
      observation. This underlines the need to take into account nonlinear
      relationships among scales and variables as well as the dynamic aspect of the
      phenomena. It is concluded that the complex conceptualization required by the
      public-health paradigm will entail epidemiologists to develop new theories and to
      familiarize themselves with approaches more akin to those used in the study of
      complex systems.

PMID- 10587999
TI  - Practical considerations in the analysis of complex sample survey data.
AB  - Large scale sample surveys often provide fertile ground for analyses by
      epidemiologists. Recently, survey organizations such as the National Center for
      Health Statistics and the United States Bureau of the Census have distributed
      data from large surveys to interested investigators via CD-ROM. Confronted by the
      richness of such databases and the historic relative lack of availability of
      suitable software to appropriately account for the survey design, researchers
      have often simply ignored the complexities of the survey and analyzed the data as
      if they resulted from a simple random sample. The availability of modern programs
      such as STATA and SUDAAN provides data analysts with the new analytical
      capabilities to perform design-based analyses whenever appropriate. We used data
      from the NHANES III and the PAQUID study to illustrate the ease of performing
      design-based analyses. We also compared results of analyses under both model
      based and design-based scenarios. When data from complex sample surveys were
      analyzed using both model-based and design-based strategies, differences in point
      estimates and standard errors of means, regression coefficients and odds ratios
      were found. The differences in regression coefficients and odds ratios between
      the two strategies were not as great as the differences in means. The potential
      for differences and the availability of survey analysis software should encourage
      researchers to use design-based techniques to analyze data from complex sample
      surveys more appropriately.

PMID- 10588000
TI  - [Markers of inflammation and prediction of diabetes in adults].

PMID- 10588001
TI  - Quality assurance of veterinary services at the international level: a proposed
      approach.
AB  - A proposal for the harmonization of quality assurance of Veterinary Services at
      the international level is made. This proposal is based on the hypothesis of
      accreditation of Veterinary Services according to the 9000 series of the
      International Standards Organisation (ISO) standards. An example of a way in
      which ISO 9000 standards can be used within the context of management of
      Veterinary Services is given, together with an explanation of the possible role
      of the Office International des Epizooties in ensuring fairness of evaluations of
      Veterinary Services at the international level.

PMID- 10588002
TI  - Foot and mouth disease in Zambia: a review of the aetiology and epidemiology and
      recommendations for possible control.
AB  - In Zambia, foot and mouth disease (FMD) has been caused by all three of the South
      African Territories serotypes (SAT 1, 2 and 3) and by European types O and A.
      Three areas of the country which have experienced repeated occurrences of the
      disease are considered high-risk areas. The three areas are as follows: the
      southern border area between Zambia and Zimbabwe, Botswana and Namibia, the Kafue
      Flats and the northern border with Tanzania in the Nakonde and Mbala districts.
      The transfer mechanism of the virus is poorly understood but the African buffalo
      (Syncerus caffer) is considered to be the natural host, acting as a reservoir of
      infection for the SAT types of the virus. Cattle are known to be carriers of the
      virus for up to two and a half years and individual semi-domesticated buffalo
      have been reported to act as carriers for up to five years. In wild herds of
      buffalo, the virus has been recorded for periods of up to twenty-five years.
      Current control measures include mass vaccination of cattle in high-risk areas
      and restrictions on the movement of cattle from areas in which contact exists
      with buffalo. New protocols should be developed for the prevention and control of
      FMD, including the enforcement of livestock movement control, improved disease
      surveillance and reporting, and the monitoring of FMD virus in carrier cattle and
      buffalo. These measures will contribute towards building the confidence of the
      regulatory bodies of importing countries in the region.

PMID- 10588003
TI  - EpiMAN-FMD: a decision support system for managing epidemics of vesicular
      disease.
AB  - A comprehensive epidemiological information system (EpiMAN-FMD) has been
      developed to assist national disease control authorities contain and eradicate
      outbreaks of animal diseases as efficiently and cost-effectively as possible. The
      system was initially developed to control an incursion of foot and mouth disease
      (FMD) or any clinically indistinguishable vesicular disease, although it has
      since been progressively expanded to manage other exotic and endemic diseases.
      Design objectives for the information management elements of EpiMAN-FMD included
      the following: the need to manage the vast quantities of data that eradication
      procedures for an FMD epidemic would generate within a very short time the
      ability to innovatively apply epidemiological understanding of disease spread to
      the data processing tasks the reduction of some of the foreseen processing
      bottlenecks the provision of decision support tools for data entry personnel.
      Design objectives for the veterinary management elements of the system included
      the following: the presentation of up-to-date status reports in formats that
      facilitate decision-making at the national or regional level the ability to
      optimise manpower resource allocation the capacity to evaluate the relative
      merits of alternative technical decisions, each of which carry different implicit
      risks. The system combines a multi-user database management system, expert system
      elements, various computer simulation models of specific aspects of FMD
      epidemiology and a range of statistical analyses designed to monitor the state of
      the epidemic. Although designed in New Zealand, EpiMAN-FMD has been constructed
      in a flexible style which makes adoption of the system possible in other
      countries with broadly similar 'stamping-out' contingency plans.

PMID- 10588004
TI  - [Epidemiology of sheep pox in Algeria].
AB  - Sheep pox constitutes a major animal health problem in Algeria, despite the
      implementation of various national control campaigns over several decades. On the
      basis of epidemiological data provided by the Veterinary Services of Algeria from
      1984 to 1997, the authors performed a statistical survey to determine possible
      correlations between factors responsible for the persistence of sheep pox, in
      particular seasonal and climatic variables. The authors propose an explanation
      for the variations observed and recommend a control programme which would be more
      appropriate to the agro-pastoral and bioclimatic conditions of the country.

PMID- 10588005
TI  - [Use of the immunoenzyme test ELISA-NS3 to distinguish horses infected by African
      horsesickness virus from vaccinated horses].
AB  - A vaccination protocol involving three horses, with five repeated injections of
      inactivated serotype 4 African horse sickness virus, was undertaken to determine
      a possible threshold for the appearance of antibodies against the non-structural
      protein NS3. Using an indirect enzyme-linked immunosorbent assay, with the
      recombinant NS3 protein as an antigen, the authors detected a response to NS3 as
      of the second injection for the first horse and after four injections for the
      second horse. No response to NS3 was detected for the third horse. The results
      show that the inactivated vaccine is insufficiently purified to eliminate the non
      structural protein NS3. Therefore using the NS3 protein as a marker did not
      enable differentiation between vaccinated and infected horses.

PMID- 10588006
TI  - The effectiveness of routine serological surveillance: case study of the 1997
      epidemic of classical swine fever in The Netherlands.
AB  - The authors describe the value of routine serological surveillance in detecting
      the introduction of classical swine fever virus into a disease-free population.
      The first investigation concerned the question of whether the epidemic of
      classical swine fever (CSF), which occurred from 1997 to 1998 in the Netherlands,
      could have been detected using the existing monitoring system for notifiable
      diseases. The investigation used data from the CSF epidemic of 1997/1998 and from
      the existing monitoring system. Secondly, the probability of detecting a case of
      CSF using routine serological surveillance was modelled both for multiplier herds
      and for finishing herds, and then for different herd size categories. The first
      investigation concluded that the probability of detecting the epidemic at the
      current level of routine serological surveillance is very low. The second
      investigation concluded that even employing a sampling scheme of sixty blood
      samples per month, the probability of detecting an outbreak of CSF within forty
      days of the introduction of the virus, is less than 40%.

PMID- 10588007
TI  - Classical swine fever: the European experience and a guide for infected areas.
AB  - Classical swine fever (CSF) (hog cholera) virus infection is still of world-wide
      concern, either because of the direct effects of the disease on swine breeding in
      areas where the virus is epizootic or enzootic, or as a threat in areas where the
      virus has been eradicated. The authors provide an overview of the characteristics
      of the disease. Special emphasis is placed on the chronic form of disease,
      particularly in the late stages of eradication programmes. In the early 1980s,
      the European Union (EU) was composed of countries which were officially free of
      the disease (absence of infection and no vaccination) and countries in which
      vaccination was either permitted or was compulsory. To ensure free trade between
      the Member States, an eradication plan was agreed upon and implemented.
      Initially, the plan consisted of a combination of vaccination with the Chinese
      strain of the virus and slaughter and removal of infected herds. Consequently,
      when the number of infected herds was low, vaccination was abandoned and the
      control of CSF was conducted exclusively by eradication (removal and slaughter).
      The United Kingdom, Austria, Denmark, Ireland, Luxembourg, Finland and Sweden
      ceased vaccination before 1980. In the other countries, vaccination was useful in
      controlling the last epidemics and was finally ceased as follows: France in 1983,
      the Netherlands in 1986, Belgium, Spain and Greece in 1988, Germany in 1989 and
      Italy in 1990. From 1990 onwards, no vaccination against CSF has been performed
      in the EU. New techniques for the diagnosis of CSF (for example, the enzyme
      linked immunosorbent assay based on the detection of the p125 antigen of the
      virus) have been shown to be of value in the early detection of infected animals.
      In enzootic areas, the use of vaccines based on the Chinese strain has been
      successful. Vaccines with at least 100 PD50 of virus per dose are able to
      significantly limit the replication of virulent virus in the tonsils.
      Consequently, shedding of virus after infection can be reduced considerably. In
      heavily infected areas, vaccination plays a crucial role. The European experience
      shows that eradication may be achieved when vaccination with highly effective
      vaccines is combined with effective identification of swine, movement control,
      early diagnosis and the rapid elimination of infected herds.

PMID- 10588008
TI  - Epidemiology and control of brucellosis in ruminants from 1986 to 1996 in Malta.
AB  - The epidemiology and control of Brucella melitensis in Malta was analysed using
      herd test data made available by the Veterinary Service of Malta. The eradication
      scheme commenced in 1987 with the introduction of a test and slaughter scheme
      using the Rose Bengal test. Herds registered with Malta Dairy Products Limited
      (MDP) showed a herd prevalence of 23% in 1987 which fell to less than 1.5% by
      1993. Prevalence rose to 13% in 1995. Herds not delivering milk to the MDP showed
      an initial herd prevalence of 4% which fell below 1% in 1994, remaining under 2%
      in 1995. The epidemic in 1995 caused approximately 300 human brucellosis cases.
      Large herds and herds with small ruminants were most at risk to brucellosis
      infection. Seasonal fluctuation of prevalence was apparent. Increased enforcement
      of regulations and motivation of farmers would accelerate eradication of
      brucellosis in Malta.

PMID- 10588009
TI  - Reliability of results of the Rose Bengal test performed for export control in
      northern Somalia.
AB  - Sera from sheep and goats in northern Somalia which are exported to countries of
      the Persian Gulf are systematically checked for brucellosis by local veterinary
      teams. The standard test used is rapid seroagglutination using the Rose Bengal
      test (RBT) and seropositive animals are not exported. In order to assess the
      reliability of the serological results, three randomised batches of samples (653
      sera), corresponding to an equivalent number of shipments (October and December
      1994 and March 1995) were counterchecked. Control RBTs were carried out by
      expatriate veterinarians working on behalf of international non-governmental
      organisations and by the Istituto Zooprofilattico Sperimentale of Padua, Italy,
      which also performed the complement fixation test (CFT). A fourth batch (n =
      100), including a group of sera found positive by the local veterinary teams, was
      also checked. Agreement ranged from 96.3% to 98.5%.

PMID- 10588010
TI  - Prevalence of bovine viral diarrhoea virus antibodies in India.
AB  - A study was undertaken regarding the prevalence of bovine viral diarrhoea virus
      (BVDV) antibodies in bovine sera which tested negative for rinderpest and peste
      des petits ruminants virus antibodies. The samples were collected between January
      1996 and December 1997. A total of 439 samples (327 cattle and 112 buffalo from
      17 states of India) were tested using a commercial enzyme-linked immunosorbent
      assay (ELISA) kit. The mean prevalence of BVDV antibodies in cattle was 15.29%
      (50/327) in 16 states compared to 23.21% (26/112) in buffalo in 9 states, with an
      overall prevalence of 17.31% (76/439) in 17 states. The serological evidence that
      BVDV infection is widespread in India is of utmost practical importance because
      of the clinical resemblance to rinderpest. A differential diagnosis between these
      two diseases is critical in view of the declaration by India of provisional
      freedom from rinderpest disease; active sero-surveillance is to begin in 2000 to
      achieve certification of freedom from rinderpest infection by the Office
      International des Epizooties.

PMID- 10588011
TI  - Observations on the recent epizootic of bovine ephemeral fever in Saudi Arabia.
AB  - Observations of the epizootic of bovine ephemeral fever which occurred in Saudi
      Arabia during 1996 are presented. The investigations included the collection of
      epidemiological data from affected farms and the testing of sera for antibodies
      to the virus. The authors report a mean morbidity rate of 50% and a mean case
      fatality rate of 0.3%. Of the infected cattle, 4% were affected by recumbency,
      the majority of these recovered (89%). The clinical signs observed in affected
      cattle were uniform throughout the region concerned. The features of the
      outbreak, obtained through field investigations, were considered in relation to
      the ecological and meteorological conditions which were prevalent at the time.
      The outbreak occurred during the summer months (May to October) in the central
      and eastern regions of Saudi Arabia, with the initial infection reported at the
      Al-Ahsa oasis. Farms which were subsequently affected were all reported to
      possess areas of stagnant water suitable for the reproduction of the vectors of
      the disease (Culicoides spp. and mosquitoes). To conclude, the authors discuss
      precautions to prevent future outbreaks of bovine ephemeral fever in Saudi
      Arabia.

PMID- 10588012
TI  - The role of houseflies (Musca domestica) in harbouring Corynebacterium
      pseudotuberculosis in dairy herds in Israel.
AB  - A study was conducted to assess the role of houseflies, Musca domestica L. in
      harbouring Corynebacterium pseudotuberculosis in dairy farms in Israel. The
      bacterium was isolated in June 1993 from 40 wild houseflies which had fed on a
      lesion on a cow, and from 28 laboratory flies fed on contaminated milk from a cow
      infected with mastitis. The bacterium was recovered from the body surface of 10
      flies (of a total of 160) 10 min after being dipped entirely in a bacterial
      broth. The bacterium was recovered from the body surface of 10 flies (of a total
      of 40) 5 min after being fed on contaminated milk. When 110 flies were fed on
      contaminated sugar cubes, the bacterium was recovered externally from 70 flies 5
      min later, and from an additional 20 flies 10 min after feeding. Of 110 flies, 80
      excreted bacteria in saliva from 5 min to 3 h after feeding on contaminated milk.
      Bacteria were isolated from the intestine of 40 of 60 flies between 1 h and 4 h
      after feeding on contaminated milk. Bacteria were found in the faeces of 30 of 60
      flies, between 1 h and 4 h after feeding on contaminated milk. In the light of
      these findings, and given the fact that this species of fly has a predilection to
      feed on milk residues of cow teats, the authors concluded that the housefly plays
      an important role in harbouring and disseminating C. pseudotuberculosis in dairy
      herds in Israel. In contrast, stable flies (Stomoxys calcitrans L.) are not
      important in the habouring and dissemination of the bacteria, since bacteria were
      not recovered 5, 10, 15, 30 min, 2 h or 24 h after membrane feeding on a mixture
      of bacterial broth and blood.

PMID- 10588013
TI  - Epizootic lymphangitis in horses: a review of the literature.
AB  - Epizootic lymphangitis is a relatively common infectious disease of horses and
      other liquids in certain parts of the world. The infection rate varies according
      to the geographic area and the age of the animal. The disease is most commonly
      characterised by a cord-like appearance of the subcutaneous lymphatic and
      cutaneous pyogranulomas, the discharge from which contains spherical or pear
      shaped bodies of the causal agent, Histoplasma farciminosum. Diagnosis can be
      made by the demonstration of typical organisms in stained smears, culture and
      tissue sections. Serological tests and a skin hypersensitivity test have been
      described. Amphotericin B is the drug of choice for the treatment of clinical
      cases. An attenuated vaccine and a killed formalized vaccine are available and
      can be used in endemic areas to control the disease.

PMID- 10588014
TI  - Representative Salmonella serovars isolated from poultry and poultry environments
      in Saudi Arabia.
AB  - The authors describe the source and prevalence of pathogenic Salmonella serovars
      among poultry farms in Saudi Arabia. A total of 1,052 (4%) Salmonella isolates
      were recovered from 25,759 samples of poultry (broilers, layers, broiler breeders
      and layer breeders) and poultry environments (box liner, litter, drag swab,
      droppings, mice and feed) were examined bacteriologically between 1988 and 1997
      at the Poultry Disease Laboratory at the National Agriculture and Water Research
      Center in Riyadh. Eleven Salmonella serogroups representing 38 different
      Salmonella serovars were identified by means of antigenic analysis. The majority
      of the 276 isolates (26.2%) of Salmonella typed, were recovered from liver, heart
      and intestines of the broilers and layers. The most prominent Salmonella
      serogroups isolated were as follows: serogroup C1 (392 isolates, 37.26%), B (289
      isolates, 27.47%) and D1 (269 isolates, 25.69%). However, untypable and multiple
      serogroups were also encountered, the most frequent isolates serotyped belonged
      to groups C1 (97 isolates, 24.7%), D1 (86 isolates, 31.9%), and B (71 isolates,
      24.6%). Salmonella Enteritidis (85 isolates, 98.8%), Salmonella Virchow (48
      isolates, 57.8%), Salmonella Paratyphi B var. Java (41 isolates, 57.7%) and
      Salmonella Infantis (30 isolates, 20.6%) were distributed the most widely as all
      were encountered in poultry and in poultry environments. S. Enteritidis phage
      type 4 (30 isolates, 35.3%), was the phage type most frequently detected among
      group D1 phage types, while 39 (45.8%) of the isolates of S. Enteritidis could
      not be phage typed.

PMID- 10588015
TI  - Emergence of Salmonella enteritidis outbreaks in broiler chickens in the Lebanon:
      epidemiological markers and competitive exclusion control.
AB  - This study investigates the first emergence of Salmonella Enteritidis outbreaks
      among chickens in the Lebanon and identifies the epidemiological markers of
      selected recovered Enteritidis strains. In addition, the authors evaluate a
      competitive exclusion approach to control infection in broiler chickens by
      Enteritidis organisms which possess the prevalent identified markers. The basic
      procedure in this investigation involved recording signs and lesions in eleven
      broiler chicken flocks on eleven farms, and culturing livers, spleens, and caeca
      of ten randomly selected birds per flock for Salmonella isolation and serotyping.
      Furthermore, culturing for Salmonella and serotyping was attempted from the
      livers, spleens, caeca and oviduct swabs of ten hens in four broiler breeder
      flocks which provided hatching eggs for the broilers under study. The
      identification of epidemiological markers in recovered S. Enteritidis included
      the determination of drug-resistance patterns and plasmid profiling. The
      competitive exclusion was evaluated by spraying the microflora on day-old
      broilers in the hatchery, followed by a controlled oral challenge at three days
      of age, with 2.85 x 10(5) colony-forming units of S. Enteritidis organisms per
      bird. Exclusion was evaluated by culturing for S. Enteritidis in anal swabs,
      spleens, livers, and caeca of individual challenged birds treated with the
      microflora and in untreated challenged birds. A total of 112 invasive S.
      Enteritidis strains were recovered on eleven farms from individual organs of
      broiler chickens with typical signs and lesions of salmonellosis. The prevalent
      resistance to drugs in such strains was to furaltadone and gentamycin, a marker
      identified in 93 strains (83%), recovered from nine out of eleven farms. The same
      resistance pattern was present in S. Enteritidis strains recovered from breeders
      on one out of four farms. The prevalent plasmid profile in nine S. Enteritidis
      organisms selected randomly from a pool of 93 strains (one per each of the nine
      broiler farms) was 14.1 kilobases (kb) and approximately 50.0 kb, a typical
      pattern to that identified in S. Enteritidis organisms recovered from oviducts of
      breeders on one out of four breeder farms. The exclusion significantly reduced
      cumulative mortality in birds of up to 45 days of age by 3.93%, in comparison to
      that observed in untreated challenged birds (P < 0.05). At 45 days of age,
      exclusion resulted in a 15.6% reduction in the percentage infection rate by S.
      Enteritidis in spleens or livers and a 34.4% reduction in the percentage
      infection rate of the caeca (P < 0.05).

PMID- 10588016
TI  - Risk of disease transmission by llama embryos.
AB  - An assessment was made of the risk of transmission of foot and mouth disease
      (FMD), vesicular stomatitis, bluetongue, tuberculosis and brucellosis by llama
      embryos. The study suggests that embryo transfer is a safe method for the
      international movement of llama embryos despite the special characteristics of
      these embryos, such as the absence of a zona pellucida, and despite the lack of
      data on pathogen-embryo interactions. For acute viral diseases such as FMD,
      vesicular stomatitis or bluetongue, embryo transfer reduces the risk of
      international embryo movement by a factor of 10(4). Therefore, if favourable
      epidemiological or ecological conditions exist in the region of origin of the
      embryos, the risk of contamination of a batch of llama embryos with the above
      agents is close to zero. The risk of contamination with Mycobacterium or Brucella
      depends on the incidence of these diseases, but under the most unfavourable
      prevalence levels, the risk does not exceed 10(-3.3), given that the results of
      diagnostic tests of the herd and of donor animals are negative before and after
      collection of the embryos. This study demonstrates that risk assessment can be a
      valuable tool to facilitate international movement of embryos, particularly for
      those species for which little or no data are available regarding embryo-pathogen
      interactions.

PMID- 10588017
TI  - Import risk analysis: the experience of Italy.
AB  - The authors propose a contribution to the possible revision of Chapters 1.4.1.
      and 1.4.2. of the International Animal Health Code (Code) of the Office
      International des Epizooties (OIE). In particular, data are presented to
      illustrate some of the inadequacies of both the rationale and the results of the
      method for risk assessment reported in the Code. The method suggested by the Code
      for risk assessment is based on the calculation of the 'probability of the
      occurrence of at least one outbreak' of a given disease following the importation
      of a given quantity of either live animals or animal products (unrestricted risk
      estimate). This is usually undertaken when dealing with rare events. For a
      country such as Italy, this method may not be particularly useful as the
      frequency of disease outbreaks is what should be estimated, so as to provide
      decision makers with appropriate and relevant information. Practical use of risk
      information generated by the use of the OIE risk assessment method for swine
      vesicular disease (SVD) would have encouraged the Chief Veterinary Officer of
      Italy to prohibit all imports of swine from the Netherlands and Belgium for at
      least two years in the early 1990s, with the consequential heavy economic losses
      for both Italy and the exporting countries. On the contrary, the number of actual
      outbreaks of the disease due to direct imports of swine from Member States of the
      European Union (EU), which occurred in Italy in 1992, 1993 and 1994 was very low
      (two to five outbreaks due to direct imports of swine from the Netherlands and
      one to two from Belgium). An example of a method for assessing the risks
      associated with high volumes of trade in commodities is also described. This
      method is based on the Monte Carlo simulation and provides the information
      required to evaluate the costs of the strategies compared. The method can be used
      to predict the number of outbreaks which are likely to occur following
      importation and enables a comparison to be made of alternative safeguards. This
      would lead to the selection of the most cost-effective one. The comparison is
      conducted using risk curves and allows a quantitative evaluation and comparison
      to be made of various scenarios, varying from an absence of safeguards to
      combinations of various safeguards.

PMID- 10588018
TI  - An epizootic of Rift Valley fever in Egypt in 1997.
AB  - An epizootic of Rift Valley fever (RVF) occurred in Egypt between April and
      August 1997. The signs among infected cattle and sheep were high fever, icterus,
      bloody diarrhoea and abortion. Aborted sheep foetuses and sera from the affected
      herds were collected in the Aswan and Assiut Provinces, Upper Egypt, for
      virological and serological examination. A cytopathic effect was detected in Vero
      cell cultures 48 h after inoculation with the foetal liver and spleen
      suspensions. The same suspensions caused paralysis and mortalities two to three
      days post intracerebral injection in mice. The isolated virus was identified
      using an agar gel precipitation test (AGPT) and a direct fluorescent antibody
      technique. Serological examination revealed that all tested sheep (57) and cattle
      (93) gave positive results to serological tests, using a complement fixation
      (CF), serum neutralisation (SN) and indirect immunofluorescence assay; while only
      48 (84.2%) out of 57 sheep sera and 69 (74.2%) out of 93 cattle sera gave
      positive results using an AGPT. Titration of the serum samples indicated that SN
      is more sensitive than CF. Importation of infected ruminants, especially camels
      from the Sudan, is the principal source of infection. Aswan, the nearest Egyptian
      province to the Sudan, is the focus of RVF virus infection in Egypt. As a result
      of high insect populations, the epizootics of RVF have usually occurred during
      the summer in Egypt. Reoccurrence of epizootics from time to time indicates
      failure of the applied RVF vaccination programme in Egypt.

PMID- 10588019
TI  - An eruptive moderate form of camelpox infection in dromedary camels (Camelus
      dromedarius) in Saudi Arabia.
AB  - An eruptive moderate form of camelpox infection is reported in camels aged three
      to four years from the Al-Ahsa region of Saudi Arabia. The clinical signs were
      moderate in nature (between the 'mild' and the 'severe' form). The morbidity rate
      was 100% while the case fatality rate was 0%. Camelpox virus was isolated and
      identified using electron microscopy and serological analysis.

PMID- 10588020
TI  - Survey of Trichinella spp. infection in pigs from commercial piggeries in
      Zimbabwe.
AB  - Trichinella spp. infection has never been reported among domestic pigs in
      Zimbabwe. Given that Trichinella spp. occurs in a sylvatic cycle in Zimbabwe and
      particularly in the light of the recent notification of the presence of the
      infection in farmed crocodiles, a survey was undertaken to evaluate the present
      epidemiological situation on commercial pig farms. Carcasses of 7,446 fattener
      pigs (average 11.7% [+/- 0.2%] of those slaughtered from each farm) were
      investigated by artificial digestion of pooled diaphragm muscle samples. These
      carcasses originated from 70 commercial piggeries and were selected by
      stratification on a farm basis from 63,602 pigs slaughtered during the survey
      period. No Trichinella spp. larvae were found in any of the 7,446 diaphragm
      muscle samples. The results demonstrated no evidence of Trichinella spp.
      infection within the pig population of the commercial piggeries in Zimbabwe.

PMID- 10588021
TI  - Bovine spongiform encephalopathy crisis in Europe and its impact on beef
      consumption in Slovenia.
AB  - The bovine spongiform encephalopathy (BSE) crisis in Member States of the
      European Union adversely affected beef consumption in Slovenia in 1996. Although
      the disease has not been reported in Slovenia to date, the controversy about the
      link between BSE and Creutzfeldt-Jakob disease and scandals related to the
      illegal trade in beef in some countries have triggered doubts among consumers.
      Beef consumption in Slovenia was estimated using a beef supply model, consisting
      of the following variables: purchase and slaughter of cattle and import and
      export of beef. The model estimated that beef consumption fell by 16% in 1996
      compared with consumption in 1995. Approximately half of the reduction was
      compensated by an increase in consumption of pork and poultry meat.

PMID- 10588022
TI  - [Abdominal aortic aneurysms. Results of surgical treatment from 1987 to 1998].
AB  - Conventional open surgery for abdominal aortic aneurysm has recently been
      challenged by a closed transfemoral approach for repair (stent-graft). The
      presented data over the past eleven years after open surgery for graft
      implantation are intended to serve for comparison with future results after
      transfemoral graft placement. In addition, it is the purpose of this study to
      investigate the prognostic importance of treatment of concomitant coronary artery
      disease. Early mortality of all 195 consecutive patients with abdominal aortic
      aneurysm repair was 1.5%; it was 0.6% after elective repair for infrarenal
      aneurysm and not dependent on the presence of coronary artery disease if the
      latter was treated. Late outcome, however, related closely to coronary artery
      disease as a major risk factor. Late graft complications are extremely rare and
      occurred only once (graft thrombosis). Incisional hernias and impotence in male
      patients are non-lethal complications affecting quality of life. Open surgical
      repair of abdominal aneurysm is safe, and long-term, complication-free survival
      is good. Coronary artery disease is the most frequent concomitant disease and
      major risk factor requiring close observation and treatment. These results need
      to be matched by the new transfemoral graft implantation technique before broad
      application of the latter.

PMID- 10588023
TI  - [Metabolic control in children and adolescents with diabetes mellitus type I in
      Berne: a cross-sectional study].
AB  - AIMS/HYPOTHESIS: In diabetes mellitus type I, good glycaemic control is crucial
      in preventing long-term diabetic complications. The aim of this study was to
      determine the current level of metabolic control in children and adolescents in
      our diabetes outpatient clinic at the University Children's Hospital, Berne.
      Furthermore, the impact of different factors such as age, pubertal stage, sex,
      duration of diabetes and insulin regimen on glycaemic control was studied.
      METHODS: In a cross-sectional, prospective study 168 children and adolescents
      with type I diabetes mellitus (f:m = 87:81; prepubertal 48 [mean age 4.4 years,
      mean duration of diabetes 2.8 years]; pubertal 120 [mean age 9.4 years; mean
      duration of diabetes 5.2 years]) were studied for three months. Clinical data and
      HbA1c levels (latex immunoagglutination test) were recorded, statistically
      analysed and compared with the international literature. RESULTS: In our type I
      diabetic children and adolescents the overall HbA1c was 8.07 +/- 1.15% (mean +/-
      SD; test-specific norm for healthy subjects: 4.1-6.1%). Glycaemic control was
      significantly worse in the pubertal group compared to the prepubertal (HbA1c 8.22
      +/- 1.25% vs. 7.81 +/- 0.87%; p < 0.01). In addition, we found better metabolic
      control in patients with duration of diabetes below 2 years in children and
      adolescents (HbA1c prepubertal < 2 years: 7.45 +/- 0.67% vs. > 2 years: 8.05 +/-
      0.93%, p < 0.05; pubertal < 2 years: 7.62 +/- 0.75% vs. > 2 years: 8.31 +/-
      1.29%, p < 0.005). Importantly, sex and insulin regimen did not significantly
      influence glycaemic control. CONCLUSION/INTERPRETATION: The current level of
      metabolic control in our children and adolescents with diabetes mellitus type I
      is comparable to the glycaemic control of the intensively treated adolescent
      group of the DCCT-study, in whom decreased risk of long-term diabetic
      complications was found. In contrast, our patients were intensively treated in
      terms of frequent contacts with the diabetes team, but were not necessarily on an
      intensified insulin regimen. The impact of biopsychosocial support from
      multidisciplinary diabetes team on good metabolic control in children and
      adolescents with type I diabetes mellitus and their families seems to be very
      important.

PMID- 10588024
TI  - [Amoebic liver abscess in chronic colitis: revision of "Crohn disease"
      diagnosis].
AB  - We present two cases initially diagnosed as Crohn's disease which were treated
      with immunosuppressive drugs. In both patients the development of an amoebic
      liver abscess led to the correct diagnosis of amoebic dysentery. The pitfalls of
      the diagnosis of amoebic colitis and the possible influence of immunosuppression
      in the development of extraintestinal amoebiasis are discussed.

PMID- 10588025
TI  - [Intracellular processing of viral and tumor antigens by proteasomes].
AB  - Cytotoxic T cells are able to recognise whether a cell of our body is infected by
      a virus or whether it has acquired mutations leading to tumour formation. The
      cells show on their surface what kind of proteins are synthesised intracellularly
      and whether non-self proteins encoded by a virus or tumour antigens are among
      them. The proteins are presented not as functionally intact proteins but as
      peptide fragments which originate from their regular intracellular degradation.
      This fragmentation is accomplished by the proteasome, a large proteinase complex
      in the cytoplasm and nucleus of all cells. Upon stimulation with the antiviral
      cytokine interferon-gamma, subunits of the proteasome are exchanged, thus leading
      to optimised production of peptide antigens. In this review we introduce the
      system of antigen processing by the proteasome and sum up our latest results on
      the question how the interferon-gamma-mediated reorganisation of the proteasome
      occurs and what consequences and benefits this has for the cytotoxic immune
      response against viruses and tumours.

PMID- 10588026
TI  - [Medical ethical guidelines for somatic gene therapy in humans. Swiss Academy of
      Medical Sciences (SAMW)].

PMID- 10588027
TI  - [Salmonella, heart and pancreas].

PMID- 10588028
TI  - The nursing role in radiation oncology.
AB  - OBJECTIVES: To reflect on the historical evolution of radiation oncology nursing.
      DATA SOURCES: Published articles and texts, historical archives of professional
      organizations, and the authors' experience. CONCLUSIONS: The radiation oncology
      nursing role is multifaceted. Role components include patient assessment, patient
      education, support and counseling, physical care, continuity of care, research,
      and administrative and leadership activities. There is wide variation in staffing
      patterns and role implementation throughout the world, and in recent years there
      has been increasing interest in the development of advanced practice nursing
      roles in this specialized area of oncology. IMPLICATIONS FOR NURSING PRACTICE:
      Changes in the health care environment make it difficult to predict how the role
      of the nurse in radiation oncology will evolve in the future. Radiation oncology
      nurses will need to be proactive in developing the knowledge and skills needed to
      meet the challenges of the future.

PMID- 10588029
TI  - Principles of radiotherapy and radiobiology.
AB  - OBJECTIVES: To review the current state of knowledge of radiation physics and
      radiobiology, combined modality treatments, the use of radiosensitizers and
      radioprotectors, new developments in radiation therapy, radiation safety
      principles, and the implications of radiation in advanced nursing practices. DATA
      SOURCES: Research and review articles, oncology nursing textbooks, and physics
      and medical oncology textbooks. CONCLUSIONS: Radiation therapy is an important
      entity in the treatment of cancer, used alone or in combination with surgery
      and/or chemotherapy. Research continues to grow in the use of radiation therapy
      to control cancer, spare surrounding normal tissue, and reduce acute long-term
      toxicity. IMPLICATIONS FOR NURSING PRACTICE: An understanding of radiobiology and
      physics will assist oncology nurses in providing proper education to the patient
      and managing radiation-induced side effects.

PMID- 10588030
TI  - Radiation therapy treatment planning and delivery.
AB  - OBJECTIVES: To provide an overview of radiation therapy treatment planning and
      delivery, and discuss technologic advances and their importance in present and
      future oncologic care. DATA SOURCES: Radiation oncology textbooks and radiation
      physics and treatment planning textbooks. CONCLUSIONS: The increased
      sophistication and complex abilities of modern radiation therapy planning and
      delivery are steadily improving cancer treatment outcomes and quality of life.
      Radiation is now an essential and integral part of cancer care and may be used
      alone or as part of combined modality therapy. Further technologic advances will
      allow improvement in the ability of radiation therapy to cure cancer and improve
      quality of life for an ever-increasing variety of patients. IMPLICATIONS FOR
      NURSING PRACTICE: Oncology nurses with an understanding of the components of
      radiation treatment plans and their delivery will be able to provide appropriate
      education for patients offered radiation and prepare them for the lengthy and
      complex process of radiation therapy.

PMID- 10588031
TI  - Organ preservation.
AB  - OBJECTIVES: To review organ preservation in cancer treatment within the context
      of organ function, treatment-related acute and late toxicities, outcome data, and
      quality of life. DATA SOURCES: Published review and research articles,
      proceedings of conferences, and oncology textbooks. CONCLUSIONS: The
      implementation of surgery, with sequential and/or concurrent chemoradiation, has
      advanced the success of organ preservation in multiple tumor types and organ
      systems. Integral to the discussion of organ preservation is consideration of
      quality of life. IMPLICATIONS FOR NURSING PRACTICE: An understanding of organ
      preservation in cancer treatment will allow oncology nurses to be more effective
      patient advocates by providing current information that can be integrated into
      patient care and education.

PMID- 10588032
TI  - Nursing assessment and patient management.
AB  - OBJECTIVES: To review contemporary knowledge and recent research in the nursing
      assessment and management of patients receiving radiation therapy. DATA SOURCES:
      Published scientific papers, review articles, book chapters, and clinical
      practice. CONCLUSIONS: Despite the enormous advances in treatment technology,
      dose-limiting acute and late effects of radiation therapy have not been
      eliminated. Astute assessment and early interventions can have a positive impact
      on the quality of life of the patient receiving radiation therapy. IMPLICATIONS
      FOR NURSING PRACTICE: Oncology nurses need to be well-informed about treatment
      advances and be able to integrate research findings into clinical practice. The
      increased use of concurrent or sequential combined modality therapy requires
      nurses to broaden their skills of assessment and management.

PMID- 10588033
TI  - Radiation therapy in childhood cancer.
AB  - OBJECTIVES: To review treatment-related issues and acute and late side effects of
      radiation therapy for the treatment of childhood malignancies. DATA SOURCES:
      Research and review articles, oncology textbooks, and clinical experience.
      CONCLUSIONS: Radiation therapy is a key component in the treatment of childhood
      malignancies. Children receiving radiation have special nursing care needs that
      are dependent on growth and developmental issues. IMPLICATIONS FOR NURSING
      PRACTICE: Nurses play an important role in the education of families and children
      receiving radiation therapy. In addition, nurses are key in the management of
      acute and late toxicities from childhood radiation therapy.

PMID- 10588034
TI  - Patterns of care in radiation oncology.
AB  - OBJECTIVES: To provide an overview of the Patterns of Care Study (PCS) in
      radiation oncology and to discuss the progress and impact of the PCS on clinical
      practice. DATA SOURCES: Research studies and review articles. CONCLUSIONS: The
      PCS has demonstrated tremendous impact on the delivery of radiation oncology
      services in the United States. The PCS surveys the discipline of radiation
      oncology to determine quality of care and provide outcome data to enhance the
      delivery of radiation treatment in diverse settings. NURSING IMPLICATIONS:
      Radiation oncology nurses occupy a pivotal place in the quest to promote quality
      clinical care. A knowledge base about the activities of the PCSs and the
      integration of nursing participation in future studies has the potential to
      enhance patient care.

PMID- 10588035
TI  - [Arguments and basic principles for continuous monitoring of social differences
      in the health of Swiss children].
AB  - On the basis of the thesis that social inequality has increased during the
      nineties in all western societies, and that this development is a reason for
      considerable concern with respect to public health, the authors propose the
      establishment of a long term monitoring system within the Swiss school health
      services. A re-analysis of the data obtained in a Swiss epidemiological study of
      seven-year-olds in the eighties demonstrates that social class was an important
      determinant of health and development of these children also during a period of
      economic boom. For various health and developmental problems odds-ratios (lower
      class vs. upper class) between 1.7 and 6.4 were found. Social class of the
      parents is considered as a reliable indicator of the socio-economic situation of
      children also for future long term observations. The number of significant
      somatic health problems as well as disorders of motor and speech development of
      six- or seven-year-olds are proposed as indicators of health status which can be
      assessed repeatedly at reasonable cost and with standardised methodology. This
      project could be started rather easily within the newly established Swiss "Health
      Observatory".

PMID- 10588036
TI  - [Instructor in the army and fortifications guard--risk occupations for acute
      acoustic trauma and for wearing a hearing aid].
AB  - In the Swiss army instructors and fortifications guards are exposed to firearms'
      noise which harms the ear. It was investigated whether the decline in the cases
      of acute acoustic traumas in non-professional soldiers serving in the army from
      1987 to 1996 also was detectable in army instructors and fortifications guards
      (professional soldiers) and whether these persons were wearing hearing aids (as
      an indicator of hearing loss) more often than the average of the male Swiss
      population. First, we analyzed a historical time series of the incidence density
      of acute acoustic traumas in non-professional soldiers as well as in army
      instructors and fortifications guards. Second, we compared the prevalence rate of
      wearing a hearing aid in army instructors and fortifications guards with the male
      Swiss population. The incidence density for acute acoustic traumas in army
      instructors and fortifications guards observed over ten years showed no
      significant change whereas among non-professional soldiers a strong decline (-12%
      per year) was observed. The prevalence rate of wearing a hearing aid in army
      instructors and fortifications guards was significantly higher (RR 3.91 [95% CI
      3.09-4.96]) than in the male Swiss population. These results suggest increased
      hearing impairment among army instructors and fortifications guards which is
      probably due to the high exposure to impulse noise events (occupational disease).
      It is recommended that these persons be subjected to a compulsory prevention
      program.

PMID- 10588037
TI  - Alcohol consumption and gender in the 20th century: the case of Switzerland.
AB  - Given the changes of gender roles in this century it is hardly justified to
      assume constant proportions of alcohol consumption for males and females. The
      purpose of the study was to reconstruct the consumption trends of males and
      females in Switzerland since the beginning of the 20th century. Cirrhosis
      mortality and survey data were used to disaggregate by sex the per capita alcohol
      consumption derived from sales data. The disaggregation of the per capita alcohol
      consumption based on liver cirrhosis mortality suggests that the evolution of
      alcohol consumption in Switzerland followed a parallel course for both sexes only
      until the 1930s. The low consumption during World War II and the evident increase
      until the beginning of the '60s seem to have resulted above all from the
      variations in consumption of beer by men. The decrease in total alcohol
      consumption observed since the '70s is also most probably due only to men; there
      is no indication of a decreasing consumption by women. The tendency of male and
      female consumption patterns to become more similar should be taken into account
      in the prevention of alcohol misuse.

PMID- 10588038
TI  - Characteristics of heroin and cocaine users unknown to treatment agencies.
      Results from the Swiss Hidden Population Study.
AB  - The aim of this study was to compare the characteristics of heroin or cocaine
      users who are not in contact with drug-treatment agencies in Switzerland to the
      characteristics of a group who are in treatment. A sample of 917 users of heroin
      and/or cocaine was recruited outside treatment settings by 31 Privileged Access
      Interviewers. Respondents were divided into a study group of 512 heroin and/or
      cocaine users not following any treatment, and a control group of 238 users who
      were following treatment. Respondents in the no-treatment group use drugs less
      frequently, are less likely to inject drugs, have a more social pattern of use
      and more often have the impression of controlling their drug use. They have less
      contact with the legal system and the police, are in a better social situation
      and more often perceive themselves to be in good health. In both groups,
      respondents whose main drug of use is heroin generally have a more problematic
      pattern of use than those who use mainly cocaine. There are no significant
      differences between the two groups regarding present HIV-risk behaviour and
      prevention. The data show no significant association between the duration of use
      of heroin or cocaine and signs for problem use. These findings support the
      hypothesis that drug users not in treatment and drug users in treatment are two
      distinct populations, in terms of profile of drug use and prevalence of social or
      health problems that are associated to it.

PMID- 10588039
TI  - [Significance of measures to optimize medical sociology research: the example of
      telephone survey of the elderly].
AB  - Based on a telephone survey of elderly people (> or = 60 years) the impact of
      measures to optimize response rate (repeated telephone calls and converting
      temporary refusals) on the sample structure is analyzed. Results show slight
      differences between persons who can be reached easily and those who are difficult
      to contact as far as their sociodemographic, socioeconomic and health related
      characteristics are concerned. Moreover there are no significant differences
      between temporary refusals and cooperative respondents on these characteristics.
      Differences are considerable however on multivariate relationships between
      sociodemographic, socioeconomic and psychosocial variables on the one hand and
      subjective health on the other. Results indicate that nonresponse has an effect
      on relationships between variables which are essential for research in medical
      sociology. This effect clearly shows the necessity of measures to increase
      response rate for reducing nonresponse bias especially in surveys of elderly
      people.

PMID- 10588040
TI  - Application of image analysis techniques to two-dimensional crossed
      immunoelectrophoresis study.
AB  - Two-dimensional crossed immunoelectrophoresis (2D-CIEP) is a technique widely
      used for studying composition of protein mixtures in biological and clinical
      studies. A low cost image analysis system with the use of an optical flatbed
      scanner and a IBM-compatible PC was set up in this work for capturing 2D-CIEP
      patterns. A computer package CIEPEASY was developed for modification and analysis
      of the image acquired to determine various peak parameters such as the migration
      distance, peak height and peak area of the constituting components for both
      qualitative and quantitative studies. In this approach, more composition
      information of the standard and sample gel patterns could be extracted from the
      proposed image analysis system. The time required for data collection and
      interpretation of 2D-CIEP images was shortened significantly and the results
      obtained have a higher accuracy than those obtained by using conventional
      methods. Moreover, a linear relationship between the peak area and the amount of
      antigen present in a sample was confirmed accurately and reported for the first
      time in the literature.

PMID- 10588041
TI  - Effect of ultrafiltration of yeast extracts on their ability to promote lactic
      acid bacteria growth.
AB  - Five yeast extracts (YE) were fractionated by ultrafiltration (UF) with 1, 3, and
      10 kDa molecular weight cutoff membranes, concentrated by freeze-drying, and the
      resulting powders of yeast extract filtrates (YEF) were evaluated for their
      growth-promoting properties on nine cultures of lactic acid bacteria (LAB). There
      was an increase in alpha-amino nitrogen content of the YEF powders as the pore
      size of the UF membranes used to filter the YE solutions decreased. The source of
      YE had a much greater effect than UF on the growth of LAB. This was also the case
      for the YEF contents in total and alpha-amino nitrogen. Growth curves of the LAB
      showed that maximum growth rate (mumax) data were on average 30% higher with
      bakers' YE than with brewers' YE, while maximum optical density (ODmax) values
      were on average 16% higher with bakers' YE. This could be related to the higher
      nitrogen content of the bakers' YE used in this study. Modification by UF of the
      YE had no significant influence on the growth of 4 of the 9 LAB strains. The
      three strains of Lactobacillus casei were negatively influenced by UF, as they
      did not grow as well in the media containing the YEF obtained after filtering
      with 1 and 3 kDa membranes. On a total solids basis, the 2.5 x retentates from
      the 10 kDa membrane gave, on average, 4% lower mumax and 5% lower ODmax values as
      compared to cultures where the corresponding YEF was used as medium supplement.
      This could also be partially related to the different nitrogen contents of the
      filtrates and retentates.

PMID- 10588042
TI  - Conjugal transfer of a TOL-like plasmid and extension of the catabolic potential
      of Pseudomonas putida F1.
AB  - Strain mX was isolated from a petrol-contaminated soil, after enrichment on
      minimal medium with 0.5% (v/v) meta-xylene as a sole carbon source. The strain
      was tentatively characterized as Pseudomonas putida and harboured a large plasmid
      (pMX) containing xyl genes involved in toluene or meta-xylene degradation
      pathways via an alkyl monooxygenase and a catechol 2,3-dioxygenase. This new TOL
      like plasmid was stable over two hundred generations and was self-transferable.
      After conjugal transfer to P. putida F1, which possesses the Tod chromosomal
      toluene biodegradative pathway, the transconjugant P. putida F1(pMX) was able to
      grow on benzene, toluene, meta-xylene, para-xylene, and ethylbenzene compounds as
      the sole carbon sources. Catechol 2,3-dioxygenases of the transconjugant cells
      presented a more relaxed substrate specificity than those of parental cells
      (strain mX and P. putida F1).

PMID- 10588043
TI  - Sequencing as a tool in yeast molecular taxonomy.
AB  - The literature on sequencing as a tool for yeast molecular taxonomy is reviewed.
      Ribosomal DNA has been preferred for sequencing over other molecules such as
      mitochondrial DNA, and a large database is now available. rDNA consists of
      regions that evolve at different rates, allowing comparison of different levels
      of relationship among yeasts. Sequences of the 18S rDNA and the 25S rDNA have
      been largely used for yeast systematics and phylogeny, but the search for regions
      with increased resolving power has led to the study of the spacer regions of the
      rDNA. Few studies are concerned with signature sequences.

PMID- 10588044
TI  - Arginine biosynthesis in Campylobacter jejuni TGH9011: determination of the
      argCOBD cluster.
AB  - Arginine biosynthetic genes from Campylobacter jejuni TGH9011 were cloned by
      functional complementation of the respective Escherichia coli arginine
      biosynthetic mutants. Complementation of argA, argB, argC, argD, argE, argF, and
      argH auxotrophs was accomplished using a pBR322-based C. jejuni TGH9011 plasmid
      library. By cross-complementation analyses, the first four steps of arginine
      biosynthesis were shown to be closely linked on the genome. Two additional clones
      complementing the first (ArgA) and fifth (ArgE) steps in arginine biosynthesis
      were obtained. Neither recombinant showed linkage to the arg cluster, to each
      other, nor to other arginine biosynthetic functions by cross-complementation.
      Genes argF and argH were not linked to other arginine biosynthetic genes by cross
      complementation analysis. Restriction enzyme patterns of recombinant plasmids
      fell into five groups. Group I contained the arg(ABCD) complementing locus. Group
      II and Group III were the two genetic loci corresponding to the argA and argE
      complementing genes. Group II contains the hipO gene encoding N-benzoylglycine
      amino-acid amidohydrolase, also known as hippurate hydrolase. Group III contains
      the hipO homolog of C. jejuni. Group IV represents the argF gene. Group V is the
      argH gene. Functional complementation of mutations in the first four steps of the
      arginine biosynthetic pathway was obtained on recombinant plasmid pARGC2. The
      predicted order of gene complementation was argCargA(argBargD). The sequence of
      the insert in plasmid pARGC2 revealed direct homologs for argC, argB, and argD.
      However, sequence analysis of the gene complementing ArgA function in two
      separate E. coli argA mutants determined that the C. jejuni gene was not a
      canonical argA gene. The gene complementing the argA defect, which we call argO,
      showed limited homology to the streptothricin acetyltransferase gene (sat) of
      Escherichia coli. The flanking open reading frames in pARGC2 showed no homologies
      to arginine biosynthetic genes. The structure of the argCOBD gene arrangement is
      discussed with reference to the presence and location of other arginine
      biosynthetic genes on the genome of C. jejuni and other bacterial organisms.

PMID- 10588045
TI  - Characterization of a Neocallimastix patriciarum xylanase gene and its product.
AB  - A xylanase gene (xynC) isolated from the anaerobic ruminal fungus Neocallimastix
      patriciarum was characterized. The gene consists of an N-terminal catalytic
      domain that exhibited homology to family 11 of glycosyl hydrolases, a C-terminal
      cellulose binding domain (CBD) and a putative dockerin domain in between. Each
      domain was linked by a short linker domain rich in proline and alanine. Deletion
      analysis demonstrated that the CBD was essential for optimal xylanase activity of
      the enzyme, while the putative dockerin domain may not be required for enzyme
      function.

PMID- 10588046
TI  - Imunosuppression by a corticosteroid fails to exacerbate Helicobacter pylori
      infection in a mouse model of gastric colonization.
AB  - Helicobacter pylori can colonize the human stomach for prolonged periods of time,
      and this colonization uniformly leads to the development of chronic active
      gastritis. In a small percentage of individuals, gastric pathology progresses to
      peptic ulceration or more rarely certain gastric cancers. In addition to non
      specific inflammation, specific systemic and local immunity develops in response
      to gastric colonization by this pathogen. However, these responses combined
      appear inadequate for eliminating H. pylori from the gastric mucosa. This is also
      the case in a mouse model of gastric colonization by H. pylori. In the present
      study, we attempted to determine whether the mammalian host response to infection
      with H. pylori exerts any overt antibacterial effects. To this end we examined H.
      pylori colonization in normal mice, and mice immunosuppressed by treatment with a
      corticosteroid. Despite obvious suppression of the immune response in the latter
      mice, H. pylori burdens remained similar in both groups after three months of
      colonization. This suggests that the murine host response, at least, exerts
      little obvious protection against H. pylori colonization.

PMID- 10588047
TI  - Protein kinase associated with ribosomes of streptomycetes.
AB  - Protein kinases can be classified into two main superfamilies on the basis of
      their sequence similarity and substrate specificity. The protein His kinase
      superfamily which autophosphorylate a His residue, and superfamily Ser/Thr and
      Tyr protein kinases, which phosphorylate Ser, Thr or Tyr residues. During the
      last years genes encoding Ser/Thr protein kinases have been identified in several
      microorganisms. Phosphorylation of proteins on Ser/Thr residues can be involved
      in many functions of prokaryotic cells including cell differentiation, signal
      transduction and protein biosynthesis. Phosphorylation of prokaryotic protein
      synthesizing systems showed that the phosphorylation of initiation and elongation
      factors is subject to alteration during cell differentiation or bacteriophage
      infection. Protein kinase associated with ribosomes of streptomycetes
      phosphorylate the elongation factor Tu and 11 ribosomal proteins even in
      bacteriophage-uninfected cells. After phosphorylation of ribosomal proteins,
      ribosomes lose about 30% of their activity at the translation of poly(U).

PMID- 10588048
TI  - Translational regulation by modifications of the elongation factor Tu.
AB  - EF-Tu from E. coli, one of the superfamily of GTPase switch proteins, plays a
      central role in the fast and accurate delivery of aminoacyl-tRNAs to the
      translating ribosome. An overview is given about the regulatory effects of
      methylation, phosphorylation and phage-induced cleavage of EF-Tu on its function.
      During exponential growth, EF-Tu becomes monomethylated at Lys56 which is
      converted to Me2Lys upon entering the stationary phase. Lys56 is in the GTPase
      switch-1 region (residues 49-62), a strongly conserved site involved in
      interactions with the nucleotide and the 5' end of tRNA. Methylation was found to
      attenuate GTP hydrolysis and may thus enhance translational accuracy. In vivo 5
      10% of EF-Tu is phosphorylated at Thr382 by a ribosome-associated kinase. In EF
      Tu-GTP, Thr382 in domain 3 has a strategic position in the interface with domain
      1; it is hydrogen-bonded to Glu117 that takes part in the switch-2 mechanism, and
      is close to the T-stem binding site of the tRNA, in a region known for many
      kirromycin-resistance mutations. Phosphorylation is enhanced by EF-Ts, but
      inhibited by kirromycin. In reverse, phosphorylated EF-Tu has an increased
      affinity for EF-Ts, does not bind kirromycin and can no longer bind aminoacyi
      tRNA. The in vivo role of this reversible modification is still a matter of
      speculation. T4 infection of E. coli may trigger a phase-exclusion mechanism by
      activation of Lit, a host-encoded proteinase. As a result, EF-Tu is cleaved site
      specifically between Gly59-Ile60 in the switch-1 region. Translation was found to
      drop beyond a minimum level. Interestingly, the identical sequence in the related
      EF-G appeared to remain fully intact. Although the Lit cleavage-mechanism may
      eventually lead to programmed cell death, the very efficient prevention of phage
      multiplication may be caused by a novel mechanism of in cis inhibition of late T4
      mRNA translation.

PMID- 10588050
TI  - Structure and function of the stalk, a putative regulatory element of the yeast
      ribosome. Role of stalk protein phosphorylation.
AB  - The ribosomal stalk is involved directly in the interaction of the elongation
      factors with the ribosome during protein synthesis. The stalk is formed by a
      complex of five proteins, four small acidic polypeptides and a larger protein
      which directly interacts with the rRNA at the GTPase center. In eukaryotes, the
      acidic components correspond to the 12 kDa P1 and P2 proteins, and the RNA
      binding component is protein P0. All these proteins are found to be
      phosphorylated in eukaryotic organisms. Previous in vitro data suggested this
      modification was involved in the activity of this structure. To confirm this
      possibility a mutational study has shown that phosphorylation takes place at a
      serine residue close to the carboxyl end of proteins P1, P2 and P0. This serine
      is part of a consensus casein kinase II phosphorylation site. However, by using a
      yeast strain carrying a temperature sensitive mutant, it has been shown that CKII
      is probably not the only enzyme responsible for this modification. Three new
      protein kinases, RAPI, RAPII and RAPIII, have been purified and compared with
      CKII and PK60, a previously reported enzyme that phosphorylates the stalk
      proteins. Differences among the five enzymes have been studied. It has also been
      found that some typical effectors of the PKC kinase stimulate the in vitro
      phosphorylation of the stalk proteins. All the data available suggest that
      phosphorylation, although it is not involved in the interaction of the acidic
      proteins with the ribosome, affects ribosome activity and might participate in
      some ribosome regulatory mechanism.

PMID- 10588049
TI  - Protein kinases phosphorylating acidic ribosomal proteins from yeast cells.
AB  - Phosphorylation of ribosomal acidic proteins of Saccharomyces cerevisiae is an
      important mechanism regulating a number of active ribosomes. The key role in the
      regulatory mechanism is played by specific phosphoprotein kinases and
      phosphoprotein phosphatases. Three different cAMP-independent protein kinases
      phosphorylating acidic ribosomal proteins have been identified and characterized.
      The protein kinase 60S (PK60S), RAP kinase, and casein kinase type 2 (CK2). All
      three protein kinases phosphorylate serine residues which are localized in the C
      terminal end of phosphoproteins. Synthetic peptides were used to determinate the
      amino acid sequence of phosphoacceptor site for PK60S. Peptide AAEESDDD derived
      from phosphoproteins YP1 beta/beta' and YP2 alpha turned out to be the best
      substrate for PK60S. A number of halogenated benzimidazoles and 2
      azabenzimidazoles were tested as inhibitors of the three protein kinases. 4,5,6,7
      Tetrabromo-2-azabenzimidazole inhibits phosphorylation only of these polypeptides
      phosphorylated by protein kinase 60S, namely YP1 beta/beta' and YP2 alpha, but
      not the other, YP1 alpha and YP2 beta phosphorylated by protein kinases RAP and
      CK2. RAP kinase has been found in an active form in the soluble fraction of S.
      cerevisiae. The enzyme uses ATP as a phosphate donor and is less sensitive to
      heparin than casein kinase 2. RAP kinase monophosphorylates the four acidic
      proteins. The ribosome-bound proteins are a better substrate for the enzyme.
      Multifunctional CK2 kinase phosphorylate all four acidic proteins. The kinase
      phosphorylates preferentially serine or threonine residues surrounded by cluster
      of acidic residues. The enzyme activity is stimulated in vitro by the presence of
      polylysine and inhibited by heparin.

PMID- 10588051
TI  - Aerobic growth and toxigenicity of Clostridium botulinum types A and B.
AB  - Clostridium botulinum types A and B cultured in association with avian skin
      flora, had similar growth patterns under both aerobic and anaerobic conditions.
      The selective "C. botulinum isolation" (CBI) medium was found to be especially
      useful for the recovery and quantitation of small numbers of type A or type B
      organisms from the mixed cultures. Enzyme immunoassay in conjunction with
      conventional mouse bioassay provided a practical means for the quantitation of
      toxigenicity of C. botulinum in avian skin cultures. The amount of toxin produced
      by type A was always higher than that produced by type B strains. The aerobically
      incubated type A or type B cultures appeared to be less toxigenic than cultures
      incubated anaerobically.

PMID- 10588052
TI  - Use of mutated PDR3 gene as a dominant selectable marker in transformation of
      prototrophic yeast strains.
AB  - For successful transformation of prototrophic industrial yeast strains dominant
      selectable markers are necessary. In the present study we show the applicability
      of a selection system based on the phenotype of multidrug resistance. The mutant
      pdr3-9 allele on centromeric or episomal vector, encoding a more efficient
      transcriptional activator with Y276H amino acid substitution, was used as a
      dominant selectable marker for selection of transformants. The pdr3-9 allele
      conferred resistance of transformed cells to cycloheximide, chloramphenicol,
      mucidin and oligomycin both in the absence and in the presence of a chromosomal
      copy of the PDR3 gene. Both multicopy YEp352/pdr3-9 and centromeric pFL38/pdr3-9
      vectors bearing the mutant pdr3-9 allele have proved to be a valuable tool for a
      direct selection of transformants of industrial strains of Saccharomyces
      cerevisiae.

PMID- 10588053
TI  - The influence of the growth phase of enteric bacteria on electrotransformation
      with plasmid DNA.
AB  - Salmonella typhimurium LB5000 and Escherichia coli JM109 were transformed by
      electroporation. In accordance with the chemical transformation methods, the
      growth phase of these electrocompetent bacteria had a strong impact on
      transformation efficiency. Survival of bacteria after the high-voltage electrical
      pulse was also influenced by the growth phase. Both bacterial species were most
      successfully electrotransformed when microbial cells were harvested at the late
      lag phase. The second optimum for transformation reached E. coli cells in the mid
      exponential and S. typhimurium cells in the late exponential phase.
      Transformation efficiencies ranged from 3.4 x 10(4) to 2.7 x 10(5) transformants
      per microgram DNA in the case of S. typhimurium and from 2.8 x 10(2) to 8.8 x
      10(5) transformants per microgram DNA in the case of E. coli. Survival of cells
      after the electrical pulse in late lag and late exponential phases was about 20%
      higher than during other phases of growth. Preparing electrocompetent cells from
      later phases of their growth is more useful for practice, because it provides
      more biomass with good yield of transformants.

PMID- 10588054
TI  - Antibacterial effect of some substituted tricyclic quinazolines and their
      synthetic precursors.
AB  - Eleven substituted tricyclic quinazolines and their synthetic precursors were
      tested for antibacterial effects. 3-Chloromethylcarbonyl-2-methylquinazolin-4
      thione and 5-phenyl-2,3-dihydro-1,2,4-triazolo[4,3-c]quinazolin-3-one had the
      highest antibacterial effect against Bacillus subtilis, the MIC values being 50
      mg/L. Two tested derivatives were more active against Pseudomonas aeruginosa than
      ampicillin, the IC50 values being 80 and 100 mg/L. The most effective derivatives
      contained in the structure generally pharmacologically active chromophores-
      methyl group in position 2 and a chloromethyl configuration on the carbonyl group
      in position 3.

PMID- 10588055
TI  - Microbial populations, ammonification and nitrification in soil treated with urea
      and inorganic salts.
AB  - Soil fertilization with urea at rates of 0.2 and 0.5 mg N/g soil was toxic for
      total counts of bacteria and fungi except with cellulolytic fungi where growth
      was promoted by addition of urea after 90-d incubation. Also, the population
      numbers of both bacteria and fungi were significantly decreased when soil was
      amended with CaCl2 and K2SO4 applied at two levels (50 and 100 mumol/g soil).
      Some alleviation of the toxic effect of either urea or the inorganic salts was
      observed when they were applied in combination. Fungal species composition was
      found to be affected in the treated soil. The most tolerant fungi were Alternaria
      alternata, Aspergillus flavus, A. fumigatus, A. niger, A. terreus, Eurotium
      amstelodami, E. chevalieri, Nectria haematococca, Paecilomyces variotii and
      Stachybotrys chartarum. Other species of fungi were either sensitive to all
      treatments or sensitive to some and tolerant to others. Ammonium nitrogen was
      found to be more accumulated in soil treated with urea mixed with inorganic salts
      compared with soil treated only with urea whereas NO3(-)-N (and NO2(-)-N) was
      decreased. The overall effect of the addition of inorganic salts on total
      mineralized nitrogen, however was promotive. Soil pH was increased in urea
      treated soil but was depressed by application of CaCl2 or K2SO4 to values lower
      than that of untreated soil. The results may be of agronomical interest in
      overcoming problems encountered with urea application as N fertilizer.

PMID- 10588056
TI  - The AgNORs.
AB  - The structure and the function of interphase AgNORs and the importance of the
      "AgNOR" parameter in tumor pathology have been reviewed. Interphase AgNORs are
      structural-functional units of the nucleolus in which all the components
      necessary for ribosomal RNA synthesis are located. Two argyrophilic proteins
      involved in rRNA transcription and processing, nucleolin and nucleophosmin, are
      associated with interphase AgNORs and are responsible for their stainability with
      silver methods, thus allowing interphase AgNORs to be visulaized at light
      microscopic level, also in routine cyto-histopathological preparations. The
      number of interphase AgNORs is strictly related to rRNA transcriptional activity
      and, in continuously proliferating cells, to the rapidity of cell proliferation.
      Evaluation of the quantitative distribution of interphase AgNORs has been applied
      in tumor pathology both for diagnostic and prognostic purposes. The "AgNOR"
      parameter has been proved to represent a reliable tool for defining the clinical
      outcome of cancer disease, being an independent prognostic factor in many types
      of tumors.

PMID- 10588057
TI  - The AgNOR proteins: qualitative and quantitative changes during the cell cycle.
AB  - AgNOR proteins are a set of argyrophilic nucleolar proteins that accumulate in
      highly proliferating cells whereas their expression is very low in non
      proliferating cells. Some of these proteins remain associated with the nucleolar
      organizer regions (NORs) during mitosis. In situ, the expression of AgNOR
      proteins is measured globally by quantification of the level of silver staining
      using morphometry and image analysis. To go deeper into the understanding of the
      relationship between the cell cycle and quantity of AgNOR proteins, it was
      necessary to determine the phases of cell cycle during which expression of AgNOR
      varies and what are the most variable proteins in each phase. To answer these
      questions, we set up the protocol permitting to detect and quantify AgNOR
      proteins on protein samples electrophoresed and transferred onto nitrocellulose
      membranes. This approach makes it possible to quantitatively evaluate individual
      AgNOR proteins and identify them, using nucleolar, nuclear and whole interphasic
      cell extracts, and chromosome-associated protein extracts. By this means, we
      identified nucleolin and protein B23 as the two major AgNOR proteins in the
      nucleolus during interphase and subunits of RNA polymerase I and transcription
      factor UBF as AgNOR proteins remaining associated with NORs during mitosis. We
      also observed that the increase in the level of nucleolin and protein B23 in rat
      liver seems to be linked with the cell cycle and not exclusively with stimulation
      of ribosomal gene (rDNA) transcription. Similarly in synchronized cells, the
      amount of nucleolin rapidly increases when cells enter the S phase (1.6-fold of
      the value of serum-deprived cells at 9 h, and 2.35-fold at 12 h after refeeding).
      The amount of protein B23 exhibits a lower and progressive increase with a
      maximum when the percentage of cells in G2 phase increased, i.e. after 24 h of
      cell cycle stimulation. We consider that the amount of AgNOR proteins can be a
      marker of proliferation, because this amount is related to cell cycle phases,
      schematically low for G1 phase and high for S-G2 phase. Thus, it is a measure of
      the relative proportion of cells in each phase, and consequently of the timing of
      each phase. The higher value indicates that the major part of the cells are in
      the S-G2 phase and correlatively few are in the G1 phase, and this characterizes
      a rapid cell cycle.

PMID- 10588058
TI  - AgNOR staining and quantification.
AB  - Nucleolar organiser regions (NORs) are defined as nucleolar components containing
      a set of argyrophilic proteins, which are selectively stained by silver methods.
      After silver-staining, the NORs can be easily identified as black dots
      exclusively localised throughout the nucleolar area, and are called "AgNORs". The
      NORs' argyrophilia is due to a group of nucleolar proteins, which have a high
      affinity for silver (AgNOR proteins). A number of studies carried out in
      different tumour types demonstrated that malignant cells frequently present a
      greater AgNOR protein amount than corresponding non-malignant cells. Moreover, in
      cancer tissues AgNOR protein expression was found to be strictly related to the
      cell duplication rate. Over the past 12 years, the "AgNOR method" has been
      applied in tumour pathology for both diagnostic and prognostic purposes. However,
      the lack of a standardised silver-staining protocol has led to much
      misinterpretation of actual structures evaluated in individual studies. Indeed,
      the absolute AgNOR scores reported by different authors for the same types of
      tumour are scarcely comparable and the results produced by these investigations
      sometimes seem to be conflicting. In order to achieve definitive standardisation
      of the AgNOR method and produce comparable data in all laboratories, the
      "International Committee on AgNOR Quantitation" was founded, and during the first
      Workshop "AgNORs in Oncology" held in Berlin in 1993 guidelines for AgNOR protein
      evaluation were first defined. The present paper discusses the main technical
      aspects of NOR silver-staining, and critically evaluates the methods commonly
      employed for AgNOR protein quantification in routine cyto-histopathology.

PMID- 10588059
TI  - Prognostic relevance of AgNORs in tumor pathology.
AB  - The importance of the analysis of the silver-stained nucleolar organizer regions
      (AgNORs) for prognostic purposes in tumor pathology has been reviewed. Current
      available data from the literature demonstrate that the evaluation of the
      quantity of interphase AgNORs is an independent prognostic factor in several
      types of human tumors. Results of our investigations indicate that AgNORs are the
      most powerful variable predicting survival in patients with pharyngeal carcinoma,
      multiple myeloma, male breast and prostate carcinoma. The combination of AgNOR
      counts and histologic pattern allows the stratification of patients with multiple
      myeloma, pharyngeal and prostate carcinoma into low- and high-risk groups, which
      could benefit from different therapy. Moreover, AgNOR analysis predicts response
      to treatment in adult patients with acute myelogenous leukemia, and appears as an
      independent prognostic factor in a prospective study on renal cell carcinoma.
      Therefore, AgNOR analysis is a really important prognostic factor for several
      human neoplasias. The experimental and theoretical justifications for AgNORs as a
      prognostic factor are also reviewed, in particular the strict correlation between
      AgNOR quantity and tumor cell doubling time. Lastly, the lack of prognostic
      significance of AgNOR analysis in some circumstances is critically discussed.

PMID- 10588060
TI  - AgNORs in breast tumours.
AB  - There is evidence that the quantitative distribution of AgNOR proteins is a
      proliferation-related parameter that can be used as a prognostic index in tumour
      pathology. In breast cancer, some authors found a significant prognostic
      correlation of AgNOR protein quantity, whereas other did not. However, in all the
      reports dealing with AgNOR area (as opposed to count) this parameter was always
      turned out to be an independent prognostic indicator. The present study tests the
      significance of AgNOR proteins in a large series of primary breast carcinomas,
      exploring the associations between the AgNOR protein amount, as evaluated by
      image cytometry, and the other well-established prognostic markers commonly
      considered for breast cancer, along with patients' survival. Our results
      demonstrated a highly significant association between AgNOR protein quantity and
      tumour prognosis. Moreover, when the AgNOR area values were entered in
      multivariate analysis together with the other predictive parameters commonly
      considered in breast carcinomas, they showed an independent prognostic value
      together with Ki67-labelling index (LI), N-status and tumour size. Considering
      node-negative and -positive cases separately, the AgNOR protein area and Ki67-LI
      both come out as a independent predictors only in the latter group: the short
      follow-up time of our series (36 months median) could be responsible for this
      discrepancy.

PMID- 10588061
TI  - Proliferation assessment in breast cancer: a double-staining technique for AgNOR
      quantification in MIB-1 positive cells especially adapted for image cytometry.
AB  - There are two ways of measuring the cell proliferation. The first one consists of
      quantifying the number of cycling cells with the help of antibodies directed
      against cells either in G1, S, G2 or M phase. The second way is to assess the
      cell cycle duration by the quantification of AgNOR proteins. Measuring both the
      features on the same slide represents an attractive way to tackle the
      proliferating activity of a cell culture or a tumor. Here, we propose a MIB-1 and
      AgNOR double staining method especially adapted to image cytometry measurement
      using MIB-1 antibody coupled to FITC in order to avoid the thresholding problems
      encountered with such a multilabeling technique. We have applied this new method
      on a series of 39 breast cancer cases, with at least 4 years follow-up, in order
      to determine the prognosis significance of this measurement. MIB-1 alone is not
      linked to prognosis, while the global mean AgNOR area is significantly linked to
      prognosis in terms of development of visceral metastasis or death. However, the
      global mean AgNOR area is insufficient to determine the time limit of appearance
      of metastasis or relapse. Our results clearly demonstrate that a high mean AgNOR
      area within a cell population having a high MIB-1 index can discern tumors with a
      high metastatic potential. By multiplying AgNOR area by the percentage of MIB-1
      positive cells we calculate the proliferative activity, P, which brings very
      important information concerning the time limit of relapse.

PMID- 10588062
TI  - In situ standardised AgNOR analysis: a simplified method for routine use to
      determine prognosis and chemotherapy efficiency in colorectal adenocarcinoma.
AB  - Standardised AgNOR analysis as recommended by the Committee on AgNOR Quantitation
      of the European Society of Pathology is now regarded as the gold standard,
      particularly when retrospective studies on archival, formalin-fixed, and paraffin
      embedded material are performed. This article deals with the implementation of
      the standardised AgNOR method in colorectal carcinoma and its consequent impact
      on clinical decision making. First, the clinical relevance of AgNOR analysis as a
      major and independent prognostic factor in exclusively surgically treated
      adenocarcinomas of the colon and rectum is elucidated. Additionally, due to the
      fact that in last 10 years 5-Fluorouracil based chemotherapy and radiotherapy
      have become standard treatment in a variety of tumour stages, the outstanding
      predictive power of AgNOR analysis with regard to chemotherapy efficiency is
      emphasised.

PMID- 10588063
TI  - Radiation response of cell organelles.
AB  - The cellular responses to various form of radiation, including ionizing- and UV
      irradiation or exposure to electromagnetic fields is manifested as irreversible
      and reversible structural and functional changes to cells and cell organelles.
      Moreover, beside the morphological signs related to cell death, there are several
      reversible alterations in the structure of different cell organelles. The
      radiation-induced changes in the supramolecular organization of the membranes,
      including plasma membrane, and different cell organelle membranes, play a
      significant role in the development of acute radiation injury. These signs of
      radiation-induced reversible perturbation biological membranes reflect changes in
      the organization and/or composition of the glycocalix, modified activity and/or
      distribution of different membrane domains, including enzymes and binding sites.
      The observed changes of the cell surface micromorphology and the alteration of
      intercellular connections are closely related to the reorganization of the
      cytoskeletal elements in the irradiated cells. The mitochondria, endoplasmic
      reticulum, Golgi-complex, the lysosomal system have long been considered to be
      direct intracellular targets of irradiation. The listed morphological alterations
      of nuclear chromatin (e.g. changes of fine structure, altered number of nucleolar
      organizing regions and micronuclei, development of chromosome aberrations) may
      originate from the radiation-induced damage to the supramolecular organization of
      DNA and/or nucleus specific proteins. These endpoints of radiation effects
      resulted as direct consequence(s) of absorbed radiation energy, and indirectly
      altered intra-, intercellular communication or modified signal transduction. Some
      complementary data suggest that all these effects are not strictly specific to
      radiation and may be best considered as general stress responses, similar to
      those observed after application of various injurious agents and treatments to
      cells. Moreover, they may be equally responsible for direct degradation of
      supramolecular component of cells, altered signal transduction, or changes in the
      amount or ratio of any extracellular mediators upon irradiation. Nevertheless,
      qualitative and/or quantitative evaluation of any changes of chromosomes by
      different techniques (morphological analysis of metaphase chromosomes,
      fluorescent in situ hybridization, development of micronuclei etc.) are useful
      biological indicators as well as "biological dosimeters" of radiation injury. It
      is suggested, that some modern methods such as immunohistochemical detection of
      different proteins, specific markers of cell organelles and cytoskeleton,
      inspection of distribution of cell surface charged sites and different membrane
      domains and application of tracer substances may all be included into protocols
      for evaluation of cell alterations induced by different types and intensities of
      radiation.

PMID- 10588064
TI  - Characterization of benzylalcohol acetyltransferases in scented and non-scented
      Clarkia species.
AB  - The floral scent of Clarkia breweri, an annual native to California, contains
      copious amounts of benzylacetate, which is synthesized by a reaction of
      benzylalcohol and acetyl-CoA that is catalyzed by acetyl-CoA:benzylalcohol
      acetyltransferase (BEAT). Here we demonstrate that different lines of C. breweri
      contain different levels of BEAT activity even though they have similar levels of
      BEAT mRNA. We also present evidence that the genome of C. breweri's non-scented
      progenitor, C. concinna, contains BEAT genes, but that its flowers have little
      BEAT enzymatic activity. This is due to the fact that although C. concinna BEAT
      genes are transcribed in the flowers, the single intron in these transcripts is
      almost never spliced out, and when the intron is spliced out, the resulting
      enzyme has higher affinity with substrates other than benzylalcohol. These
      results indicate that the regulation of BEAT activity in Clarkia involves post
      transcriptional mechanisms.

PMID- 10588065
TI  - Functional analysis of retrotransposons in pea.
AB  - The 5'-upstream regions of the plant active defense genes in pea (PSPAL2 and
      PSCHS1) exhibit significant nucleotide sequence identity to part of a copia-type
      retrotransposon. To characterize the retrotransposon in pea putative reverse
      transcriptase sequences (Psr) were amplified by PCR from cDNA prepared from
      protoplasts derived from pea suspension cultured cells. Psr genes can be
      classified into at least eight subgroups (A-H) according to their nucleotide
      sequence similarities. A subgroup PsrC was induced by the treatment of etiolated
      pea epicotyls with fungal elicitor within 30 min but was hardly induced by
      protoplasting of pea suspension cultured cells, whereas subgroups of PsrA and
      PsrB were highly induced by protoplasting. Interestingly, the retrotransposon
      sequence present at the 5'-upstream region of PSCHS1 which was induced by the
      treatment with fungal elicitor belonged to subgroup PsrC. The retrotransposon
      might play an important role in reorganization of the genes and optimization of
      the gene expression in response to various environmental stimuli such as an
      attack by phytopathogens or protoplasting.

PMID- 10588066
TI  - Stomata from npq1, a zeaxanthin-less Arabidopsis mutant, lack a specific response
      to blue light.
AB  - The Arabidopsis mutant npq1, which cannot accumulate zeaxanthin because of a
      defective violaxanthin deepoxidase, was used to investigate the role of
      zeaxanthin in the stomatal response to blue light. Neither dark-adapted nor light
      treated guard cells or mesophyll cells of the npq1 mutant contained detectable
      zeaxanthin. In contrast, wild-type guard cells had a significant zeaxanthin
      content in the dark and accumulated large amounts of zeaxanthin when illuminated.
      The well-documented red light enhancement of blue light-stimulated stomatal
      opening, in which increasing fluence rates of background red light result in
      increased response to blue light, was used to probe the specific blue light
      response of Arabidopsis stomata. Stomata from the npq1 mutant did not have a
      specific blue light response under all fluence rates of background red light
      tested. On the other hand, stomata from leaves of hy4 (cry 1), an Arabidopsis
      mutant lacking blue light-dependent inhibition of hypocotyl elongation, had a
      typical enhancement of the blue light response by background red light. The lack
      of a specific blue light response in the zeaxanthinless npq1 mutant provides
      genetic evidence for the role of zeaxanthin as a blue light photoreceptor in
      guard cells.

PMID- 10588067
TI  - Carpel, a new Arabidopsis epi-mutant of the SUPERMAN gene: phenotypic analysis
      and DNA methylation status.
AB  - The carpel (car) mutation affects the morphology of reproductive organs in
      Arabidopsis thaliana. car flowers have an increased number of carpels, on average
      2.7 +/- 0.8 instead of two in the wild type. Through allelism test with fon1-3
      and analysis of the methylation state of the SUPERMAN (SUP) gene in car mutants,
      we show that car is an epi-mutation of SUP. The methylation pattern of car is
      clearly distinct from that of fon1-3, another epi-mutation of the SUP gene.
      Methylation was found predominantly in Cp(A/T)p(A/G) triplets and in CpG pairs.
      We suggest that the extensive SUP methylation in car has arisen from an abundant
      methylation of a single CpG site that was already present in abscisic acid
      insensitive (abi3-4) mutants, from which car was segregating.

PMID- 10588068
TI  - Induction of defense responses by synthetic glycopeptides that have a partial
      structure of the elicitor in the spore germination fluid of Mycosphaerella
      pinodes.
AB  - A high molecular weight elicitor (> 70 kDa) from spore germination fluid of a pea
      pathogen, Mycosphaerella pinodes, has a partial structure of beta-D-Glc-(1-->6)
      alpha-D-Man-(1-->6)-D-Man, which is O-glycosidically attached to serine in the
      protein moiety. To elucidate the minimum structure for the elicitor activity to
      pea plants, the effects of nine glycopeptides including beta-D-Glc-(1-->6)-alpha
      D-Man-(1-->6)-D-Man-O-Ser (No. 1) to [beta-D-Glc-(1-->6)-alpha-D-Man-(1-->6)-D
      Man]3-O-Ser3-Pro3 (No. 9) on the infection by M. pinodes, superoxide generation
      and ATPase activity were measured. The glycopeptides [beta-D-Glc-(1-->6)-alpha-D
      Man-(1-->6)-D-Man]-O-Ser2-Pro2 (No. 3) to No. 9 induced rejection reaction of pea
      tissue against M. pinodes. The glycopeptides No. 3 to No. 9 also induced
      superoxide generation on uninjured pea leaves. Moreover, the glycopeptides No. 3
      to No. 9 induced in vitro the activation of cell wall-bound ATPase and superoxide
      generation system in the protein fraction solubilized from pea cell wall. The
      results indicate that the synthetic glycopeptides, No. 3 to No. 9, are available
      to analyze the signal transduction cascade leading to defense responses and the
      receptor for the elicitor.

PMID- 10588069
TI  - cDNA cloning of sesquiterpene cyclase and squalene synthase, and expression of
      the genes in potato tuber infected with Phytophthora infestans.
AB  - Sesquiterpene cyclase and squalene synthase are key branch point enzymes in
      isoprenoid pathway for the synthesis of sesquiterpenoid phytoalexins and
      sterols/steroid glycoalkaloids, respectively. cDNA clones encoding these enzymes
      were isolated from potato. A phylogenetic tree showed that the sesquiterpene
      cyclase is vetispiradiene synthase. Infection of Phytophthora infestans with
      potato tubers caused transient increases in the transcript level of
      vetispiradiene synthase in a compatible and an incompatible interactions. On the
      other hand, wound-induced expression of the squalene synthase was suppressed in
      favor of the expression of vetispiradiene synthase regardless of inoculated
      races.

PMID- 10588070
TI  - Simulating cyanobacterial growth in a lowland reservoir.
AB  - MOTIVATION: There has been a rise in the incidence of reported cyanobacterial
      bloom contamination, in England and Wales associated with freshwaters, over the
      past 10 years. These blooms can, under certain environmental conditions, produce
      toxins, which can be harmful to mammals. This paper presents a new model of
      cyanobacterial growth that incorporates the functionality of earlier buoyancy
      regulation models. The model includes algorithms allowing temperature-correction
      of the main process rates; loss of colonies; net chlorophyll-a production and
      changes in colony size. RESULTS: The model was used to simulate cyanobacterial
      growth in a lowland impoundment in Southern England for 1994 and 1995. Predicted
      results were compared to observed data for the 2 consecutive years and the model
      results compare favourably with the observed data.

PMID- 10588071
TI  - Chromium levels in potable water, fruit juices and soft drinks: influence on
      dietary intake.
AB  - Potable water, fruit juices and soft drinks are some of the most widespread
      beverages in the habitual diet, and they can contribute to chromium dietary
      intake. We determined the concentration of chromium in 90 different samples of
      beverages widely consumed in Spain. Graphite furnace atomic absorption
      spectrometry was used to analyze samples processed with a HNO3-V2O5 acid
      digestion pretreatment. In water samples Cr was directly determined. We verified
      the sensitivity, accuracy and precision of the method and ruled out matrix
      interferences. In analyzed samples, chromium values ranged from not detectable to
      11.80 micrograms/l in potable water, from not detectable to 17.60 micrograms/l in
      fruit juices and from 3.60 to 60.50 micrograms/l in soft drinks. The chromium
      levels we encountered are low and the contribution of non-alcoholic beverages to
      dietary intake of this element, have been estimated to be 0.41 microgram/day in
      the common Spanish diet.

PMID- 10588072
TI  - Use of biomarkers in an indoor air study: lack of correlation between aromatic
      VOCs with respective urinary biomarkers.
AB  - The benzene and toluene levels inside of eight homes with attached garages were
      measured during July 1998 in Fairbanks, Alaska. A thermal desorption tube method
      and charcoal tube method were used to collect and analyze samples (thermal
      desorption tube method %RDS = 1.9 for n = 6; charcoal tube method %RDS = 6.5 for
      n = 4). Results for both methods were compared and showed indoor benzene levels
      ranging between 1.2 and 72 ppbv. The charcoal tube method usually gave lower
      results than the thermal desorption method. Nevertheless, the difference observed
      in benzene levels from each method was not significant as determined by
      application of the Wilcoxon t-test to these data. Using the thermal desorption
      method, the range of toluene found in homes was 0.1-111 ppbv. A correlation
      between toluene and benzene levels suggested the same point source. The benzene
      and toluene content of the indoor air and the number of small engines stored in
      the attached garage was also correlated. There was no correlation found between
      the urinary biomarker concentrations and the level of benzene or toluene measured
      inside the homes in the summer.

PMID- 10588073
TI  - Interaction between tobacco and alcohol consumption and the risk of cancers of
      the upper aero-digestive tract in Brazil.
AB  - The authors investigated the joint effects of tobacco and alcohol consumption on
      the risk of squamous cell carcinomas of the upper aero-digestive tract (UADT)
      using data from a hospital-based case-control study conducted in southern Brazil,
      1986-1989. A total of 784 cases of cancers of the mouth, pharynx, and larynx and
      1,578 non-cancer controls matched on age, sex, hospital catchment area, and
      period of admission were interviewed about their smoking and drinking habits and
      other characteristics. Using logistic regression, evidence was found for
      interaction between the cumulative exposures for smoking and alcohol on UADT
      cancer risk. The joint effects for pharyngeal cancers exceeded the levels
      expected under a multiplicative model for moderate smokers (p = 0.007). There was
      little statistical evidence, however, for interaction on cancers of the mouth (p
      = 0.28) or larynx (p = 0.95). Among never smokers, heavy drinkers had 9.2 times
      (95% confidence interval 1.7, 48.5) greater risk of cancers of mouth, pharynx,
      and supraglottis than never drinkers, with a dose-response trend (p = 0.013) with
      cumulative consumption. The authors conclude that the interaction occurring in
      the pharynx between smoking and alcohol on UADT cancers is not uniform, with
      varying effects depending on the level of smoking exposure. Alcohol may act as
      both a promoter for tobacco and as an independent risk factor.

PMID- 10588074
TI  - Invited commentary: more evidence of increased risks of cancer among alcohol
      drinkers.

PMID- 10588075
TI  - Risk factors for progression of distal symmetric polyneuropathy in type 1
      diabetes mellitus. Sorbinil Retinopathy Trial Research Group.
AB  - In a prospective cohort study, the authors examined risk factors for progression
      of distal symmetric polyneuropathy (DSP) in type 1 (insulin-dependent) diabetes
      mellitus. The study population consisted of participants in the Sorbinil
      Retinopathy Trial, a randomized trial of aldose reductase inhibition among
      patients aged 18-56 years with type 1 diabetes mellitus of 1-15 years' duration.
      Diagnosis of DSP was based on standardized clinical neurologic evaluation. A
      total of 407 participants who did not have definite DSP at randomization and had
      at least one follow-up visit were included in the analysis. Stepwise Cox
      proportional hazards models were used to examine the independent contribution of
      baseline variables to progression of DSP. During follow-up (median, 40 months),
      68 participants (17%) showed progression to definite DSP. After adjustment for
      age and treatment assignment, independent predictors of progression to definite
      DSP were total glycosylated hemoglobin (relative risk (RR) for increase of one
      percentage point = 1.25; 95% confidence interval (CI) 1.12, 1.39), height (RR
      associated with being one inch (2.54 cm) taller = 1.15; 95% CI 1.05, 1.26),
      cigarette smoking (ever vs. never) (RR = 1.87; 95% CI 1.09, 3.21), and female
      gender (RR = 2.26; 95% CI 1.09, 4.67). These data indicate that, in addition to
      the previously established role for total glycosylated hemoglobin, other factors
      including height, cigarette smoking, and female gender may also be independent
      risk factors for progression of DSP in type 1 diabetes mellitus.

PMID- 10588076
TI  - Body weight and mortality among adults who never smoked.
AB  - In a 12-year prospective study, the authors examined the relation between body
      mass index (BMI) and mortality among the 20,346 middle-aged (25-54 years) and
      older (55-84 years) non-Hispanic white cohort members of the Adventist Health
      Study (California, 1976-1988) who had never smoked cigarettes and had no history
      of coronary heart disease, cancer, or stroke. In analyses that accounted for
      putative indicators (weight change relative to 17 years before baseline, death
      during early follow-up) of pre-existing illness, the authors found a direct
      positive relation between BMI and all-cause mortality among middle-aged men
      (minimum risk at BMI (kg/m2) 15-22.3, older men (minimum risk at BMI 13.5-22.3),
      middle-aged women (minimum risk at BMI 13.9-20.6), and older women who had
      undergone postmenopausal hormone replacement (minimum risk at BMI 13.4-20.6).
      Among older women who had not undergone postmenopausal hormone replacement, the
      authors found a J-shaped relation (minimum risk at BMI 20.7-27.4) in which BMI
      <20.7 was associated with a twofold increase in mortality risk (hazard ratio (HR)
      = 2.2, 95% confidence interval (CI) 1.3, 3.5) that was primarily due to
      cardiovascular and respiratory disease. These findings not only identify
      adiposity as a risk factor among adults, but also raise the possibility that very
      lean older women can experience an increased mortality risk that may be due to
      their lower levels of adipose tissue-derived estrogen.

PMID- 10588077
TI  - Determination of risk factor associations with questionnaire outcomes: a methods
      case study.
AB  - Increasingly in biomedical studies, health status is inferred through a series of
      questionnaire item responses. Challenges for analyzing associations between such
      responses and risk factors include multiplicity-many indicators must be combined
      to derive summary statements about health status, and measurement error-persons'
      self-report fluctuates due to causes other than substantive health changes. In
      order to deal with these challenges, the authors propose a strategy which
      comprises three methods: 1) score the item responses, then regress the score on
      predictors; 2) regress each item response on predictors, accounting for within
      person associations; and 3) summarize and analyze the item responses jointly,
      using a latent variable model. The authors develop modeling and diagnostic
      procedures for method 3. They then show how the three-method analytic strategy
      can be used to solve the problem of determining which aspects of vision are
      associated with self-reported functioning in activities that require seeing at a
      distance. They demonstrate that methods 2 and 3 illuminate basic findings from
      method 1 by adding specificity, describing patterns as well as severities of
      health impairments, and identifying isolated items that relate to risk factors
      differentially than others. They conclude that the three-method strategy
      specifies how risk factors determine questionnaire-based health outcomes
      substantially better than any of the methods in isolation.

PMID- 10588078
TI  - Method to detect genotype-environment interactions for quantitative trait loci in
      association studies.
AB  - Khoury et al. (Am J Hum Genet 1988;42:89-95 and Am J Epidemiol 1993;137:1241-50)
      presented an epidemiologic approach to examine genotype-environment interaction
      in situations where the disease is either present or absent. In this article, the
      author extends the approach of Khoury et al. to quantitative outcome variables.
      This extension is relevant for diseases that are extremes on a continuum or when
      continuous risk factors are studied. To account for a possible admixture of
      subgroups in the sample, tests for genotype-environment interaction are discussed
      for designs with parents as controls as well as without parents as controls.
      Assuming two environmental conditions, the author demonstrates how the power of
      these tests can be calculated and used to estimate the sample sizes needed to
      detect genotype-environment interaction in a variety of conditions. In addition,
      he analyzes simulated data to demonstrate the detection of different mechanisms
      of genotype-environment interaction and to study the effectiveness of this
      approach to identify the correct mechanism. Finally, extensions to multiple
      environmental conditions and designs with multiple subjects per family are
      discussed.

PMID- 10588079
TI  - Variation over time of the effects of prognostic factors in a population-based
      study of colon cancer: comparison of statistical models.
AB  - The authors compare the performance of different regression models for censored
      survival data in modeling the impact of prognostic factors on all-cause mortality
      in colon cancer. The data were for 1,951 patients, who were diagnosed in 1977
      1991, recorded by the Registry of Digestive Tumors of Cote d'Or, France, and
      followed for up to 15 years. Models include the Cox proportional hazards model
      and its three generalizations that allow for hazard ratio to change over time: 1)
      the piecewise model where hazard ratio is a step function; 2) the model with
      interaction between a predictor and a parametric function of time; and 3) the non
      parametric regression spline model. Results illustrate the importance of
      accounting for non-proportionality of hazards, and some advantages of flexible
      non-parametric modeling of time-dependent effects. The authors provide empirical
      evidence for the dependence of the results of piecewise and parametric models on
      arbitrary a priori choices, regarding the number of time intervals and specific
      parametric function, which may lead to biased estimates and low statistical
      power. The authors demonstrate that a single, a priori selected spline model
      recovers a variety of patterns of changes in hazard ratio and fits better than
      other models, especially when the changes are non-monotonic, as in the case of
      cancer stages.

PMID- 10588080
TI  - Alcohol consumption and all-cause and cancer mortality among middle-aged Japanese
      men: seven-year follow-up of the JPHC study Cohort I. Japan Public Health Center.
AB  - To examine the association between alcohol consumption and mortality in Japan,
      where mortality and lifestyle differ substantially from Western countries, a
      population-based prospective study was conducted in four public health center
      areas as part of the Japan Public Health Center-based prospective study on cancer
      and cardiovascular disease (JPHC). After excluding subjects with self-reported
      serious diseases at baseline, 19,231 men aged 40-59 years who reported their
      alcohol intake were followed from 1990 through 1996, and 548 deaths were
      documented. The association between all-cause mortality and alcohol consumption
      was J-shaped. The lowest risk was observed for men who consumed 1-149 g/week
      (relative risk (RR) = 0.64, 95% confidence interval (CI) 0.46, 0.88), while the
      highest risk was seen for men who consumed > or =450 g/week (RR = 1.32, 95% CI
      1.00, 1.74), after adjustment for possible confounders. The association did not
      change after excluding deaths that occurred in the first 2 years of follow-up.
      However, the association was modified by smoking, and beneficial effects of
      moderate drinking were largely limited to nonsmokers. The risk of cancer death
      showed a similar trend, but increased more in heavy drinkers. The background
      characteristics of moderate drinkers were healthier than either nondrinkers or
      heavy drinkers. The authors conclude that moderate alcohol consumption was
      associated with the lowest risks of all-cause and cancer mortality, especially
      among nonsmokers.

PMID- 10588081
TI  - Parental age at child's birth and son's risk of prostate cancer. The Framingham
      Study.
AB  - The authors examined the relation of parental age at birth to the risk of
      prostate cancer among sons with the use of data from the Framingham Study. During
      42 years of follow-up (1949-1993), 141 prostate cancer cases occurred in 2,164
      men. All but six cases were confirmed by histologic report. The incidence rate of
      prostate cancer increased from 1.70 per 1,000 person-years among sons in the
      lowest quartile of paternal age (<27 years), to 2.00, 2.32, and 2.74 among those
      of each increased paternal age category (27-<32, 32-<38, and > or =38 years),
      respectively. After adjustment for age and other covariates, men in the second,
      third, and oldest quartiles of paternal age had 1.2, 1.3, and 1.7 times increased
      risk of prostate cancer compared with men in the youngest quartile (p for trend =
      0.049). Further adjustment for maternal age did not change the relation
      materially. The association of older paternal age with risk of early-onset
      prostate cancer (<65 years) appeared stronger than that with late-onset disease
      (265 years). No increased risk of prostate cancer was observed among subjects in
      the older maternal age category. The effect of increased paternal age on prostate
      cancer risk may operate through increased germ cell mutation rate or by
      mechanisms not yet defined.

PMID- 10588082
TI  - Homicide mortality in the United States, 1935-1994: age, period, and cohort
      effects.
AB  - The authors analyzed homicide mortality data for the United States from 1935 to
      1994, to delineate temporal trends and birth cohort patterns. This study included
      850,822 homicide-attributed deaths documented by the National Center for Health
      Statistics, and incorporated graphical presentation, median polish, and Poisson
      regression modeling in an age-period-cohort analysis. Death rates from homicide
      in the United States doubled in the past four decades, with most of the increase
      having occurred during the 1960s and early 1970s. Poisson regression models
      confirmed that the rise of homicide mortality in both men and women was largely
      attributable to a significant period effect between 1960 and 1974. No discernible
      cohort patterns were found among women. However, homicide rates for recent male
      birth cohorts appeared to peak at younger ages and at higher levels. A
      significant increase in homicide mortality risk beginning with males born around
      1965 was found by examining the residuals of median polish, and the second-order
      changes in the regression coefficients from the age-period-cohort model. The hike
      of homicide mortality during 1985 and 1994 was explained by this cohort effect.
      Increased prevalence of substance abuse and availability of firearms are two
      likely factors underlying this disturbing cohort pattern.

PMID- 10588083
TI  - Office equipment and supplies: a modern occupational health concern?
AB  - The Helsinki Office Environment Study, a population-based cross-sectional study
      was carried out in Finland in 1991 among 2,678 workers in 41 randomly selected
      office buildings. The aim was to evaluate the relations between work with office
      equipment and supplies and the occurrence of eye, nasopharyngeal, skin, and
      general symptoms (often denoted as sick building syndrome (SBS)), chronic
      respiratory symptoms, and respiratory infections. Work with self-copying paper
      was significantly related to weekly work-related eye, nasopharyngeal, and skin
      symptoms, headache and lethargy, as well as to the occurrence of wheezing, cough,
      mucus production, sinusitis, and acute bronchitis. Photocopying was related to
      nasal irritation, and video display terminal work to eye symptoms, headache, and
      lethargy.

PMID- 10588085
TI  - Modeling the impact of subclinical measles transmission in vaccinated populations
      with waning immunity.
AB  - An increasing body of evidence suggests that a substantial proportion of
      individuals who respond to measles vaccine display an antibody boost accompanied
      by mild or no symptoms on exposure to wild virus. It is unknown whether this
      emerging class of individuals can support transmission. The epidemiologic
      consequences of vaccinated individuals able to transmit virus are investigated
      using a mathematical model. Parameters for this model are estimated using
      regression analysis on a Canadian serologic data set. The authors confirm that
      neutralizing antibodies are decaying significantly in absence of circulating
      virus. Based on a protective threshold plaque reduction neutralization (PRN)
      titer of 120, the authors estimate the mean duration of vaccine-induced
      protection in absence of reexposure to be 25 years (95% confidence interval (CI)
      18, 48). After long-term absence of circulating virus, the mathematical model
      predicts that 80% (95% CI 65, 91) of all seroconverted vaccinees have titers
      below the protective threshold. In this case, elimination of measles virus cannot
      be achieved by a single-dose routine vaccination strategy if the basic
      reproduction number in vaccinated individuals exceeds 1.24 (95% CI 1.10, 1.53).
      For this reason, there is a need to establish the intensity and duration of
      infectiousness in vaccinated individuals.

PMID- 10588084
TI  - Sources of variation in plasma lipid and lipoprotein traits in a sample selected
      for health.
AB  - Substantial variation in plasma lipid, lipoprotein, and apolipoprotein B levels
      was found in a sample of healthy white collar workers aged 23-59 years (144
      women, 371 men) devoid of most clinically identifiable manifestations of
      cardiovascular disease or major biochemical anomalies and for whom data were
      gathered in Montreal, Canada, in 1987. The nature of this variability was
      examined for each gender by means of a stepwise linear regression analysis using
      indices of biologic variation and behavioral traits. In women, age, height, and
      weight together accounted for approximately 10% and uric acid for another 7-10%
      of total cholesterol, low density lipoprotein (LDL) cholesterol, and
      apolipoprotein B level variation. In men, age alone accounted for 13-16% of the
      total variation in these traits while uric acid contributed only 3%. The
      additional contribution of behavioral traits was found to be at least double that
      associated with the indices of biologic variation for measures of very low
      density lipoprotein (VLDL) and high density lipoprotein (HDL) cholesterol in
      women and HDL cholesterol in men. After taking all of the above into account,
      genetic variation determined by the three common apo E alleles explained an
      additional 6% of LDL cholesterol variation in women and 3.5% in men. These
      results emphasize the range of variability in lipid, lipoprotein, and
      apolipoprotein values in healthy individuals as well as important gender
      differences in the contribution of biologic, behavioral, and genetic factors in
      this variability.

PMID- 10588086
TI  - Measles epidemic in Romania, 1996-1998: assessment of vaccine effectiveness by
      case-control and cohort studies.
AB  - A measles epidemic occurred in Romania with 32,915 cases and 21 deaths reported
      between November 1996 and June 1998, despite high vaccination coverage since the
      early 1980s. Most cases were unvaccinated children aged <2 years and vaccinated
      school-aged children. A case-control study among preschool children and a cohort
      study among primary-school children were conducted to estimate effectiveness of
      Romanian-produced measles vaccine, and to evaluate age at vaccination and waning
      immunity as risk factors for vaccine failure. Both studies indicated that measles
      vaccine was highly effective. One dose reduced the risk for measles by 89% (95%
      confidence interval (CI) 85, 91); two doses reduced the risk by 96% (95% CI 92,
      98). Children vaccinated at <1 year of age were not at increased risk for measles
      compared with children vaccinated at > or =1 year. Waning immunity was not
      identified as a risk factor since vaccine effectiveness was similar for children
      vaccinated 6-8, 9-11, and 12-14 years in the past. Because specific groups were
      not at risk for vaccine failure, an immunization campaign that targets all school
      aged children who lack two doses may be an effective strategy for preventing
      outbreaks. A mass campaign followed by increased first-dose coverage should
      provide the population immunity required to interrupt indigenous measles virus
      transmission in Romania.

PMID- 10588087
TI  - Re: "Magnetic field exposure and cardiovascular disease mortality among electric
      utility workers".

PMID- 10588088
TI  - Angiotensin II receptor blockers: review of the binding characteristics.
AB  - Several angiotensin II receptor blockers (ARBs), including candesartan cilexetil,
      irbesartan, losartan, telmisartan, and valsartan, are currently approved by the
      US Food and Drug Administration (FDA) for the treatment of patients with
      hypertension. These agents share a common mechanism of action-antagonism of the
      angiotensin type 1 (AT1) receptor-and as a result, they block a number of
      angiotensin II effects that are relevant to the pathophysiology of cardiovascular
      disease, including vasoconstriction, renal sodium reabsorption, aldosterone and
      vasopressin secretion, sympathetic activation, and vascular and cardiac
      hyperplasia and hypertrophy. Unlike the angiotensin converting enzyme (ACE)
      inhibitors, these new drugs block the effects of angiotensin II regardless of
      whether it is produced systemically in the circulation or locally via ACE- or non
      ACE-dependent pathways in tissues. ARBs also block the angiotensin II-induced
      feedback regulation of renin release, resulting in an increase in angiotensin II
      levels. With the AT1 receptor blocked, angiotensin II is available to activate
      the angiotensin type 2 (AT2) receptor, which mediates several potentially
      beneficial effects in the cardiovascular system, including vasodilation,
      antiproliferation, and apoptosis. Thus, ARBs provide a highly selective approach
      for regulating the effects of angiotensin II.

PMID- 10588089
TI  - Significance of angiotensin type 1 receptor blockade: why are angiotensin II
      receptor blockers different?
AB  - The angiotensin II receptor blockers (ARBs) are safe and effective agents in the
      treatment of hypertension, and they have potential in treating other
      cardiovascular disorders such as heart failure. These drugs share a common
      mechanism of action: They selectively block the angiotensin type 1 (AT1)
      receptor. A new ARB, candesartan cilexetil is a prodrug that is converted
      completely into the active metabolite candesartan during gastrointestinal
      absorption, whereas losartan is converted partially by hepatic metabolism into
      the more active compound EXP 3174. Valsartan and irbesartan are active in their
      own right. These ARBs differ pharmacologically in terms of their affinity for the
      AT1 receptor, the mechanism by which they block the receptor, and the duration of
      their receptor-blocking activity. In radioligand-binding studies, candesartan had
      a slightly higher affinity for the AT1 receptor than the other ARBs. In the
      rabbit aorta, candesartan blocked angiotensin II-induced contractions in an
      insurmountable manner, whereas losartan blocked the contractions competitively,
      and EXP 3174, valsortan and irbesartan blocked the contractions in a manner
      intermediate between competitive and insurmountable antagonism. The
      insurmountable antagonism exhibited by candesartan likely reflects its long
      lasting blockade of the AT1 receptor due to a slow dissociation rate. This
      suggests that candesartan will exhibit a longer duration of action than would be
      predicted simply from its pharmacokinetic elimination half-life. Comparative
      clinical trials with several ARBs are needed to define the clinical significance
      of these pharmacologic differences.

PMID- 10588090
TI  - Long-term benefits of angiotensin II blockade: is the consensus changing?
AB  - The treatment of hypertension and heart failure has evolved in recent years. It
      may no longer be sufficient to lower blood pressure per se or correct
      hemodynamics alone in these conditions to achieve optimal long-term outcomes;
      rather, the effects of drugs on the cellular events and structural alterations
      that occur in the vasculature, heart, and kidney must be considered. Drugs that
      target angiotensin II, which include the angiotensin-converting enzyme (ACE)
      inhibitors and angiotensin II receptor blockers (ARBs), may protect target organs
      from damage and thereby improve outcomes. Nevertheless, it remains to be
      demonstrated whether these agents are more effective in reducing cardiovascular
      morbidity and mortality in hypertensive patients than conventional treatment with
      diuretics and beta blockers. In certain subgroups of hypertensive patients,
      including those with heart failure, type 1 diabetes with proteinuria, or after
      myocardial infarction with systolic dysfunction, there is compelling evidence for
      use of ACE inhibitors. The results from animal models and initial clinical
      studies suggest that ARBs are also highly effective in these patients. Several
      large-scale clinical studies, comparing the effect of ARBs and other drug classes
      on morbidity and mortality outcomes, have been initiated to better define the
      long-term benefit of ARBs in the treatment of hypertension and heart failure.

PMID- 10588091
TI  - Do pharmacologic differences among antihypertensive agents point to clinical
      benefits?
AB  - On the basis of results of long-term trials, to date, it is reasonable to
      conclude that blood pressure lowering, per se, rather than the identity of the
      antihypertensive regimen, is associated with reducing risk for stroke and
      coronary heart disease in patients with hypertension. Clinicians should identify
      drugs within each antihypertensive class that reduce blood pressure consistently
      over a 24-hour period and have a duration appropriate for once-daily
      administration. Candesartan cilexetil is an appropriate choice among angiotensin
      II receptor blockers (ARBs); it has a trough: peak ratio of 0.9-1.1, which fully
      justifies once-daily dosing. Once genuinely long-acting antihypertensive
      medications are used routinely, it will be possible to evaluate whether the
      different drug classes provide ancillary benefits beyond blood pressure lowering.

PMID- 10588092
TI  - Comparison of angiotensin II receptor blockers: impact of missed doses of
      candesartan cilexetil and losartan in systemic hypertension.
AB  - Blood pressure remains poorly controlled in the hypertensive population due in
      large part to low or unsatisfactory patient compliance. Clinical studies that
      incorporate an intentionally missed dose have been designed to evaluate the
      impact of poor patient compliance on the effectiveness of antihypertensive
      medications. In these studies, ambulatory blood pressure monitoring is continued
      throughout the dosing interval and beyond in order to determine when systolic and
      diastolic blood pressure increase into the hypertensive range. In an 8-week,
      randomized, double-blind, placebo-controlled trial in patients with mild-to
      moderate hypertension, the antihypertensive effects of candesartan cilexetil 16
      mg were maintained after a missed dose, whereas systolic and diastolic blood
      pressure increased toward baseline levels after a missed dose of losartan 100 mg.
      Candesartan cilexetil provided a significantly greater reduction in sitting
      systolic (p = 0.004) and diastolic blood pressure (p = 0.008) than losartan when
      measured 48 hours after the last dose. Moreover, the homogeneity of
      antihypertensive effects was greater after candesartan cilexetil than losartan
      based on calculation of the smoothness index from ambulatory systolic and
      diastolic measurements during the first 24-hour period after dosing and during
      the 12-hour period after the missed dose. These results demonstrate that missing
      or delaying a dose of candesartan cilexetil has less impact on antihypertensive
      efficacy than missing or delaying a dose of losartan.

PMID- 10588093
TI  - Candesartan cilexetil in combination with low-dose hydrochlorothiazide is
      effective in severe hypertension.
AB  - This randomized, double-blind, placebo-controlled multicenter study was designed
      to evaluate the efficacy, tolerability, and safety of candesartan cilexetil in a
      diverse population of patients with severe systemic hypertension (diastolic blood
      pressure > or =110 mm Hg). After a placebo run-in period, patients were given
      hydrochlorothiazide (HCTZ) 12.5 mg once daily for 1 week. A total of 217 patients
      with sitting diastolic blood pressure >95 mm Hg while receiving HCTZ were then
      randomized in a 2:1 ratio to receive candesartan cilexetil or placebo once daily
      for 4 weeks. Candesartan cilexetil was started at 8 mg and titrated to 16 mg if
      needed for blood pressure control; background HCTZ was continued in both groups.
      Candesartan cilexetil was significantly more effective than placebo in lowering
      trough diastolic and systolic blood pressure. The mean change in trough sitting
      diastolic blood pressure from the end of the HCTZ run-in period to the week 4
      endpoint (primary study endpoint) was -9.1 mm Hg with candesartan cilexetil and 
      3.1 mm Hg with placebo (p = 0.0001). A higher percentage of patients treated with
      candesartan cilexetil than placebo responded to treatment (53% vs 29%) and
      achieved diastolic blood pressure <90 mm Hg (32% vs 15%). Subgroup analyses
      indicated that candesartan cilexetil was especially effective in patients with
      higher trough diastolic blood pressure at randomization, and it was significantly
      more effective than placebo in both black and nonblack patients alike as well as
      in women and men. Candesartan cilexetil was safe and well tolerated, with an
      adverse-event profile comparable to placebo. These results demonstrate that
      candesartan cilexetil added to background HCTZ therapy is effective and well
      tolerated in lowering blood pressure in patients with severe systemic
      hypertension.

PMID- 10588094
TI  - MR angiography of spinal vascular disease: what about normal vessels?

PMID- 10588095
TI  - MR imaging findings of enteroviral encephalomyelitis: an outbreak in Taiwan.

PMID- 10588096
TI  - Correlation between MR and clinical findings of disease activity in multiple
      sclerosis.

PMID- 10588097
TI  - The need for objective assessment of the new imaging techniques and understanding
      the expanding roles of stroke imaging.

PMID- 10588098
TI  - Spinal cord vascular disease: characterization with fast three-dimensional
      contrast-enhanced MR angiography.
AB  - BACKGROUND AND PURPOSE: Noninvasive characterization of spinal vascular lesions
      is essential for guiding clinical management, and several MR angiographic
      techniques have been applied in the past with variable results. The purpose of
      our study was to assess the potential of a dynamic 3D contrast-enhanced MR
      angiographic sequence to characterize spinal vascular lesions and to identify
      their arterial feeders and venous drainage. METHODS: A contrast-enhanced gradient
      echo 3D pulse sequence providing angiographic information within 24 seconds was
      applied prospectively in 12 consecutive patients with a presumed spinal vascular
      lesion. The images were evaluated for visibility of the arterial feeder, and the
      results were compared with those of conventional angiography performed the next
      day. RESULTS: The MR angiographic findings proved that the lesions were correctly
      characterized as spinal arteriovenous malformations (AVMs) (n = 6), spinal dural
      arteriovenous fistulas (AVFs) (n = 3), a hemangioblastoma (n = 1), a teratoma (n
      = 1), and a vertebral hemangioma (n = 1). The arterial feeder was visible in all
      six AVMs and in the hemangioblastoma, corresponding to conventional angiographic
      findings. In two of three spinal dural AVFs, an enlarged draining medullary vein
      was seen within the neural foramen, providing correct localization. The third
      fistula could not be seen owing to reduced image quality from motion artifacts.
      CONCLUSION: Fast 3D contrast-enhanced MR angiography is a noninvasive technique
      with high accuracy in the characterization of spinal vascular disease. Visibility
      of the arterial pedicles corresponds well with that of digital subtraction
      angiography, facilitating the management of these patients.

PMID- 10588099
TI  - Unusual cervical spinal cord toxicity associated with intra-arterial carboplatin,
      intra-arterial or intravenous etoposide phosphate, and intravenous
      cyclophosphamide in conjunction with osmotic blood brain-barrier disruption in
      the vertebral artery.
AB  - BACKGROUND AND PURPOSE: When the clinical and radiologic characteristics of an
      unusual cervical spinal cord complication of intra-arterial (IA) chemotherapy
      with blood brain-barrier (BBB) disruption in the vertebral circulation are
      documented. Seven cases are reported and analyzed in search of a pathophysiologic
      explanation. METHODS: We retrospectively identified 94 patients who received a
      total of 380 standardized regimens of IA carboplatin, IA or IV etoposide
      phosphate, and IV cyclophosphamide infusion in conjunction with osmotic BBB
      disruption of the vertebral artery. We describe seven of those patients in whom
      unexpected neck pain developed followed by neurologic symptoms primarily in the
      upper extremities. RESULTS: The symptoms correlated with MR abnormalities (T1
      hypointensity, T2 hyperintensity, and unusual contrast enhancement) in the
      cervical spinal cord, usually involving the gray matter. The neurologic deficits
      and MR changes were generally transient. One patient who received a flu
      vaccination 48 hours before the chemotherapy incurred progressive myelitis and
      expired. CONCLUSION: The pathophysiology of this complication is probably
      multifactorial but may be related to vascular streaming and an atypical
      inflammatory toxic reaction to carboplatin and etoposide. The complication has
      not recurred during a 6-month period following modification of the protocol.

PMID- 10588100
TI  - Magnetization-transfer histogram analysis of the cervical cord in patients with
      multiple sclerosis.
AB  - BACKGROUND AND PURPOSE: Previous studies have failed to show significant
      correlations between the number and extent of T2 spinal cord lesions and the
      clinical status of multiple sclerosis (MS) patients. We evaluated 1) whether it
      is feasible to create magnetization transfer-ratio (MTR) histograms of the
      cervical cord in patients with MS by using two different acquisition schemes, and
      2) whether cervical cord MTR histogram metrics were different from those of
      healthy control subjects and between MS patients with and without locomotor
      disability. METHODS: We obtained two sets of gradient-echo sequences with and
      without a saturation pulse from 90 MS patients and 20 sex- and age-matched
      healthy control subjects. One set consisted of 20 axial, contiguous slices with a
      thickness equal to 5 mm. The other set consisted of 17 sagittal slices with a
      thickness equal to 3 mm and an interslice gap equal to 0.3 mm. After image
      coregistration and removal of tissues around the cervical cord, MTR histograms
      were created. The average MTR, the peak height, and the peak position of the
      histograms were measured. All of these measurements were from the whole of the
      cervical cord, thus including both MS lesions and normal-appearing tissue.
      RESULTS: When comparing the MTR histograms obtained using axial, contiguous, 5-mm
      thick slices, MS patients had significantly lower average cervical cord MTR and
      peak height than did control subjects. When comparing the MTR histograms obtained
      using sagittal, 3-mm-thick slices, MS patients also had significantly lower
      average cervical cord MTR and peak location than did control subjects. Patients
      with locomotor disability had significantly lower average cord MTR and peak
      location than those without. CONCLUSION: This study shows that it is feasible to
      obtain MTR histograms of the cervical cord from MS patients by using different
      acquisition schemes. Our results also suggest that the assessment of MS cervical
      cord damage, achieved using MTR histograms, may lead to a better understanding of
      the clinical manifestations of the disease.

PMID- 10588101
TI  - Pseudohemangioma of the vertebra: an unusual radiographic manifestation of
      primary Ewing's sarcoma.
AB  - Primary Ewing's sarcoma (ES) of the spine is uncommon, exhibiting a variety of
      appearances on plain-film radiographs and cross-sectional images. We report the
      unusual CT imaging manifestations of a primary ES with a coarse trabecular
      pattern that mimicked an aggressive hemangioma of the cervical spine.

PMID- 10588102
TI  - Syndromes of bilateral symmetrical polymicrogyria.
AB  - BACKGROUND AND PURPOSE: A number of anatomicoclinical syndromes have been
      described in which bilateral symmetrical polymicrogyria is the underlying
      morphologic abnormality. We retrospectively reviewed the clinical, epileptic, and
      morphologic manifestations of bilateral symmetrical polymicrogyria in 21 patients
      to determine whether certain areas are at particular risk for these syndromes.
      METHODS: Clinical records and brain MR studies of 21 patients with bilateral
      symmetrical polymicrogyria were reviewed to confirm the presence and determine
      the location of polymicrogyria and to qualitatively correlate location with
      developmental, neurologic, and epileptic histories. The locations we found were
      compared with published reports of bilateral symmetrical polymicrogyria to
      determine whether these locations were random or whether predilections exist for
      certain areas. RESULTS: Analysis revealed six patients with bilateral frontal
      polymicrogyria, nine with bilateral perisylvian polymicrogyria, one with
      bilateral parietal polymicrogyria, one with bilateral parasagittal parieto
      occipital polymicrogyria, two with bilateral frontal polymicrogyria and bilateral
      perisylvian polymicrogyria, one with bilateral perisylvian and bilateral
      parasagittal parieto-occipital polymicrogyria, and one with bilateral
      perisylvian, bilateral parieto-occipital, and bilateral parasagittal parieto
      occipital polymicrogyria. Symptom complexes were non-specific, but seemed
      additive according to the regions of brain involved. CONCLUSION: Bilateral
      symmetrical polymicrogyria has a propensity to develop in specific regions of the
      cerebral cortex. When the regions are extensive, the areas involved often appear
      to be simple topological additions of those regions. These locations and the
      identification of several familial cases raise the possibility that genetic
      mechanisms influence the development of these malformations in some patients.

PMID- 10588103
TI  - MR-revealed myelination in the cerebral corticospinal tract as a marker for
      Pelizaeus-Merzbacher's disease with proteolipid protein gene duplication.
AB  - BACKGROUND AND PURPOSE: Pelizaeus-Merzbacher's disease (PMD) is caused by
      mutations in the proteolipid protein (PLP) gene. Recent studies have shown that
      an increased PLP dosage, resulting from total duplication of the PLP gene,
      invariably causes the classic form of PMD. The purpose of this study was to
      compare the MR findings of PMD attributable to PLP duplication with those of PMD
      arising from a missense mutation. METHODS: Seven patients with PMD, three with a
      PLP missense mutation in either exon 2 or 5 (patients 1-3), and four with PLP
      duplication (patient 4 having larger PLP duplication than patients 5-7) were
      clinically classified as having either the classic or connatal form of PMD.
      Cerebral MR images were obtained to analyze the presence of myelination and T1
      and T2 shortening in the deep gray matter. Multiple MR studies were performed in
      six of the seven patients to analyze longitudinal changes. RESULTS: Four patients
      (patients 1-4) were classified as having connatal PMD, whereas the other three
      (patients 5-7) were classified as having classic PMD. Myelination in the cerebral
      corticospinal tract, optic radiation, and corpus callosum was observed in three
      cases of classic PMD with PLP duplication. In patient 4, myelination extended to
      the internal capsule, corona radiata, and centrum semiovale over a 3-year period.
      No myelination was observed in three PMD cases with a PLP point mutation. T2
      shortening in the deep gray matter was recognized in all patients with PMD.
      CONCLUSION: The presence of myelination in the cerebral corticospinal tract with
      diffuse white matter hypomyelination on MR images could be a marker for PMD with
      PLP duplication. It is suggested that progression of myelination may be present
      in connatal PMD with large PLP duplication.

PMID- 10588104
TI  - Nontuberculous mycobacterial infection of the head and neck in immunocompetent
      children: CT and MR findings.
AB  - BACKGROUND AND PURPOSE: Infections caused by nontuberculous mycobacteria (NTM)
      commonly manifest as cervicofacial adenitis in otherwise healthy children. The
      aim of this study was to characterize the imaging findings of NTM infection of
      the head and neck in immunocompetent children. METHODS: The medical records and
      imaging examinations (CT in 10, MR in two) were reviewed in 12 immunocompetent
      children with NTM infection of the head and neck. RESULTS: The usual presentation
      (n = 9) was of an enlarging, non-tender mass with violaceous skin discoloration,
      unresponsive to conventional antibiotics. The duration of symptoms was 6 days to
      5 months. Imaging revealed asymmetric adenopathy with contiguous low-density ring
      enhancing masses in all patients. There was cutaneous extension in 10 patients.
      Inflammatory stranding of the subcutaneous fat was minimal (n = 9) or absent (n =
      2) in 11 patients. The masses involved the submandibular space (n = 3), the
      parotid space (n = 2), the cheek (n = 1), the anterior triangle of the neck (n =
      2), the submandibular and parotid spaces (n = 2), the parotid space and neck (n =
      1), and the neck and retropharyngeal space (n = 1). Surgical management included
      incision and drainage only (n = 2), incision and drainage with curettage (n = 2),
      excisional biopsy after incision and drainage (n = 1), excisional biopsy only (n
      = 5), superficial parotidectomy only (n = 1), and superficial parotidectomy with
      contralateral excisional biopsy (n = 1). All patients improved in response to
      surgery and long-term antimycobacterial antibiotics. CONCLUSION: NTM infection of
      the head and neck has a characteristic clinical presentation and imaging
      appearance. Recognition of this disease is important; appropriate treatment is
      excision and, in selected cases, antimycobacterial therapy.

PMID- 10588105
TI  - "Ivy sign" on fluid-attenuated inversion-recovery images in childhood moyamoya
      disease.
AB  - We report on MR studies of a 15-year-old girl with moyamoya disease in whom
      diffuse leptomeningeal enhancement ("ivy sign") was revealed by fluid-attenuated
      inversion-recovery (FLAIR) and contrast-enhanced imaging. We speculate that the
      mechanism behind this enhancement is caused by a retrograde slow flow of engorged
      pial vasculature via leptomeningeal anastomosis. Nevertheless, it remains unknown
      whether the precise source of a high signal on FLAIR images is attributable to
      pial vessels themselves or congested thickening of the leptomeninges or both.

PMID- 10588106
TI  - Pallister-Hall syndrome: clinical and MR features.
AB  - A 4-month-old boy with polydactyly and bifid epiglottis was found to have a large
      sellar and suprasellar mass. When the diagnosis of Pallister-Hall syndrome was
      made, conservative management was elected. When the patient was 2 years old, the
      tumor had grown proportionally with the patient, and he was developing
      appropriately. Although rare, this entity is important to recognize not only for
      clinical diagnosis but also for appropriate management and genetic counseling.

PMID- 10588107
TI  - Acute stroke evaluated by time-to-peak mapping during initial and early follow-up
      perfusion CT studies.
AB  - BACKGROUND AND PURPOSE: Early diagnosis of perfusion deficits in patients with
      acute stroke could guide treatment decisions and improve prognosis. We
      investigated the sensitivity of perfusion CT studies using parametric time-to
      peak maps to assess ischemic brain tissue with respect to early infarct signs on
      native CT scans. METHODS: First-pass, single-section perfusion CT was performed
      in 20 patients who presented with symptoms of acute stroke within 6 hours of
      onset. Initial CT perfusion studies were compared with follow-up studies within
      30 hours in 10 patients. A manual, region of interest (ROI)-based, local
      evaluation procedure was performed to determine delayed time-to-peak values and
      diminished peak amplitudes. In addition, time-to-peak parameter maps were
      processed off-line from the dynamic CT data sets to identify areas of perfusion
      deficits, which were expressed as hemispheric lesion areas (HLAs). Evolution of
      the ischemic regions was assessed by comparing the HLA on the initial and follow
      up studies as well as on the native CT scan of the follow-up studies. RESULTS:
      Diagnostic time-to-peak maps were generated in 19 of 20 initial and in nine of 10
      follow-up perfusion CT studies. The initial time-to-peak map showed perfusion
      deficits in 14 of 20 patients. Hemispheric territorial infarcts were diagnosed
      with a sensitivity of 93%. Perfusion deficits in two patients with brain stem
      infarctions and three patients with lacunar strokes were missed. Follow-up time
      to-peak maps showed the extent of reperfusion after various therapeutic
      strategies. CONCLUSION: Perfusion CT is potentially useful for detecting cerebral
      perfusion deficits in acute ischemic stroke before morphologic changes are
      observable on native CT scans. Compared with a locally restricted ROI-based
      evaluation, time-to-peak maps provide sensitive, global indications of
      malperfused brain areas, facilitate lesion localization, and allow assessment of
      the evolution of the infarction during follow-up.

PMID- 10588108
TI  - Noninvasive measurement of brain temperature after stroke.
AB  - BACKGROUND AND PURPOSE: Brain temperature may be an important factor governing
      the extent of neuronal injury associated with stroke. The goal of this study was
      to develop a noninvasive method for measuring brain temperature, both to
      characterize the extent to which temperature changes after stroke and to test
      protocols designed to reduce brain temperature. We used an animal model to test
      the ability of 1H MR spectroscopy to measure temperature from infarcted brain
      tissue at 24 hours after insult. METHODS: Unilateral permanent focal ischemia in
      the middle cerebral artery territory was induced in adult dogs by intravascular
      delivery of microfibrillar collagen. MR imaging performed at 24 hours after
      insult was used to guide the implantation of temperature probes into the basal
      ganglia infarct and into the same anatomic location on the contralateral side.
      Serial non-water-suppressed 1H MR spectra were obtained from 1.3-cm3 voxels using
      an echo time of 136 and 272 ms, alternately, from the infarcted and contralateral
      non-infarcted tissue during a period when brain temperature was raised and
      lowered by whole-body heating and cooling. RESULTS: The chemical shift difference
      between the 1H MR spectroscopy signal of water and N-acetylaspartate or water and
      trimethylamines was plotted against brain temperature for two voxel locations.
      The slope and intercept of the plots obtained for infarcted and non-infarcted
      brain were not significantly different (P < .05, t test), and there was no
      difference between the slope and intercept of plots made from data collected with
      an echo time of 136 or 272 ms. CONCLUSION: The results of this study indicate
      that brain temperature can be measured from regions of brain containing infarcted
      tissue, at least up to 24 hours after ischemia. It should be possible to apply
      the 1H MR spectroscopy method used in the present study to measure brain
      temperature after stroke.

PMID- 10588109
TI  - Xenon contrast-enhanced CT imaging of supratentorial hypoperfusion in patients
      with brain stem infarction.
AB  - BACKGROUND AND PURPOSE: The characteristics of hypoperfusion in the
      supratentorial region of patients with brain stem infarction are unclear. We
      investigated the relationships between the presence of hypoperfusion and the
      location, number, and size of the infarcts with xenon contrast-enhanced CT.
      METHODS: One hundred five patients with brain stem infarction detected by MR
      imaging underwent xenon contrast-enhanced CT to measure the regional CBF (rCBF)
      in the frontal, temporal, parietal, and occipital regions and in the putamen and
      thalamus. A decrease of more than 10% from the mean rCBF value for normal
      individuals was considered to indicate hypoperfusion. RESULTS: Thirty-six
      patients had supratentorial hypoperfusion. The mean rCBF values (measured in
      mL/100 g/minute) were as follows: frontal region, 36.2 +/- 5.1 (-14.8%, n = 28);
      parietal region, 42.3 +/- 4.7 (-19.1%, n = 29); temporal region, 41.5 +/- 2.8 (
      12.6%, n = 12); and thalamus, 50.1 +/- 3.2 (-19.6%, n = 7). Supratentorial
      hypoperfusion was associated with pontine infarction in 33 patients (upper pons
      in 15, middle pons in 18, and lower pons in seven), midbrain infarction in two,
      and medulla infarction in one. Twenty-three patients had infarcts that were
      larger than 5 mm, and 11 had infarcts that were 2 to 5 mm. Only two had infarcts
      that were smaller than 2 mm. Seven patients each had one infarct, 13 each had
      two, and 16 each had three. CONCLUSION: Supratentorial hypoperfusion was
      associated with larger infarcts, with more infarcts, and with pontine infarction.

PMID- 10588110
TI  - Hemorrhage detected using MR imaging in the setting of acute stroke: an in vivo
      model.
AB  - BACKGROUND AND PURPOSE: The treatment algorithm for acute cerebrovascular
      accidents has traditionally sorted these accidents as either hemorrhagic or
      nonhemorrhagic, and MR imaging, with its ability to allow expeditious assessment
      of vascular substrates and regional blood volume, is well suited for this
      purpose. Our purpose was to delineate the accuracy of MR imaging in acute,
      hemorrhagic forms of stroke during the time frame considered beneficial for
      intervention in an animal model. METHODS: Eighteen dogs with small, iatrogenic
      parenchymal, subarachnoid hemorrhage (SAH), or both were serially scanned over
      the initial 6-hour postictal period. Confirmatory pathologic specimens and 3-hour
      postictal CT scans were obtained in all animals. The MR and CT studies were then
      interpreted in a blinded fashion by two neuroradiologists for the presence of
      hemorrhage. The results were subjected to receiver operating characteristic
      analysis. RESULTS: MR imaging depicted acute parenchymal hemorrhage and SAH with
      a high degree of accuracy at 1.5 T. This finding was independent of each of the
      time points studied during the 6-hour window. For SAH, the MR accuracy for reader
      1 was 0.86 (95% CI, 0.76-0.97); for reader 2, accuracy was 0.85 (95% CI, 0.71
      0.99). The CT accuracy for the two readers was 0.42 (95% CI, 0.26-0.58) and 0.66
      95% CI, 0.43-0.89), respectively. Fluid-attenuated inversion-recovery images
      improved the conspicuity of SAH on MR images and, along with spin-density
      weighted spin-echo sequences, helped to establish the hemorrhagic nature. For
      parenchymal hemorrhage, the MR accuracy for reader 1 was 0.90 (95% CI, 0.81
      0.99); for reader 2, accuracy was 0.93 (95% CI, 0.84-1.00). With CT, the accuracy
      of reader 1 was 0.91 (95% CI, 0.85-0.97) whereas for reader 2 accuracy was 0.76
      (95% CI, 0.69-.83). Parenchymal hemorrhage detection and diagnosis was best with
      T2*-weighted gradient-echo images. CONCLUSION: MR imaging with appropriately
      selected sequences appears able to provide information regarding the presence (or
      absence) of hemorrhage in an acute stroke model requisite to the initiation of
      treatment.

PMID- 10588111
TI  - Hyperacute ischemic stroke missed by diffusion-weighted imaging.
AB  - We present two cases of hyperacute ischemic stroke that were initially missed by
      diffusion-weighted imaging; abnormalities in locations corresponding to focal
      neurologic deficits were discovered by MR angiography and perfusion-weighted
      imaging. Within hours, follow-up diffusion-weighted scans revealed partial
      conversion of the hypoperfused regions to complete stroke. These cases illustrate
      the potential for a nonresolving stroke-in-evolution to go undetected by
      diffusion-weighted imaging at hyperacute timepoints.

PMID- 10588112
TI  - Diffusion-negative stroke: a report of two cases.
AB  - Diffusion-weighted MR imaging is generally thought to be highly sensitive for the
      diagnosis of acute stroke. We report two cases of hyperacute stroke with absence
      of changes on diffusion-weighted images within 4 hours of symptom onset. Follow
      up studies, performed 4 days later, showed infarction in regions compatible with
      the clinical presentation and (in one case) with the initial perfusion deficit.
      These cases indicate that normal findings on diffusion-weighted images in
      patients with suspected cerebral ischemia do not rule out impending infarction.

PMID- 10588113
TI  - Transcranial Doppler of a paradoxical brain embolism associated with a pulmonary
      arteriovenous fistula.
AB  - We herein report the case of a patient who had paradoxical brain embolism owing
      to a pulmonary arteriovenous fistula (PAVF) who was diagnosed as having a right
      to-left shunt by transcranial Doppler (TCD) with saline contrast medium. TCD with
      saline contrast medium failed to detect any high-intensity transient signals
      immediately after catheter embolization of the PAVF. Thus, TCD with saline
      contrast medium was useful for identifying the presence of a right-to-left shunt
      and for confirming that the shunt had been obliterated after endovascular
      treatment.

PMID- 10588114
TI  - Central brain herniation secondary to juvenile diabetic ketoacidosis.
AB  - We present the CT, MR, and autopsy findings of central brain herniation in a 9
      year-old boy undergoing treatment for diabetic ketoacidosis (DKA). Severe
      cerebral edema resulting in central brain herniation is an uncommon complication
      of the treatment of DKA but carries with it high morbidity and mortality.
      Radiologic imaging and autopsy findings in this case revealed striking
      infarctions of central brain structures.

PMID- 10588115
TI  - MR imaging findings of enteroviral encephaloymelitis: an outbreak in Taiwan.
AB  - BACKGROUND AND PURPOSE: An outbreak of enterovirus infection occurred in Taiwan
      from late spring to early fall of 1998. Most of the pediatric infections
      presented as hand-foot-mouth disease (HFMD) and herpangina. A small portion of
      patients had symptoms of polio-like encephalitis and paralysis. The purpose of
      this study was to review the MR imaging findings in CNS involvement of
      enterovirus infection. METHODS: Twenty patients who had HFMD and clinical
      encephalitis were examined with MR imaging. T1-weighted and T2-weighted MR images
      were obtained. From the rectum, throat, CSF, and peripheral blood, the presence
      of enterovirus 71 (EV 71) was determined by virus culture, immunofluorescent
      microscopy, immunologic dot blotting, and reverse-transcription polymerase chain
      reaction. RESULTS: MR imaging studies of 20 patients showed hyperintensity in the
      brain stem and spinal cord in 15 patients, as seen on T2-weighted images. The
      major CNS lesions were in the medulla oblongata, pons, midbrain, and the dentate
      nuclei of the cerebellum. In some cases, the lesions involved the spinal cord
      (three cases) as well as the thalamus (two cases) and putamina (one case). Five
      patients had normal MR imaging results. After the appropriate management for
      tachycardia and tachypnea, 18 patients recovered within 1 to 2 weeks. In the
      follow-up MR imaging examination of five patients, the lesions completely
      disappeared within 2 weeks to 2 months. In two patients who were still respirator
      dependent, MR imaging showed the tissue destruction in the posterior portions of
      the medulla, pons, and the ventral horns of cervical spinal cord. In one patient,
      most of midbrain was damaged. The presence of EV 71 was detected in specimens
      from 18 patients. CONCLUSION: Because EV 71 was identified in 18 patients, and no
      other virus was detected, EV 71 was determined to be the major causative agent of
      this encephalomyelitis. Brain stem and cervical spinal cord involvement are
      characteristic findings of enteroviral encephalomyelitis.

PMID- 10588117
TI  - MR blood oxygenation level-dependent signal differences in parenchymal and large
      draining vessels: implications for functional MR imaging.
AB  - BACKGROUND AND PURPOSE: One major limitation of current functional MR (fMR)
      imaging is its inability to clarify the relationship between sites of cortical
      neuronal activation, small parenchymal venules that are in close proximity to
      these sites, and large draining veins distant from the active parenchyma. We
      propose to use gradient-echo blood oxygenation level-dependent (BOLD) fMR time
      courses to differentiate large draining veins from parenchymal microvasculature.
      METHODS: In eight research subjects, five of whom presented with space-occupying
      lesions near the central sulcus, gradient-echo fMR imaging was performed during
      alternating periods of rest and motor activation. MR signal time courses from
      parenchymal regions and draining veins of different diameters, which were
      identified using contrast-enhanced T1-weighted scans, were evaluated. Percent
      signal changes (deltaS) and the time to the onset of MR signal rise (T0) were
      calculated. RESULTS: Mean delta(S) for all subjects was 2.3% (SD+/-0.7%) for
      parenchymal activation, 4.3% (SD +1.0%) for sulcal macrovasculature, and 7.3
      (SD+/-1.1%) for large superficial bridging veins. The mean time to onset of MR
      signal increase was 4.4 seconds for parenchymal task-related hemodynamic changes
      and 6.6 seconds for venous hemodynamic changes, regardless of vessel size. Both
      the differences in delta(S) and T0 were statistically significant between venous
      and parenchymal activation (P < .0001). CONCLUSION: Gradient-echo fMR imaging
      reveals hemodynamic task-related changes regardless of vessel size and therefore
      might show macrovascular changes distal to the site of neuronal activity. MR
      signal time-course characteristics (delta(S) and T0) can be used to differentiate
      between small parenchymal and larger pial draining vessels, which is especially
      important in presurgical planning of neurosurgical procedures involving
      functionally important brain regions. The knowledge about the differences in
      (delta)S and T0 between micro- and macrovasculature might lead to a more accurate
      description of the spatial distribution of underlying neuronal activity.

PMID- 10588116
TI  - Progressive multifocal leukoencephalopathy in AIDS: are there any MR findings
      useful to patient management and predictive of patient survival? AIDS Clinical
      Trials Group, 243 Team.
AB  - BACKGROUND AND PURPOSE: While MR findings in progressive multifocal
      leukoencephalopathy (PML) have been described previously, usually in
      retrospective studies with limited sample size, what has not been well addressed
      is whether any are predictive of longer survival. Our participation in a large
      prospective clinical trial of AIDS patients with biopsy-proved PML and MR
      correlation allowed us to test our hypothesis that certain MR features could be
      found favorable to patient survival. METHODS: The patient cohort derived from a
      randomized multicenter clinical trial of cytosine arabinoside for PML.
      Pretreatment T1- and T2-weighted noncontrast images (n = 48) and T1-weighted
      contrast-enhanced images (n = 45) of 48 HIV-positive patients with a PML tissue
      diagnosis as well as the follow-up images in 15 patients were reviewed to
      determine signal abnormalities, lesion location and size, and the presence or
      absence of mass effect, contrast enhancement, and atrophy, and to ascertain the
      frequency of these findings. A statistical analysis was performed to determine if
      any MR abnormalities, either at baseline or at follow-up, were predictive of
      patient survival. RESULTS: No MR abnormalities either on univariate or
      multivariate analysis significantly correlated with patient survival, with the
      exception of mass effect, which was significantly associated with shorter
      survival. The mass effect, however, always minimal, was infrequent (five of 48).
      More severe degrees of cortical atrophy and ventricular dilatation, lesion
      location and size, and other MR variables were not predictive of outcome.
      CONCLUSION: Except for mass effect, we found no MR findings predictive of the
      risk of death in patients with PML. The mass effect, however, was so infrequent
      and minimal that it was not a useful MR prognostic sign.

PMID- 10588118
TI  - Echo-planar functional MR imaging of epilepsy with concurrent EEG monitoring.
AB  - BACKGROUND AND PURPOSE: The role of functional MR (fMR) imaging in the evaluation
      of patients with epilepsy has not been systematically studied. Our purpose was to
      identify the fMR correlates of interictal epileptiform discharges. METHODS:
      Twenty patients with epilepsy and frequent interictal discharges were studied
      with concurrent EEG monitoring on a 1.5-T echo-planar magnet to acquire blood
      oxygenation-level-dependent (BOLD) images in the baseline (OFF) and immediate
      post-discharge (ON) states. Analysis was performed using subtraction of average
      ON and OFF data (method I); cross-correlation analysis between the ON and OFF
      states (method II); and individual spike analysis (ISA), with which signal
      intensity in the individual ON states was statistically analyzed using a weighted
      comparison with the mean and variance of the OFF states (method III). Agreement
      of fMR activation with EEG localization was determined. RESULTS: Eighteen of 20
      patients had interictal discharges during the monitoring period. Method I yielded
      visually detectable sites of BOLD signal differences in only one patient. Method
      II resulted in two patients with sites of BOLD activation. Method III, ISA,
      resulted in regions of increased BOLD signal corresponding to the EEG focus in
      nine of 10 patients. CONCLUSION: fMR studies can often reveal sites of increased
      BOLD signal that correspond to sites of interictal EEG discharge activity.
      Because of variable intensity changes associated with discharge activity, ISA
      resulted in increased sensitivity.

PMID- 10588119
TI  - Central processing of rectal pain: a functional MR imaging study.
AB  - BACKGROUND AND PURPOSE: Although the central processing of somatic pain has been
      dealt with in numerous brain imaging studies, the neural correlates of visceral
      pain have received much more limited attention. Our goal was to assess the
      feasibility of detecting brain activation patterns induced by rectal pain by
      means of functional MR imaging. We hypothesized that the cerebral processing of
      rectal pain would exhibit strong similarities with the central processing of
      somatic pain. METHODS: Functional MR imaging data were obtained from eight
      healthy subjects. A block paradigm was applied. Rectal pain was induced by
      inflating a latex balloon catheter that had been inserted into the rectum.
      Functional responses were established by means of cross-correlation analysis.
      RESULTS: Activation was detected within the anterior cingulate gyrus, the
      prefrontal cortex, the insular cortex, the sensory-motor cortex, the inferior
      parietal lobule, the posterior cingulate gyrus, and the visual cortex.
      CONCLUSION: Functional MR imaging of visceral pain is feasible in healthy
      subjects. The activation patterns observed in this study support the hypothesis
      that the cerebral processing of visceral pain involves multiple components,
      similar to the central processing of somatic pain. Our results constitute a first
      step toward the identification of possible aberrations in the activation patterns
      of patients suffering from visceral hypersensitivity.

PMID- 10588120
TI  - The cerebellum's role in reading: a functional MR imaging study.
AB  - BACKGROUND AND PURPOSE: Long considered to have a role limited largely to motor
      related functions, the cerebellum has recently been implicated as being involved
      in both perceptual and cognitive processes. Our purpose was to determine whether
      cerebellar activation occurs during cognitive tasks that differentially engage
      the component processes of word identification in reading. METHODS: Forty-two
      neurologically normal adults underwent functional MR imaging of the cerebellum
      with a gradient-echo echo-planar technique while performing tasks designed to
      study the cognitive processing used in reading. A standard levels-of-processing
      paradigm was used. Participants were asked to determine whether pairs of words
      were written in the same case (orthographic processing), whether pairs of words
      and non-words rhymed with each other, respectively (phonologic assembly), and
      whether pairs of words belonged to the same category (semantic processing).
      Composite maps were generated from a general linear model based on a
      randomization of statistical parametric maps. RESULTS: During phonologic
      assembly, cerebellar activation was observed in the middle and posterior aspects
      of the posterior superior fissure and adjacent simple lobule and semilunar lobule
      bilaterally and in posterior aspects of the simple lobule, superior semilunar
      lobule, and inferior semilunar lobule bilaterally. Semantic processing, however,
      resulted in activation in the deep nuclear region on the right and in the
      inferior vermis, in addition to posterior areas active in phonologic assembly,
      including the simple, superior semilunar, and inferior semilunar lobules.
      CONCLUSION: The cerebellum is engaged during reading and differentially activates
      in response to phonologic and semantic tasks. These results indicate that the
      cerebellum contributes to the cognitive processes integral to reading.

PMID- 10588121
TI  - A comparison of MR imaging with fast-FLAIR, HASTE-FLAIR, and EPI-FLAIR sequences
      in the assessment of patients with multiple sclerosis.
AB  - BACKGROUND AND PURPOSE: Fast fluid-attenuated inversion-recovery (FLAIR)
      sequences are sensitive for detecting lesions in patients with multiple sclerosis
      (MS). More rapid fast-FLAIR imaging of the brain can be achieved by the
      concomitant use of half-Fourier acquisition single-shot turbo spin-echo (HASTE
      FLAIR) and echo-planar imaging (EPI-FLAIR). The present study was performed in a
      large cohort of subjects to assess and compare the number and volume of brain
      lesions detected by the fast-FLAIR, HASTE-FLAIR, and EPI-FLAIR sequences in
      patients with MS. METHODS: Fast-FLAIR, HASTE-FLAIR, and EPI-FLAIR sequences were
      obtained from 46 consecutive MS patients. Lesions seen on each type of sequence
      were counted and classified by consensus by two observers. Lesion volumes were
      measured using a semiautomated segmentation technique based on local
      thresholding. RESULTS: The quality of the fast-FLAIR images was significantly
      better than that of HASTE-FLAIR and EPI-FLAIR images. Fast-FLAIR revealed
      significantly more lesions and higher lesion volumes than did HASTE-FLAIR and EPI
      FLAIR. A similar number of large lesions was detected by the three sequences, but
      HASTE-FLAIR and EPI-FLAIR showed significantly fewer small and intermediate
      lesions than did fast-FLAIR. The number of lesions seen on HASTE-FLAIR and EPI
      FLAIR images was similar. CONCLUSION: HASTE-FLAIR and EPI-FLAIR sequences
      revealed as many large MS lesions as fast-FLAIR. Because their acquisition times
      are only a fraction of that needed for fast-FLAIR sequences, they may be useful
      for making a rapid diagnosis of MS in uncooperative patients. Their reduced
      ability to detect smaller lesions indicates that they should not be used as a
      routine approach to imaging patients with MS.

PMID- 10588122
TI  - Evolution of multiple sclerosis lesions on serial contrast-enhanced T1-weighted
      and magnetization-transfer MR images.
AB  - BACKGROUND AND PURPOSE: Magnetization-transfer imaging is a technique that could
      provide indirect evidence of the characteristics of multiple sclerosis (MS)
      lesions. The purpose of this work was to study the evolution of MS lesions on T1
      weighted MR images over time and to investigate changes in magnetization-transfer
      ratio (MTR) values of MS lesions with different initial appearances on contrast
      enhanced T1-weighted images. METHODS: Eleven patients with relapsing-remitting MS
      were studied with MR imaging. The MTRs were calculated for 47 lesions that had
      been classified according to their appearance on contrast-enhanced T1-weighted
      images. Each patient was examined at four time points over a 1-year period. The
      MTR changes observed in the selected lesions were compared with their initial T1
      weighted appearance. RESULTS: The lowest MTR values were initially found in
      hypointense nonenhancing lesions and in ring-enhancing lesions, with both types
      showing a hypointense center. Changes in MTR values were more dynamic and
      reversible in ring-enhancing than in hypointense nonenhancing plaques. Nodular
      enhancing lesions had slightly lower initial MTRs than did isointense non
      enhancing lesions. CONCLUSION: The absence or presence of contrast uptake may
      indicate a different pathologic basis for hypointense MS lesions on T1-weighted
      MR images. These differences should be kept in mind when considering T1 lesion
      load as a surrogate marker of disability in MS.

PMID- 10588124
TI  - MR lesion load and cognitive function in patients with relapsing-remitting
      multiple sclerosis.
AB  - BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a demyelinating disease most
      often associated with progressive physical impairment; however, its effects are
      noted to extend beyond physical disability. Our purpose was to determine the
      relationship between T2 lesion volume and neurocognitive and physical disability
      in relapsing-remitting multiple sclerosis. METHODS: We studied a cohort of 19
      patients with relapsing-remitting MS. Of this group, there were 15 women and four
      men from varying socioeconomic backgrounds. This volunteer sample was selected
      from a larger group of 53 patients with MS in our longitudinal MS study because
      they had been untreated with any beta-interferon medications, had been followed
      for at least 12 months, and had a clinical status of relapsing-remitting MS.
      RESULTS: Of 12 neurocognitive parameters tested, two correlated significantly
      with lesion loads. The correlation of the Symbol-Digit Modalities test, which
      analyzes information-processing speed, was significant (P = .0204). The
      correlation of the fifth trial of the Rey Auditory Verbal Learning test, which
      tests verbal long-term memory, was also significant (P = .0348). None of the
      other 10 neurocognitive examinations, however, showed a significant correlation
      with total lesion volume (Paced Auditory Serial Addition test-1.6, P = .7381;
      Paced Auditory Serial Addition test-2.0, P = .4180; Controlled Oral Word
      Association test, P = .8906; Category Fluency test, P = .4423; Bells test, P =
      .9097; Rey Auditory Verbal Learning test-delay, P = .9843, Rey Auditory Verbal
      Learning test-recognition, P = .7467; Word Span test, P = .4939; Road Map test, P
      = 0.4939). The lesion load also did not correlate with the physical disability
      scales as rated according to the Expanded Disability Status Scale (P = .68) or
      Ambulation Index (P = .95). CONCLUSION: Our results indicate that T2 lesion
      volume does not seem to be a robust surrogate marker of neuropsychological
      impairment in patients with MS. We think that global measurements of parameters
      that are more specific to the disease process may offer more precise correlation
      with cognitive dysfunction and other disability parameters.

PMID- 10588123
TI  - Serial analysis of magnetization-transfer histograms and Expanded Disability
      Status Scale scores in patients with relapsing-remitting multiple sclerosis.
AB  - BACKGROUND AND PURPOSE: Magnetization transfer ratio histogram peak height (MTR
      HPH) has been shown to correlate with macroscopic and microscopic brain disease
      in patients with multiple sclerosis (MS). We studied the changes in MTR-HPH and
      in Kurtzke's Expanded Disability Status Scale (EDSS) scores over time in a group
      of patients with relapsing-remitting MS. METHODS: Twenty adult patients with
      relapsing-remitting MS (four men and 16 women) were followed up for a period of
      334 to 1313 days. In all, 86 MR imaging studies of the brain were obtained, and
      MTR-HPH was calculated for each MR examination by using a semiautomated
      technique. Changes in MTR-HPH were compared between patients over the study's
      duration. A neurologist specialized in the care of MS patients assessed the EDSS
      score for each patient as a measure of clinical disability. RESULTS: Serial MR
      data showed a subtle but significant decline in MTR-HPH with time. No significant
      changes in EDSS scores were noted over the same period. CONCLUSION: Patients with
      relapsing-remitting MS have a significant progressive decline in normalized MTR
      HPH, which is independent of EDSS score. MTR-HPH measurements can be used to
      monitor subclinical disease in patients with relapsing-remitting MS over a short
      time frame of 1 to 4 years. This parameter might be applied in future therapeutic
      trials to assess its usefulness.

PMID- 10588125
TI  - Memory dysfunction in multiple sclerosis corresponds to juxtacortical lesion load
      on fast fluid-attenuated inversion-recovery MR images.
AB  - BACKGROUND AND PURPOSE: MR imaging is a sensitive diagnostic tool and
      paraclinical marker of disease activity and prognosis in multiple sclerosis (MS),
      yet the role of MR imaging of MS is controversial. The aim of this study was to
      describe the relationship between cognitive function and MS lesion size and
      position, as shown on comparative images from conventional spin-echo (CSE) and
      fast fluid-attenuated inversion-recovery (fast FLAIR) MR studies. METHODS: CSE
      and fast FLAIR sequences consisted of 40 noncontiguous, 3-mm-thick axial sections
      matched for geometric position in 18 patients with relapsing-remitting MS.
      Lesions were scored for size, anatomic position, and their comparative appearance
      on CSE and fast FLAIR images. The neuropsychological assessment tested general
      psychological performance, memory, and frontal lobe executive function. RESULTS:
      Fast FLAIR images showed significantly more small (146 versus six) and medium
      sized (18 versus four) juxtacortical lesions than did CSE sequences. Small
      juxtacortical lesions displayed only on fast FLAIR images had a distinctive
      appearance, suggestive of small areas of perivascular inflammation. The number of
      these lesions corresponded to reduced performance on the fifth and delayed trials
      of the Rey Auditory Verbal Learning memory function test. CONCLUSION: Fast FLAIR
      images show small lesions at the juxtacortical boundary that are not seen on CSE
      studies. The presence of such lesions correlates with impaired retention of
      information in memory tasks, which is characteristic of cognitive problems in
      patients with MS.

PMID- 10588126
TI  - Combined fat- and water-suppressed MR imaging of orbital tumors.
AB  - BACKGROUND AND PURPOSE: The use of a high-resolution T2-weighted MR sequence,
      which suppresses signal from both fat and water, has been shown to be highly
      effective for depicting areas of inflammatory damage within the optic nerve. The
      ability of this sequence to show neoplastic and inflammatory orbital lesions,
      which may mimic neuritis, is unknown. This study was designed to examine the
      characteristics of such a sequence for the investigation of orbital mass lesions.
      METHODS: Twenty-eight patients with known or suspected mass lesions of the orbit
      and six healthy volunteers were recruited for study. Imaging was performed with a
      1.5-T MR unit. Participants were examined by selective partial inversion recovery
      (SPIR) sequences with T2-weighted fast spin-echo acquisition, selective partial
      inversion recovery/fluid attenuated inversion recovery (SPIR/FLAIR) sequences
      with fast spin-echo acquisition, short tau inversion recovery (STIR) sequences
      with fast spin-echo acquisition, and SPIR sequences with contrast-enhanced T1
      weighted fast spin-echo acquisition. Two neuroradiologists, using a randomised,
      blinded method, scored images for lesion presence and extent. Lesion extent was
      defined as the number of images with visible abnormality, and was compared with
      the standard of reference established at a later date by consensus review of all
      imaging sequences. The ability of the sequences to show the presence and extent
      of pathologic lesions was compared. RESULTS: The SPIR/FLAIR sequence showed both
      the presence and extent of orbital masses significantly better than did either
      STIR or T2-weighted SPIR sequences (P<.01 and P<.001, respectively). Contrast
      enhanced T1-weighted SPIR images ranked better than SPIR/FLAIR images, although
      the difference failed to reach statistical significance. In the orbital apex, the
      SPIR/FLAIR technique was superior to all other techniques used. This reflected
      its ability to distinguish enhancing, pathologic lesions from enhancing, normal
      anatomy. CONCLUSION: SPIR/FLAIR is an appropriate screening technique for orbital
      masses and offers significant advantages over currently used fat-suppressed
      sequences for the investigation of orbital disease.

PMID- 10588127
TI  - Noninvasive direct stimulation of the cochlear nerve for functional MR imaging of
      the auditory cortex.
AB  - We herein present our preliminary experience with functional MR imaging of the
      direct electrical stimulation of the cochlear nerve using an MR imaging
      compatible electrode placed in the external auditory meatus of five patients with
      binaural sensorineural hearing loss. The stimulator was placed outside the
      imager's bore, and the electrode produced virtually no susceptibility artifacts.
      In three of five patients, it was possible to activate the superior temporal
      gyrus during functional MR imaging. No side effects were observed.

PMID- 10588128
TI  - Sound- and pressure-induced vertigo associated with dehiscence of the roof of the
      superior semicircular canal.
AB  - In many types of peripheral vertigo, imaging is not part of the initial
      evaluation. We present a patient with sound- and pressure-induced vertigo
      associated with bony dehiscence of the roof of the superior semicircular canal.
      The diagnosis of this new entity can only be made by high-resolution coronal CT
      imaging of the temporal bones. In patients with this symptom complex, CT should
      be performed early in the diagnostic workup.

PMID- 10588129
TI  - Kimura's disease with bilateral auricular masses.
AB  - We report an unusual case of Kimura's disease. An 81-year-old Japanese woman was
      shown to have bilateral auricular masses that had begun to enlarge 6 years
      before. On CT scans, slightly high-density masses with faint contrast enhancement
      were seen. The masses were heterogeneous and hypointense on T1-weighted MR
      images, were slightly hyperintense on T2-weighted MR images, and showed
      heterogeneous enhancement after the administration of contrast material. Kimura's
      disease should be included in the differential diagnosis of bilateral auricular
      tumors.

PMID- 10588130
TI  - Giant fibrovascular polyp of the oropharynx.
AB  - We describe a case of a giant fibrovascular polyp arising from the oropharynx and
      causing vague clinical symptoms. To our knowledge, this is the first description
      of an oropharyngeal fibrovascular polyp reported in the medical literature. The
      diagnosis was based on MR imaging findings, which showed the size and
      configuration of the polyp as well as the site of attachment. The patient
      underwent surgery, and the diagnosis was confirmed histologically.

PMID- 10588131
TI  - The acute diagnosis of Takayasu's arteritis based on helical CT angiography of
      the chest and neck in the emergency room.
AB  - Recently, a young woman presented acutely with a left hemispheric stroke and
      differing blood pressures in the arms as her initial manifestation of Takayasu's
      arteritis. Helical CT angiography, performed to rule out aortic dissection,
      revealed a thickened wall of the aortic arch with stenoses and occlusions of the
      great vessels, suggesting the diagnosis. The sequence of imaging studies and
      findings in this unusually catastrophic presentation of a typically insidious
      disease are highlighted.

PMID- 10588132
TI  - Development of a biologically active Guglielmi detachable coil for the treatment
      of cerebral aneurysms. Part I: in vitro study.
AB  - BACKGROUND AND PURPOSE: Stronger cellular adhesion on the surface of endovascular
      devices promotes accelerated healing of aneurysms. The purpose of this in vitro
      study was to study the cellular interaction on the surface of bioactive Guglielmi
      detachable coils (GDCs) after using the surface-modification technology, ion
      implantation. METHODS: Polystyrene (PS) dishes and platinum plates were used to
      simulate a GDC surface. They were treated with either simple collagen coating or
      collagen coating followed with ion implantation. Bovine endothelial cells (2-2.5
      x 10(4) cells in 1 mL) were suspended in medium supplemented with 10% fetal
      bovine serum on the PS dishes or platinum plates. Five days after cell seeding,
      the strength of cell adhesion was evaluated by trypsin treatment and flow shear
      stress. The cell detachment from the PS and platinum surfaces was observed
      microscopically. RESULTS: Five days after cell seeding, both simple collagen
      coated surfaces and collagen-coated ion-implanted surfaces showed uniform
      endothelial proliferation. After trypsin treatment, or under flow shear stress,
      stronger cell adhesion against chemical and flow shear stress was observed on the
      ion-implanted collagen-coated surface. In contrast, the endothelial cells were
      detached easily from the non-ion-implanted collagen-coated surface. CONCLUSION:
      Ion implantation in combination with protein coating improves the strength of
      surface cell adhesion when exposed to flow shear stress and proteolytic enzymes.
      Strong endothelial cell adhesion is reported to be important to achieve earlier
      endothelialization across the neck of an embolized aneurysm with bioactive GDCs.
      This new technology may improve long-term anatomic outcome in cerebral aneurysms
      treated with GDCs.

PMID- 10588133
TI  - Development of the biologically active Guglielmi detachable coil for the
      treatment of cerebral aneurysms. Part II: an experimental study in a swine
      aneurysm model.
AB  - BACKGROUND AND PURPOSE: Ion implantation is a surface-modification technology
      that creates a borderless surface on protein-coated platinum; this change in
      physical and chemical properties on the surface of Guglielmi detachable coils
      (GDCs) appears to enhance cell proliferation and adhesion. Our purpose was to
      evaluate the effect of ion implantation on GDCs in an experimental aneurysm
      model. METHODS: GDCs were coated with either type I collagen, fibronectin,
      vitronectin, laminin, or fibrinogen. Using He+ or Ne+ 1 x 10(14-15) ions/cm2, ion
      implantation was performed on these protein-coated GDCs (GDC-Is). A total of 56
      experimental aneurysms were constructed microsurgically in the common carotid
      arteries of 28 swine. These experimental aneurysms were embolized with standard
      GDCs (n = 23), collagen GDC-Is (n = 11), vitronectin GDC-Is (n = 6), laminin GDC
      Is (n = 4), fibrinogen GDC-Is (n = 6), and fibronectin GDC-Is (n = 6). The
      animals were sacrificed at day 14 after coil embolization. The physical
      properties of the new coils (friction on delivery, deployment into aneurysms,
      trackability, etc) and the development of tissue scarring and neoendothelium
      across the aneurysm's orifice were evaluated macroscopically and microscopically.
      RESULTS: No evidence of increased coil friction/stiffness was observed during
      delivery of GDC-Is through microcatheters in this aneurysm model. A more intense
      scar formation and neoendothelium at the neck of aneurysms were observed
      macroscopically when treated with GDC-Is. Significant differences in the
      proportion of neck coverage between standard GDCs (48.3% +/- 20.5%) and all GDC-I
      groups were observed (collagen GDC-I-89.4% +/- 14.9%, P < .01; vitronectin GDC-I
      71.5% +/- 7.0%, P < .05; laminin GDC-I-76.5% +/- 11.0%, P < .05; fibrinogen GDC-I
      74.8% +/- 13.9%, P < .05; fibronectin GDC-I-87.5% +/- 15.0%, P < .01). Light
      microscopy showed a well-organized fibrous tissue bridging the aneurysm's neck
      when using GDC-Is, whereas only a fibrin-like thin layer covered the standard GDC
      surfaces. CONCLUSION: GDC-Is indicated a more intense inflammatory response in
      the aneurysm body and dome and faster re-endothelial coverage of the neck of the
      aneurysm. This accelerated histologic response may decrease the chances of coil
      compaction and aneurysm recanalization. This technology may improve anatomic and
      clinical outcomes in patients harboring intracranial aneurysms.

PMID- 10588134
TI  - Flow dynamics in a lethal anterior communicating artery aneurysm.
AB  - We describe and analyze the flow dynamics in replicas of a human anterior
      communicating artery aneurysm. The replicas were placed in a circuit of pulsating
      non-Newtonian fluid, and flows were adjusted to replicate human physiologic
      parameters. Individual slipstreams were opacified with isobaric dyes, and images
      were recorded on film and by CT/MR angiography. When flow in the afferent
      (internal carotid) and efferent (anterior and middle cerebral) arteries was
      bilaterally equal, slipstreams rarely entered the aneurysm. When flow in either
      the afferent or efferent vessels was not symmetrical, however, slipstreams
      entered the aneurysm neck, impinged upon the aneurysm dome, and swirled within
      the aneurysm. Unequal flow in carotid or cerebral systems may be necessary to
      direct pathologic, fluid slipstreams into an aneurysm.

PMID- 10588135
TI  - Determinants of resource utilization in the treatment of brain arteriovenous
      malformations.
AB  - BACKGROUND AND PURPOSE: Preoperative embolization of arteriovenous malformations
      (AVMs) is thought to improve outcome following surgical resection of these
      lesions. The purpose of this study was to examine the cost associated with
      preoperative embolization and different surgical risk categories in the surgical
      treatment of brain AVMs. METHODS: In a review of 126 patients treated surgically
      for resection of AVMs, we noted the total days spent in the hospital and
      calculated the associated costs (from hospital and estimated professional fees).
      Surgical risk category was determined using the Spetzler-Martin grading system.
      We examined the effect of risk category, preoperative embolization, and outcome
      (Rankin score) on cost and inpatient days. RESULTS: Preoperative embolization and
      greater surgical risk were independently associated with higher total costs.
      Average adjusted cost for embolization and surgery was $78,400 +/- $4,900 versus
      $49,300 +/- $5,800 for surgery alone. Patients ranged in preoperative risk
      category from Spetzler-Martin grades II through V, with an average increase of
      $20,100 in total cost per Spetzler-Martin grade (95% CI, $13,500 to $28,100).
      Higher surgical risk category was also associated with more days spent in
      hospital, with an average increase of 6 days per increment in Spetzler-Martin
      grade (95% CI, 4 to 8). After surgical resection of an AVM, new neurologic
      deficits were associated with large differences in cost: $68,500 +/- $6,100 and
      15 +/- 2 days in hospital for patients who were neurologically worse after
      surgery, versus $44,700 +/- $3,900 and 10 +/- 1 days for patients who were
      unchanged. CONCLUSION: Preoperative embolization in the treatment of AVMs is
      associated with higher cost but not more days in the hospital. Patients with
      higher Spetzler-Martin grade AVMs utilize more hospital resources, in part
      because they have poorer neurologic outcome, and postoperative deficits are
      associated with higher costs and more days in the hospital.

PMID- 10588136
TI  - Preoperative transarterial embolization of spinal tumor: embolization techniques
      and results.
AB  - BACKGROUND AND PURPOSE: The techniques of preoperative embolization of
      hypervascular spinal tumors, which has been known to be helpful for completing
      tumor resection, have not been described in detail. The purpose of this study was
      to analyze the technique and to evaluate the safety and value of preoperative
      transarterial embolization of hypervascular spinal tumors. METHODS: Eighteen
      patients with hypervascular spinal tumors underwent transarterial embolization
      before surgery. The lesions were located between the upper cervical and lower
      lumbar spine: C1-T1 (n = 6), T5-L3 (n = 11), and L5 (n = 1); they arose
      intradurally in six patients and extradurally in 12. Thirty-one arteries were
      embolized with polyvinyl alcohol (PVA) particles (150-500 microm), and, in 18 of
      these, pieces of gelatin sponge were added for proximal pedicular embolization.
      The criteria for judging the effectiveness of embolization were completeness of
      tumor removal and estimated blood loss during surgery. RESULTS: Tumor
      embolization was total in eight patients, nearly total in seven, subtotal in one,
      and partial in two. There were no symptomatic complications associated with
      embolization. Tumors were totally removed in 17 patients and nearly totally
      removed in one. The average estimated blood loss during surgery was 1100 mL
      (range, 200-6000 mL) for all 18 patients, and 1540 mL in patients with extradural
      tumors. CONCLUSION: Preoperative embolization of hypervascular spinal tumors is
      safe and effective. It can make complete resection of a tumor possible and can
      make an unresectable tumor resectable. Superselection or flow control is
      necessary to achieve effective devascularization and to avoid complications.

PMID- 10588137
TI  - Three cases of dural arteriovenous fistula of the anterior condylar vein within
      the hypoglossal canal.
AB  - Dural arteriovenous fistulas (DAVFs) of the anterior condylar vein are an
      uncommon but important subset of fistulas occurring at the skull base that can be
      confused with DAVFs of the marginal sinus on angiography. MR angiography source
      images can document the intraosseous extent and the relationship to the
      hypoglossal canal of this type of fistula, which can have significant clinical
      implications. We present the imaging features of angiography, CT, and MR
      angiography of three cases of DAVFs localized to the anterior condylar vein and
      within the hypoglossal canal, which were confirmed by source images from MR
      angiography. Transvenous coil embolization was curative in two of three cases and
      would seem to be the treatment of choice when venous access is available.

PMID- 10588138
TI  - Safety of angioplasty for intracranial artery.

PMID- 10588139
TI  - Direct angioplasty for acute occlusion of intracranial artery.

PMID- 10588140
TI  - In re: Reversible ischemia determined by xenon-enhanced CT after 90 minutes of
      complete basilar artery occlusion.

PMID- 10588141
TI  - Pathogenesis of syringomyelia.

PMID- 10588142
TI  - Optimal pacing in first-degree AV block.

PMID- 10588143
TI  - Inhibition of ventricular stimulation in patients with dual chamber pacemakers
      and prolonged AV conduction.
AB  - Episodes of repetitive P wave undersensing have been described in dual chamber
      pacemakers due to automatic extension of the postventricular atrial refractory
      period (PVARP). Pacemaker stimulation was completely inhibited despite the
      presence of adequate P waves. This study sought to determine whether cycles of
      repetitive P wave undersensing occur even in the absence of PVARP extension. Two
      hundred fifty-five patients were investigated after DDD or VDD pacemaker
      implantation for intermittent atrioventricular (AV) block. Forty-six episodes of
      repetitive atrial undersensing were found during 24-hour Holter ECG in nine
      patients. Pacemaker syndrome-like symptoms occurred. Episodes were elicited by
      atrial or ventricular premature contractions when (1) native AV conduction was
      present but considerably prolonged, (2) intrinsic sinus rate exceeded pacemaker
      intervention rate, and (3) native AV interval plus PVARP exceeded sinus cycle
      length. Programming of a particularly short AV interval and PVARP helped to
      reduce the incidence of repetitive P wave undersensing. Patients with dual
      chamber devices and prolonged native AV conduction are prone to develop episodes
      of output inhibition. Standard timing cycles may be inappropriate in these
      patients.

PMID- 10588144
TI  - Clinical follow-up after cessation of chronic electrical neuromodulation in
      patients with severe coronary artery disease: a prospective randomized controlled
      study on putative involvement of sympathetic activity.
AB  - The present study assessed the reoccurrence of myocardial ischemia after
      withholding electrical neurostimulation. After randomization, in the study or
      withdrawal group, spinal cord stimulation (SCS) was set active during the first 4
      weeks, followed by 4 weeks of withholding stimulation. In the control group, SCS
      was switched off during 4 weeks before the end of the study. The control group
      had no crossover period. Measurements were done at baseline, then after 4 and 8
      weeks. The first periods at 4 weeks of each sequence of both groups were
      compared. In addition, a comparison of clinical variables was performed between
      the study group 4 weeks after withholding stimulation and the control group 4
      weeks following randomization. A total number of 24 patients with refractory
      angina and an implanted spinal cord stimulator were included in the study (n =
      12) and control group. Angina pectoris complaints, nitroglycerin intake,
      ischemia, and heart rate variability using 48-hour ambulatory
      electrocardiographic monitoring were assessed. In addition, neurohormonal status
      and symptom-limited aerobic capacity were evaluated. There was no increase of
      anginal complaints or ischemia after withholding stimulation. Neurohormonal
      levels and aerobic capacity were not altered. We conclude that there is no
      adverse clinical rebound phenomenon after withholding neurostimulation in
      patients with refractory angina pectoris.

PMID- 10588145
TI  - Double pulse transthoracic defibrillation in the calf using percent fibrillation
      cycle length as spacing determinate.
AB  - Recent studies have found that when multiple pulses of energy are used for
      defibrillation with implantable electrodes, the spacing between these pulses is
      better determined as a percentage of the fibrillation cycle length (CL), rather
      than as a fixed function of time. Here, this concept is further tested in the
      transthoracic defibrillation of calves, which are approximately the size of heavy
      humans. Eleven 90-110 kg calves (101 +/- 6 kg) were used in evaluating the
      effectiveness in achieving transthoracic ventricular defibrillation of ten double
      pulse waveforms (two 50 A 4-ms rectangular monopulses) having leading edge-to
      edge spacings of 4 ms (a 50 A 8-ms rectangular monopulse) and 50, 60, 70, 80, 90,
      100, 110, 120, 130 percent fibrillation CL, respectively. In each of these
      waveforms, the total time when 50 A current was flowing (on time) was 8 ms. Our
      results show an unequivocal adverse interaction between the pulses, when the
      spacing is around 60%-70% fibrillation CL; but that the two pulses combined to
      defibrillate as effectively as a single 8-ms pulse when the spacing is around
      110%-130% fibrillation CL. Electrocardiographic analysis suggests that the
      adverse interaction is due to a refibrillation phenomenon. This study confirms
      that double pulses can interact and have a negative effect on defibrillation
      efficacy. Our data suggests that the mechanism of this interaction involves the
      second pulse reinitiating fibrillation when the pulse separation is in a critical
      range of values. Our results are also compatible with the hypothesis that the
      spacing of multiple pulses is better determined as a percentage of the
      fibrillation CL than as absolute time, although more study is necessary to fully
      test this hypothesis.

PMID- 10588146
TI  - Circadian variability of late potential analysis in Holter electrocardiograms.
AB  - Appearance of ventricular tachycardia, ventricular fibrillation, and sudden
      cardiac death has diurnal variations. We retrospectively studied, using digital
      Holter electrocardiogram, whether a time course in the appearance of late
      potentials may be associated with malignant ventricular arrhythmias. The 24-hour
      recordings in 200 patients after myocardial infarction (50 patients with
      documented, sustained, monomorphic and reproducibly inducible ventricular
      tachycardia (< 270/min) (group I), 50 patients resuscitated from ventricular
      fibrillation (group II), and 100 patients without ventricular arrhythmias (group
      III) were divided into 24 segments, 60 minutes each. Late potential analysis was
      performed using the Simson method in the time domain in each segment and compared
      to a conventional short-term registration. Late potential analysis in
      conventional short-term recordings during arbitrarily chosen daytimes revealed
      late potentials in 80% of patients in group I, 38% of patients in group II, and
      in 16% of patients without ventricular arrhythmias. In at least one 60-minute
      segment late potentials were found in group I in 92%, in group II in 88% (P <
      0.05 vs conventional analysis), and in group III in 19%. Interestingly, in
      patients with a history of ventricular fibrillation late potentials appeared
      significantly more often during morning hours (6-12 AM: 82% vs 26% at 12 AM-6 PM,
      30% at 6 PM-12 PM, and 42% at 12 PM-6 AM, P < 0.05), especially during phases
      with heart rate accelerations. Late potential analysis for risk stratification in
      conventional short-term recordings is feasible for patients prone to ventricular
      tachycardia, but patients prone to ventricular fibrillation would be more
      effectively stratified using 24-hour registrations with detection of circadian
      variations of late potential appearance.

PMID- 10588147
TI  - Impact of the ECG for detection of intraatrial conduction block after atrial
      flutter ablation.
AB  - Induction of complete bidirectional conduction block via the posterior isthmus of
      the right atrium is introduced as a standard endpoint for catheter ablation of
      atrial flutter. The present study sought to investigate the impact of changes in
      P wave duration and morphology detected by the surface ECG during coronary sinus
      and posterolateral right atrial stimulation as a marker for conduction block.
      Morphology and duration changes of the paced P wave before and after
      radiofrequency catheter (RFC) ablation were estimated in 22 patients referred for
      ablation of atrial flutter. We looked for a morphology change of the terminal
      portion in the 12-lead ECG and an increment of P wave duration. In 16 of 22
      patients in whom atrial flutter ablation resulted in a complete bidirectional
      block, the conduction block was unidirectional in 4 patients and conduction times
      remained unchanged in 2 patients. After induction of complete bidirectional block
      a change of the terminal portion of the P wave towards a more positive morphology
      in one or more inferior leads was detected in 14 (88%) of 16 patients during
      coronary sinus stimulation and in 15 (94%) of 16 patients during posterolateral
      right atrial stimulation. These changes were predominantly observed in the
      inferior leads. Positive morphology changes of the terminal P wave portion in the
      inferior leads indicating conduction block with a sensitivity of 86% and a
      specificity of 100% were observed. An increment of 10 ms or more in P wave
      duration indicates conduction block with a specificity of 100% and a sensitivity
      of 67%. There was a significantly larger increment of P wave duration during
      coronary sinus (CS) stimulation compared to posterolateral right atrial
      stimulation (38 +/- 21 vs 16 +/- 21 ms). The analysis of P wave duration and
      morphology in the inferior leads of the surface ECG is a reliable tool to assess
      the intraatrial conduction after atrial flutter ablation. Different conduction
      during coronary sinus and posterolateral right atrial pacing may cause a
      different P wave duration after ablation.

PMID- 10588148
TI  - Evolution of QRS duration after myocardial infarction: clinical consequences.
AB  - The natural history of late potentials after acute myocardial infarction (AMI)
      has been studied in the first 2 years following myocardial infarction (MI). The
      purpose of the study was to assess the influence of some time delays since MI,
      including a time delay longer than 2 years on signal-averaged ECG (SAECG). SAECG
      was recorded at 40-Hz high pass filtering in 40 patients 10 days after acute MI
      (SAECG 1), then repeated 6-12 months later (mean 9 +/- 3 months) (SAECG 2), and
      then, 2-4 years later (mean 3 +/- 2 years) (SAECG 3). QRS duration, root mean
      square voltage of the last 40 ms of QRS (RMS 40), and low amplitude signal
      duration (LAS) were measured at the first (1), second (2), and third recording
      (3). RESULTS: (***P < 0.001) [table: see text] The analysis of individual results
      showed a lengthening QRS duration at the third recording only in patients who had
      a decreased left ventricular ejection fraction (LVEF) at the third recording. In
      12 patients with LVEF > 40%, QRS duration did not change at the first and third
      recording (104 +/- 15 vs 101 +/- 12 ms). In all 28 patients, but one with LVEF <
      40%, QRS duration increased from 107 +/- 12 to 128 +/- 18 ms***. There was no
      correlation between QRS duration and LVEF at the second recording and no
      correlation between QRS duration increase at the third recording and the presence
      or not of late potentials at the first recording. QRS duration lengthening at the
      third recording was significantly correlated with a left ventricular (LV)
      dilatation occurrence at the two-dimensional echocardiogram. All arrhythmic
      events, but two, occurred in patients who developed a QRS duration prolongation
      and were significantly correlated (P < 0.01) to a mean longer QRS duration (132
      +/- 20 ms) than in patients without arrhythmic events (113 +/- 17 ms). In
      conclusion, the patients with a LV impairment, and who developed a LV dilatation
      several months after AMI, presented a delayed lengthening of QRS duration noted
      only at least 2 years after infarction. These patients are at risk of arrhythmic
      events.

PMID- 10588149
TI  - Effects of body position and exercise on evoked response signal for automatic
      threshold activation.
AB  - The Autocapture function controls and optimizes the output of the ventricular
      pulse amplitude automatically. For this reason an automatic test has to be
      performed during follow-up to measure the evoked response signal and lead
      polarization for the calculation of the appropriate evoked response sensitivity
      setting. The aim of the study was to assess whether body position and exercise
      influence the evoked response and polarization. Both parameters were determined
      in the supine and upright position and subsequently during supine and upright
      symptom-limited ergometry. The study included 14 patients with the VVIR pacemaker
      Regency SR+ who had received the ventricular pacing leads Membrane E 1450 T (n =
      8), CapSure Z 5034 (n = 4), or SX 60 (n = 2). The evoked response signal was 7.4
      +/- 3.3 mV during supine and increased to 9.7 +/- 5.6 mV (+35%) during upright
      position (P < 0.05). The exercise tests were terminated at 105 +/- 36 W (supine)
      and 110 +/- 34 W (upright). There was a gradual insignificant decrease of the
      evoked response during each exercise test with a mean decrease of -1.1 +/- 0.9 mV
      (-15%; supine) and -1.6 +/- 2.1 mV (-16%; upright). The evoked response increased
      within 5 minutes during recovery to the initial values. Polarization remained
      unchanged during both tests. The pacemaker did not recommend activating
      autocapture in four patients who all had received high-ohmic pacing leads. In
      conclusions, the measurement of the evoked response in supine position seems to
      represent the worst case. Physical activities did not effect autocapture function
      in patients with the recommended lead, but the pacemaker did not always recommend
      Autocapture activation in some patients with high-ohmic pacing leads.

PMID- 10588150
TI  - External exponential biphasic versus monophasic shock waveform: efficacy in
      ventricular fibrillation of longer duration.
AB  - Ventricular fibrillation (VF) duration may be a factor in determining the
      defibrillation energy for successful defibrillation. Exponential biphasic
      waveforms have been shown to defibrillate with less energy than do monophasic
      waveforms when used for external defibrillation. However, it is unknown whether
      this advantage persists with longer VF duration. We tested the hypothesis that
      exponential biphasic waveforms have lower defibrillation energy as compared to
      exponential monophasic waveforms even with longer VF duration up to 1 minute. In
      a swine model of external defibrillation (n = 12, 35 +/- 6 kg), we determined the
      stored energy at 50% defibrillation success (E50) after both 10 seconds and 1
      minute of VF duration. A single exponential monophasic (M) and two exponential
      biphasic (B1 and B2) waveforms were tested with the following characteristics: M
      (60 microF, 70% tilt), B1 (60/60 microF, 70% tilt/3 ms pulse width), and B2
      (60/20 microF, 70% tilt/3 ms pulse width) where the ratio of the phase 2 leading
      edge voltage to that of phase 1 was 0.5 for B1 and 1.0 for B2. E50 was measured
      by a Bayesian technique with a total often defibrillation shocks in each waveform
      and VF duration randomly. The E50 (J) for M, B1, and B2 were 131 +/- 41, 57 +/-
      18,* and 60 +/- 26* with 10 seconds of VF duration, respectively, and 114 +/- 62,
      77 +/- 45,* and 72 +/- 53* with 1 minute of VF duration, respectively (*P < 0.05
      vs M). There was no significant difference in the E50 between 10 seconds and 1
      minute of VF durations for each waveform. We conclude that (1) the E50 does not
      significantly increase with lengthening VF durations up to 1 minute regardless of
      the shock waveform, and (2) external exponential biphasic shocks are more
      effective than monophasic waveforms even with longer VF durations.

PMID- 10588151
TI  - Transvenous catheter ice mapping and cryoablation of the atrioventricular node in
      dogs.
AB  - While radiofrequency catheter ablation is very effective, it does not allow for
      prediction of success prior to full delivery of the energy. We investigated the
      use of cryoablation using a new catheter on the AV node to determine (1) if a
      successful site might be identified prior to the ablation itself, and (2) the
      parameters of cryoablation of the AV node using a new cryocatheter. In eight
      dogs, the cryoablation catheter was advanced to the AV node to produce transient
      high degree AV block by lowering the temperature to a minimum of -40 degrees C
      (ice mapping). Transient high degree AV node block was obtained in seven of eight
      animals at a mean temperature of -39.9 +/- 11.6 degrees C. No significant
      pathological modification was found in all animals but one and, in all cases,
      electrophysiological parameters of the AV node measured before, 20 minutes, 60
      minutes, and up to 56 days after cryoapplication were not significantly
      different. In the 12 other dogs, after ice mapping, cryoablation of the AV node
      was attempted with a single freeze-thaw cycle in 6 dogs (group I) and a double
      freeze-thaw cycle in the other 6 dogs (group II). Chronic complete AV block was
      obtained in only one animal in group I compared to all animals in group II.
      Ablation of the AV node is effective with a double freeze-thaw cycle using a
      percutaneous catheter cryoablation system. Ice mapping of the area allows for
      identification of the targeted site.

PMID- 10588152
TI  - Percutaneous cephalic vein approach for permanent pacemaker implantation.
AB  - Implantation of permanent pacemaker leads into the cephalic vein within the
      deltopectoral groove is enhanced by introduction of a flexible guidewire into the
      brachial vein at the antecubital fossa, which is then advanced to the subclavian
      vein. The cephalic vein within the deltopectoral groove is easily found by
      incision with the guidewire as a marker. A pacing lead or leads can be inserted
      along the guidewire or by using a sheath advanced over the guidewire. The
      procedure was performed on 32 patients and the pacing leads of 28 procedures (DDD
      15, VDD 9 and WI 4) were inserted using the cephalic vein without complications.

PMID- 10588154
TI  - Optimal cardiac pacing after heart transplantation.
AB  - The transplanted heart is characterized physiologically by autonomic denervation,
      chronotropic incompetence, intermittent episodes of allograft rejection, and
      frequently by diastolic dysfunction. Sinus node dysfunction resulting in
      bradycardia is common in the early postoperative period following standard
      orthotopic cardiac transplantation. Bradycardia tends to remit spontaneously but
      there are no factors that accurately identify patients who will need long-term
      pacing. Patients in whom bradycardia persists beyond the second postoperative
      week despite treatment with theophylline require permanent pacemaker
      implantation. It has been observed that chronotropic incompetence and diastolic
      dysfunction are important determinants of exercise capacity following heart
      transplantation. Pacing that restores chronotropic competence improves exercise
      capacity, confirming the importance of impaired heart rate response. As in other
      settings, pacing that preserves atrioventricular (AV) synchrony results in
      increased cardiac output. For these reasons when pacing is necessary we recommend
      the DDDR mode (AAIR if intact AV nodal conduction is present) so that the 30%-50%
      of patients who remain pacemaker-dependent long-term obtain maximal benefit from
      their transplant.

PMID- 10588153
TI  - AV conduction with atrial rate adaptive pacing in the bradycardia tachycardia
      syndrome.
AB  - AV conduction with atrial rate adaptive pacing (AAIR) during exercise was
      investigated in 43 patients (28 men, 15 female, mean age 68 +/- 7 years) who were
      paced and medicated with antiarrhythmic drugs for the bradycardia tachycardia
      syndrome (BTS). Patients were included if they had no second- or third-degree AV
      block, no complete bundle branch or bifascicular block, and a PQ interval < or =
      240 ms during sinus rhythm at rest. The interval between the atrial spike and the
      following Q wave (SQ) was measured in the supine position at rest (R) with
      maximum AAI pacing rate (Fmax) achieved below the Wenckebach point (SQ-R-Fmax).
      Bicycle ergometry was performed using the Chronotropic Assessment Exercise
      Protocol, and AAI pacing rate was increased stepwise by programming load-adapted
      increments. Seven patients showed intrinsic rhythm during exercise. In those 36
      patients who were atrially paced throughout ergometry (E), SQ was measured with
      70 beats/min on the lowest CAEP stage (SQ-E-70) and with Fmax at maximum work
      load (SQ-E-Fmax). During exercise, no second-degree AV block was observed, but 28
      of 36 patients (78%) showed a nonphysiological increase of the SQ interval, and
      the average SQ-E-Fmax was significantly longer than SQ-E-70 (250 +/- 31 versus
      228 +/- 32 ms, P < 0.01). There was only a weak correlation between SQ-R-Fmax and
      SQ-E-Fmax (r = 0.35824, P < 0.05). When Fmax obtained during exercise was kept
      during recovery, 14 patients (39%) developed a second-degree AV block between 15
      and 240 seconds after ergometry, 8 patients within 90 seconds. Patients who had
      exhibited a P on T wave in the ECG with Fmax at the end of exercise (11 of 36
      patients) were reevaluated by Doppler echocardiography. Using the same exercise
      protocol and identical, load-adapted rate increments, only 3 of 11 patients
      showed premature mitral valve closure. It is concluded that patients paced and
      medicated for BTS are prone to a nonphysiological prolongation of AV conduction
      with AAIR pacing during and after exercise. As this risk can hardly be predicted
      by rapid atrial pacing at rest, the pacing system should be dual chamber in this
      subset of patients. This especially applies to the patients in whom mechanical AV
      timing is affected by the conduction delay.

PMID- 10588155
TI  - The use of esmolol to unmask tachycardia mechanism.

PMID- 10588157
TI  - Advocacy with payers--it's all local.

PMID- 10588156
TI  - Comparison of different methods for manual P wave duration measurement in 12-lead
      electrocardiograms.
AB  - To determine whether different methods for the manual measurement of P wave
      duration are mutually consistent, we evaluated the intraobserver and
      interobserver errors of P wave measurements obtained in three different ways: (1)
      by cursor on a high resolution computer screen (on screen), (2) by calipers and a
      magnifying glass (on paper), and (3) by a high resolution digitizing board (on
      board). The agreement between the methods was assessed in 30 normal subjects and
      30 patients with a history of atrial fibrillation. The maximum P wave duration (P
      maximum), the minimum P wave duration (P minimum), mean P wave duration (P mean),
      P wave dispersion (P dispersion = P maximum - P minimum), and the standard
      deviation of the P wave duration in all measured leads (P SD) were calculated
      from a 12-lead electrocardiogram in each subject. Only P maximum, P mean, and P
      dispersion were significantly higher in patients than in controls with all three
      methods. Intraobserver and interobserver relative errors were significantly
      different among the three methods; the lowest errors were associated with the on
      screen measurement. The agreement between the three different methods was
      acceptable for P maximum, P mean, and P SD and rather poor for P minimum and P
      dispersion in both groups. The differences of the measurement by different
      methods did not consistently differ between the two groups. Hence, the on-screen
      measurements are consistent with other manual methods and provide more stable
      results. Manual measurement of ECG patterns should be preferably performed with
      digital ECG recordings displayed on a high resolution computer screen.

PMID- 10588158
TI  - Feasibility of pacemaker therapy after dynamic cardiomyoplasty.
AB  - A 54-year-old man presented with total atrioventricular (AV) block 3 months after
      dynamic cardiomyoplasty was performed because of heart failure due to idiopathic
      dilated cardiomyopathy. Though the cardiomyostimulator acted as a back-up
      pacemaker, a DDDR pacemaker was implanted to optimize hemodynamics. During
      testing no cross-sensing or cross-stimulation between the pacemaker and the
      cardiomyostimulator was demonstrable. The synchronization delay, however, had to
      be adjusted.

PMID- 10588159
TI  - Left atrial tachycardia after right atrial separation for chronic atrial
      fibrillation with atrial septal defects.
AB  - A right atrial separation procedure was performed for the ablation of chronic
      atrial fibrillation in four cases, concomitant with the repair of the atrial
      septal defect. After the operation, chronic atrial fibrillation disappeared in
      three of them and left atrial tachycardia occurred in the other one. Left atrial
      tachycardia is an arrhythmia encountered after a right atrial separation
      procedure.

PMID- 10588160
TI  - Spurious redetection of sinus rhythm by an implantable cardioverter defibrillator
      during spontaneous ventricular fibrillation.
AB  - Implantable cardioverter defibrillator undersensing leading to delayed or aborted
      therapy delivery has been reported with induced arrhythmias and following failed
      defibrillator shocks. We describe a case in which spurious redetection of sinus
      rhythm during a spontaneous episode of ventricular fibrillation resulted in
      aborted device therapy.

PMID- 10588161
TI  - Repetitive monomorphic ventricular tachycardia of left coronary cusp origin.
AB  - Repetitive monomorphic ventricular tachycardia with a morphology of inferior axis
      and left bundle branch block pattern in patients without structural heart disease
      commonly originates from the right ventricular outflow tract. We report the case
      of a 22-year-old man with an incessant, monomorphic ventricular tachycardia with
      a similar morphology originating from the left coronary cusp, which was confirmed
      by perfect pace mapping, local ventricular activation preceding the onset of QRS
      by 25 mse, and eliminated by a single delivery of low-energy (11 W)
      radiofrequency currents.

PMID- 10588162
TI  - Peripheral pulmonary migration of a retained pacemaker lead.
AB  - We report a case of lead migration into the right middle pulmonary lobe. The
      migrated electrode reached the pleura and produced severe pleural symptoms,
      therefore, surgical removal of the retained lead was required. This case report
      demonstrates the importance of a chest X ray in the follow-up of patients with an
      implanted pacemaker to detect complications like lead fracture or migration.

PMID- 10588163
TI  - Can a deterioration in atrial sensing characteristics, after coronary artery
      bypass grafting (CABG), lead to profibrillatory asynchronous atrial pacing and to
      the development of atrial fibrillation (AF)?

PMID- 10588165
TI  - STIMAREC report.

PMID- 10588164
TI  - Relative-advantages and disadvantages of the small-surface, high-impedance
      electrodes.

PMID- 10588166
TI  - Irritable bowel syndrome: diagnosis, subgrouping, management, and clinical trial
      design. Introduction.

PMID- 10588167
TI  - Diagnostic criteria for the irritable bowel syndrome.
AB  - The Rome criteria represent a consensus viewpoint based on currently available
      data, but their development certainly does not establish that the content is
      truly indicative of a specific disease process. There is a limit to the
      repertoire of gastrointestinal symptoms; because of the low specificity of
      symptoms, it is understandable that symptoms alone are unlikely to be accurate
      enough. However, in the absence of a reproducible and accepted biological marker,
      symptoms currently remain the primary means of identifying and recruiting
      patients for research. All diagnostic criteria will continue to be controversial
      until the pathophysiology of irritable bowel syndrome (IBS) is better understood
      and treatment more appropriately targeted to relevant disturbances. The aim of
      this review is to present the current Rome criteria and critically evaluate the
      arguments for and against the individual components being included as part of the
      criteria.

PMID- 10588168
TI  - Emerging disease model for functional gastrointestinal disorders.
AB  - In response to perceived or experienced change that is considered threatening to
      the individual, the central nervous system mounts a stereotypic response that
      decreases the sensitivity to pain, modulates the autonomic nervous system
      outflow, and activates the hypothalamic-pituitary-adrenal (HPA) axis. This
      response of the "emotional motor system" may or may not be associated with the
      conscious experience of feelings of fear or anxiety. Alterations in these
      response systems (either up- or downregulation) may produce symptoms, such as
      viscero-somatic hypersensitivity, altered bowel habits, or increased anxiety.

PMID- 10588169
TI  - Diagnostic approach to the patient with irritable bowel syndrome.
AB  - Irritable bowel syndrome (IBS) is a common chronic functional bowel disorder
      characterized by abdominal pain or discomfort and alterations in bowel habits. In
      clinical practice, diagnosis is based on positive symptoms known as the Rome
      criteria and limited diagnostic screen, taking into account warning features
      suggestive of organic disease. Minimal diagnostic tests are warranted to rule out
      structural lesions in a cost-effective manner and to convince the patient of the
      diagnosis of IBS. An initial diagnosis of IBS is safe and rarely needs revision
      over time. Persistence of symptoms is to be expected and does not justify
      suspicion of other diagnoses. Only change in the clinical pattern over time
      justifies additional investigations. Other diagnostic evaluations depend on
      predominant symptoms, namely constipation, diarrhea, and pain or discomfort. It
      should be emphasized that although an initial "positive diagnosis" is safe to
      exclude other diseases with similar symptoms, a common disorder such as IBS may
      often coexist with other asymptomatic disorders.

PMID- 10588170
TI  - Therapeutic approach to the patient with irritable bowel syndrome.
AB  - This article reviews briefly the evidence to support current therapies in
      irritable bowel syndrome (IBS) and the novel therapeutic approaches on the
      threshold of clinical application. Fiber is indicated at a dose of at least 12
      grams per day in patients with constipation-predominant IBS. Loperamide (and
      probably other opioid agonists) are of proven benefit in diarrhea-predominant
      IBS; loperamide may also aid continence by enhancing resting anal tone, but there
      is no evidence that it results in pain relief. In general, smooth muscle
      relaxants are best used sparingly, on an as-needed basis, because their overall
      efficacy is unclear. The 5-HT3 antagonist, alosetron, results in adequate relief
      of pain and improvements in bowel function in female nonconstipated patients with
      IBS. Psychotropic agents are important in relieving depression and are of proven
      benefit for pain and diarrhea in patients with depression associated with IBS.
      Further trials with selective serotonin reuptake inhibitors are awaited.
      Psychological treatments including hypnotherapy are less widely available but may
      play an important role in the relief of pain. In summary, current therapies
      targeted on the predominant symptoms in IBS are moderately successful. As the
      bowel sensorimotor and limbic system disturbances of IBS are more clearly
      understood, we should anticipate other pharmacologic approaches in the near
      future, including alpha-adrenergic agonists and 5-HT4 agonists. New therapies
      directed at treatment of the syndrome, rather than relief of symptoms, are
      needed.

PMID- 10588171
TI  - Patient subgroups in irritable bowel syndrome that can be defined by symptom
      evaluation and physical examination.
AB  - Subgroups of patients with irritable bowel syndrome (IBS) are likely to respond
      differently to existing and evolving therapies. The following criteria for
      subgrouping may be considered: (1) Patients with different predominant bowel
      habits respond differently to treatment (antidepressants, 5HT3-antagonists,
      psychotherapy). (2) Postprandial exacerbation of pain or other gastrointestinal
      symptoms is seen in approximately half of patients with IBS and may identify
      patients who are more responsive to some classes of drugs (e.g., those targeted
      at motility). (3) Women appear to respond differently from men to 5HT3
      antagonists, and there may be gender differences in gastrointestinal physiology.
      (4) There is more overlap in the diagnosis of functional dyspepsia and IBS than
      would be predicted by chance, and both are associated with hyperalgesia to
      intraluminal distention.

PMID- 10588172
TI  - Do psychosocial factors define symptom severity and patient status in irritable
      bowel syndrome?
AB  - Psychological difficulties in patients with irritable bowel syndrome (IBS) are
      strongly related to symptom severity and patient status. This has important
      implications for clinical practice, and the design and conduct of clinical
      trials. Psychosocial factors (personality, psychiatric diagnosis illness
      behavior, life stress, psychological distress) distinguish patients with IBS from
      patients with no IBS. Psychosocial difficulties (e.g., history of physical or
      sexual abuse, maladaptive coping, or "catastrophizing") predict poorer health
      outcome (greater pain scores, psychologic distress and poorer daily function,
      more days spent in bed, and more frequent physician visits and surgeries). When
      using the standardized Functional Bowel Disorder Severity Index, patients
      classified as severe are distinguished from moderates by several psychosocial
      difficulties and health-care use variables. In addition, whereas patients with
      severe illness report more pain, there is no difference from patients with
      moderate illness in terms of visceral sensation threshold. Given these data, it
      is important to consider psychosocial factors as predictive of symptom severity
      and clinical outcome, and this should be considered in clinical care and the
      design of clinical trials.

PMID- 10588174
TI  - Inclusion and exclusion criteria of importance in irritable bowel syndrome
      trials.
AB  - Although numerous diseases may mimic or be confused with irritable bowel syndrome
      (IBS), a detailed and precise clinical history and a normal clinical examination
      usually lead to an accurate diagnosis of IBS. The presence of symptom criteria
      and the absence of warning signs must be established. Before entering a clinical
      trial, several routine tests are generally required: total blood count,
      erythrocyte sedimentation rate, biochemistry screen, stool culture and
      examination for occult blood, ova, and parasites, and a recent (<2 years) normal
      flexible sigmoidoscopy or colonoscopy with biopsy. Blood and stool tests are not
      necessary for the diagnosis of IBS but are important in the framework of
      controlled trials. Esophagogastroduodenoscopy, abdominal ultrasonography, and
      malabsorption tests are needed only in patients with atypical IBS or for phase II
      trials in certain subgroups of patients. Chronic diseases, drugs, and toxic
      agents that may mimic IBS symptoms or exacerbate the disorder must be excluded.
      Errors in patient inclusion will be minimized if the duration and severity of IBS
      symptoms before inclusion is sufficient and will have little effect on the result
      of the trial if the new drug is really effective and the study well randomized
      with a correct calculation of sample size.

PMID- 10588173
TI  - Entry criteria for drug trials of irritable bowel syndrome.
AB  - This review explores a broad range of patient characteristics that might be
      considered when selecting patients for inclusion into drug trials for irritable
      bowel syndrome (IBS). These characteristics have been chosen according to the
      author's perspective and a review of the literature based on a Medline search
      encompassing references to IBS (clinical, pharmacologic, and drug trials) from
      1966 to 1998. The focus is to improve patient selection, which until now has
      concentrated predominantly on physical symptoms. Irritable bowel symptoms involve
      both physical and psychological domains in an inseparable way, the interaction
      profoundly affecting the physical manifestations of the condition, the patient's
      interpretation of these physical changes, the ability of the patient to cope with
      these symptoms, the extent to which the patient feels the need to seek treatment,
      and the response to different types of treatment. Selection criteria need to take
      both physical and psychological domains into account. When defining the disorder
      for purposes of patient selection, a simple definition of long-standing abdominal
      pain and bloating associated with alternating diarrhea and constipation (after
      the exclusion of organic disease) may still be the most practical. The Manning
      and Rome criteria have been reasonably well validated, especially when the
      constellation of symptoms is used as a unit; however, their applicability to men
      and the elderly is not as well validated and deserves further attention. Other
      patient characteristics that may be useful in the future in deciding suitability
      for a trial, or predicting response, include symptom pattern, length of symptom
      history, whether the condition was triggered by enteric infection, whether a
      patient is in primary, secondary, or tertiary care, psychological
      characteristics, a history of physical or sexual abuse, and possibly visceral
      sensitivity testing or autonomic dysfunction. Different studies may be required
      for primary care and tertiary care patients, who may differ in their
      psychological characteristics. Studies should also include patients across the
      demographic spectrum who are likely to require treatment for this condition,
      including adolescents and the elderly. The type of drug being tested will also
      influence patient selection, depending on whether it is fast or slow acting, and
      its predominant pharmacologic effects and side effects. This has particular
      relevance in relation to the presence of diarrhea or constipation, how prominent
      the symptom of pain is, and whether the drug has psychotropic or anxiolytic
      effects. Because of the recognition that IBS patients compose a heterogeneous
      population, precise characterization of patients, and targeted drug therapies are
      likely to lead to better therapeutic results. Further attention also needs to be
      paid to the type of drug under investigation, in relation to these different
      patient characteristics.

PMID- 10588175
TI  - Experience with anxiety and depression treatment studies: implications for
      designing irritable bowel syndrome clinical trials.
AB  - This report highlights various considerations regarding the potential effects of
      concurrent psychiatric conditions and a history of abuse in patient volunteers
      for clinical trials in irritable bowel syndrome (IBS). Even though many studies
      have used psychological rating scales to assess personality and psychological
      traits of patients with IBS, the prevalence of the different psychiatric
      diagnoses (i.e., categorical assessment) in patients with IBS has only recently
      been assessed systematically. Recent studies of treatment-seeking patients have
      indicated that the majority of individuals (50% to 90%) who seek treatment for
      IBS have a lifetime history or currently have one or more common psychiatric
      conditions: major depressive disorder, generalized anxiety disorder, panic
      disorder, social phobia, somatization disorder, and posttraumatic stress
      disorder. Traditional clinical wisdom is that the presence of a psychiatric
      disorder increases the likelihood that an IBS patient will seek treatment.
      However, recent data suggest that IBS and psychiatric disorders are associated
      regardless of treatment-seeking status. Patients with psychiatric disorders
      should be included in clinical IBS studies, because this reflects the actual
      patient population. Extrapolating from the psychiatric literature, inclusion of
      patients with IBS with mild to moderate anxiety or depression is warranted.

PMID- 10588176
TI  - The relationship between psychosocial parameters and outcome in irritable bowel
      syndrome.
AB  - This article reviews the evidence that psychiatric disorders have an adverse
      influence on the outcome of irritable bowel syndrome (IBS) and relates this to
      the close relationship between psychological symptoms and severity of abdominal
      pain, bloating, and diarrhea. Therefore, accurate measurement of psychological
      symptoms may be an important aspect of trial design for IBS therapy. The
      importance of psychological distress and health anxiety in differentiating
      "consulters" and "nonconsulters" for IBS is reviewed. The consequences of
      excluding from a trial people with certain types of psychiatric disorder or with
      a known past history of sexual abuse are considered.

PMID- 10588177
TI  - Measurement of symptoms in irritable bowel syndrome clinical trials.
AB  - Irritable bowel syndrome (IBS) is a chronic disorder with symptoms that range in
      intensity from mild and infrequent to severe and continuous. A variety of
      approaches to symptom assessment are used in IBS, although there is little
      literature directly comparing or validating them. Determining the presence or
      absence of specific symptoms is the primary focus of diagnostic evaluation and
      categorization. In contrast, outcome assessment usually entails assessment of
      symptom severity. Symptom severity scales can themselves vary on a wide range of
      factors, including specificity (pain, discomfort, gastrointestinal problem),
      scaling properties (numerical, analogue, or descriptor), range (usual, highest,
      lowest), time frame (now, past week), response category (intensity,
      unpleasantness, change, relief), and use of modifying variables (frequency,
      impact, location). The measurement properties of similar symptom scales have been
      investigated more extensively in the context of somatic pain, and these studies
      will be reviewed in suggesting some guidelines for IBS symptom assessment in
      clinical trials.

PMID- 10588178
TI  - Likely impacts of recruitment site and methodology on characteristics of enrolled
      patient population: irritable bowel syndrome clinical trial design.
AB  - Approximately 15-20% of the general population of many western countries fulfill
      clinical diagnostic criteria for irritable bowel syndrome (IBS) and nearly 50% of
      referrals and follow-up appointments in hospital gastroenterology clinics are for
      functional bowel disorders. IBS is a common problem in the community, in primary
      care (general practice) and in secondary care (hospital, usually ambulatory)
      settings, and is also seen in tertiary (referral) centers, providing at least
      four potential settings for recruitment of patients into clinical trials.
      However, little is known about the influences that cause patients to choose
      different health-care settings or to stay away from the health-care system as
      "nonconsulters." Also, it is not known if patients seen at different health-care
      settings differ from each other. The aim of this review is to address the
      following questions: To what extent do subjects identified and enrolled in these
      settings differ from each other? What is the likely impact of different
      recruitment methods on subject selection? What problems for the interpretation
      and generalizability of data from clinical trials might these differences pose?
      What is the role of the sociomedical context (cultural beliefs and values and the
      structure of the health-care system) in different countries on the interpretation
      of clinical studies?

PMID- 10588179
TI  - Problems and challenges in the design of irritable bowel syndrome clinical
      trials: experience from published trials.
AB  - The last two decades have seen many studies that are of inadequate design and
      power. This report focuses on what we have learned from the 25 randomized,
      controlled studies that included at least 30 patients during the period 1976
      1998. The most important finding has been that the median placebo response was
      47% (range, 0-84%), which is approximately three times the size of the difference
      between placebo and drug response, median 16% (range, -17-64%). This tells us the
      importance of reassurance and the powerful nonspecific therapeutic effects of
      entering patients into clinical trials in irritable bowel syndrome (IBS).
      Patients should be stratified according to the dominant symptoms that are
      relevant to the drug's intended effect. A randomized, double-blind, controlled,
      parallel group study appears the most robust design. Minimizing the placebo
      response reduces the numbers needed to detect a significant difference. The
      optimum length of trial is probably >3 months, because the placebo effect takes
      approximately 12 weeks to start to recede. Dose titration should maximize the
      chance of detecting a benefit.

PMID- 10588180
TI  - Irritable bowel syndrome clinical trial design: future needs.
AB  - This article addresses a series of points that should be considered in the design
      of future clinical trials in irritable bowel syndrome (IBS). A precise,
      uncontroversial definition of the disorder and the affected patient is required
      that accurately describes the condition that practitioners recognize intuitively
      exists. Regarding patient source and selection, the principle should be applied
      that patients be recruited to trials from all sources to which an indication is
      intended. Because abdominal pain is the most central symptom of IBS, it should be
      used as the primary trial endpoint. Because there are currently no effective
      treatments, placebo-controlled trials pose no ethical problems. High placebo
      responses may equally well be the temporary spontaneous improvements that are
      characteristic of the condition. Clinical trials should be designed to meet
      specific aims of treatments: when taken as single doses to terminate an attack of
      pain; when taken over a brief period of time to speed resolution of a period of
      exacerbation of IBS; when taken after termination of a period of activity to
      prevent relapse; when taken regularly on a long-term basis to reduce the days on
      which a number of symptoms are experienced; when taken in form of discrete
      courses of treatment designed to achieve a pivotal change in the natural history
      of the condition.

PMID- 10588181
TI  - Effect of acute and chronic glucocorticoid treatments on epithelial cell
      proliferation in the esophagus and small intestine of rats.
AB  - Data about glucocorticoid influence on proliferation in the esophagus and small
      intestine are very contradictory and need to be reexamined. Moreover, only the
      effects of acute or short-term treatments with glucocorticoids have been
      demonstrated, whereas nothing is known about their effects under chronic
      exposure. This work was therefore carried out to examine proliferative activity
      in the esophagus and small intestine under conditions of acute and chronic
      glucocorticoid exposure. Rats were treated with either glucocorticoid
      triamcinolone acetonide or vehicle for 3, 33, or 63 days. Proliferation was
      assessed in the basal layer of esophageal epithelium and in the epithelium of
      jejunal crypts, using three criteria, as the number of mitotic, bromodeoxyuridine
      labelled, and proliferating cell nuclear antigen-labelled cells. Treatment with
      glucocorticoid for 3 days led to a slight decrease in all parameters in the
      esophageal epithelium and had almost no effect on proliferation in the epithelium
      of jejunal crypts. Long-term treatment with glucocorticoid for either 33 or 63
      days resulted in an increase in all parameters tested in both esophageal and
      jejunal crypt epithelia. Sixty-three-day treatment had a more prominent and
      significant (P < 0.05) effect. These results suggest that acute glucocorticoid
      treatment nonsignificantly reduces the number of cells in the cell cycle in the
      esophageal epithelium, whereas chronic treatment increases the number of
      proliferating cells in both esophageal and jejunal crypt epithelia.

PMID- 10588182
TI  - Helicobacter pylori infection reduces intraluminal nitric oxide in humans.
AB  - It has recently been demonstrated that nitric oxide (NO) is highly concentrated
      in the gastric lumen and plays an important role in defending against pathogenic
      microorganisms in the stomach. NO in the gastric lumen is mainly delivered by
      extrinsic sources from saliva. We studied whether Helicobacter pylori infection
      affected intraluminal NO levels in humans. H. pylori infection was diagnosed on
      the basis of histology and culture or (13C)-urea breath test. Air and gastric
      juice in the gastric lumen were collected endoscopically. The concentration of
      intraluminal NO was measured by a chemiluminescence system, using an NO analyzer.
      The concentration of nitrite in gastric juice was measured by the Griess
      reaction. The intraluminal concentration of NO in H. pylori-positive patients
      (198.2 +/- 41 parts per billion [ppb] mean +/- SE; n = 70) was significantly
      lower than that in H. pylori-negative patients (353.0 +/-57.9ppb; n = 43; P <
      0.05). In contrast, the concentration of nitrite in gastric juice in H. pylori
      positive patients (57.7 +/- 12.3 RM; n = 70) was significantly higher than that
      in H. pylori-negative patients (25.9 +/- 6.4 microM; n = 43, P < 0.01). The
      intraluminal concentration of NO in H. pylori-positive patients was markedly
      increased and the concentration of nitrite in H. pylori-positive patients was
      markedly decreased following the completion of eradication therapy. Based on
      these results, we propose that a decrease in NO and excess nitrite production in
      the gastric lumen are associated with H. pylori infection and may play an
      important role in the pathogenesis of H. pylori-related abnormalities.

PMID- 10588183
TI  - Investigation of small-intestinal transit time in normal and malnourished
      children.
AB  - We aimed to establish whether there was a variation in orocecal transit time
      (OCTT) in Myanmar children and whether shortened transit time correlated with
      malnutrition. OCTT was measured in 90 healthy Myanmar children aged 1-5 years,
      using the hydrogen breath test (10g in 10% aqueous solution). The relationships
      between OCTT, sex, age, and malnutrition status were assessed. OCTT for 1 to 5
      year old children was 90.2 +/- 20min (mean +/- SD). There was no significant
      difference in mean OCTT between boys and girls, breast-fed and weaned children,
      malnourished and non-malnourished children. There was also no difference between
      age groups (1-2 years, 2-3 years, 3-4 years, and 4-5 years), and no correlation
      was found between age and orocecal transit time. The assessment of OCTT using the
      lactulose breath hydrogen test was found to be feasible and acceptable in the
      field setting. The OCTT of Myanmar children with rice as a staple food is similar
      to that of children from developed countries having a different diet, and no
      shortening of transit time was demonstrated in children with malnutrition.

PMID- 10588184
TI  - Long-term follow-up of hepatitis G virus/GB virus C replication in liver during
      and after interferon therapy in patients coinfected with hepatitis C and G
      viruses.
AB  - We investigated changes in the titers of positive and negative strands of
      hepatitis G virus (HGV) RNA and hepatitis C virus (HCV) RNA in serum and liver
      during and 1 to 3 years after interferon therapy in patients with chronic
      hepatitis C coinfected with HGV/ GBV-C. Eight (6%) of 134 patients with chronic
      hepatitis C treated with interferon were positive for HGV RNA and were examined
      retrospectively. Titers of positive and negative strands of HGV RNA and HCV RNA
      were determined by strand-specific reverse transcriptase-polymerase chain
      reaction. Before therapy, HGV RNA titers in liver were lower than those in serum
      (P = 0.0169), while HCV RNA titers in liver were significantly higher than those
      in serum (P = 0.0074). No negative strands of HGV RNA were detected in serum,
      liver, or peripheral blood mononuclear cells in any patients. With interferon
      therapy, 5 of the 8 patients lost HCV RNA from serum and liver, with sustained
      normal liver biochemical values and significant histological improvement. HGV RNA
      disappeared transiently from serum and liver at the end of therapy in 5 patients,
      but reappeared again after therapy in 4 of them. Two of the 8 patients naturally
      lost HGV RNA after completion of therapy. These findings suggest that: (1)
      HGV/GBV-C does not appear to replicate in liver, serum, or peripheral blood
      mononuclear cells, (2) detection of HGV RNA in liver and peripheral blood
      mononuclear cells may be a mere reflection of serum HGV RNA, and (3) the long
      term clinical outcome of chronic HGV/GBV-C infection appeared to be benign.

PMID- 10588186
TI  - Combination of transileocolic vein obliteration and balloon-occluded retrograde
      transvenous obliteration is effective for ruptured duodenal varices.
AB  - Duodenal varices are a rare site of hemorrhage in patients with portal
      hypertension, but their rupture is a serious and often fatal event. We report a
      65-year-old woman who presented with hematemesis and melena. She was admitted to
      our department because of prolonged shock, despite having received transfusion of
      a large volume of blood. Upper gastrointestinal endoscopy revealed nodular
      varices with active bleeding in the second portion of the duodenum. Endoscopic
      injection sclerotherapy (EIS) was performed using a tissue adhesive agent, alpha
      cyanoacrylate monomer, with only temporary benefit. However, anemia continued to
      progress after the procedure. Therefore, we combined transileocolic vein
      obliteration (TIO) with balloon-occluded retrograde transvenous obliteration (B
      RIO), using 5% ethanolamine oleate with iopamidol to obliterate the varices.
      Complete hemostasis was achieved without complications. Neither recurrence of
      varices nor further bleeding has occurred for over 3 years. We conclude that
      combined TIO and B-RTO, which can obstruct both the feeding and the draining
      vessels of duodenal varices to retain the sclerosing agent completely in the
      varices, is a safe and effective hemostatic measure for ruptured duodenal
      varices, when EIS has failed to accomplish complete hemostasis.

PMID- 10588185
TI  - Benign gastric ulcer associated with Canidida infection in a healthy adult.
AB  - A case of benign gastric ulcer associated with Candida infection in a healthy
      adult is reported. The patient was a 46-year-old man complaining of
      epigastralgia. Endoscopic examination of the upper digestive tract revealed an
      elevated lesion with ulceration having an unclear border and thick exudates. The
      clinical diagnosis based on endoscopic findings was a benign gastric ulcer;
      however, biopsy was performed to distinguish it from malignant lymphoma.
      Histological examination of biopsy samples obtained from the base and the edge of
      the ulcer revealed numerous Candida. Therefore, the patient was diagnosed with
      Candida-infected gastric ulcer. The ulcer resolved after the administration of
      antiulcer drugs for 2 months. Predisposing factors for fungal infection were
      excluded. These observations suggest that Candida-infected gastric ulcer should
      be suspected in patients with a gastric submucosal tumor-like lesion with a
      thick, yellowish-white coated ulcer of unclear border on its summit, and this
      lesion should be distinguished from malignant diseases.

PMID- 10588187
TI  - Skip colonic ulceration in typhoid ileo-colitis.
AB  - Colonic skip lesions are typically described in Crohn's colitis, but this
      phenomenon has been recognized in ulcerative colitis (skipped appendiceal
      involvement), Behcet's colitis, cytomegaloviral colitis, and even in Aeromonas
      hydrophilia and Histoplasma capsulatum infection. However, skip lesions in
      typhoid ileo-colitis have not been reported in the English-language literature.
      We report herein a patient with skip ulcers due to typhoid fever.

PMID- 10588188
TI  - Polyarthritis nodosa with mesenteric aneurysms demonstrated by angiography:
      report of a case and successful treatment of the patient with prednisolone and
      cyclophosphamide.
AB  - Polyarteritis nodosa is a necrotizing angitis that predominantly affects small
      and medium-sized arteries. The prognosis of untreated polyarteritis nodosa is
      very poor. Since symptoms are diverse and no serologic test is specific for
      polyarteritis nodosa, the diagnosis is difficult and often delayed. We describe a
      patient with polyarteritis nodosa who had gastrointestinal involvement with
      multiple aneurysms of the inferior mesenteric artery; only abdominal angiography
      provided a conclusive diagnosis. Alleviation of symptoms and regression of
      aneurysms were observed after combination therapy of an immunosuppressive agent,
      cyclophosphamide, and prednisolone. We emphasize the importance of early
      diagnosis by angiography and aggressive therapy in patients in whom physical
      signs indicating definite polyarteritis nodosa are not present.

PMID- 10588189
TI  - Epstein-Barr virus infection resembling autoimmune hepatitis with lactate
      dehydrogenase and alkaline phosphatase anomaly.
AB  - A 73-year-old man had fever, lymphadenopathy, granulocytopenia, thrombocytopenia,
      ascites, pleural effusion, liver injury, and an allergic-like skin rash.
      Autoantibodies, such as anti-nuclear antibody, were shown, and there were lactate
      dehydrogenase and alkaline phosphatase anomalies and platelet-associated IgG. His
      liver injury resembled that in autoimmune hepatitis. He was diagnosed with
      Epstein-Barr virus (EBV) infection associated with autoimmunization because of
      his clinical course, fluctuation of anti EBV antibodies and positive EBV genome
      in circulating lymphocytes and serum. This case suggests a close relationship
      between EBV infection and autoimmunization or autoimmune-like hepatitis.

PMID- 10588190
TI  - Hepatic subcapsular hematoma after extracorporeal shock wave lithotripsy (ESWL)
      for pancreatic stones.
AB  - We present a patient with complication of huge hepatic subcapsular hematoma after
      extracorporeal shock wave lithotripsy (ESWL) for pancreatic lithotripsy. The
      hematoma measured 78-110mm. Angiography showed a subcapsular hematoma, rather
      than a hematoma in the liver. In the arterial phase, the distal end of the small
      vessel showed spotty opacification similar to microaneurysma, suggesting that it
      was an injury caused by separation of the liver and its capsule, caused by the
      shock waves. The portal vein and hepatic vein were normal. After 8 weeks of
      conservative therapy, the hematoma was gradually absorbed and the patient was
      discharged. Eight months after the accident, the hematoma had decreased to 40mm
      in size. After 20 months, it was completely absorbed. The reported rate of renal
      subcapsular hematoma after ESWL for renal or ureter stones is 0.1%-0.7%. To date,
      however, only five cases of hepatic subcapsular hematoma after right renal stone
      disintegration have been reported. This is the first report of hepatic
      subcapsular hematoma after ESWL for pancreatic stones.

PMID- 10588191
TI  - NO homeostasis in Helicobacter pylori-infected gastric mucosa.

PMID- 10588192
TI  - Does GBV-C/HGV replicate in the liver?

PMID- 10588193
TI  - 50th anniversary historical article. Myocardial infarction and coronary care
      units.
AB  - The results of treatment of 250 patients with established acute myocardial
      infarction in a coronary care unit in a university hospital are described. The
      criteria for diagnosis have been carefully defined. In 62 percent of patients
      admitted with a tentative diagnosis of acute infarction, the initial impression
      was confirmed. Fifteen percent of patients admitted to the unit were classified
      as having possible infarction; in this group, the mortality rate was 3 percent. A
      classification of functional severity based on clinical evidence of heart failure
      or shock is presented. Morbidity and mortality in acute myocardial infarction are
      related to the functional severity of the illness. Although arrhythmia is common,
      the overriding importance of five life-threatening arrhythmias is emphasized.
      Mortality of patients in the coronary care unit was not improved in comparison to
      those treated under regular care until strong central direction of therapeutic
      programs, immediate treatment of arrhythmia in cardiac arrest, and delegation of
      some medical authority to trained nurses was accomplished. The change in concept
      of the purposes and practices of special coronary care from resuscitation to
      prevention of arrhythmia is emphasized. The mortality in myocardial infarction
      complicated by shock remains high. In the absence of shock, aggressive medical
      treatment in the coronary care unit reduced mortality from 26 to 7 percent. The
      implications of these data in the management of patients admitted to a hospital
      with a diagnosis of acute myocardial infarction are discussed.

PMID- 10588194
TI  - 50th anniversary historical article. Acute coronary syndromes: the degree and
      morphology of coronary stenoses.
AB  - In 110 patients with either stable or unstable angina, the morphology of coronary
      artery lesions was qualitatively assessed at angiography. Each obstruction
      reducing the luminal diameter of the vessel by 50% or greater was categorized
      into one of the following morphologic groups: concentric (symmetric narrowing);
      type I eccentric (asymmetric narrowing with smooth borders and a broad neck);
      type II eccentric (asymmetric with a narrow neck or irregular borders, or both);
      and multiple irregular coronary narrowings in series. For the entire group, type
      II eccentric lesions were significantly more frequent in the 63 patients with
      unstable angina (p less than 0.001), whereas concentric and type I eccentric
      lesions were seen more frequently in the 47 patients with stable angina (p less
      than 0.05). Type II eccentric lesions were also present in 29 of 41 arteries in
      patients with unstable angina compared with 4 of 25 arteries in those with stable
      angina (p less than 0.0001) in whom an "angina-producing" artery could be
      identified. Therefore, type II eccentric lesions are frequent in patients with
      unstable angina and probably represent ruptured atherosclerotic plaques or
      partially occlusive thrombi, or both. A temporary decrease in coronary perfusion
      secondary to these plaques with or without superimposed transient platelet
      thrombi or altered vasomotor tone may be responsible for chest pain in some of
      these patients with unstable angina.

PMID- 10588195
TI  - Calcium channel blockers, apoptosis and cancer: is there a biologic relationship?
AB  - Calcium channel blockers (CCBs) represent a chemically and pharmacologically
      diverse group of agents that are widely used for the treatment of hypertension
      and angina. A small number of retrospective, observational analyses have raised
      concern about a potential causal link between CCB use and an increased risk for
      cancer development. Despite the absence of cancer findings in extensive
      preclinical studies, it has been proposed that CCBs may work differently in
      humans by interfering with apoptosis, leading to an increased potential for
      abnormal cell proliferation and tumor growth. This biologic hypothesis has
      attracted considerable attention in the medical community but has not been
      critically evaluated. An analysis of the basic and clinical literature was
      conducted to examine biologic relationships among cell Ca2+ modulation,
      apoptosis, and cancer. In addition to a comprehensive review of the cellular and
      animal data, the results of large observational studies were included in this
      analysis. Results of this review demonstrated that the effects of CCBs on
      apoptosis are complex as both increases and decreases in intracellular Ca2+ have
      been linked to this form of programmed cell death. Most studies show that an
      effect (either positive or negative) of CCBs on apoptosis requires doses in the
      supra-pharmacologic range, and are therefore not clinically relevant. Results of
      large and methodologically robust observational studies fail to provide support
      for the hypothesis that CCB use is associated with an increased susceptibility
      for cancer incidence. A comprehensive analysis of the basic and clinical evidence
      does not support a causal relationship between the therapeutic use of CCBs and an
      increased incidence of cancer development as a result of interfering with
      apoptosis.

PMID- 10588196
TI  - Echocardiographic assessment of the left atrial appendage.
AB  - The left atrial (LA) appendage is a common source of cardiac thrombus formation
      associated with systemic embolism. Transesophageal echocardiography allows a
      detailed evaluation of the structure and function of the appendage by two
      dimensional imaging and Doppler interrogation of appendage flow. Specific flow
      patterns, reflecting appendage function, have been characterized for normal sinus
      rhythm and various abnormal cardiac rhythms. Appendage dysfunction has been
      associated with LA appendage spontaneous echocardiographic contrast, thrombus
      formation and thromboembolism. These associations have been studied extensively
      in patients with atrial fibrillation or atrial flutter, in patients undergoing
      cardioversion of atrial arrhythmias and in patients with mitral valve disease.
      The present review summarizes the literature on the echocardiographic assessment
      of LA appendage structure, function and dysfunction, which has become an integral
      part of the routine clinical transesophageal echocardiographic examination.

PMID- 10588197
TI  - Measurement of heart rate variability: a clinical tool or a research toy?
AB  - The objectives of this review are to discuss the diversity of mechanisms that may
      explain the association between heart rate (HR) variability and mortality, to
      appraise the clinical applicability of traditional and new measures of HR
      variability and to propose future directions in this field of research. There is
      a large body of data demonstrating that abnormal HR variability measured over a
      24-h period provides information on the risk of subsequent death in subjects with
      and without structural heart disease. However, the mechanisms responsible for
      this association are not completely established. Therefore, no specific therapy
      is currently available to improve the prognosis for patients with abnormal HR
      variability. Reduced HR variability has been most commonly associated with a risk
      of arrhythmic death, but recent data suggest that abnormal variability also
      predicts vascular causes of death, progression of coronary atherosclerosis and
      death due to heart failure. A consensus is also lacking on the best HR
      variability measure for clinical purposes. Time and frequency domain measures of
      HR variability have been most commonly used, but recent studies show that new
      analysis methods based on nonlinear dynamics may be more powerful in terms of
      risk stratification. Before the measurement of HR variability can be applied to
      clinical practice and used to direct therapy, more precise insight into the
      pathophysiological link between HR variability and mortality are needed. Further
      studies should also address the issue of which of the HR variability indexes,
      including the new nonlinear measures, is best for clinical purposes in various
      patient populations.

PMID- 10588198
TI  - Clopidogrel as adjunctive antiplatelet therapy during coronary stenting.
AB  - OBJECTIVES: We examined the procedural and 30-day clinical outcomes among
      patients receiving aspirin and either ticlopidine or clopidogrel during coronary
      stenting. BACKGROUND: Ticlopidine-plus-aspirin has become standard antiplatelet
      therapy for the prevention of thrombotic complications after coronary stenting.
      Clopidogrel has a similar mechanism of action as ticlopidine, but both its
      efficacy and its safety as a pharmacologic adjunct to coronary stenting have not
      been well described. METHODS: This single-center, prospective analysis examined
      the in-hospital procedural and 30-day clinical outcomes among 875 consecutive
      patients undergoing coronary stenting who received adjunctive aspirin and either
      clopidogrel (n = 514; 58.7%) or ticlopidine (n = 361; 41.3%) therapy. RESULTS:
      Procedural success rates were similar among the clopidogrel- (99.6%) and
      ticlopidine-treated patients (99.4%). Subacute stent thrombosis (i.e., >24 h < or
      =30 days) occurred in one clopidogrel-treated (0.2%) and in one ticlopidine
      treated (0.3%) patient (p = 0.99). By 30 days following the index procedure, the
      combined rates of death, nonfatal myocardial infarction and need for target
      vessel revascularization were similar among patients who received either
      clopidogrel (2.1%) or ticlopidine (1.4%; p = 0.57) therapy. CONCLUSIONS: In this
      analysis the antiplatelet combination therapy of aspirin-plus-clopidogrel was an
      effective regimen for preventing thrombotic complications and major adverse
      cardiovascular events among a broad spectrum of patients undergoing coronary
      artery stenting.

PMID- 10588199
TI  - Clopidogrel versus ticlopidine after intracoronary stent placement.
AB  - OBJECTIVES: The study compared the safety and efficacy of ticlopidine with
      clopidogrel in patients receiving coronary stents. BACKGROUND: Stent thrombosis
      is reduced when ticlopidine is administered with aspirin. Clopidogrel is similar
      to ticlopidine in chemical structure and function but has fewer side effects; few
      data are available about its use in stent patients. METHODS: We compared 30-day
      event rates in 500 consecutive coronary stent patients treated with aspirin and
      clopidogrel (300 mg loading dose immediately prior to stent placement, and 75
      mg/day for 14 days) to 827 consecutive stent patients treated with aspirin and
      ticlopidine (500 mg loading dose and 250 mg twice daily for 14 days). RESULTS:
      Patients treated with clopidogrel had more adverse clinical characteristics
      including older age, more severe angina, and more frequent infarction within the
      prior 24 h. Nonetheless, mortality was 0.4% in clopidogrel patients versus 1.1%
      in ticlopidine patients; nonfatal myocardial infarction occurred in 0% versus
      0.5%, stent thrombosis in 0.2% versus 0.7%, bypass surgery or repeat angioplasty
      in 0.4% versus 0.5%, and any event occurred in 0.8% versus 1.6% of patients,
      respectively (p = NS). Based on the observed 30-day event rate of 1.6% with
      ticlopidine, the statistical power of the study was 43% to detect an even rate of
      0.5% with clopidogrel, and 75% to detect an event rate with of 4% with
      clopidogrel, with a p value of 0.05. CONCLUSIONS: These data indicate that
      clopidogrel can be safely substituted for ticlopidine in patients receiving
      coronary stents.

PMID- 10588200
TI  - Use of clopidrogel in coronary stenting: what was the question?

PMID- 10588201
TI  - Hyperemic coronary flow after optimized intravascular ultrasound-guided balloon
      angioplasty and stent implantation.
AB  - OBJECTIVES: This study evaluated the acute physiological gain of adjunctive
      intravascular ultrasound (IVUS) guided balloon angioplasty and stent
      implantation. BACKGROUND: Recent studies indicate safe coronary luminal
      enlargement and "stent-like" long-term outcomes using upsized balloons guided by
      IVUS. METHODS: After angiographically guided balloon angioplasty in 20 patients
      with 1-vessel disease and normal left ventricular function, IVUS was performed to
      determine the size of the adjunctive balloon using the mean of the maximal
      luminal diameter and the maximal diameter of the external elastic membrane
      measured in the adjacent proximal and distal reference segments. Serial adenosine
      induced hyperemic blood flow velocity measurements were performed using a 0.014"
      Doppler guide wire to determine the physiological lumen obstruction after
      standard balloon angioplasty, followed by IVUS-guided balloon angioplasty and
      stent implantation. RESULTS: Upsized balloon angioplasty (increase balloon size:
      0.98 +/- 0.26 mm; balloon:artery ratio 1.35 +/- 0.21) resulted in an additional
      increase of arterial dimensions: minimal lumen diameter (MLD) 2.18 +/- 0.38 mm to
      2.73 +/- 0.51 mm; percent diameter stenosis (%DS) 34 +/- 13% to 19 +/- 22%; IVUS
      assessed minimal lumen area (MLA) 7.53 +/- 1.55 mm2 to 10.24 +/- 2.22 mm2 (all p
      < 0.0001). Major dissections (> or = type C) did not occur. Hyperemic blood flow
      velocity increased from 49.8 +/- 20.1 cm/s to 59.1 +/- 22.9 cm/s (p < 0.05) after
      IVUS-guided balloon angioplasty. Adjunctive stent implantation resulted in a
      further increase of MLD to 3.84 +/- 0.51 mm, %DS to -9 +/- 21% and MLA to 13.39
      +/- 1.80 mm2 (all p < 0.0001), while hyperemic blood flow velocity remained
      unchanged (61.2 +/- 24.7 cm/s, p = 0.7). CONCLUSIONS: Upsized IVUS-guided balloon
      angioplasty increases arterial coronary dimensions and the distal hyperemic blood
      flow velocity. Adjunctive stent implantation does not yield a further gain in the
      hyperemic blood flow velocity, indicating the absence of a functional residual
      lumen obstruction after IVUS-guided balloon angioplasty. This may explain a
      similar clinical outcome reported after those coronary interventions.

PMID- 10588202
TI  - Optimal balloon angioplasty versus elective stent implantation.

PMID- 10588203
TI  - Direct coronary stenting without predilation.
AB  - OBJECTIVES: Coronary stenting is the primary therapeutic option for percutaneous
      treatment of many coronary lesions, after the risk of subacute stent thrombosis
      and bleeding complications has been reduced by improved antithrombotic regimens
      and high pressure stent expansion. BACKGROUND: Direct stent implantation (without
      predilation) has been considered a promising new technique that may reduce the
      procedure time, radiation exposure time and cost. METHODS: After having reviewed
      all cases of stent implantation from February to June 1998 (n = 585), 185 (32%)
      of these patients were retrospectively considered candidates for direct stent
      implantation without predilation, according to prespecified criteria (i.e.,
      absence of severe coronary calcifications and/or tortuosity of the lesion or the
      segment proximal to the lesion). By operator preference, direct coronary stent
      implantation was actually attempted in 123 (21%) of the 585 patients (100 men, 60
      +/- 10 years old) on 123 lesions. The impact of direct stenting in terms of cost,
      procedure time, radiation exposure time and amount of contrast dye used was
      assessed by comparing the two groups of patients who underwent single-vessel
      stenting without (n = 69) and with (n = 46) predilation. RESULTS: Direct stenting
      was successful in 118 patients (96%). No acute or subacute complications occurred
      in these patients. Procedure time, radiation exposure time and cost were
      significantly lower in the group of patients who had single-vessel direct versus
      conventional stenting (45 +/- 31 vs. 64 +/- 46 min, 12 +/- 9 vs. 16 +/- 10 min
      and 1,305 +/- 363 vs. 2,210 +/- 803 Euro, respectively; p < 0.05 for all).
      CONCLUSIONS: Direct stenting without predilation in selected lesions seems to be
      a safe and successful procedure that provides a way to contain cost and to
      shorten radiation exposure time.

PMID- 10588204
TI  - Frequency of major adverse cardiac events within one month of coronary
      angioplasty: a useful measure of operator performance.
AB  - OBJECTIVES: To test one-month outcomes in a single center for their statistical
      power to corroborate conclusions derived from large multicenter databases.
      BACKGROUND: Only with large, multicenter databases has it been possible to
      demonstrate more frequent occurrences of complications in patients treated by
      "low-volume operators." Critics feel that such analyses mask excellent
      performance by many "low-volume operators." METHODS: In a high-volume cardiac
      catheterization laboratory in a large, nonuniversity teaching hospital, baseline
      clinical and angiographic characteristics were collected for a consecutive series
      of 1,029 patients treated by 37 percutaneous transluminal coronary intervention
      (PTCI) operators over a four-month period. One-month follow-up was obtained in
      967 (94%) patients who form the basis for this analysis. RESULTS: Only the group
      of operators performing <50 cases annually had a major adverse cardiac event
      (MACE) (death, myocardial infarction or symptom-driven revascularization) rate at
      one month significantly greater than predicted from baseline characteristics.
      (Observed rate: 15.1%, expected: 9.7%, 95% confidence interval [CI]: 4.7%,
      14.6%.) The difference was driven by the significantly more frequent rate at
      which repeat revascularization was performed in patients treated by that group of
      operators (observed: 13.8%, expected: 7.1%, 95% CI: 2.8%, 11.4%). CONCLUSIONS: As
      is true of analyses of large multicenter databases, lower volume operators as a
      group have less good outcomes than those performing more. The greater statistical
      power provided by one-month MACE rate offers advantages over the use of in
      hospital complications for the analysis of operator performance.

PMID- 10588205
TI  - Time-varying spectral analysis of heart rate and left ventricular pressure
      variability during balloon coronary occlusion in humans: a sympathoexicitatory
      response to myocardial ischemia.
AB  - OBJECTIVES: We assessed time-varying spectral components of heart rate and left
      ventricular (LV) pressure variability during coronary angioplasty to elucidate
      dynamic autonomic responses to transient myocardial ischemia. BACKGROUND:
      Sympathoexcitatory reflexes elicited by acute coronary occlusion are rarely
      addressed in the clinical settings because of a lack of technique to monitor
      transient changes in sympathetic activation. METHODS: RR interval and LV pressure
      and volume were serially recorded in 14 patients with effort angina during
      balloon coronary angioplasty. Wavelet analysis was applied for determination of
      nonstationary spectral components of RR interval and LV peak pressure
      variability. RESULTS: The wavelet analysis revealed that coronary occlusion
      provoked low-frequency (LF) fluctuations of RR interval (seven patients) and LV
      peak pressure (six patients) at 0.06 +/- 0.01 Hz, but not in the remaining
      patients. Following the balloon inflation, the LF component of RR interval began
      to increase after the onset of myocardial ischemia, peaked at about 80 s, and
      then declined in the late phase of inflation. Consequently, the ratio of low to
      high frequency component rose to be significantly greater in the LF augmentation
      group than in the no LF augmentation group in the middle phase of coronary
      occlusion. The patients with no LF augmentation had little evidence of myocardial
      ischemia as reflected by changes in ST segment and LV systolic function during
      coronary occlusion. CONCLUSIONS: The wavelet analysis of RR interval and LV
      pressure variability clearly showed a dynamic profile of spectral components in
      response to transient coronary artery occlusion. The resultant regional
      myocardial ischemia elicited a profound sympathoexcitatory response followed by a
      gradual suppression. This method provides a useful tool to gain a new insight
      into the nonstationary autonomic influence on the cardiovascular system.

PMID- 10588206
TI  - The significance of persistent ST elevation versus early resolution of ST segment
      elevation after primary PTCA.
AB  - OBJECTIVES: To determine the prevalence and clinical significance of early ST
      segment elevation resolution after primary percutaneous transluminal coronary
      angioplasty (PTCA) for acute myocardial infarction (AMI). BACKGROUND: Despite
      angiographically successful restoration of coronary flow early during AMI,
      adequate myocardial reperfusion might not occur in a substantial portion of the
      jeopardized myocardium due to microvascular damage. This phenomenon comprises the
      potentially beneficial effect of early recanalization of the infarct related
      artery (IRA). METHODS: Included in the study were 117 consecutive patients who
      underwent angiographically successful [Thrombolysis in Myocardial Infarction
      (TIMI III)] primary PTCA. The patients were classified based on the presence or
      absence of reduction > or =50% in ST segment elevation in an ECG performed
      immediately upon return to the intensive cardiac care unit after the PTCA in
      comparison with ECG before the intervention. RESULTS: Eighty-nine patients (76%)
      had early ST segment elevation resolution (Group A) and 28 patients (24%) did not
      (Group B). Group A and B had similar clinical and hemodynamic features before
      referring to primary PTCA, as well as similar angiographic results. Despite this,
      ST segment elevation resolution was associated with better predischarge left
      ventricular ejection fraction (LVEF) (44.7 +/- 8.0 vs. 38.2 +/- 8.5, p < 0.01).
      Group B patients, as compared with those of Group A, had a higher incidence of in
      hospital mortality (11% vs. 2%, p = 0.088), congestive heart failure (CHF) [28%
      vs. 19%, odds ratio (OR) = 4, 95% confidence interval (CI) 1 to 15, p = 0.04],
      higher long-term mortality (OR = 7.3, 95% CI 1.9 to 28, p = 0.004 with Cox
      proportional hazard regression analysis) and long-term CHF rate (OR = 6.5, 95% CI
      1.3 to 33, p = 0.016 with logistic regression). CONCLUSIONS: Absence of early ST
      segment elevation resolution after angiographically successful primary PTCA
      identifies patients who are less likely to benefit from the early restoration of
      flow in the IRA, probably because of microvascular damage and subsequently less
      myocardial salvage.

PMID- 10588207
TI  - Myocardial perfusion and oxygen consumption in reperfused noninfarcted
      dysfunctional myocardium after unstable angina: direct evidence for myocardial
      stunning in humans.
AB  - OBJECTIVES: To positively establish the diagnosis of myocardial stunning in
      patients with unstable angina and persistent wall motion abnormalities after
      reperfusion by coronary angioplasty. BACKGROUND: Although myocardial stunning is
      thought to occur in several clinical conditions, definite proof of its existence
      in humans is still lacking, owing to the difficulty of measuring myocardial blood
      flow (MBF) in absolute terms. METHODS: We studied 14 patients with unstable
      angina due to proximal left anterior descending coronary artery disease who
      presented persistent anterior wall motion abnormalities despite revascularization
      of the culprit lesion by percutaneous coronary angioplasty (PTCA) and who did not
      have clinical evidence of necrosis. Dynamic positron emission tomography (PET)
      with [13N]-ammonia and [11C]-acetate was performed 48 h after PTCA to determine
      absolute MBF and oxygen consumption (MVO2). Regional wall thickening and regional
      cardiac work were determined using two-dimensional echocardiography. Improvement
      of segmental wall motion abnormalities was followed for a median of 4 months (1.5
      to 14 months). RESULTS: As judged from the changes in segmental wall motion
      score, regional dysfunction was spontaneously reversible in 12/14 patients and
      improved from 2.2 +/- 0.3 to 1.2 +/- 0.3 at late follow-up (p < 0.001). With PET,
      [13N]-ammonia MBF was similar among dysfunctional and remote normally contracting
      segments (85 +/- 29 vs. 99 +/- 20 ml x min (-1) x 100g(-1), p = not significant
      [n.s.]), thus demonstrating a perfusion-contraction mismatch. Despite the reduced
      contractile function, dysfunctional myocardium presented near normal levels of
      MVO2 (6.5 +/- 4.2 vs. 8.0 +/- 1.9 ml x min (-1)x 100g(-1), p = n.s.).
      Consequently, the regional myocardial efficiency (regional work divided by MVO2)
      of the dysfunctional myocardium was found to be markedly decreased as compared
      with normally contracting myocardium (6 +/- 6% vs. 26 +/- 6%, p < 0.001).
      CONCLUSIONS: This study demonstrates that human dysfunctional myocardium capable
      of spontaneously recovering contractile function after unstable angina endures a
      state of perfusion-contraction mismatch. These data for the first time provide
      unequivocal direct evidence for the existence of acute myocardial stunning in
      humans.

PMID- 10588208
TI  - Six-month outcome in unstable angina patients without previous myocardial
      infarction according to the use of tertiary cardiologic resources. RESCATE
      Investigators. Recursos Empleados en el Sindrome Coronario Agudo y Tiempos de
      Espera.
AB  - OBJECTIVES: The study assessed whether varying accessibility of patients with
      unstable angina (UA) to coronary angiography and revascularization determined
      differing usages and outcomes. BACKGROUND: The appropriate use rate of coronary
      angiography and revascularization procedures in UA remains to be established.
      METHODS: A total of 791 consecutive patients with UA without previous acute
      myocardial infarction (AMI) admitted to four reference teaching hospitals (one
      with tertiary facilities) were followed for six months. End points were six-month
      mortality and readmission for AMI, UA, heart failure, or severe ventricular
      arrhythmias. RESULTS: Patients admitted to the tertiary hospital were 3.27 (95%
      confidence interval [CI] 2.32 to 4.62) times more likely to undergo coronary
      angiography after adjustment for comorbidity and severity than were those
      admitted to nontertiary facilities (overall six-month use rates 70.1% and 48.3%,
      respectively). Revascularization procedures were performed in 36.2% of patients
      in the tertiary hospital and 24.6% in the others (p = 0.0007); adjusted relative
      risk (RR) 2.37 (95% CI 1.55 to 3.63). Median delay for urgent coronary
      angiography was shorter in the tertiary hospital (24 h vs. 4 days, p < 0.0002).
      Six-month mortality and readmission rates were similar in tertiary and
      nontertiary hospitals: 3.9% versus 5.3% and 16.9% versus 21.2%, respectively.
      Adjusted RR of death or readmission for the nontertiary hospitals was 1.23 (95%
      CI 0.57 to 2.67). CONCLUSIONS: The use of coronary angiography and
      revascularization procedures in UA patients with no previous AMI is higher in
      tertiary than in nontertiary hospitals, but the more selective use of these
      procedures in nontertiary centers does not imply worse outcome.

PMID- 10588210
TI  - Combination therapy for acute myocardial infarction.

PMID- 10588209
TI  - A randomized trial comparing primary angioplasty with a strategy of short-acting
      thrombolysis and immediate planned rescue angioplasty in acute myocardial
      infarction: the PACT trial. PACT investigators. Plasminogen-activator Angioplasty
      Compatibility Trial.
AB  - OBJECTIVES: The study evaluated the efficacy and safety of a short-acting reduced
      dose fibrinolytic regimen to promote early infarct-related artery (IRA) patency
      during the inherent delay experienced by infarct patients referred for
      angioplasty as the principal recanalization modality. BACKGROUND: Previous
      approaches using long-acting, full-dose thrombolytic infusions rarely showed
      benefit, but they did increase adverse event rates. METHODS: Following aspirin
      and heparin, 606 patients were randomized to a 50-mg bolus of recombinant tissue
      type plasminogen activator (rt-PA) (alpha half-life 4.5 min) or to placebo
      followed by immediate angiography with angioplasty if needed. The end points
      included patency rates on catheterization laboratory (cath lab) arrival,
      technical results when PTCA (percutaneous transluminal coronary angioplasty) was
      performed, complication rates, and left ventricular (LV) function by treatment
      assignment and time to restored patency following angioplasty. RESULTS: Patency
      on cath lab arrival was 61% with rt-PA (28% Thrombolysis in Myocardial Infarction
      trial [TIMI]-2, 33% TIMI-3), and 34% with placebo (19% TIMI-2, 15% TIMI-3) (p =
      0.001). Rescue and primary PTCA restored TIMI-3 in closed arteries equally (77%,
      79%). No differences were observed in stroke or major bleeding. Left ventricular
      function was similar in both treatment groups, but convalescent ejection fraction
      (EF) was highest with a patent IRA (TIMI-3) on cath lab arrival (62.4%) or when
      produced by angioplasty within an hour of bolus (62.5%). However, in 88% of
      angioplasties, the delay exceeded 1 h: convalescent EF 57.3%. CONCLUSIONS:
      Tailored thrombolytic regimens compatible with subsequent interventions lead to
      more frequent early recanalization (before cath arrival), which facilitates
      greater LV function preservation with no augmentation of adverse events.

PMID- 10588211
TI  - Evidence for the delayed effect in human ischemic preconditioning: prospective
      multicenter study for preconditioning in acute myocardial infarction.
AB  - OBJECTIVES: This study aimed to investigate prospectively the protective effect
      of a first preinfarction angina attack against acute myocardial infarction (AMI)
      in human hearts without significant collaterals. BACKGROUND: Several
      retrospective studies and the prospective studies have demonstrated the existence
      of the preconditioning (PC) effect in humans. However, collaterals were not
      examined in the prospective studies. In animal models, the PC effect on
      myocardial infarct size appears soon after PC reperfusion (classic) but
      disappears within 1 to 2 h. It then reappears 24 to 48 h after reperfusion (the
      delayed PC effect). Meanwhile, the PC effect on stunning appears 12 h after PC
      reperfusion (the delayed PC effect). The concept of the classic and delayed PC
      effects has not been investigated in human AMI studies. If the above concept is
      also correct in humans, the infarct size and/or impairment of the left
      ventricular function should be inversely correlated with the time interval
      between the first preinfarction angina attack and the onset of AMI when that time
      interval is limited to between 2 and 48 h. METHODS: The subjects were 25 patients
      with first AMI of the proximal left anterior descending artery who underwent
      successful direct percutaneous transluminal coronary angioplasty (PTCA) 2 to 6 h
      after the onset and with no (or poor) collateral circulation (grade 0 or 1). They
      were divided into two groups: preinfarction angina (PA)(+) group: 11 patients
      with new onset preinfarction angina from 2 to 48 h before the onset, PA(-) group:
      14 patients without angina before infarction. Peak creatine kinase (CK) and
      cumulative CK were examined, and the left ventricular ejection fraction (LVEF)
      and the regional wall motion (RWM) were determined from the left ventriculograms
      during the acute (immediately after the coronary reperfusion) and chronic (four
      weeks after the onset of AMI) phases. The RWM index (RWMI) was then calculated as
      the mean motion of chords (standard deviation [SD]/chord) lying in the area of
      chords of RWM < or = -2 SD in the acute phase (ischemic risk area). RESULTS The
      increase in the RWMI between the acute and chronic phases was significantly
      larger in the PA(+) group than in the PA(-) group (1.55 +/- 1.32 and 0.69 +/-
      0.75, p < 0.05, respectively) although no significant difference in the enzymatic
      infarct size was seen between the two groups. The increases in the LVEF and the
      RWMI were significantly correlated with the time interval from the first
      preinfarction angina attack to the onset of AMI (r = 0.622, p < 0.05 and r =
      0.646, p < 0.05, respectively), but the enzymatic infarct size was not.
      CONCLUSIONS: The beneficial effect of preinfarction angina on left ventricular
      wall motion, independently of collateral flows, indicates the existence of the PC
      effect in humans. The greater protective effect of a longer time interval between
      angina pectoris and AMI suggests that the protection is due to a delayed PC
      effect.

PMID- 10588213
TI  - Endotoxin: another phantom menace?

PMID- 10588212
TI  - Association of endotoxemia with carotid atherosclerosis and cardiovascular
      disease: prospective results from the Bruneck Study.
AB  - OBJECTIVES: Focus of the current study was on the significance of bacterial
      endotoxin, which shows a variety of pro-atherogenic properties and may occur at
      high concentration in the circulation of infected subjects. BACKGROUND: The
      possibility of an infectious risk factor in atherogenesis and cardiovascular
      disease has stimulated research interest, but the nature of such process remains
      obscure. METHODS: We measured plasma endotoxin levels (LAL assay) in a random
      population of 516 men and women 50 to 79 years old at the 1990 baseline
      evaluation (Bruneck Study). End points of this prospective survey were incident
      (early) atherosclerosis in the carotid arteries as assessed with high-resolution
      Duplex ultrasound (five-year follow-up rate, 98%) and incident cardiovascular
      disease (follow-up rate, 100%). RESULTS: Median endotoxin concentration amounted
      to 14.3 pg/ml (range, 6.0 to 209.2 pg/ml). Subjects with levels beyond 50 pg/ml
      (90th percentile) faced a threefold risk of incident atherosclerosis (odds ratio
      [95% confidence interval] 2.9 [1.4-6.3]; p < 0.01). The risk associated with high
      endotoxin was most pronounced in subjects with chronic infections and in current
      and ex-smokers. Notably, smokers with low endotoxin levels and nonsmokers did not
      differ in their atherosclerosis risk, whereas smokers with high levels almost
      invariably developed new lesions. All findings emerged as independent of vascular
      risk factors. Similar results were obtained for incident cardiovascular disease.
      CONCLUSIONS: The current study yields first epidemiologic evidence that
      endotoxemia constitutes a strong risk factor of early atherogenesis in subjects
      with chronic or recurrent bacterial infections and a link in the association
      between cigarette smoking and atherosclerotic disease.

PMID- 10588214
TI  - Simultaneous intracoronary velocity- and pressure-derived assessment of adenosine
      induced collateral hemodynamics in patients with one- to two-vessel coronary
      artery disease.
AB  - OBJECTIVES: The purpose of this investigation in patients with poorly and well
      developed coronary collaterals was to assess the influence of collateral and
      collateral adjacent vascular resistances and, in part, a stenotic lesion of the
      collateral supplying vessel on the hemodynamic collateral responses to adenosine.
      BACKGROUND: In humans, little is known about the functional behavior of the
      coronary collateral circulation. METHODS: In 50 patients with one- and two-vessel
      coronary artery disease (CAD) undergoing percutaneous transluminal coronary
      angioplasty (PTCA), collateral flow index (CFI, no unit) changes and vascular
      resistance index (R, cm/mm Hg) changes of the collateral (R(coll)) and the distal
      collateral receiving (R4) vessel in response to adenosine (140 microg/min/kg IV)
      were measured by intracoronary (i.c.) Doppler and pressure guidewires. The
      variables were determined at baseline and during adenosine in patients with poor
      (angiographic collateral degree before PTCA <2 of 0 to 3) and good coronary
      collaterals. RESULTS: Pressure-derived CFI (CFI(p)) decreased under adenosine in
      patients with poor collaterals, and it increased in the group with good
      collaterals. There were inverse correlations between the adenosine-induced change
      in CFI(p) and the change in R(coll) (r = 0.61, p = 0.0001). In the group with
      good, but not with poor collaterals, there was also a significant correlation
      between CFI(p) increase and the decrease in R4, between the severity of the
      contralateral stenosis and CFI(p) augmentation and among the left versus right
      coronary artery as ipsilateral vessel and CFI(p) change. CONCLUSIONS: Overall,
      patients with well, versus poorly developed coronary collaterals do better
      regarding the capacity to increase collateral flow in response to adenosine. In
      patients with good, but not poor, collaterals, an adenosine-induced collateral
      flow increase depends on the ipsilateral distal vascular resistance decrease, but
      is also directly influenced by the severity of a contralateral stenosis and
      probably by the size of the collateralized vascular bed.

PMID- 10588215
TI  - Evaluation of serum levels of solubilized adhesion molecules and cytokine
      receptors in coronary heart disease.
AB  - OBJECTIVES: The diagnostic importance of circulating solubilized tumor necrosis
      factor-alpha receptor II (sTNF-alphaRII) and interleukin-2 receptor in coronary
      heart disease (CHD) was evaluated. In addition, these variables were correlated
      with solubilized adhesion molecule levels (i.e., intracellular adhesion molecule
      [ICAM], vascular cell adhesion molecule [VCAM], and E-selectin). BACKGROUND:
      Atherosclerosis is considered to be a chronic inflammatory process. Because the
      immunologic network presents an abundance of positive and negative feedback
      mechanisms, information obtained from different immunologic variables might be
      highly redundant. METHODS: In a cross-sectional study design, 60 patients with
      angiographically proven CHD were compared with 60 individuals who had undergone
      coronary angiography but in whom no evidence of stenosis could be found (control
      subjects). Angiography was performed at least one year before the study. Cytokine
      levels were determined by enzyme-linked immunosorbent assay technique and
      evaluated by univariate and multivariate statistical methods. RESULTS: All
      immunologic variables except E-selectin (p = 0.08) significantly discriminated
      between patients and control subjects. Coronary artery bypass graft surgery after
      angiography did not lead to significant differences in the variables investigated
      in the patients with bypass surgery as compared with the subjects without bypass
      surgery. Receiver-operating characteristics analysis showed comparable test
      accuracy for solubilized adhesion molecules and cytokine receptors. Multivariate
      logistic regression analysis, including age, revealed that only ICAM and sTNF
      alphaRII were independently correlated with the presence of CHD. Patients
      belonging to the third tertile of at least one of these two variables
      demonstrated a 1.6- to 2-fold increased relative risk for the presence of CHD.
      CONCLUSIONS: We concluded that both circulating ICAM and TNF-alphaRII should be
      further evaluated as markers for atherosclerotic changes in the coronary system.

PMID- 10588216
TI  - Folic acid improves arterial endothelial function in adults with
      hyperhomocystinemia.
AB  - OBJECTIVES: To evaluate whether oral folic acid supplementation might improve
      endothelial function in the arteries of asymptomatic adults with
      hyperhomocystinemia. BACKGROUND: Hyperhomocystinemia is an independent risk
      factor for endothelial dysfunction and occlusive vascular disease. Folic acid
      supplementation can lower homocystine levels in subjects with
      hyperhomocystinemia; however, the effect of this on arterial physiology is not
      known. METHODS: Adults subjects were recruited from a community-based
      atherosclerosis study on healthy volunteers aged 40 to 70 years who had no
      history of hypertension, diabetes mellitus, hyperlipidemia, ischemic heart
      disease or family history of premature atherosclerosis (n = 89). Seventeen
      subjects (aged 54 +/- 10 years, 15 male) with fasting total homocystine levels
      above 75th percentile (mean, 9.8 +/- 2.8 micromol/liter) consented to participate
      in a double-blind, randomized, placebo-controlled and crossover trial; each
      subject received oral folic acid (10 mg/day) and placebo for 8 weeks, each
      separated by a washout period of four weeks. Flow-mediated endothelium-dependent
      dilation (percent increase in diameter) of the brachial artery was assessed by
      high resolution ultrasound, before and after folic acid or placebo
      supplementation. RESULTS: Compared with placebo, folic acid supplementation
      resulted in higher serum folate levels (66.2 +/- 7.0 vs. 29.7 +/- 14.8
      nmol/liter; p < 0.001), lower total plasma homocystine levels (8.1 +/- 3.1 vs.
      9.5 +/- 2.5 micromol/liter, p = 0.03) and significant improvement in endothelium
      dependent dilation (8.2 +/- 1.6% vs. 6 +/- 1.3%, p < 0.001). Endothelium
      independent responses to nitroglycerin were unchanged. No adverse events were
      observed. CONCLUSION: Folic acid supplementation improves arterial endothelial
      function in adults with relative hyperhomocystinemia, with potentially beneficial
      effects on the atherosclerotic process.

PMID- 10588217
TI  - Photoplethysmographic assessment of pulse wave reflection: blunted response to
      endothelium-dependent beta2-adrenergic vasodilation in type II diabetes mellitus.
AB  - OBJECTIVES: We sought to determine whether a simple index of pressure wave
      reflection may be derived from the digital volume pulse (DVP) and used to examine
      endothelium-dependent vasodilation in patients with type II diabetes mellitus.
      BACKGROUND: The DVP exhibits a characteristic notch or inflection point that can
      be expressed as percent maximal DVP amplitude (IP(DVP)). Nitrates lower IP(DVP),
      possibly by reducing pressure wave reflection. Response of IP(DVP) to endothelium
      dependent vasodilators may provide a measure of endothelial function. METHODS:
      The DVP was recorded by photoplethysmography. Albuterol (salbutamol) and glyceryl
      trinitrate (GTN) were administered locally by brachial artery infusion or
      systemically. Aortic pulse wave transit time from the root of the subclavian
      artery to aortic bifurcation (T(Ao)) was measured by simultaneous Doppler
      velocimetry. RESULTS: Brachial artery infusion of drugs producing a greater than
      threefold increase in forearm blood flow within the infused limb was without
      effect on IP(DVP), whereas systemic administration of albuterol and GTN produced
      dose-dependent reductions in IP(DVP). The time between the first and second peak
      of the DVP correlated with T(Ao) (r = 0.75, n = 20, p < 0.0001). The effects of
      albuterol but not GTN on IP(DVP) were attenuated by N(G)-monomethyl-L-arginine.
      The IP(DVP) response to albuterol (400 microg by inhalation) was blunted in
      patients with type II diabetes mellitus as compared with control subjects (fall
      5.9 +/- 1.8% vs. 11.8 +/- 1.8%, n = 20, p < 0.02), but that to GTN (500 microg
      sublingually) was preserved (fall 18.3 +/- 1.2% vs. 18.6 +/- 1.9%, p = 0.88).
      CONCLUSIONS: The IP(DVP) is influenced by pressure wave reflection. The effects
      of albuterol on IP(DVP) are mediated in part through the nitric oxide pathway and
      are impaired in patients with type II diabetes.

PMID- 10588219
TI  - Implantable defibrillator event rates in patients with unexplained syncope and
      inducible sustained ventricular tachyarrhythmias: a comparison with patients
      known to have sustained ventricular tachycardia.
AB  - OBJECTIVES: To assess the clinical significance of inducible ventricular
      tachyarrhythmias among patients with unexplained syncope. BACKGROUND: Induction
      of sustained ventricular arrhythmias at electrophysiology study in patients with
      unexplained syncope and structural heart disease is usually assigned diagnostic
      significance. However, the true frequency of subsequent spontaneous ventricular
      tachyarrhythmias in the absence of antiarrhythmic medications is unknown.
      METHODS: In a retrospective case-control study, the incidence of implantable
      cardiac defibrillator (ICD) therapies for sustained ventricular arrhythmias among
      patients with unexplained syncope or near syncope (syncope group, n = 22) was
      compared with that of a control group of patients (n = 32) with clinically
      documented sustained ventricular tachycardia (VT). Sustained ventricular
      arrhythmias were inducible in both groups and neither group received
      antiarrhythmic medications. All ICDs had stored electrograms or RR intervals.
      Clinical variables were similar between groups except that congestive cardiac
      failure was more common in the syncope group. RESULTS: Kaplan-Meier analysis of
      the time to first appropriate ICD therapy for syncope and control groups produced
      overlapping curves (p = 0.9), with 57 +/- 11% and 50 +/- 9%, respectively,
      receiving ICD therapy by one year. In both groups, the induced arrhythmia was
      significantly faster than spontaneous arrhythmias, but the cycle lengths of
      induced and spontaneous arrhythmias were positively correlated (R = 0.6, p <
      0.0001). During follow-up, three cardiac transplantations and seven deaths
      occurred in the syncope group, and two transplantations and five deaths occurred
      in the control group (36-month survival without transplant 52 +/- 11% and 83 +/-
      7%, respectively, p = 0.03). CONCLUSIONS: In patients with unexplained syncope,
      structural heart disease and inducible sustained ventricular arrhythmias,
      spontaneous sustained ventricular arrhythmias occur commonly and at a similar
      rate to patients with documented sustained VT. Thus, electrophysiologic testing
      in unexplained syncope can identify those at risk of potentially life-threatening
      tachyarrhythmias, and aggressive treatment of these patients is warranted.

PMID- 10588218
TI  - Familial polymorphic ventricular arrhythmias: a quarter century of successful
      medical treatment based on serial exercise-pharmacologic testing.
AB  - OBJECTIVES: We sought to determine whether objective tests of antiarrhythmic drug
      efficacy could produce favorable short- and long-term outcomes in a family with
      idiopathic malignant ventricular arrhythmias. BACKGROUND: In 1973 a family
      presented with a history of several generations of syncopal spells and sudden
      death. Some individuals had nonspecific electrocardiographic (ECG) changes. Their
      QT intervals were normal at rest and with exercise. Autopsies in two young family
      members showed no cardiac abnormalities, specifically no evidence of
      arrhythmogenic right ventricular dysplasia, other cardiomyopathy, myocarditis or
      gross abnormality of the conduction system. METHODS: Available family members had
      screening ECGs. Symptomatic members had a battery of tests, including
      electrophysiologic studies, ambulatory ECGs, audiograms, exercise stress testing,
      serum catecholamine levels during rest and exercise and isoproterenol infusion.
      Serial exercise-pharmacologic testing was performed in symptomatic family members
      until induction of an arrhythmia during exercise required higher work loads or
      became impossible. RESULTS: Arrhythmias were not induced during
      electrophysiologic studies. In several family members tested, ventricular
      premature beats and then rapid polymorphic ventricular arrhythmias occurred
      whenever the sinus rate exceeded 130 beats/min. Emotional stress, isoproterenol
      infusion and exercise all elicited similar arrhythmias. Catecholamine levels
      during exercise were, however, unequivocally normal in two of three family
      members tested. Beta-blockers appeared to be the most effective pharmacologic
      agent for prevention of these arrhythmias. The efficacy of treatment has been
      confirmed during a follow-up of 25 years. CONCLUSIONS: This family appears to
      have catecholamine hypersensitivity as the basis for their ventricular
      arrhythmias. Guided therapy using serial exercise-pharmacologic testing provided
      reliable protection for this familial ventricular arrhythmia during a 25-year
      follow-up.

PMID- 10588220
TI  - Higher energy synchronized external direct current cardioversion for refractory
      atrial fibrillation.
AB  - OBJECTIVES: We sought to evaluate the safety and efficacy of higher energy
      synchronized cardioversion in patients with atrial fibrillation refractory to
      standard energy direct current (DC) cardioversion. BACKGROUND: Standard external
      electrical cardioversion fails to restore sinus rhythm in 5% to 30% of patients
      with atrial fibrillation. METHODS: Patients with atrial fibrillation who failed
      to achieve sinus rhythm after at least two attempts at standard external
      cardioversion with 360 J were included in the study. Two external defibrillators,
      each connected to its own pair of R-2 patches in the anteroposterior position,
      were used to deliver a synchronized total of 720 J. RESULTS: Fifty-five patients
      underwent cardioversion with 720 J. Mean weight was 117 +/- 23 kg (body mass
      index 48.3 +/- 4.1 kg/m2). Structural heart disease was present in 76% of
      patients. Mean left ventricular ejection fraction was 45 +/- 12%. Atrial
      fibrillation was present for over three months in 55% of the patients. Sinus
      rhythm was achieved in 46 (84%) of the 55 patients. No major complications were
      observed. No patient developed hemodynamic compromise and no documented
      cerebrovascular accident occurred within one month after cardioversion. Of the 46
      successful cardioversions, 18 patients (39%) remained in sinus rhythm over a mean
      follow-up of 2.1 months. CONCLUSIONS: External higher energy cardioversion is
      effective in restoring sinus rhythm in patients with atrial fibrillation
      refractory to standard energy DC cardioversion. This method is safe and does not
      result in clinical evidence of myocardial impairment. It may be a useful
      alternative to internal cardioversion because it could be done within the same
      setting of the failed standard cardioversion and obviates the need to withhold
      protective anticoagulation for internal cardioversion.

PMID- 10588222
TI  - Ventricular rate control during atrial fibrillation by cardiac parasympathetic
      nerve stimulation: a transvenous approach.
AB  - OBJECTIVES: To identify intravascular sites for continuous, stable
      parasympathetic stimulation (PS) in order to control the ventricular rate during
      atrial fibrillation (AF). BACKGROUND: Ventricular rate control during AF in
      patients with congestive heart failure is a significant clinical problem because
      many drugs that slow the ventricular rate may depress ventricular function and
      cause hypotension. Parasympathetic stimulation can exert negative dromotropic
      effects without significantly affecting the ventricles. METHODS: In 22 dogs, PS
      was performed using rectangular stimuli (0.05 ms duration, 20 Hz) delivered
      through a catheter with an expandable electrode-basket at its end. The catheter
      was positioned either in the superior vena cava (SVC, n = 6), coronary sinus (CS,
      n = 10) or right pulmonary artery (RPA, n = 6). The basket was then expanded to
      obtain long-term catheter stability. Atrial fibrillation was induced and
      maintained by rapid atrial pacing. RESULTS: Nonfluoroscopic (SVC) and
      fluoroscopic (CS/RPA) identification of effective intravascular PS sites was
      achieved within 3 to 10 min. The ventricular rate slowing effect during AF
      started and ceased immediately after on-offset of PS, respectively, and could be
      maintained over 20 h. In the SVC, at least a 50% increase of ventricular rate (R
      R) intervals occurred at 22 +/- 11 V (331 +/- 139 ms to 653 +/- 286 ms, p <
      0.001), in the CS at 16 +/- 10 V (312 +/- 102 ms vs. 561 +/- 172 ms, p < 0.001)
      and in the RPA at 18 +/- 7 V (307 +/- 62 ms to 681 +/- 151 ms, p < 0.001).
      Parasympathetic stimulation did not change ventricular refractory periods.
      CONCLUSIONS: Intravascular PS results in a significant ventricular rate slowing
      during AF in dogs. This may be beneficial in patients with AF and rapid
      ventricular response since many drugs that decrease atrioventricular conduction
      have negative inotropic effects which could worsen concomitant congestive heart
      failure.

PMID- 10588221
TI  - Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic
      ventricular tachycardia in structurally normal hearts.
AB  - OBJECTIVES: The purpose of this study was to provide clinical and anatomical
      characteristics as well as genetic background of a malignant arrhythmogenic
      disorder. BACKGROUND: An inherited autosomally dominant cardiac syndrome causing
      stress-induced polymorphic ventricular tachycardia and syncope in the absence of
      structural myocardial changes was detected in two families. METHODS: Two
      unrelated families with six victims of sudden death and 51 living members were
      evaluated. Resting and exercise electrocardiograms (ECG), echocardiography,
      magnetic resonance imaging (MRI), cineangiography, microscopic examination of
      endomyocardial biopsies and a drug testing with a class IC antiarrhythmic agent
      flecainide were performed. A genetic linkage analysis was carried out to map the
      gene locus. RESULTS: Of the 24 affected individuals, 10 had succumbed with six
      cases of sudden death, and 14 survivors showed evidence of disease. Exercise
      stress test induced ventricular bigeminy or polymorphic ventricular tachycardia
      in affected individuals. Three children initially examined before 10 years of age
      developed arrhythmias during a four-year follow-up. Resting ECGs were normal in
      affected subjects except a slight prolongation of the QT intervals adjusted for
      heart rate (QTc) (430 +/- 18 vs. 409 +/- 19 ms, affected vs. nonaffected, p <
      0.01). Administration of flecainide did not induce ECG abnormalities encountered
      in familial idiopathic ventricular fibrillation. Ventricular volumes,
      contractility and wall measurements were normal by echocardiography, right
      ventricular cineangiography and MRI. Histopathological examination showed no
      fibrosis or fatty infiltration. The cumulative cardiac mortality by the age of 30
      years was 31%. The disease locus was assigned to chromosome 1q42-q43, with a
      maximal pairwise lod score of 4.74 in the two families combined. Only one
      heterozygous carrier was clinically unaffected suggesting high disease penetrance
      in adulthood. CONCLUSIONS: A distinct cardiac disorder linked to chromosome 1q42
      q43 causes exercise-induced polymorphic ventricular tachycardia in structurally
      normal hearts and is highly malignant. Delayed clinical manifestation
      necessitates repeated exercise electrocardiography to assure diagnosis in young
      individuals of the families.

PMID- 10588223
TI  - Computer-assisted animation of atrial tachyarrhythmias recorded with a 64
      electrode basket catheter.
AB  - OBJECTIVES: The aim of this study was to assess the value of a new mapping
      technique based on computer-assisted animation of multielectrode basket catheter
      (BC) recordings in patients with atrial arrhythmias. BACKGROUND: The three
      dimensional activation patterns of cardiac arrhythmias are not completely
      understood owing to limitations of conventional mapping techniques. METHODS: The
      study included 32 patients with atrial tachycardia (AT) and 38 patients with
      atrial flutter (AFL). A software program was developed to analyze the activation
      patterns based on 56 bipolar electrograms recorded with a 64-electrode BC
      deployed in the right atrium (RA). RESULTS: The total time needed for the
      animation of activation patterns of atrial arrhythmias was 5 +/- 0.8 min. In 22
      patients with right AT, the animated maps revealed that arrhythmia was unifocal
      in 15 patients, multifocal in 2 patients, polymorphic in 4 patients and reentrant
      in 1 patient. In 10 patients with left AT, breakthroughs on the right side of the
      septum (2 in 8 patients and 1 in 2 patients) and a left-to-right activation of
      the RA were demonstrated. In patients with typical AF, the reentrant excitation
      was a broad activation front with preferential propagation around the tricuspid
      annulus. In patients with atypical AFL, the reentry circuit involved one of the
      venae cavae and a line of block located in the posterior wall. CONCLUSIONS: The
      computer-assisted animation of multiple electrograms recorded with a BC is a
      valuable mapping tool that delineates the three-dimensional activation patterns
      of various atrial arrhythmias. The technique is appropriate for complex, short
      lived or unstable arrhythmias.

PMID- 10588225
TI  - Angiotensin-converting enzyme inhibitors and cytokines in heart failure: dose and
      effect?

PMID- 10588224
TI  - Effect of high- versus low-dose angiotensin converting enzyme inhibition on
      cytokine levels in chronic heart failure.
AB  - OBJECTIVES: We examined the effect of long-term treatment with two doses of the
      angiotensin converting enzyme (ACE) inhibitor enalapril on various immunological
      variables in patients with chronic congestive heart failure (CHF). BACKGROUND:
      Immunological mediators are increasingly recognized to play a pathogenic role in
      the pathophysiology of CHF. Whether ACE inhibitor therapy modifies immunological
      variables has not previously been investigated. METHODS: Seventy-five patients
      (mean age 52 +/- 11 years) with CHF were randomized between low-(5 m g daily) and
      high-dose (40 mg daily) enalapril in a double-blind trial. Circulating levels of
      immunological parameters (i.e., proinflammatory cytokines, chemokines and
      adhesion molecules) were measured at baseline, at 10 weeks and at the end of the
      study (34 weeks). RESULTS: All immunological parameters, except soluble
      interleukin (IL)-6 receptor, were increased in CHF compared with 21 healthy
      controls. During the study immunoreactive IL-6 levels decreased (p < 0.05) and
      soluble IL-6 receptor increased (p < 0.05) during high-dose but not during low
      dose enalapril therapy. Furthermore, IL-6 bioactivity decreased only during the
      high-dose (p < 0.001), resulting in a significant difference in change during
      treatment between the two dosage groups (p < 0.001). This decrease in IL-6
      bioactivity was significantly associated with decreased interventricular septum
      thickness as assessed by echocardiography (r = 0.56, p = 0.013). No other
      variables changed during treatment. CONCLUSIONS: In patients with severe CHF,
      high-dose enalapril therapy is associated with a significant decrease in IL-6
      activity. However, despite treatment with a high-dose ACE inhibitor, a persistent
      immune activation exists in these patients which may be of importance for the
      progression of CHF.

PMID- 10588226
TI  - Nonadherence with angiotensin-converting enzyme inhibitor therapy: a comparison
      of different ways of measuring it in patients with chronic heart failure.
AB  - OBJECTIVES: This study was designed to compare different proposed methods of
      assessing adherence with angiotensin-converting enzyme (ACE) inhibitor (ACEI)
      therapy in chronic heart failure. BACKGROUND: The use of ACEIs in chronic heart
      failure gives us a unique opportunity to assess a patient's adherence by
      measuring whether the expected biochemical effect of an ACEI is present in the
      patient's bloodstream. In fact, there are several different ways of assessing ACE
      in vivo: these are serum ACE activity itself, plasma N-acetyl-seryl-aspartyl
      lysyl-proline (AcSDKP), urine AcSDKP, plasma angiotensin I (AI), plasma
      angiotensin II (AII), or the AII/AI ratio. METHODS: Patients with chronic heart
      failure (n = 39) were randomized to regimens of ACEI nonadherence for one week,
      ACEI adherence for one week or two versions of partial adherence for one week,
      after which the above six tests were performed. RESULTS: All six tests
      significantly distinguished between full nonadherence for one week and full or
      partial adherence. Only plasma AcSDKP produced a significantly different result
      between partial adherence and either full adherence or full nonadherence for one
      week. In terms of their ability to distinguish full nonadherence from full
      adherence, plasma AcSDKP was 89% sensitive and 100% specific with an area under
      its ROC of 0.95. Corresponding figures for urine AcSDKP were 92%, 97% and 0.95
      and for serum ACE they were 86%, 95% and 0.90. CONCLUSIONS: All six tests
      distinguished full nonadherence from all other forms of adherence. The rank order
      of performance was plasma AcSDKP, urine AcSDKP, serum ACE, AII/AI ratio and
      plasma AII followed by plasma AI.

PMID- 10588228
TI  - Sudden death in mitral regurgitation: why was I so surprised?

PMID- 10588227
TI  - Sudden death in mitral regurgitation due to flail leaflet.
AB  - OBJECTIVES: We sought to assess the incidence and determinants of sudden death
      (SUD) in mitral regurgitation due to flail leaflet (MR-FL). BACKGROUND: Sudden
      death is a catastrophic complication of MR-FL. Its incidence and predictability
      are undefined. METHODS: The occurrence of SUD was analyzed in 348 patients (age
      67 +/- 12 years) with MR-FL diagnosed echocardiographically from 1980 through
      1994. RESULTS: During a mean follow-up of 48 +/- 41 months, 99 deaths occurred
      under medical treatment. Sudden death occurred in 25 patients, three of whom were
      resuscitated. The sudden death rates at five and 10 years were 8.6 +/- 2% and
      18.8 +/- 4%, respectively, and the linearized rate was 1.8% per year. By
      multivariate analysis, the independent baseline predictors of SUD were New York
      Heart Association (NYHA) functional class (p = 0.006), ejection fraction (p =
      0.0001) and atrial fibrillation (p = 0.059). The yearly linearized rate of sudden
      death was 1% in patients in functional class I, 3.1% in class II and 7.8% in
      classes III and IV. However, of 25 patients who had SUD, at baseline, 10 (40%)
      were in functional class I, 9 (36%) were in class II and only 6 (24%) in class
      III or IV. In five patients (20%), no evidence of risk factors developed until
      SUD. In patients with an ejection fraction > or =60% and sinus rhythm, the
      linearized rate of SUD was not different in functional classes I and II (0.8% per
      year). Surgical correction of MR (n = 186) was independently associated with a
      reduced incidence of SUD (adjusted hazard ratio [95% confidence interval] 0.29
      [0.11 to 0.72], p = 0.007). CONCLUSIONS: Sudden death is relatively common in
      patients with MR-FL who are conservatively managed. Patients with severe
      symptoms, atrial fibrillation and reduced systolic function are at higher risk,
      but notable rates of SUD have been observed without these risk factors.
      Correction of MR appears to be associated with a reduced incidence of SUD,
      warranting early consideration of surgical repair.

PMID- 10588229
TI  - Prevalence of valvular-regurgitation associated with dexfenfluramine three to
      five months after discontinuation of treatment.
AB  - OBJECTIVES: The goal of this study was to determine the prevalence of valvular
      regurgitation and abnormal valve morphology in patients three to five months
      after discontinuation of dexfenfluramine (Dexfen) therapy. BACKGROUND: We
      previously reported the results of a randomized, double-blind, placebo-controlled
      trial of valvular structure and function in 1,073 patients treated either with
      Dexfen, with an investigational sustained-release dexfenfluramine (Dexfen SR), or
      with a placebo, with echocardiograms performed approximately one month from the
      last dose. Using FDA criteria (aortic regurgitation [AR] > or =mild and/or mitral
      regurgitation [MR] > or =moderate) we found no statistical difference among the
      groups, but when all degrees of valvular regurgitation were considered and when
      the two Dexfen groups were combined, there was a higher prevalence of any degree
      of AR, any degree of MR, and restricted posterior mitral leaflet mobility.
      However, it was unknown whether these differences in prevalence persisted.
      METHODS: The double blind was maintained, and all patients were invited to return
      for a follow-up echocardiogram. Echocardiograms were acquired using a
      standardized protocol and assessed blindly to determine the degree of valvular
      regurgitation and valve leaflet thickness and mobility. We had an 80% power to
      detect a statistically significant change in paired proportions using the McNemar
      test (alpha = 0.05). RESULTS: Echocardiograms were obtained on 941 patients with
      a median of 137 days after drug discontinuation. Aortic regurgitation (of any
      degree) was present in 13.8% of Dexfen (p = 0.41 compared to placebo), 10.7% of
      Dexfen SR (p = 0.64 compared to placebo), and 11.9% of placebo patients. The
      minor differences between patients treated with active drug versus placebo, which
      were found in the previous study, were no longer significant even when the groups
      were combined (p = 0.83 compared to placebo). Mitral regurgitation (of any
      degree) was present in 71.5% (p = 0.15 compared to placebo), 69.8% (p = 0.30
      compared to placebo), and 70.5%, respectively. This was also not significantly
      different from placebo when both Dexfen groups were combined (p = 0.16). There
      was no difference in the prevalence of restricted posterior mitral leaflet
      mobility among the three groups (p = 0.19). CONCLUSIONS: The small increase in
      prevalence of minor degrees of AR and MR in patients treated with two to three
      months of Dexfen previously reported is no longer present three to five months
      after discontinuation of medication. These data suggest that the degree of
      regurgitation observed in patients who used Dexfen for a relatively short
      duration does not progress over time.

PMID- 10588230
TI  - Echocardiographic predictors of left ventricular outflow tract obstruction and
      systolic anterior motion of the mitral valve after mitral valve reconstruction
      for myxomatous valve disease.
AB  - OBJECTIVE: To determine predictors of systolic anterior motion and left
      ventricular outflow tract obstruction (SAM/LVOTO) after mitral valve repair
      (MVRep) in patients with myxomatous mitral valve disease. BACKGROUND: Mechanisms
      for the development of SAM/LVOTO after MVRep have been described; however,
      predictors of this complication have not been explored. We hypothesize that pre
      MVRep transesophageal echocardiography (TEE) can predict postrepair SAM/ LVOTO.
      METHODS: Using TEE, the lengths of the coapted anterior (AL) and posterior (PL)
      leaflets and the distance from the coaptation point to the septum (C-Sept) were
      measured before and after MVRep in 33 patients, including 11 who developed
      SAM/LVOTO (Group 1) and 22 who did not (Group 2). RESULTS: Group 1 patients had
      smaller AL/PL ratios (0.99 vs. 1.95, p < 0.0001) and C-Sept distances (2.53 vs.
      3.01 cm, p = 0.012) prior to MVRep than those in Group 2. Resolution of SAM/LVOTO
      was associated with increases in AL/PL ratio and C-Sept distance. This reflects a
      more anterior position of the coaptation point in those who developed SAM/ LVOTO.
      CONCLUSIONS: These data suggest that TEE analysis of the mitral apparatus can
      identify patients likely to develop SAM/LVOTO after MVRep for myxomatous valve
      disease. The findings are consistent with the concept that SAM of mitral leaflets
      is due to anterior malposition of slack mitral leaflet portions into the LVOT.
      The position of the coaptation point of the mitral leaflets is dynamic and a
      potential target and end point for surgical designs to prevent SAM/LVOTO post
      MVRep.

PMID- 10588231
TI  - Complications of endomyocardial biopsy in children.
AB  - OBJECTIVES: To evaluate the incidence of, and risk factors for, complications of
      endomyocardial biopsy in children. BACKGROUND: Endomyocardial biopsy (EMB) is a
      low risk procedure in adults, but there is a paucity of data with regard to
      performing this procedure in children. METHODS: Retrospective review of the
      morbidity and mortality of 1,000 consecutive EMB procedures. RESULTS: One
      thousand EMB procedures (right ventricle 986, left ventricle 14) were performed
      on 194 patients from July 1987 through March 1996. Indications for EMB included
      heart transplant rejection surveillance (846) and the evaluation of
      cardiomyopathy or arrhythmia for possible myocarditis (154). Thirty-seven (4%)
      procedures were performed on patients receiving intravenous inotropic support.
      There was one biopsy related death, secondary to cardiac perforation, in a two
      week-old infant with dilated cardiomyopathy. There were nine perforations of the
      right ventricle, eight occurring in patients with dilated cardiomyopathy and one
      in a transplant recipient. The transplant patient did not require immediate
      intervention; two patients required pericardiocentesis alone, and six underwent
      pericardiocentesis and surgical intervention. All nine perforations were from the
      femoral venous approach (p < 0.01). Multivariate analysis demonstrated that the
      greatest risk of perforation occurred in children being evaluated for possible
      myocarditis (p = 0.01) and in those requiring inotropic support (p < 0.01). Other
      complications included arrhythmia (5) and single cases of coronary-cardiac
      fistula, flail tricuspid leaflet, pneumothorax, hemothorax, endocardial stripping
      and seizure. CONCLUSIONS: Risk of endomyocardial biopsy is highest in sick
      children with suspected myocarditis on inotropic support. However, EMB can be
      performed safely with very low morbidity in pediatric heart transplant
      recipients.

PMID- 10588232
TI  - Abnormal cardiac function in the streptozotocin-induced non-insulin-dependent
      diabetic rat: noninvasive assessment with doppler echocardiography and
      contribution of the nitric oxide pathway.
AB  - OBJECTIVES: We sought to evaluate in vivo and in vitro left ventricular (LV)
      geometry and function in streptozotocin-induced diabetic rats and the possible
      role of the nitric oxide (NO) pathway. BACKGROUND: Diabetes results in cardiac
      dysfunction; however, the specific abnormalities are unknown. Because decreased
      NO contributes to abnormal vascular function in diabetics, we hypothesized that
      NO pathway abnormalities may contribute to diabetic cardiomyopathy. METHODS:
      Control rats and those with non-insulin-dependent diabetes mellitus (NIDDM)
      underwent echocardiography, hemodynamic assessment, isolated heart perfusion and
      measurement of exhaled NO and LV endothelial constitutive nitric oxide synthase
      (ecNOS). RESULTS: Diabetic rats had increased LV mass (3.3 +/- 0.6 vs. 2.6 +/-
      0.3 g/g body weight [BW], p < 0.001) and cavity dimensions (diastolic 2.0 +/- 0.1
      vs. 1.8 +/- 0.2 cm/cm tibial length [TL], p < 0.05). Diabetic rats had prolonged
      isovolumic relaxation time (IVRT) (40 +/- 8 vs. 26 +/- 6 ms, p < 0.0001),
      increased atrial contribution to diastolic filling (0.47 +/- 0.09 vs. 0.30 +/-
      0.08 m/s, p < 0.0001), and elevated in vivo LV end-diastolic pressure (7 +/- 6
      vs. 2 +/- 1 mm Hg, p = 0.04). Diabetic rats had increased chamber stiffness.
      Shortening was similar in both groups, despite reduced meridional wall stress in
      diabetics, suggesting impaired systolic contractility. Exhaled NO was lower in
      diabetic rats (1.8 +/- 0.2 vs. 3.3 +/- 0.3 parts per billion, p < 0.01) and
      correlated with Doppler LV filling. The ecNOS was similar between the groups.
      CONCLUSIONS: Diabetic cardiomyopathy is characterized by LV systolic and
      diastolic dysfunction, the latter correlating with decreased exhaled NO. The NO
      pathway is intact, suggesting impaired availability of NO as contributor to
      cardiomyopathy.

PMID- 10588233
TI  - Pravastatin restored the infarct size-limiting effect of ischemic preconditioning
      blunted by hypercholesterolemia in the rabbit model of myocardial infarction.
AB  - OBJECTIVES: We tested to find out whether pravastatin restores the infarct size
      (IS)-limiting effect of ischemic preconditioning (IP) and if it has any effect on
      the IP-induced activation of adenosine producing enzyme ecto-5'-nucleotidase
      which plays a key role in the IP-induced cardioprotection. BACKGROUND: The IS
      limiting effect of IP is blunted by hypercholesterolemia. Recently, HMG-CoA
      reductase inhibitors are shown to have direct cytoprotective effects. METHODS:
      Rabbits were fed with a normal or cholesterol (1%) added diet with or without
      pravastatin (5 mg/kg/day) treatment. Infarct size was measured after 30 min
      occlusion and 3 h reperfusion of circumflex coronary artery with or without the
      IP procedure (5 min occlusion and 10 min reperfusion). Additionally, ecto-5'
      nucleotidase activities of ischemic and nonischemic myocardium were measured
      immediately after IP procedure. RESULTS: This dose of pravastatin did not
      normalize the increased level of serum cholesterol. The IS-limiting effect of
      preceding IP (IS reduced from 36.7% to 9.6%, p < 0.001) was abolished by
      hypercholesterolemia (from 46.1% to 31.3%, p = NS) and restored by pravastatin
      treatment (from 35.2% to 9.4%, p < 0.001). Pravastatin treatment did not affect
      IS or the effect of IP under normocholesterolemia. The activation of ecto-5'
      nucleotidase presented as the activity ratio of ischemic to nonischemic
      myocardium (3.1-fold in normocholesterolemia) was blunted by hypercholesterolemia
      (1.8-fold, p < 0.05) and restored by pravastatin treatment (2.9-fold).
      CONCLUSIONS: Pravastatin, at the dose serum cholesterol was not normalized,
      restored the IS-limiting effect of IP and IP-induced ecto-5'-nucleotidase
      activation, which were both blunted by hypercholesterolemia. The activation of
      ecto-5'-nucleotidase may be worth further investigation as a possible mechanism
      for the hypercholesterolemia-induced retardation and pravastatin-mediated
      restoration of the cardioprotective effect of IP.

PMID- 10588234
TI  - Repeated stunning precedes myocardial hibernation in progressive multiple
      coronary artery obstruction.
AB  - OBJECTIVE: The aim of this study was to characterize a regional myocardial flow
      function relationship in collateral dependent myocardium produced by multiple
      coronary artery obstruction. METHODS: Ameroid constrictors were placed around the
      proximal right (RC) and circumflex (CX) coronary arteries and a silicon tubing
      cuff around the proximal LAD (left anterior descending artery) (luminal stenosis
      +/- 77%) in 18 dogs. Weekly two-dimensional echocardiography was performed for
      regional function (anterior [A], inferoposterior [IP], wall thickening [WT]), and
      fractional shortening (FS). Colored microspheres injected at baseline and before
      sacrifice, before and after dipyridamole (0.5 mg/kg) injection, determined
      resting flow (RF) and coronary reserve (CR), respectively. RESULTS: Coronary
      angiography performed at four weeks after surgery confirmed occlusion of RC and
      CX with collateralization and a tight stenosis of LAD. Initially, an episodic
      reduction in A and IP WT was observed which became persistent later (AWT: 16 +/-
      3%; IPWT: 16 +/- 4%, FS: 20 +/- 4%, p < 0.005 vs. baseline [BS]). With dobutamine
      a biphasic response (improvement in A and IP WT between 5-15 and dysfunction
      between 20-30 microg/kg/min) was observed. Seven dogs were sacrificed at eight
      weeks and showed normal RF but reduced transmural CR (A: 75 +/- 18%; IP: 46 +/-
      22% of control). Seven dogs underwent PTCA of the LAD at eight weeks and showed
      gradual improvement in AWT with normalization at 12 weeks (AWT: 30 +/- 5%, p <
      0.001 vs. eight weeks). At sacrifice RF and CR in the A wall were normal but
      there was reduced subendocardial RF in the IP region (64% of BS). Further, biopsy
      samples showed normal histological findings and high energy phosphate content in
      all dogs. Radioligand binding assays using 125I-iodocyanopindolol showed
      downregulation of beta-adrenergic receptor density in the dysfunctional regions
      compared with control. CONCLUSIONS: In this canine model of viable, collateral
      dependent and reversibly dysfunctional myocardium, there was early episodic
      dysfunction followed by persistent dysfunction which was initially associated
      with normal RF and later with subendocardial hypoperfusion.

PMID- 10588235
TI  - Reunion.

PMID- 10588236
TI  - President's page: integrating the internet into your practice.

PMID- 10588237
TI  - American College of Cardiology training statement on recommendations for the
      structure of an optimal adult interventional cardiology training program: a
      report of the American College of Cardiology task force on clinical expert
      consensus documents.

PMID- 10588238
TI  - Sudden death, arrhythmic events and measurements of heart rate variability.

PMID- 10588239
TI  - Carvedilol in class IV heart failure.

PMID- 10588240
TI  - Winter and cardiovascular mortality.

PMID- 10588241
TI  - Dynamic left ventricular outflow tract obstruction as a potential mechanism of
      myocardial rupture after acute myocardial infarction.

PMID- 10588242
TI  - Five things oculoplastic surgeons should know about neuro-ophthalmology.

PMID- 10588243
TI  - Prospective analysis of changes in corneal topography after upper eyelid surgery.
AB  - PURPOSE: Some patients note a decrease in visual acuity in the operated eye after
      eyelid surgery. Although, the most common cause for this change is dry eye
      syndrome, it has been hypothesized that the symptom of blurred vision may result
      from a change in the corneal curvature. The study was conducted to determine if
      there is a change in corneal curvature after upper eyelid surgery. METHODS:
      Standard keratometry and corneal videokeratography (CVK) were performed 1 and 3
      months after blepharoplasty (18 lids) and ptosis repair (24 lids). Pre- and
      postoperative images from CVK data were digitally subtracted for quantitative
      evaluation. RESULTS: After ptosis repair, the average dioptric change as measured
      by keratometry and by CVK was approximately 0.60 diopters (D); of note, nearly
      30% of these patients showed transient astigmatic changes greater than 1.00 D;
      After blepharoplasty, the average dioptric change as measured by keratometry and
      by CVK was approximately 0.55 D; of note, only 11% of patients showed astigmatic
      changes greater than 1.00 D. CONCLUSION: Repositioning of the upper eyelid after
      ptosis repair or blepharoplasty may result in visually significant astigmatic
      changes in the central and peripheral cornea and may alter the patient's
      spectacle or contact lens correction.

PMID- 10588244
TI  - A novel mechanism for benign essential blepharospasm.
AB  - PURPOSE: The purpose of this study is to test the hypothesis that the photophobia
      of benign essential blepharospasm (BEB) is caused by sympathetically maintained
      pain. METHODS: Nineteen patients with photophobia and BEB were enrolled in an
      unblinded prospective treatment trial. The intervention was blockade of the
      superior sympathetic ganglion with local anesthetic. Outcome measures included
      the patient's subjective report of ocular surface dryness, foreign body
      sensation, and eyelid spasm. We also obtained video recordings of eyelid
      movements. RESULTS: Of the 19 patients, 13 reported subjective improvement in BEB
      symptoms after cervical sympathetic blockade (CSB). Thirteen of 19 patients also
      had objective evidence of decreased light-induced eyelid spasm after CSB. Ocular
      surface disease was present in 18 of 19 patients. CONCLUSION: These data support
      the hypothesis that in many patients with BEB there is a sympathetically
      maintained pain syndrome associated with external ocular disease. We speculate on
      a neurologic circuit that may explain these findings.

PMID- 10588245
TI  - The association between cigarette smoking and basal cell carcinoma of the eyelids
      in women.
AB  - PURPOSE: To determine if there is an association between basal cell carcinoma of
      the eyelid and cigarette smoking. METHODS: A cross-sectional, retrospective, case
      controlled study was done comparing the prevalence of cigarette smoking in 112
      patients with biopsy-proven basal cell carcinoma of the eyelid to age and sex
      matched controls with other eyelid disorders. Exposure-odds ratios were computed
      for each group. RESULTS: Patients with basal cell carcinoma of the eyelid were no
      more likely to be smokers than controls (odds ratio [OR] 1.78, not statistically
      significant at the 95% confidence interval [CI]). When divided by sex however,
      there was an association between cigarette smoking and basal cell carcinoma in
      women (OR 2.87, statistically significant at the 95% CI) but not in men (OR 1.30,
      not statistically significant at the 95% CI). CONCLUSION: Basal cell carcinoma of
      the eyelid is associated with cigarette smoking in women but not in men.

PMID- 10588246
TI  - Periocular deep cutaneous basal cell carcinoma.
AB  - PURPOSE: The distinction between benign and malignant cutaneous periocular
      lesions can be difficult, as the clinical history and appearance are often quite
      similar. When present, typical cutaneous changes are often helpful in
      distinguishing between benign and malignant neoplasms. However, when tumors lack
      characteristic epidermal change, histopathologic examination may be necessary to
      confirm the diagnosis. The authors present their experience in the evaluation and
      management of two patients with periocular basal cell carcinoma who were
      initially diagnosed as having benign cysts. METHODS: The case records for two
      patients with periocular basal cell carcinoma were reviewed. Preoperative and
      postoperative photographs were available for comparison in one case. For each
      patient, the medical history, clinical presentation, histology, and surgical
      outcome were reviewed. RESULTS: In each case, the periocular mass was initially
      diagnosed as a benign process. Histopathologic examination following excisional
      biopsy established the diagnosis of basal cell carcinoma in both patients.
      Following biopsy, residual tumor was removed by the Mohs micrographic technique.
      There were no surgical complications and no tumor recurrences during follow-up of
      one year and eight years. CONCLUSIONS: Periocular basal cell carcinoma may mimic
      benign cystic lesions of the central face. Incorrect diagnosis may result in
      delayed or inappropriate therapy, or failure to submit seemingly benign lesions
      for histopathologic examination. Definitive treatment requires complete excision
      with histologic margin control.

PMID- 10588247
TI  - Follow-up methods and the apparent success of entropion surgery.
AB  - PURPOSE: To determine if follow-up methods affect the apparent success rate of
      the surgical repair of involutional entropion. METHODS: A review of articles
      published in English between 1939 and 1997, and a review of a series of 112
      patients who underwent entropion repair with a combination of a tarsal strip
      procedure, a partial pretarsal orbiculectomy, and creation of an eyelid crease.
      RESULTS: Only ten of 104 published reports contained information on the method by
      which follow-up data were attained. The apparent success rate of surgery in the
      case series declined in proportion to the effort made to detect unsuccessful
      cases. Long-term follow-up office examinations revealed cases of residual
      postoperative entropion that had not been detected by spontaneous patient
      complaints or by telephone interviews. CONCLUSION: Future reports on the results
      of entropion repair should include long-term follow-up that includes physical
      examination with testing to provoke latent entropion.

PMID- 10588248
TI  - Porous alloplastic material encasement of gold weights for the treatment of
      paralytic lagophthalmos.
AB  - PURPOSE: To determine if encasing gold weights in a porous alloplastic material
      would improve their longevity in situ. METHODS: Gold weights used for passive
      eyelid reanimation in patients with paralytic lagophthalmos were wrapped in
      either expanded polytetrafluoroethylene (E-PTFE) or porous polyurethane (PPU) to
      allow cellular infiltration and ingrowth and increase the blood supply to the
      site of the implant. A total of 14 implants, six encased in E-PTFE, six encased
      in PPU, and two with no casings (controls), were tested for biocompatibility and
      stability in rabbit eyelids for 10 months. RESULTS: Two of the PPU-encased gold
      weights showed some anterior extrusion, one at 3 months and one at 5 months after
      implantation. All of the E-PTFE-encased gold weights and both control weights
      were well tolerated for the entire study period. Histology of the alloplastic
      casings and surrounding tissues showed good tissue compatibility and cellular
      ingrowth for both alloplastic materials. CONCLUSIONS: Encasing the weights in a
      biocompatible alloplastic material, such as E-PTFE, may decrease micromovement
      and improve attachment to the eyelid tissue, as well as increase blood supply to
      the area, thereby reducing the rates of the major complications--infection and
      extrusion--associated with these implants.

PMID- 10588249
TI  - An anatomic and histologic study of the caruncle.
AB  - PURPOSE: To describe the histologic features of the caruncle and to determine its
      anatomic relationship to the common canaliculus. METHODS: Specimens from
      preserved and fresh-frozen cadavers were studied histopathologically. RESULTS:
      The average distance between the external surface of the caruncle and the common
      canaliculus was 0.85 mm, whereas the shortest distance measured was 0.50 mm.
      Several histologic abnormalities (oncocytic change, apocrine metaplasia, and
      microscopic stones) were identified in specimens that appeared clinically normal.
      CONCLUSION: Caution should be exercised when operations are performed on or near
      the caruncle to avoid inadvertent damage to the canalicular system.

PMID- 10588250
TI  - The influence of hyperbaric oxygen therapy and irradiation on hydroxyapatite
      ocular implant exposure and fibrovascular ingrowth in New Zealand white rabbits.
AB  - PURPOSE: Lack of adequate fibrovascular ingrowth has been implicated as a cause
      of exposure of hydroxyapatite (HA) implants in anophthalmic sockets. We
      investigated the vasculopathic effects of external beam irradiation, and the
      fibrovascular-enhancement effects of hyperbaric oxygen (HBO), on HA implant
      exposure and fibrovascular ingrowth in a rabbit model. METHODS: Eighteen rabbits
      underwent enucleation with implantation of a 12-mm HA sphere. Six rabbits
      received 20 Gy of external beam orbital irradiation prior to enucleation. Three
      irradiated and 6 nonirradiated rabbits received postoperative HBO. Three weeks
      postoperatively, all rabbits were evaluated clinically for evidence of implant
      exposure. Implants were then removed, and histopathologic analysis of
      fibrovascular ingrowth was performed. RESULTS: The amount of vascularization as
      measured by the depth of ingrowth was greater for nonirradiated (89% ingrowth)
      than for irradiated (71% ingrowth) animals. HA implant exposure occurred in 1 of
      12 (8%) of the nonirradiated, and 4 of 6 (67%) of the irradiated rabbit orbits.
      HBO did not protect irradiated rabbits from exposure, but did enhance
      fibrovascular ingrowth in nonirradiated rabbits (100% ingrowth vs. 77% ingrowth).
      CONCLUSION: Impaired orbital vascularization from prior irradiation appears to
      retard fibrovascular ingrowth into HA implants, and is associated with an
      increased incidence of exposure. While HBO did not diminish the likelihood of
      exposure in irradiated sockets, HA fibrovascular ingrowth in normal orbits
      appeared to increase with HBO. This may have beneficial clinical application in
      cases of exposure in nonirradiated orbits.

PMID- 10588251
TI  - A new variety of hydroxyapatite: the Chinese implant.
AB  - PURPOSE: This study was designed to evaluate a new type of hydroxyapatite (HA)
      implant (produced in China) in a rabbit model. METHODS: Three New Zealand white
      rabbits underwent enucleation of one eye followed by implantation of a 12-mm
      Chinese HA implant wrapped in Vicryl mesh (polyglactin 910). Magnetic resonance
      imaging was performed to assess host fibrovascularization of the implant 4, 8,
      and 12 weeks after implantation. One animal was sacrificed at each of these times
      for histopathologic examination. The Chinese implant was also examined chemically
      and by scanning electron microscopy. It was compared to the original BioEye and
      the third generation synthetic HA implant produced in France by FCI (FCI3).
      RESULTS: This new variety of HA implant from China is heavier than the FCI3
      implant but lighter than the original BioEye. The Chinese implant was easy to
      work with and not fragile. The pore size was more uniform than the FCI3 implant
      and similar to the BioEye implant clinically and by scanning electron microscopy.
      The pores in this implant are unidirectional. Analysis for impurities revealed a
      calcium oxide (CaO) content of 4.4%. Histopathologically, central vascularization
      occurred by 4 weeks and was similar in extent to the vascularization seen with
      the FCI3 implant and the BioEye. CONCLUSIONS: The Chinese implant is less
      expensive then the BioEye and the FCI3 implants, and appears to be a viable
      alternative to the BioEye. Further refinements are in progress to eliminate the
      CaO contaminant.

PMID- 10588252
TI  - Vertical lid split orbitotomy revisited.
AB  - PURPOSE: To report the results of anterior orbitotomy through a vertical
      transmarginal upper eyelid incision for gaining access to superonasal
      intraorbital lesions. METHODS: Retrospective case series of 13 patients
      presenting with superonasal intraorbital lesions. RESULTS: Vertical transmarginal
      upper eyelid incision allowed biopsy or removal of orbital lesions in all cases
      with satisfactory postoperative cosmesis and function. CONCLUSION: The vertical
      lid split orbitotomy, initially described for anterior orbital lesions, also is
      useful for exposure and removal of deeper intraconal orbital masses.

PMID- 10588253
TI  - Orbital volume expansion of dysthyroid ophthalmopathy by surgical placement of
      lateral rim implants: a case study.
AB  - PURPOSE: To measure the increase in orbital volume expansion effected by surgical
      placement of a lateral rim implant. METHODS: Computed tomography was used to
      obtain 1-mm axial sections of a normal human cadaver skull. A computer program
      was used to measure the orbital area of each section and integrate the sum of the
      areas to obtain the total orbital volume. Following placement of a lateral
      orbital rim implant, this procedure was repeated to obtain the new orbital
      volume. RESULTS: The orbital volume increased from 22.2 cm3 to 23.6 cm3 (an
      increase of 6%) following placement of the lateral orbital rim implant.
      CONCLUSION: Surgical placement of a lateral orbital rim implant can be an
      effective method of orbital volume expansion in dysthyroid ophthalmopathy.

PMID- 10588254
TI  - Sotradecol (sodium tetradecyl sulfate) injection of orbital lymphangioma.
AB  - PURPOSE: To describe the results of intralesional injection of the sclerosing
      agent sodium tetradecyl sulfate in patients with lymphangioma. METHODS: Three
      patients (one child and two adults) were treated. RESULTS: Two patients had
      improvement in the size of the lymphangioma, although the result was short-lived
      in one instance. Minimal change was noted in the third patient. Two patients had
      transient edema and ecchymosis, and one patient had a mild allergic reaction to
      the injected solution. CONCLUSIONS: Sodium tetradecyl sulfate may be a useful
      therapeutic option for some patients with eyelid or orbital lymphangioma,
      particularly if a previous operation has not been performed.

PMID- 10588255
TI  - Diffuse nodular eyelid lipogranuloma following sutureless transconjunctival
      blepharoplasty dressed with topical ointment.
AB  - PURPOSE: Transconjunctival blepharoplasty is becoming the approach of choice for
      many cosmetic surgeons. The authors describe a case of a diffuse, multinodular
      eyelid lipogranuloma following transconjunctival blepharoplasty, after which the
      unsutured wound was dressed with a topical ointment. METHODS: Report of clinical
      course and histopathologic findings. RESULTS: A patient developed multiple firm,
      nontender masses of the left lower eyelid that enlarged despite topical and
      systemic medical therapy. Prior to referral, the progressive lesions had recurred
      despite three successive attempts at surgical eradication. Histopathologic
      examination of excised tissue demonstrated a multifocal lipogranulomatous
      inflammation consistent with reaction to retained ointment. CONCLUSIONS:
      Sclerosing lipogranulomas are a known complication of intradermal lipid
      injection, as well as a late complication of sinus surgery after postoperative
      nasal packing with ointment-saturated gauze. The application of a topical
      ointment should be avoided until after transconjunctival lower blepharoplasty
      unless wound closure is secure or until conjunctival epithelialization is
      complete.

PMID- 10588256
TI  - Visual loss in idiopathic intracranial hypertension after resolution of
      papilledema.
AB  - PURPOSE: To demonstrate that progressive visual field loss may occur after
      resolution of papilledema in patients with idiopathic intracranial hypertension
      and persistently elevated intracranial pressure. METHODS: A patient with
      idiopathic intracranial hypertension was evaluated with serial Humphrey automated
      static perimetry after initial treatment and resolution of papilledema. RESULTS:
      The patient developed recurrent headache and elevated cerebrospinal fluid
      pressure. Optic nerve head appearance did not change. Automated perimetry
      demonstrated reproducible, worsening visual field loss; mean deviation decreased
      11 dB in each eye. Visual field defects resolved after optic nerve sheath
      fenestration. CONCLUSIONS: Increased intracranial pressure caused visual field
      loss after resolution of papilledema. Optic nerve sheath fenestration improved
      visual function in this patient.

PMID- 10588257
TI  - Extensive lower eyelid pigment spread after blepharopigmentation.
AB  - PURPOSE: To report on a complication of blepharopigmentation. METHODS: Case
      report. RESULTS: An 81-year-old woman underwent cosmetic tattooing of all four
      eyelids. The pigment immediately spread from the right lower eyelid lash line to
      the nasojugal fold. The dispersion was so extensive in surface area that
      nonsurgical techniques for ameliorating the dispersion would not be effective.
      The unintentionally tattooed skin was excised and reconstructed with a lateral
      canthal suspension and full thickness skin grafts. Pathologic examination of the
      excised tissue revealed pigmentation of all layers of the skin and the surface of
      the orbicularis muscle. CONCLUSION: This case illustrates that extensive pigment
      spread following blepharopigmentation may require extensive reconstruction to
      correct the problem.

PMID- 10588259
TI  - Solitary fibrous tumor of the lacrimal sac.
AB  - PURPOSE: Solitary fibrous tumor is a rare spindle cell tumor arising in the
      pleura. We report two cases of this tumor occurring in the lacrimal sac. METHODS:
      A 23-year-old man and a 34-year-old woman presented with a medial canthal mass.
      They underwent surgical excision of their tumors. RESULTS: Solitary fibrous
      tumors were diagnosed by light microscopy, immunohistochemical study, and
      electron microscopy. Immunohistochemical staining showed that tumor cells were
      reactive with vimentin and CD34 and demonstrated no smooth muscle or neural
      differentiation (nonreactive with desmin and S-100 protein). CONCLUSIONS: The
      findings indicate that solitary fibrous tumor can occur in the lacrimal sac and
      may recur locally if it is removed incompletely. To our knowledge, these are the
      first reported cases of solitary fibrous tumors occurring in the lacrimal sac.

PMID- 10588258
TI  - Neurothekeoma palpebrae: a rare nerve sheath tumor arising in the eyelid.
AB  - PURPOSE: To report a case of an eyelid neurothekeoma, a rare peripheral nerve
      sheath tumor. METHODS: Case report. RESULTS: An excisional biopsy, performed on a
      lesion removed from the upper eyelid of a 76-year-old woman, revealed the
      clinical and histopathologic features of a neurothekeoma, a tumor consisting of
      multiple collections of spindle cells in a myxomatous background.
      Immunohistochemical characterization showed positivity for NK1/C3, neuron
      specific enolase, and alcian blue. CONCLUSION: Neurothekeoma palpebrae should be
      considered in the differential diagnosis of solitary nodules of the eyelids.

PMID- 10588260
TI  - Primary orbital angiosarcoma: a case report.
AB  - PURPOSE: The pathogenesis, natural history, histopathology, and recommended
      treatment for orbital angiosarcoma are illustrated and reviewed. METHODS: Case
      report. RESULTS: A 71-year-old white male presented with bluish discoloration and
      swelling of the left medial canthal area. A fine needle aspiration and excisional
      biopsy with histopathologic examination was performed, which showed angiosarcoma.
      Pattern of growth was demonstrated radiographically and histopathologically,
      confirming primary orbital angiosarcoma. Subsequent wide surgical resection was
      carried out, with substantial reconstruction of the left orbital and periorbital
      area. The patient responded well to the surgery, and was free of tumor after six
      years of follow-up. CONCLUSION: Angiosarcoma is a rare and highly malignant tumor
      of epithelial origin. The aggressive nature of this tumor usually results in a
      high mortality rate despite treatment. However, early diagnosis and wide surgical
      excision has resulted in successful treatment of these tumors.

PMID- 10588261
TI  - Orbital leiomyoma: a case report.
AB  - PURPOSE: Leiomyoma is a benign tumor derived from smooth muscle, most frequently
      occurring in the uterus and gastrointestinal system. This report discusses
      clinical and pathologic findings in a 56-year-old man with orbital leiomyoma.
      METHODS: Case review. RESULTS: A lateral orbitotomy was performed.
      Immunohistochemical staining for actin and desmin was positive result. There was
      no evidence of recurrence during a two-year follow-up interval. CONCLUSIONS:
      Leiomyoma is a benign tumor of low incidence because there is little smooth
      muscle in the orbit. The differential diagnosis must include any fully
      encapsulated orbital tumor. Prognosis after surgical excision is favorable.

PMID- 10588262
TI  - Ectopic orbital meningioma: a case report and review.
AB  - PURPOSE: To describe a well-documented case of ectopic orbital meningioma, to
      review the literature on the subject, and to recommend treatment. METHODS:
      Neuroradiologic investigations were suggestive of orbital meningioma. The patient
      underwent total excision of the mass, which was subsequently examined by light
      microscopy and immunohistochemistry. RESULTS: The patient was diagnosed with
      ectopic orbital meningioma which was locally invasive. The tumor was surgically
      excised, and did not recur during a 42-month follow-up interval. CONCLUSIONS:
      Ectopic orbital meningiomas are rare tumors that develop from ectopic arachnoid
      tissue. Although locally invasive, the prognosis is favorable if the tumor is
      completely removed.

PMID- 10588263
TI  - Orbital Wegener granulomatosis without systemic findings.
AB  - PURPOSE: To describe a case of orbital Wegener granulomatosis without systemic
      disease. METHOD: Case report. RESULTS: A 69-year-old patient with bilateral
      inflammatory lacrimal gland masses underwent multiple biopsies that showed a
      nonspecific lymphoplasmacytic infiltrate consistent with orbital pseudotumor.
      After unsuccessful treatment with systemic corticosteroids and radiation, severe
      orbital disease rapidly progressed and the patient underwent unilateral
      enucleation. The enucleated specimen showed multifocal vasculitis, tissue
      necrosis, and granulomas consistent with Wegener granulomatosis (WG). Elevated
      antineutrophil cytoplasmic antibody titers supported the diagnosis of WG. The
      patient did not have any extraocular signs of WG and continues to be disease-free
      systemically. CONCLUSION: The authors believe this is the first report of
      bilateral lacrimal gland masses presenting as a localized form of WG in the total
      absence of systemic disease.

PMID- 10588264
TI  - Gamma probe localization of cranial bone lesions.
AB  - PURPOSE: Staging of cancer is essential to formulate appropriate treatment plans
      and to help predict prognosis. A solitary region of increased radionuclide uptake
      ("hot spot") on a bone scan may represent a metastasis or a masquerading lesion.
      Biopsy may be required to determine its histologic nature, but localization of
      the site may be difficult because bone scans provide poor spatial resolution.
      METHODS: In two patients with breast carcinoma, radioactive technetium was
      administered intravenously and a gamma probe was used preoperatively and
      intraoperatively to identify the site of cranial bone involvement. RESULTS: The
      lesions were resected; one was a benign fibro-osseous lesion and one was a
      metastatic breast adenocarcinoma. CONCLUSIONS: A gamma probe may be helpful in
      localizing the site of radioactive uptake identified by bone scan.

PMID- 10588265
TI  - Vesico-ureteric reflux in children. Proceedings of a state-of-the-art symposium.
      1997.

PMID- 10588266
TI  - Diagnosis of vesico-ureteric reflux.
AB  - The demonstration and grading of reflux is crucial in examination and follow-up
      of any child with upper urinary tract infection. A variety of factors can
      influence the occurrence of reflux, e.g. race, genetics, state of maturation of
      the ureterovesical valve, diuresis, infection and bladder dysfunction, including
      obstruction and neurogenic disorders. Even when reflux is investigated under
      strictly standardized conditions, two consecutive bladder fillings frequently
      show different grades of reflux. Voiding cystourethrography is, to date, the only
      method with a generally accepted, well-defined grading of reflux. It also allows
      detection of intrarenal reflux and anatomical and functional information about
      the bladder and urethra that is unobtainable by other methods. It is therefore
      usually considered the method of choice. Radionuclide cystography and, possibly,
      contrast enhanced ultrasonography can be complementary to voiding
      cystourethrography, but mainly for postoperative follow-up and screening of
      siblings.

PMID- 10588267
TI  - Imaging of renal scarring.
AB  - Children with urinary tract infection should be investigated and followed up, as
      those with pyelonephritis may develop renal scarring. In this review, after
      discussing the advantages and disadvantages of various imaging modalities for
      diagnosis of renal scarring, it is concluded that DMSA scintigraphy and urography
      can both be used to detect significant renal scarring. With DMSA scintigraphy,
      small renal lesions (functional uptake defects) not seen at urography will also
      be detected. The long-term clinical significance of these lesions is, as yet,
      unknown. A normal DMSA scintigraphy after infection indicates low risk for
      clinically significant damage. In order to allow acute, reversible lesions to
      first disappear, a follow-up DMSA examination should not be performed until at
      least 6 mo after the acute infection. Ultrasonography in isolation cannot be
      recommended for the diagnosis of renal scarring.

PMID- 10588268
TI  - Vesico-ureteric reflux: occurrence and long-term risks.
AB  - The prevalence of vesico-ureteric reflux in the general population is unknown,
      but it is increased in risk groups, such as children with symptomatic urinary
      tract infection, schoolgirls with asymptomatic bacteriuria, first-degree
      relatives of patients with reflux and children with prenatal dilatation of their
      upper urinary tract. Children and adults with pyelonephritic renal scarring are
      at risk of serious long-term complications, e.g. hypertension and renal failure.
      Modern paediatric care, with early detection and treatment of urinary tract
      infections and reflux during childhood and adolescence, may improve long-term
      prognosis. In the adult patient with established pyelonephritic renal scarring,
      careful control of hypertension may retard the rate of progression, and
      angiotensin converting enzyme inhibitors may have renal protective properties.

PMID- 10588269
TI  - Vesico-ureteric reflux and other risk factors for renal damage: identification of
      high- and low-risk children.
AB  - This article reviews the literature with respect to various risk factors for
      permanent renal damage in children with urinary tract infection. Vesico-ureteric
      reflux is an important risk factor, but renal damage can occur in the absence of
      reflux. Renal damage does not always occur in the presence of gross reflux. Renal
      scars always develop at the same site as a previous infection in the kidney.
      Recurrent pyelonephritis and delay in therapy increase the likelihood of renal
      damage, although it is not known how long a delay is dangerous to the human
      kidney. Recent studies using 99mtechnetium-dimercaptosuccinic acid (DMSA)
      scintigraphy have not confirmed the findings of previous studies showing that
      children below 1 y of age are more vulnerable to renal damage. It is more likely
      that all children run the risk of renal scarring in cases of acute
      pyelonephritis. The role of bladder pressure is still not entirely understood.
      Therefore more studies are needed in order to determine the relationship between
      high voiding pressures in some, otherwise healthy, children with urinary tract
      infection and renal scarring. The importance of bacterial virulence in the
      development of renal scarring is unclear. DMSA scintigraphy and voiding
      cystourethrography are the most reliable tools for identifying children at risk
      of renal scarring. As a single method DMSA scintigraphy appears to be better than
      voiding cystourethrography.

PMID- 10588270
TI  - Bladder dysfunction in children with vesico-ureteric reflux.
AB  - Vesico-ureteric reflux and non-neurogenic bladder dysfunction are closely
      related, although a causal relationship has been established only for severe
      forms of detrusor-sphincter dyscoordination. There are several urodynamic studies
      reporting high frequency of bladder instability and/or detrusor-sphincter
      dyscoordination in children with reflux. The latter includes an element of
      functional outflow obstruction and is the most serious, since it accompanies
      kidney damage. When instability is the only urodynamic abnormality damage is
      absent. There are indications that treatment of bladder dysfunction increases
      spontaneous resolution of reflux and, furthermore, that bladder dysfunction is a
      negative prognostic factor following antireflux surgery. Recently also, gross
      reflux in infant boys was seen to associate with bladder dysfunction in addition
      to earlier finding of congenital malformation of the ureterovesical junction.
      However, no comparisons have emerged on the outcome following treatment of
      bladder dysfunction and following observation only. In conclusion, children with
      reflux on chemoprophylaxis prior to reimplantation must always be assessed for
      bladder dysfunction. This is especially important when there are recurrent
      urinary tract infections.

PMID- 10588271
TI  - Antibacterial prophylaxis in children with urinary tract infection.
AB  - The aim, in conservative management of vesico-ureteric reflux by antimicrobial
      prophylaxis, is to prevent recurrent febrile urinary tract infections and
      consequent renal scarring. However, the effects of this prophylactic strategy are
      difficult to evaluate, since the required studies comparing children on
      prophylaxis with controls (without prophylaxis but under careful supervision) are
      lacking. Furthermore, the optimal length of prophylaxis needs to be defined.
      Since risk of renal scarring is believed to occur more frequently in young
      people, and since recurrent urinary infections mainly affect girls, the age and
      sex of subjects are important in the design of a prophylactic regimen.
      Nitrofurantoin and trimethoprim are the most common agents used for long-term,
      low-dose antibacterial prophylaxis. Break-through infections still result from
      non-compliance and from development of bacterial resistance, the latter mainly
      arising with trimethoprim. Few studies of prophylactic drugs are available that
      adequately define patient materials and include a random allocation to the
      different agents. Further studies of the effects of alternative prophylactic
      agents are called for, preferably combined with fresh insight into the ecological
      impact on the bowel and periurethral floras.

PMID- 10588272
TI  - Medical or surgical management for children with vesico-ureteric reflux?
AB  - A critical survey of the literature on treatment of children with vesico-ureteric
      reflux was carried out in order to create a basis for the new Swedish management
      policy. There are few studies that meet modern standards of scientific
      methodology and provide adequate patient numbers. The only large investigations
      that randomized patients to operative or non-operative treatment were the
      Birmingham Reflux Study and the International Reflux Study in Children. In these
      studies, long-term outcome of renal status and renal function, as well as the
      number of recurrent infections, were independent of treatment modality. Although
      pyelonephritic recurrences were less common in the surgically managed group, this
      did not influence appearance of renal damage. There is no evidence to indicate
      clear superiority of either medical or surgical management. Further studies are
      needed to address such questions as the optimal duration of antibacterial
      prophylaxis and the effect of a dilating reflux that persists into adulthood.

PMID- 10588273
TI  - Endoscopic treatment of children with vesico-ureteric reflux.
AB  - Endoscopic subureteric injection of tissue-augmenting substances has become an
      alternative to long-term antibiotic prophylaxis and open surgery in the treatment
      of children with vesico-ureteric reflux. Successful elimination of reflux in
      about 80% of patients after a single injection (and in 90% after a repeat) has
      been achieved using the foreign-body non-degradable substances Teflon and
      silicone. Few patients have required open surgery and recurrence of reflux after
      initial successful treatment has occurred in only 5-10%. Concern has arisen,
      however, about possible distant migration and granuloma formation after injection
      of particulate plastic materials. Cross-linked bovine collagen is a biodegradable
      alternative substance, but with a lower response rate of 60% after the first
      treatment and a recurrence rate of 10-20%. Dextranomer in sodium hyaluronan is a
      new biological substance with microparticles with a response rate of 69% after
      the first injection. Biological substances have caused few complications. Present
      literature on injection treatment unfortunately focuses on elimination of reflux,
      with little attention to subsequent frequency of pyelonephritis or to the long
      term development of the kidneys. Furthermore, there are no controlled, randomized
      studies with subureteric injection as one of the treatment alternatives. Thus,
      although having the advantage of being a minimally invasive procedure that can be
      performed on an outpatient basis, this technique needs to be tested in a large
      prospective study with the long-term renal outcome as the main end-point.

PMID- 10588274
TI  - Psychological reaction by children of various ages to hospital care and invasive
      procedures.
AB  - Hospital care and treatment by invasive procedures produce significant
      psychological effects on children. Urogenital surgery deserves particular study.
      The developmental aspects of different ages are highly relevant. A proposed
      multidimensional model of contributing factors includes type of medical
      treatment, any previous surgery, the child's temperament, coping strategies of
      both child and parents and their psychological health, support from parents and
      staff, information and psychological preparation and age of the child. Up to now,
      there have been no clear recommendations as to the best age for elective surgical
      procedures in children according to psychological risk. In general, older
      children adapt better psychologically after hospital care. The literature,
      however, tends to advise elective surgery before 12 mo of age, based on apparent
      psychological adjustment in the very young after surgery and from a desire to
      shorten the period of living with the malformation/disorder. However, increased
      follow-up surgery from early interventions gives a higher risk of psychological
      problems. More well-controlled studies are needed before final evaluation of the
      impact of surgical interventions on psycho-social symptoms according to age
      group. In this analysis a multidimensional model is preferred.

PMID- 10588275
TI  - Cost-analysis of management strategies for children with vesico-ureteric reflux.
AB  - This study is an economic evaluation of three treatment strategies for vesico
      ureteric reflux in children: neo-implantation; subureteric injection; and
      antibacterial prophylaxis. Cost-analysis was used to compare the strategies,
      implying that the differences in benefits between them were not measured. Direct
      and indirect costs are included, taking the analytical viewpoint of the
      community. For the surgical strategies, data from four different hospitals in
      Sweden were used, and for the prophylactic strategy, data was gathered through a
      survey of 31 hospitals. The treatment strategies were ranked in the following
      order (bilateral reflux in parentheses): (i) subureteric injection SEK 25,000
      28,000 (26,000-36,000); (ii) antibacterial prophylaxis SEK 16,000-36,000; and
      (iii) neo-implantation SEK 65,000-90,000 (72,000-95,000).

PMID- 10588276
TI  - Guidelines for management of children with urinary tract infection and vesico
      ureteric reflux. Recommendations from a Swedish state-of-the-art conference.
      Swedish Medical Research Council.
AB  - There are considerable variations in the management of children with urinary
      tract infection and reflux. These new guidelines were written after critical
      review of the literature, but are also based on clinical experience, since there
      are issues that have not been otherwise adequately studied. The aim is to limit
      renal damage and future complications, with minimal discomfort to the child, and
      to avoid unnecessary costs. The recommendations include increased attention to
      bladder dysfunction, shortening of the time of antibacterial prophylaxis and
      focus on renal development and function rather than on reflux.

PMID- 10588277
TI  - Dose calculations for external photon beams in radiotherapy.
AB  - Dose calculation methods for photon beams are reviewed in the context of
      radiation therapy treatment planning. Following introductory summaries on photon
      beam characteristics and clinical requirements on dose calculations, calculation
      methods are described in order of increasing explicitness of particle transport.
      The simplest are dose ratio factorizations limited to point dose estimates useful
      for checking other more general, but also more complex, approaches. Some methods
      incorporate detailed modelling of scatter dose through differentiation of
      measured data combined with various integration techniques. State-of-the-art
      methods based on point or pencil kernels, which are derived through Monte Carlo
      simulations, to characterize secondary particle transport are presented in some
      detail. Explicit particle transport methods, such as Monte Carlo, are briefly
      summarized. The extensive literature on beam characterization and handling of
      treatment head scatter is reviewed in the context of providing phase space data
      for kernel based and/or direct Monte Carlo dose calculations. Finally, a brief
      overview of inverse methods for optimization and dose reconstruction is provided.

PMID- 10588278
TI  - In vivo determination of the optical properties of muscle with time-resolved
      reflectance using a layered model.
AB  - We have investigated the possibility of determining the optical coefficients of
      muscle in the extremities with in vivo time-resolved reflectance measurements
      using a layered model. A solution of the diffusion equation for two layers was
      fitted to three-layered Monte Carlo calculations simulating the skin, the
      subcutaneous fat and the muscle. Relative time-resolved reflectance data at two
      distances were used to derive the optical coefficients of the layers. We found
      for skin and subcutaneous fat layer thicknesses (l2) of up to 10 mm that the
      estimated absorption coefficients of the second layer of the diffusion model have
      differences of less than 20% compared with those of the muscle layer of the Monte
      Carlo simulations if the thickness of the first layer of the diffusion model is
      also fitted. If l2 is known, the differences are less than 5%, whereas the use of
      a semi-infinite model delivers differences of up to 55%. Even if l2 is only
      approximately known the absorption coefficient of the muscle can be determined
      accurately. Experimentally, the time-resolved reflectance was measured on the
      forearms of volunteers at two distances from the incident beam by means of a
      streak camera. The thicknesses of the tissues involved were determined by
      ultrasound. The optical coefficients were derived from these measurements by
      applying the two-layered diffusion model, and results in accordance with the
      theoretical studies were observed.

PMID- 10588279
TI  - Optical tomographic reconstruction in a complex head model using a priori region
      boundary information.
AB  - In this paper we investigate the application of anatomical prior information to
      image reconstruction in optical tomography. We propose a two-stage reconstruction
      scheme. The first stage is a reconstruction into a low-dimensional region basis,
      obtained by segmentation of an image obtained by an independent imaging modality,
      into areas of distinct tissue types. The reconstruction into this basis recovers
      global averages of the optical tissue parameters of each region. The recovered
      distribution of region values provides the starting point for the second stage of
      the reconstruction into the spatially resolved final image basis. This second
      step recovers localized perturbations within the regions. The benefit of this
      method is the improved stability and faster convergence of the imaging process
      compared with a direct reconstruction into a spatially resolved basis. This is
      particularly important for the simultaneous reconstruction of absorption and
      scattering images, where ambiguities between the two parameters and the resulting
      problems of crosstalk require a good initial parameter distribution to ensure
      convergence of the reconstruction. We use a segmented brain model obtained from a
      magnetic resonance image as a test case to compare the performance of the two
      stage reconstruction and the direct reconstruction from a flat prior, and show
      that the former achieves superior results in the recovery of localized absorption
      and scattering hot spots embedded in the background tissue.

PMID- 10588280
TI  - Characterization of enzymatically induced degradation of articular cartilage
      using high frequency ultrasound.
AB  - Ultrasound may provide a quantitative technique for the characterization of
      cartilage changes typical of early osteoarthrosis. In this study, specific
      changes in bovine articular cartilage were induced using collagenase and
      chondroitinase ABC, enzymes that selectively degrade collagen fibril network and
      digest proteoglycans, respectively. Changes in cartilage structure and properties
      were quantified using high frequency ultrasound, microscopic analyses and
      mechanical indentation tests. The ultrasound reflection coefficient of the
      physiological saline-cartilage interface (R1) decreased significantly (-96.4%, p
      < 0.01) in the collagenase digested cartilage compared to controls. Also a
      significantly lower ultrasound velocity (-6.2%, p < 0.01) was revealed after
      collagenase digestion. After chondroitinase ABC digestion, a new acoustic
      interface at the depth of the enzyme penetration front was detected. Cartilage
      thickness, as determined with ultrasound, showed a high, linear correlation (R =
      0.943, n = 60, average difference 0.073 mm (4.0%)) with the thickness measured by
      the needle-probe method. Both enzymes induced a significant decrease in the
      Young's modulus of cartilage (p < 0.01). Our results indicate that high frequency
      ultrasound provides a sensitive technique for the analysis of cartilage structure
      and properties. Possibly ultrasound may be utilized in vivo as a quantitative
      probe during arthroscopy.

PMID- 10588281
TI  - An application of GafChromic MD-55 film for 67.5 MeV clinical proton beam
      dosimetry.
AB  - The purpose of this study is to explore the use of GafChromic MD-55 (RC) film for
      67.5 MeV clinical proton beam dosimetry at the Crocker Nuclear Laboratory,
      University of California, Davis. Several strips of RC film 6 cm x 6 cm in
      dimension were irradiated at a depth of 18.2 mm corresponding to the middle of a
      24 mm spread-out Bragg peak (SOBP). The films were irradiated to a proton dose in
      the range of 0.5 Gy to 100 Gy. The beam profiles were also measured at the middle
      of the 24 mm SOBP. The Bragg peak was measured by using a wedge shaped phantom
      made of Lucite. The Bragg peak measured with RC film was compared with diode and
      ionization chamber measurements. After background subtraction, the calibration of
      the dose response of RC film showed, to a maximum deviation of 10%, a linear
      increase of optical density (OD) with dose from 0.5 to 100 Gy. The uniformity of
      OD over a single sheet of film showed a variation of +/-6%. The distal-fall off
      between 90% and 20% measured with GafChromic film for the Bragg peak was 1.3 mm
      as compared to 1.1 mm for a diode measurement and 1.4 mm for an ionization
      chamber measurement. The FWHM of the Bragg peak was 7.5 mm when measured with
      GafChromic film, 5.3 mm when measured with a diode and 8.1 mm as measured by an
      ionization chamber. The peak/plateau ratio with GafChromic film was 3.3 as
      compared to 3.7 with a diode and 3.2 with an ionization chamber. In conclusion,
      GafChromic MD-55 film may be a useful and convenient detector for dose
      measurement and quality assurance programmes of proton beams.

PMID- 10588282
TI  - Study on the propagation of ultra-short pulse light in cylindrical optical
      phantoms.
AB  - A detailed study about ultra-short pulse light propagation inside cylindrical
      scattering and absorbing phantoms is presented. Some comparisons between a Monte
      Carlo code and the analytical solution of diffusion equation for a delta(t)
      source and point-like detectors placed at different angles of detection are
      shown. To better quantify the agreement between the temporal profiles obtained
      from the two different methods of calculation, a fitting procedure based on the
      Levenberg-Marquardt algorithm has been implemented. Some examples on the
      retrieval of the optical properties for both the Monte Carlo and experimental
      data are presented. In the case of inhomogeneous cylindrical phantoms, some
      comparisons between the results of the time-domain 3D model of finite element
      method and 3D Monte Carlo are also shown.

PMID- 10588283
TI  - Design and construction of a ripple filter for a smoothed depth dose distribution
      in conformal particle therapy.
AB  - The ripple filter was designed to broaden the Bragg maximum of carbon beams for
      the raster-scan technique, a special type of tumour-conformal ion beam treatment.
      In this technique the target volume is divided into individual layers that are
      treated sequentially by varying the energy from the accelerator stepwise. Because
      the unmodified Bragg maximum has a small half-width, below 1 mm for small
      energies (< 160 MeV u(-1)), homogeneous irradiation at small penetration depths
      of 2-6 cm can only be obtained by using a large number of energy steps. If the
      energy step is too large, ripples are produced in the superimposed depth dose
      distribution. The ripple filter widens a Bragg peak to a Gaussian peak with a
      half-width of more than 2 mm. This helps to smooth the extended Bragg peak and to
      reduce the number of energy steps required by a factor of two to three, leading
      to significantly shorter overall irradiation times and a higher particle fluence
      per layer. The ripple filter consists of a 2 mm thick Plexiglass (PMMA) plate
      with a periodic structure of fine grooves. It can be mounted 60 cm upstream of
      the patient as a stationary device, because the fine structure of the grooves is
      completely washed out by the lateral scattering of the beam.

PMID- 10588284
TI  - Analytic characterization of linear accelerator radiosurgery dose distributions
      for fast optimization.
AB  - Linear accelerator (linac) radiosurgery utilizes non-coplanar arc therapy
      delivered through circular collimators. Generally, spherically symmetric arc sets
      are used, resulting in nominally spherical dose distributions. Various treatment
      planning parameters may be manipulated to provide dose conformation to irregular
      lesions. Iterative manipulation of these variables can be a difficult and time
      consuming task, because (a) understanding the effect of these parameters is
      complicated and (b) three-dimensional (3D) dose calculations are computationally
      expensive. This manipulation can be simplified, however, because the prescription
      isodose surface for all single isocentre distributions can be approximated by
      conic sections. In this study, the effects of treatment planning parameter
      manipulation on the dimensions of the treatment isodose surface were determined
      empirically. These dimensions were then fitted to analytic functions, assuming
      that the dose distributions were characterized as conic sections. These analytic
      functions allowed real-time approximation of the 3D isodose surface. Iterative
      plan optimization, either manual or automated, is achieved more efficiently using
      this real time approximation of the dose matrix. Subsequent to iterative plan
      optimization, the analytic function is related back to the appropriate plan
      parameters, and the dose distribution is determined using conventional dosimetry
      calculations. This provides a pseudo-inverse approach to radiosurgery
      optimization, based solely on geometric considerations.

PMID- 10588285
TI  - Dosimetry techniques for narrow proton beam radiosurgery.
AB  - Characterization of narrow beams used in proton stereotactic radiosurgery (PSRS)
      requires special efforts, since the use of finite size detectors can lead to
      distortion of the measured dose distributions. Central axis depth doses, lateral
      profiles and field size dependence factors are the most important beam
      characteristics to be determined prior to dosimetry calculations and beam
      modelling for PSRS. In this paper we report recommendations for practical
      dosimetry techniques which were developed from a comparison of beam
      characteristics determined with a variety of radiation detectors for 126 and 155
      MeV narrow proton beams shaped with 2-30 mm circular brass collimators. These
      detectors included small-volume ionization chambers, a diamond detector, an Hi-p
      Si diode, TLD cubes, radiographic and radiochromic films. We found that both
      types of film are suitable for profile measurements in narrow beams. Good
      agreement between depth dose distributions measured with ionization chambers,
      diamond and diode detectors was demonstrated in beams with diameters of 20-30 mm.
      The diode detector can be used in smaller beams, down to 5 mm diameter. For beams
      with diameters less than 5 mm, reliable depth dose data may be obtained only with
      radiochromic film. The tested ionization chambers are appropriate for calibration
      of beams with diameters of 20-30 mm. TLD cubes and diamond detectors are useful
      to determine relative dose in beams with diameters of 10-20 mm. Field size
      factors for smaller beams should be obtained with diode and radiochromic film. We
      conclude that dosimetry characterization of proton beams down to several
      millimetres in diameter can be performed using the described procedures.

PMID- 10588286
TI  - On the initial angular variances of clinical electron beams.
AB  - Electron beam radiotherapy treatment planning systems need to be fed with the
      characteristics of the high-energy electron beams (4-50 MeV) from the
      specifically applied accelerator. Beams can be characterized by their mean
      initial energy, effective initial angular variance, virtual source position and
      the resulting central axis depth dose distribution in water. This information is
      the only input to pencil beam dose calculation models. Newer calculation models
      like macro Monte Carlo, voxel Monte Carlo and phase space evolution require as
      input the full initial phase space or a parametrization of that initial phase
      space, generally consisting of a primary beam component and one or more scatter
      components. This primary beam component is often characterized by initial energy,
      primary beam initial angular variance and virtual source distance. The purpose of
      the present investigation was to investigate to what extent standard values can
      be used both for the effective initial angular variance as input to pencil beam
      models and for the primary beam initial angular variance. Comprehensive benchmark
      data were obtained on the initial angular variance of various types of
      accelerator, for various energies and field sizes. The initial angular variance
      sigma2theta(x) has been derived from penumbra measurements in air by means of
      film dosimetry at various distances from the lower collimator. For the types of
      accelerator used in radiotherapy nowadays the measurements show values for
      sigma2theta(x)/T(E) of around 13 cm where T(E) is the ICRU-35 linear angular
      scattering power in air. This value can be chosen as standard value for the
      primary beam initial angular variance, only slightly compromising the dose
      calculation accuracy. As input to pencil beam models, an effective
      sigma2theta(x)/T(E) should be used incorporating the scatter from the lower
      collimator. For the case that the air gaps between lower collimator and patient
      are small (5-10 cm) an effective sigma2theata(x)/T(E) of 20 cm has been found and
      is recommended as the standard input for pencil beam models. Of the accelerators
      investigated, a different value was found only for the Elekta SL15, i.e. 50%
      higher for the effective sigma2theta(x)/T(E).

PMID- 10588287
TI  - Experimental comparison of data transformation procedures for analysis of
      principal components.
AB  - Results of principal component analysis depend on data scaling. Recently, based
      on theoretical considerations, several data transformation procedures have been
      suggested in order to improve the performance of principal component analysis of
      image data with respect to the optimum separation of signal and noise. The aim of
      this study was to test some of those suggestions, and to compare several
      procedures for data transformation in analysis of principal components
      experimentally. The experiment was performed with simulated data and the
      performance of individual procedures was compared using the non-parametric
      Friedman's test. The optimum scaling found was that which unifies the variance of
      noise in the observed images. In data with a Poisson distribution, the optimum
      scaling was the norm used in correspondence analysis. Scaling mainly affected the
      definition of the signal space. Once the dimension of the signal space was known,
      the differences in error of data and signal reproduction were small. The choice
      of data transformation depends on the amount of available prior knowledge (level
      of noise in individual images, number of components, etc), on the type of noise
      distribution (Gaussian, uniform, Poisson, other), and on the purpose of analysis
      (data compression, filtration, feature extraction).

PMID- 10588288
TI  - Ordered subsets algorithms for transmission tomography.
AB  - The ordered subsets EM (OSEM) algorithm has enjoyed considerable interest for
      emission image reconstruction due to its acceleration of the original EM
      algorithm and ease of programming. The transmission EM reconstruction algorithm
      converges very slowly and is not used in practice. In this paper, we introduce a
      simultaneous update algorithm called separable paraboloidal surrogates (SPS) that
      converges much faster than the transmission EM algorithm. Furthermore, unlike the
      'convex algorithm' for transmission tomography, the proposed algorithm is
      monotonic even with nonzero background counts. We demonstrate that the ordered
      subsets principle can also be applied to the new SPS algorithm for transmission
      tomography to accelerate 'convergence', albeit with similar sacrifice of global
      convergence properties as for OSEM. We implemented and evaluated this ordered
      subsets transmission (OSTR) algorithm. The results indicate that the OSTR
      algorithm speeds up the increase in the objective function by roughly the number
      of subsets in the early iterates when compared to the ordinary SPS algorithm. We
      compute mean square errors and segmentation errors for different methods and show
      that OSTR is superior to OSEM applied to the logarithm of the transmission data.
      However, penalized-likelihood reconstructions yield the best quality images among
      all other methods tested.

PMID- 10588289
TI  - Phase contrast enhancement of x-ray mammography: a design study.
AB  - This paper explores the application to mammography of phase contrast produced by
      variations in x-ray refractive index. As a spatially coherent x-ray beam
      propagates through an x-ray transparent medium, the phase of the incident
      wavefront becomes modified in a manner related to the electron density of the
      medium. The resulting phase gradient across the wavefront is equivalent to a
      small change in direction of the propagation of the wave. For a general object,
      the change in propagation direction will vary from point to point depending on
      the structures within the object. The net effect can be recorded in a
      radiographic image using an appropriate geometry to produce the visual appearance
      of edge enhancement at interfaces between materials with differing x-ray
      refractive indices. Normally these materials will also have differences in
      attenuation coefficient, so the overall effect is to increase the visibility of
      interfaces between materials. It is proposed that mammographic images can be
      subtly enhanced by the use of phase contrast information to overcome some of the
      known limitations of the imaging process whilst leaving the gross radiological
      appearance of the images substantially unchanged. The design trade-offs required
      to utilize phase contrast information were investigated using a conventional
      mammographic x-ray generator and film-screen system. The Leeds TORMAM
      mammographic image quality test object was then used to demonstrate a
      considerable improvement in image quality for the phase contrast enhanced images
      over those produced in the conventional geometry with no increase in radiation
      dose to the patient. The results are discussed in terms of their possible
      practical application.

PMID- 10588290
TI  - 1D dynamic beam modulation: methods to counteract inertia effects.
AB  - Dynamic modulation can be affected by inaccuracies when the required acceleration
      is larger than the highest allowed by the mechanical characteristics of the whole
      apparatus. In this study, inertia effects have been investigated with regard to
      the single absorber 1D modulation, analysing primarily how the acceleration
      performed by the modulating system affects the realization of 'single absorber'
      fluence profiles and the type of correction which could be devised. The observed
      percentage deviations from desired modulation at the lowest fluence coordinate of
      single minimum fluence profiles, when no correction is applied, were almost
      negligible for 'easy' modulations of the incident fluence (i.e. slow gradients);
      deviations became increasingly relevant as the moving absorber executed steeper
      gradients (a 17.6% higher dose being delivered in the minimum position when a 0.2
      modulation is required). By applying the proposed corrections, the single
      absorber performances were improved to a satisfactory level, with a maximum
      deviation from desired modulation in the minima within 1.6%.

PMID- 10588291
TI  - Uncertainty analysis in polymer gel dosimetry.
AB  - Verification of advanced radiotherapy treatment modalities requires measurement
      of three-dimensional absorbed dose distributions with high spatial resolution and
      precision. Polymer gel dosimeters combined with magnetic resonance imaging may be
      able to fulfil this requirement. However, verification requires that the
      uncertainty in the dosimeter is well known. One method of estimating the overall
      uncertainty in polymer gel dosimeters involves the propagation of the uncertainty
      in the R2 (nuclear magnetic resonance relaxation rate) map and the uncertainties
      in the calibration data. This work shows that using this method with current data
      suggests that the lowest uncertainty currently obtainable is about 3% at 8 Gy and
      7% at 2 Gy. Furthermore, the most significant reductions in overall uncertainty
      will be achieved by reducing the noise in the R2 map.

PMID- 10588292
TI  - The procedure of new drug application and the philosophy of critical rationalism
      or the limits of quality assurance with good clinical practice.
AB  - K.R. Popper's philosophy of critical rationalism is concerned with the detection
      and removal of error. Fundamental contradictions exist between Popper's theory of
      knowledge and the present-day practice of the clinical investigation of new
      drugs. Currently, the public authorities concerned with the licensing of drugs
      pass judgment on trials, which are closely linked by the one-sponsor problem: the
      assertions made by the sponsor are not independently confirmed. This lack leads
      to excessive documentation and to costly monitoring and auditing, which are
      intended to ensure the credibility of results. In Popper's view, confirmatory
      trials, independent of the sponsor and supervised by the regulatory bodies, would
      be a better way to achieve reliable knowledge. The consequence would, among other
      things, be a reorganization of phase III of the clinical investigation of new
      drugs by dividing it into independent parts, one under the control of the sponsor
      and one under the control of the public authority. The implementation of this
      suggestion would lead to a more scientific manner of dealing with new drugs and
      to savings in terms of unproductive measures during the application process.

PMID- 10588293
TI  - Statistical quality control in clinical trials.
AB  - We propose to apply statistical methods of industrial process and quality control
      to accumulating data in a statistical monitoring center of a clinical trial. We
      discuss some specific issues connected with the application of these methods over
      calendar time to patients' characteristics (at a particular individual patient
      time) or to more formal monitoring characteristics (like the number of queries
      per case record form). The tools used are Shewart charts, plots, breakpoint
      regression, and recursive residuals with cusums and V-charts, applied to
      measurement and event data. A software program based on SAS macros allows easy
      application of the methods. Some examples, with graphical outputs, from an
      ongoing trial on patients with primary malignant melanoma, illustrate the
      methods.

PMID- 10588294
TI  - Practical properties of some structural mean analyses of the effect of compliance
      in randomized trials.
AB  - We can use the structural mean model (SMM) to estimate the mean effect of dose
      timing patterns of active treatment actually taken by patients in a randomized
      placebo-controlled trial. An SMM therefore models the expected difference between
      a patient's potential response on the treatment arm and potential response on the
      placebo arm as a function of observed compliance on the treatment arm and
      baseline predictors. It accounts for the possibly selective nature of
      noncompliance without needing to model that aspect directly. It nevertheless
      enjoys the intention-to-treat property of protecting the alpha level when we are
      testing the hypothesis of no treatment effect. In the presence of selective
      compliance, classical regression methods lead to inconsistent and seriously
      biased estimates of the effects of treatment actually taken. The SMM is designed
      to reduce these problems. This paper studies selectivity and addresses some
      practical properties of the SMM estimator. Specifically, we use a blood pressure
      trial to explore the precision of the estimates in practical cases. We also
      compare mean squared errors (MSEs) of an SMM and the ordinary least-squares (OLS)
      estimator. We study the effect of baseline covariates on the precision of the SMM
      estimator and describe the potential role of a run-in period in this regard.

PMID- 10588295
TI  - Sample-size calculation for a log-transformed outcome measure.
AB  - The outcome measure of interest in clinical trials sometimes requires
      transformation to the logarithmic scale for analysis. This paper examines sample
      size calculation for both independent groups and matched-pairs trials for log
      transformed outcomes. For both types of trial, we demonstrate how the calculation
      can be formulated in terms of a relative treatment effect and a statement of
      relative variability, both specified on the original scale of measurement. For a
      comparison of two independent groups, the relative treatment effect is the ratio
      of group geometric means (or alternatively, group arithmetic means) and the
      coefficient of variation is used as a summary of relative variability. For a
      matched-pairs comparison, the appropriate relative treatment effect is the
      geometric mean of the within-pair ratios, and relative variability can be
      specified as an upper bound on within-pair ratios under a null hypothesis of the
      relative effect being equal to 1 (i.e., no difference). We discuss the clinical
      study that motivated this work and demonstrate the application of the sample-size
      calculation to this study.

PMID- 10588296
TI  - A modification of Simon's optimal design for phase II trials when the criterion
      is median sample size.
AB  - We present a modification to Simon's optimal design for phase II trials in which
      the objective is to minimize the median sample size rather than the expected
      sample size when the true response rate is poor (p = p0). We argue that the
      modified design may be preferred in smaller institutions when the focus is on a
      single or small number of phase II trials rather than a large program of phase II
      trials.

PMID- 10588297
TI  - Confirmatory trials--a new approach?

PMID- 10588298
TI  - A note on Zelen randomization: attitudes of parents participating in a neonatal
      clinical trial.

PMID- 10588300
TI  - A multicenter, randomized trial of percutaneous coronary intervention versus
      bypass surgery in high-risk unstable angina patients. The AWESOME (Veterans
      Affairs Cooperative Study #385, angina with extremely serious operative mortality
      evaluation) investigators from the Cooperative Studies Program of the Department
      of Veterans Affairs.
AB  - This multicenter, prospective randomized trial was designed to test the
      hypotheses that percutaneous coronary intervention (PCI) is a safe and effective
      alternative to coronary artery bypass grafting (CABG) for patients with
      refractory ischemia and high risk of adverse outcomes. As a comparison of
      revascularization strategies, the trial specifically allows surgeons and
      interventionists to use new techniques as they become clinically available. After
      42 months of this 72-month trial, 17,624 patients have been screened and 2022 met
      eligibility requirements: 341 have been randomized to either CABG or PCI, and the
      remaining 1681 are being prospectively followed in a registry. The 3-year overall
      survival of patients in the registry and randomized trial is comparable. To
      enhance accrual into the randomized trial, site visits were conducted, a few low
      accruing hospitals were put on probation and/or replaced, eligibility criteria
      were reviewed at annual meetings of investigators, and the accrual period was
      extended by 1 year. These data demonstrate that a prospective randomized trial
      and registry of coronary revascularization for medically refractory high-risk
      patients is feasible.

PMID- 10588299
TI  - The Age-Related Eye Disease Study (AREDS): design implications. AREDS report no.
      1.
AB  - The Age-Related Eye Disease Study (AREDS) was initially conceived as a long-term
      multicenter, prospective study of the clinical course of age-related macular
      degeneration (AMD) and age-related cataract. Data on progression rates and risk
      factors from the study will increase understanding of the clinical course of both
      conditions, generate hypotheses about etiology, and aid in the design of clinical
      trials of potential interventions. In addition to collecting natural history
      data, AREDS includes a clinical trial of high-dose vitamin and mineral
      supplements for AMD and a clinical trial of high-dose vitamin supplements for
      cataract. The clinical trials were initiated largely because of the widespread
      public use in the United States of commercially available pharmacologic doses of
      vitamins and minerals to treat these two eye conditions and the absence of
      definitive studies on the safety and efficacy of their use. Important design
      issues for the clinical trials include: defining cataract and AMD, estimating
      event rates, determining the type and dosage of vitamins and minerals to be
      tested for each condition, and identifying the parameters necessary for
      monitoring safety and efficacy. This paper describes the AREDS design, including
      the study rationale and operational structure, and the approach adopted to
      combine, for two diseases, clinical trials with a natural history study.

PMID- 10588301
TI  - Will pneumococci put quinolones in their place?

PMID- 10588302
TI  - The use of fluconazole and itraconazole in the treatment of Candida albicans
      infections: a review.
AB  - Candida albicans is responsible for most fungal infections in humans. Fluconazole
      is well established as a first-line management option for the treatment and
      prophylaxis of localized and systemic C. albicans infections. Fluconazole
      exhibits predictable pharmacokinetics and is effective, well tolerated and
      suitable for use in most patients with C. albicans infections, including
      children, the elderly and those with impaired immunity. Prophylactic
      administration of fluconazole can help to prevent fungal infections in patients
      receiving cytotoxic cancer therapy. The increasing use of fluconazole for the
      long-term prophylaxis and treatment of recurrent oral candidosis in AIDS patients
      has led to the emergence of C. albicans infections that are not responsive to
      conventional doses. Second-line therapy with a wider spectrum antifungal, such as
      itraconazole, should be sought if treatment with fluconazole fails. A solution
      formulation of itraconazole has recently been introduced to overcome the poor and
      variable absorption of its original capsule formulation. Efficacy and
      tolerability studies in HIV-positive or immunocompromised patients with C.
      albicans infections have shown that, although itraconazole solution is as
      effective as fluconazole, it is less well tolerated as first-line therapy.
      Itraconazole solution can be effective in AIDS patients with C. albicans
      infections that are non-responsive to fluconazole. No efficacy or tolerability
      data are available on the use of itraconazole solution in children or the
      elderly.

PMID- 10588303
TI  - Gradient plate method to induce Streptococcus pyogenes resistance.
AB  - In recent years, increasing numbers of Streptococcus pyogenes (GAS) strains
      displaying resistance to macrolides have been reported in Finland, Japan, Asia
      and Spain. Antibiotic use has been shown to be a risk factor for infection with
      and carriage of drug-resistant streptococci. The aim of this study was to compare
      in-vitro development of resistance of streptococci to beta-lactams (penicillin,
      amoxycillin, cefotiam and cefuroxime) and erythromycin by serial passages in
      subinhibitory concentrations of antibiotics (subMICs) by gradient plate method.
      Three clinical strains of GAS were tested. Two were susceptible to erythromycin
      (MIC = 0.015 mg/L and 0.013 mg/L) and one resistant. Serial passages were
      performed daily by gradient plate method until a four-fold increase of the MIC
      was achieved. GAS variants obtained after serial passages in beta-lactams had
      MICs increased at least four-fold. They remained susceptible to these
      antibiotics. With erythromycin, final MICs reached intermediate and resistant
      level. Results obtained in this study with erythromycin are in good correlation
      with clinical studies showing that prior exposure to macrolides may help to
      facilitate the emergence of drug-resistant strains of streptococci.

PMID- 10588304
TI  - In-vitro activity of HMR 3647 against Streptococcus pneumoniae, Haemophilus
      influenzae, Moraxella catarrhalis and beta-haemolytic streptococci.
AB  - The in-vitro activity of HMR 3647 and seven comparators (azithromycin,
      clarithromycin, erythromycin A, roxithromycin, penicillin G, ciprofloxacin and
      levofloxacin) were tested against 207 Streptococcus pneumoniae and 200 beta
      haemolytic streptococci. Ten comparators (azithromycin, clarithromycin,
      erythromycin A, roxithromycin, ampicillin, co-amoxiclav, cefuroxime, cefotaxime,
      ciprofloxacin and levofloxacin) were tested against 143 Haemophilus influenzae
      and 58 Moraxella catarrhalis. The MIC50 of HMR 3647 for S. pneumoniae was < or
      =0.008 mg/L, less than that for the macrolides or quinolones tested. Pneumococci
      with an erythromycin A MIC of 0.06 mg/L (n = 23) had an MIC50 of HMR 3647 < or
      =0.008 mg/L, whereas isolates with an erythromycin A MIC > or =1 mg/L (n = 34)
      had an MIC50 of HMR 3647 of 0.03 mg/L, a four-fold increase. In contrast, the
      difference in macrolide MIC50s for the two groups was > or =64-fold. The MIC50s
      foro beta-haemolytic streptococci, classified by Lancefield group, were in the
      range 0.015 to 0.06 mg/L for HMR 3647. H. influenzae were categorized into three
      groups according to cefuroxime MIC: <1 mg/L (n = 72); 2-4 mg/L (n = 29); and >4
      mg/L (n = 42). The MIC50 of HMR 3647 increased two-fold with increasing
      cefuroxime MICs; beta-lactam MICs increased much more markedly. The MIC50 of HMR
      3647 for M. catarrhalis was 0.03 mg/L. HMR 3647 has good activity against
      respiratory tract pathogens but in-vitro susceptibility is affected by
      erythromycin A susceptibility in S. pneumoniae and beta-haemolytic streptococci.

PMID- 10588305
TI  - Combined effects of vancomycin and imipenem against methicillin-resistant
      Staphylococcus aureus (MRSA) in vitro and in vivo.
AB  - Infectious disease caused by methicillin-resistant Staphylococcus aureus (MRSA)
      often develops in compromised hosts in whom a single administration of vancomycin
      is usually not effective. We assessed the combined antimicrobial effects of
      vancomycin and imipenem against MRSA growth in vitro as well as in vivo using a
      neutropenic mouse thigh infection model. Synergic and additive effects of the two
      drugs were observed for 34 and two, respectively, of the 36 clinical isolates of
      MRSA, as determined by the chequerboard method. For MRSA strain N, postantibiotic
      effect (PAE) values obtained in vitro were 1.9-2.6 h for vancomycin and 2.6-3.5 h
      for imipenem, while higher values of 2.7-4.4 h were obtained for the combination
      of vancomycin and imipenem. In vivo, a single administration of vancomycin at 1
      or 2 mg/kg or of imipenem/cilastatin at 5 mg/kg produced growth curves similar to
      those in controls, with a suppressive time of 0 h. Imipenem/cilastatin at 10
      mg/kg demonstrated a suppressive time of 3.1 h. Combinations of vancomycin 1
      mg/kg plus imipenem/cilastatin 5 mg/kg, vancomycin 1 mg/kg plus
      imipenem/cilastatin 10 mg/k and vancomycin 2 mg/kg plus imipenem/cilastatin 10
      mg/kg demonstrated suppressive times of 2.9, 3.9 and 5.2 h, respectively,
      indicating that combined administration was effective. Simultaneous
      administration of the two drugs was more effective than sequential
      administration. Thus, combined administration of vancomycin and
      imipenem/cilastatin proved effective for MRSA in vivo. The combined effects
      seemed to be synergic, since a single administration of either drug did not show
      anti-MRSA effects at the doses used in the combined regimen.

PMID- 10588306
TI  - Macrolide resistance mechanisms and expression of phenotypes among Streptococcus
      pneumoniae circulating in Italy.
AB  - In Italy, macrolide-resistant pneumococci have been isolated at a rate increasing
      from 6% in 1993 to 31.7% in 1998. A collection of 161 erythromycin-resistant
      Streptococcus pneumoniae recovered between 1993 and 1997 has now been
      phenotypically and genotypically characterized. Approximately 90% of these
      microorganisms possessed a constitutive MLS(B) mechanism of resistance. PCR
      detected ermB and mefE genes in strains showing MLS(B) and M phenotypes,
      respectively. Using pulsed-field gel electrophoresis of chromosomal DNA, one
      dominant restriction profile and its variations were detected in 51 S. pneumoniae
      isolates collected from different locations, indicating the circulation of a
      clone characterized by the possession of a great ability to spread.

PMID- 10588307
TI  - Amoxycillin/clavulanic acid combinations increase transmigration of leucocytes
      through endothelial cell monolayers: endothelial cells play a key role.
AB  - Postoperative inflammation is still viewed as an unresolved problem. During
      inflammation, leucocytes play a tremendous role and migrate from intravascular
      spaces into the tissue to attack microorganisms. Different agents, e.g.
      anaesthetic drugs, are able to influence leucocyte recruitment. Previous studies
      have investigated the influence of amoxycillin on chemotaxis of leucocytes alone.
      The aim of our study was to examine the effect of amoxycillin/clavulanic acid (co
      amoxiclav) on leucocyte migration through endothelial cell monolayers (ECMs).
      Human umbilical endothelial cells were cultured on microporous membranes,
      achieving a monolayer. Polymorphonuclear neutrophil leucocytes (PMNLs) were used
      in a migration assay. The numbers of untreated PMNLs migrating through untreated
      ECMs were used as control and set as 100%. PMNLs and/or ECMs were pretreated with
      co-amoxiclav using clinically relevant as well as higher and lower
      concentrations. Co-amoxiclav was able to increase PMNL migration through ECMs
      significantly (P<0.05) when both cell types were treated (291+/-18.7%). When
      PMNLs or ECMs were treated alone, it could be shown that ECMs were more affected
      than PMNLs. The greatest effect was shown when both cell types, PMNLs and ECMs,
      were treated. In conclusion, co-amoxiclav was identified as a potent drug to
      increase leucocyte transmigration through ECMs. ECMs were also critically
      involved. Co-amoxiclav also affects endothelial cells.

PMID- 10588308
TI  - Cephalosporin clinical concentration-time profile modelling and in-vitro
      bactericidal effects on Escherichia coli.
AB  - We assessed the cephalosporin concentration-time curve area (AUC), peak
      concentration, maintained concentration and duration of exposure on in-vitro
      bactericidal effects on Escherichia coli NCTC 10418, using exposures modelling
      cephazolin clinical profiles after 1 g and 2 g i.m. injection, equal AUC
      exposures (288 mg x h/L, 576 mg x h/L; 48 h) and constant exposures to 6, 12 and
      24 mg/L. Cephalosporin dosage exposures based on maintenance of concentrations at
      multiples (6-24 times) of the MIC were not as effective in early or sustained (24
      h) bactericidal effect as exposures modelling im injection profiles with equal or
      lower AUC (P<0.05, ANOVA). Similar results applied to i.m. comparisons with equal
      AUC exposures modelling extremes of concentration and time exposures. These
      results indicate a need for intermittent dosage to produce optimally effective
      profiles, and raise the possibility that these optimum dosing profiles may allow
      an extension of minimum interdose intervals beyond 8 h.

PMID- 10588309
TI  - Protective effect of trovafloxacin, ciprofloxacin and ampicillin against
      Streptococcus pneumoniae in a murine sepsis model.
AB  - Trovafloxacin is a new fluoroquinolone that has potent microbiological activity
      against the pneumococcus, including penicillin-resistant strains. To evaluate the
      protective effect of trovafloxacin, ciprofloxacin and ampicillin against
      penicillin-susceptible, -intermediate and -resistant strains of Streptococcus
      pneumoniae, an intraperitoneal, immunocompetent mouse model of sepsis was used.
      The minimum lethal dose (MLD) for each isolate was determined in duplicate. A
      single sc dose of each antibiotic was administered over a wide range of doses 1 h
      after the ip inoculation of the test isolate at the MLD. The assessment of the
      protective dose for 50% of the population (PD50) for each antimicrobial/bacteria
      combination was performed in triplicate and the PD50 value was calculated at the
      end of 5 days. Results showed that trovafloxacin provided PD50 values that were
      significantly lower than those of ciprofloxacin for all isolates. For the
      penicillin-susceptible and -intermediate isolates, the PD50 values of ampicillin
      were significantly lower than those for either of the fluoroquinolones studied;
      however, trovafloxacin was statistically superior to both ciprofloxacin and
      ampicillin against the penicillin-resistant strain. Therefore, regardless of
      penicillin susceptibility, trovafloxacin has potent activity against
      Streptococcus pneumoniae and may be a viable alternative for the treatment of
      penicillin-resistant isolates.

PMID- 10588310
TI  - Aminoglycoside resistance in Gram-negative blood isolates from various hospitals
      in Belgium and the Grand Duchy of Luxembourg. Aminoglycoside Resistance Study
      Group.
AB  - A total of 1102 consecutive clinical blood isolates, including 897
      Enterobacteriaceae and 205 non-fermenting bacilli, were obtained from 13
      university and university-affiliated hospitals, which were divided into a
      Northern and a Southern group. Resistance to gentamicin, tobramycin, netilmicin,
      amikacin and isepamicin was determined using a microdilution technique according
      to NCCLS procedures. The overall mean resistance level was 5.9% for gentamicin,
      7.7% for tobramycin, 7.5% for netilmicin, 2.8% for amikacin and 1.2% for
      isepamicin. Resistance to amikacin and isepamicin was significantly higher in the
      Northern hospitals than in the Southern hospitals. In total, 157 isolates were
      found not to be susceptible to aminoglycosides. By PCR, 179 aminoglycoside
      resistance mechanisms, i.e. 150 genes encoding modifying enzymes and 29
      permeability mechanisms, were detected in 148 isolates. A resistance mechanism
      could not be detected in nine isolates. Moreover, in a further 14 isolates the
      resistance profile was not fully explained by the detected genes. The aac(6')-I
      genes were found to be the most predominant resistance mechanism in both the
      Northern and Southern isolates, followed by aac(3) genes and permeability
      resistance. A total of 29 non-susceptible isolates harboured a combination of
      genes, 72.4% of which were a combination with the aac(6')-lb gene. The majority
      of these combinations were broad-spectrum combinations which represented 9.0% of
      the resistance mechanisms in non-susceptible Enterobacteriaceae and 19.3% in the
      non-fermenting bacilli.

PMID- 10588311
TI  - Concurrent outbreaks of extended-spectrum beta-lactamase-producing organisms of
      the family Enterobacteriaceae in a Warsaw hospital.
AB  - The increasing use of broader-spectrum cephalosporins in the first half of the
      1990s has become one of the major factors responsible for the high rate of
      selection of extended-spectrum beta-lactamase (ESBL)-producing microorganisms in
      Polish hospitals. Thirty-five isolates of seven different species of the family
      Enterobacteriaceae were identified as ESBL producers, over a 4 month period, in
      one of Warsaw's hospitals between the end of 1996 and the beginning of 1997.
      Sixteen per cent of all Klebsiella pneumoniae isolates, 16% of Citrobacter
      freundii isolates and 32% of Serratia marcescens isolates collected by the
      hospital microbiology laboratory at that time were expressing these enzymes. The
      majority of these (27 isolates) were found to express CTX-M-type ESBLs (pI 8.4).
      This outbreak was due to both plasmid dissemination among unrelated strains and
      clonal spread of some strains in several wards of the hospital. The remaining
      isolates produced ESBLs (pI 8.2) belonging to the SHV family of beta-lactamases
      and demonstrated a high degree of genetic diversity.

PMID- 10588312
TI  - Five day moxifloxacin therapy compared with 7 day clarithromycin therapy for the
      treatment of acute exacerbations of chronic bronchitis.
AB  - In this multinational, randomized, double-blind study, the efficacy and safety of
      a 5 day course of moxifloxacin 400 mg orally od was compared with that of a 7 day
      course of clarithromycin 500 mg orally bd. in 750 patients with acute
      exacerbations of chronic bronchitis, characterized by at least two of the
      symptoms: sputum purulence, increased sputum volume or increased dyspnoea. Seven
      days after the end of therapy, clinical cure was achieved for 89% (287 of 322) of
      efficacy-evaluable patients in the moxifloxacin group and 88% (289 of 327) of
      patients in the clarithromycin group (95% CI, -3.9%, 5.8%). At follow-up (21-28
      days post-treatment), the continued clinical cure rates were 89% (256 of 287) for
      moxifloxacin and 89% (257 of 289) for clarithromycin. A total of 342 pathogenic
      bacteria were isolated from the sputum of 287 patients. The most common pathogens
      were Haemophilus influenzae (37%), Streptococcus pneumoniae (31%) and Moraxella
      catarrhalis (18%). Seven days post-treatment, a successful bacteriological
      response was obtained for 77% (89 of 115) of patients in the moxifloxacin group
      and 62% (71 of 114) of patients in the clarithromycin group, indicating
      superiority of moxifloxacin (95% CI, 3.6%, 26.9%). Both treatments were well
      tolerated with few adverse events. This study demonstrated that for the treatment
      of acute exacerbations of chronic bronchitis a 5 day course of moxifloxacin 400
      mg od was clinically equivalent and bacteriologically superior to a 7 day course
      of clarithromycin 500 mg bd.

PMID- 10588313
TI  - Randomized, double-blind study of short-course (5 day) grepafloxacin versus 10
      day clarithromycin in patients with acute bacterial exacerbations of chronic
      bronchitis.
AB  - The efficacy and safety of grepafloxacin were compared with clarithromycin in a
      randomized, double-blind, multicentre clinical trial of 805 patients with acute
      bacterial exacerbations of chronic bronchitis (ABECB). Patients were randomized
      to receive grepafloxacin 400 mg od for either 5 (n = 273) or 10 days (n = 268) or
      clarithromycin 250 mg bd for 10 days (n = 261). Patients were assessed pre
      treatment, 3-5 days during treatment, 1-3 days post-treatment and at follow-up
      (21-28 days post-treatment). The clinical success rates for the evaluable
      patients were 91% in the 5 day grepafloxacin group, 95% in the 10 day
      grepafloxacin group and 86% in the clarithromycin group. At follow-up, respective
      rates were 72%, 81% and 73%. A total of 513 pathogens were isolated from the pre
      treatment sputum specimens of 400 (49%) patients. The primary pathogens were
      Haemophilus influenzae (36% of isolates), Haemophilus parainfluenzae (27%),
      Moraxella catarrhalis (12%), Streptococcus pneumoniae (11%) and Staphylococcus
      aureus (3%). Pathogens were eradicated or presumed eradicated at post-treatment
      in 85%, 91% and 58% of evaluable patients treated with grepafloxacin for 5 days,
      grepafloxacin 10 days and clarithromycin 10 days, respectively. The eradication
      rates in both grepafloxacin groups were significantly greater than the
      clarithromycin group (P<0.001). All treatments were well tolerated and incidence
      of drug-related adverse events in each group was comparable. This study
      demonstrates that both a 5 and a 10 day regimen of grepafloxacin 400 mg od are as
      clinically and bacteriologically effective as in the treatment of ABECB
      clarithromycin 250 mg bd. for 10 days.

PMID- 10588314
TI  - A double-blind, randomized study assessing the equivalence of valacyclovir 1000
      mg once daily versus 500 mg twice daily in the episodic treatment of recurrent
      genital herpes. Genival Study Group.
AB  - Valaciclovir is a prodrug of acyclovir with more favourable bioavailability.
      Twice daily oral administration of valacyclovir is recommended in patients with
      genital herpes. A double-blind, randomized, controlled, multicriteria equivalence
      trial was conducted to determine whether od treatment with valacyclovir 1000 mg
      is as effective as bd treatment with 500 mg in patients with recurrent genital
      herpes. A total of 922 immunocompetent outpatients were treated with either
      regimen for 5 days; treatment was self-initiated at the first symptoms of the
      next recurrence. The principal outcome measures were the percentage of lesions
      healed at day 6, time to healing, time to cessation of pain, discomfort or
      itching, the percentage of abortive episodes and safety. Equivalence was assessed
      by comparison of 80% confidence limits for each measure; the two regimens were
      regarded as equivalent if the lower confidence limit was higher than a pre
      determined equivalence limit calculated to show a maximum 10% inferiority of
      valacyclovir 1000 mg od against valaciclovir 500 mg bd. Intention-to-treat
      analysis showed that the two treatments were equivalent for each outcome measure.
      Hence, it is concluded that valacyclovir 1000 mg od is as effective as 500 mg bd.
      as self-initiated therapy in patients with recurrent genital herpes.

PMID- 10588315
TI  - Dual inhibitory activity of sitafloxacin (DU-6859a) against DNA gyrase and
      topoisomerase IV of Streptococcus pneumoniae.
AB  - The in-vitro inhibitory activities of sitafloxacin (DU-6859a) and other
      quinolones against Streptococcus pneumoniae DNA gyrase and topoisomerase IV were
      measured. IC50s of levofloxacin, ciprofloxacin, sparfloxacin and tosufloxacin
      against DNA gyrase were almost three to 12 times higher than those against
      topoisomerase IV. On the other hand, sitafloxacin showed dual inhibitory activity
      against both enzymes and its IC50s were the lowest among those of the quinolones
      tested. These results suggest that sitafloxacin is an effective agent against
      pneumococcal infections and that the incidence of drug-resistant mutants is low.

PMID- 10588316
TI  - Contribution of the MexAB-OprM multidrug efflux system to the beta-lactam
      resistance of penicillin-binding protein and beta-lactamase-derepressed mutants
      of Pseudomonas aeruginosa.
AB  - Deletion of the mexAB-oprM multidrug efflux operon substantially compromised the
      beta-lactam resistance of beta-lactamase-derepressed mutants of Pseudomonas
      aeruginosa, although it had only a modest impact on resistance of a penicillin
      binding protein mutant. This highlights the multifactorial nature of beta-lactam
      resistance in this organism. Moreover, the contribution of efflux to the net
      resistance seen in some beta-lactam-resistant mutants suggests that inhibition of
      MexAB-OprM-mediated drug efflux might be an effective approach to overcoming beta
      lactam resistance attributed to efflux as well as to other mechanisms of beta
      lactam resistance.

PMID- 10588317
TI  - Resistance to methicillin in isolates of Staphylococcus aureus from blood and
      cerebrospinal fluid in Wales, 1993-1997.
AB  - Surveillance data for organisms isolated from blood cultures and cerebrospinal
      fluid (CSF) specimens has been gathered electronically in Wales since 1993. Over
      this period the proportion of total reported organisms from blood cultures and
      CSF represented by methicillin-resistant staphylococci (MRSA) has risen steadily.
      This has corresponded to a rise in rates of methicillin resistance amongst
      Staphylococcus aureus isolated from blood cultures and CSF from 4 to 43%. In
      certain age/gender groups in 1997, more than 50% of isolates of S. aureus were
      resistant to methicillin, suggesting that a change in empirical treatment may be
      necessary for suspected staphylococcal sepsis.

PMID- 10588318
TI  - In-vitro activity of cefepime and seven other antimicrobial agents against 1518
      non-fermentative Gram-negative bacilli collected from 48 Canadian health care
      facilities. Canadian Afermenter Study Group.
AB  - Non-fermentative bacilli are primarily nosocomial pathogens, and are also often
      resistant in vitro to a broad range of antimicrobial agents. In this large
      Canadian study, we collected 1466 clinical, non-repeat isolates of Pseudomonas
      aeruginosa, 21 of Acinetobacter spp. and 31 Stenotrophomas maltophilia. MICs of
      eight antibiotics were determined by the NCCLS microdilution method in a central
      laboratory. Tobramycin was the most active agent against P. aeruginosa (94.5%
      susceptible); amikacin and imipenem were the most active against Acetinobacter
      spp. (100%) and ceftazidime was the most active against S. maltophilia (40.6%).
      Against each group of isolates, cefepime was active against 87, 86.4 and 15.6%,
      respectively. This in-vitro study showed that cefepime may be a useful additional
      agent in the treatment of infections caused by P. aeruginosa and Acinetobacter
      spp., but not when S. maltophilia is considered pathogenic.

PMID- 10588319
TI  - In-vitro activity of gatifloxacin against Chlamydia trachomatis and Chlamydia
      pneumoniae.
AB  - We compared the activity of gatifloxacin, a new quinolone, ofloxacin and
      erythromycin against five isolates of Chlamydia trachomatis and 20 isolates of
      Chlamydia pneumoniae, including TW183 and clinical isolates from the USA and
      Japan. Testing was done in cycloheximide-treated HEp-2 cells. Gatifloxacin was
      slightly less active against C. trachomatis and slightly more active against C.
      pneumoniae than ofloxacin, with MICs at which 90% of the isolates had no
      inclusions and minimal chlamydicidal concentrations at which 90% of the isolates
      had no inclusions after passage of 0.25 mg/L. Gatifloxacin was less active than
      erythromycin for both species.

PMID- 10588320
TI  - In-vitro susceptibility of Aspergillus spp. isolates to amphotericin B and
      itraconazole.
AB  - The MICs of amphotericin B and itraconazole for 230 isolates of Aspergillus spp.,
      comprising 156 Aspergillus fumigatus, 20 Aspergillus terreus, 22 Aspergillus
      flavus, 17 Aspergillus nidulans and 15 Aspergillus niger, were determined by a
      broth microdilution method with RPMI 1640 medium. No isolate was detected with an
      MIC of amphotericin B >2 mg/L. Itraconazole MICs >16 mg/L were detected for four
      Aspergillus fumigatus and one Aspergillus nidulans isolates.

PMID- 10588321
TI  - In-vitro antifungal susceptibilities of Basidiobolus and Conidiobolus spp.
      strains.
AB  - The in-vitro antifungal susceptibilities of nine isolates belonging to
      Basidiobolus spp. and seven to Conidiobolus spp. against six antifungals
      (amphotericin B, ketoconazole, miconazole, itraconazole, fluconazole and
      flucytosine) were tested. A broth microdilution method, generally following the
      NCCLS guidelines, was used. Inoculum concentrations of the order of 100 cfu/mL
      were obtained by culturing fungi in a broth medium (Czapeck broth supplemented
      with 2% Tween 80 and 0.07% agar). MICs and MFCs were highly variable and isolate
      dependent, with the exception of those of flucytosine which were constantly very
      high. In general, however, Basidiobolus spp. displayed low MICs of fluconazole,
      itraconazole, ketoconazole and miconazole, and Conidiobolus spp. were resistant
      to all antifungals tested.

PMID- 10588322
TI  - Modification of acquired immunity in mice by imipenem/cilastatin.
AB  - The immunomodulating properties of antimicrobial drugs may have important
      implications for clinical practice, particularly for those patients whose immune
      system has been compromised. In this study, we assessed the influence of
      different treatments with a beta-lactam antibiotic (imipenem/cilastatin) on
      several acquired immune responses of BALB/c mice; splenocyte responses to
      specific mitogens and to sheep red blood cells, IL-2 production and proportions
      of the different lympho-monocytic populations. Impenem/cilastatin was shown to
      modify some lymphocyte-associated immune functions and it would be useful to
      investigate whether immunomodulatory effects also occur in humans.

PMID- 10588323
TI  - Intracerebral activity of antibiotics against Listeria monocytogenes during
      experimental rhombencephalitis.
AB  - We used a model of rhombencephalitis in gerbils to test the efficacy of various
      antibiotics against Listeria monocytogenes. Gerbils were inoculated in the middle
      ear with strain EGD and treated subcutaneously with various antibiotics alone or
      in combination. We found that the most active antibiotics on intracerebral
      bacteria were amoxycillin, co-trimoxazole, rifampicin and imipenem. Vancomycin,
      gentamicin and ciprofloxacin were weakly or not active. The combinations
      amoxycillin-co-trimoxazole, amoxycillin-gentamicin and co-trimoxazole-rifampicin
      were highly active against intracerebral bacteria.

PMID- 10588324
TI  - Amphotericin B lipid complex at 3 mg/kg/day for treatment of invasive fungal
      infections in adults with haematological malignancies.
AB  - We treated 10 consecutive adults with a haematological malignancy, and an
      invasive aspergillosis (n = 8) or invasive candidosis (n = 2), with amphotericin
      B lipid complex (ABLC) at 3 mg/kg/day. Nine patients responded (five complete and
      four partial responses), and one died with invasive aspergillosis. Treatment was
      well tolerated, with only 4% of infusions followed by infusion-related adverse
      events, and the renal function improved in six patients who had an elevated serum
      creatinine before therapy. These data suggest that lower doses of ABLC may be
      equally effective but less toxic than higher doses. However, a controlled study
      is required to confirm these observations.

PMID- 10588326
TI  - Discrepancies associated with the measurement of itraconazole serum
      concentrations by bioassays.

PMID- 10588325
TI  - Rapid absorption and clinical effectiveness of intragastric mefloquine in the
      treatment of cerebral malaria in African children.
AB  - To obviate the lack of injectable quinine in a hospital in rural Burundi,
      mefloquine, only available as an oral formulation, was administered (25 mg/kg
      bodyweight) as a single dose by nasogastric tube to four small children with
      cerebral malaria. All patients recovered uneventfully after a mean coma duration
      of 20.5 h. Mefloquine was rapidly absorbed and therapeutic serum concentrations
      were achieved within a few hours in all subjects, with parasite reduction ratios
      after 48 h within the expected range for drug-sensitive parasites. These findings
      suggest that intragastric mefloquine deserves consideration whenever parenteral
      drugs are not available for the treatment of cerebral malaria.

PMID- 10588327
TI  - In-vitro activities of 11 antibiotics against 75 strains of Streptococcus
      pneumoniae with reduced susceptibilities to penicillin isolated from patients in
      Washington State.

PMID- 10588328
TI  - Metronidazole resistance among clinical isolates belonging to the Bacteroides
      fragilis group: time to be concerned?

PMID- 10588329
TI  - Should clindamycin be used as treatment of patients with infections caused by
      erythromycin-resistant staphylococci?

PMID- 10588330
TI  - Therapy of chronic hepatitis B virus infection: inhibition of the viral
      polymerase and other antiviral strategies.
AB  - Chronic hepatitis B infection remains a major public health problem worldwide.
      The hepatitis B virus belongs to the family of hepadnaviruses that replicate
      their DNA genome via a reverse transcription pathway. The chronicity of infection
      in infected hepatocytes is maintained by the persistence of the viral covalently
      closed circular DNA. The main strategies to combat chronic HBV infection rely on
      the stimulation of the specific antiviral immune response and on the inhibition
      of viral replication. While the prolonged administration of reverse transcriptase
      inhibitors is most often associated with a control of viral replication rather
      than eradication, it may select for resistant mutants. The search for new viral
      targets is therefore mandatory to design combination strategies to prevent the
      emergence of resistant mutants and eventually clear viral infection.

PMID- 10588331
TI  - Treatment of primary herpes simplex virus infection in guinea pigs by imiquimod.
AB  - Imiquimod (also known as R-837 and S-26308) is an imidazoquinoline immune
      response modifier and is available in the US and several other countries for the
      treatment of external genital warts. Imiquimod has no direct antiviral activity
      but demonstrates efficacy in several animal models of virus infection. The drug
      is recognized by antigen presenting cells including monocytes, macrophages, B
      cells and dendritic cells and induces these cells to produce cytokines including
      interferon-alpha (IFN-alpha) and others. Imiquimod's ability to inhibit primary
      lesion development in the guinea pig model of Herpes simplex virus (HSV)
      intravaginal infection was studied. Imiquimod given intravaginally reduced
      primary lesions, reduced virus shedding and reduced virus content of spinal cords
      from HSV infected guinea pigs. A single drug application of 0.5 mg/kg reduced
      lesion frequency when given between 24 h before inoculation to 16 h after
      inoculation. A single drug application of 5 mg/kg reduced lesion frequency and
      severity when administered between 72 h before inoculation to 24 h after
      inoculation. The antiviral effect resulting from interferon induction in the
      animal lasts much longer than the drug itself, thus imiquimod is different than
      drugs having direct antiviral activity. Twice daily drug application for 4 days
      was effective when initiated up to 72 h after inoculation, however, once lesions
      began to appear, imiquimod treatment was not able to stop lesion development.
      Imiquimod treatment inhibited lesion development and/or virus shedding in guinea
      pigs inoculated with HSV-1, HSV-2 or virus isolates resistant to acyclovir.
      Imiquimod is currently in clinical trials for treating human HSV infections.

PMID- 10588332
TI  - Isolation and characterization of an anti-HSV polysaccharide from Prunella
      vulgaris.
AB  - A water soluble substance was isolated from a Chinese herb, Prunella vulgaris, by
      hot water extraction, ethanol precipitation and gel permeation column
      chromatography. Chemical tests showed that the substance was an anionic
      polysaccharide. Using a plaque reduction assay, the polysaccharide at 100
      microg/ml was active against the herpes simplex virus types 1 and 2 (HSV-1 and
      HSV-2), but was inactive against cytomegalovirus, the human influenza virus types
      A and B, the poliovirus type 1 or the vesicular stomatitis virus. The 50% plaque
      reduction dose of the polysaccharide for HSV-1 and HSV-2 was 10 microg/ml.
      Clinical isolates and known acyclovir-resistant (TK-deficient or polymerase
      defective) strains of HSV-1 and HSV-2 were similarly inhibited by the
      polysaccharide. Pre-incubation of HSV-1 with the polysaccharide at 4, 25 or 37
      degrees C completely abrogated the infectivity of HSV-1, but pre-treatment of
      Vero cells with the polysaccharide did not protect cells from infection by the
      virus. The addition of the polysaccharide at 0, 2, 5.5 and 8 h post-infection of
      Vero cells with HSV-1 at a multiplicity of infection (MOI) of five reduced the 20
      h-yield of intracellular infectious virus by 100, 99, 99 and 94%, respectively.
      In contrast, a similar addition of heparin showed 85, 63, 53 and 3% reduction of
      intracellular virus yield, respectively. These results suggest that the
      polysaccharide may inhibit HSV by competing for cell receptors as well as by some
      unknown mechanisms after the virus has penetrated the cells. The Prunella
      polysaccharide was not cytotoxic to mammalian cells up to the highest
      concentration tested, 0.5 mg/ml and did not show any anti-coagulant activity. In
      conclusion, the polysaccharide isolated from P. vulgaris has specific activity
      against HSV and its mode of action appears to be different from other anionic
      carbohydrates, such as heparin.

PMID- 10588333
TI  - Effect of desferrioxamine (DFO) and calcium trinatrium
      diethylenetriaminepentaacetic acid (DTPA) on rat cytomegalovirus replication in
      vitro and in vivo.
AB  - Cytomegalovirus (CMV) infection is a major problem in the immunosuppressed
      patient. It is thought that besides direct CMV induced cell lysis, immunological
      damage is part of CMV pathogenesis. New antiviral drugs, which combine
      immunomodulating and antiviral qualities, could be beneficial. Recently, it has
      been described that desferrioxamine (DFO) and calcium trinatrium
      diethylenetriaminepentaacetic acid (DTPA) exhibit both properties. In this report
      the antiviral effects of both compounds against rat CMV (RCMV) are described in
      vitro and in vivo using a generalised and local infection model. In vitro, both
      compounds exhibited a significant antiviral effect, DTPA being more potent than
      DFO. However, in the generalised infection model no effect was seen on mortality,
      morbidity or presence of virus in internal organs. In rats infected
      subcutaneously in the hind paw, no effect was seen locally on paw thickness,
      presence of viral antigens and inflammatory response. In addition, these rats
      suffered from a generalised infection of low magnitude at 15 days post infection,
      although both DFO and DTPA were able to lower the level of viral replication. In
      conclusion, our data indicate that despite in vitro activity, in vivo usage of
      DFO or DTPA for acute CMV infection is not warranted.

PMID- 10588334
TI  - In vitro inhibition of the replication of haemorrhagic septicaemia virus (VHSV)
      and African swine fever virus (ASFV) by extracts from marine microalgae.
AB  - We have screened for in vitro inhibition of viral replication with extracts from
      the following marine microalgae: Porphyridium cruentum, Phaeodactylum
      tricornutum, Tetraselmis suecica, Chlorella autotrophica, Dunaliella tertiolecta,
      Dunaliella bardawil, Isochrysis galbana, Isochrysis galbana var Tiso, Ellipsoidon
      sp. and Tetraselmis tetrathele. We have used as viral models two enveloped
      viruses of significant economic importance, the viral hemorrhagic septicemia
      virus (VHSV) of salmonid fish and the African swine fever virus (ASFV). The
      aqueous extracts from P. cruentum, C. autotrophica and Ellipsoidon sp., produced
      a significant inhibition of the in vitro replication of both viruses in a dose
      dependent manner. That this inhibition could be due to sulfated polysaccharides
      was suggested because the same pattern of viral inhibition was obtained by using
      exocellular extracts from microalgae enriched in these compounds and/or dextran
      sulfate of high molecular weight. However, the inhibition of viral replication
      did not correlate with the percentage of sulfatation of the exocellular
      polysaccharides. Extracts from marine microalgae may have prophylactic utility
      against fish and mammalian viral diseases.

PMID- 10588336
TI  - Calculation of chromatographic band profiles with an implicit isotherm.
AB  - The numerical method for solving the mathematical model of chromatography process
      coupled with implicit isotherm has been proposed. The exemplary predictions of
      elution band profiles were performed for competitive adsorption data of 2
      phenylethanol and 3-phenylpropanol on ODS-silica with methanol-water as the
      mobile phase. The simulations of chromatography process with various isotherm
      models taking into account lateral interactions in adsorbed phase and surface
      heterogeneity were discussed.

PMID- 10588335
TI  - Effect of recombinant human interferon alpha B/D (rHu-IFN-alpha B/D) in
      combination with acyclovir in experimental HSV-1 encephalitis.
AB  - The efficacy of recombinant human interferon alpha B/D in experimental HSV-1
      encephalitis was investigated in the murine system. Recombinant Hu-IFN-alpha B/D
      significantly reduced the mortality in a mouse encephalitis model (about 30%, P =
      0.021), whereas natural mouse interferon was inactive. Combination of acyclovir
      with Hu-IFN-alpha B/D had an additive effect.

PMID- 10588337
TI  - Gas chromatographic-mass spectrometric separation, identification and
      determination of C6-C12 cyclic imides in thermally treated epoxy and alkyd resins
      to locate hot spots inside large electricity generators.
AB  - A simple and rapid GC-MS method for separation, identification and quantitative
      determination of long-chain cyclic imides in the 300 degrees C thermally treated
      epoxy and alkyd resins has been developed. The method provides a positive means
      of identifying C6-C12 cyclic imide derivatives by GC-MS and enables the specific
      area of overheating to be identified, thereby averting catastrophic failures of
      power generators in service.

PMID- 10588338
TI  - Synthesis and study of the cluster [Pd(AuPPh3)6(HgNO3)](NO3) by reversed-phase
      high-performance liquid chromatography, thermoanalysis, infrared, nuclear
      magnetic resonance, and fast atom bombardment mass spectrometry.
AB  - The addition reaction of Hg0 and Hg(2)2+ to the bimetallic cluster
      [(PPh3)Pd(AuPPh3)6](NO3)2 (I) has been studied. The reaction, monitored by HPLC,
      showed the time elapsed to obtain the pure cluster [Pd(AuPPh3)6(HgNO3)](NO3)
      (II). The use of 31P[1H] NMR, IR spectra, FABMS and thermoanalysis data was very
      useful for confirming the results. The reaction was monitored by taking five
      samples after 3, 6, 17, 21 and 24 h. The process was finalised after 24 h and the
      pure trimetallic cluster II, free of the intermediate, appeared in the
      chromatogram as a large, unique peak.

PMID- 10588339
TI  - Determination of bromide, bromate and other anions with ion chromatography and an
      inductively coupled plasma mass spectrometer as element-specific detector.
AB  - An implementation of the Dionex IonPac AS12A analytical column with an element
      specific ICP-MS detection is described for the simultaneous determination of
      halogen and oxyhalogen anions, sulfate, phosphate, selenite, selenate and
      arsenate. The chromatographic separation was achieved in less than 4 min with an
      aqueous 11 mM (NH4)2CO3 (pH 11.2, adjusted with aqueous ammonia) as eluent.
      Special emphasis was given to optimize the ICP-MS detection conditions for the
      reliable detection (RSD<5%) of bromate and bromide at a bromine concentration
      level of 1.0 microg l(-1) with 50 microl sample injection volume. In order to
      achieve the highest detector response for bromine species an ultrasonic nebulizer
      equipped with a membrane desolvator had to be employed. The detection limits
      (S/N=3, sample injection volume 50 microl) obtained with the IC-ICP-MS after the
      optimization were 0.67 microg l(-1) for BrO3-, 0.47 microg l(-1) for Br-, 69
      microg l(-1) for ClO2-, 4 microg l(-1) for Cl-, 47 microg l(-1) for ClO3-, 13
      microg l(-1) for SO4(2-), 36 microg l(-1) for PO4(3-), 0.4 microg l(-1) for
      SeO3(2-), 0.3 microg l(-1) for SeO4(2-), and 0.4 microg l(-1) for AsO4(3-).

PMID- 10588340
TI  - Lattice-fluid model for gas-liquid chromatography.
AB  - Lattice-fluid models describe molecular ensembles in terms of the number of
      lattice sites occupied by molecular species (r-mers) and the interactions between
      neighboring molecules. The lattice-fluid model proposed by Sanchez and Lacombe
      (Macromolecules, 1978;11:1145-1156) was used to model specific retention volume
      data for a series of n-alkane solutes with n-alkane, polystyrene, and
      poly(dimethylsiloxane) stationary liquid phases. Theoretical equations were
      derived for the specific retention volume and also for the temperature dependence
      and limiting (high temperature) values for the specific retention volume. The
      model was used to predict retention volumes within 10% for the n-alkanes phases;
      22% for polystyrene; and from 20 to 70% for PDMS using no adjustable parameters.
      The temperature derivative (enthalpy) could be calculated within 5% for all of
      the solutes in nine stationary liquid phases. The limiting value for the specific
      retention volume at high temperature (entropy controlled state) could be
      calculated within 10% for all of the systems. The limiting data also provided a
      new chromatographic method to measure the size parameter, r, for any
      chromatographic solute using characteristic and size parameters for the
      stationary phase only. The calculated size parameters of the solutes were
      consistent, i.e. independent of the stationary phase and agreed within
      experimental error with the size parameters previously reported from saturated
      vapor pressure, latent heat of vaporization or density data.

PMID- 10588341
TI  - Synthesis and analytical properties of a novel columnar metallomesogenic polymer.
AB  - A metallomesogenic side-chain polymer with copper carboxylato discotic units in
      stacks prepared by covalent bonding of 14-pentadecenoic acid, stearic acid and
      poly(methylhydrosiloxane) is described. The physico-chemical and thermal
      properties of both monomeric and polymeric metallomesogens were determined by
      elemental analysis, IR, polarizing optical microscopy, thermal gravimetric
      analysis and differential scanning calorimetry. The polymeric states showed a
      discotic lamellar phase at 50-95 degrees C and an ordered discotic hexagonal
      phase at 95-200 degrees C. By dynamic coating, the metallomesogenic polymer was
      crosslinked to the capillary wall via benzoyl peroxide. The wall-coated capillary
      columns (15 m x 0.25 mm I.D.) were used for the separation of phenols. Factors
      affecting the retention and the sample selectivity were examined. Van 't Hoff
      plots as a function of temperature indicated that phase transitions were
      occurring. Thermodynamic properties of the analytes in this system were also
      studied. For the determination of a mixture of 3-aminophenol, 2-chlorophenol, 2
      nitrophenol, 4-nitrophenol, o-methylphenol, m-methylphenol, p-methylphenol, 2,4
      dichlorophenol, 2,4-dimethylphenol, 2,4-dinitrophenol, 2,4,6-trichlorophenol,
      2,4,6-trimethylphenol, 4-bromophenol, 3-methyl-4-chlorophenol, pentachlorophenol,
      and unsubstituted phenol, the calibration graphs for most phenols were linear
      over the range of 10-1000 microg ml(-1) and the mass detection limits were in the
      ng range based on three times standard deviation of seven measurements of the
      lowest peak that could be detected.

PMID- 10588342
TI  - Gas chromatographic determination of S-alk(en)ylcysteine sulfoxides.
AB  - A new GC method for determination of S-alk(en)ylcysteine sulfoxides, important
      secondary metabolites occurring in many plant genera, has been developed. The
      method is based on isolation of the amino acid fraction by ion-exchange
      chromatography followed by derivatization with ethyl chloroformate at ambient
      temperature and reduction of derivatized S-alk(en)ylcysteine sulfoxides by sodium
      iodide. The main advantages of the new method are its high sensitivity, excellent
      resolution capability, accuracy and reliability, as well as the possibility to
      identify unknown compounds by means of GC-MS. The content of alliin and other S
      alk(en)ylcysteine sulfoxides was determined in nine different samples of garlic
      (Allium sativum L.) originating from the Czech Republic, France, and China. The
      total content of S-alk(en)ylcysteine sulfoxide pool ranged between 0.53 and 1.3%
      fresh weight, with S-allylcysteine sulfoxide (alliin) being predominant. A novel
      S-alkylcysteine derivative, S-ethylcysteine sulfoxide (ethiin), not previously
      reported to occur in Allium species, was found in some of the samples examined.

PMID- 10588343
TI  - Packed-column supercritical fluid chromatography for the purity analysis of
      clevidipine, a new dihydropyridine drug.
AB  - In this paper we describe a packed column supercritical fluid chromatography
      method that can be used for the analysis of a new dihydropyridine substance. The
      method is based on methanol-modified carbon dioxide as the mobile phase and
      Hypersil bare silica as column support at a column temperature of 50 degrees C
      and 150 bar as back pressure. Using an adjusted methanol gradient the most likely
      by-products can be separated and detected (240 nm) within 13 min. Occasionally
      the column needed treatment with 4 mM citric acid in the methanol modifier in
      order to give a narrow peak of an acidic analogue. The present method can detect
      analogues at the 0.1% (w/w) level. The precision at this level for one of the
      analogues was 5.9% RSD. This method shows a higher selectivity than a
      corresponding reversed-phase liquid chromatographic method.

PMID- 10588344
TI  - Supercritical fluid extraction of chlorpyrifos and 3,5,6-trichloro-2-pyridinol
      from garden compost.
AB  - A method was developed for the simultaneous supercritical carbon dioxide
      extraction of chlorpyrifos and its primary degradate, 3,5,6-trichloro-2-pyridinol
      (TCP), from garden compost. In situ derivatization with N,O
      bis(trimethylsilyl)trifluoracetamide was necessary for extraction of TCP.
      Recoveries for TCP and chlorpyrifos were quantitative for spiked compost samples.
      Sodium chloride was used as the packing material in extractions with in situ
      derivatization. Optimum results were obtained for air-dried samples containing 4
      7% moisture. No sample cleanup was required prior to analysis by GC-flame
      ionization detection. The effects of compost moisture content and ageing were
      investigated for chlorpyrifos recovery. No significantly negative effect on
      recovery for up to 20% (w/w) moisture for chlorpyrifos was observed. Effects of
      ageing showed a decrease in extraction efficiency over time with 52% recovery
      after 10 days.

PMID- 10588345
TI  - Analysis of nonylphenol polyethoxycarboxylates and their related metabolites by
      on-line derivatization and ion-trap gas chromatography-mass spectrometry.
AB  - This study presents a modified method to analyze nonylphenol
      polyethoxycarboxylates (NPEC) and their related metabolites (carboxyalkylphenol
      ethoxycarboxylates (CNPEC)) in water samples. The method involves extraction of
      samples by a graphitized carbon black (GCB) cartridge, and direct derivatization
      in the GC injection-port using a large-volume (10-20 microl) direct sample
      introduction (DSI) device with tetraalkylammonium (TAA) salts. The analytes are
      identified and quantitated by ion-trap GC-MS. The large-volume DSI injection-port
      derivatization technique provides sensitivity, fast and reproducible results for
      NPEC and their metabolites, to quantitation at 0.1 microg/l in 200 ml of water
      samples. The retention effect of TAA salts in the injection-port is not detected.
      In addition, the significant [M-29]+ ions and molecular ions of butylated NPEC
      and CNPEC residues are observed. Recovery of NP1EC in spiked water samples ranges
      from 90 to 108%. Moreover, relative standard deviations of replicate analyses
      ranges from 1 to 9%. However, unsatisfactory on-line derivatization of CNPEC
      residues is observed. This finding maybe owing to their lesser dissociation with
      the ion-pair reagent in chloroform.

PMID- 10588346
TI  - The role of fine needle aspiration cytology (FNAC) in the investigation of
      superficial lymphadenopathy; uses and limitations of the technique.
AB  - Aspirates (n = 163) from 157 patients with enlarged superficial lymph nodes were
      obtained over a 5-year period in a combined surgical/FNAC clinic. A definitive
      diagnosis was achieved in over 77% of the cases: benign 52.7%, malignant 25.1%.
      The diagnostic accuracy was 94.4%, sensitivity 85.4%, and specificity 100%. The
      false-negative rate was 12.5% but decreased to 3.5% when lymphoma cases were
      excluded. There were 36 cases of metastatic disease, the majority of which were
      from a primary breast carcinoma. The main diagnostic difficulty was in
      distinguishing low-grade lymphoma from reactive hyperplasia. An added advantage
      was that aspirated material could be used in ancillary tests to help with the
      differential diagnosis. FNAC has a well-defined role in the investigation of
      superficial lymphadenopathy. Used in the proper setting it will provide a
      definitive diagnosis in the majority of cases, especially relating to recurrent
      malignancy or metastatic disease. Patients with a reactive cytological picture
      and no clinically suspicious symptoms could be spared unnecessary surgery and
      reviewed through follow up. This technique is cost-effective, of high diagnostic
      accuracy, and results in considerable resource savings.

PMID- 10588348
TI  - Fluorescence microscopy of mycobacteria in pleural effusions.
AB  - The diagnostic advantage of fluorescence microscopy (FM) of Papanicolaou-stained
      cytological specimens obtained by bronchoscopy has been described previously.
      This study was designed to evaluate the method's diagnostic benefit in
      cytological preparations of pleural effusions in cases of active pulmonary
      tuberculosis. In contrast to bronchial material there is no advantage in
      cytological evaluation of pleural effusions by FM.

PMID- 10588347
TI  - Evaluation of histochemical methods for the detection of intracytoplasmic mucin
      in serous effusions.
AB  - We have studied 25 serous effusions containing definitive morphologic evidence of
      adenocarcinoma to evaluate the ability of two mucin stains (Mayer's mucicarmine,
      D-PAS) to detect intracytoplasmic mucin in both cytologic (cytospin) and
      corresponding histological (cell block) preparations. Mucicarmine stain was
      positive in six of 25 (24%) cytospins and 13 of 25 (52%) cell blocks. D-PAS was
      positive in 19 of 25 (76%) cytospins and 20 of 25 (80%) cell blocks. Eight cases
      were identified which showed mucicarmine positivity in the cell block but not the
      corresponding cytospin; prolonging incubation time resulted in a positive
      mucicarmine in cytospin preparations for seven of these cases. We conclude that:
      (i) D-PAS is a more sensitive stain for the detection of intracytoplasmic mucin
      in all preparations; (ii) mucicarmine shows preferential staining for cell
      blocks; (iii) alterations in the staining protocol may permit mucin detection by
      mucicarmine staining in cytologic preparations in a significant number of cases.

PMID- 10588349
TI  - Immunocytochemical detection of prognostic markers in breast cancer; technical
      considerations.
AB  - The purpose of this study was to establish a good technical procedure for
      immunocytochemical (IC) staining of prognostic markers in breast cancer
      specimens. The influence of various preparation, fixation and storage methods on
      ER, P53 and Ki-67 IC staining was assessed, using cells of two breast cancer cell
      lines T47D (ER/P53+) and ZR-75-ER (ER+, P53-). In addition we searched for a
      suitable transport medium. Depending on the technical procedure, great variations
      in expression of the tested antigens were found. Cytospins fixed and stored
      according to the Abbott method gave the best results. Histocon appeared to be the
      medium of choice. A good concordance of IC and immunohistochemical (IH) results
      was found when the adopted method was tested on material of 10 breast cancers.
      This study underlines the importance of quality controlled standardization of
      cell processing, fixation and storage of fine needle aspiration (FNA) aspirates
      in order to obtain reproducible and consistent IC results.

PMID- 10588350
TI  - Prospective study of PAPNET: review of 25,656 Pap smears negative on manual
      screening and rapid rescreening.
AB  - In this prospective study, 27,014 Pap smears were selected for PAPNET review on
      the request of the referring practitioner or patient. Smears that were negative
      on routine manual screening were submitted for rapid rescreening. Smears
      considered normal after these two manual screens (n = 25,656) were reviewed using
      the PAPNET testing system. Routine manual screening identified 1340 (4.96%) of
      the smears as abnormal, and a further 18 (0.07%) abnormalities were detected by
      rapid rescreening. PAPNET review identified an additional 102 (0.4%) abnormal
      smears, including 10 histologically confirmed high grade lesions. The use of
      PAPNET testing following routine manual screening and rapid rescreening in
      tandem, enables cytologists to detect additional diagnostically significant
      abnormalities and reduce the rate of false-negative smears.

PMID- 10588351
TI  - Potentially difficult smears of women with squamous cell carcinoma pose fewer
      problems when PAPNET is used for primary screening.
AB  - The diagnosis of squamous cell carcinoma (SCC) on a cervical smear is often far
      from easy. This study reports the analysis of 40 true-positive SCC smears
      detected in primary PAPNET screening and eight false-negative (FN) conventionally
      screened smears. All FN cases contained sparse abnormal material (< 10% of the
      slide). In these potentially difficult cases the diagnosis on the PAPNET images
      was not hard. Statistical analysis of the quantitative data indicated that the
      PAPNET images of the FN cases and the true-positive cases differed in some
      aspects. PAPNET highlighted the importance of background information (old blood,
      fibrin and necrosis). In addition, all FN smears contained cancer cells in the
      PAPNET images, allowing a correct diagnosis.

PMID- 10588352
TI  - Follicular dendritic cell sarcoma of lymph node--report of fine needle aspiration
      (FNA) cytological appearances.

PMID- 10588353
TI  - Cytologic findings of metastatic mucin-secreting adenocarcinoma of brain from
      parotid gland primary.

PMID- 10588354
TI  - Cytological findings of abdominal malignant leiomyoblastoma (epithelioid
      leiomyosarcoma) in ascitic fluid; a case report.

PMID- 10588355
TI  - Fine needle aspiration cytology (FNAC) detection of early renal allograft
      infection with Candida glabrata--a case report.

PMID- 10588356
TI  - Fine needle aspiration (FNA) cytology of mammary fibromatosis: a case report and
      review of literature.

PMID- 10588357
TI  - Sarcoma seeding to multinodular goitre--a diagnostic dilemma.

PMID- 10588358
TI  - The role of cytosolic reductive stress in oxidant formation and diabetic
      complications.

PMID- 10588359
TI  - Vascular stress response and endothelial vasoactive factors for vascular
      remodelling.
AB  - In response to several vascular stresses caused by hyperglycaemia, hypertension
      or hyperlipidemia, endothelial cells (EC) sense these stresses as oxidative
      stress to secrete several autocrine/paracrine factors, including growth
      factors/cytokines and vasoactive peptides to regulate vascular tone and
      remodelling. Vascular stresses induce co-ordinate gene regulation of endothelial
      vasoactive substances and their related enzymes to cause vasorelaxation and
      vascular growth inhibition. We speculate that prolonged and excessive vascular
      stresses impair endothelial function, which results in the imbalance of
      endothelial production of vasoactive substances and leads to the formation of
      proliferative vascular lesions.

PMID- 10588360
TI  - Fluid shear stress as a regulator of gene expression in vascular cells: possible
      correlations with diabetic abnormalities.
AB  - Diabetes mellitus is associated with increased frequency, severity and more rapid
      progression of cardiovascular diseases. Metabolic perturbations from
      hyperglycemia result in disturbed endothelium-dependent relaxation, activation of
      coagulation pathways, depressed fibrinolysis, and other abnormalities in vascular
      homeostasis. Atherosclerosis is localized mainly at areas of geometric
      irregularity at which blood vessels branch, curve and change diameter, and where
      blood is subjected to sudden changes in velocity and/or direction of flow. Shear
      stress resulting from blood flow is a well known modulator of vascular cell
      function. This paper presents what is currently known regarding the molecular
      mechanisms responsible for signal transduction and gene regulation in vascular
      cells exposed to shear stress. Considering the importance of the hemodynamic
      environment of vascular cells might be vital to increasing our understanding of
      diabetes.

PMID- 10588361
TI  - Characterization of three isoforms of mammalian peroxiredoxin that reduce
      peroxides in the presence of thioredoxin.
AB  - A peroxidase from yeast that reduces H2O2 with the use of electrons provided by
      thioredoxin (Trx) together with homologs from a wide variety of species
      constitute the peroxiredoxin (Prx) family of proteins. Twelve mammalian Prx
      members have been previously identified in association with various cellular
      functions apparently unrelated to peroxidase activity. These mammalian proteins
      have now been divided into three distinct types, Prx I, II, and III, on the basis
      of their deduced amino acid sequences and immunological reactivity. With the use
      of recombinant proteins, Prx I, II, and III have now been shown to possess
      peroxidase activity and to rely on Trx as a source of reducing equivalents. None
      of the three proteins exhibited peroxidase activity in the presence of
      glutaredoxin. All three enzymes showed similar kinetic properties: the Vmax was 6
      13 micromol/min per mg at 37 degrees C, the Km for Trx was 3-6 microM, and the Km
      for H2O2 was < 20 microM. Immunoblot analysis of various rat tissues and cultured
      cells indicated that most cell types contain the three Prx isoforms, the sum of
      which amounts to approximately 1-10 microg per milligram of soluble protein. Prx
      I and II are cytosolic proteins, whereas Prx IlI is localized in mitochondria.
      These results suggest that, together with glutathione peroxidase and catalase,
      Prx enzymes likely play an important role in eliminating peroxides generated
      during metabolism as well as during stimulation of cell surface receptors.

PMID- 10588362
TI  - Glutamate-stimulated calcium activation of Ras/Erk pathway mediated by nitric
      oxide.
AB  - NMDA-type glutamate receptor-mediated increases in intracellular calcium play a
      critical role in synaptic plasticity involved in learning and memory. Calcium
      dependent activation of Ras and extracellular signal-regulated kineses (Erks) may
      transmit the glutamate signal to the nucleus which is ultimately important for
      long-lasting neuronal responses. The mechanism by which changes in cytoplasmic
      calcium mediate NMDA-induced activation of Ras and Erk is not known. In cerebral
      cortical neurons, this calcium influx through NMDA receptors activates Ras and
      its downstream effector, Erk, via nitric oxide (NO) generation by calcium
      dependent neuronal NO synthase. We propose that NO is a key link between NMDA
      mediated increases in cytoplasmic calcium and activity-dependent long-term
      changes such as differentiation, survival and synaptic plasticity.

PMID- 10588363
TI  - Oxidized LDL, glomerular mesangial cells and collagen.
AB  - Lipid deposits, foam cell collection and accumulation of mesangial matrix
      components are recognized as early events in the development of focal segmental
      glomerulosclerosis (FSGS). Studies have suggested that oxidative stress is
      increased in uremic patients. Oxidized low-density lipoprotein (Ox-LDL) has been
      identified in the lesions of FSGS. Dietary antioxidants reduced not only the
      staining intensity of Ox-LDL but also the severity of renal injury in rats with
      experimental FSGS possibly by making lipoproteins resistant to oxidation. In
      vitro studies showed that LDL during its incubation with human mesangial cells
      (HMC) was peroxidatively modified and stimulated alpha1(I), alpha1(III), and
      alpha1(IV) collagen mRNA expression. Vitamin E, an antioxidant, and antibody
      against Ox-LDL caused a marked reduction in collagen mRNA stimulated by LDL.
      These findings suggest that LDL deposited and oxidized in the glomeruli may be
      implicated in the development of glomerulosclerosis by facilitating excessive
      mesangial matrix generation.

PMID- 10588364
TI  - Oxidized LDL and expression of monocyte adhesion molecules.
AB  - Accumulation of substantial numbers of monocyte/macrophages, as well as activated
      T lymphocytes, in focal areas of arterial intima appears to be a hallmark of
      atherogenesis. Our report demonstrated that lysophosphatidylcholine (lyso-PC), a
      polar phospholipid component that is increased in atherogenic lipoproteins, such
      as oxidized LDL and remnants lipoproteins in diabetic and type III hyperlipidemic
      patients, can upregulate adhesion molecules for monocytes and T lymphocytes, and
      growth factors, such as heparin-binding epidermal growth factor-like growth
      factor and PDGF-A and B chains. Recently we identified the novel receptor for
      oxidized LDL, named Lox-1. Therefore in this paper we summarize the importance of
      the interaction between oxidized LDL and its receptor, LOX-1 in terms of early
      stage of atherogenesis.

PMID- 10588365
TI  - Evidence that the mitochondrial genome is the thrifty genome.
AB  - Although mitochondrial DNA (mtDNA) abnormalities are known to cause insulin
      deficiency, insulin resistance and diabetes mellitus, it's quantitative aspect
      was not addressed well. In this review, mitochondrial genome hypothesis of
      thrifty phenomenon is proposed, based on the data and review of literatures. From
      a population based epidemiologic study, it was found that mtDNA quantity was
      decreased in the peripheral blood of diabetic subjects, and also in those
      subjects who will convert to diabetes mellitus within 2 years. In this
      population, low mtDNA subjects were found to have higher blood pressure and high
      waist hip ratio. These findings suggested mtDNA status might be quantitatively
      linked to the insulin resistance syndrome. As quantitative relationships between
      peripheral blood mtDNA levels and insulin requirement, and energy utilization
      pattern (fat and carbohydrate oxidation during hyperinsulinemic clamp studies)
      were observed in a group of male students; and maternal mtDNA content (peripheral
      blood) correlated with birth weight and peripheral blood mtDNA content of the
      offspring in another study, possibility of thrifty phenotype phenomena might be
      due to the low mitochondrial status arose. As thrifty phenotype phenomenon shows
      the quantitatively continuous relationship between involved parameters and
      characteristics of 'imprinting', a possible mechanism is suggested.

PMID- 10588366
TI  - Effects of antioxidants on nerve and vascular dysfunction in experimental
      diabetes.
AB  - Reactive oxygen species (ROS) are elevated by metabolic changes in diabetes,
      including autoxidation and increased advanced glycation. Endogenous protection by
      the glutathione redox cycle is also compromised by the competing NADPH
      requirement of elevated polyol pathway flux. Antioxidant treatment strategies
      prevent or reverse nerve conduction velocity (NCV) deficits in diabetic rats.
      These include lipophilic scavengers such as butylated hydroxytoluene, probucol
      and vitamin E, more hydrophilic agents like alpha-lipoic acid and acetyl
      cysteine, and transition metal chelators that inhibit autoxidation. In the long
      term, elevated ROS cause cumulative damage to neurons and Schwann cells, however,
      they also have a deleterious effect on nerve blood flow in the short term. This
      causes endoneurial hypoxia, which is responsible for early NCV deficits.
      Antioxidant treatment corrects the blood flow deficit and promotes normal
      endoneurial oxygenation. ROS cause antioxidant-preventable vascular endothelium
      abnormalities, neutralizing nitric oxide mediated vasodilation and increasing
      reactivity to vasoconstrictors. Unsaturated fatty acids are a major target for
      ROS and essential fatty acid metabolism is impaired by diabetes. Gamma-linolenic
      acid stimulates vasodilator prostanoid production, and there are marked
      synergistic interactions between gamma-linolenic acid and antioxidants. This has
      encouraged the development of novel drugs such as ascorbyl-gamma-linolenic acid
      and gamma-linolenic acid-lipoic acid with enhanced therapeutic potential.

PMID- 10588367
TI  - Pathogenesis of diabetic nephropathy: the role of oxidative stress and protein
      kinase C.
AB  - Hyperglycemia, a well recognized pathogenetic factor of long-term complications
      in diabetes mellitus, not only generates more reactive oxygen species but also
      attenuates antioxidative mechanisms through glycation of the scavenging enzymes.
      Therefore, oxidative stress has been considered to be a common pathogenetic
      factor of the diabetic complications including nephropathy. A causal relationship
      between oxidative stress and diabetic nephropathy has been established by
      observations that (1) lipid peroxides and 8-hydroxydeoxyguanosine, indices of
      oxidative tissue injury, were increased in the kidneys of diabetic rats with
      albuminuria; (2) high glucose directly increases oxidative stress in glomerular
      mesangial cells, a target cell of diabetic nephropathy; (3) oxidative stress
      induces mRNA expression of TGF-beta1 and fibronectin which are the genes
      implicated in diabetic glomerular injury, and (4) inhibition of oxidative stress
      ameliorates all the manifestations associated with diabetic nephropathy. Proposed
      mechanisms involved in oxidative stress associated with hyperglycemia are glucose
      autooxidation, the formation of advanced glycosylation end products, and
      metabolic stress resulting from hyperglycemia. Since the inhibition of protein
      kinase C (PKC) effectively blocks not only phorbol ester-induced but also high
      glucose- and H2O2-induced fibronectin production, the activation of PKC under
      diabetic conditions may also have a modulatory role in oxidative stress-induced
      renal injury in diabetes mellitus.

PMID- 10588369
TI  - Oxidative damage to mitochondrial DNA and its relationship to diabetic
      complications.
AB  - Increased oxidative stress induced by hyperglycemia may contribute to the
      pathogenesis of diabetic complications. Oxidative stress is known to increase the
      conversion of deoxyguanosine (dG) to 8-hydroxydeoxyguanosine (8-OHdG) in DNA,
      which is linked to increased mitochondrial DNA (mtDNA) deletions. We investigated
      mtDNA deletions and 8-OHdG in the muscle DNA of non-insulin-dependent diabetes
      mellitus (NIDDM) patients. mtDNA deletion of 4977 bp (delta mtDNA4977) and the
      content of 8-OHdG in the muscle DNA of the NIDDM patients were much higher than
      those of the control subjects. There was a significant correlation between delta
      mtDNA4977 and the 8-OHdG content (P < 0.0001). Both delta mtDNA4977 and the 8
      OHdG content were also correlated with the duration of diabetes. Delta mtDNA4977
      and the 8-OHdG content in muscle DNA increased in proportion to the severity of
      diabetic nephropathy and retinopathy. This is the first report that an increase
      in delta mtDNA4977 and 8-OHdG is proportional to the severity of diabetic
      complications. Oxidative mtDNA damage is speculated to contribute to the
      pathogenesis of diabetic complications though a defect in mitochondrial oxidative
      phosphorylation or other mechanisms. 8-OHdG and delta mtDNA4977 are useful
      markers to evaluate oxidative mtDNA damage in the diabetic patients.

PMID- 10588368
TI  - Increased superoxide anion formation in endothelial cells during hyperglycemia:
      an adaptive response or initial step of vascular dysfunction?
AB  - In diabetes mellitus, the risk for cardiovascular complications and development
      of atherosclerosis is increased compared with healthy individuals. Recently
      evidence was provided that increased production of superoxide anions occurs in
      endothelial cells during hyperglycemia. In order to evaluate the potential impact
      of the enhanced formation of this oxygen radical for vascular cell dysfunction
      and its role in tissue adaptation, it is essential to assess the effect of
      superoxide anions on endothelial cell function. Here, we present new data and
      review our previous work on the effects of superoxide anions on endothelial
      vascular function, such as intracellular Ca2+ signal cascade, formation and
      bioactivity of nitric oxide. Based on the presented data we discuss superoxide
      anion production as a two faced phenomenon. In lower concentrations, superoxide
      anions are mediators of an endothelium adaptation to ensure endothelial
      vasomotion control. However, in higher concentrations superoxide anions disrupt
      endothelial-smooth muscle crosstalk resulting in vessel wall dysfunction and
      vascular wall dysfunction.

PMID- 10588370
TI  - Can protein kinase C inhibition and vitamin E prevent the development of diabetic
      vascular complications?
AB  - Hyperglycemia causes vascular complications of diabetes possible by the
      activation of protein kinase C (PKC). We have provided substantial evidence that
      activation of PKC can lead to a whole host of vascular dysfunction in diabetes.
      The activation of PKC induced by hyperglycemia appears to be due to an increase
      in diacylglycerol (DAG) levels, a physiological activator of PKC. Studies
      involving cultural cells, animal models of diabetes and patients have shown that
      inhibition of PKC by specific PKC inhibitor was able to reverse many of the
      vascular dysfunctions in the retina, kidney and cardiovascular systems induced by
      either hyperglycemia or diabetes. In addition high doses of vitamin E were shown
      to decrease the level of DAG and PKC induced by diabetes or hyperglycemia. Thus
      animal and clinical studies have shown that high doses of vitamin E treatment can
      apparently reverse some of the changes in the retinal and renal vessels.

PMID- 10588371
TI  - d-Alpha-tocopherol prevents the hyperglycemia induced activation of
      diacylglycerol (DAG)-protein kinase C (PKC) pathway in vascular smooth muscle
      cell by an increase of DAG kinase activity.
AB  - We have reported that d-alpha-tocopherol can prevent hyperglycemia-induced
      activation of DAG and PKC levels in vascular tissues as well as normalizing
      retinal blood flow and renal hyperfiltration. The mechanism of this effect,
      however, is not clear. Aside from alpha-tocopherol's principal role as an
      antioxidant agent, it has also been shown to act as a membrane stabilizer.
      Another possibility is that the effect of alpha-tocopherol is focused on the
      activation of DAG kinase, which is a key enzyme in the metabolism of DAG.
      Therefore, in this study, we examined the effect of alpha-tocopherol on the DAG
      kinase activity in vascular smooth muscle cell. We have also examined the effect
      of alpha-tocopherol, its analogues, and probucol on DAG kinase activities and
      expression. The present study showed that d-alpha-tocopherol's inhibitory effect
      on DAG-PKC pathway is by increasing DAG kinase activity in rat and human vascular
      smooth muscle cell (VSMC). Total DAG level was increased by 40 +/- 10% (mean +/-
      S.E.) (P < 0.05) in human VSMC, after exposure to 22 vs 5 mM glucose. This
      increase was normalized by d-alpha-tocopherol treatment in a concentration
      dependent manner. In parallel, DAG kinase activation by d-alpha-tocopherol was
      also induced in a time- and dose-dependent manner. DAG kinase activity was
      increased by 57 +/- 19% (P < 0.05) in human VSMC and 112 +/- 35% (P < 0.05) in
      rat VSMC after 24 h of incubation with d-alpha-tocopherol (100 microg/ml).
      Another lipophilic antioxidant, probucol, also increased DAG kinase activity by
      124 +/- 34%, but other vitamin E analogues with much less antioxidant potencies
      were ineffective. Western blots of various DAG kinase isoforms were not changed
      by d-alpha-tocopherol treatment. These results provide strong and detailed
      evidence that d-alpha-tocopherol can prevent hyperglycemia induced DAG-PKC
      activation by enhancing DAG kinase activity, probably through an antioxidant
      effect.

PMID- 10588372
TI  - Vitamin E mediated response of smooth muscle cell to oxidant stress.
AB  - Oxidant stress is associated with diminution of antioxidant molecules, such as
      alpha-tocopherol. Alpha-tocopherol specifically decreases, in a concentration
      dependent way, the proliferation of vascular smooth muscle cells. At the same
      concentrations (10-50 microM) it induces inhibition of protein kinase C (PKC)
      activity. The latter event is not due to a decrease in PKC level or to alpha
      tocopherol binding to PKC, but it results from increase of protein phosphatase
      2A1 activity. In vitro data, as well as at a cellular level, demonstrates that
      protein phosphatase 2A1 is activated, in its trimeric structure--but not as a
      dimer by alpha-tocopherol. This activation is followed by PKC-alpha
      dephosphorylation. The activation of protein phosphatase 2A1 and deactivation of
      PKC-alpha affect the AP1 transcription factor, resulting in a change in the
      composition and the binding of this factor to DNA. By transfecting smooth muscle
      cell with a construct containing three TRE (TPA responsive elements), the
      promoter thymidine kinase and the reporter gene chloramphenicol-acetyl
      transferase a modulation of gene expression by alpha-tocopherol is observed. Beta
      tocopherol does not cause any of the responses observed with alpha-tocopherol and
      R,R,R-alpha-tocopherol is twice as potent as all-rac-alpha-tocopherol. When added
      together, beta-tocopherol prevents the effects of alpha-tocopherol indicating
      that the mechanism involved is not related to the radical-scavenging properties
      of these two molecules, which are essentially equal. By differential display
      analysis it has been found that several genes of smooth muscle cells are
      differentially transcribed in the presence of alpha-tocopherol but not beta
      tocopherol. In particular, the gene of alpha-tropomyosin shows a transient
      enhancement of transcription as a function of the cell cycle time. Alpha
      tropomyosin translation is also increased by alpha-tocopherol and not by beta
      tocopherol. Because no changes of mRNA stability can be observed in the presence
      of alpha-tocopherol, the data supports the conclusion of a transcriptional
      control exerted by alpha-tocopherol on alpha-tropomyosin. Generally, the data
      strongly suggests the existence of a ligand/receptor type of mechanism at the
      basis of alpha-tocopherol action. It is concluded that an oxidative stress
      induced diminution of alpha-tocopherol in smooth muscle cell activates a reaction
      cascade leading to changes in gene expression and increase in cell proliferation
      by a non-antioxidant mechanism.

PMID- 10588373
TI  - Free radical production in endothelial cells as a pathogenetic factor for
      vascular dysfunction in the insulin resistance state.
AB  - Impairment of nitric oxide-dependent vascular relaxation is a characteristic
      feature of the insulin-resistant state. To understand those mechanisms, we
      examined imbalance of O2-/NO production in aortic endothelial cells obtained from
      high fructose-fed, exogenous hyperinsulinemic, and control rats. Aortic segments
      from both high fructose-fed and insulin-treated rats produced a 4-fold more O2-
      than control rats evaluated by a chemiluminescence method. The O2- production in
      the aortas of both high fructose-fed and insulin-treated rats was mediated
      through activation of NADH/NADPH oxidase. In isometric tension studies, high
      fructose vessels with endothelium elicited impaired relaxation in response to
      acetylcholine or a calcium ionophore A23187 when compared with control rats,
      whereas these impaired vascular responses were not found in insulin-treated rats.
      Furthermore, endothelial constitutive NO synthase activity was increased in
      vessels from insulin-treated rats, but decreased in vessels from high fructose
      fed rats. These results indicate that relative excess of O2- production through
      activation of NADH/NADPH oxidase over NO generation in endothelial cells may
      contribute to impaired endothelial-dependent relaxation in insulin-resistant
      state.

PMID- 10588374
TI  - Non-invasive diagnosis of pregnancy in wild black rhinoceros (Diceros bicornis
      minor) by faecal steroid analysis.
AB  - The objective of this study was to determine whether faecal progestagen
      measurement could be used to diagnose pregnancy in wild black rhinoceros cows.
      Immunoreactive 20alpha-progestagens were measured in faecal samples collected
      regularly (one or two times times per week) from pregnant and non-pregnant wild
      black rhinoceros females (n = 6) in Zimbabwe. Fresh dung piles deposited by the
      study animals were serially sampled during prolonged periods of tracking with
      local game scouts. Samples were stored frozen, and dried prior to methanol
      extraction. Immunoreactivity in faecal extracts was measured with a 20alpha
      dihydroprogesterone enzyme immunoassay and was shown to reflect circulating
      progesterone concentrations. Mean concentrations of faecal 20alpha-progestagens
      during each month of gestation were significantly higher than faecal
      concentrations in non-pregnant animals (P<0.05), except during the second month
      of gestation. Faecal 20alpha-progestagens remained 5-10 times higher than
      concentrations in non-pregnant animals from the 4th to 15th month of gestation.
      It was concluded that regular non-invasive reproductive monitoring of black
      rhinoceros in the wild was possible and that pregnancy could be accurately
      diagnosed from the measurement of 20alpha-progestagens in faecal samples. The use
      of this technique in wild black rhinoceros populations will offer new
      perspectives for in situ management of this endangered species.

PMID- 10588375
TI  - Post-natal growth and development of Simmental calves derived from in vivo or in
      vitro embryos.
AB  - Large fetuses arising from embryos produced in vitro have been shown to exhibit
      altered organ development in utero, but it is not known whether this persists
      post natally. Post-natal growth and development was examined in 18 Simmental
      bulls derived from in vivo frozen-thawed (n = 6), in vitro frozen-thawed (n = 6)
      or in vitro fresh (n = 6) embryos and reared together post weaning on an ad
      libitum diet until slaughter at approximately 13 months old. Calves weighing less
      than 60 kg at birth (n = 11) were classified as normal, and heavier calves (n =
      7; all from in vitro embryos) as oversize. Lifetime growth rates and slaughter
      weights apparently were unaffected by embryo source or birthweight. Mean (+/-
      s.e.m.) post mortem liver and kidney weights were unaffected by embryo source,
      but hearts of bulls from in vitro frozen embryos were heavier than those of bulls
      from in vivo frozen embryos (2.7 +/- 0.04 v 2.3 +/- 0.07 kg, P<0.025). Heart
      weight per kilogram body weight at slaughter for the 7 perinatally oversize males
      (4.01 +/- 0.08 g) exceeded that of the other 5 bulls from in vitro embryos (3.60
      +/- 0.10 g kg(-1); P<0.04) and the 6 in vivo males (3.56 +/- 0.12 g kg(-1);
      P<0.02). Overall, one-third of the variation in heart weight at slaughter (r2 =
      0.35; P = 0.01) was due to variation in birthweight. This is the first study to
      demonstrate birthweight-related developmental effects on post-natal organ weight
      following the transfer of embryos produced in vitro.

PMID- 10588376
TI  - Minimum sperm trajectory length for reliable determination of the fractal
      dimension.
AB  - The aim of this study was to determine the minimum track length required for the
      reliable calculation of the fractal dimension of trajectories of capacitating
      human spermatozoa. Manually reconstructed trajectories classified previously as
      hyperactivated or non-hyperactivated were re-analyzed. The trajectories were
      reconstructed at 60 Hz, and each comprised 61 points (corresponding to 1 s
      movement). The trajectories were 'split' to give the equivalent of 2 x 31 point,
      3 x 21 point, 4 x 16 point and 6 x 11 point track segments and the fractal
      dimension determined for each. The fractal dimensions of each track segment
      within each trajectory were compared using paired t-tests. No significant
      difference was observed between the fractal dimensions of track segments of equal
      length, irrespective of the motility pattern. However, significant differences in
      fractal dimension values were observed when segments of different lengths were
      compared (P<0.01). For the non-hyperactivated tracks, the fractal dimension was
      consistently below the hyperactivation threshold level for only the 31 point
      segments. The hyperactivated tracks consistently had fractal dimension values
      above the threshold level when segments of 16 points or longer were analysed.
      Therefore, the minimum track length for the determination of reliable fractal
      dimension values was 31 points, corresponding to an image sampling time of 0.5 s
      at 60 Hz, although it could be used as a screening method for the identification
      of hyperactivated motility for track segments of greater than 11 points
      (corresponding to 0.17 s movement).

PMID- 10588377
TI  - Is nitric oxide an autocrine modulator of bovine granulosa cell function?
AB  - Nitric oxide (NO) is an important intra- and intercellular messenger controlling
      many biological processes. It is synthesized by NO synthases, which have been
      found also in granulosa cells. The present study examined whether NO is present
      in bovine follicular fluid and is produced by granulosa cells in culture.
      Secondly, it aimed to determine if NO affects the main parameters of granulosa
      cell function. The NO donor S-nitroso-L-acetyl-penicillamine (10(-3), 10(-4), 10(
      5) M) was used to evaluate whether NO might influence steroidogenesis,
      proliferation and apoptosis in bovine granulosa cells collected from follicles
      divided according to their size in small (<5 mm) and large (>8 mm). The data
      demonstrate the presence of NO in follicular fluid and its production by
      granulosa cells in culture: the most active cells in producing NO are those from
      the small follicles, as confirmed by the NO levels in follicular fluid. This
      study also shows that NO donor significantly (P<0.001) inhibits progesterone (P4)
      and oestradiol 17beta (E2) production by the granulosa cells from both kinds of
      follicle; moreover, the highest concentration of NO donor significantly (P<0.001)
      inhibits DNA fragmentation in all the cells whereas the lowest concentration
      stimulates (P<0.001) cellular apoptosis only in granulosa cells from large
      follicles. NO donor does not seem to modify cell proliferation. Taken together
      these data lead point to NO as a local modulator of granulosa cell function.

PMID- 10588378
TI  - Selection of immature pig oocytes for homologous in vitro penetration assays with
      the brilliant cresyl blue test.
AB  - The present study was designed to evaluate the brilliant cresyl blue (BCB) test
      as a means of selection of immature pig oocytes to improve the performance of the
      homologous in vitro penetration (hIVP) assay carried out with immature oocytes to
      assess the penetrating ability of boar spermatozoa. Immature pig oocytes
      harvested from abattoir ovaries were incubated in 13 microM BCB in phosphate
      buffered saline, and selected according to their colour (blue and colourless
      oocytes) after 90 min incubation at 39 degrees C in 5% CO2 in air. To assess the
      selection criteria of the BCB test (Experiment 1), the diameter and viability
      (FDA test) of blue and colourless oocytes were determined. Differences (P<0.01)
      were found in both mean diameter (113.08 +/- 0.65 microm v. 100.29 +/- 0.96
      microm) and the viability rate (100 v. 70.71%) between blue and colourless
      oocytes. In Experiment 2, the selection effectiveness (healthy oocytes relative
      to inseminated oocytes) and penetrability (percentage of penetrated oocytes and
      number of sperm in penetrated oocytes) of unincubated (selected by morphological
      criteria) and BCB incubated oocytes were evaluated. Blue oocytes showed the best
      (P<0.001) selection effectiveness and the highest (P<0.01) penetrability.
      Finally, the effectiveness of the BCB test to reduce interassay variability in
      the results of hIVP assays was examined (Experiment 3). It was found that more
      consistent data (P<0.05) of selection effectiveness and percentage of penetrated
      oocytes were obtained when blue oocytes were used. In summary, these results
      indicate that the BCB test improves hIVP performance when used to preselect
      immature oocytes.

PMID- 10588379
TI  - The use of DNA fingerprinting to assess monozygotic twinning in Meishan and
      Landrace x large white pigs.
AB  - The extent of embryo mortality is usually estimated by the difference between the
      numbers of corpora lutea and embryos in the same animal, which assumes that each
      corpora lutea represents one potential embryo. Recent observations from the
      authors' laboratory reveal situations in which the number of embryos exceeds the
      number of corpora lutea, implicating the presence of identical twins. The
      objective of the present study was to establish DNA fingerprinting techniques to
      investigate the prevalence of monozygotic twinning in two breeds of pig. DNA
      fingerprints of every fetus carried by 6 Meishan (MS) and 6 Landrace x Large
      White (LxLW) gilts on Day 29 +/- 2 of pregnancy were obtained. Five LxLW and 3 MS
      litters carried no identical fetuses. The remaining gilts carried a pair of
      fetuses with indistinguishable DNA profiles. No pairs of fetuses were
      monochorionic. These results suggest that monozygotic twinning in the pig occurs
      during embryo cleavage or blastocyst development and may be more prevalent in MS
      compared with indigenous breeds.

PMID- 10588380
TI  - Immunoelectronmicroscopic imaging of spermadhesin AWN epitopes on boar
      spermatozoa bound in vivo to the zona pellucida.
AB  - Spermadhesin AWN is a major protein of boar seminal plasma and a sperm surface
      associated lectin. AWN binds to beta-galactosides and to porcine zona pellucida
      glycoproteins, suggesting a role for this protein in primary gamete interaction.
      However, because capacitation induces remodelling of the sperm surface and AWN is
      peripherally bound to the plasma membrane, the present study sought to
      investigate whether AWN is present or absent in the subpopulation of spermatozoa
      that reaches the ovulated oocyte at the period of fertilization in vivo.
      Therefore, tubal tissues and oocytes from sows mated with a fertile boar were
      collected 6-8 h after ovulation. Tissues and oocyte sperm complexes were fixed,
      immunolabelled with anti-AWN monoclonal antibodies, and examined by means of
      light and scanning electron microscopy. The results show that spermadhesin AWN is
      present in spermatozoa seen along the genital tract of the natural mated sow as
      well as on plasmalemmal remnants of spermatozoa bound to the zona pellucida in
      vivo.

PMID- 10588381
TI  - Seasonal variation in ovarian response to pregnant mares serum gonadotrophin in
      the brushtail possum (Trichosurus vulpecula).
AB  - This study examined the seasonal variation in ovarian response to the exogenous
      hormone pregnant mares serum gonadotrophin (PMSG) in the brushtail possum
      (Trichosurus vulpecula). Ovarian stimulation was achieved by administration of a
      single intramuscular injection of 15 IU PMSG. Animals (n = 165) responded to this
      treatment in a variable manner depending on the month of the year. The maximum
      response (measured by the total number of large (>2 mm) follicles) was 15.8 +/-
      1.5 follicles per animal (n = 12) in May and the minimum response was 4.9 +/- 1.6
      follicles per animal (n = 7) in January. The response throughout the rest of the
      year closely paralleled the birth seasonal distribution observed in wild possums
      in published reports. In the summer months (December, January and February) when
      few females carried pouch young, 55%, 42% and 17% of PMSG-primed animals,
      respectively, exhibited a nil response to PMSG (i.e. no follicles >2 mm were
      found on the ovaries of treated animals). In addition, when wild possums were in
      lactational anoestrus after the autumnal breeding peak, possums with a nil
      response to PMSG accounted for 17% (July) and 6% (August) of those treated, but
      the other animals gave near maximal numbers of large follicles (July, 5-21;
      August, 2-25). Whether the ovaries of non-responders are downregulated in some
      manner outside the breeding season or they become insensitive to gonadotrophin
      remains to be investigated. These observations pinpoint times of the year when
      the highest productivity can be expected following PMSG treatment, and together
      with information on the timing of ovulation provide critical data for the
      development of artificial breeding strategies for the possum.

PMID- 10588382
TI  - Cytogenetic analysis of human preimplantation embryos following developmental
      arrest in vitro.
AB  - The relationship between chromosomal abnormalities in the human preimplantation
      embryo and developmental arrest in vitro was investigated. Cytogenetic analysis
      of 171 embryos that had arrested between the pronucleate and the 8-cell stages
      demonstrated that the overall incidence of chromosomal abnormality among these
      embryos was 63.4%. Of the embryos that arrested at the pronucleate stage (n =
      48), 47.9% were chromosomally abnormal, compared with 59.5% of those that
      arrested between the 2- and 4-cell stages (n = 50), and 82.8% of those arrested
      between the 5- and 8-cell stage (n = 73). The rate of abnormality in embryos with
      poor morphology (irregular shaped blastomeres and considerable extracellular
      fragmentation) was significantly higher (86.8%; n = 33) than those with good
      morphology (60%; n = 51; P<0.005). These results suggest that there is an
      association between chromosomal abnormality, developmental arrest in vitro, and
      poor morphology.

PMID- 10588383
TI  - Recent advances in the molecular understanding of voltage-gated Ca2+ channels.

PMID- 10588385
TI  - From neural stem cells to myelinating oligodendrocytes.
AB  - The potential to generate oligodendrocytes progenitors (OP) from neural stem
      cells (NSCs) exists throughout the developing CNS. Yet, in the embryonic spinal
      cord, the oligodendrocyte phenotype is induced by sonic hedgehog in a restricted
      anterior region. In addition, neuregulins are emerging as potent regulators of
      early and late OP development. The ability to isolate and grow NSCs as well as
      glial-restricted progenitors has revealed that FGF2 and thyroid hormone favor an
      oligodendrocyte fate. Analysis of genetically modified mice showed that PDGF
      controls the migration and production of oligodendrocytes in vivo. Interplay
      between mitogens, thyroid hormone, and neurotransmitters may maintain the
      undifferentiated stage or result in OP growth arrest. Notch signaling by axons
      inhibits oligodendrocyte differentiation until neuronal signals--linked to
      electrical activity-trigger initiation of myelination. To repair myelin in adult
      CNS, multipotential neural precursors, rather than slowly cycling OP, appear the
      cells of choice to rapidly generate myelin-forming cells.

PMID- 10588384
TI  - Cytokine and growth factor involvement in long-term potentiation.
AB  - Hippocampal long-term potentiation (LTP) is one of the best-studied models of
      learning and memory at the molecular level. While it has long been known that
      tetanic stimulation causes changes at the synapse within seconds to minutes,
      recent research has begun to focus on factors that may affect synaptic plasticity
      on a longer time scale. One group of factors with many of the characteristics
      predicted for both short- and long-term actions at the synapse is the cytokines
      and growth factors. In vitro, these proteins can alter neuronal morphology, gene
      expression, and proliferation, and many cytokines and their receptors are present
      in the adult CNS. Because brainderived neurotrophic factor (BDNF) is the best
      studied synaptic modulator of this class, we begin by discussing the experimental
      evidence linking BDNF to LTP. Ten cytokines and growth factors that have been
      examined in the context of hippocampal LTP are then considered. We discuss the
      effects of LTP on the expression of the cytokines and explore the regulation of
      synaptic plasticity by exogenous application or antagonist perturbation of these
      proteins. The available evidence strongly supports a role for these factors in
      synaptic modulation and should prompt further exploration of their functions at
      the synapse.

PMID- 10588386
TI  - Semaphorin III can induce death in sensory neurons.
AB  - Semaphorin III has been described to function as a guidance molecule directing
      growing axons to their target. However, its effect on the neuron cell body has
      not been characterized. Semaphorin III has a highly dynamic expression pattern,
      which generally corroborates a chemorepellent guidance function, but also
      suggests additional functions, different from axon guidance. A number of studies
      show that some sensory neurons are eliminated, while their axons are still
      pathfinding. In this study we have investigated whether Semaphorin III also
      influences the survival of sensory neurons. We here present evidence that
      Semaphorin III can function in vitro as selective death factor for NGF-dependent
      sensory neurons. Semaphorin III induces a type of cell death that is
      characterized by slow onset, cell body shrinking, nuclear condensation, and TUNEL
      positive staining of dying neurons. These are all hallmarks of neuronal
      apoptosis. We also show evidence that neurons can modulate the response to
      Semaphorin III. The novel function described here may also be relevant in vivo,
      contributing to active elimination of neurons during development or after injury.

PMID- 10588387
TI  - Neuropilin-1 is expressed on adult mammalian dorsal root ganglion neurons and
      mediates semaphorin3a/collapsin-1-induced growth cone collapse by small diameter
      sensory afferents.
AB  - Neuropilin-1 on the growth cones of NGF-dependent embryonic dorsal root ganglion
      (DRG) neurons mediates the repulsive effects of secreted semaphorin3a, but its
      role in adult neurons is unknown. Here we show that most adult rat DRG neurons,
      regardless of cell diameter/afferent phenotype, express neuropilin-1 protein in
      vitro. However, the response of growth cones belonging to these neurons (induced
      by recombinant collapsin-1/semaphorin3a and blocked by the anti-neuropilin-1
      antibody) was restricted to those of small cell body diameter (<30 microm),
      corresponding primarily to nociceptive sensory afferents. Neurotrophic factors
      had a differential effect on neuropilin-1 expression in vitro, with DRG neurons
      cultured in either NGF or GDNF expressing the highest levels on their neurites.
      These findings suggest that neuropilin-1-mediated repellent effects of
      semaphorins may regulate the behavior of nociceptive sensory axons in the adult
      as well as the embryonic peripheral nervous system.

PMID- 10588389
TI  - The intracellular domain of the nicotinic acetylcholine receptor alpha subunit
      mediates its coclustering with rapsyn.
AB  - Muscle nicotinic acetylcholine receptors (AChRs) are immobilized at the
      neuromuscular junction in high-density clusters by rapsyn, a 43-kDa protein
      located at the cytoplasmic face of the postsynaptic membrane. When expressed in
      nonmuscle cells, rapsyn induces the aggregation of both assembled and unassembled
      AChR subunits. Here, we investigated the mechanism of rapsyn-induced clustering
      of the AChR alpha subunit by testing a series of alpha subunit mutants for
      colocalization with rapsyn patches in transfected QT6 cells. Partial or total
      deletion of the large intracellular domain of the alpha subunit dramatically
      reduced its ability to colocalize with rapsyn patches. Furthermore, insertion of
      the alpha subunit large intracellular domain into a potassium channel resulted in
      a significant increase in the channel's colocalization with rapsyn patches. We
      conclude that the large intracellular domain of the alpha subunit plays an
      important role in mediating rapsyn-induced coclustering of the AChR alpha
      subunit.

PMID- 10588388
TI  - Activation of Xenopus genes required for lateral inhibition and neuronal
      differentiation during primary neurogenesis.
AB  - XNGN-1, a member of the neurogenin family of basic helix-loop-helix proteins,
      plays a critical role in promoting neuronal differentiation in Xenopus embryos.
      When ectopically expressed, XNGN-1 induces the expression of a set of genes
      required for neuronal differentiation such as XMyT1 and NeuroD. At the same time,
      however, XNGN-1 induces the expression of genes that antagonize neuronal
      differentiation by a process called lateral inhibition. Here, we present evidence
      that XNGN-1 activates the expression of genes required for differentiation and
      lateral inhibition by recruiting transcriptional coactivators p300/CBP (CREB
      binding protein) or PCAF (p3OO/CBP-associated protein), both of which contain
      histone acetyltransferase (HAT) activity. Significantly, transcriptional
      activation of the genes in the lateral inhibitory pathway is less dependent on
      the HAT activity than is the activation of the genes that mediate
      differentiation. We propose that this difference enables the genes in the lateral
      inhibition pathway to be induced prior to the genes that promote differentiation,
      thus enabling lateral inhibition to establish a negative feedback loop and
      restrict the number of cells undergoing neuronal differentiation.

PMID- 10588390
TI  - Correct coordination of neuronal differentiation events in ventral forebrain
      requires the bHLH factor MASH1.
AB  - MASH1 is a bHLH transcription factor specifically expressed in the developing
      nervous system that has an essential role in the formation of multiple neuronal
      lineages in the peripheral and central nervous systems. Here we demonstrate the
      requirement for MASH1 for normal development of ventral forebrain structures.
      MASH1 is expressed at high levels in the ventral telencephalon and specific
      regions within the ventral diencepharon. In the absence of MASH1, tissue
      morphology, proliferation, and gene expression within these forebrain regions is
      disrupted. The decreased incorporation of BrdU in the neuro-epithelium and the
      enlargement of the ventricles demonstrate a reduction in cell proliferation. A
      loss of anatomically distinct lateral and medial ganglionic eminences, and a
      disruption of axons traversing this region, indicate abnormalities in cell-type
      specification. The aberrant expression of Tuj-1, a marker of neuronal
      differentiation in the neuroepithelium, and Dlx, a marker of regional cell
      identity, in the ventricular zone in the MASH1 mutant brains suggest coordination
      of differentiation events is disrupted. In addition, the involvement of MASH1 in
      lateral inhibition processes that affect the development of these forebrain
      regions is implicated. Taken together, an essential role for MASH1 in the
      coordination of events required for correct cell-type specification and timing of
      differentiation during neural development in ventral forebrain regions is
      demonstrated.

PMID- 10588391
TI  - Receptor tyrosine phosphatase-delta is a homophilic, neurite-promoting cell
      adhesion molecular for CNS neurons.
AB  - Appropriate regulation of tyrosine phosphorylation is essential for axon growth
      and guidance; evidence from invertebrates indicates that receptor-type tyrosine
      phosphatases (RPTPs) are required for correct axon growth during CNS development.
      One vertebrate RPTP, PTP-delta, is highly expressed in brain and has a cell
      adhesion molecule-like extracellular domain (ECD) comprising three immunoglobulin
      repeats and eight fibronectin type III repeats. Using fluorescent beads
      (Covaspheres) coated with the PTP-delta ECD, as well as insect cells expressing
      PTP-delta on their surfaces, we show that PTP-delta is a homophilic cell adhesion
      molecule. A variety of chick neurons adhere strongly to an Fc fusion protein
      containing the PTP-delta ECD. Additionally, substrate-bound PTP-delta ECD fusion
      protein strongly promotes neurite outgrowth from forebrain neurons; this effect
      is separable from its effect on adhesion. Our results indicate that PTP-delta is
      a neurite-promoting cell adhesion molecule for CNS neurons.

PMID- 10588392
TI  - Astrocytes induce oligodendrocyte processes to align with and adhere to axons.
AB  - In order to study the signals that control the onset of myelination, we
      cocultured highly purified postnatal retinal ganglion cells and optic nerve
      oligodendrocytes under serum-free conditions that promote their survival for at
      least a month and found that no myelination occurred. Although the addition of
      optic nerve astrocytes induced the oligodendrocyte processes to align with, and
      adhere to, axons, myelination still did not occur. The effect of astrocytes was
      mimicked by removal of polysialic acid from both cell types using neuroaminidase.
      These findings provide evidence for a novel role for astrocytes in controlling
      the onset of myelination by promoting adhesion of oligodendrocyte processes to
      axons. They also suggest that other, as yet unidentified, cell-cell interactions
      are necessary to induce the myelination process itself.

PMID- 10588394
TI  - Setting boundaries for psychiatric disorders.

PMID- 10588393
TI  - Differential cytoskeletal changes during growth cone collapse in response to
      hSema III and thrombin.
AB  - Growth cones are known as the site of action of many factors that influence
      neurite growth behavior. To assess how different collapsing agents influence the
      growth cone cytoskeleton, we used recombinant human Semaphorin III (hSema III)
      and the serine protease thrombin. Embryonic chick dorsal root ganglion neurons
      showed a dramatic depolymerization of actin filaments within 5 min upon hSema III
      exposure and virtually no influence on microtubules (MT). Only at later time
      points (20-30 min) was the polymerization/depolymerization rate of MT
      significantly affected. Thrombin induced a morphologically and kinetically
      similar growth cone collapse. Moreover, thrombin induced an early and selective
      depolymerization of dynamic MT, accompanied by the formation of loops of stable
      MT bundles. Selective changes in the phosphorylation pattern of tau were
      associated with microtubule assembly in thrombin-induced responses. Our data
      provide evidence that different signal transduction pathways lead to distinct
      changes of the growth cone cytoskeleton.

PMID- 10588395
TI  - Images in neuroscience. Cognition: the anterior cingulate and response conflict.

PMID- 10588396
TI  - The contribution of Hughlings Jackson to an understanding of dissociation.
AB  - The author provides a preliminary framework for a systematic and dynamic
      understanding of dissociation through a consideration of the theories of
      Hughlings Jackson. Jackson's ideas are briefly reviewed. He saw the proper
      scientific investigation of mental illness as an experimental investigation of
      mind. Accordingly, his argument begins with this fundamental concept. His views
      of the brain-mind relationship and of mind, or self, resemble modern conceptions.
      He viewed the self as double and focused on those disruptions of the self system
      which he called the "dreamy state." This state involves an "uncoupling" of normal
      consciousness, resulting in the loss of the most recently developed forms of
      memory and of the stream of consciousness. Dissociation is seen here as analogous
      to the dreamy state. Jacksonian theory predicts the main features of
      dissociation, i.e., constriction of consciousness, a particular form of amnesia,
      disaggregation of perceptual phenomena, depersonalization, derealization, and
      hallucinosis. It leads to the view that dissociation can be seen, in essence, as
      an uncoupling of consciousness.

PMID- 10588397
TI  - DSM-IV diagnostic criterion for clinical significance: does it help solve the
      false positives problem?
AB  - OBJECTIVE: A major change in DSM-IV is the inclusion in almost one-half of the
      diagnostic criteria sets of a clinical significance criterion, which requires
      that symptoms cause "clinically significant distress or impairment in social,
      occupational, or other important areas of functioning." In response to concerns
      that the DSM criteria are overly inclusive, the clinical significance criterion
      attempts to minimize false positive diagnoses in situations in which the symptom
      criteria do not necessarily indicate pathology. This article examines whether the
      clinical significance criterion achieves its purpose and considers its broader
      impact on diagnostic validity. METHOD: The effect of the clinical significance
      criterion on the diagnostic validity of DSM-IV criteria for a wide range of
      disorders was examined. RESULTS: For many diagnoses to which the clinical
      significance criterion was added, the symptom criteria are inherently associated
      with significant impairment, so the clinical significance criterion is redundant
      and therefore does not affect caseness. For some diagnoses, the clinical
      significance criterion is potentially helpful in eliminating false positives by
      elevating the level of required distress. However, there may be advantages to
      obtaining the same results by modifying some of the symptom criteria. Often the
      clinical significance criterion has led to the possibility of false negative
      diagnoses. CONCLUSIONS: In the process of revising DSM-IV, the generic use of the
      clinical significance criterion should be reconsidered. For each DSM diagnosis,
      it should be determined whether there is a need to raise the threshold of any of
      the existing symptom criteria or to add a criterion that excludes normal
      reactions to psychosocial stress.

PMID- 10588398
TI  - Acute efficacy of ECT in the treatment of major depression in the old-old.
AB  - OBJECTIVE: There are few data addressing the outcome of ECT for persons over 75
      years of age. In a prospective, multisite study, the authors compared
      characteristics and treatment outcomes of adult (59 and younger), young-old (60
      to 74 years), and old-old (75 and older) patients treated with ECT for major
      depression. METHOD: At four hospitals, 268 patients with primary unipolar major
      depression and scores of at least 20 on the 24-item Hamilton Depression Rating
      Scale were treated with suprathreshold right unilateral or bilateral ECT in a
      standardized manner. Demographic variables, clinical characteristics, and short
      term outcomes of the three groups were compared. RESULTS: The demographic and
      clinical characteristics of the old-old patients were similar to those of the
      young-old patients, whereas both groups differed from the adult patients on these
      variables. Both older groups had significantly greater burdens from physical
      illness and global cognitive impairment at baseline than the adult subjects. Both
      older groups had shorter index depressive episodes and were less likely to have
      had inadequate responses to adequate medication trials before ECT. The older
      groups had higher seizure thresholds, but the three groups received similar
      courses of treatment. The adult patients experienced a significantly lower rate
      of ECT response (54%) than the young-old patients (73%), while the old-old
      patients had an intermediate rate of response (67%). CONCLUSIONS: Despite a
      higher level of physical illness and cognitive impairment, even the oldest
      patients with severe major depression tolerate ECT in a manner similar to that
      for younger patients and demonstrate similar or better acute response.

PMID- 10588399
TI  - PET imaging of serotonin type 2A receptors in late-life neuropsychiatric
      disorders.
AB  - OBJECTIVE: To determine whether there are abnormalities in the in vivo status of
      the serotonin type 2A (5-HT2A) receptor in late-life depression and Alzheimer's
      disease, the authors used positron emission tomography (PET) to assess patients
      with these two conditions and healthy subjects. METHOD: PET was performed by
      using [18F]altanserin to evaluate 5-HT2A receptor binding in 11 elderly patients
      with depression (four men, seven women; mean age = 65.0 years, SD = 5.5); nine
      Alzheimer's disease patients, including three with concurrent depression (two
      men, seven women; mean age = 69.7 years, SD = 5.0); and 10 age-matched healthy
      subjects (four men, six women; mean age = 69.8 years, SD = 5.0). Partial-volume
      correction of regional specific binding estimates was performed by using a method
      based on magnetic resonance imaging. RESULTS: No significant abnormalities in
      [18F]altanserin binding (binding potential) were observed in the patients with
      late-life depression, and no effect of depression on binding potential was
      present within the Alzheimer's disease group. However, the patients with
      Alzheimer's disease had significantly lower binding than the normal subjects in
      several brain regions, including the anterior cingulate, prefrontal cortex, and
      sensorimotor cortex. CONCLUSIONS: These results suggest that the 5-HT2A receptor
      is differentially affected in late-life depression and Alzheimer's disease, a
      finding that has implications for the etiological basis of mood and cognitive
      features of neuropsychiatric disorders of late life.

PMID- 10588400
TI  - High brain myo-inositol levels in the predementia phase of Alzheimer's disease in
      adults with Down's syndrome: a 1H MRS study.
AB  - OBJECTIVE: An extra portion of chromosome 21 in Down's syndrome leads to a
      dementia in later life that is phenotypically similar to Alzheimer's disease.
      Down's syndrome therefore represents a model for studying preclinical stages of
      Alzheimer's disease. Markers that have been investigated in symptomatic
      Alzheimer's disease are myoinositol and N-acetyl-aspartate. The authors
      investigated whether abnormal brain levels of myo-inositol and other metabolites
      occur in the preclinical stages of Alzheimer's disease associated with Down's
      syndrome. METHOD: The authors used 1H magnetic resonance spectroscopy (MRS) with
      external standards to measure absolute brain metabolite concentrations in 19
      nondemented adults with Down's syndrome and 17 age- and sex-matched healthy
      comparison subjects. RESULTS: Concentrations of myoinositol and choline
      containing compounds were significantly higher in the occipital and parietal
      regions of the adults with Down's syndrome than in the comparison subjects.
      Within the Down's syndrome group, older subjects (42-62 years, N = 11) had higher
      myo-inositol levels than younger subjects (28-39 years, N = 8). Older subjects in
      both groups had lower N-acetylaspartate levels than the respective younger
      subjects, although this old-young difference was not greater in the Down's
      syndrome group. CONCLUSIONS: The approximately 50% higher level of myo-inositol
      in Down's syndrome suggests a gene dose effect of the extra chromosome 21, where
      the human osmoregulatory sodium/myo-inositol cotransporter gene is located. The
      even higher myoinositol level in older adults with Down's syndrome extends to the
      predementia phase earlier findings of high myoinositol levels in symptomatic
      Alzheimer's disease.

PMID- 10588401
TI  - Self-reported depression and suicide attempts among U.S. women physicians.
AB  - OBJECTIVE: Studies examining suicide rates for U.S. women physicians and other
      U.S. women have found odds ratios as high as 4 to 1. Although such reports are
      controversial and are based on small groups (N = 17 to 49 suicides), they are
      often cited as evidence of a high prevalence of psychopathology among women
      physicians. METHOD: The authors used the results of the Women Physicians' Health
      Study (N = 4,501), a large, nationally distributed questionnaire, to assess the
      lifetime prevalence of self-identified depression and suicide attempts among U.S.
      women physicians. RESULTS: An estimated 1.5% (N = 61) of U.S. women physicians
      have attempted suicide, and 19.5% (N = 808) have a history of depression. Those
      who were born in the United States, were not Asian, had histories of cigarette
      smoking, alcohol abuse or dependence, sexual abuse, domestic violence, poor
      current mental health, more severe harassment, or a family history of psychiatric
      disorders were significantly more likely to report suicide attempts or
      depression. Depression was more common among those who were not partnered, were
      childless, had a household gun, had more stress at home, drank alcohol, had worse
      health, or had a history of obesity, chronic fatigue syndrome, substance abuse,
      an eating disorder, or another psychiatric disorder and among those who reported
      working too much, career dissatisfaction, less control at work, and high job
      stress. Strata reporting higher rates of depression tended to show higher
      (although usually nonsignificant) rates of suicide attempts. CONCLUSIONS:
      Depression is approximately as common among U.S. women physicians as among other
      U.S. women, but suicide attempts may be fewer. A number of conditions may help
      identify women physicians at high risk for suicide attempts and depression.

PMID- 10588402
TI  - Low phosphoinositide-specific phospholipase C activity and expression of
      phospholipase C beta1 protein in the prefrontal cortex of teenage suicide
      subjects.
AB  - OBJECTIVE: The enzyme phosphoinositide-specific phospholipase C (PI-PLC) is a
      component of the phosphoinositide signal transduction system. Other components of
      this system have been found to be abnormal in adults and adolescents who have
      committed suicide, and so the authors examined whether PI-PLC activity and
      protein expression of PLC isozymes are abnormal in postmortem brains of teenage
      suicide subjects. METHOD: PI-PLC activity and protein expression of the PLC
      beta1, delta1, and gamma1 isozymes were examined in Brodmann's areas 8 and 9 of
      postmortem brains obtained from 18 teenage suicide subjects and 18 matched
      comparison subjects. PI-PLC activity was determined by enzymatic assay, and
      protein expression of the PLC isozymes was determined by the Western blot
      technique. RESULTS: Compared with the normal subjects, the teenage suicide
      subjects had significantly lower PI-PLC activity and immunolabeling of the
      specific PLC beta1 isozyme in both membrane and cytosol fractions of Brodmann's
      areas 8 and 9 combined (prefrontal cortex). There was also a significant
      correlation between PI-PLC activity and protein levels of the PLC beta1 isozyme
      in the brains of the teenage suicide subjects. There was no significant
      difference in PI-PLC activity or level of PLC beta1 protein between the suicide
      subjects with a history of mental disorders and those with no history of mental
      disorders; however, both groups had significantly lower PI-PLC activity and
      expression of PLC beta1 protein than the normal subjects. CONCLUSIONS: Low PI-PLC
      activity and expressed levels of the PLC beta1 isozyme in postmortem brains of
      suicide subjects may have clinical relevance in the pathophysiology of suicidal
      behavior.

PMID- 10588403
TI  - Temporal dissociation between lithium-induced changes in frontal lobe myo
      inositol and clinical response in manic-depressive illness.
AB  - OBJECTIVE: The most widely accepted hypothesis regarding the mechanism underlying
      lithium's therapeutic efficacy in manic-depressive illness (bipolar affective
      disorder) is the inositol depletion hypothesis, which posits that lithium
      produces a lowering of myo-inositol in critical areas of the brain and the effect
      is therapeutic. Lithium's effects on in vivo brain myo-inositol levels were
      investigated longitudinally in 12 adult depressed patients with manic-depressive
      illness. METHOD: Medication washout (minimum 2 weeks) and lithium administration
      were conducted in a blinded manner. Regional brain myo-inositol levels were
      measured by means of quantitative proton magnetic resonance spectroscopy at three
      time points: at baseline and after acute (5-7 days) and chronic (3-4 weeks)
      lithium administration. RESULTS: Significant decreases (approximately 30%) in
      myoinositol levels were observed in the right frontal lobe after short-term
      administration, and these decreases persisted with chronic treatment. The
      severity of depression measured by the Hamilton Depression Rating Scale also
      decreased significantly over the study. CONCLUSIONS: This study demonstrates that
      lithium administration does reduce myo-inositol levels in the right frontal lobe
      of patients with manic-depressive illness. However, the acute myo-inositol
      reduction occurs at a time when the patient's clinical state is clearly
      unchanged. Thus, the short-term reduction of myo-inositol per se is not
      associated with therapeutic response and does not support the inositol depletion
      hypothesis as originally posited. The hypothesis that a short-term lowering of
      myo inositol results in a cascade of secondary signaling and gene expression
      changes in the CNS that are ultimately associated with lithium's therapeutic
      efficacy is under investigation.

PMID- 10588404
TI  - Association between lower serum free T4 and greater mood instability and
      depression in lithium-maintained bipolar patients.
AB  - OBJECTIVE: This investigation evaluated the relationship between changes in
      thyroid indices and mood stability during lithium and carbamazepine prophylaxis
      for bipolar disorder. METHOD: In the first 2 years, 30 patients with bipolar mood
      disorder were randomly assigned to 1 year of lithium and then 1 year of
      carbamazepine, or vice versa; in the third year, they received lithium plus
      carbamazepine. By stepwise regression analysis, the degree and timing of lithium-
      and carbamazepine-induced thyroid changes and their subsequent relationship to
      long-term mood stability were evaluated. RESULTS: During the lithium phase, there
      was a significant inverse relationship between morbidity and mean serum level of
      free T4, i.e., a lower mean serum level of free T4 was associated with more
      affective episodes and greater severity of depression as shown by the Beck
      Depression Inventory. During the carbamazepine phase, there was an inverse
      relationship between mean level of total T4 and global severity rating. During
      the combination phase, no relationships between thyroid indices and clinical
      outcome were significant. CONCLUSIONS: In the lithium phase, a low level of free
      T4 was associated with more affective episodes and greater severity of
      depression. Whether this mood instability is causally related to low free T4
      levels and whether it can be attenuated with T4 replacement remain to be studied
      in a controlled setting.

PMID- 10588405
TI  - Impairment in pure and comorbid generalized anxiety disorder and major depression
      at 12 months in two national surveys.
AB  - OBJECTIVE: Generalized anxiety disorder might be better conceptualized as a
      prodrome, residual, or severity marker of major depression or other comorbid
      disorders than as an independent diagnosis. The authors questioned whether
      generalized anxiety disorder itself is associated with role impairment or whether
      the impairment of patients with generalized anxiety disorder is due to depression
      or other comorbid disorders. METHOD: The authors assessed data from the National
      Comorbidity Survey and the Midlife Development in the United States Survey for
      generalized anxiety disorder and major depression at 12 months by using the DSM
      III-R criteria with modified versions of the Composite International Diagnostic
      Interview. RESULTS: The prevalences of generalized anxiety disorder at 12 months
      were 3.1% and 3.3%, respectively, in the National Comorbidity Survey and the
      Midlife Development in the United States Survey; the prevalences of major
      depression at 12 months were 10.3% and 14.1%. The majority of respondents with
      generalized anxiety disorder at 12 months in the National Comorbidity Survey
      (58.1%) and the Midlife Development in the United States Survey (69.7%) also met
      the criteria for major depression at 12 months. Comparisons of respondents with
      one versus neither disorder showed that both disorders had statistically
      significant independent associations with impairment that were roughly equal in
      magnitude. These associations could not be explained by the other comorbid DSM
      III-R disorders or by sociodemographic variables. CONCLUSIONS: These results show
      that a substantial amount of generalized anxiety disorder occurs independently of
      major depression and that the role impairment of generalized anxiety disorder is
      comparable to that of major depression.

PMID- 10588406
TI  - Mental disorders and mental health treatment among U.S. Department of Veterans
      Affairs outpatients: the Veterans Health Study.
AB  - OBJECTIVE: The authors examined the self-reported presence and treatment of
      current depressive disorder, posttraumatic stress disorder (PTSD), and alcohol
      related disorder in a group of outpatient veterans. METHOD: Data were obtained
      from the Veterans Health Study, a longitudinal investigation of male veterans'
      health. A representative sample of 2,160 outpatients (mean age = 62 years) was
      drawn from Boston-area U.S. Department of Veterans Affairs (VA) outpatient
      facilities. The participants completed screening measures for depression, PTSD,
      and alcohol-related disorder. Mental health treatment was assessed by interviews.
      RESULTS: The screening criteria for at least one current mental disorder were
      satisfied by 40% (N = 856) of the patients. Screening rates were 31% (N = 676)
      for depression, 20% (N = 426) for PTSD, and 12% (N = 264) for alcohol-related
      disorder. Patients who screened positively for current mental disorders were
      younger, less likely to be married or employed, and more likely to report
      traumatic exposure than were those without mental disorders. Of those who met the
      screening criteria for any of the targeted mental disorders, 68% (N = 579)
      reported receiving mental health treatment. Younger, Caucasian men and those who
      reported more traumatic exposure were more likely to report receiving mental
      health treatment than were others who screened positively for mental disorders.
      CONCLUSIONS: Screening rates of depression and PTSD and rates of mental health
      treatment were considerably higher among these VA outpatients than among similar
      patients in primary care in the private sector. Although the VA is currently
      meeting the mental health care needs of its patients, future fiscal constraints
      could affect most adversely the treatment of non-Caucasian and older patients and
      those with a history of traumatic exposure.

PMID- 10588407
TI  - A pilot controlled clinical trial of ABT-418, a cholinergic agonist, in the
      treatment of adults with attention deficit hyperactivity disorder.
AB  - OBJECTIVE: Despite the increasing recognition of attention deficit hyperactivity
      disorder (ADHD) in adults, there is a paucity of controlled pharmacological
      trials. Recent reports have suggested the potential usefulness of cholinergic
      agents for ADHD. To this end, the authors completed a controlled study of ABT
      418, a novel cholinergic activating agent, for the treatment of adults with ADHD.
      METHOD: This was a double-blind, placebo-controlled, randomized, crossover trial
      that compared a transdermal patch of ABT-418 (75 mg/day) to placebo in adults who
      met DSM-IV criteria for ADHD. There were two 3-week treatment periods separated
      by 1 week of washout. RESULTS: Of the 32 subjects enrolled in the study (88% were
      men; mean age = 40 years, SD = 9), 29 completed the study. At the endpoint of
      each active arm (last observation carried forward), a significantly higher
      proportion of subjects was considered improved while receiving ABT-418 than while
      receiving placebo (40% versus 13%). Similarly, at endpoint there was a
      significantly greater reduction in ADHD symptom checklist scores (28% versus
      15%). Symptoms reflective of attention, and subjects with less severe ADHD,
      responded more robustly to ABT-418. Treatment with ABT-418 was relatively well
      tolerated; dizziness and nausea were the most frequently reported adverse
      effects. CONCLUSIONS: The results of this investigation indicate that ABT-418, a
      nicotinic analog, may be a potentially useful agent for the treatment of ADHD.

PMID- 10588408
TI  - Dimensional approach to delusions: comparison across types and diagnoses.
AB  - OBJECTIVE: A dimensional approach to the characterization of delusions was used
      to examine the use of non-content-related descriptors of delusions in revealing
      differences across diagnostic categories and delusion types. METHOD: Interviews
      with 1,136 acutely hospitalized psychiatric patients identified subjects as
      definitely or possibly delusional on the basis of screening questions derived
      from the Diagnostic Interview Schedule. Subjects with delusions were given the
      MacArthur-Maudsley Delusions Assessment Schedule, which generates scores on six
      dimensions of delusions. Delusions were classified by type, and diagnoses were
      assigned by using the DSM-III-R checklist. RESULTS: A total of 328 subjects (29%)
      were rated as definitely or possibly delusional. Their ratings on dimensions of
      the MacArthur-Maudsley Delusions Assessment Schedule were significantly but
      modestly intercorrelated. Subjects with schizophrenia generally had more intense
      delusions than those in other diagnostic categories. Grandiose and religious
      delusions were held with the greatest conviction, whereas persecutory delusions
      were marked by strong negative affect and a propensity to act. Factor analysis of
      the dimensions revealed a consistent two factor solution-"intensity and scope"
      and "affect and action"-regardless of the diagnosis or delusion type.
      CONCLUSIONS: The stability of the dimensional structure of delusions across
      diagnoses and delusion types suggests that even seemingly diverse delusions are
      more like than unlike each other; this is consistent with common etiologic
      mechanisms. The utility of a dimensional approach is indicated, in addition, by
      the ability to characterize delusions of different types and diagnoses so as to
      highlight therapeutic and other implications.

PMID- 10588409
TI  - Repeatable battery for the assessment of neuropsychological status as a screening
      test in schizophrenia I: sensitivity, reliability, and validity.
AB  - OBJECTIVE: Cognitive impairment is an important feature of schizophrenia and is
      correlated with functional outcome. However, psychiatry lacks a screening
      instrument that can reliably assess the types of cognitive impairment often seen
      in schizophrenia. The authors assessed the sensitivity, convergent validity, and
      reliability of the Repeatable Battery for the Assessment of Neuropsychological
      Status (RBANS) as well as the relationship of the RBANS to symptoms and
      employment status. This newly published test takes 25 minutes to administer and
      was standardized on a U.S.-Census-matched adult population. The test provides a
      total score and five index scores, each with a mean value of 100 (SD = 15).
      METHOD: RBANS data were obtained from 129 patients with schizophrenia in the
      outpatient and inpatient programs of the Maryland Psychiatric Research Center.
      RBANS data were correlated with WAIS-III and Wechsler Memory Scale, 3rd ed.
      performance in 38 patients. Reliability data for alternate forms of the RBANS
      were obtained from 53 patients; symptom ratings were obtained from 48 patients;
      and employment status was examined in 77 patients. RESULTS: The patients with
      schizophrenia demonstrated marked impairment on the RBANS (their mean total score
      was 71.4). The patients' index scores suggested that they had relatively less
      impairment of language and visual functions than of memory and attention. The
      RBANS demonstrated high correlations with full-scale IQ and memory measures. The
      total score demonstrated good reliability. RBANS performance minimally correlated
      with Brief Psychiatric Rating Scale ratings but was strongly related to
      employment outcome. CONCLUSIONS: The RBANS appears to be a useful cognitive
      screening instrument in schizophrenia. The instrument may be a useful prognostic
      indicator and offers a means of assessing cognitive status.

PMID- 10588410
TI  - Repeatable battery for the assessment of neuropsychological status as a screening
      test in schizophrenia, II: convergent/discriminant validity and diagnostic group
      comparisons.
AB  - OBJECTIVE: In a companion article in this issue of the Journal, the authors
      presented data suggesting that the Repeatable Battery for the Assessment of
      Neuropsychological Status (RBANS) is sensitive to the types of impairments
      observed in schizophrenia, correlates highly with standard measures of
      intelligence and memory, and is related to employment status in a group of
      patients with schizophrenia drawn from a tertiary care research center. The
      objectives of the current study were 1) to determine if evidence of the
      convergent validity of the RBANS could be replicated in a diagnostically
      heterogeneous sample drawn from a public mental health system, 2) to examine the
      relationship of the RBANS to a broad neuropsychological battery, and 3) to
      compare the performance of patients with schizophrenia and patients with bipolar
      disorder on a neuropsychological battery and the RBANS. METHOD: The RBANS and a
      standard neuropsychological battery, including the WAIS-III and Wechsler Memory
      Scale, 3rd ed. (WMS-III), were given to 150 patients drawn from a larger study of
      vocational rehabilitation. RESULTS: Correlations of RBANS total scores with WAIS
      III and WMS-III variables were highly similar across study groups. The RBANS
      correlated highly with a composite z score derived from 22 standard measures of
      IQ, memory, language, motor, attention, and executive function. Principal
      component analyses of the neuropsychological battery resulted in a six-factor
      solution: the RBANS correlated most highly with a general ability factor and had
      limited correlations with measures of motor performance, vigilance, and executive
      function. Patients with schizophrenia demonstrated greater deficits on the
      neuropsychological battery and the RBANS than patients with bipolar disorder.
      CONCLUSIONS: These data suggest that the RBANS is a useful screening instrument
      for assessing the severity of cognitive impairment in psychiatric populations.

PMID- 10588411
TI  - Quantitative study of signal hyperintensities on T2-weighted magnetic resonance
      imaging in late-onset schizophrenia.
AB  - OBJECTIVE: The authors investigated the extent and distribution of signal
      hyperintensities on T2-weighted magnetic resonance imaging (MRI) of the brains of
      subjects with late-onset schizophrenia. METHOD: The study group consisted of 25
      subjects with DSM-III-R schizophrenia and onset at age 50 or more years (late
      onset schizophrenia) matched group-wise with 24 subjects with early-onset
      schizophrenia and 30 psychiatrically healthy volunteers. The subjects underwent
      clinical and neuropsychological assessments and MRI scans. Transaxial T2-weighted
      and proton-density images were analyzed manually for signal hyperintensities in
      cerebral and cerebellar white matter, the basal ganglia, thalamus, and brainstem,
      and quantitative measures were obtained. RESULTS: Subjects with late-onset
      schizophrenia had greater periventricular hyperintensities measured as widths of
      periventricular rims and frontal and occipital caps than the two comparison
      groups. Hyperintense signals elsewhere in the white matter and in the basal
      ganglia and brainstem did not differ between groups, but the late-onset
      schizophrenia group had more signal hyperintensities in the thalamus than the
      normal comparison group. Signal hyperintensities in the frontal-subcortical
      circuit regions, when considered together, did not differ between groups.
      Periventricular hyperintensities had significant negative correlations with
      intelligence, memory, and frontal-executive functioning in the total group.
      CONCLUSIONS: The finding of increased periventricular hyperintensities and
      thalamic signal hyperintensities in late-onset schizophrenia suggests the
      possibility that cerebrovascular disease, in an interaction with some
      incompletely understood vulnerability factors, may play a role in the
      pathogenesis of schizophrenia with onset in advanced age.

PMID- 10588412
TI  - Can involuntary outpatient commitment reduce hospital recidivism?: Findings from
      a randomized trial with severely mentally ill individuals.
AB  - OBJECTIVE: The goal of this study was to evaluate the effectiveness of
      involuntary outpatient commitment in reducing rehospitalizations among
      individuals with severe mental illnesses. METHOD: Subjects who were hospitalized
      involuntarily were randomly assigned to be released (N = 135) or to continue
      under outpatient commitment (N = 129) after hospital discharge and followed for 1
      year. Each subject received case management services plus additional outpatient
      treatment. Outpatient treatment and hospital use data were collected. RESULTS: In
      bivariate analyses, the control and outpatient commitment groups did not differ
      significantly in hospital outcomes. However, subjects who underwent sustained
      periods of outpatient commitment beyond that of the initial court order had
      approximately 57% fewer readmissions and 20 fewer hospital days than control
      subjects. Sustained outpatient commitment was shown to be particularly effective
      for individuals with nonaffective psychotic disorders, reducing hospital
      readmissions approximately 72% and requiring 28 fewer hospital days. In repeated
      measures multivariable analyses, the outpatient commitment group had
      significantly better hospital outcomes, even without considering the total length
      of court-ordered outpatient commitments. However, in subsequent repeated measures
      analyses examining the role of outpatient treatment among psychotically
      disordered individuals, it was also found that sustained outpatient commitment
      reduced hospital readmissions only when combined with a higher intensity of
      outpatient treatment. CONCLUSIONS: Outpatient commitment can work to reduce
      hospital readmissions and total hospital days when court orders are sustained and
      combined with intensive treatment, particularly for individuals with psychotic
      disorders. This use of outpatient commitment is not a substitute for intensive
      treatment; it requires a substantial commitment of treatment resources to be
      effective.

PMID- 10588413
TI  - Treating bipolar illness: focus on treatment algorithms and management of the
      sleep-wake cycle.

PMID- 10588415
TI  - Association among visual hallucinations, visual acuity, and specific eye
      pathologies in Alzheimer's disease: treatment implications.
AB  - OBJECTIVE: Studies suggest a link between visual acuity and visual hallucinations
      in dementia, but links with specific eye pathologies have not been evaluated.
      METHOD: Fifty patients (20 with visual hallucinations, 30 without) with probable
      Alzheimer's disease had an evaluation of psychotic symptoms. Visual acuity was
      measured before and after refractions, and ophthalmological examinations included
      standardized assessments for cataracts and macular degeneration. RESULTS:
      Impaired visual acuity and the severity of cognitive impairments were
      significantly associated with visual hallucinations. No patients with normal
      acuity (6/5 or 6/6 on the Snellen chart) experienced these symptoms. Impaired
      acuity improved with refraction in 60% (N = 12) of the patients with visual
      hallucinations. Of specific eye pathologies, only cataracts were significantly
      associated with visual hallucinations. Descriptive follow-up information suggests
      that an optician's assessment for glasses improves outcome. CONCLUSIONS: Glasses
      and cataract surgery need evaluation as prophylactic or adjunctive treatments for
      visual hallucinations in patients with probable Alzheimer's disease.

PMID- 10588416
TI  - Rostral and orbital prefrontal cortex dysfunction in the manic state of bipolar
      disorder.
AB  - OBJECTIVE: This study investigated prefrontal cortex function in the manic state
      of bipolar disorder. METHOD: High-sensitivity [15O]H2O positron emission
      tomography and a word generation activation paradigm were used to study regional
      cerebral blood flow in five manic and six euthymic individuals with bipolar
      disorder and in five healthy individuals. RESULTS: Decreased right rostral and
      orbital prefrontal cortex activation during word generation and decreased
      orbitofrontal activity during rest were associated with mania. CONCLUSIONS: The
      data support the presence of rostral and orbital prefrontal dysfunction in
      primary mania. These findings, when seen in the context of the human brain lesion
      and the behavioral neuroanatomic literatures, may help to explain some of the
      neurobehavioral abnormalities characteristic of the manic state.

PMID- 10588417
TI  - Absence of striatal volume differences between depressed subjects with no
      comorbid medical illness and matched comparison subjects.
AB  - OBJECTIVE: The striatum (caudate and putamen) appears to be important in the
      pathogenesis of depression. Some studies show smaller than normal striatal
      structure volumes in depressed subjects. This study compared striatal volumes in
      depressed and nondepressed women, screened to exclude major cerebrovascular
      disease risk factors and comorbid medical illness. METHOD: Caudate and putamen
      volumes were measured from magnetic resonance imaging scans of 24 depressed women
      and 24 matched nondepressed comparison subjects. RESULTS: Caudate and putamen
      volumes were not significantly different between depressed and nondepressed
      groups. CONCLUSIONS: These findings differ from those of previous studies,
      possibly because of the exclusion of subjects with cerebrovascular risk factors
      in this study.

PMID- 10588418
TI  - Duration of periods of euthymia in patients with dysthymic disorder.
AB  - OBJECTIVE: The purpose of this study was to assess the duration of periods of
      euthymia in patients with dysthymia. METHOD: All patients with dysthymia who came
      to the Center for Anxiety and Depression over a 10-month period (N = 22) were
      interviewed by the author regarding the duration of their euthymic episodes.
      RESULTS: The 22 patients with dysthymia reported euthymic periods from 2 to 30
      days (mean = 8.0 days, SD = 6.6). CONCLUSIONS: The euthymic period of up to 2
      months that is specified in DSM-IV for dysthymic disorder might confound the
      results of clinical trials. Data from additional groups of dysthymic patients
      would be useful when considering this issue for DSM-V.

PMID- 10588419
TI  - Influence of traumatic grief on suicidal ideation among young adults.
AB  - OBJECTIVE: The purpose of this study was to examine the influence of traumatic
      grief on suicidal ideation. METHOD: The Beck-Kovacs Scale for Suicidal Ideation
      was administered to 76 young adult friends of suicide victims. RESULTS: Traumatic
      grief was associated with a 5.08 times greater likelihood of suicidal ideation,
      after control for depression. Comorbid traumatic grief and depression were not
      associated with a greater likelihood of suicidal ideation. CONCLUSIONS: Syndromal
      traumatic grief heightens vulnerability to suicidal ideation.

PMID- 10588420
TI  - Why does postpsychotic IQ decline in childhood-onset schizophrenia?
AB  - OBJECTIVE: The authors' goal was to examine whether the postpsychotic decline in
      full scale IQ during adolescence for patients with childhood-onset schizophrenia
      is due to a dementing process or simply failure to acquire new information and
      skills. METHOD: Linear regression was used to determine the rate of change for
      scaled and raw scores on subtests of 31 patients with childhood-onset
      schizophrenia. The resulting slopes were examined and related to changes in the
      patients' brains determined by magnetic resonance imaging. RESULTS: Three
      postpsychotic subtest scaled scores declined significantly: picture arrangement,
      information, and block design. In contrast, there was no decline in the non-age
      corrected (raw) scores for any subtest. A significant correlation was found
      between decrease in hippocampal volume and a smaller increase in raw score on the
      information subtest. CONCLUSIONS: The decline during adolescence in the full
      scale IQ of patients with childhood-onset schizophrenia does not reflect dementia
      but, rather, an inability to acquire new information and abilities.

PMID- 10588421
TI  - Obsessive-compulsive disorder in patients with first-episode schizophrenia.
AB  - OBJECTIVE: The aim of the present study was to determine the rate of obsessive
      compulsive disorder (OCD) in patients with first-episode schizophrenia. METHOD:
      Fifty patients consecutively hospitalized with first-episode psychosis who met
      DSM-IV criteria for schizophrenia spectrum disorders were assessed for OCD. The
      instruments used were the Structured Clinical Interview for DSM-IV, Schedule for
      the Assessment of Positive Symptoms (SAPS), Schedule for the Assessment of
      Negative Symptoms (SANS), and Yale-Brown Obsessive Compulsive Scale. RESULTS:
      Seven (14%) of the 50 schizophrenic patients met DSM-IV criteria for OCD and
      scored significantly lower than schizophrenic patients without OCD on the formal
      thought disorder subscale of the SAPS and the flattened affect subscale of the
      SANS. CONCLUSIONS: OCD is relatively frequent in patients with first-episode
      schizophrenia and may have a "protective" effect on some schizophrenic symptoms,
      at least in the early stages of the disease.

PMID- 10588422
TI  - Treatment of acute mania with topiramate.

PMID- 10588423
TI  - Tiagabine and the treatment of refractory bipolar disorder.

PMID- 10588424
TI  - Lamotrigine-induced rash after sun exposure.

PMID- 10588425
TI  - Reduction of tardive dystonia with olanzapine.

PMID- 10588426
TI  - Creutzfeldt-Jakob disease appearing as paranoid psychosis.

PMID- 10588427
TI  - Treatment augmentation with opiates in severe and refractory major depression.

PMID- 10588428
TI  - Bupropion-induced psychosis.

PMID- 10588429
TI  - Geography of U.S. psychiatric disease by MEDLINE publications, 1990-1997.

PMID- 10588430
TI  - Haloperidol an Alzheimer's disease.

PMID- 10588431
TI  - Additional highly polymorphic microsatellite (STR) loci for estimating kinship in
      rhesus macaques (Macaca mulatta).
AB  - Thirty-four short tandem repeat (STR) loci, not previously studied in rhesus
      macaques, were amplified by PCR. About one third of these were found to clearly
      and reliably amplify and exhibit high levels of genetic heterogeneity even in
      relatively inbred populations. These loci, together with 11 loci previously
      studied, were sufficiently informative to discretely differentiate between
      related and unrelated pairs and, in most cases, between parent/offspring and
      other relative pairs. An even greater number of hypervariable STR loci might be
      required to distinguish between half-sib and full-sib pairs in most rhesus
      populations.

PMID- 10588432
TI  - Social organization of the Alaotran gentle lemur (Hapalemur griseus alaotrensis).
AB  - Knowledge of the social organization of lemurs is still limited for most species.
      Where there is sufficient information, it has been shown that lemur social
      organization differs in essential points from that of other primates. In the
      field study reported here, demographic structure and life-history processes were
      investigated in order to characterize the social organization of the Alaotran
      gentle lemur (Hapalemur griseus alaotrensis). Data were obtained through captures
      and observations. Alaotran gentle lemurs were found in small groups of up to nine
      individuals. Although most groups contained just one breeding female, a
      substantial proportion of groups (35%) had two breeding females. Therefore,
      Alaotran gentle lemurs cannot be classed as being organized in monogamous family
      groups. An extended birth season was found, and groups with two breeding females
      had significantly higher breeding output per adult than groups with a single
      adult female. Limited data suggest that females emigrate from their natal group
      while still subadult, whereas males can stay in the natal group until they are
      fully grown and disperse as adults. Variability in group composition,
      significantly higher reproductive output per adult in groups with two breeding
      females, and delayed dispersal of males suggest that Alaotran gentle lemurs
      pursue a resource-defense mating strategy, rather than a female-defense mating
      strategy. The suggestion that extant social lemurs may have evolved from a
      monogamous system, could explain the differences between lemur social systems and
      those of other primates.

PMID- 10588433
TI  - Food-neophobia in semi-free ranging rhesus macaques: effects of food limitation
      and food source.
AB  - This study characterizes food neophobia in semi-free ranging rhesus macaques. In
      experiment one, monkeys received novel and familiar foods during periods of
      normal provisioning and when provisioning was suspended. The monkeys did
      discriminate between novel and familiar foods and continued to exhibit neophobia
      when provisioning was suspended. In experiment two, food was either tossed to
      subjects or placed in the habitat so that monkeys discovered food without the
      observer in close proximity. Rhesus macaques were more likely to eat a novel food
      that was hand-tossed to them compared to food they discovered in their habitat.
      This study suggests that food neophobia is a robust trait in rhesus macaques and
      that a history of provisioning may affect the expression of the trait.

PMID- 10588434
TI  - Coalition formation among male Barbary macaques (Macaca sylvanus).
AB  - A coalition is formed when one animal intervenes in an ongoing conflict between
      two parties to support one side. Since support of one party is also an act
      against the other party, coalitions are triadic interactions involving a
      supporter, a recipient, and a target. The purpose of this study was to test which
      of three possible theories explains coalition formation among male Barbary
      macaques: 1) Males support kin to enhance their indirect fitness (kin selection).
      2) Males support nonkin to receive future reciprocal support (reciprocal
      altruism). 3) Males pursue self-interests and immediately benefit via nonkin
      support (cooperation). Coalition formation was investigated among 31 semi-free
      male Barbary macaques in the Salem Monkey Park, Germany during the mating season.
      The results show: 1) Males intervened more often in dyadic conflicts in which a
      related opponent was involved and supported related opponents more than unrelated
      opponents. Close kin supported each other more often than distant kin. 2) Some
      evidence for reciprocal support was found. However, reciprocity was probably a by
      product of targeting the same individuals for dominance. 3) Coalition formation
      among nonkin is best interpreted as cooperation, based on self-interests. Male
      Barbary macaques seem to intervene more often to stabilize and less often to
      improve their rank. Although our data were limited, the results revealed that kin
      support, reciprocal support, and cooperative support were all involved in
      coalition formation among male Barbary macaques.

PMID- 10588435
TI  - Population dynamics of the feral macaques in the Kowloon Hills of Hong Kong.
AB  - Hong Kong's feral monkey population is controversial. Many people complain about
      the aggressiveness of the monkeys, while some conservationists urge the
      government to deal with the problem in a way that will not harm the monkeys. The
      population dynamics of the macaques in the Kowloon Hills were studied in 1992 and
      1993. Vital statistics are provided from this study as a first step in resolving
      the problems of human provisioning and wildlife management. It is unlikely that
      these macaques are indigenous to the area. They are the descendents of macaques
      that were released in the early twentieth century to control the spread of a
      local poisonous plant, the strychnos, which contains alkaloids poisonous to
      livestock and humans but which is a favorite food of the macaques. The macaque
      population expanded dramatically during the 1980s. The census method employed in
      this study is direct head count and photo-identification. At the end of 1993, the
      estimated abundance was 690 (+/-6) in eight social groups in the Kowloon Hills.
      Species found were rhesus (Macaca mulatta) 65.3%, longtailed (M. fascicularis)
      2.2%, Tibetan (M. thibetana) 0.2%, and hybrids 32.3%. The overall home ranges
      occupied 2.15 km2, resulting in a very high macaque density of 326 per km2. The
      birth rates were 56.9% and 69.4% in 1992 and 1993, respectively. Mean adult sex
      ratio (M:F) was 1:2.2 for social groups and 1:1.6 including all peripheral males.
      The main mortality factor was road accidents and these contributed to the
      "missing rate" of 9.8% and 10.6% in 1992 and 1993, respectively. Population
      growth was 5.6% in 1992 and 7.8% in 1993. The estimated macaque population in the
      year 2000 will be around 1,100 if conditions remain favorable. Management
      strategies are recommended.

PMID- 10588436
TI  - Growth hormone and thyroid stimulating hormone concentrations in captive male
      orangutans: implications for understanding developmental arrest.
AB  - There are two morphs of reproductive male in orangutans. Both morphs span the age
      range from adolescent to adult, but "subadult" males are smaller in size and lack
      secondary sexual features. In this study, urine samples were collected over a 2
      year period from 23 captive male orangutans in order to define the endocrinology
      of this apparent arrest of secondary sexual development. Three males were
      juveniles, 3 to 5 years of age; seven males showed no secondary sexual trait
      development and were over 7 years of age; six males were in the process of
      developing secondary sexual features, with the youngest male being 6 years of
      age; and seven males were fully mature adults. Morning samples were analyzed by
      radioimmunoassay for levels of growth hormone (GH) and thyroid-stimulating
      hormone (TSH) and group hormone profiles were compared by analysis of variance.
      GH is the primary hormone of growth and development and its increase in teenage
      boys is associated with the adolescent growth spurt. TSH stimulates the thyroid
      to produce and secrete hormones that have metabolic effects and required for
      normal growth and development. Results show that arrested adolescent male
      orangutans have a GH level about 1/3 that of developing adolescents (P = .0006).
      TSH levels do not differ significantly between arrested and developing
      adolescents. These data complement other endocrine data showing significantly
      lower levels of sex steroids and luteinizing hormone (LH) in arrested males than
      developing males [Maggioncalda, 1995a,b; Maggioncalda et al., 1999]. Together
      with documented behavioral differences between reproductive males with and
      without secondary sexual features, these endocrine data support the hypothesis
      that in male orangutans there are alternative developmental pathways and
      corresponding alternative reproductive strategies.

PMID- 10588437
TI  - Social grooming in assamese macaques (Macaca assamensis).
AB  - Reciprocity and social bonding hypotheses were evaluated as explanations for
      observed patterns of social grooming in assamese macaques (Macaca assamensis). In
      accordance with social bonding, females, as the long-term residents of this
      matrifocal group, groomed each other and juveniles more often than males groomed
      one another or juveniles. On the other hand, males groomed females more often and
      for longer durations than females groomed males and, whereas both males and
      females groomed juveniles more often than juveniles groomed them, juveniles
      groomed their elders for longer durations. Male grooming of females did not seem
      directly related to matings as males are single mount ejaculators and use
      coercive mating tactics. Male grooming of females could not be accounted for in
      terms of reciprocity; it was not a simple function of dominance. Although both
      sexes groomed subordinate females more than vice versa, males groomed dominant
      males more and females groomed subordinate males more than they received grooming
      from them. Grooming was concluded to function to establish and maintain
      affiliative social bonds rather than as a specific mechanism to obtain matings or
      any other specific reciprocation in terms of services or favors.

PMID- 10588438
TI  - Reproductive performance of rhesus macaques (Macaca mulatta) in two outdoor
      housing conditions.
AB  - This study examined the reproductive performance of rhesus macaques maintained in
      two different housing conditions: high-density semi-sheltered gang cages and low
      density outdoor corrals. Two hundred sixteen subjects were housed in 49 gang
      cages, each of which contained one breeding male and between one and eight
      breeding females. Two hundred seven subjects were housed in 13 corrals, each of
      which contained between two and four breeding males and between 9 and 26 breeding
      females. Over a 3-year period, pregnancy, live birth, and production rates were
      significantly greater for females in corrals than for females in gang cages.
      Fetal death rate was lower in corrals than in gang cages, while neonatal death
      rates did not differ between housing conditions. These differences did not result
      from potential confounds such as differential age structures or virological
      statuses between housing conditions. We conclude that, for rhesus macaques,
      outdoor corral housing leads to better reproductive performance than does semi
      sheltered gang housing, probably as a result of increased individual space and
      relaxation of intense social stressors.

PMID- 10588439
TI  - Nonthyroid causes of extraocular muscle disease.
AB  - Extraocular muscle involvement in orbital disease is most frequently seen as a
      feature of thyroid orbitopathy (Graves' disease). However, a wide range of other
      conditions may alter the size, shape, and function of these muscles, with
      characteristic clinical manifestations or abnormalities visible on orbital
      imaging. The differential diagnosis of muscle disease can be narrowed by careful
      analysis of clinical features and ancillary tests. Imaging facilitates
      recognition in many cases, but in some instances, accurate diagnosis requires
      biopsy. This review highlights the differential diagnoses for diseases of
      extraocular muscles based on the clinical and investigative records of 103
      patients at our institution combined with data from the world literature. We
      found that the most common nonthyroid causes of muscle disease were inflammatory,
      vascular, and neoplastic processes (in decreasing order of frequency). Emphasis
      is placed on investigations that provide a logical approach to, and appropriate
      management of, disease of the extraocular muscles.

PMID- 10588440
TI  - Controversies in the management of open-globe injuries involving the posterior
      segment.
AB  - There are numerous unresolved issues and controversies regarding the management
      of open-globe injuries involving the posterior segment. These areas include, but
      are not limited to, the following issues. Although vitrectomy has been shown to
      improve visual outcomes and allow retention of the eye in many cases, the extent
      of visual improvement is often limited because of the nature of the injury.
      Timing of vitrectomy surgery has been and will continue to be debated by
      proponents of early versus delayed intervention. The multiple features of acute
      ocular injury make it very difficult to interpret retrospective data regarding
      the most appropriate timing for surgical intervention. The use of prophylactic
      cryotherapy, in the setting of a scleral laceration with possible retinal damage,
      is not as controversial at present, as there is now sufficient data indicating
      that cryotherapy may actually exacerbate intraocular proliferation and worsen the
      situation. The role and benefit of a prophylactic scleral buckle is very widely
      contested, and it is not known if it truly decreases the risk of subsequent
      retinal detachment. Another area of debate centers on the use of antibiotics.
      When there is a known clinical infection, intravitreal antibiotics are the
      mainstays of therapy. However, in the absence of clinical infection, the use of
      prophylactic antibiotics and their routes of administration are quite
      controversial. Although there are significant data regarding the use of
      antibiotics in the postoperative setting, this information cannot be extrapolated
      into the setting of open-globe injuries, as organisms and virulence factors
      differ. Similarly, the use of vitrectomy versus vitreous tap in the setting of
      traumatic endophthalmitis is not fully resolved, although vitrectomy is used in
      most cases to repair concurrent damage from the injury itself. Finally, the
      placement of intraocular lenses in the acute trauma setting is controversial, as
      the risk of complications is quite high. Prospective, controlled clinical studies
      have not been done. This article reviews pertinent data regarding these
      management issues and controversies, and provides recommendations for treatment
      based on the available published data and the authors' personal experience.

PMID- 10588441
TI  - The clinical spectrum of schwannomas presenting with visual dysfunction: a
      clinicopathologic study of three cases.
AB  - Schwannomas (neurilemomas) are benign tumors that arise from Schwann cells in the
      peripheral nervous system. The most commonly involved nerves that cause neuro
      ophthalmic manifestations are cranial nerves V and VIII. In this series of three
      women, schwannomas presented as intraconal masses that mimicked a cavernous
      hemangioma, a superior orbital mass transgressing the superior orbital fissure,
      and an expansive frontal lobe mass with clinical symptoms and signs of increased
      intracranial pressure. Although all three complained of visual blurring, none of
      our patients presented with Vth or VIIIth cranial nerve dysfunction.
      Histopathologic studies demonstrated well-circumscribed, encapsulated spindle
      cell lesions with classic Antoni A and B patterns. Histopathologic examination is
      essential to confirm the diagnosis of a schwannoma that may be otherwise
      clinically confusing. Direct optic nerve compression, globe indentation with
      induced hyperopia, or increased intracranial pressure with optic nerve compromise
      may be responsible for visual symptoms. A multidisciplinary approach is often
      required because of the size and location of schwannomas.

PMID- 10588442
TI  - Tumor suppressor genes in ophthalmology.
AB  - Tumor suppressor genes have a diversity of functions, but they have in common the
      property of inhibiting neoplastic transformation. When they become inactivated, a
      constraint is removed that allows cells to grow inappropriately. Mutations in
      these genes are now thought to be the initiating events in most cancers. The
      first tumor suppressor gene was discovered through its role in retinoblastoma,
      and many other tumor suppressor genes also have important ophthalmic
      manifestations. The first group of tumor suppressor genes to be discussed are
      those involved in retinoblastoma and uveal melanoma. These are among the most
      frequently mutated genes in human cancer and are key regulators of growth and
      homeostasis. The second group of genes is associated with specific hereditary
      tumor syndromes with ophthalmic manifestations. These genes function in a variety
      of molecular pathways and are associated with neoplastic and non-neoplastic
      abnormalities in restricted tissue distributions. Research on tumor suppressor
      genes continues to shed light on the molecular pathophysiology of ophthalmic
      tumors and will increasingly yield diagnostic and therapeutic applications.

PMID- 10588443
TI  - Not so slowly progressive visual loss.
AB  - A 51-year-old man presented with bilateral progressive visual loss during a 2
      month period. Visual acuity was 20/60 in both eyes with bilateral constricted
      visual fields. Funduscopy revealed bilateral disk pallor and arteriolar
      attenuation. His vision declined rapidly during the next 2 weeks. Investigations
      showed a positive cerebrospinal fluid Venereal Disease Research Laboratory test
      (1:8). A diagnosis of neurosyphilis was made, and treatment was started with high
      dose intravenous and intramuscular penicillin.

PMID- 10588444
TI  - From four-bed clinic to modern eye hospital: ophthalmology in Leipzig, 1820-1996.
AB  - The opening of the "Heilanstalt fur arme Augenkranke" by Friedrich Philipp
      Ritterich (1782-1866) in 1820 was an important landmark for ophthalmology in
      Leipzig and in all of Germany. The first chair of ophthalmology in Germany was
      taken by Christian Georg Theodor Ruete in 1852. In 1883 the clinic moved to a new
      domicile, a modern building in the Leipzig "medical quarter." In the ensuing
      years, the hospital developed into a well-known university center of
      ophthalmology with the scientific, clinical, and organizational work of
      ophthalmologists such as Hubert Sattler and Ernst Hertel. The extension of the
      old building in 1908-1911 and the rebuilding after the destruction in World War
      II created better opportunities for research, teaching, and patient treatment.
      Comprehensive expansion and reconstruction of the Eye Hospital since 1994 has
      created excellent conditions for both clinical and experimental ophthalmology as
      well as the training of students.

PMID- 10588446
TI  - Dipeptidyl-peptidase IV (CD26)--role in the inactivation of regulatory peptides.
AB  - Dipeptidyl-peptidase IV (DPP IV/CD26) has a dual function as a regulatory
      protease and as a binding protein. Its role in the inactivation of bioactive
      peptides was recognized 20 years ago due to its unique ability to liberate Xaa
      Pro or Xaa-Ala dipeptides from the N-terminus of regulatory peptides, but further
      examples are now emerging from in vitro and vivo experiments. Despite the minimal
      N-terminal truncation by DPP IV, many mammalian regulatory peptides are
      inactivated--either totally or only differentially--for certain receptor
      subtypes. Important DPP IV substrates include neuropeptides like neuropeptide Y
      or endomorphin, circulating peptide hormones like peptide YY, growth hormone
      releasing hormone, glucagon-like peptides(GLP)-1 and -2, gastric inhibitory
      polypeptide as well as paracrine chemokines like RANTES (regulated on activation
      normal T cell expressed and secreted), stromal cell-derived factor, eotaxin and
      macrophage-derived chemokine. Based on these findings the potential clinical uses
      of selective DPP IV inhibitors or DPP IV-resistant analogues, especially for the
      insulinotropic hormone GLP-1, have been tested to enhance insulin secretion and
      to improve glucose tolerance in diabetic animals. Thus, DPP IV appears to be a
      major physiological regulator for some regulatory peptides, neuropeptides,
      circulating hormones and chemokines.

PMID- 10588445
TI  - Structure-activity relationships of adrenomedullin in the circulation and adrenal
      gland.
AB  - Adrenomedullin (ADM) is a recently discovered vasoactive peptide that has potent
      vasodilator activity in the pulmonary and peripheral vascular beds and has
      significant effects on endocrine function. ADM is a member of the CGRP/amylin
      superfamily of peptides based largely on the presence of the six-membered ring
      structure and C-terminal amidation that is highly conserved in this family.
      Proadrenomedullin is a 185 amino acid precursor with enzymatic cleavage sites for
      both ADM and a unique 20 amino acid peptide named proadrenomedullin N-terminal 20
      peptide (PAMP). ADM and PAMP are found in a variety of organ systems, and plasma
      levels of the peptides are increased in pathophysiologic conditions. Both
      peptides have hypotensive and vasodilator activity in the pulmonary and regional
      vascular beds and have significant effects on the endocrine system, including the
      adrenal gland. ADM (15-52), which retains the six-membered ring structure,
      maintains the vasodilator activity of ADM, suggesting that the 14 amino acid N
      terminal extension is not necessary for the full agonist activity. However,
      analogs, such as ADM-(22-52) and ADM-(40-52), which do not contain the six-member
      ring structure, lack agonist activity. Unlike the full-sequence peptide, hADM-(15
      22) and ADM-(16-21), which contain the ring structure, increase systemic arterial
      pressure in the rat but not in the cat. The present review discusses the
      structure-activity relationship for the actions of ADM and related peptides and
      discusses the mechanisms which mediate responses to these widely distributed
      peptides.

PMID- 10588447
TI  - Orexins and orexin receptors: implication in feeding behavior.
AB  - Orexin-A and -B are initially identified as endogenous ligands for an orphan G
      protein coupled receptor. Since the discovery of orexins, investigations of their
      functions have been guided by their distribution in the lateral hypothalamic
      area, which has been implicated in feeding behavior. In fact, when administered
      intracerebroventricularly in early light phase, orexin-A stimulated food
      consumption. Orexin mRNA is up-regulated by fasting, suggesting their expression
      is regulated by animal's nutritional status. The orexin neurons project widely in
      the brain, and thus the physiological role of orexins is likely to be complex.
      Orexin neurons in the lateral hypothalamic area was shown to receive terminal
      appositions from NPY-, AgRP-, and a-MSH-IR fibers. The innervation of orexin
      neurons by peptidergic fibers corresponding to leptin-responsive cell types that
      reside in the arcuate nucleus may have a role in linking peripheral metabolic
      cues to autonomic regulatory sites and the cerebral cortical mantle, providing a
      neuroanatomic basis for regulation of feeding behavior. The wide distribution of
      orexin-immunoreactive fibers in the brain has also suggested their additional
      roles. Actually, orexins have been reported to have roles in regulating drinking
      behavior, neuroendocrine function and the sleep-wake cycle.

PMID- 10588448
TI  - Emerging features of brain angiotensin receptors.
AB  - In mammalian brain, angiotensin II AT1 and AT2 receptor subtypes are apparently
      expressed only in neurons and not in glia. AT1 and AT2 receptor subtypes are
      sometimes closely associated, but apparently expressed in different neurons.
      Brain AT1/AT2 interactions may occur in selective cases as inter-neuron cross
      talk. There are two AT1 isoforms in rodents. AT1A, which predominates, and AT1B.
      There are also important inter-species differences in receptor expression.
      Relative lack of amino acid conservation in the gerbil gAT1A receptor
      substantially decreases affinity for the AT1 antagonists. AT1 receptors are
      expressed in brain areas regulating autonomic and hormonal responses. AT1A
      receptors are heterogeneously regulated in a number of experimental conditions.
      In specific areas, AT1A receptors are not normally expressed, but are induced
      under influence of reproductive hormones in dopaminergic neurons. There are AT1
      and AT2 receptors also in areas related to limbic, sensory and motor functions
      and their expression is developmentally regulated. A picture is emerging of
      widespread, neuronally localized, heterogeneously regulated, closely associated
      brain angiotensin receptor subtypes, modulating multiple functions including
      neuroendocrine and autonomic responses, stress, cerebrovascular flow, and perhaps
      brain maturation, neuronal plasticity, memory and behavior.

PMID- 10588449
TI  - Neuro-hormonal control of bone metabolism: vasoactive intestinal peptide
      stimulates alkaline phosphatase activity and mRNA expression in mouse calvarial
      osteoblasts as well as calcium accumulation mineralized bone nodules.
AB  - Based upon the immunohistochemical demonstration of neuropeptides in the
      skeleton, including vasoactive intestinal peptide (VIP), we have addressed the
      question of whether neuropeptides may exert regulatory roles on bone tissue
      metabolism or not. In the present communication, we have investigated if VIP can
      affect anabolic processes in osteoblasts. Osteoblasts were isolated from neonatal
      mouse calvariae by time sequential enzyme-digestion and subsequently cultured for
      2-28 days in the presence of VIP and other modulators of cyclic AMP formation.
      VIP (10(-6) M) stimulated ALP activity and calcium content. The cyclic AMP
      phosphodiesterase inhibitors ZK 62 711 (10(-4) M) and isobutyl-methylxanthine
      (10(-4) M) stimulated ALP activity and synergistically potentiated the effect of
      VIP. Neither VIP, nor isobutyl-methylxanthine or ZK 62 711, in the absence or
      presence of VIP, affected cell number. The stimulatory effect of VIP on ALP
      activity, in the presence of ZK 62 711, was dependent on time and concentration
      of VIP. The stimulatory effects of VIP and ZK 62 711 on ALP activity was seen
      also in cells stained for ALP. VIP (10(-6) M), in the presence of ZK 62 711 (10(
      6) M), significantly enhanced mRNA for tissue non-specific ALP. VIP (10(-6) M),
      in the presence of ZK 62 711, stimulated cyclic AMP production. Forskolin and
      choleratoxin stimulated ALP activity and cyclic AMP formation in a concentration
      dependent manner, without affecting cell number. VIP (10(-6) M) and ZK 62 711
      (10(-5) M) stimulated, and their combination synergistically enhanced, calcium
      content in bone noduli. These data show that VIP, without affecting cell
      proliferation, can stimulate osteoblastic ALP biosynthesis and bone noduli
      formation by a mechanism mediated by cyclic AMP. Our observations suggest a
      possibility that anabolic processes in bone are under neurohormonal control.

PMID- 10588450
TI  - Human polyomavirus BK (BKV) load and haemorrhagic cystitis in bone marrow
      transplantation patients.
AB  - Several observations suggest an association between long-lasting haemorrhagic
      cystitis (HC) in bone marrow transplantation (BMT) recipients and human
      polyomavirus BK (BKV) reactivation, but no conclusive evidence has been obtained
      so far. The amount of BKV measured in the urine of BMT patients during an episode
      of HC was compared with that detected in the urine of BMT patients without HC and
      of immunocompetent individuals in order to better assess the association of BKV
      reactivation with HC. For this purpose a quantitative competitive PCR was
      developed. The application of this assay to clinical samples allowed us to
      distinguish asymptomatic reactivation both in healthy individuals and in
      immunocompromised patients from reactivation associated with HC, in almost all
      cases. Low levels, below the sensitivity of the quantitative assay, were shown in
      asymptomatic healthy individuals and in about 50% of immunocompromised patients.
      A significantly higher viral load than in the urine of asymptomatic
      immunocompromised patients was detected in the urine of patients with HC. These
      data strengthen the hypothesis that BKV reactivation can cause, together with
      other factors, the majority of late HC in BMT recipients as well as in patients
      treated for acute refractory lymphoblastic leukemia.

PMID- 10588451
TI  - Comparison of three commercial assays for the quantification of HIV-1 RNA in
      plasma from individuals infected with different HIV-1 subtypes.
AB  - BACKGROUND: Commercial human immunodeficiency virus 1 (HIV-1) ribonucleic acid
      (RNA) quantification assays vary in their ability to quantify different subtypes
      of HIV-1, a problem in regions where multipte HIV-1 subtypes may be circulating.
      OBJECTIVES: To assess commercial HIV-1 RNA quantification assays on two plasma
      panels. Panel 1 consisted of HIV-1 seronegative plasma 'spiked' with a known
      amount of cultured virus of different subtypes, and Panel 2 comprised plasma
      collected from individuals infected with different HIV-1 subtypes. STUDY DESIGN:
      The comparison involved the Amplicor HIV-1 reverse transcriptase-polymerase chain
      reaction (RT-PCR), Quantiplex branched DNA, and NucliSens HIV-1 QT assays. Panel
      1 consisted of 11 plasma 'spiked' with cultured viruses of HIV-1 subtypes A-F,
      and Panel 2 included 33 plasma samples from 16 patients infected with subtypes A,
      B, C, E and G. RESULTS: In Panel 1, the Quantiplex branched deoxyribonucleic acid
      (bDNA) assay quantified subtypes A-F efficiently, comparable to published results
      from two other laboratories. The Amplicor RT-PCR assay quantified subtypes B, C,
      and D but was relatively less efficient with subtypes E, F, and did not or poorly
      quantified subtype A. Testing of Panel 2 showed some inter-assay differences. In
      contrast to Panel 1, the Amplicor RT-PCR assay performed variably with subtype A
      when compared with the Quantiplex bDNA and NucliSens QT assays, and higher viral
      load levels were generated with subtype E using the Amplicor RT-PCR assay.
      Subtypes B and C showed some inter-patient differences but the Quantiplex bDNA
      generally gave a lower quantification than the Amplicor RT-PCR and NucliSens QT
      assays. CONCLUSIONS: These studies confirm that commercial HIV-1 load assays vary
      in their ability to quantify different HIV-1 subtypes. This may be more apparent
      with individual patient samples than with 'spiked' panels. This variability
      emphasizes that it is preferable for patient samples to be tested with the same
      assay, and care should be taken where infection with unusual subtypes is
      suspected.

PMID- 10588452
TI  - Relation between T-cell responses to glutamate decarboxylase and coxsackievirus
      B4 in patients with insulin-dependent diabetes mellitus.
AB  - BACKGROUND: the role of enteroviruses has been implicated in the etiology of
      insulin-dependent diabetes mellitus (IDDM). A possible connection between
      glutamate decarboxylase (GAD) autoimmunity and enterovirus infections in IDDM has
      been suggested to be based on a homology region between GAD and the non
      structural protein 2C of coxsackievirus B4 (CVB4). OBJECTIVES: the aims of the
      study were to measure the occurrence of cellular immunity to GAD and CVB4 in
      Finnish patients with newly diagnosed IDDM, and to study the relation between
      these two responses. T-cell responses to GAD and CVB4 were analyzed in relation
      to HLA DQB1 risk alleles for IDDM and antibodies to GAD and CVB4. STUDY DESIGN: T
      cell and antibody responses to GAD65 and purified CVB4 were measured in patients
      with newly diagnosed IDDM and in healthy children. The purified CVB4 did not
      contain the non-structural protein 2C thus lacking the reported homology region
      with GAD. RESULTS: high proliferative responses of PBMC to both GAD and CVB4 were
      more frequent in IDDM patients than in the control children (40 vs. 16%, 27 vs.
      10%; P = 0.03 and 0.04, respectively; Fisher's exact test), when the cut-off for
      positivity was three multiples of the median SI in the healthy children. Median
      SI to GAD was higher in the patients with IDDM than in the control subjects (3.10
      vs. 1.55; P = 0.03, Mann-Whitney U-test). T-cell responses to GAD and CVB4 showed
      a positive correlation in the patients (r = 0.62, P = 0.001), but not in the
      control children (r = 0.23; P = 0.38). CONCLUSIONS: enhanced T-cell
      responsiveness to CVB4 in patients with newly diagnosed IDDM support the
      involvement of enteroviral infections in the development of IDDM. The observed
      correlation between T-cell reactivity to GAD and CVB4, lacking the crossreactive
      protein 2C, in patients with IDDM suggests that CBV4 reactivity is associated
      with GAD autoimmunity in IDDM but does not reflect immunization to GAD.

PMID- 10588453
TI  - Simultaneous IgM reactivity by EIA against more than one virus in measles,
      parvovirus B19 and rubella infection.
AB  - BACKGROUND: A clinical diagnosis of rash-causing infections is not always
      possible and reliance has to be placed on serological evidence of infection,
      especially on the presence of specific immunoglobulin (Ig)M. However, despite the
      use of modern serological methods and validated commercial kits, reports appear
      in the literature of simultaneous IgM reactivity against more than one virus in
      cases of Epstein Barr virus, rubella, cytomegalovirus, human parvovirus B19 (HPV
      B19) and measles infections, all with implications for the pregnant woman.
      OBJECTIVES: We decided to evaluate the extent of the problem in rubella, measles
      and HPV B19 infections in a routine diagnostic laboratory. STUDY DESIGN: We
      tested sera from cases with initial clinical and serological evidence of
      infection with measles, HPV B19 or rubella for evidence of simultaneous IgM
      reactivity against more than one virus. We confirmed primary infections with
      specific-IgG antibody avidity tests, and subjected sera with IgM reactivity
      against more than one virus to avidity tests to identify which, if any, of the
      three viruses was the cause of the primary infection. Groups of monoreactive IgM
      sera were randomly selected from the presented sera to demonstrate that the
      avidity of the IgG specific for the other two viruses would be of high avidity
      compared with the low avidity of the IgG specific for the virus against which
      specific IgM had been detected. RESULTS: Our results confirm that simultaneous
      IgM reactivity against more than one virus does occur in these three infections,
      and that this is unlikely to be caused by the presence of rheumatoid factor.
      CONCLUSIONS: In the absence of seroconversion, reliance on specific IgM results
      alone for diagnosis of these infections should be avoided and tests such as
      specific IgG antibody avidity should also be employed. The simultaneous
      occurrence of IgM reactivity against more than one virus is also important for
      epidemiological and surveillance reasons as the widespread use of the mumps,
      measles and rubella vaccine makes its impact on the population. Falsely diagnosed
      cases of apparent measles or rubella could throw into question the efficacy of
      the vaccine.

PMID- 10588454
TI  - Immunoblot analysis of natural and vaccine-induced IgG responses to rubella virus
      proteins expressed in insect cells.
AB  - BACKGROUND: The three structural proteins of rubella virus (RV), the capsid
      protein C and the envelope glycoproteins E1 and E2, were produced individually in
      soluble form in Sf9 insect cells using the baculovirus system. All proteins were
      equipped with a polyhistidine tag at their C-terminal ends to enable gentle
      purification by metal ion affinity chromatography. In addition, the E1 and E2
      proteins were engineered to display the FLAG epitope tag at their N-terminal
      ends. STUDY DESIGN: The diagnostic potential of the recombinant purified proteins
      was evaluated by immunoblot and enzyme immuno assays (EIA) using a total of 57
      well-characterised serum samples obtained at various time points after natural RV
      infection, congenital rubella syndrome (CRS), MMR vaccination or from controls
      with past RV immunity. In addition, acute and convalescent phase serum pools from
      a total of 20 patients were evaluated. Authentic RV proteins were used as a
      reference. RESULTS: The recombinant E1 and C proteins were predominant in
      eliciting the immune response in both postnatal and vaccinal RV infections, being
      much weaker in the vaccinal ones. The IgG response to the recombinant C protein
      was very strong after the first month post infection and decreased with time. The
      immune response against the recombinant E2 protein, however, was generally poor,
      but notably stronger after congenital infection. Together, the results showed
      that the individual recombinant protein antigens could be suitable for diagnosis
      of RV infection and for study of the immune response to rubella vaccination.

PMID- 10588455
TI  - Comparison of VIDAS with direct immunofluorescence for the detection of
      respiratory syncytial virus in clinical specimens.
AB  - BACKGROUND: requirements for infection control measures and the decision for
      treatment with antiviral agents make the rapid detection of respiratory syncytial
      virus (RSV) essential for hospitalized, pediatric and immunocompromised patients.
      Immunofluorescence is considered to be the most rapid and sensitive method for
      direct detection of RSV in clinical specimens, but several enzyme-linked
      immunoassays have also been commercially available. OBJECTIVES: to compare the
      performance of VIDAS RSV assay (Vitek ImmunoDiagnostic Assay System, BioMerieux
      Vitek), which is an automated enzyme-linked fluorescent immunoassay (ELFA) to
      direct immunofluorescence (DFA), in rapid detection of RSV in respiratory
      specimens. STUDY DESIGN: respiratory specimens collected during the 'RSV season',
      between the months of November 1997 and February 1998, were tested by both
      methods. DFA was performed upon receipt of the sample and an aliquot of the
      original specimen was stored in -70 degrees C for batch testing with VIDAS.
      RESULTS: from 238 samples that were tested, 231 could be evaluated by both
      methods. The two assays were in agreement for 213 specimens (92%), or 32 positive
      and 181 negative results. Eighteen discrepant results were generated; seven
      specimens were VIDAS-/DFA+ and 11 specimens were VIDAS+/DFA-. In addition, seven
      specimens had an inadequate number of cells for evaluation with DFA. One of these
      samples tested positive with VIDAS. VIDAS relative sensitivity and specificity
      were 82% and 94%, respectively, when compared to DFA. CONCLUSIONS: VIDAS is
      simple to perform, does not require expertise in interpretation and appears to be
      an acceptable method for the rapid detection of RSV.

PMID- 10588456
TI  - Assessment of hepatitis C virus RNA stability in serum by the Quantiplex branched
      DNA assay.
AB  - OBJECTIVES: Quantification of hepatitis C virus (HCV) RNA in serum is used to
      assess the probability of treatment response and to monitor antiviral therapy.
      Since serum specimens often are shipped to central sites for HCV RNA testing, it
      is important to define conditions that preserve HCV RNA integrity. METHODS: We
      evaluated the stability of HCV RNA in 25 previously frozen (PF) and 11 fresh,
      never previously frozen (NPF) specimens subjected to handling and short-term
      storage conditions that mimic those encountered during interlaboratory shipping.
      All sera were separated within 4 h of collection. PF samples covering a
      approximately 3 log10 HCV RNA dynamic range were thawed, divided into aliquots,
      incubated at 4, 23, and 37 degrees C (+/- 1.5 degrees C) for 24, 48, 72 and 96 h
      (+/- 2 h), and then refrozen at -70 degrees C prior to testing with the
      Quantiplex HCV RNA 2.0 assay. Eleven NPF samples were stored at -70, -20, and 4
      degrees C (+/- 1.5 degrees C) for up to 1 month prior to testing. RESULTS: Linear
      regression analysis showed no HCV RNA degradation in PF specimens kept at 4
      degrees C over 4 days. However, HCV RNA levels in PF specimens decreased over 4
      days by 20 and 105% at 23 and 37 degrees C, respectively. Three independent
      statistical methods showed that the probability of specimen failure in PF
      specimens, defined as a loss of 20% or more of HCV RNA, was lowest at 4 degrees C
      and increased with increasing temperature. The HCV RNA quantification of the 11
      NPF specimens stored at 4 degrees C was similar to their frozen controls.
      CONCLUSION: HCV RNA in separated serum specimens is stable for at least 4 days at
      4 degrees C.

PMID- 10588457
TI  - Detection of herpes simplex virus (HSV) genome using polymerase chain reaction
      (PCR) in clinical samples comparison of PCR with standard laboratory methods for
      the detection of HSV.
AB  - BACKGROUND: Diagnosis of Herpes simplex virus (HSV) infections is achieved by
      detecting the antigen and isolating the virus from the specimen, which requires 7
      28 days. With the recently introduced molecular biological technique of
      polymerase chain reaction (PCR), the diagnosis of HSV infections has been made
      more rapid and specific. OBJECTIVE: We evaluated PCR in comparison with the
      standard laboratory methods on different types of clinical specimens referred to
      in our laboratory. STUDY DESIGN: A total of 54 specimens, from 54 patients, were
      investigated. Antigen detection on direct smears was carried out using
      fluorescent antibody test (FAT) and virus isolation was performed using
      conventional tube culture method. PCR was carried out with the DNA extracted from
      various specimens using primers, which coded for the DNA polymerase gene giving a
      179 base pair (bp) product. RESULTS: The primers were specific for HSV-1 and HSV
      2, and the sensitivity of the primers was found to be 0.5 and 0.2 fg in the
      detection of HSV-1 and HSV-2 DNA, respectively. Of the 50 specimens (excluding 4
      archival formalin fixed tissue specimens, which were not subjected to virological
      methods of detection) HSV was detected by virological methods and PCR in nine
      specimens, and by PCR alone in 15 additional specimens, thus increasing the
      analytical sensitivity significantly by 30% (McNemar test: P = 0.0001). The
      positivity of PCR in all nine virologically positive specimens and the 4 archival
      specimens obtained from proven lesions of HSV infections further confirmed the
      specificity of the PCR. CONCLUSION: PCR, in our study, was found to be a rapid,
      specific and highly sensitive method for the detection of HSV in clinical
      specimens.

PMID- 10588458
TI  - Hemostatic markers in ischemic stroke of undetermined etiology.
AB  - To evaluate the role of the coagulation and fibrinolysis abnormalities in the
      pathogenesis of ischemic stroke of undetermined etiology, we assayed plasma
      concentration of fibrinopeptide-A and thrombin-antithrombin III complex, both
      sensitive markers for thrombin activation and fibrin formation, and D-dimer, a
      marker of plasmin activity and fibrinolysis. Hemostatic markers were measured in
      32 patients with acute stroke and 20 patients with chronic stroke, and compared
      with 21 normal subjects. Fibrinopeptide-A and thrombin-antithrombin III complex
      levels were not elevated significantly, whereas the D-dimer level was markedly
      raised in acute (p<0.001) and chronic (p<0.05) phases of ischemic stroke in
      comparison with the control group. Prolonged elevation of D-dimer concentration
      suggests that hemostatic abnormalities have a primary role in the pathogenesis of
      ischemic stroke. The measurement of D-dimer concentration may help to better
      decide the indications for therapy of the patients with ischemic stroke of
      undetermined etiology.

PMID- 10588459
TI  - Relationship between triglycerides and factor VIIc and plasminogen activator
      inhibitor type-1: lack of threshold value.
AB  - Increased factor VIIc (FVIIc) and plasminogen activator inhibitor type 1 (PAI-1)
      levels may lead to a thrombotic state and subsequently to a higher risk of
      myocardial infarction. The relationships between triglycerides and plasma levels
      of both PAI-1 and FVIIc were established in previous studies. However, there is
      no data assessing whether there is a threshold value of triglycerides above which
      FVIIc and PAI-1 levels increase or whether the relationship is continuous.
      Therefore, we measured triglycerides, FVIIc, and PAI-1 levels in a large group of
      1254 asymptomatic patients with hyperlipoproteinemia. Our results showed that
      both FVIIc and PAI-1 levels increase linearly in parallel to triglyceride levels
      (p=0.0001). In the multiple regression analysis, the relationship between log
      triglycerides and FVIIc was significantly independent of total cholesterol, body
      mass index, fasting glycemia, gender, and age; the relationship between log
      triglycerides and PAI-1 was significantly independent of body mass index, fasting
      glycemia, gender, and age. Interestingly, we found that the correlation
      coefficients between triglycerides and the haemostatic parameters measured were
      almost identical in different subgroups of subjects: males, females, nonobese,
      and normoglycemic, as well as nonalcoholic. We conclude that the relationships
      between triglyceride levels and FVIIc, as well as PAI-1, are continuous without
      threshold value of triglycerides.

PMID- 10588460
TI  - Angiogenesis induced by tissue factor in vitro and in vivo.
AB  - The purpose of this study was to investigate the effects of tissue factor
      (thromboplastin), the initiating factor of the extrinsic clotting system, on
      angiogenesis in vivo and in vitro. In vivo angiogenesis was examined using a
      diffusion chamber assay in rats. After a week of implantation of the diffusion
      chambers containing tissue factor (0.5 or 5.0 mg/ mL), angiogenesis was enhanced
      two to three times as compared with the control. In vitro, an addition of 30
      microg/mL of tissue factor enhanced angiogenesis in bovine aorta endothelial
      cells, which were cultured in collagen type gel 2.3-fold as compared with the
      control, and the angiogenesis was inhibited by antitissue factor antibody.
      Furthermore, tissue factor (30 microg/mL)-induced angiogenesis in bovine aorta
      endothelial cells was inhibited by the addition of coagulation factors II, VII,
      and IX. These results suggest that tissue factor directly induce angiogenesis,
      independently of the coagulation pathway.

PMID- 10588461
TI  - Increased platelet surface expression of P-selectin and thrombospondin as markers
      of platelet activation in essential thrombocythaemia.
AB  - Essential thrombocythaemia (ET) is a clonal myeloproliferative disorder
      associated with an increased risk of both thromboembolic and bleeding
      complications. Platelet activation plays a crucial role in the pathogenesis of
      prethrombotic conditions. The platelet surface expression of p-selectin (CD62p)
      and thrombospondin (TSP) has been shown to correlate with platelet activation. In
      the present study, we used a flow cytometric assay to study whether the fraction
      of platelets expressing CD62p and TSP is increased in newly diagnosed ET. Thirty
      four patients with newly diagnosed ET and 25 healthy control subjects were
      investigated. The proportion of platelets expressing the activation-dependent
      antigens CD62p and TSP was higher in patients with ET (CD62p: 14.7+/-15.0%; TSP:
      12.4+/-9.9%) as compared with healthy control subjects (CD62p: 3.0+/-4.0%; TSP:
      3.2+/-3.2%; p< 0.001). In ET, there was a linear correlation between platelet
      surface expression of CD62p and TSP (p<0.0001, r=0.83). At diagnosis of ET, 20
      patients were symptomatic and 14 asymptomatic. Compared with asymptomatic ET
      patients there was no difference in the expression of CD62p (18.3+/-16.2% vs.
      14.5+/-13.4%) and TSP (14.4+/-9.8% vs. 12.8+/-9.5%) in symptomatic ET patients.
      In conclusion, increased expression of platelet neoantigens is present at the
      diagnosis of ET. Both activation-dependent epitopes CD62p and TSP are
      increasingly expressed on the platelet surface in newly diagnosed ET patients.

PMID- 10588462
TI  - Lupus anticoagulant testing with optical end point automation.
AB  - The dilute Russell viper venom time and kaolin clotting time (KCT) are very
      sensitive screening tests for lupus anticoagulant activity. However, due to the
      high turbidity of the kaolin reagent it is difficult to accommodate the KCT on
      the optical end point automation of today. We evaluated five recently reported
      screening tests (the silica clotting time, the Textarin/Ecarin ratio, the Taipan
      venom time, the factor V ratio, and a kaolin clotting time using low-turbidity
      kaolin) as potential alternatives to the KCT. The sensitivity and specificity of
      the silica clotting time compared well to KCT, detecting 10/12 KCT positive
      samples and showing equal sensitivity to dilution of lupus positive plasma. In
      addition, the silica clotting time allows for a confirmatory phospholipid
      correction procedure. False-positive results were seen in 2 of 15 warfarinised
      samples. A second assay utilising the ratio of extrinsic/intrinsic factor V
      assays was not affected by either warfarin or heparin. This assay also gave
      positive results with 3 of 23 samples previously screened as lupus negative but
      exhibiting anticardiolipin positivity. It was therefore concluded that a
      combination of the silica clotting time and dilute Russell viper venom time met
      the requirements of lupus sensitivity with demonstration of phospholipid
      dependence and optical end point compatibility. The factor V ratio is a useful
      second-line screen for both anticoagulated patients and anticardiolipin antibody
      positive samples.

PMID- 10588463
TI  - Changes in levels of factor VII and protein S after acute myocardial infarction:
      effects of low-dose warfarin.
AB  - Persistent coagulation activity after an acute myocardial infarction may increase
      the risk of reinfarction. We prospectively investigated the effects on plasma
      coagulation of a low, fixed dose of warfarin in combination with aspirin after
      myocardial infarction. We also evaluated the influence of coagulation activity on
      clinical outcome. Plasma samples from 97 patients, randomised to 1.25 mg of
      warfarin daily in combination with 75 mg of aspirin or aspirin alone were drawn 4
      days, 1 month, and 6 months after myocardial infarction. Patients receiving
      warfarin had a greater reduction in factor VII coagulation activity (FVII:C)
      after 6 months: 0.18 vs. 0.06 U/mL,(95% CI, 0.02-0.22), whereas no differences
      were seen in levels of protein C, protein S, or prothrombin fragment 1+2. In the
      acute phase, the level of free protein S was lower than after 6 months in both
      groups: 25.6 vs. 28.8% (95% CI, 4.19--2.35). Cardiovascular mortality,
      reinfarction, and stroke were evaluated after 4 years (median). In a survival
      analysis, every 0.1 U/mL increase in the level of FVII:C1 month after myocardial
      infarction was associated with an 15% increase in risk of cardiovascular events
      (95% C1, 1.01-1.30). Warfarin at 1.25 mg daily reduces FVII:C but not systemic
      thrombin generation measured as prothrombin fragment 1 +2. Low levels of the
      anticoagulant protein S may contribute to a procoagulant state.

PMID- 10588464
TI  - Evaluation of platelet function with the PFA-100 system in patients with
      congenital defects of platelet secretion.
AB  - The template bleeding time is still the screening test for defects of platelet
      function, although it is an invasive and poorly reproducible technique. The PFA
      100 measures platelet function at high shear. Whole blood is aspirated through a
      capillary to an aperture of a membrane coated with platelet agonists. The system
      measures the time required to obtain occlusion of the aperture by a platelet plug
      (closure time). We measured the closure times in the PFA-100 system and the
      bleeding time in seven patients with delta-storage pool deficiency, 10 patients
      with "primary secretion defect" (not due to abnormalities of platelet granules or
      the arachidonate pathway), and 40 controls. Measurements were repeated I and 4
      hours after intravenous infusion of desmopressin in six delta-storage pool
      deficiency and eight primary secretion defect patients. Baseline bleeding time
      and closure times with the collagen/epinephrine cartridge were longer in delta
      storage pool deficiency and primary secretion defect patients than in controls.
      In contrast, closure times with the collagen/adenosine diphosphate cartridge were
      normal in both delta-storage pool deficiency and primary secretion defect
      patients. Treatment with desmopressin increased the plasma von Willebrand Factor
      levels, shortened the prolonged bleeding time, shortened the closure times with
      the collagen/adenosine diphosphate cartridge, and normalized the closure times
      with the collagen/ epinephrine cartridge. Therefore, the PFA-100 test may be a
      less invasive alternative to the bleeding time in the diagnosis and therapeutic
      monitoring of patients with platelet secretion defects. The collagen/epinephrine
      cartridge is more sensitive than the collagen/adenosine diphosphate cartridge to
      defects of platelet secretion.

PMID- 10588465
TI  - Effects of fish oil supplementation on platelet survival and ex vivo platelet
      function in hypercholesterolemic patients.
AB  - Little is known about the effects of dietary supplementation on platelet survival
      with low doses of n-3 and n-6 fatty acids in patients with hypercholesterolemia.
      The effects of a 6-week intervention with fish oil capsules (daily intake: 216 mg
      eicosapentaenoic acid, 140 mg docosahexaenoic acid, 390 mg gamma-linolenic acid,
      and 3480 mg linoleic acid) on in vivo platelet survival (111 In-oxine labeled
      platelets) and on ex vivo markers of platelet activation were investigated in a
      placebo-controlled, double-blind study with 26 hypercholesterolemic patients. In
      vivo platelet survival increased in the fish oil group (T) from a mean of 159+/
      14 hours to a mean of 164+/-12 hours (p=0.025), whereas it remained unchanged in
      the placebo (P) group (T vs. P; p=0.055). Ex vivo, thromboxane B2 decreased from
      a mean of 225+/-16 to 212+/-21 ng/mL (p=0.003) in T but did not change in P (T
      vs. P: p=0.002). Malondialdehyde formation was lowered significantly by fish oil
      supplementation from a mean of 5.49+/-1.3 to 5.12+/-1.05 nM/10(9) platelets,
      p=0.005, as compared with P (T vs. P; p=0.018). The trendwise decrease in 11-DH
      thromboxane B2 plasma levels was not significant nor was the increase in platelet
      sensitivity to prostaglandin I2 by fish oil. Baseline platelet survival in
      patients with hyperlipoproteinemia type IIa was not different from those with
      hyperlipoproteinemia IIb and response to treatment in terms of platelet
      activation markers was not either. The changes in platelet activation parameters
      in T were associated with significant reductions in cholesterol (-2.9%), low
      density lipoprotein cholesterol (-3.5%), and triglycerides (-12.4%). Both ex vivo
      and in vivo platelet activation parameters exhibited signs of decreased
      activation by a 6-week diet supplemented with n-3 and n-6 fatty acids, which
      might be beneficial in reducing atherothrombotic risk, in patients with
      hyperlipoproteinemia type IIa and IIb.

PMID- 10588467
TI  - Effect of supplementation with dietary seal oil on selected cardiovascular risk
      factors and hemostatic variables in healthy male subjects.
AB  - The average daily consumption of seal oil by the Inuit people is approximately 8
      9 g, yet there is very little information on the effect of seal oil consumption
      on cardiovascular disease risk factors. In this study, 19 healthy,
      normocholesterolemic subjects consumed 20 g of encapsulated seal oil containing
      eicosapentaenoic acid (EPA; 20:5n-3), docosahexaenoic acid (DHA; 22:6n-3), and
      docosapentaenoic acid (DPA; 22:5n-3) or 20 g of vegetable oil (control) per day
      for 42 days. Levels of selected cardiovascular and thrombotic risk factors as
      well as fatty acid profiles of serum phospholipid and nonesterified fatty acid
      (NEFA) were determined. EPA levels in serum phospholipid and NEFA increased by
      4.3- and 2.7-fold, respectively, in the seal oil supplemented group. DHA levels
      rose 1.5- and 2.1-fold, respectively, and DPA levels rose 0.5- and 0.7-fold,
      respectively. Arachidonic acid (AA) levels dropped by 26% in both serum
      phospholipid and serum NEFA. There was a significant decrease in the ratio of n-6
      to n-3 fatty acids in serum phospholipid from 7.2 to 2.1 and a significant
      increase in the ratio of EPA/AA in NEFA. Ingestion of seal oil raised the
      coagulant inhibitor, protein C, values by 7% and decreased plasma fibrinogen by
      18%. No alterations in other hemostatic variables, including plasma activity of
      Factors VII, VIII, IX, and X and antithrombin, or in the concentrations of von
      Willebrand Factor, total cholesterol, high-density lipoprotein cholesterol, low
      density lipoprotein cholesterol, triglyceride, glucose, Apo A-1, or
      lipoprotein(a) were observed in either group. Other risk factors for
      cardiovascular disease, including hematocrit, white blood cell count, plasma
      viscosity, systolic and diastolic blood pressures, heart rate, and platelet
      aggregation after stimulation with ADP or collagen did not change. Our results
      indicate that seal oil supplementation in healthy, normocholesterolemic subjects
      decreased the n-6/n-3 ratio and increased EPA, DHA, and DPA and the ratio of
      EPA/AA and DHA/AA in the serum phospholipid and NEFA, while exhibiting a modest
      beneficial effect on fibrinogen and protein C levels.

PMID- 10588466
TI  - Antithrombotic activities of green tea catechins and (-)-epigallocatechin
      gallate.
AB  - The antithrombotic activities and mode of action of green tea catechins (GTC) and
      (-)-epigallocatechin gallate (EGCG), a major compound of GTC, were investigated.
      Effects of GTC and EGCG on the murine pulmonary thrombosis in vivo, human
      platelet aggregation in vitro, and ex vivo, and coagulation parameters were
      examined. GTC and EGCG prevented death caused by pulmonary thrombosis in mice in
      vivo in a dose-dependent manner. They significantly prolonged the mouse tail
      bleeding time of conscious mice. They inhibited adenosine diphosphate- and
      collagen-induced rat platelet aggregation ex vivo in a dose-dependent manner. GTC
      and EGCG inhibited ADP-, collagen-, epinephrine-, and calcium ionophore A23187
      induced human platelet aggregation in vitro dose dependently. However, they did
      not change the coagulation parameters such as activated partial thromboplastin
      time, prothrombin time, and thrombin time using human citrated plasma. These
      results suggest that GTC and EGCG have the antithrombotic activities and the
      modes of antithrombotic action may be due to the antiplatelet activities, but not
      to anticoagulation activities.

PMID- 10588468
TI  - The asymptomatic patient.

PMID- 10588469
TI  - Anterior cruciate ligament injuries in the skeletally immature patient.
AB  - Injuries of the anterior cruciate ligament (ACL) in children are more frequent
      than once thought. Special factors must be taken into consideration when treating
      ACL injuries in the skeletally immature patient. Risks of surgery must be weighed
      against potential damage to the knee caused by repeated injury. The authors
      prefer the use of both tibial and femoral centrally placed drill holes, hamstring
      tendon autografts, fixation distant from the physis, and avoidance of dissection
      near the physis. This technique will minimize damage to the physis and should not
      hinder normal growth.

PMID- 10588470
TI  - Long-term functional and radiographic follow-up of surgically treated isthmic
      spondylolisthesis.
AB  - We studied patients treated surgically for isthmic spondylolisthesis since 1968,
      with special emphasis on a detailed functional assessment. We followed up 22
      patients for an average of 15 years, with a mean age at time of surgery of 18
      years. All patients underwent a thorough physical examination and were evaluated
      with radiographs at baseline and at follow-up. The functional status of patients
      at the time of follow-up was assessed with 2 self-report pain and function
      instruments. All surgical procedures included spinal fusion, 12 of which included
      internal fixation by using Harrington distraction rods with sacral bars. At final
      follow-up, there was no statistically significant difference in mean slip
      percentage or mean slip angle compared with baseline radiographs. Functional
      evaluation was compared with a control group consisting of 52 patients. We
      conclude that the long-term radiographic and functional outcome is excellent for
      patients treated surgically for isthmic spondylolisthesis.

PMID- 10588471
TI  - Magnetic resonance imaging of the humpback scaphoid: the technique and a
      mathematical performance evaluation.
AB  - Surgical treatment of scaphoid nonunion and malunion with excessive intrascaphoid
      angulation (humpback deformity) usually involves a bone graft that is intended to
      correct the deformity. The volar bone graft length determines the degree of
      angular correction and scaphoid elongation. It is recommended that the length of
      the graft be determined by careful preoperative measurement of the deformity.
      Previous imaging techniques are inherently limited. The present paper describes a
      technique using three-dimensional magnetic resonance imaging. Scaphoid fracture
      angulation is calculated from measurements of comparable sagittal slices of the
      patient's fractured and normal scaphoid. Optimal bone graft length is determined
      by using simple trigonometric principles. Magnetic resonance imaging provides
      additional important information regarding vascularity of the proximal pole and
      the status of the periscaphoid ligaments and hyaline cartilage. Mathematical
      performance evaluation indicates that this technique is a promising method for
      planning reconstructive surgery of the scaphoid.

PMID- 10588472
TI  - Median nerve injury in an expert skier: a case report.
AB  - A 20-year-old expert skier presented with sustained ulnar arterial, median nerve,
      and multiple flexor tendon injuries. Surgery was performed repairing the nerve,
      artery, and tendons, and in subsequent follow-up, the patient had an excellent
      postoperative result.

PMID- 10588473
TI  - An unusual cause of spinal cord injury: case report and discussion.
AB  - Traumatic spinal cord injury is a devastating condition that alters every aspect
      of the victim's life. Motor vehicle accidents cause about half of the cases,
      whereas others are the result of falls, recreational and sporting accidents, or
      acts of violence. We report a case of a C3 spinal fracture with a resultant Brown
      Sequard syndrome, which occurred in a unique manner and could have easily been
      prevented. There is a need for the medical community to play a more active role
      in educating the public to prevent accidents that lead to these catastrophic
      injuries.

PMID- 10588474
TI  - Recurrent fracture of the humerus in a softball player.
AB  - Fracture of a normal humerus can occur during the act of throwing an object. We
      present the case of a young woman who sustained a spiral fracture of the distal
      humeral shaft with concomitant radial nerve palsy while throwing a softball and
      who, after clinical and radiographic evidence of bony healing, suffered a repeat
      humerus fracture, also while throwing a softball.

PMID- 10588475
TI  - Rupture of the peroneus longus tendon in a military athlete.
AB  - A 38-year-old active-duty Marine Corps officer with a history of ankle
      instability presented to the orthopedic clinic complaining of left lateral ankle
      and leg pain. A diagnosis of rupture of the tendon of the peroneus longus was
      made. This is an unusual diagnosis in an active Marine Corps officer. Surgical
      treatment markedly improved his symptoms.

PMID- 10588476
TI  - Surgical treatment of intercondylar fractures of the humerus in adults.
AB  - The rarity, complexity, and intra-articular involvement of intercondylar
      fractures, along with the osteopenic nature of the elbow joint, make surgical
      repair of these fractures a difficult and challenging task. When the procedure is
      properly executed, open reduction and internal fixation can promote proper
      reduction of the articular fragments and allow early range-of-motion exercises,
      which are so important for good functional results. We report the results of 30
      such fractures treated surgically with good or excellent results. The pros and
      cons of the transolecranon approach are discussed, along with the options of
      fracture fixation and importance of early postoperative mobilization.

PMID- 10588477
TI  - The "rubber band technique": a simple method for closing large skin defects.
AB  - Traditional methods of obtaining definitive soft-tissue cover in open wounds
      after high-energy trauma necessitate repeated surgical procedures and
      sophisticated soft-tissue reconstructions. A simple one-stage technique to treat
      skin loss in severe open fractures is described. The "rubber band technique"
      enables postoperative exposure and drainage of the fracture site. The wound
      closes gradually by facilitated mobilization of skin in response to continuous
      tension from the rubber band. This technique may prevent the need for additional
      procedures. Continuous drainage is achieved. When deep infection is suspected,
      removal of the elastic rubber band permits sufficient exposure of the deep
      tissues. The "rubber band technique" has proved to be a safe, simple, and
      efficient method for treating extensive soft-tissue loss in open fractures and
      after incisions for open reduction or fasciotomy.

PMID- 10588478
TI  - Taurine attenuates hypertension and improves insulin sensitivity in the fructose
      fed rat, an animal model of insulin resistance.
AB  - Fructose feeding induces moderate increases in blood pressure levels in normal
      rats, which is associated with hyperinsulinemia, insulin resistance, and impaired
      glucose tolerance. Increased vascular resistance, sodium retention, and
      sympathetic overactivity have been proposed to contribute to the blood pressure
      elevation in this model. Taurine, a sulphur-containing amino acid, has been
      reported to have antihypertensive and sympatholytic actions. In the present
      study, the effects of taurine on blood pressure, plasma levels of glucose and
      insulin, glucose tolerance, and renal function were studied in fructose-fed rats.
      Fructose-fed rats had higher blood pressure and elevated plasma levels of insulin
      and glucose. The plasma glucose levels were higher in fructose-fed rats than in
      controls at 15, 30, and 60 min after the oral glucose load. Treatment with 2%
      taurine in drinking water prevented the blood pressure elevation and attenuated
      the hyperinsulinemia in fructose-fed rats. The exaggerated glucose levels in
      response to the oral glucose load was also prevented by taurine administration.
      Thus, taurine supplementation could be beneficial in circumventing metabolic
      alterations in insulin resistance.

PMID- 10588479
TI  - Bezafibrate, an anti-hypertriglyceridemic drug, attenuates vascular
      hyperresponsiveness and elevated blood pressure in fructose-induced hypertensive
      rats.
AB  - A high fructose diet induces hypertension, hyperinsulinemia - insulin resistance,
      and hypertriglyceridemia (syndrome X). In this study, we investigated the role of
      an abnormal lipid profile in mediating fructose-induced hypertension. We
      hypothesized that bezafibrate, a lipid-lowering drug, would reduce elevated blood
      pressure and inhibit increased vascular reactivity in fructose-fed rats. Male
      rats were placed on four different diets: group 1 was fed standard chow (n = 6);
      group 2 was fed 60% fructose (n = 5); group 3 was fed fructose plus bezafibrate
      (30 mg x kg(-1) x day(-1); drinking water; n = 5); and group 4 was fed standard
      chow plus bezafibrate (n = 6). In addition, the direct effects of very low
      density lipoprotein (VLDL) on vascular reactivity were examined. Bezafibrate
      treatment lowered blood pressure, free fatty acids, and triglycerides in the
      fructose-fed group, suggesting that lipid abnormalities play a role in the
      elevation of blood pressure in the fructose-induced hypertensive rat. Aortae from
      fructose-fed rats were hyperresponsive to the calcium channel agonist Bay K 8644,
      which was normalized with bezafibrate treatment. Incubation of aortae in a VLDL
      medium resulted in increased responsiveness to Bay K 8644, lending further
      support to lipid abnormalities altering vascular reactivity. An altered lipid
      profile evidenced by elevated triglycerides and free fatty acids is causally
      related to the development of high blood pressure and increased vascular
      reactivity in the fructose-induced hypertensive rat.

PMID- 10588480
TI  - Effects of enalaprilat on neointimal growth of cultured rabbit aorta following
      balloon injury.
AB  - Our objective was to determine if the ability of an angiotensin-converting enzyme
      (ACE) inhibitor to attenuate neointima formation in balloon-damaged vessel is
      expressed in an isolated organ culture model of neointimal growth. In vivo
      balloon angioplasty in combination with in vitro organ culture was used to
      produce a unique model of vascular neointima formation. Aortic segments were
      cultured in medium containing a broad concentration range of the ACE inhibitor
      enalaprilat (0-100 microM). Cell proliferative indices and neointima:media
      thickness ratios were determined from vessel segments after 1, 4, and 7 days in
      culture. We observed no significant effect on either parameter at any dose of
      enalaprilat. Linear regression analysis on the rate of increase in intima to
      media thickness ratios during the 7 days of culture also showed no effect of
      enalaprilat at any concentration. We conclude that enalaprilat has no effect on
      neointimal growth or cell proliferation in this vascular organ culture model, and
      it is suggested that ACE inhibitors may act by mechanisms other than local
      converting enzyme inhibition to attenuate neointimal growth in rabbits following
      vascular ballooning in vivo.

PMID- 10588481
TI  - Functional comparison of the human isolated femoral artery, internal mammary
      artery, gastroepiploic artery, and saphenous vein.
AB  - Human femoral, internal mammary, and gastroepiploic arteries and saphenous veins
      are used as bypass grafts for coronary surgery or for reconstruction in arterial
      occlusive disease. We have characterized the contractile responses of these
      vessels to various agents that are liberated during cardiac or vascular surgery.
      In organ baths, U46619 (a stable thromboxane A2 mimetic), norepinephrine,
      endothelin-1, angiotensin II, and KCl caused concentration-dependent contractions
      in all vessels tested. Leukotriene C4 did not induce any contraction in the
      arteries, whereas a contraction was obtained in the saphenous vein rings. U46619
      induced the most powerful contraction in all vessels tested. The pD2 values for
      each agent did not differ among the different vessels. When responses were
      expressed as a percentage of KCl-induced contraction, the contraction of
      endothelin-1 (151+/-5%) and leukotriene C4 (43+/-5%) was more significant on
      saphenous veins than on arteries. In conclusion, thromboxane A2 appears to be the
      most potent endogenous constricting agent on different human vascular beds. Our
      second finding is that saphenous veins are more sensitive to contract to
      leukotriene C4 and endothelin-1 than arteries. These properties may influence
      early and (or) long-term vein graft patency.

PMID- 10588482
TI  - Nitric oxide, atrial natriuretic factor, and dynamic renal autoregulation.
AB  - Inhibition of nitric oxide (NO) synthase by N(omega)-nitro-L-arginine methyl
      ester (L-NAME) increases arterial pressure (PA) and profoundly reduces renal
      blood flow (RBF). Here we report that L-NAME causes changes in the PA-RBF
      transfer function which suggest augmentation of the approximately 0.2 Hz
      autoregulatory mechanism. Attenuation of PA fluctuations from 0.06 to 0.11 Hz was
      enhanced, indicating increased efficacy of autoregulation. Also, the rate of gain
      reduction between 0.1 and 0.2 Hz increased while the associated phase peak became
      > or = pi/2 radians, indicating emergence of a substantial rate-sensitive
      component in this system so that autoregulatory responses to rapid PA changes
      become more vigorous. Infusion of L-arginine partly reversed the pressor response
      to L-NAME, but not the renal vasoconstriction or the changes in the transfer
      function. The ability of atrial natriuretic factor (ANF), which also acts via
      cGMP, to replace NO was assessed. ANF dose dependently reversed but did not
      prevent the pressor response to L-NAME, indicating additive responses. ANF did
      not restore RBF or reverse the changes in the transfer function induced by L
      NAME. The rate-sensitive component that was enhanced by L-NAME remained
      prominent, suggesting that either ANF did not adequately replace cGMP or
      provision of a basal level of cGMP was not able to replace cGMP generated in
      response to NO. It is concluded that NO synthase inhibition changes RBF dynamics
      with the most notable change being increased contribution by a rate-sensitive
      component of the myogenic system.

PMID- 10588483
TI  - Reflex changes in heart rate during chemoreceptor stimulation in monkeys.
AB  - The changes in heart rate induced by the stimulation of arterial chemoreceptors
      by apneic asphyxia and left atrial - intracarotid injections of sodium cyanide
      were investigated in anesthetized artificially ventilated and paralysed monkeys.
      Apneic asphyxia and sodium cyanide injection caused tachycardia, bradycardia, or
      both in monkeys paralysed with decamethonium bromide and tachycardia only, in
      monkeys paralysed with gallamine. In both groups, the tachycardia was abolished
      by prior administration of propranolol and the bradycardia, by atropine. Prior
      ventilation with 100% O2 abolished the heart rate responses produced by apnea.
      Recording of phrenic efferent activity showed that the neural discharge increased
      in response to apneic asphyxia and sodium cyanide injections. It remained so
      during the manifestation of tachycardia, bradycardia, or no change in heart rate,
      suggesting that even though "higher centres" may have an important influence in
      the heart rate responses elicited, central respiratory drive may not be the only
      mechanism. The present results show that in the nonhuman primate, arterial
      chemoreceptor stimulation elicits both cardioacceleratory and cardioinhibitory
      reflexes, and the net effect of their stimulation on heart rate depends upon the
      balance between these opposing mechanisms.

PMID- 10588484
TI  - Nonselective cationic currents activated by acetylcholine in swine tracheal
      smooth muscle cells.
AB  - Membrane currents in isolated swine tracheal smooth muscle cells were
      investigated using a pipette solution containing BAPTA-Ca2+ buffer and Cs+ as the
      major cation. With a pipette solution containing 100 nM free Ca2+, acetylcholine
      (ACh; 1-100 microM), in a concentration-dependent manner, activated a current
      without inducing shortening of cells, although neither 1 mM histamine nor 1
      microM leukotriene D4 activated the current (n = 7, n is the number of cells).
      The effect of 100 microM ACh was suppressed by pretreatment with 100 microM
      atropine (n = 6) or intracellular application of preactivated pertussis toxin at
      a concentration of 0.1 microg x mL(-1) (n = 8). Genistein (0.1-100 microM), in a
      concentration-dependent manner, suppressed the activation of the inward current
      by 100 microM ACh, whereas it did not significantly suppress that of the outward
      current (n = 6-8). With a pipette solution containing 50 nM free Ca2+, outward
      current, but not inward current, was activated by 100 microM ACh (n = 10). When
      the pipette solution had free Ca2+ concentrations greater than 50 nM, the inward
      current together with the outward current was activated. The ratio between the
      amplitude of the inward and outward currents was significantly increased as the
      free Ca2+ concentration in the pipette solution increased. The steady-state
      activation curve of the ACh-activated current with the 50 nM free Ca2+ pipette
      solution was fitted by a single Boltzmann distribution (Vh = +69.8 mV, k = -11.9
      mV, n = 10). The activation time constant became smaller as the membrane
      potential was more depolarized (164.3+/-5.9 ms at +40 mV to 92.4+/-6.3 ms at +120
      mV, n = 10). The reversal potential was not significantly changed by reducing
      extracellular Cl- concentration to one-tenth of the control (n = 8), suggesting
      that the current is a nonselective cationic current. These results suggest that
      ACh activates an outward nonselective cationic current via pertussis toxin
      sensitive G-protein(s) coupled with muscarinic receptors. Involvement of
      genistein-sensitive tyrosine kinase in the activation process of the current is
      unlikely.

PMID- 10588485
TI  - Role of angiotensin II in sympathetic nervous system induced left ventricular
      dysfunction.
AB  - Experiments were undertaken to determine whether angiotensin (Ang) II
      concentration increases during massive sympathetic nervous system (SNS)
      activation and whether such an increase plays a role in the pathogenesis of SNS
      induced left ventricular (LV) dysfunction. We also sought to determine whether
      excessive Ca2+ uptake through L-type channels due to intense adrenoceptor
      activation is responsible for the LV dysfunction. AngII concentration was
      measured in the plasma and myocardium before and after massively activating the
      SNS with an intracisternal injection of veratrine. In separate experiments,
      rabbits were given losartan, enalaprilat, enalaprilat plus HOE-140, nifedipine, 
      Bay K 4866, or saline before massively activating the SNS. LV function was
      evaluated 2.5 h later. The intense SNS activity caused plasma and myocardial
      AngII to increase by 400 and 437%, respectively. AngII receptor blockade did not
      prevent LV dysfunction. In contrast, enalaprilat reduced the degree of
      dysfunction, but its cardioprotection was abolished by HOE-140. Although
      nifedipine prevented SNS-induced LV dysfunction, administration of the Ca2+
      channel opener, -Bay K 4866, did not increase its severity. Our results indicate
      that AngII is not involved in the pathogenesis of SNS-induced LV dysfunction and
      that the cardioprotection provided by angiotensin converting enzyme (ACE)
      inhibition is due to activation of a bradykinin pathway. Furthermore, the finding
      that the magnitude of the LV dysfunction was reduced by enalaprilat, and not
      increased by -Bay K 4866, suggests that intense adrenoceptor activation of L-type
      Ca2+ channels is not the primary pathogenetic mechanism.

PMID- 10588486
TI  - Hydrolysis of long-chain, n-3 fatty acid enriched chylomicrons by cardiac
      lipoprotein lipase.
AB  - The hydrolysis of chylomicrons enriched in long-chain n-3 fatty acids by cardiac
      lipoprotein lipase was studied. In 60 min, 24.8% of the triacylglycerol fatty
      acids were released as free fatty acids. The fatty acids were hydrolyzed at
      different rates. DHA (docosahexaenoic acid, 22:6n-3) and EPA (eicosapentaenoic
      acid, 20:5n-3) were released at rates significantly less than average. Stearic
      acid (18:0), 20:1n-9, and alpha-linolenic acid (18:3n-3) were released
      significantly faster than average. There was no relationship between the rate of
      release of a fatty acid and the number of carbons or the number of double bonds.
      Lipoprotein lipase selectively hydrolyzes the fatty acids of chylomicron
      triacylglycerols. This selectively will result in remnants that are relatively
      depleted in 18:0, 20:1, and 18:3 and relatively enriched in 20:5 and 22:6.

PMID- 10588487
TI  - Enhanced reactivity of the adrenal medulla in response to pituitary adenylate
      cyclase activating polypeptide1-27 (PACAP) during insulin-induced hypoglycemia in
      anesthetized dogs.
AB  - The present study was to test the hypothesis that the reactivity of the adrenal
      medulla to pituitary adenylate cyclase activating polypeptide1-27 (PACAP27) is
      enhanced during insulin-induced hypoglycemia (IIH) in anesthetized dogs. Plasma
      catecholamine (CA) concentrations in adrenal venous and aortic blood were
      determined by an HPLC method coupled with electrochemical detection, and the
      plasma glucose concentration in aortic blood was measured using a glucometer.
      PACAP27 (25 ng) was administered locally via the adrenolumbar artery to the left
      adrenal gland. The resulting CA responses were compared before and during IIH
      following an intravenous bolus injection of insulin (0.15 IU/kg, i.v.). In the
      first group with normal adrenal innervation, the basal adrenal CA secretion
      gradually increased, reaching a maximum level 45 min after the insulin injection.
      The net increase in PACAP27-induced CA secretion was significantly greater 30,
      45, and 60 min after the induction of hypoglycemia, compared with the initial net
      response to PACAP27 observed before insulin injection. In the second group
      receiving local adrenal denervation, neither the basal CA secretion nor the net
      CA response to PACAP27 significantly increased despite the presence of IIH, which
      developed to an extent similar to that found in the first group. In the third
      group, which was the normoglycemic control group, both the basal CA secretion and
      the net CA response to PACAP27 remained unchanged during the experimental period.
      The results indicate that the adrenomedullary reactivity to PACAP27 was
      significantly enhanced during IIH only when the sympathoadrenal system was
      activated. The present study suggests that PACAP27 may play a beneficial role in
      glucose counterregulatory mechanisms in the adrenal medulla during hypoglycemia.

PMID- 10588488
TI  - A novel insertion sequence increases the expression of leukotoxicity in
      Actinobacillus actinomycetemcomitans clinical isolates.
AB  - BACKGROUND: The expression of leukotoxin varies among Actinobacillus
      actinomycetemcomitans strains and is dependent in part on the structure of the
      ltx promoter region. Highly leukotoxic strains, characterized by a 530 base pair
      (bp) deletion within the ltx promoter, have been associated with juvenile
      periodontitis in the United States and Europe. In the present study, we analyzed
      the ltx promoter structure to elucidate whether A. actinomycetemcomitans from
      Japanese periodontitis patients exhibits the highly toxic phenotype. METHODS:
      Forty-five A. actinomycetemcomitans strains, including 43 clinical isolates, the
      highly leukotoxic strain JP2, and a minimally leukotoxic strain 652 were used in
      the study. The ltx promoter structure was analyzed by polymerase chain reaction
      (PCR), with oligonucleotide primers focusing the ltx promoter region, and
      nucleotide sequencing. Leukotoxic activity was determined by trypan blue
      exclusion. Western blotting assay was performed to detect the level of leukotoxin
      polypeptide. RESULTS: A 495 bp PCR product was amplified from JP2, a 1025 bp
      product from 652 and 41 of the clinical isolates, and a 1926 bp product from the
      remaining two clinical isolates (AaIS1, AaIS2). Sequencing of the 1926 bp PCR
      fragment showed that it was similar to that of strain 652 but contained an 886 bp
      region that was identified as an insertion sequence (IS). Both AaIs strains
      expressed high levels of leukotoxicity, similar to strain JP2. In addition, a
      mutant (AaIS-) that had lost the IS element expressed a significantly lower level
      of leukotoxicity compared with AaIS strains. Furthermore, the levels of
      leukotoxin polypeptide expressed by these strains were consistent with their
      whole cell leukotoxicity. CONCLUSIONS: A. actinomycetemcomitans clinical strains
      which were isolated from Japanese periodontitis patients do not possess the 530
      bp ltx promoter deletion. The results of this study suggest that a high level of
      leukotoxin expression correlates with the insertion of the transposable DNA
      element.

PMID- 10588489
TI  - Possible potentiation of toxins from Prevotella intermedia, Prevotella
      nigrescens, and Porphyromonas gingivalis by cotinine.
AB  - BACKGROUND: Smoking is a recognized risk factor for the initiation and
      progression of periodontitis. However, the mechanism by which smoking induces its
      negative effects on the periodontium is not clear. This study aimed to test the
      hypothesis that synergy may occur between cotinine and bacterial products
      isolated from 3 putative periodontopathogens. METHODS: A chick embryo toxin assay
      was used to investigate bacterial toxins (cell-free extracellular toxins and cell
      free cell lysates) from 5 species with and without cotinine. A total of 9
      putative periodontopathogens (3 species) and 2 non-oral controls (2 species) were
      studied. The periodontal species were: Prevotella intermedia (n = 4), Prevotella
      nigrescens (n = 4), and Porphyromonas gingivalis (n = 1). The control species
      tested were: Staphylococcus aureus (n = 1) and Escherichia coli (n = 1). RESULTS:
      The toxicity kill was significantly greater than expected by simple addition
      alone (P <0.05, Fisher's exact test) between cotinine (800 ng/ml) and 1) the cell
      free extracellular toxins of P. nigrescens MH1 and 2) the cell-free cell lysates
      of P. intermedia MH2. Synergy occurred with cotinine plus the cell-free
      extracellular toxins in all but 3 periodontal isolates, and the cell-free cell
      lysates in all but 2 periodontal isolates. Cotinine significantly (P <0.05,
      Fisher's exact test) enhanced the effects of cell-free extracellular toxins and
      cell lysates from one control species (E. coli), but not the other (S. aureus).
      CONCLUSIONS: These findings indicate that synergy in an in vitro assay can occur
      between cotinine and toxins from putative periodontopathogens. This may be one
      important mechanism by which smoking increases the severity of periodontitis.

PMID- 10588490
TI  - Comparison of Nd:YAG laser versus scaling and root planing in periodontal
      therapy.
AB  - BACKGROUND: The Nd:YAG laser has recently been used in the treatment of
      periodontal disease. However, although a clinical reduction of probing depth and
      gingival inflammation to this new approach has been reported, it has not been
      fully evaluated. Interleukin-1 beta (IL- 1beta), a potent stimulator of bone
      resorption, has been identified in gingival crevicular fluid (GCF), which is
      closely associated with periodontal destruction. The aim of this study was to
      compare the effects of Nd:YAG laser treatment versus scaling/root planing (SRP)
      treatment on crevicular IL-1beta levels in 52 sampled sites obtained from 8
      periodontitis patients. METHODS: One or 2 periodontitis-affected sites with a 4
      to 6 mm probing depth and horizontal bone loss from 3 adjacent single-root teeth
      in each of 4 separate quadrants were selected from patients for clinical
      documentation and IL-1beta assay. Sampling site(s) from each diseased quadrant
      was randomly assigned to one of the following groups: 1) subgingival laser
      treatment (20 pps, 150 mJ) only; 2) SRP only; 3) laser treatment first, followed
      by SRP 6 weeks later; or 4) SRP first, followed by laser therapy 6 weeks later.
      The GCF was collected and the amount of IL-1beta was assayed by enzyme-linked
      immunosorbent assay (ELISA). Clinical parameters and GCF were measured at
      baseline and biweekly after therapy for 12 weeks. RESULTS: An obvious clinical
      improvement (marked decrease in the number of diseased sites with gingival index
      > or =2) and reduction of crevicular IL- 1beta were found in all groups. The
      level of IL- 1beta was significantly lower in the SRP group (P = 0.035) than in
      the laser therapy group for the duration of the 12 weeks. The laser combined SRP
      therapy group showed a further reduction of IL- 1beta (6 to 12 weeks after
      treatment) than either laser therapy alone or SRP combined laser therapy.
      CONCLUSIONS: Our data suggest that laser therapy appeared to be less effective
      than traditional SRP treatment. Of the 4 treatment modalities, inclusion of SRP
      was found to have a superior IL- 1beta response, when compared to other therapies
      without it. In addition, no additional benefit was found when laser treatment was
      used secondary to traditional SRP therapy.

PMID- 10588491
TI  - Morphological study of root surfaces in teeth with adult periodontitis.
AB  - BACKGROUND: Our study correlates the histological alterations in the cementum
      (especially resorption areas) of teeth with the different stages of adult
      periodontitis. METHODS: Sixty-seven teeth affected by adult periodontitis and 7
      healthy teeth extracted from patients over 40 years old were used. The teeth were
      divided into 3 groups according to radiographic data: group 1: five teeth with
      bone loss less than one-third of the normal alveolar height; group 2: thirty-one
      teeth with bone loss between one and two thirds; and group 3: thirty-one teeth
      with bone loss greater than two thirds. The samples were prepared for light and
      scanning electron microscopy, considering the gingival, middle, and apical thirds
      in each root. RESULTS: Two control teeth, 4 teeth in group 1, and all teeth in
      groups 2 and 3 showed resorption areas. Regarding the gingival third, the control
      teeth did not show any resorption, while 25% of affected teeth in group 1, 38.7%
      of teeth in group 2, and 35.5% of teeth in group 3 exhibited resorption.
      Regarding the middle third, 50% of affected teeth belonging to the control group
      and group 1; 67.7% of teeth in group 2; and 87.1% of teeth in group 3 showed
      resorption. Regarding the apical third, all teeth belonging to the control group
      and group 1 showed resorption, while 93.5% and 87.1% of teeth in groups 2 and 3,
      respectively, exhibited resorption. Most of the resorptions did not extend beyond
      the cementum. However, in 29.0% of teeth in group 2 and 38.7% of teeth in group
      3, resorption had spread as far as the dentin. All the lesions in the control
      group and group 1 were practically repaired, while only 71.0% of teeth in group 2
      and 61.3% of teeth in group 3 showed some sign of reparation. However, in groups
      2 and 3, practically all lesions affecting dentin were repaired. CONCLUSIONS:
      These data suggest that the spread of root resorption is associated with
      inflammation. This study also suggests that the capacity for repair of root
      resorption is diminished with greater severity of periodontitis.

PMID- 10588492
TI  - Assessment of a novel screening test for neutrophil collagenase activity in the
      diagnosis of periodontal diseases.
AB  - BACKGROUND: Increased levels of active neutrophil collagenase (MMP-8) in the
      gingival crevicular fluid (GCF) are associated with progressive periodontitis.
      The measurement of this enzyme in GCF could facilitate diagnosis. However, assays
      with sufficient sensitivity to detect collagenase in whole-mouth GCF currently
      use radiolabeled substrates and require several days to complete. To provide more
      rapid analyses of collagenase activity that are better adapted to clinical
      studies, we developed and validated a novel assay (soluble biotinylated-collagen
      assay: SBA) based on chemiluminescent detection of biotinylated collagen
      digestion products. METHODS: The concordance of the novel SBA assay with a
      radioactive collagen substrate assay was assessed by parallel analyses of enzyme
      from 35 neutrophil preparations and from 41 samples of GCF from periodontitis
      patients, followed by Pearson correlation analysis. To test whether the assay
      appropriately measured MMP-8 activity, enzyme activity was assessed after
      incubation with specific collagenase blockers. We examined the diagnostic utility
      of the SBA in cross-sectional and longitudinal analyses of 125 patients with
      adult periodontitis, 5 patients with early-onset periodontitis, 1 edentulous
      patient, and in 32 control patients without periodontitis. RESULTS: The assay
      detected <56 pg collagen degraded/hour/microl sample, which is comparable to the
      most sensitive radioactive assay. The total assay time was 22 hours and
      reproducibility on replicate measurements was high (r = 0.96). In direct
      comparisons of MMP-8 activity in GCF with enzyme from peripheral blood
      neutrophils using the SBA and radioactive assays, there was a high correlation (r
      = 0.97). As expected, EDTA and TIMP-1 and -2, known inhibitors of MMP-8,
      completely blocked enzyme activity with this assay. Cross-sectional and
      longitudinal analyses of GCF showed that MMP-8 activity was >18-fold higher in
      severe periodontitis than in stable periodontitis and decreased to <25% of
      pretreatment levels following therapy. Based on measurements of collagenase
      activity in different disease groups, we estimated a value of 80 nano units as a
      threshold for severe periodontitis. CONCLUSIONS: These results indicate that
      active MMP-8 is detected in GCF by a novel assay that is specific, simple, rapid,
      and reproducible and which may facilitate diagnostic discrimination between
      stable and progressive lesions.

PMID- 10588493
TI  - In situ localization and characterization of active proteases in chronically
      inflamed and healthy human gingival tissues.
AB  - BACKGROUND: Studies have indicated an important role for host-derived proteases
      in the pathogenesis of periodontal disease. The objectives of this study were: 1)
      to develop an assay measuring protease activity in situ and 2) to localize and
      characterize the enzymatic activity in intact inflamed and healthy gingiva.
      METHODS: Gingival specimens were prepared and over-laid with a quenched
      fluorescent substrate. Protease activity was visualized by fluorescence
      microscopy and correlated with histologic features. RESULTS: In inflamed tissues,
      enzymatic activity was detected mainly in the connective tissue (predominantly
      matrix metalloproteases) and, to some extent, in the epithelium (predominantly
      serine proteases). In contrast, clinically healthy tissues failed to exhibit
      significant amounts of protease activity. Quantitative and qualitative
      characteristics of protease activity in intact tissues were found to be pH
      dependent. CONCLUSIONS: The method described here enabled assessment of active
      proteases in intact tissues where cell-cell and cell-matrix interactions had been
      maintained. Our results indicate that there are substantial differences in the
      distribution of specific proteases between clinically healthy and inflamed
      periodontal tissues.

PMID- 10588494
TI  - Heightened gingival inflammation and attachment loss in type 2 diabetics with
      hyperlipidemia.
AB  - BACKGROUND: Our previous studies in diabetic (DB) rats suggest that
      hyperlipidemia may cause a dysregulation of the cellular and local cytokine
      response to periodontitis (AP). The objective of the present study was to
      determine if diabetes has a similar dysregulatory effect on the gingival response
      to AP in humans. METHODS: Peripheral blood, as well as gingival tissue (GT) and
      gingival crevicular fluid (GCF), was obtained from a total of 35 patients who
      were categorized into the following groups based on level of diabetic (type 2)
      control and presence or absence of adult periodontitis (AP): group 1,
      systemically and periodontally healthy (n = 6); group 2, systemically healthy
      with adult periodontitis (n = 7); group 3, well-controlled diabetes and
      periodontally healthy (n = 6); group 4, well-controlled diabetes with adult
      periodontitis (n = 5); group 5, poorly controlled diabetes and periodontally
      healthy (n = 5); group 6, poorly controlled diabetes and adult periodontitis (n =
      6). All subjects were given a thorough periodontal examination, including probing
      depths (PD), clinical attachment levels (CAL), gingival index (GI), plaque index
      (PI), and vertical bitewing radiographs. Blood studies included levels of
      glycated hemoglobin (HbA1c), triglycerides (TG), cholesterol (CHL), low-density
      lipoproteins (LDL), and high-density lipoproteins (HDL). The levels of
      interleukin-1 beta (IL-1beta) in GCF and GT, interleukin-6 (IL-6), and platelet
      derived growth factor AB (PDGF-AB) in GT from patients in each experimental group
      were analyzed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our results
      indicate that all clinical indices except PI were significantly elevated in the
      poorly controlled and well-controlled diabetics, compared to systemically healthy
      patients, but only in the subjects without preexisiting AP (Tukey's multiple
      comparisons, P <0.05). Pairwise linear regression analysis revealed significant
      (P <0.01) positive associations between periodontal inflammation (PD, CAL, PI,
      GI) and levels of GCF IL-1beta, GT IL- 1beta GT IL-6, but not GT PDGF; moreover,
      GT IL-6 levels were significantly associated (P<0.05) with GT IL-1beta. As TG
      levels increased in the non-AP patients (group 1 < group 3 < group 5), there was
      a trend, not significant, for increased GCF IL-1beta levels and increased
      gingival inflammation. Interestingly, periodontitis resulted in increased PDGF-AB
      levels in the gingiva of systemically healthy and well-controlled diabetes
      patients, but this increase was obtunded in poorly controlled diabetes patients.
      CONCLUSIONS: This confirms our earlier work in the diabetic rat model. These
      studies indicate that decreased metabolic control in type 2 diabetics results in
      increased serum triglycerides and has a negative influence on all clinical
      measures of periodontal health, particularly in patients without preexisting
      periodontitis. Levels of the cytokine IL- 1beta showed a trend for increasing as
      diabetic control diminished. In contrast, levels of the growth factor PDGF, which
      normally increase in periodontitis, decreased in poorly controlled diabetics with
      periodontitis. These studies suggest a possible dysregulation of the normal
      cytokine/growth factor signaling axis in poorly controlled type 2 diabetics that
      may contribute to periodontal breakdown/diminished repair.

PMID- 10588495
TI  - Longitudinal study of dental implants in a periodontally compromised population.
AB  - BACKGROUND: The purpose of this longitudinal study was to determine the clinical
      status and the composition of the subgingival microbiota of dental implants and
      natural teeth in patients with a history of periodontitis. METHODS: Twenty-five
      partially edentulous patients treated for moderate to advanced adult
      periodontitis and having a total of 42 implants participated in this 3-year
      study. The assessment of clinical status was done 1, 2, and 3 years after
      prosthetic loading (T1, T2, and T3, respectively). Clinical parameters evaluated
      included probing depth (PD), clinical attachment level (CAL), gingival index
      (GI), and plaque index (PI). The subgingival microbiota at peri-implant and
      periodontal sites were analyzed at T1 and T2. RESULTS: No significant difference
      in clinical parameters between implants and teeth and within the 2 groups between
      different time points was observed through the study. PD and CAL measurements of
      sampled periodontal and peri-implant sites did not show any statistically
      significant difference through the study and between the 2 groups. PI of sampled
      periodontal sites showed a statistically significant improvement during the
      study. From the morphological observation of the subgingival microbiota, a
      significant difference in the composition of motile rods between implants and
      teeth was found at T1. There were no differences detected in the subgingival
      microbiota, culturally identified at peri-implant and periodontal sites for the
      duration of the study. CONCLUSIONS: In conclusion, implants were colonized by the
      indigenous periodontal microbiota and were well maintained in patients with a
      history of periodontitis. No significant association between progressing or non
      progressing periodontal or peri-implant sampled sites in terms of loss of
      attachment and infection with at least one of the searched periodontal pathogens
      was found, suggesting that the presence of putative periodontopathogens at peri
      implant and periodontal sites may not be associated with future attachment loss
      or implant failure.

PMID- 10588496
TI  - Microvascular changes after placement of titanium implants: scanning electron
      microscopy observations of machined and titanium plasma-sprayed implants in dogs.
AB  - BACKGROUND: The purpose of this study was to clarify the osseointegration process
      of titanium implants through study of the vascular architecture and bone
      apposition. The smooth machined-surface implant is tightly fixed to the bone by
      its threads. The rough titanium plasma-sprayed (TPS) coated implants give a
      scaffold for new bone. METHODS: Twelve beagle dogs were used, and 2 surface types
      of implants were inserted in the mandible. Vascular injection was given 14, 30,
      and 120 days after surgery. The soft tissue was digested by proteinase solution,
      and specimens were examined by scanning electron microscope (SEM). RESULTS:
      Fourteen days after placement of machined implants, new vessels could be seen
      branching out from the vascular network of the bone marrow. In TPS implants, a
      vascular network was seen between the bone-implant interface. At 30 days, the
      vessels were arranged in a groove corresponding to the machined fixture. With TPS
      implants, new bone was visible along the surface of the fixture, and the vascular
      network was buried in the bone. At 120 days after placement of machined implants,
      bone had formed a smooth surface. A few blood vessels were arranged along the
      bone surface. With TPS implants, a rough bone surface and flat vessels were
      observed on its surface. CONCLUSIONS: Implants become osseointegrated in
      different ways, depending on their structures and the characteristics of their
      surfaces. From the microcirculation point of view, the vessels are an important
      factor for the remodeling of bone.

PMID- 10588497
TI  - Merits of soft nitriding scalers.
AB  - BACKGROUND: It has been demonstrated that nitriding modifies the physical
      characteristics of metals. The purpose of this study was to evaluate the changes
      induced by 3 levels of inexpensive soft nitriding treatments on commercial sickle
      scalers. METHODS: Taglite scalers (NT) were soft nitrided for 30 (SN30), 60
      (SN60), or 90 (SN90) minutes. The cumulated scaled material was weighed every 10
      strokes x 10 and thereafter every 1,000 to 8,000 strokes by an automatic scaling
      apparatus against epoxy resin. Weight differences were used to indicate abrasion
      resistance; the relative efficiency (RE) was calculated as the ratio of scaled
      amount at a given number of strokes (SN/NT). The hardness and the tensile
      strengths were determined for each soft nitriding treatment level. The nitrided
      layer thickness of representative SN scalers was observed by electron probe x-ray
      microanalysis. RESULTS: The SN60 was not significantly different from SN30 or
      SN90, but the SN90 was more efficient than SN30 for the first 100 strokes
      (P<0.01). The RE of all SN scalers was significantly greater (2.3 to 2.7 times)
      than the NT scalers from the beginning of the study and throughout all time
      periods (SN90 > SN60 > SN30); it increased further during the first 100 strokes
      (9.7 to 15.5 times), indicating the NT scalers wore out faster than SN scalers.
      The untreated scalers' performance decreased to 10% of baseline after 100
      strokes; but even after 1,000 strokes, the SN60 and SN90 performed better than
      new untreated scalers. Thereafter, all scalers' performance, including SN
      scalers, decreased. While the NT blades ceased to cut measurable amounts after
      7,000 to 8,000 strokes, all SN scalers continued to cut. Although SN90 scalers
      had the thickest soft layer and were the hardest (P<0.01), the SN60 had the
      highest tensile strength (P <0.01), suggesting that it might be the safest in
      practice. CONCLUSIONS: Sixty minutes of soft nitriding treatment of commercially
      available taglite scalers seem to be the optimal treatment duration to increase
      their durability, on the order of 100 to 1,000 times, without jeopardizing safety
      for clinical use.

PMID- 10588498
TI  - Growth factors regulate expression of osteoblast-associated genes.
AB  - BACKGROUND: The goal of periodontal regenerative therapies is to reconstruct
      periodontal tissues such as bone, cementum, and periodontal ligament cells (PDL).
      The need to establish predictable treatment modalities is important for
      reconstruction of these tissues. The aim of this study was to determine the
      effects of a low molecular extract of bovine bone protein (BP) containing bone
      morphogenetic proteins (BMPs) 2, 3, 4, 6, 7, 12, and 13, alone or in combination
      with platelet-derived growth factor (PDGF) and/or insulin-like growth factor
      (IGF) on osteoblast differentiation in vitro. METHODS: BP, mixed with a collagen
      matrix, was added to a poly (DL-lactide-co-glycolide) polymer (PLG) and placed at
      orthotopic sites in the skullcaps of Sprague-Dawleys rats. At day 28, rats were
      sacrificed for histological analysis. All sites treated with the polymer/BP
      produced bone while control sites (without BP) showed no bone formation. Having
      established the biological activity of BP, in vitro studies were initiated using
      MC3T3-E1 cells, a mouse osteoprogenitor cell line. The ability of BP and other
      growth factors to alter cell proliferation was determined by Coulter counter, and
      differentiation was determined by Northern analysis for specific genes. RESULTS:
      When compared with cells treated with 2% serum alone, PDGF enhanced cell numbers
      at 10 and 20 ng/ml; IGF produced no significant effect at these doses; and BP at
      10 and 20 microg/ml decreased cell proliferation. Northern analysis revealed that
      PDGF blocked gene expression of osteopontin (OPN) and osteocalcin (OCN), while BP
      and IGF promoted gene expression of bone sialoprotein (BSP) and OPN. The
      combination of BP and IGF enhanced expression of OPN beyond that of either BP or
      IGF alone. PDGF was able to block the effects of IGF on gene expression, but not
      those of BP. CONCLUSIONS: These results indicate that BP, PDGF, and IGF influence
      cell activity differently, and thus raise the possibility that combining factors
      may enhance the biological activity of cells.

PMID- 10588499
TI  - Effect of periodontitis and smoking on blood leukocytes and acute-phase proteins.
AB  - BACKGROUND: We have previously found hyperreactive neutrophils, intrinsic or
      induced, in periodontitis patients by in vitro quantitation of free oxygen
      radicals. The effects of periodontitis and cigarette smoking on blood parameters
      have generally been described separately. Our aim was to compare these systemic
      effects of periodontitis and cigarette smoking, separately and in combination, in
      order to study the hyperreactivity in peripheral neutrophils. METHODS: Blood
      cells and acute-phase proteins were studied in 40 periodontitis patients and 43
      healthy controls. The generation of free oxygen radicals from neutrophils was
      measured as luminol-enhanced chemiluminescence (CL) after activation of their
      Fcgamma receptors with opsonized Staphylococcus aureus. RESULTS: An increase in
      CL in peripheral neutrophils from periodontitis patients was confirmed. Smoking
      had no significant effect on CL. The periodontitis patients had higher
      concentrations of C-reactive protein (CRP) than the controls. ANOVA analysis
      showed that the increase in neutrophil count, haptoglobin, and alpha-1
      antitrypsin levels was significantly influenced by cigarette smoking. IgG2 was
      lower in patients than in controls (P <0.017, ANOVA), and there was an
      interaction between periodontitis and smoking (P<0.047, ANOVA). The lower
      concentration of IgG2 in patients who smoke may impair neutrophil function and be
      a mechanism by which smoking aggravates periodontitis. CONCLUSIONS: In general,
      the combination of periodontitis and cigarette smoking alters the parameters
      studied. The effects of periodontitis on CRP and IgG2 means that periodontal
      lesions may also leak agents, priming the peripheral neutrophils to increased CL.

PMID- 10588500
TI  - The association between smoking cessation and periodontal status and salivary
      proteinase levels.
AB  - BACKGROUND: Little information is available about the effects of the cessation of
      cigarette smoking on oral health, although cigarette smoking has been shown to be
      associated with a variety of oral diseases. The aim of this study was to compare
      periodontal status, salivary proteolytic activity, especially collagenase-2 (MMP
      8) levels, and oral mucosal status in individuals who had quit smoking for at
      least 6 months (mean 3.5, SD 1.3 years) and in regular smokers. METHODS: The
      subjects were 409 white male smokers aged 55 to 74 years with 15 or more
      remaining teeth. They had participated in a major cancer prevention study (ATBC
      Study). Eighty-two of the men had given up smoking and 327 were smokers. The
      subjects were examined clinically to determine the prevalence of periodontal
      pockets, gingival bleeding (BOP) and suppuration, and prevalence of keratotic
      oral mucosal lesions. The loss of alveolar bone was determined radiographically.
      Candida albicans was cultivated, and lesions showing leukoplakia were examined
      histopathologically. General proteolytic activity and collagenase-2 or matrix
      metalloproteinase-8 (MMP-8) levels in saliva, salivary pH, and buffering capacity
      were measured. Linear regression, logistic regression, or Fisher's exact test
      were used in statistical analysis. RESULTS: Salivary general proteolytic activity
      and MMP-8 levels were lower in current smokers than in ex-smokers (P <0.05 and P
      <0.05, respectively). The prevalence of > or = 4 mm deep pockets, gingival
      suppuration, and loss of crestal bone were statistically significantly lower (P =
      0.003, P<0.001, and P<0.05, respectively) and salivary buffering capacity higher
      (P <0.05) in those who had quit smoking compared to current smokers; there was no
      difference in BOP. The prevalence of oral leukoplakia did not differ
      significantly between smokers and quitters, but was higher in those who smoked
      >15 cigarettes per day compared to quitters (odds ratio 3.5, 95% CI, 0.8 to
      15.3). CONCLUSIONS: These data suggest that periodontal status and oral mucosal
      health are better in those who have quit cigarette smoking compared to current
      smokers. However, the data further suggest that smoking may significantly lower
      both general proteolytic enzyme activity and MMP-8 levels in saliva. Thus, care
      should be taken in interpreting results revealing salivary/mouthrinse proteinases
      as diagnostic markers for oral/periodontal disease activity.

PMID- 10588501
TI  - A comparative evaluation of hemostatic agents in the management of soft tissue
      graft donor site bleeding.
AB  - BACKGROUND: Periodontal plastic surgery has increased the use of palatal wounds
      for donor tissue, with the most common complication being excessive bleeding from
      the palate after harvesting tissue. This study was conducted to evaluate the
      efficacy of 3 methods for achieving hemostasis on the palate after harvesting
      donor tissue for autogenous soft tissue grafts. METHODS: Thirty sites were
      evaluated at surgery for hemostasis and followed over 21 days for healing and
      adverse events. Three treatment groups were randomly selected and patients
      received either a test product or control comprising: 1) oxidized regenerated
      cellulose; 2) absorbable gelatin sponge; or 3) sterile gauze with external
      pressure as the control. All patients received a surgical stent for the palate.
      RESULTS: The results were analyzed for smokers and non-smokers, and the median
      time to hemostasis was significantly shorter when a hemostatic agent was applied
      to the palatal wounds compared to controls in both groups. Pain assessment showed
      no differences across treatment groups. However, by 21 days, only the oxidized
      regenerated cellulose group had complete healing based on blinded clinical
      evaluation with all sites rated as normal to rapid healing, compared to the
      absorbable gelatin sponge group where 40% of the sites were rated as slow
      healing. Adverse events, primarily bleeding episodes during the first 7 days
      after surgery, were found in 40% of the oxidized regenerated cellulose and gauze
      control groups, while no sites in the absorbable gelatin sponge group had an
      adverse event. The patients were followed for an average of 10 months and
      demonstrated a mean shrinkage of their recipient grafts of 24% in total surface
      area. CONCLUSIONS: This study concluded that the use of hemostatic agents for
      palatal wounds is confirmed as the treatment of choice when performing free soft
      tissue grafts.

PMID- 10588502
TI  - Bacterial adhesion of Actinobacillus actinomycetemcomitans serotypes to titanium
      implants: SEM evaluation. A preliminary report.
AB  - BACKGROUND: In this study, the adherence ability of Actinobacillus
      actinomycetemcomitans serotypes to titanium implant surfaces was evaluated to
      demonstrate if any selective adherence occurs according to the serotypes of the
      microorganism. METHODS: The study material included 3 reference strains of A.
      actinomycetemcomitans serotypes a, b, and c (ATCC 29523, ATCC 43718, ATCC 33384)
      and 2 clinical isolates of A. actinomycetemcomitans serotypes d and e (IDH 781,
      IDH 1705), together with commercially available titanium blade implants. For each
      strain, bacterial suspensions with identical concentrations (5 x 10(7) cells/ml)
      were prepared and 0.5 ml of each was added on to the implant surfaces, which had
      been precoated with glycine-bovine serum albumin (BSA). After incubation at 37
      degrees C for 60 minutes in 5% CO2 in air, the implants with attached bacteria
      were prepared for scanning electron microscopic (SEM) observations. Bacterial
      adhesion was quantified on the textured body surfaces of the implants, and
      results were statistically analyzed with analysis of variance followed by
      Duncan's test. The surface ultrastructure of the bacterial cells was also
      evaluated descriptively. RESULTS: The tested strains adhered to implant surfaces
      in different quantities. Serotype a (ATCC 29523) showed the highest adherence
      affinity (statistically significant, P <0.01). When compared with each other,
      serotypes b, c, and d (ATCC 43718, ATCC 33384, and IDH 781) attached equally
      well, whereas serotype e (IDH 1705) had a statistically significant low adherence
      capability. CONCLUSIONS: It is suggested that in vitro A. actinomycetemcomitans
      adhesion to implant surfaces is strain dependent.

PMID- 10588503
TI  - Immunohistologic and morphometric analysis of cytotoxic T lymphocytes in
      gingivitis.
AB  - BACKGROUND: Gingivitis is an inflammatory phenomenon localized in gingival
      tissues and histologically characterized by an infiltration of several
      inflammatory cell populations. The purpose of this study was to characterize,
      localize, and quantify in situ inflammatory and cytotoxic T lymphocytes using
      immunolabeled gingival tissue sections in order to specify their implication
      during human gingivitis, since it is well known that such cells play an important
      role in the defense against bacterial elements. METHODS: Paraffin gingival tissue
      sections from 7 patients with gingivitis (G) and from 7 clinically and
      histologically healthy controls (C) were immunohistochemically stained by
      specific antibodies (anti-CD45, anti-CD3, anti-CD8, anti-CD20, anti-TIA-1, anti
      GrB, and anti-CD68), allowing the quantification of inflammatory cells in upper
      gingival epithelium (Ep), in the basal epithelium layer (BEp), and in upper
      connective tissue (CT). Collagen fibers were stained by sirius red F3Ba in order
      to evaluate, by morphometric and automated image analysis, the surface occupied
      by collagen bundles and to histologically confirm the absence of pathology of the
      clinically selected healthy controls. RESULTS: In the gingivitis group, CD45+,
      CD3+, CD8+, TIA-1+, and GrB+ lymphocyte numbers were significantly increased in
      Ep (P<0.05); and CD45+, CD3+, and TIA-I+ lymphocyte numbers were significantly
      increased in BEp (P <0.05) compared respectively to Ep and BEp of group C. In Ep
      of group G, mean CD8+/CD3+ cell ratio was significantly increased (P<0.05)
      compared to BEp and CT, and 25% of TIA-1+ cytotoxic cells were activated GrB+
      cells. CONCLUSIONS: The present study suggests that intraepithelial cytotoxic T
      lymphocytes play an important role during gingivitis and CD8 expression and that
      activation of TIA-1+ cytotoxic cells could be induced in Ep in response to
      epithelial environment. Thus, gingival epithelial tissue, which is generally only
      considered as a physical barrier, in fact contains numerous immune cell
      populations preventing the infiltration of pathogenic elements into the
      connective tissue. Particular clinical attention must be taken for the
      preservation of the epithelial tissue integrity.

PMID- 10588504
TI  - Periodontal plastic surgery in a dystrophic epidermolysis bullosa patient: review
      and case report.
AB  - Epidermolysis bullosa (EB) is a group of genetic disorders in which patients
      frequently present with fragile skin and mucosal surfaces that blister following
      minor trauma; 23 subtypes have been recognized, but their precise pathogenesis
      and etiology remain obscure. There is no treatment for EB, only palliative
      therapy. Oral bullae are the most common oral finding and affect all surfaces.
      Patients with EB present a unique challenge in terms of periodontal therapy. The
      following article reviews this disorder and describes the complications
      encountered when providing periodontal plastic surgery to a patient exhibiting
      this condition. A 36-year-old female with dystrophic EB presented for treatment
      of a 3 mm recession area with minimal attached gingiva on the facial of #24 and
      25. Oral evaluation revealed multiple ulcers. The treatment consisted of a
      subepithelial connective tissue graft in conjunction with a coronally positioned
      flap and buccal frenectomy. Most of the epithelium associated with the surgical
      area and buccal vestibule sloughed. During the postoperative course, the frenum
      had regenerated at a more coronal level and was applying tension on the gingival
      tissues. It appeared that a connective tissue union had formed between the de
      epithelialized surface of the facial flap and the buccal mucosa of the vestibule.
      A second frenectomy was performed, and a clear acrylic stent was fabricated to
      prevent the union of the connective tissue of the facial flap to the buccal
      mucosa. The stent prevented the fusion of both connective tissue layers and
      allowed time for epithelium migration.

PMID- 10588505
TI  - Povidone-iodine's effects and role in the management of periodontal diseases: a
      review.
AB  - This review article addresses the effects of povidone-iodine (PVP-I) and its
      utility in the treatment of periodontal diseases. There are data to support the
      following statements: PVP-I is a potent antiseptic and, when used as a component
      in a rinse with H202, the rinse can decrease the level of gingivitis. With
      regards to patients with adult periodontitis, there is some evidence to indicate
      that PVP-I delivered via an ultrasonic device achieves better results in deep
      pockets than ultrasonic debridement when water is the irrigant. The benefits of
      PVP-I in the treatment of refractory periodontitis are unclear. Subgingival
      irrigation with PVP-I may reduce the incidence of bacteremia if it is employed as
      a pre-procedural intrasulcular irrigant; however, this technique is not
      recommended for high-risk patients. PVP-I is a safe antiseptic and does not
      appear to impede wound healing or induce resistant bacteria. It is an approved
      drug whose intraoral use is an unlabeled indication. In conclusion, the
      literature suggests that utilization of PVP-I is potentially beneficial in the
      management of some periodontal diseases. However, additional clinical trials are
      needed to verify this assessment, since it is based upon a limited number of
      studies.

PMID- 10588506
TI  - Assessment of familial patterns of microbial infection in periodontitis.
AB  - The purpose of this article is to review approaches to the assessment of familial
      patterns of microbial infection and disease in periodontitis, and to identify
      statistical methods appropriate to such considerations of family data. Previous
      studies have provided evidence for the presence of familial aggregation of
      periodontal pathogens and periodontitis and have alluded to possible
      transmissibility of these organisms within families. Modern statistical
      techniques permit the appropriate analysis of the correlated data inherent in
      families, properly allowing for these statistical dependencies while including
      the possibility of adjustment for risk factors which may also aggregate in
      families. Such approaches as multiple linear regression, multivariate logistic
      regression, and regressive modeling provide the necessary tools to assess the
      familial aggregation of risk factors and disease in periodontitis. In particular,
      regressive models permit the analysis of familiality (membership to family) as a
      risk factor without reference to a specific underlying biologic mechanism, and
      also permit the possibility of adjustment for covariates, such as age and access
      to dental care. They also allow consideration of specific mechanisms, e.g.,
      susceptibility genes of major effect. Using such techniques, it is possible to
      more completely explore and describe familial patterns of periodontal infection
      and other aspects of periodontal disease.

PMID- 10588507
TI  - Position paper: tobacco use and the periodontal patient. Research, Science and
      Therapy Committee of the American Academy of Periodontology.
AB  - This paper was prepared by the Research, Science and Therapy Committee of The
      American Academy of Periodontology and is intended for the information of the
      dental profession. The purpose of the paper is to provide the reader with a
      general overview of the relationship of tobacco use and periodontal diseases.
      This paper will review the epidemiological and clinical findings that have led to
      our understanding of the role of tobacco use in relation to periodontal diseases
      and their treatment. In addition, this paper will review the possible underlying
      mechanisms for these effects from tobacco use. The practitioner can use this
      information in treatment decisions and in giving advice to the patients who use
      tobacco products.

PMID- 10588508
TI  - Endotoxin, sepsis, and the primrose path.

PMID- 10588509
TI  - Attenuation of catecholamine-induced immunosuppression in whole blood from
      patients with sepsis.
AB  - Studies performed on healthy volunteers have revealed that catecholamines down
      regulate the lipopolysaccharide (LPS)-induced production of tumor necrosis factor
      (TNF)alpha, interleukin (IL)-6, and IL-1beta. We extended this observation and
      show that this effect is based on changes in the mRNA concentration of these
      cytokines. Catecholamines are increased in severe sepsis due to endogenous
      production and have to be administered exogenously when the disease has proceeded
      to the state of prolonged hypotension. We here investigated whether the
      immunomodulating effect of catecholamines could also be demonstrated in the blood
      of patients with prolonged severe sepsis and of those in prolonged septic shock.
      Blood was stimulated ex vivo with LPS in the presence and absence of epinephrine
      and the cytokine protein concentration was determined. In blood of healthy
      volunteers, epinephrine reduced the LPS-stimulated synthesis of TNFalpha by 62.5%
      (P< 0.0001), of IL-6 by 39% (P< 0.0001), and of IL-1beta by 40% (P= 0.015), and
      increased the LPS-stimulated IL-10 production by 77.8% (P < 0.0001).
      Correspondingly, in blood of patients with prolonged severe sepsis, TNFalpha was
      reduced by 67.2% (P < 0.0001) and IL-6 was reduced by 32.9% (P < 0.0001); IL
      1beta and IL-10 were not modulated by catecholamines in these patients. In blood
      samples of patients in prolonged septic shock, epinephrine did not modulate
      cytokine levels of IL-6 and IL-10, and decreased TNFalpha only by 36.4% (P <
      0.0001). Interestingly, epinephrine suppressed the IL-1beta production by 73% (P
      < 0.0001) in blood of patients in prolonged septic shock, which was twice as much
      as in blood samples of healthy volunteers. The altered response of septic blood
      to catecholamines might be due to an altered reactivity of leukocytes in the
      prolonged disease although an additional role of preexisting catecholamines
      cannot be completely excluded.

PMID- 10588510
TI  - CXCR2 stimulation primes CXCR1 [Ca2+]i responses to IL-8 in human neutrophils.
AB  - Neutrophil (PMN) priming and subsequent responses to the IL-8 presented on
      pulmonary endothelial surfaces may be crucial determinants of the development of
      adult respiratory distress syndrome after injury. Elevated plasma ELR+ C-X-C
      chemokine (CXC) levels might contribute to PMN priming after trauma, but the role
      of CXCs in priming circulating PMNs is unstudied. We evaluated the interactions
      of IL-8 and GRO-alpha in priming human PMN calcium fluxes [Ca2+]i within
      circulatory environments. At physiologic concentrations, GRO-alpha primes PMN for
      IL-8 mediated [Ca2+]i mobilization, whereas IL-8 abolishes GRO-alpha responses.
      Repeated GRO-alpha exposures further enhance IL-8 responses. PMN priming for IL-8
      responses in normal plasma was CXCR2 dependent. CXCR2 was more responsive than
      CXCR1 to low levels of IL-8, together suggesting that CXCR2 is the important CXC
      receptor at circulating (i.e., low) agonist concentrations. CXCR1 stimulation
      down-regulated CXCR2 surface expression, whereas CXCR2 stimulation upregulated
      CXCR1 expression. GRO-alpha/ CXCR2 signaling enhanced post-receptor IL-8
      initiated PMN [Ca2+]i influx as well as efflux. Sufficient stimulation of the
      CXCR1 terminated this cooperative relationship by downregulating surface
      expression of CXCR2. This study is the first to report that at physiologic
      concentrations, C-X-C chemokines can act on circulating human PMNs as an
      integrated system where CXCR2 agonists, rather than cross-desensitizing CXCR1,
      act to enhance signaling of IL-8 at CXCR1 both by receptor and post-receptor
      mechanisms. Such CXCR2 mediated priming of CXCR1/ IL-8 interaction may enhance
      PMN attack on the lung after injury.

PMID- 10588511
TI  - Enhanced expression of neutrophil NADPH oxidase components in intestine of rats
      after burn injury.
AB  - We have evaluated the accumulation of neutrophils in the gut and their
      infiltration into the intestinal extravascular spaces in rats subjected to a 25%
      total body surface area scald burn. The accumulation of neutrophils was assessed
      via measurements of myeloperoxidase (MPO) activity in the intestinal homogenates,
      and the immunohistochemical localization of neutrophil NADPH oxidase component
      proteins (p47phox and p67phox) within the intestinal extravascular spaces
      determined neutrophil tissue infiltration. MPO measurements demonstrated a 12-
      and 21-fold increase above the control value in the intestinal tissue at day 1
      and day 3 post-burn, respectively, suggesting that a substantial total tissue
      accumulation of neutrophils occurs in the gut after burn injury. The
      immunohistochemical staining procedures showed both a definitive presence of the
      neutrophil in the intestinal extravascular spaces and an enhanced
      immunoreactivity in neutrophils accumulating in intestine after burn injury.
      There was no evidence of either the presence of neutrophils in the extravascular
      regions or any significant neutrophil immunoreactivity to NADPH oxidase component
      proteins in the intestines of sham control rats. These findings indicate that
      burn injury causes an enhanced migration of circulating neutrophils into the
      intestinal interstitial spaces and an upregulation of NADPH oxidase activity in
      the infiltrating neutrophils.

PMID- 10588512
TI  - Expression of HSP70 is impaired at the transcriptional level in stressed murine
      neuroblastoma cells.
AB  - Although the expression of heat shock or stress proteins (hsps) is a well
      conserved response to stress, the accumulation of these proteins is different
      between various cell-types. Particularly, cells of neuronal origin show a reduced
      expression of Hsp70 after stress. The possible mechanism of this reduced Hsp70
      expression was studied in thermally stressed murine neuroblastoma cells (N18).
      These cells showed no detectable levels of Hsp70 or Hsp70 mRNA after heat shock.
      Hsp70 transcription was not detectable after stress. However, heat shock
      transcription factor 1 (HSF1) is active in these cells under stress conditions.
      Cells transiently transfected with the chloramphenicol acetyltransferase (CAT)
      gene under control of the human heat shock promoter showed a stress-dependent
      expression of CAT, suggesting that the cells contain the factors necessary for
      the expression of Hsp70. Integration of the foreign human heat shock promoter
      into genomic DNA did not affect its transcriptional inducibility. These results
      suggest that the impairment of Hsp70 expression in N18 cells is due to the
      environment (chromatin structure, methylation pattern) of the Hsp70 locus.

PMID- 10588513
TI  - A comparison of resuscitation with packed red blood cells and whole blood
      following hemorrhagic shock in canines.
AB  - Resuscitation with crystalloid and packed red blood cells has for the most part
      replaced the use of plasma and whole blood in the initial treatment of
      hemorrhagic shock. The effects of such changes on cardiovascular function
      following hemorrhagic shock remain largely unexplored. We examined cardiovascular
      function in anesthetized canines subjected to severe hemorrhagic shock. Mongrel
      canines of either gender were anesthetized with isoflurane and instrumented for
      measurement of arterial pressure, cardiac output, coronary flow, and left
      ventricular pressure and volume for the determination of end systolic elastance
      (Ees). Following a 30-min stabilization period, blood was rapidly removed to
      induce fixed pressure (mean arterial pressure = 35 mmHg) hemorrhagic shock for 90
      min or until an arterial lactate of 7.0 mM was achieved. Animals were then
      resuscitated with 2/3 of the shed volume as lactated Ringer's and an equal volume
      of either whole blood (WB, n = 8) or packed red blood cells (PRBC, n = 10)
      resuspended in lactated Ringer's (LR) solution to replace expressed plasma
      volume. PRBC resuscitated dogs showed lower values of mean arterial pressure,
      cardiac output, rates of ventricular contraction and relaxation and myocardial
      work. Increasing the maintenance infusion rate of LR (10 mL/kg/h) following PRBC
      infusion normalized mean arterial pressure, but not other indices of
      cardiovascular function. Thus, WB, but not PRBC resuscitation restores normal
      myocardial function during resuscitation from severe hemorrhagic shock.

PMID- 10588514
TI  - Heart function after severe hemorrhagic shock.
AB  - OBJECTIVE: Test whether brief deep hemorrhagic hypotension or prolonged moderate
      hemorrhagic hypotension impairs intrinsic heart function. METHODS: Pentobarbital
      anesthetized, non-anticoagulated rats were cannulated via the carotid artery.
      This study focuses on three main groups: 1) hemorrhage to a mean arterial blood
      pressure (MAP)=25 mm Hg for 1 h (1 h severe shock), 2) hemorrhage to MAP=40 mm Hg
      for 3 h (3 h moderate shock), 3) no hemorrhage (control). Hearts were either
      freeze-clamped in-situ for tissue analysis (n=6 per group) or were removed to
      study in vitro cardiac function and efficiency using a working heart perfusion
      (n=12 per group, glucose (11 mM)/palmitate (0.4 mM), 3% BSA buffer). Following
      perfusion, hearts were freeze-clamped and analyzed for free CoA, acetyl-,
      succinyl-, and malonyl-CoA, ATP content and for TNF-alpha content. RESULTS:
      Isolated working hearts obtained following 1 h of severe shock generated 20% less
      hydraulic work than hearts obtained from control rats or rats subjected to 3 h of
      moderate shock. The cardiac efficiency (work/O2 consumption) was also
      significantly reduced with 1 h severe shock (0.76 +/- 0.07 after 15 min
      perfusion) versus control (0.96 +/- 0.06) or 3 h prolonged shock (1.10 +/- 0.09).
      Myocardial Co-A ester, ATP and TNF-alpha concentrations were not different
      between control and shocked hearts, although TNF-alpha concentrations increased
      significantly in all hearts during ex vivo perfusion. CONCLUSIONS: Depth of
      hypotension is more important than duration in causing intrinsic cardiac
      dysfunction. This post-hemorrhagic cardiac dysfunction is not a result of
      substrate limitation to the heart, nor myocardial TNF-alpha accumulation, but is
      more likely a result of impaired transfer of energy from molecular oxygen into
      external cardiac work.

PMID- 10588515
TI  - Neutrophil elastase inhibitor (ONO-5046) attenuates reperfusion-induced hepatic
      microcirculatory derangement, energy depletion and lipid peroxidation in rats.
AB  - Microcirculatory derangement, energy depletion, and lipid peroxidation are
      associated with the development of ischemia-reperfusion injury in the liver. This
      study investigated the effects of a neutrophil elastase inhibitor (ONO-5046) on
      hepatic ischemia-reperfusion injury. Adult, male Sprague-Dawley rats were divided
      into four treatment groups: 1) sham-operated control (laparotomy only, no
      ischemia) and saline injection (1 mL/kg), n = 6; 2) ischemia control (1-h
      ischemia, 2-h reperfusion) and saline injection (1 mL/kg), n = 6; 3) intravenous
      injection with ONO-5046 at a dose of 1 mg/kg 5 min before ischemia and
      immediately after reperfusion plus 1-h ischemia and 2-h reperfusion, n = 6; and
      4) intravenous injection with ONO-5046 at a dose of 10 mg/kg 5 min before
      ischemia and immediately after reperfusion plus 1-h ischemia and 2-h reperfusion,
      n = 6. A laser-Doppler flowmeter and in vivo microscopy were used to investigate
      hepatic microcirculation. Tissue malondialdehyde (MDA) and adenosine triphosphate
      (ATP) levels were determined at the end of the experiment. RESULTS: Compared with
      ischemia alone, ONO-5046 significantly reduced the extent of microcirculatory and
      hemodynamic derangement after ischemia-reperfusion. ONO-5046 at both doses
      significantly attenuated decreases in mean arterial pressure. ONO-5046 lessened
      adherent leukocyte count and improved flow velocity in the sinusoids and
      postsinusoidal venules. ONO-5046 at the dose of 10m/kg reduced MDA (1.97 +/- 0.54
      micromol/g protein vs. 3.58 +/- 1.21 micromol/g protein in the ischemia and
      reperfusion group) and increased ATP levels (2.62 +/- 0.19 micromol/g wet wt vs.
      0.57 +/- 0.37 pmol/g wet wt in the ischemia and reperfusion group), whereas ONO
      5046 at a smaller dose (1 mg/kg) had lesser but significant effects on MDA and
      ATP alterations. This study demonstrates that treatment with ONO-5046, a
      neutrophil elastase inhibitor, can ameliorate ischemia-reperfusion injury of the
      rat liver.

PMID- 10588516
TI  - Effect of endotoxin shock on the clearance of lidocaine and indocyanine green in
      the perfused rat liver.
AB  - Endotoxin administration and cecal ligation and puncture produce significant
      hepatocellular dysfunction when studied in vivo. Specific factors that are
      present in vivo after endotoxin administration and cecal ligation and puncture,
      such as alterations in liver blood flow, circulating mediators, and hypoxia, can
      alter hepatic function. In this study, we used an isolated perfused liver to
      evaluate the effects of in vivo administration of endotoxin on hepatic function
      using indocyanine green (ICG) as a global marker of function and lidocaine and
      its metabolite, MEGX, as specific markers of the CYP450 enzyme system. Endotoxin
      (Escherichia coli; 45 mg/kg i.p.) was administered to rats followed by a 6-h
      monitoring before preparation of the isolated in situ perfused liver. Livers from
      control and endotoxin groups received either ICG (control, n = 6; endotoxin, n =
      5) or lidocaine (control, n = 8; endotoxin, n = 8). A separate group of rats (n =
      6) received cimetidine (an inhibitor of the CYP450 enzyme system) at a dose of 80
      mg/kg daily for 3 days. Livers were perfused via the portal vein by using a
      single-pass system with a balanced salt solution 6 h after receiving either
      endotoxin or saline or 24 h after receiving the last dose of cimetidine. After a
      40-min stabilization period, ICG or lidocaine was infused via the portal vein
      until steady-state concentrations were reached in the venous outflow. The total
      hepatic clearance and intrinsic hepatic clearance for ICG and lidocaine were
      unchanged in the livers obtained from endotoxin-treated rats. This model could
      adequately detect CYP450 inhibition because cimetidine-treated rats had
      significantly lower initial MEGX concentrations (0.63 +/- 0.03 mg/L) compared
      with control (0.77 +/- 0.03 mg/L) and endotoxin-treated (0.74 +/- 0.04 mg/L)
      rats. Septic livers had significantly higher initial hepatic oxygen consumption
      (HVO2) than did control livers (45 +/- 3 microL/min/g vs 82 +/- 9 microL/min/g).
      The HVO2 remained higher in the septic livers and significantly increased
      throughout the study, which demonstrated that the livers remained viable and
      functional. These data indicate that there is no detectable hepatocellular
      dysfunction after endotoxin shock using ICG, lidocaine, and MEGX in the isolated
      perfused liver; therefore the dysfunction reported from in vivo studies may be
      reversible when the liver is removed from the shocked environment.

PMID- 10588518
TI  - An ace in the hole?

PMID- 10588517
TI  - The effects of two new antagonists of secretory PLA2 on TNF, iNOS, and COX-2
      expression in activated macrophages.
AB  - Phospholipase A2 (PLA2) regulates eicosanoid and platelet-activating factor
      production. It also plays an important role in the regulation of critical
      mediators in inflammatory diseases in which PLA2 activity is significantly
      enhanced during sepsis and multiple organ failure. Therefore, inhibitors of PLA2
      activity offer themselves as target substances in the development of anti
      inflammatory drugs. We identified 2 biflavonoids, bilobetin and ginkgetin, that
      can inhibit PLA2 activity. In experiments using 2-linol-[1-14C]PE as substrate
      both substances potently inhibited several kinds of type II 14-kDa PLA2 while
      inhibiting type I 14-kDa PLA2 to a lesser extent. We tested these PLA2 inhibitors
      for their ability to inhibit the production of tumor necrosis factor alpha
      (TNFalpha) and 2 enzymes, inducible nitric oxide synthase (iNOS) and inducible
      cyclooxygenase (COX-2) in an assay system using lipopolysaccharide (LPS)
      stimulated Raw264.7 macrophages. In Raw264.7cells, bacterial LPS induced the
      production of COX-2 and iNOS proteins as well as TNFalpha. The inhibitors
      consistently inhibited the production of TNFalpha in a dose-dependent manner.
      Moreover, treatment of the macrophages with bilobetin and ginkgetin shut down the
      production of nitrite, one of the stable end products of NO released into the
      culture supernatant. The decrease in NO products was accompanied by a decrease in
      iNOS protein level as assessed by Western blot probed with specific anti-iNOS
      antibody. Both inhibitors also reduced the expression of COX-2 protein in the LPS
      stimulated cells, which coincided with the reduction in iNOS protein. These
      results, therefore, suggest that these two sPLA2 inhibitors may be useful for
      inhibiting the production of inflammatory cytokine and NO production in
      inflammatory diseases.

PMID- 10588519
TI  - A systematic review of foot ulcer in patients with Type 2 diabetes mellitus. II:
      treatment.
AB  - AIM: To assess the value of treatments for foot ulcers in patients with Type 2
      diabetes mellitus. METHODS: A systematic review of interventions to treat
      diabetic foot ulcers. RESULTS: The evidence base for treating infections and
      dressing wounds is poor. A number of new and potentially promising treatments are
      being developed but currently available studies are often small, inadequately
      powered and use different methods and outcomes. CONCLUSIONS: Given the
      prevalence, morbidity and healthcare costs of diabetic foot disease, it is
      surprising that available trials provide inadequate evidence to improve upon
      current empirically based treatment approaches. Substantial effort and resources
      should be deployed in order to investigate both new and existing treatments in a
      co-ordinated, systematic and consistent manner, so that a proper evidence base
      can be established for this important disease area.

PMID- 10588520
TI  - INS VNTR allelic variation and dynamic insulin secretion in healthy adult non
      diabetic Caucasian subjects.
AB  - AIMS: To elucidate the relationship between the human insulin gene INS VNTR
      regulatory polymorphism and insulin secretion. The polymorphism arises from
      tandem repetition of 14-15 bp oligonucleotides. In Caucasians, repeat number
      varies from 26 to over 200, with two main and discrete allele size classes: class
      I (26-63 repeats) and class III (141-209 repeats). Class I allele homozygosity is
      associated with elevated risk of developing Type 1 diabetes, while the class III
      allele has been associated with increased risk of Type 2 diabetes, polycystic
      ovary syndrome (PCOS) and with larger size at birth, which may influence
      development of adult disease. METHODS: Thirty-one healthy adult subjects with
      normal glucose tolerance, underwent an intravenous glucose tolerance test with
      one minute sampling. Seventeen subjects were homozygous for class I alleles (14
      excluding individuals carrying alleles associated with parent-of-origin effects
      and heterogeneity in allele transmission) and 14 homozygous for class III
      alleles. The groups were well matched. RESULTS: No significant differences in
      amount or rate of insulin secretion, or beta cell function were detected between
      the two groups. There was a difference in pattern of pulsatile insulin secretion
      with more 9-minute oscillations in class I homozygotes (P<0.026). The after-load
      glucose concentration was also higher in subjects with class I alleles (P<0.03).
      CONCLUSIONS: These results warrant further analysis of possible association
      between allelic variation of the INS VNTR and the pulsatility of insulin
      secretion.

PMID- 10588521
TI  - Predictors of the development of microalbuminuria in patients with Type 1
      diabetes mellitus: a seven-year prospective study. The Microalbuminuria
      Collaborative Study Group.
AB  - AIMS: To determine risk factors for the development of persistent
      microalbuminuria (albumin excretion rate (AER) > or =30 microg/min) in Type 1
      diabetes mellitus. METHODS: One hundred and forty-eight initially normotensive
      Type 1 diabetic patients with normal albumin excretion (<30 microg/min) were
      followed prospectively in hospital diabetes outpatient clinics for a median of 7
      years. Main outcome measures were: progression to persistent microalbuminuria
      (albumin excretion rate > or =30 microg/min on at least two consecutive
      occasions); rate of change of albumin excretion rate; development of arterial
      hypertension (systolic blood pressure >160 mm Hg and/or diastolic blood pressure
      >95 mm Hg or commencement of antihypertensive therapy). RESULTS: In a median
      follow-up period of 7 years (range 6 months to 8 years), 14 patients progressed
      to persistent microalbuminuria, a cumulative incidence of 11% (95% confidence
      interval 6.36-16.94). AER remained persistently <30 microg/min in 109 subjects
      and 25 developed intermittent microalbuminuria. In those who developed persistent
      microalbuminuria, baseline AER (16.2 (13.9-19.1) vs. 5.2 (3.8-9.2)microg/min,
      P<0.01), blood pressure (136 (123-148)/80 (74-85) vs. 121 (118-124)/72 (70-73) mm
      Hg, P<0.05), and HbA1 (10.2 (9.1-11.4) vs. 9.0 (8.7-9.4)%, P<0.05) were higher
      than in those who continued to have persistent normoalbuminuria, retinopathy was
      more severe and height (1.64 (1.57-1.71) vs. 1.70 (1.69-1.72) m, P<0.05) less. In
      multivariate analysis, baseline AER was the strongest predictor of the
      development of persistent microalbuminuria (P<0.0001), followed by mean arterial
      pressure (P = 0.02) and HbA (P = 0.05). CONCLUSIONS: The level of AER, raised
      blood pressure and poor glycaemic control are the most important predictors of
      the development of microalbuminuria in Type 1 diabetes.

PMID- 10588522
TI  - High impact of nephropathy on five-year mortality rates among patients with Type
      2 diabetes mellitus from a multi-ethnic population in New Zealand.
AB  - AIMS: Type 2 diabetes mellitus and its complications are common among Polynesians
      in New Zealand. This study investigated the mortality from diabetes among
      indigenous Maori and recent migrants from the South Pacific. METHODS: Death
      certificates and other reports were collected to enumerate those who had died in
      an across-community cohort study of 765 diabetic patients aged 40-79 years in
      1991. Five year mortality status was ascertained in 99.7% and death certificates
      were obtained from 129 (88%) of the 146 who had died. Diabetes was missed from
      36% of death certificates. RESULTS: Compared to Europeans with Type 2 diabetes,
      Maori with Type 2 diabetes were 2.66 (1.63-4.35) fold as likely to die from
      diabetes-related conditions, including a 13.1 (3.7-46.4) fold greater risk of
      death from nephropathy. Pacific Islands Polynesians with Type 2 diabetes had a
      similar mortality to Europeans with Type 2 diabetes (hazards ratio 1.06 (0.68
      1.65)). After 6 years, 10.7 (2.2-19.3)% more Maori had died than Pacific Islands
      Polynesians. CONCLUSIONS: Maori with Type 2 diabetes are dying from diabetic
      complications, particularly nephropathy, at an alarming rate. The magnitude of
      the difference between Maori and Pacific Islands Polynesians suggests
      environmental rather than inherited factors are involved and these need further
      investigation.

PMID- 10588523
TI  - High glucose increases growth and collagen synthesis in cultured human
      tubulointerstitial cells.
AB  - AIMS: Altered proximal tubular cell growth and interstitial fibrosis are features
      of diabetic nephropathy and correlate with disease progression. These
      observations are poorly understood, although it has been suggested that they are
      secondary to glomerular disease. The primary aim of this study was to assess the
      direct effects of high extracellular glucose concentrations on the human
      tubulointerstitium. METHODS: Primary cultures of human proximal tubule cells
      (PTCs) and cortical fibroblasts (CFs) were grown for 6 days in media containing
      either 6.1 mmol/l or 25 mmol/l glucose. Cell proliferation, thymidine uptake (a
      marker of DNA synthesis), protein content and collagen synthesis were measured.
      RESULTS: In PTCs, exposure to high glucose was associated with a 410+/-108%
      increase in cell numbers (P<0.001); 101+/-24% increase in thymidine uptake per
      cell (P<0.01) and a 39+/-6% decrease in protein content per cell (P<0.05).
      Collagen synthesis was increased by 37+/-11% (P<0.05). In CFs, exposure to high
      glucose was associated with an 80+/-25% increase in cell numbers (P<0.05); 137+/
      50% increase in thymidine uptake per cell (P<0.001), with protein content per
      cell unchanged. Collagen synthesis increased by 37+/-13%; however, the difference
      was not significant (P = 0.07). There were no differences between control cells
      exposed to 6.1 mmol/l glucose or an osmotic control (6.1 mmol/l D-glucose
      +18.9mmol/l L-glucose). CONCLUSIONS: Exposure of human PTCs and CFs to high
      extracellular glucose concentrations results directly in altered cell growth and
      collagen synthesis that is independent of haemodynamic, glomerular or vascular
      pathology.

PMID- 10588524
TI  - A five-year evaluation of intervention in diabetes care in Trinidad and Tobago.
AB  - AIMS: To evaluate an intervention to improve diabetes care in government-run
      heath centres in Trinidad and Tobago over 5 years. METHODS: A cross-sectional
      survey of 690 subjects with clinical diabetes attending nine health centres was
      carried out in 1993. The intervention was: reports to the Ministry of Health,
      dissemination of management guidelines and annual training workshops for
      healthcare staff. Re-evaluation was through a survey of 1579 subjects with
      diabetes, attending 23 health centres in 1998. RESULTS: Comparing 1993 with 1998,
      foot examinations in the previous year increased from 38 (6%) to 346 (22%) and
      fundoscopy from 6 (1%) to 139 (9%). For subjects attending for 1 year or less,
      34/96 (35%) had dietary advice recorded in 1993 compared with 77/143 (54%) in
      1998. Exercise advice was recorded for 3/96 (3%) in 1993 and 48/143 (34%) in
      1998. In 1993, 329 (48%) were taking chlorpropamide but this fell to 57 (4%) in
      1998. Glibenclamide use increased from 214 (31%) to 856 (54%) and gliclazide from
      four (1%) to 205 (13%). In 1993, 198/338 (56%) of hypertensive subjects were
      taking Brinerdin, this fell to 56/829 (7%) in 1998 while use of thiazide
      diuretics, methyldopa and angiotensin-converting enzyme (ACE) inhibitors
      increased. There were no changes in indicators of metabolic control, blood
      pressure control or body weight. CONCLUSIONS: Use of audit data to inform health
      policy and practice, linked with educational interventions, may modify patterns
      of care in government-run primary care health centres in a middle-income country
      with a high prevalence of diabetes.

PMID- 10588525
TI  - Modifiable risk factors for Type 2 diabetes mellitus in a peri-urban community in
      South Africa.
AB  - AIMS: To investigate the prevalence of Type 2 diabetes mellitus (DM) and its risk
      factors in a working class peri-urban community in South Africa. METHODS: A cross
      sectional descriptive study was conducted in 1996, where all persons aged 15
      years and older, who were resident in randomly selected houses in Mamre, 55 km
      from the centre of Cape Town, were sampled. Subjects underwent a 75-g oral
      glucose tolerance test. Socio-demographic and anthropometric data were obtained
      and physical activity was assessed using a 7-day activity recall questionnaire.
      The 1985 WHO criteria were used to define diabetes. RESULTS: The response rate
      was 64.5% (n = 974). The participants comprised 56% women, 44% men, mean age 37.6
      (range 15-86) years. The crude prevalence of Type 2 DM was 7.1% and impaired
      glucose tolerance (IGT) 8.0%. The age-adjusted prevalence of Type 2 DM was 10.8%
      (95% confidence interval (CI) 8.2-13.5%) and IGT 10.2% (95% CI 7.7-12.8%).
      Regression analysis indicated that age (risk ratio (RR) 7.40, 95% CI 3.45-15.86),
      waist circumference (RR 4.53, 95% CI 2.04-10.05), low total energy expenditure
      (RR 1.75, 95% CI 1.07-2.56) and family history of diabetes (RR 2.31, 95% CI 1.42
      3.77) were independent risk factors for Type 2 DM, while sex, obesity and regular
      alcohol consumption were not. CONCLUSIONS: This previously unstudied community
      has an intermediate prevalence on the international scale of Type 2 DM, which is
      linked to potentially modifiable risk factors.

PMID- 10588526
TI  - Impact of cigarette smoking on the incidence of Type 2 diabetes mellitus in
      middle-aged Japanese men: the Osaka Health Survey.
AB  - AIMS: To assess the impact of cigarette smoking on the incidence of Type 2
      diabetes mellitus (DM) in middle-aged Japanese men. METHODS: The study enrolled
      6250 men aged 35-60 years and free of diabetes, impaired fasting glucose and
      hypertension at entry. Type 2 DM was defined by a fasting plasma glucose level >
      or =7.0 mmol/l or physician-diagnosed Type 2DM. RESULTS: Four hundred and fifty
      cases of Type 2 DM were confirmed during the 60904 person-years follow-up. After
      adjustment for multiple covariates, including age, body mass index, alcohol
      consumption, physical activity, parental history of diabetes and the level of
      fasting plasma glucose, total cholesterol, triglycerides, high-density
      lipoprotein cholesterol and haematocrit, the relative risk of Type 2 DM among
      current smokers compared with non-smokers was 1.47 (95% confidence interval (CI)
      1.14-1.92). Men who smoked >30 cigarettes/day had a multivariate-relative risk of
      1.73 (95% CI 1.20-2.48) compared with non-smokers. The number of cigarettes
      smoked daily and the pack-year values were positively related to the development
      of Type 2 DM in a dose-dependent manner (P for trends = 0.0026 and 0.001,
      respectively). CONCLUSIONS: A cigarette smoking habit is an independent risk
      factor for Type 2 DM.

PMID- 10588527
TI  - Molecular genetics of diabetes mellitus in Chinese subjects: identification of
      mutations in glucokinase and hepatocyte nuclear factor-1alpha genes in patients
      with early-onset type 2 diabetes mellitus/MODY.
AB  - AIMS: To examine the prevalence of identified MODY-related genes in Chinese
      subjects with early onset Type 2 diabetes mellitus and a positive family history
      of diabetes and to look for possible associations between the gene mutations and
      the development of diabetes. METHODS: Ninety-two unrelated Chinese subjects with
      diabetes diagnosed before the age of 40 years who had a positive family history
      of diabetes were screened for mutations in hepatocyte nuclear factors (HNF-1alpha
      and HNF-4alpha) and glucokinase genes by direct sequencing. The family members of
      patients with mutations and 100 healthy controls were also examined. RESULTS:
      Mutations in the HNF-1alpha and the glucokinase genes were found in 5% and 3% of
      the diabetic subjects, respectively but no mutations were found in the coding
      region of the HNF-4alpha gene. Three mutations found in the glucokinase gene were
      novel missense mutations (I110T, A119D and G385V). The mutations in the HNF
      1alpha gene were also new and included four missense mutations (G20R, R203H,
      S432C, I618M) and one splice acceptor site mutation (IVS2nt-1G-->A). Patients
      with mutations in these genes were clinically heterogeneous with respect to
      phenotype and basal pancreatic beta cell function. CONCLUSIONS: Genetic factors
      such as mutations in the HNF-1alpha and glucokinase genes may be important in the
      development of diabetes in Chinese people, especially when the disease is of
      early onset.

PMID- 10588528
TI  - A controlled evaluation of a national continuing medical education programme
      designed to improve family physicians' implementation of diabetes-specific
      clinical practice guidelines.
AB  - AIMS: New approaches to continuing medical education will facilitate the
      implementation of clinical practice guidelines. This study assessed the short and
      long-term impact of a 7-h, small group workshop on family physicians' attitude,
      knowledge and self-reported practice patterns regarding diabetes mellitus.
      METHODS: One hundred and seventy-seven of 1807 family physicians who participated
      in this nationwide workshop, and 113 non-participant controls completed two
      validated questionnaires. Participants completed one questionnaire before the
      workshop and a second equivalent questionnaire 1 month later. Non-participant
      controls also completed the two questionnaires 1 month apart. Between 8 and 24
      months later, these individuals were mailed the same questionnaire they completed
      on the first occasion; 143 participants and 50 controls returned this third
      questionnaire. RESULTS: Participants were more likely to be female (P = 0.03),
      not certified in family practice (P = 0.02), in a smaller centre (P = 0.0005),
      recent medical graduates (P = 0.001) and seeing fewer patients per month (P =
      0.01) than controls. Compared to controls, participants had improved their
      attitude (P<0.0001), knowledge (P = 0.04) and self-reported practice patterns
      (P<0.002) regarding diabetes after 1 month but not after 1 year. CONCLUSIONS: An
      interactive, small group, diabetes continuing education programme effectively
      disseminates practice guidelines to family physicians. The impact of such a
      programme declines after 1 year.

PMID- 10588530
TI  - Randomized controlled trials--a gold standard?

PMID- 10588529
TI  - Fasting plasma glucose diagnostic criteria for diabetes mellitus.

PMID- 10588531
TI  - Functional outcome of patients with spinal cord injury: rehabilitation outcome
      study.
AB  - OBJECTIVE: To increase our knowledge of neurological recovery and functional
      outcome of patients with spinal cord injuries in order to make more successful
      rehabilitation programmes based on realistic goals. DESIGN: Descriptive analysis
      of data gathered in an information system. SETTING: Rehabilitation centre in The
      Netherlands with special department for patients with spinal cord injuries.
      SUBJECTS: Fifty-five patients with traumatic spinal cord lesions admitted to the
      rehabilitation centre from 1988 to 1994. MAIN OUTCOME MEASURES: The functional
      improvement was presented in terms of progress in independence in nine daily
      activity skills. Independence was rated on a four-point scale. RESULTS: From
      admission to discharge, lesions in 100% of patients with tetraplegia and 96% of
      patients with paraplegia remained complete. Significant progress in independence
      was made in self-care, ambulation and bladder and bowel care. Differences were
      found in the extent of functional improvement between subgroups of patients with
      different levels and extent of lesion. Contrary to expectations based on
      theoretical models, patients with complete paraplegia did not achieve maximal
      independence in self-care. Independent walking was only attained by patients with
      incomplete lesions. Regarding outcome of bladder and bowel care, poor results
      were found, especially the independence in defaecation and toilet transfers.
      CONCLUSIONS: The results of this study provided more insight into the functional
      outcome of a group of patients with traumatic spinal cord injury. More research
      is needed to evaluate the rehabilitation programmes for these patients.

PMID- 10588532
TI  - Predictive model of functional independence in stroke patients admitted to a
      rehabilitation programme.
AB  - OBJECTIVE: To develop a prognostic model to estimate the probability of patients
      being independent in ambulation and in activities of daily living (ADL) after six
      months of stroke. DESIGN: Cohort analytical study. SETTING: Rehabilitation
      departments of two district general hospitals. SUBJECTS: Ninety-two consecutive
      stroke patients admitted to a rehabilitation programme. MAIN OUTCOME MEASURES:
      Independent ambulation was defined as a Functional Ambulation Classification
      (FAC) > or =4, and the independence in ADL as a Barthel Index (BI) > or =285. All
      patients were assessed on admission to rehabilitation, and in the first, second,
      third, fourth and six months after stroke. RESULTS: Prognostic factors were
      identified by means of a multivariate survival analysis using Cox regression.
      Three variables were predictors for a FAC > or =4: (1) The patients in the motor
      (M), motor-sensitive (MS) and motor-sensitive with hemianopsia (MSH) groups
      (relative risk (RR) 5.43 of M with respect to MSH, and 2.41 of MS to MSH). (2) A
      Motricity Index >25 (RR 3.19). (3) An age <70 years old (RR 1.99). For a BI > or
      =85 three predictors were selected: (1) The classification M-MS-MSH (RR 6.02 M to
      MSH, and 1.52 MS to MSH). (2) An initial BI >20 (RR 3.45); the highest
      contribution in the achievement of an initial BI >20 was bowel and bladder
      continence. (3) The antecedent of previous independence (RR 2.68). The predictive
      models, constructed by means of multiple logistic regression correctly classified
      77% and 79% of the patients who obtained FAC > or =4 and a BI > or =85
      respectively. CONCLUSIONS: The syndromic classification M, MS and MSH, together
      with other routinely available data, such as the Motricity Index, BI, the age and
      the previous functionality, can be used to obtain a patient prognosis level with
      regard to ambulation and ADL independence.

PMID- 10588533
TI  - The development of a scale of the Guttman type for the assessment of mobility
      disability in multiple sclerosis.
AB  - OBJECTIVE: To develop a valid and reliable scale of the Guttman type for the
      assessment of mobility disability in multiple sclerosis (MS). SUBJECTS: Sixty
      eight subjects with a definite diagnosis of MS participated. They were living in
      the community and attending as outpatients at a MS unit at a District General
      Hospital. Thirty had the primary progressive pattern of disease, and 38 had the
      relapsing-remitting pattern. METHODS: Formal assessments used for neurological
      disability were inspected, and 14 test items of gross motor function were
      extracted and ordered according to criteria. These were that tests required trunk
      control and did not require isolated movement at a single limb or body segment,
      that actions progressed from lying, to sitting, to standing and walking tasks,
      proceeding from broader to narrower bases of support. All subjects carried out
      all test items which were scored as 'pass' or 'fail'. ANALYSIS: Data were tested
      for internal consistency, reliability, inter-item correlation, reproducibility
      and scalability. On the basis of the results, the items were reordered in rank,
      and reduced to 11 tests. The 11-item scale was reanalysed. RESULTS: Results
      showed that the scale had an internal consistency of 0.88 (alpha coefficient) and
      a coefficient of reproducibility (CR) of 0.95 and above for both MS subject
      groups. The coefficient of scalability (CS) for items was 0.78 for primary
      progressive subjects and 0.74 for the relapsing-remitting group. Reliability
      ranged from moderate (kappa = 0.49) for one item, to perfect for six items.
      CONCLUSION: The scale was demonstrated to be a hierarchical scale of the Guttman
      type exhibiting homogeneity and good reliability. The high CR indicated that
      scores may be summed, and the very acceptable levels of CS indicated that the
      cumulative scores are meaningful within the defined concept of hierarchy used in
      this study.

PMID- 10588534
TI  - The Northwick Park Care Needs Assessment (NPCNA): a measure of community care
      needs: sensitivity to change during rehabilitation.
AB  - OBJECTIVES: To determine whether the Northwick Park Care Needs Assessment (NPCNA)
      is sensitive to change occurring during rehabilitation and provides a reliable
      estimate of care needs in the community, and to compare the NPCNA with the
      Functional Independence Measure (FIM). DESIGN: Prospective cohort study. SETTING:
      Postacute neurorehabilitation unit for young patients with complex disabilities.
      SUBJECTS: Thirty-nine consecutive patients with brain injury admitted over six
      months. MEASUREMENTS AND METHODS: The NPCNA was assessed on admission and at
      discharge. Two subsets of patients were also assessed (a) at three-month follow
      up in the community (n = 15), and (b) both in hospital and in the home
      environments at the discharge time point (n = 28). Data were compared with FIM
      scores on admission and discharge. RESULTS: The median total weekly care hours
      fell from 52 hours (interquartile range (IQR) 25-66) on admission, to 17 hours
      (IQR 6-46) on discharge (p<0.001). There was a median reduction of approximate
      weekly cost of care from 600 pound sterling (IQR 224-824 pound sterling) to 168
      pound sterling (IQR 56-280 pound sterling) (p<0.001). These benefits were
      sustained at follow-up, and the NPCNA measured in hospital at discharge gave a
      good estimation of the care hours and weekly cost of care in the community at
      three months after discharge. There was no significant correlation with FIM gain.
      CONCLUSIONS: In this study the NPCNA, measured while the patient was still in
      hospital, gave a good estimation of care needs in the community and was sensitive
      to change occurring during rehabilitation in patients with severe complex
      disabilities.

PMID- 10588535
TI  - Screening for mobility disorders by the Mobility Control subscale of the short
      version of the Sickness Impact Profile.
AB  - OBJECTIVE: To test the usefulness of the Mobility Control subscale (MC scale) of
      the short version of the Sickness Impact Profile (SIP68) as a simple self
      administered questionnaire for screening mobility disorders in a population of
      independent living elderly. DESIGN: The SIP68-MC scale was compared with the
      results of one functional test as independent criteria. SUBJECTS AND SETTING: A
      group of 81 people of 70 years and older was selected from a potential population
      of over 200 people. All were independent living elderly persons selected from a
      general practice. INTERVENTIONS: The short version of the Sickness Impact Profile
      and questions about falling last year were applied. Three functional tests were
      carried out: walking 10 metres, get up and sit down in a chair five times and a
      test for standing balance. A trained observer rated all tests. RESULTS: It is
      shown that the sensitivity of the MC scale (cut-off point: 1) with the total
      functional score is 91%, with a relative low specificity (59%). The relationship
      between the SIP-MC score and falling frequency is significant when there is a
      falling frequency equal to or more than two times a year. CONCLUSION: It is
      concluded that the MC scale is a useful test for screening mobility disorders in
      the elderly.

PMID- 10588536
TI  - The Functional Assessment Measure (FIM + FAM) as part of the hospital discharge
      summary after brain injury rehabilitation.
AB  - OBJECTIVE: To assess the value of providing Functional Assessment Measure (FIM +
      FAM) data as part of the hospital discharge information after brain injury
      rehabilitation. DESIGN: Postal survey of general practitioners (GPs) and
      consultants. SUBJECTS: Consecutive discharges (n = 117) from an early brain
      injury rehabilitation unit over one year. RESULTS: Response rates were 81% from
      GPs and 54% from consultants. Eighty-four (89%) of GPs and 57 (82%) of
      consultants rated the information as useful; 87 (92%) and 51 (84%) respectively
      described the accompanying notes as easy to understand. CONCLUSIONS: The
      incorporation of FIM + FAM data in discharge summaries is worthwhile but the
      utility of this practice is still to be established.

PMID- 10588537
TI  - Cognitive assessment in elderly patients admitted to hospital: the relationship
      between the Abbreviated Mental Test and the Mini-Mental State Examination.
AB  - OBJECTIVE: To determine the relationship between Abbreviated Mental Test (AMT)
      and the Mini-Mental State Examination (MMSE) in elderly patients admitted to
      hospital. DESIGN: Prospective study of 364 consecutive admissions to an elderly
      medicine unit. Eighty-eight (24.2%) patients were excluded. The AMT and MMSE were
      administered to the remaining 276 patients and the relationship between the two
      tests evaluated statistically. SETTING: Inner city teaching hospital. SUBJECTS:
      Two hundred and seventy-six patients admitted to the elderly medicine unit during
      October and November 1997. MAIN OUTCOME MEASURES: Predictive efficiency of the
      AMT for cognitive state by MMSE (the percentage of patients whose cognitive state
      by the MMSE was correctly categorized by the AMT). Association and predictive
      relationship between individual AMT and MMSE scores. RESULTS: There was a
      significant relationship between cognitive state as determined by the AMT and
      MMSE: chi2 = 101.3, df = 1, p <0.001. The predictive efficiency of the AMT was
      79.0% (218/276). A strong association was found between the AMT and MMSE (Somers'
      d statistic 0.75: p <0.001). Simple linear regression allowed prediction of the
      MMSE score from the AMT score as follows: MMSE score = 7.06 + (1.94 x AMT score);
      p <0.001. CONCLUSIONS: In patients admitted to the elderly medicine unit, the AMT
      gave predictive information about cognitive status as determined by the MMSE, and
      also a prediction of likely MMSE score.

PMID- 10588538
TI  - Fear of falling in patients with stroke: a reliability study.
AB  - OBJECTIVE: To examine the scaling properties and test-retest reliability of an
      expanded version of the Falls Efficacy Scale (FES) and to compare group
      differences in the scores. The expanded version focuses on more basic, primary
      activities of daily living (ADL), which makes the scale more suitable for
      subjects with moderate to low functional ability, e.g. patients with stroke.
      DESIGN: A test-retest reliability study with one group convenience sample.
      SETTING: Two day-care units: a rehabilitation unit and a geriatric rehabilitation
      unit. SUBJECTS: A volunteer sample of 30 patients (mean age 65 years, SD 11
      years) who had sustained stroke between 5 and 84 months prior to the
      investigation. MAIN OUTCOME MEASURE: A 13-activity questionnaire (the Swedish
      modification of the Falls Efficacy Scale (FES(S)) comprising the 10 activities of
      the original FES and three additional activities was used. Falls efficacy was
      rated on a 10-point visual analogue scale for each activity on two occasions, 5
      22 (mean 10, Md 7) days apart. RESULTS: The overall test-retest reliability of
      the FES(S) was high (intraclass correlation coefficient (ICC) = 0.97). The ICC
      for the personal ADL (items 1-6) scores was 0.93 and for the instrumental ADL
      (items 8-13) 0.97. ICC for the individual items ranged from 0.76 to 0.97.
      CONCLUSIONS: On the basis of these preliminary findings, the FES(S) appears to
      have acceptable test-retest reliability. The test may be a reasonable addition
      for assessing stroke patients with balance disturbances and risk for falls.

PMID- 10588539
TI  - Development of a scale to assess nurses' knowledge of stroke: a pilot study.
AB  - OBJECTIVE: To develop and test an evidence-based scale to assess nurses'
      knowledge of stroke. DESIGN: Question development by a multidisciplinary group of
      experts in stroke. Two self-completion questionnaire surveys. SETTING: Two stroke
      units, one general medical and two elderly care wards in three hospitals in the
      North-East of England. SUBJECTS: Fifty-eight qualified nurses. INTERVENTIONS:
      Scale to assess nurses' knowledge of stroke. RESULTS: The overall response rate
      was 60%. Nurses on stroke units knew more about stroke than those in
      medical/elderly care wards. The scale was capable of discriminating between
      stroke units and medical /elderly care wards: mean difference was 4.18 (95%
      confidence intervals 1.68-6.69; p <0.001). Cronbach's alpha was 0.7 indicating
      adequate internal consistency. Item non-response did not exceed 10% for any
      question. CONCLUSIONS: We have developed a knowledge of stroke scale capable of
      discriminating between nurses based in stroke units and medical/elderly care
      wards, with low item non-response and adequate internal consistency. The scale is
      suitable for use as a component of studies evaluating the nursing of stroke
      patients.

PMID- 10588540
TI  - An evaluation of the toxicities of 2'-fluorouridine and 2'-fluorocytidine-HCl in
      F344 rats and woodchucks (Marmota monax).
AB  - The toxicities of 2'-fluorouridine (2'-FU) and 2'-fluorocytidine-HCl (2'-FC) were
      separately evaluated in 2 species, male Fischer 344 (F334) rats and woodchucks.
      Particular attention was focused on the ability of these nucleosides to induce
      toxicities similar to those induced by the antiviral drug fialuridine (FIAU). 2'
      FU or 2'-FC was administered to F344 male rats by intravenous injection at doses
      of 5, 50, and 500 mg/kg/day for 90 consecutive days and to male and female
      woodchucks at doses of 0.75 and 7.5 mg/kg/day for 90 consecutive days. Clinical
      chemistry, hematology, and urinalysis (woodchuck only) profiles were assessed
      during and at the termination of the study. At necropsy, organs were weighed and
      tissues collected for routine histologic analysis. Cytochrome c oxidase activity,
      citrate synthase activity, and mitochondrial DNA content were measured, and
      micronucleus formation in the bone marrow (rats only) was evaluated. No adverse
      clinical effects were observed in either species. Rats treated with high doses of
      either 2'-FU or 2'-FC had body weights that were 90% of those of controls. 2'-FU
      and 2'-FC both induced a moderate decrease in the median lymphocyte count, and 2'
      FC and 2'-FU induced a mild increase in mean corpuscular hemoglobin and mean
      corpuscular volume. Both compounds caused slight to moderate, reversible,
      histologic changes in the spleen and thymus. In the woodchuck, 2'-FC caused a
      slight increase in mean absolute lymphocytes, and 2'-FC and 2'-FU slightly
      increased hepatic periportal vacuolation and/or mononuclear cell infiltration. In
      summary, neither compound showed evidence of the toxicity induced by fialuridine
      in either species. Although compound effects were observed, none of these effects
      were considered to be adverse, and the no-observed adverse effect level was
      determined to be 500 mg/kg/day for both compounds in the male F344 rat and 7.5
      mg/kg/day in the woodchuck.

PMID- 10588541
TI  - Histopathology of nasal olfactory mucosa from selected inhalation toxicity
      studies conducted with volatile chemicals.
AB  - In recent years, histopathologic changes have been reported in the olfactory
      mucosa of rodents exposed, by inhalation, to a variety of volatile chemicals. In
      order to better characterize these lesions, a panel of experienced pathologists
      reviewed microscopic lesions of the olfactory epithelium of rats reported in 10
      inhalation studies conducted with 8 different chemicals. The objectives were to
      determine if the olfactory epithelial lesions are morphologically similar or
      different for the chemicals of interest, to develop and recommend appropriate
      diagnostic criteria and nomenclature to characterize the morphology of these
      olfactory lesions, and to provide specific criteria for judging the degree of
      severity of the olfactory changes in these studies. The results indicated that
      the distribution and nature of the lesions were similar in all the examined
      studies in which olfactory changes were observed. Recommended standardized
      nomenclature and diagnostic criteria and a uniform method for scoring lesion
      severity based on the extent of distribution and severity of tissue damage are
      presented.

PMID- 10588542
TI  - Anophthalmia in litters of female rats treated with the food-derived carcinogen,
      2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.
AB  - Anophthalmia in litters of pregnant rats treated with 2-amino-1-methyl-6
      phenylimidazo[4,5-b]pyridine (PhIP), a food-derived carcinogen, was incidentally
      encountered in a risk-assessment study with 2-generation exposure to PhIP. Female
      Fischer 344 animals were given 200 ppm PhIP in the diet for 4 wk before mating
      with nontreated males and also during gestation and lactation periods. Mean
      numbers of newborn rats per litter in control and PhIP-treated groups were 7.9 +/
      2.9 and 7.1 +/- 1.6 in trial 1 and 8.3 +/- 1.9 and 6.1 +/- 2.4 in trial 2. Among
      49 (trial 1) and 63 (trial 2) offspring from PhIP-treated dams, 9 (18.4%) and 32
      (50.8%) demonstrated anophthalmia, and 1 (2.0%) and 8 (12.7%) demonstrated
      hydrocephaly. Five of 7 (71.4%) and 13 of 14 (92.9%) dams delivered pups with
      malformations in trials 1 and 2, respectively. Also, in a previous study that was
      carried out with the same protocol and that used the Sprague-Dawley strain of
      rats, anophthalmia and hydrocephaly were observed in 2 and 1 out of 175 pups,
      respectively, from 100 ppm PhIP-treated dams. No congenital malformations were
      found in control groups of the same size in either experiment. In addition to
      having been previously identified as a cause of carcinogenic activity, our
      findings suggest that PhIP is capable of causing anophthalmia in rats when
      administered during the gestational period.

PMID- 10588543
TI  - Aberrant crypt foci: A review.

PMID- 10588544
TI  - Colonic mucosal aberrant crypt foci: are they useful intermediate endpoints for
      predicting and understanding the development of colonic mucosal neoplasia?

PMID- 10588545
TI  - Comparison of uroplakin expression during urothelial carcinogenesis induced by N
      butyl-N-(4-hydroxybutyl)nitrosamine in rats and mice.
AB  - The expression of uroplakins, the tissue-specific and differentiation-dependent
      membrane proteins of the urothelium, was analyzed immunohistochemically in N
      butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-treated rats and mice during bladder
      carcinogenesis. Male Fischer 344 rats were treated with 0.05% BBN in the drinking
      water for 10 wk and were euthanatized at week 20 of the experiment. BBN was
      administered to male B6D2F, mice; it was either provided at a rate of 0.05% in
      the drinking water (for 26 wk) or 5 mg BBN was administered by intragastric
      gavage twice weekly for 10 wk, followed by 20 wk without treatment. In rats, BBN
      induced, noninvasive, low-grade, papillary, transitional cell carcinoma (TCC)
      showed decreased uroplakin-staining of cells lining the lumen but showed
      increased expression in some nonluminal cells. In mice, nonpapillary, high-grade
      dysplasia, carcinoma in situ, and invasive carcinoma were induced. There was a
      marked decrease in the number of uroplakin-positive cells lining the lumen and in
      nonluminal cells. This occurred in normal-appearing urothelium in BBN-treated
      mice and in dysplasic urothelium, in carcinoma in situ, and in invasive TCC. The
      percentage of uroplakin-positive nonluminal cells was higher in control mice than
      in rats, but it was lower in the mouse than in the rat after BBN treatment.
      Uroplakin expression was disorderly and focal in BBN-treated urothelium in both
      species. These results indicate that BBN treatment changed the expression of
      uroplakins during bladder carcinogenesis, with differences in rats and mice being
      related to degree of tumor differentiation.

PMID- 10588546
TI  - Histopathology of Japanese medaka (Oryzias latipes) chronically exposed to a
      complex environmental mixture.
AB  - Japanese medaka (Oryzias latipes) were used to evaluate the carcinogenicity of a
      complex groundwater that contained 5 U.S. Environmental Protection Agency
      priority pollutant heavy metals and 13 chlorinated aliphatic hydrocarbons. A test
      protocol that used 10 mg/L diethylnitrosamine (DEN) prior to groundwater exposure
      was designed to assess both initiation and promotion. The fish were exposed
      continuously for 9 mo with 0, 1, 5, or 25% groundwater, by volume, with either
      West Branch of Canal Creek water (Aberdeen Proving Ground-Edgewood Area, Aberdeen
      Proving Ground, MD) or dechlorinated tap water as the diluent, while concurrent
      controls were run in the laboratory. Incidental findings included various
      neoplasms in the nares, ovary, skeletal muscle, skin, swim bladder, testis,
      thymus, and thyroid. Factors evaluated during statistical analyses of fish
      neoplasm prevalence included diluent type, groundwater percentage, fish gender,
      and DEN initiation. Liver neoplasm prevalence was higher in DEN-initiated fish
      and was frequently higher in males. Concentrations of up to 25% groundwater, by
      volume, showed no evidence of being a complete carcinogen and showed no
      consistent, conclusive evidence of being a promoter.

PMID- 10588547
TI  - Differential diagnosis between organic and inorganic mercury poisoning in human
      cases--the pathologic point of view.
AB  - Differences in pathology were found between acute and chronic exposure to
      methylmercury, mercury vapor, and inorganic mercury. Characteristic pathologic
      changes produced by organic mercury in the brain have previously been described
      in patients with Minamata disease. The brains of patients who presented with
      acute onset of symptoms and died within 2-mo showed loss of neurons with reactive
      proliferation of glial cells, microcavitation, vascular congestion, petechial
      hemorrhage, and edema in the cerebral cortices, predominantly in the calcarine,
      pre- and postcentral, and transverse temporal cortices and in the cerebellar
      cortex. The neuropathologic changes in the patients with acute onset of symptoms
      who survived for a long period (>10 yr) were also included neuronal loss with
      reactive proliferation of glial cells in similar anatomic locations. The
      neuropathologic changes in patients with inorganic mercury poisoning are quite
      different. Autopsies performed on 3 individuals with fatal cases of acute
      inorganic mercury poisoning who were exposed to mercury vapor for about 2 wk
      revealed diffuse organized pneumonia, renal cortical necrosis, disseminated
      intravascular coagulopathy, and infarctions in the brain and kidneys. In 2 other
      patients who worked in mercury mines for about 10 yr and who suffered from
      chronic inorganic poisoning, no specific lesions were demonstrated in the brain.
      However, the assay and the histochemistry of mercury revealed that inorganic
      mercury was present in the brain in all 3 groups irrespective of the brain
      lesions and the duration of clinical signs.

PMID- 10588548
TI  - Histologic lesions in cynomolgus monkeys (Macaca fascicularis) naturally infected
      with simian retrovirus type D: comparison of seropositive, virus-positive, and
      uninfected animals.
AB  - Simian retrovirus (SRV) type D is a common cause of simian acquired
      immunodeficiency syndrome (SAIDS), a usually fatal immunosuppressive disease of
      macaques. Associated gross and histologic lesions have been well described for
      the rhesus macaque (Macaca mulatta) in experimental and natural infections.
      However, morphologic changes induced by this virus at the gross and light
      microscopic level have not been documented in the cynomolgus macaque (Macaca
      fascicularis). In 1996, sporadic cases of anemia, weight loss, and diarrhea were
      noted in a colony of cynomolgus macaques in our research facility. Out of 28
      animals, 24 tested positive for SRV by serology or virus isolation. Animals could
      mainly be classified into 1 of 2 categories: 1) positive for virus isolation but
      negative for SRV antibody and 2) negative for virus isolation but antibody
      positive. During the process of eliminating the virus from the colony, a complete
      postmortem examination was performed on the 24 infected animals that had to be
      culled. Twelve SRV-negative animals were available as controls. Minimal to mild
      follicular lymphoid infiltrates were seen in various organ systems in 75% of the
      negative animals, compared with moderate to marked infiltrates in 83% of infected
      animals. Lymphoid infiltrates were more common in the brain, bone marrow, and
      salivary gland of viremic animals and were rare to nonexistent in seropositive or
      negative animals. Lymphoid hyperplasia was present in 38% of the infected
      animals, whereas lymphoid depletion was seen in 47% of the infected animals.
      Overall, lesions were of greater severity in viremic animals than in virus
      negative or seropositive animals. Overall, infected animals had lower,
      statistically significant hematocrit and lymphocyte values. Viremic animals had
      significantly lower hematocrit, white blood cell, lymphocyte, and neutrophil
      values than did controls. Only 1 out of 24 infected animals had clinical signs
      that were consistent with the definition of SAIDS, and none had evidence of
      opportunistic infections. Lesions were similar to those already reported in other
      species of macaques, but the absence of severe illness that was consistent with
      SAIDS in most viremic animals suggests that there may be a different
      manifestation of disease in the cynomolgus.

PMID- 10588549
TI  - The role of the toxicologic pathologist in the preclinical safety evaluation of
      biotechnology-derived pharmaceuticals.
AB  - Biotechnology-derived pharmaceuticals, or biopharmaceuticals, represent a special
      class of complex, high molecular weight products, such as monoclonal antibodies,
      recombinant proteins, and nucleic acids. With these compounds, it is not
      appropriate to follow conventional safety testing programs, and the preclinical
      "package" for each biopharmaceutical needs to be individually designed. In
      addition to standard histopathology, the use of molecular pathology techniques is
      often required either in conventional animal studies or in in vitro tests. In
      this review, the safety evaluation of biopharmaceuticals is discussed from the
      perspective of the toxicologic pathologist, and appropriate examples are given of
      the use of molecular pathology procedures. Examples include the use of in situ
      hybridization to localize gene therapy vectors, the assessment of vector
      integration into genomic DNA by the polymerase chain reaction (PCR), and the use
      of immunohistochemistry to evaluate the potential cross-reactivity of monoclonal
      antibodies. In situ PCR techniques may allow for confirmation of the germ cell
      localization of nucleic acids and may therefore facilitate the risk assessment of
      germline transmission. Increased involvement with biopharmaceuticals will present
      challenging opportunities for the toxicologic pathologist and will allow for much
      greater use of molecular techniques, which have a critical role in the
      preclinical development of these compounds.

PMID- 10588550
TI  - Spinal epidermoid tumors: will a forgotten complication rise again?

PMID- 10588551
TI  - Acute pain: lessons learned from 25,000 patients.

PMID- 10588552
TI  - NMDA receptors and pain--hopes for novel analgesics.

PMID- 10588553
TI  - Double-injection method using peripheral nerve stimulator is superior to single
      injection in axillary plexus block.
AB  - BACKGROUND AND OBJECTIVES: Axillary block using a single-injection method does
      not always provide effective analgesia. This study examined whether a double
      axillary block injection technique is superior to a single injection axillary
      block. METHOD: Fifty patients were randomly allocated to two groups. In group I
      (single injection), the whole volume of local anesthetic (0.7 mL/kg) was injected
      after locating only one of the median, radial, or ulnar nerves. In group 2
      (double injection), half of the volume was injected after locating one nerve and
      the other half after locating another peripheral nerve. Bupivacaine 0.5% and
      prilocaine 1% (1:1 volumes) were used as local anesthetic. A peripheral nerve
      stimulator was used to identify the nerves. Sensory block of seven nerves and
      motor block of four nerves were tested after 40 minutes. RESULTS: Complete
      sensory and motor block (scores 2 or 3 on scale 0-3) in all four main nerves
      (median, ulnar, radial, musculocutaneous) was achieved in 3 (12%) versus 20 (80%)
      patients in groups 1 and 2, respectively (P = .000001). Primary success rate (no
      need for supplemental nerve block) was 52% in group 1 and 92% in group 2 (P =
      .0016). CONCLUSIONS: A double-injection method in axillary block provides
      excellent analgesia and motor block compared with a single-injection method.
      Moreover, the need for supplemental nerve blocks is significantly decreased.

PMID- 10588554
TI  - 0.75% and 0.5% ropivacaine for axillary brachial plexus block: a clinical
      comparison with 0.5% bupivacaine.
AB  - BACKGROUND AND OBJECTIVES: Although ropivacaine has been extensively studied for
      epidural anesthesia, very few reports exist on brachial plexus block. We
      therefore decided to investigate the clinical features of axillary brachial
      plexus anesthesia with two different concentrations of ropivacaine (0.5% and
      0.75%) and to compare the results with those obtained with 0.5% bupivacaine.
      METHODS: Three groups of patients were randomized and prospectively studied. They
      received, in a double-blind fashion, 32 mL of the local anesthetic solution into
      the midaxilla, by a nerve-stimulator technique. Onset time in each of the
      stimulated nerves was recorded both for the sensory and motor block. Peak time
      (ready to surgery), rate of supplemental blocks, need for intraoperative opioids,
      duration of sensory and motor block, postoperative analgesic requirements, and
      patient satisfaction were also recorded. RESULTS: The rate of complete sensory
      and motor block observed with both ropivacaine groups was higher at 10, 15, and
      20 minutes postinjection (P < .001). The mean peak time was shorter with
      ropivacaine than with bupivacaine (R50 = 16.37 minutes, R75 = 14.7 minutes, B =
      22.3 minutes, P < .05). The quality of the anesthesia was higher with
      ropivacaine, as measured by the intraoperative needs for opioids and the overall
      patient's satisfaction (P < .05). No significant differences were noted with all
      the other studied parameters. CONCLUSION: Ropivacaine showed advantages over
      bupivacaine for axillary brachial plexus block. Because no statistical
      differences were found between the two ropivacaine groups, we therefore conclude
      that 0.75% does not add benefit and that 0.5% ropivacaine should be used to
      perform axillary brachial plexus blocks.

PMID- 10588555
TI  - Spinal anesthesia with 0.5% S(-)-bupivacaine for elective lower limb surgery.
AB  - BACKGROUND AND OBJECTIVES: This study examines the clinical effects of the
      subarachnoid administration of levobupivacaine, the S(-)-enantiomer of racemic
      bupivacaine. METHODS: An open, noncomparative study was performed on 20 patients
      undergoing elective lower limb surgery. Three milliliters of a plain solution of
      0.5% S(-)-bupivacaine ( 15 mg) was administered via the L2 or L3 interspace with
      the patient in the sitting position. Following injection, the patients were
      immediately placed supine. Spread of sensory analgesia, degree of motor block,
      and hemodynamic parameters were recorded. RESULTS: Satisfactory surgical
      anesthesia was achieved in 18 patients. The median time to onset of analgesia was
      2 minutes (ranging 2-10 minutes) and the median duration of analgesia was 388
      minutes (range, 295-478 minutes). This group of patients achieved complete motor
      block, with a median onset time of 5 minutes (2-10 minutes) and duration of 266
      minutes (range, 170-415 minutes). Sensory block height was inadequate for surgery
      in 2 patients, who received supplemental anesthesia. CONCLUSIONS: The results
      suggest that S(-)-bupivacaine can provide satisfactory surgical anesthesia, but
      the spread of the plain solution is unpredictable.

PMID- 10588556
TI  - The effect of age on pharmacokinetics of the local anesthetic drug articaine.
AB  - BACKGROUND AND OBJECTIVES: With increasing age, there are physiologic changes
      that could affect pharmacokinetics of drugs. More elderly patients are undergoing
      routine dental procedures for which local anesthesia could be required. The goal
      of the present study was to evaluate the effect of age on pharmacokinetics of the
      local anesthetic agent articaine. METHODS: The submucosal infiltration anesthesia
      from two different dosages of 4% articaine without epinephrine was compared in
      healthy elderly and young volunteers. High performance liquid chromatography has
      been used to determine concentrations of articaine in serum. Basic
      pharmacokinetic parameters were calculated according to standard procedures using
      a two-exponent equation. RESULTS: The clearance and volume of distribution (Vdss)
      of articaine after infiltration anesthesia were significantly lower in elderly
      volunteers compared with young volunteers. The area under the serum concentration
      time curve and maximum drug concentration (Cmax) values did not differ
      significantly with age; however, both parameters tended to be higher in elderly
      volunteers. No changes in terminal half-life and time to reach maximum serum
      concentration (t(max)) were observed. The Cmax and tmax values of the metabolite
      articainic acid were similar in young and elderly volunteers. CONCLUSIONS The
      results show that the metabolism of articaine is age-independent in healthy male
      volunteers. The smaller Vdss in the elderly results in a trend to higher serum
      levels after a given dose of articaine. No change of dosage of articaine in
      elderly patients should be necessary.

PMID- 10588557
TI  - Plasma concentrations of lidocaine and its principal metabolites during
      continuous epidural infusion of lidocaine with or without epinephrine.
AB  - BACKGROUND AND OBJECTIVES: The purpose of this study was to evaluate the effect
      of epinephrine on the absorption of lidocaine and the accumulation of active
      metabolites of lidocaine during continuous epidural anesthesia. METHODS:
      Lidocaine was administered as an initial bolus of 5 mg/kg of 2% lidocaine
      solution followed by continuous infusion at 2.5 mg/kg/h. Patients in group I (n =
      10) received lidocaine alone and patients in group II (n = 10) received lidocaine
      + epinephrine (5 pg/mL). Concentrations of lidocaine and its active metabolites,
      monoethylglycinexylidide (MEGX) and glycinexylidide (GX), were measured in plasma
      samples obtained after 15 minutes, 30 minutes, and 1, 2, and 3 hours of infusion
      using high-performance liquid chromatography with ultraviolet detection. RESULTS:
      Plasma lidocaine concentrations were higher in group I for the first 30 minutes;
      however, after 1 hour the levels were the same. Plasma MEGX and GX increased
      continuously in both groups. MEGX levels the were significantly higher in group
      I, but there was no significant difference in the sum of lidocaine + MEGX after 2
      hours. There was no significant difference in GX levels between the two groups.
      CONCLUSIONS: With respect to continuous epidural administration, addition of
      epinephrine to lidocaine solutions is ineffective after 2 hours for reducing the
      potential for systemic toxicity, because the sum of the plasma concentrations of
      lidocaine and its principal active metabolite, MEGX, are unaffected.

PMID- 10588558
TI  - Intravenous lidocaine, amantadine, and placebo in the treatment of sciatica: a
      double-blind, randomized, controlled study.
AB  - BACKGROUND AND OBJECTIVES: Sciatica is a neuropathic pain syndrome caused by
      compression and/or inflammation of spinal nerve roots by herniated disc material,
      and its treatment is therefore usually aimed at reducing compression and
      inflammation. Studies have shown that both systemic local anesthetics and N
      methyl-D-aspartate (NMDA) receptor antagonists may produce analgesia in a variety
      of neuropathic pain syndromes. The present study evaluated the analgesic efficacy
      of i.v. infusions of the local anesthetic lidocaine, the NMDA receptor antagonist
      amantadine, and a placebo in sciatica. METHODS: Thirty patients with sciatica, as
      confirmed by physical examination and imaging studies, were enrolled in a
      randomized, double-blind, three-arm crossover trial. Infusions of amantadine (2.5
      mg/kg), lidocaine (5 mg/kg), and a placebo were administered over a 2-hour
      period, 2-7 days apart from each other. Spontaneous pain (visual analog scale)
      and evoked pain (straight leg raise) were measured every 30 minutes for 3 hours.
      RESULTS: Lidocaine reduced spontaneous pain as compared with amantadine and with
      the placebo for all measurements and at a significant level at the 30 (P < .05),
      120, and 180 (P < .01) minute time points. Maximal pain reduction from the
      baseline was 62 +/- 7% for lidocaine, 43 +/- 7% for amantadine, and 47 +/- 7% for
      the placebo. Straight leg raise test also significantly improved with lidocaine
      (from 30 to 37 degrees; P < .05), as compared to amantadine (34-36 degrees) and
      to the placebo (32-34 degrees). All three treatments were relatively well
      tolerated. CONCLUSIONS: Intravenous lidocaine, rather than amantadine, reduces
      both spontaneous and evoked sciatic pain.

PMID- 10588559
TI  - The addition of epinephrine increases intensity of sensory block during epidural
      anesthesia with lidocaine.
AB  - BACKGROUND AND OBJECTIVES: Little is known about the effect of adding epinephrine
      to local anesthetic solutions on the intensity of sensory block during epidural
      anesthesia. This study examined development of sensory block during lumbar
      epidural anesthesia using a cutaneous current perception threshold (CPT)
      quantitative sensory testing device. METHODS: Twenty ASA I patients who were
      randomly divided to receive 10 mL 1% lidocaine with (group E) or without (group
      P) epinephrine 1:200,000. Current perception threshold at 2,000, 250, and 5 Hz
      stimulation at the trigeminal (V), ninth thoracic (T9), and second lumbar (L2)
      dermatomes, and the dermatomal levels of block of light touch, temperature, and
      pinprick discrimination were measured before and every 5 minutes, until 60
      minutes after injection of epidural lidocaine. RESULTS: After epidural
      administration of lidocaine with epinephrine, all CPT significantly increased at
      T9 and L2, whereas no increase was detected after epidural plain lidocaine. Areas
      under the curves, calculated to express overall magnitude and duration of CPT
      values, were significantly larger in group E than those in group P at 2,000 and
      250 Hz at T9. No differences were observed in the maximal levels of loss of cold,
      pinprick, and touch sensations between both groups. CONCLUSIONS: These results
      suggest that lumbar epidural anesthesia using 10 mL 1% lidocaine with epinephrine
      produces a more intense block of both large and small diameter sensory nerve
      fibers than that with plain lidocaine. It appears, therefore, that the addition
      of epinephrine improves the quality of sensory block during epidural anesthesia
      with lidocaine.

PMID- 10588561
TI  - The incidence of tissue coring during the performance of caudal injection in
      children.
AB  - BACKGROUND AND OBJECTIVES: The performance of caudal injection (CI) has become a
      routine part of pediatric anesthesia. The intraoperative and immediate
      postoperative complications of CIs have been reported extensively. Although the
      long-term consequences of CI are unknown, they may include the development of
      epidermoid tumors in the spinal canal. Such tumors have been attributed to tissue
      coring (the process by which pieces of tissue are removed by a needle as it
      passes through the tissue) and the subdural deposition of such tissue. METHODS:
      In this study, we examine the internal needle of 20-gauge i.v. cannulae from 50
      CIs for evidence of tissue coring. RESULTS: We found a total coring incidence of
      54% (95% confidence interval = 40-68%). Epidermal tissue was present in 33% of
      the positive samples. Fat was present in 67% of the positive samples and bloody
      material in 26%. This study provides an estimate (with a 95% confidence interval)
      of the rate of coring during CI performed with hollow point needles. CONCLUSIONS:
      These findings suggest that technical modifications may improve patient safety.
      The results also have implications for long-term follow-up of caudal anesthetics.
      Techniques for reducing the incidence of tissue coring during the performance of
      CI are discussed.

PMID- 10588560
TI  - Subarachnoid anesthesia in young patients: a comparative analysis of two needle
      bevels.
AB  - BACKGROUND AND OBJECTIVES: This prospective, randomized, double-blind study
      compares the efficacy of two spinal needles in terms of their performance
      characteristics and associated perioperative complaints in young patients.
      METHODS: ASA I and II patients aged from 20 to 40 years undergoing lower limb
      orthopedic surgery were included during a 12-month period. After application of
      the protocol, 158 patients were recruited. The patients were randomized to two
      groups: group I: 26-gauge Atraucan (n = 79) and Group II: 27-gauge Whitacre (n =
      79). A study was made of the demographic parameters, technical characteristics,
      and peri- and postoperative complications. RESULTS: No significant differences
      were found in the technical handling of the needles, number of attempts made to
      achieve the puncture, or the time required to perform the technique. No technical
      failures (spinal anesthesia inadequate for the planned surgery) were reported,
      and the frequency of complications during the procedure was identical in both
      groups. Frequency of postdural puncture headache (3.8%) or severity and duration
      showed no difference between the two groups. The overall assessment of
      postoperative complications revealed similar scores for both needles.
      CONCLUSIONS: Technical handling (ease with which block was performed) of the
      needles analyzed was extremely easy, showing a high success rate which associated
      with the similar incidence of complications. Type of bevel does not appear to be
      a determining factor in the quality or morbidity associated with subarachnoid
      block when fine-gauge needles are used in young patients.

PMID- 10588562
TI  - Cerebrospinal fluid cytokine levels after surgery with spinal or general
      anesthesia.
AB  - BACKGROUND AND OBJECTIVES: Studies show that pain may cause neuroinflammatory
      changes in the spinal cord. These inflammatory changes could be caused by
      circulating factors such as plasma cytokines or could be a primary neuroimmune
      response of the central nervous system following peripheral nerve injury. To
      identify the possible effects of peripheral trauma and pain on the cytokine
      environment of the spinal cord, interleukin-6 (IL-6) and interleukin-10 (IL-10)
      concentrations in plasma and cerebrospinal fluid (CSF) were measured before and
      after hip replacement surgery. METHODS: The investigation used a prospective,
      observational design to measure cytokine levels in samples of plasma and CSF by
      enzyme-linked immunosorbent assay (ELISA). Samples were taken from surgical
      patients before and after surgery under general anesthesia or spinal anesthesia
      performed with or without a spinal catheter. Reference samples were also obtained
      from healthy control subjects. RESULTS: Both plasma and CSF levels of IL-6
      increased substantially after major surgery with either general or spinal
      anesthesia. No significant correlation was observed between plasma IL-6 and CSF
      IL-6 levels, suggesting a central origin for increased CSF cytokine levels. IL-10
      did not change in plasma or CSF after surgery. Plasma and CSF IL-6 and IL-10
      cytokine levels were very low or undetectable in healthy controls. CONCLUSIONS:
      Major orthopedic surgery leads to elevated CSF levels of the proinflammatory
      cytokine, IL-6. The origin of increased CSF IL-6 may be central because there was
      no significant correlation with plasma levels.

PMID- 10588563
TI  - Continuous psoas compartment block for anesthesia and perioperative analgesia in
      patients with hip fractures.
AB  - BACKGROUND AND OBJECTIVES: The perioperative use of continuous psoas compartment
      block (CPCB) was compared with traditional pain management for patients with
      fracture of the femur. The anatomy of CPCB was also tested in cadavers. METHODS:
      Forty consecutive patients (range, 67-96 years old) were prospectively randomized
      either to group A (given local anesthetics using a CPCB) or group B (given
      perioperative analgesia with meperidine). In another part of the study, CPCB was
      performed in 15 fresh cadavers, and dissection of the lumbar region was performed
      after dye injection. RESULTS: Continuous psoas compartment block was performed
      successfully in all patients in group A and was used in the pre- (16-48 hours)
      and postoperative (72 hours) periods. Visual analog scale score in group A was
      lower than in group B in 5/7 preoperative and 9/9 postoperative 8 hourly
      assessments. Differences reached statistical significance (P < .05) in 3 and 5 of
      the assessments, respectively. Patient satisfaction was higher in group A in the
      pre- (P < .05) and postoperative periods (P<.03). The block failed to achieve
      surgical anesthesia in 85% (17/20) of the patients, and additional anesthesia was
      needed. The anatomic study failed to support the existence of a defined "psoas
      compartment" previously described, and supported the clinical findings. Injected
      dye was found in the region of the origin of the sciatic nerve (essential for the
      production of anesthesia for hip surgery) in only 26% (4/15) of cadavers.
      CONCLUSIONS: The CPCB seems to be an appropriate technique for efficient and safe
      perioperative pain control. However, in our dissections, the psoas compartment
      was not well defined in all patients, thus, using this route for anesthesia may
      result in only partial success.

PMID- 10588564
TI  - Pain relief by wound infiltration with bupivacaine or high-dose ropivacaine after
      inguinal hernia repair.
AB  - BACKGROUND AND OBJECTIVES: Wound infiltration with bupivacaine is often used for
      pain relief after inguinal hernia surgery. We hypothesized that the lower
      systemic toxicity of another long-acting local anesthetic of similar potency
      (ropivacaine) would make it possible to increase the dose to above that
      recommended for bupivacaine and thereby achieve more effective pain control.
      METHODS: Elective unilateral open hernia repair was performed on 144 patients at
      4 hospitals. Surgery was performed under general anesthesia and, in a double
      blind manner, the operating field was infiltrated with 40 mL ropivacaine 7.5
      mg/mL (in = 73) or bupivacaine 2.5 mg/mL (n = 71 ) for postoperative pain relief.
      Pain at rest, on mobilization, and on coughing was assessed repeatedly during 24
      hours using a visual analog scale. The patients' ability to walk and the need for
      supplementary analgesics were also recorded. RESULTS: No statistically
      significant differences were found between the two groups with respect to pain
      scores, which the patients reported to be less than 15% (median) of the worst
      pain imaginable in all examinations performed at rest, or in the consumption of
      supplementary analgesics. Those who received ropivacaine could walk with no or
      only minor problems at an earlier stage than the bupivacaine patients (P < .03).
      Both treatments were well tolerated. CONCLUSIONS: Wound infiltration with long
      acting local anesthetics resulted in low pain scores after hernia surgery.
      Bupivacaine 100 mg was as effective as ropivacaine 300 mg.

PMID- 10588565
TI  - Lack of postoperative pain relief after hysterectomy using preperitoneally
      administered bupivacaine.
AB  - BACKGROUND AND OBJECTIVES: It is well known that wound infiltration with local
      anesthetic can reduce postoperative pain in various degrees and with very few
      side effects. A previous study showed better analgesic effect when local
      anesthetic was applied in the subfascial, rather than the subcutaneous, layer.
      The present study investigated the effect of frequent bolus injections of
      bupivacaine (15 mL 2.5 mg/mL) preperitoneally through catheters placed
      intraoperatively in women who had undergone hysterectomy. METHODS: Postoperative
      pain and analgesic requirements were studied in a double-blind randomized trial
      including 41 patients. During surgery, the patients were randomized to one of two
      groups, and the investigators were blinded. Prior to closure of the peritoneum,
      the surgeon placed a catheter between the muscle layer and the peritoneum on each
      side of the wound. One group (n = 22) received bupivacaine (15 mL 2.5 mg/mL)
      every 4 hours for 48 hours via each catheter starting in the operating room. The
      placebo group (n = 19) received saline in a like manner. Postoperative pain was
      evaluated using a visual analog scale (VAS) and verbal rating scale (VRS) twice a
      day for 2 days at rest and on movement. Requirements of supplementary analgesics
      were monitored, as was wound infection after discharge. RESULTS: Bupivacaine
      administered preperitoneally did not improve analgesia at rest, during coughing,
      or during mobilization compared with saline. No difference between the groups was
      found regarding analgesic requirements. No complications of postoperative wound
      healing or toxic side effects were seen. CONCLUSION: Bolus injections of
      bupivacaine through intraoperative placed catheters did not improve analgesia
      postoperatively compared with saline injections.

PMID- 10588566
TI  - Preoperative lidocaine infiltration for reduction mammoplasty: worth the effort?

PMID- 10588567
TI  - Postoperative pain and vomiting may be decreased by regional local anesthetic
      block.

PMID- 10588568
TI  - Prophylactic caffeine sodium benzoate--postdural puncture headache versus
      caffeine withdrawal headache.

PMID- 10588569
TI  - Fixating on classical landmarks: an impediment to technical success.

PMID- 10588570
TI  - Postoperative analgesia following total knee arthroplasty: a reply.

PMID- 10588571
TI  - Comparing the confidence of the 7th cervical spinous process, the inferior angle
      of the scapula, and Tuffier's line.

PMID- 10588572
TI  - Beta-amyloid precursor protein is detectable on monocytes and is increased in
      Alzheimer's disease.
AB  - Using the anti-beta-amyloid precursor protein (betaAPP) monoclonal antibodies
      4G8, 6E10 and 22C11 and flow cytometry, we report that human circulating
      peripheral blood monocytes display surface immunoreactivity for betaAPP. In
      contrast, circulating lymphocytes do not possess cell surface betaAPP
      immunoreactivity, despite similar levels of betaAPP expression. Immunoblotting
      analysis showed that monocytes, but not lymphocytes, possess an 82 kDa C-terminal
      betaAPP fragment consistent with a processed transmembrane species. Monocyte
      surface betaAPP was upregulated approximately threefold by activation with
      lipopolysaccharide and interferon-gamma, activation did not produce detectable
      betaAPP on the cell surface of lymphocytes. Surface betaAPP immunoreactivity was
      reduced in a normal aged population compared to normal young controls (Young =
      81.07 +/- 13.67 mean fluorescence units, Aged = 36.74 +/- 3.81, p < 0.01), but
      was significantly increased in AD subjects compared to age-matched healthy
      controls (AD = 60.31 +/- 7.42, p < 0.05). Our data suggest that a proportion of
      peripheral A beta may be derived from monocyte/macrophages, and that defects in
      brain cell processing of betaAPP in AD may be shared by this readily accessible
      peripheral cell.

PMID- 10588573
TI  - Neuronal loss and beta-amyloid removal in the amygdala of people with Down
      syndrome.
AB  - The decrease in the number of neurons free of neurofibrillary changes, neurons
      with neurofibrillary degeneration, and the total volume of beta-amyloid (A beta)
      deposits in the amygdala of people with Down syndrome and in late stages of
      Alzheimer disease were estimated by using morphometry and regression analysis.
      This model predicts that the duration of neurofibrillary changes from the
      pretangle stage to ghost tangles is approximately 4.7 years. The correlation
      between the decrease in the number of neurons and the decrease in the amount of A
      beta indicates that amyloid deposition is associated with neurons and that loss
      of neurons causes decrease in A beta deposition. The presence of neurons only
      with neurofibrillary tangles, and the absence of the amyloid deposits predicted
      by regression analysis suggest that neurons with tangles are not engaged in
      amyloid deposition. The disappearance of amyloid by approximately 2.2 years after
      loss of neurons free of neurofibrillary changes indicates that A beta deposits
      are degradable and removable and that even in severely atrophic amygdala, there
      are mechanisms of amyloid resolution. This study shows that in normal aging in
      the amygdala, extracellular A beta appears later than neurofibrillary changes.

PMID- 10588574
TI  - Oxidative stress differentially modulates phosphorylation of ERK, p38 and CREB
      induced by NGF or EGF in PC12 cells.
AB  - This study assessed if oxidative stress induced by treatment of PC12 cells with
      H2O2 modulated signaling cascades induced by nerve growth factor (NGF) or
      epidermal growth factor (EGF) because oxidative stress and impaired growth factor
      function are associated with aging and aging-associated diseases such as
      Alzheimer's disease. Phosphorylation of extracellular signal-regulated kinases 1
      and 2 (ERK 1/2) and of p38 kinase was rapidly increased after treatment with NGF,
      EGF, or H2O2, with NGF causing more prolonged increases than the other agents.
      Pretreatment with H2O2 did not alter phosphorylation of ERK1/2 induced by either
      growth factor, but increased the phosphorylation of p38 kinase induced by
      treatment with NGF or EGF alone. CREB phosphorylation at SER 133 was rapidly
      increased by treatment with either NGF or EGF. Pretreatment with H2O2 reduced
      CREB phosphorylation induced by either growth factor. This seemed to be a direct
      effect because H2O2 also inhibited CREB phosphorylation induced by the adenylyl
      cyclase stimulator forskolin. These results demonstrate that oxidative stress can
      differentially modulate growth factor-initiated signaling cascades. Furthermore,
      because CREB is an evolutionarily preserved protein involved in the formation of
      long term memory, these results indicate a new target of oxidative stress that
      may be important in disorders involving impaired memory, such as Alzheimer's
      disease.

PMID- 10588575
TI  - Age-related metabolite changes and volume loss in the hippocampus by magnetic
      resonance spectroscopy and imaging.
AB  - Magnetic resonance imaging (MRI) studies have produced controversial results
      concerning the correlation of hippocampal volume loss with increasing age. The
      goals in this study were: 1) to test whether levels of N-acetyl aspartate (NAA, a
      neuron marker) change in the hippocampus during normal aging and 2) to determine
      the relationship between hippocampal NAA and volume changes. Proton magnetic
      resonance spectroscopic imaging (1H MRSI) and MRI were used to measure
      hippocampal metabolites and volumes in 24 healthy adults from 36 to 85 years of
      age. NAA/Cho decreased by 24% (r = 0.53, p = 0.01) and NAA/Cr by 26% (r = 0.61, p
      < 0.005) over the age range studied, whereas Cho/Cr remained stable, implying
      diminished NAA levels. Hippocampal volume shrank by 20% (r = 0.64, p < 0.05). In
      summary, aging effects must be considered in 1H MRSI brain studies. Furthermore,
      because NAA is considered a marker of neurons, these results provide stronger
      support for neuron loss in the aging hippocampus than volume measurements by MRI
      alone.

PMID- 10588576
TI  - Phenotypic down-regulation of glutamate receptor subunit GluR1 in Alzheimer's
      disease.
AB  - Glutamate receptors play crucial roles in cognition and memory. We have
      quantitated the protein levels of alpha-amino-isoxazolepropionic acid (AMPA)-type
      (GluR1) and N-methyl-D-aspartate-type (NMDAR1) glutamate receptors in postmortem
      brain tissues of patients with Alzheimer's disease and age-matched controls using
      western blotting. The bolts carrying fully denatured proteins were probed with
      antibodies specific to their carboxyl terminus of these receptors. In Alzheimer's
      disease, GluR1 levels were significantly decreased in the entorhinal cortex and
      dentate gyrus, but not in the motor cortex. In contrast, levels of NMDAR1 were
      not altered in the dentate gyrus, suggesting that GluR1 expression was
      specifically diminished in this structure that is known to be preserved
      histologically in patients. However, the results of immunocytochemical
      examination confirmed a previous controversial report: GluR1-immunoreactive
      structures were labeled rather intensely in the molecular layer of the dentate
      gyrus of Alzheimer's patients. Interestingly, levels of a postsynaptic density
      protein named SAP97, which recognizes and potentially masks the epitope region of
      GluR1, was positively correlated with those of GluR1 protein in the control
      group, but not in the patient group. Thus, the enhanced GluR1-like staining in
      Alzheimer's disease might be ascribed to the hampered interaction between SAP97
      and GluR1 leading to epitope unmasking of GluR1 on tissue sections. These
      findings indicate that abnormal expressions of the AMPA receptor and its
      interacting PSD molecule are associated with Alzheimer's disease and implicated
      in pathophysiology of this disease.

PMID- 10588577
TI  - The mouse C1q A-chain sequence alters beta-amyloid-induced complement activation.
AB  - In transgenic models of Alzheimer's disease (AD) neuronal loss has not been
      widely observed. The loss of neurons in AD may be due to chronic activation of
      complement (C') by beta-amyloid (A beta). A beta has been shown to activate C' by
      binding to a site on the C1q A-chain. The mouse A-chain sequence differs
      significantly from human, and a peptide based on the mouse A-chain sequence was
      ineffective at blocking activation of C' by A beta in contrast to the inhibition
      seen with the human peptide. Comparison of mouse and human serum showed that
      human C' was activated more effectively by A beta than was mouse C'. Therefore,
      additional genetic manipulations may be necessary to replicate in the murine
      model the inflammation and neurodegeneration that occur in AD.

PMID- 10588578
TI  - The effects of a novel NSAID on chronic neuroinflammation are age dependent.
AB  - Chronic inflammation may play an important role in the pathogenesis of
      Alzheimer's disease (AD). The present study compared the effects of chronic
      neuroinflammation, produced by infusion of lipopolysaccharide (LPS) into the
      fourth ventricle, upon memory in young, adult, and old rats. Nonsteroidal anti
      inflammatory drug (NSAID) therapy may delay the onset of AD. We show that NO
      Flurbiprofen (NFP), a novel NSAID that lacks gastrointestinal side effects,
      attenuated the neuroinflammatory reaction and reduced the inflammation-induced
      memory deficit. Chronic LPS infusions impaired performance of young rats but not
      adult or old rats. Treatment with NFP improved the performance of LPS-infused
      young rats, but not LPS-infused adult or old rats. LPS infusions increased the
      number of activated microglia in young and adult rats but not old rats. NFP
      treatment attenuated the effects of LPS upon microglia activation in young and
      adult rats, but not old rats. The results suggest that NSAID therapies designed
      to influence the onset of AD should be initiated in adults before age-associated
      inflammatory processes within the brain have a chance to develop.

PMID- 10588579
TI  - Relationships among cortisol (CRT), dehydroepiandrosterone-sulfate (DHEAS), and
      memory in a longitudinal study of healthy elderly men and women.
AB  - At test times 18 months apart (Time 1 and Time 2), men (n Time 1 = 31, Time 2 =
      23), women estrogen-users (n Time 1 = 14, Time 2 = 10), and women estrogen non
      users (n Time 1 = 41, Time 2 = 27), whose average age was 72.1 and 73.4 years at
      Time 1 and Time 2, respectively, were tested with a battery of neuropsychological
      tests measuring verbal memory, visual memory, concentration/attention, language
      fluency and semantic memory. Plasma levels of CRT and DHEAS were assayed by
      radioimmunoassay at both test times. The men had higher DHEAS levels than both
      groups of women at both test times (p < 0.001) and also had a higher DHEAS/CRT
      ratio compared to the estrogen non-users (p < 0.05). Although there were no group
      differences in CRT levels at either time, CRT levels increased in the estrogen
      non-using women from Time 1 to Time 2 (p < 0.001). Subjects with lower CRT levels
      performed better than those with higher levels on several tests of declarative
      memory (p < 0.05). Men and estrogen-users had higher Digit Span scores compared
      to female estrogen non-users at both test times (p < 0.01), and women estrogen
      users also had higher Backward Digit Span scores than non-users (p < 0.05). Both
      groups of women performed better than men on Category Retrieval (p < 0.01). These
      findings suggest that higher CRT levels in elderly men and women are associated
      with poorer explicit memory functioning; however, these results failed to provide
      any evidence that DHEAS is protective against declarative memory decline with
      aging.

PMID- 10588580
TI  - In vitro and in vivo oxidative stress associated with Alzheimer's amyloid beta
      peptide (1-42)
AB  - The amyloid beta-peptide (A beta)-associated free radical oxidative stress model
      for neuronal death in Alzheimer's disease (AD) brain predicts that neuronal
      protein oxidation is a consequence of A beta-associated free radicals [8]. In
      this study we have used both in vitro and in vivo models of beta-amyloid (A beta)
      toxicity to detect free radical induced oxidative stress by the measure of
      protein carbonyl levels. These model systems employed cultured hippocampal
      neurons exposed to exogenous synthetic A beta(1-42) and transgenic Caenorhabditis
      elegans (C. elegans) animals expressing A beta(1-42). We also investigated the
      importance of the A beta(1-42) Met35 residue for free radical formation in
      peptide solution and for peptide-induced protein oxidation and neuronal toxicity
      in these model systems. A beta(1-42) in solution yielded an EPR spectrum,
      suggesting that free radicals are associated with this peptide; however, neither
      the reverse [A beta(42-1)] nor methionine-substituted peptide [A beta(1
      42)Met35Nlc] gave significant EPR spectra, suggesting the importance of the
      methionine residue in free radical formation. A beta(1-42) addition to cultured
      hippocampal neurons led to both neurotoxicity (30.1% cell death, p < 0.001) and
      increased protein oxidation (158% of controls, p < 0.001). and both of those
      effects were not observed with reverse or Met35Nle substituted peptides. C.
      elegans transgenic animals expressing human A beta(1-42) also had significantly
      increased in vivo protein carbonyls (176% of control animals, p < 0.001),
      consistent with our model. In contrast, transgenic animals with a Met35cys
      substitution in A beta(1-42) showed no increased protein carbonyls in vivo, in
      support of the hypothesis that methionine is important in A beta-associated free
      radical oxidative stress. These results are discussed with reference to the A
      beta-associated free radical oxidative stress model of neurotoxicity in AD brain.

PMID- 10588581
TI  - Oxidation of cellular proteins by beta-amyloid peptide.

PMID- 10588582
TI  - The possible origin of free radicals from amyloid beta peptides in Alzheimer's
      disease.

PMID- 10588583
TI  - No loss of synaptic proteins in the hippocampus of aged, behaviorally impaired
      rats.
AB  - The levels of three different synaptic proteins in the hippocampus of young (6
      months of age) and aged (26-27 months of age) Long Evans rats were examined using
      quantitative Western blotting. An important feature to this study is that prior
      to the neurobiological analysis, hippocampal function was determined by assessing
      spatial learning ability in the Morris water maze. A subset of the aged rats was
      impaired on the learning task while the remaining aged cohort performed within
      the range of young rats. The amount of immunoreactivity for synaptophysin,
      synaptotagmin, and synaptosomal associated protein-25 did not differ between the
      young and aged rats. In addition, the aged rats with severe cognitive impairment
      had levels of these synaptic proteins that were similar to those of the aged rats
      with preserved cognitive function. This finding of no change in the levels of
      synaptic proteins suggests that substantial synapse loss in the hippocampal
      formation does not underlie cognitive decline in normal aging.

PMID- 10588584
TI  - Do synaptic markers provide a window on synaptic effectiveness in the aged
      hippocampus?

PMID- 10588585
TI  - Age-related decline in memory function: is it associated with a loss of synapses?

PMID- 10588587
TI  - Introducing the "How it really happened" series.

PMID- 10588586
TI  - Circuit and morphological specificity of synaptic change in the aged hippocampal
      formation.

PMID- 10588588
TI  - Distribution of pulmonary blood flow.

PMID- 10588589
TI  - Ventilatory assistance improves exercise endurance in stable congestive heart
      failure.
AB  - We postulated that ventilatory assistance during exercise would improve
      cardiopulmonary function, relieve exertional symptoms, and increase exercise
      endurance (T(lim)) in patients with chronic congestive heart failure (CHF). After
      baseline pulmonary function tests, 12 stable patients with advanced CHF (ejection
      fraction, 24 +/- 3% [mean +/- SEM]) performed constant-load exercise tests at
      approximately 60% of their predicted maximal oxygen consumption (V O(2)max) while
      breathing each of control (1 cm H(2)O), continuous positive airway pressure
      optimized to the maximal tolerable level (CPAP = 4.8 +/- 0.2 cm H(2)O) or
      inspiratory pressure support (PS = 4.8 +/- 0.2 cm H(2)O), in randomized order.
      Measurements during exercise included cardioventilatory responses, esophageal
      pressure (Pes), and Borg ratings of dyspnea and leg discomfort (LD). At a
      standardized time near end-exercise, PS and CPAP reduced the work of breathing
      per minute by 39 +/- 8 and 25 +/- 4%, respectively (p < 0. 01). In response to
      PS: T(lim) increased by 2.8 +/- 0.8 min or 43 +/- 14% (p < 0.01); slopes of LD
      time, V O(2)-time, V CO(2)-time, and tidal Pes-time decreased by 24 +/- 10, 20 +/
      11, 28 +/- 8, and 44 +/- 9%, respectively (p < 0.05); dyspnea and other
      cardioventilatory parameters did not change. CPAP did not significantly alter
      measured exercise responses. The increase in T(lim) was explained primarily by
      the decrease in LD- time slopes (r = -0.71, p < 0.001) which, in turn, correlated
      with the reductions in V O(2)-time (r = 0.61, p < 0.01) and tidal Pes-time (r =
      0.52, p < 0.01). in conclusion, ventilatory muscle unloading with PS reduced
      exertional leg discomfort and increased exercise endurance in patients with
      stable advanced CHF.

PMID- 10588590
TI  - Correlates of the "don't know" response to questions about snoring.
AB  - Many persons say that they "don't know" whether they snore. The purpose of this
      study was to investigate the prevalence and correlates of such responses in an
      elderly population. Subjects were 1715 members (1,155 men, 560 women) of a
      previously defined cohort (Western Group Collaborative Study) followed
      prospectively since 1960-1961 with a current mean age of 75.9 (SD = 4.3) for the
      men and 71.4 (SD = 5.3) for the women. We collected survey questionnaires and
      reviewed medical records. Results indicated that risk factors for the "don't
      know" response in this population were similar to those for frequent snoring and
      included: male sex, higher Body Mass Index, smoking, and use of sinus medication.
      Between 28 and 44% of the cohort answered questions about snoring with a "don't
      know" response. These data are compatible with the interpretation that subjects
      may disavow knowledge of their own snoring and suggest that future studies
      consider the "don't know" response to questions about snoring as a response of
      potential interest.

PMID- 10588591
TI  - Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized,
      placebo-controlled trial.
AB  - Interleukin-4 mediates important proinflammatory functions in asthma, including
      induction of the IgE isotype switch, expression of VCAM-1 on endothelium, mucin
      production, 15-lipoxygenase activity, and Th2 lymphocyte stimulation leading to
      the secondary synthesis of IL-4, IL-5, and IL-13. Soluble recombinant human IL-4
      receptor (IL-4R; Nuvance; altrakincept) inactivates naturally occurring IL-4
      without mediating cellular activation. Nebulized IL-4R has a serum half-life of
      approximately 1 wk. In this double-blind, placebo-controlled trial, 25 patients
      with moderate asthma requiring inhaled corticosteroids were randomly assigned to
      receive a single nebulized dose of IL-4R 1,500 microg, IL-4R 500 microg, or
      placebo after stopping inhaled corticosteroids. No drug-related toxicity was
      observed. Treatment with IL-4R produced significant improvement in FEV(1) on Day
      4 (1,500 microg versus placebo; p < 0.05) and in FEF(25-75) on Days 2 and 4
      (1,500 microg versus placebo; p < 0.05). Asthma symptom scores stabilized among
      patients treated with IL-4R 1, 500 microg, despite abrupt withdrawal of
      corticosteroids, but not in the IL-4R 500 microg group or the placebo group (p <
      0.05). Patients in the IL-4R 1,500 microg group also required significantly less
      beta(2)-agonist rescue use (p < 0.05). Anti-inflammatory effects were further
      demonstrated by significantly reduced exhaled nitric oxide (p < 0.05).
      CONCLUSIONS: A single dose of IL-4R appears safe and effective in moderate
      asthma. The 1,500 microg dose appears as safe but significantly more effective
      than the 500 microg dose.

PMID- 10588592
TI  - Mirtazapine, a mixed-profile serotonin agonist/antagonist, suppresses sleep apnea
      in the rat.
AB  - Serotonin enhancing drugs, including L-tryptophan and, more recently, fluoxetine
      and paroxetine, have been tested as pharmacologic treatments for sleep apnea
      syndrome. Although some patients have demonstrated reduced apnea expression after
      treatment with these compounds, this improvement has been restricted to nonrapid
      eye movement (NREM) sleep, with some patients showing no improvement. This study
      reports the effects of mirtazapine, an antidepressant with 5-HT(1) agonist as
      well as 5-HT(2) and 5-HT(3) antagonist effects, on sleep and respiration in an
      established animal model of central apnea. We studied nine adult male Sprague
      Dawley rats chronically instrumented for sleep staging. In random order on
      separate days, rats were recorded after intraperitoneal injection of: (1) saline,
      (2) 0.1 mg/kg +/- mirtazapine (labeled as Remeron), (3) 1 mg/kg mirtazapine, or
      (4) 5 mg/ kg mirtazapine. With respect to saline injections, mirtazapine at all
      three doses reduced apnea index during NREM sleep by more than 50% (p < 0.0001)
      and during REM sleep by 60% (p < 0.0001) for at least 6 h. In association with
      this apnea suppression normalized inspiratory minute ventilation increased during
      all wake/sleep states (p < 0.001 for each state). The duration of NREM sleep was
      unaffected by any dose of mirtazapine (p = 0.42), but NREM EEG delta power was
      increased by more than 30% at all doses (p = 0.04), indicating improved NREM
      sleep consolidation after mirtazapine injection. We conclude that mirtazapine,
      over a 50-fold dose range, significantly reduces central apnea expression during
      NREM and REM sleep in the rat. The efficacy of this compound to suppress apnea in
      all sleep stages most probably arises from its mixed agonist/antagonist profile
      at serotonin receptors. The implications of these findings for the management of
      sleep apnea syndrome must be verified by appropriate clinical trials.

PMID- 10588593
TI  - Risk factors for growth and decline of lung function in asthmatic individuals up
      to age 42 years. A 30-year follow-up study.
AB  - Little is known about factors determining the outcome of childhood asthma. The
      purpose of this longitudinal study was to assess the factors in childhood that
      determine the level of FEV(1) in early adulthood in asthmatic individuals, and to
      examine factors associated with decline in FEV(1) during adulthood. Between 1966
      and 1969, 119 allergic asthmatic subjects aged 5 to 14 yr were studied (Visit 1).
      Of these subjects, 101 (85%) were reinvestigated at ages 22 to 32 yr (Visit 2)
      and 32 to 42 yr (Visit 3). At the first survey and during follow-up, a
      standardized questionnaire was used, serum total IgE and peripheral blood
      eosinophils were measured, and physical examination, skin tests, lung function
      tests, and histamine challenge (provocative concentration causing a 10% decline
      in FEV(1); PC(10)) tests were performed according to the same protocol. Multiple
      linear regression analyses were performed with FEV(1) at Visit 2 and with the
      change of FEV(1) from Visit 2 to Visit 3 as outcome variables. A low FEV(1)%
      predicted at Visit 1 and PC(10) </= 16 mg/ml at Visit 1 were significantly
      associated with a lower level of FEV(1) at Visit 2. Subjects who quit smoking and
      subjects who continued to use inhaled corticosteroids had a significantly smaller
      annual decline in FEV(1) from Visit 2 to Visit 3, adjusted for attained level of
      FEV(1) at Visit 2. In conclusion, bronchial hyperresponsiveness and a low level
      of lung function in childhood are independent risk factors for a low level of
      FEV(1) in early adulthood. A smaller decline in FEV(1) after ages 22 to 32 yr
      occurs in asthmatics who quit smoking and who continue to use inhaled
      corticosteroids. Our data stress the importance of studying intervention
      strategies for asthma in young childhood and early adulthood in order to prevent
      or postpone further lung function deficits.

PMID- 10588594
TI  - The effect of acute respiratory distress syndrome on long-term survival.
AB  - Despite a great deal of information about the risk factors, prognostic variables,
      and hospital mortality in the acute respiratory distress syndrome (ARDS), very
      little is known about the long-term outcomes of patients with this syndrome. We
      conducted a prospective, matched, parallel cohort study with the goals of
      describing the survival of patients with ARDS after hospital discharge and
      comparing the long-term survival of patients with ARDS and that of a group of
      matched controls. The study involved 127 patients with ARDS associated with
      trauma or sepsis and 127 controls matched for risk factor (trauma or sepsis) and
      severity of illness who survived to hospital discharge. Time until death was used
      as the outcome measure. Survival was associated with age, risk factor for ARDS,
      and comorbidity. There was no difference in the long-term mortality rate for ARDS
      patients and that of matched controls (hazard ratio for ARDS: 1.00; 95%
      confidence interval: 0.47 to 2.09) after controlling for age, risk factor for
      ARDS, comorbidity, and severity of illness. We conclude that if sepsis or trauma
      patients survive to hospital discharge, ARDS does not increase their risk of
      subsequent death. Older patients, patients with sepsis, and patients with
      comorbidities, regardless of the presence of ARDS, have a higher risk of death
      after hospital discharge. For the purposes of clinical prognosis and cost
      effectiveness analysis, the long-term survival of patients with ARDS can be
      modeled on the basis of age, underlying risk factor for ARDS, and comorbidity.

PMID- 10588595
TI  - Serial changes in surfactant-associated proteins in lung and serum before and
      after onset of ARDS.
AB  - The goal of this study was to determine the changes that occur in surfactant
      associated proteins in bronchoalveolar lavage fluid (BAL) and serum of patients
      at risk for ARDS and during the course of ARDS. We found that the concentrations
      of SP-A and SP-B were low in the BAL of patients at risk for ARDS before the
      onset of clinically defined lung injury, whereas the concentration of SP-D was
      normal. In patients with established ARDS, BAL SP-A and SP-B concentrations were
      low during the entire 14-d observation period, but the median SP-D concentrations
      remained in the normal range. Immunoreactive SP-A and SP-D were not increased in
      the serum of patients at risk for ARDS, but both increased after the onset of
      ARDS to a maximum on Day 3 and remained elevated for as long as 14 d. The BAL SP
      A concentrations were significantly lower in at-risk patients who developed ARDS,
      and no patient with a BAL SP-A concentration greater than 1.2 microg/ml developed
      ARDS. On Days 1 and 3 of ARDS, the BAL SP-D concentration was significantly lower
      in patients who died, and the BAL SP-D concentration was significantly related to
      the PI(O(2))/FI(O(2)) ratio. Thus, surfactant protein abnormalities occur before
      and after the onset of ARDS, and the responses of SP-A, SP-B, and SP-D differ in
      important ways. The BAL SP-A and SP-D measurements can be used to classify
      patients as high or low risk for progression to ARDS and/or death after the onset
      of ARDS. Strategies to increase these surfactant proteins in the lungs of
      patients with ARDS could be useful to modify the onset or the course of ARDS.

PMID- 10588596
TI  - Markers indicating deterioration of pulmonary Mycobacterium avium-intracellulare
      infection.
AB  - To predict the natural history of pulmonary Mycobacterium avium-intracellulare
      (MAI) infection with nodular bronchiectasis, we retrospectively evaluated
      clinical manifestations, laboratory data, and bronchoalveolar lavage fluid (BALF)
      findings in 57 patients. The patients received follow-up chest computed
      tomographic scans and testing for sputum bacteriology between intervals of at
      least 12 mo. They were divided into two groups after observation for 28 +/- 13
      mo: deteriorated (n = 34) and not-deteriorated (n = 23). There were no patients
      with spontaneous improvement. At the start of observation, the mean age was
      greater in the deteriorated group (69 +/- 9 yr) than in the not-deteriorated
      group (57 +/- 9 yr). The mean body-mass index was lower in the deteriorated group
      (19.2 +/- 3.1 kg/m(2)) than in the not-deteriorated group (21.5 +/- 1.5 kg/m(2)).
      C-reactive protein, erythrocyte sedimentation rate, and carbohydrate antigen 19-9
      were significantly elevated in the deteriorated group. The BALF findings of the
      deteriorated group showed that the neutrophil cell counts were significantly
      increased. Thirty-four of 57 patients with pulmonary MAI infection with nodular
      bronchiectasis had progressive clinical and/or radiographic disease. The older
      and thinner patients tended to become worse. Neutrophil-related inflammation
      associated with a decrease in CD4+ lymphocyte might reflect the progression of
      pulmonary MAI infection with nodular bronchiectasis.

PMID- 10588597
TI  - Prognostic value of nutritional status in chronic obstructive pulmonary disease.
AB  - The association between low body mass index (BMI) and poor prognosis in patients
      with chronic obstructive pulmonary disease (COPD) is a common clinical
      observation. We prospectively examined whether BMI is an independent predictor of
      mortality in subjects with COPD from the Copenhagen City Heart Study. In total,
      1,218 men and 914 women, aged 21 to 89 yr, with airway obstruction defined as an
      FEV(1)-to-FVC ratio of less than 0.7, were included in the analyses. Spirometric
      values, BMI, smoking habits, and respiratory symptoms were assessed at the time
      of study enrollment, and mortality from COPD and from all causes during 17 yr of
      follow-up was analyzed with multivariate Cox regression models. After adjustment
      for age, ventilatory function, and smoking habits, low BMI was predictive of a
      poor prognosis (i.e., higher mortality), with relative risks (RRs) in underweight
      subjects as compared with that in subjects of normal weight of 1.64 (95%
      confidence interval [CI]: 1.20 to 2.23) in men and 1.42 (95% CI: 1.07 to 1.89) in
      women. However, the association between BMI and survival differed significantly
      with stage of COPD. In mild and moderate COPD there was a nonsignificant U-shaped
      relationship, with the lowest risk occurring in normal-weight to overweight
      subjects, whereas in severe COPD, mortality continued to decrease with increasing
      BMI (test for trend: p < 0.001). Similar results were found for COPD-related
      deaths, with the strongest associations found in severe COPD (RR for low versus
      high BMI: 7.11 [95% CI: 2.97 to 17.05]). We conclude that low BMI is an
      independent risk factor for mortality in subjects with COPD, and that the
      association is strongest in subjects with severe COPD.

PMID- 10588598
TI  - Montelukast added to inhaled beclomethasone in treatment of asthma.
      Montelukast/Beclomethasone Additivity Group.
AB  - The primary objective of this study was to determine whether montelukast, an oral
      leukotriene receptor antagonist, provides additional clinical benefit to the
      effect of inhaled corticosteroids. A total of 642 patients with chronic asthma
      (FEV(1) 50 to 85% of predicted value and at least a predefined level of asthma
      symptoms) incompletely controlled with inhaled beclomethasone, 200 microg twice
      daily using a spacer device, during the 4-wk run-in period were randomly
      allocated, in a double-blind, double-dummy manner to one of four treatment
      groups: (1) montelukast 10 mg plus continuing inhaled beclomethasone; (2) placebo
      tablet plus continuing inhaled beclomethasone; (3) montelukast 10 mg and inhaled
      placebo (after blind beclomethasone removal); and (4) placebo tablet and inhaled
      placebo (after blind beclomethasone removal). The primary endpoints were FEV(1)
      and daytime asthma symptoms score. Montelukast provided significant (p < 0.05)
      clinical benefit in addition to inhaled beclomethasone by improving FEV(1),
      daytime asthma symptom scores, and nocturnal awakenings. Blind removal of
      beclomethasone in the presence of placebo tablets caused worsening of asthma
      control, demonstrating that patients received clinical benefit from inhaled
      corticosteroids. Blind removal of beclomethasone in the presence of montelukast
      resulted in less asthma control but not to the level of the placebo group. All
      treatments were well tolerated; clinical and laboratory adverse experiences were
      generally similar to placebo treatment in this study. In conclusion, montelukast
      provided additional asthma control to patients benefitting from, but incompletely
      controlled on, inhaled beclomethasone.

PMID- 10588599
TI  - Asthma attacks with eosinophilia predict mortality from chronic obstructive
      pulmonary disease in a general population sample.
AB  - We studied the association between allergy defined as eosinophilia (>/= 275
      cells/mm(3)) and/or positive skin tests (sum score >/= 3) and mortality from
      chronic obstructive pulmonary disease (COPD) after adjustment for major risk
      factors. In addition, we investigated this association in subgroups of
      respiratory symptoms and lung function. We used data from 7,556 participants of
      the respiratory surveys in 1964 -1972 in the general populations of Vlagtwedde,
      Vlaardingen, and Meppel (The Netherlands; mean age +/- SD: 39.3 yr +/- 14 in the
      1960s). In 1995, the vital status was available (5,135 alive, 106 lost to follow
      up, 121 primary deaths from COPD, and 2,194 other primary causes of which 137 had
      a secondary death cause from COPD. Positive skin tests were not associated with
      increased COPD mortality. The association between eosinophilia and COPD mortality
      was restricted to those who had reported asthma attacks and was present for both
      COPD as a primary cause (relative risk [RR] = 4.80; 95% confidence interval [CI]
      1.9 to 11.9) and combined primary and secondary causes of death (RR = 3. 90; 95%
      CI 2.05 to 7.40). We conclude that eosinophilia with asthma attacks is a risk
      factor for COPD mortality in addition to known risk factors also found in our
      study such as male gender, older age, current smoking, low lung function,
      underweight, and dyspnea.

PMID- 10588600
TI  - Sleep-related breathing disorder is an independent risk factor for systemic
      hypertension.
AB  - The exact influence of sleep-related breathing disorder (SRBD) on blood pressure
      control remains unknown. We investigated the influence of different degrees of
      SRBD on daytime blood pressure and its association to documented hypertension by
      examining 1,190 consecutive patients referred for diagnosis of SRBD. The protocol
      includes clinical interview, physical examination, office blood pressure
      measurement, cholesterol, and blood gas analysis. Unattended home monitoring of
      nocturnal breathing was performed for assessment of SRBD activity (respiratory
      disturbance index [RDI]). RDI was independently and linearly associated with
      systolic blood pressure (unstandardized coefficient [B] = 0.07 +/- 0.03, p =
      0.03), diastolic blood pressure (B = 0.07 +/- 0.02, p = 0 < 0.001), and heart
      rate (B = 0.10 +/- 0.02, p < 0.001) at rest. The relative risk for hypertension
      (blood pressure >/= 160/95 mm Hg) increased with SRBD severity (odds ratio [OR],
      4.15 for RDI >/= 40 versus < 5 [95% CI, 2.7 to 6.5]). This relative risk was also
      elevated in younger (</= 50 yr) compared with older patients (> 50 yr) (OR, 7.15
      versus 2.70 for RDI >/= 40 versus < 5). These cross-sectional clinical data
      suggest a relationship between SRBD severity and systolic blood pressure,
      diastolic blood pressure, and heart rate after control for confounders such as
      body mass index (BMI), age, alcohol/nicotine consumption, cholesterol level, and
      daytime PO(2) and PCO(2). SRBD is an independent risk factor for systemic
      hypertension with an increased likelihood in subjects </= 50 yr of age.

PMID- 10588601
TI  - Predictors of longitudinal change in diffusing capacity over 8 years.
AB  - Low single-breath diffusing capacity (DL(CO)) values are associated with anatomic
      emphysema, but the predictors of longitudinal change in DL(CO) over many years
      are unknown. Study subjects were adult participants in the longitudinal Tucson
      Epidemiology Study of Obstructive Lung Disease who had at least one DL(CO)
      measurement during either of two surveys 8 yr apart (n = 543). Smoking status was
      determined at each examination (current, former, or never smoker). Quitters were
      defined as those currently smoking at the baseline DL(CO) examination (1982-1983)
      and self-reported as no longer smoking at the follow-up exam (1990-1991). The
      longitudinal DL(CO) data were analyzed using repeated measures analysis; because
      of missing observations this was done using a saturated random effects model. The
      results showed that males had higher levels of DL(CO) than females, current
      smokers had significantly lower levels of DL(CO) than never smokers, but there
      was no difference in their mean slopes over time. Smoking history, assessed using
      pack-years of smoking, was associated with reduced DL(CO) levels, independent of
      whether current or ex-smokers. Males and females demonstrated equivalent rates of
      decline in DL(CO) that accelerated with increasing age, and mean DL(CO) declines
      were associated with declines in FEV(1) between surveys.

PMID- 10588602
TI  - Acute and chronic effects of airway obstruction on canine left ventricular
      performance.
AB  - We used a canine model of chronic obstructive sleep apnea (OSA) to examine the
      effects of intermittent airway occlusion during sleep on left ventricular (LV)
      performance. Studies were performed in four dogs. The effects of acute airway
      occlusion on LV pressure and volume (on a background of chronic OSA) were
      determined with an impedance catheter and a high fidelity manometer. In conscious
      animals (n = 3), experiencing spontaneous episodes of sleep, acute airway
      occlusion caused significant increases in LV transmural systolic pressure that
      were associated with increased end-systolic volume and reduced stroke volume. To
      determine the effects of chronic OSA on baseline LV function, two-dimensional
      echocardiograms were performed in conscious animals (n = 4) during unobstructed
      breathing before and after a 1- to 3-mo period of OSA. During chronic OSA, there
      was a significant decrease in LV ejection fraction as a result of increases in
      end-systolic volume. We conclude that in chronic OSA acute airway occlusion
      during sleep is associated with increases in LV afterload and decreases in
      fractional shortening. Chronic OSA also leads to sustained decreases in LV
      systolic performance that could be caused by the development of systemic
      hypertension and/or transient increases in LV afterload during episodes of airway
      obstruction.

PMID- 10588603
TI  - Residual oil fly ash amplifies allergic cytokines, airway responsiveness, and
      inflammation in mice.
AB  - Particulate matter (PM) air pollution may increase symptom severity in allergic
      asthmatics. To examine possible interaction, or greater than additive responses,
      between PM effects and allergic responses, an ovalbumin-sensitized and challenged
      (OVA) mouse model of allergic airways disease was utilized. After challenge, mice
      were intratracheally instilled with saline vehicle or 3 mg/kg (approximately 60
      microg) residual oil fly ash (ROFA), a transition metal-rich emission source PM
      sample. Physiological and inflammatory responses were examined 1, 3, 8, and 15 d
      later. In response to intravenously administered methacholine, ROFA increased
      total respiratory system resistance and decreased compliance 1 d after exposure,
      whereas effects of OVA lasted at least 15 d after exposure. Significant
      interactions between OVA and ROFA were mainly observed 8 d after challenge and
      exposure, especially with respect to compliance. A strong interaction (p < 0.01)
      between OVA and ROFA exposure resulted in 8-fold (1 d) and 3-fold (3 d) increases
      in bronchoalveolar lavage (BAL) fluid eosinophil numbers. A similarly strong
      interaction (8-fold) was observed in BAL fluid interleukin-4 (IL-4) 1 d after
      challenge and exposure. Significant though less strong interactions were also
      found with respect to IL-4 and IL-5 by 3 d postchallenge/exposure. This study
      shows that allergen challenge and exposure to emission source particulate matter
      containing relatively high levels of transitions metals can interact to increase
      Th2 cytokine production, eosinophil recruitment, and airway hyperresponsiveness
      in previously sensitized mice.

PMID- 10588604
TI  - Induced sputum eicosanoid concentrations in asthma.
AB  - Further definition of the role of leukotrienes (LT) and prostaglandins (PG) in
      asthma would be helped by a noninvasive method for assessing airway production.
      The supernatant from sputum induced with hypertonic saline and dispersed using
      dithiotrietol has been successfully used to measure other molecular markers of
      airway inflammation and might be a useful method. We have measured induced sputum
      supernatant LTC(4)/D(4)/E(4) concentrations using enzyme immunoassay and PGE(2),
      PGD(2), TXB(2), and PGF(2alpha) using gas chromatography-negative ion chemical
      ionization-mass spectroscopy in 10 normal subjects and in 26 subjects with asthma
      of variable severity. Sputum cysteinyl-leukotrienes concentrations were
      significantly greater in subjects with asthma (median, 9.5 ng/ml) than in normal
      control subjects (6.4 ng/ml; p < 0.02) and greater in subjects with persistent
      asthma requiring inhaled corticosteroids (median, 11.4 ng/ml) or studied within
      48 h of an acute severe exacerbation of asthma (13 ng/ml) than in subjects with
      episodic asthma treated with inhaled beta(2)-agonists only (7.2 ng/ml). There
      were no significant differences in the concentrations of other eicosanoids
      between groups, although there was a negative correlation between the percentage
      sputum eosinophil count and sputum PGE(2) concentration (r = -0.48; p < 0.01) in
      subjects with asthma. We conclude that induced sputum contains high
      concentrations of eicosanoids and that sputum LTC(4)/D(4)/E(4) concentrations are
      significantly greater in subjects with asthma than in normal subjects. The
      inverse relationship between eosinophilic airway inflammation and sputum PGE(2)
      concentration would be consistent, with the latter having an anti-inflammatory
      role.

PMID- 10588605
TI  - Changes in collagen turnover in early acute respiratory distress syndrome.
AB  - Pulmonary fibrosis is a well-recognized feature of acute respiratory distress
      syndrome (ARDS). Using immunoassays of bronchoalveolar lavage (BAL), fluid we
      investigated the synthesis of type I procollagen (PICP) and type I/II collagen
      degradation products (COL2-3/4C(short) neoepitope) in patients with ARDS, acute
      lung injury (ALI), subjects with risk factors for ARDS (At Risk), and
      healthy/ventilated control subjects. PICP was measured by ELISA as a marker of
      type I procollagen synthesis. COL2-3/4C(short) neoepitope was measured by an
      inhibition ELISA as a marker of collagenase degradation of type I/II collagen.
      BAL was performed initially within 48 h of ventilation (Day 1) and then
      subsequently on Day 4. Dilution of epithelial lining fluid (ELF) was corrected
      for by plasma urea comparison. Increased PICP levels were observed in the ELF
      from ARDS and ALI subjects on Day 1 compared with subjects At Risk (median
      values, 124.9 and 95.0 ng/ml versus 38.0 ng/ml, respectively, p < 0.0005). By
      contrast, the levels of COL2-3/4C(short) neoepitope were significantly reduced in
      the subjects with ARDS versus the At Risk subjects (13.22 ng/ml versus 32.33
      ng/ml, p < 0.0005). This translated into a greatly increased PICP:COL2
      3/4C(short) ratio in the subjects with ARDS (p < 0.0001). There was a significant
      decline in the PICP level in the subjects with ARDS between Days 1 and 4 (n = 15,
      p < 0.05). Linear regression analysis showed a significant association between
      PICP and lung injury score in the subjects with ARDS (p = 0.01). Our data
      suggests an early shift in balance between type I collagen synthesis and
      degradation by collagenase. The resultant increase in type I collagen would favor
      matrix deposition and the development of pulmonary fibrosis in the lungs of
      subjects with ARDS.

PMID- 10588606
TI  - Does inhaled albuterol improve diaphragmatic contractility in patients with
      chronic obstructive pulmonary disease?
AB  - We tested the hypothesis that the decrease in dyspnea in patients with COPD with
      inhaled albuterol is in part due to increased diaphragmatic contractility. Eleven
      patients with COPD inhaled albuterol or placebo in a double-blind randomized
      manner. Subsequently, dyspnea was measured while patients breathed through
      inspiratory resistors, and diaphragmatic contractility was quantified during
      maximal inspiratory efforts and after twitch stimulation of the phrenic nerves.
      Albuterol produced a decrease in dyspnea (5 +/- 2 to 4 +/- 2 [SD] Borg units, p <
      0.01), and increases in maximal transdiaphragmatic pressure (92.4 +/- 37.2 to
      102.8 +/- 37.2 cm H(2)O, p < 0.03) and potentiated twitch transdiaphragmatic
      pressures (21.6 +/- 7.1 to 25.2 +/- 7.6 cm H(2)O, p < 0.02). The decrease in
      dyspnea correlated with the increases in maximal and twitch transdiaphragmatic
      pressures: r = -0.64 (p = 0. 04) and r = -0.65 (p = 0.04), respectively. Compared
      with placebo, albuterol produced an increase in inspiratory capacity (1.87 +/- 0.
      71 to 2.26 +/- 0.74 L, p = 0.002), which accounted for the increases in maximal
      and twitch transdiaphragmatic pressures. The decrease in dyspnea correlated with
      the increase in inspiratory capacity (r = -0. 62, p = 0.04), but not with the
      increase in FEV(1) (r = -0.13, p = 0. 72). In conclusion, albuterol relieves
      dyspnea and enhances respiratory muscle output in patients with COPD primarily by
      improving the length-tension relationship of the diaphragm rather than by
      improving its contractility.

PMID- 10588607
TI  - Partial liquid ventilation with and without inhaled nitric oxide in a newborn
      piglet model of meconium aspiration.
AB  - The object of this study was to determine the effects of partial liquid
      ventilation (PLV) with and without inhaled nitric oxide (NO) over a 4-h period on
      lung mechanics, gas exchange, and hemodynamics in an animal model of meconium
      aspiration syndrome (MAS). Twenty-four fentanyl-anesthetized piglets were
      instrumented and administered a slurry of human meconium to create a model with
      hypoxia, hypercarbia, acidosis, and pulmonary hypertension. They were then
      randomly assigned to conventional ventilation, conventional ventilation plus
      inhaled NO at 40 ppm, PLV using perfluorodecalin, or PLV plus inhaled NO. The
      perfluorocarbon was added until a meniscus was visible in the endotracheal tube
      during expiration. Hemodynamics, lung mechanics, and gas exchange were monitored
      for 4 h, and then the animals were killed. The conventionally ventilated animals
      continued to deteriorate, and three of the six died prior to 4 h. All the animals
      in the remaining groups survived. Oxygenation improved significantly immediately
      with the start of inhaled NO (from 43.8 SD 10.3 to 62.6 SD 11.7 mm Hg after 30
      min) and stayed elevated compared with the control group for the remainder of the
      study (62.4 SD 21.8 mm Hg at 4 h compared with 44.9 SD 1.6 mm Hg for the control
      group, p < 0.05). Oxygenation improved more slowly in the PLV alone group, being
      slightly less than control at 30 min (p = NS) but increasing to 104 SD 34.9 after
      4 h (p < 0.01 compared with the control group), at which time it was also greater
      than inhaled NO alone (p < 0.05). The combined group had an acute increase in
      oxygenation indistinguishable from the NO alone group and maintained this until
      the end of the study. Lung compliance was unaffected in the inhaled NO group. In
      both the liquid ventilation groups the lung compliance improved with the
      instillation of perfluorodecalin (from 0.46 SD 0.18 to 0.62 SD 0.09 ml/cm
      H(2)O/kg in the PLV alone group at 1 h, p < 0.05 compared with the control group)
      and remained stable for the remainder of the study. Cardiac output and pulmonary
      vascular resistance were not significantly affected by any of the treatments. It
      was concluded that in this animal model of MAS, inhaled NO led to an acute
      improvement in gas exchange and prolonged survival compared with conventional
      therapy. PLV improved lung mechanics, which was maintained over the course of the
      study. The combination of PLV and inhaled NO produced both effects, acutely
      improving both gas exchange and lung mechanics. Combined therapy with PLV and
      inhaled NO may have benefits in the MAS.

PMID- 10588608
TI  - Familial aggregation of pulmonary function in a rural Chinese community.
AB  - We investigated familial aggregation of pulmonary function among asthma index
      families and randomly selected nuclear families in a rural community in China.
      Measurements of pulmonary function and related risk factors were obtained from
      each family member. A generalized estimation equation model was used to explore
      the independent relation of pulmonary function among family members, with
      adjustment for sex, age, height, weight, education, smoking, and asthma status.
      There was a significant parent-child and sib-sib correlation of pulmonary
      function. The parent-child correlation of pulmonary function was similar for the
      first and second children. The correlation was greatest between sib-sibs,
      followed by mother-child, and less pronounced between father-child among asthma
      families. The rate of reduced pulmonary function in a subsequent sibling was
      lowest (4.0%) when both of the parents and the first sibling were in the high
      pulmonary-function tertile (high-high group) and was highest (18.4%) when both
      the parents and the first sibling were in the low-pulmonary-function tertile (low
      low group). The rates were intermediate if only the parents (7.0%, low-high
      group) or only the first sibling (11.5%, high-low group) was in the reduced
      pulmonary-function tertile. Our data indicate a strong familial aggregation of
      pulmonary function in both asthma and random families in this population.

PMID- 10588609
TI  - Induction of inflammatory mediators in human airway epithelial cells by lipid
      ozonation products.
AB  - We have proposed that exposure of epithelial cell membrane lipids in the lung
      (mainly phospholipids) to ozone will generate lipid ozonation products (LOP),
      which could be responsible for the proinflammatory effects of ozone. The
      ozonation of phosphocholine, the principal membrane phospholipid, produces a
      limited number of LOP, including hydroxyhydroperoxides and aldehydes. We now
      report that exposure of cultured human bronchial epithelial cells to the ozonized
      1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) product, 1-palmitoyl-2-(9
      oxononanoyl)-sn-glycero-3-phosphocholine (PC-ALD), a phospholipase A(2) (PLA(2))
      stimulatory LOP, resulted in a 113 +/- 11% increase in the amounts of tritiated
      platelet-activating factor ((3)H-PAF) released apically. (3)H-PAF release was
      also induced by 1-hydroxy-1-hydroperoxynonane of ozonized POPC (HHP-C9), a
      phospholipase C (PLC)- stimulatory LOP (134 +/- 40% increase in (3)H-PAF). PC-ALD
      at 10 microM, but not HHP-C9, induced a 127 +/- 24% increase in prostaglandin
      E(2) (PGE(2)) release (n = 6, p < 0.05). In contrast, HHP-C9, but not PC-ALD,
      induced interleukin (IL)-6 release (178 +/- 23% increase, n = 6, p < 0.05) and IL
      8 release (101 +/- 23% increase, n = 8, p < 0. 05). These results suggest that
      LOP-dependent release of proinflammatory mediators may play an important role in
      the early inflammatory response seen during exposure to ozone.

PMID- 10588610
TI  - Nitric oxide and proinflammatory cytokines in nasal lavage fluid associated with
      symptoms and exposure to moldy building microbes.
AB  - Epidemiological data indicate that living or working in a moldy building is
      associated with increased risk of respiratory symptoms and disease related to
      inflammatory reactions, but biochemical evidence linking cause and effect is
      still scarce. The staff working in a mold-contaminated school, and a reference
      group without such exposure, were studied. Nasal lavage was performed and health
      data were collected with a questionnaire at the end of the spring term, after a
      2.5-mo summer vacation, and at the end of the fall term. Here we show that
      concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6),
      and nitric oxide (NO) in nasal lavage fluid were significantly higher in the
      exposed than in the control subjects at the end of the first exposure period.
      These inflammatory mediators decreased to reference group concentrations during
      the period when there was no exposure and the production of NO and IL-6 increased
      again during the reexposure in the fall term. Reports of cough, phlegm, rhinitis,
      eye irritation, and fatigue paralleled the changes in the measured inflammatory
      markers. These results point to an association between inflammatory markers in
      the nasal lavage fluid, the high prevalence of respiratory symptoms among the
      occupants, and chronic exposure to molds in the indoor environment.

PMID- 10588611
TI  - Allergen-induced synthesis of F(2)-isoprostanes in atopic asthmatics. Evidence
      for oxidant stress.
AB  - It is thought that reactive oxygen species (ROS) participate in the inflammation
      which characterizes asthma, but the evidence supporting this contention is
      incomplete. F(2)-isoprostanes (F(2)-IsoPs) are arachidonate products formed on
      membrane phospholipids by the action of ROS and thereby represent a quantitative
      measure of oxidant stress in vivo. Using a mass spectrometric assay we measured
      urinary release of F(2)-IsoPs in 11 patients with mild atopic asthma after
      inhaled allergen challenge. The excretion of F(2)-IsoPs increased at 2 h after
      allergen (1.5 +/- 0.2 versus 2.6 +/- 0.3 ng/mg creatinine) and remained
      significantly elevated in all urine collections for the 8-h period of the study
      (analysis of variance [ANOVA]). The measured compounds were of noncyclooxygenase
      origin because neither aspirin nor indomethacin given before challenge suppressed
      them. Urinary F(2)-IsoPs remained unchanged after inhaled methacholine challenge.
      In nine atopic asthmatics, F(2)-IsoPs were quantified in bronchoalveolar lavage
      fluid (BALF) at baseline values and in a separate segment 24 h after allergen
      instillation. F(2)-IsoPs were elevated late in the BALF (0.9 +/- 0.2 versus 11.4
      +/- 3.0 pg /ml, baseline versus allergen, respectively, p = 0.007). The increase
      was inhibited by pretreatment of the subjects with inhaled corticosteroids. These
      findings provide a new evidence for a role for ROS and lipid peroxidation in
      allergen-induced airway inflammation.

PMID- 10588612
TI  - Eotaxin and impaired lung function in asthma.
AB  - We performed an association study of plasma eotaxin levels, eosinophil counts,
      total IgE levels, asthma diagnosis, and lung function in an ethnically diverse
      and geographically dispersed population. We studied 515 asthmatic and 519 normal
      subjects, none of whom was taking inhaled or oral corticosteroids. Logistic
      regression analysis demonstrated a direct relationship between asthma diagnosis
      and eotaxin levels (p < 0.0001). The odds of an asthma diagnosis increased with
      eotaxin quartile, with the highest quartile having an odds ratio of 5.4 (95% CI
      3.2 to 9.2, p < 0.001) compared with the lowest eotaxin quartile. Eotaxin levels
      were inversely related to lung function (p < 0.001), with the mean percent
      predicted FEV(1) in the highest eotaxin quartile being 13.5 percentage points
      (SEM 2.1, p < 0.001) less than that in the lowest quartile. Plasma eotaxin levels
      were associated with asthma and inversely related to lung function independent of
      age, race, sex, or smoking status. When combined with eosinophil counts and IgE
      levels, eotaxin levels contributed to the odds of an asthma diagnosis and of
      impaired lung function. Our results are the first to associate eotaxin levels
      with asthma diagnosis and compromised lung function in a large geographically and
      ethnically diverse population.

PMID- 10588613
TI  - Outcomes of critically ill cancer patients in a university hospital setting.
AB  - Critically ill cancer patients constitute a large percentage of admissions to
      tertiary care medical intensive care units (ICUs). We sought to describe outcomes
      of such patients, and to evaluate how conditions commonly seen in these patients
      impact mortality. A total of 348 consecutive medical ICU cancer patients were
      evaluated. Subgroup comparisons included the three most common cancer types
      (leukemia, lymphoma, lung cancer), as well as three different
      treatments/conditions (bone marrow transplant [BMT] versus non-BMT, mechanical
      ventilation [MV] versus non-MV, neutropenic versus non-neutropenic). There were
      no mortality differences between patients with leukemia, lymphoma, or lung
      cancer. By logistic regression, mortality predictors were: MV, hepatic failure,
      and cardiovascular failure for the group as a whole (41% overall mortality); MV
      and allogeneic (as compared with autologous) BMT for the BMT group (39% overall
      mortality); hepatic failure, cardiovascular failure, and persistent acute
      respiratory distress syndrome (ARDS) for the MV group (67% overall mortality);
      and MV for the neutropenic group (53% overall mortality). Neutropenia showed no
      independent association with mortality in the group as a whole or any subgroup
      analyzed. We conclude that respiratory, hepatic, and cardiovascular failure
      predict mortality, whereas neutropenia does not. Additionally, we have noted an
      encouraging improvement in survival in many groups of critically ill cancer
      patients.

PMID- 10588614
TI  - Categorizing asthma severity.
AB  - The National Asthma Education and Prevention Program (NAEPP) Expert Panel II
      recommended a stepped care pharmacotherapy approach to asthma treatment based on
      an objective assessment of asthma severity using daytime symptoms, nocturnal
      symptoms, and physiologic lung function. The worst grade of the individual
      variables determines overall asthma severity. With this approach, patterns of
      asthma severity categorization might vary among individual variables; one
      variable might have a predominant effect on overall categorization. During the
      run-in, pretreatment phase of five controlled clinical trials, data from 744
      inhaled steroid nonusers and 685 inhaled steroid users on asthma control were
      collected and asthma severity categorized. In inhaled steroid nonusers nocturnal
      symptoms classified the majority of patients as severe, persistent, but wheeze
      classified 27.3% of patients as mild, intermittent and 25.7% as mild, persistent.
      If the worst grade from the four asthma symptoms was used for severity grading,
      most patients were categorized as severe, persistent. beta-Agonist use and FEV(1)
      classified most as moderate, persistent. There was poor correlation between
      variables in severity categorization. Severity grading for European patients was
      similar to that for U.S. patients. Applying the Expert Panel II recommended
      method for asthma severity categorization to a large data set illustrates that a
      single variable, nocturnal symptoms, determined to a large extent overall
      categorization. Development of a validated method for asthma severity
      categorization is essential for using a stepped care approach to asthma
      pharmacotherapy.

PMID- 10588615
TI  - Evidence for excessive bronchial inflammation during an acute exacerbation of
      chronic obstructive pulmonary disease in patients with alpha(1)-antitrypsin
      deficiency (PiZ).
AB  - Patients with homozygous (PiZ) alpha(1)-antitrypsin (AAT) deficiency have not
      only low baseline serum AAT levels (approximately 10 to 15% normal) but also an
      attenuated acute phase response. They are susceptible to the development of
      premature emphysema but may also be particularly susceptible to lung damage
      during bacterial exacerbations when there will be a significant neutrophil
      influx. The purposes of the present study were to assess the inflammatory nature
      of acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD)
      in subjects with AAT deficiency, to compare this with COPD patients without
      deficiency, and to monitor the inflammatory process and its resolution following
      appropriate antibacterial therapy. At the start of the exacerbation, patients
      with AAT deficiency had lower sputum AAT (p < 0.001) and secretory leukoprotease
      inhibitor (SLPI; p = 0.02) with higher elastase activity (p = 0.02) compared with
      COPD patients without deficiency. Both groups had a comparable acute phase
      response as assessed by C-reactive protein (CRP) but the AAT-deficient patients
      had a minimal rise in serum AAT (to < 6 microM). After treatment with
      antibiotics, in patients with AAT deficiency, there were significant changes in
      many sputum proteins including a rise in SLPI levels, and a reduction in
      myeloperoxidase (MPO) and elastase activity (p < 0. 005 for all measures); the
      sputum chemoattractants interleukin-8 (IL-8) and leukotriene B(4) (LTB(4)) fell
      (p < 0.01), and protein leak (sputum/serum albumin ratio) became lower (p <
      0.01). The changes were rapid and within 3 d of the commencement of antibiotic
      therapy the biochemical markers had decreased significantly, but took a variable
      time thereafter to return to baseline values. In conclusion, patients with AAT
      deficiency had evidence of increased elastase activity at the start of the
      exacerbation when compared with nondeficient COPD patients which probably
      reflects a deficient antiproteinase screen (lower sputum AAT and SLPI). The
      increased bronchial inflammation at presentation resolved rapidly with 14 d of
      antibiotic therapy.

PMID- 10588616
TI  - Response of human tongue protrudor and retractors to hypoxia and hypercapnia.
AB  - It is well established that the genioglossus muscle (tongue protrudor) has a role
      in protecting or enhancing upper airway patency in individuals with obstructive
      sleep apnea. However, no investigation completed to date has addressed the role
      of the styloglossus and hyoglossus muscles (tongue retractors) in maintaining
      upper airway patency in humans. As a first step toward this goal, the present
      investigation was designed to examine the response of human tongue protrudor and
      retractor muscles during a breathhold maneuver and in steady-state hypoxic
      hypercapnia. The results showed that the protrudor and retractor muscles were
      coactivated under both conditions. Measurements of onset time of
      electromyographic activity during steady-state hypoxic hypercapnia revealed that
      phasic protrudor and retractor activity was initiated immediately before or
      during the early part of inspiration. We conclude that the tongue protrudor and
      retractor muscles are coactivated in response to hypoxia and hypercapnia, and
      that the tongue retractors may have a significant role in protecting upper airway
      patency during both apnea and hyperpnea.

PMID- 10588617
TI  - Effects of dobutamine on gastric mucosal perfusion and hepatic metabolism in
      patients with septic shock.
AB  - We prospectively evaluated the effects of dobutamine on gastric mucosal perfusion
      and hepatocytic clearance in patients with septic shock. After resuscitation with
      volume expansion and norepinephrine (12 patients) as needed, 14 hemodynamically
      stable patients (median age: 60 yr, median SAPS II score: 47) were given an
      infusion of 7.5 microg/kg/min dobutamine for 1 h. Gastric mucosal perfusion and
      hepatocytic clearance were assessed with tonometry and indocyanine green (ICG)
      elimination, respectively. All measurements were made before dobutamine infusion,
      after 1 h of dobutamine infusion, and 1 h after the infusion ended. Cardiac
      output (thermodilution technique) increased with dobutamine from a baseline
      median level of 4.0 L/min/m(2) (range: 1.7 to 7.4 L/min/m(2)) to 5.0 L/min/m(2)
      (range: 3.5 to 8.9 L/min/m(2)) (p = 0.004) and returned to baseline levels after
      dobutamine infusion ended. The gastric-arterial PCO(2) difference decreased from
      a baseline median level of 13 mm Hg (range: 5 to 54 mm Hg) to 7 mm Hg (range: 5
      to 48 mm Hg) (p = 0.005). ICG elimination was low in all patients at baseline
      (median plasma disappearance rate: 12.2%; range: 7.6 to 16.2%) and did not change
      significantly during or after dobutamine infusion. In summary, dobutamine
      increases gastric mucosal perfusion but does not alter hepatocytic clearance in
      patients with septic shock. The absence of a beneficial effect of dobutamine on
      hepatocytic clearance may be related to profound alterations in hepatocellular
      metabolism during septic shock.

PMID- 10588618
TI  - Hemodynamic response to norepinephrine with and without inhibition of nitric
      oxide synthase in porcine endotoxemia.
AB  - The objective of this study was to determine the circuit and cardiac effects of
      norepinephrine (NE) with and without endotoxin, and how these responses are
      modified by the inhibition of nitric oxide synthase (NOS). We anesthetized eight
      pigs and instrumented them for measurements of cardiac output (Q), arterial
      pressure (Part), and mean pulmonary arterial pressure (Ppa). We also placed a 40
      ml balloon in the right atrium for transient obstruction of flow and measurement
      of the mean circulatory filling pressure (MCFP) and resistance to venous return
      (RVR). After baseline measurements, animals were treated with 10 microg/kg/h of
      Escherichia coli endotoxin. At 105 min the measurements were repeated. We then
      infused 12.5 mg/kg of N(G)-nitro-L-arginine methyl ester (L-NAME) for 10 min and
      repeated the measurements. At baseline, at the end of endotoxin infusion, and
      after L-NAME infusion we infused 3, 9, and 27 microg/min of NE for 10 min each,
      and recorded hemodynamic measurements at each dose. NE shifted the venous return
      curve (i.e., increased MCFP) to the right without changing RVR, and increased
      cardiac output (CO) both at baseline and after endotoxin. Endotoxemia markedly
      flattened the dose-response curves for the change in Part, Ppa, CO, and heart
      rate with NE. The peak response of Part to NE after endotoxemia was restored with
      L-NAME, but the other dose-response curves were not affected. NE also did not
      shift the venous return curve after L-NAME. Furthermore, the increase in Part
      with NE was of shorter duration after L-NAME than in the baseline condition. In
      conclusion, NE shifts the venous return curve to the right and improves CO in
      endotoxic and nonendotoxic conditions. Endotoxemia decreases the arterial
      responsiveness to NE. L-NAME partly restored this loss of responsiveness in
      arteries but not in the venous circulation.

PMID- 10588619
TI  - Cerebral bioenergetics in stable chronic obstructive pulmonary disease.
AB  - Cerebral intracellular energy production (cerebral bioenergetics) via oxidative
      phosphorylation and the production of adenosine triphosphate (ATP) is critical to
      cerebral function. To test the hypothesis that patients with chronic stable
      hypoxia also generate neuronal ATP via an anaerobic metabolism, we studied the
      changes in cerebral (31)P magnetic resonance spectra ((31)P MRS) in patients with
      stable chronic obstructive pulmonary disease (COPD), and compared the results
      with MR spectra from similar areas of the brain in control subjects. Ten patients
      with stable COPD (age: 65 +/- 9 yr [mean +/- SD]; Pa(O(2)): 8.8 +/- 1.2 kPa;
      Pa(CO(2)): 6.1 +/- 0.8 kPa; pH 7.42 +/- 0.03, and FEV(1): 41 +/- 20% predicted)
      and five healthy volunteers underwent cerebral (31)P MRS (TR-5,000 ms) at 1.5 T.
      When COPD patients were compared with controls, the percentage MR signal with
      respect to total MR-detectable phosphorus-containing metabolites was increased
      from inorganic phosphate (Pi) (7.1 +/- 1. 3% versus 3.9 +/- 0.7%, p = 0.0001) and
      phosphomonoesters (PMEs) (9. 4 +/- 1.2% versus 6.9 +/- 0.3%, p = 0.0001), whereas
      the signal from phosphodiesters was reduced (34.8 +/- 3.2 versus 40.4 +/- 3.3%, p
      = 0.015). The ratios of Pi to betaATP (0.8 +/- 0.2 versus 0.4 +/- 0.1, p = 0.001)
      and of PME to betaATP (1.0 +/- 0.2 versus 0.7 +/- 0.1, p = 0.015) were increased,
      but the phosphocreatine-to-Pi ratio (2.1 +/- 0.6 versus 3.2 +/- 0.6, p = 0.01)
      was reduced in patients as compared with controls. This alteration in phosphorus
      containing metabolites within cerebral cells provides evidence of extensive use
      of anaerobic metabolism in hypoxic COPD patients.

PMID- 10588620
TI  - How does patient education and self-management among asthmatics and patients with
      chronic obstructive pulmonary disease affect medication?
AB  - The effect of patient education on steroid inhaler compliance and rescue
      medication utilization in patients with asthma or chronic obstructive pulmonary
      disease (COPD) has not been previously investigated in a single study. We
      randomized 78 asthmatics and 62 patients with COPD after ordinary outpatient
      management. Intervention consisted of two 2-h group sessions and 1 to 2
      individual sessions by a trained nurse and physiotherapist. A self-management
      plan was developed. We registered for 12 mo medication dispensed from pharmacies
      according to the Anatomical Therapeutic Chemical (ATC) classification index.
      Steroid inhaler compliance (SIC) was defined as (dispensed/prescribed) x 100 and
      being compliant as SIC > 75%. Among asthmatics 32% and 57% were compliant (p =
      0.04) with a median (25th/75th percentiles) SIC of 55% (27/96) and 82% (44/127)
      (p = 0.08) in the control and intervention groups, respectively. Patient
      education did not seem to change SIC in the COPD group. Uneducated patients with
      COPD were dispensed double the amount of short-acting inhaled beta(2)-agonists
      compared with the educated group (p = 0.03). We conclude that patient education
      can change medication habits by reducing the amount of short-acting inhaled
      beta(2)-agonists being dispensed among patients with COPD. Educated asthmatics
      showed improved steroid inhaler compliance compared with the uneducated patients,
      whereas this seemed unaffected by education in the COPD group.

PMID- 10588621
TI  - Assessment of reliability of lung function screening programs or longitudinal
      studies.
AB  - The aim was to determine reliability of lung function measurements performed
      according to recommendations of the American Thoracic Society (ATS) at a
      screening program in a large South African gold mine and to determine the
      usefulness of the reliability coefficient G for monitoring the reliability of
      lung function measurements in a mass screening program. The reliability
      coefficient G estimates the amount of random error of measurement, relative to
      the total variation in a measurement. The coefficient G was calculated as a
      correlation coefficient between two consecutive lung function tests performed
      within 6 mo, over a period of 43 mo on 3,378 miners. There was significant
      temporal variability in the reliability. For FEV(1), the coefficient G showed
      increased variability over the first 5 mo and stabilized at a value of 0.93 for
      the next 23 mo, after which it systematically declined over the next 15 mo. We
      estimated that in a large screening program, an optimal sample size of around 900
      miners, examined randomly throughout the year, on a yearly basis, would provide a
      sufficient sample to examine monthly or quarterly fluctuation in the reliability.
      The value of the reliability coefficient G did not change when the time between
      two consecutive tests increased up to 15 mo. In conclusion, monitoring of lung
      function reliability in a screening program by the reliability coefficient G
      should improve data quality, and provide a measure on which the confidence in a
      decision-making process could be based when examining temporal changes in lung
      function for individual subjects.

PMID- 10588622
TI  - Use of miniradiographs to detect silicosis. Comparison of radiological with
      autopsy findings.
AB  - Radiological and routine autopsy findings from 241 South African gold miners were
      compared, using pathology as the "gold standard." Previous annual screening
      miniradiographs were read independently by two readers, using the International
      Labor Office (ILO) grading system, without reference to personal identifiers.
      Individual and consensus silicosis grades were recorded for each subject. When
      pathological and radiological silicosis were defined as any abnormal grade, the
      sensitivity and specificity of the radiological diagnosis was 67.5% and 80%, with
      positive and negative predictive values of 63% and 83%. Most undetected autopsy
      silicosis was early-grade. Using higher pathological and radiological grades to
      define silicosis (5 nodules or more and ILO grades 1/1 and above), sensitivity
      and specificity increased to 71% and 96%, and positive and negative predictive
      values increased to 76% and 95%, respectively. Use of a consensus grade made
      little difference to results from individual readers. For each radiological
      definition, sensitivity was considerably higher than, but specificity was similar
      to, that found in a previous study of South African gold miners which used the
      same pathology source and standard sized films. The difference between these two
      study findings, and unexpected demonstration of higher sensitivity from
      miniradiographs, suggests that further research is required into factors
      affecting radiological interpretation before silicosis grading can be considered
      to be adequately standardized.

PMID- 10588623
TI  - Prospective randomized trial comparing bilateral lung volume reduction surgery to
      pulmonary rehabilitation in severe chronic obstructive pulmonary disease.
AB  - Several uncontrolled studies report improvement in lung function, gas exchange,
      and exercise capacity after bilateral lung volume reduction surgery (LVRS). We
      recruited 200 patients with severe chronic obstructive pulmonary disease (COPD)
      for a prospective randomized trial of pulmonary rehabilitation versus bilateral
      LVRS with stapling resection of 20 to 40% of each lung. Pulmonary function tests,
      gas exchange, 6-min walk distance, and symptom-limited maximal exercise testing
      were done in all patients at baseline and after 8 wk of rehabilitation. Patients
      were then randomized to either 3 additional months of rehabilitation or LVRS.
      Thirty-seven patients met study criteria and were enrolled into the trial.
      Eighteen patients were in the medical arm; 15 of 18 patients completed 3 mo of
      additional pulmonary rehabilitation. Thirty-two patients underwent LVRS (19 in
      the surgical arm, 13 crossover from the medical arm). After 8 wk of pulmonary
      rehabilitation, pulmonary function tests remained unchanged compared with
      baseline data. However, there was a trend toward a higher 6-min walk distance
      (285 +/- 96 versus 269 +/- 91 m, p = 0.14) and total exercise time on maximal
      exercise test was significantly longer compared with baseline values (7.4 +/- 2.1
      versus 5.8 +/- 1.7 min, p < 0.001). In 15 patients who completed 3 mo of
      additional rehabilitation, there was a trend to a higher maximal oxygen
      consumption (V O(2)max) (13.3 +/- 3.0 versus 12.6 +/- 3.3, p < 0.08). In
      contrast, at 3 mo post-LVRS, FVC (2.79 +/- 0.59 versus 2.36 +/- 0.55 L, p <
      0.001) and FEV(1) (0.85 +/- 0.3 versus 0.65 +/- 0.16 L, p < 0.005) increased
      whereas TLC (6.53 +/- 1.3 versus 7.65 +/- 2.1 L, p < 0.001) and residual volume
      (RV) (3.7 +/- 1.2 versus 4.9 +/- 1.1 L, p < 0.001) decreased when compared with 8
      wk postrehabilitation data. In addition, Pa(CO(2)) decreased significantly 3 mo
      post-LVRS compared with 8 wk postrehabilitation. Six-minute walk distance (6MWD),
      total exercise time, and V O(2)max were higher after LVRS but did not reach
      statistical significance. However, when 13 patients who crossed over from the
      medical to the surgical arm were included in the analysis, the increases in 6MWD
      (337 +/- 99 versus 282 +/- 100 m, p < 0.001) and V O(2)max (13.8 +/- 4 versus
      12.0 +/- 3 ml/kg/min, p < 0.01) 3 mo post-LVRS were highly significant when
      compared with postrehabilitation data. The Sickness Impact Profile (SIP), a
      generalized measure of quality of life (QOL), was significantly improved after 8
      wk of rehabilitation and was maintained after 3 mo of additional rehabilitation.
      A further improvement in QOL was observed 3 mo after LVRS compared with the
      initial improvement gained after 8 wk of rehabilitation. There were 3 (9.4%)
      postoperative deaths, and one patient died before surgery (2.7%). We conclude
      that bilateral LVRS, in addition to pulmonary rehabilitation, improves static
      lung function, gas exchange, and QOL compared with pulmonary rehabilitation
      alone. Further studies need to evaluate the risks, benefits, and durability of
      LVRS over time.

PMID- 10588624
TI  - Asthma-related work disability in Sweden. The impact of workplace exposures.
AB  - Work disability due to respiratory disease, especially asthma, is common and
      costly among working age adults. The goal of this analysis was to characterize
      the risk factors for such disability. We analyzed data from the Swedish part of
      the European Community Respiratory Health Survey (ECRHS), a random population
      based sample of adults age 20 to 44, enriched with symptomatic subjects at
      increased likelihood of having asthma. We analyzed structured interview data
      available for 2,065 subjects and further analyzed methacholine challenge and skin
      prick test data for 1,562 of these. We defined respiratory work disability as
      reported job change or work loss due to breathing affected by a job. We used
      binary generalized linear modeling with a log link to estimate disability risk.
      Eighty-four subjects (4%) reported such work disability. This increased to 13%
      among those with asthma (45 of 350 subjects). Adjusting for covariates,
      occupations at high risk for asthma were associated with disability (prevalence
      ratio [PR] 1.8; 95% confidence interval [CI] 1.1 to 3.0), as was self-reported
      regular exposure to environmental tobacco smoke (ETS) at work (PR 1.8; 95% CI 1.1
      to 3.1) and self- reported job exposure to vapors, gases, dust, or fumes (VGDF)
      (PR 4.3; 95% CI 2.2 to 8.6). Workplace ETS exposure was also associated with
      methacholine challenge-positive asthma reported to be symptomatic at work among
      male subjects (PR 4. 2; 95% CI 1.8 to 9.8), whereas high asthma-risk occupations
      were associated with this outcome among female subjects (PR 2.7; 95% CI 1. 05 to
      7.1). Respiratory work disability, defined as breathing-related job change due to
      work loss, was associated with workplace exposures themselves, even after taking
      into account other covariates. Better control of workplace exposures, including
      workplace ETS, may reduce work disability caused by respiratory conditions,
      especially adult asthma.

PMID- 10588625
TI  - Bronchial hyperreactivity after lung transplantation predicts early bronchiolitis
      obliterans.
AB  - Nonspecific bronchial hyperreactivity (NSBHR) has been observed in patients who
      have undergone lung transplantation, but studies have provided conflicting
      reports as to the incidence and significance of this finding. To delineate more
      clearly the natural history of NSBHR after lung transplantation, data from 111
      consecutive patients undergoing double lung transplantation between February 1988
      and May 1994 were reviewed. Methacholine challenge testing was requested in
      conjunction with regular postoperative follow-up. Among 60 patients tested at 3
      mo, 18 (30%) had a positive methacholine challenge; at 6 mo, the incidence was 14
      of 59 (24%). Of 21 patients for whom complete testing was performed for 12 mo or
      longer, 13 (62%) had exclusively negative challenges. Patients with a positive
      challenge at 3 mo were significantly more likely to develop bronchiolitis
      obliterans syndrome (BOS) (p < 0.006). Mean time to development of BOS was 16.9
      mo in the group with positive challenges versus 43.9 mo for those with negative
      challenges. We conclude that increased NSBHR is a common, but by no means
      universal, finding after lung transplantation. Furthermore, early positive
      methacholine challenges are associated with development of BOS. We hypothesize
      that NSBHR may represent an early marker of chronic rejection in these patients.

PMID- 10588626
TI  - IL-10 attenuates excessive inflammation in chronic Pseudomonas infection in mice.
AB  - Cystic fibrosis (CF) lung disease is characterized by an excessive inflammatory
      response associated with chronic Pseudomonas aeruginosa endobronchial infection.
      Compared with bronchoalveolar lavage fluid from healthy subjects, lavage fluid
      from patients with CF contains elevated proinflammatory cytokines but negligible
      amounts of the anti-inflammatory cytokine interleukin-10 (IL-10). We sought to
      determine whether IL-10 deficiency results in increased local and systemic
      morbidity in mice with chronic endobronchial infection with P. aeruginosa
      embedded in agar beads and to determine if exogenous IL-10 might reduce these
      effects. Infected IL-10 knockout mice had more severe weight loss (p = 0.04) and
      increased area of lung inflammation (28 +/- 4 versus 10 +/- 2%, p < 0.002) but no
      alterations in bacterial burden compared with wild-type mice. Infected CD-1 mice
      treated with IL-10 had improved survival (p = 0. 035), less severe weight loss (p
      < 0.005), fewer bronchoalveolar lavage neutrophils (3 x 10(5)/ml versus 5 x
      10(6)/ml, p < 0.02), and decreased area of lung inflammation (11 +/- 2 versus 35
      +/- 7%, p < 0.01) but no alterations in bacterial burden compared with placebo
      treated mice. These data suggest that IL-10 is an important regulator of the
      inflammatory response to P. aeruginosa endobronchial infection and that further
      investigation into the use of IL-10 in CF is warranted.

PMID- 10588627
TI  - Enhanced in vivo human immunodeficiency virus-1 replication in the lungs of human
      immunodeficiency virus-infected persons with Pneumocystis carinii pneumonia.
AB  - The relationship of serum human immunodeficiency virus-1 (HIV-1) RNA levels to
      HIV-1 RNA levels in other compartments, such as the lungs, is not well
      characterized. The purpose of this study was to determine the viral burden of HIV
      1 in the lungs by comparing HIV-1 RNA in cell-free bronchoalveolar lavage fluid
      (BALF) with that in serum. Specimens were examined from 77 HIV-seropositive
      adults (CD4(+) cell counts: 0 to 700 cells/mm(3); 48% receiving prescribed
      antiretroviral agents), comprising 43 asymptomatic individuals who were compared
      with 34 persons with active lung disease caused by Pneumocystis carinii (n = 26),
      bacteria (n = 3), Mycobacterium avium complex (n = 2), Nocardia sp. (n = 1),
      Aspergillus sp. (n = 1), or pulmonary Kaposi's sarcoma (n = 1). For serum HIV-1
      RNA, the proportion of subjects with detectable levels and the mean values were
      similar for asymptomatic individuals and persons with active lung disease (85%
      versus 86%, respectively) (6.64 x 10(4) versus 1. 81 x 10(5) HIV-1 RNA copies/ml;
      p = 0.13). In contrast, HIV-1 RNA in BALF was more often detected (16% versus
      62%; p = 0.001), and mean values were higher (1.04 x 10(5) versus 3.31 x 10(6)
      HIV-1 RNA copies/ml; p = 0.032), in subjects with active lung disease than in
      asymptomatic subjects, independent of early or advanced clinical stages of HIV
      related disease. For both study groups, HIV-1 RNA levels in BALF exceeded those
      in serum in 56% of cases by up to 66-fold, and did not correlate with local
      levels of tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating
      factor, or interleukin-16. HIV-1 proviral DNA in cells from BALF was detected in
      up to 86% of subjects, more frequently in persons with advanced HIV disease (p =
      0.0496), and often involved > 10% of BALF cells, but did not correlate with HIV-1
      RNA detected in BALF. These data provide evidence for active HIV-1 replication in
      the lungs. HIV-1 replication is compartmentalized relative to serum, may be
      restricted, is independent of HIV-1 proviral DNA and clinical stage of HIV, and
      may be influenced by pulmonary disease such as P. carinii pneumonia or by other
      local or lung-specific factors. The lungs represent a large reservoir for HIV-1,
      and may present a source of persistent HIV-1 replication even during periods of
      apparent clinical latency of HIV-1 infection.

PMID- 10588628
TI  - DNA from Mycobacterium bovis bacillus Calmette-Guerin (MY-1) inhibits
      immunoglobulin E production by human lymphocytes.
AB  - A DNA fraction purified from Mycobacterium bovis bacillus Calmette-Guerin (BCG)
      and designated MY-1 induced interferon (IFN)-gamma production by human peripheral
      blood mononuclear cells (PBMC). IFN-gamma is well known as a downregulator of IgE
      production. In this study we investigated whether MY-1 regulates IgE production
      by human PBMC in vitro. MY-1 inhibited IgE production in PBMC taken from normal
      donors and stimulated with interleukin (IL)-4 plus monoclonal anti-CD40 antibody,
      without affecting production of IgA. MY-1 enhanced production of IFN-gamma and IL
      12 by PBMC. Inhibition by MY-1 of IgE production was mediated by both IFN-gamma
      and IL-12, since the MY-1-induced suppression was blocked by the addition of
      monoclonal anti-IFN-gamma antibody, monoclonal anti-IL-12 antibody or a
      monoclonal antibody (mAb) directed at the IL-12 receptor. MY-1 inhibited the
      induction of epsilon germ-line transcript by IL-4. Additionally, MY-1 inhibited
      spontaneous in vitro production of IgE by PBMC from atopic donors in the absence
      of IL-4 plus anti-CD40 mAb. These results suggest that exposure to MY-1 may be a
      novel strategy for the treatment of IgE-related allergic disease.

PMID- 10588629
TI  - Bronchoalveolar lavage fluid from asthmatic subjects is mitogenic for human
      airway smooth muscle.
AB  - Airway smooth muscle proliferation may contribute to the airway wall remodeling
      seen in asthma. In this study we tested for the presence of airway smooth muscle
      mitogenic activity in bronchoalveolar lavage (BAL) fluid obtained from 12 atopic
      asthmatics before and serially after segmental allergen challenge, and from four
      normal subjects who did not undergo allergen challenge. Mitogenic effect was
      assessed by coincubating BAL fluid with human airway smooth muscle cells, and
      measuring its effect on (3)[H]thymidine incorporation and cell number. Induction
      of ERK phosphorylation and cyclin D(1) protein abundance were also assessed.
      Compared with serum-free medium alone, BAL fluid obtained from normal subjects
      increased thymidine incorporation, cell number, ERK phosphorylation, and cyclin
      D(1) abundance. BAL fluid from asthmatic subjects prior to allergen challenge
      induced even greater increases in all measures, except for cell number, which was
      similar to that observed with normal subjects' BAL fluid. Incubation with lavage
      fluid obtained 48 h after segmental allergen challenge in atopic asthmatics
      caused yet further increases in thymidine incorporation, cell number, and cyclin
      D(1) protein abundance. Molecular sieving of prechallenge BAL fluid from three
      asthmatic subjects demonstrated that mitogenic activity was present exclusively
      in the > 10 kD fraction. These results provide the first direct demonstration
      that fluid lining the airways of asthmatics contains excess mitogenic activity
      for human airway smooth muscle, and that this activity increases further after
      allergen challenge.

PMID- 10588630
TI  - Synchronization of radiograph film exposure with the inspiratory pause. Effect on
      the appearance of bedside chest radiographs in mechanically ventilated patients.
AB  - The appearance of portable chest radiographs (CXRs) may be affected by changes in
      ventilation, particularly when patients are mechanically ventilated.
      Synchronization of the CXR with the ventilatory cycle should limit the influence
      of respiratory variation on the appearance of the CXR. This study evaluates the
      effect of synchronizing the CXR film exposure with ventilation on the appearance
      of the radiograph. Twenty-five patients who remained intubated postoperatively,
      were mechanically ventilated, and required a CXR were enrolled in this triple
      blind, randomized prospective study. Each patient received one radiograph using
      conventional techniques and another using the interface. The sequence of the two
      films was randomized, and the two films were taken on the same patient within a
      few minutes of each other. Hence, each patient served as his own control and the
      position of the patient, source-film distance, intensity (Kvp), and duration of
      the exposure (mAs) were identical for the two films. Five board-certified
      radiologists were then asked to compare paired films for clarity of lines and
      tubes, definition of the pulmonary vasculature, visibility of the mediastinum,
      definition of the diaphragm, and degree of lung inflation. Radiologists were also
      asked to choose which films they preferred. A majority of board certified
      radiologists preferred CXRs taken with the interface in 21 of 25 patients (p <
      0.0001). Furthermore, four of the five criteria evaluated were improved (p <
      0.05) on synchronized CXRs. Synchronization of the bedside CXR with the end of
      inspiration ensures that they are always obtained at maximal inflation, which
      improves the appearance of a majority of radiographs by at least one of five
      criteria.

PMID- 10588631
TI  - Cholinergic contraction is altered in nNOS knockouts. Cooperative modulation of
      neural bronchoconstriction by nNOS and COX.
AB  - Endogenous nitric oxide (NO) is a bronchodilator but its physiologic role in
      small airways is not clear. In this study, we investigated the role of endogenous
      NO in the regulation of bronchiolar tone in the small airways of wild type and NO
      synthase (NOS) isoform (eNOS and nNOS)-knockout mice. Pretreatment with the
      cyclooxygenase inhibitor indomethacin significantly enhanced electrical field
      stimulation (EFS)-induced contraction in the airways from all types of mice by
      approximately 60 to 170% (n = 8 in each case), whereas pretreatment with the NOS
      inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) did not (n = 8). Combined
      pretreatment with L-NAME and indomethacin enhanced airway contraction of wild
      type and eNOS-knockout mice to a significantly greater extent (i.e., by 140 to
      290%) than did indomethacin alone (n = 8 for each). This potentiation by L-NAME
      was not seen in nNOS knockout mice (n = 8). Neither indomethacin nor L-NAME alone
      affected carbachol (CCh) potency or maximal efficacy in the airways of wild-type
      mice, whereas the combined pretreatment slightly enhanced the maximal response
      without altering the potency of CCh (n = 6). Our results show that both NO and
      prostaglandins modulate neuronal contraction of murine small airways. NO is
      produced by nNOS, which may be located in nerves, and its overall effects are
      tonically inhibited by cyclooxygenase products.

PMID- 10588632
TI  - Reversal of human neutrophil survival by leukotriene B(4) receptor blockade and 5
      lipoxygenase and 5-lipoxygenase activating protein inhibitors.
AB  - Persistent neutrophilia is a feature of chronic obstructive pulmonary disease
      (COPD). Leukotriene synthesis inhibitors and cysteinyl leukotriene receptor
      antagonists have shown efficacy in the treatment of asthma. Antagonism of
      leukotriene (LT)B(4) receptors is being considered as a mode of treating COPD. We
      examined the capacity for inhibition of leukotriene synthesis and LTB(4) receptor
      antagonism to reduce survival of neutrophils from patients with COPD and those
      from normal subjects. The basal apoptosis level of these cells was 55.4 +/- 2.4%
      (mean +/- SEM) of total cells. Separate exposure to lipopolysaccharide (LPS),
      granulocyte-macrophage colony-stimulating factor (GM-CSF), dexamethasone (DEX),
      and LTB(4) increased neutrophil survival (p < 0. 001). The LTB(4) receptor
      antagonist SB201146 abolished LPS-induced survival in a concentration-dependent
      manner (10 pmol to 0.1 microM), with an IC(50) of 1.9 nM. Combined exposure to
      SB201146 and to the cysteinyl leukotriene antagonist SKF104353 did not have a
      greater effect on survival than did exposure to SB201146 alone. Inhibition of 5
      lipoxygenase (5-LO) with BWA4C and of 5-LO-activating protein (FLAP) with MK886
      abolished GM-CSF- and DEX-induced neutrophil survival. BWA4C and MK886 abolished
      GM-CSF- induced neotrophil survival in a concentration-dependent manner (1 nM to
      10 microM), with IC(50) values of 182.0 nM and 63.1 nM, respectively. These
      findings demonstrate reversal of LPS-, GM-CSF-, and DEX-induced neutrophil
      survival by LTB(4) receptor antagonism and inhibitors of 5-LO and FLAP. They also
      suggest a potential additional antiinflammatory mode of action of these compounds
      through reduction of cell survival.

PMID- 10588633
TI  - Cellular and connective tissue changes in alveolar septal walls in emphysema.
AB  - Emphysema is commonly defined as enlargement of airspaces distal to terminal
      bronchioles accompanied by destruction of alveolar walls, but without obvious
      fibrosis. Morphometric techniques were used to correlate changes in components of
      the alveolar septa surrounding enlarged airspaces in human emphysema with the
      mean linear intercept (Lm) of those airspaces. Alveolar and capillary surface
      density decreased with increased Lm, but the ratio of these surface densities to
      each other remained close to normal for mild to moderate increases in Lm. This
      suggests that the decreased gas exchange observed in emphysema is initiated by a
      total loss of septa and not by selective pathological changes of the
      microvasculature. Increases in septal wall thickness directly correlated with
      increases in Lm. For the mild to moderate emphysema lesions included in this
      study, an increase of 100% in Lm correlated with a 130% increase in the relative
      volume of the alveolar septal interstitium. Significant increases occurred in
      both elastin (0.14 to 0.56 microm(3)/microm(2) basement membrane [BM]) and
      collagen (0.49 to 1. 63 microm(3)/microm(2) BM). The increase in elastin and
      collagen raises the possibility of a remodeling process in the connective matrix
      in alveolar walls. Whether or not the new connective tissue represents a
      disordered, nonfunctional regional response needs to be determined.

PMID- 10588634
TI  - In stable lung transplant recipients, exhaled nitric oxide levels positively
      correlate with airway neutrophilia and bronchial epithelial iNOS.
AB  - In conditions characterized by airway inflammation, exhaled nitric oxide (eNO)
      levels are increased. Variable degrees of airway inflammation are present in
      stable lung transplant recipients (LTR), and may lead to airway remodeling and
      chronic graft dysfunction. The hypothesis tested is that in stable LTR, eNO
      concentrations would reflect the expression of inducible (iNOS) (but not
      constitutive [cNOS] nitric oxide synthase) in the bronchial epithelium as well as
      the degree of airway inflammation. We determined eNO concentrations in 20 stable
      LTR, free of infection, rejection, or obliterative bronchiolitis (OB). At routine
      bronchoscopy, we measured the differential cell count on bronchoalveolar lavage
      (BAL) and a quantitative assessment of iNOS and cNOS expression in endobronchial
      biopsies by immunohistochemistry. Mean +/- SEM eNO concentrations in stable LTR
      were not significantly different from control subjects (13 +/- 0.7 ppb versus
      14.2 +/- 0.49; p = 0.42). Percent BAL neutrophils was 11.5 +/- 3.2 which was
      significantly higher than in a group of local control subjects (1.7 +/- 0.6; p <
      0.001). The bronchial epithelium and lamina propria contained abundant iNOS but
      cNOS was present only in the lamina propria. Using regression analysis, percent
      BAL neutrophils (r(2) = 0.82; p < 0.0001) and iNOS expression in the bronchial
      epithelium (r(2) = 0.75; p < 0.0001), but not in the lamina propria (r(2) = 0.16;
      p = 0.08), were positively predictive of eNO. There was an inverse relationship
      between cNOS and eNO. We conclude that eNO concentrations although normal for the
      group, still reflect the degree of airway inflammation in stable LTR. Epithelial
      iNOS appears to be the major source of eNO and expression of cNOS may be
      downregulated with increasing iNOS expression.

PMID- 10588635
TI  - Effect of leukotriene and thromboxane antagonist on propranolol-induced
      bronchoconstriction.
AB  - beta-adrenoreceptor blockers such as propranolol provoke bronchoconstriction only
      in asthmatic patients. Although cysteinyl leukotrienes (cLTs) and thromboxane A2
      (TXA2) have been proposed to be involved in the pathophysiology of asthma, the
      role of these lipid mediators in propranolol-induced bronchoconstriction (PIB)
      has not been evaluated in asthmatics. This study was conducted to elucidate it.
      Nine patients with stable asthma, in whom a 20% or more decrease in FEV(1)
      occurred by inhalation of 20 mg/ml or less propranolol, participated in this
      study. A cLT antagonist, pranlukast (225 mg twice a day), a TXA2 antagonist,
      seratrodast (80 mg once a day), and placebo were orally given for 2 wk in a
      randomized and double-blinded manner. The provocative concentration of
      propranolol causing a 20% fall in FEV(1) (PC(20)) was determined on the last day
      of each 2-wk treatment. Pranlukast, but not seratrodast, tented to increase
      FEV(1) compared with placebo (2.14 +/- 0.29 versus 1.99 +/- 0.34 L, p = 0.0543).
      Pranlukast or seratrodast did not affect the PC(20) in comparison with placebo.
      We conclude that cLTs or TXA2 are not involved in PIB of asthmatics.

PMID- 10588636
TI  - Recommendations for standardized procedures for the on-line and off-line
      measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in
      adults and children-1999. This official statement of the American Thoracic
      Society was adopted by the ATS Board of Directors, July 1999.

PMID- 10588637
TI  - International consensus conferences in intensive care medicine: Ventilator
      associated Lung Injury in ARDS. This official conference report was cosponsored
      by the American Thoracic Society, The European Society of Intensive Care
      Medicine, and The Societe de Reanimation de Langue Francaise, and was approved by
      the ATS Board of Directors, July 1999.

PMID- 10588638
TI  - Replication factor C3 of Schizosaccharomyces pombe, a small subunit of
      replication factor C complex, plays a role in both replication and damage
      checkpoints.
AB  - We report here the isolation and functional analysis of the rfc3(+) gene of
      Schizosaccharomyces pombe, which encodes the third subunit of replication factor
      C (RFC3). Because the rfc3(+) gene was essential for growth, we isolated
      temperature-sensitive mutants. One of the mutants, rfc3-1, showed aberrant
      mitosis with fragmented or unevenly separated chromosomes at the restrictive
      temperature. In this mutant protein, arginine 216 was replaced by tryptophan.
      Pulsed-field gel electrophoresis suggested that rfc3-1 cells had defects in DNA
      replication. rfc3-1 cells were sensitive to hydroxyurea, methanesulfonate (MMS),
      and gamma and UV irradiation even at the permissive temperature, and the
      viabilities after these treatments were decreased. Using cells synchronized in
      early G2 by centrifugal elutriation, we found that the replication checkpoint
      triggered by hydroxyurea and the DNA damage checkpoint caused by MMS and gamma
      irradiation were impaired in rfc3-1 cells. Association of Rfc3 and Rad17 in vivo
      and a significant reduction of the phosphorylated form of Chk1 in rfc3-1 cells
      after treatments with MMS and gamma or UV irradiation suggested that the
      checkpoint signal emitted by Rfc3 is linked to the downstream checkpoint
      machinery via Rad17 and Chk1. From these results, we conclude that rfc3(+) is
      required not only for DNA replication but also for replication and damage
      checkpoint controls, probably functioning as a checkpoint sensor.

PMID- 10588640
TI  - Phospholipase A(2) antagonists inhibit nocodazole-induced Golgi ministack
      formation: evidence of an ER intermediate and constitutive cycling.
AB  - Evidence has been presented both for and against obligate retrograde movement of
      resident Golgi proteins through the endoplasmic reticulum (ER) during nocodazole
      induced Golgi ministack formation. Here, we studied the nocodazole-induced
      formation of ministacks using phospholipase A(2) (PLA(2)) antagonists, which have
      been shown previously to inhibit brefeldin A-stimulated Golgi-to-ER retrograde
      transport. Examination of clone 9 rat hepatocytes by immunofluorescence and
      immunoelectron microscopy revealed that a subset of PLA(2) antagonists prevented
      nocodazole-induced ministack formation by inhibiting two different trafficking
      pathways for resident Golgi enzymes; at 25 microM, retrograde Golgi-to-ER
      transport was inhibited, whereas at 5 microM, Golgi-to-ER trafficking was
      permitted, but resident Golgi enzymes accumulated in the ER. Moreover, resident
      Golgi enzymes gradually redistributed from the juxtanuclear Golgi or Golgi
      ministacks to the ER in cells treated with these PLA(2) antagonists alone. Not
      only was ER-to-Golgi transport of resident Golgi enzymes inhibited in cells
      treated with these PLA(2) antagonists, but transport of the vesicular stomatitis
      virus G protein out of the ER was also prevented. These results support a model
      of obligate retrograde recycling of Golgi resident enzymes during nocodazole
      induced ministack formation and provide additional evidence that resident Golgi
      enzymes slowly and constitutively cycle between the Golgi and ER.

PMID- 10588639
TI  - Pex17p is required for import of both peroxisome membrane and lumenal proteins
      and interacts with Pex19p and the peroxisome targeting signal-receptor docking
      complex in Pichia pastoris.
AB  - Pichia pastoris PEX17 was cloned by complementation of a peroxisome-deficient
      strain obtained from a novel screen for mutants disrupted in the localization of
      a peroxisomal membrane protein (PMP) reporter. PEX17 encodes a 267-amino-acid
      protein with low identity (18%) to the previously characterized Saccharomyces
      cerevisiae Pex17p. Like ScPex17p, PpPex17p contains a putative transmembrane
      domain near the amino terminus and two carboxyl-terminal coiled-coil regions.
      PpPex17p behaves as an integral PMP with a cytosolic carboxyl-terminal domain.
      pex17Delta mutants accumulate peroxisomal matrix proteins and certain integral
      PMPs in the cytosol, suggesting a critical role for Pex17p in their localization.
      Peroxisome remnants were observed in the pex17Delta mutant by morphological and
      biochemical means, suggesting that Pex17p is not absolutely required for remnant
      formation. Yeast two-hybrid analysis demonstrated that the carboxyl terminus of
      Pex19p was required for interaction with Pex17p lacking the carboxyl-terminal
      coiled-coil domains. Biochemical evidence confirmed the interaction between
      Pex19p and Pex17p. Additionally, Pex17p cross-linked to components of the
      peroxisome targeting signal-receptor docking complex, which unexpectedly
      contained Pex3p. Our evidence suggests the existence of distinct subcomplexes
      that contain separable pools of Pex3p, Pex19p, Pex17p, Pex14p, and the peroxisome
      targeting signal receptors. These distinct pools may serve different purposes for
      the import of matrix proteins or PMPs.

PMID- 10588641
TI  - Phosphorylation of SNAP-23 by the novel kinase SNAK regulates t-SNARE complex
      assembly.
AB  - The docking and fusion of cargo-containing vesicles with target membranes of
      eukaryotic cells is mediated by the interaction of SNARE proteins present on both
      vesicle and target membranes. In many cases, the target membrane SNARE, or t
      SNARE, exists as a complex of syntaxin with a member of the SNAP-25 family of
      palmitoylated proteins. We have identified a novel human kinase SNAK (SNARE
      kinase) that specifically phosphorylates the nonneuronal t-SNARE SNAP-23 in vivo.
      Interestingly, only SNAP-23 that is not assembled into t-SNARE complexes is
      phosphorylated by SNAK, and phosphorylated SNAP-23 resides exclusively in the
      cytosol. Coexpression with SNAK significantly enhances the stability of
      unassembled SNAP-23, and as a consequence, the assembly of newly synthesized SNAP
      23 with syntaxin is augmented. These data demonstrate that phosphorylation of
      SNAP-23 by SNAK enhances the kinetics of t-SNARE assembly in vivo.

PMID- 10588642
TI  - Nuclear localization of Schizosaccharomyces pombe Mcm2/Cdc19p requires MCM
      complex assembly.
AB  - The minichromosome maintenance (MCM) proteins MCM2-MCM7 are conserved eukaryotic
      replication factors that assemble in a heterohexameric complex. In fission yeast,
      these proteins are nuclear throughout the cell cycle. In studying the mechanism
      that regulates assembly of the MCM complex, we analyzed the cis and trans
      elements required for nuclear localization of a single subunit, Mcm2p. Mutation
      of any single mcm gene leads to redistribution of wild-type MCM subunits to the
      cytoplasm, and this redistribution depends on an active nuclear export system. We
      identified the nuclear localization signal sequences of Mcm2p and showed that
      these are required for nuclear targeting of other MCM subunits. In turn, Mcm2p
      must associate with other MCM proteins for its proper localization; nuclear
      localization of MCM proteins thus requires assembly of MCM proteins in a complex.
      We suggest that coupling complex assembly to nuclear targeting and retention
      ensures that only intact heterohexameric MCM complexes remain nuclear.

PMID- 10588643
TI  - Degradation of a short-lived glycoprotein from the lumen of the endoplasmic
      reticulum: the role of N-linked glycans and the unfolded protein response.
AB  - We are studying endoplasmic reticulum-associated degradation (ERAD) with the use
      of a truncated variant of the type I ER transmembrane glycoprotein ribophorin I
      (RI). The mutant protein, RI(332), containing only the N-terminal 332 amino acids
      of the luminal domain of RI, has been shown to interact with calnexin and to be a
      substrate for the ubiquitin-proteasome pathway. When RI(332) was expressed in
      HeLa cells, it was degraded with biphasic kinetics; an initial, slow phase of
      approximately 45 min was followed by a second phase of threefold accelerated
      degradation. On the other hand, the kinetics of degradation of a form of RI(332)
      in which the single used N-glycosylation consensus site had been removed (RI(332)
      Thr) was monophasic and rapid, implying a role of the N-linked glycan in the
      first proteolytic phase. RI(332) degradation was enhanced when the binding of
      glycoproteins to calnexin was prevented. Moreover, the truncated glycoprotein
      interacted with calnexin preferentially during the first proteolytic phase, which
      strongly suggests that binding of RI(332) to the lectin-like protein may result
      in the slow, initial phase of degradation. Additionally, mannose trimming appears
      to be required for efficient proteolysis of RI(332). After treatment of cells
      with the inhibitor of N-glycosylation, tunicamycin, destruction of the truncated
      RI variants was severely inhibited; likewise, in cells preincubated with the
      calcium ionophore A23187, both RI(332) and RI(332)-Thr were stabilized, despite
      the presence or absence of the N-linked glycan. On the other hand, both drugs are
      known to trigger the unfolded protein response (UPR), resulting in the induction
      of BiP and other ER-resident proteins. Indeed, only in drug-treated cells could
      an interaction between BiP and RI(332) and RI(332)-Thr be detected. Induction of
      BiP was also evident after overexpression of murine Ire1, an ER transmembrane
      kinase known to play a central role in the UPR pathway; at the same time,
      stabilization of RI(332) was observed. Together, these results suggest that
      binding of the substrate proteins to UPR-induced chaperones affects their half
      lives.

PMID- 10588644
TI  - Two components of actin-based retrograde flow in sea urchin coelomocytes.
AB  - Sea urchin coelomocytes represent an excellent experimental model system for
      studying retrograde flow. Their extreme flatness allows for excellent microscopic
      visualization. Their discoid shape provides a radially symmetric geometry, which
      simplifies analysis of the flow pattern. Finally, the nonmotile nature of the
      cells allows for the retrograde flow to be analyzed in the absence of cell
      translocation. In this study we have begun an analysis of the retrograde flow
      mechanism by characterizing its kinetic and structural properties. The
      supramolecular organization of actin and myosin II was investigated using light
      and electron microscopic methods. Light microscopic immunolocalization was
      performed with anti-actin and anti-sea urchin egg myosin II antibodies, whereas
      transmission electron microscopy was performed on platinum replicas of critical
      point-dried and rotary-shadowed cytoskeletons. Coelomocytes contain a dense
      cortical actin network, which feeds into an extensive array of radial bundles in
      the interior. These actin bundles terminate in a perinuclear region, which
      contains a ring of myosin II bipolar minifilaments. Retrograde flow was arrested
      either by interfering with actin polymerization or by inhibiting myosin II
      function, but the pathway by which the flow was blocked was different for the two
      kinds of inhibitory treatments. Inhibition of actin polymerization with
      cytochalasin D caused the actin cytoskeleton to separate from the cell margin and
      undergo a finite retrograde retraction. In contrast, inhibition of myosin II
      function either with the wide-spectrum protein kinase inhibitor staurosporine or
      the myosin light chain kinase-specific inhibitor KT5926 stopped flow in the cell
      center, whereas normal retrograde flow continued at the cell periphery. These
      differential results suggest that the mechanism of retrograde flow has two,
      spatially segregated components. We propose a "push-pull" mechanism in which
      actin polymerization drives flow at the cell periphery, whereas myosin II
      provides the tension on the actin cytoskeleton necessary for flow in the cell
      interior.

PMID- 10588645
TI  - DNA replication in quiescent cell nuclei: regulation by the nuclear envelope and
      chromatin structure.
AB  - Quiescent nuclei from differentiated somatic cells can reacquire pluripotence,
      the capacity to replicate, and reinitiate a program of differentiation after
      transplantation into amphibian eggs. The replication of quiescent nuclei is
      recapitulated in extracts derived from activated Xenopus eggs; therefore, we have
      exploited this cell-free system to explore the mechanisms that regulate
      initiation of replication in nuclei from terminally differentiated Xenopus
      erythrocytes. We find that these nuclei lack many, if not all, pre-replication
      complex (pre-RC) proteins. Pre-RC proteins from the extract form a stable
      association with the chromatin of permeable nuclei, which replicate in this
      system, but not with the chromatin of intact nuclei, which do not replicate, even
      though these proteins cross an intact nuclear envelope. During extract
      incubation, the linker histones H1 and H1(0) are removed from erythrocyte
      chromatin by nucleoplasmin. We show that H1 removal facilitates the replication
      of permeable nuclei by increasing the frequency of initiation most likely by
      promoting the assembly of pre-RCs on chromatin. These data indicate that
      initiation in erythrocyte nuclei requires the acquisition of pre-RC proteins from
      egg extract and that pre-RC assembly requires the loss of nuclear envelope
      integrity and is facilitated by the removal of linker histone H1 from chromatin.

PMID- 10588646
TI  - Role of dynactin in endocytic traffic: effects of dynamitin overexpression and
      colocalization with CLIP-170.
AB  - The flow of material from peripheral, early endosomes to late endosomes requires
      microtubules and is thought to be facilitated by the minus end-directed motor
      cytoplasmic dynein and its activator dynactin. The microtubule-binding protein
      CLIP-170 may also play a role by providing an early link to endosomes. Here, we
      show that perturbation of dynactin function in vivo affects endosome dynamics and
      trafficking. Endosome movement, which is normally bidirectional, is completely
      inhibited. Receptor-mediated uptake and recycling occur normally, but cells are
      less susceptible to infection by enveloped viruses that require delivery to late
      endosomes, and they show reduced accumulation of lysosomally targeted probes.
      Dynactin colocalizes at microtubule plus ends with CLIP-170 in a way that depends
      on CLIP-170's putative cargo-binding domain. Overexpression studies using
      p150(Glued), the microtubule-binding subunit of dynactin, and mutant and wild
      type forms of CLIP-170 indicate that CLIP-170 recruits dynactin to microtubule
      ends. These data suggest a new model for the formation of motile complexes of
      endosomes and microtubules early in the endocytic pathway.

PMID- 10588647
TI  - The Rho GTPase Rho3 has a direct role in exocytosis that is distinct from its
      role in actin polarity.
AB  - Budding yeast grow asymmetrically by the polarized delivery of proteins and
      lipids to specific sites on the plasma membrane. This requires the coordinated
      polarization of the actin cytoskeleton and the secretory apparatus. We identified
      Rho3 on the basis of its genetic interactions with several late-acting secretory
      genes. Mutational analysis of the Rho3 effector domain reveals three distinct
      functions in cell polarity: regulation of actin polarity, transport of exocytic
      vesicles from the mother cell to the bud, and docking and fusion of vesicles with
      the plasma membrane. We provide evidence that the vesicle delivery function of
      Rho3 is mediated by the unconventional myosin Myo2 and that the docking and
      fusion function is mediated by the exocyst component Exo70. These data suggest
      that Rho3 acts as a key regulator of cell polarity and exocytosis, coordinating
      several distinct events for delivery of proteins to specific sites on the cell
      surface.

PMID- 10588648
TI  - Luminal heterodimeric amino acid transporter defective in cystinuria.
AB  - Mutations of the glycoprotein rBAT cause cystinuria type I, an autosomal
      recessive failure of dibasic amino acid transport (b(0,+) type) across luminal
      membranes of intestine and kidney cells. Here we identify the permease-like
      protein b(0,+)AT as the catalytic subunit that associates by a disulfide bond
      with rBAT to form a hetero-oligomeric b(0,+) amino acid transporter complex. We
      demonstrate its b(0,+)-type amino acid transport kinetics using a heterodimeric
      fusion construct and show its luminal brush border localization in kidney
      proximal tubule. These biochemical, transport, and localization characteristics
      as well as the chromosomal localization on 19q support the notion that the
      b(0,+)AT protein is the product of the gene defective in non-type I cystinuria.

PMID- 10588649
TI  - Promiscuity in Rab-SNARE interactions.
AB  - Fusion of post-Golgi secretory vesicles with the plasma membrane in yeast
      requires the function of a Rab protein, Sec4p, and a set of v- and t-SNAREs, the
      Snc, Sso, and Sec9 proteins. We have tested the hypothesis that a selective
      interaction between Sec4p and the exocytic SNAREs is responsible for ensuring
      that secretory vesicles fuse with the plasma membrane but not with intracellular
      organelles. Assembly of Sncp and Ssop into a SNARE complex is defective in a sec4
      8 mutant strain. However, Snc2p binds in vivo to many other syntaxin-like t
      SNAREs, and binding of Sncp to the endosomal/Golgi t-SNARE Tlg2p is also reduced
      in sec4-8 cells. In addition, binding of Sncp to Ssop is reduced by mutations in
      two other Rab genes and four non-Rab genes that block the secretory pathway
      before the formation of secretory vesicles. In an alternate approach to look for
      selective Rab-SNARE interactions, we report that the nucleotide-free form of
      Sec4p coimmunoprecipitates with Ssop. However, Rab-SNARE binding is nonselective,
      because the nucleotide-free forms of six Rab proteins bind with similar low
      efficiency to three SNARE proteins, Ssop, Pep12p, and Sncp. We conclude that Rabs
      and SNAREs do not cooperate to specify the target membrane.

PMID- 10588650
TI  - Synaptic vesicles form by budding from tubular extensions of sorting endosomes in
      PC12 cells.
AB  - The putative role of sorting early endosomes (EEs) in synaptic-like microvesicle
      (SLMV) formation in the neuroendocrine PC12 cell line was investigated by
      quantitative immunoelectron microscopy. By BSA-gold internalization kinetics,
      four distinct endosomal subcompartments were distinguished: primary endocytic
      vesicles, EEs, late endosomes, and lysosomes. As in other cells, EEs consisted of
      vacuolar and tubulovesicular subdomains. The SLMV marker proteins synaptophysin
      and vesicle-associated membrane protein 2 (VAMP-2) localized to both the EE
      vacuoles and associated tubulovesicles. Quantitative analysis showed that the
      transferrin receptor and SLMV proteins colocalized to a significantly higher
      degree in primary endocytic vesicles then in EE-associated tubulovesicles. By
      incubating PC12 cells expressing T antigen-tagged VAMP (VAMP-TAg) with antibodies
      against the luminal TAg, the recycling pathway of SLMV proteins was directly
      visualized. At 15 degrees C, internalized VAMP-TAg accumulated in the vacuolar
      domain of EEs. Upon rewarming to 37 degrees C, the labeling shifted to the
      tubular part of EEs and to newly formed SLMVs. Our data delineate a pathway in
      which SLMV proteins together with transferrin receptor are delivered to EEs,
      where they are sorted into SLMVs and recycling vesicles, respectively.

PMID- 10588652
TI  - A discrete stage of baculovirus GP64-mediated membrane fusion.
AB  - Viral fusion protein trimers can play a critical role in limiting lipids in
      membrane fusion. Because the trimeric oligomer of many viral fusion proteins is
      often stabilized by hydrophobic 4-3 heptad repeats, higher-order oligomers might
      be stabilized by similar sequences. There is a hydrophobic 4-3 heptad repeat
      contiguous to a putative oligomerization domain of Autographa californica
      multicapsid nucleopolyhedrovirus envelope glycoprotein GP64. We performed
      mutagenesis and peptide inhibition studies to determine if this sequence might
      play a role in catalysis of membrane fusion. First, leucine-to-alanine mutants
      within and flanking the amino terminus of the hydrophobic 4-3 heptad repeat motif
      that oligomerize into trimers and traffic to insect Sf9 cell surfaces were
      identified. These mutants retained their wild-type conformation at neutral pH and
      changed conformation in acidic conditions, as judged by the reactivity of a
      conformationally sensitive mAb. These mutants, however, were defective for
      membrane fusion. Second, a peptide encoding the portion flanking the GP64
      hydrophobic 4-3 heptad repeat was synthesized. Adding peptide led to inhibition
      of membrane fusion, which occurred only when the peptide was present during low
      pH application. The presence of peptide during low pH application did not prevent
      low pH-induced conformational changes, as determined by the loss of a
      conformationally sensitive epitope. In control experiments, a peptide of
      identical composition but different sequence, or a peptide encoding a portion of
      the Ebola GP heptad motif, had no effect on GP64-mediated fusion. Furthermore,
      when the hemagglutinin (X31 strain) fusion protein of influenza was functionally
      expressed in Sf9 cells, no effect on hemagglutinin-mediated fusion was observed,
      suggesting that the peptide does not exert nonspecific effects on other fusion
      proteins or cell membranes. Collectively, these studies suggest that the specific
      peptide sequences of GP64 that are adjacent to and include portions of the
      hydrophobic 4-3 heptad repeat play a dynamic role in membrane fusion at a stage
      that is downstream of the initiation of protein conformational changes but
      upstream of lipid mixing.

PMID- 10588651
TI  - Cell-matrix adhesions differentially regulate fascin phosphorylation.
AB  - Cell adhesion to individual macromolecules of the extracellular matrix has
      dramatic effects on the subcellular localization of the actin-bundling protein
      fascin and on the ability of cells to form stable fascin microspikes. The actin
      binding activity of fascin is down-regulated by phosphorylation, and we used two
      differentiated cell types, C2C12 skeletal myoblasts and LLC-PK1 kidney epithelial
      cells, to examine the hypothesis that cell adhesion to the matrix components
      fibronectin, laminin-1, and thrombospondin-1 differentially regulates fascin
      phosphorylation. In both cell types, treatment with the PKC activator 12
      tetradecanoyl phorbol 13-acetate (TPA) or adhesion to fibronectin led to a
      diffuse distribution of fascin after 1 h. C2C12 cells contain the PKC family
      members alpha, gamma, and lambda, and PKCalpha localization was altered upon cell
      adhesion to fibronectin. Two-dimensional isoelectric focusing/SDS-polyacrylamide
      gels were used to determine that fascin became phosphorylated in cells adherent
      to fibronectin and was inhibited by the PKC inhibitors calphostin C and
      chelerythrine chloride. Phosphorylation of fascin was not detected in cells
      adherent to thrombospondin-1 or to laminin-1. LLC-PK1 cells expressing green
      fluorescent protein (GFP)-fascin also displayed similar regulation of fascin
      phosphorylation. LLC-PK1 cells expressing GFP-fascin S39A, a nonphosphorylatable
      mutant, did not undergo spreading and focal contact organization on fibronectin,
      whereas cells expressing a GFP-fascin S39D mutant with constitutive negative
      charge spread more extensively than wild-type cells. In contrast, C2C12 cells
      coexpressing S39A fascin with endogenous fascin remained competent to form
      microspikes on thrombospondin-1, and cells that expressed fascin S39D attached to
      thrombospondin-1 but did not form microspikes. Blockade of PKCalpha activity by
      TPA-induced down-regulation led to actin association of wild-type fascin in
      fibronectin-adherent C2C12 and LLC-PK1 cells but did not alter the distribution
      of S39A or S39D fascins. The association of fascin with actin in fibronectin
      adherent cells was also evident in the presence of an inhibitory antibody to
      integrin alpha5 subunit. These novel results establish matrix-initiated PKC
      dependent regulation of fascin phosphorylation at serine 39 as a mechanism
      whereby matrix adhesion is coupled to the organization of cytoskeletal structure.

PMID- 10588653
TI  - A mutant of Arp2p causes partial disassembly of the Arp2/3 complex and loss of
      cortical actin function in fission yeast.
AB  - The Arp2/3 complex is an essential component of the yeast actin cytoskeleton that
      localizes to cortical actin patches. We have isolated and characterized a
      temperature-sensitive mutant of Schizosaccharomyces pombe arp2 that displays a
      defect in cortical actin patch distribution. The arp2(+) gene encodes an
      essential actin-related protein that colocalizes with actin at the cortical actin
      patch. Sucrose gradient analysis of the Arp2/3 complex in the arp2-1 mutant
      indicated that the Arp2p and Arc18p subunits are specifically lost from the
      complex at restrictive temperature. These results are consistent with
      immunolocalization studies of the mutant that show that Arp2-1p is diffusely
      localized in the cytoplasm at restrictive temperature. Interestingly, Arp3p
      remains localized to the cortical actin patch under the same restrictive
      conditions, leading to the hypothesis that loss of Arp2p from the actin patch
      affects patch motility but does not severely compromise its architecture.
      Analysis of the mutant Arp2 protein demonstrated defects in ATP and Arp3p
      binding, suggesting a possible model for disruption of the complex.

PMID- 10588654
TI  - Differentiation of chromatin during DNA elimination in Euplotes crassus.
AB  - In Euplotes crassus, most of the micronuclear genome is eliminated during
      formation of a transcriptionally active macronucleus. To understand how this is
      mediated throughout the genome, we have examined the chromatin structure of the
      macronucleus-destined sequences and Tec transposons, which are dispersed in
      15,000 copies in the micronuclear genome and completely eliminated during
      formation of the macronuclear genome. Whereas the macronucleus-destined sequences
      show a typical pattern of nucleosomal repeats in micrococcal nuclease digests,
      the Tec element chromatin structure digests to a nucleosome-like repeat pattern
      that is not typical: the minimum digestion products are approximately 300-600
      base pairs, or "subnucleosomal," in size. In addition, the excised, circular
      forms of the Tec elements are exceedingly resistant to nucleases. Nevertheless,
      an underlying nucleosomal structure of the Tec elements can be demonstrated from
      the size differences between repeats in partial micrococcal nuclease digests and
      by trypsin treatment of nuclei, which results in mononucleosome-sized products.
      Characterization of the most micrococcal nuclease-resistant DNA indicates that
      micronuclear telomeres are organized into a chromatin structure with digestion
      properties identical to those of the Tec elements in the developing macronucleus.
      Thus, these major repetitive sequence components of the micronuclear genome
      differ in their chromatin structure from the macronuclear-destined sequences
      during DNA elimination. The potential role of developmental stage-specific
      histone variants in this chromatin differentiation is discussed.

PMID- 10588655
TI  - Roles for basal and stimulated p21(Cip-1/WAF1/MDA6) expression and mitogen
      activated protein kinase signaling in radiation-induced cell cycle checkpoint
      control in carcinoma cells.
AB  - We investigated the role of the cdk inhibitor protein p21(Cip-1/WAF1/MDA6) (p21)
      in the ability of MAPK pathway inhibition to enhance radiation-induced apoptosis
      in A431 squamous carcinoma cells. In carcinoma cells, ionizing radiation (2 Gy)
      caused both primary (0-10 min) and secondary (90-240 min) activations of the MAPK
      pathway. Radiation induced p21 protein expression in A431 cells within 6 h via
      secondary activation of the MAPK pathway. Within 6 h, radiation weakly enhanced
      the proportion of cells in G(1) that were p21 and MAPK dependent, whereas the
      elevation of cells present in G(2)/M at this time was independent of either p21
      expression or MAPK inhibition. Inhibition of the MAPK pathway increased the
      proportion of irradiated cells in G(2)/M phase 24-48 h after irradiation and
      enhanced radiation-induced apoptosis. This correlated with elevated Cdc2 tyrosine
      15 phosphorylation, decreased Cdc2 activity, and decreased Cdc25C protein levels.
      Caffeine treatment or removal of MEK1/2 inhibitors from cells 6 h after
      irradiation reduced the proportion of cells present in G(2)/M phase at 24 h and
      abolished the ability of MAPK inhibition to potentiate radiation-induced
      apoptosis. These data argue that MAPK signaling plays an important role in the
      progression/release of cells through G(2)/M phase after radiation exposure and
      that an impairment of this progression/release enhances radiation-induced
      apoptosis. Surprisingly, the ability of irradiation/MAPK inhibition to increase
      the proportion of cells in G(2)/M at 24 h was found to be dependent on basal p21
      expression. Transient inhibition of basal p21 expression increased the control
      level of apoptosis as well as the abilities of both radiation and MEK1/2
      inhibitors to cause apoptosis. In addition, loss of basal p21 expression
      significantly reduced the capacity of MAPK inhibition to potentiate radiation
      induced apoptosis. Collectively, our data argue that MAPK signaling and p21 can
      regulate cell cycle checkpoint control in carcinoma cells at the G(1)/S
      transition shortly after exposure to radiation. In contrast, inhibition of MAPK
      increases the proportion of irradiated cells in G(2)/M, and basal expression of
      p21 is required to maintain this effect. Our data suggest that basal and
      radiation-stimulated p21 may play different roles in regulating cell cycle
      progression that affect cell survival after radiation exposure.

PMID- 10588656
TI  - Initiation of assembly of the cell envelope barrier structure of stratified
      squamous epithelia.
AB  - The cell envelope (CE) is a specialized structure that is important for barrier
      function in terminally differentiated stratified squamous epithelia. The CE is
      formed inside the plasma membrane and becomes insoluble as a result of cross
      linking of constituent proteins by isopeptide bonds formed by transglutaminases.
      To investigate the earliest stages of assembly of the CE, we have studied human
      epidermal keratinocytes induced to terminally differentiate in submerged liquid
      culture as a model system for epithelia in general. CEs were harvested from 2-, 3
      , 5-, or 7-d cultured cells and examined by 1) immunogold electron microscopy
      using antibodies to known CE or other junctional proteins and 2) amino acid
      sequencing of cross-linked peptides derived by proteolysis of CEs. Our data
      document that CE assembly is initiated along the plasma membrane between
      desmosomes by head-to-tail and head-to-head cross-linking of involucrin to itself
      and to envoplakin and perhaps periplakin. Essentially only one lysine and two
      glutamine residues of involucrin and two glutamines of envoplakin were used
      initially. In CEs of 3-d cultured cells, involucrin, envoplakin, and small
      proline-rich proteins were physically located at desmosomes and had become cross
      linked to desmoplakin, and in 5-d CEs, these three proteins had formed a
      continuous layer extending uniformly along the cell periphery. By this time >15
      residues of involucrin were used for cross-linking. The CEs of 7-d cells contain
      significant amounts of the protein loricrin, typically expressed at a later stage
      of CE assembly. Together, these data stress the importance of juxtaposition of
      membranes, transglutaminases, and involucrin and envoplakin in the initiation of
      CE assembly of stratified squamous epithelia.

PMID- 10588658
TI  - Nuclear accumulation of S-adenosylhomocysteine hydrolase in transcriptionally
      active cells during development of Xenopus laevis.
AB  - The oocyte nuclear antigen of the monoclonal antibody 32-5B6 of Xenopus laevis is
      subject to regulated nuclear translocation during embryogenesis. It is
      distributed in the cytoplasm during oocyte maturation, where it remains during
      cleavage and blastula stages, before it gradually reaccumulates in the nuclei
      during gastrulation. We have now identified this antigen to be the enzyme S
      adenosylhomocysteine hydrolase (SAHH). SAHH is the only enzyme that cleaves S
      adenosylhomocysteine, a reaction product and an inhibitor of all S
      adenosylmethionine-dependent methylation reactions. We have compared the spatial
      and temporal patterns of nuclear localization of SAHH and of nuclear
      methyltransferase activities during embryogenesis and in tissue culture cells.
      Nuclear localization of Xenopus SAHH did not temporally correlate with DNA
      methylation. However, we found that SAHH nuclear localization coincides with high
      rates of mRNA synthesis, a subpopulation colocalizes with RNA polymerase II, and
      inhibitors of SAHH reduce both methylation and synthesis of poly(A)(+) RNA. We
      therefore propose that accumulation of SAHH in the nucleus may be required for
      efficient cap methylation in transcriptionally active cells. Mutation analysis
      revealed that the C terminus and the N terminus are both required for efficient
      nuclear translocation in tissue culture cells, indicating that more than one
      interacting domain contributes to nuclear accumulation of Xenopus SAHH.

PMID- 10588657
TI  - The yeast GRD20 gene is required for protein sorting in the trans-Golgi
      network/endosomal system and for polarization of the actin cytoskeleton.
AB  - The proper localization of resident membrane proteins to the trans-Golgi network
      (TGN) involves mechanisms for both TGN retention and retrieval from post-TGN
      compartments. In this study we report identification of a new gene, GRD20,
      involved in protein sorting in the TGN/endosomal system of Saccharomyces
      cerevisiae. A strain carrying a transposon insertion allele of GRD20 exhibited
      rapid vacuolar degradation of the resident TGN endoprotease Kex2p and aberrantly
      secreted approximately 50% of the soluble vacuolar hydrolase carboxypeptidase Y.
      The Kex2p mislocalization and carboxypeptidase Y missorting phenotypes were
      exhibited rapidly after loss of Grd20p function in grd20 temperature-sensitive
      mutant strains, indicating that Grd20p plays a direct role in these processes.
      Surprisingly, little if any vacuolar degradation was observed for the TGN
      membrane proteins A-ALP and Vps10p, underscoring a difference in trafficking
      patterns for these proteins compared with that of Kex2p. A grd20 null mutant
      strain exhibited extremely slow growth and a defect in polarization of the actin
      cytoskeleton, and these two phenotypes were invariably linked in a collection of
      randomly mutagenized grd20 alleles. GRD20 encodes a hydrophilic protein that
      partially associates with the TGN. The discovery of GRD20 suggests a link between
      the cytoskeleton and function of the yeast TGN.

PMID- 10588659
TI  - Phosphorylated human keratinocyte ornithine decarboxylase is preferentially
      associated with insoluble cellular proteins.
AB  - Ornithine decarboxylase (ODC), the first enzyme in polyamine biosynthesis, is
      highly regulated by many trophic stimuli, and changes in its levels and
      organization correlate with cytoskeletal changes in normal human epidermal
      keratinocytes (NHEK). NHEK ODC exhibits a filamentous perinuclear/nuclear
      localization that becomes more diffuse under conditions that alter actin
      architecture. We have thus asked whether ODC colocalizes with a component of the
      NHEK cytoskeleton. Confocal immunofluorescence showed that ODC distribution in
      NHEK was primarily perinuclear; upon disruption of the actin cytoskeleton with
      cytochalasin D, ODC distribution was diffuse. The ODC distribution in untreated
      NHEK overlapped with that of keratin in the perinuclear but not cytoplasmic area;
      after treatment with cytochalasin D, overlap between staining for ODC and for
      keratin was extensive. No significant overlap with actin and minimal overlap with
      tubulin filament systems were observed. Subcellular fractionation by sequential
      homogenizations and centrifugations of NHEK lysates or detergent and salt
      extractions of NHEK in situ revealed that ODC protein and activity were
      detectable in both soluble and insoluble fractions, with mechanical disruption
      causing additional solubilization of ODC activity (three- to sevenfold above
      controls). Fractionation and ODC immunoprecipitation from [(32)P]orthophosphate
      labeled NHEK lysates showed that a phosphorylated form of ODC was present in the
      insoluble fractions. Taken together, these data suggest that two pools of ODC
      exist in NHEK. The first is the previously described soluble pool, and the second
      is enriched in phospho-ODC and associated with insoluble cellular material that
      by immunohistochemistry appears to be organized in conjunction with the keratin
      cytoskeleton.

PMID- 10588660
TI  - Receptor-mediated endocytosis in the Caenorhabditis elegans oocyte.
AB  - The Caenorhabditis elegans oocyte is a highly amenable system for forward and
      reverse genetic analysis of receptor-mediated endocytosis. We describe the use of
      transgenic strains expressing a vitellogenin::green fluorescent protein
      (YP170::GFP) fusion to monitor yolk endocytosis by the C. elegans oocyte in vivo.
      This YP170::GFP reporter was used to assay the functions of C. elegans predicted
      proteins homologous to vertebrate endocytosis factors using RNA-mediated
      interference. We show that the basic components and pathways of endocytic
      trafficking are conserved between C. elegans and vertebrates, and that this
      system can be used to test the endocytic functions of any new gene. We also used
      the YP170::GFP assay to identify rme (receptor-mediated endocytosis) mutants. We
      describe a new member of the low-density lipoprotein receptor superfamily, RME-2,
      identified in our screens for endocytosis defective mutants. We show that RME-2
      is the C. elegans yolk receptor.

PMID- 10588661
TI  - Espin contains an additional actin-binding site in its N terminus and is a major
      actin-bundling protein of the Sertoli cell-spermatid ectoplasmic specialization
      junctional plaque.
AB  - The espins are actin-binding and -bundling proteins localized to parallel actin
      bundles. The 837-amino-acid "espin" of Sertoli cell-spermatid junctions
      (ectoplasmic specializations) and the 253-amino-acid "small espin" of brush
      border microvilli are splice isoforms that share a C-terminal 116-amino-acid
      actin-bundling module but contain different N termini. To investigate the roles
      of espin and its extended N terminus, we examined the actin-binding and -bundling
      properties of espin constructs and the stoichiometry and developmental
      accumulation of espin within the ectoplasmic specialization. An espin construct
      bound to F-actin with an approximately threefold higher affinity (K(d) =
      approximately 70 nM) than small espin and was approximately 2.5 times more
      efficient at forming bundles. The increased affinity appeared to be due to an
      additional actin-binding site in the N terminus of espin. This additional actin
      binding site bound to F-actin with a K(d) of approximately 1 microM, decorated
      actin stress fiber-like structures in transfected cells, and was mapped to a
      peptide between the two proline-rich peptides in the N terminus of espin. Espin
      was detected at approximately 4-5 x 10(6) copies per ectoplasmic specialization,
      or approximately 1 espin per 20 actin monomers and accumulated there coincident
      with the formation of parallel actin bundles during spermiogenesis. These results
      suggest that espin is a major actin-bundling protein of the Sertoli cell
      spermatid ectoplasmic specialization.

PMID- 10588662
TI  - Class VI unconventional myosin is required for spermatogenesis in Drosophila.
AB  - We have identified partial loss of function mutations in class VI unconventional
      myosin, 95F myosin, which results in male sterility. During spermatogenesis the
      germ line precursor cells undergo mitosis and meiosis to form a bundle of 64
      spermatids. The spermatids remain interconnected by cytoplasmic bridges until
      individualization. The process of individualization involves the formation of a
      complex of cytoskeletal proteins and membrane, the individualization complex
      (IC), around the spermatid nuclei. This complex traverses the length of each
      spermatid resolving the shared membrane into a single membrane enclosing each
      spermatid. We have determined that 95F myosin is a component of the IC whose
      function is essential for individualization. In wild-type testes, 95F myosin
      localizes to the leading edge of the IC. Two independent mutations in 95F myosin
      reduce the amount of 95F myosin in only a subset of tissues, including the
      testes. This reduction of 95F myosin causes male sterility as a result of defects
      in spermatid individualization. Germ line transformation with the 95F myosin
      heavy chain cDNA rescues the male sterility phenotype. IC movement is aberrant in
      these 95F myosin mutants, indicating a critical role for 95F myosin in IC
      movement. This report is the first identification of a component of the IC other
      than actin. We propose that 95F myosin is a motor that participates in membrane
      reorganization during individualization.

PMID- 10588663
TI  - Involvement of type 4 cAMP-phosphodiesterase in the myogenic differentiation of
      L6 cells.
AB  - Myogenic cell differentiation is induced by Arg(8)-vasopressin, whereas high cAMP
      levels and protein kinase A (PKA) activity inhibit myogenesis. We investigated
      the role of type 4 phosphodiesterase (PDE4) during L6-C5 myoblast
      differentiation. Selective PDE4 inhibition resulted in suppression of
      differentiation induced by vasopressin. PDE4 inhibition prevented vasopressin
      induced nuclear translocation of the muscle-specific transcription factor
      myogenin without affecting its overall expression level. The effects of PDE4
      inhibition could be attributed to an increase of cAMP levels and PKA activity.
      RNase protection, reverse transcriptase PCR, immunoprecipitation, Western blot,
      and enzyme activity assays demonstrated that the PDE4D3 isoform is the major PDE4
      expressed in L6-C5 myoblasts and myotubes, accounting for 75% of total cAMP
      hydrolyzing activity. Vasopressin cell stimulation caused a biphasic increase of
      PDE4 activity, which peaked at 2 and 15 min and remained elevated for 48 h. In
      the continuous presence of vasopressin, cAMP levels and PKA activity were
      lowered. PDE4D3 overexpression increased spontaneous and vasopressin-dependent
      differentiation of L6-C5 cells. These results show that PDE4D3 plays a key role
      in the control of cAMP levels and differentiation of L6-C5 cells. Through the
      modulation of PDE4 activity, vasopressin inhibits the cAMP signal transduction
      pathway, which regulates myogenesis possibly by controlling the subcellular
      localization of myogenin.

PMID- 10588664
TI  - Modulation of endocytic traffic in polarized Madin-Darby canine kidney cells by
      the small GTPase RhoA.
AB  - Efficient postendocytic membrane traffic in polarized epithelial cells is thought
      to be regulated in part by the actin cytoskeleton. RhoA modulates assemblies of
      actin in the cell, and it has been shown to regulate pinocytosis and
      phagocytosis; however, its effects on postendocytic traffic are largely
      unexplored. To this end, we expressed wild-type RhoA (RhoAWT), dominant active
      RhoA (RhoAV14), and dominant inactive RhoA (RhoAN19) in Madin-Darby canine kidney
      (MDCK) cells expressing the polymeric immunoglobulin receptor. RhoAV14 expression
      stimulated the rate of apical and basolateral endocytosis, whereas RhoAN19
      expression decreased the rate from both membrane domains. Polarized basolateral
      recycling of transferrin was disrupted in RhoAV14-expressing cells as a result of
      increased ligand release at the apical pole of the cell. Degradation of
      basolaterally internalized epidermal growth factor was slowed in RhoAV14
      expressing cells. Although apical recycling of immunoglobulin A (IgA) was largely
      unaffected in cells expressing RhoAV14, transcytosis of basolaterally
      internalized IgA was severely impaired. Morphological and biochemical analyses
      demonstrated that a large proportion of IgA internalized from the basolateral
      pole of RhoAV14-expressing cells remained within basolateral early endosomes and
      was slow to exit these compartments. RhoAN19 and RhoAWT expression had little
      effect on these postendocytic pathways. These results indicate that in polarized
      MDCK cells activated RhoA may modulate endocytosis from both membrane domains and
      postendocytic traffic at the basolateral pole of the cell.

PMID- 10588665
TI  - Assembly of the nuclear transcription and processing machinery: Cajal bodies
      (coiled bodies) and transcriptosomes.
AB  - We have examined the distribution of RNA transcription and processing factors in
      the amphibian oocyte nucleus or germinal vesicle. RNA polymerase I (pol I), pol
      II, and pol III occur in the Cajal bodies (coiled bodies) along with various
      components required for transcription and processing of the three classes of
      nuclear transcripts: mRNA, rRNA, and pol III transcripts. Among these components
      are transcription factor IIF (TFIIF), TFIIS, splicing factors, the U7 small
      nuclear ribonucleoprotein particle, the stem-loop binding protein, SR proteins,
      cleavage and polyadenylation factors, small nucleolar RNAs, nucleolar proteins
      that are probably involved in pre-rRNA processing, and TFIIIA. Earlier studies
      and data presented here show that several of these components are first targeted
      to Cajal bodies when injected into the oocyte and only subsequently appear in the
      chromosomes or nucleoli, where transcription itself occurs. We suggest that pol
      I, pol II, and pol III transcription and processing components are preassembled
      in Cajal bodies before transport to the chromosomes and nucleoli. Most components
      of the pol II transcription and processing pathway that occur in Cajal bodies are
      also found in the many hundreds of B-snurposomes in the germinal vesicle.
      Electron microscopic images show that B-snurposomes consist primarily, if not
      exclusively, of 20- to 30-nm particles, which closely resemble the interchromatin
      granules described from sections of somatic nuclei. We suggest the name pol II
      transcriptosome for these particles to emphasize their content of factors
      involved in synthesis and processing of mRNA transcripts. We present a model in
      which pol I, pol II, and pol III transcriptosomes are assembled in the Cajal
      bodies before export to the nucleolus (pol I), to the B-snurposomes and
      eventually to the chromosomes (pol II), and directly to the chromosomes (pol
      III). The key feature of this model is the preassembly of the transcription and
      processing machinery into unitary particles. An analogy can be made between
      ribosomes and transcriptosomes, ribosomes being unitary particles involved in
      translation and transcriptosomes being unitary particles for transcription and
      processing of RNA.

PMID- 10588666
TI  - The dynamin-like protein DLP1 is essential for normal distribution and morphology
      of the endoplasmic reticulum and mitochondria in mammalian cells.
AB  - The dynamin family of large GTPases has been implicated in vesicle formation from
      both the plasma membrane and various intracellular membrane compartments. The
      dynamin-like protein DLP1, recently identified in mammalian tissues, has been
      shown to be more closely related to the yeast dynamin proteins Vps1p and Dnm1p
      (42%) than to the mammalian dynamins (37%). Furthermore, DLP1 has been shown to
      associate with punctate vesicles that are in intimate contact with microtubules
      and the endoplasmic reticulum (ER) in mammalian cells. To define the function of
      DLP1, we have transiently expressed both wild-type and two mutant DLP1 proteins,
      tagged with green fluorescent protein, in cultured mammalian cells. Point
      mutations in the GTP-binding domain of DLP1 (K38A and D231N) dramatically changed
      its intracellular distribution from punctate vesicular structures to either an
      aggregated or a diffuse pattern. Strikingly, cells expressing DLP1 mutants or
      microinjected with DLP1 antibodies showed a marked reduction in ER fluorescence
      and a significant aggregation and tubulation of mitochondria by
      immunofluorescence microscopy. Consistent with these observations, electron
      microscopy of DLP1 mutant cells revealed a striking and quantitative change in
      the distribution and morphology of mitochondria and the ER. These data support
      very recent studies by other authors implicating DLP1 in the maintenance of
      mitochondrial morphology in both yeast and mammalian cells. Furthermore, this
      study provides the first evidence that a dynamin family member participates in
      the maintenance and distribution of the ER. How DLP1 might participate in the
      biogenesis of two presumably distinct organelle systems is discussed.

PMID- 10588667
TI  - Circulation of the plasma membrane in Dictyostelium.
AB  - We have developed a fluorimetric assay with the use of the dye FM1-43 to
      determine the rate at which Dictyostelium amoebae endocytose their surface
      membrane. Our results show that they do so about once each 4-10 min. A clathrin
      null mutant takes its surface up only approximately 30% more slowly, showing that
      this membrane uptake cannot be caused by clathrin-coated vesicles. Surprisingly,
      Ax2 and its parent, NC4, which differ in their rates of fluid-phase
      internalization by approximately 60-fold, take up their surfaces at the same
      rates. These results show that, in axenic cells, the uptake of fluid and of
      surface area are separate processes. The large activity of this new endocytic
      cycle in both Ax2 and NC4 amoebae appears capable of delivering sufficient new
      surface area to advance the cells' fronts during migration.

PMID- 10588668
TI  - LvsA, a protein related to the mouse beige protein, is required for cytokinesis
      in Dictyostelium.
AB  - We isolated a Dictyostelium cytokinesis mutant with a defect in a novel locus
      called large volume sphere A (lvsA). lvsA mutants exhibit an unusual phenotype
      when attempting to undergo cytokinesis in suspension culture. Early in
      cytokinesis, they initiate furrow formation with concomitant myosin II
      localization at the cleavage furrow. However, the furrow is later disrupted by a
      bulge that forms in the middle of the cell. This bulge is bounded by furrows on
      both sides, which are often enriched in myosin II. The bulge can increase and
      decrease in size multiple times as the cell attempts to divide. Interestingly,
      this phenotype is similar to the cytokinesis failure of Dictyostelium clathrin
      heavy-chain mutants. Furthermore, both cell lines cap ConA receptors but form
      only a C-shaped loose cap. Unlike clathrin mutants, lvsA mutants are not
      defective in endocytosis or development. The LvsA protein shares several domains
      in common with the molecules beige and Chediak-Higashi syndrome proteins that are
      important for lysosomal membrane traffic. Thus, on the basis of the sequence
      analysis of the LvsA protein and the phenotype of the lvsA mutants, we postulate
      that LvsA plays an important role in a membrane-processing pathway that is
      essential for cytokinesis.

PMID- 10588669
TI  - T cell receptor-induced activation and apoptosis in cycling human T cells occur
      throughout the cell cycle.
AB  - Previous studies have found conflicting associations between susceptibility to
      activation-induced cell death and the cell cycle in T cells. However, most of the
      studies used potentially toxic pharmacological agents for cell cycle
      synchronization. A panel of human melanoma tumor-reactive T cell lines, a CD8+
      HER-2/neu-reactive T cell clone, and the leukemic T cell line Jurkat were
      separated by centrifugal elutriation. Fractions enriched for the G0-G1, S, and G2
      M phases of the cell cycle were assayed for T cell receptor-mediated activation
      as measured by intracellular Ca(2+) flux, cytolytic recognition of tumor targets,
      and induction of Fas ligand mRNA. Susceptibility to apoptosis induced by
      recombinant Fas ligand and activation-induced cell death were also studied. None
      of the parameters studied was specific to a certain phase of the cell cycle,
      leading us to conclude that in nontransformed human T cells, both activation and
      apoptosis through T cell receptor activation can occur in all phases of the cell
      cycle.

PMID- 10588671
TI  - Escapees on the X chromosome.

PMID- 10588670
TI  - Programmed ribosomal frameshifting: much ado about knotting!

PMID- 10588672
TI  - Biomimetics: materials fabrication through biology.

PMID- 10588673
TI  - Multiple functions of MutS- and MutL-related heterocomplexes.

PMID- 10588675
TI  - ADD-1 provides major new insight into the mechanism of insulin action.

PMID- 10588674
TI  - Easy passage: germline transgenesis in frogs.

PMID- 10588677
TI  - Introduction to German-American frontiers of science.

PMID- 10588676
TI  - The power of stem cells reconsidered?

PMID- 10588678
TI  - Extra-solar planetary systems.

PMID- 10588679
TI  - Carbon nanotubes: from macromolecules to nanotechnology.

PMID- 10588680
TI  - Neutrinos.
AB  - Neutrinos represent a new "window" to the Universe, spanning a large range of
      energy. We discuss the science of neutrino astrophysics and focus on two energy
      regimes. At "lower" energies ( approximately 1 MeV), studies of neutrinos born
      inside the sun, or produced in interactions of cosmic rays with the atmosphere,
      have allowed the first incontrovertible evidence that neutrinos have mass. At
      energies typically one thousand to one million times higher, sources further than
      the sun (both within the Milky Way and beyond) are expected to produce a flux of
      particles that can be detected only through neutrinos.

PMID- 10588681
TI  - Image recognition: visual grouping, recognition, and learning.
AB  - Vision extracts useful information from images. Reconstructing the three
      dimensional structure of our environment and recognizing the objects that
      populate it are among the most important functions of our visual system. Computer
      vision researchers study the computational principles of vision and aim at
      designing algorithms that reproduce these functions. Vision is difficult: the
      same scene may give rise to very different images depending on illumination and
      viewpoint. Typically, an astronomical number of hypotheses exist that in
      principle have to be analyzed to infer a correct scene description. Moreover,
      image information might be extracted at different levels of spatial and logical
      resolution dependent on the image processing task. Knowledge of the world allows
      the visual system to limit the amount of ambiguity and to greatly simplify visual
      computations. We discuss how simple properties of the world are captured by the
      Gestalt rules of grouping, how the visual system may learn and organize models of
      objects for recognition, and how one may control the complexity of the
      description that the visual system computes.

PMID- 10588682
TI  - Neotectonics: watching the earth move.

PMID- 10588683
TI  - Ancient origins of nitric oxide signaling in biological systems.

PMID- 10588684
TI  - Bionics: biological insight into mechanical design.

PMID- 10588685
TI  - Residual delay maps unveil global patterns of atmospheric nonlinearity and
      produce improved local forecasts.
AB  - We use residual-delay maps of observational field data for barometric pressure to
      demonstrate the structure of latitudinal gradients in nonlinearity in the
      atmosphere. Nonlinearity is weak and largely lacking in tropical and subtropical
      sites and increases rapidly into the temperate regions where the time series also
      appear to be much noisier. The degree of nonlinearity closely follows the
      meridional variation of midlatitude storm track frequency. We extract the
      specific functional form of this nonlinearity, a V shape in the lagged residuals
      that appears to be a basic feature of midlatitude synoptic weather systems
      associated with frontal passages. We present evidence that this form arises from
      the relative time scales of high-pressure versus low-pressure events. Finally, we
      show that this nonlinear feature is weaker in a well regarded numerical forecast
      model (European Centre for Medium-Range Forecasts) because small-scale temporal
      and spatial variation is smoothed out in the grided inputs. This is significant,
      in that it allows us to demonstrate how application of statistical corrections
      based on the residual-delay map may provide marked increases in local forecast
      accuracy, especially for severe weather systems.

PMID- 10588686
TI  - Spectral bifurcations in dispersive wave turbulence.
AB  - Dispersive wave turbulence is studied numerically for a class of one-dimensional
      nonlinear wave equations. Both deterministic and random (white noise in time)
      forcings are studied. Four distinct stable spectra are observed-the direct and
      inverse cascades of weak turbulence (WT) theory, thermal equilibrium, and a
      fourth spectrum (MMT; Majda, McLaughlin, Tabak). Each spectrum can describe long
      time behavior, and each can be only metastable (with quite diverse lifetimes)
      depending on details of nonlinearity, forcing, and dissipation. Cases of a long
      live MMT transient state dcaying to a state with WT spectra, and vice-versa, are
      displayed. In the case of freely decaying turbulence, without forcing, both
      cascades of weak turbulence are observed. These WT states constitute the clearest
      and most striking numerical observations of WT spectra to date-over four decades
      of energy, and three decades of spatial, scales. Numerical experiments that study
      details of the composition, coexistence, and transition between spectra are then
      discussed, including: (i) for deterministic forcing, sharp distinctions between
      focusing and defocusing nonlinearities, including the role of long wavelength
      instabilities, localized coherent structures, and chaotic behavior; (ii) the role
      of energy growth in time to monitor the selection of MMT or WT spectra; (iii) a
      second manifestation of the MMT spectrum as it describes a self-similar evolution
      of the wave, without temporal averaging; (iv) coherent structures and the
      evolution of the direct and inverse cascades; and (v) nonlocality (in k-space) in
      the transferral process.

PMID- 10588687
TI  - Imaging of biological macromolecules on mica in humid air by scanning
      electrochemical microscopy.
AB  - Imaging of DNA, keyhole limpet hemocyanin, mouse monoclonal IgG, and glucose
      oxidase on a mica substrate has been accomplished by scanning electrochemical
      microscopy with a tungsten tip. The technique requires the use of a high relative
      humidity to form a thin film of water on the mica surface that allows
      electrochemical reactions to take place at the tip and produce a faradaic current
      (approximately 1 pA) that can be used to control tip position. The effect of
      relative humidity and surface pretreatment with buffer solutions on the ionic
      conductivity of a mica surface was investigated to find appropriate conditions
      for imaging. Resolution of the order of 1 nm was obtained.

PMID- 10588688
TI  - HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor.
AB  - Two cannabinoid receptors have been identified: CB(1), present in the central
      nervous system (CNS) and to a lesser extent in other tissues, and CB(2), present
      outside the CNS, in peripheral organs. There is evidence for the presence of
      CB(2)-like receptors in peripheral nerve terminals. We report now that we have
      synthesized a CB(2)-specific agonist, code-named HU-308. This cannabinoid does
      not bind to CB(1) (K(i) > 10 microM), but does so efficiently to CB(2) (K(i) =
      22.7 +/- 3.9 nM); it inhibits forskolin-stimulated cyclic AMP production in CB(2)
      transfected cells, but does so much less in CB(1)-transfected cells. HU-308 shows
      no activity in mice in a tetrad of behavioral tests, which together have been
      shown to be specific for tetrahydrocannabinol (THC)-type activity in the CNS
      mediated by CB(1). However, HU-308 reduces blood pressure, blocks defecation, and
      elicits anti-inflammatory and peripheral analgesic activity. The hypotension, the
      inhibition of defecation, the anti-inflammatory and peripheral analgesic effects
      produced by HU-308 are blocked (or partially blocked) by the CB(2) antagonist SR
      144528, but not by the CB(1) antagonist SR-141716A. These results demonstrate the
      feasibility of discovering novel nonpsychotropic cannabinoids that may lead to
      new therapies for hypertension, inflammation, and pain.

PMID- 10588689
TI  - Specific mutations in a viral RNA pseudoknot drastically change ribosomal
      frameshifting efficiency.
AB  - Many viruses regulate protein synthesis by -1 ribosomal frameshifting using an
      RNA pseudoknot. Frameshifting is vital for viral reproduction. Using the
      information gained from the recent high-resolution crystal structure of the beet
      western yellow virus pseudoknot, a systematic mutational analysis has been
      carried out in vitro and in vivo. We find that specific nucleotide tertiary
      interactions at the junction between the two stems of the pseudoknot are crucial.
      A triplex is found between stem 1 and loop 2, and triplex interactions are
      required for frameshifting function. For some mutations, loss of one hydrogen
      bond is sufficient to abolish frameshifting. Furthermore, mutations near the 5'
      end of the pseudoknot can increase frameshifting by nearly 300%, possibly by
      modifying ribosomal contacts. It is likely that the selection of suitable
      mutations can thus allow viruses to adjust frameshifting efficiencies and thereby
      regulate protein synthesis in response to environmental change.

PMID- 10588690
TI  - Structural origins of the exonuclease resistance of a zwitterionic RNA.
AB  - Nuclease resistance and RNA affinity are key criteria in the search for optimal
      antisense nucleic acid modifications, but the origins of the various levels of
      resistance to nuclease degradation conferred by chemical modification of DNA and
      RNA are currently not understood. The 2'-O-aminopropyl (AP)-RNA modification
      displays the highest nuclease resistance among all phosphodiester-based analogues
      and its RNA binding affinity surpasses that of phosphorothioate DNA by 1 degrees
      C per modified residue. We found that oligodeoxynucleotides containing AP-RNA
      residues at their 3' ends competitively inhibit the degradation of single
      stranded DNA by the Escherichia coli Klenow fragment (KF) 3'-5' exonuclease and
      snake venom phosphodiesterase. To shed light on the origins of nuclease
      resistance brought about by the AP modification, we determined the crystal
      structure of an A-form DNA duplex with AP-RNA modifications at 1.6-A resolution.
      In addition, the crystal structures of complexes between short DNA fragments
      carrying AP-RNA modifications and wild-type KF were determined at resolutions
      between 2.2 and 3.0 A and compared with the structure of the complex between
      oligo(dT) and the D355A/E357A KF mutant. The structural models suggest that
      interference of the positively charged 2'-O-substituent with the metal ion
      binding site B of the exonuclease allows AP-RNA to effectively slow down
      degradation.

PMID- 10588691
TI  - Structure of the glycosylphosphatidylinositol anchor of an arabinogalactan
      protein from Pyrus communis suspension-cultured cells.
AB  - Arabinogalactan proteins (AGPs) are proteoglycans of higher plants, which are
      implicated in growth and development. We recently have shown that two AGPs,
      NaAGP1 (from Nicotiana alata styles) and PcAGP1 (from Pyrus communis cell
      suspension culture), are modified by the addition of a
      glycosylphosphatidylinositol (GPI) anchor. However, paradoxically, both AGPs were
      buffer soluble rather than membrane associated. We now show that pear suspension
      cultured cells also contain membrane-bound GPI-anchored AGPs. This GPI anchor has
      the minimal core oligosaccharide structure, D-Manalpha(1-2)-D-Manalpha(1-6)-D
      Manalpha(1-4)-D-GlcN -inositol, which is consistent with those found in animals,
      protozoa, and yeast, but with a partial beta(1-4)-galactosyl substitution of the
      6-linked Man residue, and has a phosphoceramide lipid composed primarily of
      phytosphingosine and tetracosanoic acid. The secreted form of PcAGP1 contains a
      truncated GPI lacking the phosphoceramide moiety, suggesting that it is released
      from the membrane by the action of a phospholipase D. The implications of these
      findings are discussed in relation to the potential mechanisms by which GPI
      anchored AGPs may be involved in signal transduction pathways.

PMID- 10588692
TI  - The small ribosomal subunit from Thermus thermophilus at 4.5 A resolution:
      pattern fittings and the identification of a functional site.
AB  - The electron density map of the small ribosomal subunit from Thermus
      thermophilus, constructed at 4.5 A resolution, shows the recognizable morphology
      of this particle, as well as structural features that were interpreted as
      ribosomal RNA and proteins. Unbiased assignments, carried out by quantitative
      covalent binding of heavy atom compounds at predetermined sites, led to the
      localization of the surface of the ribosomal protein S13 at a position compatible
      with previous assignments, whereas the surface of S11 was localized at a distance
      of about twice its diameter from the site suggested for its center by neutron
      scattering. Proteins S5 and S7, whose structures have been determined
      crystallographically, were visually placed in the map with no alterations in
      their conformations. Regions suitable to host the fold of protein S15 were
      detected in several positions, all at a significant distance from the location of
      this protein in the neutron scattering map. Targeting the 16S RNA region, where
      mRNA docks to allow the formation of the initiation complex by a mercurated mRNA
      analog, led to the characterization of its vicinity.

PMID- 10588693
TI  - A physical basis for protein secondary structure.
AB  - A physical theory of protein secondary structure is proposed and tested by
      performing exceedingly simple Monte Carlo simulations. In essence, secondary
      structure propensities are predominantly a consequence of two competing local
      effects, one favoring hydrogen bond formation in helices and turns, the other
      opposing the attendant reduction in sidechain conformational entropy on helix and
      turn formation. These sequence specific biases are densely dispersed throughout
      the unfolded polypeptide chain, where they serve to preorganize the folding
      process and largely, but imperfectly, anticipate the native secondary structure.

PMID- 10588694
TI  - Inorganic polyphosphate kinase is required to stimulate protein degradation and
      for adaptation to amino acid starvation in Escherichia coli.
AB  - Inorganic polyphosphate (polyP) kinase was studied for its roles in physiological
      responses to nutritional deprivation in Escherichia coli. A mutant lacking polyP
      kinase exhibited an extended lag phase of growth, when shifted from a rich to a
      minimal medium (nutritional downshift). Supplementation of amino acids to the
      minimal medium abolished the extended growth lag of the mutant. Levels of the
      stringent response factor, guanosine 5'-diphosphate 3'-diphosphate, increased in
      response to the nutritional downshift, but, unlike in the wild type, the levels
      were sustained in the mutant. These results suggested that the mutant was
      impaired in the induction of amino acid biosynthetic enzymes. The expression of
      an amino acid biosynthetic gene, hisG, was examined by using a transcriptional
      lacZ fusion. Although the mutant did not express the fusion in response to the
      nutritional downshift, Northern blot analysis revealed a significant increase of
      hisG-lacZ mRNA. Amino acids generated by intracellular protein degradation are
      very important for the synthesis of enzymes at the onset of starvation. In the
      wild type, the rate of protein degradation increased in response to the
      nutritional downshift whereas it did not in the mutant. Supplementation of amino
      acids at low concentrations to the minimal medium enabled the mutant to express
      the hisG-lacZ fusion. Thus, the impaired regulation of protein degradation
      results in the adaptation defect, suggesting that polyP kinase is required to
      stimulate protein degradation.

PMID- 10588695
TI  - The mechanism of pseudouridine synthase I as deduced from its interaction with 5
      fluorouracil-tRNA.
AB  - tRNA pseudouridine synthase I (PsiSI) catalyzes the conversion of uridine to Psi
      at positions 38, 39, and/or 40 in the anticodon loop of tRNAs. PsiSI forms a
      covalent adduct with 5-fluorouracil (FUra)-tRNA (tRNA(Phe) containing FUra in
      place of Ura) to form a putative analog of a steady-state intermediate in the
      normal reaction pathway. Previously, we proposed that a conserved aspartate of
      the enzyme serves as a nucleophilic catalyst in both the normal enzyme reaction
      and in the formation of a covalent complex with FUra-tRNA. The covalent adduct
      between FUra-tRNA and PsiSI was isolated and disrupted by hydrolysis and the FUra
      tRNA was recovered. The target FU39 of the recovered FUra-tRNA was modified by
      the addition of water across the 5,6-double bond of the pyrimidine base to form
      5,6-dihydro-6-hydroxy-5-fluorouridine. We deduced that the conserved aspartate of
      the enzyme adds to the 6-position of the target FUra to form a stable covalent
      adduct, which can undergo O-acyl hydrolytic cleavage to form the observed
      product. Assuming that an analogous covalent complex is formed in the normal
      reaction, we have deduced a complete mechanism for PsiS.

PMID- 10588696
TI  - Inhibition of human telomerase in immortal human cells leads to progressive
      telomere shortening and cell death.
AB  - The correlation between telomerase activity and human tumors has led to the
      hypothesis that tumor growth requires reactivation of telomerase and that
      telomerase inhibitors represent a class of chemotherapeutic agents. Herein, we
      examine the effects of inhibition of telomerase inside human cells. Peptide
      nucleic acid and 2'-O-MeRNA oligomers inhibit telomerase, leading to progressive
      telomere shortening and causing immortal human breast epithelial cells to undergo
      apoptosis with increasing frequency until no cells remain. Telomere shortening is
      reversible: if inhibitor addition is terminated, telomeres regain their initial
      lengths. Our results validate telomerase as a target for the discovery of
      anticancer drugs and supply general insights into the properties that successful
      agents will require regardless of chemical type. Chemically similar
      oligonucleotides are in clinical trials and have well characterized
      pharmacokinetics, making the inhibitors we describe practical lead compounds for
      testing for an antitelomerase chemotherapeutic strategy.

PMID- 10588697
TI  - A conserved serine-rich stretch in the glutamate transporter family forms a
      substrate-sensitive reentrant loop.
AB  - Neuronal and glial glutamate transporters remove the excitatory neurotransmitter
      glutamate from the synaptic cleft. The proteins belong to a large family of
      secondary transporters, which includes bacterial glutamate transporters. The C
      terminal half of the glutamate transporters is well conserved and thought to
      contain the translocation path and the binding sites for substrate and coupling
      ions. A serine-rich sequence motif in this part of the proteins is located in a
      putative intracellular loop. Cysteine-scanning mutagenesis was applied to this
      loop in the glutamate transporter GltT of Bacillus stearothermophilus. The loop
      was found to be largely intracellular, but three consecutive positions in the
      conserved serine-rich motif (S269, S270, and E271) are accessible from both sides
      of the membrane. Single-cysteine mutants in the serine-rich motif were still
      capable of glutamate transport, but modification with N-ethylmaleimide blocked
      the transport activity in six mutants (T267C, A268C, S269C, S270C, E271C, and
      T272C). Two milimolars L-glutamate effectively protected against the modification
      of the cysteines at position 269-271 from the periplasmic side of the membrane
      but was unable to protect cysteine modification from the cytoplasmic side of the
      membrane. The results indicate that the conserved serine-rich motif in the
      glutamate transporter forms a reentrant loop, a structure that is found in
      several ion channels but is unusual for transporter proteins. The reentrant loop
      is of crucial importance for the function of the glutamate transporter.

PMID- 10588698
TI  - Photoassembly of the manganese cluster and oxygen evolution from monomeric and
      dimeric CP47 reaction center photosystem II complexes.
AB  - Isolated subcomplexes of photosystem II from spinach (CP47RC), composed of D1,
      D2, cytochrome b(559), CP47, and a number of hydrophobic small subunits but
      devoid of CP43 and the extrinsic proteins of the oxygen-evolving complex, were
      shown to reconstitute the Mn(4)Ca(1)Cl(x) cluster of the water-splitting system
      and to evolve oxygen. The photoactivation process in CP47RC dimers proceeds by
      the same two-step mechanism as observed in PSII membranes and exhibits the same
      stoichiometry for Mn(2+), but with a 10-fold lower affinity for Ca(2+) and an
      increased susceptibility to photodamage. After the lower Ca(2+) affinity and the
      10-fold smaller absorption cross-section for photons in CP47 dimers is taken into
      account, the intrinsic rate constant for the rate-limiting calcium-dependent dark
      step is indistinguishable for the two systems. The monomeric form of CP47RC also
      showed capacity to photoactivate and catalyze water oxidation, but with lower
      activity than the dimeric form and increased susceptibility to photodamage. After
      optimization of the various parameters affecting the photoactivation process in
      dimeric CP47RC subcores, 18% of the complexes were functionally reconstituted and
      the quantum efficiency for oxygen production by reactivated centers approached
      96% of that observed for reconstituted photosystem II-enriched membranes.

PMID- 10588699
TI  - Transcriptional coupling between the divergent promoters of a prototypic LysR
      type regulatory system, the ilvYC operon of Escherichia coli.
AB  - The twin-domain model [Liu, L. F. & Wang, J. C. (1987) Proc. Natl. Acad. Sci. USA
      84, 7024-7027] suggests that closely spaced, divergent, superhelically sensitive
      promoters can affect the transcriptional activity of one another by
      transcriptionally induced negative DNA supercoiling generated in the divergent
      promoter region. This gene arrangement is observed for many LysR-type-regulated
      operons in bacteria. We have examined the effects of divergent transcription in
      the prototypic LysR-type system, the ilvYC operon of Escherichia coli. Double
      reporter constructs with the lacZ gene under transcriptional control of the ilvC
      promoter and the galK gene under control of the divergent ilvY promoter were used
      to demonstrate that a down-promoter mutation in the ilvY promoter severely
      decreases in vivo transcription from the ilvC promoter. However, a down-promoter
      mutation in the ilvC promoter only slightly affects transcription from the ilvY
      promoter. In vitro transcription assays with DNA topoisomers showed that
      transcription from the ilvC promoter increases over the entire range of
      physiological superhelical densities, whereas transcription initiation from the
      ilvY promoter exhibits a broad optimum at a midphysiological superhelical
      density. Evidence that this promoter coupling is DNA supercoiling-dependent is
      provided by the observation that a novobiocin-induced decrease in global negative
      superhelicity results in an increase in ilvY promoter activity and a decrease in
      ilvC promoter activity predicted by the in vitro data. We suggest that this
      transcriptional coupling is important for coordinating basal level expression of
      the ilvYC operon with the nutritional and environmental conditions of cell
      growth.

PMID- 10588700
TI  - Modification of EWS/WT1 functional properties by phosphorylation.
AB  - In many human cancers, tumor-specific chromosomal rearrangements are known to
      create chimeric products with the ability to transform cells. The EWS/WT1 protein
      is such a fusion product, resulting from a t(11;22) chromosomal translocation in
      desmoplastic small round cell tumors, where 265 aa from the EWS amino terminus
      are fused to the DNA binding domain of the WT1 tumor suppressor gene. Herein, we
      find that EWS/WT1 is phosphorylated in vivo on serine and tyrosine residues and
      that this affects DNA binding and homodimerization. We also show that EWS/WT1 can
      interact with, and is a substrate for, modification on tyrosine residues by c
      Abl. Tyrosine phosphorylation of EWS/WT1 by c-Abl negatively regulates its DNA
      binding properties. These results indicate that the biological activity of
      EWS/WT1 is closely linked to its phosphorylation status.

PMID- 10588701
TI  - Active hair-bundle movements can amplify a hair cell's response to oscillatory
      mechanical stimuli.
AB  - To enhance their mechanical sensitivity and frequency selectivity, hair cells
      amplify the mechanical stimuli to which they respond. Although cell-body
      contractions of outer hair cells are thought to mediate the active process in the
      mammalian cochlea, vertebrates without outer hair cells display highly sensitive,
      sharply tuned hearing and spontaneous otoacoustic emissions. In these animals the
      amplifier must reside elsewhere. We report physiological evidence that
      amplification can stem from active movement of the hair bundle, the hair cell's
      mechanosensitive organelle. We performed experiments on hair cells from the
      sacculus of the bullfrog. Using a two-compartment recording chamber that permits
      exposure of the hair cell's apical and basolateral surfaces to different
      solutions, we examined active hair-bundle motion in circumstances similar to
      those in vivo. When the apical surface was bathed in artificial endolymph, many
      hair bundles exhibited spontaneous oscillations of amplitudes as great as 50 nm
      and frequencies in the range 5 to 40 Hz. We stimulated hair bundles with a
      flexible glass probe and recorded their mechanical responses with a photometric
      system. When the stimulus frequency lay within a band enclosing a hair cell's
      frequency of spontaneous oscillation, mechanical stimuli as small as +/-5 nm
      entrained the hair-bundle oscillations. For small stimuli, the bundle movement
      was larger than the stimulus. Because the energy dissipated by viscous drag
      exceeded the work provided by the stimulus probe, the hair bundles powered their
      motion and therefore amplified it.

PMID- 10588702
TI  - Network formation of lipid membranes: triggering structural transitions by chain
      melting.
AB  - Phospholipids when dispersed in excess water generally form vesicular membrane
      structures. Cryo-transmission and freeze-fracture electron microscopy are
      combined here with calorimetry and viscometry to demonstrate the reversible
      conversion of phosphatidylglycerol aqueous vesicle suspensions to a three
      dimensional structure that consists of extended bilayer networks. Thermodynamic
      analysis indicates that the structural transitions arise from two effects: (i)
      the enhanced membrane elasticity accompanying the lipid state fluctuations on
      chain melting and (ii) solvent-associated interactions (including electrostatics)
      that favor a change in membrane curvature. The material properties of the
      hydrogels and their reversible formation offer the possibility of future
      applications, for example in drug delivery, the design of structural switches, or
      for understanding vesicle fusion or fission processes.

PMID- 10588703
TI  - Detection of protein fold similarity based on correlation of amino acid
      properties.
AB  - An increasing number of proteins with weak sequence similarity have been found to
      assume similar three-dimensional fold and often have similar or related
      biochemical or biophysical functions. We propose a method for detecting the fold
      similarity between two proteins with low sequence similarity based on their amino
      acid properties alone. The method, the proximity correlation matrix (PCM) method,
      is built on the observation that the physical properties of neighboring amino
      acid residues in sequence at structurally equivalent positions of two proteins of
      similar fold are often correlated even when amino acid sequences are different.
      The hydrophobicity is shown to be the most strongly correlated property for all
      protein fold classes. The PCM method was tested on 420 proteins belonging to 64
      different known folds, each having at least three proteins with little sequence
      similarity. The method was able to detect fold similarities for 40% of the 420
      sequences. Compared with sequence comparison and several fold-recognition
      methods, the method demonstrates good performance in detecting fold similarities
      among the proteins with low sequence identity. Applied to the complete genome of
      Methanococcus jannaschii, the method recognized the folds for 22 hypothetical
      proteins.

PMID- 10588704
TI  - Vibrational population relaxation of carbon monoxide in the heme pocket of
      photolyzed carbonmonoxy myoglobin: comparison of time-resolved mid-IR absorbance
      experiments and molecular dynamics simulations.
AB  - The vibrational energy relaxation of carbon monoxide in the heme pocket of sperm
      whale myoglobin was studied by using molecular dynamics simulation and normal
      mode analysis methods. Molecular dynamics trajectories of solvated myoglobin were
      run at 300 K for both the delta- and epsilon-tautomers of the distal His-64.
      Vibrational population relaxation times of 335 +/- 115 ps for the delta-tautomer
      and 640 +/- 185 ps for the epsilon-tautomer were estimated by using the Landau
      Teller model. Normal mode analysis was used to identify those protein residues
      that act as the primary "doorway" modes in the vibrational relaxation of the
      oscillator. Although the CO relaxation rates in both the epsilon- and delta
      tautomers are similar in magnitude, the simulations predict that the vibrational
      relaxation of the CO is faster in the delta-tautomer with the distal His playing
      an important role in the energy relaxation mechanism. Time-resolved mid-IR
      absorbance measurements were performed on photolyzed carbonmonoxy hemoglobin
      (Hb(13)CO). From these measurements, a T(1) time of 600 +/- 150 ps was
      determined. The simulation and experimental estimates are compared and discussed.

PMID- 10588705
TI  - Molecular dynamics and free-energy calculations applied to affinity maturation in
      antibody 48G7.
AB  - We investigated the relative free energies of hapten binding to the germ line and
      mature forms of the 48G7 antibody Fab fragments by applying a continuum model to
      structures sampled from molecular dynamics simulations in explicit solvent.
      Reasonable absolute and very good relative free energies were obtained. As a
      result of nine somatic mutations that do not contact the hapten, the affinity
      matured antibody binds the hapten >10(4) tighter than the germ line antibody.
      Energetic analysis reveals that van der Waals interactions and nonpolar
      contributions to solvation are similar and drive the formations of both the germ
      line and mature antibody-hapten complexes. Affinity maturation of the 48G7
      antibody therefore appears to occur through reorganization of the combining site
      geometry in a manner that optimizes the balance of gaining favorable
      electrostatic interactions with the hapten and losing those with solvent during
      the binding process. As reflected by lower rms fluctuations in the antibody
      hapten complex, the mature complex undergoes more restricted fluctuations than
      the germ line complex. The dramatically increased affinity of the 48G7 antibody
      over its germ line precursor is thus made possible by electrostatic optimization.

PMID- 10588706
TI  - Correlation of the structural and functional domains in the membrane protein Vpu
      from HIV-1.
AB  - Vpu is an 81-residue membrane protein encoded by the HIV-1 genome. NMR
      experiments show that the protein folds into two distinct domains, a
      transmembrane hydrophobic helix and a cytoplasmic domain with two in-plane
      amphipathic alpha-helices separated by a linker region. Resonances in one
      dimensional solid-state NMR spectra of uniformly (15)N labeled Vpu are clearly
      segregated into two bands at chemical shift frequencies associated with NH bonds
      in a transmembrane alpha-helix, perpendicular to the membrane surface, and with
      NH bonds in the cytoplasmic helices parallel to the membrane surface. Solid-state
      NMR spectra of truncated Vpu(2-51) (residues 2-51), which contains the
      transmembrane alpha-helix and the first amphipathic helix of the cytoplasmic
      domain, and of a construct Vpu(28-81) (residues 28-81), which contains only the
      cytoplasmic domain, support this structural model of Vpu in the membrane. Full
      length Vpu (residues 2-81) forms discrete ion-conducting channels of
      heterogeneous conductance in lipid bilayers. The most frequent conductances were
      22 +/- 3 pS and 12 +/- 3 pS in 0.5 M KCl and 29 +/- 3 pS and 12 +/- 3 pS in 0.5 M
      NaCl. In agreement with the structural model, truncated Vpu(2-51), which has the
      transmembrane helix, forms discrete channels in lipid bilayers, whereas the
      cytoplasmic domain Vpu(28-81), which lacks the transmembrane helix, does not.
      This finding shows that the channel activity is associated with the transmembrane
      helical domain. The pattern of channel activity is characteristic of the self
      assembly of conductive oligomers in the membrane and is compatible with the
      structural and functional findings.

PMID- 10588707
TI  - Transport of torsional stress in DNA.
AB  - It is well known that transcription can induce torsional stress in DNA, affecting
      the activity of nearby genes or even inducing structural transitions in the DNA
      duplex. It has long been assumed that the generation of significant torsional
      stress requires the DNA to be anchored, forming a limited topological domain,
      because otherwise it would spin almost freely about its axis. Previous estimates
      of the rotational drag have, however, neglected the role of small natural bends
      in the helix backbone. We show how these bends can increase the drag several
      thousandfold relative to prior estimates, allowing significant torsional stress
      even in linear unanchored DNA. The model helps explain several puzzling
      experimental results on structural transitions induced by transcription of DNA.

PMID- 10588708
TI  - Proton uptake by bacterial reaction centers: the protein complex responds in a
      similar manner to the reduction of either quinone acceptor.
AB  - In bacterial photosynthetic reaction centers, the protonation events associated
      with the different reduction states of the two quinone molecules constitute
      intrinsic probes of both the electrostatic interactions and the different kinetic
      events occurring within the protein in response to the light-generated
      introduction of a charge. The kinetics and stoichiometries of proton uptake on
      formation of the primary semiquinone Q(A)(-) and the secondary acceptor Q(B)(-)
      after the first and second flashes have been measured, at pH 7.5, in reaction
      centers from genetically modified strains and from the wild type. The modified
      strains are mutated at the L212Glu and/or at the L213Asp sites near Q(B); some of
      them carry additional mutations distant from the quinone sites (M231Arg --> Leu,
      M43Asn --> Asp, M5Asn --> Asp) that compensate for the loss of L213Asp. Our data
      show that the mutations perturb the response of the protein system to the
      formation of a semiquinone, how distant compensatory mutations can restore the
      normal response, and the activity of a tyrosine residue (M247Ala --> Tyr) in
      increasing and accelerating proton uptake. The data demonstrate a direct
      correlation between the kinetic events of proton uptake that are observed with
      the formation of either Q(A)(-) or Q(B)(-), suggesting that the same residues
      respond to the generation of either semiquinone species. Therefore, the
      efficiency of transferring the first proton to Q(B) is evident from examination
      of the pattern of H(+)/Q(A)(-) proton uptake. This delocalized response of the
      protein complex to the introduction of a charge is coordinated by an interactive
      network that links the Q(-) species, polarizable residues, and numerous water
      molecules that are located in this region of the reaction center structure. This
      could be a general property of transmembrane redox proteins that couple electron
      transfer to proton uptake/release reactions.

PMID- 10588709
TI  - Positional enhancer-blocking activity of the chicken beta-globin insulator in
      transiently transfected cells.
AB  - It is thought that insulators demarcate transcriptionally and structurally
      independent chromatin domains. Insulators are detected by their ability to block
      enhancer-promoter interactions in a directional manner, and protect a transgene
      from position effects. Most studies are performed in stably transformed cells or
      organisms. Here we analyze the enhancer-blocking activity of the chicken beta
      globin insulator in transient transfection experiments in both erythroid and
      nonerythroid cell lines. We show that four tandem copies of a 90-bp fragment of
      this insulator were able to block an enhancer in these experiments. In circular
      plasmids, placement on either side of the enhancer reduced activity, but when the
      plasmid was linearized, the enhancer-blocking activity was observed only when the
      insulator was placed between the promoter and the enhancer. These observations
      are consistent with the position-dependent enhancer-blocking activity of the
      insulator observed in stable transformation experiments.

PMID- 10588710
TI  - The polo-box-dependent induction of ectopic septal structures by a mammalian polo
      kinase, plk, in Saccharomyces cerevisiae.
AB  - Members of the polo subfamily of protein kinases play pivotal roles in cell-cycle
      control and proliferation. In addition to a high degree of sequence similarity in
      the kinase domain, polo kinases contain a strikingly conserved motif termed "polo
      box" in the noncatalytic C-terminal domain. We have previously shown that the
      mammalian polo-like kinase Plk is a functional homolog of Saccharomyces
      cerevisiae Cdc5. Here, we show that, in a polo-box- and kinase activity-dependent
      manner, ectopic expression of Plk in budding yeast can induce a class of cells
      with abnormally elongated buds. In addition to localization at spindle poles and
      cytokinetic neck filaments, Plk induces and localizes to ectopic septin ring
      structures within the elongated buds. In contrast, mutations in the polo-box
      abolish both localization to, and induction of, septal structures. Consistent
      with the polo-box-dependent subcellular localization, the C-terminal domain of
      Plk, but not its polo-box mutant, is sufficient for subcellular localization. Our
      data suggest that Plk may contribute a signal to initiate or promote cytokinetic
      event(s) and that an intact polo-box is required for regulation of these cellular
      processes.

PMID- 10588711
TI  - Nuclear tRNA aminoacylation and its role in nuclear export of endogenous tRNAs in
      Saccharomyces cerevisiae.
AB  - Nuclear tRNA aminoacylation was proposed to provide a proofreading step in
      Xenopus oocytes, ensuring nuclear export of functional tRNAs [Lund, E. &
      Dahlberg, J. E. (1998) Science 282, 2082-2085]. Herein, it is documented that
      tRNA aminoacylation also occurs in yeast nuclei and is important for tRNA export.
      We propose that tRNA aminoacylation functions in one of at least two parallel
      paths of tRNA export in yeast. Alteration of one aminoacyl-tRNA synthetase
      affects export of only cognate tRNA, whereas alterations of two other aminoacyl
      tRNA synthetases affect export of both cognate and noncognate tRNAs. Saturation
      of tRNA export pathway is a possible explanation of this phenomenon.

PMID- 10588712
TI  - Mammalian Trithorax and polycomb-group homologues are antagonistic regulators of
      homeotic development.
AB  - Control of cell identity during development is specified in large part by the
      unique expression patterns of multiple homeobox-containing (Hox) genes in
      specific segments of an embryo. Trithorax and Polycomb-group (Trx-G and Pc-G)
      proteins in Drosophila maintain Hox expression or repression, respectively. Mixed
      lineage leukemia (MLL) is frequently involved in chromosomal translocations
      associated with acute leukemia and is the one established mammalian homologue of
      Trx. Bmi-1 was first identified as a collaborator in c-myc-induced murine
      lymphomagenesis and is homologous to the Drosophila Pc-G member Posterior sex
      combs. Here, we note the axial-skeletal transformations and altered Hox
      expression patterns of Mll-deficient and Bmi-1-deficient mice were normalized
      when both Mll and Bmi-1 were deleted, demonstrating their antagonistic role in
      determining segmental identity. Embryonic fibroblasts from Mll-deficient compared
      with Bmi-1-deficient mice demonstrate reciprocal regulation of Hox genes as well
      as an integrated Hoxc8-lacZ reporter construct. Reexpression of MLL was able to
      overcome repression, rescuing expression of Hoxc8-lacZ in Mll-deficient cells.
      Consistent with this, MLL and BMI-I display discrete subnuclear colocalization.
      Although Drosophila Pc-G and Trx-G members have been shown to maintain a
      previously established transcriptional pattern, we demonstrate that MLL can also
      dynamically regulate a target Hox gene.

PMID- 10588713
TI  - Pax6 is essential for establishing ventral-dorsal cell boundaries in pituitary
      gland development.
AB  - Pax6, a highly conserved member of the paired homeodomain transcription factor
      family that plays essential roles in ocular, neural, and pancreatic development
      and effects asymmetric transient dorsal expression during pituitary development,
      with its expression extinguished before the ventral --> dorsal appearance of
      specific cell types. Analysis of pituitary development in the Small eye and Pax6 
      /- mouse mutants reveals that the dorsoventral axis of the pituitary gland
      becomes ventralized, with dorsal extension of the transcriptional determinants of
      ventral cell types, particularly PFrk. This ventralization is followed by a
      marked decrease in terminally differentiated dorsal somatotrope and lactotrope
      cell types and a marked increase in the expression of markers of the ventral
      thyrotrope cells and SF-1-expressing cells of gonadotrope lineage. We suggest
      that the transient dorsal expression of Pax6 is essential for establishing a
      sharp boundary between dorsal and ventral cell types, based on the inhibition of
      Shh ventral signals.

PMID- 10588714
TI  - Activation of a frizzled-2/beta-adrenergic receptor chimera promotes Wnt
      signaling and differentiation of mouse F9 teratocarcinoma cells via Galphao and
      Galphat.
AB  - The frizzled gene family of putative Wnt receptors encodes proteins that have a
      seven-transmembrane-spanning motif characteristic of G protein-linked receptors,
      though no loss-of-function studies have demonstrated a requirement for G proteins
      for Frizzled signaling. We engineered a Frizzled-2 chimera responsive to beta
      adrenergic agonist by using the ligand-binding domains of the beta(2)-adrenergic
      receptor. The expectation was that the chimera would be sensitive both to drug
      mediated activation and blockade, thereby circumventing the problem of purifying
      soluble and active Wnt ligand to activate Frizzled. Expression of the chimera in
      zebrafish embryos demonstrated isoproterenol (ISO)-stimulated, propranolol
      sensitive calcium transients, thereby confirming the beta-adrenergic nature of
      Wnt signaling by the chimeric receptor. Because F9 embryonic teratocarcinoma
      cells form primitive endoderm after stable transfection of Frizzled-2 chimera and
      stimulation with ISO, they were subject to depletion of G protein subunits. ISO
      stimulation of endoderm formation of F9 stem cells expressing the chimeric
      receptor was blocked by pertussis toxin and by oligodeoxynucleotide antisense to
      Galphao, Galphat2, and Gbeta2. Our results demonstrate the requirement of two
      pertussis toxin-sensitive G proteins, Galphao and Galphat, for signaling by the
      Frizzled-2 receptor.

PMID- 10588715
TI  - Germ-line transmission of transgenes in Xenopus laevis.
AB  - Adult Xenopus laevis frogs made transgenic by restriction enzyme-mediated
      integration were bred to test the feasibility of establishing lines of frogs that
      express transgenes. All of the 19 animals raised to sexual maturity generated
      progeny that expressed the transgene(s). The patterns and levels of expression of
      green fluorescent protein transgenes driven by a viral promoter, rat promoter,
      and four X. laevis promoters were all unaffected by passage through the germ
      line. These results demonstrate the ease of establishing transgenic lines in X.
      laevis.

PMID- 10588716
TI  - Chloroplast small heat shock proteins: evidence for atypical evolution of an
      organelle-localized protein.
AB  - Knowledge of the origin and evolution of gene families is critical to our
      understanding of the evolution of protein function. To gain a detailed
      understanding of the evolution of the small heat shock proteins (sHSPs) in
      plants, we have examined the evolutionary history of the chloroplast (CP)
      localized sHSPs. Previously, these nuclear-encoded CP proteins had been
      identified only from angiosperms. This study reveals the presence of the CP sHSPs
      in a moss, Funaria hygrometrica. Two clones for CP sHSPs were isolated from a F.
      hygrometrica heat shock cDNA library that represent two distinct CP sHSP genes.
      Our analysis of the CP sHSPs reveals unexpected evolutionary relationships and
      patterns of sequence conservation. Phylogenetic analysis of the CP sHSPs with
      other plant CP sHSPs and eukaryotic, archaeal, and bacterial sHSPs shows that the
      CP sHSPs are not closely related to the cyanobacterial sHSPs. Thus, they most
      likely evolved via gene duplication from a nuclear-encoded cytosolic sHSP and not
      via gene transfer from the CP endosymbiont. Previous sequence analysis had shown
      that all angiosperm CP sHSPs possess a methionine-rich region in the N-terminal
      domain. The primary sequence of this region is not highly conserved in the F.
      hygrometrica CP sHSPs. This lack of sequence conservation indicates that sometime
      in land plant evolution, after the divergence of mosses from the common ancestor
      of angiosperms but before the monocot-dicot divergence, there was a change in the
      selective constraints acting on the CP sHSPs.

PMID- 10588717
TI  - Phylogeny of rice genomes with emphasis on origins of allotetraploid species.
AB  - The rice genus, Oryza, which comprises 23 species and 9 recognized genome types,
      represents an enormous gene pool for genetic improvement of rice cultivars.
      Clarification of phylogenetic relationships of rice genomes is critical for
      effective utilization of the wild rice germ plasm. By generating and comparing
      two nuclear gene (Adh1 and Adh2) trees and a chloroplast gene (matK) tree of all
      rice species, phylogenetic relationships among the rice genomes were inferred.
      Origins of the allotetraploid species, which constitute more than one-third of
      rice species diversity, were reconstructed based on the Adh gene phylogenies.
      Genome types of the maternal parents of allotetraploid species were determined
      based on the matK gene tree. The phylogenetic reconstruction largely supports the
      previous recognition of rice genomes. It further revealed that the EE genome
      species is most closely related to the DD genome progenitor that gave rise to the
      CCDD genome. Three species of the CCDD genome may have originated through a
      single hybridization event, and their maternal parent had the CC genome. The BBCC
      genome species had different origins, and their maternal parents had either a BB
      or CC genome. An additional genome type, HHKK, was recognized for Oryza
      schlechteri and Porteresia coarctata, suggesting that P. coarctata is an Oryza
      species. The AA genome lineage, which contains cultivated rice, is a recently
      diverged and rapidly radiated lineage within the rice genus.

PMID- 10588718
TI  - Duplicated genes evolve independently after polyploid formation in cotton.
AB  - Of the many processes that generate gene duplications, polyploidy is unique in
      that entire genomes are duplicated. This process has been important in the
      evolution of many eukaryotic groups, and it occurs with high frequency in plants.
      Recent evidence suggests that polyploidization may be accompanied by rapid
      genomic changes, but the evolutionary fate of discrete loci recently doubled by
      polyploidy (homoeologues) has not been studied. Here we use locus-specific
      isolation techniques with comparative mapping to characterize the evolution of
      homoeologous loci in allopolyploid cotton (Gossypium hirsutum) and in species
      representing its diploid progenitors. We isolated and sequenced 16 loci from both
      genomes of the allopolyploid, from both progenitor diploid genomes and
      appropriate outgroups. Phylogenetic analysis of the resulting 73.5 kb of sequence
      data demonstrated that for all 16 loci (14.7 kb/genome), the topology expected
      from organismal history was recovered. In contrast to observations involving
      repetitive DNAs in cotton, there was no evidence of interaction among duplicated
      genes in the allopolyploid. Polyploidy was not accompanied by an obvious increase
      in mutations indicative of pseudogene formation. Additionally, differences in
      rates of divergence among homoeologues in polyploids and orthologues in diploids
      were indistinguishable across loci, with significant rate deviation restricted to
      two putative pseudogenes. Our results indicate that most duplicated genes in
      allopolyploid cotton evolve independently of each other and at the same rate as
      those of their diploid progenitors. These indications of genic stasis
      accompanying polyploidization provide a sharp contrast to recent examples of
      rapid genomic evolution in allopolyploids.

PMID- 10588719
TI  - The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency
      syndrome.
AB  - DNA methylation is an important regulator of genetic information in species
      ranging from bacteria to humans. DNA methylation appears to be critical for
      mammalian development because mice nullizygous for a targeted disruption of the
      DNMT1 DNA methyltransferase die at an early embryonic stage. No DNA
      methyltransferase mutations have been reported in humans until now. We describe
      here the first example of naturally occurring mutations in a mammalian DNA
      methyltransferase gene. These mutations occur in patients with a rare autosomal
      recessive disorder, which is termed the ICF syndrome, for immunodeficiency,
      centromeric instability, and facial anomalies. Centromeric instability of
      chromosomes 1, 9, and 16 is associated with abnormal hypomethylation of CpG sites
      in their pericentromeric satellite regions. We are able to complement this
      hypomethylation defect by somatic cell fusion to Chinese hamster ovary cells,
      suggesting that the ICF gene is conserved in the hamster and promotes de novo
      methylation. ICF has been localized to a 9-centimorgan region of chromosome 20 by
      homozygosity mapping. By searching for homologies to known DNA
      methyltransferases, we identified a genomic sequence in the ICF region that
      contains the homologue of the mouse Dnmt3b methyltransferase gene. Using the
      human sequence to screen ICF kindreds, we discovered mutations in four patients
      from three families. Mutations include two missense substitutions and a 3-aa
      insertion resulting from the creation of a novel 3' splice acceptor. None of the
      mutations were found in over 200 normal chromosomes. We conclude that mutations
      in the DNMT3B are responsible for the ICF syndrome.

PMID- 10588720
TI  - Genomic analysis of human and mouse TCL1 loci reveals a complex of tightly
      clustered genes.
AB  - TCL1 and TCL1b genes on human chromosome 14q23.1 are activated in T cell
      leukemias by translocations and inversions at 14q32.1, juxtaposing them to
      regulatory elements of T cell receptor genes. In this report we present the
      cloning, mapping, and expression analysis of the human and murine TCL1/Tcl1
      locus. In addition to TCL1 and TCL1b, the human locus contains two additional
      genes, TCL1-neighboring genes (TNG) 1 and 2, encoding proteins of 141 and 110 aa,
      respectively. Both genes show no homology to any known genes, but their
      expression profiles are very similar to those of TCL1 and TCL1b. TNG1 and TNG2
      also are activated in T cell leukemias with rearrangements at 14q32.1. To aid in
      the development of a mouse model we also have characterized the murine Tcl1 locus
      and found five genes homologous to human TCL1b. Tcl1b1-Tcl1b5 proteins range from
      117 to 123 aa and are 65-80% similar, but they show only a 30-40% similarity to
      human TCL1b. All five mouse Tcl1b and murine Tcl1 mRNAs are abundant in mouse
      oocytes and two-cell embryos but rare in various adult tissues and lymphoid cell
      lines. These data suggest a similar or complementary function of these proteins
      in early embryogenesis.

PMID- 10588721
TI  - Further examination of the Xist promoter-switch hypothesis in X inactivation:
      evidence against the existence and function of a P(0) promoter.
AB  - The onset of X inactivation coincides with accumulation of Xist RNA along the
      future inactive X chromosome. A recent hypothesis proposed that accumulation is
      initiated by a promoter switch within Xist. In this hypothesis, an upstream
      promoter (P(0)) produces an unstable transcript, while the known downstream
      promoter (P(1)) produces a stable RNA. To test this hypothesis, we examined
      expression and half-life of Xist RNA produced from an Xist transgene lacking P(0)
      but retaining P(1). We confirm the previous finding that P(0) is dispensable for
      Xist expression in undifferentiated cells and that P(1) can be used in both
      undifferentiated and differentiated cells. Herein, we show that Xist RNA
      initiated at P(1) is unstable and does not accumulate. Further analysis indicates
      that the transcriptional boundary at P(0) does not represent the 5' end of a
      distinct Xist isoform. Instead, P(0) is an artifact of cross-amplification caused
      by a pseudogene of the highly expressed ribosomal protein S12 gene Rps12. Using
      strand-specific techniques, we find that transcription upstream of P(1)
      originates from the DNA strand opposite Xist and represents the 3' end of the
      antisense Tsix RNA. Thus, these data do not support the existence of a P(0)
      promoter and suggest that mechanisms other than switching of functionally
      distinct promoters control the up-regulation of Xist.

PMID- 10588723
TI  - Telomeres of polytene chromosomes in a ciliated protozoan terminate in duplex DNA
      loops.
AB  - The end of a telomeric DNA sequence isolated from a polytene chromosome of a
      hypotrichous ciliate folds back and hybridizes with downstream telomeric sequence
      to form a t loop that is stable in the absence of protein and DNA cross-linking.
      The single-stranded, telomeric DNA sequence at the end of a macronuclear molecule
      does not form a t loop but, instead, is complexed with a heterodimeric, telomere
      binding protein. Thus, two mechanisms for capping the ends of DNA molecules are
      used in the same cell.

PMID- 10588722
TI  - Conserved characteristics of heterochromatin-forming DNA at the 15q11-q13
      imprinting center.
AB  - Nuclear matrix binding assays (NMBAs) define certain DNA sequences as matrix
      attachment regions (MARs), which often have cis-acting epigenetic regulatory
      functions. We used NMBAs to analyze the functionally important 15q11-q13
      imprinting center (IC). We find that the IC is composed of an unusually high
      density of MARs, located in close proximity to the germ line elements that are
      proposed to direct imprint switching in this region. Moreover, we find that the
      organization of MARs is the same at the homologous mouse locus, despite extensive
      divergence of DNA sequence. MARs of this size are not usually associated with
      genes but rather with heterochromatin-forming areas of the genome. In contrast,
      the 15q11-q13 region contains multiple transcribed genes and is unusual for being
      subject to genomic imprinting, causing the maternal chromosome to be more
      transcriptionally silent, methylated, and late replicating than the paternal
      chromosome. We suggest that the extensive MAR sequences at the IC are organized
      as heterochromatin during oogenesis, an organization disrupted during
      spermatogenesis. Consistent with this model, multicolor fluorescence in situ
      hybridization to halo nuclei demonstrates a strong matrix association of the
      maternal IC, whereas the paternal IC is more decondensed, extending into the
      nuclear halo. This model also provides a mechanism for spreading of the
      imprinting signal, because heterochromatin at the IC on the maternal chromosome
      may exert a suppressive position effect in cis. We propose that the germ line
      elements at the 15q11-q13 IC mediate their effects through the candidate
      heterochromatin-forming DNA identified in this study.

PMID- 10588724
TI  - A first-generation X-inactivation profile of the human X chromosome.
AB  - In females, most genes on the X chromosome are generally assumed to be
      transcriptionally silenced on the inactive X as a result of X inactivation.
      However, particularly in humans, an increasing number of genes are known to
      "escape" X inactivation and are expressed from both the active (Xa) and inactive
      (Xi) X chromosomes; such genes reflect different molecular and epigenetic
      responses to X inactivation and are candidates for phenotypes associated with X
      aneuploidy. To identify genes that escape X inactivation and to generate a first
      generation X-inactivation profile of the X, we have evaluated the expression of
      224 X-linked genes and expressed sequence tags by reverse-transcription-PCR
      analysis of a panel of multiple independent mouse/human somatic cell hybrids
      containing a normal human Xi but no Xa. The resulting survey yields an initial X
      inactivation profile that is estimated to represent approximately 10% of all X
      linked transcripts. Of the 224 transcripts tested here, 34 (three of which are
      pseudoautosomal) were expressed in as many as nine Xi hybrids and thus appear to
      escape inactivation. The genes that escape inactivation are distributed
      nonrandomly along the X; 31 of 34 such transcripts map to Xp, implying that the
      two arms of the X are epigenetically and/or evolutionarily distinct and
      suggesting that genetic imbalance of Xp may be more severe clinically than
      imbalance of Xq. A complete X-inactivation profile will provide information
      relevant to clinical genetics and genetic counseling and should yield insight
      into the genomic and epigenetic organization of the X chromosome.

PMID- 10588725
TI  - Mammalian Cdk5 is a functional homologue of the budding yeast Pho85 cyclin
      dependent protein kinase.
AB  - Mammalian Cdk5 is a member of the cyclin-dependent kinase family that is
      activated by a neuron-specific regulator, p35, to regulate neuronal migration and
      neurite outgrowth. p35/Cdk5 kinase colocalizes with and regulates the activity of
      the Pak1 kinase in neuronal growth cones and likely impacts on actin cytoskeletal
      dynamics through Pak1. Here, we describe a functional homologue of Cdk5 in
      budding yeast, Pho85. Like Cdk5, Pho85 has been implicated in actin cytoskeleton
      regulation through phosphorylation of an actin-regulatory protein. Overexpression
      of CDK5 in yeast cells complemented most phenotypes associated with pho85Delta,
      including defects in the repression of acid phosphatase expression, sensitivity
      to salt, and a G(1) progression defect. Consistent with the functional
      complementation, Cdk5 associated with and was activated by the Pho85 cyclins
      Pho80 and Pcl2 in yeast cells. In a reciprocal series of experiments, we found
      that Pho85 associated with the Cdk5 activators p35 and p25 to form an active
      kinase complex in mammalian and insect cells, supporting our hypothesis that
      Pho85 and Cdk5 are functionally related. Our results suggest the existence of a
      functionally conserved pathway involving Cdks and actin-regulatory proteins that
      promotes reorganization of the actin cytoskeleton in response to regulatory
      signals.

PMID- 10588726
TI  - Functioning of the Drosophila integral U1/U2 protein Snf independent of U1 and U2
      small nuclear ribonucleoprotein particles is revealed by snf(+) gene dose
      effects.
AB  - Snf, encoded by sans fille, is the Drosophila homolog of mammalian U1A and U2B"
      and is an integral component of U1 and U2 small nuclear ribonucleoprotein
      particles (snRNPs). Surprisingly, changes in the level of this housekeeping
      protein can specifically affect autoregulatory activity of the RNA-binding
      protein Sex-lethal (Sxl) in an action that we infer must be physically separate
      from Snf's functioning within snRNPs. Sxl is a master switch gene that controls
      its own pre-mRNA splicing as well as splicing for subordinate switch genes that
      regulate sex determination and dosage compensation. Exploiting an unusual new set
      of mutant Sxl alleles in an in vivo assay, we show that Snf is rate-limiting for
      Sxl autoregulation when Sxl levels are low. In such situations, increasing either
      maternal or zygotic snf(+) dose enhances the positive autoregulatory activity of
      Sxl for Sxl somatic pre-mRNA splicing without affecting Sxl activities toward its
      other RNA targets. In contrast, increasing the dose of genes encoding either the
      integral U1 snRNP protein U1-70k, or the integral U2 snRNP protein SF3a(60), has
      no effect. Increased snf(+) enhances Sxl autoregulation even when U1-70k and
      SF3a(60) are reduced by mutation to levels that, in the case of SF3a(60),
      demonstrably interfere with Sxl autoregulation. The observation that increased
      snf(+) does not suppress other phenotypes associated with mutations that reduce
      U1-70k or SF3a(60) is additional evidence that snf(+) dose effects are not caused
      by increased snRNP levels. Mammalian U1A protein, like Snf, has a snRNP
      independent function.

PMID- 10588727
TI  - Toll-like receptor-2 mediates mycobacteria-induced proinflammatory signaling in
      macrophages.
AB  - The recognition of mycobacterial cell wall components causes macrophages to
      secrete tumor necrosis factor alpha (TNF-alpha) and other cytokines that are
      essential for the development of a protective inflammatory response. We show that
      toll-like receptors are required for the induction of TNF-alpha in macrophages by
      Mycobacterium tuberculosis. Expression of a dominant negative form of MyD88 (a
      signaling component required for toll-like receptor signaling) in a mouse
      macrophage cell line blocks TNF-alpha production induced by M. tuberculosis. We
      identify toll-like receptor-2 (TLR2) as the specific toll-like receptor required
      for this induction by showing that expression of an inhibitory TLR2 (TLR2-P681H)
      blocks TNF-alpha production induced by whole M. tuberculosis. Further, we show
      that TLR2-dependent signaling mediates responses to mycobacterial cell wall
      fractions enriched for lipoarrabinomannan, mycolylarabinogalactan-peptidoglycan
      complex, or M. tuberculosis total lipids. Thus, although many mycobacterial cell
      wall fractions are identified to be inflammatory, all require TLR2 for induction
      of TNF-alpha in macrophages. These data suggest that TLR2 is essential for the
      induction of a protective immune response to mycobacteria.

PMID- 10588728
TI  - Specific therapy regimes could lead to long-term immunological control of HIV.
AB  - We use mathematical models to study the relationship between HIV and the immune
      system during the natural course of infection and in the context of different
      antiviral treatment regimes. The models suggest that an efficient cytotoxic T
      lymphocyte (CTL) memory response is required to control the virus. We define CTL
      memory as long-term persistence of CTL precursors in the absence of antigen.
      Infection and depletion of CD4(+) T helper cells interfere with CTL memory
      generation, resulting in persistent viral replication and disease progression. We
      find that antiviral drug therapy during primary infection can enable the
      development of CTL memory. In chronically infected patients, specific treatment
      schedules, either including deliberate drug holidays or antigenic boosts of the
      immune system, can lead to a re-establishment of CTL memory. Whether such
      treatment regimes would lead to long-term immunologic control deserves
      investigation under carefully controlled conditions.

PMID- 10588729
TI  - CTACK, a skin-associated chemokine that preferentially attracts skin-homing
      memory T cells.
AB  - In contrast to naive lymphocytes, memory/effector lymphocytes can access
      nonlymphoid effector sites and display restricted, often tissue-selective,
      migration behavior. The cutaneous lymphocyte-associated antigen (CLA) defines a
      subset of circulating memory T cells that selectively localize in cutaneous sites
      mediated in part by the interaction of CLA with its vascular ligand E-selectin.
      Here, we report the identification and characterization of a CC chemokine,
      cutaneous T cell-attracting chemokine (CTACK). Both human and mouse CTACK are
      detected only in skin by Southern and Northern blot analyses. Specifically, CTACK
      message is found in the mouse epidermis and in human keratinocytes, and anti
      CTACK mAbs predominantly stain the epithelium. Finally, CTACK selectively
      attracts CLA(+) memory T cells. Taken together, these results suggest an
      important role for CTACK in recruitment of CLA(+) T cells to cutaneous sites.
      CTACK is predominantly expressed in the skin and selectively attracts a tissue
      specific subpopulation of memory lymphocytes.

PMID- 10588730
TI  - Withdrawal of IL-7 induces Bax translocation from cytosol to mitochondria through
      a rise in intracellular pH.
AB  - IL-7 functions as a trophic factor during T lymphocyte development by a mechanism
      that is partly based on the induction of Bcl-2, which protects cells from
      apoptosis. Here we report a mechanism by which cytokine withdrawal activates the
      prodeath protein Bax. On loss of IL-7 in a dependent cell line, Bax protein
      translocated from the cytosol to the mitochondria, where it integrated into the
      mitochondrial membrane. This translocation was attributable to a conformational
      change in the Bax protein itself. We show that a rise in intracellular pH
      preceded mitochondrial translocation and triggered the change in Bax
      conformation. Intracellular pH in the IL-7-dependent cells rose steadily to peak
      over pH 7.8 by 6 hr after cytokine withdrawal, paralleling the time point of Bax
      translocation (a similar alkalinization and Bax translocation was also observed
      after IL-3 withdrawal from a dependent cell line). The conformation of Bax was
      directly altered by pH of 7.8 or higher and was demonstrated by increased
      protease sensitivity, exposure of N terminus epitopes, and exposure of a
      hydrophobic domain in the C terminus. Eliminating charged amino acids at the C or
      N termini of Bax induced a conformational change similar to that induced by
      raising pH, implicating these residues in the pH effect. Therefore, we have shown
      that by either cytokine withdrawal, experimental manipulation of pH, or site
      directed mutagenesis, Bax protein changes conformation, exposing membrane-seeking
      domains, thereby inducing mitochondrial translocation and initiating the cascade
      of events leading to apoptotic death.

PMID- 10588731
TI  - Hematopoietic potential of stem cells isolated from murine skeletal muscle.
AB  - We have discovered that cells derived from the skeletal muscle of adult mice
      contain a remarkable capacity for hematopoietic differentiation. Cells prepared
      from muscle by enzymatic digestion and 5-day in vitro culture were harvested, and
      18 x 10(3) cells were introduced into each of six lethally irradiated recipients
      together with 200 x 10(3) distinguishable whole bone marrow cells. After 6 or 12
      weeks, all recipients showed high-level engraftment of muscle-derived cells
      representing all major adult blood lineages. The mean total contribution of
      muscle cell progeny to peripheral blood was 56 +/- 20% (SD), indicating that the
      cultured muscle cells generated approximately 10- to 14-fold more hematopoietic
      activity than whole bone marrow. When bone marrow from one mouse was harvested
      and transplanted into secondary recipients, all recipients showed high-level
      multilineage engraftment (mean 40%), establishing the extremely primitive nature
      of these stem cells. We also show that muscle contains a population of cells with
      several characteristics of bone marrow-derived hematopoietic stem cells,
      including high efflux of the fluorescent dye Hoechst 33342 and expression of the
      stem cell antigens Sca-1 and c-Kit, although the cells lack the hematopoietic
      marker CD45. We propose that this population accounts for the hematopoietic
      activity generated by cultured skeletal muscle. These putative stem cells may be
      identical to muscle satellite cells, some of which lack myogenic regulators and
      could be expected to respond to hematopoietic signals.

PMID- 10588732
TI  - Key residues revealed in a major conformational epitope of the U1-70K protein.
AB  - Epitopes depending on three-dimensional folding of proteins have during recent
      years been acknowledged to be main targets for many autoantibodies. However, a
      detailed resolution of conformation-dependent epitopes has to date not been
      achieved in spite of its importance for understanding the complex interaction
      between an autoantigen and the immune system. In analysis of immunodominant
      epitopes of the U1-70K protein, the major autoantigen recognized by human
      ribonucleoprotein (RNP)-positive sera, we have used diversely mutated recombinant
      Drosophila melanogaster 70K proteins as antigens in assays for human anti-RNP
      antibodies. Thus, the contribution of individual amino acids to antigenicity
      could be assayed with the overall structure of the major antigenic domain
      preserved, and analysis of how antigenicity can be reconstituted rather than
      obliterated was enabled. Our results reveal that amino acid residue 125 is
      situated at a crucial position for recognition by human anti-RNP autoantibodies
      and that flanking residues at positions 119-126 also appear to be of utmost
      importance for recognition. These results are discussed in relation to structural
      models of RNA-binding domains, and tertiary structure modeling indicates that the
      residues 119-126 are situated at easily accessible positions in the end of an
      alpha-helix in the RNA binding region. This study identifies a major conformation
      dependent epitope of the U1-70K protein and demonstrates the significance of
      individual amino acids in conformational epitopes. Using this model, we believe
      it will be possible to analyze other immunodominant regions in which protein
      conformation has a strong impact.

PMID- 10588733
TI  - Identification of an early T cell progenitor for a pathway of T cell maturation
      in the bone marrow.
AB  - We have identified a rare ( approximately 0.05-0.1%) population of cells (Thy
      1(hi)CD16(+)CD44(hi)CD2(-)TCRalphabeta(-)B220(-)M ac-1(-)NK1. 1(-)) in the adult
      mouse bone marrow that generates CD4(+) and CD8(+) TCRalphabeta(+) T cells after
      tissue culture for 48 hr in the presence of Ly5 congenic marrow cells. The
      essential stages in the maturation of the progenitors were determined; the stages
      included an early transition from CD2(-)CD16(+)CD44(hi)TCRalphabeta(-) to
      CD2(+)CD16(int/-)CD44(int/-)TCRalphabeta(-) cells, and a later transition to
      CD4(+)CD8(+)TCRalphabeta(+) double-positive T cells that rapidly generate the
      CD4(+) and CD8(+) single-positive T cells. The maturation of the progenitors is
      almost completely arrested at the CD2(+)TCRalphabeta(-) stage by the presence of
      mature T cells at the initiation of cultures. This alternate pathway is supported
      by the marrow microenvironment; it recapitulates critical intermediary steps in
      intrathymic T cell maturation.

PMID- 10588734
TI  - Soluble complexes of regulated upon activation, normal T cells expressed and
      secreted (RANTES) and glycosaminoglycans suppress HIV-1 infection but do not
      induce Ca(2+) signaling.
AB  - Chemokines comprise a family of low-molecular-weight proteins that elicit a
      variety of biological responses including chemotaxis, intracellular Ca(2+)
      mobilization, and activation of tyrosine kinase signaling cascades. A subset of
      chemokines, including regulated upon activation, normal T cell expressed and
      secreted (RANTES), macrophage inflammatory protein-1alpha (MIP-1alpha), and MIP
      1beta, also suppress infection by HIV-1. All of these activities are contingent
      on interactions between chemokines and cognate seven-transmembrane spanning, G
      protein-coupled receptors. However, these activities are strongly inhibited by
      glycanase treatment of receptor-expressing cells, indicating an additional
      dependence on surface glycosaminoglycans (GAG). To further investigate this
      dependence, we examined whether soluble GAG could reconstitute the biological
      activities of RANTES on glycanase-treated cells. Complexes formed between RANTES
      and a number of soluble GAG failed to induce intracellular Ca(2+) mobilization on
      either glycanase-treated or untreated peripheral blood mononuclear cells and were
      unable to stimulate chemotaxis. In contrast, the same complexes demonstrated
      suppressive activity against macrophage tropic HIV-1. Complexes composed of
      (125)I-labeled RANTES demonstrated saturable binding to glycanase-treated
      peripheral blood mononuclear cells, and such binding could be reversed partially
      by an anti-CCR5 antibody. These results suggest that soluble chemokine-GAG
      complexes represent seven-transmembrane ligands that do not activate receptors
      yet suppress HIV infection. Such complexes may be considered as therapeutic
      formulations for the treatment of HIV-1 infection.

PMID- 10588735
TI  - Mouse model of Sanfilippo syndrome type B produced by targeted disruption of the
      gene encoding alpha-N-acetylglucosaminidase.
AB  - The Sanfilippo syndrome type B is an autosomal recessive disorder caused by
      mutation in the gene (NAGLU) encoding alpha-N-acetylglucosaminidase, a lysosomal
      enzyme required for the stepwise degradation of heparan sulfate. The most serious
      manifestations are profound mental retardation, intractable behavior problems,
      and death in the second decade. To generate a model for studies of
      pathophysiology and of potential therapy, we disrupted exon 6 of Naglu, the
      homologous mouse gene. Naglu-/- mice were healthy and fertile while young and
      could survive for 8-12 mo. They were totally deficient in alpha-N
      acetylglucosaminidase and had massive accumulation of heparan sulfate in liver
      and kidney as well as secondary changes in activity of several other lysosomal
      enzymes in liver and brain and elevation of gangliosides G(M2) and G(M3) in
      brain. Vacuolation was seen in many cells, including macrophages, epithelial
      cells, and neurons, and became more prominent with age. Although most vacuoles
      contained finely granular material characteristic of glycosaminoglycan
      accumulation, large pleiomorphic inclusions were seen in some neurons and
      pericytes in the brain. Abnormal hypoactive behavior was manifested by 4.5-mo-old
      Naglu-/- mice in an open field test; the hyperactivity that is characteristic of
      affected children was not observed even in younger mice. In a Pavlovian fear
      conditioning test, the 4.5-mo-old mutant mice showed normal response to context,
      indicating intact hippocampal-dependent learning, but reduced response to a
      conditioning tone, perhaps attributable to hearing impairment. The phenotype of
      the alpha-N-acetylglucosaminidase-deficient mice is sufficiently similar to that
      of patients with the Sanfilippo syndrome type B to make these mice a good model
      for study of pathophysiology and for development of therapy.

PMID- 10588736
TI  - Mice mutant for glucokinase regulatory protein exhibit decreased liver
      glucokinase: a sequestration mechanism in metabolic regulation.
AB  - The importance of glucokinase (GK; EC 2.7.1.12) in glucose homeostasis has been
      demonstrated by the association of GK mutations with diabetes mellitus in humans
      and by alterations in glucose metabolism in transgenic and gene knockout mice.
      Liver GK activity in humans and rodents is allosterically inhibited by GK
      regulatory protein (GKRP). To further understand the role of GKRP in GK
      regulation, the mouse GKRP gene was inactivated. With the knockout of the GKRP
      gene, there was a parallel loss of GK protein and activity in mutant mouse liver.
      The loss was primarily because of posttranscriptional regulation of GK,
      indicating a positive regulatory role for GKRP in maintaining GK levels and
      activity. As in rat hepatocytes, both GK and GKRP were localized in the nuclei of
      mouse hepatocytes cultured in low-glucose-containing medium. In the presence of
      fructose or high concentrations of glucose, conditions known to relieve GK
      inhibition by GKRP in vitro, only GK was translocated into the cytoplasm. In the
      GKRP-mutant hepatocytes, GK was not found in the nucleus under any tested
      conditions. We propose that GKRP functions as an anchor to sequester and inhibit
      GK in the hepatocyte nucleus, where it is protected from degradation. This
      ensures that glucose phosphorylation is minimal when the liver is in the fasting,
      glucose-producing phase. This also enables the hepatocytes to rapidly mobilize GK
      into the cytoplasm to phosphorylate and store or metabolize glucose after the
      ingestion of dietary glucose. In GKRP-mutant mice, the disruption of this
      regulation and the subsequent decrease in GK activity leads to altered glucose
      metabolism and impaired glycemic control.

PMID- 10588737
TI  - Identification and classification of p53-regulated genes.
AB  - Sequence-specific transactivation by p53 is essential to its role as a tumor
      suppressor. A modified tetracycline-inducible system was established to search
      for transcripts that were activated soon after p53 induction. Among 9,954 unique
      transcripts identified by serial analysis of gene expression, 34 were increased
      more than 10-fold; 31 of these had not previously been known to be regulated by
      p53. The transcription patterns of these genes, as well as previously described
      p53-regulated genes, were evaluated and classified in a panel of widely studied
      colorectal cancer cell lines. "Class I" genes were uniformly induced by p53 in
      all cell lines; "class II" genes were induced in a subset of the lines; and
      "class III" genes were not induced in any of the lines. These genes were also
      distinguished by the timing of their induction, their induction by clinically
      relevant chemotherapeutic agents, the absolute requirement for p53 in this
      induction, and their inducibility by p73, a p53 homolog. The results revealed
      substantial heterogeneity in the transcriptional responses to p53, even in cells
      derived from a single epithelial cell type, and pave the way to a deeper
      understanding of p53 tumor suppressor action.

PMID- 10588738
TI  - STEAP: a prostate-specific cell-surface antigen highly expressed in human
      prostate tumors.
AB  - In search of novel genes expressed in metastatic prostate cancer, we subtracted
      cDNA isolated from benign prostatic hypertrophic tissue from cDNA isolated from a
      prostate cancer xenograft model that mimics advanced disease. One novel gene that
      is highly expressed in advanced prostate cancer encodes a 339-amino acid protein
      with six potential membrane-spanning regions flanked by hydrophilic amino- and
      carboxyl-terminal domains. This structure suggests a potential function as a
      channel or transporter protein. This gene, named STEAP for six-transmembrane
      epithelial antigen of the prostate, is expressed predominantly in human prostate
      tissue and is up-regulated in multiple cancer cell lines, including prostate,
      bladder, colon, ovarian, and Ewing sarcoma. Immunohistochemical analysis of
      clinical specimens demonstrates significant STEAP expression at the cell-cell
      junctions of the secretory epithelium of prostate and prostate cancer cells.
      Little to no staining was detected at the plasma membranes of normal, nonprostate
      human tissues, except for bladder tissue, which expressed low levels of STEAP at
      the cell membrane. Protein analysis located STEAP at the cell surface of prostate
      cancer cell lines. Our results support STEAP as a cell-surface tumor-antigen
      target for prostate cancer therapy and diagnostic imaging.

PMID- 10588739
TI  - Elimination of prions by branched polyamines and implications for therapeutics.
AB  - We report that branched polyamines, including polyamidoamide dendimers,
      polypropyleneimine, and polyethyleneimine, are able to purge PrP(Sc), the
      protease-resistant isoform of the prion protein, from scrapie-infected
      neuroblastoma (ScN2a) cells in culture. The removal of PrP(Sc) by these compounds
      depends on both the concentration of branched polymer and the duration of
      exposure. Chronic exposure of ScN2a cells to low noncytotoxic concentrations of
      branched polyamines for 1 wk reduced PrP(Sc) to an undetectable level, a
      condition that persisted at least 3 wk after removal of the compound. Structure
      activity analysis revealed that a high surface density of primary amino groups is
      required for polyamines to eliminate PrP(Sc) effectively from cells. The removal
      of PrP(Sc) by branched polyamines is attenuated by chloroquine in living cells,
      and exposure of scrapie-infected brain extracts with branched polyamines at
      acidic pH rendered the PrP(Sc) susceptible to protease in vitro, suggesting that
      endosomes or lysozomes may be the site of action. Our studies suggest that
      branched polyamines might be useful therapeutic agents for treatment of prion
      diseases and perhaps a variety of other degenerative disorders.

PMID- 10588740
TI  - AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute
      lymphoblastic leukemia with ins(5;11)(q31;q13q23).
AB  - Infant acute lymphoblastic leukemia (ALL) with MLL gene rearrangements is
      characterized by early pre-B phenotype (CD10(-)/CD19(+)) and poor treatment
      outcome. The t(4;11), creating MLL-AF4 chimeric transcripts, is the predominant
      11q23 chromosome translocation in infant ALL and is associated with extremely
      poor prognosis as compared with other 11q23 translocations. We analyzed an infant
      early preB ALL with ins(5;11)(q31;q13q23) and identified the AF5q31 gene on
      chromosome 5q31 as a fusion partner of the MLL gene. The AF5q31 gene, which
      encoded a protein of 1,163 aa, was located in the vicinity of the cytokine
      cluster region of chromosome 5q31 and contained at least 16 exons. The AF5q31
      gene was expressed in fetal heart, lung, and brain at relatively high levels and
      fetal liver at a low level, but the expression in these tissues decreased in
      adults. The AF5q31 protein was homologous to AF4-related proteins, including AF4,
      LAF4, and FMR2. The AF5q31 and AF4 proteins had three homologous regions,
      including the transactivation domain of AF4, and the breakpoint of AF5q31 was
      located within the region homologous to the transactivation domain of AF4.
      Furthermore, the clinical features of this patient with the MLL-AF5q31 fusion
      transcript, characterized by the early pre-B phenotype (CD10(-)/CD19(+)) and poor
      outcome, were similar to those of patients having MLL-AF4 chimeric transcripts.
      These findings suggest that AF5q31 and AF4 might define a new family particularly
      involved in the pathogenesis of 11q23-associated-ALL.

PMID- 10588741
TI  - Prevention of lymphocyte cell death in sepsis improves survival in mice.
AB  - Sepsis induces extensive lymphocyte apoptosis, a process which may be beneficial
      to host survival by down-regulating the inflammatory response or, alternatively,
      harmful by impairing host defenses. To determine the beneficial vs. adverse
      effects of lymphocyte apoptosis in sepsis, we blocked lymphocyte apoptosis either
      by N-benzyloxycarbonyl-Val-Ala-Asp(O-methyl) fluoromethyl ketone (z-VAD), a broad
      spectrum caspase inhibitor, or by use of Bcl-2 Ig transgenic mice that
      selectively overexpress the antiapoptotic protein Bcl-2 in a lymphoid pattern.
      Both z-VAD and Bcl-2 prevented lymphocyte apoptosis and resulted in a marked
      improvement in survival. z-VAD did not decrease lymphocyte tumor necrosis factor
      alpha production. Considered together, these two studies employing different
      methods of blocking lymphocyte apoptosis provide compelling evidence that
      immunodepression resulting from the loss of lymphocytes is a central pathogenic
      event in sepsis, and they challenge the current paradigm that regards sepsis as a
      disorder resulting from an uncontrolled inflammatory response. Caspase inhibitors
      may represent a treatment strategy in this highly lethal disorder.

PMID- 10588742
TI  - Bacterial diversity within the human subgingival crevice.
AB  - Molecular, sequence-based environmental surveys of microorganisms have revealed a
      large degree of previously uncharacterized diversity. However, nearly all studies
      of the human endogenous bacterial flora have relied on cultivation and
      biochemical characterization of the resident organisms. We used molecular methods
      to characterize the breadth of bacterial diversity within the human subgingival
      crevice by comparing 264 small subunit rDNA sequences from 21 clone libraries
      created with products amplified directly from subgingival plaque, with sequences
      obtained from bacteria that were cultivated from the same specimen, as well as
      with sequences available in public databases. The majority (52.5%) of the
      directly amplified 16S rRNA sequences were <99% identical to sequences within
      public databases. In contrast, only 21.4% of the sequences recovered from
      cultivated bacteria showed this degree of variability. The 16S rDNA sequences
      recovered by direct amplification were also more deeply divergent; 13.5% of the
      amplified sequences were more than 5% nonidentical to any known sequence, a level
      of dissimilarity that is often found between members of different genera. None of
      the cultivated sequences exhibited this degree of sequence dissimilarity.
      Finally, direct amplification of 16S rDNA yielded a more diverse view of the
      subgingival bacterial flora than did cultivation. Our data suggest that a
      significant proportion of the resident human bacterial flora remain poorly
      characterized, even within this well studied and familiar microbial environment.

PMID- 10588743
TI  - An in vivo membrane fusion assay implicates SpoIIIE in the final stages of
      engulfment during Bacillus subtilis sporulation.
AB  - Shortly after the synthesis of the two cells required for sporulation in Bacillus
      subtilis, the membranes of the larger mother cell begin to migrate around and
      engulf the smaller forespore cell. At the completion of this process the leading
      edges of the migrating membrane meet and fuse, releasing the forespore into the
      mother cell cytoplasm. We developed a fluorescent membrane stain-based assay for
      this membrane fusion event, and we isolated mutants defective in the final stages
      of engulfment or membrane fusion. All had defects in spoIIIE, which is required
      for translocation of the forespore chromosome across the polar septum. We
      isolated one spoIIIE mutant severely defective in chromosome translocation, but
      not in membrane fusion; this mutation disrupts the ATP/GTP-binding site of
      SpoIIIE, suggesting that ATP binding and hydrolysis are required for DNA
      translocation but not for the late engulfment function of SpoIIIE. We also
      correlated relocalization of SpoIIIE-green fluorescent protein from the
      sporulation septum to the forespore pole with the completion of membrane fusion
      and engulfment. We suggest that SpoIIIE is required for the final steps of
      engulfment and that it may regulate or catalyze membrane fusion events.

PMID- 10588744
TI  - Altered states: involvement of phosphorylated CagA in the induction of host
      cellular growth changes by Helicobacter pylori.
AB  - Helicobacter pylori, present in half of the world's population, is a very
      successful pathogen. It can survive for decades in the human stomach with few
      obvious consequences to the host. However, it is also the cause of gastric
      diseases ranging from gastritis to ulcers to gastric cancer and has been
      classified a type 1 carcinogen by the World Health Organization. We have
      previously shown that phosphorylation of a 145-kDa protein and activation of
      signal transduction pathways are associated with the attachment of H. pylori to
      gastric cells. Here we identify the 145-kDa protein as the H. pylori CagA
      protein. We also show that CagA is necessary to induce a growth-factor-like
      phenotype (hummingbird) in host gastric cells similar to that induced by
      hepatocyte growth factor (HGF). Additionally, we identify a second cellular
      phenotype induced after attachment by H. pylori, which we call SFA (stress fiber
      associated). SFA is CagA independent and is produced by type I and type II H.
      pylori.

PMID- 10588745
TI  - Cannabinoid CB1 receptors and ligands in vertebrate retina: localization and
      function of an endogenous signaling system.
AB  - CB1, a cannabinoid receptor enriched in neuronal tissue, was found in high
      concentration in retinas of rhesus monkey, mouse, rat, chick, goldfish, and tiger
      salamander by using a subtype-specific polyclonal antibody. Immunolabeling was
      detected in the two synaptic layers of the retina, the inner and outer plexiform
      layers, of all six species examined. In the outer plexiform layer, CB1 was
      located in and/or on cone pedicles and rod spherules. Labeling was detected in
      some amacrine cells of all species and in the ganglion cells and ganglion cell
      axons of all species except fish. In addition, sparse labeling was found in the
      inner and/or outer segments of the photoreceptors of monkey, mouse, rat, and
      chick. Using GC/MS to detect possible endogenous cannabinoids, we found 3 nmol of
      2-arachidonylglycerol per g of tissue, but no anandamide was detectable.
      Cannabinoid receptor agonists induced a dramatic reduction in the amplitude of
      voltage-gated L-type calcium channel currents in identified retinal bipolar
      cells. The presence and distribution of the CB1 receptor, the large amounts of 2
      arachidonylglycerol found, and the effects of cannabinoids on calcium channel
      activity in bipolar cells suggest a substantive role for an endogenous
      cannabinoid signaling system in retinal physiology, and perhaps vision in
      general.

PMID- 10588746
TI  - Permeant ion regulation of N-methyl-D-aspartate receptor channel block by Mg(2+).
AB  - Block of the channel of N-methyl-D-aspartate (NMDA) receptors by external Mg(2+)
      (Mg(o)(2+)) has broad implications for the many physiological and pathological
      processes that depend on NMDA receptor activation. An essential property of
      channel block by Mg(o)(2+) is its powerful voltage dependence. A widely cited
      explanation for the strength of the voltage dependence of block is that the
      Mg(o)(2+)-binding site is located deep in the channel of NMDA receptors;
      Mg(o)(2+) then would sense most of the membrane potential field during block.
      However, recent electrophysiological and mutagenesis studies suggest that the
      blocking site cannot be deep enough to account for the voltage dependence of
      Mg(o)(2+) block. Here we describe the basis for this discrepancy: the magnitude
      and voltage dependence of channel block by Mg(o)(2+) are strongly regulated by
      external and internal permeant monovalent cations. Our data support a model in
      which access to the channel by Mg(o)(2+) is prevented when permeant ion-binding
      sites at the external entrance to the channel are occupied. Mg(o)(2+) can block
      the channel only when the permeant ion-binding sites are unoccupied and then can
      either unblock back to the external solution or permeate the channel. Unblock to
      the external solution is prevented if external permeant ions bind while Mg(2+)
      blocks the channel, although permeation is still permitted. The model provides an
      explanation for the strength of the voltage dependence of Mg(o)(2+) block and
      quantifies the interdependence of permanent and blocking ion binding to NMDA
      receptors.

PMID- 10588747
TI  - Neuropeptide release by efficient recruitment of diffusing cytoplasmic secretory
      vesicles.
AB  - Neuropeptides are slowly released from a limited pool of secretory vesicles.
      Despite decades of research, the composition of this pool has remained unknown.
      Endocrine cell studies support the hypothesis that a population of docked
      vesicles supports the first minutes of hormone release. However, it has been
      proposed that mobile cytoplasmic vesicles dominate the releasable neuropeptide
      pool. Here, to determine the cellular basis of the releasable pool, single green
      fluorescent protein-labeled secretory vesicles were visualized in neuronal growth
      cones with the use of an inducible construct or total internal reflection
      fluorescence microscopy. We report that vesicle movement follows the diffusion
      equation. Furthermore, rapidly moving secretory vesicles are used more
      efficiently than stationary vesicles near the plasma membrane to support
      stimulated release. Thus, randomly moving cytoplasmic vesicles participate in the
      first minutes of neuropeptide release. Importantly, the preferential recruitment
      of diffusing cytoplasmic secretory vesicles contributes to the characteristic
      slow kinetics and limited extent of sustained neuropeptide release.

PMID- 10588748
TI  - Electrophysiological evidence for a hyperpolarizing, galanin (1-15)-selective
      receptor on hippocampal CA3 pyramidal neurons.
AB  - The effects of the 29-amino acid neuropeptide galanin [GAL (1-29)], GAL(1-15),
      GAL(1-16), and the GAL subtype 2 receptor agonist D-tryptophan(2)-GAL(1-29) were
      studied in the dorsal hippocampus in vitro with intracellular recording
      techniques. GAL(1-15) induced, in the presence of tetrodotoxin, a dose-dependent
      hyperpolarization in hippocampal CA3 neurons. Most of the GAL(1-15)-sensitive
      neurons did not respond to GAL(1-29), GAL(1-16), or D-tryptophan(2)-GAL(1-29).
      These results indicate the presence of a distinct, yet-to-be cloned GAL(1-15)
      selective receptor on CA3 neurons in the dorsal hippocampus.

PMID- 10588749
TI  - Reduced facilitation and vesicular uptake in crustacean and mammalian
      neuromuscular junction by T-588, a neuroprotective compound.
AB  - Bath application of compound T-588, a neuroprotective agent, reduced paired-pulse
      and repetitive-pulse facilitation at mammalian and crustacean neuromuscular
      junctions. In addition, it reduced voltage-gated sodium and potassium currents in
      a use-dependent fashion, but had only a small effect on the presynaptic Ca(2+)
      conductance. By contrast, it blocked FM 1-43 vesicular uptake but not its
      release, in both species. Postsynaptically, T-588 reduced acetylcholine currents
      at the mammalian junction in a voltage-independent manner, but had no effect on
      the crayfish glutamate junction. All of these effects were rapidly reversible and
      were observed at concentrations close to the compound's acute protective level.
      We propose that this set of mechanisms, which reduces high-frequency synaptic
      transmission, is an important contributory factor in the neuroprotective action
      of T-588.

PMID- 10588750
TI  - Voltage-induced membrane displacement in patch pipettes activates
      mechanosensitive channels.
AB  - The patch-clamp technique allows currents to be recorded through single ion
      channels in patches of cell membrane in the tips of glass pipettes. When
      recording, voltage is typically applied across the membrane patch to drive ions
      through open channels and to probe the voltage-sensitivity of channel activity.
      In this study, we used video microscopy and single-channel recording to show that
      prolonged depolarization of a membrane patch in borosilicate pipettes results in
      delayed slow displacement of the membrane into the pipette and that this
      displacement is associated with the activation of mechanosensitive (MS) channels
      in the same patch. The membrane displacement, approximately 1 micrometer with
      each prolonged depolarization, occurs after variable delays ranging from tens of
      milliseconds to many seconds and is correlated in time with activation of MS
      channels. Increasing the voltage step shortens both the delay to membrane
      displacement and the delay to activation. Preventing depolarization-induced
      membrane displacement by applying positive pressure to the shank of the pipette
      or by coating the tips of the borosilicate pipettes with soft glass prevents the
      depolarization-induced activation of MS channels. The correlation between
      depolarization-induced membrane displacement and activation of MS channels
      indicates that the membrane displacement is associated with sufficient membrane
      tension to activate MS channels. Because membrane tension can modulate the
      activity of various ligand and voltage-activated ion channels as well as some
      transporters, an apparent voltage dependence of a channel or transporter in a
      membrane patch in a borosilicate pipette may result from voltage-induced tension
      rather than from direct modulation by voltage.

PMID- 10588751
TI  - Calcium electrogenesis in distal apical dendrites of layer 5 pyramidal cells at a
      critical frequency of back-propagating action potentials.
AB  - Action potentials in juvenile and adult rat layer-5 neocortical pyramidal neurons
      can be initiated at both axonal and distal sites of the apical dendrite. However,
      little is known about the interaction between these two initiation sites. Here,
      we report that layer 5 pyramidal neurons are very sensitive to a critical
      frequency of back-propagating action potentials varying between 60 and 200 Hz in
      different neurons. Bursts of four to five back-propagating action potentials
      above the critical frequency elicited large regenerative potentials in the distal
      dendritic initiation zone. The critical frequency had a very narrow range (10-20
      Hz), and the dendritic regenerative activity led to further depolarization at the
      soma. The dendritic frequency sensitivity was suppressed by blockers of voltage
      gated calcium channels, and also by synaptically mediated inhibition. Calcium
      fluorescence imaging revealed that the site of largest transient increase in
      intracellular calcium above the critical frequency was located 400-700 micrometer
      from the soma at the site for initiation of calcium action potentials. Thus, the
      distal dendritic initiation zone can interact with the axonal initiation zone,
      even when inputs to the neuron are restricted to regions close to the soma, if
      the output of the neuron exceeds a critical frequency.

PMID- 10588752
TI  - Odorants induce the phosphorylation of the cAMP response element binding protein
      in olfactory receptor neurons.
AB  - Although odorants are known to activate olfactory receptor neurons through cAMP,
      the long-term effects of odorant detection are not known. Our recent findings
      indicate that there is also a delayed and sustained cAMP response, with kinetics
      sufficient to mediate long-term cellular responses. This cAMP response is
      mediated by cGMP through activation of adenylyl cyclase by protein kinase G
      (PKG). Therefore, we investigated the ability of odorants to regulate gene
      expression in rat olfactory epithelium. The cAMP-responsive binding protein
      (CREB) is a well-characterized transcription factor regulated by cAMP. We
      examined CREB activity in rat olfactory epithelium and olfactory receptor neurons
      (ORNs) after stimulation with odorants. Odorants increased levels of
      phosphorylated CREB in olfactory epithelium in vivo, and this increase was
      localized to ORNs in vitro. Incubation with 8-bromo-cGMP or sodium nitroprusside,
      a guanylyl cyclase activator, also increased phosphorylated CREB. In vitro, cAMP
      dependent protein kinase phosphorylated CREB. In contrast, PKG failed to
      phosphorylate CREB directly in vitro. Our results demonstrate that the delayed
      odorant-induced cAMP signal activates CREB, which in turn may modulate gene
      expression in ORNs. In addition, cGMP indirectly affects CREB activation. This
      effect of cGMP on CREB activity through cAMP provides another mechanism for the
      modulation of CREB.

PMID- 10588753
TI  - Horizontal cells reveal cone type-specific adaptation in primate retina.
AB  - The human cone visual system maintains contrast sensitivity over a wide range of
      ambient illumination, a property known as light adaptation. The first stage in
      light adaptation is believed to take place at the first neural step in vision,
      within the long, middle, and short wavelength sensitive cone photoreceptors. To
      determine the properties of adaptation in primate outer retina, we measured cone
      signals in second-order interneurons, the horizontal cells, of the macaque
      monkey. Horizontal cells provide a unique site for studying early adaptational
      mechanisms; they are but one synapse away from the photoreceptors, and each
      horizontal cell receives excitatory inputs from many cones. Light adaptation
      occurred over the entire range of light levels evaluated, a luminance range of 15
      1,850 trolands. Adaptation was demonstrated to be independent in each cone type
      and to be spatially restricted. Thus, in primates, a major source of sensitivity
      regulation occurs before summation of cone signals in the horizontal cell.

PMID- 10588754
TI  - Opposite effects of nitric oxide and nitroxyl on postischemic myocardial injury.
AB  - Recent experimental evidence suggests that reactive nitrogen oxide species can
      contribute significantly to postischemic myocardial injury. The aim of the
      present study was to evaluate the role of two reactive nitrogen oxide species,
      nitroxyl (NO(-)) and nitric oxide (NO(.)), in myocardial ischemia and reperfusion
      injury. Rabbits were subjected to 45 min of regional myocardial ischemia followed
      by 180 min of reperfusion. Vehicle (0.9% NaCl), 1 micromol/kg S
      nitrosoglutathione (GSNO) (an NO(.) donor), or 3 micromol/kg Angeli's salt (AS)
      (a source of NO(-)) were given i.v. 5 min before reperfusion. Treatment with GSNO
      markedly attenuated reperfusion injury, as evidenced by improved cardiac
      function, decreased plasma creatine kinase activity, reduced necrotic size, and
      decreased myocardial myeloperoxidase activity. In contrast, the administration of
      AS at a hemodynamically equieffective dose not only failed to attenuate but,
      rather, aggravated reperfusion injury, indicated by an increased left ventricular
      end diastolic pressure, myocardial creatine kinase release and necrotic size.
      Decomposed AS was without effect. Co-administration of AS with ferricyanide, a
      one-electron oxidant that converts NO(-) to NO(.), completely blocked the
      injurious effects of AS and exerted significant cardioprotective effects similar
      to those of GSNO. These results demonstrate that, although NO(.) is protective,
      NO(-) increases the tissue damage that occurs during ischemia/reperfusion and
      suggest that formation of nitroxyl may contribute to postischemic myocardial
      injury.

PMID- 10588755
TI  - Torpor in mice is induced by both leptin-dependent and -independent mechanisms.
AB  - We tested the effect of chronic leptin treatment on fasting-induced torpor in
      leptin-deficient A-ZIP/F-1 and ob/ob mice. A-ZIP/F-1 mice have virtually no white
      adipose tissue and low leptin levels, whereas ob/ob mice have an abundance of fat
      but no leptin. These two models allowed us to examine the roles of adipose tissue
      and leptin in the regulation of entry into torpor. Torpor is a short-term
      hibernation-like state that allows conservation of metabolic fuels. We first
      characterized the A-ZIP/F-1 animals, which have a 10-fold reduction in total body
      triglyceride stores. Upon fasting, A-ZIP/F-1 mice develop a lower metabolic rate
      and decreased plasma glucose, insulin, and triglyceride levels, with no increase
      in free fatty acids or beta-hydroxybutyrate. Unlike control mice, by 24 hr of
      fasting, they have nearly exhausted their triglycerides and are catabolizing
      protein. To conserve energy supplies during fasting, A-ZIP/F-1 (but not control)
      mice entered deep torpor, with a minimum core body temperature of 24 degrees C, 2
      degrees C above ambient. In ob/ob mice, fasting-induced torpor was completely
      reversed by leptin treatment. In contrast, neither leptin nor thyroid hormone
      prevented torpor in A-ZIP/F-1 mice. These data suggest that there are at least
      two signals for entry into torpor in mice, a low leptin level and another signal
      that is independent of leptin and thyroid hormone levels. Studying rodent torpor
      provides insight into human torpor-like states such as near drowning in cold
      water and induced hypothermia for surgery.

PMID- 10588756
TI  - Repeated, but not acute, stress suppresses inflammatory plasma extravasation.
AB  - Clinical findings suggest that inflammatory disease symptoms are aggravated by
      ongoing, repeated stress, but not by acute stress. We hypothesized that, compared
      with single acute stressors, chronic repeated stress may engage different
      physiological mechanisms that exert qualitatively different effects on the
      inflammatory response. Because inhibition of plasma extravasation, a critical
      component of the inflammatory response, has been associated with increased
      disease severity in experimental arthritis, we tested for a potential repeated
      stress-induced inhibition of plasma extravasation. Repeated, but not single,
      exposures to restraint stress produced a profound inhibition of bradykinin
      induced synovial plasma extravasation in the rat. Experiments examining the
      mechanism of inhibition showed that the effect of repeated stress was blocked by
      adrenalectomy, but not by adrenal medullae denervation, suggesting that the
      adrenal cortex mediates this effect. Consistent with known effects of stress and
      with mediation by the adrenal cortex, restraint stress evoked repeated transient
      elevations of plasma corticosterone levels. This elevated corticosterone was
      necessary and sufficient to produce inhibition of plasma extravasation because
      the stress-induced inhibition was blocked by preventing corticosterone synthesis
      and, conversely, induction of repeated transient elevations in plasma
      corticosterone levels mimicked the effects of repeated stress. These data suggest
      that repetition of a mild stressor can induce changes in the physiological state
      of the animal that enable a previously innocuous stressor to inhibit the
      inflammatory response. These findings provide a potential explanation for the
      clinical association between repeated stress and aggravation of inflammatory
      disease symptoms and provide a model for study of the biological mechanisms
      underlying the stress-induced aggravation of chronic inflammatory diseases.

PMID- 10588757
TI  - Intra-ring variability of Cr, As, Cd, and Pb in red oak revealed by secondary ion
      mass spectrometry: implications for environmental biomonitoring.
AB  - Reconstructing the history of ambient levels of metals by using tree-ring
      chemistry is controversial. This controversy can be resolved in part through the
      use of selective microanalysis of individual wood cells. Using a combination of
      instrumental neutron activation analysis and secondary ion mass spectrometry, we
      have observed systematic inhomogeneity in the abundance of toxic metals (Cr, As,
      Cd, and Pb) within annual growth rings of Quercus rubra (red oak) and have
      characterized individual xylem members responsible for introducing micrometer
      scale gradients in toxic metal abundances. These gradients are useful for placing
      constraints on both the magnitude and the mechanism of heavy metal translocation
      within growing wood. It should now be possible to test, on a metal-by-metal
      basis, the suitability of using tree-ring chemistries for deciphering long-term
      records of many environmental metals.

PMID- 10588758
TI  - Overexpression of thioredoxin h leads to enhanced activity of starch debranching
      enzyme (pullulanase) in barley grain.
AB  - Biochemically active wheat thioredoxin h has been overexpressed in the endosperm
      of transgenic barley grain. Two DNA constructs containing the wheat thioredoxin h
      gene (wtrxh) were used for transformation; each contained wtrxh fused to an
      endosperm-specific B(1)-hordein promoter either with or without a signal peptide
      sequence for targeting to the protein body. Twenty-two stable, independently
      transformed regenerable lines were obtained by selecting with the herbicide
      bialaphos to test for the presence of the bar herbicide resistance gene on a
      cotransformed plasmid; all were positive for this gene. The presence of wtrxh was
      confirmed in 20 lines by PCR analysis, and the identity and level of expression
      of wheat thioredoxin h was assessed by immunoblots. Although levels varied among
      the different transgenic events, wheat thioredoxin h was consistently highly
      expressed (up to 30-fold) in the transgenic grain. Transgenic lines transformed
      with the B(1)-hordein promoter with a signal peptide sequence produced a higher
      level of wheat thioredoxin h on average than those without a signal sequence. The
      overexpression of thioredoxin h in the endosperm of germinated grain effected up
      to a 4-fold increase in the activity of the starch debranching enzyme,
      pullulanase (limit dextrinase), the enzyme that specifically cleaves alpha-1,6
      linkages in starch. These results raise the question of how thioredoxin h
      enhances the activity of pullulanase because it was found that the inhibitor had
      become inactive before the enzyme showed appreciable activity.

PMID- 10588759
TI  - Herbicide sensitivity determinant of wheat plastid acetyl-CoA carboxylase is
      located in a 400-amino acid fragment of the carboxyltransferase domain.
AB  - A series of chimeral genes, consisting of the yeast GAL10 promoter, yeast ACC1
      leader, wheat acetyl-CoA carboxylase (ACCase; EC 6.4.1.2) cDNA, and yeast ACC1 3'
      tail, was used to complement a yeast ACC1 mutation. These genes encode a full
      length plastid enzyme, with and without the putative chloroplast transit peptide,
      as well as five chimeric cytosolic/plastid proteins. Four of the genes, all
      containing at least half of the wheat cytosolic ACCase coding region at the 5'
      end, complement the yeast mutation. Aryloxyphenoxypropionate and cyclohexanedione
      herbicides, at concentrations below 10 microM, inhibit the growth of haploid
      yeast strains that express two of the chimeric ACCases. This inhibition resembles
      the inhibition of wheat plastid ACCase observed in vitro and in vivo. The
      differential response to herbicides localizes the sensitivity determinant to the
      third quarter of the multidomain plastid ACCase. Sequence comparisons of
      different multidomain and multisubunit ACCases suggest that this region includes
      part of the carboxyltransferase domain, and therefore that the
      carboxyltransferase activity of ACCase (second half-reaction) is the target of
      the inhibitors. The highly sensitive yeast gene-replacement strains described
      here provide a convenient system to study herbicide interaction with the enzyme
      and a powerful screening system for new inhibitors.

PMID- 10588760
TI  - The circadian clock controls the expression pattern of the circadian input
      photoreceptor, phytochrome B.
AB  - Developmental and physiological responses are regulated by light throughout the
      entire life cycle of higher plants. To sense changes in the light environment,
      plants have developed various photoreceptors, including the red/far-red light
      absorbing phytochromes and blue light-absorbing cryptochromes. A wide variety of
      physiological responses, including most light responses, also are modulated by
      circadian rhythms that are generated by an endogenous oscillator, the circadian
      clock. To provide information on local time, circadian clocks are synchronized
      and entrained by environmental time cues, of which light is among the most
      important. Light-driven entrainment of the Arabidopsis circadian clock has been
      shown to be mediated by phytochrome A (phyA), phytochrome B (phyB), and
      cryptochromes 1 and 2, thus affirming the roles of these photoreceptors as input
      regulators to the plant circadian clock. Here we show that the expression of
      PHYB::LUC reporter genes containing the promoter and 5' untranslated region of
      the tobacco NtPHYB1 or Arabidopsis AtPHYB genes fused to the luciferase (LUC)
      gene exhibit robust circadian oscillations in transgenic plants. We demonstrate
      that the abundance of PHYB RNA retains this circadian regulation and use a
      PHYB::Luc fusion protein to show that the rate of PHYB synthesis is also
      rhythmic. The abundance of bulk PHYB protein, however, exhibits only weak
      circadian rhythmicity, if any. These data suggest that photoreceptor gene
      expression patterns may be significant in the daily regulation of plant
      physiology and indicate an unexpectedly intimate relationship between the
      components of the input pathway and the putative circadian clock mechanism in
      higher plants.

PMID- 10588761
TI  - Invariance of brain-wave representations of simple visual images and their names.
AB  - In two experiments, electric brain waves of 14 subjects were recorded under
      several different conditions to study the invariance of brain-wave
      representations of simple patches of colors and simple visual shapes and their
      names, the words blue, circle, etc. As in our earlier work, the analysis
      consisted of averaging over trials to create prototypes and test samples, to both
      of which Fourier transforms were applied, followed by filtering and an inverse
      transformation to the time domain. A least-squares criterion of fit between
      prototypes and test samples was used for classification. The most significant
      results were these. By averaging over different subjects, as well as trials, we
      created prototypes from brain waves evoked by simple visual images and test
      samples from brain waves evoked by auditory or visual words naming the visual
      images. We correctly recognized from 60% to 75% of the test-sample brain waves.
      The general conclusion is that simple shapes such as circles and single-color
      displays generate brain waves surprisingly similar to those generated by their
      verbal names. These results, taken together with extensive psychological studies
      of auditory and visual memory, strongly support the solution proposed for visual
      shapes, by Bishop Berkeley and David Hume in the 18th century, to the long
      standing problem of how the mind represents simple abstract ideas.

PMID- 10588762
TI  - A finding of oligocene primates on the European continent.
AB  - In this paper, we provide evidence that contrary to the current view, primates on
      the European continent did survive the dramatic extinction/origination event
      across the Eocene/Oligocene boundary 34 million years ago that severely affected
      the Eurasian mammal communities (the European "Grande Coupure" and the Asian
      "Mongolian Remodeling"). The survival of a mouse-sized omomyid for at least 2
      million years, recorded in two localities of the Lower Stampian (Lower Oligocene)
      in a well dated stratigraphic series of fluviatile sediments in the north
      oriental sector of the Ebro Basin (Northeastern Spain), reflects the size-related
      survival pattern described recently for other coeval mammalian taxa.

PMID- 10588763
TI  - Ethics in health care priority-setting: a north-south double standard?

PMID- 10588764
TI  - Treating neurocysticercosis medically: a systematic review of randomized,
      controlled trials.
AB  - OBJECTIVE: To summarize the evidence from randomized controlled trials on the
      effects of cysticidal therapy used for treating human cysticercosis. METHODS:
      Published and unpublished studies in any language identified through MEDLINE
      (1966 - June 1999) specialized databases, abstracts, proceedings and contact with
      experts were analysed. Those which compared, using randomized or quasi-randomized
      methods, any cysticidal drug with placebo or symptomatic therapy were entered in
      the study. Data were extracted independently by two reviewers and trial quality
      assessed. Meta-analysis using fixed effects models calculated provided there was
      no significant heterogeneity, expressed as relative risk. RESULTS: Four trials
      met the inclusion criteria, treating intraparenchymatous neurocysticercosis with
      either albendazole or praziquantel compared to placebo or no treatment. In the
      two trials reporting clinical outcomes, treatment was not associated with a
      reduction in the risk of seizures, although numbers were small (RR 0.95, 95% CI
      0.59-1.51). Four trials reported radiological outcomes, and cysticidal treatment
      was associated with a lower risk of cyst persistence of scans taken within six
      months of start of treatment (RR 0.83, 95% CI 0.70-0.99). Subsidiary analysis
      assuming different outcomes in patients lost to follow-up did not alter the
      findings of the main analysis. CONCLUSIONS: There is insufficient evidence to
      determine whether cysticidal therapy is of any clinical benefit to patients with
      neurocysticercosis. The review does not exclude the possibility that more
      patients remain seizure-free when treated with cysticidal drugs. Further testing
      through placebo-controlled trials is required.

PMID- 10588765
TI  - Impairment of natural killer cell activity in Chlamydia trachomatis infected
      individuals.
AB  - Natural killer (NK) cell activity is impaired in Chlamydia trachomatis-infected
      patients. The mechanisms behind the altered NK functions are not clear, but data
      concerning NK and antibody-dependent cellular cytotoxicity (ADCC) activity have
      been reported. To investigate whether this impairment is related to a defect at
      the target cell binding and/or the postbinding level, we evaluated highly
      purified NK cells obtained from 125 C. trachomatis-infected patients and compared
      them with 101 normal controls for their ability to kill K-562 and U-937 cell
      lines using a 51Cr release assay; release tumour necrosis factor-alpha (TNF
      alpha) and interferon-gamma (IFN-gamma); and kill anti-IgM preincubated P-815
      cell line (ADCC activity). We found a decrease in the lytic capability of NK
      cells from C. trachomatis-infected patients against target cell lines; decreased
      ability to kill bound target cells; and low levels of released TNF-alpha and INF
      gamma after incubation with U-937 cells. Taken together, these findings suggest
      that the impaired NK cell reaction during chlamydial infection is related to
      defects both at the target and postbinding levels. However, the precise
      mechanisms remain to be determined. The inability to restore normal NK activity
      after long-term culture in the presence of high levels of recombinant IL-2
      support the hypothesis of an anergic process during chlamydial infection.

PMID- 10588766
TI  - Maintenance and sustained use of insecticide-treated bednets and curtains three
      years after a controlled trial in western Kenya.
AB  - In large experimental trials throughout Africa, insecticide-treated bednets and
      curtains have reduced child mortality in malaria-endemic communities by 15%-30%.
      While few questions remain about the efficacy of this intervention, operational
      issues around how to implement and sustain insecticide-treated materials (ITM)
      projects need attention. We revisited the site of a small-scale ITM intervention
      trial, 3 years after the project ended, to assess how local attitudes and
      practices had changed. Qualitative and quantitative methods, including 16 focus
      group discussions and a household survey (n = 60), were employed to assess use,
      maintenance, retreatment and perceptions of ITM and the insecticide in former
      study communities. Families that had been issued bednets were more likely to have
      kept and maintained them and valued bednets more highly than those who had been
      issued curtains. While most households retained their original bednets, none had
      treated them with insecticide since the intervention trial was completed 3 years
      earlier. Most of those who had been issued bednets repaired them, but none
      acquired new or replacement nets. In contrast, households that had been issued
      insecticide-treated curtains often removed them. Three (15%) of the households
      issued curtains had purchased one or more bednets since the study ended. In
      households where bednets had been issued, children 10 years of age and younger
      were a third as likely to sleep under a net as were adults (relative risk (RR) =
      0. 32; 95% confidence interval (95%CI) = 0.19, 0.53). Understanding how and why
      optimal ITM use declined following this small-scale intervention trial can
      suggest measures that may improve the sustainability of current and future ITM
      efforts.

PMID- 10588767
TI  - Home case management of malaria: an ethnographic study of lay people's
      classification of drugs in Suneka division, Kenya.
AB  - Lay people in malaria-affected regions frequently have to choose from many over
      the-counter malaria management drugs, requiring them to be able to identify these
      medications and distinguish between them. Lay people make these distinctions at
      two levels - age of the patient and the whether he or she has fever, pain or
      malaria. Sometimes decisions are based on incorrect information given by friends
      and relatives, causing prolonged suffering to the patient, exacerbating
      chloroquine resistance and leading to resistance to the sulfodoxine/pyrymethamine
      drugs now recommended as first-line treatment in Kenya.

PMID- 10588768
TI  - The impact of population level deworming on the haemoglobin levels of
      schoolchildren in Tanga, Tanzania.
AB  - The impact of albendazole (400 mg) and praziquantel (40 mg/kg body weight)
      treatment of schoolchildren was compared with placebo according to the presence
      of anaemia (haemoglobin concentration < 11. 0 g/dl) and heavy (> 5000 epg) or
      light (< 5000 epg) hookworm egg load. The study was conducted in rural Tanga.
      Medication was administered in September 1994 and children were followed-up in
      January 1995. Overall, anthelminthic treatment reduced the fall in haemoglobin
      concentration compared with that observed in the placebo group (- 0.11 g/dl vs. -
      0.35 g/dl; P = 0.02). Anthelminthic treatment was of greatest benefit to the 9%
      of children with both anaemia and heavy hookworm egg load (+ 0.67 g/dl vs. - 0.67
      g/dl) and was also of significant benefit to the 38% of children with anaemia and
      light hookworm egg load (+ 0.07 g/dl vs. - 0.21 g/dl). It was of no significant
      benefit to children who were not anaemic. This study suggests that single-dose
      anthelminthic treatment distributed in schools in this area achieves
      haematological benefits in nearly half of children infected with S. haematobium
      and geohelminths (37% of total population).

PMID- 10588769
TI  - The performance of school-based questionnaires of reported blood in urine in
      diagnosing Schistosoma haematobium infection: patterns by age and sex.
AB  - This study investigates the performance of school-based questionnaires of
      reported blood in urine as an indicator of the prevalence of Schistosoma
      haematobium infection in schools and the presence of infection in individuals. In
      most schools (87%), the prevalence of reported blood in urine underestimates the
      prevalence of S. haematobium infection. Predictive value analysis suggests that a
      threshold of 30% reported blood in urine would identify most of the high
      prevalence schools (i.e. those with 50% or more children infected with S.
      haematobium). Although the prevalence of S. haematobium infection was greater in
      males than females, girls reported a lower prevalence of blood in urine than boys
      even at comparable levels of infection. Reported blood in urine in females was
      more specific (identifying 10% more uninfected girls than the sign in boys), but
      was far less sensitive (identifying less than 20% of infected girls than boys).
      The sensitivity of reported blood in urine was also related to age, being
      significantly lower in girls over 14 years of age. The proportion of infected
      children who reported blood in urine was also lower in schools where the
      prevalence of reported blood in urine is less than 30%. The results suggest that
      the selective treatment of children based on reported blood in urine in low
      prevalence schools would miss a high proportion of infected children,
      particularly girls. It remains unclear whether other rapid assessment techniques,
      such as the use of reagent strips, would offer greater cost-effectiveness.

PMID- 10588770
TI  - Determinants of mortality among children in the urban slums of Dhaka city,
      Bangladesh.
AB  - The growing slum population in the developing world is an increasing challenge
      for local health authorities. Little is known of the patterns of disease
      occurrence including treatment types offered in this population. The paper
      describes reported child mortality and its determinants, including the main
      diseases affecting children and treatments, in the slum population of Dhaka city,
      Bangladesh. 1500 households in three slum communities were included in a cross
      sectional survey. Reported death rates in the households per 1000 children (0-107
      months) within the last year from the interview were 20.5 for boys and 27.0 for
      girls. More girls than boys died in infancy (age < 12 months). The most frequent
      reported causes of deaths were tetanus in infancy and diarrhoea among children
      aged < or = 12 months. Vaccination coverage (DPT, polio, measles and BCG) was 73%
      for children < 3 years of age. The results showed that gender difference in
      mortality may have been influenced by the patterns of treatment received during
      sickness and the choice of treatment was determined by the financial ability of
      the households. Household income, children's vaccinations, TT immunization of
      mothers and personal cleanliness appeared to be significantly associated with
      child mortality. Despite the relatively high vaccination coverage for this
      population, child mortality remained alarmingly high, indicating that
      socioeconomic and environmental conditions must be improved to substantially
      reduce morbidity and mortality in this population.

PMID- 10588771
TI  - Dengue: an evaluation of dengue severity in French Polynesia based on an analysis
      of 403 laboratory-confirmed cases.
AB  - We conducted a retrospective study of 403 laboratory-confirmed dengue cases
      hospitalized in Tahiti between August 1989 and March 1997. According to standard
      WHO criteria, 337 of these cases were dengue fever (DF) and 64 were dengue
      haemorrhagic fever (DHF). Of the 10 fatal cases, 6 were DF and 4 were DHF. As an
      alternative, we used a correspondence analysis procedure to define dengue
      severity based on basic clinical and biological criteria for which we assigned a
      severity score, and then selected the 50 most severe cases from this analysis. Of
      the latter, 17 patients had been classified as DF and 33 as DHF by the WHO
      criteria. From this analysis, haemorrhages and decreased platelets counts
      associated with hepatic disorders are the main criteria associated with the
      severe dengue cases. Thus in our study population, the WHO classification does
      not account for the overall severity of dengue; hepatic failure should be
      considered as a specific severe form of dengue since plasma leakage, which is the
      pathophysiological hallmark of DHF, is only one of the pathogenic mechanisms
      leading to severity.

PMID- 10588772
TI  - Fascioliasis: sonographic abnormalities of the biliary tract and evolution after
      treatment with triclabendazole.
AB  - Diagnosis of infection with the liver fluke Fasciola hepatica is usually
      difficult. Ultrasonography (US) might be a useful diagnostic alternative, and we
      assessed the value of sequential US in the diagnosis and monitoring of
      fascioliasis in 76 patients at baseline and for 60 days after treatment with
      triclabendazole. At baseline, biliary abnormalities were observed in 52 patients.
      Crescent-shaped parasites were seen in 11 patients; in 2 cases parasites were
      spontaneously moving and in 4 patients parasites were motionless. Postprandial
      examination revealed parasites adhering to the gallbladder wall in a further 5
      cases. In 3 further cases, gallbladder contents were mobile but did not sediment
      downwards after patients changed position. Non-specific abnormalities were:
      impaired gallbladder contractility (n = 23), gallbladder tenderness (n = 19),
      debris (n = 6), calculi (n = 5), wall thickening (n = 2) and bile duct dilatation
      (n = 12). During day 1-7, Fasciola-like crescents in the gallbladder or passing
      through the bile duct were detected in another 15 patients, impaired gallbladder
      contractility in 16, gallbladder tenderness in 16, and bile duct dilatation in an
      additional 28 patients. Thirty-two patients with these US abnormalities
      experienced colic-like abdominal pain accompanied by increased alkaline
      phosphatase in 25 cases. During day 30-60, abnormalities regressed completely in
      45 patients; 2/6 triclabendazole failures were evident by detection of living
      parasites. Biliary tract abnormalities are frequently observed by US, but the
      detection-rate of Fasciola hepatica is disappointingly low despite the parasite's
      relatively large size. US findings must therefore be interpreted together with
      other clinical measurements. The visualization of parasites being expelled
      through the dilated common bile duct allowed the causal interpretation of post
      therapeutic abdominal pain and increase of liver enzymes. When triclabendazole is
      given on suspicion, visualization of worm expulsion and bile duct dilatation by
      US may be used to confirm diagnosis.

PMID- 10588773
TI  - Antibiotic dispensing by drug retailers in Kathmandu, Nepal.
AB  - OBJECTIVES To assess over-the-counter antimicrobial dispensing by drug retailers
      in Kathmandu, Nepal, for rationality, safety, and compliance with existing
      government regulations. METHODS: Standardized cases of dysuria in a young adult
      male and acute watery diarrhoea in a child were presented by a mock patient to
      retailers at 100 randomly selected pharmacies. Questions asked by retailers and
      advice and medications given at their initiative were recorded. RESULTS: All
      retailers engaged in diagnostic and therapeutic behaviour beyond their scope of
      training or legal mandate. Historical information obtained by retailers was
      inadequate to determine the nature or severity of disease or appropriateness of
      antimicrobial therapy. 97% (95% CI = 91.5-99.4%) of retailers dispensed
      unnecessary antimicrobials in diarrhoea, while only 44% (95% CI = 34.1-54.3%)
      recommended oral rehydration therapy and only 3% (95% CI = 0.6-8.5%) suggested
      evaluation by a physician. 38% (95% CI = 28.5-48.2%) gave antimicrobials in
      dysuria, yet only 4% (95% CI = 1.1-9.9%) adequately covered cystitis. None
      covered upper urinary tract or sexually transmitted infections, conditions which
      could not be ruled out based on the interviews, and only 7% (95% CI = 2.9-13. 9%)
      referred for a medical history and physical examination necessary to guide
      therapy. CONCLUSIONS: Although legislation in Nepal mandates a medical
      prescription for purchase of antibiotics, unauthorized dispensing is clearly
      problematic. Drug retailers in our study did not demonstrate adequate
      understanding of the disease processes in question to justify their use of these
      drugs. Risks of such indiscretion include harm to individual patients as well as
      spread of antimicrobial resistance. More intensive efforts to educate drug
      retailers on their role in dispensing, along with increased enforcement of
      existing regulations, must be pursued.

PMID- 10588774
TI  - Diagnostic PCR with Leishmania donovani specificity.

PMID- 10588775
TI  - Enhanced visualization of intravascular and left atrial appendage thrombus with
      the use of a thrombus-targeting ultrasonographic contrast agent (MRX-408A1): In
      vivo experimental echocardiographic studies.
AB  - Echocardiographic evaluation for the recognition of intravascular and left atrial
      appendage thrombus remains a difficult problem. A thrombus-specific
      ultrasonographic contrast agent has the potential for an alternative approach for
      their delineation. The aim of this study was to investigate the usefulness of
      thrombus-specific contrast agent MRX-408A1 for the detection of acute
      experimentally created intravascular and intracardiac thrombus. In the first
      study, we created inferior vena cava thrombus in 9 dogs. With the use of
      fundamental 2-dimensional echocardiography imaging, we recorded images of the
      inferior vena cava thrombus at baseline (n = 9), with the thrombus-specific
      contrast agent MRX-408A1 (n = 9), and with nonspecific contrast agent MRX-113 (n
      = 6). In the second study, we created a left atrial appendage thrombus in 8 dogs.
      We imaged left atrial appendage thrombus at baseline and during MRX-113 and MRX
      408A1 infusion. Thrombus was successfully created in all dogs in study 1 and in 6
      of 8 dogs in study 2. MRX-408A1 produced a visually apparent increase in
      ultrasonographic contrast enhancement of the thrombus in all cases in which
      thrombus was found on autopsy. In both studies, MRX-408A1 increased the
      videointensity of the thrombus significantly compared with baseline images and
      images obtained during MRX-113 infusion. The size of the visually detectable
      thrombus on the image was also significantly larger during MRX-408A1 infusion
      than at baseline and during MRX-113 infusion. These data provide in vivo
      demonstration of the efficacy of a thrombus-specific contrast agent, MRX-408A1,
      in the detection of acute intravascular and intracardiac thrombus. It has the
      potential to improve the diagnostic accuracy of ultrasonography for the detection
      of acute thrombi at various cardiovascular sites in the clinical setting.

PMID- 10588776
TI  - Improved echocardiographic delineation of left ventricular thrombus with the use
      of intravenous second-generation contrast image enhancement.
AB  - Transthoracic echocardiography is the most widely used diagnostic test for left
      ventricular (LV) thrombus, which must be distinguished from other
      intraventricular structures and image artifacts. To determine whether second
      generation intravenous echocardiographic contrast agents provide better
      delineation of LV thrombus, we reviewed the results of 2-dimensional
      echocardiographic studies that were performed in 409 patients over a 1-year
      period to detect LV thrombus. Studies of 190 (46%) patients were interpreted as
      nondiagnostic for this purpose, of which 48 patients underwent an additional
      study after intravenous injection of 0.5 to 2 mL of human albumin microspheres
      within 1 to 4 days. In 43 (90%) of these 48 patients the contrast-enhanced study
      was definitive and diagnostic for either the presence or absence of an LV
      thrombus (P <.0001). Of the initial total of 409 patients, 81 had been studied at
      the bedside in intensive care units. The bedside studies were nondiagnostic for
      LV thrombus in 51 (63%) of these 81 patients. Of these 51 patients, 14 underwent
      additional imaging with contrast enhancement, and the contrast-enhanced images
      became diagnostic (P =. 004) in 11 (79%) of them. Thus intravenous contrast image
      enhancement improves the diagnostic yield of echocardiography in patients in whom
      initial images are nondiagnostic for LV thrombus.

PMID- 10588777
TI  - In vitro, animal, and human characterization of OPTISON infusions for myocardial
      contrast echocardiography.
AB  - Traditionally, performing myocardial contrast echocardiography with OPTISON
      required maximal bolus dosing. However, sustained and consistent opacification of
      the myocardium would be preferable for perfusion imaging. METHODS: Images of 5
      anesthetized dogs and 6 human volunteers were obtained with a second harmonic
      ultrasound system during bolus administration of OPTISON and 2 infusion
      techniques. One infusion technique used diluted OPTISON, and the other used the
      buoyant properties of OPTISON microspheres by placing the contrast agent between
      an infusion source and the intravenous site in a vertically oriented extension
      line (ELT). Myocardial intensities and in vitro microsphere characteristics were
      analyzed to assess the consistency of microsphere delivery over time. RESULTS: In
      addition to providing higher myocardial opacification intensity than diluted
      infusions, ELT infusions provided consistent microsphere concentration, phantom
      enhancement, and near-peak bolus-level myocardial opacification for 7 to 15
      minutes. The myocardial intensity at 3 and 5 minutes in human subjects during ELT
      infusions (30 mL/h; 2.5 mL) was lower (220 arbitrary units [au] and 165 au,
      respectively) but not significantly different (P =.3 and.1, respectively) than
      the peak myocardial intensity (265 au) after bolus administration. CONCLUSION:
      This new ELT infusion method provides an acceptable alternative to bolus
      administration of OPTISON for prolonged myocardial opacification.

PMID- 10588778
TI  - Flow convergence flow rates from 3-dimensional reconstruction of color Doppler
      flow maps for computing transvalvular regurgitant flows without geometric
      assumptions: An in vitro quantitative flow study.
AB  - OBJECTIVE: This study was designed to develop and test a 3-dimensional method for
      direct measurement of flow convergence (FC) region surface area and for
      quantitating regurgitant flows with an in vitro flow system. BACKGROUND:
      Quantitative methods for characterizing regurgitant flow events such as flow
      convergence with 2-dimensional color flow Doppler imaging systems have yielded
      variable results and may not be accurate enough to characterize those more
      complex spatial events. METHOD: Four differently shaped regurgitant orifices were
      studied: 3 flat orifices (circular, rectangular, triangular) and a nonflat one
      mimicking mitral valve prolapse (all 4 orifice areas = 0.24 cm(2)) in a pulsatile
      flow model at 8 to 9 different regurgitant flow rates (10 to 50 mL/beat). An
      ultrasonic flow probe and meter were connected to the flow model to provide
      reference flow data. Video composite data from the color Doppler flow images of
      the FC were reconstructed after computer-controlled 180 degrees rotational
      acquisition was performed. FC surface area (S cm(2)) was calculated directly
      without any geometric assumptions by measuring parallel sliced flow convergence
      arc lengths through the FC volume and multiplying each by the slice thickness
      (2.5 to 3.2 mm) over 5 to 8 slices and then adding them together. Peak
      regurgitant flow rate (milliliters per second) was calculated as the product of 3
      dimensional determined S (cm(2)) multiplied by the aliasing velocity (centimeters
      per second) used for color Doppler imaging. RESULTS: For all of the 4 shaped
      orifices, there was an excellent relationship between actual peak flow rates and
      3-dimensional FC-calculated flow rates with the direct measurement of the surface
      area of FC (r = 0.99, mean difference = -7.2 to -0.81 mL/s, % difference = -5% to
      0%), whereas a hemielliptic method implemented with 3 axial measurements of the
      flow convergence zone from 2-dimensional planes underestimated actual flow rate
      by mean difference = -39.8 to -18.2 mL/s, % difference = -32% to -17% for any
      given orifice. CONCLUSIONS: Three-dimensional reconstruction of flow based on 2
      dimensional color Doppler may add quantitative spatial information, especially
      for complex flow events. Direct measurement of 3-dimensional flow convergence
      surface areas may improve accuracy for estimation of the severity of valvular
      regurgitation.

PMID- 10588779
TI  - Three-dimensional echocardiography in adult patients: comparison between
      transthoracic and transesophageal reconstructions.
AB  - BACKGROUND: Three-dimensional (3D) echocardiography is a relatively new technique
      typically implemented with transesophageal imaging with multiplane transducers.
      OBJECTIVES: The goals of this study were (1) to test the feasibility of 3D
      reconstruction with a new transthoracic multiplane transducer in adult subjects
      with excellent quality of 2-dimensional images and (2) to compare these
      reconstructions with those obtained in the same patients with the transesophageal
      approach. METHODS: Transthoracic multiplane image acquisition was performed in 37
      patients who were selected on the basis of the quality of their 2-dimensional
      images. In addition, transesophageal acquisition was also performed in 19 of 37
      patients. Three-dimensional reconstruction of mitral and aortic valves was
      performed. Three-dimensional images were reviewed, and the visualization of
      various anatomic features was graded. RESULTS: The reconstruction of 25 mitral
      valves and 16 aortic valves, normal and pathologic, was feasible and resulted in
      visualization of anatomic detail. Score indexes of all valvular characteristics
      studied were not significantly different when transthoracic and transesophageal
      reconstructions were compared. CONCLUSIONS: Transthoracic 3D echocardiography
      with a multiplane transducer in adult patients with good acoustic windows is
      feasible. This technique will allow easy noninvasive serial assessment of
      valvular pathophysiologic characteristics.

PMID- 10588780
TI  - Appropriate 3-dimensional echocardiography data acquisition interval for left
      ventricular volume quantification: implications for clinical application.
AB  - Volume-rendered 3-dimensional echocardiography (3DE) acquired with small imaging
      intervals has been validated for accurate left ventricular (LV) volume
      measurement. However, its clinical application is often impeded by the lengthy
      acquisition time. The aim of this study was to examine the accuracy of LV volume
      measurement from 3DE data acquired at different intervals. METHODS: Transthoracic
      3DE LV data sets were acquired at intervals of 2 degrees, 6 degrees, 9 degrees,
      12 degrees, 15 degrees, 18 degrees, and 20 degrees in 10 human subjects with
      various cardiac shapes and function. The LV end-diastolic volume and end-systolic
      volume were measured from each 3DE data set with the "summation of disks" method.
      Interobserver and intraobserver variability were also examined. Measurements
      obtained from data acquired at 2 degrees intervals were used as references for
      comparison. RESULTS: From 10 subjects a total of 70 3DE data sets were obtained.
      Data acquisition time decreased from 189 +/- 143 seconds at intervals of 2
      degrees to 19 +/- 6 minutes at 20 degrees. No statistically significant
      difference was found among the measurements derived from data obtained at various
      intervals. Excellent agreement was obtained between interobserver and
      intraobserver measurements. CONCLUSION: Data acquired at 12 degrees and 15
      degrees intervals remained accurate for LV volume measurement and saved over 80%
      of time in comparison with data acquired at 2 degrees intervals. A further
      increase in imaging intervals tended to underestimate LV volumes without
      significant acceleration of the procedure.

PMID- 10588781
TI  - Assessment of global left ventricular function in normal children and in children
      with dilated cardiomyopathy.
AB  - A Doppler index combining systolic and diastolic time intervals (Tei index) has
      been reported to be useful for assessing global left ventricular (LV) function
      and predicting clinical outcome in adult patients with LV dysfunction. However,
      normal values in children and age-related changes in the index have not yet been
      clarified. The aim of this study was to prospectively determine normal values of
      the Tei index and the effect of aging on the index in children and to assess the
      global cardiac function in patients with dilated cardiomyopathy with this index.
      The subjects included 161 consecutive normal children aged 30 days to 18 years
      and 5 patients with dilated cardiomyopathy. The Tei index was defined as the sum
      of the isovolumetric contraction time and the isovolumetric relaxation time
      divided by the ejection time and was measured from conventional LV outflow and
      inflow Doppler velocity profiles. The Tei index correlated significantly with the
      logarithm of age (r = 0.51, P <. 001). The index decreased with aging until 3
      years and then did not change after age 3 years. The Tei index in children under
      age 3 years (0.40 +/- 0.09, n = 80) was significantly higher than that in
      children ranging in age from 3 to 18 years old (0.33 +/- 0.02, n = 81). The index
      in patients with dilated cardiomyopathy (0.78 +/- 0. 28) was markedly increased
      compared with that in normal subjects. Age-related changes in the Tei index may
      reflect maturational or developmental alterations in the LV properties in
      infants. The data in this study give basic information for further quantitative
      assessment of global cardiac function in children with congenital or acquired
      heart disease.

PMID- 10588782
TI  - Effect of preload alternations on a new Doppler echocardiographic index of
      combined systolic and diastolic performance.
AB  - The objective of the study was to assess the effect of preload alternations on a
      nongeometric Doppler index of combined systolic and diastolic myocardial
      performance (MPI). Doppler echocardiography was performed during Valsalva
      maneuver, passive leg lifting, and after sublingual administration of
      nitroglycerin in 50 healthy volunteers (group 1) and 25 patients (group 2) with
      previous myocardial infarction. MPI was significantly lower in group 1 (0.34 +/-
      0.04) compared with group 2 (0.52 +/- 0.14), P <.0005. In group 1 MPI was
      significantly increased during preload manipulations (P =. 001). The largest
      change in MPI was induced by nitroglycerin (0.034 +/- 0.05). In group 2 no
      significant changes in MPI were found. In both groups peak E-wave velocity (P
      <.0005), E/A-ratio (P <.0005), and E-wave deceleration time (P <.0005) were found
      to change during preload alternations. In conclusion, we found in normal subjects
      and to a lesser extent in patients with previous myocardial infarction that MPI
      is influenced by preload.

PMID- 10588783
TI  - Comparison of treadmill exercise echocardiography before and after exercise in
      the evaluation of patients with known or suspected coronary artery disease.
AB  - OBJECTIVES: We sought to compare the feasibility and accuracy of peak treadmill
      exercise echocardiography versus postexercise echocardiography imaging.
      BACKGROUND: Although peak exercise echocardiography has been reported for both
      supine and orthostatic bicycle exercise and has shown higher sensitivity than
      postexercise imaging, acquiring images at peak exercise with treadmill has not
      been explored. METHODS: Peak and post-treadmill exercise echocardiography and
      coronary angiography were performed on 89 patients with known or suspected
      coronary artery disease. Positive exercise echocardiography was defined as
      necrosis or ischemic response. Positive coronary angiography was defined as >/=1
      diseased vessels (>/=50% luminal narrowing). Images were analyzed in a blind
      manner by an expert observer. RESULTS: Postexercise images were acquired within
      80 seconds after exercise (40 +/- 14). Mean heart rate (bpm) was 139 +/- 22 at
      peak versus 118 +/- 25 at postexercise imaging (P <.001). Interpretable peak and
      postexercise images were obtained for all 89 patients. Of the 72 classified as
      having positive exercise echocardiography, 23 had new regional wall motion
      abnormality at peak (21 with positive angiography), which resolved at
      postexercise imaging. Sensitivity was higher with peak than with postexercise
      imaging (94% vs 73%, P <.001). Specificity was similar (68% vs 79%), as was
      predictive positive value (92% vs 93%). Negative predictive value was again
      higher with peak imaging (76% vs 44%, P <.05). Total accuracy was higher with
      peak imaging (89% vs 74%, P <.05). CONCLUSIONS: Peak treadmill exercise
      echocardiography is technically feasible and has higher sensitivity and accuracy
      than post-treadmill exercise echocardiography. Therefore in the clinical setting
      peak exercise echocardiography should be performed to diagnose ischemia.

PMID- 10588784
TI  - Pathophysiologic correlates of thromboembolism in nonvalvular atrial
      fibrillation: I. Reduced flow velocity in the left atrial appendage (The Stroke
      Prevention in Atrial Fibrillation [SPAF-III] study).
AB  - Stroke associated with atrial fibrillation (AF) is mainly due to embolism of
      thrombus formed during stasis of blood in the left atrial appendage (LAA).
      Pathophysiologic correlates of appendage flow velocity as assessed by
      transesophageal echocardiography (TEE) in patients with AF have not been defined.
      To evaluate the hypothesis that reduced velocity is associated with spontaneous
      echocardiographic contrast and thrombus in the LAA and with clinical embolic
      events, we measured LAA flow velocity by TEE in 721 patients with nonvalvular AF
      entering the Stroke Prevention in Atrial Fibrillation (SPAF-III) study. Patient
      features, TEE findings, and subsequent cardioembolic events were correlated with
      velocity by multivariate analysis. Patients in AF during TEE displayed lower peak
      antegrade (emptying) flow velocity (Anu(p)) than those with intermittent AF in
      sinus rhythm during TEE (33 cm/s vs 61 cm/s, respectively, P <.0001). Anu(p) < 20
      cm/s was associated with dense spontaneous echocardiographic contrast (P <.001),
      appendage thrombus (P <.01), and subsequent cardioembolic events (P <.01).
      Independent predictors of Anu(p) < 20 cm/s included age (P =.009), systolic blood
      pressure (P <.001), sustained AF (P =.01), ischemic heart disease (P =.01), and
      left atrial area (P =.04). Multivariate analysis found both Anu(p) <20 cm/s
      (relative risk 2.6, P =.02) and clinical risk factors (relative risk 3.3, P
      =.002) independently associated with LAA thrombus. LAA Anu(p) is reduced in AF
      and associated with spontaneous echocardiographic contrast, appendage thrombus,
      and cardioembolic stroke. Systolic hypertension and aortic atherosclerosis,
      independent clinical predictors of stroke in patients with AF, also correlated
      with LAA Anu(p). Our results support the role of reduced LAA Anu(p) in the
      generation of stasis, thrombus formation, and embolism in patients with AF,
      although other mechanisms also contribute to stroke.

PMID- 10588785
TI  - Pathophysiologic correlates of thromboembolism in nonvalvular atrial
      fibrillation: II. Dense spontaneous echocardiographic contrast (The Stroke
      Prevention in Atrial Fibrillation [SPAF-III] study).
AB  - We analyzed transesophageal echocardiograms from 772 participants in the Stroke
      Prevention in Atrial Fibrillation (SPAF-III) study, characterizing spontaneous
      echocardiographic contrast (SEC) in the left atrium or appendage as faint or
      dense. The association of dense SEC with stroke risk factors and anatomic,
      hemodynamic, and hemostatic parameters related to specific thromboembolic
      mechanisms was evaluated by multivariate analysis. Spontaneous echocardiographic
      contrast was present in 55% of patients and was dense in 13%. Age (odds ratio
      [OR] 2.4/decade, P <.001), constant atrial fibrillation (OR 6.9, P <.001),
      history of hypertension (OR 3. 2, P <.001), and current tobacco smoking (OR 2.6,
      P =.04) were independent clinical predictors of dense SEC. Multivariate analysis
      of clinical, echocardiographic, and hemostatic parameters yielded age as the sole
      independent clinical predictor of dense SEC (OR 2. 4/decade, P <.001). Other
      independent predictors were measures of left atrial/appendage flow dynamics, left
      atrial size (OR 2.4/cm diameter, M-mode, P <.001), atherosclerotic aortic plaque
      (OR 2.8, P =.002), and plasma fibrinogen >350 mg/dL (P <.001). Results were
      similar when SEC of any density was analyzed. In conclusion, SEC occurred in more
      than half of these patients with prospectively defined nonvalvular atrial
      fibrillation but was usually faint. Dense SEC was strongly associated with
      previously reported clinical predictors of stroke, linking them to
      thromboembolism through atrial stasis. Diverse pathophysiologic factors including
      atrial stasis, fibrinogen level, and aortic plaque influence SEC.

PMID- 10588786
TI  - When the body and appendage of the left atrium disagree: "Focal" atrial
      fibrillation-implications for atrial thrombus formation and risk of
      thromboembolism.
AB  - A case is presented of a man who had 5 hours of atrial fibrillation followed by
      spontaneous conversion and maintained sinus rhythm that persisted as shown by
      surface electrocardiography. Transesophageal echocardiography performed 24 hours
      after electrocardiographic conversion documented an atrial fibrillation pattern
      within the left atrial appendage, with a normal sinus Doppler pattern in the body
      of the left atrium. This apparent regional discrepancy in atrial function may
      partially explain the increased risk for "late" thromboembolism among patients
      with atrial fibrillation who appear to be successfully converted with sustained
      sinus rhythm.

PMID- 10588787
TI  - Spontaneous intramural atrial hematoma presenting as a left atrial mass.
AB  - We describe an unusual case of spontaneously occurring intramural atrial hematoma
      with no communication with either atrium. The diagnosis of left atrial mass was
      made from transthoracic echocardiography. Subsequent examination with
      transesophageal echocardiography confirmed a large mass essentially filling the
      whole left atrium but failed to provide an etiologic diagnosis, which was
      eventually made at surgery.

PMID- 10588788
TI  - Coronary arteriovenous fistula with a giant aneurysm: role of transesophageal
      echocardiography.
AB  - Congenital coronary arteriovenous fistulas are rare anomalies. Patients may
      present with congestive heart failure, ischemic chest pain, or endocarditis. In
      this case, transesophageal echocardiography provided valuable additional
      information to that obtained from cardiac catheterization, which was essential
      for the diagnosis and planning of surgical correction.

PMID- 10588789
TI  - Transient myocardial dysfunction associated with angiotensin-converting enzyme
      inhibitor-induced angioedema: recognition by serial echocardiographic studies.
AB  - We report a case of a 58-year-old woman who had angiotensin converting enzyme
      inhibitor-induced angioedema after she underwent a biopsy of a hypopharyngeal
      mass. The angioedema was associated with severe transient myocardial dysfunction
      documented on echocardiography. She did not have anaphylaxis or coronary artery
      disease. To our knowledge this is the first reported case of transient myocardial
      dysfunction in the setting of angiotensin converting enzyme inhibitor-induced
      angioedema without anaphylaxis.

PMID- 10588790
TI  - Early deterioration followed by improvement in contractility during dobutamine
      stress echocardiography: An unusual response.
AB  - In 2 patients with severe proximal coronary artery stenosis and normal wall
      motion in this territory, we observed marked wall motion abnormalities with low
      and intermediate doses of dobutamine, followed by marked improvement with
      continued dobutamine infusion. This unusual response suggests ischemic
      preconditioning and recruitment of coronary collaterals and would be recognized
      only by monitoring of images obtained at all stages of dobutamine infusion.

PMID- 10588791
TI  - Intermittent left coronary occlusion caused by native aortic valve thrombosis in
      a patient with protein S deficiency.
AB  - A 77-year-old woman presented with chest pain and cardiogenic shock.
      Transesophageal echocardiography showed a mobile mass occluding intermittently
      the left coronary ostium. The mass was surgically resected, and histologic
      examination revealed an organized thrombus. Coagulation study demonstrated a
      protein S deficiency. This is the first case of aortic thrombosis associated with
      protein S deficiency, and it is the first time that transesophageal
      echocardiography provided definite evidence that a mass can cause intermittent
      left ostium coronary obstruction.

PMID- 10588792
TI  - Systolic anterior movement of mitral valve during acute apical myocardial
      infarction: An unusual mechanism of acute mitral regurgitation.
AB  - We describe a singular case of a 75-year-old woman affected by an anterior acute
      myocardial infarction in the subset of a very recent orthopaedic surgery. She had
      had severe mitral regurgitation on coronary angiography. A thorough cardiac
      echocardiographic examination revealed the particular mechanism of mitral
      incompetence, consisting of a dynamic anterior mitral leaflet displacement caused
      by a sustained compensatory left ventricle hypercontractility and favored by
      postsurgical moderate anemia and mild hypertensive hypertrophy. The use of beta
      blockers and the avoidance of pure vasodilators permitted complete reversal of
      such mechanisms during the clinical course.

PMID- 10588793
TI  - Transthoracic contrast echocardiographic detection of ascending aortic
      dissection.
AB  - BACKGROUND: Ascending aortic dissection is highly lethal if left untreated.
      Therefore rapid accurate diagnosis is necessary. Diagnosis can be made with
      imaging modalities that use contrast agents to delineate anatomy reliably.
      Transthoracic echocardiography has not routinely been diagnostically useful
      because of the inability in clearly visualizing the ascending aorta. METHOD AND
      RESULTS: We describe a case in which transthoracic echocardiography with an
      echocardiographic contrast agent provided diagnostic information regarding an
      acute ascending aortic dissection, delineating both the true and false lumens.
      CONCLUSIONS: Transthoracic echocardiography combined with an echocardiographic
      contrast agent can be useful in detecting an ascending aortic dissection.

PMID- 10588794
TI  - The need for transesophageal echocardiography (TEE) documentation of thrombus
      resolution after a course of anticoagulation therapy for an initial finding of
      thrombus.

PMID- 10588795
TI  - Reply

PMID- 10588796
TI  - Improved mouth guard design for protection and comfort.
AB  - Mouth guards worn during contact sports have been shown to provide considerable
      protection against traumatic injuries to the teeth and supporting structures. Of
      the 3 types available, the custom-made mouth guard is considered superior to
      stock and mouth-formed mouth guards. The procedure for making a special mouth
      guard designed for protection and comfort is described.

PMID- 10588797
TI  - Clinical experience with a device to enhance craniofacial peri-implantary wound
      healing: A clinical report.

PMID- 10588798
TI  - Immediate dual path of insertion removable partial denture with a metal
      framework.
AB  - This article describes and illustrates an alternative procedure for making an
      immediate removable partial denture with a metal framework and a dual path of
      insertion. It has several advantages over the conventional method for making
      immediate removable partial dentures and some disadvantages.

PMID- 10588799
TI  - Effect of weight change of mandibular complete dentures on chewing and stability:
      A pilot study.
AB  - STATEMENT OF PROBLEM: Little is known as to whether denture weight contributes to
      the retention and stability of mandibular complete denture. PURPOSE: This study
      compared the jaw movements and denture retention, stability, and comfort of heavy
      and light weight mandibular complete dentures. MATERIAL AND METHODS: Mandibular
      complete dentures of 12 subjects were duplicated using an autopolymerized
      polymethyl methacrylate (PMMA) resin. The heavy weight denture was set with
      weights (20 or 60 g) and the lightweight denture was packed with wax instead of
      weights. Masticatory movements (3 times each) and denture stability (5 times
      each) were measured. The subjects expressed their denture preference for comfort
      and chewing. Results were analyzed using ANOVA and Wilcoxon tests at significance
      level of alpha=.10. RESULTS: Masticatory movements and denture retention were not
      significantly (P >.10) affected by increasing the weight. Five subjects preferred
      the heavy denture and 4 subjects preferred light denture for comfort; 3 subjects
      had no preference. CONCLUSION: The weight of a well-fitting mandibular complete
      denture did not affect jaw movements, denture stability, or patient preference.

PMID- 10588800
TI  - Foundation restorations in fixed prosthodontics: current knowledge and future
      needs.
AB  - PURPOSE: The Ad Hoc Committee on Research in Fixed Prosthodontics established by
      the Academy of Fixed Prosthodontics publishes a yearly comprehensive literature
      review on a selected topic. The subject for this year is foundation restorations.
      METHODS: Literature of various in vitro and in vivo investigations that included
      technical and clinical articles was reviewed to provide clinical guidelines for
      the dentist when selecting methods and materials for restoration of structurally
      compromised teeth. Topics discussed and critically reviewed include: (1)
      desirable features of foundation restorations, (2) foundations for pulpless
      teeth, (3) historic perspectives, (4) cast posts and cores, (5) role of the
      ferrule effect, (6) prefabricated posts, (7) direct cores, (8) foundation
      restorations for severely compromised teeth, (9) problems and limitations, (10)
      future needs, and (11) directions for future research. CONCLUSION: This
      comprehensive review brings together literature from a variety of in vitro and in
      vivo studies, along with technique articles and clinical reports to provide
      meaningful guidelines for the dentist when selecting methods and materials for
      the restoration of structurally compromised teeth.

PMID- 10588801
TI  - Effect of water temperature on the fit of provisional crown margins during
      polymerization.
AB  - STATEMENT OF PROBLEM: When fabricating a provisional crown with the direct
      technique, dentists are concerned with margin discrepancies that result from
      polymerization shrinkage. PURPOSE: This in vitro study examined the effect of
      water temperature on the fit of provisional crown margins during resin
      polymerization. MATERIAL AND METHODS: The experiment was designed to simulate a
      direct technique to fabricate provisional crowns. After mixing autopolymerizing
      methyl methacrylate resin, the material was placed in a preformed polycarbonate
      crown. The crown was seated on a prepared premolar-shaped die with a shoulder
      margin. After 1 minute and 50 seconds, the crown was removed and polymerization
      was continued under the following conditions: 20 degrees C air, and water at 0
      degrees C, 10 degrees C, 20 degrees C, 30 degrees C, 40 degrees C, 60 degrees C,
      and 80 degrees C. Six minutes after polymerization, the crown was trimmed and
      reseated on the die. Discrepancy of crown margin was measured with a 3
      dimensional digitizer. RESULTS: Margin discrepancy varied with the condition
      during resin-polymerization (ANOVA, P <.001). The crowns polymerized in 20
      degrees C and 30 degrees C water revealed the best margin fit, showing 3 times
      more accurate margin fit than those polymerized in 20 degrees C air
      (Bonferroni/Dunn procedure, P <.01). CONCLUSION: Conditions during resin
      polymerization were significant factors that affected margin fit of provisional
      crowns using the direct technique. Water temperatures of 20 degrees C and 30
      degrees C produced the best fit at the margin of the provisional crown.

PMID- 10588802
TI  - Clinical and scanning electron microscopic evaluation of fiber-reinforced inlay
      fixed partial dentures: preliminary results after one year.
AB  - STATEMENT OF PROBLEM: Restorative dentistry searches for nonmetal reinforcement
      of esthetic fixed partial dentures (FPDs). PURPOSE: This clinical study evaluated
      conservative fiber-reinforced composite FPDs bonded to inlay abutments. MATERIAL
      AND METHODS: Twenty fiber-reinforced composite inlay FPDs were made for 15
      patients. Restorations were manufactured with the Targis Vectris glass-fiber
      reinforced composite system and a simplified laboratory technique. The 20 bonded
      inlay FPDs were examined clinically and by SEM after 1 year. RESULTS: All 20 FPDs
      were intact at the 1-year examination. There were no signs of fracture, surface
      defects, or excessive wear with SEM. SEM marginal analysis exhibited 91.6% +/- 5%
      excellent margins at the tooth-luting composite interface and 86. 1% +/- 8%
      excellent margins at luting composite/restoration interface. CONCLUSION: On the
      basis of the results of this descriptive study, bonded glass-fiber-reinforced
      composite inlay FPDs were considered clinically successful at the 1-year
      examination.

PMID- 10588803
TI  - Wear of enamel and veneering ceramics after laboratory and chairside finishing
      procedures.
AB  - PURPOSE: This in vitro study compared the wear of enamel against 3 types of
      ceramics with high esthetic potential (designed for layering techniques):
      feldspathic porcelain (Creation), aluminous porcelain (Vitadur alpha), and low
      fusing glass (Duceram-LFC). Laboratory finishing (glazing/polishing) and
      chairside polishing with a Dialite kit were simulated to compare their respective
      effects on wear. METHODS: Tooth-material specimen pairs were placed in an
      artificial mouth using closed-loop servohydraulics. Constant masticatory
      parameters (13.5 N occlusal force, 0.62 mm lateral excursion; 0.23 second cuspal
      contact time) were maintained for 300, 000 cycles at a rate of 4 Hz. The occlusal
      surface of each pair was mapped and digitally recorded before and after each
      masticatory test. Quantitative changes were measured in terms of depth and volume
      of wear. Quantitative wear characteristics were assessed by SEM. RESULTS:
      Significant differences were observed (2-factor ANOVA, P <.05). Duceram-LFC
      generated increased volume loss of enamel (0.197 mm(3)) compared with Creation
      (0.135 mm(3)) and Vitadur alpha (0.153 mm(3)). Creation exhibited the lowest
      ceramic wear and lowest combined volume loss (0.260 mm(3); the sum of the data
      for enamel and the opposing material) compared with Duceram-LFC (0.363 mm(3)) and
      Vitadur alpha (0.333 mm(3)). The most significant differences among materials
      were observed in volume loss, not in depth of wear. For all 3 ceramic systems,
      qualitative SEM evaluation revealed an abrasive type of wear. Wear
      characteristics of chairside polished specimens were similar to those of
      laboratory finished specimens (glazed and polished). CONCLUSION: Duceram-LFC was
      the most abrasive ceramic for the antagonistic tooth. Creation ceramic was the
      least abrasive material and most resistant to wear. Defects, brittleness, and the
      possibly insufficient toughness of LFC may explain its increased abrasiveness.
      Laboratory and chairside finishing procedures generated similar results.

PMID- 10588804
TI  - Time-related wettability characteristic of acrylic resin surfaces treated by glow
      discharge.
AB  - STATEMENT OF PROBLEM: Adhesion and cohesion have important roles in denture
      retention, and attempts have been made to improve the wettability of the acrylic
      resin material by surface treatments. PURPOSE: This study examined the initial
      and subsequent wettability of an acrylic resin denture base material treated
      under air or argon plasma atmosphere before and after exposure to air or
      distilled water. MATERIAL AND METHODS: Acrylic resin specimens were treated with
      plasma under air or argon atmosphere and were either exposed to air or distilled
      water for up to 60 days. Wettability characteristics of the acrylic resin
      specimens were determined by contact-angle measurements after 2 hours and after
      60 days. Surface composition of the specimens also was analyzed with x-ray
      photoelectron spectroscopic (XPS) measurements. RESULTS: Statistically
      significant difference was found between control and each of the plasma treatment
      groups (P <.05). Although the storage condition and storage period caused
      statistically significant difference on contact angle values (P <.05), atmosphere
      type did not have any effect on the results (P >.05). XPS spectra of the plasma
      treated specimens differed from control specimens only in the O1s region with a
      narrower and more intense peak that could be assigned to -COH groups. During 60
      days of exposure, the O/C atomic ratios decreased within the first 2 weeks but
      settled to 0.40 and 0. 32 up to 60 days compared with 0.26 for untreated control
      specimens. CONCLUSION: Glow discharge plasma altered the surfaces of the acrylic
      resin and increased thc wettability as shown both by XPS and contact-angle
      measurements, and plasma treatment seemed to offer a durable (at least up to 60
      days) wettability.

PMID- 10588805
TI  - Dental considerations in upper airway sleep disorders: A review of the
      literature.
AB  - STATEMENT OF PROBLEM: Upper airway sleep disorders are becoming recognized as
      common medical concerns. Multiple treatment options have been advocated,
      including the use of dental devices. Dental practitioners are being asked by the
      medical profession to become a part of the treatment team. This may be a
      challenging task because of the large number of dental devices available, rapid
      advancement in the understanding of this disease, and numerous publications.
      PURPOSE: This article reviews the anatomic features and etiologic factors of
      upper airway sleep disorders and medical and dental treatment options. METHODS:
      The literature review was conducted with an accepted literature research tool,
      PubMed, developed by the National Library of Medicine. Key words searched
      included "obstructive sleep apnea," "sleep apnea," "sleep disorders," and
      "snoring". CONCLUSION: Dental devices are indicated in snoring and mild-to
      moderate obstructive sleep apnea patients after medical evaluation and referral.

PMID- 10588806
TI  - Developing a register for randomized controlled trials in prosthodontics: results
      of a search from prosthodontic journals published in the United States.
AB  - STATEMENT OF PROBLEM: Treatment decisions are often made despite absence of
      evidence from well-conducted clinical trials. Conclusions about treatment
      efficacy derived from nonexperimental approaches often overestimate treatment
      effect. Randomized controlled trials (RCTs) provide the most reliable basis for
      evaluating effectiveness of treatment interventions. PURPOSE: This study
      attempted to identify and catalog RCTs in prosthodontic journals published in the
      United States as an initial step in creating a register of clinical trials that
      would be a resource in setting up systemic overviews of prosthodontic literature.
      METHODS: The International Journal of Prosthodontics, The Journal of Prosthetic
      Dentistry, and The Journal of Prosthodontics published between 1988 and 1997 were
      searched manually to identify clinical trials. Clinical trials had to meet the
      following criteria for inclusion in the register: the trial must involve human
      subjects, must include at least 2 treatment groups, and treatment group
      allocation must be randomized. RESULTS: A total of 3,631 articles in 196 journal
      issues were screened. Sixty-two articles (1.7%) met the minimum criteria for
      inclusion in the RCT register. CONCLUSION: Given the lack of randomized
      controlled trials in prosthodontic journals, a concerted effort by the organized
      prosthodontic community should be made to screen national and international
      journals and contribute to the development of a register of randomized controlled
      trials relevant to prosthodontics.

PMID- 10588807
TI  - Sixty-eight years of experimental occlusal interference studies: what have we
      learned?
AB  - STATEMENT OF PROBLEM: Understanding is needed regarding the effect that occlusal
      interferences have on the teeth, periodontium, and especially on jaw function.
      PURPOSE: This article summarizes research in which experimental occlusal
      interferences have been placed on the teeth of animals and human volunteers.
      MATERIAL AND METHODS: Data from 18 human and 10 animals studies were reviewed.
      Experimental occlusal interferences were grouped into those that alter
      intercuspal position and those contacting on lateral jaw movement only. The
      outcome of these interferences were analyzed according to their local pulpal
      periodontal, jaw function, or bruxism effects. RESULTS: Experimental occlusal
      interferences in maximum intercuspation had a deleterious effect on periodontal
      and pulpal tissues of the affected tooth; sometimes this produces a disruption of
      smooth jaw function and occasionally jaw muscle pain and clicking. Experimental
      occlusal interferences that contact only in a lateral jaw movement are
      infrequently harmful to jaw function. Furthermore, no reliable evidence
      demonstrates that occlusal interferences can cause nocturnal bruxism, or stop it.
      CONCLUSION: Transient local tooth pain, loosening of the tooth, a slight change
      in postural muscle tension levels, chewing stroke patterns, and sometimes a
      clicking joint can be induced by an experimental occlusal interference. Because
      such findings are present in relatively asymptomatic patients, these data do not
      prove that occlusal interferences are causally related to a chronic jaw muscle
      pain or temporomandibular joint dysfunction problems.

PMID- 10588809
TI  - American board of prosthodontics

PMID- 10588808
TI  - Water immersion procedure for making light-cured custom trays with wax spacers.
AB  - This article describes a modified light-curing method that minimizes wax spacer
      heating and distortion. In addition, this method eliminates the need for tinfoil
      adaptation or use of a coating to make an air barrier in the fabrication of light
      cured custom trays for removable prosthodontics.

PMID- 10588810
TI  - Estrogen receptor beta--a new dimension in estrogen mechanism of action.

PMID- 10588811
TI  - Maternal hypothyroxinemia influences glucose transporter expression in fetal
      brain and placenta.
AB  - The influence of maternal hypothyroxinemia on the expression of the glucose
      transporters, GLUT1 and GLUT3, in rat fetal brain and placenta was investigated.
      Fetal growth was retarded in hypothyroxinemic pregnancies, but only before the
      onset of fetal thyroid hormone synthesis. Placental weights were normal, but
      placental total protein concentration was reduced at 19 days gestation (dg).
      Immunoblotting revealed a decreased abundance of GLUT1 in placental microsomes at
      16 dg, whereas GLUT3 was increased. Fetal serum glucose levels were reduced at 16
      dg. In fetal brain, the concentration of microsomal protein was deficient at 16
      dg and the abundance of parenchymal forms of GLUT1 was further depressed, whereas
      GLUT3 was unaffected. Northern hybridization analysis demonstrated normal GLUT1
      mRNA levels in placenta and fetal brain. In conclusion, maternal hypothyroxinemia
      results in fetal growth retardation and impaired brain development before the
      onset of fetal thyroid function. Glucose uptake in fetal brain parenchyma may be
      compromised directly, due to deficient GLUT1 expression in this tissue, and
      indirectly, as a result of reduced placental GLUT1 expression. Though corrected
      by the onset of fetal thyroid hormone synthesis, these deficits are present
      during the critical period of neuroblast proliferation and may contribute to long
      term changes in brain development and function seen in this model and in the
      progeny of hypothyroxinemic women.

PMID- 10588812
TI  - Nutritional regulation of IGF-II, but not IGF-I, is age dependent in sheep.
AB  - In post-natal animals, plasma concentrations of IGF-I are tightly regulated by
      nutritional status. The current study reports that plasma levels of IGF-II in
      sheep are also regulated by nutrition, but whether plasma IGF-II is increased,
      decreased or remains the same, depends on the age of the animal. Ewe lambs,
      ranging in age from 2 days to 2 years, were fed or fasted for lengths of time
      between 24 and 72 h. Blood samples were taken at intervals of 24 h throughout the
      treatment period and immediately before slaughter. Plasma concentrations of IGF-I
      increased with advancing age in fed animals (P<0.001) and were reduced by fasting
      in all age groups (P<0.001). Plasma concentrations of IGF-II also increased as
      animals matured (P<0.001), but did not show an overall effect of the fasting
      treatment. An interaction between age and nutrition (P<0.001) resulted from a
      decrease in plasma IGF-II in response to fasting in neonatal animals (P<0.01)
      and, conversely, increased levels of plasma IGF-II in fasted mature animals
      (P<0.01 or P<0.001). Fasted sheep of peripubertal age showed no change in plasma
      levels of IGF-II. The nutritional sensitivity of serum IGF-binding proteins (BPs)
      also changed with age. The 29 kDa BP, which we presume to be BP1, was elevated by
      fasting in young animals and reduced slightly in older animals. BP2 was increased
      to a similar magnitude by fasting at all ages. BP3 was depressed by fasting in
      young animals and showed little change in adults. In contrast, a 24 kDa BP, which
      is probably BP4, showed little change in young animals and was reduced
      substantially in older sheep. In conclusion, the response of plasma IGF-II to
      fasting suggests that this peptide has functions in mediating nutritional stress
      which depend on the age of the animal, and also that the role of IGF-II may
      differ from that of IGF-I in adults.

PMID- 10588813
TI  - Parathyroid hormone-related peptide stimulates DNA synthesis and insulin
      secretion in pancreatic islets.
AB  - Parathyroid hormone (PTH)-related protein (PTHrP) is present in the pancreatic
      islet. Recent data in transgenic mice suggest that PTHrP might modulate islet
      mass and insulin secretion. In the present study, we assessed the effect of the N
      terminal PTH-like region of PTHrP on DNA synthesis in isolated rat islets. PTHrP
      (1-34), between 1 pM and 10 nM, for 48 h stimulated []thymidine incorporation
      into rat islets. This effect was maximally induced, about 2.5-fold over control,
      by 10 pM of this peptide, decreasing thereafter. In contrast, PTHrP (38-64) amide
      or PTHrP (107-139) were ineffective in increasing DNA synthesis in islets. Using
      reverse transcription followed by PCR, we confirmed that rat islets express PTHrP
      and the type I PTH/PTHrP receptor. Addition of a neutralizing anti-PTHrP antibody
      to the incubation medium of proliferating islets decreased islet DNA synthesis by
      30%. The effect of a submaximal dose (30 pM) of PTHrP (1-34) on DNA synthesis in
      rat islets was abolished by 25 nM bisindolylmaleimide I, a protein kinase C (PKC)
      inhibitor, but not by 25 microM adenosine 3',5'-cyclic monophosphorothioate, Rp
      isomer, a protein kinase A inhibitor. Moreover, 100 nM phorbol-12-myristate-13
      acetate for 48 h also increased DNA synthesis 2-fold over controls in islets.
      PTHrP (1-34), at 100 nM, in contrast to 50 microM forskolin or 10 mM NaF, failed
      to affect adenylate cyclase activity in islet membranes. PTHrP, at 30 pM, was
      also found to increase 2-fold insulin released into the islet-conditioned medium
      within 24-48 h. Our results suggest that PTHrP is a modulator of pancreatic islet
      growth and/or function by a PKC-mediated mechanism.

PMID- 10588814
TI  - Involvement of inducible nitric oxide synthase in stress-impaired testicular
      steroidogenesis.
AB  - The immobilization stress induces an acute inhibition of testicular
      steroidogenesis that is mediated by the nitric oxide (NO) signaling pathway. Here
      we compared the effects of 2-h immobilization stress on in vivo and in vitro rat
      steroidogenesis at two time points, 0 h and 6 h after the end of the stress
      session. As expected, serum androgens and human chorionic gonadotropin (hCG)
      stimulated progesterone and testosterone production by testicular tissue were
      inhibited at 0 h, and also at the 6-h time point. Both the acute and sustained
      inhibitions of in vitro steroidogenesis were accompanied by a significant
      increase in nitrite, a stable oxidation product of NO. To clarify which subtype
      of NO synthase (NOS) (constitutive (cNOS) or inducible (iNOS)) participates in
      down-regulation of testicular steroidogenesis, aminoguanidine hydrochloride (AG),
      a selective iNOS inhibitor, was employed. Intratesticular injection of AG
      prevented the sustained, but not the acute, stress-induced decrease in serum
      testosterone. When added in vitro, it also prevented the sustained decrease in
      steroid production and increase in nitrite production by testicular tissue, both
      in a dose-dependent manner and with EC microM. Furthermore, AG added in vivo and
      in vitro effectively blocked the sustained decrease in 3beta-hydroxysteroid
      dehydrogenase (3betaHSD) and 17alpha-hydroxylase/C17-20 lyase (P450c17)
      activities. In all concentrations employed, AG did not affect serum androgens and
      in vitro steroid and nitrite production in unstressed animals. These results
      indicate that the NO signaling pathway participates in acute and sustained stress
      induced down-regulation of testicular steroidogenesis, presumably through its
      direct action on 3betaHSD and P450c17. The acute NO production is controlled by
      cNOS and the sustained production of this messenger is controlled by iNOS.

PMID- 10588815
TI  - Regulation of 11beta-hydroxysteroid dehydrogenase type 1 gene expression by LH
      and interleukin-1beta in cultured rat granulosa cells.
AB  - Granulosa cells from preovulatory follicles show increased expression of 11beta
      hydroxysteroid dehydrogenase type 1 (11betaHSD1) at the time of ovulation. As
      ovulation may be an inflammatory process, this may be a mechanism of local
      enhancement of the activity of anti-inflammatory glucocorticoids. In this study,
      we examined direct effects of LH, the proinflammatory cytokine, interleukin-1beta
      (IL-1beta), and pharmacological activators of protein kinase A (PKA) (forskolin
      and dibutyryl (db) cAMP) and PKC (LH-releasing hormone and phorbol 12-myristate
      13-acetate (PMA)) signalling on the expression of 11betaHSD1 mRNA in vitro.
      Granulosa cells from immature female rat ovaries were cultured (pretreatment) in
      serum-free medium 199 containing recombinant human (rh) FSH (1 ng/ml) for 48 h to
      induce responsiveness to LH. Cell monolayers were then washed and cultured (test
      treatment) for a further 12 h in the presence of rhLH (0-100 ng/ml), IL-1beta (0
      50 ng/ml), or both. Total RNA was extracted from granulosa cell monolayers and
      taken for quantitative ribonuclease protection analysis of 11betaHSD1 mRNA. The
      low level of 11betaHSD1 mRNA detectable in unstimulated (control) cultures was
      increased approximately twofold by the 48-h pretreatment with rhFSH. Subsequent
      exposure to rhLH (1-100 ng/ml) for a further 12 h dose-dependently increased
      11betaHSD1 mRNA expression by an additional two- to threefold. Forskolin (10
      microM), db-cAMP (2 mM), LH-releasing hormone (LHRH; 1 microM) and PMA (200 nM)
      were also stimulatory. IL-1beta (0.05-50 ng/ml) stimulated 11betaHSD1 mRNA
      expression in a dose-related manner, both in the absence and in the presence of
      rhLH (3 ng/ml). The interaction between IL-1beta (5 ng/ml) and rhLH (3 ng/ml) was
      additive. Co-treatment with a 50-fold excess of IL-1 receptor antagonist fully
      reversed the action of IL-1beta. We conclude that 11betaHSD1 mRNA expression in
      functionally mature granulosa cells is directly stimulated by gonadotrophins and
      IL-1beta in vitro, potentially involving post-receptor signalling via PKA- and
      PKC-mediated pathways. Thus both LH and IL-1beta may serve physiological roles in
      the upregulation of 11betaHSD1 gene expression by granulosa cells in ovulatory
      follicles.

PMID- 10588816
TI  - Regulation of 11beta-hydroxysteroid dehydrogenase isoforms and glucocorticoid
      receptor gene expression in the rat uterus.
AB  - Glucocorticoids are known to have diverse effects on the uterus, generally
      believed to be mediated by the glucocorticoid receptor (GR). To date, two
      isoforms of the enzyme 11beta-hydroxysteroid dehydrogenase (11betaHSD) have been
      identified, namely 11betaHSD1 and 11betaHSD2, which interconvert active and
      inactive glucocorticoids and regulate local levels of hormones available to the
      GR in target tissues. The aim of the present study was to examine the uterine
      expression of 11betaHSD and GR mRNA. The interplay of these parameters is
      probably an important factor in determining actions of glucocorticoids on the
      uterus. Using Northern analysis we investigated the uterine expression of
      11betaHSD1, 11betaHSD2 and GR mRNA in relation to serum levels of sex steroid
      hormones and uterine progesterone receptor mRNA expression in an animal model.
      Immature female rats were treated with 10 IU pregnant mare serum gonadotrophin
      (PMSG) followed by 10 IU human chorionic gonadotrophin (hCG) 48 h afterwards, and
      then killed at 0, 3, 6, 9, 12 and 24 h and 5 days after the hCG injection.
      Expression of both 11betaHSD1 and 11betaHSD2 mRNA in total uterine RNA was found
      to be up-regulated by more than 50% at 48 h after PMSG injection when oestradiol
      levels were also high. Following hCG treatment the expression of 11betaHSD1 and
      11betaHSD2 further increased to reach maximal levels at 24 and 12 h respectively.
      GR mRNA expression was down-regulated by more than 50% by PMSG but gradually
      recovered after hCG injection. The results show that mRNA expression of
      11betaHSD1, 11betaHSD2 and GR in the uterus is developmentally regulated,
      suggesting that these key determinants of glucocorticoid action may play an
      important role in uterine function.

PMID- 10588817
TI  - Changes in IGFs in cardiac tissue following myocardial infarction.
AB  - We have studied changes in the IGF axis in an ovine model of myocardial
      infarction (MI), in order to determine the relationship between time-based
      changes in post-infarct myocardium and IGF levels. IGF localization was studied
      by immunocytochemistry, production by in situ hybridization, and specific binding
      by radioligand studies. In surviving tissue, IGF-I peptide localized to
      cardiomyocytes, with strongest immunostaining at 1 and 2 days post-infarct in the
      immediate border area adjoining the infarct, where IGF-I mRNA also increased,
      reaching a maximum at 2 days. Binding of radiolabelled IGF-I in surviving tissue
      was initially lower than that seen in cardiomyocytes in control myocardium,
      subsequently increasing to become significantly greater by 6 days post-infarct.
      In necrotic tissue, IGF-I peptide was still detectable in cardiomyocytes at 0.5
      days post-infarct, but had cleared from this area by 1 day, becoming detectable
      again at 6 days post-infarct in macrophages and fibroblasts infiltrating the
      repair zone. IGF-I mRNA was not detected in necrotic tissue until 6 days, when
      probe hybridized to macrophages and fibroblasts. Within the necrotic zone, high
      levels of radiolabelled IGF-I binding to a combination of receptors and binding
      proteins were observed in cardiomyocytes in islands of viable tissue located
      close to the border. Weak immunostaining for IGF-II was observed in
      cardiomyocytes of the surviving tissue. IGF-II mRNA was not detected in either
      surviving or necrotic areas. Binding of radiolabelled IGF-II was predominantly to
      macrophages in both surviving and infarct areas, although as with IGF-I, high
      levels of binding of radiolabelled IGF-II to a combination of receptors and
      binding proteins were observed in islands of viable tissue close to the border
      within the necrotic area. We conclude that, following MI, surviving
      cardiomyocytes at the infarct border show marked changes in IGF-I localization,
      production, and specific binding, indicating that the IGF axis is directly
      involved in post-infarct events, possibly in the maintenance of cardiac function
      by the induction of hypertrophy and in cell survival by decreasing apoptotic cell
      death, which has been demonstrated in other cell types.

PMID- 10588818
TI  - Isolation and characterisation of the marmoset gonadotrophin releasing hormone
      receptor: Ser(140) of the DRS motif is substituted by Phe.
AB  - In order to facilitate the understanding of gonadotrophin-releasing hormone
      (GnRH) agonist and antagonist action in the primate animal model, the marmoset
      GnRH receptor (GnRH-R) was cloned and characterised. It was shown to have 95% and
      85% sequence identity with the human and rat GnRH-Rs, respectively, and, when
      transiently expressed in COS-7 cells, it exhibited high-affinity des-Gly(10), [d
      Trp(6)]-GnRH binding, with a K(d) value similar to those of both the rat and
      human forms, but with a greatly reduced B(max) value. The ED(50) for production
      of GnRH-induced total inositol phosphate (IP) for the marmoset GnRH-R was also
      similar to those of the rat and the human, but the maximal response compared with
      the rat receptor was markedly reduced. In all mammalian forms of the GnRH-R
      cloned to date, the conserved DRY region of G-protein-coupled receptors is
      substituted with DRS. The most interesting feature of the marmoset GnRH-R was the
      substitution of this motif with DRF. In order to investigate the DRS to DRF
      substitution, a Ser(140)Phe rat GnRH-R mutant was generated. The mutant had a
      K(d) value similar to that of the wild-type rat receptor, although the B(max)
      value was slightly lower, indicating that expression of functional mutant
      receptor at the cell surface was reduced. The ED(50) value for IP production was
      also similar to that of the wild-type receptor, with a reduction in maximal
      response. The level of internalisation for the rat wild-type and mutant GnRH-R
      constructs was also assessed and the Ser(140)Phe mutant was shown to have an
      increased rate of receptor internalisation, suggesting a role for this residue in
      regulating internalisation. These results show that the marmoset GnRH-R exhibits
      a substitution in the DRS motif and that this substitution may play a part in
      desensitisation and internalisation events.

PMID- 10588819
TI  - Effects of melatonin ingestion on cAMP and cGMP levels in human plasma.
AB  - The effects of daytime melatonin treatment (0.3 mg) on cAMP and cGMP levels in
      platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were investigated in 14
      normal human subjects (age+/-s.e.m. 26.2+/-3. 2 years). Plasma levels of cAMP,
      cGMP and melatonin were measured before and at intervals for 3 h after the
      treatment was administered at 1300 h. Plasma melatonin concentrations reached
      peak levels 1 h after the treatment (mean+/-s.d. 182.3+/-43.5 pg/ml). The mean
      areas under the curve (AUC) for the time-cGMP concentration curves in PPP and in
      PRP were significantly increased after melatonin treatment compared with those
      observed after placebo treatment (P=0.001). No significant difference in cGMP
      levels was observed between PPP and PRP. Increase in self-reported sleepiness
      after melatonin treatment positively correlated with increase in plasma cGMP
      levels (r=0.92). The mean AUC for the time-cAMP concentration in PRP, but not in
      PPP, was increased 1 h after melatonin treatment compared with that observed
      after placebo treatment, but not thereafter. No correlation between individual
      PRP or PPP cAMP levels and subjective sleepiness was observed. These results
      demonstrate a stimulating effect of melatonin treatment on plasma cGMP levels in
      humans and suggest a correlation between the increase in circulating cGMP levels
      and the sleep-promoting effect of the pineal hormone.

PMID- 10588820
TI  - Pregnancy, parturition, and lactation in hypophyseal stalk-transected beef
      heifers.
AB  - Progesterone secretion is crucial for maintaining pregnancy to parturition in
      mammalian species, and in cattle the corpus luteum is the primary source of this
      hormone. This study determined the roles of prolactin (PRL), growth hormone (GH)
      and luteinizing hormone (LH) in the luteotropic process in beef heifers
      hypophyseal stalk-transected (HST, n=7) or sham operated (sham operated controls,
      SOC, n=9) during midgestation. The main finding was that endogenous PRL and GH
      maintained progesterone secretion in HST heifers in a similar manner to that in
      SOC throughout pregnancy. Serum PRL averaged 37 vs 187 and GH 2 vs 4 ng/ml in HST
      heifers compared with SOC, whereas LH abruptly decreased to undetectable levels
      after HST compared with a modest 0.4 ng/ml in SOC heifers. The second finding was
      that parturition and lactation occurred in HST heifers with calf delivery induced
      to occur at the same time as SOC. Milk production in HST animals was severely
      limited, and postpartum estrus obliterated compared with SOC. The suckling
      stimulus sustained milk ejection in HST heifers in spite of diminished PRL, GH,
      thyroid stimulating hormone, thyroxine and tri-iodothyronine secretion. The
      results suggest that PRL, GH and possibly placental lactogen are luteotropic
      during pregnancy in cattle.

PMID- 10588821
TI  - Inhibition of the secretion of LH in ovariectomised pigs by sustained but not
      repeated acute elevation of cortisol in the absence but not the presence of
      oestradiol.
AB  - Prolonged stress is known to impair reproduction. It has been proposed that
      reproduction will also be impaired when a severe acute stress occurs during a
      period of elevated plasma concentrations of oestradiol, such as during the
      follicular phase of the oestrous cycle. In this experiment, we hypothesised that
      repeated acute and sustained elevation of cortisol would suppress the secretion
      of LH in ovariectomised pigs and that these effects would be enhanced in the
      presence of oestradiol negative feedback. Cortisol (or vehicle) was administered
      12 hourly to ovariectomised pigs (n=6/treatment) for 8 days in the absence of
      oestradiol treatment and for a further 8 days during treatment with oestradiol.
      Vehicle was administered to 'control' pigs, 10 or 20 mg cortisol was administered
      i.v. to pigs to produce 'repeated acute' elevation of cortisol and 250 mg
      cortisol was administered i.m. to pigs to give a 'sustained' elevation of
      cortisol. Both before and during treatment with oestradiol, plasma concentrations
      of LH were monitored on the day before treatment, on the 4th and 8th days of
      treatment and following an i.v. injection of GnRH at the end of the 8th day of
      treatment. The repeated acute elevation of cortisol did not impair any parameters
      of LH secretion (i.e. mean plasma concentrations of LH, pulse amplitude or
      frequency, pre-LH pulse nadir or the LH response to GnRH) in the absence or in
      the presence of oestradiol. In contrast, when the elevation of cortisol was
      sustained, the mean plasma concentrations of LH and the pre-LH pulse nadir were
      significantly (P<0.05) lower on the 8th day of treatment than on the day before
      treatment and on the 4th day of treatment. Nevertheless, no other parameters of
      LH secretion were affected and these effects only occurred in the absence (not in
      the presence) of oestradiol. In conclusion, cortisol needed to be elevated for
      more than 4 days to impair the secretion of LH, and oestradiol did not enhance
      the impact of cortisol on LH secretion in ovariectomised pigs.

PMID- 10588822
TI  - Insulin-like growth factor-binding protein-3 is partially responsible for high
      serum-induced apoptosis in PC-3 prostate cancer cells.
AB  - Cells are known to undergo apoptosis when cultured in high serum concentrations.
      However, the serum factors responsible for this induction of apoptosis have not
      been identified. The IGF-binding protein-3 (IGFBP-3), a negative growth
      regulator, is found at concentrations of 5 microgram/ml in serum. We have
      recently demonstrated that IGFBP-3 induces apoptosis in PC-3 cells, a prostate
      cancer cell line, at a concentration of 500 ng/ml. In this communication, we
      demonstrate the role of IGFBP-3 as one of the apoptosis-inducing agents in high
      serum concentrations. Treatment of PC-3 cells with increasing concentrations (40%
      to 90%) of intact human serum (HS) resulted in a dose-dependent decrease in cell
      growth. Valinomycin, an ionophore, was used as a positive control to measure the
      induction of apoptosis by serum treatment in PC-3 cells. Treatment with 90% serum
      showed significant suppression of growth (P<0.001) compared with the effect of
      10% serum. Treatment with increasing concentrations of HS (40% to 90%) resulted
      in a dose-dependent increase in apoptosis. Treatment with 90% HS showed a 10-fold
      increase in apoptotic index compared with cells treated with 10% HS. Treatment of
      PC-3 cells with IGFs and IGFBP-3-depleted 90% human sera (depleted serum=DS)
      demonstrated significantly lower levels of apoptosis (50% reduction in the effect
      of 90% HS) suggesting a role of IGFBP-3 in inducing apoptosis in high serum
      concentration. Furthermore, treatment with DS supplemented with recombinant IGFBP
      3 (500 ng/ml) brought the apoptotic index down close to the level of apoptosis
      induced by 90% intact serum treatment (P<0.001). However, DS supplemented with
      physiological concentrations of IGFs (500 ng/ml) showed only partial recovery of
      cell survival demonstrated by 90% DS. This data indicates that IGFBP-3 is one of
      the factors in serum that is responsible for high-serum-induced apoptosis.

PMID- 10588823
TI  - Monoclonal antibodies against the human sodium iodide symporter: utility for
      immunocytochemistry of thyroid cancer.
AB  - The recent cloning of the thyroidal protein that is responsible for iodide
      transport, the sodium iodide symporter (hNIS), has made possible studies designed
      to characterize its structure, function and expression in thyroidal tissues.
      Using a mannose binding protein (MBP)-hNIS fusion protein as antigen, we have
      developed mouse monoclonal antibodies against hNIS to utilize as tools in such
      studies. Twenty-four clones were initially recovered which recognized the MBP
      hNIS fusion protein, but only two of them were specific for hNIS while the others
      recognized MBP alone. Both antibodies were found to be immunoglobulin G (IgG)
      1kappa (kappa). The specificity of antibodies was tested by Western blotting
      using membranes prepared from COS-7 cells transiently transfected with the pcDNA3
      plasmid containing the full-length hNIS cDNA, or cells transfected with the
      pcDNA3 vector. A major band with a molecular weight (MW) of approximately 97 kDa,
      and several minor bands with MW of approximately 160 kDa, approximately 68 kDa,
      approximately 30 kDa and approximately 15 kDa, were detected specifically in the
      hNIS-transfected cells. After enzymatic deglycosylation, the major band was
      present at 68 kDa, as expected based upon the amino acid sequence of hNIS.
      Immunohistochemistry was performed with several different types of thyroid tissue
      and non-thyroidal tissues, using the monoclonal antibodies. Strong immunostaining
      was observed in Graves' tissue, with intermediate staining in papillary and
      follicular thyroid cancers and an absence of staining in Hurthle cell cancer. The
      staining was specific for the follicular epithelium and was concentrated in the
      basolateral portion of the cell membrane. These monoclonal hNIS antibodies should
      prove useful in the characterization of NIS expression in benign and malignant
      thyroid tissue and in studies characterizing its structure and function.

PMID- 10588824
TI  - Follicle-forming cat thyroid cell lines synthesizing extracellular matrix and
      basal membrane components: a new tool for the study of thyroidal morphogenesis.
AB  - Interactions between follicular epithelial cells and extracellular matrix (ECM)
      are supposed to play an important role in the development and maintenance of
      thyroid tissue architecture. In the present study we have therefore investigated
      the synthesis of ECM components by a feline thyroid cell line which is able to
      form follicle-like structures in vitro, and also in v-ras-transfected and control
      transfected sublines. Transfections were performed by lipofection with pZSR
      (viral Harvey ras gene; neo) and pSV2-neo (control, neo only) plasmids. We have
      adapted a semisolid culture system composed exclusively of polymerized alginate
      and therefore devoid of ECM components. Feline cells embedded in alginate gels as
      single cells and cultured for up to 90 days formed cell clusters within 10 days.
      Follicle-like structures were formed in the original cell lines and also in the v
      ras- and control-transfected cells. Differences in proliferation rates were
      observed, the v-ras-transfected cells growing up to two to three times faster
      than the non-transfected cells. Immunostaining was done using rabbit first
      antibodies directed against mouse collagen IV, human fibronectin, laminin (tumor
      Engelbreth-Holm-Swarm laminin), perlecan and other ECM components. For
      comparison, immunostaining was also performed on cryosections of nodular goiters
      of six hyperthyroid cats. The cell lines and their transfected clones stained
      strongly positive for collagen IV and fibronectin, and positively but less
      strongly for laminin and perlecan. The cat goiter tissue stained positively for
      collagen IV, laminin, perlecan, and fibronectin, and positive staining for S
      laminin (containing the beta2-chain) was seen in blood vessel walls in this
      tissue. In conclusion, cat cell lines grow three-dimensionally in alginate beads
      over several weeks, they form follicle-like structures and express the same ECM
      components as the native cat goiter tissue. Transfection with v-ras does increase
      proliferation rate, but does not fundamentally alter formation of follicle-like
      structures and ECM expression. Alginate gel culture is a promising new tool for
      the study of follicular morphogenesis, polarity, the expression pattern of ECM
      components and of the interaction between thyrocytes and ECM. It avoids
      interference caused by gels composed of ECM components.

PMID- 10588825
TI  - The effect of GH on estrogen receptor expression in the rat mammary gland.
AB  - Both GH and insulin-like growth factor I (IGF-I) synergize with estrogen to
      induce normal mammary gland development. However, the nature of this synergy has
      not been explored. To gain insight into the mechanism of these interactions we
      have examined the effects of these substances on the estrogen receptor (ER). ER
      levels in the mammary gland cytosols from hypophysectomized and oophorectomized
      rats, were measured using two assay systems: a dextran-coated charcoal procedure
      to measure binding to radiolabeled steroid, and an immunologic assay employing a
      specific antibody to the receptor. In both assays, levels of ER were at or near
      baseline detection (approximately 1-2 ng/mg protein). Treating animals with
      either bovine or human GH significantly increased ER activity (P<0.001), whereas
      prolactin (PRL) and/or estradiol treatment had no effect. That this increase was
      at the level of transcription was demonstrated by reverse
      transcriptase/polymerase chain reaction. Following a single injection of GH (50
      microgram), a substantial increase in ER mRNA was observed by 10 h, with levels
      returning to baseline within 24 h; a concomitant increase in ER itself was also
      observed at the 10 h time point. The effect of GH appeared to occur mainly in the
      mammary stroma, because there were no differences in GH stimulation of ER between
      gland-free and gland containing mammary fat pads. Furthermore, analysis of
      mammary gland ER by immunocytochemistry demonstrated that while ER was present in
      the epithelial cells of non-treated animals, only GH treated animals had ER
      clearly visible in both glandular and fat cells of the tissue. In contrast,
      treating animals with des(1-3)-IGF-I did not result in reproducible increases in
      ER, nor in the staining of fat cell nuclei for ER. These data demonstrate a
      specific GH effect on the ER in the mammary fat cell.

PMID- 10588826
TI  - PDX-1 and Msx-2 expression in the regenerating and developing pancreas.
AB  - We have observed pancreatic duct cell proliferation and islet regeneration in
      transgenic mice whose pancreata produce interferon gamma (IFNg mice). We have
      previously demonstrated that new islet cells derive from endocrine progenitor
      cells in the pancreatic ducts of this model. The current study was initiated to
      define these endocrine progenitor cells further and to identify novel markers
      associated with pancreatic regeneration. Importantly, we have found that PDX-1, a
      transcription factor required for insulin gene transcription as well as for
      pancreatic development during embryogenesis, is expressed in the duct cells of
      IFNg mice. This striking observation suggests an important role for PDX-1 in the
      marked regeneration observed in IFNg mice, paralleling its critical function
      during ontogeny. Also demonstrated was elevated expression of the homeobox
      containing protein Msx-2 in the pancreata of fetal mice as well as in adult IFNg
      mice, identifying this molecule as a novel marker associated with pancreatic
      development and regeneration as well. The identification of PDX-1 and Msx in the
      ducts of the IFNg transgenic pancreas but not in the ducts of the non-transgenic
      pancreas suggests that these molecules are associated with endocrine precursor
      cells in the ducts of the IFNg transgenic mouse.

PMID- 10588827
TI  - The effect of a direct arterial infusion of insulin and glucose on the ovarian
      secretion rates of androstenedione and oestradiol in ewes with an
      autotransplanted ovary.
AB  - Improving ewe nutrition even for short periods will increase ovulation rate. The
      increased nutrients must in some way affect the number of follicles that develop
      to the pre-ovulatory stage. One possible mechanism is that a nutrient or a
      metabolic hormone that responds to nutrition might act directly on the ovary to
      influence follicle development and/or follicle selection. In the study described
      here, insulin and glucose, alone or together, were infused directly into the
      ovarian artery of ewes with an autotransplanted ovary, for 13.5 h on day 11 of
      the oestrous cycle. The pattern of androstenedione and oestradiol secretion in
      response to a GnRH-stimulated LH pulse was measured 2.5 h before and 12.5 h and
      24.5 h after the start of the infusion. Glucose or insulin infused alone had no
      effect on the secretion of androstenedione and oestradiol. However, when infused
      together, they decreased significantly the secretion of androstenedione and, to a
      lesser extent, oestradiol. We suggest that the sudden availability of additional
      glucose and insulin increases insulin-stimulated glucose uptake by the follicle.
      This leads to an inhibition of LH-stimulated steroidogenesis by the ovarian
      follicle which occurs in the absence of any detectable changes in circulating
      plasma concentrations of FSH. These results show that insulin and glucose act
      together to influence ovarian function directly and suggest that the effects of
      short-term nutrition on ovulation rate may be mediated by a direct ovarian action
      of insulin and glucose.

PMID- 10588828
TI  - The effect of dexamethasone on body and organ growth of normal and IGF-II
      transgenic mice.
AB  - The physiological role of IGF-II remains unclear but there is evidence for a role
      in postnatal growth, the growth of the thymus and bone homeostasis.
      Glucocorticoids have many effects that are opposite to the effects of IGF-II such
      as growth retardation, osteoporosis and thymic involution. We therefore wondered
      whether IGF-II overexpression in transgenic mice might counteract some of the
      growth inhibitory effects of the glucocorticoid, dexamethasone (DXM). In a dose
      finding study in normal mice, 20 microg DXM/day caused a significant growth
      delay. The various organs had a different susceptibility to the growth inhibitory
      effects of DXM. Most affected were thymus and spleen, followed by liver, skeletal
      muscle and lumbar vertebrae. The weights of the kidney, tibia, and humerus were
      not significantly diminished. In a second experiment, the effects of DXM in
      normal and IGF-II-transgenic animals were compared. The IGF-II serum levels in
      the transgenic animals were more than 40-fold increased compared with control
      mice and were decreased by 35% in the DXM-treated group. IGF-I serum levels were
      identical in both mouse strains and rose slightly after DXM administration in
      controls. Transgenic mice had higher levels of IGF binding protein species of
      apparent molecular masses of 41.5 kDa, 30 kDa, and 26.5 kDa. DXM reduced the 24
      kDa band in both mice strains. In addition it reduced the bands at 38.5 kDa and
      26.5 kDa but only in the transgenic animals. The effect of DXM on body growth was
      similar in normal and IGF-II-transgenic mice. The weight reduction of the various
      organs caused by DXM was similar in both types of mice except for the skeleton.
      The weight of the tibia and the humerus were significantly higher in the DXM
      treated transgenic mice. In conclusion, we speculate that overexpression of IGF
      II in mice partially protects bone from the osteopenic effects of
      glucocorticoids.

PMID- 10588829
TI  - Effect of maternal nutrient restriction in early gestation on development of the
      hypothalamic-pituitary-adrenal axis in fetal sheep at 0.8-0.9 of gestation.
AB  - The fetal hypothalamic-pituitary-adrenal (HPA) axis has numerous key roles in
      development. Epidemiological data have linked adverse prenatal nutrition with
      altered organ development and increased incidence of disease in adult life. We
      studied HPA axis development in resting and stimulated states in late gestation
      fetal sheep, following 15% reduction in maternal nutritional intake over the
      first 70 days of gestation (dGA). Fetuses from control (C) and nutrient
      restricted (R) ewes were chronically catheterised and response profiles for ACTH
      and cortisol were determined at 113-116 and 125-127 dGA after administration of
      corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP). At 126-128
      dGA cortisol profiles were also determined following ACTH administration. Basal
      ACTH and cortisol concentrations were not different between C and R fetuses. In R
      fetuses, ACTH response to CRH+AVP was significantly smaller at 113-116 dGA
      (P<0.01), and cortisol responses were smaller at both 113-116 dGA (P<0.01) and
      125-127 dGA (P<0.0001). Cortisol response to ACTH was also smaller in R fetuses
      (P<0.001). We conclude that, in late gestation fetal sheep, pituitary and adrenal
      responsiveness is reduced following modest maternal nutrient restriction in early
      gestation.

PMID- 10588830
TI  - Abundance of leptin mRNA in fetal adipose tissue is related to fetal body weight.
AB  - Leptin mRNA was measured in adipose tissue of fetal sheep by reverse
      transcription polymerase chain reaction (RTPCR). Abundance of leptin mRNA
      relative to beta-actin mRNA in fetal perirenal adipose tissue increased (P<0.02)
      with gestation, being higher at 144 d (0.73+/-0. 10, n=5) than at 90-91 d (0.40
      +/- 0.08, n=6) or 125 d (0.40 +/- 0. 04, n=5) gestation (term approximately 147-
      150 d). There was a positive relationship between relative abundance of leptin
      mRNA (y) and fetal body weight (x) between 90 and 144 d gestation (r(2) =0.27,
      P<0.01). The slope of the linear dependence of leptin mRNA on fetal weight was 15
      fold greater (P<0.001) at 90-91d (y = 2.81x - 1.1, n=6, r(2) =0.71, P<0.025) than
      between 125-144 d gestation (y = 0.195x - 0.15, n=16, r(2) =0.39, P<0.01). Thus
      the leptin synthetic capacity of fetal adipose tissue appears to increase in late
      gestation but this is accompanied by constraint of its sensitivity to fetal body
      weight. We hypothesise that leptin synthesis in fetal adipose tissue is related
      to fetal nutrient supply and growth rate.

PMID- 10588831
TI  - Two sibs with myoclonic epilepsy, congenital deafness, macular dystrophy, and
      psychiatric disorders.
AB  - We present a family with four children born to second-cousin parents. Two of the
      children had myoclonic epilepsy, congenital deafness, a dystrophic pattern of the
      macular pigment epithelium, incomplete right bundle branch block, and psychiatric
      disorders appearing after fever episodes. Results of all laboratory
      investigations including mitochondrial DNA analysis were normal. Despite the fact
      that this condition resembles one reported by Latham and Munro in 1937, it is
      possible that we might be reporting on a new autosomal recessive syndrome.

PMID- 10588832
TI  - Unusual phenotype in partial trisomy 14.
AB  - An 8-year-old boy with partial trisomy 14q and phenotype distinct from previously
      reported cases is described. The mother carries a balanced 9;14 reciprocal
      translocation. The patient presented with minor facial anomalies, developmental
      delay, hyperphagia, and obesity. Imprinting of maternal chromosome 14 or
      disruption of one or more genes on chromosome 9 may be responsible for our
      patient's manifestations.

PMID- 10588833
TI  - Trisomy 2q35-q37 due to insertion of 2q material into 17q25: clinical,
      cytogenetic, and molecular cytogenetic characterization.
AB  - We present a 7-year-old boy with growth retardation, developmental and mental
      delay, and minor physical abnormalities. The patient had a male karyotype with
      duplicated material of unknown origin in the long arm of chromosome 17. The
      origin of the duplicated material was clarified by fluorescence in situ
      hybridization. Forward chromosome painting showed that the extra material
      originated from chromosome 2, which was inserted into 17q25. Further
      characterization of the aberrant chromosome 17 by microdissection and reverse
      chromosome painting revealed a duplication of bands 2q35 to q37.1. To our
      knowledge, no other individual with a duplication of this small segment has been
      described so far. The clinical findings of 13 cases with isolated trisomy 2q are
      reviewed in relation to the size of the duplicated region. Functional analysis of
      the duplicated 2q region suggests that critical loci for visceral and central
      nervous system development in distal trisomy 2q are proximal to 2q33.

PMID- 10588834
TI  - De novo dup(X)(q22.1q25) in a girl with an abnormal phenotype.
AB  - Duplication of a portion of Xq has been observed in males with abnormalities. In
      some cases, their mothers or even grandmothers had the same duplication but did
      not show any phenotypic abnormalities. However, a few cases of females with a de
      novo Xq duplication do present some abnormalities. We describe a 16-month-old
      girl with short stature, motor delay with hypotonia, scoliosis, right
      hemiatrophy, and ptosis of the right eye, with an Xq duplication. The duplicated
      region is read dir dup(X)(q22.1q25).

PMID- 10588835
TI  - Digynic triploid infant surviving for 46 days.
AB  - We report on a triploid infant who survived for 46 days. She had severe
      intrauterine growth retardation, relative macrocephaly, and a small, noncystic
      placenta, which are manifestations compatible with type II phenotype. Cultured
      amniotic fluid cells, skin fibroblasts, cord blood, and peripheral blood
      lymphocytes all showed a nonmosaic 69,XXX karyotype. Analysis of chromosomal
      heteromorphisms and microsatellite DNA polymorphisms in the infant and her
      parents indicated that the extra haploid set in the infant resulted from
      nondisjunction at maternal second meiosis. Postzygotic, mitotic nondisjunction
      was ruled out because of the presence of both homozygous and heterozygous markers
      of maternal origin. A search of the literature demonstrated five triploid
      infants, including the girl we described, who survived 4 weeks or more, and the
      parental origin of whose triploidy was studied: four were digynic and one was
      diandric. These findings support the notion that type II triploids are digynic in
      parental origin and that they survive longer than type I, diandric triploids.

PMID- 10588836
TI  - Novel twelve-generation kindred of fatal familial insomnia from germany
      representing the entire spectrum of disease expression.
AB  - We present a novel large German kindred of fatal familial insomnia (FFI)
      consisting of three branches and comprising more than 800 individuals of 12
      generations, the largest pedigree of any familial prion disease known today.
      There is a wide spectrum of clinical presentations leading to misdiagnoses of
      Olivo-Ponto-Cerebellar Atrophy (OPCA), Parkinson's or Alzheimer's disease in
      addition to Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker
      (GSS) syndrome. Molecular genetic analysis of the prion protein gene (PRNP)
      confirmed the mutation D178N segregating with methionine at the polymorphic codon
      129 of PRNP in all 7 patients examined. This polymorphism at codon 129 is
      supposed to discriminate between familial CJD (fCJD) and FFI; the 129M allele
      determines FFI and 129V fCJD. Furthermore, heterozygosity at this site appears to
      induce prolonged disease duration as compared to the homozygous condition. The
      variability of the clinical and pathological findings documented for our patients
      indicates the difficulty in establishing the diagnosis of FFI on clinical and on
      pathological grounds alone. In three cases (IX-97, XI-21, V-2) followed up by us
      prospectively insomnia was an early and severe symptom; however, in case notes
      analyzed retrospectively this symptom was frequently missed. In contrast to
      previous reports and in agreement with recent studies we cannot confirm a clear
      relationship between the status of the M/V polymorphism at codon 129 and the age
      of-onset of this disease.

PMID- 10588837
TI  - Neurofibromatosis type 1 growth charts.
AB  - Growth abnormalities such as macrocephaly and short stature have been described
      and are considered a consistent finding in neurofibromatosis type 1 (NF1), one of
      the most common autosomal dominant disorders in man. We present here a clinical
      study on the growth profile of a sample of NF1 patients collected through a
      population-based registry that covers three contiguous regions of North-East
      Italy (NEI-NF Registry). Auxometric traits of 528 NF1 patients have been measured
      with the aim of drawing growth charts for height, weight, and head circumference
      (OFC). Height velocity charts were based on a subset of 143 children who
      underwent multiple measurements. No differences in height were apparent between
      NF1 and normal subjects up to age 7 (girls) and 12 (boys) years; subsequently,
      the 50th centile of NF1 subjects tends to overlap with the 25th centile of normal
      subjects, and the 3rd centile is much lower in NF1 subjects than in normal
      subjects, mainly during adolescence. The negatively skewed distribution of height
      seems to indicate that height growth impairment affects only a proportion of NF1
      subjects; height growth impairment does not seem related to disease severity. As
      for weight, our data suggest that slight overweight is a characteristic of adult
      NF1 subjects (mainly among males), independent of disease severity. Height growth
      velocity is normal during childhood for both sexes, whereas the pubertal spurt is
      slightly anticipated and reduced in NF1 boys but not in girls. Our data confirm
      previous observations that macrocrania affects most NF1 subjects; the shape of
      the head growth curve is similar in NF1 and normal girls, whereas NF1 boys
      present an OFC pubertal growth spurt much more pronounced and delayed than normal
      boys. The disproportion between OFC and height seems to be related to disease
      severity in boys but not in girls. Growth charts presented here can be useful in
      neurofibromatosis clinics for the identification of the effects of secondary
      growth disorders, for growth prognosis, and for the evaluation of the effects of
      a therapy such as GH therapy after radiotherapy for optic glioma.

PMID- 10588838
TI  - Jeune syndrome and liver disease: report of three cases treated with
      ursodeoxycholic acid.
AB  - Three children with Jeune syndrome (asphyxiating thoracic dystrophy) had clinical
      and laboratory evidence of liver disease. In two patients the disease evolved to
      biliary cirrhosis, whereas in the third it was recognized when extensive fibrosis
      was developing. In the three patients, treatment with ursodeoxycholic acid
      appeared to control the progression of the hepatic dysfunction.

PMID- 10588839
TI  - Hemophagocytic lymphohistiocytosis in a patient with deletion of 22q11.2.
AB  - We report on a new patient with deletion of 22q11 associated with hemophagocytic
      lymphohistiocytosis and a fatal outcome. She had minor facial anomalies and
      cardiac malformation corresponding to those described in del (22q11) syndrome,
      normal T and B cell function and NK activity; bone marrow aspiration showed
      active erythrophagocytosis. Our case in addition to two other children reported
      previously suggest that such a rare association between lymphocyte-macrophage
      activation and deletion of 22q11 may be more frequent than previously recognized.

PMID- 10588840
TI  - Treatment of pyruvate carboxylase deficiency with high doses of citrate and
      aspartate.
AB  - A patient with severe pyruvate carboxylase deficiency presented at age 11 weeks
      with metabolic decompensation after routine immunization. She was comatose, had
      severe lactic acidemia (22 mM) and ketosis, low aspartate and glutamate, elevated
      citrulline and proline, and mild hyperammonemia. Head magnetic resonance imaging
      showed subdural hematomas and mild generalized brain atrophy. Biotin-unresponsive
      pyruvate carboxylase deficiency was diagnosed. To provide oxaloacetate, she was
      treated with high-dose citrate (7.5 mol/kg(-1)/day(-1)), aspartate (10 mmol/kg(
      1)/day(-1)), and continuous drip feeding. Lactate and ketones diminished
      dramatically, and plasma amino acids normalized, except for arginine, which
      required supplementation. In the cerebrospinal fluid (CSF), glutamine remained
      low and lysine elevated, showing the treatment had not normalized brain
      chemistry. Metabolic decompensations, triggered by infections or fasting,
      diminished after the first year. They were characterized by severe lactic and
      ketoacidosis, hypernatremia, and a tendency to hypoglycemia. At age 3(1/2) years
      she has profound mental retardation, spasticity, and grand mal and myoclonic
      seizures only partially controlled by anticonvulsants. The new treatment regimen
      has helped maintain metabolic control, but the neurological outcome is still
      poor.

PMID- 10588841
TI  - Detection of pericentric inversion of X chromosome in a male fetus.
AB  - Amniocentesis on a 32-year-old woman at risk for trisomy 21 by maternal serum
      triple screen showed a 46,Y,inv(X) (p22.1q24) karyotype in all cells analyzed. A
      blood sample was obtained from the mother for cytogenetic evaluation. Since she
      had the same inversion, DNA replication studies were performed to determine if
      the X inactivation pattern was random or not, since skewed inactivation of the
      inverted X might suggest that the breakpoints disrupted functional genes. DNA
      replication studies demonstrated that 68% of mother's cells with the inverted X
      were active, suggesting random X inactivation. The random X inactivation pattern
      suggested that the inversion is probably balanced and should not affect the
      fetus. A normal male was delivered at 40 weeks gestation.

PMID- 10588842
TI  - Hemizygosity for the COP9 signalosome subunit gene, SGN3, in the Smith-Magenis
      syndrome.
AB  - Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation
      syndrome associated with an interstitial deletion of chromosome band 17p11.2. The
      critical region is extremely gene-rich and spans approximately 1.5-2.0 Mb of DNA.
      Here we report the localization and partial characterization of the gene for
      subunit 3 of the COP9 signalosome, SGN3. SGN3 maps to the distal portion of the
      SMS critical interval, between SREBF1 and cCI17-638. We assessed the potential
      effect of haploinsufficiency of SGN3 in SMS patient lymphoblastoid cell lines
      through transfection studies and western analysis. Our results indicate that the
      COP9 signalosome assembles properly in these cells and appears to have normal
      expression and a kinase function intact. However, because the role of the COP9
      signalosome in embryogenesis or differentiation is still uncertain, we cannot
      rule out the involvement of this gene in the Smith-Magenis syndrome.

PMID- 10588843
TI  - Autosomal XX sex reversal caused by duplication of SOX9.
AB  - SOX9 is one of the genes that play critical roles in male sexual differentiation.
      Mutations of SOX9 leading to haploinsufficiency can cause campomelic dysplasia
      and XY sex reversal. We report here evidence supporting that SOX9 duplication can
      cause XX sex reversal. A newborn infant was referred for genetic evaluation
      because of abnormal male external genitalia. The infant had severe penile/scrotal
      hypospadias. Gonads were palpable. Cytogenetic analysis demonstrated a de novo
      mosaic 46,XX,dup(17)(q23.1q24.3)/46, XX karyotype. Fluorescent in situ
      hybridization (FISH) with a BAC clone containing the SOX9 gene demonstrated that
      the SOX9 gene is duplicated on the rearranged chromosome 17. The presence of SRY
      was ruled out by FISH with a probe containing the SRY gene and polymerase chain
      reaction with SRY-specific primers. Microsatellite analysis with 13 markers on
      17q23-24 determined that the duplication is maternal in origin and defined the
      boundary of the duplication to be approximately 12 centimorgans (cM) proximal and
      4 cM distal to the SOX9 gene. Thus, SOX9 duplication is the most likely cause for
      the sex reversal in this case because it plays an important role in male sex
      determination and differentiation. This study suggests that extra dose of SOX9 is
      sufficient to initiate testis differentiation in the absence of SRY. Other SRY
      negative XX sex-reversed individuals deserve thorough investigation of SOX9 gene.

PMID- 10588844
TI  - Clinical expression of Menkes disease in a girl with X;13 translocation.
AB  - Menkes disease is a rare X-linked recessive disorder of copper metabolism,
      characterised by progressive neurological degeneration, abnormal hair and
      connective tissue manifestations. We report on a girl with classic Menkes
      disease, carrying a de novo balanced translocation 46,X,t(X;13)(q13.3; q14.3).
      The translocation breakpoints at Xq13.3 and 13q14.3 coincide with the Menkes
      disease and Wilson disease loci, respectively.

PMID- 10588845
TI  - Craniomicromelic syndrome: report of a third case.

PMID- 10588846
TI  - Extragonadal germ cell tumors in brothers.

PMID- 10588847
TI  - Poland anomaly may be explained as a paradominant trait.

PMID- 10588848
TI  - Double-blind, placebo-controlled study of L-acetylcarnitine for the treatment of
      hyperactive behavior in fragile X syndrome.

PMID- 10588849
TI  - Testicular cancer

PMID- 10588850
TI  - Staging and prognostic factors in testicular cancer.
AB  - Germ cell cancers of the testis are rare malignancies that occur most commonly in
      young adult male life. These malignancies are highly curable, and adoption of
      sophisticated treatment strategies, related to known prognostic-based variables,
      has resulted in overall cure rates of approximately 95% with acceptable
      morbidity. These treatment approaches require a thorough knowledge of the
      underlying pathology and patterns of tumour spread. In recent years a number of
      prognostic factor-based staging classifications have evolved, each of which can
      accurately predict prognosis. However, in 1997, an internationally agreed-upon
      consensus classification applicable to both seminoma and non-seminoma was
      published. This classification was well validated and has now been incorporated
      into the TNM and American Joint Committee on Cancer (AJCC) staging systems.

PMID- 10588852
TI  - Management of testicular seminoma.
AB  - Testicular seminoma is highly curable with currently available treatments. Today,
      there is good evidence that patients with Stage I disease can be treated equally
      well with either immediate adjuvant para-aortic and ipsilateral pelvic
      radiotherapy or close surveillance with treatment at the time of relapse. The
      decision as to which of these management strategies is adopted in an individual
      case is a complex function of physician preference, and the emotional, social,
      and economic circumstances of the patient. Ongoing research in Stage I seminoma
      is focused at reducing the side-effects of treatment either by modifying the
      radiation treatment plan or by using adjuvant chemotherapy in lieu of radiation.
      Stage II patients with small bulk retroperitoneal lymphadenopathy have a high
      probability of long-term disease control with radiotherapy. Patients with bulky
      Stage II disease or Stage III disease should be treated with cisplatin-based
      chemotherapy.

PMID- 10588851
TI  - Surgery versus surveillance in stage I non-seminoma testicular cancer.
AB  - Today, the standard treatment for patients with clinical Stage I non-seminomatous
      testicular germ cell tumors (NSTGCT) following orchidectomy is either primary
      retroperitoneal lymph node dissection (RPLND) or close surveillance with
      cisplatin-based polychemotherapy in case of a relapse. Both treatment modalities
      provide excellent overall survival rates up to 100%. Consequently, selection of
      the most appropriate management option is not primarily guided by survival
      considerations. The choice between the available options, each having its merits
      and its drawbacks, should be made based on a number of factors including
      treatment-related morbidity, views and expertise of the physician, patient
      preferences, the expected degree of patient compliance, and prognostic factor
      analysis. To date, the role of adjuvant chemotherapy as an alternative management
      option for patients with clinical Stage I NSTGCT at high risk of occult
      metastases is limited. This systemic treatment modality would be a realistic
      alternative if the reliability of prognostic factors to identify high-risk Stage
      I patients could be improved. This review addresses relevant issues in the
      management of patients with clinical Stage I NSTGCT to provide information that
      will allow a rational selection of the most appropriate management option.

PMID- 10588853
TI  - Treatment of disseminated non-seminomatous testicular cancer: the European
      experience.
AB  - The majority of patients with disseminated germ cell cancer can be cured with
      cisplatin-based combination chemotherapy. For more than a decade the gold
      standard regimen is cisplatin, etoposide, and bleomycin (BEP). On both sides of
      the Atlantic, a number of studies have been carried out to either modify the
      toxicity of therapy in good prognosis patients or to improve the treatment
      outcome by intensifying the regimen or incorporating new agents in patients with
      intermediate or poor prognosis disease. This review discusses the trials that
      have been conducted in Europe, mainly through the European Organization of
      Research and Treatment of Cancer (EORTC) and Medical Research Council (MRC) in
      the United Kingdom, as well as the studies that are currently being conducted by
      the collaborative groups in Europe.

PMID- 10588854
TI  - Germ cell tumor clinical trials in North America.
AB  - The management of germ cell tumors (GCT) in men has been the focus of intense
      clinical investigation over the past 25 years. Following clinical trials which
      demonstrated that GCTs are curable, considerable effort has been directed at
      refinement of the multidisciplinary treatment plan. During the past decade, there
      has been a major emphasis on identifying those clinical prognostic features most
      closely associated with a high likelihood of a complete response (good risk) and
      a low likelihood of complete response (poor risk). Randomized good- and poor-risk
      clinical trials have been conducted which clarify the role of bleomycin and the
      number of cycles of therapy in good-risk patients and the role of high-dose
      cisplatin (200 mg/m(2)/cycle) and ifosfamide in poor-risk patients. The efficacy
      of high-dose chemotherapy with stem cell rescue has led to a randomized trial of
      its use following standard induction therapy as compared to standard induction
      therapy in previously untreated poor-risk patients. Salvage chemotherapy for
      patients in first or second relapse, or those who have not achieved an initial
      complete response, initially tested the role of ifosfamide; efforts are now
      focused on the role of paclitaxel and high-dose therapy in specific patient
      subgroups. High-dose chemotherapy with stem cell rescue is the treatment of
      choice for patients in second relapse with gonadal primary tumors who have
      responsive disease and factors which predict a reasonable likelihood of achieving
      a disease-free status. A general understanding of tumor biology and specific
      knowledge regarding GCTs will be very important in the next decade of discovery
      as the pathways of malignant transformation, progression, and drug resistance
      become better known and serve as targets for new therapy.

PMID- 10588855
TI  - Complications of retroperitoneal lymph node dissection in testicular cancer:
      primary and post-chemotherapy.
AB  - Retroperitoneal lymph node dissection (RPLND) is utilized in low-stage testis
      cancer as a primary diagnostic and therapeutic procedure. In the post
      chemotherapy setting, it serves as an adjuvant procedure to resect residual
      tumor. Primary RPLND entails minimal resection of lymphatic tissue in the
      retroperitoneum; the complications are minor and insignificant. Wound infection
      is the main complication, affecting less than 5% of patients. Atelectasis and
      small bowel obstruction may occur in less than 2% of patients. In post
      chemotherapy RPLND, the template and the surgical challenge are much larger.
      Extensive tumor size, difficult location, adherence to major vessels, and vital
      structures, together with inferior pre-operative status, are probably the main
      reasons for complications. The overall complication rate is 20% to 35% and
      mortality is 0.8% to 1%. Pulmonary insufficiency secondary to bleomycin-induced
      interstitial fibrosis is the cause of the most severe side effects and mortality
      in these operations. Chylous ascites may occur, especially where resection of the
      inferior vena cava is necessary. Other complications occur to a lesser extent. A
      summary of all complications is presented and measures to avoid or manage them
      are depicted.

PMID- 10588856
TI  - Treatment of recurrent germ cell tumors.
AB  - Treatment of recurrent germ cell tumors is a complex undertaking. There are a
      number of clinical scenarios that can mimic relapse and, as such, a great deal of
      experience with management of germ cell tumors is required to recognize these
      rare but important situations that simulate recurrence. If recurrence is proven,
      standard chemotherapy with cisplatin, ifosfamide, and etoposide can result in
      approximately 30% of patients being long-term, disease-free survivors. Emerging
      technologies, e.g., high-dose chemotherapy and new drugs, may augment our current
      ability to salvage this patient population. Desperation surgery offers an
      additional opportunity for selected patients with localized chemotherapy
      resistant relapse or those patients with late relapse of germ cell tumor.

PMID- 10588857
TI  - Late toxicity following curative treatment of testicular cancer.
AB  - Cisplatin appears to be the major cause for long-term toxicity in patients
      treated for testicular cancer. Long-term side effects consist mainly of
      nephrotoxicity, ototoxicity, and neurotoxicity as well as gonadal damage.
      Following standard-dose chemotherapy approximately 20% to 30% of patients will be
      affected by long-term side effects, although not all these side effects will
      cause an impaired quality of life. Several strategies have been or currently are
      being evaluated to reduce acute and long-term complications including the
      introduction of equally effective, but less toxic regimens, or the use of
      cytoprotective agents such as amifostine. Secondary acute myeloid leukemia and
      secondary myelodysplastic syndrome probably represent the worst possible long
      term complications of cancer therapy in those patients who originally were cured
      of their primary testicular cancer. Therapy-related solid tumors are mainly
      associated with the use of radiation therapy and the risk for developing a
      therapy-related solid tumor is increased approximately two to three times
      compared to the general population. In contrast, therapy-related leukemias are
      predominantly associated with chemotherapy, particularly with the use of
      topoisomerase-II inhibitors and alkylating agents. In general, the cumulative
      incidence of therapy-related leukemia following treatment of germ cell cancer is
      low. It is approximately 0.5% and 2% at 5 years of median follow-up for patients
      receiving etoposide at cumulative doses< or = 2 g/m(2) and >2 g/m(2),
      respectively. The risk-benefit analysis in patients with testicular cancer
      clearly favors the use of current treatment regimens including high-dose
      chemotherapy. However, even the acceptably low number of therapy-related long
      term complications should encourage the search for equally effective but less
      toxic therapies. This review will highlight important available data about
      therapy-related toxicity and particularly, therapy-related malignancies following
      cisplatin-etoposide-based chemotherapy.

PMID- 10588858
TI  - Peri-operative care in patients treated for testicular cancer.
AB  - The success of combination chemotherapy in treating advanced metastatic germ cell
      tumors has led to new challenges for the genitourinary oncologic surgeon in the
      peri-operative care of patients. Surgery remains an integral part of the
      management of patients with advanced germ cell tumors. Retroperitoneal node
      dissections following chemotherapy or radiation, or both, are technically more
      demanding and subject to higher rates of peri-operative complications. Overall
      post-therapy surgical complication rates range from 33% to 75%, with the highest
      rates among patients who receive both radiation and chemotherapy. Although most
      patients with testicular cancer are young and healthy, residual pulmonary, renal,
      vascular, and neurologic toxicities from chemotherapy can increase the risk of
      peri-operative complications. In addition, the volume and location of tumor can
      increase the technical demands, especially when there is a tremendous soft tissue
      reaction to the chemotherapy. Identification of pre-operative risk factors for
      peri-operative complications is imperative and the first step in pre-operative
      planning. Pulmonary toxicity and vascular (cardiac or peripheral) events are the
      two most immediately life-threatening complications that can occur in the peri
      operative period. Due to the high incidence of subclinical pulmonary toxicity,
      one must consider all patients who have received bleomycin pre-operatively at
      risk to develop postoperative pulmonary problems. Pre-operative evaluation and
      judicious fluid management have been shown to reduce the risk of life-threatening
      respiratory complications in the postoperative period.

PMID- 10588859
TI  - Dissecting hematopoiesis and disease using the zebrafish.
AB  - The study of blood has often defined paradigms that are relevant to the biology
      of other vertebrate organ systems. As examples, stem cell physiology and the
      structure of the membrane cytoskeleton were first described in hematopoietic
      cells. Much of the reason for these successes resides in the ease with which
      blood cells can be isolated and manipulated in vitro. The cell biology of
      hematopoiesis can also be illuminated by the study of human disease states such
      as anemia, immunodeficiency, and leukemia. The sequential development of the
      blood system in vertebrates is characterized by ventral mesoderm induction,
      hematopoietic stem cell specification, and subsequent cell lineage
      differentiation. Some of the key regulatory steps in this process have been
      uncovered by studies in mouse, chicken, and Xenopus. More recently, the genetics
      of the zebrafish (Danio rerio) have been employed to define novel points of
      regulation of the hematopoietic program. In this review, we describe the
      advantages of the zebrafish system for the study of blood cell development and
      the initial success of the system in this pursuit. The striking similarity of
      zebrafish mutant phenotypes and human diseases emphasizes the utility of this
      model system for elucidating pathophysiologic mechanisms. New screens for lineage
      specific mutations are beginning, and the availability of transgenics promises a
      better understanding of lineage-specific gene expression. The infrastructure of
      the zebrafish system is growing with an NIH-directed genome initiative, providing
      a detailed map of the zebrafish genome and an increasing number of candidate
      genes for the mutations. The zebrafish is poised to contribute greatly to our
      understanding of normal and disease-related hematopoiesis.

PMID- 10588860
TI  - The phosphoprotein protein PEA-15 inhibits Fas- but increases TNF-R1-mediated
      caspase-8 activity and apoptosis.
AB  - We have characterized a phosphoprotein protein with a death effector domain that
      has a novel bifunctional role in programmed cell death. The 15-kDa phosphoprotein
      enriched in astrocytes (PEA-15) inhibits Fas-mediated apoptosis and increases
      tumor necrosis factor receptor-1 (TNF-R1)-mediated apoptosis in the same cell
      type in a ligand-dependent manner. Phosphorylation appears to play a role in its
      differential effects, since point mutations at one or both phosphorylation
      consensus sites within PEA-15 destroy its effect on Fas-mediated, but not TNF-R1
      mediated, apoptosis. Furthermore, the differential effect is evident at the level
      of caspase-8 activity which is inhibited via Fas activation, but increased via
      TNF-R1 activation upon PEA-15 expression. These results show that PEA-15 provides
      a potential mechanism during development for distinguishing between diverse
      extracellular death-inducing signals that culminate either in apoptosis or in
      survival.

PMID- 10588861
TI  - In Xenopus embryos, BMP heterodimers are not required for mesoderm induction, but
      BMP activity is necessary for dorsal/ventral patterning.
AB  - The activity of bone morphogenetic protein (BMP) heterodimers has been shown to
      be more potent than that of homodimers in a number of contexts, including
      mesoderm induction. Although BMP-2/7 and -4/7 heterodimers are potent inducers of
      ventral mesoderm in ectodermal explants, we show that they are not a necessary
      component of the primary mesoderm-inducing signal in intact Xenopus embryos. The
      secreted BMP antagonists noggin and gremlin both efficiently block mesoderm
      induction by BMP homo- and heterodimers in animal caps. When these antagonists
      are ectopically expressed in the ventral marginal zone of early embryos the
      initial formation of mesoderm as indicated by panmesodermal markers remains
      unaffected. Only the subsequent dorsal/ventral patterning of this mesoderm
      appears to be altered, with expression of a number of organizer-specific
      transcripts observed in the marginal zone where BMP signaling has been abolished.
      Thus, we conclude that BMPs do not contribute an essential signal to mesodermal
      induction or patterning until gastrulation. The activities of noggin and gremlin
      are strikingly different from that of the multifunctional antagonist cerberus,
      which completely abolishes mesoderm induction when misexpressed during early
      development.

PMID- 10588862
TI  - Extrinsic modulation of retinal ganglion cell projections: analysis of the albino
      mutation in pigmentation mosaic mice.
AB  - Tyrosinase is a key enzyme involved in the synthesis of melanin in the retinal
      pigment epithelium (RPE). Mice that are homozygous for the albino allele at the
      tyrosinase locus have fewer retinal ganglion cells with uncrossed projections at
      the optic chiasm. To determine the site of the albino gene action we studied the
      projections of retinal ganglion cells in two types of pigmentation mosaic mice.
      First, we generated mosaic mice that contain a translocated allele of the wild
      type tyrosinase on one X chromosome but that also have the lacZ reporter
      transgene on the opposite X chromosome. In these lacZ/tyrosinase mice, which are
      homozygous for the albino allele on chromosome 7, X-inactivation ensures that
      tyrosinase cannot be functional within 50% of the retinal ganglion cells and that
      these individual cells can be identified by their expression of the lacZ reporter
      gene product, beta-galactosidase. The proportion of uncrossed retinal ganglion
      cells expressing beta-galactosidase was found to be identical to the proportion
      that did not express it, indicating that the albino mutation associated with
      axonal behavior at the optic chiasm must affect ganglion cells in a cell
      extrinsic manner. Second, to determine whether the RPE is the source of the
      extrinsic signal, we generated aggregation chimeras between pigmented and albino
      mice. In these mosaic mice, the extent of the uncrossed projection corresponded
      with the amount of pigmented cells within the RPE, but did not correspond with
      the genotypes of neural retinal cells. These studies demonstrate that the albino
      mutation acts indirectly upon retinal ganglion cells, which in turn respond by
      making axonal guidance errors at the optic chiasm.

PMID- 10588863
TI  - A role for GATA-4/5/6 in the regulation of Nkx2.5 expression with implications
      for patterning of the precardiac field.
AB  - Interactions between the key regulatory genes of the cardiogenic pathway,
      including those from the GATA and Nkx2 transcription factor families, are not
      well defined. Treating neurula-stage Xenopus embryos with retinoic acid (RA)
      causes a specific block in cardiomyocyte development that correlates with a
      progressive reduction in the region of the presumptive heart-forming region
      expressing Nkx2.5. In contrast, RA does not block expression of the GATA-4/5/6
      genes, which are transcribed normally in an overlapping pattern with Nkx2.5
      throughout cardiogenesis. Instead, GATA-4/5/6 transcription levels are increased,
      including an expansion of the expression domain corresponding to lateral plate
      mesoderm that is part of the early heart field, but that normally is
      progressively restricted in its ability to contribute to the myocardium. GATA
      dependent regulatory sequences of the Nkx2.5 gene that implicate GATA-4/5/6 as
      upstream positive regulators were described recently. However, our experiments
      also indicate that GATA factors might normally antagonize transcription of
      Nkx2.5. To test this hypothesis we generated a dominant negative isoform of GATA
      4 (SRG4) capable of inhibiting transcription of GATA-dependent target genes.
      Ectopic expression of SRG4 results in a transient expansion of the Nkx2.5
      transcript pattern, indicating that a normal function of GATA factors is to limit
      the boundary of the Nkx2.5 expression domain to the most anterior ventral region
      of the heart field. Regulatory mechanisms altered by excess RA must function
      normally to limit GATA-4/5/6 expression levels, to define the region of Nkx2.5
      expression and regulate myocardial differentiation.

PMID- 10588864
TI  - HRT1, HRT2, and HRT3: a new subclass of bHLH transcription factors marking
      specific cardiac, somitic, and pharyngeal arch segments.
AB  - Members of the Hairy/Enhancer of Split family of basic helix-loop-helix (bHLH)
      transcription factors are regulated by the Notch signaling pathway in vertebrate
      and Drosophila embryos and control cell fates and establishment of sharp
      boundaries of gene expression. Here, we describe a new subclass of bHLH proteins,
      HRT1 (Hairy-related transcription factor 1), HRT2, and HRT3, that share high
      homology with the Hairy family of proteins yet have characteristics that are
      distinct from those of Hairy and other bHLH proteins. Each HRT gene was expressed
      in distinct cell types within numerous organs, particularly in those patterned
      along the anterior-posterior axis. HRT1 and HRT2 were expressed in atrial and
      ventricular precursors, respectively, and were also expressed in the cardiac
      outflow tract and aortic arch arteries. HRT1 and HRT2 transcripts were also
      detected in precursors of the pharyngeal arches and subsequently in the
      pharyngeal clefts. Within somitic precursors, HRT1 and HRT3 exhibited dynamic
      expression in the presomitic mesoderm, mirroring the expression of other
      components of Notch-Delta signaling pathways. The HRT genes were expressed in
      other sites of epithelial-mesenchymal interactions, including the developing
      kidneys, brain, limb buds, and vasculature. The unique and complementary
      expression patterns of this novel subfamily of bHLH proteins suggest a previously
      unrecognized role for Hairy-related pathways in segmental patterning of the heart
      and pharyngeal arches, among other organs.

PMID- 10588865
TI  - Chondroitin sulphate-binding molecules may pattern central projections of sensory
      axons within the cranial mesenchyme of the developing mouse.
AB  - During mammalian hindbrain development, sensory axons grow along highly
      stereotyped routes within the cranial mesenchyme to reach their appropriate entry
      points into the neuroepithelium. Thus, trigeminal ganglion axons always project
      to rhombomere (r)2, whilst facial/acoustic ganglia axons always project to r4.
      Axons are never observed to enter the mesenchyme adjacent to r3, raising the
      possibility that r3 mesenchyme contains an axon growth-inhibitory activity.
      Conversely, in mice which lack the erbB4 receptor (normally expressed in r3),
      trigeminal and facial/acoustic ganglia axons misproject into r3 mesenchyme,
      suggesting that the putative axon barrier is absent. To investigate this
      hypothesis, we have developed an in vitro model in which dissociated wild-type
      embryonic trigeminal ganglion neurons are cultured on longitudinal cryosections
      of embryonic mouse head. We observed that on wild-type embryonic day 10 (E10)
      cryosections, neurites generally failed to grow into r3 mesenchyme from the
      adjacent r2 or r4 mesenchyme. This barrier was removed if cryosections were
      pretreated with chondroitinase or were washed with excess chondroitin 6-sulphate
      or hypertonic saline. By contrast, when trigeminal neurons were seeded onto
      cryosections of E10 erbB4 -/- embryo heads their neurites readily entered mutant
      r3 mesenchyme. Immunohistochemical analysis demonstrated chondroitin-sulphated
      proteoglycans throughout the cranial mesenchyme in both wild-type and erbB4 -/-
      embryos. We propose that trigeminal axons are excluded from wild-type r3
      mesenchyme by a growth-inhibitory activity which associates with chondroitin
      sulphated proteoglycans and that the synthesis of this activity may rely on
      signals transduced by erbB receptors.

PMID- 10588866
TI  - Early specification of oligodendrocytes in the chick embryonic brain.
AB  - Oligodendrocytes are the myelin-forming cells in the central nervous system of
      vertebrates. In the rodent embryo, these cells have been shown to emerge from
      restricted territories of the neuroepithelium. However, a comprehensive view of
      the development of oligodendroglial populations from their ventricular sources
      remains to be established. As a first step toward this aim, we have examined in
      vivo the spatiotemporal emergence of oligodendrocytes in the chick embryonic
      brain. We have detailed the patterns of expression of three early markers of the
      oligodendroglial lineage: the plp/dm-20 and PDGFRalpha transcripts and the O4
      reactive antigen. During embryonic development, these molecules showed a similar
      segmental pattern of expression. However, plp/dm-20(+) cells were already
      observed, in the ventricular layer, at E2.5, i.e., 2 days before the appearance
      of O4(+) and PDGFRalpha(+) cells, suggesting that oligodendrocyte precursors
      arise nearly simultaneously with neurons. In the chick embryonic brain, the onset
      of expression of plp/dm-20 appears therefore to be the earliest event indicative
      of oligodendroglial specification and we propose, based on the expression of
      plp/dm-20 transcript, a ventricular map of the foci at which oligodendrocytes
      originate. In addition, we document the precocious segregation, from E5, of
      plp/dm-20(+) and PDGFRalpha(+) oligodendroglial cells in the subventricular and
      mantle layers of the brain.

PMID- 10588867
TI  - Organogenesis of the Caenorhabditis elegans intestine.
AB  - The intestine of Caenorhabditis elegans is an epithelial tube consisting of only
      20 cells and is derived clonally from a single embryonic blastomere called E. We
      describe the cellular events that shape the intestine. These events include
      cytoplasmic polarization of cells in the intestinal primordium, the intercalation
      of specific sets of cells, the generation of an extracellular cavity within the
      primordium, and adherens junction formation. The polarization of the intestinal
      primordium is associated with the generation of an asymmetric microtubule
      cytoskeleton, and microtubule function plays a role in subsequent cell polarity.
      We show that an isolated E blastomere is capable of generating polarized
      intestinal cells, indicating that some of the major events in intestinal
      organogenesis do not depend upon interactions with surrounding tissues. We
      compare and contrast intestinal organogenesis with some of the basic steps in
      development of a second epithelial organ, the pharynx, and suggest how these
      differences lead to organs with distinct shapes.

PMID- 10588868
TI  - A role for p75 neurotrophin receptor in the control of hair follicle
      morphogenesis.
AB  - During hair follicle (HF) morphogenesis, p75 neurotrophin receptor (p75NTR)
      reportedly is the first growth factor receptor found to be expressed by those
      fibroblasts that later develop into the dermal papilla (DP) of the HF. However,
      the functional role of p75NTR in HF morphogenesis is still unknown. Studying HF
      development in fetal and neonatal C57BL/6 murine back skin, we show that p75NTR
      immunoreactivity (IR) is prominently expressed by DP fibroblasts as well as by
      skin nerves during the early steps of HF development. In contrast, p75NTR-IR
      disappears from the DP in the fully developed HF and it is expressed only in the
      epithelial outer root sheath of the HF. Compared to age-matched wild-type
      animals, p75NTR knockout (-/-) mice show significant acceleration of HF
      morphogenesis, and DP fibroblasts of p75NTR knockout mice show reduced
      proliferative activity in situ, indicating alterations in their transition from
      proliferation to differentiation. Although no significant differences in the
      expression of adhesion molecules (NCAM), selected morphogens (TGFbeta-2, HGF/SF,
      FGF-2, KGF), or their receptors (TGFbetaR-II, m-met, FGFR-1) were seen between DP
      of p75NTR knockout and wild-type mice, p75NTR mutants showed a prominent
      upregulation of FGFR-2, a high-affinity receptor for KGF, in both follicular DP
      and epithelium. Furthermore, the administration of anti-KGF neutralizing antibody
      significantly inhibited acceleration of HF morphogenesis in p75NTR knockout mice
      in vivo. These observations suggest that p75NTR plays an important role during HF
      morphogenesis, functioning as a receptor that negatively controls HF development,
      most likely via alterations in DP fibroblast proliferation/differentiation and
      via downregulation of KGF/FGFR-2 signaling in the HF.

PMID- 10588869
TI  - Tyrosinase-related protein 2 promoter targets transgene expression to ocular and
      neural crest-derived tissues.
AB  - In an effort to identify a promoter suitable for studying early ocular
      development, we generated transgenic mice carrying the lacZ reporter gene linked
      to the tyrosinase-related protein 2 (TRP2) promoter. TRP2-lacZ was expressed in
      early retinal pigment epithelium (RPE) and early neural crest cells in embryos.
      The promoter activity was robust and consistent in independent transgenic lines.
      The transgene was also expressed in the optic nerve and neural crest-derived
      neuronal cells in which the endogenous TRP2 gene is not expressed. This suggests
      that repressor elements may be missing in the promoter used in this study. To
      test whether this promoter can be used to study melanocyte development, we cross
      mated TRP2-lacZ transgenic mice with mice heterozygous for the Patch (Ph)
      mutation. The pattern of beta-galactosidase activity in the embryos correlates
      well with the pigmentation phenotype in postnatal and adult Ph/+ mice. We also
      generated transgenic mice expressing fibroblast growth factor 9 (FGF9) directed
      by the TRP2 promoter and examined the effect on ocular development. Ectopic
      expression of FGF9 in the early embryonic RPE switched its differentiation
      pathway to a neuronal fate, resulting in formation of a duplicated neural retina
      in transgenic mice. These studies demonstrate that the TRP2 promoter is valuable
      for transgenic studies of ocular differentiation and development of neural crest
      cells.

PMID- 10588870
TI  - Keratin 10 gene expression during differentiation of mouse epidermis requires
      transcription factors C/EBP and AP-2.
AB  - The epidermis forms a vital barrier composed of stratified keratinocytes and
      their differentiated products. One of these products, keratin K10, is critical to
      epidermal integrity, because mutations in k10 lead to abnormal blistering. For
      the normal expression of k10, differentiation-associated transcription factors
      C/EBPalpha, C/EBPbeta, and AP-2 are well positioned to play an important role.
      Here, regulation of the k10 gene is examined in keratinocytes in the skin of
      normal mice and in transgenic mice carrying targeted deletions of c/ebpbeta and
      ap-2alpha. In cultured cells, C/EBPalpha and C/EBPbeta are each capable of
      activating the k10 promoter via three binding sites, identified by site-directed
      mutagenesis. In a given epidermal cell in vivo, however, the selection of
      C/EBPalpha versus C/EBPbeta for k10 regulation is determined via a third
      transcription factor, AP-2. This novel regulatory scheme involves: (1) unique
      gradients of expression for each transcription factor, i.e., C/EBPbeta and AP-2
      most abundant in the lower epidermis, C/EBPalpha in the upper; (2) C/EBP-binding
      sites in the ap-2alpha gene promoter, through which C/EBPbeta stimulates ap
      2alpha; and (3) AP-2 binding sites in the c/ebpalpha promoter, through which AP-2
      represses c/ebpalpha. Promoter-analysis and gene-expression data presented herein
      support a regulatory model in which C/EBPbeta activates and maintains AP-2
      expression in basal keratinocytes, whereas AP-2 represses C/EBPalpha in those
      cells. In response to differentiation signals, loss of AP-2 expression leads to
      derepression of the c/ebpalpha promoter and activation of k10 as cells migrate
      upward.

PMID- 10588871
TI  - Sex reversal caused by Mus musculus domesticus Y chromosomes linked to variant
      expression of the testis-determining gene Sry.
AB  - When the Y chromosomes from certain populations of Mus musculus domesticus are
      introduced into the mouse strain C57BL/6 (B6), testis determination can fail,
      resulting in gonads developing either as ovotestes (with both ovarian and
      testicular components) or as ovaries. Not all Y(DOM) chromosomes cause sex
      reversal. Y(DOM) chromosomes are divided into three classes based upon their
      ability to induce testes in B6. The molecular basis underlying the three Y(DOM)
      classes is an enigma. The simplest explanation is that they harbor different
      alleles of the testis-determining gene, Sry. Sequencing of Sry(DOM) genes has
      indeed identified polymorphisms. However, none were unequivocally linked to the
      sex-reversal trait. It was concluded that all SRY(DOM) proteins are functionally
      equivalent. Using a semiquantitative RT-PCR assay, we now show that
      representatives of the three Y(DOM) classes have variant Sry expression patterns,
      that severity of sex reversal correlates with Sry mRNA titers, and that genetic
      correction of the sex reversal results in the upregulation of Sry expression. We
      propose that the variant Sry expression patterns result from polymorphisms at the
      site of a putative Sry enhancer.

PMID- 10588872
TI  - Teneurins: a novel family of neuronal cell surface proteins in vertebrates,
      homologous to the Drosophila pair-rule gene product Ten-m.
AB  - We have characterized chicken teneurin-1 and teneurin-2, two homologues of the
      Drosophila pair-rule gene product Ten-m and Drosophila Ten-a. The high degree of
      conservation between the vertebrate and invertebrate proteins suggests that these
      belong to a novel family. We propose to name the vertebrate members of this
      family teneurins, because of their predominant expression in the nervous system.
      The expression of teneurin-1 and -2 was investigated by in situ hybridization. We
      show that teneurin-1 and -2 are expressed by distinct populations of neurons
      during the time of axonal growth. The most prominent site of expression of
      chicken teneurins is the developing visual system. Recombinant teneurin-2 was
      expressed to assay its molecular and functional properties. We show that it is a
      type II transmembrane protein, which can be released from the cell surface by
      proteolytic cleavage at a furin site. The expression of teneurin-2 in neuronal
      cells led to a significant increase in the number of filopodia and to the
      formation of enlarged growth cones. The expression pattern of teneurins in the
      developing nervous system and the ability of teneurin-2 to reorganize the
      cellular morphology indicate that these proteins may have an important function
      in the formation of neuronal connections.

PMID- 10588873
TI  - Wingless modulates the effects of dominant negative notch molecules in the
      developing wing of Drosophila.
AB  - The development and patterning of the wing in Drosophila relies on a sequence of
      cell interactions molecularly driven by a number of ligands and receptors.
      Genetic analysis indicates that a receptor encoded by the Notch gene and a signal
      encoded by the wingless gene play a number of interdependent roles in this
      process and display very strong functional interactions. At certain times and
      places, during wing development, the expression of wingless requires Notch
      activity and that of its ligands Delta and Serrate. This has led to the proposal
      that all the interactions between Notch and wingless can be understood in terms
      of this regulatory relationship. Here we have tested this proposal by analysing
      interactions between Delta- and Serrate-activated Notch signalling and Wingless
      signalling during wing development and patterning. We find that the cell death
      caused by expressing dominant negative Notch molecules during wing development
      cannot be rescued by coexpressing Nintra. This suggests that the dominant
      negative Notch molecules cannot only disrupt Delta and Serrate signalling but can
      also disrupt signalling through another pathway. One possibility is the Wingless
      signalling pathway as the cell death caused by expressing dominant negative Notch
      molecules can be rescued by activating Wingless signalling. Furthermore, we
      observe that the outcome of the interactions between Notch and Wingless
      signalling differs when we activate Wingless signalling by expressing either
      Wingless itself or an activated form of the Armadillo. For example, the effect of
      expressing the activated form of Armadillo with a dominant negative Notch on the
      patterning of sense organ precursors in the wing resembles the effects of
      expressing Wingless alone. This result suggests that signalling activated by
      Wingless leads to two effects, a reduction of Notch signalling and an activation
      of Armadillo.

PMID- 10588874
TI  - The abruptex mutations of notch disrupt the establishment of proneural clusters
      in Drosophila.
AB  - The receptor encoded by the Notch gene plays a central role in preventing cells
      from making decisions about their fates until appropriate signals are present.
      This function of Notch requires the product of the Suppressor of Hairless gene.
      Loss of either Notch or Suppressor of Hairless function results in cells making
      premature and incorrect cell fate decisions, whilst increases in Notch signalling
      prevent cells from making these decisions. Here we find that the proneural
      clusters are not established correctly in certain Abruptex mutations of Notch and
      this failure to establish proneural clusters correctly is not due to increased
      Notch signalling during lateral inhibition. In addition we show that the
      overexpression of certain dominant negative Notch molecules can disrupt the
      initiation of proneural cluster development in a manner similar to the Abruptex
      mutants.

PMID- 10588875
TI  - Tissue-specific regulation of vein/EGF receptor signaling in Drosophila.
AB  - Signaling by the Drosophila EGF receptor (DER) is modulated by four known EGF
      like proteins: the agonists Vein (Vn), Spitz (Spi), and Gurken (Grk) and the
      antagonist Argos (Aos). DER is broadly expressed and thus tissue-specific
      regulation of ligand expression and activity is an important mechanism for
      controlling signaling. Here we investigate the tissue-specific regulation of Vn
      signaling by examining vn transcriptional control and Vn target gene activation
      in the embryo and the wing. The results show a complex temporal and spatial
      regulation of vn transcription involving multiple signaling pathways and tissue
      specific activation of Vn target genes. In the embryo, vn is a target of Spi/DER
      signaling mediated by the ETS transcription factor PointedP1 (PntP1). This
      establishes a positive feedback loop in addition to the negative feedback loop
      involving Aos. The simultaneous production of Vn provides a mechanism for
      dampening Aos inhibition and thus fine-tunes signaling. In the larval wing pouch,
      vn is not a target of Spi/DER signaling but is expressed along the anterior
      posterior boundary in response to Hedgehog (Hh) signaling. Repression by Wingless
      (Wg) signaling further refines the vn expression pattern by causing a
      discontinuity at the dorsal-ventral boundary. The potential for vn to activate
      DER target genes correlates with its roles in development: vn has a minor role in
      embryogenesis and does not induce DER target genes such as aos and pntP1 in the
      embryo. Conversely, vn has a major role in wing development and Vn/DER signaling
      is a potent inducer of DER target genes in the wing disc. Spi also has the
      potential to induce DER target genes in the wing disc. However, the ligands
      appear to evoke specific responses that result in different patterns of target
      gene expression. Finally, we show that other factors modulate the potential of Vn
      so that induction of Vn/DER target genes in the wing pouch is cell specific.

PMID- 10588876
TI  - Redundant enhancers mediate transcriptional repression of AGAMOUS by APETALA2.
AB  - The floral homeotic gene AGAMOUS specifies stamen and carpel fate in the central
      whorls of Arabidopsis flowers. Transcription of AGAMOUS RNA is restricted to the
      center of developing flowers by several, partially redundant negative regulators,
      one of which is the homeotic gene APETALA2. We have identified regulatory
      elements that mediate transcriptional repression of AGAMOUS by APETALA2 and found
      that several redundant elements respond independently to loss of APETALA2
      activity. Thus, redundancy at the level of cis-regulatory sequences is
      independent of redundancy at the level of trans-regulators. We have also found
      that only the early, but not the late, effects of APETALA2 on AGAMOUS require the
      meristem-identity protein LEAFY, a positive regulator of AGAMOUS.

PMID- 10588877
TI  - Gliogenesis depends on glide/gcm through asymmetric division of neuroglioblasts.
AB  - Some neurons and glial cells originate from neuroblasts and glioblasts, stem
      cells that delaminate from the ectoderm of developing fly embryos. A second class
      of glial cells and neurons differentiates from multipotent precursors, the
      neuroglioblasts. The differentiation of both glial cell types depends on glial
      cell deficient/glial cell missing (glide/gcm). Although it has been shown that
      this transcription factor promotes gliogenesis at the expense of neurogenesis,
      the cellular mechanisms underlying this fate choice are poorly understood. Using
      loss and gain of function glide/gcm mutations here we show that the cell fate
      choice takes place in the neuroglioblast, which divides and produces a glioblast
      and a neuroblast. Such choice requires the asymmetric distribution of glide/gcm
      RNA, which accumulates preferentially on one side of the neuroglioblast and is
      inherited by one cell, the presumptive glioblast. Interestingly, glial cells can
      differentiate from cells that delaminate as neuroglioblasts or they can arise
      from cells that start expressing glide/gcm several hours after delamination of a
      neuroblast. Altogether, these findings identify a novel type of asymmetric cell
      division and disclose the lineage relationships between glia and neurons. They
      also reveal the mode of action of the glide/gcm promoting factor.

PMID- 10588878
TI  - Goosecoid regulates the neural inducing strength of the mouse node.
AB  - The homeobox gene goosecoid was the first specific genetic marker of Spemann's
      organizer in vertebrate embryos to be discovered. In the frog, misexpression of
      this gene by RNA injection produces duplication of the posterior axis. For these
      reasons, the recent finding that mice lacking goosecoid function have no early
      axial defects was rather surprising. Here we assay the neural inducing strength
      of wild-type and goosecoid-mutant mouse nodes by transplantation into primitive
      streak stage chick embryos. Wild-type mouse nodes strongly induce the neural
      specific transcription factors Sox2 and Sox3 in the chick host. Homozygous
      goosecoid(-/- )nodes are severely impaired in their ability to induce both genes.
      Heterozygous goosecoid(+/-) nodes induce Sox3 as well as wild-type nodes, but
      resemble -/- nodes in their limited ability to induce Sox2. We propose that
      goosecoid does play a role in regulating the neural inducing strength of the node
      and that regulative mechanisms exist which mask the early phenotypic consequences
      of goosecoid mutations in the intact mouse embryo.

PMID- 10588879
TI  - Complementary domains of retinoic acid production and degradation in the early
      chick embryo.
AB  - Excess retinoids as well as retinoid deprivation cause abnormal development,
      suggesting that retinoid homeostasis is critical for proper morphogenesis. RALDH
      2 and CYP26, two key enzymes that carry out retinoic acid (RA) synthesis and
      degradation, respectively, were cloned from the chick and show significant
      homology with their orthologs in other vertebrates. Expression patterns of RALDH
      2 and CYP26 genes were determined in the early chick embryo by in situ
      hybridization. During gastrulation and neurulation RALDH-2 and CYP26 were
      expressed in nonoverlapping regions, with RALDH-2 transcripts localized to the
      presumptive presomitic and lateral plate mesoderm and CYP26 mRNA to the
      presumptive mid- and forebrain. The two domains of expression were separated by
      an approximately 300-micrometer-wide gap, encompassing the presumptive hindbrain.
      In the limb region, a similar spatial segregation of RALDH-2 and CYP26 expression
      was found at stages 14 and 15. Limb region mesoderm expressed RALDH-2, whereas
      the overlying limb ectoderm expressed CYP26. RA-synthesizing and -degrading
      enzymatic activities were measured biochemically in regions expressing RALDH-2 or
      CYP26. Regions expressing RALDH-2 generated RA efficiently from precursor retinal
      but degraded RA only inefficiently. Conversely, tissue expressing CYP26
      efficiently degraded but did not synthesize RA. Localized regions of RA synthesis
      and degradation mediated by these two enzymes may therefore provide a mechanism
      to regulate RA homeostasis spatially in vertebrate embryos.

PMID- 10588880
TI  - Topographic targeting and pathfinding errors of retinal axons following
      overexpression of ephrinA ligands on retinal ganglion cell axons.
AB  - In the retinotectal projection, the Eph receptor tyrosine kinase ligands ephrinA2
      and ephrinA5 are differentially expressed not only in the tectum, but also in a
      high-nasal-to-low-temporal pattern in the retina. Recently, we have shown that
      retrovirally driven overexpression of ephrinA2 on retinal axons leads to
      topographic targeting errors of temporal axons in that they overshoot their
      normal termination zones in the rostral tectum and project onto the mid- and
      caudal tectum. The behavior of nasal axons, however, was only marginally
      affected. Here, we show that overexpression of ephrinA5 affects the topographic
      targeting behavior of both temporal and nasal axons. These data reinforce the
      idea that differential ligand expression on retinal axons contributes to
      topographic targeting in the retinotectal projection. Additionally, we found that
      ectopic expression of ephrinA2 and ephrinA5 frequently leads to pathfinding
      errors at the chiasm, resulting in an increased stable ipsilateral projection.

PMID- 10588881
TI  - Spatial and temporal changes in myosin heavy chain gene expression in skeletal
      muscle development.
AB  - Seven myosin heavy chains (MyHC) are expressed in mammalian skeletal muscle in
      spatially and temporally regulated patterns. The timing, distribution, and
      quantitation of MyHC expression during development and early postnatal life of
      the mouse are reported here. The three adult fast MyHC RNAs (IIa, IIb, and IId/x)
      are expressed in the mouse embryo and each mRNA has a distinct temporal and
      spatial distribution. In situ hybridization analysis demonstrates expression of
      IIb mRNA by 14.5 dpc, which proceeds developmentally in a rostral to caudal
      pattern. IId/x and IIa mRNAs are detectable 2 days later. Ribonuclease protection
      assays demonstrate that the three adult fast genes are expressed at approximately
      equal levels relative to each other in the embryo but at quite low levels
      relative to the two developmental isoforms, embryonic and perinatal. Just after
      birth major changes in the relative proportions of different MyHC RNAs and
      protein occur. In all cases, RNA expression and protein expression appear
      coincident. The changes in MyHC RNA and protein expression are distinct in
      different muscles and are restricted in some cases to particular regions of the
      muscle and do not always reflect their distribution in the adult.

PMID- 10588882
TI  - Tinman regulates the transcription of the beta3 tubulin gene (betaTub60D) in the
      dorsal vessel of Drosophila.
AB  - During Drosophila embryogenesis, the beta3 tubulin gene is expressed in the
      visceral and somatic mesoderm as well as in the dorsal vessel. Transcription of
      the gene is limited to four pairs of cardioblasts per segment. Here we show that
      its expression in the dorsal vessel (dv) is mediated by a 333-bp enhancer located
      upstream of the gene. The homeodomain protein Tinman is also expressed in these
      cardioblasts, implying that Tinman might be a key regulator of the beta3 tubulin
      gene. Gel retardation and footprint assays indeed revealed two Tinman binding
      sites within the dv-specific enhancer. We analyzed the relevance of the Tinman
      binding sites in a transgenic fly assay and observed distinct functions for both
      sites. The BS(Tin-1460) site is absolutely required for expression in
      cardioblasts, while BS(Tin-1425) is needed for high-level expression. Thus, these
      two Tinman binding sites act in concert to drive beta3 tubulin gene expression
      during heart development. Tinman initially functions in the specification of
      visceral mesoderm and heart progenitors, but remains expressed in cardioblasts
      until dorsal closure. Overall, our data demonstrate a late function for Tinman in
      the regulation of beta3 tubulin gene expression in the forming heart of
      Drosophila.

PMID- 10588883
TI  - Hepatocyte growth factor (HGF) receptor expression and role of HGF during
      embryonic mouse testis development.
AB  - The hepatocyte growth factor (HGF) receptor, c-met, transduces the HGF multiple
      biological activities. During embryonic development the system HGF/c-met
      regulates the morphogenesis of different organs and tissues. In this study we
      examined c-met gene expression during mouse testis development and, by means of
      Northern blot and in situ hybridization, we report the receptor expression
      pattern. C-met expression is not detectable in male genital ridges isolated from
      embryos at 11.5 days postcoitum (dpc). In testes isolated from 12.5 and 13.5 dpc,
      c-met expression is detectable and essentially localized in the developing cords.
      Male genital ducts do not express c-met at the reported ages, whereas female
      ducts appear c-met positive. Moreover, we report that HGF is able to induce
      testicular morphogenesis in vitro. Male genital ridges isolated from embryos at
      11.5 dpc are morphologically nonorganized. Culturing 11.5 dpc urogenital ridges
      in the presence of HGF we obtained testis organization and testicular cord
      formation. Our data demonstrate that c-met is expressed during the beginning
      period of testis differentiation and that HGF is able to support testicular
      differentiation in vitro. All these data indicate that this growth factor,
      besides its role as mitogenic factor, plays a fundamental role during testicular
      cord formation probably inducing cell migration and/or cell differentiation.

PMID- 10588884
TI  - MAP kinase, meiosis, and sperm centrosome suppression in Urechis caupo.
AB  - Although MAP kinase is an important regulatory enzyme in many somatic cells,
      almost nothing is known about its functions during meiosis, except in frog and
      mouse oocytes. We investigated MAPK activation and function in oocytes of the
      marine worm Urechis caupo that are fertilized at meiotic prophase. Activity was
      first detected at 4-6 min after fertilization in immunoblots with anti-active
      MAPK, prior to germinal vesicle breakdown (GVBD). MAPK activation did not require
      new protein synthesis and was dependent on the increases in both intracellular pH
      and intracellular Ca(2+) that normally occur during activation. When MAPK
      activation was inhibited with PD98059 or U0126, GVBD still occurred, but meiosis
      was abnormal and there was a dramatic premature enlargement of sperm asters,
      which normally do not appear until second polar body formation. Failure of polar
      body formation and premature sperm aster enlargement also occurred when MAPK
      activation was inhibited by an entirely different treatment which involved
      lowering the pH of external seawater to interrupt the normal cytoplasmic pH
      increase. Thus, in Urechis, active MAPK appears to be required for (1) normal
      meiotic divisions and (2) suppressing the paternal centrosome until after the egg
      completes meiosis, a general phenomenon whose mechanism has been unknown.

PMID- 10588885
TI  - Contact with central nervous system myelin inhibits oligodendrocyte progenitor
      maturation.
AB  - Oligodendrocytes, the myelinating cells of the central nervous system (CNS), are
      generated during development through the proliferation and differentiation of a
      distinct progenitor population. Not all oligodendrocyte progenitors generated
      during development differentiate, however, and large numbers of oligodendrocyte
      progenitors are present in the adult CNS, particularly in white matter. These
      "adult progenitors" can be identified through expression of the NG2 proteoglycan.
      Adult oligodendrocyte progenitors are thought to develop from the original pool
      of progenitors and in vitro are capable of differentiating into oligodendrocytes.
      Why these cells fail to differentiate in the intact CNS is currently unclear.
      Here we show that contact with CNS myelin inhibits the maturation of immature
      oligodendrocyte progenitors. The inhibition of oligodendrocyte progenitor
      maturation is a characteristic of CNS myelin that is not shared by several other
      membrane preparations including adult and neonatal neural membrane fractions, PNS
      myelin, or liver. This inhibition is concentration dependent, is reversible, and
      appears not to be mediated by either myelin basic protein or basic fibroblast
      growth factor. Myelin-induced inhibition of oligodendrocyte progenitor maturation
      provides a mechanism to explain the generation of a residual pool of immature
      oligodendrocyte progenitors in the mature CNS.

PMID- 10588886
TI  - Ectopic noggin blocks sensory and nonsensory organ morphogenesis in the chicken
      inner ear.
AB  - Bone morphogenetic protein 4 (Bmp4) is expressed during multiple stages of
      development of the chicken inner ear. At the otocyst stage, Bmp4 is expressed in
      each presumptive sensory organ, as well as in the mesenchymal cells surrounding
      the region of the otocyst that is destined to form the semicircular canals. After
      the formation of the gross anatomy of the inner ear, Bmp4 expression persists in
      some sensory organs and restricted domains of the semicircular canals. To address
      the role of this gene in inner ear development, we blocked BMP4 function(s) by
      delivering one of its antagonists, Noggin, to the developing inner ear in ovo.
      Exogenous Noggin was delivered to the developing otocyst by using a replication
      competent avian retrovirus encoding the Noggin cDNA (RCAS-N) or implanting beads
      coated with Noggin protein. Noggin treatment resulted in a variety of phenotypes
      involving both sensory and nonsensory components of the inner ear. Among the
      nonsensory structures, the semicircular canals were the most sensitive and the
      endolymphatic duct and sac most resistant to exogenous Noggin. Noggin affected
      the proliferation of the primordial canal outpouch, as well as the continual
      outgrowth of the canal after its formation. In addition, Noggin affected the
      structural patterning of the cristae, possibly via a decrease of Msx1 and p75NGFR
      expression. These results suggest that BMP4 and possibly other BMPs are required
      for multiple phases of inner ear development.

PMID- 10588887
TI  - The gon-1 gene is required for gonadal morphogenesis in Caenorhabditis elegans.
AB  - In wild-type Caenorhabditis elegans, the gonad is a complex epithelial tube that
      consists of long arms composed predominantly of germline tissue as well as
      somatic structures specialized for particular reproductive functions. In gon-1
      mutants, the adult gonad is severely disorganized with essentially no arm
      extension and no recognizable somatic structure. The developmental defects in gon
      1 mutants are limited to the gonad; other cells, tissues, and organs appear to
      develop normally. Previous work defined the regulatory "leader" cells as crucial
      for extension of the gonadal arms (J. E. Kimble and J. G. White, 1981, Dev. Biol.
      81, 208-219). In gon-1 mutants, the leader cells are specified correctly, but
      they fail to migrate and gonadal arms are not generated. In addition, gon-1 is
      required for morphogenesis of the gonadal somatic structures. This second role
      appears to be independent of that required for leader migration. Parallel studies
      have shown that gon-1 encodes a secreted metalloprotease (R. Blelloch and J.
      Kimble, 1999, Nature 399, 586-590). We discuss how a metalloprotease may control
      two aspects of gonadal morphogenesis.

PMID- 10588888
TI  - The roles of changes in NADPH and pH during fertilization and artificial
      activation of the sea urchin egg.
AB  - Incubating unfertilized sea urchin eggs in weak bases activates nuclear
      centering, DNA synthesis, and chromosome cycles. These effects were initially
      attributed to raising the intracellular pH (pH(i)), but later experiments
      indicated that these weak bases also lead to increases in reduced pyridine
      nucleotides. These findings raised the question whether the activation of the
      nucleus was due to increased pH(i) or to increased NAD(P)H or possibly other
      effects. This report attempts to clarify how ammonia activates eggs by
      independently altering NADPH and pH(i). To increase the pH(i), unfertilized eggs
      were injected with zwitterionic buffers. This stimulated pronuclear centering,
      DNA synthesis, and nuclear envelope breakdown; there appeared to be a threshold
      corresponding to the fertilized pH(i). However, like incubation in ammonia,
      injection of base also increased NAD(P)H. The NAD(P)H rise caused by directly
      raising the pH(i) occurred in the presence of intracellular calcium chelators,
      indicating that calcium is not required. Increasing NAD(P)H alone did not
      activate nuclear centering, DNA synthesis, or nuclear envelope breakdown.
      Although these experiments cannot eliminate a role for the NADPH increase in
      initiating events leading to nuclear centering and entry into mitosis, they
      provide additional and strong evidence that increasing the pH(i) may be a primary
      signal.

PMID- 10588889
TI  - Nonchordate classic cadherins have a structurally and functionally unique domain
      that is absent from chordate classic cadherins.
AB  - Classic cadherins, which are adhesion molecules in cell-cell adherens junctions,
      have a large contribution to the construction of the animal body. Their molecular
      structures show clear differences between chordate and nonchordate metazoans.
      Although nonchordate classic cadherins have cadherin superfamily-specific
      extracellular repeats (CRs) and a highly conserved cytoplasmic domain (CP), these
      cadherins have a unique extracellular domain that is absent from vertebrate and
      ascidian classic cadherins. We called this the primitive classic cadherin domain
      (PCCD). To understand the roles of the PCCD, we constructed and characterized a
      series of mutant forms of the Drosophila classic cadherin DE-cadherin.
      Biochemical analyses indicated that the last two CRs and PCCD form a special
      structure with proteolytic cleavage. Mutations in the PCCD did not eliminate the
      cell-cell-binding function of DE-cadherin in cultured cells, but prevented the
      cadherin from efficiently translocating to the plasma membrane in epithelial
      cells of the developing embryo. In addition, genetic rescue assays suggested that
      although CP-mediated control plays a central role in tracheal fusion, the role of
      the PCCD in efficient recruitment of DE-cadherin to apical areas of the plasma
      membranes is also important for dynamic epithelial morphogenesis. We propose that
      there is a fundamental difference in the mode of classic cadherin-mediated cell
      cell adhesion between chordate and nonchordate metazoans.

PMID- 10588890
TI  - Stitching together RNA tertiary architectures.
AB  - The powerful explanatory paradigm of molecular biology requiring form to co
      evolve with function has again been proven successful when, over the recent two
      decades, a wealth of biological functions have been uncovered for RNA. Previously
      considered as a mere mediator of the genetic code, RNA is now acknowledged as a
      key player in a wide variety of cellular processes. Along with the discovery of
      novel biological functions of RNA molecules, a number of RNA three-dimensional
      structures have been solved which beautifully demonstrate the molecular
      adaptability which allows RNA to participate as a key player in these functions.
      A distinct repertoire of molecular motifs provides a basis for the assembly of
      complex RNA tertiary architectures.

PMID- 10588891
TI  - The formation of triple-stranded DNA prevents spontaneous branch-migration.
AB  - Branch-migration is a fundamental step in the process of DNA recombination that
      determines the location, and extent, of the exchange between the recombining
      duplexes. Four-way Holliday junctions assembled in vitro can migrate
      spontaneously in an uncatalysed reaction that mimics some of the aspects involved
      in branch-migration. Here, we have analysed the effects of a d(GA.TC)22 and a
      d(CA.TG)30 sequence on the rate of spontaneous branch-migration. Under most of
      the experimental conditions assayed, no significant effect was observed. However,
      the d(GA.TC)22 sequence induces a very strong arrest when branch-migration is
      performed at low pH, under conditions where the repeated sequence is forming an
      intramolecular [C(+)T(GA.TC)] triplex. A similar arrest is observed when the
      recombining duplexes contain intermolecular triplexes arising from the annealing
      of a d(GA.TC)22 duplex and a d(TC)22 oligonucleotide, indicating that the
      formation of triplex DNA constitutes a strong barrier for the progression of the
      Holliday junction. These results are discussed in the context of the possible
      contribution of triplex DNA to DNA recombination.

PMID- 10588892
TI  - DNA-induced conformational changes in bacteriophage 434 repressor.
AB  - Although bacteriophage 434 repressor binds to its specific DNA sites only as a
      dimer, formation of the dimers in solution occurs at concentrations three orders
      of magnitude higher than those needed to bind the 434 operator DNA. Our results
      suggest that both specific and non-specific DNA induce conformational changes in
      repressor that lead to formation of repressor dimers. The repressor
      conformational changes induced by DNA occur at concentrations much lower than
      those needed for binding of repressor, suggesting that the alternative
      conformations of repressor persist even if the protein is not in direct contact
      with DNA. Hence, DNA acts in a "catalytic" fashion to induce a steady-state
      amount of an alternative repressor conformation that has an enhanced affinity for
      its specific binding site. These findings suggest that the repressor conformer
      induced by non-specific DNA is the form of the repressor that is optimized for
      searching for DNA binding sites along non-specific DNA. Upon finding a binding
      site, the repressor protein undergoes an additional conformational change that
      allows it to "lock-on" to its specific site.

PMID- 10588893
TI  - A long-range pseudoknot in Qbeta RNA is essential for replication.
AB  - A puzzling aspect of replication of bacteriophage Qbeta RNA has always been that
      replicase binds at an internal segment, the M-site, some 1450 nt away from the 3'
      end. Here, we report on the existence of a long-range pseudoknot, base-pairing
      eight nt in the loop of the 3' terminal hairpin to a single-stranded interdomain
      sequence located about 1200 nt upstream, close to the internal replicase binding
      site. Introduction of a single mismatch into this pseudoknot is sufficient to
      abolish replication, but the inhibition is fully reversed by a second-site
      substitution that restores the pairing. The pseudoknot is part of an elaborate
      structure that seems to hold the 3' end in a fixed position vis a vis the
      replicase binding site. Our results imply that the shape of the RNA confers the
      functonality. We discuss the possible relevance of our findings for replication
      of other viral RNAs.

PMID- 10588894
TI  - Magnesium ions enhance the transfer of human papillomavirus E2 protein from non
      specific to specific binding sites.
AB  - The human papillomavirus 16 E2 protein binds to four specific DNA sequences
      present within the HPV 16 genome and regulates viral gene expression and DNA
      replication. However, the E2 protein can also bind tightly to non-specific DNA
      sequences. Here, we show that in binding reactions which contain an excess of non
      specific DNA, magnesium ions enhance the binding of E2 to its specific sites. In
      contrast, in the absence of non-specific DNA, magnesium ions have no effect on
      the binding of E2 to specific sites. Although these data suggest that magnesium
      ions decrease the binding of E2 to non-specific DNA, gel retardation assays show
      that these ions have no effect on the binding of E2 to short non-specific DNA
      fragments and have only a minor effect on the binding of E2 to long non-specific
      DNA fragments. We also show that the binding of E2 to long fragments of non
      specific DNA is highly cooperative. The E2-non-specific DNA complexes formed in
      the absence of magnesium ions are highly stable. However, the addition of
      specific DNA to E2-non-specific DNA complexes formed in the presence of magnesium
      ions rapidly results in the formation of E2-specific DNA complexes. Our data
      suggest that magnesium ions facilitate the transfer of E2 from non-specific
      binding sites to specific binding sites, and help to explain how E2 is able to
      direct human papillomavirus transcription and DNA replication in intact cells.

PMID- 10588895
TI  - Saccharomyces cerevisiae ISU1 and ISU2: members of a well-conserved gene family
      for iron-sulfur cluster assembly.
AB  - Recent studies in bacteria and eukaryotes have led to the identification of
      several new genes implicated in the biogenesis of iron-sulfur (Fe/S) cluster
      containing proteins. This report focuses on two genes of bakers yeast
      Saccharomyces cerevisiae, ISU1 and ISU2, which encode homologues to bacterial
      IscU and NifU, potential iron-binding or cluster-assembly proteins. As with other
      yeast genes implicated in Fe/S protein assembly, deletion of either ISU1 or ISU2
      results in increased accumulation of iron within the mitochondria, loss of
      activity of the [4Fe-4S] aconitase enzyme, and suppression of oxidative damage in
      cells lacking cytosolic copper/zinc superoxide dismutase. Both genes are induced
      in strains expressing an activated allele of Aft1p, the iron-sensing
      transcription factor, suggesting that they are regulated by the iron status of
      the cell. Immunoblotting studies using an antibody directed against Escherichia
      coli IscU reveal that both Isu1p and Isu2p are localized primarily in the
      mitochondria and that Isu1p is the predominant form expressed under all growth
      conditions tested. The possible role of the Isu proteins in the assembly and/or
      repair of Fe/S clusters is discussed.

PMID- 10588896
TI  - The contribution of a zinc finger motif to the function of yeast ribosomal
      protein YL37a.
AB  - Eukaryotic ribosomes have a large number of proteins but the exact nature of
      their contribution to the structure and to the function of the particle is not
      known. Of the 78 proteins in yeast ribosomes, six have zinc finger motifs of the
      C2-C2 variety. Both genes encoding the essential yeast ribosomal protein YL37a,
      which has such a zinc finger motif, were disrupteXXPd. The double deletion, which
      is lethal, can be rescued with a plasmid-encoded copy of a YL37a gene. Mutations
      were constructed in a plasmid-encoded copy of YL37a; the mutations caused the
      cysteine residues in the motif (at positions 39, 42, 57 and 60) to be replaced,
      one at a time, with serine. The cysteine residue at position 39, the first of the
      four in the motif, is essential for the function of YL37a, since a C39S mutation
      did not complement the null phenotype. However, plasmids encoding variants with
      C42S, C57S, or C60S mutations in the zinc finger motif were able to rescue the
      null mutant. YL37a binds zinc, but none of the mutant proteins, C39S, C42S, C57S,
      or C60S, was able to bind the metal. Thus, all four cysteine residues are
      essential for the binding of zinc; only one, C39, is essential for the function
      of the ribosomal protein.

PMID- 10588897
TI  - kPROT: a knowledge-based scale for the propensity of residue orientation in
      transmembrane segments. Application to membrane protein structure prediction.
AB  - Modeling of integral membrane proteins and the prediction of their functional
      sites requires the identification of transmembrane (TM) segments and the
      determination of their angular orientations. Hydrophobicity scales predict
      accurately the location of TM helices, but are less accurate in computing angular
      disposition. Estimating lipid-exposure propensities of the residues from
      statistics of solved membrane protein structures has the disadvantage of relying
      on relatively few proteins. As an alternative, we propose here a scale of
      knowledge-based Propensities for Residue Orientation in Transmembrane segments
      (kPROT), derived from the analysis of more than 5000 non-redundant protein
      sequences. We assume that residues that tend to be exposed to the membrane are
      more frequent in TM segments of single-span proteins, while residues that prefer
      to be buried in the transmembrane bundle interior are present mainly in multi
      span TMs. The kPROT value for each residue is thus defined as the logarithm of
      the ratio of its proportions in single and multiple TM spans. The scale is
      refined further by defining it for three discrete sections of the TM segment;
      namely, extracellular, central, and intracellular. The capacity of the kPROT
      scale to predict angular helical orientation was compared to that of alternative
      methods in a benchmark test, using a diversity of multi-span alpha-helical
      transmembrane proteins with a solved 3D structure. kPROT yielded an average
      angular error of 41 degrees, significantly lower than that of alternative scales
      (62 degrees -68 degrees ). The new scale thus provides a useful general tool for
      modeling and prediction of functional residues in membrane proteins. A WWW server
      (http://bioinfo.weizmann.ac.il/kPROT) is available for automatic helix
      orientation prediction with kPROT.

PMID- 10588898
TI  - Tendency for local repetitiveness in amino acid usages in modern proteins.
AB  - Systematic analyses of human proteins show that neural and immune system
      specific, and therefore, relatively "modern" proteins have a tendency for
      repetitive use of amino acids at a local scale ( approximately 1-20 residues),
      while ancient proteins (human homologues of Escherichia coli proteins) do not.
      Those protein subsegments which are unique based on homology search account for
      the repetitiveness. Simulation shows that such repetitiveness can be maintained
      by frequent duplication on a very short scale (one to two codons) in the presence
      of substitutive point mutation, while the latter tends to mitigate the
      repetitiveness. DNA analyses also show the presence of cryptic (i.e. "out of the
      codon frame") repetitiveness, which cannot fully be explained by features in
      protein sequences. Simulative modification of the amino acid sequences of immune
      system-specific proteins estimate that 2.4 duplication events occur during the
      period equivalent to ten events of substitution mutation. It is also suggested
      that the repetitiveness leads to longitudinal unevenness within a given peptide
      domain. Those peptide motifs which contain similarly charged residues are likely
      to be generated more frequently in the presence of the tendency for
      repetitiveness than in its absence. Therefore, the neutral propensity of DNA for
      duplication, which can also tend to generate repetitiveness in amino acid
      sequences, seems to be manifested primarily when the constraints on amino acid
      sequences are relatively weak, and yet may be positively contributing to
      generation of unevenness in modern proteins.

PMID- 10588899
TI  - The effect of long-range loop-loop interactions on folding of the Tetrahymena
      self-splicing RNA.
AB  - Bas?e-pairing between the terminal loops of helices P2.1 and P9.1a (P13) and P2
      and P5c (P14) stabilize the folded structure of the Tetrahymena group I intron.
      Using native gel electrophoresis to analyze the folding kinetics of a natural pre
      RNA containing the Tetrahymena intron, we show that P13 and P14 are the only
      native loop-loop interactions among six possible combinations. Other base-pairing
      interactions of the loop sequences stabilize misfolded and inactive pre-RNAs.
      Mismatches in P13 or P14 raised the midpoints and decreased the cooperativity of
      the Mg(2+)-dependent eqXuilibrium folding transitions. Although some mutations in
      P13 resulted in slightly higher folding rates, others led to slower folding
      compared to the wild-type, suggesting that P13 promotes formation of P3 and P7.
      In contrast, mismatches in P14 increased the rate of folding, suggesting that
      base-pairing between P5c and P2 stabilizes intermediates in which the catalytic
      core is misfolded. Although the peripheral helices stabilize the native structure
      of the catalytic core, our results show that formation of long-range
      interactions, and competition between correct and incorrect loop-loop base-pairs,
      decrease the rate at which the active pre-RNA structure is assembled.

PMID- 10588900
TI  - Changes in side-chain and backbone dynamics identify determinants of specificity
      in RNA recognition by human U1A protein.
AB  - The ribonucleoprotein (RNP) domain is one of the most common eukaryotic protein
      domains, and is found in many proteins involved in recognition of a wide variety
      of RNAs. Two structures of RNA complexes of human U1A protein have revealed
      important aspects of RNP-RNA recognition, but have also raised intriguing
      questions concerning how RNP domains discriminate between different RNAs. In this
      work, we extend the investigation of U1A-RNA recognition by comparing the
      dynamics of U1A protein both free and in complex with RNA. We have also
      investigated the trimolecular complex between two U1A proteins and the complete
      polyadenylation inhibition element to study the effect of RNA-dependent protein
      protein interactions on protein conformational flexibility. We report that
      changes in backbone dynamics upon complex formation identify regions of the
      protein where conformational exchange processes are quenched in the RNA-bound
      conformation. Furthermore, amino acids whose side-chains experience significant
      changes in conformational flexibility coincide with residues particularly
      important for the specificity of the U1A protein/RNA interaction. This study adds
      a new dimension to the description of the coordinated changes in structure and
      dynamics that are critical to define the biological specificity of U1A and other
      RNP proteins.

PMID- 10588901
TI  - The energetics of HMG box interactions with DNA: thermodynamic description of the
      target DNA duplexes.
AB  - The thermal properties and energetics of formation of 10, 12 and 16 bp DNA
      duplexes, specifically interacting with the HMG box of Sox-5, have been studied
      by isothermal titration calorimetry (ITC) and differential scanning calorimetry
      (DSC). DSC studies show that the partial heat capacity of these short duplexes
      increases considerably prior to the cooperative process of strand separation.
      Direct extrapolation of the pre and post-transition heat capacity functions into
      the cooperative transition zone suggests that unfolding/dissociation of strands
      results in no apparent heat capacity increment. In contrast, ITC measurements
      show that the negative enthalpy of complementary strand association increases in
      magnitude with temperature rise, implying that strand association proceeds with
      significant decrease of heat capacity. Furthermore, the ITC-measured enthalpy of
      strand association is significantly smaller in magnitude than the enthalpy of
      cooperative unfolding measured by DSC. To resolve this paradox, the heat effects
      upon heating and cooling of the separate DNA strands have been measured by DSC.
      This showed that cooling of the strands from 100 degrees C to -10 degrees C
      proceeds with significant heat release associated with the formation of intra and
      inter-molecular interactions. When the enthalpy of residual structure in the
      strands and the temperature dependence of the heat capacity of the duplexes and
      of their unfolded strands have been taken into account, the ITC and DSC results
      are brought into agreement. The analysis shows that the considerable increase in
      heat capacity of the duplexes with temperature rise is due to increasing
      fluctuations of their structure (e.g. end fraying and twisting) and this effect
      obscures the heat capacity increment resulting from the cooperative separation of
      strands, which in fact amounts to 200(+/-40) JK(-1) (mol bp)(-1). Using this heat
      capacity increment, the averaged standard enthalpy, entropy and Gibbs energy of
      formation of fully folded duplexes from fully unfolded strands have been
      determined at 25 degrees C as -33(+/-2) kJ (mol bp)(-1), -93(+/-4) J K(-1) (mol
      bp)(-1) and -5.0(+/-0.5) kJ (mol bp)(-1), respectively.

PMID- 10588902
TI  - The energetics of HMG box interactions with DNA: thermodynamics of the DNA
      binding of the HMG box from mouse sox-5.
AB  - The energetics of the Sox-5 HMG box interaction with DNA duplexes, containing the
      recognition sequence AACAAT, were studied by fluorescence spectroscopy,
      isothermal titration calorimetry (ITC) and differential scanning calorimetry
      (DSC). Fluorescence titration showed that the association constant of this HMG
      box with the duplexes is of the order 4x10(7) M(-1), increasing somewhat with
      temperature rise, i.e. the Gibbs energy is -40 kJ mol(-1) at 5 degrees C,
      decreasing to -48 kJ mol(-1) at 32 degrees C. ITC measurements of the enthalpy of
      association over this temperature range showed an endothermic effect below 17
      degrees C and an exothermic effect above, suggesting a heat capacity change on
      binding of about -4 kJ K(-1) mol(-1), a value twice larger than expected from
      structural considerations. A straightforward interpretation of ITC data in heat
      capacity terms assumes, however, that the heat capacities of all participants in
      the association reaction do not change over the considered temperature range. Our
      previous studies showed that over the temperature range of the ITC experiments
      the HMG box of Sox-5 starts to unfold, absorbing heat and the heat capacities of
      the DNA duplexes also increase significantly. These heat capacity effects differ
      from that of the DNA/Sox-5 complex. Correcting the ITC measured binding
      enthalpies for the heat capacity changes of the components and complex yielded
      the net enthalpies which exhibit a temperature dependence of about -2 kJ K(-1)
      mol(-1), in good agreement with that predicted on the basis of dehydration of the
      protein-DNA interface. Using the derived heat capacity change and the enthalpy
      and Gibbs energy of association measured at 5 degrees C, the net enthalpy and
      entropy of association of the fully folded HMG box with the target DNA duplexes
      was determined over a broad temperature range. These functions were compared with
      those for other known cases of sequence specific DNA/protein association. It
      appears that the enthalpy and entropy of association of minor groove binding
      proteins are more positive than for proteins binding in the major groove. The
      observed thermodynamic characteristics of protein binding to the A+T-rich minor
      groove of DNA might result from dehydration of both polar and non-polar groups at
      the interface and release of counterions. The expected entropy of dehydration was
      calculated and found to be too large to be compensated by the negative entropy of
      reduction of translational/rotational freedom. This implies that DNA/HMG box
      association proceeds with significant decrease of conformational entropy, i.e.
      reduction in conformational mobility.

PMID- 10588903
TI  - DNA bending due to specific p53 and p53 core domain-DNA interactions visualized
      by electron microscopy.
AB  - We have used transmission electron microscopy to analyze the specificity and the
      extent of DNA bending upon binding of full-length wild-type human tumor
      suppressor protein p53 (p53) and the p53 core domain (p53CD) encoding amino acid
      residues 94-312, to linear double-stranded DNA bearing the consensus sequence 5'
      AGACATGCCTAGACATGCCT-3' (p53CON). Both proteins interacted with high specificity
      and efficiency with the recognition sequence in the presence of 50 mM KCl at low
      temperature ( approximately 4 degrees C) while the p53CD also exhibits a strong
      and specific interaction at physiological temperature. Specific complex formation
      did not result in an apparent reduction of the DNA contour length. The
      interaction of p53 and the p53CD with p53CON induced a noticeable salt-dependent
      bending of the DNA axis. According to quantitative analysis with folded Gaussian
      distributions, the bending induced by p53 varied from approximately 40 degrees to
      48 degrees upon decreasing of the KCl concentration from 50 mM to approximately 1
      mM in the mounting buffer used for adsorption of the complexes to the carbon film
      surface. The p53CD bent DNA by 35-37 degrees for all salt concentrations used in
      the mounting buffer. The bending angle of the p53/DNA complex under low salt
      conditions showed a somewhat broader distribution (sigma approximately 39 degrees
      ) than at high salt concentration (sigma approximately 31 degrees ) or for p53CD
      (sigma approximately 24-27 degrees ). Together, these results demonstrate that
      the p53CD has a dominant role in complex formation and that the complexes formed
      both by p53 and p53CD under moderate salt conditions are similar. However, the
      dependence of the bending parameters on ambient conditions suggest that the
      segments flanking the p53CD contribute to complex formation as well. The problems
      associated with the analysis of bending angles in electron microscopy experiments
      are discussed.

PMID- 10588904
TI  - Calcium-mediated thermostability in the subtilisin superfamily: the crystal
      structure of Bacillus Ak.1 protease at 1.8 A resolution.
AB  - Proteins of the subtilisin superfamily (subtilases) are widely distributed
      through many living species, where they perform a variety of processing
      functions. They are also used extensively in industry. In many of these enzymes,
      bound calcium ions play a key role in protecting against autolysis and thermal
      denaturation. We have determined the crystal structure of a highly thermostable
      protease from Bacillus sp. Ak.1 that is strongly stabilized by calcium. The
      crystal structure, determined at 1.8 A resolution (R=0. 182, Rfree=0.247),
      reveals the presence of four bound cations, three Ca(2+) and one Na(+). Two of
      the Ca(2+) binding sites, Ca-1 and Ca-2, correspond to sites also found in
      thermitase and the mesophilic subtilisins. The third calcium ion, however, is at
      a novel site that is created by two key amino acid substitutions near Ca-1, and
      has not been observed in any other subtilase. This site, acting cooperatively
      with Ca-1, appears to give substantially enhanced thermostability, compared with
      thermitase. Comparisons with the mesophilic subtilisins also point to the
      importance of aromatic clusters, reduced hydrophobic surface and constrained N
      and C termini in enhancing the thermostability of thermitase and Ak.1 protease.
      The Ak.1 protease also contains an unusual Cys-X-Cys disulfide bridge that
      modifies the active site cleft geometry.

PMID- 10588905
TI  - Structure and function of a new phosphopeptide-binding domain containing the FHA2
      of Rad53.
AB  - The forkhead-associated (FHA) domain is a 55-75 amino acid residue module found
      in >20 proteins from yeast to human. It has been suggested to participate in
      signal transduction pathways, perhaps via protein-protein interactions involving
      recognition of phosphopeptides. Neither the structure nor the ligand of FHA is
      known. Yeast Rad53, a checkpoint protein involved in DNA damage response,
      contains two FHA domains, FHA1 (residues 66-116) and FHA2 (residues 601-664), the
      second of which recognizes phosphorylated Rad9. We herein report the solution
      structure of an "FHA2-containing domain" of Rad53 (residues 573-730). The
      structure consists of a beta-sandwich containing two antiparallel beta-sheets and
      a short, C-terminal alpha-helix. Binding experiments suggested that the FHA2
      containing domain specifically recognizes pTyr and a pTyr-containing peptide from
      Rad9, and that the binding site involves residues highly conserved across FHA
      domains. The results, along with other recent reports, suggest that FHA domains
      could have pTyr and pSer/Thr dual specificity.

PMID- 10588906
TI  - Realistic modeling of the denatured states of proteins allows accurate
      calculations of the pH dependence of protein stability.
AB  - Computational techniques based on continuum electrostatics treatments have been
      successful in predicting and interpreting the pKa values of ionizable amino acids
      in folded proteins. Despite this progress, efforts to reproduce the pH-dependence
      of protein stability have met with only limited success: agreement with
      experimental results has been only qualitative. It has been argued previously
      that the most likely reason for discrepancies is the presence of residual
      electrostatic interactions in the unfolded state, which cause pKa values to be
      shifted from their model compound values. Here we show that by constructing
      atomistic models of the unfolded state with a simple molecular mechanics protocol
      that uses the native state as a starting point, much improved reproduction of pH
      effects on protein stability can be obtained. In contrast, when a fully extended
      model of the unfolded state is used, no such improvement is obtained, a result
      that suggests that local interactions with residues nearby in the sequence are
      not sufficient to properly account for the pKa shifts in the unfolded state. In
      comparison to model compound values, the pKa values of acidic residues in "native
      like" unfolded states are typically found to be shifted downwards by
      approximately 0.3 pH unit, in good agreement with the average downward shift
      deduced from experimental measurements. Given its success in the present
      situation, the protocol employed here for developing simple models of the
      unfolded state may prove useful in other computer simulation applications.

PMID- 10588907
TI  - Insertional mutation of orfD of the DCW cluster of Streptococcus pneumoniae
      attenuates virulence.
AB  - Mutational analysis of a 5.5 kb fragment of the genome Streptococcus pneumoniae
      led to the identification of a putative new virulence gene, designated orfD.
      Insertion mutagenesis of flanking genes on the fragment suggested that the
      corresponding gene products were required for in vitro growth. In contrast,
      insertion mutation of orfD did not alter in vitro growth or the transformability
      pattern of the mutated strain. However, it did reduce bacterial growth in mice
      and attenuated virulence in an intraperitoneal model of infection. orfD is
      flanked by orfC (63 codons) and ftsL (105 codons) and all three genes are
      upstream of pbpx. orfC showed no similarity with other known proteins. ftsL of S.
      pneumoniae exhibits minimal sequence similarity with ftsL of E. coli, but shares
      16% identical residues with the ftsL homologue encoded by ylld of B. subtilis.
      Also, ftsL of S. pneumoniae has a predicted topology similar to that described
      for ftsL of E. coli. Putative promoters with an extended -10 box could be
      identified upstream of both orfC or orfD. The four open reading frames (including
      pbpx) are orientated in the same direction, and polycistronic transcription could
      theoretically start at either promoter. Interestingly, this region shows
      organizational and sequence homologies with genes controlling division and cell
      wall biosynthesis (DCW) in other bacteria. The attenuation of virulence in the
      orfD insertion mutant might be due to the loss of function of the orfD gene
      product or to an altered level of expression of downstream genes.

PMID- 10588908
TI  - The Bpel locus encodes type III secretion machinery in Bordetella pertussis.
AB  - Type III secretory genes(Bscl, J, K, L, N and O) have recently been identified in
      Bordetella bronchiseptica and shown to be under the control of the BvgAS locus.
      We examined a 35 616 byte DNA sequence amplified from Bordetella pertussis Tohama
      I for homology with known type III secretory genes in Yersinia spp. and
      Pseudomonas sppand a total of 20 homologous open reading frames were detected.
      Putative type III secretion proteins in B. pertussis were designated according to
      their homology with type III secretion proteins in B. bronchiseptica, Yersinia
      and Pseudomonas. These ORFs were arranged in two putative operons, which together
      we have designated as the BpeI locus. The first spans nucleotides 23385-7888 and
      encodes the putative proteins LcrH1, BopD, BopB, LcfH2, BscI, BscJ, BscK, BscL,
      BscN, BscO, BscQ, BscR, BscS, BscT, BscU, and BscC, in this order. The second
      spans nucleotides 23580-29863 and encodes the putative proteins LcrE, LcrD, BscD
      and BscF, in this order. The homology of these proteins to type III secretory
      proteins was B. bronchiseptica (73-99%), Yersinia spp. (17-65%), Pseudomonas spp.
      (18-64%). The B. pertussis proteins were similar to their homologues in B.
      bronchiseptica, Yersinia and Pseudomonas in terms of length, molecular weight and
      isoelectric point. Coiled-coil domains were detected in putative translocation
      proteins, BopB and BopD. BopB and BopD were similar to each other, to the RTX
      toxin family and to cyaA, cyaB, cyaD and cyaE. The percentage G+C content of the
      sequence analysed was 66.16%, which is similar to the published percentage G+C
      (67-70%) for the B. pertussis chromosome.

PMID- 10588909
TI  - The Legionella pneumophila prp locus; required during infection of macrophages
      and amoebae.
AB  - Transposon mutagenesis was performed using mTn 10phoA to identify Legionella
      pneumophila genes that are expressed under certain in vitro conditions, and are
      required for intracellular replication. Of the 1653 PhoA fusions examined, 19
      PhoA(+)fusion mutants were isolated and screened for differential expression of
      fusion proteins after growth at 30 or 37 degrees C, in the presence of low iron,
      or increased magnesium concentrations. The mutants were examined for their
      cytopathogenicity and intracellular replication within U937 macrophage-like cells
      and the protozoan Hartmannella vermiformis. One of the mutants generated, BS10,
      was defective in its multiplication within U937 macrophage-like cells and H.
      vermiformis. The defect in BS10 was complemented with a cosmid clone containing
      the wild type locus. The open reading frame interrupted by the insertion was
      homologous to prpD of Salmonella typhimurium and mmgE of Bacillus subtilis.

PMID- 10588910
TI  - Expression of Vibrio cholerae zonula occludens toxin and analysis of its
      subcellular localization.
AB  - Vibrio cholerae elaborates zonula occludens toxin (Zot), a protein that increases
      the permeability of small intestinal mucosa by opening intercellular tight
      junctions. The zot gene is located, together with the genes encoding CT and Ace
      enterotoxins, within the genome of V. cholerae filamentous phage CTXsmall ef,
      Cyrillic. Interestingly, Zot appears to be structurally and functionally related
      to the gene I product of other filamentous phages and it has been shown to be
      required for CTXsmall ef, Cyrillic morphogenesis. In this study we described the
      cloning of zot in several expression plasmid systems and we examined the
      subcellular localization of Zot by using affinity purified anti-Zot antibodies.
      We found that Zot localizes in the V. cholerae cell envelope with M(r);45 kDa
      which is consistent with the predicted primary translation product from the first
      methionine of zot (44.8 kDa). A second molecule, corresponding to the 33 kDa N
      terminal region of Zot, was also detected. Both molecules are exposed at the
      bacterial cell surface. The production of the 33 kDa Zot, that might represent a
      processing product, was abolished in mutant ZotG59. N-terminal tagged 6xHis-Zot
      fusion protein retained the capability to reach the outer membrane and the 6xHis
      tag was not cleaved off during the translocation to the periplasm, whereas the
      presence of the tag partially blocked the formation of the 33 kDa molecule. Zot
      secretion and anchorage to the bacterial outer membrane was also observed in E.
      coli strains expressing Zot, suggesting that the toxin may be directed to the
      outer membrane via the same pathway in E. coli and V. cholerae. Zot cleavage
      might be due to a V. cholerae specific protease activity, since the 33 kDa
      protein was not efficiently produced in E. coli. On the basis of these data and
      Zot amino acid sequence analysis, we suggest that while the N-terminal part of
      the molecule is involved in the morphogenesis of CTXsmall ef, Cyrillic, the C
      terminal region might carry the domain(s) responsible for Zot enterotoxic
      activity.

PMID- 10588911
TI  - Either a CD4(+)or CD8(+)T cell function is sufficient for clearance of infectious
      virus from trigeminal ganglia and establishment of herpes simplex virus type 1
      latency in mice.
AB  - Following ocular infection of normal mice, herpes simplex virus type 1 (HSV-1)
      establishes a latent infection in the trigeminal ganglia (TG) with the complete
      absence of detectable infectious virus. In this study, the role of CD4(+)and
      CD8(+)T cell dependent immune responses is examined in relation to clearing
      infectious virus from the TG following HSV-1 ocular challenge. Nude mice, which
      lack T cells, and MHC(o/o)mice, which lack both MHC class I and MHC class II,
      were challenged ocularly with wild-type HSV-1. Over 70% of the TG from mice
      surviving the infection contained infectious virus, indicative of a chronic
      infection in these TG, rather than a latent infection. No infectious virus was
      detected in TGs from infected C57BL/6 parental mice. Ocular challenge of
      CD4(o/o)A(beta(o/o, CD8(o/o)or beta(2)m(o/o)mice resulted in latent rather than
      chronic infection. Similarly, when C57BL/6 mice were depleted for CD4(+)or
      CD8(+)T cells from 4 days before ocular challenge to 26 days after ocular
      challenge, no free virus was detected in TGs of challenged mice. In contrast,
      when mice were depleted of both their CD4(+)and CD8(+)T cells, over 90% of TGs
      were positive for free virus, suggesting that the lack of virus clearance was due
      to the combined lack of both CD4(+)T cells and CD8(+)T cells (i.e. in the
      presence of either CD4(+)T cells or CD8(+)T cells alone all of the infectious
      virus was cleared and latency was established).))

PMID- 10588912
TI  - The effect of canine macrophages on the adherence and growth of Blastomyces
      dermatitidis yeast: evidence of a soluble factor that enhances the growth of B.
      dermatitidis yeast.
AB  - Blastomycosis is a medically important systemic fungal infection of dogs and
      humans. Phagocytic cells are the first line of cellular defence against B.
      dermatitidis, and are a prominent feature in the lesions and exudate of canine
      blastomycosis. The adherence of B. dermatitidis yeast to canine phagocytes, and
      the effects of such adherence on the growth of B. dermatitidis yeast, has not
      been previously reported. The results of this study demonstrate that canine
      complement enhances the adherence of B. dermatitidis yeast to canine macrophages.
      Initiation of the canine complement cascade by B. dermatitidis yeast appeared to
      occur predominantly by the classical pathway. Adherence of B. dermatitidis yeast
      to canine macrophages enhanced the growth of the yeast. In the absence of
      macrophages, this effect could be duplicated by incubating yeast in conditioned
      medium from co-cultures of macrophages and yeast. This observation suggests that
      a soluble factor is involved in the growth enhancement of the yeast, These
      findings provide new insights into the adherence of B. dermatitidis yeast to
      canine macrophages, and how adherence influences the proliferation of B.
      dermatitidis yeast.

PMID- 10588913
TI  - Identification of genes in a KG- phenotype of Lactococcus garvieae, a fish
      pathogenic bacterium, whose proteins react with antiKG- rabbit serum.
AB  - Five different clones (SA1B05, SA1B10, SA2F01, SA8A11 and SA9H10) were isolated
      from the gene library of the Lactococcus garvieae SA8201 (KG-) strain by
      immunological screening using rabbit serum against L. garvieae (KG-) phenotype
      cells. A Western blot analysis indicated that the molecular sizes of
      immunologically detected proteins of SA1B05, SA1B10, SA2F01, SA8A11 and SA9H10,
      which were fused with LacZ protein, were 25, 30, 28, 26 and 13 kDa, respectively.
      The amino acid sequences of the immunologically detected proteins of SA1B05,
      SA1B10, SA2F01 and SA8A11 were homologous to a processing protease of Bacillus
      subtilis (36.6%), dihydropteroate synthase of Escherichia coli (34.6%), trigger
      factor of B. subtilis (45.8%) and N-acetylglucosamine-6-phosphate deacetylase of
      Vibrio furnissii (37.1%), respectively. There was no significant homologous
      sequence of SA9H10 in DDBJ/EMBL/GenBank and SwissProt. We cloned and sequenced a
      longer DNA fragment (SA9H10L) of SA9H10 from the gene library. The predicted
      amino acid sequence of this clone was weak homology to M protein of Streptococcus
      pyogenes (22.7%). Five genes were specifically expressed in the KG- phenotype
      strains. However, SA8A11 and SA9H10 was expressed in the mutated strain SA8201
      TTC, whose serological phenotype was changed from KG- to KG+ by 2,3,5
      triphenyltetrazolium chloride.

PMID- 10588915
TI  - Volume contents and index

PMID- 10588914
TI  - Live Bartonella henselae enhances endothelial cell proliferation without direct
      contact.
AB  - The proliferation of human umbilical vein endothelial cells (HUVECs) cocultivated
      with live B. henselae was enhanced in a bacterial dose-dependent manner, and the
      stimulatory effect was specific to vascular endothelial cells. The inactivation
      of B. henselae by UV or heat treatment abolished its stimulatory activity,
      suggesting that live bacteria is necessary for the growth stimulation effect. To
      investigate the role of direct contact, live B. henselae were separated from
      HUVECs by a filter membrane (Millicell-CM insert). Even under this condition, an
      enhanced proliferation of HUVECs was observed. However, no morphological changes
      in the HUVECs were apparent compared to the B. henselae -infected cells.
      Furthermore, we isolated a nonpiliated strain of B. henselae that is unable to
      attach to and enter into endothelial cells. The nonpiliated strain possessed the
      ability to stimulate the proliferation of cocultivated HUVECs the same as the
      piliated strain. Moreover, the culture supernatants of B. henselae were also able
      to induce HUVEC proliferation. Our results indicate that the stimulation of HUVEC
      proliferation by B. henselae is mediated by soluble factor(s) secreted from the
      bacteria.

PMID- 10588916
TI  - Functional group I metabotropic glutamate receptors in submucous plexus of guinea
      pig ileum.
AB  - Intracellular recording methods and immunostaining revealed the existence of
      functional group I metabotropic glutamate receptors (mGluRs) in submucous plexus
      neurons of guinea-pig ileum. Selective group I, but not groups II or III
      metabotropic glutamate receptor agonists induced concentration-dependent, slowly
      activating depolarizing responses. Group I metabotropic glutamate receptor
      antagonism observed with (S)-4-carboxyphenylglycine (S-4-CPG) (100 - 600 microM)
      was competitive as determined by Schild analysis (pA(2)=3.81+/-0.02). Neither the
      group II and III metabotropic nor ionotropic glutamate receptor antagonists
      altered responses evoked by group I receptor agonists. Immunoreactivities for
      metabotropic glutamate 1alpha and 5 receptors were found to locate exclusively in
      neurons in the submucous plexus of guinea-pig ileum with the highest density
      around the cell bodies. The results suggest that group I metabotropic glutamate
      receptors are functionally expressed in the submucous plexus of guinea-pig small
      intestine.

PMID- 10588917
TI  - Functional and electrophysiological effects of a novel imidazoline-based K(ATP)
      channel blocker, IMID-4F.
AB  - 1. The functional and electrophysiological effects of IMID-4F (2-[N-(2, 6
      dichlorophenyl)-N-(4-flurorobenzyl)amino]imidazoline), a fluoro-benzyl derivative
      of clonidine, on vascular K(ATP) channels were investigated. In pig coronary
      artery, IMID-4F inhibited the vasorelaxation response to the K(ATP) channel
      opener levcromakalim with a pK(B) value of approximately 7.1. IMID-4F (30 microM)
      did not affect the vasorelaxation response to sodium nitroprusside (SNP). 2. In
      rat mesenteric artery smooth muscle cells IMID-4F (1 - 10 microM) caused a
      concentration-dependent depolarization of membrane potential. IMID-4F (10 microM)
      abolished the hyperpolarizing effects of levcromakalim (10 microM). 3. In patch
      clamp experiments using rat mesenteric artery smooth muscle cells, K(ATP) channel
      currents induced by levcromakalim (10 microM) were inhibited by IMID-4F (0.3 - 3
      microM) in a concentration-dependent manner. The calculated IC(50) for IMID-4F
      inhibiting K(ATP) channel current was approximately 0.8 microM. 4. Radioligand
      binding studies using bovine aortic smooth muscle cell membranes showed that IMID
      4F (30 microM) did not displace binding to the K(ATP) channel opener [(3)H]
      P1075. However, both levcromakalim (10 microM) and glibenclamide (10 microM)
      caused significant displacement of [(3)H]-P1075. 5. These studies show that the
      imidazoline compound IMID-4F is one of the most potent antagonists of arterial
      K(ATP) channels identified. Vasorelaxation, hyperpolarization and K(+) currents
      through K(ATP) channels were all inhibited by IMID-4F at micromolar
      concentrations. Radioligand binding studies indicate that IMID-4F does not bind
      to the same site as levcromakalim or as glibenclamide. Considering other
      evidence, it is likely that IMID-4F acts by interacting directly with the pore of
      the K(IR) channel, rather than through the sulphonylurea subunit of the K(ATP)
      channel complex.

PMID- 10588918
TI  - Vascular kinin B(1) and B(2) receptor-mediated effects in the rat isolated
      perfused kidney - differential regulations.
AB  - 1. Bradydykinin (BK) and analogs acting preferentially at kinin B(1) or B(2)
      receptors were tested on the rat isolated perfused kidney. Kidneys were perfused
      in an open circuit with Tyrode's solution. Kidneys preconstricted with
      prostaglandin F(2alpha) were used for the analysis of vasodilator responses. 2.
      BK induced a concentration-dependent renal relaxation (pD(2)=8.9+/-0.4); this
      vasodilator response was reproduced by a selective B(2) receptor agonist,
      Tyr(Me)(8)-BK (pD(2)=9.0+/-0.1) with a higher maximum effect (E(max)=78.9+/-6.6
      and 55.8+/-4.3% of ACh-induced relaxation respectively, n=6 and 19, P<0.02).
      Icatibant (10 nM), a selective B(2) receptor antagonist, abolished BK-elicited
      relaxation. Tachyphylaxis of kinin B(2) receptors appeared when repeatedly
      stimulated at 10 min intervals. 3. Des-Arg(9)-BK, a selective B(1) receptor
      agonist, induced concentration-dependent vasoconstriction at micromolar
      concentration. Maximum response was enhanced in the presence of lisinopril (1
      microM) and inhibited by R 715 (8 microM), a selective B(1) receptor antagonist.
      Des-Arg(9)-[Leu(8)]-BK behaved as an agonist. 4. A contractile response to des
      Arg(9)-BK occurred after 1 of perfusion and increased with time by a factor of
      about three over a 3 h perfusion. This post-isolation sensitization to des-Arg(9)
      BK was abolished by dexamethasone (DEX, 30 mg kg(-1) i.p., 3 h before the start
      of the experiment and 10 microM in perfusate) and actinomycin D (2 microM). Acute
      exposure to DEX (10 microM) had no effect on sensitized des-Arg(9)-BK response,
      in contrast to indomethacin (30 microM) that abolished it. DEX pretreatment
      however had no effect on BK-induced renal vasodilation. 5. Present results
      indicate that the main renal vascular response to BK consists of relaxation
      linked to the activation of kinin B(2) receptors which rapidly desensitize. Renal
      B(1) receptors are also present and are time-dependently sensitized during the in
      vitro perfusion of the rat kidneys.

PMID- 10588919
TI  - Stereoselective central nervous system effects of the R- and S-isomers of the
      GABA uptake blocker N-(4, 4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid in
      the rat.
AB  - 1. The 'effect compartment' model was applied to characterize the
      pharmacodynamics of the R- and S-isomers of tiagabine in conscious rats in vivo
      using increase in the beta activity of the EEG as a pharmacodynamic endpoint. 2.
      No pharmacokinetic differences in plasma were observed between R- and S
      tiagabine. The values for clearance and volume of distribution at steady-state
      were 103+/-10 versus 90+/-6 ml min(-1) kg(-1) and 1.8+/-0.2 versus 1.6+/-0.2 l
      kg(-1) for the R- and S-isomer, respectively. In contrast, plasma protein binding
      showed a statistically significant difference with values of the free fraction of
      5.7+/-0.5 and 11.4+/-0.6%. In addition the rate constant for transport to the
      effect compartment was also different with values of 0.027 versus 0.067 min(-1).
      3. For both isomers the relationship between concentration and EEG effect was non
      linear and successfully characterized on basis of the Hill equation. A
      statistically significant difference in the value of EC(50) of 328+/-11 versus
      604+/-18 ng ml(-1) was observed for R- and S-tiagabine respectively. The values
      of the other pharmacodynamic parameters were identical. 4. It is concluded that
      the differences in in vivo pharmacodynamics of R- and S-tiagabine can be
      explained by stereoselective differences in both the affinity to the GABA-uptake
      transporter and the degree of non-specific protein binding in plasma and at the
      effect site.

PMID- 10588921
TI  - A novel anti-diabetic drug, miglitol, markedly reduces myocardial infarct size in
      rabbits.
AB  - 1. We examined whether N-hydroxyethyl-1-deoxynojirimycin (miglitol), a new human
      anti-diabetic drug with effects to inhibit alpha-1, 6-glucosidase glycogen
      debranching enzyme and reduce the glycogenolytic rate as well as to inhibit alpha
      1,4-glucosidase, could reduce infarct size in the rabbit heart. Rabbits were
      subjected to 30-min coronary occlusion followed by 48-h reperfusion. 2. The
      infarct size as a percentage of area at risk was not reduced by pre-ischaemic
      treatment with 1 mg kg(-1) miglitol (42.7+/-4.0%, n=10) compared with the saline
      control group (41.7+/-2.3%, n=10). However, it was significantly and dose
      dependently reduced by pre-ischaemic treatment with 5 or 10 mg kg(-1) of miglitol
      (25.7+/-4. 5%, n=10, and 14.6+/-2.4%, n=10, respectively) without altering the
      blood pressure, heart rate or blood glucose level. However, there was no evidence
      of an infarct-size reducing effect after pre-reperfusion treatment with 10 mg kg(
      1) of miglitol (35.0+/-3.0%, n=10). 3. Another 40 rabbits given 1, 5 and 10 mg
      kg(-1) of miglitol or saline before ischaemia (n=10 in each) were sacrificed at
      30 min of ischaemia for biochemical analysis. Miglitol preserved significantly
      the glycogen content, and attenuated significantly the lactate accumulation in a
      dose dependent manner in the ischaemic region at 30 min of ischaemia. 4. Pre
      ischaemic treatment, but not pre-reperfusion treatment, with miglitol markedly
      reduced the myocardial infarct size, independently of blood pressure and heart
      rate. A dose-dependent effect of miglitol on infarct size, glycogenolysis and
      lactate formation suggests that the mechanism may be related to the inhibition of
      glycogenolysis. Thus, miglitol may be beneficial for coronary heart disease as
      well as diabetes mellitus.

PMID- 10588922
TI  - Intracellular pH alterations induced by tacrine in a rat liver biliary epithelial
      cell line.
AB  - 1. The effects of tacrine (THA) on intracellular pH (pH(i)) were examined in a
      rat liver biliary epithelial cell line (RLEC) in HEPES-buffered medium. pH(i) was
      recorded using the pH-sensitive fluoroprobe, carboxy-SNARF-1 (carboxy
      seminaphtorhodafluor). 2. In the steady state, short-term exposures to THA
      resulted in alkalinization and re-acidification at 0.1 and 0.25 mM. Following a
      24 h-treatment, no significant difference in pH(i) could be detected at 0.1 and
      0.25 mM THA, whereas at 0.05 mM, pH(i) was slightly more acid (7.17+/-0. 02, n=16
      versus 7.21+/-0.02, n=24 [control]). 3. In control and short-term treated cells,
      intracellular intrinsic buffering power (beta(i)) increased roughly linearly as
      pH(i) decreased. This dependence was not seen following long-term treatment. In
      all cases, beta(i) was increased by THA (by 1.6 to 3.5 fold). 4. Following an
      acid load (induced by 20 mM NH(4)Cl removal), pH(i) recovery in RLEC relied upon
      Na(+)/H(+) exchange. A short-term treatment (0.25 mM THA) did not affect total
      acid extrusion. In contrast, a 24 h-treatment with 0.05 mM THA reduced it (by
      approximately 36% at a pH(i) of 6.73) while at 0.25 mM, a large increase was
      detected (by approximately 109% at a pH(i) of 6.75). In Na(+)-free medium, THA
      (0. 25 mM) still induced an alkalinization in the steady state. Following an acid
      load, THA stimulated a Na(+)-independent acid efflux in a dose-dependent manner,
      inhibitable by alpha-cyano-4-hydroxy cinnamate (CHC, 4 mM) but not by quercetin
      (0. 125 mM). 6. In conclusion, this work demonstrates that THA affects pH(i) in
      RLEC, through a decrease in Na(+)/H(+) exchange and an increase in beta(i).
      Stimulation of a CHC-inhibitable, Na(+)-independent acid efflux is also detected.

PMID- 10588920
TI  - Selective cyclo-oxygenase-2 inhibitors aggravate ischaemia-reperfusion injury in
      the rat stomach.
AB  - 1. Effects of indomethacin, the selective cyclo-oxygenase (COX)-2 inhibitors NS
      398 and DFU, and dexamethasone on gastric damage induced by 30 min ischaemia
      followed by 60 min reperfusion (I-R) were investigated in rats. Modulation of
      gastric levels of COX-1 and COX-2 mRNA by I-R was evaluated using Northern blot
      and reverse transcription-polymerase chain reaction. 2. I-R-induced gastric
      damage was dose-dependently aggravated by administration of indomethacin (1 - 10
      mg kg(-1)), NS-398 (0.4 - 4 mg kg(-1)) or DFU (0.02 - 2 mg kg(-1)) as assessed
      macroscopically and histologically. 3. Likewise, administration of dexamethasone
      (1 mg kg(-1)) significantly increased I-R damage. 4. Low doses of 16, 16-dimethyl
      prostaglandin(PG)E(2), that did not protect against ethanol-induced mucosal
      damage, reversed the effects of the selective COX-2 inhibitors, indomethacin and
      dexamethasone. 5. I-R had no effect on gastric COX-1 mRNA levels but increased
      COX-2 mRNA levels in a time-dependent manner. Dexamethasone inhibited the I-R
      induced expression of COX-2 mRNA. 6. I-R was not associated with a measurable
      increase in gastric mucosal formation of 6-keto-PGF(1alpha) and PGE(2). PG
      formation was substantially inhibited by indomethacin (10 mg kg(-1)) but was not
      significantly reduced by NS-398 (4 mg kg(-1)), DFU (2 mg kg(-1)) or dexamethasone
      (1 mg kg(-1)). 7. The findings indicate that selective COX-2 inhibitors and
      dexamethasone markedly enhance gastric damage induced by I-R. Thus, whereas COX-2
      has no essential role in the maintenance of gastric mucosal integrity under basal
      conditions, COX-2 is rapidly induced in a pro-ulcerogenic setting and contributes
      to mucosal defence by minimizing injury. This suggests that in certain situations
      selective COX-2 inhibitors may have gastrotoxic effects.

PMID- 10588923
TI  - Cardioprotection by the phytoestrogen genistein in experimental myocardial
      ischaemia-reperfusion injury.
AB  - 1. Soybean phytoestrogens have no oestrogen agonist effects on the reproductive
      system and therefore it is reasonable to explore the potential of these naturally
      occurring plant oestrogens in the cardiovascular pathology. We therefore
      investigated the effects of genistein in a rat model of myocardial ischaemia
      reperfusion injury. 2. Anaesthetized rats were subjected to total occlusion (45
      min) of the left main coronary artery followed by 5 h reperfusion (MI/R). Sham
      operated rats were used as controls. Myocardial necrosis, myocardial
      myeloperoxidase activity (MPO), serum creatinine phosphokinase activity (CPK),
      serum and macrophage Tumour Necrosis Factor-alpha (TNF-alpha), cardiac
      intercellular adhesion molecule-1 (ICAM-1) immunostaining, cardiac mRNA for ICAM
      1 evaluated by the means of reverse transcriptase polymerase chain reaction (RT -
      PCR), ventricular arrhythmias and myocardial contractility (left ventricle
      dP/dt(max)) were evaluated. 3. Myocardial ischaemia and reperfusion in untreated
      rats produced marked myocardial necrosis, increased serum CPK activity and MPO
      activity both in the area-at-risk and in the necrotic area, reduced myocardial
      contractility, caused ventricular arrhythmias and induced a marked increase in
      serum and macrophage TNF-alpha. Furthermore myocardial ischaemia-reperfusion
      injury increased ICAM-1 expression in the myocardium. 4. Administration of
      genistein (1 mg kg(-1), i.v., 5 min after coronary artery occlusion) lowered
      myocardial necrosis and MPO activity in the area-at-risk and in the necrotic
      area, decreased serum CPK activity, increased myocardial contractility, decreased
      the occurrence of ventricular arrhythmias, reduced serum and macrophages levels
      of TNF-alpha and blunted ICAM-1 expression in the injured myocardium. Finally
      genistein added in vitro to peritoneal macrophages collected from untreated rats
      subjected to myocardial ischaemia-reperfusion injury significantly reduced TNF
      alpha production. 5. Our data suggest that genistein limits the inflammatory
      response and protects against myocardial ischaemia-reperfusion injury.

PMID- 10588924
TI  - Facilitation by 8-OH-DPAT of passive avoidance performance in rats after
      inactivation of 5-HT(1A) receptors.
AB  - 1. Pretraining administration of 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT
      0.1 mg kg(-1)), a 5-HT(1A) receptor agonist, or buspirone (1 mg kg(-1)), a 5
      HT(1A) receptor partial agonist, markedly impaired passive avoidance retention in
      rats 24 h later. The effect of 8-OH-DPAT was prevented by the 5-HT(1A) receptor
      antagonists, NAN-190 and WAY-100635, at doses without any intrinsic effect. 2. N
      ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ 10 mg kg(-1)), an alkylating
      agent that inactivates different G-protein coupled receptors, impaired retention
      performance when given 48 h pretraining. The disruptive effect of EEDQ was
      reversed by 8-OH-DPAT or buspirone, given 30 min before training. 3. Non-specific
      actions did not account for 8-OH-DPAT-induced reversal of the EEDQ effect since
      no significant difference in locomotor activity or in pain threshold was found
      between rats receiving EEDQ or EEDQ+8-OH-DPAT. 4. When NAN-190 (1 mg kg(-1)) or
      WAY-100635 (0.5 mg kg(-1)) were given before 8-OH-DPAT to EEDQ-pretreated
      animals, the reversal by 8-OH-DPAT of EEDQ-induced retention impairment was still
      more pronounced. However, no EEDQ reversal by 8-OH-DPAT was found when 5-HT(1A)
      receptors were protected by WAY-100635 (10 mg kg(-1)) 30 min before EEDQ. 5. In
      the hippocampus of EEDQ-treated rats, 5-HT(7) receptors were less inactivated
      than 5-HT(1A) receptors and significant increases were found in 5-HT(1A) but not
      in 5-HT(7) receptor mRNA levels. Ritanserin and methiothepin (10 mg kg(-1) each),
      antagonists with higher affinity at 5-HT(7) than at 5-HT(1A) receptors, prevented
      the retention impairment induced by EEDQ but did not significantly protect
      against 5-HT(7) receptor inactivation. 6. The results indicate that the
      facilitatory effect of 8-OH-DPAT is not mediated through 5-HT(1A) receptors and
      suggest that other 8-OH-DPAT-sensitive receptors could be involved in the dual
      effect of 8-OH-DPAT on passive avoidance performance in rats.

PMID- 10588925
TI  - An anti-platelet agent, OPC-29030, inhibits translocation of 12-lipoxygenase and
      12-hydroxyeicosatetraenoic acid production in human platelets.
AB  - 1. In human platelets, arachidonic acid is mainly metabolized by the two enzyme
      systems; cyclo-oxygenase and 12-lipoxygenase. Cyclo-oxygenase produces
      prostaglandin H(2) which is further converted to thromboxane B(2). 12
      Lipoxygenase synthesizes 12(S)-hydroperoxyeicosatetraenoic acid which is reduced
      to 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). 2. An anti-platelet compound,
      OPC-29030, dose-dependently inhibited 12(S)-HETE production with an IC(50) of
      0.06+/-0.01 microM, but not synthesis of thromboxane B(2) in human platelets.
      Although the compound suppressed 12(S)-HETE production in human platelets,
      cytosolic 12-lipoxygenase activity was not inhibited up to 10 microM. Essentially
      identical data were obtained with a 12-lipoxygenase of human erythroleukaemia
      cells which had megakaryocyte/platelet-like properties. 3. OPC-29030 also
      suppressed production of 5(S)-HETE, a 5-lipoxygenase product, in rat basophilic
      leukaemia cells without inhibiting enzyme activity. It has been shown that 5
      lipoxygenase binds to membrane 5-lipoxygenase-activating protein (FLAP) to
      produce 5(S)-HETE, and thus FLAP inhibitor suppresses cellular 5(S)-HETE
      production. 4. A FLAP inhibitor, L-655,238, suppressed platelet 12(S)-HETE
      production, but had no effect on the 12-lipoxygenase activity. 5. Western blot
      analysis showed that platelet 12-lipoxygenase translocated from cytosol to
      membranes upon thrombin stimulation, and OPC-29030 suppressed this process in a
      dose-dependent manner. 6. These results suggest that the 12-lipoxygenase of human
      platelets binds to FLAP or a similar protein, and OPC-29030 suppresses 12(S)-HETE
      production by inhibiting a certain step of the 12-lipoxygenase translocation.

PMID- 10588926
TI  - alpha(2)-adrenoceptor and NPY receptor-mediated contractions of porcine isolated
      blood vessels: evidence for involvement of the vascular endothelium.
AB  - 1. Enhanced contractions to the alpha(2)-adrenoceptor agonist UK14304 and
      neuropeptide Y (NPY) in the porcine ear artery can be uncovered by
      pharmacological manipulation. The aim of this study was to determine whether
      similar pharmacological manipulation can uncover enhanced contractions in the
      porcine splenic artery, and to determine whether the endothelium modulates these
      responses. 2. UK14304 (0.3 microM) and NPY (0.1 microM) produced small
      contractions of the porcine splenic artery. After pre-contraction of the tissue
      with U46619, followed by relaxation with forskolin, the responses to both UK14304
      and NPY were enhanced. Enhanced contractions to both UK14304 and NPY were also
      obtained after relaxation with SNP. These results demonstrate that, as in the
      porcine ear artery, alpha(2)-adrenoceptors and NPY receptors are able to produce
      enhanced contractile responses through both adenylyl cyclase-dependent and 
      independent signal transduction pathways. 3. Removal of the endothelium had no
      significant effect on responses to UK14304 either alone or in the presence of
      U46619 and forskolin in the porcine splenic artery. On the other hand, responses
      to UK14304 after relaxation with SNP were reduced after endothelium-denudation in
      both the porcine splenic artery and ear artery. Similar results were obtained
      with NPY in the porcine ear artery. 4. In conclusion, enhanced contractile
      responses to UK14304 and NPY in the porcine splenic artery can be uncovered using
      methods similar to those employed in the porcine ear artery. Under certain
      conditions the responses to both agents are modulated by the endothelium. These
      data highlight further the similarities in the signal transduction pathways used
      by both alpha(2)-adrenoceptors and NPY receptors to induce vasoconstriction.

PMID- 10588927
TI  - PF9404C, a new slow NO donor with beta receptor blocking properties.
AB  - 1. PF9404C is the S-S diesteroisomer of a novel blocker of beta adrenergic
      receptors with vasodilatory properties. It causes a concentration-dependent
      relaxation of rat aorta helical strips pre-contracted with 10(-6) M noradrenaline
      (NA; IC(50) 33 nM). It was equipotent to nitroglycerin (NTG; IC(50) 49 nM), but
      much more potent than isosorbide dinitrate (ISD; IC(50) 15,000 nM). 2.
      Oxyhaemoglobin (10 microM) shifted to the right the concentration-response curve
      for the relaxation induced by PF9404C (IC(50) 530 nM) or NTG (IC(50) 61 nM). 3.
      Either methylene blue (MB) or ODQ (1 microM each) largely prevented the
      vasorelaxing responses to increasing concentrations of PF9404C or NTG. 4. In rat
      aorta smooth muscle cells, PF9404C increased the formation of cyclic GMP from 3
      pmol mg(-1) protein in basal conditions, to 53 pmol mg(-1) protein in 10 microM
      PF9404C. Neither metoprolol nor carvedilol enhanced cyclic GMP. 5. In the
      electrically driven guinea-pig left atrium, PF9404C blocked the inotropic effects
      of isoprenaline in a concentration-dependent manner. Its IC(50) (30 nM) was
      similar to that for S-propranolol (22.4 nM) and lower than the IC(50)s for
      metoprolol (120 nM) and atenolol (192 nM). The beta-adrenergic ligand (-)-[(3)H]
      CGP12177 (0.2 nM) was displaced from its binding to rat brain membranes with K(i)
      of 7 nM, 17 nM, 170 nM and 1.2 microM respectively for PF9404C, S-(-)propranolol,
      metoprolol, and atenolol. 6. The data are consistent with the idea that the S-S
      diesteroisomer PF9404C, is a potent vasorelaxing agent, as well as a blocker of
      cardiac beta adrenergic receptors. The mechanism of its vasorelaxing effects
      involves the slow generation of NO. This molecule can, therefore, exhibit
      antihypertensive and cardioprotective actions through a double mechanism, NO
      donation and beta blockade.

PMID- 10588929
TI  - Bepridil differentially inhibits two delayed rectifier K(+) currents, I(Kr) and
      I(Ks), in guinea-pig ventricular myocytes.
AB  - 1. We investigated the effects of bepridil on the two components of the delayed
      rectifier K(+) current, i.e., the rapidly activating (I(Kr)) and the slowly
      activating (I(Ks)) currents using tight-seal whole-cell patch-clamp techniques in
      guinea-pig ventricular myocytes, under blockade of L-type Ca(2+) current with
      nitrendipine (5 microM) or D600 (1 microM). 2. Bepridil decreased I(Ks) under
      blockade of I(Kr) with E4031 (5 microM), in a concentration-dependent manner. The
      concentration-dependent inhibition of I(Ks) by bepridil was fitted by a curve,
      assuming one-to-one interactions between the channel and the drug molecule. The
      concentration of half-maximal inhibition (IC(50)) was found to be 6.2 microM. 3.
      The effect of bepridil on I(Kr) was assessed using an envelope-of-tails test. In
      the control condition, a ratio of the tail current to the time-dependent current
      measured during depolarization was large (>1) at shorter pulses (<200 ms), and it
      decreased to a steady state value of approximately 0.4 with increases in the
      pulse duration. Bepridil at a concentration of 2 microM did not decrease this
      ratio at shorter pulses. 4. In a short-pulse (duration=50 ms) experiment that
      largely activates I(Kr), the drug was found to block I(Kr) in a cooperative
      manner (Hill coefficient=3.03) and the IC(50) was 13.2 microM. 5. These results
      suggest that bepridil at a clinical therapeutic concentration ( approximately 2
      microM) selectively blocks I(Ks) but does not inhibit I(Kr). This may relate to
      the characteristic frequency-dependent effects of bepridil on the action
      potential duration (APD), e.g., the non-reverse use-dependent prolongation of
      APD.

PMID- 10588928
TI  - (-)1-(Benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective enhancer of
      the impulse propagation mediated release of catecholamines and serotonin in the
      brain.
AB  - 1. The brain constituents beta-phenylethylamine (PEA) and tryptamine enhance the
      impulse propagation mediated transmitter release (exocytosis) from the
      catecholaminergic and serotoninergic neurons in the brain
      ('catecholaminergic/serotoninergic activity enhancer, CAE/SAE, effect'). (
      )Deprenyl (Selegiline) and (-)1-phenyl-2-propylaminopentane [(-)PPAP] are
      amphetamine derived CAE substances devoid of the catecholamine releasing
      property. 2. By changing the aromatic ring in PPAP we developed highly potent and
      selective CAE/SAE substances, structurally unrelated to the amphetamines. Out of
      65 newly synthetized compounds, a tryptamine derived structure, (-)1-(benzofuran
      2-yl)-2-propylaminopentane [(-)BPAP] was selected as a potential follower of (
      )deprenyl in the clinic and as a reference compound for further analysis of the
      CAE/SAE mechanism in the mammalian brain. 3. (-)BPAP significantly enhanced in
      0.18 micromol 1(-1) concentration the impulse propagation mediated release of
      [(3)H]-noradrenaline and [(3)H]-dopamine and in 36 nmol 1(-1) concentration the
      release of [(3)H]-serotonin from the isolated brain stem of rats. The amount of
      catecholamines and serotonin released from isolated discrete rat brain regions
      (dopamine from the striatum, substantia nigra and tuberculum olfactorium,
      noradrenaline from the locus coeruleus and serotonin from the raphe) enhanced
      significantly in the presence of 10(-12) - 10(-14) M (-)BPAP. BPAP protected
      cultured hippocampal neurons from the neurotoxic effect of beta-amyloid in 10(
      14) M concentration. In rats (-)BPAP significantly enhanced the activity of the
      catecholaminergic and serotoninergic neurons in the brain 30 min after acute
      injection of 0.1 microg kg(-1) s.c. In the shuttle box, (-)BPAP in rats was about
      130 times more potent than (-)deprenyl in antagonizing tetrabenazine induced
      inhibition of performance.

PMID- 10588930
TI  - Individual sympathetic varicosities possess different sensitivities to alpha 2
      and P2 receptor agonists and antagonists in mouse vas deferens.
AB  - 1. The diversity of alpha(2) and purinergic autoreceptor actions on action
      potential evoked calcium transients in single varicosities has been investigated
      using the calcium indicator Oregon Green 488 BAPTA-1. 2. During long trains of
      impulses (10 Hz for 30 s), the change in calcium concentration in varicosities
      from its resting level (Delta[Ca(2+)](v)) increased in many varicosities during
      the first 3 s of stimulation before reaching a plateau. 3. The alpha(2)
      adrenoceptor agonist clonidine (1 microM) decreased Delta[Ca(2+)](v) by over 40%
      during short trains (five impulses at 5 Hz) in most varicosities, although some
      were unaffected. The alpha(2) adrenoceptor antagonist idazoxan (2 microM)
      increased the Delta[Ca(2+)](v) plateau following long trains in most
      varicosities. Hence, most varicosities possess alpha(2) adrenoceptors which are
      activated when noradrenaline accumulates extracellularly. 4. During long trains
      of impulses, the P(2y)-purinergic receptor agonist 2-methyl-thio-ATP (100 microM)
      decreased Delta[Ca(2+)](v) plateau by about 50% in most varicosities; alpha,beta
      methylene ATP (100 microM) decreased it by about 50% in a minority of
      varicosities; adenosine (200 microM) had no significant effect. Suramin (100
      microM) increased the Delta[Ca(2+)](v) during all stimulus protocols in most
      varicosities, suggesting that ambient ATP modulates Delta[Ca(2+)](v) responses.
      The P(2y) receptor antagonist reactive blue (100 microM) affected a minority of
      varicosities. Given that most varicosities respond to suramin, other P(2)
      receptor subtypes are probably present. 5. The ATP ectoenzyme antagonist ARL67157
      (50 microM) decreased the plateau Delta[Ca(2+)](v) during long trains in complete
      strings of varicosities but not in others. 6. The present technique indicates
      that varicosities have diverse autoreceptor utilization.

PMID- 10588931
TI  - Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage:
      protection by melatonin and deprenyl.
AB  - 1. There are differences between the excitotoxic actions of quinolinic acid and N
      methyl-D-aspartate (NMDA) which suggest that quinolinic acid may act by
      mechanisms additional to the activation of NMDA receptors. The present study was
      designed to examine the effect of a potent antioxidant, melatonin, and the
      potential neuroprotectant, deprenyl, as inhibitors of quinolinic acid-induced
      brain damage. Injections were made into the hippocampus of anaesthetized rats,
      which were allowed to recover before the brains were taken for histology and the
      counting of surviving neurones. 2. Quinolinic acid (120 nmols) induced damage to
      the pyramidal cell layer, which was prevented by the co-administration of
      melatonin (5 nmols locally plus 2x20 mg kg(-1) i.p.). This protective effect was
      not prevented by the melatonin receptor blocker luzindole. Neuronal damage
      produced by NMDA (120 nmols) was not prevented by melatonin. 3. Quinolinic acid
      increased the formation of lipid peroxidation products from hippocampal tissue
      and this effect was prevented by melatonin. 4. Deprenyl also prevented quinolinic
      acid-induced damage at a dose of 50 nmols but not 10 nmols plus 2x1.0 mg kg(-1)
      i.p. The non-selective monoamine oxidase inhibitor nialamide (10 and 50 nmols
      plus 2x25 mg kg(-1)) did not afford protection. 5. The results suggest that
      quinolinic acid-induced neuronal damage can be prevented by a receptor
      independent action of melatonin and deprenyl, agents which can act as a potent
      free radical scavenger and can increase the activity of endogenous antioxidant
      enzymes respectively. This suggests that free radical formation contributes
      significantly to quinolinic acid-induced damage in vivo.

PMID- 10588932
TI  - Early intracellular signalling pathway of ethanol in vascular smooth muscle
      cells.
AB  - 1. ERKs belong to MAP kinase family and are activated by several growth and
      stress factors. Although ethanol has been shown to modulate ERK1 and ERK2
      (p44(mapk) and p42(mapk)) activity, it can also act as an antiproliferative agent
      in various mammalian cells. Since the nature of the antiproliferative effect of
      ethanol in VSMCs has not been defined, we examined its effects on growth and on
      early intracellular events normally induced by growth factors in VSMCs. 2.
      Measurement of cytosolic Ca(2+) and pH in cell monolayers was performed using
      fura-2/AM and BCECF/AM, respectively. The effect of ethanol on VSMCs growth was
      assessed by [(3)H]-thymidine incorporation, by cell counting and by determination
      of the caspase 3 activity. Stimulation of ERK1 and ERK2 was examined by the
      chemiluminescence Western blotting method. The expression of c-fos was
      quantitated by Northern blotting. Determination of inositolphosphates was
      performed after labelling of VSMCs with myo-[2-(3)H]-inositol and separation of
      inositolphosphates by HPLC. 3. Ethanol (0.3 - 1.0% v v(-1), 17 - 170 mM) induced
      a dose-dependent maximal stimulation of p44(mapk)/p42(mapk) at 30 min and
      expression of c-fos mRNA with a maximum at 120 min. Intracellular events upstream
      to MAP kinase, like an increase in [Ca(2+)](i), activation of the Na(+)/H(+)
      exchanger and formation of phosphoinositol metabolites were also markedly
      activated by ethanol. Treatment of VSMCs with ethanol for 3 - 5 min induced an
      increase in DNA synthesis whereas treatment of the cells for more than 30 min was
      toxic. Caspase 3 activity was not modulated by ethanol treatment of VSMCs. 4. We
      may postulate that the activation of these mitogenic signals including the
      elevation of DNA synthesis reflects a cell effort to protect itself against the
      toxic effects of ethanol.

PMID- 10588933
TI  - Regional haemodynamic responses to infusion of lipopolysaccharide in conscious
      rats: effects of pre- or post-treatment with glibenclamide.
AB  - 1. To determine the putative contribution of K(ATP)-channels to the haemodynamic
      sequelae of endotoxaemia, three experiments were carried out in different groups
      of conscious, chronically-instrumented, unrestrained, male Long Evans rats. 2. In
      the first experiment, pretreatment with the K(ATP)-channel antagonist,
      glibenclamide, abolished the initial hypotension, but not the renal
      vasodilatation caused by LPS infusion. Subsequently, however, in the presence of
      glibenclamide and LPS there was a significant increase in mean arterial blood
      pressure, and a bradycardia, in contrast to the fall in mean arterial blood
      pressure and the tachycardia seen in the presence of vehicle and LPS. The pressor
      and bradycardic changes in the presence of glibenclamide and LPS were accompanied
      by significant reductions in hindquarters flow and vascular conductance, and
      these were significantly greater than those seen in the presence of vehicle and
      LPS, or glibenclamide and saline. 3. Administration of glibenclamide 6 h after
      the onset of saline and LPS infusion, or 6 h after the onset of saline and LPS
      infusion in the presence of the AT(1)-receptor antagonist, losartan, and the
      ET(A)-, ET(B)- receptor antagonist, SB 209670, in the absence or presence of
      dexamethasone, caused a significant increase in mean arterial blood pressure and
      reductions in renal, mesenteric and hindquarters conductances, although the
      latter was the only vascular bed in which there was a reduction in flow. 4. The
      results are consistent with a contribution from K(ATP)-channels to the
      vasodilatation caused by LPS, particularly in the hindquarters vascular bed.

PMID- 10588934
TI  - Nociceptin, Phe(1)psi-nociceptin(1 - 13), nocistatin and prepronociceptin(154 -
      181) effects on calcium channel currents and a potassium current in rat locus
      coeruleus in vitro.
AB  - 1. The actions of the neuropeptide nociceptin, the putative nociceptin receptor
      antagonist [Phe1psi(CH(2)-NH)Gly(2)]-nociceptin-(1 - 13)NH(2) (Phe(1)psi
      nociceptin(1 - 13)) and the putative nociceptin precursor products nocistatin
      (rat prepronociceptin(125 - 132)) and rat prepronociceptin(154 - 181) were
      examined on membrane properties of rat locus coeruleus (LC) neurons using whole
      cell patch clamp techniques. 2. Nociceptin inhibited I(Ba) in all LC neurons,
      (pD(2) of 8.9, maximum inhibition 50%). The inhibition of I(Ba) by nociceptin was
      associated with slowing of the activation of I(Ba) and could be significantly
      reversed by a strong depolarizing prepulse. Phe(1)psi-nociceptin(1 - 13) also
      inhibited I(Ba) in LC neurons (notional pD(2) of 7.6, maximum inhibition 18%).
      Application of Phe(1)psi-nociceptin(1 - 13) (1 microM) significantly occluded the
      subsequent effects of a co-application of nociceptin (3 nM) on I(Ba). 3. As
      previously reported for nociceptin, Phe(1)psi-nociceptin(1 - 13) caused an
      outward current in LC neurons voltage clamped at -60 mV (pD(2) of 7.1, maximum
      current 50% of that of methionine enkephalin, 10 microM). The Phe(1)psi
      nociceptin(1 - 13) induced current reversed polarity at -112 mV and exhibited
      pronounced inward rectification. Phe(1)psi-nociceptin(1 - 13) (1 microM)
      reversibly inhibited the current caused by nociceptin (300 nM) by 30%. 4. Neither
      nocistatin nor rat prepronociceptin(154 - 181) inhibited I(Ba) in LC neurons, or
      prevented the subsequent inhibition by nociceptin. Neither nocistatin or
      prepronociceptin(154 - 181) affected the membrane properties of LC neurons. 5.
      This study demonstrates that nociceptin modulates somatic I(Ba) in rat LC
      neurons. The putative ORL1 antagonist Phe(1)psi-nociceptin(1 - 13) exhibited
      partial agonist activity at inhibiting I(Ba) and opening K(+) channels in LC.
      Other putative nociceptin precursor products were without effect on LC cells.

PMID- 10588935
TI  - Role of gap junctions in the responses to EDHF in rat and guinea-pig small
      arteries.
AB  - 1. In guinea-pig internal carotid arteries with an intact endothelium,
      acetylcholine (10 microM) and levcromakalim (10 microM) each hyperpolarized the
      smooth muscle whereas a 5 mM elevation of extracellular K(+) was without effect.
      2. Incubation of the carotid artery with the gap junction inhibitors
      carbenoxolone (100 microM) or gap 27 (500 microM) essentially abolished the
      hyperpolarization to acetylcholine but it was without effect on that to
      levcromakalim. Carbenoxolone had no effect on the acetylcholine-induced
      endothelial cell hyperpolarization but inhibited the smooth muscle
      hyperpolarization induced by the endothelial cell K(+) channel opener, 1-ethyl-2
      benzimidazolinone (600 microM). 3. In rat hepatic and mesenteric arteries with
      endothelium, carbenoxolone (100 or 500 microM) depolarized the smooth muscle but
      did not modify hyperpolarizations induced by KCl or levcromakalim. In the
      mesenteric (but not the hepatic) artery, the acetylcholine-induced
      hyperpolarization was inhibited by carbenoxolone. 4. Phenylephrine (1 microM)
      depolarized the smooth muscle cells of intact hepatic and mesenteric arteries, an
      effect enhanced by carbenoxolone. Gap 27 did not have a depolarizing action. In
      the presence of phenylephrine, acetylcholine-induced hyperpolarization of both
      hepatic and mesenteric artery myocytes was partially inhibited by each of the gap
      junction inhibitors. 5. Collectively, the data suggest that gap junctions play
      some role in the EDHF (endothelium-derived hyperpolarizing factor) response in
      rat hepatic and mesenteric arteries. However, in the guinea-pig internal carotid
      artery, electrotonic propagation of endothelial cell hyperpolarizations via gap
      junctions may be the sole mechanism underlying the response previously attributed
      to EDHF.

PMID- 10588936
TI  - Cardiovascular responses to angiotensins I and II in normotensive and
      hypertensive rats; effects of NO synthase inhibition or ET receptor antagonism.
AB  - 1. We compared the cardiovascular responses to angiotensins (I and II), and any
      possible modulatory influences thereupon of nitric oxide (NO) or endothelin (ET)
      in conscious male, normotensive, Hannover Sprague-Dawley (SD) rats, and
      hypertensive, heterozygous ((mRen-2)27), transgenic (TG) rats. 2. The pressor
      effects of angiotensin I or of angiotensin II were not consistently different in
      SD and TG rats. The accompanying absolute reductions in renal and mesenteric
      vascular conductances were smaller in TG rats, but probably due to the baseline
      vasoconstriction in those animals. 3. Inhibition of NO synthase with L-NAME had
      no significant effects on the pressor responses to angiotensin I or angiotensin
      II in either SD or TG rats. L-NAME reduced the absolute, but not percentage,
      reductions in renal and mesenteric vascular conductances in response to
      angiotensin I and angiotensin II. L-NAME abolished the hindquarters vasodilator
      effects of angiotensin I and angiotensin II in both strains of rat. 4. ET
      receptor antagonism (with SB209670) had no significant influence on the pressor
      or renal or mesenteric vasoconstrictor effects of angiotensin II in SD rats. In
      TG rats, the pressor responses to angiotensin II were unaffected by SB209670; the
      accompanying falls in renal and mesenteric vascular conductances were enhanced in
      absolute, but not in percentage terms. 5. These results provide no evidence for a
      buffering action of NO, or a modulatory influence of ET, on the pressor or
      vasoconstrictor effects of angiotensin I and/or angiotensin II in SD rats.
      Furthermore, there is no evidence for an altered sensitivity to angiotensin I or
      angiotensin II, and no evidence for a differential modulatory influence of either
      NO or ET in TG, compared to SD, rats.

PMID- 10588937
TI  - Selective nitrergic neurodegeneration in diabetes mellitus - a nitric oxide
      dependent phenomenon.
AB  - 1. In vitro and in vivo studies have demonstrated a dysfunctional nitrergic
      system in diabetes mellitus, thus explaining the origin of diabetic impotence.
      However, the mechanism of this nitrergic defect is not understood. 2. In the
      penises of streptozotocin (STZ)-induced diabetic rats, here, we show by
      immunohistochemistry that nitrergic nerves undergo selective degeneration since
      the noradrenergic nerves which have an anti-erectile function in the penis
      remained intact. 3. Nitrergic relaxation responses in vitro and erectile
      responses to cavernous nerve stimulation in vivo were attenuated in these
      animals, whereas noradrenergic responses were enhanced. 4. Activity and protein
      amount of neuronal nitric oxide synthase (nNOS) were also reduced in the penile
      tissue of diabetic rats. 5. We, thus, hypothesized that NO in the nitrergic
      nerves may be involved in the nitrergic nerve damage, since only the nerves which
      contain neuronal NO synthase underwent degeneration. 6. We administered an
      inhibitor of NO synthase, N(G)-nitro-L-arginine methyl ester (L-NAME), in the
      drinking water of rats for up to 12 weeks following the establishment of diabetes
      with STZ. 7. Here we demonstrate that this compound protected the nitrergic
      nerves from morphological and functional impairment. Our results show that
      selective nitrergic degeneration in diabetes is NO-dependent and suggest that
      inhibition of NO synthase is neuroprotective in this condition.

PMID- 10588939
TI  - Corrigendum

PMID- 10588938
TI  - Anaesthetic/amnesic agents disrupt beta frequency oscillations associated with
      potentiation of excitatory synaptic potentials in the rat hippocampal slice.
AB  - 1. Anaesthetic agents produce disruption in cognitive function typified by
      reductions in sensory perception and memory formation. Oscillations within the
      EEG gamma and beta bands have been linked to sensory perception and memory and
      have been shown to be modified by anaesthetic agents. 2. Synchronous gamma
      oscillations generated by brief tetanic stimulation in two regions of hippocampal
      area CA1 in slices in vitro were seen to potentiate excitatory synaptic
      communication between the areas. This synaptic potentiation, was seen to
      contribute to a transition from gamma frequency (30 - 70 Hz) to beta frequency
      (12 - 30 Hz) oscillations. 3. Four drugs having anaesthetic/hypnotic and amnesic
      properties were tested on this synchronous gamma-induced beta oscillation.
      Thiopental 10 - 200 microM, Diazepam 0.05 - 1.0 microM, Morphine 10 - 200 microM,
      and Ketamine 10 - 200 microM were all added to the bathing medium. Each drug
      markedly disrupted the formation of beta oscillations in a manner consistent with
      their primary modes of action. Thiopental and morphine disrupted synchrony of
      gamma oscillations and prevented potentiation of recurrent excitatory potentials
      measured in stratum oriens (fEPSPs). Neither diazepam, nor ketamine produced such
      marked changes in synchrony at gamma frequencies or reduction in potentiation of
      fEPSPs. However, each disrupted expression of subsequent beta oscillation via
      changes in the magnitude of inhibitory network gamma oscillations and the
      duration and magnitude of tetanus-induced depolarization respectively. 4. The
      degree of disruption of fEPSP potentiation correlated quantitatively with the
      degree of disruption in synchrony between sites during gamma oscillations. The
      data indicate that synchronous gamma-induced beta oscillations represent a mode
      of expression of excitatory synaptic potentiation in the hippocampus, and that
      anaesthetic/amnesic agents can disrupt this process markedly.

PMID- 10588940
TI  - Oxidants and antioxidants in atherogenesis. An appraisal.
AB  - Oxidized low density lipoprotein (Ox-LDL) has a plethora of components that are
      not present in native LDL. Their presence and quantity depends on the nature,
      type, and extent of oxidation. Lipids esterified to oxidized fatty acids are the
      major components formed during the early phase of oxidation and these show a
      number of proatherogenic properties in in vitro cell culture systems. Recently,
      evidence has been forthcoming to suggest that some of these oxidized lipids also
      could elicit "antioxidant;-antiatherogenic" responses from cells. Moreover, some
      of the cellular effects of Ox-LDL that were previously interpreted as atherogenic
      could also be reinterpreted to suggest an antiatherogenic cellular response. In
      addition to the above, the antioxidants that are carried in lipoproteins could
      have anomalous behavior attributable to their metabolism, ability to be
      internalized by arterial cells, and the presence of oxidative systems that could
      render them prooxidants. In conclusion, there are numerous contributing factors
      that need to be studied and understood before antioxidant therapy becomes an
      option for the treatment for cardiovascular diseases.

PMID- 10588941
TI  - Substrate specificity of the ileal and the hepatic Na(+)/bile acid cotransporters
      of the rabbit. II. A reliable 3D QSAR pharmacophore model for the ileal
      Na(+)/bile acid cotransporter.
AB  - To design a reliable 3D QSAR model of the intestinal Na(+)/bile acid
      cotransporter, we have used a training set of 17 inhibitors of the rabbit ileal
      Na(+)/bile acid cotransporter. The IC(50) values of the training set of compounds
      covered a range of four orders of magnitude for inhibition of [(3)H]cholyltaurine
      uptake by CHO cells expressing the rabbit ileal Na(+)/bile acid cotransporter
      allowing the generation of a pharmacophore using the CATALYST algorithm. After
      thorough conformational analysis of each molecule, CATALYST generated a
      pharmacophore model characterized by five chemical features: one hydrogen bond
      donor, one hydrogen bond acceptor, and three hydrophobic features. The 3D
      pharmacophore was enantiospecific and correctly estimated the activities of the
      members of the training set. The predicted interactions of natural bile acids
      with the pharmacophore model of the ileal Na(+)/bile acid cotransporter explain
      exactly the experimentally found structure;-activity relationships for the
      interaction of bile acids with the ileal Na(+)/bile acid cotransporter (Kramer et
      al. 1999. J. Lipid. Res. 40: 1604;-1617). The natural bile acid analogues
      cholyltaurine, chenodeoxycholyltaurine, or deoxycholyltaurine were able to map
      four of the five features of the pharmacophore model: a) the five-membered ring D
      and the methyl group at position 18 map one hydrophobic site and the 21-methyl
      group of the side chain maps a second hydrophobic site; b) one of the alpha
      oriented hydroxyl groups at position 7 or 12 fits the hydrogen bond donor
      feature; c) the negatively charged side chain acts as hydrogen bond acceptor; and
      d) the hydroxy group at position 3 does not specifically map any of the five
      binding features of the pharmacophore model. The 3-hydroxy group of natural bile
      acids is not essential for interactions with ileal or hepatic Na(+)/bile acid
      cotransporters. A modification of the 3-position of a natural bile acid molecule
      is therefore the preferred position for drug targeting strategies using bile acid
      transport pathways.

PMID- 10588942
TI  - Isolation and characterization of monoacetyldiglycerides from bovine udder.
AB  - Monoacetyldiglycerides (MADGs) were isolated from an animal tissue, bovine udder,
      by solvent extraction and silica gel column chromatography. Monoacetyldiglyceride
      structures were identified using a variety of 1-D and 2-D NMR techniques and
      collision-induced dissociation (CID) tandem mass spectrometry coupled with fast
      atom bombardment. CID of sodium-adducted molecular ions ([M+ Na](+)) generated
      numerous types of product ions providing information on the double bond position
      of fatty acyl groups as well as fatty acid compositions. Structural analysis led
      to the classification of the MADGs isolated from bovine udder as 1-palmitoyl-2
      lauroyl-3-acetyl-rac-glycerol, 1, 2-dimyristoyl-3-acetyl-rac-glycerol, 1
      palmitoyl-2-myristoyl-3-acetyl-rac-glycerol, 1-oleoyl-2-myristoyl-3-acetyl-rac
      glycerol, 1-palmitoyl-2-palmitoleoyl-3-acetyl-rac-glycerol, 1, 2-dipalmitoyl-3
      acetyl-rac-glycerol, 1-linoleoyl-2-palmitoyl-3-acetyl-rac-glycerol, 1-oleoyl-2
      palmitoleoyl-3-acetyl-rac-glycerol, 1-oleoyl-2-palmitoyl-3-acetyl-rac-glycerol, 1
      stearoyl-2-palmitoyl-3-acetyl-rac-glycerol, 1-oleoyl-2-linoleoyl-3-acetyl-rac
      glycerol, 1, 2-dioleoyl-3-acetyl-rac-glycerol, and 1-stearoyl-2-oleoyl-3-acetyl
      rac-glycerol.

PMID- 10588943
TI  - Vascular effects of arachidonic acid in the rat perfused heart. Role of the
      endothelium, cyclooxygenase, cytochrome P450, and K(+) channels.
AB  - The vascular effects of arachidonic acid (AA) were addressed in the rat perfused
      heart in terms of metabolic pathways and effector mechanisms. Under basal
      perfusion pressure, AA elicited dilator responses. However, in hearts treated
      with nitroarginine to eliminate nitric oxide and to elevate perfusion pressure,
      the predominant effect of AA was vasoconstriction which was converted to a
      vasodilator effect by inhibition of cyclooxygenase or antagonism of TP receptors.
      The vasodilator effect of AA in nitroarginine- and indomethacin-treated hearts
      was greatly attenuated by clotrimazole, an inhibitor of cytochrome P450, and by
      inhibition of K(+) channels with tetraethylammonium; in the absence of
      indomethacin, clotrimazole enhanced the vasoconstrictor effect of AA. When
      endothelin was used to constrict the coronary vasculature, AA also produced
      cyclooxygenase-dependent vasoconstriction. In hearts constricted with the
      endoperoxide analogue, U46619, only endothelium-dependent vasodilator effects of
      AA were observed that were reduced by indomethacin or clotrimazole. These results
      indicate that the coronary vasoconstrictor effect of AA which is expressed with
      elevated tone, results from its conversion by cyclooxygenase to a product(s) that
      activates TP receptors. The vasodilator effect exhibits two endothelium-dependent
      components, one mediated by cyclooxygenase products and the other by a cytochrome
      P450-derived product that activates K(+) channels.

PMID- 10588944
TI  - Streptozotocin-induced diabetes in human apolipoprotein B transgenic mice.
      Effects on lipoproteins and atherosclerosis.
AB  - The effects of diabetes and lipoprotein lipase (LpL) on plasma lipids were
      studied in mice expressing human apolipoprotein B (HuBTg). Our overall objective
      was to produce a diabetic mouse model in which the sole effects of blood glucose
      elevation on atherosclerosis could be assessed. Mice were made diabetic by
      intraperitoneal injection of streptozotocin, which led to a 2- to 2. 5-fold
      increase in plasma glucose. Lipids were assessed in mice on chow and on an
      atherogenic Western type diet (WTD), consisting of 21% (wt/wt) fat and 0.15%
      (wt/wt) cholesterol. Plasma triglyceride and cholesterol were the same in
      diabetic and non-diabetic mice on the chow diet. On the WTD, male diabetic HuBTg
      mice had a >50% increase in plasma cholesterol and more very low density
      lipoprotein (VLDL) cholesterol and triglyceride as assessed by FPLC analysis. A
      Triton study showed no increase in triglyceride or apolipoprotein B production,
      suggesting that the accumulation of VLDL was due to a decrease in lipoprotein
      clearance. Surprisingly, the VLDL increase in these mice was not due to a
      decrease in LpL activity in postheparin plasma. To test whether LpL
      overexpression would alter these diabetes-induced lipoprotein changes, HuBTg mice
      were crossed with mice expressing human LpL in muscle. LpL overexpression reduced
      plasma triglyceride, but not cholesterol, in male mice on WTD. Aortic root
      atherosclerosis assessed in 32-week-old mice on the WTD was not greater in
      diabetic mice. In summary, diabetes primarily increased plasma VLDL in HuBTg
      mice. LpL activity was not decreased in these animals. However, additional LpL
      expression eliminated the diabetic lipoprotein changes. These mice did not have
      more atherosclerosis with diabetes.

PMID- 10588945
TI  - Structure and functions of human oxysterol 7alpha-hydroxylase cDNAs and gene
      CYP7B1.
AB  - Oxysterol 7alpha-hydroxylase has broad substrate specificity for sterol
      metabolites and may be involved in many metabolic processes including bile acid
      synthesis and neurosteroid metabolism. The cloned human oxysterol 7alpha
      hydroxylase (CYP7B1) cDNA encodes a polypeptide of 506 amino acid residues that
      shares 40% sequence identity to human cholesterol 7alpha-hydroxylase (CYP7A1),
      the rate-limiting enzyme in the conversion of cholesterol to bile acids in the
      liver. In contrast to the liver-specific expression of CYP7A1, CYP7B1 mRNA
      transcripts were detected in human tissues involved in steroid genesis (brain,
      testes, ovary, and prostate) and in bile acid synthesis (liver) and reabsorption
      (colon, kidney, and small intestine). The human oxysterol 7alpha-hydroxylase
      transiently expressed in 293/T cells was able to catalyze 7alpha-hydroxylation of
      27-hydroxycholesterol and dehydroepiandrosterone (DHEA). The human CYP7A1 and
      CYP7B1 both contain six exons and five introns. However, CYP7B1 spans at least 65
      kb of the genome and is about 6-fold longer than CYP7A1. The transcription start
      site (+1) was localized 204 bp upstream of the initiation codon. No TATA box-like
      sequence was found near the transcription start site. Transient transfection
      assays of CYP7B1 promoter/luciferase reporter constructs in HepG2 cells revealed
      that the promoter was highly active. The 5' upstream region from nt -83 to +189
      is the core promoter of the gene.

PMID- 10588946
TI  - Family of human oxysterol binding protein (OSBP) homologues. A novel member
      implicated in brain sterol metabolism.
AB  - Oxysterol binding protein (OSBP) is a cytosolic protein that undergoes ligand
      induced binding to the Golgi apparatus and has been implicated in the regulation
      of cellular cholesterol metabolism. In the yeast Saccharomyces cerevisiae an OSBP
      homologue is involved in membrane trafficking through the Golgi complex. Prompted
      by the multitude of OSBP-related genes in the yeast genome, we carried out a
      search for human expressed sequence tags (ESTs) displaying homology to the sterol
      binding domain of OSBP. This revealed a minimum of six novel OSBP-related
      proteins, designated ORP-1 to ORP-6. ORP cDNA probes were generated by reverse
      transcription-PCR from human liver mRNA, and used for Northern blot analysis of
      human tissue transcript panels. This verified that each of them represents a
      different gene product and showed that they display distinct tissue-specific
      expression patterns. The ORP-1 and -2 mRNA expression levels were similar to or
      higher than that of OSBP while the ORP-3 to -6 mRNAs were detected at lower
      levels in specific tissues. The most abundantly expressed new gene, ORP-1, was
      transcribed at strikingly high levels in the cortical areas of human brain and
      displayed sterol-regulated expression in a cultured human neuroblastoma cell
      line. This indicates that ORP-1 may play an important role in maintaining the
      sterol balance in cells of the central nervous system. Together with OSBP, the
      identified gene products constitute a novel human protein family that may provide
      a link between organellar sterol status and membrane dynamics.

PMID- 10588947
TI  - Efficient glycosylation site utilization by intracellular apolipoprotein B.
      Implications for proteasomal degradation.
AB  - The balance between the hepatic assembly of apolipoprotein B (apoB) and its
      presecretory degradation at the level of the endoplasmic reticulum (ER) may
      control the secretion of apoB-containing lipoproteins. In one model, apoB that
      fails to assemble with lipid undergoes translocation arrest, exposing the protein
      to the cytosolic proteasome. To examine apoB's translocation behavior under
      various metabolic conditions, glycosylation site utilization studies were
      performed. A 70-amino acid peptide containing three sites for N-linked
      glycosylation was appended to the C-terminus of apoB-50 (amino-terminal 50% of
      apoB) and expressed in both hepatic and nonhepatic cell lines. When the C
      terminal reporter peptide was released by cyanogen bromide cleavage, all of the
      sites were glycosylated irrespective of cell type, labeling time, or assembly
      status. Similar peptide mapping of endogenous apoB-100 expressed in HepG2 cells
      was performed to monitor glycosylation at Asn residues 2752 (apoB-61), 2955 (apoB
      65), and 3074 (apoB-68). N-linked glycosylation occurred at a minimum of two of
      the three sites, a frequency identical to that observed in apoB-100 recovered
      from cell media. Treatment of cells with proteasome inhibitors produced a 2. 5
      fold increase in intracellular apoB but failed to cause accumulation of an
      unglycosylated form. These results indicate that 1) the efficient translocation
      of apoB into the ER occurs independently of microsomal triglyceride transfer
      protein and its assembly with lipid and 2) despite its large size and affinity
      for lipid, delivery of misassembled apoB to the proteasome requires retrograde
      translocation from the ER lumen to cytosol.

PMID- 10588948
TI  - Specificity of endogenous fatty acid release during tumor necrosis factor-induced
      apoptosis in WEHI 164 fibrosarcoma cells.
AB  - Recombinant tumor necrosis factor alpha (rTNF-alpha)-induced release of
      endogenous fatty acids was examined in WEHI 164 clone 13 fibrosarcoma cells using
      a highly sensitive HPLC method. The initial rTNF-alpha-induced extracellular
      release of endogenous fatty acids was dominated by 20:4n;-6, 22:4n;-6, 24:4n;-6,
      and 18:1n;-9 showing relative rates of 2.9, 0.9, 1.1, and 1.0, respectively.
      Release of endogenous AA and DNA fragmentation occurred simultaneously and
      preceded cell death by approx. 2 h. Methyl arachidonoyl fluorophosphonate and
      LY311727, specific inhibitors of Ca(2+)-dependent cytosolic PLA(2) (cPLA(2)) and
      secretory PLA(2) (sPLA(2)), respectively, neither blocked rTNF-alpha-induced
      cytotoxicity or endogenous AA release. However, both inhibitors reduced rTNF
      alpha-induced release of other endogenous fatty acids. In comparison, the
      antioxidant butylated hydroxyanisole (BHA) completely inhibited the rTNF-alpha
      induced cytotoxicity as well as AA release mediated through the TNF receptor p55,
      while the very similar antioxidant butylated hydroxytoluene had no effect. BHA
      did not inhibit recombinant cPLA(2) or sPLA(2) enzyme activity in vitro.
      Furthermore, stimulation of cells with rTNF-alpha for 4 h did not increase
      cPLA(2) enzyme activity. The data indicate that neither cPLA(2) or sPLA(2)
      mediate rTNF-alpha-induced apoptosis and extracellular AA release in WEHI cells.
      The results suggest that a BHA-sensitive signaling pathway coupled to AA release
      is a key event in TNF-induced cytotoxicity in these cells.

PMID- 10588949
TI  - Apolipoprotein B overproduction by the perfused liver of the St. Thomas' mixed
      hyperlipidemic (SMHL) rabbit.
AB  - The St. Thomas' mixed hyperlipidemic (SMHL) rabbit (previously St. Thomas'
      Hospital rabbit) is a putative model of familial combined hyperlipidemia (FCH).
      When fed a low (0.08%) cholesterol diet, it exhibits elevations in both plasma
      cholesterol and triglyceride compared to New Zealand White (NZW) controls. To
      determine the mechanism for this hyperlipidemia we studied the secretion of
      apolipoprotein B (apoB)-containing lipoproteins from perfused livers of both
      young and mature rabbits. During a 3-h perfusion we measured the total
      cholesterol and triglyceride content of the medium and the cholesterol,
      triglyceride, and apoB content of very low density lipoprotein (VLDL)(1) (S(f)
      60;-400), VLDL(2) (S(f) 20;-60), intermediate (S(f) 12;-20), and low (S(f) 0;-12)
      density lipoproteins (IDL, LDL). Lipoprotein concentrations increased linearly
      throughout the perfusion period. The rate of cholesterol output was 3-fold higher
      (459 vs. 137 ng/g liver/min, P = 0.003) in SMHL versus NZW rabbits whilst that of
      triglyceride was similar (841 vs. 662 ng/g liver/min, NS). VLDL(1) cholesterol
      output was elevated 2-fold (232 vs. 123 ng/g liver/min, P < 0.05) and VLDL(2) +
      IDL + LDL cholesterol output, 4.5-fold (106 vs. 23 ng/g liver/min, P < 0. 005) in
      SMHL versus NZW rabbits. ApoB output in VLDL1 was 38 ng/g liver per min in SMHL
      and 14 ng/g liver per min in NZW (NS). In SMHL VLDL(2) + IDL + LDL apoB was
      increased 9-fold at 53 versus 6 ng/g liver per min in NZW (P < 0.001). We
      conclude that the SMHL rabbit overproduces apoB-containing lipoproteins
      particularly in the VLDL(2) + IDL + LDL fraction, a characteristic consistent
      with its use as a model of FCH.

PMID- 10588950
TI  - Phytanoyl-CoA hydroxylase from rat liver. Protein purification and cDNA cloning
      with implications for the subcellular localization of phytanic acid alpha
      oxidation.
AB  - Phytanoyl-CoA hydroxylase (PhyH) catalyzes the conversion of phytanoyl-CoA to 2
      hydroxyphytanoyl-CoA, which is the first step in the phytanic acid alpha
      oxidation pathway. Recently, several studies have shown that in humans, phytanic
      acid alpha-oxidation is localized in peroxisomes. In rat, however, the alpha
      oxidation pathway has been reported to be mitochondrial. In order to clarify this
      differential subcellular distribution, we have studied the rat PhyH protein. We
      have purified PhyH from rat liver to apparent homogeneity as judged by SDS-PAGE.
      Sequence analysis of two PhyH peptide fragments allowed cloning of the rat PHYH
      cDNA encoding a 38. 6 kDa protein. The deduced amino acid sequence revealed
      strong homology to human PhyH including the presence of a peroxisome targeting
      signal type 2 (PTS2). Heterologous expression of rat PHYH in Saccharomyces
      cerevisiae yielded a 38.6 kDa protein whereas the PhyH purified from rat liver
      had a molecular mass of 35 kDa. This indicates that PhyH is probably processed in
      rat by proteolytic removal of a leader sequence containing the PTS2. This type of
      processing has been reported in several other peroxisomal proteins that contain a
      PTS2. Subcellular localization studies using equilibrium density centrifugation
      showed that PhyH is indeed a peroxisomal protein in rat. The finding that PhyH is
      peroxisomal in both rat and humans provides strong evidence against the concept
      of a differential subcellular localization of phytanic acid alpha-oxidation in
      rat and human.

PMID- 10588951
TI  - Preparation of a stable fresh frozen primary lipoprotein[a] (Lp[a]) standard.
AB  - LP[a] is one of the most atherogenic lipoproteins consisting of an LDL-like core
      particle and a covalently linked glycoprotein of variable size. Due to its
      structural features, its heterogeneity and instability, there are great
      difficulties in standardizing quantitative immunochemical Lp[a] assays. One
      particular problem is the preparation of a pure primary standard, which is
      sufficiently stable to be used for value assignment of secondary reference
      material. Here we describe a method to purify Lp[a] to virtual homogeneity. When
      mixed with glycerol at a ratio of 1:1, the preparation is stable in the deep
      frozen state for more than 12 months. This latter material gave dose;-response
      curves in several immunochemical assays that were parallel to fresh or frozen
      sera, freshly prepared Lp[a], and other proposed reference materials. After
      determination of the protein content by amino acid analysis, it was possible to
      assign concentrations in molar and mass units to these preparations considering
      the theoretical molecular weights of the particular apo[a] isoform. Thus we
      propose to use this procedure for preparation of a "gold standard" for Lp[a]
      assays.

PMID- 10588952
TI  - Regulation of endoplasmic reticulum cholesterol by plasma membrane cholesterol.
AB  - The abundance of cell cholesterol is governed by multiple regulatory proteins in
      the endoplasmic reticulum (ER) which, in turn, are under the control of the
      cholesterol in that organelle. But how does ER cholesterol reflect cell (mostly
      plasma membrane) cholesterol? We have systematically quantitated this
      relationship for the first time. We found that ER cholesterol in resting human
      fibroblasts comprised approximately 0.5% of the cell total. The ER pool rose by
      more than 10-fold in less than 1 h as cell cholesterol was increased by
      approximately 50% from below to above its physiological value. The curve
      describing the dependence of ER on plasma membrane cholesterol had a J shape. Its
      vertex was at the ambient level of cell cholesterol and thus could correspond to
      a threshold. A variety of class 2 amphiphiles (e.g., U18666A) rapidly reduced ER
      cholesterol but caused only minor alterations in the J-curve. In contrast, brief
      exposure of cells to the oxysterol, 25-hydroxycholesterol, elevated and
      linearized the J-curve, increasing ER cholesterol at all values of cell
      cholesterol. This finding can explain the rapid action of oxysterols on
      cholesterol homeostasis. Other functions have also been observed to depend
      acutely on the level of plasma membrane cholesterol near its physiological level,
      perhaps reflecting a cholesterol-dependent structural or organizational
      transition in the bilayer. Such a physical transition could serve as a set-point
      above which excess plasma membrane cholesterol is transported to the ER where it
      would signal regulatory proteins to down-regulate its further accumulation.

PMID- 10588953
TI  - Novel plasmalogalactosylalkylglycerol from equine brain.
AB  - A novel galactosylalkylglycerol modified with a long-chain cyclic acetal at the
      sugar moiety, 3-O-(4'6'-plasmalogalactosyl) 1-O-alkylglycerol, was isolated from
      equine brain. The presence of cyclic acetal linkage, its linked position, and the
      length of the acetal chain of the natural plasmalo lipid were determined by
      proton NMR spectroscopy and fast-atom bombardment;-mass spectrometry, as well as
      gas chromatography;-mass spectrometry and gas;-liquid chromatography. To identify
      the isomeric stereostructure of the natural product, the plasmalo derivative was
      chemically synthesized from 3-O-galactosyl 2-O-acyl 1-O-alkyl glyceride through
      acetalization after deacylation. As a result, the direction and position of the
      acetal chain of the natural plasmalo lipid were characterized as an "endo"-type
      4',6'-O-acetal derivative linked to galactoside by comparison with the NMR data
      of the synthesized product. The chain lengths of alkyl and acetal groups were
      C(14) for the former and C(16) and C(18) for the latter, and those for the latter
      group were mostly similar to those of plasmalogalactosyl ceramide, which was
      previously isolated from equine brain.

PMID- 10588954
TI  - Biochemical properties, tissue expression, and gene structure of a short chain
      dehydrogenase/ reductase able to catalyze cis-retinol oxidation.
AB  - We have identified a retinol dehydrogenase (cRDH) that catalyzes the oxidation of
      9-cis- but not all-trans-retinol and proposed that this enzyme plays an important
      role in synthesis of the transcriptionally active retinoid, 9-cis-retinoic acid.
      There is little information regarding either the biochemical properties of cRDH
      or how its 9-cis-retinol substrate is formed. We now report studies of the
      properties and expression of human and mouse cRDH and of the characteristics and
      location of the murine cRDH gene. Additionally, we report mouse hepatic 9-cis
      retinol concentrations and demonstrate that 9-cis-retinol is formed in a time-
      and protein-dependent manner upon incubation of all-trans -retinol with cell
      homogenate. Human and mouse cRDH display similar substrate specificities for cis
      isomers of retinol and retinaldehyde. Moreover, human and mouse cRDH show marked
      sensitivity to inhibition by 13-cis-retinoic acid, with both being inhibited by
      approximately 50% by 0.15 microm 13-cis-retinoic acid (for substrate
      concentrations of 10 microm). Lesser inhibition is seen for 9-cis- or all-trans
      retinoic acids. Immunoblot analysis using antiserum directed against human cRDH
      demonstrates cRDH expression in several tissues from first trimester human
      fetuses, indicating that cRDH is expressed early in embryogenesis. Adult mouse
      brain, liver, kidney, and to a lesser extent small intestine and placenta express
      cRDH. The murine cRDH gene consists of at least 5 exons and spans approximately 6
      kb of genomic DNA. Backcross analysis mapped the mouse cRDH gene to the most
      distal region of chromosome 10. Taken together, these data extend our
      understanding of the properties of cRDH and provide additional support for our
      hypothesis that cRDH may play an important role in 9-cis-retinoic acid formation.

PMID- 10588955
TI  - Lipid-free apolipoproteins A-I and A-II promote remodeling of reconstituted high
      density lipoproteins and alter their reactivity with lecithin:cholesterol
      acyltransferase.
AB  - We examined the effect of lipid-free apolipoprotein A-I (apoA-I) and apoA-II on
      the structure of reconstituted high density lipoproteins (rHDL) and on their
      reactivity as substrates for lecithin:cholesterol acyltransferase (LCAT). First,
      homogeneous rHDL were prepared with either apoA-I or apoA-II using
      palmitoyloleoylphosphatidylcholine (POPC) and cholesterol. Lipid-free apoA-I and
      apoA-II were labeled with the fluorescent probe dansyl chloride (DNS). The
      binding kinetics of apoA-I-DNS to A-II-POPCrHDL and of apoA-II-DNS to A-I
      POPCrHDL were monitored by fluorescence polarization, adding the lipid-free
      apolipoproteins to the rHDL particles in a 1:1 molar ratio. For both
      apolipoproteins, the binding to rHDL was rapid, occurring within 5 min. Next, the
      effect on rHDL structure and particle size was determined after incubations of
      lipid-free apolipoproteins with homogeneous rHDL at 37 degrees C from 0.5 to 24
      h. The products were analyzed by non-denaturing gradient gel electrophoresis
      followed by Western blotting. The effect of apoA-I or apoA-II on 103 A A-II
      POPCrHDL was a rearrangement into 78 A particles containing apoA-I and/or apoA
      II, and 90 A particles containing only apoA-II. The effect of apoA-I or apoA-II
      on 98 A A-I-POPCrHDL was a rearrangement into complexes ranging in size from 78 A
      to 105 A containing apoA-I and/or apoA-II, with main particles of 78 A, 88 A, and
      98 A. Finally, the effect of lipid-free apoA-I and apoA-II on rHDL as substrates
      for LCAT was determined. The addition of apoA-I to A-II-POPCrHDL increased its
      reactivity with LCAT 24-fold, reflected by a 4-fold increase in apparent V(m)ax
      and a 6-fold decrease in apparent K(m), while the addition of apoA-II to A-II
      POPCrHDL had no effect on its minimal reactivity with LCAT. In contrast, the
      addition of apoA-II to A-I-POPCrHDL decreased the reaction with LCAT by about one
      half. The inhibition was due to a 2-fold increase in apparent K(m); there was no
      significant change in apparent V(m)ax. Likewise, the addition of apoA-I to A-I
      POPCrHDL inhibited the reaction with LCAT to about two-thirds that of A-I
      POPCrHDL without added apoA-I. In summary, both lipid-free apoA-I and apoA-II can
      promote the remodeling of rHDL into hybrid particles of primarily smaller size.
      Both apoA-I and apoA-II affect the reactivity of rHDL with LCAT, when added to
      the reaction in lipid-free form. These results have important implications for
      the roles of lipid-free apoA-I and apoA-II in HDL maturation and metabolism.

PMID- 10588956
TI  - Cholesterol sulfate and calcium affect stratum corneum lipid organization over a
      wide temperature range.
AB  - The main diffusion barrier for drugs penetrating through the skin is located in
      the intercellular lipid matrix in the upper layer of the skin, the stratum
      corneum (SC). The main lipid classes in the SC are ceramides (CER), free fatty
      acids (FFA) and cholesterol (CHOL). The lipids in SC are organized into two
      lamellar phases with periodicities of approximately 13 and 6 nm, respectively.
      Similar lipid organization has been found with equimolar CHOL:CER:FFA mixtures in
      SAXD studies performed at room temperature. However, one may conclude that the
      phase behavior of the mixtures is similar to that in SC only when the lipid
      organization of the lipid mixtures resembles that in SC over a wide temperature
      range. Therefore, in the present study, the organization of the lipid mixtures
      has been studied in a temperature range between 20 degrees and 95 degrees C. From
      these experiments it appeared that at elevated temperatures in equimolar
      CHOL:CER:FFA mixtures a new prominent 4.3 nm phase is formed between 35;-55
      degrees C, which is absent or only weakly formed in intact human and pig SC,
      respectively. As it has been suggested that gradients of pH and cholesterol
      sulfate exist in the SC and that Ca(2+) is present only in the lowest SC layers,
      the effect of pH, cholesterol sulfate, and Ca(2+) on the lipid phase behavior has
      been investigated with lipid mixtures. Both an increase in pH from 5 (pH at the
      skin surface) to 7.4 (pH at the SC;-stratum granulosum interface) and the
      presence of cholesterol sulfate promote the formation of the 13 nm lamellar
      phase. Furthermore, cholesterol sulfate reduces the amount of CHOL that is
      present in crystalline domains, causes a shift in the formation of the 4.3 nm
      phase to higher temperatures, and makes this phase less prominent at higher
      temperatures. The finding that Ca(2+) counteracts the effects of cholesterol
      sulfate indicates the importance of a proper balance of minor SC components for
      appropriate SC lipid organization. In addition, when the findings are
      extrapolated to the in vivo situation, it seems that cholesterol sulfate is
      required to dissolve cholesterol in the lamellar phases and to stabilize SC lipid
      organization. Therefore, a drop in cholesterol sulfate content in the superficial
      layers of the SC is expected to destabilize the lipid lamellar phases, which
      might facilitate the desquamation process.

PMID- 10588957
TI  - Use of naturally fluorescent triacylglycerols from Parinari glaberrimum to detect
      low lipase activities from Arabidopsis thaliana seedlings.
AB  - The aim of this study was to design a convenient, specific, sensitive, and
      continuous lipase activity assay using natural long-chain triacylglycerols
      (TAGs). Oil was extracted from Parinari glaberrimum seed kernels and the purified
      TAGs were used as a substrate for detecting low levels of lipase activities. The
      purified TAGs are naturally fluorescent because more than half of the fatty acids
      from Parinari oil are known to contain 9,11,13, 15-octadecatetraenoic acid
      (parinaric acid) in its esterified form. The presence of detergents (sodium
      taurodeoxycholate, CHAPS, Sulfobetaine SB12, Tween 20, Brij 35, Dobanol, n
      dodecylglucoside) above their critical micellar concentration dramatically
      increases the fluorescence of the parinaric acid released by various lipases.
      This increase in the fluorescence intensity is linear with time and proportional
      to the amount of lipase added. This new method, performed under non-oxidative
      conditions, was applied successfully to detecting low lipase levels in crude
      protein extracts from plant seeds and could be scaled down to microtiterplate
      measurements. Quantities as low as 0.1 ng of pure pancreatic lipase could be
      detected under standard conditions (pH 8). Lipase activity can also be assayed in
      acidic media (pH 5) using human gastric lipase. This simple and continuous assay
      is compatible with a high sample throughput and might be applied to detecting
      true lipase activities in various biological samples.

PMID- 10588958
TI  - Fractional oxidation of chylomicron-derived oleate is greater than that of
      palmitate in healthy adults fed frequent small meals.
AB  - Differences in oxidation of individual dietary fatty acids could contribute to
      the effect of dietary fat composition on risk factors for non-insulin-dependent
      diabetes mellitus and cardiovascular disease. Using a novel stable isotope
      technique, we compared fractional oxidation of chylomicron-derived oleate and
      palmitate in 10 healthy adults in a crossover study. 1-(13)C-labeled oleate or
      palmitate was emulsified into a eucaloric formula diet administered each 20 min
      for 7 h to produce a plateau in excretion of (13)C label in breath CO(2).
      Unlabeled oleate and palmitate each provided 16% of dietary energy, and other
      fatty acids provided 8% of energy. Total dietary fat was 40% of energy,
      carbohydrate was 46%, and protein was 14%. Diet without tracer was fed for 2 h
      before beginning tracer administration to establish a baseline fed state.
      Relative oxidation of oleate versus palmitate was defined as fractional oxidation
      of oleate divided by fractional oxidation of palmitate. Relative oxidation
      averaged 1.21 (99.5% confidence interval = 1.03;-1.39), indicating that
      fractional oxidation of oleate was significantly greater than that of palmitate.

PMID- 10588960
TI  - Rapid determination of apolipoprotein E genotype using a heteroduplex generator.
AB  - The apoE gene exhibits two common polymorphisms that have been associated with
      both coronary artery disease and Alzheimer's disease. The polymorphisms create
      the three allelic isoforms E2, E3, and E4 which are encoded by Cys;-Cys, Cys;
      Arg, and Arg;-Arg at amino acid positions 112 and 158, respectively. Numerous
      methods have been described to identify these three apoE alleles although there
      are disadvantages and ambiguities associated with all of them. Here we describe a
      method by which the two common apoE polymorphisms can be identified
      simultaneously. The method involves PCR of the region containing the two
      polymorphic sites, followed by hybridization of this PCR product to a synthetic
      molecule called a universal heteroduplex generator (UHG). The UHG is used to
      induce heteroduplex formation which is visualized on a non-denaturing mini-gel
      using ethidium bromide staining. This technique which can also identify other
      rare mutations in the amplified region of DNA under investigation, is an
      unequivocal method of genotyping and is simpler and faster than many methods,
      including using restriction enzyme digestion.

PMID- 10588959
TI  - VLDL-bound lipoprotein lipase facilitates the cholesteryl ester transfer protein
      mediated transfer of cholesteryl esters from HDL to VLDL.
AB  - In recent years, it has been established that lipoprotein lipase (LPL) is partly
      associated with circulating lipoproteins. This report describes the effects of
      physiological amounts of very low density lipoprotein (VLDL)-bound LPL on the
      cholesteryl ester transfer protein (CETP)-mediated cholesteryl ester transfer
      (CET) from high density lipoprotein (HDL) to VLDL. Three patients with severe LPL
      deficiency exhibited a strong decrease in net mass CET that was more than 80%
      lower than that of common hypertriglyceridemic subjects. Recombination
      experiments showed that this was due to an abnormal behavior of the VLDL
      fraction. Replacement of the latter by normal VLDL totally normalized net mass
      CET. We therefore prepared VLDL containing controlled amounts of bound LPL that
      we used as CE acceptors in experiments involving unidirectional radioisotopic CET
      measurements. These were carried out either in the absence or in the presence of
      inhibitors of LPL lipolytic activity. When LPL-induced lipolysis was totally
      blocked, the stimulating effect of the enzyme on the CETP-dependent CET was only
      reduced by about 50%, showing that it did not entirely result from its lipolytic
      action. These data were dependent upon neither the type of LPL inhibitor (E600 or
      THL) nor the source of CETP (delipidated plasma or partially purified CETP).
      Thus, in addition to the well-known stimulating effect of LPL-dependent lipolysis
      on CET, our work demonstrates that physiological amounts of VLDL-bound LPL may
      facilitate CET through a mechanism partially independent of its lipolytic
      activity.

PMID- 10588961
TI  - Differential determination of phospholipase A(2) and PAF-acetylhydrolase in
      biological fluids using fluorescent substrates.
AB  - The purpose of the present study was the development and evaluation of a
      fluorimetric method for the screening and differential determination of
      phospholipase A(2) and PAF-acetylhydrolase in bronchoalveolar lavage (BAL) fluid
      and serum. Phospholipase A(2) was determined using C(12)-NBD-PC in the presence
      of Ca(2+), from the slope of the fluorescence enhancement due to the formation of
      C(12)-NBD-fatty acid. PAF-acetylhydrolase was determined using C(6)-NBD-PC, from
      the slope of the curve due to C(6)-NBD-fatty acid formation in the absence of
      Ca(2+). The results were confirmed after TLC analysis. The method's selectivity
      was evaluated by comparing to radiometric measurements. Light scattering did not
      interfere and inner filter effects was not observed under our experimental
      conditions. The effects of pH, temperature, and Ca(2+) were investigated. Protein
      caused an increase in the background fluorescence of both NBD-PCs. The standard
      curves of both NBD-fatty acids exhibited the same slope. Linearity extended at
      least up to 4. 5 nmoles per ml of reaction mixture at the normal pH 7.4. The
      fluorescence of the NBD-fatty acids remained stable for increasing concentrations
      of BAL fluid and serum and for BSA up to 100 microg/ml of reaction mixture.
      Porcine pancreatic PLase A(2) showed preference for C(12)-NBD-PC in the presence
      of Ca(2+), while without Ca(2+), serum PAF-AcH hydrolyzed only C(6)-NBD-PC. The
      method is highly sensitive, accurate, and reproducible and can be applied for the
      differential determination of phospholipase A(2) and PAF-acetylhydrolase
      activities in BAL fluid and serum.

PMID- 10588962
TI  - Immediate hormonal therapy compared with observation after radical prostatectomy
      and pelvic lymphadenectomy in men with node-positive prostate cancer.
AB  - BACKGROUND: Because the optimal timing of the institution of antiandrogen therapy
      for prostate cancer is controversial, we compared immediate and delayed treatment
      in patients who had minimal residual disease after radical prostatectomy.
      METHODS: Ninety-eight men who underwent radical prostatectomy and pelvic
      lymphadenectomy and who were found to have nodal metastases were randomly
      assigned to receive immediate antiandrogen therapy, with either goserelin, a
      synthetic agonist of gonadotropin-releasing hormone, or bilateral orchiectomy, or
      to be followed until disease progression. The patients were assessed quarterly
      during the first year and then semiannually. RESULTS: After a median of 7.1 years
      of follow-up, 7 of 47 men who received immediate antiandrogen treatment had died,
      as compared with 18 of 51 men in the observation group (P=0.02). The cause of
      death was prostate cancer in 3 men in the immediate-treatment group and in 16 men
      in the observation group (P<0.01). At the time of the last follow-up, 36 men in
      the immediate-treatment group (77 percent) and 9 men in the observation group (18
      percent) were alive and had no evidence of recurrent disease, including
      undetectable serum prostate-specific antigen levels (P<0.001). In the observation
      group, the disease recurred in 42 men; 13 of the 36 who were treated had a
      complete response to local treatment or hormonal therapy (or both), 16 died of
      prostate cancer, and 1 died of another disease. The remaining men in this group
      were alive with progressive disease at the time of the last follow-up or had had
      a recent relapse. Except for the treatment group (immediate therapy or
      observation), no clinical or histologic characteristic significantly influenced
      the outcome. CONCLUSIONS: Immediate antiandrogen therapy after radical
      prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk
      of recurrence in patients with node-positive prostate cancer.

PMID- 10588963
TI  - The effect of bisoprolol on perioperative mortality and myocardial infarction in
      high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac
      Risk Evaluation Applying Stress Echocardiography Study Group.
AB  - BACKGROUND: Cardiovascular complications are the most important causes of
      perioperative morbidity and mortality among patients undergoing major vascular
      surgery. METHODS: We performed a randomized, multicenter trial to assess the
      effect of perioperative blockade of beta-adrenergic receptors on the incidence of
      death from cardiac causes and nonfatal myocardial infarction within 30 days after
      major vascular surgery in patients at high risk for these events. High-risk
      patients were identified by the presence of both clinical risk factors and
      positive results on dobutamine echocardiography. Eligible patients were randomly
      assigned to receive standard perioperative care or standard care plus
      perioperative beta-blockade with bisoprolol. RESULTS: A total of 1351 patients
      were screened, and 846 were found to have one or more cardiac risk factors. Of
      these 846 patients, 173 had positive results on dobutamine echocardiography.
      Fifty-nine patients were randomly assigned to receive bisoprolol, and 53 to
      receive standard care. Fifty-three patients were excluded from randomization
      because they were already taking a beta-blocker, and eight were excluded because
      they had extensive wall-motion abnormalities either at rest or during stress
      testing. Two patients in the bisoprolol group died of cardiac causes (3.4
      percent), as compared with nine patients in the standard-care group (17 percent,
      P=0.02). Nonfatal myocardial infarction occurred in nine patients given standard
      care only (17 percent) and in none of those given standard care plus bisoprolol
      (P<0.001). Thus, the primary study end point of death from cardiac causes or
      nonfatal myocardial infarction occurred in 2 patients in the bisoprolol group
      (3.4 percent) and 18 patients in the standard-care group (34 percent, P<0.001).
      CONCLUSIONS: Bisoprolol reduces the perioperative incidence of death from cardiac
      causes and nonfatal myocardial infarction in high-risk patients who are
      undergoing major vascular surgery.

PMID- 10588965
TI  - Lack of benefit of a single dose of synthetic human secretin in the treatment of
      autism and pervasive developmental disorder.
AB  - BACKGROUND: Secretin is a peptide hormone that stimulates pancreatic secretion.
      After recent publicity about a child with autism whose condition markedly
      improved after a single dose of secretin, thousands of children with autistic
      disorders may have received secretin injections. METHODS: We conducted a double
      blind, placebo-controlled trial of a single intravenous dose of synthetic human
      secretin in 60 children (age, 3 to 14 years) with autism or pervasive
      developmental disorder. The children were randomly assigned to treatment with an
      intravenous infusion of synthetic human secretin (0.4 microg per kilogram of body
      weight) or saline placebo. We used standardized behavioral measures of the
      primary and secondary features of autism, including the Autism Behavior
      Checklist, to assess the degree of impairment at base line and over the course of
      a four-week period after treatment. RESULTS: Of the 60 children, 4 could not be
      evaluated - 2 received secretin outside the study, and 2 did not return for
      follow-up. Thus, 56 children (28 in each group) completed the study. As compared
      with placebo, secretin treatment was not associated with significant improvements
      in any of the outcome measures. Among the children in the secretin group, the
      mean total score on the Autism Behavior Checklist at base line was 59.0 (range of
      possible values, 0 to 158, with a larger value corresponding to greater
      impairment), and among those in the placebo group it was 63.2. The mean decreases
      in scores over the four-week period were 8.9 in the secretin group and 17.8 in
      the placebo group (mean difference, -8.9; 95 percent confidence interval, -19.4
      to 1.6; P=0.11). None of the children had treatment-limiting adverse effects.
      After they were told the results, 69 percent of the parents of the children in
      this study said they remained interested in secretin as a treatment for their
      children. CONCLUSIONS: A single dose of synthetic human secretin is not an
      effective treatment for autism or pervasive developmental disorder.

PMID- 10588964
TI  - Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis.
AB  - BACKGROUND: There is no effective orally administered medication for any
      leishmania infection. We investigated miltefosine, which can be taken orally, for
      the treatment of Indian visceral leishmaniasis. Miltefosine is a phosphocholine
      analogue that affects cell-signaling pathways and membrane synthesis. METHODS:
      The study was an open-label, multicenter, phase 2 trial in which four 30-person
      cohorts received 50, 100, or 150 mg of miltefosine per day for four or six weeks.
      The 120 patients, who ranged in age from 12 to 50 years, had anorexia, fever, and
      splenomegaly with at least moderate (2+) leishmania in a splenic aspirate. A
      parasitologic cure was defined by the absence of parasites in a splenic aspirate
      obtained two weeks after completion of treatment. The clinical response was
      assessed at six months. RESULTS: In all 120 patients there was an initial
      parasitologic cure. Six patients had clinical and parasitologic relapses; the
      remaining 114 patients had not relapsed by six months after treatment, for a cure
      rate of 95 percent (95 percent confidence interval, 89 to 98 percent). With the
      regimen of 100 mg of miltefosine per day (approximately 2.5 mg per kilogram of
      body weight per day) for four weeks, 29 of 30 patients (97 percent) were cured.
      Gastrointestinal side effects were frequent (occurring in 62 percent of patients)
      but mild to moderate in severity, and no patient discontinued therapy because of
      gastrointestinal side effects. In two patients, treatment was discontinued
      because of elevated levels of aspartate aminotransferase or creatinine; in both
      patients the levels rapidly returned to normal. In 12 other patients, the level
      of aspartate aminotransferase increased to 100 to 150 U per liter during
      treatment. CONCLUSIONS: Orally administered miltefosine appears to be an
      effective treatment for Indian visceral leishmaniasis.

PMID- 10588966
TI  - Images in clinical medicine. Cystine crystals in Fanconi's syndrome.

PMID- 10588967
TI  - Pancreatic and biliary endoscopy.

PMID- 10588968
TI  - Inflammatory skin diseases, T cells, and immune surveillance.

PMID- 10588969
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 37-1999. A 72-year-old woman with a prosthetic aortic valve and
      intracranial hemorrhage.

PMID- 10588970
TI  - Early androgen deprivation for prostate cancer?

PMID- 10588971
TI  - Reducing cardiac risk in noncardiac surgery.

PMID- 10588972
TI  - Miltefosine--the long-awaited therapy for visceral leishmaniasis?

PMID- 10588973
TI  - Lessons from secretin.

PMID- 10588974
TI  - Death of a president.

PMID- 10588975
TI  - Correction: Prevention of Neural-Tube Defects with Folic Acid in China.

PMID- 10588977
TI  - The role of international environmental agreements in metered-dose inhaler
      technology changes.
AB  - Introduced in the 1950s, metered dose inhalers (MDIs) became a revolutionary way
      to deliver medication directly to the lungs of patients with asthma and chronic
      obstructive pulmonary disease. Since their initial introduction, MDIs have used
      chlorofluorocarbons to propel the medication out of the canister into a patient's
      lungs. This article presents an overview of the global transition away from the
      use of chlorofluorocarbon propellants in MDIs to non-ozone-depleting substitutes
      including hydrofluoroalkane (outside of the pharmaceutical industry and in the
      context of Montreal Protocol and Kyoto Protocol discussions, these gases are
      referred to as hydrofluorocarbons; hydrofluoroalkane-134a, for example, is
      referred to as hydrofluorocarbon-134a) propellants, in accordance with the terms
      of the international environmental agreement the Montreal Protocol on substances
      that deplete the ozone layer (the Montreal Protocol). This article will also
      describe the environmental characteristics of chlorofluorocarbons and
      hydrofluoroalkanes when they are used as MDI propellants. Finally, the article
      will review key provisions of the pending Kyoto Protocol to the United Nations
      Framework Convention on Climate Change (the Kyoto Protocol) that may affect the
      future of hydrofluoroalkanes.

PMID- 10588978
TI  - The chlorofluorocarbon to hydrofluoroalkane transition: the effect on pressurized
      metered dose inhaler suspension stability.
AB  - The phase out of chlorofluorocarbon (CFC) propellants has necessitated the
      reformulation of pressurized metered dose inhalers (pMDIs) with hydrofluoroalkane
      (HFA) propellants. One of the main challenges has been that conventional
      surfactants used for CFC-based pMDIs were not soluble in HFAs. Since one of the
      main aims of a pMDI is to deliver a reproducible dose of medication to the
      patient, it is vital that, for suspension-type pMDI formulations, the suspension
      is stabilized sufficiently for a reproducible dose to be delivered. A new
      technique has been developed that measures suspension stability more objectively
      than before. This technique, optical suspension characterization, was used to
      compare the performance of different formulations of respiratory drugs in HFAs.
      The optical suspension characterization data were correlated with conventional
      analytic techniques for the determination of the stability of the suspension
      formulation.

PMID- 10588979
TI  - Moisture transport into chlorofluorocarbon-free metered dose inhalers.
AB  - Moisture is known to affect the stability of some metered dose inhalers (MDIs).
      Hydrofluoroalkanes such as tetrafluoroethane (134a) and heptafluoropropane (227)
      are known to have higher affinity for moisture than the currently used
      chlorofluorocarbon propellents. An initial study was conducted to determine the
      water vapor transmission rates of various elastomers that may be used as gaskets
      in MDIs. A further study was conducted to measure the moisture ingress rates of
      various chlorofluorocarbon-free MDIs. The data indicate that moisture transport
      into chlorofluorocarbon-free MDIs is influenced by the elastomeric nature of the
      gaskets used and the type of hydrofluoroalkane formulation and storage conditions
      used.

PMID- 10588980
TI  - Pressurized metered dose inhalers: chlorofluorocarbon to hydrofluoroalkane
      transition-valve performance.
AB  - This article reviews the issues related to the performance of valves in metered
      dose inhalers with respect to chlorofluorocarbon propellant replacement.
      Reformulation of existing chlorofluorocarbon-based products with
      hydrofluoroalkane propellants has been a much more difficult task than initially
      anticipated, complicated by the need to concurrently develop better performing
      valves with cleaner extractive profiles. This paper will examine issues related
      to the reformulation and development of new valves and the tests and procedures
      used to evaluate valve performance. Evaluation of valve performance will consider
      the tests performed: mechanisms by which valves fail and analytic testing errors
      that can complicate the interpretation of results.

PMID- 10588981
TI  - A United States regulator's perspective on the ongoing chlorofluorocarbon
      transition.
AB  - The Food and Drug Administration (FDA) put in place a general ban on the use of
      chlorofluorocarbons for the products it regulates (medical devices, drugs, and
      foods) in 1978, exempting those products where chlorofluorocarbon use was
      determined to be essential for the public health. In the intervening years, as
      the international commitment to a full transition away from all
      chlorofluorocarbon use took shape under the Montreal Protocol, the FDA has worked
      with industry to facilitate the development and testing of alternative
      technologies and products for inhalation drug products. As these alternative
      products begin to move from testing through the approval process and into
      marketing, the FDA is working collaboratively with the Environmental Protection
      Agency, other governmental agencies, and nongovernmental stakeholders to develop
      a transition policy for the United States. The transition policy for metered dose
      inhalers must be one that achieves the dual aims of first protecting the patients
      who rely on these vital medical products, while also achieving the public health
      need of protecting the ozone layer. As a part of developing such a transition
      strategy, the FDA published an advance notice of proposed rulemaking (ANPRM) in
      March 1997. The ANPRM proposed mechanisms by which the FDA could determine when
      chlorofluorocarbon use in a drug product could no longer be considered essential.
      The ANPRM resulted in a large amount of valuable public debate and input. The FDA
      is now working to incorporate the knowledge gained from these public comments as
      it continues the rule-making process.

PMID- 10588982
TI  - Preparing patients and health professionals for the transition to
      chlorofluorocarbon-free inhalers: the British perspective.
AB  - The National Asthma Campaign is the independent United Kingdom charity working to
      conquer asthma in partnership with people with asthma and all who share their
      concern through a combination of research, education, and support. We are viewed
      by people with asthma, health professionals, National Health Service managers,
      and policy makers as 1 of the United Kingdom's leading authorities on asthma and,
      in particular, the leading independent charity in the field. Through historic
      precedent and current research, it was clear to us, alongside the other relevant
      stakeholders, that the transition to chlorofluorocarbon-free inhalers would be 1
      of the biggest changes in medication ever to take place in the United Kingdom and
      a potential period of considerable instability. To avoid that instability and to
      facilitate a positive transition process, the National Asthma Campaign worked
      closely with the government (Department of Health), health professionals,
      pharmaceutic industry, and other patient and?or campaigning groups to ensure
      effective information dissemination; and support was available to the appropriate
      audiences. It is difficult to conclude at this stage how successful the strategy
      has been. As the transition gains in momentum and more chlorofluorocarbon-free
      products are released on to the market, it will become more apparent how much of
      a success the process has been.

PMID- 10588983
TI  - Concepts of establishing clinical bioequivalence of chlorofluorocarbon and
      hydrofluoroalkane beta-agonists.
AB  - There are no established guidelines for judging equivalence between inhaled
      medications. The principles of establishing bioequivalence on the basis of
      bioavailability and pharmacokinetics may not be applicable to inhaled medications
      with predominantly topical and minimal systemic effects. For inhaled beta(2)
      agonists, the most practical method of showing in vivo therapeutic equivalence is
      by comparing relative potencies (RPs) of pharmacodynamic effects (bronchodilation
      and bronchoprotection). A range of doses that includes placebo should be studied
      in an appropriate design with adequate sample size, and relative potency should
      be estimated. Hydrofluoroalkane and chlorofluorocarbon salbutamol are
      bioequivalent for both their bronchodilator (RP, 1.08; 90% confidence interval,
      0.95%, 1.23%) and bronchoprotective effects (RP, 1.08; 90% confidence interval,
      0.81%, 1.46%) with similar safety profile. Eighteen subjects are required in a
      cross-over design to demonstrate bronchoprotective bioequivalence with a
      confidence interval of 67% to 150% for the relative potency (80% power). For
      salbutamol, this can be achieved with a comparison of 100 and 200 microgram
      doses. Twelve subjects would suffice for a cumulative dose-response study for
      bronchodilator bioequivalence. For both outcomes, repeatability and quality
      control of measurements have to be ensured for an accurate interpretation of the
      results.

PMID- 10588984
TI  - The pharmacokinetics of inhaled hydrofluoroalkane formulations.
AB  - To obtain the full picture of a formulation, the in vitro and the in vivo
      information can be looked upon as components of a "prediction bridge" where the
      in vitro information can be used to predict lung deposition, which in turn can be
      used to predict clinical outcome. This bridging concept can be used as a template
      to evaluate new information on emerging inhaled formulations. The concept was
      used to evaluate literature data on new hydroflouroalkane formulations of
      salbutamol and beclomethasone dipropionate (BDP). The new salbutamol
      hydroflouroalkane formulations seem to have properties similar to those of the
      old chlorofluorocarbon formulations even if the presented information on effect
      comparisons is limited. The first BDP hydroflouroalkane formulation is a solution
      formulation with in vitro properties that are quite different from those of the
      old chlorofluorocarbon suspension formulation. The BDP hydroflouroalkane
      formulation has a much greater fine particle mass, which eventually results in
      greater lung deposition and better clinical effect.

PMID- 10588985
TI  - Effect of formulation parameters on hydrofluoroalkane-beclomethasone dipropionate
      drug deposition in humans.
AB  - Chlorofluorocarbon metered dose inhalers (MDIs) and dry powder inhalers currently
      deliver drug that deposits primarily in the oropharynx and secondarily in the
      large central airways. Chlorofluorocarbon-beclomethasone dipropionate (CFC-BDP)
      MDIs deliver more than 90% of the drug in the oropharynx and less than 10% in the
      lungs. The elimination of chlorofluorocarbons from MDIs provided the opportunity
      to more optimally target corticosteroids directly to all inflammatory sites.
      Hydrofluoroalkane-BDP (HFA-BDP) MDIs (QVAR(trade mark)) deliver 50% to 60% of the
      drug to the lungs with approximately 30% delivered to the mouth. Additionally,
      the amount of drug delivered to the lungs is distributed throughout the large,
      intermediate, and small airways. Radiolabeled deposition studies have shown that
      the HFA-BDP MDI is a "forgiving" aerosol in that even the extreme discoordinated
      use of the press and breathe MDI still resulted in more than 30% lung deposition.
      The breath-actuated Autohaler inhaler provided the same lung deposition as an
      optimally used press and breathe MDI. The dose delivered from either the press
      and breathe HFA-BDP MDI or the Autohaler was consistent across a wide range of
      inspiratory flows (eg, flows of 26-137 L/min). Clinical studies have shown that
      the improvements in lung deposition of HFA-BDP result in equivalent efficacy at
      approximately one half of the total daily dose compared with current CFC-BDP
      products.

PMID- 10588986
TI  - Deposition of fenoterol from pressurized metered dose inhalers containing
      hydrofluoroalkanes.
AB  - The imaging technique of gamma scintigraphy has been used to quantify the total
      amount of drug deposited in the lungs and the pattern of regional lung
      deposition, for formulations of Berodual (Boehringer Ingelheim GmbH) delivered
      from pressurized metered dose inhalers formulated with chlorofluorocarbons, and
      with hydrofluoroalkane-134a or -227. Data were expressed as the mass of fenoterol
      deposited in the lungs from the Berodual formulations. All the formulations
      tested gave a whole lung deposition less than 20% of the metered (exvalve) dose.
      The mass of fenoterol deposited in the lungs for a solution formulation
      containing hydrofluoroalkane-134a was inversely proportional to the actuator
      nozzle diameter. The data suggest that the total and regional lung deposition of
      hydrofluoroalkane-based pressurized aerosol formulations is highly product
      specific and that changes in bioavailability can be brought about by varying both
      the constituents of the formulation and the design of the actuator.

PMID- 10588987
TI  - Comparative effects of hydrofluoroalkane and chlorofluorocarbon beclomethasone
      dipropionate inhalation on small airways: assessment with functional helical thin
      section computed tomography.
AB  - A double-blind, randomized, parallel-group pilot study compared the relative
      efficacy of hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP [QVAR];
      mass median aerodynamic diameter, 0. 8-1.2 m) versus cholorofluorocarbon-11/12
      BDP (CFC-BDP [Beclovent]; mass median aerodynamic diameter, 3.5-4.0 m) in 31
      steroid naive patients with mild to moderate asthma (PC(20,) 4 mg/mL). Functional
      high-resolution computed tomography was used to assess the relative efficacy of
      HFA-BDP and CFC-BDP on regional air trapping, as an indirect measure of small
      airways function and on regional hyperreactivity. Pretreatment functional
      computed tomography was performed at residual volume before and after
      methacholine challenge. After 4 weeks of treatment, functional imaging was
      repeated before and after the same concentration of methacholine that was
      administered before the treatment (n = 19 patients). Quantitative assessment of
      changes in distribution of lung attenuation was performed. After 4 weeks of
      treatment, the HFA-BDP group showed significantly more improvement in air
      trapping overall (a shift in the lung attenuation curve at residual volume toward
      more attenuation) on the posttreatment computed tomography scan (P <.05; Fisher's
      Exact Test). After an equal constrictor stimulus (methacholine concentration),
      subjects treated with HFA-BDP (n = 10 patients) showed less increase in air
      trapping overall than subjects treated with CFC-BDP (n = 9 patients) on the
      posttreatment scans compared with the pretreatment scans (P <.001; Fisher's Exact
      Test). No significant difference was demonstrated between the 2 treatment groups
      with respect to improvement in symptoms, spirometry, or methacholine
      responsiveness assessed by FEV(1), except for a greater reduction in
      breathlessness in the HFA-BDP group (P <.05). We conclude that HFA-BDP may have
      greater efficacy in the peripheral airways and that this effect is better
      assessed with functional imaging computed tomography techniques than with
      conventional physiologic tests.

PMID- 10588988
TI  - Chlorofluorocarbon to hydrofluoroalkane formulations: an industry perspective.
AB  - The medications prescribed to treat asthma are provided in a range of delivery
      systems, designed to give patients a choice in how they take their inhaled
      medication. These include the mainstay of asthma therapy, the metered dose
      inhaler (MDI), and the breath-operated inhalers. One of the major challenges that
      all the leading companies in the respiratory area have faced in recent years is
      the environmental effects of chlorofluorocarbons. The pharmaceutical industry
      recognized the need to reformulate MDI products containing chlorofluorocarbons,
      and a number of companies began to develop alternatives in the late 1980s. To
      help facilitate this change in products, an industry consortium was formed
      (International Pharmaceutical Aerosol Consortium), and this has managed many of
      the overarching issues. After an extensive search was conducted, the most
      suitable alternatives were the hydrofluoroalkanes, which do not contain chlorine,
      are ozone friendly, and have lower global-warming potentials than the
      chlorofluorocarbons that they are replacing. To date it is estimated that the
      industry has invested over $1.0 billion ($US) on global research and development
      efforts. The first countries to launch the nonchlorofluorocarbon MDIs have been
      in Europe, and now salbutamol and 2 inhaled steroids are widely available across
      Europe in their nonchlorofluorocarbon form. Clinical testing has been extensive,
      and patient acceptance of the new products has proved to be high. Maintaining the
      smooth progress of the global transition is important, and continued dialogue
      between all key stakeholders should ensure success in this area.

PMID- 10588990
TI  - The intrauterine and postnatal environments.
AB  - Pregnancy is associated with a strong skewing toward T(H)2 cytokine pattern,
      which enables the survival of the fetus, including fetal allergen-specific immune
      responses. The postnatal maturation of the immune system which is characterized
      by the development of a balanced T(H)1/T(H)2 immunity is genetically determined
      and modified by the environment. The process seems to proceed at a slower rate in
      atopic than in nonatopic infants. There is a close immunologic interaction
      between the mother and her offspring through the breast milk. Individual
      variations in the composition of human milk may explain the controversy with
      regard to the possible allergy-preventive effects of breast-feeding. Recurrent
      respiratory infections have been suggested to enhance immune deviation. The
      microbial flora are a more likely source, however, because they are a major
      driving force in the maturation of the immune system. Changes in its composition,
      as a consequence of an altered lifestyle and diet, may play a role in the higher
      prevalence of allergy. So far, primary prevention of allergy has failed. Future
      studies should therefore focus on factors enhancing immune deviation (ie,
      "success" factors) rather than on "risk" factors. The intestinal microflora is
      one of these factors that deserves closer analysis.

PMID- 10588991
TI  - Atopy: immunodeviation and environment.

PMID- 10588992
TI  - Defensins: key players or bystanders in infection, injury, and repair in the
      lung?
AB  - Antimicrobial peptides have been identified as key elements in the innate host
      defense against infection. Recent studies have indicated that the activity of
      antimicrobial peptides may be decreased in cystic fibrosis, suggesting a major
      role for these peptides in host defense against infection. One of the most
      intensively studied classes of antimicrobial peptides are defensins. Defensins
      comprise a family of cationic peptides that in human subjects can be divided into
      the alpha- and beta-defensin subfamilies. The alpha-defensins are produced by
      neutrophils and intestinal Paneth's cells, whereas beta-defensins are mainly
      produced by epithelial cells. Although studies on beta-defensins have so far
      focused on their antimicrobial activity, studies on alpha-defensins have
      suggested a role of these peptides in inflammation, wound repair, and specific
      immune responses. alpha-Defensins, which accumulate in airway secretions of
      patients with various chronic inflammatory lung disorders, were shown to be
      cytotoxic toward airway epithelial cells and to induce chemokine secretion in
      several cell types. Furthermore, the capacity of alpha-defensins to promote
      bacterial adherence to epithelial cells in vitro further supports a role for
      these peptides in the pathogenesis of chronic obstructive pulmonary disease and
      cystic fibrosis. Increased numbers of neutrophils are also present in the airways
      of patients with asthma, suggesting that neutrophils are involved in the
      pathogenesis of this disease. Because defensins are able to induce histamine
      release by mast cells and increase the airway hyperresponsiveness to histamine,
      it is tempting to speculate that defensins may also contribute to the
      inflammatory processes in asthma. Besides these proinflammatory effects, alpha
      defensins may also display anti-inflammatory activities, including regulation of
      complement activation and proteinase inhibitor secretion. Finally, defensins may
      be involved in wound repair because defensins increase epithelial cell
      proliferation. Thus recent defensin research has revealed potential links between
      the innate and acquired immune system.

PMID- 10588993
TI  - Genetic and environmental interaction in allergy and asthma.
AB  - Asthma is an inflammatory disorder of the airways involving coordinate up
      regulation of T(H)2-type cytokines encoded in a cluster on chromosome 5q(31-33)
      on T cells and inflammatory cells. There is also a requirement for local airway
      susceptibility factors that, together with T(H)2 polarization, results in
      hyperresponsiveness, variable airflow obstruction, and, over time, remodeling of
      the airway wall. Asthma has strong genetic and environmental components that
      interact both in the induction and subsequent expression of the disease
      phenotypes. Multiple genes are involved and probably interact. Whole genome
      screens are beginning to identify gene-rich regions of special relevance to
      asthma and atopy, although a novel disease-related gene has yet to be discovered
      from these. By contrast, there are a plethora of candidate genes whose function
      in relation to disease pathophysiologic mechanisms and response to treatment are
      known. Two examples are polymorphisms involving IL-4 receptors and the enzymes
      controlling cysteinyl leukotriene production. Abnormal signaling between the
      epithelium, which is in contact with the environment, and the underlying
      (myo)fibroblasts and dendritic cells indicating reactivation of the epithelial
      mesenchymal trophic unit, which is involved in fetal lung development and
      branching, provide a basis for asthma that encapsulates both T(H)2 polarization
      and airway wall remodeling.

PMID- 10588994
TI  - Montelukast, a leukotriene receptor antagonist, inhibits the late airway response
      to antigen, airway eosinophilia, and IL-5-expressing cells in Brown Norway rats.
AB  - BACKGROUND: Asthma is characterized by airflow obstruction, inflammatory cell
      infiltration, and the synthesis of mediators, such as T(H2) cytokines and
      leukotrienes, in the airways. Cysteinyl leukotriene (cysLT) receptor antagonists
      have recently been associated with clinical improvement of asthma and reduced
      airway inflammation. Whether the beneficial effects of cysLT antagonists are
      mediated through the modulation of cytokine expression has not been determined.
      OBJECTIVE: The aim of the study was to determine the presence of eosinophils and
      IL-5 messenger (m)RNA(+) cells within the lungs of antigen-challenged Brown
      Norway rats after treatment with the cysLT(1) receptor antagonist montelukast
      (MK). METHODS: Ovalbumin-sensitized Brown Norway rats were treated with either MK
      or saline before ovalbumin challenge. Pulmonary mechanics were monitored for 8
      hours. Subsequently, immunocytochemistry and in situ hybridization were used to
      examine bronchoalveolar lavage (BAL) fluid and lung tissue for cells expressing
      major basic protein (eosinophils) and IL-5 mRNA, respectively. Simultaneous in
      situ hybridization and immunocytochemistry was used to phenotype the cells
      expressing mRNA encoding IL-5. RESULTS: Animals treated with MK had significantly
      lower lung resistance and fewer eosinophils and IL-5 mRNA(+) cells within BAL
      fluid and lung tissue compared with that found in saline-treated animals.
      Colocalizaton studies revealed that the majority of IL-5 mRNA(+) cells were T
      cells and that the number of IL-5 mRNA(+)/CD3(+) or IL-5 mRNA(+)/major basic
      protein(+) cells were significantly less within BAL from animals treated with MK
      than from those treated with saline. CONCLUSIONS: These results indicate that the
      cysLT(1) receptor antagonist MK can diminish the pulmonary response to antigen,
      tissue eosinophilia, and the number of cells expressing IL-5 mRNA, suggesting
      that leukotrienes may also regulate the allergic response through the modulation
      of inflammation and cytokine synthesis.

PMID- 10588995
TI  - The effect of zafirlukast on repetitive exercise-induced bronchoconstriction: the
      possible role of leukotrienes in exercise-induced refractoriness.
AB  - BACKGROUND: Single doses of zafirlukast attenuate exercise-induced
      bronchoconstriction (EIB), but previous studies have not measured zafirlukast's
      effects after regular dosing or its duration of effect beyond 4 hours. OBJECTIVE:
      The purpose of this study was to assess the effects of zafirlukast 20 mg and 80
      mg twice daily compared with placebo on exercise challenges performed at 2 and 8
      hours after the last dose of regular administration. METHODS: Twenty-four adult
      patients with stable asthma taking beta(2)-agonists, inhaled corticosteroids, or
      both received treatment with zafirlukast (20 mg and 80 mg) and placebo. The
      patients were treated twice daily for 14 days in a randomized, double-blind, 3
      way cross-over fashion, with a 7-day washout period between each treatment.
      Exercise challenges were performed at 2 and 8 hours after the morning dose on day
      14. FEV(1) was measured before exercise and at set intervals after exercise until
      it returned to within 7% of its baseline value. RESULTS: Both zafirlukast
      treatments significantly reduced EIB, as measured by the area under the FEV(1)
      time curve after the 2-hour (P <.001) and 8-hour (P <.001) exercise challenges
      and maximum fall in FEV(1) at the 2-hour challenge (P <.001). The comparison at 8
      hours between treatments was affected by the unexpected finding that EIB was less
      in the placebo group after the 8-hour challenge than after the 2-hour challenge,
      as measured by the within-group change in the maximum fall in FEV(1) (P <.001)
      and the area under the FEV(1) time curve (P =.0023). CONCLUSION: Regular
      zafirlukast treatment protects against EIB for at least 8 hours after regular
      dosing. A refractory period, which may be caused by exercise-induced leukotriene
      release, may last for up to 6 hours after the initial response to exercise.

PMID- 10588996
TI  - Montelukast, a leukotriene receptor antagonist, reduces the concentration of
      leukotrienes in the respiratory tract of children with persistent asthma.
AB  - BACKGROUND: Leukotrienes are bronchoactive mediators secreted by inflammatory
      cells in the respiratory mucosa on exposure to asthma triggers. OBJECTIVE: We
      investigated the effect of montelukast, a leukotriene receptor antagonist, on the
      release of leukotrienes in the respiratory mucosa of children with persistent
      asthma. METHOD: Twenty-three children aged 6 to 11 years with moderately severe
      asthma were treated in a cross-over design starting, after a 2-week run in
      period, with either montelukast (n = 12) or cromolyn (n = 11) for 4 weeks with a
      2-week washout period between treatments. Twelve of them were then treated with
      either montelukast or beclomethasone for 6 months. The use of beta(2)-agonists
      was recorded on a diary card. The concentration of leukotriene C(4) (LTC(4)) was
      measured by HPLC in nasal washes obtained before and at the end of each treatment
      period. Eosinophilic cationic protein (ECP) was measured in the nasal washes by
      RIA. RESULTS: The LTC(4) concentration significantly decreased in the children
      treated for the first 4 weeks with montelukast, from 5.03 +/- 1.17 to 1.42 +/-
      0.33 ng/mL (P <.005), and a nonsignificant increase was noted in children treated
      with cromolyn, from 3.37 +/- 1.11 to 5.88 +/- 2.17 ng/mL (P =.17). ECP
      concentration also decreased in the children receiving montelukast (P =.12). The
      concentration of LTC(4) remained low after 3 and 6 months of treatment with
      montelukast (0.8 +/- 0.7 and 1.0 +/- 0.3 microg/mL) and was lower than with
      beclomethasone. Children treated with montelukast required significantly fewer
      beta(2)-agonists (P <.04), CONCLUSION: Montelukast reduces the concentration of
      leukotrienes in the respiratory tract of children with persistent asthma parallel
      to reduction in ECP and clinical improvement. This effect was not observed when
      the same children were treated with cromolyn.

PMID- 10588997
TI  - An in vitro analysis of the output of budesonide from different nebulizers.
AB  - BACKGROUND: Inhaled corticosteroids are increasingly used in the treatment of
      asthma, and many different nebulizers are available to aerosolize steroid
      medications. There are few comparative data on their ability to do so. OBJECTIVE:
      Our purpose was to determine the particle size and mass output of budesonide
      nebulizer suspension from different nebulizers. METHODS: In vitro measurement of
      drug particle size and total drug output from 3 nebulizers (the Pari LC Plus, the
      Pari LC Star, and the Medicaid Ventstream) was performed under simulated
      breathing conditions. Nebulizers were charged with 2 mL (500 microg) of
      budesonide suspension. A sinus pump was used to draw aerosol from the nebulizers
      onto a filter during simulated inspiration at tidal volumes of 150 and 600 mL,
      mimicking pediatric and adult use. Aerosol particle size was determined
      separately by inertial impaction. RESULTS: The LC Plus nebulizer had the highest
      initial output rate and delivered the most budesonide at both breathing patterns.
      The maximal output rates of the Ventstream and LC Star nebulizers was half that
      of the LC Plus, but the LC Star nebulizer continued nebulization for longer and
      delivered twice as much budesonide as the Ventstream did. However, the Ventstream
      produced the smallest particles, mass median diameter 3.1 microm compared with
      3.8 microm for the LC Star and 4.1 microm for the LC Plus. CONCLUSIONS: This
      study has identified differences among the nebulizers that would not have been
      apparent with current standards for nebulizer assessment. Incorporation of
      breathing simulation in the study imitates patient use and allows effective
      nebulization times to be predicted. The results suggest that the nebulizers
      studied would deliver different masses of budesonide to the lungs and to the
      upper airway. This may have important consequences in determining the efficacy
      and side effect profile of budesonide.

PMID- 10588998
TI  - Nitric oxide regulation of asthmatic airway inflammation with segmental allergen
      challenge.
AB  - BACKGROUND: Despite evidence of increased nitric oxide (NO) in asthmatic compared
      with healthy individuals, the role of NO in airway inflammation is unclear.
      OBJECTIVE: The purpose of the study was to determine the in vivo effects of
      localized allergen challenge on airway NO levels and transcription factor
      activation. METHODS: In this study localized allergen challenge was used as a
      model of asthmatic exacerbation to determine the relationship of NO to airway
      inflammation. RESULTS: With allergen challenge, asthmatic patients had a rise in
      airway NO levels, whereas NO levels in healthy controls did not change. The
      increased NO in asthma with allergen challenge compared with healthy control
      subjects was associated with an increase in inflammatory cytokines (GM-CSF and
      macrophage inflammatory protein-1) in epithelial lining fluid and eosinophilic
      infiltrate in bronchoalveolar lavage fluid (BAL) and biopsy specimens. To
      investigate the mechanisms of cytokine gene expression, activation of the
      transcription factors activator protein-1 and nuclear factor-kappaB (NF-kappaB)
      in cells from BAL were evaluated. Activator protein-1 was not activated before or
      after local allergen challenge. In contrast, NF-kappaB activation was less in BAL
      cells from asthmatic patients with increased NO in comparison with controls.
      CONCLUSION: Our studies are the first to suggest an inverse correlation between
      NF-kappaB and airway NO in a localized segmental allergen challenge model in
      allergic asthmatic patients. The current study demonstrates that activation of
      the inflammatory response (eg, cytokines, cellular infiltrate) in allergic
      asthmatic patients is temporally associated with increased airway NO. We propose
      that NO that is up-regulated by cytokines is part of an autoregulatory feedback
      loop (ie, allergen challenge stimulates inflammatory cytokine production, which
      in turn stimulates NO production, and NO down-regulates cytokine production).

PMID- 10588999
TI  - Nasal challenge with diesel exhaust particles can induce sensitization to a
      neoallergen in the human mucosa.
AB  - BACKGROUND: Diesel exhaust particles (DEPs) increase in vivo IgE and cytokine
      production at the human upper respiratory mucosa, exacerbating allergic
      inflammation. OBJECTIVE: We examined the ability of DEP exposure to lead to
      primary sensitization of humans by driving a de novo mucosal IgE response to a
      neoantigen, keyhole limpet hemocyanin (KLH). METHODS: Ten atopic subjects were
      given an initial nasal immunization with 1 mg of KLH followed by 2 biweekly nasal
      challenges with 100 microg of KLH. Identical nasal KLH immunization was then
      performed on 15 different atopic subjects, but DEPs were administered 24 hours
      before each KLH exposure. RESULTS: Exposure to KLH alone led to the generation of
      an anti-KLH IgG and IgA humoral response, which was detected in nasal fluid
      samples. No anti-KLH IgE appeared in any subjects. In contrast, when challenged
      with KLH preceded by DEPs, 9 of the 15 subjects produced anti-KLH-specific IgE.
      KLH-specific IgG and IgA at levels similar to that seen with KLH alone could also
      be detected. Subjects who received DEPs and KLH had significantly increased IL-4,
      but not IFN-gamma, levels in nasal lavage fluid, whereas these levels were
      unchanged in subjects receiving KLH alone. CONCLUSION: These studies demonstrate
      that DEPs can act as mucosal adjuvants to a de novo IgE response and may increase
      allergic sensitization.

PMID- 10589000
TI  - A 1-year study of salmeterol powder on pulmonary function and hyperresponsiveness
      to methacholine.
AB  - BACKGROUND: Long-acting beta(2)-sympathomimetic agonists such as salmeterol have
      been proved safe and effective for the treatment of asthma. However, controversy
      still exists as to the appropriateness of scheduled long-term therapy with these
      agents. OBJECTIVE: This study assessed the degree of bronchodilation provided by
      treatment with salmeterol for a period of 52 weeks and evaluated bronchial
      hyperresponsiveness to methacholine during and after the treatment period.
      METHODS: Three hundred fifty-two patients with mild to moderate asthma were
      assessed by 12-hour serial spirometry and serial methacholine challenge tests.
      RESULTS: The mean area under the FEV(1) curve above baseline over 12 hours after
      drug at day 1 was significantly greater with salmeterol powder compared with
      placebo (5.06 liter hours vs 0.77 L/h) and did not change significantly over 1
      year. The mean increase in the log(2) of the provocative cumulative methacholine
      dose producing a 20% decrease in FEV(1) (PD(20)FEV(1)) during treatment was
      significantly higher in the salmeterol-treated patients than in the placebo group
      (1.02 doubling doses vs 0.43 doubling doses at week 4, 1.06 doubling doses vs
      0.41 doubling doses at week 24). At week 52 the increase from baseline in
      log(2)PD(20)FEV(1) was not significantly different between salmeterol and placebo
      (1.08 vs 0.69 doubling doses). Seven days after treatment the log(2)PD(20)FEV(1)
      was -0.60 doubling doses lower than baseline for salmeterol compared with 0.10
      doubling doses for placebo (P =.031). Long-term salmeterol use was not associated
      with a deleterious effect on asthma control during and after treatment.
      CONCLUSION: This study demonstrates that the bronchodilator properties of
      salmeterol are sustained over 52 weeks and that bronchial hyperresponsiveness to
      methacholine is decreased to a modest degree during treatment. Clinically
      significant increases in hyperresponsiveness did not develop after
      discontinuation of salmeterol treatment.

PMID- 10589001
TI  - Increased specific airway reactivity of persons with mild allergic asthma after
      7.6 hours of exposure to 0.16 ppm ozone.
AB  - BACKGROUND: Exposure to ozone causes decrements in lung function, increased
      airway reactivity to nonspecific bronchoconstrictors, and lung inflammation.
      Epidemiology studies show an association between ambient oxidant levels and
      increased asthma attacks and hospital admissions. OBJECTIVE: The purpose of our
      study was to evaluate the response of persons with mild asthma to inhaled
      allergen after ozone exposure conditions similar to those observed in urban areas
      of the United States. METHODS: Using a double-blind, counter-balanced design, we
      exposed 9 (5 women and 4 men) subjects with mild atopic asthma (house dust mite
      sensitive) to clean air and to 0.16 ppm ozone for 7.6 hours; exposures were
      separated by a minimum of 4 weeks. During exposure, subjects performed light
      exercise (ventilation = 24 L/min) for 50 minutes of each hour, and pulmonary
      function was evaluated before and after exposures. The morning after exposure,
      subjects underwent bronchial challenge with inhaled house dust mite allergen
      (Dermatophagoides farinae). Using a series of doubling allergen concentrations,
      subjects inhaled 5 breaths of nebulized allergen (0.06 to 500 AU/mL) at 10-minute
      intervals until a minimum of a 20% decrement in FEV(1) was elicited. RESULTS:
      Compared with the change in FEV(1) during air exposure, there was a mean 9.1% +/-
      2.5% (SEM) decrement in FEV(1) observed because of ozone (P <.01). Seven of the 9
      subjects required less allergen after ozone exposure than after air exposure;
      there was a 0.58 mean dose shift in the doubling concentration of allergen
      attributable to the ozone exposure (P =.03). CONCLUSION: These findings indicate
      that exposure of subjects with mild atopic asthma to ozone at levels sufficient
      to cause modest decrements in lung function also increases the reactivity to
      allergen. To the extent that this effect occurs in response to ambient exposures,
      ozone may be contributing to the aggravation of asthma.

PMID- 10589002
TI  - The output of budesonide from spacer devices assessed under simulated breathing
      conditions.
AB  - BACKGROUND: Spacer devices are increasingly used to aid inhalational therapy, and
      many different devices are available. Patient and spacer size and spacer static
      charge may affect drug delivery, but the optimum spacer size and method of
      reducing static charge is not certain. OBJECTIVE: We sought to determine the
      output of budesonide from 3 different spacer devices when assessed by using
      simulated breathing at different tidal volumes and to assess the effect of
      washing and handling the spacer on drug output. METHODS: Three spacer types were
      assessed: 2 polycarbonate spacers, the Aerochamber and the Nebuhaler, and the
      metal Nebuchamber or Non-Electrostatic-Spacer. Breathing was simulated by using a
      sinus flow pump. Metered-dose inhalers of budesonide 200 microg were actuated
      into the spacer, which was attached to the breathing simulator for 5 simulated
      breathing cycles. Budesonide was collected on a filter placed between the spacer
      and breathing simulator and was assayed by HPLC. Spacers were assessed after they
      had been washed briefly in water, after they had been washed briefly in cetrimide
      solution in an attempt to reduce their static charge, and after they had been
      handled to simulate normal use. In separate experiments budesonide particle size
      from the spacers was measured by using a multistage liquid impinger. RESULTS:
      Drug output from the Nebuchamber was greater than that from the other 2 spacers,
      especially at lower tidal volumes. With 150 mL of tidal volume, the Nebuchamber
      delivered 36% of the nominal dose to the filter versus 13% from the Nebuhaler and
      7% from the Aerochamber. The output from the Aerochamber and Nebuhaler increased
      linearly with tidal volume, but this was not the case with the Nebuchamber, in
      which output was constant at tidal volumes of 150 mL and above. Compared with
      washing in tap water, neither washing the spacers in 0.1% cetrimide solution nor
      vigorous wiping with a paper towel changed their output. Thirty-eight percent of
      the drug from the Nebuchamber was contained in particles smaller than 4.7 microm
      in diameter compared with 47% from the Nebuhaler and 53% from the Aerochamber.
      CONCLUSIONS: The Nebuchamber increases in vitro budesonide delivery compared with
      the polycarbonate spacers tested but delivers a greater percentage of the drug in
      large particles. No increase in delivery with tidal volume was seen with the
      Nebuchamber, which would deliver a higher dose of drug per kilogram of body
      weight to smaller patients. Briefly washing the polycarbonate spacers in water or
      in a weak detergent solution, simulating household washing, did not make them as
      effective as the metal spacer. Further research is needed to determine a
      practical washing and handling method to reduce static charge on polycarbonate
      spacers.

PMID- 10589003
TI  - Mycobacterium tuberculosis infection and the subsequent development of asthma and
      allergic conditions.
AB  - BACKGROUND: Epidemiologic studies have suggested that certain viral infections,
      as well as exposure to Mycobacterium tuberculosis in early life, could, at least
      to some extent, prevent the subsequent development of atopic disease. OBJECTIVE:
      We investigated whether M tuberculosis infection in childhood or adolescence has
      any effect on the development of asthma and allergic conditions in later life.
      METHODS: The study subjects (n = 1162) were individuals notified to the National
      Tuberculosis Registry between January 1, 1966, and December 31, 1969, who were 20
      years of age or younger and had verified or justifiably probable new active
      tuberculosis of respiratory or other organs. The control subjects were age
      matched, sex-matched, and geographically matched control pairs from the
      Population Registry of the Social Insurance Institution in Finland. The subjects
      were followed for 28 to 32 years. The prevalence of persistent asthma and
      allergic conditions among men and women at the end of 1997 were calculated on the
      basis of the Drug Reimbursement Registry of the Social Insurance Institution in
      the whole study population and in the subgroup of subjects aged 16 years or
      younger at the time of M tuberculosis infection. RESULTS: In women a
      significantly lower prevalence of persistent asthma was found among those aged 16
      years or younger at the time of M tuberculosis infection than among the control
      subjects (3.7% vs 8.3%, respectively; P =.035). The women with a history of
      tuberculosis also showed a significantly lower prevalence of allergic conditions
      than the control subjects (8.3% vs 14.0%, respectively; P =.003) when the whole
      study population of women was considered. In men, however, the only significant
      difference between the cases and control subjects was found for persistent
      asthma, with the cases showing a significantly higher prevalence than the control
      subjects (4.4% and 1.8%, respectively; P =.008). CONCLUSION: M tuberculosis
      infection in childhood significantly reduced the occurrence of subsequent asthma
      in women. Moreover, this infection was also found to reduce the occurrence of
      allergic conditions in later life in women. By contrast, no suppressive effect of
      M tuberculosis infection in childhood or adolescence on the later development of
      asthma or allergic conditions could be observed in men. The differences in the
      natural history of atopic disease between the sexes and the occurrence of
      tuberculosis mostly in later childhood and adolescence may largely explain our
      findings.

PMID- 10589004
TI  - Efficacy response of inhaled beclomethasone dipropionate in asthma is
      proportional to dose and is improved by formulation with a new propellant.
AB  - BACKGROUND: This study tested the hypothesis that there would be improved asthma
      control with increasing doses of beclomethasone dipropionate (BDP) formulated in
      hydrofluoroalkane-134a (HFA-BDP) and the standard chlorofluorocarbon propellants
      (CFC-BDP). Because HFA-BDP has improved lung deposition compared with CFC-BDP,
      this study also tested the hypothesis that HFA-BDP would provide more effective
      control of asthma than CFC-BDP. METHODS: In this multicenter, randomized,
      parallel-group blinded study, asthmatic subjects who had deterioration in asthma
      control after discontinuation of inhaled corticosteroids were randomized to
      receive one of 6 possible treatments: 100 microg/d, 400 microg/d, or 800 microg/d
      of HFA-BDP or 100 microg/d, 400 microg/d, or 800 microg/d of CFC-BDP for 6 weeks.
      Changes in spirometry, daytime asthma symptom and nighttime asthma-related sleep
      disturbance scores, morning and evening peak expiratory flows, and daily use of
      inhaled beta-agonist for symptom control on diary cards were assessed over 6
      weeks of treatment. RESULTS: Three hundred twenty-three patients were randomized
      to the 6 treatment groups, which had similar demographics and baseline lung
      function. There were significantly larger changes from baseline at week 6 in
      FEV(1) percent predicted with increasing doses of both HFA-BDP and CFC-BDP. The
      FEV(1) percent predicted dose-response curve for HFA-BDP was shifted to the left
      compared with the dose-response curve for CFC-BDP. By using the Finney bioassay
      method, it was calculated that 2.6 times as much CFC-BDP would be required to
      achieve the same improvement in FEV(1) percent predicted as HFA-BDP (95%
      confidence interval, 1.1-11.6). All treatment groups except the 100 microg/d CFC
      BDP group tolerated study drug well. Ten (17%) of 59 patients in this group
      reported an acute asthma episode, increased asthma symptoms (6 of the 8 reports
      of increased asthma symptoms were classified as severe), or both, and 8 patients
      withdrew from the study (3 for adverse events related to asthma). CONCLUSIONS:
      Increasing doses of inhaled corticosteroids lead to improved lung function and
      asthma control. Moreover, the reformulation of BDP in HFA enables effective
      asthma control at much lower doses than CFC-BDP.

PMID- 10589005
TI  - Purified natural and recombinant Fel d 1 and cat albumin in in vitro diagnostics
      for cat allergy.
AB  - BACKGROUND: Current diagnostics and therapeutics for cat allergy are based on cat
      epithelial extracts originating from highly variable source materials. This gives
      rise to several problems: variability of allergen composition, contamination with
      house dust mite allergens, and potential transfer of pathogenic agents.
      OBJECTIVE: The aim of this study was to investigate the feasibility of replacing
      cat epithelial extracts with purified natural or recombinant allergens. METHODS:
      Sera (n = 509) were selected on the basis of a positive cat RAST result and
      tested in a RAST for IgE reactivity to purified Fel d 1, cat albumin (CA), or
      both. The analysis was performed with both natural and recombinant allergens. In
      addition, some sera were further analyzed by means of immunoblotting. A serum
      pool was used for cat RAST inhibition with purified natural and recombinant
      allergens as inhibitors. RESULTS: Natural and recombinant Fel d 1 caused very
      similar results: 94.1% and 96.1% positive test results, respectively. In general,
      the negative sera were low responders to cat extract. The addition of CA (16.7%
      positive sera) resulted in a decrease in the number of discrepencies between
      purified allergens and whole extract to 2.8%. Only for 2% of all sera,
      sensitization to cat was largely explained by IgE reactivity to CA. IgE
      reactivity to Fel d 1 accounts for 88% of the total IgE response to cat
      allergens, as was demonstrated by RAST, with Fel d 1 concentrations nearing
      saturation. Recombinant Fel d 1 performed equally well in the RAST analysis.
      Recombinant CA was succesfully expressed in the yeast Pichia pastoris, and its
      immune reactivity closely resembled that of its natural counterpart. CONCLUSION:
      Natural and recombinant Fel d 1 and CA are good candidates for replacing ill
      defined cat dander extracts in diagnostics for cat allergy. Although CA is not
      essential for the vast majority of cat-sensitized patients, some subjects are
      selectively sensitized to this serum protein.

PMID- 10589007
TI  - Reduced in vivo allergenicity of Bet v 1d isoform, a natural component of birch
      pollen.
AB  - BACKGROUND: The major allergen of birch pollen, Bet v 1, is present in
      structurally slightly different isoforms. It has been postulated that certain
      isoforms show a distinct ability to bind birch pollen-specific IgE, although the
      T-cell response remains similar. OBJECTIVE: We verified the hypothesis of a
      distinct allergenicity but similar T-cell immunogenicity of 2 isoforms in birch
      pollen-allergic subjects by in vivo tests and an in vitro assay for T-cell
      stimulation. METHODS: Forty-eight birch pollen-allergic, 11 grass pollen
      allergic, and 10 nonatopic control individuals were tested with 10-fold
      increasing concentrations (0.01 to 10.0 microg/mL) of recombinant (r) Bet v 1a
      and rBet v 1d by skin prick test (SPT), intradermal test (IDT), and conjunctival
      provocation test (CPT). An allergen-specific proliferation assay was performed on
      21 patients with the 2 recombinant and the natural birch pollen allergens.
      RESULTS: In each test system only birch pollen-allergic subjects but no controls
      reacted to the recombinant allergens. A positive in vivo response to 10 microg/mL
      of rBet v 1a was observed in 21 of 48 by SPT, in 48 of 48 by IDT, and in 33 of 48
      by CPT. In contrast, the IDT response to 10 microg/mL of rBet v 1d was reduced by
      a factor of 100 because it was equivalent to the response to 0.1 microg/mL of
      rBet v 1a. rBet v 1d failed to elicit a positive reaction in SPT and CPT. The
      proliferative response of T cells was similar for both recombinant isoforms
      because 8 of 21 individuals reacted to rBet v 1a and 6 of 21 to rBet v 1d. Only 1
      subject had a positive reaction to rBet v 1d alone. CONCLUSION: The natural
      isoforms rBet v 1a and rBet v 1d differ in their ability to bind IgE but are
      similar in their immunogenicity for T cells. Thus rBet v 1d might be a promising
      candidate for use in immunotherapy of birch pollen-allergic individuals.

PMID- 10589008
TI  - Ligation of CD45 and the isoforms CD45RA and CD45RB accelerates the rate of
      constitutive apoptosis in human eosinophils.
AB  - BACKGROUND: Eosinophils are important effector cells in asthma pathogenesis, and
      an understanding of the mechanisms involved in eosinophil apoptosis induction
      might thus be relevant to the resolution of asthmatic inflammation. OBJECTIVE:
      Our aim was to determine the role of the common leukocyte antigen CD45 and the
      isoforms CD45RA, CD45RB, and CD45RO in human eosinophil apoptosis induction.
      METHODS: Immmunostaining and flow cytometry were used to assess CD45 and CD45
      isoform expression by eosinophils purified with use of density gradients and
      immunomagnetic negative selection. Apoptosis induction was measured by binding of
      fluorescein isothiocyanate-labeled annexin V to eosinophils cultured for 20 hours
      alone or with saturating quantities of mAb against CD45, CD45RA, CD45RB, CD45RO,
      CD9, CD11b, and isotype-matched controls in the presence or absence of GM-CSF.
      RESULTS: Freshly isolated eosinophils had high expression of CD45 and CD45RO,
      modest expression of CD45RB, and low expression of CD45RA. Eosinophils cultured
      alone for 20 hours were found to be approximately 20% to 25% apoptotic.
      Incubation with mAb against CD45, CD45RA, and CD45RB resulted in significant (P
      <.005) enhancement (>100%) of their constitutive rate of apoptosis. Incubation
      with CD45RO, CD11b, CD9 mAb, or isotype controls had no significant effect on the
      rate of eosinophil constitutive apoptosis. The addition of GM-CSF inhibited
      eosinophil apoptosis but did not prevent CD45, CD45RA, or CD45RB mAb-dependent
      apoptosis induction. CONCLUSION: These data indicate that ligation of CD45,
      CD45RA, or CD45RB represents a novel pathway for the induction of apoptosis in
      human eosinophils.

PMID- 10589006
TI  - Immunostimulatory oligodeoxynucleotide induces TH1 immune response and inhibition
      of IgE antibody production to cedar pollen allergens in mice.
AB  - BACKGROUND: Immunotherapy for cedar pollinosis makes use of multiple injections
      of allergens, but its effectiveness remains controversial. Recent studies
      indicate that immunization with certain protein antigens and immunostimulatory
      DNA sequence (ISS) oligodeoxynucleotides (ODNs) represent a potential approach to
      allergen-specific immunotherapy. OBJECTIVE: We determined whether the
      coadministration of 2 major protein allergens, Cry j 1 and Cry j 2, of Japanese
      cedar pollen and ISS-ODN (5'-TGACTCTGAACGTTCGAGATGA-3') improves the immune
      responses induced by protein allergens in BALB/c mice. METHODS: Mice were primed
      intradermally with allergens or ISS-ODN in saline solution and boosted with
      allergens in alum, and other mice were primed with allergens in alum and boosted
      with allergens/ISS-ODN. Allergen-specific IgG2a and IgG1 antibody responses were
      measured by means of ELISA in sera after ODN injection, and allergen-specific IgE
      antibody production was measured by the passive cutaneous anaphylaxis reaction.
      IFN-gamma and IL-4 releases were also measured by ELISA in the supernatants of
      allergen-stimulated spleen cells. RESULTS: The coadministration of allergens/ISS
      ODN increased IgG2a titers and IFN-gamma release in both groups of mice, whereas
      it decreased IgG1 titers and IL-4 release in comparison with control mice
      injected with allergens/mutant ODN. The coadministration additionally inhibited
      IgE antibody production. CONCLUSION: The data demonstrate that the
      coadministration of cedar pollen allergens and ISS-ODNs before secondary T(H2)
      and IgE responses or during ongoing primary T(H2) and IgE responses brings about
      a T(H1)-shifted immune response and inhibition of IgE antibody production,
      suggesting that this coadministration strategy may provide a novel type of
      immunotherapy for cedar pollinosis.

PMID- 10589009
TI  - Transforming growth factor-beta in breast milk: a potential regulator of atopic
      disease at an early age.
AB  - BACKGROUND: According to data from animal and in vitro studies, transforming
      growth factor-beta (TGF-beta) has a crucial effect on 2 essential parts of the
      mucosal immune system: IgA production and oral tolerance induction. OBJECTIVE: We
      sought to ascertain whether TGF-beta in breast milk is associated with specific
      IgA production and atopic disease in human subjects. METHODS: Forty-seven infants
      with several atopic family members were followed during their first year of life.
      The concentrations of TGF-beta1 and TGF-beta2 in maternal colostrum, mature milk,
      and the infants' sera were determined. The enzyme-linked immunospot assay was
      used to assess the infants' specific IgA production in response to beta
      lactoglobulin, casein, gliadin, and ovalbumin. RESULTS: At 12 months, atopic
      dermatitis was confirmed in 29 of 47 infants; in 11, atopic disease had begun
      during exclusive breast-feeding (preweaning onset), whereas in 18 the disease
      manifested itself after weaning (postweaning onset). The concentrations of both
      TGF-beta1 and TGF-beta2 were higher in maternal colostrum, but not in mature milk
      and infants' serum, in infants with postweaning-onset atopic disease compared
      with those with preweaning-onset disease (P =.0008 and P =. 015, respectively).
      The concentration of TGF-beta2 was, and that of TGF-beta1 tended to be, higher in
      the colostrum of mothers whose infants had specific IgA-secreting cells at 3
      months in response to at least one of the dietary antigens tested compared with
      those who did not have such cells (P =.048 and P =.076, respectively).
      CONCLUSION: TGF-beta in colostrum may prevent the development of atopic disease
      during exclusive breast-feeding and promote specific IgA production in human
      subjects.

PMID- 10589010
TI  - CpG oligodeoxynucleotides do not require TH1 cytokines to prevent eosinophilic
      airway inflammation in a murine model of asthma.
AB  - BACKGROUND: Oligodeoxynucleotides (ODNs) containing the dinucleotide CpG in a
      specific sequence context (CpG-ODNs) have the ability to prevent the development
      of eosinophilic airway inflammation and bronchial hyperreactivity in a murine
      model of asthma. We have previously demonstrated that CpG-ODNs stimulate
      expression of the T(H1)-inducing cytokines IFN-gamma and IL-12 in a murine model
      of asthma and that this stimulation is associated with the protection against
      asthmatic inflammation. OBJECTIVE: The purpose of this study was to examine
      whether the protection conferred by CpG-ODNs in a schistosome egg-egg antigen
      murine model of asthma is dependent on the induction of IFN-gamma, IL-12, or
      both. METHODS: C57BL/6 mice were sensitized to schistosome eggs in the presence
      or absence of CpG-ODNs or control ODNs and then stimulated with soluble egg
      antigen in the airway. The protection offered by CpG-ODNs in these mice was
      compared with the protection induced by CpG-ODNs in IL-12 and IFN-gamma knockout
      mice and in mice treated with anticytokine blocking antibodies. Double-knockout
      mice (IL-12/IFN-gamma) were also generated and used in these studies.
      Determinations included airway eosinophilic inflammation and bronchial
      hyperreactivity to inhaled methacholine. RESULTS: We found that CpG-ODNs confer
      protection against both airway eosinophilia and bronchial hyperreactivity in the
      absence of IFN-gamma or IL-12 or in the presence of both cytokines together.
      However, in the absence of either IL-12 or IFN-gamma, mice require 10 times as
      much CpG-ODNs to be protected against the induction of airway eosinophilia. The
      T(H2) cytokines IL-4 and IL-5 were reduced in all of the CpG-treated mice,
      although less in the absence of IL-12 and IFN-gamma. CONCLUSION: These data
      indicate that CpG-ODNs prevent the generation of T(H2)-like immune responses by
      multiple mechanisms, which involve, but do not require, IL-12 and IFN-gamma. A
      direct suppressive effect of CpG-ODNs on T(H2) responses is suggested by their
      reduction in IFN-gamma and IL-12 knockout mice.

PMID- 10589011
TI  - Sensitization to Aspergillus species in the congenital neutrophil disorders
      chronic granulomatous disease and hyper-IgE syndrome.
AB  - BACKGROUND: Hyper-IgE syndrome (HIE) and chronic granulomatous disease (CGD) are
      congenital immunodeficiency diseases with increased susceptibility to bacterial
      and fungal infections. Both carry significant morbidity and mortality rates
      because of invasive infections by Aspergillus species. We encountered 2 patients,
      one with HIE and one with CGD, in whom detection of sensitization to Aspergillus
      species preceded the diagnosis of immunodeficiency. With high-dose systemic
      corticosteroids for allergic bronchopulmonary aspergillosis (ABPA), an
      inflammatory disorder caused by sensitization to Aspergillus species, pulmonary
      abscesses developed in the patient with HIE, and the patient with CGD succumbed
      to an overwhelming Aspergillus species-induced pneumonia. OBJECTIVE: We sought to
      assess the prevalence of sensitization to Aspergillus fumigatus and the presence
      of diagnostic criteria for ABPA in patients with CGD and HIE. METHODS: We
      measured A fumigatus-specific serum IgE, IgG, and precipitating antibodies as
      indicators for A fumigatus sensitization in the sera of 18 patients with
      neutrophil disorders (7 with HIE and 11 with CGD). Hospital records were reviewed
      for the presence of other diagnostic criteria for ABPA (asthma, elevated total
      serum IgE concentration, and radiographic abnormalities). RESULTS: Twelve (67%)
      of 18 patients were sensitized to A fumigatus, as evidenced by precipitating A
      fumigatus-specific antibodies. Six (33%) of 18 patients had serologic evidence of
      ABPA. Five of those 6 patients had radiologic abnormalities consistent with a
      diagnosis of ABPA. One patient with HIE also had asthma, thus fulfilling minimal
      essential criteria for concurrent ABPA. CONCLUSIONS: Patients with HIE syndrome
      and CGD have a high incidence of sensitization to Aspergillus species. A clinical
      picture indistinguishable from ABPA may coexist or emerge in patients with CGD or
      HIE and create a major management dilemma because systemic corticosteroids may
      accelerate tissue damage and invasive fungal infections. It is important to
      distinguish individuals with congenital neutrophil disorders from uncomplicated
      classic ABPA.

PMID- 10589012
TI  - Use of specific IgE in assessing the relevance of fungal and dust mite allergens
      to atopic dermatitis: a comparison with asthmatic and nonasthmatic control
      subjects.
AB  - BACKGROUND: Although allergens have been implicated as aggravating factors in
      atopic dermatitis (AD), there is little epidemiologic data on the significance of
      specific IgE. OBJECTIVE: We sought to compare sensitization to dust mite and
      fungi between patients with AD and asthmatic and nonasthmatic control subjects.
      METHODS: Total IgE and specific IgE to Dermatophagoides pteronyssinus, Alternaria
      alternata, Aspergillus fumigatus, Candida albicans, Malassezia furfur, and
      Trichophyton rubrum were measured in 73 patients with moderate to severe AD.
      Total IgE and IgE specific for D pteronyssinus, A alternata, and M furfur were
      also measured in sera from 156 asthmatic and 212 nonasthmatic control subjects.
      RESULTS: Positive correlations were found between total IgE and IgE antibodies
      specific for each of the antigens. IgE specific for M furfur was observed more
      frequently in adults compared with children with AD (P <.01). AD sera had higher
      levels of total IgE and a higher prevalence of positive sera to D pteronyssinus
      (95% vs 42% and 17% for subjects with AD, asthmatic subjects, and nonasthmatic
      subjects, respectively), M furfur (53% vs 1% and 0.5%), and A alternata (49% vs
      29% and 18%). Among the sera from subjects allergic to mites, the contribution of
      IgE specific for D pteronyssinus to the total IgE levels was similar regardless
      of the clinical status. CONCLUSIONS: Our results demonstrate that moderate-to
      severe AD is strongly associated with sensitization to dust mite andM furfur
      (odds ratios, 45.6 and 132 vs pooled control sera). These results suggest that
      both environmental allergens and colonizing fungi contribute to the severity of
      disease, which is consistent with the view that mite avoidance and antifungal
      treatment can be beneficial in the treatment of these patients.

PMID- 10589013
TI  - Association between severity of atopic eczema and degree of sensitization to
      aeroallergens in schoolchildren.
AB  - BACKGROUND: A subgroup of patients with atopic eczema exhibits aggravation
      through contact with aeroallergens. Little is known from population-based
      studies, however, about the association between the severity of eczematous skin
      disease and the degree of aeroallergen sensitization. OBJECTIVE: We sought to
      investigate the relationship between IgE-mediated allergic sensitization to
      aeroallergens and severity of atopic eczema in schoolchildren. METHODS: A nested
      case-control analysis on atopic eczema was performed on the basis of a cross
      sectional study of 2201 East German schoolchildren aged 5 to 14 years. Atopic
      eczema and its severity was identified by dermatologic examination. Total and
      allergen-specific IgE antibodies to grass and birch pollen, Cladosporium
      herbarum, Dermatophagoides pteronyssinus, and cat epithelium in serum were
      determined, and additional information was obtained by means of standardized
      questionnaire. RESULTS: The overall prevalence of actual atopic eczema was 2.5%.
      Thirty-seven percent of the children were sensitized to at least one allergen.
      Children with atopic eczema were significantly more often sensitized than those
      without skin disease (75.0% vs 36.3%; odds ratio, 5.27; 95% confidence interval,
      2.54-11.15). This was observed for each single allergen. The prevalence of atopic
      eczema increased significantly with increasing RAST class (chi(2) trend test for
      each allergen, P <.0001). Also, the prevalence of sensitization increased with
      the severity of the disease (chi(2) trend test for each allergen, P <.0001). This
      association was pronounced for house dust mite and cat allergen. Multiple linear
      regression analyses showed significant associations between the severity score of
      atopic eczema and concentrations of allergen-specific IgE to dust mite (P =.032)
      and cat (P =.014) allergens after adjustment for sex, age, location, and parental
      predisposition. CONCLUSIONS: The degree of sensitization is directly associated
      with the severity of atopic eczema. We speculate that early epicutaneous
      sensitization to aeroallergens may be enhanced by damage of the skin barrier
      function. The specific IgE response seems to contribute to the severity of the
      disease in a dose-dependent fashion.

PMID- 10589014
TI  - Spider mite allergy in apple-cultivating farmers: European red mite (Panonychus
      ulmi) and two-spotted spider mite (Tetranychus urticae) may be important
      allergens in the development of work-related asthma and rhinitis symptoms.
AB  - BACKGROUND: Recent investigations have suggested that the citrus red mite
      (Panonychus citri) is the most important allergen affecting citrus-cultivating
      farmers with asthma, allergic rhinitis, or both. OBJECTIVE: We sought to evaluate
      type I hypersensitivity to spider mites, particularly the European red mite
      (Panonychus ulmi) and the two-spotted spider mite (Tetranychus urticae), and to
      determine the relationship between hypersensitivity to spider mites and
      respiratory dysfunction. METHODS: We performed a cross-sectional survey.
      Questionnaires were given, and skin prick tests for 11 inhalant allergens common
      in Korea and 2 species of spider mites (European red mite and two-spotted spider
      mite) were performed in 725 apple-cultivating farmers in Korea. RESULTS: Results
      of skin prick tests in the apple farmers indicated that European red mite (23.2%)
      was the most common sensitizing allergen, followed by Tyrophagus putrescentiae
      (21.2%), two-spotted spider mite (16.6%), Dermatophagoides farinae (16.3%), D
      pteronyssinus (14.4%), cockroach (13.1%), and Hop Japanese (Humulus Japonicus)
      pollen (12.0%). Positive skin responses (mean wheal size >/=3 mm) to one or more
      of 13 inhalant allergens were found in 48.2% of farmers tested, whereas 40
      subjects (8.6%) had an isolated skin response to the spider mites. Among 119
      farmers with work-related asthmatic symptoms, the positive skin response rates to
      European red mite and two-spotted spider mite were 40.4% and 27.0%, respectively.
      These figures were significantly higher than those found among farmers without
      work-related symptoms (19.1% and 14.1%, respectively; P <.01). The prevalence of
      work-related asthma symptoms was higher in farmers with positive skin responses
      to spider mites than in those with negative skin responses to spider mites and
      those with positive skin responses to any allergen tested (31.4% vs 15.0% vs
      21.0%, respectively; P <.05). CONCLUSION: Spider mites, particularly European red
      mite and 2-spotted spider mite, are common sensitizing allergens in apple
      cultivating farmers. These spider mites may be important causative allergens in
      the development of work-related respiratory symptoms in these workers.

PMID- 10589015
TI  - IgE binding of the recombinant allergen soybean profilin (rGly m 3) is mediated
      by conformational epitopes.
AB  - BACKGROUND: Soybean proteins are constituents of a number of food products and
      represent a panel of potential allergens. Thus far, little is known about the
      molecular characteristics of soybean allergens. OBJECTIVE: The aim of this study
      was to identify the soybean profilin by PCR-based complementary (c)DNA cloning
      and to elucidate its allergenic characteristics. METHODS: Highly degenerate
      profilin-specific primers were used to identify, by means of PCR, 2 soybean
      profilin isoforms (GmPRO1 and GmPRO2) by using soybean cDNA as a target. One
      isoform (GmPRO1) with a length of 394 bp corresponding to 131 amino acid residues
      was subcloned and expressed in fusion with the maltose-binding protein. Moreover,
      3 overlapping recombinant soybean profilin fragments comprising amino acid
      residues 1-65, 38-88, and 50-131 were also prepared as maltose-binding protein
      fusion proteins. IgE-binding reactivity of the recombinant proteins and the cross
      reactivity of soybean profilin with birch profilin was studied by immunoblotting,
      enzyme-linked allergosorbent assays (EASTs), and competitive inhibition
      experiments by using serum samples from 13 soybean-sensitized subjects. RESULTS:
      Results of immunoblot analysis, EAST, and EAST-inhibition experiments indicate
      the presence of profilin in soybean extract. The recombinant soybean profilin
      (rGly m 3) was recognized by IgE in 9 (69%) of the 13 sera tested. Only the full
      length rGly m 3 was able to bind with IgE antibodies, whereas the 3 soybean
      profilin fragments did not show significant binding reactivity, indicating that
      the IgE binding to rGly m 3 depends on the integrity of a conformational
      structure, which was not present in the overlapping profilin fragments. The rGly
      m 3 cross-reacted with birch pollen profilin (Bet v 2), and the IgE binding to
      Bet v 2 could be inhibited by rGly m 3. CONCLUSIONS: rGly m 3 represents a new
      soybean allergen with well-characterized primary sequence, and its IgE-binding
      reactivity is mediated by conformational epitopes.

PMID- 10589017
TI  - Identification and cloning of a complementary DNA encoding a vicilin-like
      proprotein, jug r 2, from english walnut kernel (Juglans regia), a major food
      allergen.
AB  - BACKGROUND: Walnuts and other tree nuts are important food-allergen sources that
      have the potential to be associated with life-threatening, IgE-mediated systemic
      reactions in some individuals. OBJECTIVE: The purpose of this study was to
      characterize a complementary (c)DNA clone encoding one of the walnut food
      allergens. METHODS: A cDNA expression library prepared from walnut somatic embryo
      was screened for IgE reactivity with patient serum. A reactive clone of 2060 bp,
      which encoded a protein of 593 amino acids in length, was subcloned by excision
      into the pGEX expression vector. IgE-binding inhibition experiments were
      performed. RESULTS: A recombinant fusion protein was induced and shown to bind
      serum IgE from 9 of 15 patients tested, thus identifying a major allergen. This
      clone, named Jug r 2, exhibited significant homology with genes encoding the
      vicilin group of seed proteins. An IgE-binding inhibition experiment suggested
      that the encoded protein undergoes posttranslational modification into at least
      one major polypeptide (47 kd) and possibly several others, which is similar to
      the vicilin-like proteins characterized in cocoa bean (Theobroma cacao) and
      cottonseed (Gossypium hirsutum). N-terminal sequencing of the 47-kd band, Jug r
      2, identified it as a mature protein obtained from the precursor. A second IgE
      binding inhibition experiment showed that there is minimal or no cross-reactivity
      between Jug r 2 and pea vicilin, peanut proteins, or cacao proteins. CONCLUSION:
      Jug r 2 is the third vicilin food allergen identified in addition to vicilins
      from soy and peanut. The availability of recombinant food allergens should help
      advance studies on the immunopathogenesis and possible treatment of IgE-mediated
      food hypersensitivity.

PMID- 10589018
TI  - Local bradykinin generation in hereditary angioedema.

PMID- 10589016
TI  - Molecular and immunologic characterization of new isoforms of the Hevea
      brasiliensis latex allergen hev b 7: evidence of no cross-reactivity between hev
      b 7 isoforms and potato patatin and proteins from avocado and banana.
AB  - BACKGROUND: Hev b 7 is a Hevea brasiliensis latex allergen with sequence
      identities of 39% to 42% to patatins recently identified as potato allergens. The
      complementary DNAs encoding 2 different Hev b 7 isoforms were previously
      reported. OBJECTIVE: The aim of this study was to determine the sequence
      variation of Hev b 7 and to compare the IgE reactivity of individual isoforms in
      vitro and in vivo. A further objective was to evaluate possible cross
      reactivities between Hev b 7 and patatins and proteins from banana and avocado.
      METHODS: An H brasiliensis lambda ZAP complementary DNA (cDNA) library was
      screened with use of a Hev b 7 cDNA probe. Four Hev b 7 isoforms were produced in
      recombinant form and their IgE-binding capacities were compared. IgE immunoblot
      inhibitions and ELISA inhibition assays were used to investigate the possible
      cross-reactivity between Hev b 7 and recombinant potato patatin and proteins from
      avocado and banana. RESULTS: Two new isoforms, S2 and D2, were identified by
      sequencing 32 cDNA clones with full-length coding regions. All 4 recombinant
      isoforms displayed esterase activity and identical IgE-binding capacities. The
      new isoforms S2 and D2 were evaluated in skin prick tests and provoked responses
      equivalent to natural Hev b 7. No cross-reactivity was observed between Hev b 7
      isoforms and potato patatin and proteins from avocado and banana. CONCLUSIONS:
      All 4 recombinant Hev b 7 isoforms have equivalent IgE-binding capacity and
      therefore represent suitable reagents for the development of in vitro and in vivo
      diagnostic tests. Hev b 7, patatins, and their homologs appear not to contribute
      to cross-reactivity in the latex-fruit syndrome.

PMID- 10589019
TI  - Allergen avoidance is associated with a fall in exhaled nitric oxide in asthmatic
      children.

PMID- 10589020
TI  - Age-related changes in the hamster epididymis.
AB  - Reproductive ability is decreased in aged animals and in men. Little is known
      about the changes taking place in the epididymis, and the possible influence on
      the loss of sperm quality. We studied the age-related alterations in the
      epididymis and in epididymal spermatozoa of hamsters. Adult (6-month-old), middle
      aged (18-month-old), and aged (24-month-old) hamsters were used. Serum samples
      were obtained to determine testosterone levels. Testes and epididymides were
      removed and studied by light and electron microscopy. Epididymal sperm was also
      obtained and the motility, position of cytoplasmic droplet, and concentration
      were evaluated. Measurements of the height of the epithelium, length of
      stereocilia, external tubular diameter, and thickness of the muscular wall were
      performed. The proliferative activity was also studied. An ANOVA analysis was
      used to compare quantitative differences between epididymal zones and age groups.
      Aged hamsters presented involutive changes in the epididymis. A decrease in
      tubular diameter was found in cauda; principal cell ultrastructure showed changes
      including the appearance of damaged mitochondria, bundles of filaments, and the
      accumulation of lipofuscin. Some clear cells showed an unusual morphology by the
      presence of large electrondense vacuoles. A reduction in sperm quality was also
      observed, including a decrease in sperm motility and concentration, and
      alterations in the migration of sperm cytoplasmic droplet. Testosterone levels
      and cellular proliferative activity did not change. Aging causes a morphological
      alteration of hamster epididymis (mainly in the cauda), and a decrease in sperm
      quality.

PMID- 10589021
TI  - Occurrence of mast cells within bundles of myelinated and unmyelinated nerves in
      the rat tongue.
AB  - The rat tongue has been the subject of many cytological studies, both purely
      descriptive and experimental. To assess the suitability of the organ for
      additional cytological and histological senior research thesis projects, light
      and transmission electron microscope studies of thin and ultrathin sections,
      respectively, were conducted. Several samples from the anterior dorsal surface of
      the tongue of a male rat (Sprague-Dawley) were processed conventionally for light
      and electron microscope study. About 170 sections, each approximately 1 x 1 mm in
      area and 1.0 microm thick, collected from 12 adjacent areas, all including the
      mucosa, of a tongue were studied in the light microscope. Numerous mast cells
      were observed scattered throughout the submucosal region, adjacent to nerve
      bundles, blood vessels, and skeletal muscle, and up to six bundles each
      consisting of many myelinated and unmyelinated nerve processes were seen per
      section. Single, double, and quadruple myelinated nerve processes were also seen.
      Several of the multiple, mixed nerve bundles contained a mast cell. Mast cells
      were not found within the endoneurium or perineurium of exclusively myelinated
      processes. Ultrathin sections adjacent to the thin sections containing mast cells
      within the nerve bundles were sought and studied in the transmission electron
      microscope to confirm the identification of these mast cells. Mast cells occur
      within bundles containing both myelinated and unmyelinated nerves in the rat
      tongue, and this is an apparently previously unreported event. Furthermore, no
      clear evidence has been found in the literature of such specific mast cell
      distribution in other parts of the animal body. Single, double, and quadruple
      myelinated nerve processes were noted, but none contained a mast cell.

PMID- 10589022
TI  - Ontogeny of the immune system of the brushtail possum, Trichosurus vulpecula.
AB  - The numbers and distribution of T and B cells in the thoracic thymus, spleen and
      intestinal tissue and the proliferation of T lymphocytes were examined during
      pouch life and in the adult to determine when the developing brushtail possum
      reaches immunological maturity. CD3-positive cells were observed in the thoracic
      thymus at day 2 post-partum indicating that the thymus produces T lymphocytes at
      or soon after birth. By day 25 the thymus was fully populated with CD3-positive T
      lymphocytes and they were observed in distinct regions of the cortex and medulla.
      By day 48 post-partum, B and T lymphocytes were identified in the follicles and
      parafollicular areas of the spleen. Although the numbers of T and B cells in the
      spleen increased significantly from day 25 to day 100 post-partum (P < 0.005),
      fewer cells were present at day 150 post-partum than in the adult (P < 0.05).
      Peyer's patches were not observed in the intestines up to day 73 post-partum.
      However, both T and B cells were observed in the intestinal lymph nodes. Although
      the T lymphocytes at weaning showed a proliferative response, the response was
      not as great as that observed in the adult possum. Thus, the immune system of the
      possum is not fully developed at weaning but continues its development after
      pouch life.

PMID- 10589023
TI  - Distinct spatial and temporal distributions of aggrecan and versican in the
      embryonic chick heart.
AB  - Although chondroitin sulfate proteoglycans (CSPGs) are major components of the
      embryonic extracellular matrix, little attention has been paid to specific CSPGs
      in early heart development, in part because appropriate antibodies were not
      available. Therefore we prepared specific polyclonal antibodies against chicken
      aggrecan, versican, neurocan, and phosphacan. Western blotting and
      immunohistochemical studies revealed the presence of aggrecan and versican in
      stages 12-21 chicken embryo hearts in distinctive spatial and temporal patterns.
      Because this is the first demonstration of aggrecan in heart tissue, we further
      used RT-PCR to confirm that aggrecan is expressed in the heart and in situ
      hybridization to confirm the pattern of expression determined using antibodies.
      Versican is found in the myocardium and the myocardial basement membrane. In
      contrast, aggrecan is specifically colocalized with several groups of migrating
      cells including endocardial cushion tissue cells, epicardial cells, a mesenchymal
      cell population in the outflow tract that may be of neural crest origin, and a
      mesenchymal cell population in the inflow tract. The combined observations
      indicate that versican and aggrecan are expressed in unique patterns and suggest
      that they play very different roles in development.

PMID- 10589024
TI  - Quantitative electron microscopic study of the hypoxic fetal sheep heart.
AB  - In order to determine the effects of chronic, high-altitude hypoxia on the ovine
      fetal heart, we exposed pregnant ewes to 3,820 m beginning at 30 days gestation.
      We previously showed that following approximately 110 days of hypoxia the fetal
      heart showed significant reduction in cardiac output (76% of control) and
      contractility, and elevated levels of citrate synthase and lactate dehydrogenase.
      To investigate ultrastructural influences on these observed physiologic changes
      at altitude, we hypothesized that the volume densities of myofibrils and
      mitochondria, and glycogen content would be reduced in the ovine fetal heart and
      that this may contribute to contraction and cardiac output deficits in hypoxia.
      Mitochondria and myofibril volume density were determined by standard point
      counting techniques and glycogen content was determined by biochemical analysis.
      The glycogen content from the hypoxic right ventricle (4.8 +/- 0.3%) was
      significantly lower than in control right ventricle (6.8 +/- 0.5%) and both left
      ventricles (hypoxia, 7.2 +/- 0.5; control, 7.8 +/- 0. 4%). Total mitochondrial
      volume density was also significantly reduced following hypoxia (15.5 +/- 0.7%)
      compared to controls (16.9 +/- 0.4%). As is common in the ovine fetal heart, the
      myofibril volume density of the right ventricle from both groups was
      significantly higher than the left ventricle (RV, 58.6 +/- 1.6; LV 54.3 +/-
      0.9%). However, it was not different between control and high altitude. In
      support of our hypothesis, we may speculate that deficits in the quantity of
      myocyte glycogen and mitochondria contribute to the observed reduction in cardiac
      output and contractility, despite the upregulation of citrate synthase and
      lactate dehydrogenase. In contrast, myofibril volume density was unchanged.

PMID- 10589025
TI  - Ocular development in the oman shark, Iago omanensis (Triakidae), Gulf of Aqaba,
      Red Sea.
AB  - Ocular ontogenesis was studied in embryos of the placental viviparous shark, Iago
      omanensis, abundant in the Gulf of Aqaba, Red Sea, at depths of 150-1500 meters.
      Samples of gravid females were collected bi-monthly, and their embryos extracted.
      The eyes of 220 of those embryos of various dimensions were dissected and
      routinely prepared for histological and electron microscopic studies. The initial
      signs of eyes appear in embryos of 8 mm total length (TL). The primordial zone of
      germinal neural cells appears in 12 mmTL embryos and at 26 mm separation of the
      visual layer of the retina and the plexiform layers is initiated. From this stage
      on until 60 mmTL the nuclear and plexiform parts of the retina continue to
      develop and outer segments of the visual cells begin to form. Concomitant with
      ripening of the inner and outer plexiform layers, the tapetal layers of
      melanocytes and tapetal platelets of reflecting guanine also begin to ripen. The
      tapetum in Iago is of the cellular type. In embryos of 140-145 mmTL (6-7 months
      old), as they approach term, the visual cells, their synaptic connections and the
      intermediate cell types of the retina are all full developed. The melanocytes,
      rich in pigmentation, and sacs of tapetal platelets, penetrate deeply between the
      lamellated outer segments of the visual cells. Data are provided on growth
      parameters of the retinal cell layers and growth of the eyes during embryonic
      development. According to the position of the nuclei of the visual cells, the
      retina of Iago appears to be duplex, with rods and cones.

PMID- 10589026
TI  - Vascular anatomy of the rat ventral prostate.
AB  - The rat ventral prostate gland is a model tissue to study the effects of
      androgenic steroids on prostate cells. Recent reports suggest that the prostatic
      vascular system is a primary target of androgen action in this tissue. In order
      to better understand how the vascular system of the ventral prostate supports the
      tissue in an androgenically normal adult male rat we utilized a variety of
      microscopic imaging techniques to more fully characterize its structural anatomy
      and its interaction with other prostatic cell types. Vascular corrosion casts
      were produced from the mature ventral prostate glands of rats. These casts were
      analyzed by scanning electron microscopy (SEM) to describe gross and fine details
      of the prostate vascular anatomy. Fixed thin sections of ventral prostates were
      immunostained with antiFactor XIII and analyzed by light microscopy for the
      presence of capillary elements within the prostatic glands. Other sections were
      directly analyzed by transmission electron microscopy (TEM) to describe the
      anatomical relationship between the capillaries and the prostatic ducts and their
      associated glands. The rat ventral prostate is supplied with blood by branches of
      the inferior vesical artery which enters the apex of the tissue from the base of
      the urinary bladder. Visualization of the prostatic vascular network under SEM
      shows that this major vessel is found on the posterior-medial surface of the
      tissue (closest to the bladder). This surface also has numerous serpentine
      vessels that appear to facilitate a stable blood supply to the prostate in
      accommodation of urinary bladder distension. Examination of the opposing surface
      of the casts allowed a crude description of the structure of the prostatic ductal
      system with the distal tips of the ducts (containing the prostate glands)
      oriented towards the anterior-lateral surface of the tissue. On this surface, one
      can discern a series of adjacent basket-shaped vascular structures of
      distributing arterioles that supply a dense complex of fine capillaries to the
      glands. Analysis of the interface of the prostatic ductal system with its
      vascular elements by light microscopy and TEM shows that some capillaries lie
      immediately adjacent to the basement membranes of the glands while others can be
      found interspersed within the myofibroblast layer surrounding the ducts and
      glands. Veins accompany the arteries and combine with the superior vesical before
      entering the common iliac vein. This study gives a comprehensive and detailed
      view of the microvasculature of the rat ventral prostate gland. The findings here
      will provide the basis for future experiments to evaluate how the ventral
      prostate vascular system changes in response to androgenic manipulation and to
      other pathological conditions.

PMID- 10589027
TI  - Neuromuscular organization of the canine tongue.
AB  - The tongue manipulates food while chewing and swallowing, dilates the airway
      during inspiration, and shapes the sounds of speech in humans. While performing
      these functions the tongue morphs through many complex shapes. At present it is
      not known how the muscles of the tongue perform these complex shape changes. The
      difficulty in understanding tongue biomechanics is partly due to gaps in our
      knowledge regarding the complex neuromuscular anatomy of the tongue. In this
      study the motor and sensory nerve anatomy of four canine tongues was studied with
      Sihler's stain, a technique that renders most of the tongue tissue translucent
      while counterstaining nerves. An additional tongue specimen was serially
      sectioned to provide a reference for the muscle structure of the tongue. The
      hypoglossal nerve (XII) has approximately 50 primary nerve branches that
      innervate all intrinsic and extrinsic tongue muscles. Two extrinsic muscles, the
      styloglossus and hyoglossus, are innervated by about three to four branches from
      the lateral division of the XII. The third extrinsic muscle, the genioglossus, is
      composed of oblique and horizontal compartments, which receive about ten nerve
      branches from the medial division of the XII. The intrinsic muscles are composed
      of many neuromuscular compartments. On each side, the superior longitudinal
      muscle had an average of 40 distinct muscle fascicles that spanned the length of
      the tongue. Each of the fascicles is supplied by a nerve branch. The inferior
      longitudinal muscle had a similar organization. Each of the transverse and
      vertical muscles is composed of over 140 separate muscle sheets, and every sheet
      is innervated by a separate terminal nerve. The muscle sheets from the vertical
      and transverse alternate their orientation 90 degrees throughout the length of
      the tongue. It is concluded that the intrinsic canine tongue muscles are actually
      composed of groups of neuromuscular compartments that are arranged in parallel
      (longitudinal muscles) or in a precise alternating sequence (transverse and
      vertical muscles). This arrangement suggests that the compartments from the
      different tongue muscles could cooperate to control the three-dimensional
      contractile state of their local area. This hypothesis could explain how many
      different tongue shapes are formed, and is supported by physiologic evidence.

PMID- 10589028
TI  - Capillary changes in skeletal muscle of patients with essential hypertension.
AB  - Arterial hypertension produces changes along the vascular tree. However, there
      are few reports on its effect on human muscle capillaries. This study
      demonstrates the effects of essential hypertension on the capillaries of human
      quadriceps muscle. Muscle biopsy was taken from quadriceps femoris in eight men
      with recent diagnosis of essential hypertension, without treatment. Biopsies were
      also taken from eight normotensive men and were used as controls. Fiber types
      were classified by ATPase reaction, capillaries counted in alpha-amylase-PAS
      stained sections and ultrastructure studied by conventional methods of
      transmission electron microscopy. No changes were found in capillaries or muscle
      fiber types by histochemical methods. However, electron microscopy revealed
      abnormal capillaries with endothelial cells infoldings into the lumen, as well as
      occluded or degenerated capillaries. In some cases the endothelial cell area
      covered by pericytes was increased. Basement membrane of capillaries was
      frequently increased in width, sometimes irregularly, and in other instances it
      was reduplicated. In transversely sectioned capillaries lumen diameter was
      reduced and wall thickness was increased, although total diameter was unchanged.
      In hypertensive patients the finding of some degenerated capillaries adjacent to
      muscle fibers could be interpreted as the beginning of a process of rarefaction.
      Some capillaries showed morphological changes, and the ratio wall thickness/lumen
      was increased.

PMID- 10589029
TI  - Course and composition of the nerves that supply the mandibular teeth of the rat.
AB  - The rodent dentition has become an important model for investigations of
      interactions between dental tissues and peripheral neurons. Although experimental
      nerve injury has been widely used for such studies, there is uncertainty about
      the courses of nerve fibers supplying the mandibular teeth. In order to clarify
      this, we used a mixture of monoclonal antibodies against neurofilament proteins
      to enhance demonstration of nerve fibers so that small nerves could be readily
      traced in serial frozen sections of mandibles of Sprague Dawley rats ranging in
      age from embryonic day (E) 18 to postnatal day (P) 90. The 1st molar and anterior
      portion of the 2nd molar were innervated by small nerves that emerged as distinct
      branches of the IAN trunk at or near the mandibular foramen. In contrast, the
      nerve supply to the 3rd molar and posterior part of the 2nd molar was a branch of
      the lingual nerve that bypassed the mandibular canal altogether. The IAN trunk
      split into the mental nerve and a large branch to the incisor about 2 mm anterior
      to the mandibular foramen. Thick branches of the incisor nerve descended into the
      incisor socket to form a dense plexus of nerve fiber bundles extending along the
      length of the incisor periodontium. The sparse pulpal innervation of the incisor
      was provided by a few thin fascicles that emerged from the caudal portion of the
      periodontal plexus to enter the incisor apex. The dental branches of the IAN and
      lingual nerve seen in the adult were well established and readily identifiable at
      age E18 even though their targets were limited to the follicles of the developing
      teeth. These studies show that the trigeminal branches that supply the mandibular
      teeth can be identified at a wide range of ages as distinct nerves at a
      considerable distance proximal to their targets. This detailed information on the
      courses taken by the dental nerves can provide an anatomical basis for increased
      precision in characterization and perturbation of neural pathways from the molars
      and incisor.

PMID- 10589030
TI  - Ultrastructural analysis of polysialylated neural cell adhesion molecule in the
      suprachiasmatic nuclei of the adult mouse.
AB  - The suprachiasmatic nuclei (SCN) of the anterior hypothalamus are recognized as
      the principal circadian clock in mammals. The adult SCN express a high level of
      polysialylated neural cell adhesion molecule (PSA-NCAM), a cell surface
      sialoglycoprotein capable of modulating cell-cell interactions. In the present
      study, the expression of PSA-NCAM in the mouse SCN was studied at the
      ultrastructural level by immunolabeling using monoclonal antibodies against the
      polysialic acid (PSA) moiety of PSA-NCAM. We showed that neuronal somal
      expression of PSA-NCAM was distributed heterogeneously in the SCN, with extensive
      staining of somas in the central region of the SCN, and minimal somal staining in
      the ventral portion of the nuclei. In contrast, immunoreactive neuropil,
      including unmyelinated fine axon fascicles was distributed throughout the SCN.
      The PSA-NCAM was also detected adjacent to synaptic junctions by both
      immunoperoxidase and immunogold techniques. For astrocytes, immunostaining of
      somas and larger processes was sparse, but staining was profuse along fine
      processes. Immunostained fine astrocytic processes were frequently observed
      between apposing neuronal somas, and in close association with synaptic junctions
      and small blood vessels. These findings, together with the demonstrated role of
      PSA-NCAM in modulating cell-cell interactions in other brain regions support a
      role for PSA-NCAM in regulating cell-cell interactions in the SCN.

PMID- 10589031
TI  - Surgical oncology and the American Board of Surgery: a new and promising
      relationship.

PMID- 10589032
TI  - Should irradiation replace dissection for patients with breast cancer with
      clinically negative axillary lymph nodes?

PMID- 10589033
TI  - Surgical treatment of lung metastases: prognostic factors for long-term survival.
AB  - BACKGROUND AND OBJECTIVES: Surgical resection of lung metastases is an
      established therapy for a large number of primary tumors, but there is some
      controversy about prognostic factors for long-term survival. METHODS: From 1968
      to 1996, we performed a retrospective review of a series of 85 patients (100
      operations) that have been operated for resection of lung metastases. The Kaplan
      Meier method was used to estimate the probabilities of survival, the log-rank
      test for the univariate analysis of prognostic factors for survival, and the Cox
      model in the subsequent multivariate analysis. RESULTS: The operative mortality
      was 4% and the morbidity 18%. The mean follow-up after lung resection was 22.13
      months (1-146). The actuarial 5-year survival rate was 29.2%. By univariate
      analysis, the following factors were associated with survival after resection:
      location and histology of the primary tumor, greatest dimension of the largest
      metastasis, radicality of the resection, involvement of the resection margins,
      and use of adjuvant therapy (P < 0.05). After multivariate analysis, only the
      dimension of the metastases and involvement of surgical margins have been found
      to be independently associated with survival. CONCLUSIONS: Surgical excision is a
      safe and effective therapy for lung metastases from a large number of primary
      tumors, provided a complete resection is feasible.

PMID- 10589034
TI  - Preoperative anaplastic glioma tumor volume effects on patient survival.
AB  - BACKGROUND AND OBJECTIVES: The relationship between preoperative tumor volume and
      patient survival has long been studied, but the results have been inconsistent.
      Since geometric measurement of tumor volume was used in these studies, the aim of
      this study was to ascertain whether the inconsistency of the study results is due
      to less accurate geometric measurement. METHODS: Prognostic tumor volume effects
      were compared between the planimetry method and the geometric method using
      survival analysis, performed for 99 patients diagnosed with anaplastic glioma
      tumor. RESULTS: A significant correlation was found between planimetry tumor
      volume and patient survival, but there was no correlation between geometric tumor
      volume and patient survival. The larger planimetry tumor volume was significantly
      associated with shorter survival. CONCLUSIONS: The study indicated that in brain
      tumor research the preoperative tumor volume measured by the geometric method may
      not be prognostically important. The more accurate measurement, i.e., the
      planimetry method (based on either computed tomography or magnetic resonance
      imaging), is needed in brain tumor clinical research and prognostic diagnosis.

PMID- 10589035
TI  - Glassy cell carcinoma of the uterine cervix.
AB  - BACKGROUND AND OBJECTIVES: Glassy cell carcinoma (GCC) of the uterine cervix is a
      rare and highly malignant tumor, accounting for only 1%-2% of all cervical
      carcinomas. The purpose of this study was to investigate the clinical findings,
      treatment, and outcome of patients with cervical GCC in the south of Israel.
      METHODS: Data from the files of 5 patients with cervical GCC who were managed at
      the Soroka Medical Center, Beer-Sheva, Israel, between January 1961 and June 1999
      were evaluated. RESULTS: Age at diagnosis ranged from 32 to 84 years, with 1
      patient pregnant at the time of diagnosis. Vaginal bleeding was the prevailing
      presenting symptom. The cervical lesion was exophytic in 4 patients and
      endophytic ("barrel-shaped") in 1 patient. Mean tumor size was 3.9 cm. Three
      patients with stage IB(1) disease had radical hysterectomy and bilateral pelvic
      lymph node dissection followed by either external pelvic radiotherapy or
      brachytherapy or both. All 3 patients were alive without disease 4, 12, and 18
      months after initial diagnosis, respectively. One patient with stage IIIB disease
      had external pelvic radiotherapy alone and died of disease 12 months after
      initial diagnosis. One patient with stage IVB disease refused treatment and died
      of disease 3 months after initial diagnosis. CONCLUSIONS: Cervical GCC is a rare
      variant of cervical cancer with distinct histologic features and an alleged
      aggressive clinical behavior. For early-stage disease, the treatment of choice
      seems to be radical surgery followed by chemoradiotherapy.

PMID- 10589036
TI  - Adoptive immunotherapy for advanced cancer patients using in vitro activated
      cytotoxic T lymphocytes.
AB  - BACKGROUND AND OBJECTIVES: We evaluated the clinical efficacy of adoptive
      immunotherapy using in vitro activated cytotoxic T lymphocytes (CTL) in the
      treatment of patients with advanced cancer. METHODS: CTL were induced with the
      mixed lymphocyte and tumor cell culture method, in which lymphocytes isolated
      from patient peripheral blood mononuclear cells were mixed with inactivated
      autologous tumor cells. Activated lymphocytes were administered intravenously to
      11 patients once every 2 weeks for 10 weeks (i.e., 5 doses). RESULTS: Tumor
      reduction and decreased tumor marker were observed in 4 patients. Notably,
      successful CTL induction was identified in all of these patients. In patients who
      did not show induction of CTL response, a decreased proportion of lymphocytes,
      especially CD8(+) cells, and increased levels of CD14(+) cells were frequently
      observed. Fluorescence-activated cell sorter analysis indicated that expression
      of HLA class I and costimulatory factor B7-1 molecules was diminished on tumor
      cells. This was partly recovered with interferon-gamma, which resulted in
      successful induction of a CTL response. CONCLUSIONS: It was suggested that in
      vitro CTL induction is difficult in patients with advanced cancer. However, once
      the cells were induced successfully, some favorable clinical effects were seen by
      the adoptive transfer of such cell populations.

PMID- 10589037
TI  - Treatment of liver metastases from colon carcinoma with autologous tumor vaccine
      expressing granulocyte-macrophage colony-stimulating factor.
AB  - BACKGROUND AND OBJECTIVES: In preclinical studies, tumor cells genetically
      altered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) can
      generate systemic antitumor immunity. Clinically relevant immunotherapeutic
      approaches for the treatment of colorectal cancer should address efficacy within
      the liver, a common site of metastatic disease. We investigated the effect of
      irradiated colon cancer cells engineered to produce GM-CSF on protecting from and
      treating established liver metastases. METHODS: Using a model of liver metastasis
      by intrahepatic injection of CT-26 murine colon carcinoma cells in syngeneic
      BALB/c mice, GM-CSF-producing irradiated cells were given as an intradermal
      vaccine either 14 days prior to hepatic challenge or in animals with early
      established tumor (days 5 and 10). The presence of tumor, tumor volume, and
      survival were endpoint determinants. RESULTS: Animals receiving GM-CSF-producing
      vaccination demonstrated significant protection from subsequent hepatic challenge
      of viable tumor cells, even at the highest challenge doses. In animals with early
      established tumors, a significant response was seen with prolongation in
      survival. CONCLUSIONS: We conclude that GM-CSF autologous tumor vaccination was
      effective for the treatment of hepatic colorectal metastases in this murine
      model. These findings provide support for immunotherapeutic approaches for
      metastatic liver cancer.

PMID- 10589038
TI  - Expression of receptors for estrogen and progesterone in malignant colonic mucosa
      as a prognostic factor for patient survival.
AB  - BACKGROUND AND OBJECTIVES: Estrogen receptors (ER) and progesterone receptors
      (PR) have been detected in both normal and malignant colonic mucosa, but the
      prognostic value of this observation is unknown. We aimed to define the
      prognostic significance of the presence of ER and PR in malignant cells from
      colorectal adenocarcinoma specimens. METHODS: An immunohistochemical assay for ER
      and PR was performed on paraffinized sections from 65 colorectal adenocarcinoma
      specimens. Survival curves were analyzed to define the prognostic implications of
      ER and PR. RESULTS: Twenty nine (45%) tumors tested receptor positive (32% for ER
      and 23% for PR). Tumors of advanced stage were more likely to express receptors
      than early stage tumors (56% vs. 32%; P = 0.01). Median survival of patients with
      neoplasms expressing PR was 30 months. For patients whose tumors did not express
      any receptors, median survival had not been reached at the time of follow-up (P =
      0.04). Similarly, patients with tumors expressing both receptors had
      significantly reduced survival (median survival = 20 months; P = 0.003).
      CONCLUSIONS: Expression of receptors for sex steroids correlates with advanced
      stage disease. Expression of PR by the tumor cells is associated with a shorter
      patient survival. The results suggest that sex steroids may play a role in
      carcinogenesis and tumor progression.

PMID- 10589039
TI  - American ginseng and breast cancer therapeutic agents synergistically inhibit MCF
      7 breast cancer cell growth.
AB  - BACKGROUND AND OBJECTIVES: American ginseng (Panax quinquefolius L.) purportedly
      alleviates menopause symptoms because of putative estrogenicity. METHODS: Using a
      standardized American ginseng (AG) extract in MCF-7 breast cancer cells, the
      objectives were to evaluate the ability of AG to induce the estrogen- regulated
      gene pS2 by Northern blot analysis, determine the effect on cell growth using the
      MTT assay, and evaluate the cell cycle effects by flow cytometry. RESULTS: AG and
      estradiol equivalently induced RNA expression of pS2. AG, in contrast to
      estradiol, caused a dose-dependent decrease in cell proliferation (P < 0.005). AG
      had no adverse effect on the cell cycle while estradiol significantly increased
      the proliferative phase (percent S-phase) and decreased the resting phase (G(0)
      G(1) phase) (P < 0.005). Concurrent use of AG and breast cancer therapeutic
      agents resulted in a significant (P < 0.005) suppression of cell growth for most
      drugs evaluated. CONCLUSIONS: In vitro use of AG and breast cancer therapeutics
      synergistically inhibited cancer cell growth.

PMID- 10589040
TI  - Applications of flow cytofluorometry to red blood cell immunology.

PMID- 10589041
TI  - Evaluation of stabilized whole blood control materials for lymphocyte
      immunophenotyping.
AB  - We evaluated stabilized whole blood control materials for their performance as a
      routine control material for immunophenotyping using flow cytometry. These
      materials serve as the method control, controlling for both the binding of
      monoclonal antibodies to the cells and the efficiency of the red-blood-cell
      lysing reagent. Three products (FluoroTrol, StatusFlow, and CD-Chex): were
      tested. The controls performed very well in evaluating both CD4 and CD8
      percentages and absolute cell counts using flow cytometry. Light scattering
      patterns and fluorescence intensity of antibody binding were slightly different
      from those of normal whole blood. These products are not appropriate for
      quantitative fluorescence standards. Cytometry (Comm. Clin. Cytometry) 38:268
      273, 1999. Published 1999 Wiley-Liss, Inc.

PMID- 10589042
TI  - Single- versus dual-platform assays for human CD34+ cell enumeration.
AB  - We comparatively assessed CD34+ cell quantification by two of the recently
      available single platform assays, the IMAGN 2000 STELLer (Immucor, Lisbon,
      Portugal) microvolume fluorimetry and the ProCOUNT (BD-ENZIfarma, Lisbon,
      Portugal) flow cytometry, with our "in-house" dual-platform flow cytometric
      assay. The performance of the methods was evaluated by linearity and
      reproducibility tests. The linearity study, over a range of 0-1,200 CD34+
      cell/microl, gave a good linear relationship for the three methods, with R(2) >
      0.99. Precision tested at three different concentrations gave coefficients of
      variation ranging from 3.6-26.4% for the STELLertrade mark, 2.4-13.8% for the
      ProCOUNT, and 3.2-6.4% for flow cytometry. CD34+ cells were quantified in
      umbilical cord blood (UCB), UCB enriched-leukocyte buffy-coat (BC), mobilized
      peripheral blood (PB) and mobilized peripheral blood progenitor cells (PBPC)
      collected by leucapheresis, from a total of 72 samples. Flow cytometric results
      showed good linear correlation to the absolute counts obtained by the STELLer and
      ProCOUNT for all samples (R > 0.90 for all methods), with no differences when
      compared by paired tests (P > 0.05). Linear correlations between methods were
      also found when individually looking at the different cell sources: UCB or PB,
      BC, and PBPC, with low, intermediate and high CD34+ cell concentrations,
      respectively. Furthermore, with the exception of a significant difference between
      the ProCOUNT and STELLer results for UCB (P < 0.05), no other difference between
      methods was found for each of the individual populations (P > 0.05). To our
      knowledge, this is the first report in which the results are presented and
      analyzed according to each source of CD34+ cells. Our results show that the
      STELLer and the ProCOUNT are equally efficient for the dual-platform flow
      cytometric assay in CD34+ cell quantification.

PMID- 10589043
TI  - Increased peripheral blood gamma delta T-cells in patients with lymphoid
      neoplasia: A diagnostic dilemma in flow cytometry.
AB  - We have observed increased numbers of non-neoplastic gammadelta-T-cells in the
      peripheral blood of a series of patients with non-Hodgkin's lymphoma not of
      gammadelta-T-cell origin. The majority of normal gammadelta-T-cells are negative
      for surface CD4 and CD8 and a subpopulation does not express CD5, two
      immunophenotypic findings strongly suggestive of neoplasia in alpha beta T-cells.
      In addition, they express cytotoxic T-cell/Natural killer cell antigens. In this
      study, up to 22% of PBLs were CD4 and CD8 negative gammadelta-T-cells and up to
      33% PBLs were CD5 negative gammadelta-T-cells. In addition, as high as 42% of
      PBLS were gammadelta-T-cells expressing cytotoxic T-cell/Natural killer cell
      antigens, suggestive of a large granular lymphoproliferative disorder. Failure to
      recognize that these are normal gammadelta-T-cells could lead to the erroneous
      diagnosis of peripheral blood involvement with a T-cell neoplasm, especially in
      the setting of a history of non-Hodgkin's lymphoma. Cytometry (Comm. Clin.
      Cytometry) 38:280-285, 1999. Published 1999 Wiley-Liss, Inc.

PMID- 10589044
TI  - The bone marrow plasma cell labeling index by flow cytometry.
AB  - The bone marrow plasma cell labeling index is the most important prognostic
      indicator for patients with multiple myeloma. Traditionally, this test has been
      performed as a two color immunofluorescent microscope technique which is time
      consuming and requires a degree of subjectivity in its interpretation. We have
      assessed various adaptations of this method to flow cytometry. A
      bromodeoxyuridine method has been compared with a propidium iodide DNA method to
      detect cells in S phase and CD38-FITC has been compared with CD38-FITC + CD138
      FITC and CD38-biotin + streptavidin FITC to identify plasma cells. The mean
      channel fluorescent intensity of the plasma cell peaks for each of these markers
      was 12. 7, 17.4 and 35.3 respectively demonstrating the superiority of CD38
      biotin + streptavidin FITC. Analysis after propidium iodide staining provided a
      good correlation with the slide technique (r = 0. 71; P < 0.0001) but the
      bromodeoxyuridine method did not correlate with the slide method (r = 0.09; P =
      NS). The labeling index values obtained from either of the flow methods were
      greater than the microscopic method. Thus a labeling index of >4% will replace
      the traditional >1% threshold for identifying patients with a significantly
      increased labeling index. The advantages of the new method are that it takes less
      time to perform, is more objective and provides additional data on ploidy and
      cell cycle status.

PMID- 10589045
TI  - DNA ploidy in colorectal cancer, heterogeneity within and between tumors and
      relation to survival.
AB  - Flow cytometry was used to study the incidence of aneuploidy and to determine the
      significance of multiple sampling from colorectal tumors. DNA ploidy pattern has
      been proposed as a supplementary prognostic marker, but discrepancies in findings
      are major. DNA clonal heterogeneity, defined as two or more DNA aneuploid
      stemlines in the same tumor, is well established. However, most studies have been
      based on only one biopsy from each tumor. In our study multiple biopsies were
      taken from 163 patients (88 males and 75 females) electively operated for
      colorectal cancer. Tumor cells were harvested by fine needle aspiration from
      fresh frozen biopsies sampled at different sites of each tumor. DNA aneuploidy
      was detected in tumors from 145 patients (89%), and 18 patients (11%) had a
      solitary DNA diploid cell population. In a 79 month follow-up period 105 patients
      had died. Statistical analysis showed that distinction between diploidy and
      aneuploidy did not predict survival. However, grouping subpopulations into DNA
      diploid plus near diploid (DNA index (DI) 0. 97-1.15), DNA aneuploid with all
      aneuploid subpopulations in the interval 1.15-2.06, and DNA aneuploid with
      subpopulations with DI < 0.97 and/or DI > 2.06, showed a significant difference
      in survival in a Cox multivariate analysis including Dukes' stage P = 0.049
      comparing the second group to the first and P = 0.01 comparing the third group to
      the first. In 21 (13%) patients only one subpopulation was found, 57 (35%) had
      two, 44 (27%) had three, and 41 (25%) had four or more different subpopulations.
      The association of DNA ploidy to survival is shown to be dependent on the number
      of biopsies analysed.

PMID- 10589047
TI  - Forum: journal club

PMID- 10589048
TI  - Clinical cytometry society 14(th) annual meeting clinical applications of
      cytometry, september 26-29, 1999, Marriott's rancho las palmas resort, palm
      springs, CA: meeting program

PMID- 10589046
TI  - Computer-assisted immunocytochemical determination of breast cancer steroid
      receptors on cytological smears of excised surgical specimens compared with
      frozen sections.
AB  - BACKGROUND: Due to the widespread use of fine needle aspirate biopsy the practice
      of determining estrogen (ER) and progesterone (PR) receptors in breast carcinoma
      from cytological smears (CS) is becoming very common. The aim of this study was
      to determine concordance between ER and PR assessed by immunocytochemical assay
      (ICA) on CS and FS both evaluated by image analysis since we have found no data
      in literature on this. METHODS: 104 breast carcinoma cases were selected. For all
      cases ER and PR determination was performed on CS, obtained by light scraping of
      the freshly cut surface of the excised surgical tumors at the time of frozen
      section diagnosis, and FS using the same monoclonal antibodies. Computer-assisted
      image analysis was performed in all cases using CAS 200. Results were expressed
      as percent positive area of neoplastic nuclei compared with total nuclear area of
      the examined neoplastic cells. RESULTS: Good correlation was demonstrated between
      percent positive nuclear neoplastic area by ER-ICA on CS and FS (r = 0.759; P <
      0.0001). Concordance of results was 90.19% (P < 0.001). Good correlation was also
      demonstrated between percent positive nuclear neoplastic area by PR-ICA in CS and
      FS (r = 0.889; P < 0. 0001). Concordance of results was 97.02% (P < 0.0001).
      CONCLUSIONS: Our data suggest that ICA on CS with automated image analysis is
      efficient in evaluating ER and PR content in human breast cancer, especially when
      CS is the only method pathologists have to evaluate receptor status e.g. in
      advanced breast cancer cases when neoadjuvant therapy is necessary before surgery
      or when surgery is impossible.

PMID- 10589049
TI  - Comparison of nuchal translucency measurement and mid-gestation serum screening
      in assisted reproduction versus naturally conceived singleton pregnancies.
AB  - It has been reported that second-trimester serum markers may be affected by
      assisted reproduction leading to a higher false-positive rate. The current study
      compares 10-14 week nuchal translucency (NT) measurement and early mid-trimester
      serum screening in pregnancies resulting from assisted reproduction versus
      naturally conceived pregnancies. 75 pregnant women with a singleton pregnancy
      achieved by assisted reproduction underwent both 10-14 weeks NT measurement and
      second-trimester triple test and were followed throughout gestation. They were
      compared with matched controls for gestation and maternal ages. A risk of 1:380
      or higher or having a fetus with Down syndrome was considered as screen-positive
      in both tests. The mean maternal age (30+/-3 years) and crown-rump length (61+/-9
      mm) were similar, and there was no difference in NT thickness distribution
      between the groups. Based on NT measurement, 4 (5 per cent) women in the study
      and 2 (3 per cent) in the control groups, were defined as screen positive (p=NS).
      However, 11 (15 per cent) women in the study group and 4 (5 per cent) in the
      control group were found screen-positive by the triple test (p<0.05). A
      significantly higher amniocentesis rate of 20 per cent was noted in the study
      group compared with 8 per cent in the controls (p<0.05). All karyotypes were
      normal and no miscarriages or structural malformation were diagnosed in either
      group. We confirm the observation that assisted reproduction may adversely affect
      second-trimester screening results, which did not affect the NT screening test.
      Since these series are relatively small, larger series may be needed to clarify
      the most beneficial screening policy for this highly selected group of pregnant
      women.

PMID- 10589050
TI  - Maternal serum screening for down syndrome in pregnancies conceived by intra
      uterine insemination.
AB  - The purpose of our study was to assess the influence of intra-uterine
      insemination (IUI) on the results of maternal serum Down syndrome screening. 43
      women with IUI pregnancies and 4507 healthy women who conceived were studied.
      Ovulation in IUI pregnancies was induced by clomiphene and/or human menopausal
      gonadotrophin (hMG). Maternal serum levels of free beta-human chorionic
      gonadotrophin (hCG) and alpha-fetoprotein (AFP) were measured for Down syndrome
      screening. It was considered screen-positive when the risk of Down syndrome was 1
      in 270 or greater in the second trimester. The value of maternal serum AFP was
      significantly lower in the IUI group (median=0.760 MoM) than in the control group
      (median=1.050 MoM). However, the value of free beta-hCG was not significantly
      different between the two groups. The positive rate of maternal serum Down
      syndrome in IUI pregnancies was similar to that of the control group. Our results
      indicate that IUI pregnancy may be associated with a lower level of AFP, although
      the mechanism for this difference remains unknown.

PMID- 10589051
TI  - Acceptance of screening and abortion for Down syndrome among Finnish midwives and
      public health nurses.
AB  - In this study we evaluated how well maternal serum screening and abortions for
      Down syndrome were accepted among midwives and public health nurses, and compared
      how those who accepted and did not accept abortions for Down syndrome differed
      from each other. The questionnaire was mailed in 1998 to 400 midwives and 400
      public health nurses. 79 per cent responded. The majority said that all pregnant
      women should be offered a screening test for Down syndrome, but less than half
      accepted abortion for Down syndrome. Thus, the 'informative part' of the
      screening (serum screening itself) is supported more often than the 'operative
      part' (selective abortion)-or at least the 'operative part' was found to be a
      more difficult question. We suggest that whereas screening may be perceived as a
      question of more choices, information and self-determination, abortion is more
      clearly a moral question. The professional background characteristics and
      attitudes of those accepting and not accepting abortion for Down syndrome were
      relatively similar, but having a midwife's education, practical involvement in
      serum screening and having patients with Down syndrome were associated with a
      somewhat higher percentage of acceptance and a lower percentage of 'don't know'
      responses.

PMID- 10589052
TI  - Trends in cytogenetic prenatal diagnosis in the UK: results from UKNEQAS external
      audit, 1987-1998.
AB  - The aim of this audit was to evaluate trends in mean reporting time, culture
      success rate and abnormality rate for conventional cytogenetic prenatal diagnoses
      for amniotic fluid samples (AFS) and chorionic villus samples (CVS) in the UK.
      Anonymized data in the form of retrospective external audits were obtained from
      UKNEQAS in Clinical Cytogenetics annual reports, for AFS (1987-1997/98) and CVS
      (1988-1997/98). UK laboratories providing a prenatal service by referral criteria
      applicable at local level participated in the scheme. Over the period the number
      of AFS processed per annum increased from 28 639 to 36 817 (29 per cent) and for
      CVS from 2294 to 7918 (245 per cent). CVS made up 17.6 per cent of the total
      sample numbers in 1997/98 compared with 7.4 per cent in 1988. Reporting times and
      culture success rates have improved, notably overall reporting time means have
      fallen from 20.2 to 13.8 days for AFS and 21.3 to 14.5 days for CVS. Data
      submitted by individual laboratories suggest that further reductions in mean
      reporting times for both sample types are feasible. Such a potential improvement,
      if achieved by all laboratories, may question the value of a supplementary FISH
      or PCR-based 'rapid' aneuploidy screening test prior to karyotyping.

PMID- 10589053
TI  - Placental thickness at mid-pregnancy as a predictor of Hb Bart's disease.
AB  - The measurement of placental thickness can effectively differentiate normal
      pregnancies from affected pregnancies requiring invasive work-up. The objective
      was to evaluate the efficacy of placental thickness at mid-pregnancy in
      predicting fetal Hb Bart's disease in pregnancies at risk. Among 17 254 pregnant
      women screened for severe thalassaemia between June 1994 and December 1998, 345
      pregnancies at risk for having a fetus with Hb Bart's disease underwent
      ultrasound examinations and cordocentesis at 18-21 gestational weeks. Before
      cordocentesis, the placental thickness was measured and recorded. The definite
      fetal diagnosis was performed with high performance liquid chromatography. The
      efficacy of placental thickness in predicting Hb Bart's disease was evaluated by
      sensitivity and specificity. Various cut-off values of the placental thickness
      were used for calculation and the best cut-off value was determined by a receiver
      operating characteristic (ROC) curve. Of 345 pregnancies at risk, 70 fetuses with
      Hb Bart's disease were finally diagnosed. The mean placental thickness (+/-SD) of
      the normal pregnancies and pregnancies with Hb Bart's fetuses were significantly
      different, 24.6+/-5.2 mm and 34. 5+/-6.7 mm, respectively (Student's t-test,
      p<0.001). The sensitivity and specificity of placental thickness in prediction
      were calculated for various cut-off values. Based on the ROC curve, the best cut
      off value was 30 mm (>30 mm considered abnormal), giving a sensitivity of 88.57
      per cent, specificity of 90.18 per cent, positive-predictive value of 78.48 per
      cent and negative-predictive value of 96.87 per cent. For couples at risk, when
      sonographic placental thickness is normal, the risk of having an Hb Bart's fetus
      is markedly decreased. The measurement of placental thickness can effectively,
      though not absolutely, differentiate the normal pregnancies from affected ones
      requiring invasive work-up.

PMID- 10589054
TI  - Amniotic fluid alpha-fetoprotein is not a useful biological marker of pregnancy
      outcome.
AB  - The aim of our study was to determine if the amniotic fluid alpha-fetoprotein
      (AFP) level could be a useful predictive biochemical marker of pregnancy outcome.
      Amniotic fluid AFP measurement was prospectively carried out over a three-year
      period. After excluding factors susceptible to modifying AFP measurements, 587
      subjects with gestational age between 14 and 20 weeks were selected to compare
      the amniotic fluid AFP mean levels depending on the occurrence of an adverse
      outcome. No significant associations between amniotic fluid AFP level and poor
      pregnancy outcome, i.e. pre-eclampsia, preterm delivery, premature rupture of
      fetal membranes, fetal growth retardation and placental abnormalities were
      observed. The routine measurement of amniotic fluid alpha-fetoprotein during an
      amniocentesis procedure was not considered useful in predicting pregnancy
      complications.

PMID- 10589055
TI  - Screening for trisomy 18 by fetal nuchal translucency and maternal serum free
      beta-hCG and PAPP-A at 10-14 weeks of gestation.
AB  - In a study of 50 cases of trisomy 18 compared with 947 controls we have found the
      median multiple of the median (MoM) of maternal serum free beta human chorionic
      gonadotrophin to be significantly decreased (0.281 MoM) in samples collected
      between the 10th and 14th week of gestation. Similarly, maternal serum pregnancy
      associated plasma protein A (PAPP-A) levels are also decreased (0.177 MoM),
      whilst the median nuchal translucency is significantly higher (3.272 MoM). Free
      beta-hCG MoM was less than the 5th centile of normal in 64 per cent of cases of
      trisomy 18 and for PAPP-A was less than the 5th centile in 78 per cent of cases.
      Also, in 78 per cent of cases the nuchal translucency was above the 95th centile.
      When combined together in a multivariate algorithm with maternal age, we predict
      that 89 per cent of cases of trisomy 18 could be detected at a 1 per cent false
      positive rate. We conclude that specific trisomy 18 risks should be part of
      developing risk algorithms combining maternal serum biochemistry and nuchal
      translucency for use in first trimester screening alongside those for trisomy 21.

PMID- 10589056
TI  - Prenatal consultation after a fetal anomaly scan: videotaped exploration of
      physician's attitude and patient's satisfaction.
AB  - The main aim of the study was to evaluate the relationship between the
      physician's attitude (using the non-verbal Global Affective Measure of the Roter
      Analaysis System and the Counselor Rating Form-short version) and the
      satisfaction of the pregnant women with the prenatal consultation. A secondary
      aim was to evaluate the women's recall of essential information (i.e. location,
      severity, prognosis and cause of the anomaly). To this end, 24 prenatal
      consultations (pregnant women, partners and physicians) were videotaped following
      a fetal anomaly scan, and a few days later, the pregnant women completed
      questionnaires to assess their perception of the physician's attitude and their
      satisfaction with the consultation and the extent to which they could recall the
      essentials of the information given about the fetal anomaly. In descending order,
      the physician's dominance/assertiveness (i.e. being self-confident and decisive)
      (assessment of the videotapes by two psychologists), trustworthiness (women's
      report) and expertise were significantly positively associated with the women's
      overall satisfaction, i.e. satisfaction with the information given and affective
      behaviour on the part of the physician during the prenatal consultation. All the
      women (n=24) recalled the essentials of the information given about the location
      of the fetal anomaly. The majority of them correctly reproduced the severity, the
      prognosis and the cause of the anomaly. Our findings indicate that women in whom
      a fetal anomaly has been detected derive particular benefit from a self
      confident, decisive, expert and trustworthy physician.

PMID- 10589057
TI  - Cost-effective one-step PCR amplification of cystic fibrosis delta F508 fragment
      in a single cell for preimplantation genetic diagnosis.
AB  - The combination of in vitro fertilization (IVF) with PCR technologies enables
      diagnosis of single gene defects for preimplantation genetic diagnosis. This has
      been accomplished by two-step nested PCR, or PEP-PCR followed by nested PCR
      processes. To improve the detection of single cell genetic defects, the lysate of
      a single lymphocyte, with or without cystic fibrosis DeltaF508 mutation
      (CFDeltaF508), was incubated in a higher ionic strength solution containing
      mercaptoethanol prior to the addition of primers to the denatured cellular DNA. A
      single cell in 5 microl lysis buffer was incubated at 65 degrees C for 15 min,
      cooled, and neutralized with an equal volume of neutralizing buffer. A 5 microl
      aliquot of a solution X containing 50 mM MgCl(2), 1 M NaCl, and 10 mM
      mercaptoethanol was added to the neutralized cell lysate, followed by incubation
      at 93 degrees C for 15 min. The step was crucial to the successful amplification
      of CFDeltaF508 DNA fragment. The incubation of cell lysate in solution with the
      high level of sulphydryl reducing agent and a high ionic strength of about 0.45,
      at 93 degrees C for 15 min, might denature many chromatin-binding proteins and
      also ensure the complete dissociation of dsDNA. After the addition of PCR mix,
      the resulting reaction mixture still contained a sufficient level of sulphydryl
      reducing agent and 0.135 total ionic strength. This might reduce significantly
      the interference of various protein factors with DNA, and favour the primer
      template annealing. The efficient initial annealing of the primers to target DNA
      sequences would facilitate PCR amplification efficacy. In conclusion, in more
      than 80 single cells tested (apart from one) the CFDeltaF508 defect was
      successfully demonstrated with the present protocol (>99 per cent), without using
      fluorescent primers and expensive automatic instrumentation.

PMID- 10589058
TI  - Prenatal diagnosis of ornithine transcarbamylase deficiency.

PMID- 10589059
TI  - Prenatal diagnosis of a fetal left atrial diverticulum.
AB  - Fetal echocardiography, performed on a 22-year-old woman at 31 weeks' gestation,
      revealed a diverticulum of the left atrium. The size of the diverticulum was
      similar to the size of the fetal heart in a four-chamber view. No evidence of
      congestive heart failure or changes in size of the diverticulum were observed on
      subsequent ultrasound examinations. The echocardiographic image suggested
      presence of a thrombus within the diverticulum. Echocardiography of the newborn
      confirmed the diagnosis, and surgical correction followed five days after the
      birth. Our approach to this problem is discussed here.

PMID- 10589060
TI  - Maternal serum superoxide dismutase (SOD): a possible marker for screening Down
      syndrome affected pregnancies.
AB  - Superoxide dismutase (SOD: EC1.15.1.1) has been shown to increase in Down
      syndrome (DS) subjects and in amniotic fluid from DS affected pregnancies. In
      order to verify a possible increase of maternal serum SOD in DS affected
      pregnancies and its possible contribution in prenatal screening, the serum enzyme
      activity was retrospectively measured in samples from normal and DS affected
      pregnancies. Alpha-fetoprotein (AFP), human chorionic gonadotrophin (hCG),
      unconjugated oestriol (uE3) and serum SOD were measured in serum samples
      collected from 80 normal and 9 DS affected second-trimester pregnancies. The
      maternal serum SOD activity in the DS group (3. 12+/-0.73 U/ml) was significantly
      higher (p<0.001) than in the control one (2.20+/-0.7 U/ml). The addition of SOD
      appeared to be capable of improving the sensitivity of the conventional multi
      parametric test (AFP, uE3 and hCG) even if the small number of subjects did not
      allow the achievement of statistical significance.

PMID- 10589061
TI  - Severe intra-uterine growth retardation in a patient with maternal uniparental
      disomy 22 and a 22-trisomic placenta.
AB  - We report on a maternal uniparental disomy of chromosome 22 in a patient with
      severe intra-uterine growth retardation. Karyotyping of a placental tissue
      revealed non-mosaic trisomy 22, whereas lymphocyte chromosomes from the newborn
      were normal 46,XY. Microsatellite analysis using DNA extracted from white blood
      cells showed maternal uniparental heterodisomy for chromosome 22. Thus, the
      conceptus started as maternal trisomy due to meiotic non-disjunction, and trisomy
      rescue occurred subsequently through loss of the paternal homologue resulting in
      maternal uniparental disomy. Normal phenotypes in previous reports have suggested
      that maternal UPD 22 has no impact on the phenotype. Thus, growth retardation in
      this patient was probably caused by dysfunction of the trisomic placenta.

PMID- 10589062
TI  - The influence of smoking on maternal serum PAPP-A and free beta hCG levels in the
      first trimester of pregnancy.
AB  - In an analysis of 3111 singleton pregnancies routinely screened in the first
      trimester with nuchal translucency, free beta hCG and pregnancy associated plasma
      protein A (PAPP-A) smoking has been found to occur in 20.8 per cent of pregnant
      women. When the individual marker levels were assessed in smokers and non
      smokers, levels of PAPP-A were reduced in smokers by some 15 per cent. Despite
      free beta hCG levels being reduced by 10-14 per cent in the second trimester of
      smoking women, in the first trimester period this is not evident. Simulation
      studies would suggest that in smokers the detection of trisomy 21 using free beta
      hCG, PAPP-A and maternal age will be reduced by some 5 to 6 per cent compared
      with that of the general population.

PMID- 10589063
TI  - Autosomal recessive hydrocephalus due to congenital stenosis of the aqueduct of
      sylvius.
AB  - Isolated hydrocephalus due to congenital stenosis of the aqueduct of Sylvius is
      almost always an X-linked recessive inherited condition. We describe a brother
      and sister with isolated hydrocephalus from congenital aqueductal stenosis. We
      believe that these two occurrences represent a rare autosomal recessive form of
      this abnormality. In assessing a first known occurrence of hydrocephalus with
      stenosis of the aqueduct of Sylvius in a family, the rare possibility of
      autosomal inheritance must be considered in genetic counselling.

PMID- 10589065
TI  - Clinical management of a quadruplet pregnancy combining a triplet pregnancy with
      a classical hydatidiform mole: case report and review of literature.
AB  - A 28-year-old Taiwanese woman who had received ovulation induction by clomiphene
      citrate (CC), follicular-stimulating hormone (FSH), and human chorionic
      gonadotrophin (hCG) treatment was diagnosed with a quadruplet pregnancy
      containing a hydatidiform mole and three fetuses at nine weeks' gestation.
      Expectant management failed to achieve any viable neonate due to massive
      antepartum haemorrhage and preterm delivery at 25 weeks' gestation. Five other
      cases previously reported involving quadruplets or triplets with a complete
      hydatidiform mole and two or three fetuses are reviewed. All cases ended as
      premature non-viable fetuses. Analysis of the clinical features, management, and
      outcome both in our patient and these reports suggest that more efficacious
      treatment planning, such as selective feticide, should be considered in order to
      improve the likelihood of attaining an advanced gestational age for a single
      fetus.

PMID- 10589064
TI  - Multi-system cytomegalovirus fetopathy by recurrent infection in a pregnant woman
      with hepatitis B.
AB  - A pregnant woman with acute hepatitis B virus (HBV) infection had her second
      pregnancy terminated at 25 weeks' gestation because of fetal ascites and
      ventriculitis. Meconium peritonitis was also found at autopsy. No HBV DNA but
      cytomegalovirus (CMV) DNA was detected in the fetal liver and ascitic fluid.
      Recurrent maternal CMV infection was demonstrated by pre-existing CMV IgG
      antibodies, high IgG avidity and low IgM levels. After abortion, the patient
      developed chronic active hepatitis. Nevertheless, having become pregnant again
      with a new partner, she had an uneventful third pregnancy and gave birth to a
      healthy boy.

PMID- 10589067
TI  - Revised guidelines for the diagnosis of mosaicism in amniocytes.

PMID- 10589066
TI  - Prenatal diagnosis of fetal cerebellar lesions: a case report and review of the
      literature.
AB  - The fetal cerebellar structure, size and consistency are looked at in every
      system survey. Among the acquired cerebellar events that might change the
      cerebellar consistency are haemorrhage, infections in utero and neoplasia.
      Additional fetal malformations, if present, assist in making the final diagnosis.
      We present a case of an isolated echogenic mass in one of the cerebellar
      hemispheres along with the differential diagnosis.

PMID- 10589068
TI  - Validation of risk estimation using the quadruple test in prenatal screening for
      Down syndrome.

PMID- 10589069
TI  - When are we allowed to use a marker in Down syndrome screening?

PMID- 10589070
TI  - Maternal serum s100b protein is ineffective for Down syndrome screening.

PMID- 10589071
TI  - First trimester Down syndrome screening markers in triploidy: a case report.

PMID- 10589072
TI  - Satellited chromosome 10 detected prenatally in a fetus and confirmed as mosaic
      in a parent.

PMID- 10589073
TI  - Simplifying amniocentesis in paraplegic women-the wheelchair tilting manoeuvre.

PMID- 10589074
TI  - Acid-base and electrolyte abnormalities in patients with acute leukemia.
AB  - Disturbances of acid-base balance and electrolyte abnormalities are commonly seen
      in patients with acute leukemia. Our study aimed at illuminating the probable
      pathogenetic mechanisms responsible for these disturbances in patients with acute
      leukemia admitted to our hospital. We studied 66 patients (24 men and 44 women)
      aged between 17 and 87 years old on their admission and prior to any therapeutic
      intervention. Patients with diabetes mellitus, acute or chronic renal failure,
      hepatic failure, patients receiving drugs that influence acid-base status and
      electrolyte parameters during the last month, such as corticosteroids, cisplatin,
      diuretics, antacids, aminoglycosides, amphotericin, penicillin, and K(+), PO(4)(3
      ), or Mg(2+) supplements were excluded. Forty-one patients had at least one acid
      base or electrolyte disturbance. There were no significant differences in the
      incidence of acid-base balance and electrolyte abnormalities between patients
      with acute myeloid leukemia (AML) and patients with acute lymphoblastic leukemia
      (ALL). The most frequent electrolyte abnormality was hypokalemia, observed in 41
      patients (63%), namely in 34 patients with AML, and 7 with ALL; the main
      underlying pathophysiologic mechanism was inappropriate kaliuresis. Furthermore,
      hypokalemic patients more frequently experienced concurrent electrolyte
      disturbances (i.e., hyponatremia, hypocalcemia, hypophosphatemia, and
      hypomagnesemia), as well as various acid-base abnormalities compared to
      normokalemic patients. Hypokalemia in patients with acute leukemia may serve as
      an indicator of multiple concurrent, interrelated electrolyte disturbances,
      especially in patients with AML.

PMID- 10589075
TI  - The significance of the bone marrow biopsy pattern in chronic lymphocytic
      leukemia: a prognostic dilemma.
AB  - Although bone marrow biopsy pattern (BMBP) has long been suggested to be an
      independent prognostic factor in chronic lymphocytic leukemia (CLL), conflicting
      reports continue to appear in the literature. To investigate this issue we
      retrospectively reviewed 70 CLL patients who had undergone bone marrow biopsy at
      the time of diagnosis in a multivariate Cox regression analysis together with
      other prognostic factors. There were 51 (72.8%) males and 19 (27.2%) females with
      a median age of 60 years (range, 38-77). The median follow-up time was 24 months
      (range, 1-76), and median survival was 44 months. Thirtyfour patients (48.6%) had
      diffuse and 36 patients (51.4%) had nondiffuse BMBP (14 nodular, 11 interstitial,
      and 11 mixed). The median survival for diffuse and nondiffuse BMBP groups were 17
      and 53 months, respectively (P= 0.05). Sixteen patients (22. 9%) had stage A, 28
      (40.0%) stage B, and 26 (37.1%) stage C disease according to the Binet system,
      and four patients (5.7%) had low-risk, 39 (55.7%) intermediate-risk, and 27
      (38.6%) high-risk disease according to the modified Rai staging system. The
      difference between the median survivals of patients in different stages was
      statistically significant (P < 0.0001). The BMBP and staging systems that are
      thought to be significant predictors of prognosis were used to build a
      multivariate Cox proportional hazard model. BMBP was not found to add additional
      information to the prognostic value of the staging systems. Our results underline
      two points: first, the significance of BMBP must be investigated in multivariate
      analysis including the stage, and second, BMBP is not a dynamic prognostic
      parameter, it is an index of tumor burden and does not add any prognostic
      information beyond that provided by clinical stage.

PMID- 10589076
TI  - Morphological and functional characteristics of short-term and long-term bone
      marrow cultures in chronic myelogenous leukemia.
AB  - Clonogenic capacity of bone marrow progenitors and stromal layers established
      from bone marrow of 12 patients with CML and 13 healthy controls were evaluated.
      The initial BFU-E and CFU-GM contents were slightly higher in the CML patients (p
      > 0.05) in contrast to CFU-GEMM. CFU-GEMM was lower in the patients compared to
      healthy controls (p < 0.001). In long-term cultures, the number of non-adherent
      cell population and total clonogenic progenitor cell content decreased gradually
      in both groups. Weekly evaluation of stromal confluency of adherent cells
      revealed that establishment of adherent stromal layer was slower in CML patients
      than in control samples (p < 0.05). At the end of fourth week, the number of
      samples presenting confluency was 41.7% in the CML group compared with 92.3% in
      the controls. The initial CD34 positive cell content of the bone marrow samples
      was similar in both groups. Although CD34 positive cell number in the adherent
      stromal layer was well preserved in the control group at the end of 4 weeks, this
      figure decreased significantly in the CML group. The numbers of total adherent
      cells as well as the total clonogenic progenitor content of adherent layer were
      also lower in the CML group (3.03% vs 98.2%). When normal CD34+ cells were
      cultured on IFN-alpha-treated stromal layer followed by the assessment of the
      long-term culture initiating cells, a reduced capacity to support hemopoietic
      growth was observed with IFN-alpha-treated normal stroma. This reduction was even
      higher when CML stroma was treated with IFN-alpha followed by the seeding of the
      normal CD34+ cells on this stromal layer (26.9% vs 42.8%). These findings show
      that stromal cells are abnormal in CML patients as well as the progenitor cells,
      and IFN-alpha treatment causes further defects of the stromal cells.

PMID- 10589077
TI  - Hydroxyurea and sodium phenylbutyrate therapy in thalassemia intermedia.
AB  - Hydroxyurea (HU) and sodium phenylbutyrate (SPB) have been shown to increase
      fetal hemoglobin (Hb F) levels in patients with thalassemia intermedia. The
      reported effects of these agents in increasing total Hb, however, have been
      inconsistent and there have been no studies on the combination of these
      medications. We describe the clinical response, as determined by increases in
      total Hb and decreased transfusion needs, in five patients with thalassemia
      intermedia treated with HU alone or in combination with SPB. All of the patients
      responded with increased levels of Hb F, but the responses in total Hb varied. Of
      the five patients, two had a marked response in total Hb in excess of 3 g/dl, two
      responded modestly with an increase in total Hb of 1-2 g/dl, and one did not
      respond. Prolonged responses were achieved with low doses of HU (3-10 mg/kg/day)
      and higher doses were associated with mild reversible hematologic or hepatic
      toxicity and no further increases in Hb. Sodium phenylbutyrate was added to
      treatment with HU in two patients, but failed to produce an increase in total Hb
      despite increasing Hb F levels. Of the four patients who responded to HU with an
      increase in total Hb, all reported symptomatic improvement and three have not
      required further transfusions. We conclude that low-dose HU therapy in patients
      with thalassemia intermedia may increase total Hb levels sufficiently to
      eliminate the need for transfusions. We, therefore, recommend a trial of HU for
      thalassemia intermedia patients in whom chronic transfusion therapy is being
      contemplated.

PMID- 10589078
TI  - Cerebral and meningeal multiple myeloma after autologous stem cell
      transplantation. A case report and review of the literature.
AB  - Meningeal involvement of multiple myeloma is a very rare complication. Defining
      meningeal myelomatosis (MeM) as the presence of plasma cells in the cerebrospinal
      fluid in a patient with multiple myeloma, we have found 53 previously reported
      cases in the literature, where the diagnosis MeM has been made while the patient
      was alive. Using Kaplan Meier statistics we have found the median survival, from
      the time of diagnosis of MeM, to be 1.5 months. We report a case with MeM and
      possible cerebral myeloma shortly after autologous stem cell transplantation, and
      compare it with earlier published cases.

PMID- 10589079
TI  - Hematologic neoplasia and the central nervous system.
AB  - Central nervous system (CNS) involvement with malignant cells is a well
      recognized complication of hematologic neoplasms. A number of disorders such as
      acute lymphoblastic leukemia and high grade lymphoma frequently involve the CNS
      and prophylactic therapy is advised. Disorders such as acute myeloid leukemia
      (AML) and multiple myeloma are less likely to be associated with CNS involvement.
      This series describes three cases of CNS involvement by malignant hematologic
      disease: myelomatous meningitis, CNS chloromas complicating AML, and primary
      lymphomatous meningitis.

PMID- 10589080
TI  - Radiotherapy to control CNS lymphomatoid granulomatosis: a case report and review
      of the literature.
AB  - Lymphomatoid granulomatosis (LG) is an uncommon but potentially fatal disease.
      The disease primarily involves the lungs; however, skin, renal, and central
      nervous system (CNS) are seen in varying proportions. Neurological involvement
      occurs in one third of the patients, and confers a worse prognosis. The use of
      radiotherapy to treat CNS involvement in LG has not been well studied. We report
      a case of a 33-year-old man with multiple CNS lesions treated successfully with
      radiotherapy and review 6 other cases in the literature using similar treatment.
      These cases support the use of radiotherapy for CNS involvement in LG.

PMID- 10589081
TI  - Splenic involvement by blastic mantle cell lymphoma (large cell/anaplastic
      variant) mimicking splenic marginal zone lymphoma.
AB  - The most cases of splenic marginal zone lymphoma (SMZL) seem to respond favorably
      to splenectomy. The diagnosis of this lymphoma is mainly based on the recognition
      of a micronodular pattern of splenic involvement with marginal zone
      differentiation. However, it is possible to find so-called "marginal zone
      differentiation" in splenic involvement by other small B-cell lymphomas,
      particularly mantle cell lymphoma (MCL) and follicular lymphoma. We report a case
      of blastic MCL, large cell/anaplastic variant with a high level of clinical
      aggressiveness, showing biphasic cytology and a micronodular pattern which
      resembles SMZL. A single biopsy corresponding to this case shows two phases of
      tumoral progression in a MCL, a rare finding in MCL. In conclusion, the
      differential diagnosis of SMZL must take the possibility of a blastic MCL with
      biphasic cytology into account, as the case here.

PMID- 10589082
TI  - Tumor lysis syndrome occurring after the administration of rituximab in
      lymphoproliferative disorders: high-grade non-Hodgkin's lymphoma and chronic
      lymphocytic leukemia.
AB  - Rituximab, an anti-CD20 antibody, has been recently approved for the treatment of
      low-grade or follicular non-Hodgkin's lymphoma (NHL). Because of its relatively
      benign side effect profile, it has been considered a nontoxic alternative to
      chemotherapy. Recently, however, tumor lysis syndrome (TLS) resulting from
      rituximab has been reported in a patient with chronic lymphocytic leukemia (CLL).
      We herein present two cases of rituximab-induced TLS. The first case occurred in
      a patient with high-grade NHL, while the second case occurred in a patient with
      CLL. We also present a summary of the literature regarding TLS induced by
      immunotherapies.

PMID- 10589083
TI  - Lack of relevance of the acetylator status on dapsone response in chronic
      autoimmune thrombocytopenic purpura.
AB  - Dapsone provides an alternative treatment for patients with chronic autoimmune
      thrombocytopenic purpura (AITP) who had inadequate response to conventional
      therapy. However, the efficacy of this treatment is achieved in only 50% of
      patients. Dapsone is partly metabolized by the polymorphic N-acetyltransferase 2%
      and 50% of Caucasian patients show a genetically determined slow acetylator
      phenotype. The aim of our study was to investigate the influence of the
      acetylator status on dapsone efficacy in patients with chronic AITP. Nineteen
      caucasian adults with chronic AITP, previously treated by dapsone, were included
      in the study. Acetylator phenotype was determined by using a caffeine urinary
      test. Among the fourteen fast acetylator patients, eight patients exhibited
      positive response to dapsone and six patients did not. Among the five slow
      acetylator patients, one patient displayed a positive response to dapsone.
      Comparison of data by using the Fisher's exact test did not reach statistical
      significance. Our results do not support a relationship between dapsone efficacy
      and acetylator status in adults with chronic AITP.

PMID- 10589085
TI  - Isolated lymph node T lymphoblastic transformation of chronic myeloid leukemia
      during interferon treatment.
AB  - Isolated nodal T lymphoblastic transformation of chronic myeloid leukemia (CML)
      with the marrow still in chronic phase is rare. A case of CML treated by alpha
      interferon developed this unusual complication. However, after successful
      treatment of the blastic transformation, the patient remained responsive to
      interferon and maintained a major cytogenetic response for over 2 years. This
      case illustrated a rare clinical progression of CML on interferon treatment to
      isolated nodal T lymphoblastic transformation. This unusual form of blastic
      transformation may have a better prognosis than other forms of blastic crisis.

PMID- 10589084
TI  - Soluble fas ligand in natural killer cell lymphoma.
AB  - We measured serum soluble Fas ligand (sFasL) in a patient with natural killer
      cell lymphoma, and investigated relationship between sFasL and liver dysfunction.
      An elevated level of sFasL was decreased after local radiation therapy, and liver
      function improved. When lymphoma relapsed, liver dysfunction reappeared and the
      level of sFasL increased parallelly. Lymphoma cells expressed mRNA of FasL. This
      suggested that this liver dysfunction was induced by some remote effectors, and
      sFasL was one of candidates of these effectors.

PMID- 10589086
TI  - Pure red cell aplasia complicated by angioimmunoblastic T-cell lymphoma: humoral
      factor plays a main role in the inhibition of erythropoiesis from CD34(+)
      progenitor cells.

PMID- 10589087
TI  - A novel mutation of the protein C gene with a frameshift deletion of 3 base pair
      F ((3380)AGG) in exon 6 in type 1 deficiency associated with arterial and venous
      thrombosis.

PMID- 10589088
TI  - Unique sequence of pernicious anemia, stomach cancer, and myelodysplastic
      syndrome.

PMID- 10589089
TI  - Long-term response in accelerated-phase chronic myelogenous leukemia with
      protracted splenic irradiation and alpha-interferon.

PMID- 10589090
TI  - Electrospray ionisation tandem mass spectrometry of poly
AB  - Evaluation of polymer end-capping reactions with the aid of electrospray
      ionisation tandem mass spectrometry techniques (ESI-MS(n)) allows
      characterisation of novel poly[(R, S)-3-hydroxybutanoic acid]-(a-PHB)
      telechelics, containing primary hydroxyl groups at both polymer chain ends. The
      chemical structures of individual mass-selected macromolecules of the well
      defined a-PHB telechelics have been defined in this way, and fragmentation
      mechanisms have been proposed. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10589091
TI  - Application of liquid chromatography atmospheric pressure chemical ionization
      tandem mass spectrometry in the quantitative analysis of glyburide
      (glibenclamide) in human plasma.
AB  - Glyburide (glibenclamide) is widely prescribed in the treatment of Type II
      diabetes. A validated liquid chromatography atmospheric pressure chemical
      ionization tandem mass spectrometry (LC/APCI-MS/MS) method for the determination
      of glyburide is reported. The method uses a stable isotope labeled glyburide as
      the internal standard. Subsequent to acetonitrile protein precipitation, the
      supernatant was directly (unfiltered) injected onto the LC column (retention time
      approximately 3 min) for analysis. A lower limit of quantification (LLOQ) of 1.01
      ng/mL was attained for the human plasma assay. The method was fast, specific, and
      exhibited excellent ruggedness. It was successfully applied to the analysis of
      clinical samples from patients dosed with glyburide.

PMID- 10589092
TI  - Characterization of a serial array of miniature cylindrical ion trap mass
      analyzers
AB  - Two small (5 mm internal radius) cylindrical ion traps (CITs) are arranged in
      series and operated using a single ion source, detector and radio frequency (rf)
      trapping signal. Ions are trapped in the first CIT and later transferred to the
      second by applying a direct current (dc) pulse to the endcap electrode of the
      first trap. This process is facilitated if a second, appropriately timed,
      retarding dc pulse is applied to the exit endcap electrode of the second trap.
      Mesh endcaps are used for the CITs to increase the number of ionizing electrons
      entering the trap and to maximize the transfer efficiency and detected signal.
      The transfer efficiency is dependent on the amplitude of the dc potential applied
      to eject the ions from the first trap, the amplitude of the dc potential applied
      to retain the ions in the second trap, and the period during which the retarding
      potential is applied. The amplitude and phase of the rf also affect the transfer
      process. Ions that readily dissociate upon collision have low transfer
      efficiencies; more stable ions can be transferred with up to 50% efficiency.
      Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10589093
TI  - Analysis of intact proteins from cerebrospinal fluid by matrix-assisted laser
      desorption/ionization mass spectrometry after two-dimensional liquid-phase
      electrophoresis.
AB  - A novel combination of methods, two-dimensional liquid-phase electrophoresis (2D
      LPE) and matrix-assisted laser desorption/ionization time-of-flight mass
      spectrometry (MALDI-TOFMS), have been used for the analysis of intact brain
      specific proteins in cerebrospinal fluid (CSF). 2D-LPE is especially useful for
      isolating proteins present in low concentrations in complex biological samples.
      The proteins are separated in the first dimension by liquid-phase isoelectric
      focusing (IEF) in the Rotofor cell and in the second dimension by sodium dodecyl
      sulphate polyacrylamide gel electrophoresis (SDS-PAGE) in the Preparative cell.
      The removal of SDS by chloroform/methanol/water, followed by sample preparation
      with the addition of n-octylglucoside, easily interfaced 2D-LPE with MALDI-TOFMS
      for analysis of intact proteins. Further characterization by proteolytic
      digestion is also demonstrated. The knowledge of both the molecular weights of
      the protein and of the proteolytic fragments obtained by peptide mapping
      increases specificity for protein identification by searching in protein sequence
      databases. Two brain-specific proteins in human CSF, cystatin C and
      transthyretin, were isolated in sufficient quantity for determination of the mass
      of the whole proteins and their tryptic digest by MALDI-TOFMS. This approach
      simplified the interface between electrophoresis and MALDI-TOFMS.

PMID- 10589094
TI  - In-source fragmentation of partially oxidized mono- and polycyclic aromatic
      hydrocarbons in atmospheric pressure chemical ionization mass spectrometry
      coupled to liquid chromatography
AB  - Partially oxidized derivatives of polycyclic aromatic hydrocarbons (PAHs) are
      known to be important environmental pollutants. For the identification of these
      substances in complex mixtures, e.g. atmospheric aerosol samples, liquid
      chromatography/mass spectrometry with atmospheric pressure chemical ionization
      (LC/APCI-MS) has been found to be a suitable analytical technique. In this study
      31 derivatives of mono- and polycyclic aromatic hydrocarbons with up to five
      condensed aromatic rings carrying different functional groups (carboxyl,
      dicarboxylic anhydride, lactone, hydroxyl, and carbonyl) were characterized by
      LC/APCI-MS. Each substance was measured in positive and negative ion detection
      mode at four different fragmentor voltages (90 to 190 V). For the first time, the
      results show that characteristic and well-interpretable fragmentation patterns
      can be obtained for these classes of compounds by in-source collision-induced
      dissociation in a single quadrupole LC/APCI-MS system. For each class of
      compounds typical spectral features and optimum measurement conditions are
      reported, and fragmentation pathways are proposed. The study demonstrates the
      applicability of LC/APCI-MS for the determination of most of the investigated
      compounds at trace levels, and it provides a database for the identification of
      unknown partially oxidized aromatic hydrocarbons. Copyright 1999 John Wiley &
      Sons, Ltd.

PMID- 10589095
TI  - Electrospray ionization tandem mass spectrometry for poly(propylene oxide)
      starting and end group analysis
AB  - Electrospray ionization tandem mass spectrometry was applied to study
      poly(propylene oxide) obtained in the presence of potassium hydride. It was found
      that the polyether chains possess different starting groups, i.e. those situated
      at the beginning of the polymer backbone. These were isopropoxy, hydroxy, methoxy
      and allyloxy groups when the polymerization was stopped by the addition of methyl
      iodide. Each macromolecule was terminated by the methoxy group in this case.
      Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10589096
TI  - Use of meso- tetrakis(pentafluorophenyl)porphyrin as a matrix for low molecular
      weight alkylphenol ethoxylates in laser desorption/ ionization time-of-flight
      mass spectrometry
AB  - The use of UV-absorbing molecules as matrices in matrix-assisted laser
      desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) is well
      documented. The matrices that are currently used have low molecular weights (<300
      Da) and thus, for a typical MALDI-TOF spectrum, the low-mass range (m/z 100-500)
      is dominated by matrix ions. Consequently, the applications of MALDI-TOFMS have
      been restricted mostly to the analysis of high molecular weight analytes. This
      report demonstrates the use of meso-tetrakis(pentafluorophenyl)porphyrin (F20TPP,
      MW 974.57) as a matrix in the MALDI-TOF mass spectrometric analysis of some
      commercial nonylphenol ethoxylates (4-(C(9)H(19))-C(6)H(4)-(OCH(2)CH(2))(n)-OH),
      in which the ethoxymer ion distribution ranges from 331-771 Da. When F20TPP was
      used without a sodium ion dopant, there were no MALDI signals for the
      ethoxylates. However, addition of sodium acetate to the sample produced MALDI
      spectra in which the ethoxymer molecules were sodiated to form [M + Na](+) ions.
      A comparison of the mass spectrometric data with those obtained when alpha-cyano
      4-hydroxycinnamic acid (CHCA) was used as the matrix indicated that the F20TPP
      induced spectra provided comparable data, with the advantage of having less
      matrix interference in the low-mass range (m/z 100-500). Thus, the use of F20TPP
      and similar porphyrins may provide the means to apply MALDI-TOF to the analysis
      of low molecular weight molecules with minimum interference from matrix signals.
      Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10589097
TI  - Benzylic cleavage and McLafferty rearrangement under electron ionization
      conditions in the fragmentation of 5,6-dialkyl-2, 4-diarylpyrimidines
AB  - Several 5,6-dialkyl-2,4-diarylpyrimidines were prepared and their electron
      ionization (EI) mass spectra reported. The benzylic cleavage takes place easily
      together with an important McLafferty rearrangement. The involvement of the
      nitrogen atom appears to be important in the fragmentation of 5-methyl
      substituted pyrimidines. In contrast, the 6-methyl-substituted pyrimidines
      undergo benzylic cleavage without hydrogen transfer. Thus, the difference in the
      mass spectrometric behaviour allows the identification of these isomeric
      compounds which, in contrast, exhibit only small differences in their NMR
      spectra. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10589098
TI  - Observation of daunomycin and nogalamycin complexes with duplex DNA using
      electrospray ionisation mass spectrometry.
AB  - The noncovalent binding of the antitumour drugs daunomycin and nogalamycin to
      duplex DNA has been studied using electrospray ionisation mass spectrometry (ESI
      MS). The conditions for the preparation of drug/duplex DNA complexes and for
      their detection by ESI-MS have been optimised. Ions corresponding to these
      complexes were most abundant relative to free DNA when prepared in the pH range 8
      9, and using gentle ESI interface conditions. Self-complementary
      oligonucleotides, 5'-d(GGCTAGCC)-3' or 5'-d(CGGCGCCG)-3', annealed in the
      presence of a 5-fold molar excess of either nogalamycin or daunomycin gave ESI
      mass spectra in which the most intense ions corresponded to three molecules of
      drug bound to duplex DNA, with some evidence for four drug molecules bound. For
      binding to 5'-d(TGAGCTAGCTCA)(2)-3', complexes containing up to four nogalamycin
      and six daunomycin molecules were observed. These data are consistent with the
      neighbour exclusion principle whereby intercalation occurs between every other
      base pair such that up to four bound drugs would be expected for the 8 mers and
      up to six for the 12 mer. Competition experiments involving a single drug in an
      equimolar mixture of two oligonucleotides (5'-d(TGAGCTAGCTCA)(2)-3' with either
      5'-d(CGGCGCCG)(2)-3' or 5'-d(GGCTAGCC)(2)-3') showed ions arising from complexes
      of drug/5'-d(CGGCGCCG)(2)-3' were more intense than complexes of drug/5'
      d(GGCTAGCC)(2)-3', relative to those from the 12 mer in each mixture. While this
      suggests ESI-MS has the potential to detect differences in sequence selectivity,
      more detailed experiments involving a comparison of the relative ionisation
      efficiency of different oligonucleotides and a wider range of intercalators are
      required to establish this definitively. ESI mass spectra from experiments in
      which both drugs were reacted with the same oligonucleotide were more complex,
      such that a clear preference for one drug could not be established.

PMID- 10589099
TI  - Caerulein-like peptides from the skin glands of the Australian Blue Mountains
      tree frog Litoria citropa. Part 1. Sequence determination using electrospray mass
      spectrometry.
AB  - Sixteen caerulein-type peptides have been isolated from the skin secretions of
      the Australian Blue Mountains tree frog Litoria citropa. There are four groups of
      these peptides. The first is based on the structure of the known neuropeptide
      caerulein [pEQDY(SO(3))TGWMDF-NH(2)], now renamed caerulein 1.1. Examples of
      peptides of the other groups are as follows: caerulein 2.1 [pEQDY(SO(3))TGAHMDF
      NH(2)], caerulein 3.1 [pEQDY(SO(3))GTGWMDF-NH(2)] and caerulein 4.1
      [pEQDY(SO(3))TGSHMDF-NH(2)]. All of these peptides are accompanied by the
      associated peptide where Phe replaces Met, and all eight of the caerulein
      peptides are accompanied by the desulfated analogues. Negative ion electrospray
      mass spectrometry (ES-MS) is used to determine the molecular weights of the
      caeruleins 1-4 [from their [M - H](-) ions], while the sequences of the peptides
      are determined from the B and Y + 2 cleavage ions in the mass spectra of the
      [MH(+) - SO(3)](+) ions.

PMID- 10589101
TI  - Effect of combined changes in delayed extraction time and potential gradient on
      the mass resolution and ion discrimination in the analysis of polydisperse
      polymers and polymer blends by delayed extraction matrix-assisted laser
      desorption/ionization time-of-flight mass spectrometry
AB  - Data reported here show that, in the delayed extraction matrix-assisted laser
      desorption/ionization time-of-flight (DE-MALDI-TOF) mass spectrometric analysis
      of synthetic polydisperse polymers, different experimental conditions of spectral
      recording are required to optimize the signal in all the m/z regions of the
      spectrum. The effect of combined changes in delay time and grid voltage % values
      on both mass resolution and mass accuracy of DE spectra of a polyethylene glycol
      sample (PEG(mix), with a well-defined molar distribution of its components) is
      discussed. The necessity of a compromise between the values of these two
      parameters is shown. Furthermore, the occurrence of analyte discrimination, which
      can invalidate the composition analysis especially in the case of polymer blends,
      is demonstrated. Copyright 1999 John Wiley & Sons, Ltd.

PMID- 10589100
TI  - Strategies for locating disulfide bonds in a monoclonal antibody via mass
      spectrometry.
AB  - The location of the disulfide bonds in a recombinant monoclonal antibody was
      confirmed by matrix-assisted laser desorption/ionization-time-of-flight (MALDI
      TOF) and electrospray ionization (ESI) mass spectrometry (MS). A non-reduced
      Endoproteinase Lys-C (Endo Lys-C) digest of the antibody was analyzed directly by
      MALDI-TOFMS. The sample was then reduced on-plate by depositing dithiothreitol
      (DTT) on the sample spot and re-analyzed by MALDI-TOFMS. The disulfide bonds were
      assigned based on the disappearance of certain mass ions in the non-reduced
      digest and the appearance of product ions in the reduced digest. A rapid LC/ESI
      MS protocol was also developed to determine the location of the disulfide bonds.
      The peptides generated from the Endo Lys-C digest of the antibody were partially
      separated on a high performance liquid chromatography (HPLC) column by utilizing
      a steep gradient and analyzed by ESI-MS. The masses of the partially resolved
      peptides were determined by deconvoluting the mass spectra.

PMID- 10589102
TI  - Direct analysis of oligomeric tackifying resins in rubber compounds by automatic
      thermal desorption gas chromatography/mass spectrometry
AB  - Two analytical methods, automatic thermal desorption gas chromatography/mass
      spectrometry (ATD-GC/MS) and pyrolysis gas chromatography/mass spectrometry (Py
      GC/MS), were applied as direct methods for the analysis of oligomeric tackifying
      resins in a vulcanized rubber. The ATD-GC/MS method, based on discontinuous
      volatile extraction, was found to be an effective means for direct analysis of
      the oligomeric tackifying resins contained in a vulcanized rubber. The oligomeric
      tackifying resins, such as t-octylphenolformaldehyde (TOPF) resin, rosin-modified
      terpene resin, and cashew resin, could be directly analyzed in vulcanized rubber
      by ATD-GC/MS. Much simpler total ion chromatograms were obtained by ATD-GC/MS
      than by flash pyrolysis with a Curie-point pyrolyzer, permitting much easier
      interpretation. Ions at m/z 206, 135, and 107 were fingerprints in the
      characteristic mass spectra obtained by ATD-GC/MS for TOPF resin in the
      vulcanized rubber. 1H-Indene, styrene, and isolongifolene were observed as their
      characteristic mass spectra in the pyrolyzate of the rosin-modified terpene
      resin. From the cashew resin, phenol, 3-methylphenol, and 4-(1,1,3, 3
      tetramethylbutyl)phenol were obtained as the characteristic pyrolyzates by
      discontinuous thermal extraction via ATD-GC/MS. Copyright 1999 John Wiley & Sons,
      Ltd.

PMID- 10589103
TI  - [Molecular mechanisms of nephro-protective action of enalapril in experimental
      chronic renal failure].
AB  - Locally increased synthesis of angiotensin II (ANG II) in the kidney has been
      linked to glomerular hypertrophy, glomerulosclerosis and tubulo-interstitial
      fibrosis observed in chronic renal failure after subtotal nephrectomy. This
      action of ANG II is thought to be mediated mainly by transforming growth factor
      beta (TGF-beta), which stimulates the synthesis and decreases the degradation of
      extracellular matrix (ECM) components, including various collagen types and
      fibronectin. Some recent reports indicate that reduced ANG II activity diminishes
      TGF-beta overexpression, and in consequence renal injury. However, no studies in
      SNx models concerning the influence of ANG II on gene expression regulated by TGF
      beta have so far been performed. Therefore, the present study has been initiated
      with the following aims: 1. To develop a RT-PCR assay for evaluating gene
      expression concerning renin (REN), angiotensinogen (ATG) and the following ECM
      components: transforming growth factor-beta 1 (TGF-beta 1), fibronectin (FN),
      matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinases-2
      (TIMP-2); 2. To assess the influence of renal mass reduction (RMR) caused by
      subtotal (5/6) or partial (2/6) nephrectomy on gene expression for TGF-beta 1,
      FN, MMP-2 and TIMP-2; 3. To evaluate the correlation between expression of these
      genes and activity of the circulatory or renal renin-angiotensin systems; 4. To
      assess the influence of treatment with enalapril (angiotensin-converting enzyme
      inhibitor) on renal expression of these genes, renal morphology and function in
      rats, relative to duration of treatment and RMR. The study consisted of two
      independent experiments performed in adult male Sprague-Dawley rats. Ten days
      prior to surgery, the animals were matched for body weight and systolic blood
      pressure (SBP) values and subsequently were distributed into untreated (control)
      and enalapril treated groups. Treatment with enalapril (EN) (50 mg/l in drinking
      water) was started 9 days prior to surgery. The first (short-term) experiment was
      performed in rats with chronic renal failure caused by subtotal nephrectomy.
      Remnant kidneys were taken for molecular studies at the day of SNx and 3, 7 and
      21 days thereafter. Blood samples collected at the time of sacrifice served to
      determine plasma renin activity and plasma concentration of angiotensinogen and
      angiotensin II. The second (long-term) experiment was done in subtotally (5/6)
      and partially (2/6) nephrectomized rats. Remnant kidneys were taken for molecular
      and morphological studies at the day of surgery and 1 or 16 weeks thereafter. 24
      hour proteinuria, hematocrit, serum creatinine and creatinine clearance values
      were also measured. Quantitation of renal gene expression for REN, ATG, TGF-beta
      1, FN, MMP-2 and TIMP-2 was performed using RT-PCR assay and comparing amounts of
      respective gene mRNA with house-keeping gene mRNA encoding L19 ribosomal protein.
      The results obtained have led to the following conclusions: 1. The RT-PCR assay
      developed here ensures a reliable quantitation of gene expression for renin,
      angiotensinogen, transforming growth factor-beta 1, fibronectin, matrix
      metalloproteinase-2 and tissue inhibitor of metalloproteinases-2. 2. Renin gene
      expression in the kidney depends on renal synthesis of angiotensin II. In
      contrast, regulation of angiotensinogen mRNA expression seems to be independent
      of ANG II. 3. Long-term treatment with enalapril prevents an early increase in
      renal TGF-beta 1 and FN gene expression, retards the progression of chronic renal
      failure caused by critical renal mass reduction, and prolongs survival. 4.
      Intrarenal activity of the renin-angiotensin system is not a principal factor in
      the regulation of gene transcription for matrix metalloproteinase-2 and tissue
      inhibitor of metalloproteinases-2.

PMID- 10589104
TI  - Critical pathways: application to selected patient outcomes following coronary
      artery bypass graft.
AB  - As health care reform evolves in the United States, many hospitals are
      implementing strategies to contain the cost of coronary artery bypass graft
      (CABG) surgery. The purpose of this study was to examine the length of stay in
      the intensive care unit (ICU) after CABG surgery relative to the number of hours,
      postoperation, when ambulation occurred, and to examine the overall postoperative
      length of hospital stay. The study found a significant difference between ICU
      length of stay and the time when ambulation was initiated (t(150) = -2.68; p =
      .004). These results suggest that CABG patients with shorter ICU stays begin
      ambulation sooner, thus potentially reducing the risk of postoperative
      complications as well as cost. No other significant differences were
      demonstrated.

PMID- 10589105
TI  - New diabetes screening criteria for midlife women evaluated for coronary heart
      disease risk.
AB  - The usefulness of new, lowered diabetes diagnostic criterion to identify
      undiagnosed diabetics in a high-risk sample of women was evaluated. Participants
      were 228 midlife women undergoing screening for heart attack risk. Fasting plasma
      glucose levels of participants who were not diagnosed with diabetes were examined
      to assess the number of women who would meet diagnostic criteria for diabetes
      using old (140 mg/dL) and new 126 mg/dL) American Diabetes Association criteria.
      The new criterion identified more women than did the old criterion, particularly
      African Americans. Use of the new criterion flagged nearly 50% as many women as
      originally diagnosed as diabetic at the time of screening. Early identification
      of diabetes may afford earlier, preventive interventions that may reduce
      morbidity and mortality. Thus, findings from this study suggest that use of the
      new, lowered diabetes diagnostic criterion may have significant public health
      benefits for midlife women.

PMID- 10589106
TI  - Exercise and nutrition: what adolescents think is important.
AB  - The purpose of this qualitative study was to examine adolescents' experiences
      with health promotion, particularly physical activity and eating patterns.
      Adolescents' reported experiences were triangulated with measures of physical
      activity and food frequency to assess congruence with goals of Healthy People
      2000 (published by the U.S. Department of Health and Human Welfare in 1995).
      Fifteen ethnically and racially diverse adolescents, ages 10 to 18, were
      interviewed in an adolescent primary care clinic or in their homes. Interviews
      were transcribed and coded line-by-line for themes apparent in the data. Major
      themes were compared and contrasted with previous research as a guide for
      developmentally appropriate health promotion interventions.

PMID- 10589107
TI  - Depression among nursing home elders: testing an intervention strategy.
AB  - This study focused on the assessment of depression among nursing home elders, and
      on determining the efficacy of an intervention strategy for depression using a
      geropsychiatric nurse in conjunction with trained older adult volunteers in the
      role of mental health paraprofessionals. Nursing home residents (n = 139) were
      assessed for depression using the Geriatric Depression Scale (GDS); 94 (68%) were
      found to have depressive symptomatology. Among those receiving the intervention,
      depressive symptomatology was significantly reduced, but no significant decline
      was evident in the control group. The ability of the minimum data set (MDS) to
      detect depression as compared to the GDS was evaluated. Relationships between
      depression and health status, life satisfaction, and social support were also
      examined.

PMID- 10589108
TI  - The quick relaxation technique: effect on pain associated with chest tube
      removal.
AB  - Documentation shows that conventional methods used to prepare patients for chest
      tube removal (CTR) are not effective in reducing pain associated with this
      procedure. The quick relaxation technique (QRT) was used on 24 primary aorta
      coronary bypass surgical patients. Subjects rated their pain on the visual analog
      scale immediately following CTR and 30 minutes later. Results indicated that men
      > or = 70 years of age who received QRT in conjunction with analgesics reported
      less than half the amount of pain experienced by those who did not receive QRT.
      In comparison, women 70 years old or older reported much higher pain intensity
      scores when QRT was used. Preliminary results suggest that for most patients, the
      combination of analgesics and relaxation exercises is not more effective in
      decreasing pain during CTR than when analgesics are administered without
      relaxation exercises.

PMID- 10589109
TI  - Videotaped behavioral observations: enhancing validity and reliability.
AB  - Observing and quantifying behaviors in natural or clinical settings has long
      produced challenges for researchers and clinicians. Although nurses are uniquely
      positioned to conduct behavioral research, they may not be well acquainted with
      behavioral observation strategies. The author identifies several problems
      commonly encountered while studying behavior in natural settings and suggests
      methods for enhancing validity and reliability through videotaped observations.
      Results of a newly developed calibration procedure are discussed with
      implications for rater training. Nurse clinicians and researchers should find
      this information useful for evaluating interventions in clinics, homes, and other
      applied settings.

PMID- 10589111
TI  - How to cozy up to a research report.

PMID- 10589110
TI  - Can hospital structural and financial characteristics explain variations in
      mortality caused by acute myocardial infarction?
AB  - Each year 1 in 160 people in the United States suffers from acute myocardial
      infarction (AMI). Of these more than 1.5 million cases annually, 500,000 end in
      fatalities. This study's purpose was to describe and evaluate the role hospital
      characteristics play in rates of mortality caused by AMI in acute-care California
      hospitals. Characteristics evaluated include structural characteristics--i.e.,
      teaching status, percentage of board-certified physicians, registered nurse hours
      per patient day (RN hours/patient day), volume of cases, technological resource
      availability, and urban density; and financial characteristics--profit status and
      total operating expenses per patient day. Although part of a larger investigation
      correlating mortality and length of stay, this article reports only the results
      for significant influences on mortality.

PMID- 10589112
TI  - [Evidence-based and science-based medicine].
AB  - Routine medical practice is an admixture of scientific knowledge, uncontrasted
      physiopathological deduction and intuition based on personal experience. Evidence
      based medicine is a new approach to medical practice that is based on
      appropriately contrasted data and includes the following steps: 1) accurately
      define the problem we are dealing with, 2) investigate the medical literature
      efficiently, and 3) select the best, relevant studies and apply the corresponding
      norms to the evidence. In turn, the application of the corresponding norms to the
      evidence includes the following aspects: 1) determine if the results of the study
      are valid; i.e., evaluate the scientific quality of the article, 2) determine the
      magnitude of the results; i.e., establish is they are clinically relevant, and 3)
      evaluate their application to the point at issue; i.e., test the external
      validity of the study. The drawbacks of evidence-based medicine include its
      insufficient concern for basic research, its disregard for physiopathological
      hypotheses, and the naive inductivism of epidemiology-based medical practice.
      Undoubtedly, evidence-based medicine provides advantages for the medical practice
      and underscores the importance of data and statistical procedures. This new
      paradigm, however, should not set aside the traditional, hypothetical-deductive
      approach.

PMID- 10589113
TI  - [Bacterial content of the enucleated prostate gland].
AB  - OBJECTIVE: To determine the prevalence of prostatic colonization or infection in
      patients undergoing prostatic surgery for obstructive symptoms due to benign
      hyperplasia of the prostate (BPH), to identify and quantitate the microorganisms
      isolated in quantitative bacterial tissue cultures, and to determine the
      influence of open surgery vs endoscopy on the microbiological findings. METHODS:
      A prospective study was conducted on 175 patients undergoing surgery for BPH. All
      patients were entered into a study protocol that included quantitative bacterial
      cultures of prostatic tissue. Data of previously defined variables were entered
      into a data base for subsequent analysis comprised of redefinition of the
      variables and descriptive and analytical studies. RESULTS: 44 of the 175 patients
      (25.1%) had a positive bacterial culture of prostatic tissue. Histological
      lesions indicating prostatitis associated with BPH were found in 68 of the 175
      patients (38.9%), regardless of the presence or absence of bacteria. Of these 68
      patients with histologically demonstrated prostatic inflammation, only 19 (27.9%)
      had a positive prostatic tissue culture. The incidence of granulomatous
      prostatitis was 1.1%. CONCLUSIONS: The presence of bacteria was demonstrated in
      prostates of a significant number of patients (25.1%) undergoing prostatectomy
      for BPH. The microorganisms most frequently isolated in the quantitative
      bacterial cultures were, by order of frequency, coagulase negative Staphylococci,
      Escherichia coli and Enterococcus faecalis, which were present in concentrations
      of at least 10(4) CFU/Gm in prostatic tissue of 79.6% of the cases. No
      differences were found between the type of procedure the patient underwent and
      the presence or absence of prostatic infection.

PMID- 10589114
TI  - [Spermatic cord torsion in the Comarca del Bierzo. Clinico-epidemiological
      analysis of the 5-year period 1994-1998].
AB  - OBJECTIVE: To review the cases of torsion of the spermatic cord diagnosed at the
      emergency and urology services of our hospital over the last 5 years and analyze
      the clinical and epidemiological features. METHODS: The cases of torsion of the
      spermatic cord diagnosed at our hospital from 1994-1998 were reviewed. Age,
      reason for consultation, time from onset of symptoms to consultation, location of
      the torsion, final diagnosis, treatment, and other data were analyzed. RESULTS:
      There were 20 cases of torsion of the spermatic cord in patients aged 1 to 25
      years, with the highest incidence at age 14 years. The left testis was more
      frequently compromised. Six patients had a history of testicular pain and/or
      inflammation. The mean time from presentation of symptoms to consultation was
      13.5 hours (range 1 hour to 7 days). The diagnosis was torsion of the spermatic
      cord in 14 cases and hydatid torsion in 6. Treatment was fundamentally by surgery
      (orchidopexy), except in three cases that spontaneously resolved or were
      detorsioned by manipulation. Two patients underwent excision of the compromised
      testis. CONCLUSIONS: Torsion of the spermatic cord is a urological emergency due
      to the high risk of complications that may even require orchidectomy. The
      epidemiological findings for our area are similar to those reported in other
      series.

PMID- 10589115
TI  - [Usefulness of p53 oncoprotein immunohistochemistry in the follow-up of bladder
      carcinoma: a 5-year study].
AB  - OBJECTIVE: Mutations in the TP53 gene are frequently detected in some types of
      malignant tumors (bladder, prostate, kidney, lungs, breast, colon and rectum).
      This study analyzed the utility of semi-quantitative determination of p53 in
      transitional cell carcinoma of the bladder by an immunohistochemical technique
      and evaluated the results at 5 years. METHODS/RESULTS: A prospective clinical
      cohort study was conducted on 81 patients. The study comprised two groups:
      nontumoral bladder tissue specimens from 20 patients (group I) and tissue
      specimens from 61 patients with bladder carcinoma (group II). In both groups the
      tissue specimens were obtained between November 1992 and November 1993, and
      during the follow-up period until July 1998. p53 expression was determined by a
      semi-quantitative method based on an immunohistochemical technique (NCL-p53-DO7,
      Novocastra). CONCLUSIONS: p53 oncoprotein was not found to be useful in the
      characterization of carcinoma of the urinary bladder.

PMID- 10589116
TI  - [Use of the Indiana-type continent reservoir: review of our series].
AB  - OBJECTIVE: To report the experience of the Hospital General de Mexico on the use
      of the Indiana continent urinary reservoir in cystectomized patients. METHODS:
      From January 1995 to September 1997, 32 Indiana continent urinary reservoirs were
      performed in 22 men and 12 women with a median age of 46.1 years. Operating time,
      immediate, early and late complications, reservoir function and capacity, and
      social integration of the patient after the procedure were evaluated. RESULTS:
      The most frequent underlying disease was bladder cancer followed by neurogenic
      bladder. The mean operating time was 5.5 hours for performing cystectomy and the
      Indiana pouch. The most frequent immediate, early and late complications were
      urinary tract infection (12 patients, 35%), metabolic acidosis (4 patients, 11%),
      one case of total pouch necrosis, one case of pouch lithiasis, one case of
      uretero-colonic anastomosis dehiscence and two cases of septic shock. Reservoir
      function was evaluated clinically, radiologically and urodynamically.
      CONCLUSIONS: The Indiana continent urinary reservoir is a good alternative in
      patients undergoing cystectomy, regardless of the underlying cause. Technical
      dexterity significantly reduces the operating time and surgical complications.

PMID- 10589117
TI  - [The BTA stat test in the follow-up for bladder cancer].
AB  - OBJECTIVE: To evaluate the utility of the BTA stat test in the follow-up of
      asymptomatic patients with superficial carcinoma of the bladder. METHODS: In 122
      asymptomatic patients on follow-up for superficial bladder carcinoma, a sample of
      recently voided urine was obtained prior to cystoscopy and BTA stat test and
      cytology were performed. Thereafter we performed cystoscopy and TUR in those
      patients suspected of having recurrent bladder carcinoma. RESULTS: 51 patients
      had bladder cancer and 71 were tumor free. The sensitivity was 60.78% for the BTA
      stat test, 45% for cytology and 98% for cystoscopy. The specificity was 87.32%,
      94.36% and 90.14%, respectively. The positive predictive value and negative
      predictive value were 77.5 and 75.6, 85.16 and 70.5, and 87.7 and 98.46,
      respectively for each test. The sensitivity by grade was 23% for G1, 71.4% for G2
      and 92.8% for G3 for the BTA test versus 15.3%, 37.5% and 85.7% for cytology. The
      sensitivity by stage was 46.6% for Ta, 52% T1 and 100% for T2-4 and Tis for the
      BTA test versus 26.6%, 40% and 80% for cytology. CONCLUSIONS: The BTA stat test
      is superior to cytology in the follow-up of patients with bladder cancer.
      However, it has a low sensitivity in G1 and Ta and T1 tumors, therefore
      cystoscopy cannot be avoided.

PMID- 10589118
TI  - [High-flow priapism in the pediatric age: review].
AB  - OBJECTIVE: To review the literature on high flow priapism in children and analyze
      the etiology, pathophysiological mechanism, diagnostic tests, treatment and
      complications. METHODS: The literature is reviewed and an additional case of
      posttraumatic arterial priapism in an 11 year-old boy treated at our hospital is
      presented. RESULTS: 24 cases of high flow priapism in children were found; 18 had
      a history of genitoperineal trauma, 5 had sickle cell anemia and one child had
      Fabry's disease. Diagnosis was based on patient history, intracavernous blood
      gases and echo doppler findings. Fourteen patients with posttraumatic priapism,
      one patient with sickle cell anemia and the child with Fabry's disease were
      treated by pudendal arteriography with embolization. The immediate results and
      erectile function were good. CONCLUSIONS: Genitoperineal trauma is the most
      common cause of arterial priapism in children. High flow must be considered in
      children with sickle cell disease and priapism that do not respond to
      conventional treatment. Pudendal arteriography with embolization is the treatment
      of choice. Erectile function is recovered after treatment.

PMID- 10589119
TI  - [Hydraulic prosthesis for regulating the sling tension in the treatment of
      urinary incontinence in women].
AB  - OBJECTIVE: To improve the results of corrective surgery for severe urinary
      incontinence in the female (sphincteric lesion) utilizing a new prosthesis that
      allows adjusting the degree of tension of the band or urethrocervical sling.
      METHODS: We have added the use of a subcutaneous hydraulic device to the
      classical pubovaginal sling procedure. The device can be gradually filled by
      percutaneous punction to adjust the urethral closure pressure. RESULTS: All
      patients had previously undergone different procedures and had grade III stress
      urinary incontinence. With the hydraulic device, the success rate (complete
      continence) was 95.5% (21/22 patients) and the complication rate was 9% (2 cases;
      one developed infection and the other chronic urinary retention). CONCLUSIONS:
      The hydraulic device described herein is easy to place, low-cost and carries a
      minimum morbidity. Its use is indicated in patients who have previously undergone
      surgery, with a sphincteric lesion and who require precise adjustment of the
      urethrocervical sling. The degree of tautness can be adjusted repeatedly
      according to the clinical course of a patient without requiring reoperation.

PMID- 10589120
TI  - [Artificial sphincter implantation in women with urinary incontinence using a
      combined abdomino-vaginal approach].
AB  - OBJECTIVE: The artificial sphincter has been utilized for urinary incontinence
      due to intrinsic sphincteric insufficiency, with good fixation of the urethra and
      a maximum urethral closing pressure of 20-30 cms H2O, or after failed attempts at
      correction using other techniques. This procedure is difficult to perform since
      the patients have generally undergone several operations and it is necessity to
      prepare the cleavage between the urethra and vagina. We propose a modified
      combined vaginal and suprapubic approach of the technique described by Appell and
      Abbassian in 1988 for enhanced exposure of the urethra and bladder neck and easy
      access. METHODS: The modified combined abdominovaginal approach has been utilized
      in 18 females aged 16-62 years since 1995. RESULTS: 16 patients were continent
      (88%). One patient (5.5%) required removal of the artificial sphincter due to
      infection. Another patient (5.5%) has mild incontinence and requires 2 pads a
      day. Four patients (22%) with detrusor instability are receiving
      anticholinergics. Three patients (16%) with an underlying neurogenic incontinence
      require intermittent catheterization. Fourteen patients (77.7%) have type III
      stress urinary incontinence. We performed the Kelly procedure in 10 patients
      (55.5%), the Marshall-Marcetti-Kranz in 7 (38.8%), Gittes in 3 (16.6%), and 2
      patients (11.1%) had a sling procedure. Two techniques were simultaneously
      performed in some patients. CONCLUSIONS: Although the number of patients in this
      series is small, the fact that only one case required removal of the artificial
      spincter due to infection indicates that this is a useful alternative approach
      that significantly facilitates implantation of the artificial sphincter in these
      patients.

PMID- 10589121
TI  - [Ureteral stenosis caused by systemic sclerosis?].
AB  - OBJECTIVE: To report a case of ureteral stenosis arising from a rare cause.
      METHODS/RESULTS: A 77-year-old female with ureteral stenosis and clinical
      symptoms compatible with systemic sclerosis is described. Chronic inflammatory
      changes compatible with systemic sclerosis were found in the stenotic ureter.
      CONCLUSIONS: Ureteral stenosis could be a symptom of connective tissue disease
      and medical treatment should be considered in these cases.

PMID- 10589122
TI  - [Rapidly metastasizing renal carcinoma with intense expression of p53 and P
      glycoprotein].
AB  - OBJECTIVE: A case of rapidly metastasizing renal carcinoma is presented. METHODS:
      A 62-year-old man complained of fever for the past 6 weeks and weight loss. An
      abdominal CT disclosed two cystic hepatic lesions compatible with hydatid cysts
      and a mass in the upper pole of the left kidney suggestive of a carcinoma. The
      patient underwent resection of the kidney. RESULTS: Histopathological analysis
      demonstrated renal adenocarcinoma with pleomorphic areas. Immunohistochemical
      analysis showed a high cellular proliferation rate (Ki67) and intense expression
      of p53 and glycoprotein P. The patient developed metastasis to the brain four
      months later and pulmonary and cutaneous metastases shortly thereafter.
      CONCLUSIONS: Clear cell renal carcinoma can have a rapidly progressive course.
      Histological studies and determination of adverse immunohistological markers can
      be useful in these cases.

PMID- 10589123
TI  - [Skin metastases of primary transitional cell carcinoma of the prostate. Apropos
      of a case].
AB  - OBJECTIVE: To report on a rare case of cutaneous metastasis from primary
      transitional cell carcinoma of the prostate. METHODS: A 70-year-old patient with
      transitional cell carcinoma of the prostate presented with cutaneous metastasis
      in the left leg. RESULTS: The cutaneous lesion was resected. Pathological
      analysis of the specimen demonstrated cutaneous metastasis from transitional cell
      carcinoma. CONCLUSIONS: Primary transitional cell carcinoma of the prostate is an
      uncommon and aggressive tumor that can metastasize to distant, atypical sites, as
      in the case described herein.

PMID- 10589124
TI  - [Renal neurilemmoma. Apropos of a case].
AB  - OBJECTIVE: To report a case of renal parenchymal neurilemoma and review the
      literature. METHODS/RESULTS: A 44-year-old male patient presented with total
      hematuria. Patient evaluation by IVP, renal US and CT revealed a right renal
      mass. Radical nephrectomy was decided. The anatomopathological analysis showed a
      renal parenchymal neurilemoma. CONCLUSIONS: Renal parenchymal neurilemoma is a
      rare benign tumor. The diagnosis is based on the clinical symptoms and the IVP,
      renal US and CT findings and confirmed by the anatomopathological findings.
      Surgical resection achieves cure and there is usually no recurrence.

PMID- 10589125
TI  - [Erythrocytosis and hydronephrosis in a horseshoe kidney].
AB  - OBJECTIVE: To report a case of erythrocytosis in a patient with a hydronephrotic
      horseshoe kidney and normal erythropoietin values. METHODS/RESULTS: A
      hydronephrotic horseshoe kidney was discovered during evaluation to determine the
      etiology of the erythrocytosis in a 23-year-old male with normal erythropietin
      values. Blood parameters returned to normal following heminephrectomy. The
      hydronephrosis had been caused by stenois of the pyeloureteric junction.
      CONCLUSIONS: Although erythropoietin values may be normal, hydronephrosis can
      cause secondary erythrocytosis.

PMID- 10589126
TI  - [Bladder malacoplakia: 14-year follow-up of a case].
AB  - OBJECTIVE: To describe the clinical findings, treatment and results of long-term
      follow-up of a case of malacoplakia of the bladder. METHODS/RESULTS: After
      diagnostic endoscopic evaluation, transurethral resection of the lesion was
      performed and antibiotic therapy was administered. The same treatment was
      repeated 4 years later. During the following 10 years, the patient had a yearly
      endoscopic evaluation that showed no recurrence of the lesion. CONCLUSIONS:
      Transurethral resection combined with antibiotic therapy is effective in the
      treatment of malacoplakia of the bladder. The importance of long-term follow-up
      of the patient is emphasized.

PMID- 10589128
TI  - Competencies and conservative dentistry.

PMID- 10589127
TI  - [Jejunal obstruction by metastasis of a renal adenocarcinoma].
AB  - OBJECTIVE: To describe a case of jejunal obstruction due to metastatic renal
      adenocarcinoma. METHODS: A 66-year-old male who underwent nephrectomy 23 months
      earlier developed jejunal obstruction due to metastasis of the renal
      adenocarcinoma. The literature is reviewed and the uncommon form and site of
      presentation of this case are underscored and the different treatments are
      discussed.

PMID- 10589129
TI  - Emergency drugs.

PMID- 10589130
TI  - Bridging the gap between technicians and clinicians.

PMID- 10589131
TI  - Reports promote understanding.

PMID- 10589132
TI  - Dental accidents, diseases and disasters.

PMID- 10589133
TI  - Dental implants. 4. Treatment planning for implant restorations.

PMID- 10589134
TI  - The psychology of dental patient care. 10. Strategies for motivating the non
      compliant patient.
AB  - Both the dental health professional and the patient are responsible for the
      patient's failure to act on advice, the subsequent failure of treatment and
      worsening oral health. This paper looks at what can cause the failure and
      suggests various new ways of helping a previously non-compliant patient maintain
      their oral health.

PMID- 10589135
TI  - An alarming lack of public awareness towards oral cancer.
AB  - OBJECTIVE: To determine public awareness and knowledge of oral cancer in Great
      Britain. DESIGN: The respondents were selected according to a systematic
      probability sample designed to be representative of all adults in Great Britain
      (GB). The overall design was similar to previous omnibus surveys carried out by
      National Opinion Poll (NOP). The survey was carried out in ten regions of GB in
      September 1995 and was commissioned by the Health Education Authority (HEA).
      SUBJECTS AND METHODS: A random sample of 1,894 members of the public over the age
      of 16 years were asked in face-to-face interviews their knowledge relating to
      cancer, with particular reference to oral cancer, its causes and those at high
      risk and general attitudes to cancer. RESULTS: Oral cancer was one of the least
      heard of cancers by the public with only 56% of the participants being aware,
      whereas 96% had heard of skin cancer, 97% lung cancer and 86% cervical cancer.
      There was a 76% awareness of the link between smoking and oral cancer but only
      19% were aware of its association with alcohol misuse. Whereas 94% agreed that
      early detection can improve the treatment outcome, a disheartening 43% believed
      that whether a person developed a cancer or not was a matter of chance and
      therefore was unavoidable. CONCLUSIONS: This survey highlights a general lack of
      awareness among the public about mouth cancer and a lack of knowledge about its
      causation especially the excess risk associated with alcohol. RECOMMENDATIONS:
      There is a clear need to inform and educate the public in matters relating to the
      known risk factors associated with oral cancer. A media campaign informing the
      public about oral cancer is clearly required. The need for the reduction in the
      incidence of oral cancer should be included in 'Our healthier nation' targets. An
      overall health promotion strategy to reduce cancers should include oral cancer as
      a priority. In addition the European Code against Cancer which aims to improve
      prevention, the early detection of oral cancer and the necessity for fast track
      referral should be made more widely known. Recognition of oral cancer in local
      strategies for oral health should be encouraged.

PMID- 10589136
TI  - Enhancing dental attendance rates for children from deprived areas in the UK.
AB  - OBJECTIVES: To compare different methods being used to determine eligibility for
      enhanced capitation registration payments, which were introduced in the UK in
      April 1998 with the intention of improving the numbers of children aged 0-5 years
      from deprived areas registering with General Dental Service practitioners.
      DESIGN: Comparative study of the enhanced capitation registration payment
      schemes; data from a longitudinal study of Scottish children used to compare
      patient and dentist postcodes. OUTCOME MEASURES: Published registration rates;
      levels of agreement between patient and dentist postcodes. RESULTS: Quarterly
      registration rates for 3-5-year-olds show little improvement as yet; Scottish
      figures for 0-2-year-olds indicate a more substantial increase which may have
      been influenced by other initiatives. In Scotland, the degree of agreement
      between the deprivation scores of patient's and their dentist's postcode was less
      good among patients from deprived areas than for the sample as a whole.
      CONCLUSIONS: More detailed breakdown, using the same criteria as for the enhanced
      payments, may eventually offer more definitive results. Patient postcodes enable
      better targeting than practice postcodes, but both may omit a substantial number
      from the target group if area measures of deprivation are used.

PMID- 10589137
TI  - Information technology in dental education.
AB  - The use of information technology in dental education is continually increasing.
      In this article, IT is defined, and its uses in teaching and learning explored.
      Examples of the appropriateness of multimedia teaching in dental education are
      given. Successful multimedia teaching, especially in clinical settings, relies on
      the proper use of IT and an implementation strategy. The applications of IT to
      curriculum development, computer-assisted learning (CAL), educational
      administration, dental practice, hospital administration, and clinical research
      are also considered.

PMID- 10589138
TI  - Value, trauma, and personal reality.
AB  - It is often said that psychoanalysis is a science of meaning. However, it also
      concerns value. Although value is a central aspect of personal existence, it is
      relatively neglected in traditional theory. How value arises in the sphere of the
      personal is the main theme of this article. A second theme concerns attacks on
      value, which leave their imprints on the psychic system as unconscious memories
      that are repeatedly evoked in the therapeutic conversation.

PMID- 10589139
TI  - A model for adolescent day treatment.
AB  - Milieu treatment is cited as a therapeutic aspect of inpatient, residential, and
      day programs for seriously disturbed adolescents. However, the literature is
      generally descriptive, and does not link specific treatment recommendations with
      theoretical conceptualizations. This population has unique developmental needs
      and pressures that must be taken into account for treatment to be effective. This
      article examines the theoretical and empirical literature and proposes an
      integrated model for effective day treatment for this population.

PMID- 10589140
TI  - Music therapy in grief resolution.
AB  - The multifaceted nature of grief and the enormous variation in individual
      clients' responses to losses make it necessary for therapists to have wide
      background knowledge and well-developed skills in counseling and/or
      psychotherapy. The author describes an innovative method of facilitating grief
      resolution using precomposed music that is significant to the patient after a
      major loss. In this method, music is of equal importance with verbal processing
      as part of the overall therapeutic approach. Musical improvization is also used
      as a primary tool to reflect back to, and affirm for, the patient the affective
      content of his or her life story. This approach requires the therapist to have
      particular musical skills and a wide repertoire of genres and specific musical
      pieces, as well as intuition. Several clinical vignettes illustrate the
      application of this approach.

PMID- 10589141
TI  - Phase-specific psychosocial interventions for first-episode schizophrenia.
AB  - Phase-specific psychosocial interventions for first-episode schizophrenia are
      outlined and described using examples from clinical practice with 68 patients.
      These interventions are based on the unique aspects of the first episode and
      patients' clinical states. Although schizophrenia may run an uneven and often
      unpredictable course, most patients experience three distinct phases: (1) the
      acute phase, (2) the healing phase, and (3) the maintenance phase. The timeliness
      of phase-specific interventions is crucial in helping both patients and families
      understand the illness, evaluate options, accept treatment, and adjust to changes
      in functioning and expectations.

PMID- 10589142
TI  - Splitting: an empirical study.
AB  - In this study, the Rorschach scoring system for splitting developed by Lerner,
      Sugarman, and Gaughran (1981) was applied to the Holtzman Inkblot Technique
      (HIT). Normal individuals (n = 30), patients with neurotic disorders (n = 30),
      patients with borderline personality disorder (n = 30), patients with acute
      schizophrenia (n = 25), and patients with chronic schizophrenia (n = 25) were
      studied with respect to their use of splitting. Sufficient interrater reliability
      was demonstrated for the scoring of splitting in the HIT. Significant differences
      between borderline patients, acute schizophrenic patients, and chronic
      schizophrenic patients, on the one hand, and patients with neurotic disorders, on
      the other hand, were demonstrated. Furthermore, it was shown that the indicators
      of splitting were associated with measures of identity diffusion, primitive
      defense mechanisms, and other measures of psychopathology. The Lerner indicator
      of splitting proved to be multidimensional. Different forms of splitting seem to
      be characteristic of borderline patients and schizophrenic patients. The
      application of the Lerner criteria of primitive defenses to the HIT appears to be
      promising.

PMID- 10589143
TI  - Confessions of a psychotherapist.
AB  - The evolution of a therapist is the result of personal style, training, and
      social context. The author describes how his active involvement with people, love
      of telling stories, and desire to interact with others set the stage for his
      training as a psychoanalyst. He also discusses how the specific needs of patients
      drew him toward more active interaction with them, both within and outside
      therapeutic sessions. Supporting patients in their need to cope with a daily life
      meant intervening in their total system. The author's parallel work with
      community mental health and the development of the Healthy Cities program led to
      a broader understanding of the holistic sociopsychological experiences of people.
      As a result, he combined storytelling, assisting with job placement, dealing with
      day-to-day emergencies, and many more activities with analytic and cognitive
      therapy. Although the author recognizes that as a therapist he breaks boundaries,
      he respects the approaches of therapists who work in more standard ways, which
      are also helpful, effective, and needed.

PMID- 10589144
TI  - The female athlete triad: disordered eating, amenorrhea, and osteoporosis.
AB  - The Female Athlete Triad is a common clinical entity amongst female athletes. The
      physician caring for such athletes needs to keep the symptoms of the triad in
      mind and recognize their potential severity. Still more needs to be done in the
      areas of prevention, early detection, and early treatment. Education efforts
      should be focused on junior high and early high school girls because the rapid
      bone formation during puberty will be necessary to carry them for the rest of
      their lives. It is also important to note that the female athlete triad should
      not be used as a reason to disqualify otherwise healthy female athletes from
      athletic participation. Athletic participation and exercise are good and healthy,
      if done appropriately. Women have made great strides in the athletic realm, and
      it would be inappropriate to imply that they should not participate because of
      the risk or presence of the Female Athlete Triad.

PMID- 10589145
TI  - Physical training and injury in female cadets at the United States Military
      Academy.
AB  - Women have been enrolled at the United States Military Academy (USMA) since 1976.
      All cadets are required to participate in a rigorous physical training curriculum
      with few differences for male and female cadets. The effect this physical
      training has on the health of women at West Point has been monitored closely.
      This paper will review the physical training program at USMA and the gender
      differences that exist. The health effects of this demanding physical training on
      women will also be discussed.

PMID- 10589146
TI  - Anterior cruciate ligament injuries in female athletes.

PMID- 10589147
TI  - The female knee--anterior knee pain.
AB  - There are clear differences between men and women with regard to anterior knee
      pain. Anatomic factors including increased pelvic width and the resulting
      excessive lateral thrust on the patella are significant in female predisposition
      to anterior knee pain. Effects of estrogen on connective tissue synthesis have
      been noted, but there is no clear mechanism by which this would affect anterior
      knee pain. Postural and sociologic factors such as wearing high heels and sitting
      with legs adducted can influence the incidence and severity of anterior knee pain
      in women.

PMID- 10589148
TI  - Evaluating and managing athletes with valvular heart disease.

PMID- 10589149
TI  - Helicopter air medical transport: ten-year outcomes for trauma patients in a New
      England program.
AB  - BACKGROUND: Twenty-five years have passed since the introduction of the first
      civilian hospital-based air medical helicopter service. This study reviews the
      impact of a single air medical service during a decade of service on the survival
      of severely injured trauma patients. METHODS: A retrospective database analysis
      was performed to determine program demographics and obtain outcome data. The
      outcomes of trauma patients were compared to mortality derived from a national
      database utilizing physiologic indices of severity. RESULTS: Outcome analysis
      demonstrated an overall 13% reduction in mortality for air transported patients
      when compared to controls. Stratification based upon Trauma Score demonstrated a
      35% reduction in mortality for victims transported directly from the scene with
      scene scores between four and 13, and essentially no difference in outcome for
      patients at Trauma Score extremes. CONCLUSIONS: Rapid utilization of helicopter
      air medical transport can have a dramatic impact upon patient outcome, especially
      within a select group of scene transported trauma patients with Trauma Scores
      ranging from four to 13.

PMID- 10589150
TI  - The Internet as an equalizing, energizing, and transforming force in patient and
      physician relationships.

PMID- 10589151
TI  - [Calcinosis in goats].
AB  - Death, abortion, decreased milk yield and emaciation in dairy goats occurred due
      to calcinosis in a goat operation on 1100 meter sea level in Tyrol. This could be
      diagnosed by the clinical, sonographical and pathomorphological investigation. In
      the basic fodder yellow oat grass proportion was present with 40%. Clinically the
      apathic goats showed reduced appetite, emaciation, dyspnea, anaemic mucous
      membranes, heart noises and less activity to move. The blood-chemical examination
      of one goat revealed an increased activity of AP (199 U/l), calcium and phosphor
      concentrations were in normal range. Sonographically liquidothorax and -perikard,
      calcified pulmonary and aortic valves and a thickened aortic orifice as well as
      calcification of kidneys, enlargment of liver and ascites could be diagnosed in
      this goat. The sonographical findings were confirmed by pathomorphological
      examination.

PMID- 10589152
TI  - [Transgenic animals as bioreactors in the service of the pharmaceutical
      industry].
AB  - A modern pharmacotherapy without the use of proteins as drugs is not more
      practicable. In the clinic blood coagulation factors (factor VIII and IX), growth
      hormones (human growth hormone), enzymes (1-antitrysin, insulin), and cytokines
      are currently used. At the beginning, the proteins were isolated from biological
      sources or expressed in vitro by the use of E. coli or eukaryotic cell lines. At
      the moment efforts were undertaken to express these proteins in the milk of
      transgenic animals. This review article describes the methods for the generation
      of transgenic animals, the benefits and drawbacks of this new technique in
      comparison to established methods for the production of proteins as
      pharmaceuticals. At the end of the review possible improvements of the method are
      described.

PMID- 10589153
TI  - [Ultrasonographic examinations of fetal growth of sheep between day 20 and day 50
      of gestation].
AB  - Previous studies on embryonic and fetal growth in sheep were mostly transversal
      using animals killed at various stages of gestation. Until now it was difficult
      to monitor the development of individual embryos/foetuses during pregnancy,
      especially during the first and second pregnancy month. Real-time ultrasound as a
      non invasive method could be an appropriate method for examination of embryonic
      and early foetal development in sheep. The aim of this study was to determine the
      embryonic and foetal development of the crown-rump-length (CRL) in pregnant ewes
      in relation to the number of fetuses and/or the breed. Between the 20th and 50th
      day of pregnancy the embryos/foetuses showed an exponential growth which can be
      best described by the equation of the form CRL (mm) = W * exp (k * day of
      pregnancy). The individual variability in embryofetal growth is in part due to
      the number of embryos per sheep and the sheep breed.

PMID- 10589154
TI  - [Effect of unfractionated and low-molecular-weight heparin on platelet
      aggregation and in vitro bleeding time in dogs].
AB  - The aim of the present study was to examine the influence of unfractionated
      heparin (UFH) and low molecular weight heparin (LMWH) on the function of canine
      thrombocytes. This was performed by adding different concentrations of UFH or
      LMWH to platelet rich plasma (PRP) or blood of healthy dogs: 0.2, 0.5, 1, 2, 5,
      10, 20, and 50 I.U./ml UFH or Anti-FXaU/ml LMWH, respectively (aggregation
      induced by thrombin additionally: 0.025, 0.05, and 0.1 I.U./ml UFH or Anti
      FXaU/ml LMWH.) Platelet aggregation induced by ADP, collagen or thrombin with the
      BORN method (n = 11) as well as the in vitro bleeding time using the analyzer PFA
      100 (n = 5) were examined. Additionally, a specific test assay for ADP induced
      platelet aggregation was performed which enabled an individual adjustment of the
      aggregation maximum at 30-40% in the control measurements (n = 6). The most
      prominent effect was noted in the platelet aggregation induced by thrombin. The
      aggregation maximum of the platelet aggregation induced by 1 I.U./ml thrombin
      (final concentration) was significantly lower in all of the testet UFH
      concentrations > or = 0.025 I.U./ml UFH in comparison to control measurements. If
      the aggregation was induced by 10 I.U./ml thrombin a significant reduction of the
      aggregation maximum was restricted to UFH concentrations > or = 0.5 I.U./ml. The
      addition of LMWH to canine PRP resulted in a distinct decrease (p < 0.01) of the
      maximum aggregation induced by 1 I.U./ml thrombin in concentrations > or = 0.2
      Anti-FXaU/ml LMWH. A slight decrease of the maximum aggregation induced by
      collagen was only found for UFH at activities > or = 20 I.U./ml. No significant
      systematic influence could be demonstrated for LMWH on the aggregation induced by
      collagen as well as for LMWH and UFH on the platelet aggregation induced by ADP.
      Capillary in vitro bleeding time (closure time) was prolonged only after adding
      high concentrations of UFH (> or = 10 I.U./ml) and LMWH (> or = 50 Anti-FXaU/ml)
      to the sample material. The results document the unimportant influence of
      therapeutic levels of UFH and LMWH on platelet function in dogs. Therefore, the
      remarkable inhibition of the aggregation induced by thrombin reflects mainly the
      antithrombin effect.

PMID- 10589155
TI  - [Investigations on the dependence of hematologic and blood chemical parameters on
      the age of health lambs--a contribution to the definition of reference values in
      sheep].
AB  - Haematological and biochemical examinations were carried out in 284 clinically
      healthy lambs aged from birth to nine month. The 122 male and 164 female animals
      belonged to the following breeds: German blackheaded mutton sheep (n = 114),
      Merino (n = 21), Frisian milksheep (n = 98), Texel (n = 31), Bentheimer landrace
      (n = 16) and Leine sheep (n = 5). The lambs were selected from a larger number of
      probationers by use of outlier tests. No differences were found between sexes for
      any of examined parameters. For the period from two to eight weeks of age breed
      differences could be proven for glutamate dehydrogenase and creatinin. Many
      parameters showed a strong dependence on the age of the lambs in a linear or
      polynomial function. While lymphocytes, protein, urea, creatinin, 3
      hydroxybutyrate and copper increased, bilirubin, glucose, calcium, inorganic
      phosphate and the activities of alkaline phosphatase and gamma-glutamyl
      transferase decreased with age. Body weight had no influence on any examined
      parameter within the age dependence. Reference values (limits) are defined for
      healthy lambs and for healthy ewes, summarized from former studies.

PMID- 10589156
TI  - [The study of the distribution of Chinese surnames and the diversity of genetic
      population structure in the Song dynasty].
AB  - Surname in China, as a cultural genetic factor, is a very huge and remarkable
      human population study resource. The transmission feature of surname has been
      proved to be similar to that of the genetic markers on Y chromosome of males. It,
      therefore, has been applied in the population genetic studies since 1965's. In
      the present study, we have analyzed a group of Chinese surname data of the Song
      dynasty (AD. 960-1179). The distribution of the present surname data is
      corresponded with the Karlin-McGregor's neutral allele model. The surname
      abundance alpha and the migration rate parameter v in the Song dynasty in 16
      provincial regions reflected degrees of migration and admixture at that time.
      Surname phylogenetic dendrogram analysis demonstrated that the Han Chinese had
      been segregated into North and South two parts in Song dynasty of 1000 years ago.
      Wuyi and Nanling Mountains divided Northern and Southern Han populations into the
      two major parts of Han Chinese. The results also showed that the surname
      distribution of Song dynasty 1000 years ago was quite similar to the present
      model. The 100 high frequency surnames in Song dynasty were well corresponded
      with the current surname distribution. This phenomenon suggests that Chinese
      surnames have been steadily transmitted from ancient to the present. The present
      study improved that the Chinese surname is a very important genetic resource for
      the studies of structure of the Chinese populations, migration, and affinities
      among different populations.

PMID- 10589157
TI  - [Genetic polymorphism in natural populations of D. virilis].
AB  - In this paper we analysed the RFLP of mtDNA in Lanzhou (LZ) population of D.
      virilis. By reanalysing the RFLP data of our previous work on other natural
      populations of D. virilis, a phylogenetic tree was produced based on the UPGMA
      method. It shows three main clusters: the Northern populations (LZ QD), the East
      China populations (NJ, SH, NB) and the Southern population (QZ). With the mtDNA's
      RFLP data and the results of our former work on allozyme variation in natural
      populations of D. virilis, we suggest that there exists a latitudinal cline of
      genetic variation in natural populations of D.virilis. The mechanism for the
      maintenance of the observed latitudinal pattern is discussed.

PMID- 10589158
TI  - [The phylogeny of 5 Chinese peculiar Parnassius butterflies using noninvasive
      sampling mtDNA sequences].
AB  - This paper employs nonivasive sampling DNA sequencing technique for estimating
      molecular phylogeny of 5 Chinese peculiar Parnassius Butterflies. Of 433bp
      mitochondrial cytochrome b DNA sequences, A% + T% was 75.4%, and 40 nucleotide
      sites were substituted (about 9.24%). The molecular phylogenetic tree constructed
      by parsimony method suggests that Parnassius acco is closely related to
      Parnassius baileyi; Parnassius apollo, Parnassius orlears, and Parnassius simo
      are independent branches respectively. Parnassius simo is divergent earlier. The
      result is identical with that of morphology.

PMID- 10589159
TI  - [Establishment of two ES cell lines with good germline contribution].
AB  - Nine embryonic stem cell lines have been established from mouse strain 129/ter.
      Three of the nine ES cell lines were karyotypically normal. The nine cell lines
      showed some difference in the growth rate and the differential competence.
      Chimeras were made by injecting the ES cells into C57BL/6J blastocysts, and the
      germline compositions of the chimeras were detected by mating them with albino
      ICR mice. The results indicated that ES cell line MESPU21 and MESPU22 were both
      highly germline-competent. Comparing with other ones, these two cell lines both
      were karyotypically normal and propagated fast. The tissue composition of the
      teratocarcinomas derived from these cell lines appeared paralle to the results of
      chimera production. Careful manipulation during the process of ES cell
      establishment was helpful to obtain good cell lines.

PMID- 10589160
TI  - [Molecular mapping of the S-a locus for F1 pollen sterility in cultivated rice
      (Oryza sativa L.)].
AB  - F1 pollen sterility in cultivated rice (Oryza sativa L.) was found to be caused
      by at least six loci of F1 pollen sterility genes. At the S-a locus, one of the
      six loci for F1 pollen sterility, the allelic interaction of S-ai and S-aj causes
      the male gametes carrying S-aj allele abortive. To map the S-a locus, Taichung
      65(T65), a Keng (japonica) variety with S-aj/S-aj, its isogenic F1 sterile line
      TISL4 with S-ai/S-ai from Chin-tsao, a Hsien (indica) variety, and the F2
      population from cross T65 x TISL4 were used as materials. The polymorphism
      between T65 and TISL4 detected by RFLP and RAPD analysis was less than 1%. This
      result indicated that short segments from Chin-tsao were introgressed into the
      isogenic F1 sterile line, since the TISL4 was developed by repeatedly
      backcrossing for thirteen times. By linkage analysis of S-a and the marker loci,
      the S-a locus was mapped on chromosome 1. The genetic distances between S-a and
      RFLP markers CDO548 and RG146 are 6.4 cM and 7.2 cM respectively, and those
      between S-a and RAPD markers O11-1000 and Y13-500 are 6.8 cM and 11.2 cM
      respectively. The mapping of the S-a locus is an important step towards marker
      aided selection for overcoming the hybrid sterility in rice.

PMID- 10589161
TI  - [Fertile transgenic indica rice from microprojectile bombardment of embryogenic
      callus].
AB  - A reproducible and efficient transformation system for indica rice was developed
      based on microprojectile bombardment of embryogenic callus. Sufficient globular
      embryogenic calli were produced within 2-6 weeks from 3-4 week old calli derived
      from mature embryos. The embryogenic calli were bombarded with the plasmid pFWZ16
      containing bar gene and B.t. delta-endotoxin gene. Selection, pre-regeneration,
      regeneration and rooting were carried out on media with 2-4 mg/L Basta. Partial
      desiccation treatment was used to increase the efficiency of regeneration.
      Transformed plantlets were recovered within 4-5 months after mature seeds were
      plated. From 821 bombarded embryogenic calli of two elite rice varieties
      popularized in South China, 477 Basta resistant plants of 48 lines were obtained.
      Results of PCR, Southern blotting, RNA dot blotting, and topical application of
      Basta demonstrated that the foreign bar gene and B.t. gene were integrated into
      the genome of transgenic rice plants, and also expressed. 87.5% of the transgenic
      plants were fertile. Mendelian segregation of the foreign genes was indicated by
      Basta application and Southern blot analysis of R1 plants.

PMID- 10589162
TI  - [Favorable genes and favorable genic interactions enhancing F1 fertility in
      indica/japonica hybrids].
AB  - Two test cross populations were developed by crossing a set of DH lines as male
      parents to two wide compatibility rice lines, photoperiod-sensitive genic male
      sterile (PGMS) line-N422S and thermosensitive-genic male sterile (TGMS) line
      Peiai64S. Polymorphism of the cross parents and another set of diverse indica or
      japonica lines (as a control) was assayed by using 92 RFLP markers. 41 RFLP
      markers were detected highly associated with indica and japonica phenotypes,
      which can be used as diagnostic markers to differentiate indica and japonica. Our
      results indicated that 87.8% of the diagnostic markers were also highly
      associated with grain yield and its components in at least one of the test cross
      populations, suggesting parallel relationships between the genes involving in
      evolution and QTLs controlling grain yield and yield components in the process of
      differentiation of rice (O. sativa L.). Further analysis indicated that fertility
      was a main factor affecting the heterosis for grain yield in inter-subspecific
      rice hybrids. The fertility was conditioned by both intra-locus and inter-locus
      gene interactions and favorable genic interactions could raise it accordingly.

PMID- 10589163
TI  - [Transformation of common wheat (Triticum aestivum L.) with herbicide-resistant
      EPSPs gene].
AB  - The herbicide-resistant EPSPs (5-enolpyruvylshikimate-3-phosphate synthase) gene
      was transformed into about 1,000 young spikes and 800 young embryos of wheat
      variety, Jinghua 1, with gene gun. Thirty-eight and four regenerated plants were
      obtained respectively screened with glyphosate. All regenerated plants were
      analysed by PCR and/or Southern blotting. The results indicated that EPSPs gene
      was integrated stably into the genome of Jinghua 1, and some of the transformants
      showed fertile. So herbicide-resistant EPSPs gene could be used as selective
      marker in the transformation of monocotyledon cereal crops, such as wheat.

PMID- 10589164
TI  - [Genetic analysis of leaf-parent-type plants regenerated from somatic
      hybridization in Citrus].
AB  - The leaf indexes and stoma characteristics of leaf-parent-type regenerants were
      the same as those of the leaf parent Rough lemon, but quite different from the
      somatic hybrids. Leaf-parent-type plants were diploid (2n = 2x = 18). Patterns of
      POX, PPO, GOT isozymes were identical to those of Rough lemon. The plants were
      analyzed by using 54 arbitrary primers with polymorphisms. Most of the primers
      (52) showed that leaf-parent-type plants were in concordance with Rough lemon.
      However, with primer OPW-12, the plants contained a unique band of Hamlin sweet
      orange. Amplification products with primer OPV-04 showed slight differences among
      the accessions. The research suggested that most genetic constitutions of the
      leaf-parent-type plants were from leaf parent Rough lemon and a little from
      embryogenic suspension parent Hamlin sweet orange.

PMID- 10589165
TI  - [Scanning electron microscope observation on endosperm starch grain characters in
      multiplasmic maize].
AB  - In this article, endosperm starch grains of eleven lines in multiplasmic maize
      were studied by scanning electron microscope. The results show that different
      cytoplasm has different effects on the characters of starch grain. The starch
      grains of three sweet corn cytoplasmic lines (su1, sh2, btl) are mainly spherical
      and packed tightly, which means they have some degree of similarity. While the
      grains of four cytolasmic male sterility lines (T, S, C, 21A) are mostly
      irregular and packed loosely except (T) Mo17, in which grains are tightly packed.
      The average diameter of these eleven varieties is ranged from 9.78 microns to
      14.69 microns. Through the study of endosperm starch grain shape and size, we
      tried to explore the relationship between the property of starches and the
      quality of seeds. And this will significantly prompt the development of maize
      genetics and breeding.

PMID- 10589166
TI  - [Studies of transgene segregation and integration in maize].
AB  - The segregation, integration and stability of the transgene-Bt (Bacillus
      thuringensis) in eight transformants created by three ways of transformation were
      studied by means of PCR (Polymerase chain reaction) and DNA molecular
      hybridization. The results are as follows: (1) The transgene-Bt in most of the
      progenies of the transformants showed simple Mendelian segregation. Although some
      deviation from Mendelian fashion existed in the early generations, the normal
      Mendelian segregation would be found after R3 generations and the transgene could
      fix in the populations. (2) The integration patterns of the transgene varied to
      the some extent in the different transformants, but they were characterized by
      either smaller band and copy numbers or cascade integration or closely linked
      integration in all transformants. (3) Changes of the Southern land pattern were
      found in some families of some transformants, especially, in the two families of
      Ding 4R5.

PMID- 10589167
TI  - [Insect-resistant transgenic plants of Brassica napus and analysis of resistance
      in the plants].
AB  - Cotyledons, each with a 1-2 mm petiole at its base, were cut from axenic
      seedlings and infected with Agrobacterium tumefaciens. After 2-3 days of
      cocultivation, the cotyledon explants were transferred to MS selection medium
      containing 15 mg/L kanamycin and 4.5 mg/L 6-BA to induce shoot differentiation.
      Kanamycin-resistant shoots were subcultured on selection medium with 20-50 mg/L
      kanamycin for 3-6 months for eliminating escaped non-transformants, and then
      rooted on MS medium containing 25 mg/L kanamycin and 0.1 mg/L NAA. Whole plants
      were transplanted into soil and grew in the field. DNA Southern blot
      hybridization and polymerase chain reaction showed that some of the plants were
      positive when probed with the insecticidal crystal protein gene. The transgenic
      plants exhibited tolerant to pest insects such as Laphygma exigua and Pieris
      rapae in leaf feeding experiments Kanamycin-resistance and insect-resistance were
      maintained in the progeny. The foreign genes were delivered to the progeny
      according to Mendelian Law of single gene segregation.

PMID- 10589168
TI  - [The features of isozyme zymograms and genetic diversity in Undaria pinnatifida].
AB  - The zymogram features of 11 kinds of isozyme and gene expressions in Qingdao and
      Zhoushan population of U. pinnatifida gametophytes were investigated and genetic
      diversity was examined by PAGE (polyacrylamide gel electrophoresis) technique.
      The results showed that the level of genetic diversity in Qingdao population of
      U. pinnatifida gametophytes was higher than that in Zhoushan population. Two
      banding patterns controlled by two variant genes were found in alcohol
      dehydrogenase (Adh) of U. pinnatifida gametophytes. There were null alleles in
      the population.

PMID- 10589169
TI  - [Cloning and expression of tyrosinase gene from Pseudomonas maltophilia in E.
      coli].
AB  - The enzyme tyrosinase, encoded by tyrosinase gene (mel), is responsible for
      melanin formation. In a shotgun cloning experiment, a SalI-digested DNA fragment
      coding for tyrosinase was cloned from Pseudomonas maltophilia DNA into plasmid
      vector (pUC18) to generate the hybrid plasmid (pWSY). The recombinant plasmid
      imparted the ability of melanin synthesis to an E. coli host (HB101). The foreign
      DNA fragment (0.7 kb) possessed no recognition sites for BamHI, HindIII, EcoRI or
      BclI. Hybridization studies confirmed that the small fragment cloned in pWSY was
      from P. maltophilia DNA. Nucleotide sequence analysis identified an ORF of 504 nt
      coding tyrosinase. SDS-PAGE analysis also revealed an additional protein of 18
      kDa, which was equal to the putative tyrosinase according to the size of mel
      fragment, was expressed in the E. coli recombinant carrying the plasmid pWSY.

PMID- 10589170
TI  - Patent internal and external carotid arteries beyond an occluded common carotid
      artery: report of a case diagnosed by color Doppler.
AB  - Occlusion of the common carotid artery (CCA) is most often associated with
      thrombosis of the distal vessels. In rare cases, however, a weak antegrade flow
      can still be detected in the internal carotid artery (ICA). This patency is the
      result of a retrograde perfusion of the ipsilateral external carotid artery (ECA)
      via its collaterals. Such situation should not be ignored since bypass surgery
      can easily allow for effective restoration of flow. Most authors agree to say
      that color flow duplex imaging (CFDI) has now become the hallmark to detect a
      patent ICA in spite of a CCA occlusion.

PMID- 10589171
TI  - Modifications of the elbow induced by the practice of handball on radiography, US
      and MRI.
AB  - The objective of this study was to evaluate plain radiographs, US and MRI in
      detection of occult lesions of the elbow in asymptomatic handball players.
      Comparative plain films of both elbows were obtained in an anteroposterior and
      lateral projection. A bilateral comparative ultrasound examination was performed
      with measurement of the thickness of the flexor and extensor tendons, the triceps
      tendon, the lateral collateral ligament and the anterior bundle of the medial
      collateral ligament (MCL). Echogenicity of these structures was evaluated.
      Articular recesses were scanned for fluid and loose bodies. Axial and coronal MRI
      of the dominant elbow was performed using a T1W sequence after intravenous
      injection of gadolinium 30 minutes before the examination and by a FISP 3D T2W
      echo gradient sequence in coronal plane and reconstruction in a sagittal plane.
      Twenty-eight male asymptomatic members of the national handball team with 7 to 25
      years of experience and undergoing 3 to 4 training sessions per week were
      studied. Paraphysiological modifications such as hypertrophy of bone and muscles
      were evidenced. Flexion deformity of the elbow was present even in the youngest
      players, but valgus deformity occurred preferentially in the more experienced
      players. US was more efficient in detection of small loose bodies and gave more
      precise information on the structure of the MCL and the tendons compared with
      MRI. Plain film and US were sufficient for the detection of chronic lesions of
      the elbow. MRI did not add significant findings.

PMID- 10589172
TI  - Ectopic ureter associated with renal dysplasia.
AB  - Two patients, aged 22 and 68, were admitted for recurrent orchi-epididymitis and
      septicemia respectively. On digital rectal examination, a right pararectal mass
      was palpated. CT showed in both patients unilateral renal agenesia with a dilated
      blind ectopic ureter and an enlarged pseudocystic seminal vesicle. MRI obtained
      in one patient demonstrated a hyperintense content of the blind ureter and the
      seminal vesicle. Cross section imaging findings were in agreement with
      deferentography. Histology confirmed the diagnosis of renal dysplasia, with a
      blind ectopic ureter, opening in the seminal vesicle.

PMID- 10589173
TI  - CT of adrenal myelolipoma: report of 7 cases.
AB  - Seven cases of adrenal myelolipoma are reported. The series consisted of 1 male
      and 6 females, ranging in age from 30 to 76 years. In 5 cases the tumor
      originated from the right adrenal, in 1 case from the left adrenal and the
      remaining patients had bilateral tumors. Symptoms related to the mass were
      present in 4 cases but in contrast to other reports no hematuria was found in
      this series. All the tumors laid behind the angles formed by the lateral and
      medial limbs of adrenals. Fat density dominated in 6 tumors and soft tissue
      density dominated in 2. Calcification spots were revealed in 3 tumors. In two
      predominantly soft tissue density tumors the complete peripheral rims were
      revealed, while in the remaining 6 tumors the peripheral rims were considered
      incomplete based on the CT images. In 3 cases large amounts of fat were found
      surrounding the normal contralateral adrenal. The cause is still open to further
      investigation. Spiral CT with thin collimation provided detailed morphological
      information for adrenal myelolipoma.

PMID- 10589174
TI  - Imaging of the parapharyngeal space.
AB  - The parapharyngeal space is a deep space of the neck, always well visible on CT
      and MR imaging of the head and neck; in normal circumstances, this space should
      look symmetrical. The parapharyngeal space is often subdivided in compartments;
      such subdivision is helpful when considering the site of origin of a
      parapharyngeal space mass. Several concepts of compartmentalization of this space
      exist, sometimes leading to confusion; not the names but the anatomy is important
      to know. This manuscript reviews shortly the anatomy of the parapharyngeal space,
      the use of modern cross-sectional imaging methods in the evaluation of this
      region, and focuses somewhat more on imaging of primary parapharyngeal lesions.

PMID- 10589175
TI  - The common cavity deformity of the ear. A precursor of meningitis but now being
      implanted.
AB  - The first succinct description of otogenic meningitis related to the common
      cavity deformity of the inner ear was made from a post mortem study of 150 years
      ago. Since then there has been much confusion with less severe malformations of
      the cochlea, but these patients can now be treated by cochlear implant. It is
      therefore necessary that an accurate appraisal of the state of the cochlea is
      made beforehand by computed tomography and by Magnetic Resonance Imaging.

PMID- 10589176
TI  - Imaging in patients with vertigo.

PMID- 10589177
TI  - Images in clinical radiology. Extensive emphysematous cholecystitis.

PMID- 10589178
TI  - Minimally invasive aortic surgery: endovascular stent-graft repair of abdominal
      aortic aneurysm.
AB  - Minimally invasive surgical therapies are popular with patients and third party
      payors because they offer increased safety, decreased pain, as well as shorter
      recovery times and hospital stays when compared to standard open surgery.
      Minimally invasive aortic surgery is now a practical reality. Our experience with
      150 endovascular stent-graft aortic aneurysm repairs at Baptist Hospital East is
      detailed in the following report. In our practice, stent-grafting is now the
      treatment of choice for infrarenal abdominal aortic aneurysms within the context
      of clinical trials.

PMID- 10589179
TI  - Skull base reconstruction utilizing titanium mesh in chronic CSF leakage repair.
AB  - OBJECTIVE AND IMPORTANCE: Chronic cerebrospinal fluid leakage is a perplexing
      management problem in skull base surgery, as well as craniofacial and certain
      otolaryngologic procedures. When all less invasive techniques have been tried and
      have failed, craniotomy for direct repair is often done. CLINICAL PRESENTATION:
      This case represents one such case in which the pathology found required an
      unusual application of a common surgical adjunct for correction. The patient in
      question had experienced CSF rhinorrhea intermittently for 10 years prior to
      presentation. Several intracranial procedures had failed to curtail the
      rhinorrhea, after failure of lumbar drainage and other less invasive procedures
      had also failed. The patient was taken to surgery again for an attempt to
      directly correct the CSF leak, after demonstration of the location of the leak
      was accomplished with the assistance of contrasted coronal CT images of the
      anterior fossa. TECHNIQUE: At the time of surgery, comminuted fractures of the
      floor of the anterior fossa were noted. These fractures were associated with
      multiple sites of dural impingement. Following meticulous repair of all dural
      injuries, reconstruction of the floor of the anterior fossa was accomplished with
      the use of titanium micro mesh. The mesh placement isolated the dura from further
      contact with the fracture surfaces, preventing recurrent dural injury.
      CONCLUSION: The use of titanium mesh in skull base surgery has previously been
      reported in craniofacial and cranial vault procedures. Its use in skull base
      applications may prove useful in certain situations. This patient remains
      asymptomatic nearly 2 years after its use, longer than with any previous
      procedures to correct his chronic CSF leakage.

PMID- 10589180
TI  - Professional courtesy--a federal offense?

PMID- 10589181
TI  - Tuberculosis Control Program of the Cabinet for Health Services visited health
      departments state-wide and assessed the management of patients with tuberculosis.

PMID- 10589182
TI  - [Surgical analysis for small cell lung cancer of the lung].
AB  - Clinical features of small cell lung cancer were studied in 15 cases. The overall
      5-year survival rate of the patients with limited small cell lung cancer was
      11.4%. Surgery played substantial role for long-term survival in limited SCLC.
      The 4-year-survival rate of the patients in stage I was 50%, and that of those in
      stage II and IIIA was 50% and 37.5%, respectively. In the two survivors over four
      years in stage IIIA, all tumor was categorized as pT3 disease. The 4-year
      survival rate of the patients treated with PE was 100%, and that of those treated
      with another chemotherapy was 10%, and that difference is statistically
      significant (p < 0.05). There was no significant difference in prognosis of
      patients in any other factors such as location (central or peripheral),
      histological subtype, curability or R number, pT factor, pN factor, p stage or
      with or without thoracic irradiation. Surgical resection for limited SCLC should
      be recommended in patients with stage I, II and T3N0M0 or T3N1M0 disease. For the
      patients in stage IIIA, particularly in N2M0 disease, who showed partial response
      or no change after chemotherapy, surgery should be considered because those
      patients might have nonsmall cell carcinoma components.

PMID- 10589183
TI  - [Surgical treatment of multiple aortic aneurysm].
AB  - Ten patients with multiple aortic aneurysms of both thoracic and abdominal aortic
      aorta, were evaluated clinically. The abdominal operations preceded the thoracic
      operations in the seven patients, and the four of them underwent two-staged
      operations with good results. Residual aneurysm ruptured in two patients and one
      patient died on the first operation because of abdominal aortic aneurysm rupture.
      The thoracic operations preceded the abdominal operations in the three patients,
      and one of them underwent a two-staged operation with good result. Because the
      risk of rupture of the unrepaired aneurysm is high, the treatment of the second
      aneurysm should be done in a short period.

PMID- 10589184
TI  - [A successful surgical case of billowing mitral leaflet syndrome (Barlow
      syndrome) combined with severe mitral regurgitation].
AB  - We report a successful surgical case of billowing mitral leaflet syndrome
      combined with severe mitral regurgitation. A 45-year-old man suffered from
      congestive heart failure and admitted our institution for precise examination. A
      heart murmur was pointed out by a medical examination at his high school, and
      mitral valve prolapse was detected by echocardiography at 23 year of age. No
      medication was applied because he showed no symptom. From 44 year of age, he
      noted palpitation on exercise. Holter monitor showed blocked PAC and Wenckebach A
      V block, and transesophageal echocardiography indicated severe mitral
      regurgitation due to the billowing of voluminous both leaflets. At his operation,
      we recognized the billowing of both leaflets with torn chordae, and size of the
      mitral valve orifice was 8.5 x 5 cm. The huge mitral valve was replaced with a
      CarboMedics 31M prosthetic valve by plicating mattress stitches of native mitral
      annulus. Histopathologic findings showed accumulation of acid mucopolysaccharide.
      Postoperative echocardiography showed reduction of the left ventricular volume
      and preservation of the left ventricular function. Relatively slow progression of
      the billowing mitral leaflet syndrome did not cause apparent symptoms of heart
      failure in this patient. Therefore, proper selection of the procedure and timing
      of surgical treatments might be important for successful long-term results after
      operation of the billowing mitral leaflet syndrome.

PMID- 10589185
TI  - [Stent intubation for the airway stenosis under PCPS].
AB  - Placement of stents for the tracheal or carinal stenosis have a meaning of
      maintaining the airway. Failure of the stenting causes death. In cases of severe
      airway stenosis and low pulmonary function, the pulmonary support method should
      be performed instead of intubation and mechanical ventilation. Generally, PCPS
      (percutaneous cardio-pulmonary support system) is used as a pulmonary support.
      This method was very useful to place stents for airway stenosis. We concluded
      that PCPS was useful in emergency cases, and in cases of severe fixed type airway
      stenosis and low pulmonary function it had be on stand-by.

PMID- 10589186
TI  - [The experience of telemedicine transmitting CT image of ruptured thoracic aortic
      aneurysm on the Internet].
AB  - The report describes our experience in establishing CT image transmission of
      ruptured thoracic aortic aneurysm to Gifu university hospital on the Internet. In
      this emergent case CT image transmission to the cardiovascular surgent provided
      medical informations in detail, which is very useful to decide the operative
      method and to prepare the assist circulation devices for the operation before the
      patient get to the hospital by ambulance. The Internet may prove to be major
      vehicle for telemedicine, consulting the professionals located in remote clinical
      institute.

PMID- 10589187
TI  - [A new cardiovascular surgical instrument: aorta sizer].
AB  - A new device comprising a set of graded aorta sizers is presented. Each sizer
      consists of a disc mounted on the top a straight holder. The length of each
      holder equals the circumference of its disc (the length of the holder equals the
      diameter of the disc times 3.14). The size of the discs are graded by 2 mm from
      24 mm to 36 mm in diameter. In aneurysm operations, the proper-size vascular
      graft is selected by sizing the diameter of the transected aorta with the disc
      portion of a sizer. The proper length of the reinforcing felt strip is then
      determined by the length of the holder portion of the appropriate sizer.

PMID- 10589188
TI  - [Clinical study of serum S-100 beta protein as marker of brain injury in
      cardiovascular surgery].
AB  - There is no simple and specific marker of brain injury in cardiovascular surgery.
      S-100 beta protein is a specific protein of the central nervous system. S-100
      beta protein detected in spinal fluid and serum is a reflection of brain injury.
      The aim of this study was to investigate the influence of extracorporeal
      circulation (ECC) on the brain, with reference to serum S-100 beta protein level
      and operative factors. Twenty-two patients (12 undergoing coronary artery bypass
      grafting (CABG), 2 mitral valve replacement, 2 left ventricular aneurysmectomy, 2
      grafting of descending thoracic aneurysm, 1 aortic valve replacement (AVR), 1
      CABG with AVR, 1 closure of atrial septal defect, 1 aorto-bifemoral and left
      subclavian artery bypass grafting) without symptomatic neurological complications
      underwent cardiovascular surgery using ECC. Serum S-100 beta level was measured
      by enzyme-linked immunosorbent assay before ECC and half an hour after the end of
      ECC in cardiovascular surgery. Carotid lesions, calcification of the ascending
      aorta, history of cerebral infarction, and pulsatile or nonpulsatile flow during
      ECC were evaluated as the operative factors. The correlation of S-100 beta level
      after ECC with age, duration of ECC and aortic cross clamp time was examined.
      Serum S-100 beta level was significantly increased after ECC (0.25 +/- 0.48
      microgram/l vs. 0.99 +/- 0.64 microgram/l; p < 0.01). Calcification of the
      ascending aorta was the only significant operative factor that increased S-100
      beta level after ECC (calcification 1.35 +/- 0.71 vs. non-calcification 0.68 +/-
      0.37 p < 0.01). S-100 beta level after ECC was related to aortic cross clamp time
      (r = 0.54; p < 0.05, n = 20). It is suggested that brain injury, as reflected by
      serum S-100 beta protein, is more frequent in cases with calcification of the
      ascending aorta or a long aortic cross clamp time. It was concluded that serum S
      100 beta is a simple potential marker of cerebral injury in cardiovascular
      surgery with ECC.

PMID- 10589189
TI  - [Results and problems of thymectomy in myasthenia gravis over 65 years old].
AB  - From June 1975 to March 1999, 300 cases of myasthenia gravis (MG) have undergone
      thymectomy. Twenty-eight patients over 65 years old were examined, focusing on
      the relationship between clinical appearances and microscopic findings of the
      thymuses. Among these cases, six were classified as ocular type (one case with
      thymoma) and 22 generalized type (eight cases with thymoma). According to the
      thymoma registering stages defined by Masaoka and colleagues, those nine cases
      with thymoma associated with stages I (n = 7), II (n = 1) and III (n = 1),
      respectively. The case of stage III (74 year old female) died four years and
      eight months after surgery. The case of stage II died of old age two years after
      the surgery. Complete remission was achieved in two cases of stage I. The
      follicular hyperplasia were seen in eight cases, and all resulted in improvement.
      Nine cases with no particular findings of thymuses classified into four ocular
      type and five generalized type including one fulminating type. Post-operative
      course of all these cases were uneventful. Although one recurrent of the thymoma
      and one death of the tumor were observed, post-operative outcomes of these
      elderly patients were generally satisfactory. We concluded that there is an
      operative indication of thymectomy for MG of even elderly patients, if no
      particular findings were recognized in the thymus.

PMID- 10589190
TI  - [Surgical management of pulmonary disease due to nontuberculous mycobacteria].
AB  - Between 1983 and 1998, 9 patients with nontuberculous mycobacteriosis (NTM)
      underwent pulmonary resection. 8 patients were men and 1 was woman. Mean length
      of preoperative period was 20.3 months (range 6 months to 51 months). Most
      operative indication was localized NTM resistant to multidrug therapy. Lobectomy
      was performed in 7 patients, segmentectomy in one, partial resection in one. We
      have no operative mortality but air leaks occurred in one and he needed
      thoracoplasty. Mean postoperative follow up period was 67.7 months. Only one
      patients relapsed 34 months after the first operation. For localized NTM, early
      surgical management results good outcome.

PMID- 10589191
TI  - [Use of an expandable metallic stent in 4 patients with superior vena syndrome].
AB  - Recently developed expandable metallic stents have been adopted to superior vena
      cava syndrome with good results. We inserted stents into the superior vena cava
      in 4 patients with superior vena cava syndrome. The results were comfortable and
      no complications. We should consider the stenting as the first choice for
      superior vena cava syndrome.

PMID- 10589192
TI  - [Three cases of aortic arch aneurysm complicated with coronary artery disease].
AB  - Graft replacement for aortic arch aneurysm and concomitant coronary artery bypass
      grafting were performed in three patients between January 1994 and December 1998
      in our department. The etiology of the aneurysms was arteriosclerosis in 2, and
      aortic dissection in 1 patient who underwent aortic root replacement (Cabrol
      procedure) simultaneously. Saphenous vein grafts were anastomosed to the coronary
      artery during core cooling, and selective cerebral perfusion was performed during
      reconstruction of the aortic arch and arch vessels in all cases. All patients are
      well and no complications were observed postoperatively.

PMID- 10589193
TI  - [Preoperative autologous blood donation in coronary artery bypass grafting in
      elderly patients].
AB  - Allogeneic blood transfusion still carries risks of transfusion reaction and
      infection. We examined the effect of a preoperative autologous blood donation
      (800-1,200 g) by subcutaneous epoetin alpha injection on a series of patients
      undergoing elective coronary artery bypass grafting (CABG). CABG was being
      performed with increased frequency in elderly patients. We have performed CABG in
      18 patients over 65 years of age (elderly group). These patients were compared
      with 20 patients under 64 years of age (younger group). Postoperative bleeding
      and allogeneic blood transfusion were significantly larger in quantity in the
      elderly group than the younger group (p < 0.05). The incidence of allogeneic
      blood usage was significantly higher in the elderly group than the younger group
      (p < 0.05). Therefore, a preoperative autologous blood donation in CABG was
      considered to be not so effective for saving allogeneic blood transfusion and
      preventing transfusion reaction or infection in elderly patients.

PMID- 10589194
TI  - [A case of traumatic aneurysm of innominate artery with occlusion of right
      subclavian artery].
AB  - A 42-year-old woman with history of chest blunt trauma from an automobile
      accident 250 days earlier had suffered easy fatigability of the right upper
      extremity. She had difference of blood pressure between upper extremities, 94/60
      mmHg in the right and 126/70 mmHg in the left. Chest CT showed dilation of the
      innominate artery which compressed the trachea. Aortography showed an aneurysm of
      the innominate artery and occlusion of the right subclavian artery at its origin.
      The aneurysm of the innominate artery was resected and replaced with a 6 mm
      Dacron graft with aid of the external shunt. The right subclavian artery was also
      reconstructed with same graft. The aneurysm of the innominate artery should be
      suspected as a rare complication in blunt trauma of the chest.

PMID- 10589195
TI  - [Aortic valve papillary fibroelastoma in a patient with mitral valve
      regurgitation].
AB  - Papillary fibroelastoma is a rare cardiac tumour. We describe a patient with
      mitral valve regurgitation and aortic valve papillary fibroelastoma. The patient
      was 62-year-old woman. She was referred to us for surgical treatment of mitral
      valve. Preoperative echocardiography showed rheumatic mitral valve regurgitation
      (Sellers grade III) and it also demonstrated mobile masses of the aortic valve.
      At operation, mitral valve was repaired by a posterior annuloplasty. Through the
      aortotomy, small tumors were found to be attached to each cusps of the aortic
      valve and they were successfully removed. The histopathologic diagnosis was
      papillary fibroelastoma of the aortic valve. The postoperative course was
      uneventful.

PMID- 10589196
TI  - [Surgical treatment of septicemia after pacemaker implantation: a case report of
      removal of infected lead under median sternotomy].
AB  - A 73-year-old woman was admitted to our hospital because of septicemia associated
      with infection of an old retained pacemaker lead and a reimplanted pacemaker
      system. After general condition was recovered, the pacemaker system was removed
      and then the retained pacemaker lead was removed through median sternotomy. Then
      a new pacemaker system was implanted using myocardial leads. The postoperative
      course was uneventful.

PMID- 10589197
TI  - []

PMID- 10589198
TI  - [A successful case of simultaneous operation of aortic arch aneurysm and left
      lung cancer].
AB  - We report a simultaneous operated case of a 73-year-old man with aortic arch
      aneurysm and squamous cell carcinoma of the lung. Via median sternotomy,
      aneurysmectomy and graft replacement was performed under hypothermic circulatory
      arrest and selective brain perfusion. After changing the position, left upper
      lobectomy with lymph node dissection was performed via left posterolateral
      thoracotomy. In spite of using cardiopulmonary bypass, hemostasis was easy, and
      there was no complication through intra-operative to post-operative course. The
      cases of simultaneous operation of thoracic aortic aneurysm and lung cancer are
      rare, and only 3 cases have been reported in Japan. Under careful selection of
      the patients, simultaneous operations can be performed safely.

PMID- 10589199
TI  - [A case report treated in two-stage operations for lung cancer associated with
      arteriosclerosis obliterans (ASO)].
AB  - A case of lung cancer complicated with ASO treated surgically in two-stage
      procedures was reported. A 74-year-old male was admitted to our institution with
      the complaint of intermittent claudication. Chest X-rays showed shadows of a mass
      in the right upper lung field, and the tumor was suspected to be bronchogenic
      adenocarcinoma on the basis of findings of bronchoscopic brushing smears (class
      IIIb). Angiography revealed about 90% atherosclerotic eccentric stenosis in infra
      renal abdominal aorta. Right upper lobectomy and lymph node dissection (R 2 a)
      was underwent through posterolateral thoracotomy. Pathological diagnosis showed
      the tumor was well-differentiated papillary adenocarcinoma and pathological TNM
      classification was T2N0M0. The secondary abdominal-bilateral common iliac bypass
      using artificial graft was performed through retroperitoneal approach 6 weeks
      after the first operation. Postoperative course was uneventful and the patient
      was discharged one month after the second operation. He is now leading normal
      life with both no relapse of cancer and no symptoms at 2 years and half after
      this two-stage operations.

PMID- 10589200
TI  - [Retroperitoneal lipoma through the foramen of Bochdalek detected as a mass of
      chest roentgenogram: report of a case].
AB  - Retroperitoneal lipomas are relatively uncommon. They are generally asymptomatic
      tumors. We experienced a 70-year-old man who had retroperitoneal lipoma detected
      as a mass of chest roentgenogram. Transcutaneous needle biopsy yielded a
      diagnosis of lipoma. We performed surgical resection because the tumor was
      growing. The complete resection of the tumor was done uneventfully. The
      pathological diagnosis of the tumor was benign mature lipoma. The sagittal view
      of the chest MRI gave precise and useful anatomical informations. This tumor was
      considered to originate from the retroperitoneal fatty tissue at the
      subdiaphragmatic region and to extend into the posterior mediastinum though the
      foramen of Bochdalek. We present herein this case because of a unique growing
      form, which is the first report in the Japanese literature to our knowledge.

PMID- 10589201
TI  - Competitive behavior in local physician markets.
AB  - Competition often is viewed as a mechanism for controlling cost. Competition may
      work well in urban areas with many providers; competition may not exist in rural
      areas with few providers. The authors use the empirical framework developed by
      Bresnahan and Reiss to analyze the entry behavior of physicians into local
      markets to determine the level of physician supply consistent with competitive
      behavior. The study estimates entry patterns for total and specialty physicians
      located in nonmetropolitan health service areas using longitudinal data. The
      authors find a surprising drop in the population increments necessary for entry
      by the second provider, possibly due to the unattractiveness of being the solo
      physician in an area. Subsequent population increments stabilize at three to five
      physicians. Since more than 93 percent of the U.S. population lives in areas that
      can support three to five physicians, competition between physicians through
      mechanisms such as managed care may be feasible.

PMID- 10589202
TI  - Network structure and hospital financial performance in New York State: 1991
      1995.
AB  - As networks have proliferated, questions have arisen regarding which structure is
      optimal. To obtain an answer from the hospital perspective, the authors conducted
      a survey of New York State hospitals to determine how network integration,
      complexity, and financial risk sharing relate to measures of financial
      performance during the period of 1991-1995. Of the 64 hospitals indicating a
      network affiliation by 1995, 67.2 percent listed some network risk-sharing
      activity. The least integrated networks were associated with the smallest
      improvements in throughput, and the most complex were associated with the largest
      negative changes in operating margins. During the first 2 years of network
      membership, hospitals joining risk-sharing networks experienced operating margin
      gains averaging 12 percentage points higher than hospitals joining networks
      without risk sharing; however, this difference dissipated in later years.
      Networks with higher levels of integration, lower levels of complexity, and which
      involve some risk-sharing between affiliates are most likely to experience
      improved hospital financial performance during the network's initial years.

PMID- 10589203
TI  - Tracking the State Children's Health Insurance Program with hospital data:
      national baselines, state variations, and some cautions.
AB  - State and federal agencies are concerned with the impact of the State Children's
      Health Insurance Program (CHIP) on the health care of enrolled children. As part
      of a broad program evaluation, and at relatively low cost, analysts can track
      data on hospital admissions for ambulatory care sensitive (ACS) conditions. This
      article uses hospital data for 19 states to calculate baseline ACS rates and to
      discuss trends and cross-state variations just prior to the start of the CHIPs. A
      few cautions and limitations are discussed. An unexpected result in the
      exploration was a substantial increase in the rate of ACS admissions for self-pay
      and Medicaid-enrolled children during the period of 1990-1995. During that same
      period, the admission rate for other insured children fell by more than a third.
      The comparisons across states are meant to be illustrative; they do reveal a
      relationship between the rate of asthma admissions and the proportion of self-pay
      plus Medicaid-enrolled cases.

PMID- 10589204
TI  - Meeting information needs: lessons learned from New Jersey's Individual Health
      Insurance Reform Program.
AB  - At national and state levels, there have been significant changes in the
      regulations governing individual and small group health insurance markets.
      Reforms to the individual health insurance market in New Jersey exemplify the
      challenges of informing consumers about changes in the regulation of insurers,
      where the changes are intended to simplify and broaden access to health
      insurance. To best take advantage of expanded access to coverage under new
      regulations governing the individual health insurance market, individuals need to
      understand the changed rules under which carriers determine eligibility and
      premiums. Survey results from New Jersey indicate, however, that a significant
      proportion of people who purchased policies under the restructured individual
      health insurance market did not fully understand how the new market operates.

PMID- 10589206
TI  - Operating on policy: Dr. England goes to Washington.

PMID- 10589205
TI  - The regulation and enforcement of federal nursing home standards, 1991-1997.
AB  - This article reports historical trend data on resident characteristics and
      conditions, problems, and deficiency patterns for nursing facilities from 1991
      through 1997 from Health Care Financing Administration (HCFA) administrative
      records from the On-Line Survey, Certification, and Reporting System (OSCAR).
      Over this period, residents show some increases in dependency and conditions,
      although there was a decline in the use of restraints. The deficiencies reveal
      continued quality problems in some nursing homes, although the average number of
      deficiencies given to facilities declined by 44 percent between 1991 and 1997.
      The discussion considers possible explanations for the decline in deficiencies,
      including whether the quality of care in nursing homes has improved or whether
      the enforcement process has gradually been weakened.

PMID- 10589207
TI  - Unkind cuts.

PMID- 10589208
TI  - 'Selling' irradiated food. Will consumers warm to the idea of cold
      pasteurization?

PMID- 10589209
TI  - Food irradiation. A technology to reduce the incidence of foodborne illness.

PMID- 10589210
TI  - Influenza vaccination for healthy working adults.

PMID- 10589211
TI  - New threats from an old enemy. A physician update on pneumococcus.
AB  - Pneumonia and influenza together are the sixth-leading cause of death in this
      country. Physicians have the tools and influence to prevent many of these deaths
      and significantly improve their patients' health and quality of life. There is no
      reason for these tools to be underused.

PMID- 10589212
TI  - Rural/urban differences in chemical dependency treatment. Results from the
      Minnesota Adult Household Survey.
AB  - Research at the national level suggests fairly similar rates of substance abuse
      in rural and urban areas, with data for 1996 showing a slightly higher rate of
      drug use in urban areas but no difference in the rates of heavy alcohol use. The
      current study assesses differences between rural and urban areas in substance
      abuse and dependence, service utilization, and perceived barriers to services in
      Minnesota. Analysis of responses of a random sample of 7,508 adults stratified by
      residence reveals few differences between rural and urban settings. While urban
      residents have a slightly higher (marginally significant) rate of dependence on
      drugs and rural residents have a significantly greater tendency to talk to clergy
      about their problem, the subsamples exhibit remarkably similar patterns of abuse,
      need for treatment, propensity to seek treatment, service utilization, and
      perceived barriers to treatment.

PMID- 10589213
TI  - Can we predict recovery in chronic fatigue syndrome?
AB  - PURPOSE: To determine if selected demographic or clinical features of chronic
      fatigue syndrome (CFS) are associated with recovery. PATIENTS AND METHODS: A
      follow-up questionnaire was mailed to 341 patients who had been ill on average
      for nine years to ascertain "recovery" rate (defined as self-reported recovery on
      a visual analog scale). Baseline demographic and clinical features (functional
      status and psychological status) recorded at the time of the initial (baseline)
      clinical visit were analyzed for their association with recovery at the time of
      follow-up. RESULTS: Of the 177 patients who responded to the follow-up
      questionnaire, only 21 (12%) reported "recovery." Patients with higher levels of
      physical and social functioning and lower levels of anxiety and obsessive
      compulsiveness at baseline were more likely to report recovery at follow-up (p <
      0.05). No specific demographic characteristics were associated with recovery.
      CONCLUSION: These findings support previous research that complete recovery from
      CFS is rare and that patients with less severe illness at the initial clinic
      visit are more likely to have a positive prognosis for recovery. However,
      considerable overlap in illness severity was observed between the recovered and
      nonrecovered groups, suggesting that accurate prediction of recovery in
      individual CFS patients is not currently feasible.

PMID- 10589214
TI  - Psychology training programs need support.

PMID- 10589216
TI  - [Public health care after the Bijlmermeer airplane crash; the aftermath].
AB  - After the crash of a cargo plane on a housing estate in Amsterdam South-East, the
      Netherlands, in 1992, survivors, their families and the various emergency
      assistance personnel experienced considerable physical and mental problems,
      briefly called the posttraumatic stress syndrome. Technical defects of the plane
      and juristic clumsiness in the elucidation of the circumstances and the content
      of the cargo--like permitting resumption of flights over the disaster area after
      only two weeks--further aggravated the public health consequences. Gradually,
      however, attention shifted to the alleged shortcomings of the medical assistance
      rendered, mostly communicated by television. Although there are no indications
      for special causes of health disturbances, a large-scale medical-epidemiological
      investigation still seems necessary, which, however, is unlikely to dispel the
      anxiety, grief and uncertainties that have arisen over the years.

PMID- 10589215
TI  - [Syphilis in addicted pregnant women: better care through more awareness and
      contract between organizations involved].
AB  - Three women, aged 21, 20 and 30 years, were cocaine users and pregnant. There had
      been no prenatal monitoring until they reported with uterine contractions. Blood
      of the first two women was then tested; serology revealed active syphilis
      infections: their children had died in utero. The blood of the third woman had
      been tested as part of a street project; it revealed an active syphilitic
      infection but she could not be found for treatment. After delivery, the child
      showed withdrawal symptoms. The first and third women and the child of the third
      woman were treated with benzylpenicillin. The system for screening and treating
      drug-addicted pregnant women should be intensified.

PMID- 10589217
TI  - [Universal influenza vaccine still far in the future].
AB  - Recent publications suggest that a universal vaccine against human influenza
      might be feasible. The vaccine would be based on the M2 protein of influenza A
      viruses. As yet application of such a universal vaccine seems to be far away,
      however, since so far only pre-clinical data in a mouse model have been
      generated. Furthermore, the M2 protein is only present in influenza A viruses and
      is known to be a minor viral antigen. In addition it may become more variable
      when it is exposed to immunity in the vaccinated population.

PMID- 10589218
TI  - [Clinical thinking and decision-making in the practice. A patient with
      thrombophlebitis].
AB  - A 55-year-old man presented with deep venous thrombosis of his left leg.
      Laboratory evaluation disclosed macrocytic anaemia and leukocytosis. In the
      clinical decision process it was not verified whether all symptoms fitted in with
      the presumptive diagnosis of pernicious anaemia and stomach carcinoma. The
      ultimate diagnosis was acute lymphocytic leukaemia. A proper evaluation of a
      peripheral blood smear would have led to this diagnosis earlier.

PMID- 10589219
TI  - [Positive results from serologic screening for syphilis in pregnancy in the
      Amsterdam region, 1991-1995].
AB  - OBJECTIVE: To evaluate the results of screening of pregnant women for syphilis in
      the region of Amsterdam, the Netherlands. DESIGN: Descriptive study and cost
      benefit analysis. METHODS: In the period 1991-1995, physicians and midwives from
      the Amsterdam region sent serum samples of pregnant women to the Regional Public
      Health Laboratory of the Municipal Health Service (GG & GD) to be screened for
      syphilis. All physicians who had sent in specimens with a positive result of the
      Treponema pallidum haemagglutination assay (TPHA) and a confirming test result
      were asked, in the year of the screening, by telephone or in writing, what
      diagnosis they had made in the woman in question. Collection of these data was
      handled by the social nursing staffs of the outpatient clinics for sexually
      transmitted diseases in Amsterdam. The costs of laboratory tests and follow-up of
      the children were compared with the positive effects of special treatment and
      education avoided by antibiotic treatment. RESULTS: 54,344 serum samples were
      sent in. In the city of Amsterdam the coverage was 87.4%. In 81 women (0.15%) all
      the serological tests for syphilis were positive. From this group, 37 women had
      already been treated and 24 women were treated as a result of this screening
      programme (most of them had a foreign nationality), 10 for early syphilis and 14
      for syphilis of unknown duration, preventing the birth of an estimated five to
      six children with congenital syphilis. The cost-benefit ratio was 1:15.
      CONCLUSION: Continuation of screening for syphilis during pregnancy in the
      Amsterdam region remains useful.

PMID- 10589220
TI  - [Increase of early syphilis in Rotterdam (1995-1997): more (addicted) prostitutes
      and their clients].
AB  - OBJECTIVE: To detect risk groups in an increase of early (infectious) syphilis.
      DESIGN: Retrospective study of patient records. METHOD: Data from visitors with
      an early syphilis were collected from their respective medical records in the
      outpatient clinic for sexually transmitted diseases (STD) of the Academic
      Hospital Rotterdam-Dijkzigt, the Netherlands, over the years 1993-1997. In
      particular, data on risk behaviour and risk groups were collected. To obtain an
      indication of the (possible) causes of the increase in the number of visitors
      with early syphilis, (shifts in) characteristics of this population over the
      years were compared. RESULTS: 195 patients with early syphilis had visited the
      outpatient clinic, 130 males and 65 females, mean ages ranging from 30.9 (1993)
      to 38.1 years (1997). Most infected persons (68%) came to the outpatient clinic
      because of symptoms. The number of women who came to the outpatient clinic
      through partner notification increased considerably, from an average of 5% in
      1993-1995 to 36% in 1996. Over the years a relative increase of (drug addicted)
      prostitutes and their clients was observed (1993-1995: 39%; 1996: 56%).
      CONCLUSION: The cause of the increase, or failure to decrease, of the number of
      syphilis-infected visitors in the STD outpatient clinic of the Academic Hospital
      Rotterdam-Dijkzigt should probably be sought among (drug addicted) prostitutes
      and their visitors.

PMID- 10589221
TI  - [Partial left ventriculectomy (Batista procedure) for the treatment of terminal
      heart failure after rejection for heart transplantation].
AB  - A woman aged 64 was severely handicapped by dyspnoea due to 'terminal heart
      failure' resulting from idiopathic dilated cardiomyopathy. The mitral valve was
      seriously insufficient; the coronary vessels were normal. The patient was not
      eligible for heart transplantation. Partial left ventriculectomy by Batista's
      method was performed and the mitral valve replaced by an artificial one. The left
      ventricular ejection fraction increased from 0.12 before the operation to 0.35
      postoperatively and to 0.43 two years later. Patient was then capable of normal
      exercise (New York Heart Association (NYHA): class I-II). In the Netherlands
      partial left ventriculectomy is the last surgical option for patients rejected
      for heart transplantation.

PMID- 10589222
TI  - [Increase of early syphilis in a red light district in Rotterdam (1995-1997) and
      preventive treatment].
AB  - The number of cases of syphilis in Rotterdam has increased dramatically since
      1995. The prevalence of early syphilis in 1997 was highest among street
      prostitutes (16%). Some prostitutes could not be reached for further evaluation
      and treatment, probably due to their addiction to hard drugs. Prophylactic
      treatment for syphilis was given to most street prostitutes in a cruising zone
      during a screening programme for sexually transmitted diseases (STD) in January
      1997. Since then, STD checkups were performed regularly in the cruising zone. The
      prevalence of early syphilis in the cruising zone dropped to 1.3% in 1998. The
      total number of reported cases of syphilis in Rotterdam also decreased sharply in
      1998.

PMID- 10589223
TI  - [Female circumcision; the histories of 3 patients].

PMID- 10589224
TI  - [Female circumcision; histories of 3 patients].

PMID- 10589225
TI  - [Effectiveness, safety, and costs of measures for prevention of gastropathy due
      to the use of nonsteroidal antiinflammatory drugs].

PMID- 10589226
TI  - [Effectiveness, safety, and costs of measures for prevention of gastropathy due
      to the use of nonsteroidal antiinflammatory drugs].

PMID- 10589227
TI  - [Effectiveness, safety, and costs of measures for prevention of gastropathy due
      to the use of nonsteroidal antiinflammatory drugs].

PMID- 10589229
TI  - [In Process Citation]

PMID- 10589228
TI  - [Chromosome abnormalities in subfertile men and their partners is not a
      contraindication for intracytoplasmic sperm injection].

PMID- 10589230
TI  - [Psychiatric consultation and treatment for mentally handicapped persons
      exhibiting behavioral changes].

PMID- 10589231
TI  - [Irregular blood group antibodies during pregnancy: screening is mandatory].

PMID- 10589232
TI  - ['Diabetes mellitus type 2' guideline (first revision) of the Dutch College of
      General Practitioners].

PMID- 10589233
TI  - [Immunology in the medical practice. XXI. Laboratory tests for immunologic
      diseases].

PMID- 10589234
TI  - [X-linked juvenile retinoschisis and XLRS 1 gene abnormality].

PMID- 10589235
TI  - [Clinical and genetic features of choroideremia].
AB  - BACKGROUND: Choroideremia is an X-linked hereditary eye disease that causes
      progressive degeneration of the choroid and retina and frequently leads to legal
      blindness in later life. Recent molecular genetic studies have revealed mutations
      involving the Rab escort protein (REP-1) gene localized at Xq 21. CLINICAL
      FEATURES: The clinical picture and rate of progression may vary among affected
      individuals in different families and within the same family. Usually, hemizygous
      males develop night blindness in their teenage years, followed by progressive
      peripheral visual field constriction and visual disability in late age.
      Heterozygous female carriers are mostly asymptomatic, but their fundi show
      characteristic pigment changes in the midperiphery closely resembling the fine
      mottling observed in the initial stage of the disease in males. MOLECULAR
      GENETICS: Assessment of the REP-1 gene in European and Japanese choroideremia
      patients has revealed a wide variety of mutations, including gross deletions and
      point mutations such as nonsense, frameshift, and splice-site mutations. All
      these mutations are thought to fail in intact REP-1 protein synthesis.
      CONCLUSIONS: The recent molecular studies may open a new chapter in the research
      on choroideremia and provide the groundwork for therapeutic potential as well as
      diagnosis and genetic counseling.

PMID- 10589236
TI  - [A pathological study on rabbit corneas after laser in situ keratomileusis].
AB  - PURPOSE: To investigate pathological changes in rabbit corneas after laser in
      situ keratomileusis (LASIK). MATERIALS AND METHODS: We performed LASIK on rabbit
      corneas to theoretically correct 10.0 diopters of myopia. The corneas were
      studied pathologically at day 0, and 3 days, 1 week, 3 weeks, 4 months, and 9
      months after LASIK. RESULTS: At 3 days after LASIK, keratocytes in the ablated
      area changed morphologically into fibroblastic cells. And the structure of
      collagen fibers in the stroma was broken. These changes had disappeared almost
      entirely at 4 months after LASIK. There were no proliferative changes in the
      stroma of the ablated cornea 9 months after LASIK. No significant changes were
      observed in the endothelium. CONCLUSIONS: The damage to rabbit corneas induced by
      LASIK was mild to moderate under the present experimental conditions.

PMID- 10589237
TI  - [Genome analysis of adenovirus type 7 and adenovirus type 11].
AB  - PURPOSE: To study the epidemiology of adenovirus type 7 (Ad 7) conjunctivitis and
      adenovirus type 11 (Ad 11) conjunctivitis by determining genome types and
      subgenome types. MATERIALS AND METHODS: For Ad 7 I used twelve strains from
      patients with acute viral conjunctivitis and one strain from a patient with
      pneumonia. For Ad 11 I used seventeen strains from patients with acute viral
      conjunctivitis and three strains from patients with cystitis. For Ad 7 genome
      typing, I used eleven DNA restriction endonucleases (REs) recognizing 6- or 7
      base pair sequences and for Ad 11 genome typing, I used seven. For Ad 7 and for
      Ad 11 subgenome typing, I used Taq I and Hinf I which recognize 4- or 5-base pair
      sequences. RESULTS: The thirteen Ad 7 strains all belonged to the same genome
      type and subgenome type. Ad 11 strains showed six genome types. Ad 11 p was the
      most frequent strain. Fifteen Ad 11 p strains showed three subgenome types, but
      none of them was the same as the prototype. CONCLUSION: Ad 7 seems quite stable
      and the Ad 7 epidemic may recur again. On the other hand Ad 11 showed several
      different types. Ad 11 was probably not epidemic in the first half of the 1990's.

PMID- 10589238
TI  - [Observation of human corneal and scleral collagen fibrils by atomic force
      microscopy].
AB  - PURPOSE: We attempted to analyze the three-dimensional ultrastructure of human
      corneal and scleral collagen fibrils with an atomic force microscope (AFM).
      METHODS: A normal eye removed from a 66-year-old male was used in the study.
      Suspended corneal and scleral collagen fibrils were individually attached to
      glass slides by centrifugation. These collagen fibrils were air-dried and
      observed with a non-contact mode AFM in air. RESULTS: AFM imaging provided
      information on the surface topography of both corneal and scleral collagen
      fibrils. The corneal collagen fibrils had a height of 11.9 +/- 1.0 (mean +/-
      standard deviation) nm and the scleral fibrils of 82.5 +/- 35.6 nm. A periodic
      banding pattern of grooves and ridges was clearly found in both types of fibrils;
      the D-periodicity and the groove depth were 65.7 +/- 0.8 nm and 1.46 +/- 0.50 nm
      in the corneal fibrils, and 67.3 +/- 1.1 nm and 6.16 +/- 1.23 nm in the scleral
      fibrils. CONCLUSIONS: Surface topographic images of human corneal and scleral
      collagen fibrils were clearly obtained with the AFM. This technique provides
      quantitative information on the surface morphology of the collagen fibrils at
      high resolution.

PMID- 10589239
TI  - [A new method for quantification of metamorphopsia in patients with epiretinal
      membrane].
AB  - PURPOSE: We have developed a new method for quantification of metamorphopsia and
      applied it to study distorted vision resulting from epiretinal membrane (ERM).
      PATIENTS AND METHODS: We prepared a modified Amsler chart, which was a square
      grid formed by black lines on a white background with 12 cm on a side and divided
      into 2 cm quadrants. The patients were asked to trace any straight lines on the
      chart which appeared irregular or curved. The length of all lines traced by the
      patients was measured except for the outer frame. The total length of the chart
      itself was 1,200 mm, but it would appear longer in patients with metamorphopsia.
      In addition, the severity of metamorphopsia was scored subjectively as follows:
      1, absent; 2, slight; 3, mild; 4, moderate; and 5, severe. The relationship of
      the length to the score and to the visual acuity were analysed. Sixty-three
      patients with unilateral ERM were examined. RESULT: The length of the line ranged
      from 1,200 to 1,259 mm (mean 1,223.3 mm) and was correlated significantly to the
      score. CONCLUSION: This method might be applied usefully in evaluating the
      severity of metamorphopsia and the surgical outcome of eyes with ERM.

PMID- 10589241
TI  - [A case of juvenile retinoschisis diagnosed by analysis of the XLRS 1 gene].
AB  - BACKGROUND: We report on a 3 year-old boy who was first diagnosed with retinal
      detachment and macular hole and received surgical treatment. X-linked juvenile
      retinoschisis was determined by DNA analysis. CASE: Past or family history was
      not recognized. There was left macular hole but no typical spoke-like foveal
      retinoschisis was observed in either eye. We could not diagnose the case as X
      linked juvenile retinoschisis because there was no family history of it, central
      foveal reflex was observed in right eye with corrected visual acuity of 1.2, and
      no abnormality was recorded in the electroretinogram. High molecular weight DNA
      was extracted from peripheral leukocytes, and the XLRS 1 gene was analyzed.
      Hemizygous missense mutation, Arg102Gln, was detected. We diagnosed the disease
      as X-linked juvenile retinoschisis because the Arg102Gln mutation was detected in
      a family in Germany, two families in the United Kingdom, and two families in the
      USA. CONCLUSION: XLRS 1 gene analysis is useful if the diagnosis is difficult
      clinically due to atypical clinical findings.

PMID- 10589240
TI  - [Effect of the consumption of ethanol on the microcirculation of the human optic
      nerve head in the acute phase].
AB  - PURPOSE: The effect of the consumption of ethanol on the circulation of the optic
      nerve head (ONH) in the human eye in the acute phase and its mechanism were
      studied. METHODS: Eleven volunteers drank a bottle of beer (633 ml) with or
      without ethanol (29.5 g). Normalized blur (NB), a quantitative index of blood
      flow velocity, was measured in the temporal site of the ONH. NB, blood pressure
      (BP) and pulse rate (PR) were measured before, immediately after, and every 15
      minutes for 90 minutes after consumption. Intraocular pressure (IOP) and plasma
      ethanol concentration were measured before, and 30 and 90 minutes after
      consumption. Genotyping of the aldehyde dehydrogenase (ALDH) 2 gene was also
      performed. RESULTS: NB in the ONH increased significantly from 15 to 45 minutes
      after consumption of ethanol and the maximum increase was 14% at 15 minutes. IOP
      was lowered at 90 minutes after consumption, but it was not significant. Mean BP
      was lowered significantly after 60 minutes. PR and ocular perfusion pressure did
      not change. A significant correlation was found between plasma ethanol
      concentration at 30 minutes and maximum NB. NB in the ALDH 2-deficient group was
      significantly larger from 15 to 45 minutes after consumption than in the
      proficient group. CONCLUSION: It appeared that the consumption of ethanol can
      increase the blood flow in the human ONH in the acute phase through decreased
      resistance in blood vessels induced by acetaldehyde, a metabolite of ethanol.

PMID- 10589242
TI  - [A case of orbital lymphoproliferative lesion diagnosed as malignant lymphoma
      after recurring 11 years later].
AB  - BACKGROUND: Most primary lymphoproliferative lesions in the ocular adnexa,
      including the eyelid, conjunctiva, and orbit, are diagnosed as low-grade
      malignant lymphomas. Recurrence and dissemination of these tumors are rare in
      Japan. The long-term prognosis for this disorder still remains to be clarified.
      CASE AND METHOD: A 53-year-old woman was first referred to us for right orbital
      tumor in 1986. After subtotal resection of the tumor, the patient received no
      additional treatment. She visited us in 1997 with the complaint of bilateral
      orbital tumor. Biopsied specimens were examined histologically using hematoxylin
      eosine and immunohistological staining. Southern blot hybridization was used to
      detect immunoglobulin gene rearrangement. The paraffin-embedded specimen obtained
      in 1986 was also examined for immunoglobulin gene rearrangement using nested
      polymerase chain reaction technique. FINDINGS: The specimens from 1997 and 1986
      were both diagnosed as lymphoid type of inflammatory pseudotumor, based on
      polyclonal B cell immunohistological staining. Immunoglobulin gene rearrangement
      was present in both specimens. CONCLUSION: The orbital tumor resected in 1986 was
      a low-grade malignant lymphoma which disseminated systemically 11 years later.
      This case shows a long-term course of orbital lymphoproliferative lesion with
      positive immunoglobulin gene rearrangement. It also shows the importance of
      follow-up over 10 years in the case of low-grade malignant lymphoma of the ocular
      adnexa.

PMID- 10589243
TI  - [Hyperprolactinemia and galactorrhea].

PMID- 10589244
TI  - [Pituitary magnetic resonance in women with a clinical suspicion of
      microprolactinoma].
AB  - Seventy-seven women with clinical suspect of microprolactinoma were studied by
      means of magnetic resonance of the pituitary gland. The homogeneity and signal
      intensity of the pituitary gland, presence of intraglandular nodule, height and
      gland morphology were evaluated. Radiological findings were correlated to
      prolactinemia values and the definite clinical diagnosis. The pituitary gland was
      normal in eleven out of the thirteen patients in whom the presence of hypophyseal
      endocrine pathology was not confirmed. In the remaining 64 women with
      hyperprolactinemia, 26 hypophyseal nodules were detected (40.6%), 3 questionable
      nodules (4.7%), 8 homogeneous glands (12.5%), 6 of empty sella turcica (9.4%) and
      21 normal pituitary glands (32.8%). A correlation between radiological diagnosis,
      prolactinemia levels and definite clinical diagnosis was verified. The convexity
      degree of the pituitary gland was not useful for the diagnosis of
      microprolactinoma. In contrast, the height of the pituitary gland was indeed
      useful.

PMID- 10589245
TI  - [The usefulness of the detection of Cys282Tyr and His63Asp mutations in the
      diagnosis of hereditary hemochromatosis].
AB  - BACKGROUND: Hemochromatosis is a hereditary disease the diagnosis and early
      therapy of which is particularly relevant to prevent the appearance of
      complications. In 1996, the gene responsible for this condition was identified
      and was named HFE. OBJECTIVE: To determine the prevalence of Cys282Tyr (C282Y)
      and His63Asp (H63D) mutations in the HFE gene in a group of patients with the
      confirmed diagnosis of hereditary hemochromatosis, as well as in a control group
      of 174 healthy individuals. MATERIALS AND METHODS: Twenty-two patients with the
      diagnosis of primary hemochromatosis who were on treatment with periodic
      phlebotomies were studied. All patients had the following parameters measured:
      serum iron, ferritin, transferrin saturation, serology for hepatitis viruses B
      and C, liver function tests, abdominal echography and liver biopsy. A control
      group of 174 healthy individuals, who had their serotype analyzed, was also
      studied. RESULTS: Eighteen (81.8%) of patients with hemochromatosis were
      homozygous for the C282Y mutation. One patient was homozygous for the H63D
      mutation and in other patient no mutation was found. Among individuals in the
      control group, the allelic frequency of the C282Y mutation was 2.3%, whereas the
      allelic frequency of the H63D mutation was 19.8%. CONCLUSIONS: The results
      obtained in our study support the evident association between the C282Y mutation
      in the HFE gene and hereditary hemochromatosis in our environment.

PMID- 10589246
TI  - [The efficacy of the radioiodine treatment of toxic thyroid adenoma and
      multinodular goiter].
AB  - OBJECTIVE: To investigate the effect of radioiodine therapy of thyroid adenoma
      (TA) and toxic multinodular goitre (TMG) on function and thyroid volume.
      MATERIALS AND METHODS: Prospective study which includes 14 consecutive patients
      with TA and 15 with TMG treated with radioiodine and followed for two years. The
      therapeutic dose was fixed at 15 mCi for TA and 150 microCi x g of thyroid
      tissue/uptakes at 6 h (mean dose: 14.4 +/- 4.1 mCi) for TMG. Thyroid function and
      echographic thyroid volume were determined before and at 1, 3, 6, 12 and 24
      months. RESULTS: 90% of patients with TA and 80% with TMG recovered euthyroidism
      at the third month. One patient with TA and three with TMG required two doses.
      The latter patients were the only ones with hypothyroidism at two years. The TA
      volume decreased from 20 +/- 8.5 ml to 10.4 +/- 8.1 ml at two years (p = 0.004).
      The extranodular thyroid volume did not change (initial: 16.4 +/- 10.4 ml versus
      15.6 +/- 3.8 ml at the second year). The thyroid volume in TMG decreased from
      66.5 +/- 28 ml to 39.8 +/- 13.5 ml at two years (p = 0.006). The largest
      reductions for TA and TMG were 54% and 38%, respectively, within the first six
      months. Only one patient with TA and another patient with TMG had their volumes
      transiently increased, lower than 10%. CONCLUSIONS: Therapy with radioiodine of
      TA and TMG achieves a rapid recovery of euthyroidism and a gradual decrease in
      thyroid volume with a low incidence of hypothyroidism, with no additional
      secondary effects. It has proved to be a valid alternative to surgical therapy.

PMID- 10589247
TI  - [An analysis of patellar cartilage perfusion by dynamic magnetic resonance: its
      application to subjects with anterior pain of patellar origin].
AB  - INTRODUCTION: Patellar chondromalacia is thought to be secondary to a change in
      vascularization of subchondral tissue, which could affect the deeper layers of
      the cartilage. OBJECTIVE: To evaluate whether there are differences in joint
      cartilage perfusion and subchondral bone with dynamic studies of magnetic
      resonance (MR). MATERIALS AND METHODS: Seventeen consecutive patients were
      studied. Patients were divided into individuals with pain of likely
      femoropatellar origin (n = 11) and controls (n = 6) by means of dynamic MR after
      the administration of intravenous contrast. Parametric images were obtained by
      means of digital analysis of maximal uptake, mean uptake and maximal rate of
      contrast uptake in the joint cartilage and subchondral bone. RESULTS: Uptake and
      maximal rate of cartilage, in its outer slope, were statistically higher for
      subjects with pain of likely femoropatellar origin than for controls (40.9 +/-
      24.6 versus 23.3 +/- 4.6, p = 0.04, and 30.4 +/- 17.7 versus 17.4 +/- 2.6, p =
      0.03, respectively). A higher perfusion of the cartilage was also observed in the
      qualitative analysis in patients with pain of likely femoropatellar origin (p =
      0.009). CONCLUSIONS: The different uptake observed in the patellar cartilage
      allows to suppose that in chondromalacia there are vascular changes in the deeper
      layers of joint cartilage, characterized by an increase in perfusion.

PMID- 10589248
TI  - [A spontaneous hematoma of the rectus abdominis sheath].
AB  - The spontaneous hematoma of rectus abdominis sheath is a rare condition which
      usually presents as acute abdomen. We report our experience with 19 patients,
      most of them on treatment with oral anticoagulants. The most common symptoms were
      abdominal pain and palpable tumor. Twenty-six percent required blood transfusion.
      Echography and computerized tomography, were useful for diagnosis. Treatment was
      mainly conservative and was the mode of choice; surgery was left only for those
      patients who had hemodynamic changes or infection of the hematoma.

PMID- 10589249
TI  - [The cost effectiveness of echography biopsy].
AB  - Ecopsy is a postmortem technique which, by means of echography-guided puncture
      and/or aspiration obtains material for histological analysis. This study compared
      cost and time employed in 100 ecopsies and 100 classic necropsies and confirmed
      that cost of materials in ecopsy is 65% lower than that in necropsy. Physicians,
      necropsy technicians, laboratory technicians and secretary team personnel spent
      33%, 54%, 19% and 32% less time than in necropsy. The clinical report of ecopsy
      was finished within nine days even with the brain study included.

PMID- 10589250
TI  - [The risk of an organic lesion in mild craniocerebral injuries with loss of
      consciousness].
AB  - Despite its high frequency, there is not a consensus for the management of a
      patient with mild head trauma. In this prospective study we analyzed wether the
      transient loss of consciousness was associated with a higher risk of
      cranioencephalic injury in function of patient's age. Fifty-two patients with a
      Glasgow score of 15 at the Emergency Department but who reported a transient loss
      of consciousness were included. Patients were divided into two groups, patients
      aged > or = 60 years (n = 21) and patients aged < 60 years (n = 31). In all
      patients a head CT scan was performed. Nine abnormal CT scans were found in the
      group of patients aged > or = 60 years (three head fractures, three brain
      contusion, two subarachnoid haemorrhages, and one subdural haematoma) and one
      abnormal CT scan in the group of patients aged < 60 years (cranial fracture).
      This difference was statistically significant (p < 0.001). In conclusion, an
      urgent head CT scan should be performed in patients aged over 60 years with mild
      head trauma and loss of consciousness. In younger patients this scan should be
      performed when the patient presents with headache and vomiting.

PMID- 10589251
TI  - [Physicians and justice (III) : the physician as defendant].

PMID- 10589252
TI  - [Physicians and justice (IV): the clinical history].

PMID- 10589253
TI  - [Hypophysitis, the range of a growing pathology].

PMID- 10589254
TI  - [Selective estrogen receptor modulators].

PMID- 10589255
TI  - [Thyroid plasmacytoma as the initial manifestation of multiple myeloma].

PMID- 10589256
TI  - [Facial skin plaque and lingual maculopapular lesions].

PMID- 10589257
TI  - [A cholestatic syndrome of uncertain etiology].

PMID- 10589258
TI  - [A pustular nodular lesion of the finger].

PMID- 10589259
TI  - [A boy of 15 with autoimmune cytopenias, polyadenopathies and splenomegaly].

PMID- 10589260
TI  - [The limitations of fine-needle aspiration puncture in the diagnosis of primary
      thyroid lymphoma].

PMID- 10589261
TI  - [Phytotherapy and hepatitis].

PMID- 10589262
TI  - [Fiction and reality around the contraindications for anticoagulant treatment in
      patients of advanced age].

PMID- 10589263
TI  - [The prattle with respect to the acquired immunodeficiency syndrome].

PMID- 10589264
TI  - [Varicella pneumonia].

PMID- 10589265
TI  - [Pharmacy clinics. How I treat ... renal artery stenosis].
AB  - Renal artery stenosis is mainly due to atherosclerosis, but also to fibromuscular
      dysplasia. Treatment can consist either of angioplasty (+/- stent) or of surgical
      revascularization. Hypertension induced by atherosclerotic disease is rarely
      cured, but more easily controlled. The renal function is often improved and thus
      this disease must be searched in the presence of renal insufficiency of unknown
      cause or refractory hypertension.

PMID- 10589266
TI  - [A case of myasthenia gravis diagnosed as conversion disorder].
AB  - Conversion disorder is a difficult diagnosis. The patients' psychiatric
      backgrounds and the complexity of the diagnosis of some neurologic diseases are
      the main reasons for diagnostic errors. Based on one observation, the diagnostic
      criteria and the differential diagnosis of conversion disorder are addressed.

PMID- 10589267
TI  - [New approaches in drug therapy 1999].
AB  - The most important drugs registered and/or launched in Belgium during the last
      year in the various disciplines of internal medicine will be briefly described.
      The originality of each molecule as well as its modalities of appropriate use in
      clinical practice will be stressed.

PMID- 10589268
TI  - [Middle ear ventilation tubes: present indications and prospects].
AB  - Myringotomy and insertion of ventilation tubes, as a form of treatment of serous
      otitis media with effusion, has become one of the most frequently performed
      operations in otolaryngology. In this paper, we review the actual indications of
      artificial middle ear ventilation by the insertion of tubes. The complications of
      this surgical procedure are then discussed. Laser assisted tympanostomy offers a
      new option to achieve middle ear ventilation without tubes and appears to cure
      half of the crises with otitis media and effusion.

PMID- 10589269
TI  - [Laser-assisted hair removal: realities and calculations].
AB  - Hair removal by laser is a current topic of interest for the public. Laser
      technologies have improved over recent years, bringing new opportunities for
      efficacious treatment of hypertrichosis. However, some contra-indications, side
      effects and limitations exist. Considering these restrictions, treatment
      modalities and results are presented in a promising but still faltering medical
      field.

PMID- 10589270
TI  - [Thyroid disorders and dyslipidemias].
AB  - While overt thyroid disturbances, characterized by symptoms and/or clinical signs
      with abnormal serum levels of thyroid hormones, are generally associated with
      perturbations in the lipid profile, the situation is less clear as far as
      subclinical thyroid disturbances, defined by isolated abnormalities of thyroid
      stimulating hormone (TSH) levels, are concerned. In severe hyperthyroidism, a
      decrease of total cholesterol, LDL cholesterol and apoprotein B concentrations is
      generally observed. These biological parameters are normalized when appropriate
      antithyroid treatment is given. In profound hypothyroidism, on the contrary,
      elevated levels of total and LDL cholesterol levels are observed, which decrease
      after hormonal replacement. In both cases, the changes in serum levels of HDL
      cholesterol, triglycerides and lipoprotein (a) are less systematic, both before
      and after treatment. Lipid abnormalities associated with subclinical thyroid
      disturbances remain controversial. However, two recent meta-analyses have shown
      higher LDL cholesterol levels in presence of subclinical hypothyroidism and a
      significant reduction of such lipid abnormality after administration of
      thyroxine. Furthermore, they demonstrated a higher prevalence of subclinical
      hypothyroidism in a population with hypercholesterolaemia when compared to a
      population with normal cholesterol levels. Finally, a significant reduction in
      both total and LDL cholesterol concentrations has been reported after
      administration of thyroxine in a small group of hypercholesterolaemic patients
      with basal TSH levels in the upper range of normal values. In view of the results
      of the literature, strategies are proposed to help the clinician in the
      management of patients with overt or subclinical thyroid disturbances, associated
      with dyslipidaemia.

PMID- 10589271
TI  - [Inflammation and stress].
AB  - In the face of the tissue injury, the human organism builds three kinds of
      responses: inflammation, acute phase phenomena and stress. These responses
      correspond to three lines of a gradual defense against aggressive stimuli.
      However, the stress can be induced in the absence of any kind of inflammation. As
      the effects of these responses are often confounded, we think it was useful to
      recall the main repercussions of these responses, the links between them and the
      aspects which separate them.

PMID- 10589272
TI  - [An immunologic etiology for hyperprolactinemia: macroprolactinemia].
AB  - Besides classical etiologies of hyperprolactinaemia (pregnancy, pharmacological
      treatments, pituitary or hypothalamic perturbations), another less known cause
      may explain a spectacular idiopathic elevation of plasma concentrations of
      prolactin hormone. Macroprolactinaemia is characterized by the presence of a
      circulating high molecular weight complex of prolactin with an immunoglobulin G.
      In this article, we report the cases of 3 female patients for whom size exclusion
      chromatography technique permitted to give a precise biological diagnosis and to
      avoid heavy, expensive, time consuming and unnecessary clinical investigations or
      therapeutic actions. Patients with macroprolactinaemia do not exhibit clinical
      features of classical hyperprolactinaemia, notably as regard to menstrual and
      fertility disturbances.

PMID- 10589273
TI  - [How I explore ... abnormalities in serum calcium concentration].
AB  - Mechanisms for calcium homeostasis are complex but their understanding is
      important before investigating the calcium disorders. Hypercalcaemia is often due
      to hyperparathyroidism or cancers. The diagnosis must thus be rapid and a
      treatment decided in a global approach. Hypocalcaemia, more frequently noted, is
      often due to a general disorder with hypoalbuminemia or chronic renal failure.

PMID- 10589274
TI  - [Study of the month. The RALES study (randomized aldactone evaluation study].
AB  - RALES was a double-blind study which enrolled 1.663 patients with severe heart
      failure and a left ventricular ejection fraction of no more than 35 percent who
      were being treated with an angiotensin-converting-enzyme inhibitor, a loop
      diuretic and, in most cases, digoxin. A total of 822 patients were randomly
      assigned to receive 25 mg of spironolactone daily and 841 to receive placebo. The
      primary end point of the study was death from all causes. The trial was
      discontinued early after a mean follow-up of 24 months because an interim
      analysis determined that spironolactone was efficacious. There were indeed 386
      deaths in the placebo group (46%) and 284 in the spironolactone group (35%)
      (relative risk of death: 0.70; 95% confidence interval, 0.60-0.82; p < 0.001).
      The reduction of mortality among patients in the spironolactone group was
      attributable to a lower risk of sudden cardiac death and of death from
      progressive heart failure. Patients treated by spironolactone had a lower
      hospitalization rate for worsening heart failure; they also had a significant
      improvement in the symptoms of heart failure as assessed by the New York Heart
      Association functional class. Serious hyperkalemia was minimal in both groups of
      patients. Gynecomastia or breast pain was reported in 10% of men who were treated
      with spironolactone as compared with 1% of men in the placebo group (p < 0.001).

PMID- 10589276
TI  - [Meat with hormones and mercury].

PMID- 10589275
TI  - [Clinical study of the month. Usefulness of increasing HDL cholesterol in
      secondary prevention of coronary heart disease: results of the VA-HIT study].
AB  - The "Veterans Affairs Cooperative Studies Program High-Density Lipoprotein
      Cholesterol Intervention Trial" (VA-HIT) is a large randomised, double-blind,
      placebo-controlled clinical trial for the secondary prevention of coronary heart
      disease. It demonstrates that a fibrate treatment (gemfibrozil) significantly
      reduces the relative risk of major coronary (-22%, p = 0.006) and cardiovascular
      (-24%, p < 0.001) events in men with coronary heart disease whose primary lipid
      abnormality is a low HDL cholesterol level. These findings suggest that, in such
      a population, the rate of coronary events is reduced under gemfibrozil therapy by
      raising HDL cholesterol levels (+6%) and lowering levels of triglycerides (-31%)
      without lowering LDL cholesterol concentrations.

PMID- 10589277
TI  - [In situ hybridization techniques. Basis and applications in hematologic
      neoplasias].

PMID- 10589278
TI  - [Molecular cytogenetics in chronic lymphatic leukemia: differential diagnosis
      with other chronic B-lineage lymphoproliferative syndromes].

PMID- 10589279
TI  - [Applications of fluorescence in situ hybridization (FISH) in acute lymphoblastic
      leukemia].

PMID- 10589280
TI  - [Minimal residual disease. Methodologies and clinical implications].

PMID- 10589282
TI  - [Application of CGH to the study of non-Hodgkin's lymphomas].

PMID- 10589281
TI  - [Comparative genomic hybridization. Methodologic features].

PMID- 10589283
TI  - [Multicolor spectral karyotyping (SKY) and its application to the cytogenetic
      diagnosis of multiple myeloma].

PMID- 10589284
TI  - [Prevalence of tuberculosis infection as an important indicator of endemic
      aspects and its continuous decline in the population--past and future aspects].
AB  - For tuberculosis the prevalence of infection, i.e. the rate of occurrence of
      infection among the population, is one essential measure in defining the profile
      of this endemic disease. The present account is based primarily on a set of
      tuberculin-test records which was compiled as the result of periodic BCG
      inoculation programmes on over 200,000 people tested in the Zurich Canton. In our
      analysis figures from the period from 1950 to 1978 were included. Longitudinal
      sections indicate infection profiles within, for example, birth cohorts (BC),
      i.e. groups of people of the same age. According to various investigations by our
      group, the principle of the theory advanced by K. Styblo et al (1969), which is
      based on figures from the Netherlands, also applies to Swiss conditions.
      According to this, the progress of infection rate with time, in terms of the
      percentage incidence within the age scale of each BC, follows a rigid pattern.
      Quantitatively there are differences between the Netherlands and Swiss results.
      Where in the Netherlands within a particular BC relative percentages (R%) of 40
      R% for 4-year olds, 82 R% for 14-year olds and 95 R% for 24-year olds occur-
      compared to the maximum figure of 100% relative per cent for 50-year-olds--the
      comparable figures for Switzerland are 24.4 R%, 48.9 R% and 85 R%. Irrespective
      of the size of the observed, actual infection rate, its progress follows this
      rigid pattern. Wiping out tuberculosis without eliminating the sum of infection
      prevalence accumulated in the population as a result of earlier tuberculosis
      infections is inconceivable. According to extrapolations, the prevalence will
      still be 12.5% in our country in the year 2028. It will probably take several
      decades yet to eradicate tuberculosis in Switzerland.

PMID- 10589285
TI  - [Vitamin B12 deficiency in geriatrics].
AB  - Cobalamin deficiency increases with advancing age. The cut-off point of serum
      concentration should be raised, because many elderly people with "normal" serum
      vitamin B12 concentrations are metabolically deficient in cobalamin. The
      measurement of the metabolites homocysteine and/or methylmalonic acid is
      recommended. Cobalamin deficiency may result in a variety of atypical symptoms.
      Hematological changes typical of megaloblastic anemia are absent in a majority of
      patients with neuropsychiatric disorders. Generally underlying pernicious anemia
      is not the main cause of cobalamin deficiency in the elderly. Protein-bound
      cobalamin malabsorption due to atrophic gastritis with hypo- or achlorhydria is a
      common cause of cobalamin deficiency in elderly people. An important
      manifestation of cobalamin deficiency is cognitive impairment. Much controversy
      exists on the subject of the association of dementia of the Alzheimer type with
      cobalamin deficiency. In several studies dementia has been related to low serum
      cobalamin levels. Physicians should be liberal of cobalamin therapy. The window
      of opportunity for effective intervention may be as short as one year from the
      onset of medical symptoms. At last a compilation of recommendations is given.

PMID- 10589286
TI  - [Special aspects of borreliosis in childhood].

PMID- 10589287
TI  - [Streptococcal infection with "toxic shock-like syndrome". Patient: 29-year-old
      housewife. Symptoms: fever, myalgia and generalized macular exanthema].

PMID- 10589288
TI  - [How signal transduction systems look like after recent dramatic progress].

PMID- 10589289
TI  - [The role of Epstein-Barr virus in oncogenesis].

PMID- 10589290
TI  - [Structural changes of protein-nucleic acid complexes in oocytes and eggs].

PMID- 10589291
TI  - [What would you expect from giant microorganisms?: The H(+)-pump activity of the
      respiratory chain and F-type ATPase has been measured as electric current for the
      first time!].

PMID- 10589292
TI  - [Adrenalin affects olfactory perception: molecular mechanisms and physiological
      functions].

PMID- 10589293
TI  - [Genome biology of the nematode C. elegans].

PMID- 10589295
TI  - Assessment of human exposure to ambient particulate matter.
AB  - Recent epidemiological studies have consistently shown that the acute mortality
      effects of high concentrations of ambient particulate matter (PM), documented in
      historic air pollution episodes, may also be occurring at the low to moderate
      concentrations of ambient PM found in modern urban areas. In London in December
      1952, the unexpected deaths due to PM exposure could be identified and counted as
      integers by the coroners. In modern times, the PM-related deaths cannot be as
      readily identified, and they can only be inferred as fractional average daily
      increases in mortality rates using sophisticated statistical filtering and
      analyses of the air quality and mortality data. The causality of the relationship
      between exposure to ambient PM and acute mortality at these lower modern PM
      concentrations has been questioned because of a perception that there is little
      significant correlation in time between the ambient PM concentrations and
      measured personal exposure to PM from all sources (ambient PM plus indoor
      generated PM). This article shows that the critical factor supporting the
      plausibility of a linear PM mortality relationship is the expected high
      correlation in time of people's exposure to PM of ambient origin with measured
      ambient PM concentrations, as used in the epidemiological time series studies.
      The presence of indoor and personal sources of PM masks this underlying
      relationship, leading to confusion in the scientific literature about the strong
      underlying temporal relationship between personal exposure to PM of ambient
      origin and ambient PM concentration. The authors show that the sources of PM of
      non-ambient origin operate independently of the ambient PM concentrations, so
      that the mortality effect of non-ambient PM, if any, must be independent of the
      effects of the ambient PM exposures.

PMID- 10589294
TI  - The radium century.
AB  - Last year, the UK Government agreed that a potentially dangerous legacy of
      radiation-contaminated land should be dealt with, after decades of ignorance and
      inaction on the part of the authorities. The cost of this could run to many
      hundreds of millions of pounds, assuming that the hundreds of sites potentially
      involved, which date from the birth of the nuclear industry, can actually be
      identified. This very practical problem cannot be tackled without an
      understanding of the lost history of the production and use of radium--a history
      that is now precisely a century in duration.

PMID- 10589296
TI  - Localizing gaseous fugitive emission sources by combining real-time optical
      remote sensing and wind data.
AB  - This paper presents a new approach to localize point emissions from ground-level
      fugitive gaseous air pollution sources. We estimate the crosswind plume's ground
      level peak location downwind from the source by combining smooth basis functions
      minimization (SBFM) with pathintegrated optical remote sensing concentration data
      acquired along the crosswind direction in alternating beam path lengths. Peak
      location estimates, in conjunction with real-time measured wind direction data,
      are used to reconstruct the fugitive source location. We conducted a synthetic
      data study to evaluate the proposed peak location SBFM reconstruction.
      Furthermore, the methodology was validated with open-path Fourier transform
      infrared concentration data collected with wind direction data downwind from a
      controlled point source. This approach was found to provide reasonable estimates
      of point source location. The field study reconstructed source location was
      within several meters of the real source location.

PMID- 10589297
TI  - A meta-analytic review of experiments examining the effects of extrinsic rewards
      on intrinsic motivation.
AB  - A meta-analysis of 128 studies examined the effects of extrinsic rewards on
      intrinsic motivation. As predicted, engagement-contingent, completion-contingent,
      and performance-contingent rewards significantly undermined free-choice intrinsic
      motivation (d = -0.40, -0.36, and -0.28, respectively), as did all rewards, all
      tangible rewards, and all expected rewards. Engagement-contingent and completion
      contingent rewards also significantly undermined self-reported interest (d = 
      0.15, and -0.17), as did all tangible rewards and all expected rewards. Positive
      feedback enhanced both free-choice behavior (d = 0.33) and self-reported interest
      (d = 0.31). Tangible rewards tended to be more detrimental for children than
      college students, and verbal rewards tended to be less enhancing for children
      than college students. The authors review 4 previous meta-analyses of this
      literature and detail how this study's methods, analyses, and results differed
      from the previous ones.

PMID- 10589298
TI  - Understanding the effects of extrinsic rewards on intrinsic motivation--uses and
      abuses of meta-analysis: comment on Deci, Koestner, and Ryan (1999)
AB  - Recently, 3 different meta-analytic reviews of the literature concerning the
      effects of extrinsic rewards on intrinsic motivation have appeared, including
      that by Deci, Koestner, and Ryan (1999) in this issue. Interestingly, despite
      their common focus, these reviews have offered dramatically opposed bottom-line
      conclusions about the meaning and implications of this literature. In this
      comment, the authors examine differences among these 3 reviews and conclude that
      the findings of this literature have been more accurately captured by the reviews
      of Deci et al. and Tang and Hall (1995) than by that of Cameron and Pierce
      (1994). More broadly, the authors also suggest that there may be significant
      short- and long-term costs to the unthinking or automatic use of meta-analysis
      with theoretically derived, procedurally diverse, and empirically complex
      literatures like that concerning extrinsic rewards and intrinsic motivation.

PMID- 10589299
TI  - Effects of reward on intrinsic motivation--negative, neutral and positive:
      comment on Deci, Koestner, and Ryan (1999)

PMID- 10589300
TI  - How children and adolescents spend time across the world: work, play, and
      developmental opportunities.
AB  - The authors review studies on time use of children and adolescents around the
      world and discuss developmental implications of population differences.
      Industrialization and schooling are linked to dramatic declines in time spent on
      household and wage labor. This labor is often unchallenging, sometimes hazardous;
      developmental benefits often do not increase above a limited number of hours;
      hence, reduction in these activities opens time for activities that may be more
      developmentally beneficial. Adolescents in East Asian postindustrial societies
      spend this freed-up time in schoolwork, a use associated with lower intrinsic
      motivation but high achievement and economic productivity. Adolescents in North
      America spend more time in leisure, associated with greater self-direction but of
      an uncertain relation to development. Age, gender, and socioeconomic differences
      in activities and with whom time is spent are also considered.

PMID- 10589301
TI  - Toward an integrative perspective on bereavement.
AB  - For nearly a century, bereavement theorists have assumed that recovery from loss
      requires a period of grief work in which the ultimate goal is the severing of the
      attachment bond to the deceased. Reviews appearing in the 1980s noted a
      surprising absence of empirical support for this view, thus leaving the
      bereavement field without a guiding theoretical base. In this article, the
      authors consider alternative perspectives on bereavement that are based on
      cognitive stress theory, attachment theory, the social-functional account of
      emotion, and trauma theory. They then elaborate on the most promising features of
      each theory in an attempt to develop an integrative framework to guide future
      research. The authors elucidate 4 fundamental components of the grieving process-
      context, meaning, representations of the lost relationship, and coping and
      emotion-regulation processes--and suggest ways in which these components may
      interact over the course of bereavement.

PMID- 10589302
TI  - Individual differences in information-processing rate and amount: implications
      for group differences in response latency.
AB  - Research on group differences in response latency often has as its goal the
      detection of Group x Treatment interactions. However, accumulating evidence
      suggests that response latencies for different groups are often linearly related,
      leading to an increased likelihood of finding spurious overadditive interactions
      in which the slower group produces a larger treatment effect. The authors propose
      a rate-amount model that predicts linear relationships between individuals and
      that includes global processing parameters based on large-scale group differences
      in information processing. These global processing parameters may be used to
      linearly transform response latencies from different individuals to a common
      information-processing scale so that small-scale group differences in information
      processing may be isolated. The authors recommend linear regression and z-score
      transformations that may be used to augment traditional analyses of raw response
      latencies.

PMID- 10589303
TI  - Syndromes of retrograde amnesia: a conceptual and empirical synthesis.
AB  - This article attempts a synthesis of the range of disorders that have been
      subsumed under the rubric of retrograde amnesia. At a functional level, it is
      possible to make distinctions between various forms of retrograde amnesia,
      including a distinction between episodic amnesia for personally experienced
      events and semantic retrograde amnesia for components of knowledge, such as those
      relating to people and events. At an anatomical level, discrete lesions to limbic
      diencephalic structures usually result in a limited degree of retrograde amnesia.
      Marked episodic or marked semantic retrograde amnesia is usually associated with
      significant involvement of cortical and neocortical structures. Retrograde
      amnesia is a functionally heterogeneous rather than a unitary phenomenon.
      Discontinuities and dissociations found in published studies point to the
      potential fractionation of retrograde amnesia into component disorders, each with
      its own neural profile.

PMID- 10589304
TI  - The concept of auditory stimulus representation in cognitive neuroscience.
AB  - The sequence of neurophysiological processes elicited in the auditory system by a
      sound is analyzed in search of the stage at which the processes carrying sensory
      information cross the borderline beyond which they directly underlie sound
      perception. Neurophysiological data suggest that this transition occurs when the
      sensory input is mapped onto the physiological basis of sensory memory in the
      auditory cortex. At this point, the sensory information carried by the stimulus
      elicited process corresponds, for the first time, to that contained by the actual
      sound percept. Before this stage, the sensory stimulus code is fragmentary, lacks
      the time dimension, cannot enter conscious perception, and is not accessible to
      top-down processes (voluntary mental operations). On these grounds, 2 distinct
      stages of auditory sensory processing, prerepresentational and representational,
      can be distinguished.

PMID- 10589305
TI  - Building international public health vision through local community research: the
      El Puente-CIET partnership.

PMID- 10589306
TI  - Socioeconomic inequalities in mortality among women and among men: an
      international study.
AB  - OBJECTIVES: This study compared differences in total and cause-specific mortality
      by educational level among women with those among men in 7 countries: the United
      States, Finland, Norway, Italy, the Czech Republic, Hungary, and Estonia.
      METHODS: National data were obtained for the period ca. 1980 to ca. 1990. Age
      adjusted rate ratios comparing a broad lower-educational group with a broad upper
      educational group were calculated with Poisson regression analysis. RESULTS:
      Total mortality rate ratios among women ranged from 1.09 in the Czech Republic to
      1.31 in the United States and Estonia. Higher mortality rates among lower
      educated women were found for most causes of death, but not for neoplasms.
      Relative inequalities in total mortality tended to be smaller among women than
      among men. In the United States and Western Europe, but not in Central and
      Eastern Europe, this sex difference was largely due to differences between women
      and men in cause-of-death pattern. For specific causes of death, inequalities are
      usually larger among men. CONCLUSIONS: Further study of the interaction between
      socioeconomic factors, sex, and mortality may provide important clues to the
      explanation of inequalities in health.

PMID- 10589307
TI  - Mortality differentials among Israeli men.
AB  - OBJECTIVES: This study examined differentials in mortality among adult Israeli
      men with respect to ethnic origin, marital status, and several measures of social
      status. METHODS: Data were based on a linkage of records from a 20% sample of the
      1983 census to records of deaths occurring before the end of 1992. The study
      population included 72,527 men, and the number of deaths was 17,378. RESULTS:
      Differentials is mortality by origin show that mortality was higher among
      individuals of North African origin than among those of Asian and European
      origin. After allowance for several socioeconomic indicators, the excess
      mortality among North African Jews was eliminated. Substantial and consistent
      differences in mortality were found according to education, occupation, income,
      possession of a car, housing, and household amenities. Differentials among the
      elderly were markedly narrower than those among men younger than 70 years.
      CONCLUSIONS: Some sectors of Israeli society have higher risks of death than
      others, including, among the male population, these who are poor, less educated,
      unmarried, unskilled, out of the labor force, and of North African origin.

PMID- 10589308
TI  - Illness and treatment perceptions of Ethiopian immigrants and their doctors in
      Israel.
AB  - OBJECTIVES: Patient-provider misunderstandings arising from disparate medical and
      cultural concepts can impede health care among immigrant populations. This study
      assessed the extent of disagreement and identified the salient problems of
      communication between Israeli doctors and Ethiopian immigrant patients. METHODS:
      Semistructured interviews were conducted with 59 Ethiopian immigrants. Self
      reports of health status and effectiveness of treatment were compared with
      evaluations by the primary care physician and supplemented by qualitative data
      from descriptions of illness, observations of medical visits, informant
      interviews, and participant observations conducted by the anthropologist.
      RESULTS: Health status and effectiveness of treatment were rated significantly
      higher by the doctor than by the patients. Low doctor-patient agreement occurred
      mainly for illnesses with stress-related or culture-specific associations.
      Qualitative data suggested that more long-term immigrants may alter their
      expectations of treatment but continue to experience symptoms that are
      culturally, but not biomedically, meaningful. CONCLUSIONS: Misunderstandings
      between immigrant patients and their doctors emerge from the biomedical system's
      limitations in addressing stress-related illnesses and from culture-based
      discrepancies in concepts of illness and healing. Including trained translators
      in medical teams can reduce medical misunderstandings and increase patient
      satisfaction among immigrant populations.

PMID- 10589309
TI  - The impact of a community-based heart disease prevention program in a low-income,
      inner-city neighborhood.
AB  - OBJECTIVES: This study evaluated the impact of a 4-year, community-based
      cardiovascular disease prevention program among adults aged 18 to 65 years living
      in St-Henri, a low-income, innercity neighborhood in Montreal, Quebec. METHODS:
      Awareness of and participation in the program were monitored in 3 independent
      sample telephone surveys. Self-reported behaviors were compared in St-Henri and a
      nearby comparison community before and after program implementation in both a 3
      year repeat independent sample survey and a 5-year longitudinal cohort telephone
      survey. RESULTS: Awareness of the program reached 37.4%, but participation was
      low (2%-3%). There were no secular declines in smoking or high-fat diet; physical
      inactivity increased in both communities. There were no statistically significant
      program effects detected in the independent sample surveys, although physical
      inactivity increased more in the comparison community than in St-Henri. In the
      longitudinal cohort sample, there was a small, statistically significant increase
      favoring St-Henri in frequency of cholesterol checkups. CONCLUSIONS: Despite
      careful adaptation of the program to the local social context, there were few
      community-wide program effects. However, several component interventions showed
      promise in terms of community penetration and impact.

PMID- 10589310
TI  - Effectiveness of a social influences smoking prevention program as a function of
      provider type, training method, and school risk.
AB  - OBJECTIVES: This study determined the effect of provider (nurse or teacher) and
      training method (workshop or self-preparation) on outcomes of a social influences
      smoking prevention program. METHODS: One hundred elementary schools were
      stratified by school risk score (high risk = high smoking rate among senior
      students) and assigned randomly to conditions: (1) teacher/self-preparation, (2)
      teacher/workshop, (3) nurse/self-preparation, (4) nurse/workshop, and (5)
      control. Intervention occurred in grades 6 to 8. Smoking status at the end of
      grade 8 was the primary endpoint variable. RESULTS: Intervention reduced grade 8
      smoking rates in high-risk schools (smoking rates of 26.9% in control vs 16.0% in
      intervention schools) but not in low-risk schools. There were no significant
      differences in outcome as a function of training method and no significant
      differences in outcome between teacher-provided and nurse-provided interventions
      in high- and medium-risk schools. Although nurses achieved better outcomes than
      did teachers in low-risk schools, neither provider type achieved outcomes
      superior to the control condition in those schools. CONCLUSIONS: Workshop
      training did not affect outcomes. Teachers and nurses were equally effective
      providers. Results suggest that programming should target high-risk schools.

PMID- 10589311
TI  - Outcomes of 17,137 pregnancies in 2 urban areas of Ukraine.
AB  - OBJECTIVES: Frequent terminations of pregnancy and high rates of fetal loss have
      been reported, but not confirmed, in the former eastern bloc. A census of
      pregnancies in Ukraine, a former eastern bloc country, was conducted to determine
      the rates of these events. METHODS: All pregnancies registered in 2 urban areas
      were enumerated. During a 19-month period between 1992 and 1994, 17,137
      pregnancies and their outcomes were recorded. RESULTS: Sixty percent of the
      pregnancies were voluntarily terminated, generally before the 13th week. In
      pregnancies delivered at 20+ weeks, fetal mortality was 29 per 1000, nearly 5
      times the rate among Whites in the United States. There was a greater proportion
      of very early deliveries (20-27 weeks) in Ukraine, as well as higher death rates
      at all gestational ages. Perinatal mortality was estimated to be 35 per 1000,
      about 3 times the US rate. CONCLUSIONS: This is believed to be the first study in
      the former eastern bloc to ascertain all of the clinically recognized pregnancies
      in a specified period and to determine their outcomes. The data document elevated
      reproductive risks in a former Soviet state.

PMID- 10589312
TI  - Tobacco smoking and depressed mood in late childhood and early adolescence.
AB  - OBJECTIVES: This study builds on previous observations about a suspected causal
      association linking tobacco smoking with depression. With prospective data, the
      study sheds new light on the temporal sequencing of tobacco smoking and depressed
      mood in late childhood and early adolescence. METHODS: The epidemiologic sample
      that was studied consisted of 1731 youths (aged 8-9 to 13-14 years) attending
      public schools in a mid-Atlantic metropolitan area, who were assessed at least
      twice from 1989 to 1994. A survival analysis was used to examine the temporal
      relationship from antecedent tobacco smoking to subsequent onset of depressed
      mood, as well as from antecedent depressed mood to subsequent initiation of
      tobacco use. RESULTS: Tobacco smoking signaled a modestly increased risk for the
      subsequent onset of depressed mood, but antecedent depressed mood was not
      associated with a later risk of starting to smoke tobacco cigarettes.
      CONCLUSIONS: This evidence is consistent with a possible causal link from tobacco
      smoking to later depressed mood in late childhood and early adolescence, but not
      vice versa.

PMID- 10589313
TI  - Sexual and drug-use risk factors for HIV and STDs: a comparison of women with and
      without bisexual experiences.
AB  - OBJECTIVES: This study was done to compare risk factors for HIV/STDs in women who
      reported having had sex with both men and women and women who reported having had
      sex with men only. METHODS: Female participants in a multisite, randomized
      HIV/STD prevention study in the Seattle area reported both having had sex with a
      man in the 3 months before and having at least 1 risk factor for HIV/STDs during
      the year before the study. Of these women, 38% who reported ever having had sex
      with a woman were compared with those who reported having had sex with men only.
      RESULTS: Women who had had sex with both men and women were more likely than
      women who had had sex with men only to report drug use in the 3 months before the
      study, a greater lifetime number of male partners, a sex partner who had had sex
      with a prostitute, an earlier age at sexual debut, and forced sexual contact (P <
      .01 for all comparisons). Women who had had sex with both men and women had a
      mean of 3.2 of these 5 risk factors, vs 2.1 among women who had had sex with men
      only (P < .001). CONCLUSION: Women who had had sex with both men and women were
      more likely than women who had had sex with men only to engage in multiple risk
      behaviors. Health workers should be aware of bisexual experience among women,
      since this may be a marker for multiple risk behaviors for HIV/STDs.

PMID- 10589315
TI  - Syringe vending machines for injection drug users: an experiment in Marseille,
      France.
AB  - OBJECTIVES: This study evaluated the usefulness of vending machines in providing
      injection drug users with access to sterile syringes in Marseille, France.
      METHODS: Self-administered questionnaires were offered to 485 injection drug
      users obtaining syringes from 32 pharmacies, 4 needle exchange programs, and 3
      vending machines. RESULTS: Of the 343 respondents (response rate = 70.7%), 21.3%
      used the vending machines as their primary source of syringes. Primary users of
      vending machines were more likely than primary users of other sources to be
      younger than 30 years, to report no history of drug maintenance treatment, and to
      report no sharing of needles or injection paraphernalia. CONCLUSIONS: Vending
      machines may be an appropriate strategy for providing access to syringes for
      younger injection drug users, who have typically avoided needle exchange programs
      and pharmacies.

PMID- 10589314
TI  - Differences in program implementation between nurses and paraprofessionals
      providing home visits during pregnancy and infancy: a randomized trial.
AB  - OBJECTIVES: This study examined differences between nurses and paraprofessionals
      in implementation of a home visiting program for low-income, first-time parents
      during pregnancy and the first 2 years of the child's life. METHODS: Mothers were
      randomly assigned to either a nurse-visited (n = 236) or a paraprofessional
      visited (n = 244) condition. Nurse- and paraprofessional-visited families were
      compared on number and length of visits, topics covered, number of program
      dropouts, and relationship with home visitor. RESULTS: On average, nurses
      completed more visits than paraprofessionals (28 vs 23; P < .001) and spent a
      greater proportion of time on physical health issues during pregnancy (38% vs
      27%; P < .001) and on parenting issues during infancy (46% vs 32%; P < .001).
      Paraprofessionals conducted visits that lasted longer and spent a greater
      proportion of time on environmental health and safety issues (15% vs 7%
      pregnancy; 15% vs 8% infancy; P < .001). While home visitors were viewed equally
      positively by mothers, nurses had fewer dropouts than did paraprofessionals (38%
      vs 48%; P = .04). More paraprofessional-visited families than nurse-visited
      families experienced staff turnover. CONCLUSIONS: Nurses and paraprofessionals,
      even when using the same model, provide home visiting services in different ways.

PMID- 10589316
TI  - Mortality from infectious diseases in Israel, 1979-1992, based on revised ICD-9
      codes: implications for international comparisons.
AB  - OBJECTIVES: This study examined trends in infectious disease mortality rates in
      Israel between 1979 and 1992, using a traditional and a revised set of
      International Classification of Diseases, Ninth Revision (ICD-9) codes. METHODS:
      A revised scheme of ICD-9 codes was used to compute mortality rates from
      infectious diseases for the period 1979 through 1992 by sex and for different age
      categories. RESULTS: Age-adjusted infectious disease mortality rates based on the
      revised ICD-9 codes were 3 times higher than those based on traditional codes.
      Between 1979 and 1992, age-adjusted mortality rates declined more under the
      revised method than under the traditional method (20% vs 1.7%). CONCLUSIONS: The
      revised set of ICD-9 codes allows a more comprehensive view of the burden of
      infectious diseases on public health.

PMID- 10589317
TI  - Sonomorphologic evaluation of goiter in an iodine deficiency area in the Ivory
      Coast.
AB  - OBJECTIVES: This study evaluated the extent of thyroid abnormalities in a remote
      iodine-deficient area of the Ivory Coast. METHODS: Ultrasonography was used in
      detecting the presence of goiter. RESULTS: The overall prevalence rates of goiter
      were 64.7% among females and 53.3% among males. In children aged 6 to 15 years (n
      = 314), the prevalence of goiter was 62% regardless of sex. Thyroid volume
      increased steadily with age, with significantly larger goiters in women 25 years
      and older. Frequency of cysts and calcifications did not correlate with sex.
      CONCLUSIONS: Especially in developing countries, prophylaxis of iodine deficiency
      disorders must be improved in iodine-deficient areas to prevent substantial
      morbidity, which is more severe in women and elderly persons.

PMID- 10589318
TI  - Effectiveness of a comprehensive multisector campaign to increase seat belt use
      in the greater Athens area, Greece. Hellenic Road Traffic Police Department.
AB  - OBJECTIVES: This study assessed the effectiveness of a comprehensive campaign to
      increase seat belt use in Athens. METHODS: In 1996 a survey focusing on seat belt
      use was undertaken among occupants of 1400 passenger cars. From October 1997 to
      June 1998 the campaign was implemented; during the campaign, seat belt law
      enforcement was not intensified. In 1998 another inspection survey of 2250 cars
      was undertaken. RESULTS: The program brought only a 6% increase in compliance,
      but there was an estimated gain of about 50 averted deaths and 1500 averted
      injuries. CONCLUSIONS: An intensive campaign to increase seat belt use, conducted
      in the absence of increased law enforcement, resulted in moderate gains.

PMID- 10589319
TI  - Possible associations between computed tomography scan and cataract: the Blue
      Mountains Eye Study.
AB  - OBJECTIVES: This study examined possible associations between the presence of
      cataract and a history of computed tomography (CT) scan of the head in an older
      population. METHODS: The Blue Mountains Eye Study examined 3654 people aged 49 to
      97 years who lived west of Sydney, Australia. As part of a medical history,
      participants were asked whether they had ever had a head CT scan. Masked grading
      of lens photographs assessed cortical, nuclear, and posterior subcapsular
      cataracts. RESULTS: No significant associations were found between history of
      head CT scan and age- and sex-specific prevalence of any type of cataract.
      CONCLUSIONS: This study provided no evidence to support an association between
      routine head CT scans and development of cataract.

PMID- 10589320
TI  - Encouraging use of coupons to stimulate condom purchase.
AB  - OBJECTIVES: This study examined the feasibility of using high-value coupons to
      induce condom purchase and evaluated execution factors that can influence the
      effectiveness of this form of promotion. METHODS: Two levels of coupon discount
      value (10% off and 75% off) were used to promote condom purchase among young
      adults. Coupons were distributed according to a widespread strategy or a more
      focused in-store disbursement method. RESULTS: Redemption of coupons distributed
      through the widespread disbursement strategy was negligible. In contrast, coupons
      from the in-store distribution method, particularly the higher value coupon,
      resulted in a high redemption rate. CONCLUSIONS: This research provides strong
      evidence that discount coupons, particularly high-value ones distributed at the
      purchase location, can be used successfully as a condom promotional incentive.

PMID- 10589322
TI  - The association between switching hand preference and the declining prevalence of
      left-handedness with age.
AB  - OBJECTIVES: This study determined the prevalence of left-handedness and of
      switching hand preference among innately left-handed subjects. METHODS: Subjects
      of Swiss nationality (n = 1692), participating in a population-based survey in
      Geneva, Switzerland, completed a questionnaire on innate hand preference and
      current hand preference for writing. RESULTS: From 35 to 44 years of age to 65 to
      74 years of age, the prevalence of innate left-handedness declined from 11.9% to
      6.2% (trend P = .007). In these same age groups, the proportion of innately left
      handed subjects who switched to the right hand for writing increased from 26.6%
      to 88.9% (trend P = .0001). CONCLUSIONS: Across generations, we found an increase
      in the prevalence of switching hand preference among innately left-handed
      subjects. This phenomenon could be explained by social and parental pressure to
      use the right hand.

PMID- 10589321
TI  - Future hospital care in a population-based series of twin pairs discordant for
      physical activity behavior.
AB  - OBJECTIVES: This study investigated the association between physical activity
      behavior and morbidity, taking into account genetic selection. METHODS:
      Hospitalizations were followed from the beginning of 1977 to the end of 1986 in
      710 same-sex healthy twin pairs discordant for leisure-time physical activity and
      in 151 pairs discordant for all physical activity at base-line in 1975. RESULTS:
      During the follow-up, among twin pairs discordant for leisure activity, the
      active member spent, on average, 43% fewer days in the hospital than the inactive
      member; the corresponding percentage was 55% among pairs discordant for all
      activity. CONCLUSIONS: Physically inactive behavior is associated with increased
      need for hospital treatments, even after genetic and other confounding factors
      are taken into account.

PMID- 10589323
TI  - Cigarette smoking among gay and bisexual men.
AB  - OBJECTIVES: This study measured the prevalence of cigarette smoking among gay men
      and identified associations with smoking. METHODS: Household-based (n = 696) and
      bar-based (n = 1897) sampling procedures yielded 2593 gay male participants from
      Portland, Ore, and Tucson, Ariz, in the spring of 1992. RESULTS: Forty-eight
      percent of the combined sample reported current smoking, a rate far above
      prevalence estimates for men in Arizona (z = 14.11, P < .001) or Oregon (z =
      24.24, P < .001). Significant associations with smoking included heavy drinking,
      frequent gay bar attendance, greater AIDS-related losses, HIV seropositivity,
      lower health rating than members of same age cohort, lower educational
      attainment, and lower income. CONCLUSIONS: Rates of cigarette smoking are very
      high among gay men. Tobacco prevention and cessation campaigns should be designed
      to reach the gay male community.

PMID- 10589324
TI  - The effect of health education on the rate of ophthalmic examinations among
      African Americans with diabetes mellitus.
AB  - OBJECTIVES: This study evaluated a multicomponent educational intervention to
      increase ophthalmic examination rates among African Americans with diabetes.
      METHODS: A randomized trial was conducted with 280 African Americans with
      diabetes, enrolled from outpatient departments of 5 medical centers in the New
      York City metropolitan area, who had not had a dilated retinal examination within
      14 months of randomization (65.7% female, mean age = 54.7 years [SD = 12.8
      years]). RESULTS: After site differences were controlled, the odds ratio for
      receiving a retinal examination associated with the intervention was 4.3 (95%
      confidence interval = 2.4, 7.8). The examination rate pooled across sites was
      54.7% in the intervention group and 27.3% in the control group. CONCLUSIONS: The
      intervention was associated with a rate of ophthalmic examination double the rate
      achieved with routine medical care.

PMID- 10589325
TI  - Long-term trends in childhood infectious disease mortality rates.
AB  - OBJECTIVES: This study assessed long-term trends in US childhood infectious
      disease mortality rates (CIDMR). METHODS: We calculated age-adjusted and age
      group-specific US CIDMR (1968-1996) by using data from the Compressed Mortality
      File (1968-1992, 1996) and Multiple Cause of Death Files (1993-1995) of the
      National Center for Health Statistics and English data for historical comparison
      (1861-1964). RESULTS: US CIDMR declined continuously from 1968 to 1996, although
      the rate of decline slowed after 1974. Respiratory and central nervous system
      categories declined most; HIV-related deaths offset these declines somewhat.
      CONCLUSIONS: CIDMR declined nearly 200-fold between 1861 and 1996, but no
      substantive improvement occurred after 1986.

PMID- 10589327
TI  - Technology assessment and accountable health services for women.

PMID- 10589326
TI  - Preventable inpatient time: adequacy of electronic patient information systems.
AB  - OBJECTIVES: This study assessed hospital electronic patient information systems
      (EPIS) for inclusion of variables associated with avoidable and extended
      hospitalization (preventable inpatient time). METHODS: We searched MEDLINE and
      HealthSTAR databases to identify predictors of preventable inpatient time. We
      then audited the admissions process and the handwritten medical record at 1
      hospital, and the EPIS at all hospitals, affiliated with the Yale University
      School of Medicine for inclusion of the predictors. RESULTS: Whereas the written
      medical record included all 58 predictors, the EPIS of the 10 hospitals surveyed
      included an average of only 38% of the predictors. CONCLUSIONS: The conventional
      approach to information gathering during hospital admission is highly
      inefficient. Revising EPIS to include predictors of preventable inpatient time
      could enhance efficiency and quality, while reducing costs, of hospital care.

PMID- 10589328
TI  - Proceedings of the British Pharmacological Society Meeting. Nottingham, 14-16
      July 1999.

PMID- 10589329
TI  - [Psychotherapy in Psychiatry: a challenge for science and practice. IIIrd
      Congress on Psychotherapy of the German Society of Psychiatry, Psychotherapy and
      Neurology. Tubingen, 13-16. October 1999. Abstracts].

PMID- 10589330
TI  - [Regional meeting of the Japanese Circulation Society. Japan. 1998. Abstracts].

PMID- 10589331
TI  - The 26th annual meeting of the Japanese Society of Toxicology. Sapparo, Japan.
      July 21-23, 1999. Abstracts.

PMID- 10589333
TI  - 4th World Congress of the Osteoarthritis Research Society International (OARSI).
      Vienna, Austria, 16-19 September 1999. Abstracts.

PMID- 10589332
TI  - XXVI Annual meeting on Basic Research in Chagas Disease, XV annual meeting of
      Brazilian Society of Protozoology. Caxambu, Brazil. 9-11 November 1999.
      Abstracts.

PMID- 10589334
TI  - Osteoarthritis Research Society International (OARSI) membership directory.

PMID- 10589335
TI  - The history of surgery of the thoracic aorta.
AB  - Until the late 19th century, treatment of thoracic aortic aneurysms relied on
      ligation of the parent vessel or introduction of foreign materials to promote
      coagulation or fibrosis. A major breakthrough occurred in 1888, when Rudolph
      Matas reported an internal repair technique known as endoaneurysmorrhaphy. In
      this approach, the clot was excised from the aneurysmal sac, and the orifices of
      the arteries that entered the sac were sutured from within, reestablishing
      continuous blood flow. At the beginning of the 20th century, Alexis Carrel and
      Charles Guthrie began to lay the foundation for modern vascular anastomotic
      techniques. Although isolated successes were reported, optimal treatment of
      thoracic aortic disease awaited the development of reliable synthetic grafts in
      the 1950s and 1960s. During the past 15 years, the treatment goal has reverted to
      endoaneurysmorrhaphy, involving the use of a suitable graft to restore aortic
      continuity.

PMID- 10589336
TI  - Natural history, pathogenesis, and etiology of thoracic aortic aneurysms and
      dissections.
AB  - The natural history of thoracic aortic aneurysms and dissections is diverse,
      reflecting a broad spectrum of etiologies which include increasing aortic size,
      hypertension, and genetic factors. The pathogenesis is related to defects or
      degeneration in structural integrity of the adventitia, not the media, which is
      required for aneurysm formation. The ascending and descending aorta appear to
      have separate underlying disease processor that lead to a weakened vessel wall
      and an increased susceptibility for dissection. Etiologic factors for aortic
      aneurysms and dissections are multifactorial, reflecting genetic, environmental,
      and physiologic influences.

PMID- 10589337
TI  - Pathologic variants of thoracic aortic dissections. Penetrating atherosclerotic
      ulcers and intramural hematomas.
AB  - This article confirms the existence of two variants of acute aortic pathology,
      the penetrating atherosclerotic ulcer (PAU) and the intramural hematoma (IMH),
      which are radiologically distinct from classic aortic dissection. Table 4 reviews
      the characteristics distinguishing PAU from classic aortic dissection and IMH. We
      took as a matter of definition that classic aortic dissection involves a flap
      which traverses the aortic lumen. We defined PAU and IMH as nonflap lesions, with
      PAU demonstrating a crater extending from the aortic lumen into the space
      surrounding the aortic lumen. This categorization can be summarized with the
      expression, "no flap, no dissection." With these definitions made, re-review of
      the imaging studies for the present report identified 36 such lesions out of 214
      cases originally read as aortic dissection. Therefore, these variant lesions
      accounted for over 1 out of 8 acute aortic pathologies. Besides confirming the
      existence of the conditions, PAU and IMH, as distinct radiographic lesions, this
      series strongly suggests that these two conditions constitute distinct clinical
      entities as well. Table 4 summarizes the clinical patterns of these two entities
      as apparent from the present study, and contrasts them with classic aortic
      dissections. In particular, the following observations, some of which are
      consonant findings in smaller series, can be made regarding the typical patient
      profiles of PAU and IMH from the present study: The patients with PAU and IMH are
      distinctly older than those with type A aortic dissection (74.0 and 73.9 versus
      56.5 years, P = 0.0001). Although not statistically significant, PAU and IMH
      patients tend to be older than patients with type B aortic dissections as well.
      For PAU and IMH, unlike aortic dissection, the concentration in the elderly is
      manifested in a very small standard deviation of the mean age (see Fig. 13);
      these two entities, PAU and IMH, are essentially diseases of the seventh, eighth,
      and ninth decades of life. Patients with PAU and IMH are almost invariably
      hypertensive (about 94% of cases). The pain of PAU and IMH mimics that of classic
      aortic dissection, with anterior symptoms in the ascending aortic lesions and
      intrascapular or back pain with descending aortic lesions. Unlike classic
      dissection, PAU and IMH do not produce branch vessel compromise or occlusion and
      do not result in ischemic manifestations in the extremities or visceral organs.
      PAU and IMH are more focal lesions than classic aortic dissection, which
      frequently propagates for much or the entire extent of the thoracoabdominal
      aorta. PAU is uniformly associated with severe aortic arteriosclerosis and
      calcification, whereas classic dissection often occurs in aortas with minimal
      arteriosclerosis and calcification. PAU and IMH tend to occur in even larger
      aortas than classic aortic dissection (6.2 and 5.5 versus 5.2 cm, P = 0.01). PAU
      and IMH are strongly associated with AAA, which is seen concomitantly in 42.1% of
      PAU patients and 29.4% of IMH patients. PAU and IMH are largely diseases of the
      descending aorta (90% for PAU and 71% for IMH). Although our pathology data is
      limited, we do feel that an inherent difference in the histologic intramural
      level of the hematoma may underlie the pathophysiologic process that determines
      which patient develops a typical dissection and which develops an intramural
      hematoma. In particular, we feel that the level of blood collection is more
      superficial, closer to the adventitia, in IMH than in typical aortic dissection.
      This may explain why the inner layer does not prolapse into the aorta on imaging
      studies or when the aorta is opened in the operating room. This more superficial
      location would also explain the high rupture rates as compared to classic aortic
      dissection (Fig. 14, Table 3). We did find PAU and IMH to behave much more
      malignantly than typical descending aortic dissection. As seen in Figure 6, the
      rupture rate is much higher than for aortic dissection. Docume

PMID- 10589338
TI  - Imaging of thoracic aortic disease.
AB  - Computed tomography, magnetic resonance imaging, and transesophageal
      echocardiography represent the relatively noninvasive techniques available for
      imaging thoracic aortic disease, especially in the evaluation of aneurysms and
      dissections. The article discusses the technique and application of these
      modalities in the evaluation of thoracic aorta. Imaging appearances of the
      commonly encountered pathologies of the thoracic aorta are presented and
      discussed, and potential pitfalls of technique and diagnosis are addressed.

PMID- 10589339
TI  - The genetic basis of aortic disease. Marfan syndrome and beyond.
AB  - The Marfan syndrome and related disorders are systemic disorders of connective
      tissue. Proximal aorta is usually dilated. The molecular basis of Marfan syndrome
      has been elucidated, thus allowing prenatal diagnosis. Life expectancy has
      markedly improved due to the widespread use of beta-adrenergic receptor
      inhibitors and improved surgical management of the aortic disease.

PMID- 10589340
TI  - Medical treatment of the aorta. I.
AB  - Diseases of the thoracic aorta are serious conditions that require close
      observations. Impressive advances in imaging modalities such as magnetic
      resonance imaging, computed tomography sacs, and transesophageal echocardiography
      have aided diagnosis and provided insights into the pathogenesis and natural
      history of thoracic aortic aneurysms, dissection, and atherosclerosis. The
      current review highlights the etiology, epidemiology, and pathophysiology of
      these disorders and focuses on the diagnostic approach and suggested medical
      therapies in the current era.

PMID- 10589341
TI  - Medical treatment of the aorta. II.
AB  - Because of its elastic properties, the aorta influences left ventricular function
      and coronary blood flow. The aortic pressure-diameter relationship provides
      direct estimations of the elastic properties of the aorta in humans. Current
      research is focused on examining strategies that might improve aortic function.
      Therapeutic interventions alter the elastic properties of the aorta, and
      improvement of the elastic properties of the aorta may be beneficial in modifying
      the natural history of the disease. Certain pharmacological agents that result in
      improved aortic function have been identified.

PMID- 10589342
TI  - Surgical techniques. Ascending aorta.
AB  - Aneurysm and dissection are the most common diseases affecting the ascending
      aorta. Graft replacement of the ascending aorta is a straightforward
      cardiovascular procedure with excellent early and late results. When aneurysm or
      dissection extends into the aortic sinuses or arch, management becomes more
      complex and may entail replacement of the aortic root, aortic valve, or a portion
      of the aortic arch using hypothermic circulatory arrest. The optimal root
      prosthesis depends on several patient- and procedure-related variables. Valve
      sparing procedures confer many long-term advantages and should be considered in
      all cases where the aortic valve leaflets are normal. The Ross procedure,
      although ideally suited for isolated aortic valve disease in young patients, may
      be applicable to some patients with combined aortic valve and ascending aortic
      disease, unless there is evidence of a systemic connective tissue disorder.

PMID- 10589344
TI  - Surgical techniques. Aortic arch and deep hypothermic circulatory arrest: real
      life suspended animation.
AB  - Surgical reconstruction of the aortic arch is a complex procedure requiring
      careful preoperative analysis of the pathology and forethought toward surgical
      approach. Development of surgical techniques has brought dramatic improvement
      survival and reduction of neurological events associated with these procedures,
      yet significant morbidity is still encountered. New approaches to the patient
      with these pathologies include antegrade and retrograde perfusions to the brain.
      Continued research into physiology of hypothermic circulatory arrest offers the
      promise of pharmacological protection of the brain during aortic reconstruction
      and potentially development of therapeutic modalities to treat and limit ischemic
      brain damage.

PMID- 10589343
TI  - Surgical techniques. Thoracoabdominal aorta.
AB  - Patients presenting with impending rupture of a thoracoabdominal aortic aneurysm
      require emergency operative repair. To prevent rupture and its associated
      mortality, elective repair of thoracoabdominal aortic aneurysms exceeding 5.5 cm
      to 6.0 cm in diameter is recommended in patients with adequate physiologic
      reserve. Similarly, surgery should be considered for patients with smaller
      symptomatic aneurysms. Atypical symptoms have been associated with rupture,
      therefore, they require thorough evaluation. Whether the aortic conditions are
      caused by medial degenerative disease or chronic aortic dissection, surgical
      techniques allow for graft repair of thoracoabdominal aortic aneurysms with low
      mortality and morbidity rates. Although surgery is usually avoided in patients
      with acute distal aortic dissection, operative intervention is occasionally
      required when complications develop. Patients with acute aortic dissection
      complicated by impending rupture of the thoracoabdominal segment require graft
      repair to restore aortic integrity; although the mortality rate is acceptable,
      the incidence of postoperative paraplegia approaches 20% in this setting. For
      patients presenting with ischemic complications of acute distal aortic
      dissection, less-extensive surgical options have been effective in restoring
      perfusion. In experienced centers, overall operative survival rate following
      thoracoabdominal aortic surgery can exceed 92%. Retrospective data suggest that
      left heart bypass reduces the incidence of paraplegia following extensive
      thoracoabdominal aortic repairs. Although recent advances have led to improved
      outcomes, paraplegia continues to occur regardless of the strategy used. The
      prevention of spinal cord ischemia during thoracoabdominal aortic surgery,
      therefore, will remain a focus of controversy and investigation, just as it was
      more than 4 decades ago.

PMID- 10589345
TI  - The use of biological glue in aortic surgery.
AB  - The biologic sealants presently available on the market that are used in
      cardiovascular surgery and particularly during surgery of the aorta are described
      in this article. Two of these biological sealants, the gelatin-resorcinol
      formaldehyde (GRF) glue and two-component fibrin sealant have been in use for two
      decades. Their respective properties are described beneficial in modifying the
      natural history of the disease. Certain pharmacological agents that result in
      improved aortic function have been identified.

PMID- 10589346
TI  - Interpreting data on thoracic aortic aneurysms. Statistical issues.
AB  - Reliable information on growth rates and risk factors for growth of thoracic
      aortic aneurysms (TAA) is important for managing patients with this potentially
      lethal condition. This article reviews existing procedures for ascertaining TAA
      growth rates and describes improved statistical methodologies. Using data from
      the Yale Center for Thoracic Aortic Disease, the article demonstrates that the
      statistical procedure of instrumental variables (IV) estimation leads to
      substantially more precise and robust estimates of TAA growth rates and
      associated risk factors. We recommend that IV estimation be routinely employed in
      estimating the progression of thoracic aortic aneurysms and in identifying risk
      factors for growth. The article also discusses the issue of sample selection
      effects that arise when patients receive graft surgery and therefore are removed
      from the data set, and describes statistical procedures fro addressing this
      issue.

PMID- 10589347
TI  - Spinal cord protection for thoracic aortic surgery.
AB  - Spinal cord protection is critical for successful outcomes after descending
      thoracic and thoracoabdominal aortic aneurysm repair. For descending thoracic
      aneurysms which end above T9, optimum protection is maintained by distal aortic
      perfusion via a left atrial to distal arterial bypass circuit with a centrifugal
      pump. In repairs of extensive thoracoabdominal aneurysms, additional measures are
      required of extensive thoracoabdominaal aneurysms, additional measures are
      required including hypothermia, intercostal artery implantation into the graft,
      and spinal fluid drainage.

PMID- 10589348
TI  - Endovascular solutions for diseases of the thoracic aorta.
AB  - Technology is proceeding at a very brisk pace. Harnessing that technology for
      clinical use is both a challenge and an opportunity. This combination of surgical
      and interventional methods has allowed for improved clinical outcomes in certain
      complex aortic problems. This article explores and discusses new techniques used
      in detection and treatment of diseases of the thoracic aorta.

PMID- 10589350
TI  - Does partial control of inflammation prevent long-term joint damage? Clinical
      rationale for combination therapy with multiple disease-modifying antirheumatic
      drugs.

PMID- 10589349
TI  - Developing surgical intervention criteria for thoracic aortic aneurysms.
AB  - In summary, the development of intervention criteria is a complex and challenging
      endeavor. Specific examination of this issue is crucial to the appropriate
      clinical care of patients. With these objectives in mind, we have drawn upon our
      clinical experience to design, by way of statistical analysis, reasoned size
      criteria for intervention. These intervention criteria must be carefully weighed
      against the patient's age, overall physical condition, and anticipated life
      expectancy. We have approached the development of criteria for intervention using
      statistical methodology from the standpoint of preventing complications (i.e.,
      dissection and rupture). Symptomatic states, organ compression, concomitant
      aortic insufficiency, and acute ascending aortic dissection are well-accepted
      general indications for surgical intervention regardless of aortic size. The
      appendix incorporates the size criteria developed in the present study as an
      integral component within a comprehensive strategy for managing patients with
      TAA. This study confirms that aneurysms of the thoracic aorta are potentially
      lethal, that attentive follow-up is critical, and that adverse events can be
      anticipated based on size criteria. As we continue to expand our database, we
      hope to refine further statistically-based recommendations for surgical
      intervention. Multi-institutional patient enrollment, with the concomitant
      statistical power of larger patient numbers, would considerably strengthen this
      type of analysis.

PMID- 10589351
TI  - Early developments in combination therapy.
AB  - The concept of combination therapy implies the concurrent use of two or more slow
      acting antirheumatic drugs to treat rheumatoid arthritis. This review places such
      combination therapy into an historical context and evaluates studies carried out
      before 1990. There were no published studies before 1980 of combination therapy,
      and between 1980 and 1990 there were 11 published studies. Three were
      conventional randomised controlled trials, three were non-randomised studies of
      parallel group design, four were observational open studies, and one was a
      retrospective review. Altogether 486 patients were studied with the numbers of
      cases in each study varying between 12 and 101. The main combinations used were
      penicillamine + hydroxychloroquine or chloroquine, gold + hydroxychloroquine, and
      sulphasalzine + penicillamine. Six studies concluded that combination therapy
      helped patients, three suggested possible benefits, and two gave essentially
      negative findings. These two negative studies were randomised controlled trials.
      Most studies indicated an increase in adverse events with combination therapy.
      The average erythrocyte sedimentation rate on combination therapy fell by 21.4%.
      A majority of patients remained on the therapy for 6-12 months. The balance of
      evidence in 1990 suggested that combination therapy had a modest advantage.
      However, the trials were too small to detect its true value, and the combinations
      used were not ideal. In particular, combining gold or penicillamine with other
      drugs appeared to give too much toxicity. The future development of the field
      would depend on identifying more effective combinations of drugs and undertaking
      larger and better-designed trials.

PMID- 10589352
TI  - Pyramids to myriads: the combination conundrum in rheumatoid arthritis.
AB  - Rheumatoid arthritis continues to be a cause of significant morbidity and
      disability. Increased understanding of the immunopathogenesis of the disease, of
      its progression over time, and of patient characteristics which correlate with
      outcome, have allowed more appropriate therapy. However, currently available
      disease-modifying therapy fails to adequately control disease in many patients,
      and many combinations of these drugs have therefore been described. In this
      review, we critically evaluate the existing literature, identifying combinations
      for which reasonable evidence of efficacy exists, and highlighting important
      issues in interpreting such evidence as well as issues of drug monitoring in such
      patients.

PMID- 10589353
TI  - Mechanisms of action of second-line agents and choice of drugs in combination
      therapy.
AB  - Second-line agents are used commonly for the treatment of rheumatoid arthritis
      (RA). They suppress inflammation and ameliorate symptoms but often fail to
      substantially improve long-term disease outcome. Their use in RA was discovered
      serendipitously and their modes of action were largely unknown. Recent researches
      have identified some of their mechanisms of action. Most of them have
      antiinflammatory properties and some are immunomodulators. Traditionally, second
      line agents are used as monotherapy, but recent evidence suggests that
      combination treatment with two or more drugs may be more efficacious. However,
      the choice of agents in combination therapy is not based on their mechanisms of
      action. We review current knowledge on the modes of action of second-line agents
      and assess whether such understanding may offer a rational basis for combination
      therapy.

PMID- 10589354
TI  - Pharmacotherapeutic strategies for disease-modifying antirheumatic drug (DMARD)
      combinations to treat rheumatoid arthritis (RA).
AB  - OBJECTIVE: To provide a rational model for the use of disease-modifying
      antirheumatic drug (DMARD) combinations in the treatment of rheumatoid arthritis.
      METHODS: The DMARDs used today were examined for their mechanisms of action,
      kinetics, and toxicity, and collected into tabular formats for easier comparison.
      From these tables, matrices of potential positive or negative interfaces among
      combinations were constructed. Finally, these matrices were used to examine the
      usefulness of DMARD combinations by comparing them with published data. RESULTS:
      When clearly overlapping cells were found with respect to mechanisms of action,
      kinetics, or toxicity (e.g., methotrexate [MTX] plus azathioprine or MTX plus
      auranofin) predictions were good. When knowledge in these areas of kinetics
      and/or mechanisms of action were inadequate, predictions and results were not
      always consonant (e.g. MTX plus sulfasalazine; D-penicillamine plus
      hydroxychloroquine). CONCLUSIONS: The approach demonstrated in this paper toward
      rational combination therapy is logical and can be successful, although its
      success is circumscribed by our knowledge about the drugs we use. The rational
      approach to combination therapy demonstrated in this article can: 1) help prevent
      the use of combinations unlikely to be effective; 2) can point toward directions
      for useful research; and 3) can even be used when physicians are faced with
      patients whose needs have exceeded our present scientific knowledge.

PMID- 10589355
TI  - New approaches to imaging of early rheumatoid arthritis.
AB  - Conventional radiology (CR) is a major tool for the diagnosis and assessment of
      early arthritis. However, CR does not image the primary pathology of rheumatoid
      arthritis (RA), i.e. the synovium, and is insensitive for radiological erosions.
      New techniques, particularly magnetic resonance imaging (MRI) and ultrasonography
      (US) have shown their potential to improve on the sensitivity of CR. This article
      reviews the current status of this approach in early disease.

PMID- 10589356
TI  - Methotrexate and emerging therapies.
AB  - More publications in the medical literature have described the clinical efficacy
      and toxicity of methotrexate (MTX) than of any other drug ever used for rheumatic
      diseases. A knowledgeable clinical can thus rely on evidence-based medicine to
      guide the use of this agent. Because MTX is not remission-inducing, many new
      therapies are being combined with it in order to achieve a greater therapeutic
      response. This trend will likely continue and expand as more novel agents are
      introduced.

PMID- 10589357
TI  - Combination treatment of rheumatoid arthritis with cyclosporine and methotrexate.
AB  - In patients with rheumatoid arthritis (RA) not controlled on methotrexate (MTX)
      alone, clinical trials have shown that combination therapy with cyclosporine
      (CSA) and MTX is effective and relatively well tolerated over 12 months.
      Information regarding the long-term benefits, toxicities and tolerability of this
      combination therapy in clinical practice, and comparisons with alternative
      strategies, will determine the utility of the MTX plus CSA combination regimen in
      patients with RA not controlled with a single drug.

PMID- 10589358
TI  - Combination DMARD therapy with hydroxychloroquine, sulfasalazine, and
      methotrexate.
AB  - Triple combination therapy with hydroxychloroquine, sulfasalazine, and
      methotrexate (MTX) has been shown in double-blind, placebo-controlled studies to
      be significantly superior to MTX alone (Paulus 50% responses of 77% versus 33%).
      In long-term follow-up studies, this therapy has now been shown to be well
      tolerated with continued efficacy in the majority of patients.

PMID- 10589359
TI  - Combination DMARD therapy including corticosteroids in early rheumatoid
      arthritis.
AB  - A number of reports indicating the growing acceptance of simultaneous therapy
      with multiple disease-modifying anti-rheumatic drugs (DMARDs), as well as the use
      of more aggressive treatment measures in the early phases of disease to combat
      rheumatoid arthritis (RA), have appeared during the last decade. However, only a
      few randomized controlled clinical trials have been conducted on the use of DMARD
      combinations in early RA. We review these trials in this article. In two separate
      one-year studies combination therapy with sulphasalazine (SSZ) and methotrexate
      (MTX) seemed to offer no benefits compared to either drug used as monotherapy. On
      the other hand, the DMARD combinations so far proven to be superior to single
      DMARDs have initially also included a corticosteroid component. In the COBRA
      study (Combinatietherapie Bij Reumatoide Artritis) the combination of SSZ (2
      gm/day), MTX (7.5 mg/week for 40 weeks), and prednisolone (Prd) (initially 60
      mg/day, tapered in 6 weekly steps to 7.5 mg/day and stopped after 28 weeks)
      compared to SSZ alone (2 gm/day) resulted in significantly better clinical
      outcomes at week 28. Although the difference in clinical response between the
      treatment arms was lost at week 58, the progression of joint damage remained
      statistically significantly slower at week 80 in the patients initially assigned
      to the combination therapy. Furthermore, in the FIN-RACo trial (Finnish
      Rheumatoid Arthritis Combination Therapy Trial), therapy using a "tailored-steps"
      strategy with SSZ (1-2 gm/day), MTX (7.5-1.5 mg/week), hydroxychloroquine (300
      mg/day), and Prd (up to 10 mg/day) yielded a significantly increased remission
      rate and less peripheral joint damage at two years than the single DMARD
      treatment strategy (initially SSZ 2 gm/day), with or without Prd. Adverse effects
      in both study arms were comparable. Two additional preliminary reports (in
      abstract form) suggest that intensive local therapy in the form of intra
      articular injections added to single or combination therapy improves both local
      and systemic disease control, with increased remissions and less damage. Although
      still preliminary, these results should encourage the rheumatological community
      to treat selected RA patients with DMARD combinations from the very start.

PMID- 10589360
TI  - Methotrexate and leflunomide combination therapy for patients with active
      rheumatoid arthritis.
AB  - An open-label, one-year study was conducted to evaluate the safety and clinical
      response to leflunomide and methotrexate combination therapy for rheumatoid
      arthritis. Study results revealed tolerable safety, no significant
      pharmacokinetic interactions between methotrexate and leflunomide, and suggested
      improved clinical response with combination therapy.

PMID- 10589361
TI  - Etanercept and methotrexate combination therapy.
AB  - Tumor necrosis factor (TNF) is a major proinflammatory cytokine in the rheumatoid
      joint. TNF activity can be neutralized by administration of a recombinant version
      of its soluble p75 TNF receptor linked to the Fc portion of human immunoglobulin
      IgG1 (etanercept). The present study examined the combination of etanercept with
      methotrexate (MTX) in a group of patients with rheumatoid arthritis (RA) who had
      persistent activity despite monotherapy with MTX. The etanercept-MTX group had a
      significantly better outcome than the placebo-MTX group using American College of
      Rheumatology (ACR) criteria. At 6 months, 71% of the patients in the etanercept
      MTX group had an ACR 20% response (versus 27% in the placebo-MTX group). In the
      etanercept-MTX group, 39% had an ACR 50% response (versus 3% in the placebo-MTX
      group), and 15% in the etanercept-MTX group versus 0% in the placebo-MTX group
      met the robust ACR 70% response. The present study indicates that etanercept is a
      novel and robust drug in combination with MTX for the treatment of RA.

PMID- 10589362
TI  - Combination therapy of the chimeric monoclonal anti-tumor necrosis factor alpha
      antibody (infliximab) with methotrexate in patients with rheumatoid arthritis.
AB  - Infliximab, a chimeric anti-TNF alpha antibody, showed in two double-blind
      placebo-controlled trials efficacy in combination with methotrexate (MTX) in
      patients with severe rheumatoid arthritis (RA). Whereas in the first trial low
      dose MTX or placebo was compared to infliximab alone and in combination, the
      second trial compared infliximab to placebo in patients with active RA despite
      maximal tolerated MTX treatment. Infliximab showed synergistic effects in
      combination with MTX. The immunogenicity of infliximab was reduced by the
      combination. Infliximab in combination with high-dose MTX is effective and safe
      in long-term treatment up to 54 weeks.

PMID- 10589363
TI  - Use of combination therapy in the routine care of patients with rheumatoid
      arthritis: physician and patient surveys.
AB  - AIMS: To describe the utilization of combination therapy in the treatment of
      rheumatoid arthritis (RA). METHODS: Review of published articles and abstracts,
      and patient/physician questionnaire data. RESULTS: Combination therapy was rarely
      used in the early 1980s and is now (1999) used for about 25% of RA patients in
      the US. Physician and patient surveys indicate that methotrexate plus
      hydroxychloroquine is the most commonly used combination in North America, and
      physician surveys indicate that methotrexate plus sulfasalazine is the most
      commonly used combination in Europe. Patient questionnaire data indicate that
      13.4% of patients in the US take methotrexate and hydroxychloroquine, and between
      11% and 15% of patients with recent onset of RA receive treatment with disease
      modifying antirheumatic drug (DMARD) combinations. CONCLUSIONS: Combination
      therapy with agents such as hydroxychloroquine and methotrexate is used in up to
      25% of RA patients in the US, but the use of "aggressive combination therapy" is
      unusual. Whether combination therapy as currently practiced is beneficial remains
      to be determined.

PMID- 10589364
TI  - Combination DMARD treatment with parenteral gold and methotrexate.
AB  - INTRODUCTION: Both methotrexate (MTX) and gold sodium thiomalate (GSTM) have been
      shown to be very effective in the treatment of rheumatoid arthritis (RA) and to
      slow x-ray progression. The combination of both drugs could be useful because of
      their different and complimentary mechanisms of action. However, there is only
      one long-term study comparing this combination with MTX monotherapy. METHODS: In
      this prospective long-term observational study, all patients who started MTX
      treatment from 1980 to 1987 in one center were followed for 12-108 (mean 34.1)
      months. Ninety-seven patients were treated with MTX, while 126 patients received
      the combination MTX/GSTM, both drugs being given at the full dose. All patients
      had active disease, most of them long-lasting destructive RA not responsive to
      previous disease-modifying antirheumatic drug (DMARD) treatment. RESULTS: There
      were no significant differences in the demographic and baseline data between the
      two groups, with the exception of higher swollen joint counts (SJC) and C
      reactive protein (CRP) in the combination group. In both groups the parameters of
      disease activity (erythrocyte sedimentation rate [ESR], CRP, SJC) improved
      significantly. A > 50% improvement in the SJC after 1 and 3 years was seen in 62%
      and 70% of patients in the MTX group, and in 55% and 85% of the patients in the
      combination group, respectively. A > 50% improvement in the ESR occurred in
      54%/63% (MTX group) and in 49%/68% (combination group) for the same timepoints.
      There was no difference between the groups regarding the nature, frequency, or
      severity of side effects. A total of 20.6% (MTX) and 15.1% (combination) of
      patients were withdrawn for side effects. After 5 years, 54% of the patients in
      both groups were still being treated. CONCLUSION: This long-term observational
      study shows that the combination MTX/GSTM is well tolerated and is at least as
      effective as MTX single treatment. Taking into account the higher disease
      activity at baseline and the greater x-ray progression before baseline among the
      patients in the combination group, one may conclude that combination treatment is
      superior to monotherapy.

PMID- 10589365
TI  - Clinical experience with combination disease-modifying antirheumatic drug therapy
      with cyclosporine.
AB  - OBJECTIVES: We previously reported on the clinical use of cyclosporine (Neoral),
      alone or in combination with methotrexate (MTX), in the first 46 refractory
      rheumatoid arthritis (RA) patients treated at our centre between March 1996 and
      November 1997. Thirty of the 46 patients remained on cyclosporine at study
      completion (mean dose 2.98 mg/kg/day) with efficacy inferred by significant
      reductions in the prednisolone and MTX doses and creatinine maintained in an
      acceptable range. Early discontinuation was primarily related to non-serious side
      effects. METHODS: The 30 patients continuing cyclosporine were reviewed 12 months
      later in November 1998. Analysis included life-table techniques. RESULTS: 21 of
      the original 46 patients (46%) continued at a mean dose of 2.59 mg/kg/day after a
      mean of 23.4 months. Nine patients discontinued cyclosporine during this 12-month
      period: 3 due to inactive disease, 2 due to hypertension, 2 due to elevated
      creatinine, and 1 due to mononeuritis multiplex secondary to rheumatoid
      vasculitis, and 1 due to inefficacy. Patients continuing cyclosporine had a
      shorter disease duration (9.85 versus 15.5 years [P = 0.05]). The prednisolone
      dose decreased from a baseline value of 10.57 mg/day to 6.78 mg/day (P = 0.007)
      and the MTX dose from 15.6 mg/week to 13.1 mg/week (P = 0.02). The mean serum
      creatinine level increased from a baseline of 73.86 mumol/l to 85.8 mumol/l
      (16%). 21/30 patients on combination therapy with MTX showed no difference in
      discontinuation rates compared with those on cyclosporine alone. Life-table
      analysis showed a bimodal distribution with significantly increased cyclosporine
      discontinuation in the first 12 months (principally due to non-renal/hypertensive
      causes) versus the subsequent period. CONCLUSION: This follow-up study indicates
      that the use of cyclosporine in refractory RA allows a reduction in the
      prednisolone and MTX doses. Utilization is longer in earlier disease and is
      unaffected by combination with MTX. Renal function is maintained within an
      acceptable range. The bimodal discontinuation curve reflects early
      patient/physician concern about minor side effects, while renal/hypertension
      changes resulted in later discontinuation.

PMID- 10589366
TI  - Aim for remission or "personal best" using combination DMARD therapy with
      methotrexate and hydroxychloroquine.
AB  - Combination disease-modifying antirheumatic drug therapy with methotrexate and
      hydroxychloroquine has changed the course of rheumatoid arthritis. Better
      management requires "front of the line" care, effective drug combinations, and a
      goal of "Personal Best." The Pincus phenomenon--the discrepancy between
      subjective satisfaction and objective progression--may be minimized in clinical
      practice by questionnaires and Snapshot.

PMID- 10589367
TI  - Combination cyclosporine and (hydroxy)chloroquine in rheumatoid arthritis.
AB  - Antimalarials are attractive candidates for combination therapy. In vitro
      experiments have revealed a synergistic mode of action of cyclosporine and
      chloroquine which could not, however, be confirmed in a clinical trial.

PMID- 10589368
TI  - TNF alpha and IL-1 beta are separate targets in chronic arthritis.
AB  - Chronic arthritis is characterized by persistent joint inflammation and
      concomitant joint destruction. Using murine arthritis models and neutralizing
      antibodies as well as cytokine-specific knockout conditions, it was found that
      tumor necrosis factor alpha (TNF alpha) is important in joint swelling, whereas a
      direct role in tissue destruction is unlikely. Interleukin-1 (IL-1) is not a
      dominant cytokine in early joint swelling, but has a pivotal role in sustained
      cell infiltration and erosive cartilage damage. TNF alpha-independent IL-1
      production is a prominent feature in murine arthritis models, implying that IL-1
      as well as TNF alpha are appropriate targets for therapy. These observations
      provide evidence for the potential uncoupling of joint inflammation and erosive
      changes and underline the need for TNF alpha/IL-1 directed combination-therapy
      approaches.

PMID- 10589369
TI  - Combination therapy with DMARDs and biological agents in collagen-induced
      arthritis.
AB  - There is increasing interest in the use of combination therapy for rheumatoid
      arthritis and in the possibility of combining the conventional drug approach with
      newer biological therapies. Animal models of arthritis provide important tools
      for evaluating novel forms of therapy and for eludicating mechanisms of drug
      action. In this paper, we review the results of our own research into combination
      therapy in collagen-induced arthritis using biological therapies such as anti
      tumor necrosis factor alpha, anti-CD4, and anti-interleukin 12 monoclonal
      antibodies, and small molecular weight compounds such as cyclosporin and the
      phosphodiesterase IV (PDE IV) inhibitor rolipram.

PMID- 10589370
TI  - Combination biologic therapy.
AB  - Biologic therapies refer to genetically engineered treatments such as monoclonal
      antibodies and receptor-immunoglobulin fusion proteins. Following many
      disappointments, the introduction of anti-tumor necrosis factor (anti-TNF alpha)
      therapies into the clinic has clearly demonstrated the exciting potential of
      biologic agents. Many of these have been designed to modulate a specific aspect
      of the underlying autoimmune process, thus avoiding generalized
      immunosuppression. They include products which interfere with the trimolecular
      complex of major histocompatibility complex II-Antigen-T cell receptor
      interaction; others designed to block the secondary signals for T cell activation
      and T cell interaction with antigen-presenting cells; and cytokine agonists as
      well as antagonists. Whilst reducing the degree of global immunosuppression
      associated with therapy, this targeted specificity may reduce the likelihood that
      a single therapeutic agent will provide long-term disease control. On the other
      hand, animal models have demonstrated synergy of combination biologic therapy,
      particularly for the re-induction of self-tolerance. As our knowledge of immune
      physiology and, particularly, immune regulation improves, it can be expected that
      many combination biologic therapies will be tested in the clinic. Pilot studies
      of combined anti-CD4 and TNF alpha blockade are underway; combination use of TNF
      alpha and interleukin-1 beta inhibitors are expected. This article reviews the
      potential for combination biologic therapy, including likely adverse effects, for
      the treatment of rheumatoid arthritis and other autoimmune diseases.

PMID- 10589371
TI  - Treatment of ocular infections with topical antibacterials.
AB  - Topically applied ophthalmic antibacterial preparations are widely used in the
      treatment of patients with superficial ocular infections. In addition, they are
      frequently used to augment treatment for intraocular infection administered
      systemically or via local instillation. Direct application delivers high
      concentrations of antimicrobial agents to the surface of the eye conveniently,
      quickly and with minimal systemic exposure to the agent. However, antibacterials
      are rapidly dissipated from the tear film and intraocular penetration of topical
      antibacterial agents is generally poor, necessitating intensive application for
      successful treatment of corneal infections. Therapeutic concentrations are rarely
      achieved at other sites in the eye. This article reviews what is known of the
      pharmacokinetics of topical ocular agents and how this information can be used to
      optimise ocular persistence and penetration and minimise systemic absorption of
      antibacterials. A review of the features of the most commonly employed topical
      antibacterials suggests that for the treatment of uncomplicated bacterial
      conjunctivitis there is little difference between the various agents in terms of
      clinical efficacy, although chloram-phenicol should be used with care because of
      its potential haematological toxicity. Carefully considered therapy is imperative
      for bacterial keratitis; fortified beta-lactam/aminoglycoside combinations are
      often used for these infections. The fluoroquinolones appear promising, but
      caution is necessary in treating keratitis of unknown aetiology with these agents
      alone because of inherent and emerging acquired resistance among Gram-positive
      bacteria.

PMID- 10589372
TI  - Clinical pharmacokinetics of mexiletine.
AB  - Mexiletine, a class Ib antiarrhythmic agent, is rapidly and completely absorbed
      following oral administration with a bioavailability of about 90%. Peak plasma
      concentrations following oral administration occur within 1 to 4 hours and a
      linear relationship between dose and plasma concentration is observed in the dose
      range of 100 to 600 mg. Mexiletine is weakly bound to plasma proteins (70%). Its
      volume of distribution is large and varies from 5 to 9 L/kg in healthy
      individuals. Mexiletine is eliminated slowly in humans (with an elimination half
      life of 10 hours). It undergoes stereoselective disposition caused by extensive
      metabolism. Eleven metabolites of mexiletine are presently known, but none of
      these metabolites possesses any pharmacological activity. The major metabolites
      are hydroxymethyl-mexiletine, p-hydroxy-mexiletine, m-hydroxy-mexiletine and N
      hydroxy-mexiletine. Formation of hydroxymethyl-mexiletine, p-hydroxy-mexiletine
      and m-hydroxy-mexiletine is genetically determined and cosegregates with
      polymorphic debrisoquine 4-hydroxylase [cytochrome P450 (CYP) 2D6] activity. On
      the other hand, CYP1A2 seems to be implicated in the N-oxidation of mexiletine.
      Various physiological, pathological, pharmacological and environmental factors
      influence the disposition of mexiletine. Myocardial infarction, opioid
      analgesics, atropine and antacids slow the rate of absorption, whereas
      metoclopramide enhances it. Rifampicin (rifampin), phenytoin and cigarette
      smoking significantly enhance the rate of elimination of mexiletine, whereas
      ciprofloxacin, propafenone and liver cirrhosis decrease it. Cimetidine,
      ranitidine, fluconazole and omeprazole do not modify the disposition of
      mexiletine. Conversely, mexiletine is known to alter the disposition of other
      drugs, such as caffeine and theophylline. Factors affecting the elimination of
      mexiletine may be clinically important and dosage adjustments are often
      necessary.

PMID- 10589375
TI  - Magnetic resonance pancreatography (MRP).
AB  - Magnetic resonance pancreatography (MRP) is a technique that permits accurate
      evaluation of the pancreatic duct without instrumentation, contrast material
      administration, or ionizing radiation. Because MRP is entirely noninvasive, MRP
      avoids complications associated with endoscopic retrograde pancreatography (ERP)
      such as pancreatitis and perforation. MRP allows for the noninvasive evaluation
      of patients with acute and chronic pancreatitis, variant anatomy of the
      pancreatic duct, pancreatic duct trauma, and pancreatic neoplasia. MRP yields
      diagnostic information in the setting of a failed or incomplete ERP. When MRP is
      performed in conjunction with conventional abdominal MR, the result is a
      comprehensive examination of the pancreatic duct as well as the pancreas and
      other solid organs of the abdomen.

PMID- 10589373
TI  - Clinical pharmacokinetics of clarithromycin.
AB  - Clarithromycin is a macrolide antibacterial that differs in chemical structure
      from erythromycin by the methylation of the hydroxyl group at position 6 on the
      lactone ring. The pharmacokinetic advantages that clarithromycin has over
      erythromycin include increased oral bioavailability (52 to 55%), increased plasma
      concentrations (mean maximum concentrations ranged from 1.01 to 1.52 mg/L and
      2.41 to 2.85 mg/L after multiple 250 and 500 mg doses, respectively), and a
      longer elimination half-life (3.3 to 4.9 hours) to allow twice daily
      administration. In addition, clarithromycin has extensive diffusion into saliva,
      sputum, lung tissue, epithelial lining fluid, alveolar macrophages, neutrophils,
      tonsils, nasal mucosa and middle ear fluid. Clarithromycin is primarily
      metabolised by cytochrome P450 (CYP) 3A isozymes and has an active metabolite, 14
      hydroxyclarithromycin. The reported mean values of total body clearance and renal
      clearance in adults have ranged from 29.2 to 58.1 L/h and 6.7 to 12.8 L/h,
      respectively. In patients with severe renal impairment, increased plasma
      concentrations and a prolonged elimination half-life for clarithromycin and its
      metabolite have been reported. A dosage adjustment for clarithromycin should be
      considered in patients with a creatinine clearance < 1.8 L/h. The recommended
      goal for dosage regimens of clarithromycin is to ensure that the time that
      unbound drug concentrations in the blood remains above the minimum inhibitory
      concentration is at least 40 to 60% of the dosage interval. However, the
      concentrations and in vitro activity of 14-hydroxyclarithromycin must be
      considered for pathogens such as Haemophilus influenzae. In addition,
      clarithromycin achieves significantly higher drug concentrations in the
      epithelial lining fluid and alveolar macrophages, the potential sites of
      extracellular and intracellular respiratory tract pathogens, respectively.
      Further studies are needed to determine the importance of these concentrations of
      clarithromycin at the site of infection. Clarithromycin can increase the steady
      state concentrations of drugs that are primarily depend upon CYP3A metabolism
      (e.g., astemidole, cisapride, pimozide, midazolam and triazolam). This can be
      clinically important for drugs that have a narrow therapeutic index, such as
      carbamazepine, cyclosporin, digoxin, theophylline and warfarin. Potent inhibitors
      of CYP3A (e.g., omeprazole and ritonavir) may also alter the metabolism of
      clarithromycin and its metabolites. Rifampicin (rifampin) and rifabutin are
      potent enzyme inducers and several small studies have suggested that these agents
      may significantly decrease serum clarithromycin concentrations. Overall, the
      pharmacokinetic and pharmacodynamic studies suggest that fewer serious drug
      interactions occur with clarithromycin compared with older macrolides such as
      erythromycin and troleandomycin.

PMID- 10589376
TI  - Pregnancy, insulin resistance and nitrogen accretion.
AB  - Metabolic adaptation to pregnancy in humans and animals is aimed at provision of
      nutrients for the growth and energy metabolism of the growing conceptus, as well
      as for the mother. Kinetic studies in human pregnancy have shown that fluxes of
      energy-yielding substrates, i.e. glucose, fatty acids and glycerol, increase in
      parallel with the increasing demands of the fetus and the mother. Resistance to
      insulin action, measured by hyperinsulinemic euglycemic clamp, appears early in
      gestation and is correlated with the infant's birth weight. Adaptive responses in
      nitrogen metabolism, decreased plasma urea concentration and decreased rate of
      urea synthesis, are apparent early in pregnancy, much before any significant
      increase in fetal demands. Recent studies of branched chain aminoacid (leucine)
      kinetics show a lower flux of leucine nitrogen and an unchanged flux of leucine
      carbon in gestation. A linear correlation between rate of deamination of leucine
      and rate of urea synthesis was observed in pregnant women. It is speculated that
      decreased anaplerotic carbon flux in the tricarboxylic acid cycle, as a
      consequence of insulin resistance, may have an important role in the down
      regulation of transamination of leucine during pregnancy, and may contribute to
      the conservation and accretion of nitrogen by the mother and the fetus.

PMID- 10589374
TI  - Effects of liver disease on pharmacokinetics. An update.
AB  - Liver disease can modify the kinetics of drugs biotransformed by the liver. This
      review updates recent developments in this field, with particular emphasis on
      cytochrome P450 (CYP). CYP is a rapidly expanding area in clinical pharmacology.
      The information currently available on specific isoforms involved in drug
      metabolism has increased tremendously over the latest years, but knowledge
      remains incomplete. Studies on the effects of liver disease on specific
      isoenzymes of CYP have shown that some isoforms are more susceptible than others
      to liver disease. A detailed knowledge of the particular isoenzyme involved in
      the metabolism of a drug and the impact of liver disease on that enzyme can
      provide a rational basis for dosage adjustment in patients with hepatic
      impairment. The capacity of the liver to metabolise drugs depends on hepatic
      blood flow and liver enzyme activity, both of which can be affected by liver
      disease. In addition, liver failure can influence the binding of a drug to plasma
      proteins. These changes can occur alone or in combination; when they coexist
      their effect on drug kinetics is synergistic, not simply additive. The kinetics
      of drugs with a low hepatic extraction are sensitive to hepatic failure rather
      than to liver blood flow changes, but drugs having a significant first-pass
      effect are sensitive to alterations in hepatic blood flow. The drugs examined in
      this review are: cardiovascular agents (angiotensin converting enzyme inhibitors,
      angiotensin II receptor antagonists, calcium antagonists, ketanserin,
      antiarrhythmics and hypolipidaemics), diuretics (torasemide), psychoactive and
      anticonvulsant agents (benzodiazepines, flumazenil, antidepressants and
      tiagabine), antiemetics (metoclopramide and serotonin antagonists), antiulcers
      (acid pump inhibitors), anti-infectives and antiretroviral agents (grepafloxacin,
      ornidazole, pefloxacin, stavudine and zidovudine), immunosuppressants
      (cyclosporin and tacrolimus), naltrexone, tolcapone and toremifene. According to
      the available data, the kinetics of many drugs are altered by liver disease to an
      extent that requires dosage adjustment; the problem is to quantify the required
      changes. Obviously, this requires the evaluation of the degree of hepatic
      impairment. At present there is no satisfactory test that gives a quantitative
      measure of liver function and its impairment. A critical evaluation of these
      methods is provided. Guidelines providing a rational basis for dosage adjustment
      are illustrated. Finally, it is important to consider that liver disease not only
      affects pharmacokinetics but also pharmacodynamics. This review also examines
      drugs with altered pharmacodynamics.

PMID- 10589377
TI  - Nutrition in inflammatory bowel disease.
AB  - Clinical and basic research continues to expand our understanding of the complex
      pathogenesis of inflammatory bowel diseases. The potential roles played by fatty
      acid intake, serum leptin, and nitric oxide in the promotion of intestinal
      inflammation in Crohn's disease and ulcerative colitis will be reviewed. In
      addition, important advances in the areas of bone disease, vitamin deficiency,
      growth failure, and home parenteral nutrition will be discussed.

PMID- 10589378
TI  - Nutritional issues in cirrhosis and liver transplantation.
AB  - In the past year, some relevant papers on the mechanisms of malnutrition in
      cirrhosis have been published. Studies investigating the metabolic destiny of
      leucine after protein breakdown, which have contributed to a better understanding
      of the pathogenesis of muscle wasting and fat depletion in these patients,
      deserve particular mention. Also, the demonstration that chronically reducing
      hyperinsulinaemia in cirrhosis is able to improve insulin sensitivity opens novel
      pathogenic and therapeutic perspectives for such a metabolic derangement in these
      patients. Other papers dealt with unsaturated lipids, lipoperoxidation and
      antioxidants in chronic liver disease. However, randomized trials on parenteral
      or enteral nutrition in cirrhosis and liver transplantation are missing.

PMID- 10589379
TI  - Nutritional and metabolic aspects of gastrointestinal cancer.
AB  - The profound impact of nutrition and nutritional support on the development and
      clinical outcome of gastrointestinal cancer is undeniable. However, scientific
      investigation into this area is recent, and many questions remain unanswered.
      While the importance of 'good nutrition' is unchallenged, details relating to
      which patients should receive nutritional support, when they should receive it,
      and what type of support they should receive are not known. Recent prospective
      randomized clinical trials and meta-analysis have provided conflicting results.
      This review summarizes the results of the published studies that have addressed
      these issues, and provides specifics regarding the current role of nutritional
      support in clinical care, and the prospects for future research.

PMID- 10589380
TI  - Home artificial nutrition.
AB  - Home artificial nutrition is a mature technology that has been with us for over a
      quarter of a century. Its use appears to be more widespread in the USA than in
      other western countries. Issues of outcome, ethics, and quality of life are
      increasingly important. Complications continue to be reported, some newly
      recognized and some that we must continually relearn.

PMID- 10589381
TI  - Nutritional care of pancreatitis and its complications.
AB  - This article reviews the current literary data on the role of conservative
      supportive treatment for acute pancreatitis, with special emphasis on parenteral
      and enteral nutrition. Despite the fact that the indications for both methods
      have been discussed, defined and widely accepted in recent years, enteral
      nutrition is currently the focus of recent clinical investigations for use in
      acute pancreatitis.

PMID- 10589382
TI  - The gut: the 'motor' of multiple organ dysfunction syndrome?
AB  - Abnormal colonization, gut-origin infections, and bacterial translocation are all
      signs of gut dysfunction that may be implicated in the pathogenesis of multiple
      organ dysfunction syndrome (MODS). This review summarizes and updates relevant
      experimental and clinical data that have attempted to correlate these phenomena
      with the development of MODS and to answer whether or not the gut is the 'motor'
      of MODS. The presented data suggest that, in some patients, gut dysfunction may
      precede the development of MODS. However, in most patients, this relationship is
      less obvious. The gut may still be one of the motors of MODS; however, it does
      not appear that this motor is fueled by the systemic spread of bacteria. Bacteria
      may play a role on a local gut-associated level in initiating and perpetuating
      the production of local inflammatory mediators that may produce distant organ
      injury.

PMID- 10589383
TI  - Gastrointestinal flora and its alterations in critical illness.
AB  - The normal indigenous flora of the human gastrointestinal tract comprises a
      remarkably complex yet stable colony of more than 400 separate species, living in
      a symbiotic relationship with the human host. Stability of that flora is
      accomplished by multiple mechanisms including gastric acidity, gut motility,
      bile, products of immune cells in the gut epithelium, and competition between
      microorganisms for nutrients and intestinal binding sites. The indigenous flora
      influences multiple aspects of physiologic homeostasis and forms a key component
      of normal host defenses against infection by exogenous pathogens. Critical
      illness is associated with striking changes in patterns of microbial
      colonization, best described in the oropharynx and upper gastrointestinal tract.
      Pathological colonization occurs with the same species that is predominate in
      nosocomial infections, and descriptive studies suggest that such colonization is
      a risk factor for infection. Moreover, prophylactic measures that prevent
      pathological gut colonization in experimental circumstances reduce rates of
      nosocomial infection in critically ill patients and, in the case of selective
      decontamination of the digestive tract, reduce mortality risk. Conventional
      approaches to infectious diseases have conceptualized microorganisms as inimical
      and focused on eradicating them as rapidly and fully as possible. Insights from
      the study of critically ill patients suggest that that relationship is better
      understood as a symbiotic one and that preservation, rather than elimination, of
      the indigenous flora provides the greatest promise of clinical benefit to this
      vulnerable population.

PMID- 10589384
TI  - Nutrient absorption.
AB  - Interesting advances occurred recently in nutrient absorption. Kinetics of
      triacylglycerol appearance in endoplasmic reticulum, Golgi apparatus, and lymph
      support the hypothesis that endoplasmic reticulum-to-Golgi transport is rate
      limiting for lipid absorption. Apolipoprotein B does not appear necessary for
      initial formation of chylomicron-sized lipid particles in the endoplasmic
      reticulum, but rather for their movement out of the endoplasmic reticulum and to
      the Golgi. If peptides are protected from luminal proteolysis by fatty acylation,
      or if a nonpeptide drug, acyclovir, is esterified with valine to enhance
      bioavailability, the peptides nevertheless are absorbed by peptide transporters.
      Experimental conditions needed to use human ileal mucosa for in vitro absorption
      studies are described. Intestinal mucosa contains leptin receptors, and leptin
      inhibits galactose absorption, suggesting a new site for leptin's modulation of
      body mass. The enhancer element for the apoB gene is located much farther from
      its structural gene in the intestine than in the liver.

PMID- 10589385
TI  - Nutrition and cancer: the herbal revolution.
AB  - There is growing evidence that compounds of plant origin have the ability to
      prevent cancer. Populations with greater reliance on fruits and vegetables in the
      diet experience a reduced risk for the major cancers. Research has focused on
      specific micronutrients and nonnutrient compounds that may have health benefits.
      The term phytochemical means any compound of plant origin. This review focuses on
      the cancer-preventive aspects of phytochemicals and their mechanisms of action.
      The term phytomedicine applies to the health-maintaining aspects of these
      compounds and their implications for raising the standard of public health.

PMID- 10589386
TI  - Obesity: effects on the liver and gastrointestinal system.
AB  - Obesity, or the presence of a body mass index exceeding 30 kg/m2, has assumed
      epidemic proportions in the United States. More than a cosmetic issue, obesity is
      associated with many comorbidities that contribute to multiple organ dysfunction,
      illness, and shortened life span. This review covers new and emerging information
      on the relationship of obesity to common and debilitating hepatic and
      gastrointestinal disorders, including nonalcoholic steatohepatitis,
      gastroesophageal reflux, gallstones, and increased risk of colon cancer.
      Understanding the role of obesity in these disorders should lead to new insights
      into the pathogenesis of common liver and gastrointestinal diseases and to new
      treatment strategies for the practicing gastroenterologist.

PMID- 10589387
TI  - Bibliography. Current world literature. Nutrition and the gastrointestinal tract.

PMID- 10589389
TI  - Polymorphonuclear elastase in the intra-abdominal fluid may be activated after
      major abdominal surgery.

PMID- 10589388
TI  - Breathholding spells in childhood.

PMID- 10589390
TI  - Change and challenge. ICN during the 1970s & 1980s.
AB  - NEW leadership, new goals and a new found fiscal stability helped the
      International Council of Nurses (ICN) greatly expand its influence in
      international nursing during the decades of the 1970s and 1980s. While improving
      the socio-economic and professional welfare of nurses remained a top priority for
      the organisation, ICN also increased its involvement in other global health
      matters. ICN was challenged by issues ranging from the apartheid policies of
      South Africa to nuclear testing to the emergence of the HIV/AIDS epidemic.

PMID- 10589391
TI  - The manufacture of surgical instruments: what nurses can do about child labour.
AB  - Do you use instruments produced by companies using child labour? Approximately
      7,700 child workers help to produce surgical instruments in Sialkot, Pakistan.
      These instruments end up in the hands of nurses and doctors in thousands of
      hospitals and clinics around the world. Paul Germanotta of Public Services
      International reports on the problem and what nurses and nursing organisations
      can do to help end exploitation of child workers.

PMID- 10589392
TI  - A model for international research collaboration.

PMID- 10589393
TI  - A new perspective of human origin and dispersals derived from the microevolution
      of teeth.
AB  - Recent genetic studies have heightened the expectation that the origin of modern
      humans will be defined, but one clear vision has yet to be developed. The study
      of teeth has historically been an informative means to help define human
      dispersals. Quantitative tooth data is presented encompassing worldwide human
      populations. A null hypothesis phylogeny developed from the multivariate analysis
      of the microevolution of the dental phenotype was interpreted to be broadly in
      accord with the dominant interpretation of genetic, archaeological, and other
      dental data by showing that the first division in the dispersion of extant
      humanity was within sub-Sahara Africans; i.e., San, and Western Africans and
      Bantu. This "out-of-Africa" interpretation of the graphical results suggests that
      the first modern human African emigrants not to go extinct were Southeast Asian
      Negritos. All Eurasians then emerged and expanded through a series of extinct
      antecedent populations branching from the short lineage extending from Negritos
      to Australian aborigines. Caucasoids were the first group to fission from this
      stock. Under this hypothesis, the next to have emerged were antecedent Southeast
      Asians, from which present Southeast Asians and then antecedent east Central
      Asians then diverged. Independently, people from the region of Mongolia and all
      Native Americans arose as daughter populations from antecedent east Central
      Asians. The broad outline of humanity studied here cannot disprove the equally
      explanatory protean multiregional hypotheses, but with the inclusion of hominids
      and further modern human populations either parts of the multiregional hypothesis
      or the outlined more linear evolutionary scenario likely can be refuted.

PMID- 10589394
TI  - Confirmation of linkage of Van der Woude syndrome to chromosome 1q32: evidence of
      association with STR alleles suggests possible unique origin of the disease
      mutation.
AB  - Van der Woude syndrome (VWS) is an autosomal dominant craniofacial disorder with
      high penetrance and variable expression. Its clinical features are variably
      expressed, but include cleft lip and/or cleft palate, lip pits and hypodontia.
      All VWS families studied to date map the disease gene to a < 2 cM region of
      chromosome 1q32, with no evidence of locus heterogeneity. The aim of this study
      is to refine the localization of the VWS gene and to further assess possible
      heterogeneity. We analyzed four multiplex VWS families. All available members
      were clinically assessed and genotyped for 19 short tandem repeat markers on
      chromosome 1 in the VWS candidate gene region. We performed two-point and
      multipoint limit of detection (LOD) score analyses using a high penetrance
      autosomal dominant model. All families showed positive LOD scores without any
      recombination in the candidate region. The largest two-point LOD score was 5.87.
      Our assay method for short tandem repeat (STR) markers provided highly accurate
      size estimation of marker allele fragment sizes, and therefore enabled us to
      determine the specific alleles segregating with the VWS gene in each of our four
      families. We observed a striking pattern of STR allele sharing at several closely
      linked loci among our four Caucasian VWS families recruited at three different
      locations in the US. These results suggest the possibility of a unique origin for
      a mutation responsible for many or most cases of VWS.

PMID- 10589395
TI  - Craniofacial growth in subjects with unilateral complete cleft lip and palate,
      and unilateral incomplete cleft lip, from 2 to 22 months of age.
AB  - This paper reports a longitudinal quantitative cephalometric analysis of the
      craniofacial growth in subjects with unilateral complete cleft lip and palate
      (UCCLP), and unilateral incomplete cleft lip (UICL), from 2 to 22 months of age.
      The purpose of the study was to determine the amount and direction of growth in
      UCCLP compared to UICL (control group) from 2 months of age (just prior to lip
      repair) to 22 months of age, 20 months later. The sample comprised of 49 subjects
      with UCCLP (37 males and 11 females) and 45 with UICL (29 males and 16 females).
      The cephalometric analysis of the craniofacial morphology included lateral,
      frontal, and axial projections. The data were presented as mean plots of the
      craniofacial region including the calvaria, cranial base, orbits, nasal bone,
      maxilla, mandible, cervical column, pharynx, and soft-tissue profile. A valid
      common coordinate system (registration according to the n-s line in the lateral
      projection, latero-orbitale line in the frontal projection, and meatus acusticus
      externus line in the axial projection for the landmark positions at examination 1
      and 2) was ascertained. The growth at a specific anatomical location in a patient
      was defined as the displacement vector from the coordinate of the corresponding
      landmark in the X-ray at examination 1 to its coordinate at examination 2,
      corrected for X-ray magnification. The growth of an anatomical region in a
      patient was assessed by investigating the growth pattern formed by a collection
      of individual growth vectors in that region. The amount of growth in the UCCLP
      and UICL group was very similar. The general craniofacial growth pattern, in
      terms of the direction of growth, was also fairly similar in the UCCLP group and
      the control group. However, the maxilla and mandible showed a more vertical
      growth pattern than that observed in the control group. This study confirms that
      UCCLP is a localized deviation, and not a craniofacial anomaly, due to the fact
      that a normal growth potential has been observed in all craniofacial regions,
      except where the growth had been directly influenced by surgical intervention.
      Furthermore, the vertical growth pattern of the maxilla and mandible supports the
      hypothesis of a special facial type in cleft lip and palate individuals, and the
      facial type as a liability factor increasing the probability of cleft lip and
      palate.

PMID- 10589396
TI  - Craniofacial features associated with amelogenesis imperfecta.
AB  - Craniofacial alterations occur with increased frequency in patients with
      amelogenesis imperfecta (AI). The purpose of this study was to characterize the
      craniofacial features associated with AI in families from the US. Twenty-seven
      people with AI and 14 unaffected family members from nine separate kindreds were
      evaluated. The diagnosis was established by history, clinical, and radiographic
      examination, and histological and or biochemical analysis of enamel. The kindreds
      were generally classified as hypoplastic AI (HPAI), hypocalcified AI (HCAI), or
      hypomaturation AI (HMAI) and then further subclassified based on phenotype and
      mode of inheritance. Linear and angular cephalometric measures were converted to
      z-scores using gender/age matched values from the Bolton and Behrent's standards.
      Statistical analyses included t-tests and ANOVA accepting P < or = 0.05 as
      significant. The vertical dimension of the lower face was significantly increased
      (ANSMe; P = 0.001), especially in affected individuals compared with unaffected
      relatives, in all kindreds with HCAI and HMAI but in only one kindred with
      autosomal recessive rough AI. Clinically, an anterior open bite (overbite < 0 mm)
      was observed in 26% of all dentate individuals with AI and none of their
      unaffected relatives. Skeletal morphology was highly variable depending on the AI
      type and kindred. While this study shows an association of altered craniofacial
      morphology with certain AI kindreds, the relationship of the AI genotype to the
      observed malocclusions remains to be defined.

PMID- 10589397
TI  - Optic, olfactory, and vestibular dysmorphogenesis in the homozygous mouse
      insertional mutant Tg9257.
AB  - The transgene insertional mutation 9257 on mouse chromosome 18 was originally
      identified by the circling behavior caused by vestibular abnormalities in
      heterozygous mutants. To characterize the homozygous phenotype, we generated F2
      offspring from the cross (C57BL/6J-tg/+ x DBA/2J). Eye defects ranging in
      severity from microphthalmia to anophthalmia were observed in the tg/tg
      offspring. Dysmorphic development of the lens was evident as early as E10.5 in
      homozygous transgenic mice. Apparent agenesis of the lateral semicircular canal
      was evident at E14.5. Anomalies of nasomaxillary structures and olfactory
      neuroepithelium were present in heterozygous and homozygous transgenic mice. The
      9257 mutation provides a model for analysis of the morphogenesis of these three
      neurosensory systems and their associated bony structures.

PMID- 10589398
TI  - Cranial suture obliteration is induced by removal of transforming growth factor
      (TGF)-beta 3 activity and prevented by removal of TGF-beta 2 activity from fetal
      rat calvaria in vitro.
AB  - Cranial suture morphogenesis requires soluble, heparin-binding factors secreted
      by the dura mater to resist premature osseous obliteration. Elevated levels of
      transforming growth factor (TGF)-beta 1, TGF-beta 2, and TGF-beta 3 have
      previously been noted in cranial sutures undergoing normal and premature sutural
      obliteration. To examine the role of TGF-beta s in regulating cranial suture
      morphogenesis, an established in vitro, serum-free, calvarial culture system was
      used. In this system, fetal rat coronal sutures undergo apparently normal suture
      morphogenesis in the presence of dura mater, but undergo osseous obliteration in
      the absence of dura mater. Neutralizing polyclonal antibodies to TGF-beta 1, TGF
      beta 2, or TGF-beta 3 were added to cultures of fetal day 19 rat calvaria, which
      were harvested at 3, 4, or 5 days, processed for histology, sectioned, and
      examined. Coronal sutures from calvaria cultured in the presence of dura mater
      resisted obliteration, either alone or in the presence of TGF-beta 1 or TGF-beta
      2 neutralizing antibodies. However, sutures from calvaria cultured in the
      presence of TGF-beta 3 neutralizing antibodies became obliterated. Conversely,
      sutures from calvaria cultured in the absence of dura mater became obliterated by
      bone, either alone or in the presence of neutralizing antibodies to TGF-beta 1 or
      TGF-beta 3. However, those sutures cultured in the presence of neutralizing
      antibodies to TGF-beta 2 were rescued from osseous obliteration.

PMID- 10589399
TI  - Pathogenesis of encephaloschisis in retinoic-acid-treated hamster embryos I: a
      morphometric study of the craniofacial structures.
AB  - The severity of the developmental disorders of the paraxial mesoderm and
      neuroectoderm must objectively be compared to determine which of the two
      structures is more deeply involved in the pathogenesis of encephaloschisis. In
      the present study, hamster fetuses were obtained from dams that had been treated
      with retinoic acid, and divided into two groups: fetuses with encephaloschisis
      and those without apparent external malformations in the cranium and face. Mid
      sagittal serial sections of the head were prepared, histologically processed, and
      utilized for the reconstruction of the profile of the head structures. Using this
      reconstructed profile, we measured the length of the skull base bone structures
      (basisphenoid and basiocciput), which develop from the paraxial mesoderm, brain
      structures (mesencephalon and metencephalon), which develop from the
      neuroectoderm, and facial bone structures (nasal septum and hard palate), which
      develop from cephalic neural crest cells. The measured length of each structure
      was compared between the treated and control groups. It was found that treatment
      with retinoic acid resulted in significantly (P < 0.05) shortened lengths of the
      skull base bone structures both in fetuses with encephaloschisis and those
      without apparent external malformations in the cranium and face. In the brain
      structure of fetuses without encephaloschisis, as well as in the facial bone
      structures, however, this shortness was not observed. These results suggest that
      developmental disorders in the paraxial mesoderm may play an important role in
      the pathogenesis of encephaloschisis.

PMID- 10589400
TI  - Projections of population-based twinning rates through the year 2100.
AB  - OBJECTIVE: To present the first compilation of population-based twinning rates
      published after the year 1990 and to project population-based twinning rates
      through the year 2100. STUDY DESIGN: We searched the Internet-based MEDLINE
      database for articles published after 1990 in which population-based twinning
      rates were described. We used population-based data from national statistical
      authorities from Australia, Austria, Canada, Finland, Hong Kong, Israel, Japan,
      Norway, Singapore and Sweden, published by Y. Imaizumi in a recent article. U.S.
      figures were based on data from the National Center for Health Statistics. Annual
      growth rates of twinning were calculated and graphed, making the assumption that
      these rates would remain constant throughout the next century. RESULTS: Our
      report presents the most recent population-based twinning rates. When projected
      through the year 2015, twinning rates reach figures that could best be described
      as derived from a Jules Verne novel: Sweden, in this model, would have four times
      more twin than singleton births. CONCLUSION: We strongly suggest that physicians
      reexamine their patterns of prescribing ovulation-inducing agents, which carry a
      greatly increased risk of multiple pregnancy.

PMID- 10589401
TI  - Clinical significance of a cytologic diagnosis of atypical glandular cells of
      undetermined significance.
AB  - OBJECTIVE: To assess the clinical significance of a cytologic diagnosis of
      atypical glandular cells of undetermined significance (AGUS) and determine the
      most appropriate evaluation of these patients. STUDY DESIGN: Between 1993 and
      1995, 44,217 Papanicolaou smears were evaluated at Allegheny University
      Hospitals, Medical College of Pennsylvania Campus. There were 108 (0.24%) cases
      of AGUS smears during that time. No clinical information was available for 14
      patients, and 19 were lost to follow-up. The charts of the remaining 75 cases
      were retrospectively reviewed. RESULTS: Tissue specimens were available for 62 of
      the 75 patients. There were 26 (42%) with no significant histopathologic
      findings, 13 (21%) with polyps, 5 (8%) cases of endometrial hyperplasia, 2 (3%)
      with endometrial adenocarcinoma, 12 (19%) with cervical intraepithelial neoplasia
      (CIN), 1 (2%) with adenosquamous carcinoma of the cervix, 2 (3%) with cervical
      adenocarcinoma in situ and 1 (2%) case of metastatic breast cancer. The total
      number of patients with significant histopathology other than polyps was 23
      (37%). The median age of the patients was 49 years. There were more cases of
      endometrial hyperplasia and endometrial cancer (19%) in women 49 years or older
      than in younger women; only one (3%) case of endometrial hyperplasia was detected
      in the younger age group (P = .057). Patients who underwent more-aggressive
      evaluation (colposcopy and biopsies plus endometrial sampling, cone biopsy or
      hysterectomy) had greater numbers of abnormal histopathologic findings (55%) than
      patients who underwent endometrial sampling only (21%) or those who underwent
      colposcopy and biopsy only (33%). This difference approaches statistical
      significance (P = .057). A significant proportion of patients with a history of
      CIN and a cytologic diagnosis of AGUS were found to have CIN (47%), while 8% of
      those with no history of CIN were found to have CIN (P = .002). Fifty percent of
      patients with a history of cancer (all had breast cancer) and AGUS had abnormal
      histopathology. Patients with a subclassification of AGUS "favor neoplasia" had a
      greater proportion of significant histopathology (72%) as compared to AGUS
      "unspecified" (26%) and AGUS "favor reactive" (20%) (P = .003). CONCLUSION: A
      significant proportion of women with a cytologic diagnosis of AGUS have abnormal
      histopathology. Heightened awareness should be raised in patients with AGUS and a
      history of CIN or cancer and in those with the AGUS subclassification "favor
      neoplasia."

PMID- 10589402
TI  - Gasless laparoscopy under epidural anesthesia for adnexal cysts during pregnancy.
AB  - OBJECTIVE: To evaluate laparoscopic adnexal cystectomy during pregnancy using an
      open technique with a whole abdominal wall-lift method under epidural anesthesia.
      STUDY DESIGN: Seven cases of adnexal cysts during pregnancy were resected using a
      gasless laparoscopic (extracorporeal) method with a whole abdominal wall-lift. We
      performed this procedure without using general anesthesia or CO2
      pneumoperitoneum. RESULTS: All operations were performed successfully without
      complications. All patients resumed normal activity within one week. The
      subsequent antenatal courses of the patients were uneventful. There were no
      severe complications during the operations or postoperative courses. Six patients
      had vaginal deliveries of normal infants at term. No abnormal findings were found
      in the antenatal course of patient 7 until 30 weeks of gestation. CONCLUSION:
      Based on our limited experience, this procedure may be safe.

PMID- 10589403
TI  - Butoconazole nitrate 2% for vulvovaginal candidiasis. New, single-dose vaginal
      cream formulation vs. seven-day treatment with miconazole nitrate. Gynazole 1
      Study Group.
AB  - OBJECTIVE: To compare the safety and efficacy of a single vaginal dose of a
      butoconazole nitrate 2% bioadhesive, sustained-release cream* (butoconazole 1
      BSR) with a seven-day schedule of miconazole nitrate vaginal cream 2% (miconazole
      7). STUDY DESIGN: The clinical trial was conducted according to a randomized,
      parallel, investigator-blind, multicenter study design. The patients self
      administered the respective creams to the posterior vaginal fornix. Two hundred
      twenty-three patients started the trial and were analyzed for safety. A total of
      205 patients qualified for efficacy analysis, 101 receiving butoconazole 1-BSR
      and 104 using miconazole 7. Patients receiving butoconazole 1-BSR inserted one
      applicator full of medication once. Those assigned to receive miconazole 7
      inserted one applicator full daily for seven days. Patients were evaluated 7-10
      and 30 days after completion of therapy. RESULTS: Butoconazole 1-BSR rapidly
      relieved the signs and symptoms of vulvovaginal candidiasis. The proportion of
      patients with severe symptoms declined from the pretreatment 20% to 6% on the 1st
      day, to 3% on the 4th day, and to 2-1% on the 5th-7th day after single-dose
      application. Eight to ten days after treatment completion, clinical symptoms
      regressed in 92%, and fungal cultures were negative in 87% of patients. At the 30
      day posttreatment visit, 88% of patients remained clinically cured, and 74% had
      negative fungal cultures. In the miconazole 7 group, the proportion of patients
      with severe symptoms declined from 23% to 19% after the first dose; thereafter,
      symptom relief proceeded more rapidly. Eight to ten days after treatment
      completion, clinical symptoms regressed in 92% and fungal cultures were negative
      in 87% of patients. At the 30-day follow-up examination, 86% patients were
      clinically cured, and 77% were culture negative. After single-dose butoconazole 1
      BSR, severe symptoms receded faster than after the first dose of miconazole 7,
      and the difference was statistically significant (P = .01). In all other efficacy
      parameters, the differences between the two groups were not statistically
      significant. Neither treatment regimen caused significant adverse events.
      CONCLUSIONS: This clinical trial demonstrated that butoconazole 1-BSR is an
      effective and safe alternative to longer-term therapy with miconazole nitrate
      (seven days) for vulvovaginal candidiasis.

PMID- 10589404
TI  - Pelvic actinomycosis. Is long-term antibiotic therapy necessary?
AB  - OBJECTIVE: To describe 11 cases of actinomycosis and analyze whether long-term
      antibiotic use in necessary. STUDY DESIGN: Analysis of 11 cases of pelvic
      actinomycosis diagnosed and treated during the last nine years. Four patients had
      an intrauterine device (IUD) for 6-20 years, three patients had an IUD for 3-5
      years, and four patients had no known etiology. In most patients the symptoms
      lasted from several days to one month. The actinomycotic lesions involved one or
      both ovaries in all 11 cases. In five patients the lesion extended to other
      areas, such as the uterus, omentum, parametrium, pelvic walls, colon, bladder,
      cul-de-sac and gallbladder. RESULTS: All patients underwent surgery that included
      removal of the lesions with the ipsilateral or both adnexa and, in specific
      cases, with extension of the lesions, hysterectomy, omentectomy, hemicolectomy
      and cholecystectomy. Confirmation of the diagnosis of actinomycosis was done by
      histology in all cases, and antibiotic treatment usually began 1-14 days after
      surgery. The drug of choice was penicillin. The duration of treatment was 12
      months in 6 patients, 6 months in 3 and < or = 3 months in two. All patients were
      alive and well after two to nine years of follow-up. CONCLUSION: In contrast to
      actinomycosis at other sites, where the literature recommends antibiotic therapy
      for 6-12 months, pelvic actinomycosis could be a limited disease. We propose that
      in cases of pelvic actinomycosis where the abscess can be completely removed
      surgically, a shorter period of antibiotic therapy can be effective.

PMID- 10589405
TI  - Evaluating chronic pelvic pain. A consensus recommendation. Pelvic Pain Expert
      Working Group.
AB  - OBJECTIVE: To identify a comprehensive approach to evaluating women with chronic
      pelvic pain based on findings in the literature. STUDY DESIGN: A working group of
      gynecologist pelvic pain specialists was convened to consider principles on which
      consensus could be reached and to identify areas in which consensus is not yet
      possible. RESULTS: Chronic pelvic pain affects 15% of American women. The
      diagnostic and therapeutic approach to the complaint may be influenced
      inordinately by the specialty of the practitioner to whom the woman presents. A
      comprehensive approach to the complaint requires recognition of the multiple
      organ systems that may be involved. Evaluation of the woman with chronic pelvic
      pain begins with a comprehensive history and physical examination, followed by
      selected laboratory and imaging studies. For those women in whom the evaluation
      does not yield a likely cause of the complaint, the empiric use of nonsteroidal
      antiinflammatory agents, oral contraceptives, and perhaps antibiotics or
      antispasmodics is indicated. Women who fail to respond to empiric therapy should
      be considered highly likely to have endometriosis or adenomyosis. Further
      diagnostic (laparoscopy) or therapeutic (gonadotropin-releasing hormone agonist)
      interventions should be directed toward the high likelihood of endometriosis or
      adenomyosis. CONCLUSION: A comprehensive approach to chronic pelvic pain includes
      consideration of multiple organ systems, with empiric therapy appropriate after a
      thorough history and physical examination, to further delineate the pain problem.

PMID- 10589406
TI  - Diagnostic laparoscopy in infertile women with normal hysterosalpingograms.
AB  - OBJECTIVE: To assess the value of laparoscopy in infertile women with normal
      hysterosalpingograms, with and without risk factors suggesting pelvic disease.
      STUDY DESIGN: We retrospectively reviewed 1,022 consecutive charts from a
      tertiary infertility practice. In 265 women, laparoscopies were performed after
      normal hysterosalpingograms. RESULTS: Laparoscopies were normal in 136 (51%)
      women, whereas 129 (49%) had one or more abnormal laparoscopic findings,
      including minimal or mild endometriosis (n = 85), moderate or severe
      endometriosis (n = 11), adnexal adhesions (n = 27), subserosal myomas (n = 17),
      ovarian neoplasms (n = 5), distal phimosis (n = 1) and salpingitis isthmica
      nodosa (n = 1). Only 7% of cases had findings that might require standard
      operative laparoscopy or laparotomy, although not all were causally related to
      infertility. A history of dysmenorrhea or dyspareunia increased the likelihood of
      detecting endometriosis from 41% to 64% and 69%, respectively. The presence of
      both symptoms increased the likelihood to 83%. CONCLUSION: In the presence of a
      normal hysterosalpingogram, laparoscopy identified other pelvic disease in about
      half of patients. Because most abnormalities were mild, this knowledge can be
      used to plan a micro-laparoscopic approach for many women, reserving traditional
      or operative laparoscopy for women with an abnormal hysterosalpingogram or
      extensive disease following micro-laparoscopy. Alternately, knowledge of the
      nature and severity of the expected laparoscopic findings might lead to bypassing
      laparoscopy in favor of assisted reproduction when the perceived benefit of
      surgical intervention is small.

PMID- 10589407
TI  - Response of vulvar lichen sclerosus and squamous cell hyperplasia to graduated
      topical steroids.
AB  - OBJECTIVE: To determine whether symptomatic remission could be obtained equally
      effectively in patients with vulvar lichen sclerosus, squamous cell hyperplasia
      or mixed disease in response to a standardized course of graduated topical
      steroids. STUDY DESIGN: A retrospective analysis of 137 patients with biopsy
      proven lichen sclerosus (84), squamous cell hyperplasia (42) or mixed disease
      (11) treated between 1990 and 1997 with a standard, three-month regimen of
      graduated topical steroids was carried out. Presence or absence of symptoms and
      side effects of treatment were recorded three and six months following induction
      of the initial graduated topical steroid regimen. RESULTS: On completion of the
      graduated topical steroid course, 59% of patients were asymptomatic (P = .035),
      and at six months, 58% were asymptomatic (P = .11). Remission of symptoms was
      more easily achieved in patients with lichen sclerosus as compared to patients
      with squamous cell hyperplasia and mixed disease at both three and six months (P
      = .09 at three and P = .035 at six). Four cases of local reactions to the
      steroids were recorded, as were two cases of vulvar malignancy. CONCLUSION:
      Symptomatic remission was significantly easier to achieve in patients with vulvar
      lichen sclerosus as compared to those with squamous cell hyperplasia following
      treatment with graduated topical steroids.

PMID- 10589408
TI  - Postpartum dyspareunia. An unexplored problem.
AB  - OBJECTIVE: Postpartum dyspareunia has been attributed by authors of obstetric
      texts to episiotomy tenderness or vaginal atrophy. The nursing literature
      attributes it to low estrogen levels. This study attempts to examine these
      assumptions, to clarify the incidence of postpartum dyspareunia and the length of
      time it is likely to last. STUDY DESIGN: Sixty-two women in a private practice
      were examined between two and eight weeks postpartum and followed prospectively.
      RESULTS: Forty-five percent of parturients developed entry dyspareunia, but only
      6% had pain at the sites of vulvar repair. The median length of symptoms in the
      39% with nonfocal introital dyspareunia was 5.5 months, and tenderness lasted up
      to 1 year. Such dyspareunia developed in women having a first (42%) or second
      (47%) infant, delivering vaginally (42%) or by cesarean section (29%), and
      lactating (41%) or not lactating (22%). One-third of those affected had severe
      sexual dysfunction. CONCLUSION: Postpartum dyspareunia is quite common and can be
      a significant source of difficulty in the months after delivery. It is an
      underdetected problem and deserves more study.

PMID- 10589409
TI  - Accuracy of sonographically estimated fetal weight with and without
      oligohydramnios. A case-control study.
AB  - OBJECTIVE: To determine the accuracy of sonographically estimated fetal weight
      among women with and without oligohydramnios (amniotic fluid index [AFI] < or =
      5.0 cm) and to ascertain the ability to detect fetal growth restriction (FGR)
      (estimated birth weight < 10th percentile for gestational age [GA]) among
      patients in two groups. STUDY DESIGN: Assuming that 50% of sonographic
      predictions are within 10% of the birth weight in the study group, 300
      parturients are necessary to show a difference of 15% among controls (alpha =
      .05, beta = .02). The study group consisted of parturients with a reliable GA of
      > or = 24, no known anomalies and known AFI of < or = 5.0 cm. The control (1:1)
      was the next patient with the same GA but AFI between 5.1 and 23.9 cm. The paired
      t test was used, and the odds ratio (OR) and 95% confidence interval (CI) were
      calculated. P < .05 was considered significant. RESULTS: Among the study and
      control groups (N = 162 each), maternal demographics, mean estimate (P = .078)
      and actual birth weight (P = .091) were similar. Sonographic estimates within 10%
      of weight were not significantly different among those with (57%) and without
      oligohydramnios (59%; OR 0.92; 95% CI 0.59, 1.44). The frequency of FGR was
      higher among those with inadequate fluid (18%) than controls (9%; OR 2.13; 95% CI
      1.10, 4.16). Sensitivity, positive predictive value and likelihood ratio were
      higher among those with oligohydramnios (76%, 78% and 16) than controls (53%, 42%
      and 7). CONCLUSION: The accuracy of sonographic estimates of fetal weight is not
      influenced by whether the parturient has oligohydramnios. Moreover, the accuracy
      of identifying FGR is not diminished among those with AFI < or = 5.0 versus > 5.0
      cm.

PMID- 10589410
TI  - Unassisted conception with a normal pregnancy outcome in a woman with active
      Mycobacterium tuberculosis infection of the endometrium. A case report.
AB  - BACKGROUND: Tuberculosis of the endometrium is usually associated with
      infertility. Once a patient is diagnosed with endometrial tuberculosis, she is
      almost certain to experience infertility; in vitro fertilization and embryo
      transfer offer the only realistic treatment for tuberculous infertility. We
      describe one case of unassisted conception with a normal pregnancy outcome in a
      patient with Mycobacterium tuberculosis infection of the endometrium. CASE: A 34
      year-old woman who suffered from 10 years of infertility was investigated in the
      authors' unit. She gave no significant past medical or surgical history, and
      initial examinations and investigations were normal. Her husband was 34 years
      old, and his semen analysis was normal. The patient underwent diagnostic
      laparoscopy, chromohydrotubation and endometrial biopsy, which showed patency of
      both fallopian tubes and normal pelvic organs, with no evidence of endometriosis
      or previous pelvic inflammatory disease. Histologic examination of the biopsied
      endometrium showed no granulomas; however, culture of the endometrium yielded
      Mycobacterium tuberculosis. When the patient was called back for antituberculosis
      chemotherapy, we found that she had become pregnant within one month of the
      endometrial biopsy. Antituberculosis chemotherapy was commenced at 14 weeks'
      gestation with rifampicin, isoniazid, pyrazinamide and pyridoxine. The pregnancy
      remained uneventful, and the patient delivered a normal female infant, 3,380 g at
      term. Pathologic examination of the placenta was performed, but there were no
      granulomas or features of chronic inflammation. CONCLUSION: Despite the
      successful fertility outcome in our patient, we do not think that this case was a
      challenge to previous concepts of endometrial tuberculosis. In vitro
      fertilization and embryo transfer are usually the most suitable options for these
      patients.

PMID- 10589411
TI  - Detection of endometrial adenocarcinoma in two asymptomatic postmenopausal women
      receiving tamoxifen. A report of two cases.
AB  - BACKGROUND: Tamoxifen has been linked to an increased risk for the development of
      endometrial adenocarcinoma. The majority of these carcinomas present with
      postmenopausal bleeding. The current standard is to undertake sampling only after
      the onset of bleeding. CASES: Two cases illustrate the utility of transvaginal
      saline infusion sonohysterography (TVS/SIS) in the detection of endometrial
      carcinoma prior to the onset of bleeding. CONCLUSION: Annual TVS/SIS may be
      useful for screening asymptomatic, tamoxifen-exposed patients with a uterus in
      situ and is likely to be more acceptable to such patients than annual biopsies.

PMID- 10589412
TI  - Laparoscopic cornuostomy for interstitial pregnancy. A case report.
AB  - BACKGROUND: With recent advances in laparoscopic surgery, many reports have
      described laparoscopic cornual resection for interstitial pregnancy as a safe
      alternative to laparotomy. We report a laparoscopic cornuostomy for unruptured
      interstitial pregnancy with myometrium reconstruction. CASE: A 32-year-old woman
      presented with complaints of abdominal cramps and vaginal spotting after 6 weeks
      of amenorrhea. Ultrasonographic examination revealed a gestational sac 7 mm in
      diameter in the left uterine corner. There was clear separation between the
      endometrium and gestational sac. A 3-mm periumbilical trocar for the laparoscope
      and a 3-mm trocar in the lower abdomen were used, and the left interstitial
      pregnancy was confirmed. An additional, 5-mm trocar was used in the lower abdomen
      for the laparoscopic surgery. The patient underwent a laparoscopic cornuostomy.
      Myometrium reconstruction was performed by suturing and tying with a laparoscopic
      technique. CONCLUSION: In this case, minilaparoscopy was useful in the diagnosis
      and treatment of interstitial pregnancy.

PMID- 10589413
TI  - Abdominal sacral colpopexy resulting in a retained sponge. A case report.
AB  - BACKGROUND: During abdominal sacral colpopexy, a procedure used to correct
      vaginal vault prolapse, the vaginal cuff must be elevated intraabdominally to
      facilitate suturing. The use of a vaginal sponge stick to elevate the cuff can
      result in foreign body complications. CASE: A 70-year-old woman developed chronic
      pelvic pain and a vaginal discharge after undergoing abdominal sacral colpopexy.
      Radiographic films showed what appeared to be a retained surgical needle in the
      vaginal cuff. During an exploratory laparotomy to remove the foreign body, a
      fragment of the sponge used to elevate the vaginal cuff during abdominal sacral
      colpopexy was found to have been inadvertently incorporated into the apex of the
      vagina. CONCLUSION: An end-to-end anastomotic sizer should be used to elevate the
      vaginal cuff during abdominal sacral colpopexy to reduce the risk of foreign body
      complications.

PMID- 10589414
TI  - Gastric adenocarcinoma presenting with persistent, mild gastrointestinal symptoms
      in pregnancy. A case report.
AB  - BACKGROUND: Mild gastrointestinal symptoms are common during pregnancy but can
      also be the only symptoms in stomach cancer until the late stage. Clinicians'
      reluctance to pursue diagnostic studies appears to be a major contributing factor
      to delayed diagnosis and poor outcome. We report a case of maternal death to
      alert clinicians to this rare possibility. CASE: A 36-year-old woman had
      persistent, mild epigastric discomfort, nausea, vomiting and frequent episodes of
      dark stools since the second trimester of pregnancy. These were attributed to
      peptic ulcer and an iron supplement given, without investigation. Gastroscopy was
      performed only at 32 weeks of gestation, when the patient had heavy hematemesis.
      Biopsy confirmed the diagnosis of poorly differentiated adenocarcinoma of the
      stomach. Cesarean section was performed after steroid therapy. Advanced stomach
      cancer with stomach perforation was found. Curative surgery was not possible. The
      patient died four weeks after delivery. CONCLUSION: Stomach cancer is a rare
      complication of pregnancy. Delay in diagnosis is commonly due to clinicians'
      reluctance to request diagnostic studies and the nonspecific symptoms of the
      disease. Early recognition and diagnosis are the only possibilities for a better
      outcome. Clinicians must be alert to this possibility and include this in the
      differential diagnosis of minor gastrointestinal discomfort during pregnancy.

PMID- 10589415
TI  - Cardiac tamponade as an unusual presentation of advanced breast cancer in
      pregnancy.
AB  - BACKGROUND: Breast cancer is the most commonly diagnosed cancer in pregnancy.
      Though the prognosis by stage is not different from that in nonpregnant women, it
      is more likely to present at an advanced stage in pregnancy. CASE: A 28-year-old
      primigravida presented with dyspnea and pleuritic chest pain. The workup revealed
      cardiac tamponade. Pericardiocentesis and subsequent pericardial window were
      performed. Cytology of the pericardial fluid revealed poorly differentiated
      adenocarcinoma. Ultrasonography displayed a right breast mass, and biopsy
      identified it as the primary source of the cancer. CONCLUSION: Cardiac tamponade
      is an unusual presentation of advanced breast cancer. To the best of our
      knowledge, it has not previously been described as occurring in pregnancy.

PMID- 10589416
TI  - Corticosteroids for vulvar lichen sclerosus.

PMID- 10589417
TI  - Isolation of target gene promoter/enhancer sequences by whole genome PCR method.

PMID- 10589418
TI  - In vivo footprinting using UV light and ligation-mediated PCR.

PMID- 10589419
TI  - Identification of DNaseI hypersensitive sites within nuclei.

PMID- 10589420
TI  - Analysis of in vivo methylation.

PMID- 10589421
TI  - Detection of transcription factor partners with a yeast one hybrid screen.

PMID- 10589422
TI  - Inverse PCR (IPCR) for obtaining promoter sequence.

PMID- 10589423
TI  - PCR-directed linker scanning mutagenesis.

PMID- 10589424
TI  - Transfection technologies.

PMID- 10589425
TI  - The use of particle-mediated gene transfer for the study of promoter activity in
      somatic tissues.

PMID- 10589426
TI  - Optimizing electroporation conditions for the transformation of mammalian cells.

PMID- 10589427
TI  - Calcium phosphate transfection of mammalian cultured cells.

PMID- 10589428
TI  - DEAE-dextran transfection of mammalian cultured cells.

PMID- 10589429
TI  - Liposome-mediated transfection of mammalian cells.

PMID- 10589430
TI  - Assays for transcriptional activity based on the luciferase reporter gene.

PMID- 10589431
TI  - Transient transfection of Schneider cells in the study of transcription factors.

PMID- 10589432
TI  - Triplex-forming oligonucleotides and their use in the analysis of gene
      transcription.

PMID- 10589433
TI  - Expression and purification of histidine-tagged transcription factors.

PMID- 10589434
TI  - Generation of transcription factors in rabbit reticulocyte lysate depleted of
      endogenous DNA-binding protein.

PMID- 10589435
TI  - Electrophoretic mobility shift assays.

PMID- 10589436
TI  - In vitro promoter analysis using nuclear extracts and G-free cassette vectors.

PMID- 10589437
TI  - In vitro transcription using competitor oligonucleotides to deplete specific
      transcription factors.

PMID- 10589438
TI  - Computer software for eukaryotic promoter analysis.

PMID- 10589439
TI  - Use of visual analogue scale measurements (VAS) to asses the effectiveness of
      standardized Andrographis paniculata extract SHA-10 in reducing the symptoms of
      common cold. A randomized double blind-placebo study.
AB  - The objective of our study was to measure the effectiveness of Andrographis
      paniculata SHA-10 extract in reducing the prevalence and intensity of symptoms
      and signs of common cold as compared with a placebo. A group of 158 adult
      patients of both sexes completed the randomized double blind study in Valdivia,
      Chile. The patients were divided in two equal size groups, one of which received
      Andrographis paniculata dried extract (1200 mg/day) and the other a placebo
      during a period of 5 days. Evaluations for efficacy were performed by the patient
      at day 0, 2, and 4 of the treatment; each completed a self-evaluation (VAS) sheet
      with the following parameters: headache, tiredness, earache, sleeplessness, sore
      throat, nasal secretion, phlegm, frequency and intensity of cough. In order to
      quantify the magnitude of the reduction in the prevalence and intensity of the
      signs and symptoms of common cold, the risk (Odds Ratio = OR) was calculated
      using a logistic regression model. At day 2 of treatment a significant decrease
      in the intensity of the symptoms of tiredness (OR = 1.28; 95% CI 1.07-1.53),
      sleeplessness (OR = 1.71; 95% CI 1.38-2.11), sore throat (OR = 2.3; 95% CI 1.69
      3.14) and nasal secretion (OR = 2.51; 95% CI 1.82-3.46) was observed in the
      Andrographis SHA-10 group as compared with the placebo group. At day 4, a
      significant decrease in the intensity of all symptoms was observed for the
      Andrographis paniculata group. The higher OR values were for the following
      parameters: sore throat (OR = 3.59; 95% CI 2.04-5.35), nasal secretion (OR =
      3.27; 95% CI 2.31-4.62) and earache (OR = 3.11; 95% CI 2.01-4.80) for
      Andrographis paniculata treatment over placebo, respectively. It is concluded
      that Andrographis paniculata had a high degree of effectiveness in reducing the
      prevalence and intensity of the symptoms in uncomplicated common cold beginning
      at day two of treatment. No adverse effects were observed or reported.

PMID- 10589440
TI  - Balm mint extract (Lo-701) for topical treatment of recurring herpes labialis.
AB  - A double-blind, placebo-controlled, randomized trial was carried out with the aim
      of proving efficacy of standardized balm mint cream [active ingredient: 1% Lo-701
      -dried extract from Melissa officinalis L. leaves (70:1)] for the therapy of
      herpes simplex labialis. Sixty six patients with a history of recurrent herpes
      labialis (at least four episodes per year) in one center were treated topically;
      34 of them with verum and 32 with placebo. The cream had to be smeared on the
      affected area four times daily over five days. A combined symptom score of the
      values for complaints, size of affected area and blisters at day 2 of therapy was
      formed as the primary target parameter. There was a significant difference in the
      values of the primary target parameter between both treatment groups: verum 4.03
      +/- 0.33 (3.0); placebo 4.94 +/- 0.40 (5.0); values given are mean +/- SEM
      (median) of the symptoms score on day 2 of therapy. The tested formulation is
      effective for the treatment of herpes simplex labialis. The significant
      difference in the combined symptom score on the second day of treatment is of
      particular importance having in mind that the complaints in patients suffering
      from herpes labialis are usually most intensive at that time. In addition to the
      shortening of the healing period, the prevention of a spreading of the infection
      and the rapid effect on typical symptoms of herpes like itching, tingling,
      burning, stabbing, swelling, tautness and erythema, the balm mint cream has a
      further advantage. The different mechanism of action of the balm mint extract
      rules out the development of resistance of the herpes virus. Some indication
      exists that the intervals between the periods with herpes might be prolonged with
      balm mint cream treatment.

PMID- 10589441
TI  - Thermogenic effects of commercially available plant preparations aimed at
      treating human obesity.
AB  - Different commercially available plant preparations have been claimed to have
      anti-obesity action. We investigated the acute effects of oral administration of
      12 of these preparations in non-obese women and men. No significant increase in
      energy expenditure (EE) has been noted after treatment with any of these
      preparations. No change in respiratory quotient (RQ) was shown, except after
      treatment with mate (Ilex paraguariensis) extract, where a drop in RQ was
      observed, indicating a rise in the proportion of fat oxidized. The results
      suggested the poor potential of these plant preparations in the treatment of
      obesity, except possibly for the mate extract. Further studies are required to
      explore the influence of higher dosages of these preparations as well as chronic
      administration in man.

PMID- 10589442
TI  - Urinary metabolites of flavonoids and hydroxycinnamic acids in humans after
      application of a crude extract from Equisetum arvense.
AB  - Flavonoids and hydroxycinnamic acids are polyphenolic compounds present in our
      daily diet in form of tea and vegetables as well as in herbal remedies used in
      phytomedicine. A wide range of in-vitro activities, in particular their
      antioxidant properties, have been studied intensively. However, in-vivo-data on
      absorption, bioavailability and metabolism after oral intake are scarce and
      contradictory. In order to examine the metabolism and renal excretion of these
      compounds a standardized extract from horsetail (Equisetum arvense) was
      administered to 11 volunteers following a flavonoid-free diet for 8 d. 24 h urine
      samples were collected and analyzed by HPLC-DAD. The putative quercetin
      metabolites, 3,4-dihydroxyphenylacetic acid or 3,4-dihydroxytoluene could not be
      detected in urine in any sample. The endogenous amount of homovanillic acid,
      generally regarded as one of the main quercetin metabolites, was 4 +/- 1 mg/d and
      did not increase significantly. However, hippuric acid, the glycine conjugate of
      benzoic acid, increased twofold after drug intake. Thus, the degradation to
      benzoic acid derivatives rather than phenylacetic acid derivatives seems to be a
      predominant route of metabolism. The results of this pilot study give rise to
      additional, substantial pharmacokinetic investigations in humans.

PMID- 10589443
TI  - Effect of crude extract of Stevia rebaudiana on renal water and electrolytes
      excretion.
AB  - To evaluate the effect of crude extract of Stevia rebaudiana on renal water, Na+
      and K+ excretion, male Wistar rats (250-350 g each) under antidiuresis or water
      diuresis conditions, were evaluated. During intravenous infusion of the extract
      (0.05 mg/min/100 g) no significant differences were detected in mean arterial
      pressure or renal hemodynamics parameters. In contrast, fractional water and
      sodium excretion and solute clearance increased significantly, in both groups of
      animals. In antidiuresis rats the extract significantly increased reabsorption of
      water by the collecting duct and in water diuresis animals the extract
      significantly increased free water clearance. The data suggest preferential
      action of the extract in the proximal tubular cells involved with salt transport
      mechanism.

PMID- 10589444
TI  - Lipoxygenase inhibitors in the seeds of Aframomum danielli K. Schum
      (Zingiberaceae).
AB  - Alcohol and petrol extracts of the seeds of Aframomum danielli inhibit the soya 5
      lipoxygenase enzyme and thus may show antiinflammatory activity. Compounds
      isolated from the active fractions were shown to be long chain polyprenyl
      benzoquinone derivatives. Phytylplastoquinone was isolated from the petrol
      extract and plastoquinone-7 (heptaplastoquinone) from the alcohol extract. The
      presence of these two known benzoquinones in A. danielli and their ability to
      inhibit 5-lipoxygenase are reported here for the first time.

PMID- 10589445
TI  - Lipoprotein lipase activation by red ginseng saponins in hyperlipidemia model
      animals.
AB  - The effect of ginseng saponins isolated from red ginseng (a steamed and dried
      root of Panax ginseng) has been studied in a cyclophosphamide (CPM)-induced
      hyperlipidemia model in fasted rabbits. In this model, chylomicrons and very low
      density lipoprotein (VLDL) accumulation was known to occur as a result of
      reduction in lipoprotein lipase (LPL) activity in the heart and heparin
      releasable heart LPL. Oral administration of ginseng saponins at a dose of 0.01
      g/kg for 4 weeks was found to reverse the increase in serum triglycerides (TG)
      and concomitant increase in cholesterol produced by CPM treatment, especially in
      chylomicrons and VLDL. In addition, ginseng saponins treatment led to a recovery
      in postheparin plasma LPL activity and heparin-releasable heart LPL activity,
      which were markedly reduced by CPM treatment. In rats given 15% glycerol/15%
      fructose solution, postheparin plasma LPL activity declined to two third of
      normal rats, whereas ginseng saponins reversed it to normal levels. In the
      present study we first demonstrated that ginseng saponins sustained LPL activity
      at a normal level or protected LPL activity from being decreased by several
      factors, resulting in the decrease of serum TG and cholesterol.

PMID- 10589446
TI  - The antiinflammatory activity of Icacina trichantha tuber.
AB  - Five fractions (hexane, chloroform, ethylacetate, methanol and water) of Icacina
      trichantha tuber were obtained by gradient solvent extraction and tested for
      their ability to inhibit the Croton oil-induced ear edema in mice. The most
      active fraction was the chloroform one which significantly inhibited ear edema in
      a dose-dependent manner, showing an ID50 (dose giving 50% edema inhibition) of
      107 micrograms/cm2. The ID50 of the reference drug indomethacin was 93
      micrograms/cm2. The chloroform fraction significantly reduced also the
      carrageenin-induced paw edema in rats, after oral adiminstration: 50, 100 or 200
      mg/kg of the fraction reduced the global edematous response by 15, 20 or 34%,
      whereas 10 mg/kg of indomethacin induced 40% inhibition.

PMID- 10589447
TI  - Rhamnopyranosylgalactofuranan, a new immunologically active polysaccharide from
      Thamnolia subuliformis.
AB  - A complex polysaccharide, Ths-3, consisting mainly of rhamnopyranosyl and
      galactofuranosyl units, has been isolated from the water extract of the lichen
      Thamnolia subuliformis using ethanol fractionation, dialysis, ion-exchange
      chromatography, gel filtration and preparative GP-HPLC. The mean M(r) of Ths-3
      was determined to be 1450 kD, and the monosaccharide composition is
      gal/rha/glc/xyl/man in the ratio of 40:31:13:10:6. The structure of Ths-3 was
      further elucidated by methylation analysis by GC-MS and NMR spectroscopy and
      found to be basically composed of (1-->3)-linked beta-D-galactofuranosyl units
      with branches on C6, and rhamnosyl units being predominantly (1-->2)-linked with
      branches on C3 and C4, while some units are (1-->3)-linked. Glucose, mannose and
      galactofuranose are found as terminal units and glucose and mannose are also (1-
      >4)-linked, while xylose is only present as terminal units. The trisaccharide
      xylglcglc was detected after partial hydrolysis of the polysaccharide. The
      immunomodulating activity of Ths-3 was tested in an in vitro phagocytosis assay
      and the classical anticomplementary assay, and proved to be active in both tests.
      The authors suggest the trivial name thamnolan for Ths-3.

PMID- 10589448
TI  - Cytotoxicity of alkylphenols from Ginkgo biloba.

PMID- 10589449
TI  - Inhibition of haloperidol-induced catalepsy in rats by root extracts from Piper
      methysticum F.

PMID- 10589450
TI  - Plant adaptogens. III. Earlier and more recent aspects and concepts on their mode
      of action.
AB  - Stimulus-response coupling systems responsible for defence and adaptation of
      organism to stressors are multi-target and very complicated pharmacological
      systems, including the neuroendocrine (stress) and immune system. The mode of
      action of adaptogens is basically associated with the stress-system
      (neuroendocrine-immune complex) and can be directed on the various targets of the
      system involved in regulation (activation and inhibition) of stimulus-response
      coupling. However, clinical studies performed according to the most modern
      standards are quite limited. On the other hand there is an extensive amount of
      clinical experience and also established use in self care etc. These aspects are
      planned to be dealt within a subsequent article which will be devoted to the
      application in three areas: self care, adjuvants in medicine and curative action
      in some diseases. At this stage, nevertheless, it seems possible to define some
      most important "stress-markers" for evaluation of efficiency of adaptogens in
      experimental and clinical pharmacological studies. They can be both activating
      (catecholamines, LT-s, cytokines, NO, etc.--"switch on" system--which activates
      energetic and other resources of the organism), and deactivating (corticosteroids
      and PGE2-endogenous mediators of cellular communications, which protect cells and
      whole organism from overreacting to the activating messengers--"switch off"
      system) stress-messengers. The balance between the activities of the "switch on"
      and "switch off" systems reflects the well being of the organism. It could be
      established on different levels of the homeostasis (heterostasis) with different
      levels of the sensitivity to stressors (Figure 8). The response of stress system-
      "reactivity" is different at the various levels of heterostasis and depends on
      adaptation--capacity of the organism (or a cell) to protect itself. In the
      process of adaptation to stressor's effects the basal levels mediators of switch
      on (e.g. NO) and switch of (e.g. cortisol) systems are increasing but their
      balance (the ratio) does not change. In other words, adaptogens increase the
      capacity of stress system to respond to external signals at the higher level of
      the equilibrium of activating and deactivating mediators of stress response.
      Consequently, plant adaptogens can be defined as "smooth" pro-stressors which
      reduce reactivity of host defense systems and decrease damaging effects of
      various stressors due to increased basal level of mediators involved in the
      stress-response. In further studies of adaptogens it seems important to find
      correlation between adaptogenic activity (a decrease in the "reactivity" of the
      organism--the basal level of activating and deactivating messengers: ILs, LTB4,
      NO, PGE2, cortisol, but not their ratio) and their therapeutic efficiency
      (symptomatic evaluation).

PMID- 10589451
TI  - Integrating training systems for occupational health and safety, quality and
      environmental management.
AB  - Quality, occupational health and safety, and environmental issues are three key
      areas that, along with productivity and service, must be managed effectively.
      Organizations face the need to develop integrated systems for the management of
      these areas. As organizations increasingly need to seek efficiencies, one field
      in which such integration can bring considerable gains is training. The present
      paper examines how the requirements for training in different areas overlap and
      how an integrated training program may be developed.

PMID- 10589452
TI  - The facility between certification and accreditation.
AB  - The market, and therefore the inevitable need to produce and sell products and
      services, encourages companies to try to ensure that they themselves and their
      products can be recognized and characterized. It thus follows that the producer's
      activities must be qualified with special certificates. Over the last few years
      the number of companies wishing to qualify their organization and their products
      has increased considerably. This phenomenon also affects organizations that
      conduct research, i.e., those defined as contract research organizations, which
      provide a research service to a limited, demanding clientele, and that have long
      seen in these certifications not only simple compliance with their legal
      obligations, but also a tool for persuading the market of the validity of their
      "products." For management it may, at times, be difficult to find the way through
      the jungle of certifications because the purpose, aims and actions related to the
      different types of attestation (accreditation, certification, registration, etc.)
      are often little known or misunderstood. An investigation has been carried out to
      clarify the whole scenario of necessary, possible, and useful certificates and
      qualifications for research organizations today, as well as the terminology used.
      In addition, an attempt was made to find possible similarities between the
      various recognitions analyzed.

PMID- 10589453
TI  - Applying total quality management techniques to improve software development.
AB  - Total Quality Management (TQM) is a new management philosophy and a set of
      guiding principles that represent the basis of a continuously improving
      organization. This paper sheds light on the application of TQM concepts for
      software development. A fieldwork study was conducted on a Lebanese software
      development firm and its customers to determine the major problems affecting the
      organization's operation and to assess the level of adoption of TQM concepts.
      Detailed questionnaires were prepared and handed out to the firm's managers,
      programmers, and customers. The results of the study indicate many deficiencies
      in applying TQM concepts, especially in the areas of planning, defining customer
      requirements, teamwork, relationship with suppliers, and adopting standards and
      performance measures. One of the major consequences of these deficiencies is
      considerably increased programming errors and delays in delivery. Recommendations
      on achieving quality are discussed.

PMID- 10589454
TI  - Essentials of quality in "the gold standard veterinary clinical trial".
AB  - Quality Assurance (QA) has played a pivotal role within Good Laboratory Practice
      (GLP) since its inception in 1976. GLP is now recognized as a quality standard,
      as can be seen from the introductory statement of the recently issued OECD
      Principles of GLP (revised in 1997) that clearly state "GLP is a quality system
      concerned with the organisational process and the conditions under which non
      clinical health and environmental safety studies are planned, performed,
      monitored, recorded, archived and reported". We can, therefore, see a close
      comparison between GLP compliance and the ISO/EN accreditation systems that have
      been adopted by other institutes on a worldwide basis.

PMID- 10589455
TI  - Gauge Capability Analysis: classical versus ANOVA.
AB  - In order to use Statistical Process Control (SPC) efficiently and effectively in
      today's modern industrial environment, it is essential to analyze and determine
      the extent of gauge variability. The variation that occurs on a control chart is
      essentially a combination of product and gauge variation. Studies of measurement
      or gauge variation are absolutely a waste of resources unless they can lead to a
      substantial reduction in process variability or to an improvement in process and
      product quality. The goal of gauge capability analysis is an understanding and
      quantification of the various sources of variability present in the measurement
      process. The purpose of this paper is to illustrate the fundamental difference
      between Classical Gauge Capability Analysis (CGCA) and the use of a more powerful
      approach based on the Analysis of Variance (ANOVA). The author recommends that
      the latter approach is more useful and powerful in the presence of an interaction
      between the parts and the operators involved in the measurement process. An
      example is illustrated in the paper to demonstrate the two approaches.

PMID- 10589456
TI  - Factor structure of satisfaction in daily life of elderly residents in
      Kitakyushu.
AB  - The purpose of this study was to investigate what items elderly persons living at
      home consider important for satisfaction in daily life and what factor structure
      is obtained by a principal components analysis. Two percent of the residents 60
      years old or over of Yahatanishi Ward, Kitakyushu, were randomly sampled as
      subjects. A questionnaire asking residents to select items considered important
      in daily life was sent by mail, and 722 responses (72.5%) were eligible for
      analysis. "Health", "social security and pension" and "self-care" were considered
      important in daily life with the highest selection rates. A five-factor solution
      for 25 items with a selection rate greater than 4.5% was obtained by an oblique
      rotated principal components analysis: "health and disability", "social
      environment and activity", "socio-economic condition", "emotional stability in
      marital and family life" and "social intercourse and companionship". These
      factors appeared to be the fundamental framework of the subjective domain of
      health-related quality of life of elderly persons living at home.

PMID- 10589457
TI  - A simple estimation method for the embryonic toxicity of plastic wrapping sheets
      using an egg shell-free culture system of chick embryos.
AB  - To estimate the embryonic toxicity of food wrapping films, the shell-free chick
      embryos were cultured using plastic wrapping sheets like a suspending hammock.
      Polyethylene (PE) wrapping sheets with no additives showed much higher
      survivability than polyvinylchloride (PVC) wrapping sheets including
      plasticizers. Furthermore when a PVC wrapping sheet was autoclaved at 110 degrees
      C for 30 min, the embryonic survivability significantly decreased compared with
      the untreated PVC wrapping sheet. These observations suggest that the egg shell
      free culture method using a plastic wrapping sheet is a useful estimation method
      for the embryonic toxicity of food wrapping film.

PMID- 10589458
TI  - The occurrence of polymorphism of mannose 6-phosphate/insulin-like growth factor
      2 receptor gene in laboratory and wild rats.
AB  - Carcinogen-resistant inbred DRH rat strain was established from closed colony
      Donryu rats in the presence of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB).
      Despite using 3'-Me-DAB during the stage of selection, the DRH rats developed
      normally and did not show any spontaneous tumor at over 1 year of age. In the
      present study, we examined the polymorphism in mannose 6-phosphate/insulin-like
      growth factor 2 receptor (M6p/Igf2r) gene and found that the DRH rat showed CCC
      (Proline)-type polymorphism in exon 48 and the Donryu rat had GCC (Alanine)
      sequence. Since the DRH rat was developed from the Donryu rat, we examined
      whether this polymorphism in exon 48 of M6p/Igf2r gene was due to mutation that
      occurred at the stage of selection in the presence of 3'-Me-DAB, using several
      other laboratory and wild rats. We detected the presence of polymorphism at the
      same site of the M6p/Igf2r gene among these rats. It is likely that the
      polymorphism in exon 48 of the M6p/Igf2r gene is present broadly in rats since
      ancient times and not due to the mutation during the course of selection unless
      this site is a hot spot for chemical carcinogens.

PMID- 10589459
TI  - Therapeutic effect of topical calcium gluconate for hydrofluoric acid burn--time
      limit for the start of the treatment.
AB  - BACKGROUND: There are few studies regarding the time-dependent effectiveness of
      topical calcium gluconate treatment for the experimental hydrofluoric acid (HF)
      burn. METHODS: For producing a HF-burn, a drop of 46% or 23% HF solution was put
      on the back of rats for 3 minutes followed by washing with tap water. Calcium
      gluconate jelly or ointment was then applied to the burn area at various time
      intervals. The ointment was applied once a day thereafter. RESULTS: The topical
      calcium gluconate treatment was much more effective if the application was
      started within 3 hours. On the other hand, if the application was started after 6
      hours or more, there was no difference between the groups and the non-treatment
      groups. CONCLUSIONS: It is suggested that practitioners should be ready to
      prepare quickly the calcium gluconate ointment to treat a HF burn, since the
      calcium gluconate ointment is not commercially available in Japan.

PMID- 10589460
TI  - [Clinical usefulness of half-dose gadolinium-enhanced MR angiography of portal
      venous system (MR portography)--combined use with conventional dynamic MR
      imaging].
AB  - The clinical usefulness of half-dose Gadolinium-enhanced MR portography combined
      with the conventional full-dose dynamic MR imaging was evaluated on normal
      volunteers and patients. Half-dose MR portography was performed immediately
      following conventional full-dose Gd-enhanced dynamic MR imaging. The
      visualization of the extrahepatic portal system was either good or excellent in
      most cases excluding the splenic vein which was poor in 20.7%. That of the right
      and left main portal branches was also excellent. As for segmental branches, the
      visualization was poor of the left lobe. The comparison with digital subtraction
      angiography showed that the visualization of the right and left main portal
      branches was mostly equal. That of the splenic vein alone was worse on MR
      portography. We conclude that half-dose Gadolinium-enhanced MR portography is
      useful for the overall assessment of the portal venous system and can be added to
      the conventional dynamic MR imaging.

PMID- 10589461
TI  - [A family of hereditary neuropathy with liability to pressure palsies with a
      proband who developed right and left foot drop successively following the left
      radial nerve palsy].
AB  - A 41-year-old man developed multifocal mononeuropathies manifesting right and
      left foot drop successively, following the left radial nerve palsy as an initial
      symptom. Based on the neurological findings and the results of the genetic study
      of peripheral myelin protein (PMP) 22 gene and the histological study of the
      sural nerve on biopsy, the diagnosis of hereditary neuropathy with liability to
      pressure palsies (HNPP) was made. Two asymptomatic carriers were found among his
      family members based on the genetic study. The diagnosis of HNPP can be
      definitely established by the genetic study and this disease is relatively rare.
      In this report it is important to note that there are a few patients who show
      radial nerve palsy as an initial symptom, that we should carefully study the
      family members to obtain the prevalence of HNPP because asymptomatic carriers may
      be present, and that the carriers should be advised to avoid strenuous exercises
      and works which may produce excessive extension or compression of nerve trunks
      with the subsequent development of clinical symptoms.

PMID- 10589462
TI  - [Procainamide-induced skin eruption associated with disseminated intravascular
      coagulation in a patient with sustained ventricular tachycardia].
AB  - A 70-year-old man, who had sustained ventricular tachycardias following a
      previous anterior myocardial infarction, suffered from skin eruptions and
      abnormal blood tests after 10 days following the oral administration of 1500
      mg/day of procainamide. These abnormalities disappeared early after the
      discontinuation of oral procainamide. However, similar skin eruptions exhibited
      again when the procainamide was resumed. These results suggest that oral
      procainamide therapy induces skin eruptions and serious abnormal blood tests in
      the patient. No reports have suggested such a serious early complication by
      procainamide therapy. Careful follow-up is needed after the administration of
      oral procainamide therapy.

PMID- 10589463
TI  - [Progress in research of the blood coagulation system].
AB  - Blood coagulation is an amplification system consisting of reactions between
      enzymes and zymogens. It has been illustrated as a cascade model. However, the
      exact mechanism by which haemostasis is achieved under physiological conditions
      remains to be clarified. The solving of structure-function relation of each
      coagulation factor, analysis of the enzymological characteristics of each
      reaction, analysis of the regulation mechanism of the reactions and
      identification of novel factors involved in coagulation reactions contribute to
      the understanding of this complex system. Based on these findings, some new
      conceptions of blood coagulation are proposed. In the model introduced in this
      review, the extrinsic pathway and the intrinsic pathway of the 'classical'
      cascade model of the blood coagulation system could not be separated, and the
      suppression of fibrinolysis by TAFI (thrombin activatable fibrinolysis inhibitor)
      during coagulation reactions is thought to be a critical process for effective
      haemostasis.

PMID- 10589464
TI  - [Development of instruments for experimental research by the UOEH Research
      Developmental Facility --Wood particle producer and electric-powered model of
      knee joint movement].

PMID- 10589465
TI  - Equine cardiac disease. Clinical pharmacology and therapeutics.
AB  - Cardiac disease is often life-threatening and challenging to treat. Prolonged
      therapy is indicated in many cases, which can lead to problems with treatment
      costs, owner compliance, and potential drug toxicity. Many therapies are
      empirical or based on data from other species because of a lack of well-designed
      prospective clinical trials in horses. This article reviews the clinical
      pharmacology and therapeutics of heart failure, cardiac arrhythmias, myocardial
      disease, endocarditis, and pericardial disease.

PMID- 10589466
TI  - Gastrointestinal pharmacology.
AB  - Diseases of the gastrointestinal tract that require pharmacologic management,
      usually in combination with other treatments, are gastric ulcers (omeprazole and
      others), colic (laxatives, analgesics), diarrhea (antibiotics, protectants and
      absorbents, glucocorticoids, motility inhibitors), reperfusion injury,
      postoperative ileus (prokinetic drugs), and adhesions. There is growing evidence
      that nonsteroidal anti-inflammatory drugs can alter important physiologic
      properties of the intestine; however, these drugs are valuable analgesics for
      horses and their use should be tempered with an awareness of their harmful
      effects. The role of antibiotics in treating gastrointestinal disease is
      controversial, but their ability to induce life-threatening diarrhea is well
      known and invites caution and defensible use of these drugs in horses.

PMID- 10589467
TI  - Treatment and control of gastrointestinal parasites.
AB  - Routine anthelmintic treatments are one of the most important components of an
      equine wellness program used by horse owners and veterinarians today. Thirteen
      different compounds are available in the United States in the treatment of
      gastrointestinal parasites, most of which are available over the counter. As a
      result, there is a decreased reliance on the veterinarian to perform routine tube
      dewormings. Therefore, the future of the veterinarian's role in the management of
      gastrointestinal parasites is likely to be in the consultation and design of
      parasite control programs. With this in mind, this article covers all of the
      equine anthelmintics and their clinical applications.

PMID- 10589468
TI  - Clinical pharmacology of nervous system diseases.
AB  - The well-developed defense barriers of the CNS and the expense of drug therapy
      limit the pharmacologic options for the treatment of neurologic diseases in
      horses. New approaches to controlling inflammation in the CNS are improving the
      outcomes of bacterial meningitis. The appropriate treatment of EPM remains
      controversial. More research is needed to evaluate the pharmacokinetics and
      pharmacodynamics of drugs in the CNS of the horse. Behavioral pharmacology has
      become fashionable in human and small animal medicine, but it needs to be
      evaluated for the potential of unethical use in performance horses.

PMID- 10589469
TI  - Therapeutics of musculoskeletal disease in the horse.
AB  - Therapeutic medications play a crucial role in the successful therapy of many
      musculoskeletal diseases that occur in horses. For example, appropriate
      antibiotic therapy is extremely important in the treatment of diseases caused by
      infections with microorganisms such as botulism, tetanus, osteomyelitis, and
      muscle abscesses. In addition, numerous prescription medications and nutritional
      supplements are available for the treatment of osteoarthritis in horses. Many of
      these agents currently on the market fall into a new class of drugs called SADMO
      agents. Unfortunately, the efficacy and mechanism(s) of action for many of these
      agents have not been well defined. There does exist a fair amount of data
      indicating that the parenterally administered compounds HA and PSGAGs, commonly
      used to treat osteoarthritis, can decrease the severity of clinical signs and
      perhaps slow the progression of disease. Although there are fewer data available
      to support the efficacy of orally administered SADMO agents, these compounds are
      used commonly by lay people as osteoarthritis therapies. Finally, pharmaceutical
      agents such as acetozolamide can play an important role in the management of the
      inherited HYPP condition in horses.

PMID- 10589470
TI  - Modes of local drug delivery to the musculoskeletal system.
AB  - A number of methods for the local delivery of drugs to musculoskeletal tissues in
      the horse are now available. Further research is required to document the
      disposition of drugs delivered by such methods and to correlate this information
      with efficacy. Perhaps the greatest potential area for the methods discussed is
      the treatment of synovial and bone infections. To be able to provide high and
      sustained therapeutic concentrations of antimicrobials to the site of infection
      should increase the chances of success in such cases. These methods of drug
      delivery need to be used in conjunction with other management procedures,
      however, including bacterial culture and sensitivity procedures, systemic
      antimicrobials, surgical drainage, removal of dead bone or surgical implants,
      establishment of fracture stability, use of autogenous bone grafts, systemic
      NSAIDs, and rest.

PMID- 10589471
TI  - Equine infectious keratitis.
AB  - Corneal ulcers are one of the most common ocular disease presentations in the
      horse. With the use of correct diagnostic techniques and selection of an
      appropriate treatment regimen, most cases result in a satisfactory outcome. The
      eye does not respond well to inflammation, and in complicated ulcers, this should
      be managed aggressively using systemic NSAIDs with a high priority assigned to
      removing the infectious agent. Care needs to be taken to avoid topical or
      systemic corticosteroid use for the treatment of equine ocular disease, however,
      unless the clinician is completely sure that the corneal disease is not caused by
      an infectious process. The use of combination corticosteroid-antibiotic
      ophthalmic preparations without an appropriate treatment rationale can result in
      doing more harm than good. It is important to have a treatment plan and to
      monitor the elected treatment regimen. The clinician should decide on some
      objective criteria at initiation of treatment so that any changes are made
      rationally. This approach should also include consideration of early referral of
      the eye's care to a veterinary ophthalmologist.

PMID- 10589472
TI  - Renal pharmacology.
AB  - Pharmacologic treatment of diseases of the urinary tract of horses is limited to
      administration of antibiotics for treatment of urinary tract infections (UTIs),
      administration of drugs that alter urine pH, administration of drugs that alter
      bladder smooth muscle function or urethral sphincter tone, and treatment of acute
      renal failure. The indications, mechanisms of action, pharmacokinetic
      characteristics, and adverse effects of these agents in each of these groups are
      discussed in this article. The use of the agents is discussed within the context
      of the pathophysiology of the disease being treated.

PMID- 10589473
TI  - Equine respiratory pharmacology.
AB  - Differentiation of diseases of the equine respiratory tract is based on history,
      clinical signs, auscultation, endoscopy, imaging, and sampling of airway exudate.
      Upper respiratory therapies include surgical correction of airway obstructions;
      flushing of localized abscesses (strangles), guttural pouch disease, or
      sinusitis; and oral or parenteral antibiotic and anti-inflammatory therapy if
      deemed necessary. Pneumonia usually is treated with antimicrobials, anti
      inflammatories, and bronchodilators. Pleural drainage is indicated if significant
      pleural effusion is present. The most commonly used therapies for early
      inflammatory and chronic allergic obstructive conditions include bronchodilators
      and anti-inflammatories. Acute respiratory distress, particularly acute pulmonary
      edema, is treated with diuretics (usually furosemide), intranasal oxygen,
      bronchodilators, corticosteroids, and alleviation of the underlying cause.
      Furosemide also had been used in North America as a race-day preventative for
      exercise-induced pulmonary hemorrhage (EIPH), but recent data have shown that
      furosemide may be a performance-enhancing agent itself.

PMID- 10589474
TI  - Equine reproductive pharmacology.
AB  - This article reviews therapies and strategies commonly used to treat diseases of
      the mare's genital tract and modulate the reproductive cycle of the mare. Many
      reproductive treatments are based on historical use and empirical evidence rather
      than well controlled clinical studies. This article attempts to present practical
      information in a summary form while highlighting the need for continued research
      documenting the efficacy and safety of reproductive therapies.

PMID- 10589475
TI  - Analgesia.
AB  - Critical to reducing patient morbidity as well as heightened ethical awareness,
      alleviation of pain in animals has become integral to medical case management and
      surgical procedures. Pharmacotherapy is directed at peripheral nociceptors,
      primary and secondary spinal neurons, and pain-processing areas in the CNS.
      Accordingly, three primary pharmacologic strategies have evolved: drugs that bind
      to and activate opioid receptors, drugs that bind to and activate alpha 2
      receptors, and drugs that reduce de novo prostaglandin synthesis. In horses, the
      two predominant types of pain encountered are musculoskeletal and visceral pain.
      Several factors must be considered when devising a therapeutic strategy,
      including the etiology of the painful event, desired duration of therapy (acute
      vs chronic), desire for sedation, and potential side effects and toxicity.
      Opioids and alpha 2 agonists are particularly effective for visceral pain
      associated with colic. Butorphanol remains the only commercially available opioid
      and provides superior visceral analgesia compared with pentazocine or flunixin
      meglumine but not compared with the alpha 2 agonists. The behavioral changes such
      the sedative effects of alpha 2 agonists and the increased locomotion and CNS
      excitability seen with some opioids are important considerations when these
      agents are used as analgesics. NSAIDs may be considered for visceral pain therapy
      also, especially pain associated with an inflammatory component or endotoxemia.
      In particular, flunixin meglumine and ketoprofen provide prolonged analgesia and
      suppress the effects of endotoxin. Long-term therapy of musculoskeletal diseases
      usually necessitates chronic NSAID use. Although many NSAIDs are now available in
      approved equine formulations, there remain some important differences among
      NSAIDs for the practitioner to consider when choosing an analgesic. NSAIDs differ
      in their ability to ameliorate pyrexia, affect platelet function, alleviate pain,
      and reduce inflammation. For ease of administration, those available for oral use
      include phenylbutazone, meclofenamic acid, flunixin meglumine, and naproxen. All
      are potentially ulcerogenic, and poor tolerance to one may necessitate switching
      to another with a better toleration profile or to drug from a different analgesic
      class.

PMID- 10589476
TI  - Pharmacologic considerations in the treatment of neonatal septicemia and its
      complications.
AB  - This article focuses on the pharmacologic properties of drugs commonly used in
      the treatment of neonatal septicemia and its complications. Rational therapy
      demands an awareness of not only the pharmacology of individual drugs but also
      the interactions and anticipated fate of such drugs in the rapidly changing
      physiologic environment of the neonate. Further research in the area of equine
      neonatal pharmacology should greatly assist our understanding of the impact of
      the disease state on the unique physiology of the newborn and should allow us to
      better predict the ultimate fate of drugs commonly used for such purposes.
      Careful dosing and close monitoring of pharmacologic effects are critical for a
      successful outcome. In the future, newer therapeutic strategies that are safe and
      efficacious may provide a means to circumvent many of the problems currently
      encountered with treating the septicemic newborn foal.

PMID- 10589477
TI  - Formulary of common equine drugs.
AB  - This article presents in easily accessible form a collection of drug names and
      dose rates for the drugs recommended or referred to by the authors of the
      individual articles in this issue. Although the formulary provides
      recommendations for drug use, the reader is cautioned that the responsibility for
      the choice of agent, formulation, dose, and dose interval lies with the
      clinician. The author also addresses regulations that govern the use of drugs in
      competition horses.

PMID- 10589478
TI  - Determination of emamectin benzoate in medicated fish feed.
AB  - A method was developed to quantitate emamectin benzoate in fish feed at levels
      between 5 and 15 ppm. The active ingredient is extracted from 20 g medicated feed
      into aqueous-methanolic solvent by overnight shaking. A solid-phase extraction
      procedure using a 2 g C18 cartridge is then used to concentrate the active
      residue and remove interfering matrix components. The extracted drug and internal
      standard are eluted from the cartridge, evaporated to dryness, and reconstituted
      in methanol. A control feed sample and fortified control working standard are
      simultaneously prepared. Remaining interferences and sample analysis are further
      separated on a gradient liquid chromatographic system. Recovery of emamectin
      benzoate from fortified feeds ranged from 97 to 100%, with a coefficient of
      variation (CV) of 1.2%. Determination of emamectin benzoate in medicated feeds
      resulted in CVs ranging from 2.3 to 4.2% and recoveries of 88 to 98% of label
      claim.

PMID- 10589479
TI  - Cadmium levels in feed components and kidneys of growing/finishing pigs.
AB  - Cadmium (Cd) concentrations in pig feeds (one control feed and one feed with
      reduced nitrogen content), straw, water, and pig kidney cortex were determined in
      2 breeds of growing/finishing pigs (n = 96). The total Cd intake from feed was
      calculated. Feed mixtures and components, straw and kidney cortex samples, and
      certified reference samples were microwave-digested and analyzed by atomic
      absorption spectrometry with graphite furnace technique. Total Cd concentration
      in the control feed was 37.1 micrograms/kg wet weight (w.wt). The highest Cd
      levels were found in nonlocally produced feed components: vitamin-mineral
      mixture, lime, dicalcium phosphate, soybean meal, and rapeseed meal. These
      components contributed 70% of the Cd content in the feed. The main component,
      barley, which was locally produced, contributed 30% of the total Cd content in
      feed. The feed with reduced nitrogen content contained less soybean and rapeseed
      meal and a lower Cd level than the control feed. The Cd levels in kidney cortex
      varied from 38.0 to 105 micrograms/kg w.wt, with a mean level of 70.9
      micrograms/kg. The levels differed between breeds and feeds, but not between
      gender. There was a significant correlation between Cd level in kidney cortex and
      age at slaughter, with an increase of 2.8 micrograms/kg w.wt in the kidney for
      each additional week of survival. The contribution of Cd from nonlocally produced
      feed components could have environmental effects through application of farmyard
      manure to local soils.

PMID- 10589480
TI  - A new spectrophotometric method for the determination of dithianon in commercial
      formulations and its residues in foodstuffs.
AB  - A new, simple, and rapid spectrophotometric method for the microdetermination of
      dithianon, on the basis of its reaction with a dithiocarbamate, is described. The
      red color, which develops instantaneously when mixing the fungicide with the
      reagent in acetonitrile, is stable for at least 1 h and is measured at 520 nm.
      Beer's law is applicable up to 12 micrograms/mL dithianon concentration. The
      method has been successfully adapted to the analysis of the fungicide in
      commercial formulations and its residues on grains and apple (fruit and leaves).
      A photometric titration method for formulation analysis of the fungicide has also
      been developed.

PMID- 10589481
TI  - Liquid chromatographic determination of tylosin in mastitic cow's milk following
      therapy.
AB  - Liquid chromatographic analysis of milk samples from 6 cows treated with tylosin
      in a veterinary practice indicated that tylosin persisted in milk for more than 3
      days after the final treatment. The concentration of tylosin was not below the
      stated maximum residue limit (0.05 mg/kg). The milk from 3 cows being treated for
      mastitis catarrhalis chronica contained tylosin residues for 3.5 days after the
      last withdrawal time (72 h). No residue was detected in the milk of any animal 6
      days after cessation of therapy.

PMID- 10589482
TI  - Determination of sulfamethazine in milk by biosensor immunoassay.
AB  - A biosensor based on surface plasmon resonance (SPR) measurement was developed
      for use in an immunoassay for detection of sulfamethazine (SMZ) in milk. The
      biospecific surface was a carboxymethyl dextran-modified gold-surface sensor chip
      to which SMZ was covalently bound. The assay was based on inhibition of the
      binding of polyclonal antibodies to immobilized SMZ by SMZ in the sample. The SPR
      response changed inversely in relation to the antibiotic concentration in the
      sample. Calibration curves were constructed for SMZ in buffer and in milk at a
      concentration which included the maximum residue limit (0 to 200 micrograms/kg).
      The analysis time per sample varied from 8 to 30 min. Different flow rates and
      antibodies were modified alternatively during the study to assess their influence
      on the performance of the assay. The active antibody concentration was calculated
      at approximately 1880 and 180 nM for the antibody anti-SMZ 1 and the antibody
      anti-SMZ 2, respectively. No cross-reactivity of antibodies with other
      antibiotics was found. Under optimal conditions, the detection limits in milk for
      SMZ were 8 and 1.7 micrograms/kg, respectively, for antibody 1 and antibody 2, at
      a flow rate of 20 microL/min.

PMID- 10589484
TI  - Determination of oxytetracycline in bovine kidney and medicated milk replacer by
      liquid chromatography.
AB  - Improvements and optimization of AOAC INTERNATIONAL Official Method 995.09 for
      the detection of oxytetracycline in bovine kidney at the new U.S. tolerance of 12
      ppm are reported. Recoveries from kidney fortified at 4 concentrations over the
      range of 3-40 ppm averaged 84-98%. Results from the kidney of a calf fed
      medicated milk replacer containing oxytetracycline are also reported.
      Additionally, adaptation of this method to the detection of oxytetracycline in
      medicated milk replacer is discussed.

PMID- 10589483
TI  - Determination of propionylpromazine hydrochloride in formulation matrixes using
      reversed-phase ion-pair small bore liquid chromatography.
AB  - Propionylpromazine hydrochloride (PPZHCl) has been investigated for use with
      leghold traps to reduce the amount of self-inflicted trauma experienced by
      animals restrained by these traps. Three types of PPZHCl formulations made with
      Karo dark syrup, K-Y Jelly, and Vaseline were used in 2 types of tranquilizer
      trap devices (TTDs). A reversed-phase ion-pair liquid chromatography (LC) method
      using a small bore C18 column was used to: (1) determine the purity of the PPZHCl
      material used in these formulations, and (2) to determine the resulting PPZHCl
      content of each formulation. Analyte quantitation was done using UV absorption at
      280 nm. Regression analysis of calibration standard solutions indicated a linear
      and directly proportional relationship between analyte response and PPZHCl
      concentration over the range evaluated. Recovery data from: (1) Vaseline
      formulations containing 38.8, 16.2, and 8.78% PPZHCl were 104, 92.9, and 90.2%,
      respectively, (2) Karo dark syrup formulations containing 26.5, 18.1, and 10.3%
      PPZHCl were 97.7, 99.3, and 106%, respectively, and (3) K-Y Jelly formulations
      containing 33.0, 23.5, and 13.4% PPZHCl were 100, 99.4, and 88.7%, respectively.
      The relative standard deviation (RSD) values from triplicate analysis of these
      formulations ranged from 0.7 to 6.7%. The PPZHCl content from 9 manufactured
      TTDs, 3 for each formulation type, were analyzed in triplicate and produced RSD
      values ranging from 0.7-6.8%. These results indicate that the formulation
      extraction presented could be used to evaluate the PPZHCl content in TTDs prior
      to field use. The use of a small bore LC column reduced the amount of solvents
      consumed and hazardous waste generated, compared to sample analysis that uses a
      more conventional analytical LC column.

PMID- 10589485
TI  - Isolation of chloramphenicol from whole eggs by supercritical fluid extraction
      with in-line collection.
AB  - Egg consumption, at more than 65 billion per year in the United States,
      represents a potentially significant source of exposure to drug residues,
      particularly if the laying hens are treated with antimicrobial compounds or fed a
      diet containing medicated feed. Residues resulting from the use of
      chloramphenicol (CAP) is especially problematic if this compound is not used in
      accordance with national registration, e.g., for the control of Salmonella
      microorganisms in poultry. The most commonly used methods for the determination
      of CAP in biological samples require the use of large amounts of organic solvent.
      As a result, a less solvent intensive supercritical fluid extraction (SFE) method
      was developed for CAP in whole chicken eggs, and the results were compared with
      those for a solvent extraction procedure. In the SFE method, the egg sample is
      extracted with supercritical CO2 (without a modifier) at 10,000 psi (680 bar), 80
      degrees C, and an expanded gas flow rate of 3.0 L/min to a total volume of 150 L.
      The CAP is trapped in-line on a Florisil sorbent bed. The CAP is eluted post-SFE
      by using the liquid chromatographic mobile phase solvent (water-methanol), and
      determined on a C8 column with ultraviolet detection at 280 nm. Recovery from
      eggs fortified at the 10 ppb level (n = 6) was 81.2 +/- 4.3%. To obtain eggs
      containing incurred CAP, hens were given a single daily dose of 75 mg CAP (orally
      by gelatin capsule) for 2 consecutive days, and the eggs were collected over a 12
      day period. The mean value for "normally incurred" CAP in the eggs (n = 17)
      analyzed by SFE ranged from none detected to 174.5 ppb, with an overall mean of
      60.5 ppb, compared with a mean of 60.4 ppb for the solvent extraction method. No
      significant difference in results was found between methods. However, the SFE
      method is more rapid, uses less solvent, and gives recoveries similar to those
      for the solvent extraction method, making it ideal for regulatory monitoring.

PMID- 10589487
TI  - Determination of amoxicillin in trout by liquid chromatography with UV detection
      after derivatization.
AB  - A liquid chromatographic (LC) method based on solid-phase extraction was
      developed for determination of amoxicillin in muscle tissue of rainbow trout. The
      compound was extracted in an aqueous solution by precipitation of organic
      material with a mixture of sulfuric acid and sodium tungstate. The extract was
      processed by solid-phase extraction on an end-capped phenyl sorbent, and
      concentrated on a divinylbenzene-co-N-vinylpyrrolidone polymeric sorbent. The
      extract was derivatized and analyzed by reversed-phase gradient LC on a C18
      column with UV detection at 323 nm. The method detection limit was 2.9
      micrograms/kg. Mean recovery in muscle was 80.5% (range 10-200 micrograms/kg).
      The method was applied to fillets from trout offered feed containing amoxicillin
      in an aquaculture pilot plant. Amoxicillin was detected in muscle tissue shortly
      after administration but not 3 weeks later. The relative repeatability standard
      deviation for incurred residues in muscle tissue was 6.4% (range 11-143
      micrograms/kg).

PMID- 10589486
TI  - Multiresidue determination of abamectin, doramectin, ivermectin, and moxidectin
      in milk using liquid chromatography and fluorescence detection.
AB  - Abamectin, doramectin, ivermectin, and moxidectin are macrocyclic lactones
      derived from soil dwelling actinomycetes, and are very effective against
      nematode, insect, and arthropod infestations. These compounds, known as
      endectocides, have been approved for use in beef cattle in the United States;
      however, they are currently not approved for use in dairy cattle. Abamectin,
      doramectin, ivermectin, and moxidectin residues were isolated from milk by a
      series of liquid-liquid extraction steps, derivatized with trifluoroacetic
      anhydride, and determined by liquid chromatography with fluorescence detection.
      Recovery studies were performed in 2 laboratories. Recoveries of > 80% (1-30
      ng/mL) were achieved for all 4 compounds.

PMID- 10589489
TI  - Use of biogenic amines to evaluate spoilage in plaice (Pleuronectes platessa) and
      whiting (Merlangus merlangus).
AB  - Fish muscle decarboxylases generate biogenic amines during spoilage. We monitored
      spoilage in plaice and whiting by assaying biogenic amines represented by the
      amine index (AI), and by using expert assessors to determine a freshness index
      (FI) for each fish. First we characterized the assessor- and fish species-related
      effects on FI, and then we sought to correlate changes in AI and FI by
      statistical data analysis. We propose rejection limits on the basis of our
      findings.

PMID- 10589488
TI  - Rapid determination of citrinin in corn by fluorescence liquid chromatography and
      enzyme immunoassay.
AB  - A rapid assay procedure was developed for mycotoxin citrinin in corn using liquid
      liquid extraction (LLE) cartridges. Ground corn was extracted with methylene
      chloride and 0.5 N phosphoric acid. The extract was added to an LLE cartridge
      containing a diatomaceous-earth adsorbant, previously impregnated with sodium
      bicarbonate solution. After aspiration to dryness, the cartridge was eluted with
      methanol-water (4 + 1), and aliquots were taken for quantitation by reversed
      phase liquid chromatography with fluorescence detection. Recoveries of citrinin
      added to ground corn at 200-1600 ng/g ranged from 71.2 to 86.3%, with
      coefficients of variation between 4.1 and 10.6%. An indirect enzyme immunoassay
      was also evaluated, using sodium carbonate solution for extraction. Recoveries of
      citrinin added to ground corn at 200-2000 ng/g ranged from 53.2 to 67.2%, but the
      coefficients of variation varied between 18.4 and 51.5%. The LLE cartridge
      procedure offers the advantages of low solvent consumption and speed, and is
      amenable to automation.

PMID- 10589490
TI  - Rapid immunoaffinity-based method for determination of zearalenone in corn by
      fluorometry and liquid chromatography.
AB  - An immunoaffinity-based method was developed to determine zearalenone in corn.
      Corn samples were extracted in acetonitrile-water (90 + 10, v/v), applied to an
      immunoaffinity column, and eluted with methanol. The isolated toxin was
      quantitated either by reaction with aluminum chloride hexahydrate (AlCl3.6H2O)
      prior to measurement with a fluorometer or injection into a liquid
      chromatographic (LC) system with a fluorescence detector. Performance was
      evaluated in terms of antibody specificity, limit of detection, percentage
      recovery, precision, column capacity, assay linearity, and comparison with AOAC
      Official Method 985.18. With the immunoaffinity column cleanup procedure, only
      zearalenone and its metabolites were recognized by the antibody (> or = 75%
      recovery). Limits of detection were 0.10 microgram/g for the fluorometer and 0.10
      or 0.0025 microgram/g (sensitive method) for the LC method. Percentage recovery
      averaged 105% (fluorometer) and 93% (LC method), with average relative standard
      deviations (RSDs) of 15.7 and 9.3%. Naturally contaminated samples gave
      comparable RSDs of 8.3 and 9.9% for the fluorometer and LC methods, respectively.
      Column capacity was 4.0 micrograms with 89% recovery. Assay linearity was
      comparable for both methods (r2 = 0.998). Optimum assay ranges were 0.10-5.0
      micrograms/g for the fluorometer and 0.10-50 or 0.0025-5.0 micrograms/g
      (sensitive method) for the LC method. Comparative analysis of 17 naturally
      contaminated corn samples using Zearala Test LC and the official AOAC LC method
      for detection of zearalenone showed that Zearala Test is statistically comparable
      to the AOAC Official Method 985.18 (r2 = 0.747).

PMID- 10589491
TI  - Evaluation of the novel Soxflo technique for rapid extraction of crude fat in
      foods and animal feeds.
AB  - The new Soxflo instrument was evaluated for the determination of crude fat in
      foods and animal feeds. Samples are packed into small columns and extracted with
      petroleum ether at room temperature. The Soxflo yielded accurate data from foods,
      ranging from 0.4 to 73.2% crude fat, compared with Soxhlet extractions and
      Certified Reference Materials, for which recoveries averaged 99.7 and 100.7%,
      respectively. Relative standard deviations (1.81%) were approximately half those
      of Soxhlet extractions (3.68%). Regression analysis of the data suggested that
      there was no proportional bias. A small but acceptable constant bias was
      measured. Soxflo extractions are easy to perform and take approximately 1 h to
      complete. The main difference between the Soxflo and Soxhlet techniques lies in
      the extraction procedure. Estimated savings during extractions are in time (85%
      reduction), energy (95%), cooling water (100%), and solvents (50%). Soxflo
      extractions are, therefore, more environmentally friendly than Soxhlet
      extractions.

PMID- 10589492
TI  - Gas chromatographic determination of volatile congeners in spirit drinks:
      interlaboratory study.
AB  - An interlaboratory study of a gas chromatographic (GC) method for the
      determination of volatile congeners in spirit drinks was conducted; 31
      laboratories from 8 countries took part in the study. The method uses GC with
      flame ionization detection and incorporates several quality control measures
      which permit the choice of chromatographic system and conditions to be selected
      by the user. Spirit drink samples were prepared and sent to participants as 10
      blind duplicate or split-level test materials for the determination of 1,1
      diethoxyethane (acetal), 2-methylbutan-1-ol (active amyl alcohol), 3-methylbutan
      1-ol (isoamyl alcohol), methanol (methyl alcohol), ethyl ethanoate (ethyl
      acetate), butan-1-ol (n-butanol), butan-2-ol (sec-butanol), 2-methylpropan-1-ol
      (isobutyl alcohol), propan-1-ol (n-propanol), and ethanal (acetaldehyde). The
      precision of the method for 9 of the 10 analytes was well within the range
      predicted by the Horwitz equation. The precision of the most volatile analyte,
      ethanal, was just above statistically predicted levels. This method is
      recommended for official regulatory purposes.

PMID- 10589493
TI  - Kjeldahl nitrogen analysis as a reference method for protein determination in
      dairy products.
AB  - Measurement of total nitrogen by Kjeldahl analysis is the historical reference
      method for determination of the protein content of dairy products and is used for
      both calibration and validation of alternative methods for protein determination.
      Accurate evaluation of alternative methods is not possible if there is large
      uncertainty regarding the reference values. When Kjeldahl analysis is used to
      establish reference values, the performance of the Kjeldahl testing must be
      verified and within established expectations. Advice is given for Kjeldahl system
      optimization, evaluation of test results, and trouble-shooting. Techniques for
      successful Kjeldahl nitrogen analysis of dairy products other than milk are
      discussed.

PMID- 10589494
TI  - Determination of fluoroquinolone residues in animal tissues using Escherichia
      coli as indicator organism.
AB  - Three strains of Escherichia coli (ATCC 128, 10536, and 25922) and one strain of
      Bacillus subtilis (ATCC 3491) were compared as indicator microorganisms in
      microbial inhibition tests for their ability to detect fluoroquinolone residues.
      E. coli strains 128 and 10536 were most susceptible to fluoroquinolone residues,
      with detection limits of 35-50 micrograms/kg for enrofloxacin. Of the 2 strains,
      E. coli 10536 was slightly less susceptible. Ciprofloxacin was detected
      consistently by E. coli 128 at 30 micrograms/kg. Other fluoroquinolone drugs of
      veterinary interest detected by E. coli 128 were sarafloxacin and difloxacin at
      100-250 micrograms/kg concentration. E. coli 25922 yielded 100% sensitivity in
      detection of enrofloxacin only at the 250 micrograms/kg concentration, and
      ciprofloxacin and sarafloxacin at 200 micrograms/kg. B. subtilis detected only
      enrofloxacin 100% of the time at 250 micrograms/kg. The E. coli strains tested
      were insensitive to other antibacterials commonly used in animals, with the
      exception of ceftiofur which was detected by E. coli 128 and 10536 at 500
      micrograms/kg. The B. subtilis strain was not effective in detecting the
      fluoroquinolone drugs, whereas the E. coli strains were selective for the
      fluoroquinolones. E. coli 128 was 100% effective in detecting enrofloxacin and
      ciprofloxacin in spiked diaphragm homogenate samples at 50 micrograms/kg. Of the
      microorganisms tested, E. coli strain ATCC 128 was highly suitable as an
      indicator microorganism in a microbial inhibition assay for selective detection
      of fluoroquinolone antibacterial residues in animal tissues.

PMID- 10589495
TI  - Determination of trace metal ions in common salt by stripping voltammetry.
AB  - Sensitive voltammetric methods using cathodic and anodic differential pulse
      stripping techniques were applied for determination of trace ions cadmium(II),
      cobalt(II), copper(II), lead(II), manganese(II), nickel(II), and zinc(II), which
      are usually found in different grades of common salt as contaminants. The optimal
      conditions, i.e., deposition time, preconcentration potential, supporting
      electrolyte, and ionic strength, were investigated for each metal ion.
      Concentration of the metal ion was determined by the standard addition method.
      Metal content varied according to the quality of the table salt.

PMID- 10589496
TI  - Multiresidue analysis of pesticides in fresh fruits and vegetables using
      procedures developed by the Florida Department of Agriculture and Consumer
      Services.
AB  - Improved quality and efficiency of pesticide residue analysis were achieved by
      examining all aspects of the laboratory process. In an effort to eliminate
      methylene chloride hazardous waste, an acetonitrile extraction method, originally
      developed by the California Department of Agriculture, was modified and adopted.
      Sample size and solvent consumption were reduced with the new method. Custom
      glassware racks and disposable supplies reduced overall analysis time. Gravity
      fed, solid-phase extraction simplified sample preparation and provided cleaner
      extracts for gas chromatographic analyses. Modifications to the method were made
      to achieve the ruggedness needed to maintain quality objectives during routine
      analysis. Instrumental improvements, including new selective detectors, retention
      time locking, and mass spectrometry screening for all samples, provided the
      laboratory with efficient, reliable, and confirmed analytical results.

PMID- 10589497
TI  - Kuwait's total diet study: dietary intake of organochlorine, carbamate,
      benzimidazole and phenylurea pesticide residues.
AB  - The State of Kuwait in cooperation with the U.S. Food and Drug Administration
      (FDA) conducted a Total Diet Study (TDS) to estimate intakes of pesticide
      residues by the population. The levels of organochlorine (OC) pesticides,
      carbamates, benzimidazoles, and phenylureas in the TDS core list are reported
      here. The TDS core list was established through a national food consumption
      survey. All food items (140 for the Kuwaiti adult) were prepared as eaten and
      analyzed for the pesticides mentioned above. The FDA's multiresidue methods in
      Volume I of the Pesticide Analytical Manual were used in gas, liquid, and gel
      permeation chromatographic analyses. Only vegetable and fruit samples contained
      pesticide residues (mg/kg), including the carbamates 1-naphthol (1.4) and 3H
      carbofuran (0.94) in carrots; the OC pesticide vinclozolin (0.47), 3H-carbofuran
      (0.66), and fenuron (0.6) in kiwi fruit; the OC pesticide procymidone (0.32) and
      carbendazim (0.5) in grapes; 3H-carbofuran (5.0) in apricots; the OC pesticides
      captan (0.013) and thiabendazole (0.63) in pears; captan (0.035) in plums; and
      carbendazim (0.4) in mandarin oranges. The levels of 3H-carbofuran found in both
      apricots and kiwi fruit exceeded the maximum residue limits (MRLs) of the Food
      and Agriculture Organization/World Health Organization (FAO/WHO) of the United
      Nations. The daily intakes of pesticides by the different population groups are
      discussed in light of the FAO/WHO acceptable daily intakes.

PMID- 10589498
TI  - Analysis of interlaboratory performance in the determination of total selenium in
      water.
AB  - This study explored the performance of experienced laboratories in the analysis
      for total selenium in water by a variety of analytical methods. The goal of the
      study was to examine intra- and interlaboratory variability. Replicates (n = 7)
      of 7 sample types that included a reference material of known Se concentration,
      natural waters, and treated wastewaters were submitted to 7 laboratories with
      prequalified Se analytical experience. Results of the study indicated wide ranges
      in minimum and maximum results, distinct differences in laboratory precision, and
      routine reporting of numerical results below statistical limits of quantitation.
      Hydride generation as a sample introduction technique demonstrated superior
      performance. In general, the study supports a caution advisory about using low
      level Se data, especially results lower than about 10 micrograms Se/L, without
      quantitating the statistical uncertainty of the data. Because this study used
      data from samples that were submitted in bulk to participating laboratories
      prequalified for Se analytical expertise and experience, it can be considered a
      best-case demonstration of performance.

PMID- 10589499
TI  - Determination of benomyl, diphenyl, o-phenylphenol, thiabendazole, chlorpyrifos,
      methidathion, and methyl parathion in oranges by solid-phase extraction, liquid
      chromatography, and gas chromatography.
AB  - A simple and rapid method was developed for determination of benomyl, diphenyl
      (DP), o-phenylphenol (OPP), thiabendazole (TBZ), chlorpyrifos, methidathion, and
      methyl parathion in whole oranges. These compounds were extracted from a mixture
      of samples and anhydrous sodium acetate with ethyl acetate. The ethyl acetate
      extract was concentrated and cleaned up by passing through tandem solid-phase
      extraction columns consisting of anion-exchange and primary/secondary amine
      bonded silica. The eluate was concentrated and volume was adjusted with methanol
      for subsequent liquid chromatography (LC) and gas chromatography (GC). Benomyl
      (as methyl-2-benzimidazole carbamate, MBC), DP, OPP, and TBZ residues were
      determined by LC with fluorescence detection. Recoveries at 3 fortified levels
      (0.1, 1, and 10 micrograms/g) ranged from 63.9 to 97.4%, with coefficients of
      variation (CVs) of 1.6 to 15.5%. Limits of detection (LODs) were 0.01 microgram/g
      for DP, OPP, TBZ and 0.05 microgram/g for benomyl. Chlorpyrifos, methidathion,
      and methyl parathion residues were determined by GC with flame photometric
      detection. Recoveries ranged from 90.4 to 97.0%, with CVs of 2.1 to 5.9%. LODs
      were 0.005 microgram/g for chlorpyrifos and methyl parathion, and 0.01
      microgram/g for methidathion.

PMID- 10589501
TI  - Environmental analysis using capillary electrophoresis and related techniques,
      including capillary electrochromatography

PMID- 10589500
TI  - Determination of hexazinone in groundwater by direct-injection high-performance
      liquid chromatography.
AB  - Hexazinone has been detected at levels ranging from 0.2 to 50 micrograms/L in
      many groundwater samples from eastern Maine over the past decade. A rapid and
      inexpensive direct-injection high-performance liquid chromatographic (HPLC)
      method has been developed to monitor contamination levels of the herbicide. The
      method is sensitive (limit of quantitation = 0.33 microgram/L) and is linear to
      33.0 micrograms/L (R2 = 0.9995). Direct injection results from 50 field samples
      compared well (R2 = 0.98) with an HPLC method using solid-phase extraction for
      concentration and cleanup. The technique is very reproducible (coefficients of
      variation of 0-8.4% within day and 3.0-13.2% between day) and eliminates loss of
      analyte because of fewer steps in the procedure.

PMID- 10589502
TI  - Determination of regularly distributed plant protectants in raw and drinking
      waters, using a multiresidue method with cyclodextrin-modified micellar
      electrokinetic chromatography.
AB  - Eighteen plant protectant compounds were separated and determined by cyclodextrin
      modified micellar electrokinetic chromatography (MEKC) in a
      multiclass/multiresidue method. The pesticides included are those dispersed in
      the greatest amounts today over agricultural acreage, and they represent 8
      different classes of compounds (azoles, benzoic acids, chloroacetanilides,
      phenoxy acids, phenylureas, sulfonylureas, thiocarbamates, and triazines)
      covering a wide range of chemical reactivities and physicochemical properties. A
      500 mL sample of tap water is preconcentrated by solid-phase extraction (SPE)
      with 300 mg combined polystyrene-divinylbenzene and methacrylate macroporous
      resins. Trapped analytes are eluted collectively with diethyl ether.
      Concentration and solvent change yield 250 microL of an acetone "concentrate,"
      which is further worked up and concentrated 1:10 to produce the MEKC injection
      solution containing 10 mmol/L sodium dodecyl sulfate (SDS) surfactant. For MEKC,
      2 phosphate/SDS buffer systems were designed, each allowing complete separation
      of all pesticides in a single run. Sensitivity was enhanced by a self-etched
      bubble cell and an injection procedure which employs stacking at reversed
      polarity. The ability of MEKC to determine plant protectants in raw and drinking
      waters at the 0.1 microgram/L level, as demanded by the guidelines of the
      European Union, was demonstrated with spiked tap waters. Recoveries were between
      75 and 110%, and limits of quantification, evaluated as method detection limits
      according to guidelines of the U.S. Environmental Protection Agency, ranged
      between 0.03 and 0.10 microgram/L. The precisions of the relative migration times
      were all below 0.5%.

PMID- 10589503
TI  - Multiresidue method for determination of sulfonylurea herbicides in water by
      liquid chromatography with confirmation by capillary electrophoresis.
AB  - A liquid chromatographic method with comfirmation by capillary electrophoresis
      was used to determine 12 sulfonylurea herbicides in agricultural water. Analysis
      of 3 different water matrixes fortified at 2 levels gave good recoveries with
      adequate sensitivity at the 0.1 ppb level. A portion of the water was acidified
      with acetic acid and loaded onto an RP-102 solid-phase extraction (SPE)
      cartridge, and the extract was cleaned up on an alumina SPE cartridge. Extracts
      were desalted with an RP-102 SPE cartridge before instrumentation. Samples
      needing chemical filtration, such as pond water, required additional cleanup with
      a SAX SPE cartridge before the alumina cleanup step. Data were compiled for both
      determinative techniques and evaluated.

PMID- 10589504
TI  - Protamine-like sperm nuclear basic proteins in the primitive frog Ascaphus truei
      and histone reversions among more advanced frogs.
AB  - Sperm nuclear basic proteins (SNBPs) that condense chromatin are very diverse. In
      animals, evolution of SNBPs has proceeded from lysine-rich histone H type in
      sponges to more arginine-rich protamine-like PL and protamine P types. Yet
      sporadic PL/P to H reversions are known to occur in both protostomes and
      deuterostomes. To determine why this is the case, we have examined SNBPs in
      eleven anuran species. We find that sperm of the primitive, internally
      fertilizing archeobatrachian frog A. truei (family Ascaphidae) has PL/P type (42
      mol % arginine), with an electrophoretic profile similar to SNBPs in another
      archeobatrachian, externally fertilizing Leiopelma hochstetteri (family
      Leiopelmatidae). Cytochemistry of sperm nuclei in the advanced, externally
      fertilizing neobatrachian frogs Crinia signifera and C. deserticola (family
      Myobatrachidae) indicates that they have reverted to H type SNBPs. This is also
      known to be the case in externally fertilizing Rana (family Ranidae) and
      Silurana, a subgenus of Xenopus (family Pipidae). Such a trend, from PL/P type
      SNBPs in two archeobatrachians to sporadic reversions to H type in more advanced
      frogs, parallels the ultrastructural simplification from complex A. truei
      introsperm to neobatrachian aquasperm that Jamieson et al. (1993. Herpetologica
      49:52-65) attribute as a secondary reversion to external fertilization.

PMID- 10589505
TI  - Pharmacological characterization of the response of the leech pharynx to
      acetylcholine.
AB  - In this study we document the sensitivity of the leech pharynx to acetylcholine
      and begin to characterize the acetylcholine receptor mediating this response by
      examining the effects of selective cholinergic agonists and antagonists on the
      contractile behavior of the pharynx. The order of potency derived from the EC50
      of each agonist was (+/-)epibatidine > acetylcholine (in the presence of
      physostigmine) >> McN A-343 >> carbachol > nicotine. However, when response
      amplitude was considered, the order of potency to the tested agonists was (+/
      )epibatidine >> nicotine >> McN A-343 >> carbachol > acetylcholine. Acetylcholine
      induced contractions of the pharynx were antagonized by d-tubocurarine, but not
      by alpha-bungarotoxin, alpha-conotoxin M1, or mecamylamine. Application of high
      concentrations of hexamethonium (1 mM) augmented the acetylcholine-induced
      contractions. However, this augmentation was apparently due to inhibition of
      acetylcholinesterase by hexamethonium. The muscarinic antagonist atropine
      produced complex actions and apparently acted as a mixed agonist/antagonist.
      Atropine by itself produced an increase in basal tonus and increased the
      frequency and amplitude of phasic contractions. Atropine increased the peak
      tension of the acetylcholine-induced response; however, it reduced the amplitude
      of both the acetylcholine-induced increase in basal tonus and integrated area.
      Based on the pharmacological profile of the pharyngeal acetylcholine response, we
      conclude that the acetylcholine receptor mediating the response is a nicotinic
      receptor. However, the responsiveness of the pharynx to muscarinic agents
      diverges from that of a classical nicotinic receptor.

PMID- 10589506
TI  - Study on the concentration of circulating primordial germ cells (cPGCs) in early
      chick embryos.
AB  - Experiments were conducted to elucidate the factor that influences the
      concentration of circulating primordial germ cells (cPGCs) in two-day old chick
      embryos. The concentration of cPGCs was observed to be highest at stage 14 (66.9
      +/- 23.2 microliters) and decreased thereafter. However, considerable egg to egg
      variations in cPGC concentration, especially at stages 13, 14, 15, and 16 were
      observed. After conducting experiments to elucidate the source of egg to egg
      variation in cPGC concentration among embryos, it was revealed that there are
      hens that lay eggs which contain either constantly high (more than 80
      PGCs/microliter) or constantly low (less than 30 PGCs/microliter) concentration
      of cPGCs. The results obtained from the present experiments showed that one of
      the major source of egg to egg variation in the concentration of cPGCs was due to
      the individual differences among females that produced the eggs.

PMID- 10589507
TI  - Evidence of a progesterone receptor in the liver of the green frog Rana esculenta
      and its down-regulation by 17 beta estradiol and progesterone.
AB  - Progesterone is a versatile hormone showing an ample variety of effects. One of
      the numerous functions attributed to progesterone is the modulation of
      vitellogenesis in oviparous vertebrates. As a prerequisite for the possible
      involvement of progesterone in vitellogenesis modulation, we investigated the
      presence of a progesterone receptor (PR) in the liver of the female green frog
      Rana esculenta. 3H-Progesterone (3H-P) binding activity was found in both cytosol
      and nuclear extract of the liver of Rana esculenta. The progesterone-binding
      moiety showed the typical characteristics of a true receptor, such as high
      affinity, low capacity, and specificity for progesterone. It also bound to DNA
      cellulose and was eluted with a linear salt gradient at a concentration of 0.05 M
      of NaCl. The progesterone-binding moiety was down regulated by steroid hormones,
      in that ovariectomy resulted in a significant increase, in both cytosol and
      nuclear extract, of 3H-P binding activity with respect to intact females. On the
      contrary, 3H-P binding activity was almost undetectable after estradiol and/or
      progesterone treatment. The progesterone binding moiety of Rana esculenta was
      analyzed by Western blotting with the aid of a monoclonal antibody raised against
      the subunits A and B of the chicken PR. An immunoreactive band of about 67 kDa
      was observed in the liver of both intact and treated females. The 67 kDa band
      showed an increased intensity in ovariectomized animals, while it was faint
      following treatment with estradiol and/or progesterone. This is the first report
      on the presence of a progesterone receptor (PR) in the liver of an amphibian. PR
      of Rana esculenta is down regulated by estradiol and/or progesterone and shows
      peculiar immunological and biochemical characteristics, which make it rather
      different from the PR of other vertebrates.

PMID- 10589508
TI  - Adrenal inhibition of corticotropin-releasing hormone-induced thyrotropin
      release: a comparative study in pre- and posthatch chicks.
AB  - Recent evidence indicates that corticotropin-releasing hormone (CRH) acts as a
      potent stimulator of thyrotropin (TSH) release in the chicken. In this study
      adrenal and thyroidal feedback mechanisms were studied. Administration of
      corticosterone 30 min prior to an ovine CRH (oCRH) challenge diminished the in
      vivo sensitivity of thyrotrophs to oCRH in 19-day-old chicken embryos (E19) (20
      micrograms corticosterone; 2 micrograms oCRH) but not in 8-day-old chickens (C8)
      (40 micrograms corticosterone; 4 micrograms oCRH). At both ages studied,
      corticosterone (0.01 and 1 microM) did not alter the in vitro TSH response to
      oCRH (100 nM) indicating that an indirect mechanism is involved at the embryonic
      stage which is no longer present in posthatch chickens. In vitro, 3,5,3'
      triiodothyronine (T3) pretreatment (0.01 and 1 microM) resulted at both ages
      studied in a dose-dependent drop in the in vitro oCRH-induced TSH release. As
      recorded previously, corticosterone treatment provoked a rise in plasma T3 in
      embryonic but not in posthatch chickens. The presence of an indirect adrenal
      feedback mechanism in chicken embryos may therefore be linked to the increase in
      plasma T3 which will alter the sensitivity of thyrotrophs to hypothalamic
      releasing factors. In conclusion, corticosterone does not directly modulate the
      responsiveness of thyrotrophs to CRH, but its feedback mechanism may be dependent
      on the evoked increase in plasma T3 which is only present in embryonic chickens.
      Corticosterone may in this regard play an essential role during embryonic
      development by coordinating thyroidal feedback mechanisms at the level of the
      chicken pituitary.

PMID- 10589509
TI  - Study of demembranated, reactivated human spermatozoa with decondensed nuclei.
AB  - Reactivated movement of the axonemes in demembranated spermatozoa with
      decondensed nuclei allows decondensation to be monitored in vitro with minimal
      disruption, and provides access to the nucleus for ultrastructural investigation
      and experimental manipulation. In the present study, fresh liquefied semen
      samples with sperm concentrations > or = 13 x 10(6)/ml were diluted 1:10 with a
      demembranating solution containing 0.01-0.022% Triton X-100. Inter-sample
      variation in the concentration of Triton X-100 required to permeabilize the sperm
      membrane was observed as judged by the ability of the spermatozoa to be
      reactivated by ATP but not by an ATP-free control solution, with the extent of
      demembranation being checked by transmission electron microscopy. After exposure
      to DTT and heparin, coordinated and sometimes progressive movement of partially
      decondensed spermatozoa occurred in a reactivating solution. Unlike ram, human
      sperm heads required decondensation with heparin. An unusual ultrastructural
      feature of the decondensing human sperm nuclei, not previously reported, was the
      appearance of dense globular material extruding from the nucleus. Enzymatic
      treatment of the sections with protease but not with deoxyribonuclease removed
      this material, which was presumably protamine.

PMID- 10589510
TI  - Hepatopancreas is the likely organ of vitellogenin synthesis in the freshwater
      prawn, Macrobrachium rosenbergii.
AB  - The objective of the present study was to investigate the source of vitellogenin
      in the freshwater prawn, Macrobrachium rosenbergii. Ovarian development of M.
      rosenbergii was classified into five stages (stage I-V). Vitellin/vitellogenin
      was detected in the ovary and the hepatopancreas in different stages by native
      PAGE and Western blotting. Two and three subunits of vitellin were observed in
      the ovary at the early- (I-II), mid- and late- (III-V) stages, respectively. The
      subunit of vitellogenin was not detected in the hepatopancreas at different
      stages of prawns. Hepatopancreas had positive immunocytological staining (against
      vitellin antibody) in different ovarian stages of prawn. Only vitellogenic oocyte
      but not previtellogenic oocytes and follicle cells had a positive
      immunocytological staining. Hepatopancreas could synthesize radiolabeled
      immunoreactive proteins after incubation with radiolabeled glycine on the basis
      of immunoprecipitation (against vitellin antiserum). Therefore, it is concluded
      that hepatopancreas is the most likely organ to synthesize vitellogenin in the
      freshwater prawn, M. rosenbergii.

PMID- 10589512
TI  - Genetic relationships of grizzly bears (Ursus arctos) in the Prudhoe Bay region
      of Alaska: inference from microsatellite DNA, mitochondrial DNA, and field
      observations.
AB  - Grizzly bears are abundant in the region of the Prudhoe Bay oil fields in
      northern Alaska. We used field observations and molecular genetic data to
      identify parent-offspring and sibling relationships among bears in this region.
      We determined genotypes at 14 microsatellite DNA loci and the cytochrome b gene
      of mitochondrial DNA (mtDNA) for 36 bears. We identified 17 possible mother
      offspring pairs and 8 possible father-offspring pairs. This includes verification
      of the relationships of 14 mother-offspring pairs identified from field
      observations. Three additional mother-offspring pairs and all eight father
      offspring pairs were determined from genetic and age data. Relatedness
      coefficients based on numbers of shared alleles between individuals were as
      expected: approximately 0.50 for parent-offspring and sibling pairs and
      approximately 0.75 for a father-offspring pair resulting from a father-daughter
      mating. The level of genetic variation (mean number of alleles per locus = 6.6,
      mean heterozygosity = 70%) and allele frequencies in grizzly bears in the Prudhoe
      Bay region are similar to those in other parts of the species' range.

PMID- 10589511
TI  - The Rift Valley complex as a barrier to gene flow for Anopheles gambiae in Kenya.
AB  - Recent studies of Anopheles gambiae, the principal mosquito vector of malaria in
      Africa, suggested that the eastern Rift Valley and its surrounding areas act as a
      barrier to gene flow. To quantify the unique effect of these areas on gene flow,
      we measured genetic variation within and between populations from each side of
      the Rift. Low differentiation was measured between populations on each side of
      the Rift (mean FST < 0.008, mean RST < 0.002). However, high differentiation was
      measured across the Rift (mean FST = 0.104; mean RST = 0.032). Genetic diversity
      within populations was lower in eastern populations, suggesting that the
      effective population sizes (Ne) of these populations were lower than those of
      western populations. We partitioned the overall differentiation across the Rift
      into three factors: variation in Ne between populations contributed 7-20%;
      distance contributed 10-30%, and the remainder, corresponding to the unique
      effect of the Rift was 50-80%. The Rift's effect was highly significant based on
      FST. The greater sensitivity of FST in measuring differentiation indicated that
      drift and not mutation generated the differences between populations. Restricted
      gene exchange across several hundred kilometers on the face of intense human
      transportation implies that active mosquito dispersal is the major form of
      migration, and that migration is a multistep process, where step length is
      relatively short.

PMID- 10589513
TI  - A QTL for the degree of spotting in cattle shows synteny with the KIT locus on
      chromosome 6.
AB  - The proportion of unpigmented coat on the trunk was determined from photographs
      of 38 German Simmental and 627 German Holstein bulls distributed over three
      generations. All 665 animals were members of 18 Holstein and 3 Simmental half-sib
      families. A Bayesian estimation of heritability yielded a posterior mean of 0.88
      and a standard error of 0.08. A quantitative trait loci (QTL) scan over all
      chromosomes covered by 229 microsatellite marker loci (2926 cM) was performed by
      fitting a multiple marker regression model to 625 observations from the youngest
      generation in 18 families. On chromosome 6 a QTL for the proportion of white coat
      with large effects (experiment-wise error probability < .0001) was found and a
      less important one on chromosome 3 (chromosome-wise error probability < .009).
      Chromosome 6 is known to harbor the KIT locus (receptor tyrosinase kinase), which
      is associated with various depigmentation phenotypes in mice, humans, and pigs.
      Similarity of phenotypic KIT effects in other species and synteny with the
      reported QTL suggest that KIT is a serious candidate gene for the degree of
      spotting in cattle. The results are also discussed with respect to resistance to
      solar radiation, heat stress, and photosensitization.

PMID- 10589515
TI  - QTL for live weight traits in Pere David's x red deer interspecies hybrids.
AB  - Interspecies hybrids between Pere David's deer (Elaphurus davidianus) and red
      deer (Cervus elaphus) have proved to be a powerful resource in the search for
      quantitative trait loci (QTL) in deer. Several regions of the genome with
      significant effects on live weight and growth rates in backcross hybrids were
      detected. These include putative QTL for 6-month live weight (LOD 3.90) on
      linkage group 12, for 14-month live weight (LOD 3.19) on linkage group 1, three
      putative QTL for growth rate from 3 to 6 months (LOD 4.19 on linkage group 12,
      LOD 3.92 on linkage group 12, and LOD 3.34 on linkage group 5). In addition,
      linkage groups 20 and 1 appear to be associated with live weight traits between 9
      and 16 months. The variance in traits explained by these QTL ranged between 5.3%
      and 11.2%. Allele substitution with Pere David's alleles at different loci had
      both positive and negative effects on live weights and growth rates.

PMID- 10589514
TI  - Breeding structure of Glossina pallidipes populations evaluated by mitochondrial
      variation.
AB  - Mitochondrial DNA diversity was studied at four loci in six natural populations
      of the tsetse fly Glossina pallidipes from Zimbabwe, Mozambique, Kenya, and
      Ethiopia. Single-locus diversity varied from 0.39 at 12S to 0.65 at COII. A total
      of 32 haplotypes was found with a mean of 6.4 +/- 2.9 per locus. To study
      breeding structure, diversity at two loci, COII and 16S2, was evaluated in 18
      populations sampled from an area of approximately 1,611,000 km2 and in three
      laboratory cultures. Twenty-six haplotypes were detected at the two loci and mean
      haplotype diversity over all natural populations was 0.63. A high degree of
      population subdivision was detected within and among the Ethiopian and Kenya
      populations. The Zimbabwe and Zambia populations showed much less variation and
      differentiation than the northern populations. A population in Mozambique showed
      high levels of haplotype variation and affinities closest to populations in
      eastern Kenya, some 1700 km to the north. Analysis of variance of haplotype
      frequencies showed that 51.5% of the total lay within populations, 13% among
      populations within five nested groups, and 35.5% among the five groups. Wright's
      FST was 0.485, Nei's GST was 0.33, and Weir and Cunningham's theta = 0.45.
      Ecological data show that G. pallidipes is highly vagile. The large amount of
      genetic differentiation may be explained by genetic drift that occurred in
      scattered, relict populations during the rinderpest panzootic of the late 19th
      and early 20th centuries.

PMID- 10589516
TI  - Genetic variation detected by microsatellites in five Spanish dog breeds.

PMID- 10589517
TI  - Comparison of multilocus DNA fingerprints and microsatellites in an estimate of
      genetic distance in chicken.

PMID- 10589518
TI  - Gender differences in reasons for entering and leaving education administration:
      discriminant function analyses.
AB  - Using discriminant function analyses on survey data collected from 457 students
      in 29 education administration programs across the United States, the authors
      inquired into whether men and women decide to enter and possibly leave education
      administration for different reasons. There were statistically significant
      functions separating men and women in their reasons for entering and leaving
      education administration. Implications of the findings are discussed.

PMID- 10589519
TI  - Mood and organizational citizenship behavior: the effects of positive affect on
      employee organizational citizenship behavior intentions.
AB  - This study, involving 139 employees from a variety of industries, organizations,
      and positions in Singapore, measured the effects of mood on the intentions of
      employees to contribute actions that are organizationally desirable but are not
      part of their formal job requirements (organizational citizenship behavior).
      After effects of established patterns of historical organizational citizenship
      behavior, demographic characteristics, and employee positive and negative
      affectivity had been controlled, stepwise regression analysis revealed that the
      amount of positive affect currently experienced by an employee significantly
      influenced the employee's intention to perform specific acts of organizational
      citizenship.

PMID- 10589520
TI  - Molecular cloning and expression analysis of a gene for a sucrose transporter in
      maize (Zea mays L.).
AB  - Here we report the cloning of a sucrose transporter cDNA from maize (Zea mays L.)
      and an analysis of the expression of the gene. A cDNA clone (ZmSUT1) was
      identified as a sucrose transporter cDNA from its sequence homology at the amino
      acid level to sucrose transporters that have been cloned from other higher plant
      species. Based on the results of genomic Southern hybridization, ZmSUT1 appears
      to be a single copy gene. A Northern blot analysis of seedlings and leaf blades
      suggests that the sucrose transporter is involved in the export of accumulated
      carbohydrates from source leaf blades. From the measurements of transcript levels
      and carbohydrate contents in mature leaf blades, we propose that the expression
      of the gene for the maize sucrose transporter is positively regulated by the
      amounts of soluble sugars such as sucrose and glucose in source leaves of maize.
      In addition, based on the tissue specificity of the expression of the gene in
      maize plants at the reproductive stage, it is possible that the sucrose
      transporter acts in sink tissues such as pedicles as well as in source tissues
      such as leaf blades.

PMID- 10589521
TI  - Cloning and secondary structure analysis of caleosin, a unique calcium-binding
      protein in oil bodies of plant seeds.
AB  - Plant seed oil bodies comprise a matrix of triacylglycerols surrounded by a
      monolayer of phospholipids embedded with abundant oleosins and some minor
      proteins. Three minor proteins, temporarily termed Sops 1-3, have been identified
      in sesame oil bodies. A cDNA sequence of Sop1 was obtained by PCR cloning using
      degenerate primers derived from two partial amino acid sequences, and
      subsequently confirmed via immunological recognition of its over-expressed
      protein in Escherichia coli. Alignment with four published homologous sequences
      suggests Sop1 as a putative calcium-binding protein. Immunological cross
      recognition implies that this protein, tentatively named caleosin, exists in
      diverse seed oil bodies. Caleosin migrated faster in SDS-PAGE when incubated with
      Ca2+. A single copy of caleosin gene was found in sesame genome based on Southern
      hybridization. Northern hybridization revealed that both caleosin and oleosin
      genes were concurrently transcribed in maturing seeds where oil bodies are
      actively assembled. Hydropathy plot and secondary structure analysis suggest that
      caleosin comprises three structural domains, i.e., an N-terminal hydrophilic
      calcium-binding domain, a central hydrophobic anchoring domain, and a C-terminal
      hydrophilic phosphorylation domain. Compared with oleosin, a conserved proline
      knot-like motif is located in the central hydrophobic domain of caleosin and
      assumed to involve in protein assembly onto oil bodies.

PMID- 10589523
TI  - [Japan Epidemiological Association membership list].

PMID- 10589524
TI  - [National Days of Laboratory Medicine of Russia. Moscow, October 12-14, 1999.
      Workshop: Clinical laboratory at the brink the XXI century: synthesis of
      traditions and novel trends (analysis, diagnosis, technology, and economics).
      Abstracts].

PMID- 10589522
TI  - A cytokinin-repressed gene in cucumber for a bHLH protein homologue is regulated
      by light.
AB  - CRR12 was identified as a cytokinin-repressed gene encoding a cucumber homologue
      for a basic region/helix-loop-helix protein. The level of CRR12 mRNA decreased in
      response to either cytokinins or light in etiolated cotyledons. The level was low
      in cotyledons and leaves of light-grown plants, but it increased during dark
      incubation.

PMID- 10589525
TI  - [National Days of Laboratory Medicine of Russia. Moscow, October 12-14, 1999.
      Workshop: Clinical laboratory at the brink the XXI century: synthesis of
      traditions and novel trends (analysis, diagnosis, technology, and economics).
      Abstracts].

PMID- 10589527
TI  - [The 35th autumn meeting of the Japan Radiological Society, Okayama, Japan.
      October 6-8, 1999. Abstracts].

PMID- 10589526
TI  - [43rd Annual meeting of the Japanese Society for Medical Mycology. Tokyo, October
      7-8, 1999. Abstracts].

PMID- 10589528
TI  - [Regional meeting of the Japanese Society of Otolaryngology. Japan. 1999.
      Abstracts].

PMID- 10589529
TI  - 6th Annual Conference of the International Society for Quality of Life Research.
      Barcelona, Spain, 3-6 November 1999. Abstracts.

PMID- 10589530
TI  - [46th meeting of the Japanese Society of Clinical Pathology. Kumamoto, Japan.
      November 10-12, 1999. Abstracts].

PMID- 10589531
TI  - Calcium, glutamate, and amyotrophic lateral sclerosis: more evidence but no
      certainties.

PMID- 10589532
TI  - Reduction of GluR2 RNA editing, a molecular change that increases calcium influx
      through AMPA receptors, selective in the spinal ventral gray of patients with
      amyotrophic lateral sclerosis.
AB  - Enhancement of calcium influx through the alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionate (AMPA)/kainate receptor is a plausible mechanism underlying
      selective neuronal death in amyotrophic lateral sclerosis (ALS). The calcium
      conductance of the AMPA receptor is regulated by the GluR2 subunit that is edited
      at the glutamine/arginine residue site in the subunit assembly. We investigated
      the molecular changes of GluR2 mRNA in the spinal cord of ALS cases, those of
      cases with other neurological diseases, and those of normal cases using reverse
      transcription-polymerase chain reaction combined with restriction enzyme
      cleavage. We found that the editing efficiency was significantly lower only in
      the ventral gray of ALS cases (virtually 0% in 2 cases) than in any spinal region
      of the disease controls and normal controls. In addition, expression of GluR2
      mRNA is lower in the ventral gray of the ALS cases and disease controls than in
      that of the normal controls. The above molecular changes of GluR2 mRNA in the
      ventral gray of ALS cases may enhance calcium influx through AMPA receptors,
      thereby promoting neuronal vulnerability. The decrement of GluR2 mRNA editing
      efficiency is unique to the ventral gray of ALS cases and may be closely linked
      to the etiology of ALS.

PMID- 10589533
TI  - Epileptiform discharges in the human dysplastic neocortex: in vitro physiology
      and pharmacology.
AB  - Field potential and intracellular recordings were made in slices of human
      neocortical tissue obtained during surgery for the treatment of seizures
      associated with focal cortical dysplasia. Ictal-like epileptiform discharges,
      along with isolated field potentials, were induced by bath application of 4
      aminopyridine (50-100 microM). Some of the isolated field potentials were
      associated with fast transients representing population spikes. Field potential
      profile analysis indicated that both types of synchronous activity had maximal
      negative values at 1,400 to 1,600 microm from the pia. The intracellular
      counterpart of the ictal-like discharge was a prolonged membrane depolarization
      capped by repetitive action potential burst firing. By contrast, the isolated
      field potentials were mirrored by long-lasting depolarizations with minimal
      action potential firing; only when population spikes occurred, the isolated field
      potentials were associated with epileptiform action potential bursting. Ictal
      like discharges were abolished by either N-methyl-D-aspartate or non-N-methyl-D
      aspartate receptor antagonists. In contrast, the isolated field potentials
      continued to occur synchronously during excitatory transmission blockade
      (although they lacked fast transients) but were abolished by the gamma
      aminobutyric acid(A) receptor antagonist bicuculline methiodide (n = 2 slices).
      Our study demonstrates that focal cortical dysplasia tissue maintained in vitro
      has an intrinsic ability to generate ictal-like epileptiform events when
      challenged with 4-aminopyridine. These discharges depend on excitatory amino acid
      receptor-mediated mechanisms. Our results also show the presence in focal
      cortical dysplasia tissue of glutamatergic-independent synchronous potentials
      that are mainly contributed by gamma-aminobutyric acid(A) receptor-mediated
      conductances.

PMID- 10589534
TI  - A follow-up study of blood pressure and cerebral white matter lesions.
AB  - White matter lesions are often observed on cerebral magnetic resonance imaging
      scans of elderly people and may play a role in the pathogenesis of dementia.
      Cross-sectional studies have shown an association between elevated blood pressure
      and white matter lesions. We prospectively studied the relation between blood
      pressure and white matter lesions in 1,077 subjects aged 60 to 90 years who were
      randomly sampled from two prospective population-based studies. One study had
      blood pressure measurements 20 years before, the other 5 years before. Overall
      response for the magnetic resonance imaging study was 63%, and declined from 73%
      among 60- to 70-year-olds to 48% for 80- to 90-year-olds. Diastolic and systolic
      blood pressure levels assessed 20 years before were significantly associated with
      subcortical and periventricular white matter lesions. The association between 20
      year change in diastolic blood pressure and subcortical white matter lesions was
      J-shaped (relative risk, 2.2; 95% confidence interval, 1.0-5.2; and relative
      risk, 3.2; 95% confidence interval, 1.4-7.4, for decrease or increase of more
      than 10 mm Hg, respectively). The association between concurrent diastolic blood
      pressure level and white matter lesions was linear in subjects without, and J
      shaped in subjects with, a history of myocardial infarction. Our results indicate
      that the J-shape relationship of diastolic blood pressure is not restricted to
      cardiovascular disease, but is also manifest in cerebrovascular disease.

PMID- 10589535
TI  - Neurocognitive deficits in medulloblastoma survivors and white matter loss.
AB  - Although previous studies have documented a significant risk of intellectual loss
      after treatment for childhood medulloblastoma (MED), the pathophysiology
      underlying this process is poorly understood. The purpose of this study was to
      test the hypotheses that (1) patients treated for MED in childhood have reduced
      volumes of normal white matter (NWM) related to their treatment with craniospinal
      irradiation with or without chemotherapy, and (2) deficits in NWM among patients
      surviving MED can at least partially explain deficits in their intellectual
      performance. Eighteen pediatric patients previously treated for MED were matched
      on the basis of age at the time of evaluation to 18 patients previously treated
      for low-grade posterior fossa tumors with surgery alone (mean difference, 3.7
      months). Evaluations were conducted with age-appropriate neurocognitive testing
      and quantitative magnetic resonance imaging by using a novel automated
      segmentation and classification algorithm constructed from a hybrid neural
      network. Patients treated for MED had significantly less NWM (p < 0.01) and
      significantly lower Full-Scale IQ values than those treated for low-grade tumors
      (mean, 82.1 vs 92.9). In addition, NWM had a positive and statistically
      significant association with Full-Scale IQ among the patients treated for MED. We
      conclude that irradiation- or chemotherapy-induced destruction of NWM can at
      least partially explain intellectual and academic achievement deficits among MED
      survivors.

PMID- 10589536
TI  - Huntington aggregates may not predict neuronal death in Huntington's disease.
AB  - The mechanism by which polyglutamine expansion in Huntington's disease (HD)
      results in selective neuronal degeneration remains unclear. We previously
      reported that the immunohistochemical distribution of N-terminal huntingtin in HD
      does not correspond to the severity of neuropathology, such that significantly
      greater numbers of huntingtin aggregates are present within the cortex than in
      the striatum. We now show a dissociation between huntingtin aggregation and the
      selective pattern of striatal neuron loss observed in HD. Aggregate formation was
      predominantly observed in spared interneurons, with few or no aggregates found
      within vulnerable spiny striatal neurons. Multiple perikaryal aggregates were
      present in almost all cortical NADPH-diaphorase neurons and in approximately 50%
      of the spared NADPH-diaphorase striatal neurons from early grade HD cases. In
      severe grade HD patients, aggregates were more prominent as nuclear inclusions in
      NADPH-diaphorase neurons, with less perikaryal and neuropil aggregation. In
      contrast, nuclear or perikaryal huntingtin aggregates were present in less than
      4% of the vulnerable calbindin striatal neurons in all HD cases. These findings
      support the hypothesis that polyglutamine aggregation may not be a predictor of
      cell loss. Rather than a harbinger of neuronal death, mutant huntingtin
      aggregation may be a cytoprotective mechanism against polyglutamine-induced
      neurotoxicity.

PMID- 10589537
TI  - Effect of interferon-beta1b on magnetic resonance imaging outcomes in secondary
      progressive multiple sclerosis: results of a European multicenter, randomized,
      double-blind, placebo-controlled trial. European Study Group on Interferon-beta1b
      in secondary progressive multiple sclerosis.
AB  - A randomized placebo-controlled trial of interferon-beta1b was performed on 718
      patients with secondary progressive multiple sclerosis with follow-up of up to 3
      years. In addition to clinical variables, serial magnetic resonance imaging (MRI)
      studies were performed to determine the effect of treatment on the pathological
      evolution of the disease. All patients eligible for MRI had annual proton
      density/T2-weighted brain scans from which total lesion volume was measured and
      the number of new and enlarging lesions noted. A subgroup of 125 patients also
      underwent monthly gadolinium-enhanced and proton density/T2-weighted brain MRI
      from months 0 to 6 and 18 to 24 to determine the effect of treatment on the
      frequency of new lesion activity, defined as new enhancing lesions and
      new/enlarging T2 lesions not enhancing with gadolinium. The difference in total
      lesion volume between treatment groups was highly significant. In the placebo
      group, there was an increase of 15% from baseline to last scan, whereas in the
      interferon-beta1b group, a reduction of 2% was seen. Within the placebo group,
      there was a significant year-on-year increase in total lesion volume, with a mean
      increase of 16% at year 3 compared with baseline. In the treated group, there was
      a significant reduction at year 1 (4%) and year 2 (5%) compared with baseline;
      the 2% decrease at year 3 was not significant. The number of new or enlarging
      proton density/T2 lesions was also significantly reduced by treatment. In the
      frequent MRI subgroup, treatment was associated with a significant 65% reduction
      in new lesion activity between months 1 and 6, and 78% reduction from months 19
      to 24. Interferon-beta1b has a substantial and sustained effect on reducing the
      accumulation of new inflammatory disease foci in secondary progressive MS. This
      therapeutic mechanism may contribute to the positive clinical benefits of
      treatment on the progression of sustained neurological disability and relapse
      activity that were also identified in this trial.

PMID- 10589538
TI  - Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration
      in Alzheimer's disease.
AB  - Genetic evidence strongly supports the view that Abeta amyloid production is
      central to the cause of Alzheimer's disease. The kinetics, compartmentation, and
      form of Abeta and its temporal relation to the neurodegenerative process remain
      uncertain. The levels of soluble and insoluble Abeta were determined by using
      western blot techniques, and the findings were assessed in relation to indices of
      severity of disease. The mean level of soluble Abeta is increased threefold in
      Alzheimer's disease and correlates highly with markers of disease severity. In
      contrast, the level of insoluble Abeta (also a measure of total amyloid load) is
      found only to discriminate Alzheimer's disease from controls, and does not
      correlate with disease severity or numbers of amyloid plaques. These findings
      support the concept of several interacting pools of Abeta, that is, a large
      relatively static insoluble pool that is derived from a constantly turning over
      smaller soluble pool. The latter may exist in both intracellular and
      extracellular compartments, and contain the basic forms of Abeta that cause
      neurodegeneration. Reducing the levels of these soluble Abeta species by
      threefold to levels found in normal controls might prove to be a goal of future
      therapeutic intervention.

PMID- 10589539
TI  - Adult-derived neural precursors transplanted into multiple regions in the adult
      brain.
AB  - Neural stem cells persist in the adult brain subventricular zone (SVZ). These
      cells generate a large number of new neurons that migrate to the olfactory bulb,
      where they complete their differentiation. Here, we transplanted cells carrying
      beta-galactosidase under the control of neuron-specific enolase promoter
      (NSE::LacZ) from the SVZ of adult mice into the striatum cortex and olfactory
      bulb, with or without an excitotoxin lesion. Between 2 and 8 weeks after
      transplantation, grafted cells were present in the recipient regions, but
      extensive migration and differentiation into mature neurons of grafted cells were
      only observed in the olfactory bulb. Clusters of graft-derived neuroblasts
      forming chain-like structures were observed within or close to the grated sites
      in the cortex and striatum; electron microscopy confirmed that graft-derived
      cells in the olfactory bulb and a small number in the striatum were neurons.
      Surprisingly, most of the cells expressing NSE::LacZ outside the olfactory bulb
      were astrocytes. We conclude that primary precursors from the SVZ migrate and
      differentiate effectively only within the environment of the olfactory bulb. Only
      limited survival and differentiation were observed in other brain regions
      studied.

PMID- 10589540
TI  - A randomized trial of plasma exchange in acute central nervous system
      inflammatory demyelinating disease.
AB  - There are no established treatments for patients with acute, severe neurological
      deficits caused by multiple sclerosis or other inflammatory demyelinating
      diseases of the central nervous system who fail to recover after treatment with
      high-dose corticosteroids. We conducted a randomized, sham-controlled, double
      masked study of plasma exchange without concomitant immunosuppressive treatment
      in patients with recently acquired, severe neurological deficits resulting from
      attacks of inflammatory demyelinating disease, who failed to recover after
      treatment with intravenous corticosteroids. Patients who did not achieve moderate
      or greater improvement after the first treatment phase crossed over to the
      opposite treatment. Moderate or greater improvement in neurological disability
      occurred during 8 of 19 (42.1%) courses of active treatment compared with 1 of 17
      (5.9%) courses of sham treatment. The primary analysis was positive. Improvement
      occurred early in the course of treatment, and was sustained on follow-up.
      However, 4 of the patients who responded to the active treatment experienced new
      attacks of demyelinating disease during 6 months of follow-up. Moderate or
      greater improvement occurred during follow-up in only 2 of 13 patients who failed
      to improve during the treatment phase. Plasma exchange leads to functionally
      important neurological recovery in an important proportion of severely disabled
      patients with acute attacks of idiopathic inflammatory demyelinating disease.

PMID- 10589541
TI  - Sniff nasal pressure: a sensitive respiratory test to assess progression of
      amyotrophic lateral sclerosis.
AB  - Impairment of pulmonary function is a major prognostic indicator in amyotrophic
      lateral sclerosis (ALS). Forced vital capacity (FVC) and maximal voluntary
      ventilation (MVV) decline linearly and are commonly used to assess disease
      progression. The aim of this study was to evaluate the usefulness of testing
      respiratory muscle strength in ALS with a novel test, sniff nasal pressure
      (Pn(sn)), in parallel with more classic tests such as maximal inspiratory
      pressure (PI(max)) and maximal expiratory pressure (PE(max)). Sixteen patients
      with ALS were examined monthly over a period of 18 +/- 10 months. At the time of
      inclusion in the study, values were normal for FVC (107% of predicted value) and
      MVV (87% of predicted value) but abnormally low for Pn(sn) (67% of predicted
      value), PI(max) (69% of predicted value), and PE(max) (54% of predicted value).
      Late in the course of ALS, all patients could perform Pn(sn) whereas 6 could not
      perform PI(max) and 7 could not perform PE(max). The rate of deterioration was
      most often linear and similar for FVC (-4.1% of predicted value per month), MVV (
      4.3% of predicted value per month), and Pn(sn) (-4.2% of predicted value per
      month). We conclude that Pn(sn) was the single respiratory test combining linear
      decline, sensitivity in mild disease, and feasibility in advanced disease. Being
      easy to perform and inexpensive, Pn(sn) appears well suited to assess the decline
      of respiratory muscle strength in ALS.

PMID- 10589542
TI  - Nontumoral occipitotemporal epilepsy: localizing findings and surgical outcome.
AB  - We describe a syndrome of medically intractable occipitotemporal epilepsy of
      nontumoral developmental origin and its treatment by surgery. From our epilepsy
      surgery database of 1988 to 1996, we selected all patients without neoplasm who
      had at least two characteristics localizing to the occipital lobe (clinical
      symptoms, interictal focus, ictal onset, or a lesion on magnetic resonance
      imaging scanning) and one to the temporal lobe (interictal spikes or seizure
      onset). We discuss seizure characteristics, electroencephalographic (EEG),
      magnetic resonance imaging, positron emission tomographic, and single-photon
      emission computed tomographic findings, pathological findings, surgical approach,
      outcome from resective surgery, and implications for pathophysiology. Sixty-nine
      percent of our 16 patients with occipitotemporal syndrome had neuronal migration
      disorder, suggesting a developmental etiology of this entity. Initial signs or
      symptoms suggested occipital lobe seizure onset in 13 of 16 patients. On scalp
      EEG, interictal spikes were localized to the temporal lobe in 9 and to the
      occipital lobe in 1; seizure onset was poorly localized. Intracranial EEG
      localized seizure onset to the area of temporo-occipital junction in 77% of
      patients. Positron emission tomography and single-photon emission computed
      tomography showed occipital and temporal or widespread deficits, and
      neuropsychological performance was diffusely abnormal. Surgical results were best
      with occipital and temporal resections, but sometimes satisfactory after
      occipital resection even with temporal (ipsilateral) EEG findings. Temporal
      resection with hippocampectomy uniformly failed to control seizures. An often
      refractory, probably developmental epileptic syndrome with regional
      occipitotemporal distribution can be diagnosed by a specific constellation of
      findings, which has implications for treatment and pathophysiology.

PMID- 10589543
TI  - Evolution of functional reorganization in hemiplegic stroke: a serial positron
      emission tomographic activation study.
AB  - We used serial positron emission tomography (PET) to study the evolution of
      functional brain activity within 12 weeks after a first subcortical stroke. Six
      hemiplegic stroke patients and three normal subjects were scanned twice (PET 1
      and PET 2) by using passive elbow movements as an activation paradigm. Increases
      of regional cerebral blood flow comparing passive movements and rest and
      differences of regional cerebral blood flow between PET 1 and PET 2 in patients
      and normal subjects were assessed by using statistical parametric mapping. In
      controls, activation was found in the contralateral sensorimotor cortex,
      supplementary motor area, and bilaterally in the inferior parietal cortex with no
      differences between PET 1 and PET 2. In stroke patients, at PET 1, activation was
      observed in the bilateral inferior parietal cortex, contralateral sensorimotor
      cortex, and ipsilateral dorsolateral prefrontal cortex, supplementary motor area,
      and cingulate cortex. At PET 2, significant increases of regional cerebral blood
      flow were found in the contralateral sensorimotor cortex and bilateral inferior
      parietal cortex. A region that was activated at PET 2 only was found in the
      ipsilateral premotor area. Recovery from hemiplegia is accompanied by changes of
      brain activation in sensory and motor systems. These alterations of cerebral
      activity may be critical for the restoration of motor function.

PMID- 10589544
TI  - Prevalence of chronic inflammatory demyelinating polyneuropathy in New South
      Wales, Australia.
AB  - A prevalence study of chronic inflammatory demyelinating polyneuropathy (CIDP)
      was performed in New South Wales (NSW), Australia, with a prevalence day of
      August 6, 1996, which coincided with a national census. The population of NSW was
      5,995,544, and the crude prevalence of CIDP was 1.9 per 100,000 population. It
      was higher in male patients than in female patients, and the age-specific
      prevalence reached a maximum of 6.7 per 100,000 population in the 70- to 79-year
      old age group. The prevalence in the city of Newcastle, with a population of
      448,663, was 2.0 per 100,000 population and is representative of the whole of
      NSW. The estimated crude annual incidence was 0.15 per 100,000 population. The
      mean age of onset was 47.6 years (median, 53.5 years), 51% of patients had a
      relapsing-remitting course, the mean duration on prevalence day was 7.1 years
      (median, 5 years), and 87% of patients were able to walk without walking aids or
      other assistance.

PMID- 10589545
TI  - Germline mutations of p53 but not p16/CDKN2 or PTEN/MMAC1 tumor suppressor genes
      predispose to gliomas. The ANOCEF Group. Association des NeuroOncologues
      d'Expression Francaise.
AB  - Constitutional DNA from 44 selected patients suspected of being genetically
      predisposed to develop astrocytic tumors was analyzed for germline mutations of
      the p53, p16, and PTEN genes. Six constitutional missense mutations of the p53
      gene were identified (13.6%), but no mutations of the p16 and PTEN genes were
      found, suggesting that (1) germline p53 mutations contribute to a small portion
      of astrocytic tumors, (2) inherited mutations of the p16 and PTEN gene do not
      predispose to the development of gliomas, and (3) other genes are involved in
      glioma predisposition.

PMID- 10589546
TI  - The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS
      overlap syndrome and may be a frequent cause of MELAS.
AB  - We report on 4 male patients with clinical, radiological, and muscle biopsy
      findings typical of the mitochondrial encephalomyopathy with lactic acidosis and
      stroke-like episodes (MELAS) phenotype. Skeletal muscle mitochondrial DNA (mtDNA)
      analysis showed that all patients harbored a heteroplasmic G13513A mutation in
      the ND5 subunit gene. One of these cases (Patient 1) presented with symptoms
      characteristic of Leber's hereditary optic neuropathy (LHON) 2 years before the
      first stroke-like episode. Quantitative analysis in several postmortem tissue
      sections showed that the relative proportions of mutant mtDNA were generally
      lower than those reported with other pathogenic mtDNA mutations. Single-fiber
      polymerase chain reaction studies demonstrated significantly higher amounts of
      mutant mtDNA in ragged red fibers (RRFs) compared with non-RRFs. This study
      indicates that the G13513A transition is likely to be pathogenic, that it can
      cause an LHON/MELAS overlap syndrome, and that it may be a more frequent cause of
      MELAS than previously recognized.

PMID- 10589547
TI  - Increased 8-oxo-dGTPase in the mitochondria of substantia nigral neurons in
      Parkinson's disease.
AB  - There is growing evidence for the involvement of oxidative stress and
      mitochondrial respiratory failure in nigral neuronal death in Parkinson's disease
      (PD). We report increased immunoreactivity of 8-oxo-dGTPase (8-oxo-7, 8
      dihydrodeoxyguanosine triphosphatase [hMTH1]), an enzyme known to play an
      important role in controlling spontaneous mutagenesis, and 8-oxo-7, 8
      deoxyguanosine (8-oxo-dG) in the mitochondria of the substantia nigra of 6 PD
      patients. Our results suggest that hMTH1 might be a useful marker of oxidative
      stress and can be used to explore the relation between such oxidative stress and
      genomic instability.

PMID- 10589548
TI  - Leukoencephalopathy associated with a disturbance in the metabolism of polyols.
AB  - In vivo proton magnetic resonance spectroscopy of the brain demonstrated highly
      elevated levels of arabitol and ribitol in a 14-year-old boy with a white matter
      disorder and neuropathy of unknown origin. These polyols also were shown to be
      elevated in body fluids, suggesting an inborn error in polyol metabolism. The
      strong plasma/ cerebrospinal fluid/brain gradient, with concentrations increasing
      in that order, suggests a primary neurometabolic disorder. Thus far, a basic
      enzyme defect has not been identified.

PMID- 10589549
TI  - Early dissociation of verbal and nonverbal gestural ability in an epileptic deaf
      child.
AB  - Studies of sign language aphasia in deaf adults have provided the evidence for
      two separable verbal and nonverbal manual gesture systems. We report a
      congenitally deaf child with a idiopathic focal epilepsy of childhood who showed
      specific language impairment in French sign language. The child's amazing
      performances in miming or sketching pictures she was unable to sign support the
      notion of an early dissociation of the two gestural systems.

PMID- 10589550
TI  - Amyloid beta protein species in cerebrospinal fluid and in brain from patients
      with Down's syndrome.

PMID- 10589551
TI  - Basic fibroblast growth factor does not prolong survival in a transgenic model of
      familial amyotrophic lateral sclerosis.

PMID- 10589552
TI  - Clinical MR imaging at 8 tesla: the new frontier of ultra high field MRI.

PMID- 10589553
TI  - Design and assembly of an 8 tesla whole-body MR scanner.
AB  - PURPOSE: The purpose of this report is to describe the design and construction of
      an 8 T/80 cm whole-body MRI system operating at 340 MHz. METHOD: The 8 T/80 cm
      magnet was constructed from 414 km of niobium titanium superconducting wire. The
      winding of this wire on four aluminum formers resulted in a total inductance of
      4,155 H. Gradient subsystems included either a body gradient or a head gradient
      along with a removable shim insert. The magnet and gradient subsystems were
      interfaced to two spectrometers. These provided the control of the gradient
      amplifiers and the two sets of four RF power amplifiers. The latter provide in
      excess of 8 kW of RF power from 10 to 140 MHz and 10 kW of RF power from 245 to
      345 MHz. A dedicated computer-controlled patient table was designed and
      assembled. The entire system is located in a clinical setting, facilitating
      patient-based studies. RESULTS: The 8 T/80 cm magnet was energized without
      complication and achieved persistent operation using 198.9 A of current, thereby
      storing 81.5 MJ of magnetic energy. Exceptional performance was observed for
      nearly all components both in isolation and when combined within the complete
      system. CONCLUSION: An 8 T/80 cm MRI system has been assembled. The magnet
      subsystem is extremely stable and is characterized by good homogeneity and
      acceptable boil-off rates.

PMID- 10589554
TI  - Dielectric resonance phenomena in ultra high field MRI.
AB  - PURPOSE: Dielectric resonances have previously been advanced as a significant
      cause of image degradation at higher fields. In this work, a study of dielectric
      resonances in ultra high field MRI is presented to explore the real importance of
      dielectric resonances in the human brain in this setting. METHOD: Gradient
      recalled echo images were acquired using a transverse electromagnetic resonator
      at 1.5, 4.7, and 8 T. Images were obtained from the human head and from phantoms
      filled with pure water, saline, and mineral oil. In addition, an exact
      theoretical analysis of dielectric resonances is presented for a spherical
      phantom and for a model of the human head. RESULTS: Theoretical results
      demonstrate that distilled water can sustain dielectric resonances in head-sized
      spheres near 200 and 360 MHz, but the presence of significant conductivity
      suppresses these resonances. These findings are confirmed experimentally with
      proton images of water and saline (0.05 and 0.125 M NaCl). For lossy phantoms,
      coupling between the source and phantom overwhelms the dielectric resonance.
      Because of their low relative permittivity, mineral oil phantoms with 20 cm
      diameter do not exhibit dielectric resonances below approximately 900 MHz.
      Significant dielectric resonances were not observed in human head images obtained
      at 1.5, 4.7, and 8 T.

PMID- 10589555
TI  - Macroscopic susceptibility in ultra high field MRI.
AB  - PURPOSE: Magnetic susceptibility provides the basis for functional studies and
      image artifacts in MRI. In this work, magnetic susceptibility and the associated
      artifacts were analyzed at 8 T in phantoms and in the human head. METHOD: A
      mineral oil phantom was constructed in which three cylindrical air-filled tubes
      were inserted. This phantom was analyzed with gradient-recalled echo and SE
      imaging techniques acquired using varying TEs and receiver bandwidths. To
      visualize the presence of magnetic susceptibility artifacts in the head at 8 T,
      near axial, coronal, and sagittal GE images were also acquired from human
      volunteers. RESULTS: The use of gradient-recalled echo imaging resulted in the
      production of significant magnetic susceptibility artifacts. These artifacts
      could be readily visualized in phantom samples containing air-filled cylindrical
      tubes. In the human head, susceptibility artifacts produced significant image
      distortion in the skull base region. In this area, susceptibility artifacts often
      resulted in the complete loss of MR signal. Magnetic susceptibility artifacts
      were manifested as bands of varying signal intensity in the frontal lobe and
      temporal bone region. In addition, they produced clear distortions in the
      appearance of brain vasculature and seemed to accentuate the relative size of
      venous structures within the brain. CONCLUSION: When using gradient-recalled echo
      imaging in combination with relatively long TE values, magnetic susceptibility
      artifacts can be severe at 8 T. These artifacts could be reduced by increasing
      receiver bandwidths and by lowering effective TEs. As ultra high field MRI
      provides a fertile ground for the study of susceptibility artifacts in MRI,
      improvements obtained at this field strength will have a direct impact on studies
      performed at lower field strengths.

PMID- 10589556
TI  - Macroscopic susceptibility in ultra high field MRI. II: acquisition of spin echo
      images from the human head.
AB  - The presence of magnetic susceptibility can lead to substantial geometric
      distortions when imaging the human head at 8 T. These are particularly
      significant in gradient echo images where susceptibility often results in a
      noticeable loss of MR signal in the temporal lobe, the frontal lobe, and the
      paranasal sinus regions. In this work, anterior coronal gradient and spin echo
      images were acquired from the frontal lobe and sinus regions. The spin echo was
      shown to significantly overcome the loss of signal observed in the corresponding
      gradient echo images, resulting in data of greatly increased quality. In
      conclusion, whereas susceptibility artifacts are significant in ultra high field
      MRI, they can be largely surmounted by using spin echo techniques, as had been
      previously demonstrated in studies at lower field strength.

PMID- 10589557
TI  - RF penetration in ultra high field MRI: challenges in visualizing details within
      the center of the human brain.
AB  - PURPOSE: The purpose of this work is to discuss radio frequency (RF) penetration
      and its relevance to imaging the human head and to acquire images containing
      intricate structures located at the center of the brain with ultra high field MRI
      (UHFMRI). METHOD: A simple plane wave analysis of RF penetration was performed
      based on Maxwell equations as a function of frequency up to 900 MHz. Gradient
      recalled images were acquired at 8 T (340 MHz) using an RF resonator operating in
      quadrature. Typical acquisition parameters were as follows: TR = 750 ms, TE = 17
      ms, slice thickness = 2 mm, FOV = 20 x 20 cm, matrix = 1,024 x 1,024. The
      specific absorption rate was well below 1 W/kg. RESULTS: A simple analytical
      treatment, for a plane wave up to 900 MHz, reveals a lack of decreasing
      penetration depth with frequency beyond 200 MHz. Gradient-recalled echo images
      acquired from the human head displayed good contrast, homogeneity, and
      resolution. Importantly, excellent structural detail was observed on the
      resulting MR images, demonstrating that RF penetration is not a problem at 8 T.
      Images reveal excellent detail including the red nucleus, anterior commissure,
      fornix, mamillary body, pineal gland, and ependymal lining of the fourth
      ventricle. CONCLUSION: Structures located at the center of the human brain can be
      clearly visualized at 8 T with no detectable loss in signal intensity arising
      from RF penetration. The ability to examine these structures with UHFMRI will
      provide a powerful new modality for diagnostic radiology.

PMID- 10589558
TI  - Human leptomeningeal and cortical vascular anatomy of the cerebral cortex at 8
      Tesla.
AB  - PURPOSE: The purpose of this work was to describe the human leptomeningeal and
      cortical vascular anatomy as seen at high resolution on an 8 T UHFMRI system.
      METHOD: With a 1024 x 1024 matrix, axial gradient echo images of the cerebral
      cortex were acquired on a human volunteer at 8 T with TR 500 ms, TE 16 ms, flip
      angle 22.5 degrees, bandwidth 53 kHz, and slice thickness 2.84 mm. The same
      subject was evaluated at 1.5 T using similar parameters. The images were then
      reviewed in detail and compared with known cortical and leptomeningeal vascular
      anatomy. RESULTS: Two hundred forty micron in-plane resolution images of the
      human brain were acquired at 8 T without evident artifact from susceptibility
      distortions, RF penetration, or dielectric resonances. The CSF, gray matter, and
      white matter structures were well discerned. The microscopic leptomeningeal
      vascular anatomy was well visualized, and the course of small perforating
      cortical vessels could be followed from the cortical surface to the white matter
      junction. CONCLUSION: Initial 8 T images of the brain demonstrate detailed
      leptomeningeal and cortical vascular anatomy.

PMID- 10589559
TI  - High resolution MRI of the deep brain vascular anatomy at 8 Tesla: susceptibility
      based enhancement of the venous structures.
AB  - PURPOSE: The purpose of this work was to describe the deep vascular anatomy of
      the human brain using high resolution MR gradient echo imaging at 8 T. METHOD:
      Gradient echo images were acquired from the human head using a transverse
      electromagnetic resonator operating in quadrature and tuned to 340 MHz. Typical
      acquisition parameters were as follows: matrix = 1,024 x 1,024, flip angle = 45
      degrees, TR = 750 ms, TE = 17 ms, FOV = 20 cm, slice thickness = 2 mm. This
      resulted in an in-plane resolution of approximately 200 microm. Images were
      analyzed, and vascular structures were identified on the basis of location and
      course. RESULTS: High resolution ultra high field magnetic resonance imaging
      (UHFMRI) enabled the visualization of many small vessels deep within the brain.
      These vessels were typically detected as signal voids, and the majority
      represented veins. The prevalence of the venous vasculature was attributed
      largely to the magnetic susceptibility of deoxyhemoglobin. It was possible to
      identify venous structures expected to measure below 100 microm in size.
      Perforating venous drainage within the deep gray structures was identified along
      with their parent vessels. The course of arterial perforators was more difficult
      to follow and not as readily identified as their venous counterparts. CONCLUSION:
      The application of high resolution gradient echo methods in UHFMRI provides a
      unique detailed view of particularly the deep venous vasculature of the human
      brain.

PMID- 10589560
TI  - High resolution MRI of the deep gray nuclei at 8 Tesla.
AB  - PURPOSE: High resolution MR images obtained from a normal human volunteer at 8 T
      are utilized to describe the appearance of iron-containing deep gray nuclei at
      this field strength. METHOD: High resolution (1,024 x 1,024 matrix) near-axial
      gradient echo images of the deep gray nuclei were acquired on a human volunteer
      by using an 8 T scanner. The images were acquired using a transverse
      electromagnetic resonator operating in quadrature. The following parameters were
      utilized: TR = 750 ms, TE = 17 ms, flip angle = 45 degrees, receiver bandwidth =
      50 kHz, slice thickness = 2 mm, FOV = 20 cm. The 8 T images were reviewed and
      correlated to the known anatomy of the deep nuclei by comparing them with images
      observed at lower field strength, published diagrams, and histologic sections. In
      addition, the appearance of the nuclei was related to the known imaging
      characteristics of brain iron at lower fields. RESULTS: The caudate, globus
      pallidus, putamen, thalami, substantia nigra, and red nuclei were clearly
      identified. The structures with the highest levels of iron, the globus pallidus,
      substantia nigra, and red nuclei, demonstrated significantly decreased signal,
      providing a map of iron distribution in the human brain. CONCLUSION: Preliminary
      imaging at 8 T demonstrates the ability to acquire ultra high resolution images
      of the deep nuclei, with signal characteristics believed to represent the
      distribution of brain iron. This may prove to be important in the early diagnosis
      of several neurodegenerative disorders.

PMID- 10589561
TI  - T1- and T2-weighted imaging at 8 Tesla.
AB  - In this work, both T1- and T2-weighted fast imaging methods at 8 T are presented.
      These include the modified driven equilibrium Fourier transform (MDEFT) and rapid
      acquisition with relaxation enhancement (RARE) methods, respectively. Axial MDEFT
      images were acquired with large nutation angles, both partially suppressing gray
      and white matter and permitting the visualization of vascular structures rich in
      unsaturated spins. Sagittal RARE images, acquired from the same volunteer, were
      highly T2-weighted, thus highlighting the CSF. At the same time, they provided
      good visualization of the corpus callosum, cerebellum, and gray and white matter
      structures. Importantly, both MDEFT and RARE images could be acquired without
      violating specific absorption rate guidelines.

PMID- 10589562
TI  - Black body and transverse electromagnetic resonators operating at 340 MHz: volume
      RF coils for ultra high field MRI.
AB  - PURPOSE: The purpose of this work was to describe the newly formulated black body
      (BB) resonator with historical perspective and to outline the construction and
      assembly of the transverse electromagnetic (TEM) RF coil for use in ultra high
      field MRI (UHFMRI) studies at 340 MHz. METHOD: TEM and BB resonators were
      machined from acrylic and Teflon tubing, copper foil, and brass connectors.
      Tuning was accomplished through adjustable TEM elements. Variable Teflon-based
      capacitors were utilized to provide matching to the 50 omega line. The TEM
      resonator operated in quadrature, and the BB resonator operated in linear mode.
      The final resonators were fully adjustable from 63 to 430 MHz. Quality (Q) values
      were measured using a network analyzer over this frequency range for the unloaded
      and loaded coils. Coil performance was also evaluated using gradient and spin
      echo imaging at 8 T. RESULTS: Both resonators yielded excellent images from
      mineral oil phantoms, with good homogeneity throughout the imaging volume. The BB
      resonator was characterized with enhanced signal-to-noise ratio and greatly
      reduced RF power requirements relative to the TEM resonator. Images obtained from
      the human head at 8 T with the TEM resonator were also excellent. Tuning remains
      a tedious process. CONCLUSION: The TEM resonator provides an excellent RF coil
      for imaging studies up to 340 MHz. Its homogeneity reliability remains to be
      improved. In part as a result of its inability to sustain radiative loses, the BB
      resonator has extremely low RF power requirements. The BB resonator may have
      important uses in limiting RF power requirements and enhancing signal-to-noise
      ratio at other frequencies. Larger slightly modified versions may also prove
      useful in human imaging, depending on tolerances and final quality factors.

PMID- 10589563
TI  - Diagnostic pitfalls of breath-hold MR urography in obstructive uropathy.
AB  - Breath-hold MR urography (MRU) is being used with increasing frequency to
      evaluate urinary tract pathology. Although multiple studies have documented the
      accuracy of breath-hold MRU in the evaluation of obstructive uropathy, pitfalls
      associated with this technique may result in diagnostic errors. This essay
      illustrates both technical and interpretive pitfalls of MRU and suggests
      strategies for their recognition and avoidance.

PMID- 10589564
TI  - Pancreatitis complicated by gland necrosis: evolution of findings on contrast
      enhanced CT.
AB  - PURPOSE: The purpose of this work was to investigate the natural history of
      pancreatic necrosis on contrast-enhanced CT in patients managed nonoperatively.
      METHOD: A computer-based radiology information search revealed 32 patients with
      pancreatic necrosis who had had serial contrast-enhanced CT scans and were
      managed nonoperatively. There were 23 men and 9 women with a mean age of 51
      years. One hundred forty-five contrast-enhanced CT scans were retrospectively
      reviewed for the location and extent of necrosis. The medical records of all
      patients were reviewed. RESULTS: The 32 patients had a mean Ranson clinical grade
      of 5.8 (range 3-8). Eighteen of these 32 patients were managed nonoperatively,
      and 14 patients required a necrosectomy after initial nonoperative management. In
      the 32 patients, the location of necrosis was in the head (3), body (6), tail
      (2), head/body (2), head/body/tail (9), body/tail (9), and head/tail (1). Extent
      of necrosis was 0-25% (9), 26-50% (6), 51-75% (6), and 76-100% (11). The extent
      of necrosis remained stable during follow-up in 22 (69%) patients and increased
      during follow-up in 10 (31%). Necrosectomy was performed in six (60%) patients in
      whom there was an increase in necrosis and eight (36%) patients in whom necrosis
      was stable. No patient had restoration of normal enhancement in an area that was
      previously necrotic. There were five patients who were managed nonoperatively
      (mean follow-up 318 days) in whom the necrosis eventually resorbed, forming a
      focal parenchymal cleft reminiscent of a scar. Five of the 32 patients died.
      CONCLUSION: Pancreatic necrosis as demonstrated by CT tends to remain stable in
      most patients treated nonoperatively. If the extent of necrosis increases,
      patients are more likely to require a necrosectomy. In some patients managed
      nonoperatively, the pancreatic necrosis will resorb, resulting in a fat-replaced
      cleft reminiscent of a scar.

PMID- 10589565
TI  - Characterization of cystic tumors of the pancreas: CT accuracy.
AB  - PURPOSE: The purpose of this work was to evaluate the capabilities of CT to
      accurately characterize cystic tumors of the pancreas. METHOD: Two observers
      retrospectively evaluated the CT exams of 100 cystic masses of the pancreas, with
      pathological confirmation. The two observers, blinded about clinical information
      and the final diagnosis, tried to categorize the lesions according to well
      established morphologic features. Statistical analysis was performed to measure
      the agreement between each radiologist and the consensus diagnosis and to
      evaluate the usefulness of certain CT findings in differentiating one type of
      cystic pancreatic neoplasm from another. RESULTS: Serous cystadenoma was better
      diagnosed by CT [Youden misclassification index (Ymi) = 0.72] than mucinous
      cystic tumor (Ymi = 0.44) and solid pseudopapillary tumor (cystic variant) (Ymi =
      0.47). CONCLUSION: As patients with previous history of pancreatitis were
      excluded from the study, CT findings allowed correct characterization of only 60%
      of cystic pancreatic masses. Among the remaining 40%, 15-20% of the wrong
      diagnoses could not be corrected by means of CT, given the patterns shown by the
      tumors. In 20-25% of the cases, a nonspecific diagnosis of cystic mass was made.

PMID- 10589566
TI  - Helical hydro-CT for diagnosis and staging of gastric carcinoma.
AB  - PURPOSE: The purpose of this work was to define the accuracy of helical hydro-CT
      (HHCT) in the diagnosis and staging of gastric carcinoma. METHOD: One hundred
      twelve patients with gastric carcinoma were preoperatively imaged by HHCT.
      Gastric distension was achieved by ingestion of up to 1,500 ml of water. Bolus
      tracking was performed, and peristalsis was minimized by intravenously
      administered spasmolytics. Contrast material was then injected, and helical
      scanning was performed at the time of peak enhancement of the liver. CT images
      were analyzed for tumor infiltration of the gastric wall, and TNM staging
      criteria were applied according to the International Union Against Cancer (UICC)
      classification. The results were correlated with histopathologic findings.
      RESULTS: One hundred two of 115 (89%) gastric carcinomas were correctly diagnosed
      by HHCT. Small malignant ulcers (< or =2 cm) that corresponded to early gastric
      carcinoma were not visible on CT scans. T and N staging accuracies were 51% each;
      abdominal M staging was correct in 79% of all cases. The positive and negative
      predictive values of HHCT to foresee curative resection of gastric carcinoma were
      75 and 84%, respectively. CONCLUSION: Mural thickening as well as marked contrast
      enhancement of the gastric wall are firmly related to gastric carcinoma. The
      accuracy of HHCT is acceptable for M staging but inadequate for local staging of
      gastric carcinoma. Nonetheless, HHCT is a useful guide for choosing between tumor
      resection and nonoperative treatment of patients. We therefore recommend HHCT as
      the method of choice for preoperative imaging of gastric carcinoma.

PMID- 10589567
TI  - CT features of torsion of benign cystic teratoma of the ovary.
AB  - PURPOSE: The purpose of this work was to evaluate the usefulness of CT scans for
      distinguishing torsed from uncomplicated benign cystic teratoma (BCT). METHOD:
      Retrospective analysis was performed in 14 torsed BCTs (14 patients) and in 23
      uncomplicated BCTs (20 patients) for comparison. The features on CT scans were
      compared to the pathologic findings. RESULTS: CT findings indicating torsed BCT
      were the presence of eccentric wall thickening of >1 cm, peritumoral
      infiltration, and presence of enlarged solid tubal mass adjacent to the uterus (p
      < 0.05). CONCLUSION: The present study suggests that CT is useful in
      differentiating torsed from uncomplicated BCT. Although CT findings are not
      specific for some patients, detection of certain CT findings could increase the
      diagnostic accuracy.

PMID- 10589568
TI  - Collision tumors of the ovary associated with teratoma: clues to the correct
      preoperative diagnosis.
AB  - PURPOSE: Collision tumors represent a coexistence of two adjacent but
      histologically distinct tumors without histologic admixture in an organ. The
      purpose of this study was to describe the imaging findings of collision tumors of
      the ovary associated with teratoma and to look for clues that might lead to the
      correct preoperative diagnosis. METHOD: Seven pathologically proven cases of
      collision tumor of the ovary associated with teratoma were retrospectively
      reviewed. Ovarian teratomas were coexistent with mucinous cystadenoma (n = 4),
      borderline mucinous tumor (n = 1), mucinous cystadenocarcinoma (n = 1), and
      dysgerminoma (n = 1). US (n = 5), CT (n = 3), and/or MRI (n = 4) findings were
      evaluated. RESULTS: In addition to the typical findings of teratoma, the mass
      contained a multiloculated cystic portion filled with nonfatty fluid, suggesting
      the coexistent epithelial tumor in five cases. In one case, the mass contained a
      large solid component, suggesting the possibility of collision tumor. In the
      remaining one case, coexistent small mucinous cystadenoma could not be
      identified. CONCLUSION: Preoperative imaging for ovarian teratoma revealed a
      collision tumor in six of seven cases. The possibility of a collision tumor
      should be considered when an ovarian teratoma has imaging findings that cannot be
      explained solely by an ovarian teratoma.

PMID- 10589570
TI  - Renal involvement in multifocal fibrosclerosis: CT and MRI.

PMID- 10589569
TI  - Pancreatic metastasis from clear cell renal carcinoma: diagnosis with chemical
      shift MRI.
AB  - Some clear cell renal cell carcinomas contain intracellular lipid, which can be
      detected with chemical shift MRI. We present an example of surgically proven
      metastatic clear cell renal carcinoma to the pancreas, which was diagnosed using
      chemical shift MRI.

PMID- 10589571
TI  - Gd-DTPA: a possible alternative contrast agent for use in CT during intraarterial
      administration.

PMID- 10589572
TI  - Thin-section CT findings in rheumatoid arthritis-associated lung disease: CT
      patterns and their courses.
AB  - PURPOSE: The purpose of this study was to describe the long-term follow-up CT
      evaluation in rheumatoid arthritis (RA)-associated lung disease. METHOD: Thin
      section CT scans from 29 patients with RA and suspected associated lung disease
      were reviewed. Twenty-two patients underwent sequential CT evaluation during 3 to
      108 months of follow-up (mean 28 months). Histologic comfirmation of pulmonary
      involvement was available in 19 patients. RESULTS: Three major patterns were
      identified: reticulation with or without honey-combing (n = 19), centrilobular
      branching lines with or without bronchial dilatation (n = 5), and consolidation
      (n = 5). Reticulation and centrilobular branching lines corresponded to usual
      interstitial pneumonia (n = 14) and bronchiolitis obliterans (n = 1),
      respectively. Consolidation corresponded to bronchiolitis obliterans organizing
      pneumonia (BOOP; n = 3) and coexistent chronic eosinophilic pneumonia (CEP) and
      BOOP (n = 1). Patients with reticulation had rapid deterioration when there was
      new appearance of multifocal areas of ground-glass attenuation. Centrilobular
      branching lines progressed to bronchiectasis in one case. There was mild
      progression of existing bronchiectasis associated with centrilobular branching
      lines in one case. Area of consolidation in two patients with BOOP and one with
      coexistent CEP and BOOP evolved into honeycombing at serial CT. CONCLUSION: Thin
      section CT is a noninvasive technique for monitoring disease morphology in RA
      associated lung disease. Initial CT findings and their evolution on sequential
      examinations may be useful in evaluating prognosis.

PMID- 10589573
TI  - Fatal air embolism as a complication of CT-guided needle biopsy of the lung.
AB  - A CT-guided needle lung biopsy carries a risk of potential air embolization. We
      present a rare case of air embolization after this procedure. Postmortem CT
      revealed air in the cerebral arteries and the left ventricle. This complication
      is extremely rare; however, it becomes fatal when it happens. Several points to
      prevent this fatal complication are discussed.

PMID- 10589574
TI  - Lipoblastoma of the parietal pleura in a 7-month-old infant.
AB  - A 7-month-old infant boy with pleural lipoblastoma is presented. The diagnosis
      was confirmed by operation. Radiologic findings consisted of a pleura-based mass
      with well-defined margin. The main differentiation is from liposarcoma, which is
      extremely rare in children under 3 years of age.

PMID- 10589575
TI  - Autovagotomy by bronchial carcinoma.

PMID- 10589576
TI  - Tracheal hamartoma: CT findings in two patients.

PMID- 10589577
TI  - The cervical aortic arch with aneurysm formation.
AB  - An asymptomatic 59-year-old man was admitted with an initial suspicion of
      mediastinal tumor. He was diagnosed as having a left-sided cervical aortic arch
      (Haughton type D) with arch aneurysm by using contrast-enhanced CT and
      angiography. The arch aneurysm was surgically removed. This is the 20th reported
      case of cervical aortic arch with aneurysm formation.

PMID- 10589578
TI  - Primary angiosarcoma of the heart in identical twins.
AB  - Imaging findings of cardiac angiosarcoma in identical twins are presented and
      discussed.

PMID- 10589579
TI  - Spontaneous progression of ascending aortic intramural hematoma to Stanford type
      A dissection fortuitously witnessed during an MR examination.
AB  - Aortic intramural hematoma may occur as a primary event (spontaneous dissection
      without intimal flap) or secondary to a penetrating atherosclerotic ulcer. The
      management of intramural hematoma of the ascending aorta is somewhat
      controversial because of limited published data, but some centers advocate early
      surgical intervention. We describe a patient with an intramural hematoma of the
      ascending aorta that progressed to a classic communicating dissection during an
      MR examination. This case graphically demonstrates the potential instability of
      patients with intramural hematoma of the ascending aorta.

PMID- 10589580
TI  - MRI of marked dural sac compression by surgicel in the immediately postoperative
      period after uncomplicated lumbar laminectomy.
AB  - PURPOSE: Our purpose was to determine what represents normal findings on MR
      examinations of the lumbar spine in the immediately postoperative period
      following lumbar laminectomy with retained Surgicel. METHOD: MR examinations were
      performed immediately following lumbar laminectomy in 10 patients referred for
      symptoms of spinal stenosis. All had Surgicel retained against the dura and were
      doing well postoperatively without suggestion of adverse symptoms. Images were
      obtained within 4 days of surgery, most within 24 h. RESULTS: In 9 of 10
      patients, severe dural tube compression was present, greater than that evident on
      preoperative studies. CONCLUSION: Marked spinal canal compression can be a normal
      finding in the immediately postlaminectomy period in patients with retained
      Surgicel. There is a lack of correlation between apparent mass effect on the
      thecal sac and adverse effect. The MR appearance in such instances is not
      significant in the absence of compressive clinical symptomatology.

PMID- 10589581
TI  - Intravertebral vacuum phenomenon following fractures: CT study on frequency and
      etiology.
AB  - PURPOSE: The purpose of this work was to determine the frequency and etiology of
      the intravertebral vacuum phenomenon (IVP). METHOD: CT examinations of 96
      vertebral fractures were evaluated for IVP. Bone mineral density (BMD) was
      determined in nonfractured vertebrae. For calibration purposes, densities of a
      standard phantom measured in 30 patients who underwent quantitative CT
      examinations in the same time period were used and precision was calculated.
      RESULTS: Eleven of 96 fractures (11.5%) showed IVP. IVP was present in 4 of 20
      fractures at T12 (20%), in 4 of 23 at L1 (17.4%), and 1 IVP was found at L2-4
      each. Mean +/- SD age of patients with IVP was 68.3 +/- 10.5 years and without
      47.8 +/- 19.4 years (p < 0.001). Mean +/- SD density of nonaffected vertebra was
      45.9 +/- 17.0 mg of hydroxyapatite/ml for patients with IVP and 139.5 +/- 62.6
      mg/ml for those without IVP (p < 0.0005). An average precision of 1.2% was
      calculated for the density measurements over the investigated time. CONCLUSION:
      Following vertebral fractures, IVP on CT scans is more common than presumed and
      increases with age. There exists a significant inverse correlation between the
      BMD and the frequency of IVP.

PMID- 10589582
TI  - Vertebral hemangioendothelial sarcoma: MR findings.

PMID- 10589583
TI  - Nasopharyngeal carcinoma: review of how imaging affects staging.
AB  - Imaging plays an important role in the staging of carcinoma of the nasopharynx.
      Accurate staging is necessary as the treatment is directly dependent on stage.
      Clinical examination provides information on mucosal involvement but is unable to
      determine the deep extension or presence of skull base invasion or intracranial
      spread. The 1997 International Union Against Cancer (UICC) and American Joint
      Committee on Cancer (AJCC) staging manuals were a collaborative project that
      provided a unified classification for nasopharyngeal carcinoma (NPC). The
      majority of staging can be identified only on imaging and not by clinical
      examination. The intent of this article is to provide information on the specific
      imaging findings that will directly affect the stage and treatment of NPC.

PMID- 10589584
TI  - Short TE proton MRS and neurofibromatosis type 1 intracranial lesions.
AB  - PURPOSE: The intracranial lesions of neurofibromatosis type 1(NF-1) have variable
      pathology and growth based on molecular genetics. Because of this variable
      pathology and growth, the lesions are followed by sequential MRI. Our hypothesis
      was that MR spectroscopy (MRS) could provide a noninvasive neurochemical biopsy
      of NF-1 lesions, thereby distinguishing the different lesions, monitoring their
      variable growth, and having added value when compared with MRI. METHOD: Nineteen
      patients fulfilling the National Institutes of Health criteria for NF-1 were
      followed with sequential MRI and short TE proton MRS. MRI monitored the lesions
      by observing the area of prolonged T2, mass effect, and degree of enhancement.
      MRS monitored the lesions by following the level of neurons, cellularity, and a
      by-product of the inositol signaling pathway. A comparison was made between the
      MRI and MRS findings to determine if MRS provided added value. Sixty-nine spectra
      were obtained in 24 resions. RESULTS: MRI was able to identify hamartomas,
      gliomas, and indeterminate lesions. MRS was able to distinguish three distinct
      spectra when compared with the cellularity of normal deep white matter (DWM): a
      hamartoma spectrum with a choline/creatine (CHO/CRE) ratio below 1.5, a
      transitional spectrum with a CHO/CRE ratio above 1.5 and below 2.0, and a glioma
      spectrum with a CHO/CRE ratio above 2.0. On comparing MRS and MRI, MRS provided
      added value by identifying changes in cellularity while MR images were stable,
      identifying spectra that could distinguish hamartomas from gliomas, and
      identifying a transitional spectrum that could progress or regress into glioma or
      hamartoma spectrum. CONCLUSION: MRS was able to identify three distinct spectra
      in NF-1 lesions when compared with the cellularity of normal DWM, thereby
      providing a neurochemical means to characterize lesions.

PMID- 10589585
TI  - Early abnormalities related to postinfarction Wallerian degeneration: evaluation
      with MR diffusion-weighted imaging.
AB  - PURPOSE: Wallerian degeneration (WD) is most commonly seen after cerebral
      infarctions and results in persistent neurological deficits. MRI may detect
      changes related to WD as early as 4 weeks after the insult. We sought to
      determine if MR diffusion-weighted imaging (DWI) detects changes of WD during the
      acute period that follows a cerebral infarction. METHOD: Eleven patients with
      cerebral infarctions underwent DWI within 72 h of the onset of symptoms. DWI was
      performed using a high diffusion gradient strength (B = 1,000) in a single axis
      and trace imaging. We reviewed all images with special attention to the signal
      intensity in the location of the corticospinal tracts. RESULTS: Ten patients
      harbored 11 middle cerebral artery (MCA) infarcts, and one patient had an
      anterior cerebral artery (ACA) infarction. Only one patient with an MCA infarct
      showed a subtle abnormality in the ipsilateral corticospinal tract. The patient
      with the ACA infarct showed an abnormality in the region of the corticopontine
      tract. CONCLUSION: As used in this study, DWI depicted presumed early WD in only
      20% of instances.

PMID- 10589586
TI  - A simple method to improve image nonuniformity of brain MR images at the edges of
      a head coil.
AB  - One of the major sources of image nonuniformity in the high field MR scanners is
      the radiofrequency (RF) coil inhomogeneity. It degrades conspicuity of lesion(s)
      in the MR images of the brain and surrounding tissues and reduces accuracy of
      image postprocessing particularly at the edges of the coil. In this
      investigation, we have devised and tested a simple method to correct for
      nonuniformity of MR images of the brain at the edges of the RF head coil.
      Initially, a cylindrical oil phantom, which fit exactly in the head coil, was
      scanned on a 1.5 T imager. Then, a correction algorithm identified a reference
      pixel value in the phantom at the most homogeneous region of the RF coil. Next,
      every pixel inside the phantom was normalized relative to this reference value.
      The resulting set of coefficients or "correction matrices" was obtained for
      different types of MR contrast agent. Finally, brain MR images of normal subjects
      and multiple sclerosis patients were acquired and processed by the corresponding
      correction matrices obtained with different pulse sequences. Application of
      correction matrices to brain MR images showed a gain in pixel intensity
      particularly in the slices at the edge of the coil.

PMID- 10589587
TI  - Aunt Minnie's corner.

PMID- 10589588
TI  - Strategies to improve compliance with evidence-based clinical management
      guidelines.
AB  - BACKGROUND: Clinical management guidelines (CMGs) have been developed to
      standardize physician practices and ensure safe and cost-effective patient care.
      In June 1996, evidence-based CMGs were initiated at our urban Level I trauma
      center. This study compares physician compliance with two such CMGs before (PRE)
      and after (POST) the institution of continuous surveillance by a clinical
      resource manager. STUDY DESIGN: For 2 months PRE resource manager surveillance
      hospital records were reviewed retrospectively for compliance with two CMGs. POST
      data were collected prospectively for 2 months by the resource manager, who
      alerted practitioners to deviance from CMGs to justify or document therapy
      alternatives. The CMGs studied addressed deep venous thrombosis and stress ulcer
      prophylaxis. "Under" or "over" therapy described that which fell short of or
      exceeded guidelines. Data were analyzed by chi-square; p < 0.05 defined
      statistical significance. RESULTS: Compliance with the CMGs was 48% PRE and 74%
      POST (p=0.001). All noncompliant instances POST (and none PRE) were altered or
      justified. Deep venous thrombosis and ulcer "over" therapy was significantly
      higher PRE (19% versus 2%, p=0.003; 49% versus 19%, p=0.001), resulting in
      $22,760.35 in costs. There was no difference in pulmonary embolism or
      gastrointestinal bleed rate (1%) PRE to POST. CONCLUSIONS: The use of a clinical
      resource manager empowered to monitor and coordinate physician behavior improves
      compliance with CMGs. Further study is warranted to validate resultant outcomes
      benefit, specifically cost-effectiveness and duration of the need for such a
      program.

PMID- 10589589
TI  - Sentinel lymph node mapping in breast cancer using subareolar injection of blue
      dye.
AB  - BACKGROUND: Lymphatic mapping in breast cancer performed solely by
      intraparenchymal injections of blue dye remains an accepted method of identifying
      sentinel nodes, largely because of its simplicity. As currently practiced, the
      technique is associated with a marked learning curve, variable identification
      rates of sentinel nodes, and high false-negative rates. The purpose of this study
      is to improve dye-only lymphatic mapping of the breast by using an alternative
      site for injection of blue dye: the subareolar lymphatic plexus. STUDY DESIGN: In
      the 10 months between August 1998 and May 1999, 40 women with operable breast
      cancer in stages I and II underwent lymphatic mapping and sentinel node biopsy
      performed solely by subareolar injections of blue dye, followed by complete
      axillary node dissection. The technique involved the injection of 5 mL of 1%
      isosulfan blue into the subareolar plexus, which consists of breast tissue
      located immediately beneath the areola. No peritumoral injections of blue dye
      were performed. The ability of subareolar dye injections to identify sentinel
      nodes and accurately predict the pathologic status of the axilla was determined
      and compared with published results for dye-only lymphatic mapping using
      intraparenchymal injections. RESULTS: The identification rate of sentinel nodes
      was 98% (in 39 of 40 patients). Axillary basins harboring positive lymph nodes
      were found in 15 of these 39 patients (38.5%). Sentinel nodes correctly predicted
      the status of these 15 positive axillary basins in 100% of the patients. There
      were no false-negative sentinel node biopsies, indicating a false-negative rate
      of 0 (in 0 of 15). The overall accuracy, sensitivity, and specificity were 100%.
      CONCLUSIONS: Compared with other series of dye-directed lymphatic mapping, the
      present study of dye-only injections into the subareolar plexus demonstrates a
      high sentinel node identification rate, absent false-negative rate, and rapid
      learning curve. On the basis of these findings, we propose that injections into
      the subareolar lymphatic plexus are the optimal way to perform dye-only lymphatic
      mapping of the breast.

PMID- 10589590
TI  - Upregulation of lung chemokines associated with hemorrhage is reversed with a
      small molecule multiple selectin inhibitor.
AB  - BACKGROUND: Hemorrhage can modify the leukocyte-endothelial cell response leading
      to tissue injury. The selectin family of adhesion molecules and chemokines
      mediate the leukocyte-endothelial cell interaction, resulting in neutrophil
      sequestration and activation. This work studies whether a small molecule
      inhibitor of selectins can ameliorate the effect of hemorrhage on chemokine
      expression and neutrophil infiltration in the lung. We also aimed to assess the
      regulatory effect of this small molecule inhibitor of selectins in the lung
      functional and structural response of animals subjected to hemorrhagic shock.
      STUDY DESIGN: We subjected 36 Sprague-Dawley rats to uncontrolled hemorrhagic
      shock for a period of 150 minutes. Three groups of animals were included (n = 12
      per group)-the sham, control, and treated groups, with the latter receiving a
      small molecule selectin inhibitor (TBC-1269) at 25 mg/kg, which was given after
      tail artery transection. The following measurements were evaluated: fluid
      requirements during resuscitation for 150 minutes; PO2/FIO2 ratio, lung water,
      and lung histology, lung myeloperoxidase and lung macrophage inflammatory protein
      2 (MIP-2) mRNA and cytokine induced neutrophil chemoattractant mRNA at 6 hours.
      Statistical analysis included Student's t-test and ANOVA. RESULTS: There was
      significant improvement in lung function as expressed by PO2/FIO2 ratio and wet
      to dry lung water ratio in the treated group. There were no significant changes
      in fluid requirements between the three groups. Neutrophil infiltration, measured
      by tissue myeloperoxidase, was significantly (p < 0.05) decreased in the lungs of
      the treated animals. Lung histology was considerably improved in the treated
      group. The small molecule selectin inhibitor had a profound downregulating effect
      on macrophage inflammatory protein-2 and cytokine-induced neutrophil
      chemoattractant as expressed in lung tissue. CONCLUSIONS: Our study confirms the
      key role that selectins play in the pathogenesis of hemorrhagic shock. The
      multiple selectin blockade allowed for better function and structure of the lung.
      The mechanism of protection may be secondary to the downregulation of chemokine
      expression and neutrophil infiltration.

PMID- 10589591
TI  - Management of anastomotic leakage after nondiverted large bowel resection.
AB  - BACKGROUND: The purpose of this study was to determine the natural history of
      anastomotic leakage after elective colorectal resection and supraperitoneal
      anastomosis without temporary stoma. STUDY DESIGN: Medical records from 1990 to
      1997 were studied; 655 consecutive patients underwent colonic or rectal resection
      (without stoma). Patients were divided into two groups: those with clinical
      anastomotic leakage confirmed by laparotomy (group 1) and those without
      anastomotic leakage (group 2). Postoperative clinical and biologic findings were
      compared between the two groups. RESULTS: Anastomotic leakage occurred in 39 of
      655 patients (6%). Clinically suspected anastomotic leakage was only confirmed by
      contrast radiography in 13 of 24 patients (54%), and by CT in 8 of 9 patients
      (89%). Significantly more patients in group 1 than group 2 had the following:
      fever (> 38 degrees C) on day 2 (p < 0.001); absence of bowel action on day 4 (p
      < 0.001); diarrhea before day 7 (p < 0.001); collection of more than 400 mL of
      fluid through abdominal drains from day 0 to day 3 (p < 0.01); renal failure on
      day 3 (p < 0.02); and leukocytosis after day 7 (p < 0.02). Among the 39 patients
      in group 1, 28 (71%) had at least one of these clinical or biologic
      manifestations before day 5, but the mean delay for reoperation was only 8 days.
      The combination of signs observed before day 5 was associated with an increased
      risk of anastomotic leakage, from 18% with two signs to 67% with three signs.
      Overall mortality rate was 2% (13 of 655) and was significantly higher in group 1
      than group 2: 5 of 39 (13%) versus 8 of 616 (1%, p < 0.001). In patients with
      anastomotic leakage, death occurred in 5 of 23 patients (22%) reoperated on after
      day 5, versus 0 of 11 patients (0%) reoperated on before day 5 (NS). Univariate
      analysis showed that three clinical characteristics were associated with a
      significantly high risk of mortality after reoperation for anastomotic leakage:
      age greater than 65 years (p < 0.01), American Anesthesiologist Association score
      greater than 3 (p < 0.05), and blood transfusions during the first operation (p <
      0.02). CONCLUSIONS: In our study, some postoperative clinical and biologic signs
      were associated with a higher risk of anastomotic leakage. The knowledge of these
      findings might help in the early diagnosis and management of patients with
      anastomotic leakage after large bowel resection.

PMID- 10589592
TI  - Cholecystokinin in the early course of acute post-ERCP pancreatitis.
AB  - BACKGROUND: A high dose of cholecystokinin (CCK) agonist cerulein can induce
      acute pancreatitis in animals. The role of CCK in the induction of acute
      pancreatitis in humans is unclear. We investigated basal plasma CCK levels before
      and after induction of post-ERCP pancreatitis to determine CCK levels in the
      early course of the disease. STUDY DESIGN: We determined plasma CCK
      concentrations in four groups of patients who underwent ERCP: (1) post-ERCP
      pancreatitis patients (n = 23); (2) patients with post-ERCP hyperamylasemia
      without pancreatitis (n = 5); (3) patients with post-ERCP abdominal pain without
      hyperamylasemia (n = 18); and (4) patients with an uneventful post-ERCP period (n
      = 43). Plasma samples were taken before ERCP, 4 to 8 hours, 10 to 16 hours, and
      24 hours after ERCP. Plasma CCK concentrations were determined by a specific and
      sensitive radioimmunoassay using CCK antiserum (Euro-Diagnostica, Malmo, Sweden).
      RESULTS: Plasma CCK levels increased five-fold early in the course in post-ERCP
      pancreatitis patients, but not in post-ERCP hyperamylasemia patients or in
      uncomplicated ERCP patients, where CCK levels temporarily decreased after ERCP.
      In patients with abdominal pain, CCK levels did not change. After the early
      increase, plasma CCK levels declined to almost unmeasurable levels one day after
      the onset of symptoms in post-ERCP pancreatitis. In other groups CCK levels were
      close to the pre-ERCP level. CONCLUSIONS: It remains to be shown whether CCK is
      important in the pathogenesis of post-ERCP pancreatitis or merely a secondary
      phenomenon. There is a rationale to test CCK antagonists in preventing post-ERCP
      pancreatitis.

PMID- 10589593
TI  - An objective scoring system for laparoscopic cholecystectomy.
AB  - BACKGROUND: Direct observation with structured criteria for performance is the
      most reliable and valid method of assessing technical skill during operative
      procedures. We developed such a system to evaluate technical performance during a
      laparoscopic cholecystectomy. The reliability and validity of the system were
      tested by analyzing the correlation among three observers in a multicenter study
      and comparing performance with years of surgical experience. STUDY DESIGN: Thirty
      consecutive cases of laparoscopic cholecystectomy were recorded on videotape, 10
      from each of 3 institutions. Independent scores were generated by three observers
      examining each of the videotapes, providing a total of 90 scores. Points were
      awarded for successful completion of each of 23 different steps required to
      perform a laparoscopic cholecystectomy. Error points were tabulated based on the
      frequency and relative severity of each of 21 potential technical mistakes during
      the operation. The final score was assumed to be a relative measure of technical
      skill and was derived by subtracting error points from points awarded for
      completion of each step of the procedure. Pearson correlation coefficients were
      used to assess agreement among examiners and correlation with year of surgical
      experience. RESULTS: Agreement in final scores among the three observers was
      excellent (r = 0.74-0.96) despite the fact that one observer assigned
      significantly fewer error points. Correlation between year of experience and two
      handed technique scoring was good (r = 0.5, p = 0.057), but the correlation
      between experience and one-handed technique scores was poor (r = 0.02).
      CONCLUSIONS: The technical skills required to perform laparoscopic
      cholecystectomy can reliably be measured using this tool. This method can be used
      to track the learning curve of surgeons in training, evaluate the efficacy of
      alternative training tools, and provide a means of self-assessment for the
      trainee.

PMID- 10589594
TI  - Parenchyma-preserving hepatectomy in the surgical treatment of hilar
      cholangiocarcinoma.
AB  - BACKGROUND: Although extended hepatic resection has been shown to improve
      prognosis by increasing the surgical curability rate in hilar cholangiocarcinoma,
      high surgical morbidity and mortality rates have been reported in patients with
      obstructive jaundice. Postoperative liver failure after hepatic resection in
      patients with obstructive jaundice has been shown to depend on the volume of the
      resected hepatic mass. The aim of this study was to evaluate the results of
      parenchyma-preserving hepatectomy in a surgical treatment for hilar
      cholangiocarcinoma. STUDY DESIGN: Ninety-three resected patients with hilar
      cholangiocarcinoma were included in this retrospective study. The resected
      patients were stratified into three groups: the extended hepatectomy (EXH) group
      (n = 66), the parenchyma-preserving hepatectomy (PPH) group (n = 14), and the
      local resection (LR) group (n = 13). The EXH group had undergone hepatectomy more
      extensive than hemihepatectomy, the PPH group had undergone hepatectomy less
      extensive than hemihepatectomy, and the LR group had undergone extrahepatic bile
      duct resection without hepatic resection. Surgical curability, defined by
      histologically confirmed negative surgical margins, surgical morbidity and
      mortality, and survival rates were compared among the three groups. The
      clinicopathologic factors were studied for prognostic value by univariate and
      multivariate analyses. RESULTS: Surgical curability of the PPH and EXH groups was
      better than that of the LR group. Fifty-four percent of patients in the LR group
      showed positive surgical margins at the hepatic stump of the bile duct, compared
      with 7% in the PPH group and 20% in the EXH groups (p < 0.01 for each
      comparison). Surgical morbidity was higher in the EXH group (48%) than in the LR
      group (8%) and the PPH group (14%) (p < 0.01 and p < 0.05, respectively).
      Postoperative hyperbilirubinemia occurred more frequently in the EXH group (29%)
      than in the LR and PPH groups (0% and 0%, respectively, p < 0.05 for each
      comparison). Survival rates after resection were significantly higher in patients
      who underwent hepatectomy, including PPH and EXH, than in patients who underwent
      LR, 29% versus 8% at 5 years, respectively (p < 0.05). But no significant
      difference in survival was found between the PPH and EXH groups. Univariate and
      multivariate analyses showed that significant prognostic factors for survival
      were resected margin, lymph nodal status, and vascular resection. CONCLUSIONS: In
      conclusion, PPH could obtain a curative resection and improve the outcomes for
      patients with hilar cholangiocarcinoma that is localized at the hepatic duct
      confluence who do not require vascular resection. PPH might bring about a
      beneficial effect in highly selected patients according to extent of cancer and
      high-risk patients with liver dysfunction.

PMID- 10589596
TI  - Adenocarcinoma of the gastroesophageal junction in Japan: relevance of Siewert's
      classification applied to 177 cases resected at a single institution.
AB  - BACKGROUND: There had been a lack of international consensus about the definition
      of cancer of the gastric cardia until Siewert's classification was approved at a
      consensus conference during the second International Gastric Cancer Congress held
      in 1997. STUDY DESIGN: A review of the prospective gastric cancer database at
      Aichi Cancer Center from 1983 to 1992 identified 1,913 gastric carcinoma patients
      who underwent gastrectomy. These patients were classified retrospectively
      according to the Siewert classification, and 177 patients who fell into one of
      the three types form the basis of this study. Survival analyses were performed
      after stratifying patients by clinicopathologic variables. RESULTS: There were 33
      patients with type II and 144 with type III, although none had type I, a type
      frequently observed in the west. No evidence of a change in the frequency of
      types II or III cancers (approximately 9.3% overall) among gastric carcinoma
      patients was observed over the 10-year period. Clinical staging of gastric
      carcinoma by the TNM classification was found to reflect accurately the prognosis
      of these patients. There were no longterm survivors among the few patients with
      metastasis to the perigastric nodes of the distal stomach. CONCLUSIONS: A
      striking difference in the distribution of types of adenocarcinoma of the
      gastroesophageal junction was observed in Japan compared with previously reported
      western data. A subgroup of carcinoma of the proximal stomach identified as types
      II and III may not require proximal gastrectomy from the viewpoint of sufficient
      lymphadenectomy.

PMID- 10589595
TI  - Domino liver transplants for metabolic disorders: experience with familial
      amyloidotic polyneuropathy.
AB  - BACKGROUND: Shortage of liver donors means that new methods of liver procurement
      must be explored. In domino transplantation, organs explanted during
      transplantation in one patient are transplanted into a second patient. Domino
      procedures can be performed with livers from patients having transplantation for
      hepatic metabolic disorders that cause systemic disease without affecting other
      liver functions. Familial amyloidotic polyneuropathy (FAP) type I is one of
      these. STUDY DESIGN: We reviewed the Paul Brousse experience with a domino liver
      transplant program for FAP, hoping to extend the approach to other metabolic
      disorders. RESULTS: Livers from 10 patients transplanted for FAP type 1 were used
      for domino transplants to patients with unresectable primary or metastatic liver
      cancers. There was no perioperative mortality. Neuropathy or cardiomyopathy did
      not increase the morbidity of the domino liver explant and transplant procedures.
      Morbidity for the domino recipients did not appear to be increased. Variant
      transthyretin was detected in the serum in FAP liver recipients, with no
      immediate clinical consequences. CONCLUSIONS: The domino approach is feasible and
      requires careful planning of the surgical procedures for liver explantation,
      particularly for the nature and site of vascular anastomoses. Domino
      transplantation of metabolically dysfunctional livers creates new categories of
      potential donors and potential recipients. It raises new ethical, technical, and
      societal issues. The domino approach could be used in several genetic or
      biochemical disorders now treated by liver transplantation. It has the potential
      to increase the number of liver grafts available for transplantation.

PMID- 10589597
TI  - Attrition in graduate surgical education: an analysis of the 1993 entering cohort
      of surgical residents.
AB  - BACKGROUND: Pyramidal surgical residency programs, in which more residents are
      enrolled than can complete the program, have gradually declined in number in
      recent years. In 1996, the Residency Review Committee for Surgery established a
      policy that the number of residents appointed to a program must be consistent
      with the number who will complete the program. Even so, there is still attrition
      in the ranks of surgical residents, some of whom hold undesignated preliminary
      positions and have no guarantee of a position that will lead to completion of the
      program. This study examined the 1993 entering cohort of surgical residents to
      determine the rate of attrition as of 1998. STUDY DESIGN: Data were collected
      from the AMA's Medical Education Research Information Database, the American
      College of Surgeons Resident Masterfile, and the Association of American Medical
      Colleges GME Tracking Census database. The data were examined by specialty,
      gender, ethnic background, and type of medical school attended. RESULTS: The
      overall attrition rate from surgical GME was 12%; the rate for international
      medical graduates was 33%; and the rate for osteopathic residents was 28%.
      African-American United States and Canadian graduates had attrition rates of 16%
      for men and 8% for women, and Hispanic United States and Canadian graduates had
      attrition rates of 14% for men and 15% for women. General surgery residents had
      an attrition rate of 26%, which included residents in undesignated preliminary
      positions. Gender was not a risk factor except for the significantly higher
      attrition rate of African-American men. Most (81%) of the residents who dropped
      out of surgical GME enrolled in GME in other specialties. CONCLUSIONS: The
      attrition rate from surgical GME is low, and most residents who drop out reenter
      GME in another specialty. Of concern is the high rate of attrition of African
      American men who are United States or Canadian graduates. The highest rate of
      attrition, by far, is in the group of international medical graduates, many of
      whom are likely to have held undesignated preliminary positions.

PMID- 10589598
TI  - Prevention of chronic radiation enteritis.

PMID- 10589599
TI  - Spontaneous internal drainage of a pancreatic pseudocyst.

PMID- 10589600
TI  - Tumescent anesthetic technique for long saphenous stripping.

PMID- 10589601
TI  - A simple technique of portal vein resection and reconstruction during
      pancreaticoduodenectomy.

PMID- 10589602
TI  - Incisional hernia.

PMID- 10589603
TI  - Systemic effects and side effects of cryosurgery used in liver tissue.

PMID- 10589604
TI  - Postoperative nausea and vomiting: prophylaxis versus treatment.

PMID- 10589605
TI  - The safety and efficacy of prophylactic ondansetron in patients undergoing
      modified radical mastectomy.
AB  - We aimed to evaluate the antiemetic efficacy, safety, and clinical utility of
      prophylactic ondansetron administered at the end of the surgery for the
      prevention of postoperative nausea and vomiting (PONV) in a homogenous population
      of 54 women undergoing modified radical mastectomy (MRM). A standard general
      anesthetic and perioperative analgesic technique were used. After surgery,
      patients received either saline placebo or ondansetron 4 mg IV. Episodes of PONV,
      as well as rescue antiemetic requirements, were recorded for the first 24 h after
      surgery. The 24-h incidence of PONV (33.3% vs 81.5%; P = 0.0010) was
      significantly lower in the ondansetron group. The severity of PONV, evaluated by
      the number of emetic episodes per patient (1.59+/-1.90 vs 0.29+/-0.66; P =
      0.0029), and the rescue antiemetic requirement (59.2% vs 14.8%; P = 0.0019) was
      significantly lower, in the ondansetron group. Patient satisfaction scores and
      number needed to prevent PONV (2.07) were significantly better and
      therapeutically more favorable in the ondansetron group. The incidence of adverse
      events such as headache, dizziness, and increased liver enzyme levels (number
      needed to harm = infinity) was similar in both groups. Administered at the end of
      the surgery in adult female patients undergoing general anesthesia for MRM,
      ondansetron 4 mg is effective and safe in preventing PONV. We recommend the
      clinical practice of routine prophylactic ondansetron to prevent PONV after MRM,
      as it significantly improves perioperative patient satisfaction and outcome.
      IMPLICATIONS: We evaluated the antiemetic efficacy, safety, and routine use of
      prophylactic ondansetron, a "gold standard" antiemetic, in women undergoing
      radical breast surgery who were at a high risk of postoperative vomiting. We
      analyzed more meaningful "true" and "therapeutic" outcome measures, and we
      conclude that prophylactic ondansetron is safe and effective and that its routine
      use is justified.

PMID- 10589606
TI  - Preoperative anxiety and intraoperative anesthetic requirements.
AB  - The purpose of this study was to determine whether larger doses of anesthetics
      are required in the anxious patient to establish and maintain a clinically
      sufficient hypnotic component of the anesthetic state. Fifty-seven women
      undergoing bilateral laparoscopic tubal ligation with a propofol-based anesthetic
      regimen were enrolled in this cross-sectional study. Trait (baseline) and state
      (situational) anxiety were assessed in all patients immediately before surgery,
      and the propofol doses required for the induction and maintenance of anesthesia
      were recorded. A bispectral index monitor was used to assure that the hypnotic
      component of the anesthetic state was the same in all patients. We found that
      patients with high trait anxiety required more propofol for both the induction
      (2.1+/-0.4 vs 1.8+/-0.3 mg/kg; P = 0.01) and maintenance of anesthesia (170+/-70
      vs 110+/-20 microg x kg(-1) x min(-1); P = 0.02), compared with patients with low
      trait anxiety. State anxiety, however, was not found to affect the propofol doses
      required for the induction or maintenance of anesthesia. Multiple regression
      models confirmed that Trait anxiety is an independent predictor for
      intraoperative propofol requirements (P = 0.02). We conclude that increased
      baseline (i.e., trait) anxiety is associated with increased intraoperative
      anesthetic requirements. Thus, we suggest that the initial dose of anesthetic
      administered by an anesthesiologist should be modified based on the anxiety level
      exhibited by the patient. IMPLICATIONS: The goal of this study was to assess the
      relationship between preoperative anxiety and intraoperative anesthetic
      requirements. We found that high baseline anxiety predicts increased
      intraoperative anesthetic requirements. We suggest that anesthesiologists should
      modify the initial induction dose based on the anxiety level exhibited by the
      patient.

PMID- 10589607
TI  - Factors contributing to a prolonged stay after ambulatory surgery.
AB  - We identified predictors for prolonged postoperative stay after ambulatory
      surgery using multiple logistic regression models. We collected perioperative
      data for 16,411 ambulatory surgical patients. A log-transformed time to discharge
      variable was modeled by multiple linear regression, including patient-,
      anesthesia-, and surgery-specific variables. The impact of hypothetical
      elimination of perioperative adverse events on mean length of stay was also
      estimated. Separate analyses were performed among patients who received general
      anesthesia (GA) and monitored anesthesia care (MAC). Patients receiving GA stayed
      50 min longer than patients receiving MAC. Patients receiving GA and undergoing
      strabismus, transurethral, or otorhinolaryngological/dental procedures had the
      longest postoperative stay. Among patients receiving GA, smokers had a 4% shorter
      stay compared with nonsmokers; among patients receiving MAC, those with
      congestive heart failure (CHF) had a 11% longer stay compared with patients
      without CHF. Postoperative nausea and vomiting, dizziness, excessive pain, and
      cardiovascular events predicted 22%-79% increases in postoperative stay. The
      hypothetical elimination of all adverse events resulted in a 9.6% decrease in
      mean length of stay among patients receiving GA, but in only a 3.8% decrease
      among patients receiving MAC. The length of postoperative stay among ambulatory
      surgical patients is mainly determined by the type of surgery and by adverse
      events, such as excessive pain, postoperative nausea and vomiting, dizziness,
      drowsiness, and cardiovascular events. Patients with CHF and those who underwent
      long procedures had a higher risk of a prolonged stay. Appropriate prevention and
      management of postoperative symptoms could significantly decrease the length of
      stay among patients receiving GA. IMPLICATIONS: The length of postoperative stay
      among ambulatory surgical patients is mainly determined by the type of surgery
      and by adverse events, such as excessive pain, postoperative nausea and vomiting,
      dizziness, drowsiness, and untoward cardiovascular events. Patients with
      congestive heart failure and those who underwent long procedures had a higher
      risk of a prolonged stay. Appropriate prevention and management of postoperative
      symptoms could significantly decrease the length of stay among patients receiving
      general anesthesia.

PMID- 10589608
TI  - The effect of nitric oxide on platelets when delivered to the cardiopulmonary
      bypass circuit.
AB  - Nitric oxide (NO) decreases platelet adhesion to foreign surfaces in the in vitro
      models of cardiopulmonary bypass (CPB). We hypothesized that NO, delivered into
      the membrane oxygenator (MO), would exert a platelet-sparing effect after CPB.
      Forty-seven patients scheduled for coronary artery surgery were randomized to
      either a NO group, in which NO (100 ppm) was delivered into the MO, or a control
      group, in which CPB was conducted without NO. Platelet numbers, platelet
      aggregation response to 2.5-20 microM adenosine diphosphate, and beta
      thromboglobulin levels were measured after induction of anesthesia, after 1 h on
      CPB and 2 h after the end of CPB. Met-hemoglobin levels were measured during CPB.
      The amount of blood products administered and chest tube drainage were measured
      in the first postoperative 18 h. NO delivered into the MO for up to 180 min did
      not increase met-hemoglobin levels above 4%. NO inhibited the platelet
      aggregation response to 2.5 microM ADP during CPB, otherwise NO had no other
      detectable effect on the aggregation responses or the levels of beta
      thromboglobulin. Platelet numbers were not significantly altered by NO. NO did
      not alter the use of blood products or chest tube drainage. In conclusion, this
      study suggests that NO delivered into the MO of the CPB circuit does not
      significantly alter platelet aggregation and numbers, and does not affect
      bleeding. IMPLICATIONS: Nitric oxide affects platelet function. We demonstrated
      that nitric oxide delivered into the gas inflow of the cardiopulmonary bypass
      circuit membrane oxygenator does not significantly alter platelet numbers or
      function.

PMID- 10589609
TI  - A comparison of two techniques for cervical plexus blockade: evaluation of
      efficacy and systemic toxicity.
AB  - We compared two techniques of cervical plexus blockade (CPB) for carotid
      endarterectomy. Cervical plexus nerve block was performed with a combination of
      bupivacaine and lidocaine, with injections at the C2-C3, C3-C4, and C4-C5
      transverse processes in 11 patients (classical CPB) or with a single injection
      after localization of the cervical plexus with a nerve stimulator in 12 patients
      (interscalene CPB). Pain scores were obtained during block placement and at
      predetermined phases of the operation. Arterial blood was sampled before and 3,
      5, 8, 10, 15, 25, 40, and 60 min after CPB for measurement of bupivacaine and
      lidocaine concentrations. Interscalene CPB was less painful than classical CPB.
      The techniques appeared equally effective. Patients in both groups required
      equivalent supplementation with IV fentanyl and additional local infiltration
      with lidocaine during the most painful stages of surgery. The maximal
      concentration of bupivacaine was lower in interscalene CPB compared with
      classical CPB (1.0 microg/mL versus 1.5 microg/mL, P < 0.01). The time required
      to reach the maximal concentration of bupivacaine was 15 (10-40) min in
      interscalene CPB and 10 (5-17) min in classical CPB (P < 0.05). Lidocaine maximal
      concentration was similar in both groups, however the time required to reach the
      maximal concentration was longer (P < 0.05) in interscalene CPB (15 [10-60] min)
      than in classical CPB (10 [8-20] min). We conclude that the interscalene CPB is
      as effective as the classical CPB as a regional technique for carotid
      endarterectomy and may be associated with a lower systemic absorption of
      bupivacaine. IMPLICATIONS: Cervical plexus blockade for carotid endarterectomy
      can be effectively performed with a single injection after localization of the
      cervical plexus with a nerve stimulator. This technique is simple and was
      associated with less systemic absorption of local anesthetic than the multiple
      injection technique.

PMID- 10589610
TI  - The effects of sodium nitroprusside-induced hypotension on splanchnic perfusion
      and hepatocellular integrity.
AB  - The purpose of our study was to investigate the effects of sodium nitroprusside
      induced hypotension on splanchnic perfusion and hepatocellular integrity. Thirty
      patients undergoing radical prostatectomy were allocated randomly to a sodium
      nitroprusside (SNP) or control group (control). Regional pco2 was measured using
      gastric tonometry, and the regional to arterial difference in partial pressure of
      CO2 and intramucosal pH were calculated. The cytosolic liver enzyme alpha
      glutathione S-transferase and standard liver enzyme markers (alanine
      aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase) were
      also measured. Mean arterial pressure in the SNP group was 50 mm Hg for 97 min
      during surgery. A significant increase from baseline in regional pco2 (from
      40.0+/-4.2 mm Hg to 45.3+/-1.3 mm Hg) and regional to arterial difference in
      partial pressure of CO2 (from 4.1+/-1.1 mm Hg to 9.7+/-1.4 mm Hg) was seen at 90
      min after skin incision only in the SNP group. Intramucosal pH decreased
      significantly from 7.40+/-0.02 to 7.35+/-0.03 during the same period in this
      group. Tonometric variables returned to baseline values within 2 h
      postoperatively. Alpha-glutathione S-transferase concentrations increased
      significantly in the SNP group from baseline to peak concentrations at the end of
      surgery (SNP: 9.93+/-4.94 microg/L; control: 5.85+/-1.86 microg/L). A return to
      baseline values was seen 24 h postoperatively. No significant changes in standard
      liver enzyme markers were seen throughout the study period. It is concluded, that
      splanchnic perfusion was transiently impaired during controlled hypotension. This
      is supported by significant changes in tonometric data. Increased serum levels of
      alpha-glutathione S-transferase may indicate a disturbance in hepatocellular
      integrity. IMPLICATIONS: We studied gastric mucosal tonometry and the cytosolic
      liver enzyme alpha-glutathione S-transferase to evaluate the effects of
      controlled hypotension induced by sodium nitroprusside on splanchnic perfusion
      and hepatocellular integrity. Splanchnic perfusion decreased and alpha
      glutathione S-transferase increased during and after a hypotensive period, but
      returned to baseline values within the first postoperative day, indicating a
      transient impairment of splanchnic perfusion and hepatocellular integrity.

PMID- 10589611
TI  - Limited upper thoracic epidural block and splanchnic perfusion in dogs.
AB  - Epidural blockade leads to a sympathetic block in affected segments and an
      increase of sympathetic out-flow from various unblocked segments. A limited upper
      thoracic epidural block (LUTEB) is used during coronary artery surgery affecting
      the cardiac sympathetic fibers cephalad to the fifth thoracic segment. This block
      does not extend to the sympathetic fibers innervating the gastrointestinal
      organs. A LUTEB may lead to an increase of sympathetic activity in the unaffected
      splanchnic sympathetic segments and the decrease in splanchnic blood flow may
      contribute to gastrointestinal ischemia after cardiac surgery. We tested the
      hypothesis that a LUTEB decreases splanchnic perfusion in anesthetized dogs.
      Thirteen dogs were chronically instrumented with aortic and left atrial
      catheters, which were used for pressure measurement, as well as injection and
      withdrawal of reference samples. Thoracic epidural catheters were placed under
      general anesthesia the day before the experiment. Splanchnic blood flow was
      determined by using colored microspheres. Induction of a LUTEB did not change
      general hemodynamics in awake dogs. Propofol anesthesia induced an increase in
      heart rate that was abolished after LUTEB. LUTEB also decreased mean arterial
      pressure during propofol anesthesia. We conclude that thoracic epidural
      anesthesia had no effect on splanchnic blood flow. In propofol anesthetized
      animals, liver blood flow was increased compared with awake animals; however, it
      did not change after induction of LUTEB. IMPLICATIONS: A sympathetic block in
      certain segments leads to increased sympathetic output in unblocked segments. For
      an upper thoracic epidural block, this might lead to impaired splanchnic
      perfusion. In awake and propofol-anesthetized, chronically instrumented dogs,
      however, a limited upper thoracic epidural blockade had no compromising effect on
      gastrointestinal perfusion.

PMID- 10589612
TI  - A comparative study of the postoperative allogeneic blood-sparing effect of
      tranexamic acid versus acute normovolemic hemodilution after total knee
      replacement.
AB  - Both acute normovolemic hemodilution (NVHD) and tranexamic acid (TA) are
      potentially useful allogeneic blood conservation strategies after total knee
      replacement. However, the relative efficacy of these blood-sparing techniques is
      unknown. Therefore, to compare the postoperative allogeneic blood sparing of NVHD
      and TA after total knee replacement, we investigated 40 patients in a
      prospective, single-blinded study protocol. In Group TA, 30 min before deflating
      the limb tourniquet, an IV infusion of TA, 15 mg/kg, was administered over a 30
      min period. Thereafter, a constant IV infusion of 10 mg x kg(-1) x hr(-1) was
      administered until 12 h after deflation of the limb tourniquet. Before induction
      of anesthesia, NVHD patients were bled to a target hematocrit of approximately
      28%. Intravascular blood volume was maintained with lactated Ringer's solution.
      All autologous blood was transfused at the end of the surgery. Postoperatively,
      hematocrit was measured daily. In all cases, a hematocrit <27% was the
      postoperative transfusion trigger. Before discharge, deep vein thrombosis was
      excluded by Echo Doppler. Three months after surgery, the incidence of delayed
      thromboembolic events was assessed. The two groups were demographically
      comparable. In Group NVHD, 843 mL+/-289 of autologous blood was removed. Despite
      autologous blood transfusion, during the early postoperative period and until the
      third postoperative day, the NVHD group had significantly (P < 0.01) lower mean
      hematocrits when compared with the TA group. Thereafter, because of a
      significantly (P < 0.0008) greater allogeneic blood requirement in the NVHD
      group, no statistically significant difference in mean hematocrit recordings was
      noted among the groups. Blood accumulation in the surgical drain 12 h
      postoperatively, was significantly (P < 0.0008) higher in the NVHD group (259
      mL+/-156) when compared with the TA group (110 mL+/-62). Significantly (P <
      0.0008) more allogeneic blood was transfused in the NVHD group (19 U/13 patients)
      when compared with the TA group (2 U/2 patients). No abnormal Echo Doppler
      studies were reported. During the 3-mo follow-up period, a deep vein thrombosis
      and pulmonary embolus were documented in one patient in the NVHD group. We
      conclude that perioperative hemodynamic stability and allogeneic blood sparing is
      superior after tranexamic acid administration when compared with normovolemic
      hemodilution. IMPLICATIONS: For total knee replacement, when compared with
      normovolemic hemodilution, tranexamic acid administration is associated with
      superior perioperative hemodynamic stability and allogeneic blood sparing.

PMID- 10589613
TI  - The hemodynamic effects of anesthetic induction in vascular surgical patients
      chronically treated with angiotensin II receptor antagonists.
AB  - The use of angiotensin II receptor subtype-1 antagonists (ARA), recently
      introduced as antihypertensive drugs, is becoming more prevalent. We studied the
      prevalence and severity of hypotension after the induction of general anesthesia
      in 12 patients treated with ARA until the morning of surgery. The hemodynamic
      response to induction was compared with that of patients treated with beta
      adrenergic blockers (BB) and/or calcium channel blockers (CB) (BB/CB group, n =
      45) and angiotensin-converting enzyme inhibitors (ACEI) (ACEI group, n = 27). A
      standardized anesthesia induction protocol was followed for all patients.
      Hypotension occurred significantly (p < or = 0.05) more often in ARA-treated
      patients (12 of 12) compared with BB/CB-treated patients (27 of 45) or with ACEI
      treated patients (18 of 27). There was a significantly (P < or = 0.001) increased
      ephedrine requirement in the ARA group (21+/-3 mg) compared with the BB/CB group
      (10+/-6 mg) or the ACEI group (7+/-4 mg). Hypotension refractory to repeated
      ephedrine or phenylephrine administration occurred significantly (P < or = 0.05)
      more in the ARA group (4 of 12) compared with the BB/CB group (0 of 45) or the
      ACEI group (1 of 27), but it was treated successfully by using a vasopressin
      system agonist. Treatment with angiotensin II antagonism until the day of surgery
      is associated with severe hypotension after the induction of anesthesia, which,
      in some cases, can only be treated with an agonist of the vasopressin system.
      IMPLICATIONS: Hypotensive episodes occur more frequently after anesthetic
      induction in patients receiving Angiotensin II receptor subtype-1 antagonists
      under anesthesia than with other hypotensive drugs. They are less responsive to
      the vasopressors ephedrine and phenylephrine. The use of a vasopressin system
      agonist was effective in restoring blood pressure when hypotension was refractory
      to conventional therapy.

PMID- 10589615
TI  - Halothane attenuates myogenicity in the rabbit ear artery.
AB  - The aim of this study was to test the hypothesis that halothane interferes with
      the myogenic response to an increase in intraluminal pressure. Myogenic
      responsiveness refers to the intrinsic property of vascular smooth muscle to
      dilate and then constrict in response to an increase in intraluminal pressure, in
      an attempt to maintain vessel diameter. Vessel segments taken from the rabbit
      central ear artery were cannulated, pressurized to 60 mm Hg, and perfused with
      and suspended in Krebs solution. After exposure to extraluminal l-norepinephrine,
      vessels contracted to an initial diameter (Di) and were subjected to intraluminal
      pressure increases to 100 mm Hg. Myogenic reactivity was assessed by measurement
      of the extent of dilatation after the pressure increase from Di to a maximal
      diameter (Dm) and then the constriction and recovery (against the pressure
      increase) to a final (Df) diameter. Myogenicity was further assessed by
      determining the rate of return of the vessel diameter (angle of recovery) and
      vessel recovery (defined as Dm - Df/Dm - Di) and expressed as a percentage.
      Myogenicity was determined before and after exposure to halothane in
      concentrations of between 1-5%. Halothane significantly attenuated the myogenic
      response at all concentrations studied. The effect of halothane was maximal at a
      concentration of 5% where there was virtual abolition of the myogenic response
      with recovery assessed at 6+/-2.7% (SEM), compared with control (98+/-2.5%, P <
      0.05). The angle of recovery was likewise attenuated. These data suggest that
      halothane, in a dose-dependent manner, attenuates myogenicity in the isolated
      rabbit ear artery preparation. IMPLICATIONS: Blood pressure is controlled
      partially by the myogenic response. This refers to the capacity of arteries to
      dilate and then constrict in response to pressure increase. Using arteries from
      rabbits, we have shown that administration of halothane reduces or abolishes this
      response. This observation may be a contributing factor to hypotension caused by
      halothane.

PMID- 10589614
TI  - The effects of the new antiarrhythmic E 047/1 on postoperative ischemia-induced
      arrhythmias in dogs.
AB  - Perioperative malignant ventricular tachyarrhythmias pose an imminent clinical
      danger by potentially precipitating myocardial ischemia and severely compromising
      hemodynamics. Thus, immediate and effective therapy is required, which is not
      always provided by currently recommended IV drug regimens, indicating a need for
      more effective drugs. We examined antiarrhythmic effects of the new benzofurane
      compound E 047/1 on spontaneous ventricular tachyarrhythmia in a conscious dog
      model. One day after experimental myocardial infarction, 40 dogs exhibiting
      tachyarrhythmia randomly received (bolus plus 1-h infusion) E 047/1 6 mg/kg plus
      6 mg x kg(-1) x h(-1), lidocaine 1 mg/kg plus 4.8 mg x kg(-1) x h(-1), flecainide
      1 mg/kg plus 0.05 mg x kg(-1) x h(-1), amiodarone 10 mg/kg plus 1.8 mg x kg(-1) x
      h(-1), or bretylium 10 mg/kg plus 20 mg x kg(-1) x h(-1). Electrocardiogram was
      evaluated for number of premature ventricular contractions (PVC), normally
      conducted beats originating from the sinoatrial node, and episodes of ventricular
      tachycardia. Immediately after the bolus, E 047/1 reduced PVCs by 46% and
      increased sinoatrial beats from 4 to 61 bpm. The ratio of PVCs to total beats
      decreased from 98% to 58%. Amiodarone and flecainide exhibited antiarrhythmic
      effects with delayed onset. Lidocaine did not suppress PVCs significantly, and
      bretylium was proarrhythmic. The antiarrhythmic E 047/1 has desirable features,
      suppressing ischemia-induced ventricular tachyarrhythmia quickly and efficiently,
      and may be a useful addition to current therapeutic regimens. IMPLICATIONS: Life
      threatening arrhythmias of the heart after myocardial infarction or ischemia may
      be treated quickly and efficiently by the new drug E 047/1.

PMID- 10589616
TI  - Emergent bedside transesophageal echocardiography in the resuscitation of sudden
      cardiac arrest after tricuspid inflow obstruction and pulmonary embolism.

PMID- 10589617
TI  - Response to electroconvulsive therapy in a quadriplegic patient.

PMID- 10589618
TI  - The hemodynamic effects of propofol in children with congenital heart disease.
AB  - We studied the hemodynamic effects of propofol during elective cardiac
      catheterization in 30 children with congenital heart disease. Sixteen patients
      were without cardiac shunt (Group I), six had left-to-right cardiac shunt (Group
      II), and eight had right-to-left cardiac shunt (Group III). The mean (+/-SD) ages
      were 3.8+/-3.1 yr (Group I), 3.2+/-3.7 yr (Group II), and 1.0+/-0.6 yr (Group
      III). After sedation and cardiac catheter insertion, hemodynamic data and oxygen
      consumption were measured before and after the administration of propofol (2
      mg/kg bolus, 50- to 200-microg x kg(-1) x min(-1) infusion), and values were
      compared by using a paired t-test (significance: P < 0.05). After the propofol
      administration, systemic mean arterial pressure and systemic vascular resistance
      decreased significantly and systemic blood flow increased significantly in all
      patient groups; heart rate, pulmonary mean arterial pressure, and pulmonary
      vascular resistance were unchanged. Pulmonary to systemic resistance ratio
      increased (Group I, P = 0.005; Group II, P = 0.03; Group III, P = 0.10). In
      patients with cardiac shunt, propofol resulted in decreased left-to-right flow
      and increased right-to-left flow; the pulmonary to systemic flow ratio decreased
      significantly (Group II, P = 0.005; Group III, P = 0.01). Clinically relevant
      decreases in Pao2 (P = 0.008) and Sao2 (P = 0.01) occurred in Group III patients.
      We conclude that propofol can result in clinically important changes in cardiac
      shunt direction and flow. IMPLICATIONS: The principal hemodynamic effect of
      propofol in children with congenital heart defects is a decrease in systemic
      vascular resistance. In children with cardiac shunt, this results in a decrease
      in the ratio of pulmonary to systemic blood flow, and it can lead to arterial
      desaturation in patients with cyanotic heart disease.

PMID- 10589619
TI  - Ketamine inhibits inositol 1,4,5-trisphosphate production depending on the
      extracellular Ca2+ concentration in neonatal rat cardiomyocytes.
AB  - We investigated the effect of ketamine on inositol 1,4,5-trisphosphate (IP3)
      formation in rat cardiomyocytes. After the addition of 1 micromol/L ketamine, IP3
      production in the presence of 0.5, 1, 5, 10, and 30 mmol/L Ca2+ significantly
      decreased from 537.1+/-8.3, 590.7+/-12.9, 690.6+/-7.9, 754.8+/-12.5, and 823.7+/
      15.2 pmol/mg protein to 467.0+/-8.3, 483.8+/-11.0, 512.6+/-21.3, 612.1+/-16.9,
      and 652.6+/-17.3 pmol/mg protein, respectively. When exposed to TMB-8 (a
      intracellular calcium inhibitor), IP3 production decreased significantly from
      347.2+/-27.3 to 283.8+/-20.4 pmol/mg protein in the presence of 1 micromol/L
      ketamine, but A23187, which increases intracellular calcium, did not affect the
      inhibition of IP3 production by ketamine. These results demonstrate that ketamine
      decreases IP3 formation through inhibition of the calcium ion-sensing receptor
      and that IP3 formation reduced by ketamine is not affected by the alteration of
      intracellular calcium. IMPLICATIONS: Ketamine has a negative inotropic effect in
      isolated cardiomyocytes. The negative inotropic effect was associated with a
      decrease in inositol 1,4,5-trisphosphate production, and the inhibitory action
      was enhanced depending on the concentration of extracellular Ca2+.

PMID- 10589620
TI  - The hemodynamic and Holter-electrocardiogram changes during halothane and
      sevoflurane anesthesia for adenoidectomy in children aged one to three years.

PMID- 10589621
TI  - Methods for single-lung ventilation in pediatric patients.

PMID- 10589622
TI  - Effect of small-dose dopamine on mesenteric blood flow and renal function in a
      pig model of cardiopulmonary resuscitation with vasopressin.
AB  - Vasopressin (antidiuretic hormone) seems a promising alternative to epinephrine
      for cardiopulmonary resuscitation (CPR) in cardiac arrest victims, mediating a
      pronounced blood flow shift toward vital organs. We evaluated the effects of
      small-dose dopamine on splanchnic blood flow and renal function after successful
      resuscitation with this potent vasoconstrictor in an established porcine CPR
      model. After 4 min of cardiac arrest and 3 min of CPR, animals received 0.4 U/kg
      vasopressin and were continuously infused with either dopamine 4 microg x kg(-1)
      x min(-1) (n = 6), or saline placebo (n = 6). Defibrillation was performed 5 min
      after drug administration; all animals were observed for 6 h after return of
      spontaneous circulation. During the postresuscitation phase, average mean +/- SD
      superior mesenteric artery blood flow was significantly (P = 0.002) higher in the
      dopamine group compared with the placebo group (1185+/-130 vs 740+/-235 mL/min),
      whereas renal blood flow was comparable between groups (255+/-40 vs 250+/-85
      mL/min). The median calculated glomerular filtration rate had higher values in
      the dopamine group (70-120 mL/min) than in the placebo group (40-70 mL/min; P =
      0.1 at 0 min and P = 0.08 at 360 min). We conclude that small-dose dopamine
      administration may be useful in improving superior mesenteric artery blood flow
      and renal function after successful resuscitation with vasopressin. IMPLICATIONS:
      Long-term survival after cardiac arrest may be determined by the ability to
      ensure adequate organ perfusion during cardiopulmonary resuscitation and in the
      postresuscitation phase. In this regard, small-dose dopamine improved
      postresuscitation blood flow to the mesenteric bed when vasopressin was used as
      an alternative vasopressor in an animal model of cardiac arrest.

PMID- 10589623
TI  - Cerebrovascular carbon dioxide reactivity during general anesthesia: a comparison
      between sevoflurane and isoflurane.
AB  - We compared cerebrovascular carbon dioxide reactivity during the administration
      of sevoflurane and isoflurane anesthesia by measuring cerebral blood flow
      velocity (CBFV) as an indirect measurement of cerebral blood flow. Thirty
      patients, 20-70 yr old, undergoing lower abdominal surgery and without known
      cerebral or cardiovascular system disease, were randomly assigned to either
      sevoflurane or isoflurane treatment groups. Anesthesia was induced with
      thiopental 5 mg/kg IV and maintained with either sevoflurane or isoflurane in 67%
      nitrous oxide and oxygen. The CBFV and pulsatility index (PI) of the left middle
      cerebral artery were monitored with transcranial Doppler. The P(ETCO)2 was
      increased stepwise from 20 to 50 mm Hg by changing the respiratory rate with a
      constant tidal volume. At every 5-mm Hg stepwise change in P(ETCO)2, CBFV and PI
      were recorded. CBFV increased with increasing P(ETCO)2. CBFV was significantly
      smaller in the isoflurane group at P(ETCO)2 = 20-40 mm Hg than in the sevoflurane
      group. The rate of change of CBFV with changes in CO2 was larger in the
      isoflurane group than in the sevoflurane group. PI was constant over time and was
      not different between groups. In conclusion, hypocapnia-induced reduction of
      intracranial pressure might be more effective during the administration of
      isoflurane than sevoflurane. IMPLICATIONS: Changes in cerebral blood flow caused
      by the changes of carbon dioxide tension are greater during the administration of
      isoflurane anesthesia compared with sevoflurane anesthesia. Attempts to decrease
      intracranial pressure by decreasing carbon dioxide tension may be more successful
      during isoflurane than sevoflurane anesthesia administration.

PMID- 10589624
TI  - Isoflurane reduces N-methyl-D-aspartate toxicity in vivo in the rat cerebral
      cortex.
AB  - Recent in vitro data indicate that isoflurane can reduce N-methyl-D-aspartate
      (NMDA) receptor-mediated responses and thereby might reduce excitotoxicity.
      However, the effect of isoflurane on NMDA receptor-mediated toxicity in vivo is
      not known. We conducted the present study to evaluate the effect of isoflurane on
      injury produced by cortical injection of NMDA in vivo and to compare it with
      dizocilpine, an antagonist of the NMDA receptor. Fasted Wistar-Kyoto rats were
      anesthetized with isoflurane. NMDA 50 nmoles (5-microL volume) were
      stereotactically injected into the cortex (2.8 mm lateral and 2.8 mm rostral to
      the bregma, depth 2 mm) of animals in one of four groups. In the isoflurane
      groups, the end-tidal concentration of isoflurane was maintained at either
      electroencephalogram (EEG)-burst suppression (BS) doses (2.2%-2.3%, n = 12) or a
      1 minimum alveolar anesthetic concentration (MAC) dose (n = 10). In the
      dizocilpine group (n = 10), 10 mg/kg dizocilpine was injected IV 15 min before
      the NMDA injection. In the awake group and the dizocilpine group, anesthesia was
      discontinued on completion of the NMDA injection, and the animals were allowed to
      awaken. In the animals in the control group (n = 10), 20 microL of artificial
      cerebrospinal fluid was injected into the cortex. Injury to the cortex was
      evaluated 2 days after the NMDA injection. In 1 MAC doses and EEG-BS doses,
      isoflurane reduced the injury produced by a cortical NMDA injection compared with
      the awake state (1.74+/-0.49 and 0.96+/-0.46 vs 2.34+/-0.56 mm3; P = 0.02).
      Dizocilpine reduced cortical injury (0.56+/-0.27; P = 0.01) compared with the
      awake state. Injury in the control group was limited to the trauma produced by
      cannula insertion. In the isoflurane EEG-BS and dizocilpine groups, the injury
      was not different from the control group. IMPLICATIONS: Isoflurane can reduce N
      methyl-D-aspartate-mediated cortical injury in vivo in a dose-dependent manner.
      These data are consistent with the previously demonstrated ability of isoflurane
      to reduce N-methyl-D-aspartate receptor-mediated responses in vitro.

PMID- 10589625
TI  - The lack of transplacental movement of the cyanide antidote thiosulfate in gravid
      ewes.
AB  - A previous study reported that the co-infusion of IV sodium thiosulfate (STS)
      with sodium nitroprusside (SNP) to near-term gravid ewes prevented both maternal
      and fetal cyanide toxicity. We questioned whether maternally administered STS
      crossed the ovine placenta to enhance fetal transulfuration of cyanide, or
      whether the fetus was dependent on maternal detoxification of cyanide after
      diffusion of cyanide into the maternal circulation. Ten anesthetized, near-term
      gravid ewes underwent hysterotomies with delivery of fetal heads for venous
      catheterization. Five control ewes received IV isotonic sodium chloride solution,
      whereas five experimental ewes received IV STS (50 mg/kg over 15 min). Serial
      plasma thiosulfate concentrations in ewes and fetuses were measured over 135 min.
      Areas under the time-plasma thiosulfate concentration curves were calculated for
      experimental and control ewes at 2758+/-197 and 508+/-74 min x mg(-1) x L(-1),
      respectively (P < 0.008). Mean areas under the curve for experimental and control
      fetuses were 236+/-34 and 265+/-23 min x mg(-1) x L(-1), respectively (P > 0.5).
      Maternally administered STS may prevent fetal cyanide poisoning from SNP
      administration without relying on STS crossing the placenta into the fetal
      circulation. Fetal cyanide may cross down a concentration gradient from fetal to
      maternal circulation, to be transulfurated to thiocyanate in maternal tissues.
      IMPLICATIONS: We evaluated the mechanism of action of sodium thiosulfide (STS) in
      sodium nitroprusside-induced cyanide toxicity in the ewe. Fetal cyanide poisoning
      is alleviated by maternal administration of STS, although this cyanide antidote
      apparently does not cross the placenta.

PMID- 10589626
TI  - Assessing platelet and fibrinogen contribution to clot strength using modified
      thromboelastography in pregnant women.
AB  - The monoclonal antibody fragment c7E3 Fab (ReoPro), by binding to platelet
      surface fibrinogen receptors (glycoprotein, GPIIb/IIIa), inhibits platelet
      aggregation and its interaction with fibrinogen. In this study, we used
      thromboelastography with ReoPro to evaluate the independent contribution of
      fibrinogen and platelets to clot strength. Thromboelastography was performed in
      21 healthy, term parturients scheduled for elective cesarean delivery with 360
      microL of celite-activated whole blood and with 5 microL of (2 mg/mL) ReoPro
      added to 355 microL of celite-activated whole blood. The contribution of
      platelets to clot strength (MAplt) was derived by subtracting MAfib (maximal
      amplitude with ReoPro) from MAwb (maximal amplitude with whole blood). Thus, MAwb
      - MAfib = MAplt. The value for MAwb (mean +/- SD) was 73+/-4 mm, for MAfib it was
      33+/-5 mm, and for MAplt it was 40+/-3 mm. The contribution of fibrinogen and
      platelets to the MAplt was 45% and 55%, respectively. Modified
      thromboelastography using ReoPro in healthy parturients can be used to determine
      the contribution of fibrinogen and platelets to blood clot strength.
      IMPLICATIONS: Determining the independent contribution of platelets and
      fibrinogen to the maximal amplitude of thromboelastography using c7E3 Fab may
      further improve the use of thromboelastography in detecting and treating
      coagulation defects.

PMID- 10589627
TI  - Amniotic fluid embolism: early findings of transesophageal echocardiography.

PMID- 10589628
TI  - Gabapentin therapy for vulvodynia.

PMID- 10589629
TI  - Wound infiltration and drain lavage with ropivacaine after major shoulder
      surgery.
AB  - Subcutaneous infiltration and wound lavage with ropivacaine is an alternative to
      opioids after major shoulder surgery. However, the efficacy and potential
      toxicity of this method remain unclear. We therefore evaluated plasma ropivacaine
      concentrations after shoulder infiltration and wound lavage. We subsequently
      quantified the efficacy of two ropivacaine concentrations. Patients undergoing
      major shoulder surgery were anesthetized with alfentanil and propofol. The
      initial patients (n = 18) received ropivacaine 7.5 mg/mL and ropivacaine plasma
      concentrations were measured in 15-min intervals. The subsequent 45 patients were
      randomly assigned to: 1) isotonic saline, 2) 3.75 mg/mL ropivacaine, or 3) 7.5
      mg/mL ropivacaine. Ten milliliters of each solution was administered
      subcutaneously and 20 mL was injected into the wound drain which was clamped for
      10 min. Supplemental postoperative pain relief was provided by patient-controlled
      anesthesia using the opioid piritramid (3.5-mg boluses, 6-min lock-out).
      Postoperative pain scores were recorded on a 100-mm visual analog scale for 4 h
      in the initial patients and for 10 h in the second part of the study. Unbound
      ropivacaine plasma concentrations peaked after 15 min at 0.08+/-0.09 microg/mL;
      the maximum was 0.30 microg/mL, compared with a toxic threshold of 0.6 microg/mL.
      In the second part of the study, pain scores were significantly lower after 3.75
      mg/mL (20+/-15 mm) or 7.5 mg/mL (10+/-9 mm) ropivacaine than saline (35+/-10 mm).
      Piritramid requirements differed significantly in the three groups, being highest
      with saline and lowest with ropivacaine 7.5 mg/mL. We conclude that wound
      infiltration and lavage with 30 mL ropivacaine 7.5 mg/mL after major shoulder
      surgery resulted in very low pain scores and opioid requirement. IMPLICATIONS:
      Wound infiltration and lavage with 30 mL ropivacaine 7.5 mg/mL after major
      shoulder surgery resulted in very low pain scores and opioid requirement.

PMID- 10589630
TI  - Anatomical landmarks for femoral nerve block: a comparison of four needle
      insertion sites.
AB  - The site for needle insertion in femoral nerve block varies significantly among
      various descriptions of the technique. To determine the site with the highest
      likelihood of needle-femoral nerve contact, femoral nerve block was simulated in
      a human cadaver model (17 femoral triangles from 9 adult cadavers). Four 20-gauge
      50-mm-long styletted catheters were inserted at four frequently suggested
      insertion sites for femoral nerve block. At the levels of inguinal ligament and
      the inguinal crease, the catheters were inserted adjacent to the lateral border
      of the femoral artery and 2 cm lateral to the femoral artery. During anatomical
      dissection, we studied the number of catheter-nerve contacts for each of the four
      insertion sites, and relationships between the femoral nerve and other anatomical
      structures of relevance to femoral nerve block. Insertion of the needle at the
      level of the inguinal crease, next to the lateral border of the femoral artery
      resulted in the highest frequency of needle-femoral nerve contacts (71%). Of
      note, the femoral nerve was significantly wider (14.0 vs 9.8 mm) and closer to
      the fascia lata (6.8 vs 26.4 mm) at the inguinal crease than at the inguinal
      ligament level. We conclude that needle insertion at the inguinal crease level
      immediately adjacent to the femoral artery produced the highest rate of needle
      femoral nerve contacts. The main factors influencing this result include the
      greater width of the femoral nerve and the more predictable femoral artery
      femoral nerve relationship at the inguinal crease level, compared with the
      inguinal ligament level. IMPLICATIONS: Insertion of a needle at the inguinal
      crease level and immediately adjacent to the lateral border of the femoral artery
      results in a high rate of needle-femoral nerve contact.

PMID- 10589631
TI  - Pharmacokinetics and pharmacodynamics of ropivacaine 2 mg/mL, 5 mg/mL, or 7.5
      mg/mL after ilioinguinal blockade for inguinal hernia repair in adults.
AB  - The aim of our study was to evaluate the pharmacokinetics and pharmacodynamics of
      ropivacaine in ilioinguinal-iliohypogastric blocks (IIB). After ethics committee
      approval and informed consent, 80 male adults scheduled for inguinal hernia
      repair were enrolled and randomized into four groups. After induction of general
      anesthesia, an IIB was performed double blinded in Groups 1, 2, and 3 with 0.25
      mL/kg ropivacaine 2 mg/mL, 5 mg/mL, or 7.5 mg/mL and with saline in the Control
      group. Plasma concentration of ropivacaine was determined in venous blood using
      reversed-phase high-performance liquid chromatography. IIB with ropivacaine
      resulted in peak plasma concentrations of 0.3+/-0.15 microg/mL (Group 1) (mean +/
      SD), 0.75+/-0.45 microg/mL (Group 2), or 1.57+/-0.82 microg/mL (Group 3). These
      concentrations occurred after 30 (15-60) min, median (range), 30 (10-60) min, and
      45 (15-60) min, in the respective groups. Three of 19 patients in Group 1, 6 of
      18 in Group 2, and 5 of 20 in Group 3 did not need any additional analgesics
      within 24 h postoperatively, but all 20 control patients did. Time to the first
      demand for analgesia was significantly shorter in the Control group (median 0.3 h
      [range 0-2.8]) compared with 1.5 h (0.5-24 h), 2 h (0.5-24 h), and 2 h (1.0-24 h)
      in Groups 1, 2, and 3, respectively. Three patients in Group 3 had a
      postoperative motor block of the femoral nerve. In conclusion, a ropivacaine dose
      of 0.25 mL/kg of 5 mg/mL seems adequate for IIB accompanying general anesthesia
      for postoperative pain relief. However, the pharmacokinetic results obtained
      suggest that even larger doses (0.25 mL/kg of 7.5 mg/mL ropivacaine) for IIB do
      not result in plasma concentrations in a toxic range. IMPLICATIONS: Ropivacaine,
      a new local anesthetic, proved to be effective for pain relief after hernia
      repair in ilioinguinal blocks accompanying general anesthesia. Plasma
      concentrations peaked after 30-45 min, and were within safe limits after
      application of 0.25 mL/kg of 2, 5, or 7.5 mg/mL ropivacaine.

PMID- 10589632
TI  - Hyperalgesia caused by nerve transection: long-lasting block prevents early
      hyperalgesia in the receptive field of the surviving nerve.
AB  - The aim of our study was to test the hypothesis that a long-lasting N-butyl
      tetracaine nerve block (>2 wk) would be much more effective in the prevention of
      hyperalgesia caused by nerve transection than the short-lasting lidocaine block.
      The study was performed with the use of the saphenous nerve section model in
      rats. The saphenous nerve was exposed and injected with saline, lidocaine (37
      mM), or N-butyl tetracaine (37 mM). Ten minutes later, the nerve was transected
      in some of the rats. The development of mechanical hyperalgesia (pressure
      threshold) of the hindpaw was assessed during a 5-wk period. In rats with
      saphenous nerve transection without nerve block (saline injection), 3 h after the
      transection, the pressure threshold decreased by approximately 30% (from 175+/-11
      g to 122+/-23 g, P < 0.0001); the threshold increased somewhat the next day, then
      it remained stable for 2 wk, with a slow process of recovery afterward. N-butyl
      tetracaine block without nerve transection caused a slow-developing decrease in
      the pressure threshold with the first statistically significant change at the
      sixth day. The comparison of the preventive effects of lidocaine and N-butyl
      tetracaine blocks on early hyperalgesia caused by nerve transection demonstrated
      that both lidocaine and N-butyl tetracaine prevented hyperalgesia 3 h after the
      transection. However, the protective effect of lidocaine disappeared the next
      day. In contrast, N-butyl tetracaine prevented early hyperalgesia for almost a
      week. The slow-developing late hyperalgesia caused by long-lasting nerve block
      makes it impossible to study the protective effect of such a block on late
      hyperalgesia caused by axotomy. As far as early hyperalgesia is concerned, the
      preventive effect of the N-butyl tetracaine was much longer than that of
      lidocaine and continued for approximately 1 wk. IMPLICATIONS: A long-lasting
      nerve block can prevent early hyperalgesia caused by nerve transection.

PMID- 10589633
TI  - Quantitative comparison of leakage under the tourniquet in forearm versus
      conventional intravenous regional anesthesia.
AB  - We compared the quantitative leakage between forearm and conventional IV regional
      anesthesia (IVRA). Forearm IVRA remains unpopular because of the theoretical risk
      of local anesthetic leakage through the interosseous vessels. IVRA was simulated
      on the forearm or arm during two separate, randomized sessions using a double
      tourniquet in 14 volunteers. A radiolabeled substance, DISIDA (99m Tc-disofenin)
      with a structure similar to lidocaine, was injected instead of local anesthetic.
      Volumes of 0.4 mL/kg (maximum 25 mL), were used for forearm IVRA and 0.6 mL/kg
      (maximum 45 mL) for conventional IVRA. A gamma camera recorded radioactivity
      levels in the limb distal to the tourniquet every 30 s while the tourniquet was
      inflated (25 min) and for 20 min postdeflation. The leakage of radiolabeled
      substance during inflation was similar in both groups, 6%+/-12% (mean +/- SD)
      from the forearm and 10%+/-20% from the upper arm. After deflation, mean loss of
      radioactivity was higher in conventional IVRA, 70%+/-7% vs 57%+/-11% and 82%+/-5%
      vs 69%+/-11% at 3 and 20 min, respectively (P < 0.001). We conclude that forearm
      IVRA results in tourniquet leakage comparable to conventional IVRA and is
      potentially safer because the required dose of local anesthetic is smaller.
      IMPLICATIONS: Using a tourniquet on the forearm for IV regional anesthesia does
      not increase the risk of drug leakage. This is potentially a safer technique
      compared with conventional IV regional anesthesia because a much smaller dose of
      local anesthetic is required.

PMID- 10589634
TI  - Oral clonidine premedication enhances postoperative analgesia by epidural
      morphine.
AB  - This study was designed to evaluate the effects of oral clonidine premedication
      on postoperative analgesia by epidural morphine in a prospective, randomized,
      double-blinded design. Sixty consenting patients, scheduled for total abdominal
      hysterectomy, were randomly assigned to one of three groups (n = 20 each); the
      clonidine-morphine group received oral clonidine 5 microg/kg 90 min before
      arriving in the operating room and epidural morphine 2 mg before induction of
      general anesthesia, the clonidine-placebo group received oral clonidine 5
      microg/kg and no epidural morphine, and the placebo-morphine group received no
      clonidine and epidural morphine 2 mg. An epidural catheter was placed at the L1-2
      or L2-3 interspace, and 1.5% lidocaine was used for surgical anesthesia in all
      patients. General anesthesia was then induced with propofol, and maintained with
      a continuous infusion of propofol and 67% nitrous oxide in oxygen during surgery.
      Four patients were subsequently withdrawn from the study. After surgery, patient
      controlled analgesia using IV morphine was used to assess analgesic requirement.
      Morphine consumptions determined every 6 h after surgery in the clonidine
      morphine and placebo-morphine groups were significantly less than the clonidine
      placebo group until 12 h after surgery, whereas those of the clonidine-morphine
      group were significantly less than the placebo-morphine group from 13 to 42 h
      after surgery. Visual analog (pain) scale (VAS) scores in the clonidine-morphine
      group were significantly lower than the placebo-morphine group at 48 h at rest,
      and at 1, 24, 36, and 48 h with movement. Similarly, VAS scores in the clonidine
      morphine group were significantly lower than the clonidine-placebo group at 1 and
      6 h both at rest and with movement, whereas VAS scores in the clonidine-placebo
      group were significantly lower than the placebo-morphine group at 24, 36, and 48
      h at rest and with movement. The incidence of nausea and pruritus was similar
      between groups. We conclude that the combination of oral clonidine and epidural
      morphine produces more potent and longer lasting postoperative analgesia than
      either drug alone without increasing the incidence of adverse effects after major
      gynecologic surgeries. IMPLICATIONS: A small dose of epidural morphine is often
      used for postoperative analgesia. We found that oral clonidine premedication 5
      microg/kg improves the analgesic efficacy of epidural morphine without increasing
      the incidence of adverse side effects.

PMID- 10589635
TI  - Reproducibility of the drug effects over time on chronic lumbar epidural
      catheterization in rats.
AB  - Chronically implanted epidural catheters lead to a reaction that impedes drug
      action. The purpose of this study in a rat model with chronically implanted
      epidural catheters was to investigate the change in opiate activity and histology
      over time with this model. A skin incision of 1-2 cm was made at the T 13 level
      on the back of male Sprague-Dawley rats under halothane anesthesia. Muscles were
      dissected bluntly from the vertebrae, and the intervertebral ligament was cut to
      insert an epidural catheter (polyethylene tube, outer diameter of 0.14 mm) 2-cm
      caudally. The longer portion of the catheter was passed through a trocar
      subcutaneously to exit the dorsal neck area. One, two, and six days after
      catheterization, the effects of morphine on thermal stimulation using the hot-box
      test and histology were investigated. Analgesic effects of morphine 6 days after
      catheterization were significantly less than those on the first and second days.
      Histologically, evidence of inflammation around the catheter was noted as early
      as 4 h after catheterization. Pericatheter fibrosis was severe after 2 days. We
      conclude that this model of chronic epidural catheterization in the rat evoked a
      histologically defined, pharmacodynamically significant, local reaction 2 to 6
      days after catheter implantation. IMPLICATIONS: A rat model with chronically
      implanted epidural catheters should be used for testing the analgesic effects of
      drugs within two days after catheterization.

PMID- 10589636
TI  - A comparison of levobupivacaine 0.125%, fentanyl 4 microg/mL, or their
      combination for patient-controlled epidural analgesia after major orthopedic
      surgery.
AB  - Levobupivacaine, the isolated S(-) isomer of bupivacaine, is less cardiotoxic
      than racemic bupivacaine in animal studies. We studied the effectiveness of
      patient-controlled epidural analgesia (PCEA) with either levobupivacaine 0.125%
      or fentanyl 4 microg/mL alone, or a combination of levobupivacaine and fentanyl
      in 65 patients after total joint arthroplasty in a prospective, random, double
      blinded fashion. Intraoperatively, all patients received 20 mL of 0.75%
      levobupivacaine. Study medication was infused at an initial rate of 4 mL/h, with
      additional medication available on patient demand (2 mL/10 min). The combination
      of levobupivacaine and fentanyl produced better analgesia (longer time to first
      PCEA request; P = 0.007 combination versus fentanyl and P = 0.006 combination
      versus levobupivacaine) than either drug alone. Patients in the levobupivacaine
      groups had appreciable sensory blockade to pinprick with minimal motor
      impairment. Resting and dynamic visual analog scale pain scores were lower in the
      combination group than in the plain fentanyl group at 6 (P = 0.022 and 0.036) and
      12 h (P = 0.002 and 0.001). The 24-h overall patient- and investigator-rated
      visual analog scale pain scores were also lower in the combination group (resting
      P = 0.007, dynamic P = 0.005). There was no significant difference among the
      groups in the incidence of postoperative nausea (26.2%), pruritus (9.2%),
      hypotension (23.1%), or sedation (0%). We conclude that the analgesic effects of
      levobupivacaine 0.125% and fentanyl (4 microg/mL) are additive and beneficial for
      the management of orthopedic surgical pain by the PCEA method. Patients in this
      study began demand-dosing later, reported lower pain scores, and had no greater
      risk of adverse events than those who were given either levobupivacaine or
      fentanyl alone. IMPLICATIONS: We demonstrated a significant additive effect of
      the combination of levobupivacaine (0.125%) and fentanyl (4 microg/mL), compared
      with either drug alone, when using patient-controlled epidural analgesia in
      patients after total joint arthroplasty.

PMID- 10589637
TI  - A comparison of the analgesic efficacy of 0.25% levobupivacaine combined with
      0.005% morphine, 0.25% levobupivacaine alone, or 0.005% morphine alone for the
      management of postoperative pain in patients undergoing major abdominal surgery.
AB  - We compared the relative efficacy of the combination of the single-isomer local
      anesthetic levobupivacaine and the opioid analgesic morphine versus both drugs
      alone for postoperative epidural analgesia after major abdominal surgical
      procedures. Thoracic epidural anesthesia was produced and maintained with
      levobupivacaine 0.75% in combination with general inhaled anesthesia without
      opioids. Patients were randomized to one of three postoperative treatment groups:
      1) a combination of levobupivacaine 0.25% and morphine 0.005%; 2) levobupivacaine
      0.25%; or 3) morphine 0.005%. Postoperatively, all epidural infusions were
      commenced at a rate of 4 mL/h. Patients could receive a 4 mL-bolus dose and an
      increase in the epidural infusion rate by 2 mL/h on request for supplemental
      analgesia. Patients were also allowed ketorolac as a supplemental analgesic at
      any time after the first analgesic request. Patients in the combination group had
      longer times to request for supplemental analgesia as compared with the
      levobupivacaine only group (P < 0.05) and a trend toward longer time to request
      as compared with the morphine only group (P = 0.066). Patients in the combination
      group had lower visual analog scale pain scores at rest and activity at 4 and 8 h
      and fewer requests for supplemental ketorolac (P < 0.05). In conclusion, this
      study demonstrates a significant improvement in postoperative analgesic efficacy
      with the combination of levobupivacaine and morphine for continuous epidural
      analgesia after major abdominal surgical procedures. IMPLICATIONS: A significant
      improvement in postoperative analgesic efficacy is demonstrated with the thoracic
      epidural administration of the combination of the single-isomer local anesthetic
      levobupivacaine 0.25% and morphine 0.005% in patients after major abdominal
      surgical procedures as compared with either drug used alone.

PMID- 10589638
TI  - Attenuated additional hypocapnic constriction, but not hypercapnic dilation, of
      spinal pial arterioles during spinal ropivacaine.
AB  - Ropivacaine constricts spinal vessels. Because the CO2 response of spinal vessels
      is similar to that of cerebral vessels, we tested to see if hypocapnia would
      cause further spinal vasoconstriction during ropivacaine administration. In 12
      pentobarbital-anesthetized dogs, spinal pial arteriolar diameter was measured
      using a closed spinal window preparation. Either ropivacaine solution (0.1%; n =
      6) or artificial cerebrospinal fluid (n = 6) was infused continuously into the
      spinal window. After a period of hypocapnia (Paco2, 20-25 mm Hg) had been
      induced, inspired CO2 levels were adjusted to produce normocapnia (35-40 mm Hg)
      followed by hypercapnia (55-60 mm Hg). When the desired Paco2 was reached,
      measurements were made of the arteriolar diameter and physiological variables.
      During normocapnia, ropivacaine infusion produced a significant constriction of
      pial arterioles, whereas artificial cerebrospinal fluid caused no change.
      Hypocapnia induced a much smaller (almost nonexistent) additional
      vasoconstriction in the ropivacaine group than in the control group (P < 0.01).
      The final hypercapnic vasodilation was somewhat greater during ropivacaine (P <
      0.05 versus control group). Topical ropivacaine induced no change in hemodynamic
      variables. We conclude that hypocapnia of the magnitude tested did not cause
      further constriction in spinal vessels during spinal ropivacaine. IMPLICATIONS:
      During topical application of the local anesthetic ropivacaine in dogs,
      hypocapnia (Paco2, 20-25 mm Hg) induced almost no additional constriction of
      spinal arterioles, and the hypercapnic vasodilation was maintained. These data
      suggest that an additional constriction in spinal vessels is unlikely when
      hypocapnia occurs during spinal ropivacaine.

PMID- 10589639
TI  - The effects of combined sympathetic block and intravascular infusion of
      prostaglandin E1 on brachial arterial blood flow in dogs.
AB  - We compared the effects of stellate ganglion block (SGB) with those of SGB
      combined with an intravascular infusion of prostaglandin E1 (PGE1) on brachial
      arterial blood flow (BABF) in 24 mongrel dogs. The experimental protocol was
      designed so that the dogs received one of the following: SGB with 0.5%
      mepivacaine 1.0 mL (n = 8); combined SGB and IV infusion of PGE1 at a rate of 150
      ng x kg(-1) x min(-1) for 10 min (n = 8); or combined SGB and intraarterial (IA)
      infusion of PGE1 at a rate of 0.1 ng x kg(-1) x min(-1) for 10 min (n = 8). BABF
      increased significantly in all groups and reached a maximum of 67% 10 min after
      SGB, 124% with the combined SGB and IV infusion of PGE1, and 117% with the
      combined SGB and IA infusion of PGE1. We conclude that combined SGB and IV or IA
      infusion of PGE1 increases BABF significantly compared with SGB alone.
      IMPLICATIONS: Combined stellate ganglion block and intraarterial or IV infusion
      of prostaglandin E1 increases brachial arterial blood flow significantly compared
      with stellate ganglion block alone.

PMID- 10589640
TI  - The pain visual analog scale: is it linear or nonlinear?
AB  - The visual analog scale (VAS) is a tool widely used to measure pain, yet
      controversy surrounds whether the VAS score is ratio or ordinal data. We studied
      52 postoperative patients and measured their pain intensity using the VAS. We
      then asked them to consider different amounts of pain (conceptually twice as much
      and then half as much) and asked them to repeat their VAS rating after each
      consideration (VAS2 and VAS3, respectively). Patients with unrelieved pain had
      their pain treated with IV fentanyl and were then asked to rate their pain
      intensity when they considered they had half as much pain. We compared the
      baseline VAS (VAS1) with VAS2 and VAS3. The mean (95% confidence interval) for
      VAS2:1 was 2.12 (1.81-2.43) and VAS3:1 was 0.45 (0.38-0.52). We conclude that the
      VAS is linear for mild-to-moderate pain, and the VAS score can be treated as
      ratio data. IMPLICATIONS: A change in the visual analog scale score represents a
      relative change in the magnitude of pain sensation. Use of the VAS in comparative
      analgesic trials can now meaningfully quantify differences in potency and
      efficacy.

PMID- 10589641
TI  - The effects of intradermal fentanyl and ketamine on capsaicin-induced secondary
      hyperalgesia and flare reaction.
AB  - In this study, we evaluated the effects of intradermal fentanyl and ketamine on
      capsaicin-induced hyperalgesia and axon-reflex flare. In addition, we obtained
      dose-response curves for possible local anesthetic effects. Saline (200 microL)
      and either fentanyl (1 microg or 10 microg in 200 microL) or ketamine (100 microg
      or 1000 microg in 200 microL) were injected simultaneously into the central volar
      forearm of 12 healthy volunteers. Nine minutes later, capsaicin (10 microg in 20
      microL) was injected intracutaneously exactly between the two injection sites.
      Areas of touch-evoked allodynia and pinprick hyperalgesia, as well as intensity
      of pinprick hyperalgesia at the injection sites and axon-reflex flare, were
      evaluated. Fentanyl did not affect the area or intensity of secondary
      hyperalgesia. Only the larger concentration of fentanyl locally diminished axon
      reflex flare without affecting mechanical detection thresholds. Inhibitory
      effects of ketamine on intensity of secondary hyperalgesia and axon reflex flare
      were observed only in the larger concentration. However, this concentration also
      clearly elevated mechanical detection thresholds. No inhibitory effects of
      ketamine in the smaller concentrations were observed. We conclude that fentanyl
      inhibits neuropeptide release on peripheral application without modulating
      secondary hyperalgesia. Ketamine failed to inhibit both secondary hyperalgesia
      and axon reflex flare as long as nonlocal anesthetic concentrations were applied.
      IMPLICATIONS: We investigated the peripheral effects of fentanyl and ketamine on
      capsaicin-induced hyperalgesia and axon-reflex flare. In large concentrations,
      the opioid diminished axon-reflex flare without effects on secondary
      hyperalgesia. We found no evidence for the involvement of endogenous glutamate in
      secondary hyperalgesia or axon reflex flare.

PMID- 10589642
TI  - Toward a canon of the pain and analgesia literature: a citation analysis.
AB  - The purpose of this study was to use citation analysis to identify major themes
      and contributors to the pain and analgesia literature over the past two decades.
      A citation analysis was performed on a database of more than 110,000 articles in
      the biomedical literature from January 1981 through June 1997, and in the
      interval from January 1988 through June 1997. Articles and authors related to
      pain and analgesia research and practice were identified by searching
      approximately 7,700 journals. The 20 articles and 20 authors with the most
      citations were then checked by hand to ensure relevance to pain or analgesia.
      Most of the high-impact articles identified pertained to research on basic pain
      pathways. Nearly all the articles concerned opioids, nonsteroidal
      antiinflammatory drugs, and consequences of analgesic use. None of the highest
      impact articles address assessment of clinical pain. Few women were first authors
      of any most frequently cited paper. Citation analysis is a useful tool in
      identifying important contributions to the biomedical literature. Recent and
      continuing research trends include the use of nonsteroidal antiinflammatory
      drugs, opioid mechanisms, and persistent pain disorders. Current trends expected
      to become stronger include description of pain from the patient's perspective and
      mechanisms of the transition from acute to chronic pain. IMPLICATIONS: We
      performed a citation analysis to identify important contributions and
      contributors to the biomedical literature. Recent pain and analgesia research has
      been focused on mechanisms of pain, but evidence suggests the importance of
      understanding the pain experience from the patient's perspective and the
      transition from acute to chronic pain.

PMID- 10589643
TI  - The systemically administered competitive AMPA receptor antagonist, YM872, has
      analgesic effects on thermal or formalin-induced pain in rats.
AB  - A new competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
      receptor antagonist, (2,3-dioxo-7-[1H-imidazol-1-yl]-6-nitro-1,2,3,4-tetrahydro-1
      quinoxal inyl) acetic acid (YM872) has analgesic effects on acute thermal- and
      formalin-induced nociception by intrathecal administration. The purpose of this
      study was to determine the analgesic effects of systemically administered YM872
      in both acute thermal- and irritant-induced pain. Sprague-Dawley rats were tested
      for tail withdrawal response by the tail flick test and for paw flinches by
      formalin injection after intraperitoneal administration of YM872. The tail flick
      latency increased dose-dependently with a 50% effective dose value of 156.3
      microg. The number of flinches in both first and second phases of the formalin
      test decreased with increasing the dose of YM872. The 50% effective dose values
      were 1.0 microg in the first phase and 38.7 microg in the second phase.
      Transiently, intraperitoneal administration of 1 and 10 mg of YM872 induced motor
      disturbance and 10 mg induced loss of pinna reflex. We conclude that
      intraperitoneal administration of YM872 had analgesic effects on both acute
      thermal- and formalin-induced nociceptions in rats. Transient motor disturbance
      and loss of pinna reflex occurred only with large doses. IMPLICATIONS:
      Intraperitoneally administered YM872, a new alpha-amino-3-hydroxy-5
      methylisoxazole-4-propionic acid receptor antagonist, had analgesic effects on
      thermal- and formalin-induced pain in rats. Larger doses induced transient motor
      disturbance and loss of pinna reflex mediated in the brain.

PMID- 10589644
TI  - Identification of a new therapeutic approach for iliac crest donor site chronic
      pain: a case report.

PMID- 10589645
TI  - The failure of negative pressure rewarming (Thermostat) to accelerate recovery
      from mild hypothermia in postoperative surgical patients.
AB  - The Thermostat device (Aquarius Medical Corp., Phoenix, AZ) is used in a new
      technique to accelerate recovery from hypothermia by mechanically distending
      blood vessels in the hand, thereby increasing transfer of exogenous heat to the
      body core. We evaluated the use of the Thermostat device in patients with mild
      postoperative hypothermia (< 36 degrees C). We studied adult patients undergoing
      elective surgery, general anesthesia, and neuromuscular blockade. Patients with
      an initial postoperative tympanic membrane temperature < 36 degrees C were
      randomized into two groups: 1) Thermostat, which consisted of a hypothermia
      warming mitt/seal and thermal exchange chamber for 60 min, and 2) conventional
      treatment, which consisted of warm blankets and/or radiant heat. Of the 191
      patients enrolled, 60 (31%) developed hypothermia and were randomized to receive
      the Thermostat (n = 30) or conventional methods (n = 30). Fourteen patients in
      the Thermostat group and 17 patients in the conventional group rewarmed to 36
      degrees C before discharge from the recovery room (P is not significant). There
      were no differences in vital signs, rewarming time, time to discharge from the
      recovery room, or postoperative temperature between groups. We conclude that
      patients with mild postoperative hypothermia rewarmed in a similar fashion,
      regardless of whether the Thermostat or conventional methods were used.
      IMPLICATIONS: We found that a commercially available negative pressure rewarming
      device (Thermostat; Aquarius Medical Corp., Phoenix, AZ) was not effective in
      accelerating rewarming in postoperative hypothermic surgical patients after
      general anesthesia.

PMID- 10589646
TI  - The effects of hypothermia on a cloned human brain glutamate transporter (hGLT-1)
      expressed in Chinese hamster ovary cells: -[3H]L-glutamate uptake study.
AB  - Hypothermia provides neuroprotection that inhibits increases in extracellular
      glutamate concentration during ischemia; however, the effect of hypothermia on
      the glutamate transporter is uncertain. A human glial glutamate transporter (hGLT
      1) cDNA, isolated by screening a cDNA, library was cloned and stably transfected
      into Chinese hamster ovary cells. We assessed the effects of temperature on
      transporter activity in [3H]L-glutamate flux experiments at 23, 32, and 37
      degrees C. Hypothermia of 23 degrees C and 32 degrees C decreased [3H]L-glutamate
      uptake at 60 min, to 76.7%+/-7.3% (P < 0.05, n = 5) and 70.7%+/-7.5% (P < 0.05, n
      = 5) of uptake at 37 degrees C, respectively. Reversed uptake of preloaded [3H]L
      glutamate via hGLT-1 was not observed at any temperature. The specific uptakes
      (Q10 values) for 37 degrees C to 32 degrees C and 32 degrees C to 23 degrees C at
      30 min were 3.48 and 2.37, whereas they were 2.17 and 0.91, respectively, for 60
      min. These changes suggest that hypothermia attenuates uptake of extracellular
      glutamate via hGLT-1 in a temperature- and time-dependent manner. IMPLICATIONS:
      Under certain pathologic conditions, including cerebral ischemia and traumatic
      brain injury, glutamate neurotoxicity may initially be propagated by hypothermia
      due to relative failure of glutamate uptake via Human Glial Glutamate Transporter
      before a subsequent recovery of uptake.

PMID- 10589647
TI  - Amino acid-induced thermogenesis reduces hypothermia during anesthesia and
      shortens hospital stay.
AB  - Amino acid infusion during general anesthesia induces thermogenesis and prevents
      postoperative hypothermia and shivering. We propose that amino acid prevention of
      hypothermia during anesthesia shortens the hospital stay. Core temperatures and
      pulmonary oxygen uptake were measured in 45 patients, receiving an IV amino acid
      mixture, 126 mL/h, before and/or during isoflurane anesthesia and 30 control
      patients receiving acetated Ringer's solution. At awakening, mean core
      temperature was 36.5 degrees+/-0.1 degrees C in the amino acid group and 35.7
      degrees+/-0.1 degrees C (P < 0.001) in the controls. Energy expenditure increased
      by 54%+/-9% from baseline in amino acid patients in whom shivering was uncommon,
      but only by 5%+/-4% (P < 0.001) in control patients, of whom the majority
      developed postoperative shivering. The estimated difference in hospital stay
      between the two groups was 2.7 days (CI 95%: 1.3-4.0). Multiple regression
      analysis showed that the variables best predicting hospitalization were duration
      of surgery, amino acid treatment, and awakening temperatures. Duration of surgery
      was similar in the two groups and core temperatures at awakening were a result of
      amino acid infusion, which indicates that amino acid infusion during anesthesia
      and surgery was the most important factor for the shorter hospitalization.
      IMPLICATIONS: Amino acid infusion during general anesthesia induces thermogenesis
      and prevents postoperative hypothermia and shivering. Multiple regression
      analysis indicated that this resulted in a shorter hospital stay.

PMID- 10589648
TI  - Propofol decreases diaphragmatic contractility in dogs.
AB  - Volatile anesthetics depress diaphragmatic muscle function; however, no data are
      available regarding the effect of propofol on diaphragmatic contractility. We
      therefore studied this effect in dogs. Pentobarbital-anesthetized animals were
      divided into three groups of 10 each. Group I received only maintenance fluid;
      Group II was infused with a subhypnotic dose of propofol (0.1-mg/kg initial dose
      plus 1.5-mg x kg(-1) x h(-1) maintenance dose); Group III was infused with an
      anesthetic dose of propofol (0.1-mg/kg initial dose plus 6.0-mg x kg(-1) x h(-1)
      maintenance dose). We assessed diaphragmatic contractility by transdiaphragmatic
      pressure (Pdi). With an infusion of propofol in Groups II and III, Pdi at low
      frequency (20-Hz) stimulation decreased from the baseline values (P < 0.05),
      whereas Pdi at high-frequency (100-Hz) stimulation did not change. Compared with
      Group I, Pdi at 20-Hz stimulation decreased during propofol administration in
      Groups II and III (P < 0.05). The decrease in Pdi was more in Group III than in
      Group II (P < 0.05). We conclude that propofol is associated with a dose-related
      inhibitory effect on diaphragmatic contractility in dogs. IMPLICATIONS: Propofol
      is an effective IV anesthetic for the induction and maintenance of anesthesia.
      Subhypnotic and anesthetic doses of propofol decrease diaphragmatic contractility
      in dogs.

PMID- 10589649
TI  - The effect of remifentanil on biliary tract drainage into the duodenum.
AB  - Opioids cause spasm of the sphincter of Oddi. Remifentanil is metabolized
      enzymatically throughout the body. Its context-sensitive half-time is 3-4 min.
      The effect of remifentanil on the sphincter of Oddi, is unknown. We studied, in
      six healthy adult volunteers, the effect of remifentanil on the flow of dye from
      the gall bladder into the duodenum. Control hepatobiliary imaging with 5 mCi of
      technetium-labeled derivatives of iminodiacetic acid was performed on each
      volunteer. The time from IV dye (radiopharmaceutical) injection until its
      appearance in the duodenum was determined by continuous scanning. Two weeks
      later, each volunteer received remifentanil, 0.1 microg x kg(-1) x min(-1)
      infused for 30 min IV before the same dose of technetium-labeled derivatives of
      iminodiacetic acid was injected, and for the time of their control scan plus 10
      min after the injection. When the dye appeared in the duodenum, the total time
      from injection was compared with the control value. The time from stopping the
      infusion until the dye appeared in the duodenum was the "recovery time." Control
      scan time was 20.5+/-9.9 min (mean +/- SD; range 10-33 min). Total scan time
      during and after the remifentanil infusion was 50.3+/-17.3 min (range 30-81 min)
      (P < 0002). The recovery time was 19.8+/-12.4 min (range 5-40 min). We conclude
      that remifentanil delays the drainage of dye from the gall bladder into the
      duodenum, but the delay is shorter than that reported after other studied
      opioids. IMPLICATIONS: Radioactive dye was injected IV into healthy volunteers to
      determine the time it took for the dye to appear in the duodenum. This was
      repeated under the influence of a short-acting narcotic analgesic, remifentanil.
      Remifentanil caused a much shorter delay than previously reported after morphine
      or meperidine.

PMID- 10589650
TI  - The ulinastatin-induced effect on neuromuscular block caused by vecuronium.
AB  - We examined the effect of ulinastatin, a protease inhibitor purified from human
      urine, on neuromuscular block caused by vecuronium. Sixty adult patients were
      randomly divided into four groups of 15 patients each: ulinastatin-posttetanic
      count (U-PTC), ulinastatin-train-of-four (U-TOF), control-posttetanic count (C
      PTC) or control-train-of-four (C-TOF) group. In the U-PTC and U-TOF groups, a
      bolus dose of ulinastatin 5000 U/kg was administered 2 min before the injection
      of vecuronium 0.1 mg/kg. In the C-PTC and C-TOF groups, normal saline was
      administered instead of ulinastatin. The onset of neuromuscular block in the U
      PTC and U-TOF groups was significantly slower than in the C-PTC and C-TOF groups
      (250+/-49 vs 214+/-35 s, mean +/- SD, P < 0.05). The time from the vecuronium
      injection to the return of PTC in the U-PTC group was significantly shorter than
      in the C-PTC group (11.0+/-2.8 vs 17.6+/-6.8 min, P < 0.05). Similarly, times to
      the returns of T1, T2, T3, and T4 (first, second, third, and fourth stimulation
      of TOF) in the U-TOF group were significantly shorter than in the C-TOF group
      (18.5+/-5.0 vs 28.0+/-9.1 min for T1, P < 0.05). PTC in the U-PTC group was
      significantly higher than in the C-PTC Group 10-30 min after the administration
      of vecuronium (P < 0.05). T1/control twitch height and TOF ratios in the U-TOF
      group were significantly higher than those in the C-TOF Group 30-70 min and 40-70
      min after the administration of vecuronium, respectively (P < 0.05). Ulinastatin
      delays the onset of neuromuscular block and hastens its recovery caused by
      vecuronium. IMPLICATIONS: Ulinastatin delays the onset of neuromuscular block and
      hastens its recovery caused by vecuronium. This is because ulinastatin may
      release acetylcholine at the neuromuscular junction and increase hepatic and/or
      renal clearance of vecuronium.

PMID- 10589651
TI  - The growth of bacteria in intravenous glyceryl trinitrate and in sodium
      nitroprusside.

PMID- 10589652
TI  - Lingual hematoma as a potential cause of upper airway obstruction.

PMID- 10589653
TI  - An unexpected complication during laparoscopic herniorrhaphy.

PMID- 10589654
TI  - Increased plasma cholinesterase activity and mivacurium resistance: report of a
      family.

PMID- 10589655
TI  - A case of a nasogastric tube knotting around a tracheal tube: detection and
      management.

PMID- 10589656
TI  - IV halothane anesthesia.

PMID- 10589657
TI  - What to do with the jeweled tongue?

PMID- 10589658
TI  - No alternative to antiviral drugs for acute herpes zoster.

PMID- 10589659
TI  - Awareness of Sikh custom of restraining a beard with a cord leading to possible
      airway problems.

PMID- 10589660
TI  - Flow transducer gas leak detected after induction.

PMID- 10589661
TI  - Transcranial Doppler technique for monitoring the efficacy of selective antegrade
      cerebral perfusion.

PMID- 10589662
TI  - The high-pressure characteristics of the cuff of the intubating laryngeal mask
      endotracheal tube.

PMID- 10589663
TI  - Another perspective on postoperative nausea and vomiting.

PMID- 10589664
TI  - Capnography for safe use of the laryngeal mask during emergence from anesthesia.

PMID- 10589665
TI  - The epinephrine test dose in obstetrics.

PMID- 10589666
TI  - Another potential factor that may cause bronchial rupture by a double-lumen
      endobronchial tube.

PMID- 10589667
TI  - Pressure-assisted breathing through a laryngeal mask airway during
      transesophageal echocardiography.

PMID- 10589668
TI  - The difference between actual and calculated osmolality of IU solutions should
      not be overlooked.

PMID- 10589669
TI  - Earlier extubation after esophagectomy is successfully performed with thoracic
      epidural bupivacaine combined with thoracic and lumbar epidural morphine.

PMID- 10589670
TI  - The "dark side" of chromatin remodeling: repressive effects on transcription.

PMID- 10589671
TI  - Sin meets NuRD and other tails of repression.

PMID- 10589672
TI  - Methylation-induced repression--belts, braces, and chromatin.

PMID- 10589673
TI  - Repression: targeting the heart of the matter.

PMID- 10589674
TI  - Putting boundaries on silence.

PMID- 10589675
TI  - An auxin-dependent distal organizer of pattern and polarity in the Arabidopsis
      root.
AB  - Root formation in plants involves the continuous interpretation of positional
      cues. Physiological studies have linked root formation to auxins. An auxin
      response element displays a maximum in the Arabidopsis root and we investigate
      its developmental significance. Auxin response mutants reduce the maximum or its
      perception, and interfere with distal root patterning. Polar auxin transport
      mutants affect its localization and distal pattern. Polar auxin transport
      inhibitors cause dramatic relocalization of the maximum, and associated changes
      in pattern and polarity. Auxin application and laser ablations correlate root
      pattern with a maximum adjacent to the vascular bundle. Our data indicate that an
      auxin maximum at a vascular boundary establishes a distal organizer in the root.

PMID- 10589676
TI  - WEREWOLF, a MYB-related protein in Arabidopsis, is a position-dependent regulator
      of epidermal cell patterning.
AB  - The formation of the root epidermis of Arabidopsis provides a simple and elegant
      model for the analysis of cell patterning. A novel gene, WEREWOLF (WER), is
      described here that is required for position-dependent patterning of the
      epidermal cell types. The WER gene encodes a MYB-type protein and is
      preferentially expressed within cells destined to adopt the non-hair fate.
      Furthermore, WER is shown to regulate the position-dependent expression of the
      GLABRA2 homeobox gene, to interact with a bHLH protein, and to act in opposition
      to the CAPRICE MYB. These results suggest a simple model to explain the
      specification of the two root epidermal cell types, and they provide insight into
      the molecular mechanisms used to control cell patterning.

PMID- 10589677
TI  - Shroom, a PDZ domain-containing actin-binding protein, is required for neural
      tube morphogenesis in mice.
AB  - Using gene trap mutagenesis, we have identified a mutation in mice that causes
      exencephaly, acrania, facial clefting, and spina bifida, all of which can be
      attributed to failed neural tube closure. This mutation is designated shroom
      (shrm) because the neural folds "mushroom" outward and do not converge at the
      dorsal midline. shrm encodes a PDZ domain protein that is involved at several
      levels in regulating aspects of cytoarchitecture. First, endogenous Shrm
      localizes to adherens junctions and the cytoskeleton. Second, ectopically
      expressed Shrm alters the subcellular distribution of F-actin. Third, Shrm
      directly binds F-actin. Finally, cytoskeletal polarity within the neuroepithelium
      is perturbed in mutant embryos. In concert, these observations suggest that Shrm
      is a critical determinant of the cellular architecture required for proper
      neurulation.

PMID- 10589678
TI  - p27Xic1, a Cdk inhibitor, promotes the determination of glial cells in Xenopus
      retina.
AB  - p27Xic1, a member of the Cip/Kip family of Cdk inhibitors, besides its known
      function of inhibiting cell division, induces Muller glia from retinoblasts. This
      novel gliogenic function of p27Xic1 is mediated by part of the N-terminal domain
      near but distinct from the region that inhibits cyclin-dependent kinases.
      Cotransfections with dominant-negative and constitutively active Delta and Notch
      constructs indicate that the gliogenic effects of p27Xic1 work within the context
      of an active Notch pathway. The gradual increase of p27Xic1 in the developing
      retina thus not only limits the number of retinal cells but also increasingly
      favors the fate of the last cell type to be born in the retina, the Muller glia.

PMID- 10589679
TI  - The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle
      cell migration.
AB  - Human cytomegalovirus (HCMV) infection of smooth muscle cells (SMCs) in vivo has
      been linked to a viral etiology of vascular disease. In this report, we
      demonstrate that HCMV infection of primary arterial SMCs results in significant
      cellular migration. Ablation of the chemokine receptor, US28, abrogates SMC
      migration, which is rescued only by expression of the viral homolog and not a
      cellular G protein-coupled receptor (GPCR). Expression of US28 in the presence of
      CC chemokines including RANTES or MCP-1 was sufficient to promote SMC migration
      by both chemokinesis and chemotaxis, which was inhibited by protein tyrosine
      kinase inhibitors. US28-mediated SMC migration provides a molecular basis for the
      correlative evidence that links HCMV to the acceleration of vascular disease.

PMID- 10589680
TI  - Phosphatidylinositol 4-phosphate 5-kinase alpha is a downstream effector of the
      small G protein ARF6 in membrane ruffle formation.
AB  - Synthesis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], a signaling
      phospholipid, is primarily carried out by phosphatidylinositol 4-phosphate 5
      kinase [PI(4)P5K], which has been reported to be regulated by RhoA and Rac1.
      Unexpectedly, we find that the GTPgammaS-dependent activator of PI(4)P5Kalpha is
      the small G protein ADP-ribosylation factor (ARF) and that the activation
      strictly requires phosphatidic acid, the product of phospholipase D (PLD). In
      vivo, ARF6, but not ARF1 or ARF5, spatially coincides with PI(4)P5Kalpha. This
      colocalization occurs in ruffling membranes formed upon AIF4 and EGF stimulation
      and is blocked by dominant-negative ARF6. PLD2 similarly translocates to the
      ruffles, as does the PH domain of phospholipase Cdelta1, indicating locally
      elevated PI(4,5)P2. Thus, PI(4)P5Kalpha is a downstream effector of ARF6 and when
      ARF6 is activated by agonist stimulation, it triggers recruitment of a diverse
      but interactive set of signaling molecules into sites of active cytoskeletal and
      membrane rearrangement.

PMID- 10589681
TI  - Structure and mechanism of yeast RNA triphosphatase: an essential component of
      the mRNA capping apparatus.
AB  - RNA triphosphatase is an essential mRNA processing enzyme that catalyzes the
      first step in cap formation. The 2.05 A crystal structure of yeast RNA
      triphosphatase Cet1p reveals a novel active site fold whereby an eight-stranded
      beta barrel forms a topologically closed triphosphate tunnel. Interactions of a
      sulfate in the center of the tunnel with a divalent cation and basic amino acids
      projecting into the tunnel suggest a catalytic mechanism that is supported by
      mutational data. Discrete surface domains mediate Cet1p homodimerization and
      Cet1p binding to the guanylyltransferase component of the capping apparatus. The
      structure and mechanism of fungal RNA triphosphatases are completely different
      from those of mammalian mRNA capping enzymes. Hence, RNA triphosphatase presents
      an ideal target for structure-based antifungal drug discovery.

PMID- 10589682
TI  - Three-dimensional structure of a complex between the death domains of Pelle and
      Tube.
AB  - The interaction of the serine/threonine kinase Pelle and adaptor protein Tube
      through their N-terminal death domains leads to the nuclear translocation of the
      transcription factor Dorsal and activation of zygotic patterning genes during
      Drosophila embryogenesis. Crystal structure of the Pelle and Tube death domain
      heterodimer reveals that the two death domains adopt a six-helix bundle fold and
      are arranged in an open-ended linear array with plastic interfaces mediating
      their interactions. The Tube death domain has an insertion between helices 2 and
      3, and a C-terminal tail making significant and indispensable contacts in the
      heterodimer. In vivo assays of Pelle and Tube mutants confirmed that the
      integrity of the major heterodimer interface is critical to the activity of these
      molecules.

PMID- 10589683
TI  - Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in the human kidney.
AB  - The secosteroid hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) plays a vital role
      in calcium metabolism, tissue differentiation, and normal bone growth.
      Biosynthesis of 1,25(OH)2D3 is catalyzed by the mitochondrial cytochrome P450
      enzyme 25-hydroxyvitamin D3 1alpha-hydroxylase (1alpha-hydroxylase). Although
      activity of this enzyme has been described in several tissues, the kidneys are
      recognized to be the principal site of 1,25(OH)2D3 production. To date, enzyme
      activity studies using vitamin D-deficient animals have suggested that 1alpha
      hydroxylase is expressed exclusively in proximal convoluted tubules. With the
      recent cloning of 1alpha-hydroxylase, specific cRNA probes and in-house
      polyclonal antiserum have been used to determine the distribution of 1alpha
      hydroxylase along the human nephron. Immunohistochemistry and in situ
      hybridization studies indicated strong expression of 1alpha-hydroxylase protein
      and mRNA in the distal convoluted tubule, the cortical and medullary part of the
      collecting ducts, and the papillary epithelia. Lower expression was observed
      along the thick ascending limb of the loop of Henle and Bowman's capsule. Weaker
      and more variable expression of 1alpha-hydroxylase protein and mRNA was seen in
      proximal convoluted tubules, and no expression was observed in glomeruli or
      vascular structures. These data show for the first time the distribution of
      alpha1-hydroxylase expression in normal human kidney. In contrast to earlier
      enzyme activity studies conducted in vitamin D-deficient animals, our data
      indicate that the distal nephron is the predominant site of 1alpha-hydroxylase
      expression under conditions of vitamin D sufficiency.

PMID- 10589684
TI  - Calcitonin induces 25-hydroxyvitamin D3 1alpha-hydroxylase mRNA expression via
      protein kinase C pathway in LLC-PK1 cells.
AB  - The biosynthesis of 1alpha, 25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 is
      catalyzed by 25-hydroxyvitamin D3 1alpha-hydroxylase (CYP27B1) in renal proximal
      tubules. It was recently demonstrated that LLC-PK1 cells express CYP27B1 mRNA,
      which is regulated by intracellular cAMP but not vitamin D3. To clarify the
      effect of calcitonin on vitamin D3 metabolism in vitro, LLC-PK1 cells were
      incubated with hormonal factors, and expression of CYP27B1 mRNA was measured by
      quantitative reverse transcription-PCR. Calcitonin at 100 nmol/L significantly
      increased CYP27B1 mRNA expression by 24 h (271 +/- 21% of control). Incubation
      with calcitonin over a range of 1 micromol/L to 1 pmol/L resulted in a
      concentration-dependent increase in CYP27B1 mRNA levels. It is known that the
      calcitonin receptor has dual intracellular signaling pathways, via protein
      kinases A and C. Both 500 micromol/L 8-bromo-cAMP, a protein kinase A activator,
      and 100 nmol/L phorbol 12-myristate 13-acetate, a protein kinase C activator,
      increased CYP27B1 mRNA levels at 24 h (207 +/- 54 and 246 +/- 58% of control,
      respectively). However, calcitonin-induced CYP27B1 mRNA expression was only
      inhibited by the protein kinase C inhibitors staurosporine and calphostin C. The
      protein kinase A inhibitors Rp-cAMPS at 10 and 100 micromol/L and H-89 at 10
      micromol/L had no effect on the action of calcitonin, in spite of cAMP-activation
      by calcitonin. The present data suggest that calcitonin upregulates CYP27B1 mRNA
      expression via the protein kinase C pathway in LLC-PK1 cells.

PMID- 10589685
TI  - YB-1 regulation of the human and rat gelatinase A genes via similar enhancer
      elements.
AB  - Experimental and clinical studies strongly suggest that gelatinase A plays a
      central role in the evolution of glomerular injury and sclerosis. The sequences
      of the 5' flanking regions of the human and rat gelatinase A genes do not share
      similarities with other members of the matrix metalloproteinase gene family and
      are regulated in a distinctive manner. The human and rat gelatinase A genes
      include regions of significant homology (r2 human; RE-1 rat), which have been
      shown to act as potent cis-activators of transcription. The rat RE-1 sequence
      interacts specifically with the developmentally regulated transcription factors
      AP2 and YB-1, resulting in a synergistic activation of gelatinase A
      transcription. Although the human r2 sequence specifically interacts with AP2
      (Mol Cell Biol 10: 6524-6532, 1990), there is no clear evidence for the presence
      of a canonical YB-1 binding site (Y-box) within this sequence. This study
      demonstrates, despite the absence of a canonical Y-box sequence in the r2
      element, that YB-1 and AP2 specifically interact with r2, yielding synergistic
      transactivation of the human gelatinase A gene. It is concluded that the r2
      element is the conserved functional analog of the RE-1 element, and that
      interactions of AP2 and YB-1 govern human gelatinase A gene expression.

PMID- 10589686
TI  - Sgk, a putative serine/threonine kinase, is differentially expressed in the
      kidney of diabetic mice and humans.
AB  - Differential display PCR was used to identify alternate expression of serum
      glucocorticoid-regulated kinase (Sgk) mRNA in diabetes-induced renal disease.
      Differential expression of Sgk mRNA was identified in the kidneys of normal and
      obese db/db mice, a model of select aspects of human diabetic nephropathy. Sgk
      mRNA was selectively increased in diabetic mouse kidneys. The Sgk mRNA levels
      remained constant in other tissues from obese db/db mice. An increase in Sgk mRNA
      was also observed in the human diabetic kidney. In addition, thrombin, which may
      play a role in the progression of renal disease, increased Sgk message in cell
      culture. Because the diabetes-induced increase in Sgk was only observed in the
      kidney, which is particularly susceptible to diabetes-induced damage, Sgk may
      play a role in diabetic nephropathy.

PMID- 10589687
TI  - Regulation of rat mesangial cell migration by platelet-derived growth factor,
      angiotensin II, and adrenomedullin.
AB  - This study sought to determine whether platelet-derived growth factor (PDGF) and
      angiotensin II (AngII) stimulate migration of cultured rat glomerular mesangial
      cells. After finding that this was so, the effects of adrenomedullin (ADM) and
      cAMP-elevating agents on basal and stimulated mesangial cell migration were
      examined. Two isoforms of PDGF, AB and BB, stimulated migration in a
      concentration-dependent manner between 1 and 50 ng/ml, while the AA isoform
      lacked significant effect. AngII modestly but significantly stimulated migration
      in a concentration-dependent manner between 10(-7) and 10(-6) mol/L. Rat ADM
      significantly inhibited the PDGF BB- and AngII-stimulated migration in a
      concentration-dependent manner between 10(-8) and 10(-7) mol/L. Inhibition by rat
      ADM was accompanied by an increase in cellular cAMP. cAMP agonists or inducers
      such as 8-bromo cAMP, forskolin, and prostaglandin I2 also significantly reduced
      the stimulated migration. H 89, a protein kinase A (PKA) inhibitor, attenuated
      the inhibitory effect of ADM, and a calcitonin gene-related peptide (CGRP)
      receptor antagonist, human CGRP (8-37), abolished the inhibitory effects of rat
      ADM. These results suggest that PDGF AB and BB as well as AngII stimulate rat
      mesangial cell migration and that ADM can inhibit PDGF BB- and AngII-stimulated
      migration, at least in part through cAMP-dependent mechanisms likely to involve
      specific ADM receptors with which CGRP interacts. The adenylate cyclase/cAMP/PKA
      system may be involved in the migration-inhibitory effect of ADM in these cells.

PMID- 10589688
TI  - Mechanism of inhibitory effect of warfarin on mesangial cell proliferation.
AB  - Because proliferation of mesangial cells is a hallmark of glomerular diseases,
      understanding the regulatory mechanism of mesangial proliferation is important
      for the treatment. Warfarin has long been used to treat glomerular diseases,
      although its mechanism of effect on mesangial proliferation has remained unknown.
      Therefore, this study was conducted to examine whether warfarin can inhibit mouse
      mesangial cell proliferation by focusing on Gas6, which has been shown to be
      activated by vitamin K-dependent gamma-carboxylation. In mesangial cells, Gas6
      and its receptor Axl were expressed. In addition, exogenous Gas6 phosphorylated
      Axl, activated extracellular signal-regulated kinase, and stimulated [3H]
      thymidine incorporation in mouse mesangial cells. This study also examined
      whether endogenous Gas6 stimulates mesangial proliferation. Conditioned medium
      (CM) from serum-starved mesangial cells could stimulate [3H]-thymidine
      incorporation and phosphorylate extracellular signal-regulated kinase, whereas CM
      in the presence of warfarin could not. Simultaneous administration of vitamin K
      could cancel the inhibitory effect of warfarin. These results suggest that
      vitamin K-dependent growth factors in the CM are critical for mesangial
      proliferation. Addition of the extracellular domain of Axl to the CM inhibited
      its mitogenic effect on mesangial cells, suggesting that this vitamin K-dependent
      growth factor is Gas6. It is concluded that Gas6 is an endogenous mitogen in
      mesangial cells, and warfarin inhibits mesangial proliferation possibly by
      inhibiting gamma-carboxylation of Gas6. This study sheds light on the regulation
      of mesangial proliferation and may lead to a new therapeutic strategy for
      glomerular diseases.

PMID- 10589689
TI  - The role of selectins in glomerular leukocyte recruitment in rat anti-glomerular
      basement membrane glomerulonephritis.
AB  - Leukocytes play a central role in the pathogenesis of anti-glomerular basement
      membrane glomerulonephritis (anti-GBM GN). Understanding the mechanisms
      underlying their recruitment in the glomerulus is of critical importance, because
      this may lead to more specific anti-inflammatory drug design. The requirement for
      integrins, especially from the beta2 group, and their Ig superfamily counter
      receptors has been established, however, the role of selectins remains
      controversial. An intravital microscopy technique was developed to study
      concomitantly the glomerular and venular leukocyte kinetics and the hemodynamic
      alterations in a rat model of anti-GBM GN, induced by injection of 10 mg of
      nephrotoxic serum (NTS). Histologic studies of the kidney were performed in
      parallel and urinary protein excretion was measured. The animals received NTS
      alone or were pretreated with either a monoclonal antibody against the beta2
      integrin CD11b (OX42, 4 mg/kg) or fucoidan F7 (FF7, 8 mg/kg), an oligosaccharide
      that blocks both L- and P-selectin function. Administration of NTS resulted in a
      time-dependent increase in the number of adherent leukocytes in the glomeruli and
      a parallel decrease of the perfused glomerular capillary area. Substantial
      proteinuria was observed. Pretreatment with OX42 significantly attenuated these
      changes. FF7 almost abolished the rolling of the leukocytes in the venules, thus
      demonstrating efficient anti-selectin activity. Nevertheless, FF7 had no
      influence on the glomerular events or on the development of proteinuria. These
      results confirm that glomerular leukocyte adhesion in anti-GBM GN is CD11b
      dependent. However, selectin-mediated interaction between the leukocytes and the
      glomerular capillary endothelium does not appear to be a prerequisite for
      leukocyte adhesion in the glomerulus. These results therefore question the
      potential utility of anti-selectin therapy in the treatment of anti-GBM GN.

PMID- 10589690
TI  - Role for interactions between IP-10/Mig and CXCR3 in proliferative
      glomerulonephritis.
AB  - The mechanisms responsible for mesangial cell proliferation in proliferative
      glomerulonephritis are only partially understood. This article reports the
      results of an immunohistochemical study showing high expression of the chemokine
      receptor CXCR3 by mesangial cells of patients with IgA nephropathy,
      membranoproliferative glomerulonephritis, or rapidly progressive
      glomerulonephritis. CXCR3 was also detectable by flow cytometry in cultured human
      mesangial cells, in which it appeared to be functionally active, as determined by
      the ability of its ligand, the (interferon-gamma)-inducible protein of 10 kD (IP
      10) to induce intracellular Ca2+ influx. Both IP-10 and the monokine induced by
      interferon-gamma (Mig) were also effective in inducing proliferation of human
      mesangial cells. These data suggest that in patients with proliferative
      glomerulonephritis, the chemokines IP-10 and/or Mig not only may act as
      chemoattractants for infiltrating mononuclear cells in the inflamed tissue, but
      also may directly induce the proliferation of mesangial cells.

PMID- 10589691
TI  - A mouse model for Liddle's syndrome.
AB  - Liddle's syndrome (or pseudoaldosteronism) is an autosomal dominant form of salt
      sensitive hypertension, due to abnormal sodium transport by the renal tubule. To
      study the pathophysiology of salt sensitivity, a mouse model for Liddle's
      syndrome has been generated by Cre/loxP-mediated recombination. Under normal salt
      diet, mice heterozygous (L/+) and homozygous (L/L) for Liddle mutation (L)
      develop normally during the first 3 mo of life. In these mice, BP is not
      different from wild type despite evidence for increased sodium reabsorption in
      distal colon and low plasma aldosterone, suggesting chronic hypervolemia. Under
      high salt intake, the Liddle mice develop high BP, metabolic alkalosis, and
      hypokalemia accompanied by cardiac and renal hypertrophy. This animal model
      reproduces to a large extent a human form of salt-sensitive hypertension and
      establishes a causal relationship between dietary salt, a gene expressed in
      kidney and hypertension.

PMID- 10589692
TI  - Clinical and pathologic findings in two new allelic murine models of polycystic
      kidney disease.
AB  - Patients with inherited cystic kidney diseases have progressive cystic dilation
      of nephrons with concomitant loss of functional renal parenchyma and renal
      failure. Animal models of inherited cystic kidney disease are useful for study of
      the pathogenesis and molecular basis of cystic renal diseases. This article
      describes the clinical and pathologic features in two spontaneously occurring
      murine models of inherited polycystic kidney disease due to independent allelic
      mutations on mouse chromosome 8. The mutations, designated kat and kat2J, affect
      a chromosomal segment homologous to a region of human chromosome 4q35; the
      altered gene has not yet been identified. An allelism test showed that the
      mutations are at the same locus. The phenotype, inherited as an autosomal
      recessive, is more severe in kat2J/kat2J mice. Their kidneys are morphologically
      normal at birth, but by 3 mo of age, cysts affect all levels of the nephron.
      Adult males have testicular hypoplasia and they are sterile. A few of the oldest
      kat2J/kat2J mice have focal portal bile duct proliferation and dilation.
      kat2J/kat2J mice develop anemia and uremia and die before 1 yr of age. In kat/kat
      mice, the renal cystic disease progresses more slowly but is morphologically
      similar to that of kat2J/kat2J mice. The progressive cystic transformation of the
      kidneys in these allelic murine models resembles that seen in humans with
      autosomal dominant polycystic kidney disease.

PMID- 10589693
TI  - Heme oxygenase-1 induction attenuates inducible nitric oxide synthase expression
      and proteinuria in glomerulonephritis.
AB  - In glomerulonephritis, there is intraglomerular activation of inducible nitric
      oxide synthase (iNOS) leading to high output production of nitric oxide (NO).
      This can result in supraphysiologic amounts of NO and cause oxidative injury. It
      is unknown whether mechanisms of cellular defense against NO-mediated injury
      exist. Induction of the heme catabolizing enzyme heme oxygenase-1 (HO-1), which
      generates biliverdin, carbon monoxide (CO), and iron (Fe), may provide such a
      mechanism, as CO and Fe are two negative modulators of iNOS activity and
      expression. This study assessed whether upregulation of HO-1 by a specific
      inducer, hemin, negatively modulates iNOS expression and activity in anti
      glomerular basement membrane antibody-mediated glomerulonephritis. Glomerular HO
      1 expression in nephritic animals was upregulated by treatment with hemin (30
      micromol/kg body wt). iNOS and HO-1 mRNA expression were assessed by reverse
      transcription-PCR of glomerular total RNA from nephritic animals or nephritic
      animals pretreated with hemin. iNOS activity in glomeruli was measured by
      assessing conversion of [14C] L-arginine to [14C] L-citrulline. HO-1 protein
      levels in glomeruli were assessed by Western blot analysis. The effect of hemin
      treatment on monocyte/macrophage infiltration was assessed by enumeration of ED-1
      positive cells in nephritic glomeruli. iNOS and HO-1 were coinduced in nephritic
      glomeruli. Hemin treatment of nephritic animals resulted in upregulation of
      glomerular HO-1 levels and a two- to threefold reduction in glomerular iNOS mRNA
      levels. iNOS activity in glomeruli was significantly reduced in hemin-treated
      nephritic animals in which proteinuria was also attenuated without a change in
      monocyte/macrophage infiltration. Hemin (100 to 200 microM) also reduced iNOS
      protein levels and enzyme activity in cultured mesangial cells stimulated with
      cytokines. These studies demonstrate that in glomerular immune injury, hemin
      treatment upregulates glomerular HO-1 with an attendant downregulation of iNOS
      expression, and thus points to regulatory interaction between the two systems.
      The beneficial effect of hemin treatment on proteinuria could be linked to
      downregulation of iNOS.

PMID- 10589694
TI  - Chronic reduction in renal mass in the rat attenuates ischemia/reperfusion injury
      and does not impair tubular regeneration.
AB  - It is not known whether a kidney with chronic structural and functional changes
      is more vulnerable to an acute renal insult, and whether its regeneration
      capacity after injury is altered. To study this question, Lewis rats were
      submitted 10 wk after 5/6 nephrectomy to an ischemic insult of 60 min (remnant
      kidney [RK] group). Functional and morphologic data of the RK group were compared
      with data obtained in 10-wk uninephrectomized (1K) and normal (2K) Lewis rats
      with unilateral and bilateral renal ischemia, respectively. The acute
      postischemic decrease in creatinine clearance was smallest in the RK group,
      followed by the 2K and 1K groups, respectively. At days 1 and 3, fewer proximal
      tubules in the outer stripe of the outer medulla of the RK and 2K groups had
      undergone acute tubular necrosis compared with the 1K group. The mean percentage
      of tubules with signs of regeneration was maximal at day 3 in the three
      experimental groups. At day 10, regeneration was almost complete in the three
      groups. The number of leukocytes (OX1+ cells) present in the RK before ischemia
      did not increase after ischemia/reperfusion injury (377 +/- 146 cells/mm2 at day
      0) in contrast to the 1K and 2K groups. In the latter groups, the number of
      leukocytes had increased gradually, reaching a maximum at day 15 (1K: 960 +/- 308
      cells/mm2) and day 10 (2K: 668 +/- 164 cells/mm2), respectively. In conclusion,
      this study has shown that an RK exhibiting chronic morphologic changes of
      interstitial fibrosis and tubular atrophy is protected against
      ischemia/reperfusion injury, and that its regeneration capacity is preserved. The
      reperfusion injury is not followed by further accumulation of leukocytes, which
      were already present in the RK before ischemia.

PMID- 10589695
TI  - Mechanism of increased parathyroid hormone mRNA in experimental uremia: roles of
      protein RNA binding and RNA degradation.
AB  - Patients with chronic renal failure develop secondary hyperparathyroidism with
      increased synthesis and secretion of parathyroid hormone (PTH) resulting in
      severe skeletal complications. In rats with secondary hyperparathyroidism due to
      5/6 nephrectomy, there are increased PTH mRNA levels, and this mechanism was
      studied. Parathyroid glands were microdissected from control and 5/6 nephrectomy
      rats and analyzed for PTH mRNA and control genes, and the nuclei were used for
      nuclear run-on experiments. The cytosolic proteins of the parathyroids were used
      to study PTH mRNA protein binding by ultraviolet cross-linking and the
      degradation of the PTH transcript in vitro. Nuclear run-ons showed that the
      increase in PTH mRNA levels was posttranscriptional. Protein binding to the PTH
      mRNA 3'-UTR determines PTH mRNA stability and levels. Parathyroid proteins from
      uremic rats bound PTH mRNA similar to control rats by ultraviolet cross-linking.
      To determine the effect of uremia on PTH mRNA stability, an in vitro RNA
      degradation assay was performed with parathyroid proteins from uremic rats. When
      parathyroid proteins from control rats were incubated with PTH mRNA, there was
      transcript degradation already at 30 min, reaching 50% at 60 min and 90% at 180
      min. With uremic parathyroid proteins, the PTH mRNA was not degraded at all at
      120 min and was moderately decreased at 180 min. This decrease in degradation by
      uremic parathyroid proteins suggests a decrease in parathyroid cytosolic
      endonuclease activity in uremia resulting in a more stable PTH transcript. The
      increased PTH mRNA levels would translate into increased PTH synthesis and serum
      PTH levels, which would lead to metabolic bone disease in many patients with
      chronic renal failure.

PMID- 10589696
TI  - Glomerular hyperfiltration in experimental diabetes mellitus: potential role of
      tubular reabsorption.
AB  - An increase in Na+/glucose cotransport upstream to the macula densa might
      contribute to the increase in single nephron GFR (SNGFR) in early diabetes
      mellitus by lowering the signal of the tubuloglomerular feedback, i.e., the
      luminal Na+, Cl-, and K+ concentration sensed by the macula densa. To examine
      this issue, micropuncture experiments were performed in nephrons with superficial
      glomeruli of streptozotocin-induced diabetes mellitus in rats. First, in
      nondiabetic control rats, ambient early distal tubular concentrations of Na+, Cl
      , and K+ were about 21, 20, and 1.2 mM, respectively, suggesting collection sites
      relatively close to the macula densa. Second, glomerular hyperfiltration in
      diabetic rats was associated with a reduction in ambient early distal tubular
      concentrations of Na+, Cl-, and K+ by 20 to 28%, reflecting an increase in
      fractional reabsorption of these ions up to the early distal tubule. Third, in
      diabetic rats, early proximal tubular application of phlorizin, an inhibitor of
      Na+/glucose cotransport, elicited (1) a greater reduction in absolute and
      fractional reabsorption of Na+, Cl-, and K+ up to the early distal tubule, and
      (2) a greater increase in early distal tubular concentration of these ions, which
      was associated with a more pronounced reduction in SNGFR. These findings support
      the concept that stimulation of tubular Na+/glucose cotransport by reducing the
      tubuloglomerular feedback signal at the macula densa may contribute to glomerular
      hyperfiltration in diabetic rats. Glomerular hyperfiltration in diabetic rats
      serves to compensate for the rise in fractional tubular reabsorption to partly
      restore the electrolyte load to the distal nephron.

PMID- 10589697
TI  - Hemodynamic patterns and spectral analysis of heart rate variability during
      dialysis hypotension.
AB  - Intradialytic hypotension, a major source of morbidity during hemodialysis and
      ultrafiltration, is often accompanied by paradoxical bradycardia. Relatively
      little is known about the sequential changes in autonomic nervous system activity
      up to and during the hypotensive episode. Continuous, beat-to-beat measurements
      of BP and heart rate were made during hemodialysis in patients prone (n = 8) and
      not prone (n = 11) to develop intradialytic hypotension. Off-line spectral
      analysis of heart rate variability (HRV) was performed to assess changes in
      autonomic nervous system activity during dialysis sessions both with and without
      hypotension. The low frequency (LF) component of HRV is thought to correlate with
      sympathetic nervous system activity, the high frequency (HF) component with that
      of the parasympathetic nervous system. In the sessions not complicated by
      symptomatic hypotension (n = 26), mean arterial BP (MAP) hardly fell, whereas
      heart rate increased from 77 +/- 2 to 89 +/- 5 bpm (P < 0.05). The LF component
      of HRV increased from 45.2 +/- 5.0 normalized units (nu) to 59.9 +/- 4.9 nu (P <
      0.05), whereas the HF component fell from 54.8 +/- 5.0 to 40.2 +/- 4.4 nu (P <
      0.05). These changes agree with compensatory baroreflex-mediated activation of
      the sympathetic nervous system (and suppressed parasympathetic activity) during
      ultrafiltration-induced intravascular volume depletion. In the sessions
      complicated by severe symptomatic hypotension (n = 22), the changes in heart rate
      and the results of spectral analysis of HRV were similar to those reported above
      up to the moment of sudden symptomatic (nausea, vomiting, dizziness, cramps)
      hypotension, whereas MAP had already fallen gradually from 94 +/- 3 to 85 +/- 3
      mmHg (P < 0.05). The sudden further reduction in MAP (to 55 +/- 2 mmHg, P < 0.02)
      was invariably accompanied by bradycardia (heart rate directly before hypotension
      90 +/- 2 bpm, during hypotension 69 +/- 3 bpm, P < 0.002). The LF component of
      HRV fell from 62.8 +/- 4.6 nu directly before to 40.0 +/- 3.7 nu (P < 0.05)
      during hypotension, whereas the HF component increased from 37.9 +/- 4.7 to 60.3
      +/- 3.7 nu (P < 0.05). These findings agree with activation of the
      cardiodepressor reflex, involving decreased sympathetic and increased
      parasympathetic nervous system activity, respectively. These findings indicate
      that activation of the sympatho-inhibitory cardiodepressor reflex (Bezold-Jarisch
      reflex), which is a physiologic response to a critical reduction in intravascular
      volume and cardiac filling, is the cause of sudden intradialytic hypotension.

PMID- 10589698
TI  - Volume stress-induced peritoneal endothelin-1 release in continuous ambulatory
      peritoneal dialysis.
AB  - In long-term peritoneal dialysis, functional deterioration of the peritoneal
      membrane is often associated with proliferative processes of the involved tissues
      leading to peritoneal fibrosis. In continuous ambulatory peritoneal dialysis
      (CAPD), failure to achieve target values for adequacy of dialysis is commonly
      corrected by increasing dwell volume; in case of ultrafiltration failure,
      osmolarity of the dialysate gets increased. In a prospective study, the impact of
      increasing dwell volume from 1500 ml to 2500 ml per dwell (volume trial) or
      changing the osmolarity of the dialysate from 1.36 to 3.86% glucose
      (hyperosmolarity trial) on the peritoneal endothelin-1 (ET-1) release was
      analyzed. ET-1 is known to exert significant proliferative activities on a
      variety of cell types leading to an accumulation of extracellular matrix. A
      highly significant difference in the cumulative peritoneal ET-1 synthesis was
      found between the low- and high-volume exchange, whereas differences in the
      hyperosmolarity setting were only moderate. Sixty minutes after initiating
      dialysis, the cumulative ET-1 synthesis was 2367 +/- 1023 fmol for the 1500 ml
      versus 6062 +/- 1419 fmol for the 2500 dwell (P < 0.0001) and 4572 +/- 969 fmol
      versus 6124 +/- 1473 fmol for the 1.36 and 3.86% glucose dwell (P < 0.05),
      respectively. In conclusion, increasing dwell volume leads to a strong activation
      of the peritoneal paracrine endothelin system. Because ET-1, apart from being a
      potent vasoactive peptide, contributes to fibrotic remodeling, this study
      indicates that volume stress-induced ET-1 release might contribute to structural
      alteration of the peritoneal membrane in long-term peritoneal dialysis.

PMID- 10589699
TI  - Early experience with dual kidney transplantation in adults using expanded donor
      criteria. Double Kidney Transplant Group (DKG).
AB  - Dual transplant of marginal kidneys otherwise not considered for single
      transplant may give access to an expanded pool of cadaveric organs without
      exposing recipients to the drawbacks of a limited nephron mass supply. This
      prospective, case-control study compares adverse events and graft outcome in 24
      recipients of two marginal kidneys from donors who were >60 yr old or who had
      diabetes, hypertension, or non-nephrotic proteinuria (cases), with that of 48 age
      and gender-matched control subjects who received single ideal grafts at the same
      center and were given the same immunosuppressive therapy. Marginal kidneys with
      no macroscopic abnormalities were selected for the double transplant on the basis
      of a predefined score of histologic damage. Six-month patient and kidney survival
      was 100% with both of the procedures. Incidence (20.8% versus 20.8%) and median
      (range) duration of posttransplant anuria (5 [2 to 12] versus 7 [2 to 13] days)
      were comparable in cases and control subjects, respectively. Time to normal serum
      creatinine and mean serum creatinine values at each time visit were comparable as
      well, but with significantly lower levels in cases compared with control subjects
      from month 2 to last follow-up (1.56 +/- 0.65 versus 1.74 +/- 0.73 mg/dl, P =
      0.04). Diastolic BP values averaged during the entire posttransplant period were
      significantly lower in cases than in control subjects (83.2 +/- 11.5 versus 85.1
      +/- 12.5 mmHg, respectively, P = 0.008). Donor/recipient body weight ratio was
      the only covariate significantly associated at univariate (P = 0.002) and
      multivariate (P = 0.001) analysis with last available serum creatinine
      concentrations. Incidence of acute allograft rejections (20.8% versus 18.8%) and
      of major surgical complications was comparable in the two groups. No renal artery
      or vein thrombosis was reported in either group. Dual transplants of marginal
      kidneys are as safe and tolerated as single transplants, and possibly offer an
      improved filtration power without exposing the recipient to enhanced risk of
      delayed renal function recovery, acute allograft rejection, or major surgical
      complications.

PMID- 10589700
TI  - The PlA2 polymorphism of the platelet glycoprotein IIIA gene as a risk factor for
      acute renal allograft rejection.
AB  - Glycoprotein IIIa/IIb is a membrane receptor for fibrinogen and von Willebrand
      factor that plays an important role in platelet aggregation. The beta integrin
      chain of this receptor, GPIIIa, is polymorphic, and the allele known as PlA2 has
      been associated with coronary thrombosis. The GPIIIa genotype of a cohort of 119
      consecutive renal allograft recipients (46.3 +/- 13 yr; 85 M/34 F; 24.4% diabetic
      patients) was determined by PCR-restriction fragment length polymorphism, and
      those patients were followed for at least 12 mo. From 119 patients with at least
      1 yr of follow-up, those who suffered an acute rejection (n = 52) showed a lower
      proportion of HLA-DR beta1 identity with the donor (7.7% versus 23.9%; P = 0.03),
      a higher proportion of cytomegalovirus-positive (CMV+) donors/CMV- recipients
      (21% versus 7.5%; P = 0.05), and the PlA2 allele was more frequent (48.1% versus
      26.9%; P = 0.02) compared with patients free of acute rejection (n = 67). No
      other variable was associated with acute rejection in the univariate analysis.
      The impact of the three above-mentioned significant variables on acute rejection
      was analyzed by stepwise logistic regression. The presence of the PlA2 allele
      yielded an odds ratio of 2.75 (95% confidence interval, 1.01 to 7.93) and an HLA
      DR beta1 identity of 0.2 (95% confidence interval, 0.06 to 0.99) for suffering an
      acute rejection episode. In addition, the serum creatinine at discharge was
      higher in PlA2-positive versus PlA2-negative patients (2.2 +/- 1.6 versus 1.5 +/-
      0.6 mg/dl, respectively; P = 0.01), and the prevalence of proteinuria >1.5 g/d 1
      yr after transplantation was significantly higher among patients showing the PlA2
      allele (16% versus 3%; P = 0.02). Finally, in the entire cohort of patients, the
      2-yr graft survival was significantly lower in PlA2-positive (n = 43) compared
      with PlA2-negative (n = 76) patients (85.7% versus 97.2%; P = 0.015). No
      differences were found in patient survival (95.2% versus 98.7%, respectively).
      Proportional hazards regression analysis (Cox regression model) confirmed that
      serum creatinine level at discharge is the best predictor of allograft survival,
      followed by CMV status, delayed graft function, and the glycoprotein IIIa/IIb
      genotype. The PlA2 polymorphism is an independent risk factor for acute renal
      graft rejection, affecting short-term graft survival. Future studies aimed at
      preventing the hemostatic imbalance favoring platelet aggregation associated with
      this polymorphism may be important in preventing acute rejection and its impact
      on chronic rejection.

PMID- 10589701
TI  - Expression of megsin mRNA, a novel mesangium-predominant gene, in the renal
      tissues of various glomerular diseases.
AB  - Mesangial cells play an important role in maintaining a structure and function of
      the glomerulus and in the pathogenesis of glomerular diseases. Recently, we
      discovered a new mesangium-predominant gene termed "megsin." Megsin is a novel
      protein that belongs to the serine protease inhibitor (serpin) superfamily. To
      elucidate the pathophysiologic role of megsin in the kidney, the expression and
      localization of megsin mRNA in renal tissues of patients with IgA nephropathy
      (IgA-N), diabetic nephropathy (DN), minimal change nephrotic syndrome (MCNS),
      membranous nephropathy (MN), and normal human kidney (NHK) was evaluated by in
      situ hybridization using digoxigenin-labeled oligonucleotide. Individual cells
      positive for megsin mRNA were observed only in glomeruli in all renal tissues.
      Their localization coincided with those of mesangial cells. The percentage of
      positive cells for megsin mRNA in total glomerular cells was significantly
      greater in IgA-N than in MCNS, MN, and NHK. It was also significantly greater in
      DN than in MCNS and NHK. In IgA-N, the percentage of megsin mRNA-positive cells
      was greater in tissues from those with mesangial cell proliferation and slightly
      mesangial matrix expansion (periodic acid-Schiff-positive area in the total
      glomerulus area, <30%; cell number in mesangial matrix area, >30; assessed in
      cross-sections through their vascular poles) than in tissues from those with
      severe mesangial matrix expansion (periodic acid-Schiff-positive area in total
      glomerulus area, >30%; cell number in mesangial matrix area, <30). In conclusion,
      megsin mRNA was predominantly expressed in glomerular mesangial cells in all
      renal tissues. The expression of megsin mRNA was upregulated in IgA-N and DN,
      both of which are diseases accompanied with mesangial cell proliferation and/or
      mesangial matrix expansion. These data suggest a link of megsin expression to the
      pathogenesis of IgA-N and DN, two major causes of end-stage renal failure.

PMID- 10589702
TI  - Micropuncture analysis of tubuloglomerular feedback regulation in transgenic
      mice.
AB  - Micropuncture methods have been used widely as a means to define the function of
      single tubules and study the functional connection between tubules and afferent
      arterioles (so-called tubuloglomerular feedback [TGF]). Transgenic mouse strains
      have become a new research tool with the potential of shedding new light on the
      role of specific gene products in renal tubular and vascular function. The
      micropuncture approach has therefore been adapted to studies in the mouse kidney.
      Although the data presented here support the feasibility of using this technique
      in the mouse, technical improvements are desirable in the areas of anesthesia,
      ureteral urine collections, blood collections, volume replacement, and functional
      stability for extended time periods. During ketamine/inactin anesthesia, TGF
      responses could regularly be elicited in wild-type mice. In contrast, changes in
      loop flow did not alter stop-flow pressure in angiotensin II type 1A receptor and
      angiotensin-converting enzyme knockout mice. Infusion of angiotensin II in
      subpressor doses partially restored TGF responsiveness in angiotensin-converting
      enzyme knockout animals. Normal TGF responses compared to wild type were found in
      nitric oxide synthase I and thromboxane receptor knockout mice. Using free-flow
      micropuncture techniques, the proximal-distal single-nephron GFR difference was
      found to be augmented in aquaporin-1 and Na/H exchanger-3 knockout mice,
      suggesting TGF activation in these strains of mice. These results support an
      essential role of angiotensin II in TGF regulation mediated through the
      angiotensin II type 1A receptor. Chronic nitric oxide synthase I and thromboxane
      receptor deficiency did not change TGF responsiveness. Aquaporin-1 and Na/H
      exchanger-3 deficiency enhances TGF suppression of TGF probably by volume
      depletion-mediated TGF sensitization. The use of micropuncture methodology in
      transgenic mice combines old and new research tools in a way that promises to
      yield important new insights into single-nephron function in physiologic and
      pathophysiologic conditions.

PMID- 10589703
TI  - Renal vascular reactivity in mice: AngII-induced vasoconstriction in AT1A
      receptor null mice.
AB  - The present study describes methodology and its application to evaluate renal
      reactivity in acute studies on anesthetized mice. Renal blood flow (RBF) was
      measured using an ultrasonic transit-time flowmeter and a non-cannulating V
      shaped probe. An intrarenal artery injection technique established feasibility
      and reproducibility of studies of renal vascular reactivity to angiotensin II
      (AngII) in adult wild-type mice. The study also examined whether AngII would
      affect RBF in mice lacking AT1A receptors due to gene targeting. Mean arterial
      pressure averaged 83 and 62 mmHg, respectively, in mice with and without AT1A
      receptors. The RBF was similar in both groups, averaging 7 ml/min per g kidney
      wt. AngII injection (10-microl bolus) into the renal artery produced transient,
      dose-dependent, selective reductions in RBF in AT1A knockout mice as well as wild
      type mice. The response was considerably greater in mice with AT1A receptors: 10%
      for 0.1 ng, 30% for 1 ng, and 45% for 5 ng AngII in control animals versus
      respective decreases of 6, 15, and 17% in knockout mice. In other studies,
      angiotensin-converting enzyme (captopril) or renin (CP-71362-14) was inhibited.
      During inhibition of AngII formation, renal vascular reactivity to AngII
      increased twofold in both groups. Coadministration of the AT1 receptor antagonist
      losartan (1 to 1000 ng) elicited dose-dependent inhibition of AngII effects, with
      near maximum blockage of 80 to 90% in both groups of mice. The putative AT2
      receptor antagonist PD 123319 inhibited 30 to 40% of AngII-induced
      vasoconstriction, whereas CGP 42112 had no effect in either group. In conclusion,
      AngII can elicit renal vasoconstriction, albeit attenuated, in AT1A knockout
      mice. The weaker RBF effects are most likely due to the absence of the AT1A
      receptor. Inhibition of the response by AT1 receptor antagonist suggests
      mediation by the AT1B receptor in these animals. The residual constrictor effect
      observed during AT1 receptor blockade and sensitive to PD 123319 appears to be
      mediated by a non-AT1 receptor.

PMID- 10589704
TI  - Renal function in mice: effects of volume expansion and angiotensin II.
AB  - The present study was performed to validate a simple means for assessing renal
      function in anesthetized mice and to characterize the renal hemodynamic responses
      to acute volume expansion and how these responses are altered by concurrent
      angiotensin II (AngII) infusions. Inulin and para-aminohippurate clearances were
      used to assess GFR and renal plasma flow (RPF) in three groups of male C57Bl/6
      mice anesthetized with inactin (100 mg/kg, intraperitoneally) and ketamine (10
      mg/kg). To avoid the hypotension associated with repeated blood sampling, a
      single blood sample was taken after three timed urine collections. Renal function
      and mean arterial pressure (MAP) were measured under euvolemic conditions (2.5
      microl/min, intravenously, n = 7) during isotonic saline volume expansion (12.5
      microl/min, intravenously, n = 5) and during volume expansion with concurrent
      AngII infusion (5 ng/min x g, n = 5). MAP in the control group was 77 +/- 2 mmHg;
      volume expansion alone did not change MAP significantly (83 +/- 2 mmHg), but led
      to significantly greater values in both GFR and RPF (1.35 +/- 0.14 versus 1.01 +/
      0.1 ml/min x g and 11.26 +/- 1.39 versus 6.29 +/- 0.5 ml/min x g, respectively).
      Infusion of AngII during volume expansion led to significant elevations of MAP
      (100 +/- 3 mmHg, P < 0.05) and prevented the increases in GFR and RPF elicited by
      volume expansion (0.77 +/- 0.08 and 5.35 +/- 0.48 ml/min x g, respectively).
      Volume expansion also elicited marked increases in absolute and fractional sodium
      excretion (6.1 +/- 1.0 versus 0.62 +/- 0.2 microEq/min x g and 3.1 +/- 0.7 versus
      0.4 +/- 0.1%, respectively). AngII infusion attenuated the absolute and
      fractional sodium excretion responses to volume expansion (3.4 +/- 1.2
      microEq/min x g and 2.5 +/- 0.5%, respectively). The present findings demonstrate
      that anesthetized mice exhibit marked renal hemodynamic and excretory responses
      to isotonic saline volume expansion. Concomitant AngII infusion attenuates these
      responses in spite of greater increases in arterial pressure.

PMID- 10589705
TI  - Henoch-Schonlein purpura nephritis.

PMID- 10589706
TI  - Glomerular permeability I. Ferritin transfer across the normal glomerular
      capillary wall. 1961.

PMID- 10589707
TI  - A pair of PCR primers for Incp-9 plasmids.

PMID- 10589708
TI  - Phase variation of lic1A, lic2A and lic3A in colonization of the nasopharynx,
      bloodstream and cerebrospinal fluid by Haemophilus influenzae type b.
AB  - The role of phase variation of lic1A, lic2A and lic3A in the ability of
      Haemophilus influenzae type b to colonize the nasopharynx, bloodstream and
      cerebrospinal fluid (CSF) of infants was investigated. This was achieved by using
      PCR to determine the number of 5'-CAAT-3' repeats present in each gene, which is
      indicative of whether each ORF can be expressed. Multiple PCR products of
      different intensities were amplified from all three genes at each site sampled.
      This indicated that the nasopharynx, bloodstream and CSF were colonized by a
      heterogeneous population of organisms, expressing different combinations of lic
      genes. At each site however, a predominant PCR product was amplified from each
      gene, indicating that organisms with this genotype were the most abundant. The
      number of 5'-CAAT-3' repeats in this predominant product varied depending upon
      whether organisms were isolated from the nasopharynx, bloodstream or CSF. These
      observations suggest that the expression of different combinations of lic genes
      may influence the efficiency with which H. influenzae colonizes the nasopharynx,
      bloodstream and CSF of infant rats.

PMID- 10589709
TI  - The genetic basis of the phase variation repertoire of lipopolysaccharide
      immunotypes in Neisseria meningitidis.
AB  - Neisseria meningitidis strains express a diverse range of lipopolysaccharide
      (LPS) structures that have been classified into 12 immunotypes. A feature of
      meningococcal LPS is the reversible, high-frequency switching of expression
      (phase variation) of terminal LPS structures. A number of studies are strongly
      suggestive of a key role for these terminal structures, and their phase-variable
      expression, in pathogenesis. In a previous study, a locus of three LPS
      biosynthetic genes, IgtABE, involved in the biosynthesis of one of these terminal
      structures, lacto-N-neotetraose, was described. The molecular mechanism of phase
      variable expression of this structure is by high-frequency mutation in a
      homopolymeric tract of G residues in the IgtA gene. To investigate the genetic
      basis of the structural differences between the immunotypes, and the potential
      for strains to express alternative immunotypes, this locus was examined in all of
      the immunotype strains. Initially, the Igt locus of strain 126E, an L1 immunotype
      strain, was cloned and sequenced, revealing two active genes, IgtC and IgtE. The
      remnants of the IgtA and IgtB genes and an inactive IgtD gene were also present,
      indicating that the locus may have once contained five active genes, similar to a
      locus previously reported in Neisseria gonorrhoeae strain F62. Probes based on
      each of the Igt genes (ABCDE), and the recently reported IgtG gene, were used to
      determine the presence or absence of Igt genes within individual strains,
      allowing the prediction of the phase variation repertoire of these strains.
      Sequencing to determine the nature of homopolymeric tract regions within the Igt
      genes was carried out to establish the potential for LPS switching. In general,
      the set of strains examined could be sorted into two distinct groups: one group
      which phase-vary the alpha-chain extension via IgtA or IgtC but cannot make beta
      chain; the second group phase-vary the beta-chain extension via IgtG but do not
      vary alpha-chain (lacto-N-neotetraose).

PMID- 10589710
TI  - The Candida albicans gene for mRNA 5-cap methyltransferase: identification of
      additional residues essential for catalysis.
AB  - The 5'-cap structure of eukaryotic mRNA is methylated at the terminal guanosine
      by RNA (guanine-N7-)-methyltransferase (cap MTase). Saccharomyces cerevisiae ABD1
      (ScABD1) and human hMet (also called CMT1) genes are responsible for this enzyme.
      The ABD1 homologue was cloned from the pathogenic fungus Candida albicans and
      named C. albicans ABD1 (CaABD1). When expressed as a fusion with glutathione S
      transferase (GST), CaAbd1p displayed cap MTase activity in vitro and rescued S.
      cerevisiae abd1delta null mutants, indicating that CaABD1 specifies an active cap
      MTase. Although the human cap MTase binds to the human capping enzyme (Hce1p),
      which possesses both mRNA guanylyltransferase (mRNA GTase) and mRNA 5'
      triphosphatase (mRNA TPase) activities, yeast two-hybrid analysis demonstrated
      that in yeast neither mRNA GTase nor mRNA TPase physically interacted with the
      Abd1 protein. Comparison of the amino acid sequences of known and putative cap
      MTases revealed a highly conserved amino acid sequence motif, Phe/Val-Leu-Asp/Glu
      Leu/Met-Xaa-Cys-Gly-Lys-Gly-Gly-Asp-Leu-Xaa-Lys, which encompasses the sequence
      motif characteristic of divergent methyltransferases. Mutations in CaAbd1p of
      leucine at the second and the twelfth positions (so far uncharacterized) to
      alanine severely diminished the enzyme activity and the functionality in vivo,
      whereas those of leucine at the fourth, cysteine at the sixth, lysine at the
      eighth, and glycine at the tenth positions did not. Furthermore, valine
      substitution for the twelfth, but not for the second, leucine in that motif
      abolished the activity and functionality of CaAbd1p. Thus, it appears that
      leucine at the second and the twelfth positions in the motif, together with a
      previously identified acidic residue in the third, glycine at the sixth and
      glutamic acid at the eleventh positions, play important roles in the catalysis,
      and that side chain length is crucial for the activity at the twelfth position in
      the motif.

PMID- 10589711
TI  - The rpoS-dependent starvation-stress response locus stiA encodes a nitrate
      reductase (narZYWV) required for carbon-starvation-inducible thermotolerance and
      acid tolerance in Salmonella typhimurium.
AB  - The starvation-stress response (SSR) of Salmonella typhimurium includes gene
      products necessary for starvation avoidance, starvation survival and virulence
      for this bacterium. Numerous genetic loci induced during carbon-source starvation
      and required for the long-term-starvation survival of this bacterium have been
      identified. The SSR not only protects the cell against the adverse effects of
      long-term starvation but also provides cross-resistance to other environmental
      stresses, e.g. thermal challenge (55 degrees C) or acid-pH challenge (pH 2.8).
      One carbon-starvation-inducible lac fusion, designated stiA was previously
      reported to be a sigma(S)-dependent SSR locus that is phosphate-starvation,
      nitrogen-starvation and H2O2 inducible, positively regulated by (p)ppGpp in a
      relA-dependent manner, and negatively regulated by cAMP:cAMP receptor protein
      complex and OxyR. We have discovered through sequence analysis and subsequent
      biochemical analysis that the stiA::lac fusion, and a similarly regulated lac
      fusion designated sti-99, lie at separate sites within the first gene (narZ) of
      an operon encoding a cryptic nitrate reductase (narZYWV) of unknown physiological
      function. In this study, it was demonstrated that narZ was negatively regulated
      by the global regulator Fnr during anaerobiosis. Interestingly, narZ(YWV) was
      required for carbon-starvation-inducible thermotolerance and acid tolerance. In
      addition, narZ expression was induced approximately 20-fold intracellularly in
      Madin-Darby canine kidney epithelial cells and 16-fold in intracellular salts
      medium, which is believed to mimic the intracellular milieu. Also, a narZ1 knock
      out mutation increased the LD50 approximately 10-fold for S. typhimurium SL1344
      delivered orally in the mouse virulence model. Thus, the previously believed
      cryptic and constitutive narZYWV operon is in fact highly regulated by a complex
      network of environmental-stress signals and global regulatory functions,
      indicating a central role in the physiology of starved and stressed cells.

PMID- 10589712
TI  - Mutational analysis of the Paracoccus denitrificans c-type cytochrome
      biosynthetic genes ccmABCDG: disruption of ccmC has distinct effects suggesting a
      role for CcmC independent of CcmAB.
AB  - Each of the Paracoccus denitrificans genes in the c-type cytochrome biogenesis
      gene cluster ccmABCDG, plus the two flanking genes ORF117 and hisH, were
      individually disrupted by omega insertion. Resultant phenotypes were restored to
      the wild-type by complementation from a set of plasmids. All of the ccm genes,
      but neither ORF117 nor hisH, were required for c-type cytochrome biogenesis; only
      ccmG was also implicated in the biosynthesis of cytochrome aa3. Disruption of
      ccmC or ccmG resulted in failure to grow on rich media, but disruption of ccmA,
      ccmB or ccmD did not. The ccmC mutant, but not the ccmA, ccmB or ccmD mutants,
      also exhibited the increased sensitivity to growth inhibition by oxidized thiol
      compounds previously observed for the ccmG mutant. In contrast to the ccmG
      mutant, however, growth of the ccmC mutant on rich media could not be restored by
      DTT. Siderophore biosynthesis and/or secretion by P. denitrificans was also
      attenuated by disruption of ccmC and ccmG but not of ccmA, ccmB or ccmD. These
      results indicate that CcmC can function independently of CcmA, CcmB and CcmD
      despite other evidence that these gene products form an ATP-binding cassette
      (ABC)-type-transporter with the subunit composition (CcmA)2-CcmB-CcmC or (CcmA)2
      CcmB-CcmC-CcmD, and also suggest a possible link between the functions of CcmC
      and CcmG.

PMID- 10589713
TI  - Genetic and functional analysis of genes required for the post-modification of
      the polyketide antibiotic TA of Myxococcus xanthus.
AB  - The antibiotic TA of Myxococcus xanthus is a complex macrocyclic polyketide,
      produced through successive condensations of acetate by a type I PKS (polyketide
      synthase) mechanism. The genes encoding TA biosynthesis are clustered on a 36 kb
      DNA fragment, which has been cloned and analysed. The chemical structure of TA
      and the mechanism by which it is synthesized indicate the need for several post
      modification steps, which are introduced into the carbon chain of the polyketide
      to form the final bioactive molecule. These include the addition of several
      carbon atoms originating from acetate carbonyl, three C-methylations, O
      methylation and a specific hydroxylation. This paper reports the analysis of five
      genes which are involved in the post-modification of TA. Their functional
      analysis, by specific gene disruption, suggests that they may be essential for
      the production of the active antibiotic. The characteristics and organization of
      the genes suggest that they may be involved in the addition of the carbon atoms
      which arise from acetate.

PMID- 10589714
TI  - Direct evidence for mRNA binding and post-transcriptional regulation by
      Escherichia coli aconitases.
AB  - Escherichia coli contains a stationary-phase aconitase (AcnA) that is induced by
      iron and oxidative stress, and a major but less stable aconitase (AcnB)
      synthesized during exponential growth. These enzymes were shown to resemble the
      bifunctional iron-regulatory proteins (IRP1)/cytoplasmic aconitases of
      vertebrates in having alternative mRNA-binding and catalytic activities. Affinity
      chromatography and gel retardation analysis showed that the AcnA and AcnB apo
      proteins each interact with the 3' untranslated regions (3'UTRs) of acnA and acnB
      mRNA at physiologically significant protein concentrations. AcnA and AcnB
      synthesis was enhanced in vitro by the apoaconitases and this enhancement was
      abolished by 3'UTR deletion from the DNA templates, presumably by loss of acn
      mRNA stabilization by bound apoaconitase. In vivo studies showed that although
      total aconitase activity is lowered during oxidative stress, synthesis of the
      AcnA and AcnB proteins and the stabilities of acnA and acnB mRNAs both increase,
      suggesting that inactive aconitase mediates a post-transcriptional positive
      autoregulatory switch. Evidence for an iron-sulphur-cluster-dependent switch was
      inferred from the more than threefold higher mRNA-binding affinities of the apo
      aconitases relative to the holo-enzymes. Thus by modulating translation via site
      specific interactions between apo-enzyme and relevant transcripts, the aconitases
      provide a new and rapidly reacting component of the bacterial oxidative stress
      response.

PMID- 10589715
TI  - The hydrophobic heptad repeat in Region III of Escherichia coli transcription
      factor sigma 54 is essential for core RNA polymerase binding.
AB  - Escherichia coli transcription factor sigma 54 contains motifs that resemble
      closely those used for RNA polymerase II in mammalian cells, including two
      hydrophobic heptad repeats, a very acidic region and a glutamine-rich region.
      Triple changes in hydrophobic or multiple changes in acidic residues in Region
      III are known to severely impair core-binding ability. To investigate whether all
      the changes in triple mutants are necessary for core binding, site-directed
      mutagenesis was performed to create single and double mutants in the leucine or
      isoleucine residues in the heptad repeat in Region III. Single mutants showed no
      discernible loss of function. Double mutants showed partial protection of the -12
      promoter element of the glnAp2 promoter due to the partial loss of their ability
      to bind core RNA polymerase. These mutations were deleterious to the function of
      sigma 54, which retained only 30-40% of wild-type mRNA levels. However, double
      mutants retained nearly normal ability to form open complexes. Two triple mutants
      created during previous work lost most, if not all, of their ability to bind core
      RNA polymerase, to protect the -12 promoter element of the glnAp2 promoter and to
      open the transcription start site. The two triple mutants produced about 20% or
      less than 10% of the wild-type transcripts from the glnAp2 promoter. These
      results demonstrate that the hydrophobic heptad repeat in Region III is essential
      for core RNA polymerase binding. Progressive loss of hydrophobicity of the
      hydrophobic heptad repeat in Region III of sigma 54 resulted in a progressive
      loss of core-binding ability, leading to the loss of -12 promoter element
      recognition and mRNA production.

PMID- 10589716
TI  - Absence of RNASE III alters the pathway by which RNAI, the antisense inhibitor of
      ColE1 replication, decays.
AB  - RNAI is a short RNA, 108 nt in length, which regulates the replication of the
      plasmid ColE1. RNAI turns over rapidly, enabling plasmid replication rate to
      respond quickly to changes in plasmid copy number. Because RNAI is produced in
      abundance, is easily extracted and turns over quickly, it has been used as a
      model for mRNA in studying RNA decay pathways. The enzymes polynucleotide
      phosphorylase, poly(A) polymerase and RNase E have been demonstrated to have
      roles in both messenger and RNAI decay; it is reported here that these enzymes
      can work independently of one another to facilitate RNAI decay. The roles in RNAI
      decay of two further enzymes which facilitate mRNA decay, the exonuclease RNase
      II and the endonuclease RNase III, are also examined. RNase II does not appear to
      accelerate RNAI decay but it is found that, in the absence of RNase III,
      polyadenylated RNAI, unprocessed by RNase E, accumulates. It is also shown that
      RNase III can cut RNAI near nt 82 or 98 in vitro. An RNAI fragment corresponding
      to the longer of these can be found in extracts of an mc+ pcnB strain (which
      produces RNase III) but not of an rnc pcnB strain, suggesting that RNAI may be a
      substrate for RNase III in vivo. A possible pathway for the early steps in RNAI
      decay which incorporates this information is suggested.

PMID- 10589717
TI  - A family 26 mannanase produced by Clostridium thermocellum as a component of the
      cellulosome contains a domain which is conserved in mannanases from anaerobic
      fungi.
AB  - Cellulosomes prepared by the cellulose affinity digestion method from Clostridium
      thermocellum culture supernatant hydrolysed carob galactomannan during incubation
      at 60 degrees C and pH 6.5. A recombinant phage expressing mannanase activity was
      isolated from a library of C. thermocellum genomic DNA constructed in
      lambdaZAPII. The cloned fragment of DNA containing a putative mannanase gene
      (manA) was sequenced, revealing an ORF of 1767 nt, encoding a protein (mannanase
      A; Man26A) of 589 aa with a molecular mass of 66816 Da. The putative catalytic
      domain (CD) of Man26A, identified by gene sectioning and sequence comparisons,
      displayed up to 32% identity with other mannanases belonging to family 26.
      Immediately downstream of the CD and separated from it by a short
      proline/threonine linker was a duplicated 24-residue dockerin motif, which is
      conserved in all C. thermocellum cellulosomal enzymes described thus far and
      mediates their attachment to the cellulosome-integrating protein (CipA). Man26A
      consisting of the CD alone (Man26A") was hyperexpressed in Escherichia coli
      BL21(DE3) and purified. The truncated enzyme hydrolysed soluble and insoluble
      mannan, displaying a temperature optimum of 65 degrees C and a pH optimum of 6.5,
      but exhibited no activity against other plant cell wall polysaccharides.
      Antiserum raised against Man26A" cross-reacted with a polypeptide with a
      molecular mass of 70000 Da that is part of the C. thermocellum cellulosome. A
      second variant of Man26A containing the N-terminal segment of 130 residues and
      the CD (Man26A") bound to ivory-nut mannan and weakly to soluble Carob
      galactomannan and insoluble cellulose. Man26A" consisting of the CD alone did not
      bind to these polysaccharides. These results indicate that the N-terminal 130
      residues of mature Man26A may constitute a weak mannan-binding domain. Sequence
      comparisons revealed a lack of identity between this region of Man26A and other
      polysaccharide-binding domains, but significant identity with a region conserved
      in the three family 26 mannanases from the anaerobic fungus Piromyces equi.

PMID- 10589718
TI  - Genetic and biochemical characterization of the alpha and beta components of a
      propionyl-CoA carboxylase complex of Streptomyces coelicolor A3(2).
AB  - Two genes, accA1 and accA2, with nearly identical nucleotide sequences were
      cloned from Streptomyces coelicolor A3(2). The deduced amino acid sequences of
      the product of these two genes showed high similarity to BcpA2 of
      Saccharopolyspora erythraea and other biotin-containing proteins from different
      organisms assumed to be the alpha subunit of a propionyl-CoA carboxylase. A gene,
      pccB, encoding the carboxyl transferase subunit of this enzyme complex was also
      characterized. Strains disrupted in accA1 did not show any change in acetyl- or
      propionyl-CoA carboxylase activity, whilst cell-free extracts of a pccB mutant
      strain contained a reduced level of propionyl-CoA carboxylase. No mutants in
      accA2 could be isolated, suggesting that the gene may be essential. Heterologous
      expression of accA1, accA2 and pccB in Escherichia col and in vitro
      reconstitution of enzyme activity confirmed that PccB is the beta subunit of a
      propionyl-CoA carboxylase and that either AccA1 or AccA2 could act as the alpha
      component of this enzyme complex. The fact that accA2 mutants appear to be
      inviable suggests that this gene encodes a biotinylated protein that might be
      shared with other carboxyl transferases essential for the growth of S.
      coelicolor.

PMID- 10589719
TI  - A novel member of the subtilisin-like protease family from Bacillus subtilis.
AB  - aprX is a 1326 bp gene of Bacillus subtilis strain 168 that encodes a serine
      protease, probably intracellular, characterized by significant similarity with
      subtilisins, thermitases and pyrolysins. Transcription analysis, performed by RT
      PCR and primer extension, allowed the localization of the active promoter and
      showed that aprX is expressed in stationary phase. The pattern of expression of
      aprX and its dependence on various transition state regulatory genes (degU, degQ,
      hpr, abrB, sinR), monitored by lacZ transcriptional fusions, are distinctive from
      those of subtilisin and other degradative enzymes. aprX is not essential for
      either growth or sporulation.

PMID- 10589720
TI  - Sequence analysis of three Bacillus cereus loci carrying PIcR-regulated genes
      encoding degradative enzymes and enterotoxin.
AB  - PIcR is a pleiotropic regulator of extracellular virulence factors in the
      opportunistic human pathogen Bacillus cereus and the entomopathogenic Bacillus
      thuringiensis, and is induced in cells entering stationary phase. Among the genes
      regulated by PIcR are: pIcA, encoding phosphatidylinositol-specific phospholipase
      C (PI-PLC); plc, encoding phosphatidylcholine-preferring phospholipase C (PC
      PLC); nhe, encoding the non-haemolytic enterotoxin; hbl, encoding haemolytic
      enterotoxin BL (HBL); and genes specifying a putative S-layer like surface
      protein and a putative extracellular RNase. By analysing 37.1 kb of DNA sequence
      surrounding hbl, plcA and plcR, 28 ORFs were predicted. Three novel genes
      putatively regulated by PlcR and encoding a neutral protease (NprB), a subtilase
      family serine protease (Sfp) and a putative cell-wall hydrolase (Cwh) were
      identified. The corresponding sfp and cwh genes were located in the immediate
      upstream region of plcA and could both be regulated by a putative PlcR-binding
      site positioned between the inversely transcribed genes. Similarly, nprB was
      positioned directly upstream and transcribed in the opposite orientation to plcR.
      Genes surrounding plcA, plcR and hblCDAB that were lacking an upstream PlcR
      regulatory sequence did not appear to serve functions apparently related to PlcR
      and did not exhibit a conserved organization in Bacillus subtilis.

PMID- 10589721
TI  - Insertional inactivation of hblC encoding the L2 component of Bacillus cereus
      ATCC 14579 haemolysin BL strongly reduces enterotoxigenic activity, but not the
      haemolytic activity against human erythrocytes.
AB  - Haemolysin BL (HBL) is a Bacillus cereus toxin composed of a binding component,
      B, and two lytic components, L1 and L2. HBL is also the enterotoxin responsible
      for the diarrhoeal food poisoning syndrome caused by several strains of B.
      cereus. The three genes encoding the HBL components constitute an operon and are
      transcribed from a promoter 608 bp upstream of the hblC translational start site.
      The first gene of the hbl operon, hblC, in the B. cereus type strain, ATCC 14579,
      was inactivated in this study. Inactivation of hblC strongly reduced both the
      enterotoxigenic activity of B. cereus ATCC 14579 and the haemolytic activity
      against sheep erythrocytes, while maintaining full haemolytic activity against
      human erythrocytes.

PMID- 10589722
TI  - PepR1, a CcpA-like transcription regulator of Lactobacillus delbrueckii subsp.
      lactis.
AB  - The PepR1 protein from Lactobacillus delbrueckii subsp. lactis DSM 7290 shares
      extensive homology with catabolite-control proteins from various Gram-positive
      bacteria. Expression of the subcloned pepR1 gene allowed for partial
      complementation of a ccpA defect in Staphylococcus xylosus. The influence of
      PepR1 on transcription of the prolidase gene pepQ, which is located adjacent to
      pepR1, was examined by use of lacZ reporter gene fusions in Escherichia coli.
      PepR1 stimulated transcription initiation at the pepQ promoter about twofold, and
      this effect required the integrity of a 14 bp palindromic cre-like sequence
      located 74 nt upstream of pepQ. In gel-mobility-shift assays, PepR1 specifically
      interacted with the pepQ promoter region and also with DNA fragments covering the
      promoters of the pepX, pepl and brnQ genes of Lb. delbrueckii subsp. lactis,
      which encode two additional peptidases and a branched-chain amino acid
      transporter, respectively. cre-like elements were identified in each of these DNA
      fragments. Catabolite control of PepQ was demonstrated in Lb. delbrueckii subsp.
      lactis. During growth with lactose the enzyme activity was twofold higher than in
      the presence of glucose, and corresponding differences were also detected in the
      level of pepQ transcription.

PMID- 10589723
TI  - Synthesis of lactococcin 972, a bacteriocin produced by Lactococcus lactis IPLA
      972, depends on the expression of a plasmid-encoded bicistronic operon.
AB  - Synthesis of lactococcin 972 is plasmid-encoded. An operon composed of two genes
      that encode pre-bacteriocin and a putative immunity protein has been identified.
      The first gene encodes a 91-residue polypeptide that is exported via a sec
      dependent system to give the mature 66-aa bacteriocin. The immunity protein is a
      563-residue polypeptide with seven potential transmembrane domains. Two
      transcripts were observed from this region: one comprises the whole operon and is
      synthesized during the exponential phase of growth while the other, which
      corresponds just to the bacteriocin structural gene, presents a maximum in
      exponential cultures but is still present in late-stationary-phase cells.

PMID- 10589724
TI  - IS1626, a new IS900-related Mycobacterium avium insertion sequence.
AB  - An insertion sequence designated IS1626 was isolated and characterized from a
      Mycobacterium avium clinical strain. IS1626 was detected by high-stringency
      hybridization with the pMB22/S12 probe from IS900 of Mycobacterium
      paratuberculosis. IS1626 is 1418 bp in size and has a G+C content of 65 mol%. It
      has neither terminal inverted repeats nor flanking direct repeats. Analysis of
      three IS1626 insertion sites in the M. avium strain and the corresponding
      potential insertion sites in two IS1626-free M. avium strains indicated a
      consensus sequence of CATGCN(4-5)TCCTN(2)G for IS1626 insertion. In the three
      clones examined, IS1626 has the same orientation with respect to this target
      site. IS1626 has two major ORFs. ORF1179 encodes a predicted protein of 393 amino
      acids. ORF930, on the complementary strand of ORF1179, encodes a protein of 310
      amino acids. The Shine-Dalgarno sequence for ORF930 is partially located in the
      flanking region, similar to other IS900-related elements. Analysis of the
      comparable features of insertion sequences and their variable occurrence in
      related organisms is useful for studying the evolution of these elements and
      their hosts.

PMID- 10589725
TI  - Context-sensitive transposition of IS6110 in mycobacteria.
AB  - The rational use of IS6110 fingerprinting for studies of the molecular
      epidemiology and evolution of Mycobacterium tuberculosis requires understanding
      of the dynamics of transposition. In laboratory model systems, it has been shown
      that transposition is context-sensitive, i.e. it is influenced by the nature of
      the site in which the insertion sequence is presented. Stimulation of
      transposition by activation of an adjacent promoter supports the hypothesis that
      transposition occurs more readily from transcriptionally active locations. In
      addition, it has been shown that transposition can be enhanced by the expression
      of the transposase in trans. These findings imply that the frequency of
      transposition will vary substantially between different strains of M.
      tuberculosis, and furthermore that a hitherto stable strain may develop more
      rapid variation due to transposition into an active site. The use of IS6110
      fingerprinting for the analysis of longer-range relationships between M.
      tuberculosis isolates therefore needs to be interpreted with care.

PMID- 10589726
TI  - Alteration of a single amino acid residue reverses fosfomycin resistance of
      recombinant MurA from Mycobacterium tuberculosis.
AB  - Mycobacterium tuberculosis has innate resistance to a range of broad-spectrum
      antimicrobial agents. This may in part reflect the relative impermeability of the
      mycobacterial cell wall, but additional specific mechanisms may also be
      important. In the case of fosfomycin, it has been suggested that a key difference
      in the active site of the M. tuberculosis MurA enzyme might confer resistance. In
      Escherichia coli, fosfomycin covalently binds to a cysteine normally involved in
      the enzymic activity, while protein alignments predict an aspartate at this
      position in the M. tuberculosis MurA. In the present study, it is demonstrated
      that the wild-type M. tuberculosis MurA is indeed resistant to fosfomycin, and
      that it becomes sensitive following replacement of the aspartate residue in
      position 117 by a cysteine. In addition, the study illustrates the use of an
      inducible expression system in mycobacteria to allow functional characterization
      of an M. tuberculosis enzyme that is unstable during constitutive expression.

PMID- 10589727
TI  - Analysis of the role of 7 kDa cold-shock proteins of Lactococcus lactis MG1363 in
      cryoprotection.
AB  - Low-temperature adaptation and cryoprotection were studied in the lactic acid
      bacterium Lactococcus lactis MG1363. An approximately 100-fold increased survival
      after freezing was observed when cells were shocked to 10 degrees C for 4 h
      compared to mid-exponential-phase cells grown at 30 degrees C, indicating an
      active protection against freezing. Using two-dimensional gel electrophoresis a
      group of 7 kDa cold-induced proteins (CSPs) was identified that corresponds to a
      previously described family of csp genes of L. lactis MG1363 (Wouters et al.,
      1998, Microbiology 144, 2885-2893). The 7 kDa CSPs appeared to be the most
      strongly induced proteins upon cold shock to 10 degrees C. Northern blotting and
      two-dimensional gel electrophoresis showed that the csp genes were maximally
      expressed at 10 degrees C, while induction was lower at 20 and 4 degrees C.
      However, pre-incubation at 20 and 4 degrees C, as well as stationary-phase
      conditions, also induced cryoprotection (approx. 30-, 130- and 20-fold,
      respectively, compared to 30 degrees C mid-exponential phase). For all treatments
      leading to an increased freeze survival (exposure to 4, 10 and 20 degrees C and
      stationary-phase conditions), increased levels of three proteins (26, 43 and 45
      kDa) were observed for which a role in cryoprotection might be suggested.
      Increased freeze survival coincides with increased CSP expression, except for
      stationary-phase conditions. However, the level of observed freeze protection
      does not directly correlate with the csp gene expression levels. In addition, for
      the first time specific overproduction of a CSP in relation to freeze survival
      was studied. This revealed that L. lactis cells overproducing CspD at 30 degrees
      C show a 2-10-fold increased survival after freezing compared to control cells.
      This indicates that the 7 kDa cold-shock protein CspD may enhance the survival
      capacity after freezing but that other factors supply additional cryoprotection.

PMID- 10589728
TI  - The Q15H mutation enables Crh, a Bacillus subtilis HPr-like protein, to carry out
      some regulatory HPr functions, but does not make it an effective phosphocarrier
      for sugar transport.
AB  - Crh of Bacillus subtilis exhibits 45% sequence identity when compared to
      histidine-containing protein (HPr), a phosphocarrier protein of the
      phosphoenolpyruvate (PEP):sugar phosphotransferase system (PTS). Crh can be
      phosphorylated by ATP at the regulatory Ser-46 and similar to P-Ser-HPr, P-Ser
      Crh plays a role in carbon-catabolite repression. The sequence around the
      phosphorylatable Ser-46 in Crh exhibits strong similarity to the corresponding
      sequence of HPr of Gram-positive and a few Gram-negative bacteria. In contrast,
      the catalytic His-15, the site of PEP-dependent phosphorylation in HPr, is
      replaced with a glutamine in Crh. When Gln-15 was exchanged for a histidyl
      residue, in vitro PEP-dependent enzyme I-catalysed phosphorylation of the mutant
      Crh was observed. However, expression of the crhQ15H mutant allele did not
      restore growth of a ptsH deletion strain on the PTS sugars glucose, fructose or
      mannitol or on the non-PTS sugar glycerol. In contrast, Q15H mutant Crh could
      phosphorylate the transcriptional activator LevR as well as LevD, the enzyme IIA
      of the fructose-specific lev-PTS, which together with enzyme I, HPr and LevE
      forms the phosphorylation cascade regulating induction of the lev operon via
      LevR. As a consequence, the constitutive expression from the lev promoter
      observed in a (delta)ptsH strain became inducible with fructose when the crhQ15H
      allele was expressed in this strain.

PMID- 10589729
TI  - Glycerol transport and phosphoenolpyruvate-dependent enzyme I- and HPr-catalysed
      phosphorylation of glycerol kinase in Thermus flavus.
AB  - The genes glpK and glpF, encoding glycerol kinase and the glycerol facilitator of
      Thermus flavus, a member of the Thermus/Deinococcus group, have recently been
      identified. The protein encoded by glpK exhibited an unusually high degree of
      sequence identity (80-6%) when compared to the sequence of glycerol kinase from
      Bacillus subtilis and a similar high degree of sequence identity (64.8%) was
      observed when the sequences of the glycerol facilitators of the two organisms
      were compared. The work presented in this paper demonstrates that T. flavus is
      capable of taking up glycerol, that glpF and glpK are expressed constitutively
      and that glucose exerts a repressive effect on the expression of these genes. T.
      flavus was found to possess the general components of the phosphoenolpyruvate
      (PEP): sugar phosphotransferase system (PTS) enzyme I and histidine-containing
      protein (HPr). These proteins catalyse the phosphorylation of T. flavus glycerol
      kinase, which contains a histidyl residue equivalent to His-232, the site of PEP
      dependent, PTS-catalysed phosphorylation in glycerol kinase of Enterococcus
      casseliflavus. Purified glycerol kinase from T. flavus could also be
      phosphorylated with enzyme I and HPr from B. subtilis. Similar to enterococcal
      glycerol kinases, phosphorylated T. flavus glycerol kinase exhibited an
      electrophoretic mobility on denaturing and non-denaturing polyacrylamide gels
      that is different from the electrophoretic mobility of non-phosphorylated
      glycerol kinase. However, in contrast to PEP-dependent phosphorylation of
      enterococcal glycerol kinases, which stimulated glycerol kinase activity about 10
      fold, phosphorylation of T. flavus glycerol kinase caused only a slight increase
      in enzyme activity.

PMID- 10589730
TI  - Impairment of sterol biosynthesis leads to phosphorus and calcium accumulation in
      Leishmania acidocalcisomes.
AB  - The induction of the formation of inclusion vesicles in Leishmania amazonensis by
      the sterol biosynthesis inhibitors (SBI) ketoconazole and terbinafine has been
      reported previously. These compartments were recently identified as
      acidocalcisomes. By the use of electron spectroscopic imaging and energy loss
      spectroscopy, the presence of calcium, phosphorus and oxygen in the electron
      dense inclusions located within the acidocalcisomes has been demonstrated.
      Endoplasmic reticulum cisternae formed membrane whorls which enclosed large
      portions of the cytoplasm and sometimes circumscribed acidocalcisomes. In
      addition, acid phosphatase activity, as well as the endocytic tracers horseradish
      peroxidase and gold-labelled transferrin and cystatin C were detected within
      these organelles in both SBI-treated and untreated parasites. These data suggest
      that impairment of sterol biosynthesis induces the biogenesis of acidocalcisomes
      and triggers an autophagic process that leads to intersection of the
      endosomal/lysosomal system with the acidocalcisomes.

PMID- 10589731
TI  - The yeast endosomal Na+/H+ exchanger, Nhx1, confers osmotolerance following acute
      hypertonic shock.
AB  - Osmotolerance in yeast is regulated by at least two distinct mechanisms. The
      acquired response occurs following long-term exposure to hypertonic medium and
      requires the induction of the HOG-MAP (high-osmolarity glycerol mitogen-activated
      protein) kinase cascade to increase levels of the osmolyte glycerol. The acute
      response occurs following sudden exposure to high osmotica and appears to be
      dependent on normal vacuole function. In this study it is reported that the yeast
      endosomal/prevacuolar Na+/H+ exchanger Nhx1 contributes to osmotolerance
      following sudden exposure to hyperosmotic media. Vacuolar shrinkage and recovery
      in response to osmotic shock was altered in the (delta)nhx1 null mutant. Our
      results also show that the osmotolerance conferred by Nhx1 contributes to the
      postdiauxic/stationary-phase resistance to osmotic stress and allows for the
      continued growth of cells until the acquired osmotolerance response can occur.

PMID- 10589732
TI  - Catalase activity is necessary for heat-shock recovery in Aspergillus nidulans
      germlings.
AB  - To understand the molecular mechanisms induced by stress that contribute to the
      development of tolerance in eukaryotic cells, the filamentous fungus Aspergillus
      nidulans has been chosen as a model system. Here, the response of A. nidulans
      germlings to heat shock is reported. The heat treatment dramatically increased
      the concentration of trehalose and induced the accumulation of mannitol and mRNA
      from the catalase gene catA. Both mannitol and catalase function to protect cells
      from different reactive oxygen species. Treatment with hydrogen peroxide
      increased A. nidulans germling viability after heat shock whilst mutants
      deficient in catalase were more sensitive to a 50 degrees C heat exposure. It is
      concluded that the defence against the lethal effects of heat exposure can be
      correlated with the activity of the defence system against oxidative stress.

PMID- 10589733
TI  - Actin-related proteins in Actinobacillus pleuropneumoniae and their interactions
      with actin-binding proteins.
AB  - A group of prokaryotic actin-related proteins (PARP) with an Mr of 43000 was
      detected in Actinobacillus pleuropneumoniae. These proteins were enriched by a
      depolymerization/polymerization cycle, under similar conditions to those used to
      polymerize muscle actin, and purified by affinity chromatography on a DNase I
      Sepharose column. Three isoforms of A. pleuropneumoniae PARP (Ap-PARP) with pI
      values of 5.8, 6.15 and 6.2 were detected. Ap-PARP were recognized by four
      different anti-actin antibodies (one anti-muscle and three anti-cytoplasmic
      isoforms). Ap-PARP were also recognized by antibodies against Anabaena variabilis
      PARP (Av-PARP) and against actin-binding proteins such as alpha-actinin and
      spectrin, and also by a monoclonal antibody against heat-shock cognate protein 70
      (Hsc70). Specific binding of phalloidin to Ap-PARP was detected both in
      permeabilized cells and in vitro. Purified Ap-PARP can polymerize under similar
      conditions to those required for skeletal muscle actin polymerization and the
      filaments formed appear to be decorated with myosin subfragment-1(S1) as observed
      by transmission electron microscopy. The amino acid composition of Ap-PARP
      revealed more similarities to muscle gamma-actin and the cytoplasmic beta-actin
      isoform than to eukaryotic actin-related proteins.

PMID- 10589734
TI  - Novel Helicobacter pylori alpha1,2-fucosyltransferase, a key enzyme in the
      synthesis of Lewis antigens.
AB  - Helicobacter pylori lipopolysaccharides (LPS) contain complex carbohydrates known
      as Lewis antigens which may contribute to the pathogenesis and adaptation of the
      bacterium. Involved in the biosynthesis of Lewis antigens is an alpha1,2
      fucosyltransferase (FucT) that adds fucose to the terminal betaGal unit of the O
      chain of LPS. Recently, the H. pylori (Hp) alpha1,2-FucT-encoding gene (fucT2)
      was cloned and analysed in detail. However, due to the low level of expression
      and instability of the protein, its enzymic activity was not demonstrated. In
      this study, the Hp fucT2 gene was successfully overexpressed in Escherichia coli.
      Sufficient amounts of the protein were obtained which revealed alpha1,2
      fucosyltransferase activity to be associated with the protein. A series of
      substrates were chosen to examine the acceptor specificity of Hp alpha1,2-FucT,
      and the enzyme reaction products were identified by capillary electrophoresis. In
      contrast to the normal mammalian alpha,2-FucT (H or Se enzyme), Hp alpha1,2-FucT
      prefers to use Lewis X [betaGal1-4(alphaFuc1-3)betaGlcNAc] rather than LacNAc
      [betaGal1-4betaGIcNAc] as a substrate, suggesting that H. pylori uses a novel
      pathway (via Lewis X) to synthesize Lewis Y. Hp alpha1,2-FucT also acts on type 1
      acceptor [betaGal1-3betaGlcNAc] and Lewis a [betaGal1-3(alphaFuc1-4)betaGIcNAc],
      which provides H. pylori with the potential to synthesize H type 1 and Lewis b
      epitopes. The ability to transfer fucose to a monofucosylated substrate (Lewis X
      or Lewis a) makes Hp alpha1,2-FucT distinct from normal mammalian alpha1,2-FucT.

PMID- 10589735
TI  - The oxygenase component of the 2-aminobenzenesulfonate dioxygenase system from
      Alcaligenes sp. strain O-1.
AB  - Growth of Alcaligenes sp. strain O-1 with 2-aminobenzenesulfonate (ABS;
      orthanilate) as sole source of carbon and energy requires expression of the
      soluble, multicomponent 2-aminobenzenesulfonate 2,3-dioxygenase system
      (deaminating) (ABSDOS) which is plasmid-encoded. ABSDOS was separated by anion
      exchange chromatography to yield a flavin-dependent reductase component and an
      iron-dependent oxygenase component. The oxygenase component was purified to about
      98% homogeneity and an alpha2beta2 subunit structure was deduced from the
      molecular masses of 134,45 and 16 kDa for the native complex, and the alpha and
      beta subunits, respectively. Analysis of the amount of acid labile sulfur and
      total iron, and the UV spectrum of the purified oxygenase component indicated one
      [2Fe-2S] Rieske centre per alpha subunit. The inhibition of activity by the iron
      specific chelator o-phenanthroline indicated the presence of an additional iron
      binding site. Recovery of active protein required strictly anoxic conditions
      during all purification steps. The FAD-containing reductase could not be
      purified. ABSDOS oxygenated nine sulfonated compounds; no oxygen uptake was
      detected with carboxylated aromatic compounds or with aliphatic sulfonated
      compounds. Km values of 29, 18 and 108 microM and Vmax values of 140, 110 and 72
      pkat for ABS, benzenesulfonate and 4-toluenesulfonate, respectively, were
      observed. The N-terminal amino acid sequences of the alpha- and beta-subunits of
      the oxygenase component allowed PCR primers to be deduced and the DNA sequence of
      the alpha-subunit was thereafter determined. Both redox centres were detected in
      the deduced amino acid sequence. Sequence data and biochemical properties of the
      enzyme system indicate a novel member of the class IB ring-hydroxylating
      dioxygenases.

PMID- 10589736
TI  - Anaerobic toluene-catabolic pathway in denitrifying Thauera aromatica: activation
      and beta-oxidation of the first intermediate, (R)-(+)-benzylsuccinate.
AB  - Anaerobic catabolism of toluene is initiated by addition of the methyl group of
      toluene to the double bond of a fumarate cosubstrate to yield the first
      intermediate, benzylsuccinate. This reaction is catalysed by the glycyl-radical
      enzyme benzylsuccinate synthase, as shown for the denitrifying bacterium Thauera
      aromatica. Benzylsuccinate is further oxidized to benzoyl-CoA, the central
      intermediate of anaerobic degradation of aromatic compounds. The authors show
      here by experiments with cell extracts of toluene-grown T. aromatica that the
      pathway of benzylsuccinate oxidation requires activation of the free acid to a
      CoA-thioester, catalysed by a toluene-induced, reversible succinyl-CoA-dependent
      CoA-transferase. The product of the CoA-transferase reaction, benzylsuccinyl-CoA,
      is oxidized to benzoyl-CoA and succinyl-CoA in extracts of toluene-grown cells,
      adding proof to the proposed anaerobic toluene-catabolic pathway. The
      stereochemical preferences of the enzymes catalysing formation and activation of
      benzylsuccinate have been analysed. Benzylsuccinate synthase was found to produce
      exclusively (R)-(+)-benzylsuccinate, although the proposed reaction mechanism of
      this enzyme proceeds via radical intermediates. In accordance, the reaction of
      succinyl-CoA:benzylsuccinate CoA-transferase is also specific for (R)-(+)
      benzylsuccinate and does not proceed with the (S)-(-)-enantiomer.

PMID- 10589737
TI  - Organization of threonine biosynthesis genes from the obligate methylotroph
      Methylobacillus flagellatus.
AB  - The genes encoding aspartate kinase (ask), homoserine dehydrogenase (hom),
      homoserine kinase (thrB) and threonine synthase (thrC) from the obligate
      methylotroph Methylobacillus flagellatus were cloned. In maxicells hom and thrC
      directed synthesis of 51 and 48 kDa polypeptides, respectively. The hom, thrB and
      thrC genes and adjacent DNA areas were sequenced. Of the threonine biosynthesis
      genes, only hom and thrC were tightly linked in the order hom-thrC. The gene for
      thymidylate synthase (thyA) followed thrC and the gene for aspartate
      aminotransferase (aspC) preceded hom. All four genes (aspC-hom-thrC-thyA) were
      transcribed in the same direction. mRNA analysis indicated that hom-thrC are
      apparently transcribed in one 7.5 kb transcript in M. flagellatus. Promoter
      analysis showed the presence of a functional promoter between aspC and hom. No
      functional promoter was found to be associated with the DNA stretch between hom
      and thrC. The thrB gene encoded an unusual type of homoserine kinase and was not
      linked to other threonine biosynthesis genes.

PMID- 10589738
TI  - Population biology of Streptococcus pneumoniae isolated from oropharyngeal
      carriage and invasive disease.
AB  - The population structure of Streptococcus pneumoniae in a sample of 134 carried
      antibiotic-susceptible isolates, and 53 resistant and susceptible invasive
      isolates, was examined using a DNA-based version of multilocus enzyme
      electrophoresis: multilocus restriction typing (MLRT). This involved RFLP
      analysis of PCR products generated from nine loci of housekeeping genes located
      around the pneumococcal chromosome. The combination of alleles at each of the
      nine loci gave an allelic profile or restriction type (RT). All carried (throat
      or nasopharyngeal) isolates from children or adults in Oxford and Manchester, UK,
      and from an HIV-seropositive cohort in Nairobi, Kenya, showed an epidemic
      population structure. Twelve carried clonal groups, each with different
      serotypes, were identified at both locations within the UK. Almost all of the
      carried clones examined (16/17) were found to possess identical RTs or sequence
      types (STs) to invasive isolates, indicating that frequently carried clones are
      also associated with cases of invasive disease. As expected from previous
      studies, the population of 53 invasive, mainly penicillin-resistant, isolates was
      also found to be at linkage equilibrium. Serotype switching was identified among
      14% of RTs that possessed two or more members, or 5.7% of individual isolates
      within these RTs. In support of a population structure in which there is frequent
      recombination, there is also clear evidence that the trpA/B locus within
      pneumococci has evolved by horizontal gene transfer. A non-serotypable isolate
      from an HIV-seropositive patient in Kenya was clearly genetically distinct from
      other strains studied, with unique alleles at eight out of nine loci examined.
      However, it was initially identified as a pneumococcus by a 16S RNA gene probe
      (Gen-Probe), optochin susceptibility and the presence of pneumolysin and
      autolysin.

PMID- 10589739
TI  - Expression of cytotoxicity by potential pathogens in the standard Escherichia
      coli collection of reference (ECOR) strains.
AB  - The standard Escherichia coli collection of reference (ECOR) strains was examined
      for ability to exert cytotoxicity towards mammalian cells. A group of strains
      with functional haemolysin expression caused strong cytotoxicity and detachment
      in J774 macrophage cells as measured by lactate dehydrogenase release and as
      observed under a microscope. The expression of haemolysin was monitored by using
      antisera recognizing the E. coli alpha-haemolysin, the HlyA protein, and by
      quantitative haemolysis assays. The presence of the hlyA gene, which may be part
      of a pathogenicity island, was also confirmed. These analyses revealed that
      different ECOR strains express quantitatively different levels of haemolysin. One
      putative enteroaggregative E. coli (EAEC) strain was also found in the ECOR
      collection. The EAEC strain was characterized by the clump formation assay, PCR
      amplification of the EAEC DNA probe sequence and confirmative sequence analysis
      of the amplified fragment. The EAEC heat-stable enterotoxin 1 gene, astA, was
      found in 14% (10/72) of the ECOR strains and a consensus sequence for astA was
      proposed by comparing these sequences with those from pathogens. The astA gene
      appeared to be plasmid-located. Based on evidence from the work of other
      laboratories and from the present findings, it is concluded that the ECOR
      collection contains strains that may represent pathogenic E. coli. It is noted
      that caution is necessary when handling or disposing of those potentially
      pathogenic ECOR strains.

PMID- 10589740
TI  - Microbial diversity in marine sediments from Sagami Bay and Tokyo Bay, Japan, as
      determined by 16S rRNA gene analysis.
AB  - 16S rDNA clone libraries were analysed to investigate the microbial diversity in
      marine sediments from Sagami Bay (stations SA, water depth of 1159 m, and SB,
      1516 m) and Tokyo Bay (station TK, 43 m). A total of 197 clones was examined by
      amplified rDNA restriction analysis (ARDRA) using three four-base-specific
      restriction enzymes (Hhal, Rsal and Haelll). In SA, 57 RFLP types were detected
      from 77 clones. In SB, 17 RFLP types were detected from 62 clones. In TK, 21 RFLP
      types were detected from 58 clones. The genotypic diversity among the three
      sampling sites was 0.958, 0.636 and 0.821, respectively, indicating that the
      microbial diversity of SA was higher than at the other two stations. At SA, the
      most abundant RFLP type constituted 10% of all clones. The samples from SB and TK
      had dominant RFLP types which constituted 60% and 38% of the total clone
      libraries, respectively. The community structure of SA included many single-type
      clones, which were found only once in the clone libraries. This structure
      contrasted with that of the other two stations. Thirty-seven clones were selected
      and sequenced according to dendrograms derived from ARDRA, to cover most of the
      microbial diversity in the clone libraries. No clones were identical to any of
      the known 165 rRNA sequences or to each other. All sequences had >84.8%
      similarity to rDNA sequences retrieved from the DNA databases. Sequenced clones
      fell into five major lineages of the domain Bacteria: the gamma, delta and
      epsilon Proteobacteria, Gram-positive bacteria and the division Verrucomicrobia.
      At SA, the Verrucomicrobia and the three subclasses of the Proteobacteria were
      found. Most clone sequences belonged to the gamma Proteobacteria. The high-GC
      Gram-positive bacteria and the gamma subclass of the Proteobacteria were common
      at both SB and TK. Although the depths of SB and TK were very different, the
      community diversity inferred from ARDRA and the taxonomic position of the
      dominant clones were similar. All clones belonging to the highGC Gram-positive
      bacteria collected from both SB and TK fell into the same cluster and are
      regarded as members of an unknown actinomycete group. The clone compositions were
      different at each sampling site, and clones of the gamma Proteobacteria and high
      GC Gram-positive bacteria were dominant.

PMID- 10589741
TI  - p53 prognostication: paradigm or paradox?

PMID- 10589742
TI  - Drug resistance: still on the learning curve.

PMID- 10589743
TI  - Intrathecal depot cytarabine therapy: a welcome addition to a limited
      armamentarium.

PMID- 10589744
TI  - Rapid activation of MDR1 gene expression in human metastatic sarcoma after in
      vivo exposure to doxorubicin.
AB  - Overexpression of P-glycoprotein (Pgp), a multidrug transporter encoded by the
      MDR1 gene, is associated with chemoresistance in some human solid tumor
      malignancies. To date, analyses of MDR1 levels in solid tumors have examined
      constitutive increases in expression at relapse. In the present study, we have
      evaluated the acute induction of MDR1 gene expression in a solid human tumor as a
      function of time in response to in vivo exposure to chemotherapy. Five patients
      with unresectable sarcoma pulmonary metastases underwent isolated single lung
      perfusion with doxorubicin. Relative MDR1 gene expression was measured in
      metastatic tumor nodules and normal lung specimens after initiation of
      chemoperfusion. In four of five patients, a 3-15-fold (median, 6.8) increase in
      MDR1 RNA levels was detected in tumors at 50 min after administration of
      doxorubicin. In contrast, normal lung samples had very low levels of MDR1 RNA
      prior to perfusion, and no acute increases were observed after therapy. These
      findings demonstrate, for the first time, that MDR1 gene expression can be
      rapidly activated in human tumors after transient in vivo exposure to cytotoxic
      chemotherapy.

PMID- 10589745
TI  - Phase I study of an antisense oligonucleotide to protein kinase C-alpha (ISIS
      3521/CGP 64128A) in patients with cancer.
AB  - Protein kinase C (PKC) is an attractive target in cancer therapy. It is
      overexpressed in a variety of cancers, and nonspecific inhibitors of PKC have
      demonstrated antitumor activity. Antisense oligonucleotides targeted against PKC
      alpha, which have high specificity, can inhibit mRNA and protein expression as
      well as the growth of tumors in vitro and in vivo. This Phase I study sought to
      characterize the safety profile and to determine the maximum tolerated dose of
      antisense to PKC-alpha when administered by continuous infusion in patients.
      Patients with incurable malignancies received ISIS 3521, a 20-length
      phosphorothioate oligodeoxynucleotide specific for PKC-alpha. Treatment was
      delivered over a period of 21 days by continuous i.v. infusion followed by a 7
      day rest period. Doses were increased from 0.5 to 3.0 mg/kg/day. Patients
      continued on the study until evidence of disease progression or unacceptable
      toxicity was detected. Between August 1996 and September 1997, 21 patients were
      treated in five patient cohorts. The maximum tolerated dose was 2.0 mg/kg/day.
      The dose-limiting toxicities were thrombocytopenia and fatigue at a dose of 3.0
      mg/kg/day. Pharmacokinetic measurements showed rapid plasma clearance and dose
      dependent steady-state concentrations of ISIS 3521. Evidence of tumor response
      lasting up to 11 months was observed in three of four patients with ovarian
      cancer. The recommended dose of ISIS 3521 for Phase II studies is 2.0 mg/kg/day
      when given over a period of 21 days. Side effects are modest and consist of
      thrombocytopenia and fatigue. Evidence of antitumor activity provides the
      rationale for Phase II studies in ovarian cancer and other malignancies.

PMID- 10589746
TI  - Vascular endothelial growth factor levels and induction of permeability in
      malignant pleural effusions.
AB  - Vascular endothelial growth factor (VEGF) is an important mediator of
      angiogenesis and vascular permeability. We hypothesized that malignant pleural
      effusions may contain high levels of VEGF protein as well as other cytokines
      implicated in these processes. Pleural effusions cytologically proven to be
      malignant were collected from 39 patients with various types of cancer, and VEGF,
      interleukin-8, and angiogenin levels in the effusions were determined by
      immunoassay. Negative controls were nonmalignant ascites and serum samples from
      healthy individuals. VEGF levels were significantly higher than those of control
      samples in pleural effusions secondary to breast, mesothelioma, and non-small
      cell lung cancer and when all malignant pleural effusion samples were pooled.
      Neither interleukin-8 nor angiogenin levels were elevated in malignant pleural
      effusions relative to the control samples. Vascular permeability, which was
      measured by using the Miles assay in nude mice, was increased proportionately
      with VEGF levels in the malignant pleural effusions; this increase in
      permeability induced by injection of recombinant VEGF or the malignant effusions
      was reduced by pretreating the mice with a VEGF receptor antibody.

PMID- 10589747
TI  - A phase I and pharmacological study of protracted infusions of crisnatol mesylate
      in patients with solid malignancies.
AB  - This Phase I and pharmacological study was performed to assess the feasibility of
      administering the polycyclic aromatic hydrocarbon crisnatol in increasingly
      prolonged continuous i.v. infusions to patients with advanced solid malignancies.
      The study also sought to characterize the-principal toxicities of crisnatol on
      this schedule, to recommend doses for subsequent disease-directed studies, and to
      characterize possible associations between pharmacological parameters and
      toxicity. Sixteen patients were treated with 40 courses of crisnatol administered
      as a continuous i.v. infusion. The initial dose-schedule was 750 mg/m2/day for 6
      days, and the duration of the infusion was to be progressively increased by 3-day
      increments to 9, 12, 15, 18, and 21. Courses were to be repeated every 4 weeks.
      Moderate to severe central nervous system (CNS) toxicity precluded the
      administration of crisnatol 750 mg/m2/day for longer than 6 days, and, therefore,
      the dose of crisnatol was reduced to 600 mg/m2/day. At this dose, three of five
      patients receiving a 12-day infusion experienced dose-limiting toxicity, which
      consisted of pulmonary thromboembolism (two patients) and grade 4
      thrombocytopenia (one patient). None of the six patients completing a 9-day
      infusion at 600 mg/m2/day developed dose-limiting toxicity during the first or
      second course of crisnatol. At this dose level, the plasma concentrations at
      steady state (Css) averaged 1607.8+/-261.1 ng/ml, which exceeds minimal
      inhibitory concentrations for most tumors in vitro (1000 ng/ml). In fact, the
      administration of crisnatol at a dose of 600 mg/m2/day for 9 days resulted in the
      longest duration that biologically relevant plasma crisnatol concentrations have
      been sustained. Plasma Css values were significantly higher in patients who
      experienced severe CNS toxicity compared with those who did not (2465.3+/-1213.5
      versus 1342+/-447.3 ng/ml; P = 0.04). There were no relationships evident between
      the clearance of crisnatol and indices reflecting renal and hepatic functions.
      One patient with a glioblastoma multiforme experienced a partial response lasting
      14 months. The relative lack of intolerable CNS toxicity at the recommended dose
      for Phase II studies of crisnatol, 600 mg/m2/day for 9 days, as well as the
      magnitude of the Css values achieved and the antitumor activity observed at this
      dose, are encouraging. However, the mechanisms for the apparently increased
      thrombogenicity observed in this trial are unclear and require further
      elucidation.

PMID- 10589748
TI  - Coadministration of oral cyclosporin A enables oral therapy with paclitaxel.
AB  - i.v. paclitaxel is inconvenient and associated with significant and poorly
      predictable side effects largely due to the pharmaceutical vehicle Cremophor EL.
      Oral administration may be attractive because it may circumvent the use of
      Cremophor EL. However, paclitaxel, as well as many other commonly applied drugs,
      has poor bioavailability caused by high affinity for the mdrl P-glycoprotein drug
      efflux pump, which is abundantly present in the gastrointestinal tract.
      Consequently, inhibition of P-glycoprotein by oral cyclosporin A (CsA) should
      increase systemic exposure of oral paclitaxel to therapeutic levels. A proof-of
      concept study was carried out in 14 patients with solid tumors. Patients received
      one course of oral paclitaxel of 60 mg/m2 with or without 15 mg/kg CsA and with
      i.v. paclitaxel in subsequent courses. The pharmacokinetics of paclitaxel and its
      major metabolites were determined during the first two courses. In addition,
      levels of CsA, Cremophor EL, and ethanol were measured. Bioavailability of oral
      paclitaxel in combination with CsA was 8-fold higher than after oral paclitaxel
      alone (P<0.001). Therapeutic concentrations were achieved on average during 7.4
      h, which is comparable with an equivalent i.v. dose. The oral combination was
      well tolerated and did not induce gastrointestinal toxicity or myelosuppression.
      Cremophor EL plasma levels after oral drug administration were undetectable. In
      conclusion, coadministration of oral CsA increased the systemic exposure of oral
      paclitaxel from negligible to therapeutic levels. The combination enables
      treatment with oral paclitaxel. Undetectable Cremophor EL levels after oral
      administration may have a very beneficial influence on the safety of the
      treatment with oral paclitaxel.

PMID- 10589749
TI  - Phase I and imaging trial of a monoclonal antibody directed against gastrin
      releasing peptide in patients with lung cancer.
AB  - Small cell lung cancer (SCLC) cells express and secrete bombesin-like peptides
      (BLP) that can activate specific receptors that stimulate the growth of these
      cells. A murine monoclonal antibody, 2A11, which binds to the BLP, gastrin
      releasing peptide with high affinity, has been reported to decrease the growth of
      SCLC cells in vitro and in athymic nude mice. A Phase I trial in lung cancer
      patients was performed using multiple doses of 2A11. Thirteen patients with lung
      cancer received 12 doses of 2A11 antibody three times a week for 4 weeks at one
      of four dose levels. Serum samples were obtained prior to initiation and before
      each dose of 2A11 antibody therapy for measurement of 2A11 antibody levels and
      determination of serum human anti-mouse antibody levels. A pilot imaging
      evaluation using 111In conjugated 2A11 monoclonal antibody was also performed in
      the same patients to aid in the study of pharmacokinetics and biodistribution. No
      toxic reactions were observed, and none of the patients developed detectable
      human antimouse antibody; however, no objective antitumor responses were
      observed. The mean trough serum 2A11 levels in patients increased with increasing
      dose level: 0.26+/-0.2 microg/ml, 6.7+/-6 microg/ml, 71.5+/-60 microg/ml, 248+/
      184 microg/ml for dose levels 1 mg/m2, 10 mg/m2, 100 mg/m2, and 250 mg/m2,
      respectively. At each dose level, sustained detectable serum levels of the
      monoclonal antibody were achieved. Tumor uptake was noted in 11 of 12 patients
      who were injected with 111In conjugated 2A11. Because no dose-limiting clinical
      toxicity was observed, a mathematical model was used to define the recommended
      Phase II dose of 250 mg/m2. This trial established that repeated doses of
      monoclonal antibody 2A11 could be given safely to patients, and sustained levels
      could be achieved for a 4-week schedule. Further evaluation of the antitumor
      effects of 2A11 is warranted.

PMID- 10589750
TI  - A randomized controlled trial comparing intrathecal sustained-release cytarabine
      (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from
      solid tumors.
AB  - Standard treatment for neoplastic meningitis requires frequent intrathecal (IT)
      injections of chemotherapy and is only modestly effective. DepoCyt is a sustained
      release formulation of cytarabine that maintains cytotoxic concentrations of the
      drug in the cerebrospinal fluid (CSF) for more than 14 days after a single 50-mg
      injection. We conducted a randomized, controlled trial of DepoCyt versus
      methotrexate in patients with solid tumor neoplastic meningitis. Sixty-one
      patients with histologically proven cancer and positive CSF cytologies were
      randomized to receive IT DepoCyt (31 patients) or IT methotrexate (30 patients).
      Patients received up to six 50-mg doses of DepoCyt or up to sixteen 10-mg doses
      of methotrexate over 3 months. Treatment arms were well balanced with respect to
      demographic and disease-related characteristics. Responses occurred in 26% of
      DepoCyt-treated and 20% of methotrexate-treated patients (P = 0.76). Median
      survival was 105 days in the DepoCyt arm and 78 days in the methotrexate arm (log
      rank P = 0.15). The DepoCyt group experienced a greater median time to
      neurological progression (58 versus 30 days; log-rank P = 0.007) and longer
      neoplastic meningitis-specific survival (log-rank P = 0.074; median meningitis
      specific survival, 343 versus 98 days). Factors predictive of longer progression
      free survival included absence of visible central nervous system disease on
      neuroimaging studies (P<0.001), longer pretreatment duration of CSF disease
      (P<0.001), history of intraparenchymal tumor (P<0.001), and treatment with
      DepoCyt (P = 0.002). The frequency and grade of adverse events were comparable
      between treatment arms. In patients with solid tumor neoplastic meningitis,
      DepoCyt produced a response rate comparable to that of methotrexate and
      significantly increased the time to neurological progression while offering the
      benefit of a less demanding dose schedule.

PMID- 10589751
TI  - Classification and regression tree analysis of 1000 consecutive patients with
      unknown primary carcinoma.
AB  - The clinical features and survival times of patients with unknown primary
      carcinoma (UPC) are heterogeneous. Therefore, the goals of this study were to
      apply a novel analytical method to UPC patients to: (a) identify novel prognostic
      factors; (b) explore the interactions between clinical variables and their impact
      on survival; and (c) illustrate explicitly how the covariates interact. The 1000
      patients analyzed were referred to the University of Texas M. D. Anderson Cancer
      Center from January 1, 1987 through November 30, 1994. Clinical data from these
      patients were entered into a computerized database for storage, retrieval, and
      analysis. Multivariate analyses of survival were performed using recursive
      partitioning referred to as classification and regression tree (CART) analysis.
      The median survival for all 1000 consecutive UPC patients was 11 months. CART was
      performed with an initial split on liver involvement, and 10 terminal subgroups
      were formed. Median survival of the 10 subgroups ranged from 40 months (95%
      confidence interval, 22-66 months) for UPC patients with one or two metastatic
      organ sites, with nonadenocarcinoma histology, and without liver, bone, adrenal,
      or pleural metastases to 5 months (95% confidence interval, 4-7 months) in UPC
      patients with liver metastases, tumor histologies other than neuroendocrine
      carcinoma, age >61.5 years, and a small subgroup of patients with adrenal
      metastases. Two additional trees were also explored. These analyses demonstrated
      that important prognostic variables were consistently applied by the CART program
      and effectively segregated patients into groups with similar clinical features
      and survival. CART also identified previously unappreciated patient subsets and
      is a useful method for dissecting complex clinical situations and identifying
      homogeneous patient populations for future clinical trials.

PMID- 10589752
TI  - A feasibility study of multiple cycle therapy with melphalan, thiotepa, and
      paclitaxel followed by mitoxantrone, thiotepa, and paclitaxel with autologous
      hematopoietic cell support for metastatic breast cancer.
AB  - Dose-intensive chemotherapy appears to be important in the treatment of patients
      with recurrent solid tumors. Expanding upon our prior experience, we report the
      results of our most recent approach to administering dose-intensive therapy using
      four cycles of moderately high-dose chemotherapy with hematopoietic cell support
      for patients with metastatic breast cancer. This outpatient therapy includes high
      dose melphalan, thiotepa, and paclitaxel for two cycles followed by mitoxantrone,
      thiotepa, and paclitaxel for two cycles, with each cycle supported with
      autologous peripheral blood progenitor cells (PBPCs). Between December 1994 and
      June 1996, 16 patients with recurrent or refractory breast cancer were enrolled
      in this prospective study. They had received a median of two previous
      chemotherapy regimens, with a median of nine prior cycles of chemotherapy. For
      mobilization of autologous PBPCs, patients received cyclophosphamide, 4 g/m2,
      followed by granulocyte colony-stimulating factor (G-CSF). PBPCs were collected
      by apheresis. Each day's collection was divided into four equal fractions, and
      each fraction was infused after each cycle of combination therapy. Cycles 1 and 2
      consisted of melphalan, 80 mg/m2, thiotepa, 300 mg/m2, and paclitaxel, 200 mg/m2.
      Cycles 3 and 4 were comprised of mitoxantrone, 30 mg/m2, and thiotepa and
      paclitaxel at the same doses as in the first two cycles. The cyclophosphamide
      infusion was administered in the hospital, whereas all subsequent infusions of
      chemotherapy and PBPCs were performed on an outpatient basis. The first seven
      patients were randomized to receive alternate cycle G-CSF or placebo on day +1 of
      each cycle. Including the initial pulse of cyclophosphamide, 67 (84%) of a
      planned 80 total courses of chemotherapy were delivered. Of the planned 64 cycles
      of high-dose combination chemotherapy, 52 cycles (81%) were delivered. Treatment
      was discontinued for progressive disease (one patient) or morbidity (five
      patients). Twelve of 16 patients completed at least three cycles of therapy. Nine
      patients completed all four cycles. One death resulted from fungal sepsis. In 20
      cycles delivered to the first seven patients, day +1 G-CSF versus placebo was
      administered, with a median WBC recovery of 10 versus 13 days, respectively (P =
      0.048 in cycle 1). The median duration of response was almost 9 months, and the
      median survival was 18 months after therapy. With a median follow-up of 1.5 years
      and longest follow-up of 4.2 years, two patients continue to be without evidence
      of disease. The 3-year event-free survival, freedom from progression, and overall
      survival are 19%, 20%, and 31%, respectively. This four-cycle regimen of high
      dose combination therapy supported with hematopoietic progenitor cells is
      feasible, but it is associated with a range of posttransplant complications. The
      efficacy of such a treatment would have to be substantially superior to that of
      other currently available therapies, including single autologous transplant
      procedures, to justify the prolonged period of treatment, multiple episodes of
      pancytopenia, and associated toxicities, including infectious risks. G-CSF
      administration after each PBPC infusion appears to accelerate time to neutrophil
      recovery but does not affect red cell or platelet engraftment.

PMID- 10589753
TI  - A phase I study of paclitaxel, etoposide, and cisplatin in extensive stage small
      cell lung cancer.
AB  - This Phase I study was designed to determine the maximally tolerated dose (MTD)
      of paclitaxel with standard doses of cisplatin and etoposide for patients with
      untreated extensive stage small cell lung cancer (SCLC). Secondary objectives
      were to determine the toxicities, response rate, response duration, and overall
      survival in this cohort. Twenty-eight SCLC patients were enrolled into four dose
      levels. All patients received a fixed dose of cisplatin at 80 mg/m2, i.v., day 1.
      The first group received etoposide 50 mg/m2, i.v. day 1 and 100 mg/m2 p.o., days
      2-3, whereas all subsequent groups received etoposide 80 mg/m2, i.v., day 1 and
      160 mg/m2, p.o., days 2-3. The paclitaxel starting dose was 135 mg/m2, i.v., over
      a 3-h period and was escalated to 175 and 200 mg/m2. Cycles were repeated every
      21 days for a maximum of six cycles. Granulocyte-colony stimulating factor was
      not given prophylactically but was allowed in subsequent cycles according to the
      American Society of Clinical Oncologists guidelines. All 28 SCLC patients were
      evaluable for toxicity, and 23 patients were evaluable for response.
      Myelosuppression was the major toxicity, with grade 4 neutropenia occurring in 23
      of 28 patients (82%), but febrile neutropenia was uncommon and developed in 4
      patients (14%). Grade 4 thrombocytopenia and anemia were rare, occurring as
      isolated events in one patient each. Dose-limiting peripheral neuropathy was
      observed at a paclitaxel dose of 200 mg/m2. Grade 4 nausea/vomiting and diarrhea
      were also noted at this dose level. Five patients had complete responses (22%),
      and 14 patients had partial responses (61%). The overall response rate was 83%
      with a median time to progression of 7.5 months, a median survival of 10 months,
      and a 1-year survival rate of 39%. This three-drug combination of paclitaxel with
      cisplatin and etoposide is active with acceptable toxicity. Neurotoxicity was
      dose limiting at 200 mg/m2 of paclitaxel. Neutropenia was frequent but not
      associated with significant morbidity. The recommended doses for future clinical
      trials are 175 mg/m2 paclitaxel, i.v., over a 3-h period on day 1 with 80 mg/m2
      cisplatin, i.v., on day 1 and 80 mg/m2 etoposide, i.v., on day 1 and 160 mg/m2
      p.o. on days 2 and 3 with growth factor support. The Southwestern Oncology Group
      has instituted a Phase II study with this dose schedule.

PMID- 10589754
TI  - A predictive model for relapse in high-risk primary breast cancer patients
      treated with high-dose chemotherapy and autologous stem-cell transplant.
AB  - High-dose chemotherapy (HDCT) is currently under evaluation for high-risk primary
      breast cancer (HRPBC), defined by extensive axillary nodal involvement or
      inflammatory breast carcinoma. Phase II studies of HDCT for HRPBC show that 30
      40% of patients eventually relapse. We retrospectively reviewed 176 patients
      enrolled in clinical trials of HDCT for HRPBC at the University of Colorado and
      analyzed 23 potential predictive variables for relapse. All of the patients
      received the same regimen, with cyclophosphamide, cisplatin, and BCNU. Nine
      patients who experienced a toxic death were excluded from this analysis. The
      resulting predictive model was subsequently tested in an independent patient set
      treated at Duke University with the same HDCT regimen. Nodal ratio (number of
      involved nodes:number of sampled nodes), tumor size, grade, stage, estrogen
      receptor, progesterone receptor, and clinical inflammatory breast carcinoma
      correlated with risk of relapse. Nodal ratio, tumor size, and the combined
      estrogen receptor/progesterone receptor status were independent predictors. A
      scoring system using those three variables determines the risk of relapse, with a
      sensitivity and specificity of 60 and 90%, respectively, and a positive and
      negative predictive value of 65 and 88%, respectively. The differences in relapse
      free survival and overall survival between high- and low-score patients were
      highly significant (P<0.000001). This model was subsequently validated in the
      Duke patient set. This model can identify two subgroups of HRPBC patients with
      low (12%) and high (65%) risk for recurrence after HDCT. Future research that
      tests new therapies will focus on those patients with a high score.

PMID- 10589755
TI  - AIDS-related Kaposi's sarcoma: a phase II study of liposomal doxorubicin. The TLC
      D-99 Study Group.
AB  - TLC D-99 is a unique liposomal formulation of doxorubicin that consists of
      phosphatidyl choline/cholesterol. The objectives of the study were to evaluate
      safety and efficacy of two doses of TLC D-99 in the treatment of patients with
      AIDS-related Kaposi's Sarcoma (KS). Forty HIV-infected persons with biopsy-proven
      KS were randomized to receive TLC D-99 at doses of either 10 (low) or 20 (high)
      mg/m2 every 2 weeks. Patients assigned to the low-dose arm could be escalated to
      the high-dose arm if their KS progressed after 3 cycles of therapy. Median age
      was 35 years (range, 26-47) and median CD4 count was 13 (range, 0-440). Nineteen
      patients were assigned to receive the low dose, and 21 patients were assigned to
      the high dose. Partial response occurred in 15% (6 of 40) of the patients or in
      5% (1 of 19) and 24% (5 of 21) in the low- and high-dose arms, respectively;
      stable disease was observed in 65% (26 of 40) or in 68% (13 of 19) and 62% (13 of
      21) in the low and high doses, respectively. Neutropenia was the major toxicity
      and was observed in 68 and 81% of patients with the low- and high-dose arms,
      respectively; grade 4 neutropenia was observed in 16 and 14%, respectively. Mild
      alopecia was noted in only 8%. Therefore, TLC D-99 is active against AIDS-related
      KS, and the response is dose-dependent.

PMID- 10589756
TI  - Alpha-difluoromethylornithine as treatment for metastatic breast cancer patients.
AB  - DFMO (alpha-difluoromethylornithine) is an oral irreversible inhibitor of
      ornithine decarboxylase, the first rate-limiting enzyme in polyamine synthesis.
      DFMO has been shown to have antiproliferative effects against several human
      cancers, and some studies have suggested that DFMO may have pro-apoptotic and
      anti-invasive properties as well. DFMO is well tolerated with minimal toxicity
      but has been associated with ototoxicity with prolonged daily administration. We
      conducted a Phase I/II tolerability, pharmacokinetic, and efficacy study of high
      dose DFMO in metastatic breast cancer patients. Twenty-one patients were treated
      with 4800 mg of DFMO p.o. three times a day for 14 days, followed by a 2-week
      drug holiday on a 28-day cycle. Urinary polyamine and blood DFMO levels were
      measured at multiple time points during therapy. High-dose DFMO was well
      tolerated, and no clinically significant ototoxicity was noted. No patient
      achieved an objective antitumor response; however, one patient with heavily
      pretreated liver metastases has achieved stable disease for 18 months to date on
      DFMO. Putrescine, spermine, and spermidine urinary levels were suppressed with
      DFMO treatment and remained low during the 2-week drug holiday. High-dose DFMO on
      a schedule of 2 weeks on treatment followed by 2 weeks off is well tolerated, is
      not associated with ototoxicity, and leads to sustained suppression of urinary
      polyamine levels. Although not an active cytotoxic agent for metastatic breast
      cancer, the intriguing prolonged growth arrest of liver metastases in one patient
      highlights the potential clinical growth inhibitory properties of DFMO. We
      believe that DFMO is worthy of study as adjuvant therapy in primary breast cancer
      patients and as a chemopreventive agent.

PMID- 10589757
TI  - Discovery of differentially expressed genes associated with paclitaxel resistance
      using cDNA array technology: analysis of interleukin (IL) 6, IL-8, and monocyte
      chemotactic protein 1 in the paclitaxel-resistant phenotype.
AB  - In an attempt to define the molecular changes associated with the paclitaxel
      resistant phenotype in human cancer, a paclitaxel-resistant ovarian cancer cell
      line, SKOV-3TR, was established through stepwise selection in increasing
      paclitaxel concentrations. SKOV-3TR was cross- resistant to doxorubicin and
      vincristine and overexpressed multidrug resistance gene 1 but not multidrug
      resistance associated protein. SKOV-3TR and the paclitaxel-sensitive SKOV-3
      parent line were characterized using human cDNA array technology that examined
      expression of a wide variety of genes involved in cell growth, signal
      transduction, cell death, and immune function. cDNA probes from reverse
      transcribed mRNAs of both paclitaxel-resistant and parent cells were compared to
      identify genes differentially expressed in the paclitaxel-resistant cells. Of 588
      different human cDNA transcripts compared, 6 genes were found to be markedly
      decreased, and 12 genes increased in the resistant subline. Northern analysis
      and/or reverse transcription-PCR confirmed that 12 of these 18 genes were over-
      or underexpressed in SKOV-3TR. In addition, at least eight of the genes were
      found differentially expressed in several other paclitaxel- and/or doxorubicin
      resistant cell lines, both those with increased multidrug resistance expression
      and those without. Included in the set of overexpressed genes were the
      cytokines/chemokines interleukin 6, interleukin 8, and monocyte chemotactic
      protein 1. ELISA assays confirm that mRNA overexpression of these
      cytokine/chemokines was associated with the increased secretion of these
      molecules in the tissue culture supernatant. Evaluation of supernatants from an
      expanded collection of paclitaxel- and Adriamycin-resistant cell lines
      demonstrated that all of the resistant lines had significant overexpression of at
      least one cytokine/chemokine as compared with their drug-sensitive parent line.
      The overexpression of these cytokines seemed to be stable and associated with a
      drug-resistant phenotype with only a modest induction of cytokine expression in
      the parent line with short-term paclitaxel exposure. These findings suggest that
      the development of paclitaxel resistance is accompanied by multiple changes in
      gene expression including stable alterations in selective chemokine and cytokine
      expression. The role these associated genetic changes have in the drug-resistant
      phenotype is discussed.

PMID- 10589758
TI  - Prospective assessment of allelic losses at 4p14-16 in colorectal cancer: two
      mutational patterns and a locus associated with poorer survival.
AB  - Previous studies have shown that allelic losses in a locus mapping to the
      chromosomal region 4p14-16 are indicative of poor prognosis in colorectal cancer.
      To further characterize the region involved and to confirm earlier observations,
      we have analyzed losses of heterozygosity (LOH) in nine microsatellite markers
      spanning this region in a prospective series of 181 colorectal carcinomas. The
      extent and the nature of the allelic imbalance were also ascertained by
      comparative genomic hybridization analysis of selected cases. The minimum common
      deleted region was confined to marker D4S2397 (LOH in 35% of the informative
      cases). Surrounding markers displayed LOH in 13-25% of informative cases and
      (other than the D4S2397 marker itself) showed a higher rate of allelic imbalances
      in association with mutations in the p53 tumor suppressor gene. Tumors with lymph
      node invasion also displayed increased rates of LOH in most markers. Regarding
      patient outcome, LOH solely at the D4S2397 locus was indicative of a shorter
      disease-free survival (P = 0.027). In consequence, two patterns of allelic loss
      are defined within the 4p14-16 region: (a) gross losses associated with tumor
      progression and probably attributable to the genomic instability related to the
      inactivation of the p53 tumor suppressor gene; and (b) specific losses limited to
      the D4S2397 locus (within an estimated fragment of 2 Mb) and associated with
      increased tumor aggressiveness. The presence of one or more putative tumor
      suppressor genes in this region is postulated.

PMID- 10589759
TI  - Expression of nuclear receptor interacting proteins TIF-1, SUG-1, receptor
      interacting protein 140, and corepressor SMRT in tamoxifen-resistant breast
      cancer.
AB  - Regulation of gene transcription as a consequence of steroid receptor-DNA
      interaction is mediated via nuclear receptor interacting proteins (RIPs),
      including coactivator or corepressor proteins, which interact with both the
      receptor and components of the basic transcriptional unit and vary between cell
      types. The aim of this study was to test the hypothesis that resistance of some
      breast carcinomas to tamoxifen was associated with inappropriate expression of
      some of these RIPs. Using Northern analysis, we observed no significant
      difference between the amount of either TIF-1 or SUG-1 mRNA expressed in parental
      MCF-7 and MCF-7 tamoxifen-resistant cell lines. However, the expression of RIP140
      mRNA was lower in the resistant cell line and in the presence of estradiol, the
      level of RIP140 mRNA was higher in the resistant cells but not in the parental
      cells. In a cohort of 19 tamoxifen-resistant breast tumor samples, there was no
      significant difference in the level of the RIP140 and TIF-1 and corepressor SMRT
      mRNA compared with tamoxifen-treated tumors (n = 6) or untreated tumors (n = 21).
      However, SUG-1 mRNA was lower in resistant breast tumors. These data provide no
      support for increased expression of these RIPs or decreased expression of
      corepressor SMRT for being a mechanism for resistance of breast tumors to
      tamoxifen.

PMID- 10589760
TI  - Aberrant fragile histidine triad gene transcripts in primary hepatocellular
      carcinoma and liver cirrhosis.
AB  - To determine whether transcriptional alterations of the fragile histidine triad
      (FHIT) gene play a role in the development and progression of human
      hepatocellular carcinoma (HCC) we used reverse transcription-PCR to examine mRNA
      FHIT expression in 28 paired samples of HCC (24 in cirrhotic and 4 in
      noncirrhotic livers) and matched noncancerous tissue and in 10 normal livers. We
      also assessed loss of heterozygosity of the polymorphic D3S1300 microsatellite
      marker in the intron between exons 5 and 6 of the FHIT gene. Abnormal FHIT
      transcripts were detected in 13 cases (46.4%): 10 in the cancerous tissue only, 1
      with the same pattern in both cancerous and matched noncancerous tissue, and 2 in
      the noncancerous tissue only. The four HCCs that arose in noncirrhotic liver all
      showed abnormal FHIT transcripts. No alterations were found in normal livers.
      Sequence analysis of abnormally sized transcripts revealed that they were
      generated by the fusion of exons 3 or 4 with exons 8 or 9. Among the cancerous
      specimens, one case showed only an abnormal sized transcript derived from the
      fusion of exons 4 and 9 in the absence of any normal-sized transcript, and
      another case showed deletion of a sequence comprised between nucleotides -35 and
      399 resulting in an exon 4-9 fusion not respecting the exons' bounds. Loss of
      heterozygosity was found in two cases with abnormal FHIT transcripts and in only
      one case with normal transcript. Patients with aberrant FHIT transcripts showed a
      significantly higher relapse rate and shorter recurrence time (P = 0.001). This
      could be related to a primary genomic instability affecting particularly
      susceptible regions like FRA3B and could be associated with an increasing risk of
      recurrence without involving a causative role.

PMID- 10589761
TI  - Allelic loss in esophageal squamous cell carcinoma patients with and without
      family history of upper gastrointestinal tract cancer.
AB  - Chromosomal regions with frequent allelic loss may point to major susceptibility
      genes that will assist in understanding molecular events involved in esophageal
      carcinogenesis. Esophageal squamous cell carcinoma samples and blood from 46
      patients, including 23 patients with and 23 patients without a family history of
      upper gastrointestinal cancer, were screened using laser microdissected DNA and
      tested for loss of heterozygosity (LOH) at 18 marker loci representing 14
      chromosomal regions (on 2q, 3p, 4p, 4p, 5q, 6q, 8p, 9p, 9q, 11p, 13q, 14q, 15q,
      and 17p) identified in an earlier genome-wide scan to have frequent LOH.
      Clinical/pathological and lifestyle risk factor data were also collected. For all
      46 tumors combined, the lowest frequency LOH for any of the 18 markers was 37%,
      and 8 markers showed LOH in > or =75% of informative tumors. One marker (D13S894
      on 13q) showed greater LOH in patients with a positive family history (93% versus
      50%; P = 0.04), whereas two markers (D6S1027 on 6q and D9S910 on 9q) had
      significantly more LOH in patients with metastasis, and one marker (D4S2361 on
      4p) showed significantly higher LOH in patients with a lower pathological tumor
      grade. No relation was seen between LOH and lifestyle risk factors. This study
      confirms the previously observed high frequency LOH for these 14 chromosomal
      regions, including a locus on 13q where LOH is more common in patients with a
      family history of upper gastrointestinal cancer than in those without such
      history, suggesting that a gene in this area may be involved in genetic
      susceptibility to esophageal cancer.

PMID- 10589762
TI  - Immunohistochemical expression of somatostatin type 2A receptor in neuroendocrine
      tumors.
AB  - Somatostatin (SS) and SS analogues inhibit the growth of various kinds of
      endocrine and exocrine cells via the SS receptor (SSTR). Carcinoid tumor is
      representative of the tumors treatable by SS analogues. We examined the
      expression of SSTR2A by immunohistochemical and in situ hybridization methods
      with a specific antibody against a synthesized 20-amino acid peptide of the COOH
      terminus of human SSTR2A and oligonucleotide probes in 62 endocrine tumors of
      various kinds: pancreatic endocrine tumor; carcinoid; neuroendocrine carcinoma;
      medullary thyroid carcinoma; pheochromocytoma; and small cell carcinoma of the
      lung, neuroblastoma, and ganglioneuroma. SSTR2A was expressed in 87% of these
      tumors and at both primary and metastatic sites. The immunohistochemical
      reactivity of SSTR2A was strong on the cell membrane and less intense in the
      cytoplasm of the tumor cells. SSTR2A mRNA was also detected in the tumor cells.
      The results indicate the usefulness of SSTR2A analogues for the treatment of
      neuroendocrine tumors, even metastatic ones: metastatic carcinoids, metastatic
      pheochromocytomas, tumors that adhered to large vessels, and neuroendocrine
      carcinomas.

PMID- 10589763
TI  - Human ovarian cancer, cell lines, and primary ascites cells express the human
      Mullerian inhibiting substance (MIS) type II receptor, bind, and are responsive
      to MIS.
AB  - Six human ovarian cancer cell lines and samples of ascites cells isolated from 27
      patients with stage III or IV ovarian papillary serous cystadenocarcinoma were
      studied individually to test whether recombinant human Mullerian inhibiting
      substance (rhMIS) acts via its receptor. To do these experiments, we scaled up
      production of rhMIS and labeled it successfully with biotin for binding studies,
      cloned the human MIS type II receptor for mRNA detection, and raised antibodies
      to an extracellular domain peptide for protein detection. These probes were first
      tested on the human ovarian cancer cell lines and then applied to primary ovarian
      ascites cells. rhMIS inhibited colony growth of five of six cell lines that
      expressed the human MIS type II receptor mRNA by Northern analysis while not
      inhibiting receptor-negative COS cells. Flow cytometry performed on MIS-sensitive
      ovarian cancer cell lines demonstrated specific and saturable binding of rhMIS
      (Kd = 10.2 nM). Ascites cells from 15 of 27 or 56% of patients tested bound
      biotinylated MIS (MIS-biotin) and, of the 11 that grew in soft agarose, 9 of 11
      or 82% showed statistically significant inhibition of colony formation. Of the 15
      patients who bound biotinylated MIS, mRNA was available for analysis from 9, and
      8 of 9 expressed MIS type II receptor mRNA by reverse transcription-PCR, showing
      a statistically significant correlation, compared with binding, by chi2 analysis
      (P = 0.025). Solid ovarian cancers were positive for the MIS type II receptor
      protein by immunohistochemical staining, which colocalized with staining for
      antibody to CA-125 (OC-125). Thus, the detection of the MIS type I receptor by
      flow cytometry may be a useful predictor of therapeutic response to MIS and may
      be a modality to rapidly choose patients with late-stage ovarian cancer for
      treatment with MIS.

PMID- 10589764
TI  - TP53 accumulation predicts improved survival in patients resistant to systemic
      cisplatin-based chemotherapy for muscle-invasive bladder cancer.
AB  - To examine retrospectively the prognostic significance of TP53 immunoreactivity
      for both tumor response and patient survival in 83 patients with nonmetastatic
      muscle-invasive bladder cancer treated with a single transurethral resection
      (TUR) of tumor and combined cisplatin-based systemic chemotherapy followed by
      repeat TUR, paraffin-embedded sections of a bladder tumor obtained at TUR before
      chemotherapy (1 T2, 52 T3, and 30 T4) were immunostained for TP53 using
      monoclonal PAb1801 and DO-7 antibodies. For the entire cohort, TP53
      immunopositivity (PAb1801 or DO-7) did not predict complete response (CR),
      complete or partial response (PR), progressive disease, or time to death from
      bladder cancer. There was a highly significant correlation between PAb1801 and DO
      7 nuclear immunoreactivity (r = 0.8242; P<0.0001). In 76 patients in which
      complete clinical data were available, tumor stage (T2/T3; P = 0.0499), CR and PR
      (P = 0.0016) and CR (P<0.0001) were associated with patient survival. In a
      multivariate model, CR (P<0.0001) was the only independent predictor of improved
      survival. In complete responders, neither TP53 immunostaining nor
      clinicopathological factors stratified patients into prognostic groups. However,
      in the subset of patients (n = 38) who were chemoresistant (PR or progressive
      disease), improved survival was associated with > or =20% TP53 immunoreactivity
      (PAb1801; P = 0.0191) and tumor stage (T2/T3; P = 0.0358). TP53 immunopositivity
      (PAb1801 or DO-7) did not predict overall survival or response to systemic
      chemotherapy in patients with nonmetastatic but predominantly clinical stage > or
      =T3 bladder cancer, but it had prognostic significance within the chemoresistant
      subgroup.

PMID- 10589765
TI  - Apoptosis and expression of apoptosis regulating proteins bcl-2, mcl-1, bcl-X,
      and bax in malignant mesothelioma.
AB  - We investigated apoptosis and the expression of bcl-2, mcl-1, bcl-X, and bax in
      histological sections from 35 malignant mesotheliomas and 21 metastatic
      adenocarcinomas. Moreover, the expression of bcl-2, mcl-1, bcl-X, and bax were
      assessed by Western blotting in nonmalignant human mesothelial cells (Met5A) and
      seven malignant cell lines. The apoptotic index in mesotheliomas was 1.07+/
      1.14%. Patients with mesotheliomas showing a high apoptotic index (> or =0.75%)
      had a worse prognosis (P = 0.008). bcl-2 positivity was observed in only seven
      cases, but bcl-X, mcl-1, and bax positivity was seen in all of them. In
      immunoblotting experiments, all mesothelioma cell lines were negative for bcl-2
      but positive for bcl-X, mcl-1, and bax. The apoptotic index in bcl-2-negative
      mesotheliomas was 1.25+/-1.24% and in bcl-2-positive ones, 0.47+/-0.42% (P =
      0.014). The apoptotic index did not significantly associate with bcl-X, mcl-1, or
      bax expression (P = 0.19, P = 0.25, and P = 0.46, respectively). No significant
      difference was observed in apoptosis or expression of bcl-2, bcl-X, or bax
      between malignant mesotheliomas and metastatic adenocarcinomas. The former,
      however, showed more often weak mcl-1 immunoreactivity (P = 0.01). The results
      show that the extent of apoptosis may influence patient prognosis. bcl-2 is
      inversely associated with the apoptotic index but is relatively infrequently
      expressed in malignant mesotheliomas. Widespread expression of bcl-X, mcl-1, and
      bax suggests that these proteins may also take part in apoptosis regulation in
      mesotheliomas.

PMID- 10589766
TI  - Different patterns of angiogenesis in sarcomas and carcinomas.
AB  - Solid tumors depend on angiogenesis for growth and metastasis. It has been shown
      that blood vessel density, as determined by counting the number of capillaries in
      clustered bursts, is a significant prognostic factor in carcinomas. It is
      unclear, however, whether vessel density is a prognostic factor in sarcomas. In
      this study, we examined angiogenesis in sarcomas of various grades and compared
      their vascular patterns to those of carcinomas. Microvessels were identified by
      von Willebrand factor staining. The matrix of multiple sarcoma and breast
      carcinoma specimens were extracted and subjected to Western analysis of various
      angiogenic factors and inhibitors. Metalloproteinase inhibitor presence was also
      determined by in situ hybridization. In breast carcinomas, capillaries were
      clustered in bursts within the stroma of the tumor, whereas the sarcoma
      capillaries were homogeneously distributed in the tumor stroma. Random blood
      vessel density per high power field in sarcomas did not correlate with patient
      prognosis. The matrix of sarcomas and carcinomas contained both angiogenic
      stimulators and inhibitors. Tissue inhibitor of metalloproteinase-1 was found
      predominantly in fibroblasts and myofibroblasts in the matrix of carcinoma
      specimens. The difference in the pattern of angiogenesis in sarcomas and
      carcinomas may be attributable to the presence of fibroblasts and myofibroblasts
      in carcinomas, resulting in the compartmentalization of bursts of angiogenic
      factors. The homogeneous appearance of vessel density in sarcomas observed in the
      present study would be the consequence of the influence of a single compartment.

PMID- 10589767
TI  - Characterization of p53 mutations in colorectal liver metastases and correlation
      with clinical parameters.
AB  - The presence and type of mutations of the p53 tumor suppressor gene were
      determined in 40 patients undergoing curative hepatic resection for metastatic
      colorectal carcinoma. This represents the largest series in the literature on the
      screening of p53 mutations for liver metastases. The analysis was performed in
      exons 5-9 by denaturing gradient gel electrophoresis followed by direct
      sequencing. Forty-five percent of tumors showed mutation in p53, and this was
      observed only in exons 5-8. Mutations at codon positions 167, 196, 204, 213, 245,
      281, 282, 286, and 306; deletion of codon 251 and of the first nucleotide of
      codon 252; and Leu residue (CTC) insertion downstream codon 252 are reported for
      the first time in colorectal liver metastasis. Mutations at codon positions 163,
      248, and 273 have been reported previously. Correlation of p53 status with
      clinical parameters showed that patients with mutated p53 had a statistically
      higher number of lesions when compared with patients with wild-type p53
      (P<0.050). In particular, of patients with mutated p53, 41% had three or more
      metastases compared with 14% of patients with wild-type p53. Synchronous
      metastases were present in 70% of the patients with p53 mutations and in only 29%
      of patients with wild-type p53 (P<0.025). In addition, patients with p53
      mutations are more likely to develop recurrence (73%) compared with patients with
      wild-type p53 (33%; P<0.001). Other factors considered, including preoperative
      carcinoembryonic antigen level, bilobar distribution, and size of the lesion(s),
      did not show significant correlation with p53 status. These results suggest that
      p53 status might be an important prognostic indicator to predict the pattern and
      likelihood of treatment failure after hepatic resection.

PMID- 10589768
TI  - Circulating soluble Fas concentration in breast cancer patients.
AB  - Fas/Fas ligand (FasL) system, a major regulator of apoptosis, is involved in
      cancer cell death induced by the immune system and anticancer drugs. Fas is a
      cell-surface receptor that exists in two forms, transmembrane and soluble. The
      former induces apoptosis by ligation of FasL or agonistic anti-Fas antibody,
      whereas the latter inhibits Fas-mediated apoptosis by neutralizing its ligand. In
      this study, we examined circulating soluble Fas (sFas) concentration in 118
      healthy people, 162 primary and 71 recurrent breast cancer patients by ELISA. In
      the healthy group, men showed higher sFas concentrations than women (P<0.001). In
      both sexes, sFas levels increased with age, and the age-matched cutoff value was
      determined. The median sFas concentration in primary and recurrent cancer
      patients was 0.815 and 1.510 ng/ml, both of which were higher than in normal
      female controls (0.580 ng/ml; P = 0.024 and P<0.001, respectively). Among primary
      cancer patients, although no significant correlation was found between sFas
      concentration and clinical parameters other than menopausal status, high-sFas
      patients had a worse prognosis than low-sFas patients for both overall and
      disease-free survival (P = 0.013 and P = 0.032, respectively). The multivariate
      analysis confirmed that circulating sFas concentration was an independent
      prognostic indicator (P = 0.020 for overall survival, P = 0.025 for disease-free
      survival). We looked at the recurrent cancer patients, and sFas levels were
      higher in patients with liver metastasis compared with those with other recurrent
      sites (P = 0.010), and high-sFas patients showed a worse prognosis than low-sFas
      patients (P = 0.037). Our data demonstrate that, compared with healthy female
      controls, breast cancer patients, especially those with liver metastases, have
      higher circulating sFas levels. sFas may be useful once these results are
      confirmed by larger studies.

PMID- 10589769
TI  - Evaluation of soluble CD44v6 as a potential serum marker for head and neck
      squamous cell carcinoma.
AB  - In recent years, the measurement of soluble CD44 levels in the circulation of
      patients with malignant diseases has been introduced as a new and simple
      diagnostic tool for the detection of human cancer. The high CD44v6 expression in
      head and neck squamous cell carcinoma (HNSCC) would enable the use of soluble
      CD44v6 proteins present in the circulation of HNSCC patients as a marker of
      disease. In the present study, we determined CD44v6 plasma levels using a domain
      specific ELISA in healthy volunteers, non-cancer patients, and HNSCC patients
      before and after surgical removal of the tumor. A difference between the CD44v6
      plasma levels of HNSCC patients and controls could not be observed. Moreover,
      surgical removal of the tumor did not result in a reduction of the CD44v6 plasma
      level in the HNSCC patients. In addition, the spectrum of soluble v6-containing
      CD44 proteins present in the plasma of HNSCC patients and controls was determined
      by immunoprecipitation experiments, but again, tumor-related isoforms could not
      be distinguished in patient samples. Additional experiments to unravel the
      biological source of these circulating proteins indicated surprisingly that the
      v6-containing proteins present in the circulation of healthy individuals are only
      released in part, if at all, by activated lymphocytes or other nucleated blood
      cells. Most circulating CD44v6 proteins seem to be derived from the normal
      epithelial cell compartments, including breast cells, colon cells, and squamous
      cells. Taken together, these data do not support the use of soluble CD44v6 as a
      tumor marker in HNSCC or any other tumor type that has developed from tissues
      producing soluble isoforms.

PMID- 10589770
TI  - Importance of nuclear morphology in breast cancer prognosis.
AB  - The purpose of this study is to define prognostic relationships between computer
      derived nuclear morphological features, lymph node status, and tumor size in
      breast cancer. Computer-derived nuclear size, shape, and texture features were
      determined in fine-needle aspirates obtained at the time of diagnosis from 253
      consecutive patients with invasive breast cancer. Tumor size and lymph node
      status were determined at the time of surgery. Median follow-up time was 61.5
      months for patients without distant recurrence. In univariate analysis, tumor
      size, nuclear features, and the number of metastatic nodes were of decreasing
      significance for distant disease-free survival. Nuclear features, tumor size, and
      the number of metastatic nodes were of decreasing significance for overall
      survival. In multivariate analysis, the morphological size feature, largest
      perimeter, was more predictive of disease-free and overall survival than were
      either tumor size or the number of axillary lymph node metastases. This
      morphological feature, when combined with tumor size, identified more patients at
      both the good and poor ends of the prognostic spectrum than did the combination
      of tumor size and axillary lymph node status. Our data indicate that computer
      analysis of nuclear features has the potential to replace axillary lymph node
      status for staging of breast cancer. If confirmed by others, axillary dissection
      for breast cancer staging, estimating prognosis, and selecting patients for
      adjunctive therapy could be eliminated.

PMID- 10589771
TI  - Genetically fluorescent melanoma bone and organ metastasis models.
AB  - We report here the establishment and metastatic properties of bright, highly
      stable, green fluorescent protein (GFP) expression transductants of the B16 mouse
      malignant melanoma cell line and the LOX human melanoma line. The highly
      fluorescent malignant melanoma cell lines allowed the visualization of skeletal
      and multiorgan metastases after i.v. injection of B16 cells in C57BL/6 mice and
      intradermal injection of LOX cells in nude mice. The melanoma cell lines were
      transduced with the pLEIN expression retroviral vector containing the GFP and
      neomycin resistance genes. Stable B16F0 and LOX clones expressing high levels of
      GFP were selected stepwise in vitro in levels of G418 of up to 800 microg/ml.
      Extensive bone and bone marrow metastases of B16F0 were visualized by GFP
      expression when the animals were sacrificed 3 weeks after cell implantation.
      Metastases for both cell lines were visualized in many organs, including the
      brain, lung, pleural membrane, liver, kidney, adrenal gland, lymph nodes,
      skeleton, muscle, and skin by GFP fluorescence. This is the first observation of
      experimental skeletal metastases of melanoma, which was made possible by GFP
      expression. These models should facilitate future studies of the mechanism and
      therapy of bone and multiorgan metastasis of melanoma.

PMID- 10589772
TI  - Five novel immunogenic antigens in meningioma: cloning, expression analysis, and
      chromosomal mapping.
AB  - Tumorigenesis of meningioma has been associated with chromosome 22, most notably
      the NF2 gene, but additional genes have been implicated in meningioma
      development. Here, we report the identification of five novel immunogenic
      antigens expressed in meningioma. An expression library was generated from a
      meningioma that retained both copies of chromosome 22. Screening with autologous
      patient serum identified seven cDNA clones that were indicated by antigen
      antibody complexes. The clones were sequenced, and sequence comparison revealed
      that the seven clones represent five different genes, providing evidence that
      meningiomas express a spectrum of immunoreactive antigens, which were termed
      meningioma expressed antigens (MGEAs). One gene was identical with the connective
      tissue growth factor, one gene was in part homologous to an Alzheimer disease
      associated gene, and a third gene was in part identical to Homo sapiens
      molybdenum cofactor biosynthesis proteins A and C mRNA. One gene was partially
      homologous to previously reported cDNA sequences of unknown function, and the
      fifth gene showed no significant homologies to sequences deposited in databases.
      Using somatic hybrid mapping, three genes were localized on chromosome 6, and two
      genes were localized on chromosomes 3 and 17, respectively. To distinguish the
      MGEAs from the so-called natural autoantigenes, we also screened the library with
      12 sera from individuals without obvious disease. The clones identified by
      reactivity with normal sera were completely different from the clones identified
      by screening the same meningioma expression library with serum from the patient
      bearing the tumor. These data suggest that the newly identified MGEA genes may be
      useful for diagnosis and possibly therapy of meningioma.

PMID- 10589773
TI  - Deletion of chromosome 1p and loss of expression of alkaline phosphatase indicate
      progression of meningiomas.
AB  - Meningiomas are cytogenetically characterized by loss of one chromosome 22 as a
      typical primary aberration and progression-associated secondary chromosome
      changes, of which monosomy 1p is the most common. The aim of this study was to
      evaluate the significance of monosomy 1p and enzyme activity loss of tissue
      nonspecific alkaline phosphatase (ALPL), whose gene maps to chromosome 1p36.1
      p34, as parameters for the diagnosis of progression-prone meningiomas. We
      analyzed smear preparations of 56 meningiomas and additional paraffin sections of
      17 of the cases by two-color fluorescence in situ hybridization (FISH) using the
      D1Z1 and D1Z2 probes and by a metaphase cytogenetic analysis of 30 of these
      tumors. The results were compared to clinical and morphological parameters and
      the expression of ALPL. Smear preparations showed deletion of 1p36 in 27% of
      common-type, 70% of atypical (intermediate-type), and 100% of anaplastic
      meningiomas. Monosomy 1p, as detected by FISH or the karyotype, was strongly
      associated with complete loss of ALPL activity. Intermediate-type and anaplastic
      meningiomas of younger patients displayed an increasing rate of cells with
      trisomy 1q and relative loss of 1p. The highly significant correlation of FISH
      results and ALPL histochemistry with clinical parameters gives evidence of their
      strong prognostic relevance. The complete activity loss of ALPL and the
      immunologically detected loss of ALPL protein in areas of meningiomas with
      monosomy 1p indicate a cytogenetically undetectable inactivation of the
      homologous Alpl allele. The apparently homozygous loss of expression of ALPL
      supports the notion that Alpl is a candidate tumor suppressor gene in
      meningiomas.

PMID- 10589774
TI  - Androgen receptor gene alterations and chromosomal gains and losses in prostate
      carcinomas appearing during finasteride treatment for benign prostatic
      hyperplasia.
AB  - Finasteride is commonly used for the treatment of benign prostatic hyperplasia
      and has been suggested to prevent prostate cancer development. To gain insight to
      the molecular effects of finasteride on prostate cancer development, we studied
      six prostate cancers diagnosed during finasteride treatment for benign prostatic
      hyperplasia. Comparative genomic hybridization detected genetic alterations in
      four tumors (1-5 changes/tumor). Xq gains and 6q losses were the most common
      alterations. The recurrent Xq gains motivated us to study the involvement of the
      androgen receptor (AR) gene. One tumor with Xq gain had a 3-fold amplification of
      the AR gene, suggesting that tumor development in finasteride-treated patients
      may require increased AR copy number and expression, as has previously been shown
      for prostate cancers recurring during hormonal therapy. Furthermore, in another
      tumor, an Arg726Leu mutation of the AR gene was found. This mutation was also
      present in the germ-line DNA of the patient. Arg726Leu mutation has previously
      been reported to affect the transactivational properties of the AR. In summary,
      prostate cancers developing during finasteride therapy may have distinct
      biological properties, such as a low number of chromosomal alterations and
      frequent involvement of the AR gene. Further studies are needed to explore the
      role of germ-line AR mutations in these patients.

PMID- 10589775
TI  - A human prolactin antagonist, hPRL-G129R, inhibits breast cancer cell
      proliferation through induction of apoptosis.
AB  - Human breast cancer is the predominant malignancy and the leading cause of cancer
      death in women from Western societies. The cause of breast cancer is still
      unknown. Recently, the association between human prolactin (hPRL) activity and
      breast cancer has been reemphasized. Biologically active hPRL has been found to
      be produced locally by breast cancer cells that contain high levels of PRL
      receptor. A high incidence of mammary tumor growth has also been found in
      transgenic mice overexpressing lactogenic hormones. More importantly, it has been
      demonstrated that the receptors for sex steroids and PRL are coexpressed and
      cross-regulated. In this study, we report that we have designed and produced a
      hPRL antagonist, hPRL-G129R. By using cell proliferation assays, we have
      demonstrated that: (a) hPRL and E2 exhibited an additive stimulatory effect on
      human breast cancer cell (T-47D) proliferation; (b) hPRL-G129R possessed an
      inhibitory effect on T-47D cell proliferation; and (c) when antiestrogen (4-OH
      tamoxifen) and anti-PRL (hPRL-G129R) agents were added together, an additive
      inhibitory effect was observed. We further investigated the mechanism of the
      inhibitory effects of hPRL-G129R in four hPRLR positive breast cancer cell lines.
      We report that hPRL-G129R is able to induce apoptosis in all four cell lines in a
      dose-dependent manner as determined by the Terminal deoxynucleotidyl transferase
      mediated dUTP nick-end labeling assay. The apoptosis is induced within 2 h of
      treatment at a dose as low as 50 ng/ml. We hope that the hPRL antagonist could be
      used to improve the outcome of human breast cancer therapy in the near future.

PMID- 10589776
TI  - Antitumor activity of CEP-751 (KT-6587) on human neuroblastoma and
      medulloblastoma xenografts.
AB  - Neuroblastoma (NBL) and medulloblastoma (MBL) are tumors of the neuroectoderm
      that occur in children. NBL and MBL express Trk family tyrosine kinase receptors,
      which regulate growth, differentiation, and cell death. CEP-751 (KT-6587), an
      indolocarbazole derivative, is an inhibitor of Trk family tyrosine kinases at
      nanomolar concentrations. This study was designed to determine the effect of CEP
      751 on the growth of NBL and MBL cell lines as xenografts. In vivo studies were
      conducted on four NBL cell lines (IMR-5, CHP-134, NBL-S, and SY5Y) and three MBL
      cell lines (D283, D341, and DAOY) using two treatment schedules: (a) treatment
      was started after the tumors were measurable (therapeutic study); or (b) 4-6 days
      after inoculation, before tumors were palpable (prevention study). CEP-751 was
      given at 21 mg/kg/dose administered twice a day, 7 days a week; the carrier
      vehicle was used as a control. In therapeutic studies, a significant difference
      in tumor size was seen between treated and control animals with IMR-5 on day 8 (P
      = 0.01), NBL-S on day 17 (P = 0.016), and CHP-134 on day 15 (P = 0.034). CEP-751
      also had a significant growth-inhibitory effect on the MBL line D283 (on day 39,
      P = 0.031). Inhibition of tumor growth of D341 did not reach statistical
      significance, and no inhibition was apparent with DAOY. In prevention studies,
      CEP-751 showed a modest growth-inhibitory effect on IMR5 (P = 0.062) and CHP-134
      (P = 0.049). Furthermore, inhibition of growth was greater in the SY5Y cell line
      transfected with TrkB compared with the untransfected parent cell line expressing
      no detectable TrkB. Terminal deoxynucleotidyl transferase-mediated nick end
      labeling studies showed CEP-751 induced apoptosis in the treated CHP-134 tumors,
      whereas no evidence of apoptosis was seen in the control tumors. Finally, there
      was no apparent toxicity identified in any of the treated mice. These results
      suggest that CEP-751 may be a useful therapeutic agent for NBL or MBL.

PMID- 10589777
TI  - BAY 12-9566, a novel inhibitor of matrix metalloproteinases with antiangiogenic
      activity.
AB  - Matrix metalloproteinases (MMPs) have been implicated in tumor cell invasion,
      metastasis, and angiogenesis. BAY 12-9566, a novel, non-peptidic biphenyl MMP
      inhibitor, has shown preclinical activity on a broad range of tumor models and is
      currently in clinical development. The purpose of this study was to investigate
      the antiangiogenic activity of BAY 12-9566. In vitro, BAY 12-9566 prevented
      matrix invasion by endothelial cells in a concentration-dependent manner (IC50 =
      8.4x10(-7) M), without affecting cell proliferation. In vivo, oral daily
      administration of BAY 12-9566 (50-200 mg/kg) inhibited angiogenesis induced by
      basic fibroblast growth factor in the Matrigel plug assay, reducing the
      hemoglobin content of the pellets. Histological analysis showed a reduction in
      the amount of functional vessels within the Matrigel. We conclude that the MMP
      inhibitor BAY 12-9566 inhibits angiogenesis, a property that further supports its
      clinical development as an antimetastatic agent.

PMID- 10589778
TI  - Radiotherapy and dosimetry of 64Cu-TETA-Tyr3-octreotate in a somatostatin
      receptor-positive, tumor-bearing rat model.
AB  - 64Cu [T1/2 = 12.8 h; beta+ = 0.655 MeV (19%); beta- = 0.573 MeV (40%)] has shown
      promise as a radioisotope for targeted radiotherapy. It has been demonstrated
      previously that the somatostatin analogue 64Cu-TETA-octreotide (64Cu-TETA-OC,
      where TETA is 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid)
      significantly inhibited the growth of somatostatin receptor-positive CA20948 rat
      pancreatic tumors in Lewis rats (C. J. Anderson et al., J. Nucl. Med., 39: 1944
      1951, 1998). In this study, we evaluated the radiotherapeutic efficacy of a new
      64Cu-labeled somatostatin analogue, 64Cu-TETA-Tyr3-octreotate (64Cu-TETA-Y3
      TATE), in CA20948 tumor-bearing rats. A single dose of 15 mCi (555 MBq) of 64Cu
      TETA-Y3-TATE was shown to be more effective in reducing tumor burden than the
      same dose of 64Cu-TETA-OC. In multiple dose experiments, tumor-bearing rats were
      administered three doses of either 10 or 20 mCi (370 or 740 MBq) of 64Cu-TETA-Y3
      TATE at 48-h intervals. Rats given 3x10 mCi (3x370 MBq) showed extended mean
      survival times compared with rats given a single dose; however, no complete
      regressions occurred. Complete regression of tumors was observed for all rats
      treated with 3x20 mCi (3x740 MBq), with no palpable tumors for approximately 10
      days; moreover, the mean survival time of these rats was nearly twice that of
      controls. Toxicity was determined by physical appearance and hematological and
      enzyme analysis, which revealed no overt toxicity and only transient changes in
      blood and liver chemistry. Absorbed dose estimates showed the dose-limiting organ
      to be the kidneys. The radiotherapy results, along with absorbed dose estimates
      to target and clearance organs, confirm that 64Cu-labeled somatostatin analogues
      warrant continued consideration as agents for targeted radiotherapy.

PMID- 10589779
TI  - Synergy of topotecan in combination with vincristine for treatment of pediatric
      solid tumor xenografts.
AB  - Topotecan and vincristine were evaluated alone or in combination against 13
      independent xenografts and 1 vincristine-resistant derivative, representing
      childhood neuroblastoma (n = 6), rhabdomyosarcoma (n = 5), or brain tumors (n =
      3). Topotecan was given by i.v. bolus on a schedule found previously to be
      optimal. Drug was administered daily for 5 days on 2 consecutive weeks with
      cycles repeated every 21 days over a period of 8 weeks. Doses of topotecan ranged
      from 0.16 to 1.5 mg/kg to simulate clinically achievable topotecan lactone plasma
      systemic exposures. Vincristine was administered i.v. every 7 days at a fixed
      dose of 1 mg/kg. Given as a single agent, vincristine induced complete responses
      (CRs) in all mice bearing two rhabdomyosarcomas (Rh28 and Rh30) and some CRs in
      Rh12-bearing mice (57%) but relatively few CRs (<29%) in other tumors. As a
      single agent, topotecan induced CR in a low proportion of tumor lines. A dose
      response model with a logit link function was used to investigate whether the
      combination of topotecan and vincristine resulted in greater than expected
      responses compared with the activity of the agents when administered alone. Only
      CR was used to evaluate tumor responses. The combination resulted in
      significantly greater than expected CRs than individual agents in nine tumor
      lines (four neuroblastoma, three brain tumors, and two rhabdomyosarcomas).
      Similar event-free (failure) distributions were shown in SJ-GBM2 glioblastoma
      xenografts, whether vincristine was administered on day 1 or day 5 of each
      topotecan course. To determine whether the increased antitumor activity with the
      combination was attributable to a change in drug disposition, extensive
      pharmacokinetic studies were performed. However, little or no interaction between
      these two agents was determined. Toxicity of the combination was marked by
      prolonged thrombocytopenia and decreased hemoglobin. However, approximately 75
      and 80% of the maximum tolerated dose of each single agent, topotecan (1.5 mg/kg)
      or vincristine (1 mg/kg), could be given in combination, resulting in a
      combination toxicity index of approximately 1.5. These results show that the
      therapeutic effect of combining topotecan with vincristine was greater than
      additive in most tumor models of childhood solid tumors, and toxicity data
      suggest that this can be administered to mice with only moderate reduction in the
      dose levels for each agent.

PMID- 10589780
TI  - Enhanced antitumor activity of paclitaxel in combination with the anticarcinoma
      immunoconjugate BR96-doxorubicin.
AB  - The efficacy of chemotherapy has been improved by regimens that combine several
      cytotoxic drugs with different mechanisms of action and/or different dose
      limiting toxicities. Here we demonstrate clearly, and for the first time, that
      combined therapy using an anticarcinoma immunoconjugate, BR96-doxorubicin, and
      the cytotoxic drug paclitaxel results in a significant increase in antitumor
      activity over that of either agent alone. Synergistic activity was seen at doses
      of BR96-doxorubicin that were minimally active as single agents. A dramatic
      increase in regression rates was seen when a regimen that combined BR96
      doxorubicin and paclitaxel was used to treat both paclitaxel-sensitive and
      paclitaxel-insensitive carcinomas. Importantly, combined therapy resulted in
      increased antitumor activity against lung, colon, and breast tumors xenografted
      in athymic mice and large, paclitaxel-insensitive colon tumors xenografted in
      athymic rats that also express the Lewis(y) target antigen in normal tissues.

PMID- 10589781
TI  - A cell type-specific and gap junction-independent mechanism for the herpes
      simplex virus-1 thymidine kinase gene/ganciclovir-mediated bystander effect.
AB  - Tumor cells expressing the herpes simplex virus type 1 thymidine kinase (HSV-tk)
      gene are killed by nucleoside analogues such as ganciclovir (GCV). GCV affects
      not only the cells expressing HSV-tk but also neighboring cells that do not
      express the gene; this phenomenon commonly is called "bystander effect." GCV
      metabolites transfer via gap junctional intercellular communication (GJIC)
      accounts for the bystander effect in different cell lines, but other mechanisms
      have also been described. In this study, we analyzed the mechanisms of the
      bystander effect in two cell lines exhibiting different capacities of
      communication (DHD/K12 and 9L). The 9L cells exhibited a very good bystander
      effect, which was completely blocked by a long-term inhibitor of GJIC, 18 alpha
      glycyrrhetinic acid. DHD/K12 cells exhibited a moderate bystander effect that was
      not abolished by 18 alpha-glycyrrhetinic acid or 1-octanol, another strong
      inhibitor of GJIC. Interestingly, we also observed a bystander effect in cultures
      where HSV-tk-expressing DHD/K12 cells were physically separated from their
      untransfected counterparts but grown in the same medium. Moreover, the transfer
      of filtered conditioned medium from GCV-treated HSV-tk-expressing DHD/K12 cells
      to DHD/K12 parental cells induced a decrease of survival in a concentration
      dependent manner, suggesting that the bystander effect in this cell line was
      mediated by a soluble factor.

PMID- 10589782
TI  - Direct comparison of liposomal doxorubicin with or without polyethylene glycol
      coating in C-26 tumor-bearing mice: is surface coating with polyethylene glycol
      beneficial?
AB  - Sterically stabilized liposome is characterized by a surface coating of
      polyethylene glycol (PEG) or other polymers that can reduce opsonization of the
      liposome by plasma proteins. It has a higher plasma area under the concentration
      time curve (AUC), which is believed to correlate with better therapeutic
      efficacy. However, the presence of large molecules on the liposomal surface may
      reduce the interactions of liposomes with cells and hinder entry of liposomes
      into the tumor tissue. Using a stable liposomal system composed of distearoyl
      phosphatidylcholine/cholesterol, we examined the effect of PEG (Mr 2000) on the
      pharmacokinetics and on the efficacy of liposomal doxorubicin with C-26 syngeneic
      tumor model in BALB/c mice. The plasma AUC of liposomal doxorubicin with 6 mol-%
      PEG-modified distearoyl phosphatidylethanolamine (PEG-DSPE) was approximately
      twice that of liposomal doxorubicin without PEG at various dosages, regardless of
      whether the mice were tumor-bearing. Paradoxically, the group of mice treated
      with liposomal doxorubicin without PEG had higher tumor doxorubicin
      concentrations. The 72-h tumor AUC was 1.44 times that of liposomal doxorubicin
      with 6% PEG-DSPE. The tumor-accumulation efficiency (AUC(Tumor)/AUC(Plasma)) of
      liposomal doxorubicin without PEG was 0.87, and this was more than twice that of
      the liposomal doxorubicin with 6% PEG-DSPE (0.31). At a dose of 10 mg/kg,
      although both liposomal groups were better than the free drug group in terms of
      clinically relevant parameters, including toxicity, tumor shrinkage, and
      survival, there was no difference between the two liposomal drug groups. In this
      stable liposome system, surface coating with PEG offered no benefit for liposomal
      doxorubicin in the C-26 tumor model. To enhance the therapeutic index of
      liposomal doxorubicin, simply increasing plasma AUC by surface coating with PEG
      may not be satisfactory.

PMID- 10589783
TI  - The outcome of heregulin-induced activation of ovarian cancer cells depends on
      the relative levels of HER-2 and HER-3 expression.
AB  - Members of the epidermal growth factor receptor family of tyrosine kinases,
      including epidermal growth factor receptor, c-erbB-2 (HER-2), c-erbB-3 (HER-3),
      and c-erbB-4 (HER-4), can be coexpressed at different levels in nonhematopoietic
      tissues. Amplification and overexpression of HER-2 is found in approximately one
      third of cancers that arise in the breast and ovary. In our previous studies,
      heregulin (HRG) and anti-HER-2 antibodies inhibited proliferation, increased
      invasiveness, and enhanced tyrosine autophosphorylation of SKBr3 breast cancer
      cells that overexpressed HER-2. In the present report, the effects of HRG and
      anti-HER-2 antibody have been compared in six ovarian cancer cell lines. HRG
      inhibited anchorage-independent growth of SKOv3 cells that overexpressed HER-2
      (10(5) receptors/cell) but stimulated the growth of OVCA420, OVCA429, OVCA432,
      OVCA433, and OVCAR-3 cells that expressed lower levels of the receptor (10(4)
      receptors/cell). Thus, cell lines with a high level of HER-2 relative to HER-3 or
      HER-4 were growth inhibited, whereas cell lines with lower levels of HER-2 were
      growth stimulated by HRG. Stimulation or inhibition of clonogenic growth did not
      correlate with endogenous expression of HRG or with the impact of exogenous HRG
      on phosphorylation of HER-2, HER-3, or HER-4. Anti-HER-2 antibodies inhibited the
      growth of SKOv3 cells but failed to affect the growth of the other cell lines. In
      OVCAR-3 cells that had been transfected with HER-2 cDNA to increase expression to
      10(5) receptors/cell, HRG inhibited rather than stimulated growth. Conversely,
      when HER-2 expression by SKOv3 cells was downregulated by transfection of the
      viral E1A gene, HRG stimulated rather than inhibited growth. To evaluate the
      relative importance of HER-3 and HER-4, NIH 3T3 cells were cotransfected with HER
      2 and HER-3 or with HER-2 and HER-4. HRG inhibited the growth of cells with a
      high ratio of HER-2:HER-3, whereas HRG stimulated the growth of cells with low
      levels of the two receptors. In cells that express only HER-2 and HER-4, HRG
      stimulated the growth of cells that expressed HER-4 independent of HER-2 levels.
      Anti-HER-2 antibodies inhibited the growth of transfectants with high levels of
      HER-2 expression independent of HER-3 or HER-4 expression. In ovarian cancer
      cells that express all three receptors, the relative levels of HER-2 and HER-3
      appear to determine the response to HRG. Taken together, these studies support
      the concept that the level of HER-2 expression can modulate response to HRG,
      determining whether the response is stimulatory or inhibitory. In contrast,
      agonistic antibodies that bind to HER-2 alone inhibit anchorage-independent
      growth but fail to mimic HRG's ability to stimulate growth of cells with low HER
      2: HER-3 ratios.

PMID- 10589784
TI  - Expression of bisecting GlcNAc in pediatric brain tumors and its association with
      tumor cell response to vinblastine.
AB  - Increased expression of the bisecting GlcNAc has been correlated with tumor
      progression in several experimental tumor models. Its expression and function in
      brain tumors are, however, not yet known. In this study, we investigated
      expression of the bisecting GlcNAc structure in a series of pediatric brain
      tumors and its relationship to tumor response to vinblastine. A plant lectin (E
      PHA) that recognizes the bisecting GlcNAc structure was used for detection of
      this molecule in a total of 90 pediatric brain tumors and normal brain tissue
      specimens. Our results showed that, whereas E-PHA staining was undetectable in
      the normal brain tissue, pediatric brain tumor specimens exhibited different
      levels of reactivity. Lectin staining was particularly prominent in high-grade
      astrocytomas (73%) and ependymomas (72%). In astrocytomas, there was a positive
      correlation with the tumor grade, which suggests that the bisecting GlcNAc may be
      of particular interest as a tumor marker for diagnosis and/or prognosis. By using
      a human glioma cell culture model, we have found that treatment of these cells
      with E-PHA lectin enhances their sensitivity to vinblastine. E-PHA interacted
      directly with the drug transporter P-glycoprotein and inhibited its drug efflux
      function. In a drug-resistant glioma cell line transfected with the mdr1 gene,
      drug resistance was reversed by E-PHA. Our findings indicate that: (a) expression
      of the bisecting GlcNAc in pediatric brain tumors may have a potential relevance
      as a tumor marker; and (b) glioma response to chemotherapy may be modulated
      through the bisecting GlcNAc.

PMID- 10589785
TI  - The antiangiogenic agent linomide inhibits the growth rate of von Hippel-Lindau
      paraganglioma xenografts to mice.
AB  - The aim of this study was to ascertain the potential usefulness of the
      antiangiogenic compound linomide for treatment of von Hippel-Lindau (VHL)-related
      tumors. Paraganglioma tissue fragments obtained at surgery from a VHL type 2a
      patient were transplanted s.c. to male BALB/c nu/nu (nude) mice: (a) 2-3-mm
      fragments for "prevention" experiments; and (b) 2-3-mm fragments allowed to grow
      to 1 cm for "intervention" studies. Both groups received either 0.5 mg/ml
      linomide in drinking water or acidified water and were followed until tumor
      diameter reached 3 cm or for 4 weeks. In both the prevention and intervention
      experiments, a significant diminution of tumor size and weight was observed in
      the drug-treated animals. In vivo nuclear magnetic resonance analysis of tumor
      blood flow in linomide-treated animals showed localization of blood vessels
      almost exclusively to the periphery of the poorly vascularized tumors with a
      significant reduction of both vascular functionality and vasodilation.
      Histological examination of tumors from linomide-treated animals revealed marked
      avascularity. Treated animals also displayed a 2.4-fold reduction of tumor
      vascular endothelial growth factor mRNA levels. Taken together, our data indicate
      that in VHL disease, therapy directed at inhibition of constitutively expressed
      VEGF induction of angiogenesis by VHL tumors may constitute an effective medical
      treatment.

PMID- 10589786
TI  - Eradication of human medulloblastoma tumor xenografts with a combination of O6
      benzyl-2'-deoxyguanosine and 1,3-bis(2-chloroethyl)1-nitrosourea.
AB  - O6-Benzyl-2'-deoxyguanosine (dBG), a water-soluble inhibitor of O6-methylguanine
      DNA methyltransferase (MGMT), potentiates the efficacy of 1,3-bis(2-chloroethyl)
      1-nitrosourea (BCNU) against MGMT-positive, BCNU-resistant Daoy human
      medulloblastoma tumor xenografts in athymic mice (S. C. Schold et al., Cancer
      Res., 56: 2076-2081, 1996). Such potentiation was comparable to that observed for
      O6-benzylguanine, the prototype MGMT inhibitor that is currently undergoing
      clinical trials. In this study, we optimized the therapeutic effect of the dBG
      and BCNU combination against brain tumor xenografts without inducing substantial
      toxicity in the host by adjusting the doses of both compounds. dBG was escalated
      from 133 mg/m2 to 200 and 300 mg/m2, whereas corresponding doses of BCNU were
      reduced from 25 mg/m2 to 17 and 11 mg/m2, respectively. The growth delays of
      30.2, 38.4, and 22.3 days, respectively, observed for the above regimens suggest
      that the optimal drug combination is not achieved with maximum doses of dBG. In
      fact, the highest doses of dBG (300 mg/m2) contributed to more frequent BCNU
      related toxicities, despite the reduced BCNU dosage, and a reduction of the
      therapeutic effect. Toxicity was related to the depletion of MGMT activity in the
      gut of host mice and was manifested by edema, inflammation, and hemorrhage in the
      bowel wall by subsequent BCNU administration. With additional dosage adjustments,
      we found that tumor suppression of >90 days without toxicity was observed at 200
      mg/m2 dBG and 23 mg/m2 BCNU. At these doses, tumors were eradicated (regressed to
      an undetectable size for >90 days) in 8 of 12 animals. Thus, dBG is the first of
      the MGMT inhibitors to show a curative effect in combination with BCNU against a
      human central nervous system tumor xenograft in athymic mice.

PMID- 10589787
TI  - Pharmacokinetics of PK1 and doxorubicin in experimental colon tumor models with
      differing responses to PK1.
AB  - PK1 is a synthetic N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin (dox)
      conjugate currently undergoing Phase II evaluation in the United Kingdom. We have
      studied the activity of PK1 in three murine colon tumor models that differ in
      terms of morphology and vascularization in an attempt to determine which factors
      are most important in the tumor response to PK1. Vascular permeability was
      evaluated with Evans Blue, and pharmacokinetic studies in MAC15A and MAC26 used
      high-performance liquid chromatography to monitor both PK1 uptake and dox release
      in the tumors. Cathepsin B activity was assessed using a specific substrate. PK1
      (40 mg x kg(-1) dox equivalent) was significantly more effective than dox alone
      (10 mg x kg(-1)) was against MAC15A tumors, which possess enhanced perfusion and
      retention, but not against MAC26 tumors, although MAC15A was also responsive to
      PK1 when grown as avascular micrometastatic deposits in the lung. Pharmacokinetic
      studies showed similar levels of PK1 in both tumors. Peak tumor levels of
      released dox were 7-fold greater in the responsive MAC15A tumor (53 microg x ml(
      1)) compared with the less responsive MAC26 tumor (7.7 microg x ml(-1)) and more
      than 18-fold greater in MAC15A than when free dox was given. These differences in
      response correlated also with an increased lysosomal activity of cathepsin B.
      Calculated AUCs for intratumoral dox released were 431 microg x h x g(-1) and 775
      microg x h x g(-1) for MAC15A and MAC26, respectively. These AUCs are 4-fold and
      7-fold higher, respectively, than when dox is given alone. This study has shown
      that activity and the pharmacokinetics of PK1 and released dox are dependent on
      both the vascular properties and enzyme content of the tumors. These studies are
      likely to have clinical implications as aggressive tumors are known to have
      increased protease activity.

PMID- 10589788
TI  - Simplified production of a recombinant human angiostatin derivative that
      suppresses intracerebral glial tumor growth.
AB  - Angiostatin is an endogenous inhibitor of tumor neovascularization that inhibits
      the proliferation of endothelial cells. Production of sufficient quantities of
      biologically active angiostatin by the enzymatic cleavage of plasminogen has
      proven difficult in that it has delayed clinical testing. We have cloned,
      expressed, and purified a recombinant human angiostatin derivative (K1-3) using a
      mammalian expression system. Through the addition of a secretory signal and
      polyhistidine sequence tag, K1-3 can be purified from post-culture medium by
      simple column chromatography. Purified K1-3 protein is apparently folded in an
      active conformation, as evidenced by its ability to bind to lysine-Sepharose. In
      vitro, recombinant K1-3 significantly suppressed endothelial cell proliferation
      in a dose-dependent manner with an IC50 of 50 nM. Using an animal model of
      intracranial brain tumors in immune-competent rats, systemic administration of
      purified recombinant K1-3 resulted in up to 85% suppression of tumor growth (P =
      0.011). Growth suppression was accompanied by a 32% decrease (P = 0.01) in tumor
      neovascularization. This study demonstrates a simple method to produce a
      biologically active recombinant angiostatin derivative. The ability to suppress
      intracerebral tumor growth after systemic administration suggests that K1-3 is
      likely to have therapeutic value in the treatment of malignant glial tumors.

PMID- 10589789
TI  - Antagonistic effect of NK4, a novel hepatocyte growth factor variant, on in vitro
      angiogenesis of human vascular endothelial cells.
AB  - Hepatocyte growth factor (HGF), also known as scatter factor (SF), is known to
      act on cancer cells as well as endothelial cells and stimulate angiogenesis, thus
      playing an unwanted role in the development and progression of cancer. The
      current study examined the effects of a newly discovered HGF variant, NK4, on
      angiogenesis in vitro. Chemically generated NK4 (from recombinant human HGF/SF)
      was found to be able to inhibit HGF-induced activation (tyrosine phosphorylation)
      of the HGF/SF receptor cMET but was itself unable to activate cMET. Furthermore,
      NK4 was demonstrated to inhibit tubule formation from human umbilical vein
      endothelial cells that was induced by both HGF/SF and a HGF/SF-producing
      fibroblast (MRC5). Under the same settings, NK4 failed to increase tubular
      formation. NK4 had no effects on interleukin 8- and vascular endothelial growth
      factor-induced tubule formation. Using computer-assisted motion analysis, it was
      further shown that NK4 inhibited HGF-induced migration of human umbilical vein
      endothelial cells in a migration assay and in an endothelial wounding assay.
      These data show that NK4 is a complete antagonist to HGF. It inhibits HGF-induced
      endothelial movement and tubule formation. Thus, NK4 may have an important
      bearing on the control of cancer progression through its role in angiogenesis.
      Additional in vivo studies are warranted.

PMID- 10589790
TI  - Lysophosphatidic acid induces urokinase secretion by ovarian cancer cells.
AB  - Lysophosphatidic acid (LPA) is present at high concentrations in ascites from
      ovarian cancer patients and has potent mitogenic properties in vitro. Urokinase
      plasminogen activator (uPA), a critical component of the metastatic cascade, is
      also found at high concentrations in ovarian ascites and ovarian cancers, and the
      levels of uPA correlate inversely with prognosis. Because LPA stimulates the
      invasion of both hepatoma and lung cell lines, we investigated whether LPA could
      induce uPA secretion by ovarian epithelial cells and whether this process was
      associated with malignant transformation of ovarian epithelial cells. As
      indicated by zymography and Western blotting, physiologically relevant
      concentrations of LPA equivalent to those present in ovarian cancer ascites
      stimulated uPA secretion in the ovarian cancer cell lines OVCAR-3, SKOV-3, OVCA
      429, OVCA 432, and OVCA 433, but not from established normal ovarian epithelial
      (NOE) cells as indicated by normal epithelial cell lines NOE 033 and NOE 035 or
      from SV40 large T antigen-immortalized normal epithelial cell lines IOSE 29 and
      IOSE 80. 18:1 LPA, but not 18:0 LPA, 16:0 LPA, or lysophosphatidylcholine,
      induced uPA secretion, concordant with previous studies of LPA receptor
      selectivity. Expression of the edg-2 LPA receptor was not consistently different
      between normal epithelial cell lines and ovarian cancer cell lines. In contrast,
      expression of the edg-4 LPA receptor was markedly increased in ovarian cancer
      cell lines as compared with NOE cell lines, raising the possibility that the edg
      4 LPA receptor contributes to the ability of ovarian cancer cells but not NOE
      cells to produce uPA in response to LPA. LPA induced a consistent increase in uPA
      promoter activity and mRNA levels, suggesting that increased uPA production is,
      at least in part, transcriptional. Malignant transformation may alter LPA-induced
      cell activation by altering the pattern of LPA receptors present and may possibly
      lead to more aggressive behavior by up-regulating LPA-mediated uPA secretion and
      stimulating extracellular stromal breakdown and invasion.

PMID- 10589791
TI  - Constitutive and inducible interleukin 8 expression by hypoxia and acidosis
      renders human pancreatic cancer cells more tumorigenic and metastatic.
AB  - The role and regulation of interleukin 8 (IL-8) in the growth and metastasis of
      SG, FG, and L3.3 variants derived from COLO 357 human pancreatic cancer cells
      were determined. After orthotopic implantation in the pancreas of nude mice, SG
      cells produced the smallest tumors, whereas L3.3 cells produced the largest
      tumors. SG cells produced no liver metastasis, whereas FG cells produced numerous
      liver metastases, and L3.3 cells produced more and larger liver metastases. In
      vitro analysis of IL-8 expression indicated that SG cells expressed the lowest
      level of IL-8 gene expression as determined by both Northern blot analysis and
      ELISA, whereas L3.3 cells expressed the highest level of IL-8.
      Immunohistochemical analysis of tumor lesions indicated that IL-8 overexpression
      was predominant in the regions surrounding necrotic areas, where cells were
      exposed to low oxygen tension (hypoxia) and acidic pH. In vitro treatment of FG
      tumor cells with hypoxia or acidosis led to an increased expression of IL-8. To
      directly determine the role of IL-8 in the growth and metastasis of pancreatic
      cancer, FG cells were transfected with IL-8 sense or antisense oligonucleotide
      expression vectors. The neo-resistance gene-transfected FG cells were used as
      controls. Decreased IL-8 expression after transfection with IL-8 antisense
      oligonucleotide expression vector retarded the growth of FG cells in mice after
      intrapancreatic implantation, which correlated with decreased tumor angiogenesis.
      Our data demonstrated that hypoxia and acidosis contribute to the overexpression
      of IL-8, which in turn plays an important role in tumor angiogenesis and
      contributes significantly to the aggressive biology of human pancreatic cancer.

PMID- 10589792
TI  - Correspondence re: S. Shimoyama et al., increased serum angiogenin concentration
      in colorectal cancer is correlated with cancer progression. Clin. Cancer Res., 5:
      1125-1130, 1999.

PMID- 10589793
TI  - Correspondence re: G. Tallini et al., RET/PTC oncogene activation defines a
      subset of papillary thyroid carcinomas lacking evidence of progression to poorly
      differentiated or undifferentiated tumor phenotype. Clin. Cancer Res., 4:287-294,
      1998.

PMID- 10589795
TI  - Nonlinear EEG analysis in early Alzheimer's disease.
AB  - Nonlinear EEG analysis attempts to characterize the dynamics of neural networks
      in the brain. Abnormalities in nonlinear EEG measures have been found repeatedly
      in Alzheimer's disease (AD). The present study was undertaken to investigate
      whether these abnormalities could already be found in the early stage of AD. In a
      representative sample of 49 community-dwelling elderly, Alzheimer's disease was
      diagnosed in 7 subjects. Correlation dimension (D2) and nonlinear prediction were
      measured at 16 electrodes and in two different activational states. Also, 10
      surrogate data sets were generated for each EEG epoch in order to investigate the
      presence of nonlinear dynamics. Differences between nonlinear statistics derived
      from original and from surrogate data sets were expressed as Z-scores. We found
      lower D2 and higher predictability in the demented subjects compared to the
      normal subjects. The results obtained with the Z-scores pointed to changed
      nonlinear dynamics in frontal and temporal areas in demented subjects. However,
      the major differences between demented and healthy subjects are not due to
      nonlinearity. From this it appears that linear dynamics change first in the
      course of AD, followed by changes in nonlinear dynamics.

PMID- 10589794
TI  - Survey of the management of patients with minor head injuries in hospitals in
      Sweden.
AB  - OBJECTIVES: Development of guidelines for quality assurance in head injury care
      has to be based on knowledge about how today's management is organized. To
      address the need for guidelines in minor head injury (MHI), the authors studied
      management practice in Sweden. METHODS: We performed a cross-sectional mail
      survey including all 76 hospitals treating head-injured patients. The
      questionnaire outlined present management practice in MHI; including routines for
      clinical and radiological examinations, in-hospital observation, discharge
      criteria and follow-up. RESULTS: The initial evaluation is frequently performed
      by inexperienced physicians. The level of consciousness is assessed according to
      the Swedish Reaction Level Scale or the Glasgow Coma Scale in 96% of the
      hospitals. Routine computerized tomography is used in 4%. Skull radiography is
      not routinely performed. Eighty percent of the hospitals discharge selected
      patients without in-hospital observation and most (93%) offer no routine follow
      up. CONCLUSIONS: This survey shows a variation in the management of MHI in
      hospitals in Sweden. Routines for assessment of consciousness level are
      satisfactory, but CT scan for detection of skull fracture and early diagnoses of
      intracranial complications is usually not performed. Guidelines should be based
      on present routines including decision rules for CT scan.

PMID- 10589797
TI  - Increased type III procollagen in serum and skin of patients with amyotrophic
      lateral sclerosis.
AB  - OBJECTIVES: Collagen abnormalities of skin have been reported in patients with
      amyotrophic lateral sclerosis (ALS). However, little is known concerning the
      aminoterminal propeptide of type III procollagen (PIIIP) and type III collagen in
      ALS. The aim of this study is to measure PIIIP, a precursor form of type III
      collagen, in skin and serum of ALS. MATERIAL AND METHODS: We studied PIIIP
      immunoreactivity of skin and measured serum levels of PIIIP in ALS patients, and
      the results were compared with those of control subjects. RESULTS: Collagen
      bundles in the dermis of ALS were immunohistochemically strongly positive for
      PIIIP as compared with those of controls. The optical density of PIIIP
      immunostaining reactivity in ALS patients was significantly higher than in
      controls, and was significantly increased with duration of illness. Serum PIIIP
      levels in patients with ALS were significantly increased as compared with those
      in diseased control subjects and those in healthy control ones, and were
      positively and significantly associated with duration of illness. There was an
      appreciable positive correlation between concentrations of serum PIIIP and the
      density of PIIIP immunoreactivity of skin in ALS patients. CONCLUSION: These data
      suggest that a metabolic alteration of PIIIP may take place in the skin of ALS
      and the increased levels of serum PIIIP may reflect the increased PIIIP
      immunoreactivity of skin in ALS.

PMID- 10589796
TI  - Cerebellar activation during ataxic gait in olivopontocerebellar atrophy: a PET
      study.
AB  - OBJECTIVE: To investigate the possible abnormal regional brain metabolism during
      ataxic gait in olivopontocerebellar atrophy (OPCA), and to evaluate the response
      of the cerebellar subregions to instability during bipedal gait. MATERIAL AND
      METHODS: On 9 patients with OPCA in early phase and on 10 age-matched normal
      subjects, we performed positron emission tomography (PET) with 2-[18F]fluoro-2
      deoxy-D-glucose (FDG) under two different conditions: supine resting and 30 min
      treadmill walking. RESULTS: Both in normals and in patients with OPCA, the FDG
      uptake in the walking state (Uwalk) was significantly greater than that in the
      resting state (Urest) in the pyramis, declive-folium-tuber and culmen of the
      cerebellar vermis, and in the thalamus. In the patients, the Uwalk was also
      significantly greater than the Urest in the posterior lobe of cerebellar
      hemisphere and in the pons and midbrain. In the pyramis, the activation ratio (=
      Uwalk/Urest) of the patients was significantly lower than that of the normals.
      CONCLUSIONS: We considered that these findings reflect the pathophysiology of
      ataxic gait in OPCA patients and the compensatory mechanism for the instability
      during ataxic gait.

PMID- 10589798
TI  - Body temperature correlates with functional outcome and the lesion size of
      cerebral infarction.
AB  - INTRODUCTION: Experimental studies have demonstrated that mild hyperthermia
      exacerbates ischemia-induced neuronal injury. MATERIAL AND METHODS: We examined
      the relationship between body temperature and functional outcome in 183 patients
      suffering from cerebral infarction, and admitted within 24 h from the onset of
      stroke. Patients' functional capacities in daily life were evaluated by Rankin's
      score before the attack (RS0), on the day of admission (RS1), and 3 months after
      the onset of stroke (RS90). RESULTS: RS90 showed an independent correlation with
      RS0, RS1, age, infarct size and maximum body temperature recorded within the
      first 7 days from the onset of stroke by multivariate analysis. History of
      previous cerebrovascular accidents, atrial fibrillation, hemorrhagic
      transformation, infection, and a hypothalamic lesion showed significant
      associations with RS90 by the Mann-Whitney U-test, but not by multivariate
      analysis. Infarct size correlated with body temperature, atrial fibrillation, and
      hemorrhagic transformation. CONCLUSION: Body temperature correlated well with
      both functional outcome and infarct size in patients with an acute cerebral
      infarction.

PMID- 10589799
TI  - Polymorphonuclear leukocyte elastase in patients with stroke.
AB  - INTRODUCTION/OBJECTIVES: Polymorphonuclear leukocytes (PMNL) are involved in the
      pathogenesis of acute cerebral ischemia and atherosclerosis. Elastase is one of
      the proteolytic enzymes released by activated PMNL. We evaluated whether plasma
      levels of elastase-inhibitor complexes (EIC) are related to acute cerebral damage
      or with extension of carotid atherosclerosis in patients with stroke. METHODS:
      Plasma levels of EIC were determined in 44 patients during acute and chronic
      phases of stroke. We recorded in all patients vascular risk factors, clinical
      severity on admission, infarct volume, and extension of carotid atherosclerosis
      using B-mode ultrasound exam. RESULTS: EIC levels were not different between
      acute and chronic phases of stroke. Eleven patients (25%) had increased values of
      EIC. On multiple regression analysis diabetes, dislipemia, and coronary disease
      were predictors of abnormal EIC levels. EIC levels were not related to
      neurological severity on admission, infarct volume, or carotid atherosclerosis.
      CONCLUSION: EIC levels in stroke patients are associated to the presence of
      vascular risk factors and may reflect cellular inflammatory aspects of chronic
      vessel disease. However, whether elastase contributes to the development of
      carotid atherosclerosis in patients with stroke remains unknown.

PMID- 10589801
TI  - Gd-DTPA enhancement of cranial nerves on MR imaging. Neoplastic lesions.
AB  - This study describes a radiological finding - enhancement of cranial nerves and
      correlates patients' clinical findings and outcome. Seven patients with
      enhancement of cranial nerves on postcontrast MR were retrospectively reviewed.
      Cranial nerves having contrast enhancement were optic, oculomotor, trigeminal,
      facial, acoustic, glossopharyngeal, vagus and accessory nerves. The patients'
      underlying diseases were malignant lymphoma (3), leukemia (1 patient) and
      metastatic tumor (2 lung, 1 rectum cancer). Most of the cases (4 out of 7)
      developed parenchymatous lesion later. Seven patients had CSF cytology study,
      positive in 3 cases, negative in 4 cases at first spinal tap. In 1 case (case 5)
      of negative cytology, elevated CEA (carcinogen antibody) was noted. In 2 cases,
      initial symptoms were sudden hearing loss. Autopsy was done for 1 case of
      metastatic tumor involving cranial nerves. Contrast MR is a useful examination
      for depicting cranial nerve involvement with neoplastic change.

PMID- 10589800
TI  - Vascular risk factors for atherosclerotic lesions of the middle cerebral artery
      detected by magnetic resonance angiography (MRA).
AB  - OBJECTIVES: To examine the relationship between atherosclerotic lesions of the
      middle cerebral artery (MCA) detected on MRA and vascular risk factors. MATERIAL
      AND METHODS: We retrospectively assessed 279 patients (mean age, 69.0+/-11.3
      years) who visited the Department of Neurology of Masuda Red Cross Hospital and
      underwent three-dimensional, time-of-flight MRA of the head between January 1996
      and October 1998. Cases of cerebral embolism and internal carotid artery
      occlusion were excluded. Diagnoses were cerebral infarction (n = 152) and others
      (n = 127). We evaluated stenotic or occlusive lesions of the MCA (M1 portion),
      using MRA. Age, sex, history of hypertension, HbA1c, total cholesterol, fasting
      triglyceride, high density lipoprotein, lipoprotein(a), blood pressure,
      hematocrit, smoking and left ventricular hypertrophy (LVH) on ECG were included
      in the analysis. RESULTS: 36 patients (12.9%) had stenotic or occlusive lesions
      of the MCA on MRA. Univariate analysis showed that age, hypertension and HbA1c
      were significantly correlated with MCA lesions. Multiple logistic regression
      analysis showed that HbA C and hypertension were significant and independent
      predictors for MCA lesions. CONCLUSION: Hypertension and high serum HbAlc levels
      may contribute to the development of atherosclerotic lesions of the MCA in
      Japanese people.

PMID- 10589802
TI  - Cerebral hemorrhage after systemic fibrinolysis in a patient with severe carotid
      artery stenosis.
AB  - Despite the beneficial effect of systemic fibrinolysis in treatment within 3
      hours from ischemic stroke onset, the unpredicted occurrence of intracerebral
      hemorrhage remains a risk from such therapy. Few data exist defining patients at
      risk for this outcome. We report clinical and neuropathological data on a patient
      fulfilling NINDS rt-PA study and ECASS-2 inclusion criteria with an acute stroke
      due to high-grade carotid artery stenosis and preceded by amaurosis fugax. He
      died from an intracerebral hemorrhage after systemic fibrinolysis. The fatal
      outcome adds support to recommendations that rapid Doppler-sonographic evaluation
      of the extra- and intracranial vascular status be undertaken before systemic rt
      PA is implemented in acute ischemic stroke.

PMID- 10589803
TI  - Non-ketotic hyperglycemia in a young woman, presenting as hemiballism-hemichorea.
AB  - We report a 22-year-old girl presenting with acute onset left sided hemiballism
      hemichorea (HH) and non-ketotic hyperglycemia (NKH). Initial brain CT revealed
      faint hyperdensities, sharply confined to the contralateral nucleus caudatus and
      putamen. Sequential MRI investigations yielded increasing hypersignal intensities
      on T1-weighted images and resolving hypodensities on T2-weighted images of the
      right striatum, leaving small sequelae in the head of the right caudate nucleus.
      NKH is an unusual cause of HH. The abnormalities seen in neuroimaging are rare,
      but seem to be quite specific to this syndrome. We give an update on current
      literature regarding the possible pathophysiological processes underlying this
      specific clinical entity.

PMID- 10589804
TI  - Specific primer for AP-PCR identification of Actinobacillus
      actinomycetemcomitans.
AB  - We used arbitrarily-primed polymerase chain reaction (AP-PCR) to design and
      construct a specific primer pair for the identification of Actinobacillus
      actinomycetemcomitans. We analyzed 25 DNA samples of A. actinomycetemcomitans
      isolated from patients with localized-juvenile periodontitis. From 90 AP-PCR
      primers screened, one amplification product was selected, cloned in pCR II
      vector, and sequenced. The sequence was used to design a single pair of specific
      primers. The sequence was compared with GenBank entries using BLAST and showed no
      significant matches. PCR amplification using the new primer pair AA1416 produced
      a characteristic 3.5-Kb band in all A. actinomycetemcomitans DNAs tested. Primer
      pair AA16S produced no or different amplicon profiles using DNA samples from
      bacterial species other than A. actinomycetemcomitans. Our results show that this
      single primer pair AA1416 can be used in PCR to identify A. actinomycetemcomitans
      isolates and differentiate them from other periodontal bacteria. These approaches
      appear promising in facilitating laboratory identification and taxonomy of
      putative periodontopathogens.

PMID- 10589805
TI  - Polymorphic cytokine genotypes as markers of disease severity in adult
      periodontitis.
AB  - The distributions of the bi-allelic interleukin-1beta+3953 and tumor necrosis
      factor-alpha-308 genotypes were determined in 20 patients with advanced adult
      periodontitis, 20 patients with plaque associated gingivitis, and 45 referent
      population subjects. A significant increase in IL-1beta+3953 allele 2 frequency
      was found in patients with advanced periodontitis compared to referent subjects
      (the Fisher exact test; p=0.013). Furthermore, the frequency of TNF-alpha-308
      allele 1 was significantly greater in patients with advanced disease compared to
      those with plaque associated gingivitis (the Fisher exact test; p=0.014). No
      significant correlation was observed between genotype and cytokine production in
      these patient populations.

PMID- 10589806
TI  - Repeated local metronidazole-therapy as adjunct to scaling and root planing in
      maintenance patients.
AB  - The purpose of this investigation was to evaluate the effect of local antibiotic
      therapy with metronidazole adjunctively to scaling and root planing (SRP) versus
      mechanical treatment alone. 30 maintenance-patients were included in this single
      blind study. The subjects had to comply with the following criteria: 2 non
      adjacent sites with a probing depth > or =6 mm with bleeding on probing in
      separate quadrants, no periodontal therapy within the last 3 months, and no
      antibiotic therapy within the last 6 months. After randomization, the study sites
      were assigned to one of the following 2 treatments: SRP plus subgingival
      application of metronidazole 25% dental gel (Elyzol) 5x during 10 days (test
      site) or SRP alone (control site). Subgingival microbiological samples were taken
      prior to, and 21 days and 3 months after scaling. The samples were analyzed with
      a commercial chair-side ELISA (Evalusite) for Porphyromonas gingivalis,
      Prevotella intermedia and Actinobacillus actinomycetemcomitans. Probing pocket
      depth (PPD), attachment level (AL) and bleeding on probing (BOP) were recorded at
      baseline and 3 months later. PPD reduction and AL-gain were statistically
      significant (p<0.001) after both treatments. However, there were no statistically
      significant differences between them. The same observation was made for BOP. P.
      gingivalis was reduced significantly after both treatments without statistically
      significant differences. P. intermedia was reduced significantly only after SRP.
      A. actinomycetemcomitans was not reduced significantly after either treatment. In
      conclusion, the repeated local application of metronidazole as an adjunct to SRP
      and the mechanical treatment alone showed similar clinical and microbiological
      effects without statistically significant differences with the exception of P.
      intermedia.

PMID- 10589807
TI  - Influence of different curette insertion depths on the outcome of non-surgical
      periodontal treatment.
AB  - This study was undertaken to compare the effects of scaling and root planing
      (Sc/RP) performed from approximately 1 mm coronal to (test Sc/RP) or at the
      bottom of (control Sc/RP) the probeable pocket to the gingival margin. 2 male and
      5 female patients with moderate to severe periodontitis participated in the
      study. Initial examination was performed with respect to probing pocket depth
      (PPD) and probing attachment level (PAL) using a pressure-controlled periodontal
      probe and stents. The patients received repeated instruction in oral hygiene, and
      their plaque control reached an excellent level. Baseline examination including
      PPD and PAL measurements was then performed. Following the baseline examination,
      single-rooted teeth in 1 quadrant of each dentition were randomly selected and
      subjected to the test Sc/RP (test teeth) or control Sc/RP (control teeth). The
      PPD and PAL were measured 1 and 3 months following Sc/RP. It was demonstrated
      that: (i) the PPD reduction following Sc/RP was larger at the sites with
      initially deep pockets than at the sites with shallow pockets; (ii) the mean PPD
      reduction at the sites with an initial PPD > or =3.5 mm was significantly larger
      in the control teeth than in the test teeth; (iii) there was a significant PAL
      gain in the initially deep pockets but not in the initially shallow pockets; (iv)
      the PAL gain in the initially shallow pockets was significantly larger in the
      control teeth than in the test teeth. In the treatment of periodontitis, trauma
      caused by Sc/RP to the most coronal part of the connective tissue attachment
      seems to be of minor importance compared to the effective removal of subgingival
      deposits.

PMID- 10589808
TI  - Androgen metabolism in response to oestradiol-17beta and progesterone in human
      gingival fibroblasts (HGF) in culture.
AB  - The modulation of androgen metabolism by oestrogen and progesterone in HGF has
      been investigated, to elucidate hormone modulatory mechanisms, in periodontal
      disease presentation and healing responses. Duplicate incubations of HGF were
      performed in Eagle's MEM for 24 h with either 14C-testosterone/14C-4
      androstenedione as substrate and serial concentrations of oestradiol-17beta, or
      progesterone (0.01-50 microg/ml). The effect of the anti- oestrogen tamoxifen on
      the action of oestradiol in HGF was also investigated. The medium was analysed
      and quantified for steroid metabolites. When 14C-testosterone was used as
      substrate, oestradiol stimulated the synthesis of 5alpha-dihydrotestosterone
      (DHT), 4- androstenedione (4-A) and the diols by 35%, 25% and 2-10-fold
      respectively (n=4; p<0.01), at optimal concentrations. Tamoxifen inhibited the
      stimulatory effects of oestradiol. Similarly, when 14C-4-androstenedione was used
      as substrate, there were 60% and 2-fold increases in the yields of DHT and
      testosterone respectively, with significant increases in the formation of the
      diols in response to oestradiol (n=4; p<0.001). Progesterone inhibited the
      formation of DHT and 4-A by 10-fold and 3-5-fold at effective inhibitory
      concentrations (n=4; p<0.001), when 14C- testosterone was used as substrate.
      Similarly, when 14C-4-androstenedione was used as substrate, progesterone
      decreased the yields of testosterone, DHT and the diols substantially. These
      results reinforce the potentially anabolic and catabolic roles of oestradiol and
      progesterone, respectively. This may partly explain the modulatory mechanisms
      involved, in periodontal disease presentation during altered hormonal states and
      healing responses in the inflamed periodontium.

PMID- 10589809
TI  - Longitudinal human serum antibody responses to outer membrane antigens of
      Actinobacillus actinomycetemcomitans.
AB  - We hypothesize that serum antibody responses to antigens of a periodontopathogen
      would vary temporally and that the specificity of these host antibodies would
      relate to infection and disease activity. To test the hypothesis, we obtained
      between 6 and 13 serum samples from Actinobacillus actinomycetemcomitans (Aa)
      positive (serological and microbiological) periodontitis patients at time points
      between 18 and 42 months into the study, and evaluated specific antibody
      responses to outer membrane antigens (OMA) of Aa strain Y4. Sera from these
      patients detected 22 different OMA. Early-onset (EOP; n=7) and adult (AP; n=11)
      periodontitis patients responded to 35% and 41% of the OMA, respectively. 2 of 9
      sera from healthy subjects detected no antigens and 7/9 sera detected 7% of the
      OMA (p<0.0001 versus EOP and AP). The frequency of antibody responses to the 17
      kDa antigen were similar between diseased, infected patients and the uninfected,
      normal subjects, suggesting that it may be stimulated as a cross-reactive
      antigen. Antibody to the 28, 38, and 90 kDa antigens were significantly more
      common in diseased patients (>90%) versus normal subjects (p<0.01, p<0.002, and
      p<0.002, respectively) and were unique among diseased, infected patients, which
      may be indicative of infections with Aa. A 65 kDa antigen showed an increased
      frequency of reaction in the AP versus the EOP (p=0.01) patients, which
      exemplified a potential distinction in response to Aa between adult and early
      onset disease classifications. Seventeen of 22 OMA could be detected in every
      sample from at least one patient. Longitudinal samples from seropositive EOP and
      AP reacted 80-100% of the time with the 17, 28, and 100 kDa antigens. Finally,
      five antigens of 15, 38, 58, 65, and 79 kDa were detected in 33-83% of the
      seropositive patients; however, antibody to these OMA reacted variably at
      different sampling points, suggesting some antigenic response diversity over
      time.

PMID- 10589810
TI  - Clinical effects of root instrumentation using conventional steel or non-tooth
      substance removing plastic curettes during supportive periodontal therapy (SPT).
AB  - Although root instrumentation has been accepted as the most important cause
      related treatment of periodontal diseases, repeated scaling and root planing may
      over time result in substantive loss of tooth substance and increased sensitivity
      of the teeth. In an effort to minimize these side effects of therapy, non-root
      substance removing curettes have been developed. However, the clinical effects of
      such plastic curettes with regard to the control of the periodontal infection has
      not yet been established. The aims of this study were, therefore, to compare the
      effects of root instrumentation using plastic curettes (Universal Perio Soft
      Scaler, Hawe-Neos Dental, Bioggio, TI, Switzerland) versus conventional steel
      curettes on the periodontal conditions during supportive periodontal therapy. 40
      subjects participated in this parallel, randomized, double blind, prospective
      longitudinal clinical study following active peridontal therapy. 20 subjects
      served as a control group and were treated with conventional steel curettes
      during a supportive periodontal care visit (SPT). The other 20 subjects, the
      experimental group, were treated using plastic curettes during a similar SPT
      visit. Clinical parameters, such as bleeding on probing (BOP) and probing pocket
      depth (PPD), were assessed at baseline and 3-6 months later at the next regular
      SPT visit. In addition, the BOP percentage was determined 10 days following
      baseline. The results showed that there were no statistically significant
      differences between the 2 treatment modalities regarding BOP and PPD at any
      observation time. Both treatments were effective in reducing the BOP percentage
      which ranged from 17-42% at baseline by about 40% after 10 days (mean BOP
      baseline: 26%, mean BOP after 10 days: 16%). This clinical study suggests that
      non-root substance removing curettes may be valuable instruments for
      periodontally treated patients during maintenance care, thus minimizing trauma on
      the hard structures of the teeth.

PMID- 10589811
TI  - Estradiol enhances the production of mineralized nodules by human periodontal
      ligament cells.
AB  - A primary objective in the treatment of periodontal disease is the regeneration
      of the mineralized and soft connective tissue. PDL cells produce mineralized
      nodules in vitro which is one of the important functions of PDL cells for
      regenerative therapy. The purpose of this study was to investigate the effects of
      estradiol on mineralized nodule formation by human PDL cells. PDL cells were
      obtained from healthy donors and maintained in DMEM with 10% fetal bovine serum.
      Serum-free medium was used when the effects of estradiol were tested. ALP
      activity in the supernatant of cells disrupted by sonication was analyzed
      spectrophotometrically. The formation of mineralized nodules was assessed by
      staining the PDL cells with alizarine red and counting the number of nodules. at
      Estradiol 20 ng/ml significantly enhanced the ALP activity and mineralized nodule
      formation compared to the control. These results suggested that estrogen status
      may modify the regenerative activity of periodontal tissue.

PMID- 10589812
TI  - Comparison of video and written instructions for plaque removal by an
      oscillating/rotating/reciprocating electric toothbrush.
AB  - A previous crossover study showed that a watch-and-follow instructional video
      improved plaque removal by an electric toothbrush compared to the use of the
      instructional leaflet. This study employed a parallel design to assess the value
      of an instructional video for plaque removal by a new model
      oscillating/rotating/reciprocating electric toothbrush. 2 groups of 26 dentate
      subjects with average oral hygiene, who had never used an electric toothbrush,
      participated in this single blind, randomised parallel group designed study. On
      day 1 of the study, subjects received a professional prophylaxis to remove all
      plaque. Oral hygiene measures were then suspended and subjects returned on day 3
      when a prebrushing plaque score was recorded by plaque index and area. Subjects
      withdrew and either read the manufacturers instructional leaflet (group L) or
      observed the instructional video (group V). Groups L and V then performed
      toothbrushing with toothpaste for 2 minutes and with group V brushing in time
      with the instructional video. Post-brushing plaque indices and areas were then
      recorded. Whole mouth, lingual, upper, lower, anterior and posterior but not
      buccal % reductions in plaque index and area were significantly greater in group
      V compared to group L. % plaque removal was also significantly greater by area at
      mid and distal sites but not mesial sites. Whole-mouth plaque reductions were 10%
      greater in group V but reached >15% at lingual surfaces. Within group differences
      in plaque removal at paired sites e.g., buccal/lingual, remained similar,
      suggesting that further improvement could be achieved by modifying the video to
      devote more time to the difficult-to-clean areas. In conclusion, in the early
      period of learning the use of an electric toothbrush, plaque removal can be
      improved by using an instructional video. Such watch-and-follow video routines
      could be extended to other areas of oral hygiene practices.

PMID- 10589813
TI  - GCF levels of MMP-3 and MMP-8 following placement of bioresorbable membranes.
AB  - Matrix metalloproteinases (MMPs) are responsible for remodeling and degrading
      extracellular matrix and basement membrane components. MMP-3 and -8 levels were
      assessed in this study during the early healing phase following a guided tissue
      regeneration (GTR) procedure. 32 patients, having 2 or 3 walled intrabony defects
      of PD > or =6 mm, were stratified into 2 groups on the basis of age, sex, smoking
      status and disease severity. All intrabony defects were treated using the
      resorbable Guidor membrane but only 1 group of patients was given a pre-operative
      dosage of antibiotic (3 g amoxycillin). GCF samples for the quantification of MMP
      3 and -8 levels were obtained from the intrabony site where a membrane was placed
      (membrane site), from the non-adjacent site on the adjacent tooth which was
      involved in the surgical flap (surgical control site), and from a healthy site
      (healthy) on the contralateral side. The GCF samples taken at baseline, 1 week, 4
      weeks and 3 months after surgery were analyzed using an enzyme linked
      immunoabsorbent essay (ELISA) for MMP-3 and using a time-resolved
      immunofluorescence assay (IFMA) for MMP-8. MMP-3 was detected in a very low % of
      sites at baseline while relatively high levels of MMP-8 were detected at all 3
      types of sites at baseline. MMP-8 levels increased for all sites at week 1, and
      this was statistically significant for the membrane site, but at week 4, the
      levels decreased for both the membrane and the surgical sites. There was no
      statistically significant difference between the levels of MMP-3 and -8 in the
      antibiotic and non-antibiotic group. Collagen remodelling occurs during the early
      wound healing period following surgical and regenerative procedures. The levels
      of MMP-3 and -8 in GCF appear to reflect these processes. Interestingly, the
      presence of the membranes appeared to increase the levels of MMP-3 and -8 and may
      relate to the resorption of the resorbable membrane by host systems.

PMID- 10589814
TI  - On the dosage of antibiotics in clinical trials.

PMID- 10589815
TI  - Chairside assay for neutral protease in the gingival crevicular fluid (GCF) was
      able to predict disease progression for maintenance patients.

PMID- 10589816
TI  - The influence of several factors on the validity of measurements made on
      radiographs as compared to intrasurgical measurements made with a periodontal
      probe.

PMID- 10589817
TI  - Distribution of purinergic P2X receptors in the rat heart.
AB  - The distribution of P2X purinergic receptor subtypes has been determined in
      relation to nerve varicosities in the rat heart with immunohistochemistry. Large
      clusters (about 1 microm diameter) of co-localised and sometimes co-extensive
      P2X1 and P2X3 receptors were found at sites of tyrosine hydroxylase (TH) positive
      axon varicosities in the atrium and the ventricle. Varicosities that were
      labelled with antibodies to the synaptic vesicle epitope SV2 were frequently
      labelled also with antibodies to P2X3, P2X5 and P2X6 but not always with
      antibodies to P2X1. Especially prominent were large numbers of small clusters
      (about 400 nm diameter) of co-localised P2X2 and P2X5 receptors on the sarcolemma
      unrelated to nerves at all. During development the 1 day-old heart possessed an
      abundance of co-localised P2X2 and P2X5 small receptor clusters on the
      sarcolemma. These observations are discussed in relation to the role of
      purinergic receptors in the mammalian heart.

PMID- 10589818
TI  - NPY Y2 receptor agonist, N-acetyl [Leu28,Leu31]NPY24-36, reduces renal
      vasoconstrictor activity in anaesthetised dogs.
AB  - The actions of neuropeptide Y (NPY) at the autonomic neuroeffector junction have
      been attributed to two main receptor subtypes. At NPY Y1 receptors, located
      postsynaptically, NPY has been shown to produce vasoconstriction, or to
      potentiate the action of other vasoconstrictor agents. At NPY Y2 receptors,
      located presynaptically on nerve terminals, NPY inhibits the release of
      neurotransmitter from autonomic nerve terminals. In these experiments we have
      used the specific NPY Y2 receptor agonist, N-acetyl [Leu28,Leu31]NPY, which lacks
      local constrictor activity, and have demonstrated inhibition of nerve-evoked
      vasoconstriction in the renal circulation of anaesthetised dogs in a way that
      suggests an intra-renal regional specificity. Under control conditions
      stimulation of the renal sympathetic nerves over a range of frequencies (1-5 Hz)
      reduced renal vascular conductance and glomerular filtration rate (GFR).
      Following the injection of the selective NPY Y2 receptor agonist, N-acetyl
      [Leu28,Leu31]NPY24-36, nerve-evoked reductions in renal conductance were reduced
      by over 45%. At the lowest stimulation frequencies, reduced vasoconstrictor
      activity was associated with a marked increase in GFR in the presence N-acetyl
      [Leu28,Leu31]NPY24-36. At both higher levels of stimulation N-acetyl
      [Leu28,Leu31]NPY24-36 significantly inhibited vasoconstrictor activity and
      attenuated the nerve-evoked reductions in GFR. Full recovery of both variables
      was observed 20 min after N-acetyl [Leu28,Leu31]NPY24-36 injection. N-acetyl
      [Leu28,Leu31]NPY24-36 produced a similar inhibition of renal vasoconstrictor
      activity when the renal nerves were left intact and activated reflexly. These
      results suggest that NPY can act via NPY Y2 receptors to inhibit sympathetic
      vasoconstrictor activity in the renal circulation of dogs. On the basis of the
      demonstrated dissociation of effects on vascular conductance and GFR, we suggest
      that this might result from a preferential action of the NPY Y2 agonist on
      sympathetic nerves supplying the afferent arteriole of the kidney.

PMID- 10589819
TI  - Somatic nerve stimulation and cholera-induced net fluid secretion in the small
      intestine of the rat: evidence for an opioid effect.
AB  - The effects of somatic nerve stimulation on cholera toxin induced secretion was
      investigated in vivo in anaesthetised rats. Small intestinal secretion was
      induced with cholera toxin and measured by a gravimetric technique. Afferent
      stimulation (pulse frequency within train; 100 Hz; train duration: 50 ms; train
      frequency: 3 Hz) of the sciatic nerve over 30 min significantly reduced the net
      fluid secretion both during (P < 0.05) and after cessation of the stimulation (P
      < 0.01). The greatest effect was obtained immediately after the termination of
      the nerve stimulation when the secretion was reversed to net fluid absorption.
      The opioid receptor antagonist naloxone (10 mg kg(-1) i.v.) administrated during
      the stimulation, significantly inhibited the antisecretory effect seen after the
      stimulation, thus no significant difference was seen between the control period
      and the periods after cessation of the stimulation. The opioid receptor
      antagonist naloxone methiodide (10 mg kg(-1) i.v.), which does not cross the
      blood-brain barrier, partly inhibited the antisecretory effects but not with the
      same magnitude as naloxone, thus the net fluid secretion was still significantly
      inhibited after the stimulation (P < 0.05). We conclude that afferent stimulation
      of the sciatic nerve strongly inhibits the cholera toxin induced secretion in the
      small intestine. This inhibition involves primarily a central opioid mechanism
      and to a lesser extent peripheral opioid mechanism.

PMID- 10589820
TI  - Neuropeptide Y actions and the distribution of Ca2+-dependent Cl- conductance in
      rat dorsal root ganglion neurons.
AB  - Neuropeptide Y (NPY) increases the excitability of 'small', nociceptive, dorsal
      root ganglion (DRG) neurons. This effect, which may contribute to the etiology of
      'neuropathic' pain, has been attributed to attenuation of Ca2+-sensitive K+
      conductance(s) (gK,Ca) following suppression of Ca2+ entry via N-type Ca2+
      channels. A problem arises with this conclusion because rat DRG neurons normally
      contain high intracellular Cl- and some of them express a Ca2+-dependent Cl-
      conductance (gCl,Ca). In this study, we find that in rat DRG neurons increasing
      intracellular Cl- does not attenuate the effect of 1 microM NPY because gCl,Ca is
      not found in 'small' DRG cells and the peptide failed to affect the gCl,Ca found
      in 'large' cells. Thus, the presence of gCl,Ca in a subpopulation of 'large' DRG
      neurons does not alter the conclusion that excitatory effects of NPY result from
      attenuation of gK,Ca.

PMID- 10589821
TI  - Sensory stimulation (massage) reduces blood pressure in unanaesthetized rats.
AB  - The objective of this study was to investigate how sensory stimulation by massage
      like stroking influences blood pressure and heart rate in conscious rats. Also,
      the influence of different locations and durations of the stimulation were
      assessed. For this purpose, the ventral side of the abdomen or the dorsal side of
      the back was manually stroked at a speed of approximately 20 cm/s, with a
      frequency of 0.67 Hz and at an estimated pressure of 100 mm H2O. During the
      treatment, the rats were held across the scapula and the neck region. Blood
      pressure and heart rate were measured with the cuff technique before treatment
      and repeatedly during the post-stimulatory period. Massage-like stroking for 5
      min of the abdominal area produced a maximum decrease of approximately 20 mm Hg
      in blood pressure and 60 beats/min in heart rate. This reduction remained
      significant at 3 and 4 h after stimulation, respectively. Stimulation of the
      abdominal area for 2 min produced a less pronounced decrease in blood pressure as
      compared to the 5-min stroking. Stroking of the back resulted in a short-lasting
      blood pressure increase that gradually returned to the baseline level within the
      post-stimulatory observation time. Control animals that were handled in the same
      way as the experimental animals except for the stroking showed an increase of
      approximately 20 mm Hg in blood pressure and 60 beats/min for about 1 h after the
      cessation of the handling. The responses of the blood pressure and heart rate to
      both abdominal and back massage were significantly inhibited as compared to the
      control animals. These results suggest that massage-like stroking of the skin
      produces an inhibitory effect on the cardiovascular excitatory responses in rats.
      Especially, the results of the present study demonstrate that massage-like
      stroking of the abdomen reduces both blood pressure and heart rate below the pre
      stimulus baseline levels.

PMID- 10589822
TI  - Is the aortic depressor nerve involved in arterial chemoreflexes in rats?
AB  - Recent anatomical and physiological studies showed that chemoreceptor afferent
      fibers are present in the rat aortic depressor nerve (ADN), which has been
      considered to contain exclusively baroreceptor afferent fibers. However, it
      remains to be proven whether the chemoreceptor afferents of the ADN are
      practically involved in chemoreflexes. The present study was performed in
      chloralose/urethane-anesthetized rats of either Sprague-Dawley (SD) or Wistar
      strain to examine whether the ADN carries sufficient information regarding
      arterial hypoxia and hypercapnia, and whether the ADN indeed participates in
      chemoreflexes, the circulatory and respiratory components. It was found in either
      strain that afferent discharges of the ADN were not affected at all by hypoxia or
      hypercapnia, whereas those of the carotid sinus nerve (CSN) markedly increased
      due to these stimuli. Hypoxia produced hypertension, transient bradycardia
      followed by tachycardia, and respiratory facilitation, which characterize the
      chemoreflexes. Any of these responses was not affected at all by the ADN section,
      but all were abolished by the CSN section. Intraaortic injection of cyanide also
      induced transient bradycardia and respiratory facilitation, but any of them was
      not affected by the ADN section while all were abolished by the CSN section.
      Furthermore, electrical stimulation of the ADN produced solely baroreflex
      responses, i.e. hypotension and respiratory suppression, whereas that of the CSN
      provoked chemoreflex responses, i.e. early, transient hypertension and
      respiratory facilitation. In conclusion, the rat ADN does not contain a
      functionally significant number of chemoreceptor afferent fibers, if at all, and
      does not appreciably contribute to generation of chemoreflexes.

PMID- 10589823
TI  - Oxytocin enhances the effects of clonidine on blood pressure and locomotor
      activity in rats.
AB  - Oxytocin treatment decreases blood pressure and changes the pattern of
      spontaneous motor activity. The aim of this study was to explore if alpha 2
      adrenoreceptors that are involved in the regulation of blood pressure and
      spontaneous motor activity are influenced by oxytocin treatment. For this
      purpose, male rats were pretreated with oxytocin (1 mg/kg subcutaneously (s.c.))
      or saline once a day during 5 days. Clonidine (alpha 2-adrenoreceptor agonist)
      decreased blood pressure (2.5 microg/kg intracerebroventricularly (i.c.v.) and
      100 microg/kg s.c.) and changed spontaneous motor activity (100 microg/kg s.c.),
      observed in an open field arena, significantly more in oxytocin pretreated rats
      compared to saline pretreated controls (P < 0.05). In contrast, idazoxan (alpha 2
      adrenoreceptor antagonist) (50 microg/kg i.c.v.) caused a significantly smaller
      elevation of blood pressure in the oxytocin pretreated rats (P < 0.05). In
      addition, the effect on blood pressure of an alpha 1-adrenoreceptor agonist,
      phenylephrine, was evaluated. It increased blood pressure equally in the oxytocin
      and saline pretreated rats. The present study shows that subchronic oxytocin
      treatment increases the effects of clonidine on blood pressure and spontaneous
      motor activity in rats. These findings imply that alpha 2-adrenoreceptors are
      involved in the effects of oxytocin treatment on blood pressure and spontaneous
      motor activity.

PMID- 10589824
TI  - Changes in clinical measures of autonomic nervous system function related to
      cancer chemotherapy-induced nausea.
AB  - Individual cancer patients differ in their nausea/vomiting response to
      chemotherapy. It is not known why patients receiving the same chemotherapy have
      different severity of side effects. Several lines of research implicate the
      autonomic nervous system (ANS) in the development of chemotherapy-induced nausea.
      We examined the association between autonomic reactivity and the level of nausea
      experienced following chemotherapy in 20 patients with ovarian cancer treated
      with cisplatin or carboplatin who received the same antiemetic. We applied eight
      common non-invasive clinical tests of autonomic function prior to inpatient
      chemotherapy treatment, 2 h after treatment and again 24 h following treatment.
      Two hours after chemotherapy and before any nausea was reported by the patients,
      the nine patients who subsequently experienced high levels of nausea had a
      greater overall percentage of abnormal clinical ANS tests than the 11 patients
      who subsequently developed low levels of nausea (P < 0.01). Twenty-four hours
      after treatment, the overall number of abnormal autonomic tests remained non
      significantly higher than at the pretreatment baseline for the high nausea group.
      Demographic and clinical characteristics were not related to chemotherapy-induced
      nausea in this sample. Autonomic reactivity appears to be related to the
      development of nausea following chemotherapy. Further investigation of ANS
      involvement in chemotherapy-induced nausea could increase understanding of nausea
      etiology and potentially lead to the prediction of susceptible patients.

PMID- 10589825
TI  - Left stellate stimulation increases left ventricular ejection fraction in
      patients with essential palmar hyperhidrosis.
AB  - Left stellate stimulation increases cardiac contractility, heart rate, systolic
      blood pressure, and QT interval in experimental animals. To see if these changes
      occur in humans, we stimulated the left stellate ganglia with a monopolar
      coagulation power of 5 W in 10 patients with palmar hyperhidrosis, axillar
      hyperhidrosis, or both. We also stimulated the right stellate ganglia of the
      other 10 patients. The mean left ventricular ejection fraction (LVEF, measured
      with M-mode echocardiography), QT interval, heart rate and systolic blood
      pressure of the baseline were 54.72%, 403 ms, 65/min, and 115 mmHg, whereas those
      after 45 s of left stellate stimulation were 62.84%, 434 ms, 73/min, and 123 mmHg
      respectively. We compared these data with those of the baseline and the two
      tailed P values were 0.005 for both LVEF and QT interval, 0.052 for heart rate,
      and 0.050 for systolic blood pressure respectively (Wilcoxon Matched-Pairs Signed
      Ranks Test). The corresponding P-values for those of the right stellate
      stimulation were 0.721, 0.203, 0.260, and 0.326 respectively. All these suggest
      that the left stellate ganglia predominate the right ones in affecting LVEF, QT
      interval, heart rate and systolic blood pressure in humans, that left stellate
      stimulation increases LVEF and prolongs QT interval significantly, and that left
      stellate stimulation accelerates heart rate and elevates systolic blood pressure
      marginally.

PMID- 10589826
TI  - Defective expression of the mu3 subunit of the AP-3 adaptor complex in the
      Drosophila pigmentation mutant carmine.
AB  - The adaptor protein (AP) complexes AP-1, AP-2, and AP-3 mediate coated vesicle
      formation and sorting of integral membrane proteins in the endocytic and late
      exocytic pathways in mammalian cells. A search of the Drosophila melanogaster
      expressed sequence tag (EST) database identified orthologs of family members
      mammalian medium (mu) chain families mu1, mu2, and mu3, of the corresponding AP
      complexes, and delta-COP, the analogous component of the coatomer (COPI) complex.
      The Drosophila orthologs exhibit a high degree of sequence identity to mammalian
      medium chain and delta-COP proteins. Northern analysis demonstrated that medium
      chain and delta-COP mRNAs are expressed uniformly throughout fly development.
      Medium chain and delta-COP genes were cytologically mapped and the mu3 gene was
      found to localize to a region containing the pigmentation locus carmine (cm).
      Analysis of genomic DNA of the cm1 mutant allele indicated the presence of a
      large insertion in the coding region of the mu3 gene and Northern analysis
      revealed no detectable mu3 mRNA. Light microscopy of the cm1 mutant showed a
      reduction in primary, secondary, and tertiary pigment granules in the adult eye.
      These findings provide evidence of a role for mu3 in the sorting processes
      required for pigment granule biogenesis in Drosophila.

PMID- 10589827
TI  - The Arabidopsis transposon Tag1 is active in rice, undergoing germinal
      transposition and restricted, late somatic excision.
AB  - Tag1 is an autonomous transposable element of Arabidopsis thaliana that displays
      tight developmental control of its excision during shoot development. To
      determine how Tag1 behaves in a monocotyledonous species, Tag1 was inserted in a
      35S-GUS marker gene and the construct was introduced into rice. Tag1 showed
      somatic excision activity in four out of eleven transgenic lines examined. In
      leaves, excision was primarily restricted to vascular bundles and produced
      sectors composed of only a few cells. Excision events in flowers occurred
      predominantly in or near the major veins of the palea and lemma to produce small
      sectors. In roots, small sectors were evident, but they were few in number. These
      data show that the timing of Tag1 excision during rice shoot development is late
      and mimics the late excision behavior of Tag1 in Arabidopsis. One of the
      transgenic rice lines, which had a high frequency of somatic excision, produced
      several germinal revertants, one of which was characterized by a new Tag1
      insertion band. The pattern of Tag1 transcripts and the footprint sequences left
      behind after excision in rice were found to be very similar to those in
      Arabidopsis. These results show that key properties of Tag1 transposition and
      behavior are conserved between monocots and dicots and that Tag1 has the
      potential to serve as an insertional mutagen in rice.

PMID- 10589828
TI  - Renilla luciferase as a vital reporter for chloroplast gene expression in
      Chlamydomonas.
AB  - The use of luciferases as reporters of gene expression in living cells has been
      extended to the chloroplast genome. We show that the luciferase from the soft
      coral Renilla reniformis (Rluc) can be successfully expressed in the chloroplast
      of Chlamydomonas reinhardtii. Expression of the rluc cDNA was driven by the
      promoter and 5' untranslated regions of the atpA gene. Western analysis with an
      anti-Rluc antibody detected a single polypeptide of 38 kDa in the luminescent
      cells. This is 3 kDa larger than native Rluc, and suggests that translation of
      the chimeric mRNA begins at the atpA start codon, 29 codons upstream from the
      rluc start site. We also show that the luminescence of the transformants was
      sufficient to enable imaging of colonies using a cooled CCD camera.

PMID- 10589829
TI  - A mutation in a mitochondrial ABC transporter results in mitochondrial
      dysfunction through oxidative damage of mitochondrial DNA.
AB  - We have isolated a Saccharomyces cerevisiae mutant that shows an increased
      tendency to form cytoplasmic petites (respiration-deficient rho- or rho0 mutants)
      in response to treatment of cells growing on a solid medium with the DNA-damaging
      agent methyl methane-sulfonate or ultraviolet light. The mutation in this strain,
      atm1-1, was found to cause a single amino acid substitution in ATM1, a nuclear
      gene that encodes the mitochondrial ATP-binding cassette (ABC) transporter. When
      the mutant cells were grown in liquid glucose medium, they accumulated free iron
      within the mitochondria and at the same time gave rise to spontaneous cytoplasmic
      petite mutants, as seen previously in cells carrying a mutation in a gene
      homologous to the human gene responsible for Friedreich's ataxia. Analysis of the
      effects of free iron and malonic acid (an inhibitor of oxidative respiration in
      mitochondria) on the incidence of petites among the mutant cells indicated that
      spontaneous induction of petites was a consequence of oxidative stress rather
      than a direct effect of either a defect in the ATM1 gene or the accumulation of
      free iron. We observed an increase in the incidence of strand breaks in the
      mitochondrial DNA of the atm1-1 mutant cells. Furthermore, we found that rates of
      induction of petites and accumulation of strand breaks in mitochondrial DNA were
      enhanced in the atm1-1 mutant by the introduction of another mutation, mhr1-1,
      which results in a deficiency in mitochondrial DNA repair. These observations
      indicate that spontaneous induction of petites in the atm1-1 mutant is a
      consequence of oxidative damage to mitochondrial DNA mediated by enhanced
      accumulation of mitochondrial iron.

PMID- 10589830
TI  - The mitochondrial cytochrome c peroxidase Ccp1 of Saccharomyces cerevisiae is
      involved in conveying an oxidative stress signal to the transcription factor Pos9
      (Skn7).
AB  - In Saccharomyces cerevisiae two transcription factors, Pos9 (Skn7) and Yap1, are
      involved in the response to oxidative stress. Fusion of the Pos9 response
      regulator domain to the Gal4 DNA-binding domain results in a transcription factor
      which renders the expression of a GAL1-lacZ reporter gene dependent on oxidative
      stress. To identify genes which are involved in the oxygen-dependent activation
      of the Gal4-Pos9 hybrid protein we screened for mutants that failed to induce the
      heterologous test system upon oxidative stress (fap mutants for factors
      activating Pos9). We isolated several respiration-deficient and some respiration
      competent mutants by this means. We selected for further characterization only
      those mutants which also displayed an oxidative-stress-sensitive phenotype. One
      of the respiration-deficient mutants (complementation groupfap6) could be
      complemented by the ISM1 gene, which encodes mitochondrial isoleucyl tRNA
      synthetase, suggesting that respiration competence was important for signalling
      of oxidative stress. In accordance with this notion a rho0 strain and a wild-type
      strain in which respiration had been blocked (by treatment with antimycin A or
      with cyanide) also failed to activate Gal4-Pos9 upon imposition of oxidative
      stress. Another mutant, fap24, which was respiration-competent, could be
      complemented by CCP1, which encodes the mitochondrial cytochrome c peroxidase.
      Mitochondrial cytochrome c peroxidase degrades reactive oxygen species within the
      mitochondria. This suggested a possible sensor function for the enzyme in the
      oxidative stress response. To test this we used the previously described point
      mutant ccp1 W191F, which is characterized by a 10(4)-fold decrease in electron
      flux between cytochrome c and cytochrome c peroxidase. The Ccp1W191F mutant was
      still capable of activating the Pos9 transcriptional activation domain,
      suggesting that the signalling function of Ccp1 is independent of electron flux
      rates.

PMID- 10589831
TI  - PhoB-dependent transcriptional activation of the iciA gene during starvation for
      phosphate in Escherichia coli.
AB  - The IciA protein from Escherichia coli has been shown specifically to inhibit the
      in vitro initiation of chromosomal DNA replication. However, the in vivo role of
      IciA has not yet been established. In order to investigate the in vivo function
      of this protein, expression of the iciA gene was studied by monitoring the beta
      galactosidase activity specified by an iciA promoter-lacZ fusion inserted into
      the chromosome. Among the conditions tested (carbon starvation, the stringent
      response, phosphate starvation, and the SOS response), only phosphate depletion
      increased iciA expression. Supplementation of phosphate-depleted cultures with
      inorganic phosphate reduced the beta-galactosidase activity to basal levels.
      Enhanced expression of iciA-lacZ was dependent upon the PhoB protein. PhoB is
      known to be a transcriptional activator of the Pho regulon, expression of which
      is activated during phosphate starvation. It was also found that the iciA
      promoter contains a PhoB protein-binding sequence, termed the Pho box, which is
      necessary for the activation of genes of the Pho regulon. These results suggest
      that the iciA gene is a member of the Pho regulon.

PMID- 10589832
TI  - Isolation and functional characterisation of a novel type of carotenoid
      biosynthetic gene from Xanthophyllomyces dendrorhous.
AB  - The red heterobasidiomycetous yeast Xanthophyllomyces dendrorhous (perfect state
      of Phaffia rhodozyma) contains a novel type of carotenoid biosynthetic enzyme.
      Its structural gene, designated crtYB, was isolated by functional complementation
      in a genetically modified, carotenogenic Escherichia coli strain. Expression
      studies in different carotenogenic E. coli strains demonstrated that the crt YB
      gene encodes a bifunctional protein involved both in synthesis of phytoene from
      geranylgeranyl diphosphate and in cyclisation of lycopene to beta-carotene. By
      sequence comparison with other phytoene synthases and complementation studies in
      E. coli with various deletion derivatives of the crtYB gene, the regions
      responsible for phytoene synthesis and lycopene cyclisation were localised within
      the protein.

PMID- 10589833
TI  - RNA editing sites in tobacco chloroplast transcripts: editing as a possible
      regulator of chloroplast RNA polymerase activity.
AB  - Genetic information in chloroplast DNA is sometimes altered at the transcript
      level by a process known as RNA editing. Sequence analysis of amplified cDNAs for
      69 potential editing sites revealed 13 real editing sites in transcripts of 11
      tobacco chloroplast genes. Together with those reported previously, these bring
      the total of edited sites observed in tobacco chloroplast transcripts to 31 (all
      involve C to U conversion). Alignment of sequences around the 31 editing sites
      revealed no obvious consensus, apart from an apparent bias for U or C at position
      -1 and A at position +2. Editing in tobacco rpoA mRNA restores the conserved
      leucine residue which is known to be important for transcriptional activation of
      the alpha subunit of E. coli RNA polymerase. Editing of this site is partial and
      the extent of editing depends on developmental conditions, suggesting that
      editing is, at least in part, involved in the regulation of chloroplast-encoded
      RNA polymerase activity.

PMID- 10589834
TI  - Completion of the sexual cycle and demonstration of genetic recombination in
      Ustilago maydis in vitro.
AB  - The heterobasidiomycetes responsible for plant smuts obligatorily require their
      hosts for the completion of the sexual cycle. Accordingly, the sexual cycle of
      these fungi could so far be studied only by infecting host plants. We have now
      induced Ustilago maydis, the causative agent of corn smut, to traverse the whole
      life cycle by growing mixtures of mating-compatible strains of the fungus on a
      porous membrane placed on top of embryogenic cell cultures of its host Zea mays.
      Under these conditions, mating, karyogamy and meiosis take place, and the fungus
      induces differentiation of the plant cells. These results suggest that
      embryogenic maize cells produce diffusible compounds needed for completion of the
      sexual cycle of U. maydis, as the plant does for the pathogen during infection.

PMID- 10589835
TI  - Budding yeast Cdc6p induces re-replication in fission yeast by inhibition of
      SCF(Pop)-mediated proteolysis.
AB  - In fission yeast, overexpression of the replication initiator protein Cdc18p
      induces re-replication, a phenotype characterized by continuous DNA synthesis in
      the absence of cell division. In contrast, overexpression of Cdc6p, the budding
      yeast homolog of Cdc18p, does not cause re-replication in S. cerevisiae. However,
      we have found that Cdc6p has the ability to induce rereplication in fission
      yeast. Cdc6p cannot functionally replace Cdc18p, but instead interferes with the
      proteolysis of both Cdc18p and Rum1p, the inhibitor of the protein kinase Cdc2p.
      This activity of Cdc6p is entirely contained within a short N-terminal peptide,
      which forms a tight complex with Cdc2p and the F-box/WD-repeat protein
      Sud1p/Pop2p, a component of the SCF(Pop) ubiquitin ligase in fission yeast. These
      interactions are mediated by two distinct regions within the N-terminal region of
      Cdc6p and depend on the integrity of its Cdc2p phosphorylation sites. The data
      suggest that disruption of re-replication control by overexpression of Cdc6p in
      fission yeast is a consequence of sequestration of Cdc2p and Pop2p, two factors
      involved in the negative regulation of Rum1p, Cdc18p and potentially other
      replication proteins.

PMID- 10589836
TI  - A novel element in the promoter of the Saccharomyces cerevisiae gene SPS19
      enhances ORE-dependent up-regulation in oleic acid and is essential for de
      repression.
AB  - In Saccharomyces cerevisiae cells grown on oleic acid, genes encoding enzymes of
      beta-oxidation are induced by the interaction of a transcription factor composed
      of Pip2p and Oaflp with an oleate response element (ORE) in their promoters. The
      SPS19 gene, which encodes peroxisomal 2,4-dienoyl-CoA reductase, an auxiliary
      beta-oxidation enzyme, has been shown previously to be up-regulated by a
      canonical ORE. To determine whether additional elements contribute to this
      transcriptional upregulation, deletion analysis of the SPS19 promoter was
      conducted using SPS19-lacZ reporter genes. In a reporter construct containing a
      deletion adjacent to the ORE, transcriptional activation of SPS19 in oleic acid
      medium was impaired. Together with an additional segment that overlaps a portion
      of the canonical ORE, this region forms a continuous element (termed UAS(SPS19))
      that is essential for de-repression of SPS19 when glucose levels are low. The
      potentially bi-partite UAS(SPS19) element was able to initiate bi-directional
      transcription from a promoterless CYC1-lacZ reporter construct under de
      repression conditions, whereas the canonical ORE was not. In oleic acid
      containing medium, UAS(SPS19) stimulated transcription of the reporter gene 2.4
      fold compared to the intact SPS19 ORE, but did so only in the presence of Pip2p
      and Oaf1p. UAS(SPS19), which is similar to a transcriptional enhancer in the
      promoter of the sporulation-specific gene SPS4, was shown specifically to bind
      several proteins, including Pip2p and Oaflp. We propose that UAS(SPS19) and other
      sequences like it are required to enhance the transcriptional effects mediated by
      more specific response elements.

PMID- 10589837
TI  - A tourist element in the 5'-flanking region of the catalase gene CatA reveals
      evolutionary relationships among Oryza species with various genome types.
AB  - Tourist-OsaCatA, a transposable element, was found in the 5'-flanking region of
      the rice gene CatA. The characteristics of this element are similar to those of
      the other Tourist elements so far found in Oryza sativa. PCR and sequence
      analyses of 37 accessions of 18 species revealed that all the Oryza species
      examined, except for one accession, have either a full-length or a partial
      Tourist element at this locus. Unlike the Tourist elements previously reported,
      this Tourist element is found in all four Oryza species complexes in the Oryzeae
      tribe. All AA genome Oryza species, except O. longistaminata, contain the full
      length Tourist element. O. longistaminata and the species of the O. officinalis,
      O. meyeriana and O. ridleyi complexes contain the partial element. A phylogenetic
      tree of Oryza species based on the nucleotide sequences of these Tourist elements
      was constructed. The O. longistaminata accessions were placed near the
      neighboring cluster of the officinalis complex. We propose that the ancestor of
      O. longistaminata and that of other species with the AA genome diverged, and the
      ancestor(s) of the O. officinalis, O. ridleyi and O. meyeriana complexes then
      diverged from the ancestor of O. longistaminata in the course of the evolution of
      the Oryza species. The Tourist elements associated with CatA and its orthologs
      thus provide useful tools for examining evolutionary relationships among Oryza
      species.

PMID- 10589838
TI  - A plasmid-based vector system for the cloning and expression of Helicobacter
      pylori genes encoding outer membrane proteins.
AB  - Helicobacter pylori produces a number of proteins associated with the outer
      membrane, including adhesins and the vacuolating cytotoxin. We observed that the
      functional expression of such proteins is deleterious to Escherichia coli, the
      host bacterium used for gene cloning. Therefore, a general method was developed
      for the functional expression of such genes on a shuttle vector in H. pylori,
      which has been termed SOMPES (Shuttle vector-based Outer Membrane Protein
      Expression System). The intact, active gene is reconstituted by recombination in
      H. pylori from partial gene sequences cloned on an E. coli-H. pylori shuttle
      vector. This system was established in an H. pylori strain carrying a precise,
      unmarked chromosomal deletion of the vacA gene, which was constructed by adapting
      the streptomycin sensitivity system to H. pylori. It is based on the expression
      of the H. pylori rpsL gene as a counterselectable marker in the genetic
      background of an rpsL mutant. The utility of this approach is demonstrated by the
      expression of a recombinant gene encoding vacuolating cytotoxin (vacA) and a
      recombinant gene encoding an adherence-associated outer membrane protein (alpA)
      in H. pylori.

PMID- 10589839
TI  - Mechanism of transcription termination: PTRF interacts with the largest subunit
      of RNA polymerase I and dissociates paused transcription complexes from yeast and
      mouse.
AB  - Transcription termination by RNA polymerase I (Pol I) is a stepwise process.
      First the elongating RNA polymerase is forced to pause by DNA-bound transcription
      termination factor (TTF-I). Then the ternary transcription complex is dissociated
      by PTRF, a novel factor that promotes release of both nascent transcripts and Pol
      I from the template. In this study we have investigated the ability of PTRF to
      liberate transcripts from ternary transcription complexes isolated from yeast and
      mouse. Using immobilized, tailed templates that contain terminator sequences from
      Saccharomyces cerevisiae and mouse, respectively, we demonstrate that PTRF
      promotes release of terminated transcripts, irrespective of whether mouse Pol I
      has interacted with the murine termination factor TTF-I or its yeast homolog
      Reb1p. In contrast, mouse Pol I paused by the lac repressor remains bound to the
      template both in the presence and absence of PTRF. We demonstrate that PTRF
      interacts with the largest subunit of murine Pol I, with TTF-I and Reb1p, but not
      the lac repressor. The results imply that Pol I transcription termination in
      yeast and mouse is mediated by conserved interactions between Pol I, Reb1p/TTF-I
      and PTRF.

PMID- 10589840
TI  - PCR-based cloning and segregation analysis of functional gene homologues in Beta
      vulgaris.
AB  - To analyse genetic factors that potentially affect sugar quality and yield in
      Beta vulgaris, we designed primers based on 18 homologous ESTs and conserved
      regions of 32 heterologous ESTs encoding gene products that act in the Calvin
      cycle, the oxidative pentose phosphate cycle, photorespiration, synthesis,
      transport and degradation of sucrose, glycolysis, the citric acid cycle, nitrogen
      metabolism and osmoprotection. Data on the amplification of 54 gene homologues
      from B. vulgaris are presented. Among these are 35 homologues for which DNA
      sequence information from B. vulgaris is now available for the first time. For
      genetic mapping a PCR-based strategy using CAPS (cleaved amplified polymorphic
      sequence), DFLP (DNA fragment length polymorphism), SSCP (single-strand
      conformation polymorphism) and HD (heteroduplex) analysis was adopted. RFLP
      analysis was also used in some cases. The different techniques used for the
      detection of polymorphisms are evaluated with respect to their sensitivity and
      versatility. In all, 42 functional genes have been assigned to the nine linkage
      groups of sugar beet.

PMID- 10589841
TI  - DNA helicase mutants of bacteriophage T4 that are defective in DNA recombination.
AB  - We previously isolated a plasmid-borne, recombination-deficient mutant derivative
      of the bacteriophage T4 DNA helicase gene 41. We have now transferred this 41rrh1
      mutation into the phage genome in order to characterize its mutational effects
      further. The mutation impairs a recombination pathway that is distinct from the
      pathway involving uvsX, which is essential for strand transfer, and it also
      eliminates most homologous recombination between a plasmid and the T4 genome.
      Although 41rrh1 does not affect T4 DNA replication from some origins, it does
      inactivate plasmid replication that is dependent on ori(uvs Y) and ori(34), as
      well as recombination-dependent DNA replication. Combination of 41rrh1 with some
      uvsX alleles is lethal. Based on these results, we propose that gene 41
      contributes to DNA recombination through its role in DNA replication.

PMID- 10589842
TI  - Involvement of a MAP kinase, ZmMPK5, in senescence and recovery from low
      temperature stress in maize.
AB  - Four species of protein kinase were identified in senescent maize leaves using a
      gel assay for kinase activity with myelin basic protein (MBP) as the substrate.
      Most of these kinases were also found in healthy green leaves that had been
      exposed to low-temperature stress (5 degrees C) and then returned to 25 degrees
      C. A 41-kDa protein was activated in senescent leaves, whereas a 45-kDa protein
      was activated 3 h after up-shift from 5 degrees C to 25 degrees C as well as in
      senescent leaves. A 39-kDa protein was activated by cold stress. The other two
      proteins, of 35 kDa and 52 kDa, constitutively phosphorylated MBP during
      senescence and temperature up-shift. Judging from their molecular masses, cation
      requirements and substrate specificities, it seemed likely that the 39-kDa, 41
      kDa and 45-kDa proteins represented mitogen-activated protein kinases (MAPKs).
      Subsequently two MAPK cDNAs were isolated from a cDNA library constructed using
      mRNAs from senescent leaves. Northern analysis showed that the transcript
      corresponding to one of the cDNAs, designated ZmMPK5, accumulated in healthy
      leaves 3 h after the up-shift to 25 degrees C as well as in senescent leaves,
      suggesting that the 45-kDa protein kinase is encoded by ZmMPK5. Western analysis
      using an antiserum against the C-terminal region of ZmMPK5 showed that the level
      of the ZmMPK5 protein increased in senescent leaves. These results indicate that
      a 45-kDa MAPK is involved in the process of senescence and in recovery from low
      temperature stress in maize plants.

PMID- 10589843
TI  - RecQ and RecJ process blocked replication forks prior to the resumption of
      replication in UV-irradiated Escherichia coli.
AB  - The accurate recovery of replication following DNA damage and repair is critical
      for the maintenance of genomic integrity. In Escherichia coli, the recovery of
      replication following UV-induced DNA damage is dependent upon several proteins in
      the recF pathway, including RecF, RecO, and RecR. Two other recF pathway
      proteins, the RecQ helicase and the RecJ exonuclease, have been shown to affect
      the sites and frequencies at which illegitimate rearrangements occur following UV
      induced DNA damage, suggesting that they also may function during the recovery of
      replication. We show here that RecQ and RecJ process the nascent DNA at blocked
      replication forks prior to the resumption of DNA synthesis. The processing
      involves selective degradation of the nascent lagging DNA strand and it requires
      both RecQ and RecJ. We suggest that this processing may serve to lengthen the
      substrate that can be recognized and stabilized by the RecA protein at the
      replication fork, thereby helping to ensure the accurate recovery of replication
      after the obstructing lesion has been repaired.

PMID- 10589844
TI  - Characterization of a high-affinity phenol hydroxylase from Comamonas
      testosteroni R5 by gene cloning, and expression in Pseudomonas aeruginosa PAO1c.
AB  - Comamonas testosteroni strain R5 is a phenol-degrading bacterium which expresses
      a phenol-oxygenating activity that is characterized by low Ks (the apparent half
      saturation constant in Haldane's equation) and low K(SI) (the apparent inhibition
      constant) values. We have now cloned the gene cluster encoding a phenol
      hydroxylase (phcKLMNOP) and its cognate regulator (phcR) from strain R5.
      Transformation of Pseudomonas aeruginosa PAO1c (Phenol Catechol+) with pROR502, a
      derivative of pRO1614 containing the cloned genes, confers the ability to grow on
      phenol as the sole carbon source. The Ks and K(SI) values for the phenol
      oxygenating activity of PAO1c(pROR502) are almost identical to those of strain
      R5, suggesting that the phcKLMNOP genes encode the major phenol hydroxylase in
      strain R5. A phylogenetic analysis shows the phenol hydroxylase from strain R5 to
      be more closely related to toluene/benzene-2-monooxygenase (Tb2m) from
      Pseudomonas sp. JS150 than to the phenol hydroxylases from P. putida CF600 and
      BH, or to the phenol hydroxylase from Ralstonia eutropha E2. Analysis of the
      substrate specificity of PAO1c(pROR502) and PAO1c derivatives expressing phenol
      hydroxylase from P. putida BH or from R. eutropha E2 indicates that these phenol
      hydroxylases catalyze the oxidation not only of phenol and cresols but also of
      toluene and benzene.

PMID- 10589845
TI  - Pk-cdcA encodes a CDC48/VCP homolog in the hyperthermophilic archaeon Pyrococcus
      kodakaraensis KOD1: transcriptional and enzymatic characterization.
AB  - A gene encoding a cell division control protein from the hyperthermophilic
      archaeon Pyrococcus kodakaraensis KOD1, Pk-cdcA, was cloned and sequenced. The Pk
      cdcA gene is composed of 2508 nucleotides, encoding a protein of 835 amino acids
      with a molecular mass of 93,666 Da. Pk-CdcA has a typical Walker-type ATPase
      motif and was classified as a new member of the CDC48/VCP subfamily of so-called
      AAA proteins. In addition, Pk-CdcA possesses a unique region composed of charged
      amino acids, which is not observed in other homologs from Archaea. Transcription
      of the gene was analyzed by primer extension and Northern analyses, revealing
      that Pk-cdcA is transcribed from a site 77 bases upstream of the initiation
      codon. Pk-CdcA and its deletion mutant Pk-CdcAdelta63, which lacks the unique
      inserted region, were expressed in Escherichia coli cells as His-tagged fusion
      proteins and purified. Both Pk-CdcA and Pk-CdcAdelta63 possess an ATPase
      activity, as do other CDC48/VCP proteins. However, Pk-CdcAdelta63 showed a higher
      level of ATPase activity and greater thermostability than Pk-CdcA. Furthermore,
      Pk-CdcAdelta63 has a higher Vmax value than wild type, even though the Km was
      unchanged. These observations indicated that the inserted region affects enzyme
      stability and activity. In order to investigate intracellular expression levels
      of Pk-CdcA, Western analysis was performed using anti-Pk-CdcA antisera obtained
      from immunized BALB/C mice. Equal levels of Pk-CdcA expression were observed
      during exponential and stationary phases. Growth phase-specific fragmentation of
      Pk-CdcA was found in stationary-phase cells.

PMID- 10589846
TI  - The Corynebacterium glutamicum insertion sequence ISCg2 prefers conserved target
      sequences located adjacent to genes involved in aspartate and glutamate
      metabolism.
AB  - An IS element, termed ISCg2, was identified in the chromosome of Corynebacterium
      glutamicum ATCC 13032. After screening a cosmid library of the C. glutamicum ATCC
      13032 genome, six copies of ISCg2 including their flanking regions were sequenced
      and analyzed. ISCg2 is 1636 bp in length and has 26-bp imperfect inverted repeats
      flanked by 3-bp direct repeats. By comparisons with other IS elements, ISCg2 was
      classified as a member of the IS30 family of insertion sequences. The six copies
      of ISCg2 were identical at the nucleotide level and were located in intergenic,
      AT-rich regions of the chromosome. The regions in which the six copies of ISCg2
      were inserted displayed significant similarities. This similarity extends over a
      region of 65 bp, which was assumed to be the target region for ISCg2.
      Interestingly, five of the six copies of ISCg2 were located adjacent to genes
      that may be involved in aspartate and glutamate metabolism or its regulation.
      Investigation of the distribution of ISCg2 showed that the IS element is
      restricted to certain C. glutamicum strains. Analysis of various integration
      regions indicates active transposition of ISCg2 in C. glutamicum.

PMID- 10589847
TI  - Mapping of post-flowering drought resistance traits in grain sorghum: association
      between QTLs influencing premature senescence and maturity.
AB  - The identification of genetic factors underlying the complex responses of plants
      to drought stress provides a solid basis for improving drought resistance. The
      staygreen character in sorghum (Sorghum bicolor L. Moench) is a post-flowering
      drought resistance trait, which makes plants resistant to premature senescence
      under drought stress during the grainfilling stage. The objective of this study
      was to identify quantitative trait loci (QTLs) that control premature senescence
      and maturity traits, and to investigate their association under post-flowering
      drought stress in grain sorghum. A genetic linkage map was developed using a set
      of recombinant inbred lines (RILs) obtained from the cross B35 x Tx430, which
      were scored for 142 restriction fragment length polymorphism (RFLP) markers. The
      RILs and their parental lines were evaluated for post-flowering drought
      resistance and maturity in four environments. Simple interval mapping identified
      seven stay-green QTLs and two maturity QTLs. Three major stay-green QTLs (SGA,
      SGD and SGG) contributed to 42% of the phenotypic variability (LOD 9.0) and four
      minor QTLs (SGB, SGI. 1, SGI.2, and SGJ) significantly contributed to an
      additional 25% of the phenotypic variability in stay-green ratings. One maturity
      QTL (DFB) alone contributed to 40% of the phenotypic variability (LOD 10.0),
      while the second QTL (DFG) significantly contributed to an additional 17% of the
      phenotypic variability (LOD 4.9). Composite interval mapping confirmed the above
      results with an additional analysis of the QTL x Environment interaction. With
      heritability estimates of 0.72 for stay-green and 0.90 for maturity, the
      identified QTLs explained about 90% and 63% of genetic variability for stay-green
      and maturity traits, respectively. Although stay-green ratings were significantly
      correlated (r = 0.22, P< or =0.05) with maturity, six of the seven stay-green
      QTLs were independent of the QTLs influencing maturity. Similarly, one maturity
      QTL (DFB) was independent of the staygreen QTLs. One stay-green QTL (SGG),
      however, mapped in the vicinity of a maturity QTL (DFG), and all markers in the
      vicinity of the independent maturity QTL (DFB) were significantly (P< or =0.1)
      correlated with stay-green ratings, confounding the phenotyping of stay-green.
      The molecular genetic analysis of the QTLs influencing stay-green and maturity,
      together with the association between these two inversely related traits,
      provides a basis for further study of the underlying physiological mechanisms and
      demonstrates the possibility of improving drought resistance in plants by
      pyramiding the favorable QTLs.

PMID- 10589848
TI  - Physical activity in the prevention and treatment of obesity and its
      comorbidities: evidence report of independent panel to assess the role of
      physical activity in the treatment of obesity and its comorbidities.

PMID- 10589849
TI  - Talocrural and subtalar joint instability after lateral ankle sprain.
AB  - PURPOSE: Recurrence of lateral ankle sprain (LAS) is common among recreational
      and competitive athletes. Talocrural (TC) joint laxity has traditionally been
      seen as the cause of mechanical instability after LAS. The purpose of this study
      was to examine the use of stress fluoroscopy and physical examination in the
      assessment of TC and subtalar (ST) instability in subjects with and without a
      history of LAS. METHODS: Twelve subjects with a history of unilateral LAS and
      eight healthy controls were examined by two blinded examiners. The first examiner
      performed physical examination on each ankle by using the anterior drawer (AD),
      talar tilt (TTPE), and medial subtalar glide (MSTG) tests. Laxity in each ankle
      was assessed on a 4-point scale. The second examiner performed stress fluoroscopy
      taking AP views with and without a manually applied supination stress to assess
      TC laxity and a sidelying modified Broden view with and without stress to assess
      ST laxity. Subjective examination of the images was used to determine excessive
      TC and ST laxity. RESULTS: Seventy-five percent of previously injured subjects
      demonstrated unilateral laxity differences of the TC joint using stress
      fluoroscopy. Of the nine with excessive talar tilt on fluoroscopy, 78%
      demonstrated excessive laxity with the AD and MSTG tests, and 67% demonstrated
      laxity with the TTPE test. Sixty-seven percent of those with TC laxity also
      demonstrated either excessive unilateral or bilateral laxity of the ST joint
      under stress fluoroscopy. CONCLUSIONS: These data suggest the existence of a
      subpopulation of patients with a history of LAS who demonstrate a pattern of
      combined TC and ST laxity.

PMID- 10589850
TI  - Ultrasound-guided percutaneous longitudinal tenotomy for the management of
      patellar tendinopathy.
AB  - Thirty-eight athletes with unilateral patellar tendinopathy (17 with a
      tendinopathy of the main body of the tendon, and 21 with an insertional
      tendinopathy) underwent ultrasound-guided multiple percutaneous longitudinal
      tenotomy under local anaesthetic infiltration after failure of conservative
      management. Thirty-four patients were reviewed at least 24 months after the
      operation. Sixteen patients were rated excellent, nine good, eight fair, and five
      poor. Nine of the 13 patients with a fair or poor result had an insertional
      tendinopathy, and eight of them underwent a formal exploration of the patellar
      tendon. Before the operation, there were some areas of altered echogenicity at
      and around the site of involvement. These were still visible 6 wk after surgery
      in 70% of the patients. At the latest follow-up, in the patients with an
      excellent or good result, the tendon was generally isoechogenic but slightly
      thicker (P = 0.06) than the normal contralateral. In the patients with a fair or
      poor result, the tendon was significantly thicker than the contralateral (P =
      0.03), and showed some areas of mixed echogenicity. In the patients in whom the
      procedure was successful, the thicker operated tendon did not interfere with
      physical training. Bilateral isokinetic peak torque (Nm), average work (Joules),
      and average power (Watts) were tested at 90 degrees x s(-1). Immediately before
      the operation, there was no significant difference in peak torque, but total work
      and average power were significantly lower in the limb to be operated (0.01 < P <
      0.05). By the end of the study, although peak torque was, on average, within 7%
      of the unoperated limb, total work and average power were still significantly
      lower than in the unoperated limb (0.01 < P < 0.04). Percutaneous longitudinal
      internal tenotomy is simple, can be performed on an outpatient basis, requires
      minimal follow-up care, does not hinder further surgery should it be
      unsuccessful, and, in our experience, has produced no significant complications.
      In our hands, it has become the first line operative intervention in the
      treatment of chronic patellar tendinopathy after failure of conservative
      management. However, patients should be advised that, if they suffer from an
      tendinopathy at the attachment of the patellar tendon at the lower pole of the
      patella, a formal surgical exploration with stripping of the paratenon is
      preferable.

PMID- 10589851
TI  - A preliminary examination of cryotherapy and secondary injury in skeletal muscle.
AB  - PURPOSE: The purpose of this study was to document the presence of secondary
      injury in skeletal muscle, to quantify it, and to determine whether it is altered
      by acute cryotherapy. METHODS: Crush injuries to the triceps surae of 19 adult
      male Sprague-Dawley rats were either treated continuously with ice for 5 h (N =
      10) or received no ice treatment (N = 9). After treatment, tissues were assayed
      for the reduction of triphenyltetrazolium chloride (TTC) to triphenylformazan
      (formazan red). TTC reduction is indicative of oxidative function and serves as
      an indicator of cellular damage. RESULTS: A significantly lower TTC reduction
      rate was seen in both cold-treated injured tissue (6.59 +/- 1.01 microg x mg(-1)
      x h(-1)) and nontreated injured tissue (4.48 +/- 0.79 microg x mg(-1) x h(-1))
      compared with uninjured controls (ice group = 7.94 +/- 1.49 microg x mg(-1) x h(
      1), no-ice group = 6.62 +/- 0.75 microg x mg(-1) x h(-1)). These data indicate
      that crushing of muscle tissue produces injury measurable with the TTC reduction
      assay. Additionally, in crush-injured tissues, a significantly lower TTC
      reduction rate was seen in untreated tissues (4.48 +/- 0.79 microg x mg(-1) x h(
      1)) compared with ice treated tissues (6.59 +/- 1.01 microg x mg(-1) x h(-1)),
      indicating that cryotherapy reduces the magnitude of secondary injury.
      CONCLUSIONS: From these data, it can be concluded that secondary injury occurs
      after primary crush injury and that secondary injury is retarded by acute
      treatment with 5 h of continuous cryotherapy.

PMID- 10589852
TI  - Respiratory muscle training in neuromuscular disease: long-term effects on
      strength and load perception.
AB  - PURPOSE: Deterioration of respiratory muscle function in patients with
      neuromuscular disorders is primarily responsible for the high morbidity and
      mortality associated with these diseases. METHODS: The potential benefit of
      respiratory muscle training (RMT) on preservation of respiratory muscle strength
      and respiratory load perception (RLP) was examined in 21 children (mean age: 12.2
      +/- 1.8 yr [SD], 16 male) with Duchenne's muscular dystrophy or spinal muscular
      atrophy type III, and in 20 age-, weight-, and sex-matched controls. Subjects
      were randomly allocated to undergo incremental RMT with resistive inspiratory and
      expiratory loads for a period of 6 months (trained group, TR) or to perform
      similar exercises with no load (NT). Maximal static inspiratory (Pi(max)) and
      expiratory (Pe(max)) pressures and RLP (modified Borg visual analog scale 0-10)
      were assessed on two separate occasions before beginning of the training
      protocol, monthly throughout RMT duration, and every 3-6 months upon cessation of
      RMT for 1 yr. RESULTS: In controls, no significant changes in maximal static
      pressures or load perception occurred during RMT or thereafter. Training in
      neuromuscular disorder (NMD) patients was associated with improvements in Pi(max)
      (mean delta max: +19.8 +/- 3.8 cmH2O in TR vs +4.2 +/- 3.6 cmH2O in NT; P < 0.02)
      and in Pe(max) (mean delta max: +27.1 +/- 4.9 cmH2O in TR vs -1.8 +/- 3.4 cmH2O
      in NT; P < 0.004). Similarly, RLP significantly decreased during the RMT period
      in TR (mean delta: 1.9 +/- 0.3; P < 0.01) but did not change in NT (-0.2 +/-
      0.2). In addition, with cessation of RMT, static pressures returned to
      pretraining values in TR within approximately 3 months. However, RLP was still
      improved after 12 months. CONCLUSIONS: We conclude that in children with NMD,
      although RMT-induced increases in expiratory muscle strength are rapidly
      reversible, long-lasting improvements in RLP occur and could be associated with
      decreased respiratory symptoms.

PMID- 10589853
TI  - Effects of anabolic steroids on the muscle cells of strength-trained athletes.
AB  - PURPOSE: Athletes who use anabolic steroids get larger and stronger muscles. How
      this is reflected at the level of the muscle fibers has not yet been established
      and was the topic of this investigation. METHODS: Muscle biopsies were obtained
      from the trapezius muscles of high-level power lifters who have reported the use
      of anabolic steroids in high doses for several years and from high-level power
      lifters who have never used these drugs. Enzyme-immunohistochemical investigation
      was performed to assess muscle fiber types, fiber area, myonuclear number,
      frequency of satellite cells, and fibers expressing developmental protein
      isoforms. RESULTS: The overall muscle fiber composition was the same in both
      groups. The mean area for each fiber type in the reported steroid users was
      larger than that in the nonsteroid users (P < 0.05). The number of myonuclei and
      the proportion of central nuclei were also significantly higher in the reported
      steroid users (P < 0.05). Likewise, the frequency of fibers expressing
      developmental protein isoforms was significantly higher in the reported steroid
      users group (P < 0.05). CONCLUSION: Intake of anabolic steroids and strength
      training induce an increase in muscle size by both hypertrophy and the formation
      of new muscle fibers. We propose that activation of satellite cells is a key
      process and is enhanced by the steroid use. The incorporation of the satellite
      cells into preexisting fibers to maintain a constant nuclear to cytoplasmic ratio
      seems to be a fundamental mechanism for muscle fiber growth. Although all the
      subjects in this study have the same level of performance, the possibility of
      genetic differences between the two groups cannot be completely excluded.

PMID- 10589854
TI  - Obesity, fitness, willingness to communicate and health care costs.
AB  - BACKGROUND: Obesity and low levels of physical fitness are independently
      associated with a variety of diseases and disorders. These conditions are
      modifiable and affect health care utilization. The degree to which these health
      risks are modifiable is directly related to the readiness of individuals to
      change the underlying behaviors. This study analyzes the relationship between
      health care costs, obesity, physical fitness, and willingness to communicate. In
      addition, we tested the hypothesis that willingness to communicate is directly
      associated with an individual's readiness to change behavior. METHODS: Multiple
      regression was used to estimate the relationship between adverse behavioral
      health outcomes, willingness to communicate, and annualized health care costs
      incurred over a period of 33 months before the completion of a health risk
      assessment survey in an employed population enrolled in a Midwestern managed care
      organization (N = 8822). RESULTS: High body mass index (BMI), low physical
      fitness (predicted VO2max), and greater willingness to communicate were directly
      and significantly (P < 0.05) associated with higher health care costs. Relative
      to low-risk, annualized health care costs for each of the high-risk factors were
      8% higher for BMI (rate ratio, 1.08; 95% confidence interval, 1.01-1.15), 10%
      higher for low predicted VO2max (rate ratio 1.10, 95% confidence interval, 1.02
      1.18), and 22% higher for willingness to communicate (rate ratio, 1.22, 95%
      confidence interval, 1.14-1.30). The association between these health risks and
      health care costs was independent of age, sex, age-sex interaction, role-mental
      and role-physical limitations, and nine chronic conditions. Furthermore,
      willingness to communicate was directly related to a greater readiness to change
      behavior. CONCLUSIONS: The prevalence of obesity and low physical fitness is
      high, and these health risks are directly related to health care costs.
      Willingness of health plan members to communicate around health improvement
      opportunities appears greatest among those who incur higher costs, and these
      patients also have more favorable readiness to change profiles. Effective,
      proactive population-based health improvement efforts appear to have significant
      potential for positive economic impact.

PMID- 10589855
TI  - Therapeutic value of exercise training in Parkinson's disease.
AB  - PURPOSE: The objective of this study was to investigate the influence of an
      intensive exercise training on motor disability, mood, and subjective well-being
      in parkinsonian patients. METHODS: The study was designed as an open long-term
      pilot trial over 20 wk. Sixteen slightly to moderately affected idiopathic
      parkinsonian patients (PD) were included. An intensive standardized exercise
      training was performed twice weekly over 14 wk in all patients. Evaluations were
      performed before the start of the study (exam. 1), after 7 wk (exam 2), 14 wk
      (exam 3), and 20 wk (exam 4/long-term effect). The test battery included: 1)
      basic motor test (BMT) [test for muscle strength, flexibility, and coordination];
      2) Unified Parkinson's Disease Rating Scale (UPDRS) and Columbia University
      Rating Scale (CURS) for PD-specific motor disability; and 3) registration of
      psychometric data by Mini Mental State (MMS) for dementia and the Adjective Mood
      Questionnaire of Zeersen (AMQZ) and Sickness Impact Profile (SIP) for subjective
      well-being. RESULTS: UPDRS sigma score (P < 0.0001), CURS sigma score (P <
      0.0001) and BMT 2 score (P < 0.0001) improved significantly by exercise training.
      Six weeks after termination of the training program, the majority of the patients
      had lost only minor components of their regained motor skills. There was no
      significant change in cognitive function during the study. The results of open
      interviews referring to subjective well-being were confirmed by the AMQZ and SIP.
      As an unexpected side effect, dyskinesias seemed to be better controlled.
      CONCLUSION: Motor disability as well as mood and subjective well-being can be
      clearly improved by intensive sports activities in early to medium stage PD
      patients. A sustained ongoing benefit outlasting the active training period for
      at least 6 wk can be achieved but the exact duration of this benefit is open.

PMID- 10589856
TI  - Selected predictor variables and the lipid-lipoprotein profile of prepubertal
      girls and boys.
AB  - PURPOSE: It is still unclear how habitual physical activity (HPA), peak VO2,
      percent body fat (%BF), and dietary composition are related to the lipid
      lipoprotein profile in children. The purpose of this study was to identify
      independent contributions from these selected predictor variables to prepubertal
      children's lipid-lipoprotein profile. METHODS: Peak VO2, HPA from continuous
      heart rate monitoring, %BF, 7-d dietary analysis, total cholesterol (TC), total
      triacylglycerol (TG), high density lipoprotein (HDL) cholesterol (HDL-C), low
      density lipoprotein (LDL) cholesterol (LDL-C), TC/HDL-C, and LDL-C/HDL-C were
      determined in 33 prepubertal girls and 38 prepubertal boys (mean +/- SD age, 10.6
      +/- 0.7 yr). RESULTS: Bivariate correlation analyses revealed that peak VO2, %BF,
      and HPA were related to the lipid-lipoprotein profile in girls (P < 0.05). For
      the boys, HPA was only related to TC/HDL-C (P < 0.05) and LDL-C/HDL-C (P < 0.05),
      whereas daily energy intake (kJ x d(-1)) was associated with TC and LDL-C (P <
      0.05). Multiple linear regression analyses indicated that peak VO2, %BF and HPA
      were the main predictor variables for the girls. Peak VO2 accounted for 22.7%,
      24.8%, 22.5%, and 24.2% of the unique variance (sr(i)2) in TG, HDL-C, LDL-C/HDL
      C, and TC/HDL-C, respectively. For TC and LDL-C in girls, sr(i)2 were 18.0% and
      22.6%, respectively, from HPA. In contrast, only daily energy intake had a
      significant unique contribution to the variance of TC (15.4%) and LDL-C (22.0%)
      for the boys. SUMMARY: The main findings from this study were that the predictor
      variables are lipid-lipoprotein specific and depend on gender. These results
      would support the growing evidence that it is important to nurture an active
      lifestyle in children from an early age and that an awareness of fitness and body
      fatness is required.

PMID- 10589857
TI  - Lean body mass and leg power best predict bone mineral density in adolescent
      girls.
AB  - PURPOSE: We evaluated anthropometric and performance measures that best predict
      bone mineral density (BMD) and bone mineral content (BMC) in 54 adolescent girls
      (14.6 +/- 0.5 yr; 22.7 +/- 14.0 months past menarche). METHODS: Whole body,
      femoral neck, greater trochanter, lumbar spine (L2-L4), and mid-femoral shaft BMD
      and BMC, and whole body bone-free lean mass and fat mass were assessed using DXA
      (Hologic QDR 1000/W). Knee extensor strength and leg power were assessed by
      isokinetic dynamometry and the Wingate Anaerobic Power Test, respectively.
      RESULTS: Whole body lean mass was correlated with BMD at all bone sites (r = 0.45
      0.77; P < 0.001) and was more highly correlated with bone at all sites than was
      body weight. Leg power was also associated with BMD at all sites (r = 0.41-0.67;
      P < 0.001), whereas leg strength correlated significantly with all sites (r =
      0.41-0.53; P < 0.001) except the lumbar spine. Stepwise regression analyses
      revealed that 59% of the variance in whole body BMD was predicted by lean mass
      alone. No other variables, including fat mass, height, months past menarche, leg
      power, or leg strength, contributed additionally to the regression model.
      Similarly, lean mass was the only predictor of lumbar spine and femoral shaft BMD
      (R2 = 0.25, R2 = 0.37, respectively), while femoral neck and trochanteric BMD
      were best predicted by leg power (R2 = 0.38, R2 = 0.36, respectively). Similar
      but stronger models emerged using BMC as the outcome, with lean mass and leg
      power explaining the most variance in BMC values. CONCLUSION: In this group of
      adolescent girls, lean body mass and leg power best predicted BMC and BMD of the
      whole body, lumbar spine, femoral shaft, and hip, which may suggest an important
      role for muscle mass development during growth to maximize peak bone density.

PMID- 10589858
TI  - Effects of posture on left ventricular diastolic filling during exercise.
AB  - BACKGROUND: Measuring the transmitral flow velocity with Doppler echocardiography
      is a useful method for evaluating left ventricular diastolic function. However,
      there are few data regarding the effect of posture during exercise on transmitral
      flow velocity. METHODS: The transmitral flow velocity with pulsed-wave Doppler
      echocardiography was measured during supine and upright bicycle ergometer
      exercise in 10 normal young men without cardiac disease (26.7 +/- 5.5 yr).
      RESULTS: The ratio of the early rapid filling wave to the atrial filling wave
      (E/A) was gradually decreased with increasing exercise intensity. At rest and
      during recovery, the E/A ratio was significantly higher (P < 0.01) in the supine
      position than in the upright position. This difference was caused mainly by the
      higher E wave in the supine position. However, E wave and E/A ratio did not
      differ between the upright and supine position during exercise. CONCLUSION:
      Although measurement of left ventricular filling is completely noninvasive and
      clinically useful for evaluating diastolic function, it was found that the E/A
      ratio was profoundly influenced by posture and exercise intensity. These results
      suggest that the potential influences of posture and exercise intensity on the
      filling velocities should be taken into account when interpreting diastolic
      function by Doppler echocardiography.

PMID- 10589859
TI  - Increased fat availability enhances the capacity of trained individuals to
      perform prolonged exercise.
AB  - METHODS: After a familiarization period, six well-trained males participated in a
      diet and exercise regimen lasting 9 d and comprising three cycling tests to
      exhaustion. A work rate was selected during the familiarization period that would
      result in fatigue after approximately 90-100 min at an ambient temperature of 10
      degrees C (i.e., approximately 75% of VO2max). The first exercise test was a
      depletion trial and was preceded by a period during which the subjects' normal
      diet was consumed. A prescribed 70% carbohydrate (CHO) diet was then consumed for
      3.5 d. After this diet, a second exercise test was performed; one of two
      isoenergetic experimental meals was consumed 4 h before this test (70% CHO meal,
      CHO trial; or 90% fat meal, fat trial). The second exercise test was followed by
      a further 3.5-d period on the high CHO diet. Four hours before the third test,
      subjects consumed the other meal. Heparin was administered intravenously 30 min
      (1000 U), 15 min (500 U), and 0 min (500 U) before exercise on the fat trial.
      Subjects were assigned to the two meals in randomized order. RESULTS: Time to
      exhaustion increased from 118.2 (12.4) min on the CHO trial to 127.9 (12.1) min
      on the fat trial (P = 0.001). Although no difference in VO2, RER, HR or RPE was
      found between trials, there was an earlier reduction in RER and an earlier rise
      in RPE on the fat trial. No difference in total CHO oxidation was found between
      trials (383 +/- 70 g on the CHO trial and 362 +/- 59 g on the fat trial).
      CONCLUSIONS: These results suggest that increasing fat availability immediately
      before exercise by acute fat feeding and heparin infusion can improve endurance
      exercise in a cool environment in well-trained individuals. This study was not
      intended to have immediate application to the sports performance field but rather
      to contribute to our understanding of the factors that may limit endurance
      performance. Heparin injection to elevate plasma fatty acid concentration would
      not represent sound medical practice.

PMID- 10589860
TI  - Noninvasive measurement of muscle high-energy phosphates and glycogen
      concentrations in elite soccer players by 31P- and 13C-MRS.
AB  - PURPOSE: The purpose of this study was to measure noninvasively the absolute
      concentrations of muscle adenosine triphosphate [ATP], phosphocreatine [PCr],
      inorganic phosphate (Pi), and glycogen [Gly] of elite soccer players. METHODS:
      Magnetic resonance spectroscopy (31P- and 13C-MRS) was used to measure the
      concentrations of metabolites in the calf muscles of 18 young male players [age =
      17.5 +/- 1.0 (SD) yr]. RESULTS: Average muscle [PCr] and [ATP] were 17.8 +/- 3.3
      and 6.0 +/- 1.2 mmol x (kg wet weight)(-1), respectively. The ratios of Pi/PCr
      and PCr/ATP were 0.15 +/- 0.05 and 3.00 +/- 0.26, respectively. The muscle [Gly]
      was 144 +/- 54 mmol x (kg wet weight)(-1). There was a high correlation (r =
      0.93, P < 0.0001) between muscle ATP and PCr concentrations, but there was no
      correlation between [Gly] and [PCr] or [ATP]. The concentrations of the different
      metabolites determined in the present study with noninvasive MRS methods were
      within the ranges of values reported in human muscle from biochemical analysis of
      muscle biopsies. CONCLUSION: MRS methods can be utilized to assess noninvasively
      the muscle energetic status of elite soccer players during a soccer season. The
      high correlation between ATP and PCr might be indicative of fiber type
      differences in the content of these two metabolites.

PMID- 10589861
TI  - Muscle glycogen degradation during simulation of a fatiguing soccer match in
      elite soccer players examined noninvasively by 13C-MRS.
AB  - PURPOSE: The purpose of this research project was to noninvasively determine
      individual muscle glycogen [Gly] degradation during a test intended to predict
      individual fatigue in intense soccer matches. METHODS: The [Gly] of the calf
      muscles of 17 elite soccer players [age = 17.4 +/- 0.8 (SD)] were measured with
      13C-MRS before and after an alternating velocity test to exhaustion. Blood
      samples were taken before and 3 min after the test for determination of blood
      metabolites. RESULTS: Average muscle [Gly] was 135 +/- 53 mmol x (kg wet weight)(
      1) before and 87 +/- 27 mmol x (kg wet weight)(-1) (P < 0.001) after exhaustion
      (42 +/- 25 min). There was a high correlation (r = 0.87, P < 0.0001) between
      muscle [Gly] at rest and net muscle [Gly] utilized. There was also a more
      moderate correlation (r = 0.62, P < 0.01) between net muscle [Gly] used and time
      to exhaustion during the soccer-specific test. There was some evidence of
      correlation (r = 0.42, P = 0.09) between resting [Gly] and time to exhaustion.
      Plasma lactate increased (P < 0.001) from 0.8 +/- 0.4 before the test to 2.5 +/-
      1.0 mmol x L(-1) at exhaustion, whereas ammonia was raised (P < 0.0001) from 44.1
      +/- 10.3 to 89.7 +/- 14.9 micromol x L(-1). Similarly, plasma free fatty acids
      were elevated (P < 0.0001) from 148 +/- 106 to 797 +/- 401 micromol x L(-1), and
      glycerol was increased (P < 0.0001) from 48.3 +/- 17.7 to 182.2 +/- 61.8 micromol
      x L(-1). Insulin levels (11.9 +/- 3.7 vs 11.7 +/- 4.8 microU x mL(-1)) remained
      the same. Creatine kinase levels increased (P < 0.0001) from 486 +/- 501 to 640
      +/- 548 micromol x L(-1) after the test. CONCLUSIONS: We conclude that exhaustion
      during soccer-specific performance is related to the capacity to utilize muscle
      [Gly]. The results underline the importance of dietary counseling (glycogen
      loading and resynthesis strategies) and proper training to enhance the glycogen
      levels and glycogenolytic capacity of the players.

PMID- 10589862
TI  - Antioxidant administration inhibits exercise-induced thymocyte apoptosis in rats.
AB  - PURPOSE: The purpose of this study was to investigate the effect of antioxidant
      on exercise-induced apoptosis in rat thymocytes. METHODS: After exercise at 13.8
      m x min(-1) for 60-90 min x d(-1) on a motor-driven drum exerciser for 2
      consecutive days, rat thymocyte apoptosis was monitored by the feature of DNA
      fragmentation. To study the effect of antioxidant, rats were administered with
      butylated hydroxyanisole (BHA) for 7 d before exercise. RESULTS: Exercise could
      induce thymocyte DNA fragmentation as detected on electrophoretic gel and by cell
      death detection ELISA kit. Further studies indicated that pretreatment with
      antioxidant BHA to rats resulted in a blockage of exercise-induced DNA
      fragmentation. The concentrations of glutathione (GSH) were not significantly
      changed in rat thymocytes after exercise with or without BHA treatment.
      CONCLUSION: These results suggest that reactive oxygen species may play a role in
      thymocyte apoptosis induced by exercise. However, changes in GSH levels were not
      observed in this exercise model.

PMID- 10589863
TI  - Exercise stimulates neovascularization in occluded muscle without affecting bFGF
      content.
AB  - PURPOSE: This study was conducted to determine whether exercise-induced
      improvements in capillarity in muscle with peripheral arterial insufficiency
      (PAI) was accompanied by endothelial cell mitosis, and whether that response
      could be explained by changes in the expression of basic fibroblast growth factor
      (bFGF), a known mitogen. METHODS: After bilateral ligation of femoral arteries,
      Sprague-Dawley rats either remained sedentary or participated in a treadmill
      running protocol. Running time to exhaustion at each session was recorded. On
      days 1, 2, 3, 5, and 7 of the experimental period, trained-ligated and sedentary
      ligated animals were euthanized, and segments of muscle from the gastrocnemius
      were obtained. Capillarity was determined with histochemistry, and endothelial
      cell mitotic activity (cell proliferation) was assayed via nuclear uptake of 5'
      bromo-2'-deoxyuridine (BrdU), an analog of thymidine. Content of endogenous bFGF
      was assessed with immunoblotting techniques. RESULTS: Exercise training resulted
      in augmented function of PAI affected muscle as evidenced by a nearly threefold
      increase in running time until exhaustion. Trained-ligated muscle demonstrated
      significantly (P < 0.05) greater capillarity than sedentary-ligated muscle.
      Vascular remodeling elicited by exercise included the formation of new
      capillaries (angiogenesis) as indicated by enhanced endothelial cell
      proliferation at days 3, 5, and 7 of the study. However, exercise training did
      not alter the content of bFGF in occluded muscle. CONCLUSION: In muscle with PAI,
      exercise training improved functional capacity and capillarity. Angiogenesis was
      confirmed by the increased mitotic activity of endothelial cells. However, the
      content of bFGF, a potent angiogenic factor, was not altered. Thus, exercise
      induced angiogenesis in PAI affected muscle is not dependent upon increased
      expression of endogenous bFGF.

PMID- 10589864
TI  - Endurance training reduces the rate of diaphragm fatigue in vitro.
AB  - PURPOSE: The present study examined the effects of endurance training on the
      contractile and biochemical properties of the rat costal diaphragm in vitro.
      METHODS: Sixty-four rats were divided into two groups: exercise trained (T) and
      control (C). Training consisted of treadmill running 5 d x wk(-1), 60 min x d(-1)
      at approximately 70% of VO2max, over a 10-wk period. RESULTS: Control diaphragm
      strips produced an average of 12% less force from minute 15 to 50 of a 60-min in
      vitro fatigue protocol, compared with the T diaphragm strips (P < 0.01). T
      diaphragms had 10.1% higher citrate synthase (CS) and 12.1% higher superoxide
      dismutase (SOD) activities compared with the C (P < 0.05). Despite a significant
      decrease (P < 0.05) in Type IIb myosin heavy chains (MHC) and an increase (P <
      0.05) in Type I MHC in T diaphragms, maximal shortening velocity (Vmax) in the
      diaphragm was not different between T and C animals. No differences were observed
      in specific force or the relative proportions of myosin light chains between
      groups. CONCLUSIONS: These findings suggest that endurance training reduces the
      rate of diaphragm fatigue in vitro but has no effect on Vmax or specific force.

PMID- 10589865
TI  - Circuit weight training and its effects on excess postexercise oxygen
      consumption.
AB  - OBJECTIVE: There is a paucity of research concerning energy expenditure during
      and after circuit weight training (CWT). There is evidence that duration of rest
      between sets affects metabolic responses to resistive exercise. The purpose of
      the study was to determine the effect of rest-interval duration upon the
      magnitude of 1 h of excess postexercise oxygen consumption (EPOC). METHODS: Seven
      healthy men completed two randomized circuit weight training sessions using 20-s
      and 60-s rest intervals (20 RI, 60 RI). Sessions included two circuits of eight
      upper and lower body resistive exercises in which 20 repetitions were performed
      at 75% of a previously determined 20 repetition maximum. RESULTS: The 1 h EPOC of
      10.3 +/- 0.57 L for the 20 RI session was significantly higher than 7.40 +/- 0.39
      L for the 60 RI session. The net caloric expenditure during 1 h of recovery from
      the 20 RI session was significantly higher than that of the 60 RI session (51.51
      +/- 2.84 vs 37.00 +/- 1.97 kcal); however, total gross energy expenditure
      (exercise + 1 h recovery) was significantly greater for the 60 RI protocol
      (277.23 kcal) than the 20 RI protocol (242.21 kcal). CONCLUSION: Data demonstrate
      that shortening the rest interval duration will increase the magnitude of 1 h
      EPOC from CWT; however, the exercise + recovery caloric costs from CWT are
      slightly greater for a longer rest interval duration protocol. These data suggest
      that total caloric cost be taken into account for CWT.

PMID- 10589866
TI  - Intraindividual variability and reliability in a 7-day exercise record.
AB  - PURPOSE: High levels of day-to-day or intraindividual variability implies
      unreliability of a measure of physical activity. Unreliability in a measure leads
      to attenuation of correlations with other variables. As intraindividual
      variability increases, the number of days necessary to assess physical activity
      to achieve the desired level of reliability increases. The use of an intraclass
      correlation to assess day-to-day reliability in a measure assumes compound
      symmetry. METHODS: This study reports on these issues in a sample of 165
      elementary school teachers who maintained a 7-d record of physical activity each
      year for 3 yr. Analyses were conduced with physical activity measured as minutes,
      MET minutes, and kcal. Analyses were conducted with PROC MIXED in SAS controlling
      for the clustering effect by school. RESULTS: Compound symmetry could not be
      supported across 7 d of the record. The weekdays tended to intercorrelate,
      Saturday correlated at very low levels, and Sunday correlated with Monday only.
      Compound symmetry was supported across the three weeks. CONCLUSIONS: To achieve a
      reliability of 0.8 using a 7-d activity record requires 2 wk of assessment. The
      reliability of measures of physical activity require more careful attention, and
      likely require more points of assessment to achieve desired levels.

PMID- 10589867
TI  - Reproducibility of maximal exercise test data in the HERITAGE family study.
AB  - PURPOSE: The reproducibility of responses to maximal cycle ergometer testing was
      determined using data from the HERITAGE Family study at four Clinical Centers in
      the United States and Canada. METHODS: Reproducibility was determined from
      maximal exercise test data obtained a) on 2 d in a sample of 390 subjects (198
      men and 192 women), b) across 4 d in an Intracenter Quality Control (ICQC)
      substudy with 55 subjects who were not part of the main study, and c) across 2 wk
      in a Traveling Crew Quality Control (TCQC) substudy with the same eight subjects
      who were tested at each of the four centers. Reproducibility was evaluated using
      technical errors, coefficients of variation (CV) for repeated measures, and
      intraclass correlation coefficients (ICC) for selected variables obtained on the
      main cohort, as well as on the ICQC and TCQC substudies. RESULTS: With the
      exception of systolic and diastolic blood pressures and respiratory exchange
      ratio, all the other variables (heart rate, ventilation, VO2, and VCO2) were
      highly reproducible, with CV below 10% and ICC over 0.86. These results were
      similar to those previously reported on the same subjects at a submaximal power
      output associated with 60% VO2max. Results were consistent for the main cohort,
      the ICQC sample, the TCQC sample, and across all four Clinical Centers.
      CONCLUSIONS: Day-to-day variations are small and reproducibility is high for
      maximal values of heart rate, ventilation, VO2 and VCO2 at each of the four
      Clinical Centers of the HERITAGE Family Study.

PMID- 10589868
TI  - Three-dimensional kinetic analysis of running: significance of secondary planes
      of motion.
AB  - PURPOSE: The study of angular kinetic data provides important information
      regarding muscle function and may lend insight into the etiology of overuse
      injuries common to runners. These injuries are often due to deviations in the
      secondary planes of motion. However, little is known about the angular kinetics
      in these planes leaving no reference for comparison. METHODS: Therefore, three
      dimensional kinematic and ground reaction force data were collected on 20
      recreational runners with normal rearfoot mechanics. RESULTS: Findings suggest
      that sagittal plane kinetic data were similar to the two-dimensional studies
      reported in the literature. Sagittal plane data were least variable (CV: 9.3
      11.0%) and comprised the largest percentage of positive or negative work done
      (80.2-88.8%) at both the rearfoot and knee joints. Transverse plane kinetics were
      most variable (CV: 68.5-151.9%) and constituted the smallest percentage of work
      done at both joints (0.7-7.4%). CONCLUSIONS: Although relatively smaller than the
      sagittal plane component, a substantial amount of positive work was done in the
      frontal plane at both joints (16.1-18.9%), suggesting that this component should
      not be ignored.

PMID- 10589869
TI  - Maximal motor unit discharge rates in the quadriceps muscles of older weight
      lifters.
AB  - Although the existence of "neural factors" is regularly cited as an important
      contributor to muscular strength, we have little specific knowledge regarding the
      existence of such neural factors or how they contribute to the expression of
      muscular force. PURPOSE: The present investigation sought to assess maximal motor
      unit discharge rates in older, highly resistance-trained adults to determine
      whether maximal motor unit discharge rates might be one such neural contributor
      to maximal strength production. METHODS: Subjects consisted of seven well-trained
      older weight lifters (ages 67-79 yr) and five untrained age-matched older adults.
      While subjects performed 50 and 100% maximal voluntary knee extensor contractions
      (MVC), recordings from groups of motor units were obtained from the rectus
      femoris muscle by using an indwelling electrode. Off-line analysis was performed
      to identify individual motor unit firing occurrences and to compute maximal motor
      unit discharge rates. RESULTS: As expected, knee extension strength in the
      trained weight lifters (367.0 +/- 72.0 N) was significantly greater than that in
      the control subjects (299.9 +/- 35.9 N; P < 0.05). Motor unit discharge rates
      were similar in the two subject groups at the 50% MVC force level (P > 0.05), but
      maximal (100% MVC) motor unit discharge rate in the weight lifters (23.8 +/- 7.71
      pps) was significantly greater than that in the age-matched controls (19.1 +/-
      6.29 pps; P < 0.05). CONCLUSION: Motor unit discharge rates may comprise an
      important neural factor contributing to maximal strength in older adults.

PMID- 10589870
TI  - Asynchrony between subtalar and knee joint function during running.
AB  - PURPOSE: It has been suggested that during running proper coordination between
      subtalar joint pronation/supination and knee joint flexion/extension via tibial
      rotation is important to attenuate ground reaction impact forces (GRIF). Lack of
      coordination may produce over time a wide range of injuries. The goal of this
      study was to investigate the relationship between subtalar pronation/supination
      and knee flexion/extension with GRIF increases during distance running. METHODS:
      Eight subjects ran under different speeds (a self-selected pace, 10% faster, 10%
      slower, and 20% faster) and over different obstacle heights (5%, 10%, and 15% of
      their standing height) on their self-selected pace. Sagittal, rear-view
      kinematic, and GRIF data were collected. The biomechanical results were also
      compared with data from a clinical evaluation of the subjects. RESULTS: Speed
      changes and obstacle heights produced increases in GRIF and differences between
      rearfoot and knee angular velocities. The higher the obstacle and the faster the
      speed, the greater the GRIF and the greater the velocity differences. A change of
      the rearfoot angle curve from a unimodal (one minimum) to a bimodal (two
      minimums) parabolic configuration was also observed. The appearance of the second
      minimum was attributed to a lateral deviation of the tibia as a rebound effect
      due to the increased impact with the ground. The velocity differences between the
      actions of the subtalar and the knee joint, which in essence capture the
      antagonistic nature of their relationship, produced the highest correlation with
      the clinical evaluation. CONCLUSIONS: It was suggested that a possible mechanism
      responsible for various running injuries could be lack of coordination between
      subtalar and knee joint actions. This mechanism may have potential for predicting
      runners with susceptibility to injury.

PMID- 10589871
TI  - Comparison of Abshaper and conventionally performed abdominal exercises using
      surface electromyography.
AB  - PURPOSE: Many commercially available pieces of abdominal exercise equipment have
      been introduced to facilitate endurance training of the abdominal musculature.
      One of the latest devices is the Abshaper. The aim of this study was to
      investigate whether there is any difference between abdominal exercises performed
      while using the Abshaper compared with those performed conventionally. METHODS:
      Using surface electromyography (EMG), the upper and lower regions of rectus
      abdominis (RA), the external oblique (EO), and sternocleidomastoid (SCM) muscles
      of 22 first-year physical therapy students were assessed. Each participant
      performed five straight trunk curls and five side trunk curls both with the
      Abshaper and conventionally. To test for differences in relative peak and mean
      EMG activity between the two modes of exercise execution, paired t-tests (alpha =
      0.05) were performed. Differences in the average time percentile at which peak
      EMG activity occurred were assessed by repeated measures ANOVA (alpha = 0.05).
      RESULTS: Exercises performed while using the Abshaper resulted in significantly
      greater relative peak and mean EMG activity within the upper portion of RA. For
      both the lower portion of RA and the EO muscles, no differences were found
      between the two modes of exercise execution. For SCM, Abshaper exercises resulted
      in significantly lower relative peak and mean EMG activity. In respect to the
      timing of peak EMG activity, no difference was found between the two modes of
      exercise execution for either the upper portion of RA, the EO, or SCM muscles.
      For lower RA, peak EMG activity occurred significantly earlier during
      conventional abdominal exercises in comparison with those performed while using
      the Abshaper. CONCLUSIONS: The Abshaper has a role in exercising the abdominal
      musculature.

PMID- 10589872
TI  - Comparing cycling world hour records, 1967-1996: modeling with empirical data.
AB  - PURPOSE: The world hour record in cycling has increased dramatically in recent
      years. The present study was designed to compare the performances of
      former/current record holders, after adjusting for differences in aerodynamic
      equipment and altitude. Additionally, we sought to determine the ideal elevation
      for future hour record attempts. METHODS: The first step was constructing a
      mathematical model to predict power requirements of track cycling. The model was
      based on empirical data from wind-tunnel tests, the relationship of body size to
      frontal surface area, and field power measurements using a crank dynamometer
      (SRM). The model agreed reasonably well with actual measurements of power output
      on elite cyclists. Subsequently, the effects of altitude on maximal aerobic power
      were estimated from published research studies of elite athletes. This
      information was combined with the power requirement equation to predict what each
      cyclist's power output would have been at sea level. This allowed us to estimate
      the distance that each rider could have covered using state-of-the-art equipment
      at sea level. According to these calculations, when racing under equivalent
      conditions, Rominger would be first, Boardman second, Merckx third, and Indurain
      fourth. In addition, about 60% of the increase in hour record distances since
      Bracke's record (1967) have come from advances in technology and 40% from
      physiological improvements. RESULTS AND CONCLUSIONS: To break the current world
      hour record, field measurements and the model indicate that a cyclist would have
      to deliver over 440 W for 1 h at sea level, or correspondingly less at altitude.
      The optimal elevation for future hour record attempts is predicted to be about
      2500 m for acclimatized riders and 2000 m for unacclimatized riders.

PMID- 10589873
TI  - Racing cyclist power requirements in the 4000-m individual and team pursuits.
AB  - PURPOSE: The purpose of this paper is: 1) to present field test data describing
      the power requirements of internationally competitive individual and team
      pursuiters, and 2) to develop a theoretical model for pursuit power based upon on
      these tests. METHODS: In preparing U.S. cycling's pursuit team for the 1996
      Atlanta Olympics, U.S. team scientists measured cycling power of seven subjects
      on the Atlanta track using a crank dynamometer (SRM) at speeds from 57 to 60 kph.
      By using these field data and other tests, mathematical models were devised which
      predict both individual and team pursuit performance. The field data indicate the
      power within a pace line at 60 kph averages 607 W in lead position (100%), 430 W
      in second position (70.8%), 389 W in third position (64.1%), and 389 W in fourth
      position (64.0%). A team member requires about 75% of the energy necessary for
      cyclists riding alone at the same speed. These results compare well with field
      measurements from a British pursuit team, to recent wind tunnel tests, and to
      earlier bicycle coast down tests. RESULTS: The theoretical models predict
      performance with reasonable accuracy when the average power potential of an
      individual or team is known, or they may be used to estimate the power of pursuit
      competitors knowing race times. The model estimates that Christopher Boardman
      averaged about 520 W when setting his 1996, 4000-m individual pursuit record of 4
      min 11.114 s and the Italian 4000-m pursuit team averaged about 480 W in setting
      their record of 4:00.958. Both used the "Superman" cycling position. CONCLUSIONS:
      These records would be very difficult to break using less aerodynamic riding
      positions, due to the extraordinarily high power requirements.

PMID- 10589874
TI  - Low back pain in elite rhythmic gymnasts.
AB  - BACKGROUND: Rhythmic gymnastics is a sport that blends the athleticism of a
      gymnast with the grace of a ballerina. The sport demands both the coordination of
      handling various apparatus and the flexibility to attain positions not seen in
      any other sport. To attain perfection and reproducibility of their routines, the
      athletes must practice and repeat the basic elements of their routines thousands
      of times. In so doing, the athlete places herself at risk of a myriad of overuse
      injuries, the most common being low back pain. METHODS: To document the presence
      and severity of low back pain in elite rhythmic gymnasts, a prospective study of
      seven national team members was undertaken that documented injuries and
      complaints with daily medical reports over a 7-wk period. These findings were
      correlated with a retrospective review of 11 elite level gymnasts followed over a
      10-month period whose complaints ultimately required evaluation by a physician.
      RESULTS: Eighty-six percent of the gymnasts in the prospective study complained
      of back pain at some point over the course of the study. The only injury recorded
      that required a time loss from sport was a low back injury. The most common
      complaint requiring a physician's evaluation was low back pain with the diagnoses
      varying from muscle strains to bony stress reaction or complete fracture of the
      pars inter-articularis (spondylolysis). No athlete had a spondylolisthesis or
      ruptured disk. Two had mild scolioses which did not appear to be associated with
      their low back pain. CONCLUSIONS: It would appear that rhythmic gymnasts are at
      relative increased risk of suffering low back complaints secondary to their
      sport.

PMID- 10589875
TI  - Nomenclature for aerobic and facultative bacteria.

PMID- 10589876
TI  - Microbiology terminology update: clinically significant anaerobic gram-positive
      and gram-negative bacteria (excluding spirochetes).

PMID- 10589877
TI  - Some medically important fungi and their common synonyms and names of uncertain
      application.

PMID- 10589878
TI  - Viral taxonomy.

PMID- 10589879
TI  - Classification of human parasites, vectors, and similar organisms.

PMID- 10589880
TI  - Infectious diseases on cruise ships.

PMID- 10589881
TI  - Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis
      and acute pyelonephritis in women. Infectious Diseases Society of America (IDSA).
AB  - This is part of the series of practice guidelines commissioned by the Infectious
      Diseases Society of America (IDSA) through its Practice Guidelines Committee. The
      purpose of this guideline is to provide assistance to clinicians in the diagnosis
      and treatment of two specific types of urinary tract infections (UTIs):
      uncomplicated, acute, symptomatic bacterial cystitis and acute pyelonephritis in
      women. The guideline does not contain recommendations for asymptomatic
      bacteriuria, complicated UTIs, Foley catheter-associated infections, UTIs in men
      or children, or prostatitis. The targeted providers are internists and family
      practitioners. The targeted groups are immunocompetent women. Criteria are
      specified for determining whether the inpatient or outpatient setting is
      appropriate for treatment. Differences from other guidelines written on this
      topic include use of laboratory criteria for diagnosis and approach to
      antimicrobial therapy. Panel members represented experts in adult infectious
      diseases and urology. The guidelines are evidence-based. A standard ranking
      system is used for the strength of the recommendation and the quality of the
      evidence cited in the literature reviewed. The document has been subjected to
      external review by peer reviewers as well as by the Practice Guidelines Committee
      and was approved by the IDSA Council, the sponsor and supporter of the guideline.
      The American Urologic Association and the European Society of Clinical
      Microbiology and Infectious Diseases have endorsed it. An executive summary and
      tables highlight the major recommendations. Performance measures are described to
      aid in monitoring compliance with the guideline. The guideline will be listed on
      the IDSA home page at http://www.idsociety.org It will be evaluated for updating
      in 2 years.

PMID- 10589882
TI  - Photo quiz. Cryptococcoma.

PMID- 10589884
TI  - Editorial response: Staphylococci vs. glycopeptides--how much are the battle
      lines changing?

PMID- 10589883
TI  - Bacteremia caused by staphylococci with inducible vancomycin heteroresistance.
AB  - The clinical significance of bacteremia due to vancomycin-heteroresistant
      staphylococci and a rapid laboratory screening method were examined; 203 strains
      of staphylococci isolated from patients with clinically significant bacteremia
      were screened by the disk-agar method with use of vancomycin-salt agar to
      demonstrate satellitism around an aztreonam disk as well as by conventional
      population screening. Eighteen isolates (three Staphylococcus aureus and 15
      coagulase-negative staphylococci) were shown to be heteroresistant to vancomycin.
      A case-control clinical study showed that the interval between admission and
      bacteremia, admission to the intensive care unit, prior use of vancomycin and/or
      beta-lactams, and isolation of methicillin-resistant staphylococci were
      significantly more common among patients with bacteremia due to staphylococci
      with heteroresistance to vancomycin; these patients had an overall mortality of
      44.4%. The use of vancomycin and admission to the intensive care unit were
      independently significant risk factors on multivariate analysis. Vancomycin
      heteroresistance is inducible by salt and beta-lactams. Indiscriminate sequential
      use of beta-lactams and glycopeptides may facilitate the emergence of
      glycopeptide resistance.

PMID- 10589885
TI  - Arcanum: The 19th-century Italian pharmacist pictured here was the first to
      characterize what are now known to be bacteria of the genus Serratia.

PMID- 10589886
TI  - Randomized trial of weekly sulfadoxine/pyrimethamine vs. daily low-dose
      trimethoprim-sulfamethoxazole for the prophylaxis of Pneumocystis carinii
      pneumonia after liver transplantation.
AB  - We conducted a prospective, randomized clinical trial among liver transplant
      patients to assess the efficacy and safety of weekly sulfadoxine/pyrimethamine
      compared with daily trimethoprim-sulfamethoxazole in the prevention of
      Pneumocystis carinii pneumonia. The studied drugs were given during 6 months
      after transplantation. One hundred twenty patients were included. None of the 60
      patients receiving weekly sulfadoxine/pyrimethamine developed Pneumocystis
      carinii pneumonia, whereas two cases (3%) developed among the 60 patients who
      received trimethoprim-sulfamethoxazole. For both patients, the studied medication
      had been discontinued several weeks earlier because of adverse effects. No
      differences were observed in the incidence of adverse effects. We conclude that
      weekly sulfadoxine/pyrimethamine is as effective and safe as is daily
      trimethoprim-sulfamethoxazole in the prophylaxis of Pneumocystis carinii
      pneumonia after liver transplantation.

PMID- 10589887
TI  - A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for
      the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus
      infected persons. Terry Beirn Community Programs for Clinical Research on AIDS
      (CPCRA)
AB  - We enrolled 2,625 human immunodeficiency virus-infected patients into a
      randomized trial to assess the efficacy and tolerability of daily vs. thrice
      weekly trimethoprim-sulfamethoxazole (160 mg/800 mg) for prophylaxis of
      Pneumocystis carinii pneumonia (PCP). The rate of PCP was 3.5 and 4.1 per 100
      person-years in the daily and thrice-weekly groups, respectively, with a relative
      risk (RR) of 0.82 (95% confidence interval [CI], 0.61-1.09; P = .16) (RR of <1.0
      favors daily trimethoprim-sulfamethoxazole). The RR for PCP determined by on
      treatment analysis was 0.59 (P = .03). The RR for death was 0.91 (P = .12); for
      bacterial pneumonia, 0.82 (P = .06); and for combined PCP and bacterial
      pneumonia, 0.84 (P = .04). Discontinuation due to adverse events occurred more
      commonly in the daily trimethoprim-sulfamethoxazole group (RR, 2.14; 95% CI, 1.73
      2.66; P < .001). Overall estimates for efficacy end points favored daily
      trimethoprim-sulfamethoxazole, although rates of intolerance were higher among
      patients receiving that dose. Daily trimethoprim-sulfamethoxazole may offer
      advantages as a first choice for PCP prophylaxis; thrice-weekly dosing is an
      appropriate option for patients intolerant of the daily dose.

PMID- 10589888
TI  - Editorial response: Prophylaxis for Pneumocystis carinii pneumonia--an evolving
      tale of two populations.

PMID- 10589889
TI  - Fluid replacement in dengue shock syndrome: a randomized, double-blind comparison
      of four intravenous-fluid regimens.
AB  - Dengue hemorrhagic fever and dengue shock syndrome (DSS) are major causes of
      childhood morbidity and mortality in many tropical countries. Increased
      intravascular permeability leading to shock is the cardinal feature of DSS. Fluid
      resuscitation to counteract massive plasma leakage is the mainstay of treatment.
      A double-blind, randomized trial comparing four intravenous-fluid regimens for
      acute resuscitation of 50 children with DSS was conducted. Colloids (dextran 70
      or the protein digest gelafundin 35,000) restored cardiac index and blood
      pressure and normalized hematocrit more rapidly than crystalloids (Ringer's
      lactate or 0.9%-weight/volume saline). Dextran 70 provided the most rapid
      normalization of the hematocrit and restoration of the cardiac index, without
      adverse effects, and may be the preferred solution for acute resuscitation in
      DSS. Further large-scale double-blind trials are required to provide an evidence
      based approach to the management of DSS.

PMID- 10589890
TI  - Editorial response: Resuscitation of patients with dengue hemorrhagic
      fever/dengue shock syndrome.

PMID- 10589891
TI  - Community-acquired methicillin-resistant Staphylococcus aureus in hospitalized
      adults and children without known risk factors.
AB  - Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections
      are not commonly recognized in healthy patients without predisposing risk. We
      performed a retrospective study of patients hospitalized with community-acquired
      MRSA infections from 1992 to 1996 in Honolulu to determine if community-acquired
      MRSA infections occurred in patients without known risk. Patients hospitalized
      within the previous 6 months or transferred from other hospitals or nursing homes
      were excluded. Epidemiological and clinical data were obtained from an inpatient
      chart review. Ten (71%) of 14 patients with community-acquired MRSA infection had
      no discernible characteristics of MRSA infections. Thirteen (93%) patients had
      skin or soft-tissue infections and one patient had MRSA pneumonia. Isolates from
      patients with MRSA infection were more likely to be susceptible to ciprofloxacin
      (P = .05), clindamycin (P = .03), and erythromycin (P = .01) than were those from
      MRSA-colonized patients. In our population, the majority of community-acquired
      MRSA infections occurred in previously healthy individuals without
      characteristics suggestive of MRSA transmission.

PMID- 10589892
TI  - Editorial response: Community-acquired methicillin-resistant Staphylococcus
      aureus infections--where do we go from here?

PMID- 10589893
TI  - Effective use of polymerase chain reaction for diagnosis of central nervous
      system infections.
AB  - Polymerase chain reaction (PCR)-based testing of cerebrospinal fluid (CSF)
      specimens has become standard for confirmatory diagnosis of central nervous
      system (CNS) infections; however, these tests increase health care costs. We
      reviewed 3-year data from 974 consecutive CSF specimens submitted for detection
      of seven pathogens by PCR. In 1997, 237 of 367 specimens (64.6%) were submitted
      for multiple tests, compared with 203 of 522 (38.9%) in 1996 and 18 of 85 (21.2%)
      in 1995. In each year the arrival of new house officers coincided with a peak in
      multiple testing. Among 732 specimens submitted for herpesvirus detection,
      results were positive for 24 (4.6%) of 523 specimens with increased leukocyte
      counts or protein levels. None of 209 specimens with normal leukocyte and protein
      levels were positive for herpesviruses. None of 471 CSF specimens submitted for
      Borrelia burgdorferi detection were PCR-positive. Use of protein and leukocytes
      to screen CSF specimens before employing PCR for herpesvirus detection would save
      almost one-third of costs without reducing sensitivity.

PMID- 10589894
TI  - Human hydatidosis in the central Andes of Peru: evolution of the disease over 3
      years.
AB  - To document the natural history of Echinococcus granulosus infection and response
      to treatment of human hydatidosis, we reexamined 28 of 37 subjects with E.
      granulosus infection diagnosed in an epidemiological study conducted in 1994.
      Twenty-six (70%) of those 37 subjects underwent abdominal ultrasonography, chest
      radiography, and enzyme-linked immunoelectrotransfer blot assay in 1997. Medical
      records from two additional individuals were reviewed. Eight patients had their
      cysts surgically removed during the 3-year follow-up interval; no surgical
      complications or recurrences occurred. Among eight patients with cystic disease
      not treated by surgery, four had cyst-growth ranging from 0.4 to 1.4 cm during
      the 3-year interval. One patient developed a new cyst and another's simple cyst
      became septate; two developed new calcifications. Of 12 seropositive subjects
      with no cysts present in 1994, 10 reverted to seronegative, a finding that
      suggests a significant proportion of seropositive subjects in echinococcus
      endemic regions may have only transient infection without disease. When cysts do
      develop, their growth rates and time courses are highly variable; over the 3-year
      period, we observed growth, septation, degeneration, and calcification of cysts.

PMID- 10589895
TI  - Antilipopolysaccharide II: an antibody protective against fatal melioidosis.
AB  - This was a study of IgG antibody responses to two S-type lipopolysaccharides (LPS
      I and LPS II) and flagellin of Burkholderia pseudomallei in patients with
      melioidosis. The specificity of these antibodies was 91.7%, 90.3%, and 93.8%,
      respectively, when compared to responses in a population where the organism is
      not endemic. Only the level of antibody to LPS II (anti-LPS II) was significantly
      higher in patients who survived than in those who died, as well as in patients
      with nonsepticemic vs. septicemic melioidosis. Results of logistic regression
      analysis, controlled for confounding factors such as duration of illness before
      treatment and bacteremic status, confirmed that a high level of anti-LPS II was a
      significant factor protective against fatal melioidosis. Thus, LPS II of B.
      pseudomallei would be a potentially useful component of a vaccine developed
      against fatal melioidosis. Further studies are in progress to determine the level
      of this antibody among those with asymptomatic infection in areas where
      melioidosis is endemic.

PMID- 10589896
TI  - Cross-Canada spread of methicillin-resistant Staphylococcus aureus via transplant
      organs.
AB  - We report our investigation of the transmission of methicillin-resistant
      Staphylococcus aureus (MRSA) through transplantation. The kidneys, liver, and
      corneas were harvested from a child who died in Nova Scotia. Several days
      postmortem it was learned that culture of a premortem endotracheal tube aspirate
      from the donor yielded MRSA. Both kidneys were transplanted into a child in Nova
      Scotia and the liver into a child in Alberta. Both recipients subsequently became
      blood culture-positive for MRSA. One corneal ring from the donor was MRSA
      positive. All four MRSA isolates were mecA-positive by polymerase chain reaction
      (PCR). The relatedness of the MRSA isolates was examined by restriction fragment
      length polymorphism (RFLP) analysis, a 16S-23S ribosomal PCR typing method, and
      comparison of antibiograms. Results were identical for all four MRSA isolates.
      These findings indicate that MRSA from the donor was transferred to recipients
      during implantation of harvested organs in Alberta and Nova Scotia, a cross
      Canada spread.

PMID- 10589897
TI  - Adherence of human immunodeficiency virus-infected patients to antiretroviral
      therapy.
AB  - The impact of demographic, psychosocial, and medical regimen-related variables on
      adherence of 123 human immunodeficiency virus (HIV)-infected patients to
      antiretroviral therapy was assessed by means of refill methodology. Satisfaction
      with social support (P = .029), problem-focused coping (P = .027), and active
      behavioral coping (P = .011) correlated significantly with adherence, whereas
      loss of motivation (P = .006), hopelessness (P = .16), and avoidant coping (p =
      .015) correlated with nonadherence. At the 6-month follow-up, the mean CD4 cell
      count differed significantly among adherent versus nonadherent patients (a mean
      increase of 78/mm3 vs. a mean decrease of 5/mm3; P = .018). Adherence did not
      correlate with the number of antiretroviral medications consumed per day (mean,
      3.0 vs. 2.5). Non-Caucasian patients were more likely to be nonadherent than
      Caucasian patients (relative risk, 2.5; 95% confidence interval, 1.2-5.3; P =
      .013); this difference was not explained by age, education, employment, income,
      history of intravenous drug use, or medical regimen. Non-Caucasian patients,
      however, were less satisfied with their social support (P = .04) and
      informational support (P = .016) and were more likely to utilize emotion-focused
      coping (P = .01). Thus, satisfaction with social support and coping style
      significantly impacted adherence and likely accounted for the observed racial
      difference in adherence among HIV-infected patients.

PMID- 10589898
TI  - Skeletal muscle involvement in falciparum malaria: biochemical and
      ultrastructural study.
AB  - Biochemical evidence of skeletal muscle damage is common in malaria, but
      rhabdomyolysis appears to be rare. To investigate the relationship between serum
      creatine kinase and myoglobin levels, muscle histology, and renal function in
      Plasmodium falciparum infections, we studied 13 patients with uncomplicated
      malaria, 13 with severe noncerebral malaria, and 10 with cerebral malaria. A
      muscle biopsy specimen was obtained from each patient for light microscopy and
      electron microscopy. Mean serum creatine kinase concentrations +/- SD were raised
      but similar for the three groups (258 +/- 277, 149 +/- 158, and 203 +/- 197 U/L,
      respectively; P = .5). The mean serum myoglobin level +/- SD was highest in
      cerebral malaria (457 +/- 246 vs. 170 +/- 150 and 209 +/- 125 ng/mL in
      uncomplicated and severe malaria, respectively; P < .01) and correlated with the
      mean serum creatinine level (r = .39 for 36 patients; P = .02). The number of
      intravascular parasites, proportion of mature forms, and glycogen depletion were
      highest in biopsy specimens from patients with cerebral malaria. Myonecrosis was
      not observed. Muscle appears to be an important site for P. falciparum
      sequestration, which could contribute to metabolic and renal complications.

PMID- 10589899
TI  - Acute pulmonary schistosomiasis in travelers returning from Lake Malawi, sub
      Saharan Africa.
AB  - We describe four cases of acute schistosomiasis presenting to the Infectious
      Diseases Unit of John Radcliffe Hospital (Oxford, England) during a 2-month
      period in autumn 1997. All four patients had swum in Lake Malawi, a freshwater
      lake in sub-Saharan Africa that is associated with Schistosoma haematobium and,
      less commonly, Schistosoma mansoni infections. All four patients had a severe
      acute illness and had prominent pulmonary involvement, both clinically and
      radiologically. This represents a change in the recognized pattern of
      presentation and could possibly reflect a new parasite variant in the lake.

PMID- 10589900
TI  - African trypanosomiasis in two travelers from the United States.
AB  - African trypanosomiasis is a rare but well-documented cause of fever in United
      States travelers returning from areas where it is endemic. We report two recently
      diagnosed cases that involved tourists who went on safari in Tanzania. Review of
      these and 29 other published cases indicates that disease in returning United
      States travelers is nearly always of the East African form, a fulminant illness
      for which prompt diagnosis is necessary. In the United States, timely and
      appropriate therapy for this disease has resulted in favorable outcomes for most
      patients. Chemoprophylaxis for East African trypanosomiasis is not recommended,
      but travelers visiting areas of endemicity should practice appropriate preventive
      measures to prevent tsetse fly bites.

PMID- 10589901
TI  - Resistance in Campylobacter species: increased resistance to fluoroquinolones and
      seasonal variation.
AB  - To identify epidemiological features of culture-proven campylobacter infections
      and to determine resistance rates, we conducted a 4-year demographic survey of
      culture-proven campylobacteriosis in one Dutch region. Examination of 24,435
      fecal specimens revealed 1,315 cases of campylobacteriosis (5.4%). The ofloxacin
      resistance rate among Campylobacter isolates increased from 11% to 29%.
      Resistance against tetracycline fluctuated between 7% and 15%, and resistance
      against erythromycin remained low. Resistance against fluoroquinolones was
      seasonally influenced, with relatively high rates during winter. We conclude that
      resistance of Campylobacter isolates to fluoroquinolones is still rising,
      probably because of the use of fluoroquinolones (enrofloxacin) in animal
      husbandry.

PMID- 10589902
TI  - Lessons from diagnostic investigations of patients with poliomyelitis and their
      direct contacts for the present surveillance of acute flaccid paralysis.
AB  - One of the key strategies for the global eradication of poliomyelitis is the
      virological investigation of stool samples in cases of acute flaccid paralysis
      (AFP) to exclude poliovirus as a possible cause. Clinical specimens from a
      serotype 3 outbreak provided an opportunity to examine the potential of newly
      developed methods for the diagnosis of poliomyelitis. The virus isolation rate
      was maximal (89.6%) during the first 2 weeks after the onset of paralysis and
      then dropped sharply to 18.6%. In contrast, a high percentage of patients tested
      positive for poliovirus-specific IgM (93.9%) in the early phase of the infection
      and remained positive for up to 8 weeks. Virus isolation would have correctly
      identified only 54.9% of the AFP cases. This rate would have been increased to
      92% through the use of the poliovirus-specific IgM ELISA. The IgM ELISA could
      serve as an important additional tool for the rapid diagnosis of poliomyelitis.

PMID- 10589903
TI  - Measles inclusion-body encephalitis caused by the vaccine strain of measles
      virus.
AB  - We report a case of measles inclusion-body encephalitis (MIBE) occurring in an
      apparently healthy 21-month-old boy 8.5 months after measles-mumps-rubella
      vaccination. He had no prior evidence of immune deficiency and no history of
      measles exposure or clinical disease. During hospitalization, a primary
      immunodeficiency characterized by a profoundly depressed CD8 cell count and
      dysgammaglobulinemia was demonstrated. A brain biopsy revealed histopathologic
      features consistent with MIBE, and measles antigens were detected by
      immunohistochemical staining. Electron microscopy revealed inclusions
      characteristic of paramyxovirus nucleocapsids within neurons, oligodendroglia,
      and astrocytes. The presence of measles virus in the brain tissue was confirmed
      by reverse transcription polymerase chain reaction. The nucleotide sequence in
      the nucleoprotein and fusion gene regions was identical to that of the Moraten
      and Schwarz vaccine strains; the fusion gene differed from known genotype A wild
      type viruses.

PMID- 10589904
TI  - Aortitis due to Salmonella: report of 10 cases and comprehensive review of the
      literature.
AB  - We describe ten cases of aortitis due to Salmonella that were treated at the
      University of Toronto-affiliated Hospitals between 1978 and 1997. Predisposing
      conditions included hypertension, diabetes mellitus, and myelodysplastic
      syndrome. Main presenting symptoms were fever and abdominal and back pain. The
      most frequent site involved was the abdominal aorta, followed by the thoracic
      aorta. All but one patient were treated with intravenous bactericidal
      antibiotics; seven also underwent surgery, four with axillobifemoral grafts and
      three with in situ grafts. Four of seven patients died within 1 month of the
      surgical procedure (three patients with in situ grafts and one patient with
      axillobifemoral graft). We also reviewed the pathogenesis, clinical and
      laboratory characteristics, and treatment of 140 cases of aortitis due to
      Salmonella reported in the literature since 1948. The use of bactericidal
      antibiotics, together with early surgical intervention and long-term suppressive
      antibiotic therapy, has led to improved survival.

PMID- 10589905
TI  - Nationwide survey in Italy of treatment of Streptococcus pyogenes pharyngitis in
      children: influence of macrolide resistance on clinical and microbiological
      outcomes. Artemis-Italy Study Group.
AB  - Throat swab specimens were obtained from 3,227 children with symptoms of acute
      pharyngotonsillitis. After 14 to 21 days, a second throat swab specimen was
      obtained at a follow-up visit. Over 42% of the 934 strains of Streptococcus
      pyogenes isolated in the primary study were resistant to erythromycin,
      azithromycin, and clarithromycin. Eradication rates among the 668 patients who
      entered the follow-up study were as follows: 84.1%, penicillin recipients; 82.7%,
      cephalosporin recipients; and 71.7%, macrolide recipients. Among patients treated
      with macrolides, the eradication rate was approximately 80% when the infecting
      organisms were erythromycin-susceptible and approximately 60% when they were
      erythromycin-resistant. These results indicate substantial in vitro macrolide
      resistance among Italian isolates of S. pyogenes. However, at least for a minor
      self-limiting condition such as acute S. pyogenes pharyngitis, our findings point
      to a limited overall correlation between in vitro susceptibility (to penicillins,
      cephalosporins, or macrolides) and eradication in patients treated with these
      drugs and an even weaker correlation between in vitro resistance (to macrolides)
      and noneradication in patients receiving macrolide therapy.

PMID- 10589906
TI  - Acute Q fever in adult patients: report on 63 sporadic cases in an urban area.
AB  - We report here 63 sporadic urban cases of acute Q fever diagnosed in 1985-1997.
      Fifty-eight men and five women were included; the mean age (+/- SD) was 35.6 (+/-
      10.2) years. Twenty-six patients had pneumonia, 30 had hepatitis, and 7 had a
      self-limited febrile illness. The most frequent radiological abnormalities were
      lobar or segmental alveolar opacities involving right lower lobes. Chronic
      bronchitis was significantly more frequent among patients with pneumonic Q fever
      (P = .01). Thirty-two patients' illnesses were diagnosed through seroconversion,
      12 by a fourfold increase in serum antibody titer, and 19 by initial high titers.
      Patients who initially received doxycycline had a significantly shorter duration
      of fever than those treated with erythromycin or other antibiotics (P = .0001 and
      P = .0004, respectively). No patient died. Acute Q fever affects mainly urban
      men, most frequently causing hepatitis, except in those with chronic bronchitis,
      who more frequently develop pneumonia. Hepatic Q fever presented with more
      pronounced increases in liver function test values than did pneumonic Q fever.
      Treatment with doxycycline caused a significant reduction in the duration of
      fever.

PMID- 10589907
TI  - Community-wide implementation of targeted testing for and treatment of latent
      tuberculosis infection.
AB  - Treatment of latent infection due to Mycobacterium tuberculosis will likely
      increase in importance as a strategy to prevent tuberculosis in the United
      States. This review was undertaken to assess how targeted testing and treatment
      of latent tuberculosis infection are currently organized, with a focus on the
      extension of those services from public health clinics to other community sites.
      Targeted testing programs are now being implemented in primary care neighborhood
      clinics, syringe-exchange programs, jails, and teen health clinics.
      Organizational issues at those new sites include the need for a tracking system
      for clinical follow-up and for incentives to promote adherence. There is
      increasing experience with directly observed treatment of latent tuberculosis
      infection. Communities that receive large numbers of immigrants and refugees
      should prioritize the evaluation of those whose chest radiographs are suggestive
      of tuberculosis. Current studies continue to point out imperfections in the
      current tools, such as the tuberculin skin test and isoniazid. Finally, the
      advent of managed care, especially for Medicaid recipients, presents both
      opportunities and challenges for expansion of population-based preventive health
      services.

PMID- 10589908
TI  - The body louse as a vector of reemerging human diseases.
AB  - The body louse, Pediculus humanus humanus, is a strict human parasite, living and
      multiplying in clothing. Louse infestation is associated with cold weather and a
      lack of hygiene. Three pathogenic bacteria are transmitted by the body louse.
      Borrelia recurrentis is a spirochete, the agent of relapsing fever, recently
      cultured on axenic medium. Historically, massive outbreaks have occurred in
      Eurasia and Africa, but currently the disease is found only in Ethiopia and
      neighboring countries. Bartonella quintana is now recognized as an agent of
      bacillary angiomatosis bacteremia, trench fever, endocarditis, and chronic
      lymphadenopathy among the homeless. Rickettsia prowazekii is the agent of
      epidemic typhus. The most recent outbreak (and the largest since World War II)
      was observed in Burundi. A small outbreak was also reported in Russia in 1997.
      Louse infestation appears to become more prevalent worldwide, associated with a
      decline in social and hygienic conditions provoked by civil unrest and economic
      instability.

PMID- 10589909
TI  - Prevalence of vancomycin-resistant enterococci among children with end-stage
      renal failure. Mid-European Pediatric Peritoneal Dialysis Study Group.
AB  - To evaluate the prevalence of colonization with vancomycin-resistant enterococcus
      (VRE) in end-stage renal failure (ESRF), we screened the intestinal flora from
      338 pediatric ESRF patients treated in 13 pediatric nephrology units in mid
      Europe. Eighty-one patients were undergoing hemodialysis, 66 were undergoing
      chronic peritoneal dialysis, and 191 were transplant recipients. A total of 363
      enterococcal strains were recovered from 232 patients. Twenty-seven enterococcal
      strains from 24 patients (7.1%) had reduced susceptibility to vancomycin (minimal
      inhibitory concentration [MIC], >4 microg/mL). Although two patients (0.6%)
      carried enterococci with high-level resistance to vancomycin (MIC, >32 microg/mL;
      i.e., VRE), strains of enterococcus with reduced susceptibility to vancomycin
      (ERSV) were recovered from the other 22 subjects. Past use of vancomycin (P =
      .05) and tacrolimus therapy (P = .011) were independent risk factors for ERSV or
      VRE carriage. Enterococcal infections occurred with a similar frequency among
      enterococcal carriers and noncarriers; no infections with VRE or ERSV were
      reported. In conclusion, the prevalence of ERSV carriage and the rate of VRE
      colonization among mid-European children and adolescents with ESRF currently are
      moderate and low, respectively.

PMID- 10589910
TI  - Visceral leishmaniasis (kala-azar) in solid organ transplantation: report of five
      cases and review.
AB  - Visceral leishmaniasis is an infectious disease that occurs only rarely in
      recipients of solid organ grafts but is associated with an elevated mortality
      rate despite proper treatment. We report five cases diagnosed in our hospital.
      All the patients were men aged 30 to 60 years who had undergone kidney
      transplantation (3 patients), heart transplantation (1), or liver transplantation
      (1). Three of the patients died, one had multiple recurrences, and one developed
      post-kala-azar cutaneous leishmaniasis. We review the clinical features,
      treatments, and outcomes of 26 previously reported cases, pointing out the lower
      cure rate associated with human immunodeficiency virus infection.

PMID- 10589911
TI  - Treatment of tularemia with fluoroquinolones: two cases and review.
AB  - Streptomycin, gentamicin, and tetracycline are currently considered the
      antimicrobials of choice for the treatment of tularemia. Preliminary data suggest
      that quinolones may be effective alternative agents; however, clinical experience
      is limited, and their role in treating severe disease is uncertain. We recently
      treated two acutely ill immunocompromised patients who had presumed "atypical"
      pneumonia with levofloxacin. Both patients had an excellent clinical response and
      were diagnosed with tularemia only when blood cultures subsequently yielded
      Francisella tularensis. Neither patient relapsed during 12 months of follow-up.
      Including our two cases, a total of 10 cases of tularemia treated with quinolones
      have been reported. In all 10 cases, a favorable clinical response was
      documented, and no relapses occurred. We conclude that the quinolones appear
      promising for the treatment of even severe tularemia, and they should be
      considered efficacious alternative agents for patients who do not require
      parenteral therapy or are intolerant of more standard treatment regimens.

PMID- 10589912
TI  - Risk factors for nosocomial candiduria due to Candida glabrata and Candida
      albicans.
AB  - The aims of this study were to analyze the clinical characteristics and risk
      factors associated with catheter-associated candiduria due to Candida glabrata
      and due to Candida albicans and to compare patients with candiduria due to C.
      glabrata or C. albicans (cases) with controls. Controls were a randomly chosen
      sample of inpatients with Foley catheters for whom urine cultures were negative
      for Candida species. Univariate and multivariate analyses were performed. There
      were 40 cases of C. glabrata candiduria and 289 cases of C. albicans candiduria.
      Factors strongly associated with both C. albicans candiduria and C. glabrata
      candiduria were female gender (P <. 05) and being in the intensive care unit (P
      <. 01). Fluconazole use (adjusted odds ratio, 4.37; P <. 01) and quinolone use
      (adjusted odds ratio, 3.16; P <. 01) were specifically associated with C.
      glabrata candiduria but not with C. albicans candiduria. In conclusion, patients
      receiving fluconazole treatment are at risk of developing C. glabrata candiduria.

PMID- 10589913
TI  - Group A beta-hemolytic streptococcus meningitis: clinical and microbiological
      features of nine cases.
AB  - Group A beta-hemolytic streptococcus (GAS) meningitis is a rare disease in
      adults. We conducted a retrospective study to describe clinical and
      microbiological features of nine cases of GAS meningitis in Switzerland. Of nine
      patients, six had neurosurgical conditions, and five had upper respiratory tract
      infections. Eight cases were community-acquired. The outcome of GAS meningitis
      was favorable; only one patient died of neurosurgical complications. No patient
      presented with toxic shock syndrome. Serotyping failed to reveal a dominant
      strain, and genotyping revealed that two strains carried the gene encoding the
      streptococcal pyrogenic exotoxin C and that one strain carried the gene encoding
      the streptococcal pyrogenic exotoxin A. Our observations suggest that GAS
      meningitis in adults is associated with neurosurgical conditions and/or an upper
      respiratory tract infection.

PMID- 10589915
TI  - Increase in community-acquired methicillin-resistant Staphylococcus aureus in
      children.

PMID- 10589914
TI  - Bloodstream infections caused by small-colony variants of coagulase-negative
      staphylococci following pacemaker implantation.
AB  - Small-colony variants (SCVs) of Staphylococcus aureus cause persistent and
      relapsing infections. Relatively little is known regarding infections caused by
      SCVs of coagulase-negative staphylococci. We report two cases of pacemaker
      electrode infections due to SCVs of Staphylococcus epidermidis and Staphylococcus
      capitis. Sequence analysis of a portion of the 16S rRNA gene (16S rDNA) confirmed
      the identity of the staphylococcal species as S. capitis and S. epidermidis.
      Isolates from cultures of blood obtained over at least a 2-week interval were
      compared by pulsed-field gel electrophoresis and found to be clonal even though
      the colony morphology was very different. Analysis for auxotrophism revealed
      hemin dependencies for all isolated SCVs. The two cases have several clinical and
      laboratory characteristics (which are also seen with S. aureus SCV infections)
      and strongly suggest that SCVs of coagulase-negative staphylococci must be
      actively sought, because they grow very slowly and can be easily missed.

PMID- 10589916
TI  - Recurrent panniculitis in a patient receiving protease inhibitor therapy for
      human immunodeficiency virus infection.

PMID- 10589917
TI  - Foscarnet treatment of genital infection due to acyclovir-resistant herpes
      simplex virus type 2 in a pregnant patient with AIDS: case report.

PMID- 10589918
TI  - Corynebacterium pseudodiphtheriticum--a skin pathogen.

PMID- 10589919
TI  - Isolation of Exophiala (Wangiella) dermatitidis in a case of otitis externa.

PMID- 10589920
TI  - Scrub typhus and military operations in Indochina.

PMID- 10589921
TI  - Single dose of azithromycin or three-day course of ciprofloxacin as therapy for
      epidemic dysentery in Kenya. Acute Dysentery Study Group.

PMID- 10589922
TI  - Isolation of Legionella longbeachae serogroup 1 from potting soils in Japan.

PMID- 10589923
TI  - Disseminated acanthamoeba infection in a patient with AIDS: response to 5
      fluorocytosine therapy.

PMID- 10589924
TI  - Centers for Disease Control and Prevention group O1 bacterium-associated
      pneumonia complicated by bronchopulmonary fistula and bacteremia.

PMID- 10589925
TI  - Chronic diarrhea associated with Vibrio alginolyticus in an immunocompromised
      patient.

PMID- 10589926
TI  - Acalculous cholecystitis associated with Plasmodium falciparum infection.

PMID- 10589928
TI  - Ureaplasma urealyticum: unusual cause of culture-negative mediastinitis.

PMID- 10589927
TI  - Cidofovir-induced end-stage renal failure.

PMID- 10589929
TI  - Prevalence of transfusion-transmitted virus among human immunodeficiency virus
      infected subjects in northern Italy.

PMID- 10589930
TI  - Detection of Pneumocystis carinii DNA in the air filter of a ventilated patient
      with AIDS.

PMID- 10589931
TI  - Case of false-positive results of the urinary antigen test for Legionella
      pneumophila.

PMID- 10589932
TI  - Case of vancomycin-resistant Enterococcus faecium infection associated with a
      transjugular intrahepatic portosystemic shunt that was treated with
      quinupristin/dalfopristin after bacteremia persisted with alatrofloxacin therapy.

PMID- 10589933
TI  - Facial palsy caused by Borrelia infection in a twin pregnancy in an area of
      nonendemicity.

PMID- 10589934
TI  - Fatal gastrointestinal mucormycosis that invaded the postoperative abdominal wall
      wound in an immunocompetent host.

PMID- 10589935
TI  - Coronary flow reserve in cardiac allograft vasculopathy.

PMID- 10589936
TI  - Detoxifying activity in pig livers and hepatocytes intended for xenotherapy.
AB  - BACKGROUND: Both livers and hepatocytes from pigs have been proposed for the
      treatment of end-stage liver diseases, as an alternative to allogeneic liver
      transplants. However, little is known of the capability of porcine hepatocytes to
      fulfill the biotransformation pathways of toxic compounds, including those
      released from livers in acute failure. We have studied the activity and
      expression of detoxifying enzymes in porcine livers and in cultured hepatocytes
      and their induction by phenobarbital. METHODS: Cytochromes P450 (CYP) 1A, 2B, and
      3A and GST-like activities were tested with the following specific substrates: 7
      ethoxyresorufin, 7-pentoxyresorufin, nifedipine, testosterone, 1-chloro-2,4
      dinitrobenzene, 1,2-dichloro-4-nitrobenzene, and ethacrinic acid. CYP 1A1/2-,
      2B1/2-, 2E1- and 3A4-related and GSTalpha proteins were analyzed by Western
      blotting and CYP 1A1/2, 2B1/2, 2C6, 2E1, and 3A4, aldehyde dehydrogenase, epoxide
      hydrolase, and GSTalpha-like RNA by Northern blotting. RESULTS: Enzymatic
      activities reflecting the expression of CYP 1A-, CYP 2B-, CYP 2E1-, and CYP 3A
      like genes, that is, ethoxyresorufin-O-deethylase, pentoxyresorufin-O-deethylase,
      nifedipine oxidase and testosterone 6beta-hydroxylase, and chlorzoxazone 6
      hydroxylase, were identified in pig livers. CYP 1A and CYP 2E1, GSTalpha-like
      proteins, CYP 1A, 2C, and 2E, epoxide hydrolase, aldehyde dehydrogenase, and GST
      like RNA were expressed in vivo and in vitro. CYP 2B and CYP 3A RNA and proteins,
      and their associated activities were induced by phenobarbital. CONCLUSIONS:
      Porcine hepatocytes express the most important biotransformation enzymes and
      their corresponding activities and RNA. Thus, livers and hepatocytes from pigs
      can detoxify a large spectrum of exogenous and endogenous compounds, which makes
      them a convenient substitute for allogeneic transplants for patients with liver
      failure.

PMID- 10589937
TI  - Long-term myocardial preservation: beneficial and additive effects of polarized
      arrest (Na+-channel blockade), Na+/H+-exchange inhibition, and Na+/K+/2Cl- 
      cotransport inhibition combined with calcium desensitization.
AB  - BACKGROUND: Polarized arrest, induced by tetrodotoxin (TTX) at an optimal
      concentration of 22 micromol/L, has been shown to reduce ionic imbalance and
      improve myocardial preservation compared with hyperkalemic (depolarized) arrest.
      Additional pharmacologic manipulation of ionic changes (involving inhibition of
      Na+ influx by the Na+/H+ exchanger [HOE694] and Na+/K+/2Cl- cotransporter
      [furosemide], and calcium desensitization [BDM]) may further improve long-term
      preservation. In this study, we (i) established optimal concentrations of each
      drug, (ii) determined additive effects of optimal concentrations of each drug and
      (iii) compared our optimal preservation solution to an established depolarizing
      cardioplegia (St Thomas' Hospital solution No 2: STH2) used during long-term
      hypothermic storage for clinical transplantation. METHODS: The isolated working
      rat heart, perfused with Krebs Henseleit (KH) buffer was used; cardiac function
      was measured after 20 min aerobic working mode perfusion. The hearts (n=6/group)
      were arrested with a 2 ml infusion (for 30 sec) of the polarizing (control)
      solution (22 micromol/L TTX in KH) or control+drug and subjected to 5 hr or 8 hr
      of storage at 7.5 degrees C in the arresting solution. Postischemic function
      during reperfusion was measured (expressed as percentage of preischemic
      function). RESULTS: Dose-response studies established optimal concentrations of
      HOE694 (10 micromol/L), furosemide (1.0 micromol/L) and BDM (30 mmol/L) in the
      polarizing (control) solution. Sequential addition to the control solution (Group
      I) of optimal concentrations of HOE694 (Group II), furosemide (Group III), and
      BDM (Group IV) were compared with STH2 (Group V); postischemic recovery of aortic
      flow was 29+/-7%, 49+/-6%*, 56+/-2%*, 76+/-3%*, and 25+/-6%, respectively
      (*P<0.05 vs. I and V). Creatine kinase leakage was lowest, and myocardial ATP
      content was highest in Group IV. CONCLUSIONS: A polarizing preservation solution
      (KH+TTX) containing HOE694, furosemide, and BDM significantly enhanced long-term
      preservation compared with an optimized depolarizing solution (STH2) used
      clinically for long-term donor heart preservation.

PMID- 10589938
TI  - Effect of islet transplantation on neuroelectrophysiological abnormalities in
      diabetic inbred Lewis rats: comparison of primary versus secondary prevention.
AB  - BACKGROUND: Neuroelectrophysiological abnormalities in diabetes indicate nervous
      function failure. Restoration of euglycemia by islet transplantation may prevent
      or reverse these abnormalities. METHODS: Pancreatic islets were transplanted in
      inbred Lewis rats after 15 days (Ta12, primary prevention) or 8 months (Tb12,
      secondary prevention) from streptozotocin-induced diabetes. Transplanted and
      control (normal and diabetic) rats were followed for a total period of 12 months.
      Metabolic parameters, somato-sensory, brain-stem auditory, and visual evoked
      potentials were determined at the beginning and at the end of the study and
      before transplantation for secondary prevention. RESULTS: The metabolic
      parameters in transplanted animals were similar to those of normal animals. Ta12
      and normal group somato-sensory conduction velocities did not vary and were
      always significantly higher than those of diabetic animals. By contrast, Tb12
      group conduction velocities showed only a partial improvement, values lying
      between those of diabetic and normal rats. Brain-stem auditory (waves I, II, and
      III) latencies in Ta12 group were similar to those of normal rats and
      significantly lower than those of diabetic animals (wave I: P<0.01; waves II and
      III: P<0.05). Tb12 group wave I and II latency values remained altered (P<0.005
      and P<0.01 versus normal values respectively). Visual evoked potentials-P1 wave
      latencies in transplanted rats were always higher than those of normal and
      diabetic animals. CONCLUSIONS: After primary prevention, central and peripheral
      neurological alterations were abolished. After secondary prevention,
      transplantation beneficial effects were partial, occurring mainly at peripheral
      level. These results highlight the importance of early transplantation to prevent
      hyperglycemia-dependent neuroelectrophysiological alterations.

PMID- 10589940
TI  - Identification of kidneys subjected to preretrieval warm ischemic injury by
      simultaneous monitoring of glomerular filtration and perfusate flow during
      hypothermic perfusion preservation.
AB  - BACKGROUND: Historically, ex vivo physiological evaluation of cadaveric renal
      allografts has been limited to assessing perfusate flow (PF) during hypothermic
      perfusion preservation (HPP). Using a small animal model, we have previously
      described a method for continuous monitoring of glomerular filtration rate (GFR)
      during HPP. Our study was undertaken to determine if monitoring GFR and PF during
      HPP distinguished kidneys subjected to preretrieval warm ischemic (WI) injury
      more reliably than PF alone. METHODS: In situ WI was induced in Lewis rats (n=10)
      by extrinsic occlusion of the suprarenal aorta for 30 min. After in situ cold
      perfusion and retrieval, the left kidney underwent 16 hr of HPP. Nonischemic (NI)
      control kidneys (n=10) were retrieved in the absence of suprarenal aortic
      occlusion. Longitudinal changes in PF, GFR, and filtration fraction (FF) during
      HPP were compared in WI versus NI kidneys (FF=GFR/PF x 100%). RESULTS: PF
      remained the same in both cohorts throughout HPP. GFR, however, increased to a
      significantly greater degree in WI versus NI kidneys during the first 4 hr of HPP
      (713+/-401 vs. 26+/-23%, respectively) (P<0.05). The increase in FF at 4 hr was
      1203+/-696% in the WI kidneys versus 83+/-46% in the NI controls (P<0.05).
      CONCLUSIONS: In contrast to PF alone, measurement of both PF and GFR
      distinguished kidneys subjected to pre-WI from NI controls. The data provide a
      means to determine if monitoring of both GFR and PF during HPP will predict short
      and long-term renal allograft function more reliably than PF alone.

PMID- 10589939
TI  - Neutrophil elastase and oxygen radicals enhance monocyte chemoattractant protein-
      expression after ischemia/reperfusion in rat liver.
AB  - BACKGROUND: The monocyte chemoattractant protein-1 (MCP-1) is produced during
      reperfusion injury and induces tissue factor that is the initiator of the
      clotting cascade. Neutrophil elastase is a crucial mediator of inflammatory
      tissue damage. Activation of the coagulation system stimulates cytokine
      production by activated leukocytes. We investigated the effects of neutrophil
      elastase and oxygen radicals generated by hypoxia associated with microthrombus
      formation on MCP-1 expression after ischemia/reperfusion in rat liver. METHODS:
      In vitro MCP-1 production by macrophages after stimulation with human neutrophil
      elastase (HNE) or oxygen radicals generated by hypoxanthine and xanthine oxidase
      was examined. Liver ischemia was induced in rats by occluding the portal vein for
      30 min. An inhibitor of human neutrophil elastase (ONO-5046*Na, 10 mg/kg) and
      antithrombin III (AT-III, 250 U/kg) were injected i.v. 5 min before vascular
      clamping. Serum concentrations of MCP-1 were measured by enzyme-linked
      immunosorbent assay. RESULTS: Human neutrophil elastase or oxygen radicals
      significantly enhanced in vitro MCP-1 production by macrophage. Serum MCP-1
      concentrations reached a peak at 6 hr after reperfusion and then gradually
      decreased. However, pretreatment of animals with AT-III or ONO-5046*Na alone
      resulted in significantly smaller increases in serum concentrations of MCP-1
      after reperfusion. Pretreatment with both ONO-5046*Na and AT-III produced
      additive effects. The combined treatment with ONO-5046*Na and AT-III
      significantly reduced MCP-1 mRNA in liver after ischemia/reperfusion.
      CONCLUSIONS: MCP-1 production by macrophages is stimulated by neutrophil elastase
      and oxygen radicals generated by hypoxia, probably due to microthrombus formation
      after ischemia/reperfusion of the rat liver.

PMID- 10589942
TI  - Predictors of reduced coronary flow reserve in heart transplant recipients
      without angiographically significant coronary artery disease.
AB  - BACKGROUND: Determination of coronary flow reserve (CFR) is increasingly used to
      assess the functional significance of cardiac allograft vasculopathy. Although
      the relation between CFR and angiographically defined vasculopathy has been
      studied extensively, little is known about other factors determining CFR in heart
      transplant recipients without significant lesions by coronary angiography.
      METHODS: Sixty consecutive patients were studied 0.5 to 148 months after heart
      transplantation with intracoronary Doppler and intravascular ultrasound. An
      endothelium-independent CFR< or =2.5 was defined as abnormal. Stepwise logistic
      regression analysis was used to identify factors (demographic data of donor and
      recipient, lipid profile, epicardial vessel morphology by intravascular
      ultrasound, left ventricular hypertrophy, acute rejection episodes, and
      hemodynamics) potentially associated with a reduced CFR. RESULTS: Only the
      presence of left ventricular hypertrophy (48% vs. 14%, P=0.007 and P=0.023,
      bivariate and multivariate analysis, respectively) and higher donor ages (41+/-12
      vs. 29+/-11 years, P=0.002 and P=0.013, bivariate and multivariate analysis,
      respectively) showed an independent association with an abnormal flow reserve.
      CFR in patients with left ventricular hypertrophy was reduced due to higher
      baseline flow velocities (27+/-11 vs. 20+/-6 cm/sec, P=0.004). Furthermore,
      resting flow velocity increased as a function of donor age (r=0.264, P=0.047),
      while hyperemic flow velocity was not different. Other patient characteristics
      and hemodynamics did not affect CFR. CONCLUSION: The presence of left ventricular
      hypertrophy and higher donor ages independently contribute to a reduced CFR in
      patients after heart transplantation. This reduction in CFR is due to elevated
      baseline flow velocities rather than to a change in hyperemic flow velocities.
      These findings should be taken into account for the interpretation of reduced CFR
      values obtained by intracoronary Doppler in heart transplant recipients without
      angiographically overt coronary lesions.

PMID- 10589941
TI  - Cerebrovascular metabolic autoregulation is impaired during liver
      transplantation.
AB  - BACKGROUND: We determined whether the coupling between cerebral blood flow (CBF)
      and oxygen metabolism (CMRO2) is preserved during liver transplantation. Because
      of cerebrovascular dilatation, we hypothesized that cerebral metabolic
      autoregulation is impaired, because CBF becomes uncoupled from CMRO2 during the
      reperfusion phase of the operation. MATERIALS AND METHODS: In a prospective
      study, 13 patients (8 women, median age 46, range 21-6) with liver failure (10
      with end-stage chronic liver disease and 3 with acute liver failure) were
      enrolled. Catheters were placed in a femoral artery and in the internal jugular
      vein for calculation of the cerebral arteriovenous oxygen content difference
      (AVDO2). CBF was recorded by the 133Xenon injection technique, and by
      transcranial Doppler sonography determined mean flow velocity (Vmean) in the
      middle cerebral artery. The CMRO2 was calculated as the AVDO2 times CBF and the
      cerebrovascular resistance (CVR) as the mean arterial pressure to CBF ratio. An
      index of large cerebral artery diameter was expressed by the CBF to Vmean ratio.
      RESULTS: From induction of anesthesia to the anhepatic period, CBF decreased from
      a median of 47 (interquartiles 31-55) to 41 (37-48) ml 100 g(-1) min(-1), whereas
      the CMRO2 remained unchanged (1.3 [0.9-2.5] vs. 1.7 [0.9-2.3] ml 100 g(-1) min(
      1)). In the reperfusion phase, the CBF increased to 51 (45-54) ml 100 g(-1) min(
      1), whereas the CMRO2 remained unchanged at 1.1 (1.0-2.5) ml 100 g(-1) min(-1).
      The CVR decreased from 2.0 mm Hg (1.4-2.1) to 1.4 (1.1-1.8) mm Hg(-1) min 100 g
      ml. In the anhepatic phase, mean arterial pressure decreased from 92 mm Hg (84
      98) to 85 (80-92) mm Hg and at reperfusion it was 80 (71-105) mm Hg. From the
      anhepatic to the reperfusion phase, the CBF increased 7% (0 to 26) for each mm Hg
      concomitant increase in PaCO2. The CBF to Vmean ratio remained stable (1.0 [0.8
      1.2] vs. 0.9 [0.7-1.1] ml 100 g(-1) min(-1) cm(-1) sec). CONCLUSION: During the
      reperfusion phase of liver transplantations, cerebrovascular dilatation uncouples
      cerebral oxidative metabolism from blood flow. The increase in CBF is beyond what
      can be explained by changes in arterial carbon dioxide tension and arterial
      pressure.

PMID- 10589943
TI  - Differences in gastric motor activity in renal transplant recipients treated with
      FK-506 versus cyclosporine.
AB  - BACKGROUND: Little is known concerning gastric motility after renal
      transplantation and on the impact of immunosuppressants on gastric emptying.
      METHODS: Gastric emptying was measured in renal transplant recipients, taking
      different immunosuppressive therapy (steroids and cyclosporine/azathioprine/FK
      506), and compared with normal volunteers. RESULTS: After renal transplantation,
      gastric emptying of liquids was normal, irrespective of the type of
      immunosuppression. However, solid gastric emptying was significantly faster in FK
      506-treated patients compared with patients taking cyclosporine for all measured
      emptying parameters. Compared with normal volunteers solid gastric emptying was
      slower in patients taking cyclosporine, comparable in azathioprine treated
      patients, and characterized by an unusual short lag phase in patients taking FK
      506. CONCLUSIONS: In stable renal transplant recipients gastric emptying of
      solids was significantly faster in patients on FK-506 compared with patients
      taking cyclosporine. Therefore, FK-506 may be the immunosuppressant of choice
      after solid organ transplantation in patients with problems related to
      gastroparesis.

PMID- 10589944
TI  - The role of hepatitis C and B virus infections as risk factors for severe liver
      complications following allogeneic BMT: a prospective study by the Infectious
      Disease Working Party of the European Blood and Marrow Transplantation Group.
AB  - BACKGROUND: Severe liver disease, including fulminant hepatic failure and
      venoocclusive disease can occur after bone marrow transplantation (BMT). The aim
      of our study was to assess risk factors for veno occlusive disease and severe
      liver disease occurring within 6 months from BMT. METHODS: A total of 193
      consecutive patients from 15 BMT Centers were prospectively enrolled between
      January and June 1995. Data on donors and recipients before and after transplant
      were collected and included age, gender, alanine aminotransferase (ALT),
      hepatitis B (HBV), and hepatitis C virus (HCV) markers, hematological disease,
      status and type of BMT, conditioning regimen and graft versus host disease
      prophylaxis. Statistical analysis included univariate descriptive and
      multivariate analysis based on logistic regression on major end-points. RESULTS:
      Forty-three of 193 patients died during the study period, and liver disease was
      the main cause of death (13 of 43, 30%). Incidence of severe veno occlusive
      disease was 8%, fulminant hepatic failure 0.5% and 12% of cases had ALT >500 U/L
      (normal < or =42 U/L). A de novo HBV or HCV infection occurred in 3.2 and 7% of
      patients respectively. Predictive risk factors for life-threatening liver disease
      were: unrelated donors (relative risk=5.8, confidence interval=1.7-19.8) and
      abnormal BMT donor ALT (relative risk=6.3, confidence interval=1. 5- 25.5).
      CONCLUSIONS: This study indicates that ongoing or previous infection with HBV or
      HCV in donor or recipient is not an absolute contraindication for BMT. However,
      abnormal ALT levels in BMT donors were a significant predictor of potentially
      lethal liver complications. The occurrence of de novo HBV or HCV infection did
      not correlate with severity of liver disease observed in the first 6 months
      posttransplant. These findings should be carefully evaluated before disregarding
      HBV or HCV positive siblings with normal transaminase levels in favor of
      unrelated donors.

PMID- 10589945
TI  - Obese living kidney donors: short-term results and possible implications.
AB  - BACKGROUND: Living kidney donation has increased recently as the shortage of
      cadaveric organs continues. This increase has occurred in part, due to expanded
      donor criteria, including obese patients. This is a potential concern because
      obesity is associated with surgical complications, possibly death, and chronic
      medical problems. To address this concern, we examined the outcome of a large
      group of obese (ObD) and nonobese living kidney donors (NObD). METHODS: A total
      of 107 obese (body mass index> or =27 kg/m2) and 116 nonobese (body mass index<27
      kg/m2) living kidney donors donating at a single institution between 1990 and
      1996 were studied. Surgical complications, operative duration, and hospital
      length of stay were assessed. Preoperative blood pressure, serum creatinine,
      creatinine clearance, protein excretion, fasting glucose, and hemoglobin A1C were
      measured and first degree relatives with diabetes were identified. RESULTS:
      Overall complications were significantly more common in ObD, 16.8 vs. 3.4%
      (P=0.0012). The majority of complications in the entire cohort, 56%, were wound
      related and were significantly more common in ObD (P=0.016). There was no
      significant increase in nonwound-related infections, bleeding, or cardiopulmonary
      events. There were no deaths or major complications. Operative time was
      significantly longer in ObD 151+/-30 vs. 141+/-29 min (P<0.05) but hospital
      duration was no different. Predonation, blood pressure in ObD was significantly
      higher, (P<0.05) and they more often had a family history of diabetes, 46 vs. 30%
      (P<0.05) than nonobese donors. Renal function, proteinuria, fasting glucose, or
      hemoglobin A1C were no different. CONCLUSION: With prudent selection, the use of
      obese living kidney donors appears safe in the short term. They experience more
      minor complications, usually wound related, and slightly longer operations. Given
      a higher baseline blood pressure and family history of diabetes, the long-term
      effect on the remaining solitary kidney in ObD needs to be examined.

PMID- 10589946
TI  - Infectious complications in geriatric renal transplant patients: comparison of
      two immunosuppressive protocols.
AB  - BACKGROUND: It has been well documented that a regimen of mycophenolate mofetil
      (MMF), cyclosporine (CsA), and prednisone (Pred) reduces the incidence of acute
      rejection in renal transplant recipients, as compared with previous regimens
      based on azathioprine (AZA), CsA, and Pred. In the general renal transplant
      patient population, immunosuppressive regimens that include MMF are usually well
      tolerated. It is not clear whether this holds true for older transplant
      recipients, who may be more susceptible to complications from the greater
      immunosuppression conferred by MMF. METHODS: We retrospectively analyzed our
      geriatric renal transplant population (age >60 years, 1990-1998) and compared a
      cohort of 46 patients treated with AZA, Pred, and CsA to a cohort of 45 patients
      treated with MMF, Pred, and CsA. RESULTS: There were no significant differences
      between the groups with regard to pretransplantation demographics. Patient and
      graft survival during the first year was not significantly different between the
      groups. During the first year of follow-up, we observed 27 infections requiring
      hospitalization in 15 patients in the MMF-treated group as compared with 10
      infections in 7 patients in the AZA-treated group. A Cox proportional hazard
      model accounting for the above mentioned covariates isolated MMF versus AZA as a
      significant risk factor for the occurrence of serious infectious events (all:
      P<0.01; cytomegalovirus, fungal: P<0.01). CONCLUSION: We conclude that an
      immunosuppressive regimen of MMF, CsA, and Pred seems to be correlated with an
      increased incidence of infectious adverse events as compared with AZA, CsA, and
      Pred in elderly patients.

PMID- 10589947
TI  - Famciclovir treatment of chronic hepatitis B in heart transplant recipients: a
      prospective trial.
AB  - Hepatitis B may take a rapid and aggressive course in patients under
      immunosuppression. Nucleoside analogues have been shown to suppress viral
      replication effectively. To investigate the effect of famciclovir in
      immunosuppressed patients, 21 heart transplant recipients with chronic hepatitis
      B infection were included in a prospective study. PATIENTS AND METHODS: Patients
      have been treated with Famciclovir for a median of 14 months. Hepatitis B virus
      replication and biochemical parameters were regularly tested and liver biopsies
      were taken before treatment and after a median time of 7 months. HBV-polymerase
      was sequenced in all patients before therapy and in those patients who
      experienced virological breakthrough. RESULTS: Nineteen patients were treated for
      at least 6 months. Hepatitis B virus-DNA levels declined in all patients and
      became negative in 8 patients. Mean hepatitis B virus-DNA levels decreased from
      199+/-269 to 34+/-53 pg/ml after 24 weeks (P=0.003). During treatment HBeAg
      became negative in five patients. Mean alanine aminotransferase decreased from
      42+/-26 to 24+/-10 U/L (P=0.006). Histological analysis revealed improved
      inflammatory activity according to the Ishak-score in 11/16 (69%) patients. Total
      inflammatory activity scores decreased from 8 to 6 (median, NS), but interface
      hepatitis score (P=0.02) and lobular inflammation score (P=0.006) improved
      significantly. Median fibrosis scores fell from 5 to 3 (P=0.002). Three patients
      developed virological breakthrough on famciclovir after 7, 8, and 26 months of
      treatment showing HBV-polymerase amino acid changes L528 M, S567A, and I581K,
      respectively. CONCLUSIONS: Famciclovir improves not only biochemical and
      virological features but also hepatic inflammation and liver fibrosis in patients
      with chronic hepatitis B under heavy immunosuppression. Virological breakthrough
      may develop and requires close monitoring.

PMID- 10589948
TI  - Quantification of serum HCV core antigen by a fluorescent enzyme immunoassay in
      liver transplant recipients with recurrent hepatitis C--clinical and virologic
      implications.
AB  - BACKGROUND: Monitoring hepatitis C viremia may be useful in the management of
      liver transplant patients with recurrent hepatitis C virus (HCV) infection. The
      clinical utility of a newly described fluorescent enzyme immunoassay for the
      detection of serum HCV core antigen was evaluated. METHODS: Serum samples
      prospectively collected from 57/63 consecutive patients transplanted for HCV
      related end-stage liver disease were assayed for both serum HCV core antigen by
      fluorescent enzyme immunoassay and HCV RNA level using a branched chain DNA
      signal amplification assay. HCV genotype was determined by restriction fragment
      length polymorphism analysis based on 5' untranslated region. One- and 2-year
      annual protocol liver biopsies from these patients were graded for inflammation,
      fibrosis, and cholestasis RESULTS: Serum HCV core antigen and HCV RNA were
      detected in a similar proportion of samples (256/ 281 vs. 260/281, P=NS), and
      there was an excellent correlation between assays (r2=0.905, P<0.0001)
      independent of HCV genotype. A conversion equation between HCV core antigen and
      HCV RNA was constructed to estimate the HCV core antigen to RNA ratio to be
      around 231 to 1. Mean serum HCV core antigen levels peaked initially at 3 months
      posttransplant but there was significant interpatient variation as to when peak
      levels occurred. A high serum HCV core antigen level in the first 6 months was
      associated with histological deterioration in terms of bridging fibrosis,
      cirrhosis, severe cholestasis, or retransplantation by 2-year follow-up.
      CONCLUSION: Determination of serum HCV core antigen level reflects HCV viremia
      and may have clinical implications in liver transplant patients with HCV
      recurrence.

PMID- 10589949
TI  - Epstein-Barr virus-induced posttransplant lymphoproliferative disorders.
      ASTS/ASTP EBV-PTLD Task Force and The Mayo Clinic Organized International
      Consensus Development Meeting.
AB  - Epstein-Barr virus-induced posttransplant lymphoproliferative disease (EBV-PTLD)
      continues to be a major complication after solid organ transplantation in high
      risk patients. Despite the identification of risk factors that predispose
      patients to develop EBV-PTLD, limitations in our knowledge of its pathogenesis,
      variable criteria for establishing the diagnosis, and lack of randomized studies
      addressing the prevention and treatment of EBV-PTLD hamper the optimal management
      of this transplant complication. This review summarizes the current knowledge of
      EBV-PTLD and, as a result of two separate international meetings on this topic,
      and provides recommendations for future areas of study.

PMID- 10589950
TI  - Sirolimus reduces the incidence of acute rejection episodes despite lower
      cyclosporine doses in caucasian recipients of mismatched primary renal
      allografts: a phase II trial. Rapamune Study Group.
AB  - BACKGROUND: The novel agent sirolimus (SRL; Rapamune; rapamycin) inhibits the
      immune response by a mechanism distinct from those of calcineurin antagonists or
      antimetabolites. This randomized, controlled, multicenter, single blind, phase II
      trial examined the combination of SRL, steroids, and full versus reduced doses of
      cyclosporine (CsA) for prophylaxis of acute renal allograft rejection. METHODS: A
      total of 149 recipients of mismatched cadaveric- or living-donor primary renal
      allografts were randomized into six groups. Three groups received placebo or 1 or
      3 mg/m2/day SRL, as well as steroids and full-dose CsA (Sandimmune). Three groups
      received steroids, reduced-dose CsA (target trough level 50% of full-dose range),
      and 1, 3, or 5 mg/m2/day SRL. RESULTS: The incidence of biopsy-proven acute
      rejection episodes within the first 6 months after transplant was reduced from
      32.0% in the control group to 8.5% in patients receiving SRL (1 or 3 mg/m2/day)
      and full-dose Sandimmune CsA (P=0.018). Similar low rates of acute rejection
      episodes were observed among non-African-Americans, but not African-Americans,
      treated with SRL and reduced-dose Sandimmune CsA. Despite the augmented
      immunosuppression, 1-year patient and graft survival rates did not differ
      significantly across groups. Adverse effects attributable to CsA, including
      hypertension and new-onset diabetes mellitus, were not exacerbated by SRL. Except
      for an increased incidence of pneumonia among patients receiving full-dose CsA
      and 3 mg/m2/day SRL, the incidences of opportunistic infections were similar in
      all treatment groups. Although SRL produced more frequent, but reversible,
      hematological and lipid abnormalities, it had no apparent nephrotoxic effects to
      exacerbate CsA-induced renal dysfunction. CONCLUSIONS: SRL in combination with
      CsA and steroids not only lowers the incidence of biopsy-proven acute renal
      allograft rejection episodes, but also may permit CsA sparing, at least among
      Caucasian patients, without an increased risk of rejection.

PMID- 10589951
TI  - The effects of maintenance doses of FK506 versus cyclosporin A on glucose and
      lipid metabolism after orthotopic liver transplantation.
AB  - BACKGROUND: Posttransplant diabetes mellitus (PTDM) has gained widespread
      attention due to the micro and macro-vascular complications that increase the
      morbidity and mortality of patients receiving solid organs. The higher incidence
      of PTDM has been mainly attributed to the immunosuppressive therapy. Therefore,
      this study compares the metabolic side effects of low dose maintenance therapy of
      FK-506 and Cyclosporin A (CsA) in 14 patients 1 year after orthotopic liver
      transplant and analyzes possible factors that contribute to the development of
      PTDM. METHODS: Two groups (n=7) differing in their immunosuppressive regimen
      (FK506 or CsA) were matched to eight control subjects and compared to each other.
      The effects of in vivo insulin action were assessed by means of the euglycemic
      hyperinsulinemic clamp technique. Arginine stimulation tests at normo- (5.5 mM)
      and hyperglycemic (15 mM) levels were performed and the acute insulin, C-peptide,
      and glucagon response (2-5 min) to arginine were determined. RESULTS: Insulin
      sensitivity (total glucose disposal) was statistically lower in patients treated
      with FK-506 and CsA (5.05+/-0.47 and 5.05+/-0.42 mg/kg/min) as compared to
      controls (6.62+/-0.38 mg/kg/min) (P<0.02), with a significantly higher
      nonoxidative glucose disposal for the control group (P<0.01), and lower free
      fatty acid levels (P<0.05). Absolute values for acute insulin response were
      higher but not significantly different for the transplanted groups. The lower
      percentage of increase of insulin release after arginine stimulation observed in
      the FK-506 and CsA groups as compared with controls (754%+/-100, 644%+/-102 vs.
      1191%+/-174) (P<0.03 and 0.02, respectively), suggests a reduced beta cell
      secretory reserve in both treated groups. Also, the acute glucagon response to
      arginine during hyperglycemia declined less in the FK-506 (28%) and CsA groups
      (29%) compared with controls (48%) (P<0.05) indicating a defect in the pancreatic
      beta cell-alpha cell axis. CONCLUSIONS: There are no major metabolic differences
      on low maintenance doses between FK-506 and CsA. Both immunosuppressant agents
      contribute to the development of PTDM at different levels.

PMID- 10589952
TI  - Susceptibility of lung transplants to preformed donor-specific HLA antibodies as
      detected by flow cytometry.
AB  - BACKGROUND: Preformed anti-HLA antibodies are known to have the potential to
      induce early graft damage in organ transplant recipients. However, in lung
      transplant recipients, little information exists about the significance of
      preformed antibodies directed to either class I or class II HLA antigens.
      METHODS: A two-color flow cytometry cross-match was performed in 92 consecutive
      lung transplant recipients using serum obtained immediately before
      transplantation. The presence of preformed antibodies was correlated with the
      incidence of severe graft dysfunction manifested as pulmonary infiltrates and
      severe hypoxemia with onset in the first few hours after transplantation.
      RESULTS: Six patients (6.5%) had low-level anti-donor IgG antibodies detected by
      flow cytometry, four against T and two against B lymphocytes. Three patients
      (50%) developed severe graft dysfunction with pulmonary infiltrates and
      hypoxemia. Two patients responded to treatment, but the third, who had an
      antibody highly specific for HLA-DR11, died at 48 hr after transplant. Results of
      histopathologic studies in this patient are consistent with hyperacute rejection
      and support a pathogenic role of these antibodies. In contrast, of 86 (93.5%)
      cases with a negative flow cytometry cross-match, only 4 (5%) had severe but
      reversible early graft dysfunction with pulmonary infiltrates and hypoxemia,
      attributed to ischemia-reperfusion injury (P<0.005). CONCLUSIONS: Class II, and
      perhaps class I HLA antibodies at relatively low concentrations represent a risk
      factor for severe early pulmonary graft dysfunction, with the potential to
      progress to hyperacute rejection and death.

PMID- 10589953
TI  - A study of cytokine protein secretion, frequencies of cytokine expressing cells
      and IFN-G gene polymorphisms in normal individuals.
AB  - BACKGROUND: Cytokines are major regulators of immune responses, and there is
      evidence that they play a role in allograft rejection. Before embarking on a
      detailed study of pretransplant cytokine profiles in renal allograft recipients,
      we wished to investigate variations in cytokine protein secretion, numbers of
      cytokine expressing T cells, and cytokine gene polymorphisms in normal
      volunteers. METHODS: Twenty normal healthy volunteers were studied. Cytokine
      protein secretion [interleukin- (IL) 2, IL-4, IL-10, and interferon- (IFN) y] and
      numbers of cytokine expressing CD3+ T cells (IL-2, IL-4, IL-10, and IFN-gamma)
      were quantified by means of enzyme-linked immunosorbent assay and two-color flow
      cytometry respectively. IFN-gamma gene polymorphisms were determined by
      polymerase chain reaction and autoradio graphy. RESULTS: Large interindividual
      variations in both the quantity of IL-2, IL-4, IL-10, and IFN-gamma cytokine
      protein secreted and numbers of IL-2 and IFN-gamma expressing T cells were
      demonstrated. However, numbers of IL-4 and IL-10 expressing cells were found to
      be below detectable limits by flow cytometry. In the case of IFN-gamma, a bi
      modal distribution was seen for the quantity of protein secreted. In addition,
      correlations were observed between IL-2 protein and frequency of IL-2 expressing
      T cells. However, no relationship was found between IFN-gamma protein levels,
      numbers of IFN-gamma expressing cells and IFN-gamma gene polymorphisms.
      CONCLUSIONS: We have demonstrated large differences in both numbers of T helper 1
      cytokine expressing cells and the quantity of T helper 1 and T helper 2 cytokine
      protein secreted between normal individuals. Although the amount of IL-2 protein
      secreted appeared to be determined by the frequency of IL-2 expressing cells,
      this was not the case for IFN-gamma.

PMID- 10589954
TI  - Human T cell responses to human and porcine endothelial cells are highly
      sensitive to cyclosporin A and FK506 in vitro.
AB  - BACKGROUND: Human T cells proliferate in response to both human umbilical vein
      endothelial cells (HUVEC) and porcine aortic endothelial cells (PAEC) via the
      second signals LFA-3/CD2 and B7-2 (CD86), respectively. Previous studies have
      shown that stimulation of T cells via CD28 or phorbol myristate acetate (PMA)
      activation is highly resistant to inhibition by cyclosporine A (CsA) and
      tacrolimus (FK506), as is the response of T cells to phytohemmaglutinin in the
      presence of endothelial cells. We have investigated the inhibitory effects of CsA
      and FK506 on the direct response of human CD4+ T cells to HUVEC and PAEC and the
      effect of adding B7-1 transfectants. METHODS: T cell proliferation, interleukin-2
      release bioassays and a multiple cytokine bioassay employing the TF-1 cell line
      were used as indicators of T cell responses to HUVEC and PAEC either in the
      presence or absence of CsA and FK506. In some experiments, B7-1 transfectants
      were also added. RESULTS: Proliferative responses and interleukin-2 release were
      highly sensitive to CsA, the ID50 being significantly less for HUVEC (6.5 ng/ml)
      than PAEC (15 ng/ml). The ID50 of CsA for the mixed lymphocyte response (MLR) was
      similar to PAEC (18.6 ng/ml), all these values being significantly less than the
      T cell activation by phytohemmaglutinin (PHA) (227 ng/ml). Addition of B7-1
      transfectants significantly increased interleukin-2 production by T cells/HUVEC
      and resistance to CsA was greatly increased to an ID50 of > 1000 ng/ml. In
      contrast, addition of B7-1 transfectants to T cells/PAEC had no effect either on
      T cell proliferation, IL-2 production, or CsA resistance. Similar results were
      obtained with FK506. Using the TF-1 cell line, it was determined that cytokines
      other than IL-2 are released during CD4+ T cell/EC interactions, with similar
      sensitivity to CsA and FK506. CONCLUSIONS: It is concluded that both allogeneic
      and xenogeneic T cell/endothelial responses should be inhibited by therapeutic
      levels of CsA in vivo, assuming the absence of trans-stimulation by B7 molecules.

PMID- 10589955
TI  - Influence of the additional injection of host-type bone marrow on the immune
      tolerance of minor antigen-mismatched chimeras: possible involvement of double
      negative (natural killer) T cells.
AB  - BACKGROUND: It has previously been demonstrated that adding T cell-depleted (TCD)
      host bone marrow (BM) to an MHC-mismatched BM inoculum allows for induction of
      long-term stable chimeras without graft-versus-host disease (GVHD) even when non
      TCD allogeneic BM was used. AIMS: The present study was undertaken to investigate
      immune tolerance mechanisms in minor antigen-mismatched allogeneic BM chimeras
      when host-type BM was added to the BM inoculum. METHODS: C3H (H2k, Thy 1.2, Mls
      2a) recipients were conditioned with 9.5 gray (Gy) of total body irradiation. To
      exclude any interference with possible subclinical GVHD, 5x10(6) TCD AKR (H2k,
      Thy 1.1, Mls 1a) BM cells were injected with (syn + allo) or without (allo) 5x
      10(6) TCD C3H BM cells. Chimerism, clonal deletion, and T lymphocyte subsets were
      scored using FACS and anti-mouse Thy, Vbeta6, Vbeta3, CD3, CD4, or CD8 monoclonal
      antibodies. The stability of tolerance was studied by investigating mixed
      lymphocyte reaction and cytotoxic T cell induction in chimeras after immunization
      with host, donor, or third-party (BALB/c) splenocytes. Breaking of chimerism was
      attempted by injecting nontolerant 40x10(6) host-type splenocytes 2 months after
      BM transplantation. Cytokines and Valpha14 mRNA were assayed using real time
      quantitative reverse transcriptase-polymerase chain reaction at 4 and 48 hr,
      respectively, after injection of nontolerant host-type splenocytes. RESULTS: Both
      groups of mice became long-term stable mixed chimeras without any clinical sign
      of GVHD. Neither group was able to produce antihost nor antidonor cytotoxic T
      cells, even after immunization. The addition of syngeneic BM to the allogeneic
      inoculum reduced the overall level of allogeneic chimerism (from approximately
      70% or approximately 85% in peripheral blood lymphocytes and spleen,
      respectively, in allo chimeras versus approximately 35% and approximately 60% in
      syn + allo chimeras). Moreover, it resulted in complete clonal deletion of both
      host-reactive (Vbeta3) and donor-reactive (Vbeta6) lymphocytes in syn + allo
      chimeras in contrast to in allo chimeras, in which only donor-reactive
      lymphocytes were completely deleted. After nontolerant C3H splenocyte injection,
      high levels of interleukin 2 mRNA were produced and chimerism decreased in syn +
      allo chimeras. In contrast, in allo chimeras, this maneuver was followed by the
      production of higher levels of interleukin 4 and interferon-gamma, and of
      Valpha14 mRNA, as well as by the proliferation of CD3+CD4-CD8- (double-negative)
      T cells and by an increase of donor chimerism. CONCLUSION: The addition of host
      type BM to the allogeneic inoculum has an influence on the level of chimerism,
      the extent of clonal deletion, and the reaction of chimeras after the injection
      of nontolerant host-type splenocytes. In the latter phenomenon, cytokine
      production and proliferation of Valpha14+ CD3+CD4-CD8- (double-negative, natural
      killer T) lymphocytes may be involved.

PMID- 10589956
TI  - Strain specific effects of cytomegalovirus on endothelial cells: implications for
      investigating the relationship between CMV and cardiac allograft vasculopathy.
AB  - BACKGROUND: Cytomegalovirus (CMV) has been associated with the development of
      chronic allograft rejection. Attempts to delineate pathogenetic mechanisms for
      this association have characteristically used well-established laboratory strains
      for in vitro investigation and rodent strains for in vivo studies. There is
      substantial genetic heterogeneity not only among different laboratory strains,
      but also between laboratory strains and clinical isolates, and genetic
      differences between human and animal strains are profound. Given these genetic
      differences, one would anticipate differences in biological activity between
      strains. METHODS: Vascular endothelial cells were infected with two laboratory
      strains of CMV (Towne and AD-169) as well as two individual clinical CMV
      isolates, after genetic typing with six segments of the genome (including early
      and late genes). mRNA expression coding for a panel of mesenchymal growth factors
      was studied using quantitative reverse transcription, polymerase chain reaction.
      Major histocompatibility complex (MHC) expression was investigated using flow
      cytometry. RESULTS: There was substantial genetic variability between clinical
      and laboratory isolates. There did not appear to be differences in overall
      infectivity by the different strains as determined by expression of immediate
      early antigen at 24 hours (5-10% of endothelial cells positive for immediate
      early. Two growth factors, platelet-derived growth factor-A and basic fibroblast
      growth factor were augmented by one of the two clinical strains of CMV (Clin 2)
      (P=0.0091 and P=0.0018, respectively). Transforming growth factor -alpha and
      insulin-like growth factor expression were significantly reduced by both clinical
      strains and AD-169. Two other growth factors, heparin-binding epidermal growth
      factor and transforming growth factor-beta were not altered by infection with any
      strain. No strain altered MHC class II expression. MHC class I expression was
      increased with one of the two clinical strains (Clin 1, P=0.0006) and decreased
      by AD-169 (P=0.0016). Clin 2 and Towne had no effect on MHC class I expression.
      CONCLUSIONS: These data demonstrate that the genetic heterogeneity of CMV is
      associated with differences in transplant-relevant biologic activity even among
      clinical isolates. The relationship between CMV and chronic rejection may be
      difficult to determine given the heterogeneous nature of this complex virus.

PMID- 10589957
TI  - Donor-type chimerism determination by competitive polymerase chain reaction (PCR)
      in a primate model for bone marrow transplantation.
AB  - BACKGROUND: Evaluation of the outcome of successful bone marrow transplantation
      (BMT) and in-depth studies of transplantation biology rely increasingly on
      accurate detection of donor origin cells in the transplanted recipients. This
      study describes a quantitative competitive polymerase chain reaction (PCR) assay
      for accurate evaluation of chimerism after allogeneic BMT in a cynomologous
      primate model, based on detection of monkey Y-specific DNA. METHODS: A competitor
      standard was generated via PCR using a mutagenic primer that makes the competitor
      DNA 22 bp less than the wild type monkey Y-specific DNA. The mutated form can
      still be amplified by the primer pair for the detection of monkey Y-specific DNA.
      A fixed amount of sample subjected to chimerism detection was co-amplified with a
      range of competitor DNA using a touch down program and hot start PCR technique.
      The PCR products were analyzed by computing densitometry. The ratio of
      competitor/target (Y-specific) DNA for each sample pair was calculated. RESULTS:
      Using DNAs prepared from an artificial mixture of male and female cells, a set of
      standard curves has been obtained and the sensitivity of the established
      quantitative PCR was found to be 25 pg of male DNA, which corresponds
      approximately to 0.005 fg competitor DNA. A DNA sample taken from a female
      monkey, transplanted with purified CD34+ stem cells from a male monkey donor 26
      days after BMT, was subjected to the competitive PCR with 10% male DNA as a
      control; the level of male DNA in this sample was calculated to be around 50%.
      CONCLUSIONS: This quantitative PCR assay offers both a high degree of specificity
      as well as a very accurate and sensitive evaluation of chimerism in a sex
      mismatched monkey BMT model.

PMID- 10589958
TI  - Clinically stable human renal allografts contain histological and RNA-based
      findings that correlate with deteriorating graft function.
AB  - BACKGROUND: Chronic rejection (CR) remains idiopathic, difficult to prospectively
      identify, and once detected, unresponsive to increased immunosuppression. We
      hypothesized that clinically stable human renal allografts have ongoing evidence
      of injury and immune activity, and that this correlates with the worsening of
      allograft function characteristic of CR. METHODS: The allografts of 40 stable
      renal allograft recipients were biopsied 2-3 years after transplantation.
      Biopsies were processed for histology and RNA extraction. RNA was evaluated by
      semi-quantitative RT-polymerase chain reaction for CD3y mRNA (a marker of T cell
      receptor turnover), and mRNA from cytokine genes previously shown to be
      transcribed during acute rejection: tumor necrosis factor-alpha, interferon
      gamma, interleukin- (IL) 1beta, IL-2, IL-4, IL-6, and IL-8. Clinical parameters
      including urine protein and glomerular filtration rate were measured the day of
      biopsy. Findings were then compared with clinical outcome to establish
      associations between subclinical inflammation and graft dysfunction. Allograft
      function was measured again 2 years after biopsy and correlated with findings at
      the time of biopsy. RESULTS: Cytokine transcripts and histological evidence of
      injury were detected in more than two-thirds of stable grafts. The degree of the
      lymphocytic infiltrate correlated with the degree of proteinuria (P=0.034) and
      histological fibrosis (P=0.005). Similarly, the degree of intragraft CD3y
      transcription correlated with increasing proteinuria (P=0.043). IL-6 and IL-8
      transcripts were also correlated with evidence of graft injury. After 2 years,
      those biopsies originally found to have evidence of fibrosis, tubular atrophy, or
      CD3gamma transcription had worsening graft function as determined by creatinine
      and glomerular filtration rate. CONCLUSIONS: These data demonstrate that
      significant injury and immune activity can be detected in patients who are stable
      on clinical grounds. Undetected subclinical graft injury may be a cause of
      chronic allograft rejection.

PMID- 10589959
TI  - Pentosan polysulfate treatment reduces cyclosporine-induced nephropathy in salt
      depleted rats.
AB  - BACKGROUND: Long-term cyclosporine (CsA) treatment leads to a decreased
      glomerular filtration rate, hyalinosis of afferent arterioles, and striped
      cortical tubulo-interstitial fibrosis. We showed previously that pentosan
      polysulfate (SP54) prevented the development of microvascular and interstitial
      lesions in mouse models of progressive glomerulosclerosis. In this study, we
      examined the effect of pentosan polysulfate on the development of CsA
      nephropathy. METHODS: Pair-fed Sprague-Dawley rats were fed a low-sodium (0.03%)
      diet and received CsA (15 mg/kg, subcutaneously, in olive oil)/5% glucose,
      pentosan polysulfate (10 mg/kg, subcutaneously in 5% glucose) plus CsA, olive
      oil/pentosan polysulfate, or olive oil/5% glucose for 30 days. Creatinine
      clearance (CrCl) was determined at three time points. Afferent arteriolar
      lesions, glomerular volume, and tubulo-interstitial lesions were quantitated. RNA
      was extracted from cortex. RESULTS: Severe lesions were found in the CsA group. A
      reduction in the number of affected arterioles (32%) and the degree of chronic
      tubulo-interstitial lesions (44%) was found in pentosan polysulfate/CsA-treated
      rats. A 20% decrease in glomerular volume was found in CsA rats, but not in
      pentosan polysulfate/CsA-treated rats. Pentosan polysulfate treatment did not
      prevent the CsA-induced decrease in CrCl (approximately 30%) at 4 weeks. CsA did
      not affect cortical endothelial or neuronal nitric-oxide synthase or mRNA levels,
      but there was small increase in neuronal nitric-oxide synthase mRNA levels in the
      pentosan polysulfate/CsA-treated group. CONCLUSIONS: Pentosan polysulfate reduced
      structural renal lesions in CsA-treated, salt-depleted Sprague-Dawley rats.

PMID- 10589961
TI  - Impact of acute rejection therapy on infections and malignancies in renal
      transplant recipients.
AB  - BACKGROUND: Infections and malignancies are important causes of mortality and
      morbidity in renal allograft recipients. Their risk increases with increasing
      immunosuppression. METHODS: In an attempt to quantitate the increase in the risk
      of these complications in association with antirejection therapy, we reviewed the
      records of all renal allograft recipients of our center transplanted during the
      cyclosporin era. We sub-divided the patients into three groups based on acute
      rejection episodes during the first 6 months posttransplant, and the treatment
      for acute rejection: those who did not develop AR--group 1 (n=168); those who had
      one or more episodes of acute rejection and were treated with high dose
      corticosteroids --group 2 (n=169); those who in addition to corticosteroids
      required cytolytics (OKT3) and/or other drugs--group 3 (n=141). RESULTS: 52%
      patients in group 1, 71% patients in group 2 and 86% patients in group 3 had one
      or more episodes of infection during the first 6 months posttransplantation.
      Relative risk for group 2 and 3 were 1.56 (P=0.0002) and 2.98 (P<0.00001),
      respectively. Infection/patient rates at 6 months were 0.67, 1.23, and 2.79 in
      groups 1, 2, and 3 respectively. Groups 1 and 2 had a similar number of cases
      with squamous and basal cell carcinoma, however, there were few cases with these
      malignancies in group 3. No case of lymphoma was seen in group 1; there were four
      cases in group 2 and nine in group 3. There was no significant difference in
      patient survival in group 1 and 2, however, patients in group 3 had a reduced
      patient survival (1 vs. 3 P<0.001, 2 vs. 3 P=0.067). Graft survival was best in
      group 1 and worst in group 3 (1 vs. 2 P<0.05; 1 vs. 3 P<0.00001; 2 vs. 3 P<0.01).
      CONCLUSIONS: In renal transplant recipients the risk of infections and lymphoma
      increases with increasing immunosuppression and hence mortality and morbidity
      associated with it. When adding a potent immunosuppressive agent to rescue a
      kidney one needs to consider the serious and at times fatal side effects given
      the modest beneficial effect on long-term outcome.

PMID- 10589960
TI  - Selective deletion of antigen-specific, activated T cells by a humanized MAB to
      CD2 (MEDI-507) is mediated by NK cells.
AB  - CD2 is a 50-kDa transmembrane glycoprotein that plays an important role in T and
      natural killer (NT) lymphocyte functions. CD2 serves as both an adhesion molecule
      and as a costimulatory molecule through interactions with its ligand, CD58, on
      antigen presenting or target cells. Consistent with earlier studies using a rat
      anti-CD2 mAb, we have shown that treatment of alloantigen stimulated T
      lymphocytes with a humanized mAb, MEDI-507 (IgG1, kappa), induced
      hyporesponsiveness to subsequent stimulation with alloantigen but not to mitogen
      (phytohemagglutinin). Fluorescence-activated cell sorting analysis of cells from
      mixed lymphocyte reaction (MLR) treated with MEDI-507 revealed pronounced
      deletion of T and NK cells, consistent with lack of proliferation in the MLR.
      MEDI-507 F(ab')2 fragments did not have inhibitory activity or induce deletion of
      lymphocytes in the MLR. Removal of the NK cell subset by magnetic bead depletion
      using anti-CD16 and anti-CD56 mAbs eliminated both the T cell deletion and the
      inhibitory effect. Reconstitution of NK depleted responder populations using
      autologous NK cells restored the MEDI-507-mediated deletion activity to levels
      measured in the original MLR. Formaldehyde-fixed NK cells failed to mediate the
      MEDI-507-induced deletion effect. Altogether, our studies indicate that activated
      T cells with MEDI-507 bound to CD2 are preferential targets for autologous NK
      cells through a nonapoptotic cytotoxic mechanism.

PMID- 10589962
TI  - Effect of cyclosporine on mycophenolic acid trough levels in kidney transplant
      recipients.
AB  - BACKGROUND: Triple drug treatment consisting of mycophenolate mofetil (MMF), in a
      standard dose of 2 g daily, combined with cyclosporine (CsA) and prednisone, has
      become the standard immunosuppressive regimen after kidney transplantation in
      many centers. The need for therapeutic drug monitoring of mycophenolic acid (MPA)
      has not yet been established. Several drug interactions with MMF are known. We
      investigated the influence of CsA withdrawal on MPA trough levels in renal
      transplant patients. METHODS: Fifty-two patients were treated with 1 g of MMF
      twice daily, and prednisone and CsA targeted between 125 and 175 ng/ml for 6
      months after transplantation. At 6 months after transplantation, 19 patients were
      randomized for continuation of triple therapy (group A), 19 patients discontinued
      CsA (group B), and 14 patients discontinued prednisone (group C). We compared 12
      hr fasted MPA trough levels at 6 and 9 months after transplantation within and
      between these groups. RESULTS: MPA trough levels during treatment with CsA, MMF,
      and prednisone were significantly lower than those during treatment with MMF and
      prednisone only (group B); median levels were 1.87 mg/L (range: 0.56-5.27) vs.
      3.16 mg/L (range: 0.32-7.78), respectively (P=0.002). MPA trough levels in groups
      A and C did not change between 6 and 9 months after transplantation; group A
      median levels were 1.87 (range: 0.31-4.32) vs. 1.53 mg/L (range: 0.36-3.70), and
      group C median levels were 1.62 (range: 0.69-10.34) vs. 1.79 mg/L (range: 0.54
      6.00), respectively. At 9 months after transplantation, patients in whom CsA was
      discontinued had higher MPA trough levels as compared with patients who continued
      the use of triple therapy (P=0.001) or patients in whom steroids were withdrawn
      (P=0.014). CONCLUSION: A significant increase of MPA trough levels was found
      after discontinuation of CsA (6 months after transplantation), resulting in
      almost a doubling of MPA trough levels at 9 months after transplantation. This
      resulted in increased MPA levels in patients without CsA as compared to MPA
      levels in patients continuing triple therapy or discontinuing prednisone.

PMID- 10589963
TI  - Blood eosinophilia in tacrolimus-treated patients: an indicator of Pneumocystis
      carinii pneumonia.
AB  - BACKGROUND: Pneumocystis carinii pneumonia (PcP) in immunocompromised patients is
      suggested if the following symptoms develop: dyspnea, fever, and interstitial
      infiltrates on chest x-ray. We observed a significant blood eosinophilia in
      kidney recipients with PcP under immunosuppressive treatment with tacrolimus.
      METHODS: Blood eosinophil counts of kidney recipients under immunosuppression
      with tacrolimus suffering from PcP were compared to eosinophil counts of patients
      without evidence of PcP and to patients showing PcP under immunosuppression with
      cyclosporine. RESULTS: PcP-positive patients treated with tacrolimus showed a
      significantly higher blood eosinophil count compared to PcP-positive patients
      treated with cyclosporine (P=0.01), and to patients under immunosuppression with
      tacrolimus without PcP, respectively (P=0.006). Eosinophilia preceded the time of
      a definitive PcP diagnosis by bronchoalveolar lavage and decreased after
      successful treatment. CONCLUSIONS: An increasing blood eosinophil count can be an
      indicator of P. carinii pneumonia in patients under immunosuppressive therapy
      with tacrolimus.

PMID- 10589964
TI  - Adenocarcinoma on renal allograft as a complication at 5 years.
AB  - We report a new case of renal carcinoma in allograft kidney, 5 years after
      transplantation, which presented as a suspect allograft abscess in a complex
      history of recurrent urinary infection. Only surgical management with
      peroperative histological evaluation permitted us to confirm the diagnosis of
      malignancy.

PMID- 10589965
TI  - Living related liver transplantation from donors with the left-sided
      gallbladder/portal vein anomaly.
AB  - The presence of a left-sided gallbladder poses a unique challenge for living
      related liver donation. Associated anomalies include segment IV atrophy, absence
      of portal vein bifurcation, and abnormal intrahepatic portal branches to segments
      II and III. The complex is rare, but is more frequent in Japan. Of 379 living
      related liver transplants from our institution, the complex has been encountered
      on four occasions (incidence: 1.1%), and we herein review our experience.
      Anomalies were identified preoperatively (by computed tomography and ultrasound)
      in all instances. One donor was turned down because there was no common portal
      trunk to segment II and III branches. Three donors underwent successful retrieval
      using a modified technique. There were no complications in the donors or
      recipients relating to the complex. Thus, living related liver retrieval can be
      achieved safely in the presence of the left-sided gallbladder/portal anomaly
      complex, but technical modifications are required.

PMID- 10589966
TI  - Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal
      allograft recipients.
AB  - BACKGROUND: Campath 1H is a depleting, humanized anti-CD52 monoclonal antibody
      that has now been used in 31 renal allograft recipients. The results have been
      very encouraging and are presented herein. METHODS: Campath 1H was administered,
      intravenously, in a dose of 20 mg, on day 0 and day 1 after renal transplant. Low
      dose cyclosporine (Neoral) was then initiated at 72 hr after transplant. These
      patients were maintained on low-dose monotherapy with cyclosporine. RESULTS: At
      present, the mean follow-up is 21 months (range: 15-28 months). All but one
      patient are alive and 29 have intact functioning grafts. There have been six
      separate episodes of steroid-responsive rejection. One patient has had a
      recurrence of her original disease. Two patients have suffered from opportunistic
      infections, which responded to therapy. One patient has died secondary to
      ischemic cardiac failure. CONCLUSIONS: Campath 1H has resulted in acceptable
      outcomes in this group of renal allograft recipients. This novel therapy is of
      equal efficacy compared to conventional triple therapy, but allows the patient to
      be steroid-free and to be maintained on very-low-dose immunosuppressive
      monotherapy.

PMID- 10589967
TI  - Supraceliac aortic pseudoaneurysms after liver transplantation in infants.
AB  - BACKGROUND: Reconstruction of the hepatic artery in infants undergoing liver
      transplantation presents challenging vascular situations. Microvascular
      techniques ensure arterial blood flow via small caliber vessels but are
      insufficient when inflow is poor. In these situations, the use of allogeneic
      grafts to the supraceliac aorta have been advocated. The development of a
      pseudoaneurysm at the supraceliac aortic suture line requires urgent repair and
      restoration of arterial flow to the graft. METHODS: Our study was based on case
      reports and review of the literature. RESULTS: Definitive diagnosis and
      successful repair of supraceliac pseudoaneurysm was accomplished in two infants
      after transplantation. CONCLUSION: We advocate a thoracoabdominal retroperitoneal
      approach, which provides safe control of the aorta and primary repair or patching
      of the diseased aortic segment, and also provides access for hepatic
      revascularization via placement of an infrarenal graft. Thrombosis of the artery
      and subsequent liver necrosis are indications for retransplantation.

PMID- 10589968
TI  - Development of polycystic disease in a kidney 10 years after transplantation.

PMID- 10589969
TI  - Beta1- and beta3-adrenoceptors mediate relaxation in ovine trachealis smooth
      muscle.
AB  - Isoprenaline (non-selective) and noradrenaline (beta1-selective) concentration
      dependently relaxed ovine tracheal strips precontracted with carbachol. The pD2
      values were 7.07 +/- 0.08 and 6.13 +/- 0.10 for isoprenaline and noradrenaline,
      respectively. In the same preparation, salbutamol either produced weak relaxation
      or in some cases, contractile responses indicating the presence of very little or
      no beta2-adrenoceptors in this preparation. Isoprenaline-and noradrenaline
      induced relaxations were antagonized by propranolol and atenolol with pA2 values
      in the range reported in the literature for an action on beta1-adrenoceptors. ICI
      118551 also antagonized isoprenaline- and noradrenaline-induced relaxation but at
      concentrations much higher than are required to block beta2-adrenoceptors,
      confirming that beta2-adrenoceptors do not contribute significantly to these
      responses. The selective beta3-adrenoceptor agonist, BRL 37344A produced
      concentration-dependent relaxation of tracheal strips. BRL 37344A was a full
      agonist producing 100% relaxation of carbachol-induced tone. BRL 37344A-induced
      relaxation was weakly antagonized by propranolol confirming an action, mainly, on
      beta3-adrenoceptors. Cyanopindolol antagonized isoprenaline-induced relaxation
      (in the presence of propranolol, 10(-7) M) with a pA2 value of 8.06 +/- 0.24. It
      was therefore concluded that beta1- and beta3-adrenoceptors mediated agonist
      induced relaxation in sheep tracheal strips.

PMID- 10589970
TI  - Role of peptidase and cyclooxygenase inhibitors in the guinea-pig bronchial
      response to the synthetic endothelin ET(B) agonist IRL 1620 and antagonist BQ
      788.
AB  - In isolated guinea-pig bronchial preparations the selective endothelin ETB
      agonist, IRL 1620 caused a concentration-dependent contraction. The pD2 value
      (7.16 +/- 0.09, n = 6) was significantly increased in the presence of peptidase
      inhibitors (thiorfan 1 microM, captopril 1 microM, bestatin 1 microM) (pD2 = 7.75
      +/- 0.09, n = 6). Indomethacin (5 microM) did not appear to influence the ETB
      agonist pD2 value (6.92 + 0.11, n = 6) but potentiated its maximal response
      significantly (67.23 +/- 4.81% vs. 53.37 +/- 4.80%). The concentration-response
      curve for the contractile response to IRL 1620 (pD2=7.83 +/- 0.01, n=16); was
      reproducible, although not completely, since the second curve to this selective
      ETB agonist was shifted significantly to the right (pD2 = 7.34 +/- 0.09, n = 16)
      and a decrease in the maximal response was observed (20.0 +/- 2.0%). BQ 788, a
      selective antagonist for ETB receptors, employed in concentrations ranging from
      1.5 to 150 nM, caused a dose-dependent shift to the right of the concentration
      response curve to IRL 1620, with a pIC50 value of 8.11 +/- 0.03; this action was
      not influenced by adding enzyme inhibitors (pIC50 = 8.17 +/- 0.29). Our data show
      that IRL 1620 undergoes a hydrolytic metabolism in guinea-pig bronchial
      preparations, which could influence the calculation of the pD2. Pretreatment of
      the tissue with peptidase inhibitors and indomethacin is consequently significant
      in the evaluation of IRL 1620 activity, while it does not influence the action of
      the antagonist, BQ 788.

PMID- 10589971
TI  - Dynamics of experimental vasogenic brain oedema in the rat: changes induced by
      adrenergic drugs.
AB  - The effects of adrenergic drugs on the formation and resolution of cerebral
      oedema in a rat model of cold-induced vasogenic brain oedema were studied. Evans
      blue dye extravasation, water content and ultrastructural alterations
      (pinocytotic vesicle formation in capillary endothelial cells and apparent water
      accumulation in the brain parenchyma) were evaluated in parietal cortex. Previous
      administration of the alpha-adrenoceptor antagonist phenoxybenzamine produced a
      reduction of Evans blue extravasation and water content, diminished vesicle
      formation and reduced water accumulation. Previous administration of the beta2
      adrenoceptor agonist clenbuterol reduced Evans blue extravasation and water
      content, but did not change vesicle frequency. The effects of clenbuterol on
      Evans blue passage to the brain were blocked by timolol (beta-adrenoceptor
      antagonist) but not by metoprolol (selective beta1-adrenoceptor antagonist). When
      given after the application of cold, clenbuterol was also able to reduce Evans
      blue and water content in the brain. Isoprenaline (beta-adrenoceptor agonist that
      does not cross the blood-brain barrier) showed a reduction in Evans blue
      extravasation only when given intracerebroventricularly. Vinblastine (a drug that
      prevents vesicle formation) produced a reduction of the amount of pinocytotic
      vesicles. We conclude that there is an influence of the central adrenergic
      nervous system on the formation and/or resolution of vasogenic brain oedema and
      that the alterations on water movement and Evans blue transport mediated by
      adrenergic drugs seem to be due, at least in part, to alterations of pinocytotic
      activity in capillary endothelial cells.

PMID- 10589972
TI  - Modelling the changes due to the endothelium and hypertension in the alpha
      adrenoreceptor-mediated responses of rat aorta.
AB  - The present study focuses on the role of endothelium on alpha1-adrenoceptor
      mediated vasoconstriction in aorta from Wistar Kyoto (WKY) and spontaneously
      hypertensive rats (SHR). To define and quantify changes in the parameters
      governing agonism at alpha1-adrenoceptor by hypertension and/or endothelium, the
      operational model of analysis was used. In either endothelium intact or denuded
      aorta, the sensitivity (P < 0.001) and the maximum contraction (P < 0.05) to
      phenylephrine were smaller in SHR than in WKY. However, in each strain of rats,
      removal of endothelium increased the sensitivity (P < 0.001) to phenylephrine but
      reduced (P < 0.05) KCl-evoked vasoconstriction, suggesting a modulation of these
      responses by the endothelium. The observed differences in sensitivity and maximum
      contraction are interpreted in terms of the operational parameters: Em, the
      maximum possible effect; pK(A), the agonist affinity; alpha, the agonist efficacy
      and n, the slope for the function relating receptor occupancy to pharmacological
      effect. The estimated parameters reflected differences, between strains, in the
      signal transduction processes linked to alpha1-adrenoceptor stimulation ascribed
      to the presence of the endothelium. N(G)-nitro-L-arginine methyl ester (L-NAME),
      enhanced to a similar extend in both rat strains the sensitivity (P < 0.001) and
      the maximum contraction to phenylephrine. Indomethacin reduced the maximum
      contraction to phenylephrine by 56.85% in SHR and by 11.80% in WKY suggesting
      that contracting prostanoids play a more major role in this response in SHR than
      in WKY. Nevertheless, these inhibitors were without effect on denuded vessels
      from both strains suggesting that NO and cyclooxygenase products from the media
      or the adventitia do not play a role on the phenylephrine-mediated responses. The
      studied endothelial factors partially explain the observed differences in
      modulation of alpha1-adrenoceptor responses by the endothelium but suggest the
      participation of other compounds released by the endothelium.

PMID- 10589973
TI  - Effects of allopurinol, erythro-9-(2-hydroxy-3-nonyl)adenine and S-(4
      nitrobenzyl)-6-thioinosine on the degradation of adenosine 5'-triphosphate in the
      rat colon muscularis mucosae.
AB  - The effects on ATP breakdown of some modulators of adenosine transport or
      metabolism were studied in the rat colon muscularis mucosae, a tissue which
      contracts to ATP and is thought to contain P2Y1 receptors. The compounds tested
      were the xanthine oxidase inhibitor allopurinol, the adenosine deaminase
      inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and the adenosine uptake
      blocker S-(4-nitrobenzyl)-6-thioinosine (NBTI). The degradation of adenosine 5'
      triphosphate (ATP) (100 microM) and the appearance of metabolites was followed by
      high pressure liquid chromatography during incubation of isolated tissue
      preparations alone or in the presence of the drugs, following preincubation with
      the drugs for 1 h. In the absence of drugs ATP was rapidly degraded by the rat
      colon muscularis mucosae with a half-life of 6.1 +/- 0.7 min, the major breakdown
      product being inosine rather than adenosine. Allopurinol (1 microM) and NBTI (10
      microM) had no effect on the rate of breakdown of ATP or on the pattern of
      metabolites produced. EHNA (1 or 10 microM) also had no effect on the half-life
      of ATP, but in the presence of EHNA (1 microM) the rate of production of inosine
      was significantly reduced and some adenosine was detected, while in the presence
      of 10 microm EHNA the production of inosine was abolished and adenosine became
      the final breakdown product. These results indicate that allopurinol (1 microM)
      and NBTI (10 microM) have no detectable effect on extracellular purine metabolism
      in this tissue, and that the build-up of adenosine produced by treatment with
      EHNA does not have a feedback effect on ATP breakdown.

PMID- 10589974
TI  - Effect of hydroquinone, hydroxocobalamin and carboxy-PTIO on non-adrenergic non
      cholinergic nerve mediated relaxations of the rat duodenum.
AB  - Relaxation induced by NANC-nerve stimulation is reduced by nitric oxide synthase
      (NOS) inhibitors but not by superoxide generators or NO scavengers, casting
      doubts on the precise nature of the neurotransmitter being released by these
      nerves. The lack of effect of superoxide anion generators to inhibit nitrergic
      nerve-mediated relaxations has been attributed to the protective action of high
      tissue levels of superoxide dismutase (SOD). The effects of hydroquinone,
      hydroxocobalamin and carboxy-PTIO, three NO inactivators which do not depend on
      superoxide anion generation, upon nitrergic nerve-mediated relaxations of the rat
      proximal duodenum were determined in order to elucidate whether they are mediated
      by free NO. GABA and nicotine caused relaxations of isolated segments of the rat
      proximal duodenum in a concentration-dependent manner that were abolished by
      tetrodotoxin (TTX). Similarly, transmural electrical stimulation (TES) caused
      frequency-dependent relaxations that were also abolished by TTX. The NOS
      inhibitors L-NAME and L-NOARG reduced in a concentration-dependent manner nerve
      mediated relaxations elicited by TES, nicotine and GABA. The effect of NOS
      inhibitors was prevented by L-arginine but not D-arginine. NO caused
      concentration-dependent relaxations that were not affected by TTX or L-NOARG but
      were abolished by hydroquinone, hydroxocobalamin and carboxy-PTIO. In contrast,
      these compounds failed to affect TES-, nicotine- and GABA-induced relaxations.
      The lack of effect of hydroquinone, hydroxocobalamin and carboxy-PTIO upon nerve
      mediated relaxations was unaltered by pretreatment with the SOD irreversible
      inhibitor DETCA. The present findings show that nitrergic nerve-mediated
      relaxations of the rat duodenum are unaffected by NO inactivators that do not
      generate superoxide anion. It is suggested that either a NO-containing molecule
      that is unreactive with the inactivators tested is the inhibitory
      neurotransmitter released by nitrergic nerves or that NOS activity fulfills
      another role in nitrergic nerves which could be related to the release of an
      still unidentified transmitter.

PMID- 10589975
TI  - Effects of the chronic in vivo administration of L-NAME on the contractile
      responses of the rat perfused mesenteric bed.
AB  - The effects of the chronic in vivo inhibition of nitric oxide synthase (NOS) with
      N(omega)-nitro-L-arginine methyl ester (L-NAME) on vascular contractility were
      studied in the rat perfused mesenteric bed. The chronic treatment with L-NAME
      during 4 weeks induced a rise in systolic blood pressure (basal: 115.1 +/- 6.5
      mmHg; chronic L-NAME treatment: 171.7 +/- 7.7 mmHg, n = 16, P < 0.05). After the
      chronic NOS inhibition, the potentiation of the maximal vasoconstrictor responses
      to noradrenaline, phenylephrine and KCl was to the same extent as that observed
      after the in vitro exposure to 100 microM L-NAME. No further potentiation of the
      contractile responses was achieved when the mesenteric beds isolated from L-NAME
      treated rats were incubated in vitro with 100 microM L-NAME. The endothelium
      removal but not the inhibition of prostanoid synthesis with either 10 microM
      indomethacin or 10 microM 17-octadecynoic acid potentiated the contractions to
      noradrenaline and to KCl both under control conditions as well as after the
      chronic in vivo administration of L-NAME. These observations taken together
      suggest that after chronic L-NAME maximum inhibition of nitric oxide synthase was
      achieved and no compensatory mechanisms able to counterbalance the increase in
      contractile responses were developed. Further studies are necessary to elucidate
      the nature of the factors, other than nitric oxide, that contribute to the
      potentiation of contractile responses observed when the endothelium is removed
      after L-NAME treatment.

PMID- 10589976
TI  - Differential blockade of alpha,beta-methylene-ATP, noradrenaline and electrically
      evoked contractions of the rat vas deferens.
AB  - The present study was carried out compare the effects of nifedipine, verapamil,
      papaverine and chloroethylclonidine (CEC) on the electrically-induced
      contractions and on the contractions produced by exogenous noradrenaline and
      alpha, beta methylene-ATP in the epidydimal portion of rat vas deferens.
      Nifedipine inhibited in a concentration-dependent fashion the purinergic
      component (phase I) of the electrically evoked response. Verapamil (10(-7) M-10(
      5) M) did not inhibit significantly or even potentiated phase I of the
      contractile response to single-pulse field stimulation but inhibited the response
      to alpha,beta methylene-ATP. Papaverine left unaffected phase I but depressed the
      response to alpha,beta methylene-ATP. CEC significantly potentiated the
      purinergic component of the electrically-evoked response and the response induced
      by alpha,beta methylene-ATP. Nifedipine was devoid of any inhibitory action on
      the noradrenergic component (phase II) of the response to single shock. Verapamil
      at the highest concentration used (10(-5) M) was able to partially inhibit phase
      II. Papaverine abolished in a concentration-dependent manner the noradrenergic
      component of the response to single shock. CEC abolished the phase II of single
      shock while was devoid of any inhibitory action on exogenous noradrenaline. The
      implications of these differences among the compounds studied in the present work
      are discussed in relation to roles of calcium channels.

PMID- 10589977
TI  - Analysis of ploidy (in megabase chromosomes) in Trypanosoma brucei after genetic
      exchange.
AB  - The megabase chromosomes of Trypanosoma brucei are normally diploid, but the
      extent to which this ploidy is maintained when parasites undergo genetic exchange
      is not known. To investigate this issue, a panel of 30 recombinant clones
      resulting from the co-transmission through tsetse flies of three different
      parental T. brucei lines in all pair-wise combinations (STIB 247, STIB 386 and
      TREU 927/4) were examined. These clones are products of 28 different mating
      events; four of them result from self-fertilisation and the others are F1
      hybrids. DNA contents of the three parental lines were determined by flow
      cytometry and shown to differ only slightly with DNA content increasing in the
      order 927/4 < 247 < 386. Flow cytometry of the recombinant clones indicated DNA
      contents were similar to the parents in 28 clones and raised approximately 1.5
      times the parental values in only two. The two F1 hybrid progeny with raised DNA
      contents were shown by marker analysis to be trisomic for seven independent loci
      indicating that they were probably triploid whereas progeny with DNA contents
      similar to parental values inherited a single allele from each parent for four
      independent loci indicating that they were diploid.

PMID- 10589978
TI  - Molecular cloning and demonstration of an aminopeptidase activity in a filarial
      nematode glycoprotein.
AB  - ES-62 is an abundant phosphorylcholine-containing secreted glycoprotein of the
      filarial nematode Acanthocheilonema viteae. Using an antiserum directed against
      the parasite molecule, 3 cDNAs of size, approximately 1.5-1.6 kbp were isolated
      from an A. viteae expression library. Sequence analysis in combination with N
      terminal amino acid sequencing of purified ES-62 revealed that each clone
      contained a full-length cDNA for ES-62 corresponding to 474 amino acid residues
      but differed in their 5' and 3' untranslated regions. Characterisation of the 5'
      end of ES-62 mRNA using 5' rapid amplification of cDNA ends showed that it coded
      for a signal sequence. Several tryptic peptides were independently sequenced
      using quadruple-time-of-flight mass spectrometry and used to confirm the cDNA
      sequence. The mature protein was found to contain three potential N-linked
      glycosylation sites. Comparison of the derived amino acid sequence of ES-62 with
      the SwissProt database identified a sequence (between amino acid residues
      approximately 250 and 350 of mature ES-62) with significant similarity to several
      bacterial/fungal aminopeptidases. Incubation of ES-62 with leucine-7-amino-4
      methylcoumarin as substrate confirmed that ES-62 possessed aminopeptidase
      activity.

PMID- 10589979
TI  - Search for promoters for the GARP and rRNA genes of Trypanosoma congolense.
AB  - A search was conducted for transcriptional promoters in Trypanosoma congolense. A
      promoter test plasmid was constructed utilising the luciferase coding region
      flanked by the intergenic regions of a T. congolense gene encoding GARP, the
      glutamic acid and alanine rich protein on the surface of procyclic organisms.
      Using this plasmid, sequences located upstream of an 18S rRNA gene were tested in
      transient transfection assays for their ability to promote luciferase expression.
      A rRNA promoter fragment of 377 bp was identified that increases luciferase
      activity by as much as 35,000-fold above background levels. The rRNA
      transcription initiation site is located 961 bp upstream of the 18S rRNA gene and
      immediately downstream of 6 bp imperfect repeats. The plasmid was also used to
      examine sequences upstream of a GARP gene cluster in two different T. congolense
      strains for promoter activity. In contrast to the findings of another group, we
      were unable to detect promoter activity upstream of these GARP genes in either
      strain. We conclude that the GARP gene promoter, if it exists, has less than
      0.03% (1/3000) of the activity of the rRNA promoter in this luciferase-based
      assay.

PMID- 10589980
TI  - Expression of foreign proteins in Trypanosoma congolense.
AB  - An expression vector was constructed to express foreign genes in Trypanosoma
      congolense. The foreign gene and a neomycin phosphotransferase (NPT) gene are
      flanked by glutamate and alanine rich protein (GARP) gene processing signals and
      their expression is driven by a ribosomal RNA gene promoter. The plasmid is not
      maintained as an episome in T. congolense, but the NPT gene permits selection of
      cells in which the plasmid has integrated into the genome. We used this plasmid
      to express luciferase, green fluorescent protein and a surface protein of
      Trypanosoma brucei, glycine-proline-glutamate glutamate threonine procyclic
      acidic repetitive protein (GPEET PARP). The plasmid-derived GPEET PARP is
      expressed on the surface of procyclic T. congolense and comigrates on a
      polyacrylamide gel with native GPEET PARP from T. brucei procyclic cells. We also
      attempted to use the plasmid to overexpress a previously identified T. congolense
      cysteine protease. The plasmid-derived cysteine protease mRNA species occurs in
      the transfected cells, but we were unable to detect increased levels of protein
      or protease activity.

PMID- 10589981
TI  - Molecular characterisation of Trypanosoma brucei alkyl dihydroxyacetone-phosphate
      synthase.
AB  - Alkyl dihydroxyacetone-phosphate synthase is the second enzyme of the ether-lipid
      biosynthetic pathway which is responsible for the introduction of the ether
      linkage between a fatty alcohol and a glycerol present in a subclass of
      phospholipids, the plasmalogens and possibly in glycolipid membrane anchors. In
      this study the gene coding for alkyl dihydroxyacetone-phosphate synthase was
      isolated from Trypanosoma brucei. Southern blot analysis of total genomic DNA
      suggested the presence of a single copy gene. The analysis, together with
      sequencing of different cDNA clones showed that the two alleles of the gene
      differ in only one nucleotide. The gene encodes a protein of 612 amino acids with
      a calculated molecular mass of 68,891, not counting the initiator methionine. It
      carries a type-1 peroxisomal targeting signal (a C-terminal tripeptide--AHL) and
      a calculated overall positive charge of +10. The gene was expressed in a
      bacterial system and the corresponding protein carrying a His-tag was purified.
      The recombinant alkyl dihydroxyacetone-phosphate synthase and the enzyme isolated
      directly from the glycosomes of bloodstream-form trypanosomes have comparable
      kinetics. The Km for hexadecanol was 42 microM, while approximately 100 microM of
      palmitoyl dihydroxyacetone phosphate (DHAP) was necessary for optimal activity.
      Sodium chloride inhibited both the His-tagged protein and the enzyme isolated
      from the glycosomes of bloodstream-form and insect stage T. brucei.

PMID- 10589982
TI  - The farnesyltransferase inhibitor manumycin A is a novel trypanocide with a
      complex mode of action including major effects on mitochondria.
AB  - Eukaryotes modify numerous proteins, including small GTPases of the ras
      superfamily, with isoprenes as a mechanism for membrane attachment. Inhibition of
      farnesylation of ras has been successfully exploited to control cell growth, with
      promise in the clinic for treatment of human tumours. Using an in vitro screen of
      mammalian farnesyltransferase inhibitors, we have identified manumycin A as
      potently active against growth of both bloodstream and procyclic forms of
      Trypanosoma brucei. Other structural classes of farnesyltransferase inhibitors
      were far less effective. Exposure of T. brucei for brief periods to lethal
      concentrations of manumycin A resulted in subsequent cell death whilst the
      concentration required to achieve killing was dependent on serum concentration,
      suggesting partitioning of manumycin A into hydrophobic cellular sites. Manumycin
      A did not affect trypanosomal protein and DNA synthesis or cell cycle progression
      but altered incorporation of prenyl groups into several polypeptides indicating a
      specific effect on the prenylation without effect on other mevalonate pathway
      products, most importantly prenyl pyrophosphate levels. Morphological analysis
      indicated that manumycin A caused significant mitochondrial damage suggesting an
      additional site of action. Structural analogues of manumycin A containing a
      quinone were also highly trypanocidal and altered mitochondrial morphology,
      suggesting interference with electron/proton transport systems. Furthermore,
      manumycin A also elicited mitochondrial alterations in mammalian cells indicating
      that the effect is not confined to lower eukaryotes. Manumycin A is well
      tolerated in vivo but failed to cure experimental trypanosomiasis in mice.

PMID- 10589983
TI  - Sterol composition and biosynthesis in Trypanosoma cruzi amastigotes.
AB  - A detailed analysis of the endogenous sterols present in the clinically relevant
      intracellular (amastigote) stages of Trypanosoma cruzi, is presented. The
      parasites were grown in cultured Vero cells in the absence or presence of
      different sterol biosynthesis inhibitors, including the C14alpha demethylase
      inhibitor ketoconazole and two inhibitors of delta24(25)-sterol methyl
      transferase, 20 piperidin-2-yl-5alpha-pregnan-3beta-20-R-diol (22,26-azasterol)
      and 24-(R,S),25-epiminolanosterol. Amastigotes were isolated and purified from
      their host cells and neutral lipids were extracted, separated and analyzed by
      chromatographic and mass spectrometric methods. Control (untreated) amastigotes
      contained as main endogenous sterols 24-methyl-cholesta-7-en-3beta-ol (ergosta-7
      en-3beta-ol) and its 24-ethyl analog, plus smaller amounts of their precursor,
      ergosta-7,24(28)dien-3beta-ol; these cells also contained cholesterol (up to 80%
      by weight of total sterols), probably derived from host cells. Amastigotes that
      proliferated in the presence of 10 nM ketoconazole (minimal inhibitory
      concentration, MIC) for 24 h had a sharply reduced content of endogenous 4
      desmethyl sterols with a concomitant accumulation of 24-methyl-dihydrolanosterol
      and 24-methylene-dihydrolanosterol. On the other hand, amastigotes incubated
      during the same period of time with the two inhibitors of 24(25)-SMT at their
      respective MICs (100-300 nM) accumulated large amounts of C27 sterols whose
      structure suggested, in the case of 22,26-azasterol, that delta14 sterol
      reductase was also inhibited. Ketoconazole produced a dose-dependent reduction in
      the incorporation of [2-(14)C]-acetate into the parasite's endogenous C4
      desmethyl sterols with an IC50 of 50 nM, indistinguishable from the value
      reported previously for the extracellular epimastigote form. Taken together, the
      results showed that amastigotes have a simpler sterol biosynthetic pathway than
      that previously described for epimastigotes, lacking both delta5 and delta22
      reductases. They also suggest that the 100-fold higher potency of antifungal
      azoles as antiproliferative agents against amastigotes, when compared with
      epimastigotes, is most probably due to a smaller pool of endogenous sterols in
      the intracellular parasites.

PMID- 10589984
TI  - The Leishmania donovani LD1 locus gene ORFG encodes a biopterin transporter
      (BT1).
AB  - We have previously described two genes, ORFF and ORFG, from the LD1 locus near
      one telomere of chromosome 35, which are frequently amplified in Leishmania
      isolates. In Leishmania donovani LSB-51.1, gene conversion of the rRNA gene locus
      on chromosome 27 with these two genes resulted in their over-expression, because
      of their transcription by the RNA polymerase I-mediated rRNA promoter. The
      predicted ORFG protein has substantial sequence homology to the ESAG10 gene
      product from the Trypanosoma brucei VSG expression site and both are putative
      membrane proteins. Using successive rounds of gene replacement of the three ORFG
      genes in L. donovani LSB-51.1, ORFG null mutants were obtained. These mutant cell
      lines show a direct relationship between ORFG mRNA, protein expression levels and
      active transport of biopterin into the cells. Transformation of the null mutant
      with a plasmid containing ORFG restores biopterin transport activity. In
      addition, the null mutants are unable to grow in the absence of supplemental
      biopterin. Thus, ORFG encodes a biopterin transporter and has been renamed BTI.

PMID- 10589985
TI  - Cloning and analysis of the PTS-1 receptor in Trypanosoma brucei.
AB  - Kinetoplastid organisms, such as the protozoan parasite Trypanosoma brucei,
      compartmentalise several important metabolic pathways in organelles called
      glycosomes. Glycosomes are related to peroxisomes of yeast and mammalian cells. A
      subset of glycosomal matrix proteins is routed to the organelles via the
      peroxisome-targeting signal type 1 (PTS-1). The PEX5 gene homologue has been
      cloned from T. brucei coding for a protein of the translocation machinery, the
      PTS-1 receptor. The gene codes for a polypeptide of 654 amino acids with a
      calculated molecular mass of 70 kDa. Like its homologue in other organisms T.
      brucei PTS-1 receptor protein (TbPEX5) is a member of the tetratricopeptide
      repeat (TPR) protein family and contains several copies of the pentapeptide W-X-X
      X-F/Y. Northern and Western blot analysis showed that the protein is expressed at
      different stages of the life cycle of the parasite. The protein has been
      overproduced in Escherichia coli and purified using immobilized metal affinity
      chromatography. The purified protein specifically interacts in vitro with
      glycosomal phosphoglycerate kinase-C (PGK-C) of T. brucei, a PTS-1 containing
      protein. The equilibrium dissociation constant (Kd) of PGK-C for purified TbPEX5
      is 40 nM. Using biochemical and cytochemical techniques a predominantly cytosolic
      localization was found for TbPEX5. This is consistent with the idea of receptor
      cycling between the glycosomes and the cytosol.

PMID- 10589986
TI  - Substrate depletion upregulates uptake of myo-inositol, glucose and adenosine in
      Leishmania.
AB  - Leishmania flagellates undergo a digenetic life cycle in the gut of the sandfly
      insect vector and in macrophage phagolysosomes of the mammalian host. This
      involves vast changes of the environment to which the parasite has to adapt,
      including temperature, pH and concentration of nutrients between different types
      of meals of the insect vector or within the enclosed intracellular environment of
      the phagolysosome. The regulation of transporters for important organic
      substrates in Leishmania donovani, Leishmania mexicana and Leishmania enriettii
      has been investigated. A pronounced upregulation of inositol (25-fold), adenosine
      (11-fold) or glucose (5-fold) uptake activities was found when cells were
      depleted of the respective substrates during culture. Inositol-depleted cells
      showed a half-maximal uptake rate at nanomolar inositol concentration. Depletion
      of inositol only affected inositol uptake but did not affect uptake of glucose
      analog or proline in control experiments, indicating the specificity of the
      mechanism(s) underlying transport regulation. Adenosine-depleted cells showed an
      approximately 10-fold increase in both adenosine and uridine uptake, both
      mediated by the L. donovani nucleoside transporter 1 (LdNT1), but no change in
      guanosine uptake, which is mediated by the L. donovani nucleoside transporter 2
      (LdNT2). These results suggest that extracellular adenosine concentration
      specifically regulates LdNT1 transport activity and does not affect LdNT2. The
      data imply that upregulation of transport activities by substrate depletion is a
      general phenomenon in protozoan flagellates, which is in remarkable contrast to
      bacteria where upregulation typically follows an increase of extracellular
      organic substrate. Hence, the parasites can maximize the uptake of important
      nutrients from the host even under limiting conditions, whereas bacteria often
      have dormant stages (spores) to overcome unfavorable environmental conditions or
      are heterotrophic for organic substrates.

PMID- 10589987
TI  - Purification of the paraflagellar rod of the trypanosomatid Herpetomonas
      megaseliae and identification of some of its minor components.
AB  - The paraflagellar rod (PFR) is a component of the flagellar cytoskeleton of
      trypanosomatid protozoa, representing a filamentous structure that runs alongside
      the common 9 + 2 microtubular axoneme. The high degree of ultrastructural
      complexity and organization of the PFR suggests that it might be formed by
      numerous biochemical components. However, biochemical analysis of the PFR has
      revealed, to date, a modest degree of complexity in what concerns both major and
      minor PFR proteins. In this paper the preparation of purified PFR fractions by a
      combination of conventional cell-fractionation procedures, non-ionic detergent
      treatment and limited proteolysis is described. Comparative SDS-PAGE analysis of
      the different purification steps indicates that the purified PFR fractions
      possess high amounts of the well-known major PFR proteins (77 and 83 kDa). Also,
      bands of 147, 139, 129 and 122 kDa are clearly enriched in such fractions and may
      correspond to minor PFR components. A slight enrichment in a specific fraction of
      a doublet of bands of 181/188 kDa suggest the participation of these proteins in
      the composition of the bridges between the PFR and the axoneme.

PMID- 10589988
TI  - Characterization of intracellular Cryptosporidium parvum gene expression.

PMID- 10589989
TI  - Endothelium-derived relaxing factor: discovery, early studies, and identification
      as nitric oxide.

PMID- 10589990
TI  - Interactions at the membrane surface studied by spin label ESR spectroscopy.
AB  - A range of different types of interactions at biological membrane surfaces have
      been studied using various different spin label electron spin resonance (ESR)
      techniques. These include: (1) the interfacial ionization of local anaesthetics,
      (2) the binding of peripheral membrane proteins, (3) the membrane insertion of
      translocation-competent precursor proteins and other components of the protein
      translocation machinery, (4) the interactions of ganglioside sphingolipids with
      membrane proteins, and (5) the specific surface recognition of biotinylated
      phospholipid headgroups by avidin. A description of these illustrates both the
      capabilities of this biophysical methodology and the functional/technological
      implications of these interactions and dynamic/thermodynamic processes for cell
      membranes and their surfaces.

PMID- 10589991
TI  - Adherence of Plasmodium falciparum-infected erythrocytes to chondroitin 4
      sulfate.
AB  - Adherence of Plasmodium falciparum-infected erythrocytes (PRBCs) to the
      microvascular endothelium of specific organs and consequent sequestration is
      believed to be responsible for the development of malaria pathology. A number of
      studies have shown that cell adhesion molecules expressed on the surface of
      endothelial cells mediate the adherence. Recent studies indicate that a
      subpopulation of PRBCs adhere to chondroitin 4-sulfate (C4S). This adhesion can
      be effectively inhibited by C4S oligosaccharides. In pregnant women, the placenta
      specifically selects C4S-adherent PRBCs, and thus these phenotypes multiply and
      sequester in the intervillous spaces. Over successive pregnancies, women develop
      a protective humoral response to the C4S-adhesion phenotype. Disruption of C4S
      mediated PRBCs adhesion using either a C4S oligosaccharide mimetic or an antiC4S
      adhesion vaccine can be an efficient strategy for the treatment of malaria caused
      by C4S-adherent P. falciparum.

PMID- 10589992
TI  - Leukocyte adhesion--an integrated molecular process at the leukocyte plasma
      membrane.
AB  - Leukocyte adhesion is of pivotal functional importance, because most leukocyte
      functions depend on cell-cell contact. It must be strictly controlled, both at
      the level of specificity and strength of interaction, and therefore several
      molecular systems are involved. The most important leukocyte adhesion molecules
      are the selectins, the leukocyte-specific beta2-integrins and the intercellular
      adhesion molecules. The selectins induce an initial weak contact between cells,
      whereas firm adhesion is achieved through integrin intercellular adhesion
      molecular binding. Although studies during the past twenty years have revealed
      several important features of leukocyte adhesion much is still poorly understood,
      and further work dealing with several aspects of adhesion is urgently needed. In
      this short essay, we review some recent developments in the field.

PMID- 10589993
TI  - Lectin-carbohydrate interactions: fine specificity difference between two mannose
      binding proteins.
AB  - Two types of rat mannose-binding proteins (MBPs), MBP-A (serum type) and MBP-C
      (liver type), have similar binding specificity for monosaccharide and similar
      binding site construct according to the X-ray structure, but exhibit different
      affinity toward natural oligosaccharides and glycoproteins. To understand the
      basis for this phenomenon, we used cloned fragment of MBP-A and -C (entire
      carbohydrate-recognition domain and a short connecting piece) that exists as
      stable trimers in various binding studies. Binding of a number of mannose
      containing di- and tri-saccharides and high-mannose type oligosaccharides
      indicated that MBP-C has an extended binding area of weak interaction with the
      second and the third mannose residues, whereas MBP-A recognizes just a single
      mannose residue. In addition, MBP-C has a weak secondary binding site some 25 A
      away from the primary site. These findings explain the higher affinity of MBP-C
      for natural high-mannose type oligosaccharides as compared to MBP-A. A huge
      affinity differential manifested by natural glycoproteins (e.g., inhibitory
      potency of thyroglobulin is approximately 200 fold higher for MBP-C than for MBP
      A in a solid-phase assay) may be due to steric hindrance experienced by MBP-A in
      the competition assay, and suggests different arrangement of subunit in the MBP
      trimers.

PMID- 10589994
TI  - Role of an ABC importer in mycobacterial drug resistance.
AB  - Phosphate specific transporter (Pst) in bacteria is involved in phosphate
      transport. Pst is a multisubunit system which belongs to the ABC family of
      transporters. The import function of this transporter is known to be operative at
      media phosphate concentrations below the millimolar range. However, we found
      amplification of this transporter in a laboratory generated ciprofloxacin
      resistant Mycobacterium smegmatis colony (CIPr) which was grown in a condition
      when phosphate scavenging function of this operon was inoperative. Our results
      therefore argue the role of this ABC importer in conferring high level of
      fluoroquinolone resistance in CIPr.

PMID- 10589995
TI  - Exploring the architecture of potassium channels using chimaeras to reveal signal
      transduction.
AB  - The chimeric channel, 4N/1, generated from two outwardly rectifying K+ channels
      by linking the N-terminal cytoplasmic domain of hKv1.4 with the transmembrane
      body of hKv1.1, functions as an inward rectifier. The operating range of the
      channel is shifted to hyperpolarizing potentials and it is inactivated at resting
      membrane potentials. Co-expression of a truncated form of hKv1.1 with the N
      terminal domain of hKv1.4 results in the same physiology as the chimaera implying
      specific interactions between the two segments.

PMID- 10589996
TI  - Gangliosides are transported from the plasma membrane to intralysosomal membranes
      as revealed by immuno-electron microscopy.
AB  - A biotin-labeled derivative of the ganglioside GM1 (biotin-GM1) was used to study
      its transport along the endocytic pathway of cultured fibroblasts by immuno
      electron microscopy. Using electron dense endocytic tracers we could demonstrate
      that late endosomes and lysosomes of these cells are long living organelles with
      a high content of internal membranes. Our studies show that during endocytosis
      the biotin-GM1 was transported to these intraendosomal and intralysosomal
      membranes. These observations support the hypothesis that glycosphingolipids
      (GSL) are preferentially degraded in intralysosomal vesicles.

PMID- 10589998
TI  - Transport of (glyco)sphingolipids in and between cellular membranes; multidrug
      transporters and lateral domains.
AB  - Sphingolipids are highly enriched in the outer leaflet of the plasma membrane
      lipid bilayer. However, the first glycolipid, glucosylceramide, is synthesized in
      the opposite, cytosolic leaflet of the Golgi membrane. This has led us to
      experiments which suggest that the level of glucosylceramide in the cytosolic
      surface is carefully regulated both by the balance between synthesis and
      hydrolysis and by transport away from this surface through translocators,
      multidrug transporters, the same molecules that make cancer cells resistant to
      chemotherapy. Our data suggest a role for newly synthesized glucosylceramide not
      only in the formation of domains in the luminal leaflet of the Golgi but also on
      the cytosolic surface of this organelle.

PMID- 10589997
TI  - Role of glycosphingolipids in HIV-1 entry: requirement of globotriosylceramide
      (Gb3) in CD4/CXCR4-dependent fusion.
AB  - We have recently shown that addition of human erythrocyte glycosphingolipids
      (GSL) to non-human CD4+ or GSL-depleted human CD4+ cells rendered those cells
      susceptible to gp120-gp41-mediated cell fusion (Puri et al., BBRC, 1998). One GSL
      fraction (Fraction 3) isolated from human erythrocyte GSL mixture exhibited the
      highest recovery of fusion following incorporation into CD4+ non-human and GSL
      depleted HeLa-CD4 cells (HeLa-CD4/GSL-). Structural analysis of Fraction 3 showed
      that this GSL had identical head group as the known GSL, Gal(alpha1-->4)Gal(beta1
      ->4)Glc-Ceramide (Gb3) (Puri et al., PNAS, 1998). Here we report that presence of
      Gb3 in CD4+/CXCR4+ cells but not CD4+/CXCR4 cells allows fusion with HIV-1Lai
      envelope glycoprotein expressing cells (TF228). Therefore, Gb3 functions in
      conjunction with HIV-1 co-receptor, CXCR4 to promote fusion. We propose that Gb3
      functions by recruiting CD4 and/or CXCR4 at the fusion site through structurally
      specific interactions.

PMID- 10589999
TI  - Adjustability of refractive effect for corneal ring segments.
AB  - PURPOSE: To evaluate the safety and efficacy of adjustability of the refractive
      effect of intrastromal corneal ring segments (ICRS, Intacs). METHODS: Data from
      four patients who had their initial Intacs removed and exchanged for new Intacs
      of different thickness sizes during a United States Food and Drug Adminstration
      Phase II clinical trial were evaluated with regard to segment size, reasons for
      exchange, duration within the cornea before exchange procedure, loss or change of
      spectacle-corrected visual acuity, change of uncorrected visual acuity, manifest
      refraction, cycloplegic refraction, topography after exchange, and stability of
      refraction. RESULTS: The exchange procedure was performed in two patients due to
      undercorrection and in two for overcorrection. The length of time the segments
      remained in the cornea after initial surgery varied from 6 to 15 months (mean,
      10.25 +/- 4.03 mo). The most recent examination occurred between 4 to 18 months
      (mean, 10.0 +/- 6.32 mo) following the exchange procedure and showed improved
      uncorrected visual acuity with a range from 20/16 to 20/20 and a gain of 2 to 7
      lines of uncorrected visual acuity compared to baseline. No eyes lost any lines
      of spectacle-corrected visual acuity following the exchange procedure and all
      preserved their preoperative spectacle-corrected visual acuity of 20/16. The
      intended refractive correction was achieved in the first few days of the exchange
      procedure and remained stable. CONCLUSION: In these four eyes that were over- or
      undercorrected after initial Intacs placement, segment thickness sizes were
      exchanged after 6, 8, 12, and 15 months without complication and with final
      uncorrected visual acuities of 20/16 to 20/20.

PMID- 10590000
TI  - Ultrasound biomicroscopy of the iris-claw phakic intraocular lens for high
      myopia.
AB  - PURPOSE: To study the in situ relative intraocular position of the Ophtec Artisan
      iris-claw phakic intraocular lens (PIOL) for high myopia using ultrasound
      biomicroscopy. METHODS: Three PIOLs (13.00, 17.00 and 18.00 D lens powers) were
      implanted in phakic myopic eyes. Using ultrasound biomicroscopy, echograms were
      taken in the anterior chamber to measure the preoperative anterior chamber depth,
      postoperative distance between the PIOL and the corneal endothelium (endothelial
      optic distance), and the postoperative distance between the PIOL and the
      crystalline lens. RESULTS: Preoperative anterior chamber depth ranged from 3.10
      to 3.40 mm and the postoperative endothelial-optic distance measured 2.11 to 2.44
      mm. The distance between the crystalline lens and the posterior surface of the
      IOL ranged from 0.78 to 0.93 mm. Several echograms revealed the position of the
      PIOL on the iris. The pigment layer of the iris did not seem to be disturbed by
      the presence of the PIOL. CONCLUSION: The original anterior chamber depths were
      reduced by 28% to 34% after implantation. The PIOL-crystalline lens distance
      ranged from 0.78 to 0.93 mm. This study of 3 eyes revealed that echograms taken
      by ultrasound biomicroscopy are useful in verifying the intraocular position of
      the PIOL within the anterior chamber.

PMID- 10590001
TI  - Wound healing following anterior keratectomy and lamellar keratoplasty in the
      pig.
AB  - PURPOSE: To examine corneal wound healing in an animal model of two types of
      mechanical lamellar keratectomy. METHODS: One eye from each of 28 pigs was
      studied. Using a motorized keratome, corneas were subjected to an anterior
      lamellar keratectomy with removal of anterior stroma and epithelium, or to
      automated lamellar keratoplasty (ALK) with reapposition of a corneal flap. The
      exposed stromal surfaces were labeled intraoperatively with a fluorescent dye
      (DTAF) to assess deposition of stromal components during subsequent wound
      healing. Examination before surgery and enucleation included measurement of
      corneal curvature and intraocular pressure, and assessment of corneal haze. Eyes
      were prepared for histological examination, fluorescence microscopy, and for
      fibronectin immunohistochemistry. RESULTS: Both keratectomy procedures produced
      flattening of corneas by up to 3.80 diopters, 28 days after surgery. Corneal haze
      was more pronounced in eyes from which epithelium was removed (anterior lamellar
      keratectomy group). The increased haze in this group was associated
      histologically with appearance of many reactive keratocytes and inflammatory
      cells, deposition of new stromal material, and more widespread appearance of
      fibronectin immunoreactivity. In the lamellar keratoplasty group, only the edges
      of the corneal wound showed significant reactivity, and included keratocyte
      activation and epithelial ingrowth. CONCLUSIONS: The pig provides a useful model
      for studies of refractive surgical techniques using procedures and instruments
      designed for use in humans. Mechanized keratectomy procedures that minimize
      disruption of the epithelium and Bowman's layer produce a less reactive corneal
      wound than procedures in which an expanse of epithelium and anterior stroma are
      removed.

PMID- 10590002
TI  - Two-year follow-up of laser in situ keratomileusis for hyperopia.
AB  - PURPOSE: To evaluate excimer laser in situ keratomileusis (LASIK) for hyperopia
      and its predictability. METHODS: We performed a retrospective study of 100 eyes
      that had LASIK for hyperopia to assess predictability and long-term stability of
      refractive results. The Chiron Automated Corneal Shaper was used to create the
      flap and the Keracor 117CT Chiron-Technolas excimer laser with the plano-scan
      program was used to ablate all corneas. RESULTS: Mean baseline spherical
      equivalent manifest refraction was +4.50 +/- 1.73 D (range, +1.25 to +8.50 D).
      Six months after LASIK, mean manifest spherical equivalent refraction was +0.72
      +/- 1.87 D (range, -1.75 to +2.50 D), at 1 year, +0.88 +/- 1.73 D (range, -1.25
      to +2.50 D), and at 2 years, +0.85 +/- 1.74 D (range, -0.50 to +2.75 D). Two
      years after LASIK, 45 eyes (74%) were within +/-1.00 D of intended correction and
      within +/-1.00 D of emmetropia. Uncorrected visual acuity was 20/40 or better in
      50 eyes (82%) at 2 years; 29 eyes (37%) saw 20/20 or better. Undercorrection
      occurred more frequently in eyes with preoperative keratometric power of more
      than 45.00 D, when ablation zones less than 6 mm were used and when higher
      amounts of hyperopic correction were required. CONCLUSION: LASIK with the Keracor
      117CT excimer laser appears to be an effective and safe procedure to correct
      hyperopia. Preoperative keratometric power, amount of hyperopia, and ablation
      zone diameter affect the efficacy and long-term stability of the procedure.

PMID- 10590003
TI  - Laser in situ keratomileusis for myopic astigmatism.
AB  - PURPOSE: To evaluate the refractive results of laser in situ keratomileusis
      (LASIK) for myopic astigmatic eyes, and to assess the efficacy, accuracy,
      stability, and safety of the procedure. METHODS: LASIK was performed on 113 eyes
      of 73 patients for correction of myopic astigmatism ranging from 1.00 to 5.00 D,
      as measured by manifest refraction, with a mean baseline refractive astigmatism
      of 2.09 +/- 1.12 D. The Chiron Automated Corneal Shaper was used to create a
      corneal flap, and laser ablation was performed using the Chiron-Technolas Keracor
      116 excimer laser. Follow-up time was 12 months for all eyes. RESULTS: Refractive
      astigmatism was stable by 3 months after surgery. At 1 year after LASIK,
      refractive astigmatism was reduced to a mean of 0.25 +/- 0.31 D (range 0 to 1.00
      D). Sixty-one eyes (54%) had no residual astigmatism and 98 eyes (86.7%) had 0 to
      0.50 D of refractive astigmatism. The mean percent reduction of preoperative
      astigmatism was 87.9 +/- 14.9%. The mean axis deviation of the surgically induced
      astigmatism was 2.1 +/- 3.1 degrees, with 96 eyes (84.9%) within 5 degrees of the
      desired axis. The percent correction of preoperative astigmatism in the proper
      axis was 97.1 +/- 15.5%. Spectacle-corrected visual acuity improved by 2 lines in
      11 eyes (9.7%), and was reduced by 1 line only in 1 eye. There were no other
      significant complications. CONCLUSION: LASIK with the Chiron-Technolas Keracor
      116 excimer laser was effective for correction of myopic astigmatism, with good
      stability after 3 months. The results were predictable with an acceptable degree
      of accuracy. LASIK is a safe procedure with very few complications.

PMID- 10590004
TI  - Analgesic efficacy and safety of ketorolac after photorefractive keratectomy.
      Ketorolac Study Group.
AB  - PURPOSE: The analgesic efficacy and safety of topical ketorolac tromethamine 0.5%
      ophthalmic solution (Acular) in photorefractive keratectomy was compared to its
      vehicle. METHODS: Double-masked, multicenter, study of 200 patients dosed with 1
      drop of study medication (ketorolac or vehicle) in the operated eye immediately
      after surgery (eye patched), with four-times daily dosing for the next 3 days
      starting 3 hours after surgery. Mepergan Fortis was available as an escape pain
      medication. RESULTS: Patients (102) in the ketorolac group reported significantly
      greater pain relief and less pain intensity than the vehicle group (98) at
      several time points (P < or = .039). Time to first use of escape medication was
      significantly longer in the ketorolac than the vehicle group (mean, 16.0 vs 5.5
      hr; P =.001). Time to complete pain relief was significantly shorter in the
      ketorolac than the vehicle group (mean, 41.3 vs 50.3 hr; P =.022). Significantly
      fewer patients in the ketorolac group reported sleep difficulties, ocular
      discomfort, or other difficulties. Few adverse events were reported with
      ketorolac treatment (less than with vehicle), and there were no clinically
      significant changes in any of the safety variables monitored. CONCLUSIONS:
      Ketorolac tromethamine 0.5% ophthalmic solution (Acular) is safe and
      significantly more effective than vehicle in alleviating pain following
      photorefractive keratectomy.

PMID- 10590005
TI  - Effect of tear film stability on fluctuation of vision after photorefractive
      keratectomy.
AB  - PURPOSE: To evaluate the difference in tear film break-up between normal eyes and
      eyes after photorefractive keratectomy (PRK) and its impact on quality of vision
      in PRK eyes. METHODS: Seventy-seven normal eyes and 76 eyes with no ocular
      pathology except refractive error that had PRK were enrolled. Tear film break-up
      time was determined under slit-lamp microscopy with fluorescent staining. Two
      videokeratographs (TMS-1) were taken before and immediately after tear film break
      up. Surface asymmetry index, surface regularity index, and subtractive maps were
      analyzed to evaluate corneal topographic changes before and after tear film break
      up. RESULTS: The distribution of tear film break-up in the central cornea was
      different in PRK eyes than in normal eyes (P < .0001). Distributions of tear film
      break-up after PRK were localized more in the upper and lower temporal regions
      than in normal eyes; incidence of tear film break-up in the central cornea was
      decreased. There were no significant differences in tear film break-up between
      normal eyes and eyes after PRK (P = .69). Twelve PRK patients (24 eyes, 32%)
      experienced fluctuation of vision and fatigue during normal activities after PRK.
      We divided eyes after PRK into two groups (with and without fluctuation of
      vision) and found a statistically significant difference in surface asymmetry
      index before tear film break-up between the two groups (P = .0092). CONCLUSION:
      The distribution of tear film break-up is changed after PRK. Eyes after PRK
      experienced more fluctuation of vision than normal eyes.

PMID- 10590006
TI  - Short-term oxidative status of lens and aqueous humor after excimer laser
      photorefractive keratectomy.
AB  - PURPOSE: Oxidation in the anterior ocular segment is associated with
      cataractogenesis and possible complications to corneal endothelium. We
      investigated whether oxidation occurred in the rabbit anterior ocular segment
      shortly after excimer laser photorefractive keratectomy (PRK). METHODS: Rabbits
      were treated unilaterally with PRK, the other eye serving as a control. Aqueous
      humor sampled shortly after treatment was assayed spectrophotometrically for
      hydrogen peroxide using ferrous oxidation in xylenol in the presence (group 1;
      n=10), or absence of oxygen (group 2; n=8). Oxidized glutathione and
      malondialdehyde levels were measured in lenses by spectrophotometry and HPLC.
      RESULTS: Hydrogen peroxide concentration of aqueous humor was not different
      between treated (77 +/- 36 microM) and control eyes (88 +/- 34 microM) in the
      oxygen group or the nonoxygenated group (treated eyes: 6.7 +/- 5.4 microM and
      control eyes: 5.5 +/- 4.7 microM). Peroxide levels did not correspond to
      endogenous H2O2 but presumably reflected action on ascorbic acid. There was no
      difference in the percent of oxidized glutathione between experimental and
      control eyes. Malondialdehyde could not be detected in the lens of treated or
      control eyes, despite good sensitivity in recovery assays. CONCLUSION: Based on
      these assays, there is no evidence that PRK oxidizes the aqueous humor or the
      lens of treated rabbits within 10 minutes of treatment.

PMID- 10590007
TI  - Sterile interface keratitis after laser in situ keratomileusis: three episodes in
      one patient with concomitant contact dermatitis of the eyelids.
AB  - PURPOSE: To illustrate a case in which sterile interface keratitis after laser in
      situ keratomileusis (LASIK) occurred concomitantly with an allergic contact
      dermatitis of the eyelids. METHODS: Retrospective case review. RESULTS:
      Resolution of the interface keratitis and dermatitis occurred following an
      intense course of topical corticosteroids and brief course of oral
      corticosteroids. Despite an attempt to eliminate potential causes, the same
      patient developed interface keratitis in the fellow eye following both the
      initial LASIK and an enhancement, in which no microkeratome was used. Intense
      treatment with both topical and oral corticosteroids led to a final uncorrected
      visual acuity of 20/20 in the right eye and 20/25+2 in the left eye. CONCLUSION:
      The etiology and mechanism of sterile interface keratitis after LASIK are
      unknown, but are probably multifactorial. The concomitant contact dermatitis
      reaction may indicate a common immune mechanism.

PMID- 10590009
TI  - Folds and striae in laser in situ keratomileusis flaps.
AB  - PURPOSE: To classify striae and folds seen after laser in situ keratomileusis.
      METHODS: The authors' experience and review of the literature form the basis for
      the proposed classification. RESULTS: Five types of folds and striae are
      described: loose epithelium, hinge ridge, hinge fold, deep stromal striae, deep
      epithelial/Bowman's striae. CONCLUSION: Linear striae in laser in situ
      keratomileusis flaps have a variety of appearances and different postoperative
      courses that require accurate diagnosis and management.

PMID- 10590008
TI  - Overcorrected radial keratotomy treated with posterior chamber phakic intraocular
      lens and laser thermal keratoplasty.
AB  - PURPOSE: Modern refractive surgery is effective in a large majority of cases in
      achieving a good first time result. Some attempts at correction, however, are
      less successful and require subsequent revision. METHODS: A case of secondary
      hyperopic astigmatism (+0.75 +1.50 x 45 degrees) is reported in a patient who had
      undergone radial keratotomy for myopia of -6.00 +0.75 x 90 degrees, 8 years
      previously. Preoperative uncorrected visual acuity was 20/120 improving to 20/20
      with correction. Further refractive procedures were performed including arcuate
      keratotomy, posterior chamber phakic intraocular lens implantation and laser
      thermal keratoplasty to improve the uncorrected visual result. RESULTS: Final
      uncorrected visual acuity was 20/40, spectacle-corrected visual acuity was 20/20
      with a manifest refraction of +0.50 +1.00 x 40 degrees. CONCLUSIONS: This case
      demonstrates how the consecutive application of several procedures can
      successfully refine an initially unsatisfactory refractive result. The potential
      for reduced predictability and additional complications with each procedure
      should not be forgotten.

PMID- 10590010
TI  - Ocular biomechanics.

PMID- 10590011
TI  - Some puzzles in the microscopic structure of the stroma.
AB  - The mammalian corneal stroma has some intriguing features related to its lamellar
      structure. OPTICAL LAMINATION: Stromal sections under the polarizing microscope
      show birefringent bands that are about 5 times less numerous than the collagenous
      lamellae seen in transmission electron microscopy (TEM). Scattered light reveals
      similar laminae in the intact fresh tissue. COHESION: Very thin sections of
      stroma do not fall apart under water, indicating the presence of a structural
      framework that holds the collagen fibrils together. SHEAR DISTORTION: The stroma
      shears very readily in its plane; the shear amplitude increases and then
      decreases as the tissue hydrates. This suggests that the structural framework is
      coiled at physiological hydration and can expand about 10 times. FOLDING: When
      the stroma swells, the lamellae are thrown into waves that lie both in the plane
      of and perpendicular to its surface. It is difficult to understand how the latter
      are packed.

PMID- 10590012
TI  - Organization of collagen fibrils in the corneal stroma in relation to mechanical
      properties and surgical practice.
AB  - We have used synchrotron x-ray diffraction to obtain quantitative information
      about the precise orientation of the collagen fibrils in the human cornea and
      sclera, and how these fuse at the limbus. We have shown that the human corneal
      stroma has preferred collagen orientation in the inferior-superior and nasal
      temporal directions. At the limbus, however, the preferred orientation is
      tangential to the cornea. We demonstrated that these limbal fibrils are in the
      form of a circumcorneal annulus and quantified how this annulus varies with
      position. We have also started to unravel how the corneal collagen fibrils fuse
      with the collagen in the annulus. The results have both mechanical and surgical
      implications. Keratoplasty is performed without considering the preferred
      directions of the collagen fibrils. Surgery is increasingly used to correct
      astigmatism and myopia. The site and direction of an incision during, for
      example, cataract surgery, can influence the eventual level of astigmatism. X-ray
      diffraction helps our understanding of the underlying structural and hence
      mechanical reasons for refractive problems following surgery.

PMID- 10590013
TI  - Polarized light propagation in corneal lamellae.
AB  - The propagation of polarized light through the cornea is affected by the
      orientations of the corneal lamellae and by the refractive imbalance between the
      collagen fibrils and the ground substance. Thus, well-designed measurements and
      analyses of polarized light propagation through the cornea can be used to obtain
      information regarding the cornea's lamellar and fibrillar structures. This paper
      shows that, for the rabbit, measured values of the optical parameters strongly
      suggest that the distribution of lamellae orientations is not random, but has one
      (or two) preferred orientation directions. Also, there is considerable evidence
      that collagen is intrinsically anisotropic. The Weiner formula gives the
      effective birefringence of an assembly of parallel isotropic fibrils and its
      generalization to the case of anisotropic fibrils is presented. Finally,
      calculations based on preferred orientation models having lamellae composed of
      anisotropic fibrils show that comparison with experimental values can yield
      structural information.

PMID- 10590014
TI  - Small-angle light scattering and birefringence properties of chick cornea.
AB  - PURPOSE: Techniques employing polarized light propagation and scattering are
      useful in examining the cornea's lamellar structure. Recent advances in
      theoretical methods have significantly increased the ability to relate features
      of lamellar arrangements to measurements of transmitted polarized light. The
      chick cornea, because of its hypothesized structure of a gradual helical rotation
      of lamellar pairs, presents an interesting model for further development of this
      methodology. METHODS: Small-angle light scattering (SALS) and polarized
      transmission measurements were made on 7-week-old chick corneas under conditions
      that closely approximate the physiological state. Birefringence properties were
      determined from the transmission measurements and compared to the results of
      model calculations of polarized light propagating through lamellae organized
      according to the hypothesized structure for chick cornea. RESULTS: The I+ small
      angle light scattering pattern had 4 cloverleaf lobes aligned with the crossed
      polarizer and analyzer axes. The lobes disappeared when the transcorneal pressure
      was increased from zero to 18 mmHg. Retardation measured at 18 mmHg was very
      small (approximately 0.01 microm). CONCLUSION: The disappearance of the I+ small
      angle light scattering pattern when IOP is increased suggests that the lamellae
      undulate in their relaxed state and the undulations straighten when IOP is
      increased. Measured birefringence properties are consistent with the hypothesized
      lamellar structure.

PMID- 10590015
TI  - Techniques for stiffening the cornea.
AB  - In keratoconus, corneal stiffness is decreased. The purposes of this study were
      to search for techniques to stiffen the cornea and to determine a dose-response
      relation. The stiffness of collagenous tissues can be increased by cross-linking.
      Cross-linking techniques--riboflavin and ultraviolet irradiation (365 nm, 2
      mW/cm2, 45 min), glutaraldehyde of low concentration, and several aldehyde sugars
      -were tested on corneas of enucleated porcine eyes. The stress-strain relation
      was measured and compared to untreated corneas. Aldehyde sugars produced cross
      links by nonenzymatic glycation only after a prolonged time (realized in
      diabetics). Riboflavin and UV seems to be a promising technique to stabilize the
      cornea by artificial cross-linking.

PMID- 10590016
TI  - Spectral analysis of viscoelasticity of the human lens.
AB  - PURPOSE: In the aging lens, two different structural changes become progressively
      apparent: loss of accommodation and formation of cataract. These changes are due
      to different alterations in lens structure taking place on a molecular scale.
      METHODS: For the characterization of liquids, gels, elastic bodies and solids,
      dynamic mechanical analysis (DMA) represents a non-destructive macroscopic
      analysis method with considerable sensitivity to microscopic structural changes.
      Spectra of the shear compliance (reciprocal shear modulus) of human lenses at
      different ages were measured in a wide frequency range (1 mHz to 1 kHz). By means
      of computer analysis, the parameters of the involved relaxation processes and the
      viscous flow were determined. RESULTS: The increase in cross-linking density was
      correlated with the disappearance of viscous flow in the measured spectra. The
      accumulation of high-molecular-weight aggregates was held responsible for the
      shift of the lower frequency relaxation process to lower frequencies with
      increasing stiffness, which is likely to be correlated with a prolonged
      accommodation time. CONCLUSION: Dynamic mechanical analysis represents a useful
      method for the spectroscopic characterization and quantification of the changes
      in the macroscopic viscoelastic properties caused by molecular changes in
      cataract formation and loss of accommodation.

PMID- 10590017
TI  - The new BPD: an arrest of lung development.

PMID- 10590018
TI  - From observation to experimentation at the cotside: lessons from the past.

PMID- 10590020
TI  - Localization of transforming growth factor-beta receptor types I, II, and III in
      the postnatal rat small intestine.
AB  - Transforming growth factor-beta2 (TGF-beta2) levels in rat milk are high in early
      lactation, whereas endogenous TGF-beta1 expression in the neonatal gut increases
      toward midweaning. Three types of transmembrane TGF-beta receptors have been
      identified in mammals. The receptor III (or betaglycan) binds and presents TGF
      beta1 or beta2 to receptor II. Receptor I then interacts with receptor II,
      forming a signaling receptor complex, and propagates the signal. To determine
      whether TGF-beta receptor expression in the gut is also developmentally
      regulated, the present study assessed ontogeny of TGF-beta receptor expression in
      the postnatal rat small intestine. Jejunum and ileum tissues from rat pups at d
      3, 10, 14, 21, and 28 of age were collected. Cryostat sections were stained with
      antibodies against TGF-bea receptors I, II, and III, and various cell markers by
      immunofluorescence. In both regions, receptor I staining was seen on apical and
      basolateral membranes of the villus and crypt epithelium at all ages, and
      staining on the apical membrane increased with age; receptor II was predominantly
      expressed in the crypt, and staining on the villi appeared after d 10; receptor
      III was distributed throughout the mucosa at early ages but diminished from the
      epithelium postweaning by d 28. T cells, B cells, and dendritic cells in the
      lamina propria expressed TGF-beta receptor III but lacked expression of receptor
      I and II. The pattern of TGF-beta receptor expression changes with age in a
      manner that may reflect the change in ligand from TGF-beta2 (milk-derived) to TGF
      beta1 (endogenously produced).

PMID- 10590019
TI  - Comparative study of MSX-2, DLX-5, and DLX-7 gene expression during early human
      tooth development.
AB  - Msx and Dlx family transcription factors are key elements of craniofacial
      development and act in specific combinations with growth factors to control the
      position and shape of various skeletal structures in mice. In humans, the
      mutations of MSX and DLX genes are associated with specific syndromes, such as
      tooth agenesis, craniosynostosis, and tricho-dento-osseous syndrome. To establish
      some relationships between those reported human syndromes, previous experimental
      data in mice, and the expression patterns of MSX and DLX homeogenes in the human
      dentition, we investigated MSX-2, DLX-5, and DLX-7 expression patterns and
      compared them in orofacial tissues of 7.5- to 9-wk-old human embryos by using in
      situ hybridization. Our data showed that MSX-2 was strongly expressed in the
      progenitor cells of human orofacial skeletal structures, including mandible and
      maxilla bones, Meckel's cartilage, and tooth germs, as shown for DLX-5. DLX-7
      expression was restricted to the vestibular lamina and, later on, to the
      vestibular part of dental epithelium. The comparison of MSX-2, DLX-5, and DLX-7
      expression patterns during the early stages of development of different human
      tooth types showed the existence of spatially ordered sequences of homeogene
      expression along the vestibular/lingual axis of dental epithelium. The expression
      of MSX-2 in enamel knot, as well as the coincident expression of MSX-2, DLX-5,
      and DLX-7 in a restricted vestibular area of dental epithelium, suggests the
      existence of various organizing centers involved in the control of human tooth
      morphogenesis.

PMID- 10590021
TI  - Enhanced peptide-binding capacities of small intestinal brush border membranes in
      celiac disease.
AB  - In pathogenesis of celiac disease, the significance of prolamin peptide
      interactions with enterocytes is controversial. Changes in cellular metabolism
      induced by gliadin peptides, as well as uptake and presentation by enterocytes,
      are discussed. We analyzed peptide binding to enterocytic membranes as a
      potential key event. Binding capacities of brush border membranes isolated from
      small intestinal biopsies of untreated (n = 49) and treated celiac patients on a
      gluten-free diet (n = 30), as well as control subjects (n = 43), were measured
      with a dot blot chemiluminescence assay. Synthetic gliadin peptides comprising
      amino acid position 8-19 (G XIV) and 30-41 (G XI) of alpha-gliadins, a peptic
      tryptic digest of gliadin (PT-GLI), and a synthetic zein peptide were used.
      Comparing treated celiac patients with controls, we observed significantly
      enhanced membrane-binding of PT-GLI [mean 122.4 densitometric units/microg (95%
      confidence interval 116.0-128.9) vs 108.9 (102.1-115.7)] and of zein peptide
      [50.2 (38.4-61.9) vs 28.8 (13.4-44.2)], but only slightly increased binding of
      the synthetic gliadin peptides G XIV [65.5 (60.6-70.5) vs 62.4 (56.3-68.5) and G
      XI [75.2 (69.8-80.6) vs 65.9 (55.2-76.5)]. Independent of patient group, membrane
      binding capacities for celiac-active gliadin peptides exceeded those of the zein
      peptide. Thus, interaction of gliadin peptides with the apical enterocytic
      membrane was not found exclusively in celiac disease. Furthermore, increased
      binding capacities in treated celiac disease were not confined to celiac-active
      peptides. Quantitative differences in gliadin peptide binding as a primary
      characteristic in celiac disease might contribute to pathogenetic effects exerted
      on small intestinal epithelial cells.

PMID- 10590022
TI  - Relationship between kinetic properties of mutant enzyme and biochemical and
      clinical responsiveness to biotin in holocarboxylase synthetase deficiency.
AB  - Holocarboxylase synthetase (HCS) deficiency is a metabolic disorder that causes a
      biotin-responsive multiple carboxylase deficiency. We analyzed the kinetic
      properties of seven mutant HCS proteins. Two of these enzymes harbored mutations
      within the putative biotin-binding region of HCS and showed elevated Km values
      for biotin compared with that of the wild-type form (Km mutant; Gly581Ser: 45
      times, delThr610: 3 times). The remaining five mutations (Arg183Pro, Leu216Arg,
      Leu237Pro, Val333Glu, and Val363Asp) were located outside the biotin-binding
      region. The enzymes containing these mutations showed normal or low Km values for
      biotin (non-Km mutant). Symptoms of patients who have the non-Km, mutants, as
      well as those of patients who have the Km, mutants, responded to biotin therapy.
      This is probably because the Km value for biotin of normal HCS is higher than the
      physiologic concentration of biotin in human cells. The Vmax values of all mutant
      HCS proteins were considerably decreased, but to a variable degree. The
      responsiveness to biotin supplementation of propionyl-CoA carboxylase activity in
      cultured cells bearing the mutations correlated well with the degree of reduction
      in the Vmax of HCS. Patients who have mutant HCS proteins with lower Vmax showed
      poorer clinical and biochemical responses to biotin therapy. These observations
      suggest that the reduction of Vmax is an essential factor for pathophysiology and
      prognosis of HCS deficiency under treatment with large amounts of biotin. The
      determination of HCS genotype can be valuable for characterizing the clinical
      phenotype in HCS deficient patients.

PMID- 10590023
TI  - GLUT1-deficiency: barbiturates potentiate haploinsufficiency in vitro.
AB  - Barbiturates are known to inhibit glucose transport mediated by the facilitative
      sugar transporter GLUTI. We have studied such inhibition in children with GLUT1
      deficiency. Zero-trans influx of 14C-labeled 3-O-methyl glucose (3OMG) into
      erythrocytes of patients (n = 3) was 35% of controls (n = 6). Preincubation with
      10 mM phenobarbital or pentobarbital reduced patients' 30MG influx to 17%. In
      patients and controls, preincubation with barbiturates significantly decreased
      Vmax in a dose-dependent manner (for pentobarbital, IC50 = 0.84 mM, patient 2).
      The apparent Km in individuals remained largely unchanged. Three-OMG influx
      without preincubation resulted in a stronger inhibition at lower barbiturate
      concentrations. The patients' data are discussed in the light of individual
      missense mutations (patient 1: R126L and K256V; patient 2: T310I; patient 3:
      S66F) in the GLUTI gene. In conclusion, in controls and patients with GLUT1
      deficiency barbiturates interact with GLUT1, lowering its intrinsic activity. The
      use of barbiturates in this condition for anesthesia or as anticonvulsants could
      therefore potentially aggravate the existing glucose transport defect and may put
      these patients at increased risk.

PMID- 10590024
TI  - Clinical and molecular spectrum of somatic mosaicism in androgen insensitivity
      syndrome.
AB  - We recently found that postzygotic de novo mutations occur at the expected high
      rate of an X-linked recessive mutation in androgen insensitivity syndrome. The
      resulting somatic mosaicism can be an important molecular determinant of in vivo
      androgen action caused by expression of the wild-type androgen receptor (AR).
      However, the clinical relevance of this previously underestimated genetic
      condition in androgen insensitivity syndrome has not been investigated in detail
      as yet. Here, we present the clinical and molecular spectrum of somatic mosaicism
      considering all five patients with mosaic androgen insensitivity syndrome, whom
      we have identified since 1993: Patient 1 (predominantly female, clitoromegaly),
      172 TTA(Leu)/TGA(Stop); patient 2 (ambiguous), 596 GCC(Ala)/ACC(Thr); patient 3
      (ambiguous), 733 CAG(Gln)/ CAT(His); patient 4 (completely female), 774
      CGC(Arg)/TGC (Cys); and patient 5 (ambiguous), 866 GTG(Val)/ATG(Met). Serum sex
      hormone binding globulin response to stanozolol, usually correlating well with in
      vivo AR function, was inconclusive for assessment of the phenotypes in all tested
      mosaic individuals. An unexpectedly strong virilization occurred in patients 1,
      3, and 5 compared with phenotypes as published with corresponding inherited
      mutations and compared with the markedly impaired transactivation caused by the
      mutant ARs in cotransfection experiments. Only the prepubertal virilization of
      patients 2 and 4 matched appropriately with transactivation studies (patient 4)
      or the literature (patients 2 and 4). However, partial pubertal virilization in
      patient 4 caused by increasing serum androgens and subsequent activation of the
      wild-type AR could not be excluded. We conclude that somatic mosaicism is of
      particular clinical relevance in androgen insensitivity syndrome. The possibility
      of functionally relevant expression of the wild-type AR needs to be considered in
      all mosaic individuals, and treatment should be adjusted accordingly.

PMID- 10590025
TI  - Instantaneous orthostatic hypotension in children and adolescents: a new entity
      of orthostatic intolerance.
AB  - We are the first to report clinical characteristics and circulatory and
      catecholamine responses to postural change in 44 children with instantaneous
      orthostatic hypotension (INOH). The symptoms include chronic fatigue, orthostatic
      dizziness, weakness, sleep disturbance, syncope or near syncope, headache, and
      loss of appetite. We divided the patients into two groups: group I (30 patients)
      had either a recovery time for mean arterial pressure of >25 s or a recovery time
      of >20 s with a 60% or greater decrease in mean arterial pressure at the initial
      decrease; group II (14 patients) had a prolonged reduction in systolic arterial
      pressure of > 15% during the later stage of standing (3-7 min) in addition to the
      criteria for group I. INOH was characterized by a marked reduction in blood
      pressure at the initial decrease (mean, -55/-27 mm Hg systolic/diastolic).
      Delayed recovery time of >60 s was found in 21 of 44 patients and orthostatic
      tachycardia (>35 beats per minute) in 20 of 44. Plasma noradrenaline responses
      were significantly lower in group I and II than in controls at 1 min of standing
      and were lower in group II at 5 min of standing. These results suggest that
      mechanisms responsible for INOH may depend on insufficient sympathetic activation
      during standing, possibly due to centrally mediated sympathetic inhibition, thus
      causing impairment of quality of life including school absenteeism. INOH is an
      important pathologic condition in children with complaints of orthostatic
      intolerance and can be an unrecognized cause of chronic fatigue. This condition
      can be identified by using a noninvasive beat-to-beat continuous blood pressure
      monitoring system.

PMID- 10590026
TI  - Prediction of adult overweight during the pediatric years.
AB  - Obesity in adults is associated with an increased mortality rate from various
      diseases. Childhood overweight or obesity may persist into adulthood, and for
      this reason it is important to identify such children at risk. The data were
      taken from a larger longitudinal growth study of 3650 full-term and healthy
      Swedish babies followed from birth to 18 y of age. Body mass index (BMI) was used
      to estimate (during the pediatric years) the risk of obesity at 18 y of age. A
      probability chart for becoming overweight (>25 kg/m2) by 18 y of age was
      constructed, For example, in girls, a BMI of 16 kg/m2 at 4 y of age is associated
      with a 20% risk of attaining a BMI value over 25 kg/m2 at 18 y, and in boys at 4
      y of age, a BMI of 19 kg/m2 leads to a 60% risk that they will have a BMI value
      over 25 kg/m2 at 18 y. The probability risk charts for adult overweight developed
      here is the first one presented. They provide an easy and novel instrument to use
      to identify those children who are at high risk of becoming obese adults, so that
      they may have clinical intervention at younger ages.

PMID- 10590027
TI  - Respiratory and brain ependymal ciliary function.
AB  - The aims of this study were to compare beat frequencies of tracheal and ependymal
      cilia and the beat frequencies of ependymal cilia from infant and adult rats. The
      length of respiratory and ependymal cilia of infant and adult rats was also
      compared. We have developed an ex vivo model that allows ependymal and
      respiratory ciliary beat frequency to be measured with a high-speed video system.
      The beat frequencies of cilia, incubated at 37 degrees C, were measured after an
      incubation period of 30 min. Ependymal cilia beat at a similar frequency in 10-
      to 15-d-old rats (mean 38.8 Hz: 95% confidence intervals 37.1-40.6) as in adult
      animals (mean 40.7 Hz: 95% confidence intervals 38.5-42.9). However, respiratory
      cilia from adult animals beat (mean 20.9 Hz: 95% confidence intervals 14-27) at a
      significantly (p = 0.003) lower frequency than ependymal cilia. Ependymal cilia
      (mean length +/- SD: 8.2 +/- 0.3 microm) measured by scanning electron microscopy
      were significantly (p = 0.001) longer than respiratory cilia (5.5 +/- 0.6 microm)
      from the trachea of 9- to 15-d-old rats. Cilia did not grow longer between the
      time the rats were 9-15 d old and adulthood. Adult respiratory and ependymal
      ciliary length (mean +/- SD) were 5.6 +/- 0.5 microm and 8.1 +/- 0.2 microm,
      respectively. In summary, ependymal cilia beat at approximately twice the rate of
      respiratory cilia and are significantly longer.

PMID- 10590029
TI  - Increase in extracellular glutatione peroxidase in plasma and lungs of mice
      exposed to hyperoxia.
AB  - Extracellular glutathione peroxidase (E-GPx) is a selenium-dependent enzyme that
      can reduce hydrogen peroxide and phospholipid hydroperoxides. E-GPx is found in
      plasma and extracellular fluids such as bronchoalveolar lavage fluid. Because
      lung is one of the tissues that is capable of synthesizing and secreting E-GPx,
      the effect of exposure to hyperoxia on E-GPx in plasma and lung were studied in
      an injury model of hyperoxia exposure in adult mice. Exposure to 100% oxygen for
      72 h resulted in an increase of 55% in plasma GPx activity and an increase of 50%
      in the amount of E-GPx protein in the plasma. Exposure to hyperoxia was also
      associated with an increase in the amount of E-GPx protein in lungs. The 7-fold
      increase in the amount of E-GPx protein in lungs was not due to plasma
      contamination of lungs from mice exposed to hyperoxia. E-GPx in the lung is
      calculated to account for 10% of lung GPx activity in control mice. However, E
      GPx is calculated to account for 45% of lung GPx activity in the lungs of mice
      exposed to hyperoxia for 72 h. Further studies are needed to determine whether
      the increase in lung E-GPx is due to changes in translation or stability of E
      GPx. The role of E-GPx in protecting the lung from oxidative damage warrants
      further study.

PMID- 10590028
TI  - Surfactant protein B corrects oxygen-induced pulmonary dysfunction in
      heterozygous surfactant protein B-deficient mice.
AB  - Surfactant protein B (SP-B) is a 79-amino acid hydrophobic surfactant protein
      that plays a critical role in postnatal lung function. Homozygous SP-B (-/-)
      deficient mice die of respiratory failure at birth, associated with severe
      pulmonary dysfunction and atelectasis. Heterozygous SP-B (+/-)-deficient mice
      have 50% less SP-B protein, proprotein, and SP-B mRNA compared with control mice
      and are highly susceptible to oxygen-induced lung injury. In the current study,
      we tested whether the susceptibility of SP-B (+/-) mice to hyperoxia was restored
      by intratracheal administration of exogenous SP-B. After exposure to 95% oxygen
      for 3 d, opening pressures were increased and maximal lung volumes were
      significantly decreased in SP-B (+/-) mice compared with SP-B (+/+) mice. SP-B
      (+/-) mice were administered purified bovine SP-B (2%) with DL-alpha dipalmitoyl
      phosphatidylcholine (DPPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-rac-( 
      glycerol)] (POPG) phospholipids or DPPC and POPG phospholipids intratracheally
      and exposed to 95% oxygen. SP-B-treated SP-B (+/-) mice survived longer in 95%
      oxygen. Although decreased lung function in SP-B (+/-) mice exposed to oxygen was
      not altered by administration of DPPC and POPG, administration of lipids
      containing 2% purified bovine SP-B restored lung function when assessed after 3 d
      in oxygen. Abnormalities in pulmonary function in SP-B (+/-) mice after oxygen
      exposure were associated with increased alveolar capillary leak, which was
      corrected by administration of SP-B with DPPC and POPG. Likewise, histologic
      abnormalities caused by oxygen-induced lung injury were improved by
      administration of SP-B with DPPC and POPG. Administration of phospholipids with
      the active SP-B peptide was sufficient to restore pulmonary function and prevent
      alveolar capillary leak after oxygen exposure, demonstrating the protective role
      of SP-B during oxygen-induced lung injury.

PMID- 10590031
TI  - Plasma surfactant protein-B is elevated in infants with respiratory syncytial
      virus-induced bronchiolitis.
AB  - Respiratory syncytial virus (RSV) is the most frequent cause of bronchiolitis.
      However the pathophysiology of bronchiolitis is unclear. Leukocytes, especially
      neutrophils, may play an important role in the pathogenesis of bronchiolitis.
      Whereas we have previously shown that neutrophils augment epithelial leakage and
      detachment in RSV infection in vitro, it is unknown whether epithelial damage
      occurs in vivo in infants with RSV bronchiolitis. We hypothesized that
      respiratory epithelial damage occurs in infants with RSV bronchiolitis and that
      surfactant proteins leak into the circulation. The plasma concentrations of
      surfactant protein-A and surfactant protein-B in infants with RSV bronchiolitis
      were measured by ELISA. Plasma immunoreactive surfactant protein-B in infants
      with RSV bronchiolitis was markedly higher than that in matching controls. Our
      study suggests that alveolocapillary permeability is increased in infants with
      RSV bronchiolitis in vivo and that surfactant protein-B may be a sensitive marker
      for lung injury in such infants.

PMID- 10590032
TI  - Pulmonary vascular responses during acute and sustained respiratory alkalosis or
      acidosis in intact newborn piglets.
AB  - Acute alkalosis-induced pulmonary vasodilation and acidosis-induced pulmonary
      vasoconstriction have been well described, but responses were generally measured
      within 5-30 min of changing pH. In contrast, several in vitro studies have found
      that relatively brief periods of sustained alkalosis can enhance, and sustained
      acidosis can decrease, vascular reactivity. In this study of intact newborn
      piglets, effects of acute (20 min) and sustained (60-80 min) alkalosis or
      acidosis on baseline (35% O2) and hypoxic (12% O2) pulmonary vascular resistance
      (PVR) were compared with control piglets exposed only to eucapnia. Acute
      alkalosis decreased hypoxic PVR, but sustained alkalosis failed to attenuate
      either baseline PVR or the subsequent hypoxic response. Acute acidosis did not
      significantly increase hypoxic PVR, but sustained acidosis markedly increased
      both baseline PVR and the subsequent hypoxic response. Baseline PVR was similar
      in all piglets after resumption of eucapnic ventilation, but the final hypoxic
      response was greater in piglets previously exposed to alkalosis than in controls.
      Thus, hypoxic pulmonary vasoconstriction was not attenuated during sustained
      alkalosis, but was accentuated during sustained acidosis and after the resumption
      of eucapnia in alkalosis-treated piglets. Although extrapolation of data from
      normal piglets to infants and children with pulmonary hypertension must be done
      with caution, this study suggests that sustained alkalosis may be of limited
      efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks
      of pulmonary hypertension must be considered when using ventilator strategies
      resulting in permissive hypercapnic acidosis.

PMID- 10590030
TI  - Identification of sex-specific differences in surfactant synthesis in rat lung.
AB  - Delayed lung maturation and lower levels of surfactant phosphatidylcholine have
      been previously identified in male fetuses compared with female fetuses in
      several species. We investigated the mechanisms for sex differences in surfactant
      content by examining parameters of phosphatidylcholine turnover and biosynthesis;
      the latter was evaluated by measuring metabolic steps within the biosynthetic
      pathway. Compared with male lung cells, freshly isolated lung cells from female
      fetuses contained higher levels of disaturated phosphatidylcholine, a marker of
      surfactant lipid. Female mixed monolayer cultures exhibited a 71% increase in
      choline incorporation into disaturated phosphatidylcholine compared with male
      cultures. Male cultures exhibited significantly greater release of [3H]
      arachidonic acid into the medium compared with females, suggesting sex
      differences in phospholipase activity. However, pulse-chase studies showed no sex
      differences in degradation of disaturated phosphatidylcholine, which was
      confirmed by assays of phospholipase A2, phosphatidylcholine-specific
      phospholipase C, and phospholipase D. Female mixed lung cells, however, had
      greater rates of cellular choline transport and activity of cytidylyltransferase,
      the rate-regulatory enzyme for phosphatidylcholine synthesis. Separate studies
      showed that exposure of sex-specific pretype II cell cultures to cortisol
      stimulated fibroblast-conditioned medium plus transforming growth factor-beta
      neutralizing antibody stimulated cytidylyltransferase activity to a greater
      extent in male cells compared with female cells. These studies indicate that sex
      differences in surfactant phospholipid content are not due to differences in
      phospholipid turnover, but rather differential regulation of specific metabolic
      steps within the surfactant biosynthetic pathway. The data also support a role
      for transforming growth factor-beta as a negative regulator of a key surfactant
      biosynthetic enzyme within male lungs.

PMID- 10590033
TI  - Comparison of tissue factor pathway in human umbilical vein and adult saphenous
      vein endothelial cells: implications for newborn hemostasis and for laboratory
      models of endothelial cell function.
AB  - In this work we have undertaken a comparative study of human umbilical vein
      endothelial cells (HUVECs) and human saphenous vein endothelial cells (HSVECs)
      with respect to functional and antigenic tissue factor (TF), tissue factor
      pathway inhibitor (TFPI), and TF mRNA. Monolayers of each cell type (passage 2,
      except where specified) were grown to confluence and then activated for 4 h with
      either 50 U/mL IL-1-alpha or 10 microg/mL tumor necrosis factor-alpha. Activated
      factor X appearing in supernatant was measured using a chromogenic assay, and
      both Northern blots and quantitative RT-PCR were performed to assess
      concentrations of TF mRNA accompanying activation. The role of TFPI was
      separately determined by ELISA for supernatant TFPI antigen, and by measurements
      of production of activated factor X in the presence of 0, 5, 15, or 50 microg/mL
      of an antibody directed against TFPI. To address a non-TF pathway endothelial
      cell function, antigenic concentrations of tissue plasminogen activator for both
      cell types was also determined by ELISA. HUVECs were found to produce 2.4- to 3.5
      fold more functional TF. No significant HUVEC-HSVEC differences were detected in
      TF antigen, supernatant TFPI, anti-TFPI affinity for endothelial cell-associated
      TFPI, TF mRNA or its amplification products, and tissue plasminogen activator.
      Immunostaining for TF antigen, however, may have failed to detect a modest HUVEC
      HSVEC difference. Our finding with respect to functional TF indicates that HUVECs
      and HSVECs are not equivalent in terms of models for endothelial cell function in
      small children versus adults.

PMID- 10590034
TI  - IGF-I increases interferon-gamma and IL-6 mRNA expression and protein production
      in neonatal mononuclear cells.
AB  - Neonates are vulnerable to infections because of their immature immunity. IGF-I
      has been reported to have profound positive effects on immune function. In this
      study, we investigated the effects of IGF-I on neonatal immunity. The production
      of IL-2, IL-4, and interferon-gamma in phytohemagglutinin (PHA)-stimulated
      neonatal mononuclear cells (MNC) was significantly decreased when compared with
      that of adults. IGF-I alone induced a high level of IL-6 mRNA expression and
      protein production in neonatal MNC. IGF-I significantly increased mRNA expression
      and protein production of both IL-6 and interferon-y but had no influence on that
      of IL-2 and IL-4 in PHA-stimulated neonatal MNC. Moreover, it increased neonatal
      interferon-gamma production in PHA-stimulated MNC to a level similar to that of
      adults. IGF-I could further enhance the mRNA expression of lymphocyte-activation
      gene 3, which is associated with interferon-gamma production and differentiation
      of T-helper 1 lymphocytes, in PHA-stimulated neonatal MNC. These results suggest
      IGF-I could promote maturation of neonatal T cells, and its potential use to
      enhance neonatal immunity deserves further study.

PMID- 10590035
TI  - Adhesion defects of antibody-mediated target cell binding of neonatal natural
      killer cells.
AB  - Neonates are unusually susceptible to herpes simplex virus infection, which may
      be explained in part by defects in killing of herpes simplex virus-infected cells
      by natural killer (NK) cell cytotoxicity and antibody-dependent cellular
      cytotoxicity. The mechanism for these defects remains poorly defined. We have for
      the first time used immunomagnetically enriched NK cells to explore neonatal NK
      cell phenotype and target cell adhesion. CD56-positive neonatal NK cells had
      markedly lower CD57 expression, but adult level expression of adhesive
      glycoproteins (CD18, CD44) and Fc receptor for IgG (CD16). Although the cells
      conjugated normally with target cells in the absence of antibody, antibody
      mediated conjugation was significantly lower than that of NK cells from adults (p
      < 0.002). These results demonstrate intact adhesion in neonatal NK cell
      cytotoxicity. In contrast, defective neonatal antibody-dependent cellular
      cytotoxicity is caused, in part, by an adhesion defect in the presence of
      antibody.

PMID- 10590036
TI  - Acute laryngitis in the rat induced by Moraxella catarrhalis and Bordetella
      pertussis: number of neutrophils, dendritic cells, and T and B lymphocytes
      accumulating during infection in the laryngeal mucosa strongly differs in
      adjacent locations.
AB  - Infectious laryngotracheitis results in fulminant respiratory distress. During
      the disease, the subglottic mucosa is selectively infected and swollen, the
      reason for this preference being unknown. Therefore, in the present study the
      immunoreaction of the laryngeal mucosa was studied in the rat after inhalation of
      either heat-killed Moraxella catarrhalis (PVG rats) or application of viable
      Bordetella pertussis (BN rats). The number of neutrophils, macrophages, dendritic
      cells, and T and B lymphocytes was determined in the mucosa of the supraglottic,
      glottic, and subglottic area of the larynx as well as in the trachea. After
      application of the pathogens, the mucosa of the subglottic area was significantly
      more affected than the glottic mucosa. Already 1 h after application of M.
      catarrhalis, not only neutrophils but also dendritic cells and T and B
      lymphocytes were found both subepithelially and within the epithelium. They
      showed a similar kinetic progression, although at a different level. Two hours
      after application of M. catarrhalis, at the peak of inflammation, dendritic cells
      (173 +/- 10 cells/0.1 mm2) outnumbered neutrophils (54 +/- 9 cells/0.1 mm2), T
      lymphocytes (25 +/- 2 cells/0.1 mm2), and B lymphocytes (4.3 cells/0.1 mm2). The
      subglottic area (and the trachea) contained about three to five times more cells
      than the glottic area. In contrast, the number of local macrophages was lower in
      the subglottic area (24 +/- 5 cells/0.1 mm2) compared with that of the glottic
      area (38 +/- 6 cells/0.1 mm2), and did not change after application of both M.
      catarrhalis and B. pertussis. Thus, infectious laryngotracheitis in the rat
      closely resembles the clinical picture in children. In addition, the present
      results show a major difference in cellular influx in the mucosa of the glottic
      and subglottic area. This demonstrates that even in two closely adjacent
      locations, inflammatory responses of different magnitudes can occur, and it
      underlines the importance of regulatory mechanisms specific for the respective
      microenvironment.

PMID- 10590037
TI  - Concentrations of granulocyte colony-stimulating factor in human milk after in
      vitro simulations of digestion.
AB  - Human milk contains proteins that survive digestion in the neonatal
      gastrointestinal tract. Our group and others have reported that granulocyte
      colony-stimulating factor (G-CSF), a hematopoietic cytokine that influences
      neutrophil proliferation and differentiation, is present in human milk. We also
      reported that specific receptors for G-CSF are expressed on the villous
      enterocytes of neonates. However, the physiologic role of milk-borne G-CSF is not
      known. Thus, we sought to evaluate the capacity of human milk to protect G-CSF
      against proteolytic degradation after exposure to gastric secretions obtained
      from preterm (PT) and term (T) neonates at pH concentrations of 3.2, 5.8, and
      7.4. Specifically, we examined degradation of 1) endogenous G-CSF in PT (n = 15)
      and T (n = 15) human milk; 2) recombinant human G-CSF (rhG-CSF) added to a
      protein-free buffer (n = 10, 5 PT and 5 T); and 3) rhG-CSF added to human milk (n
      = 12, 6 PT and 6 T), various commercially prepared infant formulas (n = 15), and
      cow's milk (n = 5). Endogenous G-CSF and rhG-CSF added to human milk resisted
      degradation at 1 and 2 h. However, when rhG-CSF was added to commercial formulas,
      >95% was degraded at 1 and 2 h at each pH level. Similarly, approximately 60% of
      rhG-CSF added to cow's milk was degraded at I and 2 h. We conclude that 1)
      endogenous G-CSF and rhG-CSF added to human milk are protected from degradation
      after exposure to gastric secretions at physiologic pH levels, 2) rhG-CSF added
      to infant formulas is not protected from degradation, and 3) it is likely that
      the G-CSF present in human milk is biologically available to the neonate.

PMID- 10590038
TI  - Dual-energy X-ray absorptiometry in small subjects: influence of dual-energy X
      ray equipment on assessment of mineralization and body composition in newborn
      piglets.
AB  - There is a growing body of literature that describes the use of dual-energy x-ray
      absorptiometry (DXA) for bone mineral content (BMC) and fat mass (FM) assessment
      in neonates, but the reproducibility and accuracy of the method are still
      controversial. Two different software programs have been developed for use on
      Hologic densitometers: the Pediatric Whole Body (PWB) and the Infant Whole Body
      (IWB) programs. They differ in scan time, radiation exposure, and in the
      algorithm used to assess BMC. We evaluated the reproducibility and accuracy of
      PWB and IWB in newborn piglets. Reproducibility of body mass (BM), FM, and BMC
      measurements from PWB and IWB were similar. BM agreed well with scale weight with
      both software programs; IWB was within +/- 0.5% and PWB was within +/- 0.3% of
      scale weight. FM was highly correlated with carcass fat (PWB: r = 0.962; IWB: r =
      0.980). Errors in the DXA estimation of fat were similar with PWB and IWB. With
      both software programs, BMC was highly correlated with carcass calcium (PWB: r =
      0.925, IWB: r = 0.987), but errors in the DXA estimation of calcium were about
      twice as high with PWB (+/- 16.9%) than with IWB (+/-9.2%). In four piglets, the
      addition of a layer of porcine lard was associated with an increase in BMC; this
      effect was more pronounced with PWB (+ 156%) than with IWB (+ 15%). The IWB
      software provided BMC measurements that were more precise, accurate, and stable
      in the presence of added fat than the measurements obtained with PWB, indicating
      that IWB is superior to PWB for in vivo determination of BMC and body
      composition.

PMID- 10590039
TI  - Gene transfer by adenovectors.

PMID- 10590040
TI  - Adenovirus-mediated expression of human coagulation factor IX in the rhesus
      macaque is associated with dose-limiting toxicity.
AB  - We used a first-generation adenovirus vector (AVC3FIX5) to assess whether human
      factor IX could be expressed and detected in the rhesus macaque, which we have
      shown does not make high-titer antibodies to human factor IX protein. Three
      animals received 1 x 10(10) to 1 x 10(11) plaque-forming units per kilogram by
      intravenous injection. Human factor IX was present within 24 hours of vector
      administration and peaked 4 days later at 4,000 ng/mL in the high-dose recipient,
      and lower levels were seen in the intermediate-dose recipient. No human factor IX
      was detected in the low-dose recipient's plasma. Serum cytokine analysis and
      early hypoferremia suggested a dose-dependent acute-phase response to the vector.
      Human factor IX was detectable in rhesus plasma for 2 to 3 weeks for the high-
      and intermediate-dose recipients, but disappeared concomitant with high-titer
      antihuman factor IX antibody development. There was substantial, dose-dependent,
      dose-limiting liver toxicity that was manifest as elevated serum transaminase
      levels, hyperbilirubinemia, hypoalbuminemia, and prolongation of clotting times.
      Of particular interest was prolongation of the thrombin clotting time, an
      indicator of decreased fibrinogen or fibrinogen dysfunction. All evidence of
      liver toxicity resolved except for persistent hypofibrinogenemia in the high-dose
      recipient, indicating possible permanent liver damage. Our data suggest a narrow
      therapeutic window for first-generation adenovirus-mediated gene transfer. The
      development of antihuman factor IX antibodies and abnormalities of fibrinogen in
      the rhesus macaque is of concern for application of adenovirus (or other viral)
      vectors to hemophilia gene therapy.

PMID- 10590041
TI  - Correction of leukocyte adhesion deficiency type II with oral fucose.
AB  - We describe a simple, noninvasive, and effective therapy for leukocyte adhesion
      deficiency type II (LAD II), a rare inherited disorder of fucose metabolism. This
      disorder leads to an immunodeficiency caused by the absence of carbohydrate-based
      selectin ligands on the surface of neutrophils as well as to severe psychomotor
      and mental retardation. The fucosylation defect in LAD II fibroblasts can be
      corrected by addition of L-fucose to the culture medium. This prompted us to
      initiate dietary fucose therapy on a patient with LAD II. Oral supplementation of
      fucose in this patient induced the expression of fucosylated selectin ligands on
      neutrophils and core fucosylation of serum glycoproteins. During 9 months of
      treatment, infections and fever disappeared, elevated neutrophil counts returned
      to normal, and psychomotor capabilities improved.

PMID- 10590042
TI  - Molecular configuration of Rh D epitopes as defined by site-directed mutagenesis
      and expression of mutant Rh constructs in K562 erythroleukemia cells.
AB  - The Rh D antigen is the most clinically important protein blood group antigen of
      the erythrocyte. It is expressed as a collection of at least 37 different
      epitopes. The external domains of the Rh D protein involved in epitope
      presentation have been predicted based on the analysis of variant Rh D protein
      structures inferred from their cDNA sequences and their D epitope expression.
      This analysis can never be absolute because (1) most partial D phenotypes involve
      multiple amino acid changes in the Rh D protein and (2) deficiency for 1 or more
      epitopes may be due to gross structural alteration in the variant Rh D protein
      structure. We report here the amino acid requirements for the majority of D
      epitopes. They have been defined by generating a series of novel Rh mutant
      constructs by mutagenesis using an Rh cE cDNA as template and mutagenic
      oligonucleotide primers. When transfected into K562 cells, the D epitope
      expression of the derived mutant clones was then assessed by flow cytometry. The
      introduction of 9 externally predicted Rh D-specific amino acids on the Rh cE
      protein was sufficient to express 80% of all tested D epitopes, whereas other
      clones expressed none. We concluded from our data that the D epitope expression
      is consistent with at least 6 different epitope clusters localized on external
      regions of the Rh D protein, most involving overlapping regions within external
      loops 3, 4, and 6.

PMID- 10590043
TI  - Regulated genomic instability and neoplasia in the lymphoid lineage.

PMID- 10590044
TI  - Stromal derived factor-1-induced chemokinesis of cord blood CD34(+) cells (long
      term culture-initiating cells) through endothelial cells is mediated by E
      selectin.
AB  - Homing of hematopoietic stem cells to the bone marrow (BM) involves sequential
      interaction with adhesion molecules expressed on BM endothelium (BMEC) and
      chemokine stromal derived factor-1 (SDF-1). However, the mechanism whereby
      adhesion molecules regulate the SDF-1-induced transendothelial migration process
      is not known. E-selectin is an endothelial-specific selectin that is
      constitutively expressed by the BMEC in vivo. Hence, we hypothesized that E
      selectin may mediate SDF-1-induced transendothelial migration of CD34(+) cells.
      We show that CD34(+) cells express both E-selectin ligand and fucosyltransferase
      VII (FucT-VII). Soluble E-selectin-IgG chimera binds avidly to 75% +/- 10% of
      CD34(+) cells composed mostly of progenitors and cells with long-term culture
      initiating cell (LTC-IC) potential. To assess the functional capacity of E
      selectin to mediate CD34(+) cell migration in a transendothelial migration
      system, CD34(+) cells were placed on transwell plates coated with interleukin
      1beta-activated BMEC. In the absence of SDF-1, there was spontaneous migration of
      7.0% +/- 1.4% of CD34(+) cells and 14.1% +/- 2.2% of LTC-IC. SDF-1 induced
      migration of an additional 23.0% +/- 4.4% of CD34(+) cells and 17.6% +/- 3.6% of
      LTC-IC. Blocking MoAb to E-selectin inhibited SDF-1-induced migration of CD34(+)
      cells by 42.0% +/- 2.5% and LTC-IC by 90.9% +/- 16.6%. To define the mechanism of
      constitutive expression of E-selectin by the BMEC in vivo, we have found that
      vascular endothelial growth factor (VEGF(165)) induces E-selectin expression by
      cultured endothelial cells. VEGF-stimulated endothelial cells support
      transendothelial migration of CD34(+) cells that could be blocked by MoAb to E
      selectin. These results suggest that trafficking of subsets of CD34(+) cells with
      LTC-IC potential is determined in part by sequential interactions with E-selectin
      and SDF-1.

PMID- 10590045
TI  - Platelet factor 4-induced neutrophil-endothelial cell interaction: involvement of
      mechanisms and functional consequences different from those elicited by
      interleukin-8.
AB  - Platelet factor 4 (PF-4), a member of the CXC-subfamily of chemokines, is
      secreted in high amounts by activated platelets. In previous studies, we found
      that PF-4 specifically binds to human polymorphonuclear granulocytes (PMN), but
      requires tumor necrosis factor-alpha (TNF-alpha) as a costimulus for the
      induction of effector functions in suspended cells. In the present study, we have
      examined PF-4 in comparison with interleukin-8 (IL-8) for its ability to promote
      interaction of PMN with cultured endothelial cells (EC). We show here for the
      first time that PF-4 dose-dependently induces PMN to undergo extremely firm
      adhesion to EC as well as to exocytose secondary granule contents in the presence
      of these cells. Interestingly, costimulation by TNF-alpha was not required,
      indicating that EC could provide a corresponding signal(s). As evident from
      antibody blocking experiments, PF-4-induced adhesion involved PMN-expressed L
      selectin as well as leukocyte function-associated molecule-1 (LFA-1), whereas IL
      8 involved MAC-1. Because blocking antibodies to LFA-1 but not to L-selectin or
      MAC-1 abrogated PF-4-dependent marker exocytosis from PMN, the costimulatory
      signal provided by EC appears to be elicited through cell-cell contact via LFA-1.
      IL-8, inducing the upregulation of MAC-1, did not elicit marker exocytosis in
      contact with EC. Our results suggest a role for PF-4 in the promotion of PMN-EC
      interaction that is virtually different from that exhibited by other CXC
      chemokines such as IL-8.

PMID- 10590046
TI  - Increased incidence of cytomegalovirus disease after autologous CD34-selected
      peripheral blood stem cell transplantation.
AB  - High-dose therapy with autologous peripheral blood stem cell (PBSC) rescue is
      widely used for the treatment of malignant disease. CD34 selection of PBSC has
      been applied as a means of reducing contamination of the graft. Although CD34
      selection results in a 2 to 3 log reduction in contaminating tumor cells without
      significantly delaying engraftment, many other types of cells are depleted from
      the CD34-enriched grafts and immune reconstitution may be impaired. In the
      present study, 31 cytomegalovirus (CMV)-seropositive patients who received
      myeloablative therapy followed by the infusion of CD34-selected autologous PBSC
      were assessed for the development of CMV disease in the first 100 days
      posttransplant. Seven patients (22.6%) developed CMV disease and 4 patients
      (12.9%) died from complications of their infection. In a contemporaneous group of
      237 CMV-seropositive patients receiving unselected, autologous PBSC, only 10
      patients (4.2%) developed CMV disease, with 5 deaths (2.1%). In a multivariate
      logistic regression analysis, the use of CD34-selected autologous PBSC after high
      dose therapy was associated with a marked increase in the incidence of CMV
      disease and CMV-associated deaths.

PMID- 10590047
TI  - Hypodiploidy with less than 45 chromosomes confers adverse risk in childhood
      acute lymphoblastic leukemia: a report from the children's cancer group.
AB  - We have determined the prognostic significance of hypodiploidy (<46 chromosomes)
      in a large cohort of children with acute lymphoblastic leukemia (ALL) treated by
      the Children's Cancer Group. Among 1,880 patients, 110 (5.8%) had hypodiploid
      karyotypes: 87 had 45 chromosomes, 15 had 33 to 44 chromosomes, none had 29 to 32
      chromosomes, and 8 had 24 to 28 chromosomes (near-haploidy). Six-year event-free
      survival (EFS) estimates for patients with 45 chromosomes, 33 to 44 chromosomes,
      or 24 to 28 chromosomes were 65% (standard deviation [SD], 8%), 40% (SD, 18%),
      and 25% (SD, 22%), respectively (log rank, P =.002; test for trend, P =.0009).
      The combined hypodiploid group had worse outcome than nonhypodiploid patients,
      with 6-year EFS of 58% (SD, 7%) and 76% (SD, 2%), respectively (P <.0001). EFS
      for the subgroup with 45 chromosomes was similar to that of patients with
      pseudodiploidy (P =.43) or 47 to 50 chromosomes (P =.76). None of the patients
      with 24 to 28 chromosomes had a t(4;11), a t(9;22), or a t(1;19), and most
      received highly intensive therapy. The adverse risk associated with 33 to 44 and
      24 to 28 chromosomes remained significant in multivariate analyses adjusted for
      important risk factors including age, white blood cell count, and Philadelphia
      chromosome status. Thus, hypodiploidy with less than 45 chromosomes, particularly
      24 to 28 chromosomes, is a significant adverse risk factor despite treatment with
      contemporary intensive therapies.

PMID- 10590048
TI  - Dual or single hepatitis B and C virus infections in childhood cancer survivors:
      long-term follow-up and effect of interferon treatment.
AB  - We conducted a long-term prospective study of 89 cancer survivor children who had
      acquired hepatitis B virus (HBV) and/or hepatitis C virus (HCV) during treatment
      for neoplasia, the aim being to evaluate the natural history of the diseases and
      the effect of interferon (IFN) treatment. Patients were followed up for a median
      period of 13 years (range, 8 to 20); 46 were infected by HBV, 11 by HCV, and 32
      coinfected by HBV and HCV. A spontaneous clearance of hepatitis B surface antigen
      (HBsAg) occurred more frequently in coinfected patients (19%) than in the HBV
      infected (2%; P =.004), with an annual seroconversion rate of 2.1% and 0.2%,
      respectively (P =.008). Loss of hepatitis Be antigen (HBeAg) occurred in 44% of
      coinfected and in 28% of HBV-infected patients. Clearance of serum HCV-RNA was
      observed in 34% and 9%, respectively, of coinfected and HCV-infected patients.
      Seventeen HBV-infected, 4 HCV-infected, and 16 coinfected patients received alpha
      IFN treatment. In the HBV group, 6 patients (35%) cleared serum HBV DNA and
      seroconverted to anti-HBe; in the HCV-group, none cleared HCV-RNA. In the
      coinfected group, 1 patient cleared both HBV DNA and HCV-RNA, 6 patients cleared
      serum HCV-RNA alone, and 1 only HBV DNA and HBeAg. Overall, the diseases showed a
      mild histological course with no evidence of liver cirrhosis. A reciprocal
      interference on viral replication between HBV and HCV may occur in coinfected
      patients. Treatment seems to be effective for selected cases and is justified in
      view of the uncertain prognosis of the disease in these patients.

PMID- 10590049
TI  - Ex vivo generation of CD34(+) cells from CD34(-) hematopoietic cells.
AB  - The human Lin(-)CD34(-) cell population contains a newly defined class of
      hematopoietic stem cells that reconstitute hematopoiesis in xenogeneic
      transplantation systems. We therefore developed a culture condition in which
      these cells were maintained and then acquired CD34 expression and the ability to
      produce colony-forming cells (CFC) and SCID-repopulating cells (SRCs). A murine
      bone marrow stromal cell line, HESS-5, supports the survival and proliferation of
      Lin(-)CD34(-) cells in the presence of fetal calf serum and human cytokines
      thrombopoietin, Flk-2/Flt-3 ligand, stem cell factor, granulocyte colony
      stimulating factor, interleukin-3, and interleukin-6. Although Lin(-)CD34(-)
      cells do not initially form any hematopoietic colonies in methylcellulose, they
      do acquire the colony-forming ability during 7 days of culture, which coincides
      with their conversion to a CD34(+) phenotype. From 2.2% to 12.1% of the cells
      became positive for CD34 after culture. The long-term multilineage repopulating
      ability of these cultured cells was also confirmed by transplantation into
      irradiated NOD/SCID mice. These results represent the first in vitro
      demonstration of the precursor of CD34(+) cells in the human CD34(-) cell
      population. Furthermore, the in vitro system we reported here is expected to open
      the way to the precise characterization and ex vivo manipulation of Lin(-)CD34(-)
      hematopoietic stem cells.

PMID- 10590050
TI  - Amifostine inhibits hematopoietic progenitor cell apoptosis by activating NF
      kappaB/Rel transcription factors.
AB  - We investigated the involvement of NF-kappaB/Rel transcription factors that
      reportedly can inhibit apoptosis in various cell types in the antiapoptotic
      mechanism of the cytoprotectant amifostine. In the nontumorigenic murine myeloid
      progenitor 32D cells incubated with amifostine, we detected a reduction of the
      IkappaBalpha cytoplasmic levels by Western blotting and a raising of nuclear NF
      kappaB/Rel complexes by electrophoretic mobility shift assay. Amifostine
      inhibited by more than 30% the growth factor deprivation-induced apoptosis,
      whereas its effect failed when we blocked the NF-kappaB/Rel activity with an NF
      kappaB/Rel-binding phosphorothioate decoy oligodeoxynucleotide. In human cord
      blood CD34(+) cells, the NF-kappaB/Rel p65 subunit was detectable (using
      immunofluorescence analysis) mainly in the cytoplasm in the absence of
      amifostine, whereas its presence was appreciable in the nuclei of cells incubated
      with the cytoprotectant. In 4 CD34(+) samples incubated for 3 days in cytokine
      deficient conditions, cell apoptosis was reduced by more than 30% in the presence
      of amifostine (or amifostine plus a control oligo); the effect of amifostine was
      abolished in cultures with the decoy oligo. These findings indicate that the
      inhibition of hematopoietic progenitor cell apoptosis by amifostine requires the
      induction of NF-kappaB/Rel factors and that the latter can therefore exert an
      antiapoptotic activity in the hematopoietic progenitor cell compartment.
      Furthermore, the identification of this specific mechanism underlying the
      survival-promoting activity of amifostine lends support to the possible use of
      this agent in apoptosis-related pathologies, such as myelodysplasias.

PMID- 10590051
TI  - Distinct roles of JNKs/p38 MAP kinase and ERKs in apoptosis and survival of HCD
      57 cells induced by withdrawal or addition of erythropoietin.
AB  - Erythropoietin (EPO), a major regulator of erythroid progenitor cells, is
      essential for the survival, proliferation, and differentiation of immature
      erythroid cells. To gain insight into the molecular mechanism by which EPO
      functions, we analyzed the activation of Jun N-terminal kinases (JNKs) and
      extracellular signal-regulated kinases (ERKs) in HCD-57 cells, a murine erythroid
      progenitor cell line that requires EPO for survival and proliferation. Withdrawal
      of EPO from the cell culture medium resulted in sustained activation of JNKs plus
      p38 MAP kinase, and inactivation of ERKs, preceding apoptosis of the cells.
      Addition of EPO to the EPO-deprived cells caused activation of ERKs accompanied
      by inactivation of JNKs and p38 MAP kinase and rescued the cells from apoptosis.
      Phorbol 12-myristate 13-acetate, which activated ERKs by a different mechanism,
      also suppressed the activation of JNKs and significantly retarded apoptosis of
      the cells caused by withdrawal of EPO. Furthermore, MEK inhibitor PD98059, which
      inhibited activation of ERKs, caused activation of JNKs, whereas suppression of
      JNK expression by antisense oligonucleotides and inhibition of p38 MAP kinase by
      SB203580 caused attenuation of the apoptosis that occurs upon withdrawal of EPO.
      Finally, the activation of JNKs and p38 MAP kinase and concurrent inactivation of
      ERKs upon withdrawal of EPO were also observed in primary human erythroid colony
      forming cells. Taken together, the data suggest that activation of ERKs promotes
      cell survival, whereas activation of JNKs and p38 MAP kinase leads to apoptosis
      and EPO functions by controlling the dynamic balance between ERKs and JNKs.

PMID- 10590052
TI  - Defective proliferation of primitive myeloid progenitor cells in patients with
      severe congenital neutropenia.
AB  - Although several mechanisms have been proposed to explain the pathophysiology of
      severe congenital neutropenia (SCN), the precise defect responsible for SCN
      remains unknown. We studied the responsiveness of primitive myeloid progenitor
      cells to hematopoietic factors in 4 patients with SCN. The number of granulocyte
      macrophage (GM) colonies formed in patients was decreased in response to
      granulocyte colony-stimulating factor (G-CSF) in both serum-supplemented and
      serum-deprived culture. The polymerase chain reaction-single-strand
      conformational polymorphism analysis of the G-CSF receptor gene showed no
      variance in structure conformation between the 4 patients and the normal
      subjects. In patients with SCN, the nonadherent light density bone marrow cells
      and cells that were purified on the basis of the expression of CD34 and Kit
      receptor (CD34(+)/Kit(+) cells) showed the reduced response to the combination of
      steel factor (SF), the ligand for flk2/flt3 (FL), and interleukin-3 (IL-3) with
      or without G-CSF in serum-deprived culture. Furthermore, when individual
      CD34(+)/Kit(+) cells from patients were cultured in the presence of SF, FL, and
      IL-3, with or without G-CSF for 10 days, the number of clones proliferated and
      the number of cells per each proliferating clone was significantly less than
      those in normal subjects. These results suggest that primitive myeloid progenitor
      cells of patients with SCN have defective responsiveness to not only G-CSF, but
      also the early- or intermediate-acting hematopoietic factors, SF, FL, and IL-3.

PMID- 10590053
TI  - Ex vivo cultured megakaryocytes express functional glycoprotein IIb-IIIa
      receptors and are capable of adenovirus-mediated transgene expression.
AB  - Investigation of the molecular basis of megakaryocyte (MK) and platelet biology
      has been limited by an inadequate source of genetically manipulable cells
      exhibiting physiologic MK and platelet functions. We hypothesized that ex vivo
      cultured MKs would exhibit agonist inducible glycoprotein (GP) IIb-IIIa
      activation characteristic of blood platelets and that these cultured MKs would be
      capable of transgene expression. Microscopic and flow cytometric analyses
      confirmed that human hematopoietic stem cells cultured in the presence of
      pegylated recombinant human MK growth and development factor (PEG-rHuMGDF)
      differentiated into morphologic and phenotypic MKs over 2 weeks. Cultured MKs
      expressed functional GPIIb-IIIa receptors as assessed by agonist inducible
      soluble fibrinogen and PAC1 binding. The specificity and kinetics of fibrinogen
      binding to MK GPIIb-IIIa receptors were similar to those described for blood
      platelets. The reversibility and internalization of ligands bound to MK GPIIb
      IIIa also shared similarities with those observed in platelets. Cultured MKs were
      transduced with an adenoviral vector encoding green fluorescence protein (GFP) or
      beta-galactosidase (beta-gal). Efficiency of gene transfer increased with
      increasing multiplicities of infection and incubation time, with 45% of MKs
      expressing GFP 72 hours after viral infection. Transduced MKs remained capable of
      agonist induced GPIIb-IIIa activation. Thus, ex vivo cultured MKs (1) express
      agonist responsive GPIIb-IIIa receptors, (2) are capable of expressing
      transgenes, and (3) may prove useful for investigation of the molecular basis of
      MK differentiation and GPIIb-IIIa function.

PMID- 10590054
TI  - Distinct requirements for optimal growth and In vitro expansion of human
      CD34(+)CD38(-) bone marrow long-term culture-initiating cells (LTC-IC), extended
      LTC-IC, and murine in vivo long-term reconstituting stem cells.
AB  - Recently, primitive human bone marrow (BM) progenitors supporting hematopoiesis
      in extended (>60 days) long-term BM cultures were identified. Such extended long
      term culture-initiating cells (ELTC-IC) are of the CD34(+)CD38(-) phenotype, are
      quiescent, and are difficult to recruit into proliferation, implicating ELTC-IC
      as the most primitive human progenitor cells detectable in vitro. However, it
      remains to be established whether ELTC-IC can proliferate and potentially expand
      in response to early acting cytokines. Here, CD34(+)CD38(-) BM ELTC-IC (12-week)
      were efficiently recruited into proliferation and expanded in vitro in response
      to early acting cytokines, but conditions for expansion of ELTC-IC activity were
      distinct from those of traditional (5-week) LTC-IC and murine long-term
      repopulating cells. Whereas c-kit ligand (KL), interleukin-3 (IL-3), and IL-6
      promoted proliferation and maintenance or expansion of murine long-term
      reconstituting activity and human LTC-IC, they dramatically depleted ELTC-IC
      activity. In contrast, KL, flt3 ligand (FL), and megakaryocyte growth and
      development factor (MGDF) (and KL + FL + IL-3) expanded murine long-term
      reconstituting activity as well as human LTC-IC and ELTC-IC. Expansion of LTC-IC
      was most optimal after 7 days of culture, whereas optimal expansion of ELTC-IC
      activity required 12 days, most likely reflecting the delayed recruitment of
      quiescent CD34(+)CD38(-) progenitors. The need for high concentrations of KL, FL,
      and MGDF (250 ng/mL each) and serum-free conditions was more critical for
      expansion of ELTC-IC than of LTC-IC. The distinct requirements for expansion of
      ELTC-IC activity when compared with traditional LTC-IC suggest that the ELTC-IC
      could prove more reliable as a predictor for true human stem cell activity after
      in vitro stem cell manipulation.

PMID- 10590055
TI  - A point mutation Thr(799)Met on the alpha(2) integrin leads to the formation of
      new human platelet alloantigen Sit(a) and affects collagen-induced aggregation.
AB  - A new platelet-specific alloantigen, termed Sit(a), was identified in a severe
      case of neonatal alloimmune thrombocytopenia. The Sit(a) alloantigen is of low
      frequency (1/400) in the German population. Immunochemical studies demonstrated
      that the Sit(a) epitopes reside on platelet glycoprotein (GP) Ia. Nucleotide
      sequence analysis of GPIa cDNA derived from Sit(a)-positive platelets showed
      C(2531)-->T(2531) point mutation, resulting in Thr(799)Met dimorphism. Analysis
      of genomic DNA from 22 Sit(a)-negative normal individuals showed that the
      Thr(799) is encoded by ACG(2532) (90.9%) or ACA(2532) (9.1%). To establish a DNA
      typing technique, we elucidated the organization of the GPIa gene adjacent to the
      polymorphic bases. The introns (421 bp and 1.2 kb) encompass a 142-bp exon with
      the 2 polymorphic bases 2531 and 2532. Polymerase chain reaction-restriction
      fragment length polymorphism analysis on DNA derived from 100 donors using the
      restriction enzyme Mae III showed that the Met(799) form of GPIa is restricted to
      Sit(a) (+) phenotype. Analysis of stable Chinese hamster ovary transfectants
      expressing allele-specific recombinant forms of GPIa showed that anti-Sit(a)
      exclusively reacted with the Glu(505)Met(799), but not with the Glu(505)Thr(799)
      and the Lys(505)Thr(799) isoforms. In contrast, anti-Br(a) (HPA-5b) only
      recognized the Lys(505)Thr(799) form, whereas anti-Br(b) (HPA-5a) reacted with
      both Glu(505)Thr(799) and Glu(505)Met(799) isoforms. These results demonstrated
      that the Met(799) is responsible for formation of the Sit(a) alloantigenic
      determinants, whereas amino acid 505 (Lys or Glu) specifically controls the
      expression of Br(a) and Br(b) epitopes, respectively. Platelet aggregation
      responses of Sit(a) (+) individuals were diminished in response to collagen,
      indicating that the Thr(799)Met mutation affects the function of the GPIa/IIa
      complex.

PMID- 10590056
TI  - Glycoprotein V-deficient platelets have undiminished thrombin responsiveness and
      Do not exhibit a Bernard-Soulier phenotype.
AB  - Adhesion of platelets to extracellular matrix via von Willebrand factor (vWF) and
      activation of platelets by thrombin are critical steps in hemostasis.
      Glycoprotein (GP) V is a component of the GPIb-V-IX complex, the platelet
      receptor for vWF. GPV is also cleaved by thrombin. Deficiency of GPIb or GPIX
      results in Bernard-Soulier syndrome (BSS), a bleeding disorder in which platelets
      are giant and have multiple functional defects. Whether GPV-deficiency might also
      cause BSS is unknown as are the roles of GPV in platelet-vWF interaction and
      thrombin signaling. We report that GPV-deficient mice developed normally, had no
      evidence of spontaneous bleeding, and had tail bleeding times that were not
      prolonged compared with wild-type mice. GPV-deficient platelets were normal in
      size and structure as assessed by flow cytometry and electron microscopy. GPV
      deficient and wild-type platelets were indistinguishable in botrocetin-mediated
      platelet agglutination and in their ability to adhere to mouse vWF A1 domain.
      Platelet aggregation and ATP secretion in response to low and high concentrations
      of thrombin were not decreased in GPV-deficient platelets compared with wild
      type. Our results show that (1) GPV is not necessary for GPIb expression and
      function in platelets and that GPV deficiency is not likely to be a cause of
      human BSS and (2) GPV is not necessary for robust thrombin signaling. Whether
      redundancy accounts for the lack of phenotype of GPV-deficiency or whether GPV
      serves subtle or as yet unprobed functions in platelets or other cells remains to
      be determined.

PMID- 10590057
TI  - Hypofibrinogenemia associated with a heterozygous missense mutation gamma153Cys
      to arg (Matsumoto IV): in vitro expression demonstrates defective secretion of
      the variant fibrinogen.
AB  - We genetically analyzed a case of hypofibrinogenemia that showed no bleeding or
      thrombotic tendency. Direct sequencing of a polymerase chain reaction-amplified
      gamma-chain gene segment showed a novel nucleotide substitution. This
      heterozygous mutation encodes both Cys (TGT) and Arg (CGT) at residue 153. To
      examine the basis for the fibrinogen deficiency, we prepared expression vectors
      containing mutant gamma-chain DNAs encoding gamma153R and gamma153A for in vitro
      expression in Chinese hamster ovary (CHO) cells. Enzyme-linked immunosorbent
      assay and immunoblot analysis of the culture media and cell lysates showed that
      CHO cells transfected with gamma153R or gamma153A synthesized the variant gamma
      chain, but did not secrete variant fibrinogen into the culture medium. Metabolic
      pulse-chase experiments showed that fibrinogen assembly was impaired when either
      variant gamma-chain was expressed. In cells expressing normal fibrinogen, assem-
      bly intermediates and intact fibrinogen were seen in cell lysates prepared after
      short (3 minutes) or long (1 hour) incubation with (35)S-methionine. Neither
      intermediates nor intact fibrinogen was seen with the variant gamma-chains. These
      data suggest that gamma-chains have an important early role in fibrinogen
      assembly. Thus, our results support the model for fibrinogen assembly proposed by
      Huang et al (J Biol Chem 268:8919, 1993), in which the first step in assembly is
      the formation of alphagamma or betagamma dimers, or both. This model implies that
      gammaCys153 has a critical role in the formation of these early assembly
      intermediates. We concluded that the gamma153Cys-->Arg substitution does not
      allow fibrinogen assembly and secretion, and this is manifest in vivo as a
      fibrinogen deficiency. We designated this variant as fibrinogen Matsumoto IV.

PMID- 10590058
TI  - Anti-inflammatory actions of lipoxin A(4) stable analogs are demonstrable in
      human whole blood: modulation of leukocyte adhesion molecules and inhibition of
      neutrophil-endothelial interactions.
AB  - We have examined in whole blood the actions of 2 lipoxin A(4) (LXA(4)) stable
      analogs, 15-R/S-methyl-LXA(4) and 16-phenoxy-LXA(4), for their impact on the
      expression of adhesion molecules on human leukocytes and coronary artery
      endothelial cells (HCAEC) and on neutrophil adhesion to HCAEC in vitro. Both
      LXA(4) analogs in nanomolar to micromolar concentrations prevented shedding of L
      selectin and downregulated CD11/CD18 expression on resting neutrophils,
      monocytes, and lymphocytes. Changes in CD11/CD18 expression were blocked by the
      mitogen-activated protein kinase kinase inhibitor PD98059. The LXA(4) analogs
      also attenuated changes in L-selectin and CD11/CD18 expression evoked by platelet
      activating factor (PAF), interleukin-8, or C-reactive protein-derived peptide 201
      206 with IC(50) values of 0.2 to 1.9 micromol/L, whereas they did not affect
      lipopolysaccharide (LPS)- or tumor necrosis factor-alpha-stimulated expression of
      E-selectin and intercellular adhesion molecule-1 on HCAEC. These LXA(4) analogs
      markedly diminished adhesion of neutrophils to LPS-activated HCAEC. Inhibition of
      adhesion was additive with function blocking anti-E-selectin and anti-L-selectin
      antibodies, but was not additive with anti-CD18 antibody. Combining LXA(4)
      analogs with dexamethasone (100 nmol/L) almost completely inhibited PAF-induced
      changes in adhesion molecule expression on leukocytes and gave additive
      inhibition of neutrophil adhesion to HCAEC. Culture of HCAEC with dexamethasone,
      but not with LXA(4) analogs, also decreased neutrophil attachment. Together,
      these results indicate that LXA(4) stable analogs modulate expression of both L
      selectin and CD11/CD18 on resting and immunostimulated leukocytes and inhibit
      neutrophil adhesion to HCAEC by attenuating CD11/CD18 expression. These actions
      are additive with those of glucocorticoids and may represent a novel and potent
      regulatory mechanism by which LXA(4) and aspirin-triggered 15-epi-LXA(4) modulate
      leukocyte trafficking.

PMID- 10590059
TI  - Antiangiogenesis is produced by nontoxic doses of vinblastine.
AB  - The effects of vinblastine (VBL) on endothelial cell functions involved in
      angiogenesis, namely proliferation, chemotaxis, spreading on fibronectin (FN),
      secretion of matrix-metalloproteinase-2 (MMP-2) and MMP-9, and morphogenesis on
      Matrigel were tested in vitro, whereas its effects on angiogenesis were studied
      in vivo by using the chick embryo chorioallantoic membrane (CAM) model. In vitro,
      at noncytotoxic doses (0.1, 0.25, 0. 5, 0.75, and 1 pmol/L), VBL impacted all
      these functions, except secretion of MMPs, in a dose-dependent fashion. By
      contrast, proliferation of other primary cells such as fibroblasts and lymphoid
      tumor cells was not impacted. In vivo, VBL at 0.5, 0.75, and 1 pmol/L again
      displayed a dose-dependent antiangiogenic activity. Lack of cytotoxicity in vitro
      and in vivo was shown both morphologically, and also because the antiangiogenic
      effects were rapidly abolished when VBL was removed. Apoptosis was not induced.
      At the ultrastructural level, impairment of cell functions in vitro was
      associated with thin disturbance of the cytoskeleton, in the form of slight
      depolymerization and accumulation of microfilaments, which was equally
      reversible. Results suggest that VBL has an antiangiogenic component at very low,
      noncytotoxic doses, and that antiangiogenesis by VBL could be used to treat a
      wide spectrum of angiogenesis-dependent diseases, including certain chronic
      inflammatory diseases, Kaposi's sarcoma, and cancer.

PMID- 10590060
TI  - A key role of adenosine diphosphate in the irreversible platelet aggregation
      induced by the PAR1-activating peptide through the late activation of
      phosphoinositide 3-kinase.
AB  - Although adenosine diphosphate (ADP), per se, is a weak platelet agonist, its
      role as a crucial cofactor in human blood platelet functions has now been clearly
      demonstrated in vitro and in vivo. The molecular basis of the ADP-induced
      platelet activation is starting to be understood since the discovery that 2
      separate P2 purinergic receptors may be involved simultaneously in the activation
      process. However, little is known about how ADP plays its role as a cofactor in
      platelet activation and which signaling pathway initiated by a specific agonist
      can be modulated by the released ADP. To investigate these points, we took
      advantage of a model of platelet activation through the thrombin receptor PAR1 in
      which both ADP scavengers and phosphoinositide 3-kinase (PI 3-kinase) inhibitors
      have been shown to transform the classical irreversible aggregation into a
      reversible one. We have observed that, among the different PI 3-kinase products,
      the accumulation of phosphatidylinositol 3,4-bisphosphate [PtdIns(3,4)P(2)] was
      dramatically and specifically attenuated when ADP was removed by apyrase
      treatment. A comparison between the effects of PI 3-kinase inhibitors and apyrase
      strongly suggest that the late, ADP-dependent, PtdIns(3,4)P(2) accumulation is
      necessary for PAR1-induced irreversible aggregation. Using selective antagonists,
      we found that the effect of ADP was due to the ADP receptor coupled to inhibition
      of adenylyl cyclase. Finally, we found that both ADP and PI 3-kinase play an
      important role in PAR1-dependent reorganization of the cytoskeleton through a
      control of myosin heavy chain translocation and the stable association of
      signaling complexes with the actin cytoskeleton.

PMID- 10590061
TI  - Regulation and function of WASp in platelets by the collagen receptor,
      glycoprotein VI.
AB  - Wiskott Aldrich syndrome (WAS) is an X-linked recessive disorder associated with
      abnormalities in platelets and lymphocytes giving rise to thrombocytopenia and
      immunodeficiency. WAS is caused by a mutation in the gene encoding the
      cytoskeletal protein (WASp). Despite its importance, the role of WASp in platelet
      function is not established. WASp was recently shown to undergo tyrosine
      phosphorylation in platelets after activation by collagen, suggesting that it may
      play a selective role in activation by the adhesion molecule. In the present
      study, we show that WASp is heavily tyrosine phosphorylated by a collagen-related
      peptide (CRP) that binds to the collagen receptor glycoprotein (GP) VI, but not
      to the integrin alpha2beta1. Tyrosine phosphorylation of WASp was blocked by Src
      family kinase inhibitors and reduced by treatment with wortmannin and in patients
      with X-linked agammaglobulinemia (XLA), a condition caused by a lack of
      functional expression of Btk. This indicates that Src kinases,
      phosphatidylinositol 3-kinase (PI 3-kinase), and Btk all contribute to the
      regulation of tyrosine phosphorylation of WASp. The functional importance of WASp
      was investigated in 2 WAS brothers who show no detectable expression of WASp.
      Platelet aggregation and secretion from dense granules induced by CRP and
      thrombin was slightly enhanced in the WAS platelets relative to controls.
      Furthermore, there was no apparent difference in morphology in WAS platelets
      after stimulation by these agonists. These observations suggest that WASp does
      not play a critical role in intracellular signaling downstream of tyrosine kinase
      linked and G protein-coupled receptors in platelets.

PMID- 10590062
TI  - Induction of the plasminogen activator inhibitor-1 gene expression by mild
      hypoxia via a hypoxia response element binding the hypoxia-inducible factor-1 in
      rat hepatocytes.
AB  - Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor
      of both tissue-type and urokinase-type plasminogen activators. The balance
      between plasminogen activators and PAI-1 plays an important role in several
      physiological and pathophysiological processes such as atherosclerosis or
      thrombosis. Because these conditions are associated with hypoxia, it was the aim
      of the present study to investigate the influence of low O(2) tension on the
      expression of PAI-1 mRNA and protein using primary cultured rat hepatocytes as a
      model system. We found that PAI-1 mRNA and protein were induced by mild hypoxia
      (8% O(2)). The hypoxia-dependent PAI-1 mRNA induction was transcriptionally
      regulated because it was inhibited by actinomycin D (ActD). Luciferase (LUC)
      reporter gene constructs driven by about 800 bp of the 5'-flanking region of the
      rat PAI-1 gene were transiently transfected into primary rat hepatocytes; mild
      hypoxia caused a 3-fold induction, which was mediated by the PAI-1 promoter
      region -175/-158 containing 2 putative hypoxia response elements (HRE) binding
      the hypoxia-inducible factor (HIF-1). Mutation of the HRE-1 (-175/-168) or HRE-2
      (-165/-158) also abolished the induction by mild hypoxia. Cotransfection of a HIF
      1alpha vector and the PAI-1-LUC constructs, as well as gel shift assays, showed
      that the HRE-2 of the PAI-1 promoter was most critical for induction by hypoxia
      and HIF-1 binding. Thus, PAI-1 induction by mild hypoxia via a HIF-1 binding HRE
      in the rat PAI-1 promoter appears to be the mechanism causing the increase in PAI
      1 in many clinical conditions associated with O(2) deficiency.

PMID- 10590063
TI  - Modulation by heparin of the interaction of the A1 domain of Von Willebrand
      factor with glycoprotein Ib.
AB  - The conformation of the A1 domain of von Willebrand factor (vWF) is a critical
      determinant of its interaction with the glycoprotein (GP) Ib/V/IX complex. To
      better define the regulatory mechanisms of vWF A1 domain binding to the GPIb/V/IX
      complex, we studied vWF-dependent aggregation properties of a cell line
      overexpressing the GPIbalpha, GPIbbeta, and GPIX subunits (CHO-GPIbalphabeta/IX
      cells). We found that CHO-GPIbalphabeta/IX cell aggregation required the presence
      of both soluble vWF and ristocetin. Ristocetin-induced CHO-GPIbalphabeta/IX cell
      aggregation was completely inhibited by the recombinant VCL fragment of vWF that
      contains the A1 domain. Surprisingly, the substitution of heparin for ristocetin
      resulted in the formation of CHO-GPIbalphabeta/IX cell aggregates. Using
      monoclonal antibodies blocking vWF interaction with GPIb/V/IX or mocarhagin, a
      venom metalloproteinase that removes the amino-terminal fragment of GPIbalpha
      extending from aa 1 to 282, we demonstrated that both ristocetin- and heparin
      induced aggregations involved an interaction between the A1 domain of vWF and the
      GPIbalpha subunit of the GPIb/V/IX complex. The involvement of heparin in cell
      aggregation was also demonstrated after treatment of heparin with heparinase that
      abolished CHO-GPIbalphabeta/IX cell aggregation. These results indicated that
      heparin was able to induce vWF-dependent CHO-GPIbalphabeta/IX cell aggregation.
      In conclusion, we demonstrated that heparin is capable of positively modulating
      the vWF interaction with the GPIb/V/IX complex.

PMID- 10590064
TI  - Differential In situ cytokine profiles of Langerhans-like cells and T cells in
      Langerhans cell histiocytosis: abundant expression of cytokines relevant to
      disease and treatment.
AB  - The pathogenesis of Langerhans cell histiocytosis (LCH) remains poorly
      understood. To further elucidate LCH pathogenesis, we analyzed the expression of
      10 cytokines relevant to cellular recruitment and activation at the protein level
      in 14 patients and identified the lesional cells responsible for cytokine
      production in situ by immunohistochemistry. The cytokines investigated included
      the hematopoietic growth factors interleukin-3 (IL-3), IL-7, and granulocyte
      macrophage colony-stimulating factor (GM-CSF); the lymphocyte regulatory
      cytokines IL-2, IL-4, and IL-10; the inflammatory regulators IL-1alpha and tumor
      necrosis factor-alpha (TNF-alpha); and the effector cell-activating cytokines IL
      5 and interferon-gamma (IFN-gamma). In all specimens, CD1a(+) histiocytes (LCH
      cells) and CD3(+) T cells produced large amounts of cytokines, creating a true
      cytokine storm. IL-2, IL-4, IL-5, and TNF-alpha were produced exclusively by T
      cells, whereas only IL-1alpha was produced by LCH cells. Equal numbers of LCH
      cells, T cells, and macrophages produced GM-CSF and IFN-gamma. Equal numbers of
      LCH cells and macrophages produced IL-10, whereas IL-3 was produced by T cells
      and macrophages. IL-7 was only produced by macrophages. Eosinophils, present in
      some specimens, were partially responsible for the production of IL-5, IFN-gamma,
      GM-CSF, IL-10, IL-3, and IL-7. Expression of all cytokines, abundant in most
      biopsies, was irrespective of age, gender, or site of biopsy. These findings
      emphasize the role of T cells in LCH. The juxtaposition of T cells and LCH cells
      suggests that both cells interact in a cytokine amplification cascade, resulting
      from stimulation of autocrine and paracrine stimulatory loops. This cascade can
      be linked directly to the development of LCH through recruitment, maturation, and
      proliferation of LCH cells. The cytokines studied are known to be involved in the
      development of other characteristic features of LCH, such as fibrosis, necrosis,
      and osteolysis.

PMID- 10590065
TI  - Constitutive activation of STATs upon in vivo human immunodeficiency virus
      infection.
AB  - Infection by the human immunodeficiency virus (HIV) either upregulates or
      downregulates the expression of several cytokines and interferons (IFNs) that use
      the Janus kinase/signal transducer and activator of transcription (JAK/STAT)
      pathway for signal transduction. However, very little is known on the state of
      activation of the JAK/STAT pathway after HIV infection either in vivo or in
      vitro. In this regard, we report here that a constitutive activation of a C
      terminal truncated STAT5 (STAT5triangle up) and of STAT1alpha occurs in the
      majority ( approximately 75%) of individuals with progressive HIV disease. We
      have further demonstrated that, among peripheral blood mononuclear cells (PBMCs),
      STAT5triangle up is activated preferentially in CD4(+) T cells. In contrast to a
      published report, expression of STATs from PBMCs of infected individuals was
      comparable with that of seronegative donors. In addition, in vitro infection of
      mitogen-activated PBMCs with a panel of laboratory-adapted and primary HIV
      strains characterized by differential usage of chemokine coreceptors did not
      affect STAT protein levels. However, enhanced activation of STAT was observed
      after in vitro infection of resting PBMCs and nonadherent PBMCs by different
      viral strains. Thus, constitutive STAT activation in CD4(+) T lymphocytes
      represents a novel finding of interest also as a potential new marker of
      immunological reconstitution of HIV-infected individuals.

PMID- 10590066
TI  - Interleukin-15 as an activator of natural killer cell-mediated antiviral
      response.
AB  - Natural killer (NK) cells are large granular lymphocytes capable of efficient
      killing of virus-infected and tumor cells in a major histocompatibility complex
      independent manner. The cytotoxic killing potential of NK cells can be modulated
      by a variety of factors, including cytokines such as interleukin-12 (IL-12), IL
      15, and interferon (IFN). IL-15 also plays an important role in NK cell
      development and survival. Killing of virally infected cells by NK cells is likely
      to represent an important antiviral defense mechanism, especially during the
      early phase of infection when antigen-specific immunity has yet to be generated.
      In the present work, we studied the potential of IL-15 to act as a modulator of
      NK cell-mediated antiviral defense. Our results clearly indicate that IL-15 can
      curtail infections by 3 human herpesviruses: Herpes simplex virus type 1, Epstein
      Barr virus, and human herpesvirus 6. The antiviral activity of IL-15 is dose-,
      time-, and NK cell-dependent. IL-15-treated NK cells showed an increased killing
      potential against a variety of cells, including virus-infected target cells.
      Lastly, using highly purified cell population, we report that IL-15 triggers the
      synthesis of IFN-gamma from both CD4(+) and NK cells, which can act in both
      autocrine and paracrine fashion to modulate NK cells cytotoxic potential. In
      conclusion, IL-15 is a cytokine that can contribute to the establishment of an
      antiviral state in 2 ways: first by increasing the killing ability of NK cells
      and second by stimulating the synthesis and secretion of IFN.

PMID- 10590067
TI  - Variant genotypes of the low-affinity Fcgamma receptors in two control
      populations and a review of low-affinity Fcgamma receptor polymorphisms in
      control and disease populations.
AB  - Fcgamma-receptors (FcgammaR) provide a critical link between humoral and cellular
      immunity. The genes of the low-affinity receptors for IgG and their isoforms,
      namely, FcgammaRIIa, FcgammaRIIb, FcgammaRIIIa, FcgammaRIIIb, and SH
      FcgammaRIIIb, are located in close proximity on chromosome 1q22. Variant alleles
      may differ in biologic activity and a number of studies have reported the
      frequencies of variant FcgammaR alleles in both disease and control populations.
      No large study has evaluated the possibility of a nonrandom distribution of
      variant genotypes. We analyzed 395 normal individuals (172 African Americans [AA]
      and 223 Caucasians [CA]) at the following loci: FcgammaRIIa, FcgammaRIIIa, and
      FcgammaRIIIb, including the SH-FcgammaRIIIb. The genotypic distributions of
      FcgammaRIIa, FcgammaRIIIa, and FcgammaRIIIb conform to the Hardy-Weinberg law in
      each group. There was no strong evidence that combinations of 2-locus genotypes
      of the 3 loci deviated from random distributions in these healthy control
      populations. The distribution of SH-FcgammaRIIIb is underrepresented in CA
      compared with AA (P < .0001) controls. A previously reported variant FcgammaRIIb
      was not detected in 70 normal individuals, indicating that this allele, if it
      exists, is very rare (<1%). In conclusion, we present data that should serve as
      the foundation for the interpretation of association studies involving multiple
      variant alleles of the low-affinity FcgammaR.

PMID- 10590068
TI  - The BCR/ABL oncogene alters the chemotactic response to stromal-derived factor
      1alpha.
AB  - The chemokine stromal-derived factor-1alpha (SDF-1alpha) is a chemoattractant for
      CD34(+) progenitor cells, in vitro and in vivo. The receptor for SDF-1alpha, CXCR
      4, is a 7 transmembrane domain receptor, which is also a coreceptor for human
      immunodeficiency virus (HIV). Here we show that transformation of hematopoietic
      cell lines by BCR/ABL significantly impairs their response to SDF-1alpha. Three
      different hematopoietic cell lines, Ba/F3, 32Dcl3, and Mo7e, were found to
      express CXCR-4 and to respond to SDF-1alpha with increased migration in a
      transwell assay. In contrast, after transformation by the BCR/ABL oncogene, the
      chemotactic response to SDF-1alpha was reduced in all 3 lines. This effect was
      directly due to BCR/ABL, because Ba/F3 cells, in which the expression of BCR/ABL
      could be regulated by a tetracycline-inducible promoter, also had reduced
      chemotaxis to SDF-1alpha when BCR/ABL was induced. The reduced response to SDF
      1alpha was not due to an inability of BCR/ABL-transformed cell lines to migrate
      in general, as spontaneous motility of BCR/ABL-transformed cells was increased.
      In mice, injection of SDF-1alpha into the spleen resulted in a transient
      accumulation of untransformed Ba/F3 cells, but not Ba/F3. p210(BCR/ABL) cells
      administered simultaneously. The mechanism may involve inhibition of CXCR-4
      receptor function, because in BCR/ABL-transformed cells, CXCR-4 receptors were
      expressed on the cell surface, but SDF-1alpha calcium flux was inhibited. Because
      SDF-1alpha and CXCR-4 are felt to be involved in progenitor cell homing to
      marrow, the abnormality decribed here could contribute to the homing and
      retention defects typical of immature myeloid cells in chronic myelogenous
      leukemia.

PMID- 10590069
TI  - Role of vascular endothelial growth factor/vascular permeability factor in the
      pathogenesis of Kaposi's sarcoma-associated herpesvirus-infected primary effusion
      lymphomas.
AB  - Primary effusion lymphomas (PELs), which are rare lymphomas associated with
      Kaposi's sarcoma-associated herpesvirus (or human herpesvirus-8) infection,
      present as malignant lymphomatous effusions in body cavities. Because PELs prefer
      liquid growth, we hypothesized that increased vascular permeability would be
      required for effusions to form. We found that the PEL cell lines BC-1, BCP-1, and
      BCBL-1 produce high levels of vascular endothelial growth factor/vascular
      permeability factor (VEGF/VPF). Reverse transcriptase-polymerase chain reaction
      analysis of RNA from the PEL cell lines amplified the 3 VEGF-secreted isoforms:
      VEGF/VPF(121), VEGF/VPF(145), and VEGF/VPF(165). Two of the PEL cell lines
      expressed the VEGF/VPF receptor Flt-1, but VEGF/VPF did not stimulate
      proliferation in these cells. Most (13/14) control SCID/beige mice inoculated
      intraperitoneally with BCBL-1 cells and subsequently observed or treated with
      control antibodies developed effusion lymphoma of human cell origin with
      prominent bloody ascites. In contrast, none (0/9) of the mice treated with a
      neutralizing antihuman VEGF/VPF antibody developed ascites and effusion lymphoma.
      These results demonstrate that VEGF/VPF is critical to BCBL-1 growth as effusion
      lymphoma in mice and suggest that VEGF/VPF stimulation of vascular permeability
      may be critical to the pathogenesis of PELs.

PMID- 10590070
TI  - c-myb transactivates the human cyclin A1 promoter and induces cyclin A1 gene
      expression.
AB  - Cyclin A1 differs from other cyclins in its highly restricted expression pattern.
      Besides its expression during spermatogenesis, cyclin A1 is also expressed in
      hematopoietic progenitor cells and in acute myeloid leukemia. We investigated
      mechanisms that might contribute to cyclin A1 expression in hematopoietic cells.
      Comparison of cyclin A1 and cyclin A promoter activity in adherent and myeloid
      leukemia cell lines showed that the cyclin A1 promoter is preferentially active
      in myeloid cell lines. This preferential activity was present in a small, 335-bp
      cyclin A1 promoter fragment that contained several potential c-myb binding sites.
      Coexpression of a c-myb expression vector with the cyclin A1 promoter constructs
      significantly increased the reporter activity in adherent CV-1 as well as in
      myeloid U937 cells. Gel-shift assays demonstrated that c-myb could bind to the
      cyclin A1 promoter at a binding site located near the transcription start site.
      Site-directed mutagenesis of this site decreased promoter transactivation by 50%
      in both KCL22 cells that express high levels of c-myb and in CV-1 cells that were
      transfected with c-myb. In addition, transfection of primary human embryonic
      fibroblasts with a c-myb expression vector led to induction of the endogenous
      cyclin A1 gene. Taken together, c-myb can directly transactivate the promoter of
      cyclin A1, and c-myb might be involved in the high-level expression of cyclin A1
      observed in acute myeloid leukemia. These findings suggest that c-myb induces
      hematopoiesis-specific mechanisms of cell cycle regulation.

PMID- 10590071
TI  - Vaccines with interleukin-12-transduced acute myeloid leukemia cells elicit very
      potent therapeutic and long-lasting protective immunity.
AB  - Interleukin-12 (IL-12) is a heterodimeric cytokine mediating a dynamic interplay
      between T cells and antigen-presenting cells (APCs). Preclinical studies have
      demonstrated that recombinant murine IL-12 (rmIL-12) promotes specific antitumor
      immunity mediated by T cells in several types of tumors. However, the in vivo
      antitumor properties of IL-12 in acute myeloid leukemia (AML) have not been
      previously reported. We show here in a murine AML model that systemic
      administration of rmIL-12 significantly delays tumor growth but is incapable of
      rescuing mice from lethal leukemia. In contrast, AML cells genetically modified
      to express IL-12 (IL12-AML) using murine stem cell virus (MSCV) p40 + p35 elicit
      very potent antileukemic activity. Vaccines with lethally irradiated IL12-AML
      cells protect naive mice against challenge with wild-type AML cells and, more
      importantly, can cure mice bearing a considerable leukemic burden. Immunized mice
      show no signs of systemic IL-12 toxicity and their spleen histology is comparable
      with naive mice spleen. In vivo depletion of IL-12, interferon-gamma (IFN-gamma),
      or CD8(+) T cells after injections with live IL12-AML cells abrogates completely
      the antileukemia immune responses. Studies on the in vitro effects of IFN-gamma
      on AML cells demonstrate enhanced expression of major histocompatibility complex
      (MHC) and accessory molecules and induction of the costimulatory molecules B7.1
      and B7.2, but no significant direct antiproliferative effect. (51)Cr release
      assays show that rejection of live IL12-AML cells supports the development of
      long-lasting leukemia-specific cytotoxic T lymphocyte (CTL) activity. In
      conclusion, our results demonstrate that IL12-AML vaccination is a safe and
      potent immunotherapeutic approach that has a great potential to eliminate minimal
      residual disease in patients with AML.

PMID- 10590072
TI  - Interferon consensus sequence binding protein and interferon regulatory factor
      4/Pip form a complex that represses the expression of the interferon-stimulated
      gene-15 in macrophages.
AB  - Interferon consensus sequence binding protein (ICSBP), a transcription factor of
      the interferon (IFN) regulatory factor (IRF) family, binds to the IFN-stimulated
      response element (ISRE) in the regulatory region of IFNs and IFN-stimulated genes
      (ISG). To identify target genes, which are deregulated by an ICSBP null-mutation
      in mice (ICSBP-/-), we have analyzed transcription of an ISRE-bearing gene,
      ISG15. We have found that although ISG15 expression is unchanged in B cells, it
      is upregulated in macrophages from ICSBP-/- mice. Three factors, ICSBP, IRF-2,
      and IRF-4/Pip interact with the ISRE in B cells, however only ICSBP and IRF-4/Pip
      were found to bind this sequence in macrophages of wild-type mice. Although IRF-4
      was considered to be a lymphoid-specific factor, we provide evidence for its role
      in macrophage gene regulation. Our results suggest that the formation of cell
      type-specific heteromeric complexes between individual IRFs plays a crucial role
      in regulating IFN responses.

PMID- 10590073
TI  - Normal neutrophil function in cathepsin G-deficient mice.
AB  - Cathepsin G is a neutral serine protease that is highly expressed at the
      promyelocyte stage of myeloid development. We have developed a homologous
      recombination strategy to create a loss-of-function mutation for murine cathepsin
      G. Bone marrow derived from mice homozygous for this mutation had no detectable
      cathepsin G protein or activity, indicating that no other protease in bone marrow
      cells has the same specificity. Hematopoiesis in cathepsin G-/- mice is normal,
      and the mice have no overt abnormalities in blood clotting. Neutrophils derived
      from cathepsin G-/- mice have normal morphology and azurophil granule
      composition; these neutrophils also display normal phagocytosis and superoxide
      production and have normal chemotactic responses to C5a, fMLP, and interleukin-8.
      Although cathepsin G has previously shown to have broad spectrum antibiotic
      properties, challenges of mice with Staphylococcus aureus, Klebsiella pneumoniae,
      or Escherichia coli yielded survivals that were not different from those of wild
      type animals. In sum, cathepsin G-/- neutrophils have no obvious defects in
      function; either cathepsin G is not required for any of these normal neutrophil
      functions or related azurophil granule proteases with different specificities
      (ie, neutrophil elastase, proteinase 3, azurocidin, and/or others) can substitute
      for it in vivo.

PMID- 10590074
TI  - Mutations in ribosomal protein S19 gene and diamond blackfan anemia: wide
      variations in phenotypic expression.
AB  - Mutations of the ribosomal protein S19 (RPS19) gene were recently identified in
      10 patients with Diamond Blackfan anemia (DBA). To determine the prevalence of
      mutations in this gene in DBA and to begin to define the molecular basis for the
      observed variable clinical phenotype of this disorder, the genomic sequence of
      the 6 exons and the 5' untranslated region of the RPS19 gene was directly
      assessed in DBA index cases from 172 new families. Mutations affecting the coding
      sequence of RPS19 or splice sites were found in 34 cases (19.7%), whereas
      mutations in noncoding regions were found in 8 patients (4.6%). Mutations
      included nonsense, missense, splice sites, and frameshift mutations. A hot spot
      for missense mutations was identified between codons 52 and 62 of the RPS19 gene
      in a new sequence consensus motif W-[YFW]-[YF]-x-R-[AT]-A-[SA]-x-[AL]-R-[HRK]
      [ILV]-Y. No correlation between the nature of mutations and the different
      patterns of clinical expression, including age at presentation, presence of
      malformations, and therapeutic outcome, could be documented. Moreover, RPS19
      mutations were also found in some first-degree relatives presenting only with
      isolated high erythrocyte adenosine deaminase activity and/or macrocytosis. The
      lack of a consistent relationship between the nature of the mutations and the
      clinical phenotype implies that yet unidentified factors modulate the phenotypic
      expression of the primary genetic defect in families with RPS19 mutations.

PMID- 10590075
TI  - Formation of dense erythrocytes in SAD mice exposed to chronic hypoxia:
      evaluation of different therapeutic regimens and of a combination of oral
      clotrimazole and magnesium therapies.
AB  - We have examined the effect of hydroxyurea (HU), clotrimazole (CLT), magnesium
      oxide (Mg), and combined CLT+Mg therapies on the erythrocyte characteristics and
      their response to chronic hypoxia in a transgenic sickle mouse (SAD) model. SAD
      mice were treated for 21 days with 1 of the following regimens (administered by
      gavage): control (n = 6), HU (200 mg/d; n = 6), CLT (80 mg/kg/d, n = 5), Mg
      (1,000 mg/kg/d, n = 5), and CLT+Mg (80 and 1,000 mg/kg/d, respectively, n = 6).
      Nine normal mice were also treated as controls (n = 3), HU (n = 3), and CLT+Mg (n
      = 3). Treatment with HU induced a significant increase in mean corpuscular volume
      and cell K content and a decrease in density in SAD mice. Treatment with the CLT
      and Mg, either alone or in combination, also increased cell K and reduced density
      in SAD mice. After 21 days of treatment, the animals were exposed to hypoxia (48
      hours at 8% O(2)) maintaining the same treatment. In the SAD mice, hypoxia
      induced significant cell dehydration. These hypoxia-induced changes were blunted
      in either HU- or Mg-treated SAD mice and were completely abolished by either CLT
      or CLT+Mg treatment, suggesting a major role for the Gardos channel in hypoxia
      induced dehydration in vivo.

PMID- 10590076
TI  - Ontogeny of catecholamine and adenosine receptor-mediated cAMP signaling of
      embryonic red blood cells: role of cGMP-inhibited phosphodiesterase 3 and
      hemoglobin.
AB  - We have previously shown that the cAMP signaling pathway controls major aspects
      of embryonic red blood cell (RBC) function in avian embryos (Glombitza et al, Am
      J Physiol 271:R973, 1996; and Dragon et al, Am J Physiol 271:R982, 1996) that are
      important for adaptation of the RBC gas transport properties to the progressive
      hypercapnia and hypoxia of later stages of avian embryonic development. Data
      about the ontogeny of receptor-mediated cAMP signaling are lacking. We have
      analyzed the response of primitive and definitive chick embryo RBC harvested from
      day 3 to 18 of development towards forskolin, beta-adrenergic, and A2 receptor
      agonists. The results show a strong response of immature definitive and primitive
      RBC to adenosine A2 and beta-adrenergic receptor agonists, which is drastically
      reduced in the last stage of development, coincident with the appearance of
      mature, transcriptionally inactive RBC. Modulation of cGMP-inhibited
      phosphodiesterase 3 (PDE3) has a controlling influence on cAMP accumulation in
      definitive RBC. Under physiological conditions, PDE3 is inhibited due to
      activation of soluble guanylyl cyclase (sGC). Inhibition of sGC with the specific
      inhibitor ODQ decreases receptor-mediated stimulation of cAMP production; this
      effect is reversed by the PDE3 inhibitor milrinone. sGC is acitivated by nitric
      oxide (NO), but we found no evidence for production of NO by erythrocyte NO
      synthase. However, embryonic hemoglobin releases NO in an oxygen-linked manner
      that may activate guanylyl cyclase.

PMID- 10590078
TI  - TT virus is present in a high frequency of Italian hemophilic patients transfused
      with plasma-derived clotting factor concentrates.
AB  - The prevalence of the blood-borne TT virus (TTV) in Italian hemophiliacs treated
      with different preparations of factor VIII was determined. Of the 178 hemophilic
      patients (mean age, 29 years), TTV-DNA was found in 123 (69%), in comparison to
      22 of 100 (22%) blood donors (P <.0001). Of the 123 patients who tested positive
      for TTV, significant numbers were also infected with human hepatitis viruses
      and/or human immunodeficiency virus (HIV): 31% had TTV and hepatitis C virus
      (HCV), 22% had TTV, and at least 2 of the 4 known human blood-borne viruses
      tested, whereas 15% had TTV alone. The risk of acquiring TTV alone was only
      slightly higher in recipients of unmodified plasma factor concentrates (78%, odds
      ratio, 1.24; 95% confidence interval [CI], 0.27 to 5.79) than in patients treated
      with virus inactivated concentrates (67%), whereas the risk was significantly
      lower in recipients of recombinant factors (11%, odds ratio, 0.09; 95% CI, 0.01
      to 0.52). Serum alanine aminotransferase (ALT) levels were elevated in 2 of 27
      patients (7%) with TTV alone compared with 43 of 56 patients (77%) coinfected
      with TTV and HCV and compared with 16 of 21 patients (76%) with HCV alone. Taken
      together, these results indicate that TTV frequently infects Italian hemophiliacs
      treated with plasma-derived factor VIII concentrates, both unmodified and virus
      inactivated. Our results do not suggest a causal effect of TTV on chronic liver
      disease in these patients.

PMID- 10590077
TI  - Impaired ferritin mRNA translation in primary erythroid progenitors: shift to
      iron-dependent regulation by the v-ErbA oncoprotein.
AB  - In immortalized cells of the erythroid lineage, the iron-regulatory protein (IRP)
      has been suggested to coregulate biosynthesis of the iron storage protein
      ferritin and the erythroid delta-aminolevulinate synthase (eALAS), a key enzyme
      in heme production. Under iron scarcity, IRP binds to an iron-responsive element
      (IRE) located in ferritin and eALAS mRNA leaders, causing a block of translation.
      In contrast, IRP-IRE interaction is reduced under high iron conditions, allowing
      efficient translation. We show here that primary chicken erythroblasts (ebls)
      proliferating or differentiating in culture use a drastically different
      regulation of iron metabolism. Independently of iron administration, ferritin H
      (ferH) chain mRNA translation was massively decreased, whereas eALAS transcripts
      remained constitutively associated with polyribosomes, indicating efficient
      translation. Variations in iron supply had minor but significant effects on eALAS
      mRNA polysome recruitment but failed to modulate IRP-affinity to the ferH-IRE in
      vitro. However, leukemic ebls transformed by the v-ErbA/v-ErbB-expressing avian
      erythroblastosis virus showed an iron-dependent reduction of IRP mRNA-binding
      activity, resulting in mobilization of ferH mRNA into polysomes. Hence, we
      analyzed a panel of ebls overexpressing v-ErbA and/or v-ErbB oncoproteins as well
      as the respective normal cellular homologues (c-ErbA/TRalpha, c-ErbB/EGFR). It
      turned out that v-ErbA, a mutated class II nuclear hormone receptor that arrests
      erythroid differentiation, caused the change in ferH mRNA translation.
      Accordingly, inhibition of v-ErbA function in these leukemic ebls led to a switch
      from iron-responsive to iron-independent ferH expression.

PMID- 10590079
TI  - DAR, a new RhD variant involving exons 4, 5, and 7, often in linkage with ceAR, a
      new Rhce variant frequently found in African blacks.
AB  - The highly polymorphic Rh system is encoded by 2 homologous genes RHD and RHCE.
      Gene rearrangements, deletions, or point mutations may cause partial D and CE
      antigens. In this study, a new RHD variant, DAR, and a new RHCE variant, ceAR,
      are described in 4 Dutch African Blacks. Serologically, DAR showed weaker
      reactions with a monoclonal antibody and polyclonal antiserum against D. The DAR
      phenotype was characterized by complete loss of at least 9 of 37 Rh D epitopes.
      Erythrocytes expressing ceAR were all typed as VS(-), V(+). DNA analysis showed a
      partial D allele with only 3 mutations: C602G (exon 4), T667G (exon 5), and
      T1025C (exon 7). The ceAR allele carried G48C (exon 1), a hybrid exon 5 (A712G,
      C733G, A787G, and T800A), and A916G (exon 6). To study the frequency of these
      variants, 326 South-African Blacks was screened genomically. Of the 326 donors,
      16 (4.9%) carried the DAR allele, 20 (6.1%) the ceAR allele, and 14 (4.3%) both
      mutated alleles. Five of these donors (1.5%) had the DAR phenotype, indicating
      that they carried the DAR allele homozygously or next to a D-negative allele.
      Immunogenicity of the D antigen for individuals with the DAR phenotype was
      proven, because 1 of the 4 Dutch individuals produced allo-antibodies against D
      after multiple transfusions with D-positive blood. In a multiethnic society, the
      prevalence of this D phenotype will increase and is therefore relevant in
      transfusion practice and in prevention of hemolytic disease of the newborn.

PMID- 10590080
TI  - Inverse association between IgG-anti-kappa and antierythrocyte autoantibodies in
      patients with cold agglutination.
AB  - It has been known for a long time that IgG-anti-F(ab')(2) antibodies (Abs) are
      able to suppress the B-cell response. We showed that natural IgG-anti-F(ab')(2)
      autoantibodies appear in the serum of patients with cold agglutination. If the
      anti-F(ab')2 Ab suppresses cold agglutinin (CA)-producing B cells, one would
      expect an inverse correlation between the titers of these two Abs. Our study
      confirmed this correlation. Subsequent experiments showed that some anti
      F(ab')(2) Abs bind to the hinge region of IgG. It was difficult to explain how
      this Ab suppresses CA-producing B cells, which are of IgM isotype. Here we show
      that patients with cold agglutination have an IgG-anti-kappa light chain
      autoantibody in their serum. This is another member of the anti-F(ab')(2) Ab
      group. Because the vast majority of CAs are IgM-kappa Abs, the anti-kappa Ab
      might suppress CA-producing B cells. If this is the case, there should be an
      inverse association between the titer of anti-kappa Ab and CA. In a group of 302
      patients, we found that high titers of the anti-kappa Ab correlate with low
      titers of CA and vice versa (P =.009). Interestingly, this association is found
      only in patients whose disease is caused by noninfectious agents, including
      mainly B-cell proliferations (P =.0058). Our data show that the inverse
      correlation is not confined to a particular CA autoantibody specificity. The
      results are discussed in the light of recent findings showing that anti-IgM Abs
      may either inactivate or kill tumoral B cells by apoptosis.

PMID- 10590081
TI  - Downregulation of antigen-presenting cell functions after administration of
      mitogenic anti-CD3 monoclonal antibodies in mice.
AB  - Antibodies against CD3epsilon are widely used as immunosuppressive agents.
      Although it is generally assumed that these reagents exert their immunomodulatory
      properties by inducing T-cell deletion and/or inactivation, their precise
      mechanism of action remains to be elucidated. Using a murine model, we
      demonstrate in this report that administration of anti-CD3epsilon antibodies
      causes the migration and maturation of dendritic cells (DC) in vivo, as
      determined by immunohistochemical analysis. This maturation/migration process was
      followed by selective loss of splenic DC, which resulted in a selective
      inhibition of antigen-presenting cell (APC) functions in vitro. Spleen cells from
      anti-CD3epsilon-treated animals were unable to productively stimulate naive
      alloreactive T cells and Th1-like clones in response to antigen, while retaining
      the ability to present antigen to a T-cell hybridoma and Th2 clones. Anti
      CD3epsilon treatment was found to induce a selective deficiency in the ability of
      spleen cells to produce bioactive interleukin-12 in response to CD40 stimulation.
      APC dysfunction was not observed when nonmitogenic forms of anti-CD3epsilon
      antibodies were used, suggesting that splenic DC loss was a consequence of in
      vivo T-cell activation. Nonmitogenic anti-CD3epsilon monoclonal antibodies were
      found to be less immunosuppressive in vivo, raising the possibility that APC
      dysfunction contributes to anti-CD3epsilon-induced immunomodulation.
      Collectively, these data suggest a novel mechanism by which mitogenic anti
      CD3epsilon antibodies downregulate immune responses.

PMID- 10590082
TI  - T-Cell immune reconstitution in pediatric leukemia patients after allogeneic bone
      marrow transplantation with T-cell-depleted or unmanipulated grafts: evaluation
      of overall and antigen-specific T-cell repertoires.
AB  - To evaluate the role of T-cell selection in the thymus and/or periphery in T-cell
      immune reconstitution after allogeneic bone marrow transplantation (allo-BMT), we
      have analyzed the overall and antigen-specific T-cell repertoires in pediatric
      allo-BMT recipients treated for leukemia. We observed a lack of overall T-cell
      receptor (TCR) diversity in the repopulating T cells at 3 months after allo-BMT,
      as was deduced from complementarity determining region 3 (CDR3) size distribution
      patterns displaying reduced complexity. This was noted particularly in recipients
      of a T-cell-depleted (TCD) graft and, to a lesser extent, also in recipients of
      unmanipulated grafts. At 1 year after allo-BMT, normalization was observed of TCR
      CDR3 size complexity in almost all recipients. Analysis of the antigen-specific T
      cell repertoire at 1 year after BMT showed that the T cells responding to tetanus
      toxoid (TT) differed in TCR gene segment usage and in amino acid composition of
      the CDR3 region when comparing the recipient with the donor. Moreover, the TT
      specific TCR repertoire was found to be stable within a given allo-BMT recipient,
      because TT-specific T cells with completely identical TCRs were found at 3
      consecutive years after transplantation. These observations suggest an important
      role for T-cell selection processes in the complete restoration of the T-cell
      immune repertoire in children after allo-BMT.

PMID- 10590083
TI  - The tyrosine kinase abl-related gene ARG is fused to ETV6 in an AML-M4Eo patient
      with a t(1;12)(q25;p13): molecular cloning of both reciprocal transcripts.
AB  - The Ets variant gene 6 (ETV6/TEL) gene is rearranged in the majority of patients
      with 12p13 translocations fused to a number of different partners. We present
      here a case of acute myeloid leukemia M4 with eosinophilia (AML-M4Eo) positive
      for the CBFb/MYH11 rearrangement and carrying a t(1;12)(q25;p13) that involves
      the ETV6 gene at 12p13. By 3'rapid amplification of cDNA ends-polymerase chain
      reaction (3'RACE-PCR), a novel fusion transcript was identified between the ETV6
      and the Abelson-related gene (ARG) at 1q25, resulting in a chimeric protein
      consisting of the HLH oligomerization domain of ETV6 and the SH2, SH3, and
      protein tyrosine kinase (PTK) domains of ARG. The reciprocal transcript ARG-ETV6
      was also detected in the patient RNA by reverse transcriptase-polymerase chain
      reaction (RT-PCR), although at a lower expression level. The ARG gene encodes for
      a nonreceptor tyrosine kinase characterized by high homology with c-Abl in the
      TK, SH2, and SH3 domains. This is the first report on ARG involvement in a human
      malignancy.

PMID- 10590084
TI  - Hepatitis B virus core gene mutations which block nucleocapsid envelopment.
AB  - Recently we generated a panel of hepatitis B virus core gene mutants carrying
      single insertions or deletions which allowed efficient expression of the core
      protein in bacteria and self-assembly of capsids. Eleven of these mutations were
      introduced into a eukaryotic core gene expression vector and characterized by
      trans complementation of a core-negative HBV genome in cotransfected human
      hepatoma HuH7 cells. Surprisingly, four mutants (two insertions [EFGA downstream
      of A11 and LDTASALYR downstream of R39] and two deletions [Y38-R39-E40 and L42])
      produced no detectable capsids. The other seven mutants supported capsid
      formation and pregenome packaging/viral minus- and plus-strand-DNA synthesis but
      to different levels. Four of these seven mutants (two insertions [GA downstream
      of A11 and EHCSP downstream of P50] and two deletions [S44 and A80]) allowed
      virion morphogenesis and secretion. The mutant carrying a deletion of A80 at the
      tip of the spike protruding from the capsid was hepatitis B virus core antigen
      negative but wild type with respect to virion formation, indicating that this
      site might not be crucial for capsid-surface protein interactions during
      morphogenesis. The other three nucleocapsid-forming mutants (one insertion [LS
      downstream of S141] and two deletions [T12 and P134]) were strongly blocked in
      virion formation. The corresponding sites are located in the part of the protein
      forming the body of the capsid and not in the spike. These mutations may alter
      sites on the particle which contact surface proteins during envelopment, or they
      may block the appearance of a signal for the transport or the maturation of the
      capsid which is linked to viral DNA synthesis and required for envelopment.

PMID- 10590085
TI  - The disappearance of cyclins A and B and the increase in activity of the G(2)/M
      phase cellular kinase cdc2 in herpes simplex virus 1-infected cells require
      expression of the alpha22/U(S)1.5 and U(L)13 viral genes.
AB  - In uninfected cells the G(2)/M transition is regulated by cyclin kinase complex
      containing cdc2 and, initially, cyclin A, followed by cyclin B. cdc2 is
      downregulated through phosphorylation by wee-1 and myt-1 and upregulated by cdc
      25C phosphatase. We have examined the accumulation and activities of these
      proteins in cells infected with wild type and mutants of herpes simplex virus 1.
      The results were as follows. (i) Cyclin A and B levels were reduced beginning 4 h
      after infection and were undetectable at 12 to 16 h after infection. (ii) cdc2
      protein also decreased in amount but was detectable at all times after infection.
      In addition, a fraction of cdc2 protein from infected cells exhibited altered
      electrophoretic mobility in denaturing gels. (iii) The levels of cdk7 or myt-1
      proteins remained relatively constant throughout infection, whereas the level of
      wee-1 was significantly decreased. (iv) cdc-25C formed novel bands characterized
      by slower electrophoretic mobility that disappeared after treatment with
      phosphatase. In addition, one phosphatase-sensitive band reacted with MPM-2
      antibody that recognizes a phosphoepitope phosphorylated exclusively in M phase.
      (v) cdc2 accumulating in infected cells exhibited kinase activity. The activity
      of cdc2 was higher in infected cell lysates than those of corresponding proteins
      present in lysates of mock-infected cells even though cyclins A and B were not
      detectable in lysates of infected cells. (vi) The decrease in the levels of
      cyclins A and B, the increase in activity of cdc2, and the hyperphosphorylation
      of cdc-25C were mediated by U(L)13 and alpha22/U(S)1.5 gene products. In light of
      its normal functions, the activated cdc2 kinase may play a role in the changes in
      the morphology of the infected cell. These results are consistent with the
      accruing evidence that herpes simplex virus scavenges the cell for useful cell
      cycle proteins and subverts them for its own use.

PMID- 10590087
TI  - Mutagenesis of the signal sequence of yellow fever virus prM protein: enhancement
      of signalase cleavage In vitro is lethal for virus production.
AB  - Proteolytic processing at the C-prM junction in the flavivirus polyprotein
      involves coordinated cleavages at the cytoplasmic and luminal sides of an
      internal signal sequence. We have introduced at the COOH terminus of the yellow
      fever virus (YFV) prM signal sequence amino acid substitutions (VPQAQA mutation)
      which uncoupled efficient signal peptidase cleavage of the prM protein from its
      dependence on prior cleavage in the cytoplasm of the C protein mediated by the
      viral NS2B-3 protease. Infectivity assays with full-length YFV RNA transcripts
      showed that the VPQAQA mutation, which enhanced signal peptidase cleavage in
      vitro, was lethal for infectious virus production. Revertants or second-site
      mutants were recovered from cells transfected with VPQAQA RNA. Analysis of these
      viruses revealed that single amino acid substitutions in different domains of the
      prM signal sequence could restore viability. These variants had growth properties
      in vertebrate cells which differed only slightly from those of the parent virus,
      despite efficient signal peptidase cleavage of prM in cell-free expression
      assays. However, the neurovirulence in mice of the VPQAQA variants was
      significantly attenuated. This study demonstrates that substitutions in the prM
      signal sequence which disrupt coordinated cleavages at the C-prM junction can
      impinge on the biological properties of the mutant viruses. Factors other than
      the rate of production of prM are vitally controlled by regulated cleavages at
      this site.

PMID- 10590086
TI  - Roles of matrix, p2, and N-terminal myristoylation in human immunodeficiency
      virus type 1 Gag assembly.
AB  - Human immunodeficiency virus type 1 Gag protein is cotranslationally
      myristoylated at the N terminus and targeted to the plasma membrane, where virus
      particle assembly occurs. Particle assembly requires the ordered multimerization
      of Gag proteins, yet there is little direct evidence of intermediates of the
      reaction or of the domains that lead to each stage of the oligomerization
      process. In this study, following the expression in insect cells of C-terminally
      truncated Gag proteins and their purification, both the multimeric nature of each
      Gag protein and the ability to form Gag virus-like particles (VLP) were analyzed.
      Our results show that (i) the matrix (MA) domain forms a trimer and contributes
      to a similar level of oligomerization of the assembly-competent Gag; (ii) the p2
      domain, located at the capsid/nucleocapsid junction, is essential for a higher
      order of multimerization (>1,000 kDa); (iii) the latter multimerization is
      accompanied by a change in Gag assembly morphology from tubes to spheres and
      results in VLP production; and (iv) N-terminal myristoylation is not required for
      either of the multimerization stages but plays a key role in conversion of these
      multimers to Gag VLP. We suggest that the Gag trimer and the > 1,000-kDa multimer
      are intermediates in the assembly reaction and form before Gag targeting to the
      plasma membrane. Our data identify a minimum of three stages for VLP development
      and suggest that each stage involves a separate domain, MA, p2, or N-terminal
      myristoylation, each of which contributes to HIV particle assembly.

PMID- 10590088
TI  - Herpes simplex virus type 1 gene UL14: phenotype of a null mutant and
      identification of the encoded protein.
AB  - Herpes simplex virus type 1 (HSV-1) gene UL14 is located between divergently
      transcribed genes UL13 and UL15 and overlaps the promoters for both of these
      genes. UL14 also exhibits a substantial overlap of its coding region with that of
      UL13. It is one of the few HSV-1 genes for which a phenotype and protein product
      have not been described. Using mass spectrometric and immunological approaches,
      we demonstrated that the UL14 protein is a minor component of the virion tegument
      of 32 kDa which is expressed late in infection. In infected cells, the UL14
      protein was detected in the nucleus at discrete sites within electron-dense
      nuclear bodies and in the cytoplasm initially in a diffuse distribution and then
      at discrete sites. Some of the UL14 protein was phosphorylated. A mutant with a 4
      bp deletion in the central region of UL14 failed to produce the UL14 protein and
      generated small plaques. The mutant exhibited an extended growth cycle at low
      multiplicity of infection and appeared to be compromised in efficient transit of
      virus particles from the infected cell. In mice injected intracranially, the 50%
      lethal dose of the mutant was reduced more than 30,000-fold. Recovery of the
      mutant from the latently infected sacral ganglia of mice injected peripherally
      was significantly less than that of wild-type virus, suggesting a marked defect
      in the establishment of, or reactivation from, latent infection.

PMID- 10590090
TI  - Extended analysis of the in vitro tropism of porcine endogenous retrovirus.
AB  - We previously reported that mitogenic activation of porcine peripheral blood
      mononuclear cells resulted in production of porcine endogenous retrovirus(es)
      (PERV[s]) capable of productively infecting human cells (C. Wilson et al., J.
      Virol. 72:3082-3087, 1998). We now extend that analysis to show that additional
      passage of isolated virus, named here PERV-NIH, through a human cell line yielded
      a viral population with a higher titer of infectious virus on human cells than
      the initial isolate. We show that in a single additional passage on a human cell
      line, the increase in infectivity for human cells is accounted for by selection
      against variants carrying pig-tropic envelope sequences (PERV-C) as well as by
      enrichment for replication-competent genomes. Sequence analysis of the envelope
      cDNA present in virions demonstrated that the envelope sequence of PERV-NIH is
      related to but distinct from previously reported PERV envelopes. The in vitro
      host range of PERV was studied in human primary cells and cell lines, as well as
      in cell lines from nonhuman primate and other species. This analysis reveals
      three patterns of susceptibility to infection among these host cells: (i) cells
      are resistant to infection in our assay; (ii) cells are infected by virus, as
      viral RNA is detected in the supernatant by reverse transcription-PCR, but the
      cells are not permissive to productive replication and spread; and (iii) cells
      are permissive to low-level productive replication. Certain cell lines were
      permissive for efficient productive infection and spread. These results may prove
      useful in designing appropriate animal models to assess the in vivo infectivity
      properties of PERV.

PMID- 10590089
TI  - Adenovirus type 37 uses sialic acid as a cellular receptor.
AB  - Two cellular receptors for adenovirus, coxsackievirus-adenovirus receptor (CAR)
      and major histocompatibility complex class I (MHC-I) alpha2, have recently been
      identified. In the absence of CAR, MHC-I alpha2 has been suggested to serve as a
      cellular attachment protein for subgenus C adenoviruses, while members from all
      subgenera except subgenus B have been shown to interact with CAR. We have found
      that adenovirus type 37 (Ad37) attachment to CAR-expressing CHO cells was no
      better than that to CHO cells lacking CAR expression, suggesting that CAR is not
      used by Ad37 during attachment. Instead, we have identified sialic acid as a
      third adenovirus receptor moiety. First, Ad37 attachment to both CAR-expressing
      CHO cells and MHC-I alpha2-expressing Daudi cells was sensitive to neuraminidase
      treatment, which eliminates sialic acid on the cell surface. Second, Ad37
      attachment to sialic acid-expressing Pro-5 cells was more than 10-fold stronger
      than that to the Pro-5 subline Lec2, which is deficient in sialic acid
      expression. Third, neuraminidase treatment of A549 cells caused a 60% decrease in
      Ad37 replication in a fluorescent-focus assay. Moreover, the receptor
      sialoconjugate is most probably a glycoprotein rather than a ganglioside, since
      Ad37 attachment to sialic acid-expressing Pro-5 cells was sensitive to protease
      treatment. Ad37 attachment to Pro-5 cells occurs via alpha(2-->3)-linked sialic
      acid saccharides rather than alpha(2-->6)-linked ones, since (i) alpha(2-->3)
      specific but not alpha(2-->6)-specific lectins blocked Ad37 attachment to Pro-5
      cells and (ii) pretreatment of Pro-5 cells with alpha(2-->3)-specific
      neuraminidase resulted in decreased Ad37 binding. Taken together, these results
      suggest that, unlike Ad5, Ad37 makes use of alpha(2-->3)-linked sialic acid
      saccharides on glycoproteins for entry instead of using CAR or MHC-I alpha2.

PMID- 10590091
TI  - Identifying the target cell in primary simian immunodeficiency virus (SIV)
      infection: highly activated memory CD4(+) T cells are rapidly eliminated in early
      SIV infection in vivo.
AB  - It has recently been shown that rapid and profound CD4(+) T-cell depletion occurs
      almost exclusively within the intestinal tract of simian immunodeficiency virus
      (SIV)-infected macaques within days of infection. Here we demonstrate (by three-
      and four-color flow cytometry) that this depletion is specific to a definable
      subset of CD4(+) T cells, namely, those having both a highly and/or acutely
      activated (CD69(+) CD38(+) HLA-DR(+)) and memory (CD45RA(-) Leu8(-)) phenotype.
      Moreover, we demonstrate that this subset of helper T cells is found primarily
      within the intestinal lamina propria. Viral tropism for this particular cell type
      (which has been previously suggested by various studies in vitro) could explain
      why profound CD4(+) T-cell depletion occurs in the intestine and not in
      peripheral lymphoid tissues in early SIV infection. Furthermore, we demonstrate
      that an acute loss of this specific subset of activated memory CD4(+) T cells may
      also be detected in peripheral blood and lymph nodes in early SIV infection.
      However, since this particular cell type is present in such small numbers in
      circulation, its loss does not significantly affect total CD4(+) T cell counts.
      This finding suggests that SIV and, presumably, human immunodeficiency virus
      specifically infect, replicate in, and eliminate definable subsets of CD4(+) T
      cells in vivo.

PMID- 10590092
TI  - Functional interactions between C/EBP, Sp1, and COUP-TF regulate human
      immunodeficiency virus type 1 gene transcription in human brain cells.
AB  - Human immunodeficiency virus type 1 (HIV-1) infects the central nervous system
      (CNS) and plays a direct role in the pathogenesis of AIDS dementia. However,
      mechanisms underlying HIV-1 gene expression in the CNS are poorly understood. The
      importance of CCAAT/enhancer binding proteins (C/EBP) for HIV-1 expression in
      cells of the immune system has been recently reported. In this study, we have
      examined the role and the molecular mechanisms by which proteins of the C/EBP
      family regulate HIV-1 gene transcription in human brain cells. We found that NF
      IL6 acts as a potent activator of the long terminal repeat (LTR)-driven
      transcription in microglial and oligodendroglioma cells. In contrast, C/EBPgamma
      inhibits NF-IL6-induced activation. Consistent with previous data, our transient
      expression results show cell-type-specific NF-IL6-mediated transactivation. In
      glial cells, full activation needs the presence of the C/EBP binding sites;
      however, NF-IL6 is still able to function via the minimal -40/+80 region. In
      microglial cells, C/EBP sites are not essential, since NF-IL6 acts through the 
      68/+80 LTR region, containing two binding sites for the transcription factor Sp1.
      Moreover, we show that functional interactions between NF-IL6 and Sp1 lead to
      synergistic transcriptional activation of the LTR in oligodendroglioma and to
      mutual repression in microglial cells. We further demonstrate that NF-IL6
      physically interacts with the nuclear receptor chicken ovalbumin upstream
      promoter transcription factor (COUP-TF), via its DNA binding domain, in vitro and
      in cells, which results in mutual transcriptional repression. These findings
      reveal how the interplay of NF-IL6 and C/EBPgamma, together with Sp1 and COUP-TF,
      regulates HIV-1 gene transcription in brain cells.

PMID- 10590093
TI  - Respiratory syncytial virus that lacks open reading frame 2 of the M2 gene (M2-2)
      has altered growth characteristics and is attenuated in rodents.
AB  - The M2 gene of respiratory syncytial virus (RSV) encodes two putative proteins:
      M2-1 and M2-2; both are believed to be involved in the RNA transcription or
      replication process. To understand the function of the M2-2 protein in virus
      replication, we deleted the majority of the M2-2 open reading frame from an
      infectious cDNA clone derived from the human RSV A2 strain. Transfection of HEp-2
      cells with the cDNA clone containing the M2-2 deletion, together with plasmids
      that encoded the RSV N, P, and L proteins, produced a recombinant RSV that lacked
      the M2-2 protein (rA2DeltaM2-2). Recombinant virus rA2DeltaM2-2 was recovered and
      characterized. The levels of viral mRNA expression for 10 RSV genes examined were
      unchanged in cells infected with rA2DeltaM2-2, except that a shorter M2 mRNA was
      detected. However, the ratio of viral genomic or antigenomic RNA to mRNA was
      reduced in rA2DeltaM2-2-infected cells. By use of an antibody directed against
      the bacterially expressed M2-2 protein, the putative M2-2 protein was detected in
      cells infected with wild-type RSV but not in cells infected with rA2DeltaM2-2.
      rA2DeltaM2-2 displayed a small-plaque morphology and grew much more slowly than
      wild-type RSV in HEp-2 cells. In infected Vero cells, rA2DeltaM2-2 exhibited very
      large syncytium formation compared to that of wild-type recombinant RSV.
      rA2DeltaM2-2 appeared to be a host range mutant, since it replicated poorly in
      HEp-2, HeLa, and MRC5 cells but replicated efficiently in Vero and LLC-MK2 cells.
      Replication of rA2DeltaM2-2 in the upper and lower respiratory tracts of mice and
      cotton rats was highly restricted. Despite its attenuated replication in rodents,
      rA2DeltaM2-2 was able to provide protection against challenge with wild-type RSV
      A2. The genotype and phenotype of the M2-2 deletion mutant were stably maintained
      after extensive in vitro passages. The attenuated phenotype of rA2DeltaM2-2
      suggested that rA2DeltaM2-2 may be a potential candidate for use as a live
      attenuated vaccine.

PMID- 10590094
TI  - Different regions of hepatitis B virus X protein are required for enhancement of
      bZip-mediated transactivation versus transrepression.
AB  - The hepatitis B virus X protein (pX) interacts directly with the bZip
      transactivator CREB and the bZip repressors ICERIIgamma and ATF3, increasing
      their DNA-binding affinity in vitro and their transcriptional efficacy in vivo.
      However, the mechanism of bZip-pX interaction and of the pX-mediated increase in
      the bZip transcriptional efficacy remains to be understood. In this study with
      deletion mutants of pX, we delineated a 67-amino-acid region spanning residues 49
      to 115 required for direct CREB, ATF3, and ICER IIgamma interaction in vitro and
      in vivo and increased bZip/CRE binding in vitro. Transient transfections of the
      pX deletion mutants in AML12 hepatocytes demonstrate that pX(49-115) is as
      effective as the full-length pX in enhancing the ATF3- and ICERIIgamma-mediated
      transrepression. However, this pX region is inactive in increasing the
      transactivation efficacy of CREB; additional amino acid residues present in pX(49
      140) are required to mediate the increased transactivation efficacy of CREB in
      vivo. This requirement for different regions of pX in affecting CREB
      transactivation suggests that amino acid residues 115 to 140 integrate additional
      events in effecting pX-mediated transactivation, such as concomitant interactions
      with select components of the basal transcriptional apparatus.

PMID- 10590095
TI  - The phosphoprotein of rabies virus is phosphorylated by a unique cellular protein
      kinase and specific isomers of protein kinase C.
AB  - The phosphoprotein (P) gene of rabies virus (CVS strain) was cloned and expressed
      in bacteria. The purified protein was used as the substrate for phosphorylation
      by the protein kinase(s) present in cell extract prepared from rat brain. Two
      distinct types of protein kinases, staurosporin sensitive and heparin sensitive,
      were found to phosphorylate the P protein in vitro by the cell extract.
      Interestingly, the heparin-sensitive kinase was not the ubiquitous casein kinase
      II present in a variety of cell types. Further purification of the cell fractions
      revealed that the protein kinase C (PKC) isomers constitute the staurosporin
      sensitive kinases alpha, beta, gamma, and zeta, with the PKCgamma isomer being
      the most effective in phosphorylating the P protein. A unique heparin-sensitive
      kinase was characterized as a 71-kDa protein with biochemical properties not
      demonstrated by any known protein kinases stored in the protein data bank. This
      protein kinase, designated RVPK (rabies virus protein kinase), phosphorylates P
      protein (36 kDa) and alters its mobility in gel to migrate at 40 kDa. In
      contrast, the PKC isoforms do not change the mobility of unphosphorylated P
      protein. RVPK appears to be packaged in the purified virions, to display
      biochemical characteristics similar to those of the cell-purified RVPK, and to
      similarly alter the mobility of endogenous P protein upon phosphorylation. By
      site-directed mutagenesis, the sites of phosphorylation of RVPK were mapped at
      S(63) and S(64), whereas PKC isomers phosphorylated at S(162), S(210), and
      S(271). Involvement of a unique protein kinase in phosphorylating rabies virus P
      protein indicates its important role in the structure and function of the protein
      and consequently in the life cycle of the virus.

PMID- 10590096
TI  - Analysis of HCF, the cellular cofactor of VP16, in herpes simplex virus-infected
      cells.
AB  - Herpes simplex virus (HSV) immediate-early (IE) gene expression is initiated via
      the recruitment of the structural protein VP16 onto specific sites upstream of
      each IE gene promoter in a multicomponent complex (TRF.C) that also includes the
      cellular proteins Oct-1 and HCF. In vitro results have shown that HCF binds
      directly to VP16 and stabilizes TRF.C. Results from transfection assays have also
      indicated that HCF is involved in the nuclear import of VP16. However, there have
      been no reports on the role or the fate of HCF during HSV type 1 (HSV-1)
      infection. Here we show that the intracellular distribution of HCF is
      dramatically altered during HSV-1 infection and that the protein interacts with
      and colocalizes with VP16. Moreover, viral protein synthesis and replication were
      significantly reduced after infection of a BHK-21-derived temperature-sensitive
      cell line (tsBN67) which contains a mutant HCF unable to associate with VP16 at
      the nonpermissive temperature. Intracellular distribution of HCF and of newly
      synthesized VP16 in tsBN67-infected cells was similar to that observed in Vero
      cells, suggesting that late in infection the trafficking of both proteins was not
      dependent on their association. We constructed a stable cell line (tsBN67r) in
      which the temperature-sensitive phenotype was rescued by using an epitope-tagged
      wild-type HCF. In HSV-1-infected tsBN67r cells at the nonpermissive temperature,
      direct binding of HCF to VP16 was observed, but virus protein synthesis and
      replication were not restored to levels observed at the permissive temperature or
      in wild-type BHK cells. Together these results indicate that the factors involved
      in compartmentalization of VP16 alter during infection and that late in
      infection, VP16 and HCF may have additional roles reflected in their
      colocalization in replication compartments.

PMID- 10590097
TI  - An 80-kilodalton protein that binds to the pre-S1 domain of hepatitis B virus.
AB  - It has been suggested that hepatitis B virus (HBV) binds to a receptor on the
      plasma membrane of human hepatocytes via the pre-S1 domain of the large envelope
      protein as an initial step in HBV infection. However, the nature of the receptor
      remains controversial. In an attempt to identify a cell surface receptor for HBV,
      purified recombinant fusion protein of the pre-S1 domain of HBV with glutathione
      S-transferase (GST), expressed in Escherichia coli, was used as a ligand. The
      surface of human hepatocytes or HepG2 cells was biotinylated, and the cell lysate
      (precleared lysate) which did not bind to GST and glutathione-Sepharose beads was
      used as a source of receptor molecules. The precleared lysate of the biotinylated
      cells was incubated with the GST-pre-S1 fusion protein, and the bound proteins
      were visualized by Western blotting and enhanced chemiluminescence. An
      approximately 80-kDa protein (p80) was shown to bind specifically to the pre-S1
      domain of the fusion protein. The receptor binding assay using serially or
      internally deleted segments of pre-S1 showed that amino acid residues 12 to 20
      and 82 to 90 are essential for the binding of pre-S1 to p80. p80 also bound
      specifically to the pre-S1 of native HBV particles. Analysis of the tissue and
      species specificity of p80 expression in several available human primary cultures
      and cell lines of different tissue origin showed that p80 expression is not
      restricted to human hepatocytes. Taken together the results suggest that p80 may
      be a component of the viral entry machinery.

PMID- 10590098
TI  - Herpes simplex virus type 1 U(L)34 gene product is required for viral
      envelopment.
AB  - The herpes simplex virus type 1 U(L)34 gene encodes a protein that is conserved
      in all human herpesviruses. The association of the U(L)34 protein with membranes
      in the infected cell and its expression as a gamma-1 gene suggest a role in
      maturation or egress of the virus particle from the cell. To determine the
      function of this gene product, we have constructed a recombinant virus that fails
      to express the U(L)34 protein. This recombinant virus, in which the U(L)34
      protein coding sequence has been replaced by green fluorescent protein, forms
      minute plaques and replicates in single-step growth experiments to titers 3 to 5
      log orders of magnitude lower than wild-type or repair viruses. On Vero cells,
      the deletion virus synthesizes proteins of all kinetic classes in normal amounts.
      Electron microscopic and biochemical analyses show that morphogenesis of the
      deletion virus proceeds normally to the point of formation of DNA-containing
      nuclear capsids, but electron micrographs show no enveloped virus particles in
      the cytoplasm or at the surface of infected cells, suggesting that the U(L)34
      protein is essential for efficient envelopment of capsids.

PMID- 10590099
TI  - Identification of the minimal essential RNA sequences responsible for site
      specific targeting of the Leishmania RNA virus 1-4 capsid endoribonuclease.
AB  - The Leishmania RNA virus 1-4 capsid protein possesses an endoribonuclease
      activity responsible for single-site-specific cleavage within the 450-nucleotide
      5' untranslated region of its own viral RNA transcript. To characterize the
      minimal essential RNA determinants required for site-specific cleavage, mutated
      RNA transcripts were examined for susceptibility to cleavage by the virus capsid
      protein in an in vitro assay. Deletion analyses revealed that all determinants
      necessary for accurate cleavage are encoded in viral nucleotides 249 to 342.
      Nuclease mapping and site-specific mutagenesis of the minimal RNA sequence
      defined a stem-loop structure that is located 40 nucleotides upstream from the
      cleavage site (nucleotide 320) and that is essential for accurate RNA cleavage.
      Abrogation of cleavage by disruption of base pairing within the stem-loop was
      reversed through the introduction of complementary nucleotide substitutions that
      reestablished the structure. We also provide evidence that divalent cations,
      essential components of the cleavage reaction, stabilized the stem-loop structure
      in solution. That capsid-specific antiserum eliminated specific RNA cleavage
      provides further evidence that the virus capsid gene encodes the essential
      endoribonuclease activity.

PMID- 10590100
TI  - Cellular compartments of human immunodeficiency virus type 1 replication in vivo:
      determination by presence of virion-associated host proteins and impact of
      opportunistic infection.
AB  - Antigens derived from host cells are detectable in the envelope of human
      immunodeficiency virus type 1 (HIV-1) and result in a distinctive viral phenotype
      reflecting that of the host cell. An immunomagnetic capture assay targeting
      discriminatory host proteins was developed to differentiate between HIV-1 derived
      from macrophages and lymphocytes. HIV-1 propagated in macrophages or lymphocytes
      in vitro was selectively captured by monoclonal antibodies directed against the
      virally incorporated cell-type-specific host markers CD36 (macrophages) and CD26
      (lymphocytes). Furthermore, by targeting these markers, virus of defined cellular
      origin was selectively captured from a mixed pool of in vitro-propagated viruses.
      This technique was further refined in order to determine the impact of
      opportunistic infection on HIV-1 expression from these cellular compartments in
      vivo. Analysis of cell-free virus purified from plasma of patients with HIV-1
      infection suggested that in those with an opportunistic infection, viral
      replication occurred in activated lymphocytes. Interestingly, there was also
      significant replication in activated macrophages in those patients with untreated
      pulmonary tuberculosis. Thus, in addition to lymphocytes, the macrophage cellular
      pool may serve as an important source of cell-free HIV-1 in patients with
      opportunistic infections that lead to marked macrophage activation. This novel
      viral capture technique may allow researchers to address a wide range of
      important questions regarding virus-host dynamics.

PMID- 10590101
TI  - Mutations in the 5' trailer region of a respiratory syncytial virus minigenome
      which limit RNA replication to one step.
AB  - The 3' termini of the genomic and antigenomic RNAs of human respiratory syncytial
      virus (RSV) are identical at 10 of the first 11 nucleotide positions and 21 of
      the first 26 positions. These conserved 3'-terminal sequences are thought to
      contain the genomic and antigenomic promoters. Furthermore, the complement of
      each conserved sequence (i.e., the 5' end of the RNA it encodes) might contain an
      encapsidation signal. Using an RSV minigenome system, we individually mutated
      each of the last seven nucleotides in the 5' trailer region of the genome. We
      analyzed effects of these mutations on encapsidation of the T7 polymerase
      transcribed negative-sense genome, its ability to function as a template for RSV
      driven synthesis of positive-sense antigenome and mRNA, and the ability of this
      antigenome to be encapsidated and to function as template for the synthesis of
      more genome. As a technical complication, mutations in the last five nucleotides
      of the trailer region were found to affect the efficiency of the adjoining T7
      promoter over more than a 10-fold range, even though three nonviral G residues
      had been included between the core promoter and the trailer to maximize the
      efficiency of promoter activity. This was controlled in all experiments by
      monitoring the levels of total and encapsidated genome. The efficiency of
      encapsidation of the T7 polymerase-transcribed genome was not affected by any of
      the trailer mutations. Furthermore, neither the efficiency of positive-sense RNA
      synthesis from the genome nor the efficiency of encapsidation of the encoded
      antigenome was affected by the mutations. However, nucleotide substitution at
      positions 2, 3, 6, or 7 relative to the 5' end of the trailer blocked the
      production of progeny genome, whereas substitution at positions 1 and 5 allowed a
      low level of genome production and substitutions at position 4 were tolerated.
      Position 4 is the only one of the seven positions examined that is not conserved
      between the 3' ends of genomic and antigenomic RNA. The mutations that blocked
      the synthesis of progeny genome thus limited RNA replication to one step, namely,
      the synthesis and encapsidation of antigenome. Restoration of terminal
      complementarity for one of the trailer mutants by making a compensatory mutation
      in the leader region did not restore synthesis of genomic RNA, confirming that
      its loss was not due to reduced terminal complementarity. Interestingly, this
      leader mutation appeared to prevent antigenome synthesis with only a slight
      effect on mRNA synthesis, apparently providing a dissociation between these two
      synthetic activities. Genomes in which the terminal 24 or 325 nucleotides of the
      trailer have been deleted were competent for encapsidation and the synthesis of
      mRNA and antigenomic RNA, further confirming that terminal complementarity was
      not required for these functions.

PMID- 10590102
TI  - Ultrastructural and functional analyses of recombinant influenza virus
      ribonucleoproteins suggest dimerization of nucleoprotein during virus
      amplification.
AB  - Influenza virus ribonucleoproteins (RNPs) were reconstituted in vivo from cloned
      cDNAs expressing the three polymerase subunits, the nucleoprotein (NP), and short
      template RNAs. The structure of purified RNPs was studied by electron microscopy
      and image processing. Circular and elliptic structures were obtained in which the
      NP and the polymerase complex could be defined. Comparison of the structure of
      RNPs of various lengths indicated that each NP monomer interacts with
      approximately 24 nucleotides. The analysis of the amplification of RNPs with
      different lengths showed that those with the highest replication efficiency
      contained an even number of NP monomers, suggesting that the NP is incorporated
      as dimers into newly synthesized RNPs.

PMID- 10590104
TI  - Rainbow trout sleeping disease virus is an atypical alphavirus.
AB  - Sleeping disease (SD) is currently a matter of concern for salmonid fish farmers
      in most parts of the world. A viral etiology of SD has recently been suspected,
      since virus-like particles have been observed in infected rainbow trout cells. In
      salmonid-derived cell lines, the maximal rate of virus production was observed at
      10 degrees C, while little virus was produced at 14 degrees C. Through
      biochemical, physicochemical, and morphological studies, SD virus (SDV) was shown
      to be an enveloped virus of roughly 60 nm in diameter. The genome consists of 12
      kb of RNA, with the appearance of a 26S subgenomic RNA during the time course of
      SDV replication. The screening of a random-primed cDNA library constructed from
      the genomic RNA of semipurified virions facilitated the identification of a
      specific SDV cDNA clone having an open reading frame related to the alphavirus E2
      glycoproteins. To extend the comparison between SDV structural proteins and the
      alphavirus protein counterparts, the nucleotide sequence of the total 4.1-kb
      subgenomic RNA has been determined. The 26S RNA encodes a 1,324-amino-acid
      polyprotein exhibiting typical alphavirus structural protein organization. SDV
      structural proteins showed several remarkable features compared to other
      alphaviruses: (i) unusually large individual proteins, (ii) very low homology
      (ranging from 30 to 34%) (iii) an unglycosylated E3 protein, and (iv) and E1
      fusion domain sharing mutations implicated in the pH threshold. Although
      phylogenetically related to the Semliki Forest virus group of alphaviruses, SDV
      should be considered an atypical member, able to naturally replicate in lower
      vertebrates.

PMID- 10590103
TI  - RNA dimerization defect in a Rous sarcoma virus matrix mutant.
AB  - The retrovirus matrix (MA) sequence of the Gag polyprotein has been shown to
      contain functions required for membrane targeting and binding during particle
      assembly and budding. Additional functions for MA have been proposed based on the
      existence of MA mutants in Rous sarcoma virus (RSV), murine leukemia virus, human
      immunodeficiency virus type 1, and human T-cell leukemia virus type 1 that lack
      infectivity even though they release particles of normal composition. Here we
      describe an RSV MA mutant with a surprising and previously unreported phenotype.
      In the mutant known as Myr1E, the small membrane-binding domain of the Src
      oncoprotein has been added as an N-terminal extension of Gag. While Myr1E is not
      infectious, full infectivity can be reestablished by a single amino acid
      substitution in the Src sequence (G2E), which eliminates the addition of myristic
      acid and the membrane-binding capacity of this foreign sequence. The presence of
      myristic acid at the N terminus of the Myr1E Gag protein does not explain its
      replication defect, because other myristylated derivatives of RSV Gag are fully
      infectious (e.g., Myr2 [C. R. Erdie and J. W. Wills, J. Virol. 64:5204-5208,
      1990]). Biochemical analyses of Myr1E particles reveal that they contain wild
      type levels of the Gag cleavage products, Env glycoproteins, and reverse
      transcriptase activity when measured on an exogenous template. Genomic RNA
      incorporation appears to be mildly reduced compared to the wild-type level.
      Unexpectedly, RNA isolated from Myr1E particles is monomeric when analyzed on
      nondenaturing Northern blots. Importantly, the insertional mutation does not lie
      within previously identified dimer linkage sites. In spite of the dimerization
      defect, the genomic RNA from Myr1E particles serves efficiently as a template for
      reverse transcription as measured by an endogenous reverse transcriptase assay.
      In marked contrast, after infection of avian cells, the products of reverse
      transcription are nearly undetectable. These findings might be explained either
      by the loss of a normal function of MA needed in the formation or stabilization
      of RNA dimers or by the interference in such events by the mutant MA molecules.
      It is possible that Myr1E viruses package a single copy of viral RNA.

PMID- 10590105
TI  - Viral entry through CXCR4 is a pathogenic factor and therapeutic target in human
      immunodeficiency virus type 1 disease.
AB  - The chemokine receptors CCR5 and CXCR4 function as the principal coreceptors for
      human immunodeficiency virus type 1 (HIV-1). Coreceptor function has also been
      demonstrated for a variety of related receptors in vitro. The relative
      contributions of CCR5, CXCR4, and other putative coreceptors to HIV-1 disease in
      vivo have yet to be defined. In this study, we used sequential primary isolates
      and recombinant strains of HIV-1 to demonstrate that CXCR4-using (X4) viruses
      emerging in association with disease progression are highly pathogenic in ex vivo
      lymphoid tissues compared to CXCR4-independent viruses. Furthermore, synthetic
      receptor antagonists that specifically block CXCR4-mediated entry dramatically
      suppressed the depletion of CD4(+) T cells by recombinant and clinically derived
      X4 HIV-1 isolates. Moreover, in vitro specificity for the additional coreceptors
      CCR3, CCR8, BOB, and Bonzo did not augment cytopathicity or diminish sensitivity
      toward CXCR4 antagonists in lymphoid tissues. These data provide strong evidence
      to support the concept that adaptation to CXCR4 specificity in vivo accelerates
      HIV-1 disease progression. Thus, therapeutic intervention targeting the
      interaction of HIV-1 gp120 with CXCR4 may be highly valuable for suppressing the
      pathogenic effects of late-stage viruses.

PMID- 10590106
TI  - E1B 55-kilodalton oncoproteins of adenovirus types 5 and 12 inactivate and
      relocalize p53, but not p51 or p73, and cooperate with E4orf6 proteins to
      destabilize p53.
AB  - The p53 tumor suppressor protein represents a target for viral and cellular
      oncoproteins, including adenovirus gene products. Recently, it was discovered
      that several proteins with structural and functional homologies to p53 exist in
      human cells. Two of them were termed p51 and p73. We have shown previously that
      the E1B 55-kDa protein (E1B-55 kDa) of adenovirus type 5 (Ad5) binds and
      inactivates p53 but not p73. Further, p53 is rapidly degraded in the presence of
      E1B-55 kDa and the E4orf6 protein of this virus. Here, it is demonstrated that
      p51 does not detectably associate with E1B-55 kDa. While p53 is relocalized to
      the cytoplasm by E1B-55 kDa, p51's location is unaffected. Finally, p51 retains
      its full transcriptional activity in the presence of E1B-55 kDa. Apparently, p51
      does not represent a target of Ad5 E1B-55 kDa, suggesting that the functions of
      p51 are distinct from p53-like tumor suppression. E1B-55 kDa from highly
      oncogenic adenovirus type 12 (Ad12) was previously shown to surpass the oncogenic
      activity of Ad5 E1B-55 kDa in various assay systems, raising the possibility that
      Ad12 E1B-55 kDa might target a broader range of p53-like proteins. However, we
      show here that Ad12 E1B-55 kDa also inhibits p53's transcriptional activity
      without measurably affecting p73 or p51. Moderate inhibition of p51's
      transcriptional activity was observed in the presence of the E4orf6 proteins from
      Ad5 and Ad12. p53 and Ad12-E1B-55 kDa colocalize in the nucleus and also in
      cytoplasmic clusters when transiently coexpressed. Finally, E1B-55 kDa and E4orf6
      of Ad12 mediate rapid degradation of p53 with an efficiency comparable to that of
      the Ad5 proteins in human and rodent cells. Our results suggest that E1B-55 kDa
      of either virus type has similar effects on p53 but does not affect p73 and p51.

PMID- 10590107
TI  - B7 costimulation is critical for antibody class switching and CD8(+) cytotoxic T
      lymphocyte generation in the host response to vesicular stomatitis virus.
AB  - Antibody and cytotoxic T-lymphocyte (CTL) responses have critical roles in
      eliminating many viral infections. In addition to stimulation of the T-cell
      receptor, T cells require costimulatory signals to respond optimally. We
      evaluated the role of B7 costimulatory molecules (B7-1 and B7-2) in the immune
      response to viral infection using vesicular stomatitis virus (VSV) and mice
      lacking either B7-1 or B7-2 or both molecules. Mice lacking both B7-1 and B7-2
      had essentially no anti-VSV immunoglobulin G1 (IgG1) response, decreased IgG2a
      responses, and normal IgM responses, while mice lacking either B7-1 or B7-2 had
      unaltered anti-VSV antibody responses compared to wild-type mice. Depletion of
      CD4(+) cells further reduced the IgG2a response in mice lacking both B7
      molecules, suggesting that CD4(-) cells may supply help for IgG2a in the absence
      of B7 costimulation. The absence of both B7 molecules profoundly reduced
      generation of both primary and secondary VSV-specific class I major
      histocompatibility complex (MHC)-restricted CTL, whereas VSV-specific CTL
      responses in mice lacking either B7-1 or B7-2 were similar to those of wild-type
      animals. Class I MHC-restricted CTL in wild-type mice were not dependent on
      CD4(+) cells, suggesting that the failure of CTL in the absence of B7s is due to
      a lack of B7 costimulation directly to the CD8(+) CTL. These data demonstrate
      that B7-1 and B7-2 have critical, overlapping functions in the antibody and CTL
      responses to this viral infection.

PMID- 10590108
TI  - Immunohistochemical analysis of primary sensory neurons latently infected with
      herpes simplex virus type 1.
AB  - We characterized the populations of primary sensory neurons that become latently
      infected with herpes simplex virus (HSV) following peripheral inoculation. Twenty
      one days after ocular inoculation with HSV strain KOS, 81% of latency-associated
      transcript (LAT)-positive trigeminal ganglion (TG) neurons coexpressed SSEA3, 71%
      coexpressed Trk(A) (the high-affinity nerve growth factor receptor), and 68%
      coexpressed antigen recognized by monoclonal antibody (MAb) A5; less than 5%
      coexpressed antigen recognized by MAb KH10. The distribution of LAT-positive,
      latently infected TG neurons contrasted sharply with (i) the overall distribution
      of neuronal phenotypes in latently infected TG and (ii) the neuronal distribution
      of viral antigen in productively infected TG. Similar results were obtained
      following ocular and footpad inoculation with KOS/62, a LAT deletion mutant in
      which the LAT promoter is used to drive expression of the Escherichia coli lacZ
      gene. Thus, although all neuronal populations within primary sensory ganglia
      appear to be capable of supporting a productive infection with HSV, some neuronal
      phenotypes are more permissive for establishment of a latent infection with LAT
      expression than others. Furthermore, expression of HSV LAT does not appear to
      play a role in this process. These findings indicate that there are marked
      differences in the outcome of HSV infection among the different neuronal
      populations in the TG and highlight the key role that the host neuron may play in
      regulating the repertoire of viral gene expression during the establishment of
      HSV latent infection.

PMID- 10590109
TI  - Initial events in infectious salmon anemia virus infection: evidence for the
      requirement of a low-pH step.
AB  - We have investigated the initial steps in the interaction between infectious
      salmon anemia virus (ISAV) and cultured cells from Atlantic salmon (SHK-1 cell
      line). Using radioactively or fluorescently labelled viral particles we have
      studied the binding and fusion kinetics and the effect of pH on binding, uptake,
      and fusion of ISAV to SHK-1 cells and liposomes. As pH in the medium was reduced
      from 7.5 to 4.5, the association of virus to the cells was nearly doubled. The
      same effect of pH was observed when fusion between ISAV and liposomes was
      analyzed. In addition, the binding of ISAV to intact SHK-1 cells and to cell
      membrane proteins blotted onto filters was neuraminidase sensitive. However, the
      increased binding induced by low pH was not neuraminidase sensitive, probably
      reflecting activation of a fusion peptide at low pH. By using confocal
      fluorescence microscopy, the increased fusion of fluorescently labelled ISAV with
      the plasma membrane due to low pH could be demonstrated. When vacuolar pH in the
      cells was raised during inoculation with chloroquine or ammonium chloride, both
      electron and confocal microscopy showed accumulation of ISAV in endosomes and
      lysosomes. Production of infectious virus could be increased by lowering the
      extracellular pH during infection. Furthermore, chloroquine present during virus
      inoculation also caused a reduction in the synthesis of viral proteins in ISAV
      infected cells as well as in the production of infective virus. These results
      indicate that ISAV binds to sialic acid residues on the cell surface and that the
      fusion between virus and cell membrane takes place in the acid environment of
      endosomes. This provides further evidence for a high degree of similarity between
      ISAV and influenza virus and extends the basis for the classification of this
      virus as a member of the Orthomyxoviridae family.

PMID- 10590111
TI  - A comprehensive approach to mapping the interacting surfaces of murine
      amphotropic and feline subgroup B leukemia viruses with their cell surface
      receptors.
AB  - Because mutations in envelope glycoproteins of retroviruses or in their cell
      surface receptors can eliminate function by multiple mechanisms, it has been
      difficult to unambiguously identify sites for their interactions by site-directed
      mutagenesis. Recently, we developed a gain-of-function approach to overcome this
      problem. Our strategy relies on the fact that feline leukemia virus subgroup B
      (FeLV-B) and amphotropic murine leukemia virus (A-MLV) have closely related gp70
      surface envelope glycoproteins and use related Na(+)-dependent phosphate
      symporters, Pit1 and Pit2, respectively, as their receptors. We previously
      observed that FeLV-B/A-MLV envelope glycoprotein chimeras spliced between the
      variable regions VRA and VRB were unable to use Pit1 or Pit2 as a receptor but
      could efficiently use specific Pit1/Pit2 chimeras. The latter study suggested
      that the VRA of A-MLV and FeLV-B functionally interact with the presumptive
      extracellular loops 4 and 5 (ECL4 and -5) of their respective receptors, whereas
      VRB interacts with ECL2. We also found that FeLV-B gp70 residues F60 and P61 and
      A-MLV residues Y60 and V61 in the first disulfide-bonded loop of VRA were
      important for functional interaction with the receptor's ECL4 or -5. We have now
      extended this approach to identify additional VRA and VRB residues that are
      involved in receptor recognition. Our studies imply that FeLV-B VRA residues F60
      and P61 interact with the Pit1 ECL5 region, whereas VRA residues 66 to 78
      interact with Pit1 ECL4. Correspondingly, A-MLV VRA residues Y60 and V61 interact
      with the Pit2 ECL5 region, whereas residues 66 to 78 interact with Pit2 ECL4.
      Similar studies that focused on the gp70 VRB implicated residues 129 to 139 as
      contributing to specific interactions with the receptor ECL2. These results
      identify three regions of gp70 that interact in a specific manner with distinct
      portions of their receptors, thereby providing a map of the functionally
      interacting surfaces.

PMID- 10590110
TI  - Integrins alpha2beta1 and alpha4beta1 can mediate SA11 rotavirus attachment and
      entry into cells.
AB  - Most mammalian rotaviruses contain tripeptide amino acid sequences in outer
      capsid proteins VP4 and VP7 which have been shown to act as ligands for integrins
      alpha2beta1 and alpha4beta1. Peptides containing these sequences and monoclonal
      antibodies directed to these integrins block rotavirus infection of cells. Here
      we report that SA11 rotavirus binding to and infection of K562 cells expressing
      alpha2beta1 or alpha4beta1 integrins via transfection is increased over virus
      binding to and infection of cells transfected with alpha3 integrin or parent
      cells. The increased binding and growth were specifically blocked by a monoclonal
      antibody to the transfected integrin subunit but not by irrelevant antibodies. In
      our experiments, integrin activation with phorbol ester did not affect virus
      binding to cells. However, phorbol ester treatment of K562 parent and transfected
      cells induced endogenous gene expression of alpha2beta1 integrin, which was
      detectable by flow cytometry 16 h after treatment and quantitatively correlated
      with the increased level of SA11 virus growth observed after this time. Virus
      binding to K562 cells treated with phorbol ester 24 h previously and expressing
      alpha2beta1 was elevated over binding to control cells and was specifically
      blocked by the anti-alpha2 monoclonal antibody AK7. Virus growth in alpha4
      transfected K562 cells which had also been induced to express alpha2beta1
      integrin with phorbol ester occurred at a level approaching that in the
      permissive MA104 cell line. We therefore have demonstrated that two integrins,
      alpha2beta1 and alpha4beta1, are capable of acting as cellular receptors for SA11
      rotavirus.

PMID- 10590112
TI  - Identification of a short, hydrophilic amino acid sequence critical for origin
      recognition by the bovine papillomavirus E1 protein.
AB  - The E1 protein of bovine papillomavirus (BPV) is a site-specific DNA binding
      protein that recognizes an 18-bp inverted repeat element in the viral origin of
      replication. Sequence-specific DNA binding function maps to the region from
      approximately amino acids 140 to 300, and isolated polypeptides containing this
      region have been shown to retain origin binding in vitro. To investigate the
      sequence and structural characteristics which contribute to sequence-specific
      binding, the primary sequence of this region was examined for conserved features.
      The BPV E1 DNA binding domain (E1DBD) contains three major hydrophilic domains
      (HR1, amino acids 179-191; HR2, amino acids 218 to 230; and HR3, amino acids 241
      to 252), of which only HR1 and HR3 are conserved among papillomavirus E1
      proteins. E1DBD proteins with lysine-to-alanine mutations in HR1 and HR3 were
      severely impaired for DNA binding function in vitro, while a lysine-to-alanine
      mutation in HR2 had a minimal effect on DNA binding. Mutation of adjacent
      threonine residues in HR1 (T187 and T188) revealed that these two amino acids
      made drastically different contributions to DNA binding, with the T187 mutant
      being severely defective for origin binding whereas the T188 mutant was only
      mildly affected. Helical wheel projections of HR1 predict that T187 is on the
      same helical face as the critical lysine residues whereas T188 is on the opposing
      face, which is consistent with their respective contributions to DNA binding
      activity. To examine E1 binding in vivo, a yeast one-hybrid system was developed.
      Both full-length E1 and the E1DBD polypeptide were capable of specifically
      interacting with the E1 binding site in the context of the yeast genome, and HR1
      was also critical for this in vivo interaction. Overall, our results indicate
      that HR1 is essential for origin binding by E1, and the features and properties
      of HR1 suggest that it may be part of a recognition sequence that mediates
      specific E1-nucleotide contacts.

PMID- 10590113
TI  - Induction of antibodies in guinea pigs and rhesus monkeys against the human
      immunodeficiency virus type 1 envelope: neutralization of nonpathogenic and
      pathogenic primary isolate simian/human immunodeficiency virus strains.
AB  - We have compared the abilities of human immunodeficiency virus type 1 (HIV-1)
      envelope V3 peptides and recombinant gp120 to induce antibodies that neutralize
      simian/human immunodeficiency viruses (SHIVs). SHIV-89.6 is a nonpathogenic SHIV
      that expresses the envelope protein of primary HIV-1 isolate 89.6. SHIV-89.6P,
      clone KB9, is a pathogenic SHIV variant derived from SHIV-89.6. Infection of
      rhesus monkeys with these SHIVs rarely induces anti-V3 region antibodies. To
      determine the availability of the gp120 V3 loop for neutralizing antibody binding
      on SHIV-89.6 and KB9 virions, we have constructed immunogenic C4-V3 peptides from
      these SHIVs and induced anti-V3 antibodies in guinea pigs and rhesus monkeys. We
      found that both SHIV-89.6 and KB9 C4-V3 peptides induced antibodies that
      neutralized SHIV-89.6 but that only SHIV-KB9 C4-V3 peptide induced antibodies
      that neutralized SHIV-KB9. Immunoprecipitation assays demonstrated that SHIV-KB9
      C4-V3 peptide-induced antibodies had a greater ability to bind SHIV-KB9 envelope
      proteins than did antibodies raised against SHIV-89.6 C4-V3 peptide. We have used
      a series of mutant HIV-1 envelope constructs to map the gp120 determinants that
      affect neutralization by anti-V3 antibodies. The residue change at position 305
      of arginine (in SHIV-89.6) to glutamic acid (in SHIV-KB9) played a central role
      in determining the ability of peptide-induced anti-V3 antiserum to neutralize
      primary isolate SHIVs. Moreover, residue changes in the SHIV-89.6 V1/V2 loops
      also played roles in regulating the availability of the V3 neutralizing epitope
      on SHIV-89.6 and -KB9. Thus, SHIV-89.6 and -KB9 V3 region peptides are capable of
      inducing neutralizing antibodies against these primary isolate SHIVs, although
      the pathogenic SHIV-KB9 is less easily neutralized than its nonpathogenic variant
      SHIV-89.6. In contrast to natural infection with SHIV-89.6, in which few animals
      make anti-V3 antibodies, C4-V3 peptides frequently induced anti-V3 antibodies
      that neutralized primary isolate SHIV strains.

PMID- 10590114
TI  - In vitro transcription by the turnip yellow mosaic virus RNA polymerase: a
      comparison with the alfalfa mosaic virus and brome mosaic virus replicases.
AB  - Recently, we showed that the main determinant in the tRNA-like structure of
      turnip yellow mosaic virus RNA to initiate minus-strand synthesis in vitro is the
      3' ACCA end. By mutational analysis of the 3'-terminal hairpin, we show here that
      only a non-base-paired ACCA end is functional and that the stability of the wild
      type 3'-proximal hairpin is the most favorable, in that it has the lowest DeltaG
      value and a high transcription efficiency. With a nested set of RNA fragments, we
      show that the minimum template length is 9 nucleotides and that transcription is
      improved with increasing the length of the template. The results also suggest
      that proper base stacking contributes to efficient transcription initiation.
      Internal initiation is shown to take place on every NPyCPu sequence of a
      nonstructured template. However, the position of the internal initiation site in
      the template is important, and competition between the different sites takes
      place. Internal initiation was also studied with the RNA-dependent RNA polymerase
      of brome mosaic virus (BMV) and alfalfa mosaic virus (AlMV). The BMV polymerase
      can start internally on ACCA sequences, though inefficiently. Unexpectedly, the
      polymerases of both AlMV and BMV can start efficiently on an internal AUGC
      sequence.

PMID- 10590115
TI  - Foot-and-mouth disease virus 3C protease induces cleavage of translation
      initiation factors eIF4A and eIF4G within infected cells.
AB  - Infection of cells by foot-and-mouth disease virus (FMDV) results in the rapid
      inhibition of host cell protein synthesis. This process is accompanied by the
      early cleavage of the translation initiation factor eIF4G, a component of the cap
      binding complex eIF4F. This cleavage is mediated by the leader (L) protease.
      Subsequently, as the virus proteins accumulate, secondary cleavages of eIF4G
      occur. Furthermore, eIF4A (46 kDa), a second component of eIF4F, is also cleaved
      in these later stages of the infection cycle. The 33-kDa cleavage product of
      eIF4A has lost a fragment from its N terminus. Transient-expression assays
      demonstrated that eIF4A was not cleaved in the presence of FMDV L or with the
      poliovirus 2A protease (which also mediates eIF4G cleavage) but was cleaved when
      the FMDV 3C protease was expressed. The FMDV 3C protease was also shown in such
      assays to induce cleavage of eIF4G, resulting in the production of cleavage
      products different from those generated by the L protease. Consistent with these
      results, within cells infected with a mutant FMDV lacking the L protease or
      within cells containing an FMDV replicon lacking L-P1 coding sequences it was
      again shown that eIF4A and eIF4G were cleaved.

PMID- 10590116
TI  - Conditional site-specific integration into human chromosome 19 by using a ligand
      dependent chimeric adeno-associated virus/Rep protein.
AB  - It is of great interest for gene therapy to develop vectors that drive the
      insertion of a therapeutic gene into a chosen specific site on the cellular
      genome. Adeno-associated virus (AAV) is unique among mammalian viruses in that it
      integrates into a distinct region of human chromosome 19 (integration site
      AAVS1). The inverted terminal repeats (ITRs) flanking the AAV genome and the AAV
      encoded nonstructural proteins Rep78 and/or Rep68 are the only viral elements
      necessary and sufficient for site-specific integration. However, it is also known
      that unrestrained Rep activity may cause nonspecific genomic rearrangements at
      AAVS1 and/or have detrimental effects on cell physiology. In this paper we
      describe the generation of a ligand-dependent form of Rep, obtained by fusing a C
      terminally deleted Rep68 with a truncated form of the hormone binding domain of
      the human progesterone receptor, which does not bind progesterone but binds only
      its synthetic antagonist RU486. The activity of this chimeric protein, named Rep1
      491/P, is highly dependent on RU486 in various assays: in particular, it triggers
      site-specific integration at AAVS1 of an ITR-flanked cassette in a ligand
      dependent manner, as efficiently as wild-type Rep68 but without generating
      unwanted genomic rearrangement at AAVS1.

PMID- 10590117
TI  - Activation of a cell entry pathway common to type C mammalian retroviruses by
      soluble envelope fragments.
AB  - Mutations that negatively or positively affect the fusion properties of murine
      leukemia viruses (MLVs) have been found within all subdomains of their SU
      (surface) and TM (transmembrane) envelope units. Yet, the interrelations between
      these different regions of the envelope complex during the cell entry process are
      still elusive. Deletion of the histidine residue of the conserved PHQV motif at
      the amino terminus of the amphotropic or the ecotropic MLV SU resulted in the
      AdelH or the MOdelH fusion-defective mutant envelope, respectively. These delH
      mutant envelopes are incorporated on retroviral particles at normal densities and
      normally mediate virion binding to cells expressing the retroviral receptors.
      However, both their cell-cell and virus-cell fusogenicities were fully prevented
      at an early postbinding stage. We show here that the fusion defect of AdelH or
      MOdelH envelopes was also almost completely reverted by providing either soluble
      SU or a polypeptide encompassing the receptor-binding domain (RBD) to the target
      cells, provided that the integrity of the amino-terminal end of either
      polypeptide was preserved. Restoration of delH envelope fusogenicity was caused
      by activation of the target cells via specific interaction of the latter
      polypeptides with the retrovirus receptor rather than by their association with
      the delH envelope complexes. Moreover crossactivation of the target cells,
      leading to fusion activation of AdelH or MOdelH envelopes, was achieved by
      polypeptides containing various type C mammalian retrovirus RBDs, irrespective of
      the type of entry-defective glycoprotein that was used for infection. Our results
      indicate that although they recognize different receptors for binding to the cell
      surface, type C mammalian retroviruses use a common entry pathway which is
      activated by a conserved feature of their envelope glycoproteins.

PMID- 10590118
TI  - Measles virus structural components are enriched into lipid raft microdomains: a
      potential cellular location for virus assembly.
AB  - The process of measles virus (MV) assembly and subsequent budding is thought to
      occur in localized regions of the plasma membrane, to favor specific
      incorporation of viral components, and to facilitate the exclusion of host
      proteins. We demonstrate that during the course of virus replication, a
      significant proportion of MV structural proteins were selectively enriched in the
      detergent-resistant glycosphingolipids and cholesterol-rich membranes (rafts).
      Isolated rafts could infect the cell through a membrane fusion step and thus
      contained all of the components required to create a functional virion. However,
      they could be distinguished from the mature virions with regards to density and
      Triton X-100 resistance behavior. We further show that raft localization of the
      viral internal nucleoprotein and matrix protein was independent of the envelope
      glycoproteins, indicating that raft membranes could provide a platform for MV
      assembly. Finally, at least part of the raft MV components were included in the
      viral particle during the budding process. Taken together, these results strongly
      suggest a role for raft membranes in the processes of MV assembly and budding.

PMID- 10590119
TI  - Development of an in vivo assay to identify structural determinants in murine
      leukemia virus reverse transcriptase important for fidelity.
AB  - Error-prone DNA synthesis by retroviral reverse transcriptases (RTs) is a major
      contributor to variation in retroviral populations. Structural features of
      retroviral RTs that are important for accuracy of DNA synthesis in vivo are not
      known. To identify structural elements of murine leukemia virus (MLV) RT
      important for fidelity in vivo, we developed a D17-based encapsidating cell line
      (ANGIE P) which is designed to express the amphotropic MLV envelope. ANGIE P also
      contains an MLV-based retroviral vector (GA-1) which encodes a wild-type
      bacterial beta-galactosidase gene (lacZ) and a neomycin phosphotransferase gene.
      Transfection of ANGIE P cells with wild-type or mutated MLV gag-pol expression
      constructs generated GA-1 virus that was able to undergo only one cycle of viral
      replication upon infection of D17 cells. The infected D17 cell clones were
      characterized by staining with 5-bromo-4-chloro-3-indolyl-beta-D
      galactopyranoside (X-Gal), and the frequencies of inactivating mutations in lacZ
      were quantified. Three mutations in the YVDD motif (V223M, V223S, and V223A) and
      two mutations in the RNase H domain (S526A and R657S) exhibited frequencies of
      lacZ inactivation 1.2- to 2.3-fold higher than that for the wild-type MLV RT (P <
      0.005). Two mutations (V223I and Y598V) did not affect the frequency of lacZ
      inactivation. These results establish a sensitive in vivo assay for
      identification of structural determinants important for accuracy of DNA synthesis
      and indicate that several structural determinants may have an effect on the in
      vivo fidelity of MLV RT.

PMID- 10590120
TI  - Successful transmission of three mouse-adapted scrapie strains to murine
      neuroblastoma cell lines overexpressing wild-type mouse prion protein.
AB  - Propagation of the agents responsible for transmissible spongiform
      encephalopathies (TSEs) in cultured cells has been achieved for only a few cell
      lines. To establish efficient and versatile models for transmission, we developed
      neuroblastoma cell lines overexpressing type A mouse prion protein, MoPrP(C)-A,
      and then tested the susceptibility of the cells to several different mouse
      adapted scrapie strains. The transfected cell clones expressed up to sixfold
      higher levels of PrP(C) than the untransfected cells. Even after 30 passages, we
      were able to detect an abnormal proteinase K-resistant form of prion protein,
      PrP(Sc), in the agent-inoculated PrP-overexpressing cells, while no PrP(Sc) was
      detectable in the untransfected cells after 3 passages. Production of PrP(Sc) in
      these cells was also higher and more stable than that seen in scrapie-infected
      neuroblastoma cells (ScN2a). The transfected cells were susceptible to PrP(Sc)-A
      strains Chandler, 139A, and 22L but not to PrP(Sc)-B strains 87V and 22A. We
      further demonstrate the successful transmission of PrP(Sc) from infected cells to
      other uninfected cells. Our results corroborate the hypothesis that the
      successful transmission of agents ex vivo depends on both expression levels of
      host PrP(C) and the sequence of PrP(Sc). This new ex vivo transmission model will
      facilitate research into the mechanism of host-agent interactions, such as the
      species barrier and strain diversity, and provides a basis for the development of
      highly susceptible cell lines that could be used in diagnostic and therapeutic
      approaches to the TSEs.

PMID- 10590121
TI  - Sequential CD4-coreceptor interactions in human immunodeficiency virus type 1 Env
      function: soluble CD4 activates Env for coreceptor-dependent fusion and reveals
      blocking activities of antibodies against cryptic conserved epitopes on gp120.
AB  - We devised an experimental system to examine sequential events by which the human
      immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) interacts with
      CD4 and coreceptor to induce membrane fusion. Recombinant soluble CD4 (sCD4)
      activated fusion between effector cells expressing Env and target cells
      expressing coreceptor (CCR5 or CXCR4) but lacking CD4. sCD4-activated fusion was
      dose dependent, occurred comparably with two- and four-domain proteins, and
      demonstrated Env-coreceptor specificities parallel to those reported in
      conventional fusion and infectivity systems. Fusion activation occurred upon sCD4
      preincubation and washing of the Env-expressing effector cells but not the
      coreceptor-bearing target cells, thereby demonstrating that sCD4 exerts its
      effects by acting on Env. These findings provide direct functional evidence for a
      sequential two-step model of Env-receptor interactions, whereby gp120 binds first
      to CD4 and becomes activated for subsequent functional interaction with
      coreceptor, leading to membrane fusion. We used the sCD4-activated system to
      explore neutralization by the anti-gp120 human monoclonal antibodies 17b and 48d.
      These antibodies reportedly bind conserved CD4-induced epitopes involved in
      coreceptor interactions but neutralize HIV-1 infection only weakly. We found that
      17b and 48d had minimal effects in the standard cell fusion system using target
      cells expressing both CD4 and coreceptor but potently blocked sCD4-activated
      fusion with target cells expressing coreceptor alone. Both antibodies strongly
      inhibited sCD4-activated fusion by Envs from genetically diverse HIV-1 isolates.
      Thus, the sCD4-activated system reveals conserved Env-blocking epitopes that are
      masked in native Env and hence not readily detected by conventional systems.

PMID- 10590122
TI  - A cysteine-rich motif in poliovirus protein 2C(ATPase) is involved in RNA
      replication and binds zinc in vitro.
AB  - Protein 2C(ATPase) of picornaviruses is involved in the rearrangement of host
      cell organelles, viral RNA replication, and encapsidation. However, the
      biochemical and molecular mechanisms by which 2C(ATPase) engages in these
      processes are not known. To characterize functional domains of 2C(ATPase), we
      have focused on a cysteine-rich motif near the carboxy terminus of poliovirus
      2C(ATPase). This region, which is well conserved among enteroviruses and
      rhinoviruses displaying an amino acid arrangement resembling zinc finger motifs,
      was studied by genetic and biochemical analyses. A mutation that replaced the
      first cysteine residue of the motif with a serine was lethal. A mutant virus
      which lacked the second of four potential coordination sites for zinc was
      temperature sensitive. At the restrictive temperature, RNA replication was
      inhibited whereas translation and polyprotein processing, assayed in vitro and in
      vivo, appeared to be normal. An intragenomic second-site revertant which
      reinserted the missing coordination site for zinc and recovered RNA replication
      at the restrictive temperature was isolated. The cysteine-rich motif was
      sufficient to bind zinc in vitro, as assessed in the presence of 4-(2
      pyridylazo)resorcinol by a colorimetric assay. Zinc binding, however, was not
      required for hydrolysis of ATP. 2C(ATPase) as well as its precursors 2BC and P2
      were found to exist in a reduced form in poliovirus-infected cells.

PMID- 10590123
TI  - Identification of specific molecular structures of human immunodeficiency virus
      type 1 Tat relevant for its biological effects on vascular endothelial cells.
AB  - Human immunodeficiency virus type 1 (HIV-1) Tat transactivates viral genes and is
      released by infected cells, acting as a soluble mediator. In endothelial cells
      (EC), it activates a proangiogenic program by activating vascular endothelial
      growth factor receptor type 2 (VEGFR-2) and integrins. A structure-activity
      relationship study was performed by functional analysis of Tat substitution and
      deletion variants to define the Tat determinants necessary for EC activation.
      Variants were made (i) in the basic and (ii) in the cysteine-rich domains and
      (iii) in the C-terminal region containing the RGD sequence required for integrin
      recognition. Our results led to the following conclusions. (i) Besides a high
      affinity binding site corresponding to VEGFR-2, EC express low-affinity binding
      sites. (ii) The basic and the cysteine-rich variants bind only to the low
      affinity binding sites and do not promote tyrosine phosphorylation of VEGFR-2.
      Furthermore, they have a reduced ability to activate EC in vitro, and they lack
      angiogenic activity. (iii) Mutants with mutations in the C-terminal region are
      partially defective for in vitro biological activities and in vivo angiogenesis,
      but they activate VEGFR-2 as Tat wild type. In conclusion, regions encoded by the
      first exon of tat are necessary and sufficient for activation of VEGFR-2.
      However, the C-terminal region, most probably through RGD-mediated integrin
      engagement, is indispensable for full activation of an in vitro and in vivo
      angiogenic program.

PMID- 10590124
TI  - Adenovirus vector pseudotyping in fiber-expressing cell lines: improved
      transduction of Epstein-Barr virus-transformed B cells.
AB  - While adenovirus (Ad) gene delivery vectors are useful in many gene therapy
      applications, their broad tropism means that they cannot be directed to a
      specific target cell. There are also a number of cell types involved in human
      disease which are not transducible with standard Ad vectors, such as Epstein-Barr
      virus (EBV)-transformed B lymphocytes. Adenovirus binds to host cells via the
      viral fiber protein, and Ad vectors have previously been retargeted by modifying
      the fiber gene on the viral chromosome. This requires that the modified fiber be
      able to bind to the cell in which the vector is grown, which prevents truly
      specific vector targeting. We previously reported a gene delivery system based on
      a fiber gene-deleted Ad type 5 (Ad5) vector (Ad5.betagal.DeltaF) and packaging
      cells that express the viral fiber protein. Expression of different fibers in
      packaging cells will allow Ad retargeting without modifying the viral chromosome.
      Importantly, fiber proteins which can no longer bind to the producer cells can
      also be used. Using this approach, we generated for the first time pseudotyped
      Ad5.betagal.DeltaF particles containing either the wild-type Ad5 fiber protein or
      a chimeric fiber with the receptor-binding knob domain of the Ad3 fiber.
      Particles equipped with the chimeric fiber bound to the Ad3 receptor rather than
      the coxsackievirus-adenovirus receptor protein used by Ad5. EBV-transformed B
      lymphocytes were infected efficiently by the Ad3-pseudotyped particles but poorly
      by virus containing the Ad5 fiber protein. The strategy described here represents
      a broadly applicable method for targeting gene delivery to specific cell types.

PMID- 10590125
TI  - Simplified strategy for detection of recombinant human immunodeficiency virus
      type 1 group M isolates by gag/env heteroduplex mobility assay. Study Group on
      Heterogeneity of HIV Epidemics in African Cities.
AB  - We developed a heteroduplex mobility assay in the gag gene (gag HMA) for the
      identification of group M subtypes A to H. The assay covers the region coding for
      amino acid 132 of p24 to amino acid 20 of p7 (according to human immunodeficiency
      virus type 1 [HIV-1] ELI, 460 bp). The gag HMA was compared with sequencing and
      phylogenetic analysis of an evaluation panel of 79 HIV-1 group M isolates
      isolated from infected individuals from different geographic regions. Application
      of gag HMA in combination with env HMA on 252 HIV-1- positive plasma samples from
      Benin, Cameroon, Kenya, and Zambia revealed a high prevalence of a variety of
      intersubtype recombinants in Yaounde, Cameroon (53.8%); Kisumu, Kenya (26.8%);
      and Cotonou, Benin (41%); no recombinants were identified among the samples from
      Ndola, Zambia. The AG(IbNG) circulating recombinant form, as determined by gag
      HMA, was found to be the most common intersubtype recombinant in Yaounde (39.4%)
      and Cotonou (38.5%). Using a one-tube reverse transcriptase PCR protocol, this
      gag HMA in combination with env HMA is a useful tool for rapidly monitoring the
      prevalence of the various genetic subtypes as well as of recombinants of HIV-1.
      Moreover, this technology can easily be applied in laboratories in developing
      countries.

PMID- 10590126
TI  - Vaccination of macaques against pathogenic simian immunodeficiency virus with
      Venezuelan equine encephalitis virus replicon particles.
AB  - Vaccine vectors derived from Venezuelan equine encephalitis virus (VEE) that
      expressed simian immunodeficiency virus (SIV) immunogens were tested in rhesus
      macaques as part of the effort to design a safe and effective vaccine for human
      immunodeficiency virus. Immunization with VEE replicon particles induced both
      humoral and cellular immune responses. Four of four vaccinated animals were
      protected against disease for at least 16 months following intravenous challenge
      with a pathogenic SIV swarm, while two of four controls required euthanasia at 10
      and 11 weeks. Vaccination reduced the mean peak viral load 100-fold. The plasma
      viral load was reduced to below the limit of detection (1,500 genome copies/ml)
      in one vaccinated animal between 6 and 16 weeks postchallenge and in another from
      week 6 through the last sampling time (40 weeks postchallenge). The extent of
      reduction in challenge virus replication was directly correlated with the
      strength of the immune response induced by the vectors, which suggests that
      vaccination was effective.

PMID- 10590127
TI  - Sequence and functional analysis of EBNA-LP and EBNA2 proteins from nonhuman
      primate lymphocryptoviruses.
AB  - The Epstein-Barr virus (EBV) EBNA-LP and EBNA2 proteins are the first to be
      synthesized during establishment of latent infection in B lymphocytes. EBNA2 is a
      key transcriptional regulator of both viral and cellular gene expression and is
      essential for EBV-induced immortalization of B lymphocytes. EBNA-LP is also
      important for EBV-induced immortalization of B lymphocytes, but far less is known
      about the functional domains and cellular cofactors that mediate EBNA-LP
      function. While recent studies suggest that serine phosphorylation of EBNA-LP and
      coactivation of EBNA2-mediated transactivation are important, more detailed
      mutational and genetic studies are complicated by the repeat regions that
      comprise the majority of the EBNA-LP sequence. Therefore, we have used a
      comparative approach by studying the EBNA-LP homologues from baboon and rhesus
      macaque lymphocryptoviruses (LCVs) (baboon LCV and rhesus LCV). The predicted
      baboon and rhesus LCV EBNA-LP amino acid sequences are 61 and 64% identical to
      the EBV EBNA-LP W1 and W2 exons and 51% identical to the EBV EBNA-LP Y1 and Y2
      exons. Five evolutionarily conserved regions can be defined, and four of eight
      potential serine residues are conserved among all three EBNA-LPs. The major
      internal repeat sequence also revealed a highly conserved Wp EBNA promoter with
      strong conservation of upstream activating sequences important for Wp
      transcriptional regulation. To test whether transcriptional coactivating
      properties were common to the rhesus LCV EBNA-LP, a rhesus LCV EBNA2 homologue
      was cloned and expressed. The rhesus LCV EBNA2 transcriptionally transactivates
      EBNA2-responsive promoters through a CBF1-dependent mechanism. The rhesus LCV
      EBNA-LP was able to further enhance rhesus LCV or EBV EBNA2 transactivation 5- to
      12-fold. Thus, there is strong structural and functional conservation among the
      simian EBNA-LP homologues. Identification of evolutionarily conserved serine
      residues and regions in EBNA-LP homologues provides important clues for
      identifying the cellular cofactors and molecular mechanisms mediating these
      conserved viral functions.

PMID- 10590128
TI  - Correlation between point mutations in NS2 and the viability and
      cytopathogenicity of Bovine viral diarrhea virus strain Oregon analyzed with an
      infectious cDNA clone.
AB  - Cytopathogenicity of Bovine viral diarrhea virus (BVDV) is correlated with
      expression of the nonstructural protein NS3, which can be generated by processing
      of a fusion protein termed NS2-3. For the cytopathogenic (cp) BVDV strain Oregon,
      NS2-3 processing is based on a set of point mutations within NS2. To analyze the
      correlation between NS2-3 cleavage and cytopathogenicity, a full-length cDNA
      clone composed of cDNA from BVDV Oregon and the utmost 5'- and 3'-terminal
      sequences of a published infectious BVDV clone was established. After
      transfection of RNA transcribed from this cDNA clone, infectious virus with
      similar growth characteristics to wild-type BVDV Oregon could be recovered that
      also exhibited a cytopathic effect. Based on this cDNA construct and published cp
      and noncp infectious clones, chimeric full-length cDNA clones were constructed.
      Analysis of the recovered viruses demonstrated that the presence of the NS2 gene
      of BVDV Oregon in a chimeric construct is sufficient for NS2-3 processing and a
      cp phenotype. Since previous studies had revealed that the amino acid serine at
      position 1555 of BVDV Oregon plays an important role in efficient NS2-3 cleavage,
      mutants of BVDV Oregon with different amino acids at this position were
      constructed. Some of these mutants showed NS2-3 cleavage efficiencies in the
      range of the wild-type sequence and allowed the recovery of viruses that behaved
      similarly to wild-type virus with regard to growth characteristics and
      cytopathogenicity. In contrast, other mutants with considerably reduced NS2-3
      cleavage efficiencies propagated much more slowly and reverted to viruses
      expressing polyproteins with sequences allowing efficient NS2-3 cleavage. These
      viruses apparently induced cytopathic effects only after reversion.

PMID- 10590129
TI  - The differentiation-specific factor CDP/Cut represses transcription and
      replication of human papillomaviruses through a conserved silencing element.
AB  - The life cycles of human papillomaviruses (HPVs) are intimately linked to the
      differentiation program of infected stratified epithelia, with both viral gene
      expression and replication being maintained at low levels in undifferentiated
      basal cells and increased upon host cell differentiation. We recently identified,
      in HPV-16, a negative regulatory element between the epithelial-cell-specific
      enhancer and the E6 promoter that is capable of silencing E6 promoter activity,
      and we termed this element a papillomavirus silencing motif (PSM) and the unknown
      cellular factor that bound to it PSM binding protein (PSM-BP). Here we show that
      the homologous genomic segments of six other distantly related genital HPV types
      contain a PSM that binds PSM-BP and is capable of repressing transcription.
      Conservation of the PSM suggests that it is indispensable for the HPV life cycle.
      Purification, electrophoretic mobility shift assay experiments, and the use of
      specific antibodies proved that the cellular factor PSM-BP is identical to a
      previously described transcriptional repressor, the CCAAT displacement protein
      (CDP), also referred to as the human Cut protein (Cut). CDP/Cut repression of HPV
      16 may stem from the modification of specifically positioned nucleosomes, as
      suggested by transcriptional stimulation under the influence of the histone
      deacetylase inhibitor trichostatin A. CDP/Cut is an important developmental
      regulator in several different tissues. It was recently shown that CDP/Cut is
      expressed in basal epithelial cells but not in differentiated primary
      keratinocytes. This suggests the possibility that repression by PSM couples HPV
      transcription to the stratification of epithelia. In each of the studied HPV
      types, the two CDP/Cut binding sites of PSM overlap with the known or presumed
      binding sites of the replication initiator protein E1. Transfection of CDP/Cut
      expression vectors into cells that support HPV-16 or HPV-31 replication leads to
      the elimination of viral episomes. Similarly, two PSM-like motifs overlapping the
      E1 binding site of bovine papillomavirus type 1 bind CDP/Cut, and CDP/Cut
      overexpression reduces the copy number of episomally replicating BPV-1 genomes in
      mouse fibroblasts. CDP/Cut appears to be a master regulator of HPV transcription
      and replication during epithelial differentiation, and PSMs are important cis
      responsive targets of this repressor.

PMID- 10590130
TI  - Upregulation of the genes encoding lysosomal hydrolases, a perforin-like protein,
      and peroxidases in the brains of mice affected with an experimental prion
      disease.
AB  - In an attempt to identify the molecules involved in the pathogenesis of prion
      diseases, we performed cDNA subtraction on the brain tissues of mice affected
      with an experimental prion disease and the unaffected control. The genes
      identified as being upregulated in the prion-affected brain tissue included those
      encoding a series of lysosomal hydrolases (lysozyme M and both isoforms of beta-N
      acetylhexosaminidase), a perforin-like protein (macrophage proliferation-specific
      gene-1 [MPS-1]), and an oxygen radical scavenger (peroxiredoxin). Dramatic
      increases in the expression level occurred at between 12 and 16 weeks after
      intracerebral inoculation of the prion, coinciding with the onset of spongiform
      degeneration. The proteinase K-resistant prion protein (PrP(Sc)) became
      detectable by immunoblotting well before 12 weeks, suggesting a causal
      relationship between this and the gene activation. Immunohistochemistry paired
      with in situ hybridization on sections of the affected brain tissue revealed that
      expression of the peroxiredoxin gene was detectable only in astrocytes and was
      noted throughout the affected brain tissue. On the other hand, the genes for the
      lysosomal hydrolases and MPS-1 were overexpressed exclusively by microglia, which
      colocalized with the spongiform morphological changes. A crucial role for
      microglia in the spongiform degeneration by their production of neurotoxic
      substances, and possibly via the aberrant activation of the lysosomal system,
      would have to be considered.

PMID- 10590131
TI  - Polyuridylated mRNA synthesized by a recombinant influenza virus is defective in
      nuclear export.
AB  - The poly(A) tail of influenza virus mRNA is synthesized by reiterative copying of
      a U track near the 5' end of the virion RNA (vRNA) template by the viral RNA
      polymerase. We have engineered a novel influenza A/WSN/33 virus which contains a
      neuraminidase (NA) vRNA with its U track mutated into an A track. Instead of
      synthesizing poly(A)-tailed NA mRNA, this novel virus synthesizes poly(U)-tailed
      NA mRNA. In infected cells, most poly(U)-tailed NA mRNA was retained in the
      nucleus, while most control polyadenylated NA mRNA was transported to the
      cytoplasm. These results suggest that the poly(A) tail is important for efficient
      nuclear export of NA mRNA. The mutant virus produced a reduced amount of NA and
      showed an attenuated phenotype, suggesting that poly(A) signal mutants of this
      type might be useful as potential live attenuated virus vaccines. In addition,
      this virus mutant might provide a useful model to further elucidate the basic
      mechanisms of mRNA nuclear export.

PMID- 10590132
TI  - Development of human T-cell leukemia virus type 1-transformed tumors in rats
      following suppression of T-cell immunity by CD80 and CD86 blockade.
AB  - Host immunity influences clinical manifestations of human T-cell leukemia virus
      type 1 (HTLV-1) infection. In this study, we demonstrated that HTLV-1-transformed
      tumors could develop in immunocompetent rats by blocking a costimulatory signal
      for T-cell immune responses. Four-week-old WKA/HKm rats were treated with
      monoclonal antibodies (MAbs) to CD80 and CD86 and subcutaneously inoculated with
      syngeneic HTLV-1-infected TARS-1 cells. During MAb treatment for 14 days, TARS-1
      inoculation resulted in the development of solid tumors at the site of
      inoculation, which metastasized to the lungs. In contrast, rats not treated with
      MAbs promptly rejected tumor cells. Splenic T cells from MAb-treated rats
      indicated impairment of proliferative and cytotoxic T-lymphocyte responses
      against TARS-1 in vitro compared to untreated rats. However, tumors grown in MAb
      treated rats regressed following withdrawal of MAb therapy. Recovery of TARS-1
      specific T-cell immune responses was associated with tumor regression in these
      rats. Our results suggest that HTLV-1-specific cell-mediated immunity plays a
      critical role in immunosurveillance against HTLV-1-transformed tumor development
      in vivo.

PMID- 10590133
TI  - Identification of the novel K15 gene at the rightmost end of the Kaposi's sarcoma
      associated herpesvirus genome.
AB  - Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a distinct open reading
      frame called K15 at a position equivalent to the gene encoding LMP2A of Epstein
      Barr virus (EBV). K15 isolates from body cavity-based lymphoma (BCBL) cells
      exhibited a dramatic sequence variation and a complex splicing pattern. However,
      all K15 alleles are organized similarly with the potential SH2 and SH3 binding
      motifs in their cytoplasmic regions. Northern blot analysis showed that K15 was
      weakly expressed in latently infected BCBL-1 cells, and the level of its
      expression was significantly induced by tetradecanoyl phorbol acetate
      stimulation. K15 encoded 40- to 55-kDa proteins, as determined by sodium dodecyl
      sulfate-polyacrylamide gel electrophoresis, and was localized at the cytoplasm
      and plasma membrane. To demonstrate the signal-transducing activity of the K15
      protein, we constructed a chimeric protein in which the cytoplasmic tail of the
      human CD8alpha polypeptide was replaced with that of KSHV K15. While the CD8-K15
      chimera was not capable of eliciting cellular signal transduction upon
      stimulation with an anti-CD8 antibody, it significantly inhibited B-cell receptor
      signaling, as evidenced by a suppression of tyrosine phosphorylation and
      intracellular calcium mobilization. This inhibition required the putative SH2 or
      SH3 binding motif in the cytoplasmic region of K15. Biochemical study of CD8-K15
      chimeras showed that the cytoplasmic region of K15 was constitutively tyrosine
      phosphorylated and that the tyrosine residue within the putative SH2 binding
      motif of K15 was a primary site of phosphorylation. These results demonstrate
      that KSHV K15 resembles LMP2A in genomic location, splicing pattern, and protein
      structure and by the presence of functional signal-transducing motifs in the
      cytoplasmic region. Thus, KSHV K15 is likely a distant evolutionary relative of
      EBV LMP2A.

PMID- 10590134
TI  - Role of the cytoplasmic tail of ecotropic moloney murine leukemia virus Env
      protein in fusion pore formation.
AB  - Fusion between cells expressing envelope protein (Env) of Moloney murine leukemia
      virus and target cells were studied by use of video fluorescence microscopy and
      electrical capacitance measurements. When the full-length 632-amino-acid residue
      Env was expressed, fusion did not occur at all for 3T3 cells as target and only
      somewhat for XC6 cells. Expression of Env 616*-a construct of Env with the last
      16 amino acid residues (617 to 632; the R peptide) deleted from its C terminus to
      match the proteolytically cleaved Env produced during viral budding-resulted in
      high levels of fusion. Env 601*, lacking the entire cytoplasmic tail (CT)
      (identified by hydrophobicity), also led to fusion. Truncation of an additional
      six residues (Env 595*) abolished fusion. The kinetics of forming fusion pores
      did not depend on whether cells were first prebound at 4 degrees C and the time
      until fusion measured after the temperature was raised to 37 degrees C or whether
      cells were first brought into contact at 37 degrees C and the time until fusion
      immediately measured. This similarity in kinetics indicates that binding is
      accomplished quickly compared to subsequent steps in fusion. The fusion pores
      formed by Env 601* and Env 616* had the same initial size and enlarged in similar
      manners. Thus, once the R peptide is removed, the CT is not needed for fusion and
      does not affect formed pores. However, residues 595 to 601 are required for
      fusion. It is suggested here that the ectodomain and membrane-spanning domain of
      Env are directly responsible for fusion and that the R peptide affects their
      configurations at some point during the fusion process, thereby indirectly
      controlling fusion.

PMID- 10590135
TI  - Secondary structure analysis of a minimal avian leukosis-sarcoma virus packaging
      signal.
AB  - We previously identified a 160-nucleotide packaging signal, MPsi, from the 5' end
      of the Rous sarcoma virus genome. In this study, we determine the secondary
      structure of MPsi by using phylogenetic analysis with computer modeling and
      heterologous packaging assays of point mutants. The results of the in vivo
      studies are in good agreement with the computer model. Additionally, the
      packaging studies indicate several structures which are important for efficient
      packaging, including a single-stranded bulge containing the initiation codon for
      the short open reading frame, uORF3, as well as adjacent stem structures.
      Finally, we show that the L3 stem-loop at the 3' end of MPsi is dispensable for
      packaging, thus identifying an 82-nucleotide minimal packaging signal, microPsi,
      composed of the O3 stem-loop.

PMID- 10590136
TI  - Brain infection by neuroinvasive but avirulent murine oncornaviruses.
AB  - The chimeric murine oncornavirus FrCas(E) causes a rapidly progressive
      noninflammatory spongiform encephalomyelopathy after neonatal inoculation. The
      virus was constructed by the introduction of pol-env sequences from the wild
      mouse virus CasBrE into the genome of a neuroinvasive but nonneurovirulent strain
      of Friend murine leukemia virus (FMuLV), FB29. Although the brain infection by
      FrCas(E) as well as that by other neurovirulent murine retroviruses has been
      described in detail, little attention has been paid to the neuroinvasive but
      nonneurovirulent viruses. The purpose of the present study was to compare brain
      infection by FrCas(E) with that by FB29 and another nonneurovirulent virus, F43,
      which contains pol-env sequences from FMuLV 57. Both FB29 and F43 infected the
      same spectrum of cell types in the brain as that infected by FrCas(E), including
      endothelial cells, microglia, and populations of neurons which divide
      postnatally. Viral burdens achieved by the two nonneurovirulent viruses in the
      brain were actually higher than that of FrCas(E). The widespread infection of
      microglia by the two nonneurovirulent viruses is notable because it is infection
      of these cells by FrCas(E) which is thought to be a critical determinant of its
      neuropathogenicity. These results indicate that although the sequence of the
      envelope gene determines neurovirulence, this effect appears to operate through a
      mechanism which does not influence either viral tropism or viral burden in the
      brain. Although all three viruses exhibited similar tropism for granule neurons
      in the cerebellar cortex, there was a striking difference in the distribution of
      envelope proteins in those cells in vivo. The FrCas(E) envelope protein
      accumulated in terminal axons, whereas those of FB29 and F43 remained
      predominantly in the cell bodies. These observations suggest that differences in
      the intracellular sorting of these proteins may exist and that these differences
      appear to correlate with neurovirulence.

PMID- 10590137
TI  - The UL25 protein of pseudorabies virus associates with capsids and localizes to
      the nucleus and to microtubules.
AB  - The UL25 gene of pseudorabies virus (PrV) can encode a protein of about 57 kDa
      which is well conserved among herpesviruses. The UL25 protein of herpes simplex
      virus type 1 is a capsid constituent involved in virus penetration and capsid
      maturation. To identify and characterize the UL25 gene product of PrV, polyclonal
      mouse anti-UL25 antibodies were raised to a bacterially expressed fusion protein.
      In immunoblotting and immunoprecipitation assays of PrV-infected cell lysates,
      these anti-UL25 antisera specifically recognized a protein of the expected size
      with late expression kinetics. This 57-kDa product was also present in purified
      virions and was found to be associated with all types of capsids. Synthesis of a
      protein migrating at the same size point was directed from the eukaryotic
      expression plasmid pCG-UL25. To determine the subcellular localization of UL25,
      immunofluorescence studies with anti-UL25 antisera were performed on Nonidet P-40
      extracted COS-7 cells infected with PrV or transfected with pCG-UL25. In PrV
      infected cells, newly synthesized UL25 is directed mainly to distinct nuclear
      compartments, whereas UL25 expressed in the absence of other viral proteins is
      distributed more uniformly in the nucleus and colocalizes also with microtubules.
      To study the fate of UL25 at very early stages of infection, immunofluorescence
      experiments were performed on invading PrV particles in the presence or absence
      of drugs that specifically depolymerize components of the cytoskeleton. We found
      that the incoming nucleocapsids colocalize with microtubules during their
      transport to the nucleus and that UL25 remains associated with nucleocapsids
      during this transport.

PMID- 10590138
TI  - cis expression of the F12 human immunodeficiency virus (HIV) Nef allele
      transforms the highly productive NL4-3 HIV type 1 to a replication-defective
      strain: involvement of both Env gp41 and CD4 intracytoplasmic tails.
AB  - F12 human immunodeficiency virus type 1 (HIV-1) nef is a naturally occurring nef
      mutant cloned from the provirus of a nonproductive, nondefective, and interfering
      HIV-1 variant (F12-HIV). We have already shown that cells stably transfected with
      a vector expressing the F12-HIV nef allele do not downregulate CD4 receptors and,
      more peculiarly, become resistant to the replication of wild type (wt) HIV. In
      order to investigate the mechanism of action of such an HIV inhibition, the F12
      HIV nef gene was expressed in the context of the NL4-3 HIV-1 infectious molecular
      clone by replacing the wt nef gene (NL4-3/chi). Through this experimental
      approach we established the following. First, NL4-3/chi and nef-defective
      (Deltanef) NL4-3 viral particles behave very similarly in terms of viral entry
      and HIV protein production during the first replicative cycle. Second, no viral
      particles were produced from cells infected with NL4-3/chi virions, whatever the
      multiplicity of infection used. The viral inhibition apparently occurs at level
      of viral assembling and/or release. Third, this block could not be relieved by in
      trans expression of wt nef. Finally, NL4-3/chi reverts to a producer HIV strain
      when F12-HIV Nef is deprived of its myristoyl residue. Through a CD4
      downregulation competition assay, we demonstrated that F12-HIV Nef protein
      potently inhibits the CD4 downregulation induced by wt Nef. Moreover, we observed
      a redistribution of CD4 receptors at the cell margin induced by F12-HIV Nef.
      These observations strongly suggest that F12-HIV Nef maintains the ability to
      interact with the intracytoplasmic tail of the CD4 receptor molecule. Remarkably,
      we distinguished the intracytoplasmic tails of Env gp41 and CD4 as, respectively,
      viral and cellular targets of the F12-HIV Nef-induced viral retention. For the
      first time, the inhibition of the viral life cycle by means of in-cis expression
      of a Nef mutant is here reported. Delineation of the F12-HIV Nef mechanism of
      action may offer additional approaches to interference with the propagation of
      HIV infection.

PMID- 10590139
TI  - Structural fingerprinting: subgrouping of comoviruses by structural studies of
      red clover mottle virus to 2.4-A resolution and comparisons with other
      comoviruses.
AB  - Red clover mottle virus (RCMV) is a member of the comoviruses, a group of
      picornavirus-like plant viruses. The X-ray structure of RCMV strain S has been
      determined and refined to 2.4 A. The overall structure of RCMV is similar to that
      of two other comoviruses, Cowpea mosaic virus (CPMV) and Bean pod mottle virus
      (BPMV). The sequence of the coat proteins of RCMV strain O were modeled into the
      capsid structure of strain S without causing any distortion, confirming the close
      resemblance between the two strains. By comparing the RCMV structure with that of
      other comoviruses, a structural fingerprint at the N terminus of the small
      subunit was identified which allowed subgrouping of comoviruses into CPMV-like
      and BPMV-like viruses.

PMID- 10590141
TI  - Human cytomegalovirus infects Caco-2 intestinal epithelial cells basolaterally
      regardless of the differentiation state.
AB  - Human cytomegalovirus (CMV) causes severe disease in immunosuppressed patients
      and notably infects the gastrointestinal tract. To understand the interaction of
      CMV with intestinal epithelial cells, which are highly susceptible to CMV
      infection in vivo, we used the intestinal epithelial cell line Caco-2 and
      demonstrated that CMV enters predominantly through the basolateral surface of
      polarized Caco-2 cells. As shown by expression of all three classes of CMV
      proteins and by visualization of nucleocapsids by transmission electron
      microscopy, both poorly and fully differentiated Caco-2 cells were permissive to
      CMV replication. However, infection failed to produce infectious particles in
      Caco-2 cells, irrespective of the state of differentiation.

PMID- 10590140
TI  - Canine adenovirus vectors: an alternative for adenovirus-mediated gene transfer.
AB  - Preclinical studies have shown that gene transfer following readministration of
      viral vectors is often inefficient due to the presence of neutralizing
      antibodies. Vectors derived from ubiquitous human adenoviruses may have limited
      clinical use because preexisting humoral and cellular immunity is found in 90% of
      the population. Furthermore, risks associated with the use of human adenovirus
      vectors, such as the need to immunosuppress or tolerize patients to a potentially
      debilitating virus, are avoidable if efficient nonhuman adenovirus vectors are
      feasible. Plasmids containing recombinant canine adenovirus (CAV) vectors from
      which the E1 region had been deleted were generated and transfected into a CAV E1
      transcomplementing cell line. Vector stocks, with titers greater than or equal to
      those obtained with human adenovirus vectors, were free of detectable levels of
      replication-competent CAV and had a low particle-to-transduction unit ratio. CAV
      vectors were replication defective in all cell lines tested, transduced human
      derived cells at an efficiency similar to that of a comparable human adenovirus
      type 5 vector, and are amenable to in vivo use. Importantly, 49 of 50 serum
      samples from healthy individuals did not contain detectable levels of
      neutralizing CAV antibodies.

PMID- 10590142
TI  - Avian reticuloendotheliosis virus strain A and spleen necrosis virus do not
      infect human cells.
AB  - Spleen necrosis virus (SNV) and Reticuloendotheliosis virus strain A (REV-A)
      belong to the family of reticuloendotheliosis viruses and are 90% sequence
      related. SNV-derived retroviral vectors produced by the REV-A-based D17.2G
      packaging cell line were shown to infect human cells (H.-M. Koo, A. M. C. Brown,
      Y. Ron, and J. P. Dougherty, J. Virol. 65:4769-4776, 1991), while similar vectors
      produced by another SNV-based packaging cell line, DSH134G, are not infectious in
      human cells (reviewed by R. Dornburg, Gene Ther. 2:301-310, 1995). Here we
      describe a careful reevaluation of the infectivity of vectors produced from the
      most commonly used REV-A- or SNV-based packaging cells obtained from various
      sources with, among them, one batch of D17.2G packaging cells obtained from the
      American Type Culture Collection. None of these packaging cells produced vectors
      able to infect human cells. Thus, contrary to previously published data, we
      conclude that REV-based vectors are not infectious in human cells.

PMID- 10590143
TI  - Small dense nuclear bodies are the site of localization of herpes simplex virus 1
      U(L)3 and U(L)4 proteins and of ICP22 only when the latter protein is present.
AB  - The herpes simplex virus 1 U(L)3 and U(L)4 open reading frames are expressed late
      in infection and are not essential for viral replication in cultured cells in
      vitro. An earlier report showed that the U(L)4 protein colocalizes with the
      products of the alpha22/U(S)1.5 genes in small nuclear dense bodies. Here we
      report that the U(L)3 protein also colocalized in these small nuclear dense
      bodies and the localization of U(L)3 and U(L)4 proteins in these bodies required
      the presence of alpha22/U(S)1.5 genes. In cells infected with a mutant lacking
      intact alpha22/U(S)1.5 genes, U(L)3 was diffused throughout the nucleus even
      though the overall accumulation of the gamma2 U(L)3 protein was decreased. The
      results suggest that ICP22 acts both as a regulator of U(L)3 accumulation and as
      the structural component and anchor of these small dense nuclear bodies.

PMID- 10590144
TI  - env sequences of simian immunodeficiency viruses from chimpanzees in Cameroon are
      strongly related to those of human immunodeficiency virus group N from the same
      geographic area.
AB  - Human immunodeficiency virus type 1 (HIV-1) group N from Cameroon is
      phylogenetically close, in env, to the simian immunodeficiency virus (SIV) cpz
      gab from Gabon and SIVcpz-US of unknown geographic origin. We screened 29 wild
      born Cameroonian chimpanzees and found that three (Cam3, Cam4, and Cam5) were
      positive for HIV-1 by Western blotting. Mitochondrial DNA sequence analysis
      demonstrated that Cam3 and Cam5 belonged to Pan troglodytes troglodytes and that
      Cam4 belonged to P. t. vellerosus. Genetic analyses of the viruses together with
      serological data demonstrated that at least one of the two P. t. troglodytes
      chimpanzees (Cam5) was infected in the wild, and revealed a horizontal
      transmission between Cam3 and Cam4. These data confirm that P. t. troglodytes is
      a natural host for HIV-1-related viruses. Furthermore, they show that SIVcpz can
      be transmitted in captivity, from one chimpanzee subspecies to another. All three
      SIVcpz-cam viruses clustered with HIV-1 N in env. The full Cam3 SIVcpz genome
      sequence showed a very close phylogenetic relationship with SIVcpz-US, a virus
      identified in a P. t. troglodytes chimpanzee captured nearly 40 years earlier.
      Like SIVcpz-US, SIVcpz-cam3 was closely related to HIV-1 N in env, but not in
      pol, supporting the hypothesis that HIV-1 N results from a recombination event.
      SIVcpz from chimpanzees born in the wild in Cameroon are thus strongly related in
      env to HIV-1 N from Cameroon, demonstrating the geographic coincidence of these
      human and simian viruses and providing a further strong argument in favor of the
      origin of HIV-1 being in chimpanzees.

PMID- 10590145
TI  - Incorporation of adeno-associated virus in a calcium phosphate coprecipitate
      improves gene transfer to airway epithelia in vitro and in vivo.
AB  - Adeno-associated virus (AAV) is inefficient at infecting differentiated airway
      epithelia because of a lack of receptors at the apical surface. We hypothesized
      that incorporation of AAV in a calcium phosphate coprecipitate would circumvent
      this barrier. Interestingly, coprecipitation of AAV type 2 improved gene transfer
      to differentiated human airway epithelia in vitro and to the mouse lung in vivo.
      These results suggest that delivery of AAV as a CaP(i) coprecipitate may
      significantly enhance its utility for gene transfer to the airway epithelia in
      vivo.

PMID- 10590146
TI  - A heterologous, high-affinity RNA ligand for human immunodeficiency virus Gag
      protein has RNA packaging activity.
AB  - Retroviral RNA encapsidation depends on the specific binding of Gag proteins to
      packaging (psi) signals in genomic RNA. We investigated whether an in vitro
      selected, high-affinity RNA ligand for the nucleocapsid (NC) portion of the Gag
      protein from human immunodeficiency virus type 1 (HIV-1) could mediate packaging
      into HIV-1 virions. We find that this ligand can functionally substitute for one
      of the Gag-binding elements (termed SL3) in the HIV-1 psi locus to support
      packaging and viral infectivity in cis. By contrast, this ligand, which fails to
      dimerize spontaneously in vitro, is unable to replace a different psi element
      (termed SL1) which is required for both Gag binding and dimerization of the HIV-1
      genome. A single point mutation within the ligand that eliminates high-affinity
      in vitro Gag binding also abolishes its packaging activity at the SL3 position.
      These results demonstrate that specific binding of Gag or NC protein is a
      critical determinant of genomic RNA packaging.

PMID- 10590147
TI  - Plasmid-driven formation of influenza virus-like particles.
AB  - We established a plasmid-based system for generating infectious influenza virus
      like particles entirely from cloned cDNAs. Human embryonic kidney cells (293T)
      were transfected with plasmids encoding the influenza A virus structural proteins
      and with a plasmid encoding an influenza virus-like viral RNA (vRNA) which
      contained an antisense copy of the cDNA for green fluorescence protein (GFP)
      flanked by an RNA polymerase I promoter and terminator. Intracellular
      transcription of the latter construct by RNA polymerase I generated GFP vRNA that
      was packaged into influenza virus-like particles. This system, which produced
      more than 10(4) infectious particles per ml of supernatant, would be useful in
      studies of influenza virus replication and particle formation. It might also
      benefit efforts in vaccine production and in the development of improved gene
      therapy vectors.

PMID- 10590148
TI  - Immune complexes containing human immunodeficiency virus type 1 primary isolates
      bind to lymphoid tissue B lymphocytes and are infectious for T lymphocytes.
AB  - This study investigated the interaction of tonsil B lymphocytes with immune
      complexes containing human immunodeficiency virus (HIV IC) primary isolates and
      the infectivity of the B cell-bound HIV IC. Treatment of virus with a source of
      antibody and complement increased HIV IC binding to B cells by 5.6-fold. Most of
      the HIV IC that bound to B cells were not internalized but remained on the cell
      surface and were gradually released over 72 h. Cell-bound HIV IC were highly
      infectious for T cells while virus released by cultured B cells was only slightly
      infectious. Removal of HIV IC from the B-cell surface by protease treatment
      reduced the infection of T cells to near-background levels, indicating that
      infectious virus remained on the B-cell surface. These studies show that B
      lymphocytes can carry and transfer infectious HIV IC to T cells and thus suggest
      a novel mode of infection of T cells in lymphoid tissue that could be important
      for pathogenesis during HIV infection.

PMID- 10590149
TI  - Measles virus induces functional TRAIL production by human dendritic cells.
AB  - Measles virus infection induces a profound immunosuppression that can lead to
      serious secondary infections. Here we demonstrate that measles virus induces
      tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNA and protein
      expression in human monocyte-derived dendritic cells. Moreover, measles virus
      infected dendritic cells are shown to be cytotoxic via the TRAIL pathway.

PMID- 10590150
TI  - MxA GTPase blocks reporter gene expression of reconstituted Thogoto virus
      ribonucleoprotein complexes.
AB  - Human MxA protein accumulates in the cytoplasm of interferon-treated cells and
      inhibits the multiplication of several RNA viruses, including Thogoto virus
      (THOV), a tick-borne orthomyxovirus that transcribes and replicates its genome in
      the cell nucleus. The antiviral mechanism of MxA was investigated by using two
      alternative minireplicon systems in which recombinant viral ribonucleoprotein
      complexes (vRNPs) of THOV were reconstituted from cloned cDNAs. A chloramphenicol
      acetyltransferase reporter minigenome RNA was expressed either by T7 RNA
      polymerase in the cytoplasm of transfected cells or, alternatively, by RNA
      polymerase I in the nucleus. The inhibitory effect of MxA was studied in both
      cellular compartments by coexpressing wild-type MxA or TMxA, an artificial
      nuclear form of MxA. Our results indicate that both MxA proteins recognize the
      assembled vRNP rather than the newly synthesized unassembled components. The
      present findings are consistent with previous data which indicated that
      cytoplasmic MxA prevents transport of vRNPs into the nucleus, whereas nuclear MxA
      directly inhibits the viral polymerase activity in the nucleus.

PMID- 10590151
TI  - Alpha-glucosidase inhibitors reduce dengue virus production by affecting the
      initial steps of virion morphogenesis in the endoplasmic reticulum.
AB  - We report that endoplasmic reticulum alpha-glucosidase inhibitors have antiviral
      effects on dengue (DEN) virus. We found that glucosidase inhibition strongly
      affects productive folding pathways of the envelope glycoproteins prM (the
      intracellular glycosylated precursor of M [membrane protein]) and E (envelope
      protein): the proper folding of prM bearing unprocessed N-linked oligosaccharide
      is inefficient, and this causes delayed formation of prME heterodimer. The
      complexes formed between incompletely folded prM and E appear to be unstable,
      leading to a nonproductive pathway. Inhibition of alpha-glucosidase-mediated N
      linked oligosaccharide trimming may thus prevent the assembly of DEN virus by
      affecting the early stages of envelope glycoprotein processing.

PMID- 10590152
TI  - The S2 gene of equine infectious anemia virus is a highly conserved determinant
      of viral replication and virulence properties in experimentally infected ponies.
AB  - Equine infectious anemia virus (EIAV) is genetically one of the simplest
      lentiviruses in that the viral genome encodes only three accessory genes, tat,
      rev, and S2. Although serological analyses demonstrate the expression of the S2
      protein in persistently infected horses, the role of this viral gene remains
      undefined. We recently reported that the S2 gene is not essential for EIAV
      replication in primary equine macrophages, as EIAV mutants lacking the S2 gene
      replicate to levels similar to those of the parental virus (F. Li, B. A. Puffer,
      and R. C. Montelaro, J. Virol. 72:8344-8348, 1998). We now describe in vivo
      studies that examine the evolution and role of the S2 gene in ponies
      experimentally infected with EIAV. The results of these studies reveal for the
      first time that the S2 gene is highly conserved during persistent infection and
      that deletion of the S2 gene reduces viral virulence and virus replication levels
      compared to those of the parental virus containing a functional S2 gene. These
      data indicate that the EIAV S2 gene is in fact an important determinant of viral
      replication and pathogenic properties in vivo, despite the evident lack of S2
      influence on viral replication levels in vitro. Thus, these observations suggest
      in vivo functions of EIAV S2 that are not adequately reflected in simple
      infections of cultured cells, including natural target macrophages.

PMID- 10590153
TI  - Identification of a bovine coronavirus packaging signal.
AB  - A region of the bovine coronavirus (BCV) genome that functions as a packaging
      signal has been cloned. The 291-nucleotide clone shares 72% homology with the
      region of mouse hepatitis coronavirus (MHV) gene 1b that contains the packaging
      signal. RNA transcripts were packaged into both BCV and MHV virions when the
      cloned region was appended to a noncoronavirus RNA. This is the first
      identification of a BCV packaging signal. The data demonstrate that the BCV
      genome contains a sequence that is conserved at both the sequence and functional
      levels, thus broadening our insight into coronavirus packaging.

PMID- 10590155
TI  - Sucrose synthase and the fruit of its labor.

PMID- 10590154
TI  - Species specificity of macaque rhadinovirus glycoprotein B sequences.
AB  - All members of the Herpesviridae family contain sequences for a highly conserved
      glycoprotein B (gB) gene. We investigated the phylogenetic relationships of gB
      sequences from eight independent rhadinovirus isolates obtained from three
      species: rhesus (Macaca mulatta), cynomologus (Macaca fasicularis), and pig
      tailed (Macaca nemestrina) macaques. Samples were derived from monkeys housed at
      four separate facilities. Analysis of these eight independent gB sequences
      revealed five regions of heterogeneity within the 823- to 829-amino-acid
      polypeptides: residues 1 to 65, 120 to 185, 255 to 300, 352 to 393, and 412 to
      457. The remaining regions of gB were highly conserved among the different
      macaque isolates. Overall divergence among these gene sequences ranged from 0.1
      to 7.2% at the amino acid level. Phylogenetic trees constructed with our macaque
      rhadinovirus gB sequences and those derived from additional subfamilies or genera
      (alpha, beta, gamma-1, and gamma-2) revealed that the macaque gB sequences
      branched with other gamma-2 herpesvirus gB sequences and that within the gamma-2
      genera, the macaque gB sequences clustered as a distinct branch. The eight
      macaque rhadinovirus gB sequences were all approximately equidistant from Kaposi
      sarcoma-associated herpesvirus (KSHV) gB sequences and had a shorter evolutionary
      distance to KSHV gB sequences than to any other herpesvirus, including the gamma
      2 herpesvirus saimiri (HVS) of New World squirrel monkeys. The macaque gB
      sequences did not cluster according to the facility of origin, but did cluster
      according to the species of origin, displaying less intraspecies divergence (0.1
      to 2.9%) than interspecies divergence (3.3 to 7.2%). These results demonstrate a
      close relatedness of rhadinovirus isolates from different macaque species.

PMID- 10590156
TI  - Analysis of flanking sequences from dissociation insertion lines: a database for
      reverse genetics in Arabidopsis.
AB  - We have generated Dissociation (Ds) element insertions throughout the Arabidopsis
      genome as a means of random mutagenesis. Here, we present the molecular analysis
      of genomic sequences that flank the Ds insertions of 931 independent transposant
      lines. Flanking sequences from 511 lines proved to be identical or homologous to
      DNA or protein sequences in public databases, and disruptions within known or
      putative genes were indicated for 354 lines. Because a significant portion (45%)
      of the insertions occurred within sequences defined by GenBank BAC and P1 clones,
      we were able to assess the distribution of Ds insertions throughout the genome.
      We discovered a significant preference for Ds transposition to the regions
      adjacent to nucleolus organizer regions on chromosomes 2 and 4. Otherwise, the
      mapped insertions appeared to be evenly dispersed throughout the genome. For any
      given gene, insertions preferentially occurred at the 5' end, although disruption
      was clearly possible at any intragenic position. The insertion sites of >500
      lines that could be characterized by reference to public databases are presented
      in a tabular format at http://www.plantcell. org/cgi/content/full/11/12/2263/DC1.
      This database should be of value to researchers using reverse genetics approaches
      to determine gene function.

PMID- 10590157
TI  - Ten years of enhancer detection: lessons from the fly.

PMID- 10590158
TI  - T-DNA as an insertional mutagen in Arabidopsis.

PMID- 10590159
TI  - RNA-DNA interactions and DNA methylation in post-transcriptional gene silencing.
AB  - Post-transcriptional gene silencing (PTGS) is a homology-dependent process that
      reduces cytoplasmic RNA levels. In several experimental systems, there is also an
      association of PTGS with methylation of DNA. To investigate this association, we
      used plants carrying a transgene encoding the green fluorescent protein (GFP).
      Gene silencing was induced using potato virus X RNA vectors carrying parts of the
      coding sequence or the promoter of the GFP transgene. In each instance, homology
      based, RNA-directed methylation was associated with silencing. When the GFP
      transcribed region was targeted, PTGS affected both transgene and viral RNA
      levels. When methylation was targeted to a promoter region, transgene RNA levels
      were reduced; however, viral RNA levels were unaffected. For comparison, we
      induced PTGS of the gene encoding the endogenous ribulose-1,5-bisphosphate
      carboxylase oxygenase (Rubisco) small subunit (rbcS) by inoculation with potato
      virus X-rbcS. In this example, no methylation of the rbcS DNA was associated with
      the reduction in rbcS transcript levels, and viral RNA levels were unaffected.
      Finally, we investigated DNA methylation by using GFP-transformed plants in which
      PTGS was induced by localized introduction of a T-DNA carrying GFP sequences. In
      these plants, there was methylation of a GFP transgene associated with systemic
      spread of a gene-silencing signal from the infiltrated part of the plant. This
      transgene methylation was not affected when systemic PTGS was blocked by
      suppressors of silencing encoded by potato virus Y and cucumber mosaic virus.
      Combined, these data support an epigenetic model of PTGS in which transgene
      methylation is associated with an RNA-DNA interaction that ensures that PTGS is
      maintained.

PMID- 10590160
TI  - Meristem-localized inducible expression of a UDP-glycosyltransferase gene is
      essential for growth and development in pea and alfalfa.
AB  - PsUGT1, which encodes a microsomal UDP-glucuronosyltransferase, was cloned from
      root tips of Pisum sativum. PsUGT1 expression is correlated with mitosis and
      strongly induced in dividing cells. A region at the C terminus of the encoded
      protein is closely related to the UDP-glucuronic acid binding site consensus
      sequence, and the protein encoded by PsUGT1 catalyzes conjugation of UDP
      glucuronic acid to an unknown compound. Overexpression of PsUGT1 sense mRNA has
      no detectable effect on transgenic pea hairy root cultures or regenerated
      alfalfa. However, inhibiting PsUGT1 expression by the constitutive expression of
      antisense mRNA (under the control of the cauliflower mosaic virus 35S promoter)
      markedly retards growth and development of transgenic alfalfa. Cell structure and
      organization in the antisense plants are similar to those of controls, but plant
      growth is reduced and development is delayed. This inhibition in growth is
      correlated with a twofold delay in the time required for completion of a cell
      cycle and with a >99% inhibition of border cell production. Inhibition of PsUGT1
      expression by meristem-localized inducible expression of PsUGT1 antisense mRNA
      (under the control of its own promoter) is lethal both in pea hairy roots and in
      transgenic alfalfa plants. These results indicate that PsUGT1 expression is
      required for normal plant growth and development, and they are consistent with
      the hypothesis that this UDP-glycosyltransferase regulates activity of a
      ligand(s) needed for cell division.

PMID- 10590161
TI  - Linker histones play a role in male meiosis and the development of pollen grains
      in tobacco.
AB  - To examine the function of linker histone variants, we produced transgenic
      tobacco plants in which major somatic histone variants H1A and H1B were present
      at approximately 25% of their usual amounts in tobacco chromatin. The decrease in
      these major variants was accompanied by a compensatory increase in the four minor
      variants, namely, H1C to H1F. These minor variants are smaller and less highly
      charged than the major variants. This change offered a unique opportunity to
      examine the consequences to a plant of major remodeling of its chromatin set of
      linker histones. Plants with markedly altered proportions of H1 variants retained
      normal nucleosome spacing, but their chromosomes were less tightly packed than
      those of control plants. The transgenic plants grew normally but showed
      characteristic aberrations in flower development and were almost completely male
      sterile. These features correlated with changes in the temporal but not the
      spatial pattern of expression of developmental genes that could be linked to the
      abnormal flower phenotypes. Preceding these changes in flower morphology were
      strong aberrations in male gametogenesis. The earliest symptoms may have resulted
      from disturbances in correct pairing or segregation of homologous chromosomes
      during meiosis. No aberrations were observed during mitosis. We conclude that in
      plants, the physiological stoichiometry and distribution of linker histone
      variants are crucial for directing male meiosis and the subsequent development of
      functional pollen grains.

PMID- 10590162
TI  - Organized F-actin is essential for normal trichome morphogenesis in Arabidopsis.
AB  - Actin microfilaments form a three-dimensional cytoskeletal network throughout the
      cell and constitute an essential throughway for organelle and vesicle transport.
      Development of Arabidopsis trichomes, unicellular structures derived from the
      epidermis, is being used as a genetic system in which to study actin-dependent
      growth in plant cells. The present study indicates that filamentous actin (F
      actin) plays an important role during Arabidopsis trichome morphogenesis. For
      example, immunolocalization of actin filaments during trichome morphogenesis
      identified rearrangements of the cytoskeletal structure during the development of
      the mature cell. Moreover, pharmacological experiments indicate that there are
      distinct requirements for actin- and microtubule-dependent function during
      trichome morphogenesis. The F-actin-disrupting drug cytochalasin D does not
      affect the establishment of polarity during trichome development; however,
      maintenance and coordination of the normal pattern of cell growth are very
      sensitive to this drug. In contrast, oryzalin, an agent that depolymerizes
      microtubules, severely inhibits cell polarization. Furthermore, cytochalasin D
      treatment phenocopies a known class of mutations that cause distorted trichome
      morphology. Results of an analysis of cell shape and microfilament structure in
      wild-type, mutant, and drug-treated trichomes are consistent with a role for
      actin in the maintenance and coordination of an established growth pattern.

PMID- 10590163
TI  - Latrunculin B has different effects on pollen germination and tube growth.
AB  - The actin cytoskeleton is absolutely required for pollen germination and tube
      growth, but little is known about the regulation of actin polymer concentrations
      or dynamics in pollen. Here, we report that latrunculin B (LATB), a potent
      inhibitor of actin polymerization, had effects on pollen that were distinct from
      those of cytochalasin D. The equilibrium dissociation constant measured for LATB
      binding to maize pollen actin was determined to be 74 nM. This high affinity for
      pollen actin suggested that treatment of pollen with LATB would have marked
      effects on actin function. Indeed, LATB inhibited maize pollen germination half
      maximally at 50 nM, yet it blocked pollen tube growth at one-tenth of that
      concentration. Low concentrations of LATB also caused partial disruption of the
      actin cytoskeleton in germinated maize pollen, as visualized by light microscopy
      and fluorescent-phalloidin staining. The amounts of filamentous actin (F-actin)
      in pollen were quantified by measuring phalloidin binding sites, a sensitive
      assay that had not been used previously for plant cells. The amount of F-actin in
      maize pollen increased slightly upon germination, whereas the total actin protein
      level did not change. LATB treatment caused a dose-dependent depolymerization of
      F-actin in populations of maize pollen grains and tubes. Moreover, the same
      concentrations of LATB caused similar depolymerization in pollen grains before
      germination and in pollen tubes. These data indicate that the increased
      sensitivity of pollen tube growth to LATB was not due to general destabilization
      of the actin cytoskeleton or to decreases in F-actin amounts after germination.
      We postulate that germination is less sensitive to LATB than tube extension
      because the presence of a small population of LATB-sensitive actin filaments is
      critical for maintenance of tip growth but not for germination of pollen, or
      because germination is less sensitive to partial depolymerization of the actin
      cytoskeleton.

PMID- 10590164
TI  - Assembly of the D1 precursor in monomeric photosystem II reaction center
      precomplexes precedes chlorophyll a-triggered accumulation of reaction center II
      in barley etioplasts.
AB  - Assembly of plastid-encoded chlorophyll binding proteins of photosystem II (PSII)
      was studied in etiolated barley seedlings and isolated etioplasts and either the
      absence or presence of de novo chlorophyll synthesis. De novo assembly of
      reaction center complexes in etioplasts was characterized by immunological
      analysis of protein complexes solubilized from inner etioplast membranes and
      separated in sucrose density gradients. Previously characterized membrane protein
      complexes from chloroplasts were utilized as molecular mass standards for sucrose
      density gradient separation analysis. In etiolated seedlings, induction of
      chlorophyll a synthesis resulted in the accumulation of D1 in a dimeric PSII
      reaction center (RCII) complex. In isolated etioplasts, de novo chlorophyll a
      synthesis directed accumulation of D1 precursor in a monomeric RCII precomplex
      that also included D2 and cytochrome b(559). Chlorophyll a synthesis that was
      chemically prolonged in darkness neither increased the yield of RCII monomers nor
      directed assembly of RCII dimers in etioplasts. We therefore conclude that in
      etioplasts, assembly of the D1 precursor in monomeric RCII precomplexes precedes
      chlorophyll a-triggered accumulation of reaction center monomers.

PMID- 10590165
TI  - Phosphorylation of Thr-948 at the C terminus of the plasma membrane H(+)-ATPase
      creates a binding site for the regulatory 14-3-3 protein.
AB  - The plant plasma membrane H(+)-ATPase is activated by the binding of 14-3-3
      protein to the C-terminal region of the enzyme, thus forming an H(+)-ATPase-14-3
      3 complex that can be stabilized by the fungal toxin fusicoccin. A novel 14-3-3
      binding motif, QQXYpT(948)V, at the C terminus of the H(+)-ATPase is identified
      and characterized, and the protein kinase activity in the plasma membrane
      fraction that phosphorylates this threonine residue in the H(+)-ATPase is
      identified. A synthetic peptide that corresponds to the C-terminal 16 amino acids
      of the H(+)-ATPase and that is phosphorylated on Thr-948 prevents the in vitro
      activation of the H(+)-ATPase that is obtained in the presence of recombinant 14
      3-3 and fusicoccin. Furthermore, binding of 14-3-3 to the H(+)-ATPase in the
      absence of fusicoccin is absolutely dependent on the phosphorylation of Thr-948,
      whereas binding of 14-3-3 in the presence of fusicoccin occurs independently of
      phosphorylation but still involves the C-terminal motif YTV. Finally, by
      complementing yeast that lacks its endogenous H(+)-ATPase with wild-type and
      mutant forms of the Nicotiana plumbaginifolia H(+)-ATPase isoform PMA2, we
      provide physiological evidence for the importance of the phosphothreonine motif
      in 14-3-3 binding and, hence, in the activation of the H(+)-ATPase in vivo.
      Indeed, replacing Thr-948 in the plant H(+)-ATPase with alanine is lethal because
      this mutant fails to functionally replace the yeast H(+)-ATPase. Considering the
      importance of the motif QQXYpTV for 14-3-3 binding and yeast growth, this motif
      should be of vital importance for regulating H(+)-ATPase activity in the plant
      and thus for plant growth.

PMID- 10590166
TI  - Novel protein kinases associated with calcineurin B-like calcium sensors in
      Arabidopsis.
AB  - Members of the Arabidopsis calcineurin B-like Ca(2)+ binding protein (AtCBL)
      family are differentially regulated by stress conditions. One AtCBL plays a role
      in salt stress; another is implicated in response to other stress signals,
      including drought, cold, and wounding. In this study, we identified a group of
      novel protein kinases specifically associated with AtCBL-type Ca(2)+ sensors. In
      addition to a typical protein kinase domain, they all contain a unique C-terminal
      region that is both required and sufficient for interaction with the AtCBL-type
      but not calmodulin-type Ca(2)+ binding proteins from plants. Interactions between
      the kinases and AtCBLs require micromolar concentrations of Ca(2)+, suggesting
      that increases in cellular Ca(2)+ concentrations may trigger the formation of
      AtCBL-kinase complexes in vivo. Unlike most serine/threonine kinases, the AtCBL
      interacting kinase efficiently uses Mn(2)+ to Mg(2)+ as a cofactor and may
      function as a Mn(2)+ binding protein in the cell. These findings link a new type
      of Ca(2)+ sensors to a group of novel protein kinases, providing the molecular
      basis for a unique Ca(2)+ signaling machinery in plant cells.

PMID- 10590167
TI  - Antisense inhibition of tomato fruit sucrose synthase decreases fruit setting and
      the sucrose unloading capacity of young fruit.
AB  - The role of sucrose synthase (SuSy) in tomato fruit was studied in transgenic
      tomato (Lycopersicon esculentum) plants expressing an antisense fragment of fruit
      specific SuSy RNA (TOMSSF) under the control of the cauliflower mosaic virus 35S
      promoter. Constitutive expression of the antisense RNA markedly inhibited SuSy
      activity in flowers and fruit pericarp tissues. However, inhibition was only
      slight in the endosperm and was undetectable in the embryo, shoot, petiole, and
      leaf tissues. The activity of sucrose phosphate synthase decreased in parallel
      with that of SuSy, but acid invertase activity did not increase in response to
      the reduced SuSy activity. The only effect on the carbohydrate content of young
      fruit was a slight reduction in starch accumulation. The in vitro sucrose import
      capacity of fruits was not reduced by SuSy inhibition at 23 days after anthesis,
      and the rate of starch synthesized from the imported sucrose was not lessened
      even when SuSy activity was decreased by 98%. However, the sucrose unloading
      capacity of 7-day-old fruit was substantially decreased in lines with low SuSy
      activity. In addition, the SuSy antisense fruit from the first week of flowering
      had a slower growth rate. A reduced fruit set, leading to markedly less fruit per
      plant at maturity, was observed for the plants with the least SuSy activity.
      These results suggest that SuSy participates in the control of sucrose import
      capacity of young tomato fruit, which is a determinant for fruit set and
      development.

PMID- 10590169
TI  - Prolactin opens the sensitive period for androgen regulation of a larynx-specific
      myosin heavy chain gene.
AB  - The larynx of Xenopus laevis is a sexually differentiated vocal organ in which
      male muscle is entirely fast twitch and expresses high levels of a fast twitch
      myosin heavy chain gene, LM. Female muscle, however, is mostly slow twitch and
      expresses little LM. Androgen is unable to induce expression of LM until after
      metamorphosis is complete. The expression of LM during metamorphic and early
      postmetamorphic development parallels secretion and expression of the pituitary
      hormone prolactin. Here, we show that exposure to prolactin is necessary to allow
      androgen-induced LM expression in postmetamorphic froglets. In prolactin-deprived
      animals, androgen-induced changes in the contractile properties of laryngeal
      muscle are blocked, which prevents the rapid rates of muscle contraction required
      for males to produce courtship songs. Thus, prolactin opens the sensitive period
      for androgen-induced LM expression in the larynx and controls the ability of male
      sex hormones to masculinize the vocal system both at the level of gene expression
      and vocal organ physiology.

PMID- 10590168
TI  - Arabidopsis PAD3, a gene required for camalexin biosynthesis, encodes a putative
      cytochrome P450 monooxygenase.
AB  - Phytoalexins are low molecular weight antimicrobial compounds that are
      synthesized in response to pathogen attack. The phytoalexin camalexin, an indole
      derivative, is produced by Arabidopsis in response to infection with the
      bacterial pathogen Pseudomonas syringae. The phytoalexin deficient 3 (pad3)
      mutation, which causes a defect in camalexin production, has no effect on
      resistance to P. syringae but compromises resistance to the fungal pathogen
      Alternaria brassicicola. We have now isolated PAD3 by map-based cloning. The
      predicted PAD3 protein appears to be a cytochrome P450 monooxygenase, similar to
      those from maize that catalyze synthesis of the indole-derived secondary
      metabolite 2,4-dihydroxy-1, 4-benzoxazin-3-one. The expression of PAD3 is tightly
      correlated with camalexin synthesis and is regulated by PAD4 and PAD1. On the
      basis of these findings, we conclude that PAD3 almost certainly encodes an enzyme
      required for camalexin biosynthesis. Moreover, these results strongly support the
      idea that camalexin does not play a major role in plant resistance to P. syringae
      infection, although it is involved in resistance to a fungal pathogen.

PMID- 10590170
TI  - Primitive, crustacean-like state of blood-brain barrier in the eye of the
      apterygote insect Petrobius (Archaeognatha) determined from uptake of fluorescent
      tracers.
AB  - Compound eyes of insects in 16 orders were tested for the presence of a blood
      retina barrier (BRB) by injecting the hemolymph with Procion yellow, which was
      excluded from the eye in all Neoptera but not in two apterygotes. A primitive
      apterygote (Petrobius, Machilidae) was investigated further. Epifluorescence
      observations with small dyes Lucifer yellow (LY) and sulforhodamine 101 (SR)
      confirmed uptake by the eye within 3 min of injection. LY and SR both penetrated
      the eye, particularly the cornea, examined in sections. Uptake was quantified by
      microfluorometry, yielding entry half-times (t(1/2)) of 1-1.4 min, fitting
      predictions for a model where tracer uptake is limited by passive diffusion. A
      much larger fluorescent dextran entered at a similar rate (t(1/2) = 1.70 +/- 0.77
      min; n = 22), too fast to be diffusion-limited, pointing to an active process,
      probably flushing of hemolymph through the retina. This is not an artifact
      associated with tracer injection and may be the natural result of circulatory
      pressures. Microfluorometry gave a first estimate of hemolymph volume (2.9% of
      body weight), of hemolymph mixing time (t(0.95) = 77 min); the eyes' receptive
      fields were also determined. All results point to a primitive crustacean-like
      condition in Petrobius, with open access of hemolymph to the eye and no BRB. An
      evolutionary hypothesis is suggested to explain how a primitive central nervous
      system barrier later extended to cut off the eye in Neoptera, in the face of
      access problems for respiratory gases and metabolites.

PMID- 10590171
TI  - Peripheral specification of Ia synaptic input to motoneurons innervating foreign
      target muscles.
AB  - Muscle sensory neurons, called Ia afferents, make monosynaptic connections with
      functionally related sets of motoneurons in the spinal cord. Previous work has
      suggested that peripheral target muscles play a major role in determining the
      central connections of Ia afferents with motoneurons. Here, we ask whether
      motoneurons can also be influenced by their target muscles in terms of the
      monosynaptic input they receive from Ia afferents, by transplanting thoracic
      motoneurons into the lumbosacral spinal cord so that they innervate foreign
      muscles. Three or four segments of thoracic neural tube from stage 14-15 chicken
      embryos were transplanted to the lumbosacral region of stage 16-17 embryos, and
      electrophysiological recordings were made from transplanted motoneurons after the
      embryos had reached stage 38-40. Transplanted thoracic motoneurons innervated
      limb muscles and received monosynaptic inputs from Ia afferents. These
      connections were not random: Most of the connections were formed between Ia
      afferents and motoneurons projecting to the same muscle (homonymous connections).
      Few aberrant connections were found although the anatomical distribution of
      afferents in the transplant indicated that they had ample opportunity to contact
      inappropriate motoneurons. We conclude that although peripheral target cues are
      not sufficient to respecify an already committed motoneuron (turn a thoracic
      motoneuron into a lumbosacral motoneuron), they do provide sufficient information
      for Ia afferent input to be functionally correct.

PMID- 10590172
TI  - Cloning and analysis of small cytoplasmic leucine-rich repeat protein (SCLP), a
      novel, phylogenetically-conserved protein that is dramatically up-regulated
      during the programmed death of moth skeletal muscle.
AB  - We used the abdominal intersegmental muscles (ISMs) of the moth Manduca sexta as
      a source of transcripts that are dramatically up-regulated during programmed cell
      death. One of these transcripts, Small Cytoplasmic Leucine-Rich Repeat Protein
      (SCLP), encodes a protein of approximately 24 kD that contains four perfect and
      two imperfect leucine-rich repeat (LRR) motifs. DNA sequence database analysis
      suggests that SCLP is a phylogenetically-conserved gene of unknown function. Both
      Northern and Western blots demonstrated that SCLP is expressed in the ISMs at all
      stages examined, but increases greater than 10-fold when the cells become
      committed to die. This increase in expression is regulated by the same change in
      the circulating ecdysteroid titer that controls death. Low levels of SCLP
      expression are also seen in flight muscle and fat body, but not in ovary, male
      sexual accessory gland, or Malpighian tubules. Immunohistochemical analysis
      demonstrates that SCLP is a cytoplasmic protein. Western blot analysis of
      proteins from the fly Drosophila suggests that an SCLP-related protein is
      expressed at the larval and pupal stages, but not in embryos or adults. Targeted
      expression of moth SCLP to a variety of different tissues in Drosophila using the
      Gal4/UAS P element system failed to generate an overt phenotype. These data are
      interpreted as suggesting that whereas SCLP presumably plays an important role in
      programmed cell death of muscle, perhaps by acting as an adaptor protein, its
      expression is insufficient to initiate death by itself.

PMID- 10590173
TI  - Lysophosphatidic acid-induced Ca(2+) mobilization in the neural retina of chick
      embryo.
AB  - Lysophosphatidic acid (LPA) plays various roles in the regulation of cell growth
      as a lipid mediator. We studied the effect of LPA on intracellular Ca(2+)
      concentration ([Ca2+]i) with Fura-2 in the neural retina of chick embryo during
      neurogenesis. Bath application of LPA (1-100 microM) to the embryonic day 3 (E3)
      chick retina caused an increase in [Ca2+](i) in a dose-dependent manner, with an
      EC(50) value of 9.2 microM. The Ca(2+) rise was also evoked in a Ca(2+)-free
      medium, suggesting that release of Ca(2+) from intracellular Ca(2+) stores
      (Ca(2+) mobilization) was induced by LPA. U-73122, a blocker of phospholipase C
      (PLC), inhibited the Ca(2+) rise to LPA. Pertussis toxin partially inhibited the
      Ca(2+) rise to LPA, indicating that G(i)/G(o) protein was at least partially
      involved in the LPA response. The developmental profile of the LPA response was
      studied from E3 to E13. The Ca(2+) rise to LPA declined drastically from E3 to
      E7, in parallel with decrease in mitotic activity of retinal progenitor cells.
      The signal transduction pathway and developmental profile of the Ca(2+) response
      to LPA were the same as those of the Ca(2+) response to adenosine triphosphate
      (ATP), which enhances the proliferation of retinal progenitor cells. The
      coapplication of LPA with ATP resulted in enhancement of Ca(2+) rise in the E3
      chick retina. Our results show that LPA induces Ca(2+) mobilization in the
      embryonic chick retina during neurogenesis.

PMID- 10590174
TI  - Neural androgen receptor regulation: effects of androgen and antiandrogen.
AB  - Androgens exert profound effects on the organization and function of the central
      nervous system. These effects are mediated by the androgen receptor (AR), a
      ligand-dependent transcription factor. The mechanisms of AR regulation in neural
      tissue, however, remain to be fully elucidated. Characterizing this process can
      provide important information regarding receptor function and AR gene regulation
      in the brain. Previously, it was shown that testosterone (T) up-regulated neural
      AR in a dose-dependent manner in both male and female mice. In the present study,
      whether AR was differentially regulated by the natural agonists T and
      dihydrotestosterone (DHT) or the nonsteroidal antagonist flutamide (FLU) was
      assessed. Males were gonadectomized and AR levels were allowed to decline to
      baseline 3 days after surgery. Changes in AR protein content produced by the
      various treatments were measured by semiquantitative Western blot of limbic
      system extracts. Treatment with T or DHT significantly augmented AR 3 and 7 h
      after hormone administration, but only DHT sustained this increase for 21 h. This
      difference also was observed when males were given T plus finasteride (FIN, a
      5alpha reductase inhibitor). The findings demonstrate that the two endogenous
      ligands have differential time course effects on neural AR. The antiandrogen FLU
      failed to up-regulate AR at doses up to 100 times higher than T or DHT. When
      administered concomitantly with T or DHT, it effectively inhibited the
      augmentation of AR normally seen 3 h after androgen treatment. While
      immunohistochemical studies showed that FLU was able to promote nuclear
      translocation of AR, Western analysis revealed that FLU, in contrast to T and
      DHT, failed to maintain the integrity of AR. The results demonstrate that (a) the
      endogenous androgens T and DHT regulate AR differently, suggesting a potential
      cellular mechanism that may contribute to the difference in neural target gene
      sensitivity to these androgens; (b) up-regulation of AR occurs only in the
      presence of agonists; (c) the mechanism of action of FLU in the brain involves
      inhibition of AR protein up-regulation normally seen in response to androgen; and
      (d) FLU promotes AR nuclear translocation but not augmentation of cellular AR
      populations. These findings demonstrate that in vivo AR regulation in the brain
      basically parallels mechanisms proposed from results obtained with transfected
      cells and cell lines.

PMID- 10590175
TI  - Bilaterally symmetrical respiratory activity during lateralized birdsong.
AB  - We investigated whether activity of expiratory muscles reflects lateralized
      activity of the vocal organ during production of birdsong. Respiration and
      syringeal motor activity were assessed in brown thrashers by monitoring bilateral
      airflow and subsyringeal air sac pressure, together with the electromyographic
      activity of expiratory abdominal muscles and vocal output. Activity of expiratory
      muscles was always present on both sides, regardless of whether song was produced
      bilaterally or on only one side of the syrinx. The average amplitude of
      expiratory EMG of one side does not change significantly, even if that side is
      silent during phonation. The temporal pattern of the electromyogram (EMG) was
      similar on both sides. Bilateral bursts of EMG activity on both sides accompanied
      changes in the rate of syringeal airflow, even when these flow fluctuations were
      generated only by one side of the syrinx. Motor commands to the respiratory
      muscles therefore appear to be bilaterally distributed, in contrast to the
      lateralized motor control of the syrinx.

PMID- 10590176
TI  - Notch2 expression negatively correlates with glial differentiation in the
      postnatal mouse brain.
AB  - Notch family molecules are thought to be negative regulators of neuronal
      differentiation in early brain development. After expression in the embryonic
      period, Notch2 continues to be expressed postnatally in the specific regions in
      the rodent brain. Here, we examined Notch2 expression in the postnatal mouse
      brain using lacZ knockin animals at the Notch2 locus. Notch2 expression was
      observed in the developing cerebellum and hippocampus, characteristic regions
      where neurogenesis persists after birth. Double staining of sections revealed
      that Notch2 was expressed by Bergmann glia in the cerebellum, radial glia in the
      hippocampus, and some astrocytes in both regions. Notch2 expression by glial
      cells was clearly confirmed in dissociated cell cultures. Interestingly,
      neocortical glia, many of which did not express Notch2 in vivo, did express
      Notch2 in a dissociated culture condition. The triple staining of dissociated
      cell cultures revealed that stronger Notch2 expression correlated with the
      immature type of glial gene expressions: stronger vimentin and weaker glial
      fibrillary acidic protein expressions. In addition, Notch2 expression correlated
      with the incorporation of bromodeoxyuridine both in vivo and in vitro. Thus,
      these findings demonstrate that Notch2 is expressed not only by neuronal cells in
      the embryonic brain, but also by glial cells in the postnatal brain, and that its
      expression negatively correlates with glial differentiation, proposing its novel
      function as a negative regulator of glial differentiation in mammalian brain
      development.

PMID- 10590177
TI  - Insulin-like growth factor-I prevents caspase-mediated apoptosis in Schwann
      cells.
AB  - Both neurons and glia succumb to programmed cell death (PCD) when deprived of
      growth factors at critical periods in development or following injury. Insulin
      like growth factor-I (IGF-I) prevents apoptosis in neurons in vitro. To
      investigate whether IGF-I can protect Schwann cells (SC) from apoptosis, SC were
      harvested from postnatal day 3 rats and maintained in serum-containing media
      until confluency. When cells were switched to serum-free defined media (DM) for
      12-72 h, they underwent PCD. Addition of insulin or IGF-I prevented apoptosis.
      Bisbenzamide staining revealed nuclear condensation and formation of apoptotic
      bodies in SC grown in DM alone, but SC grown in DM plus IGF-I had normal nuclear
      morphology. The phosphatidylinositol 3-kinase (PI 3-K) inhibitor LY294002 blocked
      IGF-I-mediated protection. Caspase-3 activity was rapidly activated upon serum
      withdrawal in SC, and the caspase inhibitor BAF blocked apoptosis. These results
      suggest that IGF-I rescues SC from apoptosis via PI 3-K signaling which is
      upstream from caspase activation.

PMID- 10590178
TI  - Role of caspases in ionizing radiation-induced apoptosis in the developing
      cerebellum.
AB  - Caspase activation and dependence on caspases has been observed in different
      paradigms of apoptotic cell death in vivo and in vitro. The present study
      examines the role of caspases in ionizing radiation-induced apoptosis in the
      developing cerebellum of rats subjected to a single dose (2-Gy gamma rays) of
      whole-body irradiation at postnatal day 3. Radiation-induced apoptosis in the
      external granule cell layer, as defined by the presence of cells by extremely
      condensed, often fragmented nucleus, which were stained with the method of in
      situ end-labeling of nuclear DNA fragmentation, first appeared at 3 h and peaked
      at 6 h following irradiation. Increased expression of the precursors of caspase 1
      (ICE), 2 (Nedd2), 3 (CPP32), 6 (Mch2), and 8 (Mch5 and FLICE), and increased
      expression of active caspase 3, as revealed by immunohistochemistry, were
      observed in the external granule cell layer of the cerebellum. Radiation-induced
      apoptosis was accompanied by an increase in the expression of the poly(ADP
      ribose) polymerase (PARP) fragment of about 89 kD, as revealed by Western blots
      of cerebellar homogenates. This was not associated with modifications of protein
      kinase Cdelta and Lamin B. Concomitant injection in the culmen of the cerebellum
      in irradiated rats of high doses of Y-VAD-cmk, DEV-fmk, or IETD-fmk resulted in
      decreased expression of the PARP fragment in cerebellar homogenates. This was
      accompanied by a decrease in the expression of active caspase 3, as shown by
      immunohistochemistry. These observations suggest caspase activation following
      ionizing radiation. However, no differences in the number and morphological and
      biochemical characteristics of apoptotic cells, including strong nuclear and
      cytoplasmic c-Jun/AP-1 (N) expression, were observed between irradiated and both
      irradiated and caspase inhibitor-treated rats. Taken together, these observations
      suggest that the caspases examined are not essential for radiation-induced
      apoptosis in the developing cerebellum.

PMID- 10590179
TI  - Expression of CNTF/LIF-receptor components and activation of STAT3 signaling in
      axotomized facial motoneurons: evidence for a sequential postlesional function of
      the cytokines.
AB  - Several lines of evidence suggest that ciliary neurotrophic factor (CNTF) and
      leukemia inhibitory factor (LIF) are important for the survival and regeneration
      of axotomized motoneurons. To investigate the role of CNTF/LIF signaling in
      regenerative responses of motoneurons, we studied the expression of the three
      receptor components, CNTF receptor alpha (CNTFRalpha), LIF receptor beta
      (LIFRbeta), and gp130, and the activation of the STAT3 signal transduction
      pathway in the rat facial nucleus following peripheral nerve transection. As
      shown by in situ hybridization and immunoblotting, axotomy resulted in a rapid
      down-regulation of CNTFRalpha mRNA expression within 24 h and a concomitant
      massive up-regulation of LIFRbeta mRNA and protein in the lesioned motoneurons.
      The altered mRNA levels were maintained for 3 weeks but had returned back to
      control levels by 6 weeks postlesion after successful regeneration. In contrast,
      mRNA levels remained in the lesioned state during the 6-week period studied, when
      regeneration was prevented by nerve resection. Significant lesion-induced changes
      in gp130 mRNA levels were not detectable. Rapid (within 24 h) and sustained (for
      at least 5 days) activation of STAT3 in axotomized facial motoneurons was
      revealed by demonstrating the phosphorylation and nuclear translocation of the
      protein using immunocytochemistry and immunoblotting. In agreement with previous
      studies showing a complementary regulation of CNTF and LIF in the lesioned facial
      nerve, our observations on the postlesional regulation of CNTF/LIF receptor
      components in the facial nucleus indicate a direct and sequential action of the
      two neurotrophic proteins on axotomized facial motoneurons.

PMID- 10590180
TI  - Fate of oligodendrocytes during retinal axon degeneration and regeneration in the
      goldfish visual pathway.
AB  - Retinal axons in goldfish regenerate after optic nerve lesion, restore synaptic
      connections, and become myelinated by oligodendrocytes. The fate of
      oligodendrocytes during these events is not known and may require generation of
      new oligodendrocytes or dedifferentiation and redifferentiation of the existing
      ones. To determine the reaction of oligodendrocytes to optic nerve lesion, we
      used the terminal transferase technique to detect apoptosis, bromodeoxyuridine
      incorporation to reveal mitosis, antibodies to identify myelin and
      oligodendrocytes, and Lucifer yellow injections to reveal cell morphology. Along
      with the reappearance of the myelin molecules 36K protein, galactocerebroside,
      and myelin basic protein, myelinating oligodendrocytes (identified by Lucifer
      yellow injections) reappear 21 days postlesion. Prior to this time, the dye
      filled cells had few processes oriented along the regenerating axons. They
      resembled oligodendrocytes seen both in vitro and in vivo which express the L1
      related E587 antigen and synthesize the 36K myelin protein in coculture with
      axons. No signs of oligodendrocyte apoptosis were detected after lesion and only
      few of the oligodendrocytes present had recently arisen. 36K/E587 double-labeled
      oligodendrocytes which were most likely dedifferentiating oligodendrocytes were
      identified in 8-day postlesion nerves among E587-positive elongate cells whose
      numbers increased until 14 days postlesion. These findings suggest that
      oligodendrocytes dedifferentiate-like Schwann cells-from cells which express
      myelin molecules to elongate cells which express the L1/E587 antigen. They
      redifferentiate to myelinate axons from roughly 3 weeks onward. These findings
      suggest an adaptive plasticity of goldfish oligodendrocytes beneficial to the
      repair of the visual pathway.

PMID- 10590181
TI  - Androgens rescue avian embryonic lumbar spinal motoneurons from injury-induced
      but not naturally occurring cell death.
AB  - The regulation of survival of spinal motoneurons (MNs) has been shown to depend
      during development and after injury on a variety of neurotrophic molecules
      produced by skeletal muscle target tissue. Increasing evidence also suggests that
      other sources of trophic support prevent MNs from undergoing naturally occurring
      or injury-induced death. We have examined the role of endogenous and exogenous
      androgens on the survival of developing avian lumbar spinal MNs during their
      period of programmed cell death (PCD) between embryonic day (E)6 and E11 or after
      axotomy on E12. We found that although treatment with testosterone,
      dihydrotestosterone (DHT), or the androgen receptor antagonist flutamide (FL)
      failed to affect the number of these MNs during PCD, administration of DHT from
      E12 to E15 following axotomy on E12 significantly attenuated injury-induced MN
      death. This effect was inhibited by cotreatment with FL, whereas treatment with
      FL alone did not affect MN survival. Finally, we examined the spinal cord at
      various times during development and following axotomy on E12 for the expression
      of androgen receptor using the polyclonal PG-21 antibody. Our results suggest
      that exogenously applied androgens are capable of rescuing MNs from injury
      induced cell death and that they act directly on these cells via an androgen
      receptor-mediated mechanism. By contrast, endogenous androgens do not appear to
      be involved in the regulation of normal PCD of developing avian MNs.

PMID- 10590182
TI  - Axon regeneration in organotypic slice cultures from the mammalian auditory
      system is topographic and functional.
AB  - In vitro models have frequently been employed to investigate the specificity of
      the formation of axonal projections during both development and regeneration.
      Such studies demonstrated pathway, target, and laminar specificity, yet they did
      not tackle the problem of topography. Here, we addressed the issue of
      regeneration of spatial specificity at the topographic level by lesioning a
      precisely organized projection from the auditory system of neonatal rats in
      organotypic slice culture and by analyzing regeneration capacity. Lesioning had
      no effect on the survival of axotomized neurons or the structure of the auditory
      nuclei. Anterograde and retrograde biocytin tracing demonstrated that the
      projection regenerated topographically at the supracellular level. Whole-cell
      patch-clamp recordings revealed that the regenerated projection was functional.
      Topographic regeneration was not impaired by blocking spike activity with
      tetrodotoxin or glycinergic transmission with strychnine. However, if lesioning
      was performed after the slices had been incubated for 1 week, regeneration
      capacity was lost despite good survival of neurons. The loss of the regeneration
      capacity in vitro occurs at a developmental stage that corresponds to the age
      when the capacity for axonal reorganization is lost in vivo. We conclude that the
      developmental processes occurring in vivo and in vitro are comparable in this
      system, which is why we think that essential aspects of the loss of regeneration
      capacity may be addressed with our culture model in the future.

PMID- 10590183
TI  - Inhibition of platelet aggregation with a glycoprotein IIb-IIIa antagonist does
      not prevent thrombin generation in patients undergoing thrombolysis for acute
      myocardial infarction.
AB  - Thrombin activity has been implicated as a mechanism for failed reperfusion and
      reocclusion following thrombolysis. Aggregating platelets provide a phospholipid
      surface on which prothrombin is cleaved to form thrombin. We examined markers of
      thrombin generation and activity in patients enrolled in a randomized, placebo
      controlled, dose escalating trial of the platelet glycoprotein IIb-IIIa inhibitor
      eptifibatide (Integrilintrade mark) administered concomitantly with tissue
      plasminogen activator for the treatment of myocardial infarction. Measurements
      were obtained at baseline, at 90 minutes, and at 6, 12, and 24 hours after
      starting therapy. Eptifibatide inhibited platelet aggregation in response to 20
      microM ADP. Levels of fibrinopeptide A (FPA), thrombin-antithrombin complexes
      (TAT), and prothrombin fragment 1.2 (F1.2) were not lower in patients treated
      with eptifibatide than in the control group. In the course of dose escalation,
      two groups of patients received the same 135 microg/kg bolus of eptifibatide, one
      with and one without a heparin bolus. FPA levels were dramatically lower in the
      heparin-treated patients. Levels of FPA, TAT, and F1.2 were not higher in
      patients with than in those without recurrent ischemia, or in patients without
      than in those with Thrombolysis in Myocardial Infarction (TIMI) grade 3
      angiographic flow at 90 minutes. These data suggest that thrombin generation and
      activity persist following thrombolysis, despite inhibition of platelet
      aggregation, and that treatment with inhibitors of thrombin activity may be
      required even when glycoprotein IIb-IIIa inhibitors are used.

PMID- 10590184
TI  - Homocysteine and risk of cardiovascular disease.
AB  - This pictorial introduction to homocysteine illustrates at a glance the nature of
      homocysteine and its role in cardiovascular disease by means of eight simple
      figures and an essential bibliography. Homocysteine is a sulfur-containing
      metabolite of methionine. Conversion back to methionine or transsulfuration to
      cysteine are the two major metabolic pathways that reduce total homocysteine
      (tHcy) concentrations in cells and blood. B vitamins are essential cofactors in
      homocysteine metabolism. Median fasting total homocysteine levels in adult males
      are approximately 10 micromol/L. Increased plasma tHcy concentrations are found
      with methionine-rich diets, low vitamin B intake, male gender, age, impaired
      renal function, and genetically determined defects of the enzymes involved in
      homocysteine metabolism. An inverse relation exists between plasma tHcy and
      circulating folate or vitamin B(6) concentrations, and folic acid supplements of
      0.5 mg/d can reduce tHcy levels by approximately 25%. Homocystinuric patients,
      who have severe hyperhomocysteinemia, die prematurely of atherothrombotic
      disease. Many (but not all) cross-sectional and prospective studies indicate, on
      average, that plasma tHcy levels <.10 micromol/L are associated with, or predict
      the development of, coronary, cerebral, and peripheral vascular disease. The risk
      conferred by hyperhomocysteinemia is graded and is independent of traditional
      risk factors, with an estimated odds ratio for ischemic heart disease of 1.4 for
      every 5 micromol/L increase in plasma tHcy. In vitro and in vivo, tHcy has been
      found to impair endothelial function. It is now well established that tHcy
      represents a marker of current or subsequent ischemic vascular disease. However,
      irrefutable proof that hyperhomocysteinemia actually causes atherothrombosis will
      come only if interventions to lower plasma tHcy will produce concomitant
      reductions in cardiovascular events.

PMID- 10590185
TI  - Role of extracellular ionized calcium in the in vitro assessment of GPIIb/IIIa
      receptor antagonists.
AB  - Several preclinical studies have found a poor correlation between the ex vivo
      platelet inhibitory potency and the in vivo antithrombotic efficacy of GPIIb/IIIa
      receptor antagonists. The present study was designed to examine the differential
      in vitro potencies of c7E3, MK-383, DMP-728, and SM-20302 in inhibiting ex vivo
      platelet aggregation under normocalcemic and hypocalcemic conditions. Human blood
      was collected in either trisodium citrate (0. 37%) or PPACK (20 microg/mL).
      Platelet aggregation assays were performed in platelet-rich plasma from citrate
      anticoagulated blood (cPRP) and PPACK-anticoagulated blood (pPRP) using ADP (20
      microM) and TRAP (10 microM) as agonists in the presence of c7E3, MK-383, DMP
      728, or SM-20302. The concentration of ionized calcium in cPRP was 16-19 times
      lower than that in pPRP. The IC(50) of c7E3 for inhibiting ADP-induced platelet
      aggregation in cPRP (2.76 +/- 0.11 microg/mL) was 1.6 times lower than that in
      pPRP (4.46 +/- 0.48 microg/mL; P < 0.05). Similarly, the IC(50) for c7E3 for
      inhibiting TRAP-induced platelet aggregation in cPRP (4.52 +/- 0.34 microg/mL)
      was 1.7 times lower than that in pPRP (7.69 +/- 0.43 microg/mL; P < 0.05). MK
      383, DMP-728, and SM-20302 also demonstrated 1.96-, 1.15-, and 1.43-fold lower
      IC(50) values, respectively, in cPRP as compared with pPRP. Chelation of ionized
      calcium in pPRP led to a progressive increase in platelet inhibition by all the
      antagonists. These results suggest that the observed in vitro inhibitory potency
      of a GPIIb/IIIa receptor antagonist is markedly enhanced when trisodium citrate
      is used as an anticoagulant to collect blood for ex vivo assay. These findings
      indicate that dosing regimens for GPIIb/IIIa receptor antagonists based on the
      platelet inhibition profile in citrate may provide misleading information with
      respect to their true in vivo antithrombotic efficacy.

PMID- 10590186
TI  - Ticlopidine enhances the platelet inhibitory capacity of abciximab in vitro.
AB  - Ticlopidine and abciximab are two antiplatelet agents that are frequently
      administered during percutaneous coronary interventions. Although they have
      different mechanisms of action and pharmacological profiles, the two agents are
      often concomitantly used in complicated stent placements. The purpose of the
      study was to evaluate the effect of ticlopidine therapy on the capacity of
      abciximab to inhibit platelet aggregation, in vitro. Blood samples from 13
      ticlopidine-treated stent placement patients and 8 patients undergoing PTCA who
      did not receive ticlopidine were obtained prior to, 12-36 hours and 7-10 days
      after initiating ticlopidine treatment. For each patient, the minimal ADP and the
      thrombin receptor activating peptide (TRAP) concentrations that elicited maximal
      platelet aggregation responses at baseline were used to measure the extent of
      platelet aggregation and the abciximab concentration that gave a 50% decrease in
      aggregation (IC(50)) for both agonists at the three time points. The ticlopidine
      group baseline and 12-36 hour mean ADP aggregation responses were equivalent, but
      decreased by 34% (P = 0.009) at 7-10 days. The control group ADP and TRAP, as
      well as the ticlopidine group TRAP aggregation responses, were equivalent at all
      time points. The ticlopidine group baseline and 12-36 hour abciximab IC(50)
      values for ADP were comparable (1.58 +/- 1.1 ng/mL vs. 1.23 +/- 0.5 ng/mL; P =
      0.266), but decreased to 1.00 +/- 0.6 ng/mL (36%; P = 0.004) at 7-10 days. In
      contrast, the abciximab IC(50) for TRAP increased from 1.48 +/- 1.0 ng/mL to 1.85
      +/- 1.1 ng/mL (25%; P = 0.033) at 12-36 hours, but returned to baseline at 7-10
      days (1.40 +/- 0.8; P = 0.975). The control group IC(50) abciximab values for ADP
      and TRAP were comparable throughout the monitoring period. The results
      demonstrate that ticlopidine elicits subtle potentiation of the platelet
      inhibitory capacity of abciximab to the agonist ADP, but not TRAP, at 1 week
      after initiation of treatment.

PMID- 10590188
TI  - Incidence of factor V Leiden in patients with acute myocardial infarction.
AB  - The genetic defect of coagulation factor V known as factor V Leiden produces a
      resistance to degradation by activated protein C (APC) and increases the risk of
      venous thromboembolism. The data on arterial thrombosis associated with APC
      resistance are still not clearly defined. We conducted a study in patients
      presenting with acute myocardial infarction (MI) to assess whether factor V
      Leiden increases the risk of arterial thrombosis. We studied 109 patients who had
      a diagnosis of acute MI (69 males and 40 females, aged 25-91 years), and 112
      controls. The study population was identified by characteristic ECG changes and
      elevation of serum CK-MB, whereas the control subjects were anonymous healthy
      blood donors with no known history of coronary artery disease. Blood samples from
      the patients and controls were analyzed for the factor V Leiden mutation by DNA
      analysis, using the polymerase chain reaction. Heterozygous factor V Leiden
      mutation was found in 9 of 109 (8%) MI patients and 5 of 112 (4%) control
      subjects (P =.42). In conclusion, this study shows no evidence of an association
      between factor V Leiden and acute MI.

PMID- 10590187
TI  - Effect of short-term aspirin use on C-reactive protein.
AB  - Markers of inflammation, such as C-reactive protein (CRP) and fibrinogen, have
      been shown to be predictive of cardiovascular disease. In the Physicians Health
      Study, the magnitude of reduction in the risk of myocardial infarction with
      aspirin therapy was related to baseline CRP levels, raising the possibility that
      the protective effect of aspirin may be due to antiinflammatory properties in
      addition to its antiplatelet effect. We therefore investigated whether aspirin
      therapy lowers CRP levels. Because heavy physical exertion is a well-known
      trigger of myocardial infarction, we also investigated the effect of aspirin on
      CRP levels before and after strenuous exercise. Thirty-two healthy men, aged 29
      +/- 6 years, were enrolled in a randomized, double-blind, parallel study. Blood
      samples were obtained immediately before and after maximal treadmill exercise at
      baseline and following 7 days of aspirin therapy (81 or 325 mg). The levels of
      CRP, as measured by ELISA, increased by 13% following exercise (P < 0.0001).
      However, aspirin did not significantly alter CRP levels, either at rest (0.81 +/-
      0.13 mg/L before aspirin vs. 0.78 +/- 0.13 mg/L on aspirin) or following exercise
      (0.92 +/- 0.13 mg/L before aspirin vs. 0.86 +/- 0. 13 mg/L on aspirin), P = 0.73.
      When the resting and postexercise data were combined, the levels were 0.87 +/-
      0.13 mg/L before aspirin and 0.82 +/- 0.13 mg/L on aspirin (a nonsignificant 6%
      reduction, P = 0.20). In conclusion, in healthy male subjects CRP levels were not
      significantly reduced by short-term aspirin therapy. Our data, taking together
      with other reports, suggest that aspirin may not affect the levels of
      inflammatory markers. However, further studies are needed with a longer duration
      of therapy, among subjects with coronary heart disease, and using additional
      markers of inflammation besides CRP to determine the long-term effects of aspirin
      use.

PMID- 10590189
TI  - Prevention of left ventricular remodeling by percutaneous transluminal coronary
      angioplasty performed 24 hours after the onset of acute myocardial infarction.
AB  - It remains controversial whether percutaneous transluminal coronary angioplasty
      (PTCA) performed 24 hours after the onset of acute myocardial infarction (AMI) in
      coronary arteries with 99% stenosis is useful in preserving left ventricular
      function. We investigated the effectiveness of PTCA in preventing left
      ventricular remodeling when it was performed 24 hours after the onset of AMI in
      infarct-related coronary arteries (IRCAs) having 99% stenosis and thrombolysis in
      myocardial infarction (TIMI) grade 3 flow. The subjects were 19 patients with AMI
      (anterior wall, 9 patients; inferior wall, 7 patients; and non-Q, 3 patients)
      who, within 24 hours of the onset of AMI, underwent coronary angiography and left
      ventriculography during the acute and/ or chronic phases. The patients were
      divided into a PTCA group, comprised of patients in whom PTCA was successfully
      performed 24 hours after the onset of AMI (n = 10), and a non-PTCA group (n = 9).
      The non-PCTA group included patients who were successfully reperfused by
      thrombolysis and did not include patients who had spontaneous reperfusion or
      reperfusion after PTCA. In the non-PTCA group, the left ventricular end-diastolic
      volume (mean +/- SD) was significantly increased in the chronic phase (86 +/- 23
      mL/m(2)) as compared with the acute phase (67 +/- 13 mL/m(2)), whereas in the
      PTCA group no significant difference was observed between end-diastolic volumes
      in the acute and chronic phases (67 +/- 26 and 68 +/- 13 mL/m(2), respectively).
      Left ventricular remodeling is prevented by PTCA when it is performed 24 hours
      after the onset of AMI in IRCAs with 99% stenosis and TIMI grade 3 flow.

PMID- 10590191
TI  - Key references: Basic fibrinolysis and thrombolysis selected references: 1987
      1997.

PMID- 10590190
TI  - Soluble E-selectin is not a marker of unstable coronary plaque in serum of
      patients with ischemic heart disease.
AB  - Increased level of soluble cell adhesion molecules may be a marker for
      atherosclerosis and/or reflect complication of the atherosclerotic plaque. To
      test whether expression of cell adhesion molecules is more pronounced in unstable
      versus stable coronary plaques, we measured the serum level of soluble E-selectin
      (sE-selectin) in 99 consecutive patients admitted to the hospital for acute
      coronary syndromes (ACS) and in 61 patients with chronic coronary artery disease
      (CAD) using a commercially available ELISA kit. We also measured the sE-selectin
      concentration in 20 sex- and age-matched subjects without clinical evidence of
      atherosclerosis, who served as controls. The mean sE-selectin level was higher in
      both groups of patients compared with controls (ACS, 35.0 +/- 23.4 ng/mL; chronic
      CAD, 32.9 +/- 21.0 ng/mL; controls, 14.5 +/- 6.6 ng/mL; one-way ANOVA, P =
      0.001), but there was no difference between patients with ACS and chronic CAD.
      Furthermore, there was a trend (P = 0.08) toward a decrease in sE-selectin with
      an increase in the extent and severity of CAD. In patients with ACS, the in
      hospital cardiac event rate was 8%. Although mean sE-selectin concentration
      tended to be higher in patients with (49.2 +/- 42.1 ng/mL) than in those without
      (33.8 +/- 21.3 ng/mL) in-hospital cardiac events, the difference was not
      significant. In 53 patients with ACS, C-reactive protein was measured and showed
      no correlation with the sE-selectin concentration. These findings show that
      although sE-selectin concentration is elevated in the presence of clinically
      relevant atherosclerosis, it does not further increase during the unstable phase
      of the disease, indicating that sE-selectin is not a reliable indicator of a
      complicated atherosclerotic plaque.

PMID- 10590192
TI  - Key references: anticoagulants and coagulation monitoring.

PMID- 10590193
TI  - Key references: Cardiac rupture.

PMID- 10590194
TI  - Key references: Biochemical markers of platelet activation.

PMID- 10590195
TI  - Key references on a wide variety of topics pertaining to coronary artery blood
      flow and patency.

PMID- 10590196
TI  - Reference guide to cardiogenic shock complicating acute myocardial infarction.

PMID- 10590197
TI  - Ischemic preconditioning.

PMID- 10590198
TI  - Key references: pathology/physiology including thrombosis.

PMID- 10590199
TI  - Key references: Role of ACE inhibition in acute coronary syndromes.

PMID- 10590200
TI  - Venous thromboembolism in the elderly: introduction and overview.

PMID- 10590201
TI  - Key references: Age and the risk of venous thromboembolism.

PMID- 10590202
TI  - Key references: Antiplatelet drugs in the elderly.

PMID- 10590203
TI  - Update in unfractionated heparin, low-molecular-weight heparins, and heparinoids
      in the elderly (age >/= 65 years).

PMID- 10590204
TI  - Key references: Anticoagulants. Pharmacokinetics and pharmacodynamics.

PMID- 10590206
TI  - Key references: Drug interactions.

PMID- 10590205
TI  - Key references: Anticoagulants. Bleeding risk.

PMID- 10590208
TI  - Key references: Protein C, protein S, and antithrombin deficiencies.

PMID- 10590207
TI  - Key references: Homocysteine and atherothrombotic vascular disease.

PMID- 10590209
TI  - Key references: Antiphospholipid antibody syndrome.

PMID- 10590210
TI  - Molecular epidemiology, pathogenesis and prevention of gastric cancer.
AB  - Cancer of the stomach is one of the most commonly diagnosed malignancies and
      remains an important cause of mortality world wide. This type of cancer is not
      uniformly distributed among populations but shows a marked variation in both
      incidence and mortality. Although gastric cancer is declining in many parts of
      the world, the reasons for this decline are not well understood and its etiology
      remains unclear. Several factors are suspected to play a role in gastric
      carcinogenesis, including the effects of diet, exogenous chemicals, intragastric
      synthesis of carcinogens, genetic factors, infectious agents and pathological
      conditions in the stomach (such as gastritis). A new look at the results of
      epidemiological and experimental studies is important for the establishment of
      strategies for control. Since cancer of the stomach has a very poor prognosis in
      its more advanced stages, such a control program must have its main focus on
      primary prevention. This review describes our knowledge about cancer of the
      stomach regarding epidemiology, pathogenesis and prevention.

PMID- 10590211
TI  - Dietary polyunsaturated fatty acids and cancers of the breast and colorectum:
      emerging evidence for their role as risk modifiers.
AB  - The hypothesis that a high-fat diet promotes the development of postmenopausal
      breast cancer is supported by international data showing a strong correlation
      between fat intake and breast cancer rates and a modest positive association with
      high-fat diet in case-control studies. Dietary fat intake was found to be
      unrelated to the risk of breast cancer in cohort studies. In view of these
      conflicting findings it has been difficult to make nutritional recommendations
      for the prevention of breast cancer. Studies in animal models and recent
      observations in humans, however, have provided evidence that a high intake of
      omega-polyunsaturated fatty acids (PUFAs), stimulates several stages in the
      development of mammary and colon cancer, from an increase in oxidative DNA damage
      to effects on cell proliferation, free estrogen levels to hormonal catabolism. In
      contrast, fish oil-derived omega-3 fatty acids seem to prevent cancer by
      influencing the activity of enzymes and proteins related to intracellular
      signalling and, ultimately, cell proliferation. In this commentary, current
      evidence from experimental and human studies is summarized that implicates a high
      intake of omega-6 PUFAs in cancer of the breast, colon and, possibly, prostate
      and which indicates that omega-3 PUFAs and monounsaturated fatty acids such as
      oleic acid (omega-9) are protective. Plausible mechanisms for modulation of steps
      in the multistage carcinogenesis process by fats are discussed. Properly designed
      epidemiological studies are now needed, that integrate relevant biomarkers to
      unravel the contributions of different types of fat, their interactions with
      hormonal catabolism, protective nutritional factors and human cancer risk.

PMID- 10590212
TI  - Fractional allele loss indicates distinct genetic populations in the development
      of squamous cell carcinoma of the head and neck (SCCHN).
AB  - Loss of heterozygosity (LOH) had been widely used to assess genetic instability
      in tumours and a high LOH on chromosome arms 3p, 9p and 17p has been considered
      to be a common event in squamous cell carcinoma of the head and neck (SCCHN). We
      have investigated LOH in 52 SCCHN using a range of microsatellite markers. LOH
      was observed in 69% of individuals on 17p using seven markers, in 64% of
      individuals on 3p using 17 markers and in 61% of individuals on 9p using 11
      markers. Fractional allele loss (FAL) has been calculated for each tumour (FAL is
      the number of chromosomal arms showing LOH divided by the number of informative
      chromosomal arms) and a median FAL value of 0.25 was obtained in the 52 SCCHN
      studied. The LOH data were examined on the basis of FAL scores: low FAL (LFAL),
      0.00-0.19; medium FAL (MFAL), 0.20-0.32; high FAL (HFAL), 0.33-0.88. HFAL tumours
      demonstrated a significantly higher LOH on chromosome arms 3p, 9p and 17p, with
      94% LOH on 3p, 94% on 9p and 100% on 17p compared with LFAL tumours. Six of the
      16 patients in the LFAL group were found to have no LOH on 3p, 9p or 17p and of
      these four had LOH at other sites, on chromosomes 2p25-p24, 5q21-22, 7pter-p22,
      8q13-q22.1, 11q23.3, 13q32, 17q, 18p11.21, 18q21.31 and 19q12-q13.1. These
      results indicate that LFAL patients form a subset of SCCHN tumours with distinct
      molecular initiating events which may represent a discrete genetic population.

PMID- 10590213
TI  - Involvement of p53 in X-ray induced intrachromosomal recombination in mice.
AB  - The tumor suppressor gene Trp53 (also known as p53) is the most frequently
      mutated gene in human cancers. p53 is induced in response to DNA damage and
      effects a G(1) cell cycle arrest. It is believed that p53 plays a key role in
      maintaining genomic integrity following exposure to DNA-damaging agents. We
      determined the frequency of spontaneous and DNA damage-induced homologous
      intrachromosomal recombination in p53-deficient mouse embryos. Homologous
      intrachromosomal recombination events resulting in deletions at the pink eyed
      unstable (p(un)) locus result in reversion to the p gene. Reversions occurring in
      embryonic premelanocytes give rise to black spots on the gray fur of the
      offspring. Pregnant C57BL/6J p(un)/p(un) p53(+/-) mice were exposed to X-rays (1
      Gy) or administered benzo?apyrene (B?aP; 30 or 150 mg/kg i.p.) 10 days after
      conception. Frequencies of spontaneous p(un) reversions in p53(-/-) and p53(+/-)
      animals were not significantly different compared with their wild-type
      littermates. X-ray treatment increased the recombination frequency in wild-type
      and p53(+/-), but surprisingly not in p53(-/-) offspring. In contrast, B?aP
      treatment caused a dose-dependent increase in p(un) reversion frequencies in all
      three genotypes. Western blot analysis of embryos indicated that p53 protein
      levels increased approximately 3-fold following X-ray treatment, while B?aP had
      no effect on p53 expression. These results are in agreement with the proposal
      that p53 is involved in the DNA damage response following X-ray exposure and
      suggest that X-ray-induced double-strand breaks are processed differently in p53(
      /-) animals.

PMID- 10590214
TI  - Effects of the rodent peroxisome proliferator and hepatocarcinogen,
      perfluorooctanoic acid, on apoptosis in human hepatoma HepG2 cells.
AB  - The effects of perfluorooctanoic acid (PFOA), a potent hepatocarcinogen and
      peroxisome proliferator in rodents, on human cells have not yet been examined. In
      the present study we demonstrate that treatment of human hepatoblastoma HepG2
      cells with PFOA induces apoptosis, as well as perturbs the cell cycle. This
      apoptosis was characterized by electron microscopy, which revealed typical
      nucleosomal fragmentation (also observed as a 'DNA ladder' upon electrophoresis
      on agarose) and was quantitated using propidium iodide staining of cellular DNA
      and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling
      (TUNEL) assay. This process was dose- and time-dependent: apoptosis became
      manifest with 200 microM and maximal (45% of the cells) upon exposure to 450
      microM PFOA for 24 h. Electrophoresis of the DNA from HepG2 cells exposed to 500
      microM PFOA for 24 h or to 400 microM PFOA for 48 h revealed a smear typical of
      non-specific degradation. These findings indicate that in the presence of high
      concentrations of PFOA for long times, HepG2 cells undergo primary and secondary
      necrosis. Quantitation of trypan blue exclusion supported this conclusion. Flow
      cytometric analysis revealed that the cell cycle of HepG2 cells was perturbed by
      exposure to 50-150 microM PFOA. A 50 microM concentration resulted in a
      significant increase in the proportion of G(2)/M cells and, simultaneously, a
      decrease in the number of cells in the S phase, whereas treatment with 100 or 150
      microM PFOA increased the proportion of cells in the G(0)/G(1) phase and
      decreased the number of cells in the G(2)/M and S phases. Simultaneous flow
      cytometric analysis of apoptosis-associated DNA strand breaks using the TUNEL
      procedure and of propidium iodide staining of cellular DNA revealed DNA breaks in
      HepG2 cells exposed to 150 microM PFOA, prior to nuclear fragmentation.

PMID- 10590215
TI  - Microsatellite instability and loss of heterozygosity in radiation-associated
      thyroid carcinomas of Belarussian children and adults.
AB  - DNA from 129 paired thyroid tumorous and non-tumorous tissue samples of
      Belarussian children (102 patients; age at surgery </=18 years) and adults (27
      patients; age at surgery 19-35 years), who had been exposed to radioactive
      fallout from the Chernobyl reactor accident in 1986, was examined for
      microsatellite instability (MSI) and loss of heterozygosity (LOH). Twenty-eight
      microsatellite markers were chosen because of their vicinity to DNA repair genes
      or genes involved in tumorigenesis as well as regions of chromosomal breakpoints
      in thyroid tumours. In 40 patients (31% of 129) we detected a total of 73
      alterations, 80% of which were classified as LOH and only 20% as MSI. Amongst
      these 40 patients we identified a subgroup of 11, mainly young female patients
      (8.5% of 129), exhibiting alterations in at least two microsatellite markers. For
      comparison we examined samples from spontaneous thyroid carcinomas without
      radiation history from 20 adult patients from Munich (mean age at surgery 56 +/-
      13 years). None of the tumour samples investigated showed evidence of alterations
      in the 28 microsatellite markers tested. Taken together our data indicate an
      increased instability of microsatellite markers in thyroid cancers from
      Belarussian patients. At present, it is uncertain whether the increased genome
      instability observed in Belarussian patients is the result of the exposure to
      radioactive iodine from the Chernobyl reactor accident or due to the young age of
      the patients.

PMID- 10590216
TI  - Studies on the mechanism of cancer protection by wheat bran: effects on the
      absorption, metabolism and excretion of the food carcinogen 2-amino-3
      methylimidazo[4,5-f]quinoline (IQ).
AB  - We examined ways in which dietary supplements of wheat bran may protect against
      colon cancer. The effects of supplementing the diet of female Wistar rats with
      10% wheat bran on the disposition and metabolism of the dietary carcinogen 2
      amino-3-methylimidazo[4,5-f]quinoline (IQ) labelled with (14)C was determined.
      Our data show that the wheat bran had a major effect on both the distribution and
      metabolism of IQ. At a low dose of IQ (1 mg/kg), we unexpectedly found that up to
      2 h after gavage there were higher concentrations of radioactivity in the plasma
      of rats fed wheat bran compared with the controls, but there were lower
      concentrations of radioactivity after 2 h. At a high dose of IQ (50 mg/kg), there
      were always lower concentrations of radioactivity in the plasma of rats fed wheat
      bran compared with the control rats. One of the most marked effects of wheat bran
      was apparently to significantly retard the metabolism of IQ in the plasma when
      this was fed at either dose. There were also differences between the rats fed
      wheat bran and the control in the concentrations and types of IQ metabolites in
      the urine.

PMID- 10590217
TI  - Effect of increased vegetable and fruit consumption on markers of oxidative
      cellular damage.
AB  - The goal of this study was to test the hypothesis that increased consumption of
      vegetables and fruit would reduce markers of oxidative cellular damage that can
      be assessed in blood or urine. Twenty-eight women participated in a 14 day
      dietary intervention. The primary end-points assessed were: 8
      hydroxydeoxyguanosine (8-OHdG) in DNA isolated from peripheral lymphocytes,
      determined by HPLC with electrochemical detection; 8-OHdG excreted in urine,
      measured by ELISA; malondialdehyde (MDA) in urine, measured by fluorimetric
      detection following derivatization with thiobarituric acid and separation via
      HPLC; urinary 8-isoprostane F-2alpha (8-EPG) detected by ELISA. Pre- and post
      intervention plasma levels of selected carotenoids were determined by HPLC.
      Subjects were free living and consumed a completely defined recipe-based diet
      that increased their average daily consumption of vegetables and fruit from 5.8
      servings at baseline to 12.0 servings throughout the intervention. Overall, the
      level of 8-OHdG in DNA isolated from lymphocytes and in urine and the level of 8
      EPG in urine were reduced by the intervention, whereas urine concentrations of
      MDA were minimally affected. The reduction in lymphocyte 8-OHdG was greater in
      magnitude (32 versus 5%) in individuals with lower average pre-intervention
      levels of plasma alpha-carotene (56 ng/ml) than in individuals with higher
      average pre-intervention plasma levels of alpha-carotene (148 ng/ml). The results
      of this study indicate that consumption of a diet that significantly increased
      vegetable and fruit intake from a diverse number of botanical families resulted
      in significant reductions in markers of oxidative cellular damage to DNA and
      lipids.

PMID- 10590218
TI  - Effect of vegetable and carotenoid consumption on aberrant crypt multiplicity, a
      surrogate end-point marker for colorectal cancer in azoxymethane-induced rats.
AB  - Epidemiological studies indicate that increased vegetable consumption reduces the
      risk of colorectal cancer mortality. In the present study we have investigated
      the effect of consumption of standard diets supplemented with freeze-dried
      vegetables (peas, spinach, sprouts and broccoli) and carotenoids (all-trans beta
      carotene and palm oil carotenoid extract) on surrogate end-point markers for
      colorectal cancer in an azoxymethane-induced rat model. Mean aberrant crypt
      multiplicity was reduced (19%) by the pea-supplemented diet only (P < 0.05). The
      vegetable-induced effect was more apparent in aberrant crypt foci with higher
      multiplicity. Intervention with diets supplemented with peas, spinach, sprouts
      and a mix of all vegetables reduced the number of foci with >2 aberrant
      crypts/focus by 37, 26, 23 and 26%, respectively (P < 0.05). Even more pronounced
      effects were observed in foci with >3 aberrant crypts/focus, with reductions of
      approximately 50% in the pea and spinach intervention groups. All-trans beta
      carotene and palm oil-derived carotenoids, supplied at similar doses to those
      expected in the vegetable diets, inhibited ACM only marginally. Aberrant crypt
      foci formation in groups fed a sprout-supplemented diet prior to or following
      azoxymethane treatment was similar, indicating that this effect is due to
      inhibition of promotion rather than initiation of colorectal carcinogenesis.
      Vegetable and carotenoid consumption did not affect in situ proliferation of
      colonic crypt cells, as assessed by semi-automated image analysis of
      bromodeoxyuridine (BrdU)-positive nuclei. BrdU-negative nuclei of colonic crypt
      cells were reduced slightly in the combined vegetable groups, as compared with
      the control (P < 0.05). These data: (i) are in line with epidemiological evidence
      regarding beneficial effects of vegetable consumption on colorectal
      carcinogenesis; (ii) indicate that consumption of several types of vegetables
      inhibits early post-initiation events in colorectal carcinogenesis; (iii) suggest
      that the vegetable-induced effect is more pronounced in advanced lesions; (iv)
      indicate that the carotenoid content of the vegetables (alpha- and beta-carotene)
      contributes only marginally to the vegetable-induced effects.

PMID- 10590219
TI  - Identification and characterization of three subtypes of radiation response in
      normal human urothelial cultures exposed to ionizing radiation.
AB  - In an attempt to assess genetic variation underlying the variation in human
      responses to radiation exposure, measurements of apoptosis, necrosis and
      induction of key proteins were made in primary explant cultures of human normal
      urothelium and correlated with growth post- exposure to a range of doses of
      (60)Co. These data were validated by similar experiments using CBA/H and C57/BL6
      mouse strains, known to exhibit genetically determined differences in response to
      radiation. The data for human tissues show a wide variation in response with
      three broad categories being identifiable. The commonest had a hypersensitive
      response involving considerable apoptosis in the low dose region, followed by
      'induction' of a survival response at higher doses involving the persistence of
      abnormal cells. The pattern of gene expression was consistent with suppression of
      apoptosis. The second category showed no induction of survival and considerable
      necrosis was seen in the progeny. The rarest category showed an extremely
      hypersensitive low dose response and despite induction of a survival response,
      the sensitivity to higher doses was very severe. Considerable apoptosis and
      necrosis were seen in these cultures. In the mouse experiments, strain CBA/H
      (mice known to exhibit genetic instability post-irradiation) had lower levels of
      delayed cell death and apoptosis than C57/BL6 mice (which exhibit significantly
      less instability). It is concluded that there is a variation in response to
      radiation between human patient cultures which is detectable in this system and
      which is consistent with a pattern of radiation- induced delayed death/apoptosis
      correlating with long-term genomic stability. The mouse experiments demonstrate
      the importance of genetic factors in determining these responses.

PMID- 10590220
TI  - Characterization of the mutational profile of (+)-7R,8S-dihydroxy-9S, 10R-epoxy
      7,8,9,10-tetrahydrobenzo[a]pyrene at the hypoxanthine (guanine)
      phosphoribosyltransferase gene in repair-deficient Chinese hamster V-H1 cells.
AB  - Earlier studies have shown that the profile of mutations induced by (+)-7R,8S
      dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (+)-BPDE at the
      hypoxanthine (guanine) phosphoribosyltransferase (hprt) gene of Chinese hamster
      V79 cells was dependent on the concentration of (+)-BPDE. In the present study,
      we examined the effect of the concentration of (+)-BPDE on its mutational profile
      at the hprt gene in repair-deficient V-H1 cells (a derivative of V79 cells) to
      explore the role of DNA repair in the dose-dependent mutational profile of (+)
      BPDE. Independent hprt mutant clones were isolated after exposing V-H1 cells to
      dimethylsulfoxide (DMSO) or to low (4-6 nM; 95% cell survival) or high (40-48 nM;
      31% cell survival) concentrations of (+)-BPDE in DMSO. The mutation frequencies
      for the DMSO control and for the low and high concentration groups were 0.1, 2.1
      and 32.9 mutant colonies/10(5) survivors, respectively. The profile of mutations
      at the hprt gene was characterized for 148 (+)-BPDE-induced mutant clones and the
      results from the present study were compared with those obtained earlier with V79
      cells. The data indicated that: (i) V-H1 cells were approximately 9-fold more
      sensitive to the cytotoxic effects of (+)-BPDE than V79 cells; (ii) the mutation
      frequency in V-H1 cells was similar to that observed in V79 cells following
      exposure to similar concentrations of (+)-BPDE; (iii) (+)-BPDE-induced mutations
      at guanine on the transcribed strand of the hprt gene were common in V-H1 cells
      but were extraordinarily rare in V79 cells; (iv) (+)-BPDE-induced mutations at
      adenine on the transcribed strand of the hprt gene were common in both V-H1 and
      V79 cells; (v) although exposure of V79 cells to different doses of (+)-BPDE
      resulted in a dose-dependent mutational profile at the hprt gene, this was not
      observed in V-H1 cells. Our observations indicate a defect in the transcription
      coupled repair of (+)-BPDE-DNA adducts in V-H1 cells and that the repair activity
      deficient in V-H1 cells is essential for the dose-dependent mutational profile
      observed with (+)-BPDE in V79 cells.

PMID- 10590221
TI  - Comparison of the mutagenic properties of 8-oxo-7,8-dihydro-2'-deoxyadenosine and
      8-oxo-7,8-dihydro-2'-deoxyguanosine DNA lesions in mammalian cells.
AB  - The comparative mutagenicity of 8-oxo-7,8-dihydro-2'-deoxyadenosine (8-oxodA) and
      8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) was explored using simian kidney
      (COS-7) cells. Oligodeoxynucleotides ?5'-TCCTCCT- G(1)X(2)CCTCTC or 5'
      TCCTCCTX(1)G(2)CCTCTC (X = dA, dG, 8-oxodA or 8-oxodG) containing 8-oxodA or 8
      oxodG positioned within codon 60 or 61 of the non-coding strand of human c-Ha
      ras1 gene were inserted into a single-stranded phagemid shuttle vector. The
      vector was replicated in COS-7 cells and the progeny plasmids were used to
      transform Escherichia coli DH10B. The transformants were analyzed by
      oligodeoxynucleotide hybridization and DNA sequence analysis to establish the
      mutation frequency and specificity. When 8-oxodA was positioned at X(1), targeted
      A(oxo)-->C transversions were detected; the mutation frequency was 1.2%. When 8
      oxodA was positioned at X(2), one targeted mutant among 416 colonies screened (an
      A(oxo)-->G transition) was detected. Thus, the mutation frequency and spectrum of
      8-oxodA depend on the sequence context of the lesion. The mutation frequency of 8
      oxodG at X(1) and X(2) was 5.2 and 6.8%, respectively. G(oxo)-->T transversions
      dominated the spectrum, accompanied by small numbers of G(oxo)-->A transitions
      and G(oxo)-->C transversions. We conclude that 8-oxodA has mutagenic potential in
      mammalian cells, generating A-->C transversions. However, when tested under
      similar conditions, the mutation frequency of 8-oxodA is at least four times
      lower than that of 8-oxodG.

PMID- 10590222
TI  - Effect of carcinogen dose fractionation, diet and source of F344 rat on the
      induction of colonic aberrant crypts by 2-amino-3-methylimidazo[4,5-f]quinoline.
AB  - Carcinogen dose fractionation, diet and source of laboratory animal were examined
      as variables in the induction of colonic aberrant crypt foci (ACF) by the
      heterocyclic amine 2-amino-3-methylimidazo [4, 5-f]quinoline (IQ). In the first
      experiment, male F344 rats from the National Cancer Institute (NCI rats) were fed
      AIN-93G diet and, starting in the third week, IQ was given by gavage on
      alternating days, the total carcinogen dose of 105 mg being fractionated
      proportionally over 2, 4, 8 or 14 weeks. Only the high dose (2 week) treatment
      with IQ was effective for the induction of ACF at 16 weeks, producing on average
      3.8 ACF/colon versus 0.5 ACF/colon in all other groups (P < 0.05). The 2 week IQ
      dosing protocol was used in a second experiment in which male F344 rats from
      Simonsen Laboratories (SN) or NCI were fed AIN-93G, AIN-76A or chow diet. On
      average, SN rats on chow diet had twice the number of aberrant crypts compared
      with NCI rats given the same diet and three to four times as many aberrant crypts
      as NCI rats fed AIN diets. Hepatic cytochrome P4501A1 (CYP1A1) levels were
      essentially unaffected by diet, but methoxyresorufin O-demethylase activities and
      CYP1A2 protein levels were increased 2- to 3-fold in animals fed chow versus AIN
      diets. During the 2 week period of carcinogen administration, IQ markedly induced
      CYP1A proteins and negated the differences among groups related to diet. No
      consistent diet-related changes were detected in the activities of aryl
      sulfotransferase or N-acetyltransferase, but UDP-glucuronosyltransferase
      activities were elevated 2- to 3-fold in rats given chow versus AIN diets. In
      summary, high dose treatment with IQ was required for the induction of ACF, rats
      on the chow diet had more aberrant crypts than those given AIN diets and male
      F344 rats purchased from different vendors and fed chow diet differed with
      respect to their sensitivity to induction of ACF.

PMID- 10590223
TI  - Cell proliferation induced by 3,3',5-triiodo-L-thyronine is associated with a
      reduction in the number of preneoplastic hepatic lesions.
AB  - Previous studies have suggested that liver cell proliferation is fundamental for
      the growth of carcinogen-initiated cells. To gain further information on the
      association between cell proliferation and hepatocarcinogenesis, we have examined
      the effect of the hormone 3,3',5-triiodo-L-thyronine (T3), a strong liver
      mitogen, on the growth of diethylnitrosamine (DENA)-induced hepatic lesions
      positive for the placental form of glutathione S-transferase (GSTP). Two weeks
      after a single initiating dose of DENA (150 mg/kg), cycles of liver cell
      proliferation were induced in male Fischer rats by feeding a T3-supplemented diet
      (4 mg/kg) 1 week/month for 7 months. Rats were killed at the end of the seventh
      cycle or 1 month later. Results indicate that, in spite of an increased labelling
      index, a 70% reduction in the number/cm(2) of GSTP-positive minifoci occurred in
      T3-treated rats. A decrease in the number of GSTP-positive foci was also observed
      in T3-treated rats killed 1 month after the last exposure to the hormone (40,
      versus 67 foci/cm(2) in controls), indicating that the reduction was not due to
      an inhibitory effect on GSTP exerted by the concomitant presence of T3. In a
      second series of experiments where DENA-treated rats were fed T3 for 1 week and
      then subjected to the resistant hepatocyte (RH) model, it was found that T3
      treatment prior to promotion resulted in a decrease in the number of GSTP
      positive foci (16 GSTP(+) foci/cm(2) in T3-fed animals versus 45 in the control
      group). The results indicate that cell proliferation associated with T3
      treatment: (i) reduces the number of carcinogen-induced GSTP-positive lesions;
      (ii) does not exert any differential effect on the growth of the remaining foci;
      (iii) inhibits the capacity of putative DENA-initiated cells to be promoted by
      the RH model. Data suggest that cell proliferation may not necessarily represent
      a stimulus for the growth of putative preneoplastic lesions.

PMID- 10590224
TI  - Increased expression of cyclooxygenase-2 protein in rat urinary bladder tumors
      induced by N-butyl-N-(4-hydroxybutyl) nitrosamine.
AB  - The anti-inflammatory drugs, aspirin and piroxicam, are known to possess
      chemopreventive potential against rat superficial urinary bladder carcinogenesis
      induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Recently, we found
      similar inhibitory effects with a selective cyclooxygenase (COX)-2 inhibitor,
      nimesulide. In order to clarify the inhibitory mechanisms, we have further
      studied the expression of COX-2 protein in urinary bladder tumors induced by BBN
      in Fischer 344 male rats. For comparison, papillomatosis caused by uracil-induced
      urolithiasis, and normal epithelial cells, were also investigated. Western blot
      analysis revealed COX-2 protein to be barely expressed in the normal epithelial
      cells, whereas it was increased 13-22-fold in varying sizes of urinary bladder
      tumors and 7-fold in papillomatosis. Immunohistochemically, COX-2 protein was
      diffusely expressed in transitional cell carcinomas and nodulo-papillary
      hyperplasia but weakly expressed only in basal cells in simple hyperplasia and
      normal-looking surrounding epithelia. In papillomatosis, it was moderately
      expressed only in endothelial cells in stroma. These results indicate that COX-2
      plays important roles in the development of preneoplastic and neoplastic lesions
      in the rat urinary bladder, and therefore could be a good target for
      chemoprevention of superficial lesions.

PMID- 10590225
TI  - A diet high in fat and meat but low in dietary fibre increases the genotoxic
      potential of 'faecal water'.
AB  - To determine the effects of different diets on the genotoxicity of human faecal
      water, a diet rich in fat, meat and sugar but poor in vegetables and free of
      wholemeal products (diet 1) was consumed by seven healthy volunteers over a
      period of 12 days. One week after the end of this period, the volunteers started
      to consume a diet enriched with vegetables and wholemeal products but poor in fat
      and meat (diet 2) over a second period of 12 days. The genotoxic effect of faecal
      waters obtained after both diets was assessed with the single cell gel
      electrophoresis (Comet assay) using the human colon adenocarcinoma cell line HT29
      clone 19a as a target. The fluorescence and length of the tails of the comet
      images reflects the degree of DNA damage in single cells. The mean DNA damage,
      expressed as the ratio of tail intensity (fluorescence in the tail) to total
      intensity of the comet after incubation with faecal water from volunteers
      consuming diet 1 was about twice as high as for diet 2. The susceptibility of the
      cells incubated with faecal water to DNA damage caused by additional hydrogen
      peroxide treatment showed no significant differences between the two diets.
      Generation of oxidized pyrimidine and purine bases revealed no differences after
      pretreatment with both types of faecal water. The results indicate that diets
      high in fat and meat but low in dietary fibre increase the genotoxicity of faecal
      water to colonic cells and may contribute to an enhanced risk of colorectal
      cancer.

PMID- 10590226
TI  - Mismatch repair, G(2)/M cell cycle arrest and lethality after DNA damage.
AB  - The role of the mismatch repair pathway in DNA replication is well defined but
      its involvement in processing DNA damage induced by chemical or physical agents
      is less clear. DNA repair and cell cycle control are tightly linked and it has
      been suggested that mismatch repair is necessary to activate the G(2)/M
      checkpoint in the presence of certain types of DNA damage. We investigated the
      proposed role for mismatch repair (MMR) in activation of the G(2)/M checkpoint
      following exposure to DNA-damaging agents. We compared the response of MMR
      proficient HeLa and Raji cells with isogenic variants defective in either the
      hMutLalpha or hMutSalpha complex. Different agents were used: the cross-linker N
      (2-chloroethyl)-N'-cyclohexyl-N-nitrosourea (CCNU), gamma-radiation and the
      monofunctional methylating agent N-methyl-N-nitrosourea (MNU). MMR-defective
      cells are relatively sensitive to CCNU, while no differences in survival between
      repair-proficient and -deficient cells were observed after exposure to gamma
      radiation. Analysis of cell cycle distribution indicates that G(2) arrest is
      induced at least as efficiently in MMR-defective cells after exposure to either
      CCNU or ionizing radiation. As expected, MNU does not induce G(2) accumulation in
      MMR-defective cells, which are known to be highly tolerant to killing by
      methylating agents, indicating that MNU-induced cell cycle alterations are
      strictly dependent on the cytotoxic processing of methylation damage by MMR.
      Conversely, activation of the G(2)/M checkpoint after DNA damage induced by CCNU
      and gamma-radiation does not depend on functional MMR. In addition, the absence
      of a simple correlation between the extent of G(2) arrest and cell killing by
      these agents suggests that G(2) arrest reflects the processing by MMR of both
      lethal and non-lethal DNA damage.

PMID- 10590227
TI  - Differential regulation of canalicular multispecific organic anion transporter
      (cMOAT) expression by the chemopreventive agent oltipraz in primary rat
      hepatocytes and in rat liver.
AB  - Expression of the canalicular multispecific organic anion transporter (cMOAT), an
      efflux pump involved in biliary secretion of xenobiotics, was investigated in rat
      hepatocytes exposed to the chemopreventive agent oltipraz. Northern blotting
      indicated that this compound increased cMOAT mRNA levels in primary cultured
      hepatocytes. Such an induction of cMOAT transcripts was demonstrated to be dose
      dependent and started as early as 4 h treatment; in addition, western blotting
      showed increased levels of 190 kDa cMOAT in oltipraz-treated primary rat
      hepatocytes when compared with their untreated counterparts. In contrast,
      administration of oltipraz to rats failed to enhance hepatic cMOAT mRNA and
      protein amounts whereas it was found to induce liver expression of glutathione S
      transferase P1, a well-known oltipraz-regulated drug metabolizing enzyme. These
      data therefore suggest that cMOAT up-regulation occurring in rat hepatocytes in
      response to oltipraz may be restricted to in vitro situations and is therefore
      unlikely to be directly involved in the in vivo chemopreventive properties of
      oltipraz.

PMID- 10590228
TI  - Safrole-like DNA adducts in oral tissue from oral cancer patients with a betel
      quid chewing history.
AB  - Betel quid (BQ) chewing has been associated with an increased risk of oral
      squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF). Piper betel
      inflorescence, which contains 15 mg/g safrole, is a unique ingredient of BQ in
      Taiwan. Chewing such prepared BQ may contribute to safrole exposure in human
      beings (420 microM safrole in saliva). Safrole is a known rodent
      hepatocarcinogen, yet its carcinogenicity in human beings is largely
      undetermined. In this study, using a (32)P-post-labeling method, we have found a
      high frequency of safrole-like DNA adducts in BQ-associated OSCC (77%, 23/30) and
      non-cancerous matched tissue (NCMT) (97%, 29/30). This was in contrast to the
      absence (< 1/10(9) nucleotides) of such adducts in all of non-BQ-associated OSCC
      and their paired NCMT (P < 0.001). Six of seven OSF also exhibited the same
      safrole-like DNA adduct. The DNA adduct levels in OSF and NCMT were significantly
      higher than in OSCC (P < 0.05). Using co-chromatography and rechromatography
      techniques, we further demonstrated that these adducts were identical to
      synthetic safrole-dGMP adducts as well as DNA adducts from 1'-hydroxysafrole
      treated HepG2 cells. These results suggest that safrole forms stable safrole-DNA
      adducts in human oral tissue following BQ chewing, which may contribute to oral
      carcinogenesis.

PMID- 10590229
TI  - Establishment of a novel rat cholangiocarcinoma cell culture model.
AB  - Furan cholangiocarcinogenesis in rat liver is proving to be a unique and useful
      animal model for investigating important aspects of the cellular and molecular
      pathogenesis of cholangiocarcinoma potentially relevant to the human disease. We
      now describe the first culture model of rat cholangiocarcinoma cells derived from
      a transplantable cholangiocarcinoma originally induced in the liver of a furan
      treated rat. An epithelial cell isolate highly enriched in viable
      cholangiocarcinoma cells was consistently obtained from transplantable
      cholangiocarcinoma tissue utilizing a similar procedure to that recently
      developed by us to establish a new rat hyperplastic bile ductular epithelial cell
      culture model characterized by the appearance of polarized bile ducts in vitro.
      Primary cholangiocarcinoma cell cultures could be readily established with these
      isolated cells and, in addition, we established from one such culture a novel rat
      cholangiocarcinoma cell line designated C611B. Cultured C611B cholangiocarcinoma
      cells retained a number of important characteristic features of the carcinoma
      cells of the parent tumor, including marked expression of the tyrosine kinase
      growth factor receptor proteins c-Met and c-Neu. Under basal culture conditions,
      the C611B cell line exhibited a cell doubling time of approximately 24 h and was
      aneuploid, with a predominant chromosomal count of 43. Moreover, C611B cells on
      collagen gels were 100% tumorigenic when transplanted into inguinal fat pads of
      syngeneic rats. All tumors formed at the transplantation site were cytokeratin 19
      positive, mucin-producing tubular adenocarcinomas whose histological and
      phenotypic features closely resembled those of the furan-induced parent
      transplantable rat cholangiocarcinoma. Based on our findings, we believe that
      this novel rat cholangiocarcinoma cell culture model can serve as a valuable
      resource for investigating aberrant growth properties and tumor progression in
      biliary cancer.

PMID- 10590230
TI  - Differential expression of the splicing regulatory factor genes during two-step
      chemical transformation in a BALB/3T3-derived cell line, MT-5.
AB  - Although the alternative splicing of various genes is a common event in human
      tumors, the mechanisms behind it have not been characterized. We hypothesized
      that the expression of splicing regulatory factors would be changed during
      cellular transformation. Gene expression of three splicing regulatory factors,
      alternative splicing factor/splicing factor 2 (ASF/SF2), heterogeneous nuclear
      ribonucleoprotein A2 (hnRNP A2) and the 65 kDa subunit of U2 small nuclear
      ribonucleoprotein particles auxiliary factor (U2AF(65)), were examined by
      northern blotting in a two-step chemical transformation model. This in vitro
      model is composed of BALB/3T3 cells and a BALB/3T3-derived N-methyl-N-nitro-N
      nitrosoguanidine (MNNG)-initiated cell line (MT-5). MT-5 cells can be transformed
      on exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA). ASF/SF2 mRNA levels
      were decreased 2-fold in both MNNG-initiated cells and TPA-induced transformed
      cells compared with the normal parental cells, whereas hnRNP A2 mRNA expression
      did not significantly change between these three types of cells. U2AF(65) mRNA
      levels were markedly increased ( approximately 4.7-fold) associated with
      progression of cellular transformation. Moreover, RT-PCR analysis showed that
      distinct forms of ASF/SF2 mRNA were present in the MNNG-initiated cells and TPA
      induced transformed cells but not in the parental cells. These findings indicate
      that ASF/SF2 or U2AF(65) gene expression is altered during in vitro two-step
      chemical transformation. The data suggest that the differential expression of
      splicing regulatory factors is one cause of aberrant expression of alternatively
      spliced mRNAs encoded by various genes in tumor cells.

PMID- 10590231
TI  - The effect of dietary folate on Apc and p53 mutations in the dimethylhydrazine
      rat model of colorectal cancer.
AB  - Dietary inadequacy of folate enhances and folate supplementation suppresses
      colorectal carcinogenesis in the dimethylhydrazine rat model. Folate is an
      essential factor for DNA methylation and the de novo biosynthesis of nucleotides,
      aberrations of which play important roles in mutagenesis. This study investigated
      whether the mutational hot spots of the Apc and p53 genes for human colorectal
      cancer are mutated in dimethylhydrazine-induced colorectal neoplasms and whether
      dietary folate can modulate mutations in these regions. Rats were fed diets
      containing 0, 2 (basal requirement), 8 or 40 mg folate/kg diet. Five weeks after
      diet initiation, dimethylhydrazine was injected weekly for 15 weeks. Mutations
      were determined by direct sequencing in 11 low and seven high grade dysplasias
      and 13 invasive adenocarcinomas. A total of six Apc mutations were found in four
      dysplastic and carcinomatous lesions: two in two low grade dysplasias, two in one
      high grade dysplasia and two in one adenocarcinoma. All mutations were single
      base substitutions, four of which were A:T-->G:C transitions. Five of the six
      mutations were located upstream from the region corresponding to the human APC
      mutation cluster region. Dietary folate had no effect on the frequency and type
      of Apc mutations. No mutations were detected in exons 5-9 of the p53 gene in
      neoplastic lesions. These data suggest that in the dimethylhydrazine rat model of
      colorectal cancer, the Apc gene is mutated in early stages, albeit to a lesser
      degree than observed in human colorectal cancer, whereas the mutational hot spot
      of the p53 gene for human colorectal cancer is not commonly mutated. Although the
      low frequency of Apc mutations and the small number of neoplasms studied in this
      study might have precluded our ability to observe modulatory effects of folate,
      dietary folate appears to have no significant effect on Apc and p53 mutations.

PMID- 10590232
TI  - Effect of ionizing radiation on transgenerational appearance of p(un) reversions
      in mice.
AB  - Multiple genetic changes are required for the development of a malignant tumor
      cell and many environmentally induced cancers show a delayed onset of > 20 years
      following exposure. In fact, the frequency of genetic changes in cancer cells is
      higher than can be explained by random mutation. A high level of genetic
      instability in a subpopulation of cells may be caused by a mutator phenotype
      transmitted through many cell divisions. We have determined the effects of
      irradiation of parental male mice on the frequency and characteristics of
      mitotically occurring DNA deletion events at the p(un) locus in the offspring.
      Reversion of the p(un) marker in mouse embryos is due to deletion of 70 kb of DNA
      resulting in fur spots in the offspring. We found that irradiation of male mice
      caused a significantly higher frequency of large spots in the offspring,
      indicative of the induction of DNA deletions early in embryo development. These
      deletion events occurred, however, many cell divisions after irradiation. The
      present data indicate that exposure of the germline to ionizing radiation results
      in induction of delayed DNA deletions in offspring mice.

PMID- 10590233
TI  - Inhibition of O(6)-methylguanine-DNA methyltransferase increases azoxymethane
      induced colonic tumors in rats.
AB  - Azoxymethane (AOM) causes O(6)-methylguanine adduct formation which leads to G-
      >A transitions. Their repair is carried out by O(6)-methylguanine-DNA
      methyltransferase (MGMT). To evaluate the importance of this repair event in AOM
      induced carcinogenesis, we examined the effect of O(6)-benzylguanine (BG), a
      potent inhibitor of MGMT, on colonic tumor development. Rats were treated weekly
      for 2 weeks at 0 and 24 h with BG (60 mg/kg body wt i.p.) or vehicle (40%
      polyethylene glycol, PEG-400), followed 2 h after the first dose of BG with AOM
      (15 mg/kg body wt) or vehicle (saline) i.p. Rats were killed 35 weeks later and
      tumors harvested and DNA extracted. In the AOM-treated groups, BG caused a
      significant increase in tumor incidence with tumors in 65.9%, versus 30.8% in the
      AOM/PEG-treated group (P < 0.05). In the BG/AOM group there was also a
      significant increase in tumor multiplicity, with 2.3 tumors/tumor-bearing rat,
      versus 1.6 tumors/tumor- bearing rat in the AOM/PEG group (P < 0.05). Since O(6)
      methylguanine adducts can cause activating mutations in the K-ras and beta
      catenin genes, we examined the effects of BG on these mutations. In the BG group
      there were seven mutations in codon 12 or 13 of exon 1 of the K-ras gene in 51
      tumors examined, compared with no K-ras mutations in 17 tumors analyzed in the
      AOM/PEG group (P = 0.12). In the BG/AOM group there were 10 mutations in exon 3
      of the beta-catenin gene among 48 tumors evaluated, compared with six mutations
      in 16 tumors analyzed in the PEG/AOM group (P = 0.16). In summary, MGMT
      inhibition increases AOM-induced colonic tumor incidence and multiplicity in
      rats.

PMID- 10590234
TI  - O(6)-methylguanine-DNA methyltransferase activity, p53 gene status and BCNU
      resistance in mouse astrocytes.
AB  - We observed previously that wild-type p53 rendered neonatal mouse astrocytes
      resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in a gene dose-dependent
      fashion. This effect of p53 appeared to be unrelated to its cell cycle regulation
      or apoptotic functions. Because in many cell types O(6)-methylguanine-DNA
      methyltransferase (MGMT)-mediated DNA repair is an important mechanism of
      resistance to nitrosoureas, we measured MGMT activity in wild-type, heterozygous
      and p53 knockout neonatal mouse astrocytes. Wild-type p53 astrocytes had
      significantly greater MGMT activity than either heterozygous or p53 knockout
      astrocytes: MGMT activity was approximately 5-fold greater in wild-type p53
      astrocytes than in p53 knockout cells. However, despite successful depletion of
      MGMT activity in wild-type astrocytes by O(6)-benzylguanine (BG), resistance to
      BCNU persisted unchanged. Moreover, we excluded the possibility that continued
      resistance to BCNU at the concentrations used could be explained by a
      compensatory induction of MGMT triggered by exposure to either BCNU or BG.
      Although these studies support a role for p53 regulation of MGMT in neonatal
      mouse astrocytes, BCNU resistance in wild-type cells appears to be mediated by a
      non-MGMT mechanism. Nevertheless, regulation of DNA repair by MGMT may be another
      mechanism by which alterations of the p53 gene promote tumor initiation or
      progression.

PMID- 10590235
TI  - Signaling in late preconditioning : involvement of mitochondrial K(ATP) channels.

PMID- 10590236
TI  - Vascular tissue engineering : designer arteries.

PMID- 10590237
TI  - Transcriptional profile of mechanically induced genes in human vascular smooth
      muscle cells.
AB  - Vascular smooth muscle cells must monitor and respond to their mechanical
      environment; however, the molecular response of these cells to mechanical stimuli
      remains incompletely defined. By applying a highly uniform biaxial cyclic strain
      to cultured cells, we used DNA microarray technology to describe the
      transcriptional profile of mechanically induced genes in human aortic smooth
      muscle cells. We first identified vascular endothelial growth factor (VEGF) as a
      mechanically induced gene in these cells; VEGF served as a positive control for
      these experiments. We then used a DNA microarray with 5000 genes with putative
      functions to identify additional mechanically induced genes. Surprisingly,
      relatively few genes are mechanically induced in human aortic smooth muscle
      cells. Only 3 transcripts of 5000 were induced >2.5-fold: cyclooxygenase-1,
      tenascin-C, and plasminogen activator inhibitor-1. Downregulated transcripts
      included matrix metalloproteinase-1 and thrombomodulin. The transcriptional
      profile of mechanically induced genes in human aortic smooth muscle cells
      suggests a response of defense against excessive deformation. These data also
      demonstrate that in addition to identifying large clusters of genes that respond
      to a given stimulus, DNA microarray technology may be used to identify a small
      subset of genes that comprise a highly specific molecular response.

PMID- 10590238
TI  - Oncostatin M induces interleukin-6 and cyclooxygenase-2 expression in human
      vascular smooth muscle cells : synergy with interleukin-1beta.
AB  - Oncostatin M (OSM), a cytokine first identified from activated monocytes and T
      lymphocytes, is one of the most potent autocrine growth factor for AIDS and
      Kaposi's sarcoma. Little is known about the effects of OSM on normal vascular
      cells. We thus exposed human aortic smooth muscle cells (hASMCs) to OSM, examined
      cell proliferation and morphology, and determined interleukin-6 (IL-6) and
      cyclooxygenase-2 (COX-2) expression. OSM had a weak antiproliferative effect.
      After a 4-day incubation with 100 ng/mL OSM, cell count decreased to 69+/-3% of
      control. However, OSM induced striking changes in hASMC morphology, characterized
      by a polyclonal shape, in contrast to the spindle morphological feature of
      control hASMCs. OSM stimulated the release of IL-6 by hASMCs in a dose-dependent
      way; after a 48-hour exposure, values were 8.5+/-0.7, 29.7+/-3.5, 50.9+/-4.4, and
      73.8+/-7.6x10(3) U/mL (n=6) at OSM concentrations of 0, 1, 10, and 100 ng/mL,
      respectively. OSM induced marked expression of COX-2 protein and mRNA. Leukemia
      inhibitory factor had no effect on hASMCs, indicating that OSM effects on hASMCs
      were mediated by the OSM type II receptor and not by the leukemia inhibitory
      factor receptor. OSM used the JAK/STAT signaling pathway, as demonstrated by
      rapid phosphorylation of JAK1 and specific activation of STAT1. Interestingly,
      OSM acted in synergy with IL-1beta on IL-6 production and COX-2 expression. In
      conclusion, OSM is a novel regulator of human smooth muscle cell functions,
      acting in concert with IL-1beta, and OSM may play a role in major vascular
      diseases such as atherosclerosis.

PMID- 10590239
TI  - Disruption of cadherin-related junctions triggers autocrine expression of
      vascular endothelial growth factor in bovine aortic endothelial cells : effects
      on cell proliferation and death resistance.
AB  - The mechanisms involved in the blockade of proliferation in confluent endothelial
      cells are insufficiently understood. In this regard, the continuity of
      intercellular junctions appears to be critical to the regulation of endothelial
      monolayer cell growth. The present study examined the hypothesis that the
      disruption of the intercellular adherens junctions will trigger both endothelial
      cell proliferation and autocrine production of growth factors. With this purpose,
      we assessed the changes in growth, death resistance, and expression of vascular
      endothelial growth factor (VEGF) under conditions of disruption of the
      intercellular junctions between endothelial cells. Disruption of cell junctions
      was produced by means of a specific anti-vascular endothelial cadherin monoclonal
      antibody, EGTA, or cytochalasin D. Our results disclosed that these maneuvers
      induce an increase in VEGF mRNA production, with transcription of the 121-, 165-,
      and 189-amino acid isoforms of VEGF. Further evidence of the relationship between
      endothelial cells monolayer continuity and VEGF protein expression was obtained
      by the demonstration of an increase in VEGF protein, as determined by Western
      blot, induced by the aforementioned maneuvers, as well as by immunocytochemical
      detection of increased VEGF staining in the areas surrounding a mechanical
      endothelial injury and in endothelial cells at subconfluence. In functional
      terms, the autocrine expression of VEGF was associated with growth-promoting and
      cytoprotective effects, as assessed by [(3)H]thymidine uptake, (51)Cr release,
      and flow cytometry. In conclusion, our results reveal that disruption of
      homophilic interendothelial junctions induces VEGF expression. Under these
      conditions, autocrine VEGF appears to have a relevant role in death inhibition
      and proliferation of endothelial cells.

PMID- 10590240
TI  - Aldosterone upregulates Ca(2+) current in adult rat cardiomyocytes.
AB  - Aldosterone is associated with the pathogenesis and progression of left
      ventricular hypertrophy and heart failure, independent of its relation with
      arterial blood pressure. However, little information exists about the possible
      influence of this mineralocorticoisteroid on cardiomyocyte electrical activity.
      The present study was designed to determine the role of aldosterone on whole-cell
      Ca(2+) current (I(Ca)) in isolated adult rat ventricular myocytes using the patch
      clamp technique. We found that incubation of cells with 1 micromol/L aldosterone
      for 24 hours increases the density of I(Ca) significantly. This "long-term"
      aldosterone treatment had no significant effects on the kinetics and voltage
      dependence of I(Ca) inactivation. Moreover, no demonstrable influence of
      aldosterone on I(Ca) could be detected during short-term exposure (up to 6
      hours), under our experimental conditions. The classical aldosterone
      intracellular receptor antagonist spironolactone (250-fold excess) was able to
      blunt the aldosterone-induced increase in I(Ca) density. These effects were also
      observed with lower concentrations of aldosterone (10 and 100 nmol/L). Moreover,
      inhibitors of transcription (actinomycin D, 5 microg/mL) and protein synthesis
      (cycloheximide, 20 microg/mL) prevented the aldosterone-dependent increase in
      I(Ca). Therefore, the long latency I(Ca) stimulation effect of aldosterone might
      result from an increased channel expression. We suggest that this genomic action
      contributes to the increased I(Ca) observed during cardiac remodeling.

PMID- 10590241
TI  - Activation of mitochondrial K(ATP) channel elicits late preconditioning against
      myocardial infarction via protein kinase C signaling pathway.
AB  - Activation of mitochondrial K(ATP) (mitoK(ATP)) channel induces acute ischemic
      preconditioning (PC) against ischemic injury. The ability of this channel to
      elicit late PC remains unknown. The present study tests the hypothesis that
      stimulation of mitoK(ATP) channel induces late PC via the protein kinase C (PKC)
      signaling pathway. Rats were subjected to 30 minutes of regional ischemia and 120
      minutes of reperfusion (I/R). In other groups, rats were pretreated with
      diazoxide, a specific opener of the mitoK(ATP) channel (7 mg/kg, IV), 12, 24, 48,
      and 72 hours before they were subjected to I/R. A maximum reduction in infarct
      size was observed after 24 hours (33.3+/-2.2% versus I/R group, 62.1 +/-2.4%).
      Pretreatment with diazoxide did not reduce the infarct size significantly after
      12, 48, and 72 hours (50.2+/-4.3%, 50.5+/-4.6%, and 58.2+/-4.9%) compared with
      the I/R group. The protection was blocked with 5-hydroxydecanoic acid (5-HD, 5
      mg/kg IV), a relatively selective mitoK(ATP) channel blocker (56.5+/-2.7%), and
      chelerythrine (5 mg/kg IV), an effective PKC inhibitor (57.1+/-3.4%) administered
      either on the first day before diazoxide pretreatment or 10 minutes before I/R on
      the second day. Cell necrosis was decreased by approximately 50% in the diazoxide
      preconditioned hearts compared with control I/R hearts. Cell death by apoptosis
      was also significantly decreased in diazoxide pretreated hearts (3.2%) as
      compared with I/R (11.3%). In conclusion, activation of mitoK(ATP) channel with
      diazoxide produces late PC against reperfusion injury. The effect of mitoK(ATP)
      channel appears to be dependent on the PKC-mediated signal pathway.

PMID- 10590242
TI  - Bifunctional role of protein tyrosine kinases in late preconditioning against
      myocardial stunning in conscious rabbits.
AB  - Although protein tyrosine kinases (PTKs) have been implicated in late
      preconditioning (PC) against infarction, their role in late PC against stunning
      is unknown. Furthermore, it is unknown whether PTK signaling is necessary only to
      trigger late PC on day 1 or also to mediate it on day 2. Thus, conscious rabbits
      underwent a sequence of six 4-minute coronary occlusion/4-minute reperfusion
      cycles for 3 consecutive days (days 1, 2, and 3). In the control group (group I,
      n=7), the recovery of systolic wall thickening after the 6 occlusion/reperfusion
      cycles was markedly improved on days 2 and 3 compared with day 1, indicating the
      development of late PC against stunning. Administration of the PTK inhibitor
      lavendustin-A (LD-A, 1 mg/kg IV) before the first occlusion on day 1 (group II,
      n=7) completely prevented the late PC effect against stunning on day 2. Late PC
      against stunning was also abrogated when LD-A was given before the first
      occlusion on day 2 (group III, n=7); however, in these rabbits, the late PC
      effect became apparent on day 3, indicating that LD-A itself did not have any
      delayed deleterious actions on myocardial stunning. In group V (n=5), the
      sequence of 6 occlusion/reperfusion cycles resulted in a robust increase in the
      activity of inducible NO synthase (iNOS [assessed as Ca(2+)-independent L
      citrulline formation]) and nitrite+nitrate (NO(x)) tissue levels 24 hours later
      (on day 2), with no concomitant change in Ca(2+)-dependent NO synthase
      (endothelial NO synthase and/or neuronal NO synthase) activity. Similar results
      were obtained on day 3 (group VIII, n=6), indicating sustained upregulation of
      iNOS. Administration of LD-A either on day 1 (group VI, n=5) or on day 2 (group
      VII, n=6) abrogated the increase in iNOS activity and NO(x) levels on day 2. LD-A
      had no effect on iNOS activity or NO(x) levels in the absence of PC (group X,
      n=5). This study demonstrates that in conscious rabbits, PTK activity is
      necessary not only to trigger late PC against stunning on day 1 but also to
      mediate the protection on day 2. This investigation also provides the first
      direct evidence that cardiac iNOS activity is upregulated during the late phase
      of ischemic PC in rabbits. Furthermore, the data indicate that PTK signaling is
      essential for the augmentation of iNOS activity and that PTKs modulate this
      enzyme at two distinct levels: at an early stage on day 1 and at a late stage on
      day 2. This bifunctional role of PTKs in late PC has broad implications for the
      signaling mechanisms that underlie the response of the heart to ischemic stress
      and, possibly, other stresses.

PMID- 10590243
TI  - Differential regulation of p90 ribosomal S6 kinase and big mitogen-activated
      protein kinase 1 by ischemia/reperfusion and oxidative stress in perfused guinea
      pig hearts.
AB  - Reactive oxygen species (ROS) activate members of the Src kinase and mitogen
      activated protein kinase superfamily, including big mitogen-activated protein
      kinase 1 (BMK1) and extracellular signal-regulated kinases (ERK1/2). A
      potentially important downstream effector of ERK1/2 is p90 ribosomal S6 kinase
      (p90RSK), which plays an important role in cell growth through the activation of
      several transcription factors, as well as the Na(+)/H(+) exchanger. Previously,
      we showed that Src regulates BMK1 via a redox-sensitive signaling pathway.
      Because ROS are generated during ischemia and reperfusion after ischemia, we
      assessed the effects of these stimuli (H(2)O(2), ischemia, and reperfusion) in
      the activation of ERK1/2, p90RSK, Src, and BMK1 in perfused guinea pig hearts.
      H(2)O(2) (100 micromol/L) significantly activated all kinases. Ischemia alone
      stimulated p90RSK, Src, and BMK1 but not ERK1/2. These results suggest that
      p90RSK activation through ischemia occurs via a pathway other than ERK1/2. A role
      of Src in ischemia-mediated BMK1 activation was demonstrated through inhibition
      with the Src inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4
      d]pyrimidine. Reperfusion after ischemia stimulated both p90RSK and ERK1/2. In
      contrast, although ROS increase during reperfusion after ischemia, the activities
      of both BMK1 and its upstream regulator, Src, were markedly attenuated by
      reperfusion after ischemia. The activation of C-terminal Src kinase during
      ischemia but not during reperfusion suggests that the attenuation of Src and BMK1
      activity by reperfusion was not regulated by C-terminal Src kinase activity. The
      antioxidant N-2-mercaptopropionylglycine completely inhibited ERK1/2 and p90RSK
      activation by reperfusion but only partially inhibited ischemia-induced Src and
      BMK1 activation. The present study is the first to show the coregulation of Src
      and BMK1 by reperfusion after ischemia, which we propose to occur via a novel,
      ROS-independent pathway.

PMID- 10590244
TI  - Novel vascular graft grown within recipient's own peritoneal cavity.
AB  - A method by which to overcome the clinical symptoms of atherosclerosis is the
      insertion of a graft to bypass an artery blocked or impeded by plaque. However,
      there may be insufficient autologous mammary artery for multiple or repeat
      bypass, saphenous vein may have varicose degenerative alterations that can lead
      to aneurysm in high-pressure sites, and small-caliber synthetic grafts are prone
      to thrombus induction and occlusion. Therefore, the aim of the present study was
      to develop an artificial blood conduit of any required length and diameter from
      the cells of the host for autologous transplantation. Silastic tubing, of
      variable length and diameter, was inserted into the peritoneal cavity of rats or
      rabbits. By 2 weeks, it had become covered by several layers of myofibroblasts,
      collagen matrix, and a single layer of mesothelium. The Silastic tubing was
      removed from the harvested implants, and the tube of living tissue was everted
      such that it now resembled a blood vessel with an inner lining of nonthrombotic
      mesothelial cells (the "intima"), with a "media" of smooth muscle-like cells
      (myofibroblasts), collagen, and elastin, and with an outer collagenous
      "adventitia." The tube of tissue (10 to 20 mm long) was successfully grafted by
      end-to-end anastomoses into the severed carotid artery or abdominal aorta of the
      same animal in which they were grown. The transplant remained patent for at least
      4 months and developed structures resembling elastic lamellae. The myofibroblasts
      gained a higher volume fraction of myofilaments and became responsive to
      contractile agonists, similar to the vessel into which they had been grafted. It
      is suggested that these nonthrombogenic tubes of living tissue, grown in the
      peritoneal cavity of the host, may be developed as autologous coronary artery
      bypass grafts or as arteriovenous access fistulae for hemodialysis patients.

PMID- 10590245
TI  - Matrix metalloproteinase-9 overexpression enhances vascular smooth muscle cell
      migration and alters remodeling in the injured rat carotid artery.
AB  - Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of
      atherosclerosis as well as intimal hyperplasia after vascular injury. We used
      Fischer rat smooth muscle cells (SMCs) overexpressing MMP-9 to determine the role
      of MMP-9 in migration and proliferation as well as in vessel remodeling after
      balloon denudation. Fischer rat SMCs were stably transfected with a cDNA for rat
      MMP-9 under the control of a tetracycline-regulatable promoter. In this system,
      MMP-9 was overexpressed in the absence, but not in the presence, of tetracycline.
      In vitro SMC migration was determined using a collagen invasion assay as well as
      a Boyden chamber assay. In vivo migration was determined by measuring the
      invasion into the medial and intimal layers of transduced SMCs seeded on the
      outside of the artery. Transduced SMCs were also seeded on the luminal surface,
      and the effect of local MMP-9 overexpression on vascular structure was measured
      morphometrically at intervals up to 28 days. MMP-9 overexpression enhanced SMC
      migration in both the collagen invasion assay and Boyden chamber in vitro,
      increased SMC migration into an arterial matrix in vivo, and altered vessel
      remodeling by increasing the vessel circumference, thinning the vessel wall and
      decreasing intimal matrix content. These results demonstrate that MMP-9 enhances
      vascular SMC migration in vitro and in vivo and alters postinjury vascular
      remodeling.

PMID- 10590246
TI  - Tissue inhibitor of matrix metalloproteinases-1 impairs arterial neointima
      formation after vascular injury in mice.
AB  - The hypothesis that tissue inhibitor of metalloproteinases-1 (TIMP-1) plays a
      role in neointima formation was tested with the use of a vascular injury model in
      wild-type (TIMP-1(+/+)) and TIMP-1-deficient (TIMP-1(-/-)) mice. The neointimal
      area at 1 to 3 weeks after electric injury of the femoral artery was
      significantly higher in TIMP-1(-/-) as compared with TIMP-1(+/+) mice (0.012+/-0.
      0015 versus 0.0033+/-0.0008 mm(2) at 1 week, P<0.005). The medial areas were
      comparable, resulting in intima/media ratios that were significantly larger in
      TIMP-1(-/-) as compared with TIMP-1(+/+) arteries (1.2+/-0.22 versus 0.39+/-0.08
      at 1 week, P<0.005). Nuclear cell counts in cross-sectional areas of the intima
      of the injured region were higher in TIMP-1(-/-) as compared with TIMP-1(+/+)
      arteries (138+/-15 versus 69+/-8 at 1 week, P<0.005). Immunocytochemical analysis
      revealed that alpha-actin-positive smooth muscle cells (SMCs) at 2 weeks after
      injury were more abundant in the intima of TIMP-1(-/-) arteries than in that of
      TIMP-1(+/+) arteries, whereas after 3 weeks the intimal cell population consisted
      mainly of SMCs in both genotypes. In in vitro scrape-wounding assays, SMCs of
      TIMP-1(-/-) mice migrated faster than those of TIMP-1(+/+) mice. Zymography of
      arterial extracts revealed a higher active matrix metalloproteinase (MMP)-2 level
      at 1 to 3 weeks after injury in TIMP-1(-/-) arteries, whereas active MMP-9 was
      only detected in TIMP-1(-/-) arteries at 1 week after injury. These data are
      compatible with a role of TIMP-1 in the impairment of SMC migration and neointima
      formation after vascular injury, as a result of inhibition of MMP activity.

PMID- 10590247
TI  - Decreased neointimal thickening after arterial wall injury in inducible nitric
      oxide synthase knockout mice.
AB  - Mechanical injury in vivo results in the expression of the inducible form of
      nitric oxide synthase (iNOS) in vascular smooth muscle cells. However, the role
      of iNOS in modulating neointima formation after arterial wall injury is not
      clear. To determine whether the induction of iNOS gene expression promotes or
      attenuates the neointimal response to injury, we used a murine model of
      perivascular injury induced by placing a periadventitial collar around the
      carotid arteries in both wild-type and iNOS knockout mice (iNOS-KO mice).
      Periadventitial injury induced iNOS expression in the wild-type but not the iNOS
      KO mice. Neointimal area and the intima/media ratio were significantly less in
      the iNOS-KO mice compared with the wild-type mice at 21 days. Injury-induced
      proliferation of medial cells and vascular cell adhesion molecule-1 expression
      were also attenuated in iNOS-KO mice compared with wild-type mice. The induction
      of iNOS and the activation of the nuclear factor-kappaB-mediated pathway were
      also demonstrated in an in vitro injury model. We conclude that mechanical injury
      in vivo and in vitro induces iNOS expression and that lack of iNOS expression
      attenuates neointima formation after perivascular arterial injury. Taken
      together, these findings suggest that iNOS expression after vascular injury may
      promote neointima formation.

PMID- 10590248
TI  - Adrenomedullin receptor antagonism by calcitonin gene-related peptide(8-37)
      inhibits carotid artery neointimal hyperplasia after balloon injury.
AB  - Intimal injury by angioplasty results in a series of changes, including smooth
      muscle cell hyperplasia, that lead to vascular restenosis. Adrenomedullin, a
      potent vasodilator peptide, has natriuretic effects, and its plasma concentration
      is elevated in cardiovascular diseases. Adrenomedullin is secreted by endothelial
      and vascular smooth muscle cells, but its role in neointimal hyperplasia after
      balloon injury has not been previously described. We investigated the role of
      endogenous adrenomedullin in neointimal hyperplasia using an in vivo rat model of
      postinjury vascular restenosis. In the injured rats, bromodeoxyuridine-labeled
      nuclei in the media of untreated common carotid arteries were increased 2 days
      after injury, which were suppressed by in vivo treatment with the adrenomedullin
      receptor antagonist calcitonin gene-related peptide (CGRP)(8-37). Inhibition of
      neointimal hyperplasia by CGRP(8-37) was distinct at 7 and 14 days, whereas
      CGRP(1-37) had no effect. The expression of adrenomedullin in the media of both
      untreated and treated common carotid arteries was elevated at 2 days and further
      enhanced in hyperplastic intima of untreated common carotid arteries at 7 days.
      Our findings suggest a novel role for endogenous adrenomedullin in balloon injury
      induced restenosis and indicate that CGRP(8-37) may be useful for the prevention
      of vascular restenosis.

PMID- 10590249
TI  - A single Na(+) channel mutation causing both long-QT and Brugada syndromes.
AB  - Mutations in SCN5A, the gene encoding the cardiac Na(+) channel, have been
      identified in 2 distinct diseases associated with sudden death: one form of the
      long-QT syndrome (LQT(3)) and the Brugada syndrome. We have screened SCN5A in a
      large 8-generation kindred characterized by a high incidence of nocturnal sudden
      death, and QT-interval prolongation and the "Brugada ECG" occurring in the same
      subjects. An insertion of 3 nucleotides (TGA) at position 5537, predicted to
      cause an insertion of aspartic acid (1795insD) in the C-terminal domain of the
      protein, was linked to the phenotype and was identified in all
      electrocardiographically affected family members. ECGs were obtained from 79
      adults with a defined genetic status (carriers, n=43; noncarriers, n=36). In
      affected individuals, PR and QRS durations and QT intervals are prolonged
      (P<0.0001 for all parameters). ST segment elevation in the right precordial leads
      is present as well (P<0.0001). Twenty-five family members died suddenly, 16 of
      them during the night. Expression of wild-type and mutant Na(+) channels in
      Xenopus oocytes revealed that the 1795insD mutation gives rise to a 7.3-mV
      negative shift of the steady-state inactivation curve and an 8.1-mV positive
      shift of the steady-state activation curve. The functional consequence of both
      shifts is likely to be a reduced Na(+) current during the upstroke of the action
      potential. LQT(3) and Brugada syndrome are allelic disorders but may also share a
      common genotype.

PMID- 10590250
TI  - Vascular biology in genetically altered mice : smaller vessels, bigger insight.

PMID- 10590252
TI  - Increased c-Fos/activator protein-1 confers resistance against anergy induction
      on antigen-specific T cell.
AB  - We have studied the contribution of c-Fos/activator protein-1 (AP-1) to antigen
      specific T cell response with reference to T cell anergy by increasing c-Fos/AP-1
      in vivo and in vitro. First, after injection of a high dose of staphylococcus
      enterotoxin B (SEB), clonal deletion of SEB-reactive V(beta)8(+) CD4 T cells
      occurred both in control B6 and H2-c-fos transgenic (fos) mice, whereas
      proliferation of T cells against SEB was profoundly depressed in B6 but not in
      fos mice. Second, the keyhole limpet hemocyanin-specific CD4 T(h)1 cell clone
      produced decreasing amounts of IL-2 in response to increasing amounts of
      concanavalin A (Con A) in vitro, whereas the decrease was less significant in the
      T(h)1 clones stably transfected with c-fos gene. Electrophoretic mobility shift
      assay with nuclear protein from the transformants showed that overexpression of
      the c-fos gene compensated the amounts of AP-1 in the nuclei of Con A-treated
      T(h)1 clones. Thus, increased c-Fos/AP-1 confers resistance against anergy
      induction on antigen-specific T cells.

PMID- 10590251
TI  - ARC inhibits cytochrome c release from mitochondria and protects against hypoxia
      induced apoptosis in heart-derived H9c2 cells.
AB  - Ischemia induces apoptosis as well as necrosis of cardiac myocytes. We recently
      reported the cloning of a cDNA that encodes an apoptotic inhibitor, ARC, that is
      expressed predominantly in cardiac and skeletal muscle. In the present study, we
      examined the ability of ARC to protect rat embryonic heart-derived H9c2 cells
      from apoptosis induced by hypoxia, a component of ischemia. We found that H9c2
      cells express ARC and that exposure to hypoxia substantially reduces ARC
      expression while inducing apoptosis. Transfected H9c2 cells in which cytosolic
      ARC protein levels remain elevated during hypoxia were significantly more
      resistant to hypoxia-induced apoptosis than parental H9c2 cells or H9c2 cells
      transfected with a control vector. Loss of endogenous ARC in the cytosol of H9c2
      cells was associated with translocation of ARC from the cytosol to intracellular
      membranes, release of cytochrome c from the mitochondria, activation of caspase
      3, poly(ADP-ribose)polymerase (PARP) cleavage, and DNA fragmentation. All of
      these events were inhibited in H9c2 cells overexpressing ARC when compared with
      control cells. In contrast, caspase inhibitors prevented PARP cleavage but not
      cytochrome c release, suggesting that exogenously expressed ARC acts upstream of
      caspase activation in this model of apoptosis. These results demonstrate that ARC
      can protect heart myogenic H9c2 cells from hypoxia-induced apoptosis, and that
      ARC prevents cytochrome c release by acting upstream of caspase activation,
      perhaps at the mitochondrial level.

PMID- 10590253
TI  - The role of CTLA-4 in tolerance induction and T cell differentiation in
      experimental autoimmune encephalomyelitis: i.p. antigen administration.
AB  - Recent evidence suggests that co-stimulation provided by B7 molecules through
      CTLA-4 is important in establishing peripheral tolerance. In the present study,
      we examined the kinetics of tolerance induction and T cell differentiation
      following i.p. administration of myelin basic protein (MBP) Ac1-11 in mice
      transgenic for a TCR V(beta)8.2 gene derived from an encephalitogenic T cell
      clone specific for MBP Ac1-11. Examination of the lymph node cell response after
      antigen administration demonstrated a dependence on CTLA-4 for i.p. tolerance
      induction. Examination of splenocyte responses suggested that i.p. antigen
      administration induced a T(h)2 response, which was potentiated by anti-CTLA-4
      administration. Interestingly, i.p. tolerance was able to inhibit the induction
      of experimental autoimmune encephalomyelitis and anti-CTLA-4 administration did
      not alter this phenotype, suggesting that CTLA-4 blockade did not block tolerance
      induction. Thus, T cell differentiation and the dependence on CTLA-4 for
      tolerance induction following i.p. antigen administration differs between lymph
      node and spleen in a model of organ-specific autoimmunity.

PMID- 10590254
TI  - The role of CTLA-4 in tolerance induction and ttigen administration cell
      differentiation in experimental autoimmune encephalomyelitis: i. v. antigen
      administration.
AB  - Interactions between B7 molecules on antigen-presenting cells and CTLA-4 on T
      cells have been shown to be important in establishing tolerance. In the present
      study, we examined the kinetics of tolerance induction following i.v.
      administration of myelin basic protein (MBP) Ac1-11 in mice transgenic for a TCR
      V(beta)8.2 gene derived from an encephalitogenic T cell clone specific for MBP
      Ac1-11. Examination of the lymph node cell (LNC) response 10 days after antigen
      administration demonstrated an accentuation of i.v. tolerance induction with anti
      CTLA-4 blockade. Anergy was induced in splenocytes by i.v. antigen administration
      as shown by a decrease in MBP-specific proliferation and IL-2 production, and
      anti-CTLA-4 potentiated this effect. In addition, i.v. antigen plus anti-CTLA-4
      and complete Freund's adjuvant was not encephalitogenic. Interestingly, i.v.
      tolerance (a single injection) did not inhibit experimental autoimmune
      encephalomyelitis (EAE) and anti-CTLA-4 administration did not alter this
      phenotype. These results suggest that while the majority of MBP-specific T cells
      are tolerized by i.v. antigen and that this process is potentiated by anti-CTLA-4
      administration, a population of T cells remains that is quite efficient in
      mediating EAE.

PMID- 10590255
TI  - Definition and transfer of a serological epitope specific for peptide-empty forms
      of MHC class I.
AB  - Nascent class I molecules have been hypothesized to undergo a conformational
      change when they bind peptide based on the observation that most available
      antibodies only detect peptide-loaded class I. Furthermore recent evidence
      suggests that this peptide-facilitated conformational change induces the release
      of class I from association with transporter associated with antigen processing
      (TAP)/tapasin and other endoplasmic reticulum proteins facilitating class I
      assembly. To learn more about the structure of peptide-empty class I, we have
      studied mAb 64-3-7 that is specific for peptide-empty forms of L(d). We show here
      that mAb 64-3-7 detects a linear stretch of amino acids including principally
      residues 48Q and 50P. Furthermore, we demonstrate that the 64-3-7 epitope can be
      transferred to other class I molecules with limited mutagenesis. Interestingly,
      in the folded class I molecule residues 48 and 50 are on a loop connecting a beta
      strand (under the bound peptide) with the alpha(1) helix (rising above the ligand
      binding site). Thus it is attractive to propose that this loop is a hinge region.
      Importantly, the three-dimensional structure of this loop is strikingly conserved
      among class I molecules. Thus our findings suggest that all class I molecules
      undergo a similar conformational change in the loop around residues 48 and 50
      when they associate with peptide.

PMID- 10590256
TI  - gammadelta T cells regulate mucosally induced tolerance in a dose-dependent
      fashion.
AB  - We used gammadelta TCR-deficient (TCRdelta(-/-)) mice to examine the role of
      gammadelta T cells for induction of mucosal responses and systemic tolerance to
      high versus low doses of oral antigen. When either TCRdelta(-/-) or TCRdelta(+/+)
      mice were immunized orally with a high dose of ovalbumin (OVA) prior to
      parenteral challenge, systemic IgG and IgE antibody responses were markedly
      reduced in both types of mice, while mucosal IgA responses were reduced only in
      the TCRdelta(-/-) mice. Reduced T cell proliferative responses and delayed-type
      hypersensitivity were seen in TCRdelta(-/-) and TCRdelta(+/+) mice given the high
      dose of OVA. Antigen-induced T(h)1 and T(h)2 cytokine production by splenic
      CD4(+) T cells was severely inhibited in orally tolerized TCRdelta(-/-) and
      TCRdelta(+/+) mice. In contrast, while oral tolerance associated with increased
      levels of IL-10 synthesis was induced by a low dose of OVA in TCRdelta(+/+) mice,
      the TCRdelta(-/-) mice were not tolerized and failed to produce IL-10. Our
      findings indicate that gammadelta T cells play a significant immunoregulatory
      role in IL-10-mediated, low-dose oral tolerance induction, but are not essential
      participants in the induction of systemic tolerance to orally introduced antigens
      given in larger doses.

PMID- 10590257
TI  - Characteristics and pathogenic role of anti-beta2-glycoprotein I single-chain Fv
      domains: induction of experimental antiphospholipid syndrome.
AB  - Antiphospholipid syndrome is characterized by the presence of high titers of anti
      beta(2)-glycoprotein I (beta(2)GPI) antibodies, lupus anticoagulant associated
      with thromboembolic phenomena, thrombocytopenia and recurrent fetal loss. Single
      chain Fv (scFv) were prepared from four anti-beta(2)GPI mAb, CAM, CAL, CAR and
      2C4C2, and one anti-ssDNA. All five scFv showed the same antigen binding
      properties as the original mAb. Replacement of the pathogenic CAM V(H) domain
      with the non-pathogenic CAL V(H) or anti-ssDNA V(H) decreased the binding
      affinity of the scFv to beta(2)GPI and completely abrogated the anticoagulant
      activity. Exchanging the CAM V(H) with anti-DNA V(H) resulted in a shift from
      anti-beta(2)GPI to anti-ssDNA binding of the scFv. Replacement of the CAM V(L)
      with CAL V(L) did not affect the binding and activity. BALB/c mice were immunized
      with the anti-beta(2)GPI scFv, and the scFv resulting from the substitution of
      the heavy (H) and light (L) chains. The mice which were immunized with CAM, 2C4C2
      and CAR scFv developed clinical manifestations of experimental anti-phospholipid
      syndrome. Elevated titers of mouse anti-cardiolipin (aCL), anti-beta(2)GPI,
      associated with lupus anticoagulant activity, thrombocytopenia, prolonged
      activated partial thromboplastin time and a high percentage of fetal resorptions
      were detected, in the CAM scFv group and in the scFv composed of CAM V(H) groups.
      High titers of aCL, anti-beta(2)GPI, anti-ss/dsDNA and anti-histone associated
      with lupus findings were observed in the sera of the 2C4C2 scFv-immunized mice.
      Immunization with CAL scFv did not lead to any clinical findings. The current
      study shows that scFv of pathogenic antibodies are capable of inducing the same
      clinical manifestations as the whole antibody molecule upon active immunization.
      Replacement of H/L chains point to the importance of the V(H) domains in the
      pathogenic potential of anti-beta(2)GPI.

PMID- 10590258
TI  - CD4(+) T cells induced by virus-like particles expressing a major T cell epitope
      down-regulate IL-5 production in an ongoing immune response to Der p 1
      independently of IFN-gamma production.
AB  - It has been previously demonstrated that hybrid Ty virus-like particles (VLP)
      prime effective CD8(+) and CD4(+) T cell responses. In this study, we
      investigated the effect of treating mice with Ty VLP carrying the immunodominant
      epitope of Der p 1 after sensitizing them to the group 1 allergen of the house
      dust mite Dermatophagoides pteronyssinus (Der p 1), under conditions that induce
      T(h)2 immunity. We show that i.p. treatment with the hybrid VLP abrogated
      allergen-specific IL-5 production and reduced allergen-specific cell
      proliferation. This suppression of the response was mediated by CD4(+) T cells
      and was not accompanied by an increase in IFN-gamma production.

PMID- 10590259
TI  - Mapping and characterization of the epitope(s) of Sch 55700, a humanized mAb,
      that inhibits human IL-5.
AB  - mAb against human IL-5 inhibit pulmonary eosinophilia, tissue damage and airway
      hyper-reactivity in allergic animal models. Sch 55700 is a humanized,
      neutralizing anti-IL-5 antibody. To better understand the molecular mechanism by
      which Sch 55700 blocks IL-5 bioactivity, we have mapped its epitope by scanning
      IL-5 with synthetic peptides. Those peptides containing a region, ERRRV,
      corresponding to amino acids 89-93 of IL-5 specifically interact with both Sch
      55700 and its parental rat IgG, 39D10. Among the five residues of this region,
      all three arginine residues were particularly critical for interaction of these
      peptides with Sch 55700. We further characterized this region by alanine scanning
      using site-directed mutagenesis. Examination of COS-expressed IL-5 mutants by
      Western blot showed that single mutations of E(89), R(90), R(91) or R(92) to
      alanine caused a loss of IL-5 binding to both Sch 55700 and 39D10. We further
      demonstrated in surface plasmon resonance studies using a BIAcore biosenosor that
      E(89), R(90) or R(91) are involved in the interaction between IL-5 and its
      receptor alpha subunit. Based upon the findings here and previously reported
      structures of the IL-5 and 39D10 variable region, we propose a model suggesting
      that the molecular interactions between the IL-5 and Sch 55700 mainly involve
      several ion pair interactions. We conclude that Sch 55700 occupies a region,
      ERRR, on IL-5 that is essential for its interaction with the receptor and thereby
      blocks IL-5 bioactivity.

PMID- 10590260
TI  - Nuclear factor of activated T cells contributes to the function of the CD28
      response region of the granulocyte macrophage-colony stimulating factor promoter.
AB  - The granulocyte macrophage colony stimulating factor (GM-CSF) promoter contains a
      10 bp element known as CK-1 or CD28RE that specifically responds to the co
      stimulatory signal delivered to T cells via the CD28 surface receptor. This
      element is a variant NFkappaB site that does not function alone but requires an
      adjacent promoter region that includes a classical NFkappaB element, an Sp-1 site
      and a putative activator protein-1 (AP-1)-like binding site. The entire region is
      referred to as the CD28 response region (CD28RR). The GM-CSF CK-1 element has
      been shown to bind NFkappaB proteins, in particular c-Rel, whose binding and
      function is dependent on the architectural transcription factor HMGI(Y). It has
      been previously suggested that the nuclear factor of activated T cells (NFAT)
      family of proteins also plays a role in the activity of this region. We show here
      that recombinant NFATp but not AP-1 can bind to the GM-CSF CD28RR. NFATp present
      in activated Jurkat T cell extracts can also interact with the CD28RR. The
      binding of NFATp and Rel proteins requires the same core CK-1 sequences, and
      appears to be mutually exclusive. We investigated the functional significance of
      NFATp binding to CK-1 by overexpressing the protein in Jurkat T cells and found
      that NFATp cannot activate the CD28RR alone but can cooperate with signals
      generated by phorbol 12-myristate 13-acetate/calcium ionophore. The CD28RR is
      therefore a complex region that can bind and respond to a combination of
      transcription factors and signals.

PMID- 10590262
TI  - Characterization of the membrane-bound and a soluble form of human IL-4 receptor
      alpha produced by alternative splicing.
AB  - IL-4 plays a major role in IgE production. Its signal is conferred to effector
      cells through binding to the alpha chain of the membrane-bound human IL-4
      receptor (huIL-4Ralpha). Here we present the genomic structure and organization
      of huIL-4Ralpha. The promotor region shows binding sites for several
      transcription factors involved in inflammatory processes. HuIL-4Ralpha has been
      shown to be organized differently to that of mouse IL-4Ralpha. A soluble form of
      huIL-4Ralpha is produced by alternative splicing of the huIL-4Ralpha gene (shuIL
      4Ralpha/splice). Expression of the corresponding mRNA coding for the
      extracellular part of the receptor and an additional three amino acids is also
      shown. A second form of huIL-4Ralpha, i.e. shuIL-4Ralpha/prot, is produced by
      limited proteolysis of the receptor (shedding) and is already known. These
      results reveal a complex pattern for the regulation of the IL-4 pathway at the
      receptor level. The patterns of expression of all three receptor proteins as well
      as their individual meaning in the context of inflammation still have to be
      elucidated.

PMID- 10590261
TI  - Isolation and characterization of a novel HS1 SH3 domain binding protein, HS1BP3.
AB  - We have isolated a novel gene, HS1BP3, which encodes an HS1 binding protein.
      Analysis of HS1BP3 cDNA indicates several potentially important segments,
      including a PX domain, a leucine zipper, immunoreceptor tyrosine-based inhibitory
      motif-like motifs and proline-rich regions. HS1BP3 associates with HS1 proteins
      in vivo as confirmed by immunoprecipitation in B and T cell lines. HS1BP3
      preferentially associates with the HS1 SH3 domains rather than with other SH3
      molecules, suggesting a role of HS1BP3 as an HS1 signaling mediator.
      Overexpression of mutant HS1BP3 protein in T cell lines results in decreased IL-2
      production. Our data suggest a novel role for HS1BP3 in lymphocyte activation.

PMID- 10590263
TI  - Optimal activation of tumor-reactive T cells by selected antigenic peptide
      analogues.
AB  - Many mechanisms have been proposed to explain why immune responses against human
      tumor antigens are generally ineffective. For example, tumor cells have been
      shown to develop active immune evasion mechanisms. Another possibility is that
      tumor antigens are unable to optimally stimulate tumor-specific T cells. In this
      study we have used HLA-A2/Melan-A peptide tetramers to directly isolate antigen
      specific CD8(+) T cells from tumor-infiltrated lymph nodes. This allowed us to
      quantify the activation requirements of a representative polyclonal yet
      monospecific tumor-reactive T cell population. The results obtained from
      quantitative assays of intracellular Ca(2+) mobilization, TCR down-regulation,
      cytokine production and induction of effector cell differentiation indicate that
      the naturally produced Melan-A peptides are weak agonists and are clearly
      suboptimal for T cell activation. In contrast, optimal T cell activation was
      obtained by stimulation with recently defined peptide analogues. These findings
      provide a molecular basis for the low immunogenicity of tumor cells and suggest
      that patient immunization with full agonist peptide analogues may be essential
      for stimulation and maintenance of anti-tumor T cell responses in vivo.

PMID- 10590264
TI  - Allelic variations in rat MHC class II binding of myelin basic protein peptides
      correlate with encephalitogenicity.
AB  - The impact of the strength and promiscuity of the self peptide-MHC class II
      interaction on susceptibility to autoimmune disease is uncertain. Here we studied
      allelic differences in the affinity of rat MHC class II molecules for myelin
      basic protein (MBP) peptides spanning from position 63 to 106. Predominantly
      peptides from this region are immunogenic in the rat and the MHC class II region
      determines if the response is disease promoting or disease protective.
      Strikingly, RT1.B (DQ-like) molecules showed much more allelic variation of MBP
      peptide binding than RT1.D (DR-like) molecules. Moderate to strong binding of
      particular MBP peptides correlated with their previously documented
      encephalitogenicity. Moreover, the differences in disease susceptibility to
      certain MBP peptides observed in the different rat strains were clearly reflected
      in the allelic diversity of the peptide binding profiles. In conclusion our
      findings demonstrate that disease-inducing stretches of MBP generally comprise
      good binding peptides.

PMID- 10590265
TI  - Expression profile of active genes in mouse lymph node high endothelial cells.
AB  - High endothelial venules (HEV) allow rapid and selective lymphocyte trafficking
      from the blood into secondary lymphoid tissues. Here we report the expression
      profile of active genes in mouse high endothelial cells (HEC). HEC were first
      purified from mouse lymph nodes (LN) by magnetic cell sorting with MECA-79 mAb
      and a 3'-directed cDNA library that faithfully represents the composition of mRNA
      was constructed. A total of 1495 cDNA sequences were obtained from randomly
      selected clones. Based on their sequence identity, they were grouped into 754
      different species [gene signatures (GS)] of which 335 GS were identified in
      GenBank. Among the previously identified genes, expression of several endothelial
      cell surface molecules including endoglin and ICAM-1 was detected in HEC.
      Comparison of the gene expression profile with that of purified CD31(+) flat
      endothelial cells identified several molecules, such as KC chemokine and Duffy
      antigen/receptor for chemokines, that are known to be selectively expressed in
      activated endothelial cells or post-capillary venules. Interestingly, mac25/TAF,
      which is known to be expressed specifically in tumor vessels and implicated in
      the regulation of cell adhesion, was highly and selectively expressed in HEC in
      mouse LN, suggesting that it may participate in regulating HEC-specific
      functions. Comparison with the expression profiles obtained from 35 different
      cell types showed at least 22 GS that were apparently specific to HEC. Our
      results illustrate the expression differences between HEC and CD31(+) flat
      endothelial cells, and will be useful for the identification and characterization
      of genes specific for HEC.

PMID- 10590266
TI  - The tyrosine phosphatase SHP-1 influences thymocyte selection by setting TCR
      signaling thresholds.
AB  - Modulation of the strength of signals from the TCR determines the outcome of
      positive and negative selection in thymocyte development. Previous studies have
      demonstrated that SHP-1 plays a role in determining signal strength from the TCR.
      Here, we have taken a genetic approach to test whether SHP-1 plays a role in T
      cell selection in the thymus. Experiments in which a dominant negative mutant of
      SHP-1 was expressed in the BYDP hybridoma cell line confirmed that SHP-1
      regulated TCR signaling in a cell-autonomous manner and suggested that Lck is one
      of its targets. To examine the role of SHP-1 in T cell development, we crossed
      the ovalbumin-specific DO11.10 TCR transgene onto the motheaten background, which
      lacks SHP-1 expression. Analysis of the progeny of these crosses provided
      evidence that SHP-1 regulates thymocyte selection: (i) flow cytometric analyses
      revealed alterations in the percentages of thymocyte subpopulations in the me/me
      background; (ii) ex vivo deletion experiments demonstrated that me/me:Tg
      thymocytes undergo negative selection at lower concentrations of OVA peptide
      compared to +/+:Tg thymocytes; and (iii) ex vivo proliferation analyses indicated
      that me/me:Tg thymocytes were hyper-sensitive to stimulation by the specific OVA
      peptide. Our observation that the absence of SHP-1 leads to altered selection of
      TCR transgenic thymocytes demonstrates that SHP-1 regulates the strength of TCR
      mediated signals in vivo and, in turn, helps to set the threshold for thymocyte
      selection.

PMID- 10590267
TI  - CpG DNA rescues B cells from apoptosis by activating NFkappaB and preventing
      mitochondrial membrane potential disruption via a chloroquine-sensitive pathway.
AB  - Isolated murine splenic B cells gradually undergo spontaneous apoptosis while
      WEHI-231 B lymphoma cells undergo activation-induced apoptosis. Unmethylated CpG
      dinucleotides in a particular sequence context (CpG motif) in bacterial DNA or in
      synthetic oligodeoxynucleotides (CpG DNA) rescue both splenic B cells and WEHI
      231 cells from apoptosis, an effect which could potentially contribute to
      autoimmune disease. Chloroquine has been used as an effective therapeutic agent
      for some autoimmune diseases, although the mechanism of action is not clearly
      understood. Low concentrations of chloroquine (<5 microM) selectively abolished
      CpG DNA-mediated protection against spontaneous apoptosis of splenic B cells and
      against anti-IgM-induced apoptosis of WEHI-231 cells without affecting anti
      apoptotic activities of anti-CD40 or lipopolsaccharide. CpG DNA effectively
      prevented mitochondrial membrane potential disruption through a chloroquine
      sensitive pathway in splenic B cells. Apoptosis protection by CpG DNA was also
      associated with increased expression of several proto-oncogenes and oncoproteins
      directly and/or indirectly through a rapid and sustained activation of NFkappaB
      in splenic B cells and WEHI-231 cells. These effects were also suppressed by
      chloroquine. Our results suggest that despite the difference in maturation
      phenotype of splenic B cells and WEHI-231 cells, CpG DNA rescues both from
      apoptosis by similar pathway, which is blocked at an early step by chloroquine.

PMID- 10590268
TI  - T(h)1 but not T(h)0 cell help is efficient to induce cytotoxic T lymphocytes by
      immunization with short synthetic peptides.
AB  - Immunization of BALB/c mice with peptide HVSGHRMAWDMMMNWA, encompassing residues
      121-135 from hepatitis C virus E1 protein, induced CD4(+) T(h)1 cells as well as
      a long-lasting CD8(+) cytotoxic T lymphocyte (CTL) response in vivo when the
      peptide was administered s.c. with or without incomplete Freund's adjuvant. Using
      truncated peptides from this sequence it was shown that the determinant
      recognized by cytotoxic T cells was encompassed by residues SGHRMAWDM. Deletion
      of residues from the N-terminus or the C-terminus of the wild-type peptide
      abrogated its helper character. When Val122 of the wild peptide was replaced by
      Ala, the ability to induce a cytotoxic response was lost concomitantly with the
      loss of the T(h)1 pattern of cytokine production. Interestingly, the Ala-modified
      peptide, when co-immunized with a peptide encompassing residues 323-329 from
      ovalbumin (OVA), which is able to induce a T(h)1 response in BALB/c mice,
      restored the capacity of the modified peptide to induce CTL. However, co
      immunization of the Ala-modified peptide with a peptide encompassing residues 106
      118 from sperm whale myoglobin, which induces a T(h)0 cytokine profile in BALB/c
      mice, was much less efficient than the OVA peptide to restore CTL induction.
      These results demonstrate that CTL induction with a short synthetic peptide
      requires that this peptide contains domains recognized by T(c) cells as well as
      by T(h)1 cells. For those peptides that do not contain this type of T(h) domain,
      competent T cell help can be provided by co-immunization with a distinct peptide
      that is able to stimulate a T(h)1 response.

PMID- 10590269
TI  - CD4(+) T cell-mediated protection against a lethal outcome of systemic infection
      with vesicular stomatitis virus requires CD40 ligand expression, but not IFN
      gamma or IL-4.
AB  - To investigate the mechanism(s) whereby T cells protect against a lethal outcome
      of systemic infection with vesicular stomatitis virus, mice with targeted defects
      in genes central to T cell function were tested for resistance to i.v. infection
      with this virus. Our results show that mice lacking the capacity to secrete both
      IFN-gamma and perforin completely resisted disease. Similar results were obtained
      using IL-4 knockout mice, indicating that neither cell-mediated nor T(h)2
      dependent effector systems were required. In contrast, mice deficient in
      expression of CD40 ligand were more susceptible than wild-type mice, and residual
      resistance in these mice was almost completely abrogated by depletion of CD8(+) T
      cells. In keeping with this, mice lacking both MHC class I and class II
      expression succumbed to the infection, whereas most class II-deficient mice
      normally survive. Adoptive transfer experiments using B cell- and T cell
      deficient recipients revealed that no protection could be obtained in the absence
      of B cells, whereas treatment with virus-specific immune (IgG) serum controlled
      viral spreading to the central nervous system (CNS), but did not necessarily
      accomplish virus elimination. Taken together, these results underscore that B
      cells are essential in preventing early infection of the CNS, but T cells are
      required for long-term survival. CD4(+) T cells are most efficient in this
      context and the key function is to provide cognate help to B cells. However, if
      CD4(+) cell function is compromised, CD8(+) T cells become critical and may
      suffice for survival.

PMID- 10590271
TI  - The use of bacitracin as a growth promoter in animals produces no risk to human
      health.

PMID- 10590270
TI  - Association of a tetraspanin CD9 with CD5 on the T cell surface: role of
      particular transmembrane domains in the association.
AB  - CD9 is a member of the tetraspanin superfamily which is characterized by four
      transmembrane (TM) domains and associates with other surface molecules. This
      tetraspanin was recently found to be expressed on mature T cells. Here, we
      investigated which molecules associate with CD9 on T cells and which CD9 domains
      are required for the association. Immunoprecipitation of T cell lysates with anti
      CD9 mAb followed by immunoblotting with mAb against various T cell molecules
      showed the association of CD9 with CD3, CD4, CD5, CD2, CD29 and CD44. Because
      association with CD5 was most prominent, we determined the role of CD9 TM or
      extracellular (EC) domains in the association with CD5. CD9 mutant genes lacking
      each domain were constructed and introduced into EL4 thymoma cells deficient in
      CD9 but expressing CD5. Among various types of stable EL4 transfectants, EL4
      transfected with the mutant gene lacking TM domains (TM2/TM3) between two EC
      domains expressed a small amount of the relevant protein without showing
      association with CD5. CD9(-)CD5(-) monkey COS-7 cells transfected with this
      mutant gene and the CD5 gene expressed both transfected gene products, but the
      association of these was not detected. EL4 cells transfected with a CD9/CD81
      chimera gene (the CD9 gene containing TM2/TM3 of CD81) expressed the chimeric
      protein on the cell surface and showed association with CD5. These results
      suggest an essential role of particular CD9 TM domains in the surface expression
      of the CD9 molecule as well as the association with CD5.

PMID- 10590272
TI  - beta-lactams: variations on a chemical theme, with some surprising biological
      results.

PMID- 10590273
TI  - Mechanisms involved in the development of resistance to fluoroquinolones in
      Escherichia coli isolates.
AB  - Eighteen quinolone-resistant isolates of Escherichia coli were selected by
      exposing ten clinical isolates to increasing concentrations of norfloxacin and
      lomefloxacin. The mutant isolates showed a multiple-antibiotic-resistance
      phenotype. All of them contained single mutations in gyrA consisting of the
      substitution of Ser-83-->Leu (n = 14), Val (n = 1) or Ala (n = 1) and the
      substitution of Asp-87-->Asn (n = 2). Only one concomitant mutation in parC (Ser
      80-->Arg) was detected. Four parent isolates exhibited a single mutation in gyrA
      which required < or = 12 mg/L of norfloxacin to be inhibited. Fluoroquinolone
      resistance, in the 18 quinolone-resistant mutants, was a result of mutations
      affecting DNA gyrase plus decreased fluoroquinolone uptake. This latter mechanism
      of resistance was a combined effect of an absence of OmpF and an increase in
      active efflux in eight isolates, or an increased active efflux alone in the
      remaining ten selected mutants.

PMID- 10590274
TI  - Analysis of the mechanisms of quinolone resistance in clinical isolates of
      Citrobacter freundii.
AB  - The presence of gyrA, gyrB and/or parC mutations, quinolone uptake, outer
      membrane protein profiles and epidemiological relationship were studied in 12
      clinical isolates of Citrobacter freundii. No alterations were observed in the
      gyrB gene of any of the strains, or gyrA or parC of the four quinolone
      susceptible strains (nalidixic acid MIC of 2-4 mg/L, and a ciprofloxacin MIC of
      0.006-0.06 mg/L). The quinolone-resistant strains were classified into two
      groups: one group (group A) composed of strains resistant to nalidixic acid but
      not to ciprofloxacin and another (group B) including those resistant to both
      antibiotics with a mutation at codon 83 of the gyrA gene (Thr-->Ile), but no
      alteration in either parC or gyrB genes. In group B, three of the four resistant
      isolates, with a nalidixic acid MIC > 1024 mg/L and ciprofloxacin MIC of 8-32
      mg/L, showed concomitant mutations at codons 83 and 87 of the gyrA gene (Thr-
      >Ile and Asp-->Tyr, respectively) as well as a single mutation in codon 80 of the
      parC gene (Ser-->Ile). The fourth isolate did not possess the mutation at codon
      87 of gyrA. Two strains belong to the same clone and, although they had the same
      type of mutations in the gyrA and parC genes, showed different MICs of
      ciprofloxacin. This difference was related to an efflux pump mechanism. Mutations
      in the gyrA and parC genes play the main role in quinolone resistance development
      in Citrobacter freundii, although other factors such as overexpression of efflux
      pumps can play a complementary role and thus modulate the final quinolone MIC.

PMID- 10590275
TI  - Resistance surveillance of Streptococcus pneumoniae, Haemophilus influenzae and
      Moraxella catarrhalis isolated in the United States, 1997-1998.
AB  - A national antimicrobial resistance surveillance study was conducted from
      December 1997 to May 1998 to determine the prevalence of antimicrobial resistance
      in 6620 clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae and
      Moraxella catarrhalis. In this centralized study, which involved 163 institutions
      located in 43 states, we determined MICs for representatives of five
      antimicrobial classes: beta-lactams (penicillin, co-amoxiclav, cefuroxime,
      ceftriaxone), macrolides (azithromycin, clarithromycin), co-trimoxazole,
      glycopeptides (vancomycin) and fluoroquinolones (levofloxacin). In most S.
      pneumoniae isolates, all antimicrobials were to be found active, but amongst
      penicillin-resistant isolates (MICs > or = 2 mg/L), resistance to other beta
      lactams, macrolides and co-trimoxazole was common. For vancomycin and
      levofloxacin, however, activity was not associated with penicillin resistance.
      The prevalence of penicillin-nonsusceptible (intermediate and resistant)
      pneumococci was highest in the South Atlantic (44%) and East South Central (43%)
      regions and lowest in the Mid-Atlantic (28%) and New England (28%) regions.
      Resistance to beta-lactams, macrolides and co-trimoxazole was more commonly found
      amongst respiratory isolates than blood isolates and in strains from patients <
      or = 12 years old than from older patients. beta-lactamase, which was detected in
      33% of H. influenzae and 92% of M. catarrhalis strains, did not affect the
      activity of the beta-lactams under study other than ampicillin. Certain agents,
      such as vancomycin and the fluoroquinolones, remain highly active, and well
      designed surveillance systems that monitor MIC distributions would be needed to
      detect a potential for reduced susceptibility. In addition, surveillance
      programmes should be designed to collect information about associated resistance
      as well as differences in prevalence associated with region, specimen source and
      patient age.

PMID- 10590276
TI  - Exploration of the in-vitro pharmacodynamic activity of moxifloxacin for
      Staphylococcus aureus and Streptococci of lancefield groups A and G.
AB  - The serum concentrations associated with the oral administration of 400 mg
      moxifloxacin every 24 h over 48 h in man were simulated in an in-vitro
      dilutional, continuous bacterial culture model of infection. The initial inoculum
      was 5 x 10(7)-5 x 10(8) cfu/mL and all strains were tested on at least three
      occasions. Two strains of Staphylococcus aureus (one methicillin susceptible, the
      other resistant) with moxifloxacin MICs 0.14 mg/L and 0.06 mg/L and two strains
      of beta-haemolytic streptococci, Lancefield Group A, MIC 0. 16 mg/L and Group G,
      MIC 0.4 mg/L were used. In addition, two laboratory-generated mutants with raised
      moxifloxacin MICs were also employed: methicillin-sensitive S. aureus (MSSA) MIC
      1.0 mg/L and Group A streptococcus MIC 1.8 mg/L. The antibacterial effect of
      moxifloxacin was judged by changes in viable count over time, and the area under
      the bacterial-kill curve (AUBKC) after 24 and 48 h. For S. aureus MIC 0.14 mg/L
      the AUBKC(24) (log cfu/mL.h) was 77.8 +/- 4.6 and AUBKC(48) 92.0 +/- 6.9. For its
      mutant, moxifloxacin MIC 1.0 mg/L, the AUBKC(24) was 116.1 +/- 15.6 and AUBKC(48)
      211.9 +/- 23.1, indicating decreased killing. AUBKC(24) and AUBKC(48) values of
      110.7 +/- 10.3 and 130.9 +/- 21.3, respectively, were noted for the MRSA strain.
      The Group A streptococcus, MIC 0.16 mg/L, had an AUBKC(24) of 91.4 +/- 19.4 and
      AUBKC(48) of 157.0 +/- 70.9. The mutant, MIC 1.8 mg/L, had an AUBKC(24) of 127.0
      +/- 1.9 and AUBKC(48) of 205.1 +/- 6.4. Despite a lower MIC (0.4 mg/L) the single
      strain of Group G streptococcus tested was killed poorly, AUBKC(24) 139.9 +/- 3.6
      and AUBKC(48) 252.3 +/- 18.6. The pharmacodynamic parameters AUC/MIC, T > MIC,
      (AUC > MIC)/MIC (AUC = area under the curve, T = time) and WAUC ((AUC/MIC) (T >
      MIC/100)) (WAUC = weighted area under the curve) were related to AUBKC(24) and
      AUBKC(48) using an inhibitory sigmoid E(max) model. T > MIC was poorly related to
      AUBKC (r = 0.36) while AUC/MIC, (AUC > MIC)/MIC and WAUC were strongly related to
      AUBKC(24) (r = 0.75-0.79) and AUBKC(48) (r = 0.78-0.84). The maximum
      antibacterial effect was achieved with an AUC/MIC ratio of 150-200. AUC-related
      pharmacodynamic parameters predicted antibacterial effect better than T > MIC.

PMID- 10590277
TI  - DNA vaccination by mecA sequence evokes an antibacterial immune response against
      methicillin-resistant Staphylococcus aureus.
AB  - More than 90% of methicillin-resistant Staphylococcus aureus (MRSA) isolates
      produce a penicillin-binding protein PBP2' (or PBP2a) with low affinity for beta
      lactam antibiotics. PBP2' is encoded by the mecA gene, a foreign gene integrated
      into the chromosome of methicillin-susceptible S. aureus (MSSA). DNA vaccination
      by injection of transgene-expressing plasmids has been demonstrated to elicit an
      immune response against transgene-encoded protein. We hypothesized that the
      application of DNA vaccination with the mecA sequence would elicit protective
      immunity against MRSA. This immunity was evoked by injection of a mecA-expressing
      plasmid into BALB/c mice. Anti-PBP2' antibody was detected in the sera obtained
      from the DNA-vaccinated mice. These sera produced a five-fold increase in
      phagocytosis of MRSA compared with sera from mice treated with control plasmid.
      However, there was no difference in phagocytosis of MSSA among these groups. In
      addition, the in-vivo antibacterial effect of DNA vaccination was demonstrated in
      mice infected with MRSA. Eight days after iv inoculation of 10(8) cfu of MRSA
      into mice, the number of bacteria in the kidneys obtained from mice vaccinated
      with mecA-expressing plasmid (1.48 +/- 0.27 x 10(5) cfu/mg kidney; n = 18) was
      significantly lower than that from mice vaccinated with negative control plasmid
      (3.59 +/- 0.57 x 10(5) cfu/mg kidney; n = 17) (P < 0.02) or that from sham
      treated mice (3. 43 +/- 0.66 x 10(5) cfu/mg kidney; n = 9) (P < 0.02).
      Interestingly, PBP2' was found in both the bacterial membrane fraction and the
      supernatant, thus being accessible to serum antibodies. Together these
      observations indicate that PBP2' or the mecA sequence may be eligible as a
      candidate molecule for vaccination against MRSA.

PMID- 10590279
TI  - Antifungal activity of amphotericin B-lipid admixtures in experimental systemic
      candidosis in naive mice.
AB  - We have shown previously that admixtures of amphotericin B (AMB) and Intralipid
      (AMB-IL) obtained by vigorous and prolonged agitation are stable and can be
      standardized. These preparations exhibited in-vitro activity against various
      Candida spp., and had significantly lower toxicity. The present study was
      undertaken to evaluate the activity of AMB-IL admixtures in vivo in comparison
      with the conventional formulation of AMB (Fungizone), using a murine model of
      experimental systemic candidosis. ICR female mice (4-6 weeks old) were injected
      iv with 5 x 10(4) Candida albicans CBS 562. The animals developed a lethal
      infection (100%) within 10 days. Systemic candidosis was demonstrated by the
      presence of fungal elements in kidneys and spleen tissue, and by enumeration of
      cfu of Candida in the tissue homogenates. AMB-IL or AMB was administered iv 48 h
      post-Candida inoculation for 5 consecutive days. Four experiments with 108 mice
      treated with AMB 5 x 0.4 mg/kg and followed up for 6 weeks, showed that the mean
      survival percentages at the end of the experiment were 0, 24.9 and 52.5% for the
      untreated group, conventional AMB-treated and AMB-IL-treated groups,
      respectively. The mean survival time (MST) was 7.4, 25 and 30 days for the
      untreated, conventional AMB-treated and AMB-IL-treated groups, respectively. Use
      of increased doses of AMB showed that conventional AMB at doses greater than 5 x
      1 mg/kg caused immediate animal death. AMB-IL was used at doses of AMB up to 5 x
      2 mg/kg. Experiments with 104 mice revealed that the mean survival percentage at
      the end of the experiment was 0, 34.5, 58.6 and 97% for the untreated,
      conventional AMB-treated (5 x 1 mg/kg), AMB-IL-1-treated (5 x 1 mg/kg) and AMB-IL
      2-treated (5 x 2 mg/kg) groups, respectively. The MST was 7, 27.8, 34.8 and 41.4
      days for the untreated, conventional AMB-treated, AMB-IL-1-treated and AMB-IL-2
      treated groups, respectively. The results of this study reveal that AMB-IL is
      significantly more effective in treating systemic murine candidosis than
      conventional AMB.

PMID- 10590278
TI  - Efficacy of levofloxacin in the treatment of experimental endocarditis caused by
      viridans group streptococci.
AB  - Levofloxacin was investigated against viridans group streptococci in vitro and in
      rats with experimental aortic endocarditis. The MIC(90)s of levofloxacin and
      ciprofloxacin for 20 independent isolates of such bacteria were 1 and 8 mg/L,
      respectively. Rats were infected with two types of organism: either fully
      susceptible to levofloxacin MIC < or = 0.5 mg/L) or borderline susceptible (MIC 1
      2 mg/L). Fully levofloxacin-susceptible bacteria comprised one penicillin
      susceptible (MIC 0.004 mg/L) Streptococcus gordonii, and one penicillin-tolerant
      as well as one intermediate penicillin-resistant (MIC 0.125 mg/L) isogenic
      strains. Borderline levofloxacin-susceptible bacteria comprised one penicillin
      susceptible Streptococcus sanguis and one highly penicillin-resistant
      Streptococcus mitis (MIC 2 mg/L). Rats were treated for 5 days with drug dosages
      simulating the following treatments in humans: (i) levofloxacin 500 mg orally
      once a day (q24 h), (ii) levofloxacin 500 mg orally twice a day (q12 h), (iii)
      levofloxacin 1 g orally q24 h, (iv) ciprofloxacin 750 mg orally q12 h, and (v)
      ceftriaxone 2 g iv q24 h. Levofloxacin was equivalent or superior to ceftriaxone,
      and was successful in treating experimental endocarditis irrespective of
      penicillin resistance. Nevertheless, standard levofloxacin treatment equivalent
      to 500 mg q24 h in human was less effective than twice daily 500 mg or once daily
      1 g doses against borderline-susceptible organisms. Ciprofloxacin, used as a
      negative control, was ineffective and selected for resistant isolates. This
      underlines the importance of MIC determinations when treating severe
      streptococcal infection with quinolones. In the case of borderline-susceptible
      pathogens, total daily doses of 1 g of levofloxacin should be considered.

PMID- 10590280
TI  - Evaluation of the in-vivo activity and toxicity of amarogentin, an
      antileishmanial agent, in both liposomal and niosomal forms.
AB  - The antileishmanial property of amarogentin, a secoiridoid glycoside isolated
      from the Indian medicinal plant Swertia chirata, was examined in a hamster model
      of experimental leishmaniasis. The therapeutic efficacy of amarogentin was
      evaluated in free and two different vesicular forms, liposomes and niosomes. The
      amarogentin in both liposomal and niosomal forms was found to be a more active
      leishmanicidal agent than the free amarogentin; and the niosomal form was found
      to be more efficacious than the liposomal form at the same membrane
      microviscosity level. Toxicity studies involving blood pathology, histological
      staining of tissues and specific enzyme levels related to normal liver function
      showed no toxicity. Hence, amarogentin incorporated in liposomes or niosomes may
      have clinical application in the treatment of leishmaniasis.

PMID- 10590281
TI  - The prevalence and clonal expansion of high-level gentamicin-resistant
      enterococci isolated from blood cultures in a Dutch university hospital.
AB  - We studied the prevalence and clonality of high-level gentamicin-resistant
      enterococci (HLGRE) in a Dutch university hospital. Of 238 enterococcal strains
      isolated from blood cultures between 1991 and 1997, 57 were HLGRE. Genomic
      analysis of these strains revealed 19 different genotypes, two of which were
      encountered more frequently [type A (12/57), type B (23/57)]. The spread of these
      types largely explained the rise in HLGRE incidence from 14% in 1991 to 31% in
      1997. However, the contribution of unique strains to the total HLGRE burden also
      increased from 4% to 16%. We conclude that both clonal expansion and the
      emergence of unique HLGRE have contributed significantly to the increasing
      incidence of HLGRE.

PMID- 10590282
TI  - Levofloxacin in the empirical treatment of patients with suspected
      bacteraemia/sepsis: comparison with imipenem/cilastatin in an open, randomized
      trial.
AB  - An open, randomized, multinational, multicentre study was conducted to compare
      the efficacy, safety and tolerability of levofloxacin 500 mg twice daily with
      imipenem/cilastatin 1 g iv three-times daily in the treatment of hospitalized
      adult patients with clinically suspected bacteraemia/ sepsis. Levofloxacin
      patients could change from iv to oral administration after a minimum of 48 h iv
      treatment if clinical signs and symptoms of sepsis had improved. The primary
      efficacy analysis was based on the clinical and bacteriological response at
      clinical endpoint. A total of 503 patients were randomized and 499 included in
      the intent-to-treat population. The per-protocol population comprised 287
      patients with bacteriologically proven infection. Clinical cure rates at clinical
      endpoint in the intent-to-treat population and per-protocol population were 77%
      (184/239) and 89% (125/140), respectively, for levofloxacin and 68% (178/260) and
      85% (125/147), respectively, for imipenem/cilastatin. At follow-up, the cure
      rates in the per-protocol population were 84% for levofloxacin and 69% for
      imipenem/cilastatin. The 95% confidence interval for both populations showed that
      levofloxacin was as effective as imipenem/cilastatin. A satisfactory
      bacteriological response was obtained in 87% (96/110) of levofloxacin patients
      and 84% (97/116) of imipenem/cilastatin patients at clinical endpoint. Adverse
      events possibly related to the study drug were reported in 74 (31%) levofloxacin
      patients and 79 (30%) imipenem/cilastatin patients. There were no clinically
      appreciable differences between the treatment groups. Levofloxacin 500 mg twice
      daily, either iv or as sequential iv/oral therapy, was as effective and well
      tolerated as imipenem/cilastatin 1 g iv three-times daily in the treatment of
      hospitalized patients with suspected bacteraemia/sepsis.

PMID- 10590283
TI  - Cost-effectiveness of azithromycin for preventing Mycobacterium avium complex
      infection in HIV-positive patients in the era of highly active antiretroviral
      therapy. The Swiss HIV Cohort Study.
AB  - We conducted a cost-effectiveness analysis to determine the clinical and economic
      consequences of Mycobacterium avium complex (MAC) prophylaxis in HIV-infected
      patients in the era of highly active antiretroviral therapy (HAART) in a health
      care system with access unrestricted by financial barriers. The analysis was
      performed from a health care perspective and compared azithromycin (1200 mg/week)
      with no prophylaxis over a period of 10 years based on data from the Swiss HIV
      Cohort Study (SHCS) and randomized controlled trials. The main outcome measures
      were: expected survival; average health care costs; and cost-effectiveness in
      1997 Swiss francs ( pound1 corresponds to about 2.3 CHF) per life-year saved. In
      patients with an initial CD4 count <50 cells/mm(3) and no AIDS, azithromycin
      increased expected survival by 4 months. In patients with AIDS, HAART durability
      had a major impact on expected survival and costs. Incremental survival increased
      from 2 to 4 months if we assumed a 10 year, instead of a 3 year, HAART effect.
      The cost-effectiveness of azithromycin relative to no prophylaxis in patients
      without AIDS was between 47,000 CHF (3-year HAART effect) and 60,000 CHF (10-year
      HAART effect) per life-year saved. The cost-effectiveness ratio increased to
      118,000 CHF per life-year saved in patients with symptomatic AIDS. In conclusion,
      in the era of HAART, MAC prophylaxis with azithromycin increases expected
      survival and reduces health care costs substantially. Starting MAC prophylaxis in
      patients without AIDS is more effective and cost-effective than in patients with
      AIDS.

PMID- 10590284
TI  - Tentative minimum inhibitory concentration and zone diameter breakpoints for
      moxifloxacin using BSAC criteria.
AB  - Tentative MIC and zone diameter breakpoints were determined for moxifloxacin
      using BSAC criteria. An MIC breakpoint of < or =1 mg/L, denoting sensitivity, is
      suggested for Enterobacteriaceae, staphylococci, haemophili, moraxellae,
      pneumococci and enterococci. For pseudomonads high and low breakpoints of 4 mg/L
      and 1 mg/L are suggested to allow for an intermediate category of sensitivity. A
      1 microg moxifloxacin disc content is suggested for testing all of the organisms
      previously mentioned, except pseudomonads, for which a 5 microg disc is needed to
      discriminate between the intermediate and sensitive populations. Corresponding
      zone diameter breakpoints for a 1 microg disc are > or = 20 mm for
      Enterobacteriaceae and staphylococci, 18 mm for the respiratory pathogens
      (Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis) and
      15 mm for enterococci. For Pseudomonas aeruginosa with a 5 microg disc, three
      bands are suggested for interpretation, that of > or = 25 mm (sensitive), 18-24
      mm (intermediate) and < or = 17 mm (resistant).

PMID- 10590285
TI  - Photobactericidal activity of methylene blue derivatives against vancomycin
      resistant Enterococcus spp.
AB  - The toxicities and phototoxicities of methylene blue and its two methylated
      derivatives were measured against one standard and three vancomycin-resistant
      pathogenic strains of Enterococcus spp. Each of the compounds was bactericidal
      and the derivatives exhibited photobactericidal activity on illumination at a
      'light' dose of 6.3 J/cm(2) against one or more of the strains. Increased
      bactericidal and photobactericidal activity in the methylated derivatives is
      thought to be due to their higher hydrophobicities allowing greater interaction
      with the bacterial cell wall. In addition, the derivatives exhibited higher
      inherent photosensitizing efficacies.

PMID- 10590286
TI  - In-vitro and in-vivo activities of SCH56592 against Cryptococcus neoformans.
AB  - The in-vitro and in-vivo activities of SCH56592, a triazole antifungal agent,
      against Cryptococcus neoformans were studied. MIC(90)s for 16 strains of C.
      neoformans measured by microdilution method (NCCLS M27-A) were 1 mg/L of
      SCH56592, 16 mg/L of fluconazole, 32 mg/L of flucytosine, and 0.5 mg/L of
      amphotericin B. In a murine model of pulmonary cryptococcosis, 10 mg/kg of
      SCH56592 was more effective than fluconazole. The fungal burden of the lung of
      animals treated with SCH56592 was significantly reduced (7.40 +/- 0.21 log(10)
      cfu/g), as compared with fluconazole (7.77 +/- 0.07 log(10) cfu/g) and control
      (7.79 +/- 0.1 log(10) cfu/g) (P < 0.01). For C. neoformans-infected mice
      following 7 days treatment with 10 mg/kg of SCH56592 there was a higher
      concentration in lung (3.36 +/- 0.62 ng/ml) than in plasma (2.16 +/- 0.86 ng/mL),
      and this was maintained for 12 h after administration.

PMID- 10590287
TI  - Modified time-kill assay against multidrug-resistant Enterococcus faecium with
      novel antimicrobial combinations.
AB  - This study used a modified time-kill assay to compare the in-vitro activity of
      chloramphenicol and quinopristin/dalfopristin combined with vancomycin,
      ampicillin or gentamicin against multidrug-resistant Enterococcus faecium. The
      assay uses standardized time-kill methods with the following modifications:
      centrifugation of the test tubes at 1-2 h intervals, removal of supernatant and
      resuspension of bacteria in media containing antibiotic concentrations
      corresponding to simulated steady-state serum concentrations. None of the agents,
      alone or in combination, produced bactericidal or synergic activity. The modified
      time-kill assay more closely simulates in-vivo conditions and may provide a
      better qualitative assay to determine the interaction between antimicrobial
      agents and bacteria.

PMID- 10590288
TI  - Concentrations of moxifloxacin in serum and pulmonary compartments following a
      single 400 mg oral dose in patients undergoing fibre-optic bronchoscopy.
AB  - The concentrations of moxifloxacin achieved after a single 400 mg dose were
      measured in serum, epithelial lining fluid (ELF), alveolar macrophages (AM) and
      bronchial mucosa (BM). Concentrations were determined using a microbiological
      assay. Nineteen patients undergoing fibre-optic bronchoscopy were studied. Mean
      serum, ELF, AM and BM concentrations at 2.2, 12 and 24 h were as follows: 2.2 h:
      3.2 mg/L, 20.7 mg/L, 56.7 mg/L, 5.4 mg/kg; 12 h: 1.1 mg/L, 5.9 mg/L, 54.1 mg/L,
      2.0 mg/kg; 24 h: 0.5 mg/L, 3.6 mg/L, 35.9 mg/L, 1.1 mg/kg, respectively. These
      concentrations exceed the MIC(90)s for common respiratory pathogens such as
      Streptococcus pneumoniae (0.25 mg/L), Haemophilus influenzae (0.03 mg/L),
      Moraxella catarrhalis (0.12 mg/L), Chlamydia pneumoniae (0.12 mg/L) and
      Mycoplasma pneumoniae (0. 12 mg/L) and indicate that moxifloxacin should be
      effective in the treatment of community-acquired, lower respiratory tract
      infections.

PMID- 10590289
TI  - Multiple prescriptions of antibiotics for children aged 0 to 5 years in relation
      to type of antibiotic.
AB  - The risk of receiving more than one prescription within an antibiotic course was
      examined for all children aged 0 to 5 years in a Danish county during 1997. We
      identified 29,307 prescriptions of systemic antibiotics for 16,245 children in a
      prescription database. Ten per cent of the prescriptions were followed by a new
      prescription within 10 days. In children who received two prescriptions (n =
      3993), 19% redeemed the prescriptions within the same course. When the child was
      prescribed penicillin V, compared with broad-spectrum penicillin, the odds ratio
      of receiving a repeat prescription within 1-2 days was 2.9 (95% CI 2.5-3.4) and
      within 3-10 days 1.3 (95% CI 1.2-1.5).

PMID- 10590291
TI  - Cross-resistance analyses and molecular typing of Staphylococcus aureus and
      Streptococcus spp. isolates resistant to quinupristin/dalfopristin.

PMID- 10590290
TI  - Assessment of the efficacy, safety and quality of gentamicin use in Aberdeen
      Royal Infirmary.
AB  - Fifty-five patients who received od gentamicin were studied. The protocol for od
      gentamicin was followed in 23/55 (48%). Cure rates were 22/23 (96%) when the
      protocol was followed and 24/32 (75%) when not followed (P = 0.06). Toxicity was
      more common in those in whom the protocol was not followed (9/32; 28%) than in
      those in whom it was followed (1/23; 4%) (P< 0.05). The number needed to treat
      with the protocol to produce one additional cure was 4.84 (95% CI 2.64 to 28.66)
      and the number needed to treat to prevent one case of toxicity was 3.61 (95% CI
      2.16 to 10.99).

PMID- 10590292
TI  - New BSAC sensitivity testing guidelines.

PMID- 10590293
TI  - A method using TEM-5-beta-lactamase to assay imipenem.

PMID- 10590295
TI  - In-vitro susceptibilities of Streptococcus pneumoniae strains isolated in
      Malaysia to six antibiotics.

PMID- 10590296
TI  - Safety of metronidazole during pregnancy: a cohort study of risk of congenital
      abnormalities, preterm delivery and low birth weight in 124 women.

PMID- 10590299
TI  - Why and how are peptide-lipid interactions utilized for self-defense? Magainins
      and tachyplesins as archetypes.
AB  - Animals as well as plants defend themselves against invading pathogenic
      microorganisms utilizing cationic antimicrobial peptides, which rapidly kill
      various microbes without exerting toxicity against the host. Physicochemical
      peptide-lipid interactions provide attractive mechanisms for innate immunity.
      Many of these peptides form cationic amphipathic secondary structures, typically
      alpha-helices and beta-sheets, which can selectively interact with anionic
      bacterial membranes by the aid of electrostatic interactions. Rapid, peptide
      induced membrane permeabilization is an effective mechanism of antimicrobial
      action. This review article summarizes interactions with lipid bilayers of
      magainins (alpha-helix) and tachyplesins (beta-sheet) discovered in frog skin and
      horseshoe crab hemolymph, respectively, as archetypes, emphasizing that the mode
      of interaction is strongly dependent on the physicochemical properties not only
      of the peptide, but also of the target membrane.

PMID- 10590300
TI  - Diversity of antimicrobial peptides and their mechanisms of action.
AB  - Antimicrobial peptides encompass a wide variety of structural motifs. Many
      peptides have alpha-helical structures. The majority of these peptides are
      cationic and amphipathic but there are also hydrophobic alpha-helical peptides
      which possess antimicrobial activity. In addition, some beta-sheet peptides have
      antimicrobial activity and even antimicrobial alpha-helical peptides which have
      been modified to possess a beta-structure retain part of their antimicrobial
      activity. There are also antimicrobial peptides which are rich in a certain
      specific amino acid such as Trp or His. In addition, antimicrobial peptides exist
      with thio-ether rings, which are lipopeptides or which have macrocyclic Cys
      knots. In spite of the structural diversity, a common feature of the cationic
      antimicrobial peptides is that they all have an amphipathic structure which
      allows them to bind to the membrane interface. Indeed, most antimicrobial
      peptides interact with membranes and may be cytotoxic as a result of disturbance
      of the bacterial inner or outer membranes. Alternatively, a necessary but not
      sufficient property of these peptides may be to be able to pass through the
      membrane to reach a target inside the cell. The interaction of these peptides
      with biological membranes is not just a function of the peptide but is also
      modulated by the lipid components of the membrane. It is not likely that this
      diverse group of peptides has a single mechanism of action, but interaction of
      the peptides with membranes is an important requirement for most, if not all,
      antimicrobial peptides.

PMID- 10590301
TI  - Interaction of antimicrobial peptides with biological and model membranes:
      structural and charge requirements for activity.
AB  - Species right across the evolutionary scale from insects to mammals use peptides
      as part of their host-defense system to counter microbial infection. The primary
      structures of a large number of these host-defense peptides have been determined.
      While there is no primary structure homology, the peptides are characterized by a
      preponderance of cationic and hydrophobic amino acids. The secondary structures
      of many of the host-defense peptides have been determined by a variety of
      techniques. The acyclic peptides tend to adopt helical conformation, especially
      in media of low dielectric constant, whereas peptides with more than one
      disulfide bridge adopt beta-structures. Detailed investigations have indicated
      that a majority of these host-defense peptides exert their action by
      permeabilizing microbial membranes. In this review, we discuss structural and
      charge requirements for the interaction of endogenous antimicrobial peptides and
      short peptides that have been derived from them, with membranes.

PMID- 10590302
TI  - Mechanism of the binding, insertion and destabilization of phospholipid bilayer
      membranes by alpha-helical antimicrobial and cell non-selective membrane-lytic
      peptides.
AB  - Permeation of the cell membrane leading to cell death is a mechanism used by a
      large number of membrane-lytic peptides. Some are linear, mostly helical, and
      others contain one or more disulfide bonds forming beta-sheet or both beta-sheet
      and alpha-helix structures. They are all soluble in solution but when they reach
      the target membrane, conformational changes occur which let them associate with
      and lyse the membrane. Some lytic peptides are not cell-selective and lyse
      different microorganisms and normal mammalian cells, while others are specific to
      either type of cells. Despite extensive studies, the mode of action of membrane
      lytic peptides is not fully understood and the basis for their selectivity
      towards specific target cells is not known. Many studies have shown that peptide
      lipid interactions leading to membrane permeation play a major role in their
      activity. Membrane permeation by amphipathic alpha-helical peptides has been
      proposed to occur via one of two general mechanisms: (i) transmembrane pore
      formation via a 'barrel-stave' mechanism; and (ii) membrane
      destruction/solubilization via a 'carpet' mechanism. This review, which is
      focused on the different stages of membrane permeation induced by representatives
      of amphipathic alpha-helical antimicrobial and cell non-selective lytic peptides
      distinguishes between the 'carpet' mechanism, which holds for antimicrobial
      peptides versus the 'barrel-stave' mechanism, which holds for cell non-selective
      lytic peptides.

PMID- 10590303
TI  - Structural features of helical antimicrobial peptides: their potential to
      modulate activity on model membranes and biological cells.
AB  - Antibacterial, membrane-lytic peptides belong to the innate immune system and
      host defense mechanism of a multitude of animals and plants. The largest group of
      peptide antibiotics comprises peptides which fold into an amphipathic alpha
      helical conformation when interacting with the target. The activity of these
      peptides is thought to be determined by global structural parameters rather than
      by the specific amino acid sequence. This review is concerned with the influence
      of structural parameters, such as peptide helicity, hydrophobicity, hydrophobic
      moment, peptide charge and the size of the hydrophobic/hydrophilic domain, on
      membrane activity and selectivity. The potential of these parameters to increase
      the antibacterial activity and to improve the prokaryotic selectivity of natural
      and model peptides is assessed. Furthermore, biophysical studies are summarized
      which elucidated the molecular basis for activity and selectivity modulations on
      the level of model membranes. Finally, the knowledge about the role of peptide
      structural parameters is applied to understand the different activity spectra of
      natural membrane-lytic peptides.

PMID- 10590304
TI  - Lipid-induced conformation and lipid-binding properties of cytolytic and
      antimicrobial peptides: determination and biological specificity.
AB  - While antimicrobial and cytolytic peptides exert their effects on cells largely
      by interacting with the lipid bilayers of their membranes, the influence of the
      cell membrane lipid composition on the specificity of these peptides towards a
      given organism is not yet understood. The lack of experimental model systems that
      mimic the complexity of natural cell membranes has hampered efforts to establish
      a direct correlation between the induced conformation of these peptides upon
      binding to cell membranes and their biological specificities. Nevertheless,
      studies using model membranes reconstituted from lipids and a few membrane
      associated proteins, combined with spectroscopic techniques (i.e. circular
      dichroism, fluorescence spectroscopy, Fourier transform infra red spectroscopy,
      etc.), have provided information on specific structure-function relationships of
      peptide-membrane interactions at the molecular level. Reversed phase-high
      performance chromatography (RP-HPLC) and surface plasmon resonance (SPR) are
      emerging techniques for the study of the dynamics of the interactions between
      cytolytic and antimicrobial peptides and lipid surfaces. Thus, the immobilization
      of lipid moieties onto RP-HPLC sorbent now allows the investigation of peptide
      conformational transition upon interaction with membrane surfaces, while SPR
      allows the observation of the time course of peptide binding to membrane
      surfaces. Such studies have clearly demonstrated the complexity of peptide
      membrane interactions in terms of the mutual changes in peptide binding,
      conformation, orientation, and lipid organization, and have, to a certain extent,
      allowed correlations to be drawn between peptide conformational properties and
      lytic activity.

PMID- 10590305
TI  - The monolayer technique: a potent tool for studying the interfacial properties of
      antimicrobial and membrane-lytic peptides and their interactions with lipid
      membranes.
AB  - Erudites of the antiquity already knew the calming effect of oil films on the sea
      waves. But one had to wait until 1774 to read the first scientific report on oil
      films from B. Franklin and again 1878 to learn the thermodynamic analysis on
      adsorption developed by J. Gibbs. Then, in 1891, Agnes Pockels described a
      technique to manipulate oil films by using barriers. Finally, in 1917, I.
      Langmuir introduced the experimental and theoretical modern concepts on insoluble
      monolayers. Since that time, and because it has been found to provide invaluable
      information at the molecular scale, the monolayer technique has been more and
      more extensively used, and, during the past decade, an explosive increase in the
      number of publications has occurred. Over the same period, considerable and ever
      increasing interest in the antimicrobial peptides of various plants, bacteria,
      insects, amphibians and mammals has grown. Because many of these antimicrobial
      peptides act at the cell membrane level, the monolayer technique is entirely
      suitable for studying their physicochemical and biological properties. This
      review describes monolayer experiments performed with some of these antimicrobial
      peptides, especially gramicidin A, melittin, cardiotoxins and defensin A. After
      giving a few basic notions of surface chemistry, the surface-active properties of
      these peptides and their behavior when they are arranged in monomolecular films
      are reported and discussed in relation to their tridimensional structure and
      their amphipathic character. The penetration of these antimicrobial peptides into
      phospholipid monolayer model membranes, as well as their interactions with lipids
      in mixed films, are also emphasized.

PMID- 10590306
TI  - Differential scanning calorimetry and X-ray diffraction studies of the
      specificity of the interaction of antimicrobial peptides with membrane-mimetic
      systems.
AB  - Interest in biophysical studies on the interaction of antimicrobial peptides and
      lipids has strongly increased because of the rapid emergence of antibiotic
      resistant bacterial strains. An understanding of the molecular mechanism(s) of
      membrane perturbation by these peptides will allow a design of novel peptide
      antibiotics as an alternative to conventional antibiotics. Differential scanning
      calorimetry and X-ray diffraction studies have yielded a wealth of quantitative
      information on the effects of antimicrobial peptides on membrane structure as
      well as on peptide location. These studies clearly demonstrated that
      antimicrobial peptides show preferential interaction with specific phospholipid
      classes. Furthermore, they revealed that in addition to charge-charge
      interactions, membrane curvature strain and hydrophobic mismatch between peptides
      and lipids are important parameters in determining the mechanism of membrane
      perturbation. Hence, depending on the molecular properties of both lipid and
      peptide, creation of bilayer defects such as phase separation or membrane
      thinning, pore formation, promotion of nonlamellar lipid structures or bilayer
      disruption by the carpet model or detergent-like action, may occur. Moreover,
      these studies suggest that these different processes may represent gradual steps
      of membrane perturbation. A better understanding of the mutual dependence of
      these parameters will help to elucidate the molecular mechanism of membrane
      damage by antimicrobial peptides and their target membrane specificity, keys for
      the rationale design of novel types of peptide antibiotics.

PMID- 10590307
TI  - The structure, dynamics and orientation of antimicrobial peptides in membranes by
      multidimensional solid-state NMR spectroscopy.
AB  - Linear peptide antibiotics have been isolated from amphibians, insects and humans
      and used as templates to design cheaper and more potent analogues for medical
      applications. Peptides such as cecropins or magainins are < or = 40 amino acids
      in length. Many of them have been prepared by solid-phase peptide synthesis with
      isotopic labels incorporated at selected sites. Structural analysis by solid
      state NMR spectroscopy and other biophysical techniques indicates that these
      peptide antibiotics strongly interact with lipid membranes. In bilayer
      environments they exhibit amphipathic alpha-helical conformations and alignments
      of the helix axis parallel to the membrane surface. This contrasts the
      transmembrane orientations observed for alamethicin or gramicidin A. Models that
      have been proposed to explain the antibiotic and pore-forming activities of
      membrane-associated peptides, as well as other experimental results, include
      transmembrane helical bundles, wormholes, carpets, detergent-like effects or the
      in-plane diffusion of peptide-induced bilayer instabilities.

PMID- 10590308
TI  - Simulation studies of the interaction of antimicrobial peptides and lipid
      bilayers.
AB  - Experimental studies of a number of antimicrobial peptides are sufficiently
      detailed to allow computer simulations to make a significant contribution to
      understanding their mechanisms of action at an atomic level. In this review we
      focus on simulation studies of alamethicin, melittin, dermaseptin and related
      antimicrobial, membrane-active peptides. All of these peptides form amphipathic
      alpha-helices. Simulations allow us to explore the interactions of such peptides
      with lipid bilayers, and to understand the effects of such interactions on the
      conformational dynamics of the peptides. Mean field methods employ an empirical
      energy function, such as a simple hydrophobicity potential, to provide an
      approximation to the membrane. Mean field approaches allow us to predict the
      optimal orientation of a peptide helix relative to a bilayer. Molecular dynamics
      simulations that include an atomistic model of the bilayer and surrounding
      solvent provide a more detailed insight into peptide-bilayer interactions. In the
      case of alamethicin, all-atom simulations have allowed us to explore several
      steps along the route from binding to the membrane surface to formation of
      transbilayer ion channels. For those antimicrobial peptides such as dermaseptin
      which prefer to remain at the surface of a bilayer, molecular dynamics
      simulations allow us to explore the favourable interactions between the peptide
      helix sidechains and the phospholipid headgroups.

PMID- 10590309
TI  - The interaction of the antimicrobial peptide gramicidin S with lipid bilayer
      model and biological membranes.
AB  - Gramicidin S (GS) is a cyclic decapeptide of primary structure [cyclo-(Val-Orn
      Leu-D-Phe-Pro)(2)] secreted by Bacillus brevis. It is a powerful antimicrobial
      agent with potent cidal action on a wide variety of Gram-negative and Gram
      positive bacteria as well as on several pathogenic fungi. Unfortunately, however,
      GS is rather non-specific in its actions and also exhibits a high hemolytic
      activity, limiting its use as an antibiotic to topical applications. In a wide
      variety of environments, the GS molecule exists as a very stable amphiphilic
      antiparallel beta-sheet structure with a polar and a non-polar surface. Moreover,
      the large number of structure-activity studies of GS analogs which have been
      carried out indicate that this 'sidedness' structure is required for its
      antimicrobial action. In this review, we summarize both published and unpublished
      biophysical studies of the interactions of GS with lipid bilayer model and with
      biological membranes. In general, these studies show that GS partitions strongly
      into liquid-crystalline lipid bilayers in both model and biological membranes,
      and seems to be located primarily in the glycerol backbone region below the polar
      headgroups and above the hydrocarbon chains. The presence of GS appears to
      perturb lipid packing in liquid-crystalline bilayers and GS can induce the
      formation of inverted cubic phases at lower temperatures in lipids capable of
      forming such phases at higher temperature in the absence of peptide. The presence
      of GS at lower concentrations also increases the permeability of model and
      biological membranes and at higher concentrations causes membrane
      destabilization. There is good evidence from studies of the interaction of GS
      with bacterial cells that the destruction of the integrity of the lipid bilayer
      of the inner membrane is the primary mode of the antimicrobial action of this
      peptide. The considerable lipid specificity of GS for binding to and
      destabilization of lipid bilayer model membranes indicates that the design of GS
      analogs with an improved antimicrobial potency and a markedly decreased toxicity
      for eukaryotic cell plasma membranes should be possible.

PMID- 10590310
TI  - The lantibiotic nisin, a special case or not?
AB  - Nisin is a 34-residue-long peptide belonging to the group A lantibiotics with
      antimicrobial activity against Gram-positive bacteria. The presence of dehydrated
      residues and lanthionine rings (thioether bonds) in nisin, imposing structural
      restrains on the peptide, make it an interesting case for studying the mode of
      action. In addition, the relatively high activity (nM range) of nisin against
      Gram-positive bacteria indicates that nisin may be a special case in the large
      family of pore-forming peptides antibiotics. In this review, we attempted to
      dissect the mode of action of nisin concentrating on studies that used model
      membranes or biological membranes. The picture that emerges suggests that in
      model membrane systems, composed of only phospholipids, nisin behaves similar to
      the antimicrobial peptide magainin, albeit with an activity that is much lower as
      compared to its activity towards biological membranes. This difference can be
      contributed to a missing factor which nisin needs for its high activity. Novel
      results have identified the factor as Lipid II, a precursor in the bacterial cell
      wall synthesis. The special high affinity interaction of nisin with Lipid II
      resulting in high activity and the active role of Lipid II in the pore-formation
      process make nisin a special case.

PMID- 10590311
TI  - Alteration of cGMP metabolism during chondrogenic differentiation of
      chondroprogenitor-like EC cells, ATDC5.
AB  - Guanosine 3',5'-cyclic monophosphate (cGMP) has been recently reported to be
      involved in bone formation. ATDC5 cells were used to investigate cGMP metabolism
      during chondrogenic differentiation. Natriuretic peptide receptor (NPR)-A and NPR
      B coupled with guanylate cyclase (GC) mediate biological functions of NPs,
      whereas NPR-C uncoupled with GC is thought to be the clearance receptor for NPs.
      The amounts of NPR-A, NPR-B, and CNP transcripts were increased but the amount of
      NPR-C transcripts was decreased in association with the chondrogenic
      differentiation of ATDC5 cells. CNP, a specific ligand for NPR-B lets ATDC5 cells
      accumulate great amounts of cGMP, revealing NPR-B as a dominant biological
      receptor through differentiation. cGMP hydrolytic activities of PDE1 and PDE5
      existed in ATDC5 cells, and the activity of PDE1, which is stimulated by Ca(2+)
      and calmodulin (CaM) was major of them. Total cGMP hydrolytic activities as well
      as the amounts of PDE1 and PDE5 transcripts were enhanced during chondrogenic
      differentiation. Therefore, cGMP production and hydrolysis, cGMP metabolism was
      considered to be activated in association with chondrogenic differentiation of
      ATDC5 cells. These observations may lead to a better understanding of cGMP in the
      chondrocytes where bone formation occurs.

PMID- 10590312
TI  - Targeting of K-Ras 4B by S-trans,trans-farnesyl thiosalicylic acid.
AB  - Ras proteins regulate cell growth, differentiation and apoptosis. Their
      activities depend on their anchorage to the inner surface of the plasma membrane,
      which is promoted by their common carboxy-terminal S-farnesylcysteine and either
      a stretch of lysine residues (K-Ras 4B) or S-palmitoyl moieties (H-Ras, N-Ras and
      K-Ras 4A). We previously demonstrated dislodgment of H-Ras from EJ cell membranes
      by S-trans,trans-farnesylthiosalicylic acid (FTS), and proposed that FTS disrupts
      the interactions between the S-prenyl moiety of Ras and the membrane anchorage
      domains. In support of this hypothesis, we now show that FTS, which is not a
      farnesyltransferase inhibitor, inhibits growth of NIH3T3 cells transformed by the
      non-palmitoylated K-Ras 4B(12V) or by its farnesylated, but unmethylated, K-Ras
      4B(12) CVYM mutant. The growth-inhibitory effects of FTS followed the dislodgment
      and accelerated degradation of K-Ras 4B(12V), leading in turn to a decrease in
      its amount in the cells and inhibition of MAPK activity. FTS did not affect the
      rate of degradation of the K-Ras 4B, SVIM mutant which is not modified post
      translationally, suggesting that only farnesylated Ras isoforms are substrates
      for facilitated degradation. The putative Ras-recognition sites (within domains
      in the cell membrane) appear to tolerate both C(15) and C(20) S-prenyl moeities,
      since geranylgeranyl thiosalicylic acid mimicked the growth-inhibitory effects of
      FTS in K-Ras 4B(12V)-transformed cells and FTS inhibited the growth of cells
      transformed by the geranylgeranylated K-Ras 4B(12V) CVIL isoform. The results
      suggest that FTS acts as a domain-targeted compound that disrupts Ras-membrane
      interactions. The fact that FTS can target K-Ras 4B(12V), which is insensitive to
      inhibition by farnesyltransfarase inhibitors, suggests that FTS may target Ras
      (and other prenylated proteins important for transformed cell growth) in an
      efficient manner that speaks well for its potential as an anticancer therapeutic
      agent.

PMID- 10590313
TI  - Correlation between Ca(2+) oscillation and cell proliferation via CCK(B)/gastrin
      receptor.
AB  - Gastrin stimulates cell proliferation through the CCK(B) receptor coupled to Gq
      protein, whereas the m3 muscarinic receptor, which also couples to Gq, has no
      trophic effects. In order to elucidate the cause of the difference, we stably
      transfected CHO cells with human CCK(B) and m3 receptors. Stimulation of the
      CCK(B), but not the m3 receptor increased cell growth. Activation of MAP kinase
      via the m3 receptor was to the same extent as that via CCK(B), indicating that
      there is an initial signaling common to both receptors. Stimulation of either
      receptor induced a transient increase in [Ca(2+)](i) followed by a sustained
      plateau phase. After 2 h of stimulation, the [Ca(2+)](i) response to the m3
      receptor disappeared, whereas that to the CCK(B) receptor remained as a
      [Ca(2+)](i) oscillation. Removal of extracellular Ca(2+), which abolished
      [Ca(2+)](i) oscillation, completely inhibited DNA synthesis via CCK(B). When the
      C-terminal part of the CCK(B) receptor was truncated, the trophic effect as well
      as the [Ca(2+)](i) response after 2 h of stimulation disappeared, whereas the
      chimeric CCK(B) receptor with the C-terminal region of the m3 receptor preserved
      its ability to elicit both DNA synthesis and [Ca(2+)](i) oscillation. These
      results suggest that desensitization might be a principal determinant of cell
      proliferation, and the persistence of the [Ca(2+)](i) response as [Ca(2+)](i)
      oscillation could be essential for this type of signal transduction.

PMID- 10590314
TI  - Ryanodine-sensitive Ca(2+) release mechanism of rat pancreatic acinar cells is
      modulated by calmodulin.
AB  - The effects of calmodulin (CaM) and CaM antagonists on microsomal Ca(2+) release
      through a ryanodine-sensitive mechanism were investigated in rat pancreatic
      acinar cells. When caffeine (10 mM) was added after a steady state of ATP
      dependent (45)Ca(2+) uptake into the microsomal vesicles, the caffeine-induced
      (45)Ca(2+) release was significantly increased by pretreatment with ryanodine (10
      microM). The presence of W-7 (60 microM), a potent inhibitor of CaM, strongly
      inhibited the release, while W-5 (60 microM), an inactive CaM antagonist, showed
      no inhibition. Inhibition of the release by W-7 was observed at all caffeine
      concentrations (5-30 mM) tested. The presence of exogenously added CaM (10
      microg/ml) markedly increased the caffeine (5-10 mM)-induced (45)Ca(2+) release
      and shifted the dose-response curve of caffeine-induced (45)Ca(2+) release to the
      left. Cyclic ADP-ribose (cADPR, 2 microM)-induced (45)Ca(2+) release was enhanced
      by the presence of ryanodine (10 microM). cADPR (2 microM)- or ryanodine (500
      microM)-induced (45)Ca(2+) release was also inhibited by W-7 (60 microM), but not
      by W-5 (60 microM), and was stimulated by CaM (10 microg/ml). These results
      suggest that the ryanodine-sensitive Ca(2+) release mechanism of rat pancreatic
      acinar cells is modulated by CaM.

PMID- 10590315
TI  - Possible involvement of cytochrome c release and sequential activation of
      caspases in ceramide-induced apoptosis in SK-N-MC cells.
AB  - Ceramide is characterized as a second messenger of apoptosis induced by various
      agents such as tumor necrosis factor (TNF-alpha), Fas ligand, hydrogen peroxide,
      heat shock and ionizing radiation. In this study, we investigated the mechanism
      of ceramide-induced apoptosis using a human neuroblastoma cell line, SK-N-MC. N
      Acetyl-sphingosine (C2-ceramide), a cell-permeable ceramide analogue, was able to
      induce apoptosis in SK-N-MC cells as estimated by DNA fragmentation and chromatin
      condensation. C2-ceramide-induced DNA fragmentation was blocked by caspase
      inhibitor (Z-Asp-CH(2)-DCB). An increase in caspase-3 (CPP32)-like protease
      activity was evident during C2-ceramide-induced apoptosis, suggesting that
      caspases are involved in this apoptosis. Moreover, enzymatic cleavage of VDVAD
      AFC and LEHD-AFC (specific substrates for caspase-2 and -9, respectively) was
      increased by treatment with C2-ceramide. To elucidate which types of caspase are
      activated in C2-ceramide-treated cells, we performed Western blot analysis using
      antibodies against each isoform. Both proforms of caspase-2 and -3 were decreased
      in response to C2-ceramide in a time-dependent manner. Mitochondrial cytochrome c
      is also time-dependently released into the cytosol in response to treatment with
      C2-ceramide. Addition of cytochrome c into the S-100 fractions prepared from SK-N
      MC cells could activate caspase-2 in cell-free systems. These results suggest the
      possibility that cytochrome c released to the cytosol can activate caspases
      (caspase-9, -3, and -2) during C2-ceramide-induced apoptosis of SK-N-MC cells.

PMID- 10590317
TI  - The HPV-16 E5 oncogene and bafilomycin A(1) influence cell motility.
AB  - It is known that the proper function of the vacuolar H(+)-ATPase is inhibited by
      bafilomycin A(1). In transfected cells the E5 protein interacts with the 16 kDa
      subunit of the vacuolar H(+)-ATPase. Thereby the pH gradient in endocytic
      structures is impaired. The present study demonstrates for the first time that
      the inhibition of the vacuolar H(+)-ATPase in NIH3T3 cells with bafilomycin A(1)
      or by transfection of cells with the HPV-16 E5 oncogene leads to a changed
      morphology and a reduced motility as shown by computer-assisted video recordings
      and image analysis. Bafilomycin A(1) potentiates the effect of the E5 protein on
      cell motility and this cooperative effect indicates that the E5 protein and
      bafilomycin A(1) either target the vacuolar H(+)-ATPase differently or that the
      E5 protein has additional targets in transfected cells. Our data therefore show
      that proper function of the vacuolar H(+)-ATPase is needed for normal cell
      locomotion.

PMID- 10590316
TI  - Effects of macrophage colony-stimulating factor (M-CSF) on protease production
      from monocyte, macrophage and foam cell in vitro: a possible mechanism for anti
      atherosclerotic effect of M-CSF.
AB  - M-CSF is a growth factor that stimulates proliferation and differentiation of
      monocyte/macrophage-lineage cells. In our previous studies, M-CSF regresses
      atherosclerotic lesions preformed in aorta of high cholesterol-fed rabbit.
      Immunohistochemical analysis indicated that extracellular matrix (ECM), such as
      collagen, was especially eliminated in the intima of atherosclerotic lesion. To
      define the collagen-lowering potential of M-CSF, we have studied the effects of M
      CSF on production of collagen-degrading proteases, such as MMP-1, -9 and
      urokinase in vitro. Monocytes freshly isolated from human peripheral blood
      produced MMP-9, but not urokinase, and M-CSF enhanced MMP-9 production.
      Macrophages were prepared by culturing monocytes for 10 days in the presence or
      absence of M-CSF, and protease production was assayed. M-CSF augmented production
      of MMP-9 and urokinase in a dose-dependent manner. M-CSF also enhanced MMP-1
      production of macrophages, but not significantly. Foam cells were prepared by
      culturing macrophages in the presence of acetyl LDL, and protease production from
      these cells were also elevated by M-CSF. These results suggest that M-CSF
      exogenously administered in atherosclerotic rabbits might regress the thickened
      intima by activating macrophages to degrade collagen accumulated in the lesion.

PMID- 10590318
TI  - Cell cycle-dependent regulation of early developmental genes.
AB  - Cell cycle phase at the onset of development in Dictyostelium influences cell
      fate. Cells in the G2 phase, which tend to become spores, show a more rapid
      induction of expression of the cell surface receptor involved in the chemotaxis.
      We show that differential induction of developmental expression is restricted to
      some transcripts, including those encoding proteins required for chemotaxis, and
      thus is not due to general transcriptional repression during mitosis. We also
      show that cells showing rapid induction of one such gene are preferentially
      located at the centre of early aggregates. These results are consistent with
      cells derived from G2 phase being at the centre of early aggregates because
      selective differences in gene regulation render them more efficient at
      aggregation.

PMID- 10590319
TI  - Increased glutathione synthesis associated with platelet-derived growth factor
      stimulation of NIH3T3 fibroblasts.
AB  - Previous data show a relation between GSH content and proliferation of normal and
      tumour cells. We recently demonstrated a specific involvement of GSH in the
      autophosphorylation activity of the platelet-derived growth factor (PDGF)
      receptor in NIH3T3 fibroblasts. In this study we demonstrate that the stimulation
      by PDGF of serum-starved NIH3T3 cells increases cellular GSH content, while no
      change in oxidized GSH content was measured. Experiments performed with
      actinomycin, cycloheximide and buthionine sulfoximide, a specific inhibitor of
      the rate-limiting enzyme of the de novo synthesis of GSH gamma-glutamylcysteine
      synthetase (gamma-GCS), confirm PDGF induction of GSH synthesis. These results
      provide the first demonstration that PDGF mediated transduction signals seem
      strictly related to mechanisms involved in the increase of gamma-GCS activity
      associated with increased gamma-GCS heavy subunit mRNA levels. In fact, serum and
      epidermal growth factor (EGF) stimulation of quiescent NIH3T3 and NIH3T3, which
      overexpress EGF receptor, does not affect GSH content or its synthesis. These
      data may be related to a possible GSH role in the redox regulation of cell
      proliferation mediated by PDGF.

PMID- 10590320
TI  - Stress-induced glucose uptake in bovine chromaffin cells: a comparison of the
      effect of arsenite and anisomycin.
AB  - The effect of the toxic chemical Na-arsenite and the protein synthesis inhibitor
      anisomycin on glucose transport in primary cultures of bovine chromaffin cells
      was compared using the effect of insulin-like growth factor I (IGF-I) as a
      reference. The enhanced uptake of glucose obtained in response to arsenite and
      anisomycin reached maximum after 60 min, with the response to anisomycin being
      delayed in onset relative to that of arsenite. At maximal doses the arsenite
      effect was consistently higher than that of anisomycin and comparable to the
      approximately 2-fold effect produced by IGF-I. The selective inhibitor of stress
      activated protein kinase 2 (SAPK2), SB 203580, inhibited completely anisomycin
      induced glucose uptake but only partly suppressed uptake stimulated by arsenite.
      Both substances, in concentrations producing maximal effects on glucose
      transport, led to a strong phosphorylation of SAPK2. In contrast to the effect on
      glucose transport, the arsenite-induced phosphorylation of SAPK2 was relatively
      slow compared to the anisomycin-induced activation. The results indicate that
      glucose uptake induced by the two types of cellular stress are mediated by at
      least two different signaling pathways, which also differ from that activated by
      IGF-I.

PMID- 10590322
TI  - Prevention and early treatment of influenza in healthy adults.
AB  - INTRODUCTION: We present three systematic reviews carried out within the Cochrane
      Collaboration, focusing on a different influenza intervention in healthy adults:
      Vaccines; Ion Channel Inhibitor antivirals and Neuraminidase Inhibitor (NIs)
      antivirals. The objectives were to identify, retrieve and assess all studies
      evaluating the effects of these interventions in prophylaxis and early treatments
      of influenza and the frequency of adverse events. Additionally we present the
      results of the economic evaluation of effective alternatives in order to define
      the most cost-effective intervention. The economic evaluation is set in the
      context of the British Army. METHODS: Studies were identified using a standard
      Cochrane search strategy. Any randomised or quasi-randomised studies in healthy
      individuals aged 14-60 years were considered for inclusion in the systematic
      review. Those which met inclusion criteria were assessed for quality and their
      data meta-analysed. The economic model was constructed using Cost-effectiveness
      and Cost-utility study designs. RESULTS: Live aerosol vaccines reduced cases of
      clinical influenza A with virological confirmation (by serology and/or viral
      isolation) by 48% (95%CI: 24-64%), whilst recommended inactivated parenteral
      vaccines have an efficacy of 68% (95%CI: 49-79%). Vaccine effectiveness in
      reducing clinical influenza cases (i.e. without virological confirmation) was
      lower, with efficacies of 13 and 24% respectively. Use of the vaccine
      significantly reduced time off work, but only by 0.4 days (95%CI: 0. 1-0.8 days).
      Analysis of vaccines matching the circulating strain gave higher estimates of
      efficacy, whilst inclusion of all other vaccines reduced the efficacy. When
      compared to placebo for the prevention of influenza, oral amantadine was 61%
      (95%CI: 51-69%) efficacious (RR 0.39 - 95%CI: 0.31-0.49), and oral rimantadine
      was 64% (95%CI: 41-78%) efficacious (RR 0.36 -95%CI: 0.22-0.59). When compared to
      placebo for the treatment of influenza, oral amantadine significantly shortened
      duration of fever (by 1.00 days - 95%CI: 0. 73-1.29), and oral rimantadine
      significantly shortened duration of fever (by 1.27 days - 95%CI: 0.77-1.77). When
      compared to placebo, NIs were 74% (95%CIs: 50-87%) effective in preventing
      naturally occurring cases of clinically defined influenza. In a treatment role,
      NIs shortened the duration of symptoms by one day (Weighted Mean Difference -
      1.0; 95%CIs: -1.3 to - 0.6) when a clinical case definition is used. The economic
      results show that in healthy adults, inactivated vaccines appear the best buy.
      CONCLUSIONS: If assessed from the point of view of effectiveness and efficiency,
      vaccines are undoubtedly the best preventive means for clinical influenza in
      healthy adults. However, when safety and quality of life considerations are
      included, parenteral vaccines have such low effectiveness and high incidence of
      trivial local adverse effects that the trade-off is unfavourable. This is so even
      when the incidence of influenza is high and adverse effect quality of life
      preferences are rated low. We reached similar conclusions for antivirals and NIs
      even at high influenza incidence levels. On current evidence we conclude in
      healthy adults aged 14-60 the most cost-effective option is not to take any
      action.

PMID- 10590323
TI  - Totally synthetic lipid-containing polyoxime peptide constructs are potent
      immunogens.
AB  - A synthetic peptide corresponding to a sequence from influenza hemagglutinin was
      used as a model antigen to study the immunogenicity of polyoxime constructs. In
      the absence of any adjuvant, tetrameric forms of different polyoxime constructs
      did not elicit an antibody response. High and long-lasting levels of antibody
      were induced, however, by polyoxime constructs to which Pam3Cys (tripalmitoyl-S
      glyceryl cysteine) was attached. Comparable serum antibody levels were achieved
      with Tetraoxime-Pam3Cys administered by the intraperitoneal or intranasal routes
      to those obtained when the monomeric peptide was administered by the
      intraperitoneal route in complete Freund's adjuvant (CFA). Mice receiving
      Tetraoxime-Pam3Cys and Pam3Cys-peptide intranasally developed peptide-specific
      antibody secreting cells (ASCs) in their lungs and mediastinal lymph nodes. At
      low dose, the Tetraoxime-Pam3Cys induced higher levels of antibody compared to
      those elicited by the monomeric Pam3Cys-peptide delivered by either route. These
      results show that lipo-tetraoxime constructs assembled by polyoxime chemistry can
      be potent inducers of systemic and mucosal immunity.

PMID- 10590324
TI  - Vaccination with a single dose of a recombinant porcine adenovirus expressing the
      classical swine fever virus gp55 (E2) gene protects pigs against classical swine
      fever.
AB  - A recombinant porcine adenovirus (rPAV) with the gp55 (E2) gene from the
      classical swine fever virus (CSFV) 'Weybridge' strain inserted into the right
      hand end of the PAV serotype 3 (PAV3) genome was constructed. Expression of gp55
      was directed by the major late promoter and tri-partite leader sequences located
      and cloned from PAV3. No compensatory deletions of PAV DNA sequences were made.
      Vaccination of outbred pigs with a single dose of the recombinant virus (rPAV
      gp55) resulted in complete protection from lethal challenge with CSFV. No adverse
      clinical signs were observed in vaccinated animals following administration of
      rPAV-gp55 and following challenge, no clinical signs of CSF were observed prior
      to, or at, post mortem. The insert made into the rPAV increased the genome length
      to 106.8% of wild type and therefore exceeded the expected maximum insert size
      for a stable recombinant by almost 2%. Thus rPAV-gp55 contains the largest stable
      insertion made into a non-deleted Mastadeno virus recombinant so far reported.

PMID- 10590325
TI  - HPV6b virus like particles are potent immunogens without adjuvant in man.
AB  - Subjects with genital warts were immunized three times or more with HPV6b VLPs
      without adjuvant. All immunized subjects had DTH to HPV6b L1 protein. Of 32
      subjects, nine had HPV6b specific antibody prior to immunization and 22 acquired
      antibody with immunization. VLP specific antibody increased following a single
      immunization in 6 of 8 subjects with low level antibody at recruitment. Complete
      regression of genital warts was observed in 25 of 33 evaluable subjects over the
      20-week observation period. We conclude that immunization with HPV6b L1 VLPs
      without adjuvant induces immunity to the L1 protein epitopes recognised during
      natural infection, and may accelerate regression of warts.

PMID- 10590326
TI  - DNA vaccination of mice against rabies virus: effects of the route of vaccination
      and the adjuvant monophosphoryl lipid A (MPL).
AB  - Adjuvants are known to strongly enhance immune responses generated by traditional
      vaccines, but less is known about the effects of adjuvants on vaccination with
      DNA. In this study, we investigated the use of the immunostimulant monophosphoryl
      lipid A (MPL(R)) as an adjuvant, and analyzed three routes of DNA vaccination to
      determine if this adjuvant could enhance anti-rabies virus neutralizing antibody
      responses. Compared with antibody titers elicited with DNA only, antibody titers
      were enhanced after initial intradermal (i.d.) and gene gun immunizations with
      the combination of DNA and MPL(R). Antibody was not detected after primary
      intramuscular (i.m.) immunization unless MPL(R) was included with the DNA.
      Surprisingly, antibody titers of MPL(R)-treated mice decreased after i.d. or i.m.
      booster vaccinations, but increased after gene gun booster vaccinations. In
      contrast to these varied responses, booster immunizations without MPL(R) via the
      three different routes consistently increased antibody titers. All mice with
      detectable levels of neutralizing antibody at the time of challenge survived
      virus infection. There was no difference in the survival rate between groups of
      mice that received similar vaccinations with MPL(R)/DNA or DNA only. The data
      suggest that MPL(R) can enhance the neutralizing antibody response when used with
      the initial injection of DNA. Suppression of neutralizing antibody responses
      after i.d. or i.m. booster vaccinations that included MPL(R) suggests that the
      number of vaccinations, and the route of vaccination, should be carefully
      considered when MPL(R) is used with DNA vaccines.

PMID- 10590327
TI  - Induction of in vivo persistent anti-mycobacterial activity by interferon-gamma
      secreting fibroblasts.
AB  - To determine whether the paracrine secretion of interferon-gamma (IFN-gamma) can
      efficiently stimulate the resistance to Mycobacterium avium complex (MAC)
      infection, 3T3 fibroblasts were stably transduced to secrete IFN-gamma (500
      units/10(6) cells/48 h) and their effects on MAC infection were investigated in
      genetically susceptible BALB/c mice, compared with that of free recombinant IFN
      gamma (rIFN-gamma). Immunization with IFN-gamma-secreting fibroblasts (3T3-IFN
      gamma) during intranasal infection with MAC resulted in a significant decrease in
      bacterial load of lung during the entire 8-week observation period, while rIFN
      gamma reduced the bacterial load at initial 1 week but not by 8 weeks
      postinfection. Furthermore, immunization with the 3T3-IFN-gamma cells induced and
      maintained significantly higher levels of cytotoxic activity and nitric oxide
      production by lung cells than those of rIFN-gamma immunization. This work suggest
      that IFN-gamma-secreting fibroblasts may serve as a vehicle for paracrine
      secretion of IFN-gamma in immunotherapy of MAC infection.

PMID- 10590328
TI  - Hepatitis A and hepatitis B vaccinations: immunogenicity of combined vaccine and
      of simultaneously or separately applied single vaccines.
AB  - The vaccination success and side effects of hepatitis A and hepatitis B
      immunisation of health care employees when using a combined vaccine were compared
      to those observed with simultaneous or single immunisations. The immunological
      response of two groups of healthy participants (75 each) receiving either single
      HAV or HBV vaccination was compared with that of two groups (75 each) vaccinated
      either simultaneously with both vaccines or with the combined vaccine. There were
      no non or low responders with respect to hepatitis A vaccination. Only one
      participant failed to build up an anti-HBs titer after combined vaccination. The
      good tolerance of separate, simultaneous and combined vaccinations was confirmed.
      Both combined and simultaneous vaccination led to significantly higher anti-HAV
      titers than single immunisation, while markedly but not significantly higher anti
      HBs titers were found only with simultaneous vaccination. Considering the
      additional advantage of the higher acceptance of only one injection with the
      combined vaccine, this vaccination should be recommended for employees at risk
      for both hepatitis A and hepatitis B.

PMID- 10590329
TI  - In vitro immune function after vaccination with an inactivated, gp120-depleted
      HIV-1 antigen with immunostimulatory oligodeoxynucleotides.
AB  - We examined the effect of a synthetic oligodeoxynucleotide containing
      unmethylated CpG immunostimulatory sequences (ISS) as an adjuvant for an HIV-1
      immunogen (inactivated, gp120-depleted HIV-1 virus particles). The addition of
      the ISS to HIV-1 in incomplete Freund's adjuvant (IFA) was the optimal
      combination for the production of HIV-1-specific immune responses as measured by
      IFN-gamma (p=0.002) and IgG antibody production. Furthermore, the group that was
      immunized with HIV/IFA/ISS, as well as the group that received HIV-1 in complete
      Freund's adjuvant (CFA), stimulated significantly more RANTES (a beta-chemokine)
      (p=0.002) production from lymph node cells. These results suggest that the
      addition of CpG immunostimulatory sequences to HIV antigens in IFA may optimize
      HIV-1-specific immune responses and provides further rationale for the testing of
      ISS in combination with gp120-depleted whole-killed HIV-1 in IFA as a potential
      preventive or therapeutic HIV-1 vaccine.

PMID- 10590330
TI  - Protection against diverse highly pathogenic H5 avian influenza viruses in
      chickens immunized with a recombinant fowlpox vaccine containing an H5 avian
      influenza hemagglutinin gene insert.
AB  - A recombinant fowlpox vaccine with an H5 hemagglutinin gene insert protected
      chickens against clinical signs and death following challenge by nine different
      highly pathogenic H5 avian influenza viruses. The challenge viruses had 87.3 to
      100% deduced hemagglutinin amino acid sequence similarity with the recombinant
      vaccine, and represented diversely geographic and spatial backgrounds; i.e.
      isolated from four different continents over a 38 year period. The recombinant
      vaccine reduced detectable infection rates and shedding titers by some challenge
      viruses. There was a significant positive correlation in hemagglutinin sequence
      similarity between challenge viruses and vaccine, and the ability to reduce
      titers of challenge virus isolated from the oropharynx (r(s)=0.783, P=0.009), but
      there was no similar correlation for reducing cloacal virus titers (r(s)=-0.100,
      P=0.78). This recombinant fowlpox-H5 avian influenza hemagglutinin vaccine can
      provide protection against a variety of different highly pathogenic H5 avian
      influenza viruses and frequent optimizing of the hemagglutinin insert to overcome
      genetic drift in the vaccine may not be necessary to provide adequate field
      protection.

PMID- 10590332
TI  - Decreased antibody response among nursing home residents who received recalled
      influenza vaccine and results of revaccination, 1996-97.
AB  - In November 1996, 11 lots of one U.S. manufacturer's 1996-97 trivalent influenza
      vaccine were voluntarily recalled because of decreasing potency of the
      A/Nanchang/933/95 (H3N2) component. Because the elderly are at high risk of
      developing influenza-related complications, we assessed the postvaccination
      antibody titers of nursing home residents who received recalled vaccine and
      assessed the antibody response to revaccination. Blood samples were collected 3
      weeks after vaccination from 86 residents at three nursing homes who received
      recalled vaccine and 86 residents at three other nursing homes who received a
      different manufacturer's vaccine. Medical records were reviewed. Residents of one
      nursing home were later revaccinated. Blood samples were collected on the day of
      revaccination and again in 3 weeks. Serum was tested by hemagglutination
      inhibition for antibody to all three components of the 1996-97 influenza vaccine.
      The geometric mean antibody titer (GMT) (33 vs 55; p=0.01) and the percentage of
      residents with an antibody titer > or = 1:40 (52 vs 67%; p=0.04) to the
      A/Nanchang/933/95 component were lower among residents who received recalled
      vaccine compared to those who received non-recalled vaccine, but had similar GMTs
      against the other two vaccine components. After revaccination, the GMT to
      A/Nanchang/933/95 increased from 24 on the day of revaccination to 39 (p=0.01) in
      residents from one nursing home. Therefore, vaccination with the recalled vaccine
      was associated with lower postvaccination antibody titers to A/Nanchang/933/95,
      but not against the other two vaccine components. Revaccination was moderately
      effective in increasing antibody titers. With annual changes in influenza vaccine
      strains, routine post-release stability testing of influenza vaccine should
      continue.

PMID- 10590331
TI  - Hookworm burden reductions in BALB/c mice vaccinated with recombinant Ancylostoma
      secreted proteins (ASPs) from Ancylostoma duodenale, Ancylostoma caninum and
      Necator americanus.
AB  - Vaccination of mice with alum-precipitated recombinant Ancylostoma secreted
      protein-1 from the canine hookworm Ancylostoma caninum (Ac-ASP-1) results in
      protection against A. caninum larval challenge. Vaccine protection is manifested
      by host reductions in hookworm burden compared to control mice. The goal of this
      study was to determine whether ASP antigens cloned and expressed from different
      hookworm species will cross protect against A. caninum larval challenge. Cross
      species protection against A. caninum challenge infections was observed with
      immunizations using recombinant ASP-1 from the human hookworms Ancylostoma
      duodenale and Necator americanus. However, the degree of protection was
      proportional to the extent of amino acid sequence homology between the ASP
      immunogen used for vaccination and the Ac-ASP-1 produced by the challenge larval
      strain. Vaccine protection was noted to decrease significantly as amino acid
      sequence homologies diverged 10% or more. It was also determined that Ac-ASP-2, a
      molecule cloned from A. caninum having 55% amino acid sequence homology to the C
      terminus of Ac-ASP-1, did not elicit vaccine protection. These observations were
      partly reflected in the titer of antibodies that recognize Ac-ASP-1. The studies
      reported here will help to design immunogenic peptide vaccines based on the
      sequence divergence of hookworm ASPs.

PMID- 10590334
TI  - Factors influencing cellular immune responses to feline immunodeficiency virus
      induced by DNA vaccination.
AB  - Virus-specific effector cytotoxic T lymphocytes (CTL) were elicited in the
      peripheral blood of domestic cats following a single intramuscular inoculation of
      replication defective feline immunodeficiency virus proviral DNA (FIVDeltaRT).
      Higher levels of virus-specific cytolysis were observed in the blood when cats
      were co-inoculated with feline gamma-interferon (IFN) DNA. The responses declined
      by 12 weeks following the first DNA inoculation and were, with the exception of
      FIV Gag-specific responses in some cats, refractory to repeated DNA inoculations.
      Nevertheless, a significant proportion of the cats were protected from challenge
      with homologous virus. The effects of interval between inoculations, route of DNA
      delivery, and promoter used to regulate viral gene expression on the induction of
      virus-specific CTLs were evaluated. The highest levels of virus-specific lysis
      were recorded following intramuscular co-inoculation of FIVDeltaRT and gamma-IFN
      DNA, where FIV gene expression was under the control of a cytomegalovirus (CMV)
      promoter. However, the highest levels of protection were observed using the viral
      5'LTR as the promoter. These results suggest that a single intramuscular
      inoculation of FIVDeltaRT DNA together with gamma-IFN DNA may be sufficient to
      induce virus-specific CTLs and protection.

PMID- 10590333
TI  - Liposome encapsulation of a soluble recombinant fragment of the respiratory
      syncytial virus (RSV) G protein enhances immune protection and reduces lung
      eosinophilia associated with virus challenge.
AB  - Respiratory syncytial virus (RSV) is a leading cause of bronchiolitis and
      pneumonia in young children and infants. Previous animal studies have shown that
      immunizing intramuscularly or intraperitoneally with the RSV G protein has
      elicited protective as well as harmful immune responses upon RSV challenge. In an
      RSV immunization strategy designed to target the respiratory tract directly (the
      site of RSV replication), we immunized BALB/c mice intranasally with a liposome
      encapsulated, prokaryotically expressed thioredoxin fusion protein consisting of
      amino acids 128-229 of the RSV G protein (Trx-G(128-229)). Upon intranasal
      challenge with RSV, a 100 to 500-fold reduction in lung RSV replication was
      observed in mice immunized with liposome-encapsulated Trx-G(128-229) compared to
      a sham-immunized control group. Analysis of bronchoalveolar lavage fluids
      revealed an influx of eosinophils (18% of total cells) in mice immunized with Trx
      G(128-229) alone. Such eosinophilic infiltration was diminished (to 4.5% of total
      cells), however, in mice immunized with liposome-encapsulated Trx-G(128-229).
      Histological analysis of lung tissue revealed an accumulation of cells around the
      bronchioles and vessels in mice immunized with Trx-G(128-229) alone followed by
      RSV challenge which was not increased further in mice immunized with liposome
      encapsulated Trx-G(128-229). These results show that intranasal immunization of
      BALB/c mice with Trx-G(128-229), when encapsulated in liposomes, can reduce the
      level of RSV replication in the lung as well as specifically reduce the degree of
      eosinophilic infiltration compared to mice immunized with Trx-G(128-229) alone.
      This demonstrates the potential of liposomes and particular recombinant fragments
      of the RSV G protein as an effective combination in RSV vaccine studies.

PMID- 10590335
TI  - A DNA vaccine expressing dengue type 2 virus premembrane and envelope genes
      induces neutralizing antibody and memory B cells in mice.
AB  - A dengue DNA vaccine candidate was developed and evaluated for immunogenicity in
      mice. The vaccine, designated pcD2ME, is a pcDNA3-based plasmid encoding the
      signal sequence of premembrane (prM), prM and envelope (E) genes of the New
      Guinea C strain of dengue type 2 virus. CHO-K1 cells transfected with pcD2ME
      expressed prM and E as determined by immunochemical staining with monoclonal
      antibodies. BALB/c mice inoculated intramuscularly with 100 microg of pcD2ME two
      or three times at an interval of 2 weeks developed a low level of neutralizing
      antibody (1:10 at a 90% plaque reduction). Immunization twice with 10 microg or 1
      microg of pcD2ME or three times with 100 microg of pcDNA3 did not induce
      detectable levels of neutralizing antibody. Mice immunized two or three times
      with 100 microg of pcD2ME raised neutralizing antibody titers to 1:40 or greater
      on days 4 and 8 after challenge with 3x10(5) plaque forming units (PFU) of the
      New Guinea C strain of dengue type 2 virus, showing strong anamnestic responses
      to the challenge. In contrast, mice immunized two or three times with 100 microg
      of pcDNA3 developed no detectable neutralizing antibody on days 4 and 8 after
      challenge. These results indicate that immunization with pcD2ME induces
      neutralizing antibody and dengue type 2 virus-responsive memory B cells in mice.

PMID- 10590336
TI  - Vaccination of chickens with a temperature-sensitive mutant of Salmonella
      enteritidis.
AB  - One-day old chickens were inoculated with temperature-sensitive mutant E/1/3 of
      S. enteritidis. Two routes of inoculation were used: oral and intraperitoneal
      (ip). One group of chickens were given two oral inoculations (oral-oral). A
      second group received two ip inoculations (ip-ip). A third group received the
      first dose orally and the second ip (oral-ip) and the fourth group was given the
      first dose ip and the second dose orally (ip-oral). The vaccine strain was safe
      even when inoculated at high doses, and induced strong protection against
      virulent S. enteritidis strain after oral challenge. Results show that
      vaccination with mutant E/1/3 reduced the number of animals shedding the pathogen
      after challenge. Furthermore, animals immunized oral-oral and oral-ip showed a
      significant reduction in cecal and spleen colonization by virulent Salmonella.

PMID- 10590338
TI  - A method of measuring three-dimensional scapular attitudes using the optotrak
      probing system.
AB  - OBJECTIVE: To develop a method to obtain accurate three-dimensional scapular
      attitudes and to assess their concurrent validity and reliability. STUDY DESIGN:
      In this methodological study, the three-dimensional scapular attitudes were
      calculated in degrees, using a rotation matrix (cyclic Cardanic sequence), from
      spatial coordinates obtained with the probing of three non colinear landmarks
      first on an anatomical model and second on a healthy subject. BACKGROUND:
      Although abnormal movement of the scapula is related to shoulder impingement
      syndrome, it is not clearly understood whether or not scapular motion impairment
      is a predisposing factor. Characterization of three-dimensional scapular
      attitudes in planes and at joint angles for which sub-acromial impingement is
      more likely to occur is not known. METHODS: The Optotrak probing system was used.
      An anatomical model of the scapula was built and allowed us to impose scapular
      attitudes of known direction and magnitude. A local coordinate reference system
      was defined with three non colinear anatomical landmarks to assess accuracy and
      concurrent validity of the probing method with fixed markers. Axial rotation
      angles were calculated from a rotation matrix using a cyclic Cardanic sequence of
      rotations. The same three non colinear body landmarks were digitized on one
      healthy subject and the three dimensional scapular attitudes obtained were
      compared between sessions in order to assess the reliability. RESULTS AND
      CONCLUSIONS: The measure of three dimensional scapular attitudes calculated from
      data using the Optotrak probing system was accurate with means of the differences
      between imposed and calculated rotation angles ranging from 1.5 degrees to 4.2
      degrees. Greatest variations were observed around the third axis of the Cardanic
      sequence associated with posterior-anterior transverse rotations. The mean
      difference between the Optotrak probing system method and fixed markers was 1.73
      degrees showing a good concurrent validity. Differences between the two methods
      were generally very low for one and two direction displacements and the largest
      discrepancies were observed for imposed displacements combining movement about
      the three axes. The between sessions variation of three dimensional scapular
      attitudes was less than 10% for most of the arm positions adopted by a healthy
      subject suggesting a good reliability. The Optotrak probing system used with a
      standardized protocol lead to accurate, valid and reliable measures of scapular
      attitudes. RELEVANCE: Although abnormal range of motion of the scapula is often
      related to shoulder pathologies, reliable outcome measures to quantify three
      dimensional scapular motion on subjects are not available. It is important to
      establish a standardized protocol to characterize three-dimensional scapular
      motion on subjects using a method for which the accuracy and validity are known.
      The method used in the present study has provided such a protocol and will now
      allow to verify to what extent, scapular motion impairment is linked to the
      development of specific shoulder pathologies.

PMID- 10590339
TI  - Upper limb tension tests as tools in the diagnosis of nerve and plexus lesions.
      Anatomical and biomechanical aspects.
AB  - OBJECTIVE: To analyse the validity of nerve tension tests used in the diagnosis
      of nerve (root) and plexus lesions of the upper extremity. DESIGN: In six arms of
      embalmed human bodies, in situ measurements were performed to assess the effect
      of nerve tension tests on the median, ulnar and radial nerves and the cords of
      the brachial plexus. BACKGROUND: In clinical practice it is useful to have fast,
      easy and cheap tests for the diagnosis of nerve (root) lesions of the upper
      extremity, analogous to Lasegue's Straight Leg Raising test.Methods. The Upper
      Limb Tension Tests for the median, ulnar and radial nerves, as well as the Upper
      Limb Tension Tests combined with contralateral rotation and lateral bend of the
      cervical spine (Upper Limb Tension Test+) were used to generate tension to these
      nerves. Buckle force transducers were used to assess tensile forces in the nerves
      and in the medial, lateral and posterior cords of the brachial plexus. RESULTS:
      Nerve tension introduced in the distal part of the median, ulnar and radial
      nerves was transmitted upward to the cords of the brachial plexus. Exclusively
      the median nerve Upper Limb Tension Test and Upper Limb Tension Test+ turned out
      to be sensitive and specific tension tests. Mechanical tension caused by the
      Upper Limb Tension Test+ was not significantly higher than that caused by the
      Upper Limb Tension Tests. The Upper Limb Tension Tests cannot be used to
      selectively stress cervical nerve roots. The findings justify investigation of
      exclusively the median nerve Upper Limb Tension Test and Upper Limb Tension Test+
      on their clinical validity. RELEVANCE: Before nerve tension tests for the median,
      ulnar and radial nerves can be introduced to clinical practice it is necessary to
      assess their validity quantitatively.

PMID- 10590340
TI  - Shock accelerations and attenuation in downhill and level running.
AB  - OBJECTIVE: A study was conducted to investigate the possible effects of fatigue
      on the heel strike-initiated shock accelerations and on attenuation of these
      shocks along the body during eccentric muscle contractions. DESIGN: Level and
      decline running on a treadmill were used to acquire the experimental data on the
      foot strike-initiated shock accelerations. BACKGROUND: Eccentric contractions of
      the lower limb muscles in combination with shock generation and propagation
      during downhill running and muscle fatigue may diminish their ability to
      dissipate and attenuate loading on the system. METHODS: Fourteen young healthy
      males ran on a treadmill at a speed exceeding their anaerobic threshold by 5% for
      30 min, as follows: (a) level running and (b) downhill running with a decline
      angle of -4 degrees. The foot strike-induced shock accelerations were recorded
      every five minutes on the tibial tuberosity and sacrum. Fatigue was monitored by
      means of the respiratory parameters. RESULTS: The downhill running related with
      eccentric muscle contractions was associated with increased shock propagation
      from the tibial tuberosity to the sacrum levels, even though fatigue did not
      develop. CONCLUSIONS: Shock propagation from the tibial tuberosity to the sacrum
      is augmented due to the eccentric action of the muscles, without metabolic
      fatigue development. RELEVANCE: Eccentric muscle contraction in downhill running
      reduces the musculoskeletal ability to attenuate the heel strike-induced shock
      waves. Knowledge about the effect of fatigue on the shock propagation between the
      shank and the sacrum levels may help in understanding the mechanism of stress
      fractures and joint damage.

PMID- 10590341
TI  - Reliability of peroneal reaction time measurements.
AB  - OBJECTIVE: The purpose of this study was to demonstrate the reliability of
      reaction time-measurements on a tilting platform under consideration of various
      influencing factors. DESIGN: The peroneal reaction time of 30 healthy subjects
      was examined in an experimental study. BACKGROUND: Peroneal reaction time
      measurements have been used to objectively evaluate functional instability of the
      ankle joint, but the reliability of the method has not been proven yet. METHODS:
      The reaction time after sudden inversion of the ankle were determined by surface
      EMG. RESULTS: The median latency of the peroneus brevis was 66 ms and that of the
      peroneus longus was 63 ms. No differences between male and female subjects and
      between left and right legs could be found. An increase of reaction time was
      caused by neuromuscular fatigue (P=0.033, for both the peroneus brevis and the
      peroneus longus). A decrease in reaction time resulted if the foot was held in 15
      degrees of plantar flexion (P=0.0004 for the peroneus brevis, P=0.002 for the
      peroneus longus). The reliability was examined by circadian and by day-to-day
      measurements. The coefficient of correlation (Spearman's rho) between the
      peroneus brevis and days 1-5 was 0.67 (P=0.177) and for the peroneus longus 0. 00
      (P0.999). The same results were obtained after the circadian measurements.
      CONCLUSION: Determination of peroneal reaction time was proven as a reliable
      measurement method. RELEVANCE: Reliability and validity are basic preconditions
      of a test to become accepted as a clinical measurement method. This paper
      demonstrates the reliability of measuring the peroneal reaction time. Thus,
      assuming validity, the peroneal reaction time measurement is justified as a
      clinical test.

PMID- 10590342
TI  - An in vivo determination of patellofemoral contact positions.
AB  - OBJECTIVE: To determine patellofemoral contact patterns in two-dimensions for
      normal and implanted patients. DESIGN: An in vivo, weightbearing fluoroscopy
      analysis of 14 subjects with normal knees, 12 with anterior cruciate ligament
      deficient knees, 14 with a posterior cruciate retaining implant, and 25 with a
      posterior cruciate substituting implant. BACKGROUND: Most previous experimental
      studies involving the knee joint have been either in vitro or under
      nonweightbearing conditions. METHODS: Subjects were studied under fluoroscopic
      surveillance performing deep knee bends to maximum flexion. Video images were
      analyzed on a computer with a two-dimensional technique of digitizing discrete
      points on the patella, femur, and tibia. RESULTS: The contact position, measured
      from the patella mass center, was inferior on the patella at extension and moved
      superior during flexion. Average contact positions of the implanted knee groups
      were more superior than the normal knee group throughout the flexion cycle.
      Analysis of patellar tilt angle demonstrated a flexed posture of the patella
      relative to the tibia. Increase in patellar tilt angle with increasing
      femorotibial flexion was substantially greater in implanted knees versus normal
      knees. Separation of the patella from the femur in full extension was absent in
      normal knees, but present in 86% and 44% of posterior cruciate retaining and
      posterior cruciate substituting total knee arthroplasties, respectively.
      CONCLUSIONS: The patellofemoral kinematics of the total knee arthroplasties
      analyzed in the study was statistically different than the normal and anterior
      cruciate ligament-deficient knees. The kinematic variations observed between
      normal and implanted knees may be related to disturbed femorotibial kinematics
      previously observed to occur following total knee arthroplasty. RELEVANCE:
      Patellofemoral complications, including polyethylene wear, are a major concern in
      total knee arthroplasty. Since the causes of polyethylene wear are multi
      factorial, abnormal patellofemoral kinematics may play a role in patellar
      failure.

PMID- 10590344
TI  - A study of in-shoe plantar shear in normals.
AB  - OBJECTIVE: To quantify features of in-shoe plantar shear in asymptomatic adult
      gait. DESIGN: In order to standardize footwear conditions and facilitate later
      comparison to patient groups, measurement is made in a group of adults walking
      freely in stock orthopaedic footwear. BACKGROUND: Better data on plantar shear is
      required to complement well-documented pressure data for an overall picture of
      plantar stress. METHODS: Measurements were made locally beneath the medial four
      metatarsal heads and heel using biaxial transducers mounted flush into an inlay.
      Pressure distribution was also measured. RESULTS: The shear data revealed common
      features in the shear pattern occurring at defined phases of gait, with good
      inter-step reliability. For the five sites of interest, these values ranged from
      24 kPa to 70.4 kPa, and 31 kPa to 86.5 kPa for individuals wearing nylon hose or
      hose-free respectively. Maximum shear occurred more laterally than maximum
      pressure. CONCLUSIONS: Features of plantar shear were not always as expected; for
      example the forward thrust at push-off was not reflected in the anteroposterior
      shear stress. Because of the inter-subject variability, study of a larger group
      is indicated. RELEVANCE: Mechanical stress at the plantar interface between foot
      and shoe is of particular clinical relevance to the formation and management of
      ulcers in diabetic neuropathy. It is also of relevance to shoe and orthotic
      design for various foot pathologies. This study provides reliable data on the
      shear component of plantar stress for which, unlike the well-documented pressure
      component, there is only sparse data so far available.

PMID- 10590343
TI  - Lower limb muscle dysfunction may contribute to foot ulceration in diabetic
      patients.
AB  - OBJECTIVES: To investigate the relationship between in-shoe plantar foot pressure
      and the co-ordinated activity of five lower limb muscles of diabetic patients,
      who are known to have a higher risk of foot morbidity. DESIGN: A portable six
      channel electromyographic system has been designed, developed and synchronised in
      real time with a 16 channel piezoelectric transducer in-shoe pressure measuring
      device, Gaitscan. BACKGROUND: So far, no one has tried to establish a
      relationship between in-shoe foot pressure distribution and muscle activity of
      the lower limb in diabetes. The measurement of phasic muscle activity has been
      related to foot pressure and compared to a control group of normal volunteers.
      METHODS: Twenty nine diabetic subjects and 22 healthy non-diabetic volunteers
      have been studied by recording electromyography of lower leg muscles and in-shoe
      foot pressure measurements simultaneously. RESULTS: In diabetic subjects, the
      period of contact pressure was greater than in normal control subjects (P<0.003).
      The initial forefoot time to contact with the ground was shorter in diabetics
      when compared to controls, indicating a faster forefoot contact. Of the
      dorsiflexor muscles, the Anterior Tibialis, normally contracting eccentrically at
      heel strike, was subject to a measurable delay in the initiation of contraction,
      of mean difference of 180 ms (P<0.001), in diabetic subjects when compared to the
      normal controls. CONCLUSIONS: The late firing of Tibialis Anterior means that its
      normal modulating role in lowering the foot to the ground after heel strike
      through eccentric contraction is disturbed. The result is that the foot reaches
      the foot flat stage in a less ordered manner, subjecting it to high plantar
      pressures. RELEVANCE: The results obtained may assist in planning realignment
      procedures of the foot and help prevent development of ulcers on the sole of the
      foot in high risk diabetic subjects.

PMID- 10590345
TI  - Effects of foot orthoses on skeletal motion during running.
AB  - OBJECTIVE: To quantify the effects of medial foot orthoses on skeletal movements
      of the calcaneus and tibia during the stance phase in running. DESIGN: Kinematic
      effects of medial foot orthoses (anterior, posterior, no support) were tested
      using skeletal (and shoe) markers at the calcaneus and tibia. BACKGROUND:
      Previous studies using shoe and skin markers concluded that medially placed
      orthoses control/reduce foot eversion and tibial rotation. However, it is
      currently unknown if such orthoses also affect skeletal motion at the lower
      extremities. METHODS: Intracortical Hofman pins with reflective marker triads
      were inserted under standard local anesthetic into the calcaneus and tibia of
      five healthy male subjects. The three-dimensional tibiocalcaneal rotations were
      determined using a joint coordinate system approach. Eversion (skeletal and shoe)
      and tibial rotation were calculated to study the foot orthoses effects. RESULTS:
      Orthotic effects on eversion and tibial rotations were found to be small and
      unsystematic over all subjects. Differences between the subjects were
      significantly larger (p<0.01; up to 10 degrees ) than between the orthotic
      conditions (1-4 degrees ). Significant orthotic effects across subjects were
      found only for total internal tibial rotation; p<0.05). CONCLUSIONS: This in vivo
      study showed that medially placed foot orthoses did not change tibiocalcaneal
      movement patterns substantially during the stance phase of running. RELEVANCE:
      Orthoses may have only small kinematic effects on the calcaneus and tibia
      (measured with bone pins) as well as on the shoes (measured with shoe markers)
      during running of normal subjects. Present results showed that orthotic effects
      were subject specific and unsystematic across conditions. It is speculated that
      orthotic effects during the stance phase of running may be mechanical as well as
      proprioceptive.

PMID- 10590354
TI  - How to improve the present TNM staging system.

PMID- 10590355
TI  - Patients with superficial transitional cell carcinoma of the bladder and their
      smoking status.

PMID- 10590356
TI  - Molecular markers in renal cell carcinoma: not quite ready for "prime time".

PMID- 10590357
TI  - Mandatory second opinion of pathologic slides: is it necessary?

PMID- 10590358
TI  - Porphyrin-like fluorescence in oral cancer: In vivo fluorescence spectral
      characterization of lesions by use of a near-ultraviolet excited autofluorescence
      diagnosis system and separation of fluorescent extracts by capillary
      electrophoresis.
AB  - BACKGROUND: Red fluorescence from malignant tumors was observed in experimentally
      induced rat sarcoma by Policard (1924) and in ulcerated human oral carcinoma by
      Harris et al. (1987) by examination with ultraviolet (UV) irradiation. The
      objective of the current study was twofold: to examine in vivo the spectral
      characteristics of red fluorescence emitted from oral carcinomas and to separate
      the red fluorescent compounds in these lesions by the capillary electrophoretic
      (CE) method. METHODS: In vivo fluorescence spectral characteristics of oral
      carcinoma were examined by a near-UV excited autofluorescence diagnosis (NEAD)
      system developed by the authors. Fluorescence spectra of the extract from
      carcinomas were measured using a spectrofluorometer. CE was used to separate
      fluorescent compounds from the oral carcinomas. RESULTS: Of the 78 oral
      carcinomas examined using the NEAD system, 66 carcinomas (85%), including 2
      adenoid cystic carcinomas (ACCs) and 14 recurrent squamous cell carcinomas
      (SCCs), showed porphyrin-like fluorescence spectra. The CE study was performed on
      three oral SCCs, two of which contained fluorescent compounds other than
      protoporphyrin IX and zinc protoporphyrin IX, whereas the other SCCs contained
      the compounds with the same migration time as protoporphyrin IX. CONCLUSIONS:
      Seventy-eight oral carcinomas, including ACCs and recurrent SCCs, were examined
      using the NEAD system. When exposed to UV light at a wavelength of 410 nm, 85% of
      the carcinomas showed porphyrin-like fluorescence spectra, whereas the normal
      mucosa in the oral cavity did not. Porphyrin-like fluorescent compounds were
      extracted from oral carcinomas and separated by a CE system equipped with a
      fluorescence detector. The CE data clearly show that compounds vary in each
      individual carcinoma.

PMID- 10590359
TI  - Rationale for bladder-sparing surgery in patients with locally advanced
      colorectal carcinoma.
AB  - BACKGROUND: Total pelvic exenteration (TPE) with urinary diversion is a standard
      surgical approach for patients with locally advanced rectal carcinoma. Because
      only approximately 50% of patients undergoing TPE have tumor involving the
      bladder, the authors evaluated the feasibility of bladder salvage in this
      setting. The current study presents the results of a retrospective study of
      patients with advanced colorectal carcinoma (classification of >/= T3) to
      formulate criteria for selecting patients for bladder-sparing procedures.
      METHODS: The charts of 81 patients with rectal carcinoma classified as >/= T3
      were reviewed for age, gender, computed tomography (CT) findings, results of
      intraoperative examination under anesthesia, final pathologic evaluation,
      urologic complications, local recurrence, and patient survival. RESULTS: Among
      the 46 patients who underwent TPE, final pathologic evaluation demonstrated tumor
      involvement of the bladder in 58% of patients. Preoperative identification of a
      bladder mucosal abnormality accurately predicted bladder involvement in only 57%
      of the 30 patients who underwent cystoscopy. CT and intraoperative palpation of
      the bladder individually predicted the final pathologic findings in 69% and 70%
      of patients, respectively; of the 21 patients in whom both were positive, 90% had
      bladder involvement. Of the 35 patients (26 females and 9 males) who underwent
      bladder-sparing procedures, 22 had complete sparing of the bladder, 9 underwent
      partial cystectomy (5 with ureteroneocystostomy), 4 underwent
      ureteroneocystostomy alone, and 2 underwent prostatectomy alone. Ninety-four
      percent of these 35 patients had negative histologic margins. There was no
      difference in the incidence rate of urinary complications between patients who
      underwent TPE and those who underwent a bladder-sparing surgery (17% each). The
      incidence rates of local recurrence (14% vs. 17%) and the 3-year survival rates
      (49% vs. 39%) did not differ significantly between the 2 groups. CONCLUSIONS:
      Bladder-sparing surgery to treat patients with locally invasive colorectal
      carcinoma provides good local control without sacrificing survival. Women, whose
      reproductive organs act as a natural barrier, and selected men in whom CT and
      intraoperative evaluation identify only localized involvement of the prostate or
      bladder appear to be reasonable candidates for bladder-sparing procedures.

PMID- 10590360
TI  - Humoral hypercalcemia in patients with colorectal carcinoma: report of two cases
      and review of the literature.
AB  - BACKGROUND: Humoral hypercalcemia rarely is associated with colorectal carcinoma;
      to the authors' knowledge only nine cases have been reported to date. METHODS:
      Two cases of advanced colorectal carcinoma with humoral hypercalcemia of
      malignancy (HHM) are presented. RESULTS: The two patients had severe
      hypercalcemia without bone metastases. The diagnosis of HHM was based on findings
      of hypercalcemia, hypophosphoremia, elevated serum parathyroid hormone-related
      peptide (PTHrP), and positive tumor immunoreactivity to monoclonal PTHrP
      antiserum. One patient had a colonic adenocarcinoma with a neuroendocrine
      component and the other patient had rectal adenocarcinoma. Immunoreactive PTHrP
      was found in both tumor components. Bisphosphonate treatment normalized the
      hypercalcemia within a few days but it recurred in the patients 2 weeks and 3
      weeks later, respectively. The prognosis was extremely poor. CONCLUSIONS: To the
      authors' knowledge the two cases presented in the current study are the first to
      be reported with HHM-associated colorectal carcinoma with positive tumor
      immunoreactivity to PTHrP monoclonal antiserum.

PMID- 10590361
TI  - The prognostic importance of volume-weighted mean nuclear volume, mitotic index,
      and other stereologically measured quantitative parameters in supraglottic
      laryngeal carcinoma.
AB  - BACKGROUND: Stereologically measured mean nuclear volume has been proven to have
      prognostic importance in several types of cancer, such as malignant melanoma and
      carcinomas of the breast, oral region, bladder, and uterine cervix. The main
      purpose of the current study was to investigate the possible prognostic
      importance of mean nuclear volume and mitotic index in carcinoma of the
      supraglottic larynx. METHODS: The study was performed with a stratified, random
      sample of 113 patients from a well-defined group of 386 patients with
      supraglottic laryngeal carcinoma treated with radiotherapy at the Finsen
      Institute in Copenhagen. Histologic sections from pretreatment biopsies were used
      to estimate the following parameters: mean nuclear volume (Vv(3)(0)), mitotic
      index (MI), number of nuclei per mm(2) (QA), mean nuclear profile area (Anuc),
      and the area fraction of nuclei in cancer tissue (AA). The geometric means of the
      parameters were used as cutoff points in a single factor and in a multivariate
      survival analysis with relapse free survival as the primary endpoint. RESULTS:
      The geometric means of the measured parameters were (Vv(3)(0)) = 480 micro(3), QA
      = 3630 nuclei/micro(2) cancer tissue, MI = 0.48 mitosis/100 nuclei, AA = 0.21,
      and Anuc = 57.9 micro(2). CONCLUSIONS: None of the stereologically estimated
      parameters proved to have prognostic importance, whereas tumor size, and lymph
      node status did. The method of adaptive, stratified, random sampling used in this
      study can save a great deal of work and is highly recommended by the authors.

PMID- 10590362
TI  - Determinants of long term survival after surgery for cancer of the lung: A
      population-based study.
AB  - BACKGROUND: Even if some determinants of lung cancer (LC) prognosis have been
      established, their independent effect on long term survival remains to be seen.
      The objective of the current study was to identify the prognostic indicators of
      long term survival among LC patients treated by surgery. METHODS: All patients
      with LC recorded at the Geneva Cancer Registry between 1977 and 1987 were
      analyzed by logistic regression, considering as cases (n = 98) those patients
      alive 10 years after their initial diagnosis and as controls (n = 330) all other
      patients, excluding those who did not undergo putative curative surgery. The
      effect of each prognostic factor was evaluated after accounting for age and
      gender ("crude" effect) and also for other a priori confounding factors (adjusted
      effect). Additional models considered two staging variables simultaneously to
      identify the strongest staging determinant. Results were presented as relative
      risk estimates of long term (>/=10 years) survival. RESULTS: Age, histology, and
      stage of disease significantly influenced prognosis regardless of the confounding
      factors considered. Gender also emerged as a discriminated factor in LC outcome,
      with a 2.1-fold increased chance (95% confidence interval, 1.6-3.5) of long term
      survival for women compared with men. Method of discovery, presence of symptoms,
      period of diagnosis, socioeconomic status, and tumor differentiation did not
      appear to be associated with long term survival. Extent and size of the tumor
      were found to be the most reliable prognostic staging factors, whereas adenopathy
      had no effect after accounting for extension. CONCLUSIONS: The current population
      based study quantifies the independent effect of the factors modifying the
      chances of curability in patients with LC. In particular, it provides additional
      evidence that gender strongly influences long term survival.

PMID- 10590363
TI  - The addition of cisplatin to cyclophosphamide-doxorubicin-etoposide combination
      chemotherapy in the treatment of patients with small cell lung carcinoma: A
      randomized study of 457 patients. "Petites Cellules" Group.
AB  - BACKGROUND: To assess whether the addition of cisplatin (100 mg/m(2) administered
      intravenously on Day 1) to CDE (cyclophosphamide [1000 mg/m(2) on Day 1],
      doxorubicin [45 mg/m(2) on Day 1], and etoposide [150 mg/m(2) on Days 1 and 2]
      combination is useful in the treatment of patients with small cell lung carcinoma
      (SCLC). METHODS: In a multicenter clinical trial, 457 patients were randomized
      from May 1988 to March 1993 to receive either CDE (n = 228) or cisplatin-CDE
      (PCDE, n = 229) chemotherapy every 4 weeks for 6 cycles. As patients with limited
      SCLC were included in a concomitant trial assessing thoracic radiotherapy, the
      current study mainly included patients with extensive stage (79%) or limited
      stage disease and a contraindication for thoracic radiotherapy. RESULTS: The
      objective response rate was higher in the cisplatin-CDE group (72%) than in the
      CDE group (53%) (P = 0.0001). The median overall survival was similar for the
      groups that received CDE (266 days) and PCDE (271 days) (P = 0.93, log rank
      test). A higher fatal neutropenia rate was observed in the PCDE group (n = 23)
      than in the CDE group (n = 4) (P < 0.001, log rank test), mainly for patients
      with extensive disease (n = 26; P = 0.015, log rank test). CONCLUSIONS: The
      addition of cisplatin to a CDE regimen is toxic to patients with extensive SCLC
      and does not improve overall survival. The PCDE combination must be avoided for
      patients with extensive SCLC; CDE or cisplatin-etoposide combinations remain
      standard chemotherapy for these patients. The PCDE combination associated with
      granulocyte-colony stimulating factors could only be assessed in patients with
      good prognoses.

PMID- 10590364
TI  - A phase I-II trial of escalating doses of mitoxantrone with fixed doses of
      cytarabine plus fludarabine as salvage therapy for patients with acute leukemia
      and the blastic phase of chronic myelogenous leukemia.
AB  - BACKGROUND: Cytarabine is an essential drug for inducing remission of acute
      myelogenous leukemia, and it is also one the most effective drugs used as salvage
      therapy for patients with all types of relapsed acute leukemia. Nevertheless,
      there is considerable room for improvement in the treatment of patients with
      relapsed leukemia in terms of both the reinduction rate and the duration of
      response. Fludarabine has been shown to augment responses to cytarabine, possibly
      by increasing the intracellular concentrations of the active metabolite
      cytarabine triphosphate. Higher-than-standard doses of mitoxantrone have been
      shown to augment responses to cytarabine, possibly by increasing the DNA strand
      breaks induced by topoisomerase II; these strand breaks cannot be effectively
      repaired in the presence of cytarabine triphosphate. This preliminary study was
      designed to determine whether moderately high doses of mitoxantrone could be
      added to the combination of fludarabine and cytarabine in an attempt to improve
      the combination's antileukemic efficacy. METHODS: Fifty-five adults with relapsed
      or refractory acute leukemia or the blastic phase of chronic myelogenous leukemia
      (CML) received salvage therapy with the FLAM regimen, which consisted of
      fludarabine, cytarabine, and increasing doses of mitoxantrone. RESULTS: Even with
      doses of mitoxantrone escalated to as much as 60 mg/m(2) over 4 days, dose
      limiting toxicity was not observed. Overall, the complete response rate was 27.3%
      (15 of 55 patients, including 4 of 17 with acute myelogenous leukemia [AML], 4 of
      12 with acute lymphocytic leukemia [ALL], and 7 of 26 with the blastic phase of
      CML). The median time to complete response was 42 days. Toxicity other than
      myelosuppression was manifested primarily as hyperbilirubinemia, which was
      reversible in all cases. Poor performance status and undifferentiated blastic
      phase of CML were poor prognostic factors for response to FLAM. CONCLUSIONS: The
      FLAM regimen is an active salvage regimen and should be formally evaluated in
      Phase II studies of patients with AML, ALL, and the myeloid and lymphoid blastic
      phases of CML.

PMID- 10590365
TI  - Follow-up recommendations for patients with American Joint Committee on Cancer
      Stages I-III malignant melanoma.
AB  - BACKGROUND: Guidelines for follow-up of melanoma patients are not established. In
      1987, a follow-up protocol was instituted at the Yale Melanoma Unit to improve
      upon the detection of disease recurrence in patients with American Joint
      Committee on Cancer Stage I-III cutaneous melanoma. The follow-up protocol
      consists of a patient education program and a surveillance schedule based on
      stage of disease. METHODS: The authors retrospectively reviewed the records of
      373 patients who were seen and followed according to the surveillance protocol in
      the Yale Melanoma Unit between January 1988 and December 1994 to determine 1) the
      time interval between the initial visit and recurrence; 2) the most common method
      of detecting recurrences; 3) whether the surveillance schedule or the patient
      detects more recurrences, i.e., asymptomatic recurrences versus symptomatic
      recurrences; 4) whether there is any survival difference between asymptomatic and
      symptomatic recurrences. RESULTS: The 5-year overall survival rates for Stage I,
      II, and III patients were 95%, 72%, and 52%, respectively. Of the 78 recurrences,
      44 (56%) were detected by physician-directed surveillance examinations and 34
      (44%) by patients. Most recurrences were found within the first (47%) or second
      (32%) year of follow-up. The estimated 6-month hazard rates for death or
      recurrence were 0.0044, 0.0088, and 0.0278 for Stage I, II, and III patients,
      respectively. The group of asymptomatic patients with recurrence had a survival
      advantage over the symptomatic recurrence group. In addition, patients with
      locoregional recurrence had better survival than those with distant recurrence.
      CONCLUSIONS: Although many recurrences arise rapidly and are recognized early by
      patients, in this study more than half were found by surveillance examinations
      before symptoms were manifest. Based on the hazard ratio for recurrences, the
      authors recommend the following surveillance schedules in addition to the patient
      education program for detection of recurrences: 1) Stage I, annually; 2) Stage
      II, every 6 months for Years 1-2 and annually thereafter; 3) Stage III, every 3
      months for Year 1, every 4 months for Year 2, and every 6 months for Years 3-5;
      4) at Year 6 and beyond, all patients should have surveillance annually, due to
      the risk of late recurrence and/or metachronous multiple primaries.

PMID- 10590366
TI  - Met expression is associated with poor outcome in patients with axillary lymph
      node negative breast carcinoma.
AB  - BACKGROUND: Activation of Met, the receptor for scatter factor/hepatocyte growth
      factor, is associated with mitogenesis, motogenesis, and decreased cell adhesion.
      Elevated expression of Met has been shown in advanced cases of carcinoma of the
      prostate, stomach, pancreas, and thyroid. The authors previously demonstrated
      that Met expression is an independent prognostic marker associated with decreased
      survival in patients with breast carcinoma. METHODS: Expression of Met in 113
      archival breast carcinoma specimens from patients with axillary lymph node
      negative invasive ductal carcinoma was evaluated using a standard
      immunoperoxidase technique. Cases were scored by two pathologists using an H
      score algorithm and then analyzed for correlation with known prognostic factors
      and survival. RESULTS: Expression of Met showed a bimodal distribution with 25%
      of cases showing high levels of expression. In contrast to previous studies, the
      results of the current study showed a significant association between Met
      expression and nuclear and histologic grade. The 5-year survival rate for Met
      negative patients with tumors with low Met expression was 95% in this cohort,
      compared with 80% for patients with tumors showing high Met expression. Patients
      whose tumors had a high level of Met expression were found to have a 5-year
      relative risk (RR) of dying of metastatic disease of 5.05 (P = 0.03) independent
      of patient age and tumor size. Combined analysis of Met and nuclear grade
      resulted in a marked increase in independent predictive value (RR = 33.4; P <
      0.01). CONCLUSIONS: The results of the current study found that high levels of
      Met expression were associated with death due to metastatic disease in patients
      with axillary lymph node negative breast carcinoma. Expression of Met may be a
      useful prognostic indicator of more aggressive disease in patients whose
      prognosis is not easily stratified by current histopathologic markers.

PMID- 10590367
TI  - Chemotherapy for breast carcinoma during pregnancy: A French national survey.
AB  - BACKGROUND: During pregnancy, the need for maternal chemotherapy for breast
      carcinoma must be balanced against the fetal risk because modification of cancer
      therapy to assure the birth of a healthy infant may affect maternal prognosis
      adversely. To the authors' knowledge few studies have documented the oncologic
      and obstetric management of this association. METHODS: A retrospective nationwide
      survey was used to identify women treated with chemotherapy for breast carcinoma
      during pregnancy. Each member of the Societe Francaise d'Oncologie Gynecologique
      and the Societe Francaise de Senologie et de Pathologie Mammaire completed a
      postal questionnaire regarding cancer staging, oncologic treatment, obstetric
      details, pregnancy outcome, fetal behavior, and postdelivery follow-up. Twenty
      women were accrued to the study. RESULTS: The mean gestational age at the first
      cycle of treatment was 26 weeks. A total of 38 cycles were administered during
      pregnancy, with a median of 2 cycles. Delivery was performed at a mean of 34.7
      weeks. Two pregnancies that were exposed to chemotherapy during the first
      trimester resulted in spontaneous abortion. One pregnancy exposed in the second
      trimester resulted in intrauterine death. The remaining 17 pregnancies resulted
      in live births, although 3 women had complications related to chemotherapy
      (anemia, leukopenia, and fetal growth retardation) and 1 newborn died 8 days
      after birth without apparent etiology. Two newborns had complications related to
      prematurity (transient respiratory distress). At a mean follow-up of 42.3 months,
      all live infants were reported to have reached normal developmental milestones.
      CONCLUSIONS: The current study found that even when chemotherapy was initiated
      after the first trimester, 95% of the pregnancies resulted in live births with
      low related morbidity in the newborns.

PMID- 10590368
TI  - Is radical trachelectomy a safe alternative to radical hysterectomy for patients
      with stage IA-B carcinoma of the cervix?
AB  - BACKGROUND: The prognosis associated with lymph node negative, early stage
      carcinoma of the cervix is excellent, with 5-year survival rates greater than
      90%. Radical trachelectomy in combination with pelvic lymph node dissection (RVT
      + LPL) has emerged as an alternative to radical hysterectomy (RH) for these
      patients who desire preservation of fertility. However, there are limited data to
      support its efficacy and safety. METHODS: All patient information was collected
      prospectively and was subsequently extracted from the cervical cancer surgery
      database of the Division of Gynecologic Oncology at the University of Toronto.
      Patients treated by RVT + LPL for fertility preservation were compared with two
      groups of patients treated by RH. One control group was matched for age, tumor
      size, histology, depth of invasion, presence of capillary lymphatic space
      involvement, lymph node metastases, and use of adjuvant radiation. The other
      control group consisted of patients with tumor sizes </=2 cm, negative pelvic
      lymph nodes who had not received adjuvant radiation therapy. RESULTS: Thirty of
      32 patients treated by RVT + LPL between March 1994 and November 1998 were
      matched. The only statistically significant difference in prognostic factors
      between the patients who underwent RVT + LPL and unmatched controls (556
      patients) was the median depth of invasion in the adenocarcinomas (2. 0 mm vs.
      4.0 mm, respectively; P < 0.02). The 2-year actuarial recurrence free survival
      was 95%, 100%, and 97% for the patients who underwent RVT + LPL, matched
      controls, and unmatched controls, respectively. The actuarial conception rate at
      12 months was 37%. CONCLUSIONS: Acknowledging the small numbers and short follow
      up, RVT + LPL appears to be similar in efficacy to RH. If longer follow-up with
      more patients confirms the above, this procedure will represent an acceptable
      alternative to RH for patients with early Stage I carcinoma of the cervix who
      desire preservation of fertility.

PMID- 10590369
TI  - The Ovarian Tumor Index predicts risk for malignancy.
AB  - BACKGROUND: Prediction of ovarian malignancy by ultrasonographic findings and
      patient age in the scenario of clinically suspected adnexal masses is a desirable
      goal. METHODS: Prospective evaluation of clinically suspected adnexal masses was
      performed with transvaginal ultrasound using real-time, Doppler velocimetry, and
      color-flow mapping. Continuous ultrasound variables included ovarian volume, the
      Sassone morphology scale, and Doppler determination of angle-corrected systole,
      diastole, and time-averaged velocity, in addition to patient age. The Doppler
      pulsatility index (PI), vessel location, presence of a diastolic notch, and
      echogenic predominance of the lesion, suggestive of dermoid, also were assessed.
      RESULTS: Of 244 women with follow-up, 214 had nonmalignant findings (85 of which
      were benign neoplasms), and 30 had malignant neoplasms. Age and all ultrasound
      continuous variables except systole were found to be statistically significant (P
      < 0.05) between patients with both malignant (N = 30) and nonmalignant masses (N
      = 214), as well as those with benign (N = 85) and malignant (N = 30) neoplasms.
      By adding the continuous measures (age [in years], ovarian volume [mL], and
      Sassone morphology scale [1-15]) and weighting other variables ([-10] x PI,
      central or septal location [+10], peripheral location [-10], and echogenic [
      10]), a receiver operating characteristic curve was generated (area under the
      curve = 0.91), which was found to be discriminating, predictive, and able to
      replicate the more complex logistic regression model. Prediction of malignancy
      was generated from the population-based data of the current study. CONCLUSIONS:
      The Ovarian Tumor Index, which combines patient age with specific
      ultrasonographic markers, is an accurate method for predicting ovarian malignancy
      in the clinical scenario of suspected adnexal masses.

PMID- 10590370
TI  - A phase I trial of intravenous melphalan, paclitaxel, and cisplatin plus
      granulocyte-colony stimulating factor in patients with suboptimal advanced
      epithelial ovarian carcinoma or peritoneal carcinoma.
AB  - BACKGROUND: The primary purpose of this study was to establish the maximum
      tolerated dose (MTD) of intravenous melphalan in combination with paclitaxel and
      cisplatin plus granulocyte-colony stimulating factor (G-CSF) in patients with
      suboptimal advanced epithelial ovarian carcinoma or primary peritoneal carcinoma.
      METHODS: Patients with suboptimal (>2 cm residual tumor) Stage III or Stage IV
      epithelial ovarian carcinoma or peritoneal carcinoma were eligible for this Phase
      I study. In the first stage of the study, the doses of paclitaxel and cisplatin
      were fixed at 135 mg/m(2) and 75 mg/ m(2), respectively, and the dose of
      intravenous melphalan was escalated in consecutive cohorts of 3-6 patients
      depending on toxicity. The planned dose escalation levels of melphalan were 6
      mg/m(2), 10 mg/m(2), and 14 mg/m(2). In the second stage of the study, the doses
      of cisplatin and melphalan were fixed at 75 mg/m(2) and the MTD level,
      respectively, and the dose of paclitaxel was escalated. The planned dose
      escalation levels of paclitaxel were 150 mg/m(2), 175 mg/m(2), 200 mg/m(2), 225
      mg/m(2), and 250 mg/m(2). G-CSF was administered for 12-19 days with each cycle,
      and cycles were repeated every 4 weeks for a total of 6 cycles. Other end points
      included clinical or surgical response, progression free survival, and survival.
      RESULTS: Between January 1993 and May 1996, 34 women with untreated advanced
      stage epithelial ovarian carcinoma or primary peritoneal carcinoma were treated
      with 192 cycles of therapy. The MTD of melphalan was 10 mg/m(2), with the dose
      limiting toxicity being thrombocytopenia. Paclitaxel was escalated to a dose
      level of 200 mg/m(2) with a toxicity rate of < 33%. The clinical response rate
      was 80% in 29 patients with measurable disease. Of 11 patients who underwent
      second-look surgery, 5 (45%) had a surgical pathologic complete response. The
      median progression free survival was 16.8 months and the median survival was 32.8
      months. CONCLUSIONS: The combination of intravenous melphalan, paclitaxel, and
      cisplatin was found to have acceptable toxicity and good activity. A Phase II
      study of this combination appears to be warranted.

PMID- 10590371
TI  - Brain metastasis from prostate carcinoma: antemortem recognition and outcome
      after treatment.
AB  - BACKGROUND: In patients with prostate carcinoma, brain metastasis has most
      commonly been reported in autopsy series. Symptomatic brain metastasis from
      prostate carcinoma has occasionally been detected. METHODS: The authors
      retrospectively studied a series of 38 patients with antemortem intracerebral
      metastasis found on review of 7994 patients treated over an 18-year period at the
      University of Texas M. D. Anderson Cancer Center. RESULTS: The mean time from
      diagnosis of prostate carcinoma to discovery of brain metastasis was 28 months,
      with a mean survival of 9.2 months after the discovery of the brain metastasis.
      The brain metastasis was treated only with whole brain irradiation in 29
      patients, with craniotomy and irradiation in 8 patients, and with surgery alone
      in 1 patient. Small cell carcinomas and primary transitional cell carcinomas of
      the prostate were much more likely to produce brain metastasis than were
      adenocarcinomas. Also noted among the overall prostate carcinoma cohort was a
      second group of 16 patients with prostate carcinoma and brain metastasis that had
      developed from a second primary tumor, which in all was either lung carcinoma or
      melanoma. CONCLUSIONS: The occurrence of brain metastasis in prostate carcinoma
      patients is rare, usually signifies a late stage of the disease, and may in some
      patients be produced by a tandem extraprostatic tumor.

PMID- 10590372
TI  - Evidence that Leydig cells in Sertoli-Leydig cell tumors have a reactive rather
      than a neoplastic profile.
AB  - BACKGROUND: Leydig cells are a variable and an inconstant feature of Sertoli
      Leydig cell tumors (SLCT). Controversy exists regarding their neoplastic versus
      reactive nature, and their molecular biologic profile is unknown. METHODS: Six
      SLCT and one pure Leydig cell tumor were studied. Mitotic counts and
      immunohistochemistry for Ki-67 were performed in all cases. Leydig cells,
      neoplastic tissues, and normal nonneoplastic tissues were microdissected. DNA
      extracts of these samples were assessed for loss of heterozygosity (LOH) by
      polymerase chain reaction amplification with ten polymorphic DNA markers that
      have shown high rates of LOH in a variety of human tumors. Three SLCT and the
      Leydig cell tumor were assessed for clonality by examining the DNA methylation
      pattern at a polymorphic site on the androgen receptor gene. RESULTS: Leydig
      cells in SLCT had a low mitotic count (0-1/50 high-power fields [HPF]) compared
      with the neoplastic stroma (median, 40/50 HPF). Ki-67 was positive in < 2% of
      Leydig cells in all SLCT, compared with a median of 7% in the neoplastic stroma.
      Clonality analysis confirmed the monoclonality of the neoplastic cells in the
      Leydig cell tumor. However, the Leydig cells from three SLCT were polyclonal,
      whereas the monoclonal nature of the neoplastic Sertoli tubules was confirmed in
      one of these cases and that of mucinous heterologous elements in another case.
      The Leydig cell tumor showed LOH at four of the eight loci evaluated. Leydig
      cells from five SLCT were evaluated: one showed LOH at one locus, two showed LOH
      at two loci, and the remaining two showed no LOH. CONCLUSIONS: The demonstration
      that Leydig cells from SLCT are polyclonal strongly suggests that they are
      nonneoplastic in nature. This is supported by a low proliferation fraction and a
      lower fraction of LOH compared with the truly neoplastic Leydig cells.

PMID- 10590373
TI  - Correlation of CD44S expression in renal clear cell carcinomas with subsequent
      tumor progression or recurrence.
AB  - BACKGROUND: Recent reports have shown altered expression of CD44 in renal cell
      carcinomas. However, to the authors' knowledge there are no data correlating CD44
      expression in renal cell carcinomas with subsequent tumor progression or
      recurrence, nor is there information about the presence of particular splice
      variants of CD44 in these tumors. METHODS: The authors examined the
      immunohistochemical expression of CD44S, the standard isoform of CD44, in renal
      cell carcinomas from 43 patients using 2 different monoclonal antibodies, Mab2137
      and Hermes-3. In addition, they stained the renal cell carcinomas with antibodies
      to 2 splice variants of CD44, CD44v3 and CD44v6. RESULTS: Increased staining of
      renal clear cell carcinomas with Mab2137 was observed in high grade versus low
      grade tumors (45% vs. 0%, P = 0.013), whereas increased staining of clear cell
      carcinomas with Hermes-3 was noted in high stage versus low stage tumors (40% vs.
      0%, P = 0.006). Few tumors stained with antibodies to CD44v3. Although increased
      expression of the splice variant CD44v6 was noted in papillary versus clear cell
      carcinomas, and increased staining of papillary carcinomas with Mab2137 and with
      antibodies to CD44v6 was noted for low stage versus high stage tumors, these
      differences did not achieve statistical significance. Clinical follow-up of at
      least 43 months was available for 26 patients. Six of these patients (five with
      clear cell carcinoma and one with papillary carcinoma) developed progressive or
      recurrent disease. The primary tumors from all 5 patients with progressive or
      recurrent clear cell carcinoma showed staining with Mab2137, whereas the primary
      tumors from only 2 of the 15 patients with at least 43 months follow-up and no
      evidence of progressive or recurrent clear cell carcinoma (13%) showed staining
      with Mab2137 (P = 0.001). Alternatively, 5 of 7 clear cell carcinomas (71%) that
      stained with Mab2137 were from patients who subsequently developed recurrence or
      progression, compared with 0 of 13 clear cell carcinomas that did not stain.
      Similar findings were not observed for papillary carcinomas, which appeared to be
      biologically distinct from clear cell carcinomas. CONCLUSIONS: CD44S staining
      with Mab2137 correlates with progression or recurrence of clear cell renal cell
      carcinoma. CD44S may, therefore, play a pathogenetic role in tumor progression.

PMID- 10590374
TI  - Coexpression of cytokeratins 7 and 20 confirms urothelial carcinoma presenting as
      an intrarenal tumor.
AB  - BACKGROUND: The differentiation of epithelial tumors arising in the kidney
      (urothelial vs. renal cell carcinoma) sometimes can be difficult by clinical and
      radiologic studies. Because urothelial and renal epithelium express unique
      cytokeratin (CK) 7 and 20 profiles, the authors studied the utility of these
      markers to confirm the diagnosis of urothelial carcinomas that present clinically
      as kidney masses. METHODS: Using commercially available monoclonal antibodies,
      paraffin section immunohistochemistry was used to examine two recent cases of
      urothelial carcinomas presenting as renal tumors. Tissues were stained for CK7
      and CK20 and the expression compared between the tumor and benign tissue.
      RESULTS: Both cases showed solid renal masses that clinically and
      radiographically could have been of renal cell origin, but subsequently were
      confirmed histologically to be extensive renal involvement by urothelial
      carcinoma. The tumors coexpressed both CK7 and CK20, which is the expected
      profile for carcinomas of urothelial but not renal origin. CONCLUSIONS: The
      results of the current study show that coexpression of CK7 and CK20 is a useful
      diagnostic aid in the differential diagnosis of epithelial kidney tumors of
      urothelial cell versus renal cell origin.

PMID- 10590375
TI  - Incidence rate of satellite tumors in renal cell carcinoma.
AB  - BACKGROUND: Nephron-sparing surgery for incidentally detected small renal tumors
      has been performed. The main objection to such surgery concerns the incidence
      rate of satellite renal tumors. In this study, the authors analyzed the rate of
      incidence and proliferative potential of satellite renal tumors. METHODS: The
      tumors of 124 renal cell carcinoma patients with a clinically identified
      unilateral and single tumor measuring </=90 mm who were examined between November
      1991 and May 1997 were analyzed prospectively. The authors determined whether
      these specimens obtained by radical nephrectomy had satellite tumors, and whether
      the satellite tumors were reactive with a monoclonal antibody (MoAb), MIB-1, to
      assess their proliferative potential. RESULTS: Satellite renal cell carcinomas
      were detected in 8 of the 124 patients (6.5%). None of the pathologic variables
      examined (tumor grade, tumor stage, main tumor size, cell pattern, and vascular
      invasion) were found to be predictive of the presence of satellite tumors. Of
      these eight tumors, two main tumor specimens and three satellite tumor specimens
      reacted with the MIB-1 MoAb. The reactivity of MIB-1 correlated with the tumor
      grade. The satellite tumors were observed to have a proliferative potential
      compared with the main tumors. Among 86 kidney specimens from patients with
      urothelial tumors after total nephroureterectomy, 2 (2.3%) contained small renal
      cell carcinoma but did not show positive staining with the MoAb MIB-1.
      CONCLUSIONS: The incidence rate of satellite tumors among 124 renal cell
      carcinoma patients was 6.5% and the presence of satellite tumors was not
      predictable. Some of these satellite tumors showed positive staining with the MIB
      1 MoAb, but small renal tumors detected in kidney specimens with urothelial
      tumors did not.

PMID- 10590376
TI  - Influence of smoking status on the disease-related outcomes of patients with
      tobacco-associated superficial transitional cell carcinoma of the bladder.
AB  - BACKGROUND: The aim of this study was to assess the influence of tobacco
      exposure, at the time of diagnosis, on the disease-related outcomes of patients
      with tobacco-associated superficial transitional cell carcinoma (TCC) of the
      bladder. METHODS: A retrospective cohort study was performed using the MSKCC
      Registry to identify all institutional cases of "noninvasive" TCC (n = 1632)
      between 1985 and 1995. After employing exclusion criteria, 286 cases of incident
      tobacco-associated superficial TCC were divided into 3 strata of tobacco exposure
      (127 ex-smokers, 51 quitters, and 108 continued smokers) by chart review and post
      hoc questionnaires (n = 82). Measured outcomes included recurrence free survival
      and survival free of adverse events (defined a priori as disease progression or
      other urinary tract TCC). RESULTS: There were no significant differences among ex
      smokers, quitters, and continued smokers in terms of stage, grade, tumor size,
      multifocality, up-front bacillus Calmette-Guerin therapy, or median follow-up. Ex
      smokers presented at a later age than individuals who continued to smoke. Post
      hoc questionnaires and chart reviews were compared in terms of smoking status at
      time of diagnosis, and reliability was excellent (kappa = 0.89). Multivariate
      analyses revealed diminished recurrence free survival among continued smokers
      versus quitters or ex-smokers. Univariate analyses revealed diminished adverse
      event free survival among continued smokers versus quitters or ex-smokers.
      Multivariate models assessing adverse event free survival revealed a similar
      trend (P = 0.06). CONCLUSIONS: Continued smokers experience worse disease
      associated outcomes than patients who quit smoking. Smoking cessation should thus
      be employed as a tertiary prevention strategy for patients with superficial TCC.

PMID- 10590377
TI  - Small cell carcinoma of the bladder: long term outcome with integrated
      chemoradiation.
AB  - BACKGROUND: Small cell carcinoma of the bladder (SCCB) is an uncommon tumor with
      approximately 8% 5-year survival reported in the literature for patients with
      disease confined to the pelvis. It exhibits biologic behavior similar to that of
      small cell carcinoma of the lung (SCLC). The authors sought to determine whether
      etoposide and cisplatin chemotherapy integrated with local irradiation is
      associated with improved survival in SCCB, as has been shown in SCLC. METHODS:
      The authors performed a retrospective analysis of stage, treatment, disease free
      survival (DFS), and overall survival (OS) among 14 British Columbia Cancer Agency
      (BCCA) patients treated between 1985 and 1996 for SCCB. RESULTS: When multiagent
      chemotherapy was combined with local irradiation, the authors observed a 70% 2
      year and 44% 5-year actuarial OS among 10 patients without contraindications to
      systemic chemotherapy. Actuarial DFS was 70% at 2 and 5 years. The mean survival
      was 47 months (95% confidence interval, 18.5-76.1 months) and the median survival
      was 41 months. Nine of these patients had disease confined to the pelvis, and one
      had metastases to retroperitoneal lymph nodes. Five patients were alive and
      disease free an average of 82 months following diagnosis. Two patients had died
      of other causes without evidence of disease at 34 and 48 months following
      diagnosis. The incidence of second primary transitional cell bladder neoplasms
      following successful treatment was 60% at 2 years (3 of 5 long term survivors).
      CONCLUSIONS: Integrated chemoradiation for patients with limited stage SCCB
      generates a realistic expectation of long term survival. Prospective trials to
      confirm these findings are warranted.

PMID- 10590378
TI  - The levels of expression of galectin-1, galectin-3, and the Thomsen-Friedenreich
      antigen and their binding sites decrease as clinical aggressiveness increases in
      head and neck cancers.
AB  - BACKGROUND: The aim of this study was to investigate whether an increase in
      malignancy level is accompanied by significant modifications of the expression of
      galectin-1, galectin-3, and Thomsen-Friedenreich antigen (T antigen) as well as
      the expression of binding sites for these three markers in head and neck squamous
      cell carcinomas (HNSCCs). METHODS: Immunohistochemical and glycohistochemical
      staining reactions were carried out with antibodies, labeled lectins, and a
      custom-made neoglycoprotein on the basis of histologic slides from a
      retrospective series of 40 normal and 75 HNSCC formalin fixed, paraffin embedded
      tissues, and were quantitatively described with the aid of computer-assisted
      microscopy. RESULTS: Whatever the histologic type, the epithelial tissues in
      HNSCC exhibited very significantly (P < 0.01 to P < 0. 0001) lower amounts of
      galectin-1, galectin-3, and T antigen and their respective binding sites than
      their corresponding normal counterparts. The tumors of the larynx differed very
      significantly (P < 0.0001 to P < 0.000001) from all the other tumor types. A loss
      of differentiation in the HNSCCs is accompanied first by the loss of expression
      of galectin-3 and galectin-3-reactive sites and then by that of the T antigen and
      its binding site(s). The opposite feature was observed when the parameters
      associated with the TNM classification were taken into account. The negative
      lymph node HNSCCs could be distinguished (P = 0.02) from the positive lymph node
      HNSCCs on the basis of a loss of galectin-3 expression. The modifications
      occurring in the extent of expression of galectin-1 and galectin-1-reactive sites
      were relatively marginal in comparison with those observed for galectin-3
      dependent and T- antigen-dependent staining. CONCLUSIONS: The decrease in the
      extent of expression of galectin-3 and galectin-3-reactive sites, T antigen and T
      antigen-binding sites, and, to a lesser extent, galectin-1 and galectin-1
      reactive sites correlates significantly with an increasing level of clinically
      detectable HNSCC aggressiveness.

PMID- 10590379
TI  - Paclitaxel, cisplatin, and 5-fluorouracil for patients with advanced or recurrent
      squamous cell carcinoma of the head and neck.
AB  - BACKGROUND: The combination of cisplatin and 5-fluorouracil (5-FU) is considered
      standard therapy for patients with recurrent or metastatic squamous cell
      carcinoma of the head and neck (SCCHN). Paclitaxel has exhibited single-agent
      activity in patients with this disease. The authors conducted this study to
      evaluate the feasibility and efficacy of combining paclitaxel with cisplatin and
      5-FU for patients with advanced or recurrent SCCHN. METHODS: Patients with
      recurrent, metastatic, or locally advanced SCCHN who had measurable or evaluable
      disease and no prior chemotherapy were eligible. The starting dose level
      consisted of paclitaxel 135 mg/m(2) on Day 1, cisplatin 75 mg/m(2) on Day 2, and
      5-FU 1 gm/m(2)/day on Days 2-6. Due to Grade 4 mucositis, dose level 1 of 5-FU
      was reduced to 800 mg/m(2)/day on Days 2-6 (for 7 patients), and subsequently the
      5-FU dose was adjusted to 1 gm/m(2)/day on Days 2-5 (for 17 patients). RESULTS:
      Twenty-five patients were enrolled, with a median age of 60 years and a median
      Southwest Oncology Group performance status of 1. Of the 25 patients, 16 had
      recurrent disease, 3 had metastatic disease at diagnosis, and 6 had untreated
      locally advanced SCCHN. Ninety-nine courses of therapy were administered, with a
      median of 5 courses. Major toxicities were neutropenia and mucositis. Significant
      neurotoxicity or nephrotoxicity were not observed. There were two treatment
      related deaths (one each due to mucositis and neutropenic pneumonia), and these
      precluded further dose escalation. Fifteen of the 25 patients (60%) achieved a
      major response. Of significance is the response rate of 58% (11 of 19 patients)
      in those with recurrent or metastatic disease who had a duration of response
      ranging from 3 to 19+ months. Two of these 19 patients continue to be in
      remission of 19+ and 15+ months' duration, respectively. The median survival for
      patients with recurrent or metastatic disease was 6 months (range, 1-26 months),
      with a 1-year survival rate of 37%. CONCLUSIONS: The dose and schedule for the
      combination of paclitaxel, 5-FU, and cisplatin as determined in this study are
      feasible, with encouraging outcomes and activity in patients with recurrent or
      metastatic SCCHN. The results of this trial warrant larger-scale evaluation to
      determine the role of this combination in the management of patients with this
      disease.

PMID- 10590380
TI  - 18F-fluorodeoxyglucose dual-head positron emission tomography as a procedure for
      detecting simultaneous primary tumors in cases of head and neck cancer.
AB  - BACKGROUND: Second primary tumors are a leading cause of death among patients
      with head and neck cancer; therefore, early detection of these tumors is
      necessary. In the current study, the authors aimed to evaluate the diagnostic
      capacity of (18)F-fluorodeoxyglucose dual-head positron emission tomography (FDG
      PET) for detecting second primary tumors in patients presenting with primary head
      and neck cancer. METHODS: The authors prospectively studied a case series of 68
      consecutive patients with a primary tumor in the oral cavity or oropharynx.
      Within a period of 3 weeks, clinical examination, chest X-ray, computed
      tomography, and ultrasonography of the head and neck were performed on all
      patients. Irrespective of the results, patients underwent FDG-PET of the head,
      neck, and chest. Due to its low yield in the detection of second primary tumors,
      panendoscopy was not used in this study. All patients were followed up for at
      least 6 months to assess the number of simultaneous and synchronous tumors missed
      by FDG-PET. RESULTS: In 12 of 68 patients (18%; 95% confidence interval [CI]: 8
      28%), a second simultaneous primary malignant tumor was found by FDG-PET. Five of
      these tumors (7%; 95% CI: 1-13%) were also detected by clinical or radiologic
      examination (P = 0.016). With one exception, all tumors were found in the
      epithelium of the upper digestive and respiratory tract. However, even when the
      patient with a second primary tumor in the thyroid was excluded from evaluation,
      FDG-PET significantly improved the detection rate of second primaries (P =
      0.031). In none of the 68 patients studied were additional simultaneous or
      synchronous primary tumors found during follow-up. CONCLUSIONS: The use of FDG
      PET significantly increases the rate of detection of simultaneous second primary
      tumors. The results of our study suggest that most of the second primary tumors
      are detected in an early stage.

PMID- 10590381
TI  - Equitable access to cancer services: A review of barriers to quality care.
AB  - BACKGROUND: Barriers to cancer care have been documented in nearly all settings
      and populations; such barriers represent potentially avoidable morbidity or
      mortality. A conceptual framework was used to describe patient, provider, and
      system barriers to cancer services. METHODS: A review of the English language
      literature on cancer care from 1980-1998 was conducted; key research was
      summarized for each domain in the conceptual model. RESULTS: Key patient barriers
      are related to old age, minority race, and low socioeconomic class; the common
      pathways by which these sociodemographic factors appear to mediate cancer
      outcomes include social class and race-related or class-related attitudes.
      Providers are often ill-prepared to communicate the complexities of cancer care
      to their diverse patient populations; constraints of the medical care system also
      can impede the delivery of care. To the authors' knowledge the impact of the
      rapid growth in managed care organizations (MCOs) on access to care has yet to be
      evaluated fully. Although MCOs historically have provided high levels of cancer
      screening in healthy populations, to the authors' knowledge there are fewer data
      regarding outcomes for elderly and poor populations and for treatment services.
      CONCLUSIONS: Additional research is needed to develop and test interventions to
      overcome barriers to care and evaluate the impact of the growth of managed care
      on access to cancer care for diverse populations.

PMID- 10590382
TI  - The International Prognostic Index can be used as a guide to treatment decisions
      regarding patients with human immunodeficiency virus-related systemic non-Hodgkin
      lymphoma.
AB  - BACKGROUND: The International Prognostic Index (IPI) effectively separates
      aggressive lymphomas into four groups with significantly different responses to
      therapy and survival. The authors have applied the IPI to evaluate a series of
      patients with human immunodeficiency virus (HIV) related lymphoma, a disease for
      which treatment strategies are still controversial and prognostic indicators are
      therefore particularly important. METHODS: Sixty-nine consecutive evaluable
      patients with HIV-related systemic non-Hodgkin lymphoma (NHL) diagnosed at a
      single Institution during a 10-year period were analyzed. Primary cerebral
      lymphoma was not considered. Forty-nine patients (71%) received aggressive
      combination chemotherapy (CT), 45 of whom were treated with the same program:
      cyclophosphamide, doxorubicin, etoposide, cytarabine, bleomycin, vincristine, and
      methotrexate with lecuovorin and prednisone (ProMACE-CytaBOM). Univariate and
      multivariate methods were used for statistical analysis. End points were response
      to treatment in patients receiving aggressive CT and survival of treated patients
      and all patients. RESULTS: According to age-adjusted IPI, 5 patients (7%)
      belonged to the low risk group, 12 (17%) to the low-intermediate risk group, 16
      (23%) to the high-intermediate risk group, and 36 (52%) to the high risk group.
      Among the four groups with increasing IPI scores, the mean CD4 cell count at NHL
      diagnosis was 313, 230, 151, and 72/microL, respectively (P = 0.0085). The
      complete response (CR) rates were 100%, 88%, 50%, and 32% (P = 0. 0001) and the
      median survival of all patients was >60, 17, 10.9, and 6.8 months (P = 0.0002)
      for patients with low, low-intermediate, high-intermediate, and high risk IPI
      scores, respectively. In multivariate analysis, among patients receiving
      aggressive CT, high risk IPI (P = 0.013) and systemic symptoms (P = 0.014) were
      the only parameters related to CR, and high risk IPI (P = 0.016) and achievement
      of CR (P < 0.001) were the only parameters related to survival. When all patients
      were considered, high risk IPI had significant prognostic value for overall
      survival (P = 0.01), as did age (P = 0.019) and achievement of CR (P < 0.001).
      CONCLUSIONS: IPI was a reliable prognostic indicator in an unselected series of
      patients with HIV-related systemic NHL. The outcomes of patients without high
      risk IPI treated with aggressive CT were similar to those expected for HIV
      negative patients with lymphoma. However more than half of patients with HIV
      related NHL had IPI high risk disease, and their outcomes were poor even after
      aggressive CT. The degree of immunodeficiency was related to increasing IPI
      score, suggesting that immunodeficiency may be an important factor contributing
      to the aggressive clinical presentation of lymphoma.

PMID- 10590383
TI  - Expression of cytokeratin 20 in the blood of patients with disseminated carcinoma
      of the pancreas, colon, stomach, and lung.
AB  - BACKGROUND: Cytokeratins are constituents of the intermediate filaments of
      epithelial cells that are expressed in various combinations depending on the
      epithelial type and the degree of differentiation. The recently identified
      cytokeratin 20 (CK-20) was found to be expressed in colonic, gastric, and
      pancreatic carcinoma tumor tissues. A low rate of incidence of expression of CK
      20 was found in tumor tissue from lung carcinoma but no expression was found in
      blood even with the sensitive reverse transcriptase-polymerase chain reaction (RT
      PCR) method. The objective of the current study was to examine whether CK-20
      expression in the blood can be used as a biomarker for the detection of
      dissemination in patients with carcinoma of the colon, stomach, and pancreas.
      METHODS: In the current study, RT-PCR was used to determine the expression of CK
      20 in the blood cells from patients with metastatic colon carcinoma (n = 22),
      metastatic pancreatic carcinoma (n = 28), metastatic gastric carcinoma (n = 18),
      metastatic lung carcinoma (n = 13), no metastatic colon carcinoma (n = 13) and no
      known malignant diseases (n = 22). RNA was extracted from cell pellets and
      analyzed by RT-PCR using primers for CK-20. RESULTS: In the group of 22 patients
      with metastatic colon carcinoma, 14 were found to be CK-20 positive (sensitivity
      of 63.6% and specificity of 92.3%), 22 of the 28 pancreatic carcinoma patients
      showed positive CK-20 expression, and 12 of 18 patients with gastric carcinoma
      showed positive CK-20 expression. All patients with metastatic lung carcinoma
      except 1 were negative (12 of 13 patients), and 12 of 13 patients with colonic
      carcinoma with no known metastases also were negative. Negative CK-20 results
      were obtained in all 22 patients with no known malignant diseases. CONCLUSIONS:
      The results of the current study indicate that because of its high sensitivity,
      RT-PCR of CK-20 is a potential biomarker for detecting metastases in blood
      samples from patients with carcinoma of the colon, stomach, and pancreas.

PMID- 10590384
TI  - Lack of lymphatic vascular specificity of vascular endothelial growth factor
      receptor 3 in 185 vascular tumors.
AB  - BACKGROUND: Among the molecules important to angiogenesis and lymphangiogenesis
      is vascular endothelial growth factor receptor 3 (VEGFR-3), a member of the
      receptor tyrosine kinases of endothelial cells. This receptor is expressed
      consistently in normal lymphatics, lymphangiomas, and in Kaposi sarcoma, but data
      regarding other vascular tumors are scant. METHODS: In this study the authors
      immunohistochemically examined VEGFR-3 expression in 82 benign, 31 borderline,
      and 72 malignant vascular tumors using a monoclonal antibody to VEGFR-3, heat
      induced epitope retrieval, and an avidin-biotin-peroxidase detection system.
      RESULTS: Although normal mesenchymal tissues showed VEGFR-3 only in the
      lymphatics, benign and malignant vascular tumors and neovascularization of
      nonendothelial tumors showed widespread VEGFR-3 distribution. All lymphangiomas
      and Kaposi sarcomas showed consistent VEGFR-3 reactivity. Among the hemangiomas,
      spindle cell hemangiomas and 80% of capillary (including all lobular capillary
      hemangiomas) were positive whereas the endothelium of cavernous, venous, and
      epitheloid hemangiomas were positive in a minority of cases (20%, 27%, and 33%,
      respectively). Among the borderline lesions, Kaposiform hemangioendotheliomas
      were intensely positive whereas epithelioid hemangioendotheliomas were positive
      in 11 of 29 cases (38%). Angiosarcomas showed VEGRF-3 reactivity in the majority
      of cases (48 of 60 cases; 80%). The nonepithelioid variants more often were
      positive (40 of 45 cases; 89%) than the epithelioid variants, of which 8 of 15
      (53%) showed positive tumor cells. Nonvascular tumors (including perivascular
      tumors, other sarcomas, melanomas, carcinomas, and large cell lymphomas)
      consistently were negative whereas tumor neovascularization commonly was VEGFR-3
      positive. CONCLUSIONS: The results of the current study show that although VEGFR
      3 shows specificity toward lymphatics in normal tissues, this receptor is
      distributed extensively in benign and malignant vascular tumors and therefore can
      be considered a novel marker in the assessment of endothelial cell
      differentiation of vascular neoplasms.

PMID- 10590385
TI  - Spousal concordance for cancer incidence: A cohort study.
AB  - BACKGROUND: Because married couples share at least their home environment,
      spousal aggregation of cancer might provide clues to unsuspected etiologic
      factors. The authors sought to measure the concordance of cancer occurrence in
      married couples and explore factors that might explain greater-than-expected
      concordance. METHODS: The authors identified 25,670 cancer-free married couples
      in northern California who were followed for up to 31 years for the development
      of cancer. In Cox proportional hazards analysis, the development of cancer in a
      spouse was treated as a time-dependent, independent variable, and spouse
      with/spouse-without risk ratios were determined, controlling for age and gender.
      For selected concordant espoused pairs, additional explanatory information was
      sought in their medical records. RESULTS: There was no excess concordance for all
      cancers combined; the spouse-with/spouse-without risk ratio was 0.97 (95%
      confidence interval, 0.90-1.05). Statistically significant husband-wife
      associations were found only for cancer of the tongue and stomach and for non
      Hodgkin lymphoma. Except for cancer of the penis/endometrium and testis/vulva,
      based on one couple with each combination, gender specific cancers did not
      aggregate within married couples. Established and suspected risk factors, not
      necessarily related to the marriage, were found for some individuals who had
      concordance with their spouses. CONCLUSIONS: Little spousal concordance for
      cancer occurrence was found. The study of spousal aggregation does not appear
      useful in identifying unsuspected environmental causes of cancer in heterogeneous
      populations in urban areas of affluent Western countries. A cohort study would
      have to be much larger than this one to detect weak spousal concordance reliably.

PMID- 10590386
TI  - The addition of an audiocassette recording of a consultation to written
      recommendations for patients with advanced cancer: A randomized, controlled
      trial.
AB  - BACKGROUND: Communication between physicians and advanced cancer patients is
      frequently difficult. Patients often report poor levels of satisfaction with
      communication. The purpose of this study was to assess the impact on patients'
      recall of and overall satisfaction with their consultation by the addition of an
      audiocassette recording of a consultation to written recommendations. METHODS:
      Sixty patients with advanced cancer were randomized to either receive a tape
      recording of their consultation or receive no tape in addition to written
      recommendations in this randomized, double-blind trial. Patients gave their
      global ratings of the clinic, were tested for their recall of information given,
      and responded to questions about the utilization and role of the cassette in
      influencing family communication. RESULTS: The addition of the audiocassette to
      written communications significantly increased patient satisfaction with the
      clinic (8.7 +/- 1.7 vs. 7.7 +/- 2.0 on a scale of 0-10; P = 0.04) and
      significantly improved recall of the information given during the consultation
      (88% +/- 8.7% vs. 80% +/- 15.5%; P = 0.02). Patients expressed a high level of
      satisfaction with the audiocassette. Patients listened to the tape a median of 2
      (range 1-4) times, whereas family members and friends listened to the cassette a
      median of 2 (range 1-3) times. CONCLUSIONS: The addition of an audiocassette
      recording of an outpatient consultation to written recommendations for patients
      with advanced cancer is capable of increasing both the overall patient recall of
      the visit and satisfaction with the outpatient clinical setting. Patients
      expressed a high level of satisfaction with the audiocassette.

PMID- 10590387
TI  - Mandatory second opinion surgical pathology at a large referral hospital.
AB  - BACKGROUND: When patients are referred to one's own institution for therapy based
      on a histopathologic diagnosis rendered at another institution, many hospitals
      require a second opinion of the surgical pathology material. This quality
      assurance practice has been threatened in the era of managed care and cost
      containment. METHODS: The authors reviewed the impact of mandatory second opinion
      surgical pathology at The Johns Hopkins Hospital. Cases were collected
      prospectively over a 21-month period from April 1995 to December 1996. For the
      purposes of this study, a changed diagnosis was defined as a discordant diagnosis
      resulting in a major modification in therapy or prognosis. The majority of cases
      involved a change between benign and malignant or a major change in tumor
      classification. Changes involving a modification of tumor grade or stage were not
      included. RESULTS: Of 6171 cases reviewed, second opinion surgical pathology
      resulted in 86 changed diagnoses (1.4%). Compared with the entire group, 2 organ
      systems were significantly more likely to undergo a change in diagnosis: serosal
      surfaces (9. 5%) (P < 0.0001) and the female reproductive tract (5.1%) (P < 0.
      0001). Organ systems that were not more likely to undergo a change in diagnosis
      than the group as a whole included the skin (2.9%); central nervous system
      (2.8%); breast (1.4%); genitourinary system (1.2%); gastrointestinal tract
      (1.2%); hematologic system (1.1%); ear, nose, and throat (1.0%); bone/soft tissue
      (0.9%); lung (0.6%); endocrine (0%); mediastinum (0%); and cardiovascular system
      (0%). CONCLUSIONS: Second opinion surgical pathology can result in major
      therapeutic and prognostic modifications for patients sent to large referral
      hospitals. Although the overall percentage of affected cases is not large, the
      consistent rate of discrepant diagnosis uncovered by second opinion surgical
      pathology may have an enormous human and financial impact. Accordingly, the
      authors recommend that review of the original histologic material should be
      undertaken prior to the institution of a major therapeutic endeavor.

PMID- 10590390
TI  - Introduction

PMID- 10590388
TI  - American Joint Committee on Cancer prognostic factors consensus conference.
AB  - BACKGROUND: The American Joint Committee on Cancer (AJCC) published the 1st
      edition of the Cancer Staging Manual in 1977 and began using T (tumor extent), N
      (regional lymph node status), and M (the presence or absence of distant
      metastasis) in an organized staging scheme to express the extent of disease in a
      number of cancer sites. The goal of this program has been to provide physicians
      and others with a useful methodology to plan treatment, project prognosis, and
      measure outcome end results. Until recent years, this system has incorporated
      only elements of anatomic extent of the tumors determined by clinical and
      pathologic methods. At the present time an increasing number of nonanatomic
      cancer prognostic factors are being identified and studied. Some of these factors
      currently are being used for outcome predictions and treatment decisions.
      METHODS: To begin the process of identifying and validating these prognostic
      factors to refine the present TNM system, the AJCC convened a Prognostic Factors
      Consensus Conference to evaluate the roles of biologic, genetic, molecular, and
      other nonanatomic factors in staging cancer. Working groups were appointed for
      carcinomas of the breast, colorectum, prostate, and ovary and experts in each of
      these areas were invited to participate. Emphasis was placed on evaluating
      existing data and the correlation of these data with survival. RESULTS: None of
      the groups believed that there were sufficient data at the present time to merit
      incorporation of serum markers into the TNM system for the four tumors under
      consideration, although this soon might become possible in prostate carcinoma
      after the evaluation of survival data from multiple institutions. Recommendations
      were made regarding the emerging sentinel lymph node technique, the need for an
      increased use of histopathology in the staging of breast and ovarian carcinomas,
      and the use of additional histologic staining techniques for the detection of
      "micrometastases" in lymph nodes. A number of additional recommendations were
      made for changes to the TNM system that did not involve serum markers and other
      nonanatomic cancer prognostic factors. CONCLUSIONS: These recommendations are
      presented for the purpose of discussion and evaluation and do not yet represent
      formal proposals for a change in the AJCC TNM system of staging.

PMID- 10590391
TI  - Pregnancy outcome following gestational exposure to organic solvents: a response.

PMID- 10590392
TI  - Pregnancy outcome following gestational exposure to organic solvents: Author's
      response

PMID- 10590393
TI  - Using birth defects epidemiology to take CHARGE. Coloboma, Heart defect, choanal
      Atresia, Retardation, Genital, Ear anomaly.

PMID- 10590394
TI  - CHARGE Association in newborns: a registry-based study.
AB  - The CHARGE Association is a nonrandom occurrence of congenital malformations that
      has been described in clinical series. Reported patients have been selected on
      the basis of certain prior criteria. In this article, we try to identify a
      congenital malformation pattern corresponding to the CHARGE Association, using
      statistical methods and analyzing 5,260 infants with multiple malformations
      collected from four large registries of congenital malformations. Care was taken
      to identify a number of confounding characteristics that can influence the
      ascertainment and registration of specific congenital malformations. We have
      identified a cluster of malformations that generally agreed with the current
      clinical definition of the CHARGE Association and have added some further
      malformations (e.g., facial clefts). We demonstrate that others (e.g. ,
      esophageal atresia) are probably not part of the pattern. Heart defects (H in the
      acronym) seems to be less helpful in identifying infants with the association. We
      suggest a method to select infants who probably represent the CHARGE Association
      for analyses of possible risk factors.

PMID- 10590395
TI  - Folinic acid reduces cleft lip [CL(P)] in A/WySn mice.
AB  - The A/WySnBk strain of mice displays 25-35% spontaneous CL(P). Pregnant mice were
      treated with folinic acid continuously delivered via osmotic minipumps at the
      rate of 7.6 +/- 0.2 microl/ hr (12 mg/ 24 hr) for the period covering gestation
      day (gd) 8.5-9.5, early in the critical period for formation of the face.
      Untreated and osmotic minipump-delivered, saline-treated groups served as
      controls. Individual fetuses were examined for CL(P) and other abnormalities on
      gd 18. The treatment resulted in a decrease in the frequency of CL(P) from 40.0+/
      7.0% among untreated to 10.2+/-3.3% in the folinic acid group (P<.001). The
      difference between the folinic-exposed group and the saline-filled minipump and
      surgical control was also significant (P<.029). With respect to mortality, litter
      size, and fetal weight, the two minipump groups did not differ significantly, nor
      did they differ from the untreated group. Thus the reduction in CL(P) frequency
      was due to the presence of folinic acid and not to effects of the surgical
      procedures. This study provides evidence that administration of folinic acid
      during pregnancy has an important ameliorating effect on genetically predisposed
      CL(P).

PMID- 10590396
TI  - Pattern of skeletal malformations produced by Dominant hemimelia (Dh).
AB  - The hindlimb malformations in adult mice heterozygous for the dominant gene
      Dominant hemimelia (Dh) and +/+ littermates were characterized in skeletons that
      had been fixed, stained, and cleared. When the tibia was shortened, the
      deficiency was always an absence of the distal portion, and never the proximal
      portion. Although tibial hemimelia has been well documented in Dh mice, this
      study demonstrated a distinctive pattern of shortening of the tibia. Measurements
      of the length of the tibia (relative to the length of the humerus) showed only
      three patterns of shortening of the tibia (i.e., mild, moderate, and severe),
      rather than a continuous spectrum of shortening from mild to complete absence.
      The hindlimb malformation of Dh/+ mice occurred in association with a reduced
      number (five) of lumbar vertebrae. The interrelationship of the hindlimb
      malformations and the reduction in the vertebral number suggests a relationship
      between the development of the axial skeleton and the abnormal limb.

PMID- 10590397
TI  - Evaluation of selected characteristics of pregnancy drug registries.
AB  - Given that half of U.S. pregnancies are unintended and some prescription drugs
      are frequently used by reproductive-age women, there is an increasing interest in
      establishing pregnancy registries to monitor fetal exposures and pregnancy
      outcomes. Physicians report prenatal exposures and pregnancy outcomes, including
      birth defects, to these registries. We compared pooled data from four pregnancy
      registries with data from a population-based birth defects surveillance system,
      the Metropolitan Atlanta Congenital Defects Program (MACDP); specifically we
      compared the defect prevalence by organ system and severity, the number of
      defects per baby, and timeliness. We also compared the number of zidovudine
      exposures identified by a registry to the number identified by 29 states with HIV
      surveillance. The registries' overall defect prevalence (41/1471, 2.7%) was
      slightly lower than MACDP (6157/195642, 3.2%). The defect prevalence by organ
      system was similar, except for genitourinary defects which had a lower prevalence
      in the registries than in MACDP (RR = 0.22; 95% CI = 0.07,0.67). The prevalence
      of having an internal defect or severe defect reported was lower in the
      registries (RR = 0.75, 95% CI = 0.53,1.06, and RR = 0.82, 95% CI = 0. 57,1.19,
      respectively). The mean number of defects identified per affected infant was 2.82
      in MACDP and 1.68 in the registries. Both systems received 69% of defect reports
      by 6 months after birth. In similar 6-month periods, U.S. HIV surveillance
      identified 300 prenatal zidovudine exposures, while the registry received 134
      worldwide reports. If registries improve their ascertainment of defects and
      exposed pregnancies, they will increase their chance of detecting signs of
      possible teratogenicity. Teratology 60:356-364, 1999. Published 1999 Wiley-Liss,
      Inc.

PMID- 10590398
TI  - Teratology Society Public Affairs Committee position paper: developmental
      toxicity of endocrine disruptors to humans.

PMID- 10590400
TI  - Message from the editor

PMID- 10590401
TI  - Acknowledgment: Ad hoc reviewers

PMID- 10590399
TI  - Role of reactive oxygen species (ROS) in the diabetes-induced anomalies in rat
      embryos in vitro: reduction in antioxidant enzymes and low-molecular-weight
      antioxidants (LMWA) may be the causative factor for increased anomalies.
AB  - A disturbed embryonic antioxidant defense mechanism may play a major role in
      diabetes-induced teratogenesis. We therefore studied the antioxidant capacity of
      10.5-day-old rat embryos and their yolk sacs after culture for 28 hr in vitro
      under diabetic conditions (3 mg/ml glucose, 2 mg/ml beta-hydroxybutyrate (BHOB)
      and 10 microg/ml of acetoacetate), as compared with control embryos in vitro. We
      found a high rate of congenital anomalies, decreased growth and protein content,
      and a decrease in the activity of both superoxide dismutase (SOD) and catalase
      (CAT) under diabetic conditions, as compared with controls. The reducing power,
      which reflects the concentration and type of water-soluble and of lipid-soluble
      low-molecular-weight antioxidants (LMWA), was measured by cyclic voltammetry.
      Generally, LMWA were reduced in the embryos and yolk sacs under diabetic
      conditions. In the water-soluble fraction of control embryos and yolk sacs, two
      peak potentials were found, indicating two major groups of LMWA, while only one
      peak potential was found under diabetic conditions, indicating that an entire
      group of LMWA is missing. HPLC studies have demonstrated a decrease in vitamin C
      (water-soluble fraction) and in vitamin E (lipid-soluble fraction) under diabetic
      culture conditions, and an increase in uric acid. Generally, the concentration of
      LMWA was higher in the embryos than in the yolk sac. LMWA concentration, protein
      content, and antioxidant enzyme activity were lower in the malformed experimental
      embryos than in experimental embryos without anomalies. The addition of vitamins
      C and E to the diabetic culture medium abolished the deleterious effects of the
      diabetic serum on the embryos. The disturbed antioxidant defense mechanism under
      diabetic conditions may be explained, at least in part, by a direct effect of
      diabetic metabolic factors on the activity of antioxidant enzymes and on the
      concentration of reducing equivalents. This, in turn, may be embryotoxic.

PMID- 10590402
TI  - Genetics and pathogenesis of malignant hyperthermia.
AB  - Malignant hyperthermia (MH) is a potentially life-threatening event in response
      to anesthetic triggering agents, with symptoms of sustained uncontrolled skeletal
      muscle calcium homeostasis resulting in organ and systemic failure.
      Susceptibility to MH, an autosomal dominant trait, may be associated with
      congenital myopathies, but in the majority of the cases, no clinical signs of
      disease are visible outside of anesthesia. For diagnosis, a functional test on
      skeletal muscle biopsy, the in vitro contracture test (IVCT), is performed. Over
      50% of the families show linkage of the IVCT phenotype to the gene encoding the
      skeletal muscle ryanodine receptor and over 20 mutations therein have been
      described. At least five other loci have been defined implicating greater genetic
      heterogeneity than previously assumed, but so far only one further gene encoding
      the main subunit of the voltage-gated dihydropyridine receptor has a confirmed
      role in MH. As a result of extensive research on the mechanisms of excitation
      contraction coupling and recent functional characterization of several disease
      causing mutations in heterologous expression systems, much is known today about
      the molecular etiology of MH.

PMID- 10590403
TI  - The utility of interference pattern analysis.
AB  - The interference pattern of the electrical activity of muscle can be quantified
      by amplitude measurements, different spike counting methods, and power spectrum
      analyses. Interference pattern analysis (IPA) methods are used to describe the
      degree of activation of different muscles, muscle fatigue, occupational work,
      muscles in chronic pain syndromes, disused muscle, and dystonic muscle treated
      with botulinum toxin. In patients with neuromuscular disorders, the
      turns/amplitude analysis is useful for diagnosis. High diagnostic yields can be
      obtained without force measurements, for example, by using the amplitude as an
      indicator of force (the peak ratio method) or plotting the amplitude against the
      turns (cloud analysis). The diagnostic possibilities of the power spectrum
      analysis and the motor unit firing rate obtained by decomposition techniques are
      still unclear.

PMID- 10590404
TI  - Influence of diabetes mellitus on chronic inflammatory demyelinating
      polyneuropathy.
AB  - Patients with diabetes occasionally develop clinical and electrodiagnostic
      features suggestive of chronic inflammatory demyelinating polyneuropathy (CIDP).
      To clarify the role of diabetes in patients with a CIDP-like syndrome, we
      compared the clinical, pathological, and electrodiagnostic features of 14
      patients (10 men, 4 women) with diabetes and CIDP (DM-CIDP) to 60 patients with
      idiopathic CIDP (I-CIDP). The average duration of diabetes was 9 years. The
      patients with DM-CIDP were older and more often complained of imbalance compared
      to the idiopathic group, but the frequency of other symptoms and neurologic
      findings were similar. The mean amplitude of the ulnar compound muscle action
      potential in the DM-CIDP group was comparatively reduced, the sural sensory nerve
      action potential was more often absent, and axonal loss was more commonly
      observed on nerve biopsy. The response rate to treatment was similar, but the
      magnitude of functional recovery was greater in patients with I-CIDP. Thus, our
      patients with diabetes and CIDP had clinical features similar to those with
      idiopathic CIDP, but their nerve conduction studies and nerve biopsies showed
      more severe axonal loss and the degree of improvement following treatment was
      less favorable. These differences most likely reflect the additive effects of
      superimposed diabetic axonal polyneuropathy in patients who develop CIDP.

PMID- 10590405
TI  - Chronic intermittent stimulation of the thyroarytenoid muscle maintains dynamic
      control of glottal adduction.
AB  - Patients with laryngeal motor control disorders need improved dynamic glottal
      closure for speech and swallowing. To evaluate the functional outcome of
      intermittent chronic thyroarytenoid muscle stimulation in an animal model, 6
      canines were implanted with bilateral Medtronic Xtrel systems containing Peterson
      type electrodes in the inferior and superior portions of the thyroarytenoid
      muscle. Stimulation was on one side only at 60 Hz, for 5 s on and 5 s off, over 8
      h, 5 days per week, up to 8 months. Monthly videorecordings were done under
      anesthesia to measure the voltage threshold for detectable movement on each side,
      and vocal fold displacement and velocity during maximal stimulation of each side.
      Movement thresholds were lower in the inferior portion of the thyroarytenoid
      muscle (P </= 0.0005). Movement velocity was greater on the stimulated than on
      the nonstimulated side after 3 to 8 months (P = 0.039). No differences in the
      percentage distribution of different myosin heavy chain types were found between
      the stimulated and nonstimulated muscle samples. Sustained dynamic glottal
      adduction with no alteration in thyroarytenoid muscle function or fiber type was
      achieved with intermittent stimulation over 8 months. The results suggest that
      chronic intermittent thyroarytenoid stimulation has good potential for improving
      airway protection in dysphagia.

PMID- 10590406
TI  - Assessment of facial nerve function in acoustic tumor disease by nasal muscle F
      waves and transcranial magnetic stimulation.
AB  - Standard transcranial magnetic stimulation and nasal muscle F-wave recordings
      were used to assess proximal facial nerve function in 27 patients with unilateral
      acoustic tumors (mean diameter, 29 mm) and clinically intact facial nerve
      function. Latency measurements for F waves and cortical magnetic stimulation were
      abnormal. Moreover, F ratios, central motor conduction time, and the ratio of
      response latency to cortical and cisternal magnetic stimulation were
      significantly increased. Amplitudes were unchanged. Correlation analysis with
      tumor diameter as dependent variable yielded maximum r values for F-wave
      latencies (0.57) and F ratios (0.41), whereas for magnetic stimulation, a
      significant correlation could be found (0.4) only for cortical stimulation. Nasal
      muscle F-wave recording can reveal clinically inapparent facial nerve
      dysfunction. Its efficacy in predicting tumor diameter seems to be superior to
      that of standard magnetic stimulation.

PMID- 10590407
TI  - Expression of nitric oxide synthase in the spinal cord in C57BL/6J mice with
      congenital muscular dystrophy.
AB  - Autoradiography with the nitric oxide synthase (NOS) inhibitor ((3)H)nitro-L
      arginine ([(3)H]L-NNA) was used to quantify NOS in cervical and lumbar spinal
      cord in normal and dystrophic mice. A single homogeneous population of binding
      sites was seen in all subregions of the gray matter in normal mice and in the
      superficial dorsal horn in dystrophic mice. However, in dystrophic mice, two
      populations were revealed in the deeper dorsal, intermediate, and ventral
      subregions. Pronounced immunoreactivity for neuronal NOS (nNOS), and weak
      immunoreactivity for endothelial NOS (eNOS), were revealed in all subregions in
      normal and dystrophic mice. Inducible NOS (iNOS) immunoreactivity was negligible
      in normal mice but intense in the deeper dorsal, intermediate, and ventral
      subregions in dystrophic mice. The higher affinity ((3)H)L-NNA binding site
      colocalized with nNOS and the lower affinity site with iNOS. It is suggested that
      expression of iNOS is associated with the pathological changes occurring in
      congenital muscular dystrophy.

PMID- 10590408
TI  - Diagnostic criteria for demyelinating polyneuropathy associated with monoclonal
      gammopathy.
AB  - In order to define diagnostic criteria for the demyelinating polyneuropathy
      associated with monoclonal gammopathy of undetermined significance (MGUS), we
      compared 30 patients with idiopathic chronic inflammatory demyelinating
      polyneuropathy (CIDP) without a monoclonal gammopathy, with 29 patients with
      polyneuropathy associated with MGUS. All 59 patients fulfilled research criteria
      for CIDP. In the patients with MGUS, sensory symptoms and signs predominated,
      there was usually no cranial nerve involvement, and the neuropathy was
      symmetrical with a slowly progressive course. On electrophysiological
      examination, an abnormal median nerve sensory action potential in combination
      with a normal sural nerve action potential (AMNS) was not found. In idiopathic
      CIDP patients, a preceding infection was frequent, motor features predominated,
      there was often cranial nerve involvement, the neuropathy could be asymmetrical,
      and AMNS was frequently found. Diagnostic criteria for demyelinating
      polyneuropathy associated with MGUS are presented.

PMID- 10590409
TI  - Analysis of mtDNA deletions in muscle by in situ hybridization.
AB  - We compared the distribution of deleted mitochondrial DNA (Delta-mtDNA) in
      skeletal muscle of a patient with autosomal recessive (AR) and another with
      autosomal dominant (AD) progressive external ophthalmoplegia (PEO) by in situ
      hybridization (ISH). The patients studied had similar numbers of fibers deficient
      in cytochrome c oxidase (COX) activity (13.6% and 12.8%) and fibers with
      mitochondrial proliferation (5.5% and 5.3%). ISH suggested that each COX
      deficient fiber contained a single species of Delta-mtDNA. Most deletions ablated
      the region between the genes encoding adenosine triphosphate (ATP) synthase
      subunit 8 and cytochrome b. Fibers that appeared to be depleted of mtDNA were
      also present. We conclude that muscle from patients with autosomally inherited
      PEO contains not only Delta-mtDNA but also focal depletion of mtDNA and that the
      distribution of these mtDNA defects appears to be similar. These changes most
      likely represent the common consequence of whatever genetic factors are
      responsible for the generation of Delta-mtDNA.

PMID- 10590410
TI  - Masseter reflex latencies and amplitudes are not influenced by supratentorial and
      cerebellar lesions.
AB  - The aim of this study was to investigate possible influences of suprasegmental
      lesions on the masseter reflex. The masseter reflex was elicited in 54 patients
      with supratentorial (37 patients) or cerebellar (17 patients) lesions 3-11 days
      after the acute onset of clinical disease. Patients showing lesions within the
      pons and midbrain on thin-slice magnetic resonance imaging were excluded from
      evaluation. The testing procedure included an additional facilitating maneuver
      (opening and closing the jaw before tapping). Masseter reflex latencies,
      interside differences, and amplitudes were within the normal range in all
      patients. Latencies were not different with and without the facilitating
      maneuver. Amplitudes were significantly higher with the maneuver, but interside
      differences of amplitudes were unchanged. Masseter reflex abnormality can be
      taken as a reliable measure of direct involvement of the reflex arc.

PMID- 10590411
TI  - Mutations in MCT1 cDNA in patients with symptomatic deficiency in lactate
      transport.
AB  - We identified 5 patients with subnormal erythrocyte lactate transport plus
      symptoms and signs of muscle injury on exercise and heat exposure. All had
      transport rates below the 95% envelope for normals. Three cases had rates 40-50%
      of mean normal. One was found to have a missense mutation in monocarboxylate
      transporter 1 (MCT1), the gene for the red cell lactate transporter (also
      expressed in skeletal muscle), at a conserved site, which was not mutated in a
      cohort of 90 normal humans. The other 2 cases had a different missense mutation
      (at a nonconserved site), which was also not mutated in the normal cohort. All 3
      patients were heterozygotes. We presume that these mutations are responsible for
      their subnormal lactate transport, and hence their muscle injury under
      environmental stress; homozygous patients should be more seriously compromised.
      The other 2 cases had lactate transport rates 60-65% of mean normal, and their
      MCT1 revealed a third mutation, which proved to be a common polymorphism in the
      normal cohort. These 2 patients may be physiologic outliers in lactate transport,
      with their muscle damage arising from some other genetic defect.

PMID- 10590412
TI  - Peripheral and central effect of baclofen on ankle joint stiffness in multiple
      sclerosis.
AB  - The effect of baclofen on the soleus stretch reflex and peripheral muscle
      function was tested in 10 multiple sclerosis (MS) patients with spasticity in the
      lower extremities. Peroral baclofen (15-60 mg daily) induced a decrease in the
      twitch torque of the soleus muscle elicited by supramaximal nerve stimulation.
      The torque was 15.1 +/- 5.5 Nm with baclofen and 17.1 +/- 5.0 Nm without baclofen
      (P = 0.03). The slope of the background torque/EMG relation was also changed from
      1.53 Nm/microV with baclofen to 1.13 NM/microV without it (P = 0.03), and the
      soleus stretch reflex threshold decreased from 11.4 degrees /s (3.1-62.8) to 6.2
      degrees /s (3.1-25.1) without baclofen medication (P = 0.03) in the relaxed
      muscle. Furthermore, baclofen induced an approximately 20% decrease in the total
      stiffness at the ankle joint at all contraction levels due to a decrease in the
      short-latency stretch reflex. From a clinical point of view, the peripheral
      action of baclofen may be unfortunate. Spasticity is often accompanied by
      weakness, which may be the major cause of any disability. Consequently, reduction
      in spasticity by the central effect of baclofen may be counteracted by its
      influence on muscle properties. In addition, treatment of spasticity by baclofen
      may unmask weakness.

PMID- 10590413
TI  - Delay of muscle degeneration and necrosis in mdx mice by calpain inhibition.
AB  - Inhibition of muscle degeneration by the tripeptide calpain inhibitor, leupeptin,
      was tested in vivo in a dystrophin-deficient mdx murine model. In a short-term
      control study, intramuscular administration of leupeptin for 30 days inhibited
      muscle degeneration as assessed by histologic analysis. Calpain inhibition could
      be correlated with retention of myofiber size and our results suggest that this
      may be a promising treatment modality in human Duchenne muscular dystrophy.

PMID- 10590414
TI  - Subthreshold prefrontal repetitive transcranial magnetic stimulation reduces
      motor cortex excitability.
AB  - The prefrontal cortex plays an important role in central motor control. We have
      examined whether prefrontal repetitive transcranial magnetic stimulation (rTMS)
      induces changes of motor cortex excitability determined by motor evoked
      potentials (MEPs) following single-pulse TMS. We studied 18 healthy volunteers
      stimulated at 5 Hz with 10% subthreshold prefrontal vs. occipital rTMS for 12 s.
      MEPs from the flexor carpi radialis muscle after single-pulse vertex stimulation
      were recorded during rTMS at 0, 4, 8, and 12 s. MEP areas decreased significantly
      after 8 s of prefrontal rTMS (P < 0. 05) but not after occipital rTMS. We
      conclude that rTMS of the prefrontal cortex may inhibit the primary motor areas.

PMID- 10590415
TI  - Pseudofacilitation: A temperature-sensitive phenomenon.
AB  - With sustained isometric exercise, compound muscle action potential (CMAP)
      amplitude of normal subjects may increase, a phenomenon known as
      pseudofacilitation. To explore the mechanism of pseudofacilitation, the effect of
      exercise combined with focal heating and cooling of abductor pollicis brevis was
      examined in 10 normal subjects. After 10 s of isometric exercise, CMAP amplitude
      increased by 3.6% (median value) at 32 degrees C and 6.4% at 40 degrees C, and
      decreased by 9.1% at 20 degrees C. Duration decreased by 12.6% at 32 degrees C
      and 11.7% at 42 degrees C, but increased by 12.4% at 20 degrees C. Area decreased
      by 9.8% at 32 degrees C and 8. 6% at 42 degrees C, and increased by 1.1% at 20
      degrees C. Changes with cooling were significant (P < 0.01) as compared to
      baseline (32 degrees C); changes with heating were not. Thus, cooling reverses
      the expected increase in CMAP amplitude normally seen with exercise. Although
      providing only indirect evidence, these findings are consistent with the
      hypothesis that increased activity of muscle Na(+),K(+)-pump plays a role in
      producing pseudofacilitation.

PMID- 10590416
TI  - Muscle fiber type-specific myofibrillar Ca(2+) ATPase activity after spinal cord
      injury.
AB  - Biopsies of the vastus lateralis muscle were analyzed to determine if increased
      energy demand of contraction, as indirectly reflected by myofibrillar Ca(2+)
      adenosine triphosphate activity (qATPase), contributes to greater fatigue in
      affected muscle of spinal cord injured (SCI) patients. The qATPase activity
      showed a fiber-type effect, IIax + IIx > IIa > I. Average fiber qATPase and fiber
      specific qATPase activities were not different between SCI and able-bodied
      controls, nor did they change over time. We suggest greater fatigue in SCI
      subjects early after injury does not reflect increased energy demand of
      contraction.

PMID- 10590417
TI  - Standardization of anal sphincter electromyography: uniformity of the muscle.
AB  - The different parts of the external anal sphincter (EAS) are usually regarded as
      one muscle with common EMG characteristics. This assumption was addressed by
      comparing the number of continuously firing motor units (MUs) during relaxation,
      as well as the parameters of motor unit potentials (MUPs) and interference
      pattern (IP) in the subcutaneous and the deeper parts of EAS. MUPs and IPs were
      analyzed in 44 subjects (2008 MUPs and 3014 IPs) without uroneurological or
      proctological disorders, and the number of continuously active MUs in 34 of these
      subjects was recorded (221 positions). No significant difference was found in IP
      and most MUP parameters between the two parts of the EAS muscle, but the number
      of continuously firing MUs was lower in the deeper part. As far as MUP and IP
      characteristics are concerned, the whole EAS can be considered as one muscle, but
      some differences in patterns of activation of MUs may exist in different regions.

PMID- 10590418
TI  - A novel method of inducing muscle cramps using repetitive magnetic stimulation.
AB  - The lack of a practical model has hampered attempts to study the pathophysiology
      of muscle cramps. We investigated the feasibility, efficacy, and reproducibility
      of repetitive magnetic stimulation in producing experimental cramps. In 14
      healthy subjects, the tibial nerve at the ankle was stimulated with a magnetic
      stimulator at rates beginning at 4 Hz to a maximum of 20 Hz. The frequency was
      gradually increased until a cramp was produced. Ten of 14 subjects demonstrated a
      muscle cramp. All subjects rated the discomfort of the procedure to be mild or
      moderate. Repeat testing yielded values that were highly reproducible. This
      technique holds promise for clinical studies and therapeutic trials.

PMID- 10590419
TI  - A missense mutation W797R in the myophosphorylase gene in a Spanish patient with
      McArdle's disease.
AB  - We identified a novel missense mutation in the myophosphorylase gene (PYGM) in a
      Spanish patient with McArdle's disease. This homozygous T-to-C transition results
      in the replacement of a highly conserved tryptophan at amino acid position (aa)
      797 with an arginine in the C-terminal domain of the PYGM protein. The lack of
      enzyme activity in the proband's muscle is consistent with a crucial role of the
      aa 797 in the normal function of the PYGM protein. Our data further expand the
      genetic heterogeneity in patients with McArdle's disease.

PMID- 10590420
TI  - Hereditary neuropathy and vocal cord paralysis in a man with childhood
      diphtheria.
AB  - We present the case of a 37-year-old Afghani man with a history of childhood
      diphtheria, who was diagnosed with bilateral vocal cord paralysis at age 15
      years. At about this time he developed progressive muscular wasting and distally
      predominant weakness, and subsequently developed respiratory insufficiency,
      necessitating nocturnal ventilatory support. His examination suggested a distal
      symmetric sensorimotor neuropathy, and his brother was similarly affected,
      although to a lesser degree. Electromyography (EMG) and nerve conduction studies
      revealed this process to be purely axonal. A diagnosis of possible hereditary
      motor and sensory neuropathy (HMSN) type IIc, hereditary axonal polyneuropathy
      with vocal cord paralysis, is proposed, although the question of early
      diphtheritic involvement of the vocal cords and peripheral nerves is also
      considered.

PMID- 10590421
TI  - The "split hand syndrome".

PMID- 10590423
TI  - AAEM news and comments

PMID- 10590422
TI  - Response to carbamazepine of recessive-type myotonia congenita.

PMID- 10590424
TI  - Rapid detection of chromosomes X and Y aneuploidies by quantitative fluorescent
      PCR.
AB  - Quantitative fluorescent polymerase chain reaction (QF-PCR) assays and small
      tandem repeat (STR) markers have been successfully employed for the rapid
      detection of major numerical aneuploidies affecting human autosomes. So far, the
      analysis of chromosomes X and Y disorders has been hampered by the rarity of
      highly polymorphic markers which could distinguish normal female homozygous PCR
      patterns from those seen in patients with Turner's syndrome. A new marker (X22)
      of the X/Y chromosomes has been identified which maps in the Xq/Yq
      pseudoautosomal region PAR2; used together with the HPRT it allows the rapid
      diagnosis of numerical aneuploidies of the sex chromosomes. Blood samples from
      normal male and female subjects and from patients with X and Y chromosome
      disorders (45,X and 47, XXY) have been tested by QF-PCR with the X22 polymorphic
      pentanucleotide (12 alleles) together with the HPRT and P39 markers. The samples
      were also tested by multiplex QF-PCR with STRs specific for chromosomes 21,18,13
      and amelogenin (AMXY). Tested by QF-PCR, all samples from normal females were
      heterozygous for either the X22 or the HPRT marker with fluorescent peak ratios
      near 1:1, thus allowing a correct, rapid diagnosis of their chromosome
      complement. Turner's patients (45,X) showed only one X22 and one HPRT fluorescent
      peak, thus documenting the presence of a single X chromosome. Turner's patients
      with mosaicism showed a major fluorescent peak for the X22 and HPRT markers and a
      minor peak revealing the presence of a second minor population of cells. Two 47,
      XXY cases could also be diagnosed. Multiplex analyses can be performed using
      simultaneously STR markers for chromosomes 21,18,13 X and Y. The diagnostic value
      of a third X-linked marker (P39) was also investigated. These results suggest
      that rapid diagnosis of major numerical anomalies of the X and Y chromosomes can
      be performed using QF-PCR with a new highly polymorphic X-linked marker, X22,
      which maps in the Xq/Yq pseudoautosomal region PAR 2. Multiplex QF-PCR tests
      using the X22 STR in association with HPRT and, in rare cases, a third P39 marker
      allow the rapid diagnosis of major aneuploidies affecting chromosomes 21, 18, 13,
      X and Y. The X22 marker can also be employed for the detection of fetal cells
      present in maternal peripheral blood or the endocervical canal.

PMID- 10590425
TI  - Pregnancy outcome and nuchal translucency measurements in fetuses with a normal
      karyotype.
AB  - The aim of this study was to examine the relationship between nuchal translucency
      thickness and pregnancy and fetal outcome in fetuses with a normal karyotype and
      without structural malformations. Fetal nuchal translucency measurements were
      performed in 2088 chromosomally and structurally normal fetuses. In all fetuses
      the karyotype and pregnancy outcome were known. Likelihood ratios for different
      outcome measures were calculated. Spontaneous abortion, intra-uterine and
      neonatal death occurred in 2.4, 1.1 and 0.5 per cent respectively. The incidence
      of immature delivery was 1.1 per cent and of premature delivery 6.0 per cent. The
      only adverse pregnancy outcome recorded that was associated with increased nuchal
      translucency was spontaneous abortion. The likelihood ratio for the occurrence of
      a spontaneous abortion was 3.1 for measurements between 3.0 and 3.9 mm, and 6.8
      for measurements>/=4 mm. Increased lethality in fetuses with enlarged nuchal
      translucency and normal chromosomes may provide evidence that the same insult
      causing excessive fluid collection in the nuchal region may also be responsible
      for fetal demise.

PMID- 10590426
TI  - Acceptance of prenatal diagnosis for genetic disorders in Lebanon.
AB  - Acceptance of prenatal diagnosis and termination of pregnancy in the case of an
      affected fetus may vary from one country to another, depending on the health
      system, religious belief, cultural and educational backgrounds of the population.
      Following a previous study on couples at risk for a haemoglobin disorder in
      Lebanon, we have here interviewed 90 couples at risk for a variety of genetic
      disorders, in order to assess their acceptance of prenatal diagnosis and the
      variables that might influence their choice. Overall, 54 per cent of couples said
      they would request diagnosis in their next pregnancy, while 26 per cent were
      opposed to such a procedure. In 87. 5 per cent of cases, the reason for refusal
      was because of religious conviction against termination of pregnancy. Refusal of
      prenatal diagnosis was also related to a lower socio-economic background and
      poorer education. Only 12 per cent of couples were properly aware of their
      genetic risk. Therefore, for prevention of genetic disorders, the emphasis in
      countries such as Lebanon has probably to be placed on public awareness about
      genetic risks, the risks of consanguinity, availability of services, while taking
      into consideration the personal beliefs of the individuals.

PMID- 10590427
TI  - Current French practices for prenatal diagnosis of trisomy 21: a population-based
      study in Paris, 1992-97.
AB  - The results and limitations of current French practices for prenatal diagnosis
      (PND) of trisomy 21 were examined, using population-based data from the Paris
      Registry for 1992-97 (219 000 births). Of 670 cases of trisomy 21 reported, 71.0
      per cent were terminations of pregnancy (TOP). The PND rate among mothers 38
      years and older, all of whom were offered amniocentesis, was 89.9 per cent.
      Nearly all affected births in this age class followed maternal decisions, either
      to refuse amniocentesis or continue the affected pregnancy. In younger mothers,
      the overall French prenatal screening policy (three ultrasound examinations plus
      serum screening from January 1997) led to an overall PND rate of 67.3 per cent;
      it reached 78.8 per cent in 1997. Ultrasound accounted for 73.4 per cent of
      diagnosed cases. Increased detection by nuchal translucency measurement is
      clearly visible from 1996 onward. The birth prevalence, 8.7 per 10 000 births,
      diminished only slightly over the study period. The increase observed in the
      total number of cases in 1996 and 1997, concomitant with PND practice trends, may
      be due primarily to earlier TOP, which precedes miscarriages that would otherwise
      have occurred without being recorded. Future trends in prevalence among births
      must be observed carefully.

PMID- 10590428
TI  - Prenatal diagnosis of congenital parvovirus B19 infection: value of serological
      and PCR techniques in maternal and fetal serum.
AB  - Intrauterine infection with parvovirus B19 (B19) is associated with non-immune
      hydrops fetalis, miscarriage and stillbirth. Accurate laboratory tests for
      diagnosis of B19 infection are required to exclude other diagnoses. We analysed
      the diagnostic value of B19 IgM antibody testing and polymerase chain reaction
      (PCR) in the sera from 57 patients and their fetuses with abnormal
      ultrasonography. Viral DNA was found in 16 of the 58 fetuses (one twin pregnancy)
      whereas only 7 of these were tested positive for B19 IgM antibodies. The sera of
      all 16 mothers were also positive for B19 DNA. False-positive B19 IgM results
      were obtained from two fetuses. The study highlights the limitations of B19 IgM
      serology and shows for the first time that, if a sensitive PCR assay is used, DNA
      measurement is the best indicator of infection not only in the fetal blood but
      also in the maternal blood. This improves the diagnostic value of the laboratory
      results considerably. DNA assays are essential in cases of doubtful serological
      results.

PMID- 10590429
TI  - Intrapartum drainage of fetal pleural effusion.
AB  - Our objective was to describe our experience with intrapartum thoracocentesis in
      fetuses with severe bilateral pleural effusion. We describe the outcome of four
      consecutive cases of fetal pleural effusion due to chylothorax that were managed
      by intrapartum thoracocentesis. These fetuses were not candidates for pleuro
      amniotic shunting either because of the need for prompt delivery (three fetuses)
      or because of advanced gestational age (one fetus). Thoracocentesis was performed
      in the operating theatre under ultrasound guidance prior to Caesarean delivery.
      Gestational age at the time of diagnosis and thoracocentesis ranged between 26-34
      weeks and 31-34 weeks respectively. Bilateral thoracocentesis was performed in
      two fetuses and unilateral in the remaining two fetuses. All four infants were
      born in a relatively good condition; however, all eventually required intubation,
      ventilation and chest tubes. Chest tubes were introduced between 2 h and 5 days
      after delivery in three infants, and immediately after birth in one infant who
      was hydropic. Two infants survived and are developing normally. One infant died
      from sepsis following successful pleurodesis and one from aspiration on day 51.
      Our conclusions are that intrapartum thoracocentesis seems to be a relatively
      simple procedure, that allows newborns with pleural effusion, to breathe
      spontaneously or be more easily ventilated. This in turn, reduces the need to
      introduce chest tubes in an emergency situation.

PMID- 10590430
TI  - Second trimester levels of pregnancy associated plasma protein-A in cases of
      trisomy 18.
AB  - In a study of 70 cases of trisomy 18 and 450 matched controls in the second
      trimester we have measured the maternal serum levels of the analytes alpha feto
      protein (AFP), free beta-human chorionic gonadotrophin (hCG) and pregnancy
      associated plasma protein-A (PAPP-A). We have found the median multiple of the
      median (MoM) of maternal serum free beta-hCG to be significantly lower (0.327)
      than normal, as was the level of AFP (0.600). Levels of PAPP-A were reduced even
      further (0.108). Of the markers associated with trisomy 18 at this time PAPP-A
      was the most discriminatory, being lower than the 5 per cent centile of normal in
      93 per cent of cases, compared with 57 per cent of cases for free beta-hCG and 32
      per cent of cases for AFP. Combining free beta-hCG and PAPP-A or all three
      markers with maternal age would have the ability to detect 74 per cent of cases
      at a 0.5 per cent false positive rate (or 64 per cent at a 0.1 per cent false
      positive rate). Unlike in cases of trisomy 21, the low PAPP-A values observed in
      the first trimester are continued into the second trimester. Whether the good
      discriminatory power of PAPP-A can be realized in second trimester screening
      programmes will depend on developing two stage screening algorithms. This
      approach is unlikely to be better than the excellent detection rates achievable
      with free beta-hCG, PAPP-A and nuchal translucency in the first trimester.

PMID- 10590431
TI  - Risk of neural tube defects in the offspring of thalassaemia carriers in Hong
      Kong Chinese.
AB  - The risk of having an offspring with neural tube defect is negatively correlated
      with early pregnancy maternal folate levels. Thalassaemia carriers often have
      subnormal folate levels. We postulate that their offspring may be at increased
      risk of having neural tube defect. We retrospectively reviewed the records of
      1961 Chinese women referred to a tertiary centre for prenatal diagnosis between
      January 1997 and August 1998. Women with a mean corpuscular volume greater than
      80 fl were assumed not to be alpha-thalassaemia-1 or beta-thalassaemia
      heterozygotes. alpha- and beta-thalassaemia heterozygotes were diagnosed by
      haemoglobin studies. Of the 1961 women studied, pregnancy outcome was not
      available in 20 and thalassaemia screening was not available in 109 and these
      were excluded from the final analysis. Two-hundred-and-six women were alpha
      thalassaemia-1 heterozygotes, 102 women were beta-thalassaemia heterozygotes and
      one woman had HbE disease. Three alpha-thalassaemia carriers and one beta
      thalassaemia carrier had a pregnancy affected by anencephaly (odds=1:76). In the
      1523 non-carriers, five pregnancies were affected by spina bifida (odds=1:304).
      The odds ratio (95 per cent confidence interval) for neural tube defects in the
      alpha- and beta-thalassaemia carriers was 3.99 (1.07 to 14.94; p<0.05, Chi-square
      test). Because of the small number of affected pregnancies studied, the finding
      needs to be substantiated by a larger series. If the increased risk is genuine,
      women need to be screened for thalassaemia before conception and the thalassaemia
      carriers should be given periconceptional folate supplement to reduce the
      occurrence of neural tube defects.

PMID- 10590432
TI  - First-trimester transcervical chorionic villus sampling by biopsy forceps versus
      mid-trimester amniocentesis: a randomized controlled trial project.
AB  - Up to now, no data are available comparing amniocentesis and chorionic villus
      sampling (CVS) using biopsy forceps. A series of 1313 consecutive women referred
      to our unit before 12 weeks of pregnancy for fetal cytogenetic analysis because
      of advanced maternal age, were randomized into CVS with the use of transcervical
      biopsy forceps or mid-trimester amniocentesis. The diagnostic success rates of
      the two groups were 98 per cent and 100 per cent, and a second procedure was
      needed in 4.1 per cent (13/314) and in 0. 3 per cent (1/358), respectively.
      Follow-up was achieved in 98.7 per cent of the pregnancies. Postprocedure
      spontaneous fetal losses, until the first week after birth, in the 672
      pregnancies that completed the trial accounted for 2.2 per cent (7/314) in the
      CVS group and 2.8 per cent (10/358) in the amniocentesis group. Although the
      trial was prematurely discontinued, and therefore the sample size was smaller
      than initially planned, the results indicate that transcervical CVS was as safe
      as mid-trimester amniocentesis.

PMID- 10590434
TI  - Molecular cytogenetic analysis and clinical findings in a newborn with prenatally
      diagnosed rec(7)dup(7q)inv(7)(p22q31.3)pat.
AB  - We report prenatal and early postnatal findings in a newborn with a partial
      trisomy of chromosome 7 (7q31.3-qter), arising from meiotic recombination of a
      paternal pericentric inversion, inv(7)(p22q31.3). The inversion breakpoints were
      localized and the regions of duplication and deletion were defined by
      fluorescence in situ hybridization (FISH) analysis using a series of locus
      specific and subtelomeric probes. To our knowledge, only three cases involving a
      recombinant 7 with duplication of 7q have been reported, two of these being first
      cousins. The clinical findings in our patient included skeletal abnormalities,
      facial dysmorphism, dilated cerebral ventricles, microretrognathia and short
      neck. These findings and some aspects of the neonatal course were consistent with
      the phenotype previously reported for duplication of distal 7q, without
      associated monosomy for sequences from another chromosome.

PMID- 10590433
TI  - Analysis of a de novo complex chromosome rearrangement involving chromosomes 4,
      11, 12 and 13 and eight breakpoints by conventional cytogenetic, fluorescence in
      situ hybridization and spectral karyotyping.
AB  - A complex chromosome rearrangement (CCR) with eight breakpoints resulting in four
      derivative chromosomes (4, 11, 12 and 13) was detected prenatally in a male fetus
      of a twin pregnancy. The karyotype of the female second fetus was normal. The
      apparently balanced de novo CCR was identified by classical cytogenetic methods
      and fluorescence in situ hybridization (FISH). We compared these findings with
      results from spectral karyotyping (SKY).

PMID- 10590435
TI  - Fetal scalp cysts--dilemmas in diagnosis.
AB  - Detection of fetal scalp cysts may pose diagnostic challenges in terms of
      differentiating between structures whose origin is ectodermal, so presumed
      benign, and neuroectodermal, potentially having neurological significance. We
      describe the first case of a fetal scalp dermoid cyst to be detected antenatally
      and discuss the concept of sequested meningoceles which may not have neurological
      consequence but can be associated with other structural abnormalities.

PMID- 10590436
TI  - First prenatal diagnosis of defects in the HsPDX1 gene encoding protein X, an
      additional lipoyl-containing subunit of the human pyruvate dehydrogenase complex.
AB  - We have previously reported a genetic study of a neonatal lactic acidosis linked
      to a pyruvate dehydrogenase complex deficiency due to the absence of the protein
      X subunit. This rare autosomal recessive disorder is associated with specific
      deletions in this polypeptide which is encoded by the HsPDX1 gene, located on
      chromosome 11p1.3. The pathology of the patient was considered to arise from a
      large homozygous deletion (78del85) found at the 5' end of the HsPDX1 coding
      sequence. Her heterozygous mother underwent prenatal diagnosis during a
      subsequent pregnancy. Chorionic villus samples were used for three independent
      studies: (1) normal levels of the protein X component of the PDH complex were
      detected by immunoblotting; (2) RT-PCR analysis showed no deletion at the 5' end
      of the cDNA but the presence of a distinct heterozygous deletion (965del59) at
      its 3' end inherited from the father; (3) haplotype analysis revealed the
      presence of the father's mutated allele and the mother's normal allele. It was
      concluded that the fetus was heterozygous for this separate 3' deletion, so, it
      was likely to be not affected. This study permitted us to characterize more
      precisely the genetic abnormalities of the HsPDX1 cDNA occurring in each family's
      member.

PMID- 10590438
TI  - Molecular cytogenetic characterization of a prenatally detected supernumerary
      minute marker chromosome 8.
AB  - The characterization of a prenatally detected very small (approximately half of
      18p-(karyotype: 47,XX,+mar[16]/46,XX[7]) supernumerary marker chromosome (SMC)
      identified by GTG-banding analysis is described. The marker has been identified
      as derived from chromosome 8 centromeric material using a combination of
      different cytogenetic (GTG-, NOR-, CBG banding), molecular cytogenetic (24 colour
      fluorescent in situ hybridization [FISH], three-colour FISH using centromeric
      probes for all human chromosomes) and molecular genetic techniques
      (microsatellite analysis). This is the first case described with such a minute
      SMC derived from chromosome 8 diagnosed prenatally, the 15th case reporting on a
      SMC originating from chromosome 8 and the third such case without any severe
      clinical features.

PMID- 10590437
TI  - Two cases of prenatal analysis for the pathogenic T to G substitution at
      nucleotide 8993 in mitochondrial DNA.
AB  - We report the outcome of two prenatal analyses for the T to G mutation at
      nucleotide 8993 in the mitochondrial DNA. This mutation is associated with
      neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) and the
      neurodegenerative condition, Leigh syndrome. One prospective mother was the
      sister of a severely affected individual, and had previously had an unaffected
      child and a stillborn child. The second prospective mother had two unaffected
      children and two affected children. The mutation was not detected in the
      chorionic villus sample from one fetus nor in the amniocytes from the other
      fetus. Both pregnancies were continued, and the resulting children were healthy
      at two years and five years of age. Prenatal diagnosis of this mitochondrial DNA
      mutation is an option likely to be acceptable to some families to prevent the
      birth of a child at high risk for neurological disease.

PMID- 10590439
TI  - Prenatal diagnosis of bilateral ventriculomegaly and an enlarged cisterna magna
      in a fetus with partial trisomy 9 and partial trisomy 21.

PMID- 10590440
TI  - Trisomy 12 mosaicism in CVS culture confirmed in the fetus.

PMID- 10590441
TI  - Risk of cystic fibrosis with prenatally detected echogenic bowel.

PMID- 10590442
TI  - Down syndrome fetal loss rate in early pregnancy.

PMID- 10590443
TI  - Fetal loss in Down syndrome pregnancies.

PMID- 10590444
TI  - Twin studies of eating disorders: a review.
AB  - OBJECTIVE: Twin methodology has been used to delineate etiological factors in
      many medical disorders and behavioral traits including eating disorders. Although
      twin studies are powerful tools, their methodology can be arcane and their
      implications easily misinterpreted. METHOD: The goals of this study are to (a)
      review the theoretical rationale for twin studies; (b) provide a framework for
      their interpretation and evaluation; (c) review extant twin studies on eating
      disorders; and (d) explore the implications for understanding etiological issues
      in eating disorders. DISCUSSION: On the basis of this review, it is not possible
      to draw firm conclusions regarding the precise contribution of genetic and
      environmental factors to anorexia nervosa. Twin studies confirm that bulimia
      nervosa is familial and reveal significant contributions of additive genetic
      effects and of unique environmental factors in liability to bulimia nervosa. The
      magnitude of the contribution of shared environment is less clear, but in the
      studies with the greatest statistical power, it appears to be less prominent than
      additive genetic factors.

PMID- 10590446
TI  - Factors predictive of bone mineral density in eating-disordered women: a
      longitudinal study.
AB  - OBJECTIVE: Osteoporosis in eating-disordered women is well established, but
      factors predictive of this condition have proved elusive. The roles of behavioral
      factors, weight, menstrual status, and the degree of bone mineral density change
      over the clinical course of the eating disorder were investigated METHOD: A
      cohort of 56 eating-disordered women was subjected to bone mineral density
      measurement at Scan 1 and were followed up between 9 and 51 months later for
      repeat measurement (n = 10) at Scan 2. RESULTS: High levels of reduced bone
      mineral density were observed. Total duration of amenorrhea, body mass index,
      frequency of vomiting, and cigarette and alcohol consumption accounted for 40% of
      the variance in spinal bone mineral density measurement at Scan 1. No significant
      changes in bone mineral density were observed at Scan 2 despite increases in body
      mass index. DISCUSSION: The results suggest that increases in weight appear not
      to be sufficient to increase bone mineral density.

PMID- 10590445
TI  - Social adjustment over 10 years following diagnosis with bulimia nervosa.
AB  - OBJECTIVE: The authors sought to describe social adjustment among women diagnosed
      with bulimia nervosa more than a decade earlier. METHOD: A cohort of women who
      were diagnosed with bulimia nervosa between 1981 and 1987 were located and
      invited to participate in follow-up assessments. RESULTS: Although the current
      sample demonstrated considerable improvement in disordered eating behaviors and
      social adjustment, measures of social adjustment suggested continued impairment
      in interpersonal relationships and only a modest association with eating disorder
      outcome. DISCUSSION: Continued difficulties in social adjustment may reflect an
      underlying vulnerability from which disordered eating developed. Treatments for
      bulimia nervosa may benefit from including interpersonal skills training.

PMID- 10590447
TI  - State/trait distinctions in bulimic syndromes.
AB  - OBJECTIVE: This study compared 55 women with active bulimic symptoms, 18 in
      remission from a bulimic eating disorder, and 31 who showed no evidence of a past
      or present eating disorder, on selected personality and psychiatric features.
      METHOD: Discriminant function analyses were used to isolate dimensions that
      differentiated active patients from patients in remission, and controls (i.e.,
      that would logically constitute "state"-related disturbances), and then
      dimensions that differentiated clinical cases (whether active or in remission)
      from non-eating-disordered controls (i.e., that might reflect stable trait
      pathology associated with bulimic syndromes, whether active or not). RESULTS:
      Measures of depression, suicidality, and anxiety loaded significantly on the
      first function (differentiating active bingers from all other cases), whereas
      narcissism differentiated both clinical groups from non-eating-disordered
      controls. DISCUSSION: In light of theoretical and empirical evidence stressing
      the etiological role of narcissistic disturbances in bulimic syndromes, we
      interpret our findings as suggesting that narcissim may be a common trait
      characteristic (persisting even after remission of bulimic symptoms) in those who
      develop bulimic eating syndromes. Alternatively, depression, suicidality, and
      anxiety appear to be state-dependent features that resolve in many cases, along
      with remission of bulimic symptoms. We discuss various clinical and theoretical
      implications of our findings.

PMID- 10590448
TI  - Sleep-wake cycles in women with binge eating disorder.
AB  - OBJECTIVE: Binge eating disorder (BED) is a new diagnostic category in the 4th
      ed. of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). The
      majority of studies on sleep characteristics in overweight women have used
      nonbinging obese women. The aim of this study was to evaluate sleep
      characteristics in obese BED patients in comparison to non-BED obese (OB) and
      nonbinging normal weight (NW) women. METHOD: Eighteen females with BED, 13 OB,
      and 16 NW women were recruited. Sleep-wake patterns were monitored for 1 week
      using mini-actigraphs and self-report questionnaires. RESULTS: Their ambulatory
      sleep data revealed that BED and OB subjects had significantly lower sleep
      efficiency, had more wake during sleep, and had less zero activity than the NW
      group. The self-report questionnaires presented significantly more sleep
      disturbances in the BED and OB groups than in the NW group. DISCUSSION: The
      objective results support the subjective sleep disturbances reported by the two
      obese groups, the BED and the OB. A possible explanation for these findings could
      be weight-related physical discomfort or the existence of breathing disorders in
      sleep. Further research, for example, overnight polysomnography recordings and
      follow-up treatment, is required.

PMID- 10590449
TI  - Eating disorder symptoms in a cohort of 11 to 16-year-old black and white girls:
      the NHLBI growth and health study.
AB  - OBJECTIVE: This study sought to provide reference data for the Eating Disorder
      Inventory (EDI) with use of young adolescent black and white girls. Moreover, the
      study examined the relationship between race, age, socioeconomic status, and
      adiposity and each of the eight EDI scales. METHOD: To achieve these aims, data
      were used that had been collected in Years 3, 5, and 7 as part of the National
      Heart, Lung, and Blood Institute Growth and Health Study, a longitudinal cohort
      study of risk factors for obesity in black and white girls. For the present
      report, data were available from 2,228 girls in Year 3, 2,056 girls in Year 5,
      and 1,902 girls in Year 7. RESULTS: EDI scores were found to vary by race, age,
      socioeonomic status, and body weight of respondents. Black girls scored different
      from white girls on all EDI subscales. Scores on all but two subscales (Body
      Dissatisfaction, Drive for Thinness) decreased significantly with increasing age.
      Significant inverse associations were found between maximum parental education
      and all EDI subscales except Body Dissatisfaction and Perfectionism. Elevated
      body weight was associated significantly with Body Dissatisfaction, Drive for
      Thinness, Bulimia, Interoceptive Awareness, and Ineffectiveness. DISCUSSION: Our
      results illustrate the importance of taking into consideration the potentially
      confounding role of demographic characteristics and body weight when comparing
      different race or ethnic groups on the EDI.

PMID- 10590450
TI  - Not just a pretty face: physical attractiveness and perfectionism in the risk for
      eating disorders.
AB  - OBJECTIVE: Considerable research has examined the correlates and consequences of
      both objective and subjective ratings of physical attractiveness. Numerous
      studies have found, for example, that subjective physical attractiveness is
      inversely related to weight and diet concerns. Surprisingly, however, no research
      has examined the relationship between objective physical beauty and eating
      pathologies, despite clinical and theoretical reasons to expect a positive
      relationship between the two. METHOD: We rated 203 young women on facial
      attractiveness and obtained self-report measures of perfectionism, neuroticism,
      and weight preoccupation. RESULTS: Attractiveness was positively related to
      weight preoccupation after controlling for body size and neurotic perfectionism.
      DISCUSSION: These findings provide the first evidence of physical beauty as a
      risk for disordered eating, and confirm earlier evidence that the relationship
      between general perfectionism and disordered eating only occurs when combined
      with a tendency to be anxious and hypercritical. Results are discussed in the
      context of identity formation and the attractiveness stereotype.

PMID- 10590451
TI  - Body dissatisfaction and dieting in young children.
AB  - OBJECTIVE: To develop a broader understanding of young children's knowledge and
      beliefs about dieting and body dissatisfaction. METHOD: Sixty-two third through
      sixth-grade boys and girls completed audiotaped interviews and questionnaires
      regarding eating behavior, attitudes toward dieting, and body dissatisfaction.
      RESULTS: Fifty percent of all children wanted to weigh less and 16% reported
      attempting weight loss. Children were well informed about dieting and were most
      likely to believe that dieting meant changing food choices and exercising as
      opposed to restricting intake. Their primary source of information was the
      family. Seventy-seven percent of children mentioned hearing about dieting from a
      family member, usually a parent. DISCUSSION: Young children are knowledgeable
      about dieting and the concept of dieting does not necessarily mean caloric
      restriction to them. These data suggest that the family can play a powerful role
      in countering the development of eating concerns and body dissatisfaction in
      children.

PMID- 10590452
TI  - Effect of Western culture on women's attitudes to eating and perceptions of body
      shape.
AB  - OBJECTIVE: The current study investigated the effect of culture on two factors
      implicated in the development of eating disorders, negative attitudes toward
      eating and dissatisfaction with body shape. METHOD: Hong Kong-born and Australian
      born women from two Australian universities were surveyed using the Eating
      Attitudes Test (EAT) and the Figure Rating Scale (FRS). RESULTS: Results showed
      no difference between the groups in eating attitudes, but significant differences
      in body shape perceptions, with the Australian-born reporting greater
      dissatisfaction. Hong Kong-born subjects were separated into two groups based on
      their level of Chinese identity (Western acculturized and traditional). Their EAT
      and FRS scores were compared to the Australian-born, with Western acculturized
      Hong Kong-born subjects reporting significantly lower EAT and FRS scores than the
      Australian-born, whereas the more traditional Hong Kong-born subjects reported
      equivalent scores. DISCUSSION: Main implications center around the need for a
      cross-culturally sensitive definition of eating disorders, the effect of level of
      ethnic identity on eating attitudes and body image, and the importance of
      developing culturally appropriate measures.

PMID- 10590453
TI  - Body dissatisfaction, bulimia, and depression among women: the mediating role of
      drive for thinness.
AB  - OBJECTIVE: Past research has called into question the apparent relationship
      between body dissatisfaction and bulimia among women once effects of depression
      are statistically controlled. We further investigated interrelations among body
      dissatisfaction, depression, and bulimia, as well as considered individual
      differences in drive for thinness, within two samples of young adult women.
      METHOD: The first sample included women diagnosed with anorexia nervosa (n = 91)
      or bulimia nervosa (n = 142), whereas the second sample included college student
      women (N = 228). Respondents completed self-report measures of bulimia, drive for
      thinness, negative affect, and body dissatisfaction. RESULTS: At the univariate
      level, all of the above constructs were significantly related to body
      dissatisfaction. In multiple regression analyses using depression and bulimia as
      predictors of body dissatisfaction, both were uniquely related to body
      dissatisfaction. These findings were similar to the results of previous research.
      However, when drive for thinness was added to the regression equations, drive for
      thinness was a unique predictor of body dissatisfaction whereas bulimia was not
      (neither was depression among college women). DISCUSSION: Bulimia, depression,
      and body dissatisfaction may be the results of incorporation of cultural
      standards regarding thinness, hence the apparent relationships among these
      variables. The role of drive for thinness in the pathogenesis of depression and
      body dissatisfaction among women needs to be investigated further.

PMID- 10590454
TI  - Relationship between self-soothing, aloneness, and evocative memory in bulimia
      nervosa.
AB  - OBJECTIVE: The relationship between characteristics of self-soothing ability, the
      capacity for evocative memory, and aloneness was investigated in a clinical
      sample of 50 bulimia nervosa (BN) patients. METHOD: Individuals meeting DSM-III-R
      criteria for BN who participated in a randomized trial of guided imagery
      completed measures of Soothing Receptivity and a modified version of the UCLA
      Loneliness scale, resulting in the Aloneness/Evocative Memory Scale. RESULTS: A
      lower level of soothing receptivity (indicating a decreased capacity for self
      soothing) was correlated with a decreased capacity for evocative memory. A lower
      level of soothing receptivity and decreased capacity for evocative memory were
      associated with a greater experience of aloneness. DISCUSSION: Results suggest
      the need for a more comprehensive understanding of the role of affect regulation
      and the experience of aloneness in BN and the need to develop treatments to
      specifically address these features of the illness.

PMID- 10590455
TI  - Health-related quality of life among obese persons seeking and not currently
      seeking treatment.
AB  - OBJECTIVE: To compare sociodemographic characteristics and health-related quality
      of life (HRQL) between groups of obese persons who sought and did not seek
      university-based treatment for overweight. METHOD: Three-hundred twelve
      consecutive obese persons sought outpatient university-based weight management
      treatment. The sample of obese persons (N = 89) who indicated that they were not
      currently trying to lose weight was derived from a larger convenience sample (N =
      232) of persons surveyed in a hospital setting. Both groups completed
      sociodemographic and brief medical history questionnaires and the HRQL as
      measured by the Medical Outcomes Study Short-Form-36 Health Survey (SF-36).
      RESULTS: Obese persons who had sought treatment tended to be heavier, older,
      Caucasian, married, in white collar employment, and reported a higher prevalence
      of diabetes, hypertension, and pain. In multivariate analyses, both adjusted and
      unadjusted for these differences, obese persons who had sought treatment were
      significantly more impaired on the bodily pain, general health, and vitality HRQL
      domains than those who were not trying to lose weight. DISCUSSION: Although
      differences on sociodemographic and medical variables between the two groups may
      attenuate the obesity-HRQL relationship somewhat, obesity appears to have a
      pronounced impact on important dimensions of HRQL independent of whether or not
      the person is attempting to lose weight

PMID- 10590456
TI  - Cynical hostility, depression, and obesity: the moderating role of education and
      gender.
AB  - OBJECTIVE: We examined how education and gender moderate the association of
      obesity with cynical hostility and depression. METHOD: Body mass index (BMI),
      waist-to-hip ratio (WHR), years of education, cynical hostility (CynDis),
      depression (Beck Depression Inventory) were examined in a cross-sectional study
      of 1,547 men and 1,814 women, aged 25-64. RESULTS: Education moderates the
      positive association between cynical distrust and obesity among women in a such
      way that cynical distrust was not related to BMI or WHR among highly educated
      women. Depression had a positive association with WHR after age and education
      among both genders and among women with BMI. Bivariate associations between
      psychological factors and obesity measures were similar among men and women.
      DISCUSSION: The results suggest the importance of examining socioeconomic status
      (SES) together with psychological factors related to obesity.

PMID- 10590457
TI  - Family functioning and psychosocial adjustment in overweight youngsters.
AB  - OBJECTIVE: To analyze the relationship between family functioning and
      psychosocial adjustment in Dutch overweight children and adolescents. METHOD:
      Seventy-three overweight (weight-for-height >P90) and 70 normal-weight youngsters
      between the ages of 10 and 16 years were recruited by school physicians during
      routine medical screening. The Family Dimension Scale, the Child Behavior
      Checklist, the Teacher Report Form, the Self-Perceived Competence Scale, and the
      Body-Esteem Scale were filled out, as well as a specific weight-related
      questionnaire. RESULTS: Both parents and teachers report more behavior problems
      in overweight children, particularly in the younger than 13 age group. Lower body
      esteem was found in older overweight girls, whereas in older overweight boys
      higher levels of body-esteem were found. More significant relationships were
      found with the weight-related Parental Concern Scale than with the Family
      Dimension Scale. DISCUSSION: The results suggest that a developmental
      psychological approach reveals important age and sex differences. Weight-related
      instruments may be more useful than general questionnaires.

PMID- 10590458
TI  - A case report: treatment of severe anorexia nervosa with home total parenteral
      hyperalimentation.
AB  - In its chronic and severe phase, anorexia nervosa (AN) carries a high morbidity
      and mortality rate. In the severe stage, parenteral alimentation is often
      required. To date, the optimal regime for parenteral refeeding has not been well
      documented. Most, if not all, such treatment is performed on an inpatient basis.
      METHOD: We report here a case of an AN patient treated at home with total
      parenteral hyperalimentation which is, to the best of our knowledge, the first to
      be carried out in Israel. RESULTS: The patient has regained 10 kg during
      treatment, and has maintained her weight a year after treatment. Her
      gastrointestinal symptoms improved, and she has reduced the amount of laxatives
      she ingests. DISCUSSION: In this paper we will discuss the various issues and
      criteria applicable to this treatment, as well as the importance of collaboration
      between a primary care and specialized clinic.

PMID- 10590459
TI  - Anorexia nervosa and celiac disease: two case reports.
AB  - OBJECTIVE: Anorexia nervosa (AN) has been reported to be associated with several
      chronic medical illnesses. In this study, we report two cases of women suffering
      from AN and celiac disease. The former received the diagnosis of celiac disease
      before the onset of the eating disorder. For the latter, the diagnosis of celiac
      disease followed that of AN. Authors discuss the complex relationships between
      celiac disease and AN. They suggest that in the first case the dietary
      restriction could act as a trigger for the eating disorder, whereas in the second
      case, the onset of celiac disease could have exacerbated the clinical symptoms of
      AN.

PMID- 10590460
TI  - Transcription of some PHO genes in Saccharomyces cerevisiae is regulated by
      spt7p.
AB  - Spt7p is a new global transcription factor in Saccharomyces cerevisiae(Gansheroff
      et al., 1995). We report here that the activities of high affinity phosphate
      transport and acid phosphatase in particular were decreased in a spt7 null
      mutant. Northern blot experiments revealed that transcription of the PHO84 and
      PHO5 genes was impaired in this mutant; expression of the PHO regulatory genes,
      PHO4 and PHO2, was normal. Spt7p is thus linked with expression of several
      structural genes of the PHO regulon in yeast.

PMID- 10590462
TI  - Selection of genes repressed by cAMP that are induced by nutritional limitation
      in Saccharomyces cerevisiae.
AB  - DNA-lacZ fusion libraries of yeast Saccharomyces cerevisiae were used to select
      genes coordinately regulated by the Ras-cAMP-cAPK signalling pathway. Sixteen new
      genes (AGP1, APE2, APE3, FPS1, GUT2, MDH2, PLB2, PYK2, RNR3, SUR1, UGA1, YHR033w,
      YBR006w, YHR143w, YMR086w and YOR173w) were found to be repressed by cAMP. Most
      of these genes encode for metabolic enzymes and are induced by nutritional
      limitations. These common properties suggest a role of this pathway in the
      metabolic adjustment of the cell to nutritional variations. The induction of 10
      of these genes is reduced in the msn2,msn4 double mutant, which emphasizes the
      role of the Msn2/4p transcriptional activators in mediating the Ras-cAMP-cAPK
      signalling pathway. The Msn2p/Msn4p-independent expression of the six other genes
      suggests the existence of other regulatory systems under the control of this
      pathway.

PMID- 10590461
TI  - RGD1 genetically interacts with MID2 and SLG1, encoding two putative sensors for
      cell integrity signalling in Saccharomyces cerevisiae.
AB  - The RGD1 gene was identified during systematic genome sequencing of Saccharomyces
      cerevisiae. To further understand Rgd1p function, we set up a synthetic lethal
      screen for genes interacting with RGD1. Study of one lethal mutant made it
      possible to identify the SLG1 and MID2 genes. The gene SLG1/HCS77/WSC1 was
      mutated in the original synthetic lethal strain, whereas MID2/SMS1 acted as a
      monocopy suppressor. The SLG1 gene has been described to be an upstream component
      in the yeast PKC pathway and encodes a putative cell surface sensor for the
      activation of cell integrity signalling. First identified by viability loss of
      shmoos after pheromone exposure, and since found in different genetic screens,
      MID2 was recently reported as also encoding an upstream activator of the PKC
      pathway. The RGD1 gene showed genetic interactions with both sensors of cell
      integrity pathway. The rgd1 slg1 synthetic lethality was rescued by osmotic
      stabilization, as expected for mutants altered in cell wall integrity. The slight
      viability defect of rgd1 in minimal medium, which was exacerbated by mid2, was
      not osmoremediated. As for mutants altered in PKC pathway, the accumulation of
      small-budded dead cells in slg1, rgd1 and mid2 after heat shock was prevented by
      1 M sorbitol. In addition, the rgd1 strain also displayed dead shmoos after
      pheromone treatment, like mid2. Taken together, the present results indicate
      close functional links between RGD1, MID2 and SLG1 and suggest that RGD1 and MID2
      interact in a cell integrity signalling functionally linked to the PKC pathway.

PMID- 10590463
TI  - Facilitating functional analysis of the Saccharomyces cerevisiae genome using an
      EGFP-based promoter library and flow cytometry.
AB  - A promoter library was generated to facilitate identification of differentially
      regulated promoters in Saccharomyces cerevisiae. The library was constructed in a
      vector containing two reporter genes (EGFP and lacZ) divergently arranged about a
      unique cloning site. Approximately 2x10(5) clones were obtained and a flow
      cytometer was used to screen the library for copper-induced EGFP expression. A
      DNA fragment conferring copper-inducible expression of EGFP was rapidly
      identified. This DNA fragment, which contained several motifs associated with
      copper and oxidative stress homeostasis, lies upstream of two 'orphan' genes of
      unknown function. Further studies comparing expression from episomal vs.
      integrative vectors showed that construction of a similar library using an
      integrative vector would further enhance rapid identification of genes that are
      differentially regulated in S. cerevisiae. The ability to identify regulated
      promoters rapidly should facilitate the functional analysis of the yeast genome
      by identifying genes induced by specific physiological conditions.

PMID- 10590464
TI  - New tools for protein linkage mapping and general two-hybrid screening.
AB  - The two-hybrid system has proved to be a facile method for detecting and
      analyzing protein-protein interactions. An expanded application of this system,
      protein linkage mapping, provides a means of identifying interactions on a global
      scale and should prove a powerful tool in analyzing whole genomes as their
      sequences become available. To overcome some of the inherent difficulties in such
      a large-scale approach, we have constructed a set of new strains and vectors that
      will allow for more efficient screening. The strains contain a GAL1-URA3 reporter
      for positive and negative selection, as well as a UAS(G)-lacZ reporter. The
      strains are of opposite mating types, permitting libraries present in one strain
      to be easily screened against a second library in the companion strain. We also
      constructed a family of CEN-based vectors for expression of both Gal4 DNA-binding
      and activation domain fusions. These plasmids include a hemagglutinin epitope tag
      and different polylinkers to increase the ease of subcloning. CEN-based vectors
      are maintained at 1-2 copies per cell, limiting the number of individual cells
      containing multiple plasmids that can confuse further analyses, and ensuring that
      fusions are not expressed at toxic levels. Using these vectors, both homo- and
      heterodimeric interactions resulted in up to 10-fold higher reporter gene
      transcription than obtained with 2micro;-based plasmids, despite significantly
      lower protein levels. In addition to protein linkage mapping, these reagents
      should be generally useful in standard two-hybrid applications.

PMID- 10590465
TI  - The trp1- delta FA designer deletion for PCR-based gene functional analysis in
      Saccharomyces cerevisiae.
AB  - PCR-based gene deletion and modification are now common techniques for rapid gene
      manipulation in the yeast Saccharomyces cerevisiae. The techniques work best when
      the host strain lacks sequence homology to the PCR-amplified selectable markers.
      One of the most versatile sets of PCR deletion/modification vectors is the pFA
      system described by Longtine et al.(1998), which is based on both heterologous
      (kanMX6 and HIS3MX6) and homologous (TRP1) markers. Here we describe the trp1
      DeltaFA designer deletion allele that removes precisely from the genome TRP1
      sequences carried in the pFA vectors. The trp1-DeltaFA allele can be introduced
      easily into TRP1 and most trp1 starting strains, and its use increases the
      frequency of correct integrants when using the pFA system's TRP1-based
      constructs. Unlike trp1-Delta1, trp1-DeltaFA does not remove neighbouring GAL3
      upstream activating sequences and therefore does not interfere with GAL gene
      induction.

PMID- 10590466
TI  - Systematic analysis of S. cerevisiae chromosome VIII genes.
AB  - To begin genome-wide functional analysis, we analysed the consequences of
      deleting each of the 265 genes of chromosome VIII of Saccharomyces cerevisiae.
      For 33% of the deletion strains a growth phenotype could be detected: 18% of the
      genes are essential for growth on complete glucose medium, and 15% grow
      significantly more slowly than the wild-type strain or exhibit a conditional
      phenotype when incubated under one of 20 different growth conditions. Two-thirds
      of the mutants that exhibit conditional phenotypes are pleiotropic; about one
      third of the mutants exhibit only one phenotype. We also measured the level of
      expression directed by the promoter of each gene. About half of the promoters
      direct detectable transcription in rich glucose medium, and most of these
      exhibited only low or medium activity. Only 1% of the genes are expressed at
      about the same level as ACT1. The number of active promoters increased to 76%
      upon growth on a non-fermentable carbon source, and to 93% in minimal glucose
      medium. The majority of promoters fluctuated in strength, depending on the
      medium.

PMID- 10590467
TI  - Isolation and characterization of MELt gene from Torulaspora delbrueckii IFO
      1255.
AB  - Torulaspora delbrueckii IFO 1255 is a melibiose-fermenting strain in Torulaspora
      species. From the genome of strain IFO 1255, we obtained a 770 bp fragment by PCR
      with oligonucleotides synthesized based on the MEL genes of Saccharomyces
      cerevisiae and its related species. The region encompassing the 770 bp fragment
      was cloned by inverse PCR and sequenced. The nucleotide sequence revealed an open
      reading frame of 1422 bp encoding a 474 amino acid protein with a molecular
      weight of 52 360. The similarity of the presumed mature protein to Saccharomyces
      species and Zygosaccharomyces cidri alpha-galactosidases was 69.7-73.2% and
      58.4%, respectively. The phylogenetic relationship between these species is
      discussed. The sequence is deposited in the DDBJ/EMBL/GenBank database under
      Accession No. AB027130.

PMID- 10590468
TI  - Carrots and sticks--the fall and fall of private health insurance in Australia.

PMID- 10590469
TI  - Parental use of alcohol and children's behavioural health: a household production
      analysis.
AB  - This study uses the 1988 National Health Interview Survey (NHIS) data to examine
      the effects of both heavy and problem drinking as well as moderate or light
      parental alcohol use on children's behaviour problems. The analysis is formulated
      within Becker's household production function framework. The production of child
      behavioural health is estimated using items from the Behavior Problems Index, a
      battery of 32 questions about behaviour problems which is derived from the Child
      Behavior Checklist (CBCL), a widely-used parent report instrument. Measures of
      parents' alcohol consumption are constructed from the NHIS Alcohol Supplement
      that was administered to one randomly selected adult in each household in 1988.
      Ordinary least squares (OLS) and two-stage least squares (TSLS) results are
      presented. The results provide consistent evidence that parental alcohol use is
      an input with negative marginal product in the production of child behavioural
      health, regardless of which parent drinks. The magnitude of the effect is
      generally larger in the TSLS specification. There is also strong evidence of
      relationships between some family structure variables and child behavioural
      health and between parental physical health and child behavioural health.

PMID- 10590470
TI  - The role of a pre-scored multi-attribute health classification measure in
      validating condition-specific health state descriptions.
AB  - It is common to find specially constructed condition-specific health state
      descriptions used as the basis for benefit assessment in cost-utility analysis.
      For this approach to be valid it is necessary to have valid descriptors of health
      states. Yet the evidence demonstrating descriptive validity has been neglected in
      economic evaluation. This paper reports on the validity, reliability and
      feasibility of obtaining values from specially constructed condition-specific
      descriptions of breast cancer screening by mapping these descriptions into a pre
      scored multi-attribute health classification measure (the EuroQol instrument) and
      comparing the values obtained with those derived from a time trade-off exercise.
      In doing so, it highlights the importance of descriptive validity in explaining
      why different valuation methods produce different results. Four descriptions
      typically associated with ex post true negative, false positive, true positive
      and false negative breast screening results were considered.

PMID- 10590471
TI  - Health state after treatment: a reason for discrimination?
AB  - In this paper the issue of discrimination between patients based on the health
      improvement that each can achieve is addressed. Previous research in this area by
      Nord has shown that, in this context, society's preferences may be quite opposite
      to the principle of health maximization present in cost utility analysis. Using a
      different experimental design from that used by Nord, some results are achieved
      which suggest that social preferences may be somewhere in between two opposite
      extremes, which are that discrimination based on the degree of health improvement
      is never acceptable and that discrimination based on the degree of health
      improvement is always acceptable.

PMID- 10590472
TI  - Long-term contracts in the NHS: a solution in search of a problem?
AB  - Purchasers and providers in the National Health Service (NHS) are now required to
      move from annual contracting cycles to longer-term contracts. The benefits are
      expected to include more efficient investment and improved sharing of financial
      risk. This paper argues that the economic analysis of longer-term contracts has
      assumed implicitly that agents operate in the private sector. Once the
      constraints of the public sector are introduced, the apparent economic benefits
      of longer-term contracts become doubtful. The paper explores these issues using
      evidence collected from analysis of the contracts of a sample of Health
      Authorities and from semi-structured interviews with individuals involved in the
      contracting process. We conclude that with the property rights and financial
      structure of the public sector, the move from short- to long-term contracts is
      unlikely to produce the improvements in performance expected by the government.

PMID- 10590473
TI  - Demand inducement as cheap talk.
AB  - The doctor-patient interaction is analysed in a game of cheap talk. Causes and
      consequences of imperfect agency are examined. One form of imperfect agency,
      supplier-induced demand, is a feature of neologism proof equilibria with some
      parameter values but not with others. The model is used to evaluate two tests
      that have been used to test for the existence of supplier-induced demand. The
      analysis suggests that the two tests, which compare the medical utilization of
      informed and uninformed consumers, are not valid.

PMID- 10590474
TI  - Early development of the myotome in the mouse.
AB  - The structure and development of the myotome has been extensively studied in
      birds and amphibians but few studies have systematically addressed its
      development in mammals. We have used a transgenic mouse carrying an nLacZ marker
      coupled to a myosin light chain 3F promoter to describe the structure of the
      developing mammalian myotome. Through studies of transgene expression pattern,
      coupled with immunohistochemistry for the muscle structural proteins desmin and
      slow myosin heavy chain we describe a gradient of maturity for the cells within
      the developing myotome. Our results show that the earliest myocytes of the
      mammalian myotome span the rostrocaudal extent of the somite and have single
      large nuclei which localise centrally within the myotome. Throughout the period
      of study the myotome is more mature ventrally than dorsally and cells comprising
      the medial aspect of the myotome are younger than those lying laterally.
      Immunohistochemistry for the earliest expressed muscle regulatory factor (myf-5)
      is used to define areas of the myotome contributing new myogenic cells. In the
      early myotome small, round, myf-5-expressing cells are found extensively within
      the dorsomedial aspect of the dermamyotome and also within the entire rostral and
      caudal dermamyotomal lips. They subsequently appear within the central zone of
      the myotome, adjacent to the medially curled rostral and caudal dermamyotomal
      lips, and there begin to elongate symmetrically. As the myotome enlarges, myf-5
      expression is always restricted to the most medial aspect of the myotome,
      adjacent to the least mature myocytes, marking the site of addition of new
      myogenic cells. Together, these results allow development of a model of mammalian
      myotome formation where growth occurs medially by addition of new cells from both
      rostral and caudal dermamyotome lips, while more mature myocytes are displaced
      laterally. Furthermore, early myotomal myocytes differentiate in the absence of
      MyoD expression, unlike later myotomal myocytes. This, along with their distinct
      morphology, suggests these cells may form a separate lineage of pioneer myogenic
      cells.

PMID- 10590476
TI  - Patterns of repair of dystrophic mouse muscle: studies on isolated fibers.
AB  - Repair of damaged skeletal muscle fibers by muscle precursor cells (MPC) is
      central to the regeneration that occurs after injury or disease of muscle and is
      vital to the success of myoblast transplantation to treat inherited myopathies.
      However, we lack a detailed knowledge of the mechanisms of this muscle repair.
      Here, we have used a novel combination of techniques to study this process,
      marking MPC with nuclear-localizing LacZ and tracing their contribution to
      regeneration of muscle fibers after grafting into preirradiated muscle of the mdx
      nu/nu mouse. In this model system, there is muscle degeneration, but little or no
      regeneration from endogenous MPC. Incorporation of donor MPC into injected
      muscles was analyzed by preparing single viable muscle fibers at various times
      after cell implantation. Fibers were either stained immediately for beta-gal, or
      cultured to allow their associated satellite cells to migrate from the fiber and
      then stained for beta-gal. Marked myonuclei were located in discrete segments of
      host muscle fibers and were not incorporated preferentially at the ends of the
      fibers. All branches on host fibers were also found to be composed of myonuclei
      carrying the beta-gal marker. There was no significant movement of donor
      myonuclei within myofibers for up to 7 weeks after MPC implantation. Although
      donor-derived dystrophin was usually located coincidentally with donor myonuclei,
      in some fibers, the dystrophin protein had spread further along the mosaic
      myofibers than had the myonuclei of donor origin. In addition to repairing
      segments of the host fiber, the implanted MPC also gave rise to satellite cells,
      which may contribute to future muscle repair.

PMID- 10590475
TI  - Spatio-temporal distribution of chondromodulin-I mRNA in the chicken embryo:
      expression during cartilage development and formation of the heart and eye.
AB  - To define genes specifically expressed in cartilage and during chondrogenesis, we
      compared by differential display-polymerase chain reaction (DD-PCR) the mRNA
      populations of differentiated sternal chondrocytes from chicken embryos with mRNA
      species modulated in vitro by retinoic acid (RA). Chondrocyte-specific gene
      expression is downregulated by RA, and PCR-amplified cDNAs from both untreated
      and RA-modulated cells were differentially displayed. Amplification products only
      from RNA of untreated chondrocytes were further analyzed, and a cDNA-fragment of
      the chondromodulin-I (ChM-I) mRNA was isolated. After obtaining full length cDNA
      clones, we have analyzed the mRNA expression patterns at different developmental
      stages by RNase protection assay and in situ hybridization. Analysis of different
      tissues and cartilage from 17-day-old chicken embryos showed ChM-I mRNA only in
      chondrocytes. During somitogenesis of the chicken embryo, ChM-I transcripts were
      detected in the notochord, the floor and the roof plate of the neural tube, and
      in cartilage precursor tissues such as the sclerotomes of the somites, the
      developing limbs, the pharyngeal arches, the otic vesicle, and the sclera. ChM-I
      continued to be expressed in differentiated cartilages derived from these tissues
      and also in noncartilaginous domains of the developing heart and retina. Thus, in
      the chicken, the expression of ChM-I is not restricted to mature cartilage but is
      already present during early development in precartilaginous tissues as well as
      in heart and eye.

PMID- 10590478
TI  - Toxin injury-dependent switched expression between EF-1 alpha and its sister, S1,
      in rat skeletal muscle.
AB  - Elongation factor-1 alpha, (EF-1 alpha), a translation factor involved in peptide
      chain elongation, is found ubiquitously in all cells. Previously, we identified a
      highly homologous EF-1 alpha sister gene, S1, whose transcript is found in only
      three tissues: brain, heart, and muscle, where the tissue-specific expression of
      S1 is caused by its exclusive presence in cells such as neurons and myocytes.
      Using sequence-specific synthetic peptides, we have recently produced polyclonal
      antibodies that can distinguish the protein product of EF-1 alpha from that of
      its sister, S1. Results of Western blotting show that these two proteins appear
      in S1-positive muscle tissue in inverse relationship, i.e., when S1 protein is in
      abundance, EF-1 alpha protein is in contrast in low quantity, and vice versa.
      During early embryonic stages, EF-1 alpha is the predominant protein species,
      whereas S1 is hardly detectable. This high EF-1 alpha versus low S1 protein
      presence undergoes a switch in that by postnatal day 14, EF-1 alpha is scarce
      whereas S1 is abundant; thus, there is a development-dependent shift of EF-1
      alpha/S1 ratio from high to low, and the low EF-1 alpha/S1 ratio is maintained in
      adulthood. In this report, we describe the reversal of the EF-1 alpha/S1 ratio
      from low to high during muscle injury (experimentally induced by Marcaine
      injection), and a return to the original low ratio once the injury is repaired by
      regeneration. In this injury condition, EF-1 alpha is rapidly upregulated
      immediately after the Marcaine treatment, possibly reflecting an injury-dependent
      response of regeneration. The increase of EF-1 alpha corresponds with a decrease
      of S1 protein presence, thus resulting in a change of EF-1 alpha/S1 ratio from
      low to high. However, the high EF-1 alpha/S1 ratio eventually reverts to low,
      when regeneration-associated proliferation ceases, and fully differentiated
      myotubes are reestablished in the injured cells. This result shows that: (1) a
      high EF-1 alpha/S1 ratio is an early molecular diagnostic marker for injury
      elicited regeneration; and (2) when injury repair is accomplished, there is a
      reversion to the low EF-1 alpha/S1 ratio, reflecting the restoration of the
      muscle fiber to the preinjury functional status. Results presented here not only
      show that a high EF-1 alpha/S1 ratio is a molecular marker for injured muscle,
      but also reveal the underpinning translational regulation in muscle during
      injury.

PMID- 10590477
TI  - Psx homeobox gene is X-linked and specifically expressed in trophoblast cells of
      mouse placenta.
AB  - We previously isolated a cDNA clone for a homeobox-containing gene with its
      expression restricted to the extraembryonic tissues. In this study, Psx gene
      expression was further examined using in situ hybridization to determine the
      cellular distribution of Psx transcripts during embryo development. Psx
      expression was first detected at embryonic day 8.5 only in trophoblast giant
      cells and chorionic ectoderm. At E 9.5 and E 13.5, the expression was restricted
      to the giant cells and the labyrinthine trophoblast layer. In addition, the gene
      expression was detected in differentiated Rcho-1 trophoblast cells in vitro,
      which is typical of trophoblast giant cells in vivo, but not in proliferating
      Rcho-1 cells and HRP-1 cells. Interestingly, rat Psx homologue mRNA is about 200
      bp shorter than mouse Psx, suggesting that there is a high degree of sequence
      divergence between the mouse and rat Psx homologues. The sequence divergence,
      perhaps as a result of rapid evolution, is further supported by the zoo blot
      analysis because the Psx gene was detectable only in mouse and rat but not in
      other vertebrate species tested. Psx is localized to the murine X chromosome.
      Taken together, our results suggest that Psx gene plays a unique role in the
      function of differentiated trophoblast cells and also serves as a useful model
      for studying trophoblast cell lineages and the rapid evolution of homeobox genes.

PMID- 10590479
TI  - Role of N-cadherin in the sorting-out of mesenchymal cells and in the positional
      identity along the proximodistal axis of the chick limb bud.
AB  - Mesenchymal cells from different stages of chick limb buds sort out in monolayer
      culture, suggesting the presence of different cell affinities dependent on their
      positions along the proximodistal axis. However, it is still not clear which
      molecules are responsible for the sorting-out. Here, we propose that N-cadherin,
      a cell-adhesion molecule, is involved in the sorting-out and is likely to be a
      component of the mechanism of proximodistal patterning in the developing limb. N
      cadherin proteins accumulate in the distal region of the chick limb bud as limb
      development proceeds. In monolayer culture of distal mesenchymal cells, the stage
      dependent levels of N-cadherin proteins are maintained during cell sorting. The
      results of this study have also demonstrated that an anti-N-cadherin monoclonal
      antibody, NCD-2, clearly inhibits the cell sorting. Moreover, removal of the
      apical ectodermal ridge or retinoic-acid treatment of distal cells, which results
      in a change in the pattern of sorting-out, inhibits the accumulation of N
      cadherin proteins, suggesting that the distribution of these proteins is related
      to the positional identity that gives rise to the different shape and number of
      cartilage elements along the proximodistal axis.

PMID- 10590480
TI  - Smad1 and Smad5 have distinct roles during dorsoventral patterning of the
      zebrafish embryo.
AB  - Smad1 and smad5 encode transcription factors that have been implicated in the
      transduction of signaling by the bone morphogenetic proteins Bmp2 and/or Bmp4.
      Here we report the characterization of Smad1 and Smad5 from the zebrafish, Danio
      rerio. Although smad1, smad5, bmp2b, and bmp4 are all expressed during
      gastrulation and although all four proteins have ventralizing activities, they
      appear to play distinct roles during dorsoventral pattern formation. smad1
      expression starts shortly before the onset of gastrulation. It is expressed on
      the ventral side of the embryo, whereas smad5 transcripts are both maternally and
      zygotically provided and ubiquitously distributed. Injection studies and mutant
      analyses suggest that the ventral smad1 expression is positively regulated by
      Bmp2b, but not by Bmp4 signaling, whereas smad5 expression is independent of
      Bmp2b. Also, the dorsalized phenotype of bmp2b-mutant embryos can be rescued by
      exogenous Smad1, but not by Smad5. Together, these data suggest that smad1 acts
      later than smad5 and is itself a transcriptional target of Smad5-mediated Bmp2b
      signaling. During later stages of development, smad1 is expressed in eyes, dorsal
      cells of rhombomeres 1, 3, and 5, and somites, with highest mRNA levels in the
      presumptive sclerotome and adaxial regions near the notochord. Injection
      experiments indicate that this somitic smad1 expression is positively regulated
      by hedgehog signaling from the dorsal midline, thus perhaps accounting for the
      recently reported sonic hedgehog-induced competence of sclerotomal cells to
      Bmp2/4 signals.

PMID- 10590482
TI  - Interventional electrophysiology at the millenium

PMID- 10590481
TI  - Nerve growth factor (NGF) supports tooth morphogenesis in mouse first branchial
      arch explants.
AB  - Posterior midbrain and anterior hindbrain neuroectoderm trans-differentiate into
      cranial neural crest cells (CNCC), emigrate from the neural folds, and become
      crest-derived ectomesenchyme within the mandibular and maxillary processes. To
      investigate the growth factor requirement specific for the initiation of tooth
      morphogenesis, we designed studies to test whether nerve growth factor (NGF) can
      support odontogenesis in a first branchial arch (FBA) explant culture system. FBA
      explants containing neural-fold tissues before CNCC emigration and the anlagen of
      the FBA were microdissected from embryonic day 8 (E8) mouse embryos, and cultured
      for 8 days in medium supplemented with 10% fetal calf serum only, or serum
      containing medium further supplemented with either NGF or epidermal growth factor
      (EGF) at three different concentrations: 50, 100, or 200 ng/ml. Morphological,
      morphometric, and total protein analyses indicated that growth and development in
      all groups were comparable. Meckel's cartilage and tongue formation were also
      observed in all groups. However, odontogenesis was only detected in explants
      cultured in the presence of exogenous NGF. NGF-supplemented cultures were
      permissive for bud stage (50 ng/ml) as well as cap stage of tooth morphogenesis
      (100 and 200 ng/ml). Morphometric analyses of the volume of tooth organs showed a
      significant dose-dependent increase in tooth volume as the concentration of NGF
      increased. Whole-mount in situ hybridization and semiquantitative reverse
      transcription-polymerase chain reaction for Pax9, a molecular marker of dental
      mesenchyme, further supported and confirmed the morphological data of the
      specificity and dose dependency of NGF on odontogenesis. We conclude that (1) E8
      FBA explants contain premigratory CNCC that are capable of emigration,
      proliferation, and differentiation in vitro; (2) serum-supplemented medium is
      permissive for CNCC differentiation into tongue myoblasts and chondrocytes in FBA
      explants; and (3) NGF controls CNCC cell fate specification and differentiation
      into tooth organs.

PMID- 10590484
TI  - Changing concepts of electrophysiology testing for ventricular arrhythmias.

PMID- 10590485
TI  - Catheter mapping of spontaneous and induced atrial fibrillation in man.
AB  - The clinical electrophysiologic study of atrial fibrillation [AF] has recently
      progressed from static characterization of the substrate to the dynamic
      investigation of both induced and spontaneous AF in man. Prior studies have
      demonstrated inhomogeneity and greater dispersion of atrial refractoriness in
      patients with AF, but recently atrial electrical remodeling with consequent
      abbreviation of atrial refractory periods has also been reported. Yet further
      experimental observations have suggested the existence of additional
      arrhythmogenic mechanisms for certain AF subsets. These include studies that have
      demonstrated a stable atrial flutter circuit in one atrium with fibrillatory
      conduction or a focal atrial tachyarrhythmia arising commonly in the left atrium.
      Efforts at catheter mapping of AF are now in progress. New mapping techniques and
      novel devices are currently being employed. We have performed catheter mapping
      simultaneously in right and left atrial sites at onset and during sustained
      pacing-induced and spontaneous AF in patients with ischemic and/or hypertensive
      heart disease. Atrial premature complexes that initiated spontaneous AF typically
      had coupling intervals ranging from 260 to 400 ms and most frequently arose in
      the crista terminalis, right atrioventricular junction or superior left atrium.
      AF at onset showed discrete electrograms at virtually all right and left atrial
      regions mapped and the region of earliest atrial activation during AF was in
      close proximity to the premature complexes in over 90% of patients. The regional
      atrial activation sequence for the first 10 AF beats demonstrated stable or
      unstable patterns in individual patients. In contrast to spontaneous AF, the
      initial arrhythmia of induced AF was seen to have a significantly different site
      of earliest atrial activation but similar discrete electrograms in different
      atrial regions. However, as with spontaneous AF, the site of extrastimulus
      delivery was in close proximity to the first induced beat. We conclude that
      regional catheter mapping of AF is feasible and safe in man and organized
      electrical activity is frequently observed at AF onset in patients with heart
      disease. Both right and left atrial regions can be the source of atrial premature
      complexes and at the onset of spontaneous AF. Induced AF may have differing
      activation patterns than spontaneous AF but both demonstrate earliest activation
      in proximity to the initiating atrial premature complex. These findings may help
      explain therapeutic benefits of right and left atrial interventions and pacing
      therapies in AF.

PMID- 10590483
TI  - Impact of recent molecular studies on evaluation of ventricular arrhythmias.

PMID- 10590486
TI  - Atrial fibrillation: role of arrhythmogenic foci.
AB  - Atrial fibrillation, the most common of all sustained cardiac arrhythmias can be
      cured by Surgical atriotomies or linear RF catheter ablation. We have
      investigated the role of focal RF ablation in paroxysmal atrial fibrillation.
      METHODS: sixteen patients with focal atrial fibrillation (extrasystoles, atrial
      tachycardia and atrial fibrillation due to the same focus firing irregularly at
      different rates) and 45 with common AF initiated by extrasystolic foci were
      included. The ablation site was determined on the basis of earliest bipolar
      activity relative to a stable atrial electrogram reference or to the P wave onset
      during atrial fibrillation initiation. RESULTS: All the patients with focal
      atrial fibrillation were treated with a mean of 5 +/- 4 RF applications delivered
      on a right atrial site (n = 4) or on a pulmonary venous site (n = 13), (one
      patient had 2 foci). Sixty nine foci (located in the pulmonary veins in 94%) were
      identified in the 45 patients with common atrial fibrillation initiated by
      extrasystoles. They were ablated with a mean of 4.5 +/- 2 RF applications. Using
      a mean follow up of 8 +/- 6 months, 28/45 (62%) were cured without antiarrhythmic
      drugs. CONCLUSION: Pulmonary veins play an important role in paroxysmal atrial
      fibrillation. They are the most frequent source of focal atrial fibrillation and
      of initiating foci amenable to RF ablation.

PMID- 10590487
TI  - Secondary prevention of sudden death.

PMID- 10590488
TI  - The MUSTT study: evaluating testing and treatment.
AB  - The multicenter unsustained tachycardia trial (MUSTT) tested the value of
      electrophysiologically guided antiarrhythmic drug therapy against no therapy in
      high risk coronary artery disease with poor left ventricular function (LV-EF </=
      40%) and nonsustained ventricular tachycardia. Risk assessment was performed by
      testing inducibility of a sustained ventricular tachycardia. The primary endpoint
      of the study was sudden arrhythmic death or cardiac arrest. Significant
      information on risk stratification was gathered by the follow-up of patients that
      were noninducible. Although MUSTT was not a specific ICD trial for primary
      prevention of SCD the results of the trial revealed that only with ICD back-upa
      significant reduction of arrhythmic death or cardiac arrest can be achieved.EP
      guided antiarrhythmic drug treatment had a lower incidence of SCD/CA compared to
      no treatment (12% versus 25%, p = 0.043, hazard ratio 0. 73 after 24 months and
      18% versus 32% after 60 months). A subgroup analysis showed that the benefit of
      antiarrhythmic treatment was only due to ICD implantation. No difference was
      found between those inducible pts treated exclusively with antiarrhythmic drugs
      and those who were randomized to no drug treatment. Patients who were not
      inducible did significantly better than pts who were inducible wether or not
      treated with antiarrhythmic drugs.MUSTT results strengthen the data of the MADIT
      study. They confirm the inducibility testing as the most accurate risk
      stratifier. MUSST demonstrated the poor value of serial EP drug testing as well
      as the risk of stand alone antiarrhythmic drug treatment.

PMID- 10590489
TI  - Amiodarone: maximising survival benefit with empiric or guided therapy.
AB  - Review of available data suggests that serial drug testing in patients with a
      history of sustained ventricular tachyarrhythmias using various antiarrhythmic
      drugs including amiodarone is able to identify subgroups with favorable and
      unfavorable outcome (patient groups with suppression vs. no suppression of
      inducibility of VT/VF). These results more likely reflect patient selection
      rather than drug effects, thus limiting the role of electrophysiologically guided
      antiarrhythmic therapy to actively modify outcome. All major and actual
      antiarrhythmic drug trials including an amiodarone arm, have chosen to deliver
      this drug empirically in both patients with asymptomatic as well as severely
      symptomatic life-threatening sustained ventricular tachyarrhythmias instead of a
      guided approach. The empiric approach is therefore adequate until new valid data
      comparing the empiric with the guidedor the invasive with the non
      invasiveapproach tell us otherwise.

PMID- 10590490
TI  - The role of EP-guided therapy in ventricular arrhythmias: beta-blockers, sotalol,
      and ICD's.
AB  - Arrhythmic death can be reduced by antiarrhythmic drugs to a range of 24%.
      Electrophysiologic study by testing noninducibility of ventricular arrhythmia
      represents the classic method for evaluating the effectiveness of drug therapy.
      Several clinical studies have shown thaat sotalol suppresses VT induction and
      prevents arrhythmias recurrences at long term follow-up in 23% to 67% of
      patients. The efficacy of sotalol EP guided therapy in preventing VT/VF is not
      necessarily related to prevention of sudden death. In the ESVEM study the
      superiority of d,l-sotalol to other antiarrhythmic drugs was confirmed. The
      response to programmed ventricular stimulation was found to be strongly
      predictive for arrhythmia free state while the failure of sotalol therapy to
      suppress VT at the EP study was associated with an high recurrence rate (40%).
      However, EP study failes to predict freedom from sudden death. The beta-blocking
      activity of racemic sotalol may account for some of the observed survival
      benefit.Beta-blockers therapy reduces mortality in patients after myocardial
      infarction primarily by a reduction of sudden death. A reduction of death,
      worsening heart failure and life threatening ventricular arrhythmias was shown in
      a recent study on carvedilol. In the prospective study of Steinbeck the EP guided
      therapy did not improve the overall outcome when compared to metoprolol.
      Suppression of inducible arrhythmias by antiarrhythmic drugs was associated with
      a better outcome. The effectiveness of defibrillator therapy in reducing overall
      mortality, has been uncertain since great clinical trials have been concluded.
      MADIT, AVID and CASH trials confirmed the superiority of ICD therapy over
      antiarrhythmic drugs therapy: ICD should be considered the first choice therapy
      in post-cardiac arrest patients. The ongoing BEST Trial will give us further
      responses about the interaction between EP study and metoprolol effect compared
      to ICD in patients post myocardial infarction also focusing on tolerability and
      compliance of the beta-blocking therapy in patients with low ejection fraction.
      In this study will be useful to optimize therapy in patients at high risk of
      sudden death.

PMID- 10590492
TI  - Lessons learnt from multisite pacing for AF management-technical challenges.

PMID- 10590491
TI  - Combining antiarrhythmic drugs and implantable devices therapy: benefits and
      outcome.
AB  - At least 50% of patients who received an ICD have been treated with
      antiarrhythmic drugs (AAD). The potential indications for combining
      antiarrhythmic drugs and ICD are generally the following: reduction of the number
      of episodes of ventricular tachycardia or ventricular fibrillation and therefore
      of the number of shocks, improving patient's quality of life and extending the
      battery life of the ICD, prevention of supraventricular arrhythmias and/or
      control of their rate, lengthening of the tachycardia cycle length to allow
      ventricular tachycardia conversion by antitachycardia pacing and reduction of the
      number of episodes of syncope. Although previous papers reported conflicting
      results about pharmacologic therapy in reducing the frequency of iCD shocks, some
      recent randomized prospective studies showed the efficacy of pharmacologic
      therapy in reducing the frequency of ICD shocks. The use of antiarrhythmic drugs
      can have also adverse effect: an increase in the defibrillation threshold, an
      increase in the pacing threshold and an increase in the VT cycle length leading
      to detection failure. We have also to consider that some advantages derived from
      antiarrhythmic drugs can be reached by the new devices with atrial sensing and
      pacing and/or the possibility of atrial defibrillation or by using catheter
      ablation as adjunctive therapy to ICD. For these reasons, the concomitant use of
      antiarrhythmic drugs and ICD should be evaluated in each patient in relation to
      specific clinical and electrophysiologic features including: the frequency, the
      rate and the clinical presentation of the ventricular arrhythmia, the effect of
      the selected drug on the defibrillation threshold, the defibrillation threshold
      at the implant, the effect of the selected drug on the ventricular function and
      the likelihood of proarrhythmic events.

PMID- 10590493
TI  - Electrophysiologic assessment in selecting patients for multisite atrial pacing.
AB  - Electrophysiologic mechanisms of atrial fibrillation (AF) initiation are being
      actively studied. Multisite atrial pacing has shown, in acute studies,
      significant potential for prevention of AF. Dual site pacing reduces of intra and
      inter-atrial conduction time, atrial refractoriness dispersion, and to a limited
      extent atrial premature beats which modify the atrial remodelling induced by AF.
      Recently, two clinical trials have shown long term efficacy of multisite atrial
      pacing. At 3 years of follow-up, 56% of patients are free of AF recurrence with
      dual site right atrial pacing. Rhythm control was achieved in 86 of patients.
      Similar results are observed with biatrial resynchronization. In both studies,
      primary indication for multisite atrial pacing was AF prevention in more than 50%
      of patients. Selection of patients based solely on long P wave duration and
      prolonged interatrial conduction is not necessary as clinical outcome and
      comparable. These patients are comparable to patients who did not have these
      characteristics. Ongoing multicenter trials will likely definitively answer this
      question. However, preexcitation of diseased atrial regions or site of ectopic
      activity previously selected by high density atrial mapping or suppression of
      inducible AF may offer an interesting future development of multisite atrial
      pacing.

PMID- 10590494
TI  - Developing clinical indication for multisite pacing.
AB  - The artificial activation of the heart modifies the mechanics of contraction and
      relaxation. While only little basic research has been addressed to this question,
      clinical observations showed that for hypertrophic as well as dilated
      cardiomyopathies appropriate pacing techniques can be useful. Pacing can
      influence the activation sequence. The spread out from a single site is slow, and
      so hypercontractility deminshed. With the use of multiple electrodes, two atrial
      and/or two ventricular, conduction delays in the atria or ventricles can be
      eliminated. Synchronisation of the cardiac activation has an anti-arrhythmic and
      positiv inotropic effect. This may lead to new indications for pacemakers or
      better to be named cardiac synchronisers.

PMID- 10590495
TI  - The interpretation and clinical application of data from trials on sudden cardiac
      death.

PMID- 10590496
TI  - Evaluating AVID, CASH, CIDS, CABG-patch and MADIT: are they concordant?

PMID- 10590498
TI  - New mapping technology for atrial tachycardias.
AB  - Prerequisite for succesful radiofrequency catheter ablation of tachycardias is
      the exact mapping during the electrophysiological study. The new mapping system
      CARTO allows a three-dimensional color-coded electroanatomic map of impulse
      propagation using electromagnetic technology. The aim of this study was to
      determine the feasibility and safety of the new electromagnetic mapping
      technology CARTO for atrial tachycardias. RESULTS: Electrophysiologic study and
      CARTO mapping was performed in 38 atrial tachycardias. The mapping procedure took
      26 +/- 23 min. We created 33 maps within the right atrium and 5 maps within the
      left atrium with a mean of 74 +/- 38 different catheter positions. The mechanism
      was determined as reentrant in 9, junctional in 1 and focal in 28 tachycardias.
      In focal tachycardias the tachycardia cycle length (CL) and the total atrial
      activation time (AT) were clearly different (352 +/- 98 ms vs 99 +/- 25 ms).
      Reentrant tachycardias had a comparable CL and AT (236 +/- 44 ms vs 240 +/- 56
      ms). In 83% of the focal tachycardias and in 67% of the reentrant tachycardias,
      ablation was performed successfully. No complications occured. CONCLUSION: The
      electroanatomic mapping system allows high resolution visualization of electrical
      activity and may therefore improve precision and simplify the determination of
      the arrhythmogenic substrate during tachycardias for successful catheter
      ablation.

PMID- 10590497
TI  - Other primary prevention trials-what is clinically and economically necessary?
AB  - There are a number of important primary prevention implantable cardioverter
      defibrillator (ICD) trials underway which will help define the role of the ICD in
      high risk patients. High risk is defined by low ejection fraction, although a
      number of electrical markers (e.g., the signal averaged ECG and invasive
      electrophysiologic test) are also under evaluation. The trials currently underway
      (including SCD-HEFT, MADIT II, and the CABG-PATCH substudy) are analyzing
      patients with either coronary or idiopathic cardiomyopathy who have an EF of 35%
      or under. Patients are randomized to either ICD therapy or no antiarrhythmic drug
      therapy. Maximal congestive heart failure therapy with ACE inhibitors and beta
      blockers is used in both arms of each trial. At the conclusion of these trials we
      should have a better understanding of which group of presumably high risk
      patients, if any, will benefit from the ICD. Another group of high risk patients
      that is being encountered more frequently: those who have a high risk diagnosis.
      These patients are present in such small numbers that a large randomized trial is
      impossible. As many of these patients are receiving ICDs, a national registry of
      firing rates will be helpful.

PMID- 10590499
TI  - Predictors of success in radiofrequency catheter ablation of atrial flutter.
AB  - Radiofrequency catheter ablation of typical atrial flutter at the isthmus between
      the tricuspid annulus and the inferior vena cava is established. However in
      selected patients, the creation of a continuous linear lesion at the targeted
      isthmus requires a lengthened procedure or is not feasible at all and atrial
      flutter recurrences are common. In a retrospective analysis, we found that an
      intraoperatively determined distance between the tricuspid annulus and the
      inferior vena cava of <.2.5 cm is an independent predictor of a lengthened or
      failed ablation procedure. Additional equipment, e.g., long introducer sheaths,
      adapted ablation catheter design, or irrigated tip ablation, as well as
      alternative ablation approaches, e.g., linear lesions between the tricuspid
      annulus and Eustachian ridge, have been invented in order to increase the acute
      success rate or decrease fluoroscopy and procedure time. In a prospective study
      on the effects of various conduction properties at the isthmus between tricuspid
      annulus and inferior vena cava following radiofrequency ablation of atrial
      flutter, we showed previously that others than a complete bidirectional
      conduction block predicts a high recurrence rate of atrial flutter. For
      determination of transisthmal conduction properties following ablation,
      established mapping approaches are documentation of double potentials at the
      ablation line and right atrial activation sequence following posteroseptal and
      low lateral right atrial pacing. Novel threedimensional mapping systems, i.e.,
      Carto(R) and EnSite(R), may further enhance the accuracy of conventional mapping
      techniques.

PMID- 10590500
TI  - Novel catheter technology for ablative cure of atrial fibrillation.

PMID- 10590501
TI  - Atrial fibrillation: defining potential curative ablation targets.
AB  - The concept that atrial fibrillation (or at least certain forms of the
      arrhythmia) may be amenable to reversal or amelioration by transcatheter ablation
      techniques has become increasingly accepted in recent years. As yet, however, the
      techniques being studied for ablation of atrial fibrillation address neither
      known critical anatomic elements nor well defined electrophysiologic markers. The
      approaches, although essentially empirical, are conceptually based on the
      'multiple wavelet' or 'focal origin' hypotheses. To date, addressing 'focal
      origin' atrial fibrillation by transcatheter ablation has been the more
      encouraging. However, as technology evolves, both in terms of catheter design and
      possibly endocardial mapping techniques, approaches to wavelet or rotor
      mechanisms may become similarly effective. This communication examines concepts
      regarding the manner in which atrial fibrillation is initiated and maintained.
      The goals are to better understand the encouraging success of empirical ablation
      methods, and possibly derive insights which may help refine ablation targeting in
      the future.

PMID- 10590502
TI  - Atrial pacing to prevent atrial fibrillation?

PMID- 10590503
TI  - New concepts in atrial defibrillation.
AB  - External cardioversion of AF is an established and accepted method for
      termination of individual episodes of AF. Recent advances have taken place in the
      area of non-pharmacologic management of AF, and despite its long history and well
      established technique, defibrillation has not been spared from these advances.
      The success of low-energy internal atrial defibrillation for the termination of
      both chronic and acute onset atrial fibrillation has resulted in the development
      of implantable defibrillators that treat this arrhythmia. Many of the advances
      have come about as a result of the use of defibrillation in implanted devices for
      recurrent AF due to the substantial efforts in an attempt to make this form of
      restoration of sinus rhythm more efficacious and tolerable to the patient.
      Additionally, the use of other non-pharmacologic control of atrial fibrillation
      has also been recently explored, namely the use of ablation and atrial pacing.
      The use of these other non-pharmacologic therapies are likely to both reduce the
      recurrence rate, as well as enhance the efficacy of defibrillation. However,
      defibrillation is likely to still be needed to terminate atrial fibrillation for
      persistent episodes, and its combination with these other therapies is likely
      synergistic. Electrical therapy to restore sinus rhythm for persistent episodes
      of atrial fibrillation is likely to be perceived by the patient. Therefore, the
      concept of patient controlled therapy from implanted devices to treat atrial
      fibrillation has shown promising results and will likely be a requirement of such
      devices in the future. Major advances in defibrillation therapy for atrial
      fibrillation have been made and have resulted in the development of implantable
      atrial defibrillators. Despite these advances in defibrillation and other
      therapies for atrial fibrillation, it is likely that combined pharmacologic and
      non-pharmacologic therapies for atrial fibrillation will prevail over the
      individual entities themselves. Future study is needed to determine the best
      therapy or combination of therapies for individual patients with atrial
      fibrillation.

PMID- 10590505
TI  - The AFFIRM trial: main trial and substudies-what can We expect?
AB  - The clinical categorization of patients who present with atrial fibrillation is a
      major determinant of the most appropriate strategy for rhythm management. For
      those patients with recurrent atrial fibrillation that has not become permanent
      the two available strategies are rhythm control and anticoagulation or rate
      control and anticoagulation. There is no clear evidence that one of these
      strategies is superior to the other. In the AFFIRM trial these two strategies are
      being compared to one another in a randomized trial. Patients are randomly
      assigned to one of the two strategies and the treating physician then uses
      therapies from an approved menu as clinically indicated. Both pharmacologic and
      nonpharmacologic therapies are used. An overview of the main study protocol is
      presented. The primary endpoint is total mortality but there are a number of
      clinically important secondary endpoints. Several substudies will explore
      important ancillary questions and some of these are also described. At this time
      over 3000 patients have been enrolled and the planned enrollment is 4300.
      Enrollment will end late in 1999 and the last patient enrolled will be followed
      for two years. The AFFIRM Trial will provide important information concerning the
      management of atrial fibrillation in a large portion of the patients who have
      this arrhythmia.

PMID- 10590504
TI  - New devices and hybrid therapies and new devices for treatment of atrial
      fibrillation.

PMID- 10590506
TI  - Pacing in prevention of atrial fibrillation: the PIPAF studies.
AB  - The PIPAF trials are a set of randomized multicenter studies which seeks to
      evaluate the potential preventive effect of different modes of pacing in patients
      with drug refractory paroxysmal atrial fibrillation by means of a permanent
      pacemaker. The objective of the studies are (1) to significantly prolong the time
      to first recurrence of atrial arrhythmia and (2) to significantly reduce the
      cumulative arrhythmia duration. The role of the atrial pacing site (left or
      right), the overdriving of the sinus rate, and the suppression of the post
      extrasystolic compensatory pause are evaluated alone or in association, giving
      rise to four distinct pacing protocols. Over a period of 2 years, 220 patients
      will be included in 35 centers from 5 different countries.

PMID- 10590508
TI  - Design and preliminary data of the Metrix Atrioverter expanded indication trial.
AB  - The Metrixtrade mark Atrioverter Expanded Indication Trial evaluates the safety
      and efficacy of an implantable atrial defibrillator in patients with symptomatic,
      recurrent and drug refractory atrial fibrillation who also have structural heart
      disease. In this ongoing multicenter study, all patients are anticoagulated and
      concomitant antiarrhythmic drug treatment is left to the preference of the
      physician. Holter monitoring is performed prior to enrollment in the study.
      Spontaneous episodes of atrial fibrillation (AF) are treated under physician
      observation and when patients are ambulatory, the device is programmed in a
      monitoring mode. The atrial defibrillation threshold is measured at implantation
      and at 3, 6 and 12 months thereafter. The performance of the AF detection and R
      wave synchronization algorithm is assessed at implantation, at regular follow-up
      intervals, and each time the patient visits the hospital for treatment of a
      spontaneous episode of AF. An echocardiogram is performed prior to implantation,
      at 3 and 6 month follow-up and for patients with an implanted heart valve, after
      20 and 50 atrial defibrillation shocks have been delivered. The study started on
      October 1997 and will end after the last patient enrolled completes his/her six
      month post-implantation follow-up, unless a safety issue arises. As of September
      1998, 6 patients (2 patients with tachycardia induced cardiomyopathy, 1 patient
      with a mitral valve prosthesis, 2 patients with hypertrophic cardiomyopathy and 1
      patient with congenital heart disease) have been enrolled in the study. Over 350
      shocks have been delivered for atrial defibrillation testing or termination of
      spontaneous AF episodes. There have been no reported cases of ventricular
      proarrhythmia or inaccurately synchronized shocks and no complications of device
      therapy in this population.

PMID- 10590507
TI  - Clinical experience with implantable atrial and combined atrioventricular
      defibrillators.
AB  - The high prevalence of atrial fibrillation (AF) and its clinical complications,
      the poor efficacy of medical therapy for preventing recurrences, and
      dissatisfaction with alternative modes of therapy stimulated interest in
      implantable atrial and combined atrioventricular defibrillators. In a multicenter
      study, the safety and efficacy of a stand alone implantable atrial defibrillator,
      the Metrix system, were evaluated. The device was implanted in 51 patients with
      highly symptomatic episodes of AF refractory to pharmacological treatment. During
      a follow-up of 9 months, 96% of 227 spontaneous AF episodes were successfully
      converted to sinus rhythm in 41 patients. In 62 episodes (27%), several shocks
      and/or additional drug treatment were required to maintain stable sinus rhythm
      because of early recurrences of AF. A total of 3719 shocks were delivered and no
      induction of ventricular proarrhythmia or inaccurately synchronized shocks
      occurred. The AF detection algorithm exhibited a 100% specificity for the
      recognition of sinus rhythm and a 92.3% sensitivity for the detection of AF. The
      combined atrioventricular defibrillator, Jewel AF 7250, was evaluated in a
      multicenter, randomized, cross-over trial. The primary study objectives included:
      overall safety as determined by complications-free survival at 6 months, efficacy
      of tiered atrial pacing and defibrillation therapies for termination of
      spontaneous atrial tachycardias (AT) and AF, and relative sensitivity of a new
      dual-chamber detection algorithm. The device was implanted in 211 patients with
      either a history of ventricular tachyarrhythmias (VT/VF) alone or with a history
      of both AT/AF and VT/VF. During a mean follow-up of 4.5 months, it has been shown
      that the Jewel AF is safe and effective in treating atrial and ventricular
      tachyarrhythmias. Pace termination of 85% of AT episodes were achieved with
      painless delivery of antitachycardia pacing; additional 35% of AT episodes were
      terminated by high frequency burst pacing. CONCLUSIONS: The stand alone
      implantable atrial defibrillator may be safe and clinically useful in selected
      patients for the treatment of highly symptomatic, drug resistant recurrences of
      AF. The combined atrioventricular defibrillator may be particularly indicated in
      patients presenting with both a history of atrial and ventricular
      tachyarrhythmias.

PMID- 10590509
TI  - Quality of life in atrial fibrillation.
AB  - In patients with atrial fibrillation (AF), the restoration and maintenance of
      sinus rhythm is the primary therapeutic goal. Once sinus rhythm is maintained,
      physiological rate control is restored, and left ventricular ejection fraction,
      cardiac output, and exercise capacity are increased. This improved cardiovascular
      performance thereby enhances the patient's ability to perform the functions of
      normal daily life. The primary intervention for maintaining sinus rhythm after
      restoration is the use of anti-arrhythmic agents. Although physicians mostly use
      class 1A anti-arrhythmic drugs, these oral agents only maintain sinus rhythm in a
      limited number of cases and are accompanied by considerable side effects.
      Therefore, more effective tools are needed. Effective treatment for AF is based
      on the above objective criteria, but subjective criteria such as the quality of
      life are growing in importance. To address these quality-of-life issues, we have
      initiated a prospective study in which patients are assigned to one of two
      groups: those with paroxysmal AF who are candidates for permanent implantable
      atrial defibrillators and those with chronic or paroxysmal AF who are not
      candidates for atrial defibrillators. Specifically designed questionnaires and
      various standardized and validated instruments are used to measure quality of
      life. The questionnaires cover social demographic data, including age, education,
      occupation level, driving behavior, return to work, and sexual activity. Quality
      of life is a multidimensional construct, and thus its definition must consider
      the many factors mentioned above. In the final analysis, therefore, both
      objective and subjective criteria are necessary to define appropriate treatment
      of AF.

PMID- 10590511
TI  - Distribution of unipolar brush cells and other calretinin immunoreactive
      components in the mammalian cerebellar cortex.
AB  - We have compared the distribution of unipolar brush cells (UBCs) in the
      cerebellum of Brazilian opossum (Monodelphis domestica), mouse, guinea pig,
      rabbit, cat, and Rhesus monkey, using an antiserum to calretinin which is present
      in those cells. The morphology and calretinin staining intensity of the UBCs
      remains constant across species. As a general trend, in all species studied, UBCs
      are particularly enriched in the vestibulocerebellum. Interspecies differences,
      however, were noted in the distribution of UBCs across other regions of the
      cerebellar cortex. A major variation involves the extent of the UBC-rich region
      of the ventral portion of the paraflocculus. The distribution of UBCs in non
      vestibular vermal folia also varies substantially. UBCs are deployed in more or
      less distinct parasagittal zones in the vermis of the opossum, rabbit, cat, and
      macaque. The density of UBCs decreases progressively from medial to lateral
      portions of the same folium and is lowest in the lateral, posterior portions of
      the cerebellar hemispheres (crus II) and in the dorsal portion of the
      paraflocculus. In cat and macaque, the decrease in the density of UBCs across the
      intermediate cortex is more gradual than in the other species. The data indicate
      that the UBCs play a more prominent role in the modulation of sensorimotor
      transformations in carnivores and primates than in smaller mammals and should not
      be considered a vestigial form of neuron. In addition to the UBCs, calretinin
      antibody distinctly stains the following neurons in different species: granule
      cells and parallel fibers in all species except rabbit and cat; Golgi cells,
      especially in rat and macaque; Lugaro-like cells, especially in mouse, rat, and
      macaque; basket cells in macaque; subsets of mossy fibers in all species; and
      subsets of climbing fibers in all species but guinea pig. Usually, the
      distribution of UBCs is related to that of calretinin stained granule cells and
      mossy fibers.

PMID- 10590510
TI  - Association of actin filaments with axonal microtubule tracts.
AB  - Axoplasmic organelles move on actin as well as microtubules in vitro and axons
      contain a large amount of actin, but little is known about the organization and
      distribution of actin filaments within the axon. Here we undertake to define the
      relationship of the microtubule bundles typically found in axons to actin
      filaments by applying three microscopic techniques: laser-scanning confocal
      microscopy of immuno-labeled squid axoplasm; electronmicroscopy of conventionally
      prepared thin sections; and electronmicroscopy of touch preparations-a thin layer
      of axoplasm transferred to a specimen grid and negatively stained. Light
      microscopy shows that longitudinal actin filaments are abundant and usually
      coincide with longitudinal microtubule bundles. Electron microscopy shows that
      microfilaments are interwoven with the longitudinal bundles of microtubules.
      These bundles maintain their integrity when neurofilaments are extracted. Some,
      though not all microfilaments decorate with the S1 fragment of myosin, and some
      also act as nucleation sites for polymerization of exogenous actin, and hence are
      definitively identified as actin filaments. These actin filaments range in
      minimum length from 0.5 to 1.5 microm with some at least as long as 3.5 microm.
      We conclude that the microtubule-based tracks for fast organelle transport also
      include actin filaments. These actin filaments are sufficiently long and abundant
      to be ancillary or supportive of fast transport along microtubules within
      bundles, or to extend transport outside of the bundle. These actin filaments
      could also be essential for maintaining the structural integrity of the
      microtubule bundles.

PMID- 10590512
TI  - Immunocytochemical observations on pineal organ and retina of the Antarctic
      teleosts Pagothenia borchgrevinki and Trematomus bernacchii.
AB  - In spite of the unique conditions they have to operate under, the pineal organs
      of Antarctic fishes have not previously been examined. We determined
      immunohistochemically that in the end-vesicles and the pineal stalks of
      Pagothenia borchgrevinki (a species found directly beneath the sea-ice) as well
      as Trematomus bernacchii (a species preferring somewhat deeper water than the
      former) at least two populations of physiologically-different cells occurred that
      displayed reactions indicative of typical vertebrate photoreceptors. Comparisons
      with immunocytochemically treated retinal sections from the eyes of the same two
      species showed that anti-opsin reactivity, characteristic of rods, was
      particularly strong in the lumina of the pineal stalks of both species. Anti
      visinin reactions stained cones in the retinal sections of both fishes and
      occurred throughout the pineal organs, but in particular in the end vesicles of
      the pineals of both species. The difference in preferred habitat depth between
      the two species appears to have had very little influence on both retinal and
      pineal immunocytochemistry. It is concluded that the pineal organs of both
      species, at least during the austral summer, exhibit signs of being directly
      photo-sensitive.

PMID- 10590513
TI  - Stereological evaluation and Golgi study of the sexual dimorphisms in the volume,
      cell numbers, and cell size in the medial preoptic nucleus of the rat.
AB  - The medial preoptic nucleus (MPN) and the sexually dimorphic nucleus of the
      preoptic area (SDN-POA) stand out as prominent sexually dimorphic cell groups of
      the rat brain. However, quantitative data on sex-related differences in these
      nuclei in the adult rat are confined to their volume. We have used stereological
      methods and Golgi-impregnated material to examine whether, in young adult rats,
      the sexual dimorphism in the volume of the MPN, including its divisions, and of
      the SDN-POA, reflect similar differences in the number and size of their neurons.
      We found that the total number of neurons in all MPN divisions is higher and the
      mean somatic volume larger in males than in females. In addition, the total
      dendritic length of MPN neurons is greater, but the dendritic spine density is
      smaller, in males than in females. Likewise, in the SDN-POA the total number and
      size of its neurons is greater in males than in females. The sex differences in
      all quantitative parameters evaluated accounted for the larger volume of the MPN
      and SDN-POA in males relative to females. In addition, the MPN neuropil also
      displays sex-related differences in its volume, and these differences closely
      match those detected for the volume of each MPN division. It deserves to be
      emphasised that the numerical density of neurons was the only parameter found to
      be significantly higher in females than in males in all MPN divisions and in the
      SDN-POA. Our results show that the MPN and the SDN-POA display sex differences in
      the volume, total number of neurons, and size of neuronal cell bodies and
      dendritic trees. Furthermore, they also indicate that the neuropil is critical
      for the establishment of sexual dimorphism in the size of the MPN.

PMID- 10590514
TI  - Cellular uptake of the prion protein fragment PrP106-126 in vitro.
AB  - The aetiological agent of prion disease is proposed to be an aberrant isoform of
      the cell surface glycoprotein known as the prion protein (PrP(c)). This
      pathological isoform (PrP(Sc)) is abnormally deposited in the extracellular space
      of diseased CNS. Neurodegeneration in these disease has been shown to be
      associated with accumulation of PrP(Sc) in affected tissue. To investigate the
      possible uptake mechanisms that may be required for PrP(Sc)-induced
      neurodegeneration we studied the cellular trafficking of the neurotoxic fragment,
      PrP106-126. We were able to detect, by fluorescence microscopy, PrP106-126
      inclusions in murine neurones, astrocytes and microglia in vitro. These
      inclusions were abundant after 24 hour exposure and still present 48h post
      exposure. Shorter exposure times yielded only occasional cells with inclusions.
      Large extracellular aggregates of PrP106-126 could also be detected, which
      appeared in a time dependent manner. The appearance of inclusions or aggregates
      was not dependent on PrP(c) expression as determined by exposure of peptides from
      PrP-null mice. Using transmission electron microscopy and gold particle
      detection, positively labelled osmiophilic inclusions of peptide could be
      detected in the cytoplasm of exposed cells. These results demonstrate that
      cultured cells are capable of sequestering PrP106-126 and may indicate uptake
      pathways for PrP(Sc) in various cell types. Toxicity of PrP106-126 may thus be
      mediated via a sequestration pathway that is not effective for this peptide in
      PrP-null cells.

PMID- 10590515
TI  - Effects of neonatal capsaicin administration on the numbers and volumes of
      neurons in left and right T10 dorsal root ganglia in the rat.
AB  - The long-term effects of neonatal capsaicin were studied in left and right dorsal
      root ganglia (T10) from control and capsaicin-treated groups of Wistar rats. At
      12 hours post partum, 5 females per group were injected subcutaneously with
      capsaicin or vehicle solution and killed at 6 months of age. Tissues were
      perfusion-fixed, embedded in resin and serially sectioned. A Nissl stain was used
      to distinguish between A and B neurons and systematic random sampling schemes
      were employed to obtain stereological estimates of numbers of neurons and mean
      volumes of their perikarya. Numbers were calculated from ganglion volumes
      (estimated via the Cavalieri principle) and neuron packing densities (estimated
      using physical disectors). Mean perikaryal volumes were calculated from packing
      densities and volume densities (estimated by point counting). Data were analysed
      to isolate main and interaction effects of neuron subtype, laterality and
      treatment. There was no evidence of lateral asymmetry or interaction effects.
      Control ganglia contained 3320 (coefficient of variation, CV, 8%) neurons. Most
      (73%) were B cells with a mean volume of 13,100 microm(3) (CV 17%) of which the
      nucleus accounted for 1,800 microm(3) (CV 18%). About 22% were A cells with a
      mean volume of 79,800 microm(3) (CV 24%) and a nucleus of 6,100 microm(3) (CV
      26%). After capsaicin, over half the original population of cells was destroyed
      and B cell loss was significantly greater than that of A cells (about 80% of all
      cells lost were B cells). The mean size of A cells was greater after capsaicin
      due to selective loss of smaller cells and a greater volume of cytoplasm. B cell
      perikaryal volume was not affected but nuclear volume declined. The findings show
      that capsaicin destruction of peripheral sensory neurons is bilaterally
      symmetrical. In general, smaller neurons are selectively destroyed but this
      operates differently in A and B cells. It is size-dependent in A cells but size
      independent (possibly random) in B cells.

PMID- 10590516
TI  - [Why does the law to prevent infectious diseases need to be revised?].

PMID- 10590517
TI  - [Laws related to infection control and management of patients with infectious
      diseases--their concepts and application].

PMID- 10590518
TI  - [Health facilities designated for specific infections].

PMID- 10590519
TI  - [Type 1 and type 2 health facilities specified for the control of infections].

PMID- 10590520
TI  - [In response to the revised law for infection control--for better management of
      infection at general hospitals].

PMID- 10590521
TI  - [Public health clinics].

PMID- 10590523
TI  - [Class 1 infections: 2) Pest].

PMID- 10590522
TI  - [Class 1 infections: 1) Viral diseases].

PMID- 10590525
TI  - [Class 3 infections (enterohemorrhagic E. coli infections)].

PMID- 10590524
TI  - [Class 2 infections].

PMID- 10590526
TI  - [Class 4 infections. 1) Influenza].

PMID- 10590527
TI  - [Class 4 infections. 2) Vancomycin-resistant enterococcal infections].

PMID- 10590528
TI  - [Class 4 infections. 3) HIV infections: AIDS].

PMID- 10590529
TI  - [Class 4 infections. 4) Sexually transmitted infections].

PMID- 10590530
TI  - [Legally designated infections].

PMID- 10590531
TI  - [New infections (infections caused by unknown pathogens)].

PMID- 10590532
TI  - [Management of infections under the new Infection Control Law: discussion].

PMID- 10590533
TI  - [Case of Gitelman's syndrome].

PMID- 10590534
TI  - [Case suspected to be tuberculous myelitis with pulmonary tuberculosis].

PMID- 10590535
TI  - [Case of AIDS complicated by progressive multifocal leukoencephalopathy].

PMID- 10590536
TI  - [Case of primary racemose hemangioma of the bronchial artery without presenting
      any symptoms].

PMID- 10590537
TI  - [Case of alpha-fetoprotein-producing cancer of the ascending colon with invasion
      of the superior mesenteric vein and portal system].

PMID- 10590538
TI  - [Therapy of peripheral nerve disturbances--current progress].

PMID- 10590539
TI  - [Lung cancer and paraneoplastic syndromes].

PMID- 10590540
TI  - [Respiratory tract infections triggering bronchial asthma attacks--with special
      reference to the involvement of Chlamydia pneumoniae].

PMID- 10590541
TI  - [Diagnosis and treatment of diabetic neuropathies].

PMID- 10590542
TI  - [Blood purification treatment in multiple organ failure].

PMID- 10590543
TI  - Real-time breath analysis of vapor phase uptake of 1,1,1 trichloroethane through
      the forearm: implications for daily absorbed dose of volatile organic compounds
      at work.

PMID- 10590544
TI  - Health hazards at an egg farm.

PMID- 10590545
TI  - Control of organic dusts from bedding choppers in dairy barns. National Institute
      for Occupational Safety and Health.

PMID- 10590546
TI  - Conference summary. Oh Canada! 59th Annual American Industrial Hygiene Conference
      and Exposition.

PMID- 10590547
TI  - 1999 Stokinger Award Lecture. Unifying the standard setting process for
      carcinogens and non-carcinogens.

PMID- 10590548
TI  - Monitoring of urban particulate using an electret-based passive sampler.
AB  - Site sampling trials have been carried out in the urban environment in order to
      assess the usefulness of a passive sampling device, originally developed for
      personal monitoring of airborne dust levels in industry. The sampling element is
      a small disc of electret material (polymer carrying a permanent electric charge)
      within a metal frame weighing approximately 15 g. The sampler is designed to
      capture particles by electrostatic attraction, in which case the capture rate
      depends on their electrical mobility but is independent of the rate at which air
      flows past the device. Passive samplers, along with miniaturized cascade
      impactors, have been exposed to urban particulate for periods of up to 28 days in
      locations with significantly different levels of airborne pollution. The cascade
      impactor data enabled good estimates to be made of PM10 and PM2.5 levels, and
      data from the passive sampler correlated with the total dust sampled by the
      impactor and with both the size fractions, that with the PM10 being better. Too
      few data have yet been obtained for its accuracy to be established, but it is
      unlikely that it will approach that of pumped samplers. It has been shown to be
      potentially useful for multiple, simultaneous site sampling and for monitoring
      personal environmental exposure situations in which dispensing with a power
      source is particularly useful. Being small, the sampler is easy to hide or
      camouflage, and because it is cheap, its loss or damage is not a serious matter.

PMID- 10590549
TI  - Distribution of mesothelioma cases in different occupational groups and
      industries in Australia, 1979-1995.
AB  - Australia was a producer and user of asbestos and has one of the highest national
      incidences of mesothelioma in the world. The incidence is still rising and
      expected to do so for another 10-20 years. A study was conducted in 1996 to
      examine the past and current incidence rates of mesothelioma in a number of
      industries and occupations as the basis for predicting future outcomes.
      Occupational histories of a total of 3758 mesothelioma cases collected by two
      sequential national schemes--the Australian Mesothelioma Surveillance Program
      (1979-1985) and Australian Mesothelioma Register (1986-1995)--were reviewed and
      coded by the authors. The building industry contributed the largest number of
      cases nationwide followed by shipbuilding and repair, asbestos cement production,
      crocidolite mining and milling, railway locomotive construction and repair, coal
      fired power stations, and other engineering operations. The mean latency between
      initial occupational asbestos exposure and diagnosis of the disease was 37.4
      years (range = 4-66 years) for cases notified between 1979 and 1985, and 41.4
      years (range = 6-84 years) for those between 1986 and 1995. Trends for each
      industry group have been changing considerably in the past 16 years, with the
      traditional primary asbestos industry cases from crocidolite mining and milling
      now on the decline and cases from asbestos cement production having plateaued. In
      contrast, more recently, more cases were observed from the asbestos user
      industries such as the building industry, and from occupations such as plumbers,
      carpenters, machinists, and car mechanics. These increases might be a reflection
      of the longer latency effects of the intermittent and less severe exposures in
      these larger occupational groups.

PMID- 10590550
TI  - Occupational tuberculosis among deputy sheriffs in Connecticut: a risk model of
      transmission.
AB  - OBJECTIVES: The purpose of this study was to identify risk factors for tuberculin
      skin test conversions among non-infected deputy sheriffs in Connecticut and
      during an out-break in an urban lock-up. METHODS: 377 tuberculin skin-test
      negative sheriffs statewide in 1994-1995 and 37 sheriffs in the lock-up in 1995
      were screened and questionnaires administered. Cellblock volumetric air flow was
      measured. The Wells-Riley model of airborne transmission [C = S(1-e-Iqpt/Q)] was
      applied to the epidemiologic and ventilation data. RESULTS: Statewide, of 377
      sheriffs screened, 22 (5.8%) had positive skin tests. Risk factors included older
      age (p < .0075) and longer tenure (p < .036). In the lock-up, of 37 sheriffs
      screened, 4 (10.8%) had positive skin tests. Measured mean outside air flow per
      occupant (8.0 cfm; S.D. = 2.2) was below design (15 cfm) and recommended (20 cfm)
      standards. Mathematical modeling estimated that TB transmission would be reduced
      by 62.5 percent with ventilation at design specifications. CONCLUSIONS:
      Inadequate ventilation may increase the risk for occupational transmission of
      tuberculosis. Since lock-ups do not have the time to conduct inmate TB
      screenings, supplemental engineering controls may be required.

PMID- 10590551
TI  - Breathing zone concentration variations in the reinforced plastic industry; field
      measurements in a boat manufacturing plant.
AB  - Breathing zone samples are used to estimate worker exposure to airborne
      contaminants by collecting air from a vaguely defined zone surrounding the head.
      This zone is considered to have an airborne chemical concentration equivalent to
      the concentration breathed by the worker. It has been generally assumed that
      vapor is uniformly mixed in the breathing zone; therefore, samplers are placed on
      either lapel or on the chest of the worker. An extensive field investigation in a
      boat manufacturing plant was conducted where styrene air concentrations were
      measured by mounting four 3M one-stage diffusion samplers around the worker's
      breathing zone. Two job classes were studied: the spray gun operators and the
      rolling and tucking operators. Styrene air concentrations detected at the nose
      were significantly different than those concentrations detected at the other
      three locations and represented 90 percent, 84 percent, and 76 percent of the
      left lapel, right lapel, and chest samplers, respectively. This research revealed
      that the chest sampler provides a consistent relationship to the concentrations
      measured at the nose for a given job category. Additionally, this research
      identified the possible factors which could contribute to breathing zone
      concentration variations.

PMID- 10590552
TI  - Shoe manufacturing and solvent exposure in northern Portugal.
AB  - Shoe manufacturing is a traditional industry in northern Portugal. There are
      nearly 1500 factories that employ about 54,000 workers. Among the materials used
      in the shoe manufacturing process, that could be occupational hazards, are the
      adhesives, especially adhesives solutions based on organic solvents. The National
      Institute of Health (Oporto Branch) carried out a study of 100 factories in
      northern Portugal to study solvent exposure in shoe manufacturing. The surveyed
      population, (4615 workers) was young (mean age = 33 years; range = 18-45) and
      predominantly female (68.5%). The results from the air samples analyses show 20
      different organic compounds existing in the workplaces. The more common compounds
      found were n-hexane, toluene, and acetone. The results of the study show that in
      53.7 percent of the factories there are operations where the solvent exposure is
      significant and represents a health hazard to the workers. These operations are
      mainly gluing, waxing, and polishing stations. Occupational risk of exposure to
      solvents concerned 44.2 percent of the workers. This study points out the
      existence of inadequate ventilation in the workplaces and inappropriate personal
      protective equipment to prevent dermatitis risk from adhesives, wax, and polish.
      The organic solvents present in workplaces also increase fire risk.

PMID- 10590553
TI  - Wheat antigen content of inhalable dust in bakeries: modeling and an inter-study
      comparison.
AB  - The purposes of this study were (a) to compare wheat antigen content of inhalable
      bakery dust in Canada and the Netherlands and, (b) to evaluate the validity of
      dust exposure measurement as a surrogate of specific antigen exposure. Wheat
      antigen exposure data from the studies of Canadian and Dutch bakeries were used
      to explore the correlation between dust and antigen levels, and identify factors
      explaining variability of the antigen content of bakery dust. Direct comparison
      and pooling of the data were possible because the same antigen assay was used in
      both studies. Wheat antigen exposure samples totaling 544 were available, all
      originating from personal full-shift monitoring of bakery workers. The wheat
      antigen content of bakery dust varied greatly between the two studies and with
      different products within each study. Bakery dust from the Canadian study had a
      much higher wheat antigen content. Therefore, the interstudy difference in the
      wheat antigen content of bakery dust was by far the most significant in
      undermining the validity of the use of dust levels as a surrogate measures of
      wheat antigen exposure. The production of croissants, wheat bread and buns, puff
      pastry, bagels, and cinnamon buns was associated with increased wheat antigen
      content of bakery dust, while in rye bread production, bakery dust with less
      wheat antigen content was emitted. Although we can, in part, account for the
      pattern of variability in the wheat antigen content of bakery dust (explaining
      49% of it), we concluded that the effort involved in modeling it accurately would
      probably exceed that expended in direct measurement of the antigen level.
      Therefore, for the exposure assessments carried out for the purpose of managing
      occupational risks of aeroallergen exposure in bakeries, we recommend the use of
      analytical techniques that can directly measure antigen exposure.

PMID- 10590554
TI  - [Reflections from inside a congress. Collaborators, obstructionists or
      accomplices?].

PMID- 10590555
TI  - [Reference prices].

PMID- 10590556
TI  - [A reliability study of pediatric somatometric determinations and the level of
      agreement between 4 observers].
AB  - OBJECTIVES: Given the great importance given at present to determining
      anthropometric measurements as an indicator of child health, and its general use
      in primary care, this study aimed to find how reliable the measurements by four
      nurses at a health centre were. The measurements' internal concordance, and thus
      the weight of the observer on the values found, was studied. DESIGN: Analytical
      study of validation of infants' anthropometric measurements. SETTING: Urban
      Health Centre, Valencia. PARTICIPANTS: 37 children, selected at random by a draw
      from those attending the programme for overseeing child development. MEASUREMENTS
      AND RESULTS: Four nurses, using the methods of measurement normally followed at
      the Virgen de la Fuensanta Health Centre, consecutively determined weight, height
      and cephalic perimeter of the children. The analyses of variance of the
      anthropometric measurements for the observer showed no statistically significant
      differences. The calculation of the greatest discrepancy between observers
      regarding the mean of the values displayed no quantitatively important
      discrepancies, either. CONCLUSIONS: High consistency was found in the concordance
      of the somatometric measurements, as far as technique goes. This means that
      trained staff can find good indicators of child development and health, even when
      the staff taking the measurements alternate.

PMID- 10590557
TI  - [The quality perceived by the users of health centers and by private insurance
      companies].
AB  - OBJECTIVE: To find and analyse the views of both health centre users and users of
      private insurance companies on the quality of services offered. DESIGN:
      Descriptive, crossover study using qualitative methodology. The views of health
      centre and private insurance company users on the quality of services delivered
      were gathered through 8 focus groups. The variables of opinion analysed were
      defined according to the SERVQUAL model of Parasuraman on perceived quality.
      SETTING: Three health districts in a health area in Andalusia. PARTICIPANTS: 70
      users took part. RESULTS: Accessibility (prior appointment, information and
      reception service, hours open), capacity for response (speed and efficiency of
      processing) and internal organisational coordination were considered by health
      centre users weak-points of the primary care services, which affected negatively
      their credibility. These variables were identified by private insurance users as
      the main advantages of the care model for which they had opted. Reliability was
      valued positively by health centre users, but received a higher valuation from
      private insurance users. However, the courtesy and friendliness of health centre
      professionals was seen as an outstanding point of the service, and no different
      from that of private professionals. The use of clinical records, the competence
      of the professionals and the tangible aspects of health centres were identified
      by their users as strong points of the primary care services and give the public
      care model an advantage over the private one.

PMID- 10590558
TI  - [The validity and reliability of a questionnaire for assessing the functional
      capacity of older persons].
AB  - OBJECTIVES: Our aim was to evaluate the validity and reliability of a
      questionnaire to measure the functional capacity in older people. DESIGN:
      Observational cross-sectional study. SETTING: Community level. Three basic health
      areas. PARTICIPANTS: 519 individuals over 64 selected by systematic random
      sampling taking as sampling units a list of household living at least an
      individual over 64 years. MEASUREMENTS AND MAIN RESULTS: A new questionnaire was
      developed starting from the OARS-MFAQ, the CVA. This new questionnaire is shorter
      but it maintains the same structure. Ten interviews were recorded in a videotape
      and subsequently analyzed and marked by four different observers to evaluate the
      inter-observer agreement. To assess the criterion validity the rates of 40
      individuals in the CVA were compared with the rates assigned to the same
      individuals by experts in each area of the questionnaire (physical health, mental
      health, daily activities, economic resources, and social support). The criterion
      validity of the version to proxies of CVA (CVA-I) was studied comparing the
      answers in the CVA of 31 individuals and the answers given in the CVA-I by
      proxies of the same 31 individuals. The internal consistency in both versions of
      the questionnaire was studied in 519 individuals, agreement showed values of
      kappa coefficient between 0.43 and 0.69. Correlation coefficients Interobserver
      between expert's rates showed values between 0.54 and 0.74. Correlation
      coefficients between CVA and CVA-I showed values between 0.60 and 0.74 except in
      the social support dimension (0.16). The Cronbach alpha coefficient were 0.73 for
      CVA and 0.62 for CVA-I. CONCLUSIONS: The CVA questionnaire showed an acceptable
      validity and reliability except in the social support dimension of the CVA-I.

PMID- 10590559
TI  - [The factors that influence the use of antibiotics in primary care].
AB  - OBJECTIVE: To identify factors influencing volume, quality and power of
      antibiotic prescription in primary care. DESIGN: Descriptive, crossover study.
      SETTING: Sanitary Region Coast of Ponent, 1992. PARTICIPANTS: They were studied
      468 practitioners of primary care attention. 68 practitioners were excluded by
      various reasons. MEASUREMENTS AND MAIN RESULTS: The factors studied were: factors
      coming from the practitioner, the centre, and the assisted population. The
      following parameters were analysed: amount of prescribed antibiotics in DDDs,
      election level ("antibiotic power") and percentage of DDDs of low intrinsic
      value. It was used for the comparison of means, Student-Fisher t test and the
      confidence intervals of the difference. Also it was used the step-wise multiple
      regression analysis. Greater use of antibiotics. The variability can be explained
      through regression in a 45.7% in function of the doctors factors, not integrated
      in a team, older, doctor who works in a rural centre, of young population and of
      smaller revenue. Greater antibiotic power. It's explained in a 5.09% by the
      medical factors like man, that works in a not educational centre and of greater
      population revenue. Greater percentage of DDDs of low intrinsic value. It's
      greater in doctors not specialized in family care, permanent job, of greater age,
      men, not reformed professional and not of an educational centre. CONCLUSIONS: The
      volume of prescription of antibiotics and in minor extent its quality of
      prescription are in some part justified by variables coming from the
      practitioner, the centre and the assisted population. The antibiotic power mainly
      doesn't.

PMID- 10590560
TI  - [Does the system of prescription issuance influence the therapeutic compliance of
      hypertensive patients?].
AB  - OBJECTIVES: To find out whether the system for issuing prescriptions is linked to
      the therapeutic compliance and control of the blood pressure of a group of
      hypertense patients, and to quantify compliance with hypertension treatment
      through an indirect measurement method (counting pills). DESIGN: Crossover,
      descriptive study. SETTING: Torrelodones Health District (Madrid). PATIENTS: 54
      patients known to be hypertense, of which 27 collected their prescriptions over
      the counter with no need for a doctor's appointment and 27 received them at a
      consultation with their doctor. MEASUREMENTS AND MAIN RESULTS: To measure the
      therapeutic compliance, first a phone call and then a surprise visit to the
      patient's home were made. At this visit, all the hypertension drugs prescribed
      were counted. It was specified that patients would be considered compliant if
      they had a compliance rate of 80-110%. 53.7% of the patients were considered good
      compliers and 46.3% bad compliers (of whom 37% were under-compliers and 9.3% over
      compliers). The statistical analysis found that 59.3% of the patients who
      collected their prescriptions over the counter were good compliers, whereas 48.1%
      of those who did so at a medical consultation were (p = 0.41). 7.4% of patients
      who collected their prescriptions over the counter controlled their blood
      pressure well, whereas 22% of those who collected them at a consultation did so
      (p = 0.12). CONCLUSIONS: No statistically significant association was found
      between compliance and blood pressure figures, and systems of issuing
      prescriptions. The percentage of good compliers is high in comparison with other
      studies, but still insufficient.

PMID- 10590561
TI  - [Health care and communication with the terminal cancer patient and his family in
      a health area].
AB  - OBJECTIVES: To know the clinical, essential and communication characteristics of
      the terminal cancer patient care in a health district. DESIGN: Cross-sectional
      descriptive study. PLACEMENT: Vth health district of Asturias (Spain). PATIENTS
      AND PARTICIPANTS: 107 cancer patients dead in the first term of 1995 and their
      families. MEASUREMENT AND MAIN RESULTS: Revision of hospital and primary care
      health centres clinical records and personal interview with the patient's main
      carer by closed questionnaire, taken place between August and October of 1996. We
      revised 107 clinical records interviewing 54 relatives. 50% of the patients died
      at home, 17% in a palliative care partially dedicated hospital. 81% of patients
      suffered from pain in some moment of their process, being controlled in 69%,
      using morphine in 66% of cases with pain (mode and median of dose 60 mg/24 hours
      VO). Pain evaluation scales were registered in 32% of cases, improving the pain
      control (p < 0.01). 30% of carers were told of their relative cancer diagnosis in
      a corridor. 57% of carers were advised on symptoms that the patient could suffer;
      these patients were interned in hospital in a smaller proportion (p = 0.02) and
      attended less the casualty department (p = 0.02). 19% of patients were informed
      about their diagnosis, using less health resources (less hospitalizations, p =
      0.06). CONCLUSIONS: We use low doses of morphine. There is a low register of pain
      valoration scales, although they improve its control. Two thirds of patients dye
      in an proper place. Communication with the patients and their families is
      insufficient. Among other factors, the patient who knows his diagnosis uses less
      health resources.

PMID- 10590562
TI  - [The basic norms for managing heart failure in primary care].

PMID- 10590563
TI  - [Rigor in qualitative research].

PMID- 10590564
TI  - [The consumption of anti-ulcer agents].

PMID- 10590565
TI  - [The evaluation of the efficiency of a tetanus vaccination program in a basic
      health area].

PMID- 10590566
TI  - [The fixed drug eruption due to metamizole].

PMID- 10590567
TI  - [The length of time for a specialty in family and community medicine].

PMID- 10590568
TI  - [Thrombocytopenia in pregnancy: when and what tests to carry out in primary
      care].

PMID- 10590569
TI  - Alternative treatments and rheumatic diseases.

PMID- 10590570
TI  - The allure of alternative therapies.

PMID- 10590571
TI  - Introduction: all for saving the visual axis.

PMID- 10590572
TI  - Regional immunity and ocular immune privilege.

PMID- 10590573
TI  - Molecular and cellular aspects of allergic conjunctivitis.

PMID- 10590574
TI  - Anterior chamber-associated immune deviation.

PMID- 10590575
TI  - Ocular immunosuppressive microenvironment.

PMID- 10590576
TI  - Mechanisms of intraocular inflammation.

PMID- 10590577
TI  - Immunopathogenesis of viral ocular infections.

PMID- 10590578
TI  - Immune privilege, tumors, and the eye.

PMID- 10590579
TI  - Immunopathogenic mechanisms in intraocular inflammation.

PMID- 10590580
TI  - Immunobiology and immunopathology of corneal transplantation.

PMID- 10590582
TI  - Congress did the right thing.

PMID- 10590581
TI  - Retinal transplantation.

PMID- 10590583
TI  - Medicaid: physicians speak out.

PMID- 10590584
TI  - IMS set to tackle issues in the new millennium.

PMID- 10590585
TI  - Patients seek medical advice on the Web.

PMID- 10590586
TI  - Are you being sued for malpractice? You don't have to face it alone!

PMID- 10590587
TI  - Would you help a passenger in need? Trains, boats and planes.

PMID- 10590588
TI  - Joint audits raise concerns.

PMID- 10590589
TI  - A flip of the coin.

PMID- 10590590
TI  - Common breast problems: detection and management.
AB  - Current guidelines and techniques for cancer screening are presented. Assessment
      of risk factors and significant physical and historical findings are discussed.
      Management of the more common breast problems is outlined. The primary care
      provider is left with the following thoughts (suggestions): 1. If a patient's
      worries or concerns are not relieved by a negative work-up, a second opinion
      should be sought. 2. 80 percent of the women with breast cancer have no
      identifiable risk factors! 3. High-risk patients should have increased
      surveillance or referral to a cancer specialist. 4. Any palpable solid or
      suspicious mass should be evaluated, even with a normal mammogram.

PMID- 10590591
TI  - Health care coverage of high school athletics in South Carolina: does school size
      make a difference?
AB  - Despite an apparently high injury rate, medical coverage available to these high
      school athletes is often not immediately present during practice and games. The
      purpose of the present study was to examine the current conditions of health care
      coverage and delivery to the football program and associated athletic departments
      in the public and private high schools in South Carolina. Additionally, the
      relationship between student enrollment and medical coverage was examined. A
      survey, based upon previously utilized instruments, was sent to the athletic
      directors at the public and private high schools with interscholastic football
      programs in South Carolina. The survey included questions pertaining to the
      medical coverage, including personnel, equipment, and record systems, for
      football practices and games. Based upon the results of the survey, a majority of
      high schools in South Carolina appear to have adequate sports medicine coverage
      and compare favorably with the results of similar data from other states. The
      medical coverage does significantly vary depending upon the enrollment size of
      the high school. In spite of this finding, the health care provided high school
      athletes is often inconsistent and training and equipment required for basic
      first aid is often absent.

PMID- 10590592
TI  - The physician's covenant--sanctity in service.

PMID- 10590593
TI  - [Qualitative Health Research. Physician Patient relationship].

PMID- 10590594
TI  - [Inherited primary amenorrhea. The first gynecological disease of Finnish
      heritage].

PMID- 10590595
TI  - [Is the number of hysterectomies in Finland too high?].

PMID- 10590596
TI  - [Factors affecting prescription drugs].

PMID- 10590598
TI  - [Vaginal hysterectomy. Cost benefit analysis].

PMID- 10590597
TI  - [Laparoscopic hysterectomy].

PMID- 10590599
TI  - [Medium chain Acyl-Coa Dehydrogenase deficiency. A diagnostic challenge for
      clinicians and laboratory].

PMID- 10590600
TI  - [The treatment of anxiety with cognitive therapy].

PMID- 10590601
TI  - [Asthma as a cause of death in a young male].

PMID- 10590602
TI  - [Diagnosis of an abdominal mass after a bicycling accident].

PMID- 10590603
TI  - [Withdrawal from long term benzodiazepines use].

PMID- 10590604
TI  - [Non-surgical treatment of chest pain].

PMID- 10590605
TI  - [Progressive farmers lung. Idiopathic lung fibrosis].

PMID- 10590606
TI  - [Delay in the treatment of cerebral ischemia].

PMID- 10590607
TI  - [Ophthalmic manifestation of epidemic nephropathy].

PMID- 10590608
TI  - [The clinical picture and diagnosis of epidemic nephropathy].

PMID- 10590609
TI  - [Human gene therapy].

PMID- 10590610
TI  - [Unequal pupils].

PMID- 10590611
TI  - [Intraperitoneal insulin therapy combined with continuous ambulatory peritoneal
      dialysis (CAPD)].

PMID- 10590612
TI  - [Attitudes toward genetic testing in Finland].

PMID- 10590613
TI  - [Occupational asthma caused by decorative flowers].

PMID- 10590614
TI  - [Abuse of Carisoprodol].

PMID- 10590615
TI  - [Sandifer syndrome].

PMID- 10590616
TI  - [Extrauterine pregnancy as a cause of lower abdominal pain].

PMID- 10590617
TI  - [Immunodeficiency and HIV virus infections today].

PMID- 10590618
TI  - [Pathogenesis of HIV infections].

PMID- 10590619
TI  - [Evolution of HIV virus].

PMID- 10590620
TI  - [Treatment of HIV infections].

PMID- 10590621
TI  - [Perinatal HIV infections].

PMID- 10590622
TI  - [Intravenous drug abuse and the risk of HIV infections].

PMID- 10590623
TI  - [Sle-saccharides: a promising tool against inflammation].

PMID- 10590624
TI  - [The importance of teaching medical ethics].

PMID- 10590625
TI  - [Influence of diet in fetal and neonatal period to adolescent health].

PMID- 10590626
TI  - [Phospholipid antigens, thrombosis and repeated fetal death].

PMID- 10590627
TI  - [The role of trinucleotide repeats in human genetic diseases].

PMID- 10590628
TI  - [Radiation and chemotherapy for anus neoplasms].

PMID- 10590629
TI  - [Increasing incidence of congenital heart diseases].

PMID- 10590631
TI  - [X-linked recessive spinal and bulbar muscular atrophy. Kennedy syndrome].

PMID- 10590630
TI  - [Idiopathic ventricular tachycardia].

PMID- 10590632
TI  - [Elimination of medications. Half-life].

PMID- 10590633
TI  - [Depression of a developmentally retarded patient].

PMID- 10590634
TI  - The publication policy in Duodecim.

PMID- 10590635
TI  - [The role of enterovirus in the pathogenesis of Insulin-dependent diabetes
      mellitus].

PMID- 10590636
TI  - [Assisted reproduction and risks of superovulation].

PMID- 10590637
TI  - [The role of laparoscopic staging in the assessment of metastasis of upper
      quadrant abdominal neoplasms].

PMID- 10590638
TI  - [Detection, diagnosis and treatment of depression by primary care physicians].

PMID- 10590639
TI  - [Pneumomediastinum as a sign of sigmoid perforation].

PMID- 10590640
TI  - [Chest pain and electrocardiography].

PMID- 10590641
TI  - [Keloid or Hypertrophic scar?].

PMID- 10590642
TI  - [What effects estrogen and progesterone have in the development of breast cancer,
      thrombosis and the function of the vocal cords].

PMID- 10590643
TI  - [Finland a paradise for genetics].

PMID- 10590644
TI  - [About the effect of HUGO (Human Genome Project)].

PMID- 10590645
TI  - [What is the role of molecular biology in medicine?].

PMID- 10590646
TI  - [From pedigree analysis to gene defects].

PMID- 10590647
TI  - [Diseases and gene defects].

PMID- 10590648
TI  - [About the role of RNA].

PMID- 10590649
TI  - [Biotechnology in the development of medications and vaccines].

PMID- 10590650
TI  - [In search of the genes responsible for NIDDM].

PMID- 10590651
TI  - [The mismatch-repair genes and colon cancer].

PMID- 10590652
TI  - [Endothelial growth factor and growth factor receptor genes].

PMID- 10590653
TI  - [The metabolic-chronotropic relation in patients with heart failure--a
      correlation with functional capacity].
AB  - Previous studies on chronotropic incompetence (CI) in patients with congestive
      heart failure (CHF) have defined it as the inability to achieve > 80% of age
      predicted maximum heart rate (HR) (adequacy of HR response to submaximal exercise
      levels not being considered). The metabolic chronotropic relation (MCR) concept
      proposed by Wilkoff allows the assessment of the entire chronotropic function.
      The value of such an approach for the evaluation of CI in patients with CHF, and
      its relation to exercise capacity, is unclear at present. METHODS: We imposed
      maximal symptom-limited treadmill exercise testing while measuring breath-by
      breath oxygen consumption, using CAEP protocol, in 25 patients (19 men), 49 +/-
      10 years, all in sinus rhythm, with CHF secondary to dilated cardiomyopathy (17)
      or ischemic heart disease (8), NYHA class II-III. Anaerobic threshold (AT) was
      attained by all. No exercise was terminated due to arrhythmia or ischemia. MCR
      was calculated as the slope of the relation between the percentages of HR and
      metabolic reserves achieved at the end of each exercise stage. Using 2.0 standard
      deviations below the mean level of MCR in healthy controls, we defined an MCR
      value < 0.84 as abnormal. The parameters analysed were: age, drug therapy,
      fractional shortening (FS-%), resting HR (RHR-bpm), exercise duration (DUR-min),
      peak HR (HRp), peak oxygen consumption (VO2p-ml/kg/min), percentages of predicted
      maximal HR (% PMHR) and VO2 (% PMVO2), peak ventilatory equivalent for CO2
      (VE/VCO2-L/min), time to AT (T-AT), and VO2 at AT (VO2-AT). RESULTS: MCR was
      normal (1.01 +/- 0.18-0.86 to 1.19) in 10 patients--Group I, and abnormal (0.66
      +/- 0.13-0.42 to 0.81) in 15 (60%) patients--Group II. A similar proportion of
      patients in both groups were taking ACE inhibitors, digoxin and amiodarone.
      [table: see text] CI defined as an inability to achieve a % PMHR > 80% occurred
      only in 6 (24%) patients, all in Group 2 (p = 0.022 versus abnormal MCR).
      CONCLUSIONS: In CHF patients, CI assessed as an abnormal MCR is frequent, and
      relates to an impaired exercise capacity.

PMID- 10590654
TI  - [Arterial hypertension difficult to control in the elderly patient. The
      significance of the "white coat effect"].
AB  - OBJECTIVE: Previous studies have revealed a high prevalence of white coat effect
      among treated hypertensive patients. The difference between clinic and ambulatory
      blood pressure seems to be more pronounced in older patients. This abnormal rise
      in blood pressure BP in treated hypertensive patients can lead to a misdiagnosis
      of refractory hypertension. Clinicians may increase the dosage of
      antihypertensive drugs or add further medication, increasing costs and producing
      harmful secondary effects. Our aim was to evaluate the discrepancy between clinic
      and ambulatory blood pressure in hypertensive patients on adequate
      antihypertensive treatment and to analyse the magnitude of the white coat effect
      and its relationship with age, gender, clinic blood pressure and cardiovascular
      or cerebrovascular events. POPULATION AND METHODS: We included 50 consecutive
      moderate/severe hypertensive patients, 58% female, mean age 68 +/- 10 years (48
      88), clinic blood pressure (3 visits) > 160/90 mm Hg, on antihypertensive
      adequate treatment > 2 months with good compliance and without
      pseudohypertension. The patients were submitted to clinical evaluation (risk
      score), clinic blood pressure and heart rate, electrocardiogram and ambulatory
      blood pressure monitoring (Spacelabs 90,207). Systolic and diastolic 24 hour,
      daytime, night-time blood pressure and heart rate were recorded. We considered
      elderly patients above 60 years of age (80%). We defined white coat effect as the
      difference between systolic clinic blood pressure and daytime systolic blood
      pressure BP > 20 mm Hg or the difference between diastolic clinic blood pressure
      and daytime diastolic blood pressure > 10 mm Hg and severe white coat effect as
      systolic clinic blood pressure--daytime systolic blood pressure > 40 mm Hg or
      diastolic clinic blood pressure--daytime diastolic blood pressure > 20 mm Hg. The
      patients were asked to take blood pressure measurements out of hospital (at home
      or by a nurse). The majority of them performed an echocardiogram examination.
      RESULTS: Clinic blood pressure was significantly different from daytime
      ambulatory blood pressure (189 +/- 19/96 +/- 13 vs 139 +/- 18/78 +/- 10 mm Hg, p
      < 0.005). The magnitude of white coat effect was 50 +/- 17 (8-84) mm Hg for
      systolic blood pressure and 18 +/- 11 (-9 +/- 41) mm Hg for diastolic blood
      pressure. A marked white coat effect (> 40 mm Hg) was observed in 78% of our
      hypertensive patients. In elderly people (> 60 years), this difference was
      greater (50 +/- 15 vs 45 +/- 21 mm Hg) though not significantly. We did not find
      significant differences between sexes (males 54 +/- 16 mm Hg vs 48 +/- 17 mm Hg).
      In 66% of these patients, ambulatory blood pressure monitoring showed daytime
      blood pressure values < 140/90 mm Hg, therefore refractory hypertension was
      excluded. In 8 patients (18%) there was a previous history of ischemic
      cardiovascular or cerebrovascular disease and all of them had a marked difference
      between systolic clinic and daytime blood pressure (> 40 mm Hg). Blood pressure
      measurements performed out of hospital did not help clinicians to identify this
      phenomena as only 16% were similar (+/- 5 mm Hg) to ambulatory daytime values.
      CONCLUSIONS: Some hypertensive patients, on adequate antihypertensive treatment,
      have a significant difference between clinic blood pressure and ambulatory blood
      pressure measurements. This difference (White Coat Effect) is greater in elderly
      patients and in men (NS). Although clinic blood pressure values were
      significantly increased, the majority of these patients have controlled blood
      pressure on ambulatory monitoring. In this population, ambulatory blood pressure
      monitoring was of great value to identify a misdiagnosis of refractory
      hypertension, which could lead to improper decisions in the therapeutic
      management of elderly patients (increasing treatment) and compromise
      cerebrovascular or coronary circulation.

PMID- 10590655
TI  - [In recurrent atrial fibrillation should a sinus rhythm always try to be
      maintained? No. What are the therapeutic alternatives?].
AB  - Despite the high incidence of atrial fibrillation, and the morbidity and
      mortality associated with this arrhythmia, we are still not sure of the best
      strategy to deal with it. There is little comparative data between the two
      strategies most often used: cardioversion and prophylactic antiarrhythmics to
      maintain sinus rhythm; or pharmacological control of ventricular rate and
      antithrombotic drugs. The first strategy seems to be the most desirable, but
      there are two arguments against its use in all patients: 1. It is not indicated
      when the probability of maintaining sinus rhythm during a sufficiently long
      period of time is poor. This is case of premature recurrence despite several long
      course atrial fibrillation treatments (more than one year), and the presence of a
      very large left atrium. 2. It is not indicated when the advantages of maintaining
      sinus rhythm do not outweigh its pitfalls. These are mainly related to the use of
      antiarrhythmic drugs, the efficacy of which is not very great and may present a
      potential risk of lethal pro-arrhythmia or severe collateral effects. The
      alternative strategy is feasible with the use of less toxic drugs and the high
      efficacy and safety of anticoagulant therapy for the prevention of thromboembolic
      events is currently known. Therefore, we are able to achieve a reasonable control
      of patient symptoms with a low risk of serious incidents. Trials comparing these
      strategies have not yet been concluded, therefore therapy must be individualised
      and based on a correct evaluation of foreseeable risks and benefits.

PMID- 10590656
TI  - [In recurrent atrial fibrillation should a sinus rhythm always try to be
      maintained? How?].
AB  - This paper presents the therapeutic options for recurrent paroxysmal atrial
      fibrillation. In the majority of patients, sinus rhythm should be maintained in
      order to improve cardiac function and decrease the risk of systemic embolism.
      Therapeutic options include serial pharmacological agents (with repeated external
      cardioversion) or non-pharmacological therapy: catheter or surgical ablation and
      atrial pacing.

PMID- 10590657
TI  - [Controversies in stress echocardiography: the indications, diagnostic accuracy
      and stratification of dobutamine stress echocardiography].
AB  - In recent years, stress echocardiography has become a valuable tool in the
      diagnosis, stratification and prognostic evaluation of coronary artery disease.
      Stress echocardiography has been performed with a variety of methods, including
      exercise, atrial pacing and pharmacological stress with the use of adenosine,
      dipyridamol and dobutamine. Either of these modalities of stress echo are a good
      choice in the evaluation of ischemic disease and the selection of one over
      another should depend on the patient's characteristics, experience of the stress
      echo laboratory and clinical needs (in the detection of viability there is
      greater experience in the use of dobutamine making this the most popular choice
      when evaluating myocardial hibernation). The aim of this paper is to review the
      indications, diagnostic accuracy and prognostic stratification of dobutamine
      stress echocardiography, comparing them with those obtained with other stress
      echo modalities and with nuclear techniques.

PMID- 10590658
TI  - Cardiac papillary fibroelastoma of a mitral valve chordae revealed by stroke.
AB  - We report the case of a young male patient referred to our hospital after having
      a stroke due to a papillary fibroelastoma arising from a mitral valve chorda. The
      tumor was identified by two-dimensional echocardiography and was treated by
      surgery with preservation of valve integrity. Cardiac papillary fibroelastoma as
      an uncommon source of cerebral emboli is discussed.

PMID- 10590659
TI  - [Tricuspid valve endocarditis and pneumatocele-type pulmonary embolisms].

PMID- 10590660
TI  - [In Process Citation]
AB  - INTRODUCTION AND AIMS: Transposition of the Major Arteries (TMA) is defined as
      atrioventricular concordance with ventriculoarterial discordance. Systemic and
      pulmonary circulation are in parallel and a communication between the two is
      essential for survival. Progress in echocardiography, cardiac catheterization,
      treatment with prostaglandin and cardiac surgery have reduced mortality and
      contributed to the adoption of Jatene's operation as the treatment of choice for
      TMA. Long term success depends on the continued patency of the coronary arteries
      and on the preservation of left ventricular function. Reports of significant
      silent coronary lesions and the uncertainty of long-term growth of the arterial
      anastomosis lead us to study coronary circulation in TMA. METHODS: Anatomic
      analysis of 130 heart specimens was followed by a prospective angiographic study
      in 50 children with TMA to select appropriate views for the diagnosis of the
      coronary anatomy. Troponin-T was tested as marker of myocardial ischaemia in 54
      children and myocardial function was evaluated in 30 children after Jatene's
      operation with myocardial perfusion scintigraphy, dobutamine-induced stress
      echocardiography and angiocardiography. Permeability of the coronary arteries was
      assessed with angiocardiography. RESULTS: The morphologic study led us to
      conclude that the right-anterior aorta was present in 65% of hearts with TMA,
      followed by side-by-side great arteries; the pulmonary orifice was of the same
      size or larger than the aortic orifice in the majority of TMA. Major non
      alignment of the aortic and pulmonary comissures was recorded in 14 to 30% of TMA
      specimens. The diameter of the coronary orifices was larger in TMA when compared
      to a normal heart. In cases with right anterior aorta, normal coronary pattern
      was the most frequent, followed by the pattern where the circumflex coronary
      artery (Cx) emerged from the right coronary (RCA). In cases with side-by-side
      great arteries, both patterns were equally frequent. In TMA with normal coronary
      pattern, the angles between the right and left coronary arteries and the aorta at
      the origin were equal and similar to the RCA angle with the aorta in a normal
      heart (about 90 degrees). The RCA in TMA was longer than in a normal heart.
      Although we could not find any publication reporting the angles and lengths of
      the coronary arteries, these measurements must be considered whenever
      translocation of the coronary arteries is attempted. A laid-back aortogram led us
      to the correct diagnosis of the coronary anatomy prior to surgery. Our study
      confirmed that MBCK had very low specificity for myocardial ischaemia but cTnT
      values correctly evaluated the extent of the myocardial lesion. Postoperative
      angiograms showed patent coronary arteries with no stenosis in all cases and
      myocardial perfusion was well preserved almost three years after surgery. The
      detection of ischaemic changes in three cases, in perfusion scan with normal
      function on stress-echo and on left ventriculogram, led us to warrant on-going
      follow-up.

PMID- 10590661
TI  - Blood pressure screening, management and control in England: results from the
      Health Survey for England 1994.

PMID- 10590662
TI  - [Prevalence of high blood pressure in children and adolescents. Influence of
      obesity].

PMID- 10590663
TI  - [Diagnostic criteria for diabetes mellitus].
AB  - In the last three years, new diagnostic criteria for diabetes mellitus have been
      proposed by the American Diabetes Association (ADA, 1997), the World Health
      Organization (WHO) consultation (1998), and the Japan Diabetes Society (JDS,
      1999). The most important change from the previous WHO criteria (1985) to these
      criteria is a decrease in fasting plasma glucose level (FPG) from 140 mg/dl to
      126 mg/dl, which defines diabetes mellitus. These criteria attach more importance
      to FPG than to plasma glucose levels 2 hours after 75 g glucose load (2 hPG).
      According to these criteria, for example, in one instance with FPG > or = 126
      mg/dl, the diagnosis of diabetes mellitus is warranted, if the postprandial
      plasma glucose > or = 200 mg/dl or another FPG > or = 126 mg/dl were reconfirmed
      on a subsequent day. The ADA criteria did not recommend an oral glucose tolerance
      test (OGTT) for routine clinical use. These criteria has established a new
      category of impaired fasting glucose (IFG) (> or = 110 mg/dl and 126 < mg/dl),
      similar to impaired glucose tolerance (IGT) which is recognized by performing
      OGTT. We have reported from a cohort study that there was only one risk factor
      for IGF: worsening of metabolic derangement progressing to overt diabetes. With
      IGT, however, there are two risks: a risk for progression to diabetes, and a risk
      for development of cardiovascular disease. Therefore it seems that whether or not
      OGTT should be performed depends on the purpose: simply diagnosing for overt
      diabetes, or detecting risk factors for cardiovascular disease. The JDS criteria
      proposed the use of HbA1C as a supporting diagnostic tool, because JDS has
      achieved a fruitful standardization in Japan to a considerable extent. According
      to the JDS criteria, a diagnosis of diabetes mellitus can be made by an FPG > or
      = 126 mg/dl when HbA1C > or = 6.5% is confirmed. It is expected that these new
      criteria will promote further efforts against the increasing number of patients
      with diabetes mellitus.

PMID- 10590664
TI  - [Immunological background of plasma protein abnormalities--the relation between
      inflammation and malignant neoplasm].
AB  - Mechanisms causing negative findings of serum C-reactive protein (CRP) in
      inflammatory disorders and malignant neoplasms were investigated. Patients with
      advanced prostate cancer manifesting negative CRP and alpha 2M deficiency were
      found. This finding suggests that alpha 2M, a carrier protein of interleukin-6,
      mediates CRP synthesis by the liver. Mechanism of synthesis of acute phase
      proteins including CRP, SAA and others was shown to be different in response to
      inflammation, alpha 2M-dependence in alpha 2M deficiency, the production of CRP
      and SAA by human hepatoma cells (HepG2) and the processes on the transcriptional
      activation of acute phase protein genes. In cases of prostate cancer associated
      with serum alpha 2M deficiency metastasis to the bones was noted. This finding
      suggests that alpha 2M inhibits metastasis of prostate cancer. It was suggested
      that the alpha 2M deficiency develops from complex formation of alpha 2M with
      proteases including PSA and u-PA, and accelerated catabolism of the complex
      rather than suppressed production of alpha 2M.

PMID- 10590665
TI  - [Expanding scope and impact of services provided by clinical laboratory practice
      through molecular diagnostics].
AB  - Recent progress in molecular biology and biotechnology has facilitated assays for
      DNA or RNA sequences to diagnose infectious, neoplastic and genetic diseases.
      Many of the assays have been used clinically, and are now an essential part of
      patient care under advanced medicine. A clinical laboratory needs to ensure
      services for clinical needs such as provision of tests with required turnaround
      time and high quality as well as consulting practice for individual requests. For
      quality assurance of assays, it is particularly important to monitor clinical
      validation of the results by correlating them with the patient's status to prove
      clinically relevant. Staff need to be trained to become familiar with both
      molecular pathogenesis and technology so that they can provide informative tests
      with high quality. Along with advances in pharmacogenomics, the findings of the
      human genome project have raised the prospect of developing tests for
      individualized medicine based on genetic information such as those predicting
      individual susceptibility to diseases to facilitate prevention and indicate
      responsiveness to drugs for choice of treatment. Molecular diagnostic tests will
      contribute to an efficient process of decision making on patient care and result
      in cost savings through earlier and more accurate diagnosis. The scope and impact
      of services provided by clinical laboratory practice through molecular
      diagnostics will continue to expand in its integration into clinical practice.

PMID- 10590666
TI  - [A role of clinical pathologists in Laboratory Information (Consulting) Center].
AB  - In the 21st Century, laboratory scientists must change their concepts and
      attitude in order to supply services and information of great value. The
      laboratory tests comprise an increasing volume, and medical workers frequently
      need consultation on these tests. Effective utilization of laboratory data are
      important aspects of evidence-based medicine, and will also contribute to the
      efficiency of hospital practice and management. Clinical Laboratory of Kitasato
      University Hospital opened the "Clinical Laboratory Information (Consulting)
      Center" in July 1995 to respond to the increasing demand for consultation. It has
      been supporting medical care and research. The Center is located on the second
      floor of the Clinical Laboratory building of Kitasato University Hospital, and is
      staffed by one medical technologist and a clinical pathologist specialized in
      laboratory medicine. The Center staff consults by telephone from 9 am to 5 pm on
      weekdays, and get inquiries after-work hours and during weekends either by e-mail
      or fax. The Center aims to improve medical care by providing accurate and up-to
      date information on clinical laboratory tests and interpretations. The clinical
      pathologist of the Center attempts to advise physicians regarding appropriate
      tests for particular patients. This avoids the ordering of unnecessary tests,
      which benefits the patient, the physician, and the hospital. The clinical
      pathologist should keep abreast of new findings on a wide array of clinical
      laboratory tests. The clinical pathologist should respond immediately to requests
      and complaints, thereby always seeking to improve oneself and the Center. Our
      Center is the first clinical laboratory in Japan staffed by both a clinical
      pathologist and a medical technologist, and our Center could be a pilot study for
      a new service of hospital clinical laboratories.

PMID- 10590667
TI  - [Strategic challenges of the Internet to the laboratory informatics].
AB  - The rapid and general spread of the internet brings a lot of trials for its
      applications to our fields also. They include delivery of various information
      using the home page or e-mail, online consultation systems, quality control
      systems through the internet and more. So far, the security issues have been well
      managed with skillful administration of software and hardware. A part of them
      have been achieved the outstanding merits of the internet, but mostly more
      devices or investigation will be required to realize their intrinsic great
      virtue. The revolutionary progress of the network will never stop, rather will be
      accelerated more and more, and at last will lead us to the new era, in which all
      people in the world can communicate with each other at all times through the
      network, that may be named as the hyper-network community. So we all must
      considerate how to adapt our academic and medical field to the new era, rather
      than how to apply the internet in our field.

PMID- 10590668
TI  - [Extraordinary high elevation of serum CA19-9 levels in an apparently healthy
      subject].
AB  - We studied the woman presenting extraordinarily high serum CA19-9 levels who did
      not have any disease that was known to result in elevation of the serum CA19-9
      level. Her CA19-9 values in sera obtained by 16 determinations with the enzyme
      immunoassay (EIA) over a period of 7 years were from 820 U/ml to 1,310 U/ml
      (median 1,015 U/ml). The correlation was good between serum CA19-9 levels in this
      subject with the EIA and radio immunoassay (RIA). The molecular weight of CA19-9
      was determined by high-performance liquid chromatography (TSK gel G4000 SWXL
      column). While the molecular weights of CA19-9 in each patient with pancreatic
      cancer, cholangioma, cholecystitis or pancreatitis that were used as controls,
      were greater than 1,000 kDa, the CA19-9 of this subject had the molecular weight
      of approximately 550 kDa. To further determine whether human immunoglobulin was
      involved in the elevation of CA19-9 in the serum of this subject, we investigated
      the effect of adding rabbit anti-human IgM, IgG and IgA sera to the serum of this
      subject, CA19-9 values were unaffected by these antisera. Thus, the data obtained
      from the absorption study indicated that an anti-idiotypic antibody against the
      anti-CA19-9 antibody is unlikely to be responsible for an elevation of CA19-9 in
      the serum of this subject.

PMID- 10590669
TI  - [Inhibitory effects of therapeutic reagents on the PCR detection of hepatitis C
      virus in serum and their elimination by RNA extraction methods].
AB  - Inhibitors of enzymatic amplification in serum may cause false-negative results
      for direct detection of hepatitis C virus (HCV) by polymerase chain reaction
      (PCR). This study was undertaken to demonstrate inhibitory effects of the
      therapeutic reagents on the PCR detection of HCV and to evaluate the efficacy of
      their elimination by RNA extraction methods. RNA was extracted using a manual
      method based on organic extraction and precipitation of RNA (SepaGene RV-R, Sanko
      Junyaku) or an automated system based on specific capture of HCV-RNA with probes
      and magnetic bead/fluid (B/F) separation (Roche Molecular Systems). When RNA was
      extracted by SepaGene RV-R from serum containing 10(5) copies per ml of HCV and
      amplified for HCV-RNA in the presence of hemoglobin, bilirubin, or heparin by
      Amplicor HCV (Roche Molecular Systems), results tended to be negative. In
      addition to these, two therapeutic reagents, ATP and dextran sulfate sodium were
      also found to have inhibitory effects. When ATP at concentrations up to 5 mM was
      added to the sera and RNA was extracted with SepaGene RV-R, there were no
      inhibitory effect on the detection of either HCV-RNA or the internal control. In
      contrast, when dextran sulfate sodium up to 1 mM was added to the sera, there was
      a dose dependent inhibitory effect on detection of both HCV-RNA and the internal
      control. When HCV-RNA was extracted by the automated system, the inhibitory
      effect of dextran sulfate sodium was successfully eliminated. In conclusion,
      dextran sulfate sodium and ATP were newly identified as inhibitors that may be
      present in serum, and the efficacy of eliminating these substances varied among
      RNA extraction methods.

PMID- 10590670
TI  - [Detection of Ki-67 in liver biopsy specimens using monoclonal antibody to Mib
      1].
AB  - Ki-67 antigen was visualized in formalin-fixed, paraffin-embedded liver biopsy
      specimens using monoclonal antibody to Mib-1 to identify the proliferating
      hepatocytes. Thirty liver specimens obtained from 10 patients with chronic
      hepatitis (CH) or liver cirrhosis (LC) and 10 patients with hepatocellular
      carcinoma were studied. Liver specimens were treated with a pepsin solution or
      heated with autoclave or treated with microwave as a part of antigen retrieval
      system; then stained with an immunoperoxidase method using a monoclonal antibody
      to Ki-67 (Mib-1). Stable stainings were obtained in the sections treated with
      autoclave. Ki-67 was detected in the nuclei of hepatocytes, bile duct epithelium,
      fibroblast and infiltrating mononuclear cells. In patients with CH and LC, the
      numbers of hepatocytes positive for Ki-67 has a good co-relation with serum GPT
      level (p < 0.01), while has no relationship with the degree of fibrosis. The
      number of hepatocytes positive for Ki-67 has a good co-relation with the degree
      of the differentiation of hepatocellular carcinoma. Detection of proliferating
      hepatocytes using Mib-1 is useful to understand the degree of proliferation.

PMID- 10590671
TI  - [Increased serum soluble Fas ligand in hyperthyroid Graves' disease].
AB  - The interaction of Fas with its ligand (FasL) regulates a number of physiological
      and pathophysiological process of cell death or apoptosis. Recent studies suggest
      that Fas and Fas ligand (FasL) interactions among thyrocytes from patients with
      Hashimoto disease which is caused by thyroid autoimmunity may contribute to
      clinical hypothyroidism. The role of Fas-FasL interaction in the pathophysiology
      of Graves' disease has not well been determined. The serum levels of soluble Fas
      (sFas) and FasL (sFasL) were measured in 48 Japanese patients with Graves'
      disease (U; untreated hyperthyroidism, T; hyperthyroidism under treatment, E;
      euthyroidism under treatment and R; remission), destructive thyroiditis (D),
      subacute thyroiditis (S) and 40 normal controls using commercially available
      ELISA kits. The levels of sFas (mean +/- SD, ng/ml) were 0.93 +/- 0.30 in normal
      controls (n = 32), 2.41 +/- 1.28 in U (n = 19), 2.44 +/- 0.79 in T (n = 16), 2.37
      +/- 0.55 in E (n = 12), and 2.30 +/- 0.11 in R (n = 6), 2.42 +/- 0.37 in D (n =
      3) and 2.68 +/- 0.17 in S (n = 3). There were no significant differences of sFas
      levels among any groups. While, the mean levels of sFasL (ng/ml) of normal
      controls were 0.058 +/- 0.02 (n = 40), and those of patients with hyperthyroid
      Graves' disease (U; 0.34 +/- 0.09 and T; 0.26 +/- 0.05), were significantly
      higher than those in normal controls (p < 0.005) and with subacute thyroiditis
      (0.097 +/- 0.001, vs U; p < 0.01, vs T; p < 0.05) but not different from those in
      E, R and D (E; 0.34 +/- 0.09, R; 0.25 +/- 0.07 and D; 0.31 +/- 0.11,
      respectively). There was a significant correlation between serum thyrotropin
      receptor antibody (TRAb) and free thyroxine levels (p < 0.01) while there were no
      correlation between sFas and sFasL levels and TRAb or free thyroxine levels. The
      results indicate that the Fas-FasL system contributes to the pathophysiology of
      hyperthyroid Graves' disease although serum sFas and sFasL levels do not appear
      to be useful indicators in evaluating disease activity.

PMID- 10590672
TI  - [Clinical evaluation of PCR method for detection of cytomegalovirus DNA].
AB  - Polymerase chain reaction (PCR) to detect Cytomegalovirus (CMV)-DNA from the
      clinical specimens is useful to diagnose CMV infection. Eighty-one specimens of
      31 patients including peripheral blood, bronchioalveolar lavage fluid, biopsy
      tissues, feces, urine, sputum and etc. and normal peripheral blood from 59
      volunteers were used in this study. After DNA extraction each samples was
      amplified by the seminested PCR using primers recognizing sequences in the
      Immediate-early gene of CMV. This PCR method specifically detected more than 10
      virus copies even in the presence of the genomic DNA. CMV-DNA was detected in
      only one of 59 normal peripheral bloods (1.7%). Six of 31 patients were
      clinically diagnosed as CMV infection by anti-CMV therapy. These 6 patients were
      positive in the peripheral blood by PCR for CMV, and 5 of them were positive in
      other samples. However, 3, 5 and 1 of 25 patients, who were clinically diagnosed
      as not having CMV infection, were also positive in peripheral blood, in the other
      samples and in both, respectively. The PCR method was able to examine any
      clinical samples. To examine both the peripheral blood and the samples from
      infected organs is helpful for the diagnosis of CMV infection.

PMID- 10590673
TI  - [A case positive for the inhibitor for coagulation factor V].
AB  - We report a 71-year-old man who exhibited hepatocellular carcinoma and the
      inhibitor for coagulation factor V (FV). The inhibitor was found when his
      coagulation screening tests revealed an abnormally prolonged prothrombin time
      (71.1 sec) and activated partial thromboplastin time (more than 120 sec) but
      normal values of fibrinogen (241 mg/dl), the thrombo test (84%) and hepaplastin
      test (71%). In addition, FV-coagulation activity of the patient's plasma showed
      less than 1% of the pooled normal plasma and inhibitory activity for FV of his
      plasma was 32 Bethesda units. This inhibitory activity was neutralized by the
      addition of anti-human immunoglobulin-gamma-chain serum. The patient was treated
      with a fibrin sealant including human thrombin when he underwent an partial
      hepatectomy (32 months before onset) and received 2 doses of thrombin orally (5
      months and 2 weeks before onset) to stop bleeding from phlebeurysm. Several
      studies have reported that the inhibitor for FV was produced after treatment with
      bovine thrombin containing FV as a contaminant. These findings suggest that our
      patient may produce an immunoglobulin specific for FV after similar stimulation
      of human thrombin containing FV.

PMID- 10590674
TI  - [Subcutaneous phaeohyphomycosis of the right thumb].
AB  - Black fungi are a group of fungi that are characterized by the development of a
      pale brown to black color in the cell walls of their vegetative cells, conidia,
      or both. A mycotic infection caused by a member of black fungi can be subdivided
      into three clinical entities: phaeohyphomycosis, chromoblastomycosis, and
      mycetoma. Phaeohyphomycosis is distinguished from mycetoma by the absence of
      grain (organized, interwoven mycelial aggregates) formation, and from
      chromoblastomycosis by the absence of sclerotic bodies (thick-walled muriform
      cells). Phaeohyphomycosis is a rare disease and has been sporadically reported.
      In the present report, phaeohyphomycosis of the right thumb of a 72-year-old man
      was presented. A precipitating trauma of two months earlier at the site was
      recalled. A solitary mass, 10 mm in diameter, was gradually formed in the palm
      side of the distal right thumb and finally resected. Histological examination
      disclosed a solitary granulomatous lesion surrounded by an incomplete fibrous
      capsule. The lesion mainly involved subcutaneous tissue and was composed of
      multiple pyogranulomas. Pigmented branched septate hyphae and yeast-like cells
      were sparsely found in the periphery of the abscess and within histiocytic cells
      of the granulomas. No sclerotic cells were detected. When pigmentation of black
      fungi in tissue is as faint as in the present case, Fontana-Masson staining is
      useful to accentuate the presence of melanin-like pigment of fungal cell walls.

PMID- 10590675
TI  - [Missense mutations of the butyrylcholinesterase gene in six Japanese patients
      with low cholinesterasemia: genetic analysis using sera stored in a freezer].
AB  - Six serum samples with no detectable butyrylcholinesterase (BCHE) activity had
      been stored at -70 degrees C for more than 10 years. These sera were used for
      amplification of BCHE gene using polymerase chain reaction (PCR) and for
      nucleotide sequence analysis. Five of them demonstrated a C-->T transition at
      codon 100 (CCA-->TCA), resulting in a Pro-->Ser substitution. The other one was a
      compound heterozygote as revealed a T-->C transition mutation at codon 203 from
      TCA (Ser) to CCA (Pro) and G-->C transversion at codon 365 from GGA (Gly) to CGA
      (Arg). These results showed sera stored in a freezer could be used as a starting
      material for amplification of genomic DNA when it is not possible to obtain fresh
      blood samples.

PMID- 10590676
TI  - [Genetic examination in clinical laboratory].
AB  - Genetic technology is finding active application today in the field of clinical
      laboratory medicine. Genetic examinations are divided into following three main
      classes: 1) examination for infectious disease according to the detection of the
      gene derived from bacteria or viruses, 2) examination for inherited disease
      according to molecular analysis of the genetic variation, 3) examination for
      oncogene according to molecular analysis of genetic abnormalities. At present,
      the main genetic examination in a large number of laboratories is for infectious
      disease because of its relatively simplified technique and high demand. The
      division of genetics is not a new independent section of clinical laboratory, but
      rather an ultramodern and powerful tool for existing divisions, such as
      biochemistry, serology, hematology, microbiology, and pathology. Genetic
      technology quickly provides results with high sensitivity and reliability, and
      plays a role at the core of the clinical laboratory. We should remember that the
      genetic technology is a great present given to clinical laboratories, however, it
      will eventually change into only one of the routine examinations according to the
      method of used. Examinations utilized in the clinical laboratory must be well
      established and standardized. Genetic examinations are no exception to that rule.
      These tests require a remarkably high precision since the results have an
      extraordinarily important meaning. There are more than 8,000 inherited diseases
      for instance. It is difficult to cover all examinations for those 8,000 in one
      laboratory. We need a network of laboratories that possess a genetic division, so
      that the examinations for as many inherited disease as possible can be
      comprehensively offered.

PMID- 10590677
TI  - [The role of genetic diagnosis in clinics--from the choice of ordering until
      reading the data].
AB  - Genetic diagnosis is a revolutionary method that makes possible simultaneous
      viral isolation (detection) and identification. The method is so specific,
      sensitive, and rapid (non-culture) that leads not only to the diagnosis of viral
      infection, but also to prediction of the chemotherapy, monitoring during the
      therapy, and judging the efficacy of the treatment. Moreover, it contributes to
      understanding the disease pathophysiology. The qualitative results are sufficient
      for diagnosis, but quantitative analysis is sometimes necessary for the
      prediction of the efficacy and monitoring during treatment. It occasionally
      requires the numbers of genomic expression, the number of DNA/RNA copies, and the
      detection of point mutations for drug resistance. Many emerging and re-emerging
      infectious diseases, such as AIDS and viral hepatitis, are induced by viral
      infection via blood. The main causative agents of blood-borne viral infection are
      hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus
      (HIV), human T cell leukemia virus type 1 (HTLV1), cytomegalovirus (CMV), Epstein
      Barr virus (EBV), and human parvovirus B19. They play main roles in viral
      hospital infection. The risk of them being transmitted by transfusion of screened
      blood is very low, but it is always possible that infection may occur in a window
      period even after extensive blood screening tests. Therefore, to shorten a window
      period, genetic examinations will be accepted for screening tests in the near
      future. Prioritization of genetic examinations is needed to select the adequate
      method and sampling. After examinations, false positive and false negative
      results have to be extensively read out whether due to contamination or
      inhibition by agent such as heparin and hemoglobin. The causative virus should be
      decided by carefully eliminating passenger viruses or latent viruses. Because
      genetic examinations are so useful but occasionally yield false positive and
      negative results, genetic diagnosis should be judged totally by combination with
      other examinations, clinical signs, and clinical symptoms.

PMID- 10590678
TI  - [DNA diagnosis of hematopoietic malignancies].
AB  - The recent advances in molecular biology and gene engineering have contributed
      considerably to the diagnosis and treatment of hematopoietic malignancies, such
      as leukemia and malignant lymphoma. These advances also made possible precise
      determination of the clonal origin of malignant cells, the subtype of leukemia or
      lymphoma, and the clinical prognosis in each patient. Furthermore, minimal
      residual malignant cells in leukemia or lymphoma patients after achieving
      complete remission could be detected by DNA analysis. Based on these analyses,
      treatment can theoretically be tailored for each patient. We discuss in the
      present paper the usefulness of DNA or gene analyses of immunoglobulin heavy
      chain gene in clonal assessment of lymphocytic malignancies and in detecting
      minimal residual disease in the patient.

PMID- 10590679
TI  - [Oncogenes and tumor suppressor genes as a tool for clinical diagnosis of solid
      tumors].
AB  - Over the past few years, numerous clinical studies have examined genetic
      technology to detect physical alterations of genes, such as mutations,
      translocations and amplification of oncogenes, deletion of tumor suppressor
      genes, the presence of oncogenic viruses, and the expression of genes specific to
      cancer tissues. The ability to identify individuals at high risk for cancer holds
      the promise of improved prevention and early diagnosis of cancers. The goal of
      genetic diagnosis in cancer is to provide information on abnormal oncogenes and
      tumor suppressor genes using recent molecular biology techniques. We introduced a
      highly sensitive method of detecting micrometastasis using PCR in prostate
      cancer, and strategies for guidelines in clinical diagnosis.

PMID- 10590680
TI  - [Guidelines for performing surface antigen analysis on peripheral lymphocytes
      using flow cytometry by Japanese Committee for Clinical Laboratory Standards
      (JCCLS), Area Committee on Hematology, and Subcommittee on Flow Cytometry].

PMID- 10590681
TI  - [The possibility of acute inflammatory reaction affects the development of
      pressure ulcers in bedridden elderly patients].
AB  - To test the hypothesis that acute inflammatory reaction associates with the
      development of pressure ulcers in bedridden elderly patients, 40 hospitalized
      elderly patients suffering from bacterial pneumonia, cerebrovascular disease, and
      femoral bone fracture were enrolled in this study. All of them were divided into
      two groups with pressure ulcers (group P; 17 patients) and without one (group N;
      23 patients). The blood samples were taken from them within 5 days after the
      patients being bedridden. Although no significant difference exist in pressure
      ulcer risk factors (age, gender, Braden scale, underlying diseases, blood
      pressure, and heart rate) between the two groups, white blood cell, plasma C
      reactive protein and fibrinogen in group P increased significantly as compared
      with those in group N. Besides number of platelets and maximum platelet
      aggregation rate were significantly higher in group P than in group N. Serum
      albumin and hemoglobin of both groups decreased after being bedridden, especially
      hemoglobin in group P was significantly lower than that in group N. While the
      concentration of serum IL-6 did not indicate a significant difference between
      both the groups, serum IL-1 beta increased significantly in group P. In
      conclusion, we suggested that acute inflammatory reaction releasing
      proinflammatory cytokines affected the development of pressure ulcer in bedridden
      elderly patients.

PMID- 10590682
TI  - [Monitoring of plasma concentration of low molecular weight heparin--comparative
      evaluation with chromogenic and clotting assays].
AB  - The efficacy of low molecular weight heparin (LMWH) in the treatment of
      thrombosis is increasing interest in its clinical potential. However, the
      measurement of in vitro anticoagulant activities of LMWH has been controversial
      for its appropriate clinical dose. The study has been carried out to compare two
      methods for measurement of anti-factor Xa activity of LMWH (fragmin). One is
      'HEPTEST' recently developed as a new clotting assay method and the other is an
      authentic chromogenic assay using S-2222. The coefficients of variation in intra
      assay were 1.87-2.75% in clotting assay, and 0.61-0.89% in chromogenic assay. The
      sensitivity to detect minimum concentration was 0.02 IU/ml in clotting assay, and
      0.04 IU/ml in chromogenic assay. The correlation between two methods was good (r
      = 0.935), whereas clotting assay has been revealed as a very simple rapid method.
      LMWH (fragmin) with 75 IU/kg/day was administered to three patients with
      coagulopathy; two disseminated intravascular coagulopathy (DIC) and one veno
      occlusive disease (VOD). Hemostatic abnormalities have been improved serially
      after treatment in all patients. During treatment, the plasma concentration of
      LMWH was measured, showing 0.05-0.23 IU/ml in DIC and 0.02-0.10 IU/ml in VOD.
      These results suggest that measurement of plasma concentration of LMWH using the
      easy and rapid clotting assay method as 'HEPTEST' is clinically useful for
      monitoring to detect clinical dose of LMWH for DIC and thrombosis.

PMID- 10590683
TI  - [Monoclonal analysis in B-cell neoplasms by the semi-nested polymerase chain
      reaction using consensus primers].
AB  - Monoclonality on B-cells is well known to be determined on the basis of presence
      of a rearranged-IgH gene, which is detected by Southern blot hybridization (SBH)
      remaining to be elucidated in respects of not only time-consumed, labour and cost
      benefit and also the use of much DNA samples. Alternative to this SBH, we
      examined the clinical usefulness of monoclonal analysis by the polymerase chain
      reaction technique which amplifies rearranged-CDR III region of IgH gene (IgH
      PCR). The detective sensitivity of the IgH-PCR was different dependently upon
      each analysis for amplified products, namely 10(-2) per mononuclear cells in
      agarose gel analysis and 10(-3) in polyacrylamide gel and single strand
      conformation polymorphism analysis (PAGE and SSCP). Then, using the IgH-PCR and
      PAGE/SSCP analysis, 75 Japanese patients with B-neoplasm and 23 with T-cell
      neoplasms were examined for clonal IgH rearrangements. The diagnostic sensitivity
      in each group of B-ALL, B-CLL, B-lymphoma, HCL, AML with B-cell antigens, and non
      T cell neoplasms was 88%, 92.3%, 71.4%, 100%, 57.1%, and 0%, respectively, with
      an overall sensitivity and specificity of 88% and 100%. This indicates that PCR
      analysis is very useful in detecting the clonal rearrangement of IgH genes on B
      cell neoplasms, especially on ALL and CLL corresponding to neoplasms
      counterparting to naive B-cells.

PMID- 10590684
TI  - [Detection of K-ras mutations in colon cancer by PHA-PHFA (preferential
      homoduplex formation assay)].
AB  - The mutations of K-ras gene have been demonstrated at frequencies of about 40% in
      human colorectal cancer. We applied a developed PCR-preferential homoduplex
      formation assay (PCR-PHFA) to detect a point mutation of K-ras gene in the
      surgical specimens from thirty patients with colorectal cancer. This method is
      based on the strand competition during hybridization between a double labeled
      amplicon, prepared from biotin and DNP labeled primers, and an unlabeled
      amplicon. The procedure of this method is simple and speedy, and suitable to
      detect mutations in a small number of samples. By using this method, the
      mutations were found in 37% (11/30) and confirmed by sequencing analysis. The
      results suggest that the PCR-PHFA system may be useful for detecting low frequent
      mutation of K-ras gene even in the case of an early cancer.

PMID- 10590685
TI  - [Clinical analysis of Pseudomonas aeruginosa bacteremia].
AB  - To determine the outcome of Pseudomonas aeruginosa bacteremia and to identify
      risk factors for these infections in our University hospital, 46 cases (65
      episodes) of Pseudomonas aeruginosa bacteremia were retrospectively investigated.
      The most frequent underlying diseases or cases were from Emergency and Critical
      care center (18 cases, including 11 case of cerebrovascular accident and head
      injury) followed by hematologic malignancies (11 cases) but none of the HIV
      infection was included in this study. The overall crude mortality rate was 50%
      and mortality rate within the first 1 week was 17%. Clinical analysis of those
      cases revealed that possible risk factors were neutropenia, sever sepsis and
      prior use of antibiotics (antipseudomonal antibiotics were administered before
      positive blood culture episodes in 90% cases). But these factors were not
      statistically significant between dead and survived cases. CONCLUSION: To improve
      the prognosis of Pseudomonas aeruginosa bacteremia, we must change the management
      of the hospital infection, such as the more rational use of new antipseudomonal
      antibiotics and the more clean and reasonable management of central venous
      catheters.

PMID- 10590686
TI  - [Immunohistochemical study of Sertoli-stromal cell tumor; comparison between the
      tumor arising from the gonad of a testicular feminization syndrome bearing
      patient and from ovaries of non-bearing patients].
AB  - The association of Sertoli-stromal cell tumor with testicular feminization
      syndrome (TFS) has been elaborated in the past studies. Here, we described
      immunohistochemical studies on Sertoli cell tumor of the gonad in a TFS patient
      and compare with 2 other cases of spontaneous ovarian Sertoli-stromal tumor.
      [Case 1] The case was a 73 year-old Japanese patient (46XY karyotype), who had
      had primary amenorrhea. High level of testosterone was noted in laboratory
      investigation (1900 ng/ml). No ambiguous morphology of external genitalia was
      present, but atrophy of vagina was noted. The patient was diagnosed as TFS. A
      left gonadal tumor was identified histologically showing well differentiated
      Sertoli cell tumor. The tumor cells were positive for anti-vimentin antibody but
      negative for anti-keratin, EMA and p53 antibodies by immunohistochemistry. The
      right gonad was an immature testis. [Case 2] The case was a 33 year-old female
      with ovarian Sertoli-Leydig cell tumor. Immunohistochemically, positive reaction
      for anti-keratin and p53 antibodies were observed. [Case 3] The case was a 17
      year-old female with moderately differentiated Sertoli cell tumor of the ovary.
      The tumor cells were positive for anti-keratin, EMA and p53 antibodies by
      immunohistochemistry. Difference in immunohistochemical reactions between Sertoli
      cell tumor in TFS and Sertoli-stromal cell tumors of the ovaries was probably due
      to variation in the degree of gonadal development.

PMID- 10590687
TI  - [Transition of branched-chain amino acids and tyrosine ratio (BTR) in the blood
      of acute hepatitis patients].
AB  - The molar ratio of branched-chain amino acids to tyrosine (BTR) correlates well
      with the Fischer ratio, and can be measured in a short period of time. It is
      regarded as the method of analysis that will eventually replace the Fischer
      ratio. But clinical significance of BTR in terms of acute liver disorders has not
      been examined thoroughly as of yet. In this study, we measured BTR of 34 patients
      with acute hepatitis, and examined the transition of the acute period of acute
      hepatitis and its recovery process. Thirty-four patients diagnosed with acute
      viral hepatitis became subjects of examination (16 patients of A type, 15
      patients of B type, 1 patient of C type, 2 patients of non-A, non-B, non-C type).
      Out of the 34 patients, 11 were in serious stages (HPT under 40%), including 3 in
      fulminant condition. By using preserved serum obtained during the acute period
      (within 1 week of the highest transaminase value), recovery period (within 4
      weeks), and treatment period (3 months and later), measurements were conducted
      with Diacolor:BTR (enzymatic analysis, ONO Pharmaceutical Co., Ltd.), and the
      results were compared with those of 50 healthy subjects (25 men, 25 women). BTR
      correlated well with the Fischer ratio for chronic hepatic patients, and with
      albumin (Alb), PT, and ICGR15 as well, proving that it is useful as an indicator
      of hepatic reserve ability. But BTR has not been thoroughly examined as it
      relates to acute liver disorders. In this study, BTR fell in the acute period,
      correlating with the serious period, proving that it is a useful indicator. For
      acute liver damage, BTR supports conventional indicators (Alb, Ch-E, HGF, etc.)
      for assessing serious damage. Also, it has been suggested that measuring the
      passage of BTR could be the indicator of true recovery, including amino acid
      metabolism for liver disorders.

PMID- 10590688
TI  - [High creatine kinase MB concentration and activity in patients with
      rhabdomyosarcoma].
AB  - A 14-year-old boy with rhabdomyosarcoma (RMS) of the left palm showed increased
      concentration and activity of creatine kinase (CK; EC 2.7.3.2) MB in his serum.
      CK isoenzyme analysis revealed no extra band. Other laboratory data including
      high lactate dehydrogenase (LD) isoenzyme 2, CK isoenzyme BB and MB, neuron
      specific enolase (NSE), and clinical findings did not support the diagnosis of
      myocardial infarction. The high activity and concentration of CK-MB in serum is
      possibly originated from the tumor. We could follow his time-course and analyze
      laboratory data of him and other 6 patients with RMS. We concluded that CK-MB,
      both concentration and activity, was the more sensitive marker of disease states
      of RMS than NSE and LD to follow up the patients with RMS.

PMID- 10590689
TI  - [Recent topics on amino-acid neurotransmitters].

PMID- 10590690
TI  - [Psychiatry and care for the aged].

PMID- 10590691
TI  - [Japanese society of geriatric psychiatry].

PMID- 10590692
TI  - [Actual state of psychiatric patients admitted for medical care and custody by
      the consent of the mayor of the city, town, village or the head of the special
      ward and hospital's opinions of the custodial duties performed by the mayor of
      the city, town, village or the head of the special ward: a research report].

PMID- 10590693
TI  - [An experimental study of the patterns in the development of an inflammatory
      process in the mandibular bone tissue caused by exposure to anaerobic
      microflora].
AB  - Inflammatory process in mandibular bone was induced in 39 outbred rats by a pure
      culture of Bacteroides fragilis and by an associative culture of B. fragilis and
      Staphylococcus aureus. Anaerobic microflora notably aggravated the course of
      inflammation. In contrast to inflammation in other parts of the skeleton,
      inflammation of the jaws involves a high risk of infection of the oral cavity by
      pathogenic microflora. A variety of microorganisms is isolated from the focus:
      from gram-positive staphylococci to gram-negative enterobacteria, which fact
      should be borne in mind when planning antibiotic therapy. Combined use of
      antibiotics active towards the entire spectrum of agents detected in this study
      is the most effective.

PMID- 10590694
TI  - [The dynamics of the healing of experimentally reproduced bone defects filled
      with different polyacrylamide gel-based compounds].
AB  - Time course of healing of standard osseous defects by introduction of
      polyacrylamide gel (PAG)-based materials was studied in rat experiments. PAG did
      not prevent the formation of soft-tissue and osseous regenerate in bone defects.
      Addition of hydroxyapatite, bactericidal agent, and lysozyme to PAG-based
      composition led in some cases to development of chronic inflammation and giant
      cell reaction in osseous wound and to inhibition of the reparative processes.

PMID- 10590695
TI  - [Focal morphological changes in the bone tissue of the mandible and tibia of
      rabbits under the influence of different metal inclusions].
AB  - Morphological changes in bone tissue were studied in an experimental model with
      electrochemical polarization of the bone, which was achieved by applying
      electrodes (anode made of silver-palladium alloy SPS-250 and cathode of copper
      aluminum alloy manufactured as orthodontic ligature wire) on the mandibular
      periosteum and tibial bone of rabbits. Macroscopic changes were as follows:
      osseous tissue hypertrophy at the zone of cathode polarization with a
      corresponding increase in the area of transverse section of the mandible and
      atrophy of the bone under the anode, all this causing pronounced asymmetry of the
      jaw bones. Microscopic changes in the bone were adequate to the macroscopic and
      characterized by sharp activation of its apposition (under cathode) and
      resorption (under anode).

PMID- 10590696
TI  - [A clinical study of Solcoseryl Dental Adhesive Paste and Mundisal gel in the
      treatment of chronic recurrent aphthous and herpetic stomatitides].

PMID- 10590697
TI  - [Aseptic necrosis of the temporomandibular joint in systemic lupus
      erythematosus].
AB  - A total of 285 patients with verified systemic lupus erythematosus (SLE) were
      examined. They complained of painful temporo-mandibular joint (TMJ) and/or
      limited mobility of the mandible. Eight patients with chronic arthritis of the
      TMJ and a shortened (by 3-4 mm) mandibular branch were detected. In 4 female
      patients aged 25-38 with SLE lasting for about 5.5 years, unilateral signs of
      myoarticular dysfunction of the TMJ, flattening and decrease of the articular
      head without erosion and destruction, subcortical round foci with uneven internal
      contours were found in the central or median part of the head, with the compact
      bone above the foci thinned and the articular surface flattened; this prompted us
      to regard these changes as avascular necrosis (AN) of the joint. Shortening of
      the mandibular branch was caused by deformation of the neck of the articular
      process and its declination backwards. The detected changes in the TMJ were not
      accompanied by involvement of other joints. All these 4 patients with SLE and TMJ
      AN suffered from cerebropathy with epileptic attacks (frequent in 2 patients),
      Raynaud's syndrome, and bright capillaries of the palms and soles; 2 patients
      developed clinical picture of the antiphospholipid syndrome. Computer tomography
      and magnetic resonance findings validating the development of TMJ AN in?

PMID- 10590698
TI  - [The temporomandibular joints before and after the surgical treatment of patients
      with maxillary micro- or retrognathism and mandibular macro- or prognathism].
AB  - The temporomandibular joint has been examined in patients with combined
      deformations of the jaws (upper micro- or retrognathia and lower macro- or
      prognathism) before and after surgical treatment of the maxilla and mandible.
      Analysis of changes in the temporomandibular joint at all stages of medical
      rehabilitation showed that structural changes develop only in 8% patients only
      after planar osteotomy of the mandible through external or oral approach.

PMID- 10590699
TI  - [Changes in the level of DNA minor bases in salivary gland inflammation and its
      correction with antioxidants].
AB  - In the experiment with guinea pigs at contact sialoadenitis reproduction
      (karragenine inflammation of soft tissues of the oral cavity) it was established
      that in DNA of salivary glands cells and the neighbouring tissues the content of
      5-methylcytosine was decreased, it being normalized at "Triovit" antioxidant
      complex together with cvercitynum correction. The content of DNA 8-hydroxyguanine
      is characterized by a wide range of data and in absolute values increases in
      inflammation, but decreases after antioxidant correction. The role of the changes
      discovered is discussed.

PMID- 10590700
TI  - [The restoration of the anterior teeth with crown-root fractures].
AB  - The author suggests repair of the front teeth after crown-root fractures making
      use of the remaining crown. Due to precise coincidence of the fracture surfaces
      of both fragments of the tooth and fixation with a cast pin and composite
      materials, good results were attained.

PMID- 10590701
TI  - [The x-ray cephalometric characteristics of the mesial bite in adults].
AB  - The purpose of the study was improving the quality of diagnosis and planning of
      treatment of adult patients with maxillodental abnormalities (mesial occlusion).
      A method for differential diagnosis of facial skull abnormalities was introduced,
      a modified scheme of x-ray cephalometric analysis was created, an automated
      diagnostic computer software was developed, forms of mesial occlusion were
      studied and described and their classification created. A total of 211 adult
      patients with mesial ratio of molars were examined. The principal method of
      examination was cephalometric analysis of the lateral teleroentgenograms of the
      skull using an original computer diagnostic software. Causes leading to formation
      of mesial occlusion were defined and classification of the abnormality offered.

PMID- 10590702
TI  - [The morphological status of the maxillodental system in children living in an
      area contaminated by radionuclides as a result of the accident at the Chernobyl
      Atomic Electric Power Station].
AB  - The present study has been done in the framework of federal programme "Children
      of Chernobyl" with the aim to determine spread and structure of dental jaw
      abnormalities in children born and living in the radiation polluted regions after
      Chernobyl accident in 1986. 183 children have been examined in Donskoi town of
      Tula Province with the polluted soil by Cs-137 up to 5 Ci/km. All the examined
      children were divided into 2 groups: group 1--born in 1980-1986 and group 2--born
      in 1987-1994. It was determined that 76.5% of children have dental jaw system
      abnormalities. The most spread ones were occlusion abnormalities in combination
      with teeth abnormalities (28.9% cases) while the state of dental jaw system
      corresponding to the age standard was 2 times rarer in children born after the
      Chernobyl accident.

PMID- 10590703
TI  - [A rare case of the posttraumatic retention of the upper left central incisor].

PMID- 10590704
TI  - [Suggestive and persuasive advertising in dentistry].

PMID- 10590705
TI  - [Whither is the delivery of prosthodontic care for the population drifting in the
      coming decades?].

PMID- 10590706
TI  - [Occlusal forces].

PMID- 10590707
TI  - [Psychological research in dentistry].
AB  - The comprehensive review of literature on psychological research in dentistry is
      provided. At least 25% of adults are highly afraid of dentistry. The
      phenomenology of fear of dental treatment is described. The feared experiences
      are many, including most frequently, pain. Several studies have shown that
      anxious patients experience less pain during treatment than they expect.
      Expectations of pain are highly resistant to change. The use of psychological
      treatment to reduce psychological stress as well as to prevent onset and
      maintenance of anxiety during dental procedures is described.

PMID- 10590708
TI  - [The history of the creation of drilling machines (1)].

PMID- 10590709
TI  - [Development of asymmetric synthesis of optically active compounds including
      fluoroorganic molecules].
AB  - The synthesis of chiral fluorinated molecules is important in the biological and
      medicinal chemistry fields in view of the influence of fluorine's unique
      properties on biological activity. In recent years, we have studied asymmetric
      synthesis focussing on such optically active compounds. This review describes 1)
      diastereoselective trifluoromethylation of chiral N-acyloxazolidinones, 2)
      catalytic enantioselective aldol reactions of fluorine-substituted ketene silyl
      acetals, and 3) catalytic enantioselective allylation of aldehydes mediated by
      chiral Lewis bases. The trifluoromethylation of lithium enolates of N
      acyloxazolidinones with iodotrifluoromethane is mediated by triethylborane to
      give the corresponding trifluoromethylated products with up to 86% diastereomeric
      excess. The stereoselective reaction is considered to proceed through the attack
      of the trifluoromethyl radical on the less hindered face of the lithium imide.
      Difluoroketene and bromofluoroketene trimethylsilyl ethyl acetals react with
      various aldehydes in the presence of chiral Lewis acids to afford the
      corresponding desired aldols with up to 99% enantiomeric excess (ee). It is
      noteworthy that the aldol reactions of the fluorine-substituted acetals at -78
      degrees C and at higher temperatures (-45 or -20 degrees C) provide the (+)- and
      (-)-aldols, respectively, with excellent-to-good enantioselectivity. Chiral
      phosphoramides newly prepared from (S)-proline were found to catalyze the
      allylation and crotylation of aromatic aldehydes with allylic trichlorosilanes in
      good enantioselective yields (up to 90% ee). (S,S)-Bis(alpha
      methylbenzyl)formamide developed as an efficient catalyst for the allylation and
      crotylation of aliphatic aldehydes mediates the enantioselective addition with
      the assistance of hexamethylphosphoramide (HMPA) to afford the corresponding
      homoallylic alcohols in up to 98% ee.

PMID- 10590710
TI  - [Analysis of xenobiotic detoxification system mediated by efflux transporters].
AB  - The excretion of drugs mediated by transporters plays an important role in the
      detoxification of xenobiotics. In this article, I will summarize recent progress
      we have made in this field, particularly focusing on the roles of transporters
      responsible for exporting drugs. As far as the biliary excretion of xenobiotics
      is concerned, it has been suggested that canalicular multispecific organic anion
      transporter/multidrug resistance associated protein 2 (cMOAT/MRP2) is involved in
      the ATP-dependent export of organic anions across the bile canalicular membrane.
      By comparing the transport across this membrane between normal rats and Eisai
      hyperbilirubinemic rats whose cMOAT/MRP2 function is hereditarily defective, we
      were able to demonstrate the substrate specificity of cMOAT/MRP2. This includes
      non-conjugated anionic drugs, and glutathione- and glucuronide-conjugates of
      xenobiotics. The role of cMOAT/MRP2 in drug disposition has also been clarified.
      Moreover, the cDNA of cMOAT/MRP2 has been cloned and its functional analysis has
      been completed. Thus, it may be possible to predict in vivo transport across the
      bile canalicular membrane from in vitro data using the recombinant transporter.
      We also cloned MRP3 as an inducible transporter in the liver under the
      cholestatic conditions. Although MRP3 mediates the cellular export of non
      conjugated organic anions and glucuronide-conjugates, the substrate specificity
      of MRP3 is different from that of cMOAT/MRP2 in that glutathione-conjugates are
      poor substrates for MRP3. It is possible that MRP3 plays an important role under
      certain pathological conditions in the liver. Since it has been shown that
      cMOAT/MRP2 and MRP 3 are expressed in the small intestine under physiological
      conditions, it seems reasonable that these transporters are responsible for the
      previously reported cellular extrusion of organic anions. We also found that
      there was MRP activity in the blood-brain and blood-cerebrospinal fluid barriers.
      RT-PCR resulted in the amplification of MRP1, 5 and 6 from freshly isolated rat
      cerebral endothelial cells. It has been suggested that there is basolateral
      localization of MRP1 in the choroid plexus. In conjunction with the P
      glycoprotein located on the luminal membrane of cerebral endothelial cells, these
      transporters play significant roles in restricting the entry of xenobiotics from
      the circulating blood into the central nervous system. Regulation of the activity
      of these efflux transporters allows the disposition of drugs to be altered.

PMID- 10590711
TI  - [Physiological, genetic and pathological factors regulating the reductive
      metabolism of drugs with a ketone group].
AB  - In this review, we describe the physiological, genetic and pathological factors
      regulating the reductive metabolism of drugs with a ketone group. Acetohexamide
      (AH) was chosen as a model drug with a ketone group. Species differences of AH
      reductase activity were observed in liver cytosol and microsomes of animals
      tested. AH reductase activity in liver microsomes of rats was much higher in
      males than females. The activity was not detectable until 4 weeks of age after
      birth in both sexes, but increased markedly at puberty only in males. AH
      reductase activity in liver microsomes of male rats was decreased by testectomy,
      and restored by the treatment with testosterone propionate, indicating that the
      sex-related difference and postnatal development of the activity are regulated by
      androgens. There was a strain difference of AH reductase activity in liver
      microsomes of male rats. Of rat strains tested, only Wistar-Imamichi strain was
      found to lack male-specific microsomal enzyme activity. The inheritance pattern
      of AH reductase activity in liver microsomes of rats was determined by mating the
      genetic deficiency Wistar-Imamichi strain with Fischer-344 strain. Streptozotocin
      induced diabetes significantly decreased AH reductase activity in liver
      microsomes of male rats. Furthermore, the physiological role of AH reductase
      present in liver microsomes of male rats was examined. We propose the possibility
      that the male-specific microsomal enzyme physiologically functions as a 20 beta
      hydroxysteroid dehydrogenase.

PMID- 10590712
TI  - [Pharmacokinetic analysis of antiplatelet effect of sarpogrelate hydrochloride
      and its application to drug dosage regimen--modeling based on reversible
      inhibition of 5-HT2 serotonergic receptor in the platelet membrane by
      sarpogrelate hydrochloride and its metabolite].
AB  - Sarpogrelate hydrochloride is an antiplatelet drug, and expected to be useful in
      the treatment of chronic arterial occlusive diseases. Sarpogrelate and its active
      metabolite (M-1) are potent inhibitors of human platelet aggregation, and
      selectively inhibit 5-HT2-serotonergic receptors on human platelets. However, the
      plasma concentrations of these inhibitors do not correlate to the inhibitory
      effect on platelet aggregation after administration. Sarpogrelate disappears from
      the plasma more rapidly in comparison to the duration of its pharmacological
      effect, and the plasma concentration of M-1 is very low (< 1/10 of sarpogrelate).
      In this paper, we describe a pharmacokinetic-pharmacodynamic model for
      ascertaining the antiplatelet effects of sarpogrelate and M-1, by considering
      both the competitive reversible inhibition and the association/dissociation
      process of these drugs at the 5-HT2 receptors on platelets (Most data used for
      analysis were obtained from the literatures, except for the serum protein binding
      rate of M-1). The developed model was well fitted to the actual data, and
      suggested that M-1 was more effective for the inhibition of platelet aggregation
      than sarpogrelate. On the basis of these findings, a new method was developed for
      predicting inhibitory effects on platelet aggregation after oral administration
      of sarpogrelate hydrochloride. This method is useful for planning a rational
      dosage regimen of sarpogrelate hydrochloride and predicting the duration of
      antiplatelet activity after the discontinuance of the drug.

PMID- 10590713
TI  - [Population pharmacokinetic analysis of theophylline: relationship between serum
      concentrations and clinical effects in therapeutic drug monitoring].
AB  - Therapeutic drug monitoring (TDM) of theophylline is essential duties at hospital
      pharmacy in Japan. The relationship between serum concentrations and clinical
      effects of theophylline has been investigated. The pharmacokinetics of
      theophylline was determined from the concentration of theophylline in the serum
      which were calculated on the basis of TDM for patients administered theophylline.
      The one-compartment model as a pharmacokinetic model was assumed. The
      relationship between clinical effects of theophylline and the predicted
      concentrations calculated using population parameters was evaluated. The obtained
      parameters are ka(h-1) = 0.223, ke(h-1) = 0.047 (1-0.0025.age(y) (p.o.) and
      0.076(1-0.0025.age(y)) (d.i.v.), Vd(1/kg) = 0.733 (p.o.) and 0.830 (d.i.v.). The
      bioavailability is 0.732, and theophylline/aminophylline is 0.846. The model
      including no serum creatinine as a variational factor was considered to be best.
      The following three groups were used as a clinical evaluation; effective as
      theophylline therapy was 43%, no change of the clinical status after
      administration of theophylline was 42%, and aggravation after administration of
      theophylline was 15%. There is no relationship between the predicted
      concentration using parameters of the final model and these three groups. These
      results suggest that TDM of theophylline should be assessed in terms of clinical
      effects and also suggests that in should be kept monitoring from the viewpoint of
      the prevention of toxic effects in the theophylline therapy.

PMID- 10590714
TI  - [A rapid determination method for scopolia extract in gastrointestinal drugs by
      capillary electrophoresis].
AB  - A rapid and simple determination of tropane-alkaloids (hyoscyamine, scopolamine)
      in gastrointestinal drugs was investigated by capillary electrophoresis. Micellar
      electrokinetic capillary chromatography (MEKC) using a fused silica capillary
      (560 mm x 0.075 mm i.d.) in 0.1 M SDS 20 mM borate buffer (pH 10)/acetonitrile
      (97:3) gave complete separation of the two alkaloids within 40 min. A sample
      solution was introduced by pressure method (50 mbar, 3.7 s), separation
      conditions applied voltage 15 kV and on-column detection was performed at 210 nm.
      Calibration curves for hyoscyamine and scopolamine showed a good linearity in the
      range of 4-12 micrograms/ml (r = 0.9970) and 390-1150 ng/ml (r = 0.9976). The
      present method is applicable to the simple and rapid determination of hyoscyamine
      and scopolamine in commercial gastrointestinal drugs.

PMID- 10590715
TI  - American Society of Hematology 41st annual meeting. New Orleans, Louisiana, USA.
      December 3-7, 1999. Abstracts. Part 1 of 2.

PMID- 10590716
TI  - American Society of Hematology 41st annual meeting. New Orleans, Louisiana, USA.
      December 3-7, 1999. Abstracts. Part 2 of 2.

PMID- 10590717
TI  - 5th German Congress on Radiation Oncology, Radiation Biology and Medical Physics.
      Karlsruhe, 6-9 November 1999. Abstracts.

PMID- 10590718
TI  - Asthma management: still much to do.

PMID- 10590719
TI  - Erectile dysfunction in the Australian community.

PMID- 10590720
TI  - Screening, case finding and evidence-based guidelines.

PMID- 10590721
TI  - Helicobacter pylori eradication therapy for non-ulcer dyspepsia: what is the
      evidence?

PMID- 10590722
TI  - A South Australian population survey of the ownership of asthma action plans.
AB  - OBJECTIVE: To examine the relationships between ownership of written asthma
      action plans, asthma morbidity, use of devices, and patients' perceptions of
      their asthma management. DESIGN AND SETTING: A random population survey (in 1996)
      of the South Australian population aged 15 years or over, using interviewers to
      administer a questionnaire. PARTICIPANTS: People who reported that they had
      current, doctor-diagnosed asthma. MAIN OUTCOME MEASURES: Prevalence of written
      asthma action plans; night-time awakenings from asthma; ownership of peak flow
      meters; and people's perceptions of their asthma management. RESULTS: The
      ownership of asthma action plans by people with self-reported asthma was 33% and
      has declined since 1995 (42%; P < 0.001). Fifteen per cent were awakened weekly
      or more frequently by asthma symptoms. These people were more likely to have a
      peak flow meter and a written action plan, but less likely to consider they had
      been provided with enough information about their asthma, to feel comfortable
      managing their asthma, or to find it easy to see their doctor. Having a written
      asthma action plan was associated with regular corticosteroid use, understanding
      asthma, having enough information and owning a peak flow meter. CONCLUSIONS:
      Ownership of asthma action plans in South Australia is suboptimal. Before we
      develop new strategies to improve asthma outcomes, we must determine whether
      there is a need to target people with less severe asthma and/or improve the use
      of guidelines by health professionals.

PMID- 10590723
TI  - Erectile dysfunction in the community: a prevalence study.
AB  - OBJECTIVE: To investigate the prevalence of erectile dysfunction (ED) in the
      South Australian community, and the influence of demographic and other risk
      factors. DESIGN: Survey by mailed questionnaire (based on the University of
      California, Los Angeles prostate cancer index) of a subset (men who agreed to
      participate) of a probability sample of the South Australian community who
      completed a multiuser interview survey. PARTICIPANTS AND SETTING: Men over the
      age of 40 in South Australia. MAIN OUTCOME MEASURES: Sexual desire, orgasm,
      ability to have an erection, adequacy (firmness) of erections for intercourse,
      frequency of erections when wanted, frequency of intercourse, nocturnal or
      morning erections, and history of prostate surgery; total sexual function score
      based on these. RESULTS: 612 men (86.7%) agreed to answer the sexual function
      survey; 427 (69.8%) returned questionnaires. ED was strongly correlated with age
      in all seven domains of sexual function. Erections inadequate for intercourse
      affected 3% of 40-49-year-olds, increasing to 64% of 70-79-year-olds. The
      frequency of intercourse considered normal for age by men 50-69 years was 1-6
      times weekly; the disparity between this and reported frequency increased in men
      over 60 years, as did the difference between sexual desire and potency. A history
      of vigorous exercise was protective across all ages. High triglyceride levels,
      blood pressure medication and non-cancer surgery for prostate disease were
      independent predictors of poor sexual function at older ages. High cholesterol
      level was an independent predictor of impotence. CONCLUSIONS: We found similar or
      higher levels of ED than in comparable overseas studies. Disparity between
      potency and desire was greatest, and hence the age group in whom demand for
      treatment may be highest, in those 60 years and older. Cardiovascular risk
      factors were predictors of ED in these older men, suggesting that prevention may
      benefit sexual function. Non-cancer prostate surgery may be a greater contributor
      to ED than previously realised.

PMID- 10590724
TI  - Hormone therapy use in Australian-born women: a longitudinal study.
AB  - OBJECTIVES: To describe the pattern of use of hormone therapy (HT) among
      Australian women, and its side-effects and benefits, and to compare baseline
      characteristics of HT users with never users. DESIGN: Longitudinal community
      based study with annual interviews. SETTING: Melbourne, May 1991-October 1997.
      PARTICIPANTS: 357 Australian-born women aged 45-55 years who were pre- or
      perimenopausal and not using HT at baseline. MAIN OUTCOME MEASURES: Rates of HT
      use; baseline characteristics of users and non-users; side effects and benefits
      of HT use. RESULTS: 151 women (42%) used HT over the six years and 93 (26%) were
      current users at six-year follow-up. HT users did not differ significantly from
      non-users in lifestyle, sociodemographic and cardiovascular risk factors or in
      most health status factors at baseline. However, HT users were significantly more
      likely to have had a breast examination by a health professional (odds ratio
      [OR], 2.60; 95% CI, 1.62-4.17), to have had a tubal ligation (OR, 1.73; 95% CI,
      1.09-2.74), to report a history of premenstrual complaints (OR, 1.72; 95% CI,
      1.08-2.74), to agree that women "regret when their period stops for the last
      time" (OR, 1.69; 95% CI, 1.04-2.74), and to report that they took non
      prescription medications (OR, 1.62; 95% CI, 1.02-2.59). Most (84%) HT users
      described benefits (most commonly relief of hot flushes and improved wellbeing),
      while 53% complained of side effects (most commonly weight gain and breast
      tenderness). CONCLUSIONS: HT users did not differ significantly from non-users at
      baseline in most characteristics. Long-term follow-up of this cohort is now
      required to assess any difference in cardiovascular events or other health
      outcomes between HT users and non-users.

PMID- 10590725
TI  - General practitioners' perceptions of medicolegal risk. Using case scenarios to
      assess the potential impact of prostate cancer screening guidelines.
AB  - OBJECTIVE: To ascertain general practitioners' perceptions of medicolegal risk
      when screening for prostate cancer, and explore the potential impact of three
      national guidelines on perceptions and clinical practice. DESIGN: Postal survey
      in August 1997. PARTICIPANTS: 219 randomly selected GPs in New South Wales (65%
      response rate). MAIN OUTCOME MEASURES: Response to case scenarios; perceptions of
      medicolegal risk and protection afforded by national guidelines before and after
      reading extracts of three national guidelines; ratings of current and potential
      strategies to increase GPs' sense of medicolegal protection. RESULTS: 90% (95%
      CI, 86.5%-94.3%) would screen an asymptomatic male patient and 61% (95% CI, 54.2%
      67.2%) indicated GPs would be at risk if they did not screen. Although
      significant changes in responses were found after respondents had read guideline
      extracts, 46% (95% CI, 39.5%-52.7%) continued to perceive medicolegal risk if
      screening was not performed. About two-thirds (65%; 95% CI, 59.9%-72.5%)
      supported a clear statement about the legal status of guidelines in a court of
      law to increase their sense of medicolegal protection. CONCLUSIONS: Even when
      made aware of national evidence-based guidelines against prostate cancer
      screening, GPs in our survey perceived limited hypothetical medicolegal
      protection.

PMID- 10590726
TI  - Delay in diagnosing juvenile arthritis.
AB  - Juvenile arthritis may present as swollen fingers or toes or joint swelling after
      minor trauma. The diagnosis can easily be overlooked, as small children do not
      complain about pain. Untreated arthritis can cause deformities or, with eye
      involvement, damaged vision. Three case histories are presented, as well as an
      audit of diagnostic delay in children with juvenile arthritis presenting to a
      paediatric rheumatology service over 12 months.

PMID- 10590727
TI  - Simplified DOTS to improve tuberculosis control in Asia and the Pacific?
AB  - Simplification eases implementation and may make a real difference in the fight
      against this widespread disease.

PMID- 10590728
TI  - Sex selection: the case for.
AB  - There is a strong argument in favour of sex selection, based on respect for
      procreative autonomy--the autonomy of couples to decide for themselves how to
      procreate, and what children to have. Objections based on possible harm to the
      child, the parents, or society, are not compelling, particularly in Australia.

PMID- 10590730
TI  - Adult attention deficit disorder and child abuse.

PMID- 10590729
TI  - Leukotriene receptor antagonist drugs for asthma.

PMID- 10590731
TI  - General practice research.

PMID- 10590732
TI  - Anaphylactic or anaphylactoid reaction to Haemaccel?

PMID- 10590733
TI  - Outcomes of an educational-outreach service for community medical practitioners:
      non-steroidal anti-inflammatory drugs.

PMID- 10590734
TI  - The Bibbulung Gnarneep Project: practical implementation of guidelines on ethics
      in indigenous health research.

PMID- 10590735
TI  - Preventing suicide.

PMID- 10590736
TI  - Anorexia nervosa, infertility and pregnancy.

PMID- 10590737
TI  - Bacteraemia in febrile children presenting to a paediatric emergency department.

PMID- 10590738
TI  - Managing chest pain in the emergency department.

PMID- 10590739
TI  - Monitoring drinking water: the receding zero.

PMID- 10590740
TI  - "Problem doctors" and medical boards.

PMID- 10590741
TI  - Do management algorithms improve chest pain triage?
AB  - OBJECTIVE: To audit the use of management algorithms for chest pain in an
      emergency department. DESIGN AND SETTING: Prospective study of all patients with
      chest pain presenting to the emergency department of an urban teaching hospital
      between 12 January and 4 May 1997. Staff were asked to complete a standardised
      admission form that incorporated the risk stratification algorithms for managing
      patients with suspected acute coronary syndrome. MAIN OUTCOME MEASURES:
      Compliance with the use of management algorithms; concordance with a
      cardiologist's review of the triage grouping and admission/discharge decision;
      and major cardiovascular events over four months. RESULTS: Emergency department
      staff documented the triage group in 223 of 503 cases (45%). Concordance with the
      group assigned by a cardiologist was 70% (kappa = 0.73; SE kappa = 0.04). When
      the management algorithm was applied correctly, 92% of triage decisions were
      correct (95% confidence interval [CI], 87%-96%). The triage decision was less
      often correct when risk stratification was not done (78% [73%-83%], P < 0.001),
      overestimated (77% [66%-88%], P < 0.01), or underestimated (50% [18%-82%], P <
      0.001). The proportion of patients free of major cardiovascular events at four
      month follow-up was 50% for those with myocardial infarction with ST-segment
      elevation, 47% for those with a high short-term risk of an adverse cardiac event,
      82% for those with intermediate risk, and 99% for those with a low risk or non
      coronary chest pain (P < 0.001). CONCLUSIONS: Use of management algorithms by
      emergency staff was poor. When used, triage decisions were more likely to be
      correct. Subsequent outcome confirms that the NHMRC risk stratification
      algorithms are useful for prognostic stratification of patients with suspected
      acute coronary syndrome.

PMID- 10590742
TI  - End-stage renal disease in aboriginals in New South Wales: a very different
      picture to the Northern Territory.
AB  - OBJECTIVES: To compare the incidence of end-stage renal disease (ESRD) among
      Aboriginals in New South Wales with the incidence among Aboriginals in the
      Northern Territory, and to compare the patterns of ESRD among Aboriginals and non
      Aboriginals in NSW. DESIGN: Secondary data analysis of information from
      unpublished and published Australia and New Zealand Dialysis and Transplant
      Registry reports. MAIN OUTCOME MEASURES: Average annual incidence of ESRD
      (persons per million); form of renal replacement therapy; mortality at 31 March
      1998; patient and graft survival one and five years after transplant. RESULTS:
      Each year in NSW, 5-17 new Aboriginal patients are treated for ESRD. There was no
      increase in the average annual incidence of ESRD among NSW Aboriginals (118 per
      million in 1988-1989 and 111 per million in 1996-1997), whereas incidence in the
      NT increased from 255 per million to 800 per million. In NSW, ESRD was attributed
      to diabetes in 32% of Aboriginal patients, compared with 13% of non-Aboriginal
      patients (P < 0.001). In NSW, Aboriginal patients were younger and more likely to
      be female, a pattern similar to that in the NT. The outcome of ESRD treatment is
      not significantly different between Aboriginals and non-Aboriginals in NSW.
      CONCLUSION: There is a different pattern of incidence of ESRD and of outcomes
      with treatment among Aboriginals in NSW compared with those in the NT. A possible
      explanation is that the lower incidence in NSW reflects less profound
      socioeconomic disadvantage and better access to primary and specialist care.

PMID- 10590743
TI  - Is sudden infant death syndrome still more common in very low birthweight infants
      in the 1990s?
AB  - OBJECTIVE: To determine the rate of sudden infant death syndrome (SIDS) in very
      low birthweight children (VLBW) relative to children with low (LBW) and normal
      birthweights. DESIGN, SETTING AND SUBJECTS: Cohort study of consecutive live
      births in Victoria, 1993-1997 inclusive. MAIN OUTCOME MEASURES: All sudden
      unexpected deaths in early childhood over this five-year period; all deaths from
      SIDS (defined as a sudden unexpected death without a definite pathological
      explanation); and the proportion of SIDS in live births in three birthweight
      subgroups (VLBW, 500-1499 g; LBW, 1500-2499 g; and normal birthweight, > 2499 g).
      RESULTS: There were 316,028 live births (with known birthweight) in Victoria over
      the five-year period; 224 (0.71 per 1000 live births) died unexpectedly. In 10 of
      these deaths there was a definite pathological explanation, giving a rate of SIDS
      of 0.68 per 1000 live births. The rate of SIDS in VLBW children was 2.52 per 1000
      live births, lower than the rate reported before the 1990s. The rate of SIDS in
      VLBW children was not significantly different from the rate in LBW children of
      1.98 per 1000 live births (difference per 1000 live births, 0.53; 95% CI, -1.45
      to 2.52), but was significantly higher than the rate in normal birthweight
      children of 0.59 per 1000 live births (difference per 1000 live births, 1.93; 95%
      CI, 0.06-3.79). CONCLUSIONS: The rate of SIDS in VLBW children has fallen in the
      1990s, along with the overall fall in the rate of SIDS, but remains higher than
      that in normal birthweight children.

PMID- 10590745
TI  - Intestinal angioedema mimicking Crohn's disease.
AB  - Angioedema usually presents as episodic attacks of swelling of the face, airway
      and extremities, but it may also involve visceral tissues. A 58-year-old woman
      with repeated episodes of abdominal pain, nausea and vomiting had two
      laparotomies and was treated for Crohn's disease for two years before a diagnosis
      of acquired intestinal angioedema was made. This case provides important insights
      into the presentation of intestinal angioedema.

PMID- 10590744
TI  - Impaired practitioners notified to the Medical Practitioners Board of Victoria
      from 1983 to 1997.
AB  - OBJECTIVE: To describe the characteristics of and outcome for impaired medical
      practitioners notified to the Medical Practitioners Board of Victoria. DESIGN:
      Retrospective review of records for all impaired practitioners notified to the
      Board for the first time from January 1983 to December 1997. OUTCOME MEASURES:
      Number of notifications per year; characteristics of impaired practitioners;
      source of notification; diagnosis and diagnostic categories; actions by the
      Board; and outcomes for impaired practitioners. RESULTS: In 15 years, 170
      impaired practitioners were notified to the Board for the first time, 86 in the
      last four years. Significantly more men than women were notified to the Board
      (ratio, 4.2:1; P < 0.001). Reporting by patients was uncommon, but 46 impaired
      practitioners reported themselves. One hundred and five impaired practitioners
      had a psychiatric disorder, 73 had a drug use disorder, 35 had an alcohol use
      disorder, and 13 had a physical disorder (not exclusive categories). The Board
      suspended 73 practitioners and imposed conditional registration on 76.
      Subsequently, 88 practitioners were able to improve their registration status.
      Fifty-nine practitioners were renotified to the Board or tested positive to a
      urinary drug screen. Eleven practitioners died, four before the age of 55 years.
      CONCLUSIONS: Increasing numbers of notifications in recent years coincided with
      changes in the legislative framework, making notification compulsory but also
      giving the Board more flexibility in dealing with impaired practitioners.
      Nonetheless, comparison with population data suggests that impaired practitioners
      (particularly those with substance use disorders) may be under-reported.

PMID- 10590746
TI  - Attention deficit hyperactivity disorder in adults: conceptual and clinical
      issues.
AB  - Reports published over the past decade indicate that attention deficit
      hyperactivity disorder (ADHD) is a cause of significant psychological impairment
      in adults. The adulthood disorder occurs as a continuation of its childhood
      counterpart, with the full ADHD syndrome persisting into early adulthood in about
      a third of those with childhood ADHD. Despite advances in the understanding of
      the neurobiology of adult ADHD, the diagnosis is made clinically by establishing
      a retrospective childhood diagnosis, evaluating the current symptom profile and
      excluding alternative medical or psychiatric causes of symptoms. Adults with ADHD
      have high rates of comorbid psychiatric disorder and suffer significant
      relationship dysfunction, work and educational failure. There is emerging
      evidence for the effectiveness of specific treatments for adult ADHD, including
      stimulant medications and some antidepressants. Clinicians should be aware of
      this potentially treatable disorder in young adults presenting with psychological
      difficulties and a history of childhood ADHD symptoms.

PMID- 10590747
TI  - Cryptosporidiosis in the immunocompromised: weighing up the risk.
AB  - Cryptosporidiosis has been increasingly recognised as a cause of diarrhoeal
      illness in both immunocompetent and immunocompromised people. Massive outbreaks
      have been linked to municipal drinking water supplies in North America and
      Europe, but so far none have been reported in Australia. There is evidence that
      modes of transmission other than drinking water are more important. There can be
      no guarantee that infective Cryptosporidium oocysts will not contaminate an
      Australian water supply. Therefore, a permanent "boil water" warning may be
      warranted on medical advice in severely immunocompromised people, for whom
      cryptosporidiosis could be persistent and life threatening.

PMID- 10590748
TI  - Viruses, vaccines and villains. Highlights of the XIth International Congress of
      Virology, Sydney, 1999.

PMID- 10590749
TI  - Cardiac rehabilitation and secondary prevention.
AB  - Group programs of cardiac rehabilitation and secondary prevention provide better
      outcomes than medical consultations alone. Tightly specified goals for secondary
      prevention are now more rigorous than ever before and should be reached by all
      patients. After acute myocardial infarction, patients require beta-blockers,
      aspirin, lipid-lowering agents and angiotensin-converting enzyme inhibitors.
      Psychosocial adjustment problems are common in cardiac patients and their
      families, but these can be significantly reduced by appropriate rehabilitation
      strategies. Patients with additional needs should be identified (e.g., some
      working patients require work assessment, employer contact, additional exercise
      and specified return-to-work guidelines).

PMID- 10590751
TI  - Confidentiality and the courts.

PMID- 10590750
TI  - Mortality associated with New South Wales methadone programs.

PMID- 10590752
TI  - Australians with renal disease: a new national survey.

PMID- 10590753
TI  - Quinine-induced blindness during attempted heroin withdrawal.

PMID- 10590754
TI  - Q fever in south west Queensland.

PMID- 10590755
TI  - Treatment of severe meningitis due to antibiotic-resistant Streptococcus
      pneumoniae.

PMID- 10590756
TI  - Drug-free control of pinworms?

PMID- 10590757
TI  - Self-regulation is a failure.

PMID- 10590758
TI  - Hearing impairment data.

PMID- 10590760
TI  - Human exposures to inorganic mercury.

PMID- 10590759
TI  - Methylmercury: a new look at the risks.
AB  - In the US, exposure to methylmercury, a neurotoxin, occurs primarily through
      consumption of fish. Data from recent studies assessing the health impact of
      methylmercury exposure due to consumption of fish and other sources in the
      aquatic food web (shellfish, crustacea, and marine mammals) suggest adverse
      effects at levels previously considered safe. There is substantial variation in
      human methylmercury exposure based on differences in the frequency and amount of
      fish consumed and in the fish's mercury concentration. Although virtually all
      fish and other seafood contain at least trace amounts of methylmercury, large
      predatory fish species have the highest concentrations. Concerns have been
      expressed about mercury exposure levels in the US, particularly among sensitive
      populations, and discussions are underway about the standards used by various
      federal agencies to protect the public. In the 1997 Mercury Study Report to
      Congress, the US Environmental Protection Agency summarized the current state of
      knowledge on methylmercury's effects on the health of humans and wildlife;
      sources of mercury; and how mercury is distributed in the environment. This
      article summarizes some of the major findings in the Report to Congress and
      identifies issues of concern to the public health community.

PMID- 10590761
TI  - Mercury: a regional problem requires collaborative efforts.

PMID- 10590762
TI  - A real plan of action on mercury.

PMID- 10590763
TI  - Strengthening the links between the public health community and health
      professions regulation.

PMID- 10590765
TI  - Cyclosporiasis associated with imported raspberries, Florida, 1996.
AB  - OBJECTIVES: Until 1995, infection with Cyclospora cayetanenis, a parasite that
      causes gastroenteritis, was diagnosed in the US primarily in overseas travelers;
      its modes of transmission were largely unknown. In 1995, 45 cases of
      cyclosporiasis were diagnosed in Florida residents who had no history of recent
      foreign travel, but an investigation could not pinpoint a source for the
      parasite. In 1996, a North American outbreak of cyclosporiasis resulted in more
      than 1400 cases, 180 of them in Florida. The authors investigated the 1996
      Florida outbreak to identify the vehicle of transmission. METHODS: The authors
      conducted a matched case-control study in which each of 86 laboratory-confirmed
      sporadic cases was matched with up to four controls. They also investigated nine
      clusters of cases associated with common meals and attempted to trace implicated
      foods to their countries of origin. RESULTS: In the case control study, eating
      raspberries was strongly associated with cyclosporiasis (matched odds ratio =
      31.9; 95% confidence interval [CI] 7.4, 138.2). In the cluster investigation,
      raspberries were the only food common to all nine clusters of cases; a summary
      analysis showed a strong association between consumption of raspberries and
      confirmed or probable cyclosporiasis (risk ratio = 17.6; 95% CI 1.9, 188.8).
      Guatemala was the sole country of origin for raspberries served at six of nine
      events. CONCLUSIONS: Guatemalan raspberries were the vehicle for the 1996 Florida
      cyclosporiasis outbreak. Cyclospora is a foodborne pathogen that may play a
      growing role in the etiology of enteric disease in this country as food markets
      become increasingly international.

PMID- 10590766
TI  - The impact of a needle exchange's closure.
AB  - OBJECTIVE: The Windham, Connecticut, needle exchange closed in May 1997 after
      becoming embroiled in a public controversy in which it was blamed for the city's
      drug problem, discarded syringes, and even the economic decline of the city
      itself. The authors interviewed injection drug users and conducted a community
      survey of discarded drug paraphernalia to explore the effects of the needle
      exchange's closure. METHODS: After the needle exchange was closed in March 1997,
      the authors re-recruited former participants in an AIDS prevention research
      project, the majority of whom were clients of the needle exchange. The authors
      analyzed responses from these respondents' pre-closure interviews and from III
      post-closure initial interviews and 78 post-closure follow-up interviews as well
      as data on discarded syringes and "dope bags". RESULTS: Following the closure of
      the needle exchange, significant increases were found in the percentage of
      respondents who reported an unreliable source as their primary source of
      syringes, in respondents' reports of the frequency of reusing syringes, and in
      the percentage of respondents who reported sharing of syringes. Surveys of
      outdoor drug-use areas found that the closure of the needle exchange did not
      reduce the volume of discarded syringes and other drug-injection debris.
      CONCLUSIONS: The problems in Windham that led to the closure of the exchange
      still remain, and the city's drug injectors are engaging in higher levels of HIV
      risk behavior.

PMID- 10590767
TI  - Racial discrimination and alcohol-related behavior in urban transit operators:
      findings from the San Francisco Muni Health and Safety Study.
AB  - OBJECTIVE: A growing body of literature is documenting the health effects of
      racial discrimination. The authors investigated the association between racial
      discrimination and alcohol-related behavior in a sample of urban transit
      operators. METHODS: Using data from a 1993-1995 cross-sectional study of transit
      operators in San Francisco, California, the authors analyzed responses to two
      sets of questions about racial discrimination; the first set focused on reaction
      to unfair treatment and the second on arenas, or domains, of discrimination.
      Alcohol-related variables were: number of drinks per month, heavy drinking,
      alcohol dependence, and negative consequences of alcohol consumption. RESULTS:
      Operators who reported five or more domains of discrimination drank an average of
      13.4 more drinks per month than those who reported no domains of discrimination
      (P = 0.01). Similarly, they were more likely to be heavy drinkers (adjusted odds
      ratio [OR] = 2.16; 95% confidence interval [CI] 1.14, 4.09) and dependent on
      alcohol (adjusted OR = 2.02; 95% CI 1.08, 3.79) than operators who reported no
      domains of discrimination. The number of domains in which operators reported
      having experienced discrimination was not related to sex, age, household income,
      job seniority, or marital status, but varied significantly by educational level
      and race/ethnicity. CONCLUSIONS: Data from a sample of urban transit operators
      showed an association between the number of domains of discrimination and some
      alcohol-related outcomes, but not others.

PMID- 10590769
TI  - A comprehensive refugee health screening program.
AB  - Nationally and internationally, there is a struggle to provide adequate health
      screening and assessment programs for refugees. The Department of Family Medicine
      at the University of Colorado Health Sciences Center in partnership with the
      Colorado Refugee Services Program has developed a comprehensive refugee health
      screening and assessment program. The program was designed to ensure access to
      screening and to provide better care for this vulnerable population. Key features
      of the program include a single point of access for all family members, full
      availability of appropriate interpreting services, comprehensive health
      assessments that include a thorough mental health screening, data collection and
      evaluation, and education of health care providers to deliver culturally
      responsive care. During the first 30 months of this program, comprehensive
      assessments were provided for more than 1600 refugees. Future directions include
      improving the efficiency of daily systems, seeking alternative sources of
      funding, improving follow-up and vaccination rates, expanding mental health
      services, and tracking health outcomes and refugees' utilization of health care
      services through longitudinal research.

PMID- 10590768
TI  - Implementation of EPA's Worker Protection Standard training for agricultural
      laborers: an evaluation using North Carolina data.
AB  - The US Environmental Protection Agency has promulgated a Worker Protection
      Standard which requires that farmworkers receive pesticide safety training. The
      implementation of these regulations has not been evaluated. Using data collected
      through personal interviews with 270 Hispanic farmworkers recruited from 35 labor
      sites in an eight-county area, the authors analyzed the extent to which
      farmworkers received pesticide safety training, characteristics of the training,
      and variations in knowledge and safety behavior. Approximately a third of the
      farmworkers reported having ever received information or training on pesticide
      safety, and 25.6% reported having received training in the year in which they
      were interviewed. Workers with H2A visas were significantly more likely to have
      received training than workers without these visas. The training received varied
      in location, duration, and language. Most included the use of a video, as well as
      verbal presentation, and most included printed materials. However, few workers
      knew the ways in which they could be exposed to pesticides or reported using any
      method to protect themselves from pesticide exposure.

PMID- 10590770
TI  - [Truth after death].
AB  - Diagnosis is central to medicine. In spite of tremendous diagnostic technological
      advances, no infallible test exists and in the complex diagnostic process the
      physician may well get lost. The ultimate feedback on the accuracy of diagnosis
      is the autopsy. Five patients illustrate that the autopsy may disclose unexpected
      results. The first patient was a 9-year-old girl who suffered from daily
      abdominal spasmodic pain but each time recovered. She died suddenly; autopsy
      revealed intestinal intussusception. A 46-year-old man who was treated for
      hypertension developed pain in the chest and the lower back, but there were no
      other signs of myocardial infarction. He died suddenly; autopsy revealed a
      dissecting aortic aneurysm with rupture in the left pleural cavity. A 21-year-old
      woman, an excellent swimmer, drowned during a swim in the sea. Autopsy revealed
      severe widespread coronary disease with multiple myocardial infarction. A 32-year
      old Surinam woman developed acute coma and died from cardiorespiratory arrest. At
      autopsy she had massive pulmonary embolism and generalized lymphadenopathy due to
      sarcoidosis. The last patient, a 32-year-old woman suffered from fatigue after
      her fourth child was born. She was admitted with severe dyspnoea and her chest X
      ray showed interstitial fibrosis. She died presently and autopsy revealed
      metastatic colon carcinoma with pulmonary lymphangitis carcinomatosa. Systematic
      reviews of the results of autopsies show no decline in the percentage of false
      diagnoses and/or unexpected findings in spite of the enormous growth of the
      diagnostic armamentarium. Although we may radiologically 'slice' the body in
      incredible detail or investigate human cells at the molecular level, the autopsy
      has by no means become obsolete and is an invaluable tool for quality control and
      teaching.

PMID- 10590771
TI  - [Transmission of hepatitis B virus by a surgeon].
AB  - A Dutch surgeon transmitted hepatitis B virus (HBV) to several of his patients (8
      certain cases, 2 probable cases and 18 possible cases). To view this accident in
      the proper context, we estimated the incidence of HBV transmission in the
      Netherlands from surgeons to patients (1/37,000 surgical procedures) and from
      patients to non-immune surgeons (0.8%/surgeon/year). The incident as such is
      alarming because of the high frequency of HBV transmission that occurred.
      However, the number of infections involved was lower than the expected number of
      iatrogenic HBV infections in the Netherlands during the given period. It is
      advisable to quickly implement the WHO guidelines, demanding universal HBV
      vaccination of infants, and to organize vaccination of risk groups (including
      medical personnel) in the Netherlands.

PMID- 10590772
TI  - [Autopsies as an important indicator for quality control].
AB  - The decreasing number of autopsies, in the Netherlands as well, is deplorable
      because with it an important instrument of medical quality control is likely to
      disappear. For this not only the relatives, but also the attending physicians and
      the pathologists are to blame. To turn the tide we need some drastic changes in
      our attitude towards autopsies. The families should known that an autopsy is a
      right they have in order to check the quality of diagnosis and treatment of their
      beloved, it is not a favour towards the physician. A physician who does not see a
      reason for autopsy, should explain that to the family. Pathologists should think
      about and realize a subspecialty of autopsy pathology with a thorough training in
      pathophysiology and intensive care medicine. Autopsy reports should be of the
      highest quality and reach the physician within a few weeks. A required autopsy
      percentage should be introduced into the certification process of medical
      specialists and hospitals and the possibility of Continuous Medical Education
      credit points for physicians with a certain autopsy percentage should be
      considered.

PMID- 10590773
TI  - [Diagnosis of malignant pleural mesothelioma and asbestosis].
AB  - The incidence of malignant mesothelioma, the main consequence of exposure to
      asbestos, will increase considerably in the Netherlands in the coming decades. In
      the next 35 year, some 20,000 people will die from malignant mesothelioma. The
      diagnosis of malignant pleural mesothelioma in practice is based on histological
      examination in about 80%, on cytological examination in 15% and on other forms of
      examination, e.g., high resolution computer tomography (HRCT), in 6% of the
      cases. Using a combination of various noninvasive methods, such as anamnesis,
      physical and rontgenologic examination, HRCT and spirometry, the diagnosis of
      asbestosis is made erroneously in 5% of the patients examined. With regard to
      allowance of financial compensation to patients with pleural mesothelioma and
      asbestosis, a part is played by the fact that views differ internationally
      concerning the criteria on which the diagnosis should be based. For mesothelioma
      cytologic and histologic examination are the most important. For asbestosis, the
      Health Council considers HRCT as crucial, if necessary supplemented by
      histological examination, plus a history of exposure to asbestos and pulmonary
      dysfunction. In mesothelioma cytological and histological examination are the
      most important.

PMID- 10590774
TI  - [Clinical results and costs due to improved antibiotics policies].
AB  - Major reasons to conduct antibiotic policies are to improve the quality of
      patient care, to limit the emergence of resistance, and to contain costs. Many
      studies have addressed overconsumption and misuse of antibiotics. Studies have
      shown a correlation between antibiotic use in hospitals and the development of
      microbial resistance. Recommendations for the content and management of future
      antibiotic policy strategies in hospitals include educational programmes,
      consultation by infectious diseases physicians, restriction of the formulary,
      timely narrowing of empirical broad spectrum therapy ('streamlining'), and
      automatic stop orders. A recent study in a Dutch university hospital revealed
      overconsumption of antibiotics for prophylaxis in surgery and undertreatment with
      antibiotics in internal medicine departments. Intervention resulted in better
      compliance with guidelines, reduction of the consumption of antibiotics in
      surgical prophylaxis, and cost containment. However optimation of antimicrobial
      therapy also sometimes resulted in an increase of antimicrobial drug consumption.

PMID- 10590775
TI  - [Early change from intravenous to oral antibiotics: 'switch therapy'].
AB  - There has been growing interest in recent years in early switch therapy:
      antibiotics are administered intravenously during the early phase of the
      infection, and then continued orally. A large number of recent prospective and
      randomized studies justify the application of an early switch. There is consensus
      in the literature about the circumstances in which an early switch is justified:
      (a) the patient must show clinical improvement; (b) the oral therapy should
      result in sufficiently high levels at the infection site; (c) the patient must be
      capable of taking oral medication, there must be no signs of malabsorption and
      interactions with food or with other drugs should be taken into account; (d) if
      these rules are observed, switch to oral therapy as a rule is justified after 2
      to 3 days' intravenous administration. An early switch is more comfortable to the
      patient, eases the load on the nursing staff and considerably reduces expenses.

PMID- 10590776
TI  - [Pregnancy course and outcome in 2956 pregnancies after in-vitro fertilization in
      Netherlands].
AB  - OBJECTIVE: Description of the outcome of pregnancies after in vitro fertilisation
      (IVF) in Dutch IVF centers. DESIGN: Descriptive, retrospective. METHOD: Data were
      collected on IVF pregnancies in the period 1984-1992 from seven Dutch IVF
      centers. RESULTS: The study comprised 2956 pregnancies. Five centres provided
      data on 2133 ongoing and non-ongoing pregnancies. More than 25% ended in a
      spontaneous abortion (22.3%) or ectopic pregnancy (3.6%). From the seven centres
      there were data available on 2311 ongoing pregnancies. Of these, 30.8% were
      multiple; preterm delivery occurred in 29.2%. The birth weight of 40.6% of 3173
      neonates was lower than 2500 g and that of 10.1% lower than 1500 g. A birth
      weight under the 10th percentile of the national reference curve was found in
      16.7% and under the 2.3rd percentile in 4.3% of cases. Perinatal mortality was
      31.3 pro mille. In 1588 singleton pregnancies preterm birth occurred in 15.6%;
      41.3% of the singletons weighed less than 2500 g, of which 3.6% less than 1500 g
      while 12.3% had a birth weight below the 10th percentile. The results of our
      study are similar to those of other major studies in the literature and are
      unfavourable compared with to Dutch reference values. This is mainly due to the
      high proportion of multiple pregnancies. However, we found indications of a
      slight disturbance of pregnancy in IVF singleton and twin pregnancies.

PMID- 10590777
TI  - [Hemobilia as a complication of laparoscopic cholecystectomy].
AB  - A woman aged 38 displayed colicky pains and melaena two weeks after a
      laparoscopic cholecystectomy. The haemoglobin level was decreased, the serum
      hepatic enzyme levels were slightly increased. Diagnostic imaging examinations
      and finally, because of recurrent symptoms, an emergency laparotomy revealed a
      bleeding from a pseudoaneurysm of the proper hepatic artery next to the
      choledochus. The aneurysm was ligated. Seven months later the patient had no more
      symptoms. The possibility of haemobilia should be considered in every case of
      gastrointestinal bleeding after laparoscopic cholecystectomy.

PMID- 10590778
TI  - [Opportunistic screening for genital infections with Chlamydia trachomatis among
      the sexually active population in Amsterdam. III. Cost-effectiveness analysis of
      screening women and the role of reinfection and partner treatment].
AB  - The role of reinfection and the importance of partner treatment were added to a
      pharmacoeconomic model for the analysis of a GP-based opportunistic screening
      programme for Chlamydia trachomatis (CT) in sexually active women in Amsterdam. A
      favourable cost-effectiveness was found for partner treatment. Partner treatment
      was cost saving and overall net costs per major outcome averted by the screening
      programme were reduced by 40% or more due to partner treatment. From a
      pharmacoeconomic point of view partner treatment should be routinely provided in
      the framework of a CT screening programme for Amsterdam women.

PMID- 10590779
TI  - [Increased frequency of icterus in patients after change of parenteral lipid
      emulsion].

PMID- 10590780
TI  - [Public health care after aviation accident in Bijlmermeer; long-term sequelae].

PMID- 10590781
TI  - 1999 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer
      Therapeutics: Discovery, Development, and Clinical Validation. Washington, DC,
      USA. November 16-19, 1999. Abstracts.

PMID- 10590783
TI  - GLYCO XV. XVth International Symposium on Glycoconjugates. Tokyo, Japan. August
      22-27, 1999. Abstracts.

PMID- 10590784
TI  - The VIIth World Congress of Psychiatric Genetics. Monterey, California, USA.
      October 14-18, 1999. Abstracts.

PMID- 10590782
TI  - XIV Congress of European Association of Gynaecologists and Obstetricians (EAGO).
      Granada, 29 September-2 October 1999. Abstracts.

PMID- 10590785
TI  - Annual meeting of the North American Association for the Study of Obesity.
      Charleston, South Carolina, USA. November 14-18, 1999. Abstracts.

PMID- 10590786
TI  - Urachal cystadenoma in a filly.

PMID- 10590787
TI  - Hepatic carcinoid, hypercortisolism and hypokalaemia in a dog.
AB  - A German Shepherd dog was diagnosed with periodic myopathy secondary to
      persistent hypokalaemia. Hormone analysis revealed excess cortisol secretion. A
      neuroendocrine carcinoma, thought to be a primary hepatic carcinoid, was detected
      in the liver. Ectopic adrenocorticotrophin hormone secretion was suspected as the
      cause of hypercortisolism and hypokalaemia, although this could not be confirmed
      by immunohistochemical staining.

PMID- 10590788
TI  - Surgical removal of an ependymoma from the third ventricle of a cat.
AB  - A 10-year-old spayed domestic shorthaired cat was presented for behavioural
      changes, signs suggestive of visual deficits and aimless circling. Neuro
      ophthalmological examination suggested the cat had central blindness. CT scans
      following administration of iohexol demonstrated a contrast-enhancing mass in the
      vicinity of the third ventricle resulting in obstructive hydrocephalus. Following
      rostral tentorial craniotomy and incision through the cerebral cortex, the third
      ventricle was approached via the dilated left lateral ventricle. An ependymoma
      was seen through a dorsocaudolateral incision into the third ventricle, and
      removed by gentle manipulation and suction. The cat recovered unremarkably,
      regaining normal vision and behaviour.

PMID- 10590789
TI  - Evidence of sperm storage in the female ostrich.
AB  - OBJECTIVE: To determine the length of time following mating that fertile eggs can
      be laid by an ostrich (Struthio camelus). DESIGN: A clinical reproductive problem
      in a pair of breeding ostriches provided the opportunity to mate the birds at
      intervals of 5 to 8 days and assess the fertility of the eggs laid. PROCEDURE:
      Following prolapse of the phallus of the male ostrich during the breeding season,
      the pair were immediately separated. The hen was reintroduced to the cock at
      intervals of 5 to 8 days over a 6 week period for supervised mating. Records were
      kept of dates of mating and laying, number of eggs laid, egg weights, and
      fertility determined by candling after 2 weeks incubation. RESULTS: Over the 6
      week period, 10 eggs were laid, of which 8 were fertile and 2 infertile. Fertile
      eggs weighed 1020 to 1285 g (mean 1143). The two infertile eggs weighed 1160 and
      925 g. Six fertile eggs were laid 2 to 7 days after mating. The remaining two
      fertile eggs were laid the same days that mating occurred, suggesting that
      fertilization resulted from the last matings 5 and 8 days previously, or from
      earlier matings. CONCLUSION: Sperm storage occurs in ostrich hens and fertile
      eggs can be laid for at least 5 to 8 days after copulation. Further studies are
      required to demonstrate the maximum period during which stored sperm are capable
      of successful fertilization.

PMID- 10590790
TI  - Presumed hereditary elliptocytosis in a dog.

PMID- 10590791
TI  - Torsion of the uterus in an Awassi ewe.
AB  - The treatment of a 4-year-old pluriparous Awassi ewe with torsion of the uterus
      at parturition is described. At presentation, all the signs of imminent
      parturition were present and the rostral portion of the vagina was spirally
      twisted to the right causing complete stenosis of the birth canal with no foetal
      fluid exiting the uterus. A 360 degrees clockwise uterine torsion was diagnosed.
      Attempted treatment by rotation of the ewe's body proved unsuccessful. The
      condition was then corrected surgically via a left flank caesarean operation, and
      a dead foetus and foetal membranes were removed. The animal made an uneventful
      recovery and the sutures were removed on the 12th postoperative day.

PMID- 10590792
TI  - Repair of cranial cruciate ligament rupture in an alpaca.
AB  - A mature male alpaca with acute lameness of the left handlimb was diagnosed as
      having a rupture of the cranial cruciate ligament. Repair was achieved using a
      combination of surgical techniques. A patellar ligament autograft was passed
      under the cranial meniscal ligament, through the joint and over the femoral
      condyle, and anchored using a screw and washer. Two nylon sutures were passed
      through a hole made in the tibial crest, and secured under the screw. The alpaca
      was confined in a stall for 3 months. Exercise was then increased progressively
      for 3 months. One year after surgery the alpaca is sound and has resumed breeding
      activity.

PMID- 10590794
TI  - Effects of treadmill exercise on sweating in three breeds of goats.
AB  - OBJECTIVE: To compare the sweating responses of three breeds of goats to exercise
      at 30 degrees C. DESIGN: Factorial experiment with two goats of each of three
      breeds exercised for 60 min at 3 km/h and 30 degrees C on 6 days. PROCEDURE: Two
      mature females of the Anglo-Nubian, Saanen and Toggenburg breeds were used.
      Rectal temperature, respiration rate and sweating rate at three sites were
      recorded every 20 min during six replicates of exercise at 48 h intervals on a
      treadmill. RESULTS: Respiration rate varied with time and breed (P < 0.01) and
      increased from 20 +/- 2 breaths/min to 135, 195 and 260/min after 60 min exercise
      in Anglo-Nubian, Saanen and Tottenburg goats, respectively. Bread differences in
      rectal temperature were small but significant (P < 0.001), and mean values
      increased from 38.9 degrees C before exercise to 39.7 degrees C after 1 h
      exercise. The breed x sites interaction for sweating was significant (P < 0.01).
      On the rump breed differences in sweating rate were not significant. On the loin,
      Toggenburg goats started to sweat most rapidly and reached maximal values of 80.2
      +/- 10.6 g/m2/h after 20 min and then decreased to 70.0 +/- 4.3 g/m2/h at 60 min.
      Sweating rate on the ear was highest in Toggenburg goats, followed by those of
      Saanen and Anglo-Nubian goats (P < 0.05), but the differences were small (7
      g/m2/h); peak values of 67.3 to 76.1 g/m2/h were recorded after 20 min.
      CONCLUSION: Respiration and sweating rates increased significantly during
      exercise in all three breeds of goats, but breed differences were marked only for
      respiration rate. The goats sweated more on the rump than on the loin on ear,
      with peak values after 40 min of exercise.

PMID- 10590793
TI  - Transmission of Babesia spp by the cattle tick (Boophilus microplus) to cattle
      treated with injectable or pour-on formulations of ivermectin and moxidectin.
AB  - OBJECTIVE: To assess the efficacy of ivermectin and moxidectin to prevent
      transmission of Babesia bovis and Babesia bigemina by Boophilus microplus to
      cattle under conditions of relatively intense experimental challenge. DESIGN:
      Naive Bos taurus calves were treated with either pour-on or injectable
      formulations of either ivermectin or moxidectin and then exposed to larvae of B
      microplus infected with B bovis or larvae or adults of B microplus infected with
      B bigemina. One calf was used for each combination of haemoparasite, B microplus
      life stage, drug and application route. PROCEDURE: Groups of calves were treated
      with the test drugs in either pour-on or injectable formulation and then infested
      with B microplus larvae infected with B bovis or B bigemina. B bigemina infected
      adult male ticks grown on an untreated calf were later transferred to a fourth
      group of animals. Infections were monitored via peripheral blood smears to
      determine haemoparasite transmission. RESULTS: Cattle treated with either pour-on
      or injectable formulations of ivermectin and moxidectin became infected with B
      bovis after infestation with infected larvae. Similarly, larvae infected with B
      bigemina survived to the nymphal stage to transmit the haemoparasite to animals
      treated with each drug preparation. Cattle treated with pour-on formulations of
      ivermectin and moxidectin then infested with adult male ticks infected with B
      bigemina did not become infected with B bigemina whereas those treated with the
      injectable formulations of ivermectin and moxidectin did show a parasitaemia.
      CONCLUSIONS: Injectable or pour-on formulations of ivermectin and moxidectin do
      not prevent transmission of Babesia to cattle by B microplus. Use of these drugs
      can therefore not be recommended as a primary means of protecting susceptible
      cattle from the risk of Babesia infection.

PMID- 10590795
TI  - Campylobacter species in cats and dogs in South Australia.
AB  - BACKGROUND: Campylobacter enteritis was the most frequently notified infectious
      disease in Australia in 1996 and Campylobacter species have been associated with
      extra-intestinal infections such as purulent arthritis and Guillian-Barre
      syndrome. Dogs and cats are known to carry campylobacteria and contact with
      household pets have been implicated as possible sources of human infection.
      OBJECTIVE: To provide information on the species of campylobacter carried by cats
      and dogs in South Australia. METHODS: Faecal samples were collected from stray
      and owned cats and dogs and feral cats. Campylobacter-like organisms were
      isolated using selective media and filtration methods. They were then
      characterised by biochemical tests, antibiotic resistance and growth patterns
      under various conditions. Husbandry factors that could have influenced the
      carriage rates were examined both as single variables and in a multivariate
      logistic regression. RESULTS: Campylobacter upsaliensis and C jejuni were found
      in 11% and 4% of cats, respectively, whereas 34% dogs carried C upsaliensis, 7% C
      jejuni and 2% C coli. Intensive housing and open drains were found to be
      significant risk factors and increased the carriage rate by 2 and 2.6 times,
      respectively. CONCLUSION: Dogs and cats are a potential reservoir for human
      enteric infections with campylobacters.

PMID- 10590796
TI  - Production and oxidation of wool grease after shearing.
AB  - OBJECTIVE: To measure the production and amount of oxidation of wool grease
      secreted immediately after shearing. To identify components of wool grease that
      might act as a carrier to facilitate lateral diffusion of topically applied
      insecticides. DESIGN: Fine-wool Merino sheep were shorn and residual greasy wool
      was collected from the sheep's flank. The quantity of grease produced, and the
      amount of oxidation was measured during 18 days after shearing. Wool grease was
      fractionated into five component groups based on their polarity and the degree of
      oxidation in these fractions determined. RESULTS: There was a 24% increase in
      grease production within 2 days after shearing but secretions returned to pre
      shearing amounts after 4 days. During this period wool grease oxidized rapidly.
      Of the grease fractions examined, sterol and wax esters remained essentially
      unoxidized whereas free sterols such as cholesterol and lanosterol, fatty acids
      and polar lipids, aldehydes and alcohols were extensively oxidized within 7 days
      after shearing. CONCLUSION: The transient increase in grease production after
      shearing may facilitate diffusion of topically applied synthetic pyrethroid
      insecticides. Oxidation of grease components may then contain the insecticide and
      limit further diffusion. Incorporating the insecticide in non-oxidising fractions
      of wool grease may make insecticide dispersion more efficient.

PMID- 10590797
TI  - Plasma cortisol concentrations following cortisone infusion in dogs before and
      after treatment with cortisone acetate.
AB  - OBJECTIVE: To evaluate effects of iatrogenic hyperadrenocorticism on plasma
      cortisol concentrations produced by an infusion of hydrocortisone in dogs.
      PROCEDURE: Plasma cortisol concentrations were measured regularly during a 6 h
      infusion of hydrocortisone sodium succinate at two dose rates. The infusions were
      performed before and after treatment for 30 d with oral cortisone acetate at 10
      mg/kg/24 h, divided thrice daily. Adrenal activity during the experimental period
      was assessed by weekly ACTH stimulation tests. RESULTS: Both infusion rates
      produced lower plasma cortisol concentrations after treatment for 30 d with
      cortisone. CONCLUSION: Prior exposure to high concentrations of glucocorticoids
      may result in accelerated metabolism of glucocorticoids administered
      subsequently. This may necessitate increased dosages when using glucocorticoids
      to support inadequate adrenal function.

PMID- 10590798
TI  - Economic evaluation of three anthelmintic strategies for lamb flocks affected by
      benzimidazole-resistant nematodes.
AB  - OBJECTIVE: To compare the profitability of three anthelmintic strategies in
      growing lambs in flocks with nematodes resistant to benzimidazole anthelmintics.
      METHOD: A partial-budgeting analysis was carried out by means of a stochastic
      simulation model, which allows inputs to be described as distributions rather
      than as fixed values, and hence permits variation between farms to be considered
      in the analysis. RESULTS: The results show that control of nematode parasites by
      use of an effective anthelmintic provides the highest net returns, yielding a
      margin over ineffectively treated lambs of A$114 per 100 lambs on average.
      Suppressive treatment based on the administration of two controlled-release
      capsules and monthly with moxidectin resulted in an average loss of A$131 per 100
      lambs in comparison with animals treated with an ineffective anthelmintic.
      Analysis of the results from capsule-treated lambs did not take into account the
      unmeasured benefits associated with less contamination of pastures. Sensitivity
      analysis using a stochastic model indicates that apart from the effect of
      treatment on weight gain variation in carcase price greatly influences the
      profitability of all the parasite control programs examined. CONCLUSION: The
      results suggest that it is economically important for farmers to adjust their
      strategy in the presence of anthelmintic resistance. But as a result of
      uncertainty in the factors influencing economic return, the expected economic
      benefit is likely to vary substantially.

PMID- 10590799
TI  - Prevalence of stereotypic and other problem behaviours in thoroughbred horses.

PMID- 10590800
TI  - Variation of pesticide concentration in sheep dips operated according to
      traditional and revised methods.

PMID- 10590801
TI  - [Power generation and ecology: socio-economic collision].
AB  - The authors make analysis of the socio-economic collision between power
      generation and ecology. Russia enters the world market in the period of global
      and local ecological ill-being. The following eight dimensions of the problem
      have been reviewed: uncontrolled growth of population, limited earth resources,
      life standards and ecological crisis, national/ecological interests and power
      safety, eco- and power regionalism, religion and ethnoses (demography and energy
      reserves), eco-sitting of power installations, sanitary guidelines and standards
      and the reality.

PMID- 10590802
TI  - [Some bioengineering and hygienic aspects of incorporating sodium light
      illuminators into space life support systems].
AB  - Some bioengineering aspects of utilizating high-pressure sodium lamps (HPSL) in
      space plant growth chambers are reviewed. Comparative feasibility analysis of
      various lighting systems currently used in plant industry, and investigation of
      HPSL limitations and advantages allow the conclusion about their good prospect as
      a component of future plant growth facilities aboard long-term space
      bioengineering life support systems. High appraisal is given to the design of a
      board prototype of the DnaTSf-70 sodium lamp. Associated sanitary-hygienic
      regulations developed, HPSL are liable to be also used to lighten the spacecraft
      interior.

PMID- 10590803
TI  - [Intergral criterion and prediction of cosmonauts professional reliability in
      flight].
AB  - Discussed is the problem of professional reliability of cosmonauts simulating
      manual docking of transport vehicle SOYUZ-TM to space station MIR during acute
      adaptation to microgravity. A new concept of cosmonaut's reliability
      qualification is based on the parameters that characterize the systemic body
      response to job-related factors: integral efficiency and psychophysiological
      "cost". Justification is given to the statistic methodology of the change-over
      from prime job quality indices and the functional state of human to integral.
      Underlined is the possibility to apply this methodical approach to enhancement of
      the program of assessment and recovery of the professional reliability of
      cosmonauts in flight.

PMID- 10590804
TI  - [Informational assets of glucose tolerance test in evaluation of endurance to
      psychoemotional stress].
AB  - Psychoemotional stresses were simulated in male volunteers in order to evaluate
      the predictive value of the glucose-tolerance test patterns. As was found, the
      predictive information is provided by the following parameters: Rafalsky and
      Boduen coefficients, glucose levels during 60-min testing, and the
      hypoinsulinemia coefficient. Operator's performance under the condition of time
      constraint is directly dependent on the insulin content. Based on results of the
      discriminative analysis key guidelines for classification of individuals by their
      resistance to the psychoemotional factor were proposed. In view of the
      informational assets the authors suggest that this approach should be more
      actively used in development of programs of functional testing of humans in
      extreme environments. Analysis of determined relationships gave rise to the
      supposition that desensitization of cell membrane receptors to insulin is the
      most probable cause for the detriment of the resistance to psychoemotional
      stresses.

PMID- 10590805
TI  - [Errors in pointing under various body orientation relative to the gravity
      vector].
AB  - Errors in pointing to remembered target locations were measured in healthy
      subjects in upright, supine and prone positions, i.e. in three positions
      differing in body and arm movement orientation relative to the gravity vector.
      The X-error was unaffected by the body position, whereas the Y-error was
      dependent on subject's orientation relative to the gravity vector. In two lying
      positions, the subjects pointed below and in the vertical posture above the
      remembered target locations. On the contrary, the variable error was
      differentially affected by orientation of the movement trajectory relative to the
      gravity vector. In the supine position, the variable error was larger and in the
      prone position, smaller than in the upright posture. The gravity bias in pointing
      errors suggests that the motor program generated in the lying position is not
      modified to adapt to altered orientation relative to the gravity vector.

PMID- 10590806
TI  - [Characteristics of sound source movement perception as a basis for acoustic
      vertical construction].
AB  - The subject of inquiry was perception of moving sound along the vertical at
      various angular velocities. The sound was switched around by 13 sequential
      dynamics installed on a 180 degrees arc. Threshold values for discriminating
      angular velocities at 150, 167, 188, 214, 250, 300, 375, and 500 degrees/s were
      measured with the minimal borderlines method. Six test-subjects with normal
      hearing participated in the experiment. Acceleration of sound movement in the
      range from 167 up to 500 degrees/s leads to essentially linear increases in
      absolute threshold values and monotonous increases in relative threshold values.

PMID- 10590807
TI  - [Modeling the frontal closing and departure of sound source].
AB  - Software modeling frontal back and forth movements of a sound allowed
      determination of the best combinations in which changes in amplitude and
      frequency of sound pulses sequence invoke distinct sensations of approaching or
      departing sound factually generated at one and the same spot no matter the
      distance from the listener.

PMID- 10590808
TI  - [Potential role of serotonin-sensitive structures in amplification of duodenal
      motor activity due to irritation of sympathetic trunk].
AB  - Acute experiments with dogs showed that irritation of the sympathetic trunk in
      the thoracic cavity is more likely to amplify than inhibit duodenal contractions.
      This stimulating effect is better seen with alpha- and beta-adrenoreceptors
      blocked by phentolamine hydrochloride and inderal and cannot be eliminated with
      dizergol used to block S1,2 receptors of the cellular membranes in smooth
      muscles. On the evidence and literary data it was deduced that the sympathetic
      trunk contains some serotoninergic nervous fibers potent to stimulate
      contractions of the duodenum.

PMID- 10590809
TI  - [Cervical-ocular reflex in healthy humans].
AB  - The vestibulo-oculomotor response, i.e. the cervicoocular reflex (COR), to the
      stimulation of cervical proprioceptors by torso turns relative to the motionless
      head was studied in 15 human subjects under the conditions of labyrinthine and
      ocular differentiation. The COR coefficient of gain and phase shift were
      measured.

PMID- 10590810
TI  - [Effect of gravitation loading and retabolil on development of atrophy in muscles
      and bones of rats due to suspension].
AB  - In a 3-wk experiment with tail-suspended rats histological and histomorphometric
      methods were used to determine the effects of graded gravitational loading (GGL)
      and anabolic steroid retabolil (nortestosterone decanoate) on the course of
      atrophy in soleus m. (SM), gastrocnemius m. (GM), tibia and humerus, and
      functioning of somatotrophic hormones (STH) of the pituitary and thyrocytes of
      the thyroid. Suspension was found to produce atrophy in SM and, to a less degree,
      in GM, partial transformation of SM slow fibers into the fast ones, suppression
      of the tibial longitudinal growth, demineralization of the tibial and humeral
      spongious metaphyses; besides, functional activities of STH-cells and thyrocytes
      were inhibited. Graded gravitational loading of rats by intermittence of
      suspension for 2 hrs slowed down atrophy in both muscles and osteopenia in tibia,
      stimulated the synthetic and secretory functions of STH-cells without any marked
      effect on thyrocytes or humeral osteopenia. GGL failed to influence the slow-to
      fast transformation of SM fibers. Two injections of retabolil at the total dose
      of 3 mg/kg of the body mass somewhat interfered with the SM atrophy and humoral
      osteopenia, and were favorable to the synthetic but not secretory activity of STH
      cells. Neither SM and tibial atrophies nor thyroid activity of the gland were
      improved. The prophylactic action of GGL upon the SM and humeral atrophies was
      significantly higher when combined with retabolil, whereas GM and tibia were not
      noticeably cured by retabolil. Inhibition of the SM atrophy and humeral
      osteopenia in rats treated with GGL and retabolil concurred with elevated
      activities of STH-cells and thyrocytes indirectly suggesting their more intensive
      production of the growth hormone and thyroid hormones, respectively.

PMID- 10590811
TI  - [Effect of hypoxic hypoxia on development of atherosclerosis in rabbits].
AB  - The study was aim a evaluating effects of intermittent hypoxic training on
      experimental atherosclerosis. In a three-month experiment rabbits (n = 12) were
      fed with cholesterol (200 mg/kg of the body mass) and "ascended" to the altitude
      of 6000 m for 6 hrs per a day. The controls (n = 10) were fed with cholesterol
      only. Investigated was the dynamics of a spectrum of plasmatic lipoproteids,
      lipid peroxidation, morphologic alterations in the aorta and mononuclear
      phagocytes. Intermittent hypoxia caused less evident than in the control
      increases in total cholesterol (20.6 +/- 2.3 vs. 33.1 +/- 1.9 mmol/l, p < 0.05)
      and LDL cholesterol (19.4 +/- 2.2 vs. 32.3 +/- 2.3 mmol/l, p < 0.05). Unlike the
      controls, there were no atherosclerotic plaques in the aorta of the experimental
      rabbits. Atherosclerosis was diagnosed just by tiny dot- and strip-like lipid
      patches smaller in size when compared with the control group in which massive
      diffuse lipid deposits were found. The affected aortic areas made up 13.5% in the
      experimental group and 65% in the control. Hypoxic training brought about
      activation of the antioxidant system and was propitious for functional activity
      and oxygen-dependent and -independent metabolism of phagocytes. Exposure to
      hypoxia reduced the number of lipid inclusions in monocytes (303.0 +/- 12.5% vs.
      370.0 +/- 4.5% in the control, p < 0.05), prevented the dramatic inhibition of
      the cells observed in the animals fed with cholesterol and, eventually, blocked
      up formation of spumescent cells. These data infer that intermittent chamber
      hypoxia exerts the antiatherogenic effect on experimental atherosclerosis.

PMID- 10590812
TI  - [Total radiation risk from interplanetary and orbital missions to cosmonauts by
      the end of career and over the life time].
AB  - Models of radiation rate of mammalian mortality and algorithm for calculating the
      generalized dose from space radiations laid the basis for mathematical
      description of the probability of cosmohaut's survival in a delayed period after
      exposure as a function of generalized dose. Derived relations are intended to
      estimate the total radiation risk by any time point following exposure;
      expressions can be used to predict reduction inf mean expected lifetime after
      exposure of cosmonauts to different radiation doses. Presented are calculations
      of total radiation risk to cosmonauts from interplanetary and orbital missions of
      varying length by the end of career and over the whole lifetime. Additionally,
      calculated reduction in mean expected lifetime in consequence of space radiation
      exposure is given and the dependence of delayed radiation effects on mission
      length, spacecraft shielding, solar cycle, and age at the launch is analyzed.

PMID- 10590813
TI  - [State of cardiovascular system in immediate and delayed periods following
      exposure of organism to ionizing radiation].
AB  - Data on the progress of radiation damages and the character of shifts in the
      cardiovascular functioning following exposure to ionizing radiation as a function
      of dose were analyzed. Reviewed were experimental and clinical material, and
      records of periodic medical examinations of persons who had worked long with
      sources of ionizing radiation. A plausible character of deviations in health and
      working ability of cosmonauts in flight and at the end of career due to
      cardiovascular disorders is described.

PMID- 10590814
TI  - [Indices of lipid peroxidation and antioxidants in workers of ecologically
      unfavorable productions].
AB  - Studied was the antioxidants-lipid peroxidation balance in erythrocytes of
      workers from the shop of plasticizers cleared with ozone, known as a strong
      oxidizer. Dynamics of the dependence of accumulation of lipid peroxidation
      products including diene conjugates, coupled ketotriene, and Schiff bases on
      length of service was shown. Alterations in the activity of enzymatic
      antioxidants (catalase, superoxidismutase, glutathione reductase, and glutathione
      peroxidase) against adaptation to ecologically ill productions were assessed.

PMID- 10590815
TI  - [Noncontact system of bugs motor activity recoding].
AB  - A noncontact system for recording the motor activity of beetles is based on
      utilisation of infrared radiation. The system and digital PC input-output card
      DIO-96 were integrated into a 96-channel computerized facility to maintain,
      monitor and perform circadian studies of insects which was experimentally tested.

PMID- 10590816
TI  - Attentional inhibition or paracontrast?
AB  - In visual search experiments using asynchronous presentation of target and
      distractors, a robust and unexpected inhibition of reaction time was observed for
      the discrimination of a temporally trailing target. A number of experiments were
      required to determine the source of this inhibition. These experiments eliminated
      the possibilities that the inhibition might be a manifestation of three
      attentional processes: inhibition of return, attentional dwell time, or
      attentional capture by the temporally leading item. Other experiments eliminated
      the possible preattentional process of the temporal impulse response, the
      psychological refractory period, and a response inhibition. The characteristics
      of this inhibition lead to the conclusion that it is a manifestation of
      paracontrast.

PMID- 10590817
TI  - Verb generation priming involves conceptual implicit memory.
AB  - Brain activation patterns differ and generation latencies are reduced when
      generating verbs to repeated nouns (Raichle et al., 1994). Amnesic participants
      show normal magnitude of priming (Seger et al., 1997). Despite its importance in
      neuropsychology, verb generation priming is not well characterized
      psychologically. Six behavioral studies found that verb generation priming was
      specific to the verb rather than to the noun or the noun-verb pair, was
      equivalent after overt or covert generation and after reading verbs or generating
      verbs, was affected by levels of processing, and transferred completely across
      languages in bilinguals. These results indicate that verb generation priming
      involves priming of particular responses and happens at a conceptual level. These
      findings provide new insights about the significance of brain imaging and
      neuropsychological studies involving verb generation priming.

PMID- 10590818
TI  - Executive functioning in preschool children: performance on A-not-B and other
      delayed response format tasks.
AB  - The A-not-B (AB) task has been hypothesized to measure executive/frontal lobe
      function; however, the developmental and measurement characteristics of this task
      have not been investigated. Performances on AB and comparison tasks adapted from
      developmental and neuroscience literature was examined in 117 preschool children
      (ages 23-66 months). Age significantly predicted performance on AB, Delayed
      Alternation, Spatial Reversal, Color Reversal, and Self-Control tasks. A four
      factor analytic model best fit task performance data. AB task indices loaded on
      two factors with measures from the Self-Control and Delayed Alternation tasks,
      respectively. AB indices did not load with those from the reversal tasks despite
      similarities in task administration and presumed cognitive demand (working
      memory). These results indicate that AB is sensitive to individual differences in
      age-related performance in preschool children and suggest that AB performance is
      related to both working memory and inhibition processes in this age range.

PMID- 10590819
TI  - Variations in EEG coherence as an index of the affective content of dreams from
      REM sleep: relationships with face imagery.
AB  - EEG coherence was examined in relation to four measures of socioemotional dream
      content, including a new measure--the proportional representation of a
      character's face. Twenty-four healthy subjects, recorded for sleep stages and EEG
      activity, were awakened from REM sleep to report dream mentation and to rate it
      on these variables. Coherence scores were calculated for homologous
      interhemispheric electrode pairs (Fp1-Fp2, F3-F4, F7-F8, C3-C4, P3-P4, O1-O2, T3
      T4, T5-T6) and for left and right intrahemispheric pairs for delta, theta, alpha,
      beta1, and beta2 frequencies. These were correlated with the mentation measures.
      Positive correlations were found between average interhemispheric coherence in
      most bands and the character face measure. A breakdown by gender revealed that
      this relationship was most evident for women, whereas for men positive
      correlations were observed between coherence and negative self-feeling. That
      similar relationships also obtained for both left and right intrahemispheric
      coherence is consistent with the hypothesis that dreamed socioemotional
      interactions reflect the integrative functioning of many brain regions in both
      hemispheres.

PMID- 10590820
TI  - Associative learning impairments in patients with frontal lobe damage.
AB  - The performance of 18 frontal lobe lesion (FL) and 10 frontal lobe dementia (FLD)
      patients on an associative memory test was compared with the performance of their
      matched normal controls. The FL group was severely impaired on cued and free
      recall and was moderately impaired on a recognition condition. Left FL patients
      performed the poorest on the cued and free recall conditions. The FLD patients
      were moderately impaired on the free recall condition only but there was a
      subgroup of FLD patients with additional left temporal atrophy who appeared
      severely impaired on both cued and free recall. These findings indicate that both
      left frontal and temporal lobe damage can impair associative learning and that
      this impairment is more strikingly seen with free rather than cued recall.

PMID- 10590821
TI  - Towers of Hanoi and London: contribution of working memory and inhibition to
      performance.
AB  - The Tower of Hanoi and Tower of London have become well-established executive
      function tasks that presumably tap cognitive skills mediated by the frontal
      cortex. It has been assumed that the two tower tasks are more or less
      interchangeable and that both measure working memory and inhibition processes.
      These assumptions were tested in a study involving 37 normal college volunteers
      (M age = 20 years). Participants were administered the Tower of Hanoi (TOH),
      Tower of London-Revised (TOL-R), two working memory tests, and two tests of
      inhibition. The two tower tasks correlated significantly (r = .39), but only
      moderately. The working memory and inhibition variables explained over one-half
      of the variance in TOL-R performance; however, there was a relatively weaker
      contribution of inhibition to TOH performance.

PMID- 10590822
TI  - Schizotypy, dissociative experiences and childhood abuse: relationships among
      self-report measures.
AB  - OBJECTIVES: The traits and experiences that are seen as defining the
      schizophrenic and the dissociative disorders have been found to be present in
      continuously variable, non-pathological forms in the general population. Although
      the theoretical accounts that have been offered for the two kinds of disorder
      differ radically, there are reasons to expect that the measures that have been
      developed to assess schizotypal traits and dissociative experiences will be
      correlated. The aims of this study were to investigate the degree of correlation
      between measures and the extent to which the covariation can be explained by
      questionnaire items with similar content and experiences of childhood sexual and
      physical abuse. DESIGN: Cross-sectional data from self-report measures completed
      by 224 participants were subjected to multivariate analyses. METHOD: The
      Dissociative Experiences Scale (DES), three subscales from the Oxford-Liverpool
      Inventory of Feelings and Experiences (O-LIFE) and two items assessing childhood
      abuse were mailed to all adult members of a volunteer participant panel. RESULTS:
      Moderately large correlations were found between the DES and both the Cognitive
      Disorganization and the Unusual Experiences subscales of the O-LIFE. These
      correlations were hardly affected when items with overlapping content were
      excluded. Hierarchical multiple regression analyses showed that the measures of
      abuse accounted for small but significant proportions of the variance in both the
      DES and the Unusual Experiences subscale, but large proportions of the
      covariation between the measures of dissociative experiences and schizotypy
      remained unexplained. CONCLUSION: The substantial correlations between measures
      point to limitations in the discriminant validity of the DES and two of the O
      LIFE subscales. Three possible explanations are offered for the observed
      associations between dissociative experiences and schizotypal traits.

PMID- 10590823
TI  - The measurement of expressed emotion in relationships between staff and service
      users: the use of short speech samples.
AB  - OBJECTIVES: Research on expressed emotion (EE) has demonstrated a remarkable
      consistency across cultures and over time; the psychosocial climate in
      relationships is important in determining the course of problems in mental
      health. The rating of EE might be described as the least accessible aspect of
      this literature to those who have not undertaken a training course. The purpose
      of this study was twofold: first, to obtain EE ratings for staff-patient
      relationships via interview and speech sample methods, in order to estimate the
      validity of the shorter method (the Five-Minute-Speech-Sample, FMSS); second, to
      examine the generalizability of the FMSS rating method to raters who were not
      previously trained to rate EE. DESIGN AND METHOD: Staff (N = 15) working in a day
      hospital service for people with enduring mental health problems were interviewed
      about their work with at least one patient (N = 32), and also asked to provide an
      FMSS on each relationship. Ratings of FMSS-EE were subsequently compared with the
      Camberwell Family Interview-EE ratings. Following an hour-long training period,
      the FMSS-EE ratings of five postgraduate students were then compared with those
      of a criterion rater. RESULTS: Correspondence between the two measures of EE was
      found to be good, with overall agreement achieved in 89.7% of cases. Raters with
      very limited training in the concept and rating of EE were accurate in
      identifying the overall rating of the relationship in question, but less accurate
      in identifying specific critical comments. CONCLUSION: The FMSS technique can be
      used reliably to identify negative relationships even by raters given very
      limited training. Clinical and research applications are suggested.

PMID- 10590824
TI  - Recall of shame and favouritism in relation to psychopathology.
AB  - OBJECTIVES: There is good evidence that early rearing experiences affect
      vulnerability to subsequent psychopathology. Recent research on memories of
      rearing style have been influenced by attachment theory and have focused
      primarily on domains of emotional warmth and control. However, early experiences
      of being shamed, criticized and made to feel inferior, together with believing
      one's sibling is favoured over oneself, are also likely to play a role in
      vulnerability. This study therefore explored recall of being shamed and sibling
      favouritism. METHOD: A large community sample (N = 638) and a varied non
      psychotic patient sample (N = 213) completed two recall of parent rearing scales
      (the PBI and EMBU). These gave measures of recall of emotional warmth,
      overprotection/control, being shamed and shown up, and self or sibling favouring.
      Participants also completed the SCL-90-R scale. RESULTS: Patients recalled less
      warmth, more control, more shame and more favouring of siblings than the
      community sample. The difference was greatest for shame, and following MANOVA
      analysis shame remained significantly different between the two groups even after
      controlling for emotional warmth and control. Similarly, recalling being less
      favoured than a sibling and shamed had robust associations with indicators of
      psychopathology and these were only marginally reduced when emotional warmth was
      controlled for. Moreover, hostility (as measured by the SCL-90-R) was
      specifically related to recall of being shamed but not emotional warmth.
      CONCLUSION: This study suggests that over and above issues of emotional warmth
      and control, recall of direct experiences of being shamed, feeling inferior and
      less favoured in a family, may be particularly pathogenic. They operate
      independently of warmth and may be especially important in proneness to hostile
      feelings. Given this, therapists may wish to specifically explore shame issues
      with patients.

PMID- 10590825
TI  - The prediction of parasuicide repetition in a high-risk group.
AB  - OBJECTIVES: This study explores whether the specificity of risk assessment for
      parasuicide repetition can be improved by measurement of two psychological
      variables (over-generality of autobiographical memory and future fluency for
      positive events) in the immediate aftermath of the index parasuicide. DESIGN: In
      a longitudinal study, parasuicide patients deemed to be at high risk of
      repetition on the basis of sociodemographic factors (Kreitman & Foster, 1991)
      were followed-up over a 12-month period. METHOD: As soon as practicable after
      taking a deliberate drug overdose, patients completed the Autobiographical Memory
      Test, the Personal Future Test and the Beck Hopelessness Scale. The relative
      power of each of these measures, together with the number of sociodemographic
      risk factors, in predicting parasuicide repetition was investigated using a
      forward step-wise logistic regression analysis. RESULTS: The most potent short
      term predictor of parasuicide repetition was found to be scores on the Beck
      Hopelessness Scale, whereas in the longer term the number of previous para
      suicides was the major predictor. CONCLUSION: For the heterogeneous parasuicide
      population as a whole, psychological variables are unlikely to improve upon the
      Beck Hopelessness Scale, sociodemographic risk factors and clinical interview in
      the prediction of parasuicide repetition.

PMID- 10590826
TI  - The development and validation of the Visual Analogue Self-Esteem Scale (VASES).
AB  - OBJECTIVES: To develop a visual analogue measure of self-esteem and test its
      psychometric properties. DESIGN: Two correlational studies involving samples of
      university students and aphasic speakers. METHOD: Two hundred and forty-three
      university students completed multiple measures of self-esteem, depression and
      anxiety as well as measures of transitory mood and social desirability (Study 1).
      Two samples of aphasic speakers (N = 14 and N = 20) completed the Visual Analogue
      Self-Esteem Scale (VASES), the Rosenberg (1965) self-esteem scale and measures of
      depression and anxiety. (Study 2). RESULTS: Study 1 found evidence of good
      internal and test-retest reliability, construct validity and convergent and
      discriminant validity for a 10-item VASES. Study 2 demonstrated good internal
      reliability among aphasic speakers. CONCLUSION: The VASES is a short and easy to
      administer measure of self-esteem that possesses good psychometric properties.

PMID- 10590827
TI  - A qualitative investigation of the organization of traumatic memories.
AB  - OBJECTIVE: Previous research has indicated that cohesive organization of
      traumatic memories may be necessary for the processing and resolution of post
      trauma symptoms. The present study aimed to evaluate the qualitative features of
      memory organization, dissociation and perception of threat in traumatic memories
      recalled by individuals with and without acute stress disorder (ASD). DESIGN:
      Survivors of motor vehicle accidents (MVA) with either ASD or no ASD participated
      in a study on traumatic memories within 12 twelve days of the MVA. METHOD:
      Participants' audiotaped recollections of their memories of the MVA were coded in
      terms of disorganized structure, dissociative content and perception of threat.
      RESULT: The recollections of ASD participants were characterized by
      disorganization and dissociation more than those of non-ASD participants.
      CONCLUSION: The current findings suggest that disorganized memory structure may
      be one process that impedes access to, and modification of, trauma-related
      cognitive schema.

PMID- 10590828
TI  - Dot probe performance in two specific phobias.
AB  - OBJECTIVES: The present study applied MacLeod, Mathews & Tata's (1986) dot probe
      attentional deployment methodology to individuals with specific phobias. DESIGN:
      Attentional deployment towards spider-related, blood-related, positive, negative,
      and neutral words was examined. METHOD: Individuals with either spider phobia (N
      = 13) or blood/injury phobia (N = 14) and non-anxious controls (N = 14) completed
      the dot probe attentional deployment task. RESULTS: Individuals with specific
      phobias did not demonstrate an attentional bias towards phobia-related stimuli
      relevant to their particular fears. CONCLUSION: Semantic-based information
      processing paradigms may not be sufficiently potent to demonstrate biased
      performance towards threatening stimuli in individuals with mild specific phobias
      who are otherwise healthy.

PMID- 10590829
TI  - Intrusive memories, post-traumatic stress disorder and myocardial infarction.
AB  - OBJECTIVES: To identify the associations between two personality variables
      (alexithymia, negative affect), social support, awareness of myocardial
      infarction, and the severity of post-traumatic stress symptoms. DESIGN: A cross
      sectional design was adopted with simultaneous measures of both dependent and
      independent variables. METHOD: A random sample of 69 patients who had an MI
      between 6 and 12 months previously were sent postal questionnaires measuring
      alexithymia, negative affect, social support, awareness of myocardial infarction,
      the severity of post-traumatic stress symptoms and a number of demographic
      details. RESULTS: Forty-four individuals completed and returned all the
      questionnaires. A 10% prevalence of post-traumatic stress symptoms was found.
      Regression analyses were conducted to identify independent associates of the
      dependent variables with and without the inclusion of the measure of negative
      affect. Alexithymia, age, social support and awareness at the time of having a
      myocardial infarction, were each strongly predictive of one or all measures of
      symptoms. CONCLUSIONS: Evidence supporting the impact of each of the variables on
      the course of post-traumatic stress disorder was supported in a population of
      myocardial infarction patients. If these variables were found predictive in a
      longitudinal study, they would indicate possible risk factors for post-traumatic
      stress disorder in this population.

PMID- 10590831
TI  - Level and perceived stability of self-esteem prospectively predict depressive
      symptoms during psychoeducational group treatment.
AB  - OBJECTIVES: To investigate the combined roles of level and perceived stability of
      self-esteem in prospectively predicting depression. DESIGN: Symptoms of
      depression and anxiety were measured both before and after psychoeducational
      treatment for depression; level and perceived stability of self-esteem were
      measured before treatment. METHOD: Participants were 26 adults (16 female), age
      range 21-75 years. RESULTS: More stable self-esteem was associated with greater
      depressive symptomatology at treatment completion, particularly among
      participants who began treatment with the lowest self-esteem. Effects were
      specific to symptoms of depression in contrast with anxiety. CONCLUSION: These
      results suggest that a stable, well-consolidated negative self-concept is
      associated with prolonged depression and a poor response to psychosocial
      interventions.

PMID- 10590830
TI  - Normative data for the Novaco Anger Scale from a non-clinical sample and
      implications for clinical use.
AB  - OBJECTIVES: To provide non-clinical normative data for the Novaco Anger Scale. To
      identify the ability of the scale to discriminate between clinical and non
      clinical populations. DESIGN: Postal survey of individuals from a non-clinical
      sample. METHOD: A non-clinical sample of 212 NHS employees was sent a
      questionnaire pack, including the Novaco Anger Scale. A clinical sample of 58
      outpatient anger-management referrals was identified from a retrospective case
      note analysis. RESULTS: Descriptive data are presented for both samples. t-score
      conversions are provided, based on the non-clinical data. Results from a
      discriminant function analysis demonstrated that the Novaco Anger Scale
      classified participants as clinical or non-clinical with 94% accuracy.
      CONCLUSION: From this study it appears that the Novaco Anger Scale is able to
      discriminate between clinical and non-clinical populations. These data offer
      further support to the validity of the Novaco Anger Scale and its use in clinical
      assessment.

PMID- 10590832
TI  - The effect of training on rater reliability on the scoring of the NART.
AB  - OBJECTIVES: This study investigates whether the accuracy of judging National
      Adult Reading Test (NART) words known to have lower inter-rater reliability can
      be improved by training and use of the pronunciation guide. DESIGN: Two groups
      (Experimental and Control), were compared with three repeated measures: Occasion
      (first and second i.e. 'post-training'), Word Reliability (high and low) and
      Pronunciation Guide (without and with guide). METHODS: Ten words were selected
      from the NART: five lower reliability and five high reliability words. These were
      presented aurally in correct and incorrect form to participants (N = 20) who
      judged correctness of pronunciation without or with a pronunciation guide. Each
      group repeated the task again, the Experimental group having received training.
      RESULTS: Accuracy was significantly worse for the low reliability words. The
      experimental group's accuracy was significantly better after training than the
      control group's and their own performance prior to training. The use of the guide
      enhanced accuracy, particularly for the low reliability words. CONCLUSION:
      Training in administration of the NART improves raters' accuracy and use of the
      pronunciation guide. This offers an alternative to the suggestion of improving
      the NART's reliability by replacing lower reliability words and therefore would
      avoid the need to re-standardize a modified test.

PMID- 10590833
TI  - Detection of malingering on Raven's Standard Progressive Matrices: a cross
      validation.
AB  - A formula for detecting faked Raven's Standard Progressive Matrices profiles was
      cross-validated on 46 experimental malingerers and 381 people from the
      standardization sample. The formula yielded a cross-validated 26% false-negative
      rate and a 5% false-positive rate.

PMID- 10590834
TI  - Heat shock proteins as mediators of aggregation-induced 'danger' signals:
      implications of the slow evolutionary fine-tuning of sequences for the
      antigenicity of cancer cells.
AB  - Organisms 'tune' to their environment through adaptations which confer a
      selective advantage. However, in complex systems, a primary change of positive
      adaptive value might have multiple minor secondary effects, usually of negative
      adaptive value, which could invoke further counter-adaptations. This 'fine
      tuning', a 'debugging', mainly at the intracellular level, would appear an
      evolutionary burden detracting from the positive nature of the primary change.
      However, if the primary mutation is in a potential oncogene, secondary, short
      term effects may include the recruitment, in an apparently random manner, of
      unmutated non-oncogene products into the antigenic repertoire of the cancer cell.
      This 'danger' signal, provided by the co-aggregation of oncogene and non-oncogene
      products, would be mediated by inducible heat-shock proteins (Hsps), and lead to
      display of corresponding MHC-peptide complexes. It was argued previously that T
      cells specific for peptides from most 'self' intracellular antigens are not
      eliminated during T cell 'education', and so would be available for subsequent
      immune activation by the corresponding peptides. These considerations might
      explain why cancer specific antigens have been so elusive, why cancer
      antigenicity is often individual specific, and why therapeutic approaches
      involving complexes of peptides with Hsps may be successful.

PMID- 10590835
TI  - Constitutive and heat-inducible heat shock element binding activities of heat
      shock factor in a group of filamentous fungi.
AB  - This study represents the initial characterization of the heat shock factor (HSF)
      in filamentous fungi. We demonstrate that HSFs from Beauveria bassiana,
      Metarhizium anisopliae, Tolypocladium nivea, Paecilomyces farinosus, and
      Verticillium lecanii bind to the heat shock element (HSE) constitutively (non
      shocked), and that heat shock resulted in increased quantities and decreased
      mobility of HSF-HSE complexes. The monomeric molecular mass of both heat-induced
      and constitutive HSFs was determined to be 85.8 kDa by UV-crosslinking and the
      apparent molecular masses of the native HSF-HSE complexes as determined by pore
      exclusion gradient gel electrophoresis was 260 and 300 kDa, respectively.
      Proteolytic band clipping assays using trypsin and chymotrypsin revealed an
      identical partial cleavage profile for constitutive and heat-induced HSF-HSE
      complexes. Thus, it appears that both constitutive and heat-inducible complexes
      are formed by trimers composed of the same HSF molecule which undergoes
      conformational changes during heat shock. The mobility difference between the
      complexes was not abolished by enzymatic dephosphorylation and deglycosylation,
      indicating that the reduced mobility of the heat-induced HSF is probably due to a
      post-translational modification other than phosphorylation or glycosylation.

PMID- 10590836
TI  - Inhibition of heat shock factor activity prevents heat shock potentiation of
      glucocorticoid receptor-mediated gene expression.
AB  - Using mouse L929 cells stably transfected with a glucocorticoid receptor (GR)
      responsive murine mammary tumor virus-chloramphenicol acetyltransferase (MMTV
      CAT) reporter gene (LMCAT2 cells), we have shown that cellular stress (heat or
      chemical shock) can cause a dramatic increase in the levels of dexamethasone
      (Dex)-induced CAT gene expression. We refer to this response as the heat shock
      potentiation effect, or HSPE. As the cellular heat shock response also involves
      the activation of heat shock transcription factor (HSF), we have, in the present
      study, examined the role of HSF in the stress potentiation of GR by use of a
      flavonoid compound, quercetin, recently shown to selectively inhibit the stress
      response in a variety of human and murine cell lines. Analysis of the HSPE, as
      well as heat shock protein synthesis and activation of HSF during time-courses of
      recovery following heat shock, revealed a similar pattern for each response, with
      peak activities occurring about 16 h after stress. These data suggest a
      correlation between the activation of both GR and HSF in stressed cells. In L929
      cells stably transfected with a CAT reporter plasmid under the control of the HSF
      responsive hsp70 promoter (LHSECAT cells), pretreatment with quercetin was found
      to cause a dose- and time-dependent inactivation of HSF activity following heat
      shock, but only when added before the stress event. In LMCAT2 cells, quercetin
      similarly inhibited both heat and chemical shock potentiation of Dex-induced GR
      activity. This activity of quercetin was not the result of post-transcriptional
      or general cytotoxic properties, as quercetin (1) did not significantly affect GR
      or HSF activities when added after the stress event, (2) did not reduce CAT gene
      expression as controlled by the constitutive SV40 early promoter, and (3) did not
      alter normal (non-stress), Dex-induced MMTV-CAT expression. Thus, quercetin
      appears to be an effective and selective inhibitor of HSF stress-induced
      activation and its ability to prevent the stress potentiation of GR suggests
      either a direct or indirect involvement by stress-activated HSF in this process,
      or the existence of a regulatory step common to both the heat shock and HSPE
      responses.

PMID- 10590838
TI  - A comparison of Hsp70 expression and thermotolerance in adults and larvae of
      three Drosophila species.
AB  - Heat shock proteins (Hsps) and other molecular chaperones perform diverse
      physiological roles. One is to facilitate, in part, organismal thermotolerance,
      of which the functional consequences depend on Hsp70 concentration and
      developmental stage in Drosophila melanogaster. To test whether an Hsp70
      thermotolerance relationship is a general phenomenon within Drosophila, I assayed
      Hsp70 concentration at a range of temperatures in intact larvae and adults of
      three species, D. melanogaster, D. simulans, and D. mojavensis, and compared
      those results to the increase in survival to heat shock that occurs after an
      Hsp70 inducing pretreatment. Larvae of D. melanogaster and D. simulans responded
      similarly to heat; they expressed Hsp70 maximally at 36-37 degrees C, and their
      tolerance of 1 h heat shocks increased by 1.5-2 degrees C. By contrast, D.
      mojavensis, which tolerates higher temperatures than do D. melanogaster and D.
      simulans, expressed Hsp70 only at higher temperatures, although the 36 degrees C
      pretreatment still increased thermotolerance. Critically, the temperature that
      maximally induced Hsp70 was a poor inducer of thermotolerance in D. mojavensis
      and may have harmed larvae. Results for Drosophila adults, which tolerated heat
      poorly compared to larvae, likewise suggest that a close link between peak Hsp70
      expression and maximal induction of thermotolerance is a feature of D.
      melanogaster, and not of the other species. Neither D. simulans nor D. mojavensis
      adults increased tolerance after exposure to the temperatures that maximally
      induced Hsp70.

PMID- 10590837
TI  - Direct observation of stress response in Caenorhabditis elegans using a reporter
      transgene.
AB  - Transgenic Caenorhabditis elegans expressing jellyfish Green Fluorescent Protein
      under the control of the promoter for the inducible small heat shock protein gene
      hsp-16-2 have been constructed. Transgene expression parallels that of the
      endogenous hsp-16 gene, and, therefore, allows direct visualization,
      localization, and quantitation of hsp-16 expression in living animals. In
      addition to the expected upregulation by heat shock, we show that a variety of
      stresses, including exposure to superoxide-generating redox-cycling quinones and
      the expression of the human beta amyloid peptide, specifically induce the
      reporter transgene. The quinone induction is suppressed by coincubation with L
      ascorbate. The ability to directly observe the stress response in living animals
      significantly simplifies the identification of both exogenous treatments and
      genetic alterations that modulate stress response, and possibly life span, in C.
      elegans.

PMID- 10590839
TI  - Expression of glucose-regulated proteins (GRP78 and GRP94) in hearts and fore
      limb buds of mouse embryos exposed to hypoglycemia in vitro.
AB  - Hypoglycemia, the classic inducer of glucose-related protein (GRP) synthesis, is
      dysmorphogenic in rodent embryos and detrimentally affects the heart. This study
      compares GRP induction in a target vs non-target tissue by evaluating GRP
      expression in hearts and fore-limb buds of mouse embryos following exposure to
      hypoglycemia in vitro. Gestational day 9.5 embryos were exposed to 2, 6, and 24 h
      of either mild (80 mg/dl glucose) or severe (40 mg/dl glucose) hypoglycemia using
      the method of whole-embryo culture. GRP78 increased in a dose- and time-dependent
      fashion in embryonic hearts exposed to either 40 mg/dl or 80 mg/dl glucose,
      whereas GRP94 levels increased in hearts only after 24 h of hypoglycemia. In
      contrast to the heart, GRP induction in fore-limb buds occurred only with GRP78
      following the most severe level and duration of hypoglycemia. RT-PCR analysis
      demonstrated an elevation in GRP78 and GRP94 message levels in embryonic hearts
      following severe hypoglycemia. However, mRNA levels did not increase in response
      to mild hypoglycemia. Overall, these data demonstrate the preferential induction
      of GRPs in the heart as compared to fore-limb buds in mouse embryos exposed to
      hypoglycemia. Increases in GRP protein levels may be a more reliable biomarker of
      stress than message levels. However, both tissues and methods should be examined
      for enhanced biomarker sensitivity.

PMID- 10590840
TI  - Antibody supershift assay is inadequate for determining HSF stoichiometry in HSE
      complexes.

PMID- 10590841
TI  - Vasculitis: the historical development of the concept.

PMID- 10590842
TI  - Proposal for a working classification of cutaneous vasculitis.

PMID- 10590843
TI  - The etiology of cutaneous necrotizing vasculitis.

PMID- 10590844
TI  - Infectious etiologies of cutaneous vasculitis.

PMID- 10590845
TI  - The many faces of cutaneous vasculitis.

PMID- 10590846
TI  - Vasculitides secondary to systemic diseases.

PMID- 10590847
TI  - A clinical approach to the vasculitis patient in the dermatologic office.

PMID- 10590848
TI  - Common mistakes in the clinical approach to vasculitis.

PMID- 10590849
TI  - Unusual clinical presentations of vasculitis: what some clinical aspects can tell
      us about the pathogenesis.

PMID- 10590850
TI  - Urticarial vasculitis.

PMID- 10590851
TI  - Behcet's disease: an enigmatic vasculitis.

PMID- 10590852
TI  - Cutaneous vasculitis in children.

PMID- 10590853
TI  - Pyoderma gangrenosum, an unusual aspect of cutaneous vasculitis.

PMID- 10590854
TI  - Endothelial injury in vasculitides.

PMID- 10590855
TI  - Langerhans' cells and cutaneous necrotizing vasculitis.

PMID- 10590856
TI  - Cellular steps in pathogenesis of cutaneous necrotizing vasculitis.

PMID- 10590857
TI  - gamma/delta T lymphocytes and infection: pathogenesis of leukocytoclastic
      cutaneous necrotizing vasculitis.

PMID- 10590858
TI  - The spectrum of plasminogen activator-dependent fibrinolysis-altered
      psychoinduced vasopermeability syndrome.

PMID- 10590859
TI  - Automated peritoneal dialysis. A therapy in evolution.

PMID- 10590860
TI  - Membrane transport models and computerized kinetic modeling applied to automated
      peritoneal dialysis.

PMID- 10590861
TI  - Three-pore model applied to automated peritoneal dialysis.

PMID- 10590862
TI  - Role of drain and fill profile in automated peritoneal dialysis.

PMID- 10590863
TI  - Intraperitoneal pressure/volume effects on peritoneal transport in automated
      peritoneal dialysis.

PMID- 10590864
TI  - Rationale for tidal peritoneal dialysis.

PMID- 10590865
TI  - Patient selection for automated peritoneal dialysis on the basis of peritoneal
      transport characteristics.

PMID- 10590866
TI  - Calculation and significance of adequacy indexes in automated peritoneal
      dialysis.

PMID- 10590867
TI  - Dwell volume prescription in automated peritoneal dialysis and its assessment.

PMID- 10590868
TI  - Continuous cyclic peritoneal dialysis prescription and power.

PMID- 10590869
TI  - Nightly intermittent peritoneal dialysis prescription and power.

PMID- 10590870
TI  - Nightly tidal peritoneal dialysis prescription and power.

PMID- 10590871
TI  - Automated peritoneal dialysis prescription and results in children.

PMID- 10590872
TI  - Continuous tidal peritoneal dialysis. Prescription and power.

PMID- 10590873
TI  - Evolution of machines for automated peritoneal dialysis.

PMID- 10590874
TI  - Sodium content in automated peritoneal dialysis solutions.

PMID- 10590875
TI  - Calcium content in automated peritoneal dialysis solutions.

PMID- 10590876
TI  - Osmotic agents in automated peritoneal dialysis solutions.

PMID- 10590877
TI  - Buffer content in automated peritoneal dialysis solutions.

PMID- 10590878
TI  - Amino acids solutions and nutritional impact in children.

PMID- 10590879
TI  - Automated peritoneal dialysis as a means to maintain a peritoneal dialysis
      program.

PMID- 10590880
TI  - Peritonitis in patients on automated peritoneal dialysis.

PMID- 10590881
TI  - Residual renal function in automated peritoneal dialysis.

PMID- 10590882
TI  - Complications of automated peritoneal dialysis other than peritonitis.

PMID- 10590883
TI  - Ultrafiltration management in automated peritoneal dialysis.

PMID- 10590884
TI  - Myotonic dystrophies--how many are there?

PMID- 10590885
TI  - Distal myopathies.
AB  - Among various previously described distal myopathies, several diseases have now
      been established as clinically and genetically distinct entities. The most
      representative diseases are dominantly inherited Welander distal myopathy and
      tibial muscular dystrophy, and the recessively inherited distal myopathy with
      rimmed vacuoles and distal muscular dystrophy (Miyoshi myopathy). Since the
      discovery of the gene loci for several distal myopathies, several diseases
      previously categorized as different disorders have now proven to be the same or
      allelic disorders (e.g. distal myopathy with rimmed vacuoles and hereditary
      inclusion body myopathy, Miyoshi myopathy and limb-girdle muscular dystrophy with
      gene locus at 2p13). Except for Miyoshi myopathy, which has the typical findings
      of muscular dystrophy, most of the distal myopathies share the common pathologic
      features of myopathic changes with rimmed vacuoles. The pathologic changes are
      somewhat similar to those seen in chronic muscular dystrophy, but necrotic and
      regenerative processes are less prominent and creatine kinase levels are either
      normal or only mildly elevated. Further study is necessary to determine why
      rimmed vacuoles are so common in the distal myopathies, and what role they play
      in the pathogenesis of muscle fibre atrophy and loss, predominantly in the distal
      portions of the extremities.

PMID- 10590886
TI  - Facioscapulohumeral muscular dystrophy.
AB  - A decade's progress in facioscapulohumeral muscular dystrophy genetics has been
      marked by the discovery of novel genetic phenomena such as crossover of
      subtelomeric DNA between chromosomes 4 and 10 in normal individuals and by the
      recognition that the facioscapulohumeral muscular dystrophy deletion-mutation may
      cause a position variegation effect on more proximal DNA. The mutated DNA itself
      is probably not transcribed. Larger deletions tend to cause more severe disease.
      Antenatal diagnosis, based on detection of the short fragment of mutated DNA, is
      possible in between 95 and 100% of cases, depending on the precise nature of the
      parental facioscapulohumeral muscular dystrophy mutation. Yet remarkably, the
      nature of the gene product(s) of the affected proximal gene(s), as well as of the
      molecular pathogenesis of facioscapulohumeral muscular dystrophy muscle, retinal
      and cochlear disease, is completely unknown. Marked perivascular inflammation is
      often present in facioscapulohumeral muscular dystrophy muscle biopsies. The
      expression of facioscapulohumeral muscular dystrophy within reported monozygotic
      twinships differs greatly. This raises the question of whether variations in
      expression of the T-cell receptor gene repertoire or of other immune genes play
      an important modifying role in determining the severity of facioscapulohumeral
      muscular dystrophy. A focus on traditional scientific disciplines may now be
      appropriate. Symptomatic treatments, for instance of scapular winging and of
      lagophthalmos, are important, and timely photocoagulation of the retinal exudates
      which are a very rare, but real, complication of retinal telangiectasis can
      curtail visual loss. The results of collobarative trials of pharmacological
      agents such as albuterol which affect muscle mass and development are awaited.

PMID- 10590887
TI  - Inherited disorders of sarcomeric proteins.
AB  - The most important advances in sarcomeric protein diseases continue to be the
      identification of mutated genes responsible for human diseases. These have
      recently included those that encode skeletal muscle alpha-actin in autosomal
      dominant and autosomal recessive nemaline myopathy, nebulin and slow alpha
      tropomyosin in autosomal recessive nemaline myopathy, and desmin and alpha B
      crystallin in desminopathies.

PMID- 10590888
TI  - Inherited disorders of the extracellular matrix.
AB  - Primary and secondary defects in extracellular matrix proteins emphasize the role
      of these proteins in neuromuscular disorders; mutations have been found in the
      genes for the laminin-alpha 2 chain, for all three alpha chains of collagen VI
      and for integrin alpha 2. Secondary alterations in protein expression occur in
      association with these primary defects, and in other disorders they implicate the
      extracellular matrix. Animal models are helping to elucidate the function of some
      of these proteins, to develop therapeutic strategies and to suggest candidate
      proteins for other neuromuscular disorders.

PMID- 10590889
TI  - Inclusion body myositis.
AB  - Sporadic inclusion body myositis is a severely disabling muscle disease that
      mainly affects elderly individuals. The typical distribution of muscle weakness,
      poor response to immunosuppressive treatment, pathological accumulation of
      various proteins in vacuolated muscle fibres, inflammatory reaction and
      mitochondrial changes have all been subjects of recent research that has led to
      better understanding of the pathogenic events that leads to muscle degeneration
      and weakness.

PMID- 10590890
TI  - Muscle regeneration: molecular aspects and therapeutic implications.
AB  - With respect to diverse clinical applications for muscle regeneration, this paper
      discusses the latest markers for identifying skeletal muscle precursor cells in
      regenerating muscle, the implications of alternative sources of myogenic
      precursor cells and putative stem cells, and the current status of administration
      of exogenous factors to enhance muscle repair.

PMID- 10590891
TI  - Immunology of the neuromuscular junction and presynaptic nerve terminal.
AB  - The prevalence and incidence of myasthenia gravis is higher than previously
      thought. A potentially immunodominant T cell has been defined. The specific
      voltage-gated calcium channel subtype that is targeted by antibodies in the
      Lambert-Eaton myasthenic syndrome has been identified, and there is further
      evidence for the pathogenic role of autoantibodies in some cases of fetal
      arthrogryposis and in acquired neuromyotonia, Morvan's syndrome and Miller-Fisher
      syndrome.

PMID- 10590892
TI  - New insights into the pathogenesis of diabetic neuropathy.

PMID- 10590893
TI  - Chemotherapeutic neuropathy.
AB  - Peripheral neurotoxicity is a dose-limiting side-effect for a number of effective
      chemotherapeutic agents, including platinum compounds, taxanes, and vinca
      alkaloids. New experimental chemotherapy drugs that cause neuropathy include
      suramin and Dolostatin-10. A better understanding of cellular mechanisms will
      lead to novel treatment strategies that will protect neurons without decreasing
      therapeutic efficacy.

PMID- 10590894
TI  - Treatment of immune-mediated inflammatory neuropathies.
AB  - Experimental models have suggested potential new treatments for human
      inflammatory neuropathy, but current practice is largely based on empirical
      trials. Evidence from randomized trials supports the use of intravenous
      immunoglobulin in Guillain-Barre syndrome, chronic inflammatory demyelinating
      polyradiculoneuropathy (CIDP) and multifocal motor neuropathy with conduction
      block (MMNCB). In Guillain-Barre syndrome and CIDP intravenous immunoglobulin is
      equivalent to but more convenient than plasma exchange. In MMNCB adequate
      comparative studies of intravenous immunoglobulin and plasma exchange have not
      been performed. Corticosteroid treatment is beneficial in CIDP, but not in
      Guillain-Barre syndrome and may worsen MMNCB. More randomized trials and
      systematic reviews are needed to improve the evidence base for clinical practice.

PMID- 10590895
TI  - Pathogenesis of amyotrophic lateral sclerosis: a critical review.
AB  - Amyotrophic lateral sclerosis is a neurodegenerative disease with unknown
      pathogenesis. It is a relatively common disorder of adults (2-4 per 100,000
      incidence) and leads to death from respiratory failure. There is no cure at this
      time, and available treatment and management can at best extend survival to a
      modest degree. Increasing our understanding of the pathogenesis of this disease
      is essential to the development of more effective treatments. The level of
      research interest is very high, and yearly reviews of the literature are helpful
      in assessing progress.

PMID- 10590896
TI  - Paraproteinemia and neuropathy.
AB  - Paraprotein-associated neuropathies are a diverse group of disorders. The
      pathogenesis of many of them is poorly understood. Treatments have usually
      consisted of plasma exchange, corticosteroids, intravenous immunoglobulin, and
      other immunosuppressive therapies. Response to treatment has varied from good to
      very poor. Most recent work in this field has had two goals: achieving a better
      understanding of pathogenesis and developing better treatments. Such diverse
      entities as hepatitis C virus, vascular endothelial growth factor, and cytokines
      now appear to play a role in pathogenesis. More aggressive therapies such a bone
      marrow transplantation, interferon-alpha, and Rituximab have shown some promise.

PMID- 10590897
TI  - Entrapment neuropathies.
AB  - Entrapment neuropathies occur when nerves are chronically compressed or
      mechanically injured at specific locations. Some of these focal neuropathies such
      as carpal tunnel syndrome are common, and others such as neurogenic thoracic
      outlet syndrome are rare. This article highlights recent advances and interesting
      observations that cover a wide spectrum of such focal neuropathies. Selected
      disorders that can affect individual peripheral nerves and masquerade as
      'entrapment neuropathies' are also emphasized.

PMID- 10590898
TI  - Molecular basis of inherited neuropathies.
AB  - Considerable advances in our knowledge of the most frequently encountered group
      of inherited neuropathies, Charcot-Marie-Tooth neurpathy (CMT) and related
      disorders, have recently been made by genetic studies demonstrating that these
      disorders are caused by duplication, deletion or point mutations of specific
      genes of the peripheral myelin. The present classification of CMT and related
      disorders is based on a combination of clinical, neurophysiological, and genetic
      findings, and new genes and distinct mutations responsible for different clinical
      phenotypes are continuously being added. The genes that encode peripheral myelin
      protein of 22 kDa, protein zero, connexin-32 and early growth response-2 are the
      genes known to be involved in the pathogenesis of inherited neuropathies.
      Overexpression or underexpression of peripheral myelin protein of 22 kDa are
      causative for the most frequent forms of CMT-CMT1A and hereditary neuropathy with
      liability to pressure palsies--but the mechanisms that lead to incorrect myelin
      formation and maintenance are still unknown. Point mutations in the myelin genes
      can determine a loss of function, but in some cases an aberrant protein can act
      through a dominant negative or a toxic gain of function mechanism, disrupting the
      regular and precise relationship between the different myelin genes. Animal and
      in-vitro models of inherited neuropathies have been developed and will probably
      give the information that is necessary to clarify the pathogenetic mechanisms of
      demyelination.

PMID- 10590899
TI  - Paraneoplastic neuropathy.
AB  - Paraneoplastic neuropathies occur in various settings. This article focuses on
      recent neuroimmunologic findings regarding paraneoplastic neuropathy. Entities
      such as sensorimotor and sensory neuropathy, sensory neuronopathy; motor,
      autonomic, demyelinating and vasculitic mononeuropathies; and cranial nerve
      lesions and neuropathies in association with leukaemia and paraproteinaemas are
      discussed. Finally, the article considers the issue of 'overlap' syndromes--the
      occurrence of several paraneoplastic phenomena in the same patient.

PMID- 10590900
TI  - Vasculitic neuropathy.
AB  - The pathogenesis of primary vasculitides, which are assumed to have an autoimmune
      pathogenesis, is not well understood. The endothelial cell adhesion molecules
      seem to play an active role, which varies according to the histopathologic stage
      of vascular lesions. The role of genetic factors also seems quite important, at
      least in an experimental model. The reliability of antineutrophil cytoplasmic
      antibodies testing in diagnosis and follow-up of patients with vasculitis is
      reviewed. The conclusion is that antineutrophil cytoplasmic antibodies status can
      be a very useful diagnostic adjunct to the evaluation of patients with suspected
      Wegener's granulomatosis, but is not a substitute for clinical expertise and
      histopathologic data during the course of providing patient care. The
      neurological manifestations of Churg-Strauss syndrome (a variant of polyarteritis
      nodosa) are very similar to those that occur in polyarteritis nodosa. A role for
      vasculitis has been confirmed in proximal diabetic neuropathy, which may pave the
      way for new therapeutic developments.

PMID- 10590901
TI  - Bibliography. Current world literature. Neuromuscular diseases: muscle.

PMID- 10590902
TI  - Bibliography. Current world literature. Neuromuscular diseases: nerve.

PMID- 10590903
TI  - Cerebral palsy: diagnosing something that is not one thing.

PMID- 10590904
TI  - Causes of cerebral palsy.
AB  - Risk factors for cerebral palsy in term or near-term children include
      intrauterine exposure to infection or inflammation and disorders of coagulation.
      Interruption of the oxygen supply during birth contributes approximately 6% of
      spastic cerebral palsy. Low Apgar score, need for resuscitation, and seizures are
      nonspecific indicators of neonatal illness that do not identify cause. Although
      not entirely consistent, current evidence suggests that in utero infection may
      predispose very preterm and more mature infants to cerebral palsy and that
      antenatal exposure to steroids may be somewhat protective. Recognition of a
      broader set of causal possibilities encourages hope for new strategies for the
      prevention of cerebral palsy.

PMID- 10590905
TI  - Current concepts of cerebral malformation syndromes.
AB  - In the past, children with many brain malformations were classified as having
      static encephalopathies (cerebral palsy), often attributed to perinatal or
      prenatal distress. Understanding of the frequency and clinical manifestations of
      brain malformations, however, has increased dramatically in the past 10 to 15
      years. During this time, it has become apparent that many static encephalopathies
      in children have a brain malformation as their substrate. Most of the increase in
      our knowledge can be attributed to advances in neuroimaging and in molecular
      biology. In general, radiologic analysis of the brain allows similar
      malformations to be classified together. Subsequent genetic analysis of the
      affected children often reveals the affected gene, leading to identification of
      the gene product and, ideally, an ultimate understanding of the molecular
      mechanism of malformation. Currently, many genes involved in the complicated
      process of neuronal proliferation, migration, and organization are being
      identified. Knowledge of these genes and a better radiologic classification
      system enable the referring physician to give better care, more sophisticated
      genetic counseling, and a more precise prognosis for the child. To illustrate
      this mechanism of classification, three groups of malformations are discussed, in
      which a combination of neuroimaging analysis and molecular biologic analysis have
      led to a new understanding of the malformation syndromes.

PMID- 10590906
TI  - Neuromuscular disorders of childhood.
AB  - Neuromuscular disorders are common causes of weakness and hypotonia in the
      infantile period and in childhood. Accurate diagnosis of specific neuromuscular
      disorders depends first on identification of which aspect of the peripheral
      neuromuscular system is affected--the motor neuron in the spinal cord, the nerve
      root or peripheral nerve, the neuromuscular junction, or the muscle--and then on
      the determination of the etiology and specific clinical entity. This review
      provides an overview of the major neuromuscular disorders of childhood with
      attention to recent advances and emerging areas of research.

PMID- 10590907
TI  - Cerebral palsy and neurodegenerative disease.
AB  - Cerebral palsy refers to a neurologic disorder of motor skills that is static in
      nature and is the result of injury to the brain before its development is
      complete. Many neurodegenerative or metabolic disorders have a slow rate of
      progression and can be misdiagnosed as cerebral palsy. Diseases that have been
      misdiagnosed as cerebral palsy are presented here to provide the clinician with
      framework for the complex evaluation of these patients.

PMID- 10590908
TI  - Ethical issues in neurodevelopmental disabilities.
AB  - Ethics concerns itself with the search for the good and right option when one
      faces a choice about a potential action. In persons with significant
      neurodevelopmental disabilities, clinical ethics has concentrated on such
      pragmatic issues as justice (the means and measures by which resources are
      allocated) and informed consent. However, recent papers relevant to this topic
      have addressed more fundamental issues that underlie our entire approach to the
      field as a whole. These issues include the moral status of the disabled, the
      concept of "quality of life," our attitudes toward the disabled, the elements of
      competence and its evaluation, and models for decision making. This review
      highlights recent papers on these topics and assesses their impact on ongoing
      ethical debates.

PMID- 10590909
TI  - Two cases of hypertension-induced reversible posterior leukoencephalopathy
      syndrome secondary to glomerulonephritis.

PMID- 10590910
TI  - Autoimmune lymphoproliferative syndrome, a disorder of apoptosis.
AB  - Autoimmune Lymphoproliferative Syndrome (ALPS) is a recently recognized disease
      in which a genetic defect in programmed cell death, or apoptosis, leads to
      breakdown of lymphocyte homeostasis and normal immunologic tolerance. Some
      authors have referred to ALPS as Canale-Smith syndrome or lymphoproliferative
      syndrome with autoimmunity. Patients with ALPS have chronic enlargement of the
      spleen and lymph nodes, various manifestations of autoimmunity, and elevation of
      a normally rare population of "double negative T cells" (DNTs), T lymphocytes
      bearing alpha beta T cell receptors and expressing neither cluster
      differentiation (CD)4 nor CD8 surface antigens. When lymphocytes from patients
      with ALPS are cultured in vitro, they are resistant to apoptosis as compared to
      cells from healthy controls. Most patients with ALPS have mutations in a gene now
      named TNFRSF6 (tumor necrosis factor receptor gene superfamily member 6). This
      gene, previously known as apoptosis antigen 1 (APT1), encodes the cell surface
      receptor for the major apoptosis pathway in mature lymphocytes; this receptor has
      also had many names, including Fas (to be used here), CD95, and APO-1. ALPS is
      subdivided into: 1) Type Ia, ALPS with mutant Fas; 2) Type Ib, lymphadenopathy
      and mutation in the ligand for Fas in one patient with systemic lupus
      erythematosus; 3) Type II, ALPS with mutant caspase 10; and 4) Type III, ALPS as
      yet without any defined genetic cause.

PMID- 10590911
TI  - Recent progress in the diagnosis and treatment of patients with defects in early
      B-cell development.
AB  - Mutation detection for X-linked agammaglobulinemia (XLA) has revealed the
      heterogeneity of the clinical phenotype of patients with defects in Bruton's
      tyrosine kinase (Btk), the gene that is abnormal in XLA. Over 50% of patients
      with mutations in Btk have no family history of the disease because their cases
      are the first manifestation of a new mutation in their family. In 10% to 20% of
      patients, the serum immunoglobulins are higher than expected or the onset of
      disease is delayed; however, a marked reduction in B-cell numbers is consistent
      in all patients. Mutation detection has also shown that not all patients with
      presumed XLA have mutations in Btk. Mutations in mu heavy chain, and other
      components of the pre-B cell receptor complex, including lambda 5/14.1, cause a
      disorder that is clinically identical to XLA. Although new strategies for therapy
      are not yet available, the groundwork is being laid for cell or gene therapy.

PMID- 10590912
TI  - Supply, use, and abuse of intravenous immunoglobulin.
AB  - Intravenous immunoglobulin is used as a replacement therapy in primary
      immunodeficiency diseases as well as an immunomodulatory agent in a variety of
      autoimmune and inflammatory disorders. The mechanisms of intravenous
      immunoglobulin action are complex and, for some disorders, not well understood.
      This paper reviews the recent literature and discusses approved, new, and
      controversial indications for intravenous immunoglobulin therapy, with special
      emphasis on its mechanism of action.

PMID- 10590914
TI  - Pediatrics in the era of genetic medicine.

PMID- 10590913
TI  - Use of leukotriene antagonists in childhood asthma.
AB  - Leukotrienes have been shown to cause bronchoconstriction, increased mucus
      production, and airway inflammation, three critical features in asthma.
      Antileukotriene drugs were developed to inhibit the effects of these lipid
      mediators. This class of drugs represents the first new approach to asthma
      therapy in 25 years. The leukotriene receptor antagonists, montelukast,
      zafirlukast, and pranlukast, and the 5-lipoxygenase inhibitor, zileuton, are
      unique in their ability to target specific components of asthmatic inflammation.
      Although the role of these drugs continues to evolve, the antileukotrienes have
      demonstrated efficacy against exercise and allergen-induced bronchoconstriction
      and additive benefit for use in patients with symptomatic, moderate asthma on
      maintenance-inhaled corticosteroids. Further, they may be considered for primary
      use in patients with mild, persistent asthma, especially those who are steroid
      phobic or who have compliance issues.

PMID- 10590915
TI  - Genetic causes of nonsyndromic hearing loss.
AB  - Explosive progress is being made in genetic studies of hearing and deafness from
      the clinical and basic research perspectives. Greater than half of hearing loss
      is estimated to have a genetic basis. Recent studies of hearing and deafness have
      identified a dozen genes that cause nonsyndromic hearing disorders. Deafness can
      be inherited in an autosomal recessive, autosomal dominant, X-linked, or
      mitochondrial manner. Mutations in one gene, connexin 26 (encoding the gap
      junction protein beta 2), may be responsible for half of all autosomal recessive
      nonsyndromic deafness. With new mandates for hearing screening programs for
      newborns in many states, for the first time, the new information on the genetics
      of hearing loss can be used to diagnose the cause of hearing loss in some
      children and to understand better the molecular biology of hearing.

PMID- 10590916
TI  - Clinical and molecular genetics of Alagille syndrome.
AB  - Alagille syndrome (AGS) is a dominantly inherited disorder characterized by bile
      duct paucity and resultant liver disease in combination with cardiac, skeletal,
      ocular, and facial abnormalities. Jagged1 (JAG1) has been identified as the AGS
      disease gene. It encodes a ligand in the Notch signaling pathway that is involved
      in cell fate determination. AGS is the first developmental disorder to be
      associated with this pathway. It shows highly variable expressivity, and
      diagnosis in mildly affected persons can be difficult without molecular analysis.
      Currently, JAG1 mutations are detected in about 70% of patients with AGS and
      include total gene deletions as well as protein truncating, splicing, and
      missense mutations. Mutations are located across the gene within the
      evolutionarily conserved motifs of the protein. There is no phenotypic difference
      between patients with deletion of the entire JAG1 gene and those with intragenic
      mutations. This suggests that haploinsufficiency for JAG1 is a mechanism causing
      AGS.

PMID- 10590917
TI  - Albinism.
AB  - Albinism was one of the first genetic diseases to be noted in humans, but until
      relatively recently, little was known of the molecular mechanisms involved in its
      pathogenesis. Recent advances have shown us that mutations in at least seven
      different genes can cause a reduction in melanin pigment biosynthesis, producing
      the various associated clinical features associated with albinism, including
      hypopigmentation of the skin, hair, and eyes; optic track misrouting; foveal
      hypoplasia; and reduced visual acuity. Analysis of mutations in these seven genes
      has revealed that the phenotypic spectrum associated with albinism is broad,
      making molecular analysis an important part in the accurate diagnosis of this
      disease.

PMID- 10590918
TI  - Peroxisomal disorders.
AB  - Peroxisomes, subcellular organelles found in nearly all eukaryotic cells, are
      involved in numerous biochemical functions within the cell. There has been an
      increasing understanding of the genetic mechanism of the diseases of the single
      peroxisomal enzyme abnormalities as well as defects of peroxisome biogenesis.
      Peroxisome assembly disorders including Zellweger syndrome and rhizomelic
      chondrodysplasia punctata are caused by genetic defects in PEX genes and the
      altering of their proteins, peroxins, which are necessary for the importation of
      targeted proteins into the peroxisomes. Therapies for peroxisomal disorders have
      been unsatisfactory to date, but there has been interest in docosahexaenoic acid
      in assembly disorders and phenylbutyrate and lovastatin in adrenoleukodystrophy
      (ALD). Whether any of these therapies will result in clinical improvement awaits
      additional study.

PMID- 10590919
TI  - Childhood injury prevention at home and play.
AB  - Unintentional injuries are the leading cause of death for children and
      adolescents in the United States, and they create a significant burden of
      disability and financial cost. If motor vehicle-associated injuries are not
      considered, children are most commonly injured in their home and play
      environments. The reduction over the past 20 years in childhood deaths related to
      motor vehicle injury has been significant, but rates of childhood death due to
      other causes, such as firearms, have increased. This review focuses on several
      categories of injuries other than motor vehicle injuries and highlights a few
      recent successful community- and practice-based injury-prevention programs. In
      addition, recent epidemiologic studies describing risk factors for injury-related
      death are discussed. Injuries due to interpersonal violence and motor vehicles
      are covered elsewhere.

PMID- 10590920
TI  - Preventing motor vehicle injuries.
AB  - Prevention of injuries to child passengers is a significant public health
      priority, as motor vehicle-related injuries remain a leading cause of death for
      children. Improvements in child restraint use have contributed to significant
      declines in child occupant mortality rates over the past 20 years. However,
      although overall restraint use has improved, many children are currently not
      optimally restrained for their age. Errors in installing and using child safety
      seats, as well as the premature graduation of children to vehicle safety belts,
      contribute to reducing the effectiveness of restraints for children. Further
      prevention of motor vehicle occupant injuries to children will require the
      combined approaches of engineering, education, and enforcement. This review
      presents current information regarding inappropriate restraint of children and
      highlights current engineering, education, and legislative efforts to improve
      child occupant protection.

PMID- 10590921
TI  - Interpersonal violence.
AB  - Interpersonal violence is unfortunately part of the social landscape for many
      American children. Physicians who care for children and adolescents may find it
      challenging to incorporate techniques to "screen and intervene" for violence. In
      order to guide these youth toward safety, the clinician must recognize the scope
      of the problem, understand the risk factors for violent injury, apply this
      knowledge to clinical practice, and either refer clients to or implement
      interventions on behalf of these youth. Unfortunately, despite an overall
      decrease in firearm mortality in the past few years, the prevalence and severity
      this problem in American adolescents remain high. Recent studies have further
      elucidated the demographic, behavioral, environmental, and psychosocial factors
      that may identify the high-risk patient. Other important work has concentrated on
      applying these risk factors in clinical settings. In addition, small but
      significant steps have been made toward educating physicians about their role in
      violence prevention. Finally, we have begun to scientifically evaluate
      interventions designed to keep youth from becoming part of a very grim statistic.
      This review focuses on the most recent advances that have been made toward
      addressing violence as a public health concern.

PMID- 10590922
TI  - Adolescent pregnancy prevention.
AB  - The United States continues to have the highest rate of adolescent pregnancy in
      the western industrialized world. This review focuses on the recent decline in
      adolescent pregnancy rates and the recent slight decline in the number of
      sexually experienced youths. Risk factors for adolescent pregnancy, such as
      history of forced sexual intercourse and lack of connectedness with parents, are
      discussed. Various strategies to decrease the adolescent pregnancy rate and the
      effectiveness of these strategies are reviewed. The unique role of the primary
      health care provider in the prevention of adolescent pregnancy is also addressed.

PMID- 10590923
TI  - Nutrition interventions in childhood for the prevention of chronic diseases in
      adulthood.
AB  - As it becomes increasingly evident that the seeds of many adult disorders are
      planted in childhood, it is important that pediatric care providers 1) recognize
      risk factors for adult disease in children and 2) institute effective
      interventions. Many adult medical conditions are significantly related to or
      influenced by nutritional factors. This review evaluates three areas in
      preventive and therapeutic pediatric nutrition: obesity, lipid disorders, and
      osteoporosis.

PMID- 10590924
TI  - Office laboratory procedures, office economics, parenting and parent education,
      and urinary tract infection.
AB  - These authors review four areas of office pediatric practice: office laboratory
      procedures, office economics, parenting and parent education, and urinary tract
      infections. Thomas Ball reviews the literature published this past year on
      physician office laboratories, with updates on the Clinical Laboratories
      Improvement Amendments, laboratory utilization, and office diagnosis of
      infectious mononucleosis. Eve Shapiro offers an update on office economics,
      discussing physician organizations and managed care, and a medical ethics
      evaluation of medical economics. Burris Duncan provides an update on parenting
      and parent education, with emphasis on defining "the best interests of the
      child." Richard Wahl summarizes the past year's publications on pediatric urinary
      tract infections, reviewing the circumcision debate, dysfunctional voiding,
      vesicoureteral reflux, and the diagnosis and follow-up of acute pyelonephritis.

PMID- 10590925
TI  - Production of the 57 kDa major surface antigen by a non-agglutinating strain of
      the fish pathogen Renibacterium salmoninarum.
AB  - The major surface antigen of Renibacterium salmoninarum, p57, is associated with
      cell autoagglutination and implicated as a virulence factor in fish infections.
      An autoagglutinating strain, JD24, caused 92% mortality when 2 x 10(7) cells were
      injected intraperitoneally into rainbow trout Oncorhynchus mykiss, while a non
      agglutinating strain, MT 239, produced only 7% mortality after 100 d. The p57
      antigen was present in the supernates of broth cultures of both strains when
      examined by western immunoblotting, and the gene for p57 was detected in both
      strains by PCR. Electron microscopy of cryopreserved thin sections showed an
      amorphous layer associated with the cell surface of JD24 which was not seen with
      MT 239. While p57 from JD24 could reassociate with cells of both strains, p57
      from MT 239 failed to restore haemagglutination activity to either strain.
      Biotinylation of bacterial surfaces demonstrated the presence of a carbohydrate
      component of p57 from JD24 which was absent from the p57 produced by MT 239. The
      higher virulence of JD24 may depend not only on the production of p57, but also
      its direct association with the bacterial cell surface.

PMID- 10590926
TI  - Epizoic amoebae from the gills of turbot Scophthalmus maximus.
AB  - Species of amoebae belonging to the genera Platyamoeba Page, 1969, Vannella
      Bovee, 1965 and Flabellula Schaeffer, 1926 were found to accompany Paramoeba sp.,
      the agent of amoebic gill disease (AGD), in clinically diseased turbots. The same
      community of epizoic gymnamoebae was found on the gills of turbots which revealed
      no gill abnormalities but slight behavioral signs indicative of suboptimal health
      status. The assemblage of the above-mentioned free-living amoebae capable of
      colonizing gill tissue of turbots was supplemented with species recognized in
      samples fixed from primary isolates for transmission electron microscopy. The
      pathogenic potential of epizoic gill amoebae in turbots is discussed.

PMID- 10590927
TI  - Kabataia gen. n., a new genus proposed for Microsporidium spp. infecting trunk
      muscles of fishes.
AB  - Based on a fine structural study, a new genus, Kabataia gen. n., is proposed for
      Microsporidium arthuri Lom, Dykova and Shaharom, 1990. It develops in trunk
      muscles of a South-East Asian freshwater fish, Pangasius sutchi. The genus has
      nuclei isolated throughout the cycle, merogony stages are multinucleate,
      sporogony proceeds in 2 steps: multinucleate sporont segments into sporoblast
      mother cells which produce 2 sporoblasts. Sporoblasts and early spores are
      characterized by a dense globule at the site of the posterior vacuole. Mature
      spores are of a rather variable shape. Their exospore is raised into small,
      irregular fields. The polaroplast is relatively small and its posterior part
      consists of flat vesicles with dense contents. The polar tube makes a small
      number (4 to 6) of turns. A congeneric species is Kabataia seriolae (Egusa, 1982)
      comb. nov. from cultured marine yellowtails Seriola quinqueradiata. Kabataia
      inflicts heavy damage on muscle tissue. The sarcoplasm within which Kabataia
      develops is reduced to an amorphous mass with tubule-like fibrils, microfibrils
      and small vesicles.

PMID- 10590929
TI  - A review of virus infections of cataceans and the potential impact of
      morbilliviruses, poxviruses and papillomaviruses on host population dynamics.
AB  - Viruses belonging to 9 families have been detected in cetaceans. We critically
      review the clinical features, pathology and epidemiology of the diseases they
      cause. Cetacean morbillivirus (family Paramyxoviridae) induces a serious disease
      with a high mortality rate and persists in several populations. It may have long
      term effects on the dynamics of cetacean populations either as enzootic infection
      or recurrent epizootics. The latter presumably have the more profound impact due
      to removal of sexually mature individuals. Members of the family Poxviridae
      infect several species of odontocetes, resulting in ring and tattoo skin lesions.
      Although poxviruses apparently do not induce a high mortality, circumstancial
      evidence suggests they may be lethal in young animals lacking protective
      immunity, and thus may negatively affect net recruitment. Papillomaviruses
      (family Papovaviridae) cause genital warts in at least 3 species of cetaceans. In
      10% of male Burmeister's porpoises Phocoena spinipinnis from Peru, lesions were
      sufficiently severe to at least hamper, if not impede, copulation. Members of the
      families Herpesviridae, Orthomyxoviridae and Rhabdoviridae were demonstrated in
      cetaceans suffering serious illnesses, but with the exception of a 'porpoise
      herpesvirus' their causative role is still tentative. Herpes-like viruses and
      caliciviruses (Caliciviridae) give rise to cutaneous diseases in Monodontidae and
      Delphinidae. Antibodies to several serotypes of caliciviruses were found in
      odontocetes and mysticetes. An unrecognized Hepadnaviridae was detected by
      serology in a captive Pacific white-sided dolphin Lagenorhynchus obliquidens with
      chronic persistent hepatitis. Adenoviruses (Adenoviridae) were isolated from the
      intestinal tracts of mysticeti and a beluga Delphinapterus leucas but were not
      associated with any pathologies. We discuss the potential impact of
      Paramyxoviridae, Poxviridae and Papovaviridae on the dynamics of several
      odontocete populations.

PMID- 10590930
TI  - Shedding of Renibacterium salmoninarum by infected chinook salmon Oncorhynchus
      tschawytscha.
AB  - Laboratory studies of the transmission and pathogenesis of Renibacterium
      salmoninarum may describe more accurately what is occurring in the natural
      environment if test fish are infected by waterborne R. salmoninarum shed from
      infected fish. To quantify bacterial shedding by chinook salmon Oncorhynchus
      tschawytscha at 13 degrees C in freshwater, groups of fish were injected
      intraperitoneally with R. salmoninarum at either 1.3 x 10(6) colony forming units
      (CFU) fish (-1) (high-dose injection group) or 1.5 x 10(3) CFU fish (-1) (low
      dose injection group). R. salmoninarum infection levels were measured in the
      exposed fish by the enzyme-linked immunosorbent assay (BKD-ELISA). At regular
      intervals for 30 d, the numbers of R. salmoninarum shed by the injected fish were
      calculated on the basis of testing water samples by the membrane filtration
      fluorescent antibody test (MF-FAT) and bacteriological culture. Mean BKD-ELISA
      optical densities (ODs) for fish in the low-dose injection group were not
      different from those control fish (p > 0.05), and no R. salmoninarum were
      detected in water samples taken up to 30 d after injection of fish in the low
      dose group. By 12 d after injection a proportion of the fish from the high-dose
      infection group had high (BKD-ELISA OD > or = 1.000) to severe (BKD-ELISA OD > or
      = 2.000) R. salmoninarum infection levels, and bacteria were detected in the
      water by both tests. However, measurable levels of R. salmoninarum were not
      consistently detected in the water until a proportion of the fish maintained high
      to severe infection levels for an additional 8 d. The concentrations of R.
      salmoninarum in the water samples ranged from undetectable up to 994 cells ml(-1)
      on the basis of the MF-FAT, and up to 1850 CFU ml(-1) on the basis of
      bacteriological culture. The results suggest that chinook salmon infected with R.
      salmoninarum by injection of approximately 1 x 10(6) CFU fish (-1) can be used as
      the source of infection in cohabitation challenges beginning 20 d after
      injection.

PMID- 10590928
TI  - Efficacy of various chemotherapeutic agents on the growth of Spironucleus
      vortens, an intestinal parasite of the freshwater angelfish.
AB  - Seven chemotherapeutic agents (dimetridazole, metronidazole, pyrimethamine,
      albendazole, fenbendazole, mebendazole and magnesium sulfate) were examined for
      growth inhibition on the cultivation of Spironucleus vortens. Dimetridazole and
      metronidazole were effective in inhibiting the parasite's growth. At
      concentrations of 1 microgram ml-1 or higher, both dramatically decreased numbers
      of parasites. At 24 h exposure, 33% of parasites were inhibited when exposed to
      dimetridazole or metronidazole at concentrations of 2 and 4 micrograms ml-1,
      respectively. Dimetridazole at 4 micrograms ml-1 or higher concentrations
      decreased the number of organisms to 50% or less after 48 h exposure. During the
      same period of time, the numbers of parasites decreased to 50% or less when
      exposed to metronidazole at 6 micrograms ml-1 or higher. Pyrimethamine at
      concentrations of 1 to 10 micrograms ml-1 was not effective in inhibiting the
      parasite's growth. Albendazole and fenbendazole at concentrations of 0.1 and 0.5
      microgram ml-1 were similar in inhibiting the growth of the organism. Both
      compounds suppressed parasite growth at concentrations of 1.0 microgram ml-1 or
      higher after 24 h exposure. Mebendazole inhibited the parasite's growth at
      concentrations of 0.5 microgram ml-1 or higher. At 72 h exposure, 45 to 50% of
      the parasites were inhibited when exposed to mebendazole at concentrations higher
      than 0.5 microgram ml-1. Magnesium sulfate at concentrations of 70 mg ml-1 or
      higher also suppressed the growth of parasites after 24 h exposure. These results
      indicate that dimetridazole, metronidazole and mebendazole are the most effective
      chemotherapeutic agents in vitro at inhibiting the growth of S. vortens.

PMID- 10590931
TI  - The history and basic principles of magnetic nerve stimulation.

PMID- 10590932
TI  - EEG responses evoked by transcranial magnetic stimulation.

PMID- 10590933
TI  - Modeling of the stimulating field generation in TMS.

PMID- 10590934
TI  - Hemodynamic response to repetitive magnetic stimulation of the motor and visual
      cortex.

PMID- 10590935
TI  - Methodology and application of TMS mapping.

PMID- 10590936
TI  - Performance of a system for interleaving transcranial magnetic stimulation with
      steady-state magnetic resonance imaging.

PMID- 10590937
TI  - Stimulation at the foramen magnum level.

PMID- 10590938
TI  - Relationships between animal and human corticospinal responses.

PMID- 10590939
TI  - On the comparability of H-reflexes and MEPs.

PMID- 10590940
TI  - Recruitment order of single motor units of the anterior tibial muscle in man.

PMID- 10590941
TI  - Paired-pulse investigations of short-latency intracortical facilitation using TMS
      in humans.

PMID- 10590942
TI  - Direct recordings of descending volleys after transcranial magnetic and electric
      motor cortex stimulation in conscious humans.

PMID- 10590943
TI  - Intracortical inhibition and facilitation in the conventional paired TMS
      paradigm.

PMID- 10590944
TI  - Asymmetry in transcallosal inhibition.

PMID- 10590945
TI  - Repetitive transcranial magnetic stimulation of the parietal cortex influences
      motor imagery.

PMID- 10590946
TI  - TMS mapping studies in peripheral and central lesions.

PMID- 10590947
TI  - Applications of transcranial magnetic stimulation in studies on motor learning.

PMID- 10590948
TI  - Plasticity of movement representation in the human motor cortex.

PMID- 10590949
TI  - Mechanisms, functional relevance and modulation of plasticity in the human
      central nervous system.

PMID- 10590950
TI  - Reorganization in motor cortex in amputees and in normal volunteers after
      ischemic limb deafferentation.

PMID- 10590951
TI  - Pharmacological modulation of training-induced plastic changes in human motor
      cortex.

PMID- 10590952
TI  - Central motor conduction time studies.

PMID- 10590953
TI  - Transcranial magnetic stimulation and epilepsy.

PMID- 10590954
TI  - Transcranial magnetic stimulation and motor rehabilitation.

PMID- 10590955
TI  - First diagnostic applications of transcallosal inhibition in diseases affecting
      callosal neurones (multiple sclerosis, hydrocephalus, Huntington's disease).

PMID- 10590956
TI  - Motor system excitability in healthy children: developmental aspects from
      transcranial magnetic stimulation.

PMID- 10590957
TI  - Botulinum toxin type-A treatment in spasticity increases the central conduction
      time to brain stimulation.

PMID- 10590958
TI  - Transcranial magnetic stimulation in migraine.

PMID- 10590959
TI  - Has repetitive transcranial magnetic stimulation of the primary motor hand area a
      therapeutic application in writer's cramp?

PMID- 10590961
TI  - Lack of clinical improvement in patients with Parkinson's disease after low and
      high frequency repetitive transcranial magnetic stimulation.

PMID- 10590960
TI  - Transcranial magnetic stimulation in movement disorders.

PMID- 10590962
TI  - Changed intracortical facilitation and silent period in the motor cortex of
      patients with cerebellar degeneration.

PMID- 10590963
TI  - Is TMS therapeutic in mania as well as in depression?

PMID- 10590964
TI  - rTMS studies of mood and emotion.

PMID- 10590965
TI  - Sleep and rTMS. Investigating the link between transcranial magnetic stimulation,
      sleep, and depression.

PMID- 10590966
TI  - Language and TMS/rTMS.

PMID- 10590967
TI  - Motion perception and perceptual learning studied by magnetic stimulation.

PMID- 10590968
TI  - Differentiation of parvo- and magnocellular pathways by TMS at the occipital
      cortex.

PMID- 10590969
TI  - Rapid-rate transcranial magnetic stimulation in auditory cortex induces LTP and
      LTD and impairs discrimination learning of frequency-modulated tones.

PMID- 10590970
TI  - The ten-twenty electrode system of the International Federation. The
      International Federation of Clinical Neurophysiology.

PMID- 10590971
TI  - EEG instrumentation. The International Federation of Clinical Neurophysiology.

PMID- 10590972
TI  - IFCN standards for digital recording of clinical EEG. The International
      Federation of Clinical Neurophysiology.

PMID- 10590973
TI  - IFCN guidelines for topographic and frequency analysis of EEGs and EPs.The
      International Federation of Clinical Neurophysiology.

PMID- 10590974
TI  - A glossary of terms most commonly used by clinical electroencephalographers and
      proposal for the report form for the EEG findings. The International Federation
      of Clinical Neurophysiology.

PMID- 10590975
TI  - Recommended standards for electroretinograms. The International Federation of
      Clinical Neurophysiology.

PMID- 10590976
TI  - Recommended standards for pattern electroretinograms and visual evoked
      potentials. The International Federation of Clinical Neurophysiology.

PMID- 10590977
TI  - Short-latency auditory evoked potentials. The International Federation of
      Clinical Neurophysiology.

PMID- 10590978
TI  - Somatosensory evoked potentials. The International Federation of Clinical
      Neurophysiology.

PMID- 10590979
TI  - Cognitive event-related potentials. The International Federation of Clinical
      Neurophysiology.

PMID- 10590980
TI  - Magnetic stimulation: motor evoked potentials. The International Federation of
      Clinical Neurophysiology.

PMID- 10590981
TI  - Repetitive transcranial magnetic stimulation. The International Federation of
      Clinical Neurophysiology.

PMID- 10590982
TI  - Standards of clinical practice of EEG and EPs in comatose and other unresponsive
      states. The International Federation of Clinical Neurophysiology.

PMID- 10590983
TI  - Intraoperative monitoring. The International Federation of Clinical
      Neurophysiology.

PMID- 10590984
TI  - Neonatal EEG. The International Federation of Clinical Neurophysiology.

PMID- 10590985
TI  - Recording sleep and wake. The International Federation of Clinical
      Neurophysiology.

PMID- 10590986
TI  - Applications of magnetic cortical stimulation. The International Federation of
      Clinical Neurophysiology.

PMID- 10590987
TI  - Clinical EMG and glossary of terms most commonly used by clinical
      electromyographers. The International Federation of Clinical Neurophysiology.

PMID- 10590988
TI  - Standards of instrumentation of EMG. The International Federation of Clinical
      Neurophysiology.

PMID- 10590989
TI  - Standards for quantification of EMG and neurography. The International Federation
      of Clinical Neurophysiology.

PMID- 10590990
TI  - Electrooculography: technical standards and applications. The International
      Federation of Clinical Neurophysiology.

PMID- 10590991
TI  - The jaw reflexes. The International Federation of Clinical Neurophysiology.

PMID- 10590992
TI  - The orbicularis oculi reflexes. The International Federation of Clinical
      Neurophysiology.

PMID- 10590993
TI  - The F wave. The International Federation of Clinical Neurophysiology.

PMID- 10590994
TI  - H reflexes from the tibial and median nerves. The International Federation of
      Clinical Neurophysiology.

PMID- 10590995
TI  - Long-latency reflexes following electrical nerve stimulation. The Inter national
      Federation of Clinical Neurophysiology.

PMID- 10590996
TI  - EMG-EEG correlation. The International Federation of Clinical Neurophysiology.

PMID- 10590997
TI  - Sympathetic skin response. The International Federation of Clinical
      Neurophysiology.

PMID- 10590998
TI  - Heart rate variability. The International Federation of Clinical Neurophysiology.

PMID- 10590999
TI  - Assessment of blood pressure regulation. The International Federation of Clinical
      Neurophysiology.

PMID- 10591000
TI  - Ex-germfree mice harboring intestinal microbiota derived from other animal
      species as an experimental model for ecology and metabolism of intestinal
      bacteria.
AB  - Ex-germfree (GF) animals harboring intestinal microbiota derived from other
      animal species, e.g. human-flora-associated (HFA) and pig-flora-associated (PFA)
      mice, have been considered as a tool for studying the ecology and metabolism of
      intestinal bacteria of man and animals. Human fecal microbiota was transferred
      into the intestines of the mice with minor modification by inoculating GF mice
      with human fecal suspensions. Interestingly, bifidobacteria were eliminated from
      some of the HFA mouse groups, whereas other dominant bacterial groups remained
      constant. Elimination of bifidobacteria appeared to be dependent on the
      composition of microbiota in the inoculated sample. Human fecal microbiota
      established in the intestines of the HFA mice reproduced in the intestine of
      offspring of these HFA mice and of cage-mated ex-GF mice without any remarkable
      change in composition. Although the HFA mice could be used for studying the
      effects of diet on human intestinal microbiota, the metabolism of microbiota of
      HFA mice reflected that of human feces with respect to some metabolic activities
      but not others. PFA mice were also a good model for studying the ecosystem of pig
      fecal microbiota and the control of short chain fatty acids in pig intestines,
      but not for studying putrefactive products generated in pig intestines. In
      conclusion, HFA and PFA mice provide a stable and valuable tool for studying the
      ecosystem and metabolism of the human and animal intestinal microbiota, but they
      have some limitations as a model.

PMID- 10591001
TI  - Tissue and organ expression of catalase in acatalasemic beagle dogs.
AB  - Acatalasemic Beagle dogs which were maintained in our laboratories showed no sign
      of catalase activity at all in the erythrocytes, and glutathione peroxidase and
      superoxide dismutase were at normal levels. Immunoblotting analysis demonstrated
      that no catalase protein is detectable in their erythrocytes. On the other hand,
      catalase activity was detected in other tissues and organs, albeit at varying,
      lower levels than in normal dogs. Quantitative immunoblotting analysis
      consistently demonstrated that the catalase protein is expressed in the liver and
      kidneys of acatalasemic dogs in proportion to the activity in these organs. The
      catalase mRNA expressions in the blood, liver and kidneys in acatalasemic dogs
      were almost the same as those in normal dogs. These results suggested that
      catalytically normal catalase protein is translated from mRNA in the tissues and
      organs including erythrocytes, but in erythrocytes this enzyme protein is
      disposed of by an unknown mechanism.

PMID- 10591002
TI  - Blood pressure, heart rate and motor activity in 6 inbred rat strains and wild
      rats (Rattus norvegicus): a comparative study.
AB  - Inbreeding for many generations under optimal environmental conditions may have
      favoured the survival of alleles for blood pressure increase in phenotypically
      normotensive rat strains. To prove this hypothesis we measured telemetrically
      systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR) and motor
      activity (MA) in 6 inbred rat strains (BB, BN, LEW, DA, F344, WKY) and wild rats
      most probably possessing all of the alleles for normotension. For the first time
      it is shown that systolic blood pressure can significantly differ between
      normotensive inbred rat strains and that most probably some inbred rat strains
      will be characterised by a systolic blood pressure found in their progenitors,
      the wild rats. In addition, the typical night activity of rodents was not seen in
      2 inbred rat strains. All findings together may be interpreted in the sense that
      most, if not all inbred rats strains have more or less disturbances in blood
      pressure, HR and/or MA and that there is most probably no "healthy" inbred rat
      strain available so that wild rats may be an alternative for crossing studies
      dissecting hypertension in particular and diseases in general.

PMID- 10591003
TI  - Effective delivery of a lipophilic 6-chloro-2',3'-dideoxyguanosine (6-Cl-ddG)
      into rat lymphoid tissues.
AB  - Lipophilic 6-chloro-2',3'-dideoxyguanosine (6-Cl-ddG) was evaluated for its
      improved lymph node delivery by comparison with the parental nucleoside (ddG) in
      vitro and in vivo. The in vitro studies with rat plasma, lymph node homogenate
      and stomach content indicated that 6-Cl-ddG converted to ddG more effectively in
      the lymph node homogenate and that 6-Cl-ddG was more stable than ddG in the
      stomach content. In an in vivo study, plasma and lymph nodes were collected from
      rats after a subcutaneous or oral administration of 6-Cl-ddG or ddG. With the
      subcutaneous administrations of the drugs, the area under the concentration time
      curve (AUC) value in the plasma for converted ddG following a 6-Cl-ddG
      administration was less than half the value for ddG following a ddG
      administration but the converted ddG AUC values in the lymph nodes due to 6-Cl
      ddG administration were 1.4- to 2.0-fold higher than the ddG AUC values due to
      ddG administration. Moreover, with the oral administrations, the converted ddG
      AUC value in plasma after a 6-Cl-ddG administration was 3-fold higher than ddG
      after a ddG administration, and high levels of converted ddG were detected in the
      lymph nodes, but no ddG was detected in the lymph node following ddG
      administration. These results suggest that lipophilic 6-Cl-ddG is a useful
      prodrug for delivering ddG into the lymph nodes by oral administration.

PMID- 10591004
TI  - Diurnal variations and effects of fasting on blood constituents in minipigs.
AB  - We examined the diurnal variations and the effects of 48-hour fasting on
      hematological and serum biochemical values to obtain basic physiological data on
      ten male and seven female Gottingen minipigs 6 to 16 months of age. For all
      hematological parameters examined (RBC, HCT, HGB, WBC and PLT), there was no
      diurnal variation in either sex, but red blood cell parameters were affected by
      fasting, with an increase in males and a decrease in females. Three serum
      biochemical parameters (GOT, UN and i.p.) for males and four (GOT, UN, Ca and
      i.p.) for females exhibited diurnal variation. These variations were eliminated
      by fasting. The BIL level in males was increased by fasting, and the color of
      serum was yellowish. Fe concentration in both sexes and CRE and Mg levels in
      males were decreased by fasting. These findings are basic data for various
      experiments on minipigs, and indicate that great care is required in establishing
      feeding times and fasting intervals and in the analysis of results of experiments
      on minipigs.

PMID- 10591005
TI  - Establishment of SV40-tsA58 transgenic rats as a source of conditionally
      immortalized cell lines.
AB  - To isolate a variety of rat cell lines with differentiated functions, we
      established transgenic rat lines expressing the temperature-sensitive large T
      antigen of simian virus 40 (SV40) tsA58 mutant under the control of the SV40
      large T-antigen itself. We microinjected the DNA into 564 eggs of Wistar rat and
      23 independent transgenic candidates were obtained. Ten pups died before weaning
      and eight transgenic rats could not transmit the transgene to the progeny.
      Finally, five lines of the transgenic rat were established. Although one line
      (#1511-6) had low reproductivity, the other four lines reproduced normally. Three
      out of the four lines (#1507-2, #1509-7, #1519-8) appeared normal but the other
      line had tumors in the brain and subcutaneous tissue at 3 weeks of age (#1511-6),
      and in the kidneys and subcutaneous tissue at 18 to 19-weeks of age (#1507-5).
      Fibroblast cells prepared from transgenic fetuses of lines #1507-5 and #1519-8
      expressed the transgene and exhibited temperature-dependent growth. Both of the
      lines (#1507-5 and #1519-8) were successfully generated to be homozygous by
      sibling mating of transgenic offspring. These transgenic rat lines have bred
      through many generations and have been established to be a ready source of novel
      conditionally immortalized cell lines.

PMID- 10591006
TI  - p-Chloroamphetamine (PCA) suppresses ingestive behavior in male rats.
AB  - Ingestive behavior was activated in male rats by intraoral intake and intake from
      a bottle of 1-M solution of sucrose. Intraperitoneal injection of p
      chloroamphetamine (PCA), releasing central 5-hydroxytryptamine (5-HT) from
      serotonergic nerve terminals, inhibited ingestion of the sucrose solution.
      Significant inhibition of sucrose intake by PCA was observed at 1.25 and 2.5
      mg/kg dose in a bottle intake test, and at 5.0 mg/kg dose in an intraoral intake
      test. These findings suggested that 1.25 and 5.0 mg/kg of PCA suppressed
      appetitive ingestive behavior and consummatory ingestive behavior in male rats,
      respectively.

PMID- 10591007
TI  - Observation of marking-like behavior, marking behavior, and growth of the scent
      gland in young Mongolian gerbils (Meriones unguiculatus) of an inbred strain.
AB  - A marking-like behavior (defined by authors), a marking behavior, and growth of
      the scent glands were observed in young Mongolian gerbils of an inbred strain. In
      males and females, a marking-like behavior, in which animals rub their abdominal
      scent glands on the floor, began to be seen at the age of 19 days and could be
      seen in almost all the gerbils at 22 days of age during the suckling period. The
      frequency of this behavior was highest at 60 days of age (males: 17.9/10 min,
      females: 15.4/10 min) and there was no sex difference. Marking behavior, in which
      animals rub their abdominal scent glands on small protruding objects, began to be
      seen at the age of 40 days in males and 50 days in females. The frequency of this
      behavior tended to increase until 90 days of age in males (13.7/10 min), but the
      levels were low (2.5-5.0/10 min) in females. The values in the male group
      therefore tended to be higher than that in the female group. Macroscopic scent
      gland pads were clearly observed at the age of 30 days in males, but not until 45
      days of age in females. At the age of 45-90 days, the length of the scent gland
      pad in males and females was 2.1-2.8 and 1.6-1.7 cm, respectively and the width
      was 0.3-0.5 in males and 0.2-0.3 cm in females. During this period, the length
      and depth of the pads in males were significantly greater than those in females
      (p < 0.05). Histological examination of the structure of the scent glands after
      the age of 45 days showed that the development of clusters of acinar cells in
      females occurred much later than that in males, but the basic structure of these
      glands was similar in both sexes. These results suggest that the marking-like
      behavior was manifested although during the period when the scent glands had not
      yet developed, whereas true marking behavior first occurred when the glands were
      moderately well developed.

PMID- 10591008
TI  - Diallel cross analysis of body weight in subspecies of mice.
AB  - A complete 4 x 4 diallel cross of CF#1 (C), C57BL/6NCrj (B) C3H/HeNCrj (H) and
      Yonakuni wild mice (Y, Mus musculus molossinus yonakuni) has been conducted to
      estimate the effects of sex, degree of heterosis, general combining ability
      (gca), specific combining ability (sca), maternal ability, and reciprocal cross
      on body weight at 1 (Wk1), 3 (Wk3), 6 (Wk6) and 10 (Wk10) weeks of age. A least
      squares analysis was performed on 828 mice and all sources of variation showed
      significant effects (P < 0.01) on body weight but not sex at Wk1 (P > 0.05).
      Males were heavier than females (P < 0.01) at Wk3, Wk6 and Wk10. C and Y were the
      heaviest and lightest in body weight, whereas H and B were intermediate.
      Differences in body weight were observed between linebred and linecross at all
      ages studied: 6.57%, 10.22%, 8.70% and 5.89% heterosis for the respective ages.
      The degree of gca and maternal effects can be ranked as C > H > B > Y. Crossing
      between C and H had greater sca than other combinations at all ages studied,
      whereas B x Y had the smallest. Mean body weight of the offspring from two-line
      reciprocal cross differed according to their dam. A relatively large proportion
      of additive genetic effects in contributing to the variation in offspring body
      weight was indicated.

PMID- 10591009
TI  - Simultaneous observation of ingestive and copulatory behavior of the male rat.
AB  - In a preliminary test male rats were allowed to ingest a 1 M solution of sucrose
      from a drinking spout. After daily intake of sucrose became stabilized, the males
      were given a sexually receptive or non-receptive female and the bottle filled
      with sucrose solution simultaneously. The ingestive and copulatory behavior was
      observed for 60 min under illumination by a red lamp. The data obtained from this
      study showed that the ingestive behavior of males was suppressed by the presence
      of sexually receptive females and, conversely, the sexual behavior of males was
      not affected by the presence of a bottle of sucrose. These results suggest that
      the presence of a sexual partner inhibits appetitive ingestive behavior, i.e.,
      the responses used by male rats to obtain food.

PMID- 10591010
TI  - Salt water promotes hypertension in Dahl-S rats.
AB  - Hypertension was induced in Dahl-salt-sensitive (Dahl-S) rats by administering
      salt in drinking water. Control rats receiving tap water did not show a
      significant change in blood pressure or abnormalities in the kidney. Rats
      receiving 0.5% NaCl solution developed moderate hypertension and renal lesions.
      Rats receiving 1.0% NaCl solution showed prominent and increasing hypertension
      and severe renal damage. This method of salt administration should be simpler
      than administration in the diet as a means of promoting renal hypertension. The
      lower concentration salt water caused chronic mild hypertension in Dahl-S rats,
      and may serve as a useful model for progressive hypertension.

PMID- 10591011
TI  - Serum biochemical values in two inbred strains of mastomys (Praomys coucha).
AB  - Serum samples collected from 119 (72 male and 47 female) mastomys (Praomys
      coucha) of 2 specific-pathogen-free inbred strains (RI4 and RI7) were analyzed
      for 12 serum biochemical parameters. Sex-related differences (p < 0.01) were
      noted in alkaline phosphatase and glucose; the both higher in females than in
      males. Age-related changes (p < 0.01) were observed in total protein, albumin,
      total cholesterol, and alkaline phosphatase, with higher values for the first
      three parameters in the older group (200-250 days of age) than in the younger
      group (90-140 days of age). Four out of 12 parameters showed strain-related
      differences (p < 0.01), consistent with the large amount of genetic heterogeneity
      reported in this species. These serum biochemical reference values should provide
      information for the use of mastomys in laboratory research.

PMID- 10591012
TI  - Characterization and radiation resistance of new isolates of Rubrobacter
      radiotolerans and Rubrobacter xylanophilus.
AB  - In this study we characterized new strains of the slightly thermophilic species
      Rubrobacter radiotolerans and the thermophilic species Rubrobacter xylanophilus,
      both of which were previously represented only by the type strains isolated,
      respectively, from Japan and the United Kingdom. The new isolates were recovered
      from two hot springs in central Portugal after gamma irradiation of water and
      biofilm samples. We assessed biochemical characteristics, performed DNA-DNA
      hybridization, and carried out 16S rDNA sequence analysis to demonstrate that the
      new Rubrobacter isolates belong to the species R. radiotolerans and R.
      xylanophilus. We also show for the first time that the strains of R. xylanophilus
      and other strains of R. radiotolerans are extremely gamma radiation resistant.

PMID- 10591013
TI  - Investigation of structure and antigenic capacities of Thermococcales cell
      envelopes and reclassification of "Caldococcus litoralis" Z-1301 as Thermococcus
      litoralis Z-1301.
AB  - Fourteen strains of hyperthermophilic organotrophic anaerobic marine Archaea were
      isolated from shallow water and deep-sea hot vents, and four of them were
      characterized. These isolates, eight previously published strains, and six type
      strains of species of the order Thermococcales were selected for the study of
      cell wall components by means of thin sectioning or freeze-etching electron
      microscopy. The cell envelopes of most isolates were shown to consist of
      regularly arrayed surface protein layers, either single or double, with hexagonal
      lattice (p6) symmetry, as the exclusive constituents outside the cytoplasmic
      membrane. The S-layers studied differed in center-to-center spacing and molecular
      mass of the constituent protein subunits. Polyclonal antisera raised against the
      cells of 10 species were found to be species-specific and allowed 12 new isolates
      from shallow water hot vents to be identified as representatives of the species
      Thermococcus litoralis, Thermococcus stetteri, Thermococcus chitonophagus, and
      Thermococcus pacificus. Of the 7 deep-sea isolates, only 1 was identified as a T.
      litoralis strain. Thus, hyperthermophilic marine organotrophic isolates obtained
      from deep-sea hot vents showed greater diversity with regard to their S-layer
      proteins than shallow water isolates.

PMID- 10591014
TI  - Isolation and characterization of Thermus thermophilus Gy1211 from a deep-sea
      hydrothermal vent.
AB  - We examined a single, non-spore-forming, aerobic, thermophilic strain that was
      isolated from a deep-sea hydrothermal vent in the Guaymas Basin at a depth of
      2000 m and initially placed in a phenetic group with Thermus scotoductus (X-1).
      We identified this deep-sea isolate as a new strain belonging to Thermus
      thermophilus using several parameters. DNA-DNA hybridization under stringent
      conditions showed 74% similarity between the deep-sea isolate and T. thermophilus
      HB-8T (T = type strain). Phenotypic characteristics, such as the utilization of
      carbon sources, hydrolysis of different compounds, and antibiotic sensitivity
      were identical in the two strains. The polar lipids composition showed that
      strain Gy1211 belonged to the genus Thermus. The fatty acids composition
      indicated that this strain was related to the marine T. thermophilus strain
      isolated from the Azores. The new isolate T. thermophilus strain Gy1211 grew
      optimally at 75 degrees C, pH 8.0; and 2% NaCl. A hydrostatic pressure of 20 MPa,
      similar to the in situ hydrostatic pressure of the deep-sea vent from which the
      strain was isolated, had no effect on growth. Strain HB-8T, however, showed
      slower growth under these conditions.

PMID- 10591015
TI  - Lipid membranes from halophilic and alkali-halophilic Archaea have a low H+ and
      Na+ permeability at high salt concentration.
AB  - The influence of pH and the salt concentration on the proton and sodium ion
      permeability of liposomes formed from lipids of the halophile Halobacterium
      salinarum and the haloalkaliphile Halorubrum vacuolatum were studied. In contrast
      with liposomes formed from Escherichia coli lipids, liposomes formed from
      halophilic lipids remained stable up to 4M of NaCl and KCl. The proton
      permeability of the liposomes from lipids of halophiles was independent of the
      salt concentration and was essentially constant between pH 7 and pH 9. The sodium
      ion permeability increased with the salt concentration but was 10- to 100 fold
      lower than the proton permeability. It is concluded that the membranes of
      halophiles are stable over a wide range of salt concentrations and at elevated pH
      values and are well adapted to the halophilic conditions.

PMID- 10591016
TI  - Studies on interdomain interaction of 3-isopropylmalate dehydrogenase from an
      extreme thermophile, Thermus thermophilus, by constructing chimeric enzymes.
AB  - In our previous study, we showed that a chimeric isopropylmalate dehydrogenase,
      2T2M6T, between an extreme thermophile, Thermus thermophilus, and a mesophile,
      Bacillus subtilis, isopropylmalate dehydrogenases (the name roughly denotes the
      primary structure; the first 20% from the N-terminal is coded by the thermophile
      leuB gene, next 20% by mesophile, and the rest by the thermophile gene) denatured
      in two steps with a stable intermediate, suggesting that in the chimera some of
      the interdomain interaction was lost by amino acid substitutions in the "2M"
      part. To identify the residues involved in the interdomain interactions, the
      first and the second halves of the 2M part of the chimera were substituted with
      the corresponding sequence of the thermophile enzyme. Both chimeras, 3T1M6T and
      2T1M7T, apparently showed one transition in the thermal denaturation without any
      stable intermediate state, suggesting that the cooperativity of the
      conformational stability was at least partly restored by the substitutions. The
      present study also suggested involvement of one or more basic residues in the
      unusual stability of the thermophile enzyme.

PMID- 10591017
TI  - The first description of an archaeal hemicellulase: the xylanase from
      Thermococcus zilligii strain AN1.
AB  - A xylanase has been found in the archaeon Thermococcus zilligii strain AN1 (DSM
      2770), which grows optimally at 75 degrees C. The enzyme had a molecular mass of
      95 kDa and a unique N-terminal sequence. It had activity against all five xylans
      tested and against xylose oligomers, but not against other carbohydrate polymers.
      The K(m) values found for xylans were typical of those found for bacterial
      xylanases. The pH optimum for activity was pH 6, and the enzyme half-life at 100
      degrees C was 8 min. This is the first description of any archaeal hemicellulase.

PMID- 10591018
TI  - Catabolic pathways of glucose in Bacillus circulans var. alkalophilus.
AB  - Enzymes and the metabolic pathways of glucose catabolism of Bacillus circulans
      var. alkalophilus were studied. The metabolism of the microbe was mixed acid
      fermentative yielding mainly acetic and formic acids as end products from
      glucose. It was estimated that B. circulans var. alkalophilus partitions 90%-93%
      of the carbon from glucose into the Embden-Meyerhof-Parnas (EMP) pathway and 7%
      10% into the hexose monophosphate (HMP) and Entner-Doudoroff (ED) pathways.
      Rather low activities of glucose dehydrogenase and gluconokinase appeared in the
      early logarithmic and late stationary phases, whereas NADH oxidase was markedly
      high. This result can be explained by a demand to reduce NADH to NAD+ for the EMP
      pathway; when acetic and formic acids are produced, no NADH is regenerated to
      NAD+, which is required in the early steps of EMP and HMP pathways. A small
      percentage (1.6%-2.4%) of the total CO2 was formed from (6-C) of glucose, which
      means that the tricarboxylic acid cycle was functional but its contribution was
      insignificant. Large differences do not seem to exist between alkaliphilic and
      neutrophilic bacilli in the use of glucose pathways.

PMID- 10591019
TI  - A stress protein is induced in the deep-sea barophilic hyperthermophile
      Thermococcus barophilus when grown under atmospheric pressure.
AB  - The whole-cell protein inventory of the deep-sea barophilic hyperthermophile
      Thermococcus barophilus was examined by one-dimensional SDS gradient gel
      electrophoresis when grown under different pressure conditions at 85 degrees C
      (Topt). One protein (P60) with a molecular mass of approximately 60 kDa was
      prominent at low pressures (0.3 MPa hydrostatic pressure and 0.1 MPa atmospheric
      pressure) but not at deep-sea pressures (10, 30, and 40 MPa). About 17 amino
      acids were sequenced from the N-terminal end of the protein. Sequence homology
      analysis in the GenBank database showed that P60 most closely resembled heat
      shock proteins in some sulfur-metabolizing Archaea. A high degree of amino acid
      identity (81%-93%) to thermosome subunits in Thermococcales strains was found.
      Another protein (P35) with molecular mass of approximately 35.5 kDa was induced
      at 40 MPa hydrostatic pressure but not under low-pressure conditions. No amino
      acid sequence homology was found for this protein when the 40 amino acids from
      the N-terminal end were compared with homologous regions of proteins from
      databases. A PTk diagram was generated for T. barophilus. The results suggest
      that Phabitat is about 35 MPa, which corresponds to the in situ pressure where
      the strain was obtained.

PMID- 10591020
TI  - Characterization of an inducible nitrilase from a thermophilic bacillus.
AB  - Nitrilase activity was induced in the thermophilic bacterium Bacillus pallidus
      strain Dac521 by growth on benzonitrile-supplemented minimal medium. The enzyme
      had a subunit relative molecular mass of 41 kDa but was purified as a complex
      with a putative GroEL protein (total M(r), 600 kDa). The enzyme catalyzed the
      hydrolysis of aliphatic, aromatic, and heterocyclic nitriles with widely varying
      kcat/KM values, primarily the result of differences in substrate affinity. Of the
      nitriles tested, 4-cyanopyridine was hydrolyzed at the fastest rate. Substitution
      of benzonitrile at the meta or para position either had no effect on catalytic
      rate or enhanced kcat, while orthosubstitution was strongly inhibitory, probably
      because of steric hindrance. The effect of catalytic inhibitors was consistent
      with the presence of active site thiol residues although activity was little
      affected by putative thiol reagents such as iodoacetate, iodoacetamide, and N
      methylmaleimide. Enzymatic activity was constant between pH 6 and 9 with an
      optimum at pH 7.6. The optimal temperature for activity was 65 degrees C with
      rapid activity loss at higher temperatures. The purified nitrilase-GroEL complex
      had the following half-lives of activity: 8.4 h at 50 degrees C, 2.5 h at 60
      degrees C, 13 min at 70 degrees C, and less than 3 min at 80 degrees C.

PMID- 10591021
TI  - Reidentification of the keratinase-producing facultatively alkaliphilic Bacillus
      sp. AH-101 as Bacillus halodurans.
AB  - Alkaliphilic Bacillus sp. AH-101 was characterized in terms of physiological and
      biochemical characteristics, and 16S rDNA sequence homology and DNA-DNA
      hybridization analyses were performed. Phylogenetic analysis of strain AH-101
      based on comparison of 16S rDNA sequences revealed that this strain is closely
      related to Bacillus halodurans. DNA-DNA hybridization of AH-101 and related
      Bacillus reference strains showed that the highest level of DNA-DNA relatedness
      (88%) was found between strain AH-101 and the B. halodurans type strain (DSM497).
      Our findings demonstrate that strain AH-101 is a member of the species B.
      halodurans.

PMID- 10591022
TI  - Tumor necrosis factor-alpha at acute myocardial infarction in rats and effects on
      cardiac fibroblasts.
AB  - Tumor necrosis factor-alpha (TNF-alpha) biosynthesis by the myocardium in
      response to several diseases has not been solely associated with activation of
      the immune system but may also serve as a stress response in the context of
      neurohumoral gene activation. In this regard, beneficial as well as adverse
      effects of the cytokine on injured myocardium have been reported. TNF-alpha has
      been suggested to modulate myocyte and fibroblast cell growth and function. Now,
      in a rat model of acute myocardial infarction TNF-alpha expression and effects on
      cardiac fibroblast were determined. TNF-alpha was detected in rat hearts with
      acute myocardial infarction, parallel to the presence of proliferating
      fibroblasts, at the border zone of the infarct region, to a lesser degree in the
      infarct zone and was still present in the surviving myocardium. Similarly, the
      TNF-alpha mRNA level was, compared to sham-operated heart, higher in the infarct
      area. In the remote myocardium, a trend to an elevated TNF-alpha mRNA level was
      observed. TNF-alpha stimulated proliferation and expression of fibronectin in
      fibroblasts isolated from the infarct, non-infarct-region and sham-operated
      hearts. Angiotensin II is mitogenic for fibroblasts post-myocardial infarction
      and effects might be mediated indirectly by TNF-alpha. Addition of a neutralising
      anti-TNF-alpha antibody inhibited angiotensin II stimulated proliferation of
      fibroblasts only from the infarcted myocardium. The regional differences in TNF
      alpha protein and mRNA levels, parallel to proliferating fibroblasts and
      proliferative effects may foster the reparative, reactive and adverse post
      infarct remodeling of the heart.

PMID- 10591023
TI  - Cardioprotection: intermittent ventricular fibrillation and rapid pacing can
      induce preconditioning in the blood-perfused rat heart.
AB  - The aim of the study was to use the isolated blood-perfused rat heart to: (i)
      determine whether brief intermittent rapid pacing and ventricular fibrillation
      are able to mimic preconditioning by ischemia and thereby protect the isolated
      blood-perfused heart against ischemia-induced injury and (ii) characterize the
      effects of these interventions on cardiac metabolism. To this end, isolated,
      blood-perfused (2.4 ml/min), paced (360 beats/min) rat hearts (n = 6/group), were
      aerobically perfused for 20 min. Hearts were then randomized to four groups: (i)
      a further 16 min aerobic perfusion (UC, untreated controls), (ii) ischemic
      preconditioning (IP, 3 min ischemia + 3 min reperfusion followed by 5 min
      ischemia + 5 min reperfusion), (iii) electrically induced ventricular
      fibrillation (VF, 3 min fibrillation + 3 min sinus rhythm followed by 5 min
      fibrillation + 5 min sinus rhythm) and (iv) rapid pacing at > or = 600 beats/min
      (RP, 3 min rapid pacing + 3 min normal heart rate followed by 5 min rapid pacing
      + 5 min normal heart rate). Hearts were then subjected to 35 min of zero-flow,
      global ischemia (37 degrees C) and 40 min reperfusion. In parallel studies, blood
      samples were collected during the first 3 min of treatment and plasma taken for
      the analysis of noradrenaline. The hearts were then immediately frozen and
      assayed for high energy phosphates and noradrenaline content. Time-to-50%
      contracture during ischemia was 13.2 +/- 0.8 min in controls; this was reduced to
      6.3 +/- 1.1 min by IP but was unaffected by VF or RP (12.4 +/- 1.1 and 12.8 +/-
      1.2 min respectively). Post-ischemic left ventricular developed pressure (LVDP)
      in untreated controls recovered to only 19.9 +/- 8.4% of its pre-ischemic value
      whereas with IP, VF and RP substantial and similar improvements were observed
      (60.3 +/- 7.4, 56.2 +/- 5.7 and 45.3 +/- 10.3%, respectively, P < 0.01). This
      protection was achieved without any significant depletion of high energy
      phosphates during VF or RP. Noradrenaline was essentially unchanged in controls
      and with RP, but VF caused a loss from tissue and a large elevation in the
      plasma. Our results suggest that both RP and VF are as effective as brief
      ischemia in protecting the heart against injury during ischemia and reperfusion.
      In contrast to IP, this protection can be achieved without the exacerbation of
      ischemic contracture and without inducing ischemia during the preconditioning
      period.

PMID- 10591024
TI  - Properties of the transient outward current in rabbit sino-atrial node cells.
AB  - The electrophysiological properties of the transient outward current were
      investigated in voltage-clamped single cells from the rabbit sino-atrial node. To
      make a regional comparison, some experiments were repeated in atrial myocytes.
      The current-voltage relationship showed a characteristic outward rectification
      with an activation threshold of -30 mV. External 4-aminopyridine (0.01-5 mM)
      inhibited this current in a dose-dependent manner (IC50 = 0.28 mM, Hill
      coefficient = 1.38). The steady-state inactivation exhibited a half-maximum
      voltage of -35 mV and a slope factor of -.4 mV. The current density of the
      transient outward current was 6.3 +/- 0.5 pA/pF in sino-atrial node cells and
      12.3 +/- 1.2 pA/pF in atrial cells. The inactivation time constant was faster in
      sino-atrial node cells (time constants 4.2 +/- 0.5 and 26.0 +/- 0.6 ms,
      respectively, for the fast and slow components) than in atrial cells (9.7 +/- 1.2
      and 44.8 +/- 3.2 ms, respectively). Recovery from inactivation was much faster in
      sino-atrial node cells (time constants 44.7 +/- 9.0 ms) than in atrial cells
      (time constants 1.39 +/- 0.32 and 6.70 +/- 0.1 s, respectively, for the fast and
      slow components). These results suggest that the kinetic properties, as well as
      the current density, of the transient outward current differs between sino-atrial
      node and atrial cells. Taking the current density of Ito at +10 mV as 2.5 +/- 0.3
      pA/pF gives a total Ito of approximately 100 pA at the peak of the action
      potential in rabbit sino-atrial node cells. The action potential duration was
      increased by 24.8 +/- 1.3% by 0.5 mM 4-AP. Thus, Ito may contribute significantly
      to the repolarization phase in mammalian sino-atrial node cells.

PMID- 10591025
TI  - Blocking Na(+)-H+ exchange by cariporide reduces Na(+)-overload in ischemia and
      is cardioprotective.
AB  - In myocardial ischemia, rapid inactivation of Na(+)-K(+)-ATPase and continuing
      influx of sodium induce Na(+)-overload which is the basis of Ca(2+)-overload and
      irreversible tissue injury following reperfusion. The Na(+)-H(+)-exchanger of
      subtype 1 (NHE-1) is assumed to play a major role in this process, but previously
      available inhibitors were non-specific and did not allow to verify this
      hypothesis. Cariporide (HOE 642) is a recently synthesized NHE-1 inhibitor. We
      have investigated its effects on Na+ homeostasis (23Na NMR spectroscopy), cardiac
      function and energy metabolism (31P NMR) in ischemia and reperfusion. In the well
      oxygenated, isolated guinea-pig heart, cariporide (10 microM) had no effect on
      intracellular Na+, pH or cardiac function. NHE-1 inhibition by cariporide was
      demonstrated using the NH4Cl prepulse technique. When hearts were subjected to 15
      min of ischemia, cariporide markedly inhibited intracellular Na(+)-accumulation
      (1.3 +/- 0.1 vs 2.1 +/- 0.1-fold rise) but had no effect on the decline in pH. In
      reperfusion, NHE-1-blockade significantly delayed pH recovery. With longer
      periods of ischemia (36 min), cariporide delayed the onset of contracture,
      reduced ATP depletion, Na(+)-overload and again had no effect on pH. In
      reperfusion, hearts treated with cariporide showed an improved recovery of left
      ventricular pressure (60 +/- 1 vs 16 +/- 8 mmHg): end-diastolic pressure was
      normalized and phosphocreatine fully recovered, while there was only a partial
      recovery in controls. The data demonstrate that Na(+)-H(+)-exchange is an
      important port of Na(+)-entry in ischemia and contributes to H(+)-extrusion in
      reperfusion. By reducing Na(+)-overload in ischemia and prolonging acidosis in
      reperfusion, NHE-blockade represents a promising cardioprotective principle.

PMID- 10591026
TI  - Effect of interleukin-1 beta on cardiac hypertrophy and production of natriuretic
      peptides in rat cardiocyte culture.
AB  - This study was designed to examine the effects of interleukin-1 beta (IL-1 beta)
      on myocyte (MC) hypertrophy and the production of A-type natriuretic peptide
      (ANP) and B-type natriuretic peptide (BNP) in rat ventricular cardiocyte culture,
      and to investigate the role of nonmyocyte (NMC) in this process. We examined the
      effects of IL-1 beta on the production of ANP and BNP in comparison with the
      effects of endothelin-1 (ET-1) by using two types of neonatal rat cardiocyte
      culture; MC-enriched culture and MC-NMC coculture. In the MC-enriched culture,
      the increase in secretion of ANP and BNP was small in treatment with IL-1 beta
      (1000 pg/ml), while ET-1 (10 nM) markedly augmented the secretion of ANP and BNP.
      In the MC-NMC coculture, IL-1 beta and ET-1 each significantly augmented the
      secretion of ANP and BNP. The degree of the increase of ANP and BNP was
      equivalent between IL-1 beta and ET-1. As for the morphological changes of MCs,
      IL-1 beta induced the star-shaped MC hypertrophy characterized by elongation and
      pointed edges only in the MC-NMC coculture, while ET-1 induced the MC hypertrophy
      characterized by shapes of squares, triangles or circles in both cultures. This
      study shows that IL-1 beta induces unique cardiac hypertrophy and the marked
      secretion of ANP and BNP, and that NMC is indispensable when treated with IL-1
      beta.

PMID- 10591027
TI  - Influence of transgenic overexpression of phospholamban on postextrasystolic
      potentiation.
AB  - Twelve mice with PLB overexpression (PLBOE), and 11 isogenic FVB/N wild-type (WT)
      controls, were anesthetized and instrumented with a 1.4 F Millar catheter in the
      LV and a 1 F pacemaker in the right atrium. At a cycle length of 200 ms and a
      fixed extrastimulus of 120 ms, extrastimuli with increasing intervals (PESI) up
      to 1000 ms were introduced, and the peak rates of LV isovolumic contraction (+/-
      dP/dtmax) were normalized and fit to monoexponential equations. In a subset of
      animals, the protocols were repeated after ryanodine (4 ng/g) was given to
      deplete SR Ca2+ stores. The time constant and the plateau of the exponential
      curve fits were significantly greater in PLBOE than WT (107.8 +/- 7.0 v 75.2 +/-
      5.5 ms and 1.39 +/- 0.03 v 1.08 +/- 0.02, both P < 0.05). At 200, 600 and 1000
      ms, the normalized dP/dt was significantly greater in PLBOE than WT. After
      ryanodine, normalized dP/dt was significantly decreased in PLBOE, but unchanged
      in WT. The protein levels of the sodium-calcium exchanger normalized to
      calsequestrin were increased 3.7 +/- 0.3-fold in PLBOE compared to controls. In
      conclusion, the phospholamban level is a critical determinant of
      postextrasystolic potentiation in this transgenic model, and is differentially
      impaired by ryanodine at long diastolic intervals in PLBOE v controls. These
      differences may be due in part to changes in the protein level and resultant
      activity of the sodium calcium exchanger.

PMID- 10591028
TI  - Increased JNK, AP-1 and NF-kappa B DNA binding activities in isoproterenol
      induced cardiac remodeling.
AB  - The in vivo signal transduction pathway, responsible for isoproterenol-induced
      cardiac hypertrophy or remodeling, remains to be clarified. The purpose of this
      study was to examine c-Jun NH2-terminal kinase (JNK) and extracellular signal
      regulated kinase (ERK), activator protein-1 (AP-1) and nuclear factor-kappa B (NK
      kappa B) DNA binding activity, which seem to be important in a signal
      transduction cascade upstream of the increased level of mRNA expression observed
      in isoproterenol-induced cardiac remodeling. Rats were continuously infused with
      saline and isoproterenol by intravenous injection (a short period; 0.5
      microgram/kg/min) and an osmotic minipump (a long period; 0.5 or 3 mg/kg/day).
      Cardiac morphology was measured by echocardiography. JNK and ERK were measured by
      in gel kinase assay. AP-1 and NF-kappa B DNA binding activity was determined
      using an electrophoretic mobility shift assay. Echocardiogram showed that the
      thickness of the left ventricular anterior wall (AW) and left ventricular
      posterior wall (PW) increased at day 1 in low doses, and at day 1 in high doses.
      Isoproterenol significantly increased ERK and JNK activity at 15 min after
      intravenous infusion of 0.5 microgram/kg/min isoproterenol. At late phase about
      JNK and ERK activity, only a high dose of isoproterenol increased JNK. AP-1 DNA
      binding activities spurred by low or high doses of isoproterenol administration
      increased at 12 h, reached their peak of 24.1- and 37.1-fold (P < 0.01),
      respectively, at 24 h, and thereafter decreased. Although low doses of
      isoproterenol did not change the level of NF-kappa B DNA binding activities, high
      doses increased it to 10.9-fold (P < 0.01) at day 2. This study showed increased
      JNK, ERK, AP-1 and NF-kappa B DNA binding activities in isoproterenol-induced
      cardiac remodeling. AP-1 may contribute to the isoproterenol-induced cardiac
      remodeling, and JNK or NF-kappa B may also play some roles in it.

PMID- 10591029
TI  - The cardiac troponin I gene is not associated with hypertrophic cardiomyopathy in
      patients from eastern Finland.
AB  - Defects in seven genes encoding sarcomere proteins have been shown to cause
      hypertrophic cardiomyopathy. To date, only one study reporting defects in the
      cardiac troponin I gene associated with hypertrophic cardiomyopathy has been
      published, and the proportion of hypertrophic cardiomyopathy cases caused by
      defects in this gene is unknown. Therefore, the authors screened 37 unrelated
      Finnish patients with hypertrophic cardiomyopathy for variants in the cardiac
      troponin I gene. Exons 1-8 of the troponin I gene were screened with the
      polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP)
      method. Five different variants (four intron variants and one silent exon
      variant) were found. Most variants were also present in control samples and none
      of the variants co-segregated with the disease in families. The results of the
      present study indicate that defects in the cardiac troponin I gene do not cause
      hypertrophic cardiomyopathy in patients from Eastern Finland.

PMID- 10591030
TI  - A high-titer lentiviral production system mediates efficient transduction of
      differentiated cells including beating cardiac myocytes.
AB  - Human immunodeficiency virus (HIV, lentivirus) type-1 based vectors have a number
      of attractive features for gene therapy, including the ability to transduce non
      dividing cells and long term transgene expression. We used a three-plasmid
      expression system to generate pseudotyped lentivirus-based vectors by transient
      transfection of human embryonic kidney 293T cells in the presence of sodium
      butyrate, which is known to activate the long terminal repeat-directed expression
      of HIV. Using this system we successfully generated versatile high titer
      lentivirus at titers of up to 2 x 10(8) transducing units/ml (TU/ml), and
      improved transduction efficiency in various cell types from seven to over twenty
      fold. We demonstrate its applicability of these vectors for the efficient
      transduction of non-dividing cells, including post mitotic beating rat cardiac
      myocytes and well-differentiated rat L6 myofibers. While both lentivirus-based
      and murine retrovirus-based vectors effectively transduced dividing cardiac
      fibroblasts and L6 muscle myoblasts in culture, lentivirus-based vectors also
      efficiently transduced cardiac myocytes and yielded titers of (6.3 +/- 1.2) x
      10(5) TU/ml; however murine retrovirus-based vectors showed low transduction
      efficiency with titers reaching only (8.9 +/- 2.1) x 10(2) TU/ml. Furthermore,
      even 12 days after induction of differentiation of L6 myofibers, lentivirus
      mediated transduction of beta-galactosidase (beta-Gal) at approximately 30-40% of
      the maximum expression levels achieved in replicating myoblasts. In contrast, the
      expression of beta-Gal following transduction of the myofibers by murine
      retrovirus-based vectors fell to less than 1% of an already reduced level of
      transduction in undifferentiated confluent myoblasts. These results demonstrate
      that lentivirus-based vectors can efficiently transduce both well-differentiated
      cardiac myocytes and differentiated myofibers. This appears to be an efficient
      method and provides a new tool for research and therapy for cardiovascular
      diseases.

PMID- 10591031
TI  - Insulin-like growth factor I as a cardiac hormone: physiological and
      pathophysiological implications in heart disease.
AB  - Accumulating evidence has indicated that insulin-like growth factor-1 (IGF-1)
      plays a specific role in the intricate cascade of events of cardiovascular
      function, in addition to its well established growth-promoting and metabolic
      effects. IGF-1 is believed to mediate many effects of growth hormone (GH), IGF-1
      promotes cardiac growth, improves cardiac contractility, cardiac output, stroke
      volume, and ejection fraction. In humans, IGF-1 improves cardiac function after
      myocardial infarction by stimulating contractility and promoting tissue
      remodeling. Furthermore, IGF-1 facilitates glucose metabolism, lowers insulin
      levels, increases insulin sensitivity, and improves the lipid profile. These data
      suggest an attractive therapeutic potential of IGF-1. Both clinically observed
      and experimentally induced impairments of cardiac function are also found to be
      associated with abnormal IGF-1 levels. IGF-1 and its binding proteins have been
      considered as markers for the presence of certain cardiac abnormalities,
      indicating that IGF-1 may be a risk factor for certain cardiac disorders. The
      present review will emphasize the role of IGF-1 in the regulation of cardiac
      growth and function, and the potential pathophysiological role of IGF-1 in
      cardiac function.

PMID- 10591032
TI  - The absence of desmin leads to cardiomyocyte hypertrophy and cardiac dilation
      with compromised systolic function.
AB  - Desmin is the muscle-specific member of the intermediate filament family of
      cytoskeletal proteins, expressed both in striated and smooth muscle tissues. In
      mature striated muscle fibers, the desmin filament lattice surrounds the Z-discs,
      interconnects them to each other and links the entire contractile apparatus to
      the sarcolemmal cytoskeleton, cytoplasmic organelles and the nucleus. There have
      been increasing reports of human cardiomyopathies associated with abnormal
      accumulation and aggregation of desmin filaments. Recently identified desmin
      mutations in humans suffering from skeletal muscle myopathy and cardiomyopathy
      suggest that these diseases might arise as a consequence of impaired function of
      desmin filaments. Previous generation of desmin null mice in our laboratory
      demonstrated that the absence of desmin results in myocyte ultrastructural
      defects and myocyte cell death leading to fibrosis and calcification of the
      myocardium. However, the effects that these defects have on cardiac function were
      not addressed. To further our understanding of desmin function in vivo, and in
      order to address the direct involvement of desmin in cardiomyopathy, we
      investigated the effect of the absence of desmin on myocardial mass, myocyte size
      and shape, changes in gene expression and cardiac systolic and diastolic function
      in mice. Morphometric characterization of isolated cardiomyocytes demonstrated a
      24% increase in cell volume in the desmin null mice, solely due to an increase in
      transverse section area, suggesting for the first time that mice lacking the
      intermediate filament protein desmin develop concentric cardiomyocyte
      hypertrophy. This type of hypertrophy was accompanied by induction of embryonic
      gene expression and later by ventricular dilatation, and compromised systolic
      function. These results demonstrate that desmin is essential for normal cardiac
      function, and they suggest that the absence of an intact desmin filament system,
      rather than accumulation of the protein, may be responsible for the pathology
      seen in some of the desmin associated cardiomyopathies.

PMID- 10591033
TI  - Biochemical and physiological properties of pedicellarial lectins from the
      toxopneustid sea urchins.
AB  - Pedicellarial lectins (SUL-I, SUL-II, and TGL-I) were purified from the
      toxopneustid sea urchins, Toxopneustes pileolus and Tripneustes gratilla using
      gel filtration chromatography, affinity chromatography, and reverse-phase HPLC.
      SUL-I (Nakagawa et al., 1996) and SUL-II from the large globiferous pedicellariae
      of T. pileolus are D-galactose-binding lectins with molecular masses of 32 kDa
      and 23 kDa, respectively; while TGL-I from the globiferous pedicellariae of T.
      gratilla is a Ca(2+)-independent heparin-binding lectin with a molecular mass of
      23 kDa. SUL-I induced mitogenic stimulation on murine splenocytes but TGL-I did
      not. At higher dose ranges SUL-I exhibited inhibitory effects on the cells. The
      dual response to SUL-I was effectively inhibited by D-galactose. SUL-I enhanced
      norepinephrine-induced contraction of isolated rat mesenteric artery with
      endothelium. When endothelium was removed from the artery, acetylcholine did not
      relax the norepinephrine-induced contraction. In the same artery the enhancing
      effect of the contraction by SUL-I was abolished, suggesting that SUL-I acts on
      the endothelium of mesenteric artery, and may release prostanoids. The present
      results suggest an extracellular function for SUL-I that may have wide-ranging
      effects in physiological processes. The primary role of pedicellarial lectins
      from T. pileolus and T. gratilla might be defense against a foreign body.

PMID- 10591034
TI  - A series of bioactivity-variant neurotoxins from scorpion Buthus martensii
      Karsch: X-ray crystal structure and functional implications.
AB  - Three bioactivity-variant neurotoxins, BmK M1, M4, and M8, have been purified
      from venom of the Chinese scorpion Buthus martensii Karsch. They possess distinct
      toxic activity on mice in vivo with different electrostatic properties. The
      relative toxicities of BmK M1, M4, and M8 are 13.3:2.5:1, which interestingly
      correspond to their respective pI values, ranging from basic to acidic, of 9.01,
      7.53, and 5.30, respectively. In addition, the X-ray crystal structure of BmK M8,
      which is acidic and 1100 times less active than the most potent and basic alpha
      toxin AaH II, have been determined at 1.85 A resolution and analyzed in detail.
      In combination with information from chemical modifications and site-directed
      mutagenesis, the structural comparisons and sequence alignments suggest a
      multisite binding mode for toxin-receptor interactions, and three "toxic regions"
      with relevance to the binding process, including Face A, Face B, and Site C. Face
      A is featured in the presence of several aromatic residues and may be more
      essential for the binding; Face B may contribute to the high efficacy of the
      binding process, on which substitution by acidic residues could weaken the toxic
      activity; Site C is probably involved in binding site specificity. The main
      residues involved in these regions will be discussed.

PMID- 10591035
TI  - Anisodamine as an effective drug to treat snakebites.
AB  - Anisodamine is a natural alkaloid drug isolated from the plant Anisodus
      tanguticus growing in western China. The chemical structure and pharmacological
      action are just like the cholinergic receptor blocking agents atropine or
      scopolamine. The specific characteristic of the drug is being able to relieve the
      dangerous situation of microcirculatory failure, especially in case of DIC or
      renal failure. The prognosis of the patients will be quite good. Another
      characteristic of the drug is that no serious toxic reaction occurs even in
      successive doses given intravenously up to 500 mg a day. This is about fifty
      times greater than a common dose of 10 mg. Since we begin with the drug as a
      routine medication for the symptomatic treatment of renal failure, DIC bleeding,
      and microcirculatory failure, we should say that the specific antivenin and
      anisodamine are two treasure drugs for snakebites.

PMID- 10591037
TI  - Studies on conotoxins of Conus betulinus.
AB  - The biological activity and toxicity of crude venom from Conus betulinus, which
      was collected from the South China Sea, were studied. The venom shows Ach
      receptor activity, K+ current effect, and low toxicity. Four peptide components,
      named BeTXIa, BeTXIb, BeTXIIa, and BeTXIIb, were purified by gel-filtration with
      Sephadex followed by HPLC, and finally sequenced on an ABI model 491 sequencer.
      The low-molecular-weight peptides BeTXIa and b have 14 and 15 amino acid
      residues, respectively, while BeTXIIa and b have 27 and 30 amino acid residues,
      respectively. The results indicate that BeTXs from the venom of C. betulinus are
      a set of small peptides with a high cysteine content like known conotoxins.
      However, it is meaningful to find that these sequences have specific chemical
      characteristics in their cysteine framework which differ greatly from known
      cysteine frameworks in conotoxin structures.

PMID- 10591036
TI  - Purification and characterization of the venom phospholipases A2 from Asian
      monotypic crotalinae snakes.
AB  - Phospholipases A2 were purified from the venoms of Asian monotypic crotalinae
      snakes including Callosellasma, Hypnale, Deinagkistrodon, and Tropidolaemus by a
      combination of gel filtration and reversed-phase chromatographic methods. One to
      four isoforms of the enzyme were found in each of the venoms. The venom enzymes
      were subjected to N-terminal sequencing up to the 30th amino acids, and their
      molecular weights were analyzed by electrospray-ionization mass spectrometry.
      Homologous antiplatelet phospholipase with a conserved Glu 6 residue was found in
      each of the venoms. Basic phospholipases with Trp 6 (W6) but without detectable
      enzyme activities were also isolated from the venom of C. rhodostoma, H. hypnale,
      and T. wagleri. These W6 enzymes showed strong heparin-binding affinity and
      capable of inducing edema in rat paws. The fact that the venoms of Callosellasma
      and Hypnale contain similar types of phospholipases is in accord with recent
      reports that these two taxa formed a clade. Deinagkistrodon venom does not
      contain phospholipase variants other than the Glu-6 subtype as Trimeresurus,
      Agkistrodon, and Protobothrops venoms do. Interestingly, the Glu-6 enzyme from T.
      wagleri venom has a molecular weight of 15,319 Daltons, higher than those of most
      other venom phospholipases. Our results show that new types of the enzyme are
      more likely to be found in the venom of monotypic species; the amino acid
      sequence data or the subtypes of venom-phospholipases are potentially useful as
      markers or a character system for studying higher-order systematics of venomous
      snakes.

PMID- 10591038
TI  - Pathophysiological effects of Russell's viper venom on renal function.
AB  - Pathophysiological effects of Russell's viper venom (RVV) on renal function are
      reviewed. The evidence in experimental animals on the mechanisms of venom action
      in relation to changes in either extrarenal or intrarenal factors is considered.
      The cardiovascular system and renal hemodynamics are affected by the venom. Mean
      arterial blood pressure, heart rate, cardiac output, and renal hemodynamics
      decrease, while total peripheral vascular resistance and renal vascular
      resistance increase in the initial post-injection period of envenoming. After the
      transitory decrease, all parameters for general circulation gradually increase,
      returning to near normal level within 30 min, while an increase in renal vascular
      resistance and decreases in renal blood flow and glomerular filtration rate are
      still apparent 48 h after envenomation. The effects of venom on renal
      vasoconstriction are discussed. Possible factors, especially humoral factors,
      inducing these changes are considered. Russell's viper venom is also able to
      affect renal tubular cells directly. This can be explained based on available
      data from in vitro studies. Different studies have been performed to investigate
      venom action in the isolated perfused kidney, changes in the characteristic
      polarization of the cell membrane, changes in mitochondria activity and changes
      in Na, K-ATPase activity of the tissue of both the renal cortex and medulla
      during envenomation.

PMID- 10591039
TI  - Bioactivities of nerve growth factor from Chinese cobra venom.
AB  - The nerve growth factor, NGF, from Chinese cobra Naja naja atra venom was
      isolated by gel-filtration and ion-exchange chromatography. Cobra NGF was
      characterized by analytical HPLC techniques as well as SDS-PAGE, and was proven
      to be a glycoprotein with a mol. wt. of 23 (+/- 2) kD and a pI of 9.2. The amino
      acid analysis and N-terminal sequencing were performed using conventional
      methods. Bioassays with cultured chick embryos ganglia and rat pheochromocytoma
      PC-12 cells revealed a promotion of fiber outgrowth, which is typical of NGF
      activity. Absence of enzymatic, toxicological, and teratogenic activities were
      shown by quality inspection. Since 1994, many clinical cases about volunteers
      receiving NGF treatment have been reported in mainland China. Bioactivities of
      NGF deal with a wide range of disciplines and technologies. In this paper we will
      discuss neuronal and non-neuronal effects of NGF treatment. Does the NGF cross
      the blood-brain barrier by transcytosis into the brain tissue? How is NGF
      important in wound healing, especially in peripheral nerve injury and diabetic
      neuritis? NGF may also be useful for male volunteers suffering from sterility,
      because it is possible that the sexual cells of testis can be promoted to
      maturity.

PMID- 10591040
TI  - Predicted three-dimensional structural models of venom serine protease inhibitors
      and their interactions with trypsin and chymotrypsin.
AB  - Three homology models of trypsin and chymotrypsin inhibitor polypeptides from
      snake venom of Naja naja naja and Leaf-nosed viper in the unbound state and in
      complex with trypsin and chymotrypsin were built based on homology to bovine
      pancreatic trypsin inhibitor (BPTI). These venom inhibitors belong to the Kunitz
      type inhibitor family, which is characterized by a distinct tertiary fold with
      three-conserved disulfide bonds. The general folding pattern in these trypsin and
      chymotrypsin inhibitor homology models is conserved when compared to BPTI. The
      respective orientations of the inhibitors bound to trypsin/chymotrypsin are
      similar to that of BPTI bound to bovine trypsin/chymotrypsin. The principal
      binding loop structure of the inhibitors fills the active site of enzymes in a
      substrate-like conformation and forms a series of independent main-chain and side
      chain interactions with enzymes. In order to provide the possible fingerprints
      for molecular recognition at the enzyme-inhibitor interface, a detailed
      theoretical analysis of the interactions between the principal binding loop of
      these inhibitors and active site of trypsin/chymotrypsin is performed based on
      available crystal structural, site-directed mutagenetic, kinetic, and sequence
      analysis studies. Despite the variations present at different positions of the
      principal binding loop of trypsin and chymotrypsin inhibitor models from Leaf
      nosed viper and cobra Naja naja naja, respectively (designated as LnvTI and NCI),
      there are favorable subsite binding interactions which are expected to exhibit
      equally potent inhibitory activity as BPTI. On the contrary, significant
      mutations at several secondary specificity positions in the Naja naja naja
      trypsin inhibitor (designated as NTI) are likely to affect different inhibitor
      enzyme-subsites interactions. This may explain the observed increased inhibitory
      activity of this polypeptide on a structural basis.

PMID- 10591041
TI  - Ribotoxins and their applications in probing the topographical structure of
      ribosomes.
AB  - Ribotoxins are a group of ribosome-inactivating proteins (RIPs) isolated mostly
      from plants. They inactivate ribosomes by a mechanism as RNA N-glycosidase that
      removes a specific adenine base from the highly conserved "S/R domain" in the
      largest ribosomal RNA. In this review, we introduce the major results from our
      laboratory in recent years on the study of the structure and function of RIPs and
      ribosomes: [1] Purification and characterization of the enzymatic mechanism of
      RIPs. Several new RIPs were purified and their RNA N-glycosidase and supercoil
      dependent DNA endonuclease activities were studied. [2] The topographical
      structure of ribosomes. The relationship between the structure and function of
      ribosomes, especially of the "S/R domain" in rat 28S rRNA, were investigated by
      means of RIPs and other chemical probes. [3] The cytotoxicity of two RIPs to
      carcinoma cells. [4] Several new methods for studying RIPs and probing the
      structure of ribosomes were developed, i.e., radioassays for RNA N-glycosidase,
      glycoprotein detection by fluorescent labeling on SDS-polyacrylamide gels, and
      methods for small RNA sequencing.

PMID- 10591042
TI  - Halogeton poisoning in livestock.

PMID- 10591043
TI  - Fumonisin B1 from the fungus Fusarium moniliforme causes contact toxicity in
      plants: evidence from studies with biosynthetically labeled toxin.
AB  - Fumonisin B1 (FB1) is the most abundant of a series of sphingosine analog
      mycotoxins produced by the fungus Fusarium moniliforme, a ubiquitous contaminant
      of stored corn (maize) worldwide. FB1 exhibits a variety of biological activities
      including phytotoxicity, which is of particular interest for its potential role
      as a virulence factor to facilitate invasion of plant tissues by the fungus.
      Droplets of FB1 solution applied to the leaf surface of jimsonweed, black
      nightshade, and susceptible tomatoes caused necrosis, growth inhibition, and
      death. With Arabidopsis thaliana grown on agar plates, an IC50 (concentration
      causing half maximal phytotoxicity) of less than 1 ppm was observed. [3H]FB1 was
      prepared by biosynthetic incorporation of commercially-available radiolabeled
      presumptive precursors into the toxin in rice medium solid cultures of F.
      moniliforme JW#1. The labeled toxin produced by incorporation of [9,10
      3H]palmitate induced phytotoxic symptoms identical to unlabeled material,
      indicating it had full biological activity. The area of necrosis on treated
      leaves was similar in light and dark treated plants. Using liquid scintillation
      counting to quantify radioactivity in excised plant parts, over 95% of the
      [3H]FB1 radioactivity applied to leaves of light or dark-treated plants was
      recovered from the treated leaf. When [3H]FB1 was applied to a wound site on
      target plants, severe damage occurred at the site of FB1 application and in
      tissue above the site. These results indicate that FB1 applied to intact surfaces
      of target plants exhibits primarily contact activity. Translocation of FB1 is
      limited, occurring only when FB1 is applied to a wound site, and it results in
      damage to tissue above the point of application, indicating that FB1 is xylem
      mobile.

PMID- 10591044
TI  - Response variability and stimulus discrimination capacity of neurons in monkey
      inferior temporal cortex.
AB  - Single neurons (n = 73) were recorded from the inferior temporal cortex (IT) of
      an awake macaque monkey, while performing a visual fixation task. Shape stimuli
      that elicited different responses of the IT neurons, were found to result in
      different response variances. The response variance vs. mean response
      relationship of the IT neurons could be described by an analogous function to
      those found in previous studies of A17 in cats and of V1 in macaques. A
      comparison of the stimulus discrimination capacities of the individual neurons
      revealed that neurons which exhibit lower variances can discriminate their
      preferred and non-preferred shape stimuli more reliably than neurons with higher
      variances.

PMID- 10591045
TI  - Topical acetylsalicylic acid versus lidocaine for postherpetic neuralgia: results
      of a double-blind comparative clinical trial.
AB  - A double-blind comparative clinical trial was performed with topical aspirin
      versus lidocaine for the treatment of 40 patients with postherpetic neuralgia.
      The percentage improvement following topical aspirin application was 72.2 +/-
      19.9 S.D., while with lidocaine it was 72.8 +/- 25.3 S.D. These results suggest
      that the effect of topical treatment with aspirin is as good as that with
      lidocaine, since there was no significant difference (P = 0.778) between the two
      drugs in respect of pain reduction and accordingly the topical application of
      acetylsalicylic acid can be equally recommended.

PMID- 10591046
TI  - Determination of monoamine oxidase activity by HPLC with fluorimetric detection.
AB  - The aldehyde produced from the oxidative deamination of primary and secondary
      amines by the monoamine oxidases (EC 1.4.3.4; MAO) or the semicarbazide-sensitive
      amine oxidases (EC 1.4.3.6; SSAO) may be determined followed reaction at elevated
      temperatures with 2-diphenylacetyl-1,3-indandione-1-hydrazone (DIH), separation
      by high-performance chromatography liquid (C-8 column, eluting isocratically with
      acetonitrile, ammonium acetate, water) and fluorimetric detection (excitation and
      emission wavelengths 430 and 525 nm). The detection limits for benzaldehyde, p
      hydroxybenzaldehyde and 2-phenylacetaldehyde were 125 nM, 150 and 62.3 nM,
      respectively. Thus the assay is appropriate for determination of amine oxidase
      activities towards benzylamine, 2-phenylethylamine and tyramine. The fluorescence
      of the DIH adduct with indole-3-aldehyde was strongly quenched, giving a
      relatively high detection limit (17.5 microM). The detection limit was lower (3.8
      microM) when the absorbance at 430 nm was monitored. Enzyme activities determined
      by this procedure were shown to be linear with enzyme-protein concentration (rat
      liver mitochondria). The presence of 1-2 mM semicarbazide, necessary for
      determining MAO activities in samples also containing SSAO, did not adversely
      affect the derivatization reaction. The DIH-aldehyde adducts were sufficiently
      stable to permit their storage at low temperatures prior to assay. The product
      produced by reaction of 5-hydroxyindole acetaldehyde with DIH had no significant
      fluorescence and too low an absorbance at 430 nm to allow its determination for
      assay of activities towards 5-HT. This procedure can also measure succinic
      semialdehyde (detection limit 240 nM) and thus would be applicable to the
      determination of GABA transaminase activity.

PMID- 10591047
TI  - Involvement of monooxygenases and amine oxidases in hydroxyl radical generation
      in vivo.
AB  - The levels of hydroxyl radicals in vivo were measured in rat blood plasma by
      determining the formation of 2,3-dihydroxybenzoate (2,3-DHB) resulting from the
      attack of hydroxyl radicals on injected salicylate. This approach was used to
      study the effects of alterations in the activities of cytochrome P-540 (CYP)
      dependent hydroxylases (monooxygenases) and monoamine oxidase (MAO), two groups
      of enzymes that can produce reactive oxygen species in the reactions they
      catalyse. Pretreatment with inducers of the cytochrome P540 (CYP) hydroxylases,
      such as phenobarbital and dexamethasone, resulted in substantial increases in the
      plasma oxygen radical formation, suggesting that the action of these enzymes on
      endogenous substrates, or on exogenous substrates such as salicylate, may
      contribute to oxygen radical formation in vivo. In contrast, pretreatment with
      the monoamine oxidase (MAO) inhibitors clorgyline and deprenyl did not have any
      significant effect on the plasma 2,3-DHB levels, perhaps reflecting the different
      intracellular locations of MAO and the CYP-dependent hydroxylases. Injection of
      pentylamine, a substrate of MAO-B and semicarbazide-sensitive amine oxidase
      (SSAO) was also without significant effect.

PMID- 10591048
TI  - Neuroprotection by (R)-deprenyl and 7-nitroindazole in the MPTP C57BL/6 mouse
      model of neurotoxicity.
AB  - The neurodegenerative properties of the parkinsonian inducing agent 1-methyl-4
      phenyl-1,2,3,6-tetrahydropyridine (MPTP) are thought to result from inhibition of
      complex I of the mitochondrial respiratory chain by the monoamine oxidase-B (MAO
      B) generated 1-methyl-4-phenylpyridinium metabolite MPP+. 7-Nitroindazole (7-NI)
      both a reversible MAO-B inhibitor and a neuronal nitric oxide synthase (nNOS)
      inhibitor, and (R)-deprenyl a potent MAO-B inactivator, provide neuroprotection
      in the C57BL/6 mouse model of MPTP neurotoxicity. The results reported here
      demonstrate the complexities of the effects of 7-NI in this model and examine the
      possibility of other mechanisms of neuroprotection by (R)-deprenyl.

PMID- 10591049
TI  - Inhibition of monoamine oxidase by pirlindole analogues: 3D-QSAR analysis.
AB  - A series of pirlindole analogues were tested as inhibitors of monoamine oxidase A
      and B. Although we did not find strict dependence between 3D-size of molecules
      and their inhibitory potency, rigid analogues exhibited potent and selective
      inhibition of MAO-A. They have 3D size limits of 13 angstroms (length) x 7
      angstroms (height) x 4.4 angstroms (widths). Besides MAO-A inhibition flexible
      analogues also demonstrated potent inhibition of MAO-B. Five compounds were
      studied as inhibitors of purified human liver MAO-A. Their inhibitory potencies
      coincided with those obtained using rat liver mitochondrial MAO-A. Each compound
      induced changes in the spectrum of MAO-A but these did not correlate with the
      flexibility of the derivative. It is also possible that the oxygen bridge
      introduced with the flexibility might influence spectral patterns.

PMID- 10591050
TI  - Some peculiar aspects of monoamine oxidase inhibition.
AB  - CN- ions enhance the inhibition of monoamine oxidase by the hydrazine
      derivatives, phenelzine [2-phenylethylhydrazine] and pheniprazine [(1-methyl-2
      phenylethyl)hydrazine]. This involves partial competitive activation of the
      initial noncovalent enzyme-inhibitor complex with no significant effect on the
      subsequent reaction to give the irreversibly inhibited species. Whereas the
      maximum effects on pheniprazine inhibition of rat liver MAO-B occurred at about 5
      microM cyanide, concentrations of 5 mM were necessary for maximum stimulation of
      MAO-A inhibition. A comparison of the behaviour of rat and ox MAO revealed
      considerable differences in their sensitivities to pheniprazine and the
      potentiating effects of cyanide. Species differences were also evident in the
      interactions derivatives of milacemide [2-n-pentylaminoacetamide] as substrates
      and mechanism-based inhibitors of MAO-B. In one case there was evidence for
      apparently large difference in inhibitor sensitivities between human brain MAO-B
      from different individuals.

PMID- 10591051
TI  - Neuroprotective and neuronal rescue effects of selegiline: review.
AB  - The effect of selegiline [(-)-deprenyl] cannot be considered as a simple,
      selective inhibitor of MAO-B. Pretreatment with the drug prevented the effect of
      specific neurotoxins like MPTP, 6-OH-dopamine, DSP-4 and AF64A. Selegiline
      pretreatment prevented the depletion of noradrenaline (NA) induced by DSP-4 in
      the rat hippocampus. This can be due to the uptake inhibitory effect of
      selegiline and mainly to its metabolite methylamphetamine (MA), which is more
      potent inhibitor of the re-uptake than the parent compound. SKF-525A pretreatment
      diminished the protective effect of selegiline against DSP-4, while phenobarbital
      pretreatment decreased its MAO-B inhibitory potency. Selegiline in low oral doses
      also prevented the effect of DSP-4 due to its intensive "first pass" metabolism.
      Selegiline treatment can rescue damaged neurones. It inhibited the apoptosis in M
      1 human melanoma cells in a rather low concentration (10(-13)M). The mode of
      action of the drug regarding the inhibition of apoptosis is not known.

PMID- 10591052
TI  - The correlation between platelet MAO activity and personality--the effect of
      smoking and possible mechanisms behind the correlation.

PMID- 10591053
TI  - A second redox group in monoamine oxidase: its role in catalysis and inhibition.
AB  - The currently accepted and well-documented radical mechanism for MAO catalysis
      has certain limitations. No flavin radical has ever been observed or trapped, the
      role of the essential thiol groups is not defined, and the mechanism provides no
      clue as to how binding of substrate can raise the redox potential of the MAO
      flavin by 0.5 V and accelerate the rate of reoxidation of the reduced enzyme.
      Recent work demonstrated that 4 electrons were needed for full reduction of the
      enzyme. It is hypothesized that another redox group, in addition to the flavin,
      is located in the active site in close proximity to the cofactor and that this
      group may be a disulphide. If a new mechanism involving a disulfide can be
      established, it could explain, by formation of thiol adducts, the time-dependent
      and slowly reversible action of some inhibitors.

PMID- 10591054
TI  - Antidepressive and antihypertensive effects of MAO-A inhibition: role of N
      acetylserotonin. A review.
AB  - Acute administration of irreversible and reversible selective MAO-A inhibitors
      and high doses (or chronic administration of low doses) of relatively selective
      MAO-B inhibitors (but not of highly selective MAO-B inhibitors) suppressed MAO-A
      activity and stimulated N-acetylation of pineal serotonin into N-acetylserotonin,
      the immediate precursor of melatonin. Consequent increase of melatonin occurs
      only in > 21-days-old rats. The effect is strain (spontaneously hypertensive rats
      > Fisher344N > Wistar Kyoto > Sprague-Dawley) and gender (male > female)
      dependent. N-acetylserotonin increase after clorgyline was weaker in the light
      primed aged (or young animals with lesioned suprachiasmatic nuclei) than in young
      intact or sham-operated rats. N-acetylserotonin increase after MAO-A inhibitors
      might mediate their antidepressive (N-acetylserotonin and melatonin exerted
      antidepressant-like activity in the mouse tail-suspension and frog tests) and
      antihypertensive effects (N-acetylserotonin, but not melatonin, decreased blood
      pressure in spontaneously hypertensive rats).

PMID- 10591055
TI  - The behaviour of aryl pyrrolines with monoamine oxidase.
AB  - We have examined the effects of monoamine oxidase (MAO) on two pyrrolines, 1
      methyl-3-phenyl-delta 3-pyrroline and its 4-chlorophenyl analogue. They act as
      substrates but also inhibit the enzyme in a time-dependent manner. This behaviour
      is similar to that shown by the neural pro-toxin 1-methyl-4-phenyl-1,2,3,6
      tetrahydro pyridine (MPTP) which is metabolised by MAO to produce the toxin 4
      phenyl pyridinium (MPP+). The end product of the oxidation of the pyrrolines
      appears to be the corresponding pyrrole. The latter were found to inhibit MAO
      reversibly. The aryl pyrrolines bear close structural resemblance to MPTP and
      probably generate a pyrrolium ion, analogous to MPDP or MPP+, during the
      oxidation by MAO. Whether pyrrolines or their metabolites might mimic the effects
      of MPTP on mitochondrial respiration remains an unanswered question.

PMID- 10591056
TI  - MAO-A and -B gene knock-out mice exhibit distinctly different behavior.
AB  - MAO-A and -B are key isoenzymes that degrade biogenic and dietary amines. MAO-A
      preferentially oxidizes 5-HT and NE, whereas MAO-B preferentially oxidizes PEA.
      However, the substrate and inhibitor selectivity overlap depending on the
      concentration of the enzyme and substrate. A line of transgenic mice has been
      generated in which the gene that encodes MAO-A is disrupted. MAO-A KO mice have
      elevated brain levels of 5-HT, NE and DA and manifest aggressive behavior similar
      to men with a deletion of MAO-A. We have also generated mice deficient in MAO-B
      by homologous recombination. Interestingly, MAO-B KO mice do not exhibit
      aggression and only levels of PEA are increased. MAO-B-deficient mice are
      resistant to the Parkinsongenic neurotoxin, 1-methyl-4-phenyl-1,2,3,6
      tetrahydropyridine. Thus, studies of MAO-A and -B KO mice have clearly shown that
      MAO-A and -B have distinct functions in neurotransmitter metabolism and behavior.
      MAO KO mice are valuable models for investigating the role of monoamines in
      aggression and neurodegenerative and stress-related disorders.

PMID- 10591057
TI  - Metabolic transformation of deprenyl enantiomers in rats.
AB  - The optical isomers of deprenyl have different pharmacological activities and
      potency. Selegiline, an (-)-isomer, is the more potent monoamine oxidase B enzyme
      inhibitor, and this substance is used in the therapy of Parkinson's disease. The
      neuroprotective and neuronal rescue effects of deprenyl, as well as the
      psychostimulant action of its metabolites, methamphetamine and amphetamine are
      also different for the enantiomers. In this study the biotransformation of
      deprenyl enantiomers was compared. Stereoselective dealkylation of both optical
      isomers was found as major metabolic alteration. The difference in the ratio of
      the formed metabolites suggests the existence of preferred metabolic pathways for
      the enantiomers.

PMID- 10591058
TI  - Changes of intracellular calcium concentrations by phenylephrine in renal
      arterial smooth muscle cells.
AB  - In smooth muscle cells isolated from swine renal interlobar arteries,
      phenylephrine (PE) at concentrations of 1-10 microM produced biphasic increases
      of the intracellular calcium concentration. An early transient rise was followed
      by a maintained plateau. The maintained component was sensitive to extracellular
      calcium, in contrast to the early transient, which was still observed in
      nominally calcium-free solution. Nifedipine (1 microM) and NiCl2 (100 microM)
      only weakly affected the calcium signal, suggesting that voltage-sensitive
      calcium channels play only a minor role in the PE-induced changes in
      intracellular calcium. Thapsigargin (0.5 microM) elevated the intracellular
      calcium concentration and depressed both the early transient and the maintained
      component of the PE response. In calciumfree medium PE induced a transient rise
      of the intracellular calcium concentration with a depressed plateau. Readmission
      of calcium elevated the intracellular calcium concentration above the baseline.
      Both components of the PE-induced calcium signal were completely abolished when
      the cells were pretreated with the phospholipase C (PLC) inhibitor U73122 (2
      microM). LaCl3 (100 microM, 1 mM), an inhibitor of calcium-release-activated
      current (ICRAC), had no effect on the PE-induced calcium signal. GdCl3 (50
      microM), SKF 96365 (10 microM) and flufenamic acid (100 microM), reported to
      inhibit nonselective cation channels, blocked or transiently reduced the
      maintained calcium signal. Several protein kinase inhibitors such as genistein
      (10 microM), H7 (50 microM), H89 (1 microM) and bisindolylmaleimide (0.2 microM)
      reduced the maintained calcium signal. We conclude that the initial transient
      spike of the PE-induced calcium signal is due to release of calcium from inositol
      1,4,5-trisphosphate-sensitive calcium stores evoked by alpha 1-adrenoceptor
      coupled stimulation of PLC and that the maintained component is due to
      capacitative calcium entry, which is modulated by protein kinases.

PMID- 10591059
TI  - Effect of carbachol and prostaglandin E2 on chloride secretion and signal
      transduction in the exocrine glands of frog skin (Rana esculenta).
AB  - Carbachol (CCH) increased the short-circuit current across frog skin glands in a
      biphasic manner, which coincided with an increase in the transepithelial Cl- net
      flux. CCH also induced a biphasic increase in [Ca2+]i. Both these responses were
      mediated via muscarinic receptors. The plateau phase of the CCH-induced Cl-
      secretion was modestly inhibited by indomethacin and unaffected by tetrodotoxin
      or tetrodotoxin plus indomethacin, indicating that CCH can increase Cl- secretion
      directly via receptors on the secretory cells. Prostaglandin E2 (PGE2) increased
      secretion and cAMP production, indicating expression of EP2 and/or EP4 receptors.
      PGE2 failed to increase [Ca2+]i ruling out involvement of EP1 receptors. The
      secretory response to CCH was potentiated by prestimulation with PGE2, and it was
      investigated whether this potentiation is caused by interaction at the level of
      the messengers involved. Stimulation by CCH plus PGE2 failed to stimulate cAMP
      production further than PGE2 alone. Addition of PGE2 during the CCH-elevated
      [Ca2+]i plateau phase in most cases reduced the level of [Ca2+]i. These data show
      that the synergy between CCH and PGE2 is not based on interactions at the
      intracellular messenger level.

PMID- 10591060
TI  - A role for Na+/H+ exchange in pH regulation in Helix neurones.
AB  - We have used the pH-sensitive fluorescent dye 8-hydroxypyrene-1,3,6-trisulphonic
      acid (HPTS) to reexamine the mechanisms that extrude acid from voltage-clamped
      Helix aspersa neurones. Intracellular acid loads were imposed by three different
      methods: application of weak acid, depolarization and removal of extracellular
      sodium. In nominally CO2/HCO3-free Ringer the rate of recovery from acid loads
      was significantly slowed by the potent Na+/H+ exchange inhibitor 5-[N-ethyl-N
      isopropyl]-amiloride (EIPA, 50 microM). Following depolarization-induced
      acidifications the rate of intracellular pH (pHi) recovery was significantly
      reduced from 0.41 +/- 0.13 pH units.h-1 in controls to 0.12 +/- 0.09 pH units.h-1
      after treatment with EIPA at pHi approximately equal to 7.3 (n = 7). The
      amiloride analogue also reduced the rate of acid loading seen during
      extracellular sodium removal both in the presence and absence of the Na(+)
      dependent Cl-/HCO3- exchange inhibitor 4-acetamido-4'-isothiocyanato-stilbene
      2,2'-disulphonic acid (SITS, 50 microM). This is consistent with EIPA inhibiting
      reverse-mode Na+/H+ exchange. In 2.5% CO2/20 mM HCO3-buffered Ringer pHi recovery
      was significantly inhibited by SITS, but unaffected by EIPA. Our results indicate
      that there are two separate Na(+)-dependent mechanisms involved in the
      maintenance of pHi in Helix neurones: Na(+)-dependent Cl-/HCO3- exchange and
      Na+/H+ exchange. Acid extrusion from Helix neurones is predominantly dependent
      upon the activity of Na(+)-dependent Cl-/HCO3- exchange with a lesser role for
      Na+/H+ exchange. This adds further weight to the belief that the Na+/H+ exchanger
      is ubiquitous.

PMID- 10591061
TI  - Role of the D2 dopamine receptor in molecular adaptation to chronic hypoxia in
      PC12 cells.
AB  - We have previously shown that pheochromocytoma (PC12) cells rapidly depolarize
      and undergo Ca2+ influx through voltage-dependent Ca2+ channels in response to
      moderate hypoxia and that intracellular free Ca2+ is modulated by activation of
      dopamine D2 receptors in this cell type. The present study shows that D2
      (quinpirole-mediated) inhibition of a voltage-dependent Ca2+ current (ICa) in
      PC12 cells is dramatically attenuated after chronic exposure to moderate hypoxia
      (24 h at 10% O2). Pretreatment of cells with pertussis toxin abolished D2
      mediated inhibition of ICa. The D2-induced inhibition of ICa did not depend on
      protein kinase A (PKA), as it persisted both in the presence of a specific PKA
      inhibitor (PKI) and in PKA-deficient PC12 cells. Prolonged exposure to hypoxia
      (24 h) significantly reduced the level of Gi/o alpha immunoreactivity, but did
      not alter G beta levels. Furthermore, dialysis of recombinant G(o) alpha protein
      through the patch pipette restored the inhibitory effect of quinpirole in cells
      chronically exposed to hypoxia. We conclude that the attenuation of the D2
      mediated inhibition of ICa by chronic hypoxia is caused by impaired receptor-G
      protein coupling, due to reduced levels of G(o) alpha protein. This attenuated
      feedback modulation of ICa by dopamine may allow for a more sustained Ca2+ influx
      and enhanced cellular excitation during prolonged hypoxia.

PMID- 10591062
TI  - The relationship between acetylcholine-evoked Ca(2+)-dependent current and the
      Ca2+ concentrations in the cytosol and the lumen of the endoplasmic reticulum in
      pancreatic acinar cells.
AB  - In a study of isolated mouse pancreatic acinar cells, we used the patch-clamp
      whole-cell recording configuration to monitor the Ca(2+)-dependent inward ionic
      current and simultaneously measured the Ca2+ concentration in either the cytosol
      ([Ca2+]i) or the lumen of the endoplasmic reticulum ([Ca2+]Lu), using appropriate
      Ca(2+)-sensitive fluorescent probes. A high concentration of acetylcholine (ACh,
      10 microM) evoked an increase in [Ca2+]i, which resulted in the activation of
      Ca(2+)-dependent inward current. Continued ACh application for several minutes
      led to a marked reduction in both the current and the [Ca2+]i response and after
      about 4-10 min of sustained ACh stimulation, the inward current response had
      disappeared and [Ca2+]i was back to the pre-stimulation level. Repeated
      stimulation with shorter pulses of ACh (10 microM) resulted in responses of
      declining magnitude both in terms of inward current and [Ca2+]i rises. The ACh
      activated inward current was entirely dependent on the elevation of [Ca2+]i, but
      at a relatively high [Ca2+]i the current was saturated. ACh caused a rapid
      release of Ca2+ from the lumen of the endoplasmic reticulum and after
      discontinuation of stimulation, [Ca2+]Lu was only very slowly (10-15 min) fully
      restored to the pre-stimulation level. Repeated applications of ACh did not
      change the relationships between the Ca(2+)-dependent current and [Ca2+]i or the
      current and [Ca2+]Lu. When [Ca2+]Lu was greater than 100 microM, the ACh-evoked
      Ca2+ release from the store was so large that the current response was initially
      saturated. We conclude that the ACh-evoked current response essentially depends
      on the release of stored Ca2+. Desensitization is mainly due to the relatively
      slow reloading of the intracellular stores with Ca2+.

PMID- 10591063
TI  - Selected ambient temperatures of rats acclimated to heat given on various
      schedules.
AB  - We investigated the behavioral thermoregulation of heat-acclimated rats by
      measuring their selected ambient temperatures (Ts). Rats kept in a light:dark
      cycle of 12:12 h were subjected to one of four different heat exposure regimes
      for 10 consecutive days; a constant ambient temperature (Ta) of 32 degrees C
      (CH), a Ta of 32 degrees C for 5 h daily in the latter half of the dark phase
      (IHF), a Ta of 32 degrees C for 5 h daily at a random time of day (IHR), or a
      constant Ta of 24 degrees C (control). After the heat exposure schedule, the rats
      were placed in a thermal gradient and their intra-abdominal temperature (Tab), Ts
      and spontaneous activity were measured for 3 days. There were clear day-night
      variations of Tab and Ts in all groups. The levels of Tab and Ts of the CH rats
      were significantly higher than those of the IHF, IHR and control rats. The Tab
      and activity levels of the IHF rats were significantly lower than those of the
      IHR and control rats only in the latter half of the dark phase. The Ts values of
      the IHF rats did not differ from those of the IHR and control rats. These results
      suggest that, after rats were constantly subjected to heat, heat-seeking behavior
      was induced so that the core temperature was maintained at a high level. However,
      when rats were acclimated to heat given for several hours at a fixed time daily,
      core temperature was lowered during the same time period of previous heat
      exposure in association with a depression of thermogenic behavior.

PMID- 10591064
TI  - Investigating the relaxation rate, following diazo-2 photolysis, of a skinned
      trabecular preparation from guinea-pig hypertrophied left ventricle.
AB  - Cardiac hypertrophy in the guinea-pig is not accompanied by a large shift in the
      expression of the predominant isoform of myosin in the left ventricle; however,
      in this species, thin filament proteins do change. We examined the relaxation,
      following laser flash photolysis of the photolabile caged Ca2+ chelator diazo-2,
      of a skinned trabecular preparation from the left ventricle of guinea-pigs that
      had undergone abdominal aortic banding. Sham-operated animals were used as
      controls; no guinea-pigs showed any signs of heart failure. We report that mild
      cardiac hypertrophy does not affect the relaxation rate of Triton-skinned
      trabeculae from the guinea-pig. However, there was a 35% reduction in the maximum
      force generated by trabeculae from the left ventricle of the abdominal aortic
      banded animals. Additionally, alterations in key troponin subunits occur in the
      left ventricle of guinea-pigs with mild hypertrophy. We conclude that the thin
      filament protein changes do not influence trabecular relaxation rates, even
      though they probably affect maximal force generation. The cellular membrane
      systems of the intact guinea-pig heart, which were not a factor in this present
      study, appear to have an important role in the altered cardiac relaxation rates
      seen in hypertrophy.

PMID- 10591065
TI  - The possible role of a disulphide bond in forming functional Kir2.1 potassium
      channels.
AB  - The role of two cysteine residues--Cys122 and Cys154--in the structure of the
      strong inward rectifier K+ channel, Kir2.1, has been investigated using site
      directed mutagenesis and electrophysiology. Such cysteine residues are conserved
      across the inward rectifier family and may be expected to form a crucial
      disulphide bond. Our experiments show that when the cysteines are absent, the
      protein is expressed, but the channels are not functional, suggesting that the
      disulphide bond is essential for correct channel assembly. However, reducing
      agents applied extracellularly have little effect on current amplitude in wild
      type, so that, once the channel is assembled correctly in the membrane, the
      disulphide bonds are no longer essential for function. Molecular modelling
      suggests that a disulphide bond is formed--this may be either an intra- or an
      inter-subunit.

PMID- 10591066
TI  - Regulation of erythrocyte antioxidant enzyme activities in athletes during
      competition and short-term recovery.
AB  - We have determined "in vivo" the influence of strenuous prolonged exercise and
      short-term recovery on erythrocyte antioxidant enzyme activities. We have also
      determined the "in vitro" effects of the xanthine/xanthine-oxidase-generating
      superoxide anion system on catalase activity in haemolysed erythrocytes.
      Haematological parameters and erythrocyte superoxide dismutase (SOD), glutathione
      peroxidases and catalase activities were measured in nine healthy duathlon
      athletes under basal conditions, at the finish of a competition and after 1 h of
      recovery. We also measured catalase activity in haemolysed erythrocytes--obtained
      from four overnight-fasted well-trained sportsmen before and after an 80%
      submaximal exercise test on a cycle-ergometer--prior to and after incubation for
      3 min with the superoxide-anion-generating system. Duathlon competition and/or
      short-term recovery produced a slight haemolysis and increased the activity of
      catalase and peroxidases but not SOD enzymes. The observed changes in catalase
      activity were mimicked "in vitro" by the superoxide-anion-generating system.

PMID- 10591067
TI  - Ionic selectivity of the coupled and uncoupled currents carried by the amino acid
      transporter KAAT1.
AB  - The ability of the intestinal amino acid co-transporter KAAT-1 expressed in
      Xenopus oocytes to transport different cations in either amino acid coupled or
      uncoupled manner was studied using voltage-clamp conditions. KAAT1-expressing
      oocytes exhibit a transporter-related current in the absence of organic substrate
      (uncoupled current). In the presence of various alkali cations the amplitude of
      this current follows the sequence: ILi > INa > IK approximately equal to IRb
      approximately equal to ICs. Addition of 1 mM leucine causes large increases in K+
      and Na+ currents, while the Li+ current undergoes a more complex change and Rb+
      and Cs+ currents are only marginally affected. Pre-steady-state currents in the
      absence of organic substrate are apparent when Na+, K+, or Li+ are the bathing
      ions; analysis of these currents in terms of charge movement reveals that Na+,
      K+, and Li+ interact differently with the transporter. The uncoupled current in
      mixtures of Na+ and Li+ fails to exhibit anomalous mole-fraction behavior.
      Kinetic analysis of ion binding and uncoupled permeation argues against a multi
      ion single-file mechanism in the KAAT1 cotransporter.

PMID- 10591068
TI  - Is bradykinin a mediator of renal neuropeptide Y effects?
AB  - We have previously reported that the bradykinin receptor antagonist icatibant
      attenuates the neuropeptide-Y-induced diuresis and natriuresis in anaesthetized
      rats (Am J Physiol 275:F502-F509, 1998). Therefore, we have now determined
      whether bradykinin mimics tubular responses to neuropeptide Y in acutely
      pentobarbital-anaesthetized rats. Infusion of the neuropeptide Y receptor agonist
      peptide YY (2 micrograms kg-1 min-1) enhanced diuresis and natriuresis
      approximately equal to 2- and 4-fold, respectively, but did not increase urinary
      bradykinin excretion. Intrarenal infusion of bradykinin (100 ng kg-1 min-1)
      reduced renal blood flow by approximately equal to 12% and this was abolished by
      concomitant administration of icatibant (200 ng kg-1 min-1). However, intrarenal
      bradykinin infusion did not affect creatinine clearance, urine flow rate or
      sodium excretion (basal values: 0.8 ml min-1, 111 microliters/15 min and 7.7
      mumol/15 min, respectively). These data do not support our original hypothesis
      that bradykinin mediates the renal effects of neuropeptide Y.

PMID- 10591069
TI  - Inositol 1,4,5-trisphosphate-sensitive Ca2+ release in rat fast- and slow-twitch
      skinned muscle fibres.
AB  - Inositol 1,4,5-trisphosphate (InsP3), an intracellular messenger, induces Ca2+
      release in various types of cells, particularly smooth muscle cells. Its role in
      skeletal muscle, however, is controversial. The present study shows that the
      application of InsP3 to rat slow- and fast-twitch saponin-skinned fibres induced
      contractile responses that were not related to an effect of InsP3 on the
      properties of the contractile proteins. The amplitude of the contractures was
      dependent upon the Ca(2+)-loading period, and was larger in slow- than in fast
      twitch muscle. In both types of skeletal muscle, these responses, unlike caffeine
      contractures, were not inhibited by ryanodine (100 microM), but were abolished by
      heparin (20 micrograms.ml-1). In soleus muscle, the concentration of heparin
      required to inhibit the response by 50% (IC50) was 5.7 micrograms.ml-1, a similar
      value to that obtained previously in smooth muscle. Furthermore, the results show
      that in slow-twitch muscle, the InsP3 contractures have a "bell-shaped"
      dependency on the intracellular Ca2+ concentration. These results show that InsP3
      receptors should be present in skeletal muscle. Thus, it is possible that InsP3
      participates in the regulation of sarcoplasmic reticulum Ca2+ release in skeletal
      muscle, particularly in slow-twitch fibres.

PMID- 10591070
TI  - Calcium currents in respiratory neurons of the cat in vivo.
AB  - Under in vivo conditions, periodic burst discharges of medullary respiratory
      neurons of mature cat typically start with a rebound depolarization when
      inhibition through antagonistic neurons stops. This rebound can be blocked by
      ionophoretically applied extracellular Cd2+. A similar Cd(2+)-sensitive rebound
      depolarization is triggered by hyperpolarizing current pulses even in the
      presence of extracellular tetrodotoxin (TTX) and tetraethylammonium (TEA). In
      current-clamp mode, the current/voltage (I/V) curves rectify outwardly at
      positive voltages, and this rectification is blocked by Cd2+. Intracellular
      injection of the L-type Ca(2+)-channel blocker methoxy-verapamil changes the
      spontaneous activity patterns of neurons. In those neurons that typically show
      augmenting patterns, the membrane depolarization is slowed down, while in those
      neurons that have a declining pattern, voltage changes become augmenting. Voltage
      clamp measurements reveal a transient, low-voltage-activated T-type Ca2+ current.
      The current is deinactivated at -100 mV and almost completely inactivated at -60
      mV. Depolarizing voltage commands starting from more positive holding potentials
      evoke sustained Ca2+ currents that reach a maximum at 0 mV. The sustained L-type
      Ca2+ currents are completely blocked by extracellular Cd2+. We conclude that low-
      and high-voltage-activated Ca2+ currents are expressed in all types of
      respiratory neurons and play an essential role in rhythm generation and pattern
      formation in adult cats in vivo.

PMID- 10591071
TI  - Calcium release induced by high K+ and caffeine in cultured skeletal muscle cells
      of embryonic chicken.
AB  - To further understand the function of excitation-contraction coupling in skeletal
      muscle cells developing in vitro, Ca2+ transients elicited by high-K+
      depolarization in the presence and absence of extracellular Ca2+ were compared
      with Ca2+ release induced by caffeine in cultured skeletal muscle cells isolated
      from 9-day-old chicken embryos (E9). Almost all myoblasts and myotubes cultured
      for 1 (E9I1) to 8 (E9I8) days responded to 80 mM [K+]O with an elevation of
      [Ca2+]i. Although all myotubes cultured for more than 4 days exhibited Ca2+
      release independent of extracellular Ca2+, only about 50% of E9I1 and E9I2 cells
      maintained their response to Ca(2+)-free high-[K+]O solution. Strikingly, a
      considerable proportion of cells of short-term culture were insensitive to 10 mM
      caffeine. Moreover, 46.8% of the caffeine-insensitive E9I1 and E9I2 cells, 29 out
      of 62, was still responsive to 80 mM [K+]O in the absence of extracellular Ca2+.
      Western blot and immunocytochemistry showed that ryanodine receptor (RyRs)
      expression increases with culture. The Ca2+ release from caffeine-insensitive
      cells induced by Ca(2+)-free high-[K+]O solution could be blocked by 100-200
      microM ryanodine, which suggests the involvement of RyRs. Evidence is presented
      to show that a low resting [Ca2+]i may be one factor responsible for the caffeine
      insensitivity of RyRs in cells of short-term culture.

PMID- 10591072
TI  - Temperature sensitivity of transduction and action potential conduction in a
      spider mechanoreceptor.
AB  - Previous work has suggested that the activation energy of mechanotransduction is
      higher than expected from the simple electrochemistry of ion channels, but the
      temperature sensitivity of mechanically activated receptor current has not been
      measured directly before. We used the single-electrode voltage-clamp technique to
      measure receptor currents in sensory neurons of the VS-3 slit-sense organ in the
      spider, Cupiennius salei. Receptor currents were generated by deforming the
      cuticular slits. Conduction velocity in afferent axons from the same organ was
      also measured by recording action potentials at two locations in the leg during
      mechanical stimulation of the slits. Activation energies of mechanotransduction
      and conduction velocity were estimated by making the measurements at a range of
      temperatures. The mean activation energy for receptor current was 23.1 kcal/mol
      (96.6 kJ/mol), corresponding to a Q10 value of 3.2. Conduction velocity in the
      afferent axons was approximately equal to 5 m/s at room temperature and it was
      much less temperature sensitive, with an activation energy of 6.3 kcal/mol (26.3
      kJ/mol), corresponding to a Q10 value of 1.5. These results provide the first
      direct measurements of the activation energy of mechanically activated currents
      and support previous suggestions that a high thermal energy barrier is involved
      in mechanotransduction.

PMID- 10591073
TI  - An investigation of the role played by the E-4031-sensitive (rapid delayed
      rectifier) potassium current in isolated rabbit atrioventricular nodal and
      ventricular myocytes.
AB  - The aim of this study was to measure and compare the profile of rapid delayed
      rectifier potassium current (IKr) elicited by action potential (AP) waveforms
      applied to isolated rabbit atrioventricular nodal (AVN) and ventricular myocytes.
      All measurements were made using whole-cell patch-clamp recordings at 37 degrees
      C. In AVN myocytes, IKr during voltage steps and slow ramp depolarisations showed
      "inward rectification" (characteristic for this channel) at positive potentials.
      The E-4031-sensitive current showed half-maximal activation at -10.8 +/- 0.86 mV,
      with a slope factor for the activation relation of 6.5 +/- 0.77 mV (n = 7).
      During AVN APs, IKr rapidly reached a peak after the AP upstroke and remained at
      similar amplitude until late in AP repolarisation. At the maximum diastolic
      potential following the AVN AP, a component of IKr remained which decayed during
      the pacemaker depolarisation, consistent with a role for the current in
      generating AVN pacemaker activity. In ventricular myocytes IKr was small at the
      beginning of the AP, and increased slowly during the AP plateau. Measurement of
      Ba-sensitive-inward rectifier K current (IK1) in ventricular myocytes revealed
      that IK1 rapidly increased during the final AP repolarisation phase, whilst IKr
      declined. It is concluded that IKr may participate in both AP repolarisation and
      the pacemaker depolarisation in AVN cells, whilst in ventricular myocytes, IKr
      and IK1 participate in controlling early and final AP repolarisation
      respectively.

PMID- 10591074
TI  - Na(+)-Ca2+ exchange induces low Na+ contracture in frog skeletal muscle fibers
      after partial inhibition of sarcoplasmic reticulum Ca(2+)-ATPase.
AB  - Contractile responses due to reduction in external sodium concentration ([Na+]o)
      were investigated in twitch skeletal muscle fibers of frog semitendinosus.
      Experiments were conducted after partial inhibition of sarcoplasmic reticulum
      Ca(2+)-ATPase by cyclopiazonic acid (CPA). In the absence of CPA, Na+ withdrawal
      failed to produce any change in resting tension. In the presence of CPA (2-10
      microM), [Na+]o reduction induced a transient contracture without a significant
      change in the resting membrane potential. The amplitude of the contracture
      displayed a step dependence on [Na+]o, was increased by K(+)-free medium and was
      prevented in Ca(2+)-free medium. This contracture was inhibited by various
      blockers of the Na(+)-Ca2+ exchange but was little affected by inhibitors of
      sarcolemmal Ca(2+)-ATPase or mitochondria. When sarcoplasmic reticulum function
      was impaired, low-Na+ solutions caused no contracture. These results provide
      evidence that skeletal muscle fibers possess a functional Na(+)-Ca2+ exchange
      which can mediate sufficient Ca2+ entry to activate contraction by triggering
      Ca2+ release from sarcoplasmic reticulum when the sodium electrochemical gradient
      is reduced, and sarcoplasmic reticulum Ca(2+)-ATPase is partially inhibited. This
      indicates that when the sarcoplasmic reticulum Ca(2+)-ATPase is working (no CPA),
      Ca2+ fluxes produced by the exchanger are buffered by the sarcoplasmic reticulum.
      Thus the Na(+)-Ca2+ exchange may be one of the factors determining sarcoplasmic
      reticulum Ca2+ content and thence the magnitude of the release of Ca2+ from the
      sarcoplasmic reticulum.

PMID- 10591075
TI  - Demonstration of a Na(+)-dicarboxylate cotransporter in bovine adrenocortical
      cells.
AB  - Our study found the uptake of [14C]succinate into bovine adrenocortical cells to
      be sodium-dependent, inhibited by lithium, and to have an apparent K(m) of 146
      mumol/l. Succinate uptake was inhibited by glutarate, fumarate, alpha
      ketoglutarate, and maleate but not by 2,3-dimethylsuccinate or cis-aconitate,
      specific inhibitors of the basolateral Na(+)-dicarboxylate transporter of renal
      proximal tubule cells. Succinate uptake was highest at pH 6.0 and decreased with
      increasing pH. Transport of succinate was not significantly inhibited by citrate
      at pH 7.4 whereas at pH 6.0 inhibition of succinate uptake by citrate was small
      but significant. The affinity of the adrenal dicarboxylate transporter towards
      succinate ranges in between the low affinity of the renal luminal dicarboxylate
      transporter and the high affinity of the respective basolateral transporter. The
      pH dependency of succinate uptake and the missing inhibition by citrate at pH 7.4
      differ from both the luminal and from the basolateral dicarboxylate transporters
      in kidney, liver, intestine, and placenta. These functional characteristics
      provide evidence for the existence of a Na(+)-dicarboxylate cotransporter in
      adrenocortical cells which may supply cholesterol metabolism with reducing
      substrates.

PMID- 10591076
TI  - Inhibition of gap junctional coupling in cochlear supporting cells by gentamicin.
AB  - Gap junctional coupling of cochlear supporting cells is thought to be responsible
      for spatial potassium buffering of the microenvironment of outer hair cells
      (OHC). OHC of the organ of Corti are considered as the target of aminoglycoside
      induced ototoxicity. Due to the proposed functional relationship between OHC and
      cochlear supporting cells we investigated a possible involvement of the
      supporting Hensen cells in the ototoxic effect of the aminoglycoside gentamicin.
      Isolated Hensen cell pairs were superfused by gentamicin-containing bath
      solutions. Using the double whole-cell patch-clamp method gentamicin (10 microM)
      inhibited gap junctional conductance by about 90%, whereas the membrane potential
      of about -27 mV remained unchanged. Since the inhibitory effect was suppressed by
      the addition of catalase, the gentamicin mediated effect probably is due to
      production of free radicals. It is proposed that formation of free radicals in
      supporting cells inhibits gap junctional coupling whereby the spatial potassium
      buffer mechanism and, thus, the fine tuning of the cochlear OHC is impaired.

PMID- 10591077
TI  - The effects of oxidizing and cysteine-reactive reagents on the inward rectifier
      potassium channels Kir2.3 and Kir1.1.
AB  - The inwardly rectifying potassium channel Kir2.3 possesses extracellular cysteine
      residues at positions 113, 140, and 145, as well as at position 79 near the outer
      membrane boundary. In this study, we have investigated the roles of these
      extracellular cysteine residues in mediating inhibition of the Kir2.3 channel by
      the cysteine-reactive reagents para-chloromercuribenzenesulphonate (PCMBS) and
      thimerosal, and the oxidizing agent hydrogen peroxide (H2O2). We have also
      compared the effects of these reagents with those on Kir1.1 channels (which do
      not possess cysteine residues equivalent to 140 and 79 in Kir2.3 channels).
      Mutant channels were made in which cysteine residues were mutated to serine by
      site-directed mutagenesis. Wild-type or mutant cRNA was injected into Xenopus
      oocytes and voltage-clamp recordings made 1-2 days later. Wild-type Kir2.3
      currents were significantly inhibited by PCMBS, thimerosal and H2O2. Currents for
      mutants Kir2.3 C79S and C140S were also inhibited by PCMBS, thimerosal and H2O2.
      These mutations affected the time course of inhibition by all three reagents. For
      PCMBS, a slow component of inhibition was absent for the C79S mutation, and a
      fast component was absent for C140S. For the double mutation C79S/C140S, PCMBS no
      longer had any effect. For thimerosal, there was a slower time course for C140S,
      a faster time course for C79S, and a delayed onset for C79S/C140S. For H2O2, the
      main effect was a delayed onset for the double mutant. The reducing agent
      dithiothreitol (DTT) reversed the inhibition by both PCMBS and thimerosal of wild
      type and mutant currents, but not the inhibition due to H2O2. Finally, wild-type
      Kir1.1 currents were not significantly inhibited by the applications of either
      PCMBS or thimerosal, while H2O2 produced small inhibition. The results taken
      together indicate that inhibition by the cysteine-reactive reagent PCMBS is
      mediated through cysteine residues 79 and 140 in Kir2.3 channels, with C79
      mediating a slow component of inhibition and C140 a faster component, and that
      both residues are extracellularly exposed. The data indicate that these two
      cysteine residues are also main sites for inhibition by thimerosal and H2O2 but,
      unlike for PCMBS, an additional non-extracellular inhibitory site(s) must also be
      involved.

PMID- 10591078
TI  - Effect of the inactivating "ball" peptide of Shaker B on intermediate conductance
      Ca(2+)-dependent inwardly rectifying K+ channels of HeLa cells.
AB  - The patch-clamp technique was used to study the effect of intracellularly added
      inactivating "ball" peptide (BP) of the Shaker B K+ channel upon Ca(2+)-dependent
      inwardly rectifying K+ channels of the intermediate conductance type expressed in
      HeLa cells. Intracellular BP caused only moderate inhibition of outward K+
      currents when assayed at an intracellular Ca2+ concentration of 100 nmol/l.
      Increasing intracellular Ca2+ levels led in itself to some voltage-dependent
      blockade of K+ currents, which was absent when high extracellular K+ was used. An
      additional strong blockade by intracellular BP was nevertheless observed both in
      Na(+)- and K(+)-rich extracellular solutions. A non-inactivating BP analogue had
      no effect. At this higher intracellular Ca2+ concentration the inhibition of
      these intermediate conductance Ca(2+)-dependent channels by BP was voltage
      dependent, being absent at hyperpolarizing potentials, and could be relieved by
      increasing extracellular K+. These data suggest that BP acts at an internal pore
      site in Ca(2+)-dependent intermediate conductance K+ channels of HeLa cells, and
      that these might possess a receptor site for the peptide similar to that of other
      K+ channels such as Ca(2+)-activated maxi-K+ channels.

PMID- 10591079
TI  - Role of albumin and glomerular capillary wall charge distribution on glomerular
      permselectivity: studies on the perfused-fixed rat kidney model.
AB  - The charge-related determinants of albumin permeability are the subject of
      controversial discussion. To study this question we have developed an isolated
      perfused rat kidney model in which metabolic processes are eliminated by
      perfusion fixation with glutaraldehyde. The fixed kidneys were perfused with
      albumin solutions using the following approaches: 1. Modification of the charge
      of both the glomerular capillary wall (GCW) and albumin using different buffer
      systems in a pH range spanning the isoelectric points of albumin and the
      glomerular basement membrane (GBM), the extracellular matrix of the GCW. 2.
      Modification of the charge of the GCW by perfusing the isolated kidney with
      cations either before or after fixation. 3. Modification of the charge of albumin
      by cationization. In the model, the inulin "urine" to perfusate ratio was one.
      This shows that the tubules have no metabolic activity, that the glomerular
      filtration rate (GFR) is equal to "urine" flow rate and that the "urine"
      collected is identical to the ultrafiltrate. Therefore, sieving coefficients in
      this model can simply be calculated as the ratio between "urine" and perfusate
      protein concentrations. We could show that: 1. pH has a significant effect on the
      albumin sieving coefficient: it was maximally increased at pH 4.0 [(70.3 +/-
      15.9) x 10(-3), n = 10 versus (8.7 +/- 3.7) x 10(-3), n = 11, at pH 7.4]. Only a
      pH as low as 4.0 should lead to a pronounced neutralization of the anionic
      charges of albumin and the GBM; the charge density of the GCW calculated with
      these data is 43 mEq/l at pH 7.4. 2. Modifying the ionic composition of the GCW
      with protamine before fixation with glutaraldehyde causes a bigger increase in
      the glomerular permeability for albumin [(51.2 +/- 22.5) x 10(-3), n = 10,
      glomerular charge density 21 mEq/l] than modifying the albumin charge by
      cationization. 3. Modifying the albumin charge by cationization increases the
      glomerular permeability for albumin [(20.0 +/- 6.7) x 10(-3), n = 8]. These
      findings support the hypothesis that at the onset of proteinuria changes in the
      charge and configuration of the GCW could be more important pathogenetic factors
      than changes in the charge of serum-derived proteins.

PMID- 10591080
TI  - Phospholipase A2 enzymes in eicosanoid generation.
AB  - Phospholipase A2 (PLA2) enzymes cleave esterified fatty acids from membrane
      glycerophospholipids. The 20-carbon polyunsaturated fatty acid, arachidonic acid,
      is used as substrate by intermediate enzymes for the generation of eicosanoids,
      including leukotrienes and prostanoid products. An expanding number of PLA2
      enzymes has now been identified that may participate in arachidonic acid release
      and thus serve a rate-limiting role in eicosanoid biosynthesis. Cellular PLA2
      function for various members is regulated by constitutive or elicited expression,
      as well as by posttranslational events such as phosphorylation. In addition, the
      function of some cellular PLA2 enzymes is regulated by a requirement for calcium
      or by localization to a particular subcellular compartment. Finally, some PLA2
      enzymes are secreted from the cell where they may directly interact with plasma
      membrane or transmembrane receptors to function as autocrine or paracrine
      mediators. Evaluating the roles of a number of these functionally similar PLA2
      enzymes in the biosynthesis of leukotrienes and other eicosanoids is the focus of
      this review.

PMID- 10591081
TI  - The biology of 5-lipoxygenase: function, structure, and regulatory mechanisms.
AB  - 5-Lipoxygenase (5-LO) catalyzes the two-step conversion of arachidonic acid to
      leukotriene A4 (LTA4). The first step consists of the oxidation of arachidonic
      acid to the unstable intermediate 5-hydroperoxyeicosatetraenoic acid (5-HPETE),
      and the second step is the dehydration of 5-HPETE to form LTA4. These events are
      the first committed reactions leading to the synthesis of all leukotrienes and
      play a critical role in controlling leukotriene production. 5-LO has evolved many
      complex structural features and regulatory mechanisms to allow it to fulfill this
      highly specialized role. The biology of 5-LO is reviewed here with an emphasis on
      enzymatic function, protein and gene structure, essential cofactors, and the many
      regulatory mechanisms controlling its expression.

PMID- 10591082
TI  - The biochemical, molecular, and genomic aspects of leukotriene C4 synthase.
AB  - Leukotriene C4 (LTC4) synthase is an 18 kD integral membrane enzyme of the 5
      lipoxygenase/LTC4 synthase pathway and is positioned as the pivotal and only
      committed enzyme for the formation of the cysteinyl leukotrienes. Although its
      function is to conjugate catalytically LTA4 to reduced glutathione, LTC4 synthase
      is differentiated from other glutathione S-transferase family members by its lack
      of amino acid homology, substrate specificity, and kinetics. LTC4 synthase
      (LTC4S) protein is present in the perinuclear membranes of a limited number of
      hematopoietic cells involved in allergic inflammation, including mast cells,
      eosinophils, basophils, and macrophages. The cDNA encodes a monomeric protein of
      150 amino acids with three hydrophobic domains interspersed with two hydrophilic
      loops. Site-directed mutagenic studies reveal that the enzyme functions as a
      homodimer and that arginine-51 in the first hydrophilic loop, and tyrosine-93 in
      the second hydrophilic loop, are involved in the acid and base catalysis of LTA4
      and glutathione, respectively. Homology and secondary structural predictions
      indicate that LTC4S is a novel member of a new gene superfamily of integral
      membrane proteins, each with the capacity to participate in leukotriene
      biosynthesis. The gene for LTC4S is 2.5 kb in length and is localized on
      chromosome 5q35, distal to that of the genes for cytokines and receptors
      important in the development and perpetuation of allergic inflammation.
      Immunohistochemical studies of mucosal biopsies from the bronchi of aspirin
      intolerant asthmatics show that LTC4S is overrepresented in individuals with this
      phenotype, and this finding correlates with overproduction of cysteinyl
      leukotrienes and lysine-aspirin bronchial hyperreactivity.

PMID- 10591083
TI  - Asthma therapy with agents preventing leukotriene synthesis or action.
AB  - Elucidation of the biochemistry of leukotriene production and the pharmacology of
      its actions has led to the development of a number of therapeutic agents shown to
      be of value in the treatment of asthma. These agents either prevent the synthesis
      of the leukotrienes, by preventing the action of the 5-lipoxygenase-activating
      protein or the catalytic action of the 5-lipoxygenase, or by inhibiting the
      action of leukotrienes at the CysLT1 receptor. Numerous clinical trials in
      exercise-induced asthma, allergen-induced asthma, aspirin-induced asthma, and
      spontaneously occurring asthmatic episodes have indicated that these agents are
      safe and effective asthma treatments.

PMID- 10591084
TI  - Thematic review series. XI: Viruses in the origin of human cancer. Introduction
      and overview.

PMID- 10591085
TI  - Human retroviruses: their role in cancer.
AB  - Viruses are etiologically linked to approximately 20% of all malignancies
      worldwide. Retroviruses account for approximately 8%-10% of the total. For human
      T-cell leukemia virus 1 (HTLV-I), the viral regulatory tax gene product is
      responsible for enhanced transcription of viral and cellular genes that promote
      cell growth by stimulating various growth factors and through dysregulation of
      cellular regulatory suppressor genes, such as p53. After a long latent period,
      adult T-cell leukemia/lymphoma (ATL) occurs in 1 per 1000 carriers per year,
      resulting in 2500-3000 cases per year worldwide and over half of the adult
      lymphoid malignancies in endemic areas. Human immunodeficiency virus 1 (HIV-1)
      accounts for a significant cancer burden, and its transactivating regulatory
      protein Tat enhances direct and indirect cytokine and immunological dysregulation
      to cause diverse cancers. Kaposi's sarcoma (KS) is a very rare tumor except after
      HIV-1 infection, when its incidence is greatly amplified reaching seventy
      thousand-fold in HIV-infected homosexual men. Human herpesvirus 8 (HHV-8), which
      is also known as Kaposi's sarcoma-associated virus (KSHV), is a necessary but not
      sufficient etiological factor in KS. The dramatic decline of KS since the
      introduction of highly active antiretroviral therapy (HAART) could be due to
      suppression of HIV-1 tat. B-cell non-Hodgkin's lymphoma occurs as their first
      acquired immunodeficiency syndrome-defining diagnosis in 3%-4% of HIV-infected
      patients. Hodgkin's lymphoma is also associated with HIV infection but at a lower
      risk. Human papillomaviruses are linked to invasive cervical cancer and
      anogenital cancers among HIV-infected patients. Human retroviruses cause
      malignancy via direct effects as well as through interactions with other
      oncogenic herpesviruses and other viruses.

PMID- 10591086
TI  - Epstein-Barr virus: the first human tumor virus and its role in cancer.
AB  - The Epstein-Barr virus (EBV) is classically associated with three malignancies,
      Burkitt's lymphoma. B-cell lymphoproliferative syndromes, and nasopharyngeal
      carcinoma, and, more recently, with Hodgkin's disease, T-cell lymphomas, and
      gastric carcinoma, as well as being the causal agent for infectious
      mononucleosis. The relation of the virus to the malignancies varies from primary
      etiologic agent to necessary or contributory cofactor. Clonal EBV episomes are
      found in all the malignant conditions. EBV infects both epithelial and lymphoid
      cells, providing a pathobiological basis for these diverse associations. Most of
      the malignancies occur after years of viral dormancy and are accompanied or
      triggered by viral reactivation, in contrast to infectious mononucleosis, which
      results from primary infection with EBV. The EBV-associated malignancies offer
      insights into the causation and early detection of cancer. The molecular virology
      and pathobiology of EBV infection states provide the basis for the specific
      diagnosis of these diseases and a framework for new therapies.

PMID- 10591088
TI  - Hepatitis viruses: their role in human cancer.
AB  - Hepatitis B virus (HBV) has been shown to be linked causally to the development
      of hepatocellular carcinoma (HCC) in humans. One of the HBV gene products, the
      "X" protein, has been specifically implicated in the malignant transformation of
      hepatocytes; mutations in one or more of the HBV structural proteins have also
      been linked to HCC. HBV DNA may act as an insertional mutagen in the myc family
      of genes. Mutations within the pre-core and core promoter regions of HBV-DNA have
      also been associated with the development of HCC. Patients chronically infected
      with hepatitis C virus (HCV) often develop cirrhosis; a significant proportion of
      these patients progress to HCC. Although numerous genotypes of HCV exist, type 1b
      is most often associated with the eventual development of HCC in chronically
      infected patients. The molecular mechanisms for the malignant transformation of
      hepatocytes by HCV have not been elucidated.

PMID- 10591087
TI  - Papillomaviruses in human cancers.
AB  - Papillomaviruses have proved to be the most complex group of human pathogenic
      viruses. Eighty-five genotypes have been fully characterized; approximately 120
      additional isolates represent only partially characterized putative novel
      genotypes. Specific types, most notably human papillomavirus (HPV) types 16, 18,
      and a few others, have been shown to cause the majority of cervical cancers and
      their high-grade precursor lesions. The viral oncogenes E6 and E7 are required
      for the initiation and maintenance of the malignant phenotype in HPV-positive
      cancers. Proteins coded by these genes are multifunctional and interfere with
      important cell cycle regulatory proteins. Expression of viral oncogenes is
      tightly controlled in nondifferentiated keratinocytes by at least two signaling
      cascades, one operative at the functional level, the other at the transcriptional
      level. The latter has been partially characterized. Papillomaviruses are also
      suspected of playing a role in a subset of oropharyngeal cancers, in squamous
      cell cancers of the skin, and possibly also in esophageal cancers. Clinical
      trials are being conducted to test the preventive and therapeutic efficacy of HPV
      vaccines, directed particularly against HPV 16 and 18. If proven to be effective,
      their global application should have a measurable effect on the worldwide
      incidence of cancer.

PMID- 10591089
TI  - Human herpesvirus 8: is it a tumor virus?
AB  - Human herpesvirus 8 (HHV-8), also termed Kaposi's sarcoma-associated herpesvirus,
      was identified in Kaposi's sarcoma (KS) biopsy specimens in 1994. The
      epidemiological data available to date indicate a strong association of HHV-8
      with KS. It appears that HHV-8 is necessary for KS development. HHV-8 DNA is
      invariably found in all epidemiological forms of KS and primary effusion
      lymphomas. In contrast, HHV-8 DNA is rarely found in various tumor and nontumor
      tissues from patient groups not at risk of KS. Although current serology does not
      allow us to assess the HHV-8 prevalence in the general population, high titers of
      HHV-8 antibodies are almost exclusively found in KS risk groups. In addition, HHV
      8 seroconversion has been shown to precede KS development. The mechanisms and
      genes involved in HHV-8 pathogenesis are less clear. HHV-8 belongs to a family of
      transforming viruses, and several candidate oncogenes have been identified by
      using rodent fibroblast transformation assays. However, expression of most of
      these genes could not be shown in latently infected tumor cells. As the HHV-8
      genome encodes several cytokines and cytokine receptor homologues, HHV-8 may also
      promote KS pathogenesis through paraendocrine mechanisms.

PMID- 10591090
TI  - Physiology and pathophysiology of nitric oxide in chronic renal disease.
AB  - Nitric oxide (NO), an L-arginine derivative, exerts a variety of renal and
      extrarenal physiological and pathophysiological effects. NO is generated by three
      isoforms of nitric oxide synthases (NOS): two acutely responsive, constitutive
      isoforms, neuronal NOS (nNOS) and endothelial NOS (ecNOS), and the slower, more
      persistent, inducible NOS (iNOS). NO regulates glomerular ultrafiltration;
      tubular reabsorption, and intrarenal renin secretion. A number of recent studies,
      most of them in the experimental model of renal mass reduction (RMR) in rats,
      have raised the hypothesis that an impaired NO synthetic pathway could have a key
      role in mediating the complex renal hemodynamic and nonhemodynamic disorders
      associated with the progression of renal disease. Thus, kidneys from rats with
      RMR produce less NO than normal rats, and NO generation negatively correlates
      with markers of renal damage. The abnormality is due to a defect in iNOS in the
      kidney. Data are also available showing that drugs capable of enhancing renal NO
      activity may be renoprotective in a variety of experimental renal diseases,
      particularly those characterized by derangements of glomerular hemodynamics.
      Fewer studies are available in humans and these have shown less than conclusive
      results.

PMID- 10591091
TI  - Prospective measure of serum 3-nitrotyrosine levels in systemic lupus
      erythematosus: correlation with disease activity.
AB  - Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease.
      Overproduction of nitric oxide (NO) has been implicated in its pathogenesis.
      Several retrospective studies have indicated a correlation between serum nitrate
      and nitrite (NOx) and disease activity. This measure of NO production can be
      falsely elevated by exogenous dietary and medication sources of NOx and variably
      reduced by serum thiols. These variables can make NOx a less reliable tool for
      studying the role of NO in SLE. Peroxynitrite, a by-product of NO and superoxide,
      nitrates tyrosine moieties. The resulting 3-nitrotyrosine (3NT) serves as a long
      term indicator of NO-mediated protein modifications that is not affected by
      exogenous sources of NOx or serum thiols. We hypothesized that for these reasons
      serum 3NT levels would correlate with lupus disease activity more significantly
      than serum NOx. To address this hypothesis, we prospectively evaluated lupus
      disease activity, serum protein 3NT levels, and NOx levels in a cohort of lupus
      patients at 3-month intervals. Serum 3NT correlated with disease activity among
      African-Americans, while NOx correlated with disease activity among Caucasians.
      Subjects with active lupus nephritis had higher levels of serum 3NT than those
      without renal disease. Immunohistochemical analysis of renal biopsies from
      subjects with active proliferative lupus nephritis revealed renal expression of
      inducible NO synthase. The results of this study suggest that overproduction of
      NO may play a pathogenic role in SLE and lupus nephritis. Serum 3NT may be a
      useful, new tool for studying the contributions of NO to the pathogenesis of SLE.

PMID- 10591093
TI  - Hydrophobic dye inhibits aggregation of molten carbonic anhydrase during thermal
      unfolding and refolding.
AB  - Association-seeking surfaces on partially structured polypeptides can participate
      in interactions that are either intramolecular (folding related) or
      intermolecular (aggregative). During heat shock, intermolecular associations
      leading to aggregation are prevented through the binding of such surfaces by
      chaperones of the Hsp20 family (with Hsp70 later effecting release and
      refolding). Here we report that the hydrophobic dye, 8-anilino-1
      naphthalenesulfonate (ANS), mimics the function of the chaperones in its
      interactions with molten carbonic anhydrase (CA). At 150-fold molar excess of dye
      over protein, heat-induced aggregation of CA is almost completely inhibited by
      binding of ANS to solvent-exposed clusters of nonpolar residues. After exposure
      of ANS-containing protein solutions to temperatures as high as 95 degrees C,
      refolded CA can be recovered through cooling and dialysis, with no accompanying
      aggregation. This apparent mimicking of chaperone activity by a small dye opens
      up new approaches to understanding and manipulating protein aggregation.

PMID- 10591092
TI  - Predictors and outcomes of cardiac complications following elective coronary
      bypass grafting.
AB  - Our objective was to determine the predictors of cardiac complications among a
      cohort of elective coronary artery bypass graft (CABG) surgery patients and to
      determine the relationship of such complications to subsequent quality of life
      and symptoms. A total of 248 patients were enrolled and 237 completed 6 month
      follow-up. The combined rate of both major and minor cardiac complications was
      9.7% (n = 24). Patients in this study were evaluated preoperatively, monitored
      intraoperatively, followed immediately postoperatively and at 6 months. Major
      cardiac complications accounted for 3.6% (n = 9) and minor complications for 6%
      (n = 15). Using multivariable logistic regression analysis, the predictors of
      major cardiac complications were receiving diuretics preoperatively (p = .01) and
      increased time during cross-clamping (p = .006). At 6 months after surgery, 19%
      of the patients with postoperative cardiac complications experienced worsening of
      symptoms, in contrast to only 8% of those without cardiac complications (p =
      .03). We concluded that patients who were on preoperative diuretics and those who
      had longer cross-clamp times were at higher risk of cardiac complications. The
      majority of patients who had acute cardiac complications had improved function
      and symptoms at 6 months postoperatively.

PMID- 10591094
TI  - Molecular dynamics simulations of beta-hairpin folding.
AB  - Molecular dynamics simulations of beta-hairpin folding have been carried out with
      a solvent-referenced potential at 274 K. The model peptide V4DPGV4 formed stable
      beta-hairpin conformations and the beta-hairpin ratio calculated by the DSSP
      algorithm was about 56% in the 50-ns simulation. Folding into beta-hairpin
      conformations is independent of the initial conformations. The simulations
      provided insights into the folding mechanism. The hydrogen bond often formed in a
      beta-turn first, and then propagated by forming more hydrogen bonds along the
      strands. Unfolding and refolding occurred repeatedly during the simulations. Both
      the hydrogen bonding and the hydrophobic interaction played important roles in
      forming the ordered structure. Without the hydrophobic effect, stable beta
      hairpin conformations did not form in the simulations. With the same energy
      functions, the alanine-based peptide (AAQAA)3Y folded into helical conformations,
      in agreement with experiments. Folding into an alpha-helix or a beta-hairpin is
      amino acid sequence-dependent.

PMID- 10591095
TI  - Efficacy and selectivity in flexible database docking.
AB  - Flexible database docking with DOCK 4.0 has been evaluated for its ability to
      retrieve biologically active molecules from a database of approximately 1,000
      compounds with known activities against thrombin and the progesterone receptor.
      The retrieval of known actives and chemically similar but inactive molecules was
      monitored as a function of conformational and orientational sampling. The largest
      enrichment of actives among the 10% highest ranking molecules is obtained when
      only five conformations are used to seed the next round of ligand reconstruction
      and limited sampling is applied to place the base fragment in the binding site.
      The performance of energy and chemical scoring, as implemented in DOCK 4.0, was
      found to depend on the protein used for docking. For the progesterone receptor,
      energy scoring yields the largest enrichments (64%) in terms of actives retrieved
      among the 10% top scoring molecules, while chemical scoring performs best for
      thrombin (94%). With the exception of the application of energy scoring to the
      progesterone receptor, both energy-based scoring schemes applied in this study do
      not discriminate well between true actives and chemically similar but inactive
      compounds. In conclusion, flexible docking is able to effectively prioritize high
      throughput screening databases, using less conformational sampling than normally
      required for appropriate reconstruction of protein-ligand complexes. The more
      subtle discrimination between chemically similar classes of active and inactive
      compounds remains, however, problematic.

PMID- 10591096
TI  - Filtered neighbors threading.
AB  - We present a knowledge-based threading scoring function that exploits the
      information about protein structure contained in residue packing/neighbor
      preferences. The proposed algorithm eliminates the stereochemically improbable
      physical contacts for each possible sequence-to-structure alignment. We use this
      algorithm to "filter" the score of the sequence-to-structure alignment. Filtering
      is dynamic, in the sense that the set of neighbor pairs contributing to the
      alignment score varies during threading. Whether or not a neighbor pair
      contributes to the score depends on the threaded amino acids. We use a detailed
      structure description that encodes amino acid side-chain rotamer and physical
      contact preferences but does not imprint the fold model with the native sequence
      or native physical contacts. We discretize this description to collect accurate
      statistics for the scoring function generation. We use the original detailed
      description for the neighbor filtering. On average, the filtered neighbors
      threading (FNT) method predicts the sequence-to-structure alignment twice as
      accurately as does the "standard" unfiltered neighbors threading. For the set of
      threadings tested by the PHDthreader method, the FNT gives predictions with a
      sequence-to-structure alignment accuracy of 46.9%, which amounts to a 74%
      improvement in alignment sensitivity compared with PHDthreader predictions. These
      results show that reduction of noise from the observed neighbor pair preferences
      by filtering leads to noticeable improvements in the predicted sequence-to
      structure alignments.

PMID- 10591097
TI  - ProtoMap: automatic classification of protein sequences, a hierarchy of protein
      families, and local maps of the protein space.
AB  - We investigate the space of all protein sequences in search of clusters of
      related proteins. Our aim is to automatically detect these sets, and thus obtain
      a classification of all protein sequences. Our analysis, which uses standard
      measures of sequence similarity as applied to an all-vs.-all comparison of
      SWISSPROT, gives a very conservative initial classification based on the highest
      scoring pairs. The many classes in this classification correspond to protein
      subfamilies. Subsequently we merge the subclasses using the weaker pairs in a two
      phase clustering algorithm. The algorithm makes use of transitivity to identify
      homologous proteins; however, transitivity is applied restrictively in an attempt
      to prevent unrelated proteins from clustering together. This process is repeated
      at varying levels of statistical significance. Consequently, a hierarchical
      organization of all proteins is obtained. The resulting classification splits the
      protein space into well-defined groups of proteins, which are closely correlated
      with natural biological families and superfamilies. Different indices of validity
      were applied to assess the quality of our classification and compare it with the
      protein families in the PROSITE and Pfam databases. Our classification agrees
      with these domain-based classifications for between 64.8% and 88.5% of the
      proteins. It also finds many new clusters of protein sequences which were not
      classified by these databases. The hierarchical organization suggested by our
      analysis reveals finer subfamilies in families of known proteins as well as many
      novel relations between protein families.

PMID- 10591098
TI  - Classification of protein sequences by homology modeling and quantitative
      analysis of electrostatic similarity.
AB  - Protein electrostatics plays a key role in ligand binding and protein-protein
      interactions. Therefore, similarities or dissimilarities in electrostatic
      potentials can be used as indicators of similarities or dissimilarities in
      protein function. We here describe a method to compare the electrostatic
      properties within protein families objectively and quantitatively. Three
      dimensional structures are built from database sequences by comparative modeling.
      Molecular potentials are then computed for these with a continuum solvation model
      by finite difference solution of the Poisson-Boltzmann equation or analytically
      as a multipole expansion that permits rapid comparison of very large datasets.
      This approach is applied to 104 members of the Pleckstrin homology (PH) domain
      family. The deviation of the potentials of the homology models from those of the
      corresponding experimental structures is comparable to the variation of the
      potential in an ensemble of structures from nuclear magnetic resonance data or
      between snapshots from a molecular dynamics simulation. For this dataset, the
      results for analysis of the full electrostatic potential and the analysis using
      only monopole and dipole terms are very similar. The electrostatic properties of
      the PH domains are generally conserved despite the extreme sequence divergence in
      this family. Notable exceptions from this conservation are seen for PH domains
      linked to a Db1 homology (DH) domain and in proteins with internal PH domain
      repeats.

PMID- 10591099
TI  - The three-dimensional solution structure of Aesculus hippocastanum antimicrobial
      protein 1 determined by 1H nuclear magnetic resonance.
AB  - Aesculus hippocastanum antimicrobial protein 1 (Ah-AMP1) is a plant defensin
      isolated from horse chestnuts. The plant defensins have been divided in several
      subfamilies according to their amino acid sequence homology. Ah-AMP1, belonging
      to subfamily A2, inhibits growth of a broad range of fungi. So far, a three
      dimensional structure has been determined only for members of subfamilies A3 and
      B2. In order to understand activity and specificity of these plant defensins, the
      structure of a protein belonging to subfamily A2 is needed. We report the three
      dimensional solution structure of Ah-AMP1 as determined from two-dimensional 1H
      nuclear magnetic resonance data. The structure features all the characteristics
      of the "cysteine-stabilized alpha beta-motif." A comparison of the structure, the
      electrostatic potential surface and regions important for interaction with the
      fungal receptor, is made with Rs-AFP1 (plant defensin of subfamily A3). Thus,
      residues important for activity and specificity have been assigned.

PMID- 10591101
TI  - Study of the electrostatics treatment in molecular dynamics simulations.
AB  - This article considers the treatment of long-range interactions in molecular
      dynamics simulations. We investigate the effects of using different cutoff
      distances, constant versus distance-dependent dielectric, and different smoothing
      methods. In contrast to findings of earlier studies, we find that increasing the
      cutoff over 8 A does not significantly improve the accuracy (Arnold and Ornstein,
      Proteins 1994;18:19-33), and using a distance-dependent dielectric instead of a
      constant dielectric also does not improve accuracy (Guenot and Kollman, Protein
      Sci 1992;1:1185-1205). This might depend on differences in simulation protocols
      or force fields, or both, because we use the CHARMM22 force field with stochastic
      boundary conditions, whereas earlier studies used other protocols and energy
      functions. We also note that the stability of the simulations is highly dependent
      on the starting structure, showing that accurate molecular simulations not only
      depend on a realistic simulation protocol but also on correct initial conditions.

PMID- 10591100
TI  - Validation of nuclear magnetic resonance structures of proteins and nucleic
      acids: hydrogen geometry and nomenclature.
AB  - A statistical analysis is reported of 1,200 of the 1,404 nuclear magnetic
      resonance (NMR)-derived protein and nucleic acid structures deposited in the
      Protein Data Bank (PDB) before 1999. Excluded from this analysis were the entries
      not yet fully validated by the PDB and the more than 100 entries that contained <
      95% of the expected hydrogens. The aim was to assess the geometry of the
      hydrogens in the remaining structures and to provide a check on their
      nomenclature. Deviations in bond lengths, bond angles, improper dihedral angles,
      and planarity with respect to estimated values were checked. More than 100
      entries showed anomalous protonation states for some of their amino acids.
      Approximately 250,000 (1.7%) atom names differed from the consensus PDB
      nomenclature. Most of the inconsistencies are due to swapped prochiral labeling.
      Large deviations from the expected geometry exist for a considerable number of
      entries, many of which are average structures. The most common causes for these
      deviations seem to be poor minimization of average structures and an improper
      balance between force-field constraints for experimental and holonomic data. Some
      specific geometric outliers are related to the refinement programs used. A number
      of recommendations for biomolecular databases, modeling programs, and authors
      submitting biomolecular structures are given.

PMID- 10591102
TI  - Unusual amino acid usage in the variable regions of mercury-binding antibodies.
AB  - Monoclonal antibodies (mAb) specific for mercuric ions were isolated from BALB/c
      mice injected with a mercury-containing, hapten-carrier complex. The antibodies
      reacted by enzyme-linked immunosorbent assay with bovine serum albumin
      glutathione-mercuric chloride (BSA-GSH-HgCl) but not with BSA-GSH without
      mercury. Nucleotide sequences from polymerase chain reaction products encoding
      six of the antibody heavy-chain variable regions and seven light-chain variable
      regions revealed that all the antibodies contained an unpaired cysteine residue
      in one hypervariable region, which is unusual for murine antibodies. Mutagenesis
      of the cysteine to either tyrosine or serine in one of the Hg-binding antibodies,
      mAb 4A10, eliminated mercury binding. However, of two influenza-specific
      antibodies that contain cysteine residues at the same position as mAb 4A10, one
      reacted with mercury, although not so strongly as 4A10, whereas the other did not
      react at all. These results suggested that, in addition to an unpaired cysteine,
      there are other structural features, not yet identified, that are important for
      creating an appropriate environment for mercury binding. The antibodies described
      here could be useful for investigating mechanisms of metal-protein interactions
      and for characterizing antibody responses to structurally simple haptens.

PMID- 10591103
TI  - The crystal structure of triosephosphate isomerase (TIM) from Thermotoga
      maritima: a comparative thermostability structural analysis of ten different TIM
      structures.
AB  - The molecular mechanisms that evolution has been employing to adapt to
      environmental temperatures are poorly understood. To gain some further insight
      into this subject we solved the crystal structure of triosephosphate isomerase
      (TIM) from the hyperthermophilic bacterium Thermotoga maritima (TmTIM). The
      enzyme is a tetramer, assembled as a dimer of dimers, suggesting that the
      tetrameric wild-type phosphoglycerate kinase PGK-TIM fusion protein consists of a
      core of two TIM dimers covalently linked to 4 PGK units. The crystal structure of
      TmTIM represents the most thermostable TIM presently known in its 3D-structure.
      It adds to a series of nine known TIM structures from a wide variety of
      organisms, spanning the range from psychrophiles to hyperthermophiles. Several
      properties believed to be involved in the adaptation to different temperatures
      were calculated and compared for all ten structures. No sequence preferences,
      correlated with thermal stability, were apparent from the amino acid composition
      or from the analysis of the loops and secondary structure elements of the ten
      TIMs. A common feature for both psychrophilic and T. maritima TIM is the large
      number of salt bridges compared with the number found in mesophilic TIMs. In the
      two thermophilic TIMs, the highest amount of accessible hydrophobic surface is
      buried during the folding and assembly process.

PMID- 10591104
TI  - Conformational dynamics of chymotrypsin inhibitor 2 by coarse-grained
      simulations.
AB  - A coarse-grained dynamic Monte Carlo (MC) simulation method is used to
      investigate the conformational dynamics of chymotrypsin inhibitor 2 (CI2). Each
      residue is represented therein by two interaction sites, one at the alpha-carbon
      and the other on the amino acid side-chain. The energy and geometry parameters
      extracted from databank structures are used. The calculated rms fluctuations of
      alpha-carbon atoms are in good agreement with crystallographic temperature
      factors. The two regions of the protein that pack against each other to form the
      main hydrophobic core exhibit negatively correlated fluctuations. The
      conformational dynamics could efficiently be probed by the time-delayed
      orientational and conformational correlation functions of the virtual bonds: the
      active site loop, excluding the active site bond, the turn region, and the N
      terminal of the alpha-helix are relatively more mobile regions of the structure.
      A correlation is observed between the hydrogen/deuterium (H/D) exchange behavior
      and the long-time orientational and conformational autocorrelation function
      values for CI2. A cooperativity in the rotations of the bonds near in sequence is
      observed at all time windows, whereas the cooperative rotations of the bonds far
      along the sequence appear at long time windows; these correlations contribute to
      the stability of the secondary structures and the tertiary structure,
      respectively.

PMID- 10591105
TI  - Structure of the small G protein Rap2 in a non-catalytic complex with GTP.
AB  - We report a novel crystal form of the small G protein Rap2A in complex with GTP
      which has no GTPase activity in the crystal. The asymmetric unit contains two
      complexes which show that a conserved switch I residue, Tyr 32, contributes an
      extra hydrogen bond to the gamma-phosphate of GTP as compared to related
      structures with GTP analogs. Since GTP is not hydrolyzed in the crystal, this
      interaction is unlikely to contribute to the intrinsic GTPase activity. The
      comparison of other G protein structures to the Rap2-GTP complex suggests that an
      equivalent interaction is likely to exist in their GTP form, whether unbound or
      bound to an effector. This interaction has to be released to allow the GAP
      activated GTPase, and presumably the intrinsic GTPase activity as well. We also
      discuss the definition of the flexible regions and their hinges in the light of
      this structure and the expanding database of G protein structures. We propose
      that the switch I and switch II undergo either partial or complete disorder-to
      order transitions according to their cellular status, thus defining a complex
      energy landscape comprising more than two conformational states. We observe in
      addition that the region connecting the switch I and switch II is flexible in
      Rap2 and other G proteins. This region may be important for protein-protein
      interactions and possibly behave as a conformational lever arm, as characterized
      for Arf. Taken together, these observations suggest that the structural
      mechanisms of small G proteins are significantly driven by entropy-based free
      energy changes.

PMID- 10591106
TI  - Role of histidine-50, glutamic acid-96, and histidine-137 in the ribonucleolytic
      mechanism of the ribotoxin alpha-sarcin.
AB  - alpha-Sarcin is a ribotoxin secreted by the mold Aspergillus giganteus that
      degrades the ribosomal RNA by acting as a cyclizing ribonuclease. Three residues
      potentially involved in the mechanism of catalysis--histidine-50, glutamic acid
      96, and histidine-137--were changed to glutamine. Three different single mutation
      variants (H50Q, E96Q, H137Q) as well as a double variant (H50/137Q) and a triple
      variant (H50/137Q/E96Q) were prepared and isolated to homogeneity. These variants
      were spectroscopically (circular dichroism, fluorescence emission, and proton
      nuclear magnetic resonance) characterized. According to these results, the three
      dimensional structure of these variants of alpha-sarcin was preserved; only very
      minor local changes were detected. All the variants were inactive when assayed
      against either intact ribosomes or poly(A). The effect of pH on the
      ribonucleolytic activity of alpha-sarcin was evaluated against the ApA
      dinucleotide. This assay revealed that only the H50Q variant still retained its
      ability to cleave a phosphodiester bond, but it did so to a lesser extent than
      did wild-type alpha-sarcin. The results obtained are interpreted in terms of
      His137 and Glu96 as essential residues for the catalytic activity of alpha-sarcin
      (His137 as the general acid and Glu96 as the general base) and His50 stabilizing
      the transition state of the reaction catalyzed by alpha-sarcin.

PMID- 10591107
TI  - Predicted structure and fold recognition for the glutamyl tRNA reductase family
      of proteins.
AB  - The conserved residues of glutamyl tRNA reductase (GTR) from Hordeum vulgare
      (GTRhorvu) were found from an alignment/pile-up of 24 homologous sequences found
      using BLAST searches. A multiple alignment of sequences was used to obtain a
      prediction of the secondary structure of the GTR's. This secondary structure was
      submitted to the THREADER program to find possible homologous 3D structures. To
      help select the template for predicting the fold for GTRhorvu, we employed both
      molecular-biological and biochemical information about GTRhorvu. After fitting
      the secondary structure of GTRhorvu to the selected template, the MODELLER
      program was used to determine the fold for GTRhorvu. This model was built using
      the B subunit of succinyl CoA synthetase, 1scuB, as a template for the 3D
      structure of GTRhorvu. From the predicted structure, possible regions were
      identified for the binding of glutamyl-tRNA, NADPH and a heme inhibitor. The
      predicted structure was used to propose a detailed biochemical mechanism for the
      GTR, involving Mg catalyzed thioester formation and reduction by NADPH to
      glutamate-1-semialdehyde. Sites for these reactions are identified. The predicted
      structure has been deposited in the Brookhaven database as ID 1b61.

PMID- 10591108
TI  - Kinetic characterization of the interaction of the Z-fragment of protein A with
      mouse-IgG3 in a volume in chemical space.
AB  - The kinetic rate parameters for the interaction between a single domain analogue
      of staphylococcal protein A (Z) and a mouse-IgG3 monoclonal antibody (MAb) were
      measured in Hepes buffer with different chemical additives. Five buffer
      ingredients (pH, NaCl, DMSO, EDTA, and KSCN) were varied simultaneously in 16
      experiments following a statistical experimental plan. The 16 buffers thus
      spanned a volume in chemical space. A mathematical model, using data from the
      buffer composition, was developed and used to predict apparent kinetic parameters
      in five new buffers within the spanned volume. Association and dissociation
      parameters were measured in the new buffers, and these agreed with the predicted
      values, indicating that the model was valid within the spanned volume. The
      pattern of variation of the kinetic parameters in relation to buffer composition
      was different for association and dissociation, such that pH influenced both
      association and dissociation and NaCl influenced only dissociation. This
      indicated that the recognition mechanism (association) and the stability of the
      formed complex (dissociation) involve different binding forces, which can be
      further investigated by kinetic studies in systematically varied buffers.

PMID- 10591109
TI  - Diversity of conformational states and changes within the EF-hand protein
      superfamily.
AB  - The EF-hand motif, which assumes a helix-loop-helix structure normally
      responsible for Ca2+ binding, is found in a large number of functionally diverse
      Ca2+ binding proteins collectively known as the EF-hand protein superfamily. In
      many superfamily members, Ca2+ binding induces a conformational change in the EF
      hand motif, leading to the activation or inactivation of target proteins. In
      calmodulin and troponin C, this is described as a change from the closed
      conformational state in the absence of Ca2+ to the open conformational state in
      its presence. It is now clear from structures of other EF-hand proteins that this
      "closed-to-open" conformational transition is not the sole model for EF-hand
      protein structural response to Ca2+. More complex modes of conformational change
      are observed in EF-hand proteins that interact with a covalently attached acyl
      group (e.g., recoverin) and in those that dimerize (e.g., S100B, calpain). In
      fact, EF-hand proteins display a multitude of unique conformational states,
      together constituting a conformational continuum. Using a quantitative 3D
      approach termed vector geometry mapping (VGM), we discuss this tertiary
      structural diversity of EF-hand proteins and its correlation with target
      recognition.

PMID- 10591110
TI  - Local factors affecting bone resorption and estrogens.

PMID- 10591111
TI  - Physical factors, bone cells, and osteoporosis.

PMID- 10591112
TI  - Animal models for the preclinical testing of drugs against osteoporosis.

PMID- 10591113
TI  - How do bone resorption inhibitors increase bone mineral density?

PMID- 10591114
TI  - Biochemical markers of bone turnover: recent data and avenues for the future.

PMID- 10591115
TI  - Evaluation of trabecular microarchitecture. Prospects for predicting the risk of
      osteoporosis and fracture.

PMID- 10591116
TI  - Novel biologic approaches to the treatment of rheumatoid arthritis.

PMID- 10591117
TI  - Total shoulder arthroplasty in chronic inflammatory and degenerative disease.

PMID- 10591118
TI  - Use of morphine in nonmalignant joint pain: the Limoges recommendations. The
      French Society for Rheumatology.

PMID- 10591119
TI  - The foot: a diagnostic tool.

PMID- 10591120
TI  - [Characteristics of quantitative karyotypic variability in cell line of kidney
      from rat kangaroo (Potorous tridactylis)].
AB  - The goal of this work was to investigate the numeral karyotypic variability in
      different sublines (MT, M2). These sublines are formed spontaneously from the
      main cell line (M) and have modal number of chromosomes 9 and 10, MSVK (main
      structural variant karyotype)--3 + 3 + 1 + 2 and 3 + 4 + 2 + 1. There are general
      regulations which were originally got for the line M. In particular: 1) nonrandom
      character of cell distribution according to the number of chromosomal deviations
      from MSVK; 2) specific character of deviations of each chromosome from MSVK; 3)
      presence of significant connections between separate chromosomes by simultaneous,
      mainly single directed numeral deviations. These three lines (M, MT, M2) were
      compared and some differences were found: 1) different frequencies of deviations
      from MSVK; 2) the same chromosomes have tendency to different numeral deviation;
      3) the specificity of some significant connections between separate chromosomes
      by simultaneous numeral deviations. These results lead us to a conclusion that
      the balance of numerical karyotypic structure in cell populations depends on the
      regulations connected with the character of deviations according to the number of
      chromosomes from MSVK which has the largest selected advantage. Each line has its
      own specific limits of karyotypic variability.

PMID- 10591121
TI  - [The study of quantitative karyotypic variability by induction of chromosomal
      instability in cultured cells of the Indian muntjac skin fibroblasts].
AB  - The influence of mycoplasmal contamination and somatic cell hybridization on the
      character of karyotypic variability in cell cultures of Indian muntjac skin
      fibroblasts has been investigated. Mycoplasma arginini and Acholeplasma
      laidlawii, used as factors inducing chromosomal instability, do not break the
      main regulations peculiar to intact control. They regulations are: 1) nonrandom
      character of cell distribution according to the number of chromosomal deviations
      from MSVK; 2) specific character of deviations of each chromosome from MSVK; 3)
      presence of significant connections between separate chromosomes by simultaneous
      mainly single directed numeral deviations. However, mycoplasmal contamination
      promotes the increase in the number of deviations in the direction of a
      decreasing chromosomes number. There is a breach of some connections between
      chromosomes by simultaneous deviations. They are chromosomes with broken
      connections according to the number of deviations which form telomeric
      associations (dicentrics). The number of these associations excel essentially
      intact control. The formation of new MSVK in subline M2 cells of the Indian
      muntjac in the process of chromosomal segregation in cell hybrid (M2 x clone of
      JF1 rat Jensen sarcoma) depends on the presence of significant connections
      between chromosomes by simultaneous numerical deviations in direction of MSVK
      formation. They are chromosomes that take part in the formation of new MSVK which
      form telomeric associations. These associations can be observed till
      stabilization of new MSVK. Probably, the support of the balance of karyotypic
      structure by factors inducing chromosomal instability is connected with change of
      some connections between chromosomes according to the number by simultaneous
      deviations as well as with the formation of dicentrics.

PMID- 10591122
TI  - [Characteristics of quantitative karyotypic variability in cell line of kidney
      from rat kangaroo (Potorous tridactylis)].
AB  - The numerical regulations of karyotypic variability in cell line of rat kangaroo
      kidney, NBL-3-11, has been investigated. These regulations are similar with ones
      found for cell lines of the Indian muntjac skin fibroblasts (M, MT, M2). In
      particular the balanced karyotypic structure of cell population in vitro is
      determined by correlations of the structural variants of the karyotype (SVK).
      These correlations depend on the following regulations 1) nonrandom character of
      cell distribution according to the number of chromosomal deviations from MSVK; 2)
      specific character of deviations of each chromosome from MSVK; 3) presence of
      significant connections between separate chromosomes with simultaneous numeral
      deviations some differences in the character of significant connections between
      the individual chromosomes. These connections have either single directed
      character, mainly (+) direction, or differently directed one by deviations of
      each chromosome mainly in one direction in cell line NBL-3-11. At the same time
      single directed character of simultaneous deviations is observed in cell lines of
      the Indian muntjac skin fibroblasts (M, MT, M2) either in (+) or (-) direction.
      Represented results confirm and extend considerably the known ideas of the
      regulations of karyotypic variability in cell populations in vitro.

PMID- 10591123
TI  - [Functional morphology of nuclear organizer regions of chromosomes and of
      nucleoli in cells of human multiple myeloma cell lines. II.Relationship between
      immunoglobulin E production and argentophilia of nuclear organizer regions of
      chromosomes in U 266 cell line].
AB  - The IgE content in both cytoplasm and culture medium of U 266 myeloma cells, was
      studied by the enzyme-linked immunoassay in correlation with Ag-staining of NORs
      of chromosomes in their nuclei throughout 9 days after cell seeding.
      Proliferative activity of the cells was evaluated with 3H-thymidine labeling. The
      average values of both the cytoplasmic IgE content and its secretion level in U
      266 cell population, being in logarithmic growth phase, were higher in S-phase
      cells as compared with G1-cells. On comparison of results of the present and
      previous (Turilova et al., 1998) studies it was revealed that U 266 myeloma cell
      line had a high stability of cell proliferation kinetics and IgE secretion and
      the dynamics of Ag-NORs-staining, while the number of argentophilic grains in the
      cell nuclei in the present experiment was higher to correlate with an enhanced
      IgE production. It is suggested that Ag-NORs-staining reflects the level of
      specific functional activity of cells in the U 266 line.

PMID- 10591124
TI  - [Aquaporins of plasma membranes of epithelial cells].
AB  - The early 90s have brought us a discovery of a new class of membrane proteins-
      aquaporins with a function of transmembrane water channels. Being genetically
      closed proteins aquaporins are members of a large family of channel-forming
      proteins called MIPs (major intrinsic proteins). All aquaporins, except AQP4, are
      mercury-sensitive. Many aquaporins have been cloned and identified. Polyclonal
      antibodies grown against some of them promoted numerous studies of aquaporin
      localization and distribution in animal and plant tissues. Up to the present, 10
      and 2 aquaporins have been described in mammalian and amphibian epithelial
      tissues, respectively. One of described aquaporins, AQP2, whose localization is
      confined to kidney collecting duct principal cells, has been found to be a
      hormone-depending water channel. The insertion of apical vesicles bearing AQP2
      was shown to be regulated by vasopressin, meanwhile all other aquaporins are
      inserted into the plasma membrane constitutively. There is a vast evidence
      showing that the integrity of microtubules is necessary for both pathways of
      aquaporin insertion. AQP2 is important for normal kidney functioning and AQP2
      mutations cause water-balance disorders. On the contrary, the AQP1 mutations are
      not accompanied by any evident clinical pathology. This review is focused on a
      discussion of the data so far available on aquaporin distribution in different
      animal tissues.

PMID- 10591125
TI  - [Differentiation of osteogenic cells in culture].
AB  - The regulatory factors and cell responses during osteogenic differentiation have
      been reviewed. Evidence has been provided on hormone and mechanical regulation
      and on the extracellular matrix (ECM). The data on responses of primary cell
      culture and constant cell lines of osteogenic origin to these regulations are
      represented in the number of tables. It looks likely that the relationship with
      the ECM may mediate the rest of regulations, and therefore the most attention was
      paid to the cell-ECM interactions and, namely, to collagen-integrin interplay. A
      comparison of the reviewed data leads to an assumption that the ECM influence is
      passed through integrin receptors to the nuclear matrix connected transcriptional
      factors causing the next step of osteogenic differentiation.

PMID- 10591126
TI  - [Effect of thymus polypeptide fractions on the development of rat thymus and
      spleen in organ culture].
AB  - Peptides of the thymus--vilon, thymogen and thymalin, alone or in combination
      with concanavalin A, were used to investigate their effect on organotypic culture
      of thymus and spleen explants from 1- and 21-day old rats. Vilon, thymogen and
      thymalin in concentrations of 2 and 10 ng/ml and 5 ng/ml, resp., exerted
      stimulating effects in thymus and spleen tissue cultures from 21-day old rats as
      compared to the control explants. Vilon and thymogen showed inhibiting effect in
      the thymus tissue cultures from 1-day old rats as compared to the control
      explants. However, the peptides together with concanavalin A in concentration of
      10 mkg/ml resulted in decreasing the action of concanavalin A alone. The
      polypeptide fractions of thymus and their synthetic analogs play different roles
      in the regulation of thymus and spleen development in rats of different age.

PMID- 10591127
TI  - [Intracellular distribution of proteasomes in A-431 cells].
AB  - The intracellular proteasome distribution in A-431 cells was shown using methods
      of cell fractionation and immunofluorescence. In growing cells the distribution
      of proteasomes was EGF-dependent. In unstimulated cells and within 30 min of EGF
      treatment, proteasomes were localized in the cytoplasm and nuclei, but not on the
      plasma membrane. After 30 min of EGF treatment they were observed on the plasma
      membrane as well. In A-431 cells cultivated for 24 h in the medium with a lowered
      serum concentration, proteasomes were detected on the plasma membrane already in
      unstimulated cells. It is suggested that dephosphorylation of the EGF receptor
      and signalling proteins in unstimulated cells may depend on the proteolytic
      activity of proteasomes.

PMID- 10591128
TI  - [Analysis of correlation between some parameters depending on cell proliferation
      and life span of "stationary phase aging" cultures and maximum life span of
      mammals].
AB  - Earlier we developed a "stationary phase aging" model and introduced a definition
      of life span of "stationary phase aging" cell cultures. In this model the cells
      grow after seeding in flasks without subcultivation and medium change. They reach
      cell saturation density, stop dividing, gradually degrade ("stationary phase
      aging") and perish. By the term "culture life span" we designate the time from
      cell seeding until culture death. We designate the culture as dead when the
      number of living cells is less than 10 per cent of their number at saturation
      density of cell culture. The life span of transformed Chinese hamster cells was
      found to be proportional to the duration of their growth from cell seeding up to
      saturation density, as well as to the number of cell culture doublings and to be
      inversely proportional to the velocity of cell culture doubling for the same
      growth period. Maximum life span of mammals is known to be proportional to
      pregnancy duration and to the age at puberty. We found that maximal life span of
      mammals was proportional to the number of cell population doublings and inversely
      proportional to the velocity of cell population doubling during embryonal period
      or for the time from zygote to growth termination. The dependences for cell
      cultures and for mammals are analogous to each other.

PMID- 10591129
TI  - Non-fouling surface technologies.

PMID- 10591130
TI  - Water and the acute biological response to surfaces.
AB  - Molecular self association in water through hydrogen bonding is a powerful
      organizational force leading to a three-dimensional hydrogen-bonded network
      (water structure) that profoundly influences solvent properties. Localized
      perturbations in the chemical potential of water as by, for example, contacting
      with a solid surface, induces compensating changes in water structure that can be
      sensed tens of nanometers from the point of origin using the surface force
      apparatus (SFA) and ancillary techniques. These instruments reveal attractive or
      repulsive forces between opposing surfaces immersed in water, over-and-above that
      anticipated by continuum theory (DLVO), that are attributed to a variable density
      (partial molar volume) of a more-or-less ordered water structure, depending on
      the water wettability (surface energy) of the water-contacting surfaces. Water
      structure at surfaces is thus found to be a manifestation of hydrophobicity and,
      while mechanistic/theoretical interpretation of experimental results remains the
      subject of some debate in the literature, convergence of experimental
      observations permit a quantitative definition of the heretofore relative terms
      'hydrophobic' and 'hydrophilic'. In particular, long-range attractive forces (<
      100 nm) are detected only between surfaces exhibiting a water contact angle theta
      > 65 deg (defined as hydrophobic surfaces with pure water adhesion tension tau0 =
      gamma0 cos theta < 30 dyn cm(-1) where gamma0 is water interfacial tension = 72.8
      dyn cm(-1)). Short range repulsive forces (< 5 nm) are detected between surfaces
      exhibiting theta < 65 deg (hydrophilic surfaces, tau0 > 30 dyn cm(-1)). These
      findings together with other lines of chemical evidence suggest at least two
      distinct kinds of water structure and reactivity: a relatively less-dense water
      region against hydrophobic surfaces with an open hydrogen-bonded network and a
      relatively more-dense water region against hydrophilic surfaces with a collapsed
      hydrogen-bonded network. Solvent properties of interfacial water profoundly
      influence the biological response to materials in a surprisingly straightforward
      manner when key measures of biological activity sensitive to interfacial
      phenomenon are scaled against water adhesion tension tau0 of contacting surfaces.
      Protein adsorption, activation of blood coagulation, and bioadhesion are offered
      as examples in point, illustrating that the hydrophobic/hydrophilic contrast in
      the biological response to materials, often disputed in biomaterials science, is
      very clear when viewed from the perspective of water structure and reactivity at
      surfaces.

PMID- 10591131
TI  - Inhibition of fibroblast cell adhesion on substrate by coating with 2
      methacryloyloxyethyl phosphorylcholine polymers.
AB  - Fibroblast adhesion and growth behavior were examined on various polymers coated
      on a poly(ethylene telephthalate) (PET) substrate. The polymers are poly[2
      methacryloyloxyethyl phosphorylcholine (MPC)-co-n-butyl methacrylatel copolymer
      (PMB)s with different MPC unit compositions, and poly(2-hydroxyethyl
      methacrylate). Surface analysis by dynamic contact angle measurement revealed
      that the mobility of the polymer chain on the PET substrate depended on the MPC
      unit composition, but there was no significant difference between the PMBs with 3
      10 mol% MPC units and poly(HEMA). Fibronectin adsorption on the polymer surface
      from a cell culture medium was determined by immunoassay. The adsorbed
      fibronection was evenly distrubuted in every polymer, however, the amount was
      reduced with an increase in the MPC unit composition in the PMB. This result
      suggested that the MPC unit could weaken the interaction between the polymer
      surface and proteins. When fibroblast L-929 cells, were cultured on the polymers,
      the cells adhered and the number of cells increased on not only the hydrophobic
      poly(BMA) but also on the hydrophilic poly(HEMA). However, the number of cells
      that adhered on the PMB surface decreased with an increase in the MPC unit
      composition. This was a result of the fibronectin adsorption behavior. Thus, it
      could be concluded that since the PMB could suppress cell adhesion proteins e.g.
      fibronectin, the PMB showed excellent cell adhesive resistance properties.

PMID- 10591133
TI  - Interfacial behaviour of 'new' poly(ethylene oxide)-containing copolymers.
AB  - Block copolymers containing poly(ethylene oxide) (PEO) have a wide applicability
      within biomedical applications, not the least due to anti-fouling properties of
      surface coatings based on these copolymers. We have investigated a number of
      these, and results for PEO/poly(butylene oxide) (PEO/PBO), PEO/poly(lactide)
      (PEO/PL), and PEO/poly(ethylene imine) (PEO/PEI) copolymers, as well as for PEO
      esterified fatty acids, are presented and discussed. For the former class of
      polymers, the effects of molecular architecture on the adsorption properties are
      addressed, and experimental results obtained with ellipsometry and small-angle
      neutron scattering are presented. For the PEO/PL block copolymers, the effects of
      the PEO and PL lengths for the polymer adsorption are addressed, as are the
      effects of degradation of the PL moiety on both adsorption and protein rejection.
      For the PEO-esterified fatty acids, the effects of PEO chain length and
      interfacial density on the protein rejection capacity of such coatings are
      discussed.

PMID- 10591132
TI  - Photochemically immobilized polymer coatings: effects on protein adsorption, cell
      adhesion, and leukocyte activation.
AB  - Amphiphilic chains of 4-benzoylbenzoic acid moieties and polymer were
      photochemically immobilized onto silicone rubber to ask whether the covalently
      coupled polymers would passivate the silicone rubber by inhibiting protein
      adsorption and subsequent cell adhesion and activation. Three groups of polymers
      were utilized: the hydrophilic synthetic polymers of polyacrylamide, polyethylene
      glycol, and polyvinylpyrrolidone; the glycosaminoglycan, hyaluronic acid; and
      poly(glycine-valine-glycine-valine-proline), a polypeptide derived from the
      sequence of elastin. Each coating variant decreased the adsorption of fibrinogen
      and immunoglobulin G compared to uncoated silicone rubber. All except the methoxy
      polyethylene glycol coating nearly abolished fibroblast growth, but none of the
      coating variants inhibited monocyte or polymorphonuclear leukocyte adhesion.
      Interleukin-1beta, interleukin-1 receptor antagonist, and tumor necrosis factor
      alpha secretion by leukocytes were not statistically different between any of the
      coating variants and uncoated silicone rubber. However, the methoxy-polyethylene
      glycol and elastin-based polypeptide coatings, which supported the highest
      numbers of adherent monocytes, also elicited the lowest levels of proinflammatory
      cytokine secretion. When these in vitro data were collectively evaluated, the
      coating that most effectively passivated silicone rubber was the polypeptide
      derived from elastin.

PMID- 10591134
TI  - Surface modification with PEO-containing triblock copolymer for improved
      biocompatibility: in vitro and ex vivo studies.
AB  - Poly(ethylene oxide) (PEO) has been frequently used to modify biomaterial
      surfaces for improved biocompatibility. We have used PEO-polybutadiene-PEO
      triblock copolymer to graft PEO to biomaterials by gamma-irradiation for a total
      radiation dose of 1 Mrad. The molecular weight of PEO in the block copolymer was
      5000. In vitro study showed that fibrinogen adsorption to Silastic, polyethylene,
      and glass was reduced by 70 to approximately 95% by PEO grafting. On the other
      hand, the reduction of fibrinogen adsorption was only 30% on expanded
      polytetrafluoroethylene (e-PTFE). In vitro platelet adhesion study showed that
      almost no platelets could adhere to PEO-coated Silastic, polyethylene, and glass,
      while numerous platelet aggregates were found on the ePTFE. The platelet adhesion
      in vitro corresponded to the fibrinogen adsorption. When the PEO-grafted surfaces
      were tested ex vivo using a series shunt in a canine model, the effect of the
      grafted PEO was not noticeable. Platelet deposition on ePTFE was reduced by PEO
      grafting from 8170 +/- 1030 to 5100 +/- 460 platelets 10(-3) microm2, but
      numerous thrombi were still present on the PEO-grafted surface. The numbers of
      platelets cumulated on Silastic, polyethylene, and glass were 100 +/- 80, 169 +/-
      35, and 24 +/- 22 platelets 10(-3) microm2, respectively. This is about 35%
      reduction in platelet deposition by PEO grafting. While the numbers of deposited
      platelets were small, the decreases were not as large as those expected from the
      in vitro study. This may be due to a number of reasons which have to be clarified
      in future studies, but it appears that in vitro platelet adhesion and fibrinogen
      adsorption studies may not be a valuable predictor for the in vivo or ex vivo
      behavior of the PEO-grafted surfaces.

PMID- 10591135
TI  - Non-fouling properties of polysaccharide-coated surfaces.
AB  - Hyaluronic acid and alginic acid, examples of hydrophilic polysaccharides whose
      biological and technological properties are deeply related to strong interaction
      with water, have been coupled to substrate surfaces. These coatings can prevent
      mammalian cells adhesion and greatly reduce bacterial cells adhesion in vitro and
      in several in vivo applications. The anti-adhesive properties of these surfaces
      are discussed in terms of the surface fractional coverage by the polysaccharide,
      as evaluated by XPS analysis and water contact angle. The implications of
      chemical-molecular considerations to the properties of these coatings are
      discussed from an analytical and mechanistic point of view.

PMID- 10591136
TI  - Grafted poly(ethylene oxide) brushes as nonfouling surface coatings.
AB  - The identification of design criteria for the prevention of surface fouling by
      protein adsorption has been an elusive research goal. The current ideas in this
      domain assume two different directions. One focuses on correlating protein
      adsorption with macroscopic surface properties such as the water wettability. The
      second approach involves tailoring the molecular interactions between the
      adsorbing proteins and the surface. In this paper, we focus on the experimental
      results and theoretical ideas concerned with tuning the interfacial forces by
      means of terminally grafted PEO chains.

PMID- 10591137
TI  - Effect of molecular weight and polydispersity on kinetics of dissolution and
      release from ph/temperature-sensitive polymers.
AB  - N-isopropylacrylamide (NIPAAm) polymers exhibit a lower critical solution
      temperature (LCST). Aqueous solutions of these polymers are soluble below their
      LCST and precipitate above their LCST. The LCST is dependent on pH for polymers
      with ionizable groups because of a change in hydrophilicity with ionization and
      electrostatic repulsion that cause a shift in the LCST. We have designed a novel
      polymeric delivery system that utilizes linear, pH/temperature-sensitive
      terpolymers of NIPAAm, butyl methacrylate (BMA) and acrylic acid (AA). This
      system allows the aqueous loading of drugs in polymeric beads with high loading
      efficiency while preserving the bioactivity of the protein drug. Furthermore, the
      unique properties of the pH/temperature-sensitive polymeric bead make it a
      potential system for oral drug delivery of peptide and protein drugs to different
      regions of the intestinal tract. This study aims at investigating the effect of
      polydispersity and molecular weight (MW) of terpolymers of poly(NIPAAm-co-BMA-co
      AA) with feed mol ratio of NIPAAm/BMA/AA 85/5/10 on the polymer dissolution rate
      and on the release kinetics of a model protein, namely insulin. Varying the
      weight average MW (Mw) and polydispersity of the polymer modulated the polymer
      dissolution rate and the release rate of insulin from pH/temperature-sensitive
      polymeric beads. An increase in the polydispersity of the polymer through the
      addition of high MW polymer chains caused a decrease in the release rate of
      insulin and in the polymer dissolution rate. High MW polymer chains impose a
      certain degree of interaction between polymer chains due to chain entanglement.
      There is a limiting value of MW above which chain entanglement has no effect on
      drug release rate.

PMID- 10591138
TI  - Molecular consequences of human mast cell activation following immunoglobulin E
      high-affinity immunoglobulin E receptor (IgE-FcepsilonRI) interaction.
AB  - The cross-linking by immunoglobulin E of its high-affinity receptor, FcepsilonRI,
      on mast cells initiates a complex series of biochemical events leading to
      degranulation and the synthesis and secretion of eicosanoids and cytokines
      through the action of transcription factors, such as nuclear factor-kappaB. The
      initial activation involves the phosphorylation of FcepsilonRI beta- and gamma
      subunits through the actions of the tyrosine kinases lyn and syk. For the
      purposes of description, the subsequent events may be grouped in three cascades
      characterized by the key proteins involved. First, the phospholipase C-inositol
      phosphate cascade activates protein kinase C and is largely responsible for
      calcium mobilization and influx. Second, activation of Ras and Raf via mitogen
      activated protein kinase causes the production of arachidonic acid metabolites.
      Third, the generation of sphingosine and sphingosine-1-phosphate occurs through
      activation of sphingomyelinase. While the early signaling events tend to be
      specific for the cited cascades, there is an increasing overlap of activated
      proteins with the downstream propagation of the signal. It is the balanced
      interaction between these proteins that culminates in degranulation, synthesis,
      and release of eicosanoids and cytokines.

PMID- 10591139
TI  - The homeodomain-containing proteins: an update on their interacting partners.
AB  - Homeodomain-containing proteins are transcription regulators controlling the
      coordinated expression of genes involved in development, differentiation, and
      cellular transformation. They share a highly conserved 60-amino-acid region (the
      "homeodomain"), which allows them to bind DNA and modulate the expression of
      multiple target genes, whose identities remain largely unknown. Although each HOX
      gene product exhibits in vivo specificity, they harbor very similar DNA-binding
      affinities in vitro, suggesting that other mechanisms such as protein-protein
      interactions are critical to modulate their function. In this commentary, we
      describe the proteins that can interact with the HOX gene products, including
      newly identified partners such as CREB binding protein and the NF-kappaB/IkappaB
      alpha proteins. We also outline the molecular programs that are regulated by the
      transcriptional complexes involving the HOX gene products and where new
      pharmacological tools could find interesting targets.

PMID- 10591140
TI  - Bis(N,N-dimethylhydroxamido)hydroxooxovanadate inhibition of protein tyrosine
      phosphatase activity in intact cells: comparison with vanadate.
AB  - We have shown previously that bis(N,N-dimethylhydroxamido)hydroxooxovanadate
      (DMHV) is an excellent reversible inhibitor of protein tyrosine phosphatase (PTP)
      in vitro. DMHV does not carry a charge under physiological pH conditions and is
      anticipated to permeate cell membranes more easily than vanadate. In the present
      study, the efficacy of DMHV as a PTP inhibitor in intact cells was compared with
      that of vanadate by measuring phosphotyrosine levels in various cells treated
      with these compounds. DMHV was more effective in increasing both the
      phosphotyrosine levels of various proteins in 3T3L1 fibroblasts and the level of
      insulin-receptor phosphorylation in CHO cells overexpressing the human insulin
      receptor. DMHV was about 10- to 20-fold more effective than vanadate in
      increasing glucose transport and glycogen synthesis in 3T3L1 adipocytes. DMHV,
      unlike vanadate, also inhibited PTP in Jurkat cells. The implications of these
      observations are discussed.

PMID- 10591141
TI  - Selective inhibition of protein kinase C, mitogen-activated protein kinase, and
      neutrophil activation in response to calcium pyrophosphate dihydrate crystals,
      formyl-methionyl-leucyl-phenylalanine, and phorbol ester by O-(chloroacetyl
      carbamoyl) fumagillol (AGM-1470; TNP-470).
AB  - The effect of O-(chloroacetyl-carbamoyl) fumagillol (AGM-1470; TNP-470) was
      investigated on protein kinase C (PKC) and mitogen-activated protein kinase
      (MAPK) activation in neutrophils stimulated by plasma-opsonized crystals of
      calcium pyrophosphate dihydrate (triclinic) [CPPD(T)], formyl-Met-Leu-Phe (fMLP),
      and phorbol 12-myristate 13-acetate (PMA). Neutrophil respiratory burst responses
      also were determined in AGM-1470-pretreated cells stimulated with the same
      agonists, using chemiluminescence and superoxide anion generation assays. AGM
      1470 (5 microM) effectively inhibited PKC activation in cells treated with
      CPPD(T) crystals (50 mg/mL, 2 min) and fMLP (1 microM, 1 min), but had no effect
      on PMA-treated cells (0.5 microM, 5 min). AGM-1470 blocked MAPK activity
      completely and reduced neutrophil activation induced by fMLP and PMA but not by
      CPPD(T). The degree of inhibition of the respiratory burst plateaued at
      approximately 46+/-9 and 54+/-3% in fMLP- and PMA-treated cells, respectively.
      These data indicate that activation of neutrophil respiratory burst activity may
      be mediated through the MAPK pathway. AGM-1470 pretreatment did not inhibit
      CPPD(T) crystal- or fMLP-stimulated phosphatidylinositol 3-kinase (PI 3-kinase)
      activity. These findings, coupled with further observations that the PI 3-kinase
      inhibitor wortmannin (10 nM) inhibited fMLP- and CPPD(T) crystal-induced but not
      PMA-induced chemiluminescence, indicate that at least two distinct signaling
      pathways (mediated by PI 3-kinase or MAPK) lead to neutrophil respiratory burst
      responses. PKC may also be required in the MAPK-stimulated pathway. We propose
      that the inhibitory effect of AGM-1470 on the neutrophil respiratory burst may be
      due to its ability to inhibit PKC and MAPK activation.

PMID- 10591142
TI  - Effects of local anesthetics on phospholipase D activity in differentiated human
      promyelocytic leukemic HL60 cells.
AB  - Local anesthetics impair certain functions of neutrophils, and phospholipase D
      (PLD) is considered to play an important role in the regulation of these
      functions. To understand the mechanisms by which local anesthetics suppress the
      functions of neutrophils, we examined the effects of local anesthetics on PLD in
      neutrophil-like differentiated human promyelocytic leukemic HL60 cells.
      Tetracaine, a local anesthetic, inhibited formyl-methionyl-leucyl-phenylalanine
      (fMLP)- and 4beta-phorbol 12-myristate 13-acetate (PMA)-induced PLD activation,
      but potentiated fMLP-stimulated phospholipase C activity. All four local
      anesthetics tested suppressed PMA-induced PLD activation to different extents,
      and the order of their potency was tetracaine > bupivacaine > lidocaine >
      procaine. In a cell-free system, tetracaine suppressed guanosine 5'-O-(3
      thiotriphosphate) (GTPgammaS)-induced PLD activation as well as PMA-induced PLD
      activation. Western blot analysis revealed that tetracaine prevented the membrane
      translocation of PLD-activating factors, ADP-ribosylation factor, RhoA, and
      protein kinase Calpha. Tetracaine also inhibited the activity of recombinant
      hPLD1a in vitro. These results suggest that local anesthetics suppress PLD
      activation in differentiated HL60 cells by preventing the membrane translocation
      of PLD-activating factors, and/or by directly inhibiting the enzyme per se.
      Therefore, it could be assumed that local anesthetics would suppress the
      functions of neutrophils by inhibition of PLD activation.

PMID- 10591143
TI  - Prevention of cycloheximide-induced apoptosis in hepatocytes by adenosine and by
      caspase inhibitors.
AB  - The mechanism by which cycloheximide induces apoptosis in isolated rat
      hepatocytes was studied. Cycloheximide (1-300 microM) induced apoptosis within 3
      4 hr in the hepatocytes. Specific apoptotic characteristics such as blebbing,
      phosphatidyl serine (PS) exposure, chromatin condensation, and nuclear
      fragmentation were induced. Cycloheximide (CHX) dose dependently activated the
      caspase-3-like proteases, but not the caspase-1-like proteases. Pretreatment of
      the hepatocytes with 100 microM of the caspase inhibitors z-Val-Ala-DL-Asp
      fluoromethylketone or Ac-Asp-Glu-Val-Asp-aldehyde completely abrogated the
      caspase activation and the apoptosis. Addition of adenosine (100 microM) reduced
      phosphatidyl serine exposure and other morphological characteristics of apoptosis
      by 50%; however, it did not prevent the activation of the caspases, suggesting
      that adenosine inhibited downstream of caspase activation. The adenosine receptor
      antagonist 8-[4-[[[[(2-aminoethyl)amino]-carbonyl]methyl]oxy]phenyl]-1,3
      dipropylxa nthine abolished the capacity of adenosine to prevent apoptosis,
      indicating that prevention was receptor-mediated. During apoptosis, the
      mitochondrial membrane potential in apoptotic cells (cells with PS exposition)
      was decreased to 50-60% of the control value; in the population viable cells,
      however, the mitochondrial membrane potential remained stable. Prevention of
      apoptosis by the caspase inhibitor z-Val-Ala-DL-Asp-fluoromethylketone or
      adenosine prevented the decrease in mitochondrial membrane potential. In
      conclusion, CHX rapidly induces apoptosis in isolated rat hepatocytes, which is
      inhibited by adenosine at a relatively late step.

PMID- 10591144
TI  - The effects of methylglyoxal-bis(guanylhydrazone) on spermine binding and
      transport in liver mitochondria.
AB  - This study evaluated the effect of the anticancer drug methylglyoxal
      bis(guanylhydrazone) (MGBG) on the binding of the polyamine spermine to the
      mitochondrial membrane and its transport into the inner compartment of this
      organelle. Spermine binding was studied by applying a new thermodynamic treatment
      of ligand-receptor interactions (Di Noto et al., Macromol Theory Simul 5: 165
      181, 1996). Results showed that MGBG inhibited the binding of spermine to the
      site competent for the first step in polyamine transport; the interaction of
      spermine with this site, termed S1, also mediates the inhibitory effect of the
      polyamine on the mitochondrial permeability transition (Dalla Via et al., Biochim
      Biophys Acta 1284: 247-252, 1996). In the presence of 1 mM MGBG, the binding
      capacity and affinity of this site were reduced by about 2.6-fold; on the
      contrary, the binding capacity of the S2 site, which is most likely responsible
      for the internalization of cytoplasmic proteins (see Dalla Via et al., reference
      cited above), increased by about 1.3-fold, and its binding affinity remained
      unaffected. MGBG also inhibited the initial rate of spermine transport in a dose
      dependent manner by establishing apparently sigmoidal kinetics. Consequently, the
      total extent of spermine accumulation inside mitochondria was inhibited. This
      inhibition in transport seems to reflect a conformational change at the level of
      the channel protein constituting the polyamine transport system, rather than
      competitive inhibition at the inner active site of the channel, thereby excluding
      the possibility that the polyamine and drug use the same transport pathway.
      Furthermore, it is suggested that, in the presence of MGBG, the S2 site is able
      to participate in residual spermine transport. MGBG also strongly inhibits
      deltapH-dependent spermine efflux, resulting in a complete block in the
      bidirectional flux of the polyamine and its sequestration inside the matrix
      space. The effects of MGBG on spermine accumulation are consistent with in vivo
      disruption of the regulator of energy metabolism and replication of the
      mitochondrial genome.

PMID- 10591145
TI  - Polyamine oxidase activity in lymphoid tissues of glucocorticoid-treated rats.
AB  - Glucocorticoids are known to negatively affect lymphoid tissues, in which they
      cause programmed cell death. Polyamine depletion, which occurs in glucocorticoid
      treated animals by inhibition of biosynthesis and induction of acetylation, may
      represent a signal to thymocytes for progression into the apoptotic program.
      Since catalysis of polyamines by the catabolic pathway produces hydrogen peroxide
      as a by-product, it has been suggested that the apoptotic process may be, in
      part, due to oxidative stress as a result of hydrogen peroxide production. In
      order to verify whether polyamine oxidase (EC 1.5.3.11) may play a role in the
      process, we examined the activity of the enzyme in the thymus and spleen of
      glucocorticoid-treated rats. We administered dexamethasone (4 mg/kg) or two
      different doses of corticosterone (4 mg/kg or 30 mg/kg) to rats, which were
      killed 8 or 24 hr after hormone injection. We found that corticosterone and
      dexamethasone affected polyamine oxidase activity in both tissues, with an
      opposite dose-dependent effect of the natural hormone in the thymus. The decrease
      and increase in polyamine oxidase after the two doses of corticosterone were
      correlated with the absence and the occurrence of DNA fragmentation,
      respectively. Moreover, corticosterone affected polyamine oxidase activity
      earlier (8 hr) than dexamethasone (24 hr), but the synthetic hormone was more
      efficient than the natural hormone in thymic polyamine depletion. The polyamine
      oxidase response may represent an important event in lymphoid tissues after
      glucocorticoid treatment, suggesting a role of the enzyme in the catabolic
      effects exerted by the two hormones.

PMID- 10591146
TI  - Molecular mechanism of the short-term cardiotoxicity caused by 2',3'
      dideoxycytidine (ddC): modulation of reactive oxygen species levels and ADP
      ribosylation reactions.
AB  - The short-term cardiac side effects of 2',3'-dideoxycytidine (ddC, zalcitabine)
      were studied in rats in order to understand the biochemical events contributing
      to the development of ddC-induced cardiomyopathy. In developing animals, ddC
      treatment provoked a surprisingly rapid appearance of cardiac malfunctions
      characterized by prolonged RR, PR, and QT intervals and J point depression. The
      energy metabolism in the heart was compromised, characterized by a decreased
      creatine phosphate/creatine ratio (from 2.05 normal value to 0.75) and a
      decreased free ATP/ADP ratio (from 332 normal value to 121). The activity of
      respiratory complexes (NADH: cytochrome c oxidoreductase and cytochrome oxidase)
      also decreased significantly. Southern blot and polymerase chain reaction
      analysis did not show deletions or a decrease in the quantity of mitochondrial
      DNA (mtDNA) deriving from ddC-treated rat hearts, indicating that under our
      experimental conditions, ddC-induced heart abnormalities were not the direct
      consequence of mtDNA-related damage. The ddC treatment of rats significantly
      increased the formation of reactive oxygen species (ROS) in heart and skeletal
      muscle as determined by the oxidation of non-fluorescent dihydrorhodamine123 to
      fluorescent rhodamine123 and the oxidation of cellular proteins determined from
      protein carbonyl content. An activation of the nuclear poly-(ADP-ribose)
      polymerase (EC 2.4.2.30) and an increase in the mono-ADP-ribosylation of glucose
      regulated protein and desmin were observed in the cardiac tissue from ddC-treated
      animals. A decrease in the quantity of heat shock protein (HSP)70s was also
      detected, while the level of HSP25 and HSP60 remained unchanged. Surprisingly,
      ddC treatment induced a skeletal muscle-specific decrease in the quantity of
      three proteins, one of which was identified by N-terminal sequencing as
      myoglobin, and another by tandem mass spectrometer sequencing as triosephosphate
      isomerase (EC 5.3.1.1). These data show that the short term cardiotoxicity of ddC
      is partially based on ROS-mediated signalling through poly- and mono-ADP
      ribosylation reactions and depression of HSP70 levels, whose processes represent
      a new mtDNA independent mechanism for ddC-induced cell damage.

PMID- 10591147
TI  - Structural similitudes between cytotoxic antiestrogen-binding site (AEBS) ligands
      and cytotoxic sigma receptor ligands. Evidence for a relationship between
      cytotoxicity and affinity for AEBS or sigma-2 receptor but not for sigma-1
      receptor.
AB  - 1-Benzyl-4-(N-2-pyrrolidinylethoxy)benzene (PBPE) is a cytotoxic derivative of
      the antitumoral drug tamoxifen. PBPE binds with high-affinity and specificity to
      the microsomal antiestrogen-binding site (AEBS). PBPE, as well as some other high
      affinity AEBS ligands, shares structural features with high-affinity and
      selective sigma receptor ligands in the N-(arylethyl)-N-alkyl-2-(1
      pyrrolidinyl)ethylamine class, such as BD1008, which are cytotoxic against
      tumoral cells. Based on these structural and pharmacological similitudes, we set
      out to examine whether AEBS and sigma receptors could be related binding sites.
      We showed that BD1008 had a high affinity for AEBS. However, prototypical sigma
      receptor ligands were very low-affinity competitors on AEBS. Surprisingly, AEBS
      ligands displayed a high affinity for sigma-1 and sigma-2 receptor subtypes,
      showing that AEBS and sigma receptor-binding sites were not mutually
      exchangeable. Moreover, phenytoin, which is an allosteric modulator of sigma-1
      receptor, was a competitive inhibitor of [3H]tamoxifen on AEBS. These results
      suggest that the tamoxifen-binding site on AEBS and the sigma ligand-binding site
      on sigma receptors were not identical but related entities. We also showed here
      that the high-affinity and specific AEBS ligands also bound sigma receptors with
      high affinity. Moreover, the compounds that were capable of displacing tamoxifen
      from AEBS were cytotoxic against tumoral cells but not against the AEBS-deficient
      cell line Rtx-6. These results confirm that AEBS and sigma receptors might belong
      to the same family of proteins, and that the tamoxifen-binding site might be
      involved in the cytotoxicity of AEBS ligands and some classes of sigma compounds.

PMID- 10591148
TI  - Increase of caspase-3 activity in rat liver and plasma by thioacetamide.
AB  - Twelve and twenty-four hours after intraperitoneal administration of
      thioacetamide (200 mg/kg body weight) to rats, caspase-3 activity in the liver
      and plasma of the treated rats increased significantly compared with that of the
      control group. These results demonstrated that thioacetamide caused apoptosis,
      which involved activation of caspase-3, although there may be a number of
      pathways to apoptosis in the liver that may or may not involve the activation of
      this protein. The results also indicated that the activated caspase-3 was
      released in plasma along with glutamate-oxaloacetate transaminase (GOT) by
      successive necrosis. This is the first study that shows an increase of caspase-3
      activity in plasma.

PMID- 10591149
TI  - Interaction between osmotic and oxidative stress in diabetic precataractous lens:
      studies with a sorbitol dehydrogenase inhibitor.
AB  - Both sorbitol accumulation-linked osmotic stress and "pseudohypoxia" [increase in
      NADH/NAD+, similar to that in hypoxic tissues, and attributed to increased
      sorbitol dehydrogenase (1-iditol:NAD+ 5-oxidoreductase; EC 1.1.1.14; SDH)
      activity] have been invoked among the mechanisms underlying oxidative injury in
      target tissues for diabetic complications. We used the specific SDH inhibitor SDI
      157 [2-methyl-4(4-N,N-dimethylaminosulfonyl-1-piperazino)pyrimid ine] to evaluate
      the role of osmotic stress versus "pseudohypoxia" in oxidative stress occurring
      in diabetic precataractous lens. Control and diabetic rats were treated with or
      without SDI-157 (100 mg/kg/day for 3 weeks). Lens malondialdehyde (MDA) plus 4
      hydroxyalkenals (4-HA), MDA, GSH, and ascorbate levels, as well as the GSSG/GSH
      ratios, were similar in SDI-treated and untreated control rats, thus indicating
      that SDI-157 was not a prooxidant. Intralenticular osmotic stress, manifested by
      sorbitol levels, was more severe in SDI-treated diabetic rats (38.2+/-6.8 vs
      21.2+/-3.5 micromol/g in untreated diabetic and 0.758+/-0.222 micromol/g in
      control rats, P<0.01 for both), while the decrease in the free cytosolic
      NAD+/NADH ratio was partially prevented (120+/-16 vs 88+/-11 in untreated
      diabetic rats and 143+/-13 in controls, P<0.01 for both). GSH and ascorbate
      levels were decreased, while MDA plus 4-HA and MDA levels were increased in
      diabetic rats versus controls; both antioxidant depletion and lipid aldehyde
      accumulation were exacerbated by SDI treatment. Superoxide dismutase
      (superoxide:superoxide oxidoreductase; EC 1.15.1.1), GSSG reductase
      (NAD[P]H:oxidized-glutathione oxidoreductase; EC 1.6.4.2), GSH transferase
      (glutathione S-transferase; EC 2.5.1.18), GSH peroxidase (glutathione:hydrogen
      peroxide oxidoreductase; EC 1.11.1.9), and cytoplasmic NADH oxidase activities
      were increased in diabetic rats versus controls, and all the enzymes but GSH
      peroxidase were up-regulated further by SDI. In conclusion, sorbitol accumulation
      and osmotic stress generated oxidative stress in diabetic lens, whereas the
      contribution of "pseudohypoxia" was minor. SDIs provide a valuable tool for
      exploring mechanisms of oxidative injury in sites of diabetic complications.

PMID- 10591150
TI  - Drastic increase in nitric oxide content in rat brain under halothane anesthesia
      revealed by EPR method.
AB  - A drastic increase in nitric oxide (NO) content was revealed by the EPR method in
      rat brain cortex and cerebellum under halothane anesthesia. The NO scavenger
      diethyldithiocarbamate sodium salt (DETC) and ferrous citrate were injected into
      adult rats 30-60 min before anesthesia. Rats were anesthetized by inhalation of a
      halothane-oxygen mixture (1%, 1.5%, 2%, or 4%). After different times of
      anesthesia, rats were decapitated, and brain cortex and cerebellum were
      dissected, frozen in liquid nitrogen, and subjected to EPR spectroscopy. The
      concentration of NO was determined from the NO-Fe-DETC radical spectrum. In
      control animals, NO content in the cerebellum was only 68% of that in the cortex.
      We observed a time-dependent increase in NO content in the cortex and cerebellum
      of rats anesthetized with 1.5% halothane. In brain cortex, the NO level increased
      to six times that of waking animals after 30 min and remained at this level up to
      60 min of anesthesia. In cerebellum the changes were less drastic, the NO level
      showing only a 2-fold increase. The same effect was produced by 1% and 2%
      halothane. Ketamine, chloral hydrate, and pentobarbital were used as reference
      drugs. None of these anesthetics produced effects similar to those of halothane.
      In ketamine-anesthetized rat brain, the NO content slightly decreased.
      Pentobarbital and chloral hydrate produced an insignificant increase in NO. Data
      are discussed in the context of possible interference of halothane in the
      regulation of nitric oxide synthase activity.

PMID- 10591151
TI  - Effects of adenosine A(2A) receptor stimulation in vivo on dopamine D3 receptor
      agonist binding in the rat brain.
AB  - To investigate if adenosine A2A receptor stimulation in vivo modulates dopamine
      D3 receptor binding, we analyzed the effects of 2-[p-(carboxyethyl)
      phenylethylamino]-5'-N-ethylcarboxyamidoade nosine (CGS 21680) on the binding
      properties of the selective D3 receptor agonist [N-propyl-2,3,-3H]4aR,10bR-(+)
      trans-3,4,4a,10b-tetrahydro-4 -n-propyl2H,5H-[1]benzopyrano[4,3-b]1,4-oxazin-9-ol
      ([3H]PD 128907) in the rat forebrain using quantitative autoradiography.
      Intraperitoneally administered CGS 21680 (0.1-3 mg/kg) increased the Kd and Bmax
      values of [3H]PD 128907 binding in the islands of Calleja and in subregions of
      the caudate-putamen. These results suggest that stimulation of adenosine A2A
      receptors in vivo causes alterations in the binding characteristics of dopamine
      D3 receptors in the basal ganglia, and that this effect may relate to the
      neuroleptic-like effect of adenosine A2A receptor agonists.

PMID- 10591152
TI  - Isolation and identification of 1alpha-hydroxy-24-oxovitamin D3 and 1alpha,23
      dihydroxy-24-oxovitamin D3: metabolites of 1alpha,24(R)-dihydroxyvitamin D3
      produced in rat kidney.
AB  - 1alpha,24(R)-Dihydroxyvitamin D3 [1alpha,24(R)(OH)2D3], a synthetic vitamin D3
      analog, has been developed as a drug for topical use in the treatment of
      psoriasis. At present, the target tissue metabolism of 1alpha,24(R)(OH)2D3 is not
      understood completely. In our present study, we investigated the metabolism of
      1alpha,24(R)(OH)2D3 in the isolated perfused rat kidney. The results indicated
      that 1alpha,24(R)(OH)2D3 is metabolized in rat kidney into several metabolites,
      of which 1alpha,24(R),25-trihydroxyvitamin D3, 1alpha,25-dihydroxy-24-oxovitamin
      D3, 1alpha,23(S),25-trihydroxy-24-oxovitamin D3, and 1alpha,23-dihydroxy
      24,25,26,27-tetranorvitamin D3 are similar to the previously known metabolites of
      1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3]. In addition to these
      aforementioned metabolites, we also identified two new metabolites, namely 1alpha
      hydroxy-24-oxovitamin D3 and 1alpha,23-dihydroxy-24-oxovitamin D3. The two new
      metabolites do not possess the C-25 hydroxyl group. Thus, the metabolism of
      1alpha,24(R)(OH)2D3 into both 25-hydroxylated and non-25-hydroxylated metabolites
      suggests that 1alpha,24(R)(OH)2D3 is metabolized in the rat kidney through two
      pathways. The first pathway is initiated by C-25 hydroxylation and proceeds
      further via the C-24 oxidation pathway. The second pathway directly proceeds via
      the C-24 oxidation pathway without prior hydroxylation at the C-25 position.
      Furthermore, we demonstrated that rat kidney did not convert 1alpha
      hydroxyvitamin D3 [1alpha(OH)D3] into 1alpha,25(OH)2D3. This finding indicates
      that the rat kidney does not possess the classical vitamin D3-25-hydroxylase
      (CYP27) activity. However, from our present study it is apparent that prior
      hydroxylation of 1alpha(OH)D3 at the C-24 position in the 'R' orientation allows
      25-hydroxylation to occur. At present, the enzyme responsible for the C-25
      hydroxylation of 1alpha,24(R)(OH)2D3 is unknown. Our observation that the side
      chain of 1alpha,24(R)(OH)2D3 underwent 24-ketonization and 23-hydroxylation even
      in the absence of the C-25 hydroxyl group suggests that 1alpha,25(OH)2D3-24
      hydroxylase (CYP24) can perform some steps of the C-24 oxidation pathway without
      prior C-25 hydroxylation. Thus, we speculate that CYP24 may be playing a dual
      role in the metabolism of 1alpha,24(R)(OH)2D3.

PMID- 10591154
TI  - Influence of backbone chemistry on immune activation by synthetic
      oligonucleotides.
AB  - Depending on base sequence, DNA displays immunological activities relevant to the
      design of novel therapeutic agents. To determine the influence of backbone
      structure on these activities, we tested a series of synthetic phosphodiester and
      phosphorothioate oligonucleotides in in vitro cultures of murine spleen cells.
      These compounds were 30 bases long and consisted of either a single base or an
      immunostimulatory sequence (AACGTT) flanked on 5' and 3' ends by 12 nucleotides
      of each base. Cell activation was assessed by both thymidine incorporation and
      expression of cell surface CD69; production of interleukin-6 and interleukin-12
      was used as a measure of cytokine stimulation. In these assays, phosphorothioate
      oligonucleotides induced much higher levels of proliferation, CD69 expression,
      and cytokine production than the comparable phosphodiester compounds and had
      activity at lower concentrations. The sequence for optimal stimulation by
      phosphorothioates varied among responses, however. For example, whereas compounds
      containing an immunostimulatory sequence all induced similar levels of
      proliferation and CD69 expression, cytokine production was greatest with
      compounds with dA and dT flanks. Furthermore, while single base dG
      oligonucleotides stimulated proliferation as both phosphodiesters and
      phosphorothioates, they failed to stimulate cytokine production. Together, these
      findings indicate that base sequence as well as backbone chemistry influence
      immune activation by synthetic oligonucleotides, with the effects varying among
      responses. While suggesting differences in the structure-function relationships
      of nucleic acids in their immune activities, these findings also raise the
      possibility of the design of agents with specific patterns of immune modulation.

PMID- 10591153
TI  - Selective inhibition of formyl-methionyl-leucyl-phenylalanine (fMLF)-dependent
      superoxide generation in neutrophils by pravastatin, an inhibitor of 3-hydroxy-3
      methylglutaryl coenzyme A (HMG-CoA) reductase.
AB  - It has been shown previously that inhibitors of 3-hydroxy-3-methylglutaryl
      coenzyme A (HMG-CoA) reductase, such as compactin, lovastatin, and pravastatin,
      block cholesterol synthesis, suppress lymphocyte functions, and beneficially
      affect atherogenesis. Recently, it was reported that compactin and lovastatin
      inhibit the respiratory burst of DMSO-differentiated HL-60 cells, an effect
      reversed by mevalonic acid. The mode of action of these inhibitors in this role
      is not understood fully. Thus, we studied the mechanism of inhibition of
      neutrophil superoxide (O2*-) generation by pravastatin and found that pravastatin
      at 0.5 mM inhibited the receptor-mediated tyrosine kinase (TK)-dependent pathway
      of O2*- generation and also luminol chemiluminescence but not the protein kinase
      C (PKC)-dependent or the TK- and PKC-independent pathways of O2*- generation in
      neutrophils. Pravastatin also inhibited the tumor necrosis factor-alpha- and
      formyl-methionyl-leucyl-phenylalanine-induced phosphorylation of a tyrosine of a
      115-kDa protein. These effects were not reversed by mevalonate. From these
      results it is concluded that pravastatin inhibited receptor-mediated O2*
      generation by decreasing tyrosine phosphorylation but not by inhibiting the
      formation of an intermediate in the biosynthesis of cholesterol.

PMID- 10591155
TI  - Inhibition of allergen-induced pulmonary responses by the selective tryptase
      inhibitor 1,5-bis-[4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-phenoxy]-pen
      tane (AMG-126737).
AB  - Emerging evidence suggests that mast cell tryptase is a therapeutic target for
      the treatment of asthma. The effects of this serine protease are associated with
      both pathophysiologic pulmonary responses and pathologic changes of the asthmatic
      airway. In this study, the tryptase inhibitor 1,5-bis-[4-[(3-carbamimidoyl
      benzenesulfonylamino)-methyl]-p henoxy]-pentane (AMG-126737) was evaluated for
      its pharmacologic effects against allergen-induced airway responses. AMG-126737
      is a potent inhibitor of human lung mast cell tryptase (Ki = 90 nM), with greater
      than 10- to 200-fold selectivity versus other serine proteases. Intratracheal
      administration of AMG-126737 inhibited the development of airway
      hyperresponsiveness in allergen-challenged guinea pigs with an ED50 of 0.015
      mg/kg. In addition, the compound exhibited oral activity in the guinea pig model.
      The in vivo activity of AMG-126737 was confirmed in a sheep model of allergen
      induced airway responses, where the compound inhibited early and late phase
      bronchoconstriction responses and the development of airway hyperresponsiveness.
      These results support the proposed role of tryptase in the pathology of asthma
      and suggest that AMG-126737 has potential therapeutic utility in this pulmonary
      disorder.

PMID- 10591156
TI  - EP4 receptor mediation of prostaglandin E2-stimulated mucus secretion by rabbit
      gastric epithelial cells.
AB  - Prostaglandin (PG) E receptors are divided into four subtypes (EP1-EP4). We
      investigated the EP receptor subtype involved in PGE2-stimulated mucus secretion
      by rabbit gastric epithelial cells. Northern blot analysis revealed that
      epithelial cells express EP3 and EP4 receptor mRNAs, but neither EP1 nor EP2
      receptor mRNAs were detected. PGE2, 11-deoxy-PGE1 (an EP3/EP4/EP2 agonist) and
      16,16-dimethyl-PGE2 (an EP3/EP2/EP4 agonist) concentration-dependently promoted
      mucus secretion. In contrast, 17-phenyl-PGE2 (an EP3/EP1 agonist), sulprostone
      (an EP3/EP1 agonist), and butaprost (an EP2 agonist) failed to stimulate
      secretion. The effective concentrations of PGE2, 11-deoxy-PGE1, and 16,16
      dimethyl-PGE2 were associated with their affinities for the EP4 receptor. In
      addition, PGE2, 11-deoxy-PGE1, and 16,16-dimethyl-PGE2 increased cyclic AMP
      (cAMP) production, but the other prostanoids had no effect. SQ22536 [9
      (tetrahydro-2'-furyl)adenine; an adenylate cyclase inhibitor] inhibited both the
      increased cAMP production and mucus secretion induced by PGE2, 11-deoxy-PGE1, and
      16,16-dimethyl-PGE2. H-89 (N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinoline
      sulfonamide; a protein kinase A inhibitor) also abolished the stimulatory effects
      of the prostanoids on mucus secretion, but calphostin C (a protein kinase C
      inhibitor) did not. These results indicate that PGE2 promotes mucus secretion by
      rabbit gastric epithelial cells, mediated through EP4 receptor stimulation and
      the subsequent activation of protein kinase A.

PMID- 10591157
TI  - Reflections at the end of the millennium.

PMID- 10591158
TI  - Molecular typing methods for Neisseria meningitidis.
AB  - Neisseria meningitidis is an important pathogen because it causes life
      threatening infections. The rapid course of meningococcal disease and the
      capacity of some serogroups to cause large-scale epidemics necessitates the use
      of sensitive, reliable and rapid typing methods to characterise strains.
      Molecular typing techniques for N. meningitidis are used for epidemiological
      purposes to investigate outbreaks and the spread of organisms and to examine the
      population genetic structure of the organism to understand better its variation
      and evolution. Many investigators have employed molecular typing methods and
      shown that meningococcal disease is associated with a variety of different
      epidemiological patterns. The choice of a typing method is dependent upon the
      epidemiological questions to be answered and on the population genetics of the
      organism under investigation. With highly clonal populations comprising
      independent non-recombining lineages such as serogroup A meningococci,
      ribotyping, multilocus enzyme electrophoresis (MLEE), pulsed-field gel
      electrophoresis (PFGE), multilocus sequence typing (MLST), PCR with arbitrary
      primers (RAPD) or with other gene-based primers each provides a constant measure
      of the relationship between strains. A more restricted portfolio of molecular
      methods - PFGE, MLEE and MLST - is appropriate for the investigation of less
      clonal serogroup B and C meningococci from localised outbreaks. If a thorough
      evaluation of the overall population is sought to determine the relationship
      between new isolates and members of hyper-endemic clonal complexes then
      quantitative methods such as MLEE and MLST are necessary. Several PCR-based
      methods are used for the detection and typing of meningococcal strains, many
      requiring rigorous standardisation before they can be considered suitable for
      rapid and reliable differentiation between clones. This review examines strain
      characterisation by molecular techniques and non-culture-based subtyping of
      meningococci in clinical specimens. It assesses the importance of these
      techniques and examines the epidemiological questions that they answer and also
      their limitations.

PMID- 10591159
TI  - Differential secretion of interleukin-12 (IL-12) subunits and heterodimeric IL
      12p70 protein by CD-1 mice and murine macrophages in response to intracellular
      infection by Brucella abortus.
AB  - The secretion of interleukin-12 (IL-12) following intracellular infection with
      virulent Brucella abortus strain 2308 was investigated in CD-1 mice and in CD-1
      cultured peritoneal macrophages. Bioactive IL-12p70 and free non-immunoactive p40
      subunits (IL-12p40) were determined by enzyme-linked immunosorbent assays. In CD
      1 mice, B. abortus 2308 was a potent inducer of IL-12p40 (maximum levels were 5.9
      and 3.4 ng/ml in sera and spleen homogenates, respectively). Secretion of IL
      12p70 was also demonstrated in vivo, although at much lower levels (216.6 and
      198.9 pg/ml in sera and spleen homogenates, respectively). Production of IL-12
      over the first 7 days after infection was accompanied by active multiplication of
      B. abortus in the spleens of infected mice. CD-1 cultured peritoneal macrophages
      secreted only IL-12p40 (878.4 pg/10(7) macrophages) in response to B. abortus
      infection and no production of IL-12p70 was observed. In contrast, CD-1
      peritoneal macrophages secreted detectable amounts of IL-12p70 (16.2 pg/10(7)
      macrophages) in response to purified lipopolysaccharide (S-LPS) from B. abortus
      2308. The macrophages also secreted significant amounts of interferon-gamma (IFN
      gamma) (520.1 pg/10(7) macrophages) in response to intracellular B. abortus.
      These results indicate that B. abortus 2308 is not a potent inducer of IL-12p70
      production, whereas purified S-LPS from B. abortus 2308 induces the secretion of
      this bioactive form of IL-12 in cultured peritoneal macrophages. CD-1 peritoneal
      macrophages were able to secrete IFN-gamma, as well as high amounts of IL-12p40,
      in response to intracellular infection by B. abortus.

PMID- 10591160
TI  - Sex differences in antibody- and cell-mediated immune response to rubella re
      immunisation.
AB  - Antibody (AMI) and cell-mediated (CMI) immunity to rubella virus (RV) were
      evaluated in healthy adolescent males (n = 11) and females (n = 28) undergoing
      routine reimmunisation with RA27/3 strain RV as a component of measles-mumps
      rubella (MMR) vaccine. Blood samples were collected just before and at 2, 4 and
      10 weeks after MMR. While there were no sex differences before MMR and at week 10
      after vaccination, levels of specific IgG determined by whole RV enzyme
      immunoassay were found to be significantly higher in males at weeks 2 and 4,
      suggesting brisker onset of recall AMI. Analysis of RV protein-specific IgG by
      immunoblot assays also revealed that while there were no notable sex differences
      in the distribution of E1-specific antibodies, more males produced E2-specific
      antibodies whereas more females produced C-specific antibodies after
      immunisation. Analysis of CMI with whole inactivated RV and a panel of RV
      synthetic peptides in lymphocyte proliferation assays revealed a brisker onset of
      CMI in males which paralleled that observed for AMI. The numbers of RV antigens
      recognised by males were significantly higher at weeks 2 and 4. Also, mean and
      median stimulation indices measured at weeks 2 and 4 for certain peptides,
      including two known to contain overlapping antibody neutralisation domains and T
      cell epitopes, E1(213-239) and E1(254-285), were also found to be significantly
      higher in male subjects. These observations suggest that there are hormonal
      influences on RV-specific immunity which might result in differential handling of
      RV and, hence, may partially explain why females are more predisposed to adverse
      outcomes of rubella infection and immunisation.

PMID- 10591161
TI  - Induction of a specific antibody response to Bordetella pertussis antigens in
      cultures of human peripheral blood mononuclear cells.
AB  - The role of specific antibodies in protective immunity to Bordetella pertussis
      has not yet been clearly defined. In the present work, the induction of a
      specific antibody response to B. pertussis in cultures of human peripheral blood
      mononuclear cells (PBMC) was investigated, on the assumption that the capacity of
      circulating lymphocytes to mount a specific response in vitro may provide a
      useful parameter for the evaluation of protective immunity. When PBMC from normal
      adult donors were cultured with a heat-inactivated B. pertussis whole-cell
      suspension, cells secreting antibodies to pertussis toxin, pertactin and
      filamentous haemagglutinin were generated consistently. The antibody response
      peaked between days 7 and 11 of culture and the antibodies produced were
      exclusively of the IgM class.

PMID- 10591162
TI  - In-vivo itraconazole resistance of Aspergillus fumigatus in systemic murine
      aspergillosis. EBGA Network. European research group on Biotypes and Genotypes of
      Aspergillus fumigatus.
AB  - An animal model of disseminated aspergillosis was used to test the in-vivo
      activity of itraconazole against four isolates of Aspergillus fumigatus. Two
      reference isolates of A. fumigatus known to be resistant to itraconazole in vitro
      and in vivo were used as control isolates, and two new isolates were tested under
      the same conditions. For each isolate MICs for itraconazole and amphotericin B
      were determined by an NCCLS-based method. Mice infected intravenously were
      treated either with itraconazole 100 mg/ kg/day or amphotericin B 4.5 mg/kg/day
      for 10 days. Amphotericin B showed good in-vivo activity against all four
      isolates. For one strain, which had a low in-vitro MIC for itraconazole, in-vivo
      therapy with itraconazole prolonged the survival of mice and reduced fungal
      burdens in organs compared with untreated controls. In mice infected with a
      strain with a high MIC of >16 mg/L, itraconazole neither prolonged survival nor
      reduced fungal load in organs compared with controls. It is concluded that there
      is a relationship between MIC and treatment outcome in mice for A. fumigatus
      infection.

PMID- 10591163
TI  - Acute susceptibility of aged mice to infection with Candida albicans.
AB  - The effect of aging on host resistance to systemic candidosis was assessed by
      monitoring the course of infection in 16-month-old CBA/CaH mice (aged non-immune)
      and in a comparable group that had been infected with a sublethal dose of Candida
      albicans at 6 weeks of age (aged immune). Aged non-immune mice showed rapid
      progression of the disease, with a marked increase in the number of mycelia in
      the brain and kidney, and early morbidity. Foci of myocardial necrosis were
      evident, but inflammatory cells were sparse. The histological picture in the aged
      immune mice was similar to that in the aged non-immune group, although fewer
      mycelial aggregates were seen. Both groups of aged mice showed a significantly
      lower fungal burden in the brain on day 1 of infection, but on day 4, colony
      counts increased significantly in the aged non-immune mice. Comparison of
      cytokine gene expression in the infected brains showed that the relative amount
      of interferon-gamma and tumour necrosis factor-alpha cDNA were similar in all
      three groups. Interleukin-6 was elevated in both infected non-immune and
      uninfected aged mice. Aged immune mice showed no morbidity after challenge, and
      both colonisation and tissue damage were reduced in comparison with the aged non
      immune animals.

PMID- 10591164
TI  - Relationship between mutations in parC and gyrA of clinical isolates of
      Streptococcus pneumoniae and resistance to ciprofloxacin and grepafloxacin.
AB  - The mechanisms of resistance to ciprofloxacin and grepafloxacin were studied in
      54 clinical isolates of Streptococcus pneumoniae. Restriction fragment length
      polymorphism analysis following HinfI digestion was used with DNA sequencing to
      identify mutations in the quinolone resistance-determining regions (QRDRs) of the
      parC and gyrA genes. Ciprofloxacin MICs up to 16 mg/L were not associated with
      mutations to these genes in approximately half of the isolates. In other
      isolates, moderate levels of ciprofloxacin resistance (MIC 8-16mg/L) were
      associated with an alteration of ParC, most commonly entailing replacement of
      serine-79 by phenylalanine. High-level ciprofloxacin resistance (MIC 32-128 mg/L)
      entailed the additional mutation of GyrA with substitution of serine-83 by
      phenylalanine. Grepafloxacin MICs >4 mg/L were associated with this GyrA mutation
      alone; no relationship was detected between grepafloxacin MICs and mutation of
      the QRDR of parC.

PMID- 10591165
TI  - High incidence of penicillin resistance amongst clinical isolates of
      Streptococcus pneumoniae in northern Palestine.
AB  - One hundred and thirteen consecutive isolates of Streptococcus pneumoniae were
      collected in Nablus, Palestine between March and Aug. 1997 from children with
      acute lower respiratory tract infections. Resistance rates were: penicillin 88%,
      cefuroxime 85%, erythromycin 63%, tetracycline 45%, chloramphenicol 27% and
      ofloxacin 2%. Resistances to erythromycin and cefuroxime were significantly
      associated with penicillin resistance. Ofloxacin may be useful against
      pneumococci resistant to traditional antimicrobial agents. Factors associated
      with penicillin resistance included hospitalisation and previous use of beta
      lactam antibiotics.

PMID- 10591166
TI  - A comparison of blood agar supplemented with NAD with plain blood agar and
      chocolated blood agar in the isolation of Streptococcus pneumoniae and
      Haemophilus influenzae from sputum. Bacterial Methods Evaluation Group.
AB  - Streptococcus pneumoniae grows well and generally exhibits typical morphology on
      Columbia blood agar, whereas Haemophilus influenzae requires a more complex
      medium to meet its growth requirements - usually chocolated blood agar - on which
      S. pneumoniae is less easily recognisable. Therefore, a single medium that
      produces typical morphology of S. pneumoniae and facilitates the growth of H.
      influenzae would have considerable potential advantages. It has been claimed that
      blood agar supplemented with nicotinamide adenine dinucleotide (NAD) is such a
      medium. However, despite its routine use in several large diagnostic laboratories
      its performance has never been properly evaluated. In the present study, 1724
      sputum samples were examined in four laboratories. The isolation rates of H.
      influenzae and S. pneumoniae on NAD-supplemented blood agar (SBA) were compared
      with those on a two-plate combination of plain blood (BA) and chocolated blood
      agar (CBA). The two-plate combination performed significantly better for both
      organisms; isolation rates for H. influenzae were increased from 8.16% on SBA to
      11.07% on BA plus CBA and for S. pneumoniae from 4.18% to 4.68%. Isolation rates
      were also compared after incubation for 24 and 48 h. With the two-plate
      combination, isolation rates for H. influenzae and S. pneumoniae were increased
      by 0.98% and 0.16%, respectively, and for SBA by 0.57% and 0.32% after 48 h.
      However, despite this increase, SBA still performed less well than the two-plate
      combination.

PMID- 10591167
TI  - Demonstration by a nested PCR for Mycoplasma pneumoniae that M. pneumoniae load
      in the throat is higher in patients hospitalised for M. pneumoniae infection than
      in non-hospitalised subjects.
AB  - A nested PCR protocol to detect Mycoplasma pneumoniae DNA in throat specimens was
      developed. An amplification control (AC) template, which is amplified by the same
      primers as the M. pneumoniae target sequence, was constructed. The assay allowed
      highly specific and sensitive detection of M. pneumoniae DNA. In all, 305 throat
      samples, 62 from hospitalised patients and 243 from non-hospitalised subjects,
      were analysed by the nested PCR. Inhibition of the PCR was observed in 20% of the
      samples, but was abolished after a 1 in 10 dilution. Throat samples from 5 (8%)
      of the hospitalised patients and from 7 (3%) of the non-hospitalised subjects
      were positive for M. pneumoniae DNA. To investigate the relationship between M.
      pneumoniae load and the severity of disease, the M. pneumoniae load in 10 throat
      samples from M. pneumoniae-positive subjects was assessed semi-quantitatively by
      application of the nested PCR to a series of limiting dilutions of nucleic acid
      extracted from these throat samples. The calculated M. pneumoniae load varied
      from 20 to 3830 cfu/ml of throat sample. The mean M. pneumoniae load in samples
      from the hospitalised patients was significantly higher than that in samples from
      the non-hospitalised subjects. The nested PCR is a useful tool to detect M.
      pneumoniae DNA in the throat and to study the relationship between the load of M.
      pneumoniae in throat samples and severity of disease due to M. pneumoniae
      infection.

PMID- 10591168
TI  - A novel serotype of enteropathogenic Escherichia coli (EPEC) as a major pathogen
      in an outbreak of infantile diarrhoea.
AB  - An outbreak of infantile diarrhoea was investigated in 32 children, all <2 years
      old, in the tropical north of Australia. Rotavirus (63%) and enteropathogenic
      Escherichia coli (EPEC) (59%) were the most common pathogens identified. Of the
      19 EPEC isolates, 14 (74%) were of serotype O126:H12, hitherto unreported as an
      EPEC serotype. Other pathogens isolated included Salmonella spp. (16%),
      Campylobacter spp. (3%), Giardia (3%) and Shigella spp. (3%). EPEC-related gastro
      enteritis is an uncommon but recognised cause of diarrhoeal outbreaks in
      Australia and clinicians need to be aware of the possibility of this serotype
      being implicated. This report highlights the disadvantages of relying on
      serotyping alone for the recognition of EPEC.

PMID- 10591169
TI  - Proposed new bacterial taxa and proposed changes of bacterial names published
      during 1998 and considered to be of interest to medical or veterinary
      bacteriology.

PMID- 10591170
TI  - Selective isolation and oligotrophic growth of Candida on nutrient-free silica
      gel medium.

PMID- 10591171
TI  - Interdependence of histamine and methylhistamine kinetics: modelling and
      simulation approach.
AB  - In the article a model of histamine kinetics is described. A motivation of this
      project was to investigate the hypothesis that methylhistamine may be a marker of
      histamine appearance in plasma. A model has been made to support the hypothesis.
      Since metabolic and transport pathways of histamine and methylhistamine are
      complex and not very well known, the relationship between histamine and
      methylhistamine should be elucidated by mathematical modelling. From experimental
      data and the information in the literature, a nonlinear and time-varying four
      compartment model is proposed. Extensive release of histamine from mast cells
      when methylhistamine is injected, is modelled as histamine to methylhistamine
      ratio control loop.

PMID- 10591172
TI  - Microcomputer-based technique for 3-D reconstruction and volume measurement of
      computed tomographic images. Comparison of geometric and planimetry post
      operative tumor volume effects on patient survival.
AB  - The relationship between brain tumor size and survival has been studied since the
      advent of CT and magnetic resonance imaging (MRI), however, all published studies
      are based on tumor sizes measured by the less accurate geometric method, with
      results that are inconsistent. For example, the influence of the extent of tumor
      resection on patient survival has been debated. Jelsma and Bucy advocated
      extensive resection based on their analysis of patients with glioblastoma
      multiforme, however, Green et al. produced conflicting results, showing that the
      extent of resection was not statistically significant when all variables were
      considered simultaneously. The present study investigates whether or not the
      study inconsistency is largely due to the use of the less accurate geometric
      tumor volume measurement. The study demonstrates that the geometric tumor volume
      and the planimetry tumor volume have significantly different prognostic effects.

PMID- 10591173
TI  - Determining the Hurst exponent of fractal time series and its application to
      electrocardiographic analysis.
AB  - An alternative regression-based method for estimating the Hurst coefficient of a
      fractal time series is proposed. A formal mathematical description of the
      methodology is presented. The geometric relationship of the algorithm to the
      family of self-similar fractal curves is outlined. The computational structure of
      the algorithm is optimal for generation of real-time estimates of H. We show that
      the method can be applied to biologically-derived time series such as the cardiac
      interbeat interval and we obtain estimates of H from several diverse
      electrocardiographic data sets.

PMID- 10591174
TI  - Estimating medical resources required following a nuclear event.
AB  - Large quantities of medical resources are necessary for the treatment of patients
      suffering from acute radiation syndrome in combination with blast and thermal
      injuries (combined injuries). So far, however, there is no tool available for
      evaluating the resources required for the treatment of combined injuries. The
      purpose of this manuscript is to describe the scientific basis for a newly
      developed software tool designed to estimate the medical resources needed for
      treating the combined injuries of individuals/high numbers of casualties who may
      be involved in civil defense, emergency medical care and various military
      activities (namely out of area) in the case of a nuclear event.

PMID- 10591175
TI  - Cytokines, chaos, and complexity.

PMID- 10591176
TI  - Toxic MHC class II beta chains.

PMID- 10591177
TI  - Transcriptional regulation of the murine 3' IgH enhancer by OCT-2.
AB  - Targeted disruption of either of the B cell-specific transcription factors Oct-2
      or OCA-B/BOB-1/OBF-1 dramatically affects B cell terminal differentiation. The 3'
      enhancer of immunoglobulin heavy chain (IgH) locus is important for transcription
      of the locus in terminal plasma cells. Allele-specific suppression of mutant Oct
      2 binding sites in this enhancer by a variant Oct-2 protein revealed that in a
      mature B cell line this enhancer was specifically dependent upon Oct-2, as
      contrasted to the closely related Oct-1 transcription factor. Phosphorylation of
      the Oct-2 protein was important for this activation and was synergistic for
      coactivation by the OCA-B factor. These results indicate that Oct-2 and OCA-B
      interact with the 3' enhancer in regulation of the IgH locus during B cell
      activation.

PMID- 10591178
TI  - A negative regulatory role for Ig-alpha during B cell development.
AB  - The development of B cells requires the expression of an antigen receptor at
      distinct points during maturation. The Ig-alpha/beta heterodimer signals for
      these receptors, and mice harboring a truncation of the Ig-alpha intracellular
      domain (mb-1(delta(c)/delta(c)) have severely reduced peripheral B cell numbers.
      Here we report that immature mb-1(delta(c)/delta(c) B cells are activated despite
      lacking a critical Ig-alpha-positive signaling motif. As a consequence of
      abnormal activation, transitional immature IgMhighIgDlow B cells are largely
      absent in mb-1delta(c)/delta(c) mutants, accounting for the paucity of mature B
      cells. Thus, Ig-alpha cytoplasmic tail truncation yields an antigen receptor
      complex on immature B cells that signals constitutively. These data illustrate a
      role for Ig-alpha in negatively regulating antigen receptor signaling during B
      cell development.

PMID- 10591179
TI  - Ig-alpha cytoplasmic truncation renders immature B cells more sensitive to
      antigen contact.
AB  - To study the function of Ig-alpha in the selection of autoreactive B cells, we
      have analyzed mb-1 cytoplasmic truncation mutant mice (mb-1delta(c)/delta(c)),
      which coexpress transgenes encoding hen egg lysozyme (HEL) and HEL-specific
      immunoglobulin. We demonstrate that in the presence of soluble HEL (sHEL) and
      dependent on the mb-1delta(c) mutation, most immature B cells bearing the HEL
      specific Ig transgene undergo rearrangements of endogenous kappa light chains,
      resulting in loss of HEL specificity. Moreover, immature B cells from Ig-alpha
      mutant mice respond to BCR cross-linking with an exaggerated and prolonged
      calcium response and induction of protein tyrosine phosphorylation. Our data
      imply a negative signaling role for Ig-alpha in immature B cells.

PMID- 10591180
TI  - Abnormal development and function of B lymphocytes in mice deficient for the
      signaling adaptor protein SLP-65.
AB  - During signal transduction through the B cell antigen receptor (BCR), several
      signaling elements are brought together by the adaptor protein SLP-65. We have
      investigated the role of SLP-65 in B cell maturation and function in mice
      deficient for SLP-65. While the mice are viable, B cell development is affected
      at several stages. SLP-65-deficient mice show increased proportions of pre-B
      cells in the bone marrow and immature B cells in peripheral lymphoid organs. B1 B
      cells are lacking. The mice show lower IgM and IgG3 serum titers and poor IgM but
      normal IgG immune responses. Mutant B cells show reduced Ca2+ mobilization and
      reduced proliferative responses to B cell mitogens. We conclude that while
      playing an important role, SLP-65 is not always required for signaling from the
      BCR.

PMID- 10591181
TI  - Alpha4 integrins regulate the proliferation/differentiation balance of
      multilineage hematopoietic progenitors in vivo.
AB  - We investigated roles of alpha4 integrins during hematopoiesis using mutant and
      chimeric mice. Yolk sac erythropoiesis and migration of hematopoietic progenitors
      to fetal liver, spleen, and bone marrow can occur without alpha4 integrins.
      Although terminal differentiation of these progenitors is possible without alpha4
      integrins, these receptors are essential to maintain normal hematopoiesis in
      fetal liver, spleen, and bone marrow microenvironments. Moreover, alpha4
      deficient erythroid progenitors and pre-B cells neither transmigrate beneath the
      stroma nor expand-properly in vitro. In contrast, alpha4-null cells migrate and
      differentiate efficiently into T lymphocytes within the thymus. In summary,
      alpha4 integrins are essential for normal development of all hematopoietic
      lineages in fetal liver, bone marrow, and spleen, likely by regulating the
      proliferation/differentiation balance of hematopoietic progenitors.

PMID- 10591182
TI  - Identification of podocalyxin-like protein 1 as a novel cell surface marker for
      hemangioblasts in the murine aorta-gonad-mesonephros region.
AB  - Recent studies with avian embryos and murine embryonic stem cells have suggested
      that hematopoietic cells are derived from hemangioblasts, the common precursors
      of hematopoietic and endothelial cells. We molecularly cloned podocalyxin-like
      protein 1 (PCLP1) as a novel surface marker for endothelial-like cells in the
      aorta-gonad-mesonephros (AGM) region of mouse embryos, where long-term
      repopulating hematopoietic stem cells (LTR-HSCs) are known to arise. PCLP1+ CD45
      cells in the AGM region incorporated acetylated low-density lipoprotein and
      produced both hematopoietic and endothelial cells when cocultured with OP9
      stromal cells. Moreover, multiple lineages of hematopoietic cells were generated
      in vivo when PCLP1 +CD45-cells were injected into neonatal liver of busulfan
      treated mice. Thus, PCLP1 can be used to separate hemangioblasts that give rise
      to LTR-HSCs.

PMID- 10591183
TI  - CD8+TCR+ and CD8+TCR- cells in whole bone marrow facilitate the engraftment of
      hematopoietic stem cells across allogeneic barriers.
AB  - Although purified hematopoietic stem cells (HSC) are sufficient to engraft
      irradiated allogeneic recipients, bone marrow (BM) contains other cells that
      facilitate engraftment. Here, several candidate facilitators were tested by
      cotransplantation with HSC. Both TCR+ and TCR- CD8alpha+ BM subpopulations have
      facilitative potential. CD8+TCR+ cells are typical T lymphocytes. CD8+TCR-
      facilitators are CD3 , not CD3+, have a granular morphology, and are CD8beta- and
      CD11c+; they share phenotypic characteristics with CD8(alpha)alpha lymphoid
      dendritic cells and veto cells. We also demonstrate that lytic function is nqt
      necessary for facilitation and that the CD8alpha molecule is either important for
      facilitation or in the development of facilitators.

PMID- 10591184
TI  - Interaction of the NK cell inhibitory receptor Ly49A with H-2Dd: identification
      of a site distinct from the TCR site.
AB  - Natural killer cell function is controlled by interaction of NK receptors with
      MHC I molecules expressed on target cells. We describe the binding of bacterially
      expressed Ly49A, the prototype murine NK inhibitory receptor, to similarly
      engineered H-2Dd. Despite its homology to C-type lectins, Ly49A binds
      independently of carbohydrate and Ca2+ and shows specificity for MHC I but not
      bound peptide. The affinity of the Ly49A/H-2Dd interaction as determined by
      surface plasmon resonance is from 6 to 26 microM at 25 degrees C and is greater
      by ultracentrifugation at 4 degrees C. Biotinylated Ly49A stains H-2Dd-expressing
      cells. Competition experiments indicate that the Ly49A and T cell receptor (TCR)
      binding sites on MHC I are distinct, suggesting complex regulation of cells that
      bear both TCR and NK cell receptors.

PMID- 10591185
TI  - The inhibitory receptor LIR-1 uses a common binding interaction to recognize
      class I MHC molecules and the viral homolog UL18.
AB  - LIR-1 is a class I MHC receptor related to natural killer inhibitory receptors
      (KIRs). Binding of LIR-1 or KIRs to class I molecules results in inhibitory
      signals. Unlike individual KIRs, LIR-1 recognizes many class I alleles and also
      binds UL18, a human cytomegalovirus class I MHC homolog. Here, we show that LIR-1
      interacts with the relatively nonpolymorphic alpha3 domain of class I proteins
      and the analogous region of UL18 using its N-terminal immunoglobulin-like domain.
      The >1000-fold higher affinity of LIR-1 for UL18 than for class I illustrates how
      a viral protein competes with host proteins to subvert the host immune response.
      LIR-1 recognition of class I molecules resembles the CD4-class II MHC interaction
      more than the KIR-class I interaction, implying a functional distinction between
      LIR-1 and KIRs.

PMID- 10591186
TI  - Physical and functional association of LFA-1 with DNAM-1 adhesion molecule.
AB  - Whereas ligation of the DNAM-1 adhesion molecule triggers cytotoxicity mediated
      by normal NK and T cells, this function was defective in NK cell clones from
      leukocyte adhesion deficiency syndrome. However, genetic reconstitution of cell
      surface expression of LFA-1 restored the ability of DNAM-1 to initiate anti-DNAM
      1 mAb-induced cytotoxicity, indicating a functional relationship between DNAM-1
      and LFA-1. Further studies demonstrated that LFA-1 physically associates with
      DNAM-1 in NK cells and anti-CD3 mAb stimulated T cells, for which serine
      phosphorylation of DNAM-1 plays a critical role. In addition, cross-linking of
      LFA-1 induces tyrosine phosphorylation of DNAM-1, for which the Fyn protein
      tyrosine kinase is responsible. These results indicate that DNAM-1 is involved in
      the LFA-1-mediated intracellular signals.

PMID- 10591187
TI  - Dendritic cells require T cells for functional maturation in vivo.
AB  - We examined dendritic cell (DC) status in SCID and RAG2 -/- mice to assess the
      influence of T cells on DC development and function in vivo. These mice have
      reduced numbers of DC in the epidermis and lymph nodes draining hapten-sensitized
      skin. Epidermal DC in these mice were defective in presenting antigen in vivo to
      adoptively transferred, hapten-sensitized T cells from normal mice. Likewise,
      draining lymph node DC were deficient in their capacity to stimulate naive T
      cells in vitro and in vivo. DC numbers as well as the impaired ability to present
      antigen in vivo, were corrected by reconstituting these animals with normal T
      lymphocytes, suggesting that T cells are crucial for normal DC maturation and
      function in vivo.

PMID- 10591188
TI  - Paralysis of dendritic cell IL-12 production by microbial products prevents
      infection-induced immunopathology.
AB  - Interleukin-12 plays a major role in immunity to intracellular pathogens by
      governing the development of IFNgamma-dependent host resistance. Nevertheless,
      unregulated IL-12 synthesis can lead to immunopathology, an outcome prevented by
      the concurrent expression of interleukin-10. Dendritic cells (DC) are an
      important source of the initial IL-12 stimulated by microbial agents. Here, we
      show that, following systemic triggering, DC can no longer be restimulated to
      produce IL-12 in vivo while continuing to respond in vitro. When infected with
      Toxoplasma gondii during this refractory state, mice mount impaired acute
      IFNgamma responses and, in the case of IL-10-deficient animals, are protected
      from cytokine-induced mortality. These findings demonstrate a previously
      unrecognized form of immunologic paralysis involving DC that can protect from
      infection-induced immunopathology.

PMID- 10591189
TI  - Human chromosome 22 and the virtues of collaboration.

PMID- 10591190
TI  - 'Finishing' success marks major genome sequencing milestone...as researchers
      pounce on glut of data.

PMID- 10591191
TI  - Tiny chromosome is rich in genes and medical promise.

PMID- 10591192
TI  - Unfinished sequence--the catch on 22.

PMID- 10591193
TI  - EMBL rescue package keeps bioinformatics centre running. European Molecular
      Biology Laboratory.

PMID- 10591194
TI  - Nuclear safety and biotech boosted in Japan's budget.

PMID- 10591195
TI  - Opinion divided on images of Martian 'ocean'.

PMID- 10591196
TI  - EMBL pay settlement will cost millions. European Molecular Biology Laboratory.

PMID- 10591197
TI  - South Africa's health minister downplays AIDS drug concerns.

PMID- 10591198
TI  - This should not be the end for terminator technology in GM crops.

PMID- 10591199
TI  - Who's doing what in US protein initiative.

PMID- 10591200
TI  - The book of genes.

PMID- 10591201
TI  - Alzheimer's disease. A firm base for drug development.

PMID- 10591202
TI  - Derailed axons get on track.

PMID- 10591203
TI  - Hearing. Spreading the fluid word.

PMID- 10591204
TI  - Thomas Hughes Jukes (1906-99)

PMID- 10591205
TI  - Insecticidal toxin in root exudates from Bt corn.

PMID- 10591206
TI  - Germ cells colonized by endosymbiotic bacteria.

PMID- 10591207
TI  - Synexpression groups in eukaryotes.
AB  - In 1960, Jacob and Monod described the bacterial operon, a cluster of
      functionally interacting genes whose expression is tightly coordinated. Global
      expression analysis has shown that the highly coordinate expression of genes
      functioning in common processes is also a widespread phenomenon in eukaryotes.
      These sets of co-regulated genes, or 'synexpression groups', show a striking
      parallel to the operon, and may be a key determinant facilitating evolutionary
      change leading to animal diversity.

PMID- 10591208
TI  - The DNA sequence of human chromosome 22.
AB  - Knowledge of the complete genomic DNA sequence of an organism allows a systematic
      approach to defining its genetic components. The genomic sequence provides access
      to the complete structures of all genes, including those without known function,
      their control elements, and, by inference, the proteins they encode, as well as
      all other biologically important sequences. Furthermore, the sequence is a rich
      and permanent source of information for the design of further biological studies
      of the organism and for the study of evolution through cross-species sequence
      comparison. The power of this approach has been amply demonstrated by the
      determination of the sequences of a number of microbial and model organisms. The
      next step is to obtain the complete sequence of the entire human genome. Here we
      report the sequence of the euchromatic part of human chromosome 22. The sequence
      obtained consists of 12 contiguous segments spanning 33.4 megabases, contains at
      least 545 genes and 134 pseudogenes, and provides the first view of the complex
      chromosomal landscapes that will be found in the rest of the genome.

PMID- 10591209
TI  - The temporal requirement for endothelin receptor-B signalling during neural crest
      development.
AB  - Endothelin receptor B (EDNRB) is a G-protein-coupled receptor with seven
      transmembrane domains which is required for the development of melanocytes and
      enteric neurons. Mice that are homozygous for a null mutation in the Ednrb gene
      are almost completely white and die as juveniles from megacolon. To determine
      when EDNRB signalling is required during embryogenesis, we have exploited the
      tetracycline-inducible system to generate strains of mice in which the endogenous
      Ednrb locus is under the control of the tetracycline-dependant transactivators
      tTa or rtTA. By using this system to express Ednrb at different stages of
      embryogenesis, we have determined that EDNRB is required during a restricted
      period of neural crest development between embryonic days 10 and 12.5. Moreover,
      our results imply that EDNRB is required for the migration of both melanoblasts
      and enteric neuroblasts.

PMID- 10591210
TI  - Sympatric speciation by sexual selection.
AB  - There is increasing evidence for the process of sympatric speciation, in which
      reproductive isolation of species occurs without physical isolation. Theoretical
      models have focused on disruptive natural selection as the crucial pressure for
      splitting a species. Here we report the theoretical finding that sympatric
      speciation may be caused by sexual selection even without disruptive natural
      selection. Specifically, we show that variation in a male secondary sexual
      character with two conspicuous extremes and the corresponding variance in female
      mating preference around no preference may jointly evolve into bimodal
      distributions with increasing modal divergence of the male and female traits,
      pulling a population apart into two prezygotically isolated populations. This
      mode of speciation, driven by two runaway processes in different directions, is
      promoted by an increase in the efficiency of females in discriminating among
      males or a decrease in the cost of male conspicuousness, indicating that
      sympatric speciation may occur more readily if barrier-free or predator-free
      conditions arise. Although even a slight cost of female preference would cancel
      the runaway process of sexual selection, it would not cancel the divergent
      runaway processes of sympatric speciation.

PMID- 10591211
TI  - Direct measurement of intra-cochlear pressure waves.
AB  - The cochlear travelling wave is fundamental to the ability of the mammalian
      auditory system to resolve frequency. The seashell-shaped outer bone of the
      cochlea (the auditory inner ear) contains a spiral of cochlear fluid and the
      sensory tissue known as the cochlear partition. Sound travels down the ear canal
      to the eardrum, causing its flexible tympanic membrane to vibrate. This vibration
      is transmitted to the cochlea via the ossides. Motion of the stapes (the stirrup
      ossicle) sets the cochlear fluid in motion, which in turn sets the cochlear
      partition near the states in motion. The motion of the cochlear partition ripples
      down the cochlear spiral as a travelling wave, stimulating the cochlea's sensory
      hair cells. The wave peaks near the base (the stapes end) of the cochlea for high
      frequency tones and near the apex for low frequencies. The fundamental elements
      of the cochlear travelling wave are fluid pressure and motion and partition
      forces and motion. However, the wave's direct experimental study has to date
      relied almost solely on measurements of the partition motion. Here I report
      finely spaced measurements of intracochlear pressure close to the partition,
      which reveal the fluid component of the cochlear wave. The penetration depth of
      the wave is very limited, approximately 15 microm. Over a range of frequencies at
      least an octave wide, the depth is independent of frequency.

PMID- 10591212
TI  - Stable propagation of synchronous spiking in cortical neural networks.
AB  - The classical view of neural coding has emphasized the importance of information
      carried by the rate at which neurons discharge action potentials. More recent
      proposals that information may be carried by precise spike timing have been
      challenged by the assumption that these neurons operate in a noisy fashion-
      presumably reflecting fluctuations in synaptic input and, thus, incapable of
      transmitting signals with millisecond fidelity. Here we show that precisely
      synchronized action potentials can propagate within a model of cortical network
      activity that recapitulates many of the features of biological systems. An
      attractor, yielding a stable spiking precision in the (sub)millisecond range,
      governs the dynamics of synchronization. Our results indicate that a
      combinatorial neural code, based on rapid associations of groups of neurons co
      ordinating their activity at the single spike level, is possible within a
      cortical-like network.

PMID- 10591213
TI  - Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase
      activity.
AB  - Mutations in the gene encoding the amyloid protein precursor (APP) cause
      autosomal dominant Alzheimer's disease. Cleavage of APP by unidentified
      proteases, referred to as beta- and gamma-secretases, generates the amyloid beta
      peptide, the main component of the amyloid plaques found in Alzheimer's disease
      patients. The disease-causing mutations flank the protease cleavage sites in APP
      and facilitate its cleavage. Here we identify a new membrane-bound aspartyl
      protease (Asp2) with beta-secretase activity. The Asp2 gene is expressed widely
      in brain and other tissues. Decreasing the expression of Asp2 in cells reduces
      amyloid beta-peptide production and blocks the accumulation of the carboxy
      terminal APP fragment that is created by beta-secretase cleavage. Solubilized
      Asp2 protein cleaves a synthetic APP peptide substrate at the beta-secretase
      site, and the rate of cleavage is increased tenfold by a mutation associated with
      early-onset Alzheimer's disease in Sweden. Thus, Asp2 is a new protein target for
      drugs that are designed to block the production of amyloid beta-peptide peptide
      and the consequent formation of amyloid plaque in Alzheimer's disease.

PMID- 10591214
TI  - Purification and cloning of amyloid precursor protein beta-secretase from human
      brain.
AB  - Proteolytic processing of the amyloid precursor protein (APP) generates amyloid
      beta (Abeta) peptide, which is thought to be causal for the pathology and
      subsequent cognitive decline in Alzheimer's disease. Cleavage by beta-secretase
      at the amino terminus of the Abeta peptide sequence, between residues 671 and 672
      of APP, leads to the generation and extracellular release of beta-cleaved soluble
      APP, and a corresponding cell-associated carboxy-terminal fragment. Cleavage of
      the C-terminal fragment by gamma-secretase(s) leads to the formation of Abeta.
      The pathogenic mutation K670M671-->N670L671 at the beta-secretase cleavage site
      in APP, which was discovered in a Swedish family with familial Alzheimer's
      disease, leads to increased beta-secretase cleavage of the mutant substrate. Here
      we describe a membrane-bound enzyme activity that cleaves full-length APP at the
      beta-secretase cleavage site, and find it to be the predominant beta-cleavage
      activity in human brain. We have purified this enzyme activity to homogeneity
      from human brain using a new substrate analogue inhibitor of the enzyme activity,
      and show that the purified enzyme has all the properties predicted for beta
      secretase. Cloning and expression of the enzyme reveals that human brain beta
      secretase is a new membrane-bound aspartic proteinase.

PMID- 10591215
TI  - Axon routing across the midline controlled by the Drosophila Derailed receptor.
AB  - In nervous systems with symmetry about the midline, many neurons project axons
      from one side to the other. Although several of the components controlling
      midline crossing have been identified, little is known about how axons choose the
      appropriate pathway when crossing. For example, in the Drosophila embryo axons
      cross the midline in one of two distinct tracts, the anterior or posterior
      commissure (AC or PC, respec tively). Here we show that the Derailed (Drl)
      receptor tyrosine kinase is expressed by neurons that project in the AC, and that
      in the absence of Drl such neurons often project abnormally into the PC.
      Conversely, misexpression of Drl in PC neurons forces them to cross in the AC.
      The behaviour of Drl-misexpressing neurons and the in vivo binding pattern of a
      soluble Drl receptor probe indicate that Drl acts as a guidance receptor for a
      repellent ligand present in the PC. Our results show that Drl is a novel
      component in the control of midline crossing.

PMID- 10591216
TI  - Bazooka provides an apical cue for Inscuteable localization in Drosophila
      neuroblasts.
AB  - Asymmetric cell division generates daughter cells with different developmental
      fates from progenitor cells that contain localized determinants. During this
      division, the asymmetric localization of cell-fate determinants and the
      orientation of the mitotic spindle must be precisely coordinated. In Drosophila
      neuroblasts, inscuteable controls both spindle orientation and the asymmetric
      localization of the cell-fate determinants Prospero and Numb. Inscuteable itself
      is localized in an apical cortical crescent and thus reflects the intrinsic
      asymmetry of the neuroblast. Here we show that localization of Inscuteable
      depends on Bazooka, a protein containing three PDZ domains with overall sequence
      similarity to Par-3 of Caenorhabditis elegans. Bazooka and Inscuteable form a
      complex that also contains Staufen, a protein responsible for the asymmetric
      localization of prospero messenger RNA. We propose that, after delamination of
      the neuroblast from the neuroepithelium, Bazooka provides an asymmetric cue in
      the apical cytocortex that is required to anchor Inscuteable. As Bazooka is also
      responsible for the maintenance of apical-basal polarity in epithelial tissues,
      it may be the missing link between epithelial polarity and neuroblast polarity.

PMID- 10591217
TI  - Bazooka recruits Inscuteable to orient asymmetric cell divisions in Drosophila
      neuroblasts.
AB  - Asymmetric cell divisions can be generated by the segregation of determinants
      into one of the two daughter cells. In Drosophila, neuroblasts divide
      asymmetrically along the apical-basal axis shortly after their delamination from
      the neuroectodermal epithelium. Several proteins, including Numb and Miranda,
      segregate into the basal daughter cell and are needed for the determination of
      its correct cell fate. Both the apical-basal orientation of the mitotic spindle
      and the localization of Numb and Miranda to the basal cell cortex are directed by
      Inscuteable, a protein that localizes to the apical cell cortex before and during
      neuroblast mitosis. Here we show that the apical localizaton of Inscuteable
      requires Bazooka, a protein containing a PDZ domain that is essential for apical
      basal polarity in epithelial cells. Bazooka localizes with Inscuteable in
      neuroblasts and binds to the Inscuteable localization domain in vitro and in
      vivo. In embryos lacking both maternal and zygotic bazooka function, Inscuteable
      no longer localizes asymmetrically in neuroblasts and is instead uniformly
      distributed in the cytoplasm. Mitotic spindles in neuroblasts are misoriented in
      these embryos, and the proteins Numb and Miranda fail to localize asymmetrically
      in metaphase. Our results suggest that direct binding to Bazooka mediates the
      asymmetric localization of Inscuteable and connects the asymmetric division of
      neuroblasts to the axis of epithelial apical-basal polarity.

PMID- 10591218
TI  - A telomerase component is defective in the human disease dyskeratosis congenita.
AB  - The X-linked form of the human disease dyskeratosis congenita (DKC) is caused by
      mutations in the gene encoding dyskerin. Sufferers have defects in highly
      regenerative tissues such as skin and bone marrow, chromosome instability and a
      predisposition to develop certain types of malignancy. Dyskerin is a putative
      pseudouridine synthase, and it has been suggested that DKC may be caused by a
      defect in ribosomal RNA processing. Here we show that dyskerin is associated not
      only with H/ACA small nucleolar RNAs, but also with human telomerase RNA, which
      contains an H/ACA RNA motif. Telomerase adds simple sequence repeats to
      chromosome ends using an internal region of its RNA as a template, and is
      required for the indefinite proliferation of primary human cells. We find that
      primary fibroblasts and lymphoblasts from DKC-affected males are not detectably
      deficient in conventional H/ACA small nucleolar RNA accumulation or function;
      however, DKC cells have a lower level of telomerase RNA, produce lower levels of
      telomerase activity and have shorter telomeres than matched normal cells. The
      pathology of DKC is consistent with compromised telomerase function leading to a
      defect in telomere maintenance, which may limit the proliferative capacity of
      human somatic cells in epithelia and blood.

PMID- 10591219
TI  - The RCAF complex mediates chromatin assembly during DNA replication and repair.
AB  - Chromatin assembly is a fundamental biological process that is essential for the
      replication and maintenance of the eukaryotic genome. In dividing cells, newly
      synthesized DNA is rapidly assembled into chromatin by the deposition of a
      tetramer of the histone proteins H3 and H4, followed by the deposition of two
      dimers of histones H2A and H2B to complete the nucleosome-the fundamental
      repeating unit of chromatin. Here we describe the identification, purification,
      cloning, and characterization of replication-coupling assembly factor (RCAF), a
      novel protein complex that facilitates the assembly of nucleosomes onto newly
      replicated DNA in vitro. RCAF comprises the Drosophila homologue of anti
      silencing function 1 protein ASF1 and histones H3 and H4. The specific
      acetylation pattern of H3 and H4 in RCAF is identical to that of newly
      synthesized histones. Genetic analyses in Saccharomyces cerevisiae demonstrate
      that ASF1 is essential for normal cell cycle progression, and suggest that RCAF
      mediates chromatin assembly after DNA replication and the repair of double-strand
      DNA damage in vivo.

PMID- 10591220
TI  - Tales of the expected.

PMID- 10591221
TI  - How common are habitable planets?

PMID- 10591222
TI  - Genetics and general cognitive ability.
AB  - General cognitive ability (g), often referred to as 'general intelligence',
      predicts social outcomes such as educational and occupational levels far better
      than any other behavioural trait. g is one of the most heritable behavioural
      traits, and genes that contribute to the heritability of g will certainly be
      identified. What are the scientific and social implications of finding genes
      associated with g?

PMID- 10591223
TI  - The neurobiology of cognition.
AB  - Perhaps the deepest mysteries facing the natural sciences concern the higher
      functions of the central nervous system. Understanding how the brain gives rise
      to mental experiences looms as one of the central challenges for science in the
      new millennium.

PMID- 10591224
TI  - The future of evolutionary developmental biology.
AB  - Combining fields as diverse as comparative embryology, palaeontology, molecular
      phylogenetics and genome analysis, the new discipline of evolutionary
      developmental biology aims at explaining how developmental processes and
      mechanisms become modified during evolution, and how these modifications produce
      changes in animal morphology and body plans. In the next century this should give
      us far greater mechanistic insight into how evolution has produced the vast
      diversity of living organisms, past and present.

PMID- 10591225
TI  - From molecular to modular cell biology.
AB  - Cellular functions, such as signal transmission, are carried out by 'modules'
      made up of many species of interacting molecules. Understanding how modules work
      has depended on combining phenomenological analysis with molecular studies.
      General principles that govern the structure and behaviour of modules may be
      discovered with help from synthetic sciences such as engineering and computer
      science, from stronger interactions between experiment and theory in cell
      biology, and from an appreciation of evolutionary constraints.

PMID- 10591226
TI  - Feeding the world in the twenty-first century.
AB  - The gains in food production provided by the Green Revolution have reached their
      ceiling while world population continues to rise. To ensure that the world's
      poorest people do not still go hungry in the twenty-first century, advances in
      plant biotechnology must be deployed for their benefit by a strong public-sector
      agricultural research effort.

PMID- 10591227
TI  - The future of public health.
AB  - Public health deals with the health and well-being of the population as a whole
      and its achievements over the past century, especially in the richer countries,
      have been truly impressive. What direction should public health take in the
      future?

PMID- 10591228
TI  - Computing 2010: from black holes to biology.
AB  - By 2010, a click on the PC on your desktop will suffice to call up instantly all
      the computing power you need from what by then will be the world's largest
      supercomputer, the Internet itself. Supercomputing for the masses will trigger a
      revolution in the complexity of problems that are tackled, whole disciplines will
      go digital and, rather than spending time collecting their own data, scientists
      will organize themselves around shared data sets.

PMID- 10591229
TI  - Science's new social contract with society.
AB  - Under the prevailing contract between science and society, science has been
      expected to produce 'reliable' knowledge, provided merely that it communicates
      its discoveries to society. A new contract must now ensure that scientific
      knowledge is 'socially robust', and that its production is seen by society to be
      both transparent and participative.

PMID- 10591230
TI  - Plus ca change.
AB  - For the past couple of centuries the penchant for prediction has been prevalent
      at century turns. How much have evaluations of scientific discovery and
      predictions for future advancement changed since those of the science
      commentators at the end of the last century?

PMID- 10591231
TI  - Home visits by an occupational therapist for assessment and modification of
      environmental hazards: a randomized trial of falls prevention.
AB  - OBJECTIVE: To determine whether occupational therapist home visits targeted at
      environmental hazards reduce the risk of falls. DESIGN: A randomized controlled
      trial. SETTING: Private dwellings in the community in Sydney, Australia.
      PARTICIPANTS: A total of 530 subjects (mean age 77 years), recruited primarily
      before discharge from selected hospital wards. INTERVENTION: A home visit by an
      experienced occupational therapist, who assessed the home for environmental
      hazards and facilitated any necessary home modifications. MEASUREMENTS: The
      primary study outcome was falls, ascertained over a 12-month follow-up period
      using a monthly falls calendar. RESULTS: Thirty six percent of subjects in the
      intervention group had at least one fall during follow-up, compared with 45% of
      controls (P = .050). The intervention was effective only among subjects (n = 206)
      who reported having had one or more falls during the year before recruitment into
      the study; in this group, the relative risk of at least one fall during follow-up
      was 0.64 (95% confidence interval, 0.50-0.83). Similar results were obtained when
      falls data were analyzed using survival analysis techniques (proportional and
      multiplicative hazards models) and fall rates (mean number of falls per person
      per year). About 50% of the recommended home modifications were in place at a 12
      month follow-up visit. CONCLUSIONS: Home visits by occupational therapists can
      prevent falls among older people who are at increased risk of falling. However,
      the effect may not be caused by home modifications alone. Home visits by
      occupational therapists may also lead to changes in behavior that enable older
      people to live more safely in both the home and the external environment.

PMID- 10591232
TI  - The relationship between body composition and physical performance in older
      women.
AB  - BACKGROUND: The relationship between age-associated change in body composition
      and physical disability is still unknown. Skeletal muscle mass declines with age
      in both sexes; however, since women have less muscle mass per unit of weight than
      men, these changes may be more debilitating in women. OBJECTIVE: To evaluate the
      relationship between body composition and physical performance. DESIGN: A cross
      sectional study. PARTICIPANTS: 144 women aged 68 to 75 were selected randomly
      from the general population of Verona. MEASUREMENTS: Body composition was
      evaluated using dual energy X-ray absorptiometry and bioimpedance. Physical
      performance was evaluated using a modified version of the Activities of Daily
      Living scale. Distance walked in 6 minutes was calculated, and isometric knee
      strength was tested. RESULTS: Normal women had a significantly lower body mass
      index (BMI) and percent body fat. These women also had a higher ratio of body
      cell mass (BCM) and total fat free mass (FFM) than women with physical
      impairments. After adjusting for BMI, women in the lowest tertile of muscle
      strength had significantly lower BCM than those in the highest tertile.
      CONCLUSIONS: These cross-sectional data show that although muscle strength is
      related to fat-free mass, disability in older women is associated with heavier
      BMI and with a higher percentage of body fat.

PMID- 10591233
TI  - Weight, weight change, mortality in a random sample of older community-dwelling
      women.
AB  - OBJECTIVE: To evaluate the relationship between measured weight, weight change,
      and 6-year mortality risk in a random sample of 648 community-dwelling women aged
      65 and older from Baltimore, Maryland. MEASUREMENTS: Data were collected using a
      standardized questionnaire and administered in person by trained interviewers.
      Questionnaires were completed annually from 1984 to 1986, and body weight was
      measured at each interview. Weight was defined as body mass index (BMI) of low (<
      23 kg/m2), average (> or = 23 kg/m2 to < or = 28 kg/m2), and high (> 28 kg/m2).
      Four mutually exclusive categories of weight change of at least 4.5% in BMI over
      the three annual interviews were developed to describe all possible weight change
      patterns: weight gain, weight loss, no change, and weight cycling. RESULTS:
      During the follow-up period, 106 women (16%) died. Women with low baseline BMI,
      regardless of weight change, and those who lost weight, regardless of baseline
      BMI had increased mortality risk. Women with average baseline BMI and weight loss
      had a very high mortality risk (hazard ratio (HR) 3.84, 95% Confidence interval
      (CI) 2.14-6.89). Women who weight cycled had increased mortality risk at low and
      high baseline weights, and a nonsignificant increased risk at average baseline
      weight (P = .069). Analyses were adjusted for age, education, smoking, alcohol
      usage, and pre-existing illness and included an interaction between weight change
      and baseline BMI. CONCLUSIONS: These results suggest that white, older, community
      dwelling women are at an increased risk of mortality if they are underweight,
      lose weight, or weight cycle.

PMID- 10591234
TI  - A U-shaped association between home systolic blood pressure and four-year
      mortality in community-dwelling older men.
AB  - BACKGROUND: Several studies in older people have found a U-shaped or J-shaped
      association of blood pressure with mortality. The increased mortality associated
      with the lowest levels of blood pressure in older people have been explained by
      concurrent illnesses and frailty, but previous studies used blood pressure
      measured on a single occasion. Such a casual value is different from the long
      term average of blood pressure. We investigated the relation between the average
      level of 5-day consecutive home blood pressure and mortality in older people
      while adjusting for potential confounding factors including morbidity and frailty
      at baseline. METHODS: In 1992, 1186 community residents of a rural Japanese town,
      Kahoku, aged 65 or older, measured their blood pressure in their homes 20 times
      (four times per day, 5 consecutive days). The mean value of the 20 measurements
      was used to examine the association between home BP and subsequent 4-year
      mortality. A proportional hazards model was fitted while adjusting for activities
      of daily living impairment, medical history, antihypertensive medication,
      smoking, use of alcohol, and depression. RESULTS: A total of 134 persons died
      during the four-year follow-up period. There was no significant evidence that
      frailty is more prevalent in the lowest or highest systolic BP group than in
      intermediate groups. A U-shaped association between the average level of home
      systolic blood pressure and mortality was found in men while adjusting for
      potential confounding factors, including morbidity and frailty. We also showed
      the U-shaped curve of the association of systolic BP with all cause and
      noncardiovascular mortality in the whole population and the linear association of
      systolic BP with cardiovascular mortality. CONCLUSIONS: We showed a U-shaped
      association between the average level of systolic blood pressure measured at home
      and mortality in older men while adjusting for potential confounding factors
      including morbidity and frailty. Not only high home systolic BP, but also low
      home systolic BP, is an independent risk factor for mortality in older men. The
      mechanisms underlying the association between BP and mortality differ by levels
      of systolic BP. Cardiovascular deaths tended to be higher in the highest SBP
      group, and only noncardiovascular deaths were increased in the lowest SBP group.
      The latter finding suggests that low SBP may be not only an independent risk of
      mortality but also an indicator of a subclinical noncardiovascular comorbid
      condition.

PMID- 10591236
TI  - Use of prescribed drugs among older people in Japan: association with not having
      a regular physician.
AB  - OBJECTIVES: Minimizing the overuse of prescribed drugs among older people is a
      goal of geriatricians and healthcare policy makers. Indirect evidence indicates
      that use of prescribed drugs is more common in Japan than in some Western
      countries, but the actual situation in Japan is unknown. The first aim of this
      study was to clarify the use of prescribed drugs among older people in Japan. We
      also tested the hypothesis that using five or more prescribed drugs is associated
      with a situation that is modifiable and is relatively common in Japan: not having
      a regular physician. DESIGN: A cross-sectional survey. PARTICIPANTS: Subjects
      representing the Japanese general population aged 65 years and older were
      selected by two-stage stratified sampling; 617 persons were eligible for the
      study. MEASUREMENTS: Each subject was given a self-report questionnaire about
      current medications, sociodemographic characteristics, current state of health,
      health-related quality of life, and whether they had a regular physician. Among
      users of prescribed drugs, the association between using five or more prescribed
      drugs and not having a regular physician was assessed by univariate analysis and
      by stepwise logistic regression. RESULTS: The questionnaire was returned by 491
      (80%) of the eligible subjects, 299 (61%) of whom were taking at least one
      prescribed drug. Nearly 30% of those subjects were taking at least five
      prescribed drugs. The distribution of the number of prescribed drugs being taken
      was positively skewed; the minimum was one and the maximum was 17, the middle 50%
      of the values ranged from two to five, and the median was three. About half of
      those who were taking at least five prescribed drugs did not have a regular
      physician. Compared with those who had a regular physician, those who did not
      were 2.5 times more likely to be taking at least five prescribed drugs (95%
      confidence interval, 1.4 - 4.6). CONCLUSIONS: Older people in Japan are less
      likely to be taking many prescribed drugs if they have the continuity of care
      provided by a regular physician.

PMID- 10591235
TI  - Synthetic somatostatin analog (octreotide) suppresses daytime growth hormone
      secretion equivalently in young and older men: preserved pituitary responsiveness
      to somatostatin's inhibition in aging.
AB  - OBJECTIVE: To gain greater insight into the mechanisms controlling the low
      daytime rate of growth hormone (GH) secretion in older men. DESIGN: We conducted
      a randomized, controlled study of GH secretion during inhibition by octreotide, a
      somatostatin analog. PARTICIPANTS: Nine young (35-44 years) and ten older (62-79
      years) healthy men participated. INTERVENTION: Octreotide versus nothing, while
      subjects were on a standardized diet. MEASUREMENTS: All subjects were assessed on
      two separate occasions: baseline and at time of the intervention of octreotide
      (100 microg subcutaneously); the order of the intervention was randomly assigned.
      Octreotide was administered at 8:00 a.m. Venous sampling was performed every 10
      minutes for 8 hours (8:30 a.m. to 4:30 p.m.). To estimate the joint parameters of
      pulsatile and basal (between secretory pulses) GH secretion, we used an
      ultrasensitive chemiluminescence-based GH assay and multiparameter deconvolution
      analysis. RESULTS: Compared with baseline, octreotide markedly reduced mean (8
      hour) serum GH concentrations in both young (0.585+/-0.255 microg/L vs 0.070+/
      0.029 microg/L; P = .008) and older (0.397+/-0.107 microg/L vs 0.087+/-0.027
      microg/L; P = 0.005) men. In younger men, octreotide decreased the serum GH
      concentration primarily by suppressing the mass of GH released per secretory
      pulse (2.4+/-0.9 microg/L vs 1.0+/-.7 microg/L; P = .015) and the interpulse
      (basal) rate of GH release (0.0014+/-0.0003 microg/L/min vs 0.0006+/-0.0002
      microg/L/min; P = .051). In older men, octreotide also restrained the mass of GH
      per secretory pulse (1.5+/-0.4 microg/L vs 0.4+/-0.1 microg/L; P = .028) and
      lowered basal GH release (0.0014+/-0.0003 microg/L/min vs 0.0004+/-0.0001
      microg/L/min; P = .007). There were no significant differences when the older men
      were compared with the young controls. CONCLUSIONS: Our data suggest that the
      daytime relative GH deficiency seen in older men is not a result of excessive
      pituitary susceptibility to the inhibitory capabilities of somatostatin, but more
      likely reflects impoverished endogenous GHRH drive and/or heightened release of
      brain somatostatin.

PMID- 10591237
TI  - Impact of integrated home care services on hospital use.
AB  - OBJECTIVE: To examine the effect of a home care program based on comprehensive
      geriatric assessment and case management on hospital use and costs among frail
      older individuals. DESIGN: Quasi-experimental study with a 6-month follow-up.
      SETTING: Vittorio Veneto, a town in northern Italy. PARTICIPANTS: One hundred
      fifteen frail older people who applied for integrated home care services.
      INTERVENTION: Each patient was assessed with the Minimum Data Set for Home Care,
      and, subsequently, a case manager and a multidisciplinary team delivered social
      and health care services as indicated. MAIN OUTCOME MEASURES: We determined the
      hospital admissions and days spent in the hospital for all subjects during the
      first 6 months after the implementation of the home care program and compared
      them with the rate of hospitalization that the same patients had experienced in
      the 6 months preceding the implementation of the program. RESULTS: After the
      implementation of the integrated home care program, there was a significant
      reduction in the number of hospitalizations compared with pre-implementation (56%
      vs 46%, respectively; P < .001), associated with a reduction in the number of
      hospital days, both at the individual patient level (28+/-23 days vs 18+/-15
      days, respectively; P < .01) and for each admission (16+/-12 days vs 12+/-8 days,
      respectively; P < .01). This resulted in a 29% cost reduction with an estimated
      savings of $1260 per patient. CONCLUSIONS: The implementation of an integrated
      home care program based on the use of a comprehensive geriatric assessment
      instrument guided by a case manager has a significant impact on hospitalization
      and is cost-effective.

PMID- 10591238
TI  - Prevalence of significant knee pain among older Americans: results from the Third
      National Health and Nutrition Examination Survey.
AB  - OBJECTIVE: To assess the prevalence of persistent knee pain among older adults in
      the US. DESIGN: A nationally representative cross-sectional survey with an in
      person interview and medical examination SETTING AND PARTICIPANTS: Between 1988
      and 1994, 6596 adults aged 60 to 90+ years were examined as part of the National
      Health and Nutrition Examination Survey III. Mexican Americans and non-Hispanic
      blacks were over-sampled to produce reliable estimates for these groups. MAIN
      OUTCOME MEASUREMENTS: Participants were asked to report whether they had
      experienced knee pain on most days for the 6 weeks preceding their medical exam.
      RESULTS: Overall, 18.1% of US men and 23.5% of US women aged 60 years and older
      reported knee pain. Sixty- to ninety-year-old men reported knee pain less
      frequently than their age-matched female counterparts. There was a trend for
      reports of knee pain to increase steadily as these adults aged from 60 to 85
      years. The highest prevalence of knee pain was reported among 85- to 90-year-old
      men (23.7%) and women (30.0%). Among non-Hispanic white adults older than age 60,
      18.4% of men and 22.0% of women reported knee pain. Reports of knee pain among
      non-Hispanic black men and Mexican American men were similar to those of their
      non-Hispanic white counterparts. In contrast, 26.4% of Mexican American women and
      32.8% of non-Hispanic black women reported knee pain. We also found that
      difficulty in performing physical functioning activities was associated with a
      higher prevalence of knee pain. CONCLUSIONS: Many US adults older than age 60
      years report knee pain, and the prevalence is higher in older adults. Reports of
      knee pain are highest among non-Hispanic black women and the oldest Americans.
      Intervention strategies are needed to prevent and better manage knee pain among
      older US adults to stem the adverse health consequences and diminished quality of
      life associated with this common problem.

PMID- 10591240
TI  - Smoking and mortality in an older Chinese cohort.
AB  - OBJECTIVES: Only limited data are available regarding smoking and health in later
      life and, in particular, in the older Chinese population. This paper reports the
      relationship between smoking and mortality in a Chinese cohort aged 70 years and
      older. SETTING: A population-based study conducted in Hong Kong. PARTICIPANTS: A
      cohort comprising 2030 subjects aged 70 and older were assembled in 1991-1992 and
      followed for 36 months. DESIGN: A prospective cohort study. MEASUREMENTS:
      Baseline information regarding smoking status as well as several social and
      health variables were obtained through face-to-face interview at the respondent's
      place of residence. The outcome variables were mortality from all causes as well
      as from cancer and cardiovascular and respiratory diseases. Causes of death were
      ascertained from death certificates. RESULTS: The prevalence rates of smoking at
      baseline were 24.9% in men and 8.2% in women. A total of 534 deaths occurred
      during the 36-month follow-up period. Of these, 447 were attributable to three
      main causes: cancer, cardiovascular disease, and respiratory disease. Elevated
      mortality risks from all causes were observed among both male (RR = 1.4; 95% CI,
      0.9-1.9) and female (RR = 1.6; 95% CI, 1.0-2.5) current smokers, but the 95%
      confidence intervals overlapped. Significant association between current smoking
      and combined mortality from these three major causes was found in men; it was
      also found in women after excluding those with these diseases at baseline. More
      than a 3-fold increased risk of cancer mortality was found in current smokers of
      both sexes. Although nonsignificant associations were found between former
      smokers and mortality risks in men, women who were former smokers had increased
      mortality risks from all causes as well as from cancer and respiratory diseases.
      CONCLUSIONS: This 3-year prospective study of an older Chinese cohort reveals the
      impact of smoking on health during later life, especially in women. Smoking
      cessation, particularly in older men, should be beneficial in reducing mortality.
      Smoking cessation should begin as early as possible for women.

PMID- 10591239
TI  - Atrial natriuretic peptide levels in geriatric patients with nocturia and nursing
      home residents with nighttime incontinence.
AB  - OBJECTIVES: To determine if nocturnal polyuria in geriatric patients with
      nocturia and nocturnal incontinence is associated with elevated plasma atrial
      natriuretic peptide (ANP) levels. DESIGN: Case series. SETTING: Four nursing
      homes and two board and care facilities. PARTICIPANTS: Fifty-four nursing home
      residents and 26 board and care residents with a mean age of 86. MEASUREMENTS:
      Daytime (7:00 a.m. to 7:00 p.m.) and nighttime (7:00 p.m. to 7:00 a.m.) urine
      volumes of incontinent nursing home residents were measured over 3 days and 3
      nights by reweighing preweighed adults diapers and toileting inserts emptied by
      research staff for the board and care group. Blood was drawn in the early morning
      (5:00 a.m. to 7:00 a.m.) before subjects arose and in the evening after an hour
      of lying in bed (8:00 p.m. to 11:00 p.m.), and plasma ANP levels were determined
      by radioimmunoassay. RESULTS: Forty-nine (61%) of the subjects had nocturnal
      polyuria as defined by night/total urine volume ratios > or = 50%. There was no
      significant difference between those with night/total ratios > or = 50% versus <
      50% in plasma levels of ANP in the early morning (44.2+/-33.3, median 35.7 pg/mL
      vs 40.9+/-39.2, median 28.5; P = .36 by Mann Whitney U) or in the evening (43.4+/
      28.8, median 36.4 pg/mL vs 49.6+/-53.1, median 34.4; P = .58). Nor was there any
      significant correlation between night/total urine volume ratio and morning or
      evening ANP levels (r = .01, P = .96 and r = .23, P = .31, respectively).
      CONCLUSIONS: In this sample of geriatric patients with nocturia and nursing home
      residents with nighttime urinary incontinence, ANP levels were elevated, but
      increased nighttime urine production was not associated with higher levels.
      Because of the variability in ANP levels, our power to detect such an association
      was low, and we cannot draw any definitive conclusions. Although high plasma ANP
      levels are unlikely to be a primary cause of nocturia and nighttime incontinence,
      they may, when combined with other factors such as low antidiuretic hormone
      levels, sleep disorders, and low functional bladder capacity, contribute to these
      symptoms in some geriatric patients.

PMID- 10591241
TI  - Rapid increase of fall-related severe head injuries with age among older people:
      a population-based study.

PMID- 10591242
TI  - Urinary catheters: what type do men and their nurses prefer?
AB  - OBJECTIVES: Urinary catheters are used frequently, but the relative risks and
      benefits of different types of devices are not clear. We sought to determine the
      beliefs of both older male patients and nursing staff about the relative merits
      and problems of condom and indwelling catheters. DESIGN: Patient and nurse survey
      using convenience sampling. SETTING: A University-affiliated Veterans Affairs
      medical center. PARTICIPANTS: Men hospitalized on medical, rehabilitation and
      nursing home units using either an indwelling or a condom catheter were invited
      to participate as were all members of the nursing staff on these units. Of 116
      eligible patients, 104 were interviewed (response rate = 90%). Of 107 eligible
      nursing staff members, 99 completed the questionnaires (response rate = 92%).
      INTERVENTION AND MEASUREMENTS: Consenting patients were interviewed personally
      about their urinary catheter. The nursing staff were asked to complete a self
      administered questionnaire. RESULTS: Patients were mostly older and predominantly
      hospitalized on the medical service. Compared with those using an indwelling
      catheter, patients using a condom catheter were more likely to believe that their
      catheter was comfortable (86 vs 58%, P = .04) and less likely to believe it was
      painful (14 vs 48%, P = .008) or to restrict their activity (24 vs 61%, P =
      .002). The nursing staff had a mean of 13 years nursing experience, and the
      majority worked in the nursing home unit. Most of the nursing staff respondents
      believed that condom catheters were less painful and restrictive for patients and
      were easier to apply, but they also believed that they fell off and leaked more
      often and required more nursing time. CONCLUSIONS: Both patients and nursing
      staff prefer condom to indwelling catheters for patient comfort, but they
      recognize that dislodgment and leaking are major drawbacks of condom catheters. A
      more secure condom catheter would greatly improve the management of male
      incontinence.

PMID- 10591243
TI  - Managing dyslipidemia in older adults.
AB  - OBJECTIVES: To summarize and critically review clinical trial data regarding
      dyslipidemia as a risk factor for coronary heart disease (CHD) and the efficacy
      and safety of lipid-lowering interventions in older adults. Based on these data,
      clinical recommendations for diagnosing and managing dyslipidemia in older adults
      are provided. METHODS: Peer-reviewed journal articles were identified by a
      MEDLINE search and a review of journal article references. Studies that were
      performed exclusively in subjects older than 65 years or that included a large
      subgroup of older adults were included. CONCLUSIONS: Elevated low density
      lipoprotein and total cholesterol levels are independent risk factors for CHD
      events in patients aged older than 65 years. Older adults have a higher risk of
      mortality attributable to hypercholesterolemia. Diet and lipid-lowering
      medications safely and effectively lower cholesterol levels in this age group.
      Exercise increases high-density lipoprotein cholesterol levels and decreases
      triglyceride levels. If accompanied by weight loss, exercise may reduce low
      density lipoprotein and total cholesterol levels. Improving lipid levels in older
      adults with CHD decreases the risk of future coronary events by up to 45%, and
      significant effects on outcome measures may be observed within 2 years of the
      initiation of therapy.

PMID- 10591244
TI  - Mentoring across the professional lifespan in academic geriatrics.

PMID- 10591245
TI  - Preventing falls: to modify the environment or the individual?

PMID- 10591246
TI  - Health care quality, the older patient, and the primary care physician.

PMID- 10591247
TI  - Growth hormone: fountain of youth or death hormone?

PMID- 10591248
TI  - A new twist in the J-shape curve?

PMID- 10591249
TI  - Regarding the nursing home at night.

PMID- 10591250
TI  - Folic acid and homocysteine in older women.

PMID- 10591251
TI  - The patient relations program at Mercy Hospital.

PMID- 10591252
TI  - Falls of geriatric patients at the hospital.

PMID- 10591253
TI  - Purple urine bags: a geriatric presentation of lower urinary tract infection.

PMID- 10591254
TI  - Use of urine-based markers for detection and monitoring of bladder cancer.
AB  - Diagnosis and monitoring of bladder cancer present a difficult clinical problem.
      Urine cytology with confirmatory cystoscopy form the cornerstone of diagnosis at
      the present time. The subjectivity and low sensitivity of cytology led to the
      development of numerous tests as adjuncts to cystoscopy for the diagnosis and
      follow-up of bladder cancer patients. These tests usually are objective,
      quantitative (NMP-22, BTA TRAK, BLCA-4, telomerase activity, etc.), or
      qualitative (BTA Stat and FDP) and have higher sensitivity than cytology, but
      some have lower specificity. We review the different, new urine-based tests that
      were developed recently for the diagnosis and monitoring of patients with bladder
      cancer. The advantages and disadvantages of these tests are discussed, as well as
      their possible future role in the management of patients with bladder cancer.

PMID- 10591255
TI  - Prostate cancer gene therapy: outcome of basic research and clinical trials.
AB  - With the advances in genetic engineering, tumor biology, and immunology, gene
      therapy has been recognized as a promising new treatment option for cancer,
      including prostate cancer. Several clinical trials of prostate cancer gene
      therapy currently underway are using therapeutic genes, including suicide genes,
      immunomodulatory genes, tumor suppressor genes, and antioncogenes. Although gene
      therapy for prostate cancer as a clinical alternative is still at an early stage
      that requires several technological breakthroughs, information obtained from
      clinical trials indicates the full potential of prostate cancer gene therapy.
      Concordant progress in basic research and gene therapy technology will ready
      prostate cancer gene therapy for widescale use in the future. In this report, the
      general concept and current progress in prostate cancer gene therapy are
      summarized.

PMID- 10591256
TI  - Beneficial effect of intranasal desmopressin for men with benign prostatic
      hyperplasia and nocturia: preliminary results.
AB  - The aim of this study was to determine the efficacy of intranasal desmopressin in
      the treatment of nocturnal polyuria in men with benign prostatic hyperplasia
      (BPH). Twelve men with BPH were treated with intranasal desmopressin at bedtime
      for nocturnal polyuria. All patients underwent video-urodynamic evaluation. The
      number of nocturia episodes was the dependent variable. Exclusion criteria
      included nephrolithiasis, active urinary tact infection, and history of
      myocardial infarction, congestive heart failure, and angina. Ten of 12 patients
      improved with the intranasal desmopressin therapy. Nocturia episodes decreased
      from a median of 3.6 +/- 0.5 episodes/night before treatment to 1.8 +/- 1.1
      episodes/night 3 months after therapy (p = .01). The American Urological
      Association symptom index decreased from 19 +/- 6 before treatment to 12 +/- 6
      after therapy (p = .02). Hyponatremia did not occur. We conclude that intranasal
      desmopressin is a promising therapy for nocturnal polyuria in selected BPH
      patients.

PMID- 10591257
TI  - Absorbable mesh envelope facilitates handling of pediatric en bloc kidneys during
      transplantation.
AB  - There is increasing evidence to favor the use of pediatric en bloc kidneys in
      renal transplantation. However, from a technical standpoint, pediatric en bloc
      renal transplantation is more complex because of difficulty in optimal
      intraoperative handling and positioning, as well as a higher potential for
      vascular complications. We describe our experience with a technique that has
      helped us to minimize the technical difficulties associated with the surgical
      procedure. Use of a tailored absorbable mesh envelope improves handling of the en
      bloc pediatric kidneys during performance of the vascular anastomoses and reduces
      the risk of torsion of renal pedicles.

PMID- 10591258
TI  - Randomized trial of safety and efficacy of transurethral resection of the
      prostate using contact laser versus electrocautery.
AB  - The aim of this study was to prospectively evaluate the safety and efficacy of
      contact laser ablation of the prostate (CLAP) vs. transurethral resection of the
      prostate (TURP) in symptomatic benign prostatic hypertrophy (BPH). During a 1
      year period (1995-1996), 37 males 50 years of age or older were randomized to
      either CLAP using Nd:YAG laser treatment or TURP. Patients with Qmax <15 mL/s,
      American Urological Association (AUA) symptom score >12, and postvoid residual
      (PVR) >125 mL were enrolled. Patients were excluded if they had prior surgical
      treatment for BPH or known conditions that could affect bladder function.
      Comparisons of preoperative and postoperative symptom scores, Qmax, PVR, total
      catheter time, hospital stay, complications, and hematocrit changes were
      performed. A 2:1 randomization was used, which resulted in 26 CLAP and 12 TURP
      patients. One-year follow-up data were available for 21 CLAP and 7 TURP patients.
      The mean prostate volume, age, AUA symptom score, and Qmax were not significantly
      different between the two arms. Significant differences in favor of CLAP were
      shorter catheter time (27.2 vs. 40.4 hours; p < .05) and shorter hospital stays
      (28.5 vs. 60.0 hours; p < .05). The only other significant difference between the
      two arms was a lower AUA symptom score in favor of TURP at 1 year (4.7 vs. 8.4; p
      < .05). Qmax, PVR, and postoperative hematocrit were similar between the groups.
      The only complications included recatheterizations, which occurred more
      frequently in the TURP patients (25% vs. 14%). CLAP appears to be slightly less
      effective in AUA symptom score reduction; however, it is equally safe and is
      superior for shortening catheter time and hospital stay compared to TURP.

PMID- 10591259
TI  - Evaluation of interstitial diode laser therapy for treatment of benign prostatic
      hyperplasia.
AB  - In the last decade, a number of new device technologies were developed for benign
      prostatic hyperplasia (BPH) therapy. These technologies were introduced in an
      effort to reduce the morbidity of BPH therapy associated with conventional
      electrocautery transurethral resection of the prostate (TURP). While morbidity is
      reduced, the aim of new therapy is to achieve near equivalence in efficacy of
      outcome measures, namely, improved voided flow rate and reduced symptom score. To
      gain acceptance by urologists, these technologies should be easy to apply and
      should reduce the economic cost of BPH treatment. The Indigo 830e diode laser
      system offers simplified laser therapy from a miniaturized solid-state system.
      This pilot study demonstrates outcome equivalence to TURP in preliminary
      evaluation and shows an acceptable side effect profile.

PMID- 10591260
TI  - Stent placement for the diagnosis of upper tract obstruction.
AB  - The aim of this study was to evaluate the effectiveness of ureteral stent
      placement in diagnosing ureteropelvic junction (UPJ) obstruction in patients with
      negative or equivocal radiographic/nuclear studies and to assess relief of
      symptoms following definitive surgical procedures to relieve the obstruction.
      Patients undergoing ureteral stent placements performed by two attending
      urologists over an 18-month period were reviewed. All patients with equivocal or
      negative radiographic evaluations for ureteral obstruction in whom the stent was
      placed for diagnostic purposes were selected. Preoperative and postoperative
      information was obtained from the medical record or by telephone interview. Five
      patients were found who had equivocal radiographic studies along with symptoms of
      flank pain and who underwent diagnostic stent placement. All patients were female
      (average age 40 years, range 20-52). All had pain relief following stent
      placement and, on this basis, underwent an operative procedure to remove the
      presumed ureteral obstruction. Three underwent Acucise endopyelotomy, one had
      laparoscopic resection of the right ovarian vein, and one underwent nephrectomy.
      The average preoperative creatinine level was 0.9 mg/dL (range 0.8-1.0), and the
      average postoperative creatinine level was 1.0 mg/dL (range 0.9-1.1). All
      patients had relief of flank pain at a mean of 17 months following the surgical
      procedure. Relief of pain following stent placement in patients with clinical
      suspicion of ureteral obstruction portends a favorable outcome from procedures to
      relieve the presumed obstruction. In unusual cases where ureteral obstruction is
      suspected despite negative or equivocal radiographic findings, diagnostic stent
      placement appears to be useful.

PMID- 10591261
TI  - Endoscopic management of ureteropelvic junction obstruction in children.
AB  - A variety of endoscopic methods are available for managing ureteropelvic junction
      obstruction in children, and these methods can be considered for use in selected
      circumstances.

PMID- 10591262
TI  - Modified alpha wrap techniques for dynamic urethral graciloplasty in an animal
      model.
AB  - Urethral sphincter reconstruction with a stimulated skeletal muscle flap has been
      used for treatment of severe intrinsic sphincter deficiency. Urethral strictures
      and failures were reported in some of the initial experiences. The etiology of
      these problems is not known, but elevated resting urethral pressures and
      excessive urethral displacement with stimulation are possible causes. We modified
      two operative techniques in forming dynamic urinary graciloplasty (DUG) in an
      attempt to minimize resting urethral pressure without stimulation and urethral
      mobility during stimulation. Two types of DUG were used. In the first group, a
      small flap (partial muscle wrap) from the gracilis muscle with an attachment site
      on the muscle was constructed in four dogs. In the second group, three dogs with
      a modified alpha wrap and proximal attachments were used. All of the gracilis
      muscle wraps were stimulated using an implanted programmable pulse stimulator
      with electrodes attached over the motor nerve. Following a 2-week, postrecovery
      period, urethral pressure measurements were obtained with and without
      stimulation. Five weeks were used for stimulation to condition the muscle. This
      was followed by 4 weeks of continuous stimulation. Thus, devices were implanted
      for 11 weeks. Before conditioning of the muscles was initiated, the partial
      muscle wrap pressure at rest was 42 +/- 27 cm H2O, which was higher than the
      incomplete alpha wrap resting pressure of 20 +/- 4 cm H2O. Stimulated partial
      flap pressure was 161 +/- 50 cm H2O, and stimulated modified alpha wrap pressures
      was 71 +/- 27 cm H2O. After conditioning with the modified alpha wrap, the
      resting and stimulated pressures were unchanged from before conditioning.
      Technical problems precluded collection of data during the conditioning period in
      dogs with partial flaps. During stimulation, the partial muscle wrap demonstrated
      marked deviation, whereas the modified alpha wrap had minimal urethral movement.
      Postmortem evaluation indicated no urethral stricture or fistula formation with
      either of the two types of wraps. The modified alpha wrap had several positive
      features. Advantages over the partial wrap were minimal resting pressures,
      reduced urethral mobility, and adequate sustained pressures during stimulation.
      Therefore, in contrast to the partial gracilis muscle wrap, aspects of the
      incomplete alpha wrap should be considered further for DUG.

PMID- 10591263
TI  - Pain associated with testicular retraction treated with Gore-Tex external
      inguinal ring reconstruction.
AB  - We present our experience with three patients with chronic testicular pain due to
      retractile testes and propose a new operative solution to the problem. Three
      patients with chronic testicular pain associated with testicular retraction and
      relieved by pushing the testicle into the scrotum were identified. Full history
      and physical examinations were performed to rule out other causes of testicular
      pain. The patients underwent open inguinal exploration, aborted attempt at repair
      of an attenuated or obliterated external oblique aponeurosis, and construction of
      a neo-external inguinal ring with a Gore-Tex strip. The patients were reevaluated
      in the clinic postoperatively to determine change in physical examination and
      symptoms. All three patients had nonretractile testes on follow-up examination
      and reported improvement of their testicular pain. An attenuated or torn external
      oblique aponeurosis can result in a patulous external inguinal ring and painful
      retractile testicle. If traditional orchidopexy is insufficient to prevent severe
      retraction, reconstruction of the external inguinal ring with Gore-Tex mesh can
      correct the anatomical deficiency, reduce testicular retraction, and improve pain
      symptoms.

PMID- 10591264
TI  - Mini-percutaneous antegrade endopyelotomy.
AB  - Antegrade endopyelotomy is the endourologic treatment of choice for ureteropelvic
      junction obstruction with a coexisting renal calculus. We report the use of a
      mini-percutaneous procedure that allows us to perform an antegrade endopyelotomy
      and stone extraction through a 20F nephrostomy sheath.

PMID- 10591265
TI  - Use of a shape-memory alloy (nitinol) in a removable prostate stent.
AB  - An easily removable prostate stent would be useful in various clinical situations
      but is not currently available. Thus, we studied the safety, tolerability, and
      ease of removal of a nitinol (nickel-titanium alloy) prostate stent in 10 men
      with symptomatic benign prostatic hyperplasia. The circular-coil stent becomes
      hourglass in shape following deployment, with the narrowest diameter
      approximately 35F. A working hypothesis was that the temperature-sensitive shape
      memory of nitinol would allow for its easy removal vis-a-vis other available
      stents. Using several modifications of a prototype insertion device, we found
      that the nitinol stents were easily inserted, retained their shape during
      retention periods of 1 to 4 weeks, caused no gross tissue reaction, and were
      removed easily with gentle traction after in situ cooling with iced saline
      lavage. Stent migration was observed in two patients, but otherwise, the stents
      were well tolerated. Nitinol prostate stents appear to fulfill a theoretical
      promise of being biologically inert, "superelastic," and pliable when cooled,
      allowing for easy removal. Further clinical investigation appears warranted.

PMID- 10591266
TI  - Reengineering and the hospital staff nurse.

PMID- 10591267
TI  - National probability samples in studies of low-prevalence diseases. Part I:
      Perspectives and lessons from the HIV cost and services utilization study.
AB  - OBJECTIVE: To examine the trade-offs inherent in selecting a sample design for a
      national study of care for an uncommon disease, and the adaptations,
      opportunities and costs associated with the choice of national probability
      sampling in a study of HIV/AIDS. SETTING: A consortium of public and private
      funders, research organizations, community advocates, and local providers
      assembled to design and execute the study. DESIGN: Data collected by providers or
      collected for administrative purposes are limited by selectivity and concerns
      about validity. In studies based on convenience sampling, generalizability is
      uncertain. Multistage probability sampling through households may not produce
      sufficient cases of diseases that are not highly prevalent. In such cases, an
      attractive alternative design is multistage probability sampling through sites of
      care, in which all persons in the reference population have some chance of random
      selection through their medical providers, and in which included subjects are
      selected with known probability. DATA COLLECTION AND PRINCIPAL FINDINGS:
      Multistage national probability sampling through providers supplies uniquely
      valuable information, but will not represent populations not receiving medical
      care and may not provide sufficient cases in subpopulations of interest. Factors
      contributing to the substantial cost of such a design include the need to develop
      a sampling frame, the problems associated with recruitment of providers and
      subjects through medical providers, the need for buy-in from persons affected by
      the disease and their medical practitioners, as well as the need for a high
      participation rate. Broad representation from the national community of scholars
      with relevant expertise is desirable. Special problems are associated with
      organization of the research effort, with instrument development, and with data
      analysis and dissemination in such a consortium. CONCLUSIONS: Multistage
      probability sampling through providers can provide unbiased, nationally
      representative data on persons receiving regular medical care for uncommon
      diseases and can improve our ability to accurately study care and its outcomes
      for diseases such as HIV/AIDS. However, substantial costs and special
      circumstances are associated with the implementation of such efforts.

PMID- 10591268
TI  - National probability samples in studies of low-prevalence diseases. Part II:
      Designing and implementing the HIV cost and services utilization study sample.
AB  - OBJECTIVE: The design and implementation of a nationally representative
      probability sample of persons with a low-prevalence disease, HIV/AIDS. DATA
      SOURCES/STUDY SETTING: One of the most significant roadblocks to the
      generalizability of primary data collected about persons with a low-prevalence
      disease is the lack of a complete methodology for efficiently generating and
      enrolling probability samples. The methodology developed by the HCSUS consortium
      uses a flexible, provider-based approach to multistage sampling that minimizes
      the quantity of data necessary for implementation. STUDY DESIGN: To produce a
      valid national probability sample, we combined a provider-based multistage design
      with the M.D.-colleague recruitment model often used in non-probability site
      specific studies. DATA COLLECTION: Across the contiguous United States, reported
      AIDS cases for metropolitan areas and rural counties. In selected areas,
      caseloads for known providers for HIV patients and a random sample of other
      providers. For selected providers, anonymous patient visit records. PRINCIPAL
      FINDINGS: It was possible to obtain all data necessary to implement a multistage
      design for sampling individual HIV-infected persons under medical care with known
      probabilities. Taking account of both patient and provider nonresponse, we
      succeeded in obtaining in-person or proxy interviews from subjects representing
      over 70 percent of the eligible target population. CONCLUSIONS: It is possible to
      design and implement a national probability sample of persons with a low
      prevalence disease, even if it is stigmatized.

PMID- 10591269
TI  - The effects of managed care and prospective payment on the demand for hospital
      nurses: evidence from California.
AB  - OBJECTIVE: To examine the effects of managed care and the prospective payment
      system on the hospital employment of registered nurses (RNs), licensed practical
      nurses (LPNs), and aides. DATA SOURCES: Hospital-level data from California's
      Office of Statewide Health Planning and Development (OSHPD) Hospital Disclosure
      Reports from 1976/1977 through 1994/1995. Additional information is extracted
      from OSHPD Patient Discharge Data. STUDY DESIGN: Multivariate regression
      equations are used to estimate demand for nurses as a function of wages, hospital
      output, technology level, and ownership. Separate equations are estimated for
      RNs, LPNs, and aides for all daily services and for medical-surgical units.
      Instrumental variables are used to correct for the endogeneity of wages, and
      fixed effects are included to control for unobserved differences across
      hospitals. PRINCIPAL FINDINGS: HMOs are associated with a lower use of LPNs and
      aides, and HMOs do not have a statistically significant effect on the demand for
      RNs. Managed care has a smaller effect on nurse staffing in medical-surgical
      units than in daily service units as a whole. The prospective payment system does
      not have a statistically significant effect on nurse staffing. CONCLUSIONS: HMOs
      have affected nursing employment both because HMOs have reduced the number of
      discharges and because of a direct relationship between HMO penetration and the
      demand for LPNs and aides. Contrary to press reports, LPNs and aides have been
      affected more by HMOs than have registered nurses.

PMID- 10591270
TI  - Does what nurses do affect clinical outcomes for hospitalized patients? A review
      of the literature.
AB  - OBJECTIVE: Through a review of the literature, to identify and describe (1)
      empirical studies of inpatient nursing care quality that evaluate links between
      nursing care processes and health-related patient outcomes, (2) nursing care
      processes for which process-outcome links have been established, and (3)
      important nursing care processes that have not yet been evaluated. DATA
      SOURCES/STUDY SETTING: Published empirical studies of inpatient nursing care
      quality that evaluated links between processes of nursing care and health-related
      patient outcomes. STUDY DESIGN/DATA COLLECTION/EXTRACTION METHODS: This
      literature review used a five-step article search and review method. PRINCIPAL
      FINDINGS: Of 257 data-based studies of nursing care quality identified, 135
      investigated a process-outcome link but only 17 met study inclusion criteria. The
      literature provides evidence that the quality of nursing care processes affects
      health-related patient outcomes during and after hospitalization. Gaps in the
      literature that evaluates nursing quality are identified. CONCLUSIONS: Although
      some nursing care processes affect health-related patient outcomes, the full
      extent of nursing process-outcome links is relatively understudied. Further
      evaluation of the interrelationships between nursing care processes and outcomes
      is critical.

PMID- 10591271
TI  - Clustering and the design of preference-assessment surveys in healthcare.
AB  - OBJECTIVE: To show cluster analysis as a potentially useful tool in defining
      common outcomes empirically and in facilitating the assessment of preferences for
      health states. DATA SOURCES: A survey of 224 patients with ventricular
      arrhythmias treated at Kaiser Permanente of Northern California. STUDY
      DESIGN/METHODS: Physical functioning was measured using the Duke Activity Status
      Index (DASI), and mental status and vitality using the Medical Outcomes Study
      Short Form-36 items (SF-36). A "k-means" clustering algorithm was used to
      identify prototypical health states, in which patients in the same cluster shared
      similar responses to items in the survey. PRINCIPAL FINDINGS: The clustering
      algorithm yielded four prototypical health states. Cluster 1 (21 percent of
      patients) was characterized by high scores on physical functioning, vitality, and
      mental health. Cluster 2 (33 percent of patients) had low physical function but
      high scores on vitality and mental health. Cluster 3 (29 percent of patients) had
      low physical function and low vitality but preserved mental health. Cluster 4 (17
      percent of patients) had low scores on all scales. These clusters served as the
      basis of written descriptions of the health states. CONCLUSIONS: Employing a
      clustering algorithm to analyze health status survey data enables researchers to
      gain a data-driven, concise summary of the experiences of patients.

PMID- 10591272
TI  - Using Medicaid claims to construct dental service market areas.
AB  - OBJECTIVE: To use Medicaid claims data to construct patient origin-based market
      areas for dental services and compare constructed market areas with those based
      on the practice county. DATA SOURCES: North Carolina Medicaid claims,
      eligibility, and provider files, the Cooperative Health Information Systems'
      dentist licensure files, and the Log Into North Carolina data. STUDY DESIGN: A
      visit-level file was created from the Medicaid claims data and aggregated by
      provider practice county and patient county of residence. Using the aggregated
      file and an algorithm based on the Elzinga-Hogarty approach, patient travel
      patterns were used to construct mutually exclusive patient origin market areas.
      DATA ANALYSIS: Market area characteristics were compared across definitions using
      Pearson correlation coefficients. In addition, estimations of provider
      participation were performed using market area characteristics as control
      variables. The beta coefficients associated with market area characteristics were
      compared across market area definitions. PRINCIPAL FINDINGS: Medicaid claims
      data, when combined with provider licensure files, can be used to construct
      market areas based on patient origin data. However, measures of market area
      characteristics are correlated highly between the two types of market areas
      studied. Furthermore, beta coefficients on market area variables in models of
      provider participation are similar in sign, significance, and magnitude across
      market definitions. CONCLUSIONS: Compared with market areas constructed using
      patient origin data, county-based market areas adequately proxy for dental
      markets. Using the county as the market area also avoids the time and
      computational costs associated with using a patient origin-based approach and
      facilitates the use of widely available data.

PMID- 10591273
TI  - How well do we understand the relationship between prenatal care and birth
      weight?

PMID- 10591274
TI  - The emergence of qualitative methods in health services research.

PMID- 10591275
TI  - Qualitative methods: what are they and why use them?
AB  - OBJECTIVE: To provide an overview of reasons why qualitative methods have been
      used and can be used in health services and health policy research, to describe a
      range of specific methods, and to give examples of their application. DATA
      SOURCES: Classic and contemporary descriptions of the underpinnings and
      applications of qualitative research methods and studies that have used such
      methods to examine important health services and health policy issues. PRINCIPAL
      FINDINGS: Qualitative research methods are valuable in providing rich
      descriptions of complex phenomena; tracking unique or unexpected events;
      illuminating the experience and interpretation of events by actors with widely
      differing stakes and roles; giving voice to those whose views are rarely heard;
      conducting initial explorations to develop theories and to generate and even test
      hypotheses; and moving toward explanations. Qualitative and quantitative methods
      can be complementary, used in sequence or in tandem. The best qualitative
      research is systematic and rigorous, and it seeks to reduce bias and error and to
      identify evidence that disconfirms initial or emergent hypotheses. CONCLUSIONS:
      Qualitative methods have much to contribute to health services and health policy
      research, especially as such research deals with rapid change and develops a more
      fully integrated theory base and research agenda. However, the field must build
      on the best traditions and techniques of qualitative methods and must recognize
      that special training and experience are essential to the application of these
      methods.

PMID- 10591276
TI  - Qualitative research and the profound grasp of the obvious.
AB  - OBJECTIVE: To discuss the value of promoting coexistent and complementary
      relationships between qualitative and quantitative research methods as
      illustrated by presentations made by four respected health services researchers
      who described their experiences in multi-method projects. DATA SOURCES:
      Presentations and publications related to the four research projects, which
      described key substantive and methodological areas that had been addressed with
      qualitative techniques. PRINCIPAL FINDINGS: Sponsor interest in timely,
      insightful, and reality-anchored evidence has provided a strong base of support
      for the incorporation of qualitative methods into major contemporary policy
      research studies. In addition, many issues may be suitable for study only with
      qualitative methods because of their complexity, their emergent nature, or
      because of the need to revisit and reexamine previously untested assumptions.
      CONCLUSION: Experiences from the four projects, as well as from other recent
      health services studies with major qualitative components, support the assertion
      that the interests of sponsors in the policy realm and pressure from them
      suppress some of the traditional tensions and antagonisms between qualitative and
      quantitative methods.

PMID- 10591277
TI  - The distinctiveness of case-oriented research.

PMID- 10591279
TI  - Enhancing the quality and credibility of qualitative analysis.
AB  - Varying philosophical and theoretical orientations to qualitative inquiry remind
      us that issues of quality and credibility intersect with audience and intended
      research purposes. This overview examines ways of enhancing the quality and
      credibility of qualitative analysis by dealing with three distinct but related
      inquiry concerns: rigorous techniques and methods for gathering and analyzing
      qualitative data, including attention to validity, reliability, and
      triangulation; the credibility, competence, and perceived trustworthiness of the
      qualitative researcher; and the philosophical beliefs of evaluation users about
      such paradigm-based preferences as objectivity versus subjectivity, truth versus
      perspective, and generalizations versus extrapolations. Although this overview
      examines some general approaches to issues of credibility and data quality in
      qualitative analysis, it is important to acknowledge that particular
      philosophical underpinnings, specific paradigms, and special purposes for
      qualitative inquiry will typically include additional or substitute criteria for
      assuring and judging quality, validity, and credibility. Moreover, the context
      for these considerations has evolved. In early literature on evaluation methods
      the debate between qualitative and quantitative methodologists was often
      strident. In recent years the debate has softened. A consensus has gradually
      emerged that the important challenge is to match appropriately the methods to
      empirical questions and issues, and not to universally advocate any single
      methodological approach for all problems.

PMID- 10591278
TI  - How will we know "good" qualitative research when we see it? Beginning the
      dialogue in health services research.
AB  - OBJECTIVE: To lay the foundation for an explicit review and dialogue concerning
      the criteria that should be used to evaluate qualitative health services
      research. Clear criteria are critical for the discipline because they provide a
      benchmark against which research can be assessed. DATA SOURCES: Existing
      literature in the social sciences and health services research, particularly in
      primary care and medicine. PRINCIPAL FINDING: Traditional criteria for evaluating
      qualitative research are rooted in the philosophical perspective (positivism)
      most closely associated with quantitative research and methods. As a result,
      qualitative research and methods may not be used as frequently as they can be and
      research results generated from qualitative studies may not be disseminated as
      widely as possible. However, alternative criteria for evaluating qualitative
      research have been proposed that reflect a different philosophical perspective
      (post-positivism). Moreover, these criteria are tailored to the unique purposes
      for which qualitative research is used and the research designs traditionally
      employed. While criteria based on these two different philosophical perspectives
      have much in common, some important differences exist. CONCLUSION: The field of
      health services research must engage in a collective, "qualitative" process to
      determine which criteria to adopt (positivist or post-positivist), or whether
      some combination of the two is most appropriate. Greater clarity about the
      criteria used to evaluate qualitative research will strengthen the discipline by
      fostering a more appropriate and improved use of qualitative methods, a greater
      willingness to fund and publish "good" qualitative research, and the development
      of more informed consumers of qualitative research results.

PMID- 10591280
TI  - Enhancing the quality of case studies in health services research.
AB  - OBJECTIVE: To provide guidance on improving the quality of case studies in health
      services research. DATA SOURCES: Secondary data, drawing from previous case study
      research. RESEARCH DESIGN: Guidance is provided to two audiences: potential case
      study investigators (eight items) and reviewers of case study proposals (four
      additional items). PRINCIPAL FINDINGS: The guidance demonstrates that many
      operational steps can be undertaken to improve the quality of case studies. These
      steps have been a hallmark of high-quality case studies in related fields but
      have not necessarily been practiced in health services research. CONCLUSIONS:
      Given higher-quality case studies, the case study method can become a valuable
      tool for health services research.

PMID- 10591281
TI  - Using qualitative comparative analysis to study causal complexity.

PMID- 10591282
TI  - Analyzing qualitative data with computer software.
AB  - OBJECTIVE: To provide health services researchers with an overview of the
      qualitative data analysis process and the role of software within it; to provide
      a principled approach to choosing among software packages to support qualitative
      data analysis; to alert researchers to the potential benefits and limitations of
      such software; and to provide an overview of the developments to be expected in
      the field in the near future. DATA SOURCES, STUDY DESIGN, METHODS: This article
      does not include reports of empirical research. CONCLUSIONS: Software for
      qualitative data analysis can benefit the researcher in terms of speed,
      consistency, rigor, and access to analytic methods not available by hand.
      Software, however, is not a replacement for methodological training.

PMID- 10591283
TI  - A 14-month randomized clinical trial of treatment strategies for attention
      deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment
      Study of Children with ADHD.
AB  - BACKGROUND: Previous studies have demonstrated the short-term efficacy of
      pharmacotherapy and behavior therapy for attention-deficit/hyperactivity disorder
      (ADHD), but no longer-term (i.e., >4 months) investigations have compared these 2
      treatments or their combination. METHODS: A group of 579 children with ADHD
      Combined Type, aged 7 to 9.9 years, were assigned to 14 months of medication
      management (titration followed by monthly visits); intensive behavioral treatment
      (parent, school, and child components, with therapist involvement gradually
      reduced over time); the two combined; or standard community care (treatments by
      community providers). Outcomes were assessed in multiple domains before and
      during treatment and at treatment end point (with the combined treatment and
      medication management groups continuing medication at all assessment points).
      Data were analyzed through intent-to-treat random-effects regression procedures.
      RESULTS: All 4 groups showed sizable reductions in symptoms over time, with
      significant differences among them in degrees of change. For most ADHD symptoms,
      children in the combined treatment and medication management groups showed
      significantly greater improvement than those given intensive behavioral treatment
      and community care. Combined and medication management treatments did not differ
      significantly on any direct comparisons, but in several instances
      (oppositional/aggressive symptoms, internalizing symptoms, teacher-rated social
      skills, parent-child relations, and reading achievement) combined treatment
      proved superior to intensive behavioral treatment and/or community care while
      medication management did not. Study medication strategies were superior to
      community care treatments, despite the fact that two thirds of community-treated
      subjects received medication during the study period. CONCLUSIONS: For ADHD
      symptoms, our carefully crafted medication management was superior to behavioral
      treatment and to routine community care that included medication. Our combined
      treatment did not yield significantly greater benefits than medication management
      for core ADHD symptoms, but may have provided modest advantages for non-ADHD
      symptom and positive functioning outcomes.

PMID- 10591284
TI  - Moderators and mediators of treatment response for children with attention
      deficit/hyperactivity disorder: the Multimodal Treatment Study of children with
      Attention-deficit/hyperactivity disorder.
AB  - BACKGROUND: Intent-to-treat analyses of the study revealed that medication
      management, alone or combined with intensive behavioral treatment, was superior
      to behavioral treatment and community care in reducing attention
      deficit/hyperactivity disorder (ADHD) symptoms; but only combined treatment
      showed consistently greater benefit than community care across other outcome
      domains (disruptive and internalizing symptoms, achievement, parent-child
      relations, and social skills). We examine response patterns in subgroups defined
      by baseline variables (moderators) or variables related to treatment
      implementation (mediators). METHODS: We reconducted random-effects regression
      (RR) analyses, adding factors defined by moderators (sex, prior medication use,
      comorbid disruptive or anxiety disorder, and public assistance) and a mediator
      (treatment acceptance/attendance). RESULTS: Study outcomes (N = 579) were upheld
      in most moderator subgroups (boys and girls, children with and without prior
      medication, children with and without comorbid disruptive disorders). Comorbid
      anxiety disorder did moderate outcome; in participants without anxiety, results
      paralleled intent-to-treat findings. For those with anxiety disorders, however,
      behavioral treatment yielded significantly better outcomes than community care
      (and was no longer statistically different from medication management and
      combined treatment) regarding ADHD-related and internalizing symptoms. In
      families receiving public assistance, medication management yielded decreased
      closeness in parent-child interactions, and combined treatment yielded relatively
      greater benefits for teacher-reported social skills. In families with high
      treatment acceptance/attendance, intent-to-treat results were upheld.
      Acceptance/attendance was particularly important for medication treatments.
      Finally, two thirds of children given community care received stimulants.
      Behavioral treatment did not significantly differ from, but medication management
      was superior to, this subgroup. CONCLUSIONS: Exploratory analyses revealed that
      our study (the Multimodal Treatment Study of Children With Attention
      Deficit/Hyperactivity Disorder [MTA]) results were confirmed across most baseline
      variables and treatment acceptance/attendance. In children with ADHD plus
      anxiety, behavioral treatment surpassed community care and approached medication
      based treatments regarding parent-reported ADHD symptoms.

PMID- 10591285
TI  - Development of clinical services for attention-deficit/hyperactivity disorder.

PMID- 10591286
TI  - Attenuation of the euphoric effects of cocaine by the dopamine D1/D5 antagonist
      ecopipam (SCH 39166)
AB  - BACKGROUND: The subjective and reinforcing effects of cocaine in humans are
      associated with the enhancement of endogenous dopamine function in the mesolimbic
      system. This study examined the role of dopamine D1-like receptors in the
      behavioral and mood effects of cocaine by evaluating the effects of the selective
      D1/D5 antagonist ecopipam (SCH 39166) on subjective responses to intravenous
      cocaine in 11 subjects with cocaine dependence as defined by DSM-IV. METHODS:
      Subjects were pretreated in a randomized double-blind fashion with either placebo
      or 10 mg, 25 mg, or 100 mg of ecopipam orally on 4 separate occasions. Two hours
      later a single intravenous injection of 30 mg of cocaine was administered.
      Subjective and cardiovascular responses were measured and blood samples for
      pharmacokinetic evaluation were obtained prior to cocaine dosing and at various
      times after dosing. RESULTS: The euphoric (P = .004) and stimulating (P = .03)
      effects of cocaine were attenuated in a dose-dependent manner by ecopipam, while
      ratings of desire to take cocaine were diminished (P = .02). Ecopipam in
      combination with cocaine was safe and well tolerated. CONCLUSION: These data
      indicate a potentially important role for D1-like receptors in the acute mood
      altering and rewarding effects of cocaine in humans.

PMID- 10591287
TI  - Cocaine reward and dopamine receptors: love at first site.

PMID- 10591288
TI  - Stepped collaborative care for primary care patients with persistent symptoms of
      depression: a randomized trial.
AB  - BACKGROUND: Despite improvements in the accuracy of diagnosing depression and use
      of medications with fewer side effects, many patients treated with antidepressant
      medications by primary care physicians have persistent symptoms. METHODS: A group
      of 228 patients recognized as depressed by their primary care physicians and
      given antidepressant medication who had either 4 or more persistent major
      depressive symptoms or a score of 1.5 or more on the Hopkins Symptom Checklist
      depression items at 6 to 8 weeks were randomized to a collaborative care
      intervention (n = 114) or usual care (n = 114) by the primary care physician.
      Patients in the intervention group received enhanced education and increased
      frequency of visits by a psychiatrist working with the primary care physician to
      improve pharmacologic treatment. Follow-up assessments were completed at 1, 3,
      and 6 months by a telephone survey team blinded to randomization status. RESULTS:
      Those in the intervention group had significantly greater adherence to adequate
      dosage of medication for 90 days or more and were more likely to rate the quality
      of care they received for depression as good to excellent compared with usual
      care controls. Intervention patients showed a significantly greater decrease
      compared with usual care controls in severity of depressive symptoms over time
      and were more likely to have fully recovered at 3 and 6 months. CONCLUSIONS: A
      multifaceted program targeted to patients whose depressive symptoms persisted 6
      to 8 weeks after initiation of antidepressant medication by their primary care
      physician was found to significantly improve adherence to antidepressants,
      satisfaction with care, and depressive outcomes compared with usual care.

PMID- 10591289
TI  - Functional imaging of memory retrieval in deficit vs nondeficit schizophrenia.
AB  - BACKGROUND: Neuroimaging studies have provided evidence of abnormal frontal and
      temporal lobe function in schizophrenia. Frontal cortex abnormalities have been
      associated with negative symptoms and temporal lobe abnormalities with positive
      symptoms. The deficit and nondeficit forms of schizophrenia were predicted to
      differ in prefrontal cortical activity, but not in medial temporal lobe activity.
      METHODS: Regional cerebral blood flow was studied using oxygen 15 positron
      emission tomography during 3 different memory retrieval conditions in 8 control
      subjects, 8 patients with the deficit syndrome, and 8 patients without the
      deficit syndrome. Behavioral and positron emission tomography data were analyzed
      using a mixed-effects model to test for population differences. RESULTS: In all
      memory conditions, frontal cortex activity was higher in patients without the
      deficit syndrome than in patients with the deficit syndrome. During the attempt
      to retrieve poorly encoded words, patients without the deficit syndrome recruited
      the left frontal cortex to a significantly greater degree than did patients with
      the deficit syndrome. The 2 schizophrenia subtypes did not differ in the activity
      or recruitment of the hippocampus during memory retrieval. CONCLUSION: Frontal
      cortex function during memory retrieval is differentially impaired in deficit and
      nondeficit schizophrenia, whereas hippocampal recruitment deficits are not
      significantly different between the 2 schizophrenia groups.

PMID- 10591290
TI  - Neural correlates of eye tracking deficits in first-degree relatives of
      schizophrenic patients: a positron emission tomography study.
AB  - BACKGROUND: Schizophrenia is thought to arise from the interaction of genetically
      mediated and environmentally triggered abnormalities in brain function. Reduced
      frontal activation, reported in schizophrenic patients, may be one expression of
      genetic risk. The present study investigated whether frontal activation in
      relatives of schizophrenic patients would be related to eye tracking deficits
      (ETD), which are considered a behavioral marker of risk for schizophrenia.
      METHODS: Subjects were first-degree relatives of schizophrenic patients (n = 17)
      and controls (n = 11). Relatives were divided into those with normal and abnormal
      pursuit based on qualitative ratings. Subjects were scanned using positron
      emission tomography and the H(2)15O bolus subtraction technique while performing
      smooth pursuit and fixation. Brain areas more active in pursuit than fixation
      were identified in the 3 groups. Correlations were used to investigate the
      relationship between activation of pursuit regions and pursuit gain in the
      relatives. RESULTS: Controls significantly activated frontal eye fields (FEFs)
      and posterior areas, including the motion processing area, V5, and cuneus. The 2
      groups of relatives activated the same posterior regions as controls, but
      differed from each other in activation of FEFs. Relatives with normal tracking
      activated right dorsal FEFs while relatives with ETD did not. Individual
      subtractions revealed that 90% of controls and 100% of the relatives with normal
      tracking activated FEFs during pursuit compared with 42% of relatives with ETD (P
      = .009). Pursuit gain was significantly and selectively associated with percent
      activation of right dorsal FEFs (r = 0.74). CONCLUSIONS: Subtle frontal
      dysfunction seems to be a pathophysiological substrate of ETD in relatives of
      schizophrenic patients, and may be one aspect of genetically mediated differences
      in brain function relevant to schizophrenia.

PMID- 10591291
TI  - Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not
      glucose.
AB  - BACKGROUND: Increasing plasma glucose levels improves memory in patients with
      Alzheimer disease (AD). Increasing plasma glucose levels also increases
      endogenous insulin levels, raising the question of whether memory improvement is
      due to changes in insulin, independent of hyperglycemia. We address this question
      by examining memory and counterregulatory hormone response during hyperglycemia
      when endogenous insulin was suppressed by concomitant infusion of the
      somatostatin analogue octreotide (Sandostatin). METHODS: Twenty-three patients
      with AD and 14 similarly aged healthy adults participated in 4 metabolic
      conditions on separate days: (1) hyperinsulinemia (538 pmol/L) with fasting
      glucose (5.6 mmol/L [100 mg/dL]), achieved by insulin and variable dextrose
      infusion; (2) hyperglycemia (12.5 mmol/L [225 mg/dL]) with fasting insulin (57
      pmol/L), achieved by dextrose and somatostatin (octreotide) infusion (150 mg/h);
      (3) placebo with isotonic sodium chloride solution (saline) infusion (fasting
      insulin and glucose); and (4) an active control condition in which somatostatin
      alone was infused (150 mg/h). Declarative memory (story recall) and selective
      attention (Stroop interference test) were measured during steady metabolic
      states. RESULTS: Patients with AD showed improved memory during hyperinsulinemia
      relative to placebo (P = .05) and relative to hyperglycemia (P<.005). Memory did
      not improve during hyperglycemia when insulin was suppressed. Somatostatin
      analogue infusion alone also improved memory for patients with AD (P<.05).
      Hyperinsulinemia increased cortisol levels in subjects with AD, whereas
      somatostatin alone lowered cortisol concentrations. CONCLUSIONS: These results
      confirm that elevated insulin without hyperglycemia enhances memory in adults
      with AD, and indicate that insulin is essential for hyperglycemic memory
      facilitation. These results also suggest a potential therapeutic role for
      somatostatin in AD.

PMID- 10591292
TI  - Smoking and panic attacks: an epidemiologic investigation.
AB  - BACKGROUND: Epidemiologic studies have reported a lifetime association between
      smoking and panic disorder. In this study, we examine potential explanations for
      this association. METHODS: Analysis was conducted on data from 2 epidemiologic
      studies, the Epidemiologic Study of Young Adults in southeast Michigan (N = 1007)
      and the National Comorbidity Survey Tobacco Supplement (n = 4411). Cox
      proportional hazards models with time-dependent covariates were used to estimate
      the risk for onset of panic attacks associated with prior smoking and vice versa,
      controlling for history of major depression. The role of lung disease in the
      smoking-panic attacks association was explored. RESULTS: Daily smoking signaled
      an increased risk for first occurrence of panic attack and disorder; the risk was
      higher in active than past smokers. No significant risk was detected for onset of
      daily smoking in persons with prior panic attacks or disorder. Exploratory
      analyses suggest that lung disease might be one of the mechanisms linking smoking
      to panic attacks. CONCLUSIONS: The evidence that the association between smoking
      and panic disorder might result primarily from an influence in one direction
      (i.e., from prior smoking to first panic attack) and the possibility of a higher
      risk in active than past smokers suggest a causal hypothesis for the smoking
      panic attacks relationship.

PMID- 10591293
TI  - In the year 2099...

PMID- 10591294
TI  - Looking back: the history of psychiatry in the 21st century.

PMID- 10591295
TI  - Psychiatry 2099: commerce without conscience = practice without prudence.

PMID- 10591296
TI  - The difference between efficacy and effectiveness research in studying attention
      deficit/hyperactivity disorder.

PMID- 10591297
TI  - Use of spun urine to enhance detection of Trichomonas vaginalis in adolescent
      women.
AB  - BACKGROUND: Diagnosis of Trichomonas vaginalis infection is traditionally
      performed by microscopic examination of vaginal fluid. Although this technique is
      relatively insensitive compared with culture, it is widely used because of its
      lower cost and immediate results. OBJECTIVE: To assess the utility of microscopic
      examination of spun urine as a means of increasing the sensitivity of microscopic
      diagnosis of T. vaginalis. DESIGN AND SETTING: Retrospective observational study
      performed in a hospital-based adolescent clinic. SUBJECTS: Female patients
      enrolled between July 1995 and August 1996 into a larger study evaluating
      diagnosis of vaginal infections (N = 686). To be included, subjects had to have a
      positive culture for T. vaginalis (n = 97); those who did not have a spun urine
      examination were excluded (n = 22). MAIN OUTCOME MEASURE: Microscopic examination
      of vaginal fluid and spun urine for presence of motile trichomonads. Using a
      positive Trichomonas culture as the reference standard, the sensitivity of
      vaginal fluid alone was compared with vaginal fluid plus spun urine. The McNemar
      test for paired samples was used to test the statistical significance of the
      difference in sensitivities. RESULTS: Ninety-seven subjects had culture results
      positive for Trichomonas. Of these, 75 (77%) had a spun urine examination
      performed. Subjects were aged 13 to 22 years and all were African American.
      Seventy-three percent of the infections were detected by vaginal fluid specimen,
      64% by spun urine, and 85% by either vaginal specimen or spun urine. The
      difference in sensitivity between vaginal specimen alone and vaginal specimen
      plus spun urine was 12% (95% confidence interval, 3%-21%; P<.005). Nine patients
      who would not have been diagnosed by examination of vaginal fluid alone were
      diagnosed with the addition of spun urine examination. CONCLUSION: Microscopic
      examination of a spun urine specimen performed in conjunction with microscopic
      examination of a vaginal fluid specimen improves the detection rate of T.
      vaginalis.

PMID- 10591298
TI  - Predicting clinician injury prevention counseling for young children.
AB  - BACKGROUND: Injury is the primary cause of morbidity and mortality in children
      and an important topic for counseling. OBJECTIVE: To describe and explain
      clinicians' reported counseling behavior during the well-child examinations for
      children aged 5 years and younger on the following 4 injury prevention topics:
      motor vehicle crashes, toxic ingestion, drowning, and firearm injuries. METHODS:
      A random sample of 465 pediatricians, family physicians, and pediatric nurse
      practitioners in an urban setting received mailed questionnaires; 325 (69.9%)
      responded. Multivariate logistic regression predicting counseling on each injury
      prevention topic was performed. RESULTS: Most reported discussing motor vehicle
      occupant protection (66.2%) and toxic ingestion prevention (62.1%) during the
      well-child examination. Only 31.8% stated they counseled on drowning prevention
      and 15.7%, on firearm injury prevention. Knowledge of injury mortality and
      morbidity rates was not associated with counseling. For most topics, female
      respondents were more likely to counsel than male respondents (motor vehicle
      crash odds ratio [OR], 2.24 [P = .03]; toxic ingestion OR, 1.82 [P = .05];
      drowning OR, 1.97 [P = .04]). Health maintenance organization settings predicted
      injury prevention counseling for most topics (motor vehicle crash OR, 2.52 [P =
      .04]; toxic ingestion OR, 2.77 [P = .01]; firearm injury OR, 2.97 [P = .001]).
      Clinicians placing lower importance on counseling were less likely to counsel on
      drowning and firearm injury (drowning OR, 0.73 [P = .006]; firearm injury OR,
      0.58 [P<.001]). CONCLUSIONS: Clinicians' knowledge of local injury epidemiology
      did not influence their counseling on these topics. Clinicians and their patients
      might benefit by using programs such as The Injury Prevention Program to help
      them standardize their approach to injury prevention counseling during the
      routine well-child examination.

PMID- 10591299
TI  - How commonly are children hospitalized for dehydration eligible for care in
      alternative settings?
AB  - BACKGROUND: Avoiding unnecessary hospitalization has long been a goal of child
      health care providers. Managed care practice environments increasingly pressure
      the practicing pediatrician to avoid hospitalization. OBJECTIVES: To estimate the
      proportion of childhood dehydration hospitalizations eligible for care in
      alternative settings (eg, short-stay treatment and triage units, home nursing)
      and to assess the type and duration of services that might be required for
      alternative setting care of children with these illness episodes. DESIGN: All
      dehydration hospitalizations for the 198 593 children (aged > 1 month and < 19
      years) dwelling in Rochester, NY (Monroe County), between 1991 and 1995 were
      identified in county-wide hospital discharge computer files. Medical records were
      reviewed for a random sample of 380 of the hospitalizations. Children with major
      underlying conditions were excluded from analysis because of higher risk for
      deterioration, and greater complexity of medical care might render alternative
      settings inappropriate. Measures included a 4-item score estimating level of
      dehydration, serum bicarbonate level at presentation, and time to rehydration.
      Rehydration was defined as a drop in urine-specific gravity to 1.010 or less or
      reduction of fluid administration to the maintenance rate. RESULTS: Altogether,
      1121 dehydration hospitalizations occurred during the study period. Based on
      medical record review for a random sample of 380 of these 1121, major underlying
      problems were present in 27.4% (104) of hospitalizations sampled. Simple, acute
      gastroenteritis accounted for 75.4% (208) of 276 hospitalizations remaining in
      the sample. Levels of dehydration for these children were estimated as at least
      5% for 51.0% (106) and at least 10% for 16.3% (34) of hospital admissions, and
      serum bicarbonate levels were 12 mmol/L or less for 26.0% (54). Time from
      hospital admission to rehydration was no greater than 12 hours for 79.3% (165)
      and no greater than 24 hours for 94.7% (197). However, hospital stay was
      generally substantially longer. The time hospitalized following rehydration
      represented 85.8% of the average inpatient stay. Hospital discharge was heavily
      concentrated in daytime hours, although the children achieved rehydration at all
      hours of the day. No deterioration occurred during hospitalizations studied.
      CONCLUSION: Nearly all children hospitalized for simple, acute gastroenteritis in
      Rochester might be eligible for care in alternative settings designed to provide
      hospital-level care for short periods.

PMID- 10591300
TI  - The effect of parental monetary sanctions on the vaccination status of young
      children: an evaluation of welfare reform in Maryland.
AB  - OBJECTIVE: To determine whether financial sanctions to Aid to Families With
      Dependent Children (AFDC) recipients can be used to improve vaccination coverage
      of young children. DESIGN: Randomized controlled trial. SETTING: Six AFDC
      jurisdictions in Maryland. INTERVENTION: Recipients of AFDC were randomized to
      the experimental or control group of the Primary Prevention Initiative. Families
      in the experimental group were penalized financially for failing to verify that
      their children received preventive health care, including vaccinations; control
      families were not. PARTICIPANTS: Children aged 3 to 24 months from assigned
      families were randomly selected for the evaluation (911 in the experimental, 864
      in the control, and 471 in the baseline groups). MAIN OUTCOME MEASURES: Up-to
      date for age for diphtheria and tetanus toxoids and pertussis (DTP), polio, and
      measles-mumps-rubella (MMR) vaccines; missed opportunities to vaccinate; and
      number of visits per year. ANALYSIS: Comparisons among baseline and
      postimplementation years 1 and 2. RESULTS: Vaccination coverage of children was
      low. Less than 70% of children were up-to-date for age for polio and MMR
      vaccines; slightly more than 50% were up-to-date for DTP vaccine. Up-to-date
      rates differed little among baseline, experimental, and control groups. Over
      time, there was a decrease in missed opportunities, and more children made at
      least 1 well-child visit; however, neither improvement resulted in a change in
      vaccination status. CONCLUSIONS: The Primary Prevention Initiative did not
      contribute to an increase in vaccination coverage among these children. Minimal
      economic sanctions alone levied against parents should not be expected
      substantially to affect vaccination rates.

PMID- 10591301
TI  - The epidemiology of injuries in 4 child care centers.
AB  - OBJECTIVES: (1) To describe the pattern of injury in preschool-aged children in 4
      child care centers as compared with the results of other studies; (2) to compare
      injury rates by sex, age, and child care center; and (3) to examine environmental
      and child factors contributing to injury severity. DESIGN: A 2-year cohort study
      of 362 preschool-aged children attending 4 urban child care centers. Teachers
      completed standardized injury forms on the type of injury, body location, site of
      injury, and contributing factors. RESULTS: During the 2 years of the study, 1886
      injuries were reported. The mean and median child injury rate was 6 and 4
      injuries per 2000 exposure hours (equivalent to 1 full-time child care year),
      respectively. The majority of injuries (87%) were minor, occurred during free
      play (81%) and on the playground (74%), and were precipitated by child-related
      factors (59%), such as being pushed. Boys had significantly higher median injury
      rates than girls. Age-adjusted injury rates for each child care center were
      significantly different by center (F3 = 61, P<.001). While moderate to severe
      injuries were more often precipitated by combinations of child and environmental
      factors (chi2(4) = 20, P<.001), minor injuries were usually precipitated by child
      related factors. CONCLUSIONS: Injury data from child care centers are important
      for identifying common risk factors for frequent or severe injury events and for
      designing injury prevention programs. More research is needed to identify factors
      contributing to injuries, such as children's behavior and the child care centers'
      physical and socioemotional environments.

PMID- 10591303
TI  - Are screening echocardiograms warranted for neonates with meningomyelocele?
AB  - OBJECTIVE: To evaluate the incidence and types of congenital heart defects
      associated with meningomyelocele. DESIGN: All neonates who underwent
      meningomyelocele repair and had a perioperative echocardiogram from July 1990 to
      October 1998 were studied. Medical records were reviewed for age, weight,
      clinical cardiac examination results, meningomyelocele location, and associated
      noncardiac defects. Heart defects were identified from reviewing
      echocardiographic reports and videotapes. RESULTS: At meningomyelocele surgery,
      the 105 patients (53 female; 52 male) ranged in age from 1 to 20 days and in
      weight from 0.6 to 4.1 kg. Congenital heart disease was detected in 39 patients
      (37%). A secundum atrial septal defect was the most common defect (24%). A
      ventricular septal defect was found in 10 patients, 2 patients had anomalous
      pulmonary venous return, and 1 each had tetralogy of Fallot, bicuspid aortic
      valve, coarctation, and hypoplastic left heart syndrome. A patent ductus
      arteriosus and patent foramen ovale were not considered abnormal in these
      neonates. The cardiac examination was abnormal in only 5 of the 39 patients with
      heart defects (sensitivity = 13%). The presence of associated noncardiac defects
      (in addition to meningomyelocele) and location of the meningomyelocele
      (cervicothoracic vs lumbar) did not affect the incidence of heart disease. Of the
      patients with heart defects, girls were more frequently affected (25 of 39 vs 14
      of 39, P<.05). CONCLUSIONS: Congenital heart defects are common in neonates,
      especially girls, with meningomyelocele and are unrelated to meningomyelocele
      location or associated noncardiac defects. Because the clinical examination is
      insensitive for detecting heart defects in this group, screening echocardiograms
      are warranted. This information has important implications for ventriculoatrial
      shunting, urinary tract instrumentation (antibiotic prophylaxis), and
      neurosurgical procedures (venous air embolism).

PMID- 10591302
TI  - Psychotherapeutic medication patterns for youths with attention
      deficit/hyperactivity disorder.
AB  - OBJECTIVES: (1) To describe temporal patterns of office visits for attention
      deficit/hyperactivity disorder (ADHD) and stimulant treatment for 5- to 14-year
      old US youths; (2) to compare youth visits for ADHD with and without melication
      according to patient demographics, physician specialty, reimbursement source, and
      comorbid diagnoses; and (3) to compare office visits for youths with ADHD in
      relation to common medication patterns (stimulants alone, stimulants with other
      psychotherapeutic medication, and nonstimulant psychotherapeutic medications
      alone). DESIGN: Survey based on a national probability sample of office-based
      physicians in the United States. SETTING: Physician offices. PARTICIPANTS: A
      systematically sampled group of office-based physicians. MAIN OUTCOME MEASURES:
      National estimates of office visits for ADHD and psychotherapeutic drug visits
      for ADHD for each year and for a combined 8-year period. RESULTS: Youth visits
      for ADHD as a percentage of total physician visits had a 90% increase, from 1.9%
      in 1989 to 3.6% in 1996. Stimulant therapy within ADHD youth visits rose from
      62.6% in 1989 to 76.6% in 1996. While the majority of non-ADHD youth visits were
      conducted by primary care physicians, one third of ADHD youth visits were managed
      by psychiatry and neurology specialists. Health maintenance organization
      insurance was the reimbursement source for 17.9% of non-ADHD youth visits but
      only 11.7% of ADHD youth visits. Complex medication therapy was more likely to be
      prescribed by psychiatrists and less likely to be related to visits with health
      maintenance organization reimbursement. CONCLUSIONS: National survey estimates in
      the 1990s confirm the substantial increase in visits for youths diagnosed as
      having ADHD, with more than three quarters of these visits associated with
      psychotherapeutic medication treatment. Physician specialty and reimbursement
      source variables identify distinct patient populations with a gradient in
      psychotherapeutic medication patterns from single-drug standard (stimulant)
      therapy to complex multidrug treatment regimens for which evidence-based
      scientific information is lacking.

PMID- 10591304
TI  - Treatment of newly diagnosed pediatric epilepsy: a community-based study.
AB  - OBJECTIVE: To determine the patterns and frequency of treatment and use of
      specific drugs for newly diagnosed pediatric epilepsy. DESIGN AND SETTING:
      Prospective, community-based study. Children were recruited from physicians in
      Connecticut from 1993 to 1997. PATIENTS: Children aged 1 month through 15 years
      at the time of their first seizure, who had 2 or more unprovoked seizures, and
      who were newly diangosed during the recruitment period were eligible. MAIN
      OUTCOME MEASURE: Initiation of treatment at diagnosis and within 1 year after
      diagnosis of epilepsy. RESULTS: Of 613 children, 482 (78.6%) were treated at the
      time of initial diagnosis. By 6 months another 10.3% were treated, and by 12
      months 90% of the cohort had been treated. The most commonly prescribed
      antiepileptic drug (AED) was carbamazepine (38.8%) followed by sodium valproate
      (18.4%). Only 1 child received an investigational drug and none received any of
      the most recently approved drugs as a first AED. Children with idiopathic and
      secondarily generalized forms of epilepsy were most likely to be treated (90%
      100%), whereas children with idiopathic localization-related epilepsy were least
      likely to be treated (50.8%). Approximately 80% of those with other forms of
      epilepsy were treated at the time of diagnosis. Use of specific medications
      reflected current guidelines and recommendations for treatment of specific
      seizure types and syndromes. CONCLUSIONS: In Connecticut, approximately 20% of
      children with epilepsy are not treated at the time of initial diagnosis, and
      around 10% continue to be untreated after 1 year. This most likely reflects the
      increased understanding of the nature of pediatric epilepsy and concerns
      regarding the adverse effects of AEDs. The most commonly used first drugs are
      carbamazepine and valproate. Follow-up of this cohort may help provide
      information to guide the use of recently approved AEDs.

PMID- 10591305
TI  - Effect of newborn screening for congenital adrenal hyperplasia.
AB  - OBJECTIVE: To compare the incidence of diagnosis and morbidity in newborns who
      were screened with newborns who were not screened for congenital adrenal
      hyperplasia (CAH). DESIGN: A retrospective cohort study. SETTING: Arkansas,
      Oklahoma, and Texas. PATIENTS: An unscreened population in Arkansas and Oklahoma
      (n = 400118) was compared with a screened population in Texas (n = 1613378)
      during a 5-year period. Simultaneous data were collected on the incidence of
      diagnosis and associated morbidity in patients with CAH. MAIN OUTCOME MEASURES:
      Diagnosis of CAH, age (in days) at diagnosis, and frequency and length of initial
      hospitalization. RESULTS: The incidence of diagnosis of classic CAH per 100000
      newborns in the unscreened cohort (5.75) and in the screened cohort (6.26) was
      similar (relative risk, 0.92; 95% confidence interval, 0.58-1.44). The unscreened
      group had 0.73 fewer male newborns with salt-wasting CAH diagnosed per 100000
      newborns (relative risk, 0.73; 95% confidence interval, 0.35-1.56). The median
      age at diagnosis was 26 days for male newborns with salt-wasting CAH in the
      unscreened cohort vs 12 days in the screened cohort (z = 2.49; P = .01). Male
      newborns with simple-virilizing CAH and newborns with nonclassic CAH were
      detected only in the screened cohort. CONCLUSIONS: There was not a statistically
      significant (P = .73) increase in the diagnosis of salt-wasting CAH in the
      screened cohort. Male newborns benefited as a result of significantly (P = .01)
      earlier diagnosis, reduced morbidity, and shorter lengths of hospitalization.
      Large collaborative studies or meta-analyses are needed to determine the life
      saving benefits of screening.

PMID- 10591306
TI  - Neonatal deaths after hepatitis B vaccine: the vaccine adverse event reporting
      system, 1991-1998.
AB  - OBJECTIVE: To evaluate reports of neonatal deaths (aged 0-28 days) after
      hepatitis B (HepB) immunization reported to the national Vaccine Adverse Event
      Reporting System (VAERS). DESIGN: Case series; review of autopsy reports.
      SETTING: Voluntary reports submitted to VAERS, a passive surveillance system,
      from the US population. PATIENTS: All US neonates (0-28 days of age) whose deaths
      after HepB vaccination given alone were reported to VAERS, occurring from January
      1, 1991, through October 5, 1998. INTERVENTION: None (observational database).
      RESULTS: Of 1771 neonatal reports, there were 18 deaths in 8 boys and 9 girls (1
      patient unclassified). The mean age at vaccination for these 18 cases was 12 days
      (range, 1-27 days); median time from vaccination to onset of symptoms was 2 days
      (range, 0-20 days); and median time from symptoms to death was 0 days (range, 0
      15 days). The mean birth weight of the neonates (n = 15) was 3034 g (range, 1828
      4678 g). The causes of death for the 17 autopsied cases were sudden infant death
      syndrome for 12, infection for 3, and 1 case each of intracerebral hemorrhage,
      accidental suffocation, and congenital heart disease. CONCLUSION: Few neonatal
      deaths following HepB vaccination have been reported, despite the use of at least
      86 million doses of pediatric vaccine given in the United States since 1991.
      While the limitations of passive surveillance systems do not permit definitive
      inference, these data suggest that HepB immunization is not causing a clear
      increase in neonatal deaths.

PMID- 10591307
TI  - Early newborn hospital discharge and readmission for mild and severe jaundice.
AB  - OBJECTIVES: To further explore the relationship of early newborn hospital
      discharge and readmission for jaundice, and to determine if early hospital
      discharge was associated with increased severity of jaundice among those
      readmitted. METHODS: We performed a population-based case-control study using
      Washington State vital statistics, birth certificates, and hospital discharge
      abstracts from 1991 to 1995. Cases included 750 infants readmitted to the
      hospital for jaundice in the first 2 weeks of life; controls included 3192
      infants not readmitted. Infants with severe medical conditions and those
      delivered by cesarean section were excluded. Early hospital discharge was defined
      as fewer than 30 hours in the hospital, late hospital discharge, 30 to 78 hours.
      We assessed the risk for hospital readmission for jaundice, for hospital
      readmissions classified as brief (< or =2 days) or prolonged (>2 days), and for
      hospital readmissions classified as uncomplicated or complicated. RESULTS:
      Infants discharged from the hospital early were at increased risk for jaundice
      (odds ratio, 1.34 [95% confidence interval, 1.10-1.64] adjusted for birth year,
      gestational age, maternal race and age, parity, payer, and infant sex). The risk
      associated with early hospital discharge was similar regardless of whether the
      hospital readmission was brief or prolonged and complicated or uncomplicated. One
      hundred twenty-two infants would have to stay for longer than 30 hours to avoid 1
      jaundice readmission. CONCLUSIONS: While newborns discharged from the hospital
      early are at increased risk for hospital readmission for jaundice, the clinical
      significance is limited. Mandating longer neonatal stays may not be the most
      effective strategy to prevent hospital readmission for jaundice and its
      complications.

PMID- 10591308
TI  - Parental compliance with multiple immunization injections.
AB  - OBJECTIVE: To assess parents' (or caretakers') willingness to allow multiple
      immunization injections at a single visit. DESIGN: A survey of parental
      demographics and a medical record review to determine immunization status.
      SETTING: An inner-city pediatric clinic in Philadelphia, Pa. PARTICIPANTS: A
      convenience sample of 1059 patients who were due to receive 2 to 5 immunization
      injections at a single visit and their parents. Patients were excluded if parents
      had not previously witnessed at least 1 immunization. MAIN OUTCOME MEASURES: The
      number of immunizations due, the number of immunizations received, and the
      reasons for failure to immunize completely. RESULTS: Almost all (98.8%) of the
      children included in the study received all immunizations indicated at their
      visit. CONCLUSION: Despite potential parental resistance to multiple simultaneous
      immunization injections, this innercity population overwhelmingly complied with
      physicians' recommendations.

PMID- 10591309
TI  - Double-blind methylphenidate trials: practical, useful, and highly endorsed by
      families.
AB  - OBJECTIVE: To evaluate a 3-week, randomized, double-blind, methylphenidate
      placebo-controlled trial (MPT) in routine practice for children with attention
      deficit disorder. PATIENTS AND METHODS: School-aged children with attention
      deficit/hyperactivity disorder (Diagnostic and Statistical Manual of Mental
      Disorders, Fourth Edition criteria) who enrolled an "N of 1" trial at a pediatric
      tertiary care center were eligible. Families (n = 50) with a child eligible for
      the MPT were given 3 bottles of identical capsules. The capsules contained, in
      random order: placebo of the prescribed dose of methylphenidate (Ritalin)
      hydrochloride (0.3 mg/kg or 0.6 mg/kg). Families gave the child 1 capsule at 8 AM
      and 1 capsule at noon. The family, teacher, and physician were blinded for the
      order of medication. Conners questionnaires (Conners Parent Questionnaire and
      Conners Teacher Questionnaire) and written comments were completed by parents and
      teachers at baseline and at the end of each week. Once MPT results were known and
      following discussion with the physician, families decided whether to continue
      methylphenidate therapy. Families were interviewed by telephone 14 to 21 months
      after the MPT. RESULTS: Forty-three (86%) of the 50 eligible children (mean age,
      129 months) were contacted. No family found the MPT difficult, but 6 trials were
      incomplete, usually because of side effects. All families used the MPT to decide
      if methylphenidate was the correct treatment choice for their child and 68% (34
      of 50 families) used the results exclusively. The remaining 16 families believed
      the MPT was helpful. Overall, 31 (72%) of the 43 children had a good response to
      methylphenidate treatment--20 (47%) continued to use it for longer than 12 months
      and 8 (26%) for 2 to 12 months; 3 responders chose not to use it after the MPT.
      Nine of the 43 families chose not to use methylphenidate treatment; however, all
      indicated that participating in the MPT helped them to make that decision. In
      follow-up interviews, the same proportion of methylphenidate users and nonusers
      reported improvement in many areas of function including significantly less time
      spent doing homework. Users reported reduced aggression (P<.001) and fewer
      discipline problems (P<.01) compared with nonusers. CONCLUSIONS: An "N of 1" MPT
      was easily performed and permitted families to decide whether to use
      methylphenidate for long-term treatment of attention-deficit disorder or
      attention-deficit/hyperactivity disorder. Regardless of methylphenidate use or
      lack of use, the condition of all of these children was improved at follow-up.

PMID- 10591310
TI  - International child health electives for pediatric residents.
AB  - BACKGROUND: International child health (ICH) electives can strengthen the skills
      and shape the values of pediatric residents. Much can be learned from the
      literature on ICH electives during medical school. Yet there is little published
      information regarding ICH electives during residency, nor do educational
      guidelines for such electives exist. OBJECTIVES: To describe existing ICH
      electives among pediatric residency programs and to develop guidelines for ICH
      electives during residency training. PARTICIPANTS AND METHODS: A survey of 248
      pediatric residency programs in the United States, Canada, and Puerto Rico was
      conducted in November 1995. Consensus guidelines were developed by the executive
      committee of the American Academy of Pediatrics (AAP) Section on International
      Child Health. Consensus was achieved via full agreement among the 11 committee
      members. RESULTS: Survey response rate was 65%. International child health
      electives were offered by 25% of respondents. Most had no formal educational
      structure. An additional 42% of respondents indicated interest in ICH electives
      and requested more information. The AAP consensus guidelines for ICH electives
      focus on 4 principles: prerequisites, preceptorship, preparation, and evaluation.
      The guidelines are based on a conceptual framework that emphasizes reciprocity
      and continuity. CONCLUSIONS: While only 25% of pediatric residency programs
      currently offer ICH electives, many more express an interest in doing so.
      Educational structure for such electives is important and lacking. The AAP
      consensus guidelines provide a template for meaningful ICH experiences during
      pediatric residency. These guidelines may be applicable to other specialties as
      well.

PMID- 10591311
TI  - Radiological case of the month. Nasal foreign body simulating headache from shunt
      malfunction.

PMID- 10591312
TI  - Picture of the month. Unilateral amastia (Poland syndrome).

PMID- 10591313
TI  - Pathological case of the month. Diabetic nephropathy in cystic fibrosis.

PMID- 10591314
TI  - Bacteremia in the infant with bronchiolitis.

PMID- 10591315
TI  - Use of respiratory syncytial virus testing could safely eliminate many sepsis
      evaluations.

PMID- 10591316
TI  - A piece of my mind. A rainbow from Joanne.

PMID- 10591317
TI  - Anthrax vaccine: evidence for safety and efficacy against inhalational anthrax.

PMID- 10591318
TI  - Chest physicians explore worldwide use of home mechanical ventilation.

PMID- 10591319
TI  - Spinal cord injury research shows promise.

PMID- 10591320
TI  - From the Centers for Disease Control and Prevention. Assessment of laboratory
      tests for plasma homocysteine--selected laboratories, July-September 1998.

PMID- 10591321
TI  - From the Centers for Disease Control and Prevention. Withdrawal of rotavirus
      vaccine recommendation.

PMID- 10591322
TI  - From the Centers for Disease Control and Prevention. Shortage of intravenous
      penicillin G--United States.

PMID- 10591323
TI  - From the Centers for Disease Control and Prevention. Recommendations regarding
      the use of vaccines that contain thimerosal as a preservative.

PMID- 10591324
TI  - From the Centers for Disease Control and Prevention. Cigarette smoking among
      adults--United States, 1997.

PMID- 10591325
TI  - Recommendations for vitamin C intake.

PMID- 10591326
TI  - Recommendations for vitamin C intake.

PMID- 10591327
TI  - Increasing incidence of renal cell cancer.

PMID- 10591328
TI  - Increasing incidence of renal cell cancer.

PMID- 10591329
TI  - Moderate- vs high-dose methadone for opioid dependence.

PMID- 10591330
TI  - Moderate- vs high-dose methadone for opioid dependence.

PMID- 10591331
TI  - Moderate- vs high-dose methadone for opioid dependence.

PMID- 10591332
TI  - Resource use in liver transplantation.

PMID- 10591333
TI  - The heritability of otitis media: a twin and triplet study.
AB  - CONTEXT: Anatomical, physiological, and epidemiological data indicate that there
      may be a significant genetic component to prolonged time with and recurrent
      episodes of otitis media in children. OBJECTIVE: To determine the genetic
      component of time with and episodes of middle ear effusion and acute otitis media
      (AOM) during the first 2 years of life. DESIGN: Prospective twin and triplet
      cohort study with enrollment from 1982 through 1995. SETTING: Otitis Media
      Research Center in the ear, nose, and throat clinic of Children's Hospital of
      Pittsburgh, Pittsburgh, Pa. PATIENTS: A total of 168 healthy same-sex twin and 7
      triplet sets were recruited within the first 2 months of life; zygosity results
      were available for 140 sets; 138 (99%) of these were followed up for 1 year and
      126 (90%) for 2 years. MAIN OUTCOME MEASURES: Proportion of time with middle ear
      effusion, episodes of middle ear effusion, and episodes of AOM by zygosity
      status. RESULTS: At the 2-year end point, the estimate of heritability of time
      with middle ear effusion was 0.73 (P<.001). The estimates of discordance for 3 or
      more episodes of middle ear effusion were 0.04 for monozygotic twins and 0.37 for
      dizygotic twins (P = .01). The estimate of discordance of an episode of AOM in
      monozygotic twins was 0.04 compared with 0.49 in dizygotic twins (P = .005).
      CONCLUSIONS: Our study suggests there is a strong genetic component to the amount
      of time with middle ear effusion and episodes of middle ear effusion and AOM in
      children.

PMID- 10591334
TI  - Elevated C-reactive protein levels in overweight and obese adults.
AB  - CONTEXT: Human adipose tissue expresses and releases the proinflammatory cytokine
      interleukin 6, potentially inducing low-grade systemic inflammation in persons
      with excess body fat. OBJECTIVE: To test whether overweight and obesity are
      associated with low-grade systemic inflammation as measured by serum C-reactive
      protein (CRP) level. DESIGN AND SETTING: The Third National Health and Nutrition
      Examination Survey, representative of the US population from 1988 to 1994.
      PARTICIPANTS: A total of 16616 men and nonpregnant women aged 17 years or older.
      MAIN OUTCOME MEASURES: Elevated CRP level of 0.22 mg/dL or more and a more
      stringent clinically raised CRP level of more than 1.00 mg/dL. RESULTS: Elevated
      CRP levels and clinically raised CRP levels were present in 27.6% and 6.7% of the
      population, respectively. Both overweight (body mass index [BMI], 25-29.9 kg/m2)
      and obese (BMI, > or =30 kg/m2) persons were more likely to have elevated CRP
      levels than their normal-weight counterparts (BMI, <25 kg/m2). After adjustment
      for potential confounders, including smoking and health status, the odds ratio
      (OR) for elevated CRP was 2.13 (95% confidence interval [CI], 1.56-2.91) for
      obese men and 6.21 (95% CI, 4.94-7.81) for obese women. In addition, BMI was
      associated with clinically raised CRP levels in women, with an OR of 4.76 (95%
      CI, 3.42-6.61) for obese women. Waist-to-hip ratio was positively associated with
      both elevated and clinically raised CRP levels, independent of BMI. Restricting
      the analyses to young adults (aged 17-39 years) and excluding smokers, persons
      with inflammatory disease, cardiovascular disease, or diabetes mellitus and
      estrogen users did not change the main findings. CONCLUSION: Higher BMI is
      associated with higher CRP concentrations, even among young adults aged 17 to 39
      years. These findings suggest a state of low-grade systemic inflammation in
      overweight and obese persons.

PMID- 10591335
TI  - A prospective study of weight change and health-related quality of life in women.
AB  - CONTEXT: The mean body weight of US adults increased by 3.6 kg (7.6 lb) during
      the past 15 years, but few studies exist that examine the impact of such weight
      change on functional health status. OBJECTIVE: To investigate, prospectively, the
      association between weight change and health-related quality of life in women.
      DESIGN AND SETTING: Nurses' Health Study, a 4-year prospective observational
      study from 1992 to 1996, using the Medical Outcomes Study Short-Form 36 Health
      Status Survey (a self-administered 36-item questionnaire) to measure quality of
      life. PARTICIPANTS: A cohort of 40098 women (from 46-71 years old in 1992)
      grouped according to 3 patterns of weight change over the 4-year period: women
      whose weight remained within 2.25 kg (5 lb) of their baseline weight, women who
      lost 2.25 kg (5 lb) or more, and women who gained 2.25 kg (5 lb) or more. MAIN
      OUTCOME MEASURES: Change in scores on 7 health-related quality-of-life
      dimensions: physical functioning, vitality, bodily pain, limitations in role
      functioning due to emotional or physical problems, social functioning, and mental
      health, measured by the Short-Form 36 Health Status Survey. RESULTS: A total of
      15602 women (39%) maintained their weight, 15160 (38%) gained between 2.25 and
      9.0 kg (5-20 lb), and 6667 (17%) lost between 2.25 and 9.0 kg (5-20 lb). Weight
      gain was associated with decreased physical function and vitality, and increased
      bodily pain regardless of baseline weight. For example, the odds ratio for
      developing role limitations due to physical problems was 2.05 (95% confidence
      interval, 1.69-2.49) for the leanest women who gained 9.0 kg (20 lb) or more.
      Weight loss in overweight women was associated with improved physical function
      and vitality as well as decreased bodily pain. Weight change was more strongly
      associated with physical rather than mental health. The impact of weight change,
      especially weight gain, was just as strong in women 65 years and older as in
      women younger than 65 years. CONCLUSIONS: These longitudinal data support current
      US guidelines for women of all body mass index levels to avoid weight gain.
      Weight maintenance and, in cases of overweight, weight loss are desirable and
      likely to be beneficial for physical function, vitality, and bodily pain.

PMID- 10591336
TI  - Gender-dependent differences in outcome after the treatment of infection in
      hospitalized patients.
AB  - CONTEXT: While it is established that management strategies and outcomes differ
      by gender for many diseases, its effect on infection has not been adequately
      studied. OBJECTIVE: To investigate the role of gender among hospitalized patients
      treated for infection. DESIGN: Observational cohort study conducted during a 26
      month period from December 1996 through January 1999. SETTING: University
      affiliated hospital. PARTICIPANTS: A total of 892 patients in the surgical units
      of the hospital with 1470 consecutive infectious episodes (782 in men and 688 in
      women). MAIN OUTCOME MEASURES: Mortality during hospitalization by gender for
      infection episodes overall and for specific infectious sites, including lung,
      peritoneum, bloodstream, catheter, urine, surgical site, and skin/soft tissue.
      RESULTS: Among all infections, there was no significant difference in mortality
      based on gender (men, 11.1% vs women, 14.2%; P = .07). After logistic regression
      analysis, factors independently associated with mortality included higher APACHE
      (Acute Physiology and Chronic Health Evaluation) II score, older age, malignancy,
      blood transfusion, and diagnosis of infection more than 7 days after admission,
      but not gender (female odds ratio [OR] for death, 1.32; 95% confidence interval
      [CI], 0.90-1.94; P = .16). Mortality was higher in women for lung (men, 18% vs
      women, 34%; P = .002) and soft tissue (men, 2% vs women, 10%; P < or = .05)
      infection; for other infectious sites, mortality did not differ by gender.
      Factors associated with mortality due to pneumonia by logistic regression
      included higher APACHE II score, malignancy, diabetes mellitus, diagnosis of
      infection more than 7 days after admission, older age, transplantation, and
      female gender (OR for death, 2.25; 95% CI, 1.17-4.32; P = .02). CONCLUSIONS:
      Although gender may not be predictive of mortality among all infections, women
      appear to be at increased risk for death from hospital-acquired pneumonia, even
      after controlling for other comorbidities.

PMID- 10591337
TI  - Smoking and atherosclerotic cardiovascular disease in men with low levels of
      serum cholesterol: the Korea Medical Insurance Corporation Study.
AB  - CONTEXT: Few studies have examined the interactive effects of smoking and serum
      cholesterol level on morbidity and mortality from cardiovascular dieseases. In
      East Asia, where the prevalence of smoking is among the highest in the world,
      morbidity and mortality from ischemic heart disease (IHD) is rapidly escalating.
      OBJECTIVES: To determine whether cigarette smoking is an independent risk factor
      for atherosclerotic cardiovascular disease (ASCVD) in the Republic of Korea
      (South Korea), a population that has relatively low levels of serum cholesterol,
      and to determine whether serum cholesterol levels modify the risk relationship
      between smoking and ASCVD. DESIGN: Prospective cohort study with a follow-up
      period of 6 years (1993-1998). SETTING AND SUBJECTS: A total of 106745 Korean men
      aged 35 to 59 years who received health insurance from the Korea Medical
      Insurance Corporation and who had biennial medical evaluations in 1990 and 1992.
      MAIN OUTCOME MEASURES: Hospital admissions and deaths from IHD, cerebrovascular
      disease (CVD), and total ASCVD. RESULTS: At baseline, 61389 (58%) were current
      cigarette smokers and 64482 (60%) had a total cholesterol level of less than 5.17
      mmol/L (200 mg/dL). Between 1993 and 1998, 1006 IHD events (176 per 100000 person
      years), 1364 CVD events (238 per 100000 person-years), and 716 other ASCVD events
      (125 per 100000 person-years) occurred. In multivariate Cox proportional hazard
      models controlling for age, hypertension, hypercholesterolemia, and diabetes,
      current smoking increased the risk of IHD (risk ratio [RR], 2.2; 95% confidence
      interval [CI], 1.8-2.8), CVD (RR, 1.6; 95% CI, 1.4-1.8), and total ASCVD (RR,
      1.6; 95% CI, 1.5-1.8). For each outcome, there were significant dose-response
      relationships with amount and duration of smoking. Throughout the range of serum
      cholesterol levels, current smoking significantly increased the risk of IHD and
      CVD. In the lowest quartile of serum cholesterol levels (<4.42 mmol/L [171
      mg/dL]), the RR from current smoking was 3.3 (95% CI, 1.7-6.2) for IHD and 1.6
      (95% CI, 1.2-2.3) for CVD. There was no evidence of an interaction between
      smoking and serum cholesterol (P for interaction = .75, .87, and .92 for IHD,
      CVD, and total ASCVD, respectively). CONCLUSIONS: This study demonstrates that in
      Korea smoking is a major independent risk factor for IHD, CVD, and ASCVD and that
      a low cholesterol level confers no protective benefit against smoking-related
      ASCVD.

PMID- 10591338
TI  - Continuing screening mammography in women aged 70 to 79 years: impact on life
      expectancy and cost-effectiveness.
AB  - CONTEXT: Mammography is recommended and is cost-effective for women aged 50 to 69
      years, but the value of continuing screening mammography after age 69 years is
      not known. In particular, older women with low bone mineral density (BMD) have a
      lower risk of breast cancer and may benefit less from continued screening.
      OBJECTIVE: To compare life expectancy and cost-effectiveness of screening
      mammography in elderly women based on 3 screening strategies. DESIGN: Decision
      analysis and cost-effectiveness analysis using a Markov model. PATIENTS: General
      population of women aged 65 years or older. INTERVENTIONS: The analysis compared
      3 strategies: (1) Undergoing biennial mammography from age 65 to 69 years; (2)
      undergoing biennial mammography from age 65 to 69 years, measurement of distal
      radial BMD at age 65 years, discontinuing screening at age 69 years in women in
      the lowest BMD quartile for age, and continuing biennial mammography to age 79
      years in those in the top 3 quartiles of distal radius BMD; and (3) undergoing
      biennial mammography from age 65 to 79 years. MAIN OUTCOME MEASURES: Deaths due
      to breast cancer averted, life expectancy, and incremental cost-effectiveness
      ratios. RESULTS: Compared with discontinuing mammography screening at age 69
      years, measuring BMD at age 65 years in 10000 women and continuing mammography to
      age 79 years only in women with BMD in the top 3 quartiles would prevent 9.4
      deaths and add, on average, 2.1 days to life expectancy at an incremental cost of
      $66773 per year of life saved. Continuing mammography to age 79 years in all
      10000 elderly women would prevent 1.4 additional breast cancer deaths and add
      only 7.2 hours to life expectancy at an incremental cost of $117689 per year of
      life saved compared with only continuing mammography to age 79 years in women
      with BMD in the top 3 quartiles. CONCLUSIONS: This analysis suggests that
      continuing mammography screening after age 69 years results in a small gain in
      life expectancy and is moderately cost-effective in those with high BMD and more
      costly in those with low BMD. Women's preferences for a small gain in life
      expectancy and the potential harms of screening mammography should play an
      important role when elderly women are deciding about screening.

PMID- 10591339
TI  - Thrombolytic therapy for deep venous thrombosis?
AB  - We present the case of a man bedridden by deep venous thrombosis who was given
      intraclot instillations of recombinant tissue plasminogen activator with
      remarkable improvement. Although such aggressive treatment may be justified in
      severe cases, the role for thrombolytic agents for less symptomatic deep venous
      thrombosis is undefined. We discuss the question of when thrombolytic therapy
      should be considered. However, proper clinical trials are needed before firm
      recommendations can be made.

PMID- 10591340
TI  - Susceptibility to otitis media: strong evidence that genetics plays a role.

PMID- 10591341
TI  - Smoldering arteries? Low-grade inflammation and coronary heart disease.

PMID- 10591342
TI  - Oral contraceptives and women's health in Japan.
AB  - Japan approved the use of low-dose oral contraceptives (OCs) in June 1999, after
      more than 35 years of debate. The debate leaves a legacy of misinformation about
      and various sources of resistance to OCs. Benefits are expected to include
      greater control for women over their fertility and a reduction in the high rates
      of unplanned pregnancies and abortions. Successful implementation of the new
      policy will require a new emphasis on women's health, including the provision of
      accurate information about OCs and their associated adverse effects, a women
      centered approach to gynecological practice, and the promotion of condoms as
      protection from sexually transmitted diseases, rather than as contraception
      alone.

PMID- 10591343
TI  - JAMA Patient Page: ear infection.

PMID- 10591344
TI  - Advances and refinements in phonosurgery.
AB  - Scientific discovery, technological advances, and improved outcomes assessment
      have resulted in advances and refinements in phonosurgery. Three areas of
      substantial evolution are phonomicrosurgery, laryngeal framework surgery, and the
      use of implantable materials in vocal folds. Discovery of the importance of the
      superficial layers of the lamina propria has led to increased use of more limited
      medial microflap approaches and less frequent use of the classic lateral
      cordotomy flap approach. Alternative approaches to managing vocal fold scarring
      defects have addressed the separation of body and cover and provided suitable
      lamina propria replacement. Approaches to sulcus vocalis have been refined to
      address type II (linear vergeture) and type III (focal invasive pit) sulcus,
      where there is loss of lamina propria, while still recognizing the common
      nonpathological type I (physiological) sulcus. Technological advancements such as
      photodynamic therapy, tuned dye lasers, and laryngeal microdebridement have
      augmented the armamentarium for mechanical removal of laryngeal papillomata.
      Careful infusion-assisted microexcision and adjunctive medical management have
      been refined and made more effective. Laryngeal framework surgery has embraced
      the development of Silastic, hydroxylapatite, expanded polytetrafluoroethylene,
      and titanium shims. Anatomical studies have helped to improve operative precision
      and safety, and have led to inventive variations in arytenoid repositioning that
      improve closure of the posterior subunit. Vocal fold augmentation by injection
      has been facilitated by innovative use of the rigid telescope and intraoperative
      videostroboscopy. Anatomical studies have focused on the infrafold region and
      rheological studies have attempted to match viscoelastic properties of injectable
      substances to those of vocal fold tissues. Alloplastic materials such as Teflon
      have been largely supplanted by newer bioimplantables such as fat, collagen, and
      fascia.

PMID- 10591345
TI  - Clinical predictors of obstructive sleep apnea.
AB  - OBJECTIVE: To identify physical findings that can be standardized to predict the
      presence and the severity of obstructive sleep apnea (OSA). STUDY DESIGN: One
      hundred seventy-two patients who answered questionnaires with responses that
      suggested they might have OSA were included in this prospective study. METHODS:
      All patients underwent a physical examination and polysomnography. The physical
      examination included the measurement of four parameters used by anesthesiologists
      to identify patients likely to have difficult intubation to determine if these
      same parameters predict OSA. We recorded modified Mallampati grade (MMP), tonsil
      size, and body mass index (BMI) and measured thyroid-mental distance (TMD) and
      hyoid-mental distance (HMD) in the study population. RESULTS: When the physical
      findings were correlated singly with the respiratory disturbance index (RDI), we
      found that MMP (P < .001), tonsil size grading (P = .008), and BMI (P = .003)
      were reliable predictors of OSA. A greater correlation with OSA emerged when an
      "OSA score" was formulated by factoring the MMP, tonsil grade, and BMI grade (RDI
      = 7.816 x MMP + 3.988 x Tonsil Size + 4.675 x BMI - 7.544). A high score was not
      only predictive of OSA but also correlated well with OSA severity. Neither HMD
      nor TMD correlated with the severity of RDI. CONCLUSIONS: An OSA score may help
      identify those patients who should have a full sleep evaluation.

PMID- 10591346
TI  - Applications of distortion-product emissions to an otological practice.
AB  - OBJECTIVES: The multiple clinical applications of distortion-product emissions
      (DPEs) to an otological practice are reviewed. Through an examination of studies
      involving thousands of infants, as well as adult ears, the relationships between
      measurements of DPEs and PTTs (PTTs) are examined. The cochlear physiology
      underlying generation of DPEs and the interpretation of these measurements are
      described in some detail. We study the contribution of phase measurements of DPEs
      to calculation of delay in cochlear traveling waves. The clinical applications of
      these measurements are described. The objective of this work is to demonstrate
      the clinical utility of DPEs through an examination of the correlation of the
      features of DPEs with PTTs in patients varying in age from newborn to the
      elderly. STUDY DESIGN:  METHODS: Experimental design and methodology involved
      careful prospective selection of large numbers of subjects in each age group,
      novel techniques for recording DPEs, and multivariate statistical analysis of the
      data. Three separate experiments encompass issues surrounding the age groups of
      adults, neonates, and elderly individuals. RESULTS: The results show that current
      techniques allow a 90% correct prediction of auditory PTTs for frequencies
      varying from 1,000 to 6,000 Hz, for patients of all ages. CONCLUSION: Techniques
      for measurement of DPEs currently represent an integral diagnostic component for
      an otological practice. The potential future application of measures of DPEs to
      diagnosis of tinnitus is described. With an extension of the technique for
      measuring DPEs to the phenomenon of reflectance, there may be promise of
      application to novel approaches to the treatment of tinnitus and the design of
      hearing aids.

PMID- 10591347
TI  - Advantages of a new miniature hearing aid for mild to moderate hearing loss.
AB  - OBJECTIVES/HYPOTHESIS: To evaluate the performance of a new, miniature, behind
      the-ear hearing aid designed for individuals with mild to moderate high-frequency
      hearing loss who need an aid but are reluctant to try one. The aid is essentially
      invisible, leaves the ear canal open, and can be fit in less than 30 minutes
      without an ear impression. The cost is less than $500. STUDY DESIGN: A 4-week
      trial of the aid in 63 ears (62 subjects) with mild to moderate bilateral hearing
      loss. METHODS: A questionnaire was completed at the end of the study by each
      subject asking them to evaluate several features of the aid (cosmesis, comfort,
      understanding speech, amplification, and so forth) and to compare their unaided
      performance in quiet and in noise with the test hearing aid. A rating scale of 1
      to 10 was used, with 10 being excellent and 1 poor. RESULTS: Subjective
      improvement in understanding speech in both quiet (5.8-->7.3) and noise (4.6-
      >5.9) occurred with the aid. Cosmesis, comfort, and appearance were highly rated
      (mean scores, > 8). CONCLUSIONS: This aid appears to have several features
      (comfort, cost, performance, and cosmesis) that make it ideal as a first aid for
      patients with mild to moderate losses.

PMID- 10591348
TI  - Role of aerating mastoidectomy in noncholesteatomatous chronic otitis media.
AB  - OBJECTIVE: To assess the success rate of revision tympanoplasty with aerating
      mastoidectomy in patients with noncholesteatomatous chronic otitis media who had
      failed at least one prior tympanoplasty. STUDY DESIGN: Retrospective chart
      review. METHODS: Data were analyzed from 135 patients available for clinical and
      audiometric studies with a minimum of 18 months' follow-up. All patients had
      failed at least one prior tympanoplasty and presented with: 1) a persistent
      tympanic membrane perforation with intermittent drainage, or 2) a wet draining
      ear, unresponsive to systemic antibiotic and topical management. All patients
      underwent 1.5-mm, high-density, bone window computed tomography (CT) scanning to
      assess middle ear, epitympanic, and mastoid air cell pneumatization. All patients
      underwent revision tympanoplasty with aerating mastoidectomy via a postauricular
      approach. Patient charts were reviewed for information regarding preoperative
      radiographic findings, mucosal and ossicular findings at the time of surgery, and
      success or failure of revision tympanomastoidectomy. RESULTS: The tympanic
      membrane graft take rate for the entire group of 135 patients was 90.4% (13
      grafts failed). A majority of the patients were found to have radiographic and
      intraoperative evidence of middle ear/mastoid disease. CONCLUSION: For patients
      with noncholesteatomatous chronic otitis media who have failed prior
      tympanoplastic reconstruction, an aerating mastoidectomy may be indicated and may
      improve the success rate of the surgery.

PMID- 10591349
TI  - Combined arytenoid adduction and laryngeal reinnervation in the treatment of
      vocal fold paralysis.
AB  - OBJECTIVE/HYPOTHESIS: Glottal closure and symmetrical thyroarytenoid stiffness
      are two important functional characteristics of normal phonatory posture. In the
      treatment of unilateral vocal cord paralysis, vocal fold medialization improves
      closure, facilitating entrainment of both vocal folds for improved phonation, and
      reinnervation is purported to maintain vocal fold bulk and stiffness. A
      combination of medialization and reinnervation would be expected to further
      improve vocal quality over medialization alone. STUDY DESIGN: A retrospective
      review of preoperative and postoperative voice analysis on all patients who
      underwent arytenoid adduction alone (adduction group) or combined arytenoid
      adduction and ansa cervicalis to recurrent laryngeal nerve anastomosis (combined
      group) between 1989 and 1995 for the treatment of unilateral vocal cord
      paralysis. Patients without postoperative voice analysis were invited back for
      its completion. A perceptual analysis was designed and completed. METHODS:
      Videostroboscopic measures of glottal closure, mucosal wave, and symmetry were
      rated. Aerodynamic parameters of laryngeal airflow and subglottic pressure were
      measured. A 2-second segment of sustained vowel was used for perceptual analysis
      by means of a panel of voice professionals and a rating system. Statistical
      calculations were performed at a significance level of P = .05. RESULTS: There
      were 9 patients in the adduction group and 10 patients in the combined group.
      Closure and mucosal wave improved significantly in both groups. Airflow decreased
      in both groups, but the decrease reached statistical significance only in the
      adduction group. Subglottic pressure remained unchanged in both groups. Both
      groups had significant perceptual improvement of voice quality. In all tested
      parameters the extent of improvement was similar in both groups. CONCLUSION: The
      role of laryngeal reinnervation in the treatment of unilateral vocal cord
      paralysis remains to be established.

PMID- 10591350
TI  - A comparison of Asian and white patients with obstructive sleep apnea syndrome.
AB  - OBJECTIVE: To evaluate the possible differences between Asian and white patients
      with obstructive sleep apnea syndrome. METHODS: A retrospective review of Asian
      and white patients during a 12-month period was conducted. Patients with
      respiratory disturbance index (RDI) > or = 15 based on polysomnography were
      included in the study. Variables examined include age, sex, body mass index
      (BMI), RDI, lowest oxygen saturation (LSAT), and cephalometric analysis data.
      RESULTS: Fifty-eight Asian patients (53 men) and 293 white patients (260 men)
      were studied. The Asians were younger (44.1 +/- 9.8 vs. 47.5 +/- 11.6 y, P =
      .02), and the mean BMI (kg/m2) was 26.6 +/- 3.7 in the Asians and 30.7 +/- 5.9 in
      the whites (P < .001). The mean RDI was similar (56.6 +/- 34.9 vs. 55.6 +/- 26.9,
      P = NS), but the mean LSAT was lower in the whites (77.7 +/- 9.9% vs. 70.0 +/-
      15.6%, P < .001). Based on the cephalometric data, the Asians have
      maxillomandibular protrusion, narrower cranial base angle, larger posterior
      airway space, and more superiorly positioned hyoid bone compared with the whites.
      CONCLUSIONS: Although male gender was found to be an important risk factor for
      obstructive sleep apnea syndrome in both Asian and white patients, obesity may be
      a less significant risk factor in the Asians because the majority of our Asian
      patients were nonobese. There was also variability in the craniomandibular
      factors that contributed to obstructive sleep apnea syndrome in the two groups.

PMID- 10591351
TI  - Impact of steroids on recovery after uvulopalatopharyngoplasty.
AB  - OBJECTIVE: To determine whether perioperative systemic corticosteroid
      administration can reduce uvulopalatopharyngoplasty (UPPP) postoperative
      morbidities (e.g., pain, anorexia, sleep disturbance, mouth odor, and fatigue) or
      reduce narcotic analgesic usage. STUDY DESIGN: A prospective, double-blinded
      study with random assignment of treatment agent (placebo or corticosteroid).
      METHODS: From 1995 to 1998, a consecutive sample of 48 adults presenting for
      elective UPPP surgery alone or in combination with tonsillectomy or septoplasty,
      or both, were enrolled. Twenty-eight subjects completed the protocol and were
      equally distributed by random assignment to intramuscular (IM) and intravenous
      (IV) doses of placebo (saline) or corticosteroid (60 mg methylprednisolone IM and
      12 mg dexamethasone IV). Acetaminophen with codeine analgesic was available to
      both groups as needed. Subjects recorded a diary of symptom severity scores over
      the first postoperative week relating to eight commonly reported morbidities (1-4
      points) and the daily quantity of narcotic consumed. RESULTS: Statistical
      comparison (Wilcoxon's rank sum test) showed no significant differences between
      subjects treated with placebo or corticosteroid on postoperative day 1 or 7.
      Three subjects (21%) in each treatment group reported no postoperative use of
      narcotic analgesic. CONCLUSIONS: No statistically or clinically significant
      benefits were derived from perioperative systemic corticosteroid treatment in
      this sample of 28 adults treated with UPPP alone or in combination with
      tonsillectomy or septoplasty, or both. Some individuals tolerate post-UPPP
      discomfort without a narcotic analgesic.

PMID- 10591352
TI  - Effect of laser uvulopalatoplasty on middle ear function.
AB  - OBJECTIVES: Palatal musculature is known to be responsible for the active opening
      of the eustachian (auditory) tube. Because laser-assisted uvulopalatoplasty
      (LAUP) may involve partial division of these muscles, the effect of this
      procedure on middle ear pressures (MEPs) and middle ear volumes (MEVs) was
      investigated. STUDY DESIGN: A controlled interventional trial with one limb
      receiving treatment and the other none. Preoperative and postoperative
      measurements were carried out in both groups. METHODS: A control group of 15
      normal volunteers and a study group of 22 patients undergoing LAUP all of whom
      had normal ears and type A tympanograms before the trial were recruited. Repeat
      tympanometry was carried out after 3 months in both groups. The results of MEP
      and MEV were recorded for both groups and analyzed by the Mann-Whitney U test.
      RESULTS: A trend toward reduced MEP and MEV was noted in the LAUP group, but did
      not achieve statistical significance. A study with more patients may achieve
      significance. CONCLUSIONS: No significant effects on middle ear pressures or
      volumes 3 months after LAUP were demonstrated. A much larger study may, however,
      arrive at a statistically significant result and further work is warranted.
      Relevant palatal and tubal anatomy is discussed and a brief review of the
      relevant literature is given.

PMID- 10591353
TI  - Ketoprofen and fentanyl for pain after uvulopalatopharyngoplasty and
      tonsillectomy.
AB  - OBJECTIVES: The treatment of postoperative pain after uvulopalatopharyngoplasty
      (UPPP) and tonsillectomy presents a challenge. Opioids can cause sedation and
      respiratory depression. Nonsteroidal antiinflammatory drugs can increase
      postoperative bleeding. The authors have evaluated the severity of postoperative
      pain and the consumption of opioid in 53 adult patients undergoing either UPPP or
      tonsillectomy. STUDY DESIGN: A prospective, parallel-groups study. METHODS: A
      general endotracheal anesthesia was used in each patient. After surgery patients
      received ketoprofen 1 mg/kg as an intravenous bolus, followed by a continuous
      infusion of 4 mg/kg during 24 hours. For rescue analgesia patient-controlled
      intravenous fentanyl was used. RESULTS: Both UPPP and tonsillectomy are
      associated with intense postoperative pain. More than 40% of the patients had
      high pain scores during the first 24 postoperative hours. Postoperative pain
      after UPPP was more severe and the difference was significant during swallowing
      (P < .05). The need for fentanyl in the UPPP group was twice that of the
      tonsillectomy group (P < .01). There was a high interindividual scatter in the
      patient-controlled fentanyl attempts in both groups. The patients in the UPPP
      group needed significantly more oxygen supply during recovery (P = .007). No
      serious adverse effects occurred and none of the patients experienced
      postoperative bleeding that required any intervention. CONCLUSION: Individually
      tailored analgesic treatment protocol is essential for patients undergoing UPPP
      and tonsillectomy to ensure safe and effective pain alleviation.

PMID- 10591354
TI  - Fish bones at the cricopharyngeus: a comparison of plain-film radiology and
      computed tomography.
AB  - OBJECTIVES: To compare and contrast the use of plain film radiology and computed
      tomography (CT) scanning in the detection of fish bones at the level of the
      cricopharyngeus. STUDY DESIGN: Prospective study of 30 different fish bones
      placed at the level of the cricopharyngeus in a fresh human cadaver head and neck
      specimen and imaged using both plain films and CT scans. METHODS: Thirty
      different bones from 10 different local species of fish were selected and grouped
      as small, medium, or large in size. Both plain-film and CT images of the bones
      were reported by a radiologist as A, easily seen; B, seen on close inspection; or
      C, not seen. Results were analyzed using McNemar's test. RESULTS: CT scanning was
      superior to plain-film radiology in demonstrating the presence of fish bones at
      the level of the cricopharyngeus (P < .0001, McNemar's test, df = 1 when
      comparing report type A with B and C). CONCLUSION: The superior usefulness of CT
      scans in demonstrating the presence of fish bones lodged at the cricopharyngeus
      has been clearly shown in this study; therefore we advocated its use in selected
      cases.

PMID- 10591355
TI  - Complications in skull base surgery for malignancy.
AB  - OBJECTIVES: To review a consecutive series of skull base surgeries, establish the
      rate of complications, and outline their prevention and management. STUDY DESIGN:
      A retrospective review of 107 consecutive intracranial/extracranial operations
      performed for malignancy that transgresses the skull base. METHODS: The hospital
      charts of 107 operations performed on 98 patients at the University of California
      at Davis Medical Center. The type of operation, cause of death, and complications
      were noted. RESULTS: The complication rate was 50.5%. Forty-eight patients had no
      complications. There were six perioperative deaths. The most common surgical
      complications were cerebrospinal fluid leak (11.2%), meningitis (4.8%), and wound
      breakdown (15%). The most common medical complications were pneumonia (6.5%),
      cardiac disturbance (4.7%), and electrolyte imbalance (3.7%). The only prior
      treatment that was accompanied by a significant increase in complications was
      previous surgery. CONCLUSIONS: patients who had cranial base surgery for the
      intracranial spread of head and neck cancer. The perioperative death rate is less
      than 4%. The major complications were at an acceptable rate.

PMID- 10591356
TI  - High-dose-rate brachytherapy for primary carcinomas of the oral cavity and
      oropharynx.
AB  - OBJECTIVE: Local control for patients treated with primary radiation therapy for
      tumors of the oral cavity is improved using low-dose-rate brachytherapy.
      Oropharyngeal carcinomas have also been treated with brachytherapy. The few
      reports in the literature regarding high-dose-rate brachytherapy (HDRBT) for head
      and neck cancer involve small numbers of patients and often contain a mix of
      palliative and curative cases. The purpose of this study is to evaluate the
      feasibility of HDRBT in the largest reported cohort of primary head and neck
      cancer patients treated with primary radiation therapy. STUDY DESIGN: This is a
      prospective nonrandomized study. METHODS: Fifty-five patients with primary
      untreated squamous cell carcinomas of the oral cavity and oropharynx were
      analyzed. There were 16 patients with T1, 26 with T2, 8 with T3, and 5 with T4
      tumors. All patients received external-beam radiotherapy (EBRT) followed by
      HDRBT. Thirty-eight patients received hyperfractionated (twice daily) EBRT
      followed by HDRBT two or three times daily. Patients with cervical adenopathy
      also received hyperthermia and an electron boost to the site(s) of positive
      nodes. Median follow-up was 2.7 years. Toxicity and local control were analyzed.
      Data were analyzed by the Kaplan-Meier life-table method with statistical
      significance determined by the X2 and log-rank tests. RESULTS: High-dose-rate
      brachytherapy was extremely well tolerated. Only 9 patients (16%) developed a
      complication. Four patients developed osteoradionecrosis, and five developed soft
      tissue necrosis, all of which healed with conservative medical management. No
      complication required surgical intervention or hospitalization. Actuarial 2-year
      local control for the entire cohort was 79%. Local control was 87% for patients
      with T1 (15/16) and T2 (22/26) tumors versus 47% for T3 (5/8) and T4 (2/5) tumors
      (P < .01). CONCLUSIONS: High-dose-rate brachytherapy is feasible as a boost for
      patients with primary squamous cell carcinomas of the oral cavity and oropharynx.
      Patients with T1 and T2 tumors fared exceptionally well; those with advanced
      tumors may require more aggressive treatment, such as higher radiation doses,
      surgical resection, or systemic chemotherapy. The use of HDRBT both shortens the
      overall treatment time and limits the volume of tissue exposed to high doses of
      radiation therapy. In the future, as more patients treated with HDRBT are
      evaluable, we hope to identify potential factors that predict for local control
      so that we may select patients optimally for this treatment.

PMID- 10591357
TI  - Role of sensation in swallowing function.
AB  - OBJECTIVES: Sensation in the oral cavity and laryngopharynx has long been
      believed to be crucial for normal swallowing. One illustration of this belief has
      been intense interest in reconstruction after cancer resection using sensate
      tissue transfer as a means of improving swallowing function. A contrarian view is
      that mucosal sensation, by itself, is, in fact, relatively unimportant to
      swallowing function. STUDY DESIGN: A prospective study was designed to test the
      hypothesis that normal swallow function can occur with anesthesia of the upper
      aerodigestive tract mucosa. METHODS: Baseline (sensate) swallowing function of 13
      healthy adults was assessed via video endoscopic swallow studies (VESS). Each
      subject was then topically anesthetized with lidocaine applied to the oral
      cavity, oropharynx, hypopharynx, and larynx. Swallowing was then reassessed via
      VESS and compared to the baseline examination to look for differences in
      function. RESULTS: There was little difference in swallowing ability between
      sensate and anesthetized states, even though all the subjects felt that their
      swallowing had been profoundly disrupted after lidocaine was applied. The main
      difference was a small increase in the time from food administration to
      swallowing. A few experienced trace aspiration, which was instantly eliminated on
      subsequent swallows with simple coaching. CONCLUSION: Normal swallowing can occur
      spontaneously or with simple coaching even with complete anesthesia of the upper
      aerodigestive tract mucosa. Current beliefs about the value of sensate free flaps
      and the importance of sensation in swallowing in general may need refinement.

PMID- 10591358
TI  - Penicillin reduces new bone formation in acute otitis media.
AB  - OBJECTIVE: Previous studies have shown that acute otitis media alters modeling
      dynamics in bone tissue structures surrounding the middle ear cavity. Initial
      resorption is followed by formative activity, which is seen as massive
      osteoneogenesis. However, neither resorptive nor formative activity occurs in the
      otic capsule, supporting the theory on existence of a perilymphatic barrier of
      specialized bone. STUDY DESIGN: To investigate the effect of penicillin
      administration on the pathological bone modeling in acute otitis media, we
      employed a rat model of acute pneumococcal otitis media. METHODS: Five rats were
      sacrificed on postinoculation days 4, 8, 16, 90, and 180, preceded by oral
      administration of penicillin V 100 mg/kg per day, initiated on day 2 and lasting
      5 (2) days. Using a light microscope, bone histomorphology was registered and the
      thickness measured in four well-defined localities, followed by comparison with a
      previous study of untreated animals. RESULTS: Measured bone thickness was
      unaffected by treatment on day 4, but significantly reduced in two localities on
      day 8 and in all localities on following days of sacrifice. Bone cytomorphology
      and histomorphology were otherwise unaffected by penicillin administration.
      CONCLUSION: Penicillin reduces new bone formation in acute otitis media, leaving
      other features of histomorphology unchanged.

PMID- 10591359
TI  - Cochlear microphonics for hearing preservation in vestibular schwannoma surgery.
AB  - OBJECTIVES: To determine whether cochlear function is beneficial in decision
      making concerning the selection of hearing preservation surgery for vestibular
      schwannoma. STUDY DESIGN: Retrospective review of 44 patients undergoing tumor
      resection with a middle fossa approach. METHODS: Cochlear microphonics in
      electrocochleography together with tumor size, pure-tone average (PTA), speech
      discrimination score (SDS), auditory brainstem response (ABR), and compound
      action potentials were examined. As acoustic stimuli, short tone-bursts with
      frequencies of 0.5, 1, and 2 kHz were employed to measure cochlear microphonics
      and a click was used to obtain compound action potentials. We determined
      detection thresholds of cochlear microphonics and action potentials. RESULTS: The
      overall rate of preservation of serviceable hearing was 59.1% (26/44). There were
      significant differences between patients with and without serviceable
      postoperative hearing in PTA, SDS, finding of ABR, compound action potential
      detection threshold, and mean cochlear microphonic detection threshold (at 0.5,
      1, and 2 kHz). However, tumor size was unrelated to hearing outcome. Serviceable
      hearing was preserved in 23 (76.7%) of 30 patients, with a mean cochlear
      microphonic detection threshold of 40 dB nHL or less, suggesting normal or
      slightly impaired cochlear function. Hearing recovery was recognized in three
      patients, who also had a mean cochlear microphonic detection threshold of 40 dB
      nHL or less. Of the three patients, two had lower cochlear microphonic detection
      thresholds than audiometric thresholds, demonstrating the existence of a
      retrocochlear component in their hearing loss. CONCLUSIONS: The cochlear
      microphonic detection threshold predicts not only hearing preservation but also
      hearing improvement in patients with vestibular schwannomas.

PMID- 10591360
TI  - Prevention of nausea and vomiting after middle ear surgery: granisetron versus
      ramosetron.
AB  - OBJECTIVE/HYPOTHESIS: Middle ear surgery is associated with a relatively high
      incidence of postoperative nausea and vomiting. This study was undertaken to
      compare the efficacy of ramosetron with granisetron for preventing nausea and
      vomiting after middle ear surgery. STUDY DESIGN: Prospective, randomized, double
      blind study. METHODS: In a randomized, double-blind manner, 100 ASA I patients
      (69 women), aged 23 to 65 years, received either ramosetron 0.3 mg or granisetron
      3 mg intravenously (n = 50 of each) immediately before the induction of
      anesthesia. A standard general anesthetic technique and postoperative analgesia
      were used. Postoperative nausea and vomiting and safety assessments were
      performed continuously during the first 24 hours (0-24 h) and the next 24 hours
      (24-48 h) after anesthesia. RESULTS: A complete response, defined as no nausea
      and vomiting and no need for another rescue medication, during the first 24 hours
      after anesthesia (0-24 h) occurred in 90% of patients receiving ramosetron and in
      86% of patients receiving granisetron, respectively (P = .379); the corresponding
      incidence rates in the second 24 hours after anesthesia (24-48 h) were 90% and
      66% (P = .003). No clinically important adverse events were observed in either
      group. CONCLUSION: Prophylactic use of ramosetron is more effective than
      granisetron for long-term prevention of nausea and vomiting after middle ear
      surgery.

PMID- 10591361
TI  - Inner ear barotrauma after stapedectomy in the guinea pig.
AB  - OBJECTIVE: The safety of scuba diving after stapedectomy is controversial.
      Stapedectomy is thought to predispose to inner ear barotrauma (e.g., perilymph
      fistula); however, many individuals continue to scuba dive following stapedectomy
      without ill effects. The purpose of this study was to evaluate the cochlear
      effects of barotrauma, similar to that experienced with scuba diving, on inner
      ears previously treated with stapedectomy. STUDY DESIGN: Prospective, controlled.
      METHODS: Sixteen Hartley albino guinea pigs underwent unilateral total
      stapedectomy followed by hyperbaric dives on 5 consecutive days, beginning 3
      weeks after stapedectomy. Cochlear effects were determined using click and tone
      pip evoked electrocochleographic thresholds and cochlear hair cell counts.
      RESULTS: Mean auditory thresholds increased by 29 dB after stapedectomy (P <
      .001), then remained stable thereafter. Mean thresholds in both the operated and
      control ears did not change with hyperbaric dives. Evidence of middle ear
      barotrauma (e.g., hemorrhage or tympanic membrane perforation) was observed in
      eight poststapedectomy ears and five control ears, but none demonstrated
      significant threshold elevation greater than or equal to 10 dB. Hair cell counts
      were not different between operated and control ears. CONCLUSIONS: Stapedectomy
      does not appear to predispose to cochlear sequelae in the guinea pig model of
      diving-related barotrauma.

PMID- 10591362
TI  - Computerized dynamic posturography and seasickness susceptibility.
AB  - OBJECTIVE/HYPOTHESIS: The neural mismatch theory emphasizes the role of
      conflicting multimodal sensory interactions in producing both motion sickness and
      the rearrangement process that finally leads to habituation to the adverse motion
      conditions. If this theory is, indeed, correct, the patterns of the response to
      the integrated signal from simultaneous multisensory stimulation, characterized
      by unusual relationships between the senses responsible for spatial orientation,
      should differ according to motion sickness susceptibility. Computerized dynamic
      posturography (CDP) provides the opportunity to simultaneously change the
      interactions between visual, somatosensory, and vestibular inputs, thus giving an
      indication of the relative importance of these senses in maintaining balance. The
      objective was to investigate balance strategies in naval crew members with
      differing susceptibility to sea conditions using CDP. STUDY DESIGN: Cross
      sectional, parallel-group design. METHODS: Twenty subjects susceptible to
      seasickness (SS) and 20 nonsusceptible subjects (NSS), healthy male volunteers
      aged 18 to 25, were tested using the EquiTest system (NeuroCom, Inc., Clackamas,
      OR). RESULTS: The SS group exhibited significantly less stability than the NSS
      group in condition 5 of the sensory organization test (SOT). The ratio of the SOT
      scores of conditions 5 to 1 (the vestibular organization pattern) was also found
      to be significantly lower in the SS group. CONCLUSIONS: The results suggest that
      SS might be more dependent on somatosensory and visual inputs and less on
      vestibular inputs for maintenance of balance compared with NSS. Higher
      susceptibility to seasickness might reflect abnormal weighting of sensory
      modalities during the integration process. This would result in disruption of the
      integration process required to maintain balance and a sense of orientation in
      space in conditions producing conflicting sensory inputs.

PMID- 10591363
TI  - Localization of laminin isoforms in the guinea pig cochlea.
AB  - OBJECTIVE: To elucidate the pathogenesis of inner ear disorders by examining the
      distribution of a major component of basement membranes, the glycoprotein
      laminin. STUDY DESIGN: Animal model. METHODS: Adult guinea pig cochleae were
      fixed with methanol and sectioned. Sections were examined for the presence of
      laminins alpha2, alpha5, beta1, and gamma1 using immunohistochemistry. RESULTS:
      Laminins alpha2, alpha5, and beta1 were not detected. Laminin gamma1 was found in
      the limbus, spiral ligament, and stria vascularis. CONCLUSIONS: Anti-laminin
      antibodies have been found in patients with inner ear disorders. Laminin gamma1
      demonstrates specific staining at multiple sites in the guinea pig cochlea. These
      structures may be targets of antibodies causing sensorineural hearing loss.

PMID- 10591364
TI  - Audiologic evaluation of neonates with severe hyperbilirubinemia using
      transiently evoked otoacoustic emissions and auditory brainstem responses.
AB  - OBJECTIVES: To audiologically clarify the lesion site and to test the reliability
      of transiently evoked otoacoustic emissions (TEOAEs) in hearing screening of
      hyperbilirubinemic neonates. STUDY DESIGN: Eleven neonates with severe
      hyperbilirubinemia who had exchange transfusion in the neonatal intensive care
      unit of an academic hospital over a 3-year period were included in this study.
      They were tested with auditory brainstem response (ABR) and TEOAEs after exchange
      transfusion during hospitalization or at an immediate follow-up visit after
      discharge. Follow-up ABR tests were performed when infants showed significant
      hearing loss. METHODS: ABR and TEOAE tests were performed on the 11 neonates with
      severe hyperbilirubinemia after exchange transfusion. Follow-up ABR tests were
      carried out in 3-month intervals in the four neonates who showed abnormal or no
      response on initial ABR. RESULTS: Four neonates showed abnormal or no response
      and the other seven demonstrated normal response in ABR. All 11 neonates passed
      TEOAEs. Two neonates showed improvement in auditory function at 3- or 6-month
      follow-up ABR. CONCLUSION: The results of this study indicate that the site of
      lesion in hearing loss caused by hyperbilirubinemia may be at the retrocochlear
      location while the cochlea remains intact. TEOAEs may have limitations in
      evaluation of hearing in the neonates with hyperbilirubinemia.

PMID- 10591365
TI  - Office-based insertion of pressure equalization tubes: the role of laser-assisted
      tympanic membrane fenestration.
AB  - OBJECTIVE: To describe the role of the hand-held otoscope combined with a
      flashscanner CO2 laser, OtoLAM (ESC/Sharplan, Yokneam, Israel), for pressure
      equalization tube (PET) insertion in an office setting. STUDY DESIGN:
      Prospective, multisite, clinical cohort trial (Institutional Review Board
      approved; informed consent) in the setting of pediatric otolaryngology outpatient
      departments at four tertiary care children's hospitals. METHODS: Selected for the
      study were 54 patients (96 ears), ages 6 months to 23 years, who met standard
      indications for PET insertion using cold-knife myringotomy and tube insertion
      under general anesthesia. PETs were indicated for recurrent otitis media, chronic
      otitis media with effusion, and eustachian tube dysfunction-all unresponsive to
      medical therapy. Topical anesthesia was achieved with iontophoresis (n = 1) or
      topical anesthesia: 8% tetracaine on an Otowick (Xomed Surgical Products,
      Jacksonville, FL, catalogue No. 400141) against the tympanic membrane for 45 to
      180 minutes (n = 53). Laser-assisted tympanic membrane fenestration was performed
      with the OtoLAM set at single pulse, 2.0- to 2.6-mm spot size, and between 3 and
      18 W. Insertion of grommets was accomplished using the otomicroscope and an
      "alligator" microforceps. Restraints with papoose were used in 79% of children
      with a mean age of 34.4 months (SD = 60.9 mo). Clinical, parent/patient, and
      physician satisfaction and comparative cost impact outcomes are described.
      RESULTS: All ears but three (3%) underwent successful placement of a PET. Pain
      was described as "absent" in 39%, "present but tolerable" in 30%, and "severe" in
      30% of children at the time of procedure; 5 minutes after the procedure pain was
      described as "absent" in 75%, "present but tolerable" in 22%, and "severe" in 3%.
      Tube plugging (3 of 74 available ears; 4%) or persistent otorrhea (1 of 74 ears;
      1.4%) occurred infrequently at the 1-month follow-up. Before PET insertion,
      hearing loss was noted in 66% of cases (mild, 38%; moderate, 22%; and severe,
      6%). Mild hearing loss was noted in only 8% and moderate hearing loss in 2% of 47
      (50%) of the ears at the 3-month follow-up. Ninety-two percent of parents were
      highly satisfied with the procedure in preference to PETs in the operating room
      under general anesthesia, and 97% preferred OtoLAM with PET insertion, rather
      than further courses of antibiotics; only one parent would rather have had the
      PET insertion under general anesthesia. Cost savings to health care
      organizations, particularly payers, and to parents are substantial (32%-48%) and
      warrant attention. Cost to the physician is manageable only if an appropriate
      approach to the third party payers results in a substantial increase in
      reimbursements. CONCLUSIONS: The data indicate excellent clinical effectiveness,
      reduced risk, and high parent and physician satisfaction. Strong incentives for
      physicians to use this technique are in all stakeholders' best interests. These
      incentives need to evolve as soon as possible for the more widespread acceptance
      of OtoLAM with PET insertion in an office setting for appropriately selected
      patients.

PMID- 10591366
TI  - Increased expression of inducible nitric oxide synthase in nasal epithelial cells
      in patients with allergic rhinitis.
AB  - OBJECTIVES: Although ciliated epithelial cells of human nose and paranasal
      sinuses have recently been reported to be the major source of locally detected
      nitric oxide (NO), changes to the NO production by these cells and their
      functional roles remain uncertain in relation to allergic rhinitis. The objective
      of this study is to investigate differences in the ability of induction of nitric
      oxide synthase (NOS) isoforms by nasal epithelial cells. STUDY DESIGN: Epithelial
      cells of the inferior turbinate taken from 12 normal subjects and 12 allergic
      patients against house dust mite were used. Samples from the house dust group
      were taken both before and after antigen provocation. METHODS: Immunoreactivity
      for two NOS isoforms, inducible NOS (iNOS) and endothelial NOS (eNOS), was
      examined by the laser scanning confocal microscope. The labeled cells were
      processed into digital images, and the fluorescence intensity was assessed
      quantitatively. RESULTS: The degree of iNOS expression of the epithelial cells
      was significantly elevated in the house dust group compared with that of the
      control group. The expression appeared identical both before and after antigen
      provocation in the house dust group. On the other hand, there was no significant
      difference in eNOS expression between the two groups. CONCLUSIONS: We assume that
      the increased iNOS expression of the epithelial cells in the house dust group
      might result from stimulated secretion of proinflammatory cytokines during
      allergic responses. This further suggests profound contribution of nasal
      epithelial cells to modifying the airway clearance through the production of high
      levels of NO.

PMID- 10591367
TI  - Effects of alpha-toxin of Staphylococcus aureus on the ciliary activity and
      ultrastructure of human nasal ciliated epithelial cells.
AB  - OBJECTIVE: The in vitro effects of staphylococcal alpha-toxin on ciliary activity
      were investigated at different concentrations and exposure times. STUDY DESIGN:
      Ciliated epithelial cells of the sphenoid sinus were taken from patients operated
      on for pituitary tumors. Video-computerized analysis technique and transmission
      electron microscopy were used to analyze the effects of the toxin on ciliary
      activity. METHODS: Ciliary beat frequency (CBF) was measured in four different
      concentrations of alpha-toxin including 0.1, 1, 10, and 50 microg/mL. CBF was
      measured at 2, 4, 6, 12, 24, and 48 hours after administration of the toxin. To
      observe reversibility of the reduced ciliary activity, after 24-hour incubation
      in the media containing 10 microg/mL of alpha-toxin, the media were replaced with
      alpha-toxin-free media. The tissues were also processed for transmission electron
      microscopy to observe ultrastructural changes of the epithelial cells. RESULTS:
      CBF increased significantly at 2-hour incubation and then decreased significantly
      after 12-hour incubation in 10 microg/mL of alpha-toxin (P< .05, repeated
      measures ANOVA). The transmission electron microscopic findings showed
      mitochondrial swelling and a slight protrusion of the plasma membrane of the
      cilia. In toxin-free media, loss of ciliary activity was not recovered.
      CONCLUSIONS: CBF increased at first, but with increasing incubation time ciliary
      movements decreased gradually and stopped eventually. This loss of CBF may be an
      irreversible change associated with ultrastructural changes in the mitochondria
      and the plasma membrane of the cilia.

PMID- 10591368
TI  - The groningen cartilage cutting device: a new instrument for tympanoplasty.

PMID- 10591369
TI  - AHA addresses atherosclerosis testing. American Heart Association.

PMID- 10591370
TI  - Poor nations ravaged by AIDS need the right resources now.

PMID- 10591371
TI  - New class of anti-HIV drugs.

PMID- 10591372
TI  - From the Food and Drug Administration.

PMID- 10591373
TI  - From The Surgeon General. Tuberculosis--battling an ancient scourge.

PMID- 10591374
TI  - Antibiotic use and risk of myocardial infarction.

PMID- 10591375
TI  - Antibiotic use and risk of myocardial infarction.

PMID- 10591376
TI  - Antibiotic use and risk of myocardial infarction.

PMID- 10591377
TI  - Antibiotic use and risk of myocardial infarction.

PMID- 10591378
TI  - Antibiotic use and risk of myocardial infarction.

PMID- 10591379
TI  - National Stroke Association guidelines to prevent stroke.

PMID- 10591380
TI  - National Stroke Association guidelines to prevent stroke.

PMID- 10591381
TI  - Anemia in older patients.

PMID- 10591382
TI  - Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a
      randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism.
AB  - CONTEXT: Intravenous tissue-type plasminogen activator can be beneficial to some
      patients when given within 3 hours of stroke onset, but many patients present
      later after stroke onset and alternative treatments are needed. OBJECTIVE: To
      determine the clinical efficacy and safety of intra-arterial (IA) recombinant
      prourokinase (r-proUK) in patients with acute stroke of less than 6 hours'
      duration caused by middle cerebral artery (MCA) occlusion. DESIGN: PROACT II
      (Prolyse in Acute Cerebral Thromboembolism II), a randomized, controlled,
      multicenter, open-label clinical trial with blinded follow-up conducted between
      February 1996 and August 1998. SETTING: Fifty-four centers in the United States
      and Canada. PATIENTS: A total of 180 patients with acute ischemic stroke of less
      than 6 hours' duration caused by angiographically proven occlusion of the MCA and
      without hemorrhage or major early infarction signs on computed tomographic scan.
      INTERVENTION: Patients were randomized to receive 9 mg of IA r-proUK plus heparin
      (n = 121) or heparin only (n = 59). MAIN OUTCOME MEASURES: The primary outcome,
      analyzed by intention-to-treat, was based on the proportion of patients with
      slight or no neurological disability at 90 days as defined by a modified Rankin
      score of 2 or less. Secondary outcomes included MCA recanalization, the frequency
      of intracranial hemorrhage with neurological deterioration, and mortality.
      RESULTS: For the primary analysis, 40% of r-proUK patients and 25% of control
      patients had a modified Rankin score of 2 or less (P = .04). Mortality was 25%
      for the r-proUK group and 27% for the control group. The recanalization rate was
      66% for the r-proUK group and 18% for the control group (P<.001). Intracranial
      hemorrhage with neurological deterioration within 24 hours occurred in 10% of r
      proUK patients and 2% of control patients (P = .06). CONCLUSION: Despite an
      increased frequency of early symptomatic intracranial hemorrhage, treatment with
      IA r-proUK within 6 hours of the onset of acute ischemic stroke caused by MCA
      occlusion significantly improved clinical outcome at 90 days.

PMID- 10591383
TI  - Low risk-factor profile and long-term cardiovascular and noncardiovascular
      mortality and life expectancy: findings for 5 large cohorts of young adult and
      middle-aged men and women.
AB  - CONTEXT: Three major coronary risk factors-serum cholesterol level, blood
      pressure, and smoking-increase incidence of coronary heart disease (CHD) and
      related end points. In previous investigations, risks for low-risk reference
      groups were estimated statistically because samples contained too few such people
      to measure risk. OBJECTIVE: To measure long-term mortality rates for individuals
      with favorable levels for all 3 major risk factors, compared with others. DESIGN:
      Two prospective studies, involving 5 cohorts based on age and sex, that enrolled
      persons with a range of risk factors. Low risk was defined as serum cholesterol
      level less than 5.17 mmol/L (<200 mg/dL), blood pressure less than orequal to
      120/80 mm Hg, and no current cigarette smoking. All persons with a history of
      diabetes, myocardial infarction (MI), or, in 3 of 5 cohorts, electrocardiogram
      (ECG) abnormalities, were excluded. SETTING AND PARTICIPANTS: In 18 US cities, a
      total of 72144 men aged 35 through 39 years and 270671 men aged 40 through 57
      years screened (1973-1975) for the Multiple Risk Factor Intervention Trial
      (MRFIT); in Chicago, a total of 10025 men aged 18 through 39 years, 7490 men aged
      40 through 59 years, and 6229 women aged 40 through 59 years screened (1967-1973)
      for the Chicago Heart Association Detection Project in Industry (CHA) (N =
      366559). MAIN OUTCOME MEASURES: Cause-specific mortality during 16 (MRFIT) and 22
      (CHA) years, relative risks (RRs) of death, and estimated greater life
      expectancy, comparing low-risk subcohorts vs others by age strata. RESULTS: Low
      risk persons comprised only 4.8% to 9.9% of the cohorts. All 5 low-risk groups
      experienced significantly and markedly lower CHD and cardiovascular disease death
      rates than those who had elevated cholesterol level, or blood pressure, or
      smoked. For example, age-adjusted RRs of CHD mortality ranged from 0.08 for CHA
      men aged 18 to 39 years to 0.23 for CHA men aged 40 through 59 years. The age
      adjusted relative risks (RRs) for all cardiovascular disease mortality ranged
      from 0.15 for MRFIT men aged 35 through 39 years to 0.28 for CHA men aged 40
      through 59 years. The age-adjusted RR for all-cause mortality rate ranged from
      0.42 for CHA men aged 40 through 59 years to 0.60 for CHA women aged 40 through
      59 years. Estimated greater life expectancy for low-risk groups ranged from 5.8
      years for CHA women aged 40 through 59 years to 9.5 years for CHA men aged 18
      through 39 years. CONCLUSIONS: Based on these very large cohort studies, for
      individuals with favorable levels of cholesterol and blood pressure who do not
      smoke and do not have diabetes, MI, or ECG abnormalities, long-term mortality is
      much lower and longevity is much greater. A substantial increase in the
      proportion of the population at lifetime low risk could contribute decisively to
      ending the CHD epidemic.

PMID- 10591384
TI  - Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3
      to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled
      trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic
      Stroke.
AB  - CONTEXT: Recombinant tissue-type plasminogen activator (rt-PA) improves outcomes
      for patients with acute ischemic stroke, but current approved use is limited to
      within 3 hours of symptom onset. This restricts the number of patients who can be
      treated, since most stroke patients present more than 3 hours after symptom
      onset. OBJECTIVE: To test the efficacy and safety of rt-PA in patients with acute
      ischemic stroke when administered between 3 and 5 hours after symptom onset.
      DESIGN: The Alteplase ThromboLysis for Acute Noninterventional Therapy in
      Ischemic Stroke (ATLANTIS) study is a phase 3, placebo-controlled, double-blind
      randomized study conducted between December 1993 and July 1998, with up to 90
      days of follow-up. SETTING: One hundred forty university and community hospitals
      in North America. PATIENTS: An intent-to-treat population of 613 acute ischemic
      stroke patients was enrolled, with 547 of these treated as assigned within 3 to 5
      hours of symptom onset. A total of 39 others were treated within 3 hours of
      symptom onset, 24 were treated more than 5 hours after symptom onset, and 3 never
      received any study drug. INTERVENTION: Administration of 0.9 mg/kg of rt-PA (n =
      272) or placebo (n = 275) intravenously over 1 hour. MAIN OUTCOME MEASURES:
      Primary efficacy was an excellent neurologic recovery at day 90 (National
      Institutes of Health Stroke Scale [NIHSS] score of < or =1); secondary end points
      included excellent recovery on functional outcome measures (Barthel index,
      modified Rankin scale, and Glasgow Outcome Scale) at days 30 and 90. Serious
      adverse events were also assessed. RESULTS: In the target population, 32% of the
      placebo and 34% of rt-PA patients had an excellent recovery at 90 days (P = .65).
      There were no differences on any of the secondary functional outcome measures. In
      the first 10 days treatment with rt-PA significantly increased the rate of
      symptomatic intracerebral hemorrhage (ICH) (1.1% vs 7.0% [P<.001]), a symptomatic
      ICH (4.7% vs 11.4% [P = .004]), and fatal ICH (0.3% vs 3.0% [P<.001]). Mortality
      at 90 days was 6.9% with placebo and 11.0% with rt-PA (P = .09). Results in the
      intent-to-treat population were similar. CONCLUSIONS: This study found no
      significant rt-PA benefit on the 90-day efficacy end points in patients treated
      between 3 and 5 hours. The risk of symptomatic ICH increased with rt-PA
      treatment. These results do not support the use of intravenous rt-PA for stroke
      treatment beyond 3 hours.

PMID- 10591385
TI  - Dietary sodium intake and subsequent risk of cardiovascular disease in overweight
      adults.
AB  - CONTEXT: Dietary sodium is positively associated with blood pressure, and
      ecological and animal studies both have suggested that high dietary sodium intake
      increases stroke mortality. OBJECTIVE: To examine the risk of cardiovascular
      disease associated with dietary sodium intake in overweight and nonoverweight
      persons. DESIGN: Prospective cohort study. SETTING: The first National Health and
      Nutrition Examination Survey Epidemiologic Follow-up Study, conducted in 1982
      1984, 1986, 1987, and 1992. PARTICIPANTS: Of those aged 25 to 74 years when the
      survey was conducted in 1971 -1975 (14407 participants), a total of 2688
      overweight and 6797 nonoverweight persons were included in the analysis. MAIN
      OUTCOME MEASURES: Dietary sodium and energy intake were estimated at baseline
      using a single 24-hour dietary recall method. Incidence and mortality data for
      cardiovascular disease were obtained from medical records and death certificates.
      RESULTS: For overweight and nonoverweight persons, over an average of 19 years of
      follow-up, the total number of documented cases were as follows: 680 stroke
      events (210 fatal), 1727 coronary heart disease events (614 fatal), 895
      cardiovascular disease deaths, and 2486 deaths from all causes. Among overweight
      persons with an average energy intake of 7452 kJ, a 100 mmol higher sodium intake
      was associated with a 32% increase (relative risk [RR], 1.32; 95% confidence
      interval [CI], 1.07-1.64; P = .01) in stroke incidence, 89% increase (RR, 1.89;
      95% CI, 1.31-2.74; P<.001) in stroke mortality, 44% increase (RR, 1.44; 95% CI,
      1.14-1.81; P = .002) in coronary heart disease mortality, 61% increase (RR, 1.61;
      95% CI, 1.32-1.96; P<.001) in cardiovascular disease mortality, and 39% increase
      (RR, 1.39; 95% CI, 1.23-1.58; P<.001) in mortality from all causes. Dietary
      sodium intake was not significantly associated with cardiovascular disease risk
      in nonoverweight persons. CONCLUSIONS: Our analysis indicates that high sodium
      intake is strongly and independently associated with an increased risk of
      cardiovascular disease and all-cause mortality in overweight persons.

PMID- 10591386
TI  - Hemodynamic shear stress and its role in atherosclerosis.
AB  - Atherosclerosis, the leading cause of death in the developed world and nearly the
      leading cause in the developing world, is associated with systemic risk factors
      including hypertension, smoking, hyperlipidemia, and diabetes mellitus, among
      others. Nonetheless, atherosclerosis remains a geometrically focal disease,
      preferentially affecting the outer edges of vessel bifurcations. In these
      predisposed areas, hemodynamic shear stress, the frictional force acting on the
      endothelial cell surface as a result of blood flow, is weaker than in protected
      regions. Studies have identified hemodynamic shear stress as an important
      determinant of endothelial function and phenotype. Arterial-level shear stress
      (>15 dyne/cm2) induces endothelial quiescence and an atheroprotective gene
      expression profile, while low shear stress (<4 dyne/cm2), which is prevalent at
      atherosclerosis-prone sites, stimulates an atherogenic phenotype. The functional
      regulation of the endothelium by local hemodynamic shear stress provides a model
      for understanding the focal propensity of atherosclerosis in the setting of
      systemic factors and may help guide future therapeutic strategies.

PMID- 10591387
TI  - Preventing coronary artery disease by lowering cholesterol levels: fifty years
      from bench to bedside.
AB  - In the more than 50 years since the founding of the National Heart, Lung, and
      Blood Institute and the American Heart Association, medical science has moved
      from an era in which hypercholesterolemia, as it is now defined, was not believed
      to be abnormal to one in which controlling hypercholesterolemia is known to
      reduce not only coronary artery disease morbidity and mortality but also total
      mortality. While the efforts and successes of many researchers involved in this
      evolution are impressive, atherosclerosis is still a major cause of death and
      disability in many developed nations, mostly in the form of myocardial infarction
      and stroke, and is an increasing cause of morbidity and mortality in developing
      nations. Many questions about the detailed pathogenesis of the disease remain.
      Elucidating the roles of high-density lipoprotein, other lipoproteins, and
      homocysteine, as well as the roles of cytokines and growth factors, will permit
      better understanding and treatment of atherosclerosis. With continuing support
      for research and encouragement of physicians and patients to follow recommended
      preventive regimens, further progress can be made against this major cause of
      death.

PMID- 10591388
TI  - An evidence-based assessment of the NCEP Adult Treatment Panel II guidelines.
      National Cholesterol Education Program.
AB  - CONTEXT: The Second Report of the National Cholesterol Education Program (NCEP)
      Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in
      Adults (Adult Treatment Panel II) was issued without the benefit of multiple
      recently published large clinical trials. OBJECTIVE: To analyze the panel's
      guidelines for treatment of high cholesterol levels in the context of currently
      available clinical trial results. DATA SOURCES: MEDLINE was searched for all
      English-language clinical trial data from 1993 through February 1999 relating to
      the effects of cholesterol treatment on cardiovascular clinical outcomes. STUDY
      SELECTION: Studies that were selected for detailed review assessed the effects of
      cholesterol lowering on either coronary events, coronary mortality, stroke,
      and/or total mortality, preferably by randomized, double-blind, placebo
      controlled design. Selection was by consensus of a general internist, a lipid
      clinic director, and a researcher in atherosclerotic plaque biology. A core of 37
      of the 317 initially screened studies were selected and used as the primary means
      by which to assess the guidelines. DATA EXTRACTION: By consensus of the group,
      only prespecified end points of trials were included, unless post hoc analysis
      addressed issues not studied elsewhere. DATA SYNTHESIS: Recent clinical trial
      data mostly support the Adult Treatment Panel II guidelines for cholesterol
      management. While existing trials have validated the target low-density
      lipoprotein cholesterol (LDL-C) goals in the report, studies are lacking that
      address mortality benefit from reduction below these levels. Few lipid-lowering
      trials have treated patients with low high-density lipoprotein cholesterol and/or
      elevated triglyceride levels with LDL-C levels at or below treatment goals.
      CONCLUSIONS: Lipid-lowering therapy generally should be more aggressively applied
      to patients with diabetes and/or at the time of coronary heart disease (CHD)
      diagnosis. The evidence for statin use in secondary CHD prevention in
      postmenopausal women outweighs current evidence for use of estrogen replacement
      in this setting. Further studies are needed to address the effects of lipid
      modification in primary prevention of CHD in populations other than middle-aged
      men and to study markers of lipid metabolism other than LDL-C.

PMID- 10591389
TI  - Oral anticoagulant therapy in patients with coronary artery disease: a meta
      analysis.
AB  - CONTEXT: Despite years of use in coronary artery disease (CAD) and several
      studies of its effectiveness, the role of oral anticoagulants (OAs) remains
      controversial. OBJECTIVE: To determine the effects of long-term OA therapy,
      stratified by the intensities of anticoagulation and aspirin therapy, on outcomes
      in patients with CAD. DATA SOURCES: Studies were identified by MEDLINE, EMBASE,
      and CURRENT CONTENTS searches (1960-July 1999) and by reviewing reference lists
      and inquiring with experts and pharmaceutical companies. STUDY SELECTION: Studies
      were included if they were published between 1960 and July 1999, were randomized,
      had recruited patients with CAD, who had used OA therapy for at least 3 months.
      Of 43 articles identified, 30 articles (31 trials) were analyzed. DATA
      EXTRACTION: Information on type, duration, and method of monitoring OA therapy,
      as well as rates of death, myocardial infarction (MI), thromboembolic
      complications, stroke, and bleeding were abstracted by 2 independent observers.
      DATA SYNTHESIS: With high-intensity (international normalized ratio [INR], 2.8
      4.8) OAs vs control (16 trials, 10056 patients), clear reductions in mortality
      (odds reduction [ORed], 22%; 95% confidence interval [CI], 13%-31%), MIs (ORed,
      42%; 95% CI, 34%-48%), and thromboembolic complications including stroke (ORed,
      63%; 95% CI, 53-71%) were observed, but were associated with a 6.0-fold (95% CI,
      4.4- to 8.2-fold) increase in major bleeding. For moderate OAs (INR, 2-3) vs
      control (4 trials, 1365 patients) the ORed for death was 18% (95% CI, -6% to
      37%); for MI, 52% (95% CI, 37%-64%); and for stroke, 53% (95% CI, 19%-73%), but
      it increased bleeding by 7.7-fold (95% CI, 3.3- to 18-fold). For moderate- to
      high-intensity OAs (INR, > or =2) vs aspirin (7 trials, 3457 patients), no
      reduction in death, MI, or stroke was observed, and it was associated with a 2.4
      fold (95% CI, 1.6- to 3.6-fold) increase in major bleeding. For moderate- to high
      intensity OAs and aspirin vs aspirin alone (3 trials, 480 patients), the ORed for
      death, MI, or stroke was 56% (95% CI, 17%-77%) and major bleeding increased by
      1.9-fold (0.6- to 6.0-fold). For low-intensity OAs (INR, <2.0) and aspirin vs
      aspirin alone (3 trials, 8435 patients), no significant reduction in death, MI,
      or stroke was observed, and major bleeding increased by 1.3-fold (95% CI, 1.0- to
      1.8-fold). CONCLUSIONS: Among patients with CAD, high-intensity and moderate
      intensity OA are effective in reducing MI and stroke but increase the risk of
      bleeding. In the presence of aspirin, low-intensity OA does not appear to be
      superior to aspirin alone, while moderate- to high-intensity OA and aspirin vs
      aspirin alone appears promising and the bleeding risk is modest, but this
      requires confirmation from ongoing trials.

PMID- 10591390
TI  - Conquering cardiovascular disease: progress and promise.

PMID- 10591391
TI  - Chlamydia pneumoniae and atherosclerosis.

PMID- 10591392
TI  - Economics, ethics, and end-of-life care.

PMID- 10591393
TI  - Aging, death, and population health.

PMID- 10591395
TI  - Legal rights to health care at the end of life.

PMID- 10591394
TI  - Private and public choices in end-of-life care.

PMID- 10591397
TI  - JAMA Patient Page: general health.

PMID- 10591396
TI  - Medical students' attitudes toward physician-assisted suicide.
AB  - CONTEXT: In November 1994, Oregon became the first US state to legalize physician
      assisted suicide (PAS) as an option for end-of-life care. OBJECTIVE: This study
      compares the attitudes and experiences of medical students in Oregon regarding
      PAS to those of fourth-year medical students in the United States outside Oregon.
      DESIGN: A survey of all students at the Oregon Health Sciences University and
      fourth-year medical students at 3 non-Oregonian US medical schools. PARTICIPANTS:
      Oregon medical students returned 227 questionnaires (58%), and 113 were returned
      from control schools (33%). RESULTS: A similar percentage of both study groups
      favored the legalization of PAS (64% vs 66%; P = .74). If the practice were
      legal, 55% of the total surveyed reported they "might be willing to write a
      lethal prescription," (50% Oregon students vs 60% control; P = .13 and 44% fourth
      year Oregon students vs 60% control; P = .04). Among fourth-year students, 20%
      reported a request by a patient to the student or a preceptor for a lethal
      prescription in the past year (26% vs 16%; P = .09). CONCLUSIONS: This study
      demonstrates support for and willingness by many medical students to participate
      in PAS. Some medical students reported observation of PAS during their training
      experience. Fourth-year Oregon students reported significantly less willingness
      than other students to provide a patient with a lethal prescription, perhaps
      indicating hesitancy to include PAS in clinical practice.

PMID- 10591398
TI  - Endothelin receptor antagonist preserves microvascular perfusion and reduces
      ischemic brain damage following permanent focal ischemia.
AB  - Synthesis and release of the potent vasoconstrictor peptide endothelin-1 (ET-1)
      increases following cerebral ischemia and has previously been shown to mediate
      the delayed hypoperfusion associated with transient global ischemia. In this
      study we assessed the impact of ET-1 on perfusion and infarct volume in a focal
      model of cerebral ischemia by use of the selective ET(A) receptor antagonist Ro
      61-1790 (affinity for ET(A) receptor 1000 fold greater than ETB receptor).
      Control rats subjected to permanent middle cerebral artery occlusion (MCAO)
      showed extensive reductions in microvascular perfusion 4 h post-MCAO that were
      significantly attenuated by Ro 61-1790 pretreatment (10 mg/kg, i.v.). Ro 61-1790
      concomitantly and significantly reduced the ischemic lesion volume in the same
      animals. This effect was maintained 24 h post-MCAO providing that the animals
      received additional i.v. injections of 5 mg/kg Ro 61-1790 at 5 h and 8 h after
      MCAO. These findings demonstrate that ET(A) receptor antagonism partially
      preserves tissue perfusion following focal ischemia and that this effect is
      associated with significant neuroprotection. The results also support the
      hypothesis that vasoactive mediators, and ET-1 in particular, are important
      contributors to the pathogenesis of cerebral ischemic injury.

PMID- 10591399
TI  - Potential role of cerebral glutathione in the maintenance of blood-brain barrier
      integrity in rat.
AB  - Using the model of glutathione (GSH) depletion, possible role of GSH in the
      maintenance of blood-brain barrier (BBB) integrity was evaluated in rats.
      Administration (i.p.) of GSH depletors, diethyl maleate (DEM, 1-4 mmol/kg),
      phorone (2-3 mmol/kg) and 2-cyclohexene-1-one (CHX, 1 mmol/kg), to male adults
      was found to deplete brain and liver GSH and increase the BBB permeability to
      micromolecular tracers (sodium fluorescein and [14C]sucrose) in a dose-dependent
      manner at 2h. However, BBB permeability to macromolecular tracers such as
      horseradish peroxidase and Evan's blue remained unaltered. It was also shown that
      observed BBB permeability dysfunction was associated with brain GSH depletion. A
      lower magnitude of BBB increase in rat neonates, as compared to adults, indicated
      a possible bigger role of GSH in the BBB function of mature brain. The treatment
      with N-acetylcysteine, methionine and GSH provided a partial to full protection
      against DEM-induced brain (microvessel) GSH depletion and BBB dysfunction;
      however, the treatment with alpha-tocopherol, ascorbic acid and turmeric were not
      effective. Our studies showed that cerebral GSH plays an important role in
      maintaining the functional BBB integrity.

PMID- 10591400
TI  - Upregulation of NMDA receptors in hippocampus and cortex in the pentylenetetrazol
      induced "kindling" model of epilepsy.
AB  - "Kindling" is a phenomenon of epileptogenesis, which has been widely used as an
      experimental model of temporal lobe epilepsy. At the present work we investigated
      the contribution of NMDA receptors in the Pentylenetetrazol-induced "kindling"
      model in the mouse brain, by using quantitative autoradiography and the
      radioactive ligands [3H]MK801 and [3H]L-glutamate (NMDA-sensitive component). One
      week after establishment of kindling, a small but significant increase in
      [3H]MK801 as well as NMDA-sensitive [3H]glutamate binding was seen, being
      restricted to the molecular layer (ML) of the dentate gyrus (DG) and the CA3
      region of the hippocampus. These binding augmentations persisted one month after
      establishment of kindling. A significant increase of NMDA receptor binding was
      also observed in the cortex-somatosensory and temporal one week after acquisition
      of the kindled state. The upregulation of NMDA receptors seen in DG and CA3
      region of the hippocampus could be associated with the kindling process of this
      model especially with its maintenance phase, since it persists at long term, is
      area-specific and consistent with electrophysiological data. The increase of NMDA
      receptors seen in the cortex of the kindled animals could underlie the
      hyperexcitability detected by electrophysiological studies in this area.

PMID- 10591401
TI  - Taurine release is enhanced in cell-damaging conditions in cultured cerebral
      cortical astrocytes.
AB  - The release of preloaded [3H]taurine from cultured cerebral cortical astrocytes
      was studied under various cell-damaging conditions, including hypoxia, ischemia,
      aglycemia and oxidative stress, and in the presence of free radicals. Astrocytic
      taurine release was enhanced by K+ (50 mM), veratridine (0.1 mM) and the
      ionotropic glutamate receptor agonist kainate (1.0 mM). Metabotropic glutamate
      receptor agonists had only weak effects on taurine release. Similarly to the
      swelling-induced taurine release the efflux in normoxia seems to be mediated
      mainly by DIDS-(diisothiocyanostilbene-2,2'-disulphonate) and SITS-(4-acetamido
      4'-isothiocyanostilbene-2,2'-disulphonate) sensitive CI- channels, since these
      blockers were able to reduce both basal and K+ -stimulated release. The basal
      release of taurine was moderately enhanced in hypoxia and ischemia, whereas the
      potentiation in the presence of free radicals was marked. The small basal release
      from astrocytes signifies that taurine release from brain tissue in ischemia may
      originate from neurons rather than glial cells. On the other hand, the release
      evoked by K+ in hypoxia and ischemia was greater than in normoxia, with a very
      slow time-course. The enhanced release of the inhibitory amino acid taurine from
      astrocytes in ischemia may be beneficial to surrounding neurons, outlasting the
      initial stimulus and counteracting overexcitation.

PMID- 10591402
TI  - Prothrombin concentration in the cerebrospinal fluid is not altered in
      Alzheimer's disease.
AB  - Prothrombin, known to be expressed in brain and to possess growth modulating
      properties, has been suggested to be involved in the pathogenesis of Alzheimer's
      disease (AD). We studied prothrombin concentration in lumbar CSF (L-CSF) in
      patients with AD (n = 25), neurologic disease controls (NDC; n = 33) covering a
      wide range of neurologic disorders, and subjects with Guillain-Barre syndrome
      (GBS; n = 4) as well as in samples of non-pathological ventricular CSF (V-CSF; n
      = 4). The results were evaluated with respect to CSF flow rate, as indicated by
      the albumin quotient (Q(Alb)). The concentrations of prothrombin in L-CSF in NDC
      (mean: 0.46 mg/l, range: 0.21-0.96), and AD (mean: 0.6 mg/l, range: 0.19-1.2)
      were in the normal range reported previously. Expectedly, prothrombin
      concentration in L-CSF of GBS was increased (mean: 6.3 mg/l, range: 2.3-9.7)
      corresponding to the increased Q(Alb) in this group (mean 54.6x10(-3), range: 17
      88.1). The concentrations of both prothrombin and albumin were 5.5-fold higher in
      L-CSF than in V-CSF (mean Q(Alb) : 1.1x10(-3), mean concentration of prothrombin:
      0.088 mg/l). In conclusion, CSF prothrombin in all conditions evaluated here is
      exclusively derived from blood.

PMID- 10591403
TI  - In vitro differences between astrocytes of control and wobbler mice spinal cord.
AB  - The Wobbler mouse, a model of amyotrophic lateral sclerosis (ALS), presents
      motorneuron degeneration and pronounced astrogliosis in the spinal cord. We have
      studied factors controlling astrocyte proliferation in cultures derived from
      Wobbler and control mice spinal cord. Basal rate of [3H]thymidine incorporation
      was 15 times lower in Wobbler astrocytes. While in control cultured cells
      interleukin-1alpha (IL-1) and corticosterone (CORT) significantly increased
      proliferation, both agents were inactive in Wobbler astrocytes. The lack of
      response to CORT was not due to the absence of glucocorticoid receptors, because
      similar receptor amounts were found in Wobbler and control astrocytes. In
      contrast to IL-1 and CORT, transforming growth factor-beta1 (TGF-beta1)
      substantially increased proliferation of Wobbler astrocytes but not of control
      cells. Differences in response to TGF-beta1 were also obtained by measuring glial
      fibrillary acidic protein (GFAP) immunoreaction intensity, which was
      substantially higher in Wobbler astrocytes. Thus, abnormal responses to different
      mitogens characterized Wobbler astrocytes in culture. We suggest that TGF-beta1
      may play a role in the reactive gliosis and GFAP hyperexpression found in the
      degenerating spinal cord of this model of ALS.

PMID- 10591404
TI  - EPC-K1, a hydroxyl radical scavenger, prevents 6-hydroxydopamine-induced dopamine
      depletion in the mouse striatum by up-regulation of catalase activity.
AB  - We examined the effect of pretreatment with EPC-K1, a potent hydroxyl radical
      scavenger, on 6-hydroxydopamine (6-OHDA)-induced reduction of dopamine (DA) and
      its metabolites in the mouse striatum. EPC-K1 was mixed with diet (0.2%, wt/wt)
      for 1 or 2 weeks, and then 6-OHDA (60 microg in 2 microl of saline solution) was
      injected intracereberoventricularly. Mice continued to be fed EPC-K1-containing
      diet for another one week before they were sacrificed. The concentrations of DA
      and its metabolites in the striatum were measured by high performance liquid
      chromatography. 6-OHDA reduced the level of DA and its metabolites in the
      striatum. Pretreatment with EPC-K1 for 2 weeks, but not for 1 week, abrogated the
      neurotoxic effect of 6-OHDA on striatal concentrations of DA and its metabolites.
      Measurement of striatal concentrations of thiobarbituric acid reactive
      substances, glutathione, and malonaldehyde plus 4-hydroxynonenal, and the
      activities of superoxide dismutase and catalase in EPC-K1 treated mice showed an
      increase in catalase activity after 2 weeks of such treatment. No other changes
      in anti-oxidants levels were noted. Our results suggest that EPC-K1 counteracts
      the neurotoxicity of 6-OHDA by increasing catalase activities.

PMID- 10591405
TI  - Temporal and quantitative expression of the myelin-associated lipids,
      ethanolamine plasmalogen, galactocerebroside, and sulfatide, in the
      differentiating CG-4 glial cell line.
AB  - We determined the expression of three myelin-typical lipids in the continuous CG
      4 glial cell line of oligodendrocyte progenitor cells, as the cells
      differentiated into oligodendrocytes. On 6 different days during the first 9 days
      of oligodendrocyte development, cells were labeled for 24 h with [3H]ethanolamine
      to label ethanolamine plasmalogens or with [3H]galactose to label the
      galactocerebroside and sulfogalactocerebroside; and the amount of labeled lipid
      expressed on each day was determined. Each labeled lipid was expressed with its
      own specific time course and in a defined amount on each day of differentiation.
      Increased labeling of plasmalogens and sulfogalactocerebroside started at early
      developmental stages, and increased labeling of galactocerebroside started at
      later stages. The results indicate that the differentiating CG-4 cell line
      provides a valuable system to investigate factors affecting the early time course
      of myelin-lipid expression and the amounts expressed.

PMID- 10591406
TI  - The activities of six exo-and endopeptidases in the substantia nigra,
      neostriatum, and cortex of the rat brain.
AB  - We determined the enzymatic activity and crude subcellular distribution of four
      exopeptidases: Dipeptidylaminopeptidase IV (DAP-IV), Alanyl aminopeptidase (AAP),
      Prolyl aminopeptidase (PAP) and gamma-Glutamyl transpeptidase (gammaGTP), and two
      endopeptidases: Postproline endopeptidase (PEP) and "Trypsin-like" peptidase ("T
      L" P) in pars compacta (SNPC) and pars reticulata (SNPR) of substantia nigra,
      caudate-putamen (CAU) and cerebral cortex (CC) of the rat brain. We found: 1) DAP
      IV activity is comparatively higher in SNPC and it is equally distributed in the
      postmitochondrial precipitate (PR) and supernatant (SN) fractions of SNPC, CAU
      and CC but higher in the SN from SNPR. 2) CC shows the highest activity of AAP
      and its activity is mainly located in the SN from all areas. 3) The activity of
      PAP is comparatively higher in SNPC and it is exclusively located in the SN from
      all areas. 4) gammaGTP activity is similar in all areas but its predominance is
      in the SN for SNPC and SNPR, and in the PR for CAU and CC. 5) CAU has higher PEP
      activity (higher in the PR) than CC (higher in the SN); no activity is detected
      in the substantia nigra. 6) The activity of a "Trypsin-like" peptidase is the
      highest in SNPC and SNPR; this activity have some predominance in the SN and
      higher predominance in the same fraction from CAU and CC.

PMID- 10591407
TI  - Methamphetamine-induced stereotypies in newly-hatched decerebrated domestic
      chicks.
AB  - Metamphetamine in high dose has been reported to induce stereotypic behavior of
      abnormal form in the pigeon and domestic chick. A number of reports suggested
      that the target of metamphetamine was the paleostriatal complex, the highest
      motor center of the avian brain. The present study tested this hypothesis by
      treating newly-hatched domestic chicks with high dose of metamphetamine (10 mg/kg
      b.w.) after complete decerebration or sham operation. Stereotypic mandibulations
      were observed both in sham-operated and in decerebrated birds in similar form
      following methamphetamine treatment. The results suggested that brainstem pattern
      generators remain responsive to dopaminergic stimuli in the absence of the main
      telencephalic (striatal) targets.

PMID- 10591408
TI  - Properties of acetylcholine receptor ion channels in the acutely dissociated
      neurons of the marginal division in the rat striatum.
AB  - Cell-attached mode of patch clamp technique was employed to investigate the
      properties of acetylcholine (ACh)-induced ion channels in acutely dissociated
      neurons from the marginal division (MrD) of rat striatum. Two types of
      conductance states (25 pS and 60 pS) were recorded. The 25 pS channel (more than
      80%) was the main type in the neurons of MrD and was described here. The
      amplitudes of inward currents increased with hyperpolorization and the reversing
      potential was about 0 mV. Both single short opening and long burst openings were
      observed in MrD neurons. Two-time constants of these two kinds of ion channels
      are 0.29 ms, 1.84 ms and 1.96 ms, 18.24 ms, respectively. Average close time can
      be fitted with two exponential functions, the two time constants are 1.7 ms and
      54 ms. Probability of channel opening is about 0.012 and no voltage-dependence
      was found. The properties of reversing potential, voltage-independence and the
      form of agonist to the ion channels indicated that the recorded channel currents
      flow through AChR channels. The mAChR is involved in slow synaptic transmission
      and Ach can not induce the opening of mAChR ion channel. The binding site of ACh
      to AChR and the nAChR ion channel are the same protein, ACh can only activate
      nAChR ion channel directly. Therefore, the recorded ion channels in the present
      study are nAChR ion channels. The results suggest that nAChR ion channels exist
      in the neurons of MrD and the MrD probably is involved in learning and memory
      mechanism of the brain.

PMID- 10591409
TI  - Regulation of brain glycosylphosphatidylinositol-specific phospholipase D by
      natural amphiphiles.
AB  - Brain glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD)-catalyzed
      conversion of amphiphilic form of Zn2+ -glycerophosphocholine
      cholinephosphodiesterase (Amp-GPC PDE) into hydrophilic form was investigated in
      the presence of natural amphiphiles. Monoacylglycerols enhanced considerably the
      conversion by GPI-PLD of Amp-GPC PDE to hydrophilic form, with the enhancing
      effect of monoacylglycerols being dependent on the size of acyl group (C8-C18).
      Whereas the maximal enhancement of GPI-PLD action was the greatest with
      monodecanoylglycerol, the concentration (EC50) required to achieve 50% maximal
      effect was the smallest for monomyristoyl- or monopalmitoylglycerol. In addition,
      monolaurylglycerol or its alkyl analogue, monododecylglycerol, showed a
      remarkable decrease in enhancing effect at high concentrations (>1 mM). Presence
      of double bond in acyl chain, as exemplified by monooleoylglycerol or mono-11
      eicosenoin, further enhanced the conversion by GPI-PLD. Meanwhile,
      lysophosphatidylcholine (IC50, 25 microM) and phosphatidic acid (IC50, >100
      microM), ionic amphiphiles, inhibited the GPI-PLD activity, which was determined
      in the presence of monooleoylglycerol as a detergent. From these results, it is
      suggested that the activity of GPI-PLD in vivo system may be regulated by natural
      amphiphiles.

PMID- 10591410
TI  - Vinpocetine selectively inhibits neurotransmitter release triggered by sodium
      channel activation.
AB  - The effects of vinpocetine on internal Na+ (Na(i)), cAMP accumulation, internal
      Ca2+ (Ca(i)) and excitatory amino acid neurotransmitters release, under resting
      and under depolarized conditions, was investigated in rat striatum synaptosomes.
      Veratridine (20 microM) or high K+ (30 mM) were used as depolarizing agents.
      Results show that vinpocetine in the low microM range inhibits the elevation of
      Na(i), the elevation of Ca(i) and the release of glutamate and aspartate induced
      by veratridine depolarization. In contrast, vinpocetine fails to inhibit the rise
      of Ca(i) and the neurotransmitter release induced by high K+, which are both TTX
      insensitive responses. Results also show that the inhibition exerted by
      vinpocetine on all the above veratridine-induced responses is not reflected in
      PDE activity. Our interpretation of these results is that vinpocetine inhibits
      neurotransmitter release triggered by veratridine activation of voltage sensitive
      Na+ channels, but not that triggered by a direct activation of VSCC. Thus, the
      main mechanism involved in the neuroprotective action of vinpocetine in the CNS
      is unlikely to be due to a direct inhibition of Ca2+ channels or PDE enzymes, but
      rather the inhibition of presynaptic Na+ channel-activation unchained responses.

PMID- 10591411
TI  - Honokiol and magnolol increase the number of [3H] muscimol binding sites three
      fold in rat forebrain membranes in vitro using a filtration assay, by
      allosterically increasing the affinities of low-affinity sites.
AB  - 1. The bark of the root and stem of various Magnolia species has been used in
      Traditional Chinese Medicine to treat a variety of disorders including anxiety
      and nervous disturbances. The biphenolic compounds honokiol (H) and magnolol (M),
      the main components of the Chinese medicinal plant Magnolia officinalis, interact
      with GABA(A) receptors in rat brain in vitro. We compared the effects of H and M
      on [3H]muscimol (MUS) and [3H]flunitrazepam (FNM) binding using EDTA/water
      dialyzed rat brain membranes in a buffer containing 150 mM NaCl plus 5 mM Tris
      HCl, pH 7.5 as well as [35S]t-butylbicyclophosphorothionate (TBPS) in 200 mM KBr
      plus 5 mM Tris-HCl, pH 7.5. H and M had similar enhancing effects on [3H]MUS as
      well as on [3H]FNM binding to rat brain membrane preparations, but H was 2.5 to
      5.2 times more potent than M. 2. [3H]FNM binding. GABA alone almost doubled
      [3H]FNM binding with EC50 = 450 nM and 200 nM using forebrain and cerebellar
      membranes, respectively. In the presence of 5 microM H or M the EC50 values for
      GABA were decreased to 79 and 89 nM, respectively, using forebrain, and 39 and 78
      nM, using cerebellar membranes. H and M potently enhanced the potentiating effect
      of 200 nM GABA on [3H]FNM binding with EC50 values of 0.61 microM and 1.6 microM
      using forebrain membranes, with maximal enhancements of 33 and 47%, respectively.
      Using cerebellar membranes, the corresponding values were 0.25 and 1.1 microM,
      and 22 and 34%. 3. [3H]MUS binding. H and M increased [3H]MUS binding to whole
      forebrain membranes about 3-fold with EC50 values of 6.0 and 15 microM. Using
      cerebellar membranes, H and M increased [3H]MUS binding approximately 68% with
      EC50 values of 2.3 and 12 microM, respectively. Scatchard analysis revealed that
      the enhancements of [3H]MUS binding were due primarily to increases in the number
      of binding sites (Bmax values) with no effect on the high affinity binding
      constants (Kd values). The enhancing effect of H and M were not additive. 4.
      [35S]TBPS binding. H and M displaced [35S]TBPS binding from sites on whole rat
      forebrain membranes with IC50 values of 7.8 and 6.0 microM, respectively. Using
      cerebellar membranes, the corresponding IC50 values were 5.3 and 4.8 microM.
      These inhibitory effects were reversed by the potent GABA(A) receptor blocker
      R5135 (10 nM), suggesting that H and M allosterically increase the affinity of
      GABA(A) receptors for GABA and MUS by binding to sites in GABA(A) receptor
      complexes. 5. Two monophenols, the anesthetic propofol (2,6-diisopropylphenol, P)
      and the anti-inflammatory diflunisal (2',4'-difluoro-4-hydroxy-3-biphenyl
      carboxylic acid, D) also enhanced [3H]MUS binding, decreased the EC50 values for
      GABA in enhancing [3H]FNM binding and potentiated the enhancing effect of 200 nM
      GABA on [3H]FNM binding, although enhancements of [3H]MUS binding for these
      monophenols were smaller than those for H and M, using forebrain and cerebellar
      membranes. The enhancing effect of P and D on [3H]MUS binding were almost
      completely additive. 2,2'-biphenol was inactive on [3H]MUS and [3H]FNM binding.
      These, and other preliminary experiments, suggest that appropriate ortho (C2) and
      para (C4) substitution increases the GABA-potentiating activity of phenols. 6.
      The potentiation of GABAergic neurotransmission by H and M is probably involved
      in their previously reported anxiolytic and central depressant effects.

PMID- 10591412
TI  - Changes of [3H]muscimol binding and GABA(A) receptor beta2-subunit mRNA level by
      tolerance to and withdrawal from pentobarbital in rats.
AB  - Effects of continuous pentobarbital administration on binding characteristics of
      [3H]muscimol were examined by autoradiography, and levels of GABA(A) receptor
      beta2-subunit mRNA were investigated by in situ hybridization histochemistry in
      the rat brain. In order to eliminate the induction of hepatic metabolism by
      systemic administration of pentobarbital, an i.c.v. infusion model of tolerance
      to and withdrawal from pentobarbital was used. An experimental model of
      barbiturate tolerance and withdrawal was developed using i.c.v. infusion of
      pentobarbital (300 microg/10 microl/hr for 7 days) by osmotic minipumps and
      abrupt withdrawal from pentobarbital. The levels of [3H]muscimol binding were
      elevated in cingulate of frontal cortex (46%) and granule layer of cerebellum
      (32%) of rats 24-hr after withdrawal from pentobarbital, while it was only
      elevated in cingulate (58%) of tolerant rats. The GABA(A) receptor beta2-subunit
      mRNA was increased in the withdrawal rats only: in the cortex (9-14%),
      hippocampus (15-21%), inferior colliculus (21%), and granule layer of cerebellum
      (24%). These results show the involvement of GABA(A) receptor and its beta2
      subunit up-regulations in pentobarbital withdrawal rats, and suggest that the
      levels of [3H]muscimol binding and GABA(A) receptor beta2-subunit mRNA are
      altered in a region-specific manner during pentobarbital withdrawal.

PMID- 10591413
TI  - Acute and chronic D-fenfluramine treatments have different effects on serotonin
      synthesis rates in the rat brain: an autoradiographic study.
AB  - The effects of acute and chronic treatments with D-fenfluramine on the regional
      rates of serotonin (5-hydroxy-tryptamine; 5-HT) synthesis were investigated using
      the alpha-[14C]methyl-L-tryptophan (alpha-[14C]MTrp) autoradiographic method. In
      the first series of experiments, acute D-fenfluramine treatment (5 mg/kg; i.p.)
      given 20 min before the tracer injection significantly (p<0.05) decreased 5-HT
      synthesis in the dorsal raphe, and significantly (p<0.05) increased the rates in
      the cerebral cortices and caudate nucleus, when compared to the rates in the
      control rats (saline treated). In a second series of experiments, following a 7
      day treatment with D-fenfluramine (5 mg/kg/day; i.p.), a significant (p<0.05)
      decrease of 5-HT synthesis, in the dorsal raphe was observed, and significant
      (p<0.05) increases were observed in the hypothalamus, the dorsal thalamus, the
      medial and lateral geniculate body and some brain stem regions (locus ceruleus,
      inferior and superior colliculus). No significant changes were observed in the
      cerebral cortices.

PMID- 10591415
TI  - Pacifier--partner or peril?

PMID- 10591416
TI  - Elective delivery at "term": implications for the newborn.

PMID- 10591417
TI  - Vesico-ureteric reflux.

PMID- 10591414
TI  - Amyloid beta peptide membrane perturbation is the basis for its biological
      effects.
AB  - Experimental studies have indicated that the mechanisms offered for explaining
      the neurotoxicity of amyloid beta peptide (AbetaP) are diverse, and include
      altered enzyme activities, disrupted calcium homeostasis, and increased free
      radical formation. AbetaP appears to interact at the cell membrane with a
      multitude of receptor sites and also inserts physically into the membrane matrix.
      This membrane insertion affects the membrane fluidity and potentially influences
      the function of resident membrane proteins. We propose a unifying hypothesis to
      explain the experimental observations of the diverse cellular responses to
      AbetaP. The indiscriminate physical insertion of AbetaP into the cell membrane
      unspecifically activates a host of membrane processes by perturbation of the
      membrane proteins. This recurrent activation of membrane processes eventually
      culminates in neuronal cell death. We recommend that successful therapeutic
      interventions should be directed at reducing or preventing the interaction of
      AbetaP with neuronal cell membranes.

PMID- 10591418
TI  - Adverse events in intensively treated children and adolescents with type 1
      diabetes.
AB  - The main objective of this study was to examine the relation between adverse
      events and degree of metabolic control and multiple-dose treatment. A total of
      139 children, aged between 1 and 18 y, prospectively registered severe
      hypoglycaemia with or without unconsciousness, as well as hospitalized
      ketoacidosis, during 1994-95. Treatment from onset was multiple-dose insulin (>
      95% > or = 4 doses) combined with intense training and psychosocial support.
      Median HbA1c was 6.9% (ref. 3.6-5.4%). The incidence of severe hypoglycaemia with
      unconsciousness was 0.17 events per patient-year, having decreased from the 1970s
      to the 1990s, parallel to a change from 1-2 to > or = 4 doses per day. There was
      no correlation or association to the year mean HbA1c for severe hypoglycaemia.
      Severe hypoglycaemic episodes in 1995 correlated to severe hypoglycaemic episodes
      in 1994 (r=0.38; p<0.0001). Severe hypoglycaemia with unconsciousness increased
      during the spring season, and according to case records the assumed causes were
      mainly mistakes with insulin, food and exercise. Ketoacidosis was rare: 0.015
      episodes per patient-year. We conclude that multiple-dose insulin therapy from
      the very onset of diabetes, combined with adequate self-control, active problem
      based training and psycho-social support, may limit severe hypoglycaemia and
      ketoacidosis. Strategies aimed at minimizing severe hypoglycaemia without
      compromising metabolic control need to be evaluated.

PMID- 10591419
TI  - Infant and maternal factors in the development of breastfeeding behaviour and
      breastfeeding outcome in preterm infants.
AB  - A wide range in incidence of breastfeeding has been reported in preterm infants.
      The aim of this study was to explore the influence of infant and maternal factors
      on the development of preterm infants' breastfeeding behaviour and breastfeeding
      outcome. The sample consisted of 71 preterm infants born after a gestation of 26
      35 wk. A descriptive, prospective design was used, with direct behavioural
      observation as data collection method, based on mothers' assessments according to
      the Preterm Infant Breastfeeding Behavior Scale (PIBBS), in which higher scores
      indicate higher competence. Multiple regression analyses revealed that variables
      associated with efficient infant performance included higher birthweight, less
      need of ventilator and oxygen treatment, higher haemoglobin level, absence of
      bottle-feeding, no need of apnoea treatment with Theophylline, and no suspicion
      of infection. A short gestation was associated with high PIBBS scores during
      weeks 32-37. Maternal characteristics associated with higher infant competence
      were breastfeeding experience and low educational level. Fifty-seven infants were
      discharged with full breastfeeding and 10 infants with partial breastfeeding.
      Infants with a short gestation period achieved full breastfeeding at low
      postmenstrual and high postnatal age. Infants with Theophylline treatment, low
      haemoglobin level, and a longer period of separation from their mothers
      established full breastfeeding at higher postmenstrual and postnatal age. In
      conclusion, low gestational age at birth was associated with early emergence of
      efficient breastfeeding behaviour and a high incidence of full breastfeeding.

PMID- 10591420
TI  - Familial and environmental influences on bone growth from 11-17 years.
AB  - The influences on bone growth of familial factors, nutrition and physical
      activity are described in a cohort of 108 children (56M, 52F). Distal forearm
      bone width, mineral content and volumetric density, anthropometry, pubertal
      status, nutritional intake and physical activity were measured at ages 11, 13, 15
      and 17 y. Parental forearm bone status was also determined. Both mothers' and
      fathers' bone variables were significant predictors of the respective children's
      bone variables, but heritability estimates were greater between mothers and their
      children than between fathers and their children. By age 17 y boys had attained
      101%, 85% and 89% of their fathers' height, bone mineral content and volumetric
      density, respectively; girls had attained 103%, 95% and 98% of their mothers'
      height, bone mineral content and volumetric density, respectively. There were no
      consistent associations among nutrient variables and bone status or rate of
      change in bone status. However, there was a significantly greater increase in
      bone mineral content and density from 11-17 y in those girls with consistently
      high calcium intake. There were no significant correlations between physical
      activity and bone values or rate of change of bone values. Age, gender, pubertal
      status, height, weight and parental bone values accounted for 80%, 71% and 49% of
      the variance of bone mineral content, bone width and volumetric density,
      respectively and 52%, 55% and 58% respectively of the variance of change in these
      variables. After age, gender, sexual maturity and body size, heritability
      accounts for the greatest variance in bone values through adolescence.

PMID- 10591421
TI  - A metabolic balance study in term infants fed lactose-containing or lactose-free
      formula.
AB  - Lactose-free (L-) formulas are recommended for infants with conditions affecting
      lactose digestion. Cows' milk protein-based formulas containing other
      carbohydrate sources are most often used for such infants. This study compared
      fat absorption and absorption and retention of nitrogen, calcium, phosphorus, and
      magnesium in term infants fed either a L- or standard lactose-containing (L+)
      bovine milk protein-based formula. Data from three single-centre, double-blind,
      randomized, parallel-group metabolic balance studies were combined. After a 4-7-d
      equilibration period on either L- or L+ formula, a 72-h balance study was
      performed. Twenty infants received L- and 21 received L+ formula. Besides the L-
      group having a higher percentage of males (65%) and the L+ group a higher
      percentage of females (52.4%), other baseline measurements were similar. The
      majority of nutrient balance data was similar between the two groups. Exceptions
      were relative nitrogen absorption, calcium intake and calcium retention,
      magnesium retention, and faecal phosphorus excretion, all of which were
      significantly higher in the L- group. Vitamin D supplementation did not
      significantly affect either calcium or phosphorus data. This new L- formula
      provided similar nutrients and is a suitable alternative to a L+ formula in term
      infants requiring L- feedings.

PMID- 10591422
TI  - Bacterial flora of the lower respiratory tract in children with bronchial asthma.
AB  - The aims of this retrospective study were to (i) determine the risk of
      contamination of lower respiratory tract samples obtained during fiberoscopy in
      children; (ii) determine the incidence and profile of the bacterial flora of the
      lower respiratory tract in a selected group of asthmatic children at high risk
      for bacterial infection; and (iii) identify risk markers for such findings. In 29
      asthmatic children, comparison of bacterial cultures of specimens obtained from
      the upper and, lower respiratory tracts showed that contamination was a
      possibility in only 3.4% (1/29) of cases. The results from bacterial samples
      obtained via flexible bronchoscopy in a further 273 consecutively investigated
      physician-diagnosed asthmatic children were analysed. Patients were selected for
      bronchoscopy if they had severe chronic asthma or in order to exclude other
      diseases able to provoke wheezing. Their mean (SD) and median ages were 32.2
      (38.3) and 17.5 mo, respectively. The incidence of positive bacterial cultures
      was 12.1% (33/273 patients). Bacterial flora included H. influenzae (39.5%,
      15/38), B. catarrhalis (23.7%, 9/38), Neisseria species (7.9%, 3/38), M.
      pneumoniae (7.9%, 3/38), P. non-aeruginosa (5.3%, 2/38) and P. aeruginosa (2.6%,
      1/38). No clinical or radiological markers were significantly associated with
      lower respiratory tract bacterial infection. Large quantities of bacteria were
      present in the lower respiratory tracts of a substantial number of children (1/8)
      in this selected group of asthmatics. For the moment, however, the clinical
      implications of this finding remain unclear.

PMID- 10591423
TI  - Increased prevalence of overweight in adolescent girls with type 1 diabetes
      mellitus.
AB  - Height and weight were measured in young patients with type 1 diabetes up to the
      age of 22 y. We found no difference between birth length standard deviation
      scores (SDS), final height SDS and target height SDS. The study group of 89
      diabetic boys and girls did not differ in final height from age- and sex-matched
      healthy controls. SDS for height at diagnosis, +0.17 +/- 1.10, exceeded that for
      final height, -0.06 +/- 0.97 (p = 0.037). Height SDS decreased between the ages
      of 11 and 18 (p < 0.01). In diabetic girls, but not boys, final height SDS was
      significantly related to mean HbA1c during puberty (r = -0.40; p = 0.025). Weight
      gain occurred from age of menarche in girls with type 1 diabetes. At the age of
      18, diabetic girls were 6.5 kg heavier and had 2.7 kg/m2 higher body mass index
      (BMI) than control girls (p < 0.001). Diabetic boys were not heavier than control
      boys. There was a significant relationship between mean HbA1c during puberty and
      BMI at the age of 18 in diabetic girls (r = 0.47; p = 0.009). In diabetic
      females, body weight remained unchanged, HbA1c improved and the dose of insulin
      was significantly reduced between 18 and 22 y of age. The HbA1c improvement was
      most marked in patients with poor metabolic control. In conclusion, although mean
      final height was normal in young patients with type 1 diabetes, growth was
      increased before diagnosis and pubertal growth spurt was reduced. Adolescent
      overweight was overrepresented; it related to poor metabolic control in females
      with diabetes, but showed no further acceleration in early adulthood.

PMID- 10591424
TI  - Smith-Lemli-Opitz syndrome: in vivo and in vitro study of testicular function in
      a prepubertal patient with ambiguous genitalia.
AB  - The pathogenesis of the development of ambiguous genitalia reported in some 46,XY
      patients with Smith-Lemli-Opitz syndrome is not understood. Presumably, it is
      related to the 7-dehydrocholesterol reductase deficiency present in these
      patients. In this study we have evaluated testicular function, both in vivo and
      in vitro, in a 46,XY patient with ambiguous genitalia, reared as a girl. The
      diagnosis was based on clinical features, low serum cholesterol and high serum 7
      dehydrocholesterol levels. Serum hormone values, determined during the first
      month of age, showed normal basal testosterone (1.95 ng/ml), LH (0.91 U/l) and
      FSH (2.51 U/l). However, serum testosterone did not increase after hCG
      administration (1.98 ng/ml). On the other hand, the patient had a positive
      biological response to exogenous testosterone (decrease in sex hormone-binding
      globulin serum levels). She was orchidectomized at the age of 33 mo. Testicular
      cells were dispersed and maintained in culture for 6 d. These cells showed a very
      good capacity to secrete testosterone into the culture medium (X +/- SD, 26.1 +/-
      11.7 vs. 4.36 +/- 1.70 pmol/10(6) cells/24 h in a control group of testicular
      cells prepared from testes collected at necropsy). The patient's cells failed to
      respond to LH stimulation (18.6 +/- 4.0 pmol/10(6) cells/24 h), although they did
      respond to other stimuli. It is concluded that the severe cholesterol deficiency
      of this patient did not impair the capacity of the testes to synthesize
      testosterone. However, the LH/hCG receptor or its subsequent message was
      activated neither in vivo nor in vitro. This finding suggests that the foetal
      testes might have failed to respond to placental hCG at the time of male external
      genital differentiation. This failure could have been responsible for the
      ambiguous genitalia present in this patient.

PMID- 10591425
TI  - Combination of von Willebrand disease type 1 and partial factor XII deficiency in
      children: clinical evidence for a diminished bleeding tendency.
AB  - Factor XII deficiency can be associated with a thrombotic and VWF deficiency with
      a haemorrhagic clinical course. To study the potential influence of factor XII
      deficiency on bleeding tendency in patients suffering from VWD we retrospectively
      compared the clinical outcome of children with either an isolated factor XII
      deficiency, an isolated VWD, or a combination of both. Patients with the combined
      coagulation defect showed significantly fewer bleeding events when compared to
      patients with isolated VWD, although ristocetin cofactor activities were reduced
      to a comparable degree. As far as aPTT values are concerned, there were no
      significant differences among the three groups. Whether this combination of
      thrombophilic and haemorrhagic coagulation disorders is only coincidental or the
      result of an active modulation of one of the two counteracting coagulation
      factors is not known at present.

PMID- 10591426
TI  - Mid-term follow-up after multiple system organ failure following cardiac surgery
      in children.
AB  - Multiple system organ failure after cardiac surgery in children is a severe
      complication with unknown mid- and long-term sequelae. We therefore evaluated 11
      children (aged 20-126 mo, median: 67 mo) having survived multiple system organ
      failure after cardiac operations for congenital cardiac defects in a cross
      sectional follow-up study 12-76 mo (median: 32 mo) after surgery. Clinical and
      laboratory examinations included cardiac, pulmonary, renal, hepatic, neurological
      and psychological function tests. All patients had adequate cardiac function.
      Lung mechanics were abnormal in three children and glomerular renal function was
      abnormal in two patients. Slight elevation of gamma-glutamyl transpeptidase and
      coagulation factor deficiency was present in six and seven patients, respectively
      (five of whom had undergone the Fontan operation). Severe neurological sequelae
      such as diplegia (n = 1) and mental retardation (n = 1) were observed in two
      patients. In addition, five children presented delayed motor, graphomotor and/or
      speech development. Two children were found to have abnormal intelligence. We
      conclude that with the exception of neurological impairment, mid-term sequelae of
      multiple system organ failure after cardiac surgery in children are mild.
      However, longer follow-up using an appropriate control group is mandatory.

PMID- 10591427
TI  - Surfactant-deficient respiratory distress after elective delivery at 'term'.
AB  - Babies of 37-41 wk gestation are, by international convention, said to be born at
      'term', but some still develop respiratory distress. It is not clear how mature a
      baby has to be to be free of risk of primary surfactant deficiency. An area-based
      retrospective study of all the 179,701 babies of 34 or more weeks' gestation born
      alive in a defined area of the north of England in 1988-92 identified 149 babies
      with features of respiratory distress typical of surfactant deficiency severe
      enough to be managed with ventilatory support and with no evidence of aspiration
      or intrapartum infection. Gestation was carefully cross-validated against
      antenatal information, including at least one ultrasound assessment in the first
      half of pregnancy. Thirty-six of these babies were born at or after 37 wk
      gestation. Only 4 of the 35 delivered at 37-38 wk went into spontaneous labour.
      Seven became ill enough to be candidates for ECMO and two died. A review of all
      neonatal deaths in the study area between 1981 and 1995 identified four similar
      deaths in 1981-87 and two in 1993-95. Babies who are not premature, using the
      internationally agreed definition, can show signs of potentially lethal pulmonary
      immaturity at birth, especially if subjected to pre-labour Caesarean delivery.
      Those born at 37-38 wk are 120 times more likely to receive ventilatory support
      for surfactant deficiency than those born at 39-41 wk. Elective delivery should
      only be undertaken before 39 wk gestation for good medical reasons.

PMID- 10591428
TI  - Comparison of the efficacy of conventional special blue light phototherapy and
      fiberoptic phototherapy in the management of neonatal hyperbilirubinaemia.
AB  - The efficacy and usefulness of two types of phototherapy differing in the source,
      wavelength and irradiance of the light, conventional phototherapy consisting of
      special blue light and fiberoptic phototherapy, were compared in a relatively
      larger series of term newborns with non-haemolytic and more significant
      hyperbilirubinaemia than those in previous studies. In total, 108 newborns were
      allocated sequentially to receive either conventional phototherapy consisting of
      five special blue lamps or fiberoptic phototherapy. The average spectral
      irradiance measured at the skin surface level of newborns during the study period
      was significantly greater in the conventional phototherapy group. The special
      blue lamp of the conventional phototherapy unit had an emission spectrum almost
      identical to the bilirubin absorption spectrum, whereas the tungsten-halogen lamp
      of the fiberoptic phototherapy had a broad emission through the blue and green
      wavelengths (mainly in the green spectrum). Phototherapy was more effective in
      the conventional phototherapy group; the duration of exposure to phototherapy (h)
      was significantly shorter, and the overall bilirubin decline rate (as
      micromol/l/h and %/h) was significantly greater in the conventional phototherapy
      group. According to the nursing personnel, fiberoptic phototherapy was more
      comfortable than the conventional phototherapy frame because of the easier
      accessibility and handling of the infants during phototherapy. They complained of
      giddiness, nausea, glare, temporary blurring of vision and difficulty in
      detecting the skin colour changes of newborns with the blue light of the
      conventional phototherapy unit. Conventional phototherapy consisting of special
      blue fluorescent lamps with approximately twofold higher irradiance and an
      emission spectrum almost identical to the bilirubin absorption spectrum is
      preferable to fiberoptic phototherapy in the standard treatment of term newborns
      with non-haemolytic hyperbilirubinaemia.

PMID- 10591429
TI  - Passive immunity of premature infants against measles during early infancy.
AB  - The aim of this study was to evaluate the presence of transferred measles
      antibodies and seronegativity rates during early infancy in premature newborns
      whose mothers had infection-induced immunity. The premature group was composed of
      22 and 35 newborns of gestational ages < 32 wk and > 32 wk, respectively, and the
      control group consisted of 28 term newborns. Enzyme-linked immunosorbent assay
      (ELISA) was used for the qualitative detection of IgG antibodies to measles
      virus. Mean cord blood relative values were significantly lower in both premature
      groups, < or = 32 wk (p < 0.0001) and > 32 wk (p < 0.001), when compared with
      term infants. No seronegative infant was found in the premature group at 2 mo of
      age. At 4 mo, the seronegativity rate was 27% for premature infants < or = 32 wk
      and 35% for those > 32 wk. At 6 mo, seronegativity increased to 86% and 74% for
      premature infants born at gestational ages < or = 32 wk and > 32 wk,
      respectively. Forty-six percent of the term infants became seronegative at that
      age. The differences between term infants and those in the two premature groups
      were statistically significant (p < 0.05 and p < 0.005). Premature infants,
      regardless of their prematurity degree, were thought to be more susceptible to
      measles infection than term ones at the age of 6 mo. Policies for their
      protection from measles infection are still to be investigated.

PMID- 10591430
TI  - Use of a pacifier and behavioural features in 2-4-month-old infants.
AB  - This study aimed to analyse a possible association between the use of a pacifier
      and particular behavioural features in 2-4-month-old infants as estimated by the
      means of the Early Infancy Temperament Questionnaire (EITQ). It comprised 192
      randomly selected clinically healthy infants born in St Petersburg in 1997-1998.
      The mothers were asked to complete the questionnaires addressing infant, maternal
      and major demographic characteristics, and childcare practices, with particular
      emphasis on the use of a pacifier, as well as to fill in the EITQ. The EITQ
      scores nine different aspects of infant temperament: activity, rhythmicity,
      approach, adaptability, intensity, mood, persistence, distractibility and
      threshold. A total of 117 of 192 infants (60.9%) used pacifiers, and they
      appeared to have more rhythmic behaviour than non-users. This effect remained
      after adjustment was made for major potential confounding and/or modifying
      factors, including gender, parity, details from perinatal history and familial
      social background, feeding pattern, bed sharing and room sharing. With the
      exception of rhythmicity, no significant association was found between the use of
      a pacifier and any other particular feature of infant temperament. Use of a
      pacifier may be associated with higher rhythmicity in 2-4-month-old infants.

PMID- 10591431
TI  - Measurements of attention deficits and impulsivity: a Swedish study of the Gordon
      Diagnostic System.
AB  - The Gordon Diagnostic System (GDS) is a portable easily operated computerized
      tool developed to measure impulse control, attention and vigilance. In 1988, it
      was standardized for use among American children. The aim of this study was to
      evaluate the GDS for use among Swedish children. A clinical sample of 71 Swedish
      children, mean age 10.5 y, fulfilling the ADHD criteria according to the DSM-IV
      was compared with a control sample of 88 children, mean age 10.2-y, with no known
      psychiatric diagnosis. The clinical sample showed lower GDS scores in all age
      groups, with some exceptions. The GDS scores were not associated with gender, but
      strongly associated with age, especially in the control sample. The accuracy of
      the GDS referring a specific child to either of the samples was, as expected, not
      impressive. With respect to the practical usefulness, the GDS was well accepted
      by the children and parents in both samples. The findings in age variation and
      when comparing children with ADHD and controls are in agreement with results from
      other studies.

PMID- 10591432
TI  - Reproducibility of a survey questionnaire for the investigation of low back
      problems in adolescents.
AB  - A test-retest design was used to investigate the reproducibility of the results
      obtained using a survey questionnaire for low back problems in adolescents. A 1
      wk interval between test and retest was chosen. Participants were recruited from
      four schools. Selection of schools was based on geographic location, size of the
      school and educational level. Sixty-seven adolescents (mean age = 16.62 y; SD =
      0.57; range = 16-18) suffering from low back problems agreed to participate. A
      questionnaire on perceived characteristics of back problems and functional
      limitations was designed. Item completion rate and the reproducibility of results
      were investigated by means of percentage agreement and (weighted) kappa. High
      levels of reproducibility were found for items that evaluated perceived
      characteristics of back problems and functional limitations (Kw = 0.70-0.93).
      Results suggest that the questionnaire used in the present study provided
      reproducible information. Detailed information on low back problems in
      adolescents could be obtained using this questionnaire.

PMID- 10591434
TI  - Hospitalization for varicella in central Israel.
AB  - In order to determine the impact of chickenpox on the general population, we
      conducted a retrospective study in four medical centres in central Israel.
      Hospital records of 182 patients discharged with the diagnosis of varicella
      during a 3-y period were reviewed. The patients' mean age was 7.9 y. A total of
      14 patients (8%) were immunocompromised. Bacterial skin or soft tissue infection
      was the most common complication (32%). Other complications included
      gastrointestinal manifestations (14%), pneumonia (12%), febrile seizures (10%)
      and CNS complications (9%). Twenty-one percent of patients were discharged with
      the diagnosis of uncomplicated varicella. One patient died, one underwent liver
      transplantation for liver failure and four had persistent neurological sequelae.
      Forty-four patients (24%) received acyclovir for an average duration of 5.7 d.
      The mean hospital stay was 4.3 d; it was significantly longer for patients with
      CNS complications (8 d). We estimate that the hospitalization rate in Israel is
      1/285 cases of chickenpox. While mortality from varicella was found to be
      relatively rare, the economic burden of this infection in Israel is quite
      substantial.

PMID- 10591433
TI  - Efficacy and safety during long-term treatment of primary monosymptomatic
      nocturnal enuresis with desmopressin. Swedish Enuresis Trial Group.
AB  - The Swedish Enuresis Trial (SWEET) was conducted to evaluate the long-term safety
      and efficacy of intranasal desmopressin treatment in children with primary,
      monosymptomatic nocturnal enuresis (PMNE). The study had an open, multicentre
      design and comprised a 4-wk observation period, a 6-wk dose titration period
      (with 20-40 microg desmopressin) and a 1-y, long-term treatment period. A
      treatment-free week was introduced every 3 mo to identify dry patients. In total,
      399 children aged 6-12 y with PMNE were recruited. Of these, 245 patients (61%)
      experienced > or = 50% reduction in the number of wet nights during the last 4 wk
      of dose titration compared with the observation period. These responders entered
      the long-term phase of the trial. The mean number of wet nights per week
      decreased from a median of 5.3 (range 1.3-7.0) during the observation period to a
      median of 0.8 (range 0.0-5.0) during the last 3-mo period. Seventy-seven children
      became dry, 63 (83%) within 6 mo of treatment initiation. The percentage of
      children who became dry was similar in all age groups. Significantly fewer
      children in the lowest age group were defined as responders (52%; 95% CI 45, 59)
      among the 6-7-y-olds compared to 65% (56, 74) and 81% (72, 90) in the two older
      age groups. Desmopressin was well tolerated. No serious drug-related adverse
      events were recorded and no clinical symptoms of hyponatraemia were reported. The
      SWEET trial has demonstrated that desmopressin is both safe and effective for the
      long-term treatment of PMNE, with a significant therapeutic effect also in
      children of 6-7 y of age.

PMID- 10591435
TI  - Persistent value of air-augmented radiograph in neonatal high gastrointestinal
      obstruction, despite more modern techniques.
AB  - Air is a safe and effective natural contrast agent in neonatal high
      gastrointestinal (GIT) obstruction. Successful early decompression often results
      in plain abdominal radiographs of low diagnostic yield. We present a series of
      neonates with high GIT obstruction in whom air-augmented abdominal radiographs
      (AAAR) were performed instead. Fourteen neonates presented with suspected high
      GIT obstruction. In 12 sick babies, obstruction was confirmed and the level of
      obstruction was determined. The other two neonates required additional positive
      contrast upper GIT studies. These confirmed small bowel malrotation. For neonatal
      high GIT obstruction an AAAR can provide a rapid and accurate diagnosis. Positive
      contrast agent studies should be performed when the AAAR is non-diagnostic.

PMID- 10591436
TI  - Non-nutritive sucking in full-term and preterm infants studied at term
      conceptional age.
AB  - Non-nutritive sucking (NNS) patterns in full-term newborn and preterm infants
      were studied at term conceptional age. The preterm group showed a distinct NNS
      pattern with a higher frequency and lower amplitude. In the preterm group, gender
      differences were observed, the girls having higher frequency and larger
      amplitude. The full-term infants' NNS patterns were also related to pacifier use
      during early childhood. Experience, gender, maturity and level of tension are
      suggested as explanatory factors for differences in NNS patterns.

PMID- 10591437
TI  - Neonatal gastrointestinal mucormycosis mimicking necrotizing enterocolitis.

PMID- 10591438
TI  - Cardiomyopathy, myopathy, cataracts and CNS disorders: fourth case of a new
      familial disease?

PMID- 10591439
TI  - Prader-Labhart-Willi syndrome with central precocious puberty and empty sella
      syndrome.

PMID- 10591440
TI  - Zidovudine prophylaxis and perinatal HIV-1 transmission.

PMID- 10591441
TI  - Possible oxidative stress in healthy term newborns.

PMID- 10591442
TI  - Effect of ultrasound transducer frequency on the appearance of the fetal bowel.
AB  - We evaluated how ultrasound transducer frequency affected the appearance of the
      fetal bowel. One hundred women with singleton pregnancies, who were undergoing
      routine ultrasonographic examination, were assessed at a single institution.
      Patients with known fetal anomalies, abnormal biochemical screening results, or a
      history of cystic fibrosis were excluded. Images of the fetal abdomen were
      obtained in all patients using a single multi-Hertz transducer, with transducer
      frequencies set at 5 MHz and 8 MHz. Images were read separately by two
      radiologists, blinded to patient name and transducer frequency. Observers rated
      the presence or absence of echogenic bowel, defined as bowel with echogenicity
      greater than or equal to that of adjacent bone. Using the 8 MHz frequency, the
      radiologists interpreted 31% of the cases as having echogenic bowel, whereas
      using the 5 MHz frequency, the radiologists interpreted only 3% of the cases as
      having echogenic bowel (P<0.0001). A fetus was 10 times as likely to be given a
      diagnosis of echogenic bowel by both observers when the 8 MHz transducer was used
      than when the 5 MHz transducer was used by one observer (relative risk 10, 95% CI
      3-11). Furthermore, using the 8 MHz frequency transducer, at least one of the
      radiologists interpreted echogenic bowel in 62% of the cases. We concluded that
      echogenic fetal bowel is a very common observation when imaging is performed with
      an 8 MHz transducer, and thus echogenic bowel diagnosed with an 8 MHz transducer
      is unlikely to reflect underlying abnormality. Identification of echogenic bowel
      with an 8 MHz transducer should not prompt further testing.

PMID- 10591443
TI  - Fetal sonographic cardiothoracic ratio at midpregnancy as a predictor of Hb Bart
      disease.
AB  - The objective of this study is to evaluate the efficacy of sonographic
      cardiothoracic ratio at midpregnancy in predicting fetal hemoglobin Bart disease.
      Among 17,254 pregnant women screened for severe thalassemia between June 1994 and
      November 1998, 345 pregnant women at risk for having a fetus with hemoglobin Bart
      disease underwent ultrasonographic examination and cordocentesis at 18 to 21
      weeks' gestation. Before cordocentesis, the cardiothoracic ratio was determined
      and recorded. The definite fetal diagnosis was based on fetal blood analysis with
      high performance liquid chromatography. Among 345 pregnancies in which
      sonographic examination and cordocentesis were performed, 70 fetuses were
      affected by hemoglobin Bart disease. The mean cardiothoracic ratio was
      significantly higher than that of unaffected fetuses (0.55 versus 0.45, Student's
      t-test, P<0.001). The sensitivity and specificity of the cardiothoracic ratio in
      prediction were calculated for various cutoff values. On the basis of the
      receiver operating characteristic curve, the best cutoff value was 0.50 (greater
      than 0.50 considered abnormal), giving the sensitivity of 98.6% and a specificity
      of 98.9%. In conclusion, the cardiothoracic ratio has very high accuracy in
      predicting hemoglobin Bart disease in pregnancies at risk. This finding suggests
      that invasive diagnostic method should be reserved for only the fetuses who have
      a cardiothoracic ratio of 0.5 or more; however, further studies are needed to
      confirm this observation.

PMID- 10591444
TI  - Estimation of fetal weight: mean value from multiple formulas.
AB  - Mean fetal weight value from multiple formulas was compared to fetal weight from
      single formulas. Data were collected on 975 fetuses who had estimation of fetal
      weight by ultrasonography within 1 week before birth. Improvement in estimation
      of fetal weight occurred using either the mean value of multiple formulas or the
      Hadlock BPD/FL/AC, in comparison to fetal volume, BPD/AC, or FL/AC. BPD/FL/AC
      appeared to provide the best estimate of true weight in terms of overall accuracy
      and in terms of not showing a trend in either overestimating or underestimating
      true weight.

PMID- 10591445
TI  - Slow embryonic heart rates.

PMID- 10591446
TI  - Changes of renal resistive index in response to hydration and diuretic
      administration in normal subjects and in patients with small ureteral stone.
AB  - The renal resistive index has been measured before and after hydration and
      administration of diuretics in persons with normal kidneys and in kidneys with
      small ureteral stone, either obstructing or nonobstructing, to assess induced
      flow changes and to identify features differentiating obstructing from
      nonobstructing stones. In normal kidneys the resistive index was normal (mean,
      0.62+/-0.03); no changes in the resistive index occurred within 15 to 60 min
      after hydration alone, whereas the resistive index rose within 15 min after
      hydration plus administration of diuretics and then returned to initial values
      within 30 min. In both cases the resistive index decreased below basal values
      after 75 to 90 min. Similar changes were observed in kidneys with a
      nonobstructing ureteral stone. In kidneys with an obstructing ureteral stone the
      resistive index was higher than in normal subjects (mean, 0.73+/-0.02, P<0.01),
      increased further within 15 min after hydration and administration of diuretics
      (P<0.01), and remained higher than basal values during the following 90 min. In
      conclusion, different resistive index changes have been observed in response to
      hydration and diuretics in normal and obstructed kidneys. Duplex Doppler
      sonography and diuresis duplex Doppler sonography seem promising diagnostic tools
      to identify obstructing stones.

PMID- 10591448
TI  - Assessment of Doppler velocimetry of the fetal umbilical artery by multigate
      spectral Doppler scanning and traditional pulsed Doppler ultrasonography plus
      color flow mapping.
AB  - The Doppler signal of blood flow originates from the sonographic scattering from
      the circulating red blood cells. However, the physics of blood flow is complex as
      expressed by the Bernoulli equation, and the flow velocity at different positions
      in the laminar flow of the same vessel is variable. Using multigate spectral
      Doppler scanning, we recorded multiple Doppler flow signals over a segment of the
      umbilical artery and compared the results with traditional pulsed Doppler
      ultrasonography. The intraobserver variations of the pulsatility index, the
      resistive index, and the systolic-to-diastolic ratio were evaluated in 30 human
      fetuses between 29 and 42 weeks of gestation. The correlation coefficient was
      calculated to establish the relationship between the results of multigate
      spectral Doppler scanning and the traditional pulsed Doppler ultrasonographic
      method. The Doppler indices of these two measurements are all significantly
      correlated. However, since a significant difference exists between the Doppler
      flow measurements of multigate spectral Doppler scanning and the traditional
      pulsed Doppler ultrasonographic method, the range of measurement agreement for
      these two methods suggests that this difference should be taken into account in
      the interpretation of Doppler flow velocity measurements.

PMID- 10591447
TI  - Serial pulsatility index measurements in renal grafts before, during, and after
      episodes of urinary obstruction.
AB  - The usefulness of pulsatility index determinations for the diagnosis of
      obstructive collecting system dilatation was investigated in 10 renal transplant
      patients whose grafts developed urinary obstruction from different causes. For
      this purpose we compared pulsatility index values obtained (1) before the
      ultrasonographic detection of obstruction or baseline study, (2) 1 day before
      surgical repair, and (3) within 2 weeks after surgery. In 7 of 10 obstructed
      grafts, the pulsatility index values were increased only mildly to moderately
      preoperatively. In the remaining three grafts, a mild decrease in pulsatility
      index was observed in spite of severe collecting system dilatation. Changes in
      pulsatility index were not statistically significant. Impedance measurements
      appeared not to be useful for diagnosing obstructive collecting system
      dilatation.

PMID- 10591449
TI  - Prospective evaluation of a logistic model based on sonographic morphologic and
      color Doppler findings developed to predict adnexal malignancy.
AB  - To assess prospectively a logistic model based on sonographic morphologic and
      color Doppler findings, which had been developed to predict adnexal malignancy,
      167 consecutive and unselected patients (mean age, 45.7 yr; range, 17 to 81 yr;
      113 [67.7%] premenopausal and 54 [32.3%] postmenopausal) diagnosed as having an
      adnexal mass and scheduled for surgery were prospectively included in this study.
      All patients were evaluated by transvaginal color Doppler ultrasonography. The
      probability of adnexal malignancy was estimated prior to surgery, applying a
      logistic model developed previously. A probability of malignancy greater than 75%
      was considered to assess model performance. Sensitivity, specificity, positive
      predictive value, negative predictive value, and accuracy were calculated for the
      model. In all cases definitive histopathologic diagnosis was obtained. One
      hundred and twenty-five (74.9%) benign and 42 (25.1%) malignant tumors were
      found. The sensitivity, specificity, positive predictive value, and negative
      predictive value of the model were 85.7% (95% confidence intervals, 71.4% to
      94.6%), 100% (95% confidence intervals, 97.1% to 100%), 100% (95% confidence
      intervals, 90.3% to 100%), and 95.4% (95% confidence intervals, 90.3% to 98.3%),
      respectively. Overall accuracy was 96.4% (95% confidence intervals, 91.3% to
      98.7%). Our results confirm the validity of the proposed logistic model in
      predicting adnexal malignancy.

PMID- 10591450
TI  - Evaluation of change in blood flow by contrast-enhanced power Doppler imaging
      during norepinephrine-induced renal vasoconstriction.
AB  - We evaluated the changes in flow induced by intrarenal infusion of norepinephrine
      by an ultrasonographic contrast agent and power Doppler imaging. Hypoperfusion
      was induced in dogs (N = 5) by infusing norepinephrine directly into the renal
      artery for 30 min at doses of 0.7 microg/kg/min, 1.0 microg/kg/min, and 1.9
      microg/kg/min. Contrast agent injections were made before and after each infusion
      of norepinephrine. The transit of contrast agent through the kidney and color
      enhancement were measured by computer analysis of power Doppler images. Mean
      transit time and effective renal plasma flow were measured. The effective renal
      plasma flow decreased by 29%, 30%, and 64%, respectively, with the increasing
      doses of norepinephrine. Paralleling this change, the mean transit time, which
      corresponds to reduction in renal blood flow, increased by 26%, 43%, and 77%,
      respectively, from the preinfusion value. Regression analysis shows renal blood
      flow to decrease exponentially with norepinephrine dose. Renal blood flow changes
      measured by contrast-enhanced imaging correlated closely with the effective renal
      plasma flow measurements. Computer analysis of contrast-enhanced power Doppler
      images allowed measurement of renal blood flow. This technique may be useful in
      assessing renal perfusion during pharmacologic and other therapeutic
      interventional procedures.

PMID- 10591451
TI  - Three-dimensional ultrasonography and diagnosis of placenta percreta with bladder
      involvement.

PMID- 10591452
TI  - Unusual sonographic features of granular cell tumor of the breast.

PMID- 10591453
TI  - Effusion between the aponeuroses.

PMID- 10591454
TI  - Effects and adverse events of a dental appliance for treatment of obstructive
      sleep apnoea.
AB  - In a prospective study, 95 patients with mild to moderate obstructive sleep
      apnoea (OSA) were randomised to receive either surgical treatment,
      uvulopalatopharyngoplasty, (4-6 patients) or treatment with a nocturnal dental
      appliance for mandibular advancement (49 patients). Of the 49 dental appliance
      patients, 37 completed the 12-month follow-up. The aim of this study was to
      evaluate the effects and adverse events of dental appliance treatment from a one
      year perspective. Somnography was employed to measure treatment effects before
      and 12 months post-treatment. At the 12-month control, somnography was performed
      twice: the first time with the dental appliance and the second time without it.
      Adverse events were recorded 2 weeks and 3, 6, and 12 months after treatment was
      initiated. The patients used the dental appliance on average 6 nights/week. After
      12 months of treatment, the apnoea, apnoea/hypopnoea, oxygen desaturation, and
      snoring indices decreased significantly. Ninety-five per cent of the patients
      reduced their apnoea index by > or = 50% and 78% of the patients were normalised
      following treatment. At the somnographic registration without the dental
      appliance, the values were found comparable to what they were before treatment.
      Mandibular mobility and occlusion were constant throughout the study. The adverse
      events resulting from using the dental appliance were relatively minor and
      infrequent, and no serious complications were observed except for two patients
      who reported pain from the temporomandibular joint. In conclusion, the dental
      appliance has been shown to be a valuable treatment method for mild to moderate
      OSA with few adverse events in the stomatognathic system or other complications.

PMID- 10591455
TI  - Surgical treatment of temporomandibular joint luxation.
AB  - Eminectomy with or without diskectomy was performed in 19 patients with
      temporomandibular joint luxation. Three of them were long-standing luxations
      (duration between three months and one year). The remaining 16 patients had
      recurrent luxations. The follow-up period was three years. No complications such
      as infection or permanent palsy of the facial nerve occurred. However, transient
      palsy of the temporal branch of the facial nerve, which resolved within three
      months was seen in 4 patients (21%). After treatment two patients had recurrent
      luxations. In the remaining 17 patients, two developed painful clicking of one
      TMJ, requiring additional surgery (one patient had arthroscopic lysis and lavage
      and the other one diskectomy). If these two are also regarded as unsuccessful
      cases, the overall long-term success rate was 79%. A comparison of the subgroups
      who underwent eminectomy alone and eminectomy with diskectomy showed that all
      unsuccessful cases occurred in the former group.

PMID- 10591456
TI  - Dental care of young adults in west Sweden.
AB  - 107 Swedish subjects, all 20 years old, were studied for the first three years
      (1990-1992) after they had left the organised dental care for children and
      adolescents (which is free of charge for all youth through the age of 19). They
      were registered in four different risk-grouping systems in order to estimate the
      amount of their future dental care. Three of the systems used registrations from
      the Public Dental Service records and in the fourth one a dentist made a
      subjective estimation. The follow-up used dental insurance claims to study
      performed treatments, courses of treatments and cost. The risk group system that
      used subjective estimations appeared to be the one that most accurately predicted
      the actual dental care consumption. Approximately 70% of the subjects received
      some kind of dental care during the three years. The distribution was not
      confined to any particular risk group. Ten per cent had received complete dental
      care annually. Twenty-five per cent went to a private dentist and 75% continued
      to go to the Public Dental Service. Those who went to a private dentist received
      substantially more treatment and the annual cost was a little more than twice as
      much as in the Public Dental Service.

PMID- 10591457
TI  - Evaluation of three years of dental care of adolescents in the Public Dental
      Service in west Sweden.
AB  - 107 individuals, randomly selected from the County of Goteborg and Bohuslan, all
      born in 1970 were followed regarding the dental care received 1987-1989. The
      records of each individual from the actual time were collected and information on
      diagnosis and treatment measures was gathered. Radiographs from the actual time
      were studied by one of the authors. Sixty-two per cent of the adolescents had
      been examined and treated all 3 years. Six percent had not been seen at all. The
      sample was divided into three groups depending on the patient's DFSa value at the
      examination the first year. This classification appeared to correlate well with
      caries development in the following years. One-fourth of the sample was
      responsible for the major part of the non-attendance and late cancellations. The
      dental health of these subjects was below average, and non-attendance seemed to
      be a further risk factor. The preventive measures undertaken during the study
      appeared to correlate poorly with the actual situation of the patient and the
      presence or absence of potential risk factors.

PMID- 10591458
TI  - The palatally displaced maxillary canine. A retrospective comparison between an
      interceptive and a corrective treatment group.
AB  - The purpose of this retrospective study was to analyze palatally displaced
      maxillary canines referred for specialist treatment compared with those
      successfully treated by the general practitioner by interceptive extraction of
      either the primary canine or the primary canine and primary first molar. Special
      interest was focused on chronological age, dental age and dental maturity as well
      as the position of the canine at the time of recognition and referral. The
      Interceptive Treatment group consisted of 50 consecutive cases from computerized
      records, median age 11.7 years (range 8.9-14.11 years). The Corrective Treatment
      group comprised 47 consecutive cases, median age 14.1 years (range 11.1-18.0
      years), referred to the Department of Orthodontics. Information was obtained by
      assessing the patient charts and radiographs. The results show that age at the
      time of recognition and referral is the most important factor for the final
      outcome while the position of the canine concerning angle alpha and sector S is a
      compromising factor. The results suggest that about one third of the Corrective
      Treatment group might have had a reasonably good chance of the canine's erupting
      without corrective treatment if they had been diagnosed and treated with
      interceptive extraction of the primary canine at an earlier age.

PMID- 10591459
TI  - Optimization of the separation of mono- and dichloroanilines in ion interaction
      high-performance liquid chromatography.
AB  - To optimize the ion-interaction chromatographic separation of nine chloroaniline
      isomers, the effect on retention of six experimental parameters is investigated
      by means of multivariate analysis. The factors considered are the organic
      modifier concentration in the mobile phase; the length of the alkyl chain of the
      alkylammoniumion salts used as the ion-interaction reagents (IIRs); the
      concentration of IIRs; the pH of the mobile phase, the flow-rate and the ionic
      strength. The use of fractional factorial and star designs allowed one to draw
      out useful information on the retention mechanism involved and to build a model
      characterized by both descriptive and predictive ability. Concerning
      descriptions, the results suggest a retention mechanism mainly based on reversed
      phase partition, while the main role of the alkylamine (used as IIR) seems to
      mask the activity of the residual silanol groups on the stationary phase. As a
      result efficiency is improved. For prediction purposes, the regression models
      allow the optimization of the chromatographic separation, as regards both
      resolution and total analysis time. The study allowed one to develop a method
      able to separate the nine mono- and dichloroanilines in a total analysis time
      within 66 min and with detection limits ranging from 4.0 to 21.0 microg/l.

PMID- 10591460
TI  - Analysis of high-molecular-mass polycyclic aromatic hydrocarbons in environmental
      samples using liquid chromatography-atmospheric pressure chemical ionization mass
      spectrometry.
AB  - Polycyclic aromatic hydrocarbons (PAHs) with molecular masses higher than 300 u
      were analysed using LC-atmospheric pressure chemical ionization (APCI) MS in
      extracts of environmental samples from Hamilton, Canada including zebra mussels
      from Hamilton Harbour, air particulate and coal tar. The LC-APCI-MS profiles of
      three molecular mass classes of PAHs (326 u, 350 u and 374 u) were compared to
      identify potential sources of PAH contamination in Hamilton Harbour. The Hamilton
      air particulate profile was also compared with an urban air reference standard
      (NIST SRM 1649) from Washington, DC, USA. Profiles of all extracts were similar
      and suggested an environmental predominance of PAHs within the three isomeric
      molecular mass classes studied. However, PAHs of molecular mass 326 u and 350 u
      were detected in extracts of coal tar and zebra mussels from Hamilton Harbour but
      were not detected in Hamilton air. These results indicated that some high
      molecular-mass PAHs may be characteristic of contamination by coal tar.

PMID- 10591461
TI  - Reversed-phase liquid chromatographic separation and simultaneous profiling of
      steroidal glycoalkaloids and their aglycones.
AB  - Improved and simplified reversed-phase liquid chromatographic conditions for the
      separation and simultaneous profiling of both steroidal glycoalkaloids and their
      aglycones, having solanidane- or spirosolane-type structures, are described. The
      most reproducible retention behavior for these ionizable compounds on C18 columns
      was achieved under isocratic and gradient elution conditions using acetonitrile
      in combination with triethylammonium phosphate buffer at pH 3.0, when basic
      functional groups of solutes and silanol groups on the silica are fully
      protonated minimizing ionic interactions. Gradient elution was the only feasible
      approach for the simultaneous separation of steroidal glycoalkaloids and their
      aglycones. A Zorbax SB C18 column, specially designed for low-pH separations,
      showed good performance in critical separations. The impurities of the commercial
      tomatine and tomatidine standards were studied and confirmed using mass
      spectrometric, liquid chromatographic and thin-layer chromatographic methods.

PMID- 10591462
TI  - Rapid quantification of hexachlorobenzene in the color additives D&C Red Nos. 27
      and 28 (phloxine B) using solid-phase microextraction and gas chromatography-mass
      spectrometry.
AB  - The present paper describes the development of a method for the quantification of
      hexachlorobenzene (HCB) in the color additives D&C Red Nos. 27 and 28 (phloxine
      B) using solid-phase microextraction followed by gas chromatography-mass
      spectrometry (GC-MS) analysis. The method is simple and fast (1 h for each
      analysis), generates little solvent waste, and does not involve a solid matrix,
      thus permitting a more efficient extraction than does a previously developed
      Soxhlet extraction-GC-MS method. Test portions from 30 batches of US-certified
      color additives D&C Red Nos. 27 and 28 were analyzed for HCB using the new
      method. Those batches represent domestic (five) and foreign (one) manufacturers
      that requested certification for the colors during the past four years. All the
      samples contained HCB, ranging from 0.2 ppm to 244.3 ppm. The analyses revealed
      significant differences in the levels of HCB across batches from the same
      manufacturer as well as among different manufacturers. The range of HCB levels
      found in the analyzed batches (0.2-244.3 ppm) suggest that the contamination with
      HCB may be decreased by avoiding use of starting material (tetrachlorophthalic
      anhydride) heavily contaminated with HCB.

PMID- 10591463
TI  - Strategies for supercritical fluid extraction of hyoscyamine and scopolamine
      salts using basified modifiers.
AB  - The supercritical fluid extraction behaviors of hyoscyamine and scopolamine were
      investigated and found to be highly dependent upon the chemical nature of the
      compounds. Free bases of hyoscyamine and scopolamine were freely soluble in
      supercritical CO2 with increasing temperature and pressure; however, the salts of
      these alkaloids were not soluble under any experimental conditions. It was found
      that alkaline modifiers such as methanol basified with diethylamine could enhance
      the solubilities and extraction yields of these alkaloids from plant matrices as
      compared to other modifiers.

PMID- 10591464
TI  - Trapping efficiency of aqueous pollutants in multichannel thick-film silicone
      rubber traps for capillary gas chromatography.
AB  - Established standard methods for analysing aqueous pollutants by capillary gas
      chromatography are cumbersome, time-consuming and expensive. With the aim of
      replacing the sample preparation procedures with direct concentrating and thermal
      desorption steps multichannel silicone-rubber traps were tested to determine
      breakthrough volumes and optimum accumulation conditions as a function of water
      flow-rate. Larger multichannel traps, consisting of 32 silicone tubes in parallel
      were made to increase the collection flow-rate through the trap with the same
      extraction efficiency of the initial smaller traps. It was shown that by
      increasing the number of parallel silicone tubes in the multichannel trap the
      breakthrough volume of benzene is 37 ml at a flow-rate of 75 microl/min and the
      trap displays 11 theoretical plates under these conditions.

PMID- 10591465
TI  - Effects of organic modifiers on retention mechanism and selectivity in micellar
      electrokinetic capillary chromatography studied by linear solvation energy
      relationships.
AB  - The effects of six organic modifiers (urea, methanol, dioxane, tetrahydrofuran,
      acetonitrile and 2-propanol) on the retention mechanism and separation
      selectivity of the bulk buffer in micellar electrokinetic capillary
      chromatography (MECC) with sodium dodecyl sulfate (SDS) micelles as pseudo
      stationary phase have been investigated through linear solvation energy
      relationships (LSERs). It is found that the retention value in MECC systems with
      or without organic modifier is primarily dependent on the solvophobic interaction
      and the hydrogen bonding interaction with the solute as proton acceptor, while
      the dipolar interaction and the hydrogen bonding interaction with the solute as
      proton donor play minor roles. The effects of the organic modifiers on the
      solvophobic, dipolar and hydrogen bonding interactions are evaluated in terms of
      the relationship between regression coefficient of the LSER equations and the
      modifier concentration. The variations of the solvophobic interaction and the
      dipolar interaction with change of the modifier concentration can be
      approximately explained using the solubility parameter and the
      dipolarity/polarizability parameter of the organic modifier, respectively.
      However, the relationships between the hydrogen bond acidity and basicity of the
      bulk buffer and the organic modifiers are rather complicated. Those results may
      be caused from the displacement of organic modifiers to the water adsorbed on the
      micellar surface as well as changes in the acidity and basicity of the bulk
      buffer with the addition of organic modifiers. In addition, it is found that the
      phase ratio is influenced significantly by the use of organic modifier.

PMID- 10591466
TI  - Effect of drying on the degradation of cationic surfactants and separation
      performance in capillary zone electrophoresis of inorganic anions.
AB  - Tetradecyltrimethylammonium bromide (TTAB) is used in capillary zone
      electrophoresis (CZE) to control the direction and magnitude of the
      electroosmotic flow and the migration time of analyte anions. Drying of the
      hygroscopic TTAB at 100 degrees C overnight has been found to influence the final
      CZE separation by providing improved resolution, precision of migration times,
      and enhanced detection response for hydrogenphosphate. Chemical analysis of the
      dried TTAB using IR and GC-MS indicated the presence of small amounts of an
      unexpected tertiary alkylamine, tetradecyldimethylamine. This amine appears to
      contribute to the improved separation, probably by making more effective the
      masking of silanophilic activity at the capillary surface and/or generating a
      more stable double-layer.

PMID- 10591467
TI  - Separation of natural pyrethrum extracts using micellar electrokinetic
      chromatography.
AB  - The separation of the six pyrethrin esters in a technical pyrethrum extract
      (Riedel-de-Haen, Cresent Chemical Co. Inc. Hauppauge, NY, USA) by micellar
      electrokinetic chromatography (MEKC) using both sodium dodecyl sulfate (SDS) and
      a polymerized surfactant as pseudo-stationary phases has been investigated and
      optimized. Parameters such as pH, SDS and polymerized sodium N-undecyl sulfate
      (poly-SUS) concentration, type and concentration of background electrolyte and
      organic modifier, as well as the acetonitrile/water ratio in the sample were
      studied to optimize the resolution, efficiency, and analysis time. An optimized
      separation of the six pyrethrin esters was achieved in 25 min with 25 mM Tris,
      buffered at pH 9, containing 30 mM SDS, 25% (v/v) acetonitrile, and an equal
      volume ratio of acetonitrile/water sample matrix at a voltage of 25 kV. The use
      of 0.5% (w/v) poly-SUS enhanced resolution of the pyrethrin esters and shortened
      the total analysis time from 25 to 20 min, compared to the SDS mediated
      separation. The optimized MEKC results are compared to the HPLC separation of
      these esters and show an improvement in efficiency and total analysis time.

PMID- 10591468
TI  - Migration behavior and separation of active components in Glycyrrhiza uralensis
      Fisch and its commercial extract by micellar electrokinetic capillary
      chromatography.
AB  - A micellar electrokinetic capillary chromatography (MECC) method for the
      separation and determination of five components, glycyrrhizic acid (GA),
      glycyrrhetinic acid (GTA) and 3,4'-dimethoxy-5-hydroxychalone, fermononetin and
      isoliquiritigenin, in extracts of Glycyrrhiza uralensis Fisch root was developed.
      Migration behavior of these analytes was studied by the systematic examination of
      the borate and sodium dodecyl sulfate (SDS) concentrations in the run buffer. The
      optimum separation for these analytes was achieved using 10 mmol l(-1) of
      tetraborate and 25 mmol l(-1) of SDS as the running buffer, with 17 kV of applied
      voltage. All experiments were performed using a 50.0 cm (42.4 cm effective
      length)x75 microm I.D. of fused-silica capillary. The apparent pKa values of GA
      and GTA and the binding constants for the association between the above five
      analytes and SDS were calculated in this study. A comparison of the extraction
      efficiency for GA and GTA from Glycyrrhiza uralensis Fisch root was made using
      ethanol, distilled water and chloroform as extraction reagents, respectively.
      These results provided very useful information to select the proper solvent to
      extract the desired components in Glycyrrhiza uralensis Fisch. The MECC method
      established in this paper was employed to analysis the above five active
      components.

PMID- 10591469
TI  - On-line coupling of solid-phase extraction with mass spectrometry for the
      analysis of biological samples. I. Determination of clenbuterol in urine.
AB  - The potential of the direct coupling of solid-phase extraction (SPE) with mass
      spectrometry (MS) for the analysis of biological samples is demonstrated. For SPE
      a cartridge exchanger is used and the eluate is directly introduced into the mass
      spectrometer. This system has been investigated for the determination of
      clenbuterol in urine. With mixed-mode cartridges, a considerable ion suppression
      has been obtained. The mass spectrum at the elution time of clenbuterol is
      dominated by that of creatinine and adduct formation of clenbuterol and
      creatinine has been observed. The whole procedure including injection of 1 ml
      urine, washing and desorption has been developed with cartridges containing 8
      microm C18-bonded silica. If only a single MS step is used, the selectivity and,
      therefore, the sensitivity are insufficient. The detection limit is about 100
      ng/ml. However, with atmospheric pressure chemical ionisation and the tandem MS
      mode the detection limit has been decreased to about 2 ng/ml and the ion
      suppression is only about 10%. For the electrospray ionisation the detection
      limit is about 10-times higher and the ion suppression is less favourable. The
      repeatability for the SPE-MS-MS procedure was 6.5% at 10 ng/ml (n=5) and the
      difference between the response factors at 10 ng/ml and 100 ng/ml was only 2.5%.
      The MS behaviour of clenbuterol and the matrix under the present conditions is
      discussed.

PMID- 10591470
TI  - Separation, identification and determination of sanguinarine in argemone and
      other adulterated edible oils by reversed-phase high-performance liquid
      chromatography.
AB  - A simple, rapid and reliable reversed-phase high-performance liquid
      chromatographic method for the separation and determination of sanguinarine in
      argemone and other edible oils has been developed. The separation has been
      achieved on a C18 column with CH3OH-CH3CN-tetrahydrofuran-water as mobile phase
      using diode array detection at 280 nm. The minimum detection limit of
      sanguinarine in the adulterated edible oils is 5 microg/g.

PMID- 10591471
TI  - Neuroactive neurosteroids as endogenous effectors for the sigma1 (sigma1)
      receptor: pharmacological evidence and therapeutic opportunities.
AB  - Neuroactive neurosteroids, including progesterone, allopregnanolone, pregnenolone
      and dehydroepiandrosterone, represent steroid hormones synthesized de novo in the
      brain and acting locally on nervous cells. Neurosteroids modulate several
      neurotransmitter systems such as gamma-aminobutyric acid type A (GABA(A)), N
      methyl-D-aspartate (NMDA) and acetylcholine receptors. As physiologic
      consequences, they are involved in neuronal plasticity, learning and memory
      processes, aggression and epilepsy, and they modulate the responses to stress,
      anxiety and depression. The sigma1-receptor protein was recently purified and its
      cDNA was cloned in several species. The amino-acid sequences are structurally
      unrelated to known mammalian proteins, but shared homology with a fungal sterol
      C8-C7 isomerase. The sigma1-receptor ligands exert a potent neuromodulation on
      excitatory neurotransmitter systems, including the glutamate and cholinergic
      systems. Consequently, selective sigma1 agonists show neuroprotective properties
      and beneficial effects in memory processes, stress and depression. The evidence
      of a direct interaction between neurosteroids and sigma1 receptors was first
      suggested by the ability of several steroids to inhibit the binding of sigma1
      receptor radioligands in vitro and in vivo. A crossed pharmacology between
      neurosteroids and sigma1-receptor ligands was described in several physiological
      tests and behavioral responses. This review will detail the recent evidence for a
      common mechanism of action between neurosteroids and sigma1-receptor ligands and
      focus on the potential therapeutic interests of such interaction in the
      physiopathology of learning and memory impairments, stress, depression and
      neuroprotection.

PMID- 10591472
TI  - Acetylcholine-Induced response of coronary resistance arterioles in cholesterol
      fed rabbits.
AB  - The extent to which reported abnormal responses of the human coronary circulation
      to acetylcholine in patients with hypercholesterolemia reflect endothelial injury
      is not clear. We used an in vitro rabbit model to determine whether these
      reactions involve endothelial or vascular smooth muscle dysfunction. Coronary
      resistance arterioles were isolated from hearts of rabbits fed 1% cholesterol to
      induce hypercholesterolemia or a control diet for 4 weeks. Arterioles were double
      cannulated with glass micropipettes and pressurized in a no-flow state.
      Acetylcholine contracted the arterioles in a concentration-dependent manner
      whether or not the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine was
      added. In control but not hypercholesterolemic preparations, contraction was
      significantly greater when endothelium was removed. In the hypercholesterolemic
      group, contraction significantly exceeded that in controls. In control but not
      high-cholesterol preparations, substance P dilated vessels with intact
      endothelium in a concentration-dependent manner. Addition of N(G)-monomethyl-L
      arginine inhibited this response. With or without endothelium, norepinephrine
      contracted arterioles to a greater extent in the hypercholesterolemic group than
      in controls. We concluded that severe hypercholesterolemia decreased
      endothelially dependent factors by injuring endothelium and independently
      increased contractility of vascular smooth muscle.

PMID- 10591473
TI  - Effects of prolonged cold storage on purinergic and adrenergic components of
      sympathetic co-transmission in isolated canine splenic arteries.
AB  - The present study demonstrated the progressive inhibition by prolonged cold
      storage (4, 7 and 14 days at 4 degrees C) on prejunctional and postjunctional
      functions of purinergic and adrenergic components of double-peaked
      vasoconstrictor responses to periarterial electrical nerve stimulation in the
      isolated canine splenic artery. After the cold storage for 4 days, the first
      phase constriction was markedly decreased, whereas the second response was not
      significantly modified. Furthermore, after the 7 days of cold storage, the first
      phase was substantially depressed at low frequencies, but at high frequencies, a
      low level of contractile responses was still observed. On the other hand, the
      second phase in the cold stored artery for 7 days largely remained at any used
      frequencies. Moreover, the 14 days of cold storage almost completely inhibited
      the vasoconstrictor responses to nerve stimulation. Tyramine-induced
      constrictions were progressively decreased in the stored-days dependent manner,
      although the ATP and the noradrenaline-induced one was not modified for 4 and 7
      days of the cold storage. In conclusion, 1) the 4 degrees C cold stored artery
      for 4 days may show preferential injury of its tyramine-dependent noradrenaline
      releasing mechanisms, whereas nerve excited ones might well remain; and 2) the
      prejunctional contractile response of purinergic transmission might be damaged
      more preferentially than that of adrenergic transmission within 7 days storage.

PMID- 10591474
TI  - A novel Na+ and Ca2+ channel blocker, T-477, prevents brain edema following
      microsphere-induced permanent occlusion of cerebral arterioles in rats.
AB  - One of the most common acute complications of stroke is brain edema. Treatment of
      edema is recommended when the condition of the patients is deteriorating. The
      present study was undertaken to evaluate the effect of T-477 [(R)-(+)-2-(4
      chlorophenyl)-2,3-dihydro-4-diethyl aminoacetyl-4H-1,4-benzorthiazine
      hydrochloride], a novel neuronal Na+ and Ca2+ channel blocker, on brain edema in
      rats. Cerebral ischemia was induced by intra-arterial infusion of 1000
      microspheres into the forebrain of freely moving rats, resulting in brain edema.
      T-477 was intravenously infused continuously for 24 h or twice for 3 h with a 3-h
      interval between infusions immediately after microsphere injection. T-477 dose
      dependently inhibited the increase in brain water content by both infusion
      procedures; the inhibition was statistically significant at doses of 25 mg/kg per
      24 h and 14 mg/kg per 9 h. Additionally, infusion of T-477 at a dose of 14 mg/kg
      per 9 h significantly inhibited the decrease in K content and the increase in Ca
      content of the forebrain. In conclusion, T-477 prevents brain edema following
      microsphere-induced cerebral embolism in rats.

PMID- 10591475
TI  - (+)-[3H]isradipine and [3H]glyburide bindings to heart and lung membranes from
      rats with monocrotaline-induced pulmonary hypertension.
AB  - We examined the binding of a 1,4-dihydropyridine-sensitive Ca2+ channel ligand,
      (+)-[3H]isradipine (PN200-110), and that of an ATP-sensitive K+ (K(ATP)) channel
      ligand, [3H]glyburide, to heart, lung and brain membranes isolated from Sprague
      Dawley rats made pulmonary hypertensive by monocrotaline, a pyrrolizidine
      alkaloid. A single subcutaneous injection of monocrotaline increased right
      ventricular systolic pressure, a measure of pulmonary arterial pressure, and the
      thickness of the right ventricular free wall in 3 to 4 weeks. The (+)-[3H]PN200
      110 and [3H]glyburide binding site densities (Bmax) were reduced in hypertrophied
      right ventricles when normalized per unit protein in comparison with those of age
      matched control (sham) rats, whereas the values of the dissociation constant (Kd)
      of both ligands bound to the hypertrophied right ventricle were not significantly
      changed. The [3H]PN200-110 binding to the lung membranes of the monocrotaline
      induced pulmonary hypertensive rats was increased. The results indicate that the
      change in the binding of 1,4-dihydropyridine Ca2+ and K(ATP) channel ligands to
      heart membranes may contribute to the pathological alteration of cardiopulmonary
      structure and functions in rats with pulmonary hypertension induced by
      monocrotaline.

PMID- 10591476
TI  - The effects of a newly synthesized ATP-sensitive potassium channel opener, MJ
      355, on blood pressure and myocardial ischemia-reperfusion injury in rats.
AB  - ATP-sensitive potassium (K(ATP)) channel openers, exerting a potent vasodilatory
      action, are useful in the treatment of cardiovascular disorders; e.g.,
      hypertension and angina pectoris. This study was designed to evaluate the effect
      of MJ-355 (6-cyano-3,4-trans-3,4-dihydro-2,2-dimethyl-2H-3-hydroxy-4-[2-oxo-5S-(1
      ethoxyethoxymethyl)-1-pyrrolidinyl]-1-benzopyran), a newly synthesized K(ATP)
      channel opener, on hemodynamics in spontaneously hypertensive rats and on
      myocardial ischemia-reperfusion injury in a rat model of 45 min left coronary
      artery occlusion followed by 1-h reperfusion. Intravascular injection of MJ-355
      (0.005, 0.05 and 0.1 mg/kg) produced a dose-related reduction in mean arterial
      blood pressure. The depressor effect started 10-15 min after the administration
      and persisted for more than 3 h and was not accompanied by a reflex tachycardia.
      In myocardial ischemia, pretreatment of MJ-355 (0.02 mg/kg) significantly reduced
      the total number of ventricular premature contractions and ventricular
      tachycardia, total duration of ventricular fibrillation and the mortality.
      Additionally, a significant reduction in infarct size was noted in all of the MJ
      355-treated groups. The hemodynamic and cardioprotective effects of MJ-355 were
      virtually abolished by pretreating the rats with glibenclamide (4 mg/kg, i.v.
      bolus), a selective K(ATP) channel blocker. In conclusion, MJ-355, through the
      activation of K(ATP) channels, exhibited antihypertensive and cardioprotective
      effects. It is suggested that MJ-355 should be useful in the treatment of
      hypertension and/or acute myocardial infarction.

PMID- 10591477
TI  - Two different P2Y receptors linked to steroidogenesis in bovine adrenocortical
      cells.
AB  - Both extracellular adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate
      (UTP) induced corticoid production (steroidogenesis) concentration-dependently in
      bovine adrenocortical cells (BA cells). Pertussis toxin (PTX, approx. 2
      microg/ml) partially inhibited (approx. 55% inhibition) extracellular ATP (100
      microM)-induced steroidogenesis in BA cells. However, PTX did not inhibit
      extracellular UTP (100 microM)-induced steroidogenesis. Both ATP- and UTP-induced
      steroidogeneses were significantly inhibited by suramin (50-200 microM). These
      effects were inhibited significantly by reactive blue-2 (more than 100 microM)
      and pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (more than 100
      microM). Both nucleotides (1-100 microM) induced inositol phosphates accumulation
      and intracellular Ca2+ mobilization, but PTX did not inhibit them. The RT-PCR
      procedure identified only P2Y2-receptor mRNA in BA cells. These results suggest
      that extracellular ATP induces steroidogenesis via a unique P2 receptor linked to
      PTX-sensitive guanine nucleotide-binding protein (G-protein), while extracellular
      UTP induces steroidogenesis via P2 receptor linked to PTX-insensitive G-protein.
      Thus, it was concluded that at least two different P2Y-like receptors linking to
      steroidogenesis exist in BA cells.

PMID- 10591478
TI  - Characterization of a palytoxin-induced non-selective cation channel in mouse
      megakaryocytes.
AB  - We used the whole-cell clamp and fura-2 techniques to study the membrane current
      and intracellular Ca2+ concentration ([Ca2+]i) changes of mouse megakaryocytes in
      response to palytoxin (PTX), a highly potent marine toxin. At a holding potential
      of -60 mV, PTX induced a sustained inward current in a dose-dependent manner. The
      reversal potentials measured in the presence of various extracellular major
      cations indicated that the PTX-induced channel had a non-selective permeability
      to alkali metal ions. Although elimination of intracellular Ca2+ had no effect on
      the PTX-induced current, removal of external Ca2+ inhibited the current
      activation. During the sustained phase of the PTX-induced current, treatment with
      ADP activated an additional current. Pretreatment with ouabain, an inhibitor of
      Na+-K+-ATPase, suppressed the PTX-induced current. During the stable phase of the
      PTX-induced current, challenge with NiCl2 (5 mM) or 2,4-dichlorobenzamil (DCB, 25
      microM), a non-selective cation channel blocker, partially reversed the current.
      Simultaneous measurement of the membrane current and [Ca2+]i showed that PTX
      induced the current response without increasing the [Ca2+]i. Taken together,
      these results indicate that PTX induces a non-selective cation channel in mouse
      megakaryocytes. This channel is distinct from the ADP-operated channel and is
      sensitive to ouabain, NiCl2 and DCB.

PMID- 10591479
TI  - Time course of changes in mu-opioid receptor mRNA levels in the periaqueductal
      gray of rat brain by a single or repeated injections of antisense
      oligodeoxynucleotides.
AB  - The effect of phosphorothioated antisense oligodeoxynucleotide (AS ODN) against
      the mu-opioid receptor (MOR) on MOR mRNA level in the periaqueductal gray (PAG)
      of rat brain was investigated. The MOR mRNA levels at 3, 6, 12, 24, 48 and 72 h
      after MOR AS ODN microinjection into the PAG were determined by reverse
      transcriptase-polymerase chain reaction. The MOR mRNA level was significantly
      decreased only at 12 h after the injection of 10 microg MOR AS ODN. When 10
      microg MOR AS ODN was given three times at the interval of 48 h, MOR mRNA levels
      were significantly decreased at 6, 12 and 24 h after the last injection of the AS
      ODN. However, MOR mRNA levels were not significantly changed by three injections
      at 48-h interval of MOR sense ODN or AS ODNs against delta- and kappa-opioid
      receptors, although the two latter AS ODNs significantly reduced the respective
      targeted mRNA levels. In conclusion, the present results show that the selective
      decrease in MOR mRNA is at least one reason why the reported diminished effects
      of MOR agonists are produced in animals pretreated with MOR AS ODN, although they
      could be produced through several mechanisms in which MOR mRNA level does not
      change.

PMID- 10591480
TI  - Effect of donepezil hydrochloride (E2020) on extracellular acetylcholine
      concentration in the cerebral cortex of rats.
AB  - Donepezil hydrochloride (donepezil), a potent and selective acetylcholinesterase
      inhibitor, has been developed for the treatment of Alzheimer's disease. We
      studied the effect of oral administration of this drug on the extracellular
      acetylcholine (ACh) concentration in the cerebral cortex of rats using
      microdialysis. We also observed fasciculation, a peripheral cholinergic sign
      induced by activation of neuromuscular transmission, after oral administration of
      the drug as an index of peripheral cholinergic activation. Other cholinesterase
      inhibitors, tacrine, ENA-713 and TAK-147, were used as reference drugs. Donepezil
      significantly and dose-dependently increased the extracellular ACh concentration
      in the rat cerebral cortex within the dose range of 2.5-10 mg/kg. Tacrine, ENA
      713 and TAK-147 also elevated the extracellular concentration of ACh. The minimum
      effective doses of donepezil, tacrine, ENA-713 and TAK-147 were (< or = 2.5, 10,
      10 and < or = 10 mg/kg, respectively. Donepezil produced fasciculation at doses
      of 2.5 mg/kg and above, with a dose-dependent increase in incidence and
      intensity. The reference compounds also induced fasciculation in a dose-dependent
      manner. The threshold doses of tacrine, ENA-713 and TAK-147 for fasciculation
      were 5, 2.5 and 2.5 mg/kg, respectively. The values of the ratio of the minimum
      effective dose for the ACh-increasing action to that for the fasciculation
      producing action were: donepezil, < or = 1; tacrine, 2; ENA-713, 4; TAK-147, < or
      = 4. These results indicate that orally administered donepezil has a potent and
      selective activity on the central cholinergic system.

PMID- 10591481
TI  - Role of glutathione in stabilization of nitric oxide during hypertension
      developed by inhibition of nitric oxide synthase in the rat.
AB  - The present study examined the role of glutathione in the development of
      hypertension induced by long-term inhibition of nitric oxide (NO)-synthase. Three
      groups of rats were investigated: control group, L-NAME group: group with NO
      synthase inhibition by N(G)-nitro-L-arginine methyl ester (L-NAME, 40 mg/kg per
      day) for 2 weeks, and BSO group: group with glutathione synthesis inhibitor L
      buthionine sulfoximine (BSO, 1.4 mmol/kg per 12 h) for 3 days. All the groups
      were subjected to an acute i.v. experiment in which the given substances were
      exchanged between groups. There was no change in systolic blood pressure (SBP) in
      the control group after 1 and 2 h of acute BSO (1.4 mmol/kg, i.v.) treatment. In
      the L-NAME group, SBP increased significantly by 10% after 2 h of acute BSO
      treatment. In the BSO group, SBP did not change vs control; however, after 2 h of
      acute L-NAME (10 mg/kg, i.v.) treatment, the increase in SBP exceeded by 12%
      (P<0.05) that of the control group. Along with the increase in SBP, acute BSO
      treatment significantly potentiated the decrease in plasma nitrite/nitrate
      concentration in the L-NAME group. The acute BSO-induced glutathione decrease was
      significantly greater in the L-NAME group than in the control group. In NO
      deficient hypertensive rats, the results are indicative of a decrease in
      glutathione synthesis and a stabilizing role of glutathione.

PMID- 10591482
TI  - Stress-induced gastric lesion formation is prevented in rats with daunomycin
      induced nephrosis.
AB  - In the present study, we investigated the susceptibility to restraint plus water
      immersion stress (RWIS) in rats with daunomycin-induced nephrosis in comparison
      to that in normal rats. The severity of RWIS-induced gastric lesions was
      significantly less in nephrotic rats on the 20th and 40th days after a single
      i.v. injection of daunomycin (12 mg/kg) than in the respective control rats. Acid
      secretion in pylorus-ligated rats significantly decreased under the 3-h stress.
      On the 20th day after treatment with daunomycin, acid secretion was significantly
      less in nephrotic rats than in control rats under both stress and unstressed
      conditions. Pretreatment of normal rats with methylene blue, a guanylate cyclase
      inhibitor, or phenylephrine, a vasoconstrictor, significantly prevented the
      stress-induced gastric lesions and decreased acid secretion. N(omega)-Nitro-L
      arginine methyl ester, a nitric oxide (NO) synthase inhibitor, prevented the
      stress-induced gastric lesion formation only. These results indicate that
      nephrotic rats are more resistant to RWIS-induced gastric lesions than normal
      rats. In addition, these results suggest that the decrease in acid secretion
      related to the decrease in the release of NO from endothelial cells may
      contribute, at least in part, to the prevention of the stress-induced gastric
      lesion formation in nephrotic rats.

PMID- 10591483
TI  - Oral administration of soybean lecithin transphosphatidylated phosphatidylserine
      (SB-tPS) reduces ischemic damage in the gerbil hippocampus.
AB  - Mongolian gerbils orally administered with soybean lecithin transphosphatidylated
      phosphatidylserine (SB-tPS, 240 mg/kg) for 5 days were subjected to cerebral
      ischemia by bilateral common carotid artery occlusion. The pyramidal cell damage
      of the hippocampal CA1 subfield was classified into 4 grades according to the
      proportion of damaged neurons on the tenth day after the ischemic treatment. The
      damage score of the SB-tPS group was statistically less than that of the control
      group. This suggests that the pre-administration of SB-tPS may relieve the
      delayed neuronal cell death caused by cerebral ischemia.

PMID- 10591484
TI  - Maitotoxin-induced phosphoinositide hydrolysis is dependent on extracellular but
      not intracellular Ca2+ in human astrocytoma cells.
AB  - Since maitotoxin, a potent marine toxin, is known to cause not only Ca2+ influx
      but also phosphoinositide hydrolysis, we investigated the Ca2+ dependency of
      maitotoxin-induced phosphoinositide hydrolysis in 1321N1 human astrocytoma cells.
      Maitotoxin elicited inositol 1,4,5-trisphosphate accumulation in a time-dependent
      manner. In [3H]inositol-labeled cells, maitotoxin stimulated phosphoinositide
      hydrolysis in an extracellular Ca2+-dependent manner. Maitotoxin also caused an
      intracellular Ca2+ elevation, which was abolished by an intracellular Ca2+
      chelater BAPTA-AM. Interestingly, maitotoxin still caused phosphoinositide
      hydrolysis in the BAPTA-AM-treated cells. These results indicate that maitotoxin
      induced phosphoinositide hydrolysis is dependent on extracellular but not
      intracellular Ca2+ in 1321N1 human astrocytoma cells.

PMID- 10591485
TI  - Effects of beta-blockers and nicardipine on oxotremorine-induced tremor in common
      marmosets.
AB  - Effects of beta-blockers (propranolol, arotinolol and nipradilol) and a Ca2+
      channel blocker (nicardipine) on oxotremorine-induced tremor were studied in
      common marmosets. Generalized tremor was elicited by an intraperitoneal
      administration of 0.25 mg/kg oxotremorine. Intensity of the tremor was classified
      into 7 degrees, and it was evaluated every 10 min. The total intensity of
      oxotremorine-induced tremor for each drug was expressed as "points", which were
      the sum of tremor intensity scores evaluated every 10 min up to 190 min following
      the administration of oxotremorine. Beta-blockers significantly suppressed the
      tremor. On the other hand, the Ca2+ channel blocker exacerbated the tremor.

PMID- 10591486
TI  - Protective effect of KB-R7943, a novel Na+/Ca2+ exchange inhibitor, on ischemic
      acute renal failure in rats.
AB  - The effects of KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea
      methanesulfonate), a novel Na+/Ca2+ exchange inhibitor, on ischemic acute renal
      failure (ARF) in rats were examined. ARF was induced by clamping the left renal
      pedicle for 45 min followed by reperfusion, 2 weeks after contralateral
      nephrectomy. Renal function was markedly diminished in ARF rats. Pretreatment
      with KB-R7943 (10 mg/kg, i.v.) markedly attenuated the ARF-induced renal
      dysfunction. Histopathological examination of the kidney of ARF rats revealed
      severe renal damage, which was suppressed by KB-R7943. Activation of the reverse
      mode of Na+/Ca2+ exchange seems to play an important role in the pathogenesis of
      ARF. A selective Na+/Ca2+ exchange inhibitor may be useful in cases of ARF.

PMID- 10591487
TI  - NAD(P)H: quinone oxidoreductase polymorphism and lung cancer in Taiwan.
AB  - Lung cancer is one of the leading causes of death in Taiwan since 1996. Genetic
      variation in metabolic activation or detoxification enzymes has been associated
      with the occurrence of lung cancer. NAD(P)H:quinone oxidoreductase (NQO1) enzyme
      is a cytosolic two-electron reductase thought to be involved in bioactivation and
      detoxification of environmental carcinogens. The possible association between
      NQO1 genetic polymorphism and lung cancer risk was examined among 95 male smokers
      without cancer and 100 male smokers with lung cancer in Taiwan. There was no
      significant difference in the proportion of wild-type NQO1 among all cancer cases
      and controls. When cases were stratified according to histological subtypes, the
      wild-type NQO1 was more common in adenocarcinoma than in controls. The odds ratio
      was 2.93 (95% confidence interval, 1.23-7.02; p = .02). This is the first
      observation for the positive association of this locus with lung cancer in an
      Asian population. These results suggest that NQO1 polymorphism is an important
      genetic risk factor for lung adenocarcinoma among smokers in Taiwan.

PMID- 10591488
TI  - Chronic toxic and carcinogenic effects of oral cadmium in the Noble (NBL/Cr) rat:
      induction of neoplastic and proliferative lesions of the adrenal, kidney,
      prostate, and testes.
AB  - Based on the occurrence of pulmonary cancers in exposed populations, cadmium is
      classified as a human carcinogen. More controversial target sites for cadmium in
      humans include the prostate and kidney, where some studies have shown a link
      between cadmium and cancer. In Wistar rats cadmium induces tumors in the ventral
      prostate. The relevance of such lesions to humans is debated since the rat
      ventral lobe, unlike the dorsolateral lobe, has no embryological homolog in the
      human prostate. Cadmium has not been linked with renal tumors in rodents but is a
      potent nephrotoxin. In this work we studied the effects of oral cadmium in the
      Noble (NBL/Cr) rat with particular attention to proliferative lesions of the
      prostate and kidneys. Cadmium (as CdCl2) was given ad libitum throughout the
      study in the drinking water at doses of 0, 25, 50, 100, and 200 ppm Cd to groups
      (initial n = 30) of male rats, which were observed for up to 102 wk. At the lower
      doses of cadmium (< or =50 ppm) a clear dose-related increase in total
      proliferative lesions of the prostate (ventral and dorsolateral lesions combined)
      occurred (0 ppm = 21% incidence, 25 ppm = 46%, 50 ppm = 50%; trend p < .03).
      These lesions were described as intraepithelial hyperplasia with occasional areas
      of atypical epithelial cells without stromal invasion. The lesions occurred
      primarily in the dorsolateral prostate with cadmium exposure and most frequently
      showed three or more foci within each specimen. At higher doses, prostatic
      proliferative lesions declined to control levels. The loss of prostatic response
      at the higher doses was likely due to diminished testicular function secondary to
      cadmium treatment. This was reflected in lesions indicative of testicular
      hypofunction at the highest cadmium dose, namely, interstitial cell hyperplasia,
      and a strong correlation between cadmium dose and total proliferative lesions of
      the testes (hyperplasias and tumors combined). Renal tumors (mainly mesenchymal
      and pelvic transitional cell), although few in number, showed a positive
      correlation with cadmium dose, as did pelvic transitional epithelial hyperplasia.
      Renal lesions were not associated with any cadmium-induced changes in age-related
      chronic nephropathy. The incidence of pheochromocytomas of the adrenal was
      increased by cadmium but only at the 50 ppm dose. Inflammatory lesions of the
      liver and spleen were common at higher doses and showed strong trends based on
      dose. These results indicate that oral cadmium can induce proliferative lesions
      in the prostate and kidney of the Noble rat. The finding of proliferative lesions
      of dorsolateral prostate in rats has presumed relevance to human prostate
      cancers.

PMID- 10591489
TI  - Effects of dark-rearing on triphenyl phosphate-induced neuropathy in the visual
      system of the developing European ferret (Mustela putorius furo).
AB  - Results of a previous study in our lab (Tanaka et al., 1994) suggested that the
      onset of susceptibility to the organophosphorus compound triphenyl phosphite
      (TPP) in the developing ferret visual system might be closely related to eye
      opening and the onset of light stimulation. In order to explore this idea
      further, TPP was administered to ferret kits that had been raised for varying
      periods of time in total darkness to assess whether a delay in the onset of light
      stimulation to the visual system might also result in a delay in its
      susceptibility to TPP. Ferret kits were raised from birth either in total
      darkness or in open-sided sheds exposed to ambient light, injected subcutaneously
      with TPP (888 mg/kg body weight) at 5.5, 7.5, 9.5, or 21.5 wk of age, euthanized,
      and perfused transcardially with a 10% formalin-saline solution 4 d after
      injection. Brains were sectioned parasagittally at a thickness of 40 microm and
      subsequently processed with the Fink-Heimer silver impregnation technique to
      reveal the presence of degenerating axons and terminals, and with cresyl violet
      stain to delineate nuclear boundaries and cell soma morphology. Comparisons among
      degeneration patterns present in light-reared and dark-reared kits at the four
      ages examined revealed that the time of onset, extent, and density of TPP-induced
      axonal and terminal degeneration seen in the lateral geniculate nucleus and
      primary visual cortex did not differ significantly between light- and dark-reared
      groups, with the possible exception of dark-reared kits exposed to TPP at 7.5 wk
      of age. In addition, neurons in the primary visual cortex showed shrinkage and
      increased packing densities in kits exposed to TPP in both light and dark
      environments, as well as in dark-reared non-injected kits. The results of this
      study indicate that dark-rearing does not delay the onset or lessen the severity
      of TPP-induced axonal and terminal degeneration in the developing visual system
      of the ferret. Data suggest that light activation and stimulation of the retino
      geniculo-striatal visual pathway is not a necessary prerequisite for the onset of
      visual system susceptibility to the axonopathic effects of triphenyl phosphite.

PMID- 10591490
TI  - Effects of PCB 126 on primary immune organ development in chicken embryos.
AB  - This experiment evaluated the immunotoxic effects of developmental exposure to a
      planar polychlorinated biphenyl (3,3',4,4',5-pentachlorobiphenyl; PCB 126) in
      chicken embryos. Previous investigations on the immunotoxic effects of PCBs and
      2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in developing avian embryos were
      undertaken with embryos exposed only during the latter stages of incubation. To
      simulate exposure in embryos in the wild, chicken eggs were injected with PCB 126
      (sunflower oil carrier) into the air cell before initiation of incubation. It was
      hypothesized that exposure to PCB 126 during the complete incubation period would
      decrease immune organ masses and lymphocyte numbers. Doses of PCB 126 ranged from
      0.051 to 0.80 ng/g egg. Control groups consisted of carrier-injected and
      noninjected eggs. The thymus and bursa of Fabricius were removed and weighed on d
      20 of incubation (1 d before hatch). The immune organs were homogenized, and
      viable lymphoid cells were counted using the trypan blue exclusion method. Probit
      analysis estimated the LD20 to be 0.21 ng/g and the LD50 to be 1.01 ng/g. Thymus
      mass dropped sharply between 0.13 and 0.32 ng/g, and lymphoid cell numbers in the
      thymus fell sharply between 0.051 and 0.13 ng/g. Bursa mass began to decrease at
      the lowest dose of 0.051 ng/g and reached a minimum at 0.32 ng/g. The number of
      viable cells decreased slightly at 0.051 ng/g and reached a minimum at the 0.13-
      and 0.32-ng/g doses. In general, lymphoid cell numbers were more sensitive to PCB
      126 than organ masses, and the bursa tended to be more sensitive than the thymus.
      Doses necessary to reduce the number of viable lymphoid cells in the thymus and
      bursa were at least one order of magnitude lower with full-term incubation as
      compared to exposure only during later stages of incubation.

PMID- 10591491
TI  - Resources and estuarine health: perceptions of elected officials and recreational
      fishers.
AB  - It is important to understand the perceptions of user groups regarding both the
      health of our estuaries and environmental problems requiring management.
      Recreational fishers were interviewed to determine the perceptions of one of the
      traditional user groups of Barnegat Bay (New Jersey), and elected officials were
      interviewed to determine if the people charged with making decisions about
      environmental issues in the bay held similar perceptions. Although relative
      ratings were similar, there were significant differences in perceptions of the
      severity of environmental problems, and for the most part, public officials
      thought the problems were more severe than did the fishers. Personal watercraft
      (often called Jet Skis) were rated as the most severe problem, followed by
      chemical pollution, junk, overfishing, street runoff, and boat oil. Small boats,
      sailboats, wind surfers, and foraging birds were not considered environmental
      problems by either elected officials or fishermen. The disconnect between the
      perceptions of the recreational fishers and those of the locally elected public
      officials suggests that officials may be hearing from some of the more vocal
      people about problems, rather than from the typical fishers. Both groups felt
      there were decreases in some of the resources in the bay; over 50% felt the
      number of fish and crabs had declined, the size of fish and crabs had declined,
      and the number of turtles had declined. Among recreational fishers, there were
      almost no differences in perceptions of the severity of environmental problems or
      in changes in the bay. The problems that were rated the most severe were personal
      watercraft and overfishing by commercial fishers. Recreational fishers ranked
      sailboats, wind surfers, and fishing by birds as posing no problem for the bay.
      Most fishers felt there had been recent major changes in Barnegat Bay, with there
      now being fewer and smaller fish, fewer and smaller crabs, and fewer turtles. The
      results suggest that the views of a wide range of coastal users should be
      considered when making environmental health decisions.

PMID- 10591492
TI  - Examination of adenovirus-types in intestinal vascular endothelial inclusions in
      fatal cases of enteric disease in cattle, by in situ hybridisation.
AB  - There have been occasional reports in the literature of a severe naturally
      occurring enteric disease of cattle in which adenoviral inclusions were found in
      intestinal vascular endothelium. Bovine adenovirus type 10 (BAV-10) was
      identified by in situ hybridisation (ISH) in the inclusions of all 13 such cattle
      detected in Northern Ireland [Smyth, J.A., Benko, M., Moffett, D.A., Harrach, B.,
      1996. J. Clin. Microbiol. 34, 1270-1274]. The present paper describes ISH
      examination of the vascular endothelial inclusion bodies in a further seventeen
      cattle with enteric disease, from Canada, Great Britain, Italy and The
      Netherlands. BAV-10 was identified in the inclusions of ten cases, and Subgroup 2
      BAVs in six cases. BAV-10 was identified in cattle from Canada, The Netherlands
      and Great Britain. This is the first recognition of BAV-10 infection outside
      Northern Ireland and New Zealand. The results also show that at least two
      adenovirus serotypes may induce inclusion bodies in intestinal vascular
      endothelium of cattle. It will, therefore, be difficult in the short term to
      develop a simple test to allow diagnosis of this form of adenoviral infection in
      living animals, and thus to determine the relationship between it and clinical
      disease.

PMID- 10591493
TI  - Uterine tubal cells remain uninfected after culture with in vitro-produced
      embryos exposed to bovine viral diarrhea virus.
AB  - Bovine viral diarrhea virus (BVDV) has been isolated from washed and sonicated,
      in vitro-produced embryos, but the infectivity of BVDV associated with intact,
      developing, embryos has not been demonstrated. The objective of this study was to
      determine if a dose of BVDV infective for co-culture cells was associated with
      individual, developing embryos, following artificial exposure to the virus and
      washing. In 5 replicates, zona pellucida-intact, in vitro-produced embryos were
      assigned to a negative control embryo group, or were incubated in 10(5)-10(6)
      cell culture infective doses (50%, CCID50) per milliliter of a type I,
      noncytopathic (strain SD-1) BVDV for 2 h. Unexposed negative control embryos and
      exposed positive control embryos were washed, sonicated and assayed for BVDV
      using virus isolation with immunoperoxidase monolayer assay. Immediately or
      following cryopreservation, remaining virally-exposed, washed embryos were co
      cultured individually with BVDV-negative cultures of bovine uterine tubal cells
      in a medium free of BVDV-neutralizing activity. After two days in culture,
      uterine tubal cells and embryos (including the zona pellucida) were separated and
      washed. The culture medium, uterine tubal cells and embryos were then assayed for
      BVDV. Bovine viral diarrhea virus was not isolated from any negative control
      embryo group, but was isolated from all positive control embryo groups. Although
      all uterine tubal cell populations were confirmed to be susceptible to BVDV,
      virus was never isolated from uterine tubal cells or embryos from post-exposure
      culture. In conclusion, although BVDV remains associated with washed in vitro
      produced embryos, the virus associated with unsonicated embryos was not infective
      for uterine tubal cells in vitro.

PMID- 10591494
TI  - Detection of bovine immunodeficiency virus DNA in the blood and semen of
      experimentally infected bulls.
AB  - Five 18- to 24-month-old bulls were inoculated with either a cell suspension
      containing bovine immunodeficiency virus (BIV-FL112; 3 bulls) or a BIV-free cell
      suspension (2 bulls). Blood and semen specimens were collected once a week for 14
      weeks, and seroconversion was confirmed by indirect immunofluorescent antibody
      (IFA) testing. The presence of BIV in blood and semen was determined by virus
      isolation and/or polymerase chain reaction (PCR) assays. Antibodies to BIV were
      detected in the 3 experimentally infected bulls as early as day post inoculation
      (DPI) 17, and levels peaked at DPI 37-58. BIV was isolated from the peripheral
      blood mononuclear cells (MNCs) of the infected bulls at DPI 9 (2 bulls) and DPI
      23 (1 bull), and could be isolated from one animal up to DPI 65. PCR analysis of
      MNC DNA, using BIV pol gene primers, detected virus in all three of the
      experimentally infected bulls from DPI 9 until the termination of the experiment
      at DPI 98. Efforts to isolate a significant number of non-spermatozoal cells
      (NSC) by gradient separation from the semen of the experimentally infected bulls
      were unsuccessful. Two methods for the extraction of total NSC DNA from up to 2
      ml of non-extended semen were employed; however, no BIV pol fragment was
      amplified from these DNA preparations. Additionally, 30 bulls from artificial
      insemination (AI) centers were evaluated for BIV infection by PCR. No
      amplification products were obtained from MNC DNA from the AI submissions using
      primer sets for both the BIV pol and env genes.

PMID- 10591495
TI  - Ovine pestiviruses: their taxonomic status revealed by palindromic nucleotide
      substitutions.
AB  - We examined previously identified border disease virus (BDV) strains by using a
      newly proposed genotyping procedure based on palindromic nucleotide substitutions
      (PNS) in the 5'-untranslated region (UTR), and found 22 (41.5%) out of 53 strains
      of BDV in the nucleotide sequence databases are not of BDV. All the 22 ovine
      pestivirus strains were allocated to the BVDV species according to the PNS, and
      were compared with reference strains of pestivirus 1 (BVDV-Ia,-Ib, and-Ic
      genovars), pestivirus 2 (BVDV-II genovar), pestivirus 3 (BDV) and pestivirus 4
      (CSFV), respectively. Ten strains (Weybridge, A553, B1056, D771/1, D861, D1120/1,
      D1432/P, Q1161/1, Q1161/2, 114817) showed a palindromic structure in the 5'-UTR
      characteristic to the BVDV-Ia genovar, three strains (7535, 7546, 7548) were
      characteristic to the BVDV-Ib genovar, and nine strains (BD-78, 59386, SCP, Lees,
      C413, 167237, 168149, 173157, 175375) belonged to the BVDV-II genovar.

PMID- 10591496
TI  - Persistent infection of bovine herpesvirus type 4 in bovine endothelial cell
      cultures.
AB  - Herpesviruses can establish a persistent infection in the cells and tissues of
      their natural hosts and thus may produce diseases due to cytolytic infections. We
      have isolated a herpesvirus from a bovine vascular endothelial cell culture after
      continuous subculturing. Typical cytopathic changes were observed in bovine
      endothelial cell cultures 2 days after inoculation of the virus. The virus had an
      icosahedral nucleocapsid of 100-150 nm in diameter and an envelope. The sequences
      of some DNA fragments of the virus were highly homologous to those of the bovine
      herpesvirus type 4 (BHV-4) strains. The DNA restriction maps of the virus and the
      reference strains of BHV-4, DN 599 and Movar 33/63 were very similar but not
      identical. Therefore, the newly isolated virus has been designated Taiwan strain.
      The presence of BHV-4 DNA in apparently normal bovine endothelial cell cultures
      was shown by Southern blot hybridization with the BamHI fragment of the newly
      isolated BHV-4 and was further confirmed by digestion of the DNA with BamHI plus
      AccI. In conclusion, we have demonstrated that BHV-4 persisted in the bovine
      endothelial cell cultures and continuous subcultures could lead to the production
      of infectious viral particles.

PMID- 10591498
TI  - Molecular heterogeneity in clinical isolates of Malassezia pachydermatis from
      dogs.
AB  - Molecular investigation of 16 strains, conventionally identified to be Malassezia
      pachydermatis, isolated from dogs in Japan was carried out by random
      amplification of polymorphic DNA (RAPD) and chitin synthase 2 (CHS2) gene
      sequence analyses. The RAPD band patterns of 13 clinical isolates were identical
      to that of standard strain of M. pachydermatis (CBS-1879). The other three
      clinical isolates were different from the standard strain of M. pachydermatis in
      RAPD patterns, and two of the three isolates were identical. About 620 bp genomic
      DNA fragments of the CHS2 gene were amplified from the same 16 clinical isolates
      of M. pachydermatis by polymerase chain reaction (PCR) and sequenced. The
      phylogenetic analysis of the nucleotide sequences of CHS2 gene fragments of the
      16 clinical isolates revealed that the 13 strains were genetically very close to
      the standard strain of M. pachydermatis and the other two isolates were
      genetically close to the standard strain of M. furfur rather than M.
      pachydermatis. The remaining one isolate was phylogenetically distinct from all
      the seven Malassezia species reported so far.

PMID- 10591497
TI  - Field evaluation of the single intradermal cervical tuberculin test and the
      interferon-gamma assay for detection and eradication of bovine tuberculosis in
      Spain.
AB  - A field comparison of the interferon-gamma (IFN-gamma) assay and the single
      intradermal cervical tuberculin (SICT) test for the diagnosis of bovine
      tuberculosis was conducted. A total of 1136 cattle belonging to 85 herds placed
      in 'Castilla y Leon' (northwestern Spain) were chosen, and 21 of these herds were
      subjected to the diagnostic assays two or three times at intervals of at least 4
      months. All the animals positive to any of the tests were slaughtered and
      tuberculosis was confirmed by culture isolation method (CIM) and further
      identification by means of PCR. Only 10.6% of cattle reacted with the bovine PPD
      in the SICT test, a percentage that increased to 12.8% in the IFN-gamma assay.
      The sensitivity of the IFN-gamma assay compared to CIM was shown to be higher
      (84.9%) than that of the SICT test (80.2%), but the combination of both tests
      offered the highest sensitivity (92.9%). The number of false positive reactors
      (those animals in which CIM was negative) was considerably higher for the IFN
      gamma assay than for the SICT test and, conversely, the number of false negative
      animals (M. bovis isolation but negative immunological result) was higher for the
      skin test than for the interferon assay. In the herds tested twice, tuberculosis
      was eradicated after the second cycle of testing in 50%, and in 75% after the
      third cycle in herds tested three times. The combination of these two techniques
      instead of separately seems, therefore, to be useful in eradication programmes
      against bovine tuberculosis.

PMID- 10591499
TI  - Detection by ELISA of the humoral immune response in rabbits naturally infected
      with Trichophyton mentagrophytes.
AB  - An indirect enzyme linked immunosorbent assay (ELISA) was developed and its
      diagnostic potential evaluated for rabbits infected by Trichophyton
      mentagrophytes. Within-run and between-run coefficient of variance varied from
      2.3 to 7.7% and from 5.9 to 8.5%, respectively, indicating satisfactory
      reproducibility of the ELISA. There was no significant cross-reaction with
      antigens of Microsporum canis, Malassezia pachydermatis and Aspergillus
      fumigatus. The level of specific IgG to Trichophyton mentagrophytes was measured
      in sera of 25 11-week-old and 12 younger infected rabbits. There was no
      significant difference in the IgG level between 12 5-week-old infected rabbits
      and controls (p = 0.38). The antibody response was higher in 12 7-week-old
      rabbits compared with controls (p = 0.001). The IgG level in 25 11-week-old
      rabbits differed from the controls very significantly (p < 0.0001). Increased
      specific IgG in 11-week-old rabbits exhibited 96% sensitivity and 94%
      specificity. Predictive values of a positive and a negative test were 96 and 94%,
      respectively. Western immunoblotting associated three protein bands (21.5, 31, 44
      kDa) with Trichophyton mentagrophytes infection.

PMID- 10591500
TI  - Identification of aesculin-hydrolyzing streptococci, lactococci, aerococci and
      enterococci from subclinical intramammary infections in dairy cows.
AB  - Aesculin-hydrolyzing, catalase-negative, gram-positive cocci isolated from
      subclinical intramammary infections in dairy cows were identified to species
      level using growth characteristics and biochemical activity. The results
      indicated that the aesculin-hydrolyzing cocci associated with this type of
      infection are a very heterogenic group. S. uberis strains, including inulin- or
      beta-glucuronidase-negative isolates, accounted for only about one-third of the
      collection, and Enterococcus faecalis strains for one-fifth. Other species of
      some importance included (in descending order of isolation frequency) Aerococcus
      viridans, Streptococcus pluranimalium, Lactococcus garvieae, Streptococcus bovis
      and Streptococcus gallolyticus.

PMID- 10591501
TI  - Virulence of Streptococcus canis from canine streptococcal toxic shock syndrome
      and necrotizing fasciitis.
AB  - The recent recognition of streptococcal toxic shock syndrome (STSS) and
      necrotizing fasciitis (NF) in dogs caused by Streptococcus canis highlights our
      lack of knowledge regarding the mechanisms of virulence of this organism. Fifteen
      isolates of S. canis from cases of canine STSS and/or NF were examined for the
      presence of 10 Streptococcus pyogenes-associated virulence genes by Southern
      hybridizations using gene probes generated by PCR. The isolates lacked DNA with
      homology to eight of the 10 gene probes (speA, speB, speC, mf, ssa, scp, hasA,
      ska) under low stringency conditions. Thirteen and 15 of 15 isolates hybridized
      with streptolysin O and M protein gene probes, respectively. Twelve of 15 S.
      canis isolates were resistant to phagocytosis in canine blood. Electron
      microscopy revealed the presence of proteinaceous cell surface fibrillae. These
      results suggest that S. canis possesses M proteins and encodes streptolysin O,
      but lacks some of the other recognized virulence genes with significant homology
      to those in S. pyogenes.

PMID- 10591502
TI  - High occurrence of Shiga toxin-producing Escherichia coli (STEC) in healthy
      cattle in Rio de Janeiro State, Brazil.
AB  - In order to evaluate the prevalence of Shiga toxin-producing Escherichia coli
      (STEC) strains, 197 fecal samples of healthy cattle from 10 dairy farms, four
      beef farms and one slaughterhouse at Rio de Janeiro State, Brazil, were examined
      for Shiga toxin (Stx) gene sequences by polymerase chain reaction (PCR). For
      presumptive isolation of O157:H7 E. coli, the Cefixime-potassium tellurite
      sorbitol MacConkey Agar (CT-SMAC) was used. A high occurrence (71%) of Stx was
      detected, and was more frequently found among dairy cattle (82% vs. 53% in beef
      cattle), in which no differences were observed regarding the age of the animals.
      Dot blot hybridization with stx1 and stx2 probes revealed that the predominant
      STEC type was one that had the genes for both stx1 and stx2 in dairy cattle and
      one that had only the stx1 gene for beef cattle. Three (1.5%) O157:H7 E. coli
      strains were isolated from one beef and two dairy animals by the use of CT-SMAC.
      To our knowledge, this is the first report of O157:H7 isolation in Brazil. A PCR
      based STEC detection protocol led to the isolation of STEC in 12 of 16 randomly
      selected PCR-positive stool samples. A total of 15 STEC strains belonging to 11
      serotypes were isolated, and most of them (60%) had both stx1 and stx2 gene
      sequences. Cytotoxicity assays with HeLa and Vero cells revealed that all strains
      except two of serotype O157:H7 expressed Stx. The data point to the high
      prevalence of STEC in our environment and suggest the need for good control
      strategies for the prevention of contamination of animal products.

PMID- 10591503
TI  - Comparison of necrotoxigenic Escherichia coli isolates from farm animals and from
      humans.
AB  - Necrotoxigenic Escherichia coli (NTEC) isolated from animals and humans can
      belong to the same serogroups/types and produce or carry the genes coding for
      fimbrial and afimbrial adhesins of the same family, P, S, F17, and/or AFA,
      raising the question of a potential zoonotic source of human infection. The main
      purpose of this study was to compare 239 NTEC1 strains (45 from cattle, 65 from
      humans and 129 from piglets) and 98 NTEC2 strains from cattle, using a uniform
      and standardized typing scheme. The O serogroups and the biotypes recognized
      amongst NTEC1 and NTEC2 strains were quite varied, although some were more
      frequently observed (serogroups O2, O4, O6, O8, O18, O78, and O83 and biotypes 1,
      2, 5, 6, and 9). Hybridization, results with gene probes for the P family (PAP
      probe), S family (SFA probe), AFA family (AFA probe), F17 family (F17 probe) of
      fimbrial and afimbrial adhesins, could differentiate most NTEC1 strains, which
      are PAP-, SFA- and/or AFA-positive, from NTEC2 strains, which are mainly F17-
      and/or AFA-positive, but were of no help in differentiating between NTEC1 strains
      from cattle, humans, and piglets. All but seven (98%) NTEC1 and NTEC2 strains
      were serum resistant, 199 (59%) produced an aerobactin, and colicin (I, V, or
      unidentified) was produced by 22-34% of them. On the other hand, more than 90% of
      the NTEC1 strains were haemolytic on sheep blood agar compared with only 40% of
      the NTEC2 strains. Production of a classical haemolysin, active on sheep
      erythrocytes, and hybridization with the PAP probe were associated in a majority
      of NTEC1 strains (63-81%), but very rarely in NTEC2 strains (3%). Production of
      enterohaemolysin and hybridization with the PAP probe were much less frequently
      associated in NTEC strains (1-9%). It was thus possible neither to completely
      differentiate NTEC1 strains from cattle, humans, and pigs, nor to define a
      signature for the NTEC strains. Necrotoxigenic E. coli must still be identified
      on the basis of the production of the Cytotoxic Necrotizing Factors 1 or 2 (or of
      their encoding genes) and complete differentiation of NTEC1 strains from cattle,
      humans, and piglets, use additionnal methods.

PMID- 10591504
TI  - A rapid latex agglutination test for detection of leptospiral antibodies.
AB  - A rapid semi-quantitative latex agglutination test (LAT) has been standardized
      for the detection of leptospiral antibodies in serum samples of man and animals.
      The efficacy of the LAT was compared with the plate enzyme linked immunosorbent
      assay (ELISA). A total of 276 human serum samples were analyzed by both LAT and
      ELISA and percentage positives were 84.8 and 85.9%, respectively. Similarly, of
      65 animal samples tested, 63.1 and 69.2% positivity were observed in LAT and
      ELISA, respectively. Even though the ELISA test was slightly more sensitive than
      LAT, the rapidity, simplicity and economics of the LAT were found to fulfill the
      requirements of a screening test for leptospiral antibodies.

PMID- 10591505
TI  - Current methods and approaches to studying astrocytes: a forum position paper.
AB  - Astrocytes are becoming increasingly recognized as targets for neurotoxic agents.
      For neurotoxicologists, as for other neuroscientists, an important concern is how
      to study astrocytes. In this paper, it is argued that studies of primary
      astrocyte cultures, while they are convenient as experimental systems and have
      been of great value to a resurgence of interest in these cell types over the past
      quarter century, now need to be supplemented to a large degree by studies on
      preparations where the properties of astrocytes are less likely to deviate from
      their properties in situ. Different and alternative systems to primary astrocyte
      cultures are described and critically evaluated in this article.

PMID- 10591506
TI  - Complementarity and usefulness of in vitro approaches in lead toxicology:
      commentary on forum position paper.

PMID- 10591507
TI  - Current methods and approaches to studying astrocytes: commentary on forum
      position paper.

PMID- 10591508
TI  - Examination of complex astrocyte physiological processes in real-time: commentary
      on forum position paper.

PMID- 10591509
TI  - Strategies for studying astrocyte functions in vivo: commentary on forum position
      paper.

PMID- 10591510
TI  - L- and D- methionine provide equivalent long term protection against CDDP-induced
      ototoxicity in vivo, with partial in vitro and in vivo retention of
      antineoplastic activity.
AB  - Treatment of metastatic tumors with ionic platinum compounds is hampered by the
      potent nephrotoxic, ototoxic and neurotoxic properties of these drugs. Recent
      studies have shown that sulfur-containing antioxidants relieve the dose limiting
      side effects of cis-diamminedichloroplatinum (CDDP), the most commonly used ionic
      platinum therapy. Here we report that both isomers of the sulfur-containing
      antioxidant methionine (MET) completely block the in vivo ototoxic and
      nephrotoxic effects of CDDP, and the duration of MET otoprotection is longer than
      has been previously reported. Rats treated with either L- or D-MET in addition to
      CDDP exhibited no signs of auditory system damage after 7 days, as evaluated by
      the auditory brainstem response and scanning electron microscopic examination of
      the organ of Corti, while CDDP-treated rats exhibited pronounced evidence of
      ototoxic damage after only 3 days. Microscopic examination of kidney tissue
      revealed moderate to severe nephrotoxic damage to CDDP-treated rats after 5 days,
      while rats co-treated with either MET isomer showed no evidence of kidney damage.
      Mortality among CDDP-treated subjects increased steadily over the period of the
      study, while all of the MET-protected rats survived. Finally, the efficacy of
      CDDP in the presence of L- or D-MET was evaluated in vitro using cultures of MTLN
      3 breast tumor cell lines, and in vivo using implanted MTLN-3 tumors. Both L- and
      D-MET reduced the ability of CDDP to kill tumor cells in vitro and in vivo,
      however, our data suggest that a higher proportion of the antineoplastic activity
      of CDDP is retained in the presence of L- MET.

PMID- 10591511
TI  - Neuropathologic effects of phenylmethylsulfonyl fluoride (PMSF)-induced promotion
      and protection in organophosphorus ester-induced delayed neuropathy (OPIDN) in
      hens.
AB  - The serine/cysteine protease inhibitor phenylmethylsulfonyl fluoride (PMSF) has
      been used both to promote and to protect against neuropathic events of
      organophosphorus-induced delayed neuropathy (OPIDN) in hens (Veronesi and
      Padilla, 1985; Pope and Padilla, 1990; Lotti et al., 1991; Pope et al., 1993;
      Randall et al., 1997). This study is the first to expand upon this work by using
      high resolution microscopy provided by epoxy resin embedding and thin sectioning
      to evaluate neuropathological manifestations of promotion and protection, and to
      correlate them with associated clinical modifications. To evaluate dose-related
      effects of OPIDN, single phenyl saligenin phosphate (PSP) dosages of 0.5, 1.0, or
      2.5 mg/kg were administered to adult hens. PMSF (90 mg/kg) was given either 4
      hours after (for promotion) or 12 hours prior to (for protection) PSP
      administration. Clinical signs and pathologic changes in the biventer cervicis
      nerve, which is uniquely sensitive to OPIDN (El-Fawal et al., 1988), were
      monitored. PSP alone, 2.5 mg/kg, caused severe OPIDN (terminal clinical score 7.5
      +/- 1.0 [0-8 scale]; neuropathology score 2.7 +/- 0.3 [0-4 scale, based on
      myelinated fiber degeneration]). PMSF given 12 hours prior to PSP gave complete
      protection (clinical and neuropathology scores of 0; p<0.0001 compared to PSP
      alone). Signs and lesions of OPIDN were absent following 0.5 mg/kg PSP alone, but
      PMSF given 4 hours after PSP potentiated its neurotoxic effects (all hens had
      clinical scores of 4.0 and the average neuropathology score was 3.5 +/- 0.3;
      p<0.0001 compared to PSP alone). Although quantitative differences were noted,
      qualitative differences among nerves from hens with OPIDN were not evident,
      either with light or electron microscopy. At the time of sacrifice, there was a
      statistically linear relationship (r2 = 0.76) between the clinical scores on the
      last day of observation and the neuropathology scores (p<0.0001). This study
      demonstrates that the degree of peripheral nerve myelinated fiber degeneration
      correlates with clinical deficits in PMSF-induced potentiation of and protection
      against OPIDN.

PMID- 10591513
TI  - Comparison of visual function at adulthood and during aging in monkeys exposed to
      lead or methylmercury.
AB  - Of critical importance is the issue of whether exposure to a neurotoxic agent
      early in life or over a major portion of the lifespan can result in an age
      related accelerated decline in neurological function. There is evidence in humans
      and animals that exposure to methylmercury may produce delayed neurotoxicity
      associated with aging. While lead is a ubiquitous pollutant, the potential of
      long-term lead exposure to accelerate age-related functional decline in nervous
      system function has apparently not been explored. In the current study, visual
      function assessed during adulthood was compared to results during aging in
      monkeys exposed to 500 or 2000 microg/kg/day of lead from birth onward, 50
      microg/kg/day of methylmercury from birth to seven years, or 10, 25, or 50
      microg/kg/day of methylmercury throughout gestation to four years of age. Spatial
      contrast sensitivity functions and visual fields were assessed in methylmercury
      exposed monkeys, and spatial and temporal contrast sensitivity functions were
      assessed in monkeys exposed to lead. The frequency and amplitude at peak
      sensitivity and the high-frequency cut-off were compared at the two assessment
      periods for the contrast sensitivity functions. Age-related decrements were
      observed on both spatial and temporal visual function for all parameters.
      Treatment-related effects were observed in the monkeys exposed to methylmercury
      in utero and postnatally during the first assessment period but not during aging,
      whereas lead-exposed monkeys exhibited differences in temporal visual function at
      the first assessment but not the second. There was no evidence for accelerated
      decline in contrast sensitivity as a result of exposure to either toxicant.
      However, four of 10 methylmercury-treated monkeys exhibited slight constriction
      of visual fields at the second assessment that had not been present earlier.
      These results extend previous findings of evidence for delayed neurotoxicity in
      the somatosensory and auditory systems of these methylmercury-exposed groups.

PMID- 10591512
TI  - Expression of AP-1 transcription factors in rat hippocampus and cerebellum after
      trimethyltin neurotoxicity.
AB  - Neurotoxic insult causes neurons to degenerate due to necrosis or apoptosis.
      After this neurodegenerative phase, gene expression in surviving neurons is
      altered to undergo regeneration and repair to adapt to changes in the cellular
      environment. In this study, we examined the expression of four AP-1 transcription
      factors, Jun, JunB, JunD and FRA-2, and AP-1 DNA binding activity in the rat
      hippocampus to examine changes during the periods of degeneration and then of
      regeneration and repair after TMT-induced neurotoxicity. The expression of these
      factors in the cerebellum was examined as a control since this brain region is
      not grossly affected by TMT. AP-1 DNA binding slowly increased in both the
      cerebellum and hippocampus from one hour to eight days after TMT exposure. Levels
      of Jun in the hippocampus significantly increased at 12 hours after TMT while
      JunB and JunD expression did not change. On the other hand, FRA-2 was induced at
      8 days in the hippocampus after TMT treatment and was expressed only in
      hippocampi containing neurodegeneration as gauged by elevated glial fibrillary
      acidic protein levels. FRA-2 immunoreactivity was detected in the AP-1 DNA
      binding complex only in hippocampal extracts from rats after eight days post
      trimethyltin administration. Thus, FRA-2 is a component of the AP-1 DNA binding
      complex suggesting that it is involved in regulating genes during a later stage
      of TMT neurotoxicity.

PMID- 10591514
TI  - Electrophysiological changes in hippocampal slices isolated from rats embedded
      with depleted uranium fragments.
AB  - Although nephrotoxicity is considered to be the most serious consequence of
      uranium exposure, several studies have previously suggested the potential for
      neurotoxicity. In Operation Desert Storm, U.S. military personnel were wounded by
      fragments of depleted uranium (DU). This study was initiated to test the
      potential for DU fragments to cause electrophysiological changes in the central
      nervous system. Rats were surgically implanted with pellets of DU or tantalum
      (Ta) as a control metal. After 6, 12 and 18 months rats were euthanized,
      hippocampi removed and electrophysiological potentials analyzed by extracellular
      field potential recordings. Six months after implantation, synaptic potentials in
      DU-exposed tissue were less capable of eliciting spikes (E/S coupling). At 12
      months, amplitudes of synaptic potentials were significantly increased in tissue
      from DU treated rats compared to Ta controls. E/S coupling was reduced. The
      differences between the electrophysiological measurements in DU-treated and
      control tissue were no longer evident at the 18 month time point. An analysis of
      the changes in the synaptic potentials and E/S coupling over the three time
      points suggests that by 18 months, the effects of aging and DU exposure converge,
      thereby obscuring the effects of the metal. Since kidney toxicity was not evident
      in these animals, effects secondary to nephrotoxicity are unlikely. This study
      raises the possibility that physiological changes occur in the brain with chronic
      exposure to DU fragments, which could contribute to neurological deficits.

PMID- 10591515
TI  - The role of intracellular glutathione in methylmercury-induced toxicity in
      embryonic neuronal cells.
AB  - Previous studies indicate that the ability of cells to up-regulate levels of
      intracellular glutathione (GSH) synthesis may determine their sensitivity to MeHg
      exposure. The purpose of the current study is two-fold. First, we determined
      whether the vulnerability of the developing central nervous system (CNS) to MeHg
      lies in its intracellular GSH content. The intracellular GSH content and the
      activity of gamma-glutamyl cysteine synthetase (GCS) were determined with and
      without MeHg exposure in primary cultures of rat embryonic CNS cells. In
      addition, the effect of GSH modulation on MeHg-induced cytotoxicity was
      determined. Second, we characterized the mechanism of GCS regulation, initially
      by studying the GCS heavy chain subunit (GCS-HC). Primary embryonic limb bud
      cells were used as a reference cell type for comparing the response of CNS cells.
      The results indicate that constitutive intracellular GSH content, GCS activity,
      and GCS-HC mRNA and protein levels of CNS cells were approximately ten-, two-,
      five-, and ten-fold higher, respectively, than those in limb bud cells. A dose
      dependent increase in GSH levels and GCS activity was observed in CNS and limb
      bud cells following 1 and 2 microM MeHg exposure for 20 hr. Further
      characterization of GCS up-regulation in CNS cells showed that the increase in
      GCS activity following MeHg exposure, unlike limb bud cells, was not accompanied
      by an elevation of GCS-HC mRNA and protein levels. Pretreatment with N
      acetylcysteine led to a significant increase in intracellular GSH, while L
      buthionine-(S,R)-sulfoximine (BSO) resulted in decreased GSH levels, however
      neither pretreatment had a significant impact on MeHg-induced cytotoxicity in
      either cell type. Our results suggest that although oxidative stress may mediate
      aspects of MeHg toxicity, disruption of GSH homeostasis alone is not responsible
      for the sensitivity of embryonic CNS cells to MeHg.

PMID- 10591516
TI  - Age-related hippocampal changes in Bcl-2:Bax ratio, oxidative stress, redox
      active iron and apoptosis associated with aluminum-induced neurodegeneration:
      increased susceptibility with aging.
AB  - We propose that aging is an important factor in the susceptibility of neurons to
      oxidative stress and to subsequent apoptosis. In the present report we
      demonstrate that aged rabbits treated intracisternally with aluminum maltolate
      exhibit intense intraneuronal silver positivity indicative of the formation of
      neurofilamentous aggregates, together with oxidative stress. These changes occur
      in the CA1 region of the hippocampus as well as in cerebral cortical areas.
      Apoptosis, measured by the TUNEL in situ technique, colocalizes with oxidative
      stress. Young animals treated with aluminum show few of these alterations, while
      age-matched controls are essentially negative. Further studies on the time course
      of these and related changes demonstrate that oxidative stress and redox-active
      iron accumulation in hippocampal neurons occur very rapidly, within a period of 3
      hours, and increased in intensity at 72 hours. Changes suggestive of apoptosis
      are seen by 24 hours and are pronounced at 72 hours. In aged animals there is an
      initially intense immunopositivity at 3 hours for Bcl-2, with negative staining
      for Bax. By 72 hours, when apoptosis is strongly evident, Bcl-2 is negative and
      Bax strongly positive. In contrast to the aged rabbits, young animals treated
      similarly with aluminum exhibit much less oxidative stress with no apoptosis, and
      maintain Bcl-2 immunopositivity and negative Bax staining. Our findings strongly
      support the key role that oxidative damage plays in the process of
      neurodegeneration and in the increased vulnerability to aluminum-induced injury
      in the aged animal. These are novel observations which may have important
      implications for aiding in our understanding of the pathogenesis of
      neurodegeneration occurring in Alzheimer's disease.

PMID- 10591517
TI  - Behavioral effects of occupational exposure to organophosphorous pesticides in
      female greenhouse planting workers.
AB  - 51 women employed in gardening enterprises were studied. Of these, 26 performed
      planting jobs in greenhouses and were occupationally exposed to several
      organophosphates. The comparison group consisted of 25 women not exposed to
      neurotoxic chemicals. The groups were similar in terms of age, education, place
      of habitation, and intake of stimulants and drugs. Exposure determinations were
      performed during the period when pesticides were intensively used in the
      greenhouses (March-June). Exposure measurements included air pollution,
      contamination of skin and clothes, and work timing. The level of total exposure
      in the planting worker group was low. Psychological examinations were conducted
      twice: before and after the spraying season, and the Neurobehavioral Core Test
      Battery recommended by the WHO was administered to all subjects. The results of
      the psychological tests did not reveal effects of exposure after a single
      spraying season. Analysis of the results, however, indicated differences between
      the exposed and control groups on both occasions. The exposed female workers were
      characterized by longer reaction times and reduced motor steadiness compared to
      the unexposed workers. In addition, increased tension, greater depression and
      fatigue, more frequent symptoms of CNS disturbances were observed in the exposed
      women compared to the controls.

PMID- 10591518
TI  - Methyl bromide decreases excitability without having immediate toxic effects in
      rat hippocampal CA1 neurons in vitro.
AB  - Methyl bromide, a disinfectant gas amply used worldwide, is neurotoxic in humans
      and other mammals. To study its short-term effects on neurons, it was applied in
      aqueous solution to hippocampal slices of young rats (1.4 and 0.7 mM; for 8
      minutes). Extracellular field recordings and intracellular microelectrode
      recordings from CA1 pyramidal neurons showed that the neurons stay viable for at
      least one hour after application of the mono-halomethane. However, a moderate,
      but consistent, irreversible decrease in synaptic excitability was observed. The
      intracellular recordings indicate that this may be attributed to a decrease in
      excitatory postsynaptic potentials. No effects were observed at 0.7 mM methyl
      bromide. Bromide, in a dose-dependent, partly reversible manner (during one
      hour), produced a similar decrease in excitability. Quantitatively, the action of
      bromide at 0.5 mM resembled the one seen with methyl bromide at the concentration
      of 1.4 mM. Since methyl bromide did not induce electrophysiologic changes
      consistent with evidence of neurotoxicity during one hour of observation it is
      concluded that it lacks immediate toxic effects on hippocampal rat neurons. Its
      neurotoxicity may be entirely due to metabolites or other indirect effects. The
      slight decrease in excitability may be due to the effect of bromide that is set
      free as tissue proteins and other cell molecules are methylated.

PMID- 10591519
TI  - Association between prenatal exposure to methylmercury and developmental outcomes
      in Seychellois children: effect modification by social and environmental factors.
AB  - The Seychelles Child Development Study (SCDS) is testing the hypothesis that
      prenatal exposure to low doses of MeHg from maternal consumption of fish is
      associated with the child's developmental outcomes. No deleterious relationships
      between exposure to MeHg and cognitive functions have been identified in the
      primary analysis of the main cohort through 66 months of age. We performed
      secondary analyses to determine if effect modification (EM) from social and
      environmental factors was affecting associations between MeHg and outcomes.
      METHODS: MeHg exposure was determined by analysis of maternal hair growing during
      pregnancy. Children in our Main Study cohort were evaluated at 6.5 months (N =
      740) for visual recognition memory and visual attention using the Fagan
      Infantest, at 19 months (N = 738) and 29 months (N = 736) with the Bayley Scales
      of Infant Development (BSID). Interactions between MeHg and Caregiver
      Intelligence, Family Income and Home Environment were examined by multiple
      regression analysis. RESULTS: The median prenatal MeHg exposure was 5.9 ppm
      (Range 0.5-26.7 ppm). No EM occurred for preferential looking or visual attention
      at 6.5 months, for the BSID Psychomotor Scale at either 19 or 29 months, or for
      activity level at 29 months as measured by the BSID Infant Behavior Record.
      Interactions between MeHg level and both caregiver intelligence and family income
      were statistically significant for the BSID Mental Scale at 19 months but not at
      29 months. These showed enhancement of MDI scores with increasing maternal MeHg
      in higher caregiver IQ groups at several levels of family income. CONCLUSIONS: In
      Seychellois children, consistent major EM by social or environmental factors were
      not identified. The small EM by caregiver intelligence and social factors at 19
      months is consistent with the enhanced performance we reported when this cohort
      was examined at 66 months.

PMID- 10591520
TI  - Inhibition of spontaneous GABAergic transmission by trimethylolpropane phosphate.
AB  - Trimethylolpropane phosphate (TMPP) is a neuroactive organophosphate generated
      during partial pyrolysis of a synthetic ester turbine engine lubricant. While
      TMPP had been shown to have little affinity for acetylcholinesterase, previous
      binding studies and 6Cl- flux measurements have implicated TMPP as an antagonist
      of GABA, receptor/Cl- channels. Using the whole-cell patch clamp method,
      spontaneous inhibitory postsynaptic currents (sIPSCs) mediated by bicuculline
      sensitive GABA(A) receptors were measured in neurons cultured from the rat
      embryonic hippocampus for 13-21 days. Experiments were conducted in the presence
      of tetrodotoxin and 6-cyano-7-nitroquinoxaline to inhibit spontaneous presynaptic
      action potentials and glutamate transmission, respectively, thus isolating
      GABAergic sIPSCs for study. TMPP induced a concentration-dependent inhibition of
      sIPSC amplitude and frequency suggesting both postsynaptic and presynaptic
      actions. Administration of 5 microM TMPP reversibly diminished sIPSC amplitude by
      23 +/- 8% (mean SEM, n=5 cells) while markedly decreasing the mean sIPSC
      frequency by 40 +/- 2% (n=5). The mean time constant of sIPSC decay was
      reversibly decreased by 20 +/- 4% (n=3) in the presence of 20 microM TMPP,
      suggesting an increase in the rate of inactivation. To directly verify the
      blockade of ionotropic GABA receptors by TMPP, the effects of TMPP were examined
      on whole-cell Cl- current responses activated by exogenous GABA. Administration
      of TMPP (5 microM) depressed peak whole-cell GABA-induced currents to 73 1% (n=4)
      of control levels, consistent with the results on sIPSC amplitude. Our data
      directly demonstrate that TMPP directly inhibits GABA(A) receptor function, as
      indicated by the blockade of whole-cell GABA-mediated Cl- current and the
      reduction in sIPSC amplitude. Furthermore, TMPP exerts a presynaptic effect on
      GABAergic transmission, as evidenced by the reduction in sIPSC frequency, which
      may be independent of a GABA(A) receptor. The molecular basis for the presynaptic
      action of TMPP remains to be elucidated.

PMID- 10591521
TI  - Acute high dose arteether toxicity in rats.
AB  - Acute high dose administration of the artemisinin antimalarial, beta-arteether
      (AE), was evaluated in rats using an auditory discrimination task (ADT) and
      histology. After rats were trained on the ADT, AE (25, 75, 125 mg/kg, i.m.) or
      vehicle (sesame oil) was administered and behavioral performance was evaluated
      for 11 consecutive days. Histological evaluation of the brains was performed
      using thionine and cupric-silver staining. Damaged cells were counted in specific
      brainstem nuclei of all rats and a qualitative analysis of the rostral-caudal
      extent of selected brains was performed. Behavioral performance was not
      significantly affected by any treatment although some evidence of disruption was
      observed, particularly after the largest dose. At 125 mg/kg, AE produced
      statistically significant neuropathology, including chromatolysis, in the nucleus
      trapezoideus and nucleus superior olive. AE at 75 mg/kg, produced significant
      neuropathology in the nucleus trapezoideus. Neither AE at 25 mg/kg, nor vehicle
      produced damage. Qualitative analysis revealed a pattern of neuropathology
      focused in the brainstem. The results show that, in rats, a single dose of AE can
      produce a pattern of brainstem neuropathology and that specific brainstem nuclei,
      including auditory nuclei, are particularly vulnerable. These results are
      consistent with, and extend, previous studies demonstrating brainstem
      neurotoxicity from repeated AE administration. Moreover, early detection of AE
      induced neuropathology is problematic and may require selective examination of
      brainstem functions.

PMID- 10591522
TI  - Introduction: study of the cytochrome bc1 complex entering a new phase.

PMID- 10591523
TI  - Conformational change of the Rieske [2Fe-2S] protein in cytochrome bc1 complex.
AB  - Structures of mitochondrial bc1 complex have been reported based on four
      different crystal forms by three different groups. In these structures, the
      extrinsic domain of the Rieske [2Fe-2S] protein, surprisingly, appeared at three
      different positions: the "c1" position, where the [2Fe-2S] cluster exists in
      close proximity to the heme c1; the "b" position, where the [2Fe-2S] cluster
      exist in close proximity to the cytochrome b; and the "intermediate" position
      where the [2Fe-2S] cluster exists in-between "c1" and "b" positions. The
      conformational changes between these three positions can be explained by a
      combination of two rotations; (1) a rotation of the entire extrinsic domain and
      (2) a relative rotation between the cluster-binding fold and the base fold within
      the extrinsic domain. The hydroquinone oxidation and the electron bifurcation
      mechanism at the Q(P) binding pocket of the bc1 complex is well explained using
      these conformational changes of the Rieske [2Fe-2S] protein.

PMID- 10591524
TI  - Structure of the avian mitochondrial cytochrome bc1 complex.
AB  - There are now four structures of vertebrate mitochondrial bc1 complexes available
      in the protein databases and structures from yeast and bacterial sources are
      expected soon. This review summarizes the new information with emphasis on the
      avian cytochrome bc1 complex (PDB entries 1BCC and 3BCC). The Rieske iron-sulfur
      protein is mobile and this has been proposed to be important for catalysis. The
      binding sites for quinone have been located based on structures containing
      inhibitors and, in the case of the quinone reduction site Qi, the quinone itself.

PMID- 10591525
TI  - Structural basis of multifunctional bovine mitochondrial cytochrome bc1 complex.
AB  - The mitochondrial cytochrome bc1 complex is a multifunctional membrane protein
      complex. It catalyzes electron transfer, proton translocation, peptide
      processing, and superoxide generation. Crystal structure data at 2.9 A resolution
      not only establishes the location of the redox centers and inhibitor binding
      sites, but also suggests a movement of the head domain of the iron-sulfur protein
      (ISP) during bc1 catalysis and inhibition of peptide-processing activity during
      complex maturation. The functional importance of the movement of extramembrane
      (head) domain of ISP in the bc1 complex is confirmed by analysis of the
      Rhodobacter sphaeroides bc1 complex mutants with increased rigidity in the ISP
      neck and by the determination of rate constants for acid/base-induced
      intramolecular electron transfer between [2Fe-2S] and heme c1 in native and
      inhibitor-loaded beef complexes. The peptide-processing activity is activated in
      bovine heart mitochondrial bc1 complex by nonionic detergent at concentrations
      that inactivate electron transfer activity. This peptide-processing activity is
      shown to be associated with subunits I and II by cloning, overexpression and in
      vitro reconstitution. The superoxide-generation site of the cytochrome bc1
      complex is located at reduced bL and Q*-. The reaction is membrane potential-,
      and cytochrome c-dependent.

PMID- 10591527
TI  - The role of various domains of the iron-sulfur protein in the assembly and
      activity of the cytochrome bc1 complex of yeast mitochondria.
AB  - Assembly studies in vitro of deletion mutants of the iron-sulfur protein into the
      cytochrome bc1 complex revealed that mutants localized in the extramembranous
      regions of the protein were not assembled into the complex in contrast to the
      efficient assembly of mutants in the membrane-spanning region. Charged amino
      acids located in the extramembranous alpha1-beta4 loop and the alpha1 helix were
      mutated and expressed in yeast cells lacking the gene for the iron-sulfur
      protein. Mutating the charged amino acid residues H124, E125, R146, K148, and
      D149 as well as V132 and W152 resulted in loss of enzymatic activity due to the
      loss of iron-sulfur protein suggesting that these amino acids are required to
      maintain protein stability. By contrast, no loss of iron-sulfur protein
      accompanied the 30-50% loss of bc1 complex activity in mutants of three conserved
      alanine residues, A86, A90, and A92, suggesting that these residues may be
      involved in the proposed movement of the flexible tether of the iron-sulfur
      protein during catalysis.

PMID- 10591526
TI  - Comparison of the cytochrome bc1 complex with the anticipated structure of the
      cytochrome b6f complex: Le plus ca change le plus c'est la meme chose.
AB  - Structural alignment of the integral cytochrome b6-SU IV subunits with the solved
      structure of the mitochondrial bc1 complex shows a pronounced asymmetry. There is
      a much higher homology on the p-side of the membrane, suggesting a similarity in
      the mechanisms of intramembrane and interfacial electron and proton transfer on
      the p-side, but not necessarily on the n-side. Structural differences between the
      bc1 and b6f complexes appear to be larger the farther the domain or subunit is
      removed from the membrane core, with extreme differences between cytochromes c1
      and f. A special role for the dimer may involve electron sharing between the two
      hemes b(p), which is indicated as a probable event by calculations of relative
      rate constants for intramonomer heme b(p) --> heme b(n), or intermonomer heme
      b(p) --> heme b(p) electron transfer. The long-standing observation of flash
      induced oxidation of only approximately 0.5 of the chemical content of cyt f may
      be partly a consequence of the statistical population of ISP bound to cytfon the
      dimer. It is proposed that the p-side domain of cyt f is positioned with its long
      axis parallel to the membrane surface in order to: (i) allow its large and small
      domains to carry out the functions of cyt c1 and suVIII, respectively, of the bc1
      complex, and (ii) provide maximum dielectric continuity with the membrane. (iii)
      This position would also allow the internal water chain ("proton wire") of cyt f
      to serve as the p-side exit port for an intramembrane H+ transfer chain that
      would deprotonate the semiquinol located in the myxothiazol/MOA-stilbene pocket
      near heme b(p). A hypothesis is presented for the identity of the amino acid
      residues in this chain.

PMID- 10591529
TI  - Role of the Rieske iron-sulfur protein midpoint potential in the protonmotive Q
      cycle mechanism of the cytochrome bc1 complex.
AB  - The midpoint potential of the [2Fe-2S] cluster of the Rieske iron-sulfur protein
      (Em7 = +280 mV) is the primary determinant of the rate of electron transfer from
      ubiquinol to cytochrome c catalyzed by the cytochrome bc1 complex. As the
      midpoint potential of the Rieske cluster is lowered by altering the electronic
      environment surrounding the cluster, the ubiquinol-cytochrome c reductase
      activity of the bc1 complex decreases; between 220 and 280 mV the rate changes
      2.5-fold. The midpoint potential of the Rieske cluster also affects the presteady
      state kinetics of cytochrome b and c1 reduction. When the midpoint potential of
      the Rieske cluster is more positive than that of the heme of cytochrome c1,
      reduction of cytochrome b is biphasic. The fast phase of b reduction is linked to
      the optically invisible reduction of the Rieske center, while the rate of the
      second, slow phase matches that of c1 reduction. The rates of b and c1 reduction
      become slower as the potential of the Rieske cluster decreases and change from
      biphasic to monophasic as the Rieske potential approaches that of the
      ubiquinone/ubiquinol couple. Reduction of b and c1 remain kinetically linked as
      the midpoint potential of the Rieske cluster is varied by 180 mV and under
      conditions where the presteady state reduction is biphasic or monophasic. The
      persistent linkage of the rates of b and c1 reduction is accounted for by the
      bifurcated oxidation of ubiquinol that is unique to the Q-cycle mechanism.

PMID- 10591528
TI  - Primary steps in the energy conversion reaction of the cytochrome bc1 complex Qo
      site.
AB  - The primary energy conversion (Qo) site of the cytochrome bc1 complex is flanked
      by both high- and low-potential redox cofactors, the [2Fe-2S] cluster and
      cytochrome bL, respectively. From the sensitivity of the reduced [2Fe-2S] cluster
      electron paramagnetic resonance (EPR) spectral g(x)-band and line shape to the
      degree and type of Qo site occupants, we have proposed a double-occupancy model
      for the Qo site by ubiquinone in Rhodobacter capsulatus membrane vesicles
      containing the cytochrome bc1 complex. Biophysical and biochemical experiments
      have confirmed the double occupancy model and from a combination of these results
      and the available cytochrome bc1 crystal structures we suggest that the two
      ubiquinone molecules in the Qo site serve distinct catalytic roles. We propose
      that the strongly bound ubiquinone, termed Qos, is close to the [2Fe-2S] cluster,
      where it remains tightly associated with the Qo site during turnover, serving as
      a catalytic cofactor; and the weaker bound ubiquinone, Qow, is distal to the [2Fe
      2S] cluster and can exchange with the membrane Qpool on a time scale much faster
      than the turnover, acting as the substrate. The crystallographic data
      demonstrates that the FeS subunit can adopt different positions. Our own
      observations show that the equilibrium position of the reduced FeS subunit is
      proximal to the Qo site. On the basis of this, we also report preliminary results
      modeling the electron transfer reactions that can occur in the cytochrome bc1
      complex and show that because of the strong distance dependence of electron
      transfer, significant movement of the FeS subunit must occur in order for the
      complex to be able to turn over at the experimental observed rates.

PMID- 10591530
TI  - Control of ubiquinol oxidation at center P (Qo) of the cytochrome bc1 complex.
AB  - The unique bifurcated oxidation of ubiquinol at center P (Qo) of the cytochrome
      bc1 complex is the reaction within the Q-cycle reaction scheme that is most
      critical for the link between electron transfer and vectorial proton
      translocation. While there is a general consensus about the overall reaction at
      center P, the nature of the intermediates and the way the reaction is controlled
      to ensure obligatory bifurcation is still controversial. By reducing the reaction
      to its essential steps, a kinetic net rate model is developed in which the
      activation barrier is associated with the deprotonation of ubiquinol, but the
      steady state rate is kinetically controlled by the occupancy of the ubiquinol
      anion and the semiquinone state. This concept is used to interpret experimental
      data and is discussed in terms of various mechanistic models that are under
      discussion. It is outlined how other aspects of the center P mechanism like the
      proposed "prosthetic" ubiquinone and the moving domain of the "Rieske" protein
      could be incorporated in the kinetic framework.

PMID- 10591531
TI  - The role of the supernumerary subunit of Rhodobacter sphaeroides cytochrome bc1
      complex.
AB  - The smallest molecular weight subunit (subunit IV), which contains no redox
      prosthetic group, is the only supernumerary subunit in the four-subunit
      Rhodobacter sphaeroides bc1 complex. This subunit is involved in Q binding and
      the structural integrity of the complex. When the cytochrome bc1 complex is
      photoaffinity labeled with [3H]azido-Q derivative, radioactivity is found in
      subunits IV and I (cytochrome b), indicating that these two subunits are
      responsible for Q binding in the complex. When the subunit IV gene (fbcQ) is
      deleted from the R. sphaeroides chromosome, the resulting strain (RSdeltaIV)
      requires a period of adaptation before the start of photosynthetic growth. The
      cytochrome bc1 complex in adapted RSdeltaIV chromatophores is labile to detergent
      treatment (60-75% inactivation), and shows a four-fold increase in the Km for
      Q2H2. The first two changes indicate a structural role of subunit IV; the third
      change supports its Q-binding function. Tryptophan-79 is important for structural
      and Q-binding functions of subunit IV. Subunit IV is overexpressed in Escherichia
      coli as a GST fusion protein using the constructed expression vector, pGEX/IV.
      Purified recombinant subunit IV is functionally active as it can restore the bc1
      complex activity from the three-subunit core complex to the same level as that of
      wild-type or complement complex. Three regions in the subunit IV sequence,
      residues 86-109, 77-85, and 41-55, are essential for interaction with the core
      complex because deleting one of these regions yields a subunit completely or
      partially unable to restore cytochrome bc1 from the core complex.

PMID- 10591532
TI  - Integration of the mitochondrial-processing peptidase into the cytochrome bc1
      complex in plants.
AB  - The plant mitochondrial cytochrome bc1 complex, like nonplant mitochondrial
      complexes, consists of cytochromes b and c1, the Rieske iron-sulfur protein, two
      Core proteins, and five low-molecular mass subunits. However, in contrast to
      nonplant sources, the two Core proteins are identical to subunits of the general
      mitochondrial processing peptidase (MPP). The MPP is a fascinating enzyme that
      catalyzes the specific cleavage of the diverse presequence peptides from hundreds
      of the nuclear-encoded mitochondrial precursor proteins that are synthesized in
      the cytosol and imported into the mitochondrion. Integration of the MPP into the
      bc1 complex renders the bc1 complex in plants bifunctional, being involved both
      in electron transport and in protein processing. Despite the integration of MPP
      into the bc1 complex, electron transfer as well as translocation of the precursor
      through the import channel are independent of the protein-processing activity.
      Recognition of the processing site by MPP occurs via the recognition of higher
      order structural elements in combination with charge and cleavage-site
      properties. Elucidation of the three-dimensional (3-D) structure of the mammalian
      cytochrome bc1 complex is highly useful for understanding of the mechanism of
      action of MPP.

PMID- 10591533
TI  - Structure and function of the bacterial bc1 complex: domain movement, subunit
      interactions, and emerging rationale engineering attempts.
AB  - The ubiquinol: cytochrome c oxidoreductase, or the bc1 complex, is a key
      component of both respiratory and photosynthetic electron transfer and
      contributes to the formation of an electrochemical gradient necessary for ATP
      synthesis. Numerous bacteria harbor a bc1 complex comprised of three redox-active
      subunits, which bear two b-type hemes, one c-type heme, and one [2Fe-2S] cluster
      as prosthetic groups. Photosynthetic bacteria like Rhodobacter species provide
      powerful models for studying the function and structure of this enzyme and are
      being widely used. In recent years, extensive use of spontaneous and site
      directed mutants and their revertants, new inhibitors, discovery of natural
      variants of this enzyme in various species, and engineering of novel bc1
      complexes in species amenable to genetic manipulations have provided us with a
      wealth of information on the mechanism of function, nature of subunit
      interactions, and assembly of this important enzyme. The recent resolution of the
      structure of various mitochondrial bc1 complexes in different crystallographic
      forms has consolidated previous findings, added atomic-scale precision to our
      knowledge, and raised new issues, such as the possible movement of the Rieske Fe
      S protein subunit during Qo site catalysis. Here, studies performed during the
      last few years using bacterial bc1 complexes are reviewed briefly and ongoing
      investigations and future challenges of this exciting field are mentioned.

PMID- 10591534
TI  - Allelic, genotypic and phenotypic distributions of S-mephenytoin 4'-hydroxylase
      (CYP2C19) in healthy Caucasian populations of European descent throughout the
      world.
AB  - Impaired S-mephenytoin 4'-hydroxylation is a well-described genetic polymorphism
      affecting drug metabolism in humans. The reported population prevalence of the
      CYP2C19 poor metabolizer phenotype in Caucasians of European descent has been
      described as ranging from 0.9% to 7.7%. To address the question of whether the
      difference in the frequency of poor metabolizers represents an ethnic genetic
      microheterogeneity in the structure and expression of the CYP2C19 gene in
      Caucasian individuals, we performed a pooled analysis of available studies.
      Combined data from the 22 homogeneous studies showed that the frequency of poor
      metabolizers in healthy unrelated Caucasians determined by phenotyping was 2.8%
      (110 of 3990; 95% confidence interval 2.3-3.3). Data obtained from eight
      homogeneous studies that determined the frequency of poor metabolizers by
      genotyping showed that the genotypic frequency of poor metabolizers was 2.1% (28
      of 1356; 95% confidence interval 1.3-2.8), consistent with the poor metabolizer
      frequency determined by phenotyping. In the extensive metabolizers, 26% (471 of
      1786; 95% confidence interval 24.4-28.4) were heterozygotes. The observed
      frequencies of the three Mendelian genotypes were 73% for wt/wt, 26% for wt/m,
      and 2.1% for m/m. Based on the overall phenotypic poor metabolizer frequency of
      2.8%, the expected genotypic frequencies were 69% for wt/wt, 28% for wt/m and
      2.8% for m/m, which are in good agreement to the observed values. However, in the
      84 Caucasian phenotyped and genotyped poor metabolizers, approximately 10% of the
      putative poor metabolizer alleles (17 of 168) were unknown. This study provides a
      systematic overview of the population distribution of the CYP2C19 poor
      metabolizer phenotype and CYP2C19 alleles and genotypes in healthy Caucasians
      living in different geographical areas, and shows a similar polymorphic pattern
      in the structure and expression of the CYP2C19 gene in the worldwide Caucasian
      populations.

PMID- 10591535
TI  - Consequences of rifampicin treatment on propafenone disposition in extensive and
      poor metabolizers of CYP2D6.
AB  - Propafenone undergoes extensive metabolism both by phase I and phase II enzymes:
      cytochrome P4502D6 (CYP2D6) dependent polymorphic hydroxylation to its main
      metabolite 5-OH-propafenone, CYP3A4/1A2 dependent N-dealkylation and further
      glucuronidation and sulfation. Since CYP2D6 is not inducible by rifampicin, an
      important drug interaction between rifampicin and propafenone is not to be
      expected a priori. However, non-CYP2D6-dependent pathways may be induced as a
      case report described dramatically lowered plasma concentrations of propafenone
      with loss of dysrhythmia control associated with rifampicin treatment. Therefore,
      this study aimed to investigate induction properties of rifampicin on propafenone
      disposition in extensive metabolizers and poor metabolizers of CYP2D6. Six
      extensive metabolizers and six poor metabolizers ingested 600 mg rifampicin once
      daily for nine consecutive days. The day before the first rifampicin dose and on
      the day of the last rifampicin dose each individual received a single intravenous
      (i.v.) infusion of 140 mg unlabelled propafenone and 2 h later a single dose of
      300 mg deuterated propafenone orally (p.o.). During enzyme induction maximum QRS
      prolongation decreased significantly after propafenone p.o. (21 +/- 7% versus 13
      +/- 6% in extensive metabolizers, P < 0.01; 15 +/- 6% versus 9 +/- 6% in poor
      metabolizers, P < 0.01) and not after propafenone i.v. In parallel, there were no
      substantial differences in pharmacokinetics of propafenone i.v. by rifampicin.
      However, bioavailability of propafenone dropped from 30 +/- 15% to 10 +/- 8% in
      extensive metabolizers (P < 0.01) and from 81 +/- 6% to 48 +/- 8% in poor
      metabolizers (P < 0.001). Following propafenone p.o. clearances through N
      dealkylation (4.1 +/- 2.1 ml/min versus 23.5 +/- 12.6 ml/min in extensive
      metabolizers, P < 0.01; 3.4 +/- 1.3 ml/min versus 16.0 +/- 5.5 ml/min in poor
      metabolizers, P < 0.001) and glucuronidation (123 +/- 48 ml/min versus 457 +/-
      267 ml/min in extensive metabolizers, P < 0.05; 43 +/- 9 ml/min versus 112 +/- 34
      ml/min in poor metabolizers, P < 0.01), but not 5-hydroxylation increased
      regardless of phenotype indicating substantial enzyme induction. Clearances to
      propafenone sulfate and conjugates of 5-OH-propafenone were significantly
      enhanced by rifampicin treatment in poor metabolizers (P < 0.01). Thus, induction
      of both phase I pathways (CYP3A4/1A2) and phase II pathways (glucuronidation,
      sulfation) of propafenone by rifampicin resulted in a clinically relevant
      metabolic drug interaction which was more pronounced in extensive metabolizers
      than in poor metabolizers with regard to percentage decrease in bioavailability
      of propafenone.

PMID- 10591536
TI  - Comparative pharmacological and functional analysis of the human dopamine D4.2
      and D4.10 receptor variants.
AB  - The human dopamine D4 receptor is a D2-like receptor which is a target for most
      common neuroleptics. Previous investigations have shown that this receptor
      displays a large polymorphic variation in the third intracellular loop involving
      a variable number of direct imperfect tandem repeats (VNTR) of 16 amino acids.
      The shortest and longest repeat variants reported to date contain two and 10
      repeat units (D4.2 and D4.10). No major pharmacological differences have been
      reported for the most common variants of this receptor (D4.2, D4.4 and D4.7),
      although the D4.7 was reported by us to display a slightly lower potency for
      dopamine in functional assays. Direct pharmacological and functional comparison
      of the longest and shortest variants in this study suggest no major discrepancies
      in pharmacological or functional profile between both receptors. Both receptors
      display, on average, a 15-fold and 90-fold lower potency for epinephrine and
      norepinephrine, respectively, compared with dopamine. We observed small increases
      in functional potency and affinity for dopamine and quinpirole at the D4.10
      receptor variant compared with the D4.2 receptor. Our data indicate that there is
      no direct relationship between the length of the polymorphism and changes in
      pharmacology or functional activity. These findings are a suitable caution
      against the arbitrary pooling of D4 receptor VNTR genotypes in genetic studies,
      based on length.

PMID- 10591537
TI  - Mouse cytosolic class 3 aldehyde dehydrogenase (Aldh3a1): gene structure and
      regulation of constitutive and dioxin-inducible expression.
AB  - The mouse cytosolic aldehyde dehydrogenase ALDH3A1 (encoded by the Aldh3a1 gene)
      has previously been shown in cell culture to be markedly inducible by 2,3,7,8,
      tetrachlorodibenzo-p-dioxin (TCDD; dioxin), downregulated by the metabolism of
      functional CYP1A1/1A2 enzymes, and upregulated by a gene on Chr 7 that leads to
      endogenous oxidative stress. In order to study the regulation of Aldh3a1 gene
      expression, we isolated two overlapping genomic sequences from a B6/CBA mouse
      genomic library that included the entire Aldh3a1 gene, along with considerable 5'
      and 3' flanking sequences. The Aldh3a1 gene was shown to span approximately 10 kb
      and comprise 11 exons including a noncoding first exon. The sequence of 3.18 kb
      upstream of exon 1 reveals numerous consensus transcription factor-binding sites,
      some of which were shown to be important in the positive and negative control of
      Aldh3a1 gene expression; these include seven aromatic hydrocarbon response
      elements (AHREs), an electrophile response element (EPRE), and AP-1, C/EBP beta,
      c/EBP alpha, NF-kappaB, Sp1, and NF-1 putative binding sites. Deletion fusion
      constructs containing regions of the Aldh3a1 gene 5' flanking sequence, ligated
      to chloramphenicol experiments suggested that the 5' flanking region of the gene
      contains a strong promoter, at least four functional AHREs appear to act
      cooperatively in causing dioxin-mediated upregulation, and a putative negative
      regulatory element (NRE) controls basal gene expression independent of dioxin
      inducibility. The dioxin-mediated upregulation of Aldh3a1 expression in mouse
      hepatoma Hepa-1c1c7 cell cultures was shown to depend exclusively on the aromatic
      hydrocarbon receptor. acetyltransferase (CAT) or luciferase (LUC) reporter genes,
      were studied. Transient transfection experiments suggested that the 5' flanking
      region of the gene contains a strong promoter, at least four functional AHREs
      appear to act cooperatively in causing dioxin-mediated upregulation, and a
      putative negative regulatory element (NRE) controls basal gene expression
      independent of dioxin inducibility. The dioxin-mediated upregulation of Aldh3a1
      expression in mouse hepatoma Hepa-1c1c7 cell cultures was shown to depend
      exclusively on the aromatic hydrocarbon receptor.

PMID- 10591538
TI  - High and variable frequencies of CYP2C19 mutations: medical consequences of poor
      drug metabolism in Vanuatu and other Pacific islands.
AB  - Cytochrome P450 (CYP) 2C19 is polymorphic with poor metabolizers representing 3
      6% of Europeans and Africans, and 13-23% of Asians. Greater than 99% of the poor
      metabolizer alleles in Asian populations are defined by two single base pair
      mutations (CYP2C19*2 and CYP2C19*3). We have recently reported an unprecedentedly
      high prevalence (71%) of CYP2C19-related poor metabolizer genotype individuals
      and poor metabolism of proguanil on two malarious islands of Vanuatu in eastern
      Melanesia. To elucidate this further, a total of 5538 individuals from 24
      populations on 16 different islands of Vanuatu were genotyped. Of these, 61% had
      a poor metabolizer genotype (*2/*2, *2/*3 or *3/*3) with substantial variation
      among the populations (38-79%). The overall frequencies of CYP2C19*1 (wild-type),
      CYP2C19*2, and CYP2C19*3 were 0.223, 0.633, and 0.144, respectively. A
      significant linear correlation was observed between heterozygosity and South
      latitude (r = 0.552, P < 0.05). The genotype frequencies of 21 of the 24
      populations were consistent with Hardy-Weinberg expectations (P > 0.05).
      Comparisons of genetic, linguistic and geographical patterns among populations
      suggest that short range gene flow is largely responsible for the current
      distribution of CYP2C19 alleles in Vanuatu. Taken together with previous studies
      of nuclear genetic loci of Pacific island populations, these data predict that
      the poor metabolizer genotype is common throughout Polynesia and Micronesia and
      may be even more prevalent in western Melanesia than in Vanuatu. This suggests
      that the majority of Pacific Islanders metabolize a wide variety of clinically
      important drugs to a significantly lower degree than the average European.

PMID- 10591539
TI  - Variability at the uridine diphosphate glucuronosyltransferase 1A1 promoter in
      human populations and primates.
AB  - Variation at the UDP-glucuronosyltransferase (UGT) 1A1 gene promoter is present
      in humans. Variable numbers of TA repeats in the TATA box of this gene are found
      which are inversely related to levels of gene expression. We investigated this
      polymorphism in 658 individuals from a worldwide sample of 15 aboriginal and two
      admixed human populations. This study shows that there is a great deal of
      variability across ethnic groups with regard to UGT1A1 allele frequencies, with
      the most common allele varying in frequency from 33% to 91%. Populations of
      African origin harbor four different alleles while non-African populations appear
      to have only two alleles. In addition, alleles associated with lower gene
      expression levels reach the highest frequencies in populations of African origin
      and lowest among Asians and Amerindians. Thus, more variability in the metabolism
      of drugs eliminated by UGT1A1 glucuronidation should be expected in populations
      of Sub-Saharan African origin. The sequence analysis of nine primate species
      shows that the number of TA repeats has increased during primate evolution
      achieving the largest number in humans. We suggest that the UGT1A1 promoter
      variability does not reflect historical relationships between populations and
      that it may be maintained by natural selection. Our findings are consistent with
      the proposal that the TA repeat variation is a balanced polymorphism.

PMID- 10591541
TI  - Quantitative-trait loci analysis of cocaine-related behaviours and
      neurochemistry.
AB  - We recently conducted a dose-response study of the effects of cocaine on several
      activity measures in the panel of BxD/Ty recombinant inbred mice. Animals were
      tested in an automated activity chamber over 2 days with i.p. saline on day 1 and
      i.p. cocaine on day 2, at one of four doses, 5, 15, 30 or 45 mg kg(-1). The
      monitor recorded total distance traveled, nosepokes in a holeboard, repeated
      movements and time spent by an individual in proximity to the centre of the
      apparatus. Dose-response curves for locomotor activation, i.e. the difference
      between cocaine and saline scores, showed that for all strains tested, scores
      increased 5-30 mg kg(-1). With few exceptions, locomotor activity at 45 mg kg(-1)
      was not significantly higher than that at 30 mg kg(-1). Repeated movement scores
      showed patterns similar to locomotor activity and nosepokes tended to be
      progressively inhibited by increasing doses of cocaine. Recombinant inbred strain
      mean distributions for all behaviours and at all doses exhibited continuous,
      rather than discrete variation, thus providing evidence of multiple-gene effects
      on cocaine-related behaviours. Quantitative trait loci (QTL) analysis pointed to
      several chromosomal locations associated with variations in cocaine-related
      behaviours and some are either identical or close to QTL reported by others. In
      separate groups of animals, densities of dopamine D1, and D2 receptors and
      dopamine uptake transporters were measured in the medial prefrontal cortex,
      caudate-putamen, nucleus accumbens and ventral midbrain. In all areas, all
      measures showed distributions consistent with polygenic influence and were
      associated with QTL. Of particular interest was our finding of a large segment on
      chromosome 15, which is related to dopamine receptor densities and cocaine
      related behaviours.

PMID- 10591540
TI  - Genetic polymorphism of CYP2D6 in the Japanese population.
AB  - The frequencies of CYP2D6 mutations in a Japanese population were investigated.
      Individuals were classified into three groups: control individuals, cancer
      patients and Parkinsonians. Genotyping for CYP2D6*3, CYP2D6*4 and CYP2D6*18 was
      carried out using the polymerase chain reaction, and that for CYP2D6*5 was also
      carried out using XbaI restriction fragment length polymorphism. The frequencies
      of the CYP2D6*3, CYP2D6*4, CYP2D6*5 and CYP2D6*18 mutant alleles were 0%, 0.77%,
      4.10% and 0.53% in more than 256 Japanese control individuals, respectively.
      Based on these data, the population frequency of the CYP2D6 poor metabolizer
      phenotype was estimated to be 0.29%. The distribution of the four mutated alleles
      was not significantly different between control individuals and cancer patients
      or Parkinsonians.

PMID- 10591542
TI  - Pharmacogenetic variability in neuronal nicotinic receptor-mediated
      antinociception.
AB  - The ability to predict interindividual differences in drug efficacy or toxicity,
      based on genetic factors that influence drug disposition or drug action, is fast
      becoming a realistic goal. The purpose of the present study was to determine
      whether epibatidine, a prototypical nicotinic analgesic drug, exhibits
      pharmacogenetic variability in antinociceptive activity. Eight inbred mouse
      strains (A, AKR, BALB/c, C3H/He, C57BL/6, C57BL/10, DBA/2, and SM) were surveyed
      for their sensitivity to the antinociceptive effects of epibatidine. All strains
      exhibited statistically significant antinociception that peaked between 10 and 20
      min following the systemic injection of 50 microg/kg epibatidine. However, there
      was fourfold variability in the magnitude of peak effect between strains, with
      DBA/2, BALB/c and A strains showing much greater sensitivity than all others. A
      return to baseline nociceptive threshold at 30 min post-injection was observed
      for all but the A strain. In contrast, these mice exhibited significant
      antinociception for at least 3 h following epibatidine administration. Thus,
      expressing the data as area under the time-latency curve to take into account
      both the magnitude and duration of effect, epibatidine displayed approximately 20
      fold higher antinociceptive potency in the A strain compared with the C3H/He
      strain. The effects of epibatidine in both the A and C3H/He strains were dose
      dependent and sensitive to antagonism by the selective neuronal nicotinic channel
      blocker mecamylamine. Taken together, these data demonstrate the existence of
      pharmacogenetic variability in neuronal nicotinic receptor-mediated
      antinociception between inbred stains of mice and presage the potential for
      similar variability in analgesic response to nicotinic-based analgesics among
      humans. Future studies will seek to identify the chromosomal loci underlying this
      variability.

PMID- 10591544
TI  - Prostate cancer associated with CYP17 genotype.
AB  - Androgens play an important role in the development of prostate cancer. Androgen
      regulating genes that show allelic variation may be susceptibility factors for
      the disease. One of these genes, CYP17, encodes the cytochrome P450c17alpha
      enzyme. It catalyses steroid 17alpha-hydroxylase/17,20 lyase activities at key
      points in testosterone biosynthesis. We investigated the association between a
      polymorphism in the CYP17 gene and prostate cancer in a population-based case
      control study. All individuals studied were Caucasians born in Sweden, 178 were
      consecutive clinical prostate cancer patients, and 160 were age-matched control
      individuals randomly selected from the same catchment area. DNA was extracted
      from blood samples. A CYP17 gene fragment was amplified by polymerase chain
      reaction. The MspA1I restriction enzyme, which recognizes the base pair
      substitution, was used to identify the allelic variants CYP17A1 and CYP17A2.
      Significantly more men homozygous for the CYP17A1 allele were found among
      prostate cancer patients compared with control individuals; odds ratio 1.61 (95%
      confidence interval 1.02; 2.53), P = 0.04. According to a preliminary report, the
      CYP17A1/A1 genotype leads to higher circulating androgen levels, possibly by
      encoding for a more active androgen synthesizing CYP17 enzyme. Consequently, the
      CYP17A1/A1 genotype, which was found in a higher frequency among prostate cancer
      patients, may prove to be one of the important susceptibility factors for
      prostate cancer. If verified, this genotype is likely to convey a larger risk on
      a population basis, than the rare hereditary prostate cancer genes do.

PMID- 10591543
TI  - N-acetyltransferase-2 polymorphism, smoking and type 1 diabetic nephropathy.
AB  - The N-acetyltransferase (NAT2) polymorphism has been suggested to be related to
      diabetic microvascular complications. To study the distribution of NAT2 genotypes
      in Caucasian type 1 diabetic patients with and without diabetic nephropathy, 214
      adult type 1 diabetic patients and 53 healthy individuals were genotyped by
      polymerase chain reaction-restriction fragment length polymorphism. In addition,
      75 young type 1 diabetic patients were genotyped, and 70 of them also phenotyped
      by caffeine. Of the adult patients, 83 had normal albumin excretion, 58 had
      microalbuminuria, and 73 had overt diabetic nephropathy. NAT2 allele frequencies
      were similarly distributed between the diabetic patients and healthy individuals:
      0.29/0.2 5 (NAT2*4), 0.03/0.04 (NAT2*7B), 0.25/0.27 (NAT2*6A), and 0.43/0.44
      (NAT2*5B), and within the diabetic subgroups. Because smoking is a known risk
      factor for diabetic nephropathy, nonsmoking and smoking patients were analysed
      separately. NAT2 allele frequencies differed significantly between the nonsmoking
      normoalbuminuric, microalbuminuric and nephropathic patients: 0.18/0.41/0.30
      (NAT2*4), 0.04/0.00/0.02 (NAT2*7B), 0.35/0.18/0.17 (NAT2*6A), 0.43/0.41/0.50
      (NAT2*5B), P = 0.013. In nonsmoking fast acetylators odds ratio for
      microalbuminuria and nephropathy was 3.1 (95% confidence interval 1.36-7.05), P =
      0.007 by logistic regression. In smokers, a nonsignificant odds ratio was found
      [0.31 (95% confidence interval 0.08-1.2), P = 0.09]. Smoking is a strong
      confounding factor in relation to NAT2 analyses and diabetic nephropathy.
      According to our data, in nonsmoking type 1 diabetic patients fast NAT2 genotype
      implies an increased risk for diabetic nephropathy.

PMID- 10591545
TI  - Enhanced proteasomal degradation of mutant human thiopurine S-methyltransferase
      (TPMT) in mammalian cells: mechanism for TPMT protein deficiency inherited by
      TPMT*2, TPMT*3A, TPMT*3B or TPMT*3C.
AB  - Inheritance of the TPMT*2, TPMT*3A and TPMT*3C mutant alleles is associated with
      deficiency of thiopurine S-methyltransferase (TPMT) activity in humans. However,
      unlike TPMT*2 and TPMT*3A, the catalytically active protein coded by TPMT*3C does
      not undergo enhanced proteolysis when heterologously expressed in yeast, making
      it unclear why this common mutant allele should be associated with inheritance of
      TPMT-deficiency. To further elucidate the mechanism for TPMT deficiency
      associated with these alleles, we characterized TPMT proteolysis following
      heterologous expression of wild-type and mutant proteins in mammalian cells. When
      expressed in COS-1 cells, proteins encoded by TPMT*2, TPMT*3A, and TPMT*3C cDNAs
      had significantly reduced steady-state levels and shorter degradation half-lives
      compared with the wild-type protein. Similarly, in rabbit reticulocyte lysate
      (RRL), these mutant TPMT proteins were degraded significantly faster than the
      wild-type protein. Thus, enhanced proteolysis of TPMT*3C protein in mammalian
      cells is in contrast to its stability in yeast, but consistent with TPMT
      deficiency in humans. Proteolysis was ATP-dependent and sensitive to proteasomal
      inhibitors MG115, MG132 and lactacystin, but not to calpain inhibitor II. We
      conclude that all of these mutant TPMT proteins undergo enhanced proteolysis in
      mammalian cells, through an ATP-dependent proteasomal pathway, leading to low or
      undetectable levels of TPMT protein in humans who inherit these mutant alleles.

PMID- 10591546
TI  - Alpha1A-adrenergic receptor polymorphism: association with ethnicity but not
      essential hypertension.
AB  - The alpha1-adrenergic receptor (alpha1-AR) mediates vasoconstriction and plays an
      important role in the regulation of vascular tone. Increased alpha1-AR-mediated
      vasoconstrictor sensitivity, increased vascular reactivity to stress, and an
      increased prevalence of hypertension occur in African-Americans. The human
      alpha1A-AR is the predominant alpha1-AR subtype in vascular smooth muscle. The
      potential relevance of alpha1A-AR genetic variation to ethnic differences in
      vascular response and to the pathogenesis of hypertension prompted us to
      determine the frequency distribution of a recently identified polymorphism
      (Arg492 to Cys) in the alpha1A-AR in normotensive and hypertensive black and
      white American individuals. Polymerase chain reaction-based PstI restriction
      fragment length polymorphisms in the human alpha1A-AR gene were determined in 231
      African-American and 282 Caucasian individuals, both with and without
      hypertension. There were marked differences in the genotypic and allelic
      distributions of the Arg492 to Cys alpha1A-AR polymorphism between African
      American and Caucasian individuals (Cys492/Cys492 genotype, normotensive: 7.6%
      versus 30.1%; hypertensive: 7.1% versus 26.2%; Cys492 allele, normotensive: 29.5%
      versus 53.8%; hypertensive: 28.8% versus 55.2%; blacks versus whites, P <
      0.0001). The frequency of the variant Cys492 allele was similar in normotensive
      and hypertensive individuals, both in African-Americans (29.5% versus 28.8%) and
      Caucasians (53.8% versus 55.2%). There were no significant intergenotypic
      differences in blood pressure (all P > 0.05). The data indicate that this
      polymorphism is not associated with essential hypertension in black or white
      Americans, but that the frequency of the alpha1A-AR Arg492 allele occurs
      significantly more commonly in African-Americans than in Caucasians. The
      potential role of the Arg492 to Cys alpha1A-AR polymorphism in ethnic differences
      in vascular alpha1-adrenergic response requires further investigation.

PMID- 10591547
TI  - Ten percent of North Spanish individuals carry duplicated or triplicated CYP2D6
      genes associated with ultrarapid metabolism of debrisoquine.

PMID- 10591548
TI  - Clinical results of the shallow core-out procedure in thyroglossal duct cyst
      operation.
AB  - PURPOSE: This procedure for thyroglossal duct cyst operation based on
      pathological studies was first published in the Journal of Pediatric Surgery in
      1992. This procedure is similar to Sistrunk's operation except that the core
      depth of the tongue excision is more shallow (about 5 mm in young children). The
      purpose of this report is to report and evaluate the clinical results of this
      operation compared with our earlier operative results. METHODS: Eighty-three
      patients underwent surgery for thyroglossal duct cyst from 1970 to 1997. They
      were divided into 3 groups. Group I consisted of 31 patients undergoing
      Schlange's operation (1970 to 1988). Group II were 18 patients undergoing
      Sistrunk's operation (1989 to 1990). Group III consisted of 34 patients operated
      on with the authors' procedure (1991 through 1997). The 3 groups are compared for
      recurrence rate. RESULTS: Recurrence in group I was 6 of 31 (19.3%), 1 of 18
      (5.6%) in group II, and 1 of 34 (2.9%) in group III. The recurrence rate showed a
      statistically significant difference only between group I and III (P = .033).
      CONCLUSION: The recurrence rate with our procedure was not higher than that of
      Sistrunk's operation but was significantly lower than for Schlange's operation.

PMID- 10591550
TI  - Modified soave pull-through for Hirschsprung's disease: intraoperative internal
      sphincterotomy.
AB  - BACKGROUND/PURPOSE: Anorectal achalasia (AA) may persist after pull-through (PT)
      for Hirschsprung's disease (HD), which may cause postoperative enterocolitis
      (POE) and constipation. The authors modified the Soave PT (modified Soave PT,
      MSPT) to eliminate AA, and present their results. METHODS: This was a 16-year
      retrospective review of 43 patients with histologically proven HD of the
      rectosigmoid or sigmoid colon treated by MSPT. The MSPT involves excision of the
      posterior rectal cuff and an intraoperative internal sphincterotomy, allowing the
      PT colon to fit nicely. RESULTS: Mean age at MSPT was 16.7 months (16 were < or
      =3 months old [37%]; 7 were neonates [16%]). Mean follow-up was 9.2 years. Six of
      43 cases (14%) had preoperative enterocolitis; only 2 of 43 (5%) had single
      episodes of POE. At review, 37 of 43 were older than 4 years; 29 (78%) had normal
      bowel function (14 had experienced soiling after MSPT, which resolved after a
      mean of 6.4 years); and 8 (21%) had problematic bowel function: 3 had occasional
      soiling, 1 had soiling only before defecation, 3 (8%) had constipation requiring
      laxatives or enemas, and 1 had significant soiling. CONCLUSION: MSPT is safe and
      may contribute to a reduction in the incidence of POE and constipation.

PMID- 10591549
TI  - Relationship of the notochord to foregut development in the fetal rat model of
      esophageal atresia.
AB  - BACKGROUND/PURPOSE: The notochord (Nt) is thought to act as a primary organizer
      for adjacent axial embryonic organs. The current study used the Adriamycin
      induced fetal rat model of esophageal atresia and tracheoesophageal fistula (EA
      TEF) to determine whether anomalies of the foregut (FG) were associated with an
      abnormal Nt. METHODS: Eight experimental female Sprague-Dawley rats received
      intraperitoneal injection of Adriamycin (1.75 mg/kg) on gestational days 6 to 9
      inclusive, and 4 control rats received saline injection only. Their embryos were
      harvested on gestational days 11, 12, 13, and 14. Embryos from each age subgroup
      were serially sectioned and stained with H&E. The FG and Nt were traced from the
      primitive pharynx to the level of the stomach. RESULTS: By day 11, the Nt of
      control embryos had completely separated from the FG and was located immediately
      ventral to the neural tube. On gestational day 12, the Nt detached from the
      neural tube, and the trachea and esophagus were separating. On day 11, in the
      Adriamycin-treated embryos, the Nt was still attached to an FG that was narrowed
      or occluded. On day 12, the Nt remained adherent to the FG from the primitive
      pharynx to the level above the primitive respiratory buds, at which point it
      became thicker and branched sagittally, with the anterior branch contacting or
      merging with the FG. The FG usually loses its lumen or continuity when in contact
      with the Nt. CONCLUSIONS: Exposure of rat embryos to Adriamycin leads to abnormal
      development of the Nt, including prolonged attachment to or fusion with the FG,
      and abnormal branching. Traction on the FG by the Nt produces occlusion of its
      lumen and may result in its complete interruption. Separation of the Nt from the
      FG would appear to be a prerequisite for the normal development of the FG into
      its derivatives: the esophagus and trachea.

PMID- 10591551
TI  - Promoting effect of estrogen on the proliferation of hemangioma vascular
      endothelial cells in vitro.
AB  - PURPOSE: This study was designed to observe whether estrogen can enhance the
      proliferation of hemangioma vascular endothelial cells (VECs) and, if so, the
      possible inhibiting effect of tamoxifen against estrogen. METHODS: Two skin
      hemangiomas with positive estrogen receptor staining from 2 infants were used for
      VECs culture. Based on different culture conditions and treatment, the
      subcultured VECs of passage 3 derived from a hemangioma were divided into 5
      groups: group 1, control without endothelial cell growth supplement (ECGS) in
      medium; group 2, estradiol (E2) without ECGS; group 3, control with ECGS in
      medium; group 4, E2 with ECGS; group 5, E2 and 4OH-tamoxifen with ECGS. Cell
      counts and 3H-TdR incorporations were determined on culture days 3, 6, and 9.
      VECs from the other hemangioma were divided into 2 groups: group 3, control with
      ECGS in medium; group 4, E2 with ECGS. RESULTS: At the end of the 9-day study,
      the cell counts (x10(4)/mL) of the 5 groups were 6.31+/-1.24, 6.52+/-1.08,
      15.62+/-1.88, 36.77+/-3.96, and 6.88+/-1.20, respectively. 3H-TdR incorporations
      (cpm) were 511+/-127, 538+/-26, 1,350+/-67, 2,729+/-145, and 575+/-64,
      respectively. The results of the other hemangioma were similar to those of the
      first one. Our data showed that without ECGS in medium, E2 had no effect on the
      proliferation of VECs (group 1 v group 2, P>.05); with ECGS in medium, E2 yielded
      a 2-fold increase in the proliferation of VECs (group 3 v group 4, P<.01); when
      4OH-tamoxifen was added, the proliferation of VECs was suppressed dramatically
      (group 4 vgroup 5, P<.01). CONCLUSIONS: Estrogen in vitro can promote the
      proliferation of hemangioma VECs. This promoting effect of estrogen may depend on
      certain growth factors, which can be inhibited by tamoxifen.

PMID- 10591552
TI  - Expression of RET proto-oncogene and GDNF deficit in Hirschsprung's disease.
AB  - PURPOSE: The aim of this study was to investigate GDNF (glial cell line-derived
      neurotrophic factor) protein expression and RNA expression level of the RET proto
      oncogene in human aganglionic (AG) bowel in Hirschsprung's disease (HD) and to
      further understand the pathophysiology of HD. METHODS: To evaluate the possible
      implication of the RET gene and GDNF for the development of HD, mRNA expression
      level of the RETgene was examined by using the reverse transcription-polymerase
      chain reaction (RT-PCR) technique and protein expression level of the GDNF using
      an immunohistochemical technique in the bowel specimens of 15 HD patients.
      RESULTS: A significantly less intense signal for RETmRNA was found in the AG
      bowel compared with the ganglionic bowel. In different age groups of patients,
      the intensities of RET level had similar results. In the same patients, there was
      strong GDNF immunoreactivity in the myenteric plexuse in ganglionic bowel. In the
      myenteron in AG bowel, the number of GDNF immunoreactive neuron cells was reduced
      significantly compared with normal ganglionic bowel. CONCLUSIONS: From these
      preliminary data we conclude that the decreased RET expression in the AG bowel
      may suggest mal development of neural crest-derived cells in HD. The reduced
      level of GDNF in AG bowel may suggest a GDNF expression deficit interrupting the
      faithful signaling via RET, and both are implicated in the pathogenesis of HD.

PMID- 10591553
TI  - Characterization and management of paraesophageal hernias in children after
      antireflux operation.
AB  - PURPOSE: The aim of this study was to determine the important factors in the
      development and subsequent treatment of postoperative paraesophageal hernia
      (PPEH). METHODS: A retrospective analysis was performed in 464 consecutive
      children (ages 3 days to 18 years) for PPEH after a primary antireflux operation
      performed at a Children's Hospital and University Hospital between 1985 and 1997.
      All operations included a crural repair, but the Nissen fundoplication was
      performed with (n = 162) and without (n = 70) plication of the esophagus to the
      crus at 3 points. Patients with and without PPEH were compared with respect to
      the type of antireflux operation, the patient's age at operation, and the
      preoperative and postoperative clinical courses. A preoperative corrected gastric
      emptying value was obtained from a radionuclide gastric emptying study in 289
      patients. The treatment of PPEH also was examined. RESULTS: The incidence of PPEH
      in our patients was 4.5% (21 of 464). Although there was a lower incidence of
      PPEH in patients with crural plication compared with patients without crural
      plication during Nissen fundoplication (5 of 162, 3% v 7 of 70, 10%; P = .035), 2
      patients with crural plication had a postoperative esophageal leak. Patients with
      PPEH had a significantly increased prevalence of gagging before the initial
      antireflux operation compared with patients without PPEH (3 of 21, 14.3% v 7 of
      443, 1.6%; P = .007). A higher prevalence of slow corrected gastric emptying
      preoperatively also was seen in patients with PPEH compared with patients without
      PPEH (8 of 15, 53% v 79 of 274, 29%; P = .046). The prevalences of central
      nervous system disease, young age (<6 months) at initial operation, and a
      particular type of antireflux operation were not higher in patients with PPEH.
      Nine patients with a small PPEH treated by simple observation alone subsequently
      had resolution of symptoms. CONCLUSIONS: Patients who have gagging or slow
      corrected gastric emptying before an antireflux operation are at higher risk for
      a postoperative paraesophageal hernia. Patients with a small postoperative
      paraesophageal hernia can be treated nonoperatively. Crural plication of the
      esophagus during Nissen fundoplication reduces the occurrence of postoperative
      paraesophageal hernia, but also may result in significant morbidity.

PMID- 10591554
TI  - Highly sensitive analysis for N-myc amplification in neuroblastoma based on
      fluorescence in situ hybridization.
AB  - BACKGROUND/PURPOSE: The N-myc amplification status in neuroblastoma has been
      evaluated previously for the whole tumor by the Southern blot method. The aim of
      this study is to evaluate the effectiveness of the fluorescence in situ
      hybridization (FISH) method to analyze N-myc amplification in neuroblastoma and
      compare the findings with those using the Southern blot method. METHODS: In 26
      neuroblastoma primary tumors and metastatic lesions, the N-myc amplification
      status was evaluated by both the Southern blot method and FISH method. RESULTS:
      Of the 22 samples with no N-myc amplification using Southern blot, no cells with
      N-myc amplification using FISH were present in 21 of the samples. However, one
      metastatic liver lesion showed 16% of the nuclei to display more than 10 copies
      of N-myc based on FISH analysis. In the 4 remaining samples with N-myc
      amplification using the Southern blot method (17 copies, 15 copies, 6 copies, and
      3 copies), the rates of cells with more than 10 copies of N-myc based on a FISH
      analysis were 79%, 68%, 94%, and 9%, respectively. CONCLUSIONS: The FISH method
      can detect more accurately N-myc amplification than the Southern blot method
      either when the rate of cells with N-myc amplification is low or intratumor
      heterogeneity is present.

PMID- 10591555
TI  - Prenatally detected tumor mass in the adrenal gland.
AB  - BACKGROUND/PURPOSE: Screening programs using urinary vanillylmandelic acid have
      detected neuroblastomas in early infancy with some success. With the widespread
      use of ultrasonography in modern obstetric practice, use of ultrasonography to
      screen for fetal neuroblastoma seems to be reasonable and practical. METHODS:
      Seven fetuses had suprarenal masses detected by maternal ultrasound scan at 32 to
      37 weeks' gestation between 1993 and 1998. They were delivered normally if the
      pregnancy was uncomplicated, especially if it was without maternal preeclampsia
      or fetal hydrops. Each mass was further confirmed by ultrasound scan, computed
      tomography, or magnetic resonance imaging in the neonatal period. Tumor excision
      was performed at the age of 6 to 38 days of life. RESULTS: The size of the masses
      measured ranged from 2.0x2.0 cm to 4.5x4.5 cm. The diagnosis was adrenal
      hemorrhage in 1 neonate, Evan's stage I neuroblastoma in 3, and stage IV-S
      neuroblastoma in 3. All of the specimens with a diagnosis of neuroblastoma showed
      a favorable histology by the Shimada classification system. Infants with stage I
      disease were treated with tumor excision only, and they had survived without
      disease by 14, 18, and 25 months of follow-up. One infant with stage IV-S
      neuroblastoma was treated further with minimal chemotherapy and has survived
      without disease at the 66-month follow-up examination. Another child with stage
      IV-S neuroblastoma has survived with local recurrence and increasing liver
      metastasis and was still on chemotherapy at the 2-month follow-up examination.
      The third child with stage IV-S disease presented with massive hepatomegaly and
      bone marrow involvement, and disseminated intravascular coagulopathy had
      developed. The patient died on the 5th day of life without surgical intervention.
      CONCLUSIONS: The increasing use of obstetric ultrasonography has made the
      prenatal screening of neuroblastomas possible. The prognosis of infants with a
      suprarenal mass may be improved with this early detection and early surgical
      intervention.

PMID- 10591556
TI  - Skeletal malformations associated with congenital diaphragmatic hernia:
      experimental and human studies.
AB  - BACKGROUND/PURPOSE: Skeletal malformations are seen occasionally in infants with
      congenital diaphragmatic hernia (CDH). This study examines whether nitrofen, able
      to produce CDH in fetal rats, also induces skeletal anomalies and, if so, whether
      these are similar to those seen in CDH patients. METHODS: Pregnant rats received
      either nitrofen (100 mg, n = 7) or no treatment (n = 2) on gestational day 9.5.
      Skeletal anatomy was studied in fetuses recovered on day 21 after alcian blue
      alizarin red staining. The charts and postmortem records of 117 stillborns or
      newborns who died of CDH were investigated retrospectively for skeletal defects.
      The proportions of anomalies found in the different groups were compared.
      RESULTS: The 15 control rat fetuses were normal, whereas 57 of 90 nitrofen
      exposed animals (63%) had CDH accompanied by other malformations. Skeletal
      defects limited to vertebral segmentation or identity anomalies (split vertebra
      or absent, hypoplastic, or fused ribs) were seen at low thoracic and high lumbar
      levels in 68% of animals with CDH and in 57% of those without. Delayed
      ossification of limbs was seen in treated animals. There were skeletal
      malformations in 31.6% of the 117 human patients with CDH. Costovertebral defects
      (malformed, extra or defective vertebral bodies or ribs and spina bifida) were
      comparably frequent in infants with syndromes and in those without them (31.2% v
      17.8%, not significant), whereas limb defects were significantly more frequent in
      those with syndromes (56.2% v 13.9%, P<.05). CONCLUSION: The nature and location
      of costovertebral malformations found in both CDH patients and nitrofen-exposed
      rats suggest that the diaphragmatic defect and the associated organ malformations
      might be caused by the same early embryonal disturbance involving axial and para
      axial mesoderm.

PMID- 10591557
TI  - Reoperation after esophageal replacement in childhood.
AB  - BACKGROUND: Esophageal replacement is associated with significant morbidity that
      may lead to operative interventions. This study reviews the management and
      outcome of children who underwent reoperation after esophageal replacement.
      METHODS: Eighteen patients who underwent esophageal replacement from 1985 to 1997
      were reviewed retrospectively. Ten patients underwent reoperation. Patient
      management, perioperative morbidity, and the dietary intake at follow-up were
      recorded for each patient. RESULTS: Of the reoperated patients, 7 had esophageal
      atresia, 2 had caustic ingestion, and 1 had achalasia. Nine patients received a
      colon interposition, and 1 received a reverse gastric tube as the initial
      esophageal replacement. Seven patients required revision of the anastomoses.
      Three patients required complex esophageal reconstruction: 1 underwent gastric
      transposition, 1 underwent free jejunal graft, and 1 underwent gastric
      transposition combined with free jejunal graft. Seven patients were eating well
      at follow-up. Two patients still required partial gastrostomy tube feeding. One
      patient died 6 months postoperatively from aspiration pneumonia. CONCLUSIONS:
      Esophageal replacement continues to be a challenging operation associated with
      significant complications. Most reoperative procedures were directed toward
      strictures and persistent fistulae. Complete graft failure can be managed by
      gastric transposition or free jejunal graft. Despite the perioperative morbidity,
      most patients have good functional outcome.

PMID- 10591558
TI  - Acute respiratory failure associated with intrathoracic masses in neonates.
AB  - BACKGROUND: Intrathoracic masses are uncommon in children. Occasionally, they
      present with acute respiratory failure in the neonatal period. Although emergency
      resection usually is the treatment of choice, other modalities are sometimes
      necessary to stabilize the patient. METHODS: Seven neonates with intrathoracic
      masses were treated. Five had congenital cystic adenomatoid malformations (CCAM),
      1 had a mediastinal teratoma, and 1 had a pneumatocele. These cases were reviewed
      retrospectively. RESULTS: Four of the 7 infants had respiratory failure in the
      neonatal period. A patient with a large mediastinal teratoma and 1 with a CCAM
      that increased rapidly after presentation underwent emergency operation,
      relieving respiratory distress. The other 2 large CCAMs presented with severe
      respiratory distress immediately after birth because of pulmonary hypoplasia. One
      neonate with a Stocker-I CCAM died after emergency resection. One more recent
      patient with a Stocker-III CCAM survived after successful treatment with delayed
      resection, performed 3 days after birth. Nitric oxide (NO), and extracorporeal
      membrane oxygenation (ECMO) were instituted as supportive care because of
      profound persistent fetal circulation (PFC). CONCLUSIONS: Acute respiratory
      failure associated with intrathoracic masses in neonates may be managed in 1 of 2
      ways. A small mass that increases rapidly should be resected soon after
      presentation. In neonates with large masses with associated PFC, surgery can be
      delayed until the patient is stable. ECMO, NO, and high-frequency oscillation
      (HFO) can be used aggressively for stabilizing such neonates.

PMID- 10591559
TI  - Fetal esophageal transplantation in rats: a treatment option for long-gap
      esophageal atresia.
AB  - PURPOSE: The aim of this study is to determine if fetal esophageal
      transplantation can create viable esophageal tissue that may be used for treating
      long gap esophageal atresia. METHODS: Fetuses of gestational age 19 to 20 days
      were obtained by hysterotomy of pregnant 15-week-old Lewis rats. A 10-mm long
      segment of esophagus was obtained from each fetus by thoracolaparotomy and
      transplanted by wrapping it in a pouch created in the distal omentum of a 5-week
      old Lewis rat (syngeneic transplantation: n = 15). Transplanted fetal esophageal
      grafts were harvested 10 days post-transplantation and fixed in 10% formalin and
      embedded in paraffin. H&E was used for histological examination, and PGP 9.5 (a
      neuronal antibody) was used for immunohistochemistry. Esophageal segments
      obtained from 10-day-old Lewis rats were used as controls. RESULTS: Thirteen of
      15 (87%) grafts were transplanted successfully. The successfully transplanted
      graft could be mobilized to the thoracic cavity without tension or compromising
      of vascularity, because of the long omental pedicle. H&E staining and PGP 9.5
      immunohistochemistry showed normal esophageal structure with intact esophageal
      nervous system, comparable with control specimens. CONCLUSIONS: Fetal esophageal
      transplantation produces viable esophageal tissue that may find application for
      treating long gap esophageal atresia providing rejection can be controlled
      adequately.

PMID- 10591560
TI  - Undifferentiated embryonal sarcoma of the liver: results of clinical management
      in one center.
AB  - PURPOSE: This study was undertaken to review the authors' clinical experience
      with undifferentiated embryonal sarcoma of the liver (UES) in children, focusing
      on the clinical presentation and results of treatment. METHODS: A retrospective
      analysis of all children who have undergone treatment for UES during the 15-year
      period from 1984 through 1998 was performed. RESULTS: Seven patients (4 boys and
      3 girls) ranging in age from 20 months to 12 years at the time of diagnosis were
      identified. All presented with large abdominal masses and normal liver function
      test results. All underwent complete tumor resection; trisegmentectomy was
      required in 4 of these cases. All patients received postoperative chemotherapy.
      Two patients suffered tumor recurrence at 12 and 29 months; both of these
      patients died of their disease. Another patient died of complications related to
      chemotherapy. The other 4 patients are alive with no evidence of disease after 19
      to 150 months' follow-up. CONCLUSIONS: Undifferentiated embryonal sarcoma of the
      liver presents as a large hepatic tumor. Operative resection is difficult, but
      combined with adjuvant chemotherapy offers the best hope for cure.

PMID- 10591562
TI  - Critical timing of bladder embryogenesis in an adriamycin-exposed rat fetal
      model: a clue to the origin of the bladder.
AB  - BACKGROUND/PURPOSE: Administration of Adriamycin (ADR) in utero to pregnant rats
      (vaginal plug, day 0) on gestational days (GD) 6 to 9 resulted in the offspring
      having a cluster of malformations, including absence of bladder in 100% of cases.
      This study aimed to determine the critical timing of the embryological window in
      bladder development in this animal model. METHODS: Timed-pregnant rats were
      divided randomly and injected intraperitoneally with ADR at 2 mg/kg on GD 6 to 9;
      GD 7 to 10; GD 8 to 11; GD 9 to 12; GD 6,8, and 9 (missing GD 7); and GD 6, 7,
      and 9 (missing GD 8). The control group received saline. Fetuses were harvested
      near term on GD 21 and dissected under a dissecting microscope and examined for
      gross anorectal and urogenital anomalies. RESULTS: Administration of ADR on GD 6
      to 9 (n = 63); GD 7 to 10 (n = 42); and GD 6, 7, and 9 (n = 35) resulted in 100%,
      83%, and 77% bladder agenesis respectively, in contrast with 53% and 26% on GD 8
      to 11 (n = 36) and GD 6, 8, and 9 (n = 49), respectively. The control (n = 52)
      and the GD 9 to 12 (n = 27) groups all had normal bladder development. The
      proportion of other urogenital and anorectal anomalies mirror that of bladder
      agenesis. CONCLUSION: The results showed GD 7 to be the critical embryological
      timing in which bladder development can be affected by ADR, possibly by targeting
      the gene that is expressed in the embryonic bladder during this narrow time
      interval.

PMID- 10591561
TI  - Enhanced metastasis after local therapy in a murine model using C-1300
      neuroblastoma.
AB  - BACKGROUND/PURPOSE: In the treatment of advanced neuroblastoma, the role of
      surgery has been controversial. This study was carried out to determine the
      effect of surgery, irradiation, and chemotherapy in inhibiting or promoting
      distant metastases. METHODS: Transplanted C-1300 neuroblastomas in hind legs of
      syngeneic mice were treated by surgery, radiation, and chemotherapy. The liver
      was evaluated 18 days after each treatment modality for metastases. RESULTS: Mice
      developed no liver metastasis when leg tumors received no treatment or
      chemotherapy. In the mice who had the tumor resected, liver metastases were found
      in 8 of 16 mice that had 7-mm tumors. One hundred percent of the mice that had 9-
      or 12-mm tumors presented with metastases to the liver. In mice who received
      radiation therapy, 100% had liver metastases. CONCLUSIONS: Local control by
      surgery and single-dose radiation induced liver metastasis in a murine model.
      Surgery to remove tumors should be used in conjunction with chemotherapy to
      prevent secondary liver metastases.

PMID- 10591563
TI  - Fetal stabilization for antenatally diagnosed diaphragmatic hernia.
AB  - BACKGROUND/PURPOSE: Infants with congenital diaphragmatic hernia have pulmonary
      hypoplasia resulting in persistent pulmonary hypertension of neonates (PPHN),
      which is the main contributor to both high mortality and morbidity. The pulmonary
      artery bed in patients with congenital diaphragmatic hernia (CDH) is
      underdeveloped and is very sensitive to slight stimuli. It is, therefore, vital
      to avoid any factors that might increase pulmonary vascular resistance during the
      perinatal treatment of these patients. Recently, fetal anesthesia for perinatal
      stabilization in patients with CDH has been reported. However, the efficacy of
      this method remains controversial. The aim of this study is to analyze the
      benefits of fetal stabilization using fetal anesthesia in patients with CDH.
      METHODS: The authors have seen 9 cases of antenatally diagnosed CDH and attempted
      fetal stabilization. The indication for fetal stabilization was a lung thoracic
      ratio of less than 0.2, without any severe associated anomalies. The protocol for
      fetal stabilization was (1) monitoring the fetal respiratory movement and heart
      beat by ultrasonography, (2) the administration of morphine (20 to 30 mg) and
      diazepam (5 mg) to the mother, (3) the confirmation of any interruptions in fetal
      movement followed by a cesarean section, (4) pancuronimum (0.5 mg) was given
      through the umbilical vessels, (5) intubation before clamping of the umbilical
      cord, and (6) high-frequency oscillatory ventilation (HFO) without bagging.
      RESULTS: The lung-thratic ratio (LTR) was between 0.06 to 0.17 (average, 0.10+/
      0.04). Operation was performed in 7 of 9 patients at between 2.5 and 27 hours
      after birth. The overall survival rate was 66.7% (6 of 9). All of the patients
      who underwent operation within 5 hours after birth survived. CONCLUSIONS:
      Perinatal stabilization using fetal anesthesia was found to be effective in
      preventing PPHN and shortening the period of preoperative stabilization. It also
      improved the survival rate of patients with severe CDH.

PMID- 10591564
TI  - Ingested ring-pull causing bronchoesophageal fistula and transection of the left
      main bronchus: successful salvage of the left lung and esophagus five years after
      injury.
AB  - A 6-year-old girl with a history of ingestion of a ring-pull of a can and a
      transient episode of stridor had been asymptomatic 3 years before admission when
      left lung atelectasis with severe respiratory distress developed. Fluoroscopy and
      3-dimensional computed tomography scan showed bronchoesophageal fistula and the
      ring-pull around the left main bronchus. At operation, the ring-pull, which
      transected the left main bronchus, was extracted. The left main bronchus was
      reconstructed by end-to-end anastomosis in spite of insufficient inflation of the
      collapsed left lung. The esophageal defect was repaired. The patient's
      respiratory distress gradually disappeared, and the x-ray films 3 months after
      operation showed complete expansion of the left lung. This case shows the risk of
      the long-term retained esophageal foreign body and the possibility of pulmonary
      salvage after long-term total atelectasis of the lung.

PMID- 10591565
TI  - Contralateral reflux after unilateral ureteral reimplantation--preexistent rather
      than new-onset reflux.
AB  - PURPOSE: The authors studied the preoperative Technetium 99m-dimercaptosuccinic
      acid renal scan (DMSA) of patients undergoing unilateral vesicoureteral
      antireflux surgery to compare the amount of renal scarring between the refluxing
      and the contralateral renal units. They sought to determine whether postoperative
      contralateral vesicoureteral reflux was preexistent or new onset. METHODS: Sixty
      eight patients who underwent unilateral vesicoureteral antireflux surgery and had
      preoperative DMSA and postoperative voiding cystourethrography (VCUG)
      examinations were studied. Preoperative DMSA results were analyzed to determine
      the amount of renal scarring in each kidney. RESULTS: Sixty-four (94.1%)
      ipsilateral refluxing renal units had renal scars. Of the 68 contralateral renal
      units, scars were noted in 28 (41.2%). The rate of nonscar was 4 of 68 (5.9%) in
      reflux kidneys, which was significantly lower than 40 of 64 (62.5%, excluding 4
      with a history of resolved reflux) in nonreflux kidneys (P<.001). Of 40
      contralateral nonscarred kidneys, 1 of 40 (2.5%) had subsequent reflux, which was
      significantly lower than 5 of 28 (17.9%) of scarred kidneys (P<.005). Six
      patients (8.8%) had contralateral reflux, and 1 of them had a history of resolved
      reflux. Of the 6 contralateral kidneys with severe scarring involving 3 poles or
      contracted, 4 of 6 (66.7%) had subsequent reflux. CONCLUSIONS: Scar in the
      contralateral kidney seen on DMSA scan seems to predict contralateral reflux
      after unilateral antireflux surgery. The contralateral reflux may be preexistent.
      Postoperative VCUG should be performed routinely for patients who have
      contralateral renal scars. In patients with a history of contralateral reflux or
      severe contralateral renal scar, simultaneous contralateral ureteral
      reimplantation should be considered.

PMID- 10591566
TI  - Repair of hypospadias complications using the tubularized, incised plate
      urethroplasty.
AB  - BACKGROUND/PURPOSE: Secondary procedures to correct complications after
      hypospadias repair remain challenging especially for "hypospadias cripples." The
      tubularized, incised plate urethroplasty was first introduced by Snodgrass for
      the repair of primary hypospadias in 1993. The authors used this procedure to
      correct the complications after hypospadias repair in patients who had no
      abundant local skin flaps to be used for a neourethra. METHODS: Six patients
      underwent tubularized, incised plate urethroplasty for the correction of
      complications of hypospadias repair performed the previous year, including a
      large urethrocutaneous fistula (n = 1) and disruption of the neourethra (n = 5).
      Prior surgical procedures included transverse island tube urethroplasty in 4
      cases and 2-stage urethroplasty in 2 cases. The average patient age at the time
      of secondary procedure was 4.6 years (range, 1 to 12 years). RESULTS: The mean
      follow-up period was 6 months (range, 2 months to 1 year). All the patients
      obtained a functional neourethra with a vertical, slitlike meatus. A small
      fistula developed in one child and mild meatal retraction in another.
      CONCLUSIONS: The tubularized, incised plate urethroplasty offers few
      complications and good cosmetic results. The authors recommend its use for
      patients who have had repeated surgeries for hypospadias repair, especially those
      in whom only limited local skin flaps can be utilized for a neourethra.

PMID- 10591567
TI  - Laparoscopic bladder 'wrap' technique for repair of vesicoureteric reflux in a
      porcine model.
AB  - PURPOSE: The aim of this study was to determine if vesicoureteric reflux (VUR)
      can be successfully corrected laparoscopically by a bladder "wrap" technique in a
      pig model. METHODS: In 15 female piglets (mean weight, 22.5 kg) bilateral VUR was
      created by an open technique (11 grade 3, 2 each of grades 2 and 4). Eight weeks
      later (range, 4to 16 weeks) VUR was confirmed by fluoroscopic cystogram, and
      unilateral laparoscopic correction was performed. The contralateral ureter was
      used as a control. The bladder was emptied, and a 3F ureteric catheter was
      inserted on the repair side. Four 11-mm ports were inserted transperitoneally.
      The ureter was dissected to the ureterovesical junction (UVJ). Commencing at the
      UVJ, 2 (n = 9) or 3 (n = 6) black silk sutures were placed through the bladder
      muscle on either side of the ureter creating a bladder wrap around the distal 2
      to 4 cm of ureter. At a mean of 16 weeks (range, 4 to 24 weeks) cystograms were
      repeated. The animals were killed the bladder and ureters underwent
      histopathology examination. RESULTS: VUR was corrected in 12 animals (80%). There
      was persistence of VUR in 2 and ureteric obstruction in 1. The wrap was intact in
      all animals. CONCLUSIONS: Laparoscopic correction of VUR by the bladder wrap
      technique is successful in pigs. Long-term follow-up studies will determine if
      this will be a satisfactory alternative surgical treatment for correction of VUR
      in children.

PMID- 10591568
TI  - Complications after sigmoidocolocystoplasty: review of 100 cases at one
      institution.
AB  - BACKGROUND/PURPOSE: The aim of this study was to review complications after
      sigmoidocolocystoplasty (SCP) performed at a single institution from 1984 to
      1997. METHODS: The medical records of 100 patients who underwent SCP were
      reviewed retrospectively. RESULTS: Mean age at SCP was 10.8 years. Urinary
      control was improved in 75 cases and unchanged in 25. Post-SCP complications
      included death, abdominal wound infection or dehiscence, adhesive bowel
      obstruction, vesical calculi, vesicocolonic anastomosis stenosis, metabolic
      acidosis, and transient renal hypertension. Fifty-one patients underwent ureteric
      re-implantation (URI) at the time of, or before, SCP, and 7 had recurrence of VUR
      post-URI (spontaneous regression in 6); 3 patients had new onset of contralateral
      VUR post-URI (spontaneous regression in 2). Transient pleural effusion was seen
      after reinsertion of ventriculo-pleural shunts to ventriculo-thoracic in 12
      cases, but there was no incidence of infection. Squamous metaplasia of the
      bladder mucosa was identified in 5 patients on routine mucosal biopsy results but
      resolved in all cases after regular bladder irrigation was commenced.
      Preoperative constipation or fecal incontinence was better managed after
      sigmoidectomy in approximately one third of cases (38%). CONCLUSIONS: SCP with or
      without URI can improve the quality of life of patients with neurogenic or small
      capacity bladder, but it can be associated with long-term complications. Regular
      bladder irrigation is recommended to maintain bladder mucosa integrity.

PMID- 10591569
TI  - The pathogenesis of dysplastic kidney in a urinary tract obstruction in the
      female fetal lamb.
AB  - BACKGROUND/PURPOSE: The type of renal dysplasia resulting from obstructive
      uropathy depends on the completeness of the obstruction and its timing with
      respect to the stage of glomerulogenesis at the time of the obstruction. The
      authors created a successful obstructive uropathy model in the female fetal lamb
      to demonstrate the differing pathogenesis of renal dysplasia. METHODS: Female
      fetal lambs at 60 and 90 days' gestation had their urethra and urachus ligated
      transabdominally and were delivered by cesarean section at 145 days (full term).
      Kidney length and cortical thickness were measured, and samples were examined
      histologically. In the lambs operated on at 90 days, the urine was collected at
      delivery and Na and CI were measured and compared with the results obtained from
      normal full-term lambs. RESULTS: Seven of 10 female lambs had hydronephrosis or
      dysplastic kidneys. The cortext to kidney length ratio was 10+/-3% in the 90-days
      hydronephrotic group versus 29+/-6% in the controls (P<.001). Morphologically,
      the 90-day model had dilatation of the collecting tubules with normal glomerular
      numbers. The 60-day model had tubular cysts with fibromuscular cuffing and
      reduced glomerular numbers. The fetal urine Na was 47+/-3.3 mmol/L in controls
      versus 78+/-24 mmol/L in the hydropnephrotic lambs (P<.05). The urine CI in these
      lambs was 38+/-8.6 mmol/L in controls versus 55+/-14.5 mmol/L in the
      hydronephrotic lambs (P<.05). CONCLUSIONS: An obstructive uropathy model was
      created in female fetal lambs. There were no dysplastic changes in the kidneys in
      lambs operated on at 90 days' gestation, but there were definite dysplastic
      changes in those operated on at 60 days. Concentrations of Na and CI in the fetal
      urine are higher than normal in the 90-day model.

PMID- 10591570
TI  - Malignant transformation of mesenchymal hamartoma of the liver: case report and
      review of the literature.
AB  - Here the first case in the literature of both mesenchymal hamartoma and malignant
      mesenchymoma occurring in a 6-year-old male child, at different times and at
      different sites in the liver, and also the possible malignant transformation of a
      mesenchymal hamartoma is reported. The tumor developed from a lesion in the right
      lobe that was overlooked initially during a left lateral segmentectomy at 18
      months of age for a mesenchymal hamartoma. Malignant mesenchymoma is a rare and
      aggressive tumor. The origin of this tumor is not well understood. There has been
      no direct support to the hypothesis that malignant mesenchymoma may be the
      malignant counterpart of mesenchymal hamartoma. The authors provide clinical and
      histopathologic evidence in our case that suggests the possibility of malignant
      mesenchymoma arising from a mesenchymal hamartoma. This case emphasizes the need
      for complete removal of mesenchymal hamartoma and the need for long-term follow
      up to detect multifocal lesion or malignant transformation.

PMID- 10591571
TI  - Biliary atresia associated with congenital structural anomalies.
AB  - BACKGROUND/PURPOSE: Although biliary atresia (BA) is rarely associated with other
      congenital anomalies, the presence of a distinct subgroup of patients with
      accompanying structural anomalies such as situs inversus, polysplenia, or portal
      vein anomalies has been postulated. The authors present 7 patients with this
      association. METHODS: Of 87 patients with BA treated in the past 19 years, 7
      (8.0%) have had multiple congenital structural anomalies. RESULTS: These
      anomalies included situs inversus in 4, polysplenia in 5, preduodenal portal vein
      in 5, absent portal vein in 1, absent inferior vena cava in 2, malrotation of the
      intestine in 5, and congenital heart disease in 3 patients. In these 7 patients,
      hepatic portoenterostomy (HPE) was performed at the age from 63 to 158 days with
      an average of 92 days. The porta hepatis was abnormal in position in 1 patient.
      The connective tissue at the porta hepatis was diminished in 6 patients.
      Histologically, liver fibrosis was mild in 2 and moderate in 5 patients. Bile
      excretion was good initially in all patients but gradually diminished in 5
      patients. Five patients had multiple episodes of cholangitis, followed by sepsis,
      liver failure, or cardiac failure and subsequently died at the age from 2 months
      to 6 years. Of the other 2 patients who underwent HPE recently, 1 is doing well
      and the other has had one episode of cholangitis. CONCLUSIONS: BA in association
      with other congenital structural anomalies may have a poor prognosis. These
      patients have poor bile secretion after HPE mainly because of delayed operation.

PMID- 10591572
TI  - Management of Hirschsprung's disease with reference to one-stage pull-through
      without colostomy.
AB  - BACKGROUND/PURPOSE: The authors evaluated the safety and benefits of 1-stage pull
      through in comparison with staged repair of Hirschsprung's disease under
      circumstances prevailing in a developing country. METHODS: Forty-nine patients
      were treated for Hirschsprung's disease during a 7-year period between January
      1991 and March 1998 at our institution, which is a tertiary referral center. Nine
      patients were excluded from the study, and the medical records of the remaining
      40 patients were reviewed. RESULTS: Eighteen patients including 7 neonates
      underwent 1-stage pull-through, and 22 patients underwent staged correction.
      There was no mortality for patients undergoing one-stage treatment, but there was
      1 death caused by anastamotic leak after a 2-stage repair. There was no
      substantial difference in the incidence of complications (38.8% v 45.45%) and the
      need for additional surgical procedures (33.5% v 45.45%) between the 2 groups.
      Seventy-one percent after 1-stage treatment and 80% after staged treatment had a
      satisfactory functional result, and the incidence of incontinence was 14% and
      10%, respectively. Overall, the incidence of postoperative enterocolitis was low
      (7.5%). CONCLUSIONS: One-stage correction of Hirschsprung's disease is a safe
      procedure in all age groups. It offers economical and social advantages to
      families in developing countries. Benefits of 1-stage treatment include avoidance
      of multiple operations, elimination of complications associated with a colostomy,
      shorter duration of hospital stay, and completion of treatment at an earlier age.
      It is advisable to continue postoperative anal dilatation for a minimum period of
      6 months to 1 year to reduce the incidence of enterocolitis.

PMID- 10591573
TI  - Nonoperative management of solid organ injuries in children results in decreased
      blood utilization.
AB  - BACKGROUND: The administration of blood products to injured children has been
      recognized as a potential risk of nonoperative management. The purpose of this
      study was to evaluate blood utilization in the management of solid organ injuries
      in pediatric blunt abdominal trauma victims. METHODS: One hundred sixty-one
      children (< or =16 years old) with solid organ injuries over an 8-year study
      period (1990 through 1997) were identified from the trauma registries at 2 urban
      regional trauma centers. RESULTS: Mean age of the study patients was 7.9+/-0.4
      years, 95 (59%) were boys, and their mean injury severity score (ISS) was 17.8+/
      1.2. Patients were divided into 4-year study cohorts (1990 through 1993 and 1994
      through 1997) to examine changes in operative management and blood utilization.
      For each time period examined, those treated nonoperatively received fewer blood
      transfusions (46% v 9% and 44% v 13%, P<.05 by Fisher's Exact test), and the
      hospital length of stay was shorter (12.3+/-2.1 v 5.0+/-0.7 and 7.8+/-1.9 v 4.2+/
      0.4 days, P<.0001 by analysis of variance/Scheffe's) compared with the laparotomy
      cohort. CONCLUSIONS: The appropriate nonoperative management of injured children
      actually reduces the risks of receiving blood transfusion and decreases the
      length of hospital stay compared with aggressive operative intervention. Blood
      transfusion should be reserved only for those injured children with solid organ
      injuries who are hemodynamically unstable.

PMID- 10591574
TI  - Clinical recognition and management of pediatric blunt abdominal trauma without
      ultrasound or computed tomography scan in community hospitals in Mexico.
AB  - PURPOSE: The aim of this study was to characterize the evaluation and clinical
      course of children with blunt abdominal trauma in second-level hospitals.
      METHODS: The authors reviewed the medical records of children, age 1 to 17 years,
      admitted with blunt abdominal trauma between the years 1988 to 1998. The initial
      evaluation included a Pediatric Trauma Score (PTS) ABCD clinical assessment,
      resuscitation, diagnostic peritoneal lavage (DPL), Glasgow Coma Scale (GCS), x
      ray, and laboratory values. Surgical indications included active bleeding,
      perforated hollow viscus, or traumatic diaphragmatic hernia. Sixty-four children
      with blunt abdominal trauma were divided into 4 major groups: group I, obtunded
      children who required abdominal surgery; group II, obtunded children that did not
      require abdominal surgery; group III, responsive children that required abdominal
      surgery; group IV, responsive children that did not require abdominal surgery.
      RESULTS: Analyses of each group determined that the PTS, the GCS, and ABCD
      assessments accurately reflected the degree of injury and outcome. Jointly with
      DPL they may obviate the need of ultrasound and CT scan in hospitals of second
      level that do not have access to these resources. CONCLUSIONS: Recognition of
      blunt abdominal trauma in children may be complicated by associated multisystem
      injury. Systematic evaluation minimizes missed diagnosis and facilitates rapid
      and effective treatment. The benefit of data acquired from a good ABCD
      assessment, PTS, GCS, clinical and radiological, and DPL evaluation, facilitates
      the decision to conduct a rapid laparotomy, and they help to predict the outcome
      of this kind of patient.

PMID- 10591575
TI  - Surgical repair of rectovestibular fistula with normal anus.
AB  - PURPOSE: The aim of this study was to evaluate the authors' surgical approach and
      technique in patients with congenital rectovestibular fistula with a normal anus
      (CRF). METHODS: During the period between 1981 and 1995, 19 girls from 2 months
      to 13 years of age were treated surgically for CRF by a primary perineal
      approach. After appropriate bowel preparation, the patient was placed in a
      lithotomy position. A probing catheter was placed in the fistula. A perineal
      transverse skin incision was made on the midpoint between the posterior
      commissure and the anus, and the underlying tissue was dissected. The fistula was
      divided, and the both ends were closed by interrupted sutures. The external
      sphincter muscle was mobilized to interpose between the vestibular and rectal
      stumps of the fistula. Postoperative feeding was begun on day 6. RESULTS: A
      protecting colostomy was created in the early 4 patients. Fifteen patients
      underwent a primary fistula division without colostomy. In those without
      colostomy, 1 patient had a reopening of the fistula 6 days after the primary
      repair. In this patient, colostomy was created, and the fistula was divided 6
      months later by the same approach. After a follow-up of 3 to 17 years, all
      patients have normal bowel habit. CONCLUSION: A primary perineal approach is
      appropriate for the treatment of CRF.

PMID- 10591576
TI  - The ultrasonographic 'triangular cord' coupled with gallbladder images in the
      diagnostic prediction of biliary atresia from infantile intrahepatic cholestasis.
AB  - PURPOSE: The aim of this study was to evaluate the importance of the
      ultrasonographic "triangular cord" (TC) coupled with gallbladder images in the
      diagnostic prediction of biliary atresia (BA) from infantile intrahepatic
      cholestasis. METHODS: Seventy-nine infants with cholestatic jaundice underwent
      ultrasound examinations, focusing on the TC and gallbladder images. The TC was
      defined as visualization of a triangular or bandlike periportal echogenicity (3
      mm or greater in thickness), which represents a cone-shaped fibrotic mass cranial
      to the portal vein in infants with BA. An abnormal gallbladder (nonvisualized or
      small) was thought to be more suggestive of BA than infantile intrahepatic
      cholestasis. RESULTS: Among 25 infants with BA, 21 showed TC, whereas 4 had no
      TC. Fifty-three of 54 infants with infantile intrahepatic cholestasis had no TC,
      showing a diagnostic accuracy of 94% with 84% sensitivity and 98% specificity. As
      for positive predictive value in the diagnosis of BA by the TC coupled with
      gallbladder images, it was 100% when a positive TC was coupled with an abnormal
      gallbladder and 88% when a positive TC was coupled with a normal gallbladder. It
      decreased to 25% when a negative TC was coupled with an abnormal gallbladder.
      CONCLUSIONS: The TC appears to be a very specific and definite ultrasonographic
      finding in the early diagnosis of BA. Positive TC regardless of gallbladder
      images is highly suggestive of BA, showing a 95% positive predictive value, but
      BA cannot be ruled out when negative TC is coupled with an abnormal gallbladder,
      requiring further diagnostic modalities such as liver needle biopsy or
      hepatobiliary scintigraphy.

PMID- 10591577
TI  - Fifteen years' experience with an antirefluxing biliary drainage valve.
AB  - PURPOSE: The aim of this study was to examine the efficacy of the antirefluxing,
      mucosal-flap valve (AMFV) for biliary drainage relative to technical feasibility,
      surgical complications, and incidence of ascending cholangitis (AC). METHODS:
      Twenty-seven infants requiring biliary tract reconstruction underwent valve
      construction. Twenty biliary atresia (BA) patients received the Kasai procedure,
      and 7 choledochal cyst (CC) infants had cystectomy and hepatoenterostomy. A
      retrospective review of all patients was performed including radiographic
      evaluation of the current valve function in 10 patients. RESULTS: Construction
      was successful in all cases, and no morbidity was incurred by incorporation of
      the valve. Of 7 CC patients, there have been no known episodes of AC with mean
      follow-up of 4.4+/-4.2 years. Of 20 BA patients, there have been 5 deaths (25%),
      7 liver transplants (35%), 2 (10%) lost to follow-up, and 6 (30%) survivors. Nine
      BA patients (45%) have had AC, with patients in all 4 outcome categories
      represented. Ten patients (5 CC and 5 BA) have been evaluated with barium small
      bowel radiographs, with no reflux to the liver hilum in all cases. CONCLUSIONS:
      The AMFV has caused no morbidity and continues to prevent reflux to the liver
      hilum. Despite functioning as designed, it does not appear to influence the
      occurrence of AC. Because CC patients had no AC, we feel that infection is
      related to the underlying atresia rather than to reflux.

PMID- 10591579
TI  - Liver transplantation in infants.
AB  - PURPOSE: In view of the earlier reports that children below 1 year of age
      constitute a high-risk group for liver transplantation, the authors reviewed
      their experience in performing orthotopic liver transplantation in this age
      group. METHODS: The records of 9 children aged less than 1 year who underwent 6
      living-related liver transplants and 3 reduced-size liver transplants between
      December 1993 and June 1997 were reviewed. RESULTS: Five reexplorations were
      required for 3 children who had 1 or more of the following early complications:
      bleeding from hepatic vein to inferior vena cava anastomosis (n = 1), right
      hepatic vein stump bleeding (n = 1), intraabdominal hematoma (n = 2), jejuno
      jejunostomy leakage (n = 1), and colonic perforation (n = 1). Late complications
      include stricture at the biliary-enteric anastomosis requiring percutaneous
      balloon dilatation (n = 3) and hepatitis of undetermined etiology requiring
      retransplantation (n = 1). There was no hepatic artery thrombosis despite the
      small arteries available for anastomosis. Follow-up ranged from 19 to 61 months
      (mean, 40 months). Patient survival rate was 100%, and graft survival with good
      liver function was 89%. All living donors, 2 fathers and 4 mothers, are well.
      CONCLUSIONS: Liver transplantation in infants less than 1 year of age is
      technically demanding but feasible and still can be performed with a good
      outcome. Age alone (under 1 year) should not be considered as a contraindication
      for liver transplantation.

PMID- 10591578
TI  - Bile ductular proliferation as a prognostic factor in biliary atresia: an
      immunohistochemical assessment.
AB  - PURPOSE: The correlation between the histological findings of the intrahepatic
      biliary epithelium and postoperative bile drainage in biliary atresia (BA) was
      investigated. METHODS: The patients with BA were classified into 2 groups,
      consisting of a good bile drainage group (GBD, n = 14, mean age at initial
      operation, 57.6+/-18.0 days) and a poor bile drainage group (PBD, n = 11, mean
      age at initial operation, 86.9+/-42.7 days). Liver specimens from an initial
      Kasai's operation were examined by immunostaining using anticytokeratin 7 (CK7)
      antibody and anti-MIB-1 antibody. The number of CK7-positive cells in the bile
      ductules was microscopically calculated within the 40-microm-thick interstitium
      along the limiting plate (LP), and the CK7-positive cell number per unit length
      of the LP was estimated. In addition, the MIB-1 index in bile ductules also was
      determined. RESULTS: The number of CK7-positive cells in PBD was significantly
      higher than that in GBD (167.6+/-45.6 v 117.8+/-32.4/ mm, P<.05). However, the
      MIB-1 index in biliary cells did not differ between the 2 groups. CONCLUSION: An
      increased number of intrahepatic bile duct epithelial cells in liver specimens at
      the initial operation may be a poor prognostic factor in BA and appears to depend
      on the duration of bile stasis rather than the degree of bile stasis.

PMID- 10591580
TI  - Venous ischemia as a cause of ureteral necrosis in transplanted ureters.
AB  - BACKGROUND: Urologic complications after pediatric renal transplantation can
      adversely effect the outcome and may result in decreased graft survival. Efforts
      to prevent these complications are worthwhile. This study investigates the
      incidence of these complications in a clinical transplant program and reports on
      an animal model used to investigate one possible cause. METHODS: In the clinical
      study, the results of a pediatric renal transplant program at a large children's
      hospital for a 5(1/2)-year period were reviewed with special attention paid to
      patients suffering ureteral necrosis. In the experimental study, 9 swine
      underwent laparotomy, bilateral complete infrahilar ureteric dissection, and
      extravesical ureteroneocystostomy. On the left side only, the renal and adrenal
      veins were ligated. The arterial supply remained intact. The right side did not
      undergo vessel ligation and served as the control. Three pigs each were killed at
      3, 8, and 15 days. Kidneys, ureters and a cuff of bladder were examined
      histologically. RESULTS: In the clinical study 75 renal transplants were
      performed with a total of 5 cases of early ureteral necrosis. Two of these 5
      displayed venous congestion and ischemia, and 2 were associated with kidneys
      displaying primary nonfunction of the graft. Seventy-one of 75 grafts are
      continuing to function. One of the 4 early graft losses also had an ischemic
      ureter. In the experimental study all right kidneys and ureters were normal. All
      left kidneys had complete hemorrhagic necrosis. Necrosis also was found in 5 of 9
      proximal left ureters and in 7 of 9 distal left ureters. Viable left ureters
      displayed moderate to severe submucosal and periureteric hemorrhage. Four of 9
      ureters displayed more damage distally than proximally. The extent of necrosis
      was similar at 3, 8, and 15 days. CONCLUSION: In both clinical and experimental
      studies, venous congestion and subsequent ischemia have been shown to be
      important causes of ureteral necrosis after renal transplantation.

PMID- 10591581
TI  - The treatment of imperforate anus: experience with 108 patients.
AB  - BACKGROUND/PURPOSE: The authors present their experience and results in the
      treatment of infants with imperforate anus over a 10-year period. Differences
      between these and previously published western results are noted and discussed.
      METHODS: One hundred eight patients with imperforate anus were treated from June
      1988 to July 1998. Of these patients, 66 were boys and 42 were girls. Associated
      anomalies include congenital heart disease, anomalies of bone and cartilage, and
      Down's syndrome. Thirty-five patients with a low lesion received a limited
      posterior sagittal anorectoplasty. Seventy-one patients had a high lesion and
      received 3-staged operations including colostomy, posterior sagittal
      anorectoplasty, and takedown of colostomy. All patients underwent follow-up by
      the author. Postoperative anorectal function was evaluated based on the following
      criteria: ability to have voluntary bowel movement, soiling, and constipation.
      The duration of follow-up ranges from 6 months to 10 years. RESULTS: One patient
      died of multiple congenital anomalies after colostomy. One patient died of
      hyaline membranous disease. All except 2 patients had voluntary bowel movement.
      Three patients had soiling, and 19 suffered from constipation after operation.
      The constipation improved with medical treatment and time. Four patients who
      received the first operation at another hospital (3 underwent posterior sagittal
      anorectoplasty and 1 had cutback anoplasty) had problems with soiling. In these
      patients, soiling improved after redo posterior sagittal anorectoplasty.
      CONCLUSIONS: Utilizing the posterior sagittal operation described by Pena, most
      patients were continent and able to have voluntary bowel movements. Constipation
      occurred in a substantial number of patients with high-type lesions, but few of
      these patients needed medication or enemas. There were significantly fewer sacral
      and urogenital anomalies than have been reported in most western series. This may
      explain the excellent results.

PMID- 10591582
TI  - Y-appendicoplasty: a technique to minimize stomal complications in antegrade
      continence enema.
AB  - PURPOSE: The antegrade continence enema (ACE) is an effective method of treatment
      of fecal incontinence and constipation. However, the original procedure described
      is not easy to perform and is associated with a high complication rate,
      especially stomal stenosis-necrosis (55%). Even with introduction of orthotopic
      appendicostomy, composite series still report an incidence of 30% with stomal
      problems. The authors report a virtually complication-free simple modification,
      the Y-appendicoplasty. METHODS: The base of the appendix is imbricated into cecum
      by 2 successive rows of interrupted seromuscular stitches. A small Y-shaped
      incision is made on the abdominal wall at McBurney's point, and 3 triangular skin
      flaps are raised. The appendix is brought out of the skin incision. The tip is
      excised, and 3 vertical cuts are made 120 degrees apart. The 3 appendiceal flaps
      thus created are interdigitated with the skin flaps using interrupted sutures.
      RESULTS: Twelve children underwent Y-appendicoplasty and orthotopic
      appendicostomy. Mean operating time was 1 hour. None experienced stomal
      complications that required intervention. Control of fecal continence with ACE
      ranged from excellent to good. CONCLUSION: Y-appendicoplasty and orthotopic
      appendicostomy minimizes complications for ACE and is easy to perform.

PMID- 10591583
TI  - Nonoperative management of blunt pancreatic injury in childhood.
AB  - PURPOSE: Nonoperative management for blunt pancreatic injury in children was
      performed between 1977 and 1998. The efficiency and safety of nonoperative
      management was examined. METHODS: Pancreatic injury was diagnosed in 20 children.
      The surgical indication was determined by hemodynamic instability and the
      management of associated injuries. Children without surgical indications were
      treated initially by nonoperative management. RESULTS: Nineteen of 20 children
      were treated initially nonoperatively, and 18 of the 19 survived. Surgical
      exploration was performed in only 1 child with perforation of the duodenum and
      bile duct. One child died of complications of total parenteral nutrition.
      Ultrasound scan and computed tomography scan showed pancreatic contusion in 9,
      laceration in 6, and injury of the main pancreatic duct (MPD) in 5. Pseudocysts
      were detected in 10 (5 laceration and 5 MPD injury). Pseudocysts smaller than 10
      cm disappeared after nonoperative management, and those larger than 10 cm
      required operative management. Rupture of pseudocysts occurred in 2 children by
      rotating the upper torso. CONCLUSIONS: Nonoperative management of pancreatic
      injuries is effective in children, although careful management is required to
      avoid complications. Pseudocysts smaller than 10 cm were treated successfully by
      nonoperative management, and those larger than 10 cm required surgical
      management.

PMID- 10591584
TI  - Adverse outcome of congenital diaphragmatic hernia is determined by diaphragmatic
      agenesis, not by antenatal diagnosis.
AB  - BACKGROUND/PURPOSE: The authors studied their congenital diaphragmatic hernia
      (CDH) cases retrospectively to ascertain if classical CDH and diaphragmatic
      agenesis (DA) have separate clinical manifestations, whether antenatally
      diagnosed cases behave differently from those not diagnosed antenatally, and if
      antenatal diagnosis before 25 weeks carries a worse prognosis. METHODS: The
      authors performed a retrospective review of 23 infants with CDH treated at their
      institution between January 1996 and March 1999. The patients were divided into 3
      groups that were analyzed: DA and classical CDH, antenatally diagnosed and
      nonantenatally diagnosed, and antenatally diagnosed before 25 weeks and after 25
      weeks. RESULTS: There were 8 cases of DA and 11 cases of classical CDH. Four
      infants died without operation and could not be classified. Neonates with DA had
      significantly longer mean duration of preoperative stabilization compared with
      classical CDH (5.25+/-2.76 days v 1.36+/-1.0 days) and postoperative mechanical
      ventilatory support (15.7+/-3.0 days v 4.9+/-3.0 days). Fifty percent of DA
      patients died; all classical CDH patients survived. Twelve cases were diagnosed
      antenatally, 6 before 25 weeks' gestation. Antenatally diagnosed cases had no
      statistically significant difference in mortality rates from those not diagnosed
      antenatally; 50% of those diagnosed before 25 weeks survived. CONCLUSIONS: DA
      cases require more preoperative preparation and postoperative ventilation and
      have a bad prognosis compared with classical CDH. Antenatal diagnosis of CDH does
      not convey a different prognosis. Fifty percent of CDH patients with antenatal
      diagnosis before 25 weeks survive.

PMID- 10591585
TI  - Alcohol and aldehyde dehydrogenase gene polymorphisms influence susceptibility to
      esophageal cancer in Japanese alcoholics.
AB  - BACKGROUND: Studies have consistently demonstrated that inactive aldehyde
      dehydrogenase-2 (ALDH2), encoded by ALDH2*1/2*2, is closely associated with
      alcohol-related carcinogenesis. Recently, the contributions of alcohol
      dehydrogenase-2 (ADH2) polymorphism to alcoholism, esophageal cancer, and the
      flushing response have also been described. METHODS: To determine the effects of
      ALDH2 and ADH2 genotypes in genetically based cancer susceptibility, lymphocyte
      DNA samples from 668 Japanese alcoholic men more than 40 years of age (91 with
      and 577 without esophageal cancer) were genotyped and the results were expressed
      as odds ratios (ORs). This study also tested 82 of the alcoholics with esophageal
      cancer to determine whether cancer susceptibility is associated with patients'
      responses to simple questions about current or former flushing after drinking a
      glass of beer. RESULTS: The frequencies of ADH2*1/2*1 and ALDH2*1/2*2 were
      significantly higher in alcoholics with, than in those without, esophageal cancer
      (0.473 vs. 0.289 and 0.560 vs. 0.099, respectively). After adjustment for
      drinking and smoking, the analysis showed significantly increased cancer risk for
      alcoholics with either ADH2*1/2*I (OR = 2.03) or ALDH2*1/2*2 (OR = 12.76). For
      those having ADH2*1/2*1 combined with ALDH2*1/2*2, the esophageal cancer risk was
      enhanced in a multiplicative fashion (OR = 27.66). Responses to flushing
      questions showed that only 47.8% of the ALDH2*1/2*2 heterozygotes with ADH2*1/
      2*1, compared with 92.3% of those with ALDH2*1/2*2 and the ADH2*2 allele,
      reported current or former flushing. Genotyping showed that for alcoholics who
      reported ever flushing, the questionnaire was 71.4% correct in identifying
      ALDH2*1/2*2 and 87.9% correct in identifying ALDH2*1/2*1. CONCLUSION: Japanese
      alcoholics can be divided into cancer susceptibility groups on the basis of their
      combined ADH2 and ALDH2 genotypes. The flushing questionnaire can predict high
      risk ALDH2*1/2*2 fairly accurately in persons with ADH2*2 allele, but a reliable
      screening procedure for the highest risk gene combination (ADH2*1/2*1 and
      ALDH2*1/2*2) will require further investigation.

PMID- 10591586
TI  - Alcohol inhibition of cell adhesion in BMP-treated NG108-15 cells.
AB  - BACKGROUND: The L1 cell adhesion molecule is expressed as alternatively spliced
      neuronal and nonneuronal isoforms. We have reported that in transfected
      fibroblasts, ethanol variably inhibits cell-cell adhesion mediated by the
      nonneuronal isoform of human L1. In contrast, ethanol consistently inhibits
      morphogenetic changes and cell-cell adhesion in NG108-15 cells treated with OP-1
      (BMP-7), a powerful inducer of L1 and N-CAM gene expression. METHODS: All studies
      were performed by using NG108-15 cells cultured in serum-free medium. Cell
      morphology was assessed by a quantitative assay of cell clustering. Cell adhesion
      was measured by a short-term re-aggregation assay, and isoforms of L1 were
      characterized by RT-PCR and sequencing. RESULTS: We show that ethanol inhibits
      the morphogenetic effects of BMP-2, BMP-4, BMP-5, and BMP-6, each of which
      increases the expression of L1 and N-CAM. Pretreatment of NG108-15 cells with 25
      100 mM ethanol did not induce tolerance to ethanol's inhibition of OP-1
      morphogenesis or cell-cell adhesion. Ethanol or anti-L1 Fab fragments partially
      inhibited cell-cell adhesion in OP-1-treated NG108-15 cells. The combination of
      ethanol and Fab fragments did not inhibit cell-cell adhesion more than Fab
      fragments alone. As in L1-transfected fibroblasts, a series of n-alcohols
      displayed a cutoff between butanol and pentanol for inhibition of cell-cell
      adhesion in OP-1-treated NG108-15 cells. RT-PCR and direct sequencing revealed
      that the neuronal isoform was the sole or predominant L1 isoform in OP-1-treated
      NG108-15 cells. CONCLUSIONS: These data suggest that ethanol inhibits cell-cell
      adhesion in OP-1-treated NG108-15 cells by interacting directly or indirectly
      with the neuronal isoform of L1.

PMID- 10591587
TI  - MK-801-induced locomotor activity in long-sleep x short-sleep recombinant inbred
      mouse strains: correlational analysis with low-dose ethanol and provisional
      quantitative trait loci.
AB  - BACKGROUND: Low doses of the N-methyl-D-aspartate receptor (NMDAR) antagonist MK
      801 (dizocilpine) or ethanol increase locomotor activity to a lesser extent in
      long-sleep (LS), than in short-sleep (SS), mice. LS mice also have fewer brain
      [3H]MK-801 binding sites than SS mice. In this study, LSXSS recombinant inbred
      (RI) mice were used to investigate whether different NMDAR densities contribute
      to differential MK-801 activation and whether common genes are involved in
      initial sensitivity to MK-801-and ethanol-induced activation. METHODS: Locomotor
      activity was measured for 90 min after saline or MK-801 injection. Quantitative
      autoradiographic analysis of [3H]MK-801 binding was used to measure densities of
      NMDARs in seven brain regions. The ethanol (1-2 g/kg) activation scores from
      Erwin and colleagues (1997) were used for correlational analysis, as was their
      method for quantitative trait loci (QTL) analysis. RESULTS: Both saline and MK
      801 (0.3 mg/kg, given intraperitoneally) induced a continuum of locomotor
      responses across the LSXSS RI strains. There was a 4-fold range of MK-801
      difference scores (MK-801 score-saline baseline), with the RI 9 and RI 4 strains
      representing low and high responders, respectively. Dose-response experiments
      with these two strains confirmed that 0.3 mg/kg MK-801 produced significant
      activation, similar to previous results with LS and SS mice. However, unlike
      previous LS/SS results, lower densities of NMDARs were not observed in the RI 9
      than in the RI 4 mouse brains. No significant genetic correlations were observed
      between MK-801-induced and ethanol-induced responses in the LSXSS RI mice. Two
      provisional MK-801 activation QTLs were identified (p < 0.01) on chromosomes 11
      and 19, neither in common with those mapped for ethanol activation. CONCLUSIONS:
      Different densities of brain NMDARs are unlikely to account for the differential
      activation of LSXSS RI mice by MK-801. Additionally, in the RI mice either
      separate sets of genes regulate low dose MK-801- and ethanol-induced locomotor
      responses or the overlapping subset of genes controlling these two behaviors is
      small (< or =10%).

PMID- 10591588
TI  - Genetic association between chronic ethanol withdrawal severity and acoustic
      startle parameters WSP and WSR mice.
AB  - BACKGROUND: The present study examined the genetic association between chronic
      ethanol withdrawal severity and acoustic startle response (ASR) in replicated
      lines of mice selected for high (Withdrawal Seizure-Prone; WSP) and low
      (Withdrawal Seizure-Resistant; WSR) susceptibility to handling-induced
      convulsions after withdrawal from chronic exposure to ethanol. Any differences on
      a nonselected (correlated) trait between the opposite-selected lines is strong
      evidence for pleiotropic effects of the genes fixed by selection. METHODS: Naive
      WSP and WSR mice of both replicates were placed in startle chambers and exposed
      to a series of white noise stimuli of different intensities. In Experiment 1, two
      parameters [the maximal acoustic startle response (Rmax), and the sound intensity
      necessary to produce 50% of the maximal startle response (dB50)] were obtained
      from a least-squares nonlinear regression by fitting data for each subject to a
      sigmoidal function that best described the relationship between sound intensity
      and mean ASR. Response habituation of WSP and WSR mice to a repeated acoustic
      stimulus of high intensity was examined in Experiment 2. RESULTS: When ASR
      amplitude was plotted versus sound intensity, the sigmoid intensity-response
      curves of both WSP replicates were shifted to the right relative to the responses
      of WSR mice, which suggested decreased startle sensitivity in the WSP animals.
      Statistical analysis showed that naive WSP mice were less sensitive (higher dB50)
      to acoustic stimulation than Seizure-Resistant animals whereas Rmax was similar
      for both lines. The selected lines also differed in their responses to repeated
      acoustic stimulation, with WSP mice demonstrating greater habituation.
      CONCLUSION: Results of the present study suggest some common genetic mechanisms
      underlying behavioral responsiveness to acoustic stimulation and severity of
      ethanol withdrawal.

PMID- 10591589
TI  - Effects of benzodiazepines on acute and chronic ethanol-induced nociception in
      rats.
AB  - BACKGROUND: Acute and chronic ethanol produces antinociception, and ethanol
      withdrawal induces hyperalgesia. METHODS: A radiant heat tail-flick assay was
      used to assess the effects of benzodiazepine ligands on ethanol-induced changes
      in nociception in rats. Acute activity of cumulative doses of ethanol (0.5-2.0
      g/kg) and diazepam (0.1-10 mg/kg), a benzodiazepine agonist, was tested alone and
      after pretreatment with flumazenil (1.0-10 mg/kg), a benzodiazepine antagonist.
      Chronic effects of ethanol were tested in three groups of rats that received a
      liquid diet for 10 days. One group received ethanol alone; one group received
      ethanol and twice-daily injections of flumazenil (10 mg/kg); and one received a
      dextrin control diet. Acute withdrawal was tested at 12 hr after removal of the
      liquid diet. Effects of cumulative doses of diazepam (1.0-10 mg/kg) were tested
      during withdrawal (12 hr) in the ethanol-alone group. RESULTS: Acute doses of
      ethanol produced a small but significant degree of antinociception, which was
      fully suppressed by flumazenil. Acute doses of diazepam did not produce
      antinociception. Chronic exposure to ethanol produced antinociception on days 2
      through 8. Tolerance developed by day 10, and hyperalgesia was seen 12 hr after
      removal of ethanol. Administration of diazepam or ethanol during withdrawal
      reversed the hyperalgesia induced by ethanol withdrawal. However, flumazenil (10
      50 mg/kg) failed to reverse the antihyperalgesic effect of either diazepam or
      ethanol. No antinociception was seen in either the ethanol/flumazenil or dextrin
      control groups. CONCLUSIONS: These results suggest that the antinociceptive
      effects of both acute and chronic ethanol are at least partially mediated by GABA
      receptors, and that diazepam's antihyperalgesic effects may not be mediated by
      the GABA acid receptor.

PMID- 10591590
TI  - Mismatch negativity and auditory sensory memory in chronic alcoholics.
AB  - BACKGROUND & METHODS: Preattentive auditory processing and sensory memory were
      investigated by means of mismatch negativity (MMN) in a sample of 22 middle-aged
      abstinent chronic alcoholics and 25 age-matched healthy controls. Stimuli were
      presented at two inter-stimulus intervals (ISIs, 0.75 sec and 2.0 sec) in
      separate blocks. RESULTS: No significant differences in amplitude or latency of
      MMN were found between alcoholic and control subjects in either of the two ISI
      conditions. However, when age was included as a factor in the analysis, MMN
      amplitude was attenuated in chronic alcoholics who were older than 40 years of
      age. CONCLUSIONS: These results indicate that the automatic stimulus-change
      detector mechanism associated with MMN generation is impaired in chronic
      alcoholics over the age of 40, suggesting that the neurotoxic effects of chronic
      consumption of alcohol are more prone to appear after a critical age.

PMID- 10591591
TI  - Ethanol-associated olfactory stimuli reinstate ethanol-seeking behavior after
      extinction and modify extracellular dopamine levels in the nucleus accumbens.
AB  - BACKGROUND: Alcohol craving or automatic behavioral responses provoked by alcohol
      related cues are thought to contribute to relapse risk in abstinent individuals.
      However, there is to date only limited direct experimental evidence that supports
      this hypothesis. The present study employed an operant response-reinstatement
      model to examine the effects of ethanol-associated environmental stimuli on
      alcohol-seeking behavior and extracellular dopamine (DA) levels in the nucleus
      accumbens (NAcc). METHODS: Male Wistar rats were prepared with intracerebral
      guide cannulae for microdialysis and trained to operantly self-administer ethanol
      in the presence of discrete olfactory discriminative stimuli (Sdelta's) signaling
      the availability of ethanol (10% w/v) versus a nonrewarding stimulus (a 50 microM
      quinine HCl solution). After the discrimination learning phase, responding for
      ethanol (and quinine) was extinguished by withholding the drinking solutions as
      well as the corresponding Sdelta's. After reaching and maintaining an extinction
      criterion of < or = 5 responses/session, the rats were exposed noncontingently to
      the ethanol and nonreward Sdelta's but without the availability of ethanol or
      quinine. RESULTS: The ethanol Sdelta's, but not nonreward Sdelta's, elicited
      significant recovery of responding. Exposure to the operant chamber during a 20
      min "waiting period" before presentation of the Ss's was associated with a small
      but significant increase in dialysate DA levels. Subsequent exposure to the
      ethanol Sdelta and onset of the reinstatement session was accompanied by a small
      but significant decrease in DA efflux. Exposure to the nonreward Sdelta did not
      alter DA levels. CONCLUSIONS: The behavioral data confirm that ethanol-predictive
      discriminative stimuli reliably elicit ethanol-seeking behavior after extinction.
      The increase in DA efflux during the waiting period confirms earlier findings and
      suggests that anticipation of access to ethanol activates mesolimbic DA neurons.
      The decrease in DA efflux after onset of the reinstatement session in animals
      that were presented with the ethanol Sdelta's may reflect neurochemical events
      associated with the mismatch between the predicted (i.e., ethanol availability)
      and actual (i.e., absence of ethanol) stimulus events. This possibility is
      supported by the lack of changes in DA efflux in rats that were presented with
      the nonreward Sdelta's, a test condition that did not involve such a mismatch.
      Overall, the findings provide further evidence for a role of conditioning
      processes in the control of alcohol-seeking behavior and, by extension, support
      the hypothesis that conditioned responses to drug-related stimuli may be an
      important factor in chronic alcohol abuse and relapse.

PMID- 10591592
TI  - Suppression of alcohol intake by chronic naloxone treatment in P rats: tolerance
      development and elevation of opiate receptor binding.
AB  - BACKGROUND: This study was planned to determine the feasibility of using a slow
      release naloxone preparation to treat alcoholism, because compliance with
      medication is a significant problem in alcoholics. METHODS: Experiments were
      performed in alcohol-preferring P rats maintained either on continuous access or
      on limited access (1 hr/day) to alcohol with water and food provided ad libitum.
      Naloxone (Nx) was administered either by twice daily subcutaneous injections or
      by slow release (1.1 mg/kg/hr) osmotic minipump. In limited access experiments,
      Nx was injected immediately before access to alcohol. RESULTS: An initial
      experiment estimated the dose-effect curve for Nx subcutaneous suppression on
      alcohol intake. Nx (2.5-20 mg/kg) had a stronger effect during the first 2 hr
      after injection (ED50 = 2.1 mg/kg); however, the effect was more modest on 24-hr
      consumption. Similar results were found with chronic Nx treatment. Low doses of
      Nx (0.5 and 2.0 mg/kg) injected immediately before limited access to alcohol
      produced almost complete suppression of alcohol intake for at least 14
      consecutive days. However, 14 days of treatment with 26 mg/kg/day by minipump or
      injection produced an initial 50% suppression of 24-hr alcohol intake with the
      gradual development of tolerance. An acute challenge with Nx immediately after
      the pumps were scheduled to be empty provided additional evidence of tolerance
      development in chronically Nx-treated rats. Brain micro-opiate receptors,
      estimated autoradiographically by using the ligand [3H][D-Ala2,N-Me-Phe4, Gly
      ol5][tyrosyl-3,5-3H]-enkephalin, showed that rats chronically exposed to Nx and
      showing tolerance to Nx suppression of drinking exhibited 17% to 250% increases
      in [3H][D-Ala2,N-Me-Phe4, Gly-ol5][tyrosyl-3,5-3H]-enkephalin binding.
      CONCLUSIONS: High doses of Nx are required to suppress continuous access alcohol
      consumption in P rats, and tolerance develops to the ethanol consumption
      suppressing effect of Nx that may be related to increases in micro-opiate
      receptors.

PMID- 10591593
TI  - Impact of a stimulant-focused enhanced program on the outcome of alcohol- and/or
      stimulant-dependent men.
AB  - BACKGROUND: The approaches to the treatment of most forms of substance dependence
      are similar. It is not clear whether specific treatment components need to be
      added to address specific substances. This study asks two questions: What is the
      impact of a more intense drug treatment program, and do different substance
      problems require different treatment interventions? METHODS: The 383 veterans
      included in this study represent two groups of consecutive inpatient male
      admissions with current alcohol dependence and/or dependence on amphetamines or
      cocaine at the inpatient Alcohol and Drug Treatment Program of the Veterans
      Affairs San Diego Healthcare System. All were interviewed at intake by trained
      interviewers using a standardized semistructured assessment instrument, and a
      resource person interview also was conducted with 85% of them. The first group of
      men received the Standard Treatment Program (STP), whereas the second group
      received the Enhanced Treatment Program (ETP). The latter included an addition of
      10 hr per week of intense treatment aimed at stimulants, including two newly
      developed manual-driven groups (Relapse Prevention and Interpersonal Counseling),
      each of which met twice a week. RESULTS: The patient follow-up was 92% at 3
      months and 83% at 12 months. Abstinence from substances of abuse for ETP and STP
      were 63% vs. 49% at 3 months and 43% vs. 24% at 12 months. Logistic regressions
      demonstrated that treatment type continued to predict outcome even in the context
      of other potentially predictive variables. CONCLUSIONS: Despite the ETP emphasis
      on stimulants, both alcohol- and stimulant-dependent men appeared to benefit,
      suggesting a generic improvement in substance use.

PMID- 10591594
TI  - Ethanol consumption, amino acid and glutathione blood levels in patients with and
      without chronic liver disease.
AB  - BACKGROUND: Ethanol abuse and liver cirrhosis cause a reduction of glutathione
      blood levels; liver cirrhosis induces an alteration of the plasma amino acid
      pattern. We evaluated whether or not ethanol abuse affects amino acid levels,
      particularly those that are involved in metabolizing glutathione in the plasma
      and erythrocytes of chronic alcohol abusers with or without liver cirrhosis.
      METHODS: We studied 10 chronic alcohol abusers without liver cirrhosis, 10 with
      alcoholic cirrhosis, 10 affected by hepatitis C virus-related cirrhosis, and 10
      healthy subjects. Glutathione, y-glutamyl-cysteine, and cysteine were determined
      by fluorescent HPLC, glutamic acid, glycine, and other free amino acids by cation
      exchange chromatography both in the plasma and erythrocytes of all studied
      subjects. RESULTS AND CONCLUSIONS: In both alcoholics and cirrhotics, we found a
      significant increase of plasma-aromatic amino acid and methionine levels, whereas
      glutathione was significantly reduced. The erythrocytes of these patients showed
      a significant increase of cysteine, glutamic acid, and glycine; gamma
      glutamylcysteine was normal; and glutathione and other free amino acids were
      significantly decreased. Data suggest that, independent of liver cirrhosis,
      ethanol abuse affects the metabolism of amino acids and glutathione in both the
      plasma and the erythrocytes.

PMID- 10591595
TI  - Effects of ethanol on leptin secretion and the leptin-induced luteinizing hormone
      (LH) release from late juvenile female rats.
AB  - BACKGROUND: Chronic ethanol (EtOH) exposure lowers serum insulin-like growth
      factor-1 (IGF-1) and luteinizing hormone (LH) levels and also delays female
      puberty, similar to the deficits in the reproductive system that occur during
      leptin deficiency. Leptin administration restores fertility and gonadotropin
      secretion in the ob/ob mouse and can induce recovery of reproductive function in
      food-restricted animals. This study assessed the effects of EtOH on serum leptin
      levels, and whether exogenous leptin administration could restore IGF-1 and LH
      levels in the EtOH-treated animals. METHODS: In the first study, 29-day-old
      female rats were divided into control and EtOH-treated groups, each of which
      received their respective diet regimen for 5 consecutive days. The EtOH-treated
      animals were subdivided and received an intraperitoneal injection of either
      leptin (100 microg/0.1 ml) or saline twice daily. Control animals also received
      intraperitoneal saline injections twice daily. On day 34, animals were killed,
      and serum leptin, LH, and IGF-1 were measured by RIA. In a second study we
      assessed the acute effects of a single 3 g/kg dose of EtOH on the ability of
      leptin to act centrally to induce LH release. For this, leptin (1 microg) was
      administered via a third ventricular (3V) cannula and blood sampling via jugular
      cannula. In a third experiment, animals were again subjected to a chronic feeding
      regimen. When 34 days old, they were killed and the anterior pituitaries removed
      and incubated in a static incubation system for 60 min to establish basal LH
      release, then for an additional 60 min in medium containing leptin (10(-7) M).
      RESULTS: Chronic EtOH exposure lowered serum leptin (p < 0.01), IGF-1 (p < 0.01),
      and LH (p < 0.05) levels. Leptin administration to EtOH-treated animals did not
      restore serum IGF-1 levels. This peptide did, however, effectively restore LH
      levels to normal, but did not advance the timing of puberty. Acute EtOH
      administration was found to block leptin-induced LH release following central
      administration of the peptide. Conversely, anterior pituitaries from control and
      5-day EtOH-treated animals that were incubated in vitro released (p < 0.01) equal
      amounts of LH in response to leptin (10(-7) M). CONCLUSIONS: These data
      demonstrate that EtOH administration not only can suppress peripheral levels of
      leptin, but also blocks its central action to facilitate LH secretion. Although
      replacement of leptin can reverse the EtOH-induced suppression of LH by a direct
      action at the level of the pituitary, it cannot elevate serum IGF-1; a peripheral
      signal that acts centrally to stimulate LH releasing-hormone (LHRH)/LH release
      during the juvenile-peripubertal transition period, and thus accelerates the
      initiation of female puberty. These results demonstrate further the complex
      actions and interactions of multiple hormones involved in the pubertal process
      and the vulnerability of their actions to the toxic effects of EtOH.

PMID- 10591596
TI  - Progesterone and prostaglandin H synthase-2 involvement in alcohol-induced
      preterm birth in mice.
AB  - BACKGROUND: Recently, an association between alcohol consumption during pregnancy
      and shortened gestational length has been reported, but the underlying mechanisms
      remain unknown. Progesterone (P4) and prostaglandins have been shown to play
      important roles in parturition in both human and animal models. Recently, it has
      been suggested that prostaglandin H synthase-2 (PGHS-2) is responsible for
      prostaglandin changes associated with term and preterm labor. It is possible that
      alcohol induces preterm birth by altering P4 or PGHS-2 levels. These studies were
      designed to determine the role of P4 and PGHS-2 in alcohol-induced preterm labor
      in mice. METHODS: Experiment 1: Pregnant dams treated with either vehicle or
      alcohol (6 g/kg, intragastrically) on gestational day (GD) 16 were killed at
      various times in gestation up to the time of delivery. Plasma P4 levels were
      measured by radioimmunoassay and uterine PGHS-2 mRNA expression was measured by
      Ribonuclease Protection Assay. Results indicated that alcohol treatment was
      associated with an earlier decline in plasma P4 levels and an earlier rise in
      uterine PGHS-2 mRNA levels during gestation. Experiment 2: Pregnant C57BL/6J
      females were treated with either P4 (2.0 mg, subcutaneously) or vehicle (sesame
      oil) 2 hr before receiving either 6 g/kg alcohol (intragastrically) or vehicle
      (isocaloric sucrose) on gestational day (GD) 16. Results indicate that P4
      pretreatment effectively antagonized alcohol-induced preterm delivery. Experiment
      3: On GD16, pregnant dams received either 100 mg/kg nimesulide (a specific PGHS-2
      inhibitor) or vehicle (saline) subcutaneously, 2 hr before treatment with either
      6 g/kg alcohol (given intragastrically) or isocaloric sucrose. Nimesulide was
      effective in antagonizing alcohol-induced preterm labor. CONCLUSIONS: Together,
      these data suggest that both P4 and PGHS-2 may play roles in alcohol-induced
      preterm birth.

PMID- 10591597
TI  - Prenatal ethanol reduces the activity of adult midbrain dopamine neurons.
AB  - BACKGROUND: Prenatal ethanol exposure has been demonstrated to reduce dopamine
      (DA) neurotransmission in the forebrain area, which could be contributed by
      altered electrical activity in midbrain DA neurons. This hypothesis was tested in
      the present study. METHODS: The effects of prenatal ethanol exposure on the
      spontaneous activity of DA neurons in the substantia nigra and ventral tegmental
      area were investigated with extracellular single-unit recording techniques in
      adult male rats. Pregnant rats were administered single daily doses of 0, 3, or 5
      g/kg ethanol via intragastric intubation from gestation day 8 through 20. An
      additional control group did not receive the intubation procedure. RESULTS:
      Prenatal ethanol treatment significantly reduced the number of spontaneously
      active DA neurons in the substantia nigra and ventral tegmental area in 3- to 5
      month-old male offspring. The firing rate and firing pattern of the remaining
      spontaneously active DA neurons were not altered. There were no differences in
      the spontaneous activity of DA neurons between the nonintubated and 0 g/kg
      control groups, indicating possible intubation-induced stress did not influence
      the activity of DA neurons in adult offspring. Similar prenatal ethanol effects
      were also determined from older animals (14-16 months old), suggesting that the
      reduction in the spontaneous activity of DA neurons is a persistent phenomenon in
      adulthood after prenatal ethanol exposure. Furthermore, the reduction in the
      number of spontaneously active DA neurons was not the result of a loss in DA
      neurons per se, as revealed by the results of tyrosine hydroxylase
      immunohistochemistry. The prenatal ethanol exposure-induced reduction in DA
      neuronal activity may result from depolarization inactivation, because
      systemically administered apomorphine (20 microg) increased the spontaneous
      activity of DA neurons. CONCLUSIONS: Prenatal ethanol exposure induced a long
      lasting reduction in the activity of midbrain DA neurons in adult animals. The
      effect was not the result of cell loss but possible changes in the electrical
      properties of DA neurons. The decreased electrical activity in midbrain DA
      neurons could contribute to the prenatal ethanol exposure-induced reduction in DA
      content and metabolites observed in previous studies and the
      attention/hyperactivity problems reported in children with fetal alcohol
      effects/fetal alcohol syndrome.

PMID- 10591598
TI  - Executive functioning in children with heavy prenatal alcohol exposure.
AB  - BACKGROUND: Children with heavy prenatal alcohol exposure have well documented
      deficits in overall cognitive ability. Recently, attention has turned to the
      executive function (EF) domain in this population. Until recently, comprehensive
      measures of EF have not been available within one test battery. This study used a
      battery of tests to assess four domains of EF in alcohol-exposed children.
      METHODS: The Delis-Kaplan Executive Function Scale was used to evaluate EF in 18
      children with heavy prenatal alcohol exposure, with and without a diagnosis of
      fetal alcohol syndrome (FAS), and 10 nonexposed controls. Children ranged in age
      from 8 to 15 years. Measures from four domains of executive functioning were
      analyzed: planning ability, cognitive flexibility, selective inhibition, and
      concept formation and reasoning. Tasks consisted of primary EF measures as well
      as measures of secondary component skills. RESULTS: Alcohol-exposed children were
      deficient on EF measures compared with nonexposed controls. Furthermore, in most
      cases, children with and without the FAS diagnosis did not differ from one
      another. These deficits were not entirely explainable by concomitant deficits on
      component skills. Specific impairments were identified within the domains of
      planning and response inhibition, with additional deficits in abstract thinking
      and flexibility. CONCLUSIONS: Deficits in executive functioning were observed in
      alcohol-exposed children with or without the diagnosis of FAS and in the absence
      of mental retardation. Performance on these EF tasks provides insight into the
      cognitive processes driving overall performance and has implications for adaptive
      and daily functions. These results are consistent with anecdotal and empirical
      reports of deficits in behavioral control and with neuroanatomical evidence of
      volumetric reductions in structures within the frontal-subcortical system in
      children with heavy prenatal alcohol exposure.

PMID- 10591599
TI  - Altered GABA(A)-benzodiazepine receptor number and pharmacology in the adult
      guinea pig cerebral cortex after chronic prenatal ethanol exposure.
AB  - BACKGROUND: The effects of chronic prenatal ethanol exposure on GABA(A)
      benzodiazepine receptor number and binding pharmacology were examined in the
      cerebral cortex of the postnatal guinea pig. METHODS: [3H]Flunitrazepam binding
      to GABA(A)-benzodiazepine receptors was measured in a cerebral cortical cell
      membrane preparation obtained at postnatal days 11 (preweaning), 21
      (postweaning), and 61 (adulthood). Zolpidem, a GABA(A)-benzodiazepine type 1
      receptor-selective ligand, was used in a [3H]flunitrazepam competition study. 3a
      Hydroxy-5alpha-pregnan-20-one (allopregnanolone) potentiation of [3H]muscimol and
      [3H]flunitrazepam binding, and GABA potentiation of [3H]flunitrazepam binding
      were measured in these same animals. RESULTS: At postnatal day 61, but not at the
      younger ages studied, the following was observed: (1) [3H]Flunitrazepam binding
      exhibited an increased receptor number (Bmax) and decreased affinity (increased
      K(D)) in the ethanol-treated offspring compared with isocaloric-sucrose (with
      pair-feeding) and water-treated controls; and (2) the relative proportion of
      GABA(A)-benzodiazepine receptors that had high-affinity binding sites for
      zolpidem was decreased in the ethanol-treated offspring by 31% and 38% compared
      with the isocaloric-sucrose/pair-fed and water-treated controls, respectively.
      Chronic prenatal ethanol exposure did not alter the efficiency of coupling
      between GABA, benzodiazepine, and neurosteroid binding sites at any postnatal
      ages studied. CONCLUSIONS: These results suggest that, in the cerebral cortex of
      the adult guinea pig, chronic prenatal exposure to ethanol results in increased
      GABA(A)-benzodiazepine receptor number, decreased affinity for flunitrazepam, and
      decreased relative proportion of the GABA(A)-benzodiazepine type 1 receptor.

PMID- 10591601
TI  - Ethanol pretreatment enhances NMDA excitotoxicity in biogenic amine neurons:
      protection by brain derived neurotrophic factor.
AB  - BACKGROUND: Biogenic amine neurons are involved in a number of mental diseases
      including addiction and alcohol dependence. Because chronic ethanol is known to
      cause supersensitivity to NMDA excitotoxicity in cortical neurons, this study
      sought to determine the effect of ethanol treatment on biogenic amine neurons.
      METHODS: To determine if ethanol exposure alters the vitality of biogenic amine
      neurons, cultures were prepared from E14 rat brain. After 24 hr in culture, cells
      were divided into control or ethanol (100 mM) treatment groups, cultured an
      additional 48 hr, and then half of them exposed to NMDA for 25 min. The NMDA was
      then removed and cells cultured in fresh media for an additional 24 hr to allow
      for excitotoxic delayed neuronal death. Cultures were then stained with
      antibodies to 5-hydroxytryptamine or tyrosine hydroxylase to identify serotonin
      and dopamine neurons, respectively. Cultures were analyzed for cell number and
      neuronal morphology. RESULTS: Ethanol treatment alone had no effect on biogenic
      amine cell number, soma area, number of neurites, or terminal segments, although
      the field area of dopamine neurons was decreased. Treatment with 30 microM NMDA
      had no effect on controls, but significantly decreased dopamine neurons in
      ethanol-treated cultures as well as reduced soma area, field area, number of
      neurites and number of terminal segments. Treatment with higher concentrations of
      NMDA reduced dopamine and serotonin neurons in both controls and ethanol-treated
      groups, and ethanol treatment significantly enhanced NMDA excitotoxic effects.
      Treatment with Brain Derived Neurotrophic Factor (BDNF) prevented ethanol
      sensitization to NMDA excitotoxicity. CONCLUSIONS: These studies suggest that
      ethanol treatment sensitizes biogenic amine neurons to excitotoxic insults.
      Ethanol sensitization of biogenic amine neurons to insults could contribute to
      the development of mental disease.

PMID- 10591600
TI  - Long-term alcohol consumption in the rat affects femur cross-sectional geometry
      and bone tissue material properties.
AB  - BACKGROUND: Alcohol consumption previously has been demonstrated to reduce the
      density and strength of cortical bone of young, actively growing rats. Osteoblast
      activity and trabecular bone volume were also significantly lower. A germane
      question arising from these studies is whether the detrimental effects would
      persist into adulthood. To address this issue, a long-term study was undertaken
      with animals that consumed alcohol throughout their life and into old age.
      METHODS: One-month-old female Sprague-Dawley rats were divided into three diet
      groups: alcohol-fed, pair-fed, and chow-fed. The alcohol-fed animals received a
      modified Lieber-DeCarli diet that contained 35% ethanol-derived calories. The
      pair-fed group served as a caloric-equivalent control, and the chow-fed animals
      served as a completely untreated control. Animals were euthanized after five time
      periods on the diets that represented three stages of the life span: young (3
      months), adult (6, 9, 12 months), and aged (18 months). The left femur was
      isolated and mechanically tested in 3-point bending for mechanical properties.
      RESULTS: In the young animals, alcohol consumption produced dramatic reductions
      in both extrinsic (whole bone) and intrinsic (tissue material) properties, which
      is consistent with results from previous studies on growing rats. For the adult
      animals, however, the alcohol groups were only slightly lower and the differences
      were not statistically significant. The aged animals showed diminished properties
      due to alcohol, but only for the intrinsic material properties. The extrinsic
      properties remained similar to controls as a result of greater radial expansion
      in the femur diaphysis. Despite the cross-sectional areas being the same, this
      expansion gave rise to higher cross-sectional moment of inertia values in the
      alcohol animals. The thickness of the cortical wall was lowest in the alcohol
      group at all time points. CONCLUSIONS: Long-term alcohol consumption produced two
      major effects in the oldest animals studied: the quality of the cortical bone
      tissue was diminished, as evidenced by reduced elastic modulus and ultimate
      strength values, and the bone seemed to compensate for this by expanding the
      cross-section to produce larger cross-sectional moment of inertia values. The
      reduced bone tissue quality is consistent with the lower ash percent values in
      the alcohol animals, but other factors such as the quality of the collagen and
      mineral crystal may also be important contributors.

PMID- 10591602
TI  - Application of the capture-recapture method to epidemiological studies of alcohol
      related problems.
AB  - The capture-recapture method is used to enumerate members of populations for
      which a complete census is not possible. The use of this method to enumerate
      individuals with alcohol-related problems requires special considerations. This
      article comments on these considerations and addresses the strengths and
      weaknesses of this method for enumerating individuals with alcohol-related
      problems in a community.

PMID- 10591603
TI  - Ethanol directly excites dopaminergic ventral tegmental area reward neurons.
AB  - BACKGROUND: The mesolimbic/mesocortical dopamine pathway mediates the rewarding
      effects of ethanol and other drugs of abuse like cocaine and opiates.
      Dopaminergic neurons of the ventral tegmental area (VTA) are the cells of origin
      of the mesolimbic/mesocortical dopamine pathway. Ethanol's rewarding properties
      result from its ability to excite dopaminergic cell bodies in the VTA which
      results in increased dopamine release in the nucleus accumbens. Many recent
      papers have speculated that ethanol excitation of dopaminergic VTA neurons is
      indirect, either that ethanol acts on GABAergic or other interneurons, which in
      turn modulate the activity of dopaminergic VTA neurons, or that ethanol modulates
      the action of neurotransmitter-gated ion channels in the VTA. METHODS: VTA
      neurons were acutely dissociated and plated onto a cover slip in an
      electrophysiological recording chamber. These neurons generated spontaneous
      action potentials which could be measured with cell attached loose patch
      recording. The dissociation procedure truncated the dendritic trees, severed
      synaptic contacts and widely dispersed these neurons. Dopamine (10-50 nM) and
      ethanol (20-120 mM) were bath applied and their effects on firing rate were
      measured. After some experiments, plated cells were fixed and processed for
      immunostaining of tyrosine hydroxylase, the rate-limiting enzyme in dopamine
      synthesis. RESULTS: All neurons met electrophysiological criteria previously
      established for dopaminergic VTA neurons. Dopamine inhibited all VTA neurons
      tested, indicating the presence of dopamine autoreceptors. All neurons identified
      as dopaminergic by these electrophysiological and pharmacological criteria, and
      that were processed for immunohistochemistry, stained positive for tyrosine
      hydroxylase immunoreactivity. All acutely dissociated VTA neurons, identified as
      dopaminergic by electrophysiological, pharmacological and immunohistochemical
      criteria, were robustly excited by behaviorally relevant concentrations of
      ethanol. The ethanol-induced excitation was concentration-dependent. CONCLUSIONS:
      These data provide strong evidence that ethanol directly excites dopaminergic VTA
      neurons, as this excitation still occurs in the absence of input from surrounding
      neurons.

PMID- 10591604
TI  - Alpha-adrenergic receptors in the penis: identification, characterization, and
      physiological function.

PMID- 10591605
TI  - Alpha receptors in the central nervous system and its effects on erection.

PMID- 10591606
TI  - A dividing policy: making rules about embryo research.

PMID- 10591607
TI  - Incorporating molecular screening techniques into the modern andrology
      laboratory.

PMID- 10591608
TI  - Changes in the number, proliferation rates, and bcl-2 protein immunoexpression of
      epithelial and periductal cells from rat epididymis during postnatal development.
AB  - To investigate 1) the correlation between the proliferative activity of
      epididymal epithelium plus myoid cells and the increase in the number of these
      cells and 2) the role of the basal epithelial cells in the renewal of epididymal
      epithelium, a quantitative evaluation of the proliferation of both epithelial
      cells and periductal myoid cells in the different epididymal regions (caput,
      corpus, and cauda) has been carried out during postnatal development of the rat
      by immunohistochemical evaluation of BrdU-labeling indices. These data were
      correlated with cell numbers and counted by the optical dissector method. The
      presence of bcl-2 protein was immunohistochemically detected and evaluated. No
      significant differences in BrdU indices were observed among epididymal regions in
      any stage studied. Cell proliferation decreased from the prepubertal period to
      adulthood in both epithelial and myoid cells in the three regions of the
      epididymis, suggesting a close relationship between epithelial and mesenchymal
      components. The numbers of both cell types were significantly higher in the caput
      than in the corpus and cauda in all stages studied, suggesting functional
      differences between regions. A negative linear correlation between proliferative
      activity and cell numbers was noted that might be related to regulation of the
      cell population size. Basal cells showed a lower proliferation rate than
      principal cells, but most of the immunoreactive bcl-2 protein, in pubertal and
      adult epididymides, was observed in basal cells. Therefore, these cells might
      comprise a low-proliferating and apoptosis-resistant population.

PMID- 10591609
TI  - Varicocele-associated decrease in antioxidant defenses.
AB  - Varicocele is associated with an oxidative stress condition. We have measured the
      antioxidant defenses of varicocele patients both at the local (seminal plasma)
      and systemic (blood plasma) levels. The antioxidant defenses, as evaluated by the
      total reactive antioxidant potential parameter, decrease both in the seminal
      (controls 676+/-128; patients = 386+/-186) and blood (controls = 519+/-63;
      patients = 268+/-110) plasma of varicocele patients. Compared with controls,
      patients with both normal spermiograms and spermiograms altered in motility or
      morphology demonstrated lower values. The results obtained suggest that
      varicocele-associated oxidative stress is evidenced both at the local and
      systemic levels. This conclusion is supported by results showing that urinary
      spontaneous chemiluminescence is also significantly increased in the patients.

PMID- 10591610
TI  - Evaluation of oxidative DNA damage in human sperm and its association with male
      infertility.
AB  - Recently, there is increasing evidence suggesting that oxidative sperm DNA damage
      is closely associated with impaired sperm function and male infertility. 8
      Hydroxydeoxyguanosine (8-OHdG) is considered to be a precise and sensitive
      biomarker of oxidative DNA damage. The present study was thus designed to
      evaluate the extent of oxidative DNA damage in sperm and its association with
      male infertility by assaying the 8-OHdG levels in human sperm samples. A total of
      114 subjects (60 infertile patients and 54 age-matched healthy workers)
      participated in this study. The level of 8-OHdG in sperm DNA was determined by
      high-performance liquid chromatography with electrochemical detection, and the
      conventional seminal parameters were also measured according to World Health
      Organization guidelines. It was found that the level of sperm 8-OHdG in infertile
      patients was significantly higher than that in healthy subjects (10.03 vs. 4.79 8
      OHdG/10(5) dG; geometric mean, P < 0.001). The correlation between sperm 8-OHdG
      levels and conventional seminal parameters were also analyzed. There is a
      significant positive correlation between 8-OHdG and sperm head defects (r = 0.38,
      P < 0.001), whereas significant inverse correlations were noted for 8-OHdG with
      sperm density (r = -0.42, P < 0.001), total sperm number (r = -0.42, P < 0.001),
      sperm motility (r = -0.24, P < 0.01), and normal sperm morphology (r = -0.39, P <
      0.001). Data from this study thus indicate that oxidative damage to sperm DNA may
      be important in the etiology of male infertility and that the assay of sperm 8
      OHdG may have potential diagnostic value in the evaluation of sperm function and
      male fertility.

PMID- 10591611
TI  - Temporal variations in testicular microcirculation.
AB  - Temporal variations in microcirculatory blood flow in the testis and blood
      pressure were examined in intact, pentobarbital-anesthetized rats with a two
      channel laser Doppler flowmeter. The laser Doppler probes that measure local
      blood flow in a tissue volume of about 2 mm3 were placed either over the mid
      portion of the left and right testes or on the right testes 1 cm apart.
      Testicular microcirculation was characterized by a prominent vasomotion with a
      frequency of 5.3+/-1.4 cycles per minute and with an amplitude of 73+/-32% (mean
      +/- SD) of the mean. In addition to this large and rapid variation in local blood
      flow, there were also major variations from minute to minute in the average blood
      flow, vasomotion frequency, and vasomotion amplitude at 40 and 53 minutes. Such
      variations in local blood flow, vasomotion frequency, and vasomotion amplitude
      were correlated with each other at two different sites on the same testis (r(s) =
      0.39, r(s) = 0.82, r(s) = 0.64, respectively, P < 0.001), and they were all
      correlated with systemic blood pressure (r(s) 0.41, r(s) = 0.61, r(s) = 0.32,
      respectively, P < 0.001). Minute-to-minute variations in local blood flow,
      vasomotion frequency, and vasomotion amplitude were also correlated between the
      right and left testes (r(s) = 0.58, r(s) = 0.75, r(s) = 0.57, respectively, P <
      0.001). There are substantial temporal variations in testicular microcirculation.
      These variations are to some extent related to temporal changes in systemic blood
      pressure, but changes in the ultralocal environment are probably more important.
      The functional significance of, and the factors responsible for, local variations
      in testicular microcirculation remain to be elucidated.

PMID- 10591612
TI  - Relationship between rapid eye movement sleep and testosterone secretion in
      normal men.
AB  - The relation between the pituitary-gonadal hormones' rhythm and sleep physiology
      in men is not fully elucidated. To examine whether the reproductive hormones are
      correlated with sleep architecture, we determined the nocturnal serum levels of
      testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in
      six healthy young men. Serum hormone levels were obtained every 15 minutes from
      1900 to 0700 hours with simultaneous polysomnographic sleep recordings. Hourly
      testosterone levels were lowest when subjects were awake (1900-2200 hours) than
      during sleep (2300-0700 hours). Testosterone nocturnal rise antedated the first
      REM by about 90 minutes. The rise in testosterone levels was slower when REM
      latency was longer. Mean nocturnal testosterone levels did not correlate with the
      number of rapid eye movement (REM) episodes. Also, pre-non-REM (NREM)
      testosterone levels were higher as compared with the pre-REM periods and lower
      during the first NREM period as compared with other nocturnal NREM periods. Serum
      LH levels disclosed a nocturnal rise that preceeded a similar rise in
      testosterone by about an hour. We conclude that in young adult men, testosterone
      levels begin to rise on falling asleep, peak at about the time of first REM, and
      remain at the same levels until awakening.

PMID- 10591613
TI  - Regional variation in macrophage antigen expression by murine epididymal basal
      cells and their regulation by testicular factors.
AB  - Factors controlling the appearance in the epididymis of basal cells and their
      expression of macrophage antigens were examined by ligating the efferent ducts to
      prevent the entry of spermatozoa in adult and juvenile mice. Fixation and antigen
      retrieval techniques were developed to preserve tissue morphology and expression
      of two macrophage antigens in paraffin-embedded epididymal tissue. A combination
      of periodate-lysine-phosphate fixation, low-temperature embedding and enzyme
      predigestion of sections permitted immunohistochemical detection of the mature
      macrophage antigen Mac-1, whereas the panmacrophage marker F4/80 required
      fixation in neutral-buffered formalin. Epididymal basal cells were immunostained
      for F4/80 and quantified with avidin-biotin-peroxidase. In the adult mouse, the
      total number of basal cells per millimeter length of tubule cross section
      perimeter and the percentage expressing the F4/80-antigen were significantly
      higher in the initial segment and caput region than in all other epididymal
      regions. In the initial segment, immunostained basal cells surrounded the tubule
      in a network, and some extended towards the lumen. Ligation of the efferent ducts
      to prevent inflow of testicular secretions significantly reduced the number of
      basal cells per cross section in the initial segment of the adult and juvenile;
      the percentage of basal cells expressing macrophage antigens in the initial
      segment and the caput epididymidis was also reduced. Since basal cells still
      appeared in the ligated postpubertal epididymis, it is concluded that testicular
      exocrine secretions entering the epididymal lumen around puberty are not the
      major influence on basal cell appearance in the murine epididymis, but they may
      modulate their expression of macrophage antigens.

PMID- 10591615
TI  - FSH immunoneutralization acutely impairs spermatogonial development in normal
      adult rats.
AB  - Follicle-stimulating hormone (FSH) plays an important part in testicular
      development. Its role in the regulation of spermatogenesis in the adult, however,
      remains controversial. This study aimed to explore the role of FSH in the
      maintenance of adult rat spermatogenesis by using immunoneutralization to
      selectively withdraw FSH action for periods of up to 8.5 days and then assessing
      the outcome by quantification of germ cell number. Adult rats received either an
      ovine polyclonal rat FSH antibody (FSHAb, 2 mg/kg subcutaneous daily-a dosage
      known to neutralize >90% of FSH in serum) for 2, 4, 7, or 8.5 days or a control
      sheep immunoglobulin (ConAb, 2 mg/kg) for 8.5 days. Testes were perfusion fixed,
      and germ cell numbers per testis were quantified using the optical disector (sic)
      stereological method. The percentage of seminiferous tubules displaying apoptotic
      cells was determined by the in situ end labeling method (TUNEL). FSHAb treatment
      for 4, 7, or 8.5 days significantly reduced the number of type A/intermediate
      spermatogonia (approximately 74% of control values) associated with stages I-IV.
      Similar reductions were seen in type B spermatogonial and preleptotene
      spermatocyte numbers after 8.5 days of FSHAb treatment (approximately 69% of
      control values; P < 0.05). Decreases (P < 0.05) in the numbers of pachytene
      spermatocytes in stages I-III and VIII, round spermatids in stages I-III, VII,
      and VIII (approximately 70% of control values), and step 19 elongated spermatids
      in stage VII (51% of control values) were achieved after 8.5 days of FSHAb
      treatment. Compared with control, FSHAb treatment increased the percentage of
      stage XIV-III tubules containing TUNEL-positive cells by about twofold after 7
      days of FSHAb treatment (P < 0.05). This study supports a role for FSH in the
      maintenance of quantitatively normal adult rat spermatogenesis, specifically by
      regulating A3 and A4 spermatogonial subtypes. FSH may act on these spermatogonia
      by enhancing the stage-dependent survival of type A spermatogonia. Effects at
      other sites in spermatogenesis are suggested by the changes in spermatocyte and
      spermatid populations. However, to clarify these effects, selective FSH
      withdrawal would need to be prolonged until steady state had been achieved.

PMID- 10591614
TI  - Round spermatids show normal testis-specific H1t but reduced cAMP-responsive
      element modulator and transition protein 1 expression in men with round-spermatid
      maturation arrest.
AB  - During spermiogenesis, histones are replaced by transition proteins, which in
      turn are replaced by protamines. The TNP1 gene-encoding TP1 (transition protein
      1) protein contains a cAMP-responsive element (CRE) that serves as binding site
      for the CRE modulator (CREM). To gain further insight into the complex regulation
      of nucleoprotein exchanges in haploid spermatids and its potential role for
      spermatogenic impairment, we studied the gene expression of testis-specific
      histone H1t, CREM, and TNP1 in testicular biopsies from men with normal
      spermatogenesis (n = 20) and with round spermatid maturation arrest (n = 16).
      During normal spermatogenesis, H1t messenger RNA (mRNA) was present in 86.2%+/
      8.7% of pachytene spermatocytes (stages III-V), whereas H1t protein was
      synthesized in 83.5%+/-13.0% of pachytene spermatocytes (stages III-V) and
      persisted in 95.2%+/-3.1% of spermatids (steps 1-5). CREM mRNA was detectable in
      74.2%+/-9.4% of pachytene spermatocytes (stages IV-V) and in 78.7%+/-10.0% of
      spermatids (steps 1-3). CREM protein was synthesized in 81.2%+/-14.2% of
      spermatids (steps 1-3). TNP1 mRNA was present in 80.0%+/-13.5% of spermatids
      (steps 2-4), whereas TP1 protein was synthesized in 89.7%+/-5.3% of spermatids
      (steps 3-4). In men with round spermatid maturation arrest, spermatids only
      develop to step 3 of differentiation. These spermatids were devoid of both CREM
      and TP1 but did contain H1t. These results indicate that TP1 is likely to be an
      important parameter in the histone-to-protamine exchange and in the initiation of
      spermatid elongation. CREM is involved in the regulation of TNP1 gene expression
      and consequently plays a vital role in the correct differentiation step from
      round spermatids to mature spermatozoa.

PMID- 10591616
TI  - Secular sperm trends in stallions between 1981 and 1996.
AB  - Several reports have suggested that human semen quality has declined throughout
      the world over the last few decades. Chemicals in the environment acting as
      endocrine disrupters have been implicated as a possible cause. If this is indeed
      the case, then similar effects may be observed in animals. We analyzed 1489
      ejaculates collected from 390 Breton draught stallions between 1981 and 1996.
      Semen was collected from all the stallions at a single center, according to
      standardized semen collection protocols and laboratory methods. Semen volume
      decreased slightly but significantly and there was an increase in sperm
      concentration over the study period. However, total sperm production was
      unchanged. Seminal fluid volume is controlled by accessory sex glands, which are
      regulated by androgens. Chemicals with antiandrogenic properties have been
      detected in the environment. By affecting the development or function of
      accessory sex glands, these chemicals may be at least partly responsible for the
      observed decrease in semen volume.

PMID- 10591617
TI  - Effects of short-term methylmercury exposure on metallothionein mRNA levels in
      the testis and epididymis of the rat.
AB  - Methylmercury (MeHg) is a widespread environmental contaminant that causes
      reproductive dysfunction in men. Metallothioneins (MTs) are low-molecular-weight
      proteins that can bind heavy metals and protect the cell from metal toxicity. MT
      levels are increased by exposure to metals and physiological stressors. Although
      MTs have been identified in the testis and epididymis, little is known about
      their distribution and regulation in the epididymis or the effects of MeHg on MT
      levels in male reproductive tissues. The objective of this study was to determine
      whether MT I, II, and III mRNA are present in the epididymis, if their relative
      levels differ between epididymal segments, and if MeHg alters cellular mRNA
      levels for MT I, II, and III in the testis and epididymal segments of the rat.
      Northern blot analysis was done on total cellular RNA isolated from each of the
      four epididymal segments (initial segment [IS], caput [CT], corpus [CS], and
      cauda [CA] epididymidis) using a cDNA probe for MT I and MT II. MT I transcripts
      were present in all epididymal segments. The lowest mRNA levels were observed in
      the IS; these levels were 4-fold less than in the CT and CS and 5.5-fold less
      than in the CA. MT II mRNA levels were similar in the IS and CT but were
      eightfold higher in the CS and CA. A cDNA probe for MT III was generated by
      reverse transcription-polymerase chain reaction using testicular RNA. MT III mRNA
      was detected only in the IS and CT and not in the CS and CA. To assess whether
      exposure to MeHg alters MT mRNA levels, rats were exposed for 14 days to one of
      five MeHg doses (0, 25, 50, 100, and 200 [microg/kg/day] via a subdermal osmotic
      pump. No changes were observed in either body weight or in the weights of the
      testis, epididymis, seminal vesicles, or ventral prostate between MeHg-treated
      and control rats. Serum testosterone levels were significantly decreased only at
      the highest MeHg dose. In the testis, MeHg treatment resulted in 2.5- to 7-fold
      increases in MT I mRNA levels. There were no changes in either MT II or MT III
      mRNA levels. In the initial segment of the epididymis, MT I mRNA levels were
      significantly increased only at the 50 microg/kg/ day dose, whereas there were no
      significant differences in MT II mRNA levels. In the caput epididymis, MT I mRNA
      levels were significantly lower at the 50 and 100 microg/kg/day dose. MT II mRNA
      levels were also lower, with the exception of the 50 microg/kg/day dose. Although
      MT III mRNA levels were lower at the two lower doses, levels were not different
      from controls in the two highest doses tested. In the corpus epididymidis, MeHg
      did not alter MT I mRNA levels, and MT II was higher only in the 50 microg/kg/day
      group. In the cauda epididymidis, MT I mRNA levels were decreased in a dose
      dependent manner by up to 63%. MT II levels were unaltered. Together these data
      indicate that exposure of adult rats to MeHg can modulate MT mRNA levels in both
      the testis and epididymal segments. Furthermore, changes in MT mRNA levels
      following exposure to MeHg differ between epididymal segments, suggesting either
      differences in MeHg accumulation or differences in MT modulation.

PMID- 10591618
TI  - I. Abnormalities in cells of the testis, efferent ducts, and epididymis in
      juvenile and adult mice with beta-hexosaminidase A and B deficiency.
AB  - Beta-hexosaminidase (Hex) is a lysosomal enzyme that exists as two major
      isoenzymes: Hex A (subunit structure, alphabeta) and Hex B (betabeta). The
      presence of Hex in the testis and epididymis suggests important roles for the
      enzyme and its substrates in male fertility and reproductive functions.
      Disruption of the Hexb gene encoding the beta-subunit of Hex has led to the
      generation of a mouse model of human Sandhoff disease that survives to adulthood,
      enabling us to analyze the effects of Hex A and Hex B deficiency on epithelial
      cellular morphology of the male reproductive tract. At 1 and 3 months of age, the
      testes, efferent ducts, and epididymides of Hex-deficient (Hexb -/-) and wild
      type (Hexb +/+) mice were perfuse fixed and analyzed by routine light and
      electron microscopy (LM and EM, respectively) as well as with immunocytochemistry
      employing antibodies to lysosomal proteins. In the testis, the morphological
      appearance and topographical arrangement of the cell types of the seminiferous
      epithelium of Hexb -/- mice were similar to those of wild-type animals at both
      ages. Both Sertoli and germ cells appeared to be unaffected. However, at both
      ages, myoid cells and macrophages showed an increased number of lysosomes in
      their cytoplasm as compared with the number seen in controls. The epithelial
      cells of the efferent ducts also showed an accumulation of lysosomes that
      increased with age as compared with controls. Principal cells of the entire
      epididymis revealed an increase in the size and number of lysosomes at 1 month of
      age as compared with those of controls, and by 3 months, these lysosomes often
      filled the supranuclear and basal regions of the cells. Narrow cells of the
      distal initial segment and intermediate zone, normally slender cells showing
      several lysosomes, became greatly enlarged and entirely filled with lysosomes in
      Hexb -/- mice. Clear cells of the caput, corpus, and cauda regions also showed a
      progressive increase in the size and number of lysosomes with age as compared
      with controls; the clear cells of the mutant mice were often enlarged and at
      times bulged into the lumen. Some basal cells of each epididymal region in Hexb 
      /- mice were similar to controls at 1 and 3 months, showing few lysosomes, while
      others showed an accumulation of lysosomes. Lysosomes of all affected epithelial
      cells were of varying sizes, but many large ones were present, apparently
      resulting from lysosomal fusion. Although pale stained, their identification as
      lysosomes was confirmed by EM immunocytochemistry with anti-cathepsin D and anti
      Hex A antibodies. Predominantly in the proximal initial segment, large, pale
      cellular aggregates were noted in the LM analysis at the base of the epithelium,
      which by EM analysis were identified as belonging to two different cell types,
      narrow cells and halo cells. Taken together, these data reveal an increase in the
      size and number of lysosomes in all epithelial cell types lining the efferent
      ducts and entire epididymis as well as in myoid cells and macrophages of the
      testis. In the light of data showing epididymal defects restricted predominantly
      to the initial segment in Hexa -/- (Hex A-deficient) mice, our data on the Hexb 
      /- mice demonstrate a major role for Hex that can be fulfilled by either Hex A or
      Hex B in the epididymis.

PMID- 10591619
TI  - II. Characterization and development of the regional- and cellular-specific
      abnormalities in the epididymis of mice with beta-hexosaminidase A deficiency.
AB  - Beta-hexosaminidase (Hex) is a lysosomal enzyme that exists as two isoenzymes:
      Hex A (subunit structure alphabeta) and Hex B (betabeta). Its presence in the
      testis and epididymis suggests important roles for Hex and its substrates in male
      fertility and reproductive functions. Disruption of the Hexa gene encoding the
      alpha-subunit of Hex has led to the generation of a mildly affected mouse model
      of human Tay-Sachs disease, allowing us the opportunity to analyze the effects of
      isolated Hex A deficiency on epithelial cellular morphology of the male
      reproductive tract. At 5 weeks and at 3, 5, and 12 months, the testes, efferent
      ducts and epididymides of Hex A-deficient (Hexa -/-) and wild-type (Hexa +/+)
      mice were perfuse fixed and analyzed by routine light and electron microscopy as
      well as with immunocytochemistry employing antibodies to lysosomal enzymes. In
      the testis, the seminiferous epithelium of Hexa -/- mice appeared comparable to
      that of wild-type mice in appearance and topographical arrangement of its cell
      types at all ages examined. Also, no differences were noted for the efferent
      ducts. In contrast, there were striking abnormalities in the epididymides of the
      mutant mice; however, the abnormalities were mainly restricted to the initial
      segment and intermediate zone. Principal cells of these regions at 5 weeks showed
      a dramatic increase in the number of lysosomes as compared with those from wild
      type animals, and this progressed with increasing age. Furthermore, unlike the
      few small lysosomes present in wild-type mice, those of Hexa -/- mice were at
      times enlarged and often filled the supranuclear and basal regions of these
      cells. In the light microscope, large, dense cellular aggregates were noted at
      the base of the epithelium in the proximal initial segment that corresponded in
      the electron microscope to two different cell types, both of which increased in
      size with age. One aggregate was considered to belong to narrow cells on the
      basis of the presence of numerous cup-shaped vesicles characteristic of these
      cells; they appeared to be dislocated from the upper half of the epithelium. In
      the distal initial segment and intermediate zone, narrow cells were readily
      identified, but rather than being slender as in the control animals, they were
      greatly enlarged and filled with pale lysosomes in mutant mice. The second type
      of cellular aggregate noted in the proximal initial segment corresponded to halo
      cells. They contained numerous small and large lysosomes and small, Golgi
      related, dense, core granules characteristic of halo cells. On the basis of the
      large size of these cells, they appeared to be actively internalizing substances
      from the intercellular space. In contrast, principal and clear cells of the
      caput, corpus, and cauda regions did not appear to show a significant increase in
      number or size of lysosomes as compared with those of wild-type animals. All
      structures identified as lysosomes in the various cell types were immunoreactive
      for cathepsin D. The present data thus reveal that isolated Hex A deficiency
      results in region- and cell-specific abnormalities in the epididymis but in no
      apparent abnormalities in the testis or efferent ducts. Specific roles for Hex A
      that cannot be compensated for by other isozymes of Hex appear to exist within
      lysosomes of epithelial cells predominantly of the initial segment and
      intermediate zone. Taken together, the results also suggest that the inability to
      degrade endocytosed substrates normally acted upon by Hex A in lysosomes of
      principal and narrow cells leads to their accumulation, eventual fusion, and
      increased size.

PMID- 10591620
TI  - Human embryonic stem cells.
AB  - Embryonic stem (ES) cells are cells derived from the early embryo that can be
      propagated indefinitely in the primitive undifferentiated state while remaining
      pluripotent; they share these properties with embryonic germ (EG) cells.
      Candidate ES and EG cell lines from the human blastocyst and embryonic gonad can
      differentiate into multiple types of somatic cell. The phenotype of the
      blastocyst-derived cell lines is very similar to that of monkey ES cells and
      pluripotent human embryonal carcinoma cells, but differs from that of mouse ES
      cells or the human germ-cell-derived stem cells. Although our understanding of
      the control of growth and differentiation of human ES cells is quite limited, it
      is clear that the development of these cell lines will have a widespread impact
      on biomedical research.

PMID- 10591621
TI  - Reprogramming nuclei: insights from cloning, nuclear transfer and heterokaryons.
AB  - Mammals and amphibians can be cloned following the transfer of embryonic nuclei
      into enucleated eggs or oocytes. As nuclear functions become more specialized in
      the differentiated cells of an adult, successful cloning using these nuclei as
      donors becomes more difficult. Differentiation involves the assembly of
      specialized forms of repressive chromatin including linker histones, Polycomb
      group proteins and methyl-CpG-binding proteins. These structures compartmentalize
      chromatin into functional domains and maintain the stability of the
      differentiated state through successive cell divisions. Efficient cloning
      requires the erasure of these structures. The erasure can be accomplished through
      use of molecular chaperones and enzymatic activities present in the oocyte, egg
      or zygote. We discuss the mechanisms involved in reprogramming nuclei after
      nuclear transfer and compare them with those that occur during remodeling of
      somatic nuclei after heterokaryon formation. Finally we discuss how one might
      alter the properties of adult nuclei to improve the efficiency of cloning.

PMID- 10591622
TI  - Clathrin plays a novel role in the regulation of cell polarity, pseudopod
      formation, uropod stability and motility in Dictyostelium.
AB  - Although the traditional role of clathrin has been in vesicle trafficking and the
      internalization of receptors, a novel role in cytokinesis was recently revealed
      in an analysis of a clathrin-minus Dictyostelium mutant (chc(-)). chc(-) cells
      grown in suspension were demonstrated to be defective in assembling myosin II
      into a normal contractile ring. To test whether this defect reflected a more
      general one of cytoskeletal dysfunction, chc(-) cells were analyzed for cell
      polarity, pseudopod formation, uropod stability, cell locomotion, chemotaxis,
      cytoskeletal organization and vesicle movement. chc(-) cells crawled, chemotaxed,
      localized F-actin in pseudopods, organized their microtubule cytoskeleton in a
      relatively normal fashion and exhibited normal vesicle dynamics. Although chc(-)
      cells extended pseudopods from the anterior half of the cell with the same
      frequency as normal chc(+) cells, they extended pseudopods at twice the normal
      frequency from the posterior half of the cell. The uropods of chc(-) cells also
      exhibited spatial instability. These defects resulted in an increase in
      roundness, a reduction in polarity, a reduction in velocity, a dramatic increase
      in turning, a high frequency of 180 degrees direction reversals and a decrease in
      the efficiency of chemotaxis. All defects were reversed in a rescued strain.
      These results are the first to suggest a novel role for clathrin in cell
      polarity, pseudopod formation, uropod stability and locomotion. It is
      hypothesized that clathrin functions to suppress pseudopod formation and to
      stabilize the uropod in the posterior half of a crawling cell, two behavioral
      characteristics that are essential for the maintenance of cellular polarity,
      efficient locomotion and efficient chemotaxis.

PMID- 10591623
TI  - HTLV-1-induced cell fusion is limited at two distinct steps in the fusion pathway
      after receptor binding.
AB  - Human T-cell leukemia virus type 1 (HTLV-1) is notable among retroviruses for its
      poor ability to infect permissive cells, particularly as cell free virus. The
      virus is most efficiently transmitted between individuals by infected cells,
      where it is presumed that intracellular particles and viral RNA are transferred
      to target cells following fusion. Although the mandatory first step for HTLV-1
      fusion is the binding of envelope SU (gp46) to the receptor, the events which
      follow this interaction and lead to fusion and infection have not been well
      characterized. To investigate these events, we studied two HTLV-1 chronically
      infected cell lines with different abilities to fuse with K562 target cells.
      Although not inherently fusion incompetent, the HTLV-1 envelope protein on MT2
      cells was poorly able to undergo a change in membrane hydrophobicity required for
      fusion with the target cell membrane after binding to the receptor. High level
      expression of a fusion-competent HTLV-1 envelope protein on MT2 cells had little
      effect on improving this suggesting that the defect was encoded by the parent
      cell. Visible syncytia were seen after incubation of these cells with K562 target
      cells but complete fusion as measured by transfer of cellular contents into the
      recipient cell was not observed. In C91-PL cells, binding of SU to the receptor
      resulted in a sustained hydrophobic change of envelope accompanied by a
      cytopathic effect in mixed cell cultures and complete fusion. However, in C91-PL
      cells, overexpression of envelope protein blocked the transfer of cell contents
      after receptor engagement and initiation of cytopathic membrane changes,
      indicating that post binding fusion events were blocked. These data suggest that
      HTLV-1 fusion is a multistep process which is susceptible to inhibition at two
      seperate stages of the fusion pathway post receptor binding. This, and the
      inefficient infection by cell-free virions, may explain the poor infectivity of
      HTLV-1 in vivo and suggests strategies for preventative therapy.

PMID- 10591624
TI  - Analysis of tight junctions during neutrophil transendothelial migration.
AB  - Intercellular junctions have long been considered the main sites through which
      adherent neutrophils (PMNs) penetrate the endothelium. Tight junctions (TJs;
      zonula occludens) are the most apical component of the intercellular cleft and
      they form circumferential belt-like regions of intimate contact between adjacent
      endothelial cells. Whether PMN transmigration involves disruption of the TJ
      complex is unknown. We report here that endothelial TJs appear to remain intact
      during PMN adhesion and transmigration. Human umbilical vein endothelial cell
      (HUVEC) monolayers, a commonly used model for studying leukocyte trafficking,
      were cultured in astrocyte-conditioned medium to enhance TJ expression.
      Immunofluorescence microscopy and immunoblot analysis showed that activated PMN
      adhesion to resting monolayers or PMN migration across interleukin-1-treated
      monolayers does not result in widespread proteolytic loss of TJ proteins (ZO-1,
      ZO-2, and occludin) from endothelial borders. Ultrastructurally, TJs appear
      intact during and immediately following PMN transendothelial migration.
      Similarly, transendothelial electrical resistance is unaffected by PMN adhesion
      and migration. Previously, we showed that TJs are inherently discontinuous at
      tricellular corners where the borders of three endothelial cells meet and PMNs
      migrate preferentially at tricellular corners. Collectively, these results
      suggest that PMN migration at tricellular corners preserves the barrier
      properties of the endothelium and does not involve widespread disruption of
      endothelial TJs.

PMID- 10591625
TI  - Vascular endothelial growth factor (VEGF) in cartilage neovascularization and
      chondrocyte differentiation: auto-paracrine role during endochondral bone
      formation.
AB  - Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF)
      induces endothelial cell migration and proliferation in culture and is strongly
      angiogenic in vivo. VEGF synthesis has been shown to occur in both normal and
      transformed cells. The receptors for the factor have been shown to be localized
      mainly in endothelial cells, however, the presence of VEGF synthesis and the VEGF
      receptor in cells other than endothelial cells has been demonstrated.
      Neoangiogenesis in cartilage growth plate plays a fundamental role in
      endochondral ossification. We have shown that, in an avian in vitro system for
      chondrocyte differentiation, VEGF was produced and localized in cell clusters
      totally resembling in vivo cartilage. The factor was synthesized by hypertrophic
      chondrocytes and was released into their conditioned medium, which is highly
      chemotactic for endothelial cells. Antibodies against VEGF inhibited endothelial
      cell migration induced by chondrocyte conditioned media. Similarly, endothelial
      cell migration was inhibited also by antibodies directed against the VEGF
      receptor 2/Flk1 (VEGFR2). In avian and mammalian embryo long bones, immediately
      before vascular invasion, VEGF was distinctly localized in growth plate
      hypertrophic chondrocytes. In contrast, VEGF was not observed in quiescent and
      proliferating chondrocytes earlier in development. VEGF receptor 2 colocalized
      with the factor both in hypertrophic cartilage in vivo and hypertrophic cartilage
      engineered in vitro, suggesting an autocrine loop in chondrocytes at the time of
      their maturation to hypertrophic cells and of cartilage erosion. Regardless of
      cell exposure to exogenous VEGF, VEGFR-2 phosphorylation was recognized in
      cultured hypertrophic chondrocytes, supporting the idea of an autocrine
      functional activation of signal transduction in this non-endothelial cell type as
      a consequence of the endogenous VEGF production. In summary we propose that VEGF
      is actively responsible for hypertrophic cartilage neovascularization through a
      paracrine release by chondrocytes, with invading endothelial cells as a target.
      Furthermore, VEGF receptor localization and signal transduction in chondrocytes
      strongly support the hypothesis of a VEGF autocrine activity also in
      morphogenesis and differentiation of a mesoderm derived cell.

PMID- 10591626
TI  - Src tyrosine kinase activity down-regulates Rho-dependent responses during
      Shigella entry into epithelial cells and stress fibre formation.
AB  - Invasion of epithelial cells by Shigella, the causative agent of bacillary
      dysentery, is dependent upon the formation of characteristic membrane ruffles
      that engulf the bacteria in a macropinocytic-like process. We show here that
      Cdc42 and Rac GTPases, but not Rho;, are critical for actin polymerisation,
      whereas Rho; is necessary for the recruitment of ezrin and Src at the site of
      entry. Remarkably, cells expressing constitutively active Src did not show ezrin
      recruitment at Shigella entry foci. In these cells, formation of stress fibres
      induced by LPA stimulation, or microinjection of activated Rho; (V14Rho), was
      inhibited. Src-mediated tyrosyl-phosphorylation of p190RhoGAP correlated with
      changes in the ability of p190RhoGAP to interact with Rho;, suggesting that Src
      regulates Rho; function via p190RhoGAP. We propose that Rho; activation is
      required for proper organisation of Shigella entry foci and for Src recruitment,
      and that Src tyrosine kinase activity, in turn, down-regulates the function of
      Rho; at the site of Shigella entry. The significance of this negative regulatory
      loop on Rho;-dependent responses is discussed.

PMID- 10591627
TI  - Plastid tubules of higher plants are tissue-specific and developmentally
      regulated.
AB  - Green fluorescent stroma filled tubules (stromules) emanating from the plastid
      surface were observed in transgenic plants containing plastid-localized green
      fluorescent protein (GFP). These transgenic tobacco plants were further
      investigated by epifluorescence and confocal laser scanning microscopy (CSLM) to
      identify developmental and/or cell type specific differences in the abundance and
      appearance of stromules and of plastids. Stromules are rarely seen on chlorophyll
      containing plastids in cell types such as trichomes, guard cells or mesophyll
      cells of leaves. In contrast, they are abundant in tissues that contain
      chlorophyll-free plastids, such as petal and root. The morphology of plastids in
      roots and petals is highly dynamic, and plastids are often elongated and
      irregular. The shapes, size, and position of plastids vary in particular
      developmental zones of the root. Furthermore, suspension cells of tobacco exhibit
      stromules on virtually every plastid with two major forms of appearance. The
      majority of cells show a novel striking 'octopus- or millipede-like' structure
      with plastid bodies clustered around the nucleus and with long thin stromules of
      up to at least 40 (micro)m length stretching into distant areas of the cell. The
      remaining cells have plastid bodies distributed throughout the cell with short
      stromules. Photobleaching experiments indicated that GFP can flow through
      stromules and that the technique can be used to distinguish interconnected
      plastids from independent plastids.

PMID- 10591628
TI  - Protein phosphatases PP1 and PP2A are located in distinct positions in the
      Chlamydomonas flagellar axoneme.
AB  - We postulated that microcystin-sensitive protein phosphatases are integral
      components of the Chlamydomonas flagellar axoneme, positioned to regulate inner
      arm dynein activity. To test this, we took a direct biochemical approach.
      Microcystin-Sepharose affinity purification revealed a prominent 35-kDa axonemal
      protein, predicted to be the catalytic subunit of type-1 protein phosphatase
      (PP1c). We cloned the Chlamydomonas PP1c and produced specific polyclonal peptide
      antibodies. Based on western blot analysis, the 35-kDa PP1c is anchored in the
      axoneme. Moreover, analysis of flagella and axonemes from mutant strains revealed
      that PP1c is primarily, but not exclusively, anchored in the central pair
      apparatus, associated with the C1 microtubule. Thus, PP1 is part of the central
      pair mechanism that controls flagellar motility. Two additional axonemal proteins
      of 62 and 37 kDa were also isolated using microcystin-Sepharose affinity. Based
      on direct peptide sequence and western blots, these proteins are the A- and C
      subunits of type 2A protein phosphatase (PP2A). The axonemal PP2A is not one of
      the previously identified components of the central pair apparatus, outer arm
      dynein, inner arm dynein, dynein regulatory complex or the radial spokes. We
      postulate PP2A is anchored on the doublet microtubules, possibly in position to
      directly control inner arm dynein activity.

PMID- 10591629
TI  - Ropporin, a sperm-specific binding protein of rhophilin, that is localized in the
      fibrous sheath of sperm flagella.
AB  - The small GTPase Rho; functions as a molecular switch that regulates various
      cellular processes such as cell adhesion, motility, gene expression and
      cytokinesis. We previously isolated several putative Rho; targets including
      rhophilin which bound selectively to the GTP-bound form of Rho;. Rhophilin is
      expressed highly in testis and is localized specifically in sperm flagella. The
      presence of a PDZ domain at the carboxy terminus of rhophilin suggested that
      rhophilin works as an adaptor molecule. To test this hypothesis, we employed a
      yeast two hybrid system using the rhophilin PDZ domain as a bait, and screened a
      mouse testis cDNA library. We isolated several positive clones containing the
      same insert. The open reading frame of the cDNA encoded a novel protein of 212
      amino acids designated as ropporin from a Japanese word 'oppo' (the tail). The
      amino-terminal 40 amino acid sequence of ropporin showed high homology to that of
      the regulatory subunit of type II cAMP-dependent protein kinase, which is
      involved in dimerization and binding to A-kinase anchoring proteins.
      Consistently, a yeast two hybrid assay and gel filtration of recombinant ropporin
      indicated that ropporin dimerizes through this domain. Deletion analysis
      indicated that the carboxy-terminal four amino acids are essential for binding of
      ropporin to rhophilin, and ropporin and RhoV14 coprecipitated in the presence of
      rhophilin in vitro. Northern blot analysis showed that ropporin is exclusively
      expressed in testis, and induced at the late stage of spermatogenesis. This
      induction paralleled that of rhophilin. Immunocytochemistry using anti-ropporin
      antibody showed that ropporin is localized in the principal piece and the end
      piece of sperm flagella. Electronmicroscopy revealed that ropporin is mostly
      localized in the inner surface of the fibrous sheath while rhophilin is present
      in the outer surface of the outer dense fiber. These results suggest that
      rhophilin and ropporin may form a complex in sperm flagella.

PMID- 10591630
TI  - Source, catabolism and role of the tetrapeptide N-acetyl-ser-asp-lys-Pro within
      the testis.
AB  - The tetrapeptide N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (AcSDKP) is a natural
      regulator of hematopoietic stem cell proliferation. The present study was aimed
      at investigating the presence and the role of AcSDKP in rat testis. Specific
      immunoreactivity was always observed in the interstitial tissue at all stages of
      testicular development and in elongated spermatids at 45 days of age and in
      adults. In accordance with the interstitial labeling, high AcSDKP levels were
      detected in Leydig cell and testicular macrophage culture media and cell
      extracts, as well as in the testicular interstitial fluid (TIF). Much lower
      concentrations were found in peritubular cells and Sertoli cells cultures,
      whereas very low concentrations were present in cultured spermatocytes and
      spermatids. In contrast to the slight degradation rate of AcSDKP observed in the
      spermatocyte and spermatid culture media, no catabolism of the peptide was seen
      in testicular somatic cell culture medium. Furthermore, the degradation rate of
      AcSDKP was much lower in TIF than in peripheral blood plasma. Despite the very
      strong evidence indicating that Leydig cells and testicular macrophages produce
      AcSDKP, the selective destruction of these cells did not result in any change in
      AcSDKP levels in TIF or in plasma. This suggests a compensatory mechanism
      ensuring constant levels of the peptide in TIF when interstitial cells are
      absent. Finally, in vitro, in the presence of AcSDKP, significantly more
      [(3)H]thymidine incorporation was found in A spermatogonia. In conclusion, this
      study establishes the presence of very high concentrations of AcSDKP in rat
      testis and demonstrates its Leydig cell and testicular macrophage origin. The
      presence of AcSDKP in the TIF and its stimulatory effect on thymidine
      incorporation in spermatogonia very strongly suggest its implication in the
      paracrine control of spermatogenesis.

PMID- 10591631
TI  - Extracellular signal-regulated kinase functions in the urokinase receptor
      dependent pathway by which neutralization of low density lipoprotein receptor
      related protein promotes fibrosarcoma cell migration and matrigel invasion.
AB  - The low density lipoprotein receptor-related protein (LRP) has been reported to
      regulate cellular migration. In this study, an antisense RNA expression strategy
      was used to reduce LRP to undetectable levels in HT 1080 fibrosarcoma cells. The
      LRP-deficient cells demonstrated increased levels of cell-surface uPAR, higher
      levels of uPA in conditioned medium, increased migration on vitronectin-coated
      surfaces, and increased invasion of Matrigel. LRP-deficient cells also
      demonstrated increased levels of phosphorylated extracellular signal-regulated
      kinase (ERK) in the absence of exogenous stimulants. Antibodies which block
      binding of endogenously produced uPA to uPAR reduced ERK phosphorylation and
      migration of LRP-deficient cells to the levels observed with control cells.
      Inhibitors of ERK activation, including PD098059 and dominant-negative MEK1, also
      decreased the migration of LRP-deficient but not control cells. By contrast,
      constitutively active MEK1 stimulated the migration of control but not LRP
      deficient cells. Although Matrigel invasion by LRP-deficient cells was inhibited
      by the proteinase inhibitor, aprotinin, PD098059 in combination with aprotinin
      was necessary for an optimal effect. Expression of the VLDL receptor in LRP
      deficient cells reversed the changes in cellular migration and invasion. These
      studies demonstrate that binding of endogenously produced uPA to uPAR may serve
      as a major determinant of basal levels of activated ERK and, by this mechanism,
      regulate cellular migration and invasion. By regulating the uPA/uPAR system, LRP
      may also regulate ERK activation, cellular migration, and invasion.

PMID- 10591632
TI  - COPI vesicles accumulating in the presence of a GTP restricted arf1 mutant are
      depleted of anterograde and retrograde cargo.
AB  - Microinjection of the slowly hydrolyzable GTP analogue GTP(gamma)S or the ectopic
      expression of a GTP restricted mutant of the small GTPase arf1 (arf1[Q71L]) leads
      to the rapid accumulation of COPI coated vesicles and buds in living cells. This
      effect is blocked at 15 degrees C and by microinjection of antibodies against
      (beta)-COP. Anterograde and retrograde membrane protein transport markers, which
      have been previously shown to be incorporated into COPI vesicles between the
      endoplasmic reticulum and Golgi complex, are depleted from the GTP(gamma)S or
      arf1[Q71L] induced COPI coated vesicles and buds. In contrast, in control cells
      30 to 60% of the COPI carriers co-localize with these markers. These in vivo data
      corroborate recent in vitro work, suggesting that GTP(gamma)S and arf1[Q71L]
      interfere with the sorting of membrane proteins into Golgi derived COPI vesicles,
      and provide the first in vivo evidence for a role of GTP hydrolysis by arf1 in
      the sorting of cargo into COPI coated vesicles and buds.

PMID- 10591633
TI  - Yeast Golgi SNARE interactions are promiscuous.
AB  - The transport of proteins between various compartments of the secretory pathway
      occurs by the budding of vesicles from one membrane and their fusion with
      another. A key event in this process is the selective recognition of the target
      membrane by the vesicle and the current view is that SNARE protein interactions
      likely play a central role in vesicle-target recognition and or membrane fusion.
      In yeast, only a single syntaxin (Sed5p) is required for Golgi transport and
      Sed5p is known to bind to at least 7 SNARE proteins. However, the number of Sed5p
      containing SNARE complexes that exist in cells is not known. In this study we
      examined direct pair-wise interactions between full length soluble recombinant
      forms of SNAREs (Sed5p, Sft1p, Ykt6p, Vti1p, Gos1p, Sec22p, Bos1p, and Bet1p)
      involved in ER-Golgi and intra-Golgi membrane trafficking. In the binding assay
      that we describe here the majority of SNARE-binary interactions tested were
      positive, indicating that SNARE-SNARE interactions although promiscuous are not
      entirely non-selective. Interactions between a number of the genes encoding these
      SNAREs are consistent with our binding data and taken together our results
      suggest that functionally redundant Golgi SNARE-complexes exist in yeast. In
      particular, over-expression of Bet1p (a SNARE required for ER-Golgi and Golgi-ER
      traffic) and can bypass the requirement for the otherwise essential SNARE Sft1p
      (required for intra-Golgi traffic), suggesting that Bet1p either functions in a
      parallel pathway with Sft1p or can be incorporated into SNARE-complexes in place
      of Sftp1. None-the-less this result suggests that Bet1p can participate in two
      distinct trafficking steps, cycling between the ER and Golgi as well as in
      retrograde intra-Golgi traffic. In addition, suppressor genetics together with
      the analysis of the phenotypes of conditional mutations in Sft1p and Ykt6p, are
      consistent with a role for these SNAREs in more than one trafficking step. We
      propose that different combinations of SNAREs form complexes with Sed5p and are
      required for multiple steps in ER-Golgi and intra-Golgi vesicular traffic. And
      that the apparent promiscuity of SNARE-SNARE binding interactions, together with
      the requirement for some SNAREs in more than one trafficking step, supports the
      view that the specificity of vesicle fusion events cannot be explained solely on
      the basis of SNARE-SNARE interactions.

PMID- 10591634
TI  - Skh1, the MEK component of the mkh1 signaling pathway in Schizosaccharomyces
      pombe.
AB  - We previously reported the identification of Mkh1, a MEK kinase in
      Schizosaccharomyces pombe that is required for cell wall integrity, and we
      presented genetic evidence that Pmk1/Spm1, a MAP kinase, functions downstream
      from Mkh1 in the same pathway. Here, we report the identification of Skh1, a MEK
      (MAP kinase kinase) in S. pombe. The sequence of Skh1 is nearly identical to that
      of the recently reported Pek1 sequence. We present biochemical and genetic
      evidence that Skh1 is the MEK component of the Mkh1-Spm1 MAP kinase cascade. Our
      yeast two-hybrid results indicate that Mkh1, Skh1, and Spm1 physically interact
      to form a ternary complex. Deletion of mkh1, skh1 or spm1 results in identical
      phenotypes, including sensitivity to (beta)-glucanase treatment, growth
      inhibition on media containing KCl, and filamentous growth on medium containing
      caffeine. Double mutant strains exhibit phenotypes that are identical to the
      single mutant strains. Furthermore, expression of an activated HA-Skh1(DD
      )protein suppressed these defects in mkh1(delta) cells, and overexpression of
      Spm1 suppressed these defects in skh1(delta) cells. We also show that HA-Spm1 is
      hyper-phosphorylated on tyrosine residues in cells co-expressing the activated HA
      Skh1(DD) protein. Furthermore, we found the phosphorylated/activated form of GFP
      HA-Spm1 at detectable levels in wild-type cells, but not at appreciable levels in
      mkh1(delta) or skh1(delta) cells expressing this fusion protein. Together, our
      results indicate that Mkh1, Skh1 and Spm1 constitute a MAPK cascade in fission
      yeast.

PMID- 10591635
TI  - Stem cell factor protects germ cells from apoptosis in vitro.
AB  - Stem cell factor (SCF) plays an important role in migration, adhesion,
      proliferation, and survival of primordial germ cells and spermatogonia during
      testicular development. However, the function of SCF in the adult testis is
      poorly described. We have previously shown that, in the presence of SCF, there
      were more type A spermatogonia incorporating thymidine at stage XII of rat
      seminiferous tubules cultured in vitro than in the absence of SCF, implying that
      the increased DNA synthesis might result from enhanced survival of spermatogonia.
      To explore the potential pro-survival function of SCF during spermatogenesis, the
      seminiferous tubules from stage XII were cultured in the presence or absence of
      SCF (100 ng/ml) for 8, 24, 48, and 72 hours, respectively, and apoptosis was
      analyzed by DNA laddering and in situ 3'-end labeling (ISEL) staining.
      Surprisingly, not only spermatogonia, but also spermatocytes and spermatids, were
      protected from apoptosis in the presence of SCF. Apoptosis took place much later
      and was less severe in the SCF-treated tubules than in the controls. Based on
      previous studies showing that FSH prevents germ cells from undergoing apoptosis
      in vitro, and that SCF level is increased dramatically in response to FSH
      stimulation, we also tested if the pro-survival effect of FSH is mediated through
      SCF by using a function-blocking monoclonal antibody, ACK-2, to block SCF/c-kit
      interaction. After 24 hours of blockade, the protective effect of FSH was
      partially abolished, as manifested by DNA laddering and ISEL analyses. The
      present study demonstrates that SCF acts as an important survival factor for germ
      cells in the adult rat testis and FSH pro-survival effect on germ cells is
      mediated partially through the SCF/c-kit pathway.

PMID- 10591636
TI  - Lymphoid adhesion promotes human thymic epithelial cell survival via NF-(kappa)B
      activation.
AB  - Inside the thymus, thymic epithelial cells and thymocytes show an interdependent
      relationship for their functional differentiation and development. As regards
      possible interdependency for their mutual survival, it is clear that lympho
      epithelial adhesion can control the survival of developing thymocytes whereas the
      effects of lymphoid adhesion on epithelial cell survival have never been
      described. To address this issue, we performed co-cultures between normal human
      thymic epithelial cells (TEC) and a mature lymphoid T cell line (H9) or
      unfractionated thymocytes. TEC were induced to apoptosis by growth factor
      deprivation and the level of cell death was measured by flow cytometry. TEC
      stimulated by cell adhesion showed a significant reduced apoptosis when compared
      to the control and this phenomenon was associated with increased binding activity
      of NF-(kappa)B, as measured by gel shift analysis. The activation of NF-(kappa)B
      was necessary to promote survival, since its inhibition by acetyl salicylic acid
      prevented the promoting effect. The mAb-mediated crosslinking of
      (alpha)(3)(beta)(1) was considered as a potential inducer of TEC survival, since
      we have previously demonstrated that the engagement of this integrin was able to
      induce NF-(kappa)B activation in TEC. The crosslinking of (alpha)(3)(beta)(1),
      which clustered at the lympho-epithelial contact sites, partially reproduced the
      promoting activity of cell adhesion. These results highlight that lympho
      epithelial adhesion can control the survival of thymic epithelial cells through
      an intracellular pathway which requires the activation of NF-(kappa)B and is
      triggered by integrins of the (beta)(1) family.

PMID- 10591638
TI  - Biological and chemical response of the equatorial pacific ocean to the 1997-98
      El Nino
AB  - During the 1997-98 El Nino, the equatorial Pacific Ocean retained 0. 7 x 10(15)
      grams of carbon that normally would have been lost to the atmosphere as carbon
      dioxide. The surface ocean became impoverished in plant nutrients, and
      chlorophyll concentrations were the lowest on record. A dramatic recovery
      occurred in mid-1998, the system became highly productive, analogous to coastal
      environments, and carbon dioxide flux out of the ocean was again high. The
      spatial extent of the phytoplankton bloom that followed recovery from El Nino was
      the largest ever observed for the equatorial Pacific. These chemical and
      ecological perturbations were linked to changes in the upwelling of nutrient
      enriched waters. The description and explanation of these dynamic changes would
      not have been possible without an observing system that combines biological,
      chemical, and physical sensors on moorings with remote sensing of chlorophyll.

PMID- 10591637
TI  - Implication of tubby proteins as transcription factors by structure-based
      functional analysis.
AB  - Tubby-like proteins (TULPs) are found in a broad range of multicellular
      organisms. In mammals, genetic mutation of tubby or other TULPs can result in one
      or more of three disease phenotypes: obesity (from which the name "tubby" is
      derived), retinal degeneration, and hearing loss. These disease phenotypes
      indicate a vital role for tubby proteins; however, no biochemical function has
      yet been ascribed to any member of this protein family. A structure-directed
      approach was employed to investigate the biological function of these proteins.
      The crystal structure of the core domain from mouse tubby was determined at a
      resolution of 1.9 angstroms. From primarily structural clues, experiments were
      devised, the results of which suggest that TULPs are a unique family of bipartite
      transcription factors.

PMID- 10591639
TI  - Constraints on slow earthquake dynamics from a swarm in central italy
AB  - Several clustered slow earthquakes have been recorded by a geodetic
      interferometer in central Italy. The strain rise times of the events range from
      tens to thousands of seconds, and the seismic moment scales with the square root
      of the rise time. This scaling law contrasts with the conservative assumption of
      constant rupture velocity in fault modeling but is consistent with the occurrence
      of a slow rupture propagation analogous to heat diffusion in a slab.

PMID- 10591640
TI  - Possible ancient oceans on Mars: evidence from Mars Orbiter Laser Altimeter data.
AB  - High-resolution altimetric data define the detailed topography of the northern
      lowlands of Mars, and a range of data is consistent with the hypothesis that a
      lowland-encircling geologic contact represents the ancient shoreline of a large
      standing body of water present in middle Mars history. The contact altitude is
      close to an equipotential line, the topography is smoother at all scales below
      the contact than above it, the volume enclosed by this contact is within the
      range of estimates of available water on Mars, and a series of extensive terraces
      parallel the contact in many places.

PMID- 10591641
TI  - More than 200 meters of lake ice above subglacial Lake Vostok, Antarctica.
AB  - Isotope studies show that the Vostok ice core consists of ice refrozen from Lake
      Vostok water, from 3539 meters below the surface of the Antarctic ice sheet to
      its bottom at about 3750 meters. Additional evidence comes from the total gas
      content, crystal size, and electrical conductivity of the ice. The Vostok site is
      a likely place for water freezing at the lake-ice interface, because this
      interface occurs at a higher level here than anywhere else above the lake.
      Isotopic data suggest that subglacial Lake Vostok is an open system with an
      efficient circulation of water that was formed during periods that were slightly
      warmer than those of the past 420,000 years. Lake ice recovered by deep drilling
      is of interest for preliminary investigations of lake chemistry and bedrock
      properties and for the search for indigenous lake microorganisms. This latter
      aspect is of potential importance for the exploration of icy planets and moons.

PMID- 10591642
TI  - Geomicrobiology of subglacial ice above Lake Vostok, Antarctica.
AB  - Data from ice 3590 meters below Vostok Station indicate that the ice was accreted
      from liquid water associated with Lake Vostok. Microbes were observed at
      concentrations ranging from 2.8 x 10(3) to 3.6 x 10(4) cells per milliliter; no
      biological incorporation of selected organic substrates or bicarbonate was
      detected. Bacterial 16S ribosomal DNA genes revealed low diversity in the gene
      population. The phylotypes were closely related to extant members of the alpha-
      and beta-Proteobacteria and the Actinomycetes. Extrapolation of the data from
      accretion ice to Lake Vostok implies that Lake Vostok may support a microbial
      population, despite more than 10(6) years of isolation from the atmosphere.

PMID- 10591643
TI  - Microorganisms in the accreted ice of Lake Vostok, Antarctica.
AB  - Analysis of a portion of Vostok ice core number 5G, which is thought to contain
      frozen water derived from Lake Vostok, Antarctica (a body of liquid water located
      beneath about 4 kilometers of glacial ice), revealed between 2 x 10(2) and 3 x
      10(2) bacterial cells per milliliter and low concentrations of potential growth
      nutrients. Lipopolysaccharide (a Gram-negative bacterial cell biomarker) was also
      detected at concentrations consistent with the cell enumeration data, which
      suggests a predominance of Gram-negative bacteria. At least a portion of the
      microbial assemblage was viable, as determined by the respiration of carbon-14
      labeled acetate and glucose substrates during incubations at 3 degrees C and 1
      atmosphere. These accreted ice data suggest that Lake Vostok may contain viable
      microorganisms.

PMID- 10591644
TI  - Nanotube nanotweezers
AB  - Nanoscale electromechanical systems-nanotweezers-based on carbon nanotubes have
      been developed for manipulation and interrogation of nanostructures. Electrically
      conducting and mechanically robust carbon nanotubes were attached to independent
      electrodes fabricated on pulled glass micropipettes. Voltages applied to the
      electrodes closed and opened the free ends of the nanotubes, and this
      electromechanical response was simulated quantitatively using known nanotweezer
      structure and nanotube properties. The mechanical capabilities of the
      nanotweezers were demonstrated by grabbing and manipulating submicron clusters
      and nanowires. The conducting nanotube arms of the tweezers were also used for
      measuring the electrical properties of silicon carbide nanoclusters and gallium
      arsenide nanowires.

PMID- 10591645
TI  - Three-dimensional structures of the TAFII-containing complexes TFIID and TFTC.
AB  - TBP (TATA-binding protein)-associated factors (TAF(II)s) are components of large
      multiprotein complexes such as TFIID, TFTC, STAGA, PCAF/GCN5, and SAGA, which
      play a key role in the regulation of gene expression by RNA polymerase II. The
      structures of TFIID and TFTC have been determined at 3.5-nanometer resolution by
      electron microscopy and digital image analysis of single particles. Human TFIID
      resembles a macromolecular clamp that contains four globular domains organized
      around a solvent-accessible groove of a size suitable to bind DNA. TFTC is larger
      and contains five domains, four of which are similar to TFIID.

PMID- 10591646
TI  - Three-dimensional structure of the human TFIID-IIA-IIB complex.
AB  - The multisubunit transcription factor IID (TFIID) is an essential component of
      the eukaryotic RNA polymerase II machinery that works in concert with TFIIA (IIA)
      and TFIIB (IIB) to assemble initiation complexes at core eukaryotic promoters.
      Here the structures of human TFIID and the TFIID-IIA-IIB complex that were
      obtained by electron microscopy and image analysis to 35 angstrom resolution are
      presented. TFIID is a trilobed, horseshoe-shaped structure, with TFIIA and TFIIB
      bound on opposite lobes and flanking a central cavity. Antibody studies locate
      the TATA-binding protein (TBP) between TFIIA and TFIIB at the top of the cavity
      that most likely encompasses the TATA DNA binding region of the supramolecular
      complex.

PMID- 10591647
TI  - Control of early viral and bacterial distribution and disease by natural
      antibodies.
AB  - Natural antibodies are often dismissed from immunological analysis as
      "background," but they may play an important role in conferring immunity against
      infections. In antibody-free mice infected with various viruses or with Listeria
      monocytogenes, viral or bacterial titers in peripheral organs, including the
      kidney and brain, were 10 to 100 times greater than in antibody-competent mice
      (and enhanced their susceptibility to some infections), and titers in secondary
      lymphoid organs were 10 to 100 times lower than in antibody-competent mice. Thus,
      natural antibodies play a crucial role by preventing pathogen dissemination to
      vital organs and by improving immunogenicity through enhanced antigen-trapping in
      secondary lymphoid organs.

PMID- 10591648
TI  - The role of CCR7 in TH1 and TH2 cell localization and delivery of B cell help in
      vivo.
AB  - Subsets of murine CD4+ T cells localize to different areas of the spleen after
      adoptive transfer. Naive and T helper 1 (TH1) cells, which express the chemokine
      receptor CCR7, are home to the periarteriolar lymphoid sheath, whereas activated
      TH2 cells, which lack CCR7, form rings at the periphery of the T cell zones near
      B cell follicles. Retroviral transduction of TH2 cells with CCR7 forces them to
      localize in a TH1-like pattern and inhibits their participation in B cell help in
      vivo but not in vitro. Thus, differential expression of chemokine receptors
      results in unique cellular migration patterns that are important for effective
      immune responses.

PMID- 10591649
TI  - Impaired immunoproteasome assembly and immune responses in PA28-/- mice.
AB  - In vitro PA28 binds and activates proteasomes. It is shown here that mice with a
      disrupted PA28b gene lack PA28a and PA28b polypeptides, demonstrating that PA28
      functions as a hetero-oligomer in vivo. Processing of antigenic epitopes derived
      from exogenous or endogenous antigens is altered in PA28-/- mice. Cytotoxic T
      lymphocyte responses are impaired, and assembly of immunoproteasomes is greatly
      inhibited in mice lacking PA28. These results show that PA28 is necessary for
      immunoproteasome assembly and is required for efficient antigen processing, thus
      demonstrating the importance of PA28-mediated proteasome function in immune
      responses.

PMID- 10591650
TI  - Global transposon mutagenesis and a minimal Mycoplasma genome.
AB  - Mycoplasma genitalium with 517 genes has the smallest gene complement of any
      independently replicating cell so far identified. Global transposon mutagenesis
      was used to identify nonessential genes in an effort to learn whether the
      naturally occurring gene complement is a true minimal genome under laboratory
      growth conditions. The positions of 2209 transposon insertions in the completely
      sequenced genomes of M. genitalium and its close relative M. pneumoniae were
      determined by sequencing across the junction of the transposon and the genomic
      DNA. These junctions defined 1354 distinct sites of insertion that were not
      lethal. The analysis suggests that 265 to 350 of the 480 protein-coding genes of
      M. genitalium are essential under laboratory growth conditions, including about
      100 genes of unknown function.

PMID- 10591651
TI  - Functional human corneal equivalents constructed from cell lines.
AB  - Human corneal equivalents comprising the three main layers of the cornea
      (epithelium, stroma, and endothelium) were constructed. Each cellular layer was
      fabricated from immortalized human corneal cells that were screened for use on
      the basis of morphological, biochemical, and electrophysiological similarity to
      their natural counterparts. The resulting corneal equivalents mimicked human
      corneas in key physical and physiological functions, including morphology,
      biochemical marker expression, transparency, ion and fluid transport, and gene
      expression. Morphological and functional equivalents to human corneas that can be
      produced in vitro have immediate applications in toxicity and drug efficacy
      testing, and form the basis for future development of implantable tissues.

PMID- 10591652
TI  - Mouse models of tumor development in neurofibromatosis type 1.
AB  - Neurofibromatosis type 1 (NF1) is a prevalent familial cancer syndrome resulting
      from germ line mutations in the NF1 tumor suppressor gene. Hallmark features of
      the disease are the development of benign peripheral nerve sheath tumors
      (neurofibromas), which can progress to malignancy. Unlike humans, mice that are
      heterozygous for a mutation in Nf1 do not develop neurofibromas. However, as
      described here, chimeric mice composed in part of Nf1-/- cells do, which
      demonstrates that loss of the wild-type Nf1 allele is rate-limiting in tumor
      formation. In addition, mice that carry linked germ line mutations in Nf1 and p53
      develop malignant peripheral nerve sheath tumors (MPNSTs), which supports a
      cooperative and causal role for p53 mutations in MPNST development. These two
      mouse models provide the means to address fundamental aspects of disease
      development and to test therapeutic strategies.

PMID- 10591654
TI  - Microarray analysis of Drosophila development during metamorphosis.
AB  - Metamorphosis is an integrated set of developmental processes controlled by a
      transcriptional hierarchy that coordinates the action of hundreds of genes. In
      order to identify and analyze the expression of these genes, high-density DNA
      microarrays containing several thousand Drosophila melanogaster gene sequences
      were constructed. Many differentially expressed genes can be assigned to
      developmental pathways known to be active during metamorphosis, whereas others
      can be assigned to pathways not previously associated with metamorphosis.
      Additionally, many genes of unknown function were identified that may be involved
      in the control and execution of metamorphosis. The utility of this genome-based
      approach is demonstrated for studying a set of complex biological processes in a
      multicellular organism.

PMID- 10591655
TI  - Impact of El Nino and logging on canopy tree recruitment in borneo
AB  - Dipterocarpaceae, the dominant family of Bornean canopy trees, display the
      unusual reproductive strategy of strict interspecific mast-fruiting. During 1986
      99, more than 50 dipterocarp species dispersed seed only within a 1- to 2-month
      period every 3 to 4 years during El Nino-Southern Oscillation events. Synchronous
      seed production occurred across extensive areas and was essential for satiating
      seed predators. Logging of dipterocarps reduced the extent and intensity of these
      reproductive episodes and exacerbated local El Nino conditions. Viable seed and
      seedling establishment have declined as a result of climate, logging, and
      predators. Since 1991, dipterocarps have experienced recruitment failure within a
      national park, now surrounded by logged forest.

PMID- 10591653
TI  - Mouse tumor model for neurofibromatosis type 1.
AB  - Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by
      increased incidence of benign and malignant tumors of neural crest origin.
      Mutations that activate the protooncogene ras, such as loss of Nf1, cooperate
      with inactivating mutations at the p53 tumor suppressor gene during malignant
      transformation. One hundred percent of mice harboring null Nf1 and p53 alleles in
      cis synergize to develop soft tissue sarcomas between 3 and 7 months of age.
      These sarcomas exhibit loss of heterozygosity at both gene loci and express
      phenotypic traits characteristic of neural crest derivatives and human NF1
      malignancies.

PMID- 10591656
TI  - IL-10: An "immunologic scalpel" for atherosclerosis?

PMID- 10591657
TI  - Dissecting the genetic architecture of lipids, lipoproteins, and apolipoproteins:
      lessons from twin studies.
AB  - We review the ways in which twin studies have been used to investigate the
      genetic architecture of lipids, lipoproteins, and apolipoproteins. We focus on
      the age dependency of genetic effects and the importance of pleiotropy for the
      lipid system. Finally, consequences are discussed of age dependency and
      pleiotropy for the design and power of twin studies aimed at detecting the actual
      quantitative trait loci (QTLs) involved. It is concluded that twin studies have
      played an important role and will remain highly valuable for the elucidation of
      the genetic architecture of lipids, lipoproteins, and apolipoproteins. Twins can
      efficiently be used to identify the location and function of QTLs. Taking account
      of pleiotropy and age-dependent gene expression in study design and data analysis
      will improve the power and efficiency to find these QTLs for components of the
      lipid system.

PMID- 10591658
TI  - Platelet glycoprotein IIb/IIIa inhibitors: basic and clinical aspects.

PMID- 10591659
TI  - Procoagulant expression in platelets and defects leading to clinical disorders.
AB  - Hemostasis is a result of interactions between fibrillar structures in the
      damaged vessel wall, soluble components in plasma, and cellular elements in blood
      represented mainly by platelets and platelet-derived material. During formation
      of a platelet plug at the damaged vessel wall, factors IXa and VIIIa form the
      "tenase" complex, leading to activation of factor X on the surface of activated
      platelets. Subsequently, factors Xa and Va form the "prothrombinase" complex,
      which catalyzes the formation of thrombin from prothrombin, leading to fibrin
      formation. An enhanced expression of negatively charged phosphatidylserine in the
      outer membrane leaflet resulting from a breakdown of the phospholipid asymmetry
      is essential for the formation of the procoagulant surface. An ATP-driven and
      inward-acting aminophospholipid "translocase" and a "floppase" counterbalancing
      this have been postulated to maintain the dynamic state of phospholipid
      asymmetry. A phospholipid-nonspecific "scramblase," believed to be responsible
      for the fast breakdown of the asymmetry during cell activation, has recently been
      isolated from erythrocytes, cloned, and characterized. An intracellular calcium
      binding segment and one or more thioesterified fatty acids are probably of
      importance for calcium-induced activation of this transporter protein. Cytosolic
      calcium ions also activate the calcium-dependent protease calpain associated with
      shedding of microvesicles from the transformed platelet membrane. These are shed
      with a procoagulant surface and with surface-exposed P-selectin from the alpha
      granules. Theoretically, therefore, microvesicles can be involved in both
      coagulation and inflammation. Scott syndrome is probably caused by a defect in
      the activation of an otherwise normal scramblase, resulting in a relatively
      severe bleeding tendency. In Stormorken syndrome, the patients demonstrate a
      spontaneous surface expression of aminophospholipids. Activated platelets and the
      presence of procoagulant microvesicles have been demonstrated in several clinical
      conditions, such as thrombotic and idiopathic thrombocytopenia, disseminated
      intravascular coagulation, and HIV-1 infection, and have been found to be
      associated with fibrin in thrombosis. Procoagulant microvesicles may also be
      formed from other cells as a result of apoptosis.

PMID- 10591660
TI  - Interleukin-10 blocks atherosclerotic events in vitro and in vivo.
AB  - Atherosclerosis can be viewed in part as an inflammatory disease process and may
      therefore be susceptible to manipulation of the immune state. Interleukin 10 (IL
      10) is an inhibitory cytokine produced by activated lymphocytes and monocytes.
      These studies present evidence that IL-10 can inhibit minimally oxidized LDL (MM
      LDL)-induced monocyte-endothelium interaction as well as inhibit atherosclerotic
      lesion formation in mice fed an atherosclerotic diet. Pretreatment of human
      aortic endothelial cells (HAECs) for 18, but not 4, hours with recombinant IL-10
      caused a significant decrease in MM-LDL-induced monocyte binding. IL-10 was found
      to be maximally effective at 10 ng/mL. Transfection of HAECs with adenovirus
      expressing viral bcrf-1 IL-10 (Ad-vIL-10) in a sense but not antisense
      orientation completely inhibited the ability of MM-LDL to induce monocyte
      binding. Similar results were obtained with IL-10 or Ad-vIL-10 in HAECs
      stimulated with oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3
      phosphorylcholine (OxPAPC). We have previously shown increases in cAMP associated
      with MM-LDL activation of endothelial cells. The MM-LDL-induced increase in cAMP
      levels was not inhibited by preincubation with IL-10. In vivo studies
      demonstrated that mice with a murine IL-10 transgene under the control of the
      human IL-2 promoter have decreased lesions versus controls on an atherogenic diet
      (5433+/-4008 mm(2) versus 13 574+/-4212 mm(2); P<0.05), whereas IL-10 null mice
      have increased lesions (33 250+/-9117 mm(2); P<0.0001) compared with either
      controls or IL-10 transgenic mice. These studies suggest an important role for IL
      10 in the atherosclerotic disease process.

PMID- 10591661
TI  - Augmented expression of inducible NO synthase in vascular smooth muscle cells
      during aging is associated with enhanced NF-kappaB activation.
AB  - Vascular smooth muscle cells (SMCs) are important targets for endothelium-derived
      nitric oxide (NO), but this production is attenuated in injured and diseased
      arteries and during aging. However, SMCs can produce NO themselves by expressing
      an inducible form of NO synthase (iNOS) under inflammatory conditions and in the
      repair process after arterial injury. We examined iNOS expression in SMCs derived
      from the aortic media of newborn, young adult, and old rats. Our results show
      that SMCs from newborn rats cannot produce significant amounts of NO on
      stimulation with interferon-gamma plus lipopolysaccharide or interleukin-1beta.
      In contrast, SMCs from old rats exhibit markedly enhanced iNOS activity. The
      difference in iNOS activity between the newborn and the old SMCs was closely
      correlated with levels of iNOS protein, mRNA, and gene promoter activity.
      Similarly, intercellular adhesion molecule-1 (ICAM-1) was also expressed more
      abundantly in the old than in the newborn SMCs in response to cytokines. Both
      iNOS and ICAM-1 are transcriptionally regulated by nuclear factor kappaB (NF
      kappaB). Our data demonstrate an intense transactivation of NF-kappaB in old SMCs
      on tumor necrosis factor-alpha stimulation but only a weak one in newborn SMCs.
      The difference in the NF-kappaB activation could be explained by a much faster
      and more extensive IkappaBalpha degradation in old than in newborn SMCs. These
      data indicate that the capability to respond to proinflammatory stimuli by
      activating NF-kappaB differs between SMCs at different stages of development.
      This results in differential capability to express NF-kappaB-dependent genes such
      as iNOS and ICAM-1, which could have implications for host defense and the
      pathogenesis of vascular diseases.

PMID- 10591662
TI  - Accelerated neointima formation after vascular injury in mice with stromelysin-3
      (MMP-11) gene inactivation.
AB  - The hypothesis that stromelysin-3 (MMP-11), a unique member of the matrix
      metalloproteinase (MMP) family, plays a role in neointima formation was tested
      with the use of a vascular injury model in wild-type (MMP-11(+/+)) and MMP-11
      deficient (MMP-11(-/-)) mice. Neointima formation 2 to 3 weeks after electric
      injury of the femoral artery was significantly enhanced in MMP-11(-/-) as
      compared with MMP-11(+/+) mice, in both mice of a pure 129SV genetic background
      (0.014 versus 0.0010 mm(2) at 2 weeks, P<0.001) and those of a 50/50 mixed
      129SV/BL6 background (0.030 versus 0.013 mm(2) at 3 weeks, P<0.05). The medial
      areas were comparable, resulting in intima/media ratios that were significantly
      increased in MMP-11(-/-) as compared with MMP-11(+/+) arteries, in mice of both
      the 129SV (1. 0 versus 0.18, P<0.001) and mixed (1.5 versus 0.70, P<0.05)
      backgrounds. Nuclear cell counts in cross-sectional areas of the intima of the
      injured region were higher in arteries from MMP-11(-/-) mice than in those from
      MMP-11(+/+) mice (210 versus 48, P<0.001, in pure 129SV mice and 290 versus 150,
      P<0.01, in mice of the mixed genetic background). Immunocytochemical analysis
      revealed that alpha-actin-positive and CD45-positive cells were more abundant in
      intimal sections of MMP-11(-/-) mice. Degradation of the internal elastic lamina
      was more extensive in arteries of MMP-11(-/-) mice than in those of MMP-11(+/+)
      mice (39% versus 6.8% at 3 weeks, P<0. 005). The mechanisms by which MMP-11 could
      impair elastin degradation and cellular migration in this model remain, however,
      unknown.

PMID- 10591663
TI  - eNOS gene transfer inhibits smooth muscle cell migration and MMP-2 and MMP-9
      activity.
AB  - Vascular smooth muscle cell (SMC) migration is a critical step in the development
      of neointima after angioplasty. Matrix metalloproteinases (MMPs) degrade the
      basement membrane and the extracellular matrix, facilitating SMC migration.
      Transfer of the endothelial nitric oxide synthase (eNOS) gene to the injury site
      inhibits neointima formation. Neither the signaling pathways leading to NO
      mediated inhibition of SMC migration and proliferation nor the alterations in
      these pathways have been characterized. We hypothesize that NO inhibits SMC
      migration in part by regulating MMP activity. To test this hypothesis, we
      transfected cultured rat aortic SMCs with replication-deficient adenovirus
      containing bovine eNOS gene and analyzed the conditioned medium for MMP activity.
      We observed that eNOS gene transfer significantly (P<0.05) inhibited SMC
      migration and significantly (P<0.05) decreased MMP-2 and MMP-9 activities in the
      conditioned medium. Similarly, addition of the NO donor DETA NONOate and 8-bromo
      cGMP to the culture medium significantly decreased MMP-2 and MMP-9 activities in
      the conditioned medium collected 24 hours after treatment. Furthermore, Western
      blot analysis of the conditioned medium collected from eNOS gene-transfected SMCs
      showed a significant increase in tissue inhibitor of metalloproteinases-2 (TIMP
      2) levels. Our data suggest that NO decreases MMP-2 and MMP-9 activities and
      increases TIMP-2 secretion, and this shifts the balance of MMP activity, which
      may favor the inhibition of cell migration because of inhibition of extracellular
      matrix degradation.

PMID- 10591664
TI  - Stretch induces mitogen-activated protein kinase activation and myogenic tone
      through 2 distinct pathways.
AB  - The aim of this study was to evaluate the involvement of the mitogen-activated
      protein kinase (ERK1/2) pathway in response to stretch in a blood vessel
      developing myogenic tone on stretch. Indeed, in resistance arteries and veins,
      the main effect of pressure is to induce a maintained vasoconstrictor (myogenic)
      tone. Isolated segments of rabbit facial vein were mounted in organ baths and
      submitted to isometric stretch. In this experimental model, myogenic tone was
      absent when the bath temperature was 33 degrees C. ERK1/2 activity was determined
      in each isolated segment by an in-gel kinase assay. Wall tension and ERK1/2
      activity were measured in the same samples in the presence (39 degrees C) or in
      the absence of myogenic tone (33 degrees C). At 39 degrees C, a 5-mN wall tension
      induced myogenic tone (5.7+/-1.8 mN) and an increase in ERK1/2 activity (282+/
      52% versus unstretched vessels, P<0.05). At 33 degrees C, in the absence of
      myogenic tone, ERK1/2 activity was similarly increased by stretch (254+/-35%
      versus unstretched vessels). The calcium-dependent and -independent protein
      kinase C (PKC) blocker Ro-31-8220 (5 x 10(-7) mol/L), but not the calcium
      dependent PKC blocker Go-6976 (10(-6) mol/L), inhibited myogenic tone. However,
      ERK1/2 activity was not affected by either PKC blocker. Genistein (10(-7) mol/L),
      a general tyrosine kinase inhibitor, but not herbimycin A (5 x 10(-7) mol/L), a
      cSrc-family tyrosine kinase inhibitor, suppressed stretch-induced ERK1/2
      activation (P<0.05) without affecting myogenic tone. Nifedipine (10(-6) mol/L), a
      voltage-dependent calcium entry inhibitor, and ryanodine (10(-6) mol/L), which
      depletes calcium stores, both inhibited ERK1/2 activity (113+/-12% and 121+/-7%,
      respectively; P<0. 05) without affecting myogenic tone. The mitogen-activated
      protein kinase kinase inhibitor PD 98059 (5 x 10(-6) mol/L) also inhibited ERK1/2
      activation without affecting myogenic tone. The present results suggest that
      stretching the rabbit facial vein induced 2 distinct pathways, one leading to
      myogenic tone (via a non-calcium-dependent PKC activation) and one leading to
      ERK1/2 activation through a calcium-dependent pathway involving tyrosine kinase.

PMID- 10591665
TI  - Subendothelial cells from normal bovine arteries exhibit autonomous growth and
      constitutively activated intracellular signaling.
AB  - The arterial media is comprised of heterogeneous smooth muscle cell (SMC)
      subpopulations with markedly different growth responses to pathophysiological
      stimuli. Little information exists regarding the intracellular signaling pathways
      that contribute to these differences. Therefore, we investigated the growth
      related signaling pathways in a unique subset of subendothelial SMCs (L1 cells)
      from normal, mature, bovine arteries and compared them with those in
      "traditional" SMCs derived from the middle media (L2 SMCs). Subendothelial L1
      cells exhibited serum-independent autonomous growth, not observed in L2 SMCs.
      Autonomous growth of L1 cells was driven largely by the constitutively activated
      extracellular signal-regulated kinase (ERK-1/2) cascade. Inhibition of upstream
      activators of ERKs (MAP kinase kinase-1, p21(ras), receptor tyrosine kinases, and
      Gi protein-coupled receptors) led to suppression of autonomous growth in these
      cells. L1 cells also exhibited constitutive activation of important downstream
      targets of ERKs (cytosolic phospholipase A(2), cyclooxygenase-2) and secreted
      large amounts of prostaglandins. Importantly, L1 cells secreted potent mitogenic
      factor(s), which could potentially contribute in an autocrine fashion to the
      constitutive activation of these cells. Our data suggest that unique arterial
      cells with autonomous growth potential and constitutively activated signaling
      pathways exist in normal arteries and may contribute selectively to the
      pathogenesis of vascular diseases.

PMID- 10591666
TI  - Simvastatin inhibits leukocyte-endothelial cell interactions and protects against
      inflammatory processes in normocholesterolemic rats.
AB  - Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
      inhibitor, has been shown to lower serum cholesterol levels and normalize
      endothelial cell function. Moreover, HMG-CoA reductase inhibitors exert
      beneficial effects in coronary artery and cerebrovascular diseases. We examined
      the effects of simvastatin on leukocyte-endothelial cell interaction in vivo by
      intravital microscopy. Simvastatin (12.5 or 25 microg per rat) was given 18 hours
      before study. Superfusion with the NO synthase inhibitor N(G)-nitro-L-arginine
      methyl ester (L-NAME, 50 micromol/L) significantly increased leukocyte rolling
      from 12+/-2 to 60+/-8 leukocytes per minute, increased adherence to the
      mesenteric endothelium from 1.8+/-0.5 to 17+/-1.2 leukocytes per 100 microm of
      venular length, and raised leukocyte transmigration from 2.5+/-1.0 to 10+/-2
      leukocytes per perivessel area (P<0.01). Similar results were obtained with
      thrombin (0.5 U/mL) superfusion of the mesentery. In contrast, pretreatment with
      simvastatin (25 microg per rat IP) significantly attenuated L-NAME-stimulated
      leukocyte rolling, to 12+/-2 (P<0.01); adherence, to 5+/-0.5 leukocytes per 100
      microm (P<0.01); and leukocyte transmigration, to 3.5+/-1.5 leukocytes per
      perivessel area (P<0.01). Similar results were obtained in thrombin-superfused
      mesenteries. Moreover, immunohistochemical analysis demonstrated significantly
      increased P-selectin expression on the mesenteric venular endothelium after
      superfusion with either L-NAME (P<0.01) or thrombin (P<0.01), which was
      significantly attenuated by simvastatin. These results clearly demonstrate that
      simvastatin is a potent and effective endothelium-protective agent that reduces
      leukocyte-endothelial cell interactions independently of its well-known lipid
      lowering effects. This effect was found to be at least partially mediated via
      downregulation of P-selectin expression on the microvascular endothelium. Thus,
      HMG-CoA reductase inhibitors like simvastatin have important anti-inflammatory
      effects besides their well-known lipid-lowering action.

PMID- 10591667
TI  - 25-hydroxycholesterol increases eicosanoids and alters morphology in cultured
      pulmonary artery smooth muscle and endothelial cells.
AB  - 25-hydroxycholesterol (25-OHC) is an oxidized derivative of cholesterol that has
      been implicated in the early development of arteriosclerosis. Changes in arterial
      smooth muscle cell (SMC) migration and proliferation have also been linked to the
      pathophysiology of arteriosclerosis. SMCs undergo "activation" in response to
      vascular injury by changing phenotypically and by increasing prostaglandin G/H
      synthase-2 (PGHS-2) protein levels and eicosanoid release. Activation is thought
      to be important in atheroma formation and arteriosclerosis progression. 25-OHC
      induces SMCs to change morphologically, increase PGHS-2, and increase eicosanoid
      release. Confluent monolayers were treated with 25-OHC (10 microg/mL) or the PGHS
      2 inducer interleukin-1beta (1 ng/mL) for 18 hours at 37 degrees C. The 18-hour
      treatment resulted in morphological changes. After uptake of [(14)C]arachidonic
      acid, released radiolabeled arachidonic acid products were extracted and
      chromatographed by both normal and reverse-phase high-performance liquid
      chromatography systems. 25-OHC-treated cells increased their prostaglandin
      production, with the major component comigrating with a prostaglandin-E(2)
      standard. HETEs and epoxyeicosatrienoic acids were not affected.
      Immunoprecipitation analysis of treated and control cell lysates using anti-PGHS
      1 and -2 and anti-alpha-actin primary antibodies indicated PGHS-2 induction over
      control and no change in contractile proteins. These changes are consistent with
      SMC activation, which occurs in vascular injury models. The notion that
      oxysterols can activate vascular SMCs may be important in ultimately
      understanding the pathophysiology of atheroma formation.

PMID- 10591668
TI  - Lipoprotein-associated phospholipase A(2), platelet-activating factor
      acetylhydrolase, is expressed by macrophages in human and rabbit atherosclerotic
      lesions.
AB  - We studied the expression of lipoprotein-associated phospholipase A(2) (Lp
      PLA(2)), an enzyme capable of hydrolyzing platelet-activating factor (PAF), PAF
      like phospholipids, and polar-modified phosphatidylcholines, in human and rabbit
      atherosclerotic lesions. Oxidative modification of low-density lipoprotein, which
      plays an important role in atherogenesis, generates biologically active PAF-like
      modified phospholipid derivatives with polar fatty acid chains. PAF is known to
      have a potent proinflammatory activity and is inactivated by its hydrolysis. On
      the other hand, lysophosphatidylcholine and oxidized fatty acids released from
      oxidized low-density lipoprotein as a result of Lp-PLA(2) activity are thought to
      be involved in the progression of atherosclerosis. Using combined in situ
      hybridization and immunocytochemistry, we detected Lp-PLA(2) mRNA and protein in
      macrophages in both human and rabbit atherosclerotic lesions. Reverse
      transcriptase-polymerase chain reaction analysis indicated an increased
      expression of Lp-PLA(2) mRNA in human atherosclerotic lesions. In addition,
      approximately 6-fold higher Lp-PLA(2) activity was detected in atherosclerotic
      aortas of Watanabe heritable hyperlipidemic rabbits compared with normal aortas
      from control rabbits. It is concluded that (1) macrophages in both human and
      rabbit atherosclerotic lesions express Lp-PLA(2), which could cleave any
      oxidatively modified phosphatidylcholine present in the lesion area, and (2)
      modulation of Lp-PLA(2) activity could lead to antiatherogenic effects in the
      vessel wall.

PMID- 10591669
TI  - Enhanced reduction of fasting total homocysteine levels with supraphysiological
      versus standard multivitamin dose folic acid supplementation in renal transplant
      recipients.
AB  - The mild fasting hyperhomocysteinemia commonly observed in chronic (ie, >/=6
      months posttransplantation) renal transplant recipients (RTRs) can be effectively
      treated with combined B-vitamin supplementation featuring supraphysiological
      doses of folic acid. There are no controlled data evaluating the comparative
      efficacy of supraphysiological versus standard multivitamin dose folic acid
      supplementation in reducing fasting total homocysteine (tHcy) levels among RTRs.
      We block-randomized 60 chronic, stable RTRs on the basis of their screening
      fasting tHcy level to 3 groups of 20 subjects treated for 12 weeks with folic
      acid at either 2.4 (group 1), 0.4 (ie, standard multivitamin dose) (group 2), or
      0.0 (group 3) mg/d. All 60 study participants also received 50 mg/d vitamin B(6)
      and 0.4 mg/d vitamin B(12). The mean percent reductions (+/-SEM) in fasting tHcy
      were as follows: group 1, 32.3+/-2.4%; group 2, 23.4+/-2.3%; and group 3, 19.1+/
      2.3%. ANCOVA accounting for the pretreatment matching and adjusted for
      pretreatment levels of fasting tHcy, folate, and albumin; change in creatinine
      during the study; and cyclosporine A use revealed significant overall group
      differences (P=0.005) and significant differences between groups 1 and 2 (P=0.
      038) and groups 1 and 3 (P=0.001), but not between groups 2 and 3 (P=0.153).
      Moreover, a chi(2) analysis of participants with pretreatment tHcy levels >/=15
      micromol/L (n=29) indicated that a significantly greater proportion of those in
      group 1 achieved posttreatment levels <12 micromol/L: group 1, 5 of 10 (50%);
      group 2, 1 of 11 (9%); and group 3, 0 of 8 (0%) (P=0.016; test of trend P=0.
      007). We conclude that a supraphysiological dose of folic acid is superior to
      standard multivitamin dosing for the reduction of fasting tHcy levels in chronic
      RTRs.

PMID- 10591670
TI  - Physiological increments in plasma homocysteine induce vascular endothelial
      dysfunction in normal human subjects.
AB  - We hypothesized that physiological increments in plasma homocysteine after low
      dose oral methionine or dietary animal protein induce vascular endothelial
      dysfunction and that there is a graded, inverse relationship between homocysteine
      concentration and endothelial function. We studied 18 healthy volunteers aged 18
      to 59 years. Brachial artery flow-mediated and glyceryltrinitrate-induced
      dilatation were measured after 1) oral L-methionine (10, 25, and 100 mg/kg), 2)
      dietary animal protein (lean chicken 551+/-30 g, comprising 3.2+/-0.2 g
      methionine), and 3) methionine-free amino acid mix (100 mg/kg). Methionine (10,
      25, and 100 mg/kg) induced a dose-related increase in homocysteine (9.4+/-1.3 to
      12.2+/-2.1, 17. 6+/-2.6, and 26.1+/-4.2 micromol/L, respectively; P<0.001) and a
      reduction in flow-mediated dilatation (4.1+/-0.8 to 2.1+/-0.8, 0. 3+/-0.8, and 
      0.7+/-0.8%, respectively; P<0.001) at 4 hours. Compared with usual meal, animal
      protein increased plasma homocysteine (9.6+/-0.8 to 11.2+/-0.9 micromol/L,
      P=0.005) and reduced flow-mediated dilatation (4.5+/-0.7% to 0.9+/-0.6%,
      P=0.003). Methionine-free amino acid mix did not induce any changes.
      Glyceryltrinitrate-induced dilatation was unchanged throughout. In this study,
      small physiological increments in plasma homocysteine after low-dose methionine
      and dietary animal protein induced vascular endothelial dysfunction. We propose
      that protein intake-induced increments in plasma homocysteine may have
      deleterious effects on vascular function and contribute to the development and
      progression of atherosclerosis.

PMID- 10591671
TI  - Evidence that acute insulin administration enhances LDL cholesterol
      susceptibility to oxidation in healthy humans.
AB  - Increased free radical production and hyperinsulinemia are thought to play a role
      in experimental and human atherosclerosis, but the relation between the 2
      abnormalities has not been studied. In 23 healthy volunteers, we measured the
      susceptibility of circulating low-density lipoprotein (LDL) cholesterol particles
      to in vitro copper sulfate oxidation (measured as the lag phase) and cell
      mediated oxidative modification (measured as malondialdehyde generation in LDL
      during incubation with human umbilical vein endothelial cells), as well as the
      vitamin E content of LDL cholesterol at baseline and after 2 hours of
      physiological hyperinsulinemia (euglycemic insulin clamp). The lag time of LDL
      oxidation decreased from control values of 108+/-3 and 107+/-3 minutes (at
      baseline and after 2 hours of saline infusion) to 101+/-3 minutes after 2 hours
      of clamping (P<0.0001). At corresponding times, cell-mediated malondialdehyde
      generation in LDL rose from 4.96+/-0.11 and 4.98+/-0.10 to 5.28+/-0.10 nmol/L
      (P=0. 0006), whereas the LDL vitamin E content decreased from 6.78+/-0.06 and
      6.77+/-0.06 to 6.64+/-0.06 microg/mg (P<0.04). The insulin-induced shortening of
      the lag phase was directly related to the decrement of vitamin E in LDL;
      furthermore, in subjects with higher baseline serum triglyceride levels, insulin
      induced a greater shortening of the lag phase than in subjects with low baseline
      triglycerides. We conclude that in healthy humans acute physiological
      hyperinsulinemia enhances the oxidative susceptibility of LDL cholesterol
      particles. This effect may have pathogenic significance for atherogenesis in
      insulin resistant states.

PMID- 10591672
TI  - In the femoral artery bifurcation, differences in mean wall shear stress within
      subjects are associated with different intima-media thicknesses.
AB  - In elastic arteries, intima-media thickening is more pronounced in areas with low
      than with high mean and peak wall shear stress. These findings in elastic
      arteries are not necessarily representative of the situation in muscular
      arteries. The former arteries have to store volume energy, whereas the latter are
      mainly conductive vessels. It was the aim of the present study to investigate
      noninvasively whether differences in wall shear stress within a muscular artery
      bifurcation, if any, were associated with different intima-media thicknesses
      (IMTs). The effect of age on the possible differences was assessed as well. We
      determined IMT and mean, peak systolic, and the maximum cyclic change in shear
      stress near the posterior wall in the common (FC) and the superficial (FS)
      femoral artery 20 to 30 mm from the flow divider in 54 presumed healthy subjects
      between 21 and 74 years of age. Results were considered in terms of intrasubject
      differences. Before the study, the reliability of the ultrasonic system to assess
      wall shear rate and IMT was determined in terms of intrasubject variability. IMT
      at the posterior wall was significantly larger in the FC than in the FS, probably
      owing to the significantly lower mean wall shear stress at this site in the FC.
      The relative differences in IMT and mean wall shear stress between FC and FS were
      independent of age. The difference in wall shear stress between both arteries can
      likely be explained by a different influence of reflections. In both the FC and
      FS, mean, peak systolic, and maximum cyclic change in shear stress near the
      posterior wall did not change significantly with age, whereas IMT did increase
      significantly with age.

PMID- 10591673
TI  - Peroxisome proliferator-activated receptor gamma gene locus is related to body
      mass index and lipid values in healthy nonobese subjects.
AB  - The peroxisome proliferator-activated receptor gamma (PPARgamma) gene has been
      implicated in morbid obesity and is important to lipid and carbohydrate
      metabolism. However, the relevance of gene variations in healthy nonobese
      subjects has not been defined. We recruited monozygotic and dizygotic healthy
      nonobese twin subjects to test the hypothesis that the PPARgamma gene is
      important to body mass index and lipid concentrations in healthy nonobese
      subjects. Both linkage and association strategies were used in the same dizygotic
      twins. The PPARgamma gene locus was linked (P<0.01) to high-density lipoprotein
      cholesterol, low-density lipoprotein cholesterol, and body mass index as
      quantitative traits. A biallelic variant in the PPARgamma gene was associated
      with high-density lipoprotein cholesterol and body mass index (P<0.05). We also
      looked for linkage between the same variables and the retinoic X receptor gene
      locus. This locus was linked to total and low-density lipoprotein cholesterol as
      well as triglycerides. We conclude that the PPARgamma gene is highly relevant to
      lipid metabolism and body mass index, not only in the morbidly obese but also in
      healthy nonobese subjects. The same appears to be true for its binding partner.
      Sequencing these genes in twins would serve to identify gene variations
      contributing to body mass index and lipid concentrations in healthy nonobese
      subjects.

PMID- 10591674
TI  - Hyperlipidemia of ApoE2(Arg(158)-Cys) and ApoE3-Leiden transgenic mice is
      modulated predominantly by LDL receptor expression.
AB  - To investigate the relative roles of the LDL receptor- and non-LDL receptor
      mediated pathways in the clearance of apolipoprotein E (apoE) variants in vivo,
      we have generated apoE2(Arg(158)-Cys) (apoE2) and apoE3-Leiden transgenic mice
      deficient for the endogenous mouse Apoe and Ldl receptor genes (Apoe-/-.Ldlr-/-
      mice). Unexpectedly, on the Apoe-/-.Ldlr-/- background, expression of neither
      apoE2 nor apoE3-Leiden results in a decrease of the hyperlipidemia. In contrast,
      serum cholesterol levels are increased by the introduction of apoE2 and apoE3
      Leiden in Apoe-/-.Ldlr-/- mice (to 39.1+/-7.1 and 37.6+/-7.6 mmol/L,
      respectively, from 25. 9+/-6.5 mmol/L). In addition, in these transgenic mice,
      the serum triglyceride levels are substantially increased (to 9.6+/-7.0 and 5.
      8+/-2.8 mmol/L, respectively, from 0.7+/-0.5 mmol/L), which is associated with a
      decreased efficiency of in vitro LPL-mediated lipolysis of circulating VLDL. The
      VLDL-triglyceride secretion rate is not affected by the expression of apoE2 or
      apoE3-Leiden on the Apoe-/-.Ldlr-/- background. These results indicate that in
      the absence of the LDL receptor, clearance of triglyceride-rich apoE2 and apoE3
      Leiden-containing lipoproteins via alternative hepatic receptors, such as the LDL
      receptor-related protein (LRP) is inefficient. Although apoE2 and apoE3-Leiden
      are disturbed in binding to the LDL receptor in vitro, expression of 1 or 2 mouse
      Ldlr alleles in an apoE2.Apoe-/- or apoE3-Leiden.Apoe-/- background results in a
      gene dose-dependent decrease of the hyperlipidemia. Furthermore, overexpression
      of the LDL receptor via adenovirus-mediated gene transfer rescues the
      hyperlipidemia associated with apoE2 and apoE3-Leiden expression. These data
      indicate that in apoE2 and apoE3-Leiden transgenic mice, the LDL receptor
      constitutes the predominant route for clearance of VLDL remnants, carrying even
      poorly binding apoE variants, and that this pathway is functional despite an apoE
      mediated disturbance in VLDL triglyceride lipolysis.

PMID- 10591675
TI  - Overexpression of apolipoprotein E3 in transgenic rabbits causes combined
      hyperlipidemia by stimulating hepatic VLDL production and impairing VLDL
      lipolysis.
AB  - The differential effects of overexpression of human apolipoprotein (apo) E3 on
      plasma cholesterol and triglyceride metabolism were investigated in transgenic
      rabbits expressing low (<10 mg/dL), medium (10 to 20 mg/dL), or high (>20 mg/dL)
      levels of apoE3. Cholesterol levels increased progressively with increasing
      levels of apoE3, whereas triglyceride levels were not significantly affected at
      apoE3 levels up to 20 mg/dL but were markedly increased at levels of apoE3 >20
      mg/dL. The medium expressers had marked hypercholesterolemia (up to 3- to 4-fold
      over nontransgenics), characterized by an increase in low density lipoprotein
      (LDL) cholesterol, while the low expressers had only slightly increased plasma
      cholesterol levels. The medium expressers displayed an 18-fold increase in LDL
      but also had a 2-fold increase in hepatic very low density lipoprotein (VLDL)
      triglyceride production, an 8-fold increase in VLDL apoB, and a moderate decrease
      in the ability of the VLDL to be lipolyzed. However, plasma clearance of VLDL was
      increased, likely because of the increased apoE3 content. The increase in LDL
      appears to be due to an enhanced competition of VLDL for LDL receptor binding and
      uptake, resulting in the accumulation of LDL. The combined hyperlipidemia of the
      apoE3 high expressers (>20 mg/dL) was characterized by a 19-fold increase in LDL
      cholesterol but also a 4-fold increase in hepatic VLDL triglyceride production
      associated with a marked elevation of plasma VLDL triglycerides, cholesterol, and
      apoB100 (4-, 9-, and 25-fold over nontransgenics, respectively). The VLDL from
      the high expressers was much more enriched in apoE3 and markedly depleted in apoC
      II, which contributed to a >60% inhibition of VLDL lipolysis. The combined
      effects of stimulated VLDL production and impaired VLDL lipolysis accounted for
      the increases in plasma triglyceride and VLDL concentrations in the apoE3 high
      expressers. The hyperlipidemic apoE3 rabbits have phenotypes similar to those of
      familial combined hyperlipidemia, in which VLDL overproduction is a major
      biochemical feature. Overall, elevated expression of apoE3 appears to determine
      plasma lipid levels by stimulating hepatic VLDL production, enhancing VLDL
      clearance, and inhibiting VLDL lipolysis. Thus, the differential expression of
      apoE may, within a rather narrow range of concentrations, play a critical role in
      modulating plasma cholesterol and triglyceride levels and may represent an
      important determinant of specific types of hyperlipoproteinemia.

PMID- 10591676
TI  - Estrogen increases apolipoprotein (apo) A-I secretion in hep G2 cells by
      modulating transcription of the apo A-I gene promoter.
AB  - Estrogen administration to postmenopausal women has been shown to increase plasma
      levels of apolipoprotein (apo) A-I. A human hepatoma cell line, Hep G2, was used
      to test the hypothesis that estrogen increases the hepatic production of apo A-I
      by modulating gene expression. When Hep G2 cells were treated for 24 hours with
      E(2), the apo A-I content in the medium increased 4.3+/-1.0-fold at 10 micromol/L
      E(2) and 1.8+/-0.4-fold at 1 micromol/L E(2) compared with untreated cells. A
      time-course experiment indicated that there was no E(2)-dependent (10 micromol/L)
      increase in apo A-I medium content at 1 hour and 2 hours and that apo A-I was
      165% of controls at 6 hours and 440% at 24 hours. Hep G2 cells were transfected,
      by the cationic lipid method, with constructs containing serial deletions of the
      5' region of the apo A-I gene (-41/+397, -256/+397, and -2500/+397) cloned in
      front of the luciferase gene and with or without a 7-kb region spanning the apo C
      III/A-IV intergenic region, which has been shown to contain regulatory elements
      for the expression of the apo A-I gene. With the exception of the construct
      containing only the basal promoter (-41/+397), the expression of all constructs
      was 2- to 3-fold greater in the presence of E(2). The smallest construct that
      maintained E(2) responsiveness, the -256/+397 construct, does not contain a
      typical estrogen-responsive element. In the same transfection experiments, the 4
      fold increase in apo A-I in the culture medium was preserved. However, when the
      same set of transfections was performed by the calcium phosphate precipitation
      method, the E(2) effect on the apo A-I content in the culture medium and on
      transcription activation was nearly abolished. This effect was probably mediated
      by Ca(2+), because incubation of cells with 20 mmol/L CaCl(2) abolished the E(2)
      response. In conclusion, E(2) increases apo A-I production in hepatic cells by
      increasing the transcription of the apo A-I gene.

PMID- 10591677
TI  - Human apolipoprotein (Apo) B-48 and ApoB-100 kinetics with stable isotopes.
AB  - The kinetics of apolipoprotein (apo) B-100 and apoB-48 within triglyceride-rich
      lipoproteins (TRLs) and of apoB-100 within IDL and LDL were examined with a
      primed-constant infusion of (5,5,5-(2)H(3)) leucine in the fed state (hourly
      feeding) in 19 subjects after consumption of an average American diet (36% fat).
      Lipoproteins were isolated by ultracentrifugation and apolipoproteins by SDS
      gels, and isotope enrichment was assessed by gas chromatography/mass
      spectrometry. Kinetic parameters were calculated by multicompartmental modeling
      of the data with SAAM II. The pool sizes (PS) of TRL apoB-48, VLDL apoB-100, and
      LDL apoB-100 were 17+/-10, 273+/-167, and 3325+/-1146 mg, respectively. There was
      a trend toward a faster fractional catabolic rate (FCR) for VLDL apoB-100 than
      for TRL apoB-48 (6.73+/-3.48 versus 5.02+/-2.07 pools/d, respectively, P=0.06).
      The mean FCRs for IDL and LDL apoB-100 were 10.07+/-7.28 and 0.27+/-0.08 pools/d,
      respectively. The mean production rate (PR) of TRL apoB-48 was 6.5% of VLDL apoB
      100 (1. 3+/-0.90 versus 20.06+/-6.53 mg. kg(-1). d(-1), P<0.0001). TRL apoB-48 PS
      was correlated with apoB-48 PR (r=0.780, P<0.0001) but not FCR (r=-0.1810,
      P=0.458). VLDL apoB-100 PS was correlated with both PR (r=0.713, P=0.0006) and
      FCR (r=-0.692, P=0.001) of VLDL apoB-100 and by apoB-48 PR (r=0.728, P=0.0004).
      LDL apoB-100 PS was correlated with FCR (r=-0.549, P=0.015). These data indicate
      that (1) the FCRs of TRL apoB-48 and VLDL apoB-100 are similar in the fed state,
      (2) TRL apoB-48 PS is correlated with TRL apoB-48 PR, (3) VLDL apoB-100 PS is
      correlated with both PR and FCR of VLDL apoB-100 and PR of TRL apoB-48, and (4)
      LDL apoB-100 PS is correlated with LDL FCR.

PMID- 10591678
TI  - A common mutation of the insulin receptor substrate-1 gene is a risk factor for
      coronary artery disease.
AB  - Insulin resistance is associated with increased risk of atherosclerosis. Insulin
      receptor substrate-1 (IRS-1) plays a key role in tissue insulin sensitivity. A
      common mutation (G972R) of the IRS-1 gene has been shown to impair IRS-1
      function, and it has been associated with reduced insulin sensitivity and lipid
      abnormalities. This led us to investigate the role of the G972R mutation in
      predisposing individuals to coronary artery disease (CAD). The DNA of 318
      subjects with angiographically documented coronary atherosclerosis (>50%
      stenosis) and 208 population control subjects was analyzed for the presence of
      the G972R mutation. This mutation was detected by nested polymerase chain
      reaction and BstNI restriction enzyme digestion. The frequency of the G972R
      mutation was significantly higher among patients with CAD than controls (18. 9%
      versus 6.8%, respectively; P<0.001). After controlling for other coronary risk
      factors, the relative risk of CAD associated with the G972R mutation was 2.93
      (95% CI 1.30 to 6.60; P<0.02) in the entire cohort. This risk was found to be
      even higher in the subgroups of obese subjects (odds ratio [OR] 6.97, 95% CI 2.24
      to 21.4; P<0.001) and subjects with clinical features of insulin resistance
      syndrome (OR 27.3, 95% CI 7.19 to 104.0; P<0.001). The IRS-1 gene variant was
      associated with a higher frequency of diabetes mellitus (14.9% among carriers
      versus 6.5% among noncarriers; P<0.01) and with a 60% increase of plasma total
      triglycerides (P<0.001). Also, plasma concentrations of total cholesterol and the
      ratio of total cholesterol to HDL cholesterol were significantly (P<0.001) higher
      among carriers than noncarriers, although to lesser a extent. These effects were
      independent of CAD status. The G972R mutation in the IRS-1 gene was found to be a
      significant independent predictor of CAD. Moreover, this mutation greatly
      increased the risk of CAD in obese subjects and in patients with the cluster of
      abnormalities of insulin resistance syndrome. Besides the increased frequency of
      diabetes, carriers showed a more atherogenic lipid profile, suggesting a
      potential role of the IRS-1 gene in the pathogenesis of lipid abnormalities
      associated with CAD.

PMID- 10591679
TI  - Dyslipidemia and vascular dysfunction in diabetic pigs fed an atherogenic diet.
AB  - Diabetic patients typically have not only hyperglycemia but also dyslipidemia.
      Study of the pathogenic components of the diabetic milieu and mechanisms of
      accelerated atherosclerosis is hindered by inadequate animal models. A
      potentially suitable animal model for human diabetic dyslipidemia is the pig,
      because it carries a large fraction of total cholesterol in low-density
      lipoprotein (LDL), similar to humans. In this study, male Sinclair miniature pigs
      were made diabetic by destroying the insulin-producing cells of the pancreas with
      alloxan and then were fed a high fat and high cholesterol diet for comparison
      with pigs fed a nondiabetic high fat and high cholesterol diet and control pigs.
      Diabetic pigs exhibited hyperglycemia, but plasma urea nitrogen, creatinine, and
      transaminase levels were in the normal range, indicating no adverse effects on
      kidney and liver function. The lipoprotein profile in diabetic pigs was similar
      to that found in human diabetic patients and was characterized by
      hypertriglyceridemia (2.8-fold increase versus control and high fat-fed pigs) and
      a profound shift of cholesterol distribution into the LDL fraction (81%) versus
      the distribution in high fat-fed (64%) and control (57%) pigs. LDL particles were
      lipid-enriched and more heterogeneous in diabetic pigs. Apolipoprotein B was
      distributed among a much broader spectrum of LDL particles, and apolipoprotein E
      was partially redistributed from high-density lipoprotein to apolipoprotein B
      containing lipoproteins in diabetic pigs. There was little change in
      apolipoprotein A-I distribution. Diabetic pigs showed several early signs of
      excess vascular disease. In diabetic pigs, 75% of the coronary artery segments
      showed contractile oscillations in response to prostaglandin F(2alpha) compared
      with 25% in high fat-fed pigs and 10% in control pigs. Endothelium-dependent
      relaxation of brachial arteries was nearly abolished in diabetic pigs but
      unchanged in high fat-fed versus control pigs. Carotid artery Sudan IV staining
      for fatty streaks was significantly increased only in diabetic pigs. This porcine
      model should provide insights into the etiology of human diabetic dyslipidemia
      and facilitate study of peripheral vascular and coronary artery disease in
      diabetic patients.

PMID- 10591680
TI  - Both raloxifene and estrogen reduce major cardiovascular risk factors in healthy
      postmenopausal women: A 2-year, placebo-controlled study.
AB  - Currently raloxifene, a selective estrogen receptor modulator, is being
      investigated as a potential alternative for postmenopausal hormone replacement to
      prevent osteoporosis and cardiovascular disease. We compared the 2-year effects
      of raloxifene on a wide range of cardiovascular risk factors with those of
      placebo and conjugated equine estrogens (CEEs). Analyses were based on 56
      hysterectomized but otherwise healthy postmenopausal women aged 54. 8+/-3.5
      (mean+/-SD) years who entered this double-blind study and who were randomly
      assigned to raloxifene hydrochloride 60 mg/d (n=15) or 150 mg/d (n=13), placebo
      (n=13), or CEEs 0.625 mg/d (n=15). At baseline and after 6, 12, and 24 months of
      treatment, we assessed serum lipids, blood pressure, glucose metabolism, C
      reactive protein, and various hemostatic parameters. Compared with placebo, both
      raloxifene and CEEs lowered the level of low density lipoprotein cholesterol by
      0.53 to 0.79 mmol/L (all P<0.04) and lowered, at 24 months, the level of
      fibrinogen by 0.71 to 0.86 g/L (all P<0.05). The effects of raloxifene and CEEs
      did not differ significantly. In contrast to raloxifene, from 6 months on CEEs
      increased high density lipoprotein cholesterol by 0.25 to 0.29 mmol/L and reduced
      plasminogen activator inhibitor-1 antigen by 30.6 to 48.6 ng/mL (all P<0.02
      versus both placebo and raloxifene). CEEs transiently increased C-reactive
      protein by 1.0 mg/L at 6 months (P<0.05 versus placebo) and prothrombin-derived
      fragment F1+2 by 0. 79 nmol/L at 12 months (P<0.001 versus placebo). Finally,
      from 12 months on, CEEs increased triglycerides by 0.33 to 0.56 mmol/L (all
      P<0.05 versus both placebo and raloxifene). Our findings suggest that in healthy
      postmenopausal women, raloxifene and estrogen monotherapy have similar beneficial
      effects on low density lipoprotein cholesterol and fibrinogen levels. These
      treatments differ, however, in their effects on high density lipoprotein
      cholesterol, triglycerides, and plasminogen activator inhibitor-1 and possibly in
      their effects on prothrombin fragment F1+2 and C-reactive protein.

PMID- 10591681
TI  - Pattern of alcohol drinking and progression of atherosclerosis.
AB  - Most studies that examine the role of alcohol consumption in atherosclerosis and
      cardiovascular disease have overlooked the possible effect of drinking pattern.
      We investigated the association between the habit of heavy acute intake of beer
      and spirits (binging) and the 4-year progression of carotid atherosclerosis in a
      population-based sample of middle-aged Finnish men. Data from the Kuopio Ischemic
      Heart Disease Risk Factor Study (KIHD) were used to estimate changes in maximum
      and mean intima-media thickness (IMT) and the maximum plaque height in 764 KIHD
      participants who reported using beer and in 871 participants who used spirits.
      After adjustment for age, baseline carotid atherosclerosis, and average weekly
      alcohol consumption level, we observed the highest atherosclerosis progression in
      men who usually consumed a whole bottle of vodka or more in 1 session. For beer
      binging (>6 beers at a time), the magnitude of IMT progression was even higher,
      although this association was only marginally significant (P<0.1) because of
      smaller numbers. The associations were largely unaffected by adjustments for
      blood pressure, lipids, smoking, BMI, and medication. The magnitude of the
      difference was generally higher in a subgroup that was free of IHD at baseline.
      We conclude that the pattern of drinking associates with the progression of
      carotid atherosclerosis independently of the total level of alcohol consumption
      and risk factors.

PMID- 10591682
TI  - Age and sex differences in the distribution and ultrasound morphology of carotid
      atherosclerosis: the Tromso Study.
AB  - Atherosclerosis begins early in life and is the major underlying cause of
      cardiovascular morbidity and death. Yet, population-based information on age and
      sex differences in the extent and morphology of atherosclerosis throughout life
      is scarce. Carotid atherosclerosis can be visualized with B-mode ultrasound and
      is a marker of atherosclerosis elsewhere in the circulation. We assessed both the
      prevalence and the morphology of carotid atherosclerosis by B-mode ultrasound in
      3016 men and 3404 women, 25 to 84 years old, who participated in a population
      health survey. The participation rate was 88%. Plaque morphology was graded
      according to whether a plaque was predominantly soft (echolucent) or hard
      (echogenic). Atherosclerotic plaques were found in 55.4% of the men and 45.8% of
      the women. In men, there was a linear increase with age in the prevalence of
      carotid atherosclerosis, whereas in women, there was a curvilinear age trend,
      with an inflection in the prevalence rate of women at approximately 50 years of
      age. The male predominance in atherosclerosis declined after the age of 50 years,
      the plaque prevalence being similar in elderly men and women. Men had softer
      plaques than women; this sex difference in plaque morphology increased
      significantly (P=0.005) with age. The sex difference in the prevalence of
      atherosclerosis and the female age trend in atherosclerosis show significant
      changes at the age of approximately 50 years, suggesting an adverse effect of
      menopause on atherosclerosis. The higher proportion of soft plaques in men
      compared with women increases with age and may partly account for the prevailing
      male excess risk of coronary heart disease in the elderly despite a similar
      prevalence of atherosclerosis in elderly men and women.

PMID- 10591683
TI  - Altered vascular injury responses in mice deficient in protease-activated
      receptor-1.
AB  - Expression of protease-activated receptor-1 (PAR-1), a cell-surface receptor for
      thrombin, is increased in balloon-injured rat carotid artery and human
      atherosclerotic tissue. To examine the role of PAR-1 in vascular injury, we
      compared vascular injury responses in wild-type (WT) and PAR-1-deficient (PAR-1(
      /-)) mice. Arterial injury was induced by inserting a flexible guidewire into the
      common carotid artery and withdrawing it 6 times with rotation.
      Bromodeoxyuridine, delivered subcutaneously by osmotic minipump, was used to
      measure cellular proliferation. Mice were perfusion-fixed at 1, 2, 5, 10, and 14
      days after injury. Extensive endothelial damage, mural thrombosis, platelet
      adherence, and medial smooth muscle cell loss and necrosis were apparent at day 1
      in both WT and PAR-1(-/-) mice. The incidence of thrombosis or platelet
      deposition in WT and PAR-1(-/-) mice declined from 100% at day 1 to 25% and 21%,
      respectively, at 14 days. Endothelial disruption, as assessed by Evan's blue
      uptake, was maximum at day 1 and declined by day 14. This apparent endothelial
      regrowth was similar in WT and PAR-1(-/-) mice. Significant medial thickening at
      14 days after injury was similar in WT (from 22.8+/-1.7 to 30.7+/-1.9 microm) and
      PAR-1(-/-) (from 23.2+/-2.1 to 30.5+/-2.2 microm) mice. Medial area also
      increased in response to injury but to a lesser extent in PAR-1(-/-) mice (from
      0.0250+/-0.0044 to 0.0312+/-0.0047 mm(2)) than in WT mice (from 0.0266+/-0.0040
      to 0.0398+/-0.0050 mm(2)). Neointima was variable and occurred in 6 of 13 WT and
      5 of 12 PAR-1(-/-) mice. However, intimal area tended to be less in PAR-1(-/-)
      mice (0. 0016+/-0.0007 mm(2)) compared with WT mice (0.0082+/-0.0032 mm(2)),
      although this difference did not achieve statistical significance (P=0.06). Cell
      density was significantly greater in normal carotids from PAR-1(-/-) (6.4+/-0.5 x
      10(3)/mm(2)) compared with WT (4.3+/-0. 8 x 10(3)/mm(2)) mice and remained
      elevated after injury. Vessel and lumen diameters tended to increase in WT mice
      after injury, whereas vessel diameter was unchanged and lumen diameter actually
      decreased in PAR-1(-/-) mice. Cell proliferation in injured carotid arteries was
      similar in PAR-1(-/-) and WT mice. These data suggest that PAR-1(-/-) may play a
      role in vascular injury responses in this mouse model via possible effects on
      extracellular matrix regulation.

PMID- 10591684
TI  - Oxidized LDL and lysophosphatidylcholine stimulate plasminogen activator
      inhibitor-1 expression in vascular smooth muscle cells.
AB  - Plasminogen activator inhibitor-1 (PAI-1) functions as an important regulator of
      fibrinolysis by inhibiting both tissue-type and urokinase-type plasminogen
      activator. PAI-1 is produced by smooth muscle cells (SMCs) in atherosclerotic
      arteries, but the mechanisms responsible for induction of PAI-1 in SMCs are less
      well understood. In cultured human aortic SMCs, PAI-1 mRNA expression and protein
      secretion were increased after incubation with oxidized low-density lipoprotein
      (LDL) and the lipid peroxidation product lysophosphatidylcholine, whereas the
      effects of native LDL on PAI-1 production and release were more variable and did
      not reach statistical significance. The effect of LDL on arterial expression of
      PAI-1 in vivo was also studied in an animal model. Intravenous injection of human
      LDL in Sprague-Dawley rats resulted in accumulation of apolipoprotein B in the
      aorta within 12 hours as assessed by immunohistochemical testing. Epitopes
      specific for oxidized LDL began to develop in the aorta 12 hours after injection
      of LDL and peaked at 24 hours; this peak was accompanied by intense expression of
      PAI-1 immunoreactivity in the media. Also, increased aortic expression of PAI-1
      mRNA after LDL injection was detected by using in situ hybridization. The
      transcription factor activator protein-1, which is known to bind to the promoter
      of the PAI-1 gene, was activated in the aortic wall 24 hours after LDL injection
      as assessed by electrophoretic mobility shift assay. Pretreatment of LDL with the
      antioxidant probucol decreased expression of oxidized LDL and PAI-1
      immunoreactivity and activator protein-1 induction in the aorta but did not
      affect expression of apolipoprotein B immunoreactivity. These findings
      demonstrate that LDL oxidation enhances secretion of PAI-1 from cultured SMCs and
      that a similar mechanism may be involved in vascular expression of PAI-1.

PMID- 10591685
TI  - Studies of adhesion-dependent platelet activation: distinct roles for different
      participating receptors can be dissociated by proteolysis of collagen.
AB  - The molecular differences between native-type collagen type I fibrils (NC) and
      their pepsinated monomers (PC) were used to uncover receptors involved in
      platelet-collagen interaction along the adhesion-activation axis. The platelet
      depositing capacity of NC and PC under blood flow and their adhesive properties
      and respective morphologies, aggregation, procoagulant capacity, and tyrosine
      phosphorylation were compared under different cationic milieus, including or
      excluding the glycoprotein (GP) Ia/IIa. NC was consistently a more preferable and
      activating substrate than PC during flow (5 minutes) and in platelet aggregation.
      In PPACK-treated blood, both NC (3.3-fold) and PC (2.7-fold) increased platelet
      attachment on elevation of the shear rate from 500 to 1640 s(-1), whereas in
      citrated blood, adhesion and thrombus growth on PC were negligible under the high
      shear rate, unlike on NC (1.9-fold increase). The complete lack of platelet
      deposition on PC in citrated blood could be overcome by restoring physiological
      Mg(2+) concentration, and in contrast to NC, platelets interacting with PC were
      highly dependent on Mg(2+) during adhesion, aggregation, and procoagulant
      response. Monoclonal antibody (mAb 131.7) against GP IV inhibited platelet
      deposition to NC in citrated blood (2 minutes) by 49%, which was not further
      increased by coincubation with mAb against GP Ia (6F1). These results stress the
      importance of GP Ia/IIa in shear-resistant platelet deposition on collagen
      monomers. In native fibers, however, the preserved quaternary structure with
      telopeptides activates additional platelet receptors capable of substituting GP
      Ia/IIa and GP IV.

PMID- 10591686
TI  - Activation of protein kinase C is required for the stable attachment of adherent
      platelets to collagen but is not needed for the initial rapid adhesion under flow
      conditions.
AB  - We have investigated the role of protein kinase C (PKC) in the initial events of
      alpha(2)beta(1)-integrin-mediated platelet adhesion to collagen under flow
      conditions. Although adhesion caused activation of PKC, as evidenced by
      pleckstrin phosphorylation, the PKC inhibitors GF 109203X and Go 6976 had no
      effect on adhesion, even though they prevented pleckstrin phosphorylation. The
      initial kinetics and extent of platelet adhesion to collagen (<5 seconds) and
      tyrosine phosphorylation of p125(FAK) and p72(syk) were not influenced by the PKC
      inhibitors, whereas adhesion to polylysine was prevented. These results indicate
      that adhesion to collagen and polylysine involve different mechanisms and
      requirements for PKC activation. Pretreatment with GF 109203X destabilized
      collagen-adherent platelets, accelerating their detachment, which was associated
      with tyrosine dephosphorylation of p125(FAK). Thus, although PKC activation was
      not required for rapid platelet adhesion to collagen, it appears to play an
      important role in stabilizing the attachment of adherent platelets to collagen.
      We also examined the effect of PKC activation by the phorbol ester phorbol 12
      myristate 13-acetate (PMA) on platelet adhesion to collagen. PMA at 100 nmol/L
      strongly potentiated adhesion and tyrosine phosphorylation of p125(FAK) and
      p72(syk) and activated beta(1)-integrins, as determined by increased exposure of
      the 15/7 epitope. The PMA-stimulated adhesion was partially blocked by an anti
      alpha(2)beta(1) antibody, was completely inhibited by GF 109203X, and was not
      correlated with the extent of pleckstrin phosphorylation. Therefore, strong PKC
      activation may lead to inside-out signaling, enhancing the role of beta(1)
      integrins in adhesion. Pleckstrin phosphorylation does not appear to be involved
      in the initial phase of basic or PMA-stimulated adhesion but may help stabilize
      the adherent platelets.

PMID- 10591687
TI  - In vivo regulation of von willebrand factor synthesis: von Willebrand factor
      production in endothelial cells after lung transplantation between normal pigs
      and von Willebrand factor-deficient pigs.
AB  - To evaluate the regulation of plasma von Willebrand factor (vWF) and its in situ
      production by endothelial cells (ECs), 12 swine leukocyte antigen (SLA)
      compatible left lung transplantations were performed. Normal lungs were
      transplanted into 10 pigs homozygous for von Willebrand disease and into 2 normal
      pigs. Additionally, 1 normal pig underwent pneumonectomy, and 1 SLA-incompatible
      lung transplantation between normal pigs was performed. None of the transplanted
      animals received immunosuppressive therapy. Plasma vWF level was evaluated by
      ELISA and multimeric pattern. EC vWF content was assessed by
      immunohistochemistry. Global hemostasis was assessed by standardized ear bleeding
      time. Six of 12 SLA-compatible lung transplantations and the incompatible
      transplantation were successful and were used for the study. The functions and
      the viability of ECs, reflected by their ability to produce vWF and normal
      multimeric plasma vWF pattern, were preserved in SLA-compatible and -incompatible
      lung transplantations. vWF production was preserved in ECs that initially
      synthesized it. EC constitutive and storage pathways are modulated differently
      according to transplantation compatibility and severity of rejection. In SLA
      compatible lung transplantations without histological evidence of rejection, the
      production of vWF was preserved, whereas constitutive vWF secretion appeared to
      be altered in cases with minor histological signs of rejection. In pigs with von
      Willebrand disease that were transplanted with normal lungs without sign of
      rejection, plasma vWF was significantly increased in an amount expected from the
      estimated production of a normal lung. In the transplanted normal lung, there was
      no vWF overexpression by the ECs and no recruitment of ECs that initially did not
      express vWF. In SLA-incompatible transplantation, ECs were morphologically normal
      with increased and blurred vWF labeling, whereas plasma vWF levels remained
      normal, reflecting that EC activation is associated with an increased vWF
      production with probable diversion to storage pathway. This model depicts the
      changes of EC regulation of vWF secretion in pig lung transplants. However, this
      model cannot be directly extrapolated to human organ transplantation because
      animals did not receive any immunosuppressive therapy, which may be toxic to ECs.

PMID- 10591688
TI  - Two common, functional polymorphisms in the promoter region of the beta
      fibrinogen gene contribute to regulation of plasma fibrinogen concentration.
AB  - Plasma fibrinogen is a major risk factor for coronary heart disease, stroke, and
      peripheral artery disease. There is evidence that genetic variation in the beta
      fibrinogen gene contributes to the rate of synthesis of fibrinogen, but the
      molecular mechanism underlying the genetic heritability of the plasma fibrinogen
      concentration is largely unknown. We evaluated the physiological roles of 5
      common nucleotide substitutions in the promoter region of the beta-fibrinogen
      gene at positions -148, -249, -455, -854, and -993 from the transcriptional start
      site. Electrophoretic mobility shift assays revealed distinct differences in the
      binding characteristics of nuclear proteins between wild-type and mutant
      fragments of both the -455G/A and -854G/A polymorphisms, whereas no clear
      differences were observed for the -148C/T, -249C/T, and -993C/T sites.
      Transfection studies in HepG2 cells showed increased basal rates of transcription
      for both the G-to-A substitution at position -455 (+50%, P<0.05) and the G-to-A
      substitution at -854 (+51%, P<0.05). Additional transfection studies using
      proximal promoter constructs confirmed that both the -455A and -854A alleles
      independently enhance the basal rate of transcription of the beta-fibrinogen
      gene. The rare alleles of the nonrelated -455G/A and -854G/A polymorphisms were
      also associated with significantly increased plasma fibrinogen levels in healthy
      middle-aged men. Overall, the 2 polymorphisms together explained approximately
      11% of the variation in plasma fibrinogen concentration. It is concluded that the
      -455G/A and -854G/A polymorphisms of the beta-fibrinogen gene are physiologically
      relevant mutations with a significant impact on the plasma fibrinogen
      concentration.

PMID- 10591690
TI  - Coping with winter bed crises. New surveillance systems might help.

PMID- 10591689
TI  - von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and
      nondiabetic subjects: the Hoorn Study.
AB  - Increased levels of von Willebrand factor (vWf) and C-reactive protein (CRP)
      predict cardiovascular mortality in selected populations. It is uncertain whether
      vWf and CRP predict mortality in a general population and whether vWf and CRP
      predict mortality through similar pathways. This study investigated the
      association of vWf and CRP with cardiovascular and all-cause mortality among
      diabetic and nondiabetic subjects. An age-, sex-, and glucose tolerance
      stratified sample (n=631) of a population-based cohort aged 50 to 75 years was
      followed prospectively for 5 years. After 5 years of follow-up, 58 subjects had
      died (24 of cardiovascular causes). vWf (>1.56 IU/mL) and CRP (>2.84 mg/L) levels
      in the upper tertile were associated with, respectively, a 3- and 2-fold increase
      in cardiovascular mortality after adjustment for age, sex, and glucose tolerance
      status. Analyses in nondiabetic and diabetic subjects separately gave similar
      results. After further adjustment for hypertension, levels of HDL cholesterol and
      triglyceride, smoking habits, ischemic heart disease, and peripheral arterial
      disease, the relative risks (RRs) were 3.0 (95% CI 1.2 to 7.9) for vWf and 1.4
      (95% CI 0.6 to 3.5) for CRP. When both vWf and CRP were included in the latter
      multivariate analysis, the RRs were 3.0 (95% CI 1.1 to 7.9) for vWf and 1.3 (95%
      CI 0.5 to 3.4) for CRP. The association between vWf and risk of cardiovascular
      mortality was independent of blood group (O versus non-O) and, moreover, similar
      among subjects with different blood groups. Repeating the analyses for all-cause
      mortality gave similar results for CRP. For vWf, the RR was 2.0 (95% CI 1.1 to
      3.5) after adjustment for all other risk factors. Increased levels of vWf are
      independently associated with cardiovascular and all-cause mortality in both
      diabetic and nondiabetic subjects. The association between increased levels of
      CRP and cardiovascular mortality was partly explained by other risk factors.
      Mutual adjustment of vWf and CRP did not markedly change the results, favoring
      the hypothesis that vWf and CRP predict mortality through different pathways.

PMID- 10591691
TI  - Screening for familial intracranial aneurysms.

PMID- 10591692
TI  - Improving reperfusion after myocardial infarction.

PMID- 10591693
TI  - Netprints: the next phase in the evolution of biomedical publishing.

PMID- 10591694
TI  - Patients dialysed at for-profit centres do worse

PMID- 10591695
TI  - United States issues guidelines on embryo cell research.

PMID- 10591696
TI  - COX 2 inhibitors can affect the stomach lining

PMID- 10591697
TI  - Government orders inquiry into removal of children's organs.

PMID- 10591698
TI  - In brief

PMID- 10591699
TI  - Medical errors kill almost 100000 Americans a year.

PMID- 10591700
TI  - Bristol manager dismissed warnings as "exaggerated"

PMID- 10591701
TI  - NHS cancer patients denied supportive treatments.

PMID- 10591702
TI  - Scotland cracks down on antiabortion harassment.

PMID- 10591703
TI  - Canadian politicians propose expansion of private health care.

PMID- 10591705
TI  - Zinc supplementation prevents diarrhoea and pneumonia

PMID- 10591704
TI  - US changes trade policy on essential medicines.

PMID- 10591706
TI  - Report finds persisting poverty and social exclusion.

PMID- 10591708
TI  - Passive smoking more risky for women with a missing gene

PMID- 10591707
TI  - Irish government plans a "junior" consultant grade.

PMID- 10591709
TI  - Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis
      of effects on lipids and haemostatic factors.
AB  - OBJECTIVE: To summarise quantitatively the association between moderate alcohol
      intake and biological markers of risk of coronary heart disease and to predict
      how these changes would lower the risk. DESIGN: Meta-analysis of all experimental
      studies that assessed the effects of moderate alcohol intake on concentrations of
      high density lipoprotein cholesterol, apolipoprotein A I, fibrinogen,
      triglycerides, and other biological markers previously found to be associated
      with risk of coronary heart disease. PARTICIPANTS: Men and women free of previous
      chronic disease and who were not dependent on alcohol. Studies were included in
      which biomarkers were assessed before and after participants consumed up to 100 g
      of alcohol a day. INTERVENTIONS: Alcohol as ethanol, beer, wine, or spirits. MAIN
      OUTCOME MEASURES: Changes in concentrations of high density lipoprotein
      cholesterol, apolipoprotein A I, Lp(a) lipoprotein, triglycerides, tissue type
      plasminogen activator activity, tissue type plasminogen activator antigen,
      insulin, and glucose after consuming an experimental dose of alcohol for 1 to 9
      weeks; a shorter period was accepted for studies of change in concentrations of
      fibrinogen, factor VII, von Willebrand factor, tissue type plasminogen activator
      activity, and tissue type plasminogen activator antigen. RESULTS: 61 data records
      were abstracted from 42 eligible studies with information on change in biological
      markers of risk of coronary heart disease. An experimental dose of 30 g of
      ethanol a day increased concentrations of high density lipoprotein cholesterol by
      3.99 mg/dl (95% confidence interval 3.25 to 4.73), apolipoprotein A I by 8.82
      mg/dl (7.79 to 9.86), and triglyceride by 5.69 mg/dl (2.49 to 8.89). Several
      haemostatic factors related to a thrombolytic profile were modestly affected by
      alcohol. On the basis of published associations between these biomarkers and risk
      of coronary heart disease 30 g of alcohol a day would cause an estimated
      reduction of 24.7% in risk of coronary heart disease. CONCLUSIONS: Alcohol intake
      is causally related to lower risk of coronary heart disease through changes in
      lipids and haemostatic factors.

PMID- 10591711
TI  - Hypericum extract versus imipramine or placebo in patients with moderate
      depression: randomised multicentre study of treatment for eight weeks.
AB  - OBJECTIVES: To assess the efficacy and safety of hypericum extract (STEI 300,
      Steiner Arzneimittel, Berlin) compared with imipramine and placebo in patients in
      primary care with a current episode of moderate depression. DESIGN: Randomised,
      double blind, multicentre, parallel group trial for 8 weeks. SETTING: Trained
      panel of 18 general practitioners from four German states: Bavaria, Berlin,
      Rhineland Palatinate, and Saxony. PARTICIPANTS: 263 patients (66 men, 197 women)
      with moderate depression according to ICD-10 (international classification of
      diseases, 10th revision) codes F32. 1 and F33.1. INTERVENTIONS: 1050 mg hypericum
      extract (350 mg three times daily), 100 mg imipramine (50 mg, 25 mg, and 25 mg
      daily), or placebo three times daily. MAIN OUTCOME MEASURES: Change from baseline
      score on the 17 item version of the Hamilton depression scale, the Hamilton
      anxiety scale, the clinical global impressions scale, Zung's self rating
      depression scale, and SF-36, and adverse events profile. RESULTS: Hypericum
      extract was more effective at reducing Hamilton depression scores than placebo
      and as effective as imipramine (mean -15.4 (SD 8.1), -12.1 (7.4), and -14.2 (7.3)
      respectively). Comparable results were found for Hamilton anxiety and clinical
      global impressions scales and were most pronounced for the Zung self rating
      depression scale. Quality of life was more improved in the standardised mental
      component scale of the SF-36 with both active treatments than with placebo but in
      the physical component scale was improved only by hypericum extract compared with
      placebo. The rate of adverse events with hypericum extract was in the range of
      the placebo group but lower than that of the imipramine group (0.5, 0.6, and 1.2
      events per patient respectively). CONCLUSIONS: At an average dose of 350 mg three
      times daily hypericum extract was more effective than placebo and at least as
      effective as 100 mg imipramine daily in the treatment of moderate depression.
      Treatment with hypericum extract is safe and improves quality of life.

PMID- 10591710
TI  - Population based cost utility study of interferon beta-1b in secondary
      progressive multiple sclerosis.
AB  - OBJECTIVE: To evaluate the cost utility of interferon beta-1b in secondary
      progressive multiple sclerosis. DESIGN: Population based cost utility model
      (healthcare perspective). Data on use of health services were obtained from case
      records and routine morbidity data and utility values from a EuroQol survey.
      Local and published costs were used. Effectiveness was modelled using data on
      relative risk reductions from a randomised trial of interferon beta-1b. SETTING:
      Tayside region, 1993-5. SUBJECTS: 132 ambulatory people with secondary
      progressive multiple sclerosis. MAIN OUTCOME MEASURES: Cost per quality adjusted
      life year (QALY) gained. Rate of relapse and proportion becoming wheelchair
      dependent over three years. RESULTS: The number needed to treat for 30 months to
      delay time to wheelchair dependence in one person by nine months was 18 (95%
      confidence interval 5 to 26). For every 18 people treated for 30 months, six
      relapses would be prevented, gaining 0.397 discounted QALYs. The cost per QALY
      gained was 1 024 667 pounds sterling (276 466 pounds sterling to 485 499 pound
      sterling). If treatment was restricted to patients attending neurology services,
      the number needed to treat was 14 (cost per QALY gained 833 pounds sterling 514
      (161 358 pounds sterling to infinity)). The cost per QALY gained was not
      sensitive to changes in cost which took account of a societal perspective.
      CONCLUSIONS: The cost per QALY gained from interferon beta is high because of the
      high drug cost and modest clinical effect. Resources could be used more
      efficiently elsewhere.

PMID- 10591712
TI  - Scarring in Molluscum contagiosum: comparison of physical expression and phenol
      ablation.

PMID- 10591713
TI  - Accuracy of hepatic adverse drug reaction reporting in one English health region.

PMID- 10591715
TI  - Wise advice

PMID- 10591714
TI  - Email submissions from outside the united kingdom

PMID- 10591716
TI  - On ageing: the optimist

PMID- 10591718
TI  - Abandoning babies safely

PMID- 10591717
TI  - Randomised controlled trial of effectiveness of Leicester hospital at home scheme
      compared with hospital care.
AB  - OBJECTIVE: To compare effectiveness of patient care in hospital at home scheme
      with hospital care. DESIGN: Pragmatic randomised controlled trial. SETTING:
      Leicester hospital at home scheme and the city's three acute hospitals.
      PARTICIPANTS: 199 consecutive patients referred to hospital at home by their
      general practitioner and assessed as being suitable for admission. Six of 102
      patients randomised to hospital at home refused admission, as did 23 of 97
      allocated to hospital. INTERVENTION: Hospital at home or hospital inpatient care.
      MAIN OUTCOME MEASURES: Mortality and change in health status (Barthel index,
      sickness impact profile 68, EuroQol, Philadelphia geriatric morale scale)
      assessed at 2 weeks and 3 months after randomisation. The main process measures
      were service inputs, discharge destination, readmission rates, length of initial
      stay, and total days of care. RESULTS: Hospital at home group and hospital group
      showed no significant differences in health status (median scores on sickness
      impact profile 68 were 29 and 30 respectively at 2 weeks, and 24 and 26 at 3
      months) or in dependency (Barthel scores 15 and 14 at 2 weeks and 16 for both
      groups at 3 months). At 3 months' follow up, 26 (25%) of hospital at home group
      had died compared with 30 (31%) of hospital group (relative risk 0. 82 (95%
      confidence interval 0.52 to 1.28)). Hospital at home group required fewer days of
      treatment than hospital group, both in terms of initial stay (median 8 days v
      14.5 days, P=0.026) and total days of care at 3 months (median 9 days v 16 days,
      P=0.031). CONCLUSIONS: Hospital at home scheme delivered care as effectively as
      hospital, with no clinically important differences in health status. Hospital at
      home resulted in significantly shorter lengths of stay, which did not lead to a
      higher rate of subsequent admission.

PMID- 10591719
TI  - Getting at the truth

PMID- 10591720
TI  - Economic evaluation of hospital at home versus hospital care: cost minimisation
      analysis of data from randomised controlled trial.
AB  - OBJECTIVES: To compare the costs of admission to a hospital at home scheme with
      those of acute hospital admission. DESIGN: Cost minimisation analysis within a
      pragmatic randomised controlled trial. SETTING: Hospital at home scheme in
      Leicester and the city's three acute hospitals. PARTICIPANTS: 199 consecutive
      patients assessed as being suitable for admission to hospital at home for acute
      care during the 18 month trial period (median age 84 years). INTERVENTION:
      Hospital at home or hospital inpatient care. MAIN OUTCOME MEASURES: Costs to NHS,
      social services, patients, and families during the initial episode of treatment
      and the three months after admission. RESULTS: Mean (median) costs per episode
      (including any transfer from hospital at home to hospital) were similar when
      analysed by intention to treat-hospital at home 2569 pounds sterling (1655 pounds
      sterling), hospital ward 2881 pounds sterling (2031 pounds sterling), bootstrap
      mean difference -305 (95% confidence interval -1112 to 448). When analysis was
      restricted to those who accepted their allocated place of care, hospital at home
      was significantly cheaper-hospital at home 2557 pounds sterling(1710 pounds
      sterling), hospital ward 3660 pounds sterling (2903 pounds sterling), bootstrap
      mean difference -1071 (-1843 to -246). At three months the cost differences were
      sustained. Costs with all cases included were hospital at home 3671 pounds
      sterling (2491 pounds sterling), hospital ward 3877 pounds sterling (3405 pounds
      sterling), bootstrap mean difference -210 (-1025 to 635). When only those
      accepting allocated care were included the costs were hospital at home 3698
      pounds sterling (2493 pounds sterling), hospital ward 4761 pounds sterling (3940
      pounds sterling), bootstrap mean difference -1063 (-2044 to -163); P=0.009. About
      25% of the costs for episodes of hospital at home were incurred through transfer
      to hospital. Costs per day of care were higher in the hospital at home arm (mean
      207 pounds sterling v 134 pounds sterling in the hospital arm, excluding
      refusers, P<0.001). CONCLUSIONS: Hospital at home can deliver care at similar or
      lower cost than an equivalent admission to an acute hospital.

PMID- 10591721
TI  - Science, medicine, and the future: functional magnetic resonance imaging in
      neuropsychiatry.

PMID- 10591723
TI  - A case of rupture of the heart

PMID- 10591724
TI  - ABC of complementary medicine: complementary medicine and the doctor.

PMID- 10591725
TI  - William harvey, hypothermia, and battle injuries

PMID- 10591722
TI  - Lesson of the week: hyponatraemic seizures and excessive intake of hypotonic
      fluids in young children.

PMID- 10591726
TI  - When can a risk factor be used as a worthwhile screening test?

PMID- 10591727
TI  - Registering clinical trials.

PMID- 10591728
TI  - Health and human rights in contemporary humanitarian crises: is Kosovo more
      important than Sierra Leone?

PMID- 10591729
TI  - Understanding of the world

PMID- 10591730
TI  - Cancer survival in Britain. Cancer chemotherapy costs money.

PMID- 10591731
TI  - Article on bayesian methods was right.

PMID- 10591732
TI  - Evidence based palliative care. General palliative care should be evaluated.

PMID- 10591733
TI  - Spurious asystole with use of manual defibrillators. Users should not rely on
      monitoring through paddles, using any type of gel pad, once shocks have been
      delivered.

PMID- 10591734
TI  - Relation of C pneumoniae antibodies to ischaemic heart disease. Why were samples
      weakly positive for IgG antibodies not tested for IgA antibodies?

PMID- 10591735
TI  - Breast feeding and obesity. Relation may be accounted for by social factors.

PMID- 10591736
TI  - Subspecialist psychiatrists are sometimes selective about whom they will treat.

PMID- 10591737
TI  - Effectiveness of glucocorticoids in treating croup. Authors acknowledge Cochrane
      Collaboration.

PMID- 10591738
TI  - Overreaction to the Paddington rail disaster may not be beneficial in the long
      run.

PMID- 10591740
TI  - Obituaries

PMID- 10591739
TI  - Doctors are still committing genocide.

PMID- 10591741
TI  - Sports medicine handbook

PMID- 10591743
TI  - The messenger: the story of joan of Arc

PMID- 10591742
TI  - In the blood: sickle cell anemia and the politics of race

PMID- 10591745
TI  - Don't Be ashamed

PMID- 10591744
TI  - Birdsong

PMID- 10591746
TI  - Open archives

PMID- 10591748
TI  - Playing the guru

PMID- 10591747
TI  - Millennium pay

PMID- 10591750
TI  - Costs outweigh benefits of interferon in multiple sclerosis

PMID- 10591749
TI  - Alcohol lowers risk of heart disease through effect on lipids and haemostatic
      factors

PMID- 10591752
TI  - Hypericum extract improves depression and quality of life

PMID- 10591751
TI  - Hospital at home scheme is acceptable alternative to hospital care and is cost
      effective

PMID- 10591754
TI  - Nearly half reported hepatic adverse drug reactions are unrelated to incriminated
      drug

PMID- 10591753
TI  - Squeezing causes less scarring than phenol ablation in molluscum contagiosum

PMID- 10591755
TI  - [The biological reaction in atrophic and hypertrophic pseudarthrosis of diaphysis
      of long bone. Causes and forms of appearance].
AB  - The grading of long-tubular-bone pseudarthrosis depends on the biological
      reaction or lack of reaction in pseudarthrosis or non-unions. Hypertrophic and
      oligotrophic pseudarthrosis belongs to biologically reacting non-unions, whereas
      non-reacting non-unions are necrotic pseudarthrosis and defective non-unions with
      partial decline or complete destruction of cortical substance. Pseudarthrosis is
      a serious disturbance or disorder within the regulation cycle in fracture
      healing, which consists of osteoregeneration, osteovascularization and
      stabilization. The causes and underlying reasons for disturbance of this
      regulation cycle are primarily massive destruction of the biological and
      functional very important unity of periost, cortical substance and medullary
      space. This can occur from trauma, but it happens more often from surgical
      procedures that do not take the biological principles of bone-healing into
      account. Surgical strategies and interventions that respect the importance of
      periosteal tissue, cortical tissue and medullary space do fill the biological
      principles of fracture-healing and fracture union.

PMID- 10591756
TI  - [Nonunion of the humeral diaphysis - operative and nonoperative treatment].
AB  - Operative treatment of acute humeral shaft fractures represents a major source of
      nonunions. The analysis of the biomechanical and biological causes of diaphyseal
      nonunions of the humerus is a prerequisite for the successful treatment of
      ununited humeral shaft fractures. Biologically active nonunions heal after
      debridement and correction of deformities with an improvement of mechanical
      stability, preferably by fixation with a compression plate. In atrophic
      nonunions, the restoration of the biologic capacity to restore osteogenesis by
      bone grafting is additionally necessary. The treatment of synovial pseudarthrosis
      and infected nonunion requires removal of bone and debridement of synovial and
      infected avascular tissues, respectively. Intramedullary nails to improve
      mechanical stability and nonoperative treatment with extracorporeal shock waves
      should only be used in a few special cases which do not have any severe
      deformities.

PMID- 10591757
TI  - [Pertrochanteric pseudarthrosis. Implant failure - technical error - destiny?].
AB  - Pain is not always the leading symptom of a failed union. High primary stability
      often allows full weight bearing in spite of fracture instability. The difficult
      diagnosis of a pseudarthrosis is a reason for late intervention. Implant failure
      and implant breakage are typical signs of surgical underestimation. Finally, the
      diagnosis "pseudarthrosis" is a fluent one and is defined as a failed fracture
      healing despite implant stability. Recognition of biological and biomechanical
      failure, this demands correct evaluation of the global situation and extensive
      experience in revision surgery on the part of the surgeon.

PMID- 10591758
TI  - [Arthrodesis - non-union of the ankle. Arthrodesis failed].
AB  - Non-unions after fracture dislocation of the ankle joint are extremely rare with
      predominantly operative treatment. In contrast, after fractures of the tibial
      plafond (pilon fractures) infections are seen in the literature in 37 % and non
      unions are seen in 27 % after open reduction and internal fixation, requiring
      secondary ankle arthrodesis in about one quarter of all cases. In contrast to
      aseptic non-union or arthrosis, which can be salvaged with screw arthrodesis,
      with prevailing infection and severe osteoporosis external fixation (either one-
      or two-sided) is the treatment of choice. In isolated non-unions of the malleoli,
      either plate osteosynthesis with 3.5 low-contact dynamic compression plate or
      tension banding with autologous bone graft interposition, or alternatively
      sliding graft technique, is performed with good results.

PMID- 10591759
TI  - [Operative versus non operative treatment of odontoid non unions. How dangerous
      is it not to stabilize a non union of the dens?].
AB  - INTRODUCTION: Injuries precede the vast majority of all odontoid pseudarthroses.
      Because of specific anatomic conditions type II injuries lead more often than
      other types to non unions. For its development insufficient internal or external
      fixation and a persisting fracture gap are crucial. METHODS AND RESULTS: In 71
      patients after operative stabilization of odontoid fractures with two anterior
      lag-screws we detected 8 non unions. In 3 patients the interval between accident
      and operation amounted to more than 5 weeks, seven times we did not succeed in
      closing the fracture gap. Technical mistakes like insufficient reduction (n = 1)
      or screw misplacement (n = 3) were additional reasons. According to the
      literature and own observations an os odontoideum must be considered in most
      instances as a pseudarthrosis after a lesion of the subdental synchondrosis in
      childhood. The most important diagnostic tool in odontoid non unions is a dynamic
      examination of the upper cervical spine under fluoroscopic control in maximum
      flexion and extension. We propose a classification of posttraumatic dens non
      unions into 4 types. Type I corresponds to a stable "non union" in approximate
      anatomical position of the dens and without signs of instability in the former
      fracture zone. Type II describes a relatively stable grossly displaced non union
      that is not to be reduced by simple, closed means. Type III means an unstable non
      union and Type IV a posttraumatic os odontoideum. CONCLUSIONS: Therapeutical
      recommendations need to be differentiated. Unstable non unions are most often
      responsible for persistent pain, may result in acute or chronic myelopathy++ and
      therefore - as well as ossa odontoidea - need operative fixation. In considerably
      displaced non unions a closed reduction manoeuver with long term traction should
      be tried. The operative treatment of choice is the posterior transarticular screw
      fixation C1/C2 desirably in a percutaneous technique. Tight, "stable"
      pseudarthroses in the sense of a persisting fracture gap in painfree patients
      should first be controlled radiologically. If the odontoid position remains
      unchanged, non operative treatment may be continued.

PMID- 10591760
TI  - [Pseudarthrosis].
AB  - Understanding the pathophysiology of non-union is a prerequisite for successful
      treatment of this disorder. Fracture healing may be impeded by mechanical or
      biological factors as well as a combination of these. A thorough evaluation of
      each individual case before surgery is necessary to prevent either undertreatment
      or overtreatment. The whole spectrum of methods of internal fixation may be
      utilized for stabilization. To optimize the biological component, classic methods
      such as decortication and cancellous autograft may be employed. It is too early
      yet to determine if alternative techniques (e.g. ultrasound) will successfully
      replace these long-standing options. In any case, these newer modalities cannot
      supplant the need for skeletal stabilization. For infected pseudarthroses the
      first step is eradication of infection, after which measures can be taken to
      unite the fracture. Callus distraction has opened new and safe ways to treat
      large bone defects.

PMID- 10591761
TI  - [Modern diagnostic workup of blunt abdominal trauma].
AB  - Lethality and morbidity of blunt abdominal trauma are directly dependent on the
      immediately valid diagnostic work-up. Since blunt abdominal trauma usually occurs
      in the setting of multisystem injury and patients are no longer cooperative,
      clinical methods of diagnosis are unreliable. In regard to the imaging
      procedures, the practical approach has been simplified and standardized in the
      last few years. Initially, ultrasonography of the abdomen is performed. If the
      patient is hemodynamically unstable because of intra-abdominal loss of blood,
      this can be reliably detected by ultrasound and emergency laparotomy is
      indicated. If patients are hemodynamically stable, more sophisticated assessment
      of the abdomen can be achieved by computed tomography. The next step depends on
      direct or indirect signs of an intra-abdominal lesion. Angiography may be
      indicated in injuries to the liver, spleen, kidney, mesenteric root or caval
      vein. If lesions to the liver, biliary or pancreas are detected, ERCP may be
      required. Lacerations of hollow organs are identified by fine-needle aspiration
      of free intra-abdominal fluid. Findings on computed tomography are usually
      reliable enough to support a more conservative approach in the treatment of
      parenchymal lesions in blunt abdominal trauma. Since the facilities to perform
      ultrasound are provided in all emergency units and knowledge of ultrasonography
      is an essential part of surgical training, competitive diagnostic procedures like
      peritoneal lavage have completely lost their former important clinical role.
      Similarly, diagnostic laparoscopy is - in contrast to abdominal perforations - no
      longer of importance.

PMID- 10591762
TI  - [Current management of hepatic, biliary and pancreatic trauma].
AB  - The management of hepatic trauma should be, if possible, non-operative and is
      initially determined by hemodynamic stability, absence of coagulopathy and
      limited need for blood transfusions. In hemodynamically unstable patients
      specific attempts to control intraparenchymal hemorrhage and resection are
      contraindicated. Perihepatic packing is the therapy of choice. If the hemorrhage
      cannot be controlled, parenchymal resection or hepatectomy with subsequent
      transplantation must be performed. Biliary leakage is the cause of chronic
      complications. The current management of intraparenchymal lesions consists of
      longterm drainage or stenting as combined radiological and endoscopical
      techniques. Pancreatic ruptures without ductal injury are treated non-operatively
      or by external drainage. Ductal lesions with persistent fistulas are handled
      depending on localization either by distal resection, pancreaticojejunostomy of
      the injured segment, or partial pancreaticoduodenectomy if massive disruption of
      the pancreatic head, duodenum or bile duct are present.

PMID- 10591763
TI  - [Current therapy of injuries of the colon and retroperitoneum].
AB  - Injuries of the colon and retroperitoneum are rarely observed after blunt
      abdominal trauma and occur in about 5 - 20 % of the patients. The majority of
      complications are due to initial misdiagnoses and a delay in treatment. Lesions
      of the pancreas and duodenum are the most frequent diagnoses in the
      retroperitoneal space, while major vascular traumata or urogenital injuries are
      rare. Retroperitoneal hematoma are most likely due to pelvic fractures. The
      survival of patients after colon or retroperitoneal injuries depends on the
      severity of concomitant organ trauma, the time of diagnosis, and a situation
      adapted therapeutic strategy. The treatment of the typical caudal retroperitoneal
      hematoma following pelvic fractures is conservative in most patients. Early
      pelvic stabilization, e. g., with external fixation, is recommended in these
      patients. Central retroperitoneal hematoma in the supra - or inframesocolic space
      should be treated surgically, as major vascular injuries are most likely in these
      patients. Duodenal or pancreatic injuries need surgical exploration in the
      majority of patients; the therapeutic spectrum ranges from simple sutures to
      pancreatoduodenal resection. The treatment of colon injuries depends on the
      degree of peritonitis and the severity of concomitant trauma. Early diagnosed
      injuries are suitable for primary repair, while deviation stomata or a Hartmann
      procedure with or without resection should be offered to patients with delayed
      diagnoses, peritonitis, or severe concomitant diseases. Long-lasting procedures
      should be abandoned in the emergency situation; in these severe cases, laparotomy
      should be aimed towards primary "damage control" and followed by definite surgery
      after stabilization of the patient.

PMID- 10591764
TI  - [Medical, ethical and economical limitations in the treatment of multitrauma
      patients].
AB  - In the early post-traumatic period severe traumatic brain injuries and massive
      bleeding from disrupted parenchymal organs, large vessels or crush injuries of
      the pelvis may present as morphological damage that renders survival impossible,
      although aggressive fluid and blood replacement therapy in conjunction with
      immediately stopping blood loss surgically may result in survival in selected
      cases. In contrast, late mortality from multiple organ failure - which in the
      past limited survival in 10 to 30 % of patients in that condition - has in recent
      years reduced this as the cause of death to less than 5 %. Part of the
      responsibility of the surgeon caring for the severely injured into consider the
      ethical limitations to avoid futile use of the sophisticated life-support
      measures in the intensive care setting. A threat to optimal care of the severely
      injured patient may arise from the economical restraints imposed on health-care
      providers. When one considers the enormous political and socioeconomical
      importance of rehabilitating the predominantly young trauma patients and
      reintegrating them into the work world, an appeal has to be made to all those
      responsible to secure optimal care for severely injured patients in the future.

PMID- 10591765
TI  - [Biosurgery--revival of the maggot].

PMID- 10591766
TI  - [Optimal timing for secondary surgery in polytrauma patients: an evaluation of
      4,314 serious-injury cases].
AB  - INTRODUCTION: It has been argued that secondary operations in multiple trauma
      patients impose an additional systemic burden, representing an additional risk of
      organ dysfunction. We investigated whether the timing of a secondary operation of
      > 3 h duration is related with the development of organ dysfunction. METHODS: In
      a retrospective analysis, 4,314 polytrauma patients treated at our institution
      between January 1975 and January 1999 were investigated. Patients were divided
      according to the presence ( + MOF) or absence (-MOF) of organ failure (Goris'
      criteria). RESULTS: In both groups, the injury severity, rescue time, duration
      and incidence of primary operations were comparable. Secondary surgery in
      patients who later developed organ failure was significantly more often performed
      between day 2 and 4, whereas patients without organ failure were usually operated
      between day 6 and 8 (P < 0.0001). The initial laboratory data in these two groups
      were comparable. If patients with organ failure were operated on days 6-8,
      significantly worse initial laboratory data were determined, indicating that
      these patients were at high risk of developing MOF. CONCLUSION: In patients with
      severe trauma requiring secondary operations of > 3 h duration, performance of
      this operation should be avoided on post trauma days 2-4.

PMID- 10591768
TI  - [Results of posttraumatic elbow arthrolyses: a prospective study].
AB  - INTRODUCTION: Posttraumatic stiffened joints are mostly well restored by means of
      operation, however, the range of motion remains restricted by secondary soft
      tissue shrinking and scarring. Conservative treatment yields only limited success
      rates. Open arthrolysis is a useful tool in regaining function; in postoperative
      treatment, immediate passive mobilization and prevention of heterotopic
      ossification are most important. METHODS: Sixty-nine patients were arthrolyzed on
      average 25.3 months post trauma, with an average of 1.5 previous operations
      (range 0-8) and a follow-up period of 14.7 months. RESULTS: By means of the open
      arthrolysis, an increase in range of motion for flexion and extension of 62.3
      degrees (preoperative 38.4 degrees, postoperative 87.9 degrees, at follow-up
      100.7 degrees ) and 29.3 degrees for pro- and supination was achieved on average.
      The highly important range of motion between 0-30 degrees and 110 degrees was
      accomplished in 78.2 % of the patients. We analyzed the postoperative management
      including irradiation, pharmacological ossification prophylaxis with indomethacin
      and immediate passive motion. Whenever the time to arthrolysis exceeded 9 months,
      clearly worse results were obtained, thus we measured a difference in the
      correlated increase of motion from 54.3 % - 34.6 %. Comparisons of our results
      with German (after Blauth and Hipp) and French (after Cauchoix and Deburge)
      standard follow-up forms are made, and the rehabilitation program is underlined
      and explained. Another task of this study was to discuss the complication rate.

PMID- 10591767
TI  - [Knee dislocation. Long-term results after operative treatment].
AB  - INTRODUCTION: Traumatic dislocation is the most severe ligamentous injury of the
      knee. The indications for operative and conservative treatment are still
      controversial. METHODS AND RESULTS: From 1974 to 1994, 38 patients with
      documented knee dislocation were treated operatively in our department. Thirty
      four of these patients were followed up for 3-16 years (mean: 8.6 years). In 29
      cases of the follow-up group, reconstruction of both cruciate ligaments was
      performed. In the remaining cases the cruciate ligaments were left alone. At the
      time of follow-up, 90 % of the patients showed good knee stability, but 90 % had
      lack of motion as well. Post-traumatic osteoarthritis was mostly mild to
      moderate. Thirty-five percent of the patients achieved excellent to good results
      in the Lysholm Score. CONCLUSIONS: Positive prognostic factors were an age less
      than 40 years at the time of the accident, a low-energy trauma, e. g., a sports
      related injury, early reconstruction of both cruciate ligaments, and initial
      postoperative functional treatment.

PMID- 10591769
TI  - [Medialization of the tibial tuberosity in habitual dislocation of the kneecap].
AB  - Referring to relevant literature, various concepts are discussed in the treatment
      of habitual dislocation of the kneecap. Between 1987 and 1997, 88 patients have
      been treated surgically in our clinic by uni- or bilateral medial transfer of the
      tibial tuberositas. In 21 of the cases lateral release was also performed. In the
      follow-up, after an average of 4.9 years, 79 patients were examined clinically,
      radiologically and isokinetically (Kintrex-Dynamometer). Isokinetic measurement
      of the extension showed an average deficit of 19 nm compared to the contralateral
      side. Using the Juliusson and Markhede scores, 51 cases had a good, 18 a fair and
      10 a poor clinical outcome. In 79 % of the cases, the postoperative sports
      activity level was the same as preoperatively. Isokinetic measurement with the
      Kintrex is a useful method of evaluating the development of muscle strength.

PMID- 10591770
TI  - [ [In Process Citation]

PMID- 10591771
TI  - [The treatment of unstable fractures of the distal radius using a bridging
      external fixator. Results from a long-term evaluation].
AB  - INTRODUCTION: The aim of our study was to evaluate external fixation in the
      treatment of unstable distal radius fractures in a long-term follow-up. METHODS:
      Within 8 years 174 patients with severely displaced distal radius fractures were
      included in a prospective study and treated with an external wrist fixator
      (Orthofix Srl, Italy). A total of 148 patients were reviewed with an average
      follow-up time of 28 months. RESULTS: Using the functional outcome score
      according to Gartland and Werley, we obtained 29.3 % excellent, 42.5 % good, 10.3
      % fair and 2.9 % poor results; 14.9 % of the patients were not available for
      follow-up. Additional procedures were carried out in 54.1 % to obtain dorsal
      stabilization. The list of complications included two major pin-tract infections
      requiring surgical intervention, one pin cut out of the second metacarpal bone,
      one fixator dislocation, and one patient had algodystrophy. The length of the
      radius and joint congruity did not significantly from the situation when the
      fixator has been removed at the end of the treatment. CONCLUSION: The results
      show the importance of anatomical reduction, and especially restoration of radial
      length, in order to obtain good functional outcome.

PMID- 10591772
TI  - [Predictive value of different injured components in ankle fractures].
AB  - Injuries of the medial ankle side or the posterior tibial margin do not
      necessarily predict a negative outcome in ankle fractures, as shown in this
      comprehensive retrospective study on 342 consecutive patients. A negative
      predictive value results from the combination of different injured ankle
      components. Clinical and radiological results correlate well with each other and
      with the severity of the fracture. They deteriorate according to the number of
      injured ankle components. Thickening of the soft tissues most often results from
      complex injuries. It leads to a decrease in range of motion and therefore
      determines the clinical outcome. Eighty-nine percent of the patients with a
      personal follow-up and 94 % of those with a written investigation had good to
      very good results, which represent the upper range of other presentations. This
      can be achieved by a subtle surgical technique with exact anatomic reduction
      including primary treatment of at least the severe injuries within the first few
      hours after trauma. Complications occurred in 9 % of cases, which coincides with
      the findings of other authors. Especially elderly and obese patients are at
      higher risk.

PMID- 10591774
TI  - [ [In Process Citation]

PMID- 10591773
TI  - [Fracture of femoral neck: analysis of the results of external quality assurance.
      A report on 22,556 patients].
AB  - Since 1993 a report card system for fractures of the neck of the femur has been
      established in the Department of External Quality Assurance of the Chamber of
      Physicians of Westphalia-Lippe. Several indicators of good quality have changed
      significantly since then: conservative treatment decreased from 6.8 % in 1993 to
      4.2 % in 1997, lethality decreased from 6.9 % to 5.4 %, average length of stay
      decreased from 30.9 days to 24.9 days, average length of stay before operation
      decreased from 2.6 to 2.1 days, the frequency of operations on weekends
      increased, complications in wound healing increased from 4.9 to 6.0 %, and
      cardiopulmonary complications decreased from 11.2 % to 7.8 %. Between 1993 and
      1997, 54.3 % were dismissed to go home; the percentage of patients sent to
      rehabilitation facilities after acute care rose from 8.3 % in 1993 to 20.1 % in
      1997. The most frequent and still increasing procedure was implantation of
      hemiprosthesis/bipolar prosthesis (from 38.8 % in 1993 to 41.0 % in 1997)
      followed by total hip replacement (decreasing from 37.4 % in 1993 to 34.2 % in
      1997). Operative treatment was performed in more than 90 % of all fractures in
      all counties of Westphalia-Lippe. However, there was a wide and significant
      geographical variation in the choice between osteosynthesis and hip replacement:
      the percentage of hip replacements differed between 57 % and 82 % among different
      counties. Average length of stay before the operative procedure for patients
      undergoing reduction and rigid internal fixation of the fracture is still too
      long (1.6 days in 1997).

PMID- 10591776
TI  - [ [In Process Citation]

PMID- 10591775
TI  - [Biosurgery - maggots, are they really the better surgeons?].
AB  - Between 1 October 1996 and 31 December 1998 123 patients (74 men, 43 women)
      suffering from acute (n = 17) and chronic (n = 21) infections and chronic wounds
      (n = 85) were treated with sterile maggots (Lucilia sericata). In most patients
      the indication for the use of maggots was a failure to respond to standard
      therapy. Healing occurred in all patients with acute infections, and chronic
      infections showed excellent short-term results. In chronic wounds disturbances of
      healing in diabetics responded best to maggot therapy, the etiologically
      inhomogeneous group of leg ulcers asked for a polypragmatic approach, and the
      worst results were seen in chronic arterial occlusive disease (stage 4). Our
      limited experience with "biosurgery", biased selection of patients, and lack of
      late results reduce the significance of our data; nevertheless, sterile maggots
      seem to be an astonishingly workable tool for solving problems in surgical wound
      treatment.

PMID- 10591777
TI  - [Cardiac troponin T as a biochemical marker of myocardial injury early after
      trauma. Diagnostic value of a qualitative bedside test].
AB  - INTRODUCTION: To evaluate within a trauma population the diagnostic value of a
      qualitative test (TROPT Rapid Assay) for the specific detection of circulating
      cardiac troponin T (cTnT) in comparison with the traditionally used CK/CK-MB
      ratio especially in the early in-hospital phase. METHODS: Prospective study in
      trauma patients over a 12-month period. Multifaceted diagnostic approach to
      myocardial cell injury based on quantitative as well as qualitative cTnT and CK
      MB/CK measurements, electrocardiographic (ECG) and echocardiographic (TTE)
      findings. SETTING: A regional trauma centre, the Federal Armed Forces Medical
      Centre Ulm, Germany. SUBJECTS: One hundred and twenty-five patients with major
      blunt trauma admitted to the Federal Armed Forces Medical Centre Ulm between
      October 1995 and November 1996. RESULTS: The TROPT Rapid Assay results
      significantly correlated with the results of the quantitative cTnT determinations
      (P < 0.001; sensitivity 1.0 and 0. 86/specificity 0.96 and 0.94 upon hospital
      admission and completion of diagnostic procedures). There was no significant
      correlation between CK-MB/CK ratio and quantitative cTnT findings. Upon hospital
      admission all patients whose quantitative cTnT measurement showed a positive test
      result (>/= 0.2 microg/l) also had a positive TROPT Rapid Assay result (negative
      prediction value 1.0). There was a significant correlation of TROPT Rapid Assay
      results and the diagnosis of a concomitant rising "chest trauma" (P < 0.002).
      While a significant correlation between the TROPT Rapid Assay results and
      specific ECG changes was observed (P < 0.008), the findings relating to CK-MB/CK
      ratio did not show any significant relation to specific ECG or specific TTE
      changes. A significant correlation between TROPT Rapid Assay results and
      myocardial lesion related specific therapeutic interventions was observed (P <
      0.01; specificity 1.0, sensitivity 0.11). CONCLUSIONS: Within a multifaceted
      diagnostic approach to blunt cardiac trauma, cTnT should replace CK-MB as the
      biochemical marker of choice. The TROPT Rapid Assay is a test which rapidly and
      accurately enables the trauma team to differentiate patients with and without
      myocardial cell injury. It does not efficiently identify trauma patients at risk
      for the development of cardiac complications.

PMID- 10591778
TI  - [Rare indication for a simple hip prosthesis with an extra-large femoral head
      following multiple failed exchange operations].
AB  - In certain rare cases of failure following multiple exchange arthroplasty at the
      hip, it is possible to create a strong and reliable connection between the pelvis
      and the femur, without replacing the acetabulum, by fitting a custom-made extra
      large femoral head into the existing and stable large cavity. Two cases in which
      this method was used are described here and recommended for consideration in
      similar situations.

PMID- 10591779
TI  - [Bilateral elastofibroma dorsi].
AB  - A 75-year-old man had painless, slowly enlarging tumors in the right and left
      infrascapular regions. Clinically, the tumors were nontender and semimobile. MR
      imaging and the operative exploration revealed tumors infiltrating the lateral
      thoracic muscles and periost of the scapula and underlying ribs. At surgery, the
      tumors were thought to be malignant, most likely liposarcomas. The histological
      examination showed the characteristic appearance of elastofibromas with spindle
      shaped fibroblasts, which were separated by thick eosinophilic collagenous and
      elastic fibers. Elastofibromas are benign mesenchymal soft-tissue lesions that
      mainly affect elderly women. In 10 % of the patients bilateral, often
      asynchronous tumors are seen. Ninety-nine percent of the lesions are located in
      the subscapular region. Occasional elastofibromas have been described in the
      extremities, head, and in the abdominal and thoracic cavities.

PMID- 10591780
TI  - [The subacromial shoulder dislocation].
AB  - We report on a case of subacromial shoulder dislocation, which resulted from a
      combination of a cranial glenoid fracture and an acromial fracture. The patient
      sustained this rare injury while playing handball. The whole implication of the
      injury was revealed only after extensive workup with CT scan of the shoulder.
      After reduction of the shoulder dislocation, the glenoid fracture was stabilized
      by osteosynthesis. The postoperative results showed anatomical reconstruction of
      the glenoid joint surface. After completion of therapy, the patient has achieved
      good functional results with a full range of motion (abduction 180 degrees ) and
      has been able to work full-time again.

PMID- 10591781
TI  - [A scale for measuring symptoms related to degenerative diseases of the cervical
      spine. A reference in determining indications and evaluating surgical outcome].
AB  - A scale for measuring symptoms related to degenerative diseases of the cervical
      spine is presented. Twenty typical symptoms are listed, e. g., neck pain,
      dysesthesia, and reduced mobility. Responses are assessed via a 6-point scaling
      ("did not have symptom" - "had symptom and suffered very strongly".) The cervical
      spine scale was tested in three samples: patients having undergone cervical spine
      surgery (n = 70), patients with other orthopedic diagnoses (n = 104), and healthy
      students (n = 100). The single items of the scale were aggregated into four
      scores: total number of symptoms, degree of overall symptom distress, functional
      disability, and pain/psychological distress. Statistical analyses proved the high
      reliability (Cronbach's alpha = 0.85 to 0.95) and validity (content, convergent,
      discriminant) of all scores. The scale differs clearly between cervical spine
      patients, other orthopedic patients and healthy individuals, and between cervical
      spine patients with different subjective operative outcomes. For applied clinical
      purposes the cervical spine scale can be included in a quality of life profile
      (QL-profile); this allows for a readily understandable graphic depiction of
      individual patients' QL-status.

PMID- 10591782
TI  - [Pioneers in the lengthening of the extremities].
AB  - Successful lengthening of the extremities was first published at the beginning of
      the twentieth century. Those reports in which methods such as the distraction of
      fragments, callus or epiphysis were mentioned for the first time are reviewed.
      Lengthening of the extremities by epiphyseal distraction was first mentioned by
      Bernhard v. Langenbeck in 1869 in an animal experiment. The publications of
      Codivilla, who introduced lengthening by fragment distraction, Kirschner, Bier
      and others are cited and analyzed critically. Thus, the historical development of
      the lengthening of the extremities is reported from 1869 to the middle of the
      twentieth century.

PMID- 10591784
TI  - [ [In Process Citation]

PMID- 10591783
TI  - [Distal radius fractures. II. Surgical therapy].

PMID- 10591785
TI  - [ [In Process Citation]

PMID- 10591786
TI  - [Patch testing with sodium lauryl sulfate: benefits and drawbacks in research and
      practice].
AB  - Patch testing with sodium lauryl sulfate (SLS) has been frequently used in the
      last decade. The evaluation of the SLS test can be performed visually, or with
      bioengineering methods. Among these, the transepidermal water loss is the most
      appropriate method, but measurements by laser Doppler flowmetry, colorimetry or
      corneometry may yield additional relevant data. Various factors such as age, area
      of testing or climatic conditions may also influence the SLS test, so such
      factors should be considered when different studies are compared. If correctly
      used, the SLS test can provide valuable information regarding the skin
      susceptibility to irritation. An overestimation of the test, just based on
      objective measurements with bioengineering methods, should be avoided, as the
      bioengineering data are capable of great precision and reproducibility, but can
      only define phenomena and not the causal event.

PMID- 10591787
TI  - [Congenital melanocytic nevi].
AB  - Congenital melanocytic nevi are benign skin tumours with a population-based
      prevalence of 1-6%. They run an increased life-time risk of transformation into
      malignant melanoma. Additionally, they can be associated with an involvement of
      the leptomeninges (neurocutaneous melanosis), and may cause considerable cosmetic
      and psychic problems. In contrast to the past, the risk of congenital melanocytic
      nevi developing into melanoma is now regarded as well-established. Thus, excision
      is recommended whenever possible. Large lesions which do not allow complete
      excision should be treated by dermabrasion within the first weeks of life.

PMID- 10591788
TI  - [Correlation between epiluminescence microscopy characteristics of malignant
      melanomas and Clark's level of invasion].
AB  - Many epiluminescence microscopy (ELM) characteristics of malignant melanoma
      support the differential diagnosis of pigmented skin tumors. A preinvasive
      evaluation of level of invasion would be valuable for planning the excision
      margins. Since sonography for tumor thickness measurement is rarely available in
      a practice we searched for specific ELM criteria correlating with Clark's level
      of invasion. In our retrospective study of 120 malignant melanomas of 30 ELM
      features were studied for their correlation and the association was significant
      for 15 features.The following criteria were found only in level III-IV melanomas:
      intralesional horizontally elongated blood vessels, spontaneous microhemorrhages,
      plaster-of-Paris-like lacunae, grey-blue/yellowish-brown/reddish saccular pattern
      and eccentric nodes (reddish, livid, blue). 7 characteristics were predominantly
      found in level III-IV melanomas and seldom in "thin" melanomas (level I-II):
      deeply localized gray-blue/-brown fragmentary network, whitish-opaque septa,
      whitish- or bluish-opaque veil, negative pigmented network, areola with evenly
      arranged capillaries, polymorphic capillaries. Perivascular melanophages,
      eccentric dark blotches, pseudotrabeculae of melanophages and greyish-blue
      annular perifollicular pigmentations were the most significant association of ELM
      criteria in "thin" melanomas (level I-II). Epiluminescence microscopy is not only
      a tool for the differentiation of melanocytic lesions but also for a preinvasive
      evaluation of Clark's level of invasion.

PMID- 10591789
TI  - [Effects of combined dermatological and behavioural medicine therapy in
      hospitalized patients with psoriasis and atopic dermatitis].
AB  - The present study examined the effectiveness of combined dermatological and
      behavioural medicine therapy on the skin status and disease-specific stress of
      eighty-six patients with psoriasis and fifty-eight patients with atopic
      dermatitis who were hospitalized in the PsoriSol Clinic, Hersbruck, Germany. In
      addition to receiving instruction about their stain disease, the patients were
      offered, practice in relaxation techniques, social contacts and scratching
      control as well as individual psychological counselling. The clinical change was
      assessed by PASI and SCORAD, respectively. The Marburg questionnaire for coping
      with skin diseases (MHF) and a questionnaire for health-related control
      attributes (GKU-S) served as psychometric measures. Patients showed significant
      improvement in skin status and psychosocial parameters in pre-post comparison.
      Social fears, avoidance and helplessness were reduced by significant improvement
      of the emotional status in both groups. Patients with psoriasis also showed an
      increase in internal control attributes. Dermatological treatment combined with
      behavioural medicine therapy can be considered an effective method in patients
      with atopic dermatitis and psoriasis.

PMID- 10591790
TI  - [Pilot study on hairdresser eczema].
AB  - From 1990 to 1992 the allergy profile of 1042 prospective hairdressers (personal
      and family history, atopic skin, serum IgE, patch and prick tests) was determined
      and their occupational suitability was evaluated. Up to 1997 a follow up of 375
      hairdressers was obtained by way of questionnaires, re-examination, official
      reports and expert opinions of the social accident insurance. The frequency of
      initial eczema was 30%. A change of occupation on account of hairdresser eczema
      was documented in 11%. The prognostic evaluation of occupational suitability
      proved to be unsatisfactory. In this longitudinal study, the frequency of pre
      occupational skin symptoms increased from 13 to 18%. The other atopic criteria
      indicated no uniform tendency. There was a significant increase in nickel allergy
      from 18.7 to 45.5% resulting partly from sensitization after entering the
      occupation and partly from an increase in nickel allergy at time of entry. Both
      atopic skin and pre-occupational nickel allergy increase the risk of hairdresser
      eczema, it is not so great as to justify dissuading such young people from
      entering the profession.

PMID- 10591791
TI  - [Extragenital lichen sclerosus et atrophicus - treatment with pulsed dye laser].
AB  - A 17-year old female patient with extragenital lichen sclerosus et atrophicus was
      treated with the pulsed dye laser. Local and systemic therapy before treatment
      showed no effect. The lesions were removed completely with four treatment
      sessions. As for side effects, no pigment changes and no visible scarring was
      observed. The patient experienced no recurrence within a follow-up time of 7
      months. The mechanism whereby lichen sclerosus et atrophicus is altered by the
      pulsed dye laser is unknown.

PMID- 10591792
TI  - [Henoch-Schonlein purpura: successful treatment with Dapsone].
AB  - A 26-year old patient who suffered from purpura for four years evolved into the
      complete clinical picture of Henoch-Schonlein-purpura in the past two years. A
      causative agent was never found. Multiple therapeutic approaches including
      systemic steroids, azathioprine as well as pentoxyfylline failed to control the
      arthralgias, intestinal symptoms and skin lesions. Therefore dapsone therapy was
      initiated at a dosage of 100 mg daily after checking the glucose-6-phosphate
      dehydrogenase and with regular control of the blood methemoglobin level. Within
      two weeks, the patient's symptoms completely cleared, he has now been in
      remission for the past six months. As noted elsewhere, dapsone is an effective
      therapy for severe cases of Henoch-Schonlein- purpura.

PMID- 10591793
TI  - [Successful therapy of an ILVEN in a 7-year-old girl with calcipotriol].
AB  - A 7-year-old otherwise healthy girl presented with a 2-year history of an ILVEN
      (inflammatory linear verrucous epidermal nevus) located on the inner part of her
      right upper arm. The diagnosis was histologically confirmed. Different
      conservative therapeutic strategies with corticosteroids, antibiotics and
      antimycotics produced little or no improvement. Because of encouraging reports
      describing the successful use of 0.005% calcipotriol ointment in patients with
      ILVEN, we treated our patient with this regimen. After 4 weeks we could recognize
      a impressive improvement and after 8 weeks the ILVEN had nearly completely
      disappeared. 25 weeks after withdrawal of calcipotriol, no relapse had occurred.
      The dramatic response to calcipotriol suggests some pathological links between
      ILVEN and psoriasis.

PMID- 10591794
TI  - [Finasteride: also effective in acne vulgaris?].

PMID- 10591795
TI  - [Comment on the continuing education article by R. Hoffmann and R. Happle
      "Alopecia areata". Position of the Psychosomatic Dermatology Professional Circle
      of German Dermatology Society].

PMID- 10591797
TI  - ?

PMID- 10591796
TI  - [Is the contribution of the Dermatology and Venereology Section of UEMS(European
      Union of Medical Specialists) of marginal significance for German language
      dermatology?].

PMID- 10591799
TI  - [Reports of the Dermatologic Angiology Professional Group].

PMID- 10591798
TI  - [Gene and protein family of matrix metalloproteinases. Structure, function and
      expression in the skin].

PMID- 10591800
TI  - [Reproductive medicine and andrology].

PMID- 10591801
TI  - [Operative sperm retrieval - the urological aspects].
AB  - Nowadays operative sperm retrieval in connection with assisted reproduction is a
      well established procedure in urological-gynecological co-working-groups. MESA
      (microsurgical epididymal sperm aspiration) and TESE (testicular sperm
      extraction) are the fundamental procedures in case of non-reconstructable
      obstructive azoospermia or testicular azoospermia. Percutaneous techniques as
      PESA (percutaneous epididymal sperm aspiration) or PTESE (percutaneous testicular
      sperm extraction), as they are often favorised in the anglo-american countries
      and the countries of Northern Europe have to be discussed to their efficacy
      (number of retrieved spermatozoa) and the possible testicular injury due to the
      blind or ultrasound-guided puncture.

PMID- 10591802
TI  - [Limitations of reproductive medicine from an andrological/urological point of
      view].
AB  - Since the first child was born after in-vitro fertilization in 1978, different
      techniques of ovarian stimulation, oocyte retrieval and embryo culture have
      improved significantly. The development of microinjection techniques was a mile
      stone in reproductive medicine. Even in cases of severe impairment of semen
      quality, using the Intracytoplasmic Sperm Injection (ICSI), pregnancy rates of
      approximately 20 % per treatment cycle can be achieved. However for using
      artificial reproductive techniques (ART) the female age is a major limiting
      factor as well as the development of premature ovarian failure (POF). Crucial for
      the male is the question whether or not sperm cells can be retrieved. Today an
      interdisciplinary approach is recommended to take care of the afflicted couple in
      order to address the complex problem of infertility. There is evidence that
      children born after microinjection techniques bare a higher risk for chromosomal
      aberrations compared to the normal population. However rates of major
      malformations seem to be identical in both groups. An evaluation of the potential
      risks and efforts and an extensive counseling of the infertile couple has to be
      taken before initiating invasive ART.

PMID- 10591803
TI  - [Limitations of reproduction medicine in male subfertility. Treatment of severe
      spermatogenesis disorders].
AB  - Treatment of severe male subfertility has become available since the
      intracytoplasmic injection of a single sperm into an oocyte was successfully
      applied for the first time in 1992. Moreover, also with the use of testicular
      spermatozoa for this procedure fertilization and pregnancies could be
      accomplished. This review addresses the development of these techniques and
      discusses achievements and problems as well as future aspects of the feasibility
      of early spermatid injection are stressed. Furthermore it includes the basic
      elements of spermatogenesis and the major concerns regarding the underlying
      genetic reasons for spermatogenic failure.

PMID- 10591804
TI  - [Renal cell carcinoma. Immunohistological study to the expression of the inactive
      form of the pyruvate kinase].
AB  - PURPOSE: The inactive form of pyruvatekinase could be established in different
      tumours. Purpose of this study was to demonstrate the presence or absence of the
      inactive form of pyruvatekinase in renal cell carcinoma, metastases and benign
      renal tissue by immunohistology. METHOD: After deparaffinization of formaline
      fixed tissue (5 original tumours, 2 metastases and 5 benign renal tissues) cells
      were stained (APAAP-method) with Clon DF4 (ScheBo Tech). RESULTS: All malign
      tissue showed a positive reaction, inside benign tissue we saw a positive
      reaction of endothelial cells however we saw no reaction with benign renal cells.
      CONCLUSION: Renal cell carcinoma and metastatic cells show a strong
      immunohistological reaction against the inactive form of pyruvatekinase, no
      reaction of benign renal cells. It should be possible to develop a serological
      tumour marker for renal cell carcinoma.

PMID- 10591805
TI  - [Amifostine as protective agent in cisplatin-based chemotherapy of advanced
      bladder cancer].
AB  - Amifostine is an organic thiophsophate which protects normal cells from the
      effects of chemotherapy with reduced nadir and duration of cyclophosphamide
      induced neutropenia, reduced cisplatin derived renal and neurological
      complications being described. However, no data are available for urological
      malignancies treated with cisplatin-based chemotherapy. Aim of the study was to
      assess the efficacy of pretreatment with amifostine in terms of prevention of
      renal, hematopoietic and neurologic toxicity. 17 patients (mean age: 62.6 [45
      74]) with advanced transitional cell carcinoma of the urinary bladder received
      inductive or adjuvant cisplatin based chemotherapy (1-6 cycles) with a cisplatin
      dose of 70 mg/m(2). Amifostine (740-910 mg/m(2)) was administered intravenously
      30 minutes prior to chemotherapy. For all patients creatinine clearance, serum
      creatinine and electrolytes including magnesium, and blood cell count were
      determined prior to and after each cycle. A group of 12 patients (mean age: 61.9
      [51-67]) did undergo MVEC chemotherapy (1-4 cycles) without receiving amifostine
      and served as control group. Amifostine was well tolerated and only 1 patient
      suffered from gastrointestinal discomfort, blood pressure remained unchanged in
      all patients. Amifostine prevented a significant reduction of creatinine
      clearance even in the 2 patients with known renal insufficiency: mean creatinine
      clearance was 125 +/- 20 ml/min prior to and 115 +/- 25 ml/min after
      chemotherapy. In the control group, however, creatinine clearance dropped from
      121 +/- 30 ml/min to 85 +/- 20 ml/min after completion of MVEC chemotherapy.
      Serum creatinine levels did not increase significantly (1.1 mg/dl prior to and
      1.2 mg/dl after chemotherapy), magnesium levels did not decrease significantly
      and normalized at the end of chemotherapy. Significant neutropenia and
      thrombocytopenia developed in 29 % and 12 % of the patients in the amifostine
      group and in 67 % and 33 % of the patients in the control group. Amifostine was
      shown to have a protective effect against cisplatin induced nephrotoxicity in the
      elderly patient undergoing systemic chemotherapy. Based on our data amifostine
      should be applied in the supportive management to prevent chemotherapy induced
      complications.

PMID- 10591806
TI  - [Coagulating intermittent cutting. Improved high-frequency surgery in
      transurethral prostatectomy].
AB  - In spite of the high and lasting efficiency of transurethral prostatectomy,
      intraoperative blood loss results in increased morbidity in this procedure. This
      led to the development of many alternative treatment modalities in the last
      years. To minimize the risk of bleeding, we improved the high-frequency
      technology in several steps. To achieve this, the output signals of commercially
      available high-frequency generators were modulated to the effect that each cut
      results in an efficient coagulation zone in the tissue at excellent cutting
      quality. Laboratory and in vitro studies using porcine kidneys as well as
      clinical trials showed good cutting characteristics accompanied by a significant
      reduction of bleeding. As a result, blood transfusions were less necessary, the
      transurethral catheter could be removed earlier in the postoperative period, and
      hospitalization time was significantly reduced. In conclusion, the improved high
      frequency technology in form of the "coagulating intermittent cutting" results in
      a blood-sparing tissue resection with a consecutive reduction of morbidity.

PMID- 10591807
TI  - [Spontaneous kidney rupture after delivery due to an urothelial carcinoma].
AB  - The case of a spontaneous kidney rupture due to an urothelial carcinoma one week
      after delivery is presented. Diagnosis was made during operation. In comparison
      to the carcinoma, which is diagnosed and treated in time, the prognosis is poor.
      The patient deserved continuous gynecological follow-up and showed the classic
      symptoms of an urothelial carcinoma for six months. In spite of regular
      sonographic controls during pregnancy the tumor was not diagnosed. Diagnosis and
      management of renal carcinomas during pregnancy are discussed.

PMID- 10591808
TI  - [Evaluation of gene therapy in the treatment of urological tumors].

PMID- 10591809
TI  - Ethnicity, class and schizotypy.
AB  - BACKGROUND: This study investigated whether, similarly to schizophrenia, there is
      an increased rate of schizotypy among African-Caribbeans in the general
      population compared with white people in the UK. Since social adversity has been
      associated with schizophrenia in a number of studies, social class as well as
      ethnicity was explored. In addition, any differences between the groups in
      neurotic pathology were investigated. METHODS: Four groups of 12 participants
      (African-Caribbean, working-class; African-Caribbean, middle-class; white, middle
      class; white, working-class) were interviewed using The Oxford-Liverpool
      Inventory of Feelings and Experiences (O-LIFE), The Peters et al. Delusions
      Inventory (PDI), The Delusions-Symptoms-State-Inventory (DSSI) and The Hospital
      Anxiety and Depression Scale (HADS). RESULTS: As predicted, African-Caribbean
      participants scored higher than the white participants on the PDI. There was a
      significant interaction between ethnicity and class, with African-Caribbean,
      working-class participants scoring higher than the other three groups on the PDI
      as well as on the DSSI. There was an unexpected effect of class, with the middle
      classes scoring higher than the working-classes on the O-LIFE category of
      'impulsive non-conformity'. CONCLUSIONS: These findings suggest that it is
      delusional ideation specifically, rather than general schizotypy, that is higher
      in the African-Caribbean population. However, whether this is a reflection of
      their social reality or their psychosis proneness is unclear. Furthermore, the
      results suggest that class is a significant factor in the expression of
      delusional ideation in African-Caribbeans.

PMID- 10591810
TI  - Clinical and social needs of schizophrenic outpatients living in the community:
      the relationship between needs and subjective quality of life.
AB  - BACKGROUND: The aims of this study were to assess self-perceived clinical and
      social needs among 120 schizophrenic outpatients, and the relationship between
      needs and subjective quality of life. METHOD: The Camberwell Assessment of Need
      instrument (CAN) was used to assess needs and the Lancashire Quality of Life
      Profile was employed to assess subjective quality of life. RESULTS: More than
      half of the patients expressed needs in areas concerning psychotic symptoms,
      daytime activity, company, physical health and information about their condition
      or treatment. The areas with the highest proportion of unmet needs were
      information, company, intimate relationship, physical health, daytime activity
      and psychological distress. A more severe need of care and support in the areas
      of company, psychological distress, daytime activity and sexual expression was
      associated with a worse subjective quality of life, controlling for the influence
      of symptomatology. CONCLUSIONS: The results point to a need to further emphasise
      interventions towards the treatment of psychotic symptoms and psychological
      distress as well as to focus on interventions concerning the social relations and
      occupational situation of long-term mentally ill patients.

PMID- 10591811
TI  - The Finnmark study. Social support, social network and mental distress in a
      prospective population study.
AB  - BACKGROUND: Earlier studies on the direct effect of social support and social
      network upon mental health have mostly been done in cross-sectional studies and
      the results have been conflicting. METHODS: The direct effect of social network
      and social support upon mental distress was tested in population-based health
      surveys conducted in 1987, 1990 and 1993. The population consisted of all persons
      aged 40-62 years and a random sample of persons aged between 20 and 39 years
      living in five small municipalities in Finnmark, the northernmost county in
      Norway. The attendance rates were 77%, 74% and 70% for the three health surveys,
      respectively. All those who had attended the health surveys more than once and
      answered the key questions about mental distress, social support and social
      network were selected for analyses (966 persons who attended both the two first
      health surveys and 1425 persons attending both the two last surveys). A
      theoretical full cross-lagged panel model was used to search for the predictive
      effects of time 1 variables (mental distress, social network and social support)
      upon corresponding subsequent variables. RESULTS: Mental distress, social support
      and social network at time 1 strongly predicted the corresponding variable at the
      next time point. Emotional support at time 1 exerted a weak positive effect upon
      mental distress on the next time point, explaining approximately 1% of the
      variance. Neither the social network nor instrumental support at time 1 predicted
      degree of mental distress at the subsequent time point. CONCLUSION: We conclude
      that social network and social support have very little direct predictive effect
      upon mental distress 3 years later in this population.

PMID- 10591812
TI  - Comorbidity of schizophrenia and prelingual deafness: its impact on social
      network structures.
AB  - BACKGROUND: Prelingually deaf persons usually gain only a rudimentary command of
      speech and prefer sign language to communicate within the deaf community without
      the handicap they experience in the hearing world. Maintaining social contact
      within this rather scattered community, however, requires higher degrees of
      social initiative and mobility. The aim of the present paper was to study the
      quantity and quality of social integration among a group of prelingually deaf
      schizophrenic patients (n = 49) and two control groups comprising prelingually
      deaf psychiatric but non-psychotic patients (n = 38) and hearing schizophrenic
      patients (n = 30), with account being taken of the special socialisation
      conditions of deaf persons and of their cultural standards and values. METHOD:
      Data were collected with the help of semi-structured interviews; with the deaf
      patients these were conducted in German sign language. Using rating procedures we
      assessed seven social support components, selected items from a history schedule
      for schizophrenia, and the probands' visual and verbal language skills. RESULTS:
      The social networks of the two deaf groups were found to have larger gaps than
      those of the hearing schizophrenic patients, with significant differences being
      registered most clearly in the comparison between deaf schizophrenic and hearing
      schizophrenic patients. Comparison of the verbal and visual language skills of
      the two deaf groups revealed a substantial deficit among the deaf schizophrenics.
      Visual language skills were found to correlate more strongly than verbal language
      skills with the social support components. CONCLUSION: Prelingual deafness has a
      strong impact on the course of schizophrenia. In the long run, many of these
      patients belong to a "minority within a minority".

PMID- 10591813
TI  - Psychosocial characteristics in young men as predictors of early disability
      pension with a psychiatric diagnosis.
AB  - BACKGROUND: There is little knowledge about disability pensions (DPs) in
      psychiatric diagnoses. The aim of this study was to analyse risk factors among
      men for receiving an early disability pension with a psychiatric diagnosis.
      METHODS: The study is based on data from a nationwide survey of 49 285 young
      Swedish men who were conscripted into military service in 1969/1970. Potential
      psychosocial and behavioural risk factors were linked to records from the Swedish
      Social Insurance Board up until 1993. RESULTS: The majority (63.4%) of the men
      granted a DP during follow-up had a psychiatric diagnosis as the main and/or
      secondary diagnosis. Among those conscripts analysed (41 702), 599 had been
      granted a disability pension with a psychiatric diagnosis. Of these, 35.4% had a
      diagnosis of psychosis, 23.2% an alcohol- or drug-related diagnosis, and 41.4%
      'other' psychiatric diagnosis. Receiving a psychiatric diagnosis at conscription,
      showing low emotional control, unemployment after graduation, and ranking low on
      an "IQ" test were strong predictors of all categories of DP with psychiatric
      diagnoses. In multivariate analysis controlling for the effect of all other risk
      indicators included in the model, DP with non-alcohol- and non-drug-related
      psychiatric diagnoses was related to low social support at adolescence but not to
      signs of extrovert deviant behaviour (risky use of alcohol or contact with police
      and child authorities). In contrast, DP with an alcohol- or drug-related
      diagnosis had strong associations with signs of extrovert deviant behaviour. The
      risk pattern of DP without psychiatric diagnoses was similar to that of DP with a
      psychosis but also, though to a lesser extent, to that of DP with 'other'
      psychiatric diagnosis. These similarities could be interpreted as showing that
      the diagnoses on the records of disability pensions have a low sensitivity and/or
      specificity or, alternatively, that the risk factors found are risk factors for
      life careers steering toward a disability pension rather than toward the specific
      health outcomes per se. CONCLUSIONS: The results illustrate the importance of
      psychosocial factors established in late adolescence in the complex pathway of a
      decision of an early DP.

PMID- 10591814
TI  - Collecting psychiatric resources utilisation data to calculate costs of care: a
      comparison between a service receipt interview and a case register.
AB  - BACKGROUND: Economic assessment of interventions and policies is becoming
      increasingly common, in large measure because of the growing emphasis on cost
      containment within health care. Comprehensive and reliable outcome and cost data
      are required to advise policy makers and clinicians as to the best use of their
      limited resources. The process of costing can be broken down into three connected
      tasks: the collection of service receipt or utilisation data relative to
      individual clients or patients over a defined period; the costing of each of the
      services used; and the combination of these two sets of information in order to
      calculate individual costs. The aim of this study was to compare two
      methodologies of collecting data on individual service use - a customized
      interview schedule, ICAP, and the psychiatric case register (PCR) - and to
      calculate costs, testing the extent of agreement between them. METHOD: The
      agreement between the ICAP and the PCR costs measurement was evaluated using the
      concordance correlation coefficient rho(c). From all patients (n = 543) who had
      at least one contact with a psychiatrist or a psychologist during the period
      October-December 1996, 339 patients were interviewed using the ICAP. The overall
      number of patients in contact with the South-Verona CPS in the same period was
      630. RESULTS: The agreement between the two sources was very different for each
      diagnostic group and each professional category. However, the overall agreement
      on total costs was satisfactory (rho(c) < 0.95). This result is probably due to
      the effect of the good agreement observed on more costly services: inpatient care
      and sheltered accommodation. CONCLUSION: The results suggested practical
      implications for the use of the service receipt interview: interviewers should be
      trained in order to avoid misinterpretation of the definitions given in the form;
      the sources of information should be clearly defined to tease out all the items
      of services provided for the users; the professionals (i.e. psychiatrists) could
      influence the reliability of data collection by underestimating services provided
      by different professionals (nurses, social workers, etc.). The findings confirm
      that it is possible to use this approach when the aim is to estimate the whole
      cost of the services; however, the importance of adopting adequate procedures for
      analysing the complexity of cost components should be pointed out. Only a trained
      interviewer who thoroughly knows each component of the health and social services
      provided could guarantee an accurate data collection.

PMID- 10591815
TI  - Rearing style and depressive disorder in adulthood: a controlled study in a
      Spanish clinical sample.
AB  - OBJECTIVE: The aim of this study was to investigate the style of rearing in a
      sample of depressive patients and compare it with a control group of normal
      subjects of similar age, sex, and civil status. The hypothesis to verify was that
      among the depressives the style of rearing is characterised by a deficit in
      Emotional Warmth and an excess of Rejection and Protection. We analysed whether
      the severity of the depression - Major Depressive Disorders versus Depressive
      Disorders Not Otherwise Specified - was associated with differences in the
      perceived rearing conditions. DESIGN: It was an observational study of the
      case/control type. There were 50 patients, whose first depressive episode (DSM
      III-R criteria) began in the 6 months prior to the interview. They were entered
      sequentially into the study sample. The control group comprised 50 subjects with
      no depressive pathology, matched by age, sex, and social class. METHOD: The EMBU
      questionnaire was applied to all the subjects. RESULTS: Only 35% of all
      depressive patients, as against 64% of the controls, had experienced an optimum
      upbringing. It is shown that a deficit in Emotional Warmth and a high level of
      Rejection constitute parental attitudes that are significantly more frequent
      among depressives than among subjects with no psychiatric pathology. Type of
      depression or degree of intimacy did not influence the scores obtained in the
      subscales of the EMBU. Depressives pertaining to lower social classes tended to
      score higher in Overprotection and Rejection scales.

PMID- 10591816
TI  - Diagnosis and treatment of mental disorders: a survey of Singapore mental health
      professionals.
AB  - BACKGROUND: A series of surveys of mental health literacy have been undertaken in
      Australia, involving members of the general public as well as general
      practitioners and mental health professionals, whereby respondents consider
      vignettes of depression and of schizophrenia, offer a diagnosis and rate a series
      of possible interventions for their judged helpfulness. A similar survey was
      undertaken in Singapore and is reported in this paper. METHODS: The survey was
      undertaken at a large state psychiatric hospital with staff (psychiatrists,
      allied health professionals, psychiatrically and generally trained nursing staff)
      rating a vignette of mania, in addition to the vignettes derived in Australia for
      depression and schizophrenia, and with the Australian intervention options
      extended somewhat to respect Singapore facilities. RESULTS: Responses of those in
      the four professional groups were compared. The psychiatrists were highly
      accurate in generating diagnoses, other staff somewhat less so for diagnosing
      depression (with a percentage instead choosing a diagnosis of stress) and mania
      (with a percentage instead diagnosing a schizophrenic condition). Reported
      helpfulness ratings identified those interventions judged consensually as likely
      to be helpful or harmful, as well as establishing some differences across the
      four professional groups. CONCLUSIONS: The consensus decisions of helpful
      treatments for depression and schizophrenia revealed very similar findings to
      judgements made by Australian professionals. The treated outcome of schizophrenia
      was judged as somewhat worse than that for mania and depression. While non
      medical staff differed from psychiatrists in judging the comparative utility of
      some drug interventions and lifestyle issues, there was clear evidence of a
      relatively dominant 'medical model' to recommended treatments, while traditional
      healing practices and services were rated as distinctly unhelpful.

PMID- 10591817
TI  - A protocol for imaging paediatric brain tumours. United Kingdom Children's Cancer
      Study Group (UKCCSG) and Societe Francaise D'Oncologie Pediatrique (SFOP)
      Panelists.

PMID- 10591818
TI  - Management of neuroendocrine tumours.

PMID- 10591819
TI  - Stereotactically delivered cranial radiation therapy: a ten-year experience of
      linac-based radiosurgery in the UK.
AB  - In 1989, linear accelerator (linac)-based cranial stereotactic radiation therapy
      ('radiosurgery') was introduced in the UK at St Bartholomew's Hospital; a new,
      relocatable stereotactic frame was first used at the same time, allowing
      fractionated stereotactic radiotherapy. In the first decade of clinical practice
      using this technology, some 200 patients with blood vessel tumours/malformations
      have been treated, together with another 200 suffering from other conditions. The
      usefulness of this technique for cerebral arteriovenous malformations (AVM) has
      been demonstrated, and also a significant cure rate for AVM of >3 cm diameter
      (which is larger than for those previously reported after treatment on the gamma
      unit), albeit attended by a higher complication rate. The epilepsy associated
      with AVM is much improved by successful radiotherapy. The usefulness of
      radiosurgery for glomus tumours has been confirmed and new data published on the
      efficacy of the technique for haemangioblastoma, with new radiation therapy
      strategies designed for patients with von Hippel-Lindau disease. The acoustic
      neuroma treatment results have included improvements in hearing (a result not
      reported in the gamma unit literature), which are ascribed to the lower internal
      dose gradient within the target volume. Fractionation will, it is argued, also
      lead to sparing of the special sensory cochlear nerve. The risks of radiosurgery
      to the brainstem for chordoma of the mid-clivus are reduced by using a 'spacer'
      technique for the prepontine space. For meningiomas involving the cavernous
      sinus, conventionally fractionated radiotherapy is recommended when the meningeal
      base diameter exceeds 3.0 cm and radiosurgery (utilizing fractionation where
      appropriate) is advised for smaller lesions. Thus far, radiosurgery indications
      for pituitary adenomas have been restricted to recurrences after conventional
      radiotherapy, usually those in the cavernous sinus. In therapy for recurrent
      craniopharyngioma, it is argued that fractionation delivered via the relocatable
      frame will be important, particularly when the disease envelops the optic
      chiasma. For semicystic/semisolid craniopharyngiomas, the stereotactic delivery
      of colloidal yttrium-90 into a cystic element is useful, while stereotactic
      radiosurgery is delivered to the solid component. Staff at this centre consider
      that radiosurgery for low-grade gliomas, perhaps as boost therapy after
      conventional fractionation, is worthy of more research. We have been extremely
      selective in the use of radiosurgery for brain metastases (2% of patients,
      compared with about 30% in some Gamma Knife units), but future indications may
      become broader, probably using it as a booster technique after whole-brain
      conventionally-fractionated radiotherapy. Positron emission tomography scanning,
      co-registered with magnetic resonance imaging, allows the 'boost' concept in
      radiosurgery to become a sophisticated and accurate reality. Post-radiosurgical
      sequelae have been placed within a standard framework classification. New
      observations are being made with regard to subacute reactions: late-responding
      intrinsic and extra-axial tumours may swell in the subacute period, prior to
      shrinkage, and be attended by symptomatic surrounding brain oedema.

PMID- 10591820
TI  - Stereotactic radiosurgery, X: clinical isodosimetry of gamma knife versus linear
      accelerator X-knife for pituitary and acoustic tumours.
AB  - Several review articles have compared gamma unit versus linear accelerator
      (linac)-based radiosurgery systems, concluding that the dose gradient 'fall-off'
      at the margin of the target (expressed as the distance between isodoses) is very
      similar for both techniques as far as single isocentre treatment volumes up to
      1.5 cm diameter are concerned, and that the two radiosurgical systems are, in
      general, comparable. 'Fine tuning' of the gamma unit can be carried out by using
      multiple isocentre plans, the differential use of small collimator sizes (down to
      4 mm) and field weightings, and adroit use of the gamma angle, and selective beam
      blocking. Multiple isocentre plans, beam modification, restriction of gantry
      angles and arc lengths, and microcollimation can similarly improve the isodose
      gradients from linac units. In both instances, the dosimetric advantages occur
      along selected aspects of the target perimeter border. However, the more frequent
      use of multiple isocentred 'shots' on the gamma unit achieves greater conformity
      indices for more complex target volumes, but at the expense of steeper internal
      dose gradients. We studied two patients with tumours close to or arising from
      radiosensitive special sensory nerves (optic and cochlear) to compare and
      contrast fine tuning of the two technologies. In a previously irradiated patient
      with a pituitary adenoma, the dose gradient achieved at the rostral margin,
      adjacent to the optic chiasma, was steeper on the gamma unit (due to the
      concentration of small collimator shots rostrally and beam blocking), which was
      therefore the dosimetrically preferred technique. In contrast, the vastly smaller
      internal dose gradient (11% for linac/X-knife versus 100% for Gamma Knife) and
      the ability to fractionate on the X-knife system, gave a large dosimetric
      advantage to the X-knife plan in the treatment of an acoustic neuroma, where the
      intracanalicular component of the cochlear nerve traversed the target volume.
      This advantage also pertains to the cochlear ramus of the internal auditory
      (labyrinthine) artery and the facial nerve. Our published work on X-knife
      radiosurgery of acoustic neuroma has documented improvement of hearing after
      therapy and may be relevant in this regard. That there are advantages in physical
      dose distribution and fractionation, producing a reduction in the biological dose
      in normal tissue, argues for the use of linac technology in acoustic neuromas.
      Craniopharyngiomas enveloping the optic nerve/chiasma will similarly be better
      treated by the linac X-knife system. It is apparent that different radiosurgery
      systems may be indicated in particular neuro-oncological situations.

PMID- 10591821
TI  - Hypofractionated radiotherapy for patients with carcinoma of the bladder.
AB  - In order to develop a low toxicity regimen of bladder radiotherapy for the
      palliation of patients with poor performance status we carried out a Phase II
      study of weekly 6 Gy fractions to a maximum dose of 30-36 Gy in 65 patients with
      T(2)-T(4) bladder cancer (median age 81 years). A complete response was obtained
      in 23/37 (62%) assessable patients at cystoscopy. Local control was achieved in
      16/65 (25%) patients. The median survival of all 65 patients was 35 weeks, and
      the 2-year actuarial survival 21%. The main acute toxicity was urinary frequency
      as often as hourly at the peak of the reaction (Radiation Therapy Oncology Group
      (RTOG) grade 3) in seven patients, and urinary obstruction (RTOG grade 4) in one.
      The reactions may have been compounded by the effects of locally advanced tumour.
      Late bladder toxicity amongst the 16 patients who were evaluable after 1 year
      included four patients with persisting frequency, one with severe haematuria
      (RTOG grade), and one with a bladder capacity <100 ml (RTOG grade 4). One patient
      experienced RTOG grade 4 late bowel and bladder morbidity. Weekly 6 Gy fractions
      to a total dose of 30-36 Gy is a satisfactory palliative regimen for patients
      with advanced bladder cancer who cannot tolerate standard radical radiotherapy,
      but it may produce significant late bladder morbidity.

PMID- 10591822
TI  - A pilot study of continuous, hyperfractionated, accelerated radiotherapy in
      rectal adenocarcinoma.
AB  - This pilot study investigated the feasibility, toxicity and effect of continuous,
      hyperfractionated, accelerated radiotherapy (CHART) in 19 patients with
      adenocarcinoma of the rectum who were treated at Mount Vernon Hospital between
      April 1992 and April 1994. A total dose of 54 Gy was given in 36 fractions over
      12 consecutive days; three fractions of 1.5 Gy were employed each day with an
      interfraction interval of 6 hours. Of these 19 patients, 13 had local pelvic
      recurrence from rectal carcinoma, four had a primary rectal carcinoma (which was
      unsuitable for abdominoperineal resection because of patient frailty), and two
      had large, fixed, unresectable tumours and were given radiotherapy preoperatively
      to a lower dose of 42 Gy in 28 fractions over 10 days to facilitate surgery.
      However, none of the 19 patients subsequently underwent surgical resection.
      Treatment compliance with radiotherapy was 95%. Acute bowel toxicity was assessed
      by means of a daily bowel chart for 6 weeks and then at 8, 12 and 26 weeks after
      the completion of radiotherapy. Patients were subsequently scored using the World
      Health Organization (WHO) grading system. No toxic deaths were observed in this
      study. There were five grade 3 and one grade 4 toxicities (WHO scale) observed in
      six patients. There has been minimal acute bladder toxicity in two patients and
      skin reactions have been surprisingly minimal in all but three patients. Small
      bowel obstruction and late bowel damage, possibly attributable to radiotherapy,
      occurred in three patients. Complete pain relief was achieved in recurrent rectal
      cancer in 100% of patients, at a median of 15 days since commencing radiotherapy
      (range 7-63 days), and has been maintained for mean and median durations of 19
      and 18 months respectively (range 1.5-45 months). Five patients have had a
      recurrence of pain at 3, 4, 8, 9 and 18 months respectively. All four patients
      with primary rectal adenocarcinoma achieved a complete response, which has been
      sustained for 4 months (until death), 54 and 57 months, although one patient
      relapsed locally at 8 months. In summary, CHART appears to be a feasible
      treatment for pelvic tumours with regard to toxicity. Patients with pain from a
      locoregional recurrence achieved rapid complete pain relief, which was sustained
      for many months.

PMID- 10591823
TI  - Efficacy of an ondansetron orally disintegrating tablet: a novel oral formulation
      of this 5-HT(3) receptor antagonist in the treatment of fractionated radiotherapy
      induced nausea and emesis. Emesis Study Group for the Ondansetron Orally
      Disintegrating Tablet in Radiotherapy Treatment.
AB  - A significant number of patients who are receiving radiotherapy experience the
      distressing side effects of emesis and nausea. Although prophylactic antiemetics
      are often given to patients who are receiving single-fraction, high-dose
      radiotherapy to the abdomen, a survey has revealed that antiemetic prophylaxis is
      not routinely offered to those receiving fractionated radiotherapy. Hence there
      is a need for an effective treatment of emesis for use in this group of patients.
      Ondansetron is an effective and well-tolerated antiemetic, which is used for the
      prevention of both chemotherapy and radiotherapy-induced emesis and nausea. This
      agent has been developed as a novel freeze-dried oral formulation. Ondansetron
      orally disintegrating tablets (ondODT) disperse rapidly when placed on the
      tongue. As the tablet does not need to be swallowed with water, it is a
      particularly useful formulation for patients who have difficulty with swallowing
      or who do not feel able to drink. This study was undertaken to investigate the
      efficacy of ondODT in the treatment of established emesis and nausea induced by
      radiotherapy. Two doses of ondODT, 8 mg and 16 mg, were compared with placebo in
      patients who developed emesis and/or moderate/severe nausea after receiving
      fractionated radiotherapy to sites located between the thorax and the pelvis. The
      study showed that ondODT was clinically superior to placebo in treating emesis
      and nausea successfully over a 12-hour period after taking the medication. There
      were no statistically significant differences between the two doses of ondODT. In
      the 2 hours after taking the study medication, patients who received ondODT (8 mg
      and 16 mg) had significantly fewer emetic episodes compared with those who
      received placebo. They also experienced significantly less nausea. In conclusion,
      ondODT 8 mg is effective in the treatment of radiotherapy-induced emesis and
      nausea and provides an effective alternative to the conventional ondansetron
      tablet.

PMID- 10591824
TI  - Solitary bone plasmacytoma: management of isolated local relapse following
      radiotherapy.
AB  - Radiotherapy is the prime treatment modality for solitary plasmacytomas of bone
      (SPB). Although local control rates are excellent, progression to multiple
      myeloma is frequent, albeit with varying latency. Local failure in the absence of
      dissemination is rare and thus management is poorly documented. We discuss such a
      patient who presented 3 years after local radiation for a pelvic SPB and review
      the relevant literature. Radiation doses, portals employed and prognostic factors
      that may predict progression to myeloma are discussed. This report shows that an
      isolated recurrence of SPB in a previously irradiated field was successfully
      treated with orthopaedic surgery. This resulted in good pain relief and mobility
      for the patient, who remains free of disease 6 months after operation.

PMID- 10591825
TI  - Superior vena cava obstruction in prostate cancer.
AB  - This report describes the case history of a man with adenocarcinoma of the
      prostate. After an initial response to maximal androgen blockade, he developed
      massive mediastinal and cervical lymphadenopathy, causing left recurrent
      laryngeal nerve palsy and superior vena cava obstruction. Biopsy confirmed
      metastatic prostate cancer and he responded well to local radiotherapy. The
      hormonal treatment of advanced prostate cancer is discussed.

PMID- 10591826
TI  - HIV complicates the management of oncological emergencies: a case involving the
      superior vena cava syndrome.
AB  - An association exists between human immunodeficiency virus (HIV) and an increased
      incidence of lung cancer. Superior vena cava syndrome (SVCS) is an oncological
      emergency seen in the presence of chest tumours. We report on an otherwise well
      HIV-positive male who presented with SVCS due to lung cancer. He was commenced on
      dexamethasone and radiotherapy with curative intent. Treatment was complicated by
      accelerated steroid- and radiation-induced morbidity. The patient died of
      disseminated aspergillosis after receiving 27 of 35 planned radiotherapy
      fractions. The management of SVCS in those with HIV is challenging and requires
      the judicious use of steroids, antifungal prophylaxis and palliative radiotherapy
      doses.

PMID- 10591827
TI  - Abstracts

PMID- 10591828
TI  - Guidelines on the management of prostate cancer.

PMID- 10591831
TI  - Changing views about 'Osteoporoses' (a 1998 overview).
AB  - Recent realizations have begun to change how 'osteoporoses' are diagnosed,
      managed and studied. This article explains the nature and basis of some resulting
      controversies, chiefly for clinicians who manage such patients but do not
      participate in resolving those controversies. Currently the size of a bone 'mass'
      deficit serves to diagnose 'osteoporosis', but recently clarified physiology
      suggests at least three different kinds of osteoporosis could occur in people
      with identical bone 'mass' deficits. Indeed, they do occur. (a) In one kind,
      people have less bone than 'normal' but no bone problems unless they sustain
      injuries. Most of their resulting fractures, usually from falls, affect extremity
      bones. This condition can affect children, men and women. (b) In a second kind an
      osteopenia exists in which voluntary physical activities (not injuries) cause
      spontaneous fractures and/or bone pain, mainly in the spine, more often in women
      than men and seldom in children (osteogenesis imperfecta excepted). (c) A third
      kind combines features of the first two. As for the physiology involved in those
      affections, bone modeling can increase bone strength and 'mass', while BMU (Bone
      Multicellular Unit)-based bone remodeling can reduce them. Mainly bone strains
      control those two activities and muscles cause the largest strains, so muscle
      strength should strongly influence bone modeling, remodeling, strength and
      'mass'. If so chronic muscle weakness should usually cause an osteopenia and
      weakened bones. Excessive amounts of fatigue damage or microdamage can also
      weaken bones. From that physiology one could argue that chiefly chronic muscle
      weakness instead of an intrinsic bone disorder would cause (a), while intrinsic
      but still enigmatic modeling and remodeling disorders would cause (b), and (c)
      could combine features of both conditions. If so, these ideas could have
      significant effects on the future criteria used to diagnose osteoporoses and
      osteopenias, on how they are studied in the clinic and laboratory, and on how
      they are prevented or, if they occur, are managed.

PMID- 10591832
TI  - High-resolution computed tomography for architectural characterization of human
      lumbar cancellous bone: relationships with histomorphometry and biomechanics.
AB  - The aim of the present study on human vertebral cancellous bone was to validate
      structural parameters measured with high-resolution (150 microm) computed
      tomography (HRCT) by referring to histomorphometry and to try to predict
      mechanical properties of bone using HRCT. Two adjacent vertical cores were
      removed from the central part of human L2 vertebral body taken after necropsy in
      22 subjects aged 47-95 years (10 women, 12 men; mean age 79 +/- 14 years). The
      right core was used for structural analysis performed by both HRCT and
      histomorphometry. Two cancellous bone specimens were extracted from the left
      core: a cube for HRCT and a compression test, and a cylinder for a shear test.
      Significant correlations were found between HRCT and histomorphometric
      measurements (BV/TV, trabecular thickness, separation and number, and node-strut
      analysis), but with higher values for most of the tomographic parameters (BV/TV
      and trabecular thickness determined by HRCT were overestimated by a factor 3.5
      and 2.5 respectively, as compared with histomorphometry). The maximum compressive
      strength and Young's modulus were highly correlated (rho = 0.99, p<0.0005).
      Significant correlation was obtained between bone mineral density (determined
      using dual-energy X-ray absorptiometry) and the maximum compressive strength (rho
      = 0. 64, p = 0.002). In addition the maximum compressive strength and
      architectural parameters determined by HRCT or histomorphometry showed
      significant correlations (e.g., for HRCT, BV/TV: rho = 0.88, p<0.0005, N.Nd/TV:
      rho = 0.73, p<0.001). The shear strength was significantly correlated with BV/TV
      (rho = 0.62, p = 0.002), Tb.Sp (rho = -0.58, p = 0.004) and TSL (rho = 0.55, p =
      0.006) measured by HRCT. In conclusion, an HRCT system with 150 microm resolution
      is not sufficient to predict the true values of the structural parameters
      measured by histomorphometry, although high correlations were found between the
      two methods. However, we showed that a resolution of 150 microm allowed us to
      predict the mechanical properties of human cancellous bone. In vivo peripheral
      systems with such a resolution should be of interest and would deliver an
      acceptable radiation dose to the patient.

PMID- 10591833
TI  - The impact of intense training on endogenous estrogen and progesterone
      concentrations and bone mineral acquisition in adolescent rowers.
AB  - The effect of 18 months of training on the ovarian hormone concentrations and
      bone mineral density (BMD) accrual was assessed longitudinally in 14 adolescent
      rowers and 10 matched controls, aged 14-15 years. Ovarian hormone levels were
      assessed by urinary estrone glucuronide (E(1)G) and pregnanediol glucuronide
      (PdG) excretion rates, classifying the menstrual cycles as ovulatory or
      anovulatory. Total body (TB), total proximal femur (PF), femoral neck (FN) and
      lumbar spine (LS) (L2-4) bone mass were measured at baseline and 18 months using
      dual-energy X-ray densitometry. Results were expressed as bone mineral content
      (BMC), BMD and bone mineral apparent density (BMAD). Five rowers had anovulatory
      menstrual cycles compared with zero prevalence for the control subjects. Baseline
      TB BMD was significantly higher in the ovulatory rowers, with PF BMD, FN BMD and
      LS BMD similar for all groups. At completion, the LS bone accrual of the
      ovulatory rowers was significantly greater (BMC 8.1%, BMD 6.2%, BMAD 6.2%) than
      that of the anovulatory rowers (BMC 1.1%, BMD 3.9%, BMAD 1.6%) and ovulatory
      controls (BMC 0.5%, BMD 1.1%, BMAD 1.1%). No difference in TB, PF or FN bone
      accrual was observed among groups. This study demonstrated an osteogenic response
      to mechanical loading, with the rowers accruing greater bone mass than the
      controls at the lumbar spine. However, the exercise-induced osteogenic benefits
      were less when rowing training was associated with low estrogen and progesterone
      metabolite excretion.

PMID- 10591834
TI  - The new selective estrogen receptor modulator MDL 103,323 increases bone mineral
      density and bone strength in adult ovariectomized rats.
AB  - Selective estrogen receptor modulators (SERMs) can prevent the bone loss induced
      by ovariectomy (OVX), but it is not established whether they can increase bone
      mass and strength in a curative protocol in ovariectomized osteopenic animals. We
      investigated the influence of a SERM of the new generation, MDL 103,323, on areal
      bone mineral density (BMD), as measured by dual-energy X-ray absorptiometry, bone
      strength and remodeling in OVX osteopenic rats. Nine weeks after OVX, 8-month-old
      rats were divided into six groups of 10 animals. MDL 103,323 was given by gavage
      at doses of 0.01, 0.1 or 0.6 mg/kg body weight, 5 days a week. The effect of MDL
      103,323 was compared with that of the bisphosphonate pamidronate (APD), which was
      injected subcutaneously at a dose of 1.6 mmol/kg body weight for 5 days every 4
      weeks. Lumbar spine (LS), femoral neck (FN), proximal tibia (PT) and midshaft
      tibia (MT) BMD, bone strength, and proximal tibia histomorphometry, serum
      osteocalcin, urinary total deoxypyridinoline and serum insulin-like growth factor
      I (IGF-I) were measured. After 16 weeks of treatment, BMD changes (means +/- SEM)
      were -11.4 +/- 2. 2, +4.0 +/- 2.1 and +6.4 +/- 1.0% respectively in OVX controls,
      in rats treated with 0.1 mg/kg MDL 103,323 (p<0.05) and in APD-treated rats
      (p<0.02) at the level of LS; -0.4 +/- 1.1, +6.7 +/- 1.4, +7.2 +/- 1.8% (p<0.01
      and NS) at the level of FN; and -2.6 +/- 1.2%, +5.8 +/- 1.2, +6.9 +/- 1.4%
      (p<0.03 and 0.01) at the level of PT. MDL 103, 323-treated animals had a higher
      trabecular bone volume, a higher number of trabeculae and smaller intertrabecular
      spaces compared with OVX controls. Vertebral body ultimate strength was 186 +/-
      13, 292 +/- 16, 249 +/- 23 N (p<0.05) in OVX controls, MDL 103, 323-treated rats
      and APD-treated rats, respectively. The administration of 0.6 mg/kg of MDL
      103,323 did not further increase BMD or bone strength, indicating a bell-shaped
      dose-response curve. MDL 103,323 lowered plasma osteocalcin concentration and
      urinary deoxypyridinoline excretion. In rats treated with 0.1 mg/kg MDL 103, 323,
      plasma IGF-I was increased as compared with OVX controls (664 +/- 36 ng/ml vs 527
      +/- 39 ng/ml, p<0.05). In conclusion, these results indicate that this new SERM
      positively influences BMD and lumbar spine bone strength in estrogen-deficient
      rats.

PMID- 10591835
TI  - Effects of menopause on age-dependent bone loss in the axial and appendicular
      skeletons in healthy Japanese women.
AB  - To determine the effects of menopause on bone loss in different parts of the
      skeleton, bone mineral density (BMD) values were measured longitudinally in 85
      healthy women. BMD values included the lumbar spine measured by dual-energy X-ray
      absorptiometry (DXA) and quantitative CT (QCT) and the distal and midradius
      measured by DXA obtained over 5 years. BMD at the calcaneus was measured using
      DXA for 3 years, and the BMD values of the distal metaphyses and diaphyses of
      radius and tibia were measured using peripheral QCT (pQCT) for 4 years. The
      subjects were 19 premenopausal, 17 perimenopausal, 12 early postmenopausal and 38
      late postmenopausal women with the respective average ages of 39.1 +/- 7.1 (SD),
      51.9 +/- 2.9, 55.8 +/- 1.8 and 61.9 +/- 3.9 years at the start of measurement.
      Average years since menopause were 1.4 +/- 1.8, 3.3 +/- 1.3 and 12.7 +/- 5.3
      years, respectively. In the perimenopausal group, the annual rate of bone loss
      for lumbar trabecular bone measured by QCT, and for the calcaneus, and
      metaphyseal trabecular bone at the radius and tibia by pQCT were higher than the
      respective values in the premenopausal group. These values in the late
      postmenopausal group became significantly lower compared with those in the
      perimenopausal group, coming down to the level of the premenopausal group. While
      the annual rates of bone loss at the tibial diaphysis in the perimenopausal group
      were also higher than those in the premenopausal group, the values at the radial
      diaphysis by DXA or pQCT did not differ significantly. The reductions in the
      annual rates of bone loss with the passage of time after menopause were not
      marked in these cortical bone dominated sites. These data indicated that the
      annual rates of bone loss at trabecular bone dominated sites were accelerated in
      both axial and appendicular skeletons. Diaphyseal cortical bone, however, seemed
      to be less sensitive to estrogen withdrawal. Other factors, such as genetics and
      calcium/vitamin D metabolism, would also affect the age-dependent bone loss at
      the cortical bone dominated sites after menopause.

PMID- 10591836
TI  - Determinants of bone loss in elderly men and women: a prospective population
      based study.
AB  - While several studies have described the rate and pattern of involutional bone
      loss in women, far less information is available for men. Furthermore, the roles
      of lifestyle and body build in determining bone loss rate in both sexes have been
      largely extrapolated from cross-sectional studies. We addressed this issue in a
      population-based longitudinal study which sought to ascertain rates of bone loss
      at the femoral neck and lumbar spine in a cohort of men and women aged 60-75
      years at baseline, and to relate this loss to anthropometric and lifestyle
      variables. We additionally investigated the capacity of biochemical markers of
      bone turnover to predict bone loss rates in these subjects. Women lost bone at
      all sites; this ranged from 0.20%/year at the lumbar spine to 1.43%/year at the
      femoral trochanteric region. By contrast, men lost only 0. 20%/year at the
      trochanteric region, and gained at the lumbar spine (0.33%/year) and at Ward's
      triangle (0.27%/year) over the 4-year period. Anthropometric measurements were
      associated with bone loss in both sexes; lower baseline body mass index (BMI) and
      a greater rate of loss of adiposity over the follow-up period were both
      associated with greater bone loss at all proximal femoral sites. These attained
      statistical significance after Bonferroni correction at the total proximal femur
      among both men (r = 0.29), p<0.01) and women (r = 0.31, p<0.05). Lifestyle
      factors associated with lower rates of bone loss (after adjustment for BMI)
      included alcohol consumption at the femoral neck among women (p = 0.007) and
      physical activity at the lumbar spine among men (p = 0.05). Serum parathyroid
      hormone, 25-hydroxyvitamin D and biochemical markers of bone turnover did not
      predict bone loss after adjustment for adiposity.

PMID- 10591837
TI  - The contribution of vitamin D receptor gene polymorphisms in osteoporosis and
      familial osteoporosis.
AB  - It is well established that genetic factors play a major role in the pathogenesis
      of osteoporosis. Previous reports have suggested that vitamin D receptor (VDR)
      gene polymorphisms, particularly the BB, tt and AA genotypes, are associated with
      low bone mineral density (BMD). If these VDR genotypes are indeed an important
      determinant of BMD, then a population of related osteoporotic individuals (mother
      daughter or sister-sister relationship) should have a high prevalence of the BB,
      tt or AA VDR genotypes. To test this hypothesis we determined the VDR genotypes
      in 26 osteoporotic persons (age 44.3 +/- 12.7 years, mean +/- SD) belonging to 12
      families. Furthermore, for comparison with existing studies, we applied the VDR
      genotype analysis in a population of 53 unrelated healthy subjects (age 45.2 +/-
      9.8 years, mean +/- SD) and 59 unrelated osteoporotic subjects (age 52.1 +/- 9.0
      years, mean +/- SD). The menopausal status of the healthy and osteoporotic
      populations was pre-, peri- and mostly early postmenopausal. The proportions of
      the three genotypes, BB, tt and AA, within the 12 osteoporotic families were 15%,
      12% and 27%, respectively, whereas the proportions of the other three homozygous
      genotypes (bb, TT, aa) were 50%, 50% and 23%. The distribution of the BB, tt and
      AA genotypes in the normal population was 21%, 21% and 36%, respectively (vs bb,
      TT, aa: 36%, 38%, 21%), whereas in the osteoporotic population it was 24%, 20%
      and 34% (vs bb, TT, aa: 27%, 34%, 14%). Our data indicate that there is not a
      statistically significant (p>0.05) difference in the VDR genotype frequencies
      within osteoporotic families as compared with the same genotypes in the
      population of unrelated normal or osteoporotic subjects. VDR genotype analysis
      showed no significant relation between VDR polymorphisms and BMD or Z-score
      values at the lumbar spine. This study demonstrates the lack of a heritability
      pattern between the BB, tt and AA genotypes and low BMD.

PMID- 10591838
TI  - Changes in bone mass and bone turnover following distal forearm fracture.
AB  - Bone loss occurs close to a fracture and is associated with increased bone
      turnover. Fracture healing itself results in increased markers of bone turnover.
      But the exact patterns of these changes after different fractures are unclear. We
      aimed to investigate the changes in bone density and biochemical markers
      following distal forearm fracture. Twenty women (mean age 63 years) were
      recruited following fracture of the distal radius and ulna. Bone mineral density
      (BMD) of the hand and forearm were measured by dual-energy X-ray absorptiometry
      (DXA) and quantitative ultrasound (QUS) of the fingers was measured at 0, 6, 12,
      26 and 52 weeks after fracture. Serum and urine samples were collected at 0, 3
      and 7 days and at 2, 4, 6, 12, 26 and 52 weeks after fracture to measure markers
      of bone turnover. For bone formation we measured: bone alkaline phosphatase
      (iBAP), osteocalcin (Oc), procollagen type I N-terminal propeptide (PINP); and
      for bone resorption: tartrate-resistant acid phosphatase (TRAcP), free
      deoxypyridinoline (iFDpd), N-telopeptides of type I collagen (NTx). We used the
      nonfractured limb to calculate values for baseline BMD and amplitude-dependent
      speed of sound (AD-SoS). There was a decrease in BMD at the hand and in AD-SoS of
      the fingers after forearm fracture (p<0.001). This bone loss was maximal for BMD
      by 6 weeks at 9% (p<0. 001) and remained decreased at 52 weeks. AD-SoS decreased
      at 12 weeks by 3% (p<0.01) and recovered completely by 52 weeks. Bone formation
      markers increased between 2 and 4 weeks by 13-52% (p<0. 001), and were still
      elevated at 52 weeks. Bone resorption markers increased between 2 and 6 weeks by
      18-35% and returned to baseline at 52 weeks (TRAcP remained elevated). We
      conclude that BMD decreased distal and immediately proximal to the fracture line
      when measured with DXA and QUS. Bone loss after distal forearm fracture did not
      recover by 52 weeks and most bone turnover markers did not return to baseline.

PMID- 10591839
TI  - Changes in bone mass and bone turnover following ankle fracture.
AB  - Bone loss and increased bone turnover are recognized local changes after a
      fracture, but the exact patterns of these changes after different fractures are
      unclear. We aimed to investigate the changes in bone density and biochemical
      markers following ankle fracture. Fourteen subjects (7 postmenopausal women and 7
      men, mean age 63 years) were recruited following fracture of the distal tibia and
      fibula. Bone mineral density (BMD) of the ankle and proximal femur were measured
      by dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) of
      the calcaneus at 0, 6, 12, 26 and 52 weeks after fracture. Serum and urine
      samples were collected at 0, 3 and 7 days and at 2, 4, 6, 12, 26 and 52 weeks
      after fracture to measure markers of bone turnover. For bone formation we
      measured: bone alkaline phosphatase (iBAP), osteocalcin (Oc), procollagen type I
      N-terminal propeptide (PINP); and for bone resorption: tartrate-resistant acid
      phosphatase (TRAcP), deoxypyridinoline (iFDpd), N-telopeptides of type I collagen
      (NTx). We used the nonfractured limb to calculate values for baseline BMD and
      QUS. There was a significant decrease in BMD at the ultradistal ankle (p<0.001),
      the trochanteric region of the hip (p<0.01) and QUS of the heel after ankle
      fracture. This bone loss was maximal for ultradistal ankle BMD by 6 weeks at 13%
      (p<0.001) and for the trochanter by 26 weeks at 3% (p<0.01). The ankle BMD
      returned to baseline at 52 weeks but the trochanter BMD did not. Velocity of
      sound (VOS) decreased at 6 weeks by 2% (p<0.01) and broadband ultrasound
      attenuation (BUA) by 15% (p<0.01). VOS recovered completely by 52 weeks, but BUA
      did not return to baseline. Bone formation markers increased significantly
      between 1 and 4 weeks by 11-78% (p<0.01), and iBAP returned to baseline at 52
      weeks but PINP and Oc remained elevated. Bone resorption markers did not increase
      and NTx was decreased at 52 weeks. We conclude that BMD decreased distal and
      immediately proximal to the fracture line when measured with DXA and QUS. Ankle
      BMD and heel VOS recovered at 52 weeks (trochanteric BMD and heel BUA did not)
      and the bone turnover markers returned toward baseline.

PMID- 10591840
TI  - Correlates of quantitative ultrasound in the Women's Healthy Lifestyle Project.
AB  - Quantitative ultrasound (QUS) assessment of bone is a strong predictor of hip
      fractures and is currently an FDA-approved tool to identify women at risk of
      osteoporosis. However, few studies have investigated the lifestyle and genetic
      correlates of QUS in women. This study investigated the cross-sectional
      associates of several lifestyle, demographic and genetic factors with calcaneal
      QUS parameters (broadband ultrasound attenuation (BUA) and speed of sound (SOS))
      in 393 women aged 45-53 years. Leisure-time and historical physical activity,
      dietary calcium and protein, body composition, vitamin D receptor genotypes,
      menopause status, other health behaviors, calcaneal QUS parameters and bone
      mineral density (BMD) were assessed at a single clinic visit. Lean mass, recent
      physical activity and African-American race were the strongest correlates of SOS
      whereas dietary protein, calcium and recent physical activity were the strongest
      correlates of BUA. These predictors explained 13% and 6% of the variance in SOS
      and BUA, respectively. Smoking, alcohol intake, education, hormone replacement
      therapy, calcium and vitamin D supplements, historical physical activity and
      vitamin D receptor genotypes were not significantly associated with BUA or SOS.
      Lean body mass and premenopausal status were the strongest correlates of lumbar
      BMD whereas lean body mass, physical activity, African-American race and body
      mass index were significantly related to femoral neck BMD. Physical activity
      remained predictive of SOS after controlling for lumbar BMD. The spectrum and
      magnitude of risk factors for SOS and BUA, including lean body mass, physical
      activity, race, protein and calcium intake, parallel previously observed
      predictors of BMD.

PMID- 10591841
TI  - The Tromso Study: artifacts in forearm bone densitometry--prevalence and effect.
AB  - Suboptimal performance of bone densitometer, operator and/or subject may cause
      artifacts of consequence both for individual patient management and research. The
      prevalence and effects of such artifacts are largely unknown in densitometry. A
      cross-sectional population-based study was carried out of artifacts in forearm
      bone densitometry with single X-ray Absorptiometry (SXA) of the nondominant hand
      (distal and ultradistal site). After the screening, all scans were reviewed for
      artifact detection and reanalysis. The effect on the bone mineral density (BMD)
      result was found by comparing artifactual scans with a reanalyzed version or with
      normal repeat scans. All women aged 50-74 years, all men aged 55-74 years and 5
      10% samples of other age groups aged >/=25 years attending the fourth Tromso
      health study were invited to have bone densitometry. The response rate from the
      background population was 80% (n = 7948). Fourteen percent of subjects had a
      movement artifact at either the distal or ultradistal site. The individual BMD
      variation was twice as large in scans with a movement artifact (0.94%) compared
      with normal scans (0.58%) (p = 0.0027). The radial endplate was inaccurately
      detected in 74% of the scans. Reanalysis of these scans led to a mean 3.8%
      decrease in the BMD value and an increase in the prevalence of osteoporosis of
      10%. Artifacts were thus common, and their effects were clinically relevant in
      forearm bone densitometry. Artifacts and their effects need to be characterized
      in other bone densitometry settings also.

PMID- 10591843
TI  - Microbial metabolism of methanesulfonic acid
AB  - Methanesulfonic acid is a very stable strong acid and a key intermediate in the
      biogeochemical cycling of sulfur. It is formed in megatonne quantities in the
      atmosphere from the chemical oxidation of atmospheric dimethyl sulfide (most of
      which is of biogenic origin) and deposited on the Earth in rain and snow, and by
      dry deposition. Methanesulfonate is used by diverse aerobic bacteria as a source
      of sulfur for growth, but is not known to be used by anaerobes either as a sulfur
      source, a fermentation substrate, an electron acceptor, or as a methanogenic
      substrate. Some specialized methylotrophs (including Methylosulfonomonas,
      Marinosulfonomonas, and strains of paragraph signHyphomicrobium and
      Methylobacterium) can use it as a carbon and energy substrate to support growth.
      Methanesulfonate oxidation is initiated by cleavage catalysed by methanesulfonate
      monooxygenase, the properties and molecular biology of which are discussed.

PMID- 10591844
TI  - Carboxylase genes of Sulfolobus metallicus.
AB  - Carbon dioxide limitation of Sulfolobus metallicus resulted in increased cellular
      concentrations of polypeptides that were predicted to be biotin carboxylase and
      biotin carboxyl-carrier-protein components of a protein complex. These
      polypeptides were coeluted from a native polyacrylamide gel and were estimated at
      19 and 59 kDa after separation by denaturing gel electrophoresis. Their encoding
      genes were identified, sequenced and shown to code for polypeptides of 18,580 and
      58,235 Da with similarities to biotin carboxyl carrier proteins and biotin
      carboxylases, respectively. The genes overlapped at the second of two stop codons
      that terminated the carboxylase gene. A third gene occurred on the opposite
      strand, 293 bp upstream of the biotin carboxylase gene. Its deduced amino acid
      sequence was similar to those of carboxyl transferase subunits of carboxylase
      enzymes, in particular to those of the propionyl-CoA carboxylases. It is proposed
      that the three described genes could encode the key enzyme complex responsible
      for carbon dioxide fixation during autotrophic growth of the thermoacidophilic
      archaea.

PMID- 10591845
TI  - Identification and molecular characterization of the eugenol hydroxylase genes
      (ehyA/ehyB) of Pseudomonas sp. strain HR199.
AB  - The gene loci ehyA and ehyB, which are involved in the bioconversion of eugenol
      to coniferyl alcohol by Pseudomonas sp. strain HR199 (DSM 7063), were identified
      as the structural genes of a eugenol hydroxylase that represents an enzyme of the
      flavocytochrome c class. These genes were localized downstream of the eugenol
      catabolism genes vanA and vanB, encoding vanillate-O-demethylase, on an EcoRI
      fragment (E230) that has recently been cloned from a Pseudomonas sp. strain HR199
      genomic library. The gene encoding the cytochrome c subunit (ehyA) was identified
      on a subfragment (K18) of E230 by complementation of a nitrosoguanidine-induced,
      eugenol-negative mutant of strain HR199. The nucleotide sequences of fragment K18
      and adjacent regions were determined, revealing open reading frames of 354 and
      1,554 bp that represent ehyA and ehyB, respectively. These genes are most
      probably organized in one operon together with a third open reading frame (ORF2)
      of 687 bp that was located between ehyA and ehyB. The deduced amino acid
      sequences of ehyA and ehyB exhibited up to 29 and 55% amino acid identity to the
      corresponding subunits of p-cresol methylhydroxylase from Pseudomonas putida.
      Moreover, the amino-terminal sequences of the alpha- and beta-subunits reported
      recently for a eugenol dehydrogenase of Pseudomonas fluorescens E118 corresponded
      well with appropriate regions of ehyA and ehyB. The sequence of ORF2 and the
      deduced amino acid sequence exhibited no significant similarities to any DNA or
      amino acid sequence from the databases. The eugenol hydroxylase genes were
      amplified by PCR, cloned in pBluescript SK(-), and functionally expressed in
      Escherichia coli. Transfer of a DNA fragment comprising ehyA and ehyB to various
      strains of Pseudomonas species that were unable to utilize eugenol as a carbon
      source conferred to these bacteria the ability to grow on this substrate.

PMID- 10591846
TI  - Identification of three genes expressed primarily during development in Physarum
      polycephalum.
AB  - During the life cycle of Physarum polycephalum, uninucleate amoebae develop into
      multinucleate syncytial plasmodia. These two cell types differ greatly in
      cellular organisation, behaviour and gene expression. Classical genetic analysis
      has identified the mating-type gene, matA, as the key gene controlling the
      initiation of plasmodium development, but nothing is known about the molecular
      events controlled by matA. In order to identify genes involved in regulating
      plasmodium formation, we constructed a subtracted cDNA library from cells
      undergoing development. Three genes that have their highest levels of expression
      during plasmodium development were identified: redA, redB (regulated in
      development) and mynD (myosin). Both redA and redB are single-copy genes and are
      not members of gene families. Although redA has no significant sequence
      similarities to known genes, redB has sequence similarity to invertebrate
      sarcoplasmic calcium-binding proteins. The mynD gene is closely related to type
      II myosin heavy-chain genes from many organisms and is one of a family of type II
      myosin genes in P. polycephalum. Our results indicate that many more red genes
      remain to be identified, some of which may play key roles in controlling
      plasmodium formation.

PMID- 10591847
TI  - Identification of salt-regulated genes in the genome of the cyanobacterium
      Synechocystis sp. strain PCC 6803 by subtractive RNA hybridization.
AB  - To identify genes transcribed preferentially under salt stress, a subtractive RNA
      hybridization procedure was applied to the cyanobacterium Synechocystis sp. PCC
      6803. The screening of a genomic library led to the identification of several RNA
      species that were more abundant in salt-stressed cells than in control cells.
      Salt-dependent transcription of the identified genes was verified in Northern
      blot experiments. In addition to the previously characterized genes cpn60
      (encoding GroEL; a molecular chaperone) and isiA (encoding a chlorophyll-binding
      protein), genes encoding a protein of unknown function (slr0082) and a putative
      RNA helicase (slr0083) were identified as salt-regulated genes in Synechocystis.
      Genes slr0082 and slr0083, located at sites adjacent to each other on the
      Synechocystis chromosome, were transcribed from separate promoters and showed the
      most significant induction 1-3 h after salt shock. The salt-regulated promoters
      of these two genes were mapped. Genes cpn60, slr0082, and slr0083 were also found
      to be induced by a cold shock. The possible role of the identified gene products
      for salt adaptation of Synechocystis is discussed.

PMID- 10591848
TI  - Desulfonation of propanesulfonic acid by comamonas acidovorans strain P53:
      evidence for an alkanesulfonate sulfonatase and an atypical sulfite dehydrogenase
AB  - Evidence is presented for the presence in propanesulfonate-grown Comamonas
      acidovorans strain P53 of a cytoplasmically located sulfonatase that does not
      sediment at 100,000 x g. This enzyme catalysed the sulfonate-dependent oxidation
      of NADH or NADPH, indicating a monooxygenase that effects the addition of
      molecular oxygen to C(3)-C(6) 1-alkanesulfonates. Enzyme activity was
      proportional to protein concentration only above approximately 2 mg cytoplasmic
      fraction protein ml(-1), suggesting that the sulfonatase is a multicomponent
      enzyme, possibly comparable with methanesulfonate monooxygenase. Enzyme activity
      was strongly inhibited by divalent metal-chelating agents, but was insensitive to
      cyanide and azide. Sulfite released from sulfonates by Comamonas acidovorans was
      oxidized by an unusual sulfite dehydrogenase. This was purified approximately 230
      fold and was shown to have a molecular mass of 74.4 kDa, comprising two or more
      subunits. The enzyme activity was specific in vitro for ferricyanide as an
      electron acceptor and, unlike other bacterial sulfite dehydrogenases, did not
      contain native cytochrome c or reduce added cytochrome c. It was a basic protein,
      insensitive to chloride and sulfate, and exhibited a K(m) for sulfite of
      approximately 45 &mgr;M.

PMID- 10591849
TI  - Degradation of chlorinated and brominated hydrocarbons by Methylomicrobium album
      BG8.
AB  - The degradation kinetics of ten halogenated hydrocarbons by Methylomicrobium
      album BG8 expressing particulate methane monooxygenase (pMMO) and the inhibitory
      effects of these compounds on microbial growth and whole-cell pMMO activity were
      measured. When M. album BG8 was grown with methane, growth was completely
      inhibited by dichloromethane (DCM), bromoform (BF), chloroform (CF), vinyl
      chloride (VC), 1,1-dichloroethylene (1,1-DCE), and cis-dichloroethylene (cis
      DCE). Trichloroethylene (TCE) partially inhibited growth on methane, while
      dibromomethane (DBM), trans-dichloroethylene (trans-DCE), and 1,1,1
      trichloroethane (1,1, 1-TCA) had no effect. If the cells were grown with
      methanol, DCM, BF, CF, and 1,1-DCE completely inhibited growth, while VC, trans
      DCE, TCE, and 1,1,1-TCA partially inhibited growth. Both DBM and cis-DCE had no
      effect on growth with methanol. Whole-cell pMMO activity was also affected by
      these compounds, with all but 1,1,1-TCA, DCM, and DBM reducing activity by more
      than 25%. DCM, DBM, VC, trans-DCE, cis-DCE, 1,1-DCE, and TCE were degraded and
      followed Michaelis-Menten kinetics. CF, BF, and 1,1,1-TCA were not measurably
      degraded. These results suggested that the products of DCM, TCE, VC, and 1,1-DCE
      inactivated multiple enzymatic processes, while trans-DCE oxidation products were
      also toxic but to a lesser extent. cis-DCE toxicity, however, appeared to be
      localized to pMMO. Finally, DBM and 1,1,1-TCA were not inhibitory, and CF and BF
      were themselves toxic to M. album BG8. Based on these results, the compounds
      could be separated into four general categories, namely (1) biodegradable with
      minimal inactivation, (2) biodegradable with substantial inactivation, (3) not
      biodegradable with minimal inactivation, and (4) not biodegradable but
      substantial inactivation of cell activity.

PMID- 10591850
TI  - Phosphofructokinase activities within the order spirochaetales and the
      characterisation of the pyrophosphate-dependent phosphofructokinase from
      spirochaeta thermophila
AB  - The subtype of phosphofructokinase activity, either ATP-, ADP- or pyrophosphate
      dependent, present in members of three genera from the Spirochaetales was
      investigated. The individual species/strains examined included Spirochaeta
      alkalica, S. asiatica, S. halophila, S. isovalerica, S. litoralis, S. zuelzerae,
      S. thermophila, two thermophilic spirochetes, Treponema bryantii, T. denticola,
      paragraph signT. pectinovorum, Leptospira biflexa and L. interrogans. All of the
      Spirochaeta strains, regardless of their phenotype, possessed primarily a
      pyrophosphate-dependent phosphofructokinase. In contrast, T. bryantii, T.
      denticola and L. biflexa had predominantly an ATP-dependent activity, whereas no
      activity was detected in T. pectinovorum or paragraph signL. interrogans. The
      results suggest that pyrophosphate-dependent phosphofructokinase activity may be
      a reliable phenotypic marker for the genus Spirochaeta and that there are
      potentially interesting differences in how the catabolism of saccharides is
      controlled among members of genera within the Spirochaetales. The pyrophosphate
      dependent phosphofructokinase from S. thermophila strain RI 19.B1 was purified
      (303-fold) to homogeneity and biochemically characterised. The S. thermophila
      enzyme displayed hyperbolic kinetics with respect to both the forward and reverse
      cosubstrates and was not significantly affected by traditional activators or
      inhibitors of phosphofructokinase. The biochemical characterisation represents
      the first spirochete phosphofructokinase to be described.

PMID- 10591851
TI  - Differential enumeration and in situ localization of microorganisms in the
      hindgut of the lower termite mastotermes darwiniensis by hybridization with rRNA
      targeted probes
AB  - We examined the abundance and spatial distribution of major phylogenetic groups
      of the domain Bacteria in hindguts of the Australian lower termite Mastotermes
      darwiniensis by using in situ hybridization with group-specific, fluorescently
      labeled, rRNA-targeted oligonucleotide probes. Between 32.0 +/- 7.2% and 52.3 +/-
      8.2% of the DAPI-stained cells in different hindgut fractions were detected with
      probe EUB338, specific for members of the domain Bacteria. About 85% of the
      prokaryotic cells were associated with the flagellates of the thin-walled
      anterior region (P3a) and the thick wall of the posterior region (P3b/P4) of the
      hindgut, as shown by DAPI staining. At most, half of the EUB338-detected cells
      hybridized with one of the other probes that targeted a smaller assemblage within
      the bacterial domain. In most fractions, cells were found in varying numbers with
      probe ALF1b, which targeted members of the alpha-Proteobacteria, whereas
      substantial amounts of sulfate-reducing bacteria, gram-positive bacteria with a
      high DNA G+C content and members of the Cytophaga-Flavobacterium cluster of the
      Cytophaga-Flavobacterium-Bacteroides (CFB) phylum could be detected only in the
      wall fraction of P3b/P4. This clearly indicates that the hindgut microhabitats
      differ in the composition of their microbial community. In situ hybridization of
      cryosections through the hindgut showed only low numbers of bacteria attached to
      the P3a wall. In contrast, the wall of P3b was densely colonized by rod- and
      coccus-shaped bacteria, which could be assigned to the Cytophaga-Flavobacterium
      cluster of the CFB phylum and to the group of gram-positive bacteria with a high
      DNA G+C content, respectively. Oxygen concentration profiles determined with
      microelectrodes revealed steep oxygen gradients both in P3a and P3b. Oxygen was
      consumed within 100 &mgr;m below the gut surface, and anoxic conditions prevailed
      in the central portions of both gut regions, indicating that oxygen consumption
      in the hindgut does not depend on the presence of a biofilm on the hindgut wall.

PMID- 10591852
TI  - Methyl ketone formation during degradation of phenoxybutyric acid by Penicillium
      canescens SBUG-M 1139.
AB  - Penicillium canescens SBUG-M 1139 was shown to be able to grow using
      phenoxybutyric acid as the sole carbon source. The rapid conversion of the
      phenoxyalkanoic acid resulted in the formation of phenol, which was metabolized
      completely. These reactions were accompanied by an accumulation of the methyl
      ketone phenoxypropan-2-one. Furthermore, during the metabolism of phenoxybutyric
      acid, 4-phenoxy-2,3-dehydrobutyric acid, 4-phenoxy-3-hydroxybutyric acid,
      phenoxyacetic acid, and phenoxypropan-2-ol accumulated in minor amounts. Clearly,
      fungi can metabolize phenoxyalkanoic acids to produce methyl ketones in a manner
      analogous to that used for the conversion of short- or medium-chain fatty acids
      by fungi.

PMID- 10591853
TI  - Genes, drugs and behavior: polygenic behavioral phenotypes and single gene
      manipulations.

PMID- 10591854
TI  - Hierarchical strategy for phenotypic analysis in mice.

PMID- 10591855
TI  - Complications associated with genetic background effects in research using
      knockout mice.

PMID- 10591856
TI  - Microbehavioral methods for measuring the motor and associative effects of
      dopamine receptor antagonists and related drugs in rodents.

PMID- 10591857
TI  - Assessing prepulse inhibition of startle in wild-type and knockout mice.

PMID- 10591858
TI  - Murine models of depression.

PMID- 10591859
TI  - Aggressive and social stress responses in genetically modified mice: from
      horizontal to vertical strategy.

PMID- 10591860
TI  - Combined use of mutant mice and classical pharmacology to characterise receptor
      functions: the case of dopamine D2 and D3 receptors.

PMID- 10591861
TI  - Method for training operant responding and evaluating cocaine self-administration
      behavior in mutant mice.

PMID- 10591862
TI  - Assessment of nicotinic acetylcholine receptor subunit contributions to nicotine
      self-administration in mutant mice.

PMID- 10591863
TI  - Methodology for analyzing the parallel between cocaine psychomotor stimulant and
      reinforcing effects in mice.

PMID- 10591864
TI  - Application of microdialysis and voltammetry to assess dopamine functions in
      genetically altered mice: correlation with locomotor activity.

PMID- 10591865
TI  - The use of microdialysis in the mouse: conventional versus quantitative
      techniques.

PMID- 10591866
TI  - Comparison of transgenic strategies for behavioral neuroscience studies in
      rodents.

PMID- 10591867
TI  - Effects of haloperidol and clozapine on tongue dynamics during licking in CD-1,
      BALB/c and C57BL/6 mice.
AB  - RATIONALE: In an initial effort to describe how genetic background influences the
      differential motor effects of haloperidol, a drug with high extrapyramidal side
      effect (EPS) liability, and clozapine, an antipsychotic low in EPS, both drugs
      were studied in inbred strains of mice (BALB/c and C57BL/6) previously shown to
      have differential sensitivities to haloperidol. OBJECTIVES: Behavioral
      differences in lick dynamics for male BALB/c, C57BL/6 and CD-1 (an outbred
      strain) were characterized. Effects of dose ranges of haloperidol and clozapine
      were then evaluated in the three strains. METHODS: The mice learned to lick milk
      from a force-sensing disk during daily 2-min sessions, while a computer counted
      the number of licks and measured lick peak force and lick rhythm. After training,
      acute doses of haloperidol (0.08-2.0 mg/kg) or clozapine (0.5-8.0 mg/kg) were
      administered i.p. 45 min before sessions. RESULTS: Prior to drug treatment,
      substantial quantitative strain differences in licking behavior were observed:
      C57BL/6 mice made fewer licks, licked with lower peak force per lick, and had a
      slower lick rhythm than the BALB/c and CD-1 mice. As in rats, clozapine slowed
      the lick rhythm in all three mouse strains much more than haloperidol did.
      Haloperidol produced a 50% greater suppression of number of licks in BALB/c than
      in C57BL/6 mice (ED50 values were 0.82 mg/kg and 1.22 mg/kg, respectively). For
      clozapine, lick suppression was greater in the C57BL/6 than in the BALB/c strain
      (ED50 values were 1.88 mg/kg and 2.65 mg/kg, respectively). Among the three
      strains examined, CD-1 was the most sensitive to haloperidol's suppression of
      licking, while its sensitivity to clozapine's lick-suppressing effect was similar
      to C57BL/6 mice. Clozapine lowered the lick peak force in the CD-1 and BALB/c
      strains more than in the C57BL/6 strain. CONCLUSIONS: Overall, the results
      suggest that genetic variables may influence both mice's tongue dynamics and
      their alteration by both typical and atypical antipsychotic drugs. In addition,
      while the BALB/c strain was more sensitive to haloperidol's lick-disruptive
      effects than the C57BL/6 strain, the size of the difference between strains was
      much smaller than the reported difference between the strains in the catalepsy
      test.

PMID- 10591868
TI  - Glucocorticoid-reinforced responding in the rhesus monkey.
AB  - RATIONALE: Glucocorticoids have been reported to have rewarding effects in rats
      and may lead to drug-seeking behavior in humans under some circumstances.
      OBJECTIVES: The present study investigated whether glucocorticoids would be self
      administered intravenously by rhesus monkeys (Macaca mulatta). METHODS: Ten
      monkeys, 7 male and 3 female, were maintained on a fixed ratio 10 (30 or 100),
      time-out 10-s schedule for 0.1 mg/kg methohexital or saline injections.
      Dexamethasone (0.03-0.3 mg/kg), methylprednisolone (0.1-1.0 mg/kg) and
      hydrocortisone (0.3-3.0 mg/kg) were periodically substituted for methohexital or
      saline. RESULTS: Dexamethasone (0.3 mg/kg) was self-administered by all of the
      male monkeys on the first, but not on subsequent occasions. It was hypothesized
      that suppression of hypothalamic-pituitary-adrenal (HPA) activity by these
      exogenous glucocorticoids following their first presentation may have interfered
      with their reinforcing effects on subsequent evaluation. Subsequently, plasma
      adrenocorticotropin and cortisol were measured in four male monkeys to ascertain
      that normal basal HPA activity had resumed prior to each glucocorticoid
      substitution. Of the ten monkeys that were tested, only one reliably self
      administered dexamethasone, methylprednisolone and hydrocortisone, and he did so
      regardless of whether his basal HPA activity was suppressed. This monkey differed
      from some of the other monkeys both behaviorally and in his response to
      intravenous corticotropin releasing hormone. None of the three female monkeys
      that were tested with selected glucocorticoid doses showed any evidence of
      glucocorticoid reinforcement on any occasion. CONCLUSIONS: The results indicate
      that glucocorticoids were not reinforcing to the majority of monkeys in this
      study; nevertheless, large individual differences may exist in proclivity of
      monkeys to self-inject these compounds.

PMID- 10591869
TI  - Altered neuroendocrine and behavioral responses to m-chlorophenylpiperazine in
      3,4-methylenedioxymethamphetamine (MDMA) users.
AB  - RATIONALE: (+/-) 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") is a popular
      drug of abuse and a brain serotonin neurotoxin in animals. Growing evidence
      indicates that humans are also susceptible to MDMA's neurotoxic effects, although
      few functional consequences of MDMA-induced 5-HT damage have been identified.
      OBJECTIVE: The present study sought to determine whether possible differences
      between MDMA users and control subjects could be unmasked by utilizing a
      pharmacological challenge with the mixed 5-HT agonist, meta
      chlorophenylpiperazine (m-CPP). It was postulated that 5-HT neurotoxicity in MDMA
      users would be associated with altered 5-HT responsivity, exemplified by altered
      physiological and behavioral responses to m-CPP. METHODS: Twenty-five MDMA users
      who had not taken MDMA for at least 3 weeks and 25 controls received intravenous
      placebo (normal saline) and m-CPP (0.08 mg/kg) in a fixed order, single blind
      design. Repeated measures of mood, physical symptoms, and blood samples for
      neuroendocrine analyses were collected during the 90 min after each infusion.
      RESULTS: MDMA users reported more positive and fewer negative emotions and
      physical symptoms following m-CPP than controls, and were significantly less
      likely to report an m-CPP-induced panic attack. Male MDMA users had diminished
      cortisol and prolactin responses to m-CPP. CONCLUSIONS: The present data indicate
      that MDMA users have alterations in 5-HT neuronal function, possibly as a
      consequence of MDMA-induced brain serotonin neural injury.

PMID- 10591870
TI  - A neurotoxic regimen of MDMA suppresses behavioral, thermal and neurochemical
      responses to subsequent MDMA administration.
AB  - RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) produces a long-term
      depletion of serotonin (5-HT) in the rat brain; this depletion may have some
      functional consequences. OBJECTIVE: The aim of the present study was to evaluate
      the acute effects of MDMA on the extracellular concentrations of dopamine and 5
      HT, body temperature and the 5-HT behavioral syndrome in rats 7 days following a
      neurotoxic regimen of MDMA. METHODS: One week after the rats were treated with a
      neurotoxic regimen of MDMA (10 mg/kg, i.p., every 2 h for a total of four
      injections), the rats were injected with a subsequent injection of MDMA. In vivo
      microdialysis combined with HPLC was utilized to measure the extracellular
      concentration of 5-HT and dopamine in the striatum. The increase in body
      temperature was determined by rectal temperature measurements, and the 5-HT
      behavioral syndrome was scored using a rating scale following the administration
      of MDMA. RESULTS: The neurotoxic regimen produced a 45% reduction in brain 5-HT
      concentrations. The magnitude of the MDMA-induced increase in the extracellular
      concentration of 5-HT, but not dopamine, in the striatum produced by an acute
      injection of MDMA (7.5 mg/kg, i.p.) was reduced in rats treated previously with
      the neurotoxic regimen of MDMA when compared with that in control animals. In
      addition, the magnitude of the 5-HT behavioral syndrome, as well as the
      hyperthermic response, produced by MDMA was markedly diminished in rats that had
      previously received the neurotoxic regimen of MDMA. CONCLUSIONS: It is concluded
      that the long-term depletion of brain 5-HT produced by MDMA is accompanied by
      impairments in 5-HT function, as evidenced by the deficits in the neurochemical,
      thermal and behavioral responses to subsequent MDMA administration.

PMID- 10591871
TI  - Effects of E-2078, a stable dynorphin A(1-8) analog, on sedation and serum
      prolactin levels in rhesus monkeys.
AB  - RATIONALE: The dynorphins are endogenous opioid peptides with relative binding
      selectivity for kappa-receptors. It is unclear whether the dynorphins share the
      pharmacological profile observed with synthetic kappa-agonists in primates.
      OBJECTIVE: The main objective of this study was to compare the effects of s.c. E
      2078, a stable dynorphin A(1-8) analog, with two synthetic kappa-opioid ligands,
      spiradoline (a reference arylacetamide kappa-agonist) and ICI204,448 (a
      "peripherally selective" kappa-agonist) in behavioral and neuroendocrine
      endpoints in rhesus monkeys. METHODS: Dose-effect curves were determined for s.c.
      E-2078, spiradoline and ICI204,448 in causing overt sedation and muscle
      relaxation (as detected in observational rating scales), in increasing latency to
      retrieve and consume a food pellet and in increasing serum levels of the anterior
      pituitary hormone, prolactin, in intact female rhesus monkeys. RESULTS: E-2078
      and ICI204,448 (0.1-3.2 mg/kg) caused increases in sedation and muscle relaxation
      scores, but were less potent and apparently less effective than spiradoline
      (0.001-0.1 mg/kg) up to the highest doses presently studied. All three agonists
      were equieffective and approximately equipotent in increasing the latency to
      retrieve and consume a pellet. Furthermore, E-2078 (0.001-0.032 mg/kg) was
      equipotent and equieffective with spiradoline in increasing serum prolactin
      levels, whereas ICI204,448 was less potent, but slightly more effective than the
      former two agonists. The effects of E-2078 on serum prolactin levels were
      surmountably antagonized by quadazocine (1 mg/kg) and naltrexone (0.1 mg/kg).
      CONCLUSIONS: The present studies show that serum prolactin levels are a highly
      sensitive, quantitative endpoint to study the potency and effectiveness of
      systemically administered E-2078, and show that the dynorphins may be potent and
      effective in causing some, but not all, the effects that are observed after the
      administration of synthetic kappa-agonists.

PMID- 10591872
TI  - The delta 2-opioid receptor antagonist naltriben reduces motivated responding for
      ethanol.
AB  - RATIONALE: Given that alcoholics drink for different reasons, it is not likely
      that a single pharmacotherapeutic agent will be equally effective for all
      alcoholics. Hence, the development of new pharmacotherapeutic agents that are
      capable of reducing alcohol intake remains an important focus in the field of
      alcohol research. OBJECTIVE: The objective of the present study was to examine
      the effects of the delta 2 receptor antagonist naltriben (0.60-4.0 mg/kg) on
      operant responding maintained by the presentation of ethanol (EtOH) or saccharin
      in alcohol-preferring (P) rats. METHODS: P rats were trained under a concurrent
      schedule [fixed ratio (FR)4-FR4] to press one lever for EtOH (10% v/v) and
      another for saccharin (0.0125-0.05% w/v) during a 60-min session. Naloxone, a non
      specific opioid receptor antagonist, served as a reference antagonist. RESULTS:
      When responding maintained by EtOH and saccharin were equated under baseline
      conditions, naloxone (0.003125-0.75 mg/kg) reduced levels of EtOH-maintained
      responding by 46-82%. None of the naloxone doses significantly reduced responding
      maintained by saccharin. Naltriben (0.9-4.0 mg/kg) reduced EtOH-maintained
      responding by 44-76%, while saccharin-maintained responding was reduced only by
      the highest dose of naltriben (4.0 mg/kg). Analysis of the EtOH within-session
      response pattern revealed that naloxone suppressed EtOH-maintained responding
      during the entire operant session and led to early termination of responding. Low
      doses of naltriben (0.90 mg/kg and 1.2 mg/kg) suppressed responding during the
      latter portion of the operant session, while higher doses (2.0, 3.0, 4.0 mg/kg)
      decreased responding during the entire session and led to early termination of
      responding. CONCLUSIONS: The results of the present study strengthen previous
      reports from our laboratory suggesting that naltriben, the selective delta 2
      opioid receptor antagonist, suppresses EtOH self-administration in rats
      selectively bred for high EtOH consumption. The results also suggest that
      naltriben may be a potential candidate for use as a pharmacotherapeutic agent in
      the treatment of EtOH dependence.

PMID- 10591873
TI  - Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy
      and hypokinesia caused by reserpine or MPTP.
AB  - RATIONALE: Current treatment of Parkinson's disease (PD) is based on dopamine
      replacement therapy, but this leads to long term complications, including
      dyskinesia. Adenosine A2A receptors are particularly abundant in the striatum and
      would be a target for an alternative approach to the treatment of PD. OBJECTIVES:
      The purpose of this study is to examine the efficacy and potency of the novel
      selective adenosine A2A receptor antagonist (E)-1,3-diethyl-8-(3,4
      dimethoxystyryl)-7-methyl-3,7-dhydro- 1H-purine-2,6- dione (KW-6002) in
      ameliorating the motor deficits in various mouse models of Parkinson's disease.
      METHODS: We evaluated the efficacy and potency of KW-6002 and other reference
      compounds in the selective adenosine A2A receptor agonist 2-[p-(2
      carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680)-,
      haloperidol- or reserpine-induced catalepsy models. The effect of KW-6002 on
      reserpine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride(MPTP)
      induced hypolocomotion was also examined. RESULTS: The ED50s of KW-6002 in the
      reversal of CGS21680-induced and reserpine-induced catalepsy were 0.05 mg/kg, PO
      and 0.26 mg/kg, PO, respectively. Compared to the ED50 of other adenosine
      antagonists and dopamine agonist drugs, KW-6002 is over 10 times as potent in
      these models. KW-6002 also ameliorated the hypolocomotion (minimum effective
      dose; 0.16 mg/kg) induced by nigral dopaminergic dysfunction with MPTP or
      reserpine treatment. Combined administrations of subthreshold doses of KW-6002
      and L-dopa (50 mg/kg, PO) exerted prominent effects on haloperidol-induced and
      reserpine-induced catalepsy, suggesting that there may be a synergism between the
      adenosine A2A receptor antagonist KW-6002 and dopaminergic agents. CONCLUSIONS:
      To our knowledge, KW-6002 is the most potent and orally active adenosine A2A
      receptor antagonist in experimental models of Parkinson's disease, and may offer
      a new therapeutic approach to the treatment of Parkinson's disease.

PMID- 10591874
TI  - Dynamic changes in sensitivity occur during the acute response to cocaine and
      methylphenidate.
AB  - RATIONALE: We have previously shown that during the acute response to
      amphetamine, a stimulant that released dopamine, behavioral sensitivity to the
      drug undergoes dynamic changes, as evident in the altered behavioral profile
      expressed to the subsequent administration of a low dose of the drug. OBJECTIVE:
      The present studies were designed to determine if these dynamic changes in
      sensitivity occur with amphetamine-like stimulants that act primarily by blocking
      dopamine uptake. METHODS: Groups of animals were primed with 40 mg/kg cocaine or
      30 mg/kg methylphenidate, then during the acute response, a low, locomotor
      stimulant dose of amphetamine (1.5 mg/kg) was administered to probe for changes
      in sensitivity. Conversely, to determine whether the manifestation of the
      increased responsivity is idiosyncratic to amphetamine, animals were also primed
      with amphetamine (4 mg/kg), then probed with low doses of cocaine (10 and 20
      mg/kg) or methylphenidate (10 mg/kg). Parallel microdialysis studies were
      performed to assess the caudate-put-amen and nucleus accumbens extracellular
      dopamine responses. RESULTS: Priming with the uptake blockers each resulted in a
      stereotypy response to the subsequent low-dose amphetamine probe. Likewise, after
      priming with amphetamine, the uptake blockers each induced a pronounced
      stereotypy response. In each case, these changes in behavioral responsivity were
      expressed in the absence of corresponding changes in the probe-induced regional
      dopamine responses. CONCLUSIONS: Dynamic changes in behavioral sensitivity during
      the response to acute stimulant administration are a characteristic common to
      both dopamine releasers and uptake blockers. These rapid changes in sensitivity
      may contribute to the behaviors associated with binge patterns of drug abuse.

PMID- 10591875
TI  - Spatial memory improvement by levodopa in parkinsonian MPTP-treated monkeys.
AB  - RATIONALE: The ameliorative effects of levodopa (L-3,4-dihydroxy-phenylalanine)
      on the motor impairment in Parkinson's disease patients is well established, but
      characterization of its effects on the associated cognitive deficits is still
      incomplete. OBJECTIVE: The present study determined the effect of different doses
      of levodopa on performance on a test of working memory in MPTP-treated rhesus
      monkeys, an animal model of Parkinson's disease. METHODS: Four MPTP-treated
      monkeys and their age-matched controls with the same experimental history as the
      MPTP-treated monkeys were tested on a spatial delay response task. Each daily
      session consisted of five trials at each of seven randomly presented delays (0,
      10, 20, 30, 40, 50 and 60 s). Training was continued for 5 days in each of five
      different conditions. In the first condition, control and MPTP-treated animals
      performed the task without levodopa. In the second condition, both groups were
      tested with a dose of 100 mg of levodopa. In the third and fourth conditions, in
      which the doses of levodopa were increased to 250 and 500 mg, respectively, only
      the MPTP-treated animals were tested. In the final condition, the MPTP-treated
      animals where retested without levodopa. RESULTS: Significant improvement was
      observed at all doses tested (range 100-500 mg). CONCLUSIONS: Levodopa can
      ameliorate memory impairments in this parkinsonian model.

PMID- 10591876
TI  - Role of estradiol in puerperal psychosis.
AB  - RATIONALE: Postpartum period has been considered a time of increased risk for the
      development of psychiatric disorders with long-lasting adverse consequences.
      Psychoses are the most severe of these illnesses and can be resistant to
      psychiatric medication. OBJECTIVE: We present two women with puerperal psychosis
      who had low serum estradiol, were refractory to neuroleptic medication but
      responded successfully to estradiol treatment. METHODS: Serum estradiol
      concentration was measured at baseline and during the treatment with sublingual
      17-beta estradiol. Treatment effect was evaluated using Brief Psychiatric Rating
      Scale. RESULTS: Both patients had a low pretreatment estradiol concentration (28
      and 54 pmol/l). During treatment with estradiol, the rise in serum estradiol
      coincided with a decline of psychotic symptoms. Discontinuation of estradiol
      treatment resulted in a rebound of florid psychotic symptoms in both cases.
      CONCLUSIONS: Estradiol may have a causal relation to postpartum psychosis and
      significance in the treatment of this illness.

PMID- 10591877
TI  - The relationship between 6-sulphatoxymelatonin rhythm phase and age in self
      reported good sleeping controls and sleep maintenance insomniacs aged 55-80
      years.

PMID- 10591878
TI  - Oral self-administration of ethanol, phencyclidine, methadone, pentobarbital and
      quinine in rhesus monkeys.
AB  - RATIONALE: Simultaneous and sequential drug use among clinical populations is the
      norm, whereas the pattern of self-administration of multiple drugs among non
      human primate populations has not been thoroughly explored. OBJECTIVES: To
      determine the relationship between the preferences and intakes of a large group
      of rhesus monkeys exposed to various orally available solutions. METHODS:
      Thirteen male and eleven female young adult rhesus monkeys (Macaca mulatta) were
      exposed to orally available drug solutions using a concurrent choice (drug and
      water) procedure, where fluid delivery was made contingent upon single spout
      contacts (fixed ratio one). RESULTS: Ethanol (0.25-16% w:v) produced biphasic
      effects on the number of fluid deliveries obtained, with peak ethanol preferences
      over water demonstrated at the 1-2% w:v concentrations. No preferences for the N
      methyl-d-aspartate receptor antagonist phencyclidine or water were demonstrated
      at lower concentrations (0. 0078125-0.125 mg/ml) and, at higher concentrations
      (0.25, 0.5 mg/ml), a preference for water was demonstrated. The mu opioid
      receptor agonist methadone (0.001-0.3 mg/ml) and the prototypic bitter substance
      quinine (0.001-0.3 mg/ml) failed to produce preferences for drug or water. A
      large preference for water over the barbiturate pentobarbital (0.01-3 mg/ml) was
      also demonstrated. After rank-ordering the subjects based on their drug
      preferences or intakes, modest to no correlations across drugs were demonstrated.
      CONCLUSIONS: These results reveal that a robust ethanol preference is not
      predictive of a preference for drugs of abuse from other classes and suggests
      that fluid intakes were correlated, irrespective of the presence or absence of
      drug in the solution.

PMID- 10591879
TI  - The effect of previous exposure to amphetamine on drug-induced locomotion and
      self-administration of a low dose of the drug.
AB  - RATIONALE AND OBJECTIVES: In order to assess directly the relationship between
      locomotor activity and drug self-administration, the present experiment
      simultaneously measured these two behaviors in rats with different histories of
      pre-exposure to amphetamine either following or in the absence of priming
      injections of the drug. METHODS: Different groups of rats were exposed to ten
      daily injections of either saline (1.0 ml/kg, i.p.) or amphetamine (1.5 mg/kg,
      i.p.) and, in each of 13 daily sessions starting 10 days later, were given the
      opportunity to lever press for a low dose of amphetamine (10 microg/kg per i.v.
      infusion) in a two-lever (active versus inactive) continuous reinforcement task.
      Animals were administered a priming injection of amphetamine (1.0 mg/kg, i.p.)
      immediately before testing on the first 8 days, a saline injection (1.0 ml/kg,
      i.p.) on the next 3 days and amphetamine on the final 2 days of testing. RESULTS:
      Consistent with previous reports, prior exposure to amphetamine led to an
      enhanced locomotor response to the priming injection of amphetamine on the first
      day of testing. Little pressing for drug was observed on this day. Following
      priming injections on the subsequent test days, evidence for enhanced locomotion
      by amphetamine-pre-exposed rats diminished and both groups showed comparable and
      progressive increases in active versus inactive lever pressing. When priming
      injections were not made, however, only animals previously exposed to amphetamine
      maintained lever pressing for the drug. Under these conditions, these animals
      emitted more active lever presses and time-out responses and exhibited higher
      levels of locomotor activation in proximity to the active drug administering
      lever than did saline-pre-exposed rats. CONCLUSIONS: These results are consistent
      with the view that previous exposure to amphetamine produces a long-lasting
      enhancement in the behavioral activation animals will direct toward stimuli
      associated with the drug. This enhancement was displayed initially as a
      sensitized locomotor response to amphetamine on the first day of testing and was
      subsequently observed on those test days when no priming injections were given
      when animals continued to self-administer a low dose of amphetamine under a
      simple schedule of reinforcement. The implications of these findings for our
      understanding of the excessive expression of drug-directed behaviors are
      discussed.

PMID- 10591880
TI  - Nicotine self-administration in rats on a progressive ratio schedule of
      reinforcement.
AB  - RATIONALE: Robust intravenous (i.v.) nicotine self-administration (SA) in rats
      has been reported by several laboratories, including our own, using fixed ratio
      (FR) schedules of reinforcement. Studies on other drugs of abuse, however,
      suggest that progressive ratio (PR) schedules may provide additional information
      not gained using FR schedules. OBJECTIVE: Here, we attempt to establish and
      characterize nicotine SA on a PR. METHODS: One study allowed animals to acquire
      SA on a FR at four doses of nicotine (0.02, 0.03, 0.06, 0. 09 mg/kg) before being
      switched to a PR. A second study examined extinction by saline substitution or
      pretreatment with the nicotinic antagonist, mecamylamine, including a preliminary
      analysis into the role of secondary reinforcers in the extinction process.
      RESULTS: SA of nicotine on a PR was stable across repeated sessions. The number
      of infusions earned on a PR correlated with infusion rate on a FR; however, a
      large portion of the variance in SA on a PR could not be accounted for by
      infusion rate on a FR. Infusions on a PR increased across the same range of doses
      that produced a decrease in the infusion rate on a FR. Extinction of responding
      occurred after saline substitution or pretreatment with mecamylamine, and animals
      re-acquired when nicotine was again available without pretreatment. The presence
      of drug-paired stimuli appeared to lengthen the extinction process. CONCLUSIONS:
      Nicotine supports stable SA on a PR. Since PR and FR schedules may measure
      different aspects of nicotine reinforcement, PR schedules may be valuable in
      further characterizing group and individual differences in nicotine
      reinforcement.

PMID- 10591881
TI  - The effects of benzamide analogues on cocaine self-administration in rhesus
      monkeys.
AB  - RATIONALE: Based on the differential distribution of dopamine (DA) D(3) receptors
      in mesolimbic regions relative to nigrostriatal regions, the hypothesis was that
      D(3)-selective antagonists (i.e., higher affinity at D(3)- than D(2)-receptors)
      would be more potent than D(2)-selective antagonists at decreasing total cocaine
      intake relative to disrupting rates of responding. OBJECTIVE: To evaluate the
      effects of acute administration of seven DA antagonists with varying affinities
      for D(2) and D(3) receptors in monkeys self-administering cocaine. METHODS:
      Rhesus monkeys were trained to self-administer intravenous cocaine (0.01-0.3
      mg/kg per injection) under a fixed-interval (FI) 5-min schedule during daily 4-h
      sessions. The use of a FI schedule allowed for independent assessment of rate
      effects and changes in reinforcement frequency as a consequence of drug
      pretreatments. The compounds examined, in order of D(3) binding affinity, were:
      2,3-dimethoxy-N-(9-p-fluorobenzyl)-azabicyclo[3.3. 1]nonan-3beta-yl benzamide
      (MABN) = eticlopride = 5-bromo- 2, 3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin-4
      yl]benz-amide (BBP) > spiperone > fluoroclebopride (FCP) > 2, 3-dimethoxy-N-(p
      fluorobenzyl)piperdin-4-yl benzamide (MBP) > haloperidol. RESULTS: In the absence
      of any pretreatments, cocaine-maintained responding varied as a function of dose
      and was characterized as an inverted U-shaped function, while cocaine intake
      increased in a dose-related fashion. When the dose of cocaine that maintained
      peak rates was available, all DA antagonists decreased response rates and cocaine
      intake in a dose- dependent manner. Increases in cocaine dose attenuated the
      effects of the DA antagonists, resulting in rightward shifts of the cocaine dose
      response curves. Based on the ratio of behavioral potency at decreasing response
      rates relative to intake (ED(50) rate/ED(50) intake) when the highest cocaine
      dose was available, the order of potency and ED(50) ratio values were: MABN (2.5)
      > eticlopride (1. 63) > BBP = spiperone (1.5) > FCP (1.35) > MBP = haloperidol
      (0.89). This order parallels each compound's affinity at D(3) receptors
      (r(2)=0.84) to a greater degree than D(2) receptor affinity (r(2)=0. 34).
      CONCLUSIONS: These results, using a FI schedule of cocaine self-administration,
      suggest that D(3) receptor antagonists are more likely to selectively decrease
      intake relative to response rates than D(2) receptor antagonists.

PMID- 10591882
TI  - The behavioral effects of sertraline, fluoxetine, and paroxetine differ on the
      differential-reinforcement-of-low-rate 72-second operant schedule in the rat.
AB  - RATIONALE: Recent evidence indicates that specific serotonin (5
      hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) are not a clinically or
      experimentally homogeneous class of drugs. Because the differential-
      reinforcement-of-low-rates 72-second (DRL 72-s) operant schedule has been
      extensively used as a screen for antidepressant effects of drugs, different SSRIs
      were compared on the task to further examine their behavioral effects.
      OBJECTIVES: These experiments were designed with two main purposes in mind:
      first, to determine whether all three SSRIs tested would produce antidepressant
      like effects on the DRL 72-s (as measured primarily by an increase in
      reinforcement rate) and, second, to identify differences between the drugs using
      peak-deviation analysis of inter-response times (IRTs). METHODS: Different groups
      of rats were injected with one of three SSRIs: fluoxetine, sertraline, or
      paroxetine. Following drug administration, rats were tested on the DRL 72-s
      operant schedule. RESULTS: All three SSRIs produced significant increases in
      reinforcement rate, but only sertraline and fluoxetine significantly decreased
      response rate. Additionally, paroxetine was observed to disrupt the pattern of
      responding as indicated by decreases in peak area (PkA). Sertraline and
      paroxetine, but not fluoxetine, produced increases in peak location (PkL).
      CONCLUSIONS: These results indicate that, although SSRIs are correctly identified
      as antidepressants by the DRL 72-s operant schedule, they may exert their effects
      in subtly different ways, as indicated by the differences observed to exist
      between the drugs. It appears unlikely that the behavioral effects of the SSRIs
      are attributable solely to 5-HT transporter binding. Instead, the differential
      behavioral effects may be the result of a combination of factors, including 5-HT
      transporter binding, 5-HT(1A) autoreceptor activation, and binding to other
      receptors.

PMID- 10591883
TI  - Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the
      rat forced swimming test.
AB  - RATIONALE: The forced swimming test (FST) is a behavioral test in rodents that
      predicts the clinical efficacy of many types of antidepressant treatments.
      Recently, a behavior sampling technique was developed that scores individual
      response categories, including swimming, climbing and immobility. Although all
      antidepressant drugs reduce immobility in the FST, at least two distinct active
      behavioral patterns are produced by pharmacologically selective antidepressant
      drugs. Serotonin-selective reuptake inhibitors increase swimming behavior, while
      drugs acting primarily to increase extracellular levels of norepinephrine or
      dopamine increase climbing behavior. Distinct patterns of active behaviors in the
      FST may be mediated by distinct neurotransmitters, but this has not been shown
      directly. OBJECTIVES: The present study examined the role of serotonin in
      mediating active behaviors in the forced swimming test after treatment with two
      antidepressant drugs, the selective serotonin reuptake inhibitor, fluoxetine and
      the selective norepinephrine reuptake inhibitor, desipramine. METHODS: Endogenous
      serotonin was depleted by administering para-cholorophenylalanine (PCPA, 150
      mg/kg, IP.) to rats 72 h and 48 h prior to the swim test. Fluoxetine (10 mg/kg,
      SC) or desipramine (10 mg/kg, SC) was given three times over a 24-h period prior
      to the FST. Behavioral responses, including immobility, swimming and climbing,
      were counted during the 5-min test. RESULTS: Pretreatment with PCPA blocked
      fluoxetine-induced reduction in immobility and increase in swimming behavior
      during the FST. In contrast, PCPA pretreatment did not interfere with the ability
      of desipramine to reduce immobility and increase climbing behavior. CONCLUSIONS:
      Depletion of serotonin prevented the behavioral effects of the selective
      serotonin reuptake inhibitor fluoxetine in the rat FST. Furthermore, depletion of
      serotonin had no impact on the behavioral effects induced by the selective
      norepinephrine reuptake inhibitor, desipramine. The effects of antidepressant
      drugs on FST-induced immobility may be exerted by distinguishable contributions
      from different neurotransmitter systems.

PMID- 10591884
TI  - Naltrexone potentiates the anxiolytic effects of chlordiazepoxide in rats exposed
      to novel environments.
AB  - RATIONALE: Both novelty and naloxone have been reported to modify the anxiolytic
      like effect of benzodiazepines in the elevated plus maze. In addition, it has
      been largely demonstrated that novelty alters endogenous opioid activity.
      OBJECTIVES: The present study was designed to examine a possible interaction
      between novelty and naltrexone effects on the behavior of chlordiazepoxide
      treated rats in two animal models of anxiety. METHODS: Thirty minutes after acute
      intraperitoneal treatment with saline or naltrexone and saline or
      chlordiazepoxide, male Wistar rats were exposed for the first time to the
      elevated plus maze apparatus or the social interaction arena for the
      quantification of the percentage of time spent in the open arms or the time of
      active social interaction, respectively. The effects of naltrexone and/or
      chlordiazepoxide on the plus maze and the social interaction tests were also
      evaluated after previous exposure to the respective apparatus. RESULTS:
      Naltrexone dose dependently increased the percentage of time spent in the open
      arms of the elevated plus maze in chlordiazepoxide-treated (5 mg/kg i.p.) rats
      exposed for the first time to the apparatus. Similarly, naltrexone (5 mg/kg i.p.)
      increased the time spent in active social interaction by chlordiazepoxide-treated
      rats exposed to an unfamiliar arena. In both experiments, naltrexone had no
      effect when administered alone. When both the plus maze and the social
      interaction tests were conducted after previous exposure to the respective
      apparatus, naltrexone did not modify the behavior of chlordiazepoxide- or saline
      treated rats. CONCLUSIONS: These data suggest that the anxiolytic-like effects of
      chlordiazepoxide can be modified by opioid mechanisms in novel environments.

PMID- 10591885
TI  - Differential anxiolytic efficacy of a benzodiazepine on first versus second
      exposure to a predatory odor in rats.
AB  - RATIONALE AND OBJECTIVES: Rodents tested in the elevated plus maze model of
      anxiety only show an anxiolytic response to benzodiazepines on their first
      exposure to the maze. The present study investigated whether a similar phenomenon
      occurs with benzodiazepines in a different model of anxiety that involves
      exposing rats to the odor of a predator. METHODS: Testing took place in a
      rectangular arena containing a cat odor-exuding collar at one end and a small
      "hide box" at the opposite end. Rats were initially familiarized with the odor
      free apparatus for 20 min and then placed back in the apparatus 24 and 48 h later
      in the presence of cat odor. RESULTS: Vehicle-treated rats displayed marked
      avoidance of the cat odor on both first and second exposures, spending most of
      the session in the hide box and very little time near the odor source. In
      contrast, rats given a low dose of midazolam (0.375 mg/kg) during first exposure
      spent considerable time in close proximity to the odor source and much less time
      in the hide box. Rats given midazolam (0. 375 mg/kg) on their second exposure to
      cat odor displayed no such anxiolytic effect of the drug. Rats given midazolam
      (0.375 mg/kg) on both exposures showed a potent anxiolytic effect of the drug on
      each occasion. This pattern of results was replicated with a higher dose of
      midazolam (0.75 mg/kg). A further experiment showed that rats previously exposed
      to cat odor showed high levels of hiding in the test environment 24 h later even
      when the cat odor was no longer present. This conditioned fear was blocked by
      midazolam (0.75 mg/kg) suggesting that the ineffectiveness of midazolam on second
      exposure to cat odor is not due to a failure of the drug to affect conditioned
      fear. CONCLUSIONS: The ineffectiveness of midazolam in odor-experienced rats
      parallels the results obtained with benzodiazepines in the elevated plus maze.
      Such results may help illuminate the comparative lack of efficacy of
      benzodiazepines in treating certain types of anxiety disorders in humans.

PMID- 10591886
TI  - Low alcohol preference among the "high alcohol preference" C57 strain of mice;
      preference increased by saline injections.
AB  - RATIONALE AND OBJECTIVE: This study investigated individual alcohol preference
      among the "high alcohol preferring" strain of C57BL10 (line ScSn) mice. METHODS:
      Alcohol preference was assessed in free choice two-bottle preference tests, using
      8% ethanol and tap water, under various conditions. RESULTS: Between 15 and 40%
      of the mice, bred in house, showed a low preference for alcohol with
      ethanol/water ratios of 0.4 or less. There was a biphasic distribution of
      preference, and no relationship between alcohol preference and gender. Mice of
      the C57BL/6 strain from an outside breeder also contained animals with low
      preference for alcohol. Selective breeding from "in house" stock did not
      demonstrate evidence of a simple genetic link. Ethanol preference showed no
      correlation with locomotor activity or the effects of alcohol on such activity.
      Daily intraperitoneal injections of saline increased the preference of low
      preference mice, an effect prevented by the CCK(B) antagonist, CAM1028. The
      preference of "low preference" mice was significantly increased when the effects
      of saline injections were compared with those of handling alone. Diazepam, at 1
      mg/kg, did not affect the low preference, compared with Tween vehicle. This
      demonstration of C57 strain mice with low preference for alcohol may provide a
      valuable model for the effects of stress on alcohol consumption.

PMID- 10591887
TI  - d-amphetamine "cue" generalizes to social defeat stress: behavioral sensitization
      and attenuated accumbens dopamine.
AB  - RATIONALE: Psychomotor stimulant drugs engender intense euphoria as well as
      anxiogenic effects, both potentially involving the mesolimbic dopamine system.
      OBJECTIVES: (1) Do animals that discriminate a psychomotor stimulant drug from
      saline generalize to a non-pharmacological stressful event such as social defeat?
      (2) How does the generalization from d-amphetamine to social defeat stress relate
      to dopamine overflow in the mesocorticolimbic system in response to this stress?
      METHODS: Adult male Long-Evans rats were trained to discriminate either 1.0 mg/kg
      d-amphetamine or 10 mg/kg cocaine from saline in a two-lever drug discrimination
      task; each injection-appropriate tenth lever press was reinforced by milk
      presentation (fixed ratio, FR10). After confirming systematic cocaine and d
      amphetamine dose-effect curves, additional discrimination tests involved exposure
      to several stress conditions; (1) brief confrontations with an aggressive
      resident rat that resulted in the intruder's defeat. Rats were administered
      saline, then exposed to aggressive threats behind a protective screen for 15 min,
      and subsequently performed the two-lever discrimination task; (2) exposure for 15
      min to aggressive threats without prior defeat; (3) exposure to a novel cage for
      15 min. A subgroup of rats was prepared for in vivo microdialysis after they
      generalized the social stress response to the d-amphetamine cue. RESULTS: Nine of
      35 d-amphetamine-trained and six of 18 cocaine-trained animals responded at least
      80% at the drug-appropriate lever after social defeat stress. Social defeat
      stress increased dopamine in nucleus accumbens, with a closely similar dopamine
      response in amphetamine-discriminating rats that were behaviorally sensitized
      versus those that were not sensitized by amphetamine. CONCLUSIONS: Generalization
      from social stress to the stimulant "cue" differs among individuals, which may be
      relevant to the anxiety-like effects of stimulants. By contrast, mesolimbic DA
      activity and motor activity was increased in response to social defeat stress or
      a d-amphetamine challenge, regardless of the qualitatively different stimulant
      stress generalization. Mesolimbic DA in response to stress or amphetamine appears
      significant in behavioral activation, but not in the qualitatively divergent
      internal stimulus properties.

PMID- 10591889
TI  - Comparing the reinforcing efficacy of nicotine containing and de-nicotinized
      cigarettes: a behavioral economic analysis.
AB  - RATIONALE: Smoking-related respiratory stimuli produced by de-nicotinized
      cigarettes may function as conditioned reinforcers, but behavioral data on such
      reinforcing effects are limited. OBJECTIVES: The present experiment compared the
      reinforcing efficacy of cigarettes that provided only smoking-related stimuli (de
      nicotinized cigarettes) and cigarettes that provided both smoking-related stimuli
      and nicotine. METHODS: Eight human subjects responded on a progressive-ratio
      schedule in which the number of plunger pulls required for standardized cigarette
      puffs increased across sessions. In one phase, the breakpoints, number of puffs
      earned per session, peak response rates, ratio producing peak response rates, and
      the elasticity of demand for cigarette puffs were compared for nicotine
      containing and de-nicotinized cigarettes when each cigarette type was the only
      one available. In another phase, subjects chose between the two cigarette types
      at some of the prices examined in the previous phase. RESULTS: Nicotine
      containing and de-nicotinized cigarettes produced similar measures of reinforcing
      efficacy when each was presented alone, but there was a strong preference for
      nicotine-containing cigarettes when subjects were given a choice. CONCLUSIONS:
      These data support suggestions that smoking-produced sensory stimuli may function
      as conditioned reinforcers and that the relative reinforcing efficacy of
      cigarettes is determined by the combined effects of the nicotine/conditioned
      reinforcing complex provided by smoking.

PMID- 10591888
TI  - A controlled study of flumazenil-precipitated withdrawal in chronic low-dose
      benzodiazepine users.
AB  - RATIONALE: Preclinical studies of the benzodiazepine antagonist flumazenil
      (Romazicon) have contributed to the understanding of the physical dependence
      associated with chronic benzodiazepine use; when administered to animals
      chronically pretreated with benzodiazepines, flumazenil precipitates a withdrawal
      syndrome. However, few controlled clinical studies have been conducted.
      OBJECTIVES: The objective was to characterize the effects of flumazenil in long
      term users of therapeutic doses of benzodiazepines. METHODS: The acute
      physiological, participant-rated, and observer-rated effects of intravenously
      administered flumazenil (1 mg/70 kg) and caffeine (300 mg/70 kg; active drug
      control) were evaluated in an experimental group of 13 long-term users (mean 4.6
      years) of low therapeutic doses (mean 11.2 mg/day diazepam equivalent) relative
      to a matched group of 13 volunteers without prior exposure to benzodiazepines in
      a double-blind, placebo-controlled, mixed design. RESULTS: Whereas the
      experimental group did not differ from the control group with respect to the
      effects of placebo, and both groups showed some changes in response to caffeine
      (e.g., increased blood pressure and anxiety scores), only the experimental group
      showed considerable changes in physiological measures, participant ratings (e.g.,
      increased ratings of dizziness, blurred vision, heart pounding, feelings of
      unreality, pins and needles, nausea, sweatiness, noises louder than usual,
      jitteriness, things moving, sensitivity to touch), and observer ratings in
      response to flumazenil; in addition, four participants developed panic attacks.
      CONCLUSIONS: This study clearly demonstrates that flumazenil can precipitate
      symptoms commonly associated with benzodiazepine withdrawal in chronic low-dose
      benzodiazepine users.

PMID- 10591890
TI  - Different strains and substrains of rats show different levels of neuropathic
      pain behaviors.
AB  - This study compared and contrasted the manifestation of neuropathic pain
      behaviors in several strains of rats. These included ACI, Brown-Norway, Fischer
      344, Lewis, Long-Evans, Sprague-Dawley, and Wistar-Furth, all obtained from
      Harlan Sprague-Dawley Inc. Comparison was also made between two substrains of
      Sprague-Dawley rats: one from Harlan and the other from Sasco. Neuropathic injury
      was produced by tightly ligating the left L5 and L6 spinal nerves with the
      animals under halothane anesthesia. Tests were conducted for 2 weeks to examine
      behavioral signs representing mechanical allodynia, cold allodynia, and
      spontaneous pain. There was no difference between strains in any of the tested
      behaviors before surgery. After neuropathic injury, rats in most groups developed
      high levels of behavioral signs of various components of neuropathic pain;
      however, some strains of rats showed weak behavioral signs of neuropathic pain.
      When a comparison was made between two substrains of Sprague-Dawley rats from two
      different sources, the ones from Sasco showed weaker behavioral signs than those
      from Harlan. When comparisons were made between different strains of rats from
      the same source (Harlan), Brown-Norway and Long-Evans rats showed the smallest
      magnitude of neuropathic pain behaviors. The data indicate that different strains
      and substrains of rats display different degrees of pain behaviors, suggesting
      that strains and substrains are important variables in the development of
      neuropathic pain after peripheral nerve injury.

PMID- 10591891
TI  - Effects of inhibitory neurotransmitters on the mudpuppy (Necturus maculatus)
      locomotor pattern in vitro.
AB  - Effects of inhibitory neurotransmitters on the locomotor rhythm and pattern
      generation were investigated using an in vitro preparation isolated from the
      mudpuppy (Necturus maculatus). The preparation consisted of the first five
      segments of the spinal cord and the right forelimb attached by the brachial
      nerves. During N-methyl-d-aspartate (NMDA)-induced locomotion, the rhythmic motor
      output (EMG) was recorded unilaterally from elbow flexor and extensor muscles.
      While neither glycine nor gamma-aminobutyric acid (GABA)-related substances
      induced locomotion in the absence of NMDA, they modulated NMDA-induced
      locomotion. Bath application of glycine and GABA suppressed the rhythmic motor
      pattern induced by NMDA. Addition of glycine receptor antagonist strychnine or
      GABA(A) receptor antagonist bicuculline disrupted the phase relationship between
      antagonistic motor pools during ongoing locomotion, thereby changing the normal
      alternating pattern into synchronous EMG bursts. Both the GABA(A) receptor
      agonist muscimol and GABA(B) receptor agonist baclofen mimicked the effects of
      GABA as they either slowed down or stopped locomotion. Nipecotic acid, a GABA
      uptake blocker, had a similar effect. This suggested that an endogenous release
      of GABA modulated the locomotor rhythm. The endogenous release was antagonized by
      the GABA(A) and GABA(B) receptor antagonists bicuculline and CGP-35348,
      respectively. Immunocytochemistry revealed that glycine and GABA-positive neurons
      and fibers were present in mudpuppy spinal cord. Although the GABAergic neurons
      were more numerous than glycinergic neurons, both cell types contributed
      processes directed towards the white matter and occasionally towards the
      ependymal lining of the central canal. Our results suggest that inhibitory
      neurotransmitters exert powerful actions upon the neuronal network governing
      forelimb locomotion in the mudpuppy. The effects we observed may be mediated by a
      network of segmentally distributed glycinergic and GABAergic spinal neurons.

PMID- 10591892
TI  - Role of the medial prefrontal cortex in the development of conditioned
      bradycardia in rabbits with lesions of the cerebellar vermis.
AB  - The effects on the expression of conditioned bradycardia of pairing an early
      (fourth postnatal day) cerebellar vermal lesion with a lesion of the medial
      prefrontal cortex (mPFC) were studied in adult New Zealand rabbits. In the
      conditioning procedure, an auditory stimulus (5 s, 1000 Hz) served as a
      conditioning stimulus (CS) and a train of electrical impulses applied to the ear
      (500 ms, 100 Hz, 1.5 mA) was used as the unconditioned stimulus (US). Heart rate
      (HR) responses exhibited by rabbits with the early double lesion (PFCBs) during
      orientation (CS-alone) and conditioning (CS-US paired) were analyzed and compared
      with those shown by unoperated controls as well as by a group of animals in which
      a cerebellar lesion alone had been performed on the fourth postnatal day (CBs).
      In all the experimental groups vermal lesions were localized in the cortex of
      lobules V-VII and the underlying white matter. As for mPFC ablation, the lesioned
      area involved the agranular precentral region (Brodmann's area 8), the anterior
      cingulate cortex (Brodmann's area 24) and the prelimbic area (Brodmann's area
      32). All the experimental animals had a normal baseline HR as well as a marked
      orientation response, both comparable with those exhibited by controls. In
      contrast, while CB rabbits showed an increase in the amplitude of the conditioned
      bradycardic response when compared with controls, the HR conditioned response of
      PFCB animals was comparable to that exhibited by controls. These results suggest
      that, since the double lesion produces a conditioned bradycardia similar to that
      of the controls, the increase in the amplitude of this response observed after
      early cerebellar removal may depend on the mPFC which, in the absence of specific
      cerebellar circuits, is unable to produce a properly calibrated HR conditioned
      response.

PMID- 10591893
TI  - Excitatory and inhibitory synaptic inputs shape the discharge pattern of pump
      neurons of the nucleus tractus solitarii in the rat.
AB  - The second-order relay neurons of the slowly-adapting pulmonary stretch receptors
      (SARs) are called pump neurons (P cells) and are located in the nucleus tractus
      solitarii (NTS). We have shown recently that P cells do not act merely as simple
      relay neurons of SAR afferents but also receive rhythmic inputs from the central
      respiratory system. This study aimed to analyze two aspects of the respiratory
      inputs to P cells: (1) suppression of P cell firing at early inspiration (eI
      suppression) and (2) facilitation of P cell firing at around the period from late
      inspiration to early expiration (IE facilitation). This study employed
      extracellular recordings combined with iontophoretic applications of neuroactive
      drugs to single P cells, in Nembutal-anesthetized, paralyzed, and artificially
      ventilated rats. The results showed that several excitatory and inhibitory
      neurotransmitters were involved in these synaptic events. First, the glycine
      antagonist strychnine and the GABA(A) antagonist bicuculline were applied to
      identify the neurotransmitters acting in eI suppression. Strychnine greatly
      diminished eI suppression, but bicuculline had little effect. This suggested that
      eI suppression was elicited by inspiratory neurons that were glycinergic and had
      a decrementing firing pattern. Second, on the other hand bicuculline markedly
      enhanced IE facilitation as well as the baseline frequency of P cell firing. The
      enhancement of IE facilitation was distinctive even when the effects of increased
      baseline firing on this enhancement were taken into account. Third, IE
      facilitation was diminished by applications of the NMDA glutamate receptor
      antagonists D-2-amino-5-phosphonovaleric acid (APV) and dizocilpine (MK-801).
      These results suggested that glutamatergic synapses on P cells from some
      unidentified respiratory neurons form excitatory inputs for IE facilitation and
      GABA(A) receptor-mediated processes control the strength of IE facilitation,
      possibly at the presynaptic level. Finally, iontophoretic application of the non
      NMDA glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2, 3-dione
      disodium (CNQX), almost completely abolished P cell firing in response to both
      lung inflation and electrical stimulation of the vagus nerve. This confirmed the
      previous report that glutamate is the primary neurotransmitter at the synapses
      between SAR afferents and P cells. We concluded that complicated synaptic inputs
      involving glycinergic and GABAergic inhibitions, and non-NMDA and NMDA glutamate
      receptor-mediated excitations form the basic pattern of P cell firing.

PMID- 10591894
TI  - Viewer-centered and body-centered frames of reference in direct visuomotor
      transformations.
AB  - It has been hypothesized that the end-point position of reaching may be specified
      in an egocentric frame of reference. In most previous studies, however, reaching
      was toward a memorized target, rather than an actual target. Thus, the role
      played by sensorimotor transformation could not be disassociated from the role
      played by storage in short-term memory. In the present study the direct process
      of sensorimotor transformation was investigated in reaching toward continuously
      visible targets that need not be stored in memory. A virtual reality system was
      used to present visual targets in different three-dimensional (3D) locations in
      two different tasks, one with visual feedback of the hand and arm position (Seen
      Hand) and the other without such feedback (Unseen Hand). In the Seen Hand task,
      the axes of maximum variability and of maximum contraction converge toward the
      mid-point between the eyes. In the Unseen Hand task only the maximum contraction
      correlates with the sight-line and the axes of maximum variability are not viewer
      centered but rotate anti-clockwise around the body and the effector arm during
      the move from the right to the left workspace. The bulk of findings from these
      and previous experiments support the hypothesis of a two-stage process, with a
      gradual transformation from viewer-centered to body-centered and arm-centered
      coordinates. Retinal, extra-retinal and arm-related signals appear to be
      progressively combined in superior and inferior parietal areas, giving rise to
      egocentric representations of the end-point position of reaching.

PMID- 10591895
TI  - Under which conditions do the skin and probe decouple during sinusoidal
      vibrations?
AB  - Previous experiments performed on monkey and human fingertips suggested that the
      skin surface and stimulus probe decouple for sinusoidal displacements applied
      perpendicularly to the skin surface. From these observations, it was concluded
      that sinusoidal vibration may not be a suitable stimulus for understanding and
      modeling the tactile system. We repeated these experiments on human observers
      using stimulus frequencies ranging from 0.5 to 240 Hz and with displacement
      amplitudes up to 1 mm peak-to-peak (p-p). The skin and probe movements were
      measured in the steady-state using stroboscopic illumination and video
      microscopy. Contrary to previous conclusions, we found that decoupling did not
      occur for amplitudes less then 0.25 mm p-p, regardless of stimulus frequency.
      Decoupling was only observed for stimulus amplitudes greater than 0.25 mm over
      the stimulus-frequency range investigated. To further investigate this effect, a
      modified stimulus contactor was used, which permitted the measurement of the
      skin's movement using reflected light. Measurements were made on both the index
      fingertip and the thenar eminence. Regardless of body site, no decoupling between
      the skin and stimulus probe was observed for frequencies ranging from 20 to 100
      Hz up to displacements of 0.25 mm p-p. These levels are well within the range
      used in most human psychophysical experiments performed on these parts of the
      body. We conclude that sinusoidal vibration can be used reliably to stimulate the
      tactile system and is an appropriate stimulus for developing models of touch.

PMID- 10591896
TI  - Sensory nerve endings in the hard palate and papilla incisiva of the goat.
AB  - The sensory innervation of the papilla incisiva in the hard palate of the
      domestic goat was studied with light and electron microscopy, supplemented by
      electrophysiological studies of free nerve endings. The goat lacks incisor teeth.
      Grass and leaves are not bitten, but pulled off by pressing them between the
      tongue and papilla incisiva. Thus, the masticatory mucosa is subject to
      particularly heavy mechanical loads requiring functional specialization of the
      horny epithelium in the form of thickening, i.e., the papilla incisiva and 12-14
      pairs of rugae palatinae. A thin layer of firm connective tissue (lamina propria)
      attaches the mucosa to the periost of the hard palate. Sensory nerve fibers were
      found most abundantly in the papilla incisiva. Their number decreased drastically
      in aboral direction. A section through the first four rugae palatinae contains
      only about 10% of the number of free nerve endings found in the same area of
      mucosa from the papilla incisiva. Four types of sensory nerve endings were found.
      Free nerve endings were seen ubiquitously in the epithelium and superficial layer
      of the lamina propria. Merkel nerve endings were found in the bases of the
      epithelial thickenings in the papilla incisiva and rugae palatinae. Few Ruffini
      corpuscles were found in the deeper layer of the lamina propria, while lamellated
      corpuscles were seen just below the basement membrane of the epithelial pegs.
      Thus, a variety of sensory nerve endings were found in the hard palate,
      especially in those areas that are in close contact with the tongue during
      chewing of food. This rich innervation suggests an important role in monitoring
      the mechanical properties of food. Recordings were made from cell bodies
      supplying these terminals. Classic low-threshold, slowly adapting responses were
      observed in Ass afferent populations. This activity was probably mediated by
      Merkel type endings. Alternately, high-threshold and suprathreshold responses
      obtained from Adelta category afferents were likely to be nociceptive. In support
      of this, threshold and suprathreshold sensitization was observed following
      injection of serotonin into the receptive field of Adelta populations. This
      activity was likely to be derived from the aforementioned free nerve endings.

PMID- 10591897
TI  - Glycine- and GABA-immunoreactive nerve terminals apposed to alpha-motoneurons
      during postnatal development in kittens: a quantitative study using the disector.
AB  - The distribution of gamma-aminobutyric acid (GABA) and/or glycine-immunoreactive
      (IR) terminal-like structures apposed to somatic and dendritic membrane of lumbar
      alpha-motoneurons in column 2 was examined in 1- and 3-week-old kittens and in
      the adult cat. This quantitative study was carried out using a postembedding
      technique on semithin sections and a stereological method, the disector. Analysis
      of immunoreactive terminals showed that the percentages of GABA-IR and glycine-IR
      terminals (these populations include terminals containing both GABA and glycine)
      apposed to somatic and proximal dendritic compartments of alpha-motoneurons are
      almost the same in kittens, while in the adult glycinergic innervation becomes
      predominant. This change results from: (1) the decrease in numbers of GABA-IR
      terminals contacting the somatic compartment between 3 weeks and adult stage,
      while the numbers of glycine-IR terminals show no significant changes after birth
      and the numbers of terminals containing both neurotransmitters (GABA-IR+glycine
      IR) present transient changes and (2) the postnatal increase in the dendritic
      compartment, in numbers of GABA-IR, glycine-IR and GABA-IR+glycine-IR terminals;
      the increase being larger for glycine-IR terminals. Furthermore, using a
      postembedding immunogold technique, observations by electron microscopy showed
      that GABA-IR P boutons apposed to M boutons can already be identified at 1 week
      after birth.

PMID- 10591898
TI  - Increased blood flow in the basal ganglia when using cues to direct attention.
AB  - We used positron emission tomography (PET) in ten subjects to study the brain
      regions involved in voluntary shifts of attention. For six scans, subjects
      performed a visual target detection task in which the location of the target was
      indicated in advance on some proportion of trials by the appearance of an arrow
      cue at fixation. The informative cues were successful in speeding reaction time
      to the target. Blood flow in the left putamen was correlated with the proportion
      of informative cues provided within a scan. We discuss this finding in terms of
      three possible interpretations: attentional shifts, response inhibition, and
      motor preparation related to the use of the right hand to respond. Blood flow in
      cortical regions commonly associated with attention was not related to cue ratio,
      a finding that may reflect automatization of the processes involved in
      interpreting and using the cues.

PMID- 10591899
TI  - Visual stimulation elicits locked and induced gamma oscillations in monkey
      intracortical- and EEG-potentials, but not in human EEG.
AB  - Stimulus-related fast oscillations in the gamma-range (30-100 Hz) were clearly
      demonstrated with microelectrode recordings in visual cortex of awake monkeys,
      and they were also reported for recordings of human electroencephalograms (EEG).
      However, the presence of stimulus-related gamma-modulation in human EEG has
      repeatedly been disputed. To clarify this dispute, we recorded the scalp EEG of
      man and monkey as well as intracortical field potentials (LFP) from monkey
      primary visual cortex (V1) during identical visual stimulation (large-field
      sinusoidal gratings, which proved to induce the largest gamma-amplitudes in
      monkey V1 and V2). We found a strong stimulus-related increase of gamma
      oscillations in monkey LFP and EEG, but no modulation of gamma-activity in human
      EEG. In contrast to previous results, gamma-oscillations in the monkey were
      strongly phase-locked to stimulus onsets in early response periods (80-160 ms)
      and became gradually independent in later periods. Our negative result on gamma
      modulation in human subjects contradicts several published findings. We conclude
      from our results that visually evoked gamma-modulations in humans EEG are not as
      accessible as in the monkey.

PMID- 10591901
TI  - The control of an action in Parkinson's disease.
AB  - We studied, in Parkinson's disease (PD) patients and healthy control subjects,
      the kinematics of the action formed by two successive motor acts: reaching
      grasping an object (first target) and placing it on a second target. We examined
      the effects of extrinsic (i.e., distance) and intrinsic (i.e., size) properties
      of the second target on the various kinematic phases of reaching-grasping. We
      randomly varied distance and size of both stimuli across the experimental
      session. The kinematics of the reach initial phase of both patients and controls
      was influenced by the distance of both the first and the second target. In
      particular, peak acceleration increased for farther position of the second
      target. However, in the subsequent phase, patients, differently from controls,
      modified their reaching kinematics, removing the effects of second target
      position. These results were due neither to a visual interference effect of the
      second target on reaching-grasping nor to the complexity of movement sequence.
      Finally, the size of the second target did not affect grasp kinematics of both
      patients and controls. The results of the present study support the hypothesis
      that PD patients are able to compute the general program of an action in which
      extrinsic properties of both the actual and the final target are computed.
      However, PD patients re-program movement during its execution. This suggests a
      decay of the motor program. That is, basal ganglia can be involved in storing the
      plan of an action and in controlling its correct execution.

PMID- 10591900
TI  - A comparative study of the effects of morphine in the dorsal periaqueductal gray
      and nucleus accumbens of rats submitted to the elevated plus-maze test.
AB  - We studied the effects of morphine injected either systemically or into the
      dorsal periaqueductal gray (DPAG) or nucleus accumbens (NA) using conventional
      and ethological analyses of behavior of rats submitted to the elevated plus-maze
      test with transparent walls. Intraperitoneal morphine (0.1 mg/kg and 0.3 mg/kg)
      increased both standard and ethological measures, expressing general exploratory
      activity such as total arm entries, end-exploration, scanning, head-dipping, and
      rearing. Morphine 10 (7.6 microg/microl) and 30 nmol (23 microg/microl) injected
      into nucleus accumbens produced similar effects, which were blocked by i.p.
      naltrexone (2.0 mg/kg), an opioid antagonist with good affinity for mu-opioid
      receptors. Morphine injected into the DPAG produced either antiaversive (10 nmol)
      or aversive effects (30 nmol), which respectively reduced and increased entries
      and time spent in the open arms and behaviors associated with risk assessment
      (peeping out, stretched attend postures, and flat back approach). The proaversive
      effects were inhibited by i.p. norbinaltorphimine (2.0 mg/kg), a selective
      inhibitor for kappa-opioid receptors. These findings support the contention that
      at least some of the motivational effects of morphine may be due to activation of
      opioid mechanisms in nucleus accumbens, and DPAG has neural substrates for
      antiaversive and aversive effects of morphine. Moreover, on the basis of previous
      and present data obtained in this laboratory, it is suggested that stimulation of
      mu-opioid receptors inhibits and stimulation of kappa-receptors activates the
      neural substrate of aversion in the DPAG. On the other hand, the increase in
      exploratory behavior due to interaction of morphine with mu-opioid receptors in
      the nucleus accumbens may be due to the stimulation of the interface between
      neural substrates of motivation and motor output in this structure.

PMID- 10591902
TI  - Dependence of stretch reflexes on amplitude and bandwidth of stretch in human
      wrist muscle.
AB  - The tonic stretch reflex was investigated using small-amplitude displacements
      (<4.2 degrees ) of the wrist while subjects maintained average contraction levels
      of 25% of maximum in flexor carpi radialis. The wrist displacements were designed
      to preclude voluntary following but at the same time were confined to the
      frequency range most relevant to voluntary movements. They included a broad
      frequency band (0-12 Hz) signal as well as sets of narrow-band signals spanning
      the range from 0 to 10 Hz. The maximum frequency was set so as to remain within
      the linear encoding bandwidth of the reflex system and thereby minimize
      distortion. The effects of frequency bandwidth and amplitude of the displacement
      perturbations were tested in separate experiments. The coherence square, gain and
      phase between the EMG and angular displacement were calculated in order to
      characterize the stretch reflex under these conditions. It was found that the
      phase of the reflex response was dependent on both bandwidth and amplitude. For
      narrow-band displacements, the phase advance was about 30 degrees greater over
      the frequency range tested than for broad-band displacements, suggesting that the
      reflex response may be influenced by the predictability of the perturbation. At
      the smallest amplitude of 0.3 degrees, the peak phase advance was about 20
      degrees greater than at the largest amplitude of 4.2 degrees. The gain was also
      higher and rose more steeply with frequency at smaller amplitudes. In the
      frequency range up to 12 Hz, the tonic stretch reflex responds most effectively
      to smaller-amplitude, more regular, higher-frequency inputs and this is
      consistent with a role for the reflex in counteracting small-amplitude
      oscillations, tremors and errors of voluntary movement.

PMID- 10591903
TI  - The frontal eye field is involved in spatial short-term memory but not in
      reflexive saccade inhibition.
AB  - Physiological studies in monkeys have shown that the frontal eye field (FEF) is
      involved in the preparation and triggering of purposive saccades. However,
      several questions of FEF function remain unclear: the role of the FEF in visual
      short-term memory, its ability to update its spatial map and its role in
      reflexive saccade inhibition. We have addressed these issues in a patient with a
      small acute ischemic lesion whose location corresponded very accurately to the
      region of the left FEF according to the most recent cerebral blood flow studies.
      An initial study was conducted on days 7 and 8 after the stroke, i.e., before
      substantial recovery. A first group of paradigms (smooth pursuit, simple saccade
      tasks) was performed to assess FEF dysfunction. In a second group of paradigms,
      (1) visual short-term memory was tested by means of memory-guided saccade
      paradigms with short and long delays (1 and 7 s), (2) spatial updating abilities
      were tested by a double-step saccade task and two memory-guided saccade tasks in
      which the central fixation point was displaced during the memorization delay, and
      (3) reflexive saccade inhibition was tested by the antisaccade task. Results show
      that the FEF is involved in short-term memorization of the parameters of the
      forthcoming memory-guided saccade encoded in oculocentric coordinates. Normal
      results in the antisaccade task suggest that the FEF is not involved in reflexive
      saccade inhibition.

PMID- 10591904
TI  - Bimanual coupling during the specification of isometric forces.
AB  - The present study investigated the generalizability of the hypothesis of
      transient coupling during the preparation of bimanual movements (Spijkers and
      Heuer 1995) to the specification of isometric forces. In the first experiment we
      used the timed response paradigm (TRP) to examine the time course of the
      specification process. Subjects had to generate bimanual isometric force pulses
      while preparation time was controlled by the TRP. Target forces were weak (20% of
      maximal voluntary force, MVF) or strong (40% MVF) and assigned randomly to each
      hand. The first experiment revealed the predicted pattern of correlations between
      the peak forces but, because the subjects tended to delay responding when time
      for preparation was very brief, the time course of the specification process did
      not fully match expectations. In the second experiment we improved force
      trajectory feedback and presented two initial cues that were expected to induce
      better preparation of the default force (30% MVF). Both changes were successful
      and the results further corroborate the transient-coupling hypothesis.

PMID- 10591905
TI  - Characterisation of paired-pulse transcranial magnetic stimulation conditions
      yielding intracortical inhibition or I-wave facilitation using a threshold
      hunting paradigm.
AB  - Short-interval, paired-pulse transcranial magnetic stimulation (TMS) is usually
      used to demonstrate intracortical inhibition. It was shown recently that with
      short-interval, paired-pulse TMS a facilitation - called intracortical I-wave
      facilitation - can also be demonstrated. It was the aim of this study to
      investigate which stimulus conditions lead to intracortical inhibition and what
      conditions yield an intracortical I-wave facilitation in a hand muscle of normal
      subjects. Paired-pulse TMS responses with an interstimulus interval of 1.2 ms
      were obtained from the abductor digiti minimi muscle of four normal subjects. A
      threshold-hunting paradigm with hunting through first or second stimulus
      variation was used to obtain a curve of threshold-pair strengths. All subjects
      showed two branches of stimulus interaction on this diagram. If the first
      stimulus of a threshold pair was below approximately 65% of resting motor
      threshold it modified the response primarily due to the second stimulus through
      intracortical inhibition. However, if the first stimulus of a threshold pair
      exceeded approximately 65% of resting motor threshold it became responsible for
      the spinal action-potential initiation. The subsequent second stimulus served as
      a "booster" for the ongoing intracortical I-wave activity, making it impossible
      to observe the intracortical inhibition evoked by the first stimulus.

PMID- 10591906
TI  - Parieto-frontal coding of reaching: an integrated framework.
AB  - In the last few years, anatomical and physiological studies have provided new
      insights into the organization of the parieto-frontal network underlying visually
      guided arm-reaching movements in at least three domains. (1) Network
      architecture. It has been shown that the different classes of neurons encoding
      information relevant to reaching are not confined within individual cortical
      areas, but are common to different areas, which are generally linked by
      reciprocal association connections. (2) Representation of information. There is
      evidence suggesting that reach-related populations of neurons do not encode
      relevant parameters within pure sensory or motor "reference frames", but rather
      combine them within hybrid dimensions. (3) Visuomotor transformation. It has been
      proposed that the computation of motor commands for reaching occurs as a
      simultaneous recruitment of discrete populations of neurons sharing similar
      properties in different cortical areas, rather than as a serial process from
      vision to movement, engaging different areas at different times. The goal of this
      paper was to link experimental (neurophysiological and neuroanatomical) and
      computational aspects within an integrated framework to illustrate how different
      neuronal populations in the parieto-frontal network operate a collective and
      distributed computation for reaching. In this framework, all dynamic (tuning,
      combinatorial, computational) properties of units are determined by their
      location relative to three main functional axes of the network, the visual-to
      somatic, position-direction, and sensory-motor axis. The visual-to-somatic axis
      is defined by gradients of activity symmetrical to the central sulcus and
      distributed over both frontal and parietal cortices. At least four sets of reach
      related signals (retinal, gaze, arm position/movement direction, muscle output)
      are represented along this axis. This architecture defines informational domains
      where neurons combine different inputs. The position-direction axis is identified
      by the regular distribution of information over large populations of neurons
      processing both positional and directional signals (concerning the arm, gaze,
      visual stimuli, etc.) Therefore, the activity of gaze- and arm-related neurons
      can represent virtual three-dimensional (3D) pathways for gaze shifts or hand
      movement. Virtual 3D pathways are thus defined by a combination of directional
      and positional information. The sensory-motor axis is defined by neurons
      displaying different temporal relationships with the different reach-related
      signals, such as target presentation, preparation for intended arm movement,
      onset of movements, etc. These properties reflect the computation performed by
      local networks, which are formed by two types of processing units: matching and
      condition units. Matching units relate different neural representations of
      virtual 3D pathways for gaze or hand, and can predict motor commands and their
      sensory consequences. Depending on the units involved, different matching
      operations can be learned in the network, resulting in the acquisition of
      different visuo-motor transformations, such as those underlying reaching to
      foveated targets, reaching to extrafoveal targets, and visual tracking of hand
      movement trajectory. Condition units link these matching operations to
      reinforcement contingencies and therefore can shape the collective neural
      recruitment along the three axes of the network. This will result in a
      progressive match of retinal, gaze, arm, and muscle signals suitable for moving
      the hand toward the target.

PMID- 10591907
TI  - Effect of viewing distance on the generation of vertical eye movements during
      locomotion.
AB  - Vertical head and eye coordination was studied as a function of viewing distance
      during locomotion. Vertical head translation and pitch movements were measured
      using a video motion analysis system (Optotrak 3020). Vertical eye movements were
      recorded using a video-based pupil tracker (Iscan). Subjects (five) walked on a
      linear treadmill at a speed of 1.67 m/s (6 km/h) while viewing a target screen
      placed at distances ranging from 0.25 to 2.0 m at 0. 25-m intervals. The
      predominant frequency of vertical head movement was 2 Hz. In accordance with
      previous studies, there was a small head pitch rotation, which was compensatory
      for vertical head translation. The magnitude of the vertical head movements and
      the phase relationship between head translation and pitch were little affected by
      viewing distance, and tended to orient the naso-occipital axis of the head at a
      point approximately 1 m in front of the subject (the head fixation distance or
      HFD). In contrast, eye velocity was significantly affected by viewing distance.
      When viewing a far (2-m) target, vertical eye velocity was 180 degrees out of
      phase with head pitch velocity, with a gain of 0. 8. This indicated that the
      angular vestibulo-ocular reflex (aVOR) was generating the eye movement response.
      The major finding was that, at a close viewing distance (0.25 m), eye velocity
      was in phase with head pitch and compensatory for vertical head translation,
      suggesting that activation of the linear vestibulo-ocular reflex (lVOR) was
      contributing to the eye movement response. There was also a threefold increase in
      the magnitude of eye velocity when viewing near targets, which was consistent
      with the goal of maintaining gaze on target. The required vertical lVOR
      sensitivity to cancel an unmodified aVOR response and generate the observed eye
      velocity magnitude for near targets was almost 3 times that previously measured.
      Supplementary experiments were performed utilizing body-fixed active head pitch
      rotations at 1 and 2 Hz while viewing a head-fixed target. Results indicated that
      the interaction of smooth pursuit and the aVOR during visual suppression could
      modify both the gain and phase characteristics of the aVOR at frequencies
      encountered during locomotion. When walking, targets located closer than the HFD
      (1.0 m) would appear to move in the same direction as the head pitch, resulting
      in suppression of the aVOR. The results of the head-fixed target experiment
      suggest that phase modification of the aVOR during visual suppression could play
      a role in generating eye movements consistent with the goal of maintaining gaze
      on targets closer than the HFD, which would augment the lVOR response.

PMID- 10591908
TI  - Timing a one-handed catch. I. Effects of telestereoscopic viewing.
AB  - The aim of this study was to examine the role of binocular and monocular
      information sources in specifying time-to-contact. More specifically, it was
      investigated whether the timing of the one-handed catch is consistent with a
      binocular tau-function strategy. Subjects (n=8) were required to time their grasp
      to catch a ball approaching with a constant spatial trajectory. The ball
      approached at three different constant velocities (1.5, 2.0 and 2.5 m/s).
      Vergence and disparity were manipulated through subjects wearing a
      telestereoscope to increase the effective interocular separation, under both
      binocular and monocular viewing. Subjects performed 24 trials in each of the four
      conditions. Subjects' started the opening of the hand earlier in the binocular
      telestereoscope condition when a ball approached with velocity of 1. 5 m/s. They
      then closed the hand earlier in the binocular telestereoscope condition at all
      ball approach velocities. There were no effects of telestereoscope on the timing
      of hand opening and closing under monocular viewing. This finding suggests the
      use of the binocular information in timing the grasp. However, there were effects
      of approach velocity under all conditions of monocular and binocular viewing.
      Subjects' closed the hand earlier as a function of increasing approach velocity.
      Together, the effects of the telestereoscope and approach velocity indicate that
      timing of the one-handed catch is not consistent with the use of a binocular "tau
      function" variable. Rather, it is concluded that multiple sources of monocular
      and binocular information contribute to the regulation of timing.

PMID- 10591909
TI  - Timing a one-handed catch. II. Adaptation to telestereoscopic viewing.
AB  - A pre-exposure, exposure, post-exposure design was used to assess the adaptation
      of the timing of a one-handed catch during telestereoscopic viewing. More
      specifically, it was examined whether the adaptation involved: (1) ignoring
      binocular sources of information and selecting other information, or (2) a
      recalibration of the coupling between the effected binocular information and the
      catching movement, and (3), if it is recalibration, whether it is restricted to
      the manipulated binocular information. To test these hypotheses, subjects (n=16)
      were assigned to one of two groups, each group performing three blocks of 15
      trials in the dark with only the ball visible. In the exposure condition, both
      groups were required to catch balls under binocular telestereoscopic viewing. In
      the pre-exposure and post-exposure conditions, subjects performed under binocular
      and monocular viewing, respectively. Kinematics of the grasping movement were
      recorded. It was predicted that, in the case of a selection process, no after
      effects would occur in the post-exposure condition, whereas, in the case of
      recalibration, aftereffects would occur. Moreover, if the recalibration is
      restricted to the manipulated information, only the group that was provided with
      binocular vision during the pre- exposure and post-exposure conditions would show
      aftereffects. Significant condition (pre-exposure, exposure, post-exposure) by
      block (first three trials, last three trials) effects were found for the moments
      of grasp onset, peak opening velocity and hand closure, indicating that the hand
      was opened and closed earlier in the first three trials of telestereoscopic
      viewing. This coincided with an increase in catching failures. In addition, for
      the moments of hand closure and peak closing velocity, negative aftereffects were
      found in the post-exposure condition. The hand was closed later in the first
      three trials after removal of telestereoscope. With respect to the presence of
      the aftereffects, no differences were found between the groups. It was concluded
      that adaptation to telestereoscopic viewing in the timing of a one-handed catch
      is due to the recalibration of the coupling between information and movement,
      rather than a selection of another source of information. Moreover, it is likely
      that the recalibration was not restricted to the single, manipulated information.
      Rather, the recalibration involves multiple binocular and monocular optical and
      oculomotor sources of information.

PMID- 10591910
TI  - Changed visuomotor transformations during and after prolonged microgravity.
AB  - A series of step-tracking experiments was conducted before, during, and after a 3
      week space mission to assess the effects of prolonged microgravity on a non
      postural motor-control task. In- and post-flight accuracy was affected only
      marginally. However, kinematic analyses revealed a considerable change in the
      underlying movement dynamics: too-small force and, thus, too-low velocity in the
      first part of the movements was mainly compensated by lengthening the
      deceleration phase of the primary movement, so that accuracy was regained at its
      end. The observed in-flight decrements in peak velocity and peak acceleration
      point to an underestimation of mass, in agreement with the re-interpretation
      hypothesis of Bock et. al. Post-flight no reversals of the in-flight changes
      (negative aftereffects) were found. Instead, there was a general slowing down,
      which could be due to post-flight physical exhaustion.

PMID- 10591911
TI  - Three-dimensional organization of vestibular-related eye movements to off
      vertical axis rotation and linear translation in pigeons.
AB  - During linear accelerations, compensatory reflexes should continually occur in
      order to maintain objects of visual interest as stable images on the retina. In
      the present study, the three-dimensional organization of the vestibulo-ocular
      reflex in pigeons was quantitatively examined during linear accelerations
      produced by constant velocity off-vertical axis yaw rotations and translational
      motion in darkness. With off-vertical axis rotations, sinusoidally modulated eye
      position and velocity responses were observed in all three components, with the
      vertical and torsional eye movements predominating the response. Peak torsional
      and vertical eye positions occurred when the head was oriented with the lateral
      visual axis of the right eye directed orthogonal to or aligned with the gravity
      vector, respectively. No steady-state horizontal nystagmus was obtained with any
      of the rotational velocities (8-58 degrees /s) tested. During translational
      motion, delivered along or perpendicular to the lateral visual axis, vertical and
      torsional eye movements were elicited. No significant horizontal eye movements
      were observed during lateral translation at frequencies up to 3 Hz. These
      responses suggest that, in pigeons, all linear accelerations generate eye
      movements that are compensatory to the direction of actual or perceived tilt of
      the head relative to gravity. In contrast, no translational horizontal eye
      movements, which are known to be compensatory to lateral translational motion in
      primates, were observed under the present experimental conditions.

PMID- 10591912
TI  - Responses to spinal microstimulation in the chronically spinalized rat and their
      relationship to spinal systems activated by low threshold cutaneous stimulation.
AB  - We describe the responses evoked by microstimulation of interneuronal regions of
      the spinal cord in unanesthetized rats chronically spinalized at T10-T12. One to
      three weeks after spinalization, sites in the lumbar spinal cord were stimulated
      using trains of low current microstimulation. The isometric force produced by
      stimulation of a spinal site was measured at the ankle. Responses were reliably
      observed from stimulation of a region within the first 1250 microm from the
      dorsal surface of the spinal cord. These responses were clearly not due to direct
      motoneuronal activation and were maintained after chronic deafferentation. The
      force evoked by microstimulation and measured at the ankle varied smoothly across
      the workspace. Simultaneous stimulation of two sites in the spinal cord produced
      a response that was a simple linear summation of the responses evoked from each
      of the sites alone. Microstimulation generally produced a highly non-uniform
      distribution of response directions, biased toward responses which pulled the
      limb toward the body. Within these distributions there appeared to be two main
      types of responses. These different types of responses were preferentially evoked
      by microstimulation of different rostrocaudal regions of the spinal cord. This
      anatomical organization paralleled the spinal cutaneous somatotopy, as assessed
      by recording cutaneous receptive fields of neurons at sites to which the
      microstimulation was applied. This relationship was maintained after chronic
      deafferentation. The findings described here in the rat spinal cord in large part
      replicate those previously described in the frog.

PMID- 10591913
TI  - Bimanual coordination between isometric contractions and rhythmic movements: an
      asymmetric coupling.
AB  - Interactions between rhythmically moving limbs typically result in attraction to
      a limited number of coordination modes, which are distinguished in terms of their
      stability. In addition, the stability of coordination typically decreases with
      elevations in movement frequency. To gain more insight into the
      neurophysiological mechanisms underlying these stability characteristics, the
      effects of phasic voluntary muscle activation onto the movement pattern of the
      contralateral limb as well as onto the stability of interlimb coordination were
      examined. This was done in circumstances in which a minimal degree of movement
      elicited afferent information was available to mediate the coupling influences.
      The task involved rhythmic application of isometric torque by one hand, while the
      other hand was moving rhythmically with unconstrained amplitude. The effects of
      two levels of applied torque, two coordination patterns (inphase and antiphase),
      and two movement frequencies were determined, both at the behavioural level
      (movement kinematics and kinetics) and the neuromuscular level (EMG). The
      isometric applications of torque clearly influenced the muscle-activation profile
      and movement pattern of the other limb, affecting both temporal variability and
      amplitude. Surprisingly, there were no differences between the two coordination
      patterns or between the tempo conditions. As such, the results did not conform to
      the Haken-Kelso-Bunz model for rhythmic movement coordination. These data suggest
      that the archetypal differences in stability of rhythmic bimanual coordination
      are contingent upon a correspondence between the limbs in terms of their
      respective tasks. This interpretation is elaborated in terms of the role of
      sensory feedback and the functional specificity of motor unit recruitment in
      rhythmic interlimb coordination.

PMID- 10591915
TI  - Time course and temporal order of changes in movement kinematics during learning
      of fast and accurate elbow flexions.
AB  - Learning of a motor task, such as making accurate goal-directed movements, is
      associated with a number of changes in limb kinematics and in the EMG activity
      that produces the movement. Some of these changes include increases in movement
      velocity, improvements in end-point accuracy, and the development of a
      biphasic/triphasic EMG pattern for fast movements. One question that has remained
      unanswered is whether the time course of the learning-related changes in movement
      parameters is similar for all parameters. The present paper focuses on this
      question and presents evidence that different parameters evolve with a specific
      temporal order. Neurologically normal subjects were trained to make horizontal,
      planar movements of the elbow that were both fast and accurate. The performance
      of the subjects was monitored over the course of 400 movements made during
      experiments lasting approximately 1.5 h. We measured time-related parameters
      (duration of acceleration, duration of deceleration, and movement duration) and
      amplitude-related parameters (peak acceleration, peak deceleration, peak
      velocity), as well as movement distance. In addition, each subject's reaction
      time and EMG activity was monitored. We found that reaction time was the
      parameter that changed the fastest and that reached a steady baseline earliest.
      Time-related parameters decreased at a somewhat slower rate and plateaued next.
      Amplitude-related parameters were slowest in reaching steady-state values. In
      subjects making the fastest movements, a triphasic EMG patterns was observed to
      develop. Our findings reveal that movement parameters change with different time
      courses during the process of motor learning. The results are discussed in terms
      of the neural substrates that may be responsible for the differences in this
      aspect of motor learning and skill acquisition.

PMID- 10591914
TI  - Effects of intrathecal clonidine injection on spinal reflexes and human
      locomotion in incomplete paraplegic subjects.
AB  - We studied the effect of the intrathecal (i.t.) injection of clonidine (30, 60
      and 90 microg) on the polysynaptic spinal reflexes (PSR) elicited by electrical
      stimulation of flexor reflex afferents (FRA), monosynaptic reflex and gait of 11
      subjects with spinal cord injuries. The effect of clonidine administration on
      gait velocity, stride amplitude and duration was measured in eight subjects who
      were able to walk. Five subjects were able to walk after intrathecal injection of
      clonidine and three were not able to stand up. Three subjects improved their gait
      velocity after clonidine administration; one (S6) increased his stride amplitude;
      the two others decreased their cycle durations. The tibialis anterior seemed to
      be more regularly activated during gait. Spasticity was reduced dramatically
      (P<0.0001) after i.t. clonidine injection, but there was no statistically
      significant difference in the soleus H reflex (no effect on Hmax/Mmax). Clonidine
      administration decreased the amplitude of the early PSR (90-120 ms, N=4) and the
      threshold and maximal integrated EMG corresponding to the late response (140-450
      ms, N=7). This effect was dose dependent (30, 60 and 90 microg). Placebo
      injection (N=4) caused no change. The changes in spinal reflexes, with a large
      reduction in spasticity, no change in motoneurone excitability and a large
      decrease in PSR, suggest that clonidine acts at a premotoneuronal level, possibly
      by presynaptic inhibition of group II fibres. The increase in gait velocity in
      three subjects could have been due to reduced spasticity or activation of spinal
      circuitry.

PMID- 10591916
TI  - Effects of adrenalectomy and gonadectomy on sex and stress-induced differences in
      bicuculline-induced convulsions.
AB  - The effects of adrenalectomy, gonadectomy and combined adrenalectomy plus
      gonadectomy on the previously described sex-dependent anticonvulsive effect of
      swim stress were studied in rats. The convulsive signs (myoclonic twitch,
      generalized convulsions, tonic hindlimb extension) were produced by constant i.v.
      infusion of gamma-aminobutyric acid(A) (GABA(A)) antagonist bicuculline, which
      started 15 min after termination of swim stress (10-min swim at 18-19 degrees C).
      Adrenalectomy decreased the threshold doses of bicuculline producing the first
      myoclonic twitch and the onset of generalized convulsions only in females. In
      adrenalectomized females, but not in males, swim stress enhanced the threshold
      dose of bicuculline producing generalized convulsions, but, unlike in adrenal
      intact animals, it failed to enhance the dose of bicuculline producing tonic
      hindlimb extension. In gonadectomized stressed and unstressed animals all sex
      differences disappeared, and swim stress enhanced in both sexes only the
      threshold doses of bicuculline producing tonic hindlimb extension.
      Adrenalectomized plus gonadectomized animals displayed clear sex differences in
      doses of bicuculline necessary to produce all the convulsive signs. In the same
      animals swim stress postponed, especially in females, the onset of the first
      myoclonic twitch and generalized convulsions, but not the onset of tonic hindlimb
      extension. In summary, our results suggest that hormones of the adrenal and
      gonadal glands are only partly responsible for decreased susceptibility,
      especially of female rats, to the GABA(A) antagonist bicuculline. Moreover, they
      have demonstrated that stress produces a gender-specific anticonvulsive effect
      even in the animals completely deprived of steroid hormones of peripheral origin.

PMID- 10591917
TI  - Human motor-cortex oxygenation changes induced by cyclic coupled movements of
      hand and foot.
AB  - Near-infrared spectroscopy (NIRS) was used to assess human motor-cortex
      oxygenation changes in response to cyclic coupled movements of hand and foot.
      Using a highly sensitive NIRS instrument, we showed that it was possible to
      detect reproducible oxygenation patterns using single cycles (20 s) of easy and
      difficult association tasks. No significant differences in the time corresponding
      to the maximal changes in concentration of oxy- and deoxyhemoglobin ([O(2)Hb] and
      [HHb], respectively) were found during easy and difficult association as well as
      cycles. Only [O(2)Hb] showed a significantly higher value at the end of the
      difficult association during the first cycle. No significant differences were
      found for [O(2)Hb] and [HHb] in the other cycles. We conclude that NIRS is a
      useful addition to functional magnetic resonance imaging in investigating the
      time course of cortical activation.

PMID- 10591918
TI  - Do centrally programmed anticipatory postural adjustments in fast stepping affect
      performance of an associated "touche" movement?
AB  - Ensuring maximum speed in executing a sequence of two voluntary movements
      requires the second movement to be triggered only after some delay. This is due
      to the existence of a "relative refractory period." If the second movement is
      initiated during the refractory period, its speed decreases (movement time
      increases). In the present study we tested the existence of a refractory period
      during the execution of a sequence of movements involving both the upper and the
      lower limbs. More precisely, we examined whether the maximal speed of the touche
      fencing movement is affected by the anticipatory postural adjustments (APA)
      preceding a voluntary lunge. The touche and the lunge are similar to a pointing
      task and a stepping forward movement, respectively. touche consists of hitting a
      target with a foil at maximal velocity. The results show that (a) when the touche
      was initiated prior to the onset of the APA of the lunge, the maximal foil
      velocity remains similar to that of an isolated touche, and (b) when the touche
      is initiated during the development of the APA of the lunge, the maximal foil
      velocity is lower than in the isolated touche. Furthermore, the maximal foil
      velocity decreases with the temporal progression of the APA and reaches its
      minimal value when initiated at the time of voluntary lunge execution ('foot
      off'). The discussion suggests that the centrally programmed APA that are
      elicited in the stepping forward movement induces a refractory period which
      affects performance of the pointing task.

PMID- 10591919
TI  - Distal-proximal somatotopy in the human hand somatosensory cortex: a reappraisal.
AB  - The distal-proximal representation of the finger and palm in the first
      somatosensory cortex was reexamined. Somatosensory evoked magnetic fields (SEFs)
      were measured with a 37-channel first-order axial gradiometer system. Sensory
      stimulus comprising a 20-ms vibration at a frequency of 200 Hz was delivered to
      five successive sites in 3-cm increments along the distal-proximal direction over
      the volar surface of the right index finger and palm. Using a single dipole
      model, the sources and the signal strengths of the main peak (M50) of the SEFs
      were estimated. All of the sources were located in the 3b area. There were no
      statistically significant differences between the locations of dipoles evoked by
      stimulation of different sites. The results support those of our previous study
      using a 122-channel whole-head planar gradiometer system that orderly distal
      proximal representation of the hand, as described in monkeys, is blurred in the
      adult human somatosensory cortex.

PMID- 10591920
TI  - Transferrin receptors on the plasma membrane of cultured rat astrocytes.
AB  - It is generally accepted that transferrin receptor is located in the endothelial
      cells of the brain, but its existence in other brain cell types is less
      established. In this study, a [(125)I]transferrin binding assay was used to
      determine whether there is transferrin receptor on the membrane of cultured rat
      cortical astrocytes (type 1) in vitro. The results demonstrated that cortical
      astrocytes (type 1) in suspension attracted [(125)I]transferrin with a saturable
      and specific binding. Scatchard and Hill plot analysis showed that the
      dissociation constant (K(D)) of the binding was about 3.5x10(-8) M and the number
      of receptors was about 7.1x10(4)/cell. The Hill coefficient was 0.99, approaching
      1, indicating the absence of cooperativity. The receptor was specific both for
      rat and human transferrin. The binding of rat [(125)I]transferrin could be
      competitively and specifically inhibited by unlabeled iron-saturated rat and
      human transferrin, and no difference was found between interaction of rat or
      human transferrin with this receptor. The interaction of duck or camel
      transferrin with this receptor was found to be very weak. This study provides
      evidence for the presence of transferrin receptor on the plasma membrane of
      cultured rat brain astrocytes.

PMID- 10591921
TI  - Effects of visual feedback on manual tracking and action tremor in Parkinson's
      disease.
AB  - Visual feedback is one of the key elements in on-line control of smooth manual
      tracking. To in- vestigate the effects basal ganglia dysfunction have on visual
      feedback control, we have tested six advanced Parkinson's disease (PD) patients
      in comparison with normal controls using visually guided wrist tracking tasks.
      Tracking performance was assessed under three visual conditions: (1) both guiding
      target and movement cursor were displayed continuously; (2) the target display
      was turned off for the second half of each trial; or (3) the cursor display, but
      not the target, was turned off for the second half of each trial. Thus, for the
      second half of each trial under conditions 2 and 3, no visual feedback of the
      relationship between the target and the cursor was available. Results showed that
      although PD patients had significantly larger tracking errors than controls, and
      errors significantly increased in both PD patients and controls after withdrawing
      either visual cue, increases in tracking errors in PD were not significantly
      different from those in controls. Nor were any significant changes found in the
      frequency (6-8 Hz) or magnitude of the PD patient's action tremor after
      withdrawing visual feedback. These results suggest that on-line movement control
      of wrist tracking movements in advanced PD is not especially reliant on visual
      feedback. In conjunction with our previous study of multiple sclerosis (MS)
      patients, the present results confirm that the basal ganglia is less involved in
      visual guidance of smooth manual tracking than the cerebellar circuits.

PMID- 10591922
TI  - Radiography in osteoarthritis of the knee.
AB  - Osteoarthritis (OA) is a multifactorial process affecting cartilage and
      subchondral bone. Conventional radiographs are inexpensive and readily available.
      The increased knowledge with regard to interpreting weightbearing radiographs of
      the tibiofemoral joint and axial radiographs of the patellofemoral joint will
      enable these examinations to remain competitive techniques compared with more
      expensive and sophisticated methods, such as MR imaging, when investigating knee
      pain to establish the diagnosis and the severity of OA.

PMID- 10591923
TI  - The septic versus nonseptic inflamed joint: MRI characteristics.
AB  - OBJECTIVE: To differentiate the MR features of septic versus nonseptic inflamed
      joints. DESIGN AND PATIENTS: Thirty patients were referred for MRI with inflamed
      joints (19 were subsequently found to be septic and 11 nonseptic). At 1.5 T
      enhanced MRI five groups of signs related to joint space, synovium, cartilage,
      bone and peri-articular soft tissue respectively were assessed and compared
      between the septic and nonseptic groups. RESULTS: The prevalence of MRI findings
      in septic versus nonseptic joints (respectively) was as follows: effusion (79% vs
      82%), fluid outpouching (79% vs 73%), fluid heterogeneity (21% vs 27%), synovial
      thickening (68% vs 55%), synovial periedema (63% vs 55%), synovial enhancement
      (94% vs 88%), cartilage loss (53% vs 30%), bone erosions (79% vs 38%), bone
      erosions enhancement (77% vs 43%), bone marrow edema (74% vs 38%), bone marrow
      enhancement (67% vs 50%), soft tissue edema (63% vs 78%), soft tissue enhancement
      (67% vs 71%), periosteal edema (11% vs. 10%). The presence of bone erosions
      appeared to be an indicator for an infected joint (P=0.072); coexistence of bone
      marrow edema slightly improves the significance (0.068). A similar trend was
      obtained when combining bone erosions with either synovial thickening, synovial
      periedema, bone marrow enhancement or soft tissue edema (P=0.075). CONCLUSIONS:
      The combination of bone erosions with marrow edema is highly suggestive for a
      septic articulation; the additional coexistence of synovial thickening, synovial
      edema, soft tissue edema or bone marrow enhancement increases the above level of
      confidence. Similar to conventional radiography, the single sign that appeared to
      show a significant trend was the presence of bone erosions. However, no single
      sign or combination could either be considered pathognomonic or exclude the
      presence of a joint infection.

PMID- 10591924
TI  - A clinicopathologic study of transient osteoporosis of the hip.
AB  - OBJECTIVE: It has been proposed that transient osteoporosis of the hip (TOH) may
      represent the early reversible phase of osteonecrosis of the femoral head (ON).
      The purpose of this study was to investigate the clinicopathologic
      characteristics of three cases of TOH. DESIGN AND PATIENTS: A bone biopsy was
      performed on three patients who had been diagnosed as having TOH based on the
      clinical course, radiograph, bone scintigram, and MR images. The biopsy specimens
      were studied histopathologically by light and electron microscopy. RESULTS: The
      most characteristic feature of TOH was focal areas of thin and disconnected bone
      trabeculae covered by osteoid seams and active osteoblasts. The surrounding bone
      marrow tissue showed edematous changes and mild fibrosis, frequently associated
      with vascular congestion and/or interstitial hemorrhage. No osteonecrotic region
      was observed in either the bone trabeculae or the bone marrow tissue. All
      patients have improved clinically and in the 3.5-9 years of follow-up have shown
      no evidence of ON. CONCLUSIONS: This study supports the concept that transient
      osteoporosis of the hip is a distinct entity.

PMID- 10591925
TI  - MR imaging after therapeutic injection of the subacromial bursa.
AB  - OBJECTIVE: As a therapeutic injection into the subacromial bursa (SAB) is
      commonly performed for impingement syndrome, it is important to know whether this
      fluid can be retained for a period of time and cause confusion with a pathologic
      collection of fluid. This study identifies and describes the appearance of recent
      subacromial injection using MR imaging, and the appearance of a potential
      complication. DESIGN AND PATIENTS: Fourteen asymptomatic shoulders were studied
      with MR imaging using fast spin echo T2-weighted imaging (1.5 T) prior to
      injection with 7 cm(3) of xylocaine. Four shoulders had subacromial fluid and
      were eliminated from the study. The remaining 10 (9 men, 1 woman; age range 27-36
      years, average age 33 years) were then re-imaged immediately, and at 6, 12 and 24
      h after the injection or until fluid resolved. Each set of images was reviewed
      for the presence of fluid in the SAB and for additional abnormalities. RESULTS:
      Fluid was identified in all subjects in the SAB in the immediate, 6 and 12 h post
      injection images. At 24 h, fluid was not identified within the SAB in eight of 10
      patients. In one patient fluid resolved in 48 h. The other continued to
      demonstrate fluid in the SAB and in the joint as well as abnormal signal in the
      infraspinatus muscle from a presumed myositis. Imaging was performed up to 10
      days after the injection in this patient. CONCLUSIONS: It is known that fluid
      identified in the SAB without evidence of a cuff tear may be due to bursitis.
      However, if MR imaging is performed within 24 h of injection, the presence of the
      fluid may be iatrogenic. In addition, the history of recent therapeutic injection
      is very important as complications such as myositis can occur as a result of the
      injection. Knowledge of injection prior to imaging is vital for accurate
      interpretation of MR shoulder examinations.

PMID- 10591926
TI  - Three-dimensional computed tomography in the assessment of congenital scoliosis.
AB  - OBJECTIVE: Patients with congenital vertebral anomalies frequently are afflicted
      with kyphoscoliosis, with the curvatures often being severe and progressive.
      Spinal fusion almost always is the treatment of choice in such patients. This
      report examines the use of three-dimensional computed tomography (3D CT) in the
      preoperative investigation of patients with congenital scoliosis. DESIGN AND
      PATIENTS: Twelve spinal CT examinations on 11 pediatric patients with congenital
      scoliosis underwent image processing to produce 3D images. The 3D images were
      compared with both the axial sections from the CT examinations and multiplanar
      reformations with regard to the detection of malformations liable to cause
      progression of scoliosis (i. e., hemivertebrae and unsegmented bars). RESULTS AND
      CONCLUSIONS: In six of the 12 cases, the 3D images provided improved depiction of
      the congenital anomalies and their interrelationships compared with planar CT
      images. This work suggests that 3D CT can be a useful tool in the assessment of
      patients with congenital scoliosis.

PMID- 10591927
TI  - Radiographic evaluation of the lumbosacral disc height.
AB  - OBJECTIVE: To establish criteria for the radiographic evaluation of narrowing of
      the L5-S1 disc height, which varies widely with transition of the L5 vertebra.
      DESIGN AND PATIENTS: Nondegenerated disc heights of L3-4 to L5-S1 and the
      thickness and length of the L5 transverse process were measured on plain
      radiographs of the lumbar spine in 166 outpatients, aged 18-35 years (mean 26.3
      years), in whom at least the L3-4 and L5-S1 discs both showed normal signal
      intensity on magnetic resonance imaging. The level of the iliac crest was
      recorded semiquantitatively. The disc height was expressed as a percentage of the
      L3-4 disc height, namely "relative disc height". The ratio of disc height to the
      sagittal diameter of the overlying vertebral body was termed the "disc height
      index". RESULTS AND CONCLUSION: The relative disc height and disc height index of
      L5-S1 showed strong negative correlations with two anatomic variables, which were
      the relative thickness of the transverse process and the level of the iliac crest
      (P<0.0001). The results of linear regression analysis suggest that narrowing of
      the L5-S1 disc height can be evaluated on plain radiographs alone in relation to
      these anatomic variables.

PMID- 10591928
TI  - Malignant chondroblastoma presenting as a recurrent pelvic tumor with DNA
      aneuploidy and p53 mutation as supportive evidence of malignancy.
AB  - We report a rare case of malignant chondroblastoma, which presented in a 47-year
      old man as a recurrent tumor, 18 years following wide excision of a typical
      pelvic chondroblastoma. Radiologic studies of the recurrent tumor showed a large,
      lytic, destructive lesion of the right pelvic bones and femur, with a pathologic
      fracture of the latter, a large pelvic soft tissue mass, and multiple pulmonary
      metastases. Biopsy tissue showed typical features of chondroblastoma, but also
      increased nuclear atypia, hyperchromasia, and pleomorphism, compared to the
      original tumor, and, most significantly, abnormal mitotic figures.
      Immunohistochemical studies of the recurrent tumor revealed p53 mutation and
      extensive proliferative activity, and flow cytometric studies showed DNA
      aneuploidy, none of which was present in the original tumor. The patient received
      chemotherapy and radiation, but died of disease eight months after presentation.
      We also review chondroblastoma in general, to assign this unusual lesion to a
      tumor subtype.

PMID- 10591929
TI  - Ebb and flow rickets in a premature infant: the Afghan turban sign.
AB  - The pattern of alternating dense and lucent bands, with straight outer edges, at
      the youngest metaphysis of long bones, the "Afghan turban" sign, occurs when
      incompletely treated rickets has recurred and been retreated. Recognition of
      this, and other, rickets patterns allows the radiologist to influence treatment,
      as described in a very low birth weight infant.

PMID- 10591930
TI  - Locking of metacarpophalangeal joints in a patient with acromegaly.
AB  - A 39-year-old man with acromegaly exhibited locking of metacarpophalangeal (MCP)
      joints of both index fingers. Large osteophytes were found at the metacarpal
      heads by radiography and computerized tomography (CT). Magnetic resonance (MR)
      images revealed hypertrophy of volar plates. We suggest that these characteristic
      acromegalic features caused locking of MCP joints. Surgery was required on one of
      the joints to release the locking.

PMID- 10591931
TI  - Intra-articular entrapment of the medial collateral ligament: radiographic and
      MRI findings.
AB  - Displacement of the medial collateral ligament (MCL) into the medial knee joint
      is an extremely rare finding associated with MCL tears, and is easily diagnosed
      on magnetic resonance imaging. A case of intra-articular interposition of the MCL
      during a severe knee injury is presented. A radiolucent "fat stripe" sign and
      adjacent skin dimpling on radiographs may be relatively specific indicators of
      this injury.

PMID- 10591932
TI  - Non-traumatic necrosis of the femoral head.

PMID- 10591933
TI  - The morphometry of the coracoid process - its aetiologic role in subcoracoid
      impingement syndrome.
AB  - Anatomical morphometric studies of the coracoid process and coraco-glenoid space
      were carried out on 204 dry scapulae. No statistically significant correlations
      were found between length, or thickness of the coracoid process, prominence of
      the coracoid tip, coracoid slope, coraco-glenoid distance, or position of the
      coracoid tip with respect to the uppermost point of the glenoid. These anatomical
      characteristics were independent of the dimensions of the scapulae. Three
      configurations of the coraco-glenoid space were identified. Type I configuration
      was found in 45% of scapulae and Type II and Type III, in 34% and 21% of
      specimens, respectively. The lowest value of the coraco-glenoid distance were
      seen in Type I scapulae. Morphometric characteristics which might predispose to
      subcoracoid impingement were found in 4% of Type I scapulae. A total of 27
      scapulae, nine with each type of configuration were submitted to CT scanning.
      Scapulae with a Type I configuration were found to have low values for the coraco
      glenoid angle and coracoid overlap, which are known to be associated with a short
      coraco-humeral distance. Subjects with a Type I configuration, and severe
      narrowing of the coraco-glenoid space, appear to be predisposed to coraco-humeral
      impingement. These morphometric characteristics may be easily evaluated on CT
      scans.

PMID- 10591934
TI  - Blood flow of the gluteus medius muscle. An animal study.
AB  - We investigated the effects of subperiosteal dissection on blood flow in the
      gluteal medius muscle in adult rabbits using the hydrogen washout technique.
      After the control blood-flow rate was determined, 8 rabbits were separated into 2
      groups according to the direction of the dissection. The gluteal medius muscle
      was dissected from the iliac crest in the proximal-distal direction in 10 hips.
      In another 6 hips, the greater trochanter was osteomised and the gluteus medius
      muscle was dissected from the ilium in the distal-proximal direction. Dissection
      of the middle third of the gluteus medius muscle caused the most significant
      reduction in blood flow, more than 50% in both groups. This result indicates that
      minimising damage to the mid-portion of the gluteus medius muscle is important
      for reducing the incidence of post-operative complications.

PMID- 10591935
TI  - The use of disharmonic motion curves in problems of the cervical spine.
AB  - Cervical spine motion was investigated by three-dimensional electrogoniometry in
      257 asymptomatic volunteers and in 32 patients with cervical disc hernia or
      whiplash syndrome. Maximal ranges of main and coupled motions were considered.
      Motion curves were analysed qualitatively and using fitting of sixth degree
      polynomials. Motion ranges obtained were in agreement with previous observations.
      Significant differences between patients and volunteers concerned several primary
      and coupled components but not all. Qualitatively, patients displayed less
      harmonic curves, with irregularities and plateau-like appearances. Root mean
      square differences between data and fit were significantly modified in patients.
      Although cervical spine motion ranges may remain within normal limits in
      patients, motion patterns were altered qualitatively and quantitatively. Motion
      pattern analysis might prove a useful discrimination parameter in patients in
      whom anatomical lesions are not clearly identifiable.

PMID- 10591936
TI  - Neurological complications of spinal tuberculosis in children.
AB  - Neurological complications of thoracic and lumbar spinal tuberculosis were
      studied in 32 patients under the age of 16 years. The majority had lesions
      involving three or more vertebral bodies. Paraplegia occurred in 8 patients and
      was always associated with bladder and bowel dysfunction. Lesions located at T4/5
      were most commonly accompanied by paraplegia. Deterioration of the neurological
      status was related to the degree of spinal stenosis, whereas the degree of
      kyphosis was of less importance. Radiculopathy is rare in children with Pott's
      disease.

PMID- 10591937
TI  - Early diagnosis of stress fracture of the lumbar spine in athletes.
AB  - Thirty-three athletes complaining of back pain of more than 1 months' duration
      and with normal radiography of the lower spine were all studied by scintigraphy
      and in 24 of them with single photon emission computerized tomography. A stress
      fracture was considered present if localized increased uptake was seen at a
      vertebral level. Scintigraphy showed increased uptake in 17 of 33 patients and
      single photon emission computerized tomography in 16 of 24 patients.

PMID- 10591938
TI  - Trapeziectomy for basal thumb joint osteoarthritis: 3- to 19-year follow-up.
AB  - A consecutive series of 40 trapeziectomies in 30 patients with basal thumb joint
      osteoarthritis was reviewed. Sixteen thumbs had pan-trapezial and 24 thumbs
      trapeziometacarpal osteoarthritis. Simple excision without soft tissue
      interposition was performed by the same surgeon using an identical surgical
      technique. Twenty-eight patients were female (mean age 57 years) with a mean
      follow-up of 11 (3-19) years. Twenty-eight patients were satisfied with their
      operation, with 26 thumbs being pain free. Thumb pinch strength was improved by
      40% compared to preoperative values, but still remained 22% weaker than the non
      operated side.

PMID- 10591939
TI  - Stem length and canal filling in uncemented custom-made total hip arthroplasty.
AB  - We reviewed 60 custom-made femoral components of two different lengths : 125 mm
      (group A) and 100 mm (group B), in order to investigate the relationship between
      stem length and canal filling in uncemented custom-made total hip arthroplasty.
      There were no statistical differences between the two groups in age, gender,
      height, body weight, canal flare index, or bowing angle of the femur.
      Postoperatively there was no statistical difference between the two groups in the
      proximal canal filling, but significant difference in the distal canal filling
      (75.5% vs 85.8% on the anteroposterior view and 76.0% vs 82.5% in the lateral
      view, P<0.001). The distal canal filling inversely correlated with the ratio of
      the proximal portion and the distal portion of the stem curvature on the lateral
      view (lateral curve ratio of the stem, P=0.002). We conclude that superior
      filling at both the proximal and the distal levels can be obtained by using 100
      mm custom made components with a small lateral curve ratio.

PMID- 10591940
TI  - Computer assisted implantation of the femoral stem in THA - an experimental
      study.
AB  - Fourteen femoral stems were implanted either manually by an experienced surgeon
      or by a robot in fresh human cadaveric femora. The neck-shaft angle, the
      anteversion, the length of the femoral neck and the gap between stem and bone was
      measured in each specimen. Implantation by robot showed higher precision in
      reconstructing the true anatomic situation as well as providing a better press
      fit.

PMID- 10591941
TI  - Bone-patellar tendon-bone reconstruction of the anterior cruciate ligament. A
      long-term comparison of early and late repair.
AB  - Ninety-one patients were assessed 5-9 years after an anterior cruciate ligament
      reconstruction (bone patella-tendon bone autograft). Forty-eight patients had
      been treated within 6 weeks of the injury (Group I) and 43 patients more than 3
      months after the injury (Group II). 73 patients had either a normal or nearly
      normal final outcome. The mean Lysholm score was 82 and the mean Marshall score
      was 42. Eighty nine patients had normal or nearly normal stability in the
      operated knee when compared to the contralateral joint. In none of these results
      was there any significant difference between the groups. Results of functional
      and of isokinetic strength tests, as well as the presence of anterior knee pain,
      were also similar in both groups. However, patients with early reconstruction had
      fewer degenerative changes in the tibio-femoral joint and were more satisfied
      with the result. They also returned to their pre-injury level of sports activity
      more often than those patients in the late reconstruction group.

PMID- 10591942
TI  - Discoid lateral menisci in older patients. A radiographic study of 21 cases.
AB  - Twenty-three knees of 21 patients over 40 years of age with discoid lateral
      menisci were examined by radiography. The mean age of the patients was 59.7 years
      (range: 40-78 years). No patient had symptoms before the age of 40 and only 12
      knees gave symptoms from the lateral compartment, although tears of a discoid
      lateral meniscus were diagnosed by arthrography in 21 of the 23 knees. Varus
      inclination occurred more frequently than valgus inclination. Subchondral bone
      sclerosis was more common in the medial compartment. However, high incidences of
      marginal osteophytes in the lateral compartment and morphological anomalies
      (cupping or flattening) of the lateral tibial plateau were revealed by
      radiography.

PMID- 10591943
TI  - Distal femoral fractures after knee arthroplasty.
AB  - In seven patients who sustained eight distal femoral fractures following knee
      arthroplasty all fractures were treated operatively. Seven with open reduction
      internal fixation and one with external fixation. Seven of eight fractures had an
      unsatisfactory result. This was due not only to bone quality and fracture
      comminution, but also to technical problems and choice of implant. Revision
      surgery is often required.

PMID- 10591944
TI  - Replacement arthroplasty for hallux rigidus. 21 patients with a 2-year follow-up.
AB  - 21 patients underwent replacement arthroplasty of the metatarsophalangeal joint
      of the great toe. The indication for surgery was hallux rigidus in 16 patients
      and failed resection arthroplasty in 5 patients. The minimum follow-up period was
      24 months. Clinical review showed an increased range of passive dorsiflexion from
      10 degrees to 50 degrees postoperatively. 17 patients reported less pain or no
      pain and activity levels that were increased or maintained. Functional
      complications such as lack of toe purchase (n=5) or metatarsalgia (n=4) were
      successfully treated with orthotics.

PMID- 10591945
TI  - Transient osteoporosis of the hip.
AB  - We report four cases of transient hip osteoporosis studied between 1995 and 1997.
      All patients were men. The diagnosis was based on clinical symptoms, absence of
      abnormal laboratory tests, increased uptake in the femoral head and neck on Tc-99
      bone scans and magnetic resonance imaging showing Oedema of the bone marrow. In
      three patients radiographs showed osteopenia of the head and neck of the involved
      femur, whereas no major radiographic changes were seen in the fourth patient. The
      clinical symptoms lasted 7 months and there was no recurrence after 8-24 months'
      follow-up.

PMID- 10591946
TI  - Tetraparesis associated with ossification of the posterior longitudinal ligament
      of the cervical spine.
AB  - This is a case report of tetraparesis associated with extraordinarily severe
      ossification of the posterior longitudinal ligament (OPLL) of the cervical spine.
      There was no history of trauma. The object of this paper is to show that OPLL can
      progress relentlessly to a nearly complete quadriplegia even without trauma, but
      that adequate decompression can produce almost complete recovery.

PMID- 10591947
TI  - Prevention of skin and soft tissue entrapment in tibial segment transportation.
AB  - We report of a ten year old patient with soft tissue damage and bone defect of
      the tibia as a sequel of osteomyelitis. After excision and stabilization with an
      Ilizarov fixateur segment transportation was started. In order to avoid skin and
      soft tissue entrapment in the docking region, we used a metal cage as a space
      provider, which was shortened as segment transportation progressed. To our
      knowledge this simple method has not been described so far.

PMID- 10591949
TI  - [Cytophotometric investigations in recurrent gliomas: correlation of DNA
      parameters with WHO-grade, proliferation index and recurrence-free interval].
AB  - DNA-cytophotometry is one of the methods that may contribute to a more precise
      evaluation of the biological behaviour of tumours in addition to the WHO
      classification. In this study 121 tumour specimens of 50 patients suffering from
      gliomas with one or up to three recurrencies were investigated. In all cases the
      histological type and WHO-grade and the Ki-67/MIB1 labeling index were
      determined. DNA cytophotometry was performed after single cell preparation on
      Feulgen-stained preparations, and the following parameters were calculated:
      stemline ploidy, 5c-exceeding rate, and 2c-deviation index. Statistical
      evaluation revealed a highly significant correlation between recurrence-free
      interval and WHO-grade only. The DNA parameters, however, furnished additional
      information about increasing genetic instability in the majority of the
      recurrencies independently of changes in the WHO-grade. They thus seem to be
      useful as additional parameters for the determination of glioma progression.

PMID- 10591950
TI  - [Chondroid lipoma. Clinicopathological, immunohistochemical, and ultrastructural
      analysis of six cases of a distinct entity in the spectrum of lipomas].
AB  - A series of six cases of chondroid lipoma is reported in this paper. The age of
      the patients, four women and two men, ranged from 34 to 75 years. Four tumours
      arose in the lower and two in the upper extremities between 4.5 and 8 cm in size.
      Whereas two neoplasms were located in the subcutis, four lesions were seen in
      perifascial or intramuscular tissues. Histologically, all neoplasms were
      encapsulated and characterized by a somewhat lobular growth pattern. The
      neoplasms were composed of mature adipocytes, uni - and multivacuolated
      lipoblasts, and nests and strands of cells reminiscent to hibernoma cells or
      chondrocytes. Immunohistochemically and ultrastructurally the lipogenic nature of
      the latter type of cells was confirmed. Interestingly, focal immunopositivity of
      tumour cells for cytokeratin was found in two cases. Tumour cells were set in a
      myxohyaline matrix showing different degrees of degeneration. Chondroid lipoma
      represents a distinct entity in the spectrum of lipomatous lesions and has to be
      distinguished from benign and malignant neoplasms (extraskeletal chondroma,
      hibernoma, lipoblastoma, chondrolipoangioma, myoepithelioma, myxoid/round cell
      liposarcoma, and extraskeletal myxoid chondrosarcoma). Because they are easily
      misdiagnosed as malignant tumours, familiarity with the features of chondroid
      lipoma is of practical importance to avoid an overtreatment.

PMID- 10591951
TI  - [Metaplastic meningioma with cartilaginous differentiation].
AB  - A meningioma with cartilaginous areas is described. The tumour arose in the
      region of the right sphenoid wing in a 74-year-old woman. Histologically, it
      showed large areas of a typical meningothelial meningioma, among which numerous
      cartilaginous islands and some chondroid regions, obviously of intermediate
      (meningothelial/cartilaginous) differentiation, could be seen. Cartilaginous
      tumour areas showed lower MIB1-labelling indices than typical meningioma regions,
      where an increased proliferative activity was seen focally. The current WHO
      classification lists such tumours as metaplastic meningiomas, reflecting the
      potential of meningioma cells for mesenchymal differentiation. Metaplastic
      meningiomas may show different metaplasias (xanthomatous, osseous, lipomatous,
      cartilaginous, etc.). Extensive cartilaginous metaplasias are very uncommon.
      Identification of typical meningioma areas is the key for the diagnosis of this
      meningioma variant.

PMID- 10591952
TI  - [Polyvinylpyrrolidone deposits in the pleura].
AB  - We report on the case of a 45-years old woman with repeated pleural effusions
      lasting for 2 years. She had a history of breast carcinoma 6 years ago, which was
      treated by breast amputation and radiation. After repeated histological and
      cytological examinations no tumorous compromise of the pleura or other cause for
      the effusions could be found. A pleural resection was performed. On the
      histological and electron microscopical examination deposits of a foreign
      substance were found, which was identified as polyvinylpyrrolidone. This
      substance was obviously introduced in the pleural cavity by the attempts to treat
      the effusions by pleurodesis with Diclofenac and Tetracycline (Vibravenos). The
      diagnosis is suggested by the histological findings, but it must be confirmed by
      anamnesis, also for PVP deposits in other organs.

PMID- 10591953
TI  - [Malignant epithelioid hemangioendothelioma of the liver - a very rare tumor in
      children].
AB  - We report on a 12-year old boy suffering from malignant epithelioid
      hemangioendothelioma of the liver, which is a very rare tumor in childhood. The
      tumor was detected by ultrasound examination at the age of 10 and appeared at
      that time as a solitary intrahepatic nodular lesion. During the following 2 years
      multiple nodular lesions developed in both hepatic lobes. There were neither any
      suspect anamnestic findings nor abnormal clinical or laboratory data. The tumor
      showed the typical histomorphological, immunohistochemical, and ultrastructural
      features of this entity, which is usually seen in older patients. We investigated
      proliferative activity, apoptotic regulation, and expression of VEGF and VEGF
      receptor flk-1 by means of immunohistochemical techniques. According to the known
      slow growth activity of these tumors we found only a few Ki-67 positive tumor
      cells. We did not detect any apoptotic cells using TUNEL technique. The positive
      immunoreaction of the tumor cells with antibodies against VEGF and VEGF-receptor
      flk-1 may indicate the regulation of tumor growth by angiogenetic factors. We
      present our findings together with a summary of the most important publications
      of recent years concerning these tumors.

PMID- 10591954
TI  - [Malakoplakia of the colon].
AB  - We report on a 62-year-old female patient with melena in which polypoid lesions
      of the cecum were discovered endoscopically. Histological examination of mucosal
      biopsies revealed an inflammatory process with lots of histiocytes and so-called
      Michaelis-Gutmann bodies, leading to the diagnosis of a malakoplakia of the
      colon. No other organs were found affected. In the course of an antibiotic
      therapy, there was no melena detectable over a period of six months.
      Malakoplakia, an inflammation usually affecting the urogenital tract, is rarely
      found in the colon, with only 35 cases published until now. It is frequently
      associated with other diseases like neoplastic or inflammatory disorders, immune
      defect syndromes or heroin abuse. This spectrum is expanded by our report in
      which a long-standing alcohol abuse was found as an attendant disease.

PMID- 10591955
TI  - [Acute appendicitis caused by pregnancy-associated ectopic decidua. Case report
      and discussion of pathogenesis].
AB  - The occurrence of pregnancy-associated ectopic decidua is a well-documented
      phenomenon. It has been observed most often in the ovaries, uterus, and cervix.
      An extragenital localization is less frequent and usually an asymptomatic,
      incidental finding. We report on a 32-year-old woman in her third trimester of
      pregnancy who developed acute appendicitis caused by ectopic decidua. This case
      illustrates a rare differential diagnosis of acute appendicitis and discusses the
      pathogenesis of pregnancy-associated ectopic decidua in such cases.

PMID- 10591956
TI  - [Primary osteosarcoma of the liver. Case report and literature review].
AB  - Primary sarcomas of the liver are rare. Most of them are angiosarcomas often
      related to exposure to thorotrast or polyvinyl chloride. We report a case of
      primary osteosarcoma of the liver in a 72-year-old man and compare it with the
      seven cases from the literature

PMID- 10591957
TI  - [Restrictive dermopathy].
AB  - Restrictive dermopathy is a rare, fatal, autosomal recessive, congenital skin
      disease. Rigidity of translucent thin skin, which is thus highly vulnerable and
      tears, spontaneously causes intra-uterine fetal akinesia or hypokinesia
      deformation sequence (FADS), characteristic dysmorphic facies with fixed open
      mouth in O position, and generalized joint contractures (arthrogryposis).
      Polyhydramnios and pulmonary hypoplasia are distinctive manifestations, leading
      to respiratory insufficiency and premature delivery at about 31 weeks of
      gestation. We report on a case of a prematurely born infant who presented with
      the typical morphological features and describe the light- and electron
      microscopical findings as described in the literature.

PMID- 10591958
TI  - [Laudatio for Dr. med. Wolfgang Oemichen on the occasion of becoming an honorary
      member of the Professional Society of German Dermatologists 28 May in Jena].

PMID- 10591959
TI  - [Rapid biopsy diagnosis per "telepathology". Risk of transgressing specialty
      boundaries].

PMID- 10591960
TI  - [ [In Process Citation]

PMID- 10591961
TI  - [ [In Process Citation]

PMID- 10591962
TI  - [ [In Process Citation]

PMID- 10591963
TI  - [ [In Process Citation]

PMID- 10591964
TI  - Analysis of strains of Saccharomyces cerevisiae with amino acid substitutions in
      the Cu(A)-binding region of subunit II of cytochrome c oxidase.
AB  - Cytochrome c oxidase accepts electrons from cytochrome c and transfers them to
      oxygen to form water. Electrons enter the complex through the Cu(A) site, formed
      by two copper atoms bound to mitochondrially encoded subunit II. The effect of
      amino-acid alterations in one of the Cu(A) ligands and in an amino acid adjacent
      to another of the ligands in the yeast enzyme is examined. Substitution of
      tyrosine for the Cu(A) ligand, cysteine 221, completely abolishes enzyme
      activity. In addition, 19 independent revertants of this mutant yeast strain
      recover function by restoring the cysteine codon. Replacement of a non-conserved
      glycine at position 228 by valine, adjacent to the Cu(A)-ligand histidine 229,
      virtually blocks enzyme activity. Activity is restored by inserting alanine or
      phenylalanine at position 228 or by amino-acid substitutions at nearby codons.
      Our results demonstrate that the Cu(A) ligand appears to be essential for enzyme
      function while other residues in the copper-binding region are less functionally
      constrained.

PMID- 10591965
TI  - Analysis of the genes activated by the FLO8 gene in Saccharomyces cerevisiae.
AB  - It is thought that the FLO8 gene encodes a transcriptional activator of the
      dominant flocculation gene FLO1 in Saccharomyces cerevisiae. To determine other
      genes which are regulated by FLO8, a detailed comparison of the transcripts from
      the FLO8 and Deltaflo8 strains was carried out. In addition to the FLO1 gene, it
      was found that transcription of the FLO11 and STA1 genes is positively regulated
      by FLO8. In flo8 strains, not only transcripts of the FLO11, STA1, and FLO1 genes
      but also invasive growth, extracellular glucoamylase production, and flocculation
      were undetected. From these results, it is suggested that FLO8 regulates these
      characteristics via the transcriptional regulation of the FLO11, STA1, and FLO1
      genes.

PMID- 10591966
TI  - A Pichia pastoris VPS15 homologue is required in selective peroxisome autophagy.
AB  - Methylotrophic yeasts contain large peroxisomes during growth on methanol. Upon
      exposure to excess glucose or ethanol these organelles are selectively degraded
      by autophagy. Here we describe the cloning of a Pichia pastoris gene (PpVPS15)
      involved in peroxisome degradation, which is homologous to Saccharomyces
      cerevisiae VPS15. In methanol-grown cells of a P. pastoris VPS15 deletion strain,
      the levels of peroxisomal marker enzymes remained high after addition of excess
      glucose or ethanol. Electron microscopic studies revealed that the organelles
      were not taken up by vacuoles, suggesting that PpVPS15 is required at an early
      stage in peroxisome degradation.

PMID- 10591967
TI  - Recombinational landscape across a 650-kb contig on the right arm of linkage
      group V in Neurospora crassa.
AB  - We have established a 650-kb walk spanning the sp to ure-1 interval on Neurospora
      crassa linkage group V. Loci covered by the walk are, from proximal to distal,
      sp; rec-2; ure-2; DNA polymerase delta; am; gul-1; ace-5; and ure-1. We have
      found extensive DNA polymorphism in this region and used this to examine the
      recombinational landscape. Crossovers are not evenly distributed over the region
      covered by the contig.

PMID- 10591968
TI  - Transfer of Neurospora kalilo plasmids among species and strains by
      introgression.
AB  - There are four different variants of the kalilo "family" of linear mitochondrial
      plasmids. This family is found in several heterothallic species and one
      pseudohomothallic species of Neurospora, as well as in one homothallic species of
      Gelasinospora. The mode of dispersal of these plasmids is not known. Horizontal
      transmission has proved difficult to demonstrate. Another possibility is transfer
      by introgression, and this is modelled in the present paper. We have used
      introgression and subsequent heterokaryosis to successfully transfer the LA
      kalilo plasmid from a Haitian strain of Neurospora crassa to the standard Oak
      Ridge N. crassa background, the LA-kalilo plasmid from the pseudohomothallic
      Neurospora tetrasperma to N. crassa, and the kalilo plasmid from N. crassa to N.
      tetrasperma. Thus, introgression is shown to be a possible avenue of dispersal
      between species. The recipient strains were all senescent but the mechanism of
      this senescence is not known. It could be caused by the plasmids, but if so the
      mechanism is novel since plasmid/mtDNA junction fragments of the type found in
      the standard mode of mtDNA insertion could not be detected. However, mtDNA
      changes were observed in the senescent recipients.

PMID- 10591969
TI  - Characterisation of the nitrite reductase gene (NII1) and the nitrate
      assimilation gene cluster of Stagonospora (Septoria) nodorum.
AB  - By sequencing downstream of the cloned nitrate reductase gene (NIA1) in the
      phytopathogenic fungus Stagonospora (Septoria) nodorum, a second open reading
      frame was found. Further analysis revealed this to be the nitrite reductase gene
      (NII1). Both genes are transcribed in the same direction, and are separated by an
      intergenic region of 829-bp. The coding sequence of NII1 is interrupted by three
      small introns and corresponds to a predicted protein of 1141 amino acids in
      length. Consensus binding sites for regulatory proteins are present in the
      promoter region of NII1. There is no indication, however, from hybridisation or
      sequence analysis that the nitrate transporter gene is closely associated with
      the NIA1-NII1 cluster, as has been found for a number of fungi.

PMID- 10591970
TI  - Intra-specific and inter-specific conservation of mating-type genes from the
      discomycete plant-pathogenic fungi Pyrenopeziza brassicae and Tapesia yallundae.
AB  - In previous work, four genes involved in mating-type determination were cloned
      from reference strains of Pyrenopeziza brassicae; three genes, PAD1, PMT1, and
      PHB1 (re-named henceforth as MAT-1-1, MAT-1-4, and MAT1-3, respectively), are
      encoded by the MAT-1 idiomorph, and one gene, PHB2 (re-named MAT-2), by the
      corresponding MAT-2 idiomorph. To assess MAT gene organisation within field
      populations of P. brassicae, 30 field-isolates of both mating-types from
      different geographical locations were analysed by PCR using primers designed for
      the MAT genes of P. brassicae. The results indicate that mating-type gene
      structure and organisation within these isolates is conserved and is consistent
      with the mating-type designations established by crossing experiments. The four
      P. brassicae MAT genes were then used as probes against gel blots of the genomic
      DNA of a discomycete Tapesia yallundae from the same family (Dermateaceae, order
      Helotiales) and one, Ascobolus stercorarius, from a distantly related family
      (Ascobolaceae, order Pezizales), in order to determine whether P. brassicae MAT
      gene homologs were present. MAT-specific hybridisation signals were obtained with
      T. yallundae using all four probes. In particular, MAT-1 DNA of T. yallundae gave
      a strongly hybridising signal with MAT-1-4 (PMT1), a putative metallothionein
      gene found in the P. brassicae MAT-1 idiomorph but not in any other MAT idiomorph
      examined to-date. No MAT-specific hybridisation was obtained with A.
      stercorarius. A fragment of the MAT-2 gene of T. yallundae was obtained by PCR
      using degenerate primers designed to amplify the high-mobility group (HMG) domain
      present in other ascomycete MAT genes. Sequencing of this PCR product revealed
      similarities to MAT HMG domains from other ascomycetes with the greatest degree
      of similarity exhibited with P. brassicae. The T. yallundae HMG-DNA sequence was
      shown to co-segregate with mating type (MAT-2) in progeny from a sexual cross.

PMID- 10591971
TI  - Diversity within natural progenies of the grapevine dieback fungus Eutypa lata.
AB  - The diversity within 16 natural progenies of the grapevine dieback fungus, Eutypa
      lata, was investigated by sampling single-ascospore isolates mainly in France and
      using random amplified polymorphic DNA (RAPD) markers, vegetative compatibility
      (VC), and pathogenicity testing. The combination of RAPD and VC data identified
      each isolate as a unique genotype within each progeny. Only three RAPD haplotypes
      did not cluster within the expected groups, i.e. the ascospore families. Within
      each set of clustering haplotypes, Mendelian 1:1 ratios for absence and presence
      were observed for RAPD markers, indicating that each progeny was the result of a
      biparental cross. Only one mycelium was obtained when isolation was performed
      from the discolored wood sustaining the perithecial stroma. This mycelium was
      identified as a likely parent of the corresponding progeny by RAPD analysis. The
      level of diversity measured by the average distance between haplotypes calculated
      from RAPD data, the percentage of vegetatively compatible pairs and the range of
      pathogenicity appeared similar between all but one progeny, indicating that
      crosses occurred within a random-mating population. All the results were
      consistent with the hypothesis that E. lata is a random-mating species having a
      high degree of genetic diversity.

PMID- 10591972
TI  - Ric1, a Phytophthora infestans gene with homology to stress-induced genes.
AB  - From a set of Phytophthora infestans cDNA clones that were randomly selected from
      a potato- P. infestans interaction cDNA library, a relatively high proportion (5
      out of 22) appeared to be derived from the same gene. The gene was designated
      ric1. P. infestans contains two copies of ric1 which share 98% homology at the
      nucleotide-sequence level and 100% at the amino-acid level. The nucleotide
      sequence predicts an open reading frame of 171 bp encoding a 57 amino-acid
      hydrophobic-peptide with two potential membrane-spanning domains. The predicted
      peptide shows high homology to a peptide encoded by plant genes whose expression
      is specifically induced during stress conditions. Southern-blot analysis of
      genomic DNA of several Phytophthora species indicated that most species contain
      ric1 homologues. During the life cycle of P. infestans, ric1 was expressed in all
      developmental stages but the level of expression varied. Sporangia and
      germinating cysts appeared to contain only very little ric1 mRNA whereas in the
      mycelium and during in planta growth higher levels were detected. Subjecting the
      mycelium to osmotic stress or to a high pH resulted in increased ric1 expression.

PMID- 10591973
TI  - [Present importance of direct immunologically based intervention strategies using
      anticytokines in rheumatoid arthritis].
AB  - Rheumatoid arthritis (RA) is a chronic inflammatory multisystemic autoimmune
      disease of unknown origin. RA is clinically characterized by recurrent
      inflammation of joints, synovialitis, progressive destruction of cartilage or
      bone tissue and multiorgan involvement. Today all established therapies of RA are
      still unable to stop or even cure the disease. In most cases these therapies can
      only reduce progression. Furthermore, these therapies have substantial side
      effects, which can contribute to the increased mortality of disease. Therefore
      more effective therapies with fewer side effects are needed. In this context
      direct immunological intervention strategies increasingly gained interest to
      inhibit proinflammatory cytokines. In vivo and in vitro studies as well as
      experimental therapies documented the important role of the proinflammatory
      cytokines TNFalpha and IL-1 in RA. The therapy with TNFalpha-antibodies or
      receptor fusion proteins as well as IL-1 receptor antagonists proved to be
      clinically as well as immunologically highly effective as therapy of RA. The
      single dose treatment is associated with mild side effects only. In addition,
      trials using combined TNFalpha-antibody and methotrexate therapy gave promising
      results. However, potential severe side effects may occur after repeated therapy
      cycles or may be discovered after prolonged time of observation only (e.g.,
      allergic reactions, induction of autoantibodies or malignancies). Therefore, at
      present these therapy options can only be recommended for selected patients, who
      are included into controlled clinical trials. In addition, repeated courses of
      therapy seem to lead to reduced therapeutical efficacy (especially in TNFalpha
      antibody therapy). Further controlled studies with cytokine antagonists should
      especially address these problems and focus in particular on potential inductions
      of autoantibodies or malignancies as well as on additional long-term side
      effects. In contrast to direct inhibition of TNFalpha or IL-1 several further
      therapies indirectly influence these cytokines by interference with their
      synthesis or by alteration of the respective receptors. The importance of these
      therapeutical options has to be determined as well as the possibility of
      combination of established therapies with immunological intervention strategies.

PMID- 10591974
TI  - Long-term application of disease modifying antirheumatic drugs (DMARD). A single
      center, observational study of 1681 patients with rheumatoid arthritis (RA).
AB  - OBJECTIVE: To study the long-term efficacy and safety of methotrexate (MTX),
      intramuscular gold, azathioprine (AZA), chloroquine (CQ), sulphasalazine (SASP),
      and D-penicillamine (DPA) in rheumatoid arthritis (RA) patients. METHODS: Between
      1979 and 1994, clinical data were prospectively gathered in a single center. 1681
      patients were followed-up for at least 4 years. A 50% reduction of the swollen
      joint count was required to continue therapy. In addition, a modified Lansbury
      index, the Keitel function test, and laboratory parameters were determined every
      six months. Side effects leading to the discontinuation of treatment were
      recorded as well. RESULTS: After an observation period of more than four years,
      39.6% and 28.3% of patients were taking MTX and AZA, respectively; 18.2% were
      receiving gold, 16.9% remained on DPA. SASP and CQ were still applied in 13.5%
      and 6.6%. MTX, AZA and SASP had a drop-out rate due to toxicity of 15.9%, 15.3%
      and 17.7%, whereas 34.8% had to discontinue CQ (gold: 27.4%, DPA: 26.9%). The
      majority of dropouts occurred within the first year of treatment. Subgroups of
      seropositive patients and patients with rheumatoid nodules had a poorer treatment
      efficacy irrespective of the DMARD. CONCLUSION: In the long-term application, MTX
      was the most efficient compound, followed by AZA, whereas CQ had the poorest drug
      survival. Our results underline the value of long-term observations under the
      conditions of clinical practice as a supplement to controlled clinical trials.

PMID- 10591975
TI  - [Lesional pattern and clinical symptoms in rheumatoid flexor tendon disease].
AB  - OBJECTIVES: To assess complaints and clinical findings of rheumatoid hand flexor
      tendon disease in relationship to the anatomical site and the type of lesion in
      order to improve the diagnosis and enable early operative treatment with
      preservation of hand function. METHODS: 123 patients of the hands of 78 patients
      (66 female, 12 male) with a mean age of 57 years were analyzed retrospectively.
      Preoperative complaints and clinical findings were recorded according to their
      frequency. Three different types of flexor tendon disease were distinguished
      intraoperatively: isolated tenosynovitis, tenosynovitis with tendon lesion, and
      complete tendon rupture. RESULTS: 188 tendons showed isolated synovitis, 208 had
      a tendon lesion with synovitis, and 30 tendons a rupture. Tenosynovitis was found
      in the palm and wrist mainly. The 2nd, 3rd and 4th finger were most frequently
      involved. 81 tendon adhesions, 12 nodules, 63 superficial lesions and 52 defects
      were detected. These lesions were found mainly in the palm and the second and
      third ray. The profundus tendon was affected most often. Ruptures were detected
      most often in the wrist caused by bony spurs and tenosynovitis. A clinical
      difference between tenosynovitis with and without tendon lesion was not found.
      However, complaints and findings were different in the digit, palm, wrist and
      forearm. Ruptures had characteristic clinical findings. CONCLUSIONS: Rheumatoid
      flexor tendon disease is common. Tenosynovitis is often accompanied by tendon
      lesions. Ruptures occur as disease progresses. Exact assessment of complaints and
      clinical findings is mandatory to diagnose and localize flexor tendon disease.
      Early operative intervention helps to preserve the function of the hand.

PMID- 10591976
TI  - [Influence of osteoarthrosis, osteoporosis, and rheumatoid arthritis at precision
      of osteodensitometry of lumbar spine and proximal femur].
AB  - Precision of osteodensitometric measurements using dual energy X-ray
      absorptiometry (DEXA) depends on various known factors, such as positioning,
      aortic calcification or vertebral fractures. The purpose of this study was to
      investigate the influence of various diseases or bone density on the
      reproducibility of measurements in the lumbar spine and the proximal femur.
      Measurements in the LWS p.a. , LWS lat. and at Ward's triangle were made in a
      total of 100 patients. The subjects were repositioned between measurements. In
      order to be able to determine the influence of various diseases, four groups of
      25 patients each were formed: three with the diagnosis osteoarthrosis,
      osteoporosis and rheumatoid arthritis and one control group. The mean percentual
      difference and coefficient of variation were calculated as the measure for
      reproducibility. Mean percentual differences of 0.18 to 2.6% were found in the
      four groups at the three measurements sites. After calculation of coefficient of
      variation, a value between 1.2 and 2.7% was found for LWS p.a., between 7.1 and
      15.7% for LWS lat. and between 4.1 and 9.9% at Ward's triangle. It was also
      conspicuous that the difference in coefficient of variation in osteoporosis
      patients was nearly double that in the control group in all measured areas.
      CONCLUSION: Lateral lumbar spinal measurements using DEXA cannot presently be
      recommended. LWS p.a. measurements and, with limitations, measurements at Ward's
      triangle have good precision and could be used for course documentation of bone
      density.

PMID- 10591977
TI  - [Jaccoud-arthritis].

PMID- 10591979
TI  - Abstracts of main lectures

PMID- 10591978
TI  - Glucocorticoid hormone action in rheumatic autoimmune diseases. International
      conference october 14-16, 1999 paragraph signBad nauheim - germany

PMID- 10591980
TI  - Abstracts of short communications and poster session

PMID- 10591981
TI  - [Reports by the German Society of Rheumatology. Membership meeting of the German
      Society of Rheumatology e.V. on Friday, 17 September 1999, in Rostock].

PMID- 10591983
TI  - [ [In Process Citation]

PMID- 10591982
TI  - [Reports by the Swiss Society of Rheumatology. Word of the president... they
      measure not, what they do].

PMID- 10591984
TI  - Two-prong splint in the treatment of proximal humeral fracture.
AB  - Twenty-nine patients with two-, three- and four-part proximal humeral fractures
      were treated by two-prong splint. At the latest follow-up, 22 patients had
      excellent and satisfactory results according to the Neer criteria, with only two
      failures. Avascular necrosis was detected in only one patient. Given these
      results, we conclude that the present method can be the treatment of choice for
      these injuries.

PMID- 10591985
TI  - Stable bony integration with and without short-term indomethacin prophylaxis.A 5
      year follow-up.
AB  - We included in a prospective study of a standardized indomethacin protocol 134
      consecutive patients undergoing primary cementless endoprosthetic hip replacement
      between January and June 1990. Periarticular heterotopic ossification (HO) was
      graded according to the Arcq classification (grades 0 to III). At final follow
      up, all patients were analyzed clinically and radiographically for HO and aseptic
      loosening. A similar group of 44 patients (mean age of 64 years, range 38-82
      years) undergoing total hip replacement (THR) with the same prosthesis and
      technique in 1987 did not receive HO prophylaxis and served as a control group.
      The average age of the 134 prophylaxis patients was 66.5 years (range 32-85
      years), and the average follow-up was 65 months (range 60-71 months). Thirty
      patients (25%) were lost to final follow-up (19 died, 10 unknown, 1 amputation).
      In the study group, 77% had HO grade 0, while none had HO grade III, compared
      with 18% HO grade 0 and 16% HO grade III in the control goup. These differences
      were statistically significant (P = < 0.001). At a minimum of 60 months follow
      up, clinical and radiographic evaluation revealed no aseptic loosening in the
      study group: 4 cases of prosthesis subsidence during the first year did not
      progress. In the control group, there was a higher incidence of radiolucency
      around the femoral component, and one patient met all criteria for radiographic
      evidence of aseptic loosening. Statistical analysis revealed no significant
      difference between the two groups (P = 0.104). Based on our clinical and
      radiological results, indomethacin does not inhibit stable bony integration of
      the femoral component.

PMID- 10591986
TI  - Extrapyramidal side effects during chronic combined dopamine D1 and D2 antagonist
      treatment in Cebus apella monkeys.
AB  - Previous studies in non-human primates have shown that tolerance to dystonia
      occurs during chronic dopamine D1 (D1) but not D2 antagonism and
      induction/aggravation of oral dyskinesia (TD) during D2 but not D1 antagonism. We
      were therefore interested in determining the effects of combined chronic D1 + D2
      antagonism on dystonia and dyskinesia. To this intent, 8 male Cebus apella
      monkeys were treated 10 weeks with gradually increasing doses of D1 antagonist
      (NNC 112) + a D2 antagonist (raclopride), followed by 2 weeks of treatment with
      the D2 antagonist alone. Due to previous neuroleptic exposure, 5 monkeys had TD
      and all were sensitized to dystonia. During the combined antagonist treatment,
      tolerance to dystonia occurred; the tolerance disappearing upon discontinuation
      of the D1 antagonist and continuation of the D2 antagonist alone. Parallel to
      these results, improvement of TD was seen during the combined antagonist
      treatment with worsening during the D2 antagonist alone. Both the combined
      antagonists and the D2 antagonist alone resulted in moderate/severe bradykinesia,
      with no tolerance. These findings indicate that supplementation of traditional D2
      antagonism with a D1 antagonist would lessen the risk of dystonia and allow
      alleviation of preexisting TD, though parkinsonian side effects might still
      occur. The findings further indicate that separate dopaminergic mechanisms
      control dystonia/dyskinesia and parkinsonism.

PMID- 10591987
TI  - Early onset of lithium prophylaxis as a predictor of good long-term outcome.
AB  - The recurrence rates during lithium preventive treatment were investigated in a
      sample of 270 Mood Disorder subjects subdivided according to their onset time for
      lithium prophylaxis as very early (within 5 years from the onset of illness),
      early (6-10 years), late (11-20 years) and very late (more than 21 years). 131
      subjects of the sample followed for 4 years prolonged the observation for a
      further period of 8 years. Results indicated that beginning lithium therapy
      within the first ten years of illness predicts better preventive outcomes than
      beginning prophylaxis later, both in major depression, recurrent and bipolar
      patients.

PMID- 10591988
TI  - How to preserve the antidepressive effect of sleep deprivation: A comparison of
      sleep phase advance and sleep phase delay.
AB  - Total sleep deprivation (TSD) leads to an immediate amelioration of depressed
      mood in approximately 70 % of patients with the melancholic subtype of
      depression. The clinical utility of this procedure is limited, as the improvement
      usually subsides after the next night of sleep. In the present study, 40
      depressed inpatients, being free of psychoactive medication for at least 7 days
      and who had responded to a TSD were then distributed (according to a matched-pair
      design) to a sleep phase advance (SPA = time in bed scheduled from 1700-2400 hrs)
      or a sleep phase delay (SPD = time in bed from 0200-0700 hrs) with a succeeding
      shift back (for one hour in the SPA group per day) respectively shift forward
      (for 30 minutes in the SPD group per day), until the initial sleep phase (2300
      0600 hrs) was reached after seven days again. Based on previous observations it
      was hypothesized that a phase advance of the sleep period should prevent
      responders to TSD from relapsing. Whereas 75% of the TSD responders were
      stabilized by the phase advanced condition and did not relapse over a period of
      seven days, only 40% of the patients in the phase delayed condition did not
      relapse. Polysomnography during the course of the study gave no evidence that the
      unusual sleep schedules caused prolonged sleep deprivation. Abnormalities of REM
      sleep persisted both in the clinical responders and non-responders after the
      sleep wake manipulation. It is concluded that the clinical effectiveness of TSD
      can be significantly improved by combining TSD with a following phase advance of
      the sleep period.

PMID- 10591989
TI  - Elevated cellular immune response to human heat-shock protein-60 in schizophrenic
      patients.
AB  - Heat shock protein-60 (HSP60) is implicated in several autoimmune diseases as a
      triggering antigen. Based on the autoimmune hypothesis of schizophrenia, we
      examined cellular and humoral responses against HSP60 and a series of its peptide
      fragments with peripheral blood samples of schizophrenic patients and healthy
      subjects each of group size between 12 to 32 participants. The average
      stimulation indices of peripheral blood mononuclear cells (PBMC) to HSP60 were
      3.17 +/- 0.36 (mean +/- SE) for schizophrenic patients and 2.23 +/- 0.24 (mean +/
      SE) for healthy subjects, with a significant difference between the groups (P =
      0.0457). In parallel, 38 synthetic peptide fragments of HSP60, each of 18-21
      amino acids, were tested for in vitro sensitization of PBMC. With one peptide
      (p32) the average stimulation index of PBMC from schizophrenic patients was
      significantly higher than that obtained for PBMC of control subjects (P =
      0.0006). Comparing the cellular immune response to p32 between patients who were
      distinctive responders (n = 10) or non-responders (n = 10) to neuroleptic
      treatment indicated a similar elevation of cellular response in these groups.
      Antibodies against HSP60 were screened by dot-blot and ELISA in the sera of the
      above blood samples. Titers of IgG and IgM against HSP60 were found to be of
      similar magnitude in schizophrenic patients and in controls. Titers of IgA
      against HSP60 were somewhat higher in the sera of schizophrenic patients in
      comparison to sera of control subjects (P = 0.0605).

PMID- 10591990
TI  - Dimensions of psychopathology in paranoid schizophrenia.
AB  - Recently, there has been a great deal of interest in understanding the latent
      organisation of the phenomenology of schizophrenia through examination of the fit
      of dimensional models to observed symptoms date. A group of 66 DSM-IV paranoid
      schizophrenic in-patients were assessed three times using the SAPS, SANS, BPRS
      and PAS. The interrelations between individual symptoms of each scale were
      examined by means of principal component analysis. The results of factor analysis
      of the findings from SANS and SAPS confirm the three-factor model, composed of a
      negative, disorganisation and psychotic factor. Extending the range of
      symptomatology using BPRS resulted in a five-factor model, composed of the
      following factors: paranoid, negative, affective, cognitive and disorganised
      behaviour. In view of the findings based on Strauss' work (1974) the PAS has been
      added to the SANS, SAPS and BPRS, whose results were examined by factor analysis.
      The findings indicate that it is possible to consider a six-factor model,
      composed of the following dimensions: paranoid, negative, affective, cognitive,
      disorganised behaviour and premorbid social adjustment deficits. The number of
      factors that best reflect the structure of the symptomatology of paranoid
      schizophrenia depends on the range of the symptoms under study, i.e., on the type
      of scales. It follows from our study that six-factor model appears to be the most
      suitable and clear model in rendering the multidimensionality of paranoid
      schizophrenia phenomenology.

PMID- 10591992
TI  - Announcements of the german society of biological psychatry (Deutsche
      gesellschaft fur biologische psychiatrie DGBP)

PMID- 10591991
TI  - A multinational study of the relationships between nighttime urinary melatonin
      production, age, gender, body size, and latitude.
AB  - Overnight urines were collected each month for 12-16 months from 321 normal
      subjects at 19 medical centers in 14 countries distributed on 5 continents at
      latitudes from 31 01 South to 77 00 North. Mean melatonin concentration was found
      to negatively correlate with age, weight, and height. When the sexes were
      considered separately melatonin only correlated with age for female and with age
      and weight for males. A weak correlation with latitude, but not longitude, was
      also found.

PMID- 10591993
TI  - Induction of coiled body-like structures in Xenopus oocytes by U7 snRNA.
AB  - The coiled bodies, or "sphere organelles," of amphibian oocytes, first identified
      by their unique morphology, are large structures of up to 10 microm in diameter.
      There are 40 to 120 coiled bodies per oocyte nucleus. Most of the coiled bodies
      are in the nucleoplasm but a few are attached to specific chromosomal loci
      containing the histone gene repeats. Like the coiled bodies of somatic cells,
      they contain high concentrations of U7 snRNA, a small nuclear RNA required for 3'
      end formation of histone transcripts, and of a unique protein called coilin/SPH
      1. We show here that increasing the nuclear concentration of U7 snRNA, by
      injection of either in vitro synthesized U7 snRNA or functional U7 snRNA genes,
      induces the formation of coiled body-like structures in vivo. In contrast, the
      formation of these structures is not induced when either a promoterless U7 snRNA
      gene construct is injected or when functional U7 snRNA genes are co-injected with
      alpha-amanitin. Increasing the concentration of U1 snRNA or histone mRNA does not
      induce the formation of these structures, indicating that the formation of these
      coiled body-like structures is specifically induced by the U7 snRNA. These
      results suggest that U7 snRNA may be a central nucleating factor of coiled bodies
      and that the appearance of coiled bodies at histone gene loci results from an
      increased local concentration of U7 snRNA near the nascent histone pre-mRNAs.

PMID- 10591994
TI  - Subnuclear distribution of the entire complement of linker histone variants in
      Arabidopsis thaliana.
AB  - Linker histones (e.g. H1, H5, H1 degrees ) are thought to exert control on
      chromatin function by restricting nucleosomal dynamics. All higher eukaryotes
      possess a diverse family of linker histones, which may exhibit functional
      specialization. Arabidopsis thaliana apparently contains a minimal complement of
      linker histone structural variants and therefore is an ideal model for
      investigating functional differentiation among linker histones. Histones H1-1 and
      H1-2 are relatively similar proteins that are expressed in a wide variety of
      tissues and make up the majority of linker histone while H1-3 is a highly
      divergent minor variant protein that is induced by drought stress. We are
      interested in determining whether the in vivo distribution of each of these
      proteins also differs. To this end, we have produced subtype-specific antibodies
      and have localized each of the three proteins at the intranuclear and DNA
      sequence levels by indirect immunofluorescence and immunoprecipitation,
      respectively. Antibodies against linker histones H1-1 and H1-2 decorate nuclei in
      patterns very similar to 4',6-diamidino-2-phenylindole (DAPI) staining, but
      different than the staining pattern of total histones. In contrast, antibodies
      made against two regions of H1-3 bind to chromatin in a diffuse pattern distinct
      from the DAPI-staining pattern. We also describe a technique to determine the
      localization of plant linker histone variants along regions of chromatin,
      employing in vivo chemical DNA-protein cross-linking to preserve native
      associations followed by immunoprecipitation with subtype-specific antibodies. We
      use this technique to demonstrate that, in contrast to the major linker histones,
      H1-3 does not bind the repetitive sequences pAL1 and 5S rDNA. In addition, we
      show that linker histones are bound to the compacted nucleosomal arrays at the
      telomere but with reduced stoichiometry. Taken together, our results suggest that
      plants, as has been shown for animals, possess a variant linker histone that is
      differentially localized.

PMID- 10591995
TI  - The characterization of DINE-1, a short, interspersed repetitive element present
      on chromosome and in the centric heterochromatin of Drosophila melanogaster.
AB  - The banded portion of chromosome 4 (the "dot" chromosome) in Drosophila
      melanogaster displays some properties of beta-heterochromatin, which is normally
      found within the centric domain of the chromosomes. The nature and distribution
      of repetitive elements on chromosome 4 could play a role in the establishment of
      this unusual chromatin configuration. We describe here one such element: a short,
      interspersed repetitive sequence named DINE-1. Determination of a consensus
      sequence for the element reveals that there are two conserved regions (A and B)
      separated by a highly variable spacer. The conserved sequences are approximately
      400 bp long but degenerate at both ends, opening the possibility that a yet-to-be
      discovered mother element may be present in the genome. DINE-1 bears few of the
      properties of the mammalian short interspersed elements (SINEs) to which it bears
      a superficial resemblance in size. It does not appear to be the product of
      reverse transcription and lacks any polymerase III promoter consensus. The
      elements are not flanked by target site duplications and their termini lack
      direct or inverted repeats, suggesting that they themselves are not transposable.
      Our analysis of cosmid clones from chromosome 4, and elsewhere in the genome,
      revealed that the euchromatic locations of DINE-1 are almost exclusively confined
      to chromosome 4. In situ hybridization of a DINE-1 probe to polytene chromosomes
      confirmed the preferential distribution along 4, in addition to its presence in
      the centric heterochromatin. This unusual genomic distribution of bias toward
      chromosome 4 is also seen in the sibling species, D. simulans, whose dot
      chromosomes exhibit poorly resolved polytene bands and lack crossing over during
      meiosis like those of D. melanogaster. However, the dot chromosome of D. virilis,
      which exhibits a well-defined banded structure on polytene chromosomes and can
      cross over, has only a single, discrete site of DINE-1 element hybridization. The
      presence of DINE-1 within these regions suggests a role in the heterochromatic
      nature of chromosome 4 in D. melanogaster and supports the contention that
      repeats accumulate in regions of diminished crossing over.

PMID- 10591996
TI  - CENP-A associated complex satellite DNA in the kinetochore of the Indian muntjac.
AB  - The centromere/kinetochore complex is a chromosomal assembly that mediates
      chromosome motility and mitotic regulation by interacting with microtubules of
      the mitotic spindle apparatus. Centromere protein A (CENP-A) is a histone H3
      homolog that is concentrated in the chromatin of the inner kinetochore plate of
      human chromosomes. To identify DNA sequences associated with the inner
      kinetochore plate, we used anticentromere autoantibodies to immunoprecipitate
      CENP-A associated chromatin selectively from Indian muntjac fibroblasts. DNA was
      cloned from immunoprecipitated CENP-A- associated chromatin and characterized by
      DNA sequence and hybridization analyses. A novel centromeric satellite DNA
      sequence was identified and shown by fluorescence in situ hybridization analysis
      to be present at all centromeres of the Indian muntjac. This satellite DNA
      constitutes a 972 bp monomer repeat and shows partial homology with satellite II
      DNA of the white-tailed deer. Southern blot analysis of muntjac genomic DNA
      suggests that this satellite DNA is present in repetitive tandem arrays and
      contains complex internal arrangements. In conjunction with previous work showing
      the association of CENP-A with human alpha-satellite DNA, we conclude that the
      mammalian inner kinetochore plate contains a unique form of chromatin that
      contains CENP-A in association with complex satellite DNA.

PMID- 10591997
TI  - Evidence for an antagonistic relationship between the boundary element-associated
      factor BEAF and the transcription factor DREF.
AB  - Boundary elements interfere with communication between enhancers and promoters,
      but only when interposed. Understanding this activity will require identifying
      the proteins involved. The boundary element-associated factor BEAF is one protein
      that is implicated in boundary element function. Three genomic fragments (scs',
      BE76 and BE28) containing BEAF binding sites function as boundary elements in
      transgenic Drosophila, suggesting that this is an intrinsic property of the
      numerous genomic regions to which BEAF binds. To characterize additional proteins
      that interact with boundary elements, we have isolated a protein that binds to
      two of these boundary elements (BE76 and BE28) and have identified it as the
      transcription factor DREF. We present evidence that BEAF and DREF compete for
      binding to overlapping binding sites, and that this competition occurs in vivo.
      DREF is believed to regulate genes whose products are involved in DNA replication
      and cell proliferation, suggesting that the activation of transcription predicted
      to result from the displacement of BEAF by DREF might be limited to certain
      rapidly proliferating tissues. This is the first suggestion that the activity of
      a subset of boundary elements might be regulated.

PMID- 10591998
TI  - Homolog pairing and meiotic progression in Coprinus cinereus.
AB  - We have used fluorescence in situ hybridization to examine homolog pairing during
      the synchronous meiosis of the basidiomycete Coprinus cinereus. Using spread
      preparations of meiotic nuclei, we confirmed previous studies that showed that at
      6 h post-karyogamy essentially all meiotic nuclei are in pachytene. We found that
      homolog pairing occurs rapidly after karyogamy, that a 1 Mb chromosome does not
      associate more quickly than a 2.5 Mb chromosome, and that interstitial, single
      copy sites can associate stably prior to nucleolar fusion. Analysis of two probes
      for the same pair of homologs revealed that by 4 h after karyogamy each
      chromosome examined was at least partially paired in all meiotic cells. In
      addition, these studies showed that chromatin condensation increases after
      pairing and that chromatin shows stable compaction at pachytene.

PMID- 10591999
TI  - Defining the ancestral karyotype of all primates by multidirectional chromosome
      painting between tree shrews, lemurs and humans.
AB  - We used multidirectional chromosome painting with probes derived by bivariate
      fluorescence-activated flow sorting of chromosomes from human, black lemur
      (Eulemur macaco macaco) and tree shrew (Tupaia belangeri, order Scandentia) to
      better define the karyological relationship of tree shrews and primates. An
      assumed close relationship between tree shrews and primates also assists in the
      reconstruction of the ancestral primate karyotype taking the tree shrew as an
      "outgroup" species. The results indicate that T. belangeri has a highly derived
      karyotype. Tandem fusions or fissions of chromosomal segments seem to be the
      predominant mechanism in the evolution of this tree shrew karyotype. The 22 human
      autosomal painting probes delineated 40 different segments, which is in the range
      found in most mammals analyzed by chromosome painting up to now. There were no
      reciprocal translocations that would distinguish the karyotype of the tree shrew
      from an assumed primitive primate karyotype. This karyotype would have included
      the chromosomal forms 1a, 1b, 2a, 2b, 3/21, 4-11, 12a/22a, 12b/22b, 13, 14/15,
      16a, 16b, 17, 18, 19a, 19b, 20 and X and Y and had a diploid chromosome number of
      2n=50. Of these forms, chromosomes 1a, 1b, 4, 8, 12a/22a, and 12b/22b may be
      common derived characters that would link the tree shrew with primates. To define
      the exact phylogenetic relationships of the tree shrews and the genomic
      rearrangements that gave rise to the primates and eventually to humans further
      chromosome painting in Rodentia, Lagomorpha, Dermoptera and Chiroptera is needed,
      but many of the landmarks of genomic evolution are now known.

PMID- 10592000
TI  - Occupational health services in Croatia.
AB  - A short historic review of the development of occupational health problems and
      activities in Croatia as well as of relevant legislation, organization of
      occupational health services, and approaches to education is given. Workers'
      morbidity patterns are also briefly discussed. The present orientation and
      foreseeable needs and tasks are critically evaluated. The role of research in the
      development of occupational health practice is emphasized.

PMID- 10592001
TI  - The epidemiology of occupational contact dermatitis.
AB  - Occupational contact dermatitis (OCD) ranks first of all occupational diseases in
      many countries. The incidence rate is believed to be around 0.5-1.9 cases per
      1000 full-time workers per year. Epidemiological studies play an important role
      in observing disease trends, analysing risk factors, and monitoring the effect of
      preventive measures. In this review article the lack of truly epidemiologic data
      on OCD and the difficulties of those studies are illustrated. The following
      issues are highlighted: case ascertainment and bias, the distribution of allergic
      and irritant contact dermatitis in the working population, the interrelationship
      between exogenous (allergens, irritants) and endogenous factors, the prognosis,
      the social and economic impact, and the need for intervention studies.

PMID- 10592002
TI  - Inflammation markers in nasal lavage, and nasal symptoms in relation to
      relocation to a newly painted building: a longitudinal study.
AB  - INTRODUCTION: There is a need to evaluate possible health effects of ventilation
      improvements and emissions from new buildings, in longitudinal studies. New
      methods to study biological effects on the eyes and upper airways are now
      available. MATERIAL AND METHODS: A longitudinal study was performed on 83 trained
      social workers in two offices in Uppsala, Sweden. The exposed group (n = 57)
      moved to a newly redecorated building nearby. Low emitting building material had
      been used, including a new type of solvent-free water-based paint. The control
      group (n = 26) worked in the same office during the study period (November 1995
      to February 1996). Hygiene management was carried out in both offices, at the
      beginning and the end of the investigation. Tear film stability (BUT) was
      measured. Nasal patency was measured by acoustic rhinometry, and eosinophilic
      cationic protein (ECP), myeloperoxidase (MPO), lysozyme and albumin were analyzed
      in nasal lavage fluid (NAL). RESULTS: The relocation resulted in an increase in
      the personal outdoor airflow rate from 11 to 22 l/s. Indoor concentrations of
      terpenes were higher in the new building, and powdering of the new linoleum floor
      was observed. Measurements showed low levels of volatile organic compounds (VOC),
      formaldehyde, carbon dioxide (CO(2)), nitrogen dioxide, respirable dust, and
      microorganisms in the air of all buildings. The move resulted in an increased
      nasal patency and an increase of ECP and lysozyme in NAL, after adjusting for
      changes in the control group. No changes were observed for nasal or ocular
      symptoms. A seasonal effect, with a decrease of ECP, was observed in the control
      group. CONCLUSSION A well-ventilated office building can be redecorated without
      any major ocular or nasal effects, or measurable increase of indoor air pollution
      if low-emitting building materials are selected. In agreement with previous
      evidence, the improved ventilation flow may explain the increase of nasal
      patency. The increase of ECP and lysozyme in NAL suggested an inflammatory effect
      in the new building. Since this building had increased ventilation flow,
      increased concentrations of terpenes, and powdering from the polish on the new
      linoleum floor, identification of causative agents was difficult. The hygiene
      measures did not give any evidence that emissions from the new type of solvent
      free water-based paints or building dampness were responsible for the observed
      nasal effects. Considering the higher emissions of VOC reported from older types
      of water-based latex paints and solvent-based wall paints, the new type of
      solvent-free water-based paint seems to be a good choice from the hygiene point
      of view.

PMID- 10592003
TI  - Urinary lead as a possible surrogate of blood lead among workers occupationally
      exposed to lead.
AB  - OBJECTIVES: The aim of the present study is to investigate whether lead (Pb) in
      urine (Pb-U) can be a valid surrogate of lead in blood (Pb-B), the traditional
      biomarker of exposure to lead in occupational health. METHODS: Blood and spot
      urine samples were collected from 258 workers of both sexes occupationally
      exposed to lead. The samples were analyzed for lead by graphite furnace atomic
      absorption spectrometry, and the correlation between Pb-B and Pb-U was examined
      by linear regression analysis before and after logarithmic conversion. RESULTS:
      The correlation coefficient (0.824; P < 0.01) was largest when the relationship
      between Pb-B and Pb-U was examined with 214 cases of one sex (i.e., men) after Pb
      U was corrected for a specific gravity (1.016) of urine (Pb-Usg) and both Pb-B
      and Pb-Usg were converted to logarithms. The geometric means (GMs) of Pb-B and Pb
      Usg for the 214 men were 489 microG/l and 81 microg/l, respectively. When Pb-Usg
      was assumed to be 100 microg/l in this set of correlations, the 95% confidence
      range of Pb-B for the group mean was narrow, i.e., 543-575 microg/l (with GM of
      559 microg/l), whereas that for individual Pb-B values was as wide as 355-881
      microg/l. CONCLUSIONS: The correlation of Pb-U with Pb-B among workers
      occupationally exposed to Pb was close enough to suggest that Pb-U may be a good
      alternative to Pb-B on a group basis, but not close enough to allow Pb-U to
      predict Pb-B on an individual basis.

PMID- 10592004
TI  - Biomonitoring of manganese in blood, urine and axillary hair following low-dose
      exposure during the manufacture of dry cell batteries.
AB  - OBJECTIVES: A cross-sectional study was carried out on 100 workers from three
      different workplace areas in a dry cell battery manufacturing plant and on 17
      currently nonexposed referents, to examine the relationship between the external
      exposure to manganese dioxide (MnO(2)) and the body burden of manganese in blood,
      urine and hair. METHODS: Inhalable dust was measured gravimetrically after
      stationary active sampling. Manganese was analyzed in dust samples, blood, urine
      and axillary hair by atomic absorption spectro- metry. RESULTS: The average air
      concentrations of manganese in the three workplace areas were 4 microg/m(3)
      (range: 1-12 microg/m(3)), 40 microg/m(3) (12-64 microg/m(3)) and 400 microg/m(3)
      (137-794 microg/m(3)). Manganese in blood and axillary hair correlated with
      airborne manganese in group-based calculations but not on an individual level.
      The manganese concentrations varied between 3.2 microg/l and 25.8 microg/l in the
      blood (mean: 12.2 +/- 4.8 microg/l) and between 0.4 microg/g and 49.6 microg/g in
      hair (mean: 6.2 +/- 6.2 microg/g in the proximal sequence), respectively. The
      results for the nonexposed referents were 7.5 +/- 2.7 microg/l (mean) in the
      blood (range: 2.6-15.1 microg/l) and 2.2 +/- 1.8 microg/g (mean) in axillary hair
      (range: 0.4-6.2 microg/g). In these matrices, manganese differed significantly
      between the highly exposed workers and both the reference and the low-exposure
      group. Manganese in blood revealed the lowest background variance. No differences
      for manganese in urine were observed between workers (mean: 0.36 +/- 0.42
      microg/l, range: 0.1-2.2 microg/l) and referents (mean: 0.46 +/- 0.47 microg/l,
      range: 0.1-1.7 microg/l). CONCLUSIONS: Manganese in blood is a specific and
      suitable parameter for the biomonitoring of MnO(2) exposure, although its
      validity is limited to group-based calculations. Urinary manganese failed to
      allow a differentiation between exposed workers and referents. The suitability of
      manganese analysis in hair for biomonitoring purposes suffers from a relatively
      great background variation as well as from analytical problems.

PMID- 10592005
TI  - Dermal exposure assessment of polycyclic aromatic hydrocarbons: in vitro
      percutaneous penetration from lubricating oil.
AB  - OBJECTIVES: Percutaneous penetration of polycyclic aromatic hydrocarbons (PAHs)
      is affected by various factors connected to exposure conditions. The nature of
      the matrix, such as that of oil, can strongly affect their percutaneous
      penetration. Risk assessment should consider these effects. We examined the
      effect of matrix on percutaneous penetration of PAHs, particularly that of
      lubricating oil. METHODS: The test apparatus consisted of an in vitro static
      diffusion cell system using full-thickness monkey (Cercopithecus aetiops) skin as
      the membrane and saline solution with gentamycin sulfate and 4% bovine serum
      albumin as receptor fluid. Chemical analysis of PAHs in the samples obtained from
      cells was carried out by inverse-phase HPCL, and the results were read by
      spectrofluorimetry. RESULTS: Comparing the penetration of 13 PAHs from a
      lubricating oil and from acetone solution with artificial sweat resulted in a
      significantly slower passage from the oil matrix for acenaphthene, anthracene,
      phenanthrene, fluoranthene, naphthalene, pyrene, fluorene (Mann-Whitney U test, P
      < 0.05). No significant differences in the passage were found for chrysene
      because, in the test with oil, its concentration was very often below the
      detection limit. For benzo[a]anthracene, benzo[b]fluoranthene,
      benzo[k]fluoranthene, and benzo[a]pyrene it was possible to demonstrate a passage
      through the skin only when compounds were applied in acetone solution with
      artificial sweat. CONCLUSIONS: The results of the study suggest the necessity of
      dermal penetration data relevant for risk assessment, obtained under experimental
      conditions similar to the real exposure conditions.

PMID- 10592006
TI  - A cross-sectional study of workers in the chemical industry with occupational
      exposure to hexamethylenetetramine.
AB  - OBJECTIVES: To assess the health effects of hexamethylenetetramine (HMT) on the
      airways and the skin of workers in the chemical industry. METHODS: A cross
      sectional study was performed with 17 employees of a HMT-producing chemical plant
      and 16 control subjects from the plant. In addition, we examined 4 out of 5
      subjects who had left the production for medical reasons during the last 10
      years. Anamnestic data, total and specific IgE to four environmental allergens,
      lung function and bronchial responsiveness to methacholine were assessed by
      standard procedures. Skin prick tests (SPT) and patch tests were performed with
      known sensitizing substances and HMT 100 mg/ml and 2% pet and aq. RESULTS: A high
      number of exposed subjects and controls reported symptoms during the previous
      year (64.7% vs 68.8%), most of them were not related to work. Work-related
      symptoms and objective parameters did not show differences between groups. No
      sensitizations to HMT as assessed by SPT or patch tests were found. Among those
      who had left the HMT production for medical reasons, 2 former baggers showed
      sensitizations to HMT by patch tests. These reported eczema during exposure but
      lost symptoms after removal from exposure. Geometric mean HMT concentrations as
      assessed by personal sampling were 0.3 [95% confidence intervals (CI) 0.1; 0.9]
      mg/m(3) in shiftleaders and 0.6 (95% CI 0.3; 1.1) mg/m(3) in baggers. CONCLUSION:
      High exposures to HMT may cause allergic contact dermatitis. There was no
      evidence of an increased risk for occupational asthma at mean airborne HMT
      concentrations below 1 mg/m(3).

PMID- 10592007
TI  - Occupational exposure to alkoxysilanes in a fibreglass manufacturing plant.
AB  - OBJECTIVE: To assess the exposure of workers to alkoxysilanes and to determine
      the main route of exposure during the manufacture of fibreglass. METHODS:
      Occupational hygiene samples were taken from workers and their environment in a
      fibreglass factory during filament forming and the handling of coated fibres. The
      total exposure of workers to silanes was assessed by the collection of air
      samples into impinger flasks at stationary sampling sites, by the use of
      absorbent patch samples on workers' clothes or skin and from handwash samples.
      During the time of our field survey, 3-aminopropyltriethoxysilane, 3
      glycidoxypropyltrimethoxysilane and 3-methacryloxypropyltrimethoxysilane were
      being used in different sizing mixtures. The samples were analysed by gas and
      liquid chromatography. RESULTS: The silane concentrations in the air samples were
      below the detection limits of the analytical methods. The mean dermal exposure to
      3-glycidoxypropyltrimethoxysilane, analysed from the patch samples, was 2,800 mg
      h(-1) in the forming room and 800 mg h(-1) in the winder room. The corresponding
      figures for 3-methacryloxypropyl-trimethoxysilane were 3 and 9 mg h(-1). As
      determined in the handwash samples, the mean exposure to 3
      glycidoxypropyltrimethoxysilane through the hands was 1,500 mg h(-1) in the
      forming room and 1,800 mg h(-1) in the winder room, the respective values for 3
      methacryloxypropyltrimethoxysilane being 110 mg h(-1) and 90 mg h(-1). Only small
      quantities of 3-aminopropyltriethoxysilane were found in a few handwash samples.
      CONCLUSIONS: Our results showed that the workers in the fibreglass factory were
      clearly exposed to silanes. The main route of potential exposure was through the
      skin, especially the hands, which emphasised the importance of wearing
      appropriate protective gloves. According to the patch sampling, on average two
      thirds of the total dermal exposure was caused by exposure of the forearm, as
      indicated by the amounts of silanes analysed in the forearm patches. Since almost
      every worker was wearing protective gloves, the main occupational health finding
      concerning exposure to silanes was that short-sleeved T-shirts did not provide
      any protection to the arms.

PMID- 10592008
TI  - Manganese exposure in foundry furnacemen and scrap recycling workers.
AB  - OBJECTIVES: Cast iron products are alloyed with small quantities of manganese,
      and foundry furnacemen are potentially exposed to manganese during tapping and
      handling of smelts. Manganese is a neurotoxic substance that accumulates in the
      central nervous system, where it may cause a neurological disorder that bears
      many similarities to Parkinson's disease. The aim of the study was to investigate
      the sources and levels of manganese exposure in foundry furnacemen by a combined
      measuring of blood-manganese (B-Mn) and manganese in ambient air (air-Mn).
      METHODS: During a period of 16 months, Air-Mn and B-Mn (denoted 'exposure
      values') were measured involving 24 furnacemen employed in three small size
      foundries and 21 scrap recycling workers from one plant. In the study period, 18
      furnacemen had B-Mn measured 3-4 weeks after decreasing or stopping exposure
      (denoted 'post-exposure values'). The reference group for the B-Mn measurements
      consisted of 90 Danish male subjects. RESULTS: Furnacemen who work in
      insufficiently ventilated smelting departments inhale, absorb, and retain
      significant amounts of manganese in their blood (approx. 2.5-5 microg/l above
      reference values) despite a generally low measured airborne level of manganese
      fumes (0.002-0.064 mg/m(3)). The 'exposure values' compared with 'post-exposure
      values' revealed a significant decrease in the B-Mn (on average 3.7 microg/l)
      level of the most exposed furnacemen. Two persons in our study were suspected of
      suffering clinically subacute manganese intoxication as both had B-Mn levels
      beyond the normal limit (25 and 29 microg/l, respectively). The potential problem
      disappeared completely after cessation of exposure, and the B-Mn levels decreased
      to 9.4 and 14.1 microg/l, respectively. CONCLUSIONS: Risk assessment based on
      combined measurements of B-Mn and air-Mn seems to be valid in the interpretation
      of workers' hazard. Our study indicates that B-Mn may be a valuable parameter for
      estimating recent exposure (within 1-2 weeks). However, more knowledge is needed
      about the B-Mn level and its relation to neurological symptoms.

PMID- 10592009
TI  - Medial plantar nerve conduction velocities among patients with vibration syndrome
      due to chain-saw work.
AB  - OBJECTIVE: The present study examined the effect of the vibration syndrome (VS)
      on the peripheral nervous system in the lower extremities. METHODS: Thirty-eight
      patients with VS due to previous exposure to vibration from chain-saw work and 55
      age-matched controls were examined for sensory nerve conduction velocities in the
      medial plantar nerve (SCV-P). The patient group was divided into two subgroups,
      one with (n=19) and the other without vibration-induced white finger (VWF; n=19).
      RESULTS: Analysis of variance of SCV-P for the three groups showed significant
      difference (F(2,89)=10.65, P < 0.0001). A significant difference was found
      between the controls and the VWF(+) group (P < 0.0001) but not between the
      controls and the VWF(-) group (P=0.0508) by multiple comparison using Scheffe's
      method. CONCLUSION: These findings suggest that VS affects the peripheral nervous
      system function in the lower extremities via mediation of circulatory disturbance
      manifested as VWF.

PMID- 10592013
TI  - Announcements

PMID- 10592010
TI  - Italian legislation adopts European Union directives: values and drawbacks.

PMID- 10592014
TI  - Delayed reverberation through time windows as a key to cerebellar function.
AB  - We present a functional model of the cerebellum comprising cerebellar cortex,
      inferior olive, deep cerebellar nuclei, and brain stem nuclei. The discerning
      feature of the model being time coding, we consistently describe the system in
      terms of postsynaptic potentials, synchronous action potentials, and propagation
      delays. We show by means of detailed single-neuron modeling that (i) Golgi cells
      can fulfill a gating task in that they form short and well-defined time windows
      within which granule cells can reach firing threshold, thus organizing neuronal
      activity in discrete 'time slices', and that (ii) rebound firing in cerebellar
      nuclei cells is a robust mechanism leading to a delayed reverberation of Purkinje
      cell activity through cerebellar-reticular projections back to the cerebellar
      cortex. Computer simulations of the whole cerebellar network consisting of
      several thousand neurons reveal that reverberation in conjunction with long-term
      plasticity at the parallel fiber-Purkinje cell synapses enables the system to
      learn, store, and recall spatio-temporal patterns of neuronal activity. Climbing
      fiber spikes act both as a synchronization and as a teacher signal, not as an
      error signal. They are due to intrinsic oscillatory properties of inferior
      olivary neurons and to delayed reverberation within the network. In addition to
      clear experimental predictions the present theory sheds new light on a number of
      experimental observation such as the synchronicity of climbing fiber spikes and
      provides a novel explanation of how the cerebellum solves timing tasks on a time
      scale of several hundreds of milliseconds.

PMID- 10592015
TI  - Exact digital simulation of time-invariant linear systems with applications to
      neuronal modeling.
AB  - An efficient new method for the exact digital simulation of time-invariant linear
      systems is presented. Such systems are frequently encountered as models for
      neuronal systems, or as submodules of such systems. The matrix exponential is
      used to construct a matrix iteration, which propagates the dynamic state of the
      system step by step on a regular time grid. A large and general class of dynamic
      inputs to the system, including trains of delta-pulses, can be incorporated into
      the exact simulation scheme. An extension of the proposed scheme presents an
      attractive alternative for the approximate simulation of networks of integrate
      and-fire neurons with linear sub-threshold integration and non-linear spike
      generation. The performance of the proposed method is analyzed in comparison with
      a number of multi-purpose solvers. In simulations of integrate-and-fire neurons,
      Exact Integration systematically generates the smallest error with respect to
      both sub-threshold dynamics and spike timing. For the simulation of systems where
      precise spike timing is important, this results in a practical advantage in
      particular at moderate integration step sizes.

PMID- 10592016
TI  - A model-based interpretation of the biphasic daily pattern of sleepiness.
AB  - We developed a thermoregulatory model of sleep control based on the hypothesis
      that non-rapid eye-movement sleep participates in homeostatic thermoregulation.
      This model successfully reproduced several qualitative features of human
      sleep/wake cycles during entrained as well as the internally desynchronized
      states. Among the reproduced features, generation mechanisms of the biphasic
      sleepiness distribution are studied here in the light of the model structure.
      Harmonic analysis is employed for this purpose. Through linearizations and
      confining the harmonics of the masking process to the fundamental component, a
      simplified representation of sleepiness is obtained. The simplified sleepiness is
      constructed with the fundamental circadian, the second harmonic components, and
      the constant (DC). The bimodality of the sleepiness is shown to be made by the
      second harmonic which is added to the fundamental component. The behavior of
      their amplitudes and phase positions are investigated under the varied sleep/wake
      durations and phase differences between the oscillators. Since the sleepiness
      generated by our model is roughly mimicked by the simplified representation under
      diverse conditions, this simplification can be regarded as adequate. From the
      behavior of the constituents of respective harmonic components, the fundamental
      component is shown to originate from the sleep/wake masking process and the
      circadian oscillators; the second harmonic from the multiplicative interactions
      between the circadian oscillators and the sleep/wake masking process. These
      results indicate that the rhythmic processes are principal constituents of the
      sleepiness, at least in the steady state.

PMID- 10592017
TI  - Nonlinear EEG analysis based on a neural mass model.
AB  - The well-known neural mass model described by Lopes da Silva et al. (1976) and
      Zetterberg et al. (1978) is fitted to actual EEG data. This is achieved by
      reformulating the original set of integral equations as a continuous-discrete
      state space model. The local linearization approach is then used to discretize
      the state equation and to construct a nonlinear Kalman filter. On this basis, a
      maximum likelihood procedure is used for estimating the model parameters for
      several EEG recordings. The analysis of the noise-free differential equations of
      the estimated models suggests that there are two different types of alpha
      rhythms: those with a point attractor and others with a limit cycle attractor.
      These attractors are also found by means of a nonlinear time series analysis of
      the EEG recordings. We conclude that the Hopf bifurcation described by Zetterberg
      et al. (1978) is present in actual brain dynamics.

PMID- 10592018
TI  - Recurrent V1-V2 interaction in early visual boundary processing.
AB  - A majority of cortical areas are connected via feedforward and feedback fiber
      projections. In feedforward pathways we mainly observe stages of feature
      detection and integration. The computational role of the descending pathways at
      different stages of processing remains mainly unknown. Based on empirical
      findings we suggest that the top-down feedback pathways subserve a context
      dependent gain control mechanism. We propose a new computational model for
      recurrent contour processing in which normalized activities of orientation
      selective contrast cells are fed forward to the next processing stage. There, the
      arrangement of input activation is matched against local patterns of contour
      shape. The resulting activities are subsequently fed back to the previous stage
      to locally enhance those initial measurements that are consistent with the top
      down generated responses. In all, we suggest a computational theory for recurrent
      processing in the visual cortex in which the significance of local measurements
      is evaluated on the basis of a broader visual context that is represented in
      terms of contour code patterns. The model serves as a framework to link
      physiological with perceptual data gathered in psychophysical experiments. It
      handles a variety of perceptual phenomena, such as the local grouping of
      fragmented shape outline, texture surround and density effects, and the
      interpolation of illusory contours.

PMID- 10592019
TI  - Iterative manual control model of human operator.
AB  - In this paper, we present an iterative manual control model of a human operator
      performing some repetitive task. Various aspects of the model are discussed in
      detail. Experiments have been done to study the human capability to perform the
      tasks by learning iteratively. Results of the experiments show the ability of the
      human operator to perform the tracking of a desired trajectory for some unknown
      non-linear system with quite reasonable accuracy during the iteration process. It
      is concluded that the human operator performs the repetitive task by modifying
      his control action using error and error rate in each iteration. During the
      modification, the human operator assigns different weights to the error and error
      rate in each iteration. These results can be implemented in designing more
      efficient iterative learning control algorithms.

PMID- 10592020
TI  - Numerical fourier transform spectroscopy of EMG half-waves: fragmentary
      decomposition-based approach to nonstationary signal analysis.
AB  - A nonstationary signal analysis technique is introduced, which regards an
      oscillatory physiological signal as a sum of its fragments, presented in the form
      of a fragmentary decomposition (FD). The virtue of FD is that it is free of the
      necessity to choose a priori the basis functions intended for signal analysis or
      synthesis. FD uses an unchanged signal fragment between adjacent zero-crossings,
      as a natural basis function called the half-wave function (HWF). To show that
      such a function is a physically meaningful object, Fourier transform methods were
      employed, supported by the similar basis function (SBF) algorithm, which provides
      the means for numerical Fourier transform spectroscopy of separate half-waves and
      their frequency domain description in terms of both amplitude and phase. The
      application of this method to parameter identification of 751 EMG half-waves from
      the eye blink EMG records of ten normal subjects showed that HWF's frequency
      domain image represents a Gaussian distribution, which applies over a defined
      range of relative frequencies. This empirical evidence shows that HWFs are
      produced by a specific system of first-order nonlinear differential equations,
      whose dependency on a number of random factors is characteristic of deterministic
      chaos. The particular form of solutions indicates that statistical regularities
      relevant to the central limit theorem are likely to underlie the genesis of the
      mass potentials studied. FD shows potential utility in a range of nonstationary
      physiological signals.

PMID- 10592021
TI  - Cooperative mechanism for improving the discriminating ability in the
      chemoreceptor neuron binomial case.
AB  - The discriminating ability (selectivity) of the chemoreceptor neuron is compared
      with that of its receptor proteins. The process of neuronal triggering is
      expected to be cooperative and threshold type in a sense that the neuron fires a
      spike if and only if the number of receptor proteins which are bound with odor
      molecules is above a definite threshold. The binomial distribution is utilized to
      estimate the firing probability if a definite odor is applied. It is established
      that a chemoreceptor neuron can have a much higher selectivity than its
      individual receptor proteins, provided that the chemical stimuli are presented at
      low concentrations. A possibility for the above mechanism to be valid in other
      sensory systems is discussed.

PMID- 10592022
TI  - Impedance characteristics of a neuromusculoskeletal model of the human arm I.
      Posture control.
AB  - The mechanical impedance of neuromusculoskeletal models of the human arm is
      studied in this paper. The model analysis provides a better understanding of the
      contributions of possible intrinsic and reflexive components of arm impedance,
      makes clear the limitations of second-order mass-viscosity-stiffness models and
      reveals possible task effects on the impedance. The musculoskeletal model
      describes planar movements of the upper arm and forearm, which are moved by six
      lumped muscles with nonlinear dynamics. The motor control system is represented
      by a neural network which combines feedforward and feedback control. It is
      optimized for the control of movements or for posture control in the presence of
      external forces. The achieved impedance characteristics depend on the conditions
      during the learning process. In particular, the impedance is adapted in a
      suitable way to the frequency content and direction of external forces acting on
      the hand during an isometric task. The impedance characteristics of a model,
      which is optimized for movement control, are similar to experimental data in the
      literature. The achieved stiffness is, to a large extent, reflexively determined
      whereas the approximated viscosity is primarily due to intrinsic attributes. It
      is argued that usually applied Hill-type muscle models do not properly represent
      intrinsic muscle stiffness.

PMID- 10592023
TI  - Impedance characteristics of a neuromusculoskeletal model of the human arm II.
      Movement control.
AB  - The modulation of neuromusculoskeletal impedance during movements is analysed
      using a motor control model of the human arm. The motor control system combines
      feedback and feedforward control and both control modes are determined in one
      optimization process. In the model, the stiffness varies at the double movement
      frequency for 2-Hz oscillatory elbow movements and has high values at the
      movement reversals. During goal-directed two-degrees-of-freedom arm movements,
      the stiffness is decreased during the movement and may be increased in the
      initial and final phases, depending on the movement velocity. The stiffness has a
      considerable curl during the movement, as was also observed in experimental data.
      The dynamic stiffness patterns of the model can be explained basically by the
      alpha-gamma coactivation scheme where feedback gains covary with motor control
      signals. In addition to the modulation of the gain factors, it is argued that the
      variation of the intrinsic stiffness has a considerable effect on movement
      control, especially during fast movements.

PMID- 10592024
TI  - Biomechanical properties and a kinetic simulation model of the smooth muscle I2
      in the buccal mass of Aplysia.
AB  - The muscle I2 is a smooth muscle from the buccal mass of the marine mollusc
      Aplysia californica whose neural control, in vivo kinematics, and behavioral role
      have been extensively analyzed. In this study, we measured the activation and
      contractile dynamics of the muscle in order to construct a Hill-type kinetic
      model of the muscle. This is the first study to our knowledge, of Aplysia muscle
      contractile dynamics. The isometric force-frequency relationship of I2 had a
      frequency threshold of about 6-8 Hz, and its force output saturated at 20-25 Hz,
      properties that match the high frequency (20 Hz) bursts generated by the B31/B32
      neurons that innervate it. Peak isometric force was generated at about 118% of
      the in situ relaxed length. These results and I2's estimated in vivo kinematics
      suggest that it generates maximum force at the onset of protraction. The muscle
      tension during iso-velocity lengthening and shortening was an asymmetric function
      of velocity. Short range stiffness and yielding responses were observed in
      lengthening, whereas muscle tension decreased smoothly in shortening. These visco
      elastic properties suggest that the I2 muscle can serve to brake forceful
      retraction movements. A Hill-type model, parameterized from the measurements,
      captured many of the mechanical properties of I2. Our results provide a
      quantitative understanding of the biomechanical significance of the muscle's
      neural control and provide a basis for simulation studies of the control of
      feeding behavior.

PMID- 10592025
TI  - Interaction of ON and OFF pathways for visual contrast measurement.
AB  - We propose a novel model of visual contrast measurement based on segregated On
      and Off pathways. Two driving forces have shaped our investigation: (1)
      establishing a mechanism selective for sharp local transitions in the luminance
      distribution; (2) generating a robust scheme of oriented contrast detection. Our
      starting point was the architecture of early stages in the mammalian visual
      system. We show that the circuit behaves as a soft AND-gate and analyze the scale
      space selectivity properties of the model in detail. The theoretical analysis is
      supplemented by computer simulations in which we selectively investigate key
      functionalities of the proposed contrast detection scheme. We demonstrate that
      the model is capable of successfully processing synthetic as well as natural
      images, thus illustrating the potential of the method for computer vision
      applications.

PMID- 10592026
TI  - Novel phenotypes and developmental arrest in early embryo specific mutants of
      maize
AB  - Embryo specific (emb) mutants exhibit aberrant embryo development without
      deleterious effects on endosperm development. We have analyzed five emb mutants
      of maize, which, based on their developmental profiles can be divided into two
      groups: mutants arrested at early stages and mutants with novel phenotypes. The
      members of the first group resemble wild-type proembryos and never reach other
      developmental stages. In the second group the tube-shaped mutants emb*-8522 and
      emb*-8535 completely lack apical-basal differentiation, while in mutant emb*-8516
      a second embryo-like structure arises from the suspensor. The five emb mutations
      analyzed are non-allelic and two of the mutations are very likely caused by
      insertion of the transposon mutator, opening the door for their molecular
      analysis.

PMID- 10592027
TI  - Phosphoenolpyruvate carboxykinase plays a role in interactions of carbon and
      nitrogen metabolism during grape seed development
AB  - Phosphoenolpyruvate carboxykinase (PEPCK) was shown to be present in a range of
      developing seeds by measurement of its activity and by immunoblotting. Its
      function was investigated during grape (Vitis vinifera L.) seed development. The
      maximum abundance of PEPCK coincided with the deposition of storage reserves. At
      this stage of development, immunohistochemistry showed that PEPCK was very
      abundant in a layer of cells located at the boundary of developing storage
      tissues and in the chalaza (close to the termination of the vascular supply to
      the seed) and was also present in the palisade layer of the seed coat (the inner
      layer of the outer integument). Earlier in development PEPCK was also present in
      the developing palisade layer and in the inner region of the nucellus which
      surrounds the developing endosperm. At later stages of development, PEPCK was
      located in the outer region of the endosperm. However, PEPCK was present in the
      phloem of the seed at all stages of development. Feeding of asparagine to
      developing grape seeds led to a strong induction of PEPCK. We suggest that, in
      developing grape seeds, both the chalaza and palisade tissue may distribute
      imported assimilates from the vasculature to the developing storage tissues and
      that PEPCK may play a role in the metabolism of nitrogenous assimilates during
      their delivery from the vasculature to the storage tissues.

PMID- 10592028
TI  - Expression of a conifer glutamine synthetase gene in transgenic poplar
AB  - The assimilation of ammonium into organic nitrogen catalyzed by the enzyme
      glutamine synthetase (GS; EC 6.3.1.2) has been suggested to be the limiting step
      for plant nitrogen utilization (H-M. Lam et al. 1995, Plant Cell 7: 887-898). We
      have developed a molecular approach to increase glutamine production in
      transgenic poplar by the overexpression of a conifer GS gene. A chimeric
      construct consisting of the cauliflower mosaic virus 35S promoter fused to pine
      cytosolic GS cDNA and nopaline synthetase polyadenylation region was transferred
      into pBin19 for transformation of a hybrid poplar clone (INRA 7171-B4, Populus
      tremula x P. alba) via Agrobacterium tumefaciens. Transformed poplar lines were
      selected by their ability to grow on selective medium containing kanamycin. The
      presence of the introduced gene in the poplar genome was verified by Southern
      blotting and polymerase chain reaction analysis. Transgene expression was
      detected in all selected poplar lines at the mRNA level. The detection of the
      corresponding polypeptide (41 kDa) and increased GS activity in the transgenics
      suggest that pine transcripts are correctly processed by the angiosperm
      translational machinery and that GS1 subunits are assembled in functional
      holoenzymes. Expression of the pine GS1 gene in poplar was associated with an
      increase in the levels of total soluble protein and an increase in chlorophyll
      content in leaves of transformed trees. Furthermore, the mean net growth in
      height of GS-overexpressing clones was significantly greater than that of non
      transformed controls, ranging from a 76% increase in height at 2 months to a
      21.3% increase at 6 months. Our results suggest that the efficiency of nitrogen
      utilization may be engineered in trees by genetic manipulation of glutamine
      biosynthesis.

PMID- 10592029
TI  - The maize mutant polymitotic affects cell cycle events during microspore
      development
AB  - The maize (Zea mays L.) male-sterile mutant polymitotic (po) was analyzed
      utilizing in-vitro cell culture and immunocytochemistry methods to better
      understand the relationship between the mutant phenotype and cell cycle events
      during microspore development. Using a live meiocyte culture system, initiation
      and progression through abnormal post-meiotic cell cycles at the end of meiosis
      II was documented in the po mutant with a CCD camera and a computer image
      analysis system. Our results showed that premature chromosomal condensation
      precedes abnormal post-meiotic cell cycle progression in the po mutant at the end
      of meiosis II. Temporal analysis of the po mutant in-vitro revealed that
      unsynchronized post-meiotic divisions occurred immediately following the end of
      meiosis II and did not require interaction with the surrounding somatic tissue.
      Furthermore, the altered distribution of p34(cdc2) protein kinase from a nuclear
      to a cytoplasmic location was identified in tetrads during onset of the
      unsynchronized divisions in the po mutant. In contrast, a predominantly nuclear
      location of p34(cdc2) was observed during interphase of the wild-type tetrads at
      the same stage.

PMID- 10592030
TI  - Sucrose metabolism in cyanobacteria: sucrose synthase from Anabaena sp. strain
      PCC 7119 is remarkably different from the plant enzymes with respect to substrate
      affinity and amino-terminal sequence.
AB  - The pathway of sucrose metabolism in cyanobacteria is just starting to be
      elucidated. The present study describes the first isolation and biochemical
      characterization of a prokaryotic sucrose synthase (SS, EC 2.4.1.13). Two SS
      forms (SS-I and SS-II) were detected in Anabaena sp. strain PCC 7119. The isoform
      SS-II was purified 457-fold and its amino-terminal portion sequenced. Substrate
      specificity, kinetic constants, native protein and subunit molecular masses, and
      the effect of different ions and metabolites were studied for SS-II. Anabaena SS
      was shown to be a tetramer with a 92-kDa polypeptide that was recognized by maize
      SS polyclonal antibodies. Some striking differences from plant enzymes were
      demonstrated with respect to substrate affinities, regulation by metal ions and
      ATP, and the amino-acid sequence of the N-terminal region.

PMID- 10592031
TI  - Sucrose synthase activity does not restrict glycolysis in roots of transgenic
      potato plants under hypoxic conditions
AB  - The effect of hypoxia on root development and carbon metabolism was studied using
      potato (Solanum tuberosum L.) plants as a model system. Hypoxia led to a
      cessation of root elongation, and finally to the death of meristematic cells.
      These changes were accompanied by a 4- to 5-fold accumulation of hexoses,
      suggesting that insufficient carbohydrate supply was not the cause of cell death.
      In addition, prolonged hypoxia (96 h) resulted in a 50% increase in activity of
      most glycolytic enzymes studied and the accumulation of glycerate-3-phosphate and
      phosphoenolpyruvate. This indicates that endproduct utilisation may restrict
      metabolic flux through glycolysis. As expected, the activities of alcohol
      dehydrogenase (EC 1.1.1.1) and pyruvate decarboxylase (EC 4.1.1.17) increased
      during hypoxia. Apart from the enzymes of ethanolic fermentation the activity of
      sucrose synthase (SuSy; EC 2.4.1.13) was enhanced. To investigate the in-vivo
      significance of this increase, transgenic plants with reduced SuSy activity were
      analysed. Compared to untransformed controls, transgenic plants showed a reduced
      ability to resume growth after re-aeration, emphasising the crucial role of SuSy
      in the toleration of hypoxia. Surprisingly, analysis of glycolytic intermediates
      in root extracts from SuSy antisense plants revealed no change as compared to
      wildtype plants. Therefore, limitation of glycolysis is most likely not
      responsible for the observed decreased ability for recovery after prolonged
      oxygen starvation. We assume that the function of SuSy during hypoxia might be to
      channel excess carbohydrates into cell wall polymers for later consumption rather
      than fuelling glycolysis.

PMID- 10592032
TI  - Diurnal variations in hydraulic conductivity and root pressure can be correlated
      with the expression of putative aquaporins in the roots of lotus japonicus
AB  - The hydraulic conductivity of excised roots (Lp(r)) of the legume Lotus japonicus
      (Regel) K. Larsen grown in mist (aeroponic) and sand cultures, was found to vary
      over a 5-fold range during a day/night cycle. This behaviour was seen when Lp(r)
      was measured in roots exuding, either under root pressure (osmotic driving
      force), or under an applied hydrostatic pressure of 0.4 MPa which produced a rate
      of water flow similar to that in a transpiring plant. A similar daily pattern of
      variation was seen in plants grown in natural daylight or in controlled
      environment rooms, in plants transpiring at ambient rates or at greatly reduced
      rates, and in plants grown in either aeroponic or sand culture. When detached
      root systems were connected to a root pressure probe, a marked diurnal variation
      was seen in the root pressure generated. After excision, this circadian rhythm
      continued for some days. The hydraulic conductivity of the plasma membrane of
      individual root cells was measured during the diurnal cycle using a cell pressure
      probe. Measurements were made on the first four cell layers of the cortex, but no
      evidence of any diurnal fluctuation could be found. It was concluded that the
      conductance of membranes of endodermal and stelar cells may be responsible for
      the observed diurnal rhythm in root Lp(r). When mRNAs from roots were probed with
      cDNA from the Arabidopsis aquaporin AthPIP1a gene, an abundant transcript was
      found to vary in abundance diurnally under high-stringency conditions. The
      pattern of fluctuations resembled closely the diurnal pattern of variation in
      root Lp(r). The plasma membranes of root cells were found to contain an abundant
      hydrophobic protein with a molecular weight of about 31 kDa which cross-reacted
      strongly to an antibody raised against the evolutionarily conserved N-terminal
      amino acid sequence of AthPIP1a.

PMID- 10592033
TI  - Monoclonal antibodies to adhesive cell coat glycoproteins secreted by zoospores
      of the green alga enteromorpha
AB  - Zoospores of Enteromorpha compressa (L.) Grev. secrete an adhesive cell coat
      which is involved in their attachment to various substrata. Two monoclonal
      antibodies (mAbs), designated Ent 1 and Ent 6, were raised against settled
      zoospores displaying secreted adhesive. Both antibodies labelled specifically the
      anterior region of the cell containing putative adhesive vesicles. During
      settlement the antigens recognised by both mAbs were secreted but whereas Ent 6
      recognised a fibrillar material released within a few minutes of settlement, Ent
      1 recognised components which were associated predominantly with the developing
      cell wall at later time points. Both mAbs also labelled a Golgi-rich region of
      settled spores, suggesting that these antigens are also synthesised after
      settlement. Both mAbs labelled the cell walls of vegetative tissue. Competitive
      enzyme-linked immunosorbent assay indicated that the two antibodies recognise
      separate, but overlapping epitopes. In spore settlement assays the Ent 6
      immunoglobulin strongly reduced initial adhesion at low concentration whereas the
      inhibitory effects of Ent 1 occurred at later time points. On analysis by sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis, (SDS-PAGE) both MAbs
      recognised a major buffer- and SDS-soluble, polydisperse 110-kDa antigen. The 110
      kDa component was present in extracts of zoospores and sporulating tissue, but
      absent, in soluble form, from vegetative tissue. Deglycosylation of zoospore
      extract with anhydrous HF and peptide N-glycosidase digestion, showed that the
      major 110-kDa antigen is an N-linked glycan, and that the epitope is borne by the
      protein component. Time-course experiments showed that the Ent 6 antigen became
      progressively insoluble after zoospore attachment. Taken together, the data
      indicate that the two antibodies recognise separate but closely related antigens
      which have distinctive roles in adhesion and cell wall development.

PMID- 10592034
TI  - Synthesis and degradation of a 28-kDa pod storage protein in french bean
      (Phaseolus vulgaris) plants
AB  - Pod storage protein (PSP) accumulated in developing pods of French bean
      (Phaseolus vulgaris L.) plants, and increasing the PSP mRNA level by pod removal
      resulted in the enhancement of PSP accumulation in pods that formed later. Pod
      storage protein was detected in flowers, young leaves and young stem internodes
      in addition to pods. Accumulation of PSP and its mRNA was induced by sink-removal
      in an organ-specific manner. In addition, wounding induced PSP accumulation
      systemically in leaves. Methyl jasmonate did not induce PSP synthesis but
      enhanced the synthesis that was induced by wounding. In senescing pods, PSP was
      degraded, and degradation products with molecular masses of 20 and 17 kDa were
      detected in the pods. The amount of 20-kDa degradation product was greater than
      that of the 17 kDa product.

PMID- 10592035
TI  - Osmotic water permeability of isolated vacuoles
AB  - We measured the osmotic water permeability (P(os)) of vacuoles isolated from
      onion (Allium cepa L.), rape (Brassica napus L.), petunia (Petunia hybrida Hook.)
      and red beet (Beta vulgaris L.). For all the vacuolar types investigated, P(os)
      values were in the range 200-1000 &mgr;m s(-1). The change in membrane surface
      area induced by an osmotic gradient was smaller than 2-6%. The vacuolar P(os)
      values for red beet and onion were reduced by 1 mM HgCl(2), to 14% and 30% of the
      control values, respectively, but were partially restored to 51% and 76% by 5 mM
      beta-mercaptoethanol. These results suggest that aquaporins were present in all
      the vacuoles tested. In HgCl(2)-treated onion vacuoles, the reduced P(os) (56
      &mgr;m s(-1)) had a low activation energy (approx. 6 kJ mol(-1)), indicating that
      water permeation was still occurring mainly via aquaporins, and that the water
      permeability of the lipid part of the vacuolar membrane is probably very low.

PMID- 10592036
TI  - Rubber particles from four different species, examined by transmission electron
      microscopy and electron-paramagnetic-resonance spin labeling, are found to
      consist of a homogeneous rubber core enclosed by a contiguous, monolayer
      biomembrane
AB  - The physical characteristics of rubber particles from the four rubber (cis-1,4
      polyisoprene) producing species Euphorbia lactiflua Phil., Ficus elastica Roxb.,
      Hevea brasiliensis Mull. Arg., and Parthenium argentatum Gray, were investigated
      using transmission electron microscopy (TEM) and electron-paramagnetic-resonance
      (EPR) spin labeling spectroscopy. Transmission electron microscopy showed the
      rubber particles to be composed of a spherical, homogeneous, core of rubber
      enclosed by a contiguous, electron-dense, single-track surface layer. The
      biochemical composition of the surface layer and its single-track TEM suggested
      that a monolayer biomembrane was the surface structure most compatible with the
      hydrophobic rubber core. The EPR spectra for a series of positional isomers of
      doxyl stearic acid, used to label the surface layer of the rubber particles,
      exhibited flexibility gradients and evidence for lipid-protein interactions for
      all four rubber particle types that is consistent with a biomembrane-like
      surface. The EPR spectra confirmed that the surface biomembrane is a monolayer.
      Thus, rubber particles appear similar to oil bodies in their basic architecture.
      The EPR spectra also provided information on protein location and degree of
      biomembrane penetration that correlated with the known properties of the rubber
      particle-bound proteins. The monolayer biomembrane serves as an interface between
      the hydrophobic rubber interior and the aqueous cytosol and prevents aggregation
      of the particles. An unexpected observation for the probes in pure polyisoprene
      was evidence of an intrinsic flexibility gradient associated with the stearic
      acid molecule itself.

PMID- 10592037
TI  - Harpin induces mitogen-activated protein kinase activity during defence responses
      in Arabidopsis thaliana suspension cultures.
AB  - Elicitation of Arabidopsis thaliana (L.) Heynh. suspension cultures with the
      bacterial protein harpin (from Pseudomonas syringae pv. syringae) induced the
      activation of two kinases of 39 and 44 kDa, as demonstrated by in-gel kinase
      assays using myelin basic protein (MBP) as a substrate. Both these kinases
      appeared to be tyrosine-phosphorylated upon activation, as demonstrated by
      treatment with tyrosine phosphatase and immunoprecipitation using an anti
      phosphotyrosine monoclonal antibody. An inhibitor of mammalian mitogen-activated
      protein kinase (MAPK) activation, PD98059, inhibited harpin-induced MBPK
      activation, but did not inhibit the activity of these kinases. PD98059 also
      inhibited harpin-induced programmed cell death and defence gene expression,
      suggesting the involvement of harpin-induced MAPKs in defence responses in
      Arabidopsis thaliana.

PMID- 10592038
TI  - Acclimation of the summer annual species, lolium temulentum, to CO(2) enrichment
AB  - Lolium temulentum L. Ba 3081 was grown hydroponically in air (350 &mgr;mol mol(
      1) CO(2)) and elevated CO(2) (700 &mgr;mol mol(-1) CO(2)) at two irradiances (150
      and 500 &mgr;mol m(-2) s(-1)) for 35 days at which point the plants were
      harvested. Elevated CO(2) did not modify relative growth rate or biomass at
      either irradiance. Foliar carbon-to-nitrogen ratios were decreased at elevated
      CO(2) and plants had a greater number of shorter tillers, particularly at the
      lower growth irradiance. Both light-limited and light-saturated rates of
      photosynthesis were stimulated. The amount of ribulose-1, 5-bisphosphate
      carboxylase-oxygenase (Rubisco) protein was increased at elevated CO(2), but
      maximum extractable Rubisco activities were not significantly increased. A
      pronounced decrease in the Rubisco activation state was found with CO(2)
      enrichment, particularly at the higher growth irradiance. Elevated-CO(2)-induced
      changes in leaf carbohydrate composition were small in comparison to those caused
      by changes in irradiance. No CO(2)-dependent effects on fructan biosynthesis were
      observed. Leaf respiration rates were increased by 68% in plants grown with CO(2)
      enrichment and low light. We conclude that high CO(2) will only result in
      increased biomass if total light input favourably increases the photosynthesis-to
      respiration ratio. At low irradiances, biomass is more limited by increased rates
      of respiration than by CO(2)-induced enhancement of photosynthesis.

PMID- 10592039
TI  - Photosynthetic acclimation of maize to growth under elevated levels of carbon
      dioxide
AB  - The effects of elevated CO(2) concentrations on the photochemistry, biochemistry
      and physiology of C(4) photosynthesis were studied in maize (Zea mays L.). Plants
      were grown at ambient (350 &mgr;L L(-1)) or ca. 3 times ambient (1100 &mgr;L L(
      1)) CO(2) levels under high light conditions in a greenhouse for 30 d. Relative
      to plants grown at ambient CO(2) levels, plants grown under elevated CO(2)
      accumulated ca. 20% more biomass and 23% more leaf area. When measured at the
      CO(2) concentration of growth, mature leaves of high-CO(2)-grown plants had
      higher light-saturated rates of photosynthesis (ca. 15%), lower stomatal
      conductance (71%), higher water-use efficiency (225%) and higher dark respiration
      rates (100%). High-CO(2)-grown plants had lower carboxylation efficiencies (23%),
      measured under limiting CO(2), and lower leaf protein contents (22%). Activities
      of a number of C(3) and C(4) cycle enzymes decreased on a leaf-area basis in the
      high-CO(2)-grown plants by 5-30%, with NADP-malate dehydrogenase exhibiting the
      greatest decrease. In contrast, activities of fructose 1,6-bisphosphatase and ADP
      glucose pyrophosphorylase increased significantly under elevated CO(2) condition
      (8% and 36%, respectively). These data show that the C(4) plant maize may benefit
      from elevated CO(2) through acclimation in the capacities of certain
      photosynthetic enzymes. The increased capacity to synthesize sucrose and starch,
      and to utilize these end-products of photosynthesis to produce extra energy by
      respiration, may contribute to the enhanced growth of maize under elevated CO(2).

PMID- 10592040
TI  - Heterogeneous inhibition of photosynthesis over the leaf surface of rosa
      rubiginosa L. during water stress and abscisic acid treatment: induction of a
      metabolic component by limitation of CO(2) diffusion
AB  - The contribution of changes in stomatal conductance and metabolism in determining
      heterogeneous photosynthesis inhibition during dehydration and abscisic acid
      (ABA) feeding was investigated using detached leaves of Rosa rubiginosa L. The
      steady-state and maximal rates of electron transport under a transient high CO(2)
      concentration were monitored using chlorophyll fluorescence imaging. The decrease
      in electron transport rate induced by dehydration and ABA treatment almost
      reverted to the control rate under transient high CO(2) availability. Therefore,
      inhibition of photosynthesis was mainly mediated through stomatal closure.
      However, since reversion was not complete, a metabolic inhibition was also
      identified as a decrease in the maximal electron transport rate driven by
      carboxylation. Under dehydration or ABA feeding, as under low ambient CO(2)
      treatment, in 21% or 0.4% O(2), the lower the steady-state electron transport
      was, the lower was the maximal electron transport rate during transient high
      CO(2) availability. We conclude that low CO(2) availability reduced the capacity
      of ribulose-1,5-bisphosphate carboxylase-oxygenase (Rubisco) to drive electron
      transport. The potential contribution of Rubisco deactivation mediated by
      stomatal closure is discussed.

PMID- 10592041
TI  - Gravitropism in Phycomyces: a role for sedimenting protein crystals and floating
      lipid globules.
AB  - To elucidate the graviperception of the unicellular fungus, Phycomyces
      blakesleeanus, sporangiophores were inspected for intracellular structures which
      relocate with respect to gravity. Two structures, paracrystalline proteins (so
      called octahedral crystals) and an aggregate of lipid globules, were identified
      which showed redistribution upon reorientation of the sporangiophore. Octahedral
      crystals occur throughout the sporangiophore, including the apical growing zone,
      and are localized inside vacuoles in which they reside singly or in clusters of
      up to 40 loosely associated individuals. Upon a 90 degrees reorientation of
      sporangiophores, crystal clusters sedimented in approximately 50-200 s from the
      upper to the lower side, corresponding to a speed of 0.5-2 micrometers s-1. Stage
      4 sporangiophores (with sporangium) of three mutants which lack the crystals
      displayed anormal kinetics of gravitropism and substantially reduced bending
      angles in comparison to sporangiophores of the wild type. While horizontally
      placed wild-type sporangiophores reached the vertical position after 10-12 h, the
      crystal-lacking mutants bent maximally 40 degrees-50 degrees upward. In stage-1
      sporangiophores a conspicuous aggregate of lipid globules is positioned about 50
      micrometers below the apex. The globules floated upwards when the sporangiophore
      was placed horizontally forming in this way a cap-like aggregate. It is proposed
      that both the sedimenting protein crystals and the upward-floating globules are
      involved in gravisensing.

PMID- 10592042
TI  - Characterization of two fungal-elicitor-induced rice cDNAs encoding functional
      homologues of the rab-specific GDP-dissociation inhibitor.
AB  - By using the mRNA differential display approach to isolate defense signaling
      genes active at the early stage of fungal infection two cDNA fragments with high
      sequence homology to rab-specific GDP-dissociation inhibitors (GDIs) were
      identified in rice (Oryza sativa L.) suspension cells. Using polymerase-chain
      reaction products as probes, two full-length cDNA clones were isolated from a
      cDNA library of fungal-elicitor-treated rice, and designated as OsGDI1 and
      OsGDI2. The deduced amino acid sequences of the isolated cDNAs exhibited
      substantial homology to Arabidopsis rab-GDIs. Northern analysis revealed that
      transcripts detected with the 3'-gene-specific DNA probes accumulated to high
      levels within 30 min after treatment with a fungal elicitor derived from
      Magnaporthe grisea. The functionality of the OsGDIs was demonstrated by their
      ability to rescue the Sec19 mutant of Saccharomyces cerevisiae which is defective
      in vesicle transport. The proteins, expressed in Escherchia coli, cross-reacted
      with a polyclonal antibody prepared against bovine rab-GDI. Like bovine rab-GDI,
      the OsGDI proteins efficiently dissociated rab3A from bovine synaptic membranes.
      Using the two-hybrid system, it was shown that the OsGDIs specifically interact
      with the small GTP-binding proteins belonging to the rab subfamily. The specific
      interaction was also demonstrated in vitro by glutathione S-transferase resin
      pull-down assay.

PMID- 10592043
TI  - Biosynthetic origin and longevity in vivo of alpha-d-mannopyranosyl-(1 --> 4)
      alpha-d-glucuronopyranosyl-(1 --> 2)-myo-inositol, an unusual extracellular
      oligosaccharide produced by cultured rose cells
AB  - A non-reducing trisaccharide, alpha-D-mannopyranosyl-(1 --> 4)-alpha-D
      glucuronopyranosyl-(1 --> 2)-myo-inositol (MGI) accumulated in the spent medium
      of cell-suspension cultures of 'Paul's Scarlet' rose (Rosa sp.) predominantly
      during the period of rapid cell growth. This trisaccharide was also produced by
      cultures of sycamore (Acer pseudoplatanus L.) but not by those of the
      graminaceous monocots maize (Zea mays L.) and tall fescue grass (Festuca
      arundinacea Schreb.). When added to cultured Rosa cells, [(14)C]MGI was neither
      taken up by the cells nor bound to the cell surface and was not metabolised
      extracellularly. When D-[6-(14)C]glucuronic acid was fed to cultured Rosa cells,
      extracellular [(14)C]MGI started to appear only after a 5-h lag period, compared
      with a 0.5-h lag period for labelling of extracelluar polysaccharides.
      Furthermore, [(14)C]MGI continued to accumulate in the medium for at least 20 h
      after the accumulation of (14)C-polymers had ceased. These observations indicate
      that extracellular MGI was produced from a slowly turning-over pool of a pre
      formed intermediate. Structural considerations indicate that the intermediate
      could be a glucuronomannan or a phytoglycolipid (glycophosphosphingolipid). No
      Rosa polysaccharides could be found that generated MGI in the presence of living
      Rosa cells. We therefore favour phytoglycolipids as the probable biosynthetic
      origin of MGI.

PMID- 10592044
TI  - Alfalfa and tobacco cells react differently to chitin oligosaccharides and
      sinorhizobium meliloti nodulation factors
AB  - Alfalfa (Medicago sativa L.) suspension cultures respond to yeast elicitors with
      a strong alkalinization of the culture medium, a transient synthesis of activated
      oxygen species, and typical late defence reactions such as phytoalexin
      accumulation and increased peroxidase activity. The alkalinization reaction as
      well as the oxidative burst were also observed when tobacco (Nicotiana tabacum L.
      ) cell-suspension cultures were treated with yeast elicitors. Depending on the
      degree of polymerization, N-acetyl chitin oligomers induced the alkalinization
      response in both plant cell-suspension cultures, while only tobacco cell cultures
      developed an oxidative burst. Suspension-cultured tobacco cells responded to
      Sinorhizobium meliloti nodulation factors with a maximal alkalinization of 0.25
      pH units and a remarkable oxidative burst. In contrast, addition of Sinorhizobium
      meliloti nodulation factors to suspension-cultured alfalfa cells induced a slight
      acidification of the culture medium, instead of an alkalinization, but no
      oxidative burst.

PMID- 10592045
TI  - Assembly and disassembly of the peripheral architecture of the plant cell nucleus
      during mitosis
AB  - The architecture of the nuclei of higher plants includes a structure similar to
      the nuclear lamina of vertebrates. Changes in this structure were monitored
      during mitosis in carrot (Daucus carota L.) and celery (Apium graveolens L.)
      cells by immunofluorescence microscopy using an antibody that recognized the
      nuclear-matrix protein NMCP1. This protein has been shown to be localized
      exclusively at the periphery of the nucleus (K. Masuda et al. 1997, Exp Cell Res
      232: 173-187). Immunofluorescence was recognized throughout cells in mitotic
      metaphase, although it was distributed predominantly in the mitotic spindle zone.
      At late anaphase or telophase, the immunofluorescence was localized around each
      set of daughter chromosomes. Immunofluorescence in newly formed daughter nuclei
      was restricted to the periphery of nuclei. This behavior was very similar to that
      of the nuclear lamina of vertebrates, suggesting that the structure located
      between the nuclear envelope and the chromosomes in plants disassembles and
      assembles in parallel with the disintegration and re-formation of the nuclear
      envelope.

PMID- 10592047
TI  - Units, symbols, abbreviations

PMID- 10592046
TI  - Apoptosis detected in hybrids between nicotiana glutinosa and N. repanda
      expressing lethality
AB  - Hybrid lethality is one of the mechanisms for reproductive isolation. Apoptotic
      features were detected in the cells of hybrid seedlings of Nicotiana glutinosa L.
      x N. repanda Willd. Condensation of chromatin and fragmentation of nuclei were
      observed in the leaf protoplasts isolated from hybrid seedlings expressing this
      lethality. Fragmentation of nuclei was correlated with the progression of lethal
      symptoms, as confirmed by fluorimetry of the nuclear DNA using laser scanning
      cytometry. Agarose gel analysis of DNA extracted from hybrid leaves showing
      lethality revealed a specific ladder pattern suggesting nucleosomal fragmentation
      associated with nuclear fragmentation. In-situ detection of DNA fragmentation
      using terminal deoxyribonucleotidyl transferase-mediated dUTP-fluorescein nick
      end labeling (TUNEL) showed that this process occurred in all leaf cells. This is
      the first evidence that apoptosis can induce suicide of hybrid plants, thus
      leading to reproductive isolation.

PMID- 10592048
TI  - Duct changes and K-ras mutations in the disease-free pancreas: analysis of type,
      age relation and spatial distribution.
AB  - Recent molecular studies have suggested that hyperplastic duct lesions of the
      pancreas are potential precursors of pancreatic ductal carcinoma. This study
      examines the type, distribution, age-related incidence and K-ras codon 12
      mutation rate of duct lesions in the normal pancreas. Postmortem pancreases from
      140 patients were screened for the presence of mucinous cell hypertrophy (MHT),
      ductal papillary hyperplasia (DPH), adenomatoid ductal hyperplasia (ADH), and
      squamous metaplasia (SQM). Microdissected cell samples were analyzed for K-ras
      codon 12 mutations by polymerase chain reaction amplification of exon 1 of the K
      ras gene, combined with constant denaturing gel electrophoresis, and analyzed by
      sequencing. Of the 140 specimens 114 showed duct lesions. The lesions were evenly
      distributed throughout the pancreas. They were more common beyond the age of 40.
      MHT was present in 68%, DPH in 36%, ADH in 40%, and SQM in 36% of the cases. K
      ras mutations were found in 19 samples from 15 out of 79 pancreases (18%),
      including all types of duct lesions and a variant of ADH with dense stroma. 67%
      of the K-ras-positive specimens showed the transition GGT to GAT (8) or GTT (5).
      Hyperplastic/metaplastic duct changes of the pancreas increase with age, but
      their distribution pattern in the pancreas differs from that of ductal
      carcinomas.

PMID- 10592049
TI  - 20q13.2 amplification in intraductal hyperplasia adjacent to in situ and invasive
      ductal carcinoma of the breast.
AB  - The 20q13 region harboring recently described putative oncogenes is frequently
      amplified in invasive ductal carcinoma (IDC). The aim of this study was to
      examine the 20q13 copy number in intraduct hyperplasia (IH), atypical duct
      hyperplasia (ADH), and ductal carcinoma in situ (DCIS) adjacent to IDC. In 5
      patients, comparative genomic hybridization (CGH) after laser microdissection
      revealed 20q13 amplification in four of five cases of IH, in all of three cases
      of IH with atypia, all five of DCIS, and all five of IDC. Fluorescence in situ
      hybridization (FISH) confirmed the amplification at 20q13.2 in IH in the two
      specimens analyzed. The amplification rate, however, was higher in DCIS and IDC.
      In phenotypically normal ductal epithelium normal values were found for 20q13
      copy number by FISH (n=2) and CGH (n=5). Although the number of cases presented
      here is small, our results suggest that mutations in the 20q13.2 region in IH may
      be associated with accelerated proliferation and hyperplasia of the ductal
      epithelium. Progression to DCIS and ICD is accompanied by a further increase in
      the 20q13.2 copy number.

PMID- 10592050
TI  - Intravascular ("intimal") epithelioid angiosarcoma: clinicopathological and
      immunohistochemical analysis of three cases.
AB  - Angiosarcomas are rare malignant mesenchymal tumours, characterized
      morphologically by anastomosing vascular channels lined by atypical and
      proliferative active endothelial cells. An epithelioid cytomorphology of tumour
      cells is often seen focally in angiosarcoma, whereas purely epithelioid
      angiosarcomas are rare. Although angiosarcomas show a vascular differentiation
      they are almost never confined to pre-existing blood vessels. We describe three
      cases of intravascular epithelioid angiosarcoma arising in the carotid artery of
      a 60-year-old man, in the infrarenal part of the abdominal aorta and both renal
      arteries of a 69-year-old woman, and in the abdominal aorta of a 68-year-old man.
      In all cases malignant tumour tissue was found incidentally after disobliteration
      of thrombosed vessels. Histologically, purely epithelioid angiosarcoma composed
      of solid sheets of epithelioid tumour cells was seen; immunohistochemistry
      confirmed the endothelial differentiation of neoplastic cells. The reported cases
      show that angiosarcoma can occasionally arise within a pre-existing vessel.

PMID- 10592051
TI  - Mucins and mucin-associated carbohydrate antigens expression in gastric carcinoma
      cell lines.
AB  - Mucins are high-molecular-mass glycoproteins with high carbohydrate content and
      marked heterogeneity both in the apoprotein and in the oligosaccharide side
      chains. Mucin genes are expressed in a regulated manner, namely in the human
      stomach. The first aim of the present study was to characterise the expression of
      mucins and mucin-associated carbohydrate antigens in seven gastric carcinoma cell
      lines, and to compare their expression profiles with those of normal gastric
      tissues and human gastric carcinomas. Secondly, we aimed to see whether or not
      there is an association between the expression of mucins and mucin-associated
      carbohydrate antigens. Our results show that mucin expression in gastric
      carcinoma cell lines: (a) follows in part the mucin expression profile of normal
      gastric mucosa and gastric carcinomas with wide expression of MUC1 and MUC5AC;
      (b) parallels the aberrant pattern of mucin expression observed in human gastric
      carcinomas with occasional expression of MUC2, MUC3, MUC4 and MUC5B; (c) does not
      include, at least in our series, the expression of MUC6 mucin; and (d) follows in
      part the differentiation pattern of the carcinomas from which the cell lines
      originated, keeping S-Tn expression in cell lines derived from glandular
      carcinomas. Our results further demonstrate that there is no apparent
      relationship between the mucin core proteins and the simple mucin-type or Lewis
      carbohydrate antigens.

PMID- 10592052
TI  - Immunocytochemical investigation of catalase and peroxisomal lipid beta-oxidation
      enzymes in human hepatocellular tumors and liver cirrhosis.
AB  - A significant reduction of catalase activity, a peroxisomal marker enzyme, occurs
      in human hepatic neoplasias, but no information is available on other peroxisomal
      proteins. We have studied by means of immunohistochemistry four specific proteins
      of peroxisomes (catalase and three enzymes of lipid beta-oxidation) in human
      hepatocellular tumors of various differentiation grades from adenoma to
      anaplastic carcinoma. In all tumors, except the adenomas, the tumor cells
      contained fewer peroxisomes than extrafocal hepatocytes and the reduction of
      antigenic sites in the tumor types generally correlated with the degree of tumor
      dedifferentiation as assessed by classical histopathological criteria. Two poorly
      differentiated tumors had no detectable peroxisomes at all. There were no major
      differences in the intensities of the immunocytochemical staining for all four
      studied peroxisomal antigens in different tumors, suggesting that the neoplastic
      transformation affects the biogenesis of the entire organelle and not merely the
      individual peroxisomal enzyme proteins. Some tumors exhibited a distinct
      peripheral distribution of peroxisomes. In cases with associated liver cirrhosis,
      the hepatocytes in the adjacent liver showed marked peroxisome proliferation,
      forming large perinuclear aggregates, occupying occasionally the entire
      cytoplasm. Taken together, our observations indicate that peroxisomes are
      significantly altered in both hepatocellular tumors and liver cirrhosis and,
      thus, could be responsible for some of the metabolic derangements observed in
      those disease processes.

PMID- 10592053
TI  - Involvement of tenascin-C in proliferation and migration of laryngeal carcinoma
      cells.
AB  - Tenascin-C (TN-C) is an extracellular matrix glycoprotein upregulated in various
      pathological processes. In this study, we investigated its distribution in
      dysplasia and carcinoma of the human larynx using immunohistochemistry and in
      situ hybridization (ISH) techniques. In all cancer tissues, TN-C immunostaining
      was markedly increased in the stroma, especially around the cancer cell nests. In
      addition, cytoplasmic staining of cancer cells was also observed in 62.5% of the
      invasive cases, the cells being distributed in the periphery of the nests
      adjacent to the stroma. TN-C mRNA signals in cancer cells were detected in all
      six cases examined by ISH. Furthermore, in vitro evaluation of the roles of TN-C
      demonstrated an increase in the proliferating cell fraction in a dose-dependent
      manner. In a wound closure assay, the addition of TN-C promoted migration. We
      conclude that TN-C secreted by cancer cells may be involved in their
      proliferation and migration in an autocrine fashion.

PMID- 10592054
TI  - Expression of the fibroblast growth factor receptor 1-4 genes in glomeruli in
      anti-Thy1.1 mesangial proliferative glomerulonephritis.
AB  - Basic fibroblast growth factor (FGF2) is generally known to induce proliferation
      of cultured mesangial cells and is expressed in proliferative mesangial cells in
      anti-Thy1.1 mesangial proliferative glomerulonephritis (anti-Thy1.1 GN). The
      distribution of the FGF receptor (FGFR) has not been studied in anti-Thy1.1 GN,
      so we used in situ hybridization to determine whether cells expressing FGFR1-4
      mRNAs could be detected. In normal rats, all glomeruli were negative for FGFR1-4
      mRNA, but those of the mesangial proliferative phase expressed FGFR1-4 mRNA in
      proliferative mesangial cells. Proliferation of mesangial cells has not been
      observed in normal rats injected with FGF2( )but it has been noted in anti-Thy1.1
      rats injected with FGF2. These data and our results demonstrate that mesangial
      cells produce and release FGF2( )after injury and that during the proliferative
      phase these cells upregulate FGFR in vivo. This study is the first to demonstrate
      expression of FGFR1-4 mRNAs in pathological glomeruli of anti-Thy1.1 GN. The FGF2
      and FGFR1-4 genes were expressed in the proliferative mesangial cells.
      Upregulation of FGFR is necessary for mesangial proliferation by FGF2.

PMID- 10592055
TI  - Relaxin promotes differentiation of human breast cancer cells MCF-7 transplanted
      into nude mice.
AB  - Previous studies showed that the hormone relaxin acts on human breast cancer MCF
      7 cells in vitro by modulating cell proliferation and promoting cell
      differentiation toward a duct epithelial phenotype. The present study was
      designed to investigate whether relaxin retains these properties when acting in
      vivo on MCF-7 cell tumors developed in athymic nude mice. Mice bearing MCF-7 cell
      tumors transplanted under the mammary fat pad and estrogenized to sustain tumor
      growth were treated systemically with relaxin (10 microg/day) for 19 days.
      Vehicle-treated mice were used as controls. Thirty days later, the mice were
      sacrificed and tumor fragments were analyzed by light and electron microscopy and
      immunocytochemistry. Measurements of tumor volume were recorded weekly for the
      overall experimental period. The results obtained indicate that relaxin treatment
      promotes differentiation of tumor cells towards both myoepithelial-like and
      epithelial-like cells, as judged by the ultrastructural features of the cells and
      by the increased expression of smooth muscle actin and cadherins. Measurements of
      tumor size and of the number of cycling cells show that relaxin, at the doses and
      times of exposure used in this study, does not significantly influence tumor
      growth and cell proliferation.

PMID- 10592056
TI  - Malignant myoepithelioma of the breast metastasizing to the jaw.
AB  - A breast tumor in a 52-year-old female was interpreted as a malignant
      myoepithelioma based on morphological and immunohistochemical studies. The tumor
      consisted of elongated cells with clear cytoplasm and lacked glandular
      components. The tumor cells were stained positively for keratin, S-100 protein,
      glial fibrillary acidic protein (GFAP) and muscle-specific actin. Distant
      metastasis in the right jaw developed 8 years after the initial surgery and the
      metastatic deposit showed a similar morphology and immunoreactivity.
      Myoepithelial tumors are generally considered as benign or low-grade lesions and
      distant metastasis has been rarely documented. The present case presents the
      possibility of delayed occurrence of distant metastasis in myoepithelial tumor of
      the breast.

PMID- 10592057
TI  - Extraskeletal myxoid chondrosarcoma: multimodal diagnosis and identification of a
      new cytogenetic subgroup characterized by t(9;17)(q22;q11).
AB  - Extraskeletal myxoid chondrosarcoma is a rare malignant soft tissue tumour that
      can be difficult to diagnose correctly, especially preoperatively. We describe
      four cases of extraskeletal myxoid chondrosarcoma of the extremities diagnosed by
      a multimodal approach. The cytological examination of fine-needle aspirates
      showed small and round, mildly pleomorphic cells lying in sheets and cords, but
      also dispersed within a myxoid and metachromatic intercellular substance.
      Histological, electron microscopic and immunocytochemical examination also
      yielded findings compatible with the diagnosis of extraskeletal myxoid
      chondrosarcoma. Cytogenetic analysis demonstrated a t(9;22)(q22;q12) in two
      tumours and a t(9;17)(q22;q11) in the third and fourth. The translocation
      t(9;22)(q22;q12) has been described repeatedly in extraskeletal myxoid
      chondrosarcoma but never in other tumours; hence, the detection of this
      pathognomonic chromosome abnormality in short-term cultured cells from fine
      needle aspirates verified the diagnosis in two of the cases. The t(9;17)(q22;q11)
      found in the last two cases probably represents a new cytogenetic subgroup of
      extraskeletal myxoid chondrosarcoma as it, too, is unknown in other contexts. The
      multimodal approach taken in these four cases enabled a definite diagnosis of a
      rare malignant tumour whose cytological and histological features alone are
      usually not sufficiently distinct to rule out other differential diagnostic
      possibilities.

PMID- 10592058
TI  - Announcements

PMID- 10592059
TI  - Newsletter of the european society of pathology

PMID- 10592060
TI  - Comparative anatomy and ontogeny of the ductus arteriosus, a vascular outsider.
AB  - In its function of separating pulmonary and systemic arterial blood flow, the
      ductus arteriosus, which connects both circuits, either closes permanently at a
      certain stage in development or attains a capacity to close and reopen depending
      on the physiological needs in certain species. In air-breathing vertebrates
      varying from lungfish to mammals, the ductus arteriosus derives from the sixth
      pharyngeal arch artery, and in preparation for its specific task, undergoes its
      own unique differentiation programme, starting early in development. To date, the
      mechanisms involved in defining this unique status, as compared to the other
      great arteries, are unclear. This review clarifies some of the elusiveness of the
      ductus arteriosus. It includes a comparative description of this artery in
      species exemplifying the different classes of air-breathing vertebrates, and
      illustrates similarities and differences in morphogenesis and closure mechanisms
      among the species. It also deals with possible influences of vascular innervation
      and with congenital anomalies in which the ductus arteriosus is involved. New
      data suggest that HOXB5 expression in the neural crest along the dorsal half of
      the sixth arch artery may be involved in the instigation of ductus arteriosus
      differentiation.

PMID- 10592061
TI  - Morphogenesis of the primary arterial trunks of the forelimb in the rat embryos:
      the trunks originate from the lateral surface of the dorsal aorta independently
      of the intersegmental arteries.
AB  - It has been believed that the primary arterial trunk of the mammalian forelimb is
      derived from the 7th intersegmental artery. Here we examined the early
      morphogenesis of the arteries and nerves in the forelimb region by adopting a
      method that combined intravascular dye-injection with nerve staining to whole
      mounted rat embryos. The study was carried out on greater numbers of specimens at
      smaller intervals of embryonic stages and from earlier stages than those in
      previous reports. We report that: (1) The multiple primary arterial trunks in the
      forelimb region (primary subclavians) originate directly from the lateral surface
      of the dorsal aorta independently of the intersegmental arteries, previous to the
      formation of limb buds. (2) The tips of the 8th (and the 9th) primary subclavians
      that originate from the aorta near the origin of the 8th (or the 9th)
      intersegmental artery bend cranially and/or caudally. With the formation of limb
      bud, they extend to form the longitudinal trunks in the presumptive axillary
      region. The primary arteries in the free arm region branch off from this
      longitudinal trunk, and one of them develops into the axial artery. (3) The
      origins of the primary subclavians shift their positions on the surface of the
      dorsal aorta and approach the origins of the neighboring intersegmental arteries
      to join them, and then replace the latter. Consequently, the primary subclavians
      appear to be "the lateral branches of the in tersegmental arteries." (4) The 8th
      primary subclavian is dominant at first, but is replaced by the 7th primary
      subclavian, which develops into the definitive subclavian artery. (5) With the
      brachial nerve plexus formation, the axillary arterial plexus derived from the
      longitudinal trunk develops to form two stems of the axillary artery.

PMID- 10592062
TI  - Differential development of cholinergic-like neurons in the superior olive: a
      light microscopic study.
AB  - To better understand the development of cholinergic-like neurons within the
      superior olivary complex, we investigated the onset and distribution of two well
      known markers of cholinergic-like neurons in hamsters: choline acetyltransferase
      (ChAT) and acetylcholinesterase (AChE). From embryonic day (E) 14 through
      postnatal day (P) 0, olivary cells immunopositive for ChAT were restricted to the
      rostral periolivary (RPO) area. Between P0 and P3, ChAT-positive cells are found
      in progressively more caudal and ventral periolivary locations. Although rostral
      and ventral periolivary cells exhibited an early onset of ChAT expression, stable
      numbers were not reached until P4. In contrast, ChAT expression within the
      lateral superior olive (LSO) is not visible until after P0 and higher numbers of
      ChAT-positive cells are obtained by P5. The AChE expression lags several days but
      follows roughly the same pattern of onset as for ChAT. Additionally in rostral
      and ventral periolivary regions as well as in the LSO, there were fewer AChE
      labeled cells than ChAT-labeled cells. The observed temporal relationships in
      cholinergic-like expression within olivary cells suggest that different
      cholinergic-like populations may be defined on the basis of the onset of
      neurotransmitter-related enzymes: RPO cells are first, cells in ventral
      periolivary regions are second, and cells associated with the LSO are last. The
      differences observed in the onset of ChAT and AChE expression may reflect
      differences in the timing of target innervation as well as differences in
      synaptogenesis.

PMID- 10592063
TI  - Increase of segments of elastic-type blood vessel walls in fetal placental stem
      villi during pre-eclampsia at term.
AB  - In recent studies we described the presence of elastic-type blood vessels within
      trunci and rami chorii of human placental stem villi. For systemic and pulmonary
      hypertension it is known that elastic fibres are enhanced in arteries. The aim of
      our study was, therefore, to examine whether pre-eclampsia may lead to an
      increase of elastic tissue fibres in blood vessel walls of placental stem villi
      and whether there are differences in the thickness of blood vessel walls within
      these villi when compared to normotensive pregnant women. Twenty-six women with
      uncomplicated pregnancies and 25 patients with pre-eclampsia were investigated.
      Unfixed cryostat serial sections were processed for conventional orcein staining
      and for the demonstration of alpha-actin-immunoreactivity. The intensity of
      orcein staining of stem villus blood vessel walls was evaluated by a
      semiquantitative score method. Significant higher intensities of orcein staining
      (P<0.00001) were calculated for blood vessel walls of placentae with pre
      eclampsia. The amount of thick stem villus vessels (>41 microm) increased during
      pre-eclampsia from 39 gestational weeks onwards. Our study demonstrates that
      segments of thick blood vessel walls and elastic-type vessel walls are increased
      in placental stem villi of patients with pre-eclampsia. This reaction may protect
      the fetal placental vessels and avert an increase of the fetal hypertension.

PMID- 10592064
TI  - Unusual cell ultrastructure in ventral epidermis of the African reed frog
      Hyperolius viridiflavus, (Anura; Hyperoliidae).
AB  - The stratum corneum of the epidermis of Hyperolius viridiflavus contains several
      replacement layers. The outer layer is covered by mucopolysaccharide secretion.
      H. viridiflavus in their dry phase do not moult the sloughed off layers; these
      remain attached to the stratum corneum. Long and slender pillar-like cells
      situated under the stratum corneum extend through the stratum granulosum, stratum
      germinativum, and the basement membrane into the dermis. These cells abound in
      tonofilaments. Flask-shaped cells rich in mitochondria, reaching under the
      stratum corneum, extend into the stratum granulosum. They show delicate,
      membranous infoldings in their neck-like apical part. Granule-cells, arranged in
      2 or 3 layers are situated in the stratum granulosum between the stratum corneum
      and germinativum. The germinative cells are large and separated from each other
      by wide intercellular spaces. ATPase activity was localized cytochemically in the
      baso-lateral cell membranes bordering with the intercellular spaces under the
      stratum corneum.

PMID- 10592065
TI  - The extracellular matrix of rat pacinian corpuscles: an analysis of its fine
      structure.
AB  - The Pacinian corpuscle consists of a sensory axon terminal that is enveloped by
      two different structures, the inner core and the capsule. Since proteoglycans are
      extremely water soluble and are extracted by conventional methods for electron
      microscopy, the current picture of the structural composition of the
      extracellular matrix in the inner core and the capsule of the Pacinian corpuscle
      is incomplete. To study the structural composition of the extracellular matrix of
      the Pacinian corpuscles, cationic dyes (ruthenium red, alcian blue, acridine
      orange) and tannic acid were applied simultaneously with the aldehyde fixation.
      The interosseal Pacinian corpuscles of the rat were fixed either in 2%
      formaldehyde and 1.5% glutaraldehyde, with the addition of one of these cationic
      dyes or, in Zamboni's fixative, with tannic acid added. The cationic dyes and
      tannic acid revealed a different structural pattern of proteoglycans in the
      extracellular matrix in the inner core and in the capsule of the rat Pacinian
      corpuscles. The inner core surrounding the sensory axon terminal is a compartment
      containing proteoglycans that were distributed not only in the extracellular
      matrix but also in the cytoplasm of the lamellae. In addition, this excitable
      domain was separated from the capsular fluid by a thick layer of proteoglycans on
      its surface. An enlarged interlamellar space of the capsule contained large
      amounts of proteoglycans that were removed by digestion with chondroitinase-ABC.
      Ruthenium red and alcian blue provided only electron dense granules, probably
      corresponding to collapsed monomeric proteoglycan molecules. Acridine orange and
      tannic acid preserved proteoglycans very well and made it possible to visualize
      them as "bottlebrush" structures in the electron microscope. These results show
      that the inner core and the capsule of rat Pacinian corpuscles have different
      structural patterns of proteoglycans, which are probably involved in different
      functions.

PMID- 10592066
TI  - Development of the rat phrenic nerve and the terminal distribution of phrenic
      afferents in the cervical cord.
AB  - The development of the right phrenic nerve and the distribution of phrenic nerve
      afferents to the spinal cord have been examined with the aid of electron
      microscopy and carbocyanine dye retrograde diffusion along the phrenic nerve,
      respectively. The formation of fascicles in the right phrenic nerve commenced at
      E15, while Schwann cells penetrated the nerve from E17 and myelination began at
      P0. The total number of axons in the right phrenic nerve decreased from E15 (943,
      965 in two animals) to E19 (539, 582), remained steady until P0 (564, 594) before
      rising to almost adult values by P7 (689, 934). The postnatal rise in number of
      axons appears to be due to a large influx of unmyelinated axons. Carbocyanine dye
      tracing revealed that at E13, neurons in dorsal root ganglia C(2) to C(6)
      contributed peripheral processes to the phrenic nerve. Phrenic afferents arrived
      in the spinal cord by E13 and penetrated the dorsal horn at E14. Three terminal
      fields for phrenic afferents became apparent by E17. These were:(1) in the
      central parts of laminae I to V, (2) medially in laminae V to VII or adjacent
      area X near the central canal, (3) in laminae VIII and IX, around the
      differentiating phrenic motoneurons. Around the time of birth, some phrenic
      afferents in the second group were distributed across the midline and could be
      seen to approach the ventromedial dendritic bundle of phrenic motoneurons on the
      contralateral side, but these were no longer seen by P4. Just before birth (E21),
      afferents in the third group divided into two further subsets, supplying the
      dorsolateral and ventromedial groups of phrenic motoneuron dendritic bundles,
      respectively. Our findings strongly suggest that phrenic afferent differentiation
      is largely complete by birth.

PMID- 10592067
TI  - Retinoic acid acts during peri-implantational development to alter axial and
      brain formation.
AB  - All-trans retinoid acid (RA) induces a stereotypic spectrum of stage-specific
      malformations in vertebrate conceptuses. The present work evaluated the anatomic
      and biochemical effects of exposure to RA in mouse embryos at a peri
      implantational stage of development - gestational day (GD) 5. The RA receptors
      (RARs) beta and gamma, the retinoid X receptors (RXRs) alpha and beta, and the
      cellular retinoid acid binding proteins (CRABPs) I and II were detected by RT-PCR
      in both control and treated individual GD 5 decidua/embryo complexes 3 h after RA
      injection, indicating the presence of the mRNAs coding for the proteins that
      mediate the effects of RA. In contrast, the RAR alpha mRNA was detected in some
      but not all decidua/embryo complexes, both control and treated, suggesting that
      its expression is initiated at approximately GD 5, while RXR gamma mRNA was not
      detected. Examination of the control and RA-exposed embryos on GD 10, 12, or 17
      showed that greater than 50% of the RA-exposed embryos were adversely affected,
      many with defects found only after serial histopathological examination. The
      malformations were localized primarily in the central nervous system, the
      branchial arches, and their derivatives. These terata included excessive folding
      and elevation of the neural tube floor plate, exencephaly (with detachment of the
      cephalic neuroepithelium and rarefied cephalic mesenchyme), persistent patency of
      Rathke's pouch, small trigeminal ganglia, neural diverticula (chiefly from the
      spinal cord), and/or various optic and otic defects. Unexpectedly, limb
      reduplications were not apparent in RA-exposed fetuses. Those litters examined on
      GD 17 had a high percentage of resorbed or malformed implantations, and the few
      apparently normal fetuses were developmentally delayed with respect to bone
      ossification. These data confirm that the development of neural- and neural crest
      derived structures are severely disrupted by RA exposure prior to initial
      specification of the neural plate and suggest that many of the proteins that
      regulate RA signaling are available in early vertebrate embryos at this
      developmental stage.

PMID- 10592068
TI  - 46, XY, del (3) (pter-->p25) syndrome: further delineation of the clinical
      phenotype.
AB  - A boy with monosomy for the distal part of the short arm of chromosome 3 is
      described. The clinical features this patient has in common with the previously
      reported cases include pre- and post-natal growth delay, microcephaly,
      craniofacial dysmorphism and mental retardation. In addition, minor abnormalities
      not previously reported were observed, such as snapping thumbs, dorsiflected big
      toes, connecting anterior and posterior fontanelles at birth, nasolacrimal duct
      stenosis and double urethral meatus. Conclusion These five new clinical findings
      may help in further delineation of the syndrome and allow its early recognition.
      A complete revision of clinical findings published in literature is reported.

PMID- 10592069
TI  - A search for chromosome 22q11.2 deletions in a series of 176 consecutively
      catheterized patients with congenital heart disease: no evidence for deletions in
      non-syndromic patients.
AB  - Microdeletions in chromosome 22q11.2 are associated with DiGeorge syndrome (DGS),
      velo-cardio-facial syndrome (VCFS), and several other syndromes, collectively
      referred to as DG/VCF. Non-dysmorphic patients with cardiac defects have also
      been attributed to deletions in this chromosomal region. In this study 157
      consecutively catheterized patients with isolated, non-syndromic cardiac defects,
      and 25 patients with cardiac defects and additional stigmata (10 of whom were
      clinically diagnosed as DG/VCF cases prior to chromosome analysis) were analysed
      by fluorescence in situ hybridization with the DGS-specific probe D0832.
      Chromosome 22q11.2 deletions were observed only in the ten patients with the
      clinical diagnosis of DG/VCF. Conclusion In a large unselected cohort of patients
      with congenital heart disease no association between isolated or non-syndromic
      heart defects and the 22q11.2 microdeletion was observed. One can conclude that
      testing for the 22q11.2 microdeletion is clearly indicated in cases when even
      mild extracardiac abnormalities are present, particularly in very young infants.

PMID- 10592070
TI  - Breast-feeding influences thymic size in late infancy.
AB  - We have previously shown that breast-fed infants have a considerably larger
      thymus at 4 months than formula-fed infants. The aim of the present study was to
      investigate whether breast-feeding also influences the thymic size in late
      infancy. In a cohort of 50 infants, all being partially breast-fed when recruited
      at 8 months, ultrasound assessment of the thymic index (a volume estimate) was
      performed at both 8 and 10 months of age. At 10 months the thymic index was
      significantly higher in those still being breast-fed compared to infants who had
      stopped breast-feeding between 8 and 10 months of age (P=0.05). This difference
      became more significant when controlled for the influence of infectious diseases
      (P=0.03). In infants still breast-fed at 10 months there was a significant
      correlation between the number of breast-feeds per day and their thymic index
      (P=0.01). Conclusion The effect of breast-feeding on thymus size is likely to be
      caused by immune modulating factors in breast milk. Breast milk influences thymic
      size in late infancy.

PMID- 10592071
TI  - Neonatal Escherichia coli meningitis: spinal adhesions as a late complication.
AB  - We describe two boys who had severe spinal complications in adolescence after a
      favorable initial recovery from neonatal Escherichia coli meningitis. Due to
      spinal granulomatous adhesions, one boy died after an attempted scoliosis
      operation (high cord lesion). The other showed severe progressive neurological
      deterioration with spinal and cerebellar symptoms. Conclusion The severe
      complication of chronic arachnoiditis with spinal adhesion may occur many years
      after neonatal acute bacterial meningitis.

PMID- 10592072
TI  - Hepatic steatosis: a frequent non-specific finding in HIV-infected children.
AB  - Thirty HIV-infected children were cross-sectionally examined for morphologic
      hepatic abnormalities, using ultrasonography or histology. Abdominal
      ultrasonography was performed in 27 children. The liver structure was normal in
      four patients, one of whom had moderate symptoms of the HIV infection and three
      of them severe symptoms. Abnormal liver structure, compatible with hepatic
      steatosis, was found in 23 (85%) patients. Five of them were in an early stage of
      the HIV infection (category N or A), three patients were ranked in category B and
      15 patients in category C. Histological examination of the liver was performed in
      11 children and steatosis was documented in ten (91%). In seven (70%) of these
      ten children steatosis had been suspected by ultrasonography. In conclusion,
      steatosis is common in HIV-infected children. It is non-specific and has no
      impact on disease, diagnostic evaluation or management. Conclusion
      Ultrasonography is a sensitive, accurate, non-invasive screening tool. It is more
      reliable than liver function tests.

PMID- 10592073
TI  - Ceftriaxone-associated nephrolithiasis and biliary pseudolithiasis.
AB  - Biliary pseudolithiasis has been reported in patients who received ceftriaxone
      therapy. In addition to biliary sludge formation occasional reports of
      ceftriaxone-induced nephrolithiasis have been published. In general, these
      adverse effects will develop after seven to ten days of treatment. We report on a
      seven-year-old boy with ceftriaxone-associated biliary pseudolithiasis and
      nephrolithiasis four days after initiation of treatment. Patients receiving a
      high dose of ceftriaxone and developing colicky abdominal pain should be
      considered for ultrasound and a change in antibiotic therapy if appropriate.

PMID- 10592074
TI  - Glucose transporter type 1 deficiency: a study of two cases with video-EEG.
AB  - Glucose transporter type 1 (GLUT1) deficiency is an inborn error of glucose
      transport. Clinical manifestations are presumed secondary to reduced glucose
      transport across the blood brain barrier, and include seizures, abnormal tone,
      developmental delay and hypoglycorrhachia. A high index of suspicion is important
      as GLUT1 deficiency is a potentially treatable cause of mental retardation. We
      studied two affected children by continuous video-EEG in order to better
      understand the cause of the clinical manifestations and improvement on a
      ketogenic diet. The EEG was characterized by generalized paroxysmal 2-2.5 Hz
      spike-wave discharges, although normal EEGs were also obtained. Atypical absence
      seizures were the most prominent clinical seizure. Epileptiform activity and
      clinical seizures occurred in both children while acutely ketotic and non
      ketotic, but were markedly more frequent in one child when non-ketotic.
      Discharges were not associated with a reduction in substrate for brain metabolism
      in the blood at that time. Conclusion Atypical absence seizures are common in
      glucose transporter type 1 deficiency and should alert the clinician to the
      possibility of this treatable disorder when present in a young child with
      developmental delay. Our data suggest that the therapeutic mechanism of the
      ketogenic diet in this disorder is more complicated than simply delivering
      ketones as an alternative substrate for brain metabolism.

PMID- 10592075
TI  - Quality assurance in day surgery: do we do enough for the parents to prevent
      stress?
AB  - In order to identify and analyse the factors associated with stress for the
      parents during day surgery, we performed a survey analysis of 568 parents whose
      children underwent surgery consecutively during an 18-month period. Of 368
      parents who returned the questionnaire, (follow up rate=65%), 16% experienced the
      stress associated with day surgery as moderate to severe. The following factors
      had a significant positive association with the amount of stress: feeling of
      insufficient preparation (odds ratio; 95% confidence interval) 3. 34 (1.36-8.26;
      P=0.002), insecurity in nursing care at home 3.36 (1. 43-11.01; P=0.01), problems
      at home such as fever, vomiting, sleep disorders and others 3.15 (1.72-5.8;
      P=0.0007), problems with postoperative pain at home 2.43 (1.38-4.3); P=0.008),
      speaking a foreign language 2.28 (1.08-4.78); P < 0.0001) and no previous surgery
      1.31 (0.76-2.27); P=0.03). Analysing these factors showed that often not the
      problems per se, but rather the insecurity in dealing with them contributed to
      the experienced stress. Conclusion In order to improve the quality of health
      care, more pronounced attention has to be given to the parents needs and
      expectations.

PMID- 10592076
TI  - Local reactions and IgE antibodies to pertussis toxin after acellular diphtheria
      tetanus-pertussis immunization.
AB  - Local reactions and pertussis toxin specific immunoglobulin E antibodies (PT-IgE)
      were investigated in healthy children following primary and booster immunization
      with a combined diphtheria tetanus acellular pertussis vaccine (DTPa) including
      pertussis toxin, filamentous haemagglutinin and pertactin. A primary series of
      DTPa was administered to 150 infants, and 104 of them received a booster dose of
      DTPa combined with inactivated polio vaccine at 2 years of age. PT-IgE was
      measured in serum samples from 72 children using a modified nitrocellulose RAST.
      Primary immunization was associated with low incidence of local reactions (1%
      5%). After the booster dose 21% of children had a local reaction >/=20 mm. Local
      reactions after the booster dose tended to be more common in children who had
      experienced reaction at primary immunization. PT-IgE was detected in 18% and 86%
      of children following primary and booster vaccinations, respectively. Allergic
      and non-allergic children did not differ in PT-IgE responses. After primary
      immunization, elevated PT-IgE levels were found more often in children with a
      family history of allergy than in those without known allergy in the family.
      Children with local reactions had significantly higher pre- and post-booster PT
      IgE levels and median post-booster pertactin IgG and diphtheria-IgG levels than
      children without local reactions. Conclusion Acellular pertussis immunization
      induces IgE antibodies to pertussis toxin, especially after booster vaccination.
      The higher median pre- and post-booster levels of pertussis toxin specific
      immunoglobulin E and post-booster levels of IgG to pertactin and diphtheria in
      children with local side-effects reflect a multifactorial immunological mechanism
      of such reactions.

PMID- 10592077
TI  - Shwachman-Diamond syndrome: early bone marrow transplantation in a high risk
      patient and new clues to pathogenesis.
AB  - Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterised
      by exocrine pancreas insufficiency, metaphyseal dysostosis and bone marrow
      dysfunction. Recurrent severe bacterial infections and susceptibility to
      leukaemia are the major causes of morbidity and mortality occurring
      preferentially in patients with pancytopenia and features of myelodysplasia. Here
      we report a patient with SDS leading to recurrent bacterial infections and a
      deteriorating condition since early infancy. Extensive investigations disclosed
      severe pancytopenia, myelodysplasia and a clonal cytogenetic abnormality,
      inv(14)(q11q32), as risk factors of leukaemic transformation. He therefore
      underwent allogeneic geno-identical bone marrow transplantation which resulted in
      correction of all haematological and immunological abnormalities within an 18
      month follow up period. Conclusion Bone marrow transplantation may be considered
      early as a valuable treatment option especially in high risk Schwachman-Diamond
      syndrome patients anticipating malignant transformation, life-threatening severe
      infections or further organ damage.

PMID- 10592078
TI  - A 7-month-old child with a clavicular swelling since birth. Diagnosis: congenital
      pseudarthrosis of the clavicle.

PMID- 10592079
TI  - A 15-year-old girl with a large lumbosacral abscess. Diagnosis: spinal
      tuberculosis.

PMID- 10592080
TI  - Community acquired pneumonia: review of investigations, aetiology, treatment and
      outcome for inpatients from a UK centre.

PMID- 10592081
TI  - Confirmation of Angelman syndrome in a boy previously reported as having Becker
      muscular dystrophy and severe mental retardation.

PMID- 10592082
TI  - Beta-blocker therapy in an infant with pulmonary hypertension.

PMID- 10592083
TI  - Inhalation of helium, a simple test to identify pneumoperitoneum secondary to
      pulmonary air leakage.

PMID- 10592084
TI  - Oesophageal varices in a child after neonatal correction of an infradiaphragmatic
      total anomalous pulmonary venous return.

PMID- 10592085
TI  - Chronic enteroviral meningo-encephalitis in X-linked agammaglobulinaemia:
      favourable response to anti-enteroviral treatment.

PMID- 10592086
TI  - Hyperinsulinism and weight loss in obese children.

PMID- 10592087
TI  - An unusual presentation of trisomy 9p syndrome with a partial Dandy-Walker
      malformation.

PMID- 10592089
TI  - Preface

PMID- 10592090
TI  - The prevention of preterm birth with the use of antibiotics.
AB  - Infection is a well recognised cause of spontaneous early preterm labour. Preterm
      labour of infective aetiology is refractory to the use of tocolytic agents and
      affected women have a higher risk of subsequent chorio-amnionitis and neonatal
      infection. Antibiotics used prophylactically for the prevention of preterm labour
      are more likely to be successful if given systemically. Intravaginal antibiotics
      are only likely to be of benefit if they are used early in the second trimester
      and in those women in whom there is full expression of abnormal genital tract
      flora (grade III bacterial vaginosis on Gram stain of vaginal secretions).
      Antibiotic treatment for women far removed from term offers significant benefit
      with respect to pregnancy prolongation. The value of extended antibiotic
      treatment is unclear since this may lead to the development of resistant
      bacterial strains. CONCLUSION: The evidence with respect to the use of
      antibiotics for women in preterm labour is inconsistent though there is a trend
      toward benefit.

PMID- 10592091
TI  - Cooling the asphyxiated brain - ready for clinical trials?
AB  - Recent research using newborn animal models of hypoxia-ischaemia has shown that
      cooling the subject from 3 to 6 degrees C starting after the insult and lasting
      up to 72 h offers long-lasting neuroprotection. One concern is that additional
      stress during hypothermia seems to reduce the beneficial effect. Phase 1 studies
      on cooling severely asphyxiated infants have not yet revealed any systemic
      adverse effects. CONCLUSION: The evidence is strongly in favor of hypothermia
      reducing brain damage after asphyxia and the time has come for undertaking
      randomized trials.

PMID- 10592092
TI  - Hypoglycaemia and the neonatal brain.
AB  - There has been much controversy and confusion regarding potential damage caused
      to the neonatal brain by low blood glucose levels. Previous studies of outcome
      after neonatal hypoglycaemia are flawed by many factors including retrospective
      data collection and inability to control for co-existing clinical complications.
      There is no doubt that hypoglycaemic brain damage does occur but the severity and
      duration of low blood glucose levels required to cause lasting harm varies
      between subjects and is related to the ability of each baby to mount a protective
      response such as the production of ketone bodies which are alternative cerebral
      fuels. Evidence from studies of humans and other animals suggests that cortical
      damage and long-term sequelae occur after prolonged hypoglycaemia sufficiently
      severe to cause neurological signs. CONCLUSION: Prolonged hypoglycaemia should be
      avoided by close clinical observation of vulnerable infants whilst avoiding
      excessively invasive management in populations of neonates which may jeopardize
      the successful establishment of breast feeding.

PMID- 10592093
TI  - Some ethical considerations in the neonatal intensive care area.

PMID- 10592094
TI  - Inflammatory mechanisms in neonatal chronic lung disease.
AB  - Chronic lung disease (CLD) of preterm infants has a multifactorial aetiology.
      Oxygen toxicity, mechanical injury (barotrauma), volutrauma as well as prenatal
      and postnatal infections most likely contribute to pulmonary injury in the
      immature lung of preterm infants. There is sufficient evidence that respiratory
      distress syndrome and CLD are associated with a significant inflammatory response
      of the airways and the interstitium of the lungs; besides neutrophils, alveolar
      and interstitial macrophages immunoreactive for tumour necrosis factor-alpha (TNF
      alpha) are found in large numbers. Phagocyte influx is possibly mediated by
      chemotactic and chemokinetic factors present in the broncho-alveolar secretions:
      interleukin-8, leukotriene B(4), C5a, elastin fragments, macrophage-inflammatory
      protein-1alpha and other chemokines. Increased concentrations of soluble
      selectins and intercellular adhesion molecule-1 in broncho-alveolar secretions
      and the serum of infants with CLD possibly reflect neutrophil diapedesis. Lipid
      mediators including leukotrienes, prostacyclin, platelet activating and other
      mediators such as the pro-inflammatory cytokines TNF-alpha, interleukin-1 and -6,
      exert various effects on the airways and the vascular system by increasing the
      microvascular permeability which is one of the most important pathophysiological
      factors of early CLD. Pulmonary cells of preterm infants may be unable to
      downregulate inflammation through the expression of the anti-inflammatory
      cytokine interleukin-10. Inflammatory cells can cause severe lung damage by
      release of potent proteases (elastase), cytokines and by generation of toxic
      oxygen radicals (O(2)-, (*)OH). The presence of free elastase activity and the
      protease-antiprotease imbalance has been well documented. In fact, increased
      concentrations of products of elastolytic fibre degradation and of oxygen radical
      mediated lipid peroxidation were detected in infants with CLD. CONCLUSION: The
      complex interaction between mediators of inflammation and fibrosis has still to
      be defined. Moreover, the possible interference of inflammation with postnatal
      lung development especially with the alveolarization process has not been
      evaluated yet.

PMID- 10592095
TI  - Inhaled prostacyclin in the treatment of pulmonary hypertension.
AB  - Pulmonary hypertension can occur primarily with an unknown aetiology or secondary
      in association with cardiac or pulmonary disorders such as congenital
      diaphragmatic hernia, idiopathic respiratory distress syndrome, acute respiratory
      distress syndrome (ARDS), congenital heart disease with malformation of the
      pulmonary blood vessels, chronic obstructive lung disease and following cardiac
      surgery. Prostacyclin (PGI(2)), an arachidonic acid metabolite, has been
      evaluated for its efficacy in the treatment of pulmonary hypertension and for its
      use in assessing the reversibility of the disorder prior to surgical
      interventions. While the intravenous application of PGI(2) can cause a decrease
      not only of the pulmonary but also of the systemic vascular tone, aerosolised
      PGI(2) results in a selective pulmonary vasodilation without affecting the
      systemic blood pressure. Furthermore, aerosolised PGI(2) can improve gas exchange
      and pulmonary shunt in clinical settings of impaired ventilation/perfusion ratio
      such as ARDS, due to the redistribution of pulmonary blood flow from
      nonventilated to ventilated, aerosol-accessible lung regions. CONCLUSION:
      Aerosolised prostacyclin can be a valuable tool in the treatment and diagnostic
      evaluation of elevated pulmonary vascular resistance and impaired pulmonary gas
      exchange. Reservations must be made for its long-term use, as its short half-life
      necessitates continuous inhalation.

PMID- 10592096
TI  - Liquid assisted ventilation update.
AB  - The purpose of this summary is to highlight several areas of recent research
      performed in liquid assisted ventilation techniques. These areas were chosen
      specifically based on their contribution to elucidate mechanisms of improved
      pulmonary support or provoke additional and novel applications of this modality
      to reduce pulmonary complications of immaturity or acute lung injury.

PMID- 10592097
TI  - Activation of neu by missense point mutation in the transmembrane domain in
      schwannomas induced in C3H/HeNCr mice by transplacental exposure to N
      nitrosoethylurea.
AB  - Transplacentally initiated schwannomas in mice and rats arise preferentially in
      the Gasserian ganglion of the trigeminal nerve and spinal root ganglia, while
      those of the Syrian golden hamster most commonly occur subcutaneously. Rat and
      hamster schwannomas almost invariably contain a mutationally activated neu
      oncogene. In rat schwannomas, the mutant allele predominates, while the relative
      abundance of mutant alleles is very low in hamster nerve tumors. We investigated
      whether neu is mutated in mouse schwannomas and whether the pattern and allelic
      ratio of the mutation resemble those for the hamster or the rat. Pregnant
      C3H/HeNCr mice received 0.4 micromol N-nitrosoethylurea/g body weight on day 19
      of gestation. Ten trigeminal and one peripheral nerve schwannomas developed in 11
      of the 201 offspring. Missense T --> A transversion mutations were detected in
      the neu transmembrane domain in eight of ten schwannomas analyzed, as determined
      by MnlI digestion of polymerase chain reaction products. The mutant allele was
      predominantly detected in two tumors and was abundant in six others. Transfection
      of eight out of ten mouse tumor DNAs into hamster cells yielded transformed foci;
      seven out of eight contained mutant mouse neu. Mouse schwannomas closely
      resembled those of rats both in the preferred anatomical site and in the
      mutant/wild-type neu allele ratios.

PMID- 10592098
TI  - Induction of apoptosis in metastatic foci from human gastric cancer xenografts in
      nude mice and reduction of circulating tumor cells in blood by 5-FU and 1
      hexylcarbamoyl-5-fluorouracil.
AB  - Antimetastatic effects of 5-FU and its derivative, 1-hexylcarbamoyl-5
      fluorouracil (HCFU) on human gastric cancer micrometastasis and their mode of
      action were evaluated, using a spontaneous lung metastasis model (HY-1) in nude
      mice. Metastases were first detected in the lung from 4 weeks after subcutaneous
      transplantation, growing intravascularly and forming micrometastases at 100%
      incidence by 6 weeks after implantation. Lung metastasis in mice bearing
      subcutaneous tumors was significantly inhibited by HCFU at doses of 100-150 mg
      kg(-1) day(-1) without severe toxic side-effects, when orally administered three
      times per week either from week 4 or week 6 to 9 weeks after implantation.
      Spontaneous lung metastasis was also inhibited by the administration of 5-FU, but
      to lesser extent than with HCFU at equimolar low doses. Apoptosis within primary
      tumors and lung metastatic foci, as detected by the terminal
      deoxynucleotidyltransferase-mediated dUTP nick-end labeling method, was found to
      be significantly enhanced by HCFU as well as 5-FU administration at doses of more
      than 100 mg kg(-1) day(-1) and 50 mg kg(-1) day(-1) respectively. However,
      proliferating activity of the metastatic foci, as evaluated by MIB-1
      immunostaining, was not significantly suppressed by HCFU or 5-FU treatment.
      Furthermore, polymerase chain reaction analysis using human specific primers for
      the beta-globin gene, which proved to be capable of detecting 10 tumor cells/ml
      mouse blood, revealed that circulating tumor cells in the peripheral blood of
      mice bearing primary tumors were reduced by HCFU or 5-FU administration. These
      results indicate that circulating tumor cells in blood and micrometastases in the
      lung are sensitive to these chemotherapeutic agents, and suggest that the anti
      metastatic effect of these agents is mediated, at least in part, by enhanced
      apoptosis rather than by inhibition of cell proliferation.

PMID- 10592099
TI  - Evaluation of the reverse transcriptase/polymerase chain reaction for
      carcinoembryonic antigen for the detection of breast cancer dissemination in bone
      marrow and peripheral blood.
AB  - This study evaluated the specificity and sensitivity of the reverse
      transcriptase/polymerase chain reaction (RT-PCR) for carcinoembryonic antigen
      (CEA) for identification of breast tumour cells in bone marrow and in peripheral
      blood. Using one primer set from the A2/B3 domains of CEA with five to seven
      mismatches to other CEA-family members allowed reproducible detection of 1 colon
      tumour cell and 10 breast tumour cells in 10(7) mononuclear cells. Bone marrow
      samples from 181 patients with breast cancer were analysed by CEA-RT-PCR; 50 of
      these samples were analysed in parallel by routine immunocytochemistry. CEA-mRNA
      positive bone marrow cells were found in 27.6% of the patients (50/181) with
      breast cancer. Five immunocytochemistry-positive samples were negative when
      analysed by CEA-RT-PCR. Limiting factors in the detection of micrometastatic
      breast tumour cells by CEA-RT-PCR are the heterogeneity of the tumour cells and
      the deficient expression of CEA in some of these cells. However, CEA-RT-PCR using
      the specific primer could detect 1 colon tumour cell in 1 x 10(7) normal
      peripheral blood mononuclear cells.

PMID- 10592100
TI  - 5-ethyl-2'-deoxyuridine, a modulator of both antitumour action and
      pharmacokinetics of 5-fluorouracil.
AB  - The aim of the present studies was to elucidate the effects and optimal
      modulatory conditions of 5-ethyl-2'-deoxyuridine (EtdUrd) on the antitumour
      efficacy, pharmacokinetics and catabolism of 5-fluorouracil (5-FU) on Colon-26
      and Colon-38 murine tumours. HPLC and GC-MS techniques were used to measure the
      concentrations of 5-FU, dihydro-5-fluorouracil, EtdUrd, 5-ethyluracil and uridine
      in the plasma and that of 5-FU and 5-fluoro-2'-deoxyuridine monophosphate (FdUMP)
      in the tumours. It was shown that EtdUrd, given 1 h before 5-FU, selectively
      enhanced the antitumour action of 5-FU, without significantly increasing its
      toxic side-effects, thus resulting in an approximately three times higher
      therapeutic index. Pharmacokinetic studies revealed that 1 h after 400 mg/kg
      EtdUrd administration - i.e. at the time of 5-FU treatment - the plasma
      concentration of EtdUrd was 269 microM, and that of 5-ethyluracil, as the major
      metabolite of EtdUrd, was 421 microM. It is of interest that EtdUrd pretreatment
      did not change the maximal plasma concentration of 5-FU; however, the half-life
      of the terminal elimination increased from 114.5 min to 171.2 min and thus the
      mean residence time of 5-FU rose significantly (P < 0.05). After the combined
      treatment, the maximal concentration of dihydro-5-fluorouracil in the plasma
      decreased from 61.06 microM to 29.70 microM (P < 0.01). The intratumoral
      concentrations of 5-FU were 34%-158% higher 6-96 h after the combined treatment
      than after the single 5-FU treatment. EtdUrd also caused a moderate increase in
      the intratumoral level of FdUMP. It is noteworthy, that EtdUrd increased the
      endogenous uridine concentration in the plasma from 18 microM to a maximum of 249
      microM, and the level remained high for longer than 6 h. The present studies
      indicate that EtdUrd enhances the therapeutic index of 5-FU by reducing the
      catabolism, prolonging the plasma and intratumoral concentrations of 5-FU and, at
      the same time, offering protection to normal organs by increasing the endogenous
      uridine level.

PMID- 10592101
TI  - MAGE-1 and related MAGE gene expression may be associated with hepatocellular
      carcinoma.
AB  - PURPOSE: The possibility of tumor rejection antigen, encoded by the MAGE-1 gene,
      being a target for immunotherapy in hepatocellular carcinoma (HCC) patients and
      the cloning of the full-length cDNA of this gene for subsequent studies were
      explored with the aim of discovering new immunotherapeutic strategies for HCC.
      METHODS: Expression of the MAGE-1 gene in HCC specimens and HCC cell lines was
      examined by the reverse transcription/polymerase chain reaction (RT-PCR) with a
      pair of specific primers, which gave a 421-bp fragment. Another pair of primers
      were then used to amplify the full-length MAGE-1 cDNA by the same method. The PCR
      products were then digested by restriction endonucleases and inserted into the
      plasmid PUC19. After primary selection of the recombinants by endonuclease
      digestion, the sequences of the inserted gene fragments were confirmed by DNA
      sequence analysis. RESULTS: In 45 HCC patients, MAGE-1 mRNA was expressed in 27
      tumor tissues (60%) and 5 paratumor tissues (11.1%). All the four HCC cell lines
      positively expressed the MAGE-1 gene. Owing to the high homology of the MAGE gene
      family, we obtained three clones of different MAGE genes using the same pair of
      cloning primers. The three clones were confirmed to be a full-length MAGE-1 gene,
      a 750-bp fragment of the MAGE-3 gene and a fragment highly homologous to MAGE-6
      and MAGE-12 but not identical to any known MAGE genes. CONCLUSION: The high
      expression frequency of MAGE-1 gene in HCC suggests the possibility of using it
      as a target for immunotherapy in HCC patients. Some MAGE genes other than MAGE-1
      may also be expressed in HCC together with an unknown MAGE gene that might
      introduce new targets for immune attacks. The three gene clones obtained in this
      study can be used in further investigations and especially in the development of
      new liver cancer vaccines.

PMID- 10592102
TI  - Effect of thiols exported by cancer cells on the stability and growth-inhibitory
      activity of Pt(IV) complexes.
AB  - PURPOSE: The role of thiols in the reduction of Pt(IV) antitumor agents to Pt(II)
      is well recognized and it is widely thought that this reaction is required for
      activity. The sources of extracellular thiols in cell culture have been less
      studied. The purpose of the present work was to determine whether the stability
      of Pt(IV) complexes in culture medium can be affected by thiols that are released
      by cancer cells. METHODS: A two-column HPLC assay with UV/visible detection was
      used to determine the stability of two Pt(IV) complexes in culture medium with
      and without cells. The kinetics of the thiol release from a human ovarian cancer
      cell line SK-OV-3 and a human glioblastoma cell line U-87 MG were determined by a
      modification of the Ellman's method. RESULTS: The stability of a Pt(IV) complex
      with equatorial iodo ligands, trans, cis-[Pt(en)(OAc)(2)I(2)], was dramatically
      lower in culture medium in the presence of cells than in fresh culture medium,
      whereas the half-life of the dichloro analog, trans,cis-[Pt(en)(OAc)(2)Cl(2)],
      was somewhat increased. Although both complexes showed similar in vitro cell
      growth-inhibitory activity, trans, cis-[Pt(en)(OAc)(2)Cl(2)] required a longer
      incubation time than the iodo analog to reach its maximal effect. The thiol
      content of the culture medium in the presence of cells was measured after 2 days:
      the concentrations from cultures of U-87 MG and SK-OV-3 cells were 3. 6 +/- 0.1
      microM and 9.3 +/- 0.1 microM respectively, compared to 0. 07 +/- 0.04 microM in
      fresh medium. During the rapid growth phase, the extracellular thiol content
      reached a maximum of 20.0 +/- 0.5 microM and 47.8 +/- 0.2 microM for U-87 MG and
      SK-OV-3 cells respectively. CONCLUSIONS: These findings show that the culture
      medium conditioned by cancer cells can influence the stabilities of certain
      Pt(IV) complexes in cytotoxicity studies.

PMID- 10592103
TI  - Serum CA-125 as a marker of disease activity in uterine papillary serous
      carcinoma.
AB  - Papillary serous carcinoma of the endometrium exhibits many clinical features of
      ovarian cancer, including a high metastatic potential and response to platinum
      based chemotherapy. We investigated the clinical utility of the serum CA-125
      antigen level, an established marker of response or progression in ovarian
      cancer, to serve as a indicator of these events in patients with this highly
      malignant subtype of endometrial cancer. Of 21 individuals with this cancer
      treated in our program from 11/91 to 6/97, 16 had baseline CA-125 determinations
      prior to the administration of chemotherapy, of whom 13 were elevated above the
      normal range. Of these 13 patients, 8 (57%) experienced either a major reduction
      or normalization of CA-125 levels following therapy, consistent with their
      clinical course at that point in time. Similarly, of 11 patients who ultimately
      relapsed, 8 (73%) were found to have a rise in the CA-125 antigen level which
      closely corresponded to, or proceeded, clinical relapse. A single patient was
      demonstrated to have disease progression with a declining level of CA-125. We
      conclude the serum CA-125 antigen level is a useful indicator of disease response
      or progression in individuals with papillary serous carcinoma of the endometrium.

PMID- 10592104
TI  - Histological indications of a favorable prognosis with far-advanced gastric
      carcinomas after preoperative chemotherapy.
AB  - PURPOSE: Although preoperative chemotherapy for advanced gastric cancer is now
      commonly applied with favorable results, convincing evidence for life
      prolongation and predictive markers for a good prognosis are both lacking. We
      report here 5 cases that have shown a distinct positive effect of preoperative
      chemotherapy together with the results of a precise histological examination of
      materials indicating features predicting a favorable outcome. PATIENTS AND
      METHODS: A total of 18 patients with a far-advanced gastric carcinoma subjected
      to gastrectomy after FLEP (5-fluorouracil, leucovorin, etoposide, cisplatin) in
      the Cancer Institute Hospital of the Japanese Foundation for Cancer Research,
      Tokyo, could be divided into two distinct groups: 5 surviving over 5 years (group
      A) and 13 who died within 13 months (group B). Histological features (subtypes)
      of the carcinomas and chemotherapeutic effects were studied with reference to
      biopsy materials and resected stomachs and lymph nodes. RESULTS: In group A, 3 of
      5 patients had solid-type poorly differentiated adenocarcinomas. In contrast, in
      group B, 9 had tubular adenocarcinomas (well or moderately differentiated) and 3
      non-solid or diffuse-type poorly differentiated adenocarcinomas and there was
      only one solid-type tumor. In group A, remarkable therapeutic effects were
      apparent histologically in 4 of the 5 patients with almost complete disappearance
      of cancer cells from metastases in lymph nodes, whereas no such changes were
      evident in group B. CONCLUSION: FLEP is distinctly beneficial for certain types
      of advanced gastric carcinoma, especially solid-type poorly differentiated
      adenocarcinomas, and favorable results can be predicted, to a certain extent, on
      the basis of findings for the material resected after chemotherapy.

PMID- 10592105
TI  - Antitumoral activity of oxaliplatin/cisplatin-based combination therapy in
      cisplatin-refractory germ cell cancer patients.
AB  - PURPOSE: Only 20-30% of patient with advanced germ cell tumors, relapsing after
      standard first-line therapy, are curable with current second-line cisplatin-based
      regimens. New salvage combinations incorporating new active agents are needed. We
      report the toxicity/tolerance of a new salvage regimen based on the oxaliplatin
      (Eloxatin)/cisplatin combination, evaluated in patients with recurrent, mostly
      cisplatin-refractory germ cell tumors. PATIENTS AND METHODS: Thirteen patients
      were enrolled in this study. All except one had received cisplatin-based
      chemotherapy. Eight had progressive disease as the best response on their last
      platinum-based chemotherapy, and three had potentially sensitive tumors. The
      median interval since the last platinum-based chemotherapy was 6 months (range: 1
      36 months). One untreated patient with poor prognosis was also enrolled. Twelve
      patients had pathological markers [median alpha-fetoprotein 14 800 ng/ml (58
      10(6)), median human chorionic gonadotrophin beta subunit 7000 IU/ml (37-723
      700)]. Patients received either oxaliplatin (130 mg/m(2)) and cisplatin (100
      mg/m(2)) every 3-4 weeks (Bi regimen, four patients), or the same regimen
      combined with one to four of the following cytotoxic agents: ifosfamide,
      epirubicin, vinorelbine, methotrexate, dactinomycin, etoposide and bleomycin (BiC
      regimen, 9 patients). Treatment was individualized according to each individual
      patient's pretreatment and clinical characteristics. RESULTS: Seven objective
      responses were obtained (overall response rate = 54%), all with the BiC regimens
      (two complete and five partial responses). Two patients with recurrent disease
      achieved a long-term complete response lasting over 5 years. Four partial
      responders were seen in the eight cisplatin-refractory tumors, lasting 4-8
      months. All objective responses had a corroborating major decrease in tumor
      marker blood levels (median decrease: 99.7%). The median survival for the whole
      group was 8 months. The commonest severe toxicity was hematological (grade 4
      neutropenia in 78% and thrombopenia in 74% of the BiC cycles). CONCLUSION: Our
      combined salvage regimen induced significant antitumoral activity in recurrent,
      cisplatin-refractory germ cell tumors. Oxaliplatin merits further evaluation as a
      component of combination therapy for this disease.

PMID- 10592106
TI  - Rapid determination of creatinine in serum and urine by ion-pair high-performance
      liquid chromatography.
AB  - We report a simple and reliable high performance liquid chromatography method for
      measuring creatinine in serum and urine. The chromatographic run is performed on
      a C(18) column after protein precipitation with acetone and addition of
      cimetidine as an internal standard. The separation is carried out in 20 min at a
      flow rate of 0.8 ml/min, with a mobile phase consisting of 100 mmol/l sodium
      dihydrogen phosphate solution, containing 30 mmol/l sodium lauryl sulfate pH 3.0
      and acetonitrile (60:36, v/v). The absorbance is monitored at 200 nm. The
      relationship between creatinine concentration and the creatinine/internal
      standard peak area is linear up to 1,088 micromol/l. Within-run precision
      measured at three different creatinine concentrations ranges from 0.89% to 2.34%
      in serum and from 0.34% to 1.10% in urine. Between-run precision varies from
      1.68% to 3.17% in serum and from 1.58% to 1.85% in urine over a wide range of
      concentrations. Analytical recovery is between 98.71% and 101.25% in serum and
      between 98.96% and 100.27% in urine. The detection limit is 3.24 micromol/l for a
      signal-to-noise ratio of 3. The method shows a good linearity with the reference
      isotope dilution gas chromatography-mass spectrometry procedure (r=0.999),
      without interferences, even in the presence of high bilirubin concentrations.

PMID- 10592107
TI  - Measurement of hepatocyte growth factor in serum and plasma.
AB  - To investigate whether serum or plasma should be used for the measurement of
      blood hepatocyte growth factor, the levels were compared in 28 normal subjects
      and 30 patients who had undergone surgery. The serum level was significantly
      higher than the plasma level. The serum and plasma hepatocyte growth factor
      levels differed markedly depending on the subjects, although overall there was a
      significant correlation between levels (r=0.862, P=0.0001). In serum obtained by
      the clotting of platelet- or leukocyte-containing plasma with thrombin,
      hepatocyte growth factor increased in proportion to the number of leukocytes. The
      difference between serum and plasma hepatocyte growth factor levels also
      correlated with the number of leukocytes in the patients (r=0.642, P=0.0004).
      Such a correlation was not observed for platelets. These findings suggest that
      the serum hepatocyte growth factor level does not strictly reflect the in vivo
      blood level, due to the release from leukocytes during sample preparation (i.e.,
      blood clotting ) and that plasma is more suitable for assay of blood hepatocyte
      growth factor.

PMID- 10592108
TI  - Lundh meal: a single non-invasive challenge test for evaluation of exocrine and
      endocrine pancreatic function in cystic fibrosis patients.
AB  - The determination of endocrine and exocrine pancreatic function in cystic
      fibrosis patients is clinically important. Recently, a new non-invasive test, in
      which pancreatic stimulation by a Lundh meal is followed by sequential serum
      lipase measurements, was found to be a good indicator of exocrine pancreatic
      status. Since the Lundh meal also contains glucose, the present study assessed
      whether it also might be suitable for evaluation of the pancreatic endocrine
      axis. After an overnight fast, 10 healthy non-diabetic subjects and 14 cystic
      fibrosis patients ingested a Lundh meal. Glucose, insulin, and C peptide levels
      were measured at various time intervals following the meal. For purposes of
      comparison, the oral glucose tolerance test was also performed on the cystic
      fibrosis patients. All healthy subjects demonstrated an increase in glucose
      levels post Lundh meal, peaking at 45 min (mean 140+/-21 mg/dl) and then
      gradually declining and reaching the normal range at 120 min. Concordant peaks of
      insulin (46.3+/-20 IU/ml) and C peptide (5.8+/-1. 5 ng/ml) levels were noted at
      60 min. All 14 cystic fibrosis patients had normal basal glucose levels: in 8,
      the pattern of glucose, insulin, and C peptide post Lundh meal was similar to
      that of the healthy controls. These 8 patients also had a normal oral glucose
      tolerance test, and their hemoglobin A(1C) levels were within the normal range.
      The other 6 cystic fibrosis patients demonstrated glucose levels above 200 mg/dl
      30-60 min post Lundh meal, and all also had an impaired oral glucose tolerance
      test. Of these 6, 4 had high levels of hemoglobin A(1C). This study demonstrates
      that the Lundh meal challenges the endocrine pancreas as well as the oral glucose
      tolerance test. Thus, determination of both exocrine and endocrine pancreatic
      status can be achieved by a single non-invasive test.

PMID- 10592109
TI  - The hololipoprotein complex of beta(2)-glycoprotein I and dicaproyl
      phosphatidylserine.
AB  - The ability of beta(2)-glycoprotein I (formerly referred to as apolipoprotein H)
      to act as an autoantigen for antibodies from patients with antiphospholipid
      syndrome is dependent upon its binding in vivo to anionic phospholipid surfaces
      or to surfaces in vitro which mimic their surface characteristics. The ability of
      the autoepitope(s) of beta(2)-glycoprotein I to be exposed by binding a short
      chain (6-carbon), anionic phospholipid has not been explored. Here, we describe
      our studies of the hololipoprotein generated by reacting beta(2)-glycoprotein I
      with dicaproyl phosphatidylserine. The formation of the complex is accompanied by
      inhibition of beta(2)-glycoprotein I binding to phospholipid-coated polystyrene
      surfaces, with 50% reduction in binding occurring at about 10 mM. At
      concentrations >10 mM, dicaproyl phosphatidylserine also displaces beta(2)
      glycoprotein I bound to anionic phospholipid surfaces. Physicochemical studies
      suggest that at DCPS concentrations >6 mM, the solutions are colloidal and that
      beta(2)-glycoprotein I forms a supramolecular complex with organized phospholipid
      structures. Using a standard human autoimmune anti-beta(2)-glycoprotein I plasma,
      as well as a series of six additional sera from patients with antiphospholipid
      syndrome, the complex did not generate a detectable epitope. We conclude that
      lipid binding, per se, is not sufficient for the presentation of the epitope(s)
      of beta(2)-glycoprotein I or its recognition by autoantibodies from patients with
      antiphospholipid syndrome.

PMID- 10592110
TI  - Inducible nitric oxide synthase and nitric oxide production in Leishmania
      infantum-infected human macrophages stimulated with interferon-gamma and
      bacterial lipopolysaccharide.
AB  - Nitric oxide produced by an inducible nitric oxide synthase constitutes one of
      the main microbicidal mechanisms of murine macrophages and its importance is now
      being recognized for human macrophages. In this study we evaluated inducible
      nitric oxide synthase expression, nitric oxide release, and parasitocidal ability
      of Leishmania infantum-infected monocyte-derived human macrophages. The inducible
      nitric oxide synthase was detected by immunofluorescence and western blotting and
      nitric oxide production was measured by the Griess reaction for nitrites.
      Parasite killing was microscopically evaluated by fluorescent dyes. Experiments
      were performed on macrophages with or without previous stimulation with
      recombinant human interferon-gamma and bacterial lipopolysaccharide. Inducible
      nitric oxide synthase expression and nitric oxide release were higher in
      Leishmania-infected stimulated macrophages than in uninfected cells or infected
      cells without previous stimulation. Nitric oxide production and parasitocidal
      activity against Leishmania infantum were reduced in macrophages treated with the
      nitric oxide synthase inhibitor L-N(G) monomethylarginine. These results suggest
      a microbicidal role for nitric oxide in human leishmaniasis, with the possible
      practical application of immunological or pharmacological regulation of nitric
      oxide synthesis in the treatment of this infection.

PMID- 10592111
TI  - The rate of plasmin formation after in vitro clotting is inversely related to
      lipoprotein(a) plasma levels.
AB  - Lipoprotein(a) levels are largely genetically determined and are linked to
      increased risk of coronary artery disease. The hypothesis that elevated
      lipoprotein(a) levels lead to decreased fibrinolysis, due to the close structural
      homology with plasminogen, could in part explain the genesis of this risk,
      although contrasting results have been obtained in different studies. The aim of
      our study was to evaluate whether the rate of plasmin formation, enhanced in
      vitro by a fixed amount of human tissue plasminogen activator after clotting, was
      related to plasma lipoprotein(a) levels in 45 healthy subjects. Aliquots of human
      plasma were clotted with calcium chloride and thrombin followed by addition of
      tissue plasminogen activator. We then measured the time course of plasmin
      formation, determined as hydrolysis of H-D-valyl-L-leucyl-L-lysine-p-nitroanilide
      dihydrocortide (S-2251). The log of lipoprotein(a) level was negatively related
      to the rate of plasmin formation (r(s)=-0.46, P=0. 002), and multiple regression
      analysis indicated that this relationship was not influenced by the amount of
      plasminogen, fibrinogen, plasminogen activator inhibitor-1, tissue plasminogen
      activator, or by the size of apo(a) isoforms. These data support the concept that
      lipoprotein(a) can inhibit plasminogen activation and plasmin formation and can
      thereby play an important role in the genesis of atherosclerosis as an
      antifibrinolytic agent.

PMID- 10592112
TI  - Interpretation of serum CK-MB activity measured by immunoinhibition assay
      requires special care in patients with neoplastic pathology.

PMID- 10592113
TI  - Gamma Knife radiosurgery of the glomus jugulare tumour - early multicentre
      experience.
AB  - Leksell Gamma Knife was used to treat 66 patients with glomus jugulare tumour at
      6 European sites between 1992-1998. The age of the patients ranged between 18-80
      years (median 54 years). Gamma Knife radiosurgery was a primary treatment in 30
      patients (45. 5%). Open surgery preceded radiosurgery in 24 patients (36.4%),
      embolisation in 14 patients (21.2%) and fractionated radiotherapy in 5 patients
      (7.6%). The volume of the tumour ranged 0.5-27 cm(3) (median 5,7 cm(3)). The
      minimal dose to the tumour margin ranged between 10-30 Gy (median 16.5 Gy). After
      radiosurgery 52 patients were followed, the follow up period was 3-70 months
      (median 24 months). Neurological deficit improved in 15 patients (29%) and
      deteriorated in 3 patients (5,8%), one transient and two persistant.
      Neuroradiological follow up using MRI or CT was performed in 47 patients 4-70
      months (median 24 months) after radiosurgery. Tumour size decreased in 19
      patients (40%) while in the remaining 28 patients (60%) no change in the tumour
      volume was observed. None of the tumours increased in volume during the
      observation period. Control angiography was performed in 6 patients. Pathological
      vascularisation completely disappeared in one patient, reduced in two and there
      was no change in the remaining three. Radiosurgery proves to be a safe treatment
      for glomus jugulare tumour with no mortality and no acute morbidity. Because of
      its naturally slow growth rate, up to 10 years of follow up will be necessary to
      establish a cure rate after radiosurgery for these lesions.

PMID- 10592114
TI  - Long-term prognosis of haemangioblastoma of the CNS: impact of von Hippel-Lindau
      disease.
AB  - The aim was to assess the frequency of von Hippel-Lindau disease (VHL) and the
      long-term prognosis of VHL and non-VHL patients among 110 consecutive patients
      with haemangioblastoma (HB) of the CNS treated between 1953 and 1993 at one
      neurosurgical unit. To reveal VHL manifestations we performed a detailed clinical
      and radiological examination (neuraxis and abdomen) (61/110), VHL-gene mutation
      analysis (40/110), and collection of all available clinical, imaging, operative
      and autopsy data from the hospitals involved. All patients were followed-up with
      a median of 14 years (excluding 14 operative deaths), and no patient was lost to
      follow-up. Altogether 49 patients died during the follow-up. In the 14 VHL
      patients (13%), HB(s) of the CNS were detected at a median age of 33 years,
      retinal HB(s) at 39 years, and renal cell carcinoma (RCC) at 43 years. The
      frequency of VHL in patients operated on for HB(s) was 29% before the age of 25
      years, 19% between 25 and 45 years, and only 2% after 45 years. HB patients not
      meeting the VHL criteria had internal organ cysts in 14%. One non-VHL patient
      (4%) had two adjacent HBs in the same cyst wall. The growth rates of non-VHL and
      VHL-related HBs were similar as indicated by the median time to recurrence and
      the proliferation indices (MIB-1). Recurrence of the HB in patients whose primary
      operation was considered radical developed in four of the 10 VHL patients at a
      median of 19 years, and in nine of the 74 non-VHL patients at a median of 11
      years. The median length of life of all VHL and non-VHL patients was 46 and 63
      years, respectively. In VHL, RCC and HBs were equal causes of death.

PMID- 10592115
TI  - Intra-operative direct electrical stimulations of the central nervous system: the
      Salpetriere experience with 60 patients.
AB  - Indications of surgical treatment for lesions in the central nervous system
      depend on the risk of a definitive neurological deficit, related to the benefit
      of resection. Detection of eloquent areas is then necessary because of major
      individual variability. Neuro-imaging functional techniques are in development
      and are beginning to be efficient for cortical sensorymotor mapping, but still
      lack sensitivity and specificity for language mapping, and remain unable to give
      real-time data during surgery and to perform sub-cortical mapping. The more
      precise and reliable method of functional mapping is represented by the intra
      operative direct electrical stimulations (DES), which allow identification and
      preservation of essential pathways for motricity, sensibility and language, at
      each level of the central nervous system (cortico-subcortical). We report our
      experience of DES in the surgery of tumours and vascular malformations located in
      supra-tentorial brain eloquent areas, with a consecutive series of 60 patients
      operated on under general or local anaesthesia, from November 1996 until May 1999
      in our department at La Salpetriere Hospital. Presenting symptoms in the 60
      subjects (39 males, 21 females, mean age: 45 years) were seizures in 37 cases
      with normal clinical examination, and mild neurological deficit in 29 cases. MRI
      showed 60 supra-tentorial brain lesions: 30 precentral, 12 postcentral, 14
      perisylvian in the dominant hemisphere, 4 deep-seated. All subjects underwent
      surgical resection using DES, with supratentorial cortico-subcortical mapping
      under general anaesthesia for motor areas detection in 43 cases and under local
      anaesthesia for sensori-motor and/or language tasks in 17 cases. The final
      histological diagnosis was 44 gliomas (31 low-grade and 13 high-grade), 9
      metastasis, 3 cavernomas, 4 arteriovenous malformations (AVM). Resection was
      total or subtotal in 52 cases (87%) and partial in 8 cases (13%). 29 patients had
      no post-operative deficit, while the other 31 patients were impaired post
      operatively, with in all cases, except 3, a complete recovery delayed for 15 days
      to 3 months (overall morbidity: 5%). The median follow up was 14 months. Intra
      operative direct electrical stimulations of the central nervous system constitute
      a reliable, precise and safe method, allowing the realization of a functional
      mapping useful for all operations of lesions located in eloquent areas. This
      technique allows a minimization of definitive post-operative neurological
      deficit, and concurrently an improvement in the quality of resection.

PMID- 10592116
TI  - Intraspinal primitive neuroectodermal tumour: report of two cases and review of
      the literature.
AB  - Two patients with primary intraspinal primitive neuroectodermal tumour are
      presented. In a 32-year-old man, the tumour evolved intradurally from a sacral
      nerve root. Despite repeated surgery and radiochemotherapy, the patient suffered
      multiple intraspinal tumour relapses and intracranial seedings, and died 29
      months after the first diagnosis. In a 17-year-old male adolescent, the tumour
      was located in the lumbar epidural space, extending into the paraspinal muscles.
      Following resection and radiochemotherapy, the patient is free from disease 23
      months after the initial presentation. The clinical, radiological,
      histopathological and cytogenetic findings of both patients are presented and the
      relevant literature is reviewed. Particular attention is given to the
      histogenetic relationship between peripheral primitive neuroectodermal tumour and
      Ewing's sarcoma.

PMID- 10592117
TI  - Surgery and stenting As combined treatment of a symptomatic tandem stenosis of
      the carotid artery.
AB  - International co-operative studies have demonstrated a benefit from surgery for
      symptomatic and asymptomatic patients affected by internal carotid artery
      stenosis of 60-70%. The presence of a tandem lesion, intracranial or
      extracranial, may annul the benefit of surgery. Such patients may thus represent
      a challenging problem for management if age, good general conditions and a normal
      neurological status favour a therapy. A 54-year-old man developed transient
      ischaemic attacks of the left hemisphere; his general condition was good, and
      neurological status was normal. Angiography showed a tight stenosis at the left
      common carotid artery near the ostium and at the homolateral carotid bifurcation.
      At first, a self-expanding wall stent was placed at the level of the common
      carotid artery stenosis, and immediately after a standard endarterectomy under
      general anaesthesia was performed. The postoperative course was normal and was
      complicated only by the presence of a mild deficit of the hypoglossal nerve due
      to the presence of a high bifurcation. The early and late outcome of our case
      suggests that stenosis of the proximal common carotid artery may be successfully
      treated by stenting. While awaiting additional data about this new technology,
      endovascular techniques and surgery may be complementary in the management of
      patients suffering from such tandem lesions.

PMID- 10592118
TI  - Carotid rete mirabile presenting subarachnoid haemorrhage. Report Of two cases.
AB  - Carotid rete mirabile (CRM) consists of arterial channels between the internal
      and external carotid arteries in some lower mammals. It is a very rare
      pathological condition in humans. We report two patients who presented with
      clinical signs of subarachnoid haemorrhage (SAH). Their sudden-onset SAH was
      thought to have been due to rupture of cerebral aneurysms, however, angiograms
      revealed an abnormal vascular network around the cavernous sinus. To our
      knowledge, 2 of 7 reported patients with CRM presented with SAH, however, only
      one of these patients had a probable cerebral aneurysm. We suggest that in
      patients with CRM, the rupture of anastomosing vessels be a probable cause of
      SAH.

PMID- 10592119
TI  - Diamox((R)) challenge test to decide indications for cerebrospinal fluid shunting
      in normal pressure hydrocephalus.
AB  - OBJECTIVE: The indications for cerebrospinal fluid (CSF) shunting in patients
      with normal pressure hydrocephalus (NPH) have not been established. Establishment
      of clear-cut indications for this procedure is essential to ensure cost
      effective, and safe treatment. We report the usefulness of the Diamox((R))
      challenge test in evaluating indications for CSF shunting in patients with NPH.
      METHODS: Pre- and post-operative responses in cerebral blood flow (CBF) and
      intracranial pressure (ICP) to intravenous administration of Diamox((R)) 1000mg
      (Diamox((R)) administration) were analysed in 41 patients with NPH who were
      treated by ventriculoperitoneal (VP) shunt with a programmable valve and an on
      off valve. RESULTS: The preoperative response of ICP to Diamox((R))
      administration was more than 10 mmHg in most patients in whom the shunt was
      effective (shunt effective group), however, it was less than 10 mmHg in most
      patients in whom the shunt was ineffective (shunt non-effective group).
      Furthermore, the postoperative response of ICP to Diamox((R)) administration
      decreased to less than 10 mmHg in most patients in the shunt effective group. The
      increases in CBF in response to Diamox((R)) administration were similar in the
      two groups both before and after placement of the VP shunt. CONCLUSION: Patients
      in whom ICP increased by more than 10 mmHg in response to Diamox((R))
      administration were regarded to have poor CSF circulation and to thus be
      candidates for CSF shunting. The Diamox((R)) challenge test is a simple, safe
      procedure, useful in evaluating the response to treatment.

PMID- 10592120
TI  - Contribution of neurophysiological guidance to stereotactic posteroventral
      pallidotomy for Parkinson's disease.
AB  - The usefulness of microrecording guidance to adequately place pallidotomy lesions
      is not thoroughly accepted. We have analysed in 23 consecutive Parkinsonian
      patients the deviation of the first recording track (FRT), which was directed to
      the theoretical stereotactic target, from the sensorimotor area of the internal
      pallidum, the internal capsule and the center of the lesion. Standard
      stereotactic co-ordinates were calculated applying a digitized brain atlas
      adapted to neuro-imaging techniques. The first recording track (FRT) was located
      out of the sensorimotor area of the pallidum in 13 cases and out of the internal
      pallidum in 11 cases. In four of these cases the FRT was within the fibers of the
      internal capsule. The FRT was displaced posteriorly in 9 patients, anteriorly in
      11, medially in 9 and laterally in 9. The mean deviation was 1.8 mm (+/- 1.5) in
      the medial-lateral axis, and 2.5 mm (+/- 1.9) in the antero-posterior plane. In
      none of the patients the center of the lesion was co-incident with the
      theoretical anatomical target. The center of the lesion presented a mean
      deviation from the theoretical anatomical target of 1,4 mm (+/- 1,1) in the
      medial-lateral, plane, and 2.5 mm (+/- 1.3) in the antero-posterior plane. In
      addition, 8 patients presented a deviation from the theoretical anatomical target
      of more than 3 mm in the antero-posterior plane (mean 4.2+/-0.7 mm) and 4
      patients presented deviation in the medial-lateral plane of more than 3 mm (mean
      3,4+/-0,2 mm). Lesion location was checked by magnetic resonance imaging. All
      patients improved to a similar extent to that previously reported by the other
      groups performing pallidotomy under neurophysiological guidance. At 3 months
      follow-up, pallidotomy ameliorated contralateral bradykinesia in the off
      condition by 41%, rigidity by 38%, tremor by 52% and dyskinesias by 92%. No major
      side effects were noted. We conclude that microrecording guidance is a useful
      tool for avoiding damage to adjacent structures and to precisely localize the
      sensorimotor area of the internal pallidum in order to obtain optimal clinical
      results.

PMID- 10592121
TI  - The effect of implementation of guidelines for the management of severe head
      injury on patient treatment and outcome.
AB  - The authors retrospectively analysed two groups of consecutive patients who were
      similarly matched for brain injury severity. From a total of 39 severe head
      injury patients, 23 were treated according to the Guidelines for the Management
      of Severe Head Injury with intracranial pressure (ICP) monitoring ("Guidelines
      group"). Such an approach allowed the maintenance of ICP within normal values,
      especially in patients with intraventricular ICP monitoring allowing the release
      of cerebrospinal fluid (CSF) from the ventricular system. In the Guidelines group
      only two patients were administered barbiturates, after all other means of ICP
      lowering had been exhausted. The second group consisted of 16 patients who were
      not monitored for ICP ("non-Guidelines group"). In this group, management
      consisted of the prophylactic administration of barbiturates, high dose osmotic
      diuretics and hyperventilation usually at levels below 25 mm Hg. In the
      Guidelines group the mortality rate was 30% compared to 44% in the non-Guidelines
      group. Almost twice as many patients achieved a "favourable" (good recovery and
      moderate disability) outcome (49%) compared to the non-Guidelines treated
      patients (25%). Furthermore, there was a 32% decrease in severe neurological
      disabilities in those patients in the Guidelines group. It seems that the
      implementation of "Guidelines" in the treatment of severe head injury, based on
      the result of our clinical study, reduces death and disability rates in patients
      with severe head injury. The administration of therapy based on the "Guidelines
      principles" and monitoring of ICP, can minimise the application of those
      therapeutic modalities (barbiturate coma and prolonged hyperventilation) which,
      in addition to favourable effects, may also have harmful effects on patients with
      severe head injury.

PMID- 10592122
TI  - Effect of oral administration of dotarizine on cerebrovasculature subjected to
      constriction followed by dilatation in rabbits.
AB  - In the study presented the effect of Dotarizine on blood flow velocity in
      cerebral arteries - in middle cerebral artery (MCA), and basilar artery (BA)- was
      investigated and compared utilising transcranial Doppler sonography during
      normoventilation, 15 min hyperventilation with subsequent 3 min anoxia in
      anaesthetized rabbits. In the Dotarizine treated group (12 rabbits) 25 mg/kg of
      Dotarizine dissolved in 0,25% agar was administered orally for five days twice
      daily. In the control group (9 rabbits) animals were fed with agar of the same
      concentration. The results revealed that decrease of flow velocity caused by
      hyperventilation and increase during anoxia were less pronounced in the
      Dotarizine treated group than in control group of animals. A difference between
      changes of flow velocity in MCA and BA during anoxia was found and the different
      reactivity of both vessels was established.

PMID- 10592123
TI  - Disturbance of cerebral blood flow autoregulation in hypertension is attributable
      to ischaemia following subarachnoid haemorrhage in rats: A PET study.
AB  - The effects of subarachnoid haemorrhage (SAH) on cerebral blood flow (CBF)
      autoregulation during induced hypertension were studied by positron emission
      tomography (PET) during chronic vasospasm in anaesthetized Sprague-Dawley rats.
      SAH was induced by intracisternal injection of autologous blood. In the control
      animals saline was injected instead. This method produced angiographical
      vasospasm of major arteries 48 h after injection. During this period, CBF was
      measured at each side of fronto-parietal and occipital sections using PET with or
      without induced hypertension. Mean arterial blood pressure (MABP) was increased
      from 94+/-2.4 to 140+/-0.3 mmHg by the injection of phenylephrine. An
      autoregulatory index (AI) expressed as delta CBF (%) per 10-mmHg increase in MABP
      was employed to analyse CBF response. SAH significantly reduced (p<0. 0001) basal
      CBF (ml/100 g/min) by 26.2% (control 60.0+/-1.9 n=24, SAH 44.3+/-4.5 n=20). A
      territorial CBF that decreased by 50% or more over the mean control value was
      used to define ischaemia and was identified in five out of 20 regions (25%) in
      the SAH group. AI (%/10-mmHg) was 13.5+/-2.4 in the control group (n=24). In the
      SAH group, AI decreased (p<0.05) to 4.5+/-2.5 in non-ischaemic areas (n=15),
      while in the ischaemic areas (n=5) AI increased (p<0.05) to 25.2+/-4.1. Since the
      spastic artery is intrinsically resistant to hypertension, the marked increase in
      CBF during hypertension can be attributable to ischaemia following SAH.

PMID- 10592124
TI  - Assessment of critical closing pressure in the cerebral circulation as a measure
      of cerebrovascular tone.
AB  - Critical closing pressure (CCP) calculated from the blood flow velocity (FV) and
      arterial blood pressure (ABP) waveforms has been previously reported to be useful
      in the assessment of the dynamics of cerebral circulation. We investigated the
      relationship between CCP and intracranial pressure (ICP) and cerebrovascular tone
      in a model of intracranial hypertension in 22 anaesthetised New Zealand White
      rabbits during manipulations of arterial CO2, ABP and vasodilatation caused by
      hypoxia. Recordings were made of FV in the basilar artery, ABP and ICP during
      subarachnoid infusion of saline. During infusion ICP and CCP were significantly
      correlated (R=0.68; p<0.001), but the magnitude of increase in ICP and CCP during
      infusion were not correlated to each other. Linear regression between the
      difference: CCP-ICP (representing a factor due to vasogenic tone) and cerebral
      perfusion pressure (CPP=ABP-ICP) was highly significant (R=-0.87; p<0.01).
      Generally, CCP decreased significantly (p<0.05) with hypercarbia, arterial
      hypotension and after and post-hypoxia and the difference: CCP-ICP decreased
      consistently after each vasodilatatory manoeuvre studied. Our data confirmed the
      linear relationship between CCP and ICP, and between the difference: CCP-ICP and
      cerebrovascular tone. However, because the magnitude of increase in ICP was not
      correlated to magnitude of change in CCP, CCP cannot be use for detection of
      increasing ICP quantitatively.

PMID- 10592125
TI  - Possible role of an endovascular provocative test in the diagnosis of
      glossopharyngeal neuralgia as a vascular compression syndrome.
AB  - We utilized endovascular provocative techniques to identify the indications for
      microvascular decompression surgery in a serious case of glossopharyngeal
      neuralgia. This is the first reported case in which an endovascular provocative
      test was applied for diagnosis of glossopharyngeal neuralgia as a vascular
      compression syndrome. A 68-year-old woman presented with severe paroxysmal facial
      pain which could not be controlled by medical therapy. Partial effectiveness to
      carbamazepine led us to wonder whether or not the selection of microvascular
      decompression surgery would be appropriate. Pre-operative angiography was
      performed. During the examination a microcatheter was inserted into the right
      posterior inferior cerebellar artery (PICA), and an attack of typical
      glossopharyngeal neuralgia occurred. The patient thus underwent microvascular
      decompression surgery. The PICA was verified to compress the glossopharyngeal
      nerve and therefore was moved to induce decompression. The patient has since
      experienced no further pain for one year postoperatively. The diagnosis of
      glossopharyngeal neuralgia is sometimes complex and it is difficult to select the
      most appropriate surgical modality. In such cases this endovascular provocative
      technique may thus be useful for making a definitive decision or microvascular
      decompression surgery.

PMID- 10592126
TI  - Ruptured aneurysm at the trunk of the accessory middle cerebral artery.
AB  - We present a 32-year-old woman with intracranial haemorrhage due to rupture of a
      saccular aneurysm arising from the trunk of an accessory middle cerebral artery.
      This is the first report of an aneurysm arising distally to the anomalous
      vessel's origin from the A1 segment of the anterior cerebral artery.

PMID- 10592127
TI  - Complex coloured visual hallucinations during transient hemianopia.

PMID- 10592129
TI  - The Cochrane Collaboration: shared evidence for improving decision-making in
      human health.

PMID- 10592128
TI  - Epidural haematoma after lumbar disc surgery causing radiculopathy.

PMID- 10592130
TI  - Nutritional evaluation of children with phenylketonuria.
AB  - CONTEXT: Dietary phenylalanine (PA) restriction is the most effective form for
      reducing its excess in the blood and is the only efficient method for treating
      phenylketonuria. The diet is complex and should be adapted to combine the
      patients' eating habits, growth and development. It depends basically on the use
      of industrialized products as substitutes free of PA for proteins that are not
      fully supplied. OBJECTIVE: To evaluate the nutritional status of children with
      phenylketonuria (PKU) by anthropometric measurements and food intake. DESIGN:
      Cross-sectional study. SETTING: Children with PKU attending the Association of
      Parents and Friends of Handicapped Children (Associacao de Pais e Amigos dos
      Excepcionais - APAE) and normal children attending at municipal day care centers
      in Sao Paulo. PARTICIPANTS: 42 children with PKU and 31 normal children aged 1 to
      12 of both sexes were assessed in two groups, under and over 7 years of age. MAIN
      MEASUREMENTS: Weight and height measurements. RESULTS: Children with PKU ingested
      calories, calcium, iron, zinc, and copper below the recommended values, whereas
      the protein intake was within the normal range. Food intake in the group of
      normal children was within normality rates. The height/weight Z-score means for
      children with PKU were 0.47 for those under 7 years and 1.86 for 7 year-olds and
      over; in normal children the means were 0.97 <7 years and 1.54 >/=7 years, with
      no statistically significant difference. The height/age Z-score means were
      significantly lower in the PKU children <7 years (-1.23) than in the normal
      controls (0.91). CONCLUSIONS: The data presented demonstrate the importance of
      nutritional surveillance in patients with PKU so as to support adequacy of
      nutrient intake and to guarantee growth within the relevant standards.

PMID- 10592131
TI  - Comparison between the Comfort and Hartwig sedation scales in pediatric patients
      undergoing mechanical lung ventilation.
AB  - CONTEXT: A high number of hospitalized children do not receive adequate sedation
      due to inadequate evaluation and use of such agents. With the increase in
      knowledge of sedation and analgesia in recent years, concern has also risen, such
      that it is now not acceptable that incorrect evaluations of the state of
      children's pain and anxiety are made. OBJECTIVE: A comparison between the Comfort
      and Hartwig sedation scales in pediatric patients undergoing mechanical lung
      ventilation. DESIGN: Prospective cohort study. SETTING: A pediatric intensive
      care unit with three beds at an urban teaching hospital. PATIENTS: Thirty
      simultaneous and independent observations were conducted by specialists on 18
      patients studied. DIAGNOSTIC TEST: Comfort and Hartwig scales were applied, after
      3 minutes of observation. MAIN MEASUREMENTS: Agreement rate (kappa). RESULTS: On
      the Comfort scale, the averages for adequately sedated, insufficiently sedated,
      and over-sedated were 20.28 (SD 2.78), 27.5 (SD 0.70), and 15.1 (SD 1.10),
      respectively, whereas on the Hartwig scale, the averages for adequately sedated,
      insufficiently sedated, and over-sedated were 16.35 (SD 0.77), 20.85 (SD 1.57),
      and 13.0 (SD 0.89), respectively. The observed agreement rate was 63% (p = 0.006)
      and the expected agreement rate was 44% with a Kappa coefficient of 0.345238 (z =
      2.49). CONCLUSIONS: In our study there was no statistically significant
      difference whether the more complex Comfort scale was applied (8 physiological
      and behavioral parameters) or the less complex Hartwig scale (5 behavioral
      parameters) was applied to assess the sedation of mechanically ventilated
      pediatric patients.

PMID- 10592132
TI  - The effect of chronic nitric oxide inhibition on vascular reactivity and blood
      pressure in pregnant rats.
AB  - CONTEXT: The exact mechanism involved in changes in blood pressure and peripheral
      vascular resistance during pregnancy is unknown. OBJECTIVE: To evaluate the
      importance of endothelium-derived relaxing factor (EDRF) and its main component,
      nitric oxide, in blood pressure and vascular reactivity in pregnant rats. DESIGN:
      Clinical trial in experimentation animals. SETTING: University laboratory of
      Pharmacology. SAMPLE: Female Wistar rats with normal blood pressure, weight (152
      to 227 grams) and age (90 to 116 days). INTERVENTION: The rats were divided in to
      four groups: pregnant rats treated with L-NAME (13 rats); pregnant control rats
      (8 rats); virgin rats treated with L-NAME (10 rats); virgin control rats (12
      rats). The vascular preparations and caudal blood pressure were obtained at the
      end of pregnancy, or after the administration of L-NAME in virgin rats. MAIN
      MEASUREMENTS: The caudal blood pressure and the vascular response to
      acetylcholine in pre-contracted aortic rings, both with and without endothelium,
      and the effect of nitric oxide inhibition, Nw-L-nitro-arginine methyl-ester (L
      NAME), in pregnant and virgin rats. The L-NAME was administered in the drinking
      water over a 10-day period. RESULTS: The blood pressure decreased in pregnancy.
      Aortic rings of pregnant rats were more sensitive to acetylcholine than those of
      virgin rats. After L-NAME treatment, the blood pressure increased and relaxation
      was blocked in both groups. The fetal-placental unit weight of the L-NAME group
      was lower than that of the control group. CONCLUSION: Acetylcholine-induced
      vasorelaxation sensitivity was greater in pregnant rats and that blood pressure
      increased after L-NAME administration while the acetylcholine-induced
      vasorelaxation response was blocked.

PMID- 10592133
TI  - Severity and prognosis in intensive care: prospective application of the APACHE
      II index.
AB  - CONTEXT: The performance of each ICU needs to be assessed within the overall
      context of medical care, as well as by the institution which the ICU forms part
      of. Evaluation mechanisms in the field of intensive care have been developed that
      are recognized worldwide within the scientific literature. OBJECTIVE: To study
      outcomes from groups of critical patients and to compare their actual and
      estimated mortality rates. DESIGN: Prospective study of patients' outcomes.
      SETTING: A tertiary care unit for a period of 13 months (anesthesiology intensive
      care unit at the Escola Paulista de Medicina). PARTICIPANTS: 520 patients
      selected according to sex, age and nature of hospitalization. DIAGNOSTIC TEST:
      The modified APACHE II prognostic index was applied in order to assess clinical
      severity and anticipation of mortality in three groups who had non-surgical
      treatment, emergency surgery and elective surgery. MAIN MEASUREMENTS: The APACHE
      II index. RESULTS: The application of this index allowed patients to be
      stratified and expected death risks for both subgroups and the entire sample
      population to be calculated. The observed mortality rate was greater than the
      expected rate (28. 5% versus 23.6%, respectively), with a statistically
      significant difference. The standardized mortality rate was 1.20. Patients who
      obtained scores above 25 presented a significant outcome towards death. The most
      severe and worst evolving cases were, in decreasing order: non-surgical,
      emergency surgical and scheduled surgical patients; the actual general mortality
      rate was higher than the expected one. CONCLUSIONS: The use of the APACHE II
      index made it possible to stratify critical patient groups according to the
      severity of their condition.

PMID- 10592134
TI  - Clinical management of six cases of low-risk primary tonsillar non-Hodgkin's
      lymphoma.
AB  - CONTEXT: There have been many reports that favor aggressive systemic treatment
      with chemotherapy and radiotherapy, even for well-localized lymphomas, avoiding
      the need for tonsillectomy of the normal tonsil. CASE REPORT: We report six cases
      of primary tonsillar lymphoma with a median patient age of 42 years. There were
      two lymphoma cases with diffuse large cells, two cases with mixed small and large
      cells, one with small cells and one indeterminate. They were treated with six
      cycles of chemotherapy and cervical radiotherapy. All patients achieved durable
      complete remission. Our data agree with previous reports that suggested that
      primary tonsillar high-grade B-cell NHL has a good prognosis if aggressively
      treated.

PMID- 10592135
TI  - Use of a platysma myocutaneous flap for the reimplantation of a severed ear:
      experience with five cases.
AB  - CONTEXT: The traumatic loss of an ear greatly affects the patient because of the
      severe aesthetic deformity it entails. The characteristic format of the ear, with
      a fine skin covering a thin and elastic cartilage, is not found anywhere else in
      the human body. Thus, to reconstruct an ear, the surgeon may try to imitate it by
      sculpting cartilage and covering it with skin. OBJECTIVE: To use a platysma
      myocutaneous flap for the reimplantation of a severed ear in humans. DESIGN: Case
      report. SETTING: Emergency unit of the university hospital, Faculty of Medicine,
      Ribeirao Preto - USP. CASE REPORT: Five cases are reported, with whole ear
      reimplantation in 3 of them and only segments in 2 cases. The surgical technique
      used was original and was based on the principle of auricular cartilage
      revascularization using the platysma muscle. We implanted traumatically severed
      auricular cartilage into the platysma muscle. The prefabricated ear was later
      transferred to its original site in the form of a myocutaneous-cartilaginous
      flap. Of the 5 cases treated using this technique, 4 were successful. In these 4
      cases the reimplanted ears showed no short- or long-term problems, with an
      aesthetic result quite close to natural appearance. In one case there was
      necrosis of the entire flap, with total loss of the ear. The surgical technique
      described is simple and utilizes the severed ear of the patient. Its application
      is excellent for skin losses in the auricular region or for the ear itself, thus
      obviating the need for microsurgery or the use of protheses or grafts.

PMID- 10592136
TI  - Angled telescopic surgery, an approach for laryngeal diagnosis and surgery
      without suspension.
AB  - CONTEXT: Many methods have been used successfully for the diagnosis and treatment
      of laryngeal diseases. Microscopic and, recently, telescopic surgery represent
      the state of the art in endoscopic laryngeal surgery but drawbacks are possible
      during their application. To keep the suspension apparatus adequately positioned,
      excessive force is sometimes placed on the upper teeth and tongue with the
      laryngoscope tube causing damage. Complications in relation to the pharynx,
      larynx and cardiovascular system have also been reported. OBJECTIVE: In order to
      reduce complications resulting from the manipulation or stimulation of the upper
      aerodigestive tract and from torque forces on the upper teeth. We present a
      method of larynx surgery in which laryngeal suspension is not required. DESIGN:
      Technical report. TECHNIQUES: We have devised a fiber-optic telescope with its
      40mm distal portion deviated 60 degrees from the direction of the proximal
      portion. This angle was taken by measuring patients immediately before standard
      microlaryngeal surgery was performed. The surgical instruments have the same
      angle as the telescope, in order to work on the larynx. This technique provides
      an image that is not limited by the distal aperture of the laryngoscope and has
      an advantage in that magnification and illumination may be provided by changing
      the distance of the lesion from the tip of the instrument. we have operated on
      four patients with laryngeal diseases and have had no complications as a result
      of this approach. We feel that this technique gives us the freedom to view the
      lesions better and helps to minimize the drawbacks caused by laryngeal
      suspension.

PMID- 10592137
TI  - Medical journals and the popular media

PMID- 10592138
TI  - Occupational exposure to environmental tobacco smoke and health risk assessment.
AB  - This article addresses concepts of environmental tobacco smoke (ETS) exposure
      assessment relevant for health risk assessment based on human studies. We present
      issues that should be considered when selecting a method for ETS exposure
      assessment for the purposes of health risk assessment and review data on ETS
      exposure levels in the workplace and in home environments. Two types of estimates
      are needed for a quantitative risk assessment of the health effects resulting
      from occupational ETS exposure: (italic)a(/italic)) an unbiased estimate of the
      exposure-effect (or dose-response) relation between ETS and the health effect of
      interest, and (italic)b(/italic)) estimates of the distribution of ETS exposure
      in different workplaces. By combining the estimated exposure-effect relation with
      information on exposure distribution for a population of interest, we can
      calculate the proportions of disease cases attributable to occupational ETS
      exposure as well as the excess number of cases due to specified exposure
      conditions. Several dimensions of the exposure profile should be considered when
      assessing ETS exposure for estimating the exposure-effect relation, including the
      magnitude of exposure and the biologically relevant time specificity of exposure.
      The magnitude of exposure is determined by the ETS source strength, environmental
      factors modifying concentrations, and duration of exposure. Time specificity
      considerations include the latency period for each health outcome of interest,
      the time-exposure profile relevant for different disease mechanisms, and the
      sensitive age period with regard to health effects. The most appropriate
      indicator of ETS exposure depends on these factors and on the time period that
      can be assessed with different methods.

PMID- 10592139
TI  - Environmental tobacco smoke and measures of subclinical vascular disease.
AB  - Assessing the relationship of exposure to environmental tobacco smoke (ETS) with
      subclinical measures of atherosclerotic disease supplements the epidemiologic
      data on fatal and nonfatal cardiovascular events. In addition, such assessment
      offers the opportunity to study smaller populations (including subgroups within
      larger studies) through improved statistical precision relative to the analysis
      of the relationship of ETS and clinical events and provides insights into the
      mechanisms of the harmful effects of ETS. In this article we review the published
      literature on the relationship of ETS with several indices of subclinical
      atherosclerosis including carotid artery intimal-medial thickness, brachial
      artery endothelial functioning, and silent cerebral infarctions. In each of these
      domains, exposure to ETS is associated with evidence of increased subclinical
      vascular disease.

PMID- 10592140
TI  - Epidemiologic studies of fatal and nonfatal cardiovascular disease and ETS
      exposure from spousal smoking.
AB  - This article reviews the epidemiologic studies of the association of ischemic
      heart disease risk and environmental tobacco smoke (ETS) exposure from a spouse
      who smokes. Seventeen studies (nine cohort, eight case-control) comprising more
      than 485,000 lifelong nonsmokers and 7,345 coronary heart disease (CHD) events
      were included in a meta-analysis. Together, these studies include 36% more CHD
      events and 58% more study subjects than were available for review by the U. S.
      Occupational Safety and Health Administration (OSHA) in 1994. The relative risk
      (RR) for fatal or nonfatal coronary events among never smokers married to
      smokers, compared to those whose spouses did not smoke, was RR = 1.25 (95%
      confidence interval [95% CI], 1.17-1.33) across the combined studies. This
      association was statistically similar in men (RR = 1.24; 95% CI, 1.15-1.32) and
      women (RR = 1.23; 95% CI, 1.15-1.32); in studies of cohort (RR = 1.23; 95% CI,
      1.15-1. 31) and case-control (RR = 1.47; 95% CI, 1.19-1.81) design; in the United
      States (RR =1.22; 95% CI, 1.13-1.30) and other countries (RR = 1.41; 95% CI, 1.21
      1.65); and in studies of fatal (RR = 1.22; 95% CI, 1.14-1.30) and nonfatal (RR =
      1.32; 95% CI, 1.04-1.67) heart disease. In three studies that presented data
      separately for nonsmokers married to current or former smokers, the association
      was stronger when the spouses continued to smoke (RR = 1.16, 1.06-1.28) than with
      former smokers (RR = 0.98; 95% CI, 0.89-1.08). The aggregate data are unlikely to
      be attributable to chance, publication bias, confounding, or misclassification of
      exposure. The evidence linking heart disease and ETS exposure from a spouse has
      become substantially stronger since OSHA first proposed including heart disease
      in its risk assessment of ETS in 1994.

PMID- 10592141
TI  - Workplace exposure to passive smoking and risk of cardiovascular disease: summary
      of epidemiologic studies.
AB  - We reviewed the published epidemiologic studies addressing the relationship
      between workplace exposure to environmental tobacco smoke (ETS) and
      cardiovascular disease risk in three case-control studies and three cohort
      studies. Although the point estimates of risk for cardiovascular disease exceeded
      1.0 in five of six studies, none of the relative risks was statistically
      significant because of the small number of cardiovascular end points occurring in
      individual studies. In common with most epidemiologic investigations of the
      health risks of ETS, none of the workplace studies included independent
      biochemical validation of ETS exposure. In contrast to the evidence on increased
      cardiovascular disease risk from exposure to spousal ETS, studies of ETS exposure
      in the workplace are still sparse and inconclusive. Conversely, there is no
      biologically plausible reason to believe that the hazards of ETS exposure that
      have been demonstrated in the home should not also apply to the workplace.

PMID- 10592142
TI  - Why is environmental tobacco smoke more strongly associated with coronary heart
      disease than expected? A review of potential biases and experimental data.
AB  - Despite exposure levels estimated to be equivalent to smoking only 0. 1-1.0
      cigarettes per day, exposure to environmental tobacco smoke (ETS) is estimated to
      increase the risk of death from coronary heart disease (CHD) between 25 and 35%
      above the risk of nonexposed persons. This surprisingly large risk associated
      with a seemingly small exposure has raised doubts about the validity of
      attributing the increased CHD risk to ETS exposure. This paper reviews various
      biases that have been hypothesized to account for the increased CHD risk
      associated with ETS in the epidemiologic studies and characterizes the adverse
      effects of ETS on thrombosis, vascular endothelium, and exercise tolerance
      observed in experimental studies of humans and laboratory animals. None of the
      identified factors that has been proposed to introduce a spurious association
      between ETS and heart disease seem to invalidate the epidemiologic findings,
      either separately or in combination. In addition, experimental studies of ETS and
      heart disease demonstrate that acute exposure of humans and other species to ETS
      affects platelet function, vascular endothelium, and myocardial exercise
      tolerance at exposure concentrations widely prevalent in the workplace. Because
      exposure to ETS affects multiple physiologic pathways, it appears biologically
      plausible that ETS could cause the substantial increase in CHD risk that has been
      observed in epidemiologic studies.

PMID- 10592143
TI  - Risk assessment for heart disease and workplace ETS exposure among nonsmokers.
AB  - In 1994 the U.S. Occupational Health and Safety Administration (OSHA) published a
      study of risk assessment for heart disease and lung cancer resulting from
      workplace exposure to environmental tobacco smoke (ETS) among nonsmokers. This
      assessment is currently being revised. The present article considers different
      possible approaches to a risk assessment for heart disease among nonsmokers
      resulting from workplace ETS exposure, reviews the approach taken by OSHA in
      1994, and suggests some modifications to that approach. Since 1994 the literature
      supporting an association between ETS exposure and heart disease among never
      smokers (sometimes including long-term former smokers) has been strengthened by
      new studies, including some studies that have specifically considered workplace
      exposure. A number of these studies are appropriate for inclusion in a meta
      analysis, whereas a few may not be due to methodological problems or problems in
      exposure definition. A meta-analysis of eight relative risks (either rate ratios
      or odds ratios) for heart disease resulting from workplace ETS exposure, based on
      one reasonable selection of appropriate studies, yields a combined relative risk
      of 1.21 (95% confidence interval [CI], 1.04-1.41). This relative risk, which is
      similar to that used by OSHA in 1994, yields an excess risk of death from heart
      disease by age 70 of 7 per 1000 (95% CI 0.001-0.013) resulting from ETS exposure
      in the workplace. This excess risk exceeds OSHA's usual threshold for regulation
      of 1 per 1000. Approximately 1,710 excess ischemic heart disease deaths per year
      would be expected among nonsmoking U.S. workers 35-69 years of age exposed to
      workplace ETS.

PMID- 10592144
TI  - Epidemiologic evidence for workplace ETS as a risk factor for lung cancer among
      nonsmokers: specific risk estimates.
AB  - Exposure to environmental tobacco smoke (ETS) among individuals who have never
      smoked tobacco products has been well established as a risk factor for lung
      cancer. Most of the epidemiologic evidence for this association has come from
      studies of exposure to a spouse who smokes. Fewer studies have explicitly
      evaluated this risk relationship for workplace sources of ETS exposure. These are
      reviewed here in the context of study design issues and their contributions to
      the overall evidence for risks of ETS exposure in the workplace. Although most
      studies have low power to detect workplace risk estimates in the modest range
      suggested by the larger studies, risk estimates tend to be consistent with those
      for exposure from a smoking spouse.

PMID- 10592145
TI  - Exposure misclassification bias in studies of environmental tobacco smoke and
      lung cancer.
AB  - It is now recognized that exposure to environmental tobacco smoke (ETS) in the
      workplace and other settings outside the home may be equally as important as
      residential ETS exposure. This review examines the sources of misclassification
      in the assessment of workplace ETS exposure in questionnaire-based epidemiologic
      studies. Cogent to this discussion is the role of misclassification of ever
      smokers as never smokers, which is important in studies of both workplace and
      residential ETS exposure and lung cancer and is discussed first. The collective
      evidence from studies that have used direct or indirect approaches to estimate
      smoker misclassification shows that although some misclassification of ever
      smokers as never smokers exists in studies of ETS and lung cancer, the potential
      bias from the misclassification of smokers is unlikely to explain the observed
      increased risk of lung cancer associated with ETS exposure.

PMID- 10592146
TI  - Estimating lung cancer risk with exposure to environmental tobacco smoke.
AB  - Estimates of lung cancer in nonsmokers due to exposure to environmental tobacco
      smoke (ETS) in the workplace or in the home may be developed in several ways.
      Estimates may be based on (italic)a(/italic)) models developed using the full
      range of data in smokers; (italic)b(/italic)) models developed using data
      restricted to smokers with a low smoking rate, for example, (3/4) 10 cigarettes
      per day; (italic)c(/italic)) models developed using data from studies of
      residential exposure to ETS of nonsmokers, with exposures based on smoking rates
      of spouses; and (italic)d(/italic)) models using data from studies of
      occupational exposure to ETS of nonsmokers. Methods (italic)a(/italic) and
      (italic)b(/italic) require an estimate of cigarette equivalent exposure for ETS
      as well as assumptions on the cigarette equivalent dose to target cells from ETS
      and on the comparability of lung cancer risk per unit dose from smokers and
      nonsmokers. Summary relative risks (RRs) and 95% confidence intervals (CI) from
      ETS studies of nonsmokers with exposures based on smoking patterns of spouses are
      1.24 (1.1, 1.4) for females and 1.34 (1.0, 1.8) for males, whereas the RR
      estimate for occupational ETS exposure and its 95% CI is 1.39 (1.2, 1.7). Using
      RR estimates for ETS exposure, cigarette equivalents for ETS range from 0.1 to
      1.0, based on a range of descriptive and biologically motivated models in active
      smokers; a cigarette equivalent is 0.2 based on a comparison of log-linear trends
      in RR with number of cigarettes smoked per day in active smokers and in spouses
      of nonsmokers.

PMID- 10592148
TI  - Lung cancer and environmental tobacco smoke: occupational risk to nonsmokers.
AB  - The principal epidemiologic evidence that environmental tobacco smoke (ETS)
      increases the risk of lung cancer in (lifelong) nonsmokers is from studies of
      nonsmoking women married to smokers. This article estimates exposure-response
      curves for 14 studies (1, 249+ cases, 7 countries) with data on lung cancer
      categorized by the number of cigarettes/day smoked by the husband. The pooled
      results from the five U.S. studies alone are extrapolated to ETS levels in the
      workplace using measures of serum cotinine and nicotine samples from personal
      monitors as markers of exposure to ETS. It is predicted that the increase in lung
      cancer risk for nonsmoking women from average ETS exposure at work (among those
      exposed at work) is on the order of 25% (95% confidence interval (CI) = 8, 41)
      relative to background risk (i.e., with no ETS exposure from any source). This
      compares to an estimate of 39% (95% CI = 5, 65) for nonsmoking women whose
      husbands smoke at the adult male smoker's average of 25 cigarettes/day. At the
      95th percentiles of exposure, the estimate from spousal smoking is 85% (95% CI =
      32, 156), compared to 91% (95% CI = 34, 167) from workplace ETS exposure. Subject
      to the validity of the assumptions required in this approach, the outcome
      supports the conclusion that there is a significant excess risk from occupational
      exposure to ETS. The excess risk from ETS at work is typically lower than that
      from spousal smoking, but may be higher at the 95th percentiles of exposure.

PMID- 10592147
TI  - Environmental tobacco smoke and low birth weight: a hazard in the workplace?
AB  - Low birth weight (LBW) increases infant morbidity and mortality worldwide. One
      well-established risk factor is maternal smoking. Environmental tobacco smoke
      (ETS) exposure has recently been focused on as another potential risk factor. In
      this article, we review epidemiologic literature on the effects of ETS on LBW and
      intrauterine growth retardation (IUGR), the cause of LBW related to maternal
      smoking. As we consider the feasibility of modifying women's exposure, we focus
      our discussion on workplace exposure to ETS. The workplace is particularly
      important to consider because women of child-bearing age are present in the
      workplace in greater numbers now than ever before. In addition, certain subgroups
      of working women may be particularly at risk from the effects of ETS on pregnancy
      because they work in environments with higher exposure or they are more
      susceptible to its effects. We conclude that there is consistent evidence to
      relate maternal ETS exposure to an increased risk of adverse pregnancy outcomes
      and that this association may be generalized to the work environment. In studies
      with positive findings, infants exposed to ETS antenatally were 1.5-4 times more
      likely to be born with LBW, but few studies examined LBW. Most studies looked at
      measures of IUGR. ETS was associated with reductions in birth weight (adjusted
      for gestational age) ranging from 25 to 90 g. Infants born to women exposed to
      ETS were generally 2-4 times more likely to be born small-for-gestational age.
      ETS exposure in the workplace can and should be minimized to protect pregnant
      women from its adverse effects.

PMID- 10592149
TI  - Environmental tobacco smoke exposure and asthma in adults.
AB  - Environmental tobacco smoke (ETS) contaminates indoor air in homes and
      workplaces. Although the adverse effects of active cigarette smoking on the
      respiratory tract have been extensively characterized, the effects of ETS
      exposure on adult asthma have not yet been investigated extensively and the
      available data are limited. This article examines the evidence for ETS exposure
      as a cause of asthma and asthma exacerbation in adults, and for ETS exposure in
      the workplace specifically as contributing to these health effects. It addresses
      methodological barriers that limit the available data and evaluates the adequacy
      of the data for risk assessment.

PMID- 10592150
TI  - Pharmaceuticals and personal care products in the environment: agents of subtle
      change?
AB  - During the last three decades, the impact of chemical pollution has focused
      almost exclusively on the conventional "priority" pollutants, especially those
      acutely toxic/carcinogenic pesticides and industrial intermediates displaying
      persistence in the environment. This spectrum of chemicals, however, is only one
      piece of the larger puzzle in "holistic" risk assessment. Another diverse group
      of bioactive chemicals receiving comparatively little attention as potential
      environmental pollutants includes the pharmaceuticals and active ingredients in
      personal care products (in this review collectively termed PPCPs), both human and
      veterinary, including not just prescription drugs and biologics, but also
      diagnostic agents, "nutraceuticals," fragrances, sun-screen agents, and numerous
      others. These compounds and their bioactive metabolites can be continually
      introduced to the aquatic environment as complex mixtures via a number of routes
      but primarily by both untreated and treated sewage. Aquatic pollution is
      particularly troublesome because aquatic organisms are captive to continual life
      cycle, multigenerational exposure. The possibility for continual but undetectable
      or unnoticed effects on aquatic organisms is particularly worrisome because
      effects could accumulate so slowly that major change goes undetected until the
      cumulative level of these effects finally cascades to irreversible change--change
      that would otherwise be attributed to natural adaptation or ecologic succession.
      As opposed to the conventional, persistent priority pollutants, PPCPs need not be
      persistent if they are continually introduced to surface waters, even at low
      parts-per-trillion/parts-per-billion concentrations (ng-microg/L). Even though
      some PPCPs are extremely persistent and introduced to the environment in very
      high quantities and perhaps have already gained ubiquity worldwide, others could
      act as if they were persistent, simply because their continual infusion into the
      aquatic environment serves to sustain perpetual life-cycle exposures for aquatic
      organisms. This review attempts to synthesize the literature on environmental
      origin, distribution/occurrence, and effects and to catalyze a more focused
      discussion in the environmental science community.

PMID- 10592151
TI  - Summary: workshop on health risks attributable to ETS exposure in the workplace.
AB  - This 1998 workshop was convened to address the health risks of exposure to
      environmental tobacco smoke (ETS) in the workplace. It was paired with a 1997
      workshop on issues related to ETS exposure in work environments
      ((italic)1(/italic)). In the 1998 workshop, a multidisciplinary group of
      participants was charged with reviewing evidence on the quantitative risks to
      health posed by ETS and to discuss development of risk assessment methodology for
      the future. The overall charges for the present workshop were to consider various
      health outcomes and make recommendations regarding those health outcomes to be
      included in assessment of health risk resulting from ETS in the workplace; to
      consider available studies addressing these health outcomes and to evaluate the
      validity of data for estimating risk from occupational ETS exposure; to review
      and evaluate mathematical models useful for estimating the risk due to ETS
      exposure; to examine dose-response models and to characterize the models
      regarding validity and uncertainty in estimating health risk attributable to ETS
      exposure in the workplace.

PMID- 10592153
TI  - Recent developments in clinical photography.
AB  - A system comprising a clinical camera, specialized retractors, and a new occlusal
      mirror are described to maximize the quality of both intra-oral and extra-oral
      photography in the multi-user situation.

PMID- 10592152
TI  - Optident-ormco 'A' company prize 1998.

PMID- 10592154
TI  - Random errors in localization of landmarks in postero-anterior cephalograms.
AB  - The aim of the present study was to evaluate the random error in localization of
      the most common landmarks in postero-anterior cephalograms (PAC). The study took
      place at the Department of Orthodontics of Aarhus University during the period
      1993-1995. The material consisted of 30 standardized PAC taken in natural head
      position. Five examiners had to identify 34 landmarks on each cephalogram.
      Subsequently, all examiners had to identify again the same 34 landmarks on one
      randomly selected cephalogram five times with a time interval of at least 24
      hours. All landmarks were digitized, related to an X-Y co-ordinate system, and an
      arithmetical mean was calculated. The accuracy of digitizing was evaluated by
      digitizing one randomly selected cephalogram 10 times. The main findings of this
      study are: (1) The digitizing error is negligible compared to the errors
      introduced by landmark identification. (2) Each landmark has its own
      characteristic pattern of variance, which is very similar on both sides. (3)
      Significant differences in accuracy exist between the various postero-anterior
      landmarks. The six most accurate landmarks are mastoid left (l) and right (r),
      latero-orbitale (l) and (r), and antegonion (l) and (r). The six least accurate
      landmarks are coronoid (l) and (r), condylar (l) and (r), and mandibular foramen
      (l) and (r). (4) A significant difference in the accuracy of landmark
      identification between the five examiners was only seen for seven of the 34
      landmarks. (5) No evidence was found that one examiner was consistently
      better/worse than the others. (6) No improvement in the accuracy was found after
      repeated identification, thus there seems to be no short-term 'learning process'.
      Refereed Paper

PMID- 10592155
TI  - Factors affecting the shear bond strength of orthodontic brackets to porcelain.
AB  - The aim of this investigation was to establish a regime for orthodontic bonding
      to feldspathic porcelain, which ensures adequate bond strength (6-8 MPa) with
      minimal damage on debond and consisted of an ex vivo investigation measuring the
      effects of porcelain surface preparation and thermocycling on shear bond strength
      of orthodontic brackets. One-hundred-and-twenty feldspathic porcelain bonded
      crown surfaces were divided into 12 equally-sized groups to assess the effects
      of: (1) glaze removal, (2) application of hydrofluoric acid, phosphoric acid, or
      omission of acid treatment, and (3) silane priming upon the bond strength of
      premolar brackets bonded with Right-on (TM) composite resin adhesive. Specimens
      were subjected to thermocycling and then to shear debonding forces on an Instron
      machine. Removal of the porcelain glaze, or use of hydrofluoric acid, prior to
      bonding were found to be unnecessary to secure the target bond strength.
      Hydrofluoric acid application was associated with increased porcelain surface
      damage. Thermocycling caused a significant reduction in shear bond strength to
      porcelain (P < 0*001). The best regime for orthodontic bonding to feldspathic
      porcelain was to apply phosphoric acid for 60 seconds, and prime with silane
      prior to bonding. Usually the porcelain surfaces could be repolished. Refereed
      Paper

PMID- 10592158
TI  - Editorial: british journal of orthodontics & millennium-drawing to a close!

PMID- 10592156
TI  - The potential of digital dental radiography in recording the adductor sesamoid
      and the MP3 stages.
AB  - The current study was undertaken to evaluate the reliability of using a recent
      advance in clinical radiographic technique, digital dental radiography, in
      recording two growth indicators: the adductor sesamoid and MP3 stages. With an
      exposure time five times less than that used in the conventional approach, this
      method shows greatest flexibility in providing a high quality digitized
      radiographic images of the two growth indicators under investigation. Refereed
      Paper

PMID- 10592157
TI  - Orthodontics and infective endocarditis.
AB  - Infective endocarditis associated with orthodontics is a rare occurrence.
      Unfortunately, many orthodontic practitioners do not treat patients potentially
      at risk of developing endocarditis due to the lack of practical guidelines and
      fear of precipitating the infection. Additionally, many patients that undergo
      orthodontic treatment are inappropriately prescribed antibiotic cover for
      procedures that have a minimal bacteraemic risk. In this paper the literature
      linking orthodontic treatment and infective endocarditis is examined.
      Recommendations are made for the appropriate management of patients at risk of
      infective endocarditis for orthodontic procedures. Refereed Paper

PMID- 10592159
TI  - Electronic orthodontics.

PMID- 10592160
TI  - A medico-legal review of some current UK guidelines in orthodontics: a personal
      view.
AB  - This article is a critical analysis from a medico-legal perspective of some
      current authoritative UK clinical guidelines in orthodontics. Two clinical
      guidelines have been produced by the Royal College of Surgeons of England and
      four by the British Orthodontic Society. Each guideline is published with the
      analysis immediately following it. Following recent UK case law (Bolitho v City &
      Hackney Health Authority, 1997) which allows the courts to choose between two
      bodies of responsible expert medical opinion where they feel one opinion is not
      'logical', it is likely that the UK courts will increasingly turn to
      authoritative clinical guidelines to assist them in judging whether or not an
      appropriate standard of care has been achieved in medical negligence cases. It is
      thus important for clinicians to be aware of the recommendations of such
      guidelines, and if these are not followed the reasons should be discussed with
      the patient and recorded in the clinical case notes. This article attempts to
      highlight aspects of the guidelines that have medico-legal implications.

PMID- 10592161
TI  - Cortical bone screws for maxillomandibular fixation in orthognathic surgery.

PMID- 10592162
TI  - Digital cameras.

PMID- 10592163
TI  - Re: Orthologic 'A' company award for 1997.

PMID- 10592164
TI  - Re: Forestadent travel award.

PMID- 10592165
TI  - Reviews and abstracts

PMID- 10592166
TI  - The bedfordshire PDS orthodontic pilot.
AB  - Throughout the 50-year history of the NHS, the Government has sought to cash
      limit the GDS. PDS (Personal Dental Services) pilots represent another attempt at
      cash limiting and a new system for delivering dental services in NHS practice.
      The development of the Bedfordshire Orthodontic PDS pilot is described. The basis
      is the prioritization of orthodontic services to child patients with the greatest
      oral health need through a cost and volume contract with the local Health
      Authority. A brief outline of the Bedfordshire PDS contract is given. The
      experiences of the first 9 months of the PDS pilot are related.

PMID- 10592167
TI  - The molecular biology database collection: an online compilation of relevant
      database resources.
AB  - The Molecular Biology Database Collection represents an effort geared at making
      molecular biology database resources more accessible to biologists. This online
      resource, available at http://www.oup.co.uk/nar/Volume_28/Issue_01/html
      /gkd115_gml.html, is intended to serve as a searchable, up-to-date, centralized
      jumping-off point to individual Web sites. An emphasis has also been placed on
      including databases where new value is added to the underlying data by virtue of
      curation, new data connections, or other innovative approaches.

PMID- 10592168
TI  - DBcat: a catalog of 500 biological databases.
AB  - The DBcat (http://www.infobiogen.fr/services/dbcat ) is a comprehensive catalog
      of biological databases, maintained and curated at Infobiogen. It contains 500
      databases classified by application domains. The DBcat is a structured flat-file
      library, that can be searched by means of an SRS server or a dedicated Web
      interface. The files are available for download from Infobiogen anonymous ftp
      server.

PMID- 10592169
TI  - Database resources of the National Center for Biotechnology Information.
AB  - In addition to maintaining the GenBank(R) nucleic acid sequence database, the
      National Center for Biotechnology Information (NCBI) provides data analysis and
      retrieval and resources that operate on the data in GenBank and a variety of
      other biological data made available through NCBI's Web site. NCBI data retrieval
      resources include Entrez, PubMed, LocusLink and the Taxonomy Browser. Data
      analysis resources include BLAST, Electronic PCR, OrfFinder, RefSeq, UniGene,
      Database of Single Nucleotide Polymorphisms (dbSNP), Human Genome Sequencing
      pages, GeneMap'99, Davis Human-Mouse Homology Map, Cancer Chromosome Aberration
      Project (CCAP) pages, Entrez Genomes, Clusters of Orthologous Groups (COGs)
      database, Retroviral Genotyping Tools, Cancer Genome Anatomy Project (CGAP)
      pages, SAGEmap, Online Mendelian Inheritance in Man (OMIM) and the Molecular
      Modeling Database (MMDB). Augmenting many of the Web applications are custom
      implementations of the BLAST program optimized to search specialized data sets.
      All of the resources can be accessed through the NCBI home page at:
      http://www.ncbi.nlm.nih. gov

PMID- 10592170
TI  - GenBank.
AB  - The GenBank((R))sequence database incorporates publicly available DNA sequences
      of >55 000 different organisms, primarily through direct submission of sequence
      data from individual laboratories and large-scale sequencing projects. Most
      submissions are made using the BankIt (Web) or Sequin programs and accession
      numbers are assigned by GenBank staff upon receipt. Data exchange with the EMBL
      Data Library and the DNA Data Bank of Japan helps ensure comprehensive worldwide
      coverage. GenBank data is accessible through NCBI's integrated retrieval system,
      Entrez, which integrates data from the major DNA and protein sequence databases
      along with taxonomy, genome, mapping and protein structure information, plus the
      biomedical literature via PubMed. Sequence similarity searching is provided by
      the BLAST family of programs. Complete bimonthly releases and daily updates of
      the GenBank database are available by FTP. NCBI also offers a wide range of WWW
      retrieval and analysis services based on GenBank data. The GenBank database and
      related resources are freely accessible via the NCBI home page at
      http://www.ncbi.nlm.nih.gov

PMID- 10592171
TI  - The EMBL nucleotide sequence database.
AB  - The European Molecular Biology Laboratory (EMBL) Nucleotide Sequence Database
      (http://www.ebi.ac. uk/embl/index.html ) is maintained at the European
      Bioinformatics Institute (EBI) in an international collaboration with the DNA
      Data Bank of Japan (DDBJ) and GenBank (USA). Data is exchanged amongst the
      collaborative databases on a daily basis. The major contributors to the EMBL
      database are individual authors and genome project groups. WEBIN is the preferred
      web-based submission system for individual submitters, whilst automatic
      procedures allow incorporation of sequence data from large-scale genome
      sequencing centres and from the European Patent Office (EPO). Database releases
      are produced quarterly. Network services allow free access to the most up-to-date
      data collection via Internet and WWW interfaces. EBI's Sequence Retrieval System
      (SRS) is a network browser for databanks in molecular biology, integrating and
      linking the main nucleotide and protein databases plus many specialised
      databases. For sequence similarity searching a variety of tools (e.g., BLITZ,
      FASTA, BLAST) are available which allow external users to compare their own
      sequences against the most currently available data in the EMBL Nucleotide
      Sequence Database and SWISS-PROT.

PMID- 10592172
TI  - DNA data bank of Japan (DDBJ) in collaboration with mass sequencing teams.
AB  - We at DDBJ (http://www.ddbj.nig.ac.jp) process and publicise the massive amounts
      of data submitted mainly by Japanese genome projects and sequencing teams. It is
      emphasised that the collaboration between data producing teams and the data bank
      is crucial in carrying out these processes smoothly. The amount of data submitted
      in 1999 is so large that it alone exceeds the total amount submitted in the
      preceding 10 years. To cope with this situation, we have developed tools not only
      for processing such massive amounts of data but also for efficiently retrieving
      data on demand.

PMID- 10592173
TI  - KEGG: kyoto encyclopedia of genes and genomes.
AB  - KEGG (Kyoto Encyclopedia of Genes and Genomes) is a knowledge base for systematic
      analysis of gene functions, linking genomic information with higher order
      functional information. The genomic information is stored in the GENES database,
      which is a collection of gene catalogs for all the completely sequenced genomes
      and some partial genomes with up-to-date annotation of gene functions. The higher
      order functional information is stored in the PATHWAY database, which contains
      graphical representations of cellular processes, such as metabolism, membrane
      transport, signal transduction and cell cycle. The PATHWAY database is
      supplemented by a set of ortholog group tables for the information about
      conserved subpathways (pathway motifs), which are often encoded by positionally
      coupled genes on the chromosome and which are especially useful in predicting
      gene functions. A third database in KEGG is LIGAND for the information about
      chemical compounds, enzyme molecules and enzymatic reactions. KEGG provides Java
      graphics tools for browsing genome maps, comparing two genome maps and
      manipulating expression maps, as well as computational tools for sequence
      comparison, graph comparison and path computation. The KEGG databases are daily
      updated and made freely available (http://www. genome.ad.jp/kegg/).

PMID- 10592174
TI  - The genome sequence DataBase.
AB  - The Genome Sequence DataBase (GSDB) is a database of publicly available
      nucleotide sequences and their associated biological and bibliographic
      information. Several notable changes have occurred in the past year: GSDB stopped
      accepting data submissions from researchers; ownership of data submitted to GSDB
      was transferred to GenBank; sequence analysis capabilities were expanded to
      include Smith-Waterman and Frame Search; and Sequence Viewer became available to
      Mac users. The content of GSDB remains up-to-date because publicly available data
      is acquired from the International Nucleotide Sequence Database Collaboration
      databases (IC) on a nightly basis. This allows GSDB to continue providing
      researchers with the ability to analyze, query and retrieve nucleotide sequences
      in the database. GSDB and its related tools are freely accessible from the URL:
      http://www.ncgr.org

PMID- 10592175
TI  - The COG database: a tool for genome-scale analysis of protein functions and
      evolution.
AB  - Rational classification of proteins encoded in sequenced genomes is critical for
      making the genome sequences maximally useful for functional and evolutionary
      studies. The database of Clusters of Orthologous Groups of proteins (COGs) is an
      attempt on a phylogenetic classification of the proteins encoded in 21 complete
      genomes of bacteria, archaea and eukaryotes (http://www. ncbi.nlm. nih.gov/COG).
      The COGs were constructed by applying the criterion of consistency of genome
      specific best hits to the results of an exhaustive comparison of all protein
      sequences from these genomes. The database comprises 2091 COGs that include 56
      83% of the gene products from each of the complete bacterial and archaeal genomes
      and approximately 35% of those from the yeast Saccharomyces cerevisiae genome.
      The COG database is accompanied by the COGNITOR program that is used to fit new
      proteins into the COGs and can be applied to functional and phylogenetic
      annotation of newly sequenced genomes.

PMID- 10592176
TI  - MIPS: a database for genomes and protein sequences.
AB  - The Munich Information Center for Protein Sequences (MIPS-GSF), Martinsried, near
      Munich, Germany, continues its longstanding tradition to develop and maintain
      high quality curated genome databases. In addition, efforts have been intensified
      to cover the wealth of complete genome sequences in a systematic, comprehensive
      form. Bioinformatics, supporting national as well as European sequencing and
      functional analysis projects, has resulted in several up-to-date genome-oriented
      databases. This report describes growing databases reflecting the progress of
      sequencing the Arabidopsis thaliana (MATDB) and Neurospora crassa genomes
      (MNCDB), the yeast genome database (MYGD) extended by functional analysis data,
      the database of annotated human EST-clusters (HIB) and the database of the
      complete cDNA sequences from the DHGP (German Human Genome Project). It also
      contains information on the up-to-date database of complete genomes (PEDANT), the
      classification of protein sequences (ProtFam) and the collection of protein
      sequence data within the framework of the PIR-International Protein Sequence
      Database. These databases can be accessed through the MIPS WWW server
      (http://www. mips.biochem.mpg.de).

PMID- 10592177
TI  - The protein information resource (PIR).
AB  - The Protein Information Resource (PIR) produces the largest, most comprehensive,
      annotated protein sequence database in the public domain, the PIR-International
      Protein Sequence Database, in collaboration with the Munich Information Center
      for Protein Sequences (MIPS) and the Japan International Protein Sequence
      Database (JIPID). The expanded PIR WWW site allows sequence similarity and text
      searching of the Protein Sequence Database and auxiliary databases. Several new
      web-based search engines combine searches of sequence similarity and database
      annotation to facilitate the analysis and functional identification of proteins.
      New capabilities for searching the PIR sequence databases include annotation
      sorted search, domain search, combined global and domain search, and interactive
      text searches. The PIR-International databases and search tools are accessible on
      the PIR WWW site at http://pir.georgetown.edu and at the MIPS WWW site at
      http://www. mips.biochem.mpg.de. The PIR-International Protein Sequence Database
      and other files are also available by FTP.

PMID- 10592178
TI  - The SWISS-PROT protein sequence database and its supplement TrEMBL in 2000.
AB  - SWISS-PROT is a curated protein sequence database which strives to provide a high
      level of annotation (such as the description of the function of a protein, its
      domains structure, post-translational modifications, variants, etc.), a minimal
      level of redundancy and high level of integration with other databases. Recent
      developments of the database include format and content enhancements, cross
      references to additional databases, new documentation files and improvements to
      TrEMBL, a computer-annotated supplement to SWISS-PROT. TrEMBL consists of entries
      in SWISS-PROT-like format derived from the translation of all coding sequences
      (CDSs) in the EMBL Nucleotide Sequence Database, except the CDSs already included
      in SWISS-PROT. We also describe the Human Proteomics Initiative (HPI), a major
      project to annotate all known human sequences according to the quality standards
      of SWISS-PROT. SWISS-PROT is available at: http://www.expasy.ch/sprot/ and
      http://www.ebi.ac.uk/swissprot/

PMID- 10592179
TI  - ProtoMap: automatic classification of protein sequences and hierarchy of protein
      families.
AB  - The ProtoMap site offers an exhaustive classification of all proteins in the
      SWISS-PROT database, into groups of related proteins. The classification is based
      on analysis of all pairwise similarities among protein sequences. The analysis
      makes essential use of transitivity to identify homologies among proteins. Within
      each group of the classification, every two members are either directly or
      transitively related. However, transitivity is applied restrictively in order to
      prevent unrelated proteins from clustering together. The classification is done
      at different levels of confidence, and yields a hierarchical organization of all
      proteins. The resulting classification splits the protein space into well-defined
      groups of proteins, which are closely correlated with natural biological families
      and superfamilies. Many clusters contain protein sequences that are not
      classified by other databases. The hierarchical organization suggested by our
      analysis may help in detecting finer subfamilies in families of known proteins.
      In addition it brings forth interesting relationships between protein families,
      upon which local maps for the neighborhood of protein families can be sketched.
      The ProtoMap web server can be accessed at http://www.protomap.cs.huji.ac.il

PMID- 10592180
TI  - The EcoCyc and MetaCyc databases.
AB  - EcoCyc is an organism-specific Pathway/Genome Database that describes the
      metabolic and signal-transduction pathways of Escherichia coli, its enzymes, and
      a new addition-its transport proteins. MetaCyc is a new metabolic-pathway
      database that describes pathways and enzymes of many different organisms, with a
      microbial focus. Both databases are queried using the Pathway Tools graphical
      user interface, which provides a wide variety of query operations and
      visualization tools. EcoCyc and MetaCyc are available at
      http://ecocyc.PangeaSystems.com/ecocyc/

PMID- 10592181
TI  - EcoGene: a genome sequence database for Escherichia coli K-12.
AB  - The EcoGene database provides a set of gene and protein sequences derived from
      the genome sequence of Escherichia coli K-12. EcoGene is a source of re-annotated
      sequences for the SWISS-PROT and Colibri databases. EcoGene is used for genetic
      and physical map compilations in collaboration with the Coli Genetic Stock
      Center. The EcoGene12 release includes 4293 genes. EcoGene12 differs from the
      GenBank annotation of the complete genome sequence in several ways, including (i)
      the revision of 706 predicted or confirmed gene start sites, (ii) the correction
      or hypothetical reconstruction of 61 frame-shifts caused by either sequence error
      or mutation, (iii) the reconstruction of 14 protein sequences interrupted by the
      insertion of IS elements, and (iv) pre-dictions that 92 genes are partially
      deleted gene fragments. A literature survey identified 717 proteins whose N
      terminal amino acids have been verified by sequencing. 12 446 cross-references to
      6835 literature citations and s are provided. EcoGene is accessible at a new
      website: http://bmb.med.miami.edu/EcoGene/EcoWeb. Users can search and retrieve
      individual EcoGene GenePages or they can download large datasets for
      incorporation into database management systems, facilitating various genome-scale
      computational and functional analyses.

PMID- 10592182
TI  - RegulonDB (version 3.0): transcriptional regulation and operon organization in
      Escherichia coli K-12.
AB  - RegulonDB is a database on transcription regulation and operon organization in
      Escherichia coli. The current version describes regulatory signals of
      transcription initiation, promoters, regulatory binding sites of specific
      regulators, ribosome binding sites and terminators, as well as information on
      genes clustered in operons. These specific annotations have been gathered from a
      constant search in the literature, as well as based on computational sequence
      predictions. The genomic coordinates of all these objects in the E.coli K-12
      chromosome are clearly indicated. Every known object has a link to at least one
      MEDLINE reference. We have also added direct links to recent expression data of
      E.coli K-12. The version presented here has important modifications both in the
      structure of the database, as well as in the amount and type of information
      encoded in the database. RegulonDB can be accessed on the web at URL:
      http://www.cifn.unam. mx/Computational_Biology/regulondb/

PMID- 10592183
TI  - EMGLib: the enhanced microbial genomes library (update 2000).
AB  - As the number of complete microbial genomes publicly available is still growing,
      the problem of annotation quality in these very large sequences remains unsolved.
      Indeed, the number of annotations associated with complete genomes is usually
      lower than those of the shorter entries encountered in the repository
      collections. Moreover, classical sequence database management systems have
      difficulties in handling entries of such size. In this context, the Enhanced
      Microbial Genomes Library (EMGLib) was developed to try to alleviate these
      problems. This library contains all the complete genomes from prokaryotes
      (bacteria and archaea) already sequenced and the yeast genome in GenBank format.
      The annotations are improved by the introduction of data on codon usage, gene
      orientation on the chromosome and gene families. It is possible to access EMGLib
      through two database systems set up on WWW servers: the PBIL server at
      http://pbil.univ-lyon1.fr/emglib.html and the MICADO server at
      http://locus.jouy.inra.fr/micado

PMID- 10592184
TI  - CyanoBase, the genome database for Synechocystis sp. strain PCC6803: status for
      the year 2000.
AB  - CyanoBase provides an online resource for access to data on genomic information
      about the cyanobacterium Synechocystis sp. strain PCC6803. The database contains
      annotations for each protein-coding gene deduced from the entire nucleotide
      sequence of the genome, gene classification lists, and keyword and similarity
      search engines. Core portions of CyanoBase consist of annotations for each of the
      3168 protein genes deduced from the entire nucleotide sequence of this genome.
      The contents of each gene were improved by updating with the results of
      similarity searches and by introducing references for analysis in bioinformatics.
      The database now contains repository facilities that store and provide
      experimental information, in addition to providing proposals for the function of
      each gene. This information should help to avoid unnecessary, overlapping
      experiments and should assist communication between scientists who wish to
      elucidate the function of putative genes on the cyanobacteria genome. The current
      URL of CyanoBase is http://www.kazusa.or.jp:8080/cyano/

PMID- 10592185
TI  - The yeast proteome database (YPD) and Caenorhabditis elegans proteome database
      (WormPD): comprehensive resources for the organization and comparison of model
      organism protein information.
AB  - The Yeast Proteome Database (YPDtrade mark) has been for several years a resource
      for organized and accessible information about the proteins of Saccharomyces
      cerevisiae. We have now extended the YPD format to create a database containing
      complete proteome information about the model organism Caenorhabditis elegans
      (WormPDtrade mark). YPD and WormPD are designed for use not only by their
      respective research communities but also by the broader scientific community. In
      both databases, information gleaned from the literature is presented in a
      consistent, user-friendly Protein Report format: a single Web page presenting all
      available knowledge about a particular protein. Each Protein Report begins with a
      Title Line, a concise description of the function of that protein that is
      continually updated as curators review new literature. Properties and functions
      of the protein are presented in tabular form in the upper part of the Report, and
      free-text annotations organized by topic are presented in the lower part. Each
      Protein Report ends with a comprehensive reference list whose entries are linked
      to their MEDLINE s. YPD and WormPD are seamlessly integrated, with extensive
      links between the species. They are freely accessible to academic users on the
      WWW at http://www. proteome.com/databases/index.html, and are available by
      subscription to corporate users.

PMID- 10592186
TI  - Integrating functional genomic information into the Saccharomyces genome
      database.
AB  - The Saccharomyces Genome Database (SGD) stores and organizes information about
      the nearly 6200 genes in the yeast genome. The information is organized around
      the 'locus page' and directs users to the detailed information they seek. SGD is
      endeavoring to integrate the existing information about yeast genes with the
      large volume of data generated by functional analyses that are beginning to
      appear in the literature and on web sites. New features will include searches of
      systematic analyses and Gene Summary Paragraphs that succinctly review the
      literature for each gene. In addition to current information, such as gene
      product and phenotype descriptions, the new locus page will also describe a gene
      product's cellular process, function and localization using a controlled
      vocabulary developed in collaboration with two other model organism databases. We
      describe these developments in SGD through the newly reorganized locus page. The
      SGD is accessible via the WWW at http://genome-www.stanford.edu/Saccharomyces/

PMID- 10592187
TI  - TRIPLES: a database of gene function in Saccharomyces cerevisiae.
AB  - Using a novel multipurpose mini-transposon, we have generated a collection of
      defined mutant alleles for the analysis of disruption phenotypes, protein
      localization, and gene expression in Saccharomyces cerevisiae. To catalog this
      unique data set, we have developed TRIPLES, a Web-accessible database of
      TRansposon-Insertion Phenotypes, Localization and Expression in Saccharomyces.
      Encompassing over 250 000 data points, TRIPLES provides convenient access to
      information from nearly 7800 transposon-mutagenized yeast strains; within
      TRIPLES, complete data reports of each strain may be viewed in table format, or
      if desired, downloaded as tab-delimited text files. Each report contains external
      links to corresponding entries within the Saccharomyces Genome Database and
      International Nucleic Acid Sequence Data Library (GenBank). Unlike other yeast
      databases, TRIPLES also provides on-line order forms linked to each clone report;
      users may immediately request any desired strain free-of-charge by submitting a
      completed form. In addition to presenting a wealth of information for over 2300
      open reading frames, TRIPLES constitutes an important medium for the distribution
      of useful reagents throughout the yeast scientific community. Maintained by the
      Yale Genome Analysis Center, TRIPLES may be accessed at
      http://ycmi.med.yale.edu/ygac/triples.htm

PMID- 10592188
TI  - YIDB: the Yeast Intron DataBase.
AB  - The Yeast Intron DataBase (YIDB) contains currently available information about
      all introns encoded in the nuclear and mitochondrial genomes of the yeast
      Saccharomyces cerevisiae. Introns are divided according to their mechanism of
      excision: group I and group II introns, pre-mRNA introns, tRNA introns and the
      HAC1 intron. Information about the host genome, the type of RNA in which they are
      inserted and their primary structure are provided together with references. For
      nuclear pre-mRNA introns, transcription frequencies, as determined by microarray
      experiments, have also been included. This updated database is accessible at:
      http://www.embl-heidelberg. de/ExternalInfo/seraphin/yidb.html

PMID- 10592189
TI  - The phytophthora genome initiative database: informatics and analysis for
      distributed pathogenomic research.
AB  - The Phytophthora Genome Initiative (PGI) is a distributed collaboration to study
      the genome and evolution of a particularly destructive group of plant pathogenic
      oomycete, with the goal of understanding the mechanisms of infection and
      resistance. NCGR provides informatics support for the collaboration as well as a
      centralized data repository. In the pilot phase of the project, several
      investigators prepared Phytophthora infestans and Phytophthora sojae EST and
      Phytophthora sojae BAC libraries and sent them to another laboratory for
      sequencing. Data from sequencing reactions were transferred to NCGR for analysis
      and curation. An analysis pipeline transforms raw data by performing simple
      analyses (i.e., vector removal and similarity searching) that are stored and can
      be retrieved by investigators using a web browser. Here we describe the database
      and access tools, provide an overview of the data therein and outline future
      plans. This resource has provided a unique opportunity for the distributed,
      collaborative study of a genus from which relatively little sequence data are
      available. Results may lead to insight into how better to control these
      pathogens. The homepage of PGI can be accessed at http:www.ncgr.org/pgi, with
      database access through the database access hyperlink.

PMID- 10592191
TI  - Gene discovery using the maize genome database ZmDB.
AB  - Zea mays DataBase (ZmDB) is a repository and analysis tool for sequence,
      expression and phenotype data of the major crop plant maize. The data accessible
      in ZmDB are mostly generated in a large collaborative project of maize gene
      discovery, sequencing and phenotypic analysis using a transposon tagging strategy
      and expressed sequence tag (EST) sequencing. ESTs constitute most of the current
      content. Database search tools, convenient links to external databases, and novel
      sequence analysis programs for spliced alignment are provided and together serve
      as an efficient protocol for gene discovery by sequence inspection. ZmDB can be
      accessed at http://zmdb. iastate.edu. ZmDB also provides web-based ordering of
      materials generated in the project, including EST and genomic DNA clones, seeds
      of mutant plants and microarrays of amplified EST and genomic DNA sequences.

PMID- 10592190
TI  - The intronerator: exploring introns and alternative splicing in Caenorhabditis
      elegans.
AB  - The Intronerator (http://www.cse.ucsc.edu/ approximately kent/intronerator/ ) is
      a set of web-based tools for exploring RNA splicing and gene structure in
      Caenorhabditis elegans. It includes a display of cDNA alignments with the genomic
      sequence, a catalog of alternatively spliced genes and a database of introns. The
      cDNA alignments include >100 000 ESTs and almost 1000 full-length cDNAs. ESTs
      from embryos and mixed stage animals as well as full-length cDNAs can be compared
      in the alignment display with each other and with predicted genes. The alt
      splicing catalog includes 844 open reading frames for which there is evidence of
      alternative splicing of pre-mRNA. The intron database includes 28 478 introns,
      and can be searched for patterns near the splice junctions.

PMID- 10592192
TI  - INE: a rice genome database with an integrated map view.
AB  - The Rice Genome Research Program (RGP) launched a large-scale rice genome
      sequencing in 1998 aimed at decoding all genetic information in rice. A new
      genome database called INE (INtegrated rice genome Explorer) has been developed
      in order to integrate all the genomic information that has been accumulated so
      far and to correlate these data with the genome sequence. A web interface based
      on Java applet provides a rapid viewing capability in the database. The first
      operational version of the database has been completed which includes a genetic
      map, a physical map using YAC (Yeast Artificial Chromosome) clones and PAC (P1
      derived Artificial Chromosome) contigs. These maps are displayed graphically so
      that the positional relationships among the mapped markers on each chromosome can
      be easily resolved. INE incorporates the sequences and annotations of the PAC
      contig. A site on low quality information ensures that all submitted sequence
      data comply with the standard for accuracy. As a repository of rice genome
      sequence, INE will also serve as a common database of all sequence data obtained
      by collaborating members of the International Rice Genome Sequencing Project
      (IRGSP). The database can be accessed at http://www. dna.affrc.go.jp:82/giot/INE.
      html or its mirror site at http://www.staff.or.jp/giot/INE.html

PMID- 10592193
TI  - DAtA: database of Arabidopsis thaliana annotation.
AB  - The Database of Arabidopsis thaliana Annotation (D At A) was created to enable
      easy access to and analysis of all the Arabidopsis genome project annotation. The
      database was constructed using the completed A.thaliana genomic sequence data
      currently in GenBank. An automated annotation process was used to predict coding
      sequences for GenBank records that do not include annotation. D At A also
      contains protein motifs and protein similarities derived from searches of the
      proteins in D At A with motif databases and the non-redundant protein database.
      The database is routinely updated to include new GenBank submissions for
      Arabidopsis genomic sequences and new Blast and protein motif search results. A
      web interface to D At A allows coding sequences to be searched by name, comment,
      blast similarity or motif field. In addition, browse options present lists of
      either all the protein names or identified motifs present in the sequenced
      A.thaliana genome. The database can be accessed at http://baggage.
      stanford.edu/group/arabprotein/

PMID- 10592194
TI  - UK CropNet: a collection of databases and bioinformatics resources for crop plant
      genomics.
AB  - The UK Crop Plant Bioinformatics Network (UK CropNet) was established in 1996 in
      order to harness the extensive work in genome mapping in crop plants in the UK.
      Since this date we have published five databases from our central UK CropNet WWW
      site (http://synteny.nott.ac.uk/) with a further three to follow shortly. Our
      resource facilitates the identification and manipulation of agronomically
      important genes by laying a foundation for comparative analysis among crop plants
      and model species. In addition, we have developed a number of software tools that
      facilitate the visualisation and analysis of our data. Many of our tools are made
      freely available for use with both crop plant data and with data from other
      species.

PMID- 10592195
TI  - The Mouse Genome Database (MGD): expanding genetic and genomic resources for the
      laboratory mouse. The Mouse Genome Database Group.
AB  - The Mouse Genome Database (MGD) is a comprehensive public database of mouse
      genomic, genetic and phenotypic information (http://www. informatics.jax.org).
      This community database provides information about genes, serves as a mapping
      resource of the mouse genome, details mammalian orthologs, integrates
      experimental data, represents standardized mouse nomenclature for genes and
      alleles, incorporates links to other genomic resources such as sequence data, and
      includes a variety of additional information about the laboratory mouse. MGD
      scientists and annotators work cooperatively with the research community to
      provide an integrated, consensus view of the mouse genome while also providing
      experimental data including data conflicting with the consensus representation.
      Recent improvements focus on the representation of phenotypic information and the
      enhancement of gene and allele descriptions.

PMID- 10592196
TI  - Mouse tumor biology database (MTB): enhancements and current status.
AB  - The Mouse Tumor Biology Database (MTB) is a Web-based resource that provides
      access to information on tumor frequency and latency, genetics and pathology in
      genetically defined mice (transgenics, targeted mutations and inbred strains).
      MTB is designed to serve as an information resource for cancer genetics
      researchers who use the laboratory mouse as a model system for understanding
      human disease processes. Data in MTB are obtained from the primary scientific
      literature and direct submissions by the research community. MTB is accessible
      from the Mouse Genome Informatics Web site (http://www. informatics.jax.org).
      User support is available for MTB via Email at mgi-help@informatics.jax.org

PMID- 10592197
TI  - GXD: a Gene Expression Database for the laboratory mouse: current status and
      recent enhancements. The Gene Expresison Database group.
AB  - The Gene Expression Database (GXD) is a community resource of gene expression
      information for the laboratory mouse. The database is designed as an open-ended
      system that can integrate different types of expression data. New expression data
      are made available on a daily basis. Thus, GXD provides increasingly complete
      information about what transcripts and proteins are produced by what genes;
      where, when and in what amounts these gene products are expressed; and how their
      expression varies in different mouse strains and mutants. GXD is integrated with
      the Mouse Genome Database (MGD). Continuously refined interconnections with
      sequence databases and with databases from other species place the gene
      expression information in the larger biological and analytical context. GXD is
      accessible through the Mouse Genome Informatics Web site at
      http://www.informatics.jax.org/ or directly at
      http://www.informatics.jax.org/menus/expression_menu.shtm l

PMID- 10592198
TI  - XREFdb: cross-referencing the genetics and genes of mammals and model organisms.
AB  - XREFdb supports the investigation of protein function in the context of
      information available through work in multiple organisms. In addition to
      facilitating the association of functional data among known genes from multiple
      organisms, XREFdb has developed strategies that provide access to information
      associated with as-yet unstudied genes. The database organizes protein similarity
      and genetic map positional information from diverse sources in the public domain
      to facilitate investigator evaluation of potential functional significance.
      XREFdb is found at URL www.ncbi.nlm.nih.gov/XREFdb

PMID- 10592199
TI  - WIT: integrated system for high-throughput genome sequence analysis and metabolic
      reconstruction.
AB  - The WIT (What Is There) (http://wit.mcs.anl.gov/WIT2/) system has been designed
      to support comparative analysis of sequenced genomes and to generate metabolic
      reconstructions based on chromosomal sequences and metabolic modules from the
      EMP/MPW family of databases. This system contains data derived from about 40
      completed or nearly completed genomes. Sequence homologies, various ORF
      clustering algorithms, relative gene positions on the chromosome and placement of
      gene products in metabolic pathways (metabolic reconstruction) can be used for
      the assignment of gene functions and for development of overviews of genomes
      within WIT. The integration of a large number of phylogenetically diverse genomes
      in WIT facilitates the understanding of the physiology of different organisms.

PMID- 10592200
TI  - NCBI's LocusLink and RefSeq.
AB  - The NCBI has introduced two new web resources-LocusLink and RefSeq-that
      facilitate retrieval of gene-based information and provide reference sequence
      standards. These resources are designed to provide a non-redundant view of
      current knowledge about human genes, transcripts and proteins. Additional
      information about these resources is available on the LocusLink web site at
      http://www.ncbi.nlm.nih.gov/LocusLink/

PMID- 10592201
TI  - Human BAC ends.
AB  - The Human BAC Ends database includes all non-redundant human BAC end sequences
      (BESs) generated by The Institute for Genomic Research (TIGR), the University of
      Washington (UW) and California Institute of Technology (CalTech). It incorporates
      the available BAC mapping data from different genome centers and the annotation
      results of each end sequence for the contents of repeats, ESTs and STS markers.
      For each BAC end the database integrates the sequence, the phred quality scores,
      the map and the annotation, and provides links to sites of the library
      information, the reports of GenBank, dbGSS and GDB, and other relevant data. The
      database is freely accessible via the web and supports sequence or clone searches
      and anonymous FTP. The relevant sites and resources are described at
      http://www.tigr.org/ tdb/humgen/bac_end_search/bac_end_intro.html

PMID- 10592202
TI  - MAGEST: MAboya gene expression patterns and sequence tags.
AB  - MAGEST is a database for newly identified maternal cDNAs of the ascidian,
      Halocynthia roretzi, which aims to examine the population of the mRNAs. We have
      collected 3' and 5' tag sequences of mRNAs and their expression data from whole
      mount in situ hybridi-zation in early embryos. To date, we have determined more
      than 2000 tag-sequences of H.roretzi cDNAs and input them into public databases.
      The tag sequences and the expression data as well as additional information can
      be obtained through MAGEST via the WWW at http://www.genome.ad.jp/magest/

PMID- 10592203
TI  - BodyMap: a human and mouse gene expression database.
AB  - BodyMap is a human and mouse gene expression database that has been maintained
      since 1993. It is based on site-directed 3'-ESTs collected from non-biased cDNA
      libraries constructed at Osaka University and contains >270 000 sequences from 60
      human and 38 mouse tissues. The site-directed nature of the sequence tags allows
      unequivocal grouping of tags representing the same transcript and provides
      abundance information for each transcript in different parts of the body. Our
      collection of ESTs was compared periodically with other public databases for
      cross referencing. The histological resolution of source tissues and unique
      cloning strategy that minimized cloning bias enabled BodyMap to support three
      unique mRNA based experiments in silico. First, the recurrence information for
      clones in each library provides a rough estimate of the mRNA composition of each
      source tissue. Second, a user can search the entire data set with nucleotide
      sequences or keywords to assess expression patterns of particular genes. Third,
      and most important, BodyMap allows a user to select genes that have a desired
      expression pattern in humans and mice. BodyMap is accessible through the WWW at
      http://bodymap.ims.u-tokyo.ac.jp

PMID- 10592204
TI  - Axeldb: a Xenopus laevis database focusing on gene expression.
AB  - Axeldb is a database storing and integrating gene expression patterns and DNA
      sequences identified in a large-scale in situ hybridization study in Xenopus
      laevis embryos. The data are organised in a format appropriate for comprehensive
      analysis, and enable comparison of images of expression pattern for any given set
      of genes. Information on literature, cDNA clones and their availability,
      nucleotide sequences, expression pattern and accompanying pictures are available.
      Current developments are aimed toward the interconnection with other databases
      and the integration of data from the literature. Axeldb is implemented using an
      ACEDB database system, and available through the web at http://www.dkfz
      heidelberg.de/abt0135/axeldb.htm

PMID- 10592206
TI  - RHdb: the radiation hybrid database.
AB  - Since July 1995, the European Bioinformatics Institute (EBI) has maintained RHdb
      (http://www.ebi.ac.uk/RHdb ), a public database for radiation hybrid data.
      Radiation hybrid mapping is an important technique for determining high
      resolution maps. RHdb is also served by CORBA servers. The EBI is an Outstation
      of the European Molecular Biology Laboratory (EMBL).

PMID- 10592205
TI  - The TIGR gene indices: reconstruction and representation of expressed gene
      sequences.
AB  - Expressed sequence tags (ESTs) have provided a first glimpse of the collection of
      transcribed sequences in a variety of organisms. However, a careful analysis of
      this sequence data can provide significant additional functional, structural and
      evolutionary information. Our analysis of the public EST sequences, available
      through the TIGR Gene Indices (TGI; http://www.tigr.org/tdb/tdb.html ), is an
      attempt to identify the genes represented by that data and to provide additional
      information regarding those genes. Gene Indices are constructed for selected
      organisms by first clustering, then assembling EST and annotated gene sequences
      from GenBank. This process produces a set of unique, high-fidelity virtual
      transcripts, or tentative consensus (TC) sequences. The TC sequences can be used
      to provide putative genes with functional annotation, to link the transcripts to
      mapping and genomic sequence data, and to provide links between orthologous and
      paralogous genes.

PMID- 10592208
TI  - Update of AMmtDB: a database of multi-aligned metazoa mitochondrial DNA
      sequences.
AB  - The AMmtDB database (http://bio-www.ba.cnr.it:8000/srs6/ ) has been updated by
      collecting the multi-aligned sequences of Chordata mitochondrial genes coding for
      proteins and tRNAs. The genes coding for proteins are multi-aligned based on the
      translated sequences and both the nucleotide and amino acid multi-alignments are
      provided. AMmtDB data selected through SRS can be viewed and managed using
      GeneDoc or other programs for the management of multi-aligned data depending on
      the user's operative system. The multiple alignments have been produced with
      CLUSTALW and PILEUP programs and then carefully optimized manually.

PMID- 10592207
TI  - MitBASE : a comprehensive and integrated mitochondrial DNA database. The present
      status.
AB  - MitBASE is an integrated and comprehensive database of mitochondrial DNA data
      which collects, under a single interface, databases for Plant, Vertebrate,
      Invertebrate, Human, Protist and Fungal mtDNA and a Pilot database on nuclear
      genes involved in mitochondrial biogenesis in Saccharomyces cerevisiae. MitBASE
      reports all available information from different organisms and from intraspecies
      variants and mutants. Data have been drawn from the primary databases and from
      the literature; value adding information has been structured, e.g., editing
      information on protist mtDNA genomes, pathological information for human mtDNA
      variants, etc. The different databases, some of which are structured using
      commercial packages (Microsoft Access, File Maker Pro) while others use a flat
      file format, have been integrated under ORACLE. Ad hoc retrieval systems have
      been devised for some of the above listed databases keeping into account their
      peculiarities. The database is resident at the EBI and is available at the
      following site: http://www3.ebi.ac.uk/Research/Mitbase/mitbas e.pl. The impact of
      this project is intended for both basic and applied research. The study of
      mitochondrial genetic diseases and mitochondrial DNA intraspecies diversity are
      key topics in several biotechnological fields. The database has been funded
      within the EU Biotechnology programme.

PMID- 10592209
TI  - MITOP, the mitochondrial proteome database: 2000 update.
AB  - MITOP (http://www.mips.biochem.mpg.de/proj/medgen/mitop/) is a comprehensive
      database for genetic and functional information on both nuclear- and
      mitochondrial-encoded proteins and their genes. The five species files-
      Saccharomyces cerevisiae, Mus musculus, Caenorhabditis elegans, Neurospora crassa
      and Homo sapiens--include annotated data derived from a variety of online
      resources and the literature. A wide spectrum of search facilities is given in
      the overlapping sections 'Gene catalogues', 'Protein catalogues', 'Homologies',
      'Pathways and metabolism' and 'Human disease catalogue' including extensive
      references and hyperlinks to other databases. Central features are the results of
      various homology searches, which should facilitate the investigations into
      interspecies relationships. Precomputed FASTA searches using all the MITOP yeast
      protein entries and a list of the best human EST hits with graphical cluster
      alignments related to the yeast reference sequence are presented. The orthologue
      tables with cross-listings to all the protein entries for each species in MITOP
      have been expanded by adding the genomes of Rickettsia prowazeckii and
      Escherichia coli. To find new mitochondrial proteins the complete yeast genome
      has been analyzed using the MITOPROT program which identifies mitochondrial
      targeting sequences. The 'Human disease catalogue' contains tables with a total
      of 110 human diseases related to mitochondrial protein abnormalities, sorted by
      clinical criteria and age of onset. MITOP should contribute to the systematic
      genetic characterization of the mitochondrial proteome in relation to human
      disease.

PMID- 10592211
TI  - MitoNuc and MitoAln: two related databases of nuclear genes coding for
      mitochondrial proteins.
AB  - Mitochondria, besides their central role in energy metabolism, have recently been
      found to be involved in a number of basic processes of cell life and to
      contribute to the pathogenesis of many degenerative diseases. All functions of
      mitochondria depend on the interaction of nuclear and organellar genomes.
      Mitochondrial genomes have been extensively sequenced and analysed and the data
      collected in several specialised databases. In order to collect information on
      nuclear coded mitochondrial proteins we developed MitoNuc and MitoAln, two
      related databases containing, respectively, detailed information on sequenced
      nuclear genes coding for mitochondrial proteins in Metazoa and yeast, and the
      multiple alignments of the relevant homologous protein coding regions. MitoNuc
      and MitoAln retrieval through SRS at http://bio-www.ba.cnr.it:8000/srs6/ can
      easily allow the extraction of sequence data, subsequences defined by specific
      features and nucleotide or amino acid multiple alignments.

PMID- 10592210
TI  - PLMItRNA, a database for tRNAs and tRNA genes in plant mitochondria: enlargement
      and updating.
AB  - The current version of PLMItRNA has been realized to constitute a database for
      tRNA molecules and genes identified in the mitochondria of all green plants (
      Viridiplantae ). It is the enlargement of a previous database originally
      restricted to seed plants [Ceci,L.R., Volpicella,M., Liuni,S., Volpetti,V.,
      Licciulli,F. and Gallerani,R. (1999) Nucleic Acids Res., 27, 156-157]. PLMItRNA
      reports information and multialignments on 254 genes and 16 tRNA molecules
      detected in 25 higher plants (one bryophyta and 24 vascular plants) and seven
      green algae. PLMItRNA is accessible via the WWW at http://bio
      WWW.ba.cnr.it:8000/srs6/

PMID- 10592212
TI  - 5S ribosomal RNA database Y2K.
AB  - This paper presents the updated version (Y2K) of the database of ribosomal 5S
      ribonucleic acids (5S rRNA) and their genes (5S rDNA),
      http://rose.man/poznan.pl/5SData/index.html. This edition of the database
      contains 1985primary structures of 5S rRNA and 5S rDNA. They include 60
      archaebacterial, 470 eubacterial, 63 plastid, nine mitochondrial and 1383
      eukaryotic sequences. The nucleotide sequences of the 5S rRNAs or 5S rDNAs are
      divided according to the taxonomic position of the source organisms.

PMID- 10592213
TI  - The tmRNA website.
AB  - The tmRNA Website collects all available tmRNA sequences into a single public
      resource, along with alignments and a guide to searching for new sequences. Over
      the last year, several sequences have been updated or newly found by monitoring
      ongoing genome sequencing projects; tmRNA sequence data from 70 species are now
      available. New features include: color-coding of sequences to mark suggested base
      paired regions, a list of the literature concerning tmRNA, careful crediting of
      tmRNA sequence identifications, and a split browser window. Updates are very
      frequent. The tmRNA Website has a new URL: http:www.indiana.edu/tmrna

PMID- 10592214
TI  - tmRDB (tmRNA database).
AB  - The tmRNA database (tmRDB) is maintained at the University of Texas Health
      Science Center at Tyler, Texas, and is accessible on the WWW at URL
      http://psyche.uthct.edu/dbs/tmRDB/tmRDB.++ +html. A tmRDB mirror site is located
      on the campus of Auburn University, Auburn, Alabama, reachable at the URL
      http://www.ag.auburn.edu/mirror/tmRDB/. Since April 1997, the tmRDB has provided
      sequences of tmRNA (previously called 10Sa RNA), a molecule present in most
      bacteria and some organelles. This release adds 17 new sequences for a total of
      60 tmRNAs. Sequences and corresponding tmRNA-encoded tag peptides are tabulated
      in alphabetical and phylo-genetic order. The updated tmRNA alignment improves the
      secondary structures of known tmRNAs on the level of individual basepairs. tmRDB
      also provides an introduction to tmRNA function in trans-translation (with links
      to relevant literature), a limited number of tmRNA secondary structure diagrams,
      and numerous three-dimensional models generated interactively with the program
      ERNA-3D.

PMID- 10592215
TI  - SRPDB (signal recognition particle database).
AB  - The signal recognition particle database (SRPDB) is maintained at the University
      of Texas Health Science Center at Tyler, Texas, and organizes SRP-related
      information about SRP RNA, SRP proteins and the SRP receptor. SRPDB is accessible
      on the WWW at the URL http://psyche.uthct.edu/dbs/SRPDB/SRPDB.++ +html. A mirror
      site of the SRPDB is located in Europe at the University of Goteborg, Sweden
      (http://www.medkem. gu.se/dbs/SRPDB/SRPDB.html ). This release of SRPDB adds 10
      new SRP RNA sequences (a total of 117 SRP RNAs), four protein SRP19 sequences (a
      total of 15), seven new SRP54 (ffh) sequences (a total of 52), and eight
      sequences of the SRP receptor alpha subunit (FtsY) (total of 36). Sequences are
      arranged in alphabetical and phylogenetic order and alignments are provided which
      highlight base paired and conserved regions. SPRDB also provides motifs to find
      new sequences, a brief introduction to SRP function in protein secretion,
      numerous SRP RNA secondary structure diagrams, 3-D SRP RNA models, and recently
      obtained crystal structure PDB coordinates of the human SRP54m domain.

PMID- 10592216
TI  - The RDP (Ribosomal Database Project) continues.
AB  - The Ribosomal Database Project (RDP-II), previously described by Maidak et al.,
      continued during the past year to add new rRNA sequences to the aligned data and
      to improve the analysis commands. Release 7.1 (September 17, 1999) included more
      than 10 700 small subunit rRNA sequences. More than 850 type strain sequences
      were identified and added to the prokaryotic alignment, bringing the total number
      of type sequences to 3324 representing 2460 different species. Availability of an
      RDP-II mirror site in Japan is also near completion. RDP-II provides aligned and
      annotated rRNA sequences, derived phylogenetic trees and taxonomic hierarchies,
      and analysis services through its WWW server (http://rdp.cme.msu.edu/ ). Analysis
      services include rRNA probe checking, approx-i-mate phylogenetic placement of
      user sequences, screening user sequences for possible chimeric rRNA sequences,
      automated alignment, production of similarity matrices and services to plan and
      analyze terminal restriction fragment length polymorphism (T-RFLP) experiments.

PMID- 10592217
TI  - The European small subunit ribosomal RNA database.
AB  - The European database of the Small Subunit (SSU) Ribosomal RNA is a curated
      database that strives to collect all information about the primary and secondary
      structure of completely or nearly-completely sequenced rRNAs. Furthermore, the
      database compiles additional information such as literature references and
      taxonomic status of the organism the sequence was derived from. The database can
      be consulted via the WWW at URL http://rrna.uia.ac.be/ssu/. Through the WWW,
      sequences can be easily selected either one by one, by taxonomic group, or by a
      combination of both, and can be retrieved in different sequence and alignment
      formats.

PMID- 10592218
TI  - The European large subunit ribosomal RNA database.
AB  - The European Large Subunit (LSU) Ribosomal RNA (rRNA) database is accessible via
      the rRNA WWW Server at URL http://rrna.uia.ac.be/lsu/. It is a curated database
      that compiles complete or nearly complete LSU rRNA sequences in aligned form, and
      also incorporates secondary structure information for each sequence. Taxonomic
      information, literature references and other information about the sequences are
      also available, and can be searched via the WWW interface.

PMID- 10592219
TI  - The database of the smallest known auto-replicable RNA species: viroids and
      viroid-like RNAs.
AB  - This is an online database in order to facilitate research on viroid, viroid-like
      RNAs and human hepatitis delta virus by presenting a large number of sequences
      and related data in a comprehensive and user-friendly format (e.g., position of
      their self-catalytic domains, open reading frame, prediction of the most stable
      secondary structures, etc.). This online database is available on the WWW at
      http://www.callisto.si. usherb.ca/jpperra

PMID- 10592220
TI  - The IDB and IEDB: intron sequence and evolution databases.
AB  - A non-redundant database of nuclear, protein-encoding, genomic DNA sequences
      highlighting nuclear pre-mRNA introns was constructed using information contained
      in the SWISS-PROT and GenBank sequence databases. This Intron DataBase (IDB)
      contains information about (i) introns (including nucleotide sequence, location,
      phase, length, GC content and consensus-sequence rule violations), (ii) exons
      (including nucleo-tide sequence, length and GC content), (iii) protein coding
      regions (including amino acid sequence and length), and (iv) descriptive
      information about the source gene and organism (including gene designations and
      species taxonomy). The Intron Evolution DataBase (IEDB) provides a statistical
      analysis of the exon and intron sequences catalogued in IDB as well as data
      concerning intron penetration (relative number of coding regions with introns),
      density (number of introns per kb of total coding sequence DNA), distribution,
      and consensus sequences for each species present in IDB. This supplement is
      provided to furnish insights into the phylogenetic distribution and evolution of
      introns. Both databases are extensively cross-referenced to the SWISS-PROT and
      GenBank databases. IDB currently contains information on over 63 000 genes and
      154 000 introns; IEDB summarizes information on over 2800 species. IDB and IEDB
      will be updated twice a year and are available via the internet
      (http://nutmeg.bio.indiana. edu/intron/index.html ).

PMID- 10592221
TI  - EID: the Exon-Intron Database-an exhaustive database of protein-coding intron
      containing genes.
AB  - To aid studies of molecular evolution and to assist in gene prediction research,
      we have constructed an Exon-Intron Database (EID) in FASTA format. Currently, the
      database is derived from GenBank release 112, and it contains 51 289 protein
      coding genes (287 209 exons) that harbor introns, along with extensive
      descriptions of each gene and its DNA and protein sequences, as well as splice
      motif information. There is 17% redundancy inherited from GenBank-a purge at the
      99% identity level reduced the database to 42 460 genes (243 589 exons). We have
      created subdatabases of genes whose intron positions have been experimentally
      determined. One such database, constructed by comparing genomic and mRNA
      sequences, contains 11 242 genes (62 474 exons). A larger database of 22 196
      genes (105 595 exons) was constructed by selecting on keywords to eliminate
      computer-predicted genes. By examining the two nucleotides adjacent to the intron
      boundary, we infer that there is a 2% rate of errors or other deviations from the
      standard GTellipsisAG motif in nuclear genes. This criterion can be used to
      eliminate 4921 genes from the overall database. Various tools are provided to
      enable generation of user-specific subsets of the EID. The EID distribution can
      be obtained from http://mcb.harvard.edu/gilbert/EID

PMID- 10592222
TI  - ExInt: an Exon/Intron database.
AB  - The Exon/Intron (ExInt) database incorporates information on the exon/intron
      structure of eukaryotic genes. Features in the database include: intron
      nucleotide sequence, amino acid sequence of the corresponding protein, position
      of the introns at the amino acid level and intron phase. From ExInt, we have also
      generated four additional databases each with ExInt entries containing predicted
      introns, introns experimentally defined, organelle introns or nuclear introns.
      ExInt is accessible through a retrieval system with pointers to GenBank. The
      database can be searched by keywords, locus name, NID, accession number or length
      of the protein. ExInt is freely accessible at
      http://intron.bic.nus.edu.sg/exint/exint.html

PMID- 10592223
TI  - UTRdb and UTRsite: specialized databases of sequences and functional elements of
      5' and 3' untranslated regions of eukaryotic mRNAs.
AB  - The 5' and 3' untranslated regions of eukaryotic mRNAs may play a crucial role in
      the regulation of gene expression controlling mRNA localization, stability and
      translational efficiency. For this reason we developed UTRdb, a specialized
      database of 5' and 3' untranslated sequences of eukaryotic mRNAs cleaned from
      redundancy. UTRdb entries are enriched with specialized information not present
      in the primary databases including the presence of nucleotide sequence patterns
      already demonstrated by experimental analysis to have some functional role. All
      these patterns have been collected in the UTRsite database so that it is possible
      to search any input sequence for the presence of annotated functional motifs.
      Furthermore, UTRdb entries have been annotated for the presence of repetitive
      elements. All internet resources implemented for retrieval and functional
      analysis of 5' and 3' untranslated regions of eukaryotic mRNAs are accessible at
      http://bigarea.area.ba.cnr.it:8000/EmbIT/UTRH ome/

PMID- 10592224
TI  - Non-coding, mRNA-like RNAs database Y2K.
AB  - In last few years much data has accumulated on various non-translatable RNA
      transcripts that are synthesised in different cells. They are lacking in protein
      coding capacity and it seems that they work mainly or exclusively at the RNA
      level. All known non-coding RNA transcripts are collected in the database:
      http://www. man.poznan.pl/5SData/ncRNA/index.html

PMID- 10592225
TI  - PseudoBase: a database with RNA pseudoknots.
AB  - PseudoBase is a database containing structural, functional and sequence data
      related to RNA pseudo-knots. It can be reached at http://wwwbio. Leiden Univ.nl/
      approximately Batenburg/PKB.html. This page will direct the user to a retrieval
      page from where a particular pseudoknot can be chosen, or to a submission page
      which enables the user to add pseudoknot information to the database or to an
      informative page that elaborates on the various aspects of the database. For each
      pseudoknot, 12 items are stored, e.g. the nucleotides of the region that contains
      the pseudoknot, the stem positions of the pseudoknot, the EMBL accession number
      of the sequence that contains this pseudoknot and the support that can be given
      regarding the reliability of the pseudoknot. Access is via a small number of
      steps, using 16 different categories. The development process was done by
      applying the evolutionary methodology for software development rather than by
      applying the methodology of the classical waterfall model or the more modern
      spiral model.

PMID- 10592227
TI  - The RESID database of protein structure modifications: 2000 update.
AB  - The RESID Database contains supplemental information on post-translational
      modifications for the standardized annotations appearing in the PIR-International
      Protein Sequence Database. The RESID Database includes: systematic and frequently
      observed alternate names, Chemical s Service registry numbers, atomic formulas
      and weights, enzyme activities, indicators for N-terminal, C-terminal or peptide
      chain cross-link modifications, keywords, literature citations with database
      cross-references, structural diagrams and molecular models. Since 1995 updates of
      the RESID Database have appeared as often as weekly, and full releases appear
      quarterly. The database is freely accessible through the PIR Web site
      http://pir.georgetown.edu/pirwww/dbinfo/resid.html and by FTP.

PMID- 10592226
TI  - SELEX_DB: an activated database on selected randomized DNA/RNA sequences
      addressed to genomic sequence annotation.
AB  - SELEX_DB is a novel curated database on selected randomized DNA/RNA sequences
      designed for accumulation of experimental data on functional site sequences
      obtained by using SELEX and SELEX-like technologies from the pools of random
      sequences. This database also contains the programs for DNA/RNA functional site
      recognition within arbitrary nucleotide sequences. The first release of SELEX_DB
      has been installed under SRS and is available through the WWW at
      http://wwwmgs.bionet.nsc.ru/mgs/systems/selex/

PMID- 10592228
TI  - The prostate expression database (PEDB): status and enhancements in 2000.
AB  - The Prostate Expression Database (PEDB) is an online resource designed to access
      and analyze gene expression information derived from the human prostate. PEDB
      archives >55 000 expressed sequence tags (ESTs) from 43 cDNA libraries in a
      curated relational database that provides detailed library information including
      tissue source, library construction methods, sequence diversity and sequence
      abundance. The differential expression of each EST species can be viewed across
      all libraries using a Virtual Expression Analysis Tool (VEAT), a graphical user
      interface written in Java for intra- and inter-library species comparisons.
      Recent enhancements to PEDB include: (i) the functional categorization of
      annotated EST assemblies using a classification scheme developed at The Institute
      for Genome Research; (ii) catalogs of expressed genes in specific prostate tissue
      sources designated as transcriptomes; and (iii) the addition of prostate proteome
      information derived from two-dimensional electrophoreses and mass spectrometry of
      prostate cancer cell lines. PEDB may be accessed via the WWW at
      http://www.mbt.washington.edu/PEDB/

PMID- 10592229
TI  - Kabat database and its applications: 30 years after the first variability plot.
AB  - The Kabat Database was initially started in 1970 to determine the combining site
      of antibodies based on the available amino acid sequences at that time. Bence
      Jones proteins, mostly from human, were aligned, using the now-known Kabat
      numbering system, and a quantitative measure, variability, was calculated for
      every position. Three peaks, at positions 24-34, 50-56 and 89-97, were identified
      and proposed to form the complementarity determining regions (CDR) of light
      chains. Subsequently, antibody heavy chain amino acid sequences were also aligned
      using a different numbering system, since the locations of their CDRs (31-35B, 50
      65 and 95-102) are different from those of the light chains. CDRL1 starts right
      after the first invariant Cys 23 of light chains, while CDRH1 is eight amino acid
      residues away from the first invariant Cys 22 of heavy chains. During the past 30
      years, the Kabat database has grown to include nucleotide sequences, sequences of
      T cell receptors for antigens (TCR), major histocompatibility complex (MHC) class
      I and II molecules and other proteins of immunological interest. It has been used
      extensively by immunologists to derive useful structural and functional
      information from the primary sequences of these proteins. An overall view of the
      Kabat Database and its various applications are summarized here. The Kabat
      Database is freely available at http://immuno.bme.nwu.edu

PMID- 10592231
TI  - FIMM, a database of functional molecular immunology.
AB  - FIMM database (http://sdmc.krdl.org.sg:8080/fimm ) contains data relevant to
      functional molecular immunology, focusing on cellular immunology. It contains
      fully referenced data on protein antigens, major histocompatibility complex (MHC)
      molecules, MHC-associated peptides and relevant disease associations. FIMM has a
      set of search tools for extraction of information and results are presented as
      lists or as reports.

PMID- 10592230
TI  - IMGT, the international ImMunoGeneTics database.
AB  - IMGT, the international ImMunoGeneTics database (http://imgt.cines. fr:8104 ), is
      a high-quality integrated database specialising in Immunoglobulins (Ig), T cell
      Receptors (TcR) and Major Histocompatibility Complex (MHC) molecules of all
      vertebrate species, created in 1989 by Marie-Paule Lefranc, Universite
      Montpellier II, CNRS, Montpellier, France (lefranc@ligm.igh.cnrs.fr ). At
      present, IMGT includes two databases: IMGT/LIGM-DB, a comprehensive database of
      Ig and TcR from human and other vertebrates, with translation for fully annotated
      sequences, and IMGT/HLA-DB, a database of the human MHC referred to as HLA (Human
      Leucocyte Antigens). The IMGT server provides a common access to expertized
      genomic, proteomic, structural and polymorphic data of Ig and TcR molecules of
      all vertebrates. By its high quality and its easy data distribution, IMGT has
      important implications in medical research (repertoire in autoimmune diseases,
      AIDS, leukemias, lymphomas), therapeutic approaches (antibody engineering),
      genome diversity and genome evolution studies. IMGT is freely available at
      http://imgt.cines.fr:8104. The IMGT Index is provided at the IMGT Marie-Paule
      page (http://imgt.cines.fr:8104/textes/IMGTindex.html).

PMID- 10592232
TI  - PRINTS-S: the database formerly known as PRINTS.
AB  - The PRINTS database houses a collection of protein family fingerprints. These are
      groups of motifs that together are diagnostically more potent than single motifs
      by virtue of the biological context afforded by matching motif neighbours. Around
      1200 fingerprints have now been created and stored in the database. The September
      1999 release (version 24.0) encodes approximately 7200 motifs, covering a range
      of globular and membrane proteins, modular polypeptides and so on. In addition to
      its continued steady growth, we report here several major changes to the
      resource, including the design of an automated strategy for database maintenance,
      and implementation of an object-relational schema for more efficient data
      management. The database is accessible for BLAST, fingerprint and text searches
      at http://www.bioinf.man.ac. uk/dbbrowser/PRINTS/

PMID- 10592233
TI  - Increased coverage of protein families with the blocks database servers.
AB  - The Blocks Database WWW (http://blocks.fhcrc.org ) and Email
      (blocks@blocks.fhcrc.org ) servers provide tools to search DNA and protein
      queries against the Blocks+ Database of multiple alignments, which represent
      conserved protein regions. Blocks+ nearly doubles the number of protein families
      included in the database by adding families from the Pfam-A, ProDom and Domo
      databases to those from PROSITE and PRINTS. Other new features include improved
      Block Searcher statistics, searching with NCBI's IMPALA program and 3D display of
      blocks on PDB structures.

PMID- 10592234
TI  - SMART: a web-based tool for the study of genetically mobile domains.
AB  - SMART (a Simple Modular Architecture Research Tool) allows the identification and
      annotation of genetically mobile domains and the analysis of domain architectures
      (http://SMART.embl-heidelberg.de ). More than 400 domain families found in
      signalling, extra-cellular and chromatin-associated proteins are detectable.
      These domains are extensively annotated with respect to phyletic distributions,
      functional class, tertiary structures and functionally important residues. Each
      domain found in a non-redundant protein database as well as search parameters and
      taxonomic information are stored in a relational database system. User interfaces
      to this database allow searches for proteins containing specific combinations of
      domains in defined taxa.

PMID- 10592235
TI  - The Protein Data Bank.
AB  - The Protein Data Bank (PDB; http://www.rcsb.org/pdb/ ) is the single worldwide
      archive of structural data of biological macromolecules. This paper describes the
      goals of the PDB, the systems in place for data deposition and access, how to
      obtain further information, and near-term plans for the future development of the
      resource.

PMID- 10592236
TI  - MMDB: 3D structure data in Entrez.
AB  - Three-dimensional structures are now known for roughly half of all protein
      families. It is thus quite likely, in searching sequence databases, that one will
      encounter a homolog with known structure and be able to use this information to
      infer structure-function properties. The goal of Entrez's 3D structure database
      is to make this information accessible and useful to molecular biologists. To
      this end, Entrez's search engine provides three powerful features: (i) Links
      between databases; one may search by term matching in Medline((R)), for example,
      and link to 3D structures reported in these articles. (ii) Sequence and structure
      neighbors; one may select all sequences similar to one of interest, for example,
      and link to any known 3D structures. (iii) Sequence and structure visualization;
      identifying a homolog with known structure, one may view a combined molecular
      graphic and alignment display, to infer approximate 3D structure. Entrez's MMDB
      (Molecular Modeling DataBase) may be accessed at:
      http://www.ncbi.nlm.nih.gov/Entrez/structure.html

PMID- 10592237
TI  - The IMB Jena Image Library of biological macromolecules.
AB  - The IMB Jena Image Library of Biological Macro-molecules (http://www. imb
      jena.de/IMAGE.html ) is aimed at a better dissemination of information on three
      dimensional biopolymer structures with an emphasis on visualization and analysis.
      It provides access to all structure entries deposited at the Protein Data Bank
      (PDB) and Nucleic Acid Database (NDB). By combining automatic and manual
      processing it is possible to keep pace with the rapidly growing number of known
      biopolymer structures and to provide, for selected entries, information not
      available from automatic procedures. Each entry page contains basic information
      on the structure, various visualization and analysis tools as well as links to
      other databases. The visualization techniques adopted include static mono/stereo
      raster or vector graphics representations, virtual reality modeling (VRML),
      RasMol/Chime scripts and Java applets. A helix and bending analysis tool provides
      consistent information on about 750 DNA and RNA duplex structures. Access to
      metal-containing PDB entries is possible via the Periodic Table of Elements.
      Finally, general information on amino acids, cis -peptide bonds, structural
      elements in proteins, base pairs, nucleic acid model conformations and
      experimental methods for biopolymer structure determination is provided.

PMID- 10592238
TI  - MODBASE, a database of annotated comparative protein structure models.
AB  - MODBASE is a queryable database of annotated comparative protein structure
      models. The models are derived by MODPIPE, an automated modeling pipeline relying
      on the programs PSI-BLAST and MODELLER. The database currently contains 3D models
      for substantial portions of approximately 17 000 proteins from 10 complete
      genomes, including those of Caenorhabditis elegans, Saccharomyces cerevisiae and
      Escherichia coli, as well as all the available sequences from Arabidopsis
      thaliana and Homo sapiens. The database also includes fold assignments and
      alignments on which the models were based. In addition, special care is taken to
      assess the quality of the models. ModBase is accessible through a web interface
      at http://guitar.rockefeller.edu/modbase/

PMID- 10592239
TI  - The ASTRAL compendium for protein structure and sequence analysis.
AB  - The ASTRAL compendium provides several databases and tools to aid in the analysis
      of protein structures, particularly through the use of their sequences. The SPACI
      scores included in the system summarize the overall characteristics of a protein
      structure. A structural alignments database indicates residue equivalencies in
      superimposed protein domain structures. The PDB sequence-map files provide a
      linkage between the amino acid sequence of the molecule studied (SEQRES records
      in a database entry) and the sequence of the atoms experimentally observed in the
      structure (ATOM records). These maps are combined with information in the
      SCOPdatabase to provide sequences of protein domains. Selected subsets of the
      domain database, with varying degrees of similarity measured in several different
      ways, are also available. ASTRALmay be accessed at http://astral.stanford.edu/

PMID- 10592240
TI  - SCOP: a structural classification of proteins database.
AB  - The Structural Classification of Proteins (SCOP) database provides a detailed and
      comprehensive description of the relationships of known protein structures. The
      classification is on hierarchical levels: the first two levels, family and
      superfamily, describe near and distant evolutionary relationships; the third,
      fold, describes geometrical relationships. The distinction between evolutionary
      relationships and those that arise from the physics and chemistry of proteins is
      a feature that is unique to this database so far. The sequences of proteins in
      SCOP provide the basis of the ASTRAL sequence libraries that can be used as a
      source of data to calibrate sequence search algorithms and for the generation of
      statistics on, or selections of, protein structures. Links can be made from SCOP
      to PDB-ISL: a library containing sequences homologous to proteins of known
      structure. Sequences of proteins of unknown structure can be matched to distantly
      related proteins of known structure by using pairwise sequence comparison methods
      to find homologues in PDB-ISL. The database and its associated files are freely
      accessible from a number of WWW sites mirrored from URL http://scop.mrc
      lmb.cam.ac.uk/scop/

PMID- 10592241
TI  - The SBASE protein domain library, release 7.0: a collection of annotated protein
      sequence segments.
AB  - SBASE 7.0 is the seventh release of the SBASE protein domain library sequences
      that contains 237 937 annotated structural, functional, ligand-binding and
      topogenic segments of proteins, cross-referenced to all major sequence databases
      and sequence pattern collections. The entries are clustered into over 1811 groups
      and are provided with two WWW-based search facilities for on-line use. SBASE 7.0
      is freely available by anonymous 'ftp' file transfer from ftp.icgeb. trieste.it.
      Automated searching of SBASE with BLAST can be carried out with the WWW servers
      http://www.icgeb.trieste.it/sbase/and http://sbase.abc.hu/sbase/

PMID- 10592242
TI  - The Pfam protein families database.
AB  - Pfam is a large collection of protein multiple sequence alignments and profile
      hidden Markov models. Pfam is available on the WWW in the UK at
      http://www.sanger.ac.uk/Software/Pfam/, in Sweden at http://www.cgr.ki.se/Pfam/
      and in the US at http://pfam.wustl.edu/. The latest version (4.3) of Pfam
      contains 1815 families. These Pfam families match 63% of proteins in SWISS-PROT
      37 and TrEMBL 9. For complete genomes Pfam currently matches up to half of the
      proteins. Genomic DNA can be directly searched against the Pfam library using the
      Wise2 package.

PMID- 10592243
TI  - ProDom and ProDom-CG: tools for protein domain analysis and whole genome
      comparisons.
AB  - ProDom contains all protein domain families automatically generated from the
      SWISS-PROT and TrEMBL sequence databases (http://www.
      toulouse.inra.fr/prodom.html ). ProDom-CG results from a similar domain analysis
      as applied to completed genomes (http://www.toulouse. inra.fr/prodomCG.html ).
      Recent improvements to the ProDom database and its server include: scaling up to
      include sequences from TrEMBL, addition of Pfam-A entries to the set of expert
      validated families, assignment of stable accession numbers, consistency
      indicators for domain families, domain arrangements of sub-families and links to
      Pfam-A.

PMID- 10592244
TI  - The SYSTERS protein sequence cluster set.
AB  - The SYSTERS (short for SYSTEmatic Re-Searching) protein sequence cluster set
      consists of the classification of all sequences from SWISS-PROT and PIR into
      disjoint protein family clusters and hierarchically into superfamily and
      subfamily clusters. The cluster set can be searched with a sequence using the
      SSMAL search tool or a traditional database search tool like BLAST or FASTA.
      Additionally a multiple alignment is generated for each cluster and annotated
      with domain information from the Pfam database of protein domain families. A
      taxonomic overview of the organisms covered by a cluster is given based on the
      NCBI taxonomy. The cluster set is available for querying and browsing at
      http://www.dkfz-heidelberg. de/tbi/services/cluster/systersform

PMID- 10592245
TI  - ProClass protein family database.
AB  - ProClass is a protein family database that organizes non-redundant sequence
      entries into families defined collectively by PIR superfamilies and PROSITE
      patterns. By combining global similarities and functional motifs into a single
      classification scheme, ProClass helps to reveal domain and family relationships
      and classify multi-domain proteins. The database currently consists of >155 000
      sequence entries retrieved from both PIR-International and SWISS-PROT databases.
      Approximately 92 000 or 60% of the ProClass entries are classified into
      approximately 6000 families, including a large number of new members detected by
      our GeneFIND family identification system. The ProClass motif collection contains
      approximately 72 000 motif sequences and >1300 multiple alignments for all
      PROSITE patterns, including >21 000 matches not listed in PROSITE and mostly
      detected from unique PIR sequences. To maximize family information retrieval, the
      database provides links to various protein family, domain, alignment and
      structural class databases. With its high classification rate and comprehensive
      family relationships, ProClass can be used to support full-scale genomic
      annotation. The database, now being implemented in an object-relational database
      management system, is available for online sequence search and record retrieval
      from our WWW server at http://pir.georgetown.edu/gfserver/proclass.html

PMID- 10592246
TI  - Assigning genomic sequences to CATH.
AB  - We report the latest release (version 1.6) of the CATH protein domains database
      (http://www.biochem.ucl. ac.uk/bsm/cath ). This is a hierarchical classification
      of 18 577 domains into evolutionary families and structural groupings. We have
      identified 1028 homo-logous superfamilies in which the proteins have both
      structural, and sequence or functional similarity. These can be further clustered
      into 672 fold groups and 35 distinct architectures. Recent developments of the
      database include the generation of 3D templates for recognising structural
      relatives in each fold group, which has led to significant improvements in the
      speed and accuracy of updating the database and also means that less manual
      validation is required. We also report the establishment of the CATH-PFDB
      (Protein Family Database), which associates 1D sequences with the 3D homologous
      superfamilies. Sequences showing identifiable homology to entries in CATH have
      been extracted from GenBank using PSI-BLAST. A CATH-PSIBLAST server has been
      established, which allows you to scan a new sequence against the database. The
      CATH Dictionary of Homologous Superfamilies (DHS), which contains validated
      multiple structural alignments annotated with consensus functional information
      for evolutionary protein superfamilies, has been updated to include annotations
      associated with sequence relatives identified in GenBank. The DHS is a powerful
      tool for considering the variation of functional properties within a given CATH
      superfamily and in deciding what functional properties may be reliably inherited
      by a newly identified relative.

PMID- 10592247
TI  - ProTherm, version 2.0: thermodynamic database for proteins and mutants.
AB  - ProTherm 2.0 is the second release of the Thermo-dynamic Database for Proteins
      and Mutants that includes numerical data for several thermodynamic parameters,
      structural information, experimental methods and conditions, functional and
      literature information. The present release contains >5500 entries, an
      approximately 67% increase over the previous version. In addition, we have
      included information about reversibility of data, details about buffer and ion
      concentrations and the surrounding residues in space for all mutants. A WWW
      interface enables users to search data based on various conditions with different
      sorting options for outputs. Further, ProTherm has links with other structural
      and literature databases, and the mutation sites and surrounding residues are
      automatically mapped on the structures and can be directly viewed through
      3DinSight developed in our laboratory. The ProTherm database is freely available
      through the WWW at http://www.rtc.riken.go.jp/protherm.html

PMID- 10592248
TI  - The 1999 SWISS-2DPAGE database update.
AB  - SWISS-2DPAGE (http://www.expasy.ch/ch2d/ ) is an annotated two-dimensional
      polyacrylamide gel electro-phoresis (2-DE) database established in 1993. The
      current release contains 24 reference maps from human and mouse biological
      samples, as well as from Saccharomyces cerevisiae, Escherichia coli and
      Dictyostelium discoideum origin. These reference maps have now 2824 identified
      spots, corresponding to 614 separate protein entries in the database, in addition
      to virtual entries for each SWISS-PROT sequence or any user-entered amino acids
      sequence. Last year improvements in the SWISS-2DPAGE database are as follows:
      three new maps have been created and several others have been updated; cross
      references to newly built federated 2-DE databases have been added; new functions
      to access the data have been provided through the ExPASy proteomics server.

PMID- 10592249
TI  - DIP: the database of interacting proteins.
AB  - The Database of Interacting Proteins (DIP; http://dip.doe-mbi.ucla.edu) is a
      database that documents experimentally determined protein-protein interactions.
      This database is intended to provide the scientific community with a
      comprehensive and integrated tool for browsing and efficiently extracting
      information about protein interactions and interaction networks in biological
      processes. Beyond cataloging details of protein-protein interactions, the DIP is
      useful for understanding protein function and protein-protein relationships,
      studying the properties of networks of interacting proteins, benchmarking
      predictions of protein-protein interactions, and studying the evolution of
      protein-protein interactions.

PMID- 10592250
TI  - Codon usage tabulated from international DNA sequence databases: status for the
      year 2000.
AB  - The frequencies of each of the 257 468 complete protein coding sequences (CDSs)
      have been compiled from the taxonomical divisions of the GenBank DNA sequence
      database. The sum of the codons used by 8792 organisms has also been calculated.
      The data files can be obtained from the anonymous ftp sites of DDBJ, Kazusa and
      EBI. A list of the codon usage of genes and the sum of the codons used by each
      organism can be obtained through the web site http://www.kazusa.or.jp/codon/. The
      present study also reports recent developments on the WWW site. The new web
      interface provides data in the CodonFrequency-compatible format as well as in the
      traditional table format. The use of the database is facilitated by keyword based
      search analysis and the availability of codon usage tables for selected genes
      from each species. These new tools will provide users with the ability to further
      analyze for variations in codon usage among different genomes.

PMID- 10592251
TI  - Transterm: a database of messenger RNA components and signals.
AB  - Transterm facilitates studies of messenger RNAs and translational control
      signals. Each messenger RNA (mRNA) from GenBank is extracted and broken into its
      functional components, its coding sequence, initiation context, termination
      context, flanking sequence representing its 5' UTR (untranslated region), 3' UTR
      and translational signals. In addition, numerical parameters characterising each
      coding region in Transterm, including codon and GC bias, are available. For each
      species in Transterm, the initiation and termination regions are aligned by their
      start or stop codons and presented as base frequency matrices and tables of the
      information content of the bases in the alignments. Users can obtain summaries of
      characteristics of the mRNAs for species of their choice and search for
      translational signals both in the Transterm database and in their own sequence.
      The current release contains data from over 10 000 species, including the
      complete genomes of 20 prokaryotes and three eukaryotes. Both flat-file and
      relational database forms of Transterm are accessible via the WWW at
      http://biochem.otago.ac.nz/Transterm/

PMID- 10592252
TI  - ASDB: database of alternatively spliced genes.
AB  - Version 2.1 of ASDB (Alternative Splicing Data Base) contains 1922 protein and
      2486 DNA sequences. The protein entries from SWISS-PROT are joined into clusters
      corresponding to alternatively spliced variants of one gene. The DNA division
      consists of complete genes with alternative splicing mentioned or annotated in
      GenBank. The search engine allows one to search over SWISS-PROT and GenBank
      fields and then follow the links to all variants. The database can be assessed at
      the URL http://cbcg.nersc.gov/asdb

PMID- 10592253
TI  - Transcription regulatory regions database (TRRD): its status in 2000.
AB  - Transcription Regulatory Regions Database (TRRD) has been developed for
      accumulation of experimental information on the structure-function features of
      regulatory regions of eukaryotic genes. Each entry in TRRD corresponds to a
      particular gene and contains a description of structure-function features of its
      regulatory regions (transcription factor binding sites, promoters, enhancers,
      silencers, etc.) and gene expression regulation patterns. The current release,
      TRRD 4.2.5, comprises the description of 760 genes, 3403 expression patterns, and
      >4600 regulatory elements including 3604 transcription factor binding sites, 600
      promoters and 152 enhancers. This information was obtained through annotation of
      2537 scientific publications. TRRD 4.2.5 is available through the WWW at
      http://wwwmgs.bionet.nsc.ru/mgs/dbases/trrd4/

PMID- 10592254
TI  - The eukaryotic promoter database (EPD).
AB  - The Eukaryotic Promoter Database (EPD) is an annotated non-redundant collection
      of eukaryotic POL II promoters for which the transcription start site has been
      determined experimentally. Access to promoter sequences is provided by pointers
      to positions in nucleotide sequence entries. The annotation part of an entry
      includes a description of the initiation site mapping data, exhaustive cross
      references to the EMBL nucleotide sequence database, SWISS-PROT, TRANSFAC and
      other databases, as well as bibliographic references. EPD is structured in a way
      that facilitates dynamic extraction of biologically meaningful promoter subsets
      for comparative sequence analysis. WWW-based interfaces have been developed that
      enable the user to view EPD entries in different formats, to select and extract
      promoter sequences according to a variety of criteria, and to navigate to related
      databases exploiting different cross-references. The EPD web site also features
      yearly updated base frequency matrices for major eukaryotic promoter elements.
      EPD can be accessed at http://www.epd.isb-sib.ch

PMID- 10592255
TI  - The ENZYME database in 2000.
AB  - The ENZYME database is a repository of information related to the nomenclature of
      enzymes. In recent years it has became an indispensable resource for the
      development of metabolic databases. The current version contains information on
      3705 enzymes. It is available through the ExPASy WWW server
      (http://www.expasy.ch/enzyme/ ).

PMID- 10592256
TI  - REBASE - restriction enzymes and methylases.
AB  - REBASE is a comprehensive database of information about restriction enzymes and
      related proteins. It contains published and unpublished references, recognition
      and cleavage sites, isoschizomers, commercial availability, methylation
      sensitivity, crystal and sequence data. DNA methyltransferases, homing
      endonucleases, nicking enzymes, specificity subunits and control proteins are
      also included. Most recently, putative DNA methyltransferases and restriction
      enzymes, as predicted from analysis of genomic sequences, are also listed. The
      data is distributed via Email, ftp (ftp.neb.com), and the Web
      (http://rebase.neb.com).

PMID- 10592257
TI  - Object-oriented transcription factors database (ooTFD).
AB  - ooTFD (object-oriented Transcription Factors Database) is an object-oriented
      successor to TFD. This database is aimed at capturing information regarding the
      polypeptide interactions which comprise and define the properties of
      transcription factors. ooTFD contains information about transcription factor
      binding sites, as well as composite relationships within transcription factors,
      which frequently occur as multisubunit proteins that form a complex interface to
      cellular processes outside the transcription machinery through protein-protein
      interactions. In the past year, a few additions and changes were made to this
      database and associated tools, which are accessible through the IFTI-MIRAGE web
      site at http://www.ifti.org/

PMID- 10592258
TI  - COMPEL: a database on composite regulatory elements providing combinatorial
      transcriptional regulation.
AB  - COMPEL is a database on composite regulatory elements, the basic structures of
      combinatorial regulation. Composite regulatory elements contain two closely
      situated binding sites for distinct transcription factors and represent minimal
      functional units providing combinatorial transcriptional regulation. Both
      specific factor-DNA and factor-factor interactions contribute to the function of
      composite elements (CEs). Information about the structure of known CEs and
      specific gene regulation achieved through such CEs appears to be extremely useful
      for promoter prediction, for gene function prediction and for applied gene
      engineering as well. The structure of the relational model of COMPEL is
      determined by the concept of molecular structure and regulatory role of CEs.
      Based on the set of a particular CE, a program has been developed for searching
      potential CEs in gene regulatory regions. WWW search and browse routines were
      developed for COMPEL release 3.0. The COMPEL database equipped with the search
      and browse tools is available at http://compel.bionet.nsc.ru/. The program for
      prediction of potential CEs of NFAT type is available at
      http://compel.bionet.nsc. ru/FunSite.html and
      http://transfac.gbf.de/dbsearch/funsitep/ s_comp.html

PMID- 10592259
TI  - TRANSFAC: an integrated system for gene expression regulation.
AB  - TRANSFAC is a database on transcription factors, their genomic binding sites and
      DNA-binding profiles (http://transfac.gbf.de/TRANSFAC/). Its content has been
      enhanced, in particular by information about training sequences used for the
      construction of nucleotide matrices as well as by data on plant sites and
      factors. Moreover, TRANSFAC has been extended by two new modules: PathoDB
      provides data on pathologically relevant mutations in regulatory regions and
      transcription factor genes, whereas S/MARt DB compiles features of
      scaffold/matrix attached regions (S/MARs) and the proteins binding to them.
      Additionally, the databases TRANSPATH, about signal transduction, and CYTOMER,
      about organs and cell types, have been extended and are increasingly integrated
      with the TRANSFAC data sources.

PMID- 10592260
TI  - The histone database: a comprehensive WWW resource for histones and histone fold
      containing proteins.
AB  - The Histone Database (HDB) is an annotated and searchable collection of all full
      length sequences and structures of histone and non-histone proteins containing
      the histone fold motif. These sequences are both eukaryotic and archaeal in
      origin. Several new histone fold-containing proteins have been identified,
      including Spt7p, and a few false positives have been removed from the earlier
      version of HDB. Database contents include compilations of post-translational
      modifications for each of the core and linker histones, as well as genomic
      information in the form of map loci for the human histone gene complement, with
      the genetic loci linked to Online Mendelian Inheritance in Man (OMIM). Conflicts
      between similar sequence entries from a number of source databases are also
      documented. Newly added to the HDB are multiple sequence alignments in which
      predicted functions of histone fold amino acid residues are annotated. The
      database is freely accessible through the WWW at
      http://genome.nhgri.nih.gov/histones/

PMID- 10592261
TI  - MEROPS: the peptidase database.
AB  - Important additions have been made to the MEROPS database
      (http://www.bi.bbsrc.ac.uk/Merops/Merops.htm). These include sequence alignments
      and cladograms for many of the families of peptidases, and these have proved very
      helpful in the difficult task of distinguishing the sequences of peptidases that
      are simply species variants of already known enzymes from those that represent
      novel enzymes.

PMID- 10592262
TI  - Aminoacyl-tRNA synthetases database Y2K.
AB  - The aminoacyl-tRNA synthetases (AARS) are a diverse group of enzymes that ensure
      the fidelity of transfer of genetic information from DNA into protein. They
      catalyse the attachment of amino acids to transfer RNAs and thereby establish the
      rules of the genetic code by virtue of matching the nucleotide triplet of the
      anticodon with its cognate amino acid. Currently, 818 AARS primary structures
      have been reported from archaebacteria, eubacteria, mitochondria, chloro-plasts
      and eukaryotic cells. The database is a compilation of the amino acid sequences
      of all AARSs, known to date, which are available as separate entries or
      alignments of related proteins via the WWW at
      http://rose.man.poznan.pl/aars/index.html

PMID- 10592263
TI  - The homeodomain resource: a prototype database for a large protein family.
AB  - The Homeodomain Resource is an annotated collection of non-redundant protein
      sequences, three-dimensional structures and genomic information for the
      homeodomain protein family. Release 2.0 contains 765 full-length homeodomain
      containing sequences, 29 experimentally derived structures and 116 homeobox loci
      implicated in human genetic disorders. Entries are fully hyperlinked to
      facilitate easy retrieval of the original records from source databases. A simple
      search engine with a graphical user interface is provided to query the component
      databases and assemble customized data sets. A new feature for this release is
      the addition of more automated methods for database searching, maintenance and
      implementation of efficient data management. The Homeodomain Resource is freely
      available through the WWW at http://genome.nhgri.nih.gov/homeodomain

PMID- 10592264
TI  - HUGE: a database for human large proteins identified in the Kazusa cDNA
      sequencing project.
AB  - HUGE is a database for human large proteins newly identified in the Kazusa cDNA
      project, the aim of which is to predict the primary structure of proteins from
      the sequences of human large cDNAs (>4 kb). In particular, cDNA clones capable of
      coding for large proteins (>50 kDa) are the current targets of the project. HUGE
      contains >1100 cDNA sequences and detailed information obtained through analysis
      of the sequences of cDNAs and the predicted proteins. Besides an increase in the
      number of cDNA entries, the amount of experimental data for expression profiling
      has been largely increased and data on chromosomal locations have been newly
      added. All of the protein-coding regions were examined by GeneMark analysis, and
      the results of a motif/domain search of each predicted protein sequence against
      the Pfam database have been newly added. HUGE is available through the WWW at
      http://www.kazusa.or.jp/huge

PMID- 10592265
TI  - The DExH/D protein family database.
AB  - DExH/D proteins are essential for all aspects of cellular RNA metabolism and
      processing, in the replication of many viruses and in DNA replication. DExH/D
      proteins are subject to current biological, biochemical and biophysical research
      which provides a continuous wealth of data. The DExH/D protein family database
      compiles this information and makes it available over the WWW
      (http://www.columbia.edu/ ej67/dbhome.htm ). The database can be fully searched
      by text based queries, facilitating fast access to specific information about
      this important class of enzymes.

PMID- 10592266
TI  - SENTRA, a database of signal transduction proteins.
AB  - SENTRA, available via URL http://wit.mcs.anl.gov/WIT2/Sentra/, is a database of
      proteins associated with microbial signal transduction. The database currently
      includes the classical two-component signal transduction pathway proteins and
      methyl-accepting chemotaxis proteins, but will be expanded to also include other
      classes of signal transduction systems that are modulated by phosphorylation or
      methylation reactions. Although the majority of database entries are from
      prokaryotic systems, eukaroytic proteins with bacterial-like signal transduction
      domains are also included. Currently SENTRA contains signal transduction proteins
      in 34 complete and almost completely sequenced prokaryotic genomes, as well as
      sequences from 243 organisms available in public databases (SWISS-PROT and EMBL).
      The analysis was carried out within the framework of the WIT2 system, which is
      designed and implemented to support genetic sequence analysis and comparative
      analysis of sequenced genomes.

PMID- 10592267
TI  - HOX Pro: a specialized database for clusters and networks of homeobox genes.
AB  - It is now clear that the homeobox motif is well conserved across metazoan phyla.
      It has been established experimentally that a subset of genes containing this
      motif plays key roles in the orchestration of gene expression during development.
      Auto- and cross-regulatory functional interactions join homeobox genes into
      genetic networks. We have developed a specialized database HOX-Pro in order to
      arrange all available data on structure, function, phylogeny and evolution of Hox
      genes, Hox clusters and Hox networks. Its primary location is
      http://www.iephb.nw.ru/hoxpro. The database is also mirrored at
      http://www.mssm.edu/molbio/hoxpro. The HOX-Pro database is aimed at: (i) analysis
      and classification of regulatory and coding regions in diverse homeobox and
      related genes; (ii) comparative analysis of organization of 'Hox-based' genetic
      networks in the sea urchin Strongylocentrotus purpuratus, the fruit fly
      Drosophila melanogaster and the mouse Mus musculus; and (iii) analysis of
      phylogeny and evolution of homeobox genes and clusters.

PMID- 10592268
TI  - Olfactory receptor database: a sensory chemoreceptor resource.
AB  - The Olfactory Receptor Database (ORDB) is a WWW-accessible database that has been
      expanded from an olfactory receptor resource to a chemoreceptor resource. It
      stores data on six classes of G-protein-coupled sensory chemoreceptors: (i)
      olfactory receptor-like proteins, (ii) vomeronasal receptors, (iii) insect
      olfactory receptors, (iv) worm chemo-receptors, (v) taste papilla receptors and
      (vi) fungal pheromone receptors. A complementary database of the ligands of these
      receptors (OdorDB) has been constructed and is publicly available in a pilot
      mode. The database schema of ORDB has been changed from traditional relational to
      EAV/CR (Entity-Attribute-Value with Classes and Relationships), which allows the
      interoperability of ORDB with other related databases as well as the creation of
      intra-database associations among objects. This inter-operability facilitates
      users to follow information from odor molecule binding to its putative receptor,
      to the properties of the neuron expressing the receptor, to a computational model
      of activity of olfactory bulb neurons. In addition, tools and resources have been
      added allowing users to access interactive phylogenetic trees and alignments of
      sensory chemoreceptors. ORDB is available via the WWW at http://ycmi.med.
      yale.edu/senselab/ordb/

PMID- 10592269
TI  - InBase, the Intein Database.
AB  - InBase, the Intein Database (http://www.neb.com/neb/inteins.html ), is a
      comprehensive on-line resource that includes the Intein Registry. Inteins are
      protein splicing elements that mediate a self-catalytic protein splicing
      reaction. InBase presents general information as well as detailed data for each
      intein, including tabu-lated comparisons and a comprehensive bibliography.

PMID- 10592270
TI  - Human immunodeficiency virus reverse transcriptase and protease sequence
      database.
AB  - The HIV RT and Protease Sequence Database is an online relational database that
      catalogs evolutionary and drug-related human immunodeficiency virus (HIV) reverse
      transcriptase (RT) and protease sequence variation (http://hivdb.stanford.edu).
      The database contains a compilation of nearly all published HIV RT and protease
      sequences including International Collaboration database submissions (e.g.,
      GenBank) and sequences published in journal articles. Sequences are linked to
      data about the source of the sequence sample and the antiretroviral drug
      treatment history of the individual from whom the isolate was obtained. The
      database is curated and sequences are annotated with data from >230 literature
      references. Users can retrieve additional data and view alignments of sequence
      sets meeting specific criteria (e.g., treatment history, subtype, presence of a
      particular mutation). A gene-specific sequence analysis program, new user-defined
      queries and nearly 2000 additional sequences were added in 1999.

PMID- 10592271
TI  - Atlas of genetics and cytogenetics in oncology and haematology, an interactive
      database.
AB  - The 'Atlas of Genetics and Cytogenetics in Oncology and Haematology'
      (http://www.infobiogen.fr/services/chromcancer ) is a database devoted to
      chromosome abnormalities in cancer, cancer-prone diseases and genes involved in
      cancer. Information presented in each page is concise and updated. This database
      is made for and by: cytogeneticists, molecular biologists, clinicians in oncology
      and in haematology, and pathologists, who are encouraged to contribute.

PMID- 10592272
TI  - dbSNP: a database of single nucleotide polymorphisms.
AB  - In response to a need for a general catalog of genome variation to address the
      large-scale sampling designs required by association studies, gene mapping and
      evolutionary biology, the National Cancer for Biotechnology Information (NCBI)
      has established the dbSNP database. Submissions to dbSNP will be integrated with
      other sources of information at NCBI such as GenBank, PubMed, LocusLink and the
      Human Genome Project data. The complete contents of dbSNP are available to the
      public at website: http://www.ncbi.nlm.nih.gov/SNP. Submitted SNPs can also be
      downloaded via anonymous FTP at ftp://ncbi.nlm.nih.gov/snp/

PMID- 10592273
TI  - HGBASE: a database of SNPs and other variations in and around human genes.
AB  - Human genome polymorphism is expected to play a key role in defining the
      etiologic basis of phenotypic differences between individuals in aspects such as
      drug responses and common disease predisposition. Relevant functional DNA changes
      will probably be located in or near to transcribed sequences, and include many
      single nucleotide polymorphisms. To aid the future analysis of such genome
      variation, HGBASE (Human Genic Bi-Allelic SEquences) was constructed as a means
      to gather human gene-linked polymorphisms from all possible public sources, and
      show these as a non-redundant set of records in a standardized and user-friendly
      database endowed with text and sequence based search facilities. After 1 year of
      presence on the WWW, the HGBASE project has compiled data for over 22 000
      records, and this number continues to triple every 6-12 months with data
      harvested or submitted from all major public genome databases and published
      literature from the previous decade. Extensive annotation enhancement, internal
      consistency checking and manual review of every record is undertaken to address
      potential errors and deficiencies sometimes present in the original source data.
      The fully polished and comprehensive database is made freely available to all at
      http://hgbase.cgr.ki.se

PMID- 10592274
TI  - ALFRED: an allele frequency database for diverse populations and DNA
      polymorphisms.
AB  - We have developed a publicly accessible database (ALFRED, the ALlele FREquency
      Database) that catalogues allele frequency data for a wide range of population
      samples and DNA polymorphisms. This database is web-accessible through our
      laboratory (Kidd Lab) Web site: http://info.med.yale.edu/genetics/kkidd. ALFRED
      currently contains data on 60 populations and 156 genetic systems including
      single nucleotide polymorphisms (SNPs), short tandem repeat polymorphisms
      (STRPs), variable number of tandem repeats (VNTRs) and insertion-deletion
      polymorphisms. While data are not available for all population-DNA polymorphism
      combinations, over 2000 allele frequency tables have been entered. Our database
      is designed (i) to address our specific research requirements as well as broader
      scientific objectives; (ii) to allow researchers and interested educators to
      easily navigate and retrieve data of interest to them; and (iii) to integrate
      links to other related public databases such as dbSNP, GenBank and PubMed.

PMID- 10592275
TI  - Keio Mutation Database (KMDB) for human disease gene mutations.
AB  - A database of mutations in human disease-causing genes has been constructed and
      named as Keio Mutation Database (KMDB). This KMDB utilizes a database software
      called MutationView which was designed to compile various mutation data and to
      provide graphical presentation of data analysis. Currently, the KMDB accommodates
      mutation data of 38 different genes for 35 different diseases which are involved
      in eye, heart, ear and brain. These KMDBs are accessible through
      http://mutview.dmb.med.keio.ac.jp with advanced internet browsers.

PMID- 10592276
TI  - KinMutBase, a database of human disease-causing protein kinase mutations.
AB  - KinMutBase (http://www.uta.fi/imt/bioinfo/KinMutBase/) is a registry of mutations
      in human protein kinases related to disorders. Kinases are essential cellular
      signaling molecules, in which mutations can lead to diseases, including
      immunodeficiencies, cancers and endocrine disorders. The first release of
      KinMutBase contained information for protein tyrosine kinases. The current
      release includes also serine/threonine protein kinases, as well as an update of
      the tyrosine kinases. There are 251 entries altogether, representing 337 families
      and 621 patients. Mutations appear both in conserved hallmark residues of the
      kinases as well as in non-homologous sites. The KinMutBase WWW pages provide
      plenty of information, namely mutation statistics and display, clickable
      sequences with mutations and changes to restriction enzyme patterns.

PMID- 10592277
TI  - Update of KEYnet: a gene and protein names database for biosequences functional
      organisation.
AB  - KEYnet is a database where gene and protein names are hierarchically structured.
      Particular care has been devoted to the search and organisation of synonyms. The
      structuring is based on biological criteria in order to assist the user in data
      search and to minimise the risk of information loss. Links to the EMBL data
      library by the entry name and the accession number are implemented. KEYnet is
      available through the WWW at the following site: http://www.ba.cnr.it/keynet.html

PMID- 10592278
TI  - AAindex: amino acid index database.
AB  - AAindex is a database of amino acid indices and amino acid mutation matrices. An
      amino acid index is a set of 20 numerical values representing various physico-
      chemical and biochemical properties of amino acids. An amino acid mutation matrix
      is generally 20 x 20 numerical values representing similarity of amino acids.
      AAindex consists of two sections: AAindex1 for the collection of published amino
      acid indices and AAindex2 for the collection of published amino acid mutation
      matrices. Each entry of either AAindex1 or AAindex2 consists of the definition,
      the reference information, a list of related entries in terms of the correlation
      coefficient and the actual data. The database may be accessed through the
      DBGET/LinkDB system at GenomeNet (http://www. genome.ad.jp/aaindex/ ) or may be
      downloaded by anonymous FTP (ftp://ftp.genome.ad.jp/db/genomenet/aaindex/ ).

PMID- 10592279
TI  - Database of non-canonical base pairs found in known RNA structures.
AB  - Atomic resolution RNA structures are being published at an increasing rate. It is
      common to find a modest number of non-canonical base pairs in these structures in
      addition to the usual Watson-Crick pairs. This database summarizes the occurrence
      of these rare base pairs in accordance with standard nomenclature. The database,
      http://prion.bchs.uh.edu/, contains information such as sequence context, sugar
      pucker conformation, anti / syn base conformations, chemical shift, p K
      (a)values, melting temperature and free energy. Of the 29 anticipated pairs with
      two or more hydrogen bonds, 20 have been encountered to date. In addition, four
      unexpected pairs with two hydrogen bonds have been reported bringing the total to
      24. Single hydrogen bond versions of five of the expected geometries have been
      encountered among the single hydrogen bond interactions. In addition, 18
      different types of base triplets have been encountered, each of which involves
      three to six hydrogen bonds. The vast majority of the rare base pairs are
      antiparallel with the bases in the anti configuration relative to the ribose. The
      most common are the GU wobble, the Sheared GA pair, the Reverse Hoogsteen pair
      and the GA imino pair.

PMID- 10592280
TI  - The University of Minnesota Biocatalysis/Biodegradation database: microorganisms,
      genomics and prediction.
AB  - The University of Minnesota Biocatalysis/Biodegradation Database
      (http://www.labmed.umn.edu/umbbd/ ) begins its fifth year having met its initial
      goals. It contains approximately 100 pathways for microbial catabolic metabolism
      of primarily xenobiotic organic compounds, including information on approximately
      650 reactions, 600 compounds and 400 enzymes, and containing approximately 250
      microorganism entries. It includes information on most known microbial catabolic
      reaction types and the organic functional groups they transform. Having reached
      its first goals, it is ready to move beyond them. It is poised to grow in many
      different ways, including mirror sites; fold prediction for its sequenced
      enzymes; closer ties to genome and microbial strain databases; and the prediction
      of biodegradation pathways for compounds it does not contain.

PMID- 10592281
TI  - LIGAND: chemical database of enzyme reactions.
AB  - LIGAND is a composite database comprising three sections: ENZYME for the
      information of enzyme molecules and enzymatic reactions, COMPOUND for the
      information of metabolites and other chemical compounds, and REACTION for the
      collection of substrate-product relations. The current release includes 3390
      enzymes, 5645 compounds and 5207 reactions. The database is indispensable for the
      reconstruction of metabolic pathways in the completely sequenced organisms. The
      LIGAND database can be accessed through the WWW
      (http://www.genome.ad.jp/dbget/ligand.html ) or may be downloaded by anonymous
      FTP (ftp://kegg.genome.ad.jp/molecules/ligand/ ).

PMID- 10592282
TI  - Morphological and functional demonstration of rat dura mater mast cell-neuron
      interactions in vitro and in vivo.
AB  - Mast cells derive from a distinct bone marrow precursor and mature in tissues
      under the influence of stem cell factor, nerve growth factor (NGF) and certain
      interleukins. Intracranial mast cells first appear in the meninges and are
      located perivascularly close to neurons. They can be activated by antidromic
      stimulation of the trigeminal nerve, as well as by acute immobilization stress.
      Substance P (SP) and corticotropin-releasing hormone (CRH) are particularly
      potent in stimulating mast cell release of vasoactive, inflammatory and
      nociceptive molecules. These findings have suggested that mast cells may be
      involved in neuroinflammatory conditions, such as migraines. In this study, dura
      mast cells were shown to have characteristics of connective tissue mast cells
      (CTMC) as they contained histamine, heparin and rat mast cell protease I (RMCP
      I). Mast cells were localized close to SP-positive neurons immunocytochemically
      and mast cell-neuron contacts were also documented using scanning electron
      microscopy. Dura stimulated by SP and carbachol in situ released histamine.
      Preincubation of dura with estradiol slightly augmented histamine release by SP,
      an effect possibly mediated through estrogen receptors identified on dura mast
      cells. Acute stress by immobilization led to dura mast cell degranulation which
      was prevented by pretreatment with a neutralizing antibody to CRH or a CRH
      receptor antagonist. The present results further clarify the biology of
      intracranial mast cells and support their involvement in the pathophysiology of
      migraines which are precipitated or worsened by stress.

PMID- 10592284
TI  - Cells of the carotid body express connexin43 which is up-regulated by cAMP.
AB  - We identified a gap junction protein subunit, connexin43 (Cx43) by
      immunofluorescence and immunoblotting, in cultured rat carotid body cells and in
      whole organs. In 1-week-old cultures, all cells were flat but after 3 h exposure
      to 8Br-cAMP (1 mM), tyrosine hydroxylase (TH) positive cells (chemoreceptors),
      but not TH negative cells, adopted a round body with multiple thin arborization
      processes. The incidence of dye coupling between cultured cells of the same type
      increased from 26% in controls to 73% after treatment with 8Br-cAMP. In control
      cultures, Cx43 immunoreactivity showed a diffuse perinuclear distribution and
      after 8Br-cAMP treatment, it was also found at cell-cell contacts. Both 8Br-cAMP
      induced dye coupling and cellular redistribution of Cx43 were blocked by
      pretreatment with actinomycin D (5 microM), a mRNA transcription blocker.
      Moreover, 3 h exposure to 8Br-cAMP increased the levels of Cx43 in entire organs.
      We suggest that conditions that promote a sustained increase in cytosolic cAMP up
      regulate coupling between carotid body cells in a transcription-dependent manner.
      The possible functional significance of these findings is discussed.

PMID- 10592283
TI  - Role of the thalamic intergeniculate leaflet and its 5-HT afferences in the
      chronobiological properties of 8-OH-DPAT and triazolam in syrian hamster.
AB  - The 5-HT(1A/7) receptor agonist 8-hydroxy-2-[di-n-propylamino]-tetralin (8-OH
      DPAT) has chronobiological effects on the circadian system and, in the Syrian
      hamster, it is known that serotonergic (5-HT) projections connecting the median
      raphe nucleus to the suprachiasmatic nuclei (SCN) of the hypothalamus are a
      prerequisite for the expression of 8-OH-DPAT-induced phase advance of locomotor
      activity rhythm. We examined the possible involvement of the thalamic
      intergeniculate leaflet (IGL) in the phase-shifting properties of 8-OH-DPAT
      injections at CT7. Bilateral electrolytic lesions of the IGL blocked phase-shift
      responses to 8-OH-DPAT of the activity rhythm. Phase changes induced by
      injections of 8-OH-DPAT at CT7 and triazolam (Tz), a short-acting benzodiazepine,
      at CT6 were also studied after bilateral chemical lesion of the 5-HT fibres
      connecting the dorsal raphe nucleus (DR) to IGL. Destruction of 5-HT fibres
      within the IGL blocked the phase-shift response to Tz, but not the phase-shift
      response to 8-OH-DPAT. In conclusion, (a) IGL is essential for the phase-shifting
      effect of peripheral 8-OH-DPAT injections; (b) 5-HT fibres connecting DR to IGL
      are necessary for the expression of the phase-shifting effect of Tz but not of 8
      OH-DPAT.

PMID- 10592285
TI  - NMDA and AMPA glutamate receptor subtypes in the thoracic spinal cord in lean and
      obese-diabetic ob/ob mice.
AB  - Quantitative autoradiography was used to characterise the binding of selective
      radiolabelled antagonists for the N-methyl-D-aspartate (NMDA) receptor and the
      alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor in the
      dorsal, intermediate and ventral subregions of the grey matter of the upper
      thoracic spinal cord in male and female lean and obese-diabetic (ob/ob) mice. The
      density of binding sites for both receptor subtypes was greater in diabetic mice,
      in all three subregions of the grey matter, than the corresponding subregions in
      the lean mice. The affinity of the binding site for the NMDA antagonist was
      significantly higher in obese mice than lean mice, consistent with the presence
      of two subpopulations of NMDA receptors with different ligand binding affinities
      in obese mice. The increase in expression of the glutamate receptor subtypes, and
      altered ligand affinity for the NMDA receptor subtype in the obese mice may be
      causally involved in the peripheral neuropathies which can accompany diabetes
      mellitus.

PMID- 10592286
TI  - Modulation of paired-pulse responses in the dentate gyrus: effects of prenatal
      protein malnutrition.
AB  - Since our major hypothesis is that prenatal protein malnutrition significantly
      affects hippocampal neuroplasticity, this study examined the effects of prenatal
      protein malnutrition on the modulation of dentate granule cell excitability in
      freely moving rats at 15, 30 and 90 days of age across the vigilance states of
      quiet waking (QW), slow-wave sleep (SWS) and rapid eye movement (REM) sleep.
      Using paired-pulse stimulation, the paired-pulse index (PPI), a measure of the
      type and degree of modulation of dentate granule cell excitability elicited by
      stimulation of the medial perforant path, was obtained for each vigilance state
      at each stage of development. Four specific measures of granule cell excitability
      were computed, namely, PPI using both population spike amplitude (PSA) and EPSP
      slope measures, absolute values of PSA(1) and EPSP(1) slope. PPI values obtained
      at 15, 30 and 90 days of age, however, were altered during normal ontogenetic
      development, but not by vigilance state. At 15 days of age, the malnourished
      group exhibits greater early inhibition of the PPI using the PSA measure at IPIs
      between 20 and 30 ms regardless of vigilance state, while at 30 days of age, the
      malnourished group exhibits greater facilitation at IPIs between 50 and 70 ms
      during QW and SWS, but not during REM sleep. In the control adult (PND90) and
      juvenile (PND30) animal, PSA(1) values are significantly higher during SWS than
      in QW or REM sleep. However, for the younger malnourished animals (PND15 and
      PND30), PSA(1) values were found to be significantly greater during REM sleep
      rather than SWS. Therefore, as the animal matures, there appears to be a shift in
      vigilance state dependent synaptic transmission through the hippocampal
      trisynaptic circuit from REM sleep to SWS in both control and malnourished
      animals, with the change occurring later in malnourished animals when compared to
      control ones. Furthermore, our findings suggests that prenatal protein
      malnutrition significantly alters modulation of dentate granule cell excitability
      (i.e., PPI values using the PSA measure) during the earlier stages of development
      but not in adulthood.

PMID- 10592288
TI  - DNA strand breaks in Alzheimer's disease.
AB  - The goal of this study was to investigate the presence of DNA damage in
      Alzheimer's disease (AD) utilizing independent assays for three different types
      of DNA strand breaks. Sections from hippocampi of AD brains, brains with
      Alzheimer neurofibrillary changes (Ch) from non-demented individuals, and
      controls (C) were labeled with (1) the TUNEL assay to identify blunt-ended and 3'
      protruding termini of breaks in double-stranded DNA, (2) the Klenow assay to
      detect single-stranded and double-stranded breaks with protruding 5' termini, and
      (3) the Apostain assay which utilizes a monoclonal antibody to single-stranded
      DNA and is based on the decreased stability of apoptotic DNA to thermal
      denaturation caused by DNA breaks. The highest incidence of nuclei positive for
      either molecular form of DNA strand breaks was detected in AD, followed by Ch,
      and controls (C). In either AD and Ch, the incidence of TUNEL- or Klenow-positive
      nuclei did not differ significantly, but was higher than the incidence of
      Apostain-positive nuclei. With all three assays, the highest incidence of
      positive nuclei was in the molecular layer of CA1. In the majority of nuclei
      positive for either the Klenow or the Apostain assay, the product of the labeling
      reaction was localized either to the periphery of the nucleus or to distinct
      clumps of chromatin (or both). With the TUNEL assay, the majority of positive
      nuclei were diffusely labeled. In both AD and Ch, the individual positive nuclei
      were labeled with both the Klenow and the TUNEL assays. The results indicate high
      incidence of nuclei with either double-stranded or single-stranded DNA breaks in
      AD, which, for the forms detectable with the Klenow or TUNEL assays, were
      colocalized.

PMID- 10592287
TI  - Neuronal adhesion molecule telencephalin induces rapid cell spreading of
      microglia.
AB  - Telencephalin (TLCN) is a neuronal surface glycoprotein whose expression is
      restricted to the telencephalon, the most rostral segment of the brain. TLCN
      binds to lymphocyte function-associated antigen-1 (LFA-1) integrin. In the
      central nervous system, LFA-1 is selectively and constitutively expressed by
      microglia, suggesting that TLCN/LFA-1 binding may mediate cell-cell interactions
      between telencephalic neurons and microglia. In the present study, we
      investigated the effects of recombinant TLCN protein on the morphology of
      microglia. TLCN induced an intensive spreading of lamellipodia, causing a rapid
      change in microglial morphology. In contrast, TLCN induced no significant change
      in morphology of neuroblastoma and fibroblasts. Furthermore, the TLCN-induced
      spreading of microglia was accompanied by a clustering of LFA-1 on cell surface
      membrane. These results provide evidence that TLCN binding to the surface of
      microglia transduces signals into microglia that mediate or accelerate cell
      spreading and LFA-1 redistribution, implying that neuronal TLCN may control the
      state and/or function of microglia in both physiological and pathological
      conditions.

PMID- 10592289
TI  - Expression of citrulline-nitric oxide cycle in lipopolysaccharide and cytokine
      stimulated rat astroglioma C6 cells.
AB  - Nitric oxide (NO) is involved in many physiological and pathological processes in
      the brain. NO is synthesized from arginine by nitric oxide synthase (NOS), with
      citrulline generated as a by-product of the reaction. Thus, citrulline can by
      recycled to arginine by argininosuccinate synthetase (AS) and argininosuccinate
      lyase (AL) via the citrulline-NO cycle. Rat astroglioma C6 cells were treated
      with bacterial lipopolysaccharide (LPS), interferon-gamma (IFNgamma) and tumor
      necrosis factor-alpha, and the expression of the enzymes of the citrulline-NO
      cycle was investigated by RNA blot and immunoblot analyses. NO production from
      arginine and citrulline was also assessed. iNOS mRNA and protein were induced 6
      12 h after stimulation with LPS and cytokines and decreased at 24 h. AS mRNA
      increased up to 12 h and decreased at 24 h. AS protein increased gradually up to
      48 h. On the other hand, AL mRNA remained unchanged by stimulation. NO production
      from arginine was enhanced by the treatment with LPS and cytokines. NO production
      was also observed when arginine was replaced by citrulline. These results
      indicate that NO production is enhanced in LPS- and cytokine-stimulated C6 cells
      due to induction of iNOS and that the citrulline-arginine recycling is important
      for NO production.

PMID- 10592290
TI  - Isoflurane anesthesia enhances the inhibitory effects of cocaine and GBR12909 on
      dopamine transporter: PET studies in combination with microdialysis in the monkey
      brain.
AB  - The effects of the dopamine transporter (DAT) inhibitors cocaine and GBR12909 on
      DAT and dopamine D(2) receptors were evaluated in the brains under awake and
      isoflurane-anesthetized monkeys using high-resolution positron emission
      tomography (PET) in combination with microdialysis. The striatal DAT availability
      and dopamine D(2) receptor binding were assayed with [11C]beta-CFT (WIN35,428)
      and [11C]raclopride, respectively. Cocaine or GBR12909 at a dose of 2 mg/kg was
      administered intravenously 30 min prior to the injection of labeled compounds. In
      the awake state, the in vivo binding of [11C]beta-CFT to DAT was significantly
      decreased by administration of cocaine or GBR12909 at a dose of 2 mg/kg. In
      contrast, [11C]raclopride binding to dopamine D(2) receptors was decreased only
      by GBR12909. Under isoflurane anesthesia, dopamine concentration in the striatal
      extracellular fluid (ECF), as measured by microdialysis, was markedly increased
      by cocaine or GBR12909 compared to the awake state. Isoflurane anesthesia more
      markedly enhanced the binding of [11C]beta-CFT in the saline-injected animals,
      and the degrees of reduction by cocaine and GBR12909 were more marked than those
      observed in the awake state. Under isoflurane anesthesia, the binding of
      [11C]raclopride was reduced not only by GBR12909 but also by cocaine which did
      not affect the binding in the awake state. Taken together, these observations
      indicated that isoflurane anesthesia enhanced not only the direct inhibitory
      effects of cocaine and GBR12909 on DAT, but also their indirect effects on
      dopamine D(2) receptors.

PMID- 10592291
TI  - Emergence of excitotoxicity in cultured forebrain neurons coincides with larger
      glutamate-stimulated [Ca(2+)](i) increases and NMDA receptor mRNA levels.
AB  - We examined several factors related to the increase in susceptibility to
      excitotoxicity that occurs in embryonic forebrain neurons over time in culture.
      Neuronal cultures were resistant to a 5-min exposure to 100 microM glutamate/10
      microM glycine at 5 days in vitro (DIV), but became vulnerable to the same
      stimulus by 14 DIV. We used the fluorescent indicators, fura-2 and magfura-2,
      which have high and low affinity for Ca(2+), respectively, to measure changes in
      [Ca(2+)](i). Glutamate-stimulated increases in the fura-2 and magfura-2 ratio
      reached maximum values by 10 DIV. Fura-2 reported similar [Ca(2+)](i) changes
      with exposure to 3 or 100 microM glutamate for 5 min, whereas magfura-2 reported
      larger [Ca(2+)](i) increases with 5-min exposure to 100 microM glutamate than
      with exposure to 3 microM glutamate, 100 microM kainate or 50 mM K(+) from 10 DIV
      onward. This suggests that the magnitude of the [Ca(2+)](i) changes correlated
      with the excitotoxicity potential of a stimulus when magfura-2, but not fura-2,
      was used to measure Ca(2+). We also used RNase protection assays to measure NMDA
      receptor subunit mRNA levels. NR1 and NR2A mRNA increased continuously over time
      in culture, whereas NR2B mRNA increased dramatically during the first 10 days and
      subsequently remained stable. The time course of the increase in NR2B mRNA most
      closely followed the increase in glutamate-stimulated changes in the magfura-2
      signal and neuronal injury. Therefore, the increases in the glutamate-stimulated
      [Ca(2+)](i) responses and NMDA receptor subunit mRNA levels (especially NR2B) are
      likely involved in the development of susceptibility to excitotoxicity in
      cultured rat forebrain neurons.

PMID- 10592293
TI  - Acidosis enhances translocation of protein kinase C but not Ca(2+)/calmodulin
      dependent protein kinase II to cell membranes during complete cerebral ischemia.
AB  - Systemic hyperglycemia and hypercapnia severely aggravate ischemic brain damage
      when instituted prior to cerebral ischemia. An aberrant cell signaling following
      ischemia has been proposed to be involved in ischemic cell death, affecting
      protein kinase C (PKC) and the calcium calmodulin kinase II (CaMKII). Using a
      cardiac arrest model of global brain ischemia of 10 min duration, we investigated
      the effect of hyperglycemia (20 mM) and hypercapnia (pCO(2) 300 mmHg) on the
      subcellular redistribution of PKC (alpha, beta, gamma) and CaMKII to synaptic
      membranes and to the microsomes, as well as the effect on PKC activity. We
      confirmed the marked translocation of PKC and CaMKII to cell membranes induced by
      ischemia, concomitantly with a decrease in the PKC activity in both the membrane
      fraction and cytosol. Hyperglycemia and hypercapnia markedly enhanced the
      translocation of PKC-gamma to cell membranes while other PKC isoforms were less
      affected. There was no effect of acidosis on PKC activity, or on translocation of
      CaMKII to cell membranes. Our data strongly suggest that the enhanced
      translocation of PKC to cell membranes induced by hyperglycemia and hypercapnia
      may contribute to the detrimental effect of tissue acidosis on the outcome
      following ischemia.

PMID- 10592292
TI  - Correlation of glutamate-induced apoptosis with caspase activities in cultured
      rat cerebral cortical neurons.
AB  - In cultured rat cortical neurons lactate dehydrogenase (LDH) activity in the
      medium, a cell-death marker, increased gradually after exposure to glutamate (100
      microM to 1 mM) for 60 min and reached a plateau at 24 to 30 h. Neuronal death
      was mainly apoptotic as suggested by typical electron microscopic findings,
      fluorescent double staining with membrane-permeating and nonpermeating chromatin
      dyes, nick end labeling, and assessment of DNA fragmentation by agarose gel
      electrophoresis. After 1 mM glutamate exposure, a rise of interleukin-1beta
      converting enzyme (ICE)-like protease activity in neurons was parallel to
      cysteine protease p32 (CPP32)-like protease activity and declined before CPP32
      like protease activity reached the peak (at 6 h). LDH activity in the medium of
      glutamate-exposed neurons was decreased by specific ICE and/or CPP32 inhibitors,
      acetyl-L-tyrosyl-L-valyl-L-alanyl-L-aspart-1-al (Ac-YVAD-CHO) and acetyl-L
      aspartyl-L-glutamyl-L-valyl-L-aspart-1-al (Ac-DEVD-CHO), respectively, in a dose
      dependent manner. Fluorescent double staining of nuclei also demonstrated that at
      100 microM each inhibitor prevented neuronal apoptosis and that this effect was
      additive. Among agonists corresponding to various glutamate receptor subtypes, N
      methyl-D-aspartate (NMDA) and kainate induced apoptosis in cortical neuronal
      cultures while alpha-amino-3-hydroxy-5-methylisoxazole-4-propinate (AMPA) did
      not. The metabotropic glutamate receptor agonist, 1-aminocyclopentane-1S, 3R
      dicarboxylate (ACPD) prevented apoptosis. Interestingly, apoptosis at 24 h after
      agonist or antagonist exposure correlated closely with caspase activity 6 h after
      exposure.

PMID- 10592294
TI  - Synthesis, assembly, and turnover of alpha and beta-erythroid and nonerythroid
      spectrins in rat hippocampal neurons.
AB  - The synthesis and turnover of alpha-erythroid, beta-erythroid, alpha-nonerythroid
      and beta-nonerythroid spectrins was investigated in cultured rat hippocampal
      neurons. [35S]methionine and subunit specific antibodies were used to label and
      immunoprecipitate newly synthesized spectrins in 12- to 14-day-old cultures.
      Synthesis experiments, performed under normal resting conditions, showed that the
      ratio of newly synthesized alpha-erythroid/beta-erythroid and alpha
      nonerythroid/beta-nonerythroid spectrins is 1/1 (mol/mol) both in the soluble and
      insoluble fractions. Soluble and insoluble alpha and beta erythroid spectrin turn
      over rapidly (half-life=16-24 min). Soluble nonerythroid alpha-spectrin (half
      life=80 min) and beta spectrin (half-life=53 min) turn over more slowly than
      their insoluble counterparts (30-34 min). The nonerythroid alpha spectrin
      turnover was significantly different (p<0.05) from the other measurements except
      for nonerythroid beta spectrin, indicating that these subunits are protected from
      rapid proteolytic degradation until they are assembled in the membrane skeleton.

PMID- 10592295
TI  - Re-entrant activity in a presubiculum-subiculum circuit generates epileptiform
      activity in vitro.
AB  - The retrohippocampal cortices form the transition between neocortex and the
      hippocampus. Area CA3 of the hippocampus and the entorhinal cortex (EC) of the
      retrohippocampal region are established as brain regions that generate
      epileptiform activity. Interictal activity generated in EC consists of a primary
      population burst followed by multiple afterdischarges. The presubiculum is
      similar to EC in its six-layered structure, but lacks a columnar circuitry that
      the EC possesses. Isolated presubicular tissue cannot generate afterdischarges
      and isolated subicular tissue generates no spontaneous activity under some
      conditions. We report epileptiform activity in combined presubiculum-subiculum
      slices that consists of synchronous population bursts and multiple
      afterdischarges. Intracellular and field potential recordings reveal two re
      entrant paths for interaction of presubicular and subicular neurons. We
      demonstrate a deep presubicular input to subiculum and separate return paths from
      subicular bursting neurons onto deep and superficial layer pre-/parasubicular
      neurons. Recordings from subicular cell apical dendrites showed repetitive burst
      firing during sustained depolarizing current injection. We conclude that re
      entrant activity in a presubiculum-subiculum circuit generates epileptiform
      activity in both regions. Presubicular inputs to subiculum depolarize apical
      dendrites which can then burst repetitively. These bursts are transmitted back to
      the presubiculum. We suggest that iterations on this circuit act to prolong the
      dendritic depolarization of subicular bursting neurons and to entrain the
      activity across subicular cells resulting in multiple afterdischarges.

PMID- 10592296
TI  - Cloning, sequencing, expression and function of a cDNA encoding a receptor for
      the opioid growth factor, [Met(5)]enkephalin.
AB  - The native opioid growth factor (OGF), [Met(5)]enkephalin, is a tonic inhibitory
      peptide that modulates cell proliferation and tissue organization during
      development, cancer, cellular renewal, wound healing and angiogenesis. OGF action
      is mediated by a receptor mechanism. We have cloned and sequenced a 2.1-kilobase
      (kb) cDNA for a receptor to OGF (OGFr). The open reading frame was found to
      encode a protein of 580 amino acids, and eight imperfect repeats of nine amino
      acids each were a prominent feature. The protein encoded by this cDNA exhibited
      the pharmacological, temporal and spatial characteristics of the OGFr. Functional
      studies using antisense technology demonstrated an enhancement in cell growth.
      The molecular organization of the OGFr has no homology to classical opioid
      receptors. These results provide molecular validity for the interaction of OGF
      and OGFr in the regulation of growth processes.

PMID- 10592297
TI  - Regeneration of olfactory receptor neurons following chemical lesion: time course
      and enhancement with growth factor administration.
AB  - Although it has been known for over 50 years that olfactory receptor neuron (ORN)
      neurogenesis and subsequent reinnervation of the olfactory bulb (OB) occurs
      following ORN injury, the precise intrinsic and extrinsic factors that regulate
      this dynamic process have not yet been fully identified. In the first of two
      experiments, we characterized the time course of anatomical recovery following
      zinc sulfate (ZnSO(4)) lesion of ORNs in adult male Sprague-Dawley rats. ZnSO(4)
      produced a near complete deafferentation of OB within 3 days following intranasal
      administration. A time-dependent increase in ORN reinnervation of OB was observed
      following 10, 20, and 30 day recovery intervals. Given the evidence that bFGF,
      EGF, and TGF-alpha have mitogenic effects on ORNs in vitro, a second experiment
      examined the extent to which these growth factors (GFs) might enhance ORN
      regeneration and subsequent reinnervation of OB in vivo. Rats received intranasal
      infusions of ZnSO(4) on day 0, followed by subcutaneous injections of either bFGF
      (5, 10, or 50 microgram/kg), EGF (5, 10, or 50 microgram/kg), or TGF-alpha (5 or
      10 microgram/kg) on days 3-6. Horseradish peroxidase (HRP) histochemistry of OB
      following a 10-day recovery period revealed a dose-related enhancement in
      reinnervation of OB for each of the three growth factors examined, with the
      greatest enhancement produced by TGF-alpha. These data suggest that GFs may
      regulate ORN mitogenesis in vivo in a way similar to that which has been
      characterized in vitro.

PMID- 10592298
TI  - The absence of resurgent sodium current in mouse spinal neurons.
AB  - The Scn8a gene encodes a neuronal, voltage-gated sodium channel, which is highly
      expressed in both cerebellar Purkinje neurons and spinal motoneurons [D.L.
      Burgess, D.C. Kohrman, J. Galt, N.W. Plummer, J.M. Jones, B. Spear, M.H. Meisler,
      Mutation of a new sodium channel gene, Scn8a, in the mouse mutant 'motor endplate
      disease', Nature Genetics 10 (1995) 461-465; K.L. Schaller, D.M. Krzemien, P.J.
      Yarowsky, B.K. Krueger, J.H. Caldwell, A novel, abundant sodium channel expressed
      in neurons and glia, J. Neurosci. 15 (1995) 3231-3242]. Sodium channels in
      Purkinje cells produce an unusual, "resurgent" current when the cells are
      repolarized to intermediate potentials (-60 to -20 mV) following a strong
      depolarization that completely inactivates transient sodium current [I.M. Raman,
      L.K. Sprunger, M.H. Meisler, B.P. Bean, Altered subthreshold sodium currents and
      disrupted firing patterns in Purkinje neurons of Scn8a mutant mice, Neuron 19
      (1997) 881-891; I.M. Raman, B.P. Bean, Resurgent sodium current and action
      potential formation in dissociated cerebellar Purkinje neurons, J. Neurosci. 17
      (1997) 4517-4526]. Here, we have examined whether large spinal neurons
      (predominantly motoneurons), isolated from P6-P8 mice and cultured overnight,
      produce sodium currents resembling those either of Purkinje cells or of Xenopus
      oocytes after heterologous expression of Scn8a. We found that P10-P14 Purkinje
      cells exhibited resurgent current (ranging from -3.6 to -15.4 pA/pF in 16 cells
      at -40 mV), but cultured spinal neurons had little or no such current (<0.5 pA/pF
      in 13 of 16 cells; -1.2 to -2.3 pA/pF in three of 16 cells). Furthermore, unlike
      Scn8a channels heterologously expressed in Xenopus oocytes [M.R. Smith, R.D.
      Smith, N.W. Plummer, M.H. Meisler, A.L. Goldin, Functional analysis of the mouse
      Scn8a sodium channel. J. Neurosci. 18 (1998) 6093-6102], there was not a
      prominent component of persistent sodium current in either Purkinje neurons or
      large spinal neurons. Based on analysis of cells from mice with a Scn8a null
      mutation, Scn8a channels appear to contribute significantly to total sodium
      current in both in P10-P14 Purkinje cells (approximately 40%; [21]) and cultured
      P7-P8 spinal motoneurons (approximately 70% [K.D. Garcia, L.K. Sprunger, M.H.
      Meisler, K.G. Beam, The sodium channel Scn8a is the major contributor to the
      postnatal developmental increase of sodium current density in spinal motoneurons,
      J. Neurosci. 18 (1998) 5234-5239]). Thus, the presence or absence of resurgent
      current, and of persistent sodium current, appears to depend on cellular factors
      other than the mere presence of the Scn8a transcript.

PMID- 10592300
TI  - A photothrombotic ring stroke model in rats with or without late spontaneous
      reperfusion in the region at risk.
AB  - This study aimed at developing a dual setup of the photothrombotic ring stroke
      model with or without late spontaneous reperfusion in the region at risk and to
      explore the morphological consequences. The exposed crania of adult male Wistar
      rats were subjected to a ring-shaped laser-irradiation beam (o.d. 5.0 mm, 0.35 mm
      thick) for 2 min simultaneously with intravenous erythrosin B (17 mg/kg)
      infusion. Transcardial carbon-black perfusion revealed that a laser intensity of
      0.90 W/cm(2) resulted in late, that is, starting at 72 h, spontaneous
      reperfusion, whereas the lowest laser intensity that produced lack of reperfusion
      at 7 days post-irradiation was 1.84 W/cm(2). Laser-Doppler flowmetry showed
      prompt cortical cerebral blood flow (cCBF) reduction both in the ring lesion and
      region at risk (12% and 25% of control values) after high-intensity irradiation;
      these reduced flow values were more rapid and pronounced than in the low
      intensity irradiation setup as previously shown. The high- compared with low
      intensity irradiation setup produced more frequent occurrence of thrombi in the
      ring-lesion region and a larger ischemic cortical lesion with a more rapid pace
      of ischemic cellular changes in the ring-lesion region and the region at risk.
      The region at risk transformed into pannecrosis in the high-intensity, but
      recovered morphologically in the low-intensity irradiation setup. This dual
      photothrombotic setup with or without spontaneous reperfusion enables the study
      of events related to ischemic cell survival or death in an anatomically
      predefined region at risk.

PMID- 10592299
TI  - The nitric oxide-cGMP system of the locus coeruleus and the hypnotic action of
      alpha-2 adrenergic agonists.
AB  - Dexmedetomidine (Dex), a potent, selective alpha-2 adrenergic agonist, injected
      bilaterally directly into the locus coeruleus (LC), 7 microgram/LC, or ip, 100
      microgram/kg, produced a maximum decrease in LC cGMP (-38 and -46%,
      respectively). Atipamezole, a selective alpha-2 adrenergic antagonist, given into
      the LC, 10 microgram/LC, prevented the decrease in LC cGMP induced by Dex, given
      i.p. or into the LC. Dex produced a loss of righting reflex in about 80% of the
      animals, an effect which was prevented by pretreatment with atipamezole. The
      nitric oxide synthase antagonist L-Name injected bilaterally into the LC, 20
      microgram/LC, produced by itself a maximum decrease in LC cGMP of 54.5%. Dex, 100
      microgram/kg, ip, given after L-Name, did not further decrease LC cGMP. L-Name,
      by itself, did not produce a loss of righting reflex, while 6 out of 9 rats
      pretreated with L-Name lost their righting reflex in response to Dex. A role of
      the nitric oxide-cGMP system of the LC in the modulation of the hypnotic effect
      of alpha-2 adrenergic agonists remains uncertain.

PMID- 10592301
TI  - Altered distribution of Schwann cells in the periodontal ligament of the rat
      incisor following resection of the inferior alveolar nerve: an
      immunohistochemical study on S-100 proteins.
AB  - The present study employed immunohistochemistry for the detection of S-100
      proteins to reveal the alteration in the distribution of Schwann cells in the
      periodontal ligament of the rat incisor following resection of the inferior
      alveolar nerve (IAN). In normal animals, S-100-immunostaining demonstrated the
      profiles of Ruffini endings, primary mechanoreceptors in the periodontal
      ligament, in the alveolus-related part of the ligament. Under the electron
      microscope, S-100-like immunoreactivity (-LI) was observed in the cytoplasm of
      the terminal Schwann cell elements and in some axon profiles of the Ruffini
      endings. During the regeneration, S-100-like immunoreactive (-IR) terminal
      Schwann cells in the alveolus-related part of the ligament gradually decreased in
      number. In contrast, S-100-LI was found in the spindle-shaped cells at the shear
      zone (the border between alveolus-related and tooth-related parts) and in the
      tooth-related part, where S-100-LI was rarely detected in normal animals.
      Immunoelectron microscopic observations revealed that some S-100-IR spindle
      shaped cells contained fibrous long spacing (FLS) fibers, suggesting that they
      were Schwann cells. Some regenerating axons were observed at the shear zone, but
      were rarely found in the tooth-related part. With the progress of the
      regeneration of the periodontal Ruffini endings, S-100-IR terminal Schwann cells
      became rearranged in the alveolus-related part by 42-56 days post injury, whereas
      the S-100-IR spindle-shaped Schwann cells in the shear zone and tooth-related
      part disappeared when the regeneration was complete.

PMID- 10592302
TI  - Involvement of sympathetic activation and brown adipose tissue in calcitonin gene
      related peptide-induced heat production in the rat.
AB  - We previously reported that microinjection of calcitonin gene-related peptide
      (CGRP; 1.6-8.0 pmol, 0.2-1.0 microliter) into the ventromedial hypothalamus (VMH)
      increased oxygen consumption (VO(2)), heart rate (HR), colonic temperature
      (T(co)), and temperature of interscapular brown adipose tissue (T(IBAT)). In the
      present study, we investigated whether the autonomic nervous system is involved
      in the CGRP-induced heat production in urethane-anesthetized rats.
      Intraperitoneal administration of the ganglion blocker hexamethonium (20 mg/kg)
      or the beta-adrenergic antagonist propranolol (5 mg/kg) suppressed the CGRP
      induced increases in VO(2), HR, T(co), and T(IBAT). Pretreatment with the alpha
      adrenergic antagonist phentolamine (5 mg/kg) partly attenuated the heat
      production response but did not affect the tachycardiac response. Bilateral
      sectioning of the nerves supplying the IBAT attenuated the CGRP-induced increase
      in T(IBAT) but not significantly that in VO(2) or T(co). In rats with adrenal
      demedullation, the effects of CGRP were similar to those in intact rats. These
      results suggest that the CGRP-induced heat production is mediated by the
      sympathetic nervous system and, at least in part, by the BAT through the alpha-
      and beta-adrenoceptors.

PMID- 10592304
TI  - Release of cytochrome c from mitochondria to cytosol in gerbil hippocampal CA1
      neurons after transient forebrain ischemia.
AB  - We examined cytosolic cytochrome c in gerbil hippocampal CA1 and CA3 regions
      after induction of 5-min ischemia by immunoblotting. In the CA1 region,
      cytochrome c was detected in the cytosolic fraction from 1 to 6 h after ischemia
      by Western blotting, while it was not detected in the CA3 region. Following
      intraventricular administration of cyclosporin A (CsA), detectable cytosolic
      cytochrome c was dramatically decreased, and about 80% of CA1 neurons survived
      after ischemia. The present studies demonstrate that cytochrome c is translocated
      from mitochondria to the cytosol in the early stage of delayed neuronal cell
      death, and suggest the involvement of the mitochondrial permeability transition.

PMID- 10592303
TI  - Mu opioid receptors are in somatodendritic and axonal compartments of GABAergic
      neurons in rat hippocampal formation.
AB  - Activation of mu opioid receptors (MORs) has a net excitatory effect in the
      hippocampal formation through inhibition of gamma-amino butyric acid (GABA)
      containing interneurons. To determine the precise subcellular targets of MOR
      agonists, immunoreactivity against MOR1 and GABA was examined in single sections
      of the hippocampal formation prepared for dual-labeling electron microscopy. In
      both the CA1 region of hippocampus and the dentate gyrus, MOR-like
      immunoreactivity (-li) was present in neuronal somata, dendrites, axons, and axon
      terminals, as well as a very few glial processes. Axon terminals with MOR-li
      formed symmetric synapses with principal cell dendrites and somata. Many MOR
      labeled profiles of all types also contained GABA-li, and the vast majority
      possessed the ultrastructural characteristics of interneurons. Additionally, in
      the dentate gyrus a very small proportion of granule cell dendrites contained MOR
      li. MOR-li, identified using immunogold-silver particles, was often affiliated
      with the extrasynaptic regions of neuronal plasma membranes, consistent with
      responsiveness to diffusing endogenous neuropeptide ligands. Semiquantitative
      analysis of the distribution of MOR-li revealed significantly more "presynaptic"
      (axons and terminals) than "postsynaptic" (somata and dendrites) labeled profiles
      in most laminae. We conclude that in addition to previously described
      somatodendritic MOR-li, a substantial amount of MOR-li in hippocampal formation
      is presynaptic. Furthermore, MORs are almost exclusively in GABAergic
      interneurons.

PMID- 10592305
TI  - Comparative distribution of GABAergic and peptide-containing neurons in the
      lateral lemniscal nuclei of the rat.
AB  - By immunostaining, neurons expressing peptides (dynorphin and corticotropin
      releasing factor, CRF) and glutamate decarboxylase (GAD), a GABA-synthesizing
      enzyme, were precisely mapped in the rat lateral lemniscal nuclei. While GAD
      neurons were numerous and preferably localized in the dorsal (DLL) and ventral
      (VLL) nuclei, neurons expressing these peptides were less numerous and localized
      primarily in the intermediate (ILL) nucleus of the lateral lemniscus. The ILL
      nucleus was shown to project to the inferior colliculus and to express Fos
      rapidly in response to peripheral acoustic stimulation, suggesting that the ILL
      nucleus may take part in non-GABAergic relay of acoustic information in the
      lateral lemniscus.

PMID- 10592306
TI  - Ultrastructural analysis of the hippocampus of adult rats after long-term
      adrenalectomy.
AB  - Removal of adrenal steroids modulates various functions in the brain. However,
      adrenalectomy (ADX) induced cell death in the hippocampal formation of the adult
      rat is a recently described phenomenon. We undertook this ultrastructural study
      on long-term adrenalectomized (5 months) rats to investigate the mode of cell
      death in the hippocampus. Our results showed apoptotic changes in the
      hippocampus. In addition we have observed other types of degeneration in the
      hippocampal neurons. The novel finding in this study is that different
      morphological patterns of cell death were evident both in the dentate gyrus and
      in the pyramidal areas, which may reflect different stages of the same death
      process.

PMID- 10592307
TI  - Light-dependent regulation and postnatal development of the interferon-gamma
      receptor in the rat suprachiasmatic nuclei.
AB  - The interferon-gamma receptor gene was detected in the rat hypothalamic
      suprachiasmatic nuclei (SCN), the main pacemaker for circadian rhythms, and the
      molecular identity of the transcript was confirmed by sequencing. The expression
      of the receptor protein showed a daily rhythm that was dependent on light. It
      reached its adult pattern in the SCN between postnatal day 11 and 20, i.e., at a
      time when capacity for photic entrainment of the pacemaker is established.

PMID- 10592308
TI  - BDNF atelocollagen mini-pellet accelerates facial nerve regeneration.
AB  - We investigated the effect of BDNF mini-pellet on the GAP-43 mRNA expression and
      functional status of facial nerve in a rat model of facial nerve transection and
      immediate repair. The facial function started to recover at 17 days in the
      placebo group and 14 days in the BDNF group. BDNF group had shorter period of
      increased GAP-43 mRNA expression than the placebo group. Topically applied BDNF
      may accelerate the facial nerve regeneration.

PMID- 10592309
TI  - Multinucleated giant cell formation by microglia: induction by interleukin (IL)-4
      and IL-13.
AB  - To investigate the cellular origin and the mechanisms of multinucleated giant
      cell (MGC) formation in the CNS, various cytokines were applied to isolated
      murine microglia. All the single cytokines failed to induce MGC. However,
      interleukin (IL)-13 and IL-4 induced microglial MGC formation in the presence of
      colony stimulating factors, which was inhibited by either anti-IL-13 or anti-fms
      antibody. T helper 2 (Th2)-derived cytokines can induce MGC formation even in the
      absence of infectious agents.

PMID- 10592310
TI  - Ectopic discharges and adrenergic sensitivity of sensory neurons after spinal
      nerve injury.
AB  - At various times after spinal nerve injury, dorsal root ganglia (DRGs) from
      injured segments were removed with attached dorsal roots and spinal nerves. In an
      in vitro recording chamber, spontaneously active units were recorded from teased
      dorsal root fascicles. Sustained spontaneous activity could first be recorded at
      13 h after the ligation, but adrenergic sensitivity did not develop until 24 h
      after the injury. Almost all recorded activity originated from the DRG. Thus, the
      DRG is the most common site for ectopic discharge generation after spinal nerve
      injury and separate mechanisms seem to be involved in the development of ectopic
      discharges and adrenergic sensitivity.

PMID- 10592311
TI  - Chronic intracerebroventricular administration of orexin-A to rats increases food
      intake in daytime, but has no effect on body weight.
AB  - Orexins are recently identified neuropeptides, and have been shown to increase
      food intake when administered intracerebroventricularly. We examined the effects
      of chronic administration of orexin in rats by continuous intracerebroventricular
      administration by means of an osmotic minipump. Continuous administration of
      orexin-A (0.5 nmol/h) for 7 days in rats resulted in a significant increase in
      food intake in the daytime. Daytime food intake increased to 180% of the control
      value. However, it resulted in a slight decrease nighttime food intake as
      compared with vehicle-treated rats. The total amount of food intake per day was
      almost comparable with that of vehicle-administered rats. The gain of body weight
      and blood glucose, total cholesterol and free fatty acid levels were normal.
      Chronic orexin-A treatment did not cause obesity in rats. We observed abnormal
      behavior during the daytime after starting administration of orexin-A; these rats
      kept awake during the daytime. Our present observation showed that continuous
      administration of orexin-A could not overcome the regulation of energy
      homeostasis and body weight. However, orexin-A might be implicated in short-term,
      immediate regulation of feeding behavior.

PMID- 10592312
TI  - Estrogen receptor immunoreactivity within subregions of the rat forebrain:
      neuronal distribution and association with perikarya containing choline
      acetyltransferase.
AB  - Administration of the neuroactive steroid hormone estrogen has been shown to
      effect cholinergic basal forebrain neuronal function. Antibodies directed against
      the estrogen receptor alpha (ERalpha) revealed dark (type 1) and light (type 2)
      nuclear positive neurons within the islands of Calleja, endopiriform nucleus,
      lateral septum, subfields of the cholinergic basal forebrain, bed nucleus of the
      stria terminalis, striohypothalamic region, medial preoptic region,
      periventricular, ventromedial, arcuate and tuberal mammillary nuclei of the
      hypothalamus, reuniens and anterior medial thalamic nuclei, amygdaloid complex,
      piriform cortex and subfornical organ. In contrast, only a few scattered ERalpha
      labeled neurons were found in cortex and hippocampus. ERalpha stained cell bodies
      were not seen in the striatum. Counts of ERalpha labeled neurons in intact female
      rats revealed significantly more type 2 neurons within the basal forebrain
      subfields. Quantitation of ERalpha immunoreactive neurons revealed a significant
      decrease in the relative number of type 1 neurons within the medial septum (MS),
      horizontal limb of the diagonal band (HDB) and substantia innominata/nucleus
      basalis (SI/NB) following ovariectomy. Quantitation following choline
      acetyltransferease (ChAT) immunohistochemistry revealed a significant decrease in
      the number of ChAT positive neurons within the MS, HDB and SI/NB, but not VDB
      following ovariectomy. Following ovx, the percentage of double labeled
      cholinergic basal forebrain neurons also declined significantly within the MS,
      VDB, HDB and SI/NB. These observations suggest that estrogen effects a
      subpopulation of cholinergic basal forebrain neurons and may provide insight into
      the biologic actions of this steroid in Alzheimer's disease.

PMID- 10592313
TI  - A novel assay for allelic discrimination that combines the fluorogenic 5'
      nuclease polymerase chain reaction (TaqMan) and mismatch amplification mutation
      assay.
AB  - Recently much attention has been focused on single nucleotide polymorphisms
      (SNPs) within fundamentally important genes, such as those involved in
      metabolism, cell growth regulation, and other disease-associated genes.
      Methodologies for discriminating different alleles need to be specific (robust
      detection of an altered sequence in the presence of wild-type DNA) and
      preferably, amenable to high throughput screening. We have combined the
      fluorogenic 5' nuclease polymerase chain reaction (TaqMan) and the mismatch
      amplification mutation assay (MAMA) to form a novel assay, TaqMAMA, that can
      quickly and specifically detect single base changes in genomic DNA. TaqMan
      chemistry utilizes fluorescence detection during PCR to precisely measure the
      starting template concentration, while the MAMA assay exploits mismatched bases
      between the PCR primers and the wild-type template to selectively amplify
      specific mutant or polymorphic sequences. By combining these assays, the
      amplification of the mutant DNA can be readily detected by fluorescence in a
      single PCR reaction in 2 hours. Using the human TK6 cell line and specific HPRT
      mutant clones as a model system, we have optimized the TaqMAMA technique to
      discriminate between mutant and wild-type DNA. Here we demonstrate that
      appropriately designed MAMA primer pairs preferentially amplify mutant genomic
      DNA even in the presence of a 1,000-fold excess of wild-type DNA. The ability to
      selectively amplify DNAs with single nucleotide changes, or the specific
      amplification of a low copy number mutant DNA in a 1,000-fold excess of wild-type
      DNA, is certain to be a valuable technique for applications such as allelic
      discrimination, detection of single nucleotide polymorphisms or gene isoforms,
      and for assessing hotspot mutations in tumor-associated genes from biopsies
      contaminated with normal tissue.

PMID- 10592314
TI  - Analysis of sequence alterations in a defined DNA region: comparison of
      temperature-modulated heteroduplex analysis and denaturing gradient gel
      electrophoresis.
AB  - The ability to detect DNA sequence heterogeneity quickly and reliably is becoming
      increasingly important as more genes involved in disease processes are
      discovered. We have assessed the ability of a high pressure liquid chromatography
      technique (HPLC) termed temperature-modulated heteroduplex analysis (TMHA) to
      detect a collection of 20 point mutations distributed throughout a 279 base pair
      fragment spanning the exon 8 region of the human HPRT gene. All mutant/wild type
      heteroduplexes formed from mutations in the lowest temperature melting domain of
      the fragment were easily resolved from the corresponding mutant and wt
      homoduplexes, while those generated from mutants in the next higher melting
      domain barely resolved from their parental homoduplexes. For comparison,
      identical heteroduplex samples were subjected to denaturing gradient gel
      electrophoresis (DGGE). Heteroduplexes in the lowest temperature melting domain
      were easily resolved, while no resolution was achieved with those in the next
      higher melting domain. These results suggest that TMHA and DGGE are measuring
      similar melting characteristics in heteroduplex molecules. TMHA appears to be a
      robust approach for detecting and/or purifying a wide variety of mutations in a
      defined region of DNA, provided that the melting characteristics of the fragment
      under study are carefully considered.

PMID- 10592315
TI  - Multiple mutations in a shuttle vector modified by ultraviolet irradiation, (+/-)
      7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10
      tetrahydrobenzo[a]pyrene, and aflatoxin B(1) have different properties than
      single mutations and may be generated during translesion synthesis.
AB  - Shuttle vector-based systems are extensively employed to study the mutational
      properties of various mutagens in mammalian cells. Such vectors are designed for
      the detection of point mutations, that is small deletions and single base and
      tandem substitutions. However, mutant target genes carrying two or more point
      mutations, referred to as multiple mutations, can also be found in various
      proportions depending on the mutagen and the cells used. To evaluate the
      frequency and characteristics of multiple mutations, we used a system where the
      plasmid, pYZ289, was treated by ultraviolet irradiation, aflatoxin B(1) or (+/-)
      7 beta,8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10
      tetrahydrobenzo[a]pyrene before transfection into mouse fibroblast cells. The
      kinds of mutations and the mutational spectra were different for single and
      multiple mutations. In addition, in at least 75% of the cases, mutations of
      multiples appeared to arise in the same strand. Furthermore, mutational spectra
      for multiple mutations were different for 5' and 3' members of multiple sets.
      These observations suggest that multiple mutations arise via a different
      mechanism than single mutations. Moreover, these findings suggest that multiples
      arise during translesion DNA synthesis and involve an error-prone polymerase able
      to introduce a base opposite misinstructive or noninstructional DNA lesions and
      subject to subsequent misincorporation errors.

PMID- 10592316
TI  - The aromatic amine carcinogens o-toluidine and o-anisidine induce free radicals
      and intrachromosomal recombination in Saccharomyces cerevisiae.
AB  - Aniline-based aromatic amine carcinogens are poorly detected in short-term
      mutagenicity assays such as the Salmonella reverse mutation (Ames) assay. More
      information on the mechanism of toxicity of such Salmonella-negative carcinogens
      is needed. Aniline and o-toluidine are negative in the Ames assay, but induce
      deletions (DEL) due to intrachromosomal recombination in Saccharomyces cerevisiae
      with an apparent threshold. We show here that the DEL assay also detects the
      genotoxic activity of another aromatic amine carcinogen, o-anisidine, which is
      also negative in the Salmonella assay. We also show that the DEL assay
      distinguishes between o-anisidine and its non-carcinogenic structural analog 2, 4
      dimethoxyaniline. We have investigated whether the ability of the DEL assay to
      detect the carcinogens and to distinguish between the carcinogen/non-carcinogen
      pair is linked to rises in intracellular free radical species following exposure
      to the carcinogens. Toxicity induced by all three compounds was reduced in the
      presence of the free radical scavenger and antioxidant N-acetyl cysteine,
      recombination induced by o-anisidine and o-toluidine was also reduced by N-acetyl
      cysteine. All three compounds induced oxidation of the free radical-sensitive
      reporter compound dichlorofluorescin diacetate. Superoxide dismutase-deficient
      strains, however, were hypersensitive to cytotoxicity induced by o-toluidine and
      o-anisidine but not by the non-carcinogen 2,4-dimethoxyaniline, indicating a
      different potential for generating superoxide radical between the carcinogens and
      the non-carcinogen analog. The results indicate that the yeast DEL assay is a
      useful tool for investigating the genotoxic activity of aromatic amine
      carcinogens.

PMID- 10592317
TI  - Chromosome aberrations induced by aphidicolin.
AB  - The expression of aphidicolin (apc)-produced common fragile sites and chromosome
      aberrations observed 24 h after apc treatment was studied in a normal individual.
      The chromosome lesions (gaps and breaks) induced by apc are expressed as full
      chromosomal aberrations in later cell divisions. We compared chromosome
      rearrangements or anomalies induced by apc (detected in 45.4% of metaphases
      analyzed) with those present in human neoplasia or involved in primate evolution.
      We found that 55.7% of deletions observed in our study coincided with deletions
      implicated in several types of neoplasia. However, none of 49 translocations
      observed in our study coincided with those described as recurrently associated
      with human neoplasia, probably due to their unbalanced nature. When chromosome
      aberrations detected in our study (only deletions and inversions were taken into
      account) were compared to those involved in primate evolution, we found a low
      rate of coincidence. The low coincidence between chromosome alterations in
      neoplasia and evolution and those observed in our study could be explained
      because we analyzed chromosome alterations that had not been selected, whereas
      those present in chromosome evolution and in neoplasia had been subjected to a
      selection process.

PMID- 10592318
TI  - Similarity pattern analysis in mutational distributions.
AB  - The validity and applicability of the statistical procedure - similarity pattern
      analysis (SPAN) - to the study of mutational distributions (MDs) was demonstrated
      with two sets of data. The first was mutational spectra (MS) for 697 GC to AT
      transitions produced with eight alkylating agents (AAs) in the lacI gene of
      Escherichia coli. The second was a recently summarized data on the distributions
      of 11562 spontaneous, radiation- and chemical-induced forward mutations in the ad
      3 region of heterokaryon 12 of Neurospora crassa. They were analyzed as large two
      way contingency tables (CTs) where two kinds of profiles were compared: site (or
      genotypic class) profiles and origin (or mutagen) profiles. To measure similarity
      (homogeneity) between any pair of profiles, the relevant sufficient statistics,
      Kastenbaum-Hirotsu squared distance (KHi(2)), was used. Collapsing the similar
      profiles into distinct internally homogeneous clusters named 'collapsets'
      revealed their similarity pattern. To facilitate the procedure, the computer
      program, COLLAPSE, was elaborated. The results of SPAN for the lacI spectra were
      found comparable with the results of their previous analysis with two
      multivariate statistical methods, the factor and cluster analyses. In the ad-3
      data set, five collapsets were revealed among origin profiles (OPs): (I) ENU =
      4NQO = 4HAQO = FANFT = SQ18506; (II) AF-2 = EI = MMS = DEP; (III) ETO = UV; (IV)
      AHA = PROCARB; and (V) He ions = protons. Moreover, the previous observation that
      MDs are dose-dependent was confirmed for X-ray-induced MDs. Profiles induced with
      the low doses of X-rays are similar to that induced with 85Sr, and profiles
      induced with the medium X-ray doses to those induced with protons and He ions.
      Evaluated similarities appear to be rather reasonable: mutagens with similar mode
      of action induce similar MDs. Similarity pattern revealed among genotypic class
      profiles (GCPs) seems to be also interpretable. When supplemented with
      descriptive cluster analysis, SPAN appears to be a fruitful methodology in MS
      analysis.

PMID- 10592319
TI  - Intraclonal polymorphism in the bacterium Streptomyces ambofaciens ATCC23877:
      evidence for a high degree of heterogeneity of the wild type clones.
AB  - In Streptomyces ambofaciens a genetic instability generates a high degree of
      polymorphism consisting of four main phenotypes: pigmented colonies (Pig(+)
      qualified as WT phenotype), pigment-defective colonies, pigmented colonies with
      pigment-defective sector and pigmented colonies with pigment-defective papillae.
      Molecular analysis of Pig(col)(-) and Pig(sec)(-) (pigment-defective mutant
      derived from a colony and a sector, respectively) produced by genetic instability
      and isolated in five Pig(+) subclones progenies revealed a new aspect of
      polymorphism in S. ambofaciens ATCC23877. Frequencies of Pig(col)(-) and
      Pig(sec)(-) mutants deleted at the chromosome ends varied from one WT progeny to
      another. Two main types of deleted mutants were observed: deleted for one or both
      chromosomal extremities. The relative proportion of these two categories differed
      according to the WT progeny. These results argue for heterogeneity of the WT
      clones, i.e., Pig(+) colonies, originated from S. ambofaciens ATCC23877.

PMID- 10592320
TI  - The effects of oral administration with 17 alpha-methyltestosterone on
      chromosomal synapsis in Oreochromis niloticus (Pisces, Cichlidae).
AB  - The pattern of chromosomal synapsis after treatment with 17 alpha
      methyltestosterone (MT), a testosterone analogue routinely used for the reversal
      of phenotypic sex in aquaculture, was investigated using the Nile tilapia
      (Oreochromis niloticus) as a model teleost species. Progeny-tested, monosex
      diploid (2n = 44) individuals were orally administered with diets containing 50
      mg/kg MT for 30 days after first feeding (XX(MT) neomales and XY(MT) males) and
      compared to controls (XY males). The formation and structure of the synaptonemal
      complex (SC) and the nature of chromosomal synapsis were investigated in control
      and treated groups by computer-assisted image analysis of transmission electron
      microscope (TEM) microphotographs taken from SC spreads. Nuclei at the pachytene
      stage were first observed in XX(MT) neomales, indicating an earlier commitment of
      genetically female spermatocytes to enter the first meiotic prophase.
      Administration of MT did not result in obvious SC lesions, breakage, asynapsis or
      formation of multivalents in genotypic females (XX(MT) neomales). Administration
      of MT resulted in a significant increase in the SC lengths in XY(MT) males,
      although it did not significantly alter the pattern of synapsis (SC structure and
      number and morphology of bivalents) in comparison to XY controls. The
      significance of the effects and the putative mode(s) of action of MT on
      chromosomal synapsis in teleosts is discussed.

PMID- 10592321
TI  - Methionine reduces spontaneous and alkylation-induced mutagenesis in
      Saccharomyces cerevisiae cells deficient in O6-methylguanine-DNA
      methyltransferase.
AB  - The exposure of DNA to reactive intracellular metabolites is thought to be a
      major cause of spontaneous mutagenesis. DNA alkylation is implicated in the above
      process by the fact that bacterial and yeast cells lacking DNA alkylation
      specific repair genes exhibit elevated spontaneous mutation rates. The origin of
      the intracellular alkylating molecules is not clear; however, S
      adenosylmethionine (SAM) has been proposed as one source because it has a
      reactive methyl group known to methylate proteins and DNA. We supplemented yeast
      cultures with excess methionine and examined the effects of increased endogenous
      SAM concentration on spontaneous and alkylation-induced mutagenesis in the
      absence of various DNA repair pathways. Our results show that either the excess
      methionine, or the increased SAM produced as a result of this treatment, is able
      to protect yeast cells from mutagenesis, and that this effect is alkylation
      damage-specific. The protective effect was observed only in the mgt1 mutant
      deficient in the O(6)-methylguanine-DNA repair methyltransferase, but not in the
      wild type or other DNA repair-deficient strains, indicating that the protection
      is specific for O-methyl lesions. Thus, our results may lend support to the
      recently reported chemopreventive effect of SAM in rodents and further suggest
      that the observed tumor prevention by SAM may be, in part, due to its suppression
      of spontaneous mutagenesis in mammals. Given that a strong correlation has been
      established between O(6)-methylguanine and carcinogenicity, this study may offer
      a novel approach to preventing carcinogenesis.

PMID- 10592322
TI  - A case of elevated spontaneous micronucleus frequency derived from chromosome 2.
AB  - This work tested the hypothesis that the content of spontaneous micronuclei in
      lymphocytes in an apparently healthy normal human subject, who exhibited an
      unusually high micronucleus frequency, was non-random. Several DNA probes were
      used in fluorescent in-situ hybridization (FISH), beginning with a probe
      generated from the subject's micronuclei. Micronuclei obtained from peripheral
      blood lymphocytes by microdissection were subjected to random amplification of
      polymorphic DNA (RAPD-PCR), and a unique PCR product was then used to isolate a
      cosmid clone from a human genomic library. This clone hybridized to chromosome 2.
      Subsequently, commercial probes were included in FISH analyses of micronuclei
      from the subject and age- and sex-matched controls. No significant differences
      were found between subject and controls in the percentages of micronuclei
      hybridizing with a centromere probe for the X chromosome or a painting probe for
      chromosome 3. However, the subject had a very highly significant increase
      (p<0.0001) in chromosome 2 in micronuclei over a level that might be expected to
      be present by chance. Characterization of micronuclei may be a promising tool in
      studies of mechanisms of inherited or induced chromosome instability. The
      strength of the strategy employed in this study is that, by characterizing the
      chromosomes present in micronuclei, this work has advanced from an observation of
      chromosomal instability to a foundation for study of the mechanism underlying the
      observation.

PMID- 10592323
TI  - 4-chloro-o-phenylenediamine induces a dose-related increase in G:C > T:A
      transversions and one major DNA adduct in the liver of Big Blue mice after 26
      weeks in feed treatment.
AB  - The monocyclic aromatic amine 4-chloro-o-phenylenediamine (4-C-o-PDA), a known
      mutagen and mouse hepatocarcinogen, was tested for its in vivo mutagenic
      potential in the Big Blue transgenic mouse assay system. Genomic DNA was isolated
      from liver tissue of control and treated animals and lacI mutants were recovered.
      In an initial 2-week study 4-C-o-PDA was administered daily per os to groups of
      male and female C57BL/6 Big Blue mice at doses of 0 and 200 mg/kg for 2 weeks (on
      working days) followed by a treatment free expression time of 10 days. Only a
      weak increase in the mutant frequencies in females was observed. In a 26-week
      study, where 4-C-o-PDA was given to groups of male and female Big Blue mice in
      feed at dietary concentrations of 0, 5,000 and 10,000 ppm, 4-C-o-PDA was found to
      induce a pronounced dose-dependent increase in mutant frequencies in either sex.
      In the present work, we analyzed the mutation spectrum by automated DNA
      sequencing of lacI mutants from both studies. Following the 2-week administration
      of 4-C-oT:A transversions in both sexes. In addition, upon 26-week treatment with
      4-C-o-PDA, one major DNA adduct was detected by 33P postlabelling and subsequent
      multidimensional thin layer chromatography. It is concluded that 4-C-oT:A
      transversions after 26 weeks in feed treatment. This result indicates that the
      sensitivity of the Big Blue transgenic assay system, in detecting a unique
      chemically induced mutation spectrum, is dependent on experimental parameters,
      such as treatment time. The data suggest that the formation of one major DNA
      adduct upon 4-C-o-PDA treatment may be critical for its mutagenicity.

PMID- 10592324
TI  - Codon 249 of the human TP53 tumor suppressor gene is no hot spot for aflatoxin B1
      in a heterologous background.
AB  - Mutations in the TP53 tumor suppressor gene are the most common alteration in
      cancer, and human primary liver cancers related to previous dietary exposure to
      the mycotoxin aflatoxin B1 (AFB1) exhibit a specific hot spot mutation at TP53
      codon 249. We have asked whether the 249 hot spot is related to a particular
      susceptibility to AFB1 of this TP53 region or whether it is related to a
      phenotype of the 249S p53 mutant protein. This was addressed by constructing a
      metabolically competent variant of Saccharomyces cerevisiae strain yIG397
      expressing human cytochrome P450 1A2 and P450-reductase and isolating AFB1
      induced mutants that failed to express the genomic ADE2 reporter gene. Molecular
      analysis revealed that only 8/40 mutants had a mutation in the TP53 target gene,
      whereas 32/40 mutants were due to a recombination event eliminating the ADE2
      reporter gene. None of 19 mutations identified in the eight mutant TP53 plasmids
      altered codon 249, thus this codon was no hot spot if the TP53 gene was in the
      heterologous background yeast. The genotoxic action of AFB1 was completely
      different from that of the alkylating agent ethyl-methane-sulfonate, where 28/30
      induced mutations were linked to the TP53 target gene.

PMID- 10592325
TI  - Radon, tobacco-specific nitrosamine and mutagenesis in mammalian cells.
AB  - The mutagenicity of 4-methylnitrosamine-1-3-pyridyl-1-butanone (NNK), either
      alone or in combination with low dose alpha particle irradiation, was examined
      using the human-hamster hybrid (A(L)) cell assay. NNK induced a dose-dependent
      toxicity in A(L) cells. In combination with a 25 cGy dose of alpha particles, the
      induced survival fraction fell within the statistical range of the calculated
      values assuming an additive interaction of the two agents. In addition, NNK is
      mutagenic in A(L) cells at the CD59 locus. Furthermore, a low dose of NNK, when
      combined with radon alpha particles, resulted in a combined mutagenic effect in
      A(L) cells that was consistent with an additive model but less than additive at
      higher NNK concentrations. The majority of NNK induced CD59(-) mutants (77.6%)
      lost at least one additional marker in addition to the CD59 which encodes the
      cell surface antigen. When combined with alpha particles, the proportion of
      mutants with additional marker loss increased with increasing dose of NNK. Our
      study further confirms that NNK is mutagenic in mammalian cells, induces mostly
      deletions, and provides an in vitro assessment of the combined genotoxic effects
      of NNK and alpha particles at low environmentally relevant doses. This finding
      should be helpful in understanding the molecular mechanism of the mutagenic
      process as a result of multi-agent interaction.

PMID- 10592326
TI  - Attenuation of bleomycin-induced Hprt mutant frequency in female and male rats by
      calorie restriction.
AB  - Calorie restriction modulates spontaneous and chemically induced tumors and
      increases maximal life span in experimental animals; however, the mechanism by
      which calorie restriction exerts its ameliorating effects is not fully
      elucidated, although reduced levels of reactive oxygen species (ROS) by calorie
      restriction has generated much interest. In the present study, we have determined
      whether or not calorie restriction would affect the mutagenic response in rats
      treated with bleomycin (BLM) a radiomimetic drug that is associated with DNA
      damage by a free radical mechanism. Fourteen weeks after weaning, the rats were
      divided into two groups; ad libitum (AL)-fed and 40% calorie restriction. Both AL
      and calorie-restricted animals were injected with 2.5, 5.0 and 10.0 mg BLM/kg, or
      with phosphate-buffered saline (PBS), and they were killed 4 weeks post drug
      treatment. Lymphocytes from the spleens were seeded in 96-well microtiter plates
      to determine mutant frequency in the hypoxantine guanine phosphoribosyl
      transferase (Hprt) gene. The mutant frequency in the BLM-treated rats was higher
      in AL males (P=0.001), and AL females (P=0.0174) than in their calorie-restricted
      counterparts. The difference in mutagenic response relative to AL males and AL
      females appeared unrelated to a low percent cloning efficiency seen in the males,
      since the mean absolute number of Hprt mutant clones was higher in the AL males
      compared to the females. A reduction in animal weight by calorie restriction was
      significant in both sexes (P<0.001), but the dose effect appeared non
      significant. The results indicate that calorie intake of 60% reduced the
      mutagenic response of BLM, a compound known to induce oxidative DNA damage, and
      suggest a possible decrease in ROS as a function of calorie restriction.

PMID- 10592327
TI  - Frameshift mutation, microsatellites and mismatch repair.
AB  - The structure of eukaryotic DNA, with its repeated sequences, makes base addition
      and loss a major obstacle to the maintenance of genetic stability. As compared to
      the bacteria, much of the mismatch repair capacity of the eukaryotic cell must be
      devoted to the surveillance of frameshift changes. Any alteration in the activity
      of proteins which recognize frameshifts or which hold the DNA in place during
      replication is likely to result in genomic instability.

PMID- 10592328
TI  - The MYC dualism in growth and death.
AB  - Over-expression of the transcription factor c-Myc immortalizes primary cells and
      transforms in co-operation with activated ras. Therefore, c-myc is considered a
      proto-oncogene. Since its discovery c-Myc has been shown to render cells growth
      factor independent, accelerates passage through G1 of the cell cycle, inhibits
      differentiation and elicits apoptosis. Whereas the effects on immortalization,
      proliferation and inhibition of differentiation are in conceivable accordance
      with gain of function, as it is defined for a proto-oncogene, its pro-apoptotic
      activity disables a straight forward explanation of the physiological role of c
      Myc and suggests a highly complex contribution during development. The recent
      accomplishments in c-Myc research shed some light on the difficile regulatory
      network which keeps check on c-Myc activity such as by binding to proteins some
      of which are transcription factors for non-c-Myc targets. Moreover, it was shown
      that genes are targeted by c-Myc depending on the sequence of flanking regions
      adjacent to the E-box or in dependence on the availability of binding partners
      which is most probably specific to the cellular context. Cdc25A and ornithine
      decarboxylase, both described to be c-Myc targets, have been brought forward as
      downstream effectors in the induction of proliferation under serum rich
      conditions, or in the induction of apoptosis when serum factors are limited.
      These genes seem to be regulated by c-Myc in a cell type-specific manner. H
      ferritin, IRP2 and telomerase are the most recently discovered direct targets of
      c-Myc. The regulation of H-ferritin and IRP2 might explain the potential of c-Myc
      to promote proliferation and the regulation of telomerase could be responsible
      for the immortalizing properties of c-Myc. In the future, H-ferritin and
      telomerase have to be analyzed whether or not these genes are also Myc targets in
      other cell systems. Although the intense research efforts regarding the function
      of c-Myc last already two decades the role of this gene is still enigmatic.

PMID- 10592330
TI  - The NF-kappaB/Rel family of transcription factors in oncogenic transformation and
      apoptosis.
AB  - Recent progress in the identification and functional analysis of protein kinases
      and adapter molecules that lead to activation of NF-kappaB family transcription
      factors has lead to a quite detailed understanding of one of the major signalling
      pathways that mediate a cell's response to environmental stress in a variety of
      host-defense situations. NF-kappaB is recognized as a key regulatory factor
      mediating the coordinate expression of genes which are part of the cellular
      machinery that functions to protect an organism against damage posed by physical,
      chemical or microbial noxae. In a wide variety of patho-physiological situations
      such as immune and inflammatory reactions, the expression of cytokines,
      interleukins and adhesion molecules in cells of the immune system including T and
      B cells, endothelial as well as phagocytic/antigen presenting cells is to a large
      extent regulated by NF-kappaB. Moreover, this transcription factor appears to
      play a central role in the regulation of apoptosis, an important cellular program
      that decides upon a cell's fate not only during embryonic development but also on
      its way from normal to the transformed phenotype. Thus, NF-kappaB has emerged
      also as an attractive target for therapeutic interference in a variety of
      pathological situations, including chronic inflammatory and autoimmune diseases,
      HIV infection and cancer.

PMID- 10592329
TI  - Post-transcriptional control via iron-responsive elements: the impact of
      aberrations in hereditary disease.
AB  - Tight regulation of iron metabolism is crucial to avoid formation of deleterious
      radicals and is mainly executed at the post-transcriptional level. The regulatory
      loops are exerted by trans-acting iron regulatory proteins (IRPs) and cis-acting
      stem-loop motifs, termed iron-responsive elements (IREs), located in the
      untranslated regions (UTRs) of target mRNAs. Iron scarcity induces binding of
      IRPs to a single IRE in the 5'-UTR of ferritin, eALAS, aconitase and SDHb mRNAs,
      which specifically suppresses translation initiation. Simultaneous interaction of
      IRPs with multiple IREs in the 3'-UTR of transferrin receptor (TfR) mRNA
      selectively causes its stabilization. The pattern is reverted under iron
      overload: IRP-mRNA binding affinity is reduced, which results in efficient
      protein synthesis of target transcripts harboring IREs in the 5'-UTR and rapid
      degradation of TfR mRNA. Although multiple evidences support this model, several
      studies reported massive alterations in the regulation of iron homeostasis under
      specific physiological conditions, raising the possibility for additional
      regulatory events. Intensive analysis of the palindromic IRE consensus sequence
      revealed the critical elements for the formation of a functional structure and
      demonstrated the consequences of IRE mutations in IRP binding. Recent
      investigations indicated the involvement of naturally occurring IRE mutations of
      the ferritin L subunit in the hyperferritinemia-cataract syndrome, a hereditary
      disorder. This review summarizes the apparent links between iron-dependent post
      transcriptional control and its abnormalities, governed by the properties of a
      single mRNA stem-loop structure.

PMID- 10592331
TI  - Organotypic culture system of chicken retina.
AB  - Analysis of developmental mechanisms during neuroembryogenesis, evaluation of
      toxicological effects and testing of neuroprotheses rely to an increasing extent
      on in vivo-like in vitro models. We have developed a novel organotypic culture
      system of the chick retina. Tissue slices of embryonic retinae were immobilized
      on glass coverslips by a fibrin clot and permanently rotated between the gas and
      medium phase, resulting in regular formation and the maintenance of the retinal
      cytoarchitecture. Selection of embryonic stage, slice thickness and specimen
      processing were optimized for culturing. Scanning electron microscopy revealed
      degradation during increasing culture periods of the fibrin clot, which was used
      for initial immobilization of explants on glass coverslips. Simultaneously,
      retinal cells became exposed on the tissue surface. Even after several weeks in
      vitro, formation and maintenance of plexiform and nuclear layers was evident as
      revealed by two specific monoclonal antibodies. Immunocytochemistry employing two
      additional photoreceptor- and radial Muller-antibodies indicated differentiation
      of neuronal and glial cells specific for the retina. The organotypic culture
      system promises to facilitate developmental studies of retinal development.
      Quantitative evaluation of Na(+)-channel blocker mexiletine impact on the
      histogenesis of retinal explants proved the organotypic culture system to be a
      valuable tool also for neurotoxicological investigations.

PMID- 10592332
TI  - A model of cochlear function assessment during reversible ischemia in the
      Mongolian gerbil.
AB  - An in vivo model in the Mongolian gerbil is used to assess the auditory changes
      during reversible cochlear ischemia. This model allows the recordings of cochlear
      potentials (microphonics, summating potential and compound action potential) and
      otoacoustic emissions (cubic difference tones, CDTs), together with laser Doppler
      cochlear blood flow (CBF) measurements, over reversible cochlear ischemia.
      Ischemia is achieved by compression of the eighth nerve complex at the porus of
      the internal acoustical meatus, whereas the compression release allows the
      reperfusion to occur. While CBF monitoring permits to objectively determine the
      degree of ischemia and reperfusion, the combined analysis of cochlear potentials
      and CDTs makes it possible to point out the preferential site of main functional
      damage within the cochlea, i.e., outer hair cells (OHCs), inner hair cells, or
      ganglia cells. At least three ischemia-reperfusion sequences can be used on one
      side, and sometimes both ears can serve for experiments. This model could be
      applicable for testing drugs with alleged protective effects against cochlear
      ischemia and/or reperfusion, in treated vs. non-treated animals.

PMID- 10592333
TI  - Detection of ecto-ATPase activity in synaptic plasma membranes for studying
      extracellular ATP-induced signal transduction.
AB  - This paper describes protocol for the correlated light and electron microscopical
      histochemical visualization of the reaction product of ecto-ATPase activity in
      brain. The protocol employs a biochemically optimized incubation medium to adjust
      the appropriate kinetical parameters for detection of the histochemical reaction
      product by means of confocal laser scanning and electron microscopy. The reaction
      product is formed when the liberated inorganic phosphate is captured in
      histochemical reaction by the cerium ions. Confocal microscopy is performed in
      reflectance mode due to sufficient reflectance properties of the cerium
      containing reaction product. Using this procedure, the prominent reaction of ecto
      ATPase activity is readily detectable in hippocampus and cerebellum at sites
      where ATP is supposed to act as a synaptic neurotransmitter: on synapses of
      neurons in the pyramidal cell layer of hippocampus, in the granule cell layer of
      the dentate gyrus, and around synapse-containing areas in the granule cell layer
      of cerebellum. Reaction product is seen in close association with both pre- and
      postsynaptic membranes and exclusively extracellularly. Specificity of the
      visualization is justified in control experiments with diethyl pyrocarbonate,
      specific inhibitor of ecto-ATPase. The procedure is easy to perform, sensitive,
      and reproducible. It is recommended as a valuable tool in the arsenal of
      biochemical, immunochemical, and physiological techniques in studying signal
      transduction induced by extracellular ATP.

PMID- 10592334
TI  - Detection of reactive oxygen species in primary cultures of cerebellar granule
      cells.
AB  - The aim of this work was to develop a novel procedure useful to detect the
      formation of two reactive oxygen species, i.e. superoxide and singlet oxygen, in
      neuron monolayer primary cultures, thus, making possible the investigation of the
      effect of certain compounds on reactive oxygen species formation. Thus, use was
      made of two reactive oxygen species detecting systems consisting of
      ferricytochrome c (Fe-cyt c) and imidazole-RNO (N, N-dimethyl-4-nitrosoaniline)
      which allow for the photometric detection of superoxide anion and singlet oxygen,
      respectively. Both of them were used to assess the formation of reactive oxygen
      species in cerebellar granule cells exposed to glutamate: both superoxide anion
      and singlet oxygen proved to be generated in glutamate neurotoxicity in a way
      sensitive to glutamate NMDA-receptor inhibitor, MK-801 ((+)-5-methyl-10,11
      dihydro-5H-dibenzo(a, d)cyclohepten-5,10-imine hydrogen maleate), to Ca(2+)
      complexing agent, EGTA, and to certain antioxidants. In principle, the reported
      protocol can be applied to any cell type in culture.

PMID- 10592335
TI  - A method for detection of a cytokine and its mRNA in the central nervous system
      of the developing rat.
AB  - We report here an effective and concise method to determine the localization of
      macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, and its
      mRNA in the central nervous system of pre- and postnatal rats. This method allows
      for double staining to demonstrate localization of different molecules on the
      same tissue specimen at the levels of mRNA and proteins by in situ hybridization
      and immunohistochemistry, respectively. Additionally, the present method gives
      results more quickly than the conventional isotopic techniques. By use of this
      method, we carried out immunohistochemistry with an anti-rat MIF polyclonal
      antibody and demonstrated positive staining using the avidin-biotin complex
      method (ABC method). To detect its mRNA, we performed nonradioactive in situ
      hybridization using a digoxigenin (DIG)-labeled RNA probe prepared from a full
      length fragment of rat MIF cDNA. MIF was strongly expressed in the telencephalon
      on embryonic day 16. Non-radioactive in situ hybridization with a DIG-labeled RNA
      probe as well as the immunohistochemistry described here could be applicable to
      characterize localization of mRNA and proteins of different molecules on the same
      tissue specimen.

PMID- 10592337
TI  - A novel method to determine the localization of high and low-affinity GABA
      transporters to the luminal and antiluminal membranes of brain capillary
      endothelial cells.
AB  - Some evidence has shown that the luminal plasma membrane and the antiluminal
      plasma membrane of the blood-brain barrier (BBB) are functionally distinct. This
      polarity permits brain capillary endothelial cells (BCECs) to actively regulate
      the internal milieu of the brain. Especially, polarity also exists concerning the
      transport of some endogenous substances such as amino acids and glucose. It is
      important to determine the luminal and antiluminal membrane localization of some
      transporters of endogenous substances, which will contribute to a better
      understanding of the transport mechanisms of the endogenous substances at the
      BBB. The present paper describes a novel procedure for combining isolated brain
      capillaries with primary cultured BCECs to determine the subcellular localization
      of some transporters, which is relatively simpler than the methods described
      previously. This method was used for the first time to determine successfully the
      luminal and antiluminal distribution of high and low-affinity GABA transporters.
      The low-affinity GABA transporter is probably localized to the luminal membrane
      of BCECs, and the high-affinity GABA transporter may be localized to the
      antiluminal membrane.

PMID- 10592336
TI  - Evaluation of free radical production, mitochondrial membrane potential and
      cytoplasmic calcium in mammalian neurons by flow cytometry.
AB  - The overexcitation of glutamate receptors is believed to be the cause of several
      neurodegenerative disorders. The determination of calcium fluxes, mitochondrial
      membrane potential (MMP) variations or the production of reactive oxygen species
      (ROS) in mammalian cells are usually measured during the development of
      potentially useful drugs that might interfere in the events induced by glutamate
      receptor activation. By using flow cytometry with dissociated cerebellar granule
      cells, we have developed a rapid and economical method to measure changes in
      biochemical parameters that are involved in neuronal cell death. The formation of
      intracellular ROS is measured using 2',7'-dichlorofluorescin diacetate (DCFH-DA).
      The mitochondrial membrane potential is assessed by the retention of rhodamine
      123 (Rh123), a specific fluorescent cationic dye that is readily sequestered by
      active mitochondria, depending on their transmembrane potential. Finally,
      intracellular calcium increases are detected by using the calcium-selective
      indicator Indo-1. Cell viability is also assessed by using propidium iodide (PI)
      which stains DNA strands of permeabilized cells. This method might be useful for
      the screening of new drugs with potential neuroprotective activity, with improved
      cost/effectiveness ratio compared to other techniques.

PMID- 10592338
TI  - Recovery of high-integrity mRNA from brains of rats killed by high-energy focused
      microwave irradiation.
AB  - Following decapitation, during the brief time period of postmortem brain tissue
      collection, significant changes in neuro-metabolite levels can occur. To
      circumvent such changes, we routinely kill rats using 1 to 2 sec pulses of
      focused high-energy microwave irradiation (10 kW). The effects of high-energy
      microwave irradiation on total RNA and mRNA integrity in brain however, are
      unknown. Total RNA recovery, per gram wet weight, in brain regions of microwaved
      rats was less than 50% of that in rats killed by decapitation. Formaldehyde
      agarose gel electrophoresis showed that ribosomal RNA components were highly
      degraded in all brain regions of microwaved rats. In contrast, poly A+mRNA, as
      measured by poly A+driven cDNA synthesis and Northern analysis, in brain samples
      of microwaved or decapitated rats was of equal integrity and quantity when
      expressed per mg tissue weight. Furthermore, positive RT-PCR products for GAPDH
      and TNF-alpha were observed in brain regions of both microwaved and decapitated
      rats. These observations indicated that high-energy focused microwave irradiation
      does not reduce mRNA abundance and integrity. Thus, this method of animal
      sacrifice can be used to simultaneously study, accurately and precisely, levels
      of brain metabolites as well as molecular biological events in discrete brain
      regions of experimental animals without postmortem interference.

PMID- 10592339
TI  - Long-term neural recording characteristics of wire microelectrode arrays
      implanted in cerebral cortex.
AB  - This paper describes a detailed protocol for obtaining chronic, multi-site unit
      recordings in cerebral cortex of awake animals for periods of three months or
      more. The protocol includes details for making relatively simple and inexpensive
      implantable multichannel electrodes that consist of arrays of separate
      microwires. The results reported in this paper suggest that a viable implant will
      have discriminable unit activity on about 80% of the electrodes, resulting in, on
      average, the simultaneous unit recording of upwards of 60 units during a daily
      recording session. The active electrodes during one recording session tend to
      remain active in subsequent recording sessions for several weeks. Using the
      methods described here, implants have been constructed which incorporate several
      different electrode materials, coatings, sizes, and electrode separation within a
      single array. These microwire electrode arrays provide the basic technology for
      obtaining unit recordings for several months. This provides a model system for
      studying biocompatibility of neural implants, which is a critical component for
      the development of neural implants that have an indefinite working span.

PMID- 10592340
TI  - Rapid assay for one-run determination of purine and pyrimidine nucleotide
      contents in neocortical slices and cell cultures.
AB  - The present study describes the measurement of endogenous nucleoside di- and
      triphosphate contents (ATP, GTP, UTP, CTP, ADP, GDP and UDP) in rat neocortical
      brain slices and mixed neuronal/astrocytic corticoencephalic cultures.
      Determination was by means of anion-exchange HPLC using a binary gradient of 0.3
      M ammonium carbonate and water. In addition, a new method is described for the
      identification of nucleoside triphosphates, using digestion of the nucleotides by
      phosphoglycerate kinase and partial splitting of nucleoside diphosphates to shift
      the equilibrium of the phosphoglycerate kinase reaction in direction of breakdown
      of nucleoside triphosphates. Finally, the determination of the sum of creatine
      and creatine phosphate is suggested as an alternative reference value instead of
      protein under conditions when cells are cultured in protein-containing medium.

PMID- 10592341
TI  - Application of the polymerase chain reaction to the RNase protection assay for 5
      HT(1B) receptor mRNA levels measurement in rat brain tissues.
AB  - The RNase protection assay (RPA) is an extremely sensitive procedure for
      detection of messenger RNA (mRNA) in complex sample mixture of total RNA.
      However, its usefulness has been limited by the requirement for the DNA to be
      cloned onto an appropriate vector. We have utilized the polymerase chain reaction
      (PCR) to directly incorporate a T7 RNA polymerase promoter sequence onto the cDNA
      for the 5-hydroxytryptamine(1B) (5-HT(1B)) receptor. Radiolabeled riboprobe was
      then synthesized using the PCR product as a template and used in RPA to detect
      mRNA for 5-HT(1B) receptor in rat brain. The internal control was the beta-Actin
      mRNA. Due to the simplicity of its design and the lack of need for subcloning,
      the DNA template synthesis by PCR facilitates the implementation of the RPA.
      Since the 5-HT(1B) receptors are the predominant auto- and heteroreceptors
      located on serotonergic and non-serotonergic terminals where they regulate the
      neuronal release of neurotransmitters and the protocol described here permits the
      determination of 5-HT(1B) receptor mRNA levels in the rat cerebellum, striatum,
      hippocampus and frontal cortex, this protocol is helpful in understanding the
      involvement of 5-HT(1B) receptors in various physiological phenomena.

PMID- 10592342
TI  - Quantitative investigation of mitochondrial function in single rat hippocampal
      slices: a novel application of high-resolution respirometry and laser-excited
      fluorescence spectroscopy.
AB  - Highly sensitive techniques are needed for the quantitative determination of
      mitochondrial oxidative phosphorylation function in single rat hippocampal slices
      or isolated hippocampal subfields. We determined the oxygen consumption of single
      hippocampal slices or subfields applying high-resolution respirometry adapted for
      slice measurements and measured the redox state of mitochondrial NAD(P)H in
      single hippocampal slices by laser-excited fluorimetry. These methods allow the
      sensitive detection of two parameters of mitochondrial oxidative phosphorylation
      which depend on supply of substrates and respiratory chain function.

PMID- 10592343
TI  - A rapid and efficient method for preparation of genomic DNA suitable for analysis
      of both high and low molecular weight DNA fragmentation during neuronal
      apoptosis.
AB  - In this paper, we describe a fast (within 1 h) and efficient method for the
      preparation of intact genomic DNA suitable for the analysis of DNA integrity in
      neuronal cells undergoing apoptosis. The procedure involves the embedding of
      apoptotic cells into low-melting point agarose, in situ cell lysis and
      purification of DNA samples followed by resolution of fragmented DNA by agarose
      gel electrophoresis. The method has no restrictions on the number of simultaneous
      DNA preparations, allows detection of both high and low molecular weight DNA
      fragments, and is suitable for the preparation of DNA samples from cultured
      cells, fresh or frozen tissues, as well as from purified nuclei. This procedure
      is also applicable for the preparation of intact genomic DNA for the megabase
      scale analysis.

PMID- 10592344
TI  - Quantitation of GABA transporter 3 (GAT3) mRNA in rat brain by competitive RT
      PCR.
AB  - Gamma-amino butyric acid is the major inhibitory neurotransmitter in the brain.
      GABA transporters (GATs) remove GABA from the synaptic cleft. Till now, five
      distinct GABA transporters have been cloned and termed consecutively GAT1 to GAT4
      and vGAT. To study the mechanisms by which tolerance and dependence associated
      with drugs enhancing GABAergic transmission is brought upon we analysed the mRNA
      expression levels of GATs in various brain regions under different conditions. In
      this paper, we describe our protocol for measurement of GAT3 mRNA expression, and
      its validation through control experiments for the various steps. We performed
      competitive reverse transcription and polymerase chain reaction (RT-PCR) with a
      competitor cRNA as internal standard. Different amounts of competitor cRNA were
      added to total RNA prepared from different tissue samples, reverse-transcribed
      and PCR amplified. The PCR amplification gave two products: the GAT wild type
      fragment and the competitor fragment. PCR products were separated by gel
      electrophoresis and band intensities were determined from which the relative and
      absolute abundance of GAT3 mRNA was calculated by regression analysis. Validation
      experiments in our laboratory showed a 6% intra-assay and a 15% inter-assay
      variability of this method.

PMID- 10592345
TI  - Anatomical and functional imaging of the auditory cortex in awake mustached bats
      using magnetic resonance technology.
AB  - The auditory cortex of mustached bats, Pteronotus parnellii, has been studied
      extensively using neuroanatomical tract-tracing and electrophysiological
      techniques to elucidate the functional organization and neural mechanisms
      important for auditory processing. While these techniques have identified several
      cortical maps involved in processing auditory information, there has been no
      direct observation of the dynamics of simultaneous activation of several discrete
      areas. We applied magnetic resonance (MR) imaging techniques for visualizing
      brain structures in awake bats using a 7-Tesla magnet system; we also
      investigated functional MR imaging by measuring changes in stimulus-correlated
      blood oxygenation levels to detect cortical areas exhibiting evoked neural
      activity. High resolution (100 microm) anatomical images were successfully
      acquired without any motion artifacts. It was possible to reconstruct the whole
      brain image and analyze brain surface structures with three dimensional (3D) MR
      imaging data. These data provide detailed morphometric measurements that will
      allow localization of stimulus specific neural activity patterns using modified
      functional magnetic-resonance-imaging (fMRI) protocols. Motion artifacts is the
      primary disadvantage of using awake bats; our study shows that fMRI of a bat's
      brain is feasible and may prove to be an important advancement for a further
      understanding of auditory processing in this species.Themes: Sensory systems,
      Neural basis of behavior.

PMID- 10592346
TI  - A global hypoxia preconditioning model: neuroprotection against seizure-induced
      specific gravity changes (edema) and brain damage in rats.
AB  - Hypoxia preconditioning states that a sublethal hypoxia episode will afford
      neuroprotection against a second challenge in the near future. We describe and
      discuss a procedure for the development of global hypoxia preconditioning in
      adult male Wistar rats, using a mildly hypoxic (9% O(2), 91% N(2)) atmospheric
      exposure of 8 h. The persistence of neuroprotection was analyzed using a kainic
      acid (KA) model of brain injury. Rats were challenged with KA (14 mg/kg, i.p.) on
      1-14 days post-hypoxia. The effects of hypoxia preconditioning on seizure score,
      weight loss, brain edema and histopathology were assessed. Brain edema,
      predominantly of vasogenic origin, was measured 24 h after KA administration
      using a reproducible and quantitative method based on the specific gravities of
      tissue samples. A density gradient column (1.0250-1.0650 g/cm(3)) comprised of
      kerosene and bromobenzene was used to assess the presence of edema in regions
      involved in seizure initiation and propagation that are normally extensively
      damaged (i.e., piriform cortex and hippocampus). Specific gravities of tissues
      were calculated through extrapolation with known NaCl standards. We found that
      hypoxia preconditioning prevented the formation of edema in these brain regions
      when KA challenge was given 1, 3, and 7, but not 14 days post-hypoxia exposure.
      Furthermore, neuroprotection was observed in animals that had robust seizures.
      The described procedure may be used to examine the neuroprotective mechanisms
      induced by global hypoxia preconditioning against many subsequent challenges
      reflecting a variety of experimental models of brain injury, and will provide a
      better understanding of the brain response to hypoxia and stress.

PMID- 10592347
TI  - Detection of mRNA species in bulbospinal neurons isolated from the rostral
      ventrolateral medulla using single-cell RT-PCR.
AB  - The rostral ventrolateral medulla (RVL) contains neurons which are critically
      involved in the tonic and reflex control of blood pressure. Some of these neurons
      project to the intermediolateral cell column of the thoracolumbar spinal cord and
      excite preganglionic sympathetic neurons. In order to gain a better understanding
      of the properties of the RVL neurons at the cellular and molecular level, a
      protocol was developed utilizing acute dissociation and the reverse transcription
      polymerase chain reaction (RT-PCR) to study the expression of several genes in
      single RVL neurons. Neurons were dissociated from the RVL region of young rats,
      and classified as spinally projecting or non-spinal by the presence or absence of
      retrogradely transported fluorescent beads injected into the upper thoracic
      segments of the spinal cord. Individual neurons were collected by aspiration into
      a glass micropipette and analysed by RT-PCR. The presence of either
      glyceraldehyde 3-phosphate dehydrogenase (GAPDH) or neuron-specific enolase (NSE)
      mRNA was used as the criterion for selecting cells for further analysis. A
      subpopulation (50%) of spinally projecting, GAPDH- or NSE-positive neurons
      expressed mRNA for tyrosine hydroxylase (TH) or phenylethanolamine N
      methyltransferase (PNMT), indicative of catecholaminergic or C1 adrenergic
      neurons, respectively. Some bulbospinal RVL neurons, including those that were TH
      or PNMT-positive, were also found to express mRNA for the mineralocorticoid
      receptor (MR), the glucocorticoid receptor (GR), noradrenaline transporter (NET),
      and neuronal glutamate transporter (EAAC1). The glial glutamate transporter
      (GLT), glycine transporter (GLYT2), glutamic acid decarboxylase (GAD67) and gamma
      amino butyric acid (GABA) transporter (GAT-1) were not expressed. The single-cell
      RT-PCR protocol is a powerful, yet simple and relatively rapid method for
      analysis of mRNA expression in a defined neuronal population. It can be combined
      with whole-cell patch-clamp recording prior to RT-PCR analysis, allowing linkage
      of the molecular analysis of mRNA expression to the electrophysiological and
      pharmacological properties of single neurons. The method is very sensitive,
      enabling mRNA transcripts in low abundance to be detected, and its application in
      our recent studies provided novel information about neurons involved in blood
      pressure regulation at the molecular and cellular level.

PMID- 10592348
TI  - Neurochemical determination of the location of NMDA and GABA receptors on rat
      striatal cholinergic neurons.
AB  - This paper reports on the protocol for neurochemical determination of the
      location of various receptors on cholinergic neurons in various brain regions. We
      applied this protocol to investigate whether NMDA and GABA receptors are located
      on rat striatal cholinergic neurons. When striatal cholinergic neurons were
      selectively destroyed by intrastriatal injection of cholinergic neurotoxin,
      ethylcholine mustard aziridinium ion (AF64A), the number of NMDA and GABA(A)
      receptors decreased. However, no significant changes were observed on the number
      of GABA(B) receptors. These results suggest that NMDA and GABA(A), but not
      GABA(B) receptors are located on cholinergic neurons in the striatum. These
      results also indicate the usefulness and scientific applicability of the present
      protocol.

PMID- 10592349
TI  - The in vivo minigene approach to analyze tissue-specific splicing.
AB  - The exact mechanisms leading to alternative splice site selection are still
      poorly understood. However, recently cotransfection studies in eukaryotic cells
      were successfully used to decipher contributions of RNA elements (cis-factors),
      their interacting protein components (trans-factors) or the cell type to
      alternative pre-mRNA splicing. Splice factors often work in a concentration
      dependent manner, resulting in a gradual change of alternative splicing patterns
      of a minigene when the amount of a trans-acting protein is increased by
      cotransfections. Here, we give a detailed description of this technique that
      allows analysis of large gene fragments (up to 10-12 kb) under in vivo condition.
      Furthermore, we provide a summary of 44 genes currently investigated to
      demonstrate the general feasibility of this technique.

PMID- 10592350
TI  - Multiplex semi-quantitative reverse transcriptase-polymerase chain reaction of
      low abundance neuronal mRNAs.
AB  - The sequential use of reverse transcriptase and the polymerase chain reaction (RT
      PCR) has provided molecular biology research with an exquisitely sensitive and
      fast technique for studying gene expression. This method is particularly useful
      to study transcripts in the nervous system, which are on average present at low
      levels and the amount of tissue or cells to be analyzed is often limited. Here,
      we describe a RT-PCR assay which allows the simultaneous detection and semi
      quantitation of several transcripts (multiplex). Multiple PCR primer pairs are
      used to detect different target transcripts in a single reaction, together with a
      pair of primers able to amplify the hypoxantine-phosphoribosyl-transferase
      (HPRT), a gene constitutively expressed at low levels throughout the nervous
      system. HPRT levels remain constant also during neurogenesis and it is thus apt
      to be used in developmental neurobiology. This internal standard is the mRNA of
      reference to evaluate sample variation in RT and PCR reactions and to monitor the
      degradation and recovery of RNAs. Normalization with respect to HPRT cDNA allows
      to estimate the relative abundance of each target mRNA.

PMID- 10592351
TI  - Quantification of neurotrophin-3 mRNA in the rat hippocampal subregions using the
      RT-PCR-based coamplification method.
AB  - Quantitative reverse transcription-polymerase chain reaction (RT-PCR) is a
      suitable method for determining the expression levels of rare mRNAs in small
      amounts of tissue. To compare the mRNA expression levels across specific brain
      regions, we adopted an RT-PCR method in which a target gene was coamplified with
      an endogenous internal standard gene in single reaction tubes. Use of the
      endogenous internal standard can control fluctuations in target quantification
      resulting from various factors, including tube-to-tube variation in amplification
      efficiency and variation in mRNA content among the total RNAs prepared from
      different tissues. In this study, we quantitatively determined the mRNA
      expression levels for NT-3, a member of the neurotrophin family of growth
      factors, in the hippocampal subregions: the entorhinal cortex, dentate gyrus and
      CA1. NT-3 gene was simultaneously coamplified with an endogenous internal
      standard gene, hypoxanthine-guanine phosphoribosyltransferase (HPRT), in the same
      reaction tube. Using this RT-PCR coamplification method, we detected a regional
      difference in the NT-3 mRNA expression levels across the hippocampal subregions.
      Our method can serve as a useful quantification method to investigate molecular
      signaling cascades in a specific cortical region.

PMID- 10592352
TI  - Measurement of total nitric oxide metabolite (NO(x)(-)) levels in vivo.
AB  - The measurement of the total level of nitric oxide (NO) metabolite (NO(x)(-)) by
      microdialysis has recently been used to assess the production of NO in the in
      vivo brain [D. Luo, S. Knezevich, S.R. Vincent, N-Methyl-D-aspartate-induced
      nitric oxide release: an in vivo microdialysis study, Neuroscience, 57 (1993),
      897-900; K. Ohta, N. Arai, M. Shibata, J. Hamada, S. Komatsumoto, K. Shimazu, Y.
      Fukuuchi, A novel in vivo system for consecutive measurement of brain nitric
      oxide production combined with the microdialysis technique, Neurosci. Lett., 176
      (1994), 165-168; K. Shintani, S. Kanba, T. Nakai, K. Sato, G. Yagi, R. Kato, M.
      Arai, Measurement by in vivo microdialysis of nitric oxide release in the rat
      cerebellum, J. Psychiatr. Neurosci., 3 (1994), 217-221; H. Togashi, K. Mori, K.
      Ueno, M. Matsumoto, N. Suda, H. Saito, M. Yoshika, Consecutive evaluation of
      nitric oxide production after transient cerebral ischemia in the rat hippocampus
      using in vivo brain microdialysis, Neurosci. Lett., 240 (1998), 53-57]. Although
      several methods are available for detecting NO(x)(-) levels in dialysates, these
      methods are either not sensitive enough or require expensive experimental
      equipment. The method described herein provides a convenient and sensitive
      procedure for determining NO(x)(-) levels in dialysates. This method is useful
      for the in vivo study of NO production from various brain regions in various
      pathological conditions, and can be applied to other tissues.

PMID- 10592353
TI  - A method for the determination of activated receptor phosphorylation state
      following in vivo drug treatment.
AB  - Reversible phosphorylation events can alter many critical cellular functions and
      has been hypothesized to play a role in the development of tolerance to
      chronically administered agonists. The technique described here was developed to
      assess the phosphorylation state of mu-opioid receptor protein isolated from
      rodent brain tissue following 4 days of continual, subcutaneously released
      morphine. We have adapted and combined two techniques: back-phosphorylation
      reactions, which make use of tissue from animal models, and phosphorylation
      followed by immunoprecipitation, an approach used in cell culture models. mu
      receptor protein is precipitated using a receptor-specific antibody, and the
      protein phosphorylation state is preserved by the use of phosphatase inhibitors.
      Phosphorylation sites that are dephosphorylated on the isolated protein are then
      radiolabelled by the addition of purified cAMP-dependent protein kinase (PKA)
      catalytic subunit and [32P]ATP. The samples are separated by gel electrophoresis,
      and the resulting bands are quantified using a phosphoimager. The amount of 32P
      incorporated into the protein is assumed to be inversely related to the degree of
      phosphorylation prior to the reaction (i.e., the in vivo state of the protein).
      These estimates of micro-opioid receptor phosphorylation can then be correlated
      with a behavioral endpoint such as antinociception, to better understand the role
      of phosphorylation events in tolerance development.

PMID- 10592355
TI  - Prescription of twice-weekly hemodialysis in the USA.
AB  - BACKGROUND/AIMS: The purpose of this study was to investigate the frequency and
      characteristics of two hemodialysis sessions/week, to identify factors which
      influence or predict this prescription, and to examine the outcomes of patients
      receiving hemodialysis two times/week as compared to the more common treatment of
      three times/week. METHODS: Data from a national sample of 15,067 adult
      hemodialysis patients were utilized to compare twice-weekly with thrice-weekly
      therapy by logistic regression. RESULTS: Patients treated less than one year were
      more likely to be treated twice-weekly (6.1%) than patients on dialysis for one
      year or more (2.7%) (AOR = 1.49, p = 0.002). Treatment schedules also varied
      significantly by geographic region. Factors predictive of twice-weekly
      hemodialysis (p < 0.05) were older age, Caucasian race, female gender, higher
      serum albumin, lower serum creatinine levels, and lower body mass index. A higher
      estimated renal function at the start of ESRD was also predictive of a twice
      weekly schedule among incident patients (AOR = 1.05, p = 0.05). In addition, Cox
      adjusted survival analysis indicated a lower mortality risk (RR = 0.76, p = 0.
      02) for twice-weekly hemodialysis compared to thrice-weekly among prevalent
      patients. For incident patients, however, the results were not significant when
      adjusted for GFR at ESRD onset (RR = 0.85, p = 0.31). CONCLUSION: Geographic
      differences in prescribed treatment remained unexplained by measured
      characteristics. The survival advantage associated with twice-weekly hemodialysis
      is likely to be related to patient selection and greater residual renal function.

PMID- 10592354
TI  - Organotypic slice cultures for analysis of proliferation, cell death, and
      migration in the embryonic neocortex.
AB  - Dynamic cellular interactions during neocortical neurogenesis are critical for
      proper cortical development, providing both trophic and tropic support. Although
      cell proliferation and programmed cell death have been characterized in
      dissociated primary cell cultures, many in vivo processes during cortical
      neurogenesis depend on cell-cell interactions and therefore on the three
      dimensional environment of the proliferating neuroblasts and their progeny. Here
      we describe a murine organotypic neocortical slice preparation that retains major
      morphological and functional in vivo characteristics of the developing neocortex
      and is viable (exhibits very low levels of cell death) for up to three days.
      Moreover, this slice preparation is amenable to direct experimental manipulation
      of potential diffusible regulators of neurogenesis. Using a variety of
      biochemical and physiological methods including time-lapse and quantitative
      confocal microscopy, we demonstrate that this system can be used effectively to
      investigate cellular mechanisms important for brain growth and maturation,
      including neurogenesis, apoptosis, and neuronal migration.

PMID- 10592356
TI  - Predicting factors of long-term results of OKT3 therapy for steroid resistant
      acute rejection following cadaveric renal transplantation.
AB  - In this retrospective study, we evaluated the histological and biological
      predictors of long-term response of renal transplant (RT) patients treated with
      orthoclone OKT3 for steroid resistant acute rejection (AR). Seventy-three
      patients, aged 37 +/- 12 years, were included in this study between March 1987
      and December 1996. All the patients but one had received sequential quadruple
      immunosuppression (polyclonal antilymphocyte globulins; steroids; azathioprine,
      and cyclosporin A). OKT3 (5 mg/day for 10 days) was administered for biopsy
      proven steroid resistant AR i.e., after 3 consecutive pulses of
      methylprednisolone (10 mg/kg each). This was the first AR in 46 cases, the second
      AR in 22 cases and the third AR in 4 cases. Renal histology (Banff) showed
      borderline (BL) changes in 18 patients, grade I AR in 28 patients; grade II AR in
      22 patients, and grade III AR in 5 patients. When treatment with OKT3 commenced
      (107 +/- 18 days post-transplantation) the mean serum creatinine (SCr) level was
      325 +/- 195 micromol/l; this had decreased to 191 +/- 106 micromol/l by the end
      of OKT3 therapy. The immediate response to OKT3 therapy i. e., within the first
      month, was not dependent on the histological score. Twenty-six patients (35%)
      subsequently experienced at least one more AR episode of whom 4 were retreated
      with OKT3. The overall patient's survival was 94.5% at last follow-up. The
      overall cumulative graft survival was 64.5% at 2 years, 52.5% at 5 years, and
      40.5% at 8 years. The graft survival (5 years) tended to depend on the initial
      histological score, i.e. BL 30%; grade I 66%; grades II and III 55.5% (p = 0.08).
      In a multiple logistic regression analysis we tried to identify independent
      factors that would predict that a graft would still be functioning at least 2
      years after OKT3 therapy. We therefore analyzed the following parameters: donor
      and recipient's age; gender; cold ischemia time; HLA matching; panel reactive
      antibodies (PRA) prior to grafting; previous transplantation(s); total number of
      AR episodes; the time of onset of the AR treated by OKT3 compared to the other
      AR; the time of onset of the AR treated by OKT3; SCr levels at days 0, 10 and 30
      after OKT3 therapy; histological score (Banff) i.e., the magnitude of AR and the
      presence or absence of chronic lesions. The only independent factors which would
      predict that a graft was still functioning 2 years after OKT3 therapy were: PRA
      <25% (Odds ratio (OR) 7.68 (1.15-51.3); p = 0.035); a grade I AR (OR 10.52 (1.18
      93. 5); p = 0.035); SCr level 1 month after OKT3 therapy (OR 0.935 (0. 87-1.002);
      p = 0.05). HLA matching and the presence of histological chronic lesions were
      nearly significant (p = 0.06 and 0.09 respectively). In conclusion, this
      retrospective study shows that independent predictors of the long-term response
      to OKT3 therapy for AR in RT patients are the magnitude of pre-transplant PRA,
      the histological score, and the SCr level one month after OKT3 therapy.

PMID- 10592357
TI  - Association of dialyzer reuse and hospitalization rates among hemodialysis
      patients in the US.
AB  - OBJECTIVES: To determine if reuse of hemodialyzers is associated with higher
      rates of hospitalization and their resulting costs among end-stage renal disease
      (ESRD) patients. METHODS: Noncurrent cohort study of hospitalization rates among
      27,264 ESRD patients beginning hemodialysis in the United States in 1986 and
      1987. RESULTS: Dialysis in free-standing facilities reprocessing dialyzers was
      associated with a greater rate of hospitalization than in facilities not
      reprocessing (relative rate (RR) = 1.08, 95% confidence interval (CI), 1.02
      1.14). This higher rate of hospitalization was observed with dialyzer reuse using
      peracetic/acetic acids (RR = 1.11, CI 1. 04-1.18) and formaldehyde (RR = 1.07, CI
      1.00-1.14), but not glutaraldehyde (p = 0.97). There was no difference among
      hospitalization rates in hospital-based facilities reprocessing dialyzers with
      any sterilant and those not reprocessing. Hospitalization for causes other than
      vascular access morbidity in free-standing facilities reusing dialyzers with
      formaldehyde was not different from hospitalization in facilities not reusing.
      However, reuse with peracetic/acetic acids was associated with higher rates of
      hospitalization than formaldehyde (RR = 1.08, CI 1.03-1.15). CONCLUSIONS:
      Dialysis in free-standing facilities reprocessing dialyzers with peracetic/acetic
      acids or formaldehyde was associated with greater hospitalization than dialysis
      without dialyzer reprocessing. This greater hospitalization accounts for a large
      increment in inpatient stays in the USA. These findings raise important concerns
      about potentially avoidable morbidity among hemodialysis patients.

PMID- 10592358
TI  - Hyperfibrinogenemia is an independent risk factor for atherosclerotic renal
      artery stenosis.
AB  - It is important to identify patients at risk for atherosclerotic renal artery
      stenosis because renal artery stenosis is a progressive disease and a potentially
      correctable problem. To determine the risk factors for atherosclerotic renal
      artery stenosis, we performed renal arteriography at the time of cardiac
      catheterization in 270 patients (M:F, 193:77, mean age: 59 years) with clinical
      ischemic heart disease. Before the procedure, demographic data, medical history,
      physical findings and laboratory data were obtained. The degree of coronary
      artery stenosis and renal artery stenosis was quantified with automatic edge
      detection technique. Significant renal artery stenosis, defined as a narrowing of
      the diameter by more than 50%, was identified in 28 (10%) patients. Three
      patients (1%) had bilateral disease. Significant coronary artery disease, defined
      as a narrowing of the diameter by more than 50%, was present in 231 patients
      (85%). By univariate logistic regression analysis, older age (68 +/- 8 vs. 58 +/-
      10 years), the presence of hypertension (61% vs. 38%), the extent of coronary
      artery disease, a high fibrinogen level (391 +/- 93 mg/dl vs. 335 +/- 109 mg/dl),
      a low albumin level (3.9 +/- 0.4 g/dl vs. 4.1 +/- 0.4 g/dl), and a low hemoglobin
      level (12.5 +/- 1.6 g/dl vs. 13.5 +/- 1.6 g/dl) were associated with the presence
      of renal artery stenosis (p < 0.05). Serum lipids, lipoprotein(a), creatinine,
      sex, smoking, or diabetes were not associated. By multivariate logistic
      regression analysis, older age (OR: 2.43 analyzed by 10 years increment, p =
      0.0001), the presence of hypertension (OR: 2.68, p = 0.039) and a higher
      fibrinogen level (OR: 1.63 analyzed by 100 mg/dl increment, p = 0. 038) were
      significant risk factors of renal artery stenosis. Fibrinogen level was
      negatively correlated with albumin level (r = -0.18, p = 0.004). These results
      suggest that hyperfibrinogenemia as well as old age and hypertension are
      independent risk factors for atherosclerotic renal artery stenosis.

PMID- 10592359
TI  - Is the prevalence of HIV-associated nephropathy decreasing?
AB  - Initial reports have suggested that approximately 10% of patients with HIV
      infection develop HIV-associated nephropathy (HIVAN). It has also been predicted
      that by the end of the decade, HIVAN is likely to become a third leading cause of
      end-stage renal disease (ESRD) in African-Americans between the ages of 20-64
      years. As the morbidity and mortality from HIV-infection has decreased in the
      last few years, it is possible that prevalence of HIVAN is also changing. We
      therefore screened HIV-1-infected patients followed in our hospital for HIVAN. A
      screening urinalysis was performed in 557 HIV-1-infected adult patients between
      March and May 1998. Of these, 252 were outpatients and 305 were Texas Department
      of Criminal Justice inmates (TDCJI). Demographic and laboratory data of these
      patients was obtained from the HIV patients' database. Fifty percent of the
      patients were African-American, 36.6% were Caucasian and 12. 7% were Hispanic.
      The mean age of patients was 37 +/- 8 years. Seventy-nine percent of the patients
      were males and a history of intravenous drug abuse (IVDA) was present in 28%.
      Twenty-three percent of the patients were concomitantly infected with hepatitis C
      virus, 4.1% were positive for hepatitis B surface antigen, and rapid plasma
      reagin test for syphilis was positive in 9.1%. In 38 patients who had more than
      100 mg/dl (2+) proteins on screening urinalysis, total urinary proteins were
      quantitated by collecting 24 h urine specimens. Fifteen of these patients had
      urinary proteins more than 1.5 g/day (12 patients >3.5 g/24 h and 3 patients >1.5
      g/24 h). A renal biopsy was done in 14 of these patients and clinical diagnosis
      of HIVAN was made in one patient who refused biopsy. Renal biopsies revealed
      HIVAN [9], diabetic nephropathy [2], membranoproliferative glomerulonephritis
      [2], Fibrillary glomerulonephritis [1]. All 10 patients (5 TDCJI and 5
      outpatients) with HIVAN were African-American. Two of these 10 patients had a
      history of IVDA and another two were concomitantly infected with hepatitis C
      virus. The plasma viral load (Pvl) and total CD4 count was not different in
      patients with or without HIVAN [(Pvl log 10.05 +/- 1.39 vs. 9.9 +/- 2.18
      copies/ml, p = 0.78) (CD4: 187 +/- 192 vs. 288 +/- 249 cells/microl, p = 1.17)
      mean +/- SD]. We conclude that in our HIV-infected population HIVAN exclusively
      affected African-Americans and the prevalence in them was 3.5%.

PMID- 10592360
TI  - Seasonal blood pressure and body weight variation in patients on chronic
      hemodialysis.
AB  - AIM: The relation of ambient temperature (AMT) and relative humidity to systolic
      blood pressure (SBP), diastolic blood pressure (DBP), body weight (BW), and body
      weight gain between dialysis sessions (DeltaBW) was examined in hemodialysis
      patients by Fourier analysis. METHODS AND RESULTS: The authors recruited 144
      dialysis patients from a hemodialysis center in Okinawa, Japan where there is
      distinct seasonal variation in monthly AMT but a constant intradiurnal
      temperature change throughout the year. All patients had been undergoing chronic
      and regular hemodialysis three times per week. SBP, DBP, and BW before dialysis
      sessions and DeltaBW were recorded in 1994. Mean monthly Okinawa AMT in 1994 was
      highest in August and lowest in February and March, and the mean monthly relative
      humidity in 1994 was highest in June and lowest in January. Mean SBP and DBP were
      lowest in August and June respectively, and greatest in December. BW was lowest
      in July and September, and greatest in February and March; DeltaBW was lowest in
      July and greatest in January. These seasonal patterns were well reproduced by the
      first Fourier component. The cross-correlation coefficient showed that monthly
      mean AMT and SBP, DBP, BW, and DeltaBW were correlated with a lag time of 5 or 6
      months. The cross correlation coefficient showed that relative humidity and SBP,
      DBP and DeltaBW were also correlated with a 6-month lag time. In analyzing
      subgroups of patients according to the presence or absence of antihypertensive
      medications, a seasonal change was observed in the SBP and DBP of patients not
      being treated with antihypertensives, and in the DBP of patients taking
      antihypertensive medications, but not in the SBP of patients taking
      antihypertensive medications. CONCLUSION: Seasonal variations in SBP, DBP, BW and
      DeltaBW were evident. AMT and the relative humidity correlated strongly with SBP,
      DBP, BW and DeltaBW. The clinical implications of these findings in hemodialysis
      patients warrant further investigation.

PMID- 10592361
TI  - Urea kinetics with dialyzer reuse--a prospective study.
AB  - We performed a prospective study to examine the impact of dialyzer reuse on KT/V
      under rigidly standardized conditions on 3 membrane types. Heparin dosage was
      standardized with ACT during an eight week run-in period and remained unchanged
      through the study. Post dialysis BUN and weight were obtained at five minutes
      after exactly 80 +/- 0.5 l of blood were processed through the dialyzer.
      Dialyzers were reused after automated glutaraldehyde processing and after
      ensuring >80% open fiber bundles. Each membrane type was utilized 3 times on a
      set of 3 patients; each individual dialyzer was reused 8 times. KT/V was done on
      the 1st, 2nd, 4th and 8th uses of each dialyzer (36 measurements) starting mid
      week; BUN measurements were grouped. The KT/V (mean +/- SD) for the 1st, 2nd,
      4th, and 8th uses of the cellulose acetate dialyzer were 1.3 +/- 0.2, 1.3 +/-
      0.3, 1.3 +/- 0.2, 1.3 +/- 0.2 respectively; the corresponding values of the
      cuprophane dialyzer were 1.4 +/- 0.3, 1.4 +/- 0.3, 1.3 +/- 0.4, 1.3 +/- 0.3
      respectively; and those of the polysulfone dialyzer 1.7 +/- 0.3, 1.6 +/- 0.2, 1.6
      +/- 0.2 respectively. By a 3 way ANOVA there were no significant differences
      between the 1st and subsequent uses of any of the dialyzers tested. CONCLUSIONS:
      Reuse of dialyzers up to 8 times does not result in a loss of urea clearance. We
      believe this model is useful for further studies on reuse and quality assurance.

PMID- 10592362
TI  - Ehrlichia chaffeensis in a renal transplant recipient.
AB  - Since its first description in human beings in 1986, ehrlichiosis is now
      increasingly recognized as a cause of tick-borne febrile illnesses. However, the
      disease has been reported only rarely in immunosuppressed patients. We report a
      case of human ehrlichiosis in a patient with a cadaveric renal transplant. The
      diagnosis was confirmed initially by a positive polymerase chain reaction (PCR)
      for E. chaffeensis. The antibody titer became positive several weeks later. The
      patient responded promptly to treatment with doxycycline. Ehrlichiosis should be
      considered in the differential diagnosis of an acute febrile illness in
      transplant recipients. PCR provides a rapid means to confirm the diagnosis,
      particularly in settings in which antibody response may be suppressed.

PMID- 10592363
TI  - Human granulocytic ehrlichiosis presenting with acute renal failure and mimicking
      thrombotic thrombocytopenic purpura. A case report and review.
AB  - We present the case of an elderly female patient presenting with recurrent acute
      renal failure, fever, altered mental status, abdominal pain, thrombocytopenia and
      a small number of fragmented red cells on peripheral smear mimicking recurrent
      thrombotic thrombocytopenic purpura (TTP). Eventually, however, she was diagnosed
      to have human granulocytic ehrlichiosis (HGE), and after treatment for HGE her
      clinical and laboratory abnormalities resolved. Ehrlichiosis mimicking TTP,
      diagnosed at postmortem examination, has been described in a single prior case.
      As illustrated in this case, there are potential difficulties in diagnosing HGE
      after plasma exchange, blood transfusion and immunosuppressive therapy.
      Ehrlichiosis, a potentially curable disease, should be considered in the
      differential diagnosis of thrombotic microangiopathic disorders.

PMID- 10592364
TI  - Outcome of an opportunistic infection after polymicrobial peritonitis in an HIV
      infected patient treated with peritoneal dialysis.
AB  - The prevalence of human immuodeficiency virus (HIV)-infected patients with end
      stage renal disease (ESRD) is likely to increase and many of them will be on
      peritoneal dialysis as renal replacement therapy. Infectious complications are a
      major problem associated with peritoneal dialysis (PD). It has been speculated
      that the HIV-positive peritoneal dialysis population may develop peritonitis more
      frequently than other peritoneal dialysis patients. We present the complications
      and unexpected good response to medical management of PD-associated peritonitis
      in a young HIV-infected black male. He had two unusual and serious infections;
      the first was a polymicrobial peritonitis which predisposed the patient to an
      unusual infection caused by Corynebacteria JK for which he was successfully
      treated without catheter removal.

PMID- 10592365
TI  - High-resolution ultrastructural comparison of renal glomerular and tubular
      basement membranes.
AB  - BACKGROUND/AIMS: Glomerular basement membranes (GBM) and tubular basement
      membranes (TBM) consist of a fine meshwork composed mainly of type IV collagen.
      Each segment of tubules has specialized physiologic functions, and thus we
      investigated the ultrastructure of various basement membranes in rat kidneys.
      METHODS: Since purifying basement membranes from different tubule segments is
      technically challenging, we employed tissue negative staining rather than
      conventional negative staining to compare the ultrastructures of proximal and
      distal TBM and GBM in normal rats. We also assessed the distribution of
      extracellular matrix components including type IV collagen, laminin, heparan
      sulfate proteoglycan, and fibronectin in the basement membranes by
      immunohistochemistry. RESULTS: TBM and GBM of normal rats showed a fine meshwork
      structure consisting of fibrils forming small round to oval pores. Short- and
      long-pore diameters in proximal tubules were 3.3 +/- 0.5 and 3.9 +/- 0.6 nm,
      respectively, and in distal tubules 3.5 +/- 0.7 and 4.3 +/- 0.8 nm, respectively.
      For GBM the respective diameters were 2.5 +/- 0.5 and 3.0 +/- 0.5 nm.
      Immunohistochemical analysis showed no significant difference in distribution of
      extracellular matrix components between proximal and distal TBM. However,
      immunofluorescence scores of alpha1 chain of type IV collagen, fibronectin, and
      laminin were higher in the TBM than in the GBM. On the other hand, heparan
      sulfate proteoglycan was higher in the GBM. CONCLUSION: Ultrastructural
      differences in renal basement membranes may be related to differences in
      physiologic function in each segment.

PMID- 10592366
TI  - Renal myofibroblasts contract collagen I matrix lattices in vitro.
AB  - Myofibroblasts, cells with both fibroblastic and smooth muscle cell features,
      have been implicated in renal scarring. In addition to synthetic properties,
      contractile features and integrin expression may allow myofibroblasts to
      rearrange and contract interstitial collagenous proteins. Myofibroblasts from
      normal rat kidneys were grown in cell-populated collagen lattices to measure cell
      generated contraction. Following detachment of cell populated collagen lattices,
      myofibroblasts progressively contracted collagen lattices, reducing lattice
      diameter by 42% at 24 h. Alignment of myofibroblasts, rearrangement of fibrils
      and beta(1) integrin expression were observed within lattices. We postulate that
      interstitial myofibroblasts contribute to renal scarring through manipulation of
      collagenous proteins.

PMID- 10592367
TI  - High density lipoprotein catabolism in primary cultured hepatocytes from
      daunomycin-induced nephrotic rats.
AB  - We investigated into HDL (high density lipoprotein) catabolism with primary
      cultured hepatocytes to elucidate the causes of increased HDL apolipoproteins in
      the plasma of daunomycin-induced nephrotic rats (D rats). The phospholipid,
      triglyceride, cholesterol, cholesteryl ester and apolipoprotein contents in HDL
      increased in D rats compared with control rats (C rats). The uptake (binding plus
      internalization) of (125)I-HDL from D rats to two groups of hepatocytes was
      significantly greater than that of (125)I-HDL from C rats. Uptake of (125)I-HDL
      from D rats to D rats' hepatocytes was significantly greater than that of (125)I
      HDL from C rats to C rats' hepatocytes. The degradation of (125)I-HDL from D rats
      was greater than that of (125)I-HDL from C rats using two groups of hepatocytes.
      These results demonstrated that the uptake and degradation of HDL to D rats'
      hepatocytes were greater than those of HDL to C rats' hepatocytes. The increased
      HDL apolipoprotein content in the plasma of D rats may not be due to decreased
      uptake and degradation of HDL in hepatocytes compared with C rats.

PMID- 10592368
TI  - EPIC-Germany--A source for studies into diet and risk of chronic diseases.
      European Investigation into Cancer and Nutrition.
AB  - The 'European Investigation into Cancer and Nutrition (EPIC)' represents one of
      the main scientific activities of the EU program 'Europe against Cancer' and is a
      large-scale cohort study on diet and chronic diseases, especially cancer, with
      approximately 475,000 study participants. The German contribution amounted to
      53,000 study participants recruited between 1994 and 1998. The study instruments
      of the baseline examination included self-administered questionnaires for optical
      reading, PC-guided interviews, and physical examinations. These instruments
      covered different aspects of lifestyle, with a particular focus on diet. In
      addition, about 95% of the participants provided 30 ml of blood. The blood was
      stored in liquid nitrogen for further use, preferentially in nested case-control
      studies. All interviews and examinations were conducted by trained interviewers
      in examination centers established for this study in local health offices. Every
      2 years, a follow-up questionnaire is mailed to the study participants. The
      follow-up questionnaires will be used as the major source of outcome information
      and to update exposure information. The self-reported diseases are verified by
      medical data. In the future, record linkage with local cancer registries will
      help to support the identification and collection of incident cancer cases. Only
      an outline of hypotheses was formulated at the very beginning of EPIC in 1992. In
      the future, each etiological study will be based on detailed research hypotheses
      according to the existing knowledge and identified research gaps. These studies
      will be conducted on cancer at the international level and on non-cancer diseases
      at the national or local level.

PMID- 10592369
TI  - Recruitment procedures of EPIC-Germany. European Investigation into Cancer and
      Nutrition.
AB  - EPIC is among the largest cohort studies, with approximately 475,000 study
      participants, on the etiological influence of diet and chronic diseases. During a
      4-year recruitment period, two German EPIC centers, located in Heidelberg and
      Potsdam, aimed to recruit a total of 60,000 study participants from the local
      populations. The recruitment process was based on addresses from general
      population registries and started 4-5 weeks in advance with an initial invitation
      by mail to the basic examination for this study. Subjects not responding within 2
      weeks were reminded. In Potsdam, this was done by mail and telephone, and in
      Heidelberg by telephone. During the recruitment phase, from 1994 to 1998, 53,162
      subjects in total were examined for the cohort studies in Heidelberg (n = 25,546)
      and Potsdam (n = 27,616). The participation rate, compared to the invited number
      of subjects, was 22.7% in Potsdam and 38.3% in Heidelberg, with a considerable
      variation by municipality and gender. A comparison with data from the National
      Health Survey 1991/1992 revealed that the cohort populations were of higher socio
      economic status and were healthier than the source population. We concluded that
      the selective participation would help to ensure high maintenance of the cohort
      during active follow-up. Selective participation does not harm etiological
      conclusions because disease associations are derived internally as relative risk.
      The relative risk estimates can be used to calculate population-attributable risk
      and preventable proportion, based on exposure prevalence derived by surveys and
      other studies.

PMID- 10592370
TI  - Measures of quality control in the German component of the EPIC study. European
      Prospective Investigation into Cancer and Nutrition.
AB  - Quality control is an indispensable part of quality assurance in any study,
      intending to ensure high standards during data acquisition. The aim of this paper
      is to describe the measures of quality control undertaken in the German EPIC
      study centers and to present selected results of these procedures (EPIC =
      European Prospective Investigation into Cancer and Nutrition). For all data
      assessment tools applied in the German EPIC study, procedures were developed to
      monitor both the personnel as well as the technical instruments. These procedures
      combined quantitative and qualitative measurements of quality control.
      Interviewer performance was evaluated through direct observation and rated
      according to an evaluation score. Blood pressure and anthropometric measurements
      were both controlled through direct observation of measurement procedures as well
      as through periodical technical control of measurement devices. Blood sampling
      procedures were directly monitored and subsequent handling of the probes tightly
      recorded, including information on time sequence of work-up and room temperature.
      With these diverse control measurements and the obtained rating of assessment
      procedures a broad pool of information has been made available to support a
      critical evaluation of the data obtained in the EPIC study centers in Heidelberg
      and Potsdam.

PMID- 10592371
TI  - Follow-up procedures in EPIC-Germany--data quality aspects. European Prospective
      Investigation into Cancer and Nutrition.
AB  - With 475,000 participants throughout Europe, EPIC is one of the largest cohort
      studies investigating the association between diet and cancer and other chronic
      diseases. The German part of EPIC comprises about 53,000 participants in Potsdam
      (n = 27,616) and in Heidelberg (n = 25,546). In the German study centers, follow
      up started in 1998 and will be continued in 2-year intervals over the next 10-15
      years. To ensure high follow-up data quality at an European level, an
      international working group developed guidelines for endpoint data collection in
      every country. A follow-up phase in Germany comprises mailing of a questionnaire,
      tracing of individuals to whom mail could not be delivered, obtaining information
      on deceased participants including cause of death, and verifying self- reported
      diagnoses. Furthermore, activities aimed at motivating study participants are
      part of the follow-up. The first round of follow-up of those who entered the
      study in 1994 and 1995 included 8, 706 participants in Potsdam and 6,289 in
      Heidelberg. Due to a comprehensive and intensive reminder and tracing system,
      vital status of the study subjects is known from almost 100% in Potsdam and 99%
      in Heidelberg. Two years after baseline examination, and with twice as many
      addresses in Potsdam as in Heidelberg, addresses had to be traced or checked via
      population registry (13 versus 6%). Tracing, the application of different mailing
      strategies, and intensive reminder activities resulted in a 95% return of the
      questionnaire in Potsdam and 90% in Heidelberg. The system of follow-up data
      entry and control, including completion of missing information via telephone,
      verification of self-reports and causes of death, has been set up for EPIC
      Germany and works efficiently and successfully. The aim of this paper is to
      describe the follow-up procedures in EPIC-Germany with a focus on the generation
      of valid and complete outcome data.

PMID- 10592372
TI  - Quantitative food intake in the EPIC-Germany cohorts. European Investigation into
      Cancer and Nutrition.
AB  - The EPIC-Heidelberg and the EPIC-Potsdam studies with about 53,000 study
      participants represent the German contribution to the EPIC (European
      Investigation into Cancer and Nutrition) cohort study. Within the EPIC study,
      standardized 24-hour dietary recalls were applied as a quantitative calibration
      method in order to estimate the amount of scaling bias introduced by the varying
      center-specific dietary assessment methods. This article presents intake of food
      items and food groups in the two German cohorts estimated by 24-hour quantitative
      dietary recalls. Recalls from 1,013 men and 1,078 women in Heidelberg and 1,032
      men and 898 women in Potsdam were included in the analysis. The intake of
      recorded food items or recipe ingredients as well as fat used for cooking was
      summarized into 16 main food groups and a variety of different subgroups
      stratified by sex and weighted for the day of the week and age. In more than 90%
      of the recalls, consumption of dairy products, cereals and cereal products,
      bread, fat, and non-alcoholic beverages, particularly coffee/tea, was reported.
      Inter-cohort evaluations revealed that bread, potatoes, fruit and fat were
      consumed in higher amounts in the Potsdam cohort while the opposite was found for
      pasta/rice, non-alcoholic, and alcoholic beverages. It was concluded that the
      exposure variation was increased by having two instead of one EPIC study centers
      in Germany.

PMID- 10592373
TI  - Dietary habits in the German EPIC cohorts: food group intake estimated with the
      food frequency questionnaire. European Investigation into Cancer and Nutrition.
AB  - In the baseline assessment of the two EPIC-Germany cohorts Heidelberg and
      Potsdam, dietary information was obtained with an identical food frequency
      questionnaire (FFQ). The optically readable FFQ was designed to assess the usual
      food and nutrient intake of individuals during the past 12 months. The present
      analysis was based on dietary data from 25,212 participants in Heidelberg (11,776
      men, 13,436 women) and 26,270 participants in Potsdam (10,249 men, 16,021 women).
      This paper presents the first results of a descriptive dietary analysis on a food
      group level based on 16 food groups and selected subgroups. Each of these food
      groups and subgroups was divided into quintiles, and the age-adjusted mean intake
      for each quintile was calculated. The comparison of dietary habits between the
      two cohorts, as well as the comparison between men and women within each cohort
      showed clear differences both in the quintiles of most food groups as well as in
      the range between the lowest and highest quintile. Except for the food groups non
      alcoholic and alcoholic beverages, sugar and confectionery, sauces, and soups,
      men and women participating in Potsdam reported higher intakes of all the other
      food groups. The amount of food intake was generally lower in women than in men,
      with the exception of vegetables, fruit, dairy products, and non-alcoholic
      beverages. Further differences between the study centers were observed regarding
      the use of cooking fat for meat and vegetable preparation. In conclusion, the
      dietary variation, e.g. the exposure variation, was increased by recruiting two
      geographically distinct cohorts, instead of only one, in Germany.

PMID- 10592374
TI  - Patterns of past alcohol consumption in the EPIC-Germany cohorts. European
      Investigation into Cancer and Nutrition.
AB  - Information on life-long history of alcohol consumption might be more relevant to
      chronic diseases than current intake. The aim of this study was to describe past
      alcohol intake and consumption patterns in the EPIC-Germany cohorts, by sex and
      age, from 1949 to 1998. Past daily consumption of alcoholic beverages - beer,
      wine, and spirits - was assessed through a lifestyle questionnaire administered
      to 27,099 subjects of the EPIC-Potsdam and 25,449 subjects of the EPIC-Heidelberg
      cohort. Recruitment of the cohorts concentrated on men aged 40-64 and on women
      aged 35-64. For each alcoholic beverage, the consumption at ages 20, 30, and 40
      was asked. The data were used to calculate previous mean consumption in 10-year
      intervals from 1949 to 1998. Alcohol intake was observed to be higher in the
      Heidelberg than in the Potsdam cohort. Differences between cohorts were most
      marked for wine consumption which was considerably higher in the Heidelberg
      cohort. Men consumed approximately 3 times the amount of alcohol of women. Men
      preferred to drink beer, women preferred to drink wine. For the Potsdam cohort,
      alcohol intake was observed to increase since 1949. For the Heidelberg cohort, a
      recent decrease in alcohol intake in males and females of 30 and 40 years of age
      was noted. The data indicate that collection of alcohol consumption data at
      various discrete points in time is essential to depict life-long history of
      alcohol consumption.

PMID- 10592375
TI  - Calcium signalling in squid olfactory receptor neurons.
AB  - Isolated squid olfactory receptor neurons respond to dopamine and betaine with
      hyperpolarizing conductances. We used Ca(2+) imaging techniques to determine if
      changes in intracellular Ca(2+) were involved in transducing the hyperpolarizing
      odor responses. We found that dopamine activated release of Ca(2+) from
      intracellular stores while betaine did not change internal Ca(2+) concentrations.
      Application of 10 mM caffeine also released Ca(2+) from intracellular stores,
      suggesting the presence of ryanodine-like receptors. Depletion of intracellular
      stores with 100 microM thapsigargin revealed the presence of a Ca(2+) store
      depletion-activated Ca(2+) influx. The influx of Ca(2+) through the store
      operated channel was reversibly blocked by 10 mM Cd(2+). Taken together, these
      data suggest a novel odor transduction system in squid olfactory receptor neurons
      involving Ca(2+) release from intracellular stores.

PMID- 10592376
TI  - Cyclic nucleotide-gated channel activation is not required for activity-dependent
      labeling of zebrafish olfactory receptor neurons by amino acids.
AB  - The olfactory epithelium of fish is heterogeneous both with respect to the types
      of receptor cells (ORNs) present and the families of odorant receptors expressed
      in these cells. As a consequence of this diversity, the transduction cascade(s)
      activated by odorants has yet to be unambiguously established. In the current
      study, electrophysiological and activity-dependent labeling techniques were used
      to assess the role of the cyclic nucleotide-gated channel in zebrafish olfactory
      transduction. Both amino acid and bile salt odorants elicited robust
      electrophysiological responses, however, activity-dependent labeling of ORNs
      could be stimulated only by the amino acid odorants. An adenylate cyclase (AC)
      activator (forskolin) and a phosphodiesterase inhibitor (3-isobutyl-1
      methylxanthine, IBMX) also elicited robust electrophysiological responses;
      generally larger than the responses elicited by either the amino acid or bile
      salt odorants. However, neither forskolin alone or a mixture of forskolin and
      IBMX stimulated activity-dependent labeling. Bathing the olfactory epithelium
      with forskolin, which presumably increased the intracellular concentration of
      cAMP, reduced the responses to bile salt odorants to a significantly greater
      extent than amino acid odorants. Collectively, these findings suggest that the
      transduction of amino acid input does not rely primarily on cyclic nucleotide
      gated (CNG) channel activation and that CNG channel activation may be required
      for the transduction of bile salt input.

PMID- 10592377
TI  - GABA-mediated inhibition of primary olfactory receptor neurons.
AB  - Applying GABA (1 microM-1 mM) to the soma of cultured lobster olfactory receptor
      neurons evokes an inward current (V(m) = -60 mV) accompanied by an increase in
      membrane conductance, with a half-effect of 487 microM GABA. The current-voltage
      relationship of this current is linear between -100 and 100 mV and reverses
      polarity at the equilibrium potential for Cl(-). The current is blocked by
      picrotoxin and bicuculline methiodide, and is evoked by trans-aminocrotonic acid,
      isoguvacine, muscimol, imidazole-4-acetic acid, and 3-amino-1-propanesulfonic
      acid, but not by the GABA(C)-receptor agonist cis-4-aminocrotonic acid and the
      GABA(B)-receptor agonist 3-aminopropylphosphonic. Applying GABA to the soma of
      the cells in situ reversibly suppresses the spontaneous discharge and
      substantially decreases the odor-evoked discharge. The effects of GABA on the
      cell soma in situ are antagonized by both picrotoxin and bicuculline methiodide.
      Taken together with evidence that GABA directly activates a chloride channel in
      outside-out patches excised from the soma of these neurons, we conclude that
      lobster olfactory receptor neurons express an ionotropic GABA receptor that can
      potentially regulate the output of these cells.

PMID- 10592378
TI  - Co-localization of epithelial sodium channels and glutamate receptors in single
      taste cells.
AB  - Umami taste is elicited by monosodium glutamate (MSG), a compound consisting of
      two potent taste stimuli, Na(+) and glutamate. In rat fungiform taste cells,
      amiloride-sensitive epithelial sodium channels (ENaCs) mediate Na(+)
      transduction, while glutamate is transduced by a combination of ionotropic and
      metabotropic glutamate receptors. We used giga-seal whole-cell recording to
      determine if responses to glutamate and Na(+) occur in the same taste cells.
      Approximately 68% of the cells tested responded to amiloride, indicating that
      they express functional ENaCs. Responses to glutamate occurred in about 58% of
      the cells tested. Interestingly, responses to glutamate occurred in the subset of
      cells that also responded to amiloride, indicating that glutamate receptors are
      located preferentially in the same taste cells that also express ENaCs. Further
      experiments showed that amiloride did not suppress responses to glutamate under
      voltage-clamp conditions. Taken together, the data suggest that although ENaCs
      are not involved directly in glutamate transduction, their co-localization with
      glutamate receptors provides a substrate for the cellular integration of these
      independent pathways.

PMID- 10592379
TI  - Protein phosphorylation signaling mechanisms in carotid body chemoreception.
AB  - Chemotransduction in the carotid body occurs in specialized type I cells and
      likely involves a complex series of regulated events which culminates in the
      release of neurotransmitter agents and the excitation of afferent nerve fibers.
      Previous studies have shown that multiple factors, including the levels of
      calcium and cyclic nucleotide second messengers, are important regulators of the
      chemoreceptor transduction cascade in type I cells. In addition, increases in
      electrical excitability induced in type I cells by chronic exposure to hypoxia
      are mimicked by agents which elevate intracellular cyclic AMP levels [Stea et
      al., J Neurosci 1995;15:2192-2202]. These and other findings suggest that protein
      kinases, and the phosphorylation of specific protein targets are important
      components of the hypoxic transduction machinery. Moreover, protein kinase
      mediated cascades may participate in the well-known physiological adjustments
      which occur in the carotid body during prolonged stimulation. In the current
      study, our data demonstrate (1) the presence of specific protein kinases and
      target phosphoproteins in the carotid body, and also in the morphologically
      similar small intensely fluorescent cells of the superior cervical sympathetic
      ganglia. (2) Nitric oxide production and efferent inhibition in the chemosensory
      tissue is reduced in the presence of the specific tyrosine kinase inhibitor,
      lavendustin A. (3) Hypoxia-induced catecholamine release from type I cells is
      inhibited by the protein kinase A antagonist, Rp-cAMPs. And finally (4), exposure
      to chronic hypoxia up-regulates the expression of the tyrosine kinase, fyn, and
      an important growth regulatory phosphoprotein, growth associated protein-43 (GAP
      43). These findings suggest that second messenger-mediated phosphorylation and
      dephosphorylation of specific protein targets is a mechanism capable of
      regulating diverse cellular functions in the carotid body during acute and
      chronic stimulation.

PMID- 10592380
TI  - A quantitative immunocytochemical approach to the analysis of type I cells in the
      cat carotid body.
AB  - Digital image analysis of immunostained semithin plastic sections indicates that
      experimentally induced changes in levels of transmitter-related reaction product
      in single cells fails to support the concept of clearly defined subsets of type I
      cells in the carotid body. This objective approach to the quantitation of
      staining product on a cell-by-cell basis appears to indicate that the observed
      changes are related to global shifts in the expression of a given neuronal marker
      throughout a single population of highly labile chemoreceptor elements.

PMID- 10592381
TI  - Chemosensitivity of the rat type I slowly adapting mechanoreceptor.
AB  - An in vitro lateral thoracic skin preparation of the adult rat was used to test
      the effect of serotonin (5, 50, 500 microM) and control solutions on the response
      of the type I slowly adapting mechanoreceptor to a standard mechanical stimulus.
      Serotonin (5-HT) significantly increased the magnitude of the type I response to
      mechanical indentation: 50 microM 5-HT infusion enhanced responsiveness more
      effectively than 5 microM 5-HT. In the absence of mechanical stimulation, little
      or no change in spontaneous discharge relative to control was observed, and
      recovery to baseline levels occurred within three stimulus trials. In vitro and
      in vivo control experiments showed no statistically significant change in
      responsiveness over a similar number of stimulus cycles. It was concluded that 5
      HT modulates, but does not activate the rat type I receptor or alter its ability
      to encode the depth and/or velocity of mechanical displacement.

PMID- 10592382
TI  - Sonic motor nucleus and its connections with octaval and lateral line nuclei of
      the medulla in a rockfish, Sebastiscus marmoratus.
AB  - The sonic motor nucleus and its fiber connections were examined in a rockfish,
      Sebastiscus marmoratus by means of tracer methods using horseradish peroxidase
      (HRP), biocytin, and carbocyanine dye (DiI). Sebastiscus has a swimbladder and a
      pair of extrinsic sonic/drumming muscles. The sonic muscle is ipsilaterally
      innervated by the occipital nerve which is composed of two ventral roots arising
      from the sonic motor nucleus. The sonic motor neurons are distributed in the most
      ventral part of the ventral column from the caudal medulla to the rostral spinal
      cord, and form a ventrally located columnar nucleus. Each neuron in this nucleus
      possesses a long thick dendrite and several short dendrites. The long dendrite
      extends dorsolaterally and branches in the lateral funiculus, whereas the short
      dendrites branch around their cell bodies. After biocytin injections into the
      sonic motor nucleus, two groups of premotor neurons were retrogradely labeled
      bilaterally, one in the dorsomedial portion of the descending octaval nucleus
      (DO) and the other in the medial zone of the reticular formation (RF) in the
      medulla. The DO premotor neurons were multipolar with several dendrites branching
      near the cell bodies, and the RF premotor neurons were bipolar. One of the two
      dendrites of the RF premotor neurons extends laterally into the ventral portion
      of the DO, and the other dendrite extends into the ventromedial area in the
      medulla. In the ventromedial dendritic field of the RF premotor neurons,
      descending fibers arising from the optic tectum (TO) and torus semicircularis
      (TS) traverse in the tractus tectobulbaris and terminate bilaterally. After DiI
      insertion into the ventromedial dendritic field, retrogradely labeled neurons
      were found bilaterally in the TS and TO. The majority of tectal neurons were
      located in the stratum griseum centrale. These neurons had two short basal
      dendrites branching in the cell layer and a long apical dendrite extending to the
      stratum fibrosum et griseum superficiale and stratum opticum. The toral neurons
      were bipolar and were distributed throughout the TS. Furthermore, biocytin
      injections into the medial nucleus of the lateral line system revealed that the
      nucleus projects bilaterally to the RF premotor neurons. These results show that
      premotor neurons for the sonic motor nucleus are located in the dorsomedial
      portion of the DO and the medial zone of the RF in the medulla. It is suggested
      that the sonic motor nucleus receives auditory input via the DO premotor neurons
      and input from RF premotor neurons which receive lateral line input via the
      medial nucleus, vestibular input through the lateral dendrite extending into the
      ventral portion of the DO, and information from the TO and TS via the tractus
      tectobulbaris.

PMID- 10592383
TI  - Motor patterns of herbivorous feeding: electromyographic analysis of biting in
      the parrotfishes Cetoscarus bicolor and Scarus iseri.
AB  - The motor patterns of the herbivorous feeding bite were investigated in two
      species of parrotfish (Cetoscarus bicolor and Scarus iseri) with functionally
      distinct biting modes using electromyographic recordings. Behavioral data
      revealed that S. iseri utilized faster bites, took more bites per feeding bout,
      and bit at a higher frequency than did C. bicolor. EMGs recorded from the
      epaxialis (EP), levator operculi (LOP), 3 subdivisions of the adductor mandibulae
      (A1-A3), and the sternohyoideus (SH) muscles displayed a high degree of within
      individual variance. Duration of muscle activity and onset time relative to LOP
      were shorter in S. iseri than in C. bicolor and S. iseri displayed a greater EMG
      amplitude in the LOP and SH muscles than did C. bicolor. We calculated the duty
      factors of the muscles as the relative timing of EMG variables divided by the
      total feeding cycle time. Patterns of duty factors of the feeding muscles were
      similar in both species, though muscles were active for a longer portion of the
      total bite cycle in S. iseri. In addition to its typical bite, S. iseri employed
      additional motor patterns when taking particularly hard bites. A multivariate
      comparison of EMGs from biting and suction feeding taxa revealed that the biting
      motor pattern was significantly different from suction feeding, although there
      was a high degree of overlap among all feeding strikes. The activity of the
      sternohyoideus muscle was significantly different between suction feeders and
      biters. Despite strong similarities of the general motor pattern in a wide range
      of teleost fishes, components of this pattern are shown to be evolutionarily
      plastic.

PMID- 10592384
TI  - Apomorphine alters prey-catching patterns in the common toad: behavioral
      experiments and (14)C-2-deoxyglucose brain mapping studies.
AB  - Previous studies on the dopaminergic modulation of visuomotor functions in
      amphibians showed that the dopamine agonist apomorphine (APO) alters prey
      catching strategies. After systemic administration of APO in common toads Bufo
      bufo, prey-oriented turning and locomotion was attenuated whereas snapping toward
      prey was facilitated in a dose dependent manner. With systemic APO
      administration, toads which had previously been hunting, that is pursuing prey,
      behaved in a waiting position, that is sitting motionless and waiting for prey.
      This suggests that APO facilitates the ingestive component and inhibits the
      orientational and locomotory components of prey capture. To help unravel the
      cerebral sites of action of APO, the present study employs the (14)C-2
      deoxyglucose method to compare the rate of local glucose utilization in 41 brain
      structures. The retinal projection fields - e.g. superficial optic tectum,
      pretectal nuclei, and anterior dorsal thalamic nucleus - showed an elevation in
      glucose utilization due to APO-induced increases in retinal output. The medial
      tectal layers and the ventral striatum, both involved in visuomotor functions
      related to prey-oriented turning and locomotion, displayed APO-induced decreases
      in glucose utilization. APO-induced increases in glucose utilization were
      observed in the medial reticular formation and the hypoglossal nucleus which
      participate in the motor pattern generation of snapping. APO-induced increases in
      glucose utilization were also detected in the nucleus accumbens and the ventral
      tegmentum (mesolimbic system) as well as in the ventromedial pallium ('primordium
      hippocampi') and the septum, both of which belonging to the limbic system. These
      structures contribute to motivational level control and may be responsible for
      the APO-induced elevation of the snapping rate. Various other structures revealed
      APO-induced increases in glucose utilization. These structures include the
      olfactory bulb, lateral pallium, suprachiasmatic nucleus, nucleus of the
      periventricular organ, and the nucleus of the solitary tract. The lateral
      amygdala displayed APO-induced decreases in glucose utilization. The APO-induced
      alterations in local cerebral glucose utilization are evaluated with reference to
      the distribution of dopaminergic structures, and this is compared with similar
      data obtained in the rat by other authors. A neural network explaining the APO
      induced behavioral syndrome in the common toad is discussed.

PMID- 10592385
TI  - Signaling mechanisms regulating self-renewal and differentiation of pluripotent
      embryonic stem cells.
AB  - An ability to propagate pluripotent embryonic cells in culture is the foundation
      both for defined germline modification in experimental rodents and for future
      possibilities for broad-based cellular transplantation therapies in humans. Yet,
      the molecular basis of the self-renewing pluripotent phenotype remains ill
      defined. The relationship between factors that influence embryonic stem cell
      propagation in vitro and mechanisms of stem cell regulation operative in the
      embryo is also uncertain. In this article we discuss the role of intracellular
      signalling pathways in the maintenance of pluripotency and induction of
      differentiation in embryonic stem cell cultures and the mammalian embryo.

PMID- 10592386
TI  - Oct-4: lessons of totipotency from embryonic stem cells.
AB  - The Oct-4 transcription factor is expressed in embryonic stem cells and germ
      cells of the mouse embryo. Cells that are driven into embryonic and
      extraembryonic somatic differentiation lose Oct-4 expression. Oct-4 is crucial
      for the maintenance of the totipotency of embryonic cells at early developmental
      stages as demonstrated recently by homologous recombination. Since during
      embryogenesis Oct-4 is restricted to germ cells, it is possible that it plays a
      key role for the germline lineage by preventing differentiation of these cells
      during gastrulation. Thus, Oct-4 appears to be a key regulator of totipotency
      during the life cycle of mammals.

PMID- 10592387
TI  - Establishment of ionic channels and signalling cascades in the embryonic stem
      cell-derived primitive endoderm and cardiovascular system.
AB  - The first organ system to be established in early embryogenesis is the
      cardiovascular system which develops upon interaction with hypoblastic cells of
      the primitive endoderm. Here we focus on recent work on embryoid bodies derived
      from pluripotent embryonic stem (ES) cells. Ca(2+) oscillations and Ca(2+)
      signalling pathways during the differentiation of primitive endodermal cell
      layers are reported. Furthermore, the development-dependent expression of ion
      channels and the buildup of signalling cascades involved in the modulation of
      voltage-dependent L-type Ca(2+) channels during early cardiomyogenesis and the
      formation of functional vascular structures in the process of vasculogenesis and
      angiogenesis are reviewed. We also report on the use of green fluorescent protein
      reporter gene expression under the control of cardiac-specific promoters, e.g.
      the human cardiac alpha-actin promoter, which enables the identification and in
      vivo characterization of cardiomyocytes at very early stages of cardiomyogenesis.

PMID- 10592388
TI  - An in vitro pathway from embryonic stem cells to neurons and glia.
AB  - Mouse embryonic stem (ES) cells can be induced to differentiate into neurons and
      glia in vitro. Induction protocols are straightforward and involve culture in the
      presence of retinoic acid. They result in an efficient conversion of
      undifferentiated ES cells to neural cells. Mature neurons produced have the key
      physiological, morphological and molecular properties of primary cultured neurons
      derived from the central nervous system. Most significantly, they form functional
      chemical synapses that utilize either glutamate, GABA or glycine as
      neurotransmitters. ES cell-derived glial cells also correspond well with their
      normal counterparts. During induction, ES cells undergo a series of developmental
      steps that resemble key stages in the early mouse embryo. This supports the
      hypothesis that the in vitro pathway is a valid model of the normal developmental
      pathway leading to neurons and glia. The in vitro system combines three
      experimental strengths. It is suitable for genetic manipulation, affords large
      numbers of cells and allows precise manipulation of the culture environment. It
      is thus suitable for a wide variety of mechanistic studies in the areas of neural
      development and cell biology.

PMID- 10592389
TI  - Embryonic stem cell-derived adipogenesis.
AB  - Key events leading to terminal differentiation of preadipocytes into adipocytes
      have been characterized in the recent years. However, master genes that commit
      progression from multipotent mesenchymal stem cell to the adipoblast stage of
      development have not yet been identified. The use of embryonic stem (ES) cells as
      a route to study early events in adipogenesis and to characterize factors
      involved in the decision of stem cells to follow the adipogenic pathway is
      described in this paper. The capacity of lif-/- and lifr-/- ES cells to undergo
      adipocyte differentiation is reported as an application of mutant ES cells to
      study gene function during the development of adipose cells.

PMID- 10592390
TI  - Embryonic stem cell-derived haematopoiesis.
AB  - Embryonal stem (ES) cells are pluripotent cell types that in chimaeric mice can
      give rise to all cellular lineages. Early studies showed that they also had the
      potential to form mature erythrocytes following in vitro differentiation. In
      recent years ES cells have been demonstrated to be competent both to produce all
      haematopoietic lineages following in vitro differentiation and long-term
      repopulating haematopoietic stem cells. This review discusses the approaches that
      have been used to produce these haematopoietic cells and the nature of the
      haematopoietic stem cells that can be isolated. The utility of the system to both
      isolate genes involved in control of haematopoiesis and to assess their function
      following transgenesis is demonstrated. The prospectives for this field are then
      discussed in the context of recent developments in human ES cells and evidence of
      stem cell plasticity.

PMID- 10592391
TI  - Induction of cellular differentiation by retinoic acid in vitro.
AB  - Cellular differentiation by the vitamin A derivative retinoic acid (RA) has been
      studied with undifferentiated pluripotent embryonic carcinoma (EC) and embryonic
      stem (ES) cells in vitro. Both cellular systems are suitable to study
      differentiation of various cell types, because they recapitulate early stages of
      mouse embryogenesis. In vivo, RA was identified as a morphogenic and teratogenic
      compound and furthermore as a signalling molecule influencing gene expression in
      a complex manner via a family of RA receptors. Here, we summarize in vitro
      studies with ES and EC cells in comparison to in vivo studies that have
      contributed to our understanding how RA influences differentiation and regulates
      gene expression. We demonstrate that modulation of ES cell differentiation in
      vitro by RA depends on the concentration and developmental stage of application
      which is comparable to its stage-dependent influence on embryonic development in
      vivo.

PMID- 10592393
TI  - Chicken embryonic stem cells and transgenic strategies.
AB  - The production of transgenic birds is an important goal for both fundamental and
      applied biology. Different methods have been employed to generate transgenic
      chickens, including microinjection, use of retroviruses and transfection of
      primordial germ or embryonic germ cells. In this review we will briefly describe
      these techniques and our efforts to obtain genetically modified avian embryonic
      stem (ES) cells using liposomes. This latter technique should allow us to modify
      chicken ES cells with a high efficiency, permitting the rapid generation of
      transgenic bird lines.

PMID- 10592392
TI  - Embryotoxicity screening using embryonic stem cells in vitro: correlation to in
      vivo teratogenicity.
AB  - Blastocyst-derived pluripotent embryonic stem (ES) cells of the mouse can be
      induced to differentiate in culture into a variety of cell types, including
      cardiac muscle cells. The embryonic stem cell test that makes use of the
      differentiation of ES cells into cardiomyocytes in a standardized in vitro model
      was developed to offer an alternative method to comprehensive in vivo studies in
      reproductive toxicology about toxic effects of chemicals. ES cells of the mouse
      cell line D3 are investigated for their preserved capability to differentiate
      following drug exposure, and both ES cells and differentiated fibroblast cells of
      the mouse cell line 3T3 are comparatively analyzed for effects on viability. The
      following endpoints are used to classify the embryotoxic potential of chemicals
      into three classes of in vitro embryotoxicity (non-, weakly or strongly
      embryotoxic). These endpoints are: (1) the inhibition of differentiation of ES
      cells into cardiomyocytes after 10 days of treatment, and the decrease of
      viability (cytotoxicity) of (2) 3T3 cells and (3) ES cells after 10 days of
      treatment, determined by a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium
      bromide (MTT) test. 50% inhibition concentrations for differentiation (ID(50))
      and cytotoxicity (IC(50)D3 and IC(50)3T3) are calculated from concentration
      response curves. Applying linear analysis of discriminance, a biostatistical
      prediction model (PM) was developed. This procedure identified three variables,
      the lg(IC(50)D3), the lg(IC(50)3T3) and the relative distance between IC(50)3T3
      and ID(50), that improved the separation of the three classes of embryotoxicity
      compared to the prediction model that was originally proposed after test
      development. Unlike the original PM, the improved PM incorporates as one variable
      the relative distance between IC(50)3T3 and ID(50), instead of the ratio
      ID(50)/IC(50)D3 that was used previously.

PMID- 10592394
TI  - Establishment of pluripotent cell lines from vertebrate species--present status
      and future prospects.
AB  - Pluripotent embryonic stem (ES) cells are undifferentiated cell lines derived
      from early embryos and are capable of unlimited undifferentiated proliferation in
      vitro. They retain the ability to differentiate into all cell types including
      germ cells in chimeric animals in vivo, and can be induced to form derivatives of
      all three germ layers in vitro. Mouse ES cells represent one of the most
      important tools in genetic research. Major applications include the targeted
      mutation of specific genes by homologous recombination and the discovery of new
      genes by gene trap strategies. These applications would be of high interest for
      other model organisms and also for livestock species. However, in spite of
      tremendous research activities, no proven ES cells colonizing the germ line have
      been established for vertebrate species other than mouse and chicken thus far.
      This review summarizes the current status of deriving pluripotent embryonic stem
      cell lines from vertebrates and recent developments in nuclear transfer
      technology, which may provide an alternative tool for genetic modification of
      livestock animals.

PMID- 10592395
TI  - Can exogenous stem cells be used in transplantation?
AB  - Today's most urgent problem in transplantation is the lack of suitable donor
      organs and tissues and as the population ages, demands for organs and tissue
      therapies will only increase. One alternative to organ transplantation is cell
      therapy whose aim is to replace, repair or enhance the biological function of
      damaged tissue or diseased organs. One goal of cellular transplantation thus has
      been to find a renewable source of cells that could be used in humans. Embryonic
      stem (ES) cells have the potential to proliferate in vitro in an undifferentiated
      and pluripotent state. Theoretically, ES cells are capable of unlimited
      proliferation in vitro. ES cells spontaneously differentiate into derivatives of
      all three primary germ layers: endoderm, ectoderm and mesoderm, hence providing
      cells in vitro which can theoretically be isolated and used for transplantation.
      Furthermore, these pluripotent stem cells can potentially be used to produce
      large numbers of cells that can be genetically modified in vitro. Once available,
      this source of cells may obviate some of the critical needs for organ
      transplantation. Murine ES cells have been extensively studied and all available
      evidence indicates that all aforementioned expectations are indeed fulfilled by
      ES cells. ES cells as well as embryonic germ cells have recently been isolated
      and maintained in culture. The recent descriptions of human ES cells portend the
      eventual use of allogeneic in vitro differentiated cells for human therapy. This
      goal, however, is fraught with obstacles. Our aim is first to review the recent
      advances made with murine ES cells and then to point out potentials and
      difficulties associated with the use of human ES cells for transplantation.

PMID- 10592396
TI  - Embryonic stem cells: An exciting field for basic research and tissue
      engineering, but also an ethical dilemma?

PMID- 10592397
TI  - Does mountaineering increase the incidence of cutaneous melanoma? A hypothesis
      based on cancer registry data.
AB  - Exposure to ultraviolet radiation is considered a major risk factor for the
      development of cutaneous melanoma. In white populations in Australia or the USA,
      the melanoma incidence increases with the vicinity of residence to the equator.
      In Europe decreasing incidence rates towards southern countries may be due to the
      darker pigmentation of the Mediterranean population. The comparison of age
      standardized incidence rates (world standard population) in Europe shows that
      Swiss cancer registries and the Austrian Tyrol registry have much higher
      incidence rates for cutaneous melanoma than other Central European cancer
      registries. The excess of Swiss/Austrian incidence rates is even more pronounced
      when head localization is analysed separately. Due to the altitude-related
      increase in UV radiation two possible explanations for the Swiss/Austrian excess
      rates may be considered: firstly, as a result of the altitude of residence,
      higher UV exposure is generally present in these countries; secondly,
      mountaineering activities may additionally increase UV exposure.

PMID- 10592398
TI  - Nevus comedonicus.
AB  - The nevus comedonicus (NC) is an uncommon variant of adnexal hamartoma which
      appears clinically as linear groups of open comedones. Its name may be a misnomer
      since, according to some, true comedones are not present. NC usually occurs by
      itself but may be linked with a variety of systemic findings such as skeletal or
      ocular anomalies. Although the nevus comedonicus is viewed by many as a hamartoma
      arising from a defective mesoderm, others consider this lesion to be an epidermal
      nevus involving the hair follicle or an appendageal nevus of sweat ducts.

PMID- 10592399
TI  - Differentiating squamous cell carcinoma from keratoacanthoma using
      histopathological criteria. Is it possible? A study of 296 cases.
AB  - BACKGROUND: Squamous cell carcinoma (SCC) and keratoacanthoma (KA) are sometimes
      difficult to distinguish by histopathological examination, since cytological
      features are similar in both tumors. Distinctive criteria - mainly architectural 
      have therefore been proposed as an aid in diagnosis. OBJECTIVE: The purpose of
      this study was to evaluate the reliability of some of the criteria used to make a
      distinction between SCC and KA. METHODS: 296 fully excised tumors previously
      classified as SCC or KA were randomized and examined independently by two
      examiners. Fourteen criteria, mainly based on the architecture of the tumors,
      were determined on the 262 slides for which a consensual diagnosis was made.
      RESULTS: No single criterion was sufficiently sensitive and specific to allow a
      clear-cut differential diagnosis. The 5 most relevant criteria were epithelial
      lip, sharp outline between tumor and stroma in favor of KA and ulceration,
      numerous mitoses and marked pleomorphism/ anaplasia in favor of SCC.
      Intraepithelial polymorphonuclear abscesses, intraepithelial elastic fibers,
      parakeratosis and dyskeratosis and extension more lateral than downward were not
      distinctive criteria, although they are considered as classic distinctive
      features. CONCLUSION: Many of the criteria commonly used for the differential
      diagnosis of SCC and KA are not reliable. The combination of the 5 most useful
      criteria does not significantly increase the specificity or sensitivity of the
      histological diagnosis in difficult cases. Atypical or difficult cases should
      therefore be considered and treated as SCC, since a clear-cut distinction is not
      possible even with the aid of the most relevant criteria.

PMID- 10592400
TI  - Development and validation of a quality of life measurement for chronic skin
      disorders in french: VQ-Dermato. The ReseaudEpidemiolo gie en Dermatologie.
AB  - BACKGROUND: Quality of life (QoL) assessment is crucial to assess the severity of
      dermatological diseases. PURPOSE: To construct and validate the first dermatology
      specific instrument in French. METHODS: Items were generated from the interview
      of patients. The final self-administered questionnaire, the VQ-Dermato, included
      28 questions. Validity in terms of content and construct, reliability in terms of
      reproducibility and internal consistency, responsiveness and acceptability were
      tested in a population of 231 patients with 12 categories of chronic skin
      disorders, who were recruited and followed in hospital and private practice in
      France. RESULTS: Item analysis revealed that discrimination indices were high.
      After factor analysis, 7 dimensions were retained, which accounted for 72% of the
      total variance. Cronbach's alpha coefficient ranged between 0. 67 and 0.88. A
      strong correlation was found between dimensions of the VQ-Dermato and the
      corresponding dimensions of the SF36. Scores were significantly different in each
      category of chronic skin disease and significantly higher when there was a
      function restriction or when the lesions were visible to others. The scale was
      proven to be stable by test-retest correlation. The VQ-Dermato was more
      responsive to clinical improvement after a 1- or 2-month treatment than the SF36.
      The percentage of missing responses was under 10 and the time for completing the
      questionnaire always under 13 min. CONCLUSION: The VQ-Dermato is the first valid
      and reliable dermatology-specific QoL instrument in French, and the first based
      on the concept of 'chronic skin disorders'. It is acceptable for routine use and
      has a better responsiveness than a general health instrument.

PMID- 10592401
TI  - Vulval diseases need an interdisciplinary approach.
AB  - BACKGROUND: Vulval diseases are common, but their frequency and importance are
      often underestimated. OBJECTIVE: The study intended to evaluate the number of
      patients with vulval diseases seen in medical practice. Furthermore, the
      acceptance of an interdisciplinary vulval disease clinic, managed by a
      dermatologist in cooperation with a gynaecologist and a psychologist, was
      evaluated. METHODS: In April and Mai 1998, a mailing survey of all gynaecologists
      (n = 239), general practitioners (n = 244) and dermatologists (n = 96) in
      Thuringia, Germany, containing 7 questions concerning patients with vulval
      diseases was performed. RESULTS: 49% (n = 286) of the questionnaires were
      returned. On average, 97% of the physicians regularly treated females with
      genital diseases. The most common diseases mentioned by all specialities were
      local fungal and bacterial infections. The further ranking of diagnosis was
      different between the specialities. It was estimated that 83% of patients with
      chronic disorders would develop additional psychological problems. The necessity
      of an interdisciplinary vulval disease clinic in Thuringia was stated by 71% of
      the interviewed physicians. 76% of the gynaecologists and 75% of the general
      practitioners welcomed the introduction of the clinic. Interestingly, only 51% of
      the dermatologists felt that a vulval disease clinic was necessary. CONCLUSION:
      The majority of the physicians in Thuringia welcomed an interdisciplinary vulval
      disease clinic to improve the conditions for women suffering from genital
      diseases.

PMID- 10592402
TI  - Acquired angioedema with C1 inhibitor deficiency: is the distinction between type
      I and type II still relevant?
AB  - BACKGROUND: Acquired angioedemas are divided into type I associated with
      lymphoproliferation and type II caused by anti-C1-inhibitor antibodies. Recent
      reports have suggested that this distinction is not so clear-cut, mainly because
      of the presence of antibodies against the C1 inhibitor in some cases belonging to
      the type I group. We report herein 2 additional cases of acquired angioedema with
      anti-C1-inhibitor antibody. MATERIAL AND METHODS: One man and 1 woman had had
      acquired angioedema for several years. In the man, a monoclonal component had
      been detected several years before the present study. In the second patient, a
      monoclonal component was detected during the study. The following data were
      studied on successive blood samples collected during angioedema manifestations:
      complement component levels, functional activity of the classical pathway,
      functional and antigenic C1 inhibitor doses, ELISA test to detect autoantibodies
      to C1 inhibitor and Western blot analysis of the C1 inhibitor. RESULTS: In both
      patients, CH50 and C4 activities were decreased, and an autoantibody to C1
      inhibitor was detected. In 1 case, the antibody appeared after the monoclonal
      component; in the second case, it appeared before and belonged to a different
      immunoglobulin class. CONCLUSION: Our data suggest that the distinction between
      type I and type II acquired angioedema is no longer valid because of overlapping
      in some cases.

PMID- 10592404
TI  - Evaluation on the antipruritic role of transcutaneous electrical nerve
      stimulation in the treatment of pruritic dermatoses.
AB  - BACKGROUND: Pruritus is a common and sometimes distressing symptom in many
      dermatological conditions. Response to conventional pharmaceutical agents may not
      be satisfactory, and adverse effects are real problems. OBJECTIVE: To evaluate
      the short-term efficacy and adverse effects of transcutaneous electrical nerve
      stimulation (TENS) for ameliorating pruritus in patients with dermatoses.
      METHODS: A prospective 1-week study using TENS given once daily for treating
      pruritic dermatoses in 5 patients. RESULTS: Significant amelioration of pruritus
      was obtained without adverse effect referable to TENS treatment, and a subjective
      reduced use of conventional topical drugs was also reported by all patients.
      CONCLUSIONS: TENS is a useful aramentarium for short-term amelioration of
      pruritus in pruritic dermatoses. Long-term efficacy and safety await further
      studies.

PMID- 10592403
TI  - Effect of gentian violet, corticosteroid and tar preparations in Staphylococcus
      aureus-colonized atopic eczema.
AB  - BACKGROUND: In atopic eczema (AE), skin colonization with Staphylococcus aureus
      plays a possible role in the pathophysiology of the disease. METHODS: Thirty
      eight patients with AE were screened for their cutaneous colonization with S.
      aureus. The antibacterial and clinical efficacy of topical therapy with the
      antiseptic dye gentian violet, a potent glucocorticosteroid or a tar solution
      (liquor carbonis detergens) was evaluated in vivo in 21 patients with a density
      of >10(4) CFU/cm(2) and in vitro. Skin sites were treated twice daily for 4 days
      with the active drug or a corresponding control. Quantification of S. aureus was
      done daily during therapy as well as 3 days thereafter. The severity of the
      lesions was rated by a regional SCORAD. RESULTS: In gentian-violet-treated skin,
      bacterial density decreased significantly in lesional (p < 0.001) and unaffected
      skin (p < 0. 001). Bacterial densities did not decrease during therapy with
      glucocorticosteroid or liquor carbonis detergens but dropped afterwards. All
      therapeutics reduced the severity score, reduction being greatest for the
      glucocorticosteroid and lowest for liquor carbonis detergens. In vitro, a high
      antibactericidal efficacy was demonstrated only for gentian violet. CONCLUSIONS:
      Antibacterial therapy with gentian violet not only reduces S. aureus
      dramatically, but also reduces the severity of the eczema. Reduction of S. aureus
      after therapy with glucocorticosteroids and LCD seems to be secondary to
      improvement of the skin condition.

PMID- 10592405
TI  - A placebo-controlled clinical trial to compare a gel containing a combination of
      isotretinoin (0.05%) and erythromycin (2%) with gels containing isotretinoin
      (0.05%) or erythromycin (2%) alone in the topical treatment of acne vulgaris.
AB  - PURPOSE: To compare the clinical benefit of isotretinoin (0.05%) and erythromycin
      (2%) gels alone and in combination (Isotrexintrade mark) in acne patients.
      PROCEDURE: The study was a randomised placebo-controlled trial in acne patients
      who should benefit from topical therapy. RESULTS: All treatment groups except
      placebo produced a time-related reduction in lesion counts, with the combined
      therapy producing the largest mean decrease. Between-group comparisons showed
      several significant differences. CONCLUSION: Isotrexin was significantly better
      than placebo at all time points for inflamed and total lesions, and was better
      than isotretinoin at week 4. Side-effects were minimal.

PMID- 10592406
TI  - The use of itraconazole to treat cutaneous fungal infections in children.
AB  - BACKGROUND: Cutaneous mycoses such as tinea capitis, onychomycosis and some cases
      of tinea corporis/cruris, and tinea pedis/manus require oral antifungal therapy.
      There is relatively limited data regarding the use of the newer oral antifungal
      agents, e.g. itraconazole, in the treatment of these mycoses in children.
      OBJECTIVE: We wished to determine the efficacy and safety of itraconazole
      continuous therapy in the management of cutaneous fungal infections in children.
      METHODS: Children with cutaneous mycoses were treated with itraconazole in an
      open-label manner in 4 studies. For tinea capitis, the treatment regimens using
      itraconazole continuous therapy were: study 1, 3 mg/kg/day for 4 or 8 weeks;
      study 2, 5 mg/kg/day for 6 weeks, and study 3, 5 mg/kg/ day for 4 weeks. In a
      different trial, study 4, itraconazole continuous therapy 5 mg/kg/day was used to
      treat toenail onychomycosis (duration: 12 weeks), tinea corporis/ cruris
      (duration: 1 week) and tinea pedis/manus (duration: 2 weeks). RESULTS: The
      efficacy rates at follow-up 12 weeks from the start of therapy in children with
      tinea capitis treated using the itraconazole continuous regimen were: clinical
      cure (CC) and mycological cure (MC) in study 1 (n = 10, Trichophyton violaceum
      all patients), CC 50%, MC 86%; in study 2 (n = 35, Microsporum canis 22 patients,
      Trichophyton sp. 12 patients), CC 82.8%, MC 80%, and in study 3 (n = 16, M. canis
      11 patients, Trichophyton sp. 5 patients), (CC 66.7%, MC 78.5%. Itraconazole was
      also effective in the treatment of dermatomycoses in 24 children (study 4). The
      CC and MC rates at the follow-up 8 weeks from the start of therapy in children
      with dermatomycoses and 12 months in children treated for onychomycosis were:
      onychomycosis (n = 1, T. rubrum), CC 100%, MC 100%; tinea corporis (n = 12, M.
      canis 10 patients), CC 100%, MC 90%; tinea cruris (n = 3, Trichophyton sp. 2
      patients), CC 100%, MC 100%; tinea manus (n = 1, T. rubrum), CC 100%, MC 100%,
      and tinea pedis (n = 7, T. rubrum), CC 100%, MC 100%). Adverse effects consisted
      of a cutaneous eruption in 1 (1.2%) of the 85 children, with mild, transient,
      asymptomatic elevation of liver function tests (less than twice the upper limit
      of normal) in 2 (3.4%) of 58 children in whom monitoring was performed.
      CONCLUSIONS: Itraconazole is effective and safe in the treatment of tinea capitis
      and other cutaneous fungal infections in children.

PMID- 10592407
TI  - IgG autoantibodies from a lichen planus pemphigoides patient recognize the NC16A
      domain of the bullous pemphigoid antigen 180.
AB  - Lichen planus pemphigoides (LPP) most likely encompasses a heterogeneous group of
      subepidermal autoimmune blistering disorders occurring in association with lichen
      planus. We describe the case of a 49-year-old patient with features
      characteristic of LPP. Direct immunofluorescence microscopy studies demonstrated
      linear deposits of C3 along the cutaneous basement membrane, while circulating
      IgG autoantibodies directed against the epidermal side of skin separated by 1 M
      NaCl were detected. The patient's serum contained IgG autoantibodies
      immunoblotting a recombinant form of bullous pemphigoid antigen 180 (BP180), but
      not the COOH-terminus of BP230. By using deletion mutants, it was found that IgG
      reactivity was restricted to the NC16A domain of BP180, the region harboring the
      major antigenic sites targeted by IgG autoantibodies from patients with the
      bullous pemphigoid group of disorders. Our findings provide support to the idea
      that a subset of patients with LPP have a distinct form of bullous pemphigoid
      associated with lichen planus.

PMID- 10592408
TI  - Assessing hair shedding in children.
AB  - BACKGROUND: The wash test is currently used to assess hair shedding, though it
      lacks a cut-off point of normality and any evidence of being reliable. The aim of
      this study is to provide data to fulfil those needs. METHODS: The wash test was
      employed in a standardized way on 31 children aged 3-11 years. RESULTS: The test
      yielded 10.68 +/- 3.91 hairs, a figure which may be considered as 'normal' for
      children of that age. The chi(2) test granted the validity of the method. The
      number of shed hairs counted in the washing basin increased with the age of the
      subjects. COMMENT: The wash test proved to be reliable and to be a useful tool
      for monitoring hair shedding. The increasing trend with age may suggest a
      possible prepubertal onset of androgenetic alopecia.

PMID- 10592409
TI  - A baboon syndrome induced by intravenous human immunoglobulins: report of a case
      and immunological analysis.
AB  - Following the second series of intravenous human immunoglobulins (IVIg; 0.4 g/kg)
      prescribed to treat a sensorimotor polyneuritis, a 28-year-old woman developed
      pompholyx that recurred after each of the following monthly treatments with IVIg.
      During the administration of the 10th series, the patient developed a typical
      baboon syndrome. Immunohistochemical studies of a skin biopsy revealed an
      unexpected epidermal expression of P-selectin, usually expressed by endothelial
      cells. Patch, prick and intradermal tests performed with IVIg on the back, arms
      and buttocks gave negative results on immediate and delayed readings. IVIg were
      re-administered, with the informed consent of the patient, and induced a
      generalized maculopapular rash. This is the first reported case of baboon
      syndrome induced by IVIg. Although extensive skin testing was performed, all test
      sites remained negative. We wonder whether IVIg could reproduce immunological
      mechanisms involved in the 3 types of systemic contact dermatitis (pompholyx,
      baboon syndrome and maculopapular rash), including the epidermal expression of P
      selectin.

PMID- 10592410
TI  - Successful treatment of progressive vitiligo with high-dose intravenous
      methylprednisolone 'pulse' therapy.
AB  - We report on the successful therapy of rapid progressive generalized vitiligo in
      a 24-year-old woman. After intravenous injection of 500 mg of methylprednisolone
      on 3 consecutive days, the disease progression was stopped and repigmentation was
      induced. The treatment was repeated monthly and after 6 cycles, repigmentation
      was achieved on vast parts of most vitiligo lesions. The treatment was well
      tolerated by the patient, and no side effects were noted. We conclude that high
      dose glucocorticoid pulse therapy may represent a therapeutic alternative in
      selected patients with generalized rapid progressive vitiligo.

PMID- 10592411
TI  - Frontal mucocele presenting as a subcutaneous tumour on the forehead.
AB  - A 57-year-old Japanese woman had a 3-month history of an asymptomatic
      subcutaneous tumour on the forehead. The patient presented a slightly elevated,
      elastic soft subcutaneous mass, 3 cm in diameter, on the mid to left-side
      forehead. Slight swelling of the left upper eyelid was observed. CT scanning and
      magnetic resonance images revealed a sharply demarcated cystic mass from the
      subcutaneous area on the forehead expanding into the frontal sinus and
      intracranial space. The tumour was diagnosed as a frontal mucocele and combined
      external and endoscopic approaches were performed. It is rare that a patient with
      a frontal mucocele is initially referred as a case of a subcutaneous tumour
      because most of the patients complain primarily of the ophthalmic symptoms.
      However, the present case reminds us that frontal mucocele is one of the
      differential diagnoses for a subcutaneous mass on the forehead.

PMID- 10592412
TI  - Mutilating facial sarcoidosis.
AB  - We report a patient with massive facial sarcoidosis. While skin involvement is a
      common manifestation of sarcoidosis, it is unusual to see it in the dramatic form
      of cutaneous tumors with mutilation of the central face. There are few reports of
      tumoral cutaneous sarcoidosis like that of our patient.

PMID- 10592413
TI  - Skin invasion of Hodgkin's disease mimicking scrofuloderma.
AB  - We report a case of direct skin invasion by Hodgkin's disease from a left
      supraclavicular lymph node. Clinical and pathological presentations mimicked
      infectious disease such as scrofuloderma. The nodule later developed a fistula
      following a biopsy that never healed despite numerous antibiotic treatments. Ten
      months later, other nodules with spontaneous fistula formation appeared on the
      anterior neck. A diagnosis of Hodgkin's disease was then made. Subsequent COPP
      cytostatic therapy remarkably improved the skin lesions and lymph nodes achieving
      complete remission.

PMID- 10592414
TI  - Lipodermatosclerosis - report of three cases and review of the literature.
AB  - We report 3 cases of lipodermatosclerosis (LDS) and discuss the nosology of
      similar disorders caused by venous insufficiency of the legs. These cases are
      characterized by (1) occurrence in middle-aged or aged woman, (2) painful,
      indurated erythema with hyperpigmented scleroderma-like hardening on the lower
      leg, (3) lobular panniculitis with membranocystic fat necrosis and various
      degrees of septal fibrosis. Although the designation LDS has been used
      particularly in the UK and in the USA, this entity is not familiar in other
      countries including Japan. LDS clinically represents a wide spectrum from an
      acute, inflammatory phase to a chronic, fibrotic state. The clinicopathologic
      findings of LDS are similar or identical to the disease previously reported as
      chronic indurated cellulitis, hypodermitis sclerodermiformis, stasis panniculitis
      or sclerosing panniculitis. These diseases are probably related conditions, which
      depend upon the various stages.

PMID- 10592415
TI  - Spindle cell hemangioma.
AB  - A 27-year-old woman presented with multiple nodules closely grouped on her right
      upper distal extremity. The lesions, dating from childhood, increased slowly in
      time. Microscopic examination of one nodule showed the histologic features of
      spindle cell hemangioendothelioma (SCH). At the periphery of the nodule there
      were also some features of the so-called sinusoidal hemangioma. Clinically, SCH
      can present as a solitary lesion or as multiple lesions in zonal distribution.
      When the lesions are multiple, the diagnosis of Maffucci's syndrome should be
      considered. SCH may be interpreted as a reactive process secondary to thrombosis
      and recanalization occurring in angiomatous lesions with different clinical
      presentations. Spindle cells are probably mesenchymal cells modified by blood
      pressure. For this entity the term hemangioma seems to be preferable to that of
      hemangioendothelioma.

PMID- 10592416
TI  - Diphenylcyclopropenone: an important agent known to cause depigmentation.

PMID- 10592417
TI  - A case of arteriovenous hemangioma associated with liver cirrhosis.

PMID- 10592418
TI  - Darier-White disease and dermatofibrosarcoma protuberans.

PMID- 10592420
TI  - Accelerated allergic contact dermatitis to a transcutaneous electrical nerve
      stimulation device.

PMID- 10592419
TI  - Urolithiasis in lichen planus.

PMID- 10592421
TI  - Eosinophilic fasciitis following idiopathic thrombocytopenic purpura, autoimmune
      hemolytic anemia and Hashimoto's disease.

PMID- 10592422
TI  - Discordance between fetal RhD typing using molecular methods and neonatal typing
      with serology.
AB  - Polymerase chain reaction (PCR)-based genotyping on amniotic fluid in an RhD
      negative alloimmunized woman predicted an RhD-negative fetal blood type. The
      neonate was RhD-positive and developed hemolytic disease. Discrepant results were
      also observed on paternal testing. PCR analysis with a different set of primers
      correctly predicted the RhD-positive fetal and paternal blood type. Use of more
      than one set of primers and parental testing can avoid some of the problems
      associated with use of PCR genotyping.

PMID- 10592423
TI  - Evaluation of treatment of hyperemesis gravidarum using parenteral fluid with or
      without diazepam. A randomized study.
AB  - OBJECTIVE: Hyperemesis gravidarum is a relatively unknown disease, and is
      generally self-limiting. In some women the symptoms are so severe as to threaten
      the health of the mother and fetus. Therapies proposed for hyperemesis gravidarum
      are therefore rather empirical. Medical treatment includes parenteral fluid
      replacement and nutrition, electrolytes, antiemetics, vitamins, sedation and
      psychological counseling. Diazepam and benzodiazepines have been widely studied
      in pregnancy but the results are contradictory. The aim of the present study was
      to investigate the efficacy of parenteral fluids with vitamins, with or without
      diazepam sedation. METHODS: Fifty women with hyperemesis gravidarum were enrolled
      in the study. They were treated with infusions of normal saline, glucose,
      vitamins and randomly with diazepam. RESULTS: The results show that the mean stay
      in the hospital was shorter in the diazepam group: 4.5 +/- 1.9 vs. 6 +/- 1.6 days
      (p < 0.05) and readmission to the hospital was 4% in the diazepam group versus
      27% in other group (p < 0.05). There was a significant reduction in nausea in the
      diazepam group (p < 0.05). A significant reduction in vomiting was observed in
      both groups. No side effects or congenital neonatal malformations were found in
      the diazepam group. CONCLUSIONS: Intravenous administration of fluids and
      vitamins is the standard treatment for women hospitalized for hyperemesis
      gravidarum. The addition of diazepam to the treatment is effective in reducing
      nausea and does not have teratogenic effects.

PMID- 10592424
TI  - Fetal middle cerebral artery Doppler waveforms in twin-twin transfusion syndrome.
AB  - The aim of this study was to compare the fetal middle cerebral artery (MCA)
      Doppler waveforms in growth-retarded twin fetuses with (n = 11) and without (n =
      24) twin-twin transfusion syndrome (TTTS). Umbilical artery (UA) and fetal MCA
      Doppler velocity waveforms were recorded on admission. The mean values of the UA
      pulsatility index (PI) of smaller twin fetuses with and without TTTS were
      significantly higher than those of normal singleton pregnancies. The mean values
      of the MCA PI of smaller twin fetuses in the TTTS group (+0.7 +/- 1 SD) were
      significantly higher than those of normal singleton pregnancies on admission, and
      these levels did not markedly change following amniocentesis. On the other hand,
      the values of the MCA of the growth-retarded fetuses without TTTS (-0.9 +/- 1 SD)
      were significantly lower than those of normal singleton pregnancies. Our findings
      suggest that measurement of fetal MCA PI is a useful method to assess growth
      retarded fetuses in monochorionic twin pregnancies.

PMID- 10592425
TI  - Is carbohydrate metabolism altered among women who have undergone a preeclamptic
      pregnancy?
AB  - OBJECTIVE: To compare women after a preeclamptic pregnancy with women after a
      normal pregnancy with respect to androgenic-anabolic status and carbohydrate and
      lipid profiles. METHOD: Twenty-one patients and 22 controls were followed up to
      26-119 weeks after delivery. Blood was sampled for analyses of insulin, glucose,
      insulin growth factor-1, lipids, androgens, sex hormone-binding globulin (SHBG)
      and uric acid. Anthropometric data and blood pressure were recorded. Data are
      presented as median and ranges (within parentheses) or mean +/- SEM where
      appropriate. Comparisons were made by unpaired t test or Mann-Whitney U test,
      respectively. RESULTS: Significantly higher values were found in the preeclampsia
      than in the control group for fasting insulin, fasting glucose, fasting insulin
      resistance index (FIRI, fasting glucose x fasting insulin/25), serum
      triglycerides, uric acid and blood pressure. There were no differences in
      androgen status and IGF-1 levels. CONCLUSION: Patients with a recent history of
      preeclampsia demonstrate signs of relative insulin resistance,
      hypertriglyceridemia and hyperuricemia as well as increased blood pressure as
      compared with women who had a normal pregnancy. However, in contrast to other
      women with insulin resistance, they have a normal androgen status.

PMID- 10592426
TI  - Plasma nitric oxide metabolites and lipid peroxide levels in preeclamptic
      pregnant women before and after delivery.
AB  - It has been suggested that oxidative stress may cause endothelial dysfunction and
      that endothelial dysfunction may lead to hypertension by reduced release of
      vasodilating agents such as nitric oxide (NO). In this study, we investigated the
      relationship between serum NO and lipid peroxides in preeclamptic and normal
      pregnant women before and after delivery. Plasma from women with preeclampsia had
      significantly lower nitrate/nitrite concentrations and significantly higher lipid
      peroxide levels than normal pregnant women before the delivery. Lipid peroxide
      levels were significantly elevated in preeclamptic placenta. After delivery in
      the preeclamptic group the plasma concentration of nitrate/nitrite was increased
      and plasma thiobarbituric acid reactive substance levels decreased, while these
      parameters remained unchanged in the normal pregnants women. These results
      indicate that high levels of lipid peroxides in the circulation may be the cause
      of lowered NO synthesis and hypertension observed in preeclamptic women.

PMID- 10592427
TI  - Timing of subsequent pregnancy following treatment of molar pregnancy.
AB  - OBJECTIVE: To assess the practice habits and recommendations of members of
      American Society of Gynecologic Oncologists (ASGO) dealing with follow-up
      management of molar pregnancy. MATERIALS AND METHODS: A questionnaire was mailed
      to ASGO members requesting their recommended waiting period for subsequent
      pregnancy following treatment of molar pregnancy. Year of Fellowship completion
      was determined for each respondent. RESULTS: Only 36.8% still recommended the
      traditionally accepted 12-month waiting period, and 31.3% recommended 6 months.
      The trend was toward shorter waiting periods among younger, more recently trained
      oncologists, although differences were not statistically significant. CONCLUSION:
      It appears time to review the recommendation of a 12-month waiting period. A
      reduction of at least down to 6 months may be appropriate, but needs further
      investigation.

PMID- 10592428
TI  - Timing of sonohysterography in menstruating women.
AB  - A prospective, blind study was carried out on 44 patients to evaluate the most
      suitable time to perform transvaginal sonohysterography. On the day of arrival at
      our unit, regardless of their cycle day, the women underwent sonohysterographic
      evaluation, which was repeated during the first 10 days of the next cycle.
      Patients with sonohysterographic findings underwent hysteroscopy. According to
      the timing of the first examination, they were divided into two groups, i.e.
      group 1 for the first 10 days of the cycle, and group 2 for days 16 through 28.
      At the end of the study the groups were compared. The results showed a false
      positive rate of 27% in group 2, while no false-positive was found in group 1. We
      concluded that the best time for sonohysterography in patients who still have
      their menstrual period is during the first 10 days of the cycle.

PMID- 10592429
TI  - A sensitive, nonradioactive method for the detection of a low level of apoptosis
      in rat ovary and human placenta. Technical note.
AB  - Apoptosis is often characterized by internucleosomal DNA fragmentation, which is
      classically visualized in standard agarose gel electrophoresis. However, this
      technique is not sufficiently sensitive for the detection of a modest apoptotic
      level in intact tissues. We developed a sensitive, nonradioactive method for the
      qualitative and quantitative analyses of apoptotic DNA fragmentation in intact
      tissues. An ultrasensitive chemiluminescent substrate, CDP-Star, was used for the
      visualization of digoxigenin (DIG)-labeled DNA fragments, and banding patterns
      were densitometrically quantified. Serially diluted DNA samples from rat ovaries
      were labeled with DIG. As a result, only 1.56 ng of DNA could be analyzed for the
      presence of apoptotic DNA cleavage. The sum intensity of these bands increased
      almost linearly by increasing the amount of labeled DNA. In human placental
      tissues, clear apoptotic DNA ladders were visualized by this method, and the
      quantification of apoptotic DNA fragmentation was also possible. This new method
      provides a nonradioactive, highly sensitive and semiquantitative analysis of
      apoptotic DNA fragmentation and may be highly useful for the study of a low,
      physiological level of apoptosis.

PMID- 10592430
TI  - Urodynamic investigation of women operated on for genuine stress incontinence.
AB  - Anterior colporrhaphy (Kelly-Stoeckel suture) was performed on 22 women suffering
      from grade-I or grade-II genuine stress incontinence. Urodynamic investigation
      was performed on every patient before surgery and 6 months postoperatively. 21
      patients were cured and 1 patient improved. After operation the functional
      urethral length was increased by 28.8%, and urethrovesical pressure transmission
      was improved by 22.9%. Maximum urethral closure pressure decreased
      postoperatively by 21.1%. Pressure transmission was clearly improved by the
      surgical intervention and urinary continence was restored in spite of the fact
      that maximal urethral closure pressure decreased. Based on these results it is
      suggested to consider performing anterior colporrhaphy in cases of weak urethral
      closure pressure, because of the increased risk of worsening the complaints of
      these patients.

PMID- 10592431
TI  - A three-year postoperative evaluation of tension-free vaginal tape.
AB  - The aim of this study was to evaluate the outcome of tension-free vaginal tape
      (TVT) 3 years after surgery. Fifty-one women (mean age 52.9) with a genuine
      stress incontinence underwent the TVT operation. In 10 patients, a prolapse
      repair was also done simultaneously. The majority of the patients were operated
      under local anesthesia. All patients were evaluated 3 years after the procedure
      using a protocol for objective and subjective assessment of the outcome including
      an evaluation of quality of life related to urinary incontinence. According to
      the protocol, 46 women (90%) were successfully cured, another 3 patients (6%)
      were improved, whereas 2 patients (4%) were classified as failures. Few
      complications occurred. We conclude that TVT is a simple and well-accepted
      minimal invasive surgery for treatment of female urinary stress incontinence. The
      outcome 3 years after the operation showed no signs of deterioration compared to
      the results shortly after surgery. The cure rate of 90% is comparable with the
      best results of other surgical treatments for female urinary incontinence.

PMID- 10592432
TI  - Neurochemical characterization of the vestibular nerves in women with vulvar
      vestibulitis syndrome.
AB  - Women with vulvar vestibulitis syndrome (VVS) have a distinct burning pain
      provoked by almost any stimuli in the area around the vaginal introitus. In a
      previous study we observed an increased number of intraepithelial free nerve
      endings in women with VVS. The aim of the present study was to neurochemically
      characterize the superficial nerves in the vulvar vestibular mucosa of women with
      VVS. Immunohistochemical methods were used to detect neuropeptides normally found
      in various types of nerve fibers. Calcitonin gene-related peptide, which is known
      to exist in nociceptive afferent nerves, was the only neuropeptide detected in
      the superficial nerves of the vestibular mucosa. These findings confirm our
      previous theory that the free nerve endings within the epithelium are
      nociceptors.

PMID- 10592433
TI  - GnRH analogues and uterine leiomyomas. Effect of hormone replacement therapy on
      cell proliferation.
AB  - Cell proliferation in uterine leiomyomas treated preoperatively with either
      nafarelin (400 microg/day) for 3 months (7 patients) or nafarelin plus hormone
      (oestradiol + norethisterone) add-back therapy (6 patients) was investigated by
      automatic image analysis of frozen tissue sections using immunohistochemistry
      with anti-proliferating cell nuclear antigen antibody. GnRHa therapy decreased
      cell proliferation in leiomyomas to a level corresponding to the situation
      previously seen in postmenopausal leiomyomas. However, there was no consistent
      correlation between cell proliferation and shrinkage of leiomyomal size. The
      hormone add-back therapy moderated the influence of GnRHa on cell proliferation
      and completely blocked a decrease in size of leiomyomas in our patients.

PMID- 10592434
TI  - Granulocyte colony-stimulating factor on the growth of human ovarian carcinoma
      cells in vitro.
AB  - Granulocyte colony-stimulating factor (GCSF) is a member of a family of
      glycoprotein hormones that stimulates the proliferation and differentiation of
      hematopoietic cells in vivo and in vitro. In ovarian cancer chemotherapy, GCSF is
      used clinically to build up bone marrow function after severe cytotoxicity to
      granulocytes by chemotherapy. Little is known about the effects of these
      cytokines on the growth of cancer cells. To study the influence of GCSF on the
      proliferation of ovarian cancer cells in vitro, five established ovarian cancer
      cell lines (OC-89-VGH, OC-117-VGH, OCPC-2-VGH, NIH-OVCAR-3, and NIH-SK-OV-3) were
      treated with the concentration ranging from 0.1 pg to 10 ng GCSF for 5 days and
      compared with vehicle control. In addition, we also examined the effect of GCSF
      (0. 01-1.0 ng) on eight primary cultures of fresh ovarian cancer tissues. Cell
      viability after treatment was measured by Cell Titer AQueous assay and expressed
      as a percentage of untreated control cultures. A decrease in cell growth (75-85%)
      was observed in OC-89-VGH, OC-117-VGH and OCPC-2-VGH cell lines while NIH-OVCAR-3
      and NIH-SK-OV-3 cells showed minimal growth stimulation. However, all dose
      response curves were nonsignificant, suggesting indirect effects. In the eight
      fresh tumor primary cultures treated with GCSF, no statistical significant
      difference in growth was observed. In conclusion, our data suggest that GCSF has
      little or no growth-modulatory effect on human ovarian carcinoma in vitro.
      Therefore, the clinical use of GCSF is unlikely to have a direct effect on tumor
      growth.

PMID- 10592435
TI  - Salpingectomy for unilateral hydrosalpinx may improve in vivo fecundity.
AB  - The objective of this study was to determine whether unilateral salpingectomy for
      hydrosalpinx could improve fecundity in women with an apparently normal
      contralateral tube. Two women with unilateral hydrosalpinx and with an apparently
      normal contralateral tube, and a long history of infertility, including failure
      to conceive despite several cycles of in vitro fertilization (IVF), had
      unilateral salpingectomies prior to considering subsequent IVF cycles. Case 1
      conceived after 1 month following surgery and case 2 after 8 months without the
      use of assisted reproductive technology. Though the ensuing pregnancies may have
      been fortuitous, the possibility exists that in cases of unilateral hydrosalpinx,
      the performance of salpingectomy may improve fecundity without the need for IVF.
      Hopefully the outcome of these 2 case reports may generate interest in a larger
      cooperative prospective study.

PMID- 10592436
TI  - Leiomyomas in uterine remnants associated with vaginal agenesis.
AB  - A premenopausal woman with vaginal agenesis underwent surgery for leiomyomas in
      rudimentary uterine horns. Immunohistochemical study of surgical specimens
      revealed that progesterone receptors are distributed in the nuclei of a majority
      of the leiomyoma cells and in the nuclei of a minority of the myometrial cells.
      Estrogen receptors are not detected in the surgical specimens.

PMID- 10592437
TI  - Growth hormone releasing substances: types and their receptors.
AB  - A series of structurally diverse growth hormone (GH) releasing substances have
      been synthesized that are distinct from the naturally occurring GH releasing
      hormone (GHRH). These synthetic molecules range from the family of GH releasing
      peptides and mimetics such as MK-0677. The physiological importance of these
      molecules and their receptor is exemplified by studies in the elderly. For
      example, when MK-0677 was administered chronically to 70- to 90-year-old
      subjects, once daily, the age-related reduced amplitude of GH pulses was reversed
      to that of the physiological profile typical of young adults. In 1996, the
      synthesis of (35)S-MK-0677 was reported and used as a ligand to characterize a
      common receptor (GH secretagogue receptor [GHS-R]) for the GH releasing
      substances. The GHS-R is distinct from the GHRH receptor. Subsequently, the GHS-R
      gene was cloned and shown to encode a unique G-protein coupled receptor with a
      deduced protein sequence that was 96% identical in human and rat. Because of the
      physiological importance of the GHS-R, a search for family members (FMs) was
      initiated and its molecular evolution investigated. Three FMs GPR38, GPR39 and
      FM3 were isolated from human genomic libraries. To accelerate the identification
      of other FMs, a vertebrate organism with a compact genome distant in evolutionary
      terms from humans was exploited. The pufferfish (Spheroides nephelus) genome
      provides an ideal model for the discovery of human genes. Three distinct full
      length clones encoding proteins of significant sequence identity to the human GHS
      R were cloned from the pufferfish. Remarkably, the pufferfish gene with highest
      sequence homology to the human receptor was activated by the hexapeptide and non
      peptide ligands. These intriguing results show that the structure and function of
      the ligand binding pocket of the human GHS-R has been highly conserved in
      evolution ( approximately 400 million years) and strongly suggests that an
      endogenous natural ligand has been conserved. This new information is consistent
      with a natural ligand for the GHS-R playing a fundamentally important and
      conserved role in physiology.

PMID- 10592438
TI  - Endocrine and non-endocrine activities of growth hormone secretagogues in humans.
AB  - Growth hormone (GH) secretagogues (GHS) are synthetic peptidyl and non-peptidyl
      molecules which possess strong, dose-dependent and reproducible GH releasing
      effects as well as significant prolactin (PRL) and adrenocorticotropic hormone
      (ACTH) releasing effects. The neuroendocrine activities of GHS are mediated by
      specific receptors mainly present at the pituitary and hypothalamic level but
      also elsewhere in the central nervous system. GHS release GH via actions at the
      pituitary and (mainly) the hypothalamic level, probably acting on GH releasing
      hormone (GHRH) secreting neurons and/or as functional somatostatin antagonists.
      GHS release more GH than GHRH and the coadministration of these peptides has a
      synergistic effect but these effects need the integrity of the hypothalamo
      pituitary unit. The GH releasing effect of GHS is generally gender-independent
      and undergoes marked age-related variations reflecting age-related changes in the
      neural control of anterior pituitary function. The PRL releasing activity of GHS
      probably comes from direct pituitary action, which indeed is slight and
      independent of both age and gender. The acute stimulatory effect of GHS on
      ACTH/cortisol secretion is similar to that of corticotropin releasing hormone
      (CRH) and arginine vasopressin (AVP). In physiological conditions, the ACTH
      releasing activity of GHS is mediated by central mechanisms, at least partially,
      independent of both CRH and AVP but probably involving GABAergic mechanisms. The
      ACTH releasing activity of GHS is gender-independent and undergoes peculiar age
      related variations showing a trend towards increase in ageing. GHS possess
      specific receptors also at the peripheral levels in endocrine and non-endocrine
      human tissues. Cardiac receptors are specific for peptidyl GHS and probably
      mediate GH-independent cardiotropic activities both in animals and in humans.

PMID- 10592439
TI  - Clinical and experimental effects of growth hormone secretagogues on various
      organ systems.
AB  - A new class of growth hormone (GH) secretagogues (GHS) has been developed. In
      rats, the GHS hexarelin exerts cardioprotective effects. In humans, GHS increase
      growth velocity in children with short stature/GH deficiency. In adults, a
      combined infusion of GH releasing peptide-2 and thyrotropin releasing hormone
      increases circulating concentrations of GH as well as that of insulin-like growth
      factor-I. In healthy volunteers, oral GHS administration reverses diet-induced
      catabolism, and in healthy obese men, oral GHS treatment increases fat-free mass.
      However, little is known about the possible direct effects of GHS and there are
      few long-term studies. Therefore, it is not yet possible to fully evaluate the
      use of GHS.

PMID- 10592440
TI  - Growth hormone secretagogues in critical illness.
AB  - Alterations within the somatotropic axis occurring during the course of critical
      illness follow a biphasic pattern. The initial stress response consists of
      activated growth hormone (GH) release whereas circulating levels of GH-dependent
      insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 fall and
      IGFBP-1 concentrations rise. In contrast, in the chronic intensive care-dependent
      phase of severe illness, pulsatile GH secretion substantially decreases whereas
      the non-pulsatile fraction remains relatively elevated, resulting in an
      abnormally flat GH secretory pattern and low-normal mean nocturnal GH serum
      concentrations. Specifically the reduced amount of GH released in pulses is found
      to be related to low circulating levels of IGF-I, IGFBP-3 and acid-labile subunit
      (ALS), which suggests that a relative hyposomatotropism may participate in the
      pathogenesis of the wasting syndrome distinctively in the chronic phase of
      critical illness. The relative hyposomatotropism seems at least in part of
      hypothalamic origin since the whole somatotropic axis has been found to be very
      responsive to continuous infusion of GH releasing peptide (GHRP), administered
      alone or in combination with GH releasing hormone (GHRH), as evidenced by
      reactivated pulsatile GH secretion followed by substantial increases in
      circulating levels of IGF-I, IGFBP-3 and ALS. GHRH alone, however, is unable to
      exert the same effect, which may point to an underlying reduced availability of
      the endogenous ligand for the GHRP receptor. The presence of considerable
      responsiveness to restored endogenous pulsatile GH secretion using GHRPs not only
      further delineates the distinct pathophysiological paradigm of the chronic phase
      of critical illness, as opposed to the acute phase, which is thought to be
      primarily a condition of GH resistance, but may also have important therapeutic
      consequences. Recent data revealed that this novel strategy evokes metabolic
      improvement related to the balanced endocrine responses. Whether GH secretagogues
      also enhance clinical recovery of protracted critically ill patients remains to
      be elucidated.

PMID- 10592441
TI  - Growth hormone secretagogues: the clinical future.
AB  - Growth hormone (GH) releasing hexapeptide (GHRP)-6 and other peptidergic and non
      peptidergic compounds collectively designated GH secretagogues (GHS) are potent
      releasers of GH in man. Their clinical future may be envisioned in three areas:
      therapy of GH-deficient (GHD) states, diagnosis of GHD, and non-endocrinological
      actions. As therapeutic agents and compared with GH itself, GHS have the
      disadvantage of lower potency but have a more physiological and safer profile of
      GH secretion. GHS administration could be indicated for states in which medium GH
      doses have been shown to be effective. As a diagnostic tool, the combined
      administration of GH releasing hormone plus GHRP-6, both at saturating doses, is
      currently the most powerful releaser of GH, devoid of side effects and convenient
      for the patient; it may also be an alternative to the insulin tolerance test for
      the diagnosis of GHD in adult patients. Their potential action at cardiovascular
      level is highly promising. Although the clinical future of GH releasing
      substances is appealing, probably the most relevant contribution has yet to be
      discovered. Once the endogenous ligand of the GHS receptor is identified, we will
      have an insight into the real hypothalamic control of GH secretion in man. With
      this knowledge it is likely that some diagnostic and therapeutic actions that are
      commonly undertaken will significantly change.

PMID- 10592442
TI  - Insulin-like growth factor-I and binding protein-3 and risk of cancer.
AB  - Insulin-like growth factor (IGF)-I is an important mitogen required by some cell
      types to progress from the G1 phase to the S phase of the cell cycle. IGF binding
      proteins (IGFBPs) can have opposing actions, in part by binding IGF-I, but also
      by direct inhibitory effects on target cells. As mitogens and anti-apoptotic
      agents, IGFs may be important in carcinogenesis, possibly by increasing the risk
      of cellular transformation by enhancing cell turnover. Indeed, many types of
      neoplastic cells express or overexpress IGF-I receptors, which stimulate
      mitogenesis when activated by IGF-I in vitro. In vivo, tissue IGF bioactivity is
      determined not only by circulating IGF-I and IGFBP levels, but also by local
      production of IGFs, IGFBPs, and possibly IGFBP proteases that enhance IGF-I
      availability by cleaving IGFBPs. Because determinants of tissue IGF bioactivity
      appear to be regulated in parallel with circulating IGF-I level, it is reasonable
      to hypothesize that the substantial intraindividual variability in circulating
      levels of IGF-I and IGFBP-3 may be important in determining risk of some cancers.
      In recent epidemiologic studies, relatively high plasma IGF-I and low IGFBP-3
      levels have been independently associated with greater risk of prostate cancer in
      men, breast cancer among premenopausal women, and colorectal adenoma and cancer
      in men and women and possibly lung cancer. These include prospective data from
      the Physicians' Health Study and the Nurses' Health Study. In general, two- to
      fourfold elevated risks have been observed for prostate cancer in men in the top
      quartile of IGF-I relative to those in the bottom quartile, and low levels of
      IGFBP-3 were associated with an approximate doubling of risk. For breast cancer,
      an association with IGF-I for postmenopausal women was not apparent, but strong
      associations were observed for premenopausal cases in the Nurses' Health Study.
      Further study is needed to confirm this subgroup finding in women. Recent data
      also indicate that high IGF-I and low IGFBP-3 increase risk of colorectal cancer
      and large or villous adenomas. Of note, for colorectal neoplasia, fourfold
      elevated risks were observed in men and women with low IGFBP-3, whereas high IGF
      I was associated with a doubling of risk. These emerging epidemiologic data
      indicate that high levels of IGF-I and low levels of IGFBP-3 are associated with
      an increased risk of at least several types of carcinoma that are common in
      economically developed countries. Further study is required to determine the
      clinical relevance of these findings.

PMID- 10592443
TI  - IGFs and human cancer: implications regarding the risk of growth hormone therapy.
AB  - Perturbations of the insulin-like growth factor (IGF) axis, including the
      autocrine production of IGFs, IGF binding proteins (IGFBPs) and IGFBP proteases
      such as prostate specific antigen (PSA), and cathepsin D have been identified in
      prostate, lung and breast cancer cells and tissues. Serum IGFBP-3 levels have
      been found to be negatively correlated to the risk of cancer. Interestingly,
      IGFBP-3 is a potent inhibitor of IGF action and also mediates apoptosis via an
      IGF-independent mechanism. Recent case-control studies have found an
      approximately 10% increase in the serum levels of IGF-I in patients with
      prostate, breast and lung cancers, which are among the most frequently diagnosed
      cancers. While the studies indicate an association between serum IGF-I levels and
      cancer risk, causality has not been established. Thus, serum IGF-I level may
      actually be a confounding variable, serving as a marker for autocrine tissue IGF
      I production. Growth hormone (GH) therapy raises both IGF-I and IGFBP-3 levels in
      serum. However, the role of GH in controlling prostate, breast and lung growth
      and carcinogenesis remains unclear from animal studies. Increased GH levels as
      seen in acromegaly have been associated with benign prostatic hyperplasia but not
      with prostate, breast or lung cancers, although colon cancer mortality may be
      increased. Should serum IGF-I levels be proven to play a causal role in the
      pathogenesis of cancer, interpreting the risk associated with therapies such as
      GH replacement must take into account both the duration of exposure and the risk
      magnitude associated with the degree of serum IGF-I elevation. Since GH-deficient
      patients often have a subnormal IGF-I serum level, which normalizes on therapy,
      their cancer risk on GH therapy probably does not increase substantially above
      that of the normal population. Until further research in the area dictates
      otherwise, ongoing surveillance and routine monitoring of IGF-I levels in GH
      recipients should become standard of care.

PMID- 10592444
TI  - Mechanism of puberty.
AB  - The hypothalamo-pituitary-gonadal axis in children is fully functional in fetal
      life and immediately after birth. The reason why it declines with advancing years
      of childhood is not clear but gonadotropin pulsatility is at a nadir at 6 years
      of age. From that time pulsatile gonadotropin starts to reappear but, again, the
      reason why this happens is completely unknown. All of the events of puberty can
      be ascribed to pulsatile gonadotropin-releasing hormone stimulation causing
      pulsatile gonadotropin stimulation of sex steroids. The sex steroids explain the
      development of the pubertal characteristics; the fact that girls have an earlier
      growth spurt than boys is explained by the differential effect of oestradiol and
      testosterone on hypothalamic control of pituitary growth hormone secretion.

PMID- 10592445
TI  - A role for leptin in sexual maturation and puberty?
AB  - Leptin, the ob gene product, is involved in the regulation of body weight in
      rodents, primates and humans. It provides a molecular basis for the lipostatic
      theory of the regulation of energy balance. White adipose tissue and placenta are
      the main sites of leptin synthesis. There is also evidence of ob gene expression
      in brown fat. Leptin seems to play a key role in the control of body fat stores
      by coordinated regulation of feeding behaviour, metabolic rate, autonomic nervous
      system regulation and body energy balance. Apart from the function of leptin in
      the central nervous system on the regulation of energy balance, it may well be
      one of the hormonal factors that signal to the brain the body's readiness for
      sexual maturation and reproduction. During late pregnancy and at birth when
      maternal fat stores have been developed, leptin levels are high. During these
      developmental stages leptin could be a messenger molecule signalling the adequacy
      of the fat stores for reproduction and maintenance of pregnancy. At later stages
      of gestation leptin could signal the expansion of fat stores in order to prepare
      the expectant mother for the energy requirements of full-term gestation, labour
      and lactation. Leptin serum concentrations change during pubertal development in
      rodents, primates and humans. In girls, leptin serum concentrations increase
      dramatically as pubertal development proceeds. The pubertal rise in leptin levels
      parallels the increase in body fat mass. In contrast, leptin levels increase
      shortly before and during the early stages of puberty in boys and decline
      thereafter. Testosterone has been found to suppress leptin synthesis by
      adipocytes both in vivo and in vitro. The decline of leptin levels in late
      puberty in boys accompanies increased androgen production during that time and
      most likely reflects suppression of leptin by testosterone and a decrease in fat
      mass and relative increase in muscle mass during late puberty in males. This
      overview focuses on those topics of leptin research which are of particular
      interest in reproductive and adolescent medicine.

PMID- 10592446
TI  - Gonadotropin releasing hormone agonist treatment for central precocious puberty.
AB  - Several methodological problems complicate the evaluation of final statural
      height (FH) benefit after treatment with gonadotropin releasing hormone (GnRH)
      agonists for central precocious puberty (CPP). Since no controlled study has been
      performed, we have to rely on indirect methods, comparison with predicted height
      or with historical controls. FH of 58 girls, uniformly treated with triptorelin
      slow release formulation (triptorelin-SR, Decapeptyl((R))) for CPP were compared
      with predicted height before treatment and with FH of an historical group of
      patients not treated with GnRH agonist. The comparison with predicted height
      revealed an improvement of 4.8 +/- 5.8 cm; comparison with the historical control
      group showed a mean improvement of 8.3 cm. The post-treatment growth spurt
      (DeltaFH - height at the end of treatment) was a strong predictor of FH in
      multivariate analysis. The data suggest that continuing treatment beyond the age
      of 11 in girls does not improve and could actually decrease FH.

PMID- 10592447
TI  - Dosing of growth hormone in growth hormone deficiency.
AB  - Growth hormone (GH) treatment of GH-deficient (GHD) children is to a certain
      extent standardized worldwide. Recombinant 22 kDa GH is injected once daily by
      the subcutaneous route, mostly in the evening. The amount of GH injected
      (calculated per kg body weight or body surface area, expressed in terms of IU or
      mg) in prepubertal children mimics the known production rate (approximately 0.02
      mg [0. 06 IU]/kg body weight per day). However, there is a wide variation in
      dosage, the reasons for which are partly unknown and partly due to national
      traditions and regimes imposed by authorities regulating reimbursement. The
      situation during puberty is less standardized, with most clinicians still not
      increasing the dosage according to known production rates. The results of these
      approaches in terms of adult height outcome are not always satisfactory. In order
      to achieve optimal height development during childhood, puberty and adulthood,
      strategies must be developed to individualize GH dosing according to set
      therapeutical goals taking into account efficacy, safety and cost. The
      implementation of prediction algorithms will help us to reach these goals. In
      addition, other response variables will have to be monitored during treatment in
      order to correct for deficits resulting from GHD.

PMID- 10592448
TI  - Global situation of growth hormone treatment in growth hormone- deficient
      children.
AB  - Diagnostic criteria and treatment modalities were investigated through
      questionnaires from eleven countries and compared with those in Japan. All
      countries but Australia, where the patients can be treated with GH judged by only
      auxological data, use the combination of auxological data and peak GH value in
      provocation tests. GH value is still gold standard, but the cut off value differs
      among countries. Apart from the differences in cut off value, since it is well
      known that GH concentrations vary according to the assay methods and measurement
      kits, standardization of the measurement kits is mandatory. GH dose ranges
      between 0.5 and 0.7 IU/kg/week in most countries. The lowest dose (fixed dose of
      0.5 IU/kg/week) is used in Japan and the heightest dose (1.05 IU/kg/week) is used
      in the USA. The costs for GH treatment are most expensive in Japan.

PMID- 10592450
TI  - Diagnosis of late puberty.
AB  - Late puberty is defined as the lack of pubertal development at two standard
      deviations above the mean age for the general population of the geographical
      area. In practical terms, this is a chronological age of 14 years for males
      (testicular volume <4 ml) and 13 years for girls (lack of thelarche). The goal of
      the assessment is to determine whether the delay or lack of development is due to
      a lag in normal pubertal maturation or represents an abnormality that must be
      investigated. Etiologies of pubertal delay and pubertal failure include: a)
      Constitutional delay of puberty (healthy patients with a clinical history of
      delayed growth and development; b) Hypogonadotropic states (congenital
      abnormalities, tumours, endocrinopathies); c) Hypergonadotropic states
      (chromosomal alterations, syndromes, genetic disorders,
      radiotherapy/chemotherapy); d) Secondary to chronic illness (organic
      abnormalities, oncological diseases, malnutrition, eating disorders and
      endocrinopathies). Diagnostic evaluation must include: a detailed physical
      examination, including auxological parameters (height and bone maturation),
      personal and familial antecedents, measurements of general hematological and
      biochemical parameters, gonadotropins, prolactin, thyroid hormones, sex steroids,
      growth hormone and growth factors. When necessary, an MRI must be performed. A
      karyotype is indicated in girls with delayed puberty and short stature and in
      boys who have small testes and hypergonadotropism.

PMID- 10592449
TI  - The diagnosis and differential diagnosis of Cushing's syndrome.
AB  - Cushing's syndrome is defined as the symptoms and signs of glucocorticoid excess,
      but the precise diagnosis may be difficult to establish and harder to localise.
      The clinicial, biochemical and imaging features of the syndrome are discussed in
      the light of our own extensive experience and the published literature. We
      describe the optimal diagnostic routines currently recommended in major centres,
      and analyse the sensitivities and specialities of the various tests employed.
      Only by means of establishing a precise diagnosis can the disorder be
      successfully treated.

PMID- 10592451
TI  - Treatment of late puberty.
AB  - The induction of puberty is physically and emotionally disturbing. For that
      reason, low doses of medication need to be introduced and increased slowly,
      regardless of the age at which treatment is started. In boys with growth delay,
      the growth spurt may be induced earlier in the sequence of pubertal developmental
      by using oxandrolone, but puberty itself is induced by slowly increasing doses of
      testosterone. For girls with ovarian failure, oestradiol should be introduced
      from the age of 8 or 9 years, but doses should be very cautiously increased in
      order to allow time for cosmetic development of breasts and growth of the uterus.

PMID- 10592452
TI  - Compliance with growth hormone treatment - is it a problem?
AB  - Treatments fail for a number of reasons. These include the failure of medicines
      at a molecular level, failure to achieve the correct diagnosis and therefore use
      of the correct medication, problems surrounding the doctor-patient relationship,
      and failure of the service to meet patients' expectations. Compliance is
      characteristically viewed as the major cause of treatment failures but implicit
      in the use of the term compliance is the reliance on an imbalance of power where
      the patient follows what is ordered. Such an approach is likely to lead to
      failure. A better model is concerned with promoting the full participation of the
      patient to generate a therapeutic alliance. Despite the need for parental
      administration and a daily therapeutic regimen there appears to be little
      evidence to suggest that concordance is a major problem in growth hormone
      therapy. This is probably because treatment administration relies on the presence
      of a carer and there are tangible effects. However, concordance is likely to be
      an issue where there is mismatch between the patient's expectations and those of
      the doctor. Such a situation may arise when the therapeutic margin is narrow or
      the therapeutic effect minimal. To resolve this situation, adequate pre
      intervention discussion is essential, which should include a clear statement of
      short- and long-term treatment targets and the likelihood of these being achieved
      or not. Carefully constructed health care plans are the key and should include
      educational programmes, home support and regular reinforcement. When concordance
      problems are suspected, careful consideration needs to be given as to whether the
      diagnosis is correct, is the treatment really effective and appropriate and does
      the patient really want the treatment.

PMID- 10592453
TI  - Norditropin SimpleXx: a liquid human growth hormone formulation, a pen system and
      an auto-insertion device.
AB  - Patient compliance is of vital importance for the outcome of any medical therapy.
      Compliance is especially a problem in long-term treatment of non-life threatening
      diseases, such as growth retardation in children. Until recently, all human
      growth hormone (hGH) products required a reconstitution process. Norditropin((R))
      SimpleXx(TM) is a liquid formulation of the biosynthetic hGH product
      Norditropin((R)), and, together with an improved NovoPen((R)) 1.5, NordiPen(TM),
      and an auto-insertion device, PenMate(TM)/NordiPenMate(TM), it has been developed
      in order to ease the injection process for patients. A randomized, open,
      multicentre, crossover trial compared Norditropin((R)) SimpleXx(TM)/improved
      NovoPen((R)) 1.5 with freeze-dried Norditropin((R)) PenSet((R))/Nordiject((R)). A
      total of 67 children with GH deficiency, aged 5-18 years, were treated with
      either Norditropin((R)) SimpleXx(TM) for 6 weeks followed by Norditropin((R)) for
      6 weeks or the opposite (sequences I and II, respectively).
      Acceptability/convenience and pain perception were evaluated by questionnaire
      after each period. The function and handling of the PenMate(TM) were evaluated in
      a Dutch trial by 27 GH-treated children with intrauterine growth retardation,
      aged 4-16 years, and their parents. All children were accustomed to using the
      Nordiject((R)) pen. The evaluation of the PenMate(TM) was based on a
      questionnaire. A similar trial was conducted in England, in which the
      NordiPen(TM) and the NordiPenMate(TM) were evaluated by 25 GH-treated children
      and their parents. Norditropin((R)) SimpleXx(TM) was found to be easier to inject
      by 64% of the children, and 98% of the children found the system easier to use
      overall. There was no difference in pain perception between the two
      administration systems, as judged by questionnaires and visual analogue scale
      score. Three out of four patients preferred to continue treatment with
      Norditropin((R)) SimpleXx(TM). The safety profiles of the two systems were
      similar. In the Dutch trial, the PenMate(TM) was found to be easy and safe to
      handle, even for very young children (aged 4-5 years). Of patients who took a
      long time to get used to the injections, 73% found that the new pen would help. A
      total of 88% of the children would prefer to use the PenMate(TM) in the future.
      Positive results of the handling tests were also reported in the British trial.
      The use of Norditropin((R)) SimpleXx(TM) and the auto-insertion device may
      improve patient compliance.

PMID- 10592454
TI  - The clinical usefulness of liquid human growth hormone (hGH) (Norditropin
      SimpleXx in the treatment of GH deficiency.
AB  - Human growth hormone (hGH) is an essential therapeutic drug for the treatment of
      GH deficiency. The development of recombinant GH using a pen injection system has
      enabled easy and safe treatment of GH-deficient patients; however, the process of
      dissolving hGH in the powder form is complicated and dangerous. In this study, we
      investigated the usefulness of a newly developed liquid form of hGH
      (Norditropin((R)) SimpleXx(TM)) in the treatment of 51 patients with GH
      deficiency. Fifteen previously untreated patients with GH deficiency were treated
      with liquid hGH (group A), and 36 patients who had previously used hGH in the
      powder form were changed to the liquid form (group B). Both groups were treated
      with liquid hGH 0.5 IU/kg per week for 6 months. The growth rate of patients in
      group A increased from 4.0 +/- 2.4 cm/year to 9.2 +/- 2.9 cm/year. The patients
      in group B continued to grow at the same rate as before using the liquid hGH
      therapy. Questionnaires to the patients in group B demonstrated that 85%
      preferred the convenience of using the new liquid form of hGH. Our results
      indicate that liquid hGH has similar efficacy to that of powder hGH, but its
      improved convenience may have a beneficial effect on patient compliance.

PMID- 10592455
TI  - Growth hormone and fluid retention.
AB  - A major side effect of growth hormone (GH) administration is fluid retention.
      Most data indicate that adult GH-deficient patients are dehydrated, i.e. they
      have low total body water, low extracellular water and low plasma volume. When GH
      substitution is initiated in these patients their body fluid compartments are
      restored to normal. The fluid retaining capacity of GH should therefore be
      regarded as a desirable physiological normalization of fluid homeostasis rather
      than an unpleasant side effect.

PMID- 10592456
TI  - Impact of growth hormone administration on other hormonal axes.
AB  - Growth hormone regulates several other hormonal systems and vice versa. The
      present review focusses on the effect of GH administration in adults on selected
      hormonal systems. Growth hormone treatment has been linked to development of
      central hypothyroidism in hypopituitary children. We now know that GH enhances
      the extra-thyroidal conversion of T(4) to T(3). Lowering of T(4) during GH
      treatment therefore reflects biochemical unmasking of subclinical central
      hypothyroidism. In normal adults GH administration does not affect the pituitary
      gonadal axis. There is, however, evidence to suggest that GH substitution in
      hypopituitary adults enhances peripheral actions of sex steroids (males) and
      stimulates gonadal function (females). Both increased, unchanged and reduced
      basal and ACTH stimulated glucocorticoid levels have been reported during GH
      treatment. Several groups have recorded reduced levels of cortisol binding
      globulin with unchanged free cortisol concentrations. Regular assessment of
      thyroid and glucocorticoid status during GH substitution in GH-deficient patients
      is recommended.

PMID- 10592457
TI  - Final height of growth hormone-treated GH-deficient children and girls with
      Turner's syndrome: the Dutch experience. The Dutch Advisory Group on Growth
      Hormone.
AB  - In the Dutch growth hormone (GH) registration database there are currently 552 GH
      deficient children being treated, subcutaneously, with recombinant human GH six
      to seven times per week. Of those, 112 who have been treated for at least 2 years
      have reached final height. Mean age at start of therapy was 11.70 years. Mean GH
      dose was 15.5 IU/m(2) body surface per week. Mean final height was 173.2 cm
      (boys) and 159.7 cm (girls) and -1.36 SD of the population mean. Of the patients,
      73.2% and 63.4%, respectively, reached a final height above -2 SD of the
      population or within target limits. FH-SDS was higher compared with the results
      of earlier cohorts with different treatment regimens. Target height, GH peak
      value at diagnosis, age at start of GH therapy, height SDS (HSDS) at start of
      puberty, and duration of GH therapy were significantly correlated with final
      height. These results, combined with those of a prospective GH dose-response
      study, suggest that better long-term results can be obtained with early and
      prolonged treatment and if the GH dose is individually adapted to the short-term
      growth response. In an ongoing dose-response study, 68 girls with Turner's
      syndrome, aged 2-11 years, were randomized into three dosage groups with a daily
      GH dose of: (group A) 4 IU/m(2) body surface; (group B) 4 IU/m(2) in the first
      year of therapy and 6 IU/m(2) thereafter; (group C) 4 IU/m(2) in the first year,
      6 IU/m(2) in the second year, and 8 IU/m(2) thereafter. After 4 years of GH
      therapy, girls aged 12 years or older started low-dose oestrogen therapy. After 7
      years of GH therapy, mean HSDS in all three groups had increased to values above
      the third percentile for healthy girls. Mean final height and final height gain
      of 25 girls was 159.1 and 12.5 cm, 161.8 and 14.6 cm, and 162.7 and 16.0 cm in
      groups A, B and C respectively. These long-term and final height results are more
      favourable than the results of earlier Dutch Turner's syndrome studies. Possible
      explanations are the higher GH doses and/or the younger age at start of GH
      therapy.

PMID- 10592458
TI  - Body composition as a clinical endpoint in the treatment of growth hormone
      deficiency.
AB  - Endpoints in the treatment and management of adults with growth hormone (GH)
      deficiency (GHD) can be problematic. Changes in body composition with recombinant
      human GH (rhGH) treatment may be one of the most objective measures that could be
      applied in judging the effectiveness and long-term efficacy. The relative
      strengths and weaknesses of measures of body composition and their potential for
      clinical utility in the setting of rhGH replacement in GHD in adults are
      discussed. Measurement of changes in body fat, regardless of the method employed,
      from pretreatment baseline through 2-6 months of treatment may be quite useful in
      demonstrating the efficacy of rhGH in each patient. Other changes in body
      composition are compromised by the imprecision of the measurements, shifts in
      extracellular water, and the small real changes which occur in bone and muscle in
      the GHD subject. Use of body composition measures of change in fat content as an
      endpoint in determining the efficacy of rhGH treatment in adults with GHD cannot
      be implemented on the basis of current data and would require a carefully
      designed prospective, controlled study. Until such criteria are established and
      accepted, endocrinologists must continue to manage these patients purely on the
      basis of their clinical judgment.

PMID- 10592459
TI  - Determination of insulin-like growth factor-I in the monitoring of growth hormone
      treatment with respect to efficacy of treatment and side effects: should
      potential risks of cardiovascular disease and cancer be considered?
AB  - Insulin-like growth factor (IGF)-I has proven to be important in the diagnosis of
      childhood-onset growth hormone (GH) deficiency (GHD). However, the variability of
      IGF-I should be taken into account before it can be used in a clinical setting.
      GH replacement therapy in GHD patients increases IGF-I into the normal range,
      although there is a large variation. Excessively high (supranormal) GH-induced
      IGF-I levels are associated with increased prevalence of side effects in adults
      with GHD. Consequently, at most centres, GH doses are titrated according to IGF-I
      levels in GHD adults. Whether or not this should also be done in children has not
      been established. Due to the known variability of IGF-I, individual changes in
      IGF-I must exceed approximately 35% to be sufficiently significant to warrant a
      dose adjustment. Novel epidemiological studies have suggested that higher IGF-I
      levels are associated with an increased risk of prostate, breast and colorectal
      cancer compared with lower IGF-I levels in otherwise healthy subjects.
      Consequently, life-time exposure to IGF-I should be considered in all patients
      treated with GH, and IGF-I should preferably be kept within normal age-related
      ranges in children as well as in adults.

PMID- 10592460
TI  - A personal view on the early history of the insulin-like growth factors.
AB  - Salmon and Daughaday, when trying to set up an in vitro assay for Growth Hormone
      (GH), failed to obtain a direct effect on sulphate uptake in cartilage of
      hypophysectomized (hypox) rats. They recognised that this was not the consequence
      of poor methodology or materials, but an encrypted message from the examined
      system. They decided to turn around and to try and decipher it. Treatment with GH
      appeared to render hypox rat serum active in stimulating sulphation in hypox rat
      cartilage. They proposed that GH induced an intermediary substance, responsible
      for this biological effect: sulphation factor (SF), later renamed to
      Somatomedin(s) (SM). This hypothesis met with great criticism and very few took
      on to study this hypothetical substance. Besides disbelief, slow progress was
      also due to initial lack of a practical assay and to the failure to find a tissue
      with enriched concentration from which to extract the activity. From experimental
      evidence, the concept gradually evolved that SF/SM was insulin-like and might be
      identical to NSILA (non-suppressible insulin-like activity). This again generated
      controversy. This characteristic was too far away from the known effects of GH to
      be readily acceptable as a physiological phenomenon. The subsequent recognition
      of the distinct characteristics of the receptors for SM/NSILA and insulin, the
      discovery of the SM/NSILA binding proteins and, much later, a beginning
      understanding of their interactions, modifications and breakdown, have gradually
      resolved this apparent contradiction. When the sequence of two NSILA molecules
      became known, they were named IGF-I and -II. Structural similarity with
      proinsulin and identity of IGF-I with SM-C and -A were established and it was
      found that Multiplication Stimulating Activity (MSA), a growth factor isolated
      from fetal calf serum and subsequently from conditioned media of a rat liver cell
      line, was the rat equivalent of IGF-II. Structure-function relations could be
      studied, a quest which is not yet brought to an end. Meanwhile, the endocrine
      profile of SF/SM had gradually emerged by measuring plasma levels with bioassays.
      The main determinants were found to be age, body size, GH and the nutritional
      state. Later, radioimmunoassays were developed, enabling consolidation and
      detailing of these early observations, and allowing explorations at the tissue
      level. As another aspect of the endocrine paradigm, in vivo effects of IGFs were
      studied. The initial demonstration of an effect of crude preparations on
      longitudinal growth in experimental animals raised heavy scepticism, since the
      effect might have been an artefact caused by contaminants. It took confirmation
      with highly purified preparations and biosynthetic IGF-I to ease this concern.
      Still, not until recent years it was demonstrated, by knocking out the genes,
      that a true physiological and not a pharmacological effect had been induced
      previously. When it was found that most tissues produce SMs and are sensitive to
      their actions, the concept emerged that IGFs may have para- and autocrine
      functions. Early experiments with combinations of growth factors in cell cultures
      had begun to define their specific roles in the cell cycle as competence or
      progression factors. SM-C fell in the latter category. Still, the awareness grew
      that, for obtaining physiologically meaningful results on the role of IGFs in
      complex, dynamic and tissue-specific environments, involving interactions of many
      hormones and growth factors, the intactness of tissue was a prerequisite. One
      result of this approach was the discovery of a direct interaction of GH with
      cartilage, leading, in concert with IGFs, to a clonal expansion of the cartilage
      cells of the growth plate. The isolation and sequencing of the IGF-I and -II
      genes, and later, of six IFG-BPs initiated the gradual elucidation of structure
      and function at the DNA and RNA level and the study of natural and synthetic IGF
      variants. The generation of transgenic animals became feasible

PMID- 10592461
TI  - The vascular perspective of systemic sclerosis: of chickens, mice and men.
AB  - Systemic sclerosis (SSc), or scleroderma, is an autoimmune connective tissue
      disease characterized by structural and functional vascular abnormalities,
      perivascular mononuclear cell infiltration, and increased deposition of
      extracellular matrix in skin and internal organs. The initial stages of SSc are
      generally not accessible for analysis in man, therefore, the availability of
      appropriate animal models is of great importance for the elucidation of the
      pathogenesis of this disease. UCD-200 chickens show the entire clinical,
      histopathological and serological spectrum of SSc, whereas tight skin (Tsk)1/+
      and Tsk2/+ mice, other animal models of scleroderma, lack the vascular injury. A
      parallel comparative study of skin biopsies of UCD-200 chickens and human SSc
      patients revealed that endothelial cell apoptosis, induced by anti-endothelial
      cell antibody (AECA)- dependent cellular cytotoxicity, is a primary event in the
      pathogenesis of SSc. This review focuses on recently established data on
      endothelial cell injury in animals with spontaneous disease and humans, AECA,
      adhesion molecules and cytokine profiles that support a vascular pathogenesis in
      scleroderma.

PMID- 10592462
TI  - Concepts of the pathogenesis of allergic disease: possible roles of Epstein-Barr
      virus infection and interleukin-2 production.
AB  - The prevalence of atopic diseases in so-called developed countries has risen over
      the past several decades, which is too short a period for genetic changes to have
      taken place. Furthermore, the increase has occurred irrespective of race or
      geographical differences in the prevalence of atopic diseases. These facts
      strongly suggest that the increase is due not to genetic factor(s) but to
      environmental factor(s). In this article, previous investigations into the
      pathogenesis of allergic disease are reviewed. The roles of immune cells,
      cytokines, oncoproteins and viral infections are examined.

PMID- 10592463
TI  - High-molecular-weight allergens of the house dust mite: an apolipophorin-like
      cDNA has sequence identity with the major M-177 allergen and the IgE-binding
      peptide fragments Mag1 and Mag3.
AB  - BACKGROUND: A 349-residue recombinant polypeptide of Dermatophagoides farinae,
      Mag 3, has been shown to represent part of a larger 177-kD (M-177) allergen with
      very high IgE-binding activity. METHODS: Cloning and sequencing of cDNA from the
      house dust mites Dermatophagoides pteronyssinus and Euroglyphus maynei was used
      to characterise the polypeptide containing the Mag 3 sequence. RESULTS: cDNA
      clones containing the complete sequence of the E. maynei homologue of the M-177
      allergen were isolated and analysed. The translation contained not only an amino
      acid sequence with 90% identity to the 349-residue Mag-3 fragment but also a
      further sequence with 90% identity to another IgE-binding recombinant D. farinae
      polypeptide designated Mag 1. The complete sequence encoded a mature polypeptide
      of 1,650 residues and a molecular mass of 189.5 kD. cDNA clones from D.
      pteronyssinus also encoded sequences equivalent to the Mag 1 and 3 polypeptides.
      The M-177 sequence showed strong similarity to the lipid transport apolipophorins
      found in insect lipophorins. CONCLUSIONS: cDNA sequence data show that the D.
      pteronyssinus and E. maynei homologues of the M-177 high-molecular-weight D.
      farinae allergen contain sequences equivalent to both the Mag 1 and Mag 3
      recombinant IgE-binding fragments. The N-terminal sequence of the full-length
      1,650 amino-acid allergen showed strong similarity to the insect apolipophorins
      which are poorly soluble in aqueous extracts and exist in the lipid transport
      particles in haemolymph. It is proposed that presentation in lipid particles
      could be a factor which enhances the immunogenicity of this group of allergens.

PMID- 10592464
TI  - Clinical significance of IgE-binding activity to enzymatic digests of ovomucoid
      in the diagnosis and the prediction of the outgrowing of egg white
      hypersensitivity.
AB  - BACKGROUND: We frequently encounter subjects without overt symptoms despite high
      IgE antibodies to egg white and its components. The measurements of these
      antibodies are not necessarily efficient for the diagnosis or the prediction of
      the outcome of egg allergy in children. METHODS: Specific IgE antibodies to egg
      white and its components, including ovomucoid, ovalbumin, ovotransferrin and
      lysozyme, were measured by direct RAST assays. IgE-binding activity to ovomucoid
      degraded by pepsin, trypsin and chymotrypsin was examined by RAST inhibition.
      Thirty subjects were divided into two groups with positive (n=18; mean age +/- SD
      = 42 +/-25 months) and negative (n=12; mean age +/- SD = 48 +/-31 months) oral
      challenge tests with egg white antigens. The individuals with positive results to
      the first challenge tests were given the second provocation tests at mean
      intervals of 32 months. IgE-binding activity of the sera collected on the first
      challenge to these ovomucoid fragments was compared between subjects with
      positive and negative reactions to the follow-up challenge tests. RESULTS: There
      were no significant differences in IgE antibody titers to egg white and its
      components between the positive and negative groups at the first and the second
      challenge tests. IgE-binding activity to ovomucoid digests after treatments with
      pepsin (p = 0.000008) and trypsin (p=0.037), except chymotrypsin (p=0.062), were
      significantly higher in subjects with positive challenge tests than in those with
      negative results. The difference was most remarkable in the IgE-binding to pepsin
      digests; the average concentrations (mean - SD and mean + SD) needed for 50% RAST
      inhibition in the positive group and in the negative group were 2.6 microg/ml
      (0.3 and 25) and 94.2 microg/ml (24.7 and 358.7), respectively. A significant
      difference was still observed in the inhibition tests using filtrates of pepsin
      digests with a membrane with MW 10,000 (p=0.014) and 3,000 (p=0.042) of cutoff.
      The concentration (mean= 0.8, mean - SD=0.2, mean + SD=3.4; microg/ml) of pepsin
      treated ovomucoid required for 50% RAST inhibition in the subjects with positive
      second challenge results was significantly (p=0.033) lower than that (mean=6.8,
      mean-SD=0.6, mean + SD=73.9) of the negative group. CONCLUSION: IgE-binding
      activity to pepsin-digested ovomucoid was of diagnostic value to distinguish the
      challenge-positive subjects from the negative subjects. Subjects with high IgE
      binding activity to pepsin-treated ovomucoid are unlikely to outgrow egg white
      allergy.

PMID- 10592466
TI  - Eotaxin and nitric oxide production as markers of inflammation in allergic
      cynomolgus monkeys.
AB  - BACKGROUND: Cynomolgus monkeys have a natural hypersensitivity to Ascaris suum
      antigen. Inhalation of antigen produces immediate and delayed allergic reactions
      and an influx of inflammatory cells into the lungs. This study investigated the
      production of nitric oxide (NO) and the chemokine eotaxin during this allergic
      response. The effect of bronchoscopy alone on lung inflammatory cells was also
      investigated along with the time course of the eosinophil influx into the lung.
      METHODS: Allergic cynomolgus monkeys were challenged with antigen.
      Bronchoalveolar lavage (BAL) was performed before and after challenge, and end
      tidal NO was measured before and 24 h after challenge. Eotaxin was measured in
      the BAL fluid 6, 24 and 72 h after challenge. One group of animals was treated
      with dexamethasone before challenge to block the influx of cells into the lung.
      RESULTS: BLA alone induced an influx of neutrophils, but not eosinophils, into
      the lung 24 h later. A single antigen challenge produced a marked increase in BAL
      eosinophils that was apparent at 6 h but increased at 72 h after challenge. The
      increase at 6 h was largely blocked by dexamethasone. Three antigen challenges
      produced elevated BAL eosinophil levels that persisted for at least 8 weeks.
      Eotaxin levels rose dramatically 6 h after challenge and remained the same after
      24 h. By 72 h, the eotaxin levels had returned to baseline. The increase in
      eotaxin at 6 h was nonsignificantly reduced by dexamethasone. Exhaled NO levels
      doubled 24 h after challenge and were not affected by dexamethasone. CONCLUSIONS:
      Eotaxin and NO production were increased after airway challenge in allergic
      monkeys. The rise in NO was not blocked by dexamethasone. The effects of
      bronchoscopy on the BAL can be avoided by using alternate lungs on consecutive
      occasions. Eosinophils persist in the BAL for many weeks after antigen challenge.

PMID- 10592465
TI  - Antigen-specific, IgE-selective unresponsiveness induced by antigen-liposome
      conjugates. Comparison of four different conjugation methods for the coupling of
      antigen to liposome.
AB  - BACKGROUND: We have previously reported that ovalbumin (OVA) coupled with
      liposome via glutaraldehyde (GA) induced OVA-specific- and IgE-selective
      unresponsiveness in mice. METHODS: In this study, OVA-liposome conjugates were
      made using four different coupling protocols: via GA, N-(6-maleimidocaproyloxy)
      succinimide (EMCS), disuccinimidyl suberate (DSS) and N-succimidyl-3(2
      pyridyldithio)propionate (SPDP) and the induction of antigen-specific IgG and IgE
      antibody production was investigated for each. In addition, antigen-specific
      cytokine production by spleen cells of mice immunized either with OVA-liposome or
      with OVA adsorbed with aluminum hydroxide was investigated. RESULTS: OVA-liposome
      conjugates coupled via GA or DSS did not induce anti-OVA IgE antibody production
      but induced substantial anti-OVA IgG antibody production. On the other hand, the
      induction of anti-OVA IgE unresponsiveness by OVA-liposome conjugates coupled via
      EMCS or SPDP was incomplete. The amount of interleukin 4 (IL-4) produced by
      spleen cells stimulated in vitro with OVA correlated well with anti-OVA IgE
      antibody production in donor mice. However, the production of no other cytokine,
      i.e., IL-2, IL-5, IL-10 or interferon-gamma, was correlated with in vivo IgE
      antibody production. CONCLUSION: OVA-liposome coupled via GA or DSS induced
      complete suppression of anti-OVA IgE production. The results in this study
      further suggest that the regulation of IgE antibody production does not
      necessarily correlate with so-called Th1 cytokine production.

PMID- 10592467
TI  - Systemic immunological changes induced by administration of grass pollen
      allergens via the oral mucosa during sublingual immunotherapy.
AB  - Twenty-four patients suffering from grass pollen allergy underwent sublingual
      immunotherapy (SLIT) with standardized grass pollen extract for 1 year. In order
      to investigate immunological changes induced by the administration of allergens
      via the oral mucosa, the SLIT-spit method was applied. The cumulative dose of
      approximately 80 microg of major allergen (grass group 5 allergen), was
      relatively low. During the time of treatment, we could observe a significant
      increase in the levels of specific IgG and IgG4 antibodies. However, the titers
      of allergen-specific IgE antibodies showed a significant increase in the course
      of SLIT as well. Analyzing lymphoproliferative responses, a significant decrease
      in reactivity in response to stimulation with complete grass pollen extract (p =
      0. 001) and to recombinant Phl p 1 (a major allergen of timothy grass, p<0.001)
      could be observed, indicating the induction of immunological tolerance.
      Proliferative responses to a control antigen (tetanus toxoid) were not influenced
      by the treatment. At different time points during SLIT, allergen (Phl p 1)
      specific T cell clones (TCC) were established from the peripheral blood of the
      patients. Cytokine production by allergen-stimulated T cells did not reveal any
      changes consistent with immune deviation, i.e. the ratio of Th1/Th2 TCC did not
      change during SLIT. In conclusion, we provide evidence that sublingual treatment
      leads to systemic changes in immunoreactivity to the administered allergen.

PMID- 10592468
TI  - Distinct serum cytokine levels in drug- and measles-induced exanthema.
AB  - BACKGROUND: Macular or maculopapular skin reactions are frequent events in drug
      allergy as well as in viral infections. Clinically, the differentiation may be
      difficult in the absence of a clear relationship to drug intake or failure to
      detect virus-specific antibodies of the IgM class. Studies on drug-specific T
      cell lines and T cell clones isolated from drug-allergic patients have suggested
      that these cells may represent a significant source of IL-5. On the other hand,
      viral infections are frequently associated with elevated IFN-gamma levels.
      OBJECTIVE: Determination of serum-cytokine levels to differentiate between drug-
      and virally induced skin eruptions. PATIENTS: 18 patients suffering from acute
      drug allergy and 19 patients with acute measles, rubella or parvovirus infection.
      MEASUREMENTS: Cytokine-ELISA (IL-5, IL-4 and IFN-gamma) of sera collected during
      acute drug allergy or during acute measles, rubella or parvovirus infection.
      RESULTS: In 12/18 patients with drug allergy, IL-5 and/or IL-4 were elevated. A
      significant correlation (r(Spearman) = 0.84) between IL-5 serum levels and
      eosinophil counts in the blood was found. No correlation was detected between IL
      4 and blood eosinophilia or between IL-4 and IL-5 levels. After remission, IL-5
      and IL-4 decreased to undetectable levels. IFN-gamma on the other hand was not
      measurable in patients with drug allergy while elevated IFN-gamma serum levels
      were detected in 17/19 patients with measles, rubella or parvovirus infection; 2
      patients with acute virus infection had elevated IL-5, and/or IL-4 and IFN-gamma
      levels. CONCLUSION: These data underline the distinct pathogenesis of these
      morphologically similar exanthemas and suggest that the combined analysis of
      eosinophilia in the blood, IL-4 and IFN-gamma might help in differentiating skin
      eruptions.

PMID- 10592469
TI  - Nuclear factor kappa B mediates interleukin-8 production in eosinophils.
AB  - BACKGROUND: Recent reports indicate that in response to various stimuli,
      eosinophils produce a variety of cytokines (e.g. IL-8) which play pivotal roles
      in allergic inflammation. In that regard, the transcription factor, nuclear
      factor, Kappa B (NF-kappaB), is an important activator of tumor-necrosis-factor
      alpha (TNF-alpha)-induced IL-8 gene expression in monocytes, lymphocytes and
      neutrophils. We therefore investigated the role played by NF-kappaB in cytokine
      production induced by stimulation of eosinophils with the proinflammatory
      cytokines, granulocyte-monocyte colony-stimulating factor (GM-CSF) and TNF-alpha.
      METHODS: Peripheral blood samples were obtained from human subjects with slight
      to moderate eosinophilia. NF-kappaB activation elicited by exposing cells to GM
      CSF and/or TNF-alpha was investigated using immunohistochemistry and gel shift
      assays. To functionally assess the effects of NF-kappaB translocation, IL-8
      production was also examined using an enzyme-linked immunosorbent assay. RESULTS:
      Stimulation of eosinophils with GM-CSF + TNF-alpha induced significant increases
      in the synthesis and secretion of IL-8 which were associated with translocation
      of NF-kappaB p50 into the nucleus. The binding of NF-kappaB to the DNA was
      verified by the gel shift assays. IL-8 production was significantly inhibited by
      N-acetyl-L-cysteine, FK506 and MG-132, inhibitors of NF-kappaB activation and
      translocation. CONCLUSION: On the basis of our findings, we conclude that
      activation and translocation of NF-kappaB plays a crucial role in the signal
      transduction pathway leading to the synthesis and release of IL-8 by eosinophils.

PMID- 10592470
TI  - Vascular-endothelial cadherin (CD144)- but not PECAM-1 (CD31)-based cell-to-cell
      contacts convey the maintenance of a quiescent endothelial monolayer.
AB  - BACKGROUND: In vivo, all blood vessels are lined by a single layer of flattened
      noncycling endothelial cells. We tested the hypothesis that the maintenance of
      such a quiescent endothelial monolayer depends on homotypic contacts between not
      yet defined growth-inhibitory molecules located at interendothelial junctions.
      METHODS: ECV304 cells, which lack endogenous vascular endothelial cadherin (VE
      cadherin) or CD31 expression, were transfected with cDNA encoding for the
      respective proteins or with the empty vector. RESULTS: In VE cadherin
      transfectants, beta-catenin was targeted to junctional regions and the F-actin
      based cytoskeleton formed parallel bundles reaching from one cell border to the
      other. In contrast, in CD31 transfectants and in empty vector cells, beta-catenin
      was dispersed throughout the cytoplasm, and F-actin formed short, plump and criss
      cross bundles. On a two-dimensional plastic matrix, both, VE cadherin and CD31
      transfectants formed clusters of polygonal cells, whereas in three-dimensional
      gels, only VE cadherin cells were able to form tubes. Empty vector cells grew in
      a fibroblast-like pattern and neither formed clusters nor tubes. Most
      importantly, whereas CD31 and empty vector cells grew on top of each other,
      formed polylayers and maintained cycling even after reaching confluence, VE
      cadherin cells strictly maintained a single layer of flattened cells and the
      numbers of cycling cells dramatically dropped after reaching a continuous
      monolayer. CONCLUSION: The insertion of VE cadherin into ECV304 cells produces a
      cell type which mimics endothelial growth characteristics seen in vivo.

PMID- 10592471
TI  - Elevated soluble interleukin-2 receptor: a marker of T cell activation in
      children with acute asthma exacerbation?

PMID- 10592472
TI  - Reply

PMID- 10592473
TI  - Stereotactic radiation in primary brain tumors in children and adolescents.
AB  - To evaluate treatment outcome and morbidity of stereotactic external-beam
      irradiation (SEBI) in pediatric patients, we reviewed 14 children treated with
      SEBI, using a 10-MV isocentric linear accelerator at McGill University between
      1988 and 1994. The median follow-up was 46 months (range 6-82 months). The median
      age was 14 years. There were 8 low-grade astrocytomas, 3 neuromas and 4 other
      histologies. Twelve patients received fractionated treatments. The median
      collimator diameter was 2.5 cm (range 1-5 cm). The median biological effective
      dose delivered to the entire tumor volume was 57 Gy for astrocytomas and 43 Gy
      for the other histologies. The overall actuarial survival rate and disease-free
      survival rate at 5 years were 83 and 62%, respectively. For the patients with low
      grade astrocytomas, the 5-year survival and disease-free survival rates were 100
      and 60%, respectively. Four children had recurrence at a median of 37 months.
      Four patients developed treatment-related complications: 1 had edema alone, 2 had
      necrosis and 1 had edema associated with necrosis. Neither the physical nor
      radiobiological parameters were predictive of the treatment outcome or the
      treatment complications. Stereotactic irradiation is a valid option for
      progressive nonresectable tumors in children.

PMID- 10592474
TI  - Measurement of ventricular size: reliability of the frontal and occipital horn
      ratio compared to subjective assessment.
AB  - INTRODUCTION: The frontal and occipital horn ration (FOR) has recently been
      described as a simple, linear measurement of ventricular size that correlates
      very well with ventricular volume. This study further characterizes the
      measurement properties of the FOR by investigating its interobserver reliability
      and comparing it to a subjective assessment of ventricular size. METHODS: Axial
      images (CT and MR) of children with hydrocephalus taken before and after third
      ventriculostomy were reviewed by 4 independent observers. Two observers were
      blinded to patient identity and clinical status and 2 observers were nonblinded.
      Each observer independently recorded linear measurements from which the FOR was
      calculated for each image. Each reviewer also made a separate subjective
      assessment of the degree of hydrocephalus on a 9-point adjectival scale.
      Reliability was calculated using a repeated-measures analysis of variance (ANOVA)
      and an intraclass correlation coefficient (ICC) with random image and observer
      effects. RESULTS: There were 120 separate observations (4 observers, 30 images).
      The FOR ranged from 0.33 to 0.75 (mean 0.55, standard deviation 0.11). The
      reliability coefficient was 0.93 (95% confidence interval, CI 0.80-0.97) between
      the 2 blinded observers and 0.98 (95% CI, 0.95-0.99) between the 2 nonblinded
      observer. The overall interobserver reliability for all 4 observers was 0.95 (95%
      CI 0.92-0.98). The mean FOR for each observer was very similar, regardless of the
      observer's blinding status. However, the reliability of the observers' subjective
      assessment of the hydrocephalus was much lower (ICC = 0.77, 95% CI 0. 60-0.88).
      CONCLUSIONS: The FOR demonstrates excellent interobserver reliability (>0.9) and
      was superior to subjective assessments of hydrocephalus. In this study, excellent
      reliability was maintained regardless of the blinding status of the observers.
      This further demonstrates the properties of the FOR as a simple and reproducible
      measure of ventricular size. It is suitable for use in clinical studies, possibly
      even in situations in which observer blinding is not possible.

PMID- 10592475
TI  - Down syndrome and craniovertebral instability. Topic review and treatment
      recommendations.
AB  - The diagnosis and management of occipital-atlantal and atlantoaxial instability
      in Down syndrome patients is a challenging problem in pediatric spine surgery. To
      date, no systematic review of this topic has been presented on this confusing and
      sometimes contentious issue. This topic review will focus on the biomechanical
      and radiographic foundations for which treatment recommendations in Down syndrome
      patients are made. In addition, otolaryngologic and anesthetic considerations in
      Down syndrome are also discussed, as well as advances in surgery that have made
      the operative fusion of these patients easier and safer.

PMID- 10592476
TI  - Achondroplasia and cervicomedullary compression: prospective evaluation and
      surgical treatment.
AB  - The association between sudden death and cervicomedullary compression in infants
      with achondroplasia has been well described. Prospective clinical and imaging
      evaluations have been recommended to identify those infants with achondroplasia
      who are at risk of dying suddenly from respiratory arrest secondary to
      unrecognized cervicomedullary compression. Since 1988, we have prospectively
      evaluated 11 infants (average age 13 weeks) with achondroplasia who were
      asymptomatic for cervicomedullary compression on initial clinical evaluation.
      Craniocervical magnetic resonance imaging (MRI) findings included narrowing of
      the foramen magnum, effacement of the subarachnoid spaces at the cervicomedullary
      junction, abnormal intrinsic cord signal intensity and mild to moderate
      ventriculomegaly. Two patients with severe cord compression underwent immediate
      decompression. Two patients developed opisthotonic posturing within 3 months of
      evaluation and underwent foramen magnum decompression, including suboccipital
      craniectomy and atlantal laminectomy. Surgery in all cases revealed forward
      extension of the squamous portion of the occipital bone, thickened posterior rim
      of the foramen magnum and a dense fibrotic epidural band. There were no
      complications from surgery. Seven patients did not require surgery and were
      followed closely. All 11 patients remain asymptomatic at follow-up (mean 4.6
      years; range 16 months to 7.3 years), and no patient has required a diversionary
      shunt procedure. The results of this prospective study confirm that early
      clinical and MRI evaluations are necessary to determine whether infants with
      achondroplasia have cervicomedullary compression. With early recognition, an
      immediate decompression can be performed safely to avoid serious complications
      associated with cervicomedullary compression, including sudden death.

PMID- 10592477
TI  - Long-term outcome after selective posterior rhizotomy in children with spastic
      cerebral palsy.
AB  - A retrospective analysis of data collected prospectively was performed to
      determine the long-term outcome of lumbosacral selective posterior rhizotomy
      (SPR) in children with spastic cerebral palsy (CP). The study population
      comprised children with spastic CP, who had SPR more than 4 years prior to the
      time of the study and had quantitative standardized assessments of lower limb
      spasticity (Ashworth scale), range of motion measured goniometrically, muscle
      strength (MRC scale) and ambulatory function, both preoperatively and at 1 year
      after SPR. Children meeting these criteria were reassessed at 5 years after SPR
      using the same measures. Hip adductor spasticity, hip abduction range of motion
      and quadriceps strength were chosen as the primary outcome measures for
      statistical analysis. Of 80 patients who met the entry criteria for the study, 33
      completed the 5-year assessments. Significant improvements in spasticity, range
      of motion and muscle strength were noted both at 1 year and at 5 years after SPR.
      The preoperative, 1-year and 5-year values were as follows: hip adductor
      spasticity (Ashworth scale) = 4.1, 2.1, 2.2; hip abduction range of motion
      (degrees) = 20.4, 39.9, 31.7, and quadriceps strength (MRC scale) = 3.6, 4.0,
      4.1. Ambulatory function seemed to be better at 1 and 5 years compared to
      baseline, but no statistical analysis was done for this secondary outcome
      measure. It was concluded that improvements in lower limb motor outcome are
      present at 1 year after SPR, and that these improvements are generally maintained
      at 5 years.

PMID- 10592478
TI  - Successful surgical treatment of a thalamic hydatid cyst with contralateral
      transcallosal approach. Case report and review of the literature.
AB  - An extremely rare case of a thalamic hydatid cyst is presented and the literature
      is reviewed. A right thalamic hydatid cyst without rim enhancement or perifocal
      edema was detected by computed tomography and magnetic resonance. This lesion was
      extirpated successfully with intact contents via contralateral transcallosal
      approach. To our knowledge, this is the second hydatid cyst of the thalamus, an
      unusual location, and the first hydatid cyst to be removed completely with intact
      contents reported in the literature.

PMID- 10592479
TI  - A 3-year-old girl with headaches and ataxia.

PMID- 10592480
TI  - Colloid cyst of the third ventricle.

PMID- 10592481
TI  - Histiocytosis X.

PMID- 10592482
TI  - An alternate technique to close neurosurgical incisions using octylcyanoacrylate
      tissue adhesive.
AB  - The present authors have applied the use of tissue adhesive octylcyanoacrylate,
      recently approved by the FDA, in the closure of routine neurosurgical cases. The
      authors find this to be an excellent substitute for nylon, staples, vicryl or
      steristrip final layer closure of the surgical incision. This is especially
      useful in the pediatric neurosurgical practice where young children can be
      emotionally traumatized by the experience of suture or staple removal. We
      recommend octylcyanoacrylate closure as a safe, simple, quick, cost-effective
      method of skin closure that has superior applications in pediatric neurosurgical
      wound closure when used with proper technique.

PMID- 10592483
TI  - Renal cell carcinoma. Guidelines for diagnosis and treatment.
AB  - Diagnosis of renal cell carcinoma (RCC) is established using sonography and
      confirmation by computed tomography (CT). Due to the widespread use of these
      imaging techniques for numerous indications, small renal tumors are increasingly
      detected by chance. As the sensitivity of CT is very high, treatment of RCC is
      routinely initiated without histological confirmation. Standard therapy of
      locally confined tumors without evidence of lymph node or hematogenic metastases
      is nephrectomy. However, the results of tumor excision equal those of nephrectomy
      if tumor size does not exceed 4 cm in diameter. Whereas the prognosis of organ
      confined tumors is excellent, no curative treatment for primary metastasized RCC
      is available to date. Immunotherapy - the only systemic treatment modality with
      clinically relevant response rates - has so far failed to effect a survival
      advantage for the patient. Surgery is only potentially curative for asychronous
      metastases occurring more than 2 years after surgery.

PMID- 10592484
TI  - Operative therapy in disease progression and local recurrence of renal cell
      carcinoma.
AB  - When local recurrence or distant metastasis occurs, the question arises as to
      which therapeutic concept should be applied. In contrast to the data on systemic
      immunotherapy, there are no systematic studies on surgical management of
      metastasis. Local recurrence (a rare condition) is frequently resected, whereby a
      prolongation of life can be achieved in individual cases. The complete surgical
      resection of pulmonary metastases has been shown, in a number of studies, to
      achieve a survival rate of 5 years in up to 44% of the cases. There are only few
      data regarding resection of osseous metastases; although in this respect some
      studies have reported an average survival rate of 34 months, the indication for
      this condition has, up to now, usually been seen as palliative. The prognosis of
      liver or brain metastasis is unfavorable; the survival rates achieved with the
      help of surgical procedures are scarcely higher than those resulting from the
      spontaneous progression of metastatic renal carcinoma (12 months). Thus, there is
      an urgent need for further studies in order to define the indication for the
      surgical management of metastasis.

PMID- 10592485
TI  - Immunotherapy of renal cell carcinoma. A critical appraisal from a urologist's
      point of view.
AB  - Treatment of choice for nondisseminated disease is surgery. However, the 5-year
      survival rates for all stages do not exceed 60%, even in contemporary series.
      Further improvement will most likely have to await the development of a more
      effective systemic therapy and the application of combined treatment modalities
      to counter the relatively high number of patients presenting with advanced
      stages. Treatment options in metastatic disease include nephrectomy, sometimes in
      combination with metastasectomy in selected cases, alone or cytoreductive surgery
      followed by immunotherapy. Alternatively, one may apply immunotherapy initially
      and perform adjuvant nephrectomy in the case of a response, or proceed to
      immunotherapy as a monotherapy. Nevertheless, long-term survival ranges merely
      from 5 to 10% depending strongly on patient selection criteria. Concepts and
      progress in this field appear to be of major interest for modern uro-oncologists
      following the advent of immunotherapeutic strategies that require a surgical
      intervention at some stage of the treatment cascade.

PMID- 10592486
TI  - Tumor-adopted diagnosis of bladder cancer.
AB  - 70% of our patients suffering from bladder cancer present themselves initially
      with a superficial tumor (Tis, Ta, T1) and only 30% are initially seen with a
      muscle-invasive carcinoma (T2, T3-4, N+, M+). Clinical history, physical
      examination, urine cytology, IVP and cystoscopy in combination with adequate
      tissue harvest by transurethral resection are the basis of our diagnostic
      procedures. Bimanual palpation, systematic biopsies, sonography, computed
      tomography, bone scan and further procedures are not to be considered as routine
      examinations and are only used in special situations. Only exactly defined
      diagnostic algorithms permit the development and use of valid prognostic
      parameters. They further allow to perform a tumor-orientated therapy and to
      compare patient groups which have been treated in different institutions
      according to similar or different therapeutic regimens. This includes the
      importance of a TNM-oriented therapy. It has to be stressed though that the
      prevalence of distinct pathological changes, such as bone metastases in T1
      tumors, as well as financial resources, have to be taken into account. Further,
      definite therapeutic intention such as a curative vs. palliative regimen is a
      decisive criterium for the amount of performed diagnostic procedures. It also is
      of importance that new diagnostic modalities, if introduced into the clinical
      routine, have to be investigated concerning their validity in relevant and large
      patient cohorts and their rationale in our diagnostic algorithm has to be
      defined. This is predominantly not the case in radiological imaging techniques
      and thus a large amount of resources are wasted.

PMID- 10592487
TI  - 5-Aminolevulinic acid-induced fluorescence endoscopy for the detection of lower
      urinary tract tumors.
AB  - The use of a photodynamic fluorescence marker for diagnosis of tumors is an
      intriguing concept to improve the thoroughness of surgical tumor resection.
      Complete surgical resection of multifocal bladder tumors and flat lesions such as
      carcinoma in situ is known to be difficult, and thus a source of recurrences. We
      report on the recent experience with the intravesical application of the
      photosensitizer prodrug 5-aminolevulinic acid (5-ALA), which is a nontoxic
      physiological heme substrate. Initial results from fluorescence diagnosis using
      krypton laser light, and recent results with a modified incoherent light source
      constantly showed a 25% increase in urothelial tumor detection in comparison to
      white light endoscopy. Due to the high sensitivity, the number of biopsies could
      be decreased constantly in comparison to routine random biopsies taken under
      white light endoscopy. The results show about 25-30% of cases with fluorescent
      lesions which are histologically benign. 5-ALA is a promising tool for the
      diagnosis of bladder cancer. The outcome of the admission study for 5-ALA in
      urology in Germany is positive, and is being continued by prospective multicenter
      clinical studies to prove the hypothesis of reduction of tumor recurrence with
      this method. 5-ALA-based fluorescence endoscopy is strongly recommended for
      further clinical testing.

PMID- 10592488
TI  - Therapy of superficial bladder carcinomas.
AB  - Treatment of superficial bladder carcinoma was derived by several large
      randomized trials. This group of cancers is stratified by differentiation grade
      and stage in three groups of different risk profiles (Ta G1-2 vs. T1 G1-2 vs.
      Tis/T1 G3). Standard therapy is fractionated transurethral resection (TUR).
      Adjuvant therapy after transurethral resection is not indicated in primary Ta G1
      2 tumors because there is a low recurrence rate and no risk of tumor progression.
      The recurrence rate can be decreased up to 15% in recurrent Ta or T1 G1-2 tumors
      by intravesical therapy with mitomycin C (20 mg/instillation) or adriamycin (50
      mg/instillation). Therapy should be limited to early (within 24 h post-TUR) and
      short-term treatment (4 x weekly, 5 x monthly). Alternatively, patients can be
      treated by intravesical BCG (strain Connaught or strain RIVM). Maintenance
      therapy is advantageous according to recurrence rate. Tumors with great malignant
      ability (Tis or T1 G3) will be treated initially with adjuvant BCG. Patients who
      fail are candidates for radical cystectomy within 3-6 months after initial
      diagnosis. There is no need - except in clinical trials - for the administration
      of unverified or not admitted drugs.

PMID- 10592489
TI  - Follow-up after urinary diversion.
AB  - With modern forms of urinary diversion being widely employed during recent years,
      the awareness of possible complications and appropriate follow-up strategies
      gains rising importance and current follow-up strategies are reviewed herewith.
      Follow-up investigations after urinary diversion have to address possible
      surgical complications, metabolic changes as well as the risk of secondary
      malignancies in the incorporated bowel segments. The most important and possible
      deleterious surgical complication is upper tract dilation and obstruction
      following ureteroenteric anastomotic stenosis and occurs in 2-30% depending on
      the surgical technique and evaluated series. The most appropriate follow-up study
      to detect upper tract dilation is ultrasonography while the associated
      obstructional component can best be estimated by functional renographic studies
      (MAG(3) renal scan). The significance of reflux associated with urinary diversion
      remains controversial although experimental studies and clinical observations
      suggest a risk of renal functional deterioration associated with reflux which is
      certainly true in ureterosigmoidostomy following pyelonephritic changes. Possible
      metabolic changes include hyperchloremic metabolic acidosis and problems related
      to malabsorption due to bowel resection and incorporation of bowel segments into
      the urinary tract. The incidence of hyperchloremic acidosis is related to the
      form of urinary diversion, being higher in continent forms than in incontinent
      diversions, while hyperchloremic metabolic acidosis is most frequently
      encountered in ureterosigmoidostomy. While acute complications of metabolic
      acidosis may encompass hyperventilation as well as severe changes of serum
      electrolytes and acid base balance leading to cardiac arrhythmias necessitating
      immediate hospital treatment with intravenous alkalinizing, chronic acidosis may
      lead to osteopenia through hypocalcemia and stimulation of osteoclastic activity.
      Metabolic acidosis can be best detected by regular blood gas analysis. To prevent
      these complications prophylactic administration of alkalinizing agents (e.g.
      potassium citrate) should be readily performed. Malabsorption of bile acid
      strongly correlates with the length of ileum resected and can induce both
      chologenic diarrhea and malabsorption of liposoluble vitamins (A, D, E, K).
      Vitamin B(12) is exclusively absorbed in the distal ileum, serum levels therefore
      may be reduced following resection of distal ileum. This will not occur during
      the first 3-5 years following diversion because B(12) deposits usually will last
      for this period. Later, however, serum levels of vitamin B(12) should be checked
      annually while others favor routine substitution of this vitamin. The incidence
      of cancer occurring at the ureterointestinal anastomosis seems to be highest in
      patients with ureterosigmoidostomy varying between 2 and 29% with polypoid benign
      lesions being more frequent. The most common type of tumor is adenocarcinoma
      which has also been reported in colonic and ileal conduits as well as
      augmentation cystoplasty using either colon or ileum. Since the time interval
      between surgery and cancer occurrence is longer than 10 years, the newer forms of
      continent diversion theoretically also inherit the risk of tumor formation,
      which, however, has yet to be established because these diversions are only in
      wide use since 10 years. Currently, annual endoscopic controls are recommended in
      those patients with diversions where feces and urine are in contact with
      urothelium starting 5 years after surgery. Although formal guidelines for follow
      up after urinary diversion have not yet been established by the working group on
      oncology of the German urological association, this paper suggests a follow-up
      strategy addressing surgical complications, metabolic changes and the risk of
      secondary malignancies.

PMID- 10592490
TI  - Guidelines for the diagnosis and therapy of testicular cancer and new
      developments.
AB  - The guidelines of testicular cancer were elaborated and agreed upon
      interdisciplinarily. Standard therapy of stage I seminoma is infradiaphragmatic
      radiotherapy. Possible alternatives are adjuvant carboplatin therapy (still in
      test procedure) and, in case of lacking risk factors, the watch-and-wait
      strategy. If small metastases of lymph nodes exist, radiotherapy requires a
      higher dose and a larger beam field. Standard therapy in clinical stage IIC-III
      is cisplatin-based multidrug chemotherapy. In regard to nonseminomatous germ cell
      tumor there are no universal recommendations: retroperitoneal lymphadenectomy
      (RLA) with protection of ejaculation function, watch-and-wait strategy as well as
      adjuvant chemotherapy have the same cure rate but differ in relapse rate and
      morbidity. Knowing the crucial risk factors - depending on the expected relapse
      rate - it will be possible to recommend adjuvant chemotherapy or wait-and-see
      strategy in the future. In case of lymph nodes up to 5 cm, three different
      therapeutic strategies are possible. They reach the same cure rate, but are
      associated with different morbidity: primary nerve-sparing RLA plus adjuvant
      chemotherapy, primary nerve-sparing RLA without adjuvant chemotherapy, and
      primary chemotherapy. Advanced stages are related to three different groups in
      reference to their prognosis. At present, they are still treated with three or
      four cycles of PEB. In current protocols, patients with 'poor prognosis' receive
      high-dose therapy afterwards. These results have to be taken in consideration
      when updating the guidelines. The present guidelines also give notes for the
      therapy of TIN, residual tumor resection (RTR), management of CNS metastases, and
      therapy of recurrences.

PMID- 10592491
TI  - Diagnosis and staging of prostatic carcinoma: what is really necessary?
AB  - Diagnosis and staging of prostatic carcinoma should be considered in men in whom
      treatment with curative intent is possible. The primary tools for detection of
      cancer are digital rectal examination (DRE) and serum prostate-specific antigen
      (PSA), whereas transrectal ultrasonography is best used to guide the needle for
      biopsy. Staging should be based on the TNM system. The most reliable staging
      methods include a combination of DRE, PSA and systematic biopsies for local tumor
      extension, pelvic lymphadenectomy for regional lymph nodes, and PSA and bone
      scintigraphy for distant metastases. Computed tomography and magnetic resonance
      imaging are not necessary in most cases.

PMID- 10592492
TI  - Prognostic factors for carcinoma of the prostate.
AB  - Prognostic factors for prostatic carcinoma should be significant, independent and
      clinically important. They should be of practical use, and their determination
      should be affordable in everyday practice. Prognostic factors may be grouped into
      patient-related, tumor-related and treatment-related. They should meet certain
      requirements, such as possession of a clear biological significance, an adequate
      sample size (possibly more than 150 patients), no patient population bias, an
      adequate statistical test, such as Cox regression analysis, as well as optimized
      cut-off values and reproducibility. From a pathologist's view, prognostic factors
      with established values are grade, margin involvement, capsular penetration,
      seminal vesical involvement, metastases and invasion of fat in needle biopsies.
      In contrast to this, factors with little value are, among others, zone location
      or nuclear shape. If these guidelines for assessment of prognostic factors are
      not met, the prognostic factors grow exponentially, as an individual patient can
      only belong to one prognostic group. If one considers all three categories of
      prognostic factors together, the clinical stage matters most despite all
      uncertainties. The same holds true for grading; particularly, the well
      differentiated grades on biopsy cores have the drawback of being reflected in the
      specimen only infrequently. The use of biomarkers to give a better prognostic
      information is also disappointing, as only PSA and PAP have a reliable value
      among 28 biomarkers. It is of note that new biomarkers are continuously being
      discovered and examined, such as cyclin A or D. Due to these deficiencies in all
      three categories of prognostic factors for prostatic carcinoma, prognostic
      indices in the form of nomograms were constructed. But, if these indices are
      employed to answer the most important question at the time of diagnosis, i.e.,
      'is this man a candidate for surveillance?', neoadjuvant treatment plus
      irradiation, neoadjuvant treatment plus radical prostatectomy, perineal radical
      prostatectomy, because of a low probability of extracapsular extension or
      positive lymph nodes, adjuvant therapy after local treatment with curative intent
      as opposed to progression-based treatment or immediate systemic treatment, let
      alone intermittent endocrine manipulation, are not reliably possible. The
      outcomes of the few available studies based on prognostic factors should be
      studied carefully. If considered, a valuable new way of estimating artificial
      neural networks is a possibility to come to practical terms.

PMID- 10592493
TI  - Curative treatment of prostate cancer.
AB  - The guidelines for the curative treatment of prostate cancer presented by the
      German Society of Urology are discussed. They are based on the current knowledge
      of the outcomes of surgical and radiotherapeutic treatment for prostate cancer.
      Radical prostatectomy is recommended as the first-line treatment for organ
      confined prostate cancer in patients with an individual life expectancy of at
      least 10 years. Radiotherapy can be considered as an alternative treatment
      modality, although current knowledge does not allow a definite assessment of the
      relative value of radiotherapy compared to radical prostatectomy. Locally
      advanced cT3 prostate cancer is overstaged in about 20% and curative treatment is
      possible in selected cases. Guidelines represent rules based on the available
      evidence. This implies that exceptions must be made whenever appropriate and that
      guidelines have to be reviewed regularly as new information becomes available.

PMID- 10592494
TI  - Hormonal therapy of prostate cancer: is there any news?
AB  - Androgen ablative therapy was introduced in the early 1940s and, even today, has
      remained the golden standard for the treatment of advanced prostate cancer.
      During the past decades, a variety of improvements have been achieved which,
      however, primarily aimed at a better tolerance or improved acceptance of androgen
      deprivation. However, after almost six decades of hormonal therapy it is
      appropriate to ask whether progress was also made in terms of efficacy,
      particularly as far as prolongation of survival or quality of life is concerned.
      During the last few years, two therapeutic strategies, maximal androgen blockade
      and intermittent androgen suppression, have been considered true conceptual
      advances. However, despite tremendous efforts and a huge number of studies so
      far, these concepts appear to produce more questions rather than answers.
      Therefore, it seems appropriate to raise some critical issues of maximal androgen
      blockade and intermittent androgen suppression.

PMID- 10592495
TI  - Brachytherapy for prostate cancer.

PMID- 10592496
TI  - Factors determining analgesic and sedative drug requirements during
      extracorporeal shock wave lithotripsy.
AB  - PURPOSE: The aim of this study was to determine what factors influence the
      analgesic and sedative requirements during extracorporeal shock wave lithotripsy
      (ESWL). MATERIALS AND METHODS: A retrospective study was carried out on 2,103
      lithotripsy treatments performed over a 7-year period using an electromagnetic
      lithotriptor. Treatment with analgesics and anxiolytic drugs administered during
      ESWL was evaluated, and two new variables to determine the analgesic and sedative
      requirements were defined. A multivariant analysis model was established to
      determine which variables are related to or could predict the analgesic and/or
      sedative drug requirements. RESULTS: The most frequently used sedative drug was
      potassium chlorazepate which was used in 2,059 patients at a mean total dose of
      25.6 mg. Pethidine was used in 2, 006 patients at a mean total dose of 56.3 mg,
      and fentanyl in 995 patients at a dose of 93.3 microg. In 52.4% of patients
      analgesic requirements were low, and in 76.6% sedative requirements were low. In
      21.1% of patients analgesic drug requirements were high, and in 1. 8% of patients
      sedative drug requirements were high. The multivariant analysis showed that those
      requiring most analgesics were, the younger patients (p = 0.003), those who
      received a higher number of shock waves (p < 0.001) and those who needed more
      sedation (p < 0.001). Those who received the greatest amount of sedatives were
      women (p = 0.0026); younger patients (p < 0.001); those treated with higher
      voltages (p = 0.032), and patients with the highest analgesic requirements (p <
      0.001). CONCLUSIONS: Predicting the analgesic drug requirements prior to ESWL is
      very difficult. The present study shows that young age, a greater discharge of
      shock waves and a high sedative drug requirement are factors clearly related to
      greater analgesic drug requirements. Higher sedative drug requirements are needed
      by women, younger patients, those receiving high discharge voltages and those
      with higher analgesic requirements.

PMID- 10592497
TI  - Possibility of improving the acceptance rateof early detection testing for
      prostate cancerwith a one-step test for prostate-specific antigen in whole blood.
AB  - In order to increase the acceptance rate of early detection testing for prostate
      cancer, a qualitative prostate-specific antigen (PSA) one-step test has been
      developed. Determining the PSA level with this test system takes 10 min. The
      blood samples of 190 men were tested in this qualitative assay, which uses 50
      microl of EDTA whole blood and in which the results are ascertained visually.
      Parallel samples were tested in serum-based, quantitative assays (Abbott Imx,
      EIA). The findings of the two kinds of assays were compared and evaluated
      regarding their correspondence (<4.0 and > or = 4.0 ng/ml). For the 74 blood
      samples in which the quantitative assay showed PSA levels <4.0 ng/ml, the PSA one
      step test showed 83.8% correct negative results (corresponds to diagnostic
      specificity). For the 116 samples in which the classic assay showed PSA levels >
      or = 4.0 ng/ml, the one-step test showed 90.5% correct positive results
      (sensitivity). The noted deviations appear especially around the cut-off value of
      4.0 ng/ml, i.e. within the PSA concentration range of 3.0 < 4.0 and 4.0 < 5.0
      ng/ml. The qualitative PSA one-step test presented here demonstrates good
      reproducibility. It can be conducted by the patient and is easy to use. The test
      offers a simple, feasible method for early detection programs for prostate
      cancer.

PMID- 10592498
TI  - Effect of lower infundibulopelvic angle, lower infundibulum diameter and inferior
      calyceal length on stone formation.
AB  - The effect of anatomical factors such as lower infundibulopelvic angle (LIPA),
      lower infundibulum diameter (LID) and inferior calyceal length (ICL) on renal
      stone formation was investigated. These parameters were measured from
      noncalculous kidneys of 40 healthy kidney donors. The same parameters from 119
      patients with single, unilateral, nonobstructive lower calyceal stone were also
      measured. LID and ICL were significantly higher in calculous kidneys when
      compared to the control group. On the other hand, the difference between the LIPA
      of the two groups was not significant. It is concluded that LID and ICL could be
      good indices in determining lower calyceal stone formation.

PMID- 10592499
TI  - Semiquantitative evaluation of testicular histology after testicular torsion:
      protective effect of external cooling.
AB  - To evaluate the protective effect of external cooling on testicular histology and
      tubular diameter, an experimental study was performed on rat testes that
      underwent a torsion procedure for a defined period of time (4 h). In a second
      group of animals external cooling for 90 min was performed during the torsion
      procedure. Evaluation of both the semiquantitative testicular histology and
      tubular diameter demonstrated a relatively well-preserved histology and tubular
      diameter. However, significant changes were noted in testes that underwent the
      torsion procedure without any protective measure. Our results indicate the
      protective effects of hypothermia in ischemic testes undergoing torsion with
      regard to both histologic and tubular alterations.

PMID- 10592500
TI  - Apoptosis, mitosis, p53, bcl(2), Ki-67 and clinical outcome in prostate carcinoma
      treated by androgen ablation.
AB  - A prospective study on 16 patients with advanced (stage III and IV) prostate
      cancer was carried out. TNM stage, general clinical status, serum PSA level, the
      histological type and Gleason's grade of the tumor were registered. Total
      androgen blockade or single-drug therapy (flutamide) was performed. On average,
      4.81 months after the start of therapy rebiopsy, serum PSA determination and
      general clinical examination were performed. Histologic examination before and
      after treatment of HE-stained slides, as well as apop-tag reaction to show
      apoptotic cells, p53, bcl(2), and Ki-67 immunostaining. Clinical improvement
      manifested by regression or lack of progression was observed in 10 patients.
      Increase of the apoptotic index and decrease of the mitotic index was detected in
      these cases. Serum PSA level decreased in all patients except in 3 fatal cases.
      The 6 clinically nonresponders who died after the second biopsy did not show an
      increased apoptotic or decreased mitotic index. Ki-67 positivity correlated well
      with the mitotic activity. Mutant p53 expression was higher in patients in whom
      antiandrogen therapy was ineffective. The bcl(2) expression was a characteristic
      of the tumors of patients who later died. These results show that the degree of
      induction of apoptosis in prostate carcinoma by hormonal therapy varies from case
      to case. A given prostate cancer patient's response to therapy may be predicted
      by following apoptotic and mitotic activity, as well as Ki-67 and p53 expression
      in repeated biopsies.

PMID- 10592501
TI  - A phase II trial of gallium nitrate in patients with androgen-metastatic prostate
      cancer.
AB  - INTRODUCTION: Due to in vitro data suggesting antitumor activity with gallium
      nitrate, we sought to evaluate the safety and activity in patients with androgen
      independent prostate cancer. METHOD: Patients were eligible for this study if
      they had an ECOG performance status of < or = 2, stage D2 metastatic prostate
      cancer that was progressing following combined androgen ablation (medical or
      surgical castration plus antiandrogen) and had failed antiandrogen withdrawal.
      Therapy consisted of gallium nitrate (200 mg/m(2)/day) as a continuous infusion
      for 7 days, administered every 21 days, with hydration (100 ml/m(2)/h).
      Individuals that had previously received suramin were treated at a dose of 150
      mg/m(2)/day of gallium nitrate. RESULTS: Eight patients were enrolled: 4 patients
      at the 200 mg/m(2)/day dose level and 4 patients at the lower dosage (150
      mg/m(2)/day). One of 8 patients had a >75% decline in prostate-specific antigen
      (PSA), 3 patients had stable PSA values for 17, 18 and 22 weeks, and 4 patients
      had progression by PSA (>50% increase over baseline). Anemia requiring
      transfusion occurred in 5 of 8 patients (63%). Two patients (25%) developed grade
      4 toxicity: 1 patient developed complete blindness with partial reversal over 12
      months, and another patient had pulmonary infiltrates, hypoxemia, and fever.
      Serious adverse events were not correlated to prior suramin exposure, or gallium
      plasma concentrations (total or free), but appeared to be related to cumulative
      cycles of gallium nitrate. Remaining adverse events were grade 1 or 2. No
      patients developed renal or neurological toxicity. CONCLUSION: This trial was
      prematurely terminated because repeated administration of gallium nitrate was
      poorly tolerated in an elderly population with androgen-independent prostate
      cancer. Gallium had modest clinical activity in this disease.

PMID- 10592502
TI  - Cushing's syndrome in prostate cancer. An aggressive course of prostatic
      malignancy.
AB  - We report a case with an initial diagnosis of adenocarcinoma of the prostate in
      whom Cushing's syndrome developed. The disease did not respond to estrogen
      treatment and the patient died of severe septicemia. Histopathologic examination
      of the autopsy specimens revealed a small cell carcinoma intermingled with a
      moderately differentiated adenocarcinoma in the prostate and widespread
      metastases of small cell carcinoma. Immunoreactivity for neuroendocrine
      differentiation was found only in the small cell carcinoma. Determination of
      different tumor markers in plasma samples showed markedly elevated levels of
      prostate-specific antigen as well as carcinoembryonic antigen prior to treatment,
      with no significant changes after treatment. The concentration of the
      neuroendocrine marker chromogranin A was initially within the normal range, but
      increased during estrogen treatment, whilst neuron-specific enolase was
      moderately elevated throughout the observation period.

PMID- 10592503
TI  - Loss of tissue immunoreactive androgen receptor in prostate cancer presenting
      initially as an intracranial tumor.
AB  - We report a case of prostate cancer that presented initially as an intracranial
      tumor. Biopsy specimens of the prostate before endocrine treatment were nearly
      negative immunohistochemically for prostate-specific antigen and the androgen
      receptors. All metastases including those in the brain expressed neither androgen
      receptor nor prostate-specific antigen at the protein and mRNA levels. The tumor,
      which did not respond to the anti-androgen therapy, had an aggressive course. In
      this case, the androgen-independent growth and rapid progression might be
      associated with the initial loss of the antigen and androgen characteristics of
      the prostate.

PMID- 10592506
TI  - Bilateral giant adrenal myelolipoma and polycystic ovarian disease.
AB  - We report a case of a nonfunctioning, synchronous, bilateral, very large adrenal
      myelolipoma in an obese woman. She had diabetes mellitus and oligomenorrhea due
      to polycystic ovarian disease, and for that, she was taking progesterone
      medication for over 12 years. The principal clinical findings, the etiology and
      pathogenesis, the diagnostic-tools including US-guided fine-needle biopsy to
      preoperative differential diagnosis, are discussed.

PMID- 10592504
TI  - Transrectal ultrasound appearance of squamous cell carcinoma involving the
      prostate.
AB  - PURPOSE: This report describes the transrectal ultrasound appearance of squamous
      cell carcinoma of the prostate. CASE REPORTS: One case of squamous cell carcinoma
      involving the prostate by extension from a primary urethral carcinoma and a
      second case of radiation-induced primary prostatic squamous cell carcinoma are
      presented and the ultrasound findings discussed. CONCLUSIONS: In these 2 cases,
      squamous cell carcinomas involving the prostate exhibited similar transrectal
      ultrasound appearances. Both lesions demonstrated an irregular, anterior,
      relatively hyperechoic appearance.

PMID- 10592505
TI  - Primary renal malignant fibrous histiocytoma: case report.
AB  - We report on a case of primary renal malignant fibrous histiocytoma. Primary
      manifestation in the kidney is rare with only 22 cases reported in the
      literature. Preoperatively, a renal cell carcinoma cannot be distinguished from a
      malignant mesenchymal tumor with clinical or imaging techniques. We discuss the
      pathologic differential diagnosis, therapeutic strategies and prognosis of this
      infrequent tumor.

PMID- 10592507
TI  - Rhabdomyosarcoma of the bladder in an adult.
AB  - We report a case of rhabdomyosarcoma of the bladder in an adult. A 73-year-old
      male was referred to our hospital due to macrohematuria. Ultrasonography, CT and
      MRI revealed a bladder tumor, and cystoscopic biopsy of the tumor pathologically
      revealed rhabdomyosarcoma. Total cystectomy with ileal conduit urinary diversion
      was performed.

PMID- 10592508
TI  - Single ectopic vaginal ureter diagnosed by computed tomography.
AB  - A case of a single ectopic vaginal ureter in a 6-year-old girl with urinary
      incontinence is reported. Excretory urography and renal sonography failed to
      visualize the dysplastic kidney, but enhanced computed tomography clearly
      demonstrated a poorly functioning hypoplastic kidney, ectopic ureter and vagina
      filled with contrast medium.

PMID- 10592509
TI  - Determination of beta-amylase activity by a fluorimetric 2-p
      toluidinylnaphthalene-6-sulfonate flow-injection analysis (2, 6-TNS-FIA) method,
      using amylose and amylopectin as substrates.
AB  - 2-p-Toluidinylnaphthalene-6-sulfonate (2,6-TNS) is a compound which is barely
      fluorescent in pure water but whose fluorescence can be strongly enhanced if the
      environment becomes hydrophobic, i.e. by the addition of suitable substrates such
      as proteins or 1, 4-alpha-D-glucans. The enhancement of fluorescence results from
      the formation of a 2,6-TNS/substrate complex. For linear and ramified 1, 4-alpha
      D-glucans, the fluorescence intensities of the complexes depend linearly on their
      concentrations but nonlinearly on their average molecular weights (AMW). Thus,
      the fluorescence detector acts simultaneously as a linear detector concerning the
      concentration of 1,4-alpha-D-glucan and as a nonlinear mass-selective detector
      concerning its AMW. These properties have been used for the development of a
      fluorimetric 2,6-TNS-FIA methodology for the determination of beta-amylase
      activity, using amylose and amylopectin as substrates. The experimental data
      points, corresponding to the concentration of "detectable" substrate vs
      depolymerization time, were fitted using a two-parameter exponential decay curve,
      and the depolymerization rates at time zero were calculated. The depolymerization
      rates at time zero vs the corresponding initial substrate concentrations were
      fitted using the Michaelis-Menten hyperbola and the enzymic constants k(3) and
      K(m) for amylose (5.93 x 10(-3) g/microKat. min and 1.49 g/L, respectively) and
      for amylopectin (7.40 x 10(-3) g/microKat+. min and 1.65 g/L, respectively) were
      determined.

PMID- 10592510
TI  - Engineering CHO cells to overexpress a secreted reporter protein upon induction
      from mouse mammary tumor virus promoter.
AB  - The mouse mammary tumor virus (MMTV) promoter is induced by the addition of a
      glucocorticoid hormone or analog such as dexamethasone. The hormone binds to its
      specific transcription factor, glucocorticoid receptor (GR), and the activated
      complex then binds to the glucocorticoid response elements (GREs) in the enhancer
      region of the MMTV promoter to induce the overexpression of downstream genes. We
      have constructed an expression vector for a reporter protein, secreted alkaline
      phosphatase (SEAP),controlled by the MMTV promoter and co-transfected this vector
      along with a GR expression cassette into Chinese hamster ovary (CHO) cells. High
      producers were cloned and grown in suspension cultures. A very high titer, over
      0.4 mg/mL, of SEAP was obtained from this inducible overexpression system, about
      ten times that achievable with the same reporter protein using the strong
      constitutive SV40 promoter in CHO cells. A peak production rate of 187 pg SEAP
      per cell per day was observed within 3 days after induction, compared to the peak
      rate of 23 pg SEAP per cell per day expressed using the constitutive SV40
      promoter. With the reduced or zero growth rate during the protein production
      phase, this novel MMTV overexpression system is highly suited for optimizing
      glycoprotein synthesis rates in high cell density fed-batch or perfusion
      bioreactors.

PMID- 10592511
TI  - Potential of an antibacterial ultraviolet-irradiated nylon film.
AB  - The antibacterial effectiveness of an ultraviolet-irradiated nylon 6, 6 film was
      investigated for potential use as a food-packaging material to reduce the surface
      microbial contamination of foods. The film-surface analyses showed that UV
      irradiation induced conversion of surface amide groups to amines. Irradiation
      also increased the dimensional scale of the film surface topography (depth of
      valleys) approximately 5-fold on the scale of nanometers. The irradiated nylon
      demonstrated antagonistic activity against Staphylococcus aureus 25923 and
      Escherichia coli TV1058 with 4.5 and 6 log reductions, respectively, of an
      initial population of 10(6) cfu mL(-1). The irradiated nylon was ineffective
      against Pseudomonas fluorescens 13525 and Enterococcus faecalis 19433 under
      similar conditions. The film demonstrated increased antimicrobial activity
      against S. aureus 25923 with increasing temperatures up to 45 degrees C, the
      highest temperature tested. Protein and salt inhibited the antibacterial nature
      of the irradiated film. Amines in solution (4.31 x 10(-8) M; the calculated
      equivalent of amines on the film) killed at least 1 x 10(4) cfu mL(-1) E. coli
      TV1058, and 4. 31 x 10(-7) M amines killed up to 1 x 10(7) cfu mL(-1) E. coli
      TV1058. The amines in solution required similar exposure time to the bacteria for
      population reduction as was observed with the irradiated film.

PMID- 10592512
TI  - Enhanced production of L-(+)-lactic acid in chemostat by Lactobacillus casei DSM
      20011 using ion-exchange resins and cross-flow filtration in a fully automated
      pilot plant controlled via NIR.
AB  - Due to the lack of suitable in-process sensors, on-line monitoring of
      fermentation processes is restricted almost exclusively to the measurement of
      physical parameters only indirectly related to key process variables, i.e.,
      substrate, product, and biomass concentration. This obstacle can be overcome by
      near infrared (NIR) spectroscopy, which allows not only real-time process
      monitoring, but also automated process control, provided that NIR-generated
      information is fed to a suitable computerized bioreactor control system. Once the
      relevant calibrations have been obtained, substrate, biomass and product
      concentration can be evaluated on-line and used by the bioreactor control system
      to manage the fermentation. In this work, an NIR-based control system allowed the
      full automation of a small-scale pilot plant for lactic acid production and
      provided an excellent tool for process optimization. The growth-inhibiting effect
      of lactic acid present in the culture broth is enhanced when the growth-limiting
      substrate, glucose, is also present at relatively high concentrations. Both
      combined factors can result in a severe reduction of the performance of the
      lactate production process. A dedicated software enabling on-line NIR data
      acquisition and reduction, and automated process management through feed
      addition, culture removal and/or product recovery by microfiltration was
      developed in order to allow the implementation of continuous fermentation
      processes with recycling of culture medium and cell recycling. Both operation
      modes were tested at different dilution rates and the respective cultivation
      parameters observed were compared with those obtained in a conventional
      continuous fermentation. Steady states were obtained in both modes with high
      performance on lactate production. The highest lactate volumetric productivity,
      138 g L(-1) h(-1), was obtained in continuous fermentation with cell recycling.

PMID- 10592513
TI  - A new biological strategy for high productivity of recombinant proteins in animal
      cells by the use of hypoxia-response enhancer.
AB  - Oxygen supply is one of the major problems in the production of useful proteins
      by cultured animal cells and therefore it is of importance to devise a system by
      which a high productivity of human therapeutic recombinant proteins can be
      maintained or enhanced under low oxygen concentrations. A number of hypoxia
      inducible genes have been found in animal cells and the induction in most cases
      is due to hypoxic activation of the gene transcription. A consensus sequence (HRE
      = hypoxia-response enhancer) responsible for the hypoxic activation exists in
      these genes and the binding of a protein, which is widely distributed in animal
      cells, to this sequence responding to hypoxia activates the promoter activity.
      The promoter of lactate dehydrogenase A gene is active in Chinese hamster ovary
      (CHO) cells and the vicinal HRE stimulates the promoter activity efficiently in
      hypoxia. We have prepared a number of permanent CHO cell lines producing
      recombinant human erythropoietin (Epo) under control of this promoter/HRE. Epo
      production was highly hypoxia-inducible when the wild-type of HRE was used but
      uninducible when the mutant HRE was used. There was little difference in the in
      vitro and in vivo activities, and glycosylation between Epo produced by the cells
      cultured in 21% and 2% oxygen. Furthermore, forced expression of hypoxia
      inducible factor-1alpha (HIF-1alpha) enhanced Epo production in all oxygen
      concentrations. These results indicate that a biological strategy based on the
      hypoxic induction of gene transcription provides a novel system which guarantees
      a high productivity even uner low oxygen concentrations.

PMID- 10592514
TI  - Inhibition of caspase activity delays apoptosis in a transfected NS/0 myeloma
      cell line.
AB  - The productivity of NS/0 myeloma batch cultures is often compromised by the
      premature induction of apoptosis, now established to be the predominant method of
      cell death during culture decline. Caspase proteases have recently been shown to
      play a major role in the transmission of signals for apoptotic cell death. Using
      a specific inhibitor that targets a range of caspases (Z-VAD-fmk) we assessed
      whether inhibition of caspase activity could prolong the viability of NS&vbar;h=0
      cells under conditions that cause apoptotic cell death in batch cultures. Z-VAD
      fmk was found to significantly reduce apoptotic cell death (by approximately 50%)
      induced by cytotoxins and to preserve membrane integrity to a similar extent. In
      conditions of low serum, Z-VAD-fmk reduced certain features of apoptosis (e.g.,
      DNA fragmentation), but only marginally improved viability. In medium-depleted
      batch cultures, Z-VAD-fmk afforded a delay of between 24 and 48 h in both the
      induction of apoptosis and loss of viability. Despite an apparent increase in
      viability in Z-VAD-fmk-treated NS&vbar;h=0 cultures, no improvement in
      productivity could be demonstrated, suggesting that at least some normal pathways
      for protein production are shut down upstream of caspase activation. An
      examination of mitochondrial membrane potential (Deltapsim) in Z-VAD-fmk-treated
      and untreated NS&vbar;h=0 cells revealed only a small initial difference (5%) in
      the levels of Deltapsim depolarization. Similar levels of mitochondrial
      dysfunction, despite caspase inactivity, may therefore be responsible for the
      comparable productivity in untreated and Z-VAD-fmk-treated cultures. Thus, this
      study suggests that, while a delay in cell death due to caspase inhibition may
      reduce problems associated with cellular disintegration, it does not permit
      productivity improvements in this type of culture.

PMID- 10592515
TI  - Protein modification during antiviral heat bioprocessing.
AB  - Heat treatment is routinely used in the preparation of therapeutic protein
      biopharmaceuticals as a means of viral inactivation. However, in undertaking
      virucidal heat treatments, a balance must be found between the bioprocessing
      conditions, virus kill, and the maintenance of protein integrity. In this study,
      we utilize a simple model protein, hen egg-white lysozyme, to investigate the
      relationship between antiviral bioprocess conditions (protein formulation and
      temperature) and the extent and type of protein modification. A variety of
      industrially relevant wet- and dry-heat treatments were undertaken, using
      formulations that included sucrose as a thermostabilizing excipient. Although
      there was no evidence of lysozyme aggregation or crosslinking during any of the
      heat treatments, using liquid chromatography-electrospray ionization-mass
      spectroscopy (LC-ESI-MS) and peptide mapping we show that protein modifications
      do occur with increasingly harsh heat treatment. Modifications were predominantly
      found after wet-heat treatment, the major covalent modification of lysozyme under
      these conditions being glycation of Lys(97), by either glucose or fructose
      derived from hydrolyzed sucrose. The extent of sucrose hydrolysis was itself
      dependent on both the duration of heat treatment and formulation composition.
      Advanced glycation end products (AGEs) and additional unidentified products were
      also present in protein samples subjected to extended heat treatment. AGEs were
      derived primarily from initial glycation by fructose and not glucose. These
      findings have implications for the improvement of bioprocesses to ensure protein
      product quality.

PMID- 10592516
TI  - Considerations for osmolality measurement under elevated pCO(2): comparison of
      vapor pressure and freezing point osmometry.
AB  - Osmolality increases with pCO(2) in bioreactors with pH control, and it has been
      shown that osmolality compensation by decreasing the basal NaCl concentration
      partially mitigates the adverse effects of elevated pCO(2) on animal cell growth,
      protein production, and glycosylation. Thus, measurement of osmolality is
      important for a complete characterization of the culture environment under
      elevated pCO(2). However, osmolality measurement may be compromised by CO(2)
      evolution. Freezing point depression and vapor pressure depression osmometry were
      directly compared for the measurement of osmolality in samples at elevated pCO(2)
      (up to 250 mmHg) and at a variety of pH values (6.7-7.5). More extensive
      degassing may be expected with the vapor pressure osmometer due to the smaller
      sample volume and larger surface area employed. However, both types of osmometer
      yielded similar results for all pCO(2) and pH values studied. Moreover, the
      measured values agreed with osmolality values calculated using a semi-empirical
      model. Further analysis showed that, while sample degassing may result in a large
      decrease in pCO(2), there is little associated decrease in osmolality. The great
      majority of total CO(2) in solution is present as bicarbonate (HCO(3)(-)).
      Although a small amount of HCO(3)(-) is converted to CO(2) to compensate for
      CO(2) evolution, further depletion of HCO(3)(-) is inhibited by the associated
      increase in medium pH and by the need for HCO(3)(-) to maintain charge neutrality
      in solution. This explanation is consistent with the observed similarity in
      osmolality values for the two types of osmometer. It was also observed that
      osmolality did not change in samples that were frozen at -20 degrees C for up to
      1 year.

PMID- 10592517
TI  - Dynamic optimization of hybridoma growth in a fed-batch bioreactor.
AB  - This study addressed the problem of maximizing cell mass and monoclonal antibody
      production from a fed-batch hybridoma cell culture. We hypothesized that
      inaccuracies in the process model limited the mathematical optimization. On the
      basis of shaker flask data, we established a simple phenomenological model with
      cell mass and lactate production as the controlled variables. We then formulated
      an optimal control algorithm, which calculated the process-model mismatch at each
      sampling time, updated the model parameters, and re-optimized the substrate
      concentrations dynamically throughout the time course of the batch. Manipulated
      variables were feed rates of glucose and glutamine. Dynamic parameter adjustment
      was done using a fuzzy logic technique, while a heuristic random optimizer (HRO)
      optimized the feed rates. The parameters selected for updating were specific
      growth rate and the yield coefficient of lactate from glucose. These were chosen
      by a sensitivity analysis. The cell mass produced using dynamic optimization was
      compared to the cell mass produced for an unoptimized case, and for a one-time
      optimization at the beginning of the batch. Substantial improvements in reactor
      productivity resulted from dynamic re-optimization and parameter adjustment. We
      demonstrated first that a single offline optimization of substrate concentration
      at the start of the batch significantly increased the yield of cell mass by 27%
      over an unoptimized fermentation. Periodic optimization online increased yield of
      cell mass per batch by 44% over the single offline optimization. Concomitantly,
      the yield of monoclonal antibody increased by 31% over the off-line optimization
      case. For batch and fed-batch processes, this appears to be a suitable
      arrangement to account for inaccuracies in process models. This suggests that
      implementation of advanced yet inexpensive techniques can improve performance of
      fed-batch reactors employed in hybridoma cell culture.

PMID- 10592518
TI  - Facilitated downstream processing of a histidine-tagged protein from unclarified
      E. coli homogenates using immobilized metal affinity expanded-bed adsorption.
AB  - The facilitated downstream processing of an intracellular, polyhistidine-tagged
      protein, glutathione S-transferase [GST-(His)(6)], direct from unclarified E.
      coli homogenates using expanded beds of STREAMLINE chelating, has been
      investigated. A series of pilot experiments were used to develop preparative
      scale separations of GST-(His)(6), initially in packed and then in expanded beds.
      Packed beds of Ni(2+)-loaded STREAMLINE chelating proved to have the highest 5%
      dynamic capacity for GST-(His)(6), of 357 U mL(-1) (36 mg mL(-1)). When using
      immobilized Cu(2+) or Zn(2+), metal ion transfer was observed from the
      iminodiacetate ligands to the high-affinity chelator, GST-(His)(6). The
      subsequent metal affinity precipitation of this homodimer resulted in operational
      problems. An equilibrium adsorption isotherm demonstrated the high affinity of
      GST-(His)(6) for immobilized Ni(2+), with a q(m) of 695 U mL(-1) (70 mg mL(-1))
      and a K(d) of 0.089 U mL(-1) (0.0089 mg mL(-1)). Ni(2+)-loaded STREAMLINE
      chelating was therefore selected to purify GST-(His)(6) from unclarified E. coli
      homogenate, resulting in an eluted yield of 80% and a 3.34-fold purification. The
      high dynamic capacity in the expanded mode of 357 U mL(-1) (36 mg mL(-1))
      demonstrates that this specific interaction was not affected by the presence of
      E. coli cell debris.

PMID- 10592520
TI  - Dynamic modeling and optimal fed-batch feeding strategies for a two-phase
      partitioning bioreactor.
AB  - A dynamic model for the degradation of phenol in a two-phase partitioning
      bioreactor has been developed based on mechanistic balances around the
      bioreactor. The key process characteristics including substrate transfer between
      the organic and aqueous phases, substrate inhibition, oxygen limitation, and cell
      entrainment were incorporated into the model. The model predictions were
      validated against existing experimental data obtained for a 2-L bioreactor, and
      good correlation was observed for the time frames of the simulations, as well as
      for trends in cell and substrate concentrations. Optimal fed-batch, phenol
      feeding strategies were then developed based on two approaches: (1) maximization
      of phenol consumption in a fixed time interval and (2) consumption of a fixed
      amount of phenol in minimal time. The optimal feeding policies, determined using
      the Iterative Dynamic Programming algorithm, provided substantial improvements in
      the amount of phenol consumed when compared to a typical experimental heuristic
      approach. For example, 45.73 g of phenol was predicted to be consumed in 50 h
      (not including lag phase) using the optimal feeding profile compared to 10.26 g
      of phenol consumed in the simulated experimental approach. Oxygen limitation was
      predicted to be a recurring operational challenge in the partitioning bioreactor,
      and had a strong impact on the optimization results.

PMID- 10592519
TI  - Design of imidazole-containing endosomolytic biopolymers for gene delivery.
AB  - The development of safe and effective gene delivery agents poses a great
      challenge in the quest to make human gene therapy a reality. Cationic polymers
      represent one important class of materials for gene delivery, but to date they
      have shown only moderate efficiency. Improving the efficiency will require the
      design of new polymers incorporating optimized gene delivery properties. For
      example, inefficient release of the DNA/polymer complex from endocytic vesicles
      into the cytoplasm is one of the primary causes of poor gene delivery. Here we
      report the synthesis of a biocompatible, imidazole-containing polymer designed to
      overcome this obstacle. DNA/polymer polyplexes incorporating this polymer were
      shown to have desirable physico-chemical properties for gene delivery and are
      essentially nontoxic. Using this system, mammalian cells in vitro were
      transfected in the absence of any exogenous endosomolytic agent such as
      chloroquine.

PMID- 10592521
TI  - Development of an on-line monitoring system of human keratinocyte growth by image
      analysis and its application to bioreactor culture.
AB  - Human keratinocytes were cultured in serum-free medium for the purpose of on-line
      cell growth monitoring by image analysis. The validity of a process using a newly
      developed video microscopy system with image analysis for growth-rate monitoring
      in real time was verified by the measurement of the degree of confluence of
      keratinocytes in T-flasks and Petriperm dishes. The growth rate of keratinocytes
      was calculated subsequently from the linear relationship between average degree
      of confluence and cell concentration. This technique was applied to the culture
      in the bioreactor "KERATOR" in which a special video microscopy system using a
      CCD camera was built. The cell concentration evaluated by image analysis agreed
      well with that evaluated by conventional direct cell counting after enzymatic
      digestion, and the on-line monitoring of the specific growth rate allowed
      identification of both lag- and exponential-growth phases of the culture.

PMID- 10592522
TI  - Production of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) by high-cell-density
      cultivation of Aeromonas hydrophila.
AB  - The newly screened Aeromonas hydrophila produces copolymer consisting of 3
      hydroxybutyrate (3HB) and 3-hydroxyhexanoate (3HHx). The characteristics of cell
      growth and polymer accumulation were examined using various carbon sources. P(3HB
      co-3HHx) was produced from lauric acid and oleic acid only. P(3HB-co-3HHx)
      content can be increased by limitation of phosphorus. A maximal P(3HB-co-3HHx)
      content of 28.8 wt% could be obtained in flask culture. By applying the optimally
      designed nutrient feeding strategy, cell dry weight, P(3HB-co-3HHx) content, and
      3HHx fraction obtained over the course of 43 h were 95.7 g/L, 45.2 wt%, and 17
      mol%, respectively, resulting in a productivity of 1.01 g polyhydroxyalkanoate
      (PHA)/L. h.

PMID- 10592523
TI  - Identification and monitoring of protease activity in recombinant Saccharomyces
      cerevisiae.
AB  - An assay for the detection of yeast (Saccharomyces cerevisiae) protease activity,
      using partially purified yeast-derived recombinant hepatitis B surface antigen
      (rHBsAg) as substrate, was developed to monitor proteolysis of rHBsAg that may
      occur through fermentation and isolation. The method consists of incubating small
      amounts of yeast lysate (protease source) with the substrate at 35 degrees C for
      about 16 h. Substrate proteolysis is assessed by subjecting the incubation
      mixtures to SDS-PAGE followed by silver-staining. The type of protease
      responsible for particular cleavages can be identified by treating the yeast
      lysates with specific protease inhibitors prior to incubation with substrate. The
      treatment of lysates with PMSF indicated that while many lysates possessed only
      serine protease activity (Protease B), some possessed proteolytic activity that
      could not be quenched with high levels of PMSF or other serine protease
      inhibitors. The use of the aspartyl protease inhibitor Pepstatin A in conjunction
      with PMSF virtually eliminated all proteolytic activity in these lysates,
      indicating that an aspartyl protease (Protease A) is expressed under some
      fermentation conditions. The relative amount of each protease in a lysate can be
      determined semiquantitatively by scanning the SDS gels densitometrically and
      plotting the ratio of degradates to intact antigen in the presence and absence of
      protease inhibitors. This method was used successfully to monitor the time
      dependent expression of these proteases throughout production-scale
      fermentations. The impact of fermentation and purification changes on those
      proteases specifically responsible for the rHBsAg degradation can be easily
      evaluated.

PMID- 10592524
TI  - Microanatomy and function of the spleen.

PMID- 10592525
TI  - Instrumentation of biotechnological processes.
AB  - Modern bioprocesses are monitored by on-line sensing devices mounted either in
      situ or externally. In addition to sensor probes, more and more analytical
      subsystems are being exploited to monitor the state of a bioprocess on-line and
      in real time. Some of these subsystems deliver signals that are useful for
      documentation only, other, less delayed systems generate signals useful for
      closed loop process control. Various conventional and non-conventional monitoring
      instruments are evaluated; their usefulness, benefits and associated pitfalls are
      discussed.

PMID- 10592526
TI  - Electronic noses for bioreactor monitoring.
AB  - Electronic noses provide new possibilities for monitor the state of a cultivation
      non-invasively in real-time. The electronic nose uses an array of chemical gas
      sensors that monitors the off-gas from the bioreactor. By taking advantage of the
      off-gas components' different affinities towards the sensors in the array it is
      possible with the help of pattern recognition methods to extract valuable
      information from the culture in a way similar to the human nose. For example,
      with artificial neural networks, metabolite and biomass concentration can be
      predicted, the fermentability of a medium before starting the fermentation
      estimated, and the growth and production stages of the culture visualized. In
      this review these and other recent results with electronic noses from monitoring
      microbial and cell cultures in bioreactors are described.

PMID- 10592527
TI  - Rapid analysis of high-dimensional bioprocesses using multivariate spectroscopies
      and advanced chemometrics.
AB  - There are an increasing number of instrumental methods for obtaining data from
      biochemical processes, many of which now provide information on many (indeed many
      hundreds) of variables simultaneously. The wealth of data that these methods
      provide, however, is useless without the means to extract the required
      information. As instruments advance, and the quantity of data produced increases,
      the fields of bioinformatics and chemometrics have consequently grown greatly in
      importance. The chemometric methods nowadays available are both powerful and
      dangerous, and there are many issues to be considered when using statistical
      analyses on data for which there are numerous measurements (which often exceed
      the number of samples). It is not difficult to carry out statistical analysis on
      multivariate data in such a way that the results appear much more impressive than
      they really are. The authors present some of the methods that we have developed
      and exploited in Aberystwyth for gathering highly multivariate data from
      bioprocesses, and some techniques of sound multivariate statistical analyses (and
      of related methods based on neural and evolutionary computing) which can ensure
      that the results will stand up to the most rigorous scrutiny.

PMID- 10592528
TI  - On-line and off-line monitoring of the production of cephalosporin C by
      Acremonium chrysogenum.
AB  - Process monitoring of cephalosporin C formation by Acremonium chrysogenum in
      laboratory investigations is considered. The goal of these investigations is the
      identification of bottlenecks in the biosynthesis and the improvement of the
      process performance. Based on reports of other research groups and own experience
      the key parameters were selected, which influence the process performance. They
      are: dissolved oxygen and pH values. In addition the concentrations of biomass,
      DNA, glucose and reducing sugars (glucose, maltose, maltotriose and
      oligosaccharides), methionine, other nitrogen sources (ammonium ion, other amino
      acids), organic acids, phosphate, sulfate, dissolved organic carbon, proteins,
      product and precursors in the cell free cultivation medium are monitored. In
      addition the intracellular concentrations of RNA, DNA, proteins, amino acids as
      well as the activities of the enzymes of the biosynthesis of cephalosporin C are
      determined. The influence of these parameters on the biosynthesis is discussed.

PMID- 10592529
TI  - Biomass quantification by image analysis.
AB  - Microbiologists have always rely on microscopy to examine microorganisms. When
      microscopy, either optical or electron-based, is coupled to quantitative image
      analysis, the spectrum of potential applications is widened: counting, sizing,
      shape characterization, physiology assessment, analysis of visual texture,
      motility studies are now easily available for obtaining information on biomass.
      In this chapter the main tools used for cell visualization as well as the basic
      steps of image treatment are presented. General shape descriptors can be used to
      characterize the cell morphology, but special descriptors have been defined for
      filamentous microorganisms. Physiology assessment is often based on the use of
      fluorescent dyes. The quantitative analysis of visual texture is still limited in
      bioengineering but the characterization of the surface of microbial colonies may
      open new prospects, especially for cultures on solid substrates. In many
      occasions, the number of parameters extracted from images is so large that data
      mining tools, such as Principal Components Analysis, are useful for summarizing
      the key pieces of information.

PMID- 10592530
TI  - Monitoring the physiological status in bioprocesses on the cellular level.
AB  - The trend in bioprocess monitoring and control is towards strategies which are
      based on the physiological status of the organism in the bioprocess. This
      requires that the measured process variables should be biologically meaningful in
      order to apply them in physiologically based control strategies. The on-line
      monitoring equipment available today mostly derives information on the
      physiological status indirectly, from external variables outside the cells. The
      complementary approach reviewed here is to analyse the microbial cells directly,
      in order to obtain information on the internal variables inside the cells. This
      overview covers methods for analysis of whole cells (as a population or as a
      single cell), for groups of cellular components, and for specific compounds which
      serve as markers for a certain physiological status. Physico-chemical separation
      methods (chromatography, electrophoresis) and reactive analysis can be used to
      analyse elemental and macromolecular composition of cells. Spectroscopic methods
      (mass, dielectric, nuclear magnetic, infrared, and Raman) have only recently been
      applied to such complex multicomponent mixtures such as microbial cells.
      Spectroscopy and chemical separation methods produce large amounts of data, which
      can often be used in the best way by applying chemometrics. Some of the methods
      can yield information not just on the average of the microbial cell population,
      but also on the distribution of sub-populations. The suitability of the methods
      for on-line coupling to the bioprocess is discussed. Others not suitable for on
      line coupling can be established in routine off-line analysis procedures. The
      information gained by the methods discussed can mainly be used to establish
      better knowledge of the basis for monitoring and control strategies. Some are
      also applicable in real-time monitoring and control.

PMID- 10592531
TI  - Metabolic network analysis. A powerful tool in metabolic engineering.
AB  - Metabolic network analysis is a tool for investigating the features that identify
      the topology of a metabolic network and the relative activities of its individual
      branches. The pillars of metabolic network analysis are mathematical modeling,
      allowing for a quantitative analysis, biochemical knowledge of, for example,
      reaction stoichiometry, and the experimental techniques, providing input for the
      modeling part. The modeling part includes metabolite balancing, usually the basis
      for metabolic flux analysis, and isotope balancing. Isotope balancing can be used
      for both identification of active pathways and for estimation of the relative
      fluxes through two pathways leading to the same metabolite, aspects that are
      difficult to investigate using metabolite balancing. The combination of
      metabolite and isotope balancing is very powerful and constitutes the basis of
      metabolic network analysis. With the main focus being on investigating the
      metabolic network structure, this review describes how central metabolic
      features, for example, pathway identification, flux distribution, and
      compartmentation, can be addressed using a combination of metabolite balancing
      and labeling experiments.

PMID- 10592532
TI  - [Termino-terminal urethroplasty using microsurgical technique in the treatment of
      bulbar urethral stenosis: evaluation of long-term results and preservation of
      potency].
AB  - The Authors report their experience, at long term, on the use of overlap
      anastomosis sec. Turner Warwick's technique for the treatment of posterior
      urethral strictures. 12 patients, from 17 to 58 years, were observed. Minimum
      follow-up was 43.3 months. All patients performed, pre and post-operatively, a
      retrograde cystogram, an uroflowmetry, a questionnaire to evaluate sexual potency
      by IIEF and AUA score, and some cases underwent also a cystoscopy post
      operatively. Results demonstrated the effectiveness of technique five years later
      too, which is the period with the greater incidence of recurrences.

PMID- 10592533
TI  - [Male urogenital amicrobial phlogosis: effects of the treatment with amtolmetin
      guacyl on some sperm parameters].
AB  - To examine if some inflammation-related sperm abnormalities were influenced by
      leucocytospermia (sWBC) alone, WBC-specific Radical oxygen species (WBC-ROS) over
      production, and/or by different infected sexual gland sites and if these
      abnormalities were possibly reversible following treatment with an antiphlogistic
      drug, a total of 43 infertile male patients with amicrobial male accessory gland
      infections (MAGI) associated with prostatitis (P, n = 16), prostato-vesiculitis
      (PV, n = 14) or prostato-vesiculo-epididymitis (PVE, n = 13) as confirmed by
      ultrasound, were studied. The patients were then further subdivided into two
      subsets: one of the subsets (P, n = 10; PV, n = 8; PVE, n = 7) was administered
      amtolmetina guacyl (Eufans) 600 mg once daily for 14 consecutive days per month,
      for a 2-months period. The second subset (six patients for each category)
      received no treatment (matched-control). Mean outcome measures included a follow
      up of sperm analysis with assessment of sperm forward motility (M), sperm
      viability (V). In addition, sWBC as well as basal and maximal fMLP-mediated WBC
      ROS production were also carried out by conventional immunocytochemistry staining
      and chemiluminescence analysis respectively. In the pre-treatment, in all
      patients (treated and not treated subsets) median values of the sperm M and V
      were significantly different among categories (P > PV > PVE), and necrozoospermia
      (sperm viability < 25%) were present in the 70% out of group P patients and in
      all (100%) patients from groups PV and PVE. Median sWBC concentrations, elevated
      (values > 1 mil/ml) in all groups, in the PV and PVE groups were significantly
      higher compared to those found in the group P. Furthermore, PVE group generated
      baseline and fMLP-stimulated ROS productions from low density 45% Percoll
      fraction (Pc45), significantly higher than those found in P or PV groups. Sperm
      outcome measures were significantly different compared with the matched-controls
      (exhibiting 0% case-responders), in a time- and infected gland site-dependent
      manner. Thus, either in terms of median values and percentages of responders
      (defined as parameters ensued within the conventional normal range) sperm M and V
      percentages, as well as sWBC improved after the first (T1) antiphlogistic course
      in the group P only, but after the second (T2) antiphlogistic course in the other
      groups (PV or PVE). Moreover, treated patients of each group had amounts of
      generated basal and fMLP-stimulated ROS signals significantly reduced, with
      values ensued within a fertile control range at T2, in 80, 62.5 and 42.8% out of
      the P, PV and PVE groups respectively. We concluded that long-term amtolmetina
      guacyl administration demonstrated efficacy and safety in the treatment of
      amicrobial MAGI, exhibiting a positive impact on all sperm parameters studied and
      no side-effects.

PMID- 10592534
TI  - Ureteral stent forgotten in renal transplanted patient. Its removal.
AB  - The emblematic case of a forgotten ureteral stent in a renal transplanted patient
      is reported. The removal was performed with no more difficulties than in a not
      transplanted patient, but we would emphasize the importance of removing the stent
      when its function of protecting the anastomosis finished, but before its
      permanence could compromise the graft.

PMID- 10592535
TI  - High grade phyllodes tumour of the prostate.
AB  - A case of malignant variant of prostatic phyllodes tumour in a 61-yr-old man is
      reported. This is an extremely rare neoplasm that closely resembles the not
      uncommon tumour of the female breast. Only 18 previous cases have been described.
      Although an initially benign clinical behavior has been presumed a high
      probability of local recurrence or aggressive behavior may occur.

PMID- 10592536
TI  - [Hematuria of appendiceal etiology].
AB  - We report our experience on a case of acute appendicitis which presented with
      gross hematuria; manifestations of acute appendicitis sometimes can mimics
      various disorders of the genitourinary tract as reported by data of several
      authors. Thus, the "pelvic" position of the appendix and its proximity to
      surrounding structures of the genitourinary tract, mainly the bladder, appears to
      determine the associated symptoms and signs. We should not forget that only half
      of appendicitis occurs with "classic" symptoms. Some cases appear with "urologic"
      symptoms.

PMID- 10592538
TI  - [Abdomino-scrotal hydrocele].
AB  - In this paper two cases of abdomino-scrotal hydrocele are described. One of these
      cases resulted really singular due to its rare dimensions as well as to its
      secondary renal obstruction. After a careful description of the cases a detailed
      review of the literature as well as of the etiopathogenetic theories of this rare
      pathology are reported.

PMID- 10592537
TI  - [Intestinal metaplasia of the bladder].
AB  - Intestinal metaplasia is a rare condition characterized by the presence of
      colonic epithelium and mucin-containing goblet cells in the bladder. According to
      its extension we can distinguish localized from widespread intestinal metaplasia.
      We describe a case of glandular cystitis intestinal-type in a 58-year-old man
      whose clinical history and diagnostic work-up are consistent with this
      proliferative abnormality. We also discuss the pathogenesis and the propensity of
      intestinal metaplasia to undergo neoplastic transformation.

PMID- 10592539
TI  - [Retroperitoneal lymphadenectomy and disorders of ejaculation].
AB  - Retrograde ejaculation is a frequent and permanent complication after bilateral
      retroperitoneal lymphadenectomy (RPLND). Seminal emission and ejaculation are
      primarily under sympathetic control. Several studies after RPLND in patients with
      nonseminomatous testis cancer proved the role of preservation of the efferent
      fibers originating from the lumbar sympathetic ganglia. Based on the results of
      anatomical studies, a modified unilateral operative technique and nerve-sparing
      approach permit to preserve normal anterograde ejaculation without reduction of
      long-term survival.

PMID- 10592540
TI  - [Psychosexual problems in patients with neoplasms].
AB  - The Author's aim is to highlight the importance of psychic dynamics which play a
      role when a patient, suffering from cancer, turns to a therapist for sexual
      rehabilitation.

PMID- 10592541
TI  - [Transurethral alprostadil (MUSE) in erectile dysfunction].
AB  - The ideal therapy for erectile dysfunction should be easy, non invasive,
      painless, with a high success and a low side effects rate. Alternative methods of
      delivery drugs to the erectile body, instead of intracavernosal injection of
      vasoactive drugs such as prostaglandin, have been evaluated. Vasoactive agents
      can be administered topically into the urethral mucosa for absorption into the
      corpus spongiosum and transfer into the corpora cavernosa via small communicating
      veins. We report data from the literature and our experience with MUSE (Medicated
      Urethral System for Erection) for the treatment of erectile dysfunction. Penile
      pain or discomfort is the common adverse effect reported, while no priapism of
      fibrotic complication is reported. But local discomfort, limited efficacy, and
      cost are to be considered.

PMID- 10592542
TI  - [Pharmaco-erection in erectile deficiency after surgical therapy].
AB  - This report emphasizes the fact that the patients operated show a bigger
      motivation in facing the problem of erectile deficit; this motivation lacks in
      patients treated with chemotherapy, radiotherapy and hormonotherapy. The results
      are anyway very interesting because the pharmacology prosthesis is generally well
      accepted and tolerated; very rare are the complications.

PMID- 10592543
TI  - [Chemotherapy: its repercussions on fertility and potency].
AB  - In the past twenty years, combined therapeutic regimens have improved the
      survival rare in many human tumors. Chemotherapy plays a significant role on this
      outcome. Unfortunately, many chemotherapeutic agents have adverse effects on
      gonadal function. The Authors examine the pathophysiology of gonadal damage in
      male diagnosed with cancer and treated with chemotherapeutic agents. Infertility
      and/or impotence can occur on these patients: the relationships between
      chemotherapy and tumors, towards seminal and sexual dysfunctions, are focused.
      Moreover, current possibilities to preserve recovery both fertility and sexual
      functions and discussed.

PMID- 10592544
TI  - [Preservation of potency by supra-ampullar cystectomy in patients with bladder
      neoplasms].
AB  - Between May 1984 and November 1998 a total of 27 consecutive patients with
      bladder tumor (26 transitional cell carcinomas and 1 leiomyosarcoma) underwent
      supra-ampullar cystectomy and ileal orthotopic neobladder (2 Camey I and 25 Camey
      II). Mean patients age was 51.1 years (range 23-65). Pre-operatively 22 patients
      had superficial bladder carcinoma. An involvement of prostatic urethra was
      excluded by biopsy. The bladder, part of the prostate with prostatic urethra and
      regional lymph nodes were removed while was deferens, deferential ampullae,
      seminal vesicles, ejaculatory ducts and peripheral portion of the prostate were
      saved. Mean follow-up was 56.5 months (range 4-178). One patient was lost to
      follow-up at 60 months. Of the 27 patients 6 died of bladder cancer (1 with local
      relapse, 1 with local and distant recurrence and 5 with metastases) and the
      remaining 21 had neither local nor distant relapse. Four patients died of other
      causes. Potency was preserved in 25 patients (92.5%) who reported satisfactory
      sexual intercourse. Sixteen patients (59.2%) also maintained ejaculation allowing
      procreation in two of them. Supra-ampullar cystectomy provides good results in
      term of quality of life allowing to preserve sexual function in nearly all the
      cases without compromise the control of the neoplastic disease. The indication
      must be restricted to bladder cancer without risk of local recurrence and
      concomitant prostatic carcinoma.

PMID- 10592545
TI  - [Generic drug lines: all is not gold that glitters].

PMID- 10592546
TI  - [A cost-effectiveness analysis of alendronate compared to placebo in the
      prevention of hip fracture].
AB  - OBJECTIVE: To examine if the treatment with alendronate to prevent hip fracture
      (HF) in female with established osteoporosis is more cost-effectiveness than
      placebo, and if changes in efficacy, cost and incidence of adverse reactions of
      the treatment can affect the ratio, and the direction of decision. DESIGN: The
      study is based on a decision tree model to examine the cost-effectiveness ratio
      (CE) of alendronate (10 mg/d alendronate, 500 mg/d calcium and 250 IU vitamin D3)
      versus placebo (500 mg/d calcium and 250 IU vitamin D3). The treatment of 1000
      patients with established osteoporosis and its course of events and probabilities
      during three years of treatment is simulated. RESULTS: The efficacy of each
      alternative is obtained by controlled clinical trials. The considered costs, from
      the first perspective of the services provider, and expressed in pesetas per year
      in 1998, are direct health tangibles: pharmacological treatment, HF surgery and
      treatment of serious adverse reactions (SAR). An analysis of simple univariate
      sensibility and one of incremental is applied on the efficacy, cost and incidence
      of adverse reactions to alendronate. The ratio CE of alendronate is 297.879
      pesetas/success (patient without fracture and without SAR) and 23.301
      pesetas/success for placebo. For the hypothesis of a 100% alendronate efficacy,
      the ratio CE is 287.217 pesetas/success and without SAR is 297.830
      pesetas/success. A cost of 210 pesetas/alendronate box will determine that this
      alternative is as cost-effective as placebo. CONCLUSIONS: The administration of
      alendronate to prevent HF on postmenopausal female with established osteoporosis
      is not the option to take into account. Just a decrease of the cost of
      alendronate below its crossing value will turn it into a cost-effective
      alternative.

PMID- 10592547
TI  - [When and how do we treat our hypercholesterolemic patients?].
AB  - OBJECTIVES: To compare patients with hypercholesterolaemia (HC) for factors
      relating to the decision to treat a patient with medication or not; and to assess
      the suitability of a previously established protocol of HC diagnosis and
      treatment. DESIGN: Retrospective, descriptive study. SETTING: Primary care
      centre. PATIENTS: 331 patients diagnosed with HC in the register of risk factors
      at our centre. 175 patients treated with medication (TM) and 156 not treated with
      medication. RESULTS: Mean age was 61.2 and 191 were women. 68.8% of the
      population under study had 2 or more factors of cardiovascular risk (FCVR). 56
      patients were in secondary prevention (71.4% TM). 275 patients (83.08%) were in
      primary prevention. 135 of these received TM, which was indicated only in 45
      (37.5%). Mean plasma concentrations (PC) of cholesterol (total and LDL) were
      greater in the patients treated. 99.3% of non-treated patients and 96.9% of
      treated patients received dietary counselling. This was maintained in 95% of non
      treated patients. The reduction of cholesterol in the PC reached 8% in diet
      treated patients by the end of the study. Initially 42.8% were treated with
      fibrates, 38.9% with statins and 18.3% with resins. By the end of the study 53.6%
      were treated with statins. CONCLUSIONS: The association of HC and other FCVR is
      common. In primary prevention, a high proportion of patients treated present
      cardiovascular risk which does not justify medical prescription. In secondary
      prevention we are closer to the current guidelines.

PMID- 10592548
TI  - [Morbidity in the caregivers of patients confined to their homes].
AB  - OBJECTIVE: To study the presence of physical and psychological morbidity in the
      main carers of patients in home care programmes. DESIGN: A descriptive crossover
      study with a control group. SETTING: Primary care. PATIENTS: The study group
      consisted of 79 main carers of patients in the home care programme. The control
      group was 82 people, paired by age and sex, and chosen at random from the list of
      individual health cards. MEASUREMENTS AND MAIN RESULTS: 84.8% of carers were
      women, with mean age 58.7 +/- 11.6, and 45.1% were daughters of the invalid, with
      an average 7.6 +/- 7.9 years as carer. 78.5% had some chronic illness related to
      stress versus 59.8% in the control group (p = 0.01). 69.6% had psychological
      malaise connected with anxiety, and 43% connected with depression, versus 45.1%
      (p = 0.002) and 25.6% (p = 0.02), respectively, in the control group. There were
      no significant differences in mean frequency of attendance over the preceding 6
      months between carers and controls (3.7 +/- 3.8 versus 3 +/- 4.6 times).
      CONCLUSIONS: There is a significantly greater amount of psychological malaise
      related to anxiety and depression among carers than in the control group. Many of
      them may be untreated. Carers have significantly more chronic illnesses, possibly
      related to stress, than the control group and receive little help in their work.
      However, they do not generate greater demand for medical care than the control
      group.

PMID- 10592549
TI  - [The results of an active screening program for tuberculosis in immigrants from
      the Maghreb: acceptability and adherence].
AB  - OBJECTIVE: To assess acceptability and adherence to a tuberculosis screening
      programme (TSP) in Maghrebi immigrants (MI). DESIGN: A descriptive crossover
      study. SETTING: Primary health care service. INDIVIDUALS: MI residing in a
      periurban health district. All people who attended clinic for consultation at a
      primary care center were systematically recommended to be screened for
      tuberculosis. INTERVENTION: Individuals accomplished a questionnaire in arabic
      (with interpreter assistance) and were subjected to tuberculosis
      infection/illness screening tests till they were assigned one of the definitive
      diagnostic classes of the American Thoracic Society. RESULTS: 219 individuals
      were offered the TSP (sex ratio 6.2:1). 166 individuals (76.1%) accepted the test
      and kept their first appointment: 147 males (78.2%) versus 19 females (63.3%);
      difference in acceptance by gender was not significant (chi 2 = 3.14; p = 0.07).
      Fourteen individuals did not complete the study (8.6%): one did not attend clinic
      for Mantoux reading, four did not have the chest X-ray, three did not present
      themselves on their Mantoux reading, nor did they have the chest X-ray and, six
      did not deliver sputum samples (11.1% of the required samples). Six cases of TB
      were diagnosed. CONCLUSIONS: Given the special features of the MI (communication
      difficulties, illegal status, no fixed abode ...) acceptance and adherence to TSP
      are considered to be high. The diagnostic effectiveness, though considerable, was
      affected by the high number of individuals which did not deliver sputum samples.
      TSP directed to MI must have a specific design in order to facilitate acceptance
      and adherence.

PMID- 10592551
TI  - [The prevalence of urinary incontinence in a population over 60 treated in
      primary care].
AB  - OBJECTIVES: To determine the prevalence of urine incontinence (UI) among the over
      60 population treated in primary care, identifying the types and associated
      epidemiological factors. DESIGN: Descriptive and crossover. SETTING: Primary
      care. PATIENTS: Sample of 400 people aged 60 or over, stratified by sex and
      chosen from those who attended their health centre spontaneously for a
      consultation. MEASUREMENTS AND RESULTS: Age, sex, chronic illnesses, treatments,
      previous childbirths, grade of immobility and presence or absence of involuntary
      discharge of urine. If the reply was positive: frequency, characteristics and
      evolution of UI, and prior consultations on the problem were also measured. 400
      people (254 women and 146 men). Mean age: 71 (SD = 7.3 years). 145 people (36.2%)
      recognised they had UI. 43.3% of women and 23.9% of men (p < 0.001) were
      incontinent. UI prevalence increased with age: 31.7% among the 60-69 year old
      group; 35% among the 70-79 group; and 53.3% in those over 80. Among women the
      most common types are stress and urge incontinence, whereas among men the most
      common are urge and overflow UI. UI prevalence is greater among women with
      previous childbirths and among immobile patients. Of the 145 people who
      recognised their UI, only 31 (21.3%) had previously consulted the doctor on this
      problem, although men had consulted significantly more than women (40% vs. 15.4%;
      p < 0.01). CONCLUSIONS: Over a third of the people over 60 in our clinics suffer
      from UI. Prevalence increases with age and is greater among women, especially if
      there is a history of childbirth. Urge UI predominates among men and stress UI
      among women. Most people with UI do not consult concerning their problem, for
      which reason, so as to identify it and adopt corrective measures, women
      especially must be systematically asked about the symptom.

PMID- 10592552
TI  - [Observation in qualitative research. An experience in the health area].

PMID- 10592550
TI  - [A strategic family medicine model for controlling borderline and mild arterial
      hypertension].
AB  - OBJECTIVE: To research on the relationship of the patient and his/her family as a
      non-pharmacological factor for blood hypertension. To determine whether a
      hyposodic, hypocaloric, hypofat, and hypocholesterolemic diet decreases the blood
      tension. To determine whether physical exercises in the patient and his/her
      family help to reduce the hypertension. To observe whether the psychological
      therapy of muscles relaxation helps to reduce the hypertension. To evaluate in
      the sample of families, the experience of each member, as well as their
      suggestions and complaints about the programme. To design the strategic model to
      control the blood tension by ambulatory means. DESIGN: Controlled intervention
      study, descriptive, non-randomized, prospective. PLACEMENT: Primary care.
      PATIENTS AND OTHER PARTICIPANTS: Study group of 10 patients, 10 wives, and 12
      children, and control group of 10 patients excluding family members.
      INTERVENTIONS: With both groups (study and control) there were meetings every 15
      days for 6 months according to an established schedule. In the meetings there
      were given talks, pamphlets, physical exercises, muscles relaxation therapy, all
      about blood hypertension. There were questionnaires before and after each
      activity. MEASURING AND MAIN RESULTS: In both groups (study and control) there
      was a statistically significant (t < 0.01) reduction in the weight. The blood
      systolic tension decreased in both positions, seated and standing, in the study
      group (difference statistically significant) but not so in the control group,
      although there was a non-significant difference (decrease of 1.5 mmHg) in the
      seated position. The diastolic tension decreased significantly in the study group
      both in seated and standing positions, not so in the control group. CONCLUSIONS:
      The study sample showed that systolic tension seated and standing had a
      statistically significant reduction in the study group but not so in the control
      group. The weight had statistically significant reduction in both study and
      control groups. Total cholesterol had statistically significant decrease in the
      study group but not in the control group. HDL-C had statistically significant
      reduction in the study group; in the control group there was a decrease but not
      statistically significant. The triglycerides did not decrease statistically
      significant in any of the groups (study and control).

PMID- 10592554
TI  - [The use of the intrauterine device].

PMID- 10592553
TI  - [Research in primary care. The clinical trial and observational studies of
      pharmaceutical products].

PMID- 10592555
TI  - [Blood glucose self-measurement and the glycemia mean in diabetes mellitus
      patients].

PMID- 10592556
TI  - [How to inform patients of the efficacy of statins].

PMID- 10592557
TI  - [Thinking as professionals of palliative care].

PMID- 10592558
TI  - [Proposals for realistic home care in primary care].

PMID- 10592559
TI  - Current concepts in oral cancer.
AB  - Over 750 new intra-oral squamous cell carcinomas are registered in Australia each
      year. In this article, the authors review the epidemiology, aetiology, genetics
      and spread of intra-oral squamous cell carcinoma. The mechanisms of field
      cancerization are discussed. The prevention of intra-oral squamous cell carcinoma
      is highlighted and future treatments are presented.

PMID- 10592560
TI  - The clinical performance of ceramic inlays: a review.
AB  - The availability of improved ceramic materials, bonding techniques, new
      technology and issues of amalgam safety have led to a revival of interest in
      ceramic inlays in dentistry over the past ten years. Clinical studies have been
      carried out during this time using various evaluation techniques to assess the
      clinical performance of these restorations. In this paper, recent clinical
      studies are examined and a review of the current state of knowledge regarding the
      clinical performance and survival statistics of ceramic inlays is presented. The
      major problems associated with ceramic inlay therapy appear to be fracture,
      hypersensitivity, degree of fit, maintenance of marginal integrity, microleakage,
      bond failures and cement wear. Other areas which also affect the clinical
      performance of ceramic inlays are ceramic wear, opposing tooth wear, plaque
      accumulation, gingivitis, secondary caries, colour stability, anatomic form and
      radiopacity. Recommendations based on the findings of clinical studies are also
      presented and whilst no specific material or technique has been shown to be
      clearly superior, certain principles which predispose to success can be
      identified. When compared with other forms of aesthetic intracoronal
      restorations, ceramic inlays perform well. However, their high cost and extreme
      technique sensitivity would appear to restrict their use to certain limited
      clinical situations.

PMID- 10592561
TI  - Dye-assisted diode laser ablation of carious enamel and dentine.
AB  - Carious dentine and enamel from extracted human teeth were ablated using a
      semiconductor diode laser in conjunction with an applied dye, indocyanine green.
      This technique offers selective ablation with minimal risk of thermal damage to
      surrounding dental tissues because uptake of the dye and its irradiation by the
      laser together control the ablation. In this study, various laser powers and dye
      concentrations were used to ablate previously extracted human teeth with moderate
      caries. The mass of material ablated and the temperature rise in the pulp and at
      the surface were recorded, and the ablated surface was examined by microscopy.
      The ablation was efficient and the rise in the pulp temperature slight. Ablation
      efficiency and surface temperature were both found to increase with laser
      irradiance and with dye concentration. No surface cracks or fissures were seen in
      electron microscope examination and the hardness of the laser-treated surfaces
      was comparable to that of healthy tissue. The dye-assisted laser ablation
      technique offers considerable potential for clinical caries removal and dentine,
      enamel and pulp sterilization, whilst leaving healthy tissue intact. The diode
      laser can deliver its energy via simple optical fibre and is cheaper and much
      smaller than the conventional high power lasers used in other studies.

PMID- 10592562
TI  - Dental cervical lesions associated with occlusal erosion and attrition.
AB  - Acid demineralization of teeth causes occlusal erosion and attrition, and shallow
      and wedge-shaped cervical lesions putatively involving abfraction. From 250
      patients with tooth wear, 122 with cervical lesions were identified. From epoxy
      resin replicas of their dentitions, associations of occlusal attrition or erosion
      or no wear with cervical lesions were recorded at 24 tooth sites (total 2928
      sites). Criteria used to discriminate occlusal attrition from erosion, and
      shallow from grooved, wedge-shaped or restored cervical lesions were delineated
      by scanning electron microscopy. A 96 per cent association was found between
      occlusal and cervical pathology. Shallow cervical lesions were more commonly
      found in association with occlusal erosion. Wedge-shaped lesions were found
      equally commonly in association with occlusal erosion, as with attrition. Grooved
      and restored cervical lesions were uncommon. Differences were appreciated in the
      associations within incisor, canine, premolar and molar tooth sites which related
      more to the site-specificity of dental erosion than to attrition from occlusal
      forces. Non-carious lesions on teeth then have multifactorial aetiology and
      pathogenesis in which erosion and salivary protection play central roles.
      Dentists should primarily consider erosion in the diagnosis, prevention and
      treatment of tooth wear.

PMID- 10592563
TI  - Incidence of complicated healing and osteoradionecrosis following tooth
      extraction in patients receiving radiotherapy for treatment of nasopharyngeal
      carcinoma.
AB  - A group of 43 patients requiring tooth extraction after radiotherapy for
      nasopharyngeal carcinoma (NPC) was studied retrospectively to determine the
      incidence of post-extraction complications. It was found that because of the
      method used in the delivery of radiation, extraction of maxillary posterior teeth
      resulted in the greatest risk of complications (28.9 per cent), including a 10.5
      per cent risk of osteoradionecrosis (ORN). Based on the findings, a protocol was
      established for the dental care of such patients. It was concluded that when
      extraction of maxillary posterior teeth was necessary, prophylactic antibiotics
      were not sufficient to prevent the complication of delayed healing. The risk of
      ORN was 10.5 per cent within the field of maximal radiation dose. Hyperbaric
      oxygen may be the better choice of preventive measures. However, in view of the
      low risk of ORN, wholesale prescription of hyperbaric oxygen therapy may not be
      indicated. An additional patient who had tooth extraction two weeks prior to
      radiotherapy was included to show that if adequate time for wound healing was not
      allowed, ORN could develop.

PMID- 10592564
TI  - Custom-made titanium mandibular reconstruction tray.
AB  - Reconstruction of the mandible after ablative surgery can be achieved by using
      preformed trays or trays formed from models produced by computer-assisted
      modelling systems. The former presents difficulty in matching the required facial
      contour, jaw relationship and condylar position; while the latter is expensive.
      This paper presents a simple and inexpensive method of fabricating a custom-made
      titanium bone grafting tray. The dimensions of the patient's mandible are
      obtained by clinical measurement. Such measurements are used to construct a
      mandibular replica. The region to be reconstructed is carved to produce the ideal
      shape and dimensions of an edentulous segment. The tray is made either by casting
      or by swaging. Twenty-one custom-made titanium bone grafting trays have been
      fitted in patients with encouraging results. This method of bone grafting tray
      construction is a simple, inexpensive technique for achieving excellent facial
      contour and functional reconstruction after mandibulectomy.

PMID- 10592565
TI  - Integrating the surgical and prosthodontic stages of implant therapy with a
      sterile implant position registration.
AB  - A new implant position registration technique utilizing an autoclavable
      thermoplastic material is described. This technique, which has been in use since
      1994, allows the clinician to fabricate a provisional restoration for insertion
      at stage II surgery to enhance the soft tissue contour and the aesthetics of the
      final restoration.

PMID- 10592567
TI  - Oral health and systemic health.

PMID- 10592566
TI  - Metastatic neuroblastoma of the mandible mimicking osteogenic sarcoma
      radiologically. Case report.
AB  - This paper presents a case of a neuroblastoma of the adrenal gland metastasizing
      to the mandible of a 21-month-old infant, which presented radiographically as the
      so-called 'sun-ray' appearance, characteristic of osteogenic sarcoma.

PMID- 10592568
TI  - Could depression and anxiety be a looming epidemic?

PMID- 10592569
TI  - Integration in general practice.

PMID- 10592571
TI  - Tennis elbow.

PMID- 10592570
TI  - Insulin and type 2 diabetes.

PMID- 10592572
TI  - Tennis elbow.

PMID- 10592573
TI  - Sexual health series.

PMID- 10592574
TI  - The post acute cardiac patient in general practice.

PMID- 10592575
TI  - The new genetics. What are the everyday clinical applications?
AB  - BACKGROUND: Our understanding of human genetics has changed exponentially in
      recent years, but genetic research is sometimes perceived as an esoteric and
      expensive pursuit with few practical implications for the majority of the
      population. As the human genome project nears completion, we need to assess how
      we can use this vast knowledge effectively. OBJECTIVE: To focus on the role of
      new genetics in the understanding of both single gene disorders and the
      inheritance of complex traits (which have genetic and environmental components)
      and to discuss the role of the general practitioner (GP) utilising this knowledge
      in daily practice. DISCUSSION: Genetic data is often best used to understand and
      modify environmental causes of disease in regard to the susceptibility of an
      individual or family. This article discusses the role of GPs in identifying those
      at high risk of disease by history, prenatal diagnostic techniques and
      appropriate genetic testing and providing practical, cost effective strategies
      for individuals and the community to minimise risk of illness.

PMID- 10592576
TI  - Haemochromatosis. A personal viewpoint.
AB  - BACKGROUND: Hereditary haemochromatosis is an inherited disorder of iron
      metabolism. It is the commonest inherited disorder in people of Celtic or
      northern European descent. The early symptoms are nonspecific and the diagnosis
      is often delayed or missed. Early treatment prevents complications and leads to a
      normal life expectancy. OBJECTIVE: This article describes the common early
      symptoms and the initial tests for the detection of haemochromatosis. It also
      gives the current recommendations for the screening of relatives. DISCUSSION:
      Patients in the early stages of iron overload are usually seen by general
      practitioners. An increased awareness of haemochromatosis among doctors will lead
      to earlier diagnosis and improved outcomes for these patients.

PMID- 10592577
TI  - Diagnosing disease through DNA. An exciting new frontier.
AB  - BACKGROUND: The family physician is at the forefront of the modern genetics (DNA)
      revolution. Advances in genetics will continue to escalate as the human genome
      project reaches its conclusion. The result will be a vast compendium of newly
      discovered genes and demand from both patients and doctors for more information
      about them. OBJECTIVE: To describe the role of DNA testing in diagnosing and
      predicting disease. DISCUSSION: DNA is an ideal medium to search for gene
      mutations. The DNA content of our cells does not age, thereby expanding the scope
      for DNA testing. The general practitioner will often be the first contact for
      those with a genetic disorder. Following DNA diagnosis, ongoing support may be
      required. To do this effectively will require a new approach to continuing
      education, as well as active participation in the 'molecular medicine' team.
      Sourcing reliable and accurate information may be a problem with many turning to
      the Internet for this.

PMID- 10592578
TI  - Designing new drugs through DNA.
AB  - BACKGROUND: The human genome project will sequence the human genome within the
      next 2 years. Tools have been created that allow the use of genetics to study
      inherited diseases in humans where the genetic component may be complex. Most
      human genes have been identified and tools exist to use this information to
      search for abnormal expression of genes in diseased tissues. Many medically
      important pathogens have already had their genomes sequenced. OBJECTIVE: Can this
      deluge of information be used effectively to design new drugs? Will it help in
      producing new therapies. Where are the bottlenecks in pharmacologic development
      and will the genome information revolution lift some of these blocks? This
      article addresses some of these issues and seeks to demonstrate that the genome
      project will inject an enthusiasm into the development of new pharmacologic
      agents against a large range of hitherto unknown target molecules. DISCUSSION:
      Pharmaceutical development is target limited. This is especially true in the
      microbiological arena where there have been no new targets used for the past
      decade or more. New genes will be uncovered that play a role in disease
      processes. These may not be the causative genes but will modulate the course of
      disease. These new target proteins will be identified either as a result of the
      large scale sequencing efforts, now underway in a small number of large
      laboratories in the USA and Europe or will be found as a result of applying this
      knowledge to find genes that are inappropriately expressed in diseased tissue.

PMID- 10592579
TI  - Common red scaly rashes. Traps for the unwary--Part 2.
AB  - BACKGROUND: Red scaly rashes often provide difficulties for GPs leading to a 'try
      and see' approach which, although successful on many occasions, may delay
      adequate treatment when there is lack of a correct diagnosis. OBJECTIVE: A study
      of 61 GPs' knowledge of the diagnosis and treatment of a number of red scaly
      rashes, was undertaken with the use of photographs and clinical history. The
      study highlighted areas of uncertainty particularly in diagnosis, but also in
      treatment of common red scaly rashes. On the basis of their responses, practical
      tips have been suggested to overcome them. DISCUSSION: Simple diagnostic
      procedures that can be done within the general practice setting include biopsy,
      skin scrapings and fungal microscopy. They have been highlighted as an important
      component of the approach to diagnosis of common red scaly rashes. While the
      study showed a substantial proportion of correct treatment being recommended,
      there was still an area of need, particularly in diagnosis, which could be
      enhanced by learning these simple techniques.

PMID- 10592581
TI  - Conditions responding to lasers. Vascular abnormalities and tattoos.

PMID- 10592580
TI  - Treating Helicobacter pylori.
AB  - BACKGROUND: The treatment for Helicobacter pylori infection has changed
      continuously during the past decade and recommended treatments have not always
      been readily available in primary care. These factors have contributed to
      confusion and considerable variation in prescribing. OBJECTIVE: This short review
      outlines the key aspects of current treatment of H pylori. DISCUSSION: With the
      advent of single script, effective therapies, there should be more uniformity in
      treating this common infection. With appropriate choice of therapy and patient
      counselling to maximise compliance, excellent H pylori eradication rates are
      achievable in general practice.

PMID- 10592582
TI  - Drug selection. Old versus new.

PMID- 10592583
TI  - The perimenopause and contraception.

PMID- 10592584
TI  - Testicular ultrasound.

PMID- 10592585
TI  - Could this be a hamstring injury?

PMID- 10592587
TI  - Elderly drug abuse will rise as boomers age.

PMID- 10592586
TI  - Western psychology meets eastern philosophy.

PMID- 10592588
TI  - Vigilance needed to prevent epidemics in Kosovo.

PMID- 10592589
TI  - Asthma, the general practitioner and the divisions.

PMID- 10592590
TI  - Australian divisions of general practice asthma survey 1997. General
      Practitioner's Asthma Group of the National Asthma Campaign.
AB  - AIM: To conduct an attitudinal postal survey of all 118 divisions of general
      practice known to the National Asthma Campaign. METHOD: A questionnaire aimed to
      determine the perceived barriers to improved asthma care in the divisions,
      current asthma projects and the most suitable way that the General Practitioners
      Asthma Group (GPAG) and the National Asthma Campaign (NAC) could assist divisions
      of general practice. RESULTS: Eighty seven (74%) replies were received. Twenty
      four divisions (28%) were running asthma projects, mostly about asthma education.
      The greatest barrier to asthma care for the doctor was a lack of time (57% of
      respondents) and the greatest barrier for the patient was perceived to be a lack
      of asthma education (34% of respondents). Asthma educators employed by the
      division or individual surgeries were ranked as the preferred method for
      overcoming these difficulties. CONCLUSIONS: Divisions of general practice are
      becoming involved in the management of asthma throughout Australia although there
      are considerable hurdles to overcome. The role of the GPAG and NAC in this
      process is discussed.

PMID- 10592591
TI  - Consumers' after hours health care decisions. Comparison between those who did
      and those who did not seek care in an Australian provincial city.
AB  - OBJECTIVE: To compare the demographic and illness characteristics of people who
      sought after hours care with those who did not, to identify differences that
      might be exploited in patient education regarding 'appropriate' use of after
      hours care. METHOD: Structured telephone interview survey of randomly selected
      householders in Townsville. RESULTS: An 88% response rate was achieved
      (1227/1402). A total of 10.8% (133/1227) of respondents had sought after hours
      care for themselves in the 3 months before interview. A further 10.9% (134/1227)
      had decided against seeking care during that period. The two groups were
      demographically similar, except in terms of health care training and perceived
      travel time to after hours care. Self reported conditions varied only for ICPC
      general, musculoskeletal and skin chapters. Symptom related issues were most
      important in the decision to seek care, while self care procedures were the most
      common reason for not seeking care, followed by access related issues.
      CONCLUSIONS: The decision to seek care is an individual process that cannot be
      reliably predicted by demographic characteristics. Broad scale community
      education programs aimed at reducing 'inappropriate' use of after hours services
      would need to find a balance between increasing knowledge for self care of minor
      conditions and emphasising the importance of being alert to signs and symptoms of
      life threatening conditions.

PMID- 10592592
TI  - Incorporating evidence based medicine (EBM) into general practice.
AB  - BACKGROUND: The increased application of evidence based medicine (EBM) to health
      care practice has been endorsed in national health policy. This paper focuses on
      what EBM means for GPs. OBJECTIVES: To present the outcomes of engaging
      practising GPs in applying EBM principles to a general practice scenario.
      DISCUSSION: Caution about the potential for misuse of EBM has been voiced by GPs
      based on the biopsychosocial model of general practice and concerns about the
      limited utility of largely biomedical evidence in general practice. The EBM
      process begins with converting information needs into questions, but this first
      step presupposes that the doctor has obtained a good history including eliciting
      any hidden agenda. It is important to recognise the context in which people's
      health issues and problems arise, the paucity of evidence that is derived within
      the biopsychosocial model of general practice, and the difficulties that GPs face
      in accessing evidence.

PMID- 10592593
TI  - [Active Campylobacter Pylori infection diagnosed by the urea breath test].

PMID- 10592594
TI  - [Contrast media and renal function].

PMID- 10592595
TI  - [Prostaglandins. What is new?].

PMID- 10592596
TI  - [Quality control in surgery].

PMID- 10592597
TI  - [The genetics of inherited bullous diseases of the skin. Future aspects in
      perinatal and prenatal diagnosis].

PMID- 10592598
TI  - [Intravascular ultrasonography, a novel method in vascular imaging].

PMID- 10592599
TI  - [Child's sexual abuse, the role of children testimony during trial].

PMID- 10592600
TI  - [Torticollis versus cervical dystonia].

PMID- 10592601
TI  - [How do orthopedic surgeons learn?].

PMID- 10592602
TI  - [X-linked lymphoproliferative syndrome].

PMID- 10592603
TI  - [Heparin induced thrombocytopenia and thrombosis].

PMID- 10592604
TI  - [Is it safe and efficient to use nonsteroidal anti-inflammatory agent by
      selective reduction of prostaglandin production?].

PMID- 10592605
TI  - [Histopathological diagnosis of liver cirrhosis by aspiration biopsy].

PMID- 10592606
TI  - [Dyspnoea of a young male patient].

PMID- 10592607
TI  - [Results of the 110 year Duodecim anniversary competition].

PMID- 10592608
TI  - [Functioning primary care in the accident and emergency is the show case of
      general practice].

PMID- 10592609
TI  - [Setting limits in doctor-patient relationship].

PMID- 10592610
TI  - [Guidelines for the diagnosis and treatment of patients with acute ischemic
      stroke].

PMID- 10592611
TI  - [The acute care of patients with psychotic disorder].

PMID- 10592612
TI  - [Delirium, underdiagnosed acute confusional state with poor prognosis].

PMID- 10592613
TI  - [Management of patient with acute infection].

PMID- 10592614
TI  - [Febrile infant].

PMID- 10592615
TI  - [Foodborne epidemic infections].

PMID- 10592616
TI  - [The principles of primary care management and follow-up of patients during
      transportation to the hospital].

PMID- 10592617
TI  - [Clinical application of technology in acute medical practice].

PMID- 10592618
TI  - [Physician accused of malpractice in primary care].

PMID- 10592619
TI  - [The diagnosis is in Finnish language first].

PMID- 10592620
TI  - [Asthma-like inflammation].

PMID- 10592621
TI  - [Interleukin-6 reflects the disease severity and prognosis of myeloma].

PMID- 10592622
TI  - [Acute liver failure].

PMID- 10592623
TI  - [Scintigraphy detection of somatostatin receptor in tumor diagnosis].

PMID- 10592624
TI  - [Overnight dexamethasone suppression test in the screening of Cushing's
      syndrome].

PMID- 10592625
TI  - [Mortality in juvenile rheumatoid arthritis is diminished].

PMID- 10592626
TI  - [Diarrhea of a five year old male child].

PMID- 10592627
TI  - [Yersinia Pseudotuberculosis, a rare cause of septicemia].

PMID- 10592628
TI  - [Arteriovenous fistula, an uncommon cause of lower extremities ischemia].

PMID- 10592629
TI  - [New therapeutic application of thalidomide].

PMID- 10592630
TI  - [Future aspects concerning Health Science].

PMID- 10592631
TI  - [Tremor during radiation therapy].

PMID- 10592632
TI  - [A scientist has to have permission to become pregnant].

PMID- 10592633
TI  - [Consultation policy, second opinion and quality in Finish health care].

PMID- 10592634
TI  - [Recent genetic association in Alzheimer's disease].

PMID- 10592635
TI  - [About guidelines for the treatment of anorexia nervosa].

PMID- 10592636
TI  - [Sexuality and pregnancy of spinal cord damaged women].

PMID- 10592637
TI  - [Drug induced sexual dysfunction].

PMID- 10592638
TI  - [Outpatient management of anorexia nervosa].

PMID- 10592639
TI  - [Bulimia and tooth erosion].

PMID- 10592640
TI  - [Local skin redness and irritation five months after Bacillus Calmette Guerin
      (BCG) vaccination as a sign for Kawasaki's disease].

PMID- 10592642
TI  - [Patient controlled analgesia].

PMID- 10592641
TI  - [Bilateral lower leg pain as a sign of Clostridium Septicum infection].

PMID- 10592643
TI  - [Multiple lung infiltration of a smoker].

PMID- 10592644
TI  - [Conjunctivitis and febrile lymphadenitis as a sign of Francisella Tularensis].

PMID- 10592645
TI  - [The treatment and prognosis of acute low back pain].

PMID- 10592646
TI  - [Spontaneous dissection of cephalic artery as a cause of subarachnoidal
      bleeding].

PMID- 10592647
TI  - [What can we learn about the sudden death of a young male patient with asthma?].

PMID- 10592648
TI  - [Sudden death of a young male patient with asthma].

PMID- 10592649
TI  - [Posttraumatic stress disorder].

PMID- 10592650
TI  - [Response to Duodecim 1/96 for Mustonen, Brummer-Korvenkontio and Vaheri].

PMID- 10592651
TI  - Cryptosporidiosis associated with swimming pools.

PMID- 10592652
TI  - AIDS and HIV infection in the United Kingdom: monthly report.

PMID- 10592653
TI  - Studies of non-A, non-B hepatitis and characterization of the hepatitis C virus
      in chimpanzees.

PMID- 10592654
TI  - Hepatitis C epidemiology.
AB  - Hepatitis C virus infection occurs in all parts of the world. Infection is
      generally due to percutaneous exposures, though sexual and perinatal transmission
      may occur. While further study is needed to elucidate the biology of HCV
      transmission and develop vaccines for prevention, new HCV infections can be
      reduced by economic development and education regarding blood-borne infections.

PMID- 10592655
TI  - Natural history and disease manifestations of hepatitis C infection.

PMID- 10592656
TI  - Overview of hepatitis C virus genome structure, polyprotein processing, and
      protein properties.

PMID- 10592657
TI  - Internal ribosome entry site-mediated translation in hepatitis C virus
      replication.

PMID- 10592658
TI  - Hepatitis C virus core protein: possible roles in viral pathogenesis.

PMID- 10592659
TI  - Folding, assembly and subcellular localization of hepatitis C virus
      glycoproteins.

PMID- 10592660
TI  - Structure and function of the hepatitis C virus NS3-NS4A serine proteinase.

PMID- 10592661
TI  - Structure and function of hepatitis C virus NS3 helicase.
AB  - Hepatitis C Virus helicase activity has been mapped to the COOH-terminal 450
      residues of the NS3 protein. Due to its complexity and presumed essentiality for
      viral replication, the helicase is an attractive target for drug discovery. The
      elucidation of the atomic structure of the HCV NS3 helicase in complex with
      oligonucleotide and with ADP has helped clarify our understanding of potential
      sites for inhibitor binding. Molecular details of the mechanism of this enzyme,
      and in particular, a better understanding of the mechanism by which ATP
      hydrolysis is coupled to unwinding of double-stranded substrate may facilitate
      more efficient structure-based drug design.

PMID- 10592662
TI  - Evading the interferon response: hepatitis C virus and the interferon-induced
      protein kinase, PKR.

PMID- 10592663
TI  - Hepatitis C virus RNA-dependent RNA polymerase (NS5B polymerase).

PMID- 10592664
TI  - Systems to culture hepatitis C virus.

PMID- 10592665
TI  - Characterization of hepatitis C virus infectious clones in chimpanzees: long-term
      studies.

PMID- 10592666
TI  - Cell mediated immune response to the hepatitis C virus.

PMID- 10592667
TI  - Strategies and prospects for vaccination against the hepatitis C viruses.

PMID- 10592668
TI  - The GB viruses.

PMID- 10592669
TI  - [Arterial complications after liver transplantation: early and late forms].
AB  - Arterial complications after liver transplantation (OLT) was related with high
      morbimortality rates, with variable consequences on patient and graft survival.
      234 patients who underwent 270 liver transplantation between april of 1990 and
      december 1996 have been evaluated. Arterial complications were detected in 34
      patients (12.5%), hepatic artery stenosis in 10 patients (29.4%), thrombosis in
      24 (70.6%) and aneurysm in 2 (5.9%). It was considered early artery complications
      those diagnosed at the first month after OLT, and late complications the latest
      ones. Diagnosis was realized by Doppler sonography in all cases, and confirmed by
      celiac arteriography in those with Doppler abnormal findings. Clinical appearance
      of early artery complications were as acute liver failure (61.1%) or graft
      disfunction (38.8%). On the other hand, late complications were diagnosed
      incidentally in 46% of the patients due a programmed Doppler follow up. Actuarial
      survival at 24 months was higher in patients with late arterial complication (50
      vs 30%; p < 0.01). Therapeutic measures applied were retransplantation, surgical
      artery reconstruction and angioplasty. Early complications required more
      frequently retransplantation or surgical reconstruction. Risk factors related
      with artery complications development were analyzed, but not significant
      differences between both types of arterial complications were found. It is
      concluded that programmed follow up by Doppler or arteriography is necessary to
      make an earlier diagnose and to detect silent arterial complications.

PMID- 10592670
TI  - [Prospective study of gastroesophageal reflux after esophageal variceal band
      ligation].
AB  - In recent years, variceal ligation has been introduced as an alternative
      treatment to endoscopic sclerotherapy. AIM: To evaluate the occurrence of excess
      gastroesophageal reflux in cirrhotic patients with esophageal varices eradicated
      by band ligation. PATIENTS AND METHODS: Twenty-six cirrhotic patients with
      esophageal varices underwent band ligation until variceal eradication. pH
      monitoring was carried out in all patients before inclusion in the eradication
      program and again at the end. The results were evaluated according to De
      Meester's criteria. RESULTS: Five patients presented excess gastroesophageal
      reflux before the beginning of treatment. A further six patients developed excess
      gastroesophageal reflux after endoscopic treatment. The only factor implicated in
      the development of excess gastroesophageal reflux was the use of sclerosant at
      the end of treatment to ensure complete eradication: five of the eight who needed
      sclerosant developed excess gastrophageal reflux, while only two of the 16
      treated without sclerosant did so (p < 0.01). CONCLUSION: Esophageal variceal
      band ligation does not significantly provoke excess gastroesophageal reflux if
      sclerosant is not used in the endoscopic technique.

PMID- 10592671
TI  - [Endoscopic drainage with polyethylene endoprosthesis of malignant obstructive
      jaundice].
AB  - AIM: To evaluate the efficacy and complications of endoscopic drainage of
      malignant obstructive jaundice with plastic endoprosthesis as well as to identify
      possible factors related with occlusion. PATIENTS AND METHODS: One-hundred and
      forty patients with malignant obstructive jaundice were retrospectively
      evaluated. The site of obstruction was proximal in 35 patients (25.0%), distal in
      64 (45.7) and ampullary in 41 (29.3). Amsterdam or pigtail polyethylene
      prostheses of variable caliber and length were used. Drainage was preoperative in
      41 patients and palliative in 99. Seventy-seven patients who underwent with
      palliative drainage were followed up long-term. RESULTS: Drainage was
      satisfactory in 132 patients (94.2%). Early morbidity was 10.7% (14/140) and
      early mortality related with the technique was 5% (7/140). Time free of
      obstruction was 4.6 +/- 1.0 months and in 47/77 (60%) the prostheses were still
      working at the end of follow-up. The actuarial rate of obstruction at 6 months
      was 42%, the majority (61%) occurring in the first 3 months. The median survival
      was 5.9 +/- 1.3 months. Of all the factors analyzed, greater permeability was
      found only in the ampullary tumors (p < 0.01) and in prostheses of caliber equal
      or superior to 10 French (p < 0.01). CONCLUSIONS: Endoscopic biliary drainage
      using plastic prostheses is satisfactory in the majority of patients with
      malignant jaundice. It has a low complication rate and provides acceptable
      palliation: the majority of patients do not require prostheses to be replaced
      and, when they becomes clogged, substitution usually solves the problem.
      Ampullary tumors and prostheses of higher caliber (> or = 10F) have been
      associated with greater permeability.

PMID- 10592672
TI  - [Acute hepatitis due to heatstroke].
AB  - The hepatic injury is a nearly constant event in the course of a heatstroke,
      which rarely evolves to a severe liver failure. In these cases, the patient's
      survival is conditioned to an early treatment and, sometimes, an orthotopic liver
      transplantation is needed. We report a case of severe acute hepatitis in a 17
      year-old man, due to a heatstroke during a vigorous exercise in a training
      program. High ambient temperature and a long time without training predisposed to
      the development of heatstroke in this patient. Outcome was favourably, with a
      total recovery in a few weeks.

PMID- 10592673
TI  - [Acute cholestatic hepatitis induced by dextromethorphan].
AB  - A case of a 68-years-old female who was symptomatically treated with the codeine
      analog dextromethorphan because of a flu-like syndrome is herein reported. Five
      days later, she developed a cholestatic syndrome without fever or abdominal pain.
      Dextrometorphan was withdrawn and a rapid clinical improvement was observed,
      associated with decreasing levels of biochemical markers of cholestasis. Normal
      values were reached two months later. This type of adverse drug reaction, its
      potential pathogenic mechanisms and the therapeutic consequences are discussed.

PMID- 10592674
TI  - [Ultrasound guided percutaneous drainage of splenic abscesses].
AB  - We present our experience of ultrasound-guided percutaneous drainage with a
      catheter in 5 splenic abscesses. All the cases were resolved and there was only
      one relevant complication. The advantages of this treatment compared with surgery
      and isolated medical treatment are discussed and this technique is proposed as
      the treatment of choice.

PMID- 10592675
TI  - [Bleeding of the upper digestive tract due to gastric metastasis of squamous lung
      carcinoma].
AB  - Bronchogenic lung carcinoma, melanoma and breast cancer are the neoplasms which
      have most frequently been reported to metastasize to the stomach. These lesions
      are usually located on the fundus and on the upper part of the gastric body. They
      are usually asymptomatic with the diagnosis being made at necropsy. We present a
      patient who developed gastrointestinal bleeding as the first symptom of squamous
      lung cancer secondary to a gastric metastasis.

PMID- 10592676
TI  - [Percutaneous endoscopic gastrostomy: clinical indications and results].

PMID- 10592677
TI  - [Hereditary hemochromatosis: clinical implications of genetic diagnosis].

PMID- 10592678
TI  - [Hereditary cancer registers].

PMID- 10592679
TI  - [Peritoneal tuberculosis with elevated CA-125 in serum and ascitic fluid].

PMID- 10592680
TI  - [Treatment of liver cirrhosis due to hepatitis B with lamivudine].

PMID- 10592681
TI  - [Hepatoxicity due to ebrotidine: report of two cases].

PMID- 10592682
TI  - Deletion polymorphism in the human COL1A2 gene: genetic evidence of a non-African
      population whose descendants spread to all continents.
AB  - We report the frequencies of a deletion polymorphism at the alpha 2 (1) collagen
      gene (COL1A2) and argue that this distribution has major implications for
      understanding the evolution of modern humans immediately after their exodus from
      sub-Saharan Africa as well as their subsequent spread to all continents. The high
      frequency of the deletion in non-African populations and its complete absence in
      sub-Saharan African groups suggest that the deletion event occurred just before
      or shortly after modern humans left Africa. The deletion probably arose shortly
      after the African exodus in a group whose descendants were among the ancestors of
      all contemporary populations, except for sub-Saharan Africans. This, of course,
      does not imply that there was a single migration out of Africa. The GM
      immunoglobulin haplotype GM*A,X G displays a similar distribution to that for the
      COL1A2 deletion, and these 2 polymorphisms suggest that the exodus from Africa
      may not have been a rapid dispersion to all other regions of the world. Instead,
      it may have involved a period of time for the savanna-derived gene pool to adapt
      to novel selective agents, such as bacteria, viruses, and/or environmental
      xenobiotics found in both animal and plant foods in their new environment. In
      this context these polymorphisms are indicators of the evolution that occurred
      before the diaspora of these populations to the current distribution of modern
      peoples.

PMID- 10592683
TI  - Y-chromosome-specific microsatellite variation in Australian aboriginals.
AB  - The frequency distributions of 4 highly polymorphic Y-chromosome-specific
      microsatellites (DYS19, DYS390, DYS391, and DYS392) were determined in 79
      unrelated Australian Aboriginal males from the Northern Territory. These results
      are compared with those observed in worldwide populations at both the locus and
      the haplotype level. Common alleles in Aboriginals are DYS19*15 (49%), DYS19*14
      (28%), DYS390*19 (39%), DYS390*24 (20%), DYS391*10 (72%), DYS392*11 (63%), and
      DYS392*13 (28%). No evidence of reduced gene diversity was observed for these Y
      chromosome alleles. DYS390 exhibits the most complex arrangement, displaying a
      bimodal distribution composed of common alleles (*22-*26), and rare short alleles
      (*18-*20), with an intermediate allele (*21) being absent. DYS390*20, previously
      reported only in Papuans and Samoans, is observed for the first time in
      Aboriginals. Compared with a recent study of Aboriginals, our sample exhibits
      considerable diversity in the haplotypes associated with the rare DYS390*19
      allele, indicating that this allele is of considerable antiquity, if it arose as
      a single deletion event. Combining all 4 Y-chromosome-linked microsatellites
      produced 41 unique haplotypes, which were linked using a median-joining network.
      This network shows that most (78%) of our Aboriginal haplotypes fall into 2
      distinct clusters, which likely represent 2 separate lineages. Seven haplotypes
      are shared with haplotypes found in a recent study of Aboriginals, and 7 are
      shared with a Spanish population. The cluster of Aboriginal haplotypes associated
      with the short DYS390 alleles does not share any haplotypes with the Spanish,
      indicating that this cluster of haplotypes is unique to Australian Aboriginals.
      Limited data from 4 worldwide populations used to construct haplotypes based on 3
      loci (DYS19, DYS390, DYS392) show that only 4 of these haplotypes are seen in
      Australian Aboriginals. Shared haplotypes may be the result of admixture and/or
      recurrent mutation at these loci. Expanding the haplotype analysis to include
      biallelic markers on the Y chromosome will resolve this issue.

PMID- 10592684
TI  - Apolipoprotein B, apolipoprotein E, and angiotensin-converting enzyme
      polymorphisms in 2 Italian populations at different risk for coronary artery
      disease and comparison of allele frequencies among European populations.
AB  - Polymorphisms at the apolipoprotein B (APOB XbaI, EcoRI, insertion-deletion),
      apolipoprotein E (APOE), and angiotensin-converting enzyme (ACE) loci are thought
      to be involved in susceptibility to coronary artery disease (CAD) and myocardial
      infarction. The aim of this study was to determine whether the allele
      distribution of the APOB, APOE, and ACE polymorphisms is different in 2 Italian
      regions with higher (northern Italy) and lower (Sardinia) CAD occurrence. The
      frequencies of the APOB and APOE alleles that are considered CAD risk factors
      were higher in northern Italy (APOB X- = 0.655; APOB R- = 0.198; APOB insertion =
      0.757; APOE*4 = 0.110) than in Sardinia (APOB X- = 0.568; APOB R- = 0.159; APOB
      insertion = 0.680; APOE*4 = 0.052), although only APOE allele frequencies
      differed significantly (p = 0.001). ACE deletion allele frequencies in the 2
      geographic areas showed an opposite pattern (northern Italy = 0.658; Sardinia =
      0.721). Furthermore, we investigated the impact of APOB and APOE polymorphisms on
      interindividual variation in total cholesterol level in the 2 Italian samples,
      which differ in dietary habits. Only APOE phenotypes showed different mean levels
      of total cholesterol; the association was significant only in northern Italy (p =
      0.04), where continental dietary habits and higher mean cholesterol levels
      prevail. These results support the suggestion that the cholesterol increasing
      effect of APOE*4 is environmentally mediated. Analysis of allele distributions
      among European populations, with remarkable differences in CAD prevalence,
      revealed a constant positive relationship between APOE*4 allele frequency and CAD
      incidence. The highest frequencies of APOB X- and R- were observed in Finland,
      where the incidence of CAD is high, and there is a partial agreement between APOB
      R- frequency and CAD occurrence across Europe, while APOB insertion and ACE
      deletion alleles are evenly distributed among European populations.

PMID- 10592685
TI  - Isonymy and isolation by distance in Italy.
AB  - The isonymy structure of Italy was studied using the surname distribution of
      5,043,580 private telephone users selected from a 1996 commercial CD-ROM that
      contains all 24 million users in the country. The users were distributed in 123
      towns selected on a geographic basis. The 123 towns were either on the main
      communication roads of the country or at the ends of such roads. The shortest
      distance between nearest neighbor towns was 5.3 km (Carrara and Massa), and the
      largest distance was 1,136 km (Aosta and Castrignano del Capo). The number of
      different surnames found in the whole analysis was 215,623. Lasker's distance,
      the negative value of the logarithm of random isonymy between localities, was
      linearly and significantly correlated with the logarithm of geographic distance,
      with r = 0.63 +/- 0.008. A dendrogram was built from the matrix of isonymy
      distances, using UPGMA. It separates the Italian towns into 5 main clusters: 1 in
      the southern portion of the country, a second cluster toward the center, and 3 in
      the northern area of Italy. Within each cluster small subclusters with specific
      geographic distributions could be related to regional borders. Comparisons with
      the results of a previous analysis of Switzerland and Germany's structures are
      given. From the present analysis isolation by distance emerges clearly, although
      it is less strong than in Switzerland and stronger than in Germany. The random
      component of inbreeding estimated from isonymy indicates that the southern area
      of Italy is on average more inbred than the northern area. In fact, the
      heterogeneity is greater in the northern area, particularly in the plain of the
      Po River, than anywhere else in Italy.

PMID- 10592686
TI  - Mating pattern and population structure in Escazu, Costa Rica: a study using
      marriage records.
AB  - A primary focus of historical demographic research is to understand how a
      population's mating pattern can affect its genetic structure. By using surnames,
      researchers can reconstruct gene flow into a population as well as within it: the
      population structure. Indeed, Lasker (1988a) noted that the distribution of
      surnames reflects the effect of mate choice on a population's genetic structure.
      Here, we study the mating pattern of a small, clearly established breeding
      population in Costa Rica (Escazu) during 1800-1839 and 1850-1899. We found that a
      large proportion of marriages involved individuals who were members of long
      standing or core families. Indeed, 27 families provided 56% of all consorts
      throughout the period under study. When new surnames appeared in the records
      (presumably as a result of immigration), they were introduced more frequently by
      males, indicating that more males than females migrated into the community. The
      core families did not mate preferentially among themselves but appear to have
      readily accepted the migrants. Indeed,the greatest preponderance of repeated
      surname marriages was that expected by chance. However, nonrandom surname
      repetition is evident when marriages between nonillegitimate consorts are
      analyzed. That is, the frequency of repeated-pair surname marriages is
      statistically significant in marriages involving brides and grooms who carried 2
      surnames. Interestingly, significant departures from random repetition of
      surnames occurred during the decade in which the great cholera epidemic affected
      Costa Rica and during the decade following it. This departure from panmixia
      supports the notion that mating patterns were altered as a result of the
      epidemic, a suggestion we made previously when we reported that inbreeding
      increased in these same decades (Madrigal and Ware 1997).

PMID- 10592687
TI  - Potential effects of ethnicity in genetic and environmental sources of
      variability in the stature, mass, and body mass index of children.
AB  - We examined sources of variability in stature, body mass, and body mass index
      (BMI) in families of black and white elementary schoolchildren from Philadelphia,
      Pennsylvania. The sample consisted of 445 black and 379 white children, 7-13
      years old, and their parents (total n = 2016). The sample was distributed among
      596 nuclear families, each representing an independent pedigree. Maximum
      likelihood-based variance decomposition methods were used to simultaneously
      estimate ethnic group-specific effects of genes, sex, age by sex, and unmeasured
      environmental factors on stature, body mass, and BMI. Likelihood ratio tests were
      performed to assess the significance of h2 estimates and differences in sigma g
      and sigma e between black and white families. Genes account for moderate
      proportions of the phenotypic variance (h2) of these traits in black and white
      children. In black and white children, respectively, h2 estimates were 0.37 and
      0.53 for stature, 0.37 and 0.31 for body mass, and 0.38 and 0.24 for BMI (p <
      0.0005). Although the differences in h2 between ethnic groups were not
      significant (stature, p = 0.23; body mass, p = 0.49; BMI, p = 0.14), black
      children exhibited a significantly greater total residual phenotypic standard
      deviation (sigma e and sigma g) in body mass and BMI and a significantly greater
      sigma e for stature compared with white children. The larger residual phenotypic
      variance in the black sample is likely due to exposure to unmeasured
      environmental factors that are not accounted for in this model. Given that sigma
      g for stature is not significantly different between ethnic groups, the slightly
      lower estimates in black children are due to the increased contribution of the
      environment to the phenotypic variance in this trait.

PMID- 10592688
TI  - Origins of Falasha Jews studied by haplotypes of the Y chromosome.
AB  - DNA samples from Falasha Jews and Ethiopians were studied with the Y-chromosome
      specific DNA probe p49a to screen for TaqI restriction polymorphisms and
      haplotypes. Two haplotypes (V and XI) are the most widespread in Falashas and
      Ethiopians, representing about 70% of the total number of haplotypes in Ethiopia.
      Because the Jewish haplotypes VII and VIII are not represented in the Falasha
      population, we conclude that the Falasha people descended from ancient
      inhabitants of Ethiopia who converted to Judaism.

PMID- 10592689
TI  - Apolipoprotein B signal peptide polymorphism distribution among south Amerindian
      populations.
AB  - We report the distribution of the APOB signal peptide polymorphism in 5 native
      populations of South America: 2 samples of Mataco and 1 sample each of Pilaga and
      Toba from the Argentinian Chaco and 1 sample of Ache from the Paraguay forest. A
      randomly selected subsample of a previously studied sample from the Cayapa of
      Ecuador (Scacchi et al. 1997) was reanalyzed to investigate probable differences
      attributable to sampling, laboratory techniques, or interobserver error. The
      polymorphism observed in the signal peptide region of the APOB gene among native
      populations of South America exhibits the same range of variation found among
      geographic continental populations, confirming the high genetic heterogeneity of
      South Amerindians. Extremes in the allele prevalences were found among the Mataco
      and Ache, populations not far apart geographically. The small differences in
      genotype and allele frequencies between the subsample of the Cayapa analyzed here
      and the original Cayapa sample and between the 2 Mataco samples were not
      statistically significant and most likely were due to sampling error.

PMID- 10592690
TI  - Haplotype analysis of the apolipoprotein E and apolipoprotein C1 loci in Portugal
      and Sao Tome e Principe (Gulf of Guinea): linkage disequilibrium evidence that
      APOE*4 is the ancestral APOE allele.
AB  - The joint distributions of phenotypes from the apolipoprotein E gene (APOE) and
      from a closely linked restriction site polymorphism at the apolipoprotein C1
      locus (APOC1) were studied in population samples from Portugal and Sao Tome e
      Principe (Gulf of Guinea), a former Portuguese colony that was originally
      populated by slaves imported from the African mainland. The frequencies of the
      APOE alleles (*2, *3, and *4) in Portugal and Sao Tome fitted the ranges of
      variation generally observed in European and African populations, respectively.
      Haplotype analysis showed that in both populations the strength of linkage
      disequilibrium was highest for the APOE*2 allele and lowest for the APOE*4
      allele, suggesting that the origin of the APOE alleles followed a 4-->3-->2
      pathway and thus providing independent confirmation of the results from sequence
      homology studies with nonhuman primates. In accordance with global trends in the
      distribution of human genetic variation, the European sample from Portugal
      presented more intense linkage disequilibrium between APOE and APOC1 than the
      African sample from Sao Tome where, despite the short 4-kb distance that
      separates the 2 loci, the level of association between the APOC1 alleles and
      APOE*4 was nonsignificant.

PMID- 10592691
TI  - Adenosine deaminase polymorphisms at the protein and DNA levels.
AB  - Adenosine deaminase (ADA, E.C. 3.5.4.4) exhibits a well-known polymorphism at the
      protein level. We have studied ADA and an STR polymorphism exhibiting variation
      of a TTTA repeat motif at intron 3 of the ADA gene in random samples from
      northern Portugal (N = 218) and southwestern Germany (N = 114). The ADA phenotype
      distribution and population data on the worldwide distribution of ADA favor
      recurrent mutation as an explanation for the maintenance of the ADA*2 gene
      product at polymorphic frequencies.

PMID- 10592692
TI  - 40th Annual conference of the Indian Society of Gastroenterology in association
      with the Indian Association for Study of the Liver and Society of
      Gastrointestinal Endoscopy of India. Calcutta, India, November 17-20, 1999.
      Abstracts.

PMID- 10592693
TI  - A polymerase chain reaction 'PCR' for a quick diagnosis of aspergillosis.
AB  - A polymerase chain reaction (PCR) was developed from sequencing data generated
      from a specific target band that is unique for Aspergillus fumigatus DNA digested
      with EcoR1. The target band was detected through Southern blot hybridization of a
      non-radioactive probe labelled with DIG-dUTP and DNAs of different aspergilli.
      The DNA of the target band was purified, concentrated and subjected to
      sequencing. The size of the sequenced band was approximately 445 bp. One pair of
      primers was designed and synthesized from the sequencing data of the band. The
      oligonucleotide primers were specific in amplifying an identical band of A.
      fumigatus in a population mix containing DNAs of different Aspergillus spp.;
      Pencillium spp.; yeasts; bacterial and viral organisms that are commonly
      encountered in clinical specimens of respiratory origin. The reaction proved
      highly sensitive and as little as 0.0001 microgram of A. fumigatus DNA was
      detected in the reaction.

PMID- 10592694
TI  - Chlamydospore formation on Staib agar as a species-specific characteristic of
      Candida dubliniensis.
AB  - Staib agar (Syn. Guizotia abyssinica creatinine agar) was evaluated for
      differentiation between the highly related yeast species Candida albicans and
      Candida dubliniensis. On these agar plates C. dubliniensis formed rough colonies
      due to mycelial growth and produced abundant chlamydospores whereas C. albicans
      grew only in smooth colonies and without chlamydospore formation. The rough
      colonies of C. dubliniensis could be readily distinguished from the smooth C.
      albicans colonies. These results demonstrate that, under certain growth
      conditions, mycelial growth with chlamydospore formation is a species-specific
      marker that can be used for the identification of C. dubliniensis.

PMID- 10592695
TI  - Identification of dermatophytes by Fourier transform infrared spectroscopy (FT
      IR).
AB  - Fourier transform infrared spectroscopy is an established method in the routine
      diagnosis of various micro-organisms, including bacteria and yeasts, on a species
      level. Its possible value in the diagnostics of dermatophytes was analysed using
      three clinical isolates each of the three most frequently found species, namely
      Trichophyton rubrum, Trichophyton mentagrophytes and Microsporum canis. The
      results encourage further work to establish a library which would allow the use
      of this method in the clinical setting. This might help to make repeated
      subcultures, which are money- and time-consuming, redundant.

PMID- 10592696
TI  - Candida albicans clinical isolates inactivated by formalin with different
      adherence to buccal epithelial cells induce proinflammatory and regulatory
      cytokines in human peripheral blood mononuclear cells.
AB  - Besides the activation of phagocytes, the release of cytokines is the most
      important immunological defence mechanism of an organism against infection with
      Candida albicans. On the other hand cytokines induced in the organism by the
      yeast itself are able to modulate the immune responses of the host. We
      investigated whether eight clinically isolated strains of C. albicans inactivated
      by formalin as well as a laboratory strain were able to induce proinflammatory
      and regulatory cytokines in peripheral blood mononuclear cells (PBMC) of four
      different donors. Under our assay conditions the yeast strains induced the
      cytokines interleukin-1 beta (IL-1 beta), interferon-gamma (IFN-gamma) and
      interleukin-10 (IL-10) in PBMC to varying extents, but not the cytokine
      interleukin-4 (IL-4). We observed a difference in the reaction of the individual
      donors to the stimulus C. albicans but on the other hand the extent of the
      cytokine signal seemed to be dependent on the yeast strain as well. No
      correlation was found between the ability of the individual C. albicans strains
      to induce cytokines in PBMC and their ability to adhere to buccal epithelial
      cells. Determination of the cytokine induction potential of C. albicans strains
      possibly may contribute to the detection of new virulence factors of this yeast.

PMID- 10592697
TI  - Colorimetric method for susceptibility testing of voriconazole and other
      triazoles against Candida species.
AB  - A microdilution assay using Alamar Blue, a colorimetric indicator, was compared
      with the NCCLS macrodilution broth assay for voriconazole, fluconazole, and
      itraconazole against Candida albicans, Candida glabrata, and Candida krusei.
      Concordance (+/- 2 dilutions) between the two methods was highest for
      voriconazole (98.3%), and for fluconazole and itraconazole it was 94.3 and 95.4%,
      respectively. Twenty-six of 32 (81.2%) discordant readings (> or = 3 dilutions
      different) were noted in C. glabrata isolates, and all but two isolates showing
      discordance had higher minimum inhibitory concentration readings with the
      colorimetric method.

PMID- 10592698
TI  - Fungaemia survey: a 10-year experience in Bergamo, Italy.
AB  - The authors analysed 10 years of experience of fungaemia at a Regional Italian
      Hospital, the Azienda Ospedaliera (A.O.) 'Ospedali Riuniti di Bergamo', Bergamo,
      Italy, from 1988 to 1997. One hundred and sixty-eight cases were observed, with a
      global incidence corresponding to 3.43/10,000 in-patients. Median age was 38.5
      years and mean age was 38.9 years (range: 0-94 years). Female:male ratio was
      1:1.75. Fungaemia occurred 25.7 days (mean value) after admission to the
      hospital. Aetiology was: 134 Candida spp. (70%), 11 Cryptococcus neoformans
      (6.5%), seven Torulopsis inconspicua (4.1%), three Trichosporon beigelii (1.8%),
      one Hansenula anomala (0.6%); three Fusarium verticillioides (1.8%), three
      Geotrichum candidum (1.8%) and one Histoplasma capsulatum (0.6%). Total mortality
      was 50.6%, and particularly related to Candida kefyr and Candida krusei, to Cr.
      neoformans and Fusarium spp.

PMID- 10592699
TI  - Alterations in spore production in Trichophyton rubrum treated in vitro with 1
      amino-6-methyl-4-phenylpyrazolo[3,4-d]-1,2,3-triazole.
AB  - The effects of the newly synthesized triazole, 1-amino-6-methyl-4
      phenylpyrazolo[3,4-d]-1,2,3-triazole (V5), on the dermatophyte Trichophyton
      rubrum were tested. Optical and electron microscopy showed that the treatment
      suppressed the various forms of saprophytic conidia, induced the formation of
      chlamydospores and accelerated the formation of arthroconidia. This new triazole
      did not reveal any fungistatic or fungicidal activity and could not be considered
      as an antifungal substance.

PMID- 10592700
TI  - Oral terbinafine (Lamisil) in the short-term treatment of fungal infections of
      the skin: results of a post-marketing surveillance study.
AB  - Oral terbinafine (Lamisil, Novartis Pharma AG, Basel, Switzerland) is an
      effective therapy for fungal infections of the skin and nails. A post-marketing
      surveillance study was undertaken to evaluate the clinical efficacy and safety of
      oral terbinafine. A total of 454 patients with clinically and mycologically
      confirmed superficial fungal infections of the skin were enrolled from 79
      dermatology clinics. Patients received oral terbinafine (250 mg day-1) for 2
      weeks. Specific signs and symptoms were assessed by standard questionnaire
      before, immediately after, and 4 weeks after treatment. Observed improvements in
      patients after 2 weeks treatment were: erythema 81%, blistering 33%, exudation
      50%, scaling 89%, pruritus 83%. After 4 weeks treatment, erythema was absent in
      85% of patients, blistering and exudation in 99.7%, scaling in 82%, and pruritus
      in 94%. Overall clinical efficacy was assessed as good to excellent in 97% of
      patients. Adverse effects--mainly gastrointestinal and minor skin rashes--were
      reported in 5.3% of patients. The results of this study confirm that oral
      terbinafine is safe and highly effective for the short-term treatment of fungal
      skin infections.

PMID- 10592701
TI  - Tinea capitis in Siena, Italy. An 18-year survey.
AB  - In the period 1980-1998, 181 cases of tinea capitis out of a total of 1480 cases
      of dermatophytosis were observed in Siena, Italy; 176 cases were children (mean
      age 6 years, range 45 days to 14 years; 91 boys, 85 girls) and the other five
      cases were postmenopausal women. Diagnosis was made on the basis of culture which
      was positive in 179 cases, and direct microscopic observation which was positive
      in 155 of 179 cases. In two cases, positive direct microscopic results were not
      confirmed by the culture. The most frequently isolated mycete was Microsporum
      canis (162 cases, 90.5%) and the main source of infection was the cat, which was
      often a healthy carrier. The second most frequent mycete was Trychophyton
      mentagrophytes. Trichophyton violaceum, a dermatophyte practically absent from
      our province since the 1960s, was isolated in five patients. All patients were
      successfully treated. One adult was treated with oral ketoconazole and the other
      four with oral itraconazole. The children were all treated with griseofulvin and
      topical antimycotics. Two children, observed in 1997-1998, who did not respond to
      griseofulvin, achieved clinical and mycological recovery with oral itraconazole.

PMID- 10592702
TI  - Epidemiology of dermatomycoses of humans in central Poland. Part III. Tinea
      pedis.
AB  - The total number of dermatophytoses (7393) included 2025 (27.4%) tinea pedis
      cases. Etiological factors in descending order by contribution were: Trichophyton
      rubrum (41.7%), Trichophyton mentagrophytes var. granulosum (30.9%), T.
      mentagrophytes var. interdigitale (10.0%), Epidermophyton floccosum (7.4%), T.
      mentagrophytes var. quinckeanum (6.9%), Trichophyton tonsurans (2.3%),
      Trichophyton spec. (0.4%), Trichophyton terrestre (0.2%), Trichophyton violaceum
      (0.1%). In the years 1987-93 the incidence of tinea pedis substantially increased
      over 1994-96. Today tinea pedis is second by incidence among all clinical forms
      of dermatophyte infections of skin and skin appendages in the Lodz region.

PMID- 10592703
TI  - Case report. Histoplasmosis in an AIDS paediatric patient.
AB  - Histoplasmosis has been little reported among HIV-infected children. We report a
      case of a 4-year old boy with AIDS who presented with disseminated histoplasmosis
      diagnosed by lung biopsy. The patient had a good clinical response to
      amphotericin B followed by itraconazole oral solution.

PMID- 10592704
TI  - Case report. Sporotrichosis successfully treated with itraconazole in Japan.
AB  - A case of lymphocutaneous sporotrichosis that had developed from the dorsum nasi
      to the left buccal region of a 65-year-old woman was treated with itraconazole
      100 mg day-1. The lesion healed in 10 weeks after starting treatment leaving
      crusts, mild erythema and pigmentation, and the treatment was completed 16 weeks
      after the start of treatment. Neither adverse reactions nor abnormal clinical
      laboratory values were noted. Until the present time, 1 year and 2 months after
      the completion of treatment, no recurrence has been observed. In Japan, 43 cases
      of sporotrichosis have been treated with itraconazole, and 38 cases (88%) have
      been assessed as effective or better. The mean dose of itraconazole and the mean
      duration of administration are 100 mg day-1 and 11 weeks, respectively, in these
      reported Japanese cases. The use of itraconazole is expected to be one of the
      effective therapies for sporotrichosis.

PMID- 10592705
TI  - Case report. Osteomyelitis caused by high resistant Candida guilliermondii.
AB  - We describe a case of a 57-year-old patient with osteomyelitis at a finger of his
      right hand caused by Candida guilliermondii. The strains isolated were highly
      resistant to fluconazole and itraconazole. Using the three methods,
      microdilution, agardilation and E-test, the highest minimum inhibitory
      concentrations (MICs) amounted to > 256 micrograms ml-1 for fluconazole and > 32
      micrograms ml-1 for itraconazole. To our knowledge, this is the first time such
      high values have been described for C. guilliermondii. They correlated with the
      therapeutic non-response to a triazole therapy in our patient. The patient was
      cured by partial amputation of the affected finger.

PMID- 10592706
TI  - Case report. Kerion Celsi effectively treated with terbinafine. Characteristics
      of kerion Celsi in the elderly in Japan.
AB  - A 75-year-old non-working male living in Sagamihara, Kanagawa Prefecture, had
      erythematous plaques with scales associated with follicular pustules in the head
      area extending from the occipital to right temporal regions about 1 month prior
      to his initial visit, when hair loss increased. The diagnosis was kerion Celsi.
      Trichophyton rubrum was isolated from scales and tissues taken from lesions in
      the head. Histopathological examinations showed irregular epidermal thickening
      with dense cell infiltration from the dermis to subcutaneous adipose tissues.
      Granulomatous reactions involving neutrophils, histiocytes and giant cells were
      seen mainly in the hair follicles. Periodic acid-Schiff (PAS) and Grocott
      positive microbial elements were detected in the horny layer, and inside and
      outside the hair follicles. Pustules disappeared 1 week after starting the oral
      treatment with terbinafine (125 mg day-1). A cure was achieved 2 weeks after
      starting the treatment, with only slight scales remaining. No recurrence has been
      observed to date. Terbinafine was thought to be very effective and safe for
      kerion Celsi. We reviewed 27 cases of kerion Celsi reported in patients, aged at
      least 70 years, in Japan and found that the major characteristics of this disease
      in Japan include the following: (1) female cases outnumber male cases; (2) the
      causative organism was T. rubrum in 14 of 27 patients (51.9%); and (3) topical
      application of steroids often induces this disease in patients with superficial
      tinea capitis.

PMID- 10592707
TI  - Case report. Tinea corporis purpurea.
AB  - We report a case of tinea corporis purpurea localized to a calf in a 36-year-old
      woman. The patient, who was also affected by mild superficial venous
      insufficiency of lower limbs, complained of intense pruritus. Microsporum canis
      was the aetiological agent. Clinically atypical varieties of tinea corporis were
      sometimes reported in the literature, particularly in HIV-positive patients,
      although they are uncommon in immunocompetent patients; in particular, tinea
      corporis purpurea is very rare.

PMID- 10592708
TI  - [In Process Citation]

PMID- 10592709
TI  - [Electron microscopy of Candida albicans].
AB  - The multiplicity of information which electronmicroscopy has contributed to our
      knowledge of Candida albicans and its relationship to the human host is reviewed
      and by means of examples presented.

PMID- 10592710
TI  - [Taxonomy and ecology of the genus Candida].
AB  - Candida is a heterogeneous genus which contains about a quarter of all yeast
      species. It includes not only species of uncertain affiliation but also unrelated
      strains whose phylogenetic relationships have not been resolved. A great variety
      of CoQ types are present in the genus, the mol % G + C ranges from 30-63%, and
      species that were found to sporulate have teleomorphic counterparts in 11
      different genera. Candida species are mainly associated with plants, rotting
      vegetation, with insects which feed on plants or with food. In line with this,
      71% of Candida species utilize xylose (wood degradation), 57% of species use
      cellobiose (cellulose degradation), 29% oxidize aliphatic hydrocarbons
      (components of plant cuticula), 27% of species degrade starch as a plant storage
      material, and 7% utilize methanol as a possible metabolite from pectin
      catabolism. 85% of species require individual vitamins produced mainly in plant
      materials. 65% of Candida species are not able to grow at temperatures of 37
      degrees C. In comparison only relatively few species occur normally in humans and
      other warm blooded animals. About 16% of type strains and selected strains for
      comparative purposes (CBS) were isolated from human specimens. Perhaps up to 10%
      of Candida species may be of medical importance, though this has so far only been
      clearly demonstrated for less than 5% of currently known species.

PMID- 10592711
TI  - [Habitats for Candida in medical and hygienic respects].
AB  - The at present acknowledged 163 species of the genus Candida are living in
      different habitats. Agents of human candidosis have a comparatively restricted
      natural distribution, and have been discovered primarily in association with men
      and animals. Candida albicans holds an exceptional position opposite to the
      nearly 20 non-C. albicans-species with medical importance. Primary habitat is the
      digestive tract of men and warm-blooded animals. C. albicans is not ubiquitously
      distributed in the nature. Carriers of Candida may contaminate their immediate
      environment with yeasts, but that contamination does not usually spread far. C.
      albicans survives poorly on dry surfaces, a little bit longer in moist materials.
      Some non-C. albicans-species have their habitat also in the digestive tracts of
      men and animals, but different to C. albicans they are also ubiquitously
      distributed in the surroundings (soil, plants, foods, forages) and are much more
      resistant to environmental influences. The most important source of Candida
      species in human diseases is endogenous. The via exogen contamination arising
      mycoses are involved above all by non-C. albicans-species. The different habitats
      of the Candida species are decisive for the direct and indirect transmission of
      yeasts to humans and also for the preventive measures against endogenous and
      exogenous nosocomial Candida mycoses.

PMID- 10592712
TI  - [Gastrointestinal microecology of humans and Candida].
AB  - Microecology looks for the relationships between microorganisms and their natural
      environment in definite sites and their physiological and pathological effects.
      From birth Candida spp. are often but not always detectable in the human
      gastrointestinal tract. In cases of reduced defense the tract may be a source of
      infection to the macroorganism. In healthy subjects the incidence of Candida is
      between 23% and 76% in quantities between 10(2)-10(4) CFU/ml or g dependent on
      site. Evidence is most frequent in oral cavity and faeces. Tolerance for Candida
      spp. is different in the stomach and duodenum due to differences in acidity.
      Changes in the occurrence of Candida spp. are possible depending on age,
      different diseases and exogenous influences as nutrition, stress and drugs. In an
      endocrine stress model we found no yeasts in the duodenal juices of 7 subjects
      before and after stress situation, but a clear decrease of yeasts in the faeces.
      The formation of metabolic products by Candida is secondary to the whole of
      microbial fermentation in the human orointestinal tract. Colonizing strains of C.
      albicans are normally present in small or moderate numbers and only they are
      regarded as part of the resident gastrointestinal microflora.

PMID- 10592713
TI  - [Analysis of the "innate" immune system].

PMID- 10592714
TI  - [Adherence and invasion-two pathogenicity factors in bacterial and fungal
      pathogens].
AB  - Pathogenicity factors such as adhesins, toxins, capsules, and other microbial
      gene products are involved as causative agents for infectious diseases.
      Therefore, the pathogenicity of organisms is increasingly studied on a molecular
      level. In bacteriology, unspecific adherence mechanisms and receptor-specific
      adhesins have to be distinguished. An adhesin-mediated invasion of pathogenic
      organisms in eukaryotic host cells could be relevant for pathogenesis. In
      mycology, various specific adhesins are involved in colonization of the host.
      Aspartyl proteases and phospholipases are relevant for adherence and invasion of
      host structures by pathogenic yeasts. Resistance factors have a central function
      in the distribution of infectious organisms. Gene-transfer, point mutations and
      efflux mechanisms are involved in the development of antibiotic drug resistance.
      Antifungal drug resistance does occur predominantly in Candida albicans against
      azole drugs. As underlying mechanisms point mutations in the ERG11 gene, encoding
      for the target enzyme of azoles, as well as energy-dependent efflux mechanisms
      were identified. Whether these mycotic factors are specific virulence factors or
      "fitness-factors" for a better survival of these organisms in the host, and if a
      possible alternating effect exists between resistance and virulence mechanisms is
      currently under investigation.

PMID- 10592715
TI  - [Adhesion of clinical Candida albicans isolate to buccal epithelial cells].
AB  - Mucosal adherence and germ tube formation are considered to be important
      virulence factors of C. albicans. Adherence is a precondition for colonisation
      and invasion. We investigated 11 clinical isolates (among them 5 cases recovered
      from oesophageal thrush) for quantification of the two characteristics and
      correlated the results with clinical data. Adherence was measured on buccal
      epithelial cells and the continuous flow culture was used for quantification of
      germ tube formation. Adherence of strains recovered from clinically, culturally
      and serologically confirmed oesophageal thrush adhered stronger to buccal
      epithelial cells than isolates from patients with heavy colonisation without
      signs of candidosis. Strains with stronger adherence showed a significantly
      faster and an increased germ tube formation in the continuous flow culture.
      Strains from oesophageal thrush therefore show a more marked expression of the
      investigated virulence factors. Therefore a good adherence is a necessity for
      infection of the oesophagus by C. albicans. The preferential isolation of C.
      albicans from oesophageal thrush (> 90%) supports this assumption.

PMID- 10592716
TI  - [Proteinases of pathogenic fungi].
AB  - The present knowledge on the pathogenetic relevance of extracellular and cell
      wall-attached proteinases from fungal pathogens is briefly reviewed.

PMID- 10592717
TI  - [Candidiasis in cancer patients: Epidemiology, diagnosis, prophylaxis and
      therapy].
AB  - New approaches in successful treatment of cancer patients are impaired by
      increasing incidence of fungal infections with high mortality. Relevant
      prognostic factors could be identified by numerous trials, such as age, kind and
      status of disease, intensity of previous chemotherapy, bone marrow
      transplantation, advanced fungal colonization of gastrointestinal tract. In
      clinical practice options for prompt and sensitive diagnostics are limited
      despite of new PCR-techniques. Prophylactic efficiency of polyenes or azoles is
      proven in high risk patients. Amphotericin B is established for treatment in case
      of documented or assumed invasive fungal infection. Liposomal preparations are
      less toxic and at least as effective as conventional amphotericin B in randomized
      trials.

PMID- 10592718
TI  - [Disseminated candidiasis in premature twins. Case report].
AB  - A case of disseminated candidosis in a premature newborn twin I (26th weeks of
      pregnancy) is reported. A severe mycotic infection of the organs, especially the
      kidneys was present. Even Candida in the pancreatic islets of Langerhans cells
      could be demonstrated. Twin II also suffered a Candida infection but in contrast
      to twin I she survived after therapy. Candida infection of twins is rarely
      reported in the literature.

PMID- 10592719
TI  - [Candida in dermatology].
AB  - Regarding Candida in dermatology, two pathogenetic pathways must be taken into
      account: 1. on infection of the skin 2. immunological reactions with skin
      alterations as a result of Candida infection or colonization in the mouth and/or
      intestine. Case reports describe typical situations of napkin dermatitis,
      intertriginous candidosis, the intrauterine Candida infection of the foetus,
      Candida granuloma, Candida folliculitis and Candida paronychia. In the second
      part results of investigations of patients suffering from psoriasis, atopic
      dermatitis and urticaria are presented. There were no differences in the
      colonization with Candida albicans and in the level of Candida antibody titres
      between patients and a healthy control group.

PMID- 10592720
TI  - [Orointestinal candidiasis with special emphasis on esophageal candidiasis].
AB  - Orointestinal mycoses are localized mainly in the oral cavity and in the
      oesophagus. Candida oesophagitis is not only found in AIDS-patients, also in
      patients of risk admitted to intensive care units. Upper intestinoscopies were
      made in 124 patients. Oesophageal candidosis was found in 6 patients, two of them
      had also Candida plaques in the stomach. The patients of the intensive care unit
      had an Apache-II-score of 26.7, those with Candida oesophagitis were 29.5. A
      significant increase in Candida antibodies was observed with 59 of 124 patients
      (47.6%), including all patients with oesophageal candidosis. Obviously also
      Candida infections of other localisations must be suspected. There was a
      correlation between the severity of endoscopic aspects and the invasiveness
      observed microscopically.

PMID- 10592722
TI  - [The role of beta-adrenergic blocking agents in treatment of heart failure].

PMID- 10592721
TI  - [Review article. Molecular basis of antimycotic therapy].
AB  - A review is presented on the hitherto clinically administered antimycotic drugs,
      their action mechanisms and limitations as well as on the presently newly
      developed antifungals and their molecular targets.

PMID- 10592723
TI  - [Studies of arrhythmia incidence and heart rate variability in patients with
      stable angina pectoris].
AB  - Continuous Holter ECG monitoring is a valuable, easy to perform, non-invasive
      method of assessing not only cardiac arrhythmias but also heart rate variability
      and autonomic nervous system function. The aim of the study was to determine
      cardiac arrhythmias and HRV in patients with stable angina with and without
      previous myocardial infarction. 156 patients, 92 with and 64 without previous
      myocardial infarction, were examined. The control group consists of 50 healthy
      volunteers of the same age and sex. No pharmacological treatment except
      nitroglycerin was applied 2 days before and during examination, blood
      electrolytes were normal and 24-hour activity was the same in both examined
      groups. Heart rate variability was assessed by calculation of indices based on
      statistical operations on RR intervals (time-domain analysis). As a result of the
      study it was found out that in patients with stable angina pectoris cardiac
      arrhythmias occur more often and 24-hour heart rate variability is depressed as
      well as during daily activity and night resting than in healthy persons. In
      patients without previous myocardial infarction it was found out that 24-hour
      heart rate was slower than in patients with previous myocardial infarction, which
      depended mainly on slower heart rate during night, heart rate variability was not
      significantly different between these groups.

PMID- 10592724
TI  - [Oxidation phenotype as a risk factor for development of allergic diseases].
AB  - The relationship between genetically determined polymorphic metabolism and
      susceptibility to allergic diseases has aroused much interest. The aim of our
      study was to evaluate whether patients with allergic diseases, like atopic asthma
      and allergic rhinitis differ from healthy persons in their ability to oxidize
      sparteine as a model drug. The study was completed by 200 persons, 40 patients
      with allergic diseases--20 with atopic asthma and 20 with allergic rhinitis and
      160 healthy volunteers as a control group. The results of our study revealed a
      predominance of very extensive metabolizers of sparteine among patients with
      allergic diseases in comparison with healthy volunteers. The difference in the
      oxidation metabolic ratio (MR) frequency distribution between patients with
      allergic diseases and healthy persons was statistically significant. Relative
      risk (odds ratio) of development of atopic asthma was 3.29 times higher, and that
      of allergic rhinitis 2.94 times higher for persons with very extensive oxidation
      phenotype. Our results represent some evidence for a possible relationship
      between extensive, rapid oxidation phenotype and the higher susceptibility to
      development of atopic asthma and allergic rhinitis.

PMID- 10592725
TI  - [Venous blood gas analysis sampled from the basilic vein before and after
      exercise of the antebrachial muscles--preliminary evaluation of estimated
      stability parameters].
AB  - The aim of the study was to compare venous blood gasometry parameters of blood
      sampled twice from basilic vein on different days and at different hours. In the
      group of 8 healthy volunteers, parameters of venous blood gasometry sampled from
      basilic vein before and after exercise of antebrachial muscles, twice--on
      different days and at different hours were estimated. CONCLUSIONS: 1. In the
      first and in the second sample venous blood gasometry parameters before and after
      exercise were different: values of pCO2, pO2, O2sat increased, pH, BE, BEexe and
      BB decreased and HCO3 was not changed. 2. Venous blood gasometry parameters
      before exercise in the first and in the second sample and after exercise in the
      first and in the second sample were not different.

PMID- 10592726
TI  - [Troponin T--is it a marker of restenosis after transluminal percutaneous
      angioplasty in unstable angina patients?].
AB  - Troponin T (TpT) is a protein implicated in skeletal muscle contractions,
      including myocardium. It was shown that the presence of troponin TpT in unstable
      angina patients' blood is associated with poor prognosis. In the present study
      amongst 25 patients with unstable angina 12 were found to have TpT present in
      their blood. TpT concentration was higher in patients with III and IVo CCS
      symptoms in comparison with class I and IIo CCS symptoms: 0.207 +/- 0.275 and
      0.144 +/- 0.186 ng/mL respectively (p = 0.053; nonparametric Kolmogorow-Smirnov
      test). Patients were subjected to percutaneous transluminal coronary angioplasty
      (PTCA). After 3 months of follow up 17 patients (the rest of them dropped out)
      were assigned to two groups: A (n = 8)--without and B (n = 9)--with clinical and
      electrocardiographic signs of restenosis. Retrospective analysis revealed the
      presence of TpT before PTCA in 6 group B patients and 2 group A patients.
      Relative risk of stenocardia recurrence was calculated as 2.25. TpT was present
      in the blood of 20 patients in the first 24 hours after PTCA, and group B
      patients had higher mean TpT concentration; that could result from reperfusion of
      more ischaemic myocardium. It seems that the presence of TpT in unstable angina
      patients' blood may be an important factor characterizing patients with more
      serious prognosis.

PMID- 10592727
TI  - [Coexistence of bronchial asthma and diabetes mellitus type 2--retrospective
      analysis].
AB  - Bronchial asthma and diabetes mellitus type 2 are often found among adult
      patients. However, coincidence of these two diseases is very rare. The aim of the
      study was the retrospective analysis of all patients with bronchial asthma and
      diabetes mellitus type 2 hospitalised in Department and Clinic of Internal
      Diseases and Allergology in Zabrze, Silesian School of Medicine in Katowice in
      1988-1997. Diabetes mellitus type 2 was diagnosed according to WHO criteria of
      1985 and bronchial asthma was diagnosed with the use of American Thoracic Society
      criteria. Bronchial asthma and diabetes mellitus type 2 occurring together were
      found in 18 patients (0.3% of all hospitalized patients). In most patients the
      symptoms of bronchial asthma preceded the diagnosis of diabetes mellitus by a few
      years. All these cases were heterogeneous in terms of the duration of the
      diseases, clinical picture, and therapeutical approaches. In patients with
      bronchial asthma the existence of diabetes mellitus type 2 was not related to use
      of glikocorticosteroids. Patients in whom the coexistence of bronchial asthma and
      diabetes mellitus type 2 was found should be subjects of further studies to
      extend our knowledge of patomechanism of these diseases.

PMID- 10592728
TI  - [Atrial fibrillation in mitral valve disease--risk factors].
AB  - Atrial fibrillation is frequently found in association with rheumatic mitral
      valve disease. However, the risk factors of atrial fibrillation have not been
      well established. The aim of this study was to assess risk factors of atrial
      fibrillation in patients with mitral valve disease. METHODS: The study group
      consisted of 141 patients (pts) with isolated mitral valve disease. Pts were
      divided into 3 groups (45 pts--mitral stenosis, 29 pts--mitral regurgitation, 67
      pts--combined mitral valve disease). Mean age--52.5 years. Atrial fibrillation
      before operation was in 102 pts (72.3%). The clinical history of each patient was
      taken to obtain the patient's age, likely etiology of the valve lesion time of
      onset of atrial fibrillation. Echocardiografic and electrocardiografic records
      were performed in each patient. RESULTS: In all three groups of patients age and
      left atrial size were the most important factors of atrial fibrillation (atrial
      fibrillation was rare when left atrial dimension was below 40 mm). CONCLUSIONS:
      Atrial fibrillation was strongly associated with mitral stenosis and combined
      mitral disease. The most important factors of atrial fibrillation was age, left
      atrial dimension and hemodynamic class.

PMID- 10592729
TI  - [Hemodialysis--is it a method of acute intermittent porphyria treatment? Case
      report].
AB  - In this paper a female patient with severe acute intermittent porphyria is
      presented in whom routine pharmacological treatment was unsuccessful. After five
      haemodialysis sessions a dramatic improvement of the clinical status was observed
      in spite of markedly elevated urinary excretion of porphyrin metabolites. Further
      studies are mandatory in order to evaluate the effectiveness of acute
      intermittent porphyria treatment.

PMID- 10592730
TI  - [Renovascular hypertension with high serum zinc in serum of a patient with ceroid
      lipofuscinosis and genome 46,XY,9qh+].
AB  - A case of a 38-year-old patient with severe renovascular hypertension high serum
      zinc concentration and ceroidlipofuscinosis was presented. The diagnosis of
      ceroidlipofuscinosis was based on electron microscope picture of mucosus tissue
      of rectum where the secondary lisosoms, so characteristic of this disease, were
      found in cells of connective tissue.

PMID- 10592731
TI  - [Multiple primary neoplasms in a century of research].

PMID- 10592732
TI  - [Multiple primary neoplasms--etiopathogenic aspects].

PMID- 10592733
TI  - [Opinions on the cardioprotective influence of ischemic preconditioning].

PMID- 10592734
TI  - [Antibiotic resistance: an always present problem].

PMID- 10592735
TI  - [Trends in the treatment of rheumatic diseases].

PMID- 10592736
TI  - [Epidemiology of multi-drug resistant tuberculosis in AIDS].

PMID- 10592737
TI  - [Determination of interleukin-6 messenger RNA as malignant progression index in
      monoclonal gammapathy of undetermined significance].
AB  - The monoclonal gammopathy of undetermined significance (MGUS) could be considered
      a preneoplastic condition since no clinical and laboratory features are able to
      identify in advance the patients at high risk of disease progression. In this
      study we analysed IL-6mRNA expression on both bone marrow mononuclear cells and
      peripheral blood mononuclear cells sample of multiple myeloma (MM) and MGUS
      patients for evaluation if IL-6mRNA expression could be considered diagnostic or
      prognostic aspect of progression disease risk to MM. We concluded that expression
      of IL-6mRNA hasn't prognostic significance for the progression disease risk to
      multiple myeloma but could have a discriminant significance the MM and MGUS
      pathologies when combined with gene rearrangements and immunochemicals analysis.

PMID- 10592738
TI  - [Transformation of Waldenstrom disease into chronic myeloid leukemia].
AB  - The authors describe a case of a 83 years old patient affected with Waldenstrom
      disease whose shift in chronic myelogenous leukaemia is surprising because the
      quickness of the fact and, even more, because the following very fast appearance
      of quickly fatal paravertebral granulocytic sarcoma, as extramedullary blast
      crisis expression. This feature appears unusual in old subject.

PMID- 10592739
TI  - [Amyloidosis and renal failure].
AB  - A heterogeneous group of disorders associated with abnormal extracellular
      deposition of fibrillar proteins is defined amyloidosis. The renal involvement
      may occur in the absence of a recognized underlying disease or the kidney is
      affected as a result of systemic amyloidosis. Even if the diagnosis can only be
      confirmed by demonstrating the presence of amyloid deposits in the tissues, the
      development of a radiolabelled serum amyloid P component as a diagnostic nuclear
      tracer and the reduced urinary excretion of glycosaminoglycans as a decrease in
      the synthesis of functioning glomeruli and trapping by amyloid fibrils allow new
      diagnostic insight for the future. Patients maintained on haemodialysis or
      continuous ambulatory peritoneal dialysis for long develop amyloid deposits
      composed of beta 2 microglobulin that are predominantly osteoarticular,
      associated with carpal tunnel syndrome, large-joint pain, stiffness and
      pathological fractures. Systemic amyloidosis and some local forms are progressive
      and no treatment specifically resolves the amyloid deposits but therapy may
      reduce amyloid precursor proteins and improve survival.

PMID- 10592740
TI  - [Treatment of multiple sclerosis. The present and the future. Study Group on
      Diagnosis and Therapy of Multiple Sclerosis].
AB  - The last years have produced a plethora of new information including extensive
      studies, retrospective analysis and new perspectives on data interpretation on
      multiple sclerosis (MS) treatment. Considering how difficult it is to study a
      disease such MS with its variability, unpredictability and duration, it seems
      hard to resemble definite results from this experience. However, corticosteroids
      have been the mainstay of treatment for the management of acute relapses, showing
      the capacity to shorten the duration of relapses, accelerate the recovery. At
      present, interferon beta is generally considered to be the treatment of choice
      for patients with relapsing remitting disease. Glatiramer acetate is still not
      available in many parts of Europe, but its results demonstrate a reduction of
      relapses in 30% of cases. Most European experts only consider as alternative
      treatment the immunosuppressive drugs, chosen if patients demonstrate
      unacceptable side effects of interferon or clearly do not respond. Very different
      and even more confusing data still come from experimental trial in secondary
      progressive MS, where the target of treatment is to slow the progression of
      disability. Different drugs (methotrexate, mitoxantrone, linomide, steroids and
      even interferons) are employed, but the results are still debated. Future
      therapies are being derived from constantly changing and evolving concept of MS
      immunopathogenesis: therefore many experimental and clinical trials use anti
      integrin antibodies or insulin growth factors, metallo-proteinase inhibitors or T
      cell vaccination. Some of the above treatment may have a chance of producing the
      gaining control of the disease without much inner toxicity.

PMID- 10592741
TI  - [Epidemiology and therapy of mycotic infections in immunocompromised host with
      special regard to the role of lipid formulations of amphotericin B].
AB  - The extensive use of antifungal prophylaxis may have played a role in the
      increased incidence of invasive fungal infections in immunocompromised patients.
      Amphotericin B remains the antifungal agent with the broadest spectrum of action
      available and is thus the standard treatment for immunocompromised patients with
      proven or suspected fungal infections, especially aspergillosis. However, its
      potential for nephrotoxicity limits its usefulness. Lipid formulations of
      amphotericin B may allow therapy to be administered with reduced renal toxicity.
      Three different lipid formulations of amphotericin B are currently available.
      These compounds have different pharmacokinetics properties and usually achieve
      higher serum and/or tissue concentrations than amphotericin B. At present, there
      are no studies comparing the lipid formulations with each other and only a few
      randomized trials comparing them with conventional amphotericin B. However, a
      number of open clinical trials and compassionate-use protocols suggest that lipid
      based forms of amphotericin B can achieve good response rates with minimal
      toxicity in patients with a variety of invasive mycoses, including those who have
      proved refractory or intolerant to previous therapy with conventional
      amphotericin B. Unfortunately, the cost of these compounds remains very high and
      may represent a limiting factor to their use.

PMID- 10592742
TI  - [The new pharmacy law--for the best of the state or the patients?].

PMID- 10592743
TI  - [Who is to be vaccinated against rotaviruses?].

PMID- 10592744
TI  - [Allergic rhinitis].

PMID- 10592745
TI  - [Is organ transplantation beneficial?].

PMID- 10592746
TI  - [Measurement of troponin I levels in suspected myocardial infarction].
AB  - Serum cardiac troponin I-values were compared to conventionally obtained
      diagnosis in 319 consecutive patients suspected of having myocardial infarction,
      of which 46 patients were given this diagnosis. All patients with troponin I > 20
      micrograms/l (n = 40) also had abnormal creatine kinase and abnormal creatine
      kinase isoenzyme MB activity. All patients with troponin I values in the range
      1.0-19.9 micrograms/l (n = 50) had a diagnosis of heart disease (myocardial
      angina pectoris, myocardial infarction, arrythmia, heart insufficiency). In this
      patient group, the creatine kinase measurements showed pathological values in
      only 12 cases. Troponin I seems to be a sensitive indicator of cardiac cell
      injury, and measurements of troponin I seems to be useful in ruling out cardiac
      injury.

PMID- 10592747
TI  - [Life situation of patients with ileoanal anastomosis].
AB  - Ileal pouch-anal anastomosis is an alternative to ileostomy for patients with
      ulcerative colitis. Results of a questionnaire survey answered by 155 patients
      organised in a support group are presented. Consequences of the operation were
      mainly faecal incontinence, experienced by half of the group in the daytime, and
      frequent defaecations (5-7 per day, 1-2 per night). One half of the patients used
      medication every day to decrease the number of defaecations. 64% had changed
      their diet, while social and physical activities were reduced for 43% of the
      patients. Changes in lifestyle after the operation lead to increased expenses for
      70% of the group. Women were more often incontinent than men and experienced it
      as a serious problem, and more women than men had changed their dietary habits.
      The quality of sleep was inferior to that of the preoperative period for 47% of
      the patients. 50% felt restricted in daily life activities due to frequent
      defaecations. These patients are living with a concealed disability. In spite of
      this, their assessments of self-esteem, health and quality of life were mainly
      positive.

PMID- 10592748
TI  - [Children exposed to "earth rays" are not more frequently ill than other
      children].
AB  - From time to time newspapers bring reports on "earth rays" and their alleged
      damaging effects on health. There is, however, no objective evidence which
      suggests the existence of earth rays. In spite of this, dowsers claim that earth
      rays are a main cause of disease, also in children. In this study we wanted to
      evaluate, using a double-blind design, the alleged effects of earth rays on young
      children. A total of 44 children in four nursery schools in the Bergen area were
      recruited. Two dowsers and one interviewer visited the homes of all the children.
      The dowsers evaluated the presence of earth rays over the child's bed while the
      parents were interviewed in an independent procedure about the child's medical
      history over the past 12 months. Whether or not earth rays where found over the
      child's bed, there where no differences in the reported health of the child with
      regard to upper and lower respiratory tract infections, stomach aches, allergies
      or sleeping habits. Parents' report on restlessness and hyperactivity were also
      the same. The study failed to find any health effects, adverse or not, of earth
      rays.

PMID- 10592749
TI  - [Cerebellar hemorrhage--a rare, but serious complication in decompression
      disease].
AB  - Since 1978, five conferences on diving-related illness have failed to conclude
      that diving could lead to brain damage. We present a case history of a diver with
      decompression disease who also experienced brain damage. He performed a normal
      dive down to a depth of ten metres, when suddenly he had to go up to the surface.
      The patient was brought to the nearest hospital with a decompression chamber and
      treated according to standard procedure, yet his condition did not improve as
      expected. A CT scan showed bilateral, cerebellar bleeding and a secondary
      hydrocephalus. A CT scan one year after the accident showed a normalisation. The
      changes in the cerebellum could be related to decompression disease. Neurosurgery
      may be necessary in some cases of decompression disease.

PMID- 10592750
TI  - [Normal implantation is important in order to avoid pregnancy complications and
      diseases later in life].
AB  - Normal placentation is important to avoid complications in pregnancy and diseases
      later in life. Infertility, spontaneous abortions, intrauterine growth
      retardation and preeclampsia may be a spectrum of disorders all caused by poor
      placentation. The aetiology may in all instances be due to decreased interaction
      between the trophoblasts and the endometrium/decidua, although in different
      degrees. Implantation is to a large extent controlled by a complex interplay
      between surface molecules on trophoblasts and cells in the uterus. Different
      cytokines, enzymes, receptors and adhesion molecules play an essential role.
      Defect placentation may lead to "programming", whereby an insult suffered at a
      critical period of development results in a permanent effect on the structure or
      function of the organ or tissue. Poor growth in utero is associated with diseases
      like hypertension and diabetes later in life. Over-invasion of trophoblasts may
      result in placenta accreta/pancreata and uterine rupture. Under-invasion may lead
      to preecklampsia, growth retardation and spontaneous abortion. Therefore, the
      balance between trophoblast invasion and maternal defence must be maintained in
      order to obtain successful pregnancy outcomes. Unravelling how this is done
      remains a major challenge in reproductive biology.

PMID- 10592751
TI  - [Paroxysmal nocturnal hemoglobinuria--diagnosis with the help of flow cytometry].
AB  - Paroxysmal nocturnal haemoglobinuria is a clonal, acquired disease affecting the
      membrane of the blood cells, arising from a somatic mutation at the
      haematopoietic stem cell level. It results in clones of blood cells deficient in
      membrane bound proteins, such as the complement regulating molecules Decay
      Accelerating Factor (DAF = CD55) and Membrane Inhibitor of Reactive Lysis (MIRL =
      CD59). For many years, Ham's test has been essential for diagnostic testing of
      erythrocytes for paroxysmal nocturnal haemoglobinuria. We present a 3-colour
      flowcytometry method used for quantification of CD59-negative erythrocytes and
      CD55/CD59-negative leukocytes. The results from analysis of blood samples from
      six patients suffering from paroxysmal nocturnal haemoglobinuria and six healthy
      blood donors, using the flowcytometry method, Ham's test and a microtyping
      gelcard method are compared. Our flow cytometric method, using directly
      conjugated monoclonal antibodies to test both erythrocytes and leukocytes, is the
      most sensitive method. It is specific and delivers fast results. The method
      involves a minimum of manipulation of the fragile cells and can be recommended as
      an alternative to Ham's test and the gelcard test.

PMID- 10592752
TI  - [HIV infection, gonorrhea and syphilis from Thailand to Norway].
AB  - Thailand, a popular tourist destination for Norwegians, is experiencing an
      increasing epidemic of HIV infection. We used the Norwegian surveillance system
      for communicable diseases to assess the connections between the Norwegian and
      Thai epidemics. Before 1999, 1,869 cases of HIV-infection had been reported in
      Norway. From 1993 to 1998, 1,334 cases of gonorrhoea and 62 cases of syphilis
      were reported. We studied cases with a Thai patient or source partner and cases
      acquired in Thailand. 56 (3%) of HIV-infection cases, 64 (5%) of gonorrhoea cases
      and two (3%) of syphilis cases were connected to Thailand. All the Norwegians who
      acquired HIV in Thailand were males, with a median age of 39. Eight of them were
      diagnosed in 1998 as compared to 16 during the previous ten-year period. 21 Thai
      women and seven males were diagnosed with HIV infection in Norway, eight in 1998
      and 20 in the previous ten-year period. The Norwegian HIV epidemic is influenced
      by the Thai epidemic. Norwegian men are infected in Thailand during holidays.
      Thai women come with their Norwegian partner to Norway and later discover their
      HIV status. We recommend raising the awareness of the Thai epidemic among
      Norwegian tourists. Immigrants to Norway from highly endemic countries should be
      offered HIV counselling and testing.

PMID- 10592753
TI  - [Patients' quality of life after transplantation--what do we know?].
AB  - The number of organ transplantations has increased considerably over the last 30
      years. The aim of organ transplantation is to increase the life expectancy of the
      patients and to give them a meaningful life with better quality. Transplantation
      of kidney, heart, lung, liver and bone marrow leads to considerably higher health
      related quality of life. If the somatic adverse reactions are controlled, quality
      of life in transplant recipients is reported to be almost as good as in the
      general population.

PMID- 10592754
TI  - [Organ transplantation in children].
AB  - Over a period of close to 30 years, children in Norway with organ failure have
      been offered the option of a transplanted organ. Kidney transplantations have
      been performed since 1971, heart and liver transplantations since 1983, when
      ciclosporin was introduced. We present a review of somatic aspects on kidney
      transplantation in children, with special emphasis on 136 renal transplantations
      in 107 Norwegian children, eight of whom have died. Organ transplantation has a
      major psychosocial impact on the child and the child's family. A review of the
      psychosocial aspects of organ transplantation is given.

PMID- 10592755
TI  - [Hereditary breast cancer in Norway].
AB  - Women at risk for inherited breast cancer have been evaluated in two
      collaborating Norwegian cancer genetics centres and offered follow-up in the out
      patient clinics of all major Norwegian hospitals for the last 11 years. The
      families were identified on the basis of clinical criteria. The breast cancer
      genes BRCA1 and BRCA2 were identified in 1994-95. Even though several hundred
      different mutations in these genes have been described, a significant proportion
      of Norwegian families with breast cancer appears to have a few frequent
      mutations. This most probably is a result of the changes in the population
      structure of Norway as the population went through a genetic bottleneck during
      the Black Death, which was followed by rapid population expansion. Mutation
      analysis has now been put in use to identify Norwegian breast cancer families.
      Such analysis should be offered to all Norwegian patients with breast or ovarian
      cancers regardless of age of onset or positive family history. For the time
      being, analysis should be restricted to the detection of the demonstrated
      frequent mutations in BRCA1.

PMID- 10592756
TI  - [Hereditary colorectal cancer].
AB  - About 13% of all colorectal cancer may be dominantly inherited. This amounts to
      about 300 new cases a year in Norway. Colorectal cancer can be cured by early
      diagnosis and treatment. Coloscopy with polypectomy may prevent infiltrating
      cancer. Affected families should be offered genetic evaluation, and family
      members subjected to regular colonoscopy. The genetic bases of five colorectal
      cancer syndromes, accounting for most cases of hereditary early onset colorectal
      cancer, have now been determined. These are familial adenomatous polyposis, colon
      endometrial cancer (hereditary non-polyposis colon cancer), Cowden's syndrome,
      Peutz-Jegher's syndrome and juvenile polyposis. These account for at most 3% of
      all colorectal cancers. In this group, predictive genetic testing may be employed
      in families with known mutation. Demonstration of mutation carriers by predictive
      testing must be based on health service available to the persons at risk. With
      regard to prophylactic measures, experimental and epidemiological data suggest a
      preventive effect of aspirin and resistant starch. Empirical information on the
      effect of intervention is insufficient; multicentre studies are needed.

PMID- 10592757
TI  - [British health reforms--also in primary health care].

PMID- 10592759
TI  - [Ritual circumcision should be performed in private practice].

PMID- 10592758
TI  - [Will the shape of children's heads be standardized?].

PMID- 10592760
TI  - Brassinosteroids.

PMID- 10592761
TI  - Chemistry of the neem tree (Azadirachta indica A. Juss.).

PMID- 10592762
TI  - Cost analysis of second-line therapies for platinum-refractory ovarian cancer:
      reimbursement dilemmas for Medicare patients.
AB  - Currently used options for salvage therapy for epithelial ovarian cancer include
      intravenously administered paclitaxel or topotecan and orally administered
      altretamine or etoposide. The response rates for these agents are similar (14
      26%), whereas the type and incidence of adverse events differ. Under current
      legislation, Medicare will reimburse intravenous outpatient chemotherapy regimens
      only or oral regimens with a marketed intravenous formulation, despite that 89%
      of cancer patients prefer oral therapies. To compare the out-of-pocket costs and
      costs to the Medicare system, a cost minimization analysis of treatment with
      these agents was conducted using published phase II and phase III data. The total
      cost of treatment was $15,767 for paclitaxel, $18,635 for topotecan, $4477 for
      altretamine, and $5016 for etoposide. The out-of-pocket costs to the patient were
      $83, $37, $4477, and $6, respectively. Although a physician's first consideration
      in choosing a therapy is efficacy and toxicity, current Medicare reimbursement
      policies restrict patient options for cancer care. Because Medicare adopts
      managed care and health maintenance organizations into the management of patient
      care, cost effectiveness will likely become an important consideration in the
      treatment of cancer.

PMID- 10592763
TI  - Monitoring therapeutic response in skeletal metastases using dual-energy x-ray
      absorptiometry: a prospective feasibility study in breast cancer patients.
AB  - Response to systemic therapy in breast cancer patients with lytic skeletal
      metastases manifests as a shift from increased bone resorption to new bone
      formation. We hypothesized that dual-energy x-ray absorptiometry (DXA) could be
      used to prospectively quantitate changes in bone mineral density (BMD) in
      metastatic skeletal lesions in breast cancer patients receiving systemic therapy.
      Nine metastatic breast cancer patients with one or more assessable lytic skeletal
      metastases receiving systemic therapy were prospectively evaluated with DXA,
      skeletal radiographs, computed tomography (CT), and radionuclide bone scans at
      baseline (t = 0 months, 2 months, and 6 months). The median (range) percentage
      change in BMD in skeletal lesions among patients responding to systemic therapy
      was 10.7% (0.1-21.85), 5.0% (-1.3-23.8), and 16.7% (-2.0-50.8) at 0-2, 2-6, and 0
      6 months, respectively. Changes in BMD between 0-2, and 0-6 months were
      significant (Wilcoxin signed rank test; p = 0.013 and p = 0.017, respectively).
      The percentage change in BMD skeletal lesions between 0-2 and 2-6 months
      correlated with the changes imaged on skeletal x-rays (Spearman rank order
      correlation coefficient [Rs] = 0.511, p = 0.011) and CTs (Rs = 0.416, p = 0.046)
      but less so with bone scans (Rs = 0.293, p = 0.189). It is technically feasible
      to use DXA to prospectively monitor changes in lytic skeletal metastases in
      breast cancer patients receiving systemic therapy. The BMD of skeletal metastases
      increases in patients responding to treatment and was significantly correlated
      with the changes imaged on skeletal x-rays and CTs. Additional studies of DXA to
      evaluate response in skeletal metastasis are warranted.

PMID- 10592764
TI  - Response evaluation of bone metastases in breast cancer: value of magnetic
      resonance imaging.
AB  - The clinical utility of magnetic resonance imaging (MRI) in judging therapeutic
      response of bone metastases was evaluated in 18 patients with advanced breast
      cancer. Treatment efficacy was assessed by MRI and conventional methods such as
      plain radiograph, bone scan, pain and analgesic scale, and serum CA15-3. The
      response by MRI was evaluated mainly on T1-weighted sequences by measuring the
      volume of the bone lesion and soft tissue component. The patient was assumed to
      be a conventional responder if a complete or partial response was observed in any
      of the conventional methods described above. Response was most concordant between
      plain radiographs and MRI findings (91%, 10/11, 95% confidence interval [CI]:
      58.7-99.8). The rate of concordance was 61% (11/18, 95% CI 35.8-82.7) for all
      conventional methods and MRI. MRI revealed response in four patients in whom
      progressive disease was observed by bone scan and the marker response was not
      measurable. This pilot study suggests that posttherapy evaluation with MRI may
      provide useful clinical information in breast cancer patients with bone
      metastases and may be a valuable adjunct to conventional methods with conflicting
      results.

PMID- 10592765
TI  - Evaluation of the prognostic value of serum soluble CD 44 in patients with breast
      cancer.
AB  - The outcome of breast carcinoma is usually determined by multiple factors.
      Aberrant expression of the cell adhesion molecule CD 44 has been claimed to be
      associated with poor prognosis in various human malignancies. This study was
      designed to investigate any correlation between the soluble adhesion molecule CD
      44 and the clinicopathologic variables and to evaluate the possible prognostic
      significance of soluble CD 44. Venous blood samples were preoperatively collected
      from 100 patients with invasive breast carcinoma. The serum levels of different
      soluble CD 44 molecules (CD 44 standard form and CD 44 splice variant V6) were
      measured with an enzyme immunoassay method. The data of primary tumor status,
      age, estrogen receptor status, lymph node status, histologic grading, distant
      metastases status, TNM staging, S-phase fraction, and ploidy pattern were
      collected and evaluated simultaneously with the serum levels of soluble CD 44 st
      and CD 44 V6. Twenty healthy subjects were used as the control group. The serum
      levels of soluble CD 44 st showed no significant elevation in patient group. The
      mean value of soluble CD 44 V6 in patient group was 269.2 +/- 94.3 ng/ml and that
      of the control group was 179.5 +/- 50.7 ng/ml; the difference was significant (p
      < 0.01). In multivariate analysis, distant metastasis (p < 0.05) and TNM staging
      (p < 0.01) appeared as independent factors regarding the significant higher serum
      levels of soluble CD 44 V6. Based on our preliminary results, preoperative serum
      soluble CD 44 V6 is closely related to distant metastases and TNM staging. The
      possible role of soluble CD 44 V6 in the prognostic value of breast carcinoma
      deserves further elucidation and evaluation with long-term patient follow-up.

PMID- 10592766
TI  - A dose-escalation phase II clinical trial of infusional mitomycin C for 7 days in
      patients with advanced measurable colorectal cancer refractory or resistant to 5
      fluorouracil.
AB  - Chemotherapy for 5-fluorouracil (5-FU)-resistant colorectal cancer is largely
      ineffective with new and innovative therapeutic strategies needed to benefit
      patients developing progressive disease while receiving 5-FU or 5-FU-based
      programs. The tumor antibiotic mitomycin C is an alkylating agent with a broad
      range of clinical activity in a variety of gastrointestinal malignancies and is
      therefore a reasonable agent to test for clinical activity in the setting of 5-FU
      resistant or -refractory colorectal cancer. The principal goal of this study is
      to investigate the logistical feasibility and clinical efficacy of a 7-day
      infusion of mitomycin C, delivering an equitoxic dose to the standard bolus
      delivery in patients with progressive disease while receiving 5-FU-based
      chemotherapy. Twenty-five patients with advanced measurable colorectal cancer,
      resistant or refractory to 5-FU-based chemotherapy, were treated with a 7-day
      intravenous infusion of mitomycin C. Doses ranged between 1.5 and 3.0 mg/M2/day
      for total cumulative mitomycin C, ranging between 10.5 and 21.0 mg/M2 per
      chemotherapy cycle. Forty-four courses of infusional mitomycin C were delivered
      to 25 patients via surgically implanted venous access devices. The median age of
      all patients was 63 years (range, 27-83); there were 11 men and 14 women. Eleven
      patients had received two or more prior chemotherapy combinations, with the
      average number of prior therapies before mitomycin C being 1.6. The median number
      of cycles of mitomycin C administered was two (range, one to six). Thirty-seven
      of 44 cycles were administered at the dose range of 2.0-3.0 mg/M2/day.
      Hematologic toxicity was mild, with only three courses associated with grade III
      thrombocytopenia and one course with grade III neutropenia. No extrahematologic
      toxicities were observed. No patient had a complete response; two patients (8%)
      showed partial responses that lasted for 145 and 190 days. One patient had stable
      disease for 180 days. Twenty-two of 25 patients (88%) developed progressive
      disease during mitomycin C administration. Infusional mitomycin C for 7 days,
      cycled every 42 days, is logistically feasible and associated with minimal
      clinical toxicity. Used on this schedule and with these doses in 5-FU
      resistant/refractory colorectal cancer, however, there is no meaningful clinical
      activity for this agent, and it cannot be recommended as a salvage or second-line
      therapy in the treatment of metastatic colorectal cancer.

PMID- 10592767
TI  - Factors promoting tumor angiogenesis.

PMID- 10592768
TI  - Management of nonpalpable breast lesions: techniques in breast biopsy.

PMID- 10592769
TI  - Psychosexual implications of breast and gynecologic cancer.

PMID- 10592770
TI  - Medicare managed care.

PMID- 10592771
TI  - Genetic susceptibility to tobacco carcinogenesis.
AB  - Lung cancer risk is thus defined by the balance between metabolic activation and
      detoxification of xenobiotic compounds and by the efficiency of DNA repair. It is
      most likely that multiple susceptibility factors must be accounted for to
      represent the true dimensions of gene-environment interactions. The ability to
      identify smokers with the highest risks of developing cancer has substantial
      preventive implications. These subgroups could be targeted for the most intensive
      screening and smoking cessation interventions and could be enrolled into
      chemoprevention trials. Studying susceptibility to common cancers and widely
      prevalent exposures may provide further insights into the basic mechanisms of
      carcinogenesis. Issues that will need to be addressed in the very near future
      include risk communication to study subjects and the ethical, legal, and social
      consequences of such testing.

PMID- 10592772
TI  - Things we don't talk about.

PMID- 10592773
TI  - Additional clues to lung cancer risk.

PMID- 10592774
TI  - Website review.

PMID- 10592775
TI  - [Attention salt or attention fat?].

PMID- 10592776
TI  - [The clinical diagnosis of aortic isthmus stenosis].
AB  - BACKGROUND AND OBJECTIVE: Unfortunately, congenital coarctation of the aorta
      (CoA) is in many cases not diagnosed until adulthood., even though this defect is
      known to cause serious complications if treated too late. This retrospective
      study of patients was undertaken to ascertain whether early, exclusively
      clinical, diagnosis would have been possible. PATIENTS AND METHODS: The case
      notes of 61 patients with native CoA (n = 45) or restenosis in adulthood after
      earlier surgical repair (n = 16) were analysed with regard to the findings on
      physical examination and the patients' symptoms. RESULTS: The patients' age
      ranged from 15 to 54 years (mean 23 +/- 15.5 years). 48 of 58 patients (83%;
      incomplete data excluded three patients) had hypertension in the brachial
      arteries and 50 of 58 (86%) had a pressure difference between the arms. 51 of 53
      patients (96%) had a heart murmur, while a pressure gradient between the arms and
      legs was recorded in in 49 of 51 patients (96%). Notching of the ribs was noted
      in the chest radiogram of 47 of the 58 patients in whom it was taken. 35 patients
      had reported one, 23 more than one symptom. CONCLUSION: In all patients (with
      native CoA or restenosis after surgical repair) it would have been possible to
      make the correct diagnosis of CoA on the basis of hypertension in the arms, a
      difference in pulse amplitude and/or a pressure gradient between arms and legs,
      as well as a cardiac murmur. Normal pressures in ten patients could be explained
      by marked collateral circulation (rib notching), but even in these patients their
      symptoms plus at least two other main signs could have provided the correct
      diagnosis at an earlier time.

PMID- 10592777
TI  - [Hypertension in obesity: its epidemiology, physiopathology and treatment
      efforts].

PMID- 10592778
TI  - [The restriction of salt intake for the prevention and treatment of high blood
      pressure].

PMID- 10592779
TI  - [Cum grano salis].

PMID- 10592780
TI  - [Guidelines for the treatment of arterial hypertension in diabetes mellitus. The
      consensus recommendations of the German League for the Fight against High Blood
      Pressure, Inc., the German Diabetes Society and the Society for Nephrology].

PMID- 10592781
TI  - New technologies in medicine: biotechnology and nanotechnology.
AB  - In February 1997, researchers created Dolly, a lamb cloned from the DNA of an
      adult sheep. This was supposed to be impossible (or at least generations away),
      but suddenly it was here--a clone of a higher mammal. Whatever Dolly's ultimate
      significance, she conclusively demonstrated the growing power of biotechnology.
      Many have come to the conclusion that advances in biotechnology will
      fundamentally transform medicine during the coming decade. Society is in the
      midst of a technical revolution that will have the same relevance as the
      development of the printing press, the internal combustion engine, and the
      microprocessor. Computers have become the key tools in the accelerating progress
      that is occurring in the field of biotechnology. At the same time, genetic,
      evolutionary, and other biologic processes are providing new models for the
      development of computer hardware and software. Today represents the early stages
      of what has been called the "bionic convergence": the convergence of the biologic
      revolution with the information revolution, the joining of biology with
      electronics. Virtually everything that is important to health care practitioners
      and patients--diagnostic techniques, means of understanding disease causes,
      methods of treatment, approaches to prevention, health care facility design,
      medical education, and legal and ethical issues--will be changed by the
      revolutions currently underway in the fields of biotechnology and genetic
      medicine. The following monograph includes several forecasts about a range of
      possible opportunities that may have enormous effects on health care during the
      next century. These forecasts address the potential impacts of biotechnology on
      disease detection and diagnosis, treatment, prevention, nanotechnology, and other
      areas of medical significance. Every area of beneficiary care will be affected as
      the changes implied by these forecasts begin to develop. Beneficiary care will
      continue to see the emergence of a "forecast, prevent, and manage" paradigm. The
      emphasis will be on disease prevention, health promotion, and the creation of
      healthy communities. New diagnostic and treatment opportunities will be available
      as a consequence of breakthroughs in genetic medicine. The health care system
      will view health as a whole, as a person's overall sense of well-being--an entity
      that encompasses much more than the absence of symptoms.

PMID- 10592782
TI  - Different V beta usage in antigen-specific and alloreactive T cells specific for
      the same MHC elements.
AB  - V beta 8 has been shown to be used in the majority of antigen specific T cell
      hybridomas restricted by I-Ad and I-Ed. The usage of V beta 8 in these T cell
      responses in vivo was confirmed as V beta 8 depleted BALB/c mice responded weakly
      to these I-Ad- and I-Ed-restricted antigens. We used this deletion assay to
      further examine if V beta 8 is similarly dominantly used in alloreactive T cell
      specific for I-Ad/Ed. The depletion of V beta 8-population in allogenic mice did
      not affect the alloreactive responses toward I-Ad/Ed. Although specific for the
      same MHC, there is no apparent overlap on the use of TCR V beta 8 between
      alloreactive T cells and antigen-specific T cells.

PMID- 10592783
TI  - Seroepidemiology of Helicobacter pylori among adolescents in Taiwan.
AB  - Helicobacter pylori has been documented to be associated with chronic type B
      gastritis, peptic ulcer and gastric cancer. In order to examine the
      seroprevalence and risk factors for Helicobacter pylori infection in Taiwan, a
      total of 871 adolescents were selected randomly from junior high school children
      in 20 study precincts and townships. Serum samples collected were tested for IgG
      antibodies against Helicobacter pylori by enzyme-linked immunosorbent assay using
      commercial kits. The overall seropositive rate was 21.1% showing no gender
      difference. There was a striking geographical variation in seroprevalence of
      Helicobacter pylori infection ranging from 4.6% to 37.1% in 20 precincts and
      townships. The seroprevalence was highest in the north (25.4%), medium in central
      Taiwan (21.9%), and lowest in the south (18.7%). The higher the age-adjusted
      mortality from gastric cancer in a given study area, the higher the
      seroprevalence of Helicobacter pylori in the area. Metropolitan and aboriginal
      areas had higher seroprevalences than urban and rural areas, but the difference
      was not statistically significant. The seroprevalence was higher for those who
      had no sibling (29.4%) or had a sibship size of > or = 6 (31.1%) than for those
      with a sibship size of 1-5 (20.0%), but the difference was not statistically
      significant either.

PMID- 10592784
TI  - Effect of vapor phase corrosion inhibitor on microbial corrosion of aluminum
      alloys.
AB  - Vapor phase corrosion inhibitors were used to investigate the antimicrobial
      activities and anticorrosion of aluminum alloy. Aspergillus flavus, A. niger, A.
      versicolor, Chaetomium globosum and Penicillium funiculosum had moderate to
      abundant growth on the aluminum alloy AA 1100 at Aw 0.901, while there was less
      growth at Aw 0.842. High humidity stimulated microbial growth and induced
      microbial corrosion. Dicyclohexylammonium carbonate had a high inhibitory effect
      on the growth of test fungi and the microbial corrosion of aluminum alloy,
      dicyclohexylammonium caprate and dicyclohexylammonium stearate were the next.
      Aluminum alloy coating with vapor phase corrosion inhibitor could prevent
      microbial growth and retard microbial corrosion.

PMID- 10592785
TI  - [Sequence analyses of Epstein-Barr virus (EBV) Bam HI F DNA fragment in EBV
      associated diseases].
AB  - In order to compare nucleotide differences of Epstein-Barr virus (EBV) Bam HI F
      DNA fragment from various EBV associated diseases, polymerase chain reactions
      (PCR) were used to amplify a subfragment (nucleotides 55,381-56,020) of the F
      fragment from different tissue DNAs, including 20 NPCs, 2 B-cell lymphomas, 2 T
      cell lymphomas, 3 infectious mononucleosis (IM), and 3 normal controls. DNA
      sequences were determined by PCR direct sequencing or sequencing after DNA
      cloning. The PCR products were cloned into pGEM-3Z vector, then the resulting
      recombinant plasmids were used to transform DH5 alpha competent cells. Plasmid
      DNAs from the correct transformants were prepared for DNA sequencing. The results
      showed that the proportion of the f variant in NPCs, B-cell lymphomas, T-cell
      lymphomas, IMs, and normals were 40%, 0%, 0%, 33%, and 33%, respectively. Because
      the f variant was not specifically more prevalent in NPC tissues compared to the
      non-tumor tissues, we speculate that there is no strong association between the f
      variant and NPC. These results were different from other reports. Coinfection of
      the F strain and the f variant was found both in some NPC patients and normal
      individuals. Analyses of Bam HI F subfragments of 35 EBV isolates from the 30
      tissue DNAs revealed that there were changes at four corresponding positions of
      the B95-8 strain. They were nucleotide T at 55,473 replaced by G, an insertion of
      TGT after nucleotide 55,543, nucleotide A at 55,564 replaced by G, and nucleotide
      T at 55,958 replaced by C. These 4 nucleotide changes may confer a character of
      Taiwan strains. The nucleotides of the F strain at coordinates 55,519, 55,596,
      55,680, 55,703, and 55,895 were T, T, A, A, and C, and those for the f variant
      were C, C, C, C, and T. These two patterns were not correlated with types A and B
      of EBV.

PMID- 10592786
TI  - [Laboratory evaluation of automated enzyme linked fluorescent assay for detecting
      serum specific IgG antibodies against rubella virus].
AB  - The VIDAS rubella IgG(RBG) is a new, automated, enzyme-linkad fluorescent
      assay(ELFA) for detecting IgG antibodies to rubella virus in serum. The purpose
      of this study was to evaluate the usefulness of the qualitative and quantitative
      VIDAS RBG as laboratory tests in the rapid detecting anti-rubella IgG antibodies.
      Simultaneous parallel testing was performed by using the qualitative and
      quantitative RBG along with RUBAZYME(ABBOTT LABORATORIES) and the standard
      hemagglutination-inhibition(HI) test(R-HI kit, SEIKEN) on 200 blood samples
      submitted for anti-rubella IgG antibodies testing from patients at the VGH
      Kaohsiung(Mar.-Sep., 1993). The qualitative and quantitative VIDAS RBG and
      RUBAZYME assay were compared to the standard R-HI test. Significant differences
      among the sensitivities of these three methods were found (100% sensitivity for
      the qualitative VIDAS RBG, 88.89% for the quantitative VIDAS RBG and 97.67% for
      the RUBAZYME). However, the specificities of these three methods were all the
      same, 100%. With these results we can conclude that the qualitative VIDAS RBG
      will provide a very good, precise and reliable method to determine serum specific
      IgG antibodies against rubella virus. Furthermore, the VIDAS RBG is fully
      automated and time-saving procedures (for every batch of test, it takes 25
      minutes with VIDAS RBG, 2.5 hours with RUBAZYME and 4.5 hours with R-HI) in
      clinical laboratories.

PMID- 10592787
TI  - [Study on the stability of Japanese encephalitis vaccine--development of freeze
      dry dosage form].
AB  - In order to prolong shelf-life and improve the quality of the vaccine product,
      not only an effective stabilizer but also a more proper dosage form has been
      sought. The stability of a Japanese encephalitis (JE) vaccine produced from mouse
      brain along with a variety of stabilizers and lyophilization protocols was
      evaluated. Without any stabilizers added, almost 90% of the antigenicity would
      vanish after freeze-drying process. Comparative studies of various compounds,
      including carbohydrates, amino acids, peptides and medium 199, on both
      antigenicity preservation and thermostability of the vaccine were carried out.
      The results indicated that the best reconstituted vaccines were prepared with two
      stabilizer formulations, sucrose and sucrose/gelatin. They were further examined
      by accelerated stability test at room and higher temperatures. The sucrose-added
      lyophilized vaccine can retain its original antigenicity for more than 60 days
      both at 37 degrees C and 45 degrees C. We conclude the thermostability efficiency
      of each of the stabilizers tested is as that follows: sucrose > sucrose/gelatin >
      gelatin/medium > gelatin.

PMID- 10592788
TI  - Use of bacterially expressed GST/EBNA-1 fusion proteins for detection of
      antibodies in sera from patients with nasopharyngeal carcinoma and healthy
      donors.
AB  - Epstein-Barr virus nuclear antigen-1 (EBNA-1) is a protein expressed consistently
      in EBV infected cells and in EBV related malignant tissues. Antibodies against
      EBNA-1 may therefore possibly be used as a marker for disease screening. Western
      blot analysis of serum antibodies was performed using GST (glutathione-S
      transferase) fusion proteins containing different regions of EBNA-1 as antigens.
      Serum samples were collected from 38 patients with nasopharyngeal carcinoma (NPC)
      and 38 healthy individuals in Taiwan. All samples were found IgG positive for
      EBNA-1 when a truncated protein GST/E1 (70-102, 325-641) was used as the antigen.
      Thirty-three out of 38 NPC sera (86.8%) were positive for IgA antibody against
      EBNA-1. The positive rate was higher in comparison with IgA antibody against VCA
      (65.7%) or antibody against DNase (60.5%). Only 2.6% of sera from normal
      individuals were positive for an IgA response against EBNA-1. The major antigenic
      determinants for NPC serum IgA response were between amino acid(aa) 390 to aa 459
      when different portions of EBNA-1 were used as antigens. The results suggest that
      IgA response against EBNA-1 could be used in combination with other EBV serology
      markers for NPC screening.

PMID- 10592789
TI  - Screening of drugs inhibiting Epstein-Barr virus replication.
AB  - At the present moment, drugs which can inhibit Epstein-Barr virus replication are
      very rare, and their effects are not satisfactory. Therefore, it is necessary to
      develop new drugs to obtain a better treatment. Forty-one synthetic chemical
      compounds including purine analogs and nucleoside analogs were collected. These
      compounds were serially diluted and added to Akata cells, an EBV-containing cell
      line derived from Burkitt's lymphoma. The cells were immediately added with anti
      human IgG to activate EBV replication within the cells. After one day of
      incubation, reduction of EBV protein synthesis was determined by indirect
      immunofluorescence assay and Western blotting. Inhibition of viral DNA
      replication was assayed by slot blot hybridization. The results showed that
      nucleoside analogs 2-methyl-5, 6-dichloro-1-(beta-D-ribofuranosyl) benzimidazole
      and 2-ethyl-5, 6-dichloro-1-(beta-D-ribofuranosyl) benzimidazole appeared to be
      the best drugs analyzed.

PMID- 10592790
TI  - Comparison of three typing methods for Pseudomonas aeruginosa.
AB  - Fifty-seven independent isolates of Pseudomonas aeruginosa from blood specimens
      were typed with 3 different methods: ribotyping, random amplified polymorphic DNA
      (RAPD) typing, and pyocin typing. Ribotyping was performed by probing the rRNA
      genes of genomic DNA that was digested separately with 4 different restriction
      enzymes. Digestion of DNA from 57 P. aeruginosa isolates with BamHI, ClaI, EcoRI,
      and PstI produced 4, 4, 6, and 7 patterns, respectively. As a result, ribotyping
      classified the 57 isolates into 22 types. Six new ribotypes that had not been
      described previously were found. One BamHI, 1 ClaI, 2 EcoRI, and 2 PstI patterns
      were novel. RAPD typing was performed with two different polymerase chain
      reaction (PCR) primers (RAPD1 and RAPD2). Both primers classified the 57 isolates
      into 15 RAPD types and produced identical patterns. The pyocin typing method
      classified the 57 isolates into 10 types. According to the results obtained in
      this study, the ribotyping has a discriminatory index of 0.865, RAPD, 0.785, and
      pyocin typing, 0.676, respectively. The ribotyping method was the most effective
      among the 3 methods compared for typing P. aeruginosa isolates.

PMID- 10592791
TI  - [Comparison of immunoassay kits for detection of staphylococcal enterotoxins
      produced by Staphylococcus aureus].
AB  - Four commercial kits, SET-RPLA, RIDASCREEN, SET-EIA, and TECRA, were compared for
      the efficiency of detecting staphylococcal enterotoxins (SE). There was no non
      specific reaction for detection of SE produced by 21 Staphylococcus aureus
      strains from 5 outbreaks of food poisoning using SET-RPLA, SET-EIA and TECRA
      kits. The background of the results of RIDASCREEN kit was high and non-specific
      reactions were present in some strains. IN CONCLUSION: (i) TECRA kit is suggested
      to be used for screening SE producing strains; (ii) SET-RPLA and RIDASCREEN kits
      are suitable for epidemiological investigation of SE types, but the lack of
      ability for detecting SEE, long time required for testing with SET-RPLA kit and
      high background when using RIDASCREEN kit must be overcome; and (iii) because of
      the complicated test procedures and the lack of ability for detecting SEE, the
      practicality of SET-EIA kit in screening and epidemiological research purposes is
      low.

PMID- 10592792
TI  - Comparison of antigen binding capabilities of various membrane filters and filter
      papers in dot immunoassay.
AB  - Antigen binding activities of 25 kinds of filter papers, including nitrocellulose
      (NC), nylon or polyvinylidine difluoride (PVDF), in the binding of 5 viruses, 3
      bacteria, 2 mycoplasmas and 1 chicken serum protein antigens in dot immunoassay
      were compared. Immobilon affinity membrane type D (IAM-D) was found best in
      binding viral antigens, followed by Ultrabind SV-450 (SV-450). SV-450 was found
      best in binding bacterial antigen, followed by Ultrabind US-450 (US-450), IAM-D
      and NC 0.45 micron. IAM-D was the best in binding mycoplasma antigen, followed by
      Ultrabind HP, US-450, NC 0.2 micron. Overall, IAM-D had the best capability in
      the binding of the antigens.

PMID- 10592793
TI  - Identification of serotypes of Rickettsia tsutsugamushi by nested polymerase
      chain reaction.
AB  - Nested polymerase chain reaction (PCR) was applied to identify the serotypes of
      Rickettsia tsutsugamushi isolated from patients. The primers used for PCR were
      based on the nucleotide sequences encoding a 56 kDa antigen of rickettsiae.
      Comparing to the conventional immunofluorescence assay (IFA), which displays a
      considerable degree of cross-reactivity among different species, the result
      obtained suggests that the polymerase chain reaction method is much more reliable
      than IFA.

PMID- 10592794
TI  - Dietary frying oil influences immune regulation in autoimmune-prone NZBxNZW F1
      mice.
AB  - To further elucidate the role of dietary frying oil in the pathogenesis of
      autoimmune diseases, two groups of NZB/W F1 mice were fed with diets containing
      20% fresh oil and frying oil, respectively. All these mice were followed up serum
      anit-DNA antibody levels, proteinuria and life span regularly. Our data
      suggested: 1) higher IgG anti-ss, dDNA antibody levels were noted in mice fed
      with fresh oil compared to those of the frying oil group; 2) lipopolysaccharide
      (LPS)-stimulated spleen cells of mice fed with frying oil produced higher IL-10
      compared to that of fresh oil group; 3) IL-6, TNF-alpha and PGE2 produced by
      macrophages of dietary frying oil group were higher, although not statistically
      significant, than those of fresh oil group. Different degree of deterioration of
      dietary oil has been found to affect immune response in autoimmune mice.

PMID- 10592795
TI  - Helicobacter pylori in tumor tissues of patients with advanced gastric
      adenocarcinoma: high prevalence but failure to detect integration.
AB  - Helicobacter pylori has been known to be associated with gastric adenocarcinoma
      by case control studies. However, significant portion of patients with gastric
      carcinoma are negative for H. pylori by serological test. To further detect the
      presence of H. pylori infection in serum and tissue of patients with gastric
      adenocarcinoma, paired tissues and serum samples from 32 patients with gastric
      adenocarcinoma were tested. Antibodies to H. pylori were tested by an enzyme
      linked immunosorbent assay (ELISA) and a Western blot analysis. H. pylori in
      tumor and non-tumor parts of gastric tissues were examined by histology and
      polymerase chain reaction (PCR). For serum antibody, eighteen (56%) of these
      patients were positive by ELISA while 24 (75%) were positive by Western blot. For
      tissue H. pylori genome, 14 were positive by histology while 28 (87%) were
      positive by PCR. Southern blot analysis of both tumor and non-tumor tissues
      revealed no evidence of integration of H. pylori DNA in the human genomes. These
      results suggest that H. pylori infection can be detected in most patients with
      gastric adenocarcinoma, and PCR and Western blot can further identify
      seronegative patients.

PMID- 10592796
TI  - Large-scale Vero cell culture on microcarriers in a twenty-liter stirred tank
      fermentor.
AB  - In biotechnology, animal cell culture is an important process for the production
      of many biologicals such as vaccines, monoclonal antibodies, or other recombinant
      products. Among many established continuous cell lines, Vero cells can be
      maintained in many passages in cultures without inducing tumorigenicity and have
      been recommended by World Health Organization for the production of human
      biologicals. Owing to its anchorage-dependent growth characteristics, Vero cells
      can be grown on microcarrier in a suspension vessel where microcarrier provides
      the culture system with a high culture surface to volume ratio. In this paper we
      compared the growth kinetics of Vero cells on Cytodex 1 microcarrier in a 20
      liter fermentor vs. 100 ml spinner flask culture. The kinetics of Vero cell
      growth in the 20-liter fermentor was similar to the results obtained from small
      spinner flask culture, as determined by cell specific growth rate or
      corresponding doubling time. The approximately 150-fold increase in culture
      vessel volume did not compromise the growth kinetics of Vero cells, suggesting
      the system is applicable for large stirred-tank fermentor cultures.

PMID- 10592797
TI  - [Serotype distribution and antimicrobial susceptibility of group A streptococci
      (Streptococcus pyogenes) isolated in Taiwan].
AB  - T-protein serotypes and antimicrobial susceptibility of a total of 139 group A
      streptococci (GAS) strains isolated in Taiwan area in 1993 and during the
      outbreak of scarlet fever in 1994 were analyzed. All strains were T-typable, and
      T12 (42.46%) and T4 (38.85%) were the dominant T types. According to the results
      of analysis of antimicrobial susceptibility, all GAS strains were divided into 9
      resistotypes, A (all susceptible), B (resistant to tetracycline), C (resistant to
      erythromycin and tetracycline), D (resistant to chloramphenicol and
      tetracycline), E (resistant to chloramphenicol and clindamycin), F (resistant to
      chloramphenicol, clindamycin and tetracycline), G (resistant to clindamycin,
      erythromycin and tetracycline), H (resistant to chloramphenicol, clindamycin,
      erythromycin and tetracycline), and I (resistant to chloramphenicol, clindamycin,
      erythromycin, tetracycline and vancomycin). Type B (37.42%) was the dominant
      type. Type A (25.91%), and type H (26.63%) also appered with high incidence. Most
      of strains isolated from Mid-Taiwan were type H. Only one strain, that was
      isolated in I-lan, was resistant to vancomycin, in addition to resistant to
      chloramphenicol, clindamycin, erythromycin, and tetracycline. All strains were
      susceptible to penicillin G, ampicillin, and ceftriaxone. Some strains were
      resistant to chloramphenicol (32.38%), clindamycin (30.22%), erythromycin
      (31.66%), tetracycline (73.39%), and vancomycin (0.70%). During the outbreak of
      scarlet fever in 1994, the dominant T types of strains isolated in North-Taiwan
      and Mid-Taiwan were T4 and T12, respectively, and the major resistotypes of those
      strains were B and H types, respectively. These clues suggested that the
      outbreaks occurring in North-Taiwan and Mid-Taiwan may have no epidemiological
      linkage between each other.

PMID- 10592798
TI  - Human foamy virus genome in the thymus of myasthenia gravis patients.
AB  - The etiological relationship of human foamy virus (HFV), which is a
      spumaretrovirus, with human diseases is not clear. We analyzed thymus specimens
      from four patients with myasthenia gravis for the presence of HFV proviral genome
      by polymerase chain reaction (PCR). The results showed the presence of both 257
      base pair (bp) and 299 bp DNA fragments representing a part of gag and bel-2
      sequences, respectively, in all four thymuses. Their specificity was confirmed by
      Southern blot hybridization with the corresponding probes. This was also
      confirmed by sequence analysis, although there were some point mutations. We
      confirmed the presence of gag related sequence, a 1353 bp Xba I-cleaved DNA
      fragment in all four thymus samples, a 693 bp fragment in two (#3 and #4) and a
      4300 bp Hind III-cleaved DNA fragment in another two (#1 and #4), indicating
      possible chromosomal integration of the HFV partial genome. To our knowledge,
      this is the first report on the presence of HFV genome in thymus tissues of
      myasthenia gravis patients. Our efforts to isolate the infectious HFV by
      cultivation of the tissues were not successful. Low titers of neutralizing
      antibody were detected in all four patients' serum samples. The possible role of
      the HFV in this autoimmune disease needs further investigation.

PMID- 10592799
TI  - Bile medium for rapid presumptive identification of group B streptococci.
AB  - A bile medium was developed for rapid presumptive identification of beta
      hemolytic group B streptococci. Of 131 clinical isolates of group B streptococci,
      125 (95.4%) yielded positive reaction within 6 h incubation. No false positive
      reaction was found in 134 clinical isolates of groups A, C, F, and G beta
      hemolytic streptococci. The sensitivities of the bile medium, rapid hippurate
      hydrolysis and modified LAL-1 medium were 95.4, 98.5 and 93.1%, respectively. All
      three media showed 100% specificity. Therefore, the bile medium provides as an
      additional medium for rapid presumptive identification of group B streptococci.

PMID- 10592800
TI  - Enhancement of v-src transforming activity by simian virus 40 small t antigen.
AB  - The simian virus 40 (SV40) small t (t) antigen is known to be able to induce cell
      proliferation and to enhance the transforming activity of SV40 large T antigen.
      Here we report that t could also enhance the transforming activity of v-src
      oncogene. When t was transfected into the v-src-transformed NIH3T3 cells, the t
      expressing stable clones grew faster and grew to higher density than did the
      parental or vector-transfected cells. Furthermore, these t-expressing cells also
      showed better plating efficiency and grew more efficiently in soft agar than did
      the parental or vector-transfected cells. More importantly, the t-expressing
      cells displayed high tendency to aggregate and detached easily from the dishes,
      while the parental or vector-transfected cells never exhibited such phenotype.
      This last observation suggests that t may affect the expression of adhesion
      molecules in the v-src-transformed NIH3T3 cells. Taken together, we concluded
      that t could enhance the transforming activity of v-src and alter the transformed
      morphology of v-src-transformed NIH3T3 cells.

PMID- 10592801
TI  - Microbial corrosion of aluminum alloy.
AB  - Several microbes were isolated from the contaminated fuel-oil in Taiwan and the
      microbial corrosion of aluminum alloy A356-T6 was tested by MIL-STD-810E test
      method. Penicillium sp. AM-F5 and Cladosporium resinac ATCC 22712 had significant
      adsorption and pitting on the surface of aluminum alloy, Pseudomonas acruginosa
      AM-B5 had weak adsorption and some precipitation in the bottom, and Candida sp.
      AM-Y1 had the less adsorption and few cavities formation on the surface. pH of
      the aqueous phase decreased 0.3 to 0.7 unit for 4 months of incubation. The
      corrosion of aluminum alloy was very significant in the cultures of Penicillium
      sp. AM-F2, Penicillium sp. AM-F5 and C. resinac ATCC 22712. The major metabolites
      in the aqueous phase with the inoculation of C. resinac were citric acid and
      oxalic acid, while succinic acid and fumaric acid were the minors.

PMID- 10592802
TI  - Survey on the distribution of Vibrionaceae at the seaport areas in Taiwan, 1991
      1994.
AB  - A monthly survey on the distribution of human-pathogenic Vibrionaceae of the
      seawater from five principal harbors in Taiwan was conducted by National
      Quarantine Service from July, 1991 to February, 1994. Of the total 1,167
      Vibrionaceae isolates, strains of Vibrio alginolyticus (449 strains) were the
      most frequently isolated, followed by Vibrio parahaemolyticus (262) , Aeromonas
      hydrophila (153), Vibrio cholerae non-O1 (86), and Vibrio vulnificus (67). None
      of Vibrio cholerae O1 was isolated. The pH, salinity, and water temperature in
      this study ranged from 5.8 to 8.6, 0.1 to 4.2% , and 15 to 34 degrees C,
      respectively. It is concluded that the family Vibrionaceae exists autochthonously
      around the coastal waters in Taiwan.

PMID- 10592803
TI  - [K-serotype analyses of Vibrio parahaemolyticus isolated in northern Taiwan, 1983
      through 1993].
AB  - From 1983 through 1993, 786 strains of Vibrio parahaemolyticus were collected
      from food-borne disease outbreaks and sporadic cases of diarrheal illness in
      northern Taiwan, involving 42 K-serotypes. Five top leading serotypes were K8
      (36.8%), K15 (10.8%), K12 (8.7%), K56 (7.9%) and K63 (4.7%). However, a variation
      of K-serotypes was found during this study period. From 112 food-borne outbreaks
      associated with this microorganism, only 54 (48.2%) outbreaks were caused by a
      single serotype, while 58 (51.8%) were caused by multiple K-serotypes. Numbers of
      outbreaks caused by two, three and more than three K-serotypes were 29 (26%), 16
      (14.2%), and 13 (11.6%), respectively. In a special outbreak, eight K-serotypes
      was found. Outbreaks caused by party caterers were most frequently associated
      with multiple K-serotypes.

PMID- 10592804
TI  - Differential display and cloning of messenger RNA from human normal nasal
      epithelial cells versus nasopharyngeal carcinoma cell lines.
AB  - Carcinogenesis is a multi-process event that has been characterized both by
      activation of cellular oncogenes and by loss of function of tumor suppressor
      genes. However, no systemic study has been performed to understand the
      involvement of oncogenes and tumor suppressor genes in the oncogenesis of
      nasopharyngeal carcinoma (NPC). Differential display was performed to identify
      genes specifically expressed in normal nasal epithelial cells or NPC cell line
      HONE-1. Using Ltk3 and T11CA as primers, a 379-bp cDNA fragment (CN3) obtained
      from normal nasal epithelial cells was able to show specificity by northern blot
      analysis. A 3.5-kb mRNA was detected in normal nasal epithelial cells but not in
      NPC cell line HONE-1 by using 32P-end-labeled CN3 fragment as a probe. Sequence
      analysis of the 379 bp cDNA fragment indicated unique sequences from nts 1 to
      230. Nts 231 to 379 are Alu-like sequences. Northern blot analysis using 32p
      labeled PCR product amplified from nts 36 to 222 of CN3 cDNA fragment was also
      able to detect the 3.5-kb mRNA in normal nasal epithelial cells but not in HONE-1
      and two other NPC cell lines NPC-TWO1, NPC-TWO4.

PMID- 10592805
TI  - [The development of shrimp blood agar for testing the hemolysis of shrimp's
      haemocyte by bacteria].
AB  - A new plating medium, shrimp blood agar, was developed by using the haemolymph of
      shrimp plus 200 ppm rose bengal as the substrate. The colorless shrimp haemocytes
      were dyed by rose bengal to red. On the present agar, the hemolytic bacteria
      strain may show a clear zone surrounding the bacterial colony. The result on
      hemolysis of 45 bacteria representing 12 genera isolated from aquaculture
      environments against shrimp blood agar and sheep blood agar was also evaluated.
      There are 11 strains with different results. The study showed that, with the aim
      of screening the hemolytic bacteria to shrimp, shrimp blood agar might reveal a
      relatively quick and accurate results than that of sheep blood agar.

PMID- 10592806
TI  - Evidence for arylamine N-acetyltransferase in Hymenolepis nana.
AB  - N-acetyltransferase activities with p-aminobenzoic acid and 2-aminofluorene were
      determined in Hymenolepis nana, a cestode found in the intestine of the Sprague
      Dawley rats. The N-acetyltransferase activity was determined using an acetyl CoA
      recycling assay and high pressure liquid chromatography. The N-acetyltransferase
      activities from a number of Hymenolepis nana whole tissue homogenizations were
      found to be 2.83 +/- 0.31 nmole/min/mg for 2-aminofluorene and 2.07 +/- 0.24
      nmole/min/mg for p-aminobenzoic acid. The apparent Km and Vmax were 1.06 +/- 0.38
      mM and 8.92 +/- 1.46 nmol/min/mg for 2-aminofluorene, and 2.16 +/- 0.19 mM and
      12.68 +/- 2.26 nmol/min/mg for p-aminobenzoic acid. The optimal pH value for the
      enzyme activity was pH 8.0 for both substrates tested. The optimal temperature
      for enzyme activity was 37 degrees C for both substrates. The N-acetyltransferase
      activity was inhibited by iodacetamide. At 0.25 mM iodacetamide the activity was
      reduced 50% and 1.0 mM iodacetamide inhibited activity more than 90%. Among a
      series of divalent cations and salts, Fe2+, Ca2+ and Zn2+ were demonstrated to be
      the most potent inhibi-tors. Among the protease inhibitors, only
      ethylenediaminetetraacetic acid significantly protected N-acetyltransferase.
      Iodoacetate, in contrast to other agents, markedly inhibited N-acetyltransferase
      activity. This is the first demonstration of acetyl CoA:arylamine N
      acetyltransferase activity in a cestode and extends the number of phyla in which
      this activity has been found.

PMID- 10592807
TI  - [Identification of Candida albicans by specific primers of polymerase chain
      reaction and DNA probes].
AB  - Candida albicans is a pathogenic yeast. Two sets of universal primers were used
      for specific identification of Candida albicans with PCR-amplified ribosomal DNA
      internal transcribed spacers (ITS). Among the species of Candida, the amplified
      ITSI and ITSII of DNA fragments were similar in size. The PCR product was
      purified and labeled with digoxigenin and used as DNA probe in the detection with
      target DNA of Candida albicans by hybridization. Two sets of specific primers
      (CA1 and CA2 to amplify ITSI, CA3 and CA4 to amplify ITSII) were designed by
      alignment of ribosomal ITS sequence of pathogenic Candida albicans with other
      species to detect C. albicans by PCR. The sensitivity of PCR using the specific
      primers to detect pure culture of C. albicans was 0.1 ng (about 10(3)-10(4)
      cells). If the yeast cells were mixed with two other strains, there was a 10-fold
      decrease in sensitivity (1 ng or 10(4)-10(5) cells) under the same PCR
      conditions.

PMID- 10592808
TI  - [Characterization of haemolysis of the Vibrio parahaemolyticus no.93].
AB  - Vibrio parahaemolyticus is a causative bacterium of food poisoning, and the
      haemolysin produced by this organism has been considered as one of the important
      virulence factors. In order to understand the pathogenic mechanism of this
      bacterium, the characteristics of haemolysin from Vibrio parahaemolyticus
      isolated from Taiwan were studied. One of the clinical strains, V.
      parahaemolyticus No.93, presents a weak hemolytic zone on 7% NaCl-Wagatsuma
      medium. The DNA hybridization results show that V. parahemolyticus has neither
      tdh nor trh gene. V. parahaemolyticus No.93 shows obviously hemolytic zone on 3%
      NaCl Wagatsuma medium (human blood). The crude extracellular protein of V.
      parahaemolyticus No. 93 was evaluated for its heat tolerance and enzyme
      activities by media assay. The results show that this crude extracellular protein
      is thermolabile. The crude extracellular protein of V. parahaemolyticus No.93 was
      analyzed on 10% SDS-PAGE and an apparent band of 64 kDa protein was observed.
      Furthermore, the crude extracellular protein was analyzed by running gelatin-SDS
      PAGE and hemoglobin-SDS-PAGE, and three clear zones on 62 kDa, 52 kDa and 41 kDa
      were observed on both SDS-PAGEs. Thus we propose that the crude extracellular
      protein of the V. parahaemolyticus No.93 can degrade gelatin as well as
      hemoglobin. Whether these protease being the virulence factors of Vibrio
      parahaemolyticus No.93 needs to be further studied.

PMID- 10592809
TI  - [Diagnosis of Yersinia pestis].
AB  - There is no plaque case report in Taiwan since 1952. However, it is necessary to
      set up a laboratory system to investigate the distribution of Yersinia pestis in
      the natural environment to implement the public policy for preventing plague.
      Besides the traditional methods; e.g. culture, microscopic observation,
      biochemical characteristics, anti-F1 antigen detection by slide agglutination,
      immunofluorescence, and phage lytic assay, PCR was used as rapid screening test
      in our study. These laboratory methods were used to examine whether the flea
      samples harvested in King-Men island carry Y. pestis. The results showed that the
      flea index per mouse was high but no Y. pestis was detected in the fleas.

PMID- 10592810
TI  - Screening for acyclovir-resistant herpes simplex virus isolates from clinical
      samples.
AB  - The ID90 or ID50 values of acyclovir for the herpes simplex virus strains
      isolated in VGH-Taipei were determined by plaque reduction method. Twenty HSV
      isolates of 1980's (1980-1985) and thirty of 1990's (1990-1995) were subjected to
      plaque reduction assay for susceptibility test to acyclovir. There were fifteen
      HSV isolates of 1990's whose ID90 were higher than those of 1980's, indicating a
      trend of more acyclovir resistant isolates in 1990's.

PMID- 10592811
TI  - [Pathogenic strains of Escherichia coli in Taiwan].
AB  - From July 1994 through June 1996, 28 strains of Escherichia coli were isolated
      from 1,260 patients with acute diarrhea. These strains were further
      differentiated with serotypes and virulence factors. Enterotoxigenic E. coli
      (ETEC), enteropathogenic E. coli (EPEC), enterohemorrhagic E. coli (EHEC), and
      enteroinvasive E. coli (EIEC) were accounted for 53.6 (15 of 28 strains), 28.6 (8
      of 28), 10.7 (3 of 28) and 7.1% (2 of 28), respectively. Therefore, ETEC and EPEC
      are playing an important role in food-borne illness in Taiwan. Escherichia coli
      O157:H7, a new emerging pathogen of food-borne disease, has not been isolated in
      this study.

PMID- 10592812
TI  - Prevalence and heterogeneity of Helicobacter pylori in gastric biopsies of
      patients with gastroduodenal diseases.
AB  - Helicobacter pylori is a risk factor for development of peptic ulcers and
      adenocarcinoma of distal stomach. There are several highly specialized virulence
      factors, such as the production of sialic acid-specific hemagglutinins,
      cytotoxins and enzymes. This study was designed to study the in vivo prevalence
      of H. pylori in patients with gastroduodenal diseases, the in vivo correlation
      between H. pylori infection and blood group O, and the heterogeneity of H. pylori
      isolates in central Taiwan. We enrolled 776 symptomatic patients residing in the
      central Taiwan area. The age-specific in vivo prevalence of H. pylori in patients
      with gastroduodenal diseases increased from 11.1% in those between the ages of 1
      to 20, 73.1% in those between the ages of 21 and 30, and to 79.8% in those
      between the ages of 51 and 60. In conclusion, H. pylori was present in 70% of
      biopsied specimens of symptomatic patients with gastroduodenal diseases and had
      the highest incidence (86%) in patients with peptic ulcers. The prevalence of H.
      pylori cag A expression positive strains in central Taiwan was 92.5%. This study
      has also demonstrated the high correlation between H. pylori and the blood group
      O-positive patients with gastroduodenal diseases. The prevalence of H. pylori
      infection in blood O-positive patients in central Taiwan was 86.4%.

PMID- 10592813
TI  - Production and purification of Bordetella pertussis toxin.
AB  - Pertussis toxin (PT) is the major protective antigen of acellular pertussis
      vaccine (aP). We have established an optimal culture condition for the growth of
      B. pertussis and the production of PT in a laboratory scale fermentor. It was
      found that when the dissolved oxygen in medium was supplied with pure oxygen
      instead of air, the yield of PT was dramatically increased (i.e. from 2-3 mg/l
      using air to 8-10 mg/l using pure oxygen). PT was purified by affinity
      chromatography using hydroxyapatite and fetuin-sepharose columns. SDS-PAGE
      analysis and CHO cell clustering test showed that the purified PT was comparable
      to the reference PT in purity and biological activity. The purified PT could be
      detoxified by formaldehyde (d-PT). The results of CHO cell clustering
      neutralization assay and ELISA showed that the antibody induced by d-PT in mice
      was comparable to that induced by PT contained in a commercial DTaP. These
      results indicated that the immunogenicity of our d-PT was retained after the
      purification and detoxification procedures.

PMID- 10592814
TI  - Clinical experience of HIV/AIDS in a municipal hospital in Taiwan.
AB  - To describe the spectrum of epidemiological and major clinical manifestations of
      patients infected by human immunodeficiency virus type 1 (HIV-1) in a municipal
      hospital, a retrospective review was done of 53 HIV-1-infected patients who had
      been admitted to Taipei Municipal Jen-Ai Hospital between January 1990, and July
      1996. The majority (94.3%) of the patients in the cohort were male. Peak
      incidence was found in the fourth decade (28.3%). Forty-four (83%) patients
      presented in the first hospital stay with acquired immunodeficiency syndrome
      (AIDS). The mean duration between establishment of diagnosis of HIV-1 infection
      and that of AIDS was 11.2 (0-84) months. Heterosexual transmission accounted for
      54.7% of the infections in the study group, and bi-/homosexual men made up
      another 32%. Psychosis of new onset was noted in two patients. In all AIDS
      indicator conditions, Pneumocystis carinii pneumonia (PCP) was the leading
      opportunistic infection among AIDS patients. PCP was also on the top of initial
      manifestations of HIV-1 infection. One patient with Penicillium marneffei
      infection was diagnosed to have AIDS. The mean CD4 count at admission of AIDS
      patients was much lower than that of non-AIDS patients (32 vs. 297/microliter, p
      < 0.0005). During the follow-up period 24 of 53 patients died. Mean survival time
      of 23 expired patients after establishment of diagnosis of AIDS was 6.4 (0-29)
      months. The results indicated that males outnumbered females greatly in the
      number of cases. Sexual activity remained the most important route of infection.
      Psychosis of new onset may be an early manifestation of HIV-associated
      encephalopathy and requires more attention. In addition, the outcome was poor as
      most patients in this area did not become aware of risk of HIV-1 infection until
      they were seriously illed with full-blown AIDS that they would seek medical help.
      PCP was the most common incentive for medical consultation. Penicillium marneffei
      infection is endemic in southeast Asia, and should be classified as an AIDS
      indicator condition in Taiwan.

PMID- 10592815
TI  - Immunogenicity of Haemophilus influenzae b conjugate vaccine (HibTITER) and
      safety of HibTITER and a combination vaccine of diphtheria, tetanus, pertussis
      and HibTITER in infants two months of age: a preliminary report.
AB  - A study was undertaken to evaluate the safety and immunongenicity of a conjugate
      Haemophilus influenzae type b (Hib) vaccine (HibTITER) when administered
      concurrently with DTP (diphteria, tetanus and pertussis) vaccine in separate
      syringes. A total of 90 healthy children (45 per group) were randomized to
      receive either TETRAMUNE, a vaccine combining HibTITER with whole-cell DTP (group
      A), or DTP and HibTITER administered concurrently (group B) in separate syringes
      at approximately 2, 4 and 6 months of age in Taiwan. All children in group B
      achieved anti-Hib PRP (polyribosylribitol phosphate) antibody titers above 0.15
      microgram/ml and 91% developed antibody titers above 1.0 microgram/ml following
      the third immunization. Incidences of adverse reactions were comparable between
      groups A and B. Besides, the incidences of adverse reactions were not
      significantly more frequent compared with DTP vaccination alone. We concluded
      that HibTITER was highly immunogenic and safe when administered concurrently with
      DTP vaccine to Taiwanese children. TETRAMUNE was also safe and the number of
      injections may be reduced in the future.

PMID- 10592816
TI  - Molecular subtyping of the HIV-1 V3 loop sequences detected in HIV-1-positive
      patients in southern Taiwan.
AB  - Polymerase chain reaction and nucleotide sequence analysis were performed to
      amplify and determine the V3 loop sequences of human immunodeficiency virus type
      1 (HIV-1) from ten seropositive patients at National Cheng Kung University
      Hospital, Tainan. The nucleotide sequences and the deduced amino acid (a. a.)
      sequences of these V3 regions were compared with those of known HIV-1 prototypes.
      The V3 loop a. a. sequences detected in eight individuals belong to subtype B
      which predominates in North America and Europe, whereas two individuals were
      infected with HIV-1 subtype E which is mainly found in the heterosexual
      populations of Thailand. Sequence analysis of these variant HIV-1 strains
      revealed a number of interesting features and a phylogenetic tree was also
      constructed according to the V3 loop nucleotide sequences of these variant
      strains and HIV-1 isolates from other parts of the world. Furthermore, our
      results suggest that the north vs south geographical separation in terms of HIV-1
      epidemiology in Taiwan is insignificant.

PMID- 10592817
TI  - [Primary surveillance of spotted fever group antibodies on rats in the Kinmen
      area].
AB  - The positive rate of rickettsial antibodies of 107 rats in the Kinmen area by
      indirect immunofluorescent antibody (IFA) technique was 0% (0/107) in typhus
      fever, 38.3% (41/107) in scrub typhus and 66.4% (71/107) in spotted fever group;
      the positive rate (42.9%) of spotted fever group of 21 rats in Taiwan island also
      higher than scrub typhus (19.0). It suggests that spotted fever group patients
      may be present in our country but have not been discovered.

PMID- 10592818
TI  - Transfer of the E6 and E7 genes of human papillomavirus type 18 into human
      epithelial cells via recombinant retrovirus infection.
AB  - A retroviral vector carrying the E6 and E7 genes of HPV type 18 was transfected
      into a packaging cell line, Ampho psi 2. Thirteen recombinant viruses carrying
      the E6 and E7 genes were obtained. The titers of these recombinant viruses were
      estimated by infecting BALB/c3T3 cells and then counting the number of G418r
      colonies. Presence of HPV E6/E7 genes was confirmed by the PCR method and
      sequence-specific primers. The expression of E7 gene was examined by RT-PCR
      method. Results showed that the titers were ranged between 0.2 and 1.2 x 10(3)
      CFU/ml and the E7 transcripts were detected in all 13 cell clones. These E6 and
      E7-containing cell clones were able to grow in soft agar, indicating the E6/E7
      delivered by the recombinant retroviruses retained their transformation function.
      These recombinant viruses were then used to infect human NPC cell lines, NPC
      TW076 and -TW039 and cell clones resistant to G418 were obtained. Using Western
      blot analysis and HPV type 18 E6-specific monoclonal antibody, HPV-CIP5, these
      cells were shown to contain a protein with a molecular mass of 18 kDa. Our data
      indicated that the HPV E6/E7-containing recombinant retroviruses were capable of
      infecting human cell lines. The potential of using these recombinant retroviruses
      to immortalize human primary epithelial cells was discussed.

PMID- 10592819
TI  - Strategies for diagnosing HIV-1 infection in atypical Western blots.
AB  - The Western blot (WB) has long been used to confirm positive ELISAs for
      diagnosing HIV-1 infections. However, some WB patterns may result in
      "indeterminate" or controversial reports thus impeding early diagnoses or
      accurate diagnoses. The interpretation of HIV-1 WB has no "gold standard"
      criterion. Incomplete antibody profiles on WB strips can be interpreted as
      positive or indeterminate according to different criteria. The possibility of HIV
      2 infection was further checked in these serum samples. However, no reactivity to
      synthetic peptide of HIV-2 gp36 had been found. Serial WB analyses are important
      for attaining early diagnoses of HIV-1 infections as well as for evaluating
      clinical stages. Temporal changes on WB patterns of serial serum samples provide
      the evidence of seroconversion in individuals with risk behaviours and
      indeterminate WB. In late stage of HIV-1 infection, the reactivity to gag, pol
      and env antigen groups may decrease and result in indeterminate WB. We propose to
      diagnose HIV-1 infection and to differentiate the infection of HIV-1 from HIV-2
      in these cases by using nested polymerase chain reaction (PCR) to demonstrate the
      presence of HIV-1 specific vpu gene.

PMID- 10592820
TI  - Autopsy findings on patients with AIDS in Taiwan.
AB  - At National Taiwan University Hospital, from 1986 to 1996, autopsies were
      performed on 16 patients with acquired immunodeficiency syndrome. There were 15
      men and 1 woman. Fourteen of these male patients had contracted the disease as a
      result of sexual practice, among which 9 were homosexual, 1 was bisexual and 4
      were heterosexual. One of the patients had become infected by sharing a syringe
      during intravenous drug use. The female was a sex worker. Among these patients,
      only 2 had been tested for HIV before developing AIDS. On autopsy, lymphoid
      depletion and thymus atrophy were found in all patients. Testicular atrophy was
      noted in all the male patients. Three patients died of malignant lymphoma. Twelve
      patients died of opportunistic infections and 1 committed suicide. The initial
      opportunistic infection was usually oral candidiasis. Pneumocystis carinii
      pneumonia (PCP) was the most common opportunistic infection developed in the
      early stage while cytomegalovirus (CMV) infection was the most common one found
      in the late stage. Mycobacterium infection had developed in 8 patients. Six
      patients had disseminated Kaposi's sarcoma (KS) and 4 of them were homosexual. In
      4 patients, biopsy specimens were proved to have KS associated viral (HHV-8)
      genome. Malignant lymphoma was found in 4 cases, all were of high grade B cell
      type. Epstein-Barr virus (EBV) encoding small RNA (EBER1) was demonstrated in all
      the lymphomas. In conclusion, (1) the prevalence of tuberculosis (38%) in
      patients with AIDS in Taiwan is high; (2) the most common opportunistic
      infections in this series are candidiasis, PCP and CMV infections; (3) the
      incidence of AIDS related non-Hodgkin's lymphoma in Taiwan has increased since
      1995.

PMID- 10592821
TI  - Rapid detection of Mycobacterium tuberculosis in various clinical specimens by
      using polymerase chain reaction combined with a nonradioactive hybridization
      system.
AB  - A DNA amplification system using the polymerase chain reaction (PCR) combined
      with a nonradioactive digoxigenin-labeled probe hybridization was employed to
      detect Mycobacterium tuberculosis in clinical specimens. One hundred and thirty
      specimens were tested by several methods including routine culture method, acid
      fast staining, BACTEC 460 detection system, PCR, and PCR-hybridization
      techniques. Sixteen out of 130 specimens were culture positive on Middlebrook
      7H11 agar, 10 were positive with acid-fast staining, 18 were positive with BACTEC
      460 detection system, 23 were positive with PCR technique, and 62 were positive
      with PCR-nonradioactive hybridization technique. When compared with culture
      results, PCR-nonradioactive hybridization had an overall sensitivity of 100%
      (16/16) and a specificity of 59.7% (68/114). However, 28 out of 46 (60.9%) PCR
      nonradioactive hybridization positive specimens which were culture negative had
      clinical data supporting the diagnosis of tuberculosis. In addition, 4 specimens
      which were negative by routine culture but positive by BACTEC 460 detection
      system and two specimens which were negative by routine culture but positive by
      acid-fast staining were all positive by PCR-hybridization technique. These data
      suggest that routine culture method may not be sensitive enough to detect M.
      tuberculosis in all kinds of clinical specimens. Taking this deviation into
      account, the specificity of PCR-nonradioactive hybridization technique may be
      rectified range from 63% (68/108) to 79.1% (68/86). PCR itself is not
      satisfactory enough to detect M. tuberculosis in specimens (the sensitivity and
      specificity were 56.3% and 87.7%, respectively) in this study. However, when it
      combines with DNA hybridization technique, they can be a very powerful and rapid
      diagnostic tool to detect M. tuberculosis in clinical specimens.

PMID- 10592822
TI  - Arylamine N-acetyltransferase activity in Staphylococcus aureus.
AB  - N-Acetyltransferase (NAT) activities were determined by incubation of
      Staphylococcus aureus cytosols with p-aminobenzoic acid (PABA) or 2-aminofluorene
      (2-AF) followed by high pressure liquid chromatography assays. The NAT activities
      from S. aureus were found to be 0.67 +/- 0.04 nmol/min/mg protein for the
      acetylation of 2-AF and 0.46 +/- 0.02 nmol/min/mg protein for the acetylation of
      PABA. The apparent K(m) and Vmax values obtained were 2.85 +/- 0.65 mM and 7.51
      +/- 0.86 nmol/min/mg protein for 2-AF, and 2.35 +/- 0.39 mM and 9.43 +/- 0.78
      nmol/min/mg protein for PABA, respectively. The optimal pH value for the enzyme
      activity was 7.0 for both substrates tested. The optimal temperature for enzyme
      activity was 37 degrees C for both substrates. The NAT activity was inhibited by
      iodoacetamide at 0.25 mM, and activity was reduced 50%. At 1.0 mM iodoacetamide
      activity was inhibited more than 90%. Among a series of divalent cations and
      salts, Zn2+, Ca2+, and Fe2+ were demonstrated to be the most potent inhibitors.
      The molecular weight of NAT from S. aureus was found to be 44.9 kDa. This report
      is the first demonstration of acetyl CoA: arylamine NAT activity in S. aureus.

PMID- 10592823
TI  - Preparation and characterization of Pertussis toxin subunits.
AB  - Pertussis toxin (PT), a typical A-B oligomer exotoxin of Bordetella pertussis,
      has been demonstrated to be an essential protective antigen for acellular
      pertussis vaccine against whooping cough. In order to investigate the associated
      functionality ascribed to its components, we have purified A and B oligomers for
      the activity study. The A oligomer (S1 subunit) of PT was expressed in E. coli
      B834 (DE3) harboring expression vector (pET-20b) with the insert of S1 coding
      region and purified by metal-chelating column. The B oligomer was isolated by a
      single-step purification procedure. Individually, recombinant S1 and B oligomer
      exhibited quite distinct biological activities in vivo. S1 subunit induced
      leukocytosis-promoting (LP) activity, but did not affect mouse body weight-gain.
      On the contrary, B oligomer reduced mouse body weight-gain but did not reveal LP
      activity. In vitro, the combination of S1 subunit and B oligomer could enhance
      the toxic activities as exhibited by native PT and showed an additive toxicity in
      CHO cell clustering test and hemagglutination assay.

PMID- 10592824
TI  - [Seroepidemiology of Japanese encephalitis viral infection among 3-6 years old
      children from mountainous and plains townships located in the northern, central,
      southern and eastern Taiwan].
AB  - In order to evaluate the Japanese encephalitis virus (JEV) vaccination program in
      rural Taiwan, we conducted a seroepidemiological survey of JEV among rural
      children 3 to 6 years of age in Taiwan. The children were selected through a
      systemic sampling following stratification by age of children in 4 selected
      aboriginal villages and 4 adjacent nonaboriginal villages. The overall vaccine
      coverage rate for the primary (2 doses) dose was 81.2% (1853/2281) with higher
      rates (87.7%-87.9%) found among the more recent birth cohort of 3 to 4 years of
      age. The neutralizing antibody (NT) against JEV was measured with plaque
      reduction neutralization test (PRNT) using Nakayama strain as the virus. With a
      positive NT antibody defined as > or = 1:10 dilution of serum yielding more than
      50% plaque reduction, the overall JEV NT antibody positive rate among children
      receiving 3 doses of vaccine was 67%. However, the age-specific positive rates
      varied significantly with varying ages; the lowest of 47% being among children 4
      years of age which was lower than the rates of 68%, 76% and 87% among children of
      3, 5 and 6 years of age, respectively. This trend of rising seropositive rates of
      JEV antibody with increasing age among 4 and 6 years of age was also noted among
      children who had received no vaccine, suggesting the importance of natural
      infection among rural Taiwanese children. Despite the high frequency of natural
      infection, the seropositive rates of JEV antibody still correlated well with the
      dose of vaccine received, i.e., 67% (1122/1664), 66% (65/97), 33% (4/12) and 40%
      (19/47) for children receiving 3, 2, 1, and 0 dose of JE vaccines, respectively
      (P < 0.0001 Chi-square for trend test). When stratified analysis by dose and by
      type of vaccines was conducted, a significantly higher seropositive rate of JEV
      NT antibody was noted among children receiving JE vaccine of Beijing type (87%)
      than children receiving Nakayama type (39%) (p < 0.0001, Chi-square test). Our
      data indicated that the JEV vaccination, in conjunction with JEV natural
      infection, has maintained high JEV NT antibody level among rural children of
      Taiwan.

PMID- 10592825
TI  - Studies on the serological cross-reaction between dengue and Japanese
      encephalitis.
AB  - Antibody responses of sero-confirmed flavivirus-infected patients were
      investigated by hemagglutination-inhibition (HI) tests against acute phase sera
      (S1) and convalescent phase sera (S2) using JE virus (JEV) JaGAr# 01 strain
      antigen (J-Ag) and dengue virus (DV) type 1 Hawaiian strain antigen (D-Ag).
      Analysis of the test results showed that depending on the combinations of HI
      responses to both antigens, the sero-confirmed patients could be divided into
      five classes: primary JE, secondary JE, primary D (JEV-uncontracted), primary
      D(JEV-contracted), and secondary D(JEV-contracted) patients. The diagnostic
      combinations of responses to HI tests for the infections were discussed and
      defined in this paper.

PMID- 10592826
TI  - Evaluation of CLO test and polymerase chain reaction for biopsy-dependent
      diagnosis of Helicobacter pylori infection.
AB  - Helicobacter pylori is now recognized as possibly playing an etiologic role on
      the development of chronic gastritis, peptic ulcers and adenocarcinoma of the
      distal stomach. CLO test and polymerase chain reaction (PCR) assay are rapid,
      biopsy-dependent diagnostic tests for H. pylori identification. In this study, we
      assessed four diagnostic methods (CLO test, PCR assay, culture and histological
      examination) for H. pylori detection in biopsy specimens from 78 patients with
      gastroduodenal diseases and investigating the efficiency of CLO test and PCR
      assay for the diagnosis of H. pylori infection. H. pylori was identified in
      75.6%, 75.6%, 64.1%, 69.2% of patients by CLO test, PCR assay, culture and
      histological examination, respectively. Compared with the detection of H. pylori
      by culture and/or histological examination, the sensitivity and specificity of
      the CLO test were 98.2% and 81.8%, respectively, whereas the sensitivity and
      specificity of PCR assay were 96.4% and 77.3%, respectively. According to the H.
      pylori infection state as determined from the results of three concordant tests,
      the sensitivities of culture, CLO test, histological examination, and PCR assay
      were 90.9%, 96.4%, 98.2% and 100%, respectively. Whereas, the specificity was
      100%, 95%, 95% and 90% for culture, CLO test, histological examination, and PCR
      assay, respectively. We found that both CLO test and PCR assay were highly
      sensitive and specific for H. pylori identification; however, PCR assay was more
      sensitive than other methods for detecting the specimens after patients received
      treatment. The results of this study suggest that CLO test is a rapid and
      sensitive method of screening for H. pylori infection and that PCR assay could
      provide an accurate indication of the state of infection both during treatment
      for eradication of H. pylori and at follow-up.

PMID- 10592827
TI  - Purification and characterization of a 94 KD high molecular weight allergen from
      house dust mite, Dermatophagoides pteronyssinus.
AB  - House dust mite allergens from Dermatophagoides pteronyssinus is an important
      cause of severe allergic asthma and rhinitis in many countries. Although several
      low to medium molecular weight allergens had been well characterized, limited
      studies on the high molecular weight IgE-binding components were reported. In
      this study, a 94 kD high molecular weight allergen from crude mite body extract
      of D. pteronyssinus was purified and characterized. Monoclonal antibody (mAb)
      affinity chromatography and high performance liquid chromatography were used to
      purify 94 kD allergen. Its antigenicity and allergenicity were confirmed by in
      vitro and in vivo studies. Two mAbs 2205-3.45 and 2220-7.25 specific to 94 kD
      high molecular weight component of D. pteronyssinus were generated. The epitopes
      recognized by these mAbs were species-specific. Enzyme-linked immunosorbent assay
      (ELISA) of IgE reactivity in the sera from 40 asthmatic children allergic to D.
      pteronyssinus showed that 37.5% of them had significantly higher optical density
      values (range 0.011 to 0.452) than normal (range 0.013 to 0.035). In in vivo skin
      test showed that 9 out of 20 (45%) asthmatic children were positive to 94 kD
      allergen. The results demonstrate that 94 kD high molecular weight component is
      an important allergen existing in house dust mite in Taiwan.

PMID- 10592828
TI  - Population cell differentiation of Serratia marcescens on agar surface and in
      broth culture.
AB  - The bacterium Serratia marcescens shows population surface migration (swarming)
      phenomenum on an LB swarming plate, and differentiated cells can be observed at
      the swarming front. How the cell population differentiates during swarming on the
      agar surface is not known, neither is it clear whether cells with differentiated
      characteristics can be observed in broth culture. To monitor the population cell
      differentiation in a highly sensitive way without cell destruction, experiments
      were designed using bacterial luciferase genes luxAB as the reporter genes to
      allow direct monitoring of the differentiating cells through bioluminescence. An
      isogenic S. marcescens strain was constructed with luxAB under the control of the
      promoter of flagellin gene hag (phag::luxAB). Patterns of cell differentiation
      were monitored either by direct X-ray film exposure and/or by Autolumat
      luminometer detection. Results show that population cell differentiation on the
      agar surface occurs first in a temporal and then spatial way during colonial
      growth. It was also found that cells harvested from both the spreading agar plate
      and broth culture showed differentiation patterns similar to those from swarming
      cells, suggesting that the agar surface culture may not be essential for the
      formation of differentiated cells.

PMID- 10592829
TI  - [Detection of neutralizing antibodies to Japanese encephalitis virus by enzyme
      linked immunosorbent assay (ELISA)].
AB  - Competitive ELISA was used for the detection of neutralizing antibody to JE.
      Based on the principle that human serum JE antibody competed with JE monoclonal
      antibody (MAb) for JE antigen, it was found that 3 JE MAbs (E3-3, NPF-5 and NNN
      5) were suitable for competitive ELISA for the detection of JE neutralizing
      antibody. The sensitivity of cometitive ELISA for 29 JE confirmed serum specimens
      with titer of plaque reduction neutralization test (PRNT) was checked to be 82.1%
      (23/28). The specificity of E3-3 MAb to JE used in competitive ELISA was 100%.
      Correlation coefficient of JE confirmed cases of 57 hemagglutination inhibition
      (HI) titers in 1995 and 37 PRNT titers in 1994 compared with competitive ELISA
      were 0.744 and 0.732, respectively. Compared the competitive ELISA titers of 154
      sera of healthy people with PRNT titers, the results showed that 70% of the sera
      could be detected by competitive ELISA which saved a lot of time and manpower.

PMID- 10592830
TI  - [Isolation of bacteria which could perform nitrification and denitrification
      simultaneously by gene probe].
AB  - The bacteria which could perform nitrification and denitrification simultaneously
      from nitrogen containing wastes in Taiwan were isolated by using the probes made
      from random DNA fragments of Thiosphaera pantotropha. Two isolates were
      identified and named Alcaligenes faecalis subsp. faecalis strain 1 and strain 2
      respectively. The effects on nitrification and denitrification by different
      medium pH, oxygen content, addition of different electron donors or inhibitors
      were studied. The isolates not only could perform nitrification, but also
      denitrification even in the presence of oxygen. Potassium cyanide could inhibit
      denitrification; hydrazine and hydroxyamine could inhibit nitrification.
      Alcaligenes faecalis subsp. faecalis strain 2 shows better denitrification.

PMID- 10592831
TI  - [Identification of Staphylococcus epidermidis by desferrioxamine susceptibility
      and trehalose fermentation tests].
AB  - The importance of coagulase-negative staphylococci, especially Staphylococcus
      epidermidis in clinical and nosocomial infection are recognized increasingly in
      recent years. A rapid and accurate identification of S. epidermidis is therefore
      important and necessary. A new test, susceptibility to desferrioxamine, coupled
      with trehalose fermentation has been recommended for the identification of this
      organism. However, the medium and method used are different from what has been
      recommended by the NCCLS. To investigate the feasibility of using the
      desferrioxamine susceptibility test in conjunction with the routinely used disc
      agar diffusion test, we employed 111 staphylococcal strains (including 51 S.
      epidermidis isolates, 15 S. hominis and 45 other coagulase-negative
      staphylococci) as test organisms, and followed the procedures recommended by the
      NCCLS in which Mueller-Hinton agar and standard inoculum were used. Results
      indicated that all strains of S. epidermidis and S. hominis were susceptible to 1
      mg desferrioxamine (the diameter of the inhibition zone were 28-37 mm). The
      minimum inhibitory concentrations of desferrioxamine to S. epidermidis and S.
      hominis isolates were determined to be 125 micrograms/ml. Further differentiation
      of S. hominis and S. epidermidis can be made by their ability to ferment
      trehalose, the former could while the latter could not. We conclude that the
      desferrioxamine susceptibility test of coagulase-negative staphylococci can be
      used in conjunction with the routine disc agar diffusion method. S. epidermidis
      can be identified rapidly and accurately by its susceptibility to 1 mg
      desferrioxamine and inability to ferment trehalose.

PMID- 10592833
TI  - A decade of WHO Information Exchange System 'ALERT'.

PMID- 10592832
TI  - When to withdraw or withhold treatment.

PMID- 10592834
TI  - Evidence of the work of the 'resurrection men' in a country churchyard.

PMID- 10592835
TI  - 1,2-dibromoethane--a toxicological review.
AB  - DBE is transported in the UK in road tankers and there is always the possibility
      of an accident. The consequences could be serious, since this chemical is
      absorbed by all routes, rapidly penetrates clothing and there is no effective
      antidote. Severe cases of poisoning are difficult to treat and there is a high
      mortality. Prevention of exposure is therefore essential.

PMID- 10592836
TI  - The dud cigar?--Cochrane collaboration and the saga of human albumin.

PMID- 10592837
TI  - Effects of acupuncture at pai-hui on the deficit of memory storage in rats.
AB  - In this study, we investigated the effects of Pai-Hui by acupuncture on
      cycloheximide (CXM)-induced impairment of the passive avoidance response in rats.
      Acupuncture at Pai-Hui (Go-20) treated 15 min before or immediately after
      training trial for 15 min significantly attenuated CXM-induced impairment of
      passive avoidance response in rats, but did not have the same effect 30 and 60
      min before or 30 min after the training trial or before the retention trial.
      Acupuncture at Pai-Hui 15 min before the training trial for 15, 30 and 60 min
      significantly attenuated CXM-induced impairment of passive avoidance response in
      rats, and its efficacy paralleled the acupuncture duration. Furthermore,
      acupuncture at Pai-Hui did not attenuate scopolamine (SCOP)-induced impairment of
      passive avoidance response, but was slightly inhibited by SCOP at 0.3 mg/kg.
      Second, acupuncture at Pai-Hui attenuated p-chloroamphetamine (PCA)-induced
      impairment of passive avoidance response and was significantly antagonized by PCA
      at 1 mg/kg. These results suggest that acupuncture at Pai-Hui mainly affects the
      memory storage process and has preventive and immediate therapeutic effects on
      CXM-induced impairment of passive avoidance response. Its efficacy paralleled the
      acupuncture duration. The preventive effect of acupuncture at Pai-Hui on CXM
      induced impairment is significantly reduced by serotonergic 5-HT releaser, and
      slightly by cholinergic manipulations.

PMID- 10592838
TI  - Effects of acupuncture on exercise-induced muscle soreness and serum creatine
      kinase activity.
AB  - The purpose of this study was to determine the effects of acupuncture on delayed
      onset muscle soreness (DOMS) produced by exercise. Baseline data were collected
      on 20 male subjects for intensity of muscle soreness and serum creatine kinase
      (CK) activity. All values were subsequently reassessed 24, 48 and 72 hours after
      exercise. The experimental group received acupuncture treatment while the control
      group received no treatment. Muscle soreness perception was significantly less (P
      < 0.05) at 72 hours in the acupuncture treated group compared to control group.
      However, the change in CK was not significantly different between groups. These
      results suggest that acupuncture is effective in decreasing muscle soreness but
      does not prevent CK release from muscle.

PMID- 10592839
TI  - A Minnesota multiphasic personality inventory profile of ChunDoSunBup qi
      trainees: a preliminary study.
AB  - The aim of this study is to explore the effects of ChunDoSunBup Qi-training on
      personality traits. Twenty-six normal healthy subjects (mean age = 26.58 +/-
      6.56) and 26 CDSB Qi-trainees (mean age = 27.74 +/- 5.21) participated in this
      study. Analysis of MMPI profiles showed that CDSB Qi-trainees scored
      significantly lower on Depression (D), Hysteria (Hy), Paranoia (Pa),
      Schizophrenia (Sc) and Frequency (F) and significantly higher on the Correction
      (K) Scales. In addition, CDSB Qi-trainees reported a significantly lower Cook
      Medley Hostility (Ho) scale than that of controls. This preliminary study
      suggests that CDSB Qi-training may be effective in protection as well as
      restoration of emotional, psychological symptomatology and personality trait
      disorder.

PMID- 10592840
TI  - Studies on the psychosomatic functioning of ill-health according to eastern and
      Western medicine. 3. Two treatment methods using kampo medication for stress
      related and lifestyle disease.
AB  - In this study, we examine the modality of improvement in psychosomatic function
      to verify the suitability of two treatment methods previously described. The
      subjects were nine medical students with no history of blood stasis-related
      illness (average age, 24.8; SD, 1.4 years) and 21 patients of our outpatient
      clinic (average age, 54.3; SD, 10.4 years). For purposes of our research, Kampo
      medication was selected based on the diagnosis and treatment of unbalanced qi,
      blood, and body fluid developed by the authors in their previous report. As a
      result, the therapeutic features of the preventive treatment group of nine
      medical students and the final treatment group of 21 patients of the outpatient
      clinic were essentially identical. There were two such features: 1. At the
      psychological level, this consisted an improvement in stress-related emotional
      reaction, centered on anxiety and depression, and at the physiological level,
      this consisted of an improvement in peripheral blood circulation (an increase of
      the fractal dimension of the plethysmogram, p = 0.0357). 2. The improvement of
      the foregoing psychosomatic function is related to the improvement of blood
      stasis (strictly speaking, vital energy stagnation and blood stasis) in Oriental
      medicine, and the improvement of blood rheological abnormalities in Western
      medicine. Therefore, this research confirmed the significance of two treatment
      methods proposed by the authors for stress-related illness and lifestyle disease
      in individuals with an anxiety-affinitive constitution.

PMID- 10592841
TI  - Panax quinquefolium L. inhibits thrombin-induced endothelin release in vitro.
AB  - Endothelial cell damage is considered to be the initial step in the genesis of
      thrombosis and arteriosclerosis, the common precursors of cardiovascular
      disorders. In this study, we evaluated the protective effects of American ginseng
      or Panax quinquefolium L. extracts on endothelial cell injury, and investigated
      effects of ginseng extracts on thrombin-induced endothelin release using cultured
      human umbilical vein endothelial cells. We observed that when endothelial cells
      pretreated with 1, 10, and 100 micrograms/ml of Panax quinquefolium L. extracts
      were incubated for 4 and 24 hr with thrombin, the concentration of endothelin was
      significantly decreased in a concentration dependent, time related manner (at 4
      hr, IC50 = 5.1 micrograms/ml; at 24 hr, IC50 = 6.2 micrograms/ml). We further
      evaluated the effects of NG-nitro-L-arginine (NLA), a nitric oxide (NO)
      synthetase inhibitor, on the activity of Panax quinquefolium L. extracts.
      Following pretreatment of cultured endothelial cells with NLA, the inhibition of
      thrombin-induced endothelin release by Panax quinquefolium L. was significantly
      reduced (P < 0.05). This result suggests that the pharmacological action of Panax
      quinquefolium L. is, at least partially, due to NO release. Our data demonstrate
      that American ginseng may play a therapeutic role in facilitating the hemodynamic
      balance of vascular endothelial cells.

PMID- 10592842
TI  - Effect of Uncariae ramulus et Uncus on endothelium in spontaneously hypertensive
      rats.
AB  - The protective effect of the extract of Uncariae ramulus et Uncus (URE) against
      endothelium disorder due to hypertension was investigated. We administered low
      (150 mg/kg/day) and high (450 mg/kg/day) doses of URE orally to spontaneously
      hypertensive rats for 8 weeks. Endothelium dependent vasodilatation by
      acetylcholine increased significantly in the high URE group compared with the
      control group. Endothelium dependent vasocontraction by xanthine oxidase
      decreased significantly in the high URE group compared with the control group.
      Serum NO2-/NO3- were tended to increase in the high URE group. It is suggested
      that URE may have a protective effect for the endothelium against the influence
      of hypertension.

PMID- 10592843
TI  - Effects of ginseng radix on sugar absorption in the small intestine.
AB  - Ginseng radix (GR) is often used in traditional Japanese kampo medicine. We
      studied the effect of GR on glucose and maltose transport in rat and human
      duodenal mucosa by Ussing's method, and on smooth muscle movement in rat duodenal
      muscle by Magnus' method. GR inhibited absorption of glucose or maltose in rat
      and human duodenal mucosa, but increased duodenal muscle movement. It suggests
      that the inhibition of sugar absorption by GR is more dominant than enhancement
      of duodenal muscle movement by GR.

PMID- 10592844
TI  - A Chinese traditional medicine, sho-saiko-to (xiao-chaihu-tang), reduces the
      bioavailability of tolbutamide after oral administration in rats.
AB  - The effects of Sho-saiko-to on the pharmacokinetics of tolbutamide were
      investigated in rats. After intravenous administration of tolbutamide (5 mg/kg),
      no significant change in the pharmacokinetics of tolbutamide was observed in both
      groups of single and multiple (7 days) pre-administration of Sho-saiko-to (500
      mg/kg). In the study of single oral administration of tolbutamide (50 mg/kg), co
      administration of Sho-saiko-to tended to accelerate the initial absorption rate
      of tolbutamide. The area under the plasma concentration-time curve of tolbutamide
      after oral administration was significantly reduced by Sho-saiko-to.
      Subsequently, a significant decrease was observed in the oral bioavailability of
      this drug when Sho-saiko-to was given concomitantly. These findings suggest that
      Sho-saiko-to reduces the bioavailability of tolbutamide after oral administration
      in rats, and that this change is not related to hepatic metabolism.

PMID- 10592845
TI  - A comparative study of Embelia schiperi and Embelia keniensis on blood glucose
      and triglycerides in normal and epinephrine-induced hyperglycemic mice.
AB  - Intraperitoneal administration of the methanol extract of Embelia schiperi (ES)
      to normal mice caused a significant decrease in blood glucose (p < 0.01) and a
      significant increase in triglycerides 4 hours after administration at 100 mg/kg
      (p < 0.01). The toluene fraction of Embelia keniensis methanol extract (TS)
      showed hypoglycemic and lipid lowering activity 7 hours after intraperitoneal
      administration at 100 mg/kg. In addition, TS (100 mg/kg) administration
      significantly decreased blood glucose in epinephrine-induced hyperglycemic mice
      (p < 0.01). Moreover, ES tended to increase while TS tended to decrease the blood
      triglycerides in epinephrine-induced hyperglycemic mice. On the other hand, no
      changes in blood cholesterol were observed after the administration of ES or TS
      in normal and epinephrine-induced hyperglycemic mice. We found that two species
      from Embelia, ES and TS, have different activities on blood glucose and
      triglycerides in normal and epinephrine-induced hyperglycemic mice.

PMID- 10592846
TI  - Effects of punicalagin and punicalin on carrageenan-induced inflammation in rats.
AB  - Punicalagin and punicalin were isolated from the leaves of Terminalia catappa L.
      In this study, we evaluated the anti-inflammatory activity of punicalagin and
      punicalin carrageenan-induced hind paw edema in rats. After evaluation of the
      anti-inflammatory effects, the edema rates were increased by carrageenan
      administration and reduced by drug treatment. After 4 hr of carrageenan
      administration, the best effect group was the punicalagin (10 mg/kg) treated
      group (inhibition rate was 58.15%), and the second was the punicalagin (5 mg/kg)
      treated group (inhibition rate was 39.15%). However, even if the anti
      inflammatory activity of punicalagin was the same as punicalin at the 5 mg/kg
      dose, the inhibition effect from larger doses of punicalagin was increased, but
      there was a decrease with a larger dose of punicalin. The data showed that both
      punicalagin and punicalin exert anti-inflammatory activity, but treatment with
      larger doses of punicalin may induce some cell damages.

PMID- 10592847
TI  - Shini-san inhibits mast cell-dependent immediate-type allergic reactions.
AB  - Shini-San has been used for treatment of allergic disease in Korea. However, its
      effect in experimental models remains unknown. The mast cell plays a pivotal role
      in initiating allergic response by secreting intracytoplasmic granular mediators
      such as histamine. The present report describes an inhibitory effect of Shini-San
      on mast cell-mediated immediate-type allergic reactions. Topical application of
      compound 48/80 can induce an ear swelling response in normal (WBB6F1(-)+/+) mice
      but not in congenic mast cell-deficient WBB6F1-W/WV mice. Shini-San inhibited
      concentration-dependent mast cell-dependent ear swelling response induced by
      compound 48/80 in normal mice. Shini-San inhibited concentration-dependent
      passive cutaneous anaphylaxis induced by anti-dinitrophenyl (DNP) immunoglobulin
      E (IgE) in rats by topical application. Shini-San also inhibited in concentration
      dependent fashion the histamine release from the rat peritoneal mast cells by
      compound 48/80 or anti-DNP IgE. Moreover, Shini-San had a significant inhibitory
      effect on compound 48/80-induced systemic anaphylactic reaction. These results
      indicate that Shini-San inhibits immediate type allergic reactions by inhibition
      of mast cell degranulation in vivo and in vitro.

PMID- 10592848
TI  - Radioprotective effects of two traditional Chinese medicine prescriptions: si-wu
      tang and si-jun-zi-tang.
AB  - We performed this study to determine the effect of Si-Wu-Tang, a basic
      prescription of traditional Oriental medicine as a blood-building decoction
      (Chinese medical concept: Bu-Xie), Si-Jun-Zi-Tang, a basic prescription as an
      energy tonic (Chinese medical concept: Bu-Qi) and its major ingredients on
      jejunal crypt survival, endogenous spleen colony formation, and apoptosis in
      jejunal crypt cells of mice irradiated with high and low dose of gamma
      irradiation. Si-Wu-Tang administration before irradiation protected the jejunal
      crypts (p < 0.0005), increased the formation of endogenous spleen colonies (p <
      0.05) and reduced the frequency of radiation-induced apoptosis (p < 0.05). In an
      experiment on the effect of ingredients of Si-Wu-Tang, the result indicated that
      extract of Danggui and Baishaoyao might have a major radioprotective effect. The
      radioprotective effect of Si-Jun-Zi-Tang and its ingredients were not as
      significant as that of Si-Wu-Tang. Although the mechanisms of this inhibitory
      effect remain to be elucidated, these results indicate that Si-Wu-Tang might be a
      useful radioprotector, especially since it is a relatively nontoxic natural
      product. Further studies are needed to characterize better the protective nature
      of Si-Wu-Tang extract and its ingredients.

PMID- 10592849
TI  - Effects of various levels of dietary Lepidium sativum L. seeds in rats.
AB  - A toxicity study was made on Lepidium sativum L. seeds used in Saudi traditional
      medicine for the treatment of various ailments. Lepidium sativum L. seed fed to
      Wistar albino rats at 2% (w/w) was non-toxic, Ten percent (w/w) was toxic but not
      fatal and 50% (w/w) of the diet for 6 weeks was lethal and caused depression in
      growth rate and entero-hepato-nephrotoxicity. Organ lesions accompanied by anemia
      and leukopenia were correlated with alterations in serum AST and ALT activities
      and concentrations of total protein, cholesterol, urea, and other serum
      constituents.

PMID- 10592850
TI  - Effects of lu-duo-wei capsule on prolonging life span of housefly and Drosophila
      melanogaster.
AB  - Lu-Duo-Wei capsule is a product of Chinese medicine having high efficacy in
      scavenging superoxide and hydroxyl radicals. It contains antioxidants, which may
      increase longevity, but whether Lu-Duo-Wei capsule has such an effect is unknown.
      In this study, supplementing the basic diet with Lu-Duo-Wei resulted in
      prolonging the life span of houseflies and fruit flies. Moreover, the effect of
      prolonging the life span of houseflies by Lu-Duo-Wei was significantly higher
      than that of tea polyphenol. The result not only confirms our previous report but
      also supports the free radical theory of aging.

PMID- 10592851
TI  - Prophylactic antibiotics for intrauterine device insertion: a metaanalysis of the
      randomized controlled trials.
AB  - We evaluated the effectiveness of prophylactic antibiotic administration before
      IUD insertion in reducing the incidence of pelvic inflammatory disease,
      unscheduled visits back to the clinician, and IUD discontinuations within 3
      months of insertion. We performed a metaanalysis of all known randomized
      controlled trials comparing an antibiotic (either oral doxycycline or
      azithromycin) versus a placebo or no treatment. Use of prophylaxis significantly
      reduced the frequency of unscheduled return visits (odds ratio 0.82; 95% CI 0.70,
      0.98). The protection against pelvic inflammatory disease was smaller and not
      statistically significant 0.89 (95% CI 0.53, 1.51). No significant effect on
      premature IUD discontinuation was evident. Use of either doxycycline or
      azithromycin before IUD insertion offered little observable benefit in the US.
      Prophylaxis reduced unscheduled visits and possibly PID in developing countries,
      which have higher rates of sexually transmitted diseases than in the US. A more
      important finding in these trials is the low incidence of pelvic inflammatory
      disease with or without prophylactic antibiotics.

PMID- 10592852
TI  - The TwoDay Algorithm: a new algorithm to identify the fertile time of the
      menstrual cycle.
AB  - Women who monitor their fertility signs and recognize when they are fertile can
      use this knowledge to conceive or to avoid pregnancy. Studies have shown that
      there is a rather small fertile window of several days during each menstrual
      cycle. Established methods of identifying the fertile window, such as the
      Ovulation and the Symptothermal methods of Natural Family Planning, can be very
      effective in helping couples avoid pregnancy. A new algorithm for identifying the
      fertile window has been developed, based on monitoring and recording of cervical
      secretions. The TwoDay Algorithm appears to be simpler to teach, learn, and use
      than current natural methods. A large existing data set from a World Health
      Organization study of the Ovulation Method, along with Natural Family Planning
      charts from women using the Ovulation Method and the Symptothermal Method, were
      used to determine the potential effectiveness of the TwoDay Algorithm in
      identifying the fertile window. Results suggest that the algorithm can be an
      effective alternative for low literacy populations or for programs that find
      current Natural Family Planning methods too time consuming or otherwise not
      feasible to incorporate into their services. Further studies are needed to
      determine the efficacy of the TwoDay Algorithm in avoiding pregnancy and to
      assess its acceptability to users and providers.

PMID- 10592853
TI  - A comparative study of the safety and efficacy of FemCap, a new vaginal barrier
      contraceptive, and the Ortho All-Flex diaphragm. The FemCap Investigators' Group.
AB  - The FemCap is a new silicone rubber barrier contraceptive shaped like a sailor's
      hat, with a dome that covers the cervix, a rim that fits into the fornices, and a
      brim that conforms to the vaginal walls around the cervix. It was designed to
      result in fewer dislodgments and less pressure on the urethra than the cervical
      cap and diaphragm, respectively, and to require less clinician time for fitting.
      This was a phase II/III, multicenter, randomized, open-label, parallel group
      study of 841 women at risk for pregnancy. A subset of 42 women at one site
      underwent colposcopy. Women were randomized to use the FemCap or Ortho All-Flex
      contraceptive diaphragm, both with 2% nonoxynol-9 spermicide, for 28 weeks. The
      objectives were to compare the two devices with regard to their safety and
      acceptability and to determine whether the probability of pregnancy among FemCap
      users was no worse than that of the diaphragm (meaning not more than 6 percentage
      points higher). The 6-month Kaplan-Meier cumulative unadjusted typical use
      pregnancy probabilities were 13.5% among FemCap users and 7.9% among diaphragm
      users. The adjusted risk of pregnancy among FemCap users was 1.96 times that
      among diaphragm users, with an upper 95% confidence limit of 3.01. Clinical
      equivalence (noninferiority) of the FemCap compared with the diaphragm, as
      defined in this study, would mean that the true risk of pregnancy among FemCap
      users was no more than 1.73 times the pregnancy risk of diaphragm users. Because
      the observed upper 95% confidence limit (and even the point estimate) exceeded
      1.73, the probability of pregnancy among FemCap users, compared with that among
      diaphragm users, did not meet the definition of clinical equivalence used in this
      study. The FemCap was believed to be safe and was associated with significantly
      fewer urinary tract infections. More women reported problems with the FemCap with
      regard to insertion, dislodgement, and especially removal, although their general
      assessments were positive. The two devices were comparable with regard to safety
      and acceptability, but a 6-point difference in the true 6-month pregnancy
      probabilities of the two devices could not be ruled out. Further studies are
      needed to determine whether design modifications can simplify insertion and
      removal.

PMID- 10592854
TI  - Use of placebo controls in an oral contraceptive trial: methodological issues and
      adverse event incidence.
AB  - Two multicenter, double-blind, placebo-controlled studies were conducted to
      evaluate the effectiveness of triphasic norgestimate/ethinyl estradiol (Ortho Tri
      Cyclen) for the treatment of acne vulgaris. To our knowledge, these studies were
      the first double-blind, placebo-controlled trials to evaluate the efficacy of an
      oral contraceptive (OC) in the treatment of acne; in fact, they are probably the
      first placebo-controlled trials ever completed using modern OC. This article
      examines the conduct and feasibility of these studies including discussions on
      study planning enrollment, maintenance of the blind, continuation rates, and
      pregnancy prevention. Subjects were between the ages of 15 and 49 years, with
      moderate acne vulgaris, no contraindications to oral contraceptive use, and were
      willing to use a nonsteroidal method of birth control during the 6 months of the
      trial. More than 500 participants were enrolled in 1 year. Discontinuation rates
      between groups were similar. To explore the reasons for the similar and low
      discontinuation rates, OC-related side effects were evaluated in comparison to
      placebo. This analysis revealed that the OC exhibited a side effect profile that
      was similar, in many cases, to that of placebo. Although pregnancies occurred in
      the placebo arm, the incidence was consistent with expected failure rates for
      users of nonsteroidal methods in the general population.

PMID- 10592855
TI  - Once-a-month injectable contraceptives, Cyclofem and Mesigyna, in Egypt.
      Efficacy, causes of discontinuation, and side effects.
AB  - A clinical trial of the two once-a-month injectable contraceptives, Cyclofem and
      Mesigyna, used for 1 year was carried out in Egypt involving a total of 2252
      women living in different Egyptian localities, representing urban/rural and
      Upper/Lower Egyptian populations. Women were randomly assigned to either one of
      the two study preparations and followed a standard protocol for a comparative
      assessment of the efficacy, side effects, and acceptability of the two
      preparations. Both contraceptives proved to be highly acceptable, with
      continuation rates of 63.2 per 100 women-years for Cyclofem and 61.6 for Mesigyna
      at the end of 12 months of use. The cumulative discontinuation rates per 100
      women-years for method failure were 0.19 for Cyclofem users and 0.41 for Mesigyna
      users. Menstrual problems were the most frequently reported side effects in both
      groups. Discontinuation rates because of amenorrhea were 2.74 in the Cyclofem
      group compared to 1.38 in the Mesigyna group, whereas the rates of
      discontinuation because bleeding problems were significantly higher among
      Mesigyna users (11.54) compared to the Cyclofem group (7.39). There was no
      significant difference between the two groups regarding the discontinuation rates
      from other medical and personal causes. There were insignificant changes in the
      systolic and diastolic blood pressure values recorded at follow-up; only one
      Cyclofem user developed systemic hypertension (160/100 mm Hg) after 6 months of
      use and was discontinued for that reason. On the other hand, a constant weight
      gain averaging 0.33 kg/month was observed in both groups; however, weight gain
      was not considered a major cause of method discontinuation.

PMID- 10592856
TI  - The prevalence of anemia among clients of family planning clinics in Egypt.
AB  - A hospital-based study of the prevalence of anemia among clients of family
      planning clinics in Egypt was carried out in collaboration with a number of
      university hospitals. The study aimed to estimate the prevalence of anemia among
      the clients of family planning clinics and to determine the underlying risk
      factors for developing anemia in this population, with special emphasis on the
      role played by different contraceptive methods. The study was designed as a cross
      sectional study and was carried out in seven family planning clinics of
      Alexandria, Mansoura, Cairo, Al-Azhar, Ein Shams, El Minia, and Assiut University
      Hospitals during August 1993 to March 1994. A total of 1039 clients of family
      planning services who fulfilled the selection criteria were recruited in the
      study. A standardized interview questionnaire was used to record pertinent
      information on study subjects. As well, laboratory investigations were made to
      determine the hemoglobin level and the presence of bilharzial infection. The
      prevalence of anemia in the studied population reached 49.6%, with variations
      among centers. Anemia was more prevalent among urban compared to rural residents
      (55.7% and 42.0%, respectively). Anemia was more common in Lower Egypt, followed
      by urban governorates and Upper Egypt. Other independent determinants associated
      with high prevalence of anemia included: young age (20-39 years), lack of
      obesity, heavy menstrual periods, low parity, use of the intrauterine device
      (IUD), low intake of iron-rich foods, and bilharzial infection. Use of IUD were
      significantly associated with the highest prevalence of anemia among all
      contraceptive users (64.9%), and IUD users had the lowest level of hemoglobin
      compared to nonusers or users of other methods. Given the increasing prevalence
      of IUD use in Egypt, a major recommendation of this study would be to introduce
      the prescription of iron supplementation tablets as part of IUD services provided
      in family planning clinics, both to new users and to current users. Other
      recommendations include early treatment of menstrual disturbances and parasitic
      infections (including schistosomiasis), as well as improvement of the nutritional
      status of women at high risk for developing anemia, through mass media campaigns
      addressing dietary patterns and the health benefits of intake of iron-rich,
      inexpensive food items.

PMID- 10592857
TI  - The effect of 1-year use of the CuT 380A and oral contraceptive pills on
      hemoglobin and ferritin levels.
AB  - This is a longitudinal study of the effect of 1 year of use of Cu-T 380A
      intrauterine device (IUD) and oral hormonal contraceptives (OC) on the hemoglobin
      (Hb) content, serum ferritin, and percent iron saturation (serum iron/total iron
      binding capacity) of women with initial Hb level of 9-12 g/dL. It was carried out
      by the Egyptian Fertility Care Society in collaboration with seven University and
      Ministry of Health Teaching Hospitals. Women were followed-up at fixed intervals
      when laboratory tests conducted at admission were repeated. The use of Cu-T380A
      IUD produced a statistically significant drop in the Hb content and percent iron
      saturation levels after 12 months of use, as compared to the use of OC for the
      same period. The drop was greater with longer IUD use, initial high Hb levels,
      and among urban and semiurban residents. It is recommended that iron
      supplementation be part of the IUD services provided in family planning units in
      view of the high prevalence of anemia among women in the childbearing age in
      Egypt.

PMID- 10592858
TI  - Abortion complications in Abidjan (Ivory Coast).
AB  - The aim of this study was to describe the various methods of abortion used by
      women admitted to an obstetrics department in Abidjan (Ivory Coast) for abortion
      complications. The study was retrospective, and was based on the medical files of
      all 472 women admitted for abortion complications during a 3-year period (1993
      1995). The introduction of plant stems into the uterus, the use of certain
      instruments, use of vaginal preparations, and ingestion of plants were the most
      common abortion methods. Seventeen maternal deaths were registered, giving a
      maternal mortality rate of 3.6%. A high number of previous pregnancies and the
      ingestion of plants to provoke abortion were factors associated with the highest
      risk for maternal death. Complications of "local" abortion methods accounted for
      a high proportion of maternal deaths.

PMID- 10592859
TI  - Effect of estradiol and selected antiestrogens on pro- and antioxidant pathways
      in mammalian uterus.
AB  - In this study, we examined the effect of 17 beta-estradiol and selected
      antiestrogens on uterine NADPH-oxidase activity, superoxide dismutase (SOD)
      activity, hydride (H.-), dienyl radical and O2 -radical generation, and membrane
      fluidity. NADPH oxidase activity was positively modulated in estradiol-treated
      animals and negatively regulated in animals that received injections of AF-45, RU
      39411, tamoxifen, or ICI-182780. The SOD activity was markedly reduced in
      estradiol-treated animals when compared with the control animals. A positive
      modulation of SOD activity was observed upon treatment with AF45, RU39411,
      tamoxifen, and ICI 182780, though the potency varied among the individual test
      compounds. We observed detectable H(.-)-radical generation as evidenced from MNP
      H.- adduct formation in the uterine cell preparations from untreated control
      animals. Estradiol produced a tremendous augmentation in the superoxide radical
      profiles in uterine cell preparations compared to the control levels. All the
      other compounds that were tested significantly lowered the superoxide levels in
      the test set-up. AF-45, RU-39411, tamoxifen, and ICI-182780 induced varying
      orders of suppression of H(.-)-radical generation in the test subjects. There was
      a significant enhancement in membrane fluidity, hydride radical levels, and
      dienyl radical generation in the estradiol-treated group. All the antiestrogens
      did not exhibit a similar action on these parameters. RU-39411 exhibited
      antiestrogen-like activity in modulating hydride levels and membrane fluidity,
      whereas it stimulated dienyl radical generation. Thus our tests showed that the
      selected antiestrogens failed to show estrogen-like activity in these assays. It
      appears that estradiol exerts feedback control over pro- and antioxidant pathways
      and that markers of oxidative status could be used as a measure to evaluate the
      antiestrogenic activity of estradiol agonists/antagonists.

PMID- 10592860
TI  - Adverse metabolic disorders during highly active antiretroviral treatments
      (HAART) of HIV disease.
AB  - Protease inhibitor treatment has dramatically improved rates of morbidity and
      mortality in HIV-infected patients. However, it has recently been shown that this
      medication is associated with long-term side effects characterized by metabolic,
      clinical and biological alterations. These modifications have been described in
      patients treated with highly active antiretroviral therapy (HAART), including
      nucleoside analogue reverse transcriptase inhibitors (NRTI) and generally (but
      not always) protease inhibitors (PI). Clinical alterations are characterised by a
      body fat redistribution syndrome or lipodystrophy, with peripheral lipoatrophy
      and/or central fat accumulation. They are often associated with biological
      alterations, i.e. insulin resistance, hyperglycaemia and dyslipidaemia, which can
      also be observed alone. The pathophysiology of these alterations is presently
      unknown. The deleterious effect of PI on adipose tissue could be direct or
      indirect, and is probably modulated by genetic or environmental factors. NRTI
      could also be involved because of their mitochondrial toxicity. The purpose of
      the treatment is to control metabolic disturbances in order to prevent immediate
      complications such as acute pancreatitis and limit possible cardiovascular and
      diabetic complications at longer term. Studies are in progress to evaluate the
      possibility of therapeutic alternatives to PI when major metabolic disturbances
      are present.

PMID- 10592861
TI  - Cardiovascular risk factors associated with diabetes in an Indian community of
      Guadeloupe. A case control study.
AB  - Indians of Guadeloupe have an especially high prevalence type 2 diabetes mellitus
      and a particular susceptibility to coronary heart disease. This case-control
      study conducted from September 15 to 24, 1997, analysed cardiovascular risk
      factors associated with diabetes and particularly dyslipidaemia in the Indian
      community of Guadeloupe. The 172 subjects included 86 diabetic patients of Indian
      origin and 86 age- and sex-matched non-diabetic controls. All subjects underwent
      a physical examination by the same observer. Obesity and hypertension were
      assessed, and fasting lipid concentrations were measured. The body mass index and
      waist-to-hip ratio were higher among patients than controls: 27.8 vs 25.1 Kg/m2
      (p < 0.001) and 0.94 vs 0.90 (p < 0.001). Mean arterial systolic and diastolic
      pressures were higher for patients than controls (p < 0.001). Median HDL
      cholesterol was 1.23 mmol/L for patients vs 1.4 mmol/L for controls (p < 0.001),
      and median triglycerides were 2.0 vs 1.3 mmol/L (p < 0.001). Mean apolipoprotein
      B was 1.40 +/- 0.36 g/L for patients vs 1.23 +/- 0.35 g/L for controls (p <
      0.001). Our results show slight hypertension, central obesity, a lower plasma HDL
      cholesterol concentration, a higher triglyceride concentration, and a higher
      apolipoprotein B concentration for diabetics. These data would appear to have
      important implications for the prevention of cardiovascular disease in this
      population.

PMID- 10592862
TI  - Ca(2+)-ATPase activity in streptozotocin-induced diabetic rat kidneys.
AB  - Kidney Ca(2+)-ATPase activity was altered in streptozotocin (STZ)-induced
      diabetic rats. Male rats, 200-250 g, were rendered diabetic by injection of STZ
      45 mg/kg body weight via the tail vein. Following injection, control rats and
      diabetic rats at 1, 4, 8 or 15 weeks were sacrificed. Kidney tissues were
      obtained for the isolation of Ca(2+)-ATPase. Ca(2+)-ATPase activity was
      determined spectrophotometrically. Total calcium was measured by atomic
      absorption spectrophotometry. Diabetic rats had significantly elevated blood
      glucose levels compared to controls. Blood glucose levels were 92.92 +/- 1.215
      mg/dl (mean +/- S.E.M.) for the control group, and 362.50 +/- 9.613 mg/dl at one
      week and > 500 mg/dl at 4, 8 and 15 weeks of diabetes. Enzyme activities were
      significantly higher at 4, 8 and 15 weeks of diabetes than in the control group
      (p < 0.001). There was no significant increase at one week of diabetes. Ca(2+)
      ATPase activity was 0.43 +/- 0.003 U/L, 0.517 +/- 0.058 U/L, 0.707 +/- 0.078 U/L,
      0.730 +/- 0.006 U/L and 0.715 +/- 0.055 U/L respectively for controls and rats at
      1, 4, 8 and 15 weeks of diabetes. Calcium levels in diabetic rat kidneys were
      also significantly higher than for controls. The increase in enzyme activity may
      have been caused by higher calcium levels in diabetic kidneys resulting from a
      compensatory response of the enzyme to high levels of the ion.

PMID- 10592863
TI  - Analysis of mortality in French diabetic patients from death certificates: a
      comparative study.
AB  - This study was implemented in France to determine the causes of death in diabetic
      patients, whether diabetes was mentioned or not on the death certificate, and to
      assess the underestimation of the prevalence of diabetes at death. Two stratified
      random samples of death certificates were selected in the national mortality data
      base. The first included certificates mentioning diabetes as a cause of death
      (cases). The second, included certificates with no mention of diabetes
      (controls). For each certificate, a record form was sent to the certifying
      physician to ascertain diabetes in the first group and to trace unrecorded
      diabetes in the second group. In case of diabetes, the characteristics of the
      patient and his disease were collected (age at onset, treatment, complications
      ...). We obtained complete data for 325 cases and 959 controls. Among cases, 1%
      of the subjects were not confirmed as diabetic, while almost 10% of the controls
      were identified as having diabetes. The corresponding ratio of the corrected
      prevalence at death to that provided by the French statistics was estimated to
      4.0 in men and 3.1 in women. Particular features are that 2% of the total
      diabetic decedents died from acute metabolic complications (diabetic or
      hyperosmolar coma, acidoketosis, or acute hypoglycemia), and that 33% of the
      unreported diabetic decedents under 45 died from trauma or poisoning. These
      results show that in France, the death rates published in the statistics for
      diabetes dramatically underestimate the impact of diabetes. A high risk of death
      is linked to this disease, particularly in people aged under 45, a problem that
      health deciders should address.

PMID- 10592864
TI  - Severity of diabetic retinopathy is linked to lipoprotein (a) in type 1 diabetic
      patients.
AB  - To determine the relationship between plasma Lp(a) concentration and the risk of
      developing diabetic retinopathy, 341 Type 1 diabetic patients underwent an annual
      retinal fluorescein angiography and were assigned to one of 3 groups according to
      the stage of their diabetic retinopathy: no retinopathy (NR), non-proliferative
      diabetic retinopathy (N-PDR), or proliferative diabetic retinopathy (PDR). One
      hundred and twenty-three Type 1 diabetic patients had no retinopathy, 188 had N
      PDR and 30 had PDR. The ages of the three groups and the duration of diabetes
      were significantly different. Hypertension, microalbuminuria and diabetic
      nephropathy were more frequent in PDR than in NR or N-PDR (p < 0.0001). Plasma
      HbA1c was higher in PDR than in NR or N-PDR (p < 0.01). Type 1 patients who had
      been diabetic for at least 20 years included 30 NR, 108 N-PDR and 24 PDR. Type 1
      diabetic patients with PDR had microalbuminuria and macroproteinuria more
      frequently than other patients (p < 0.0001 and 0.01, respectively). Type 1
      diabetic patients with PDR had the highest median plasma Lp(a) and the highest
      frequency of Lp(a) above 30 mg/dl (p < 0.05). Multivariate analysis carried out
      in Type 1 diabetic patients with a duration of diabetes of at least 20 years
      showed that microproteinuria, HbA1c and Lp(a) accounted significantly for 21% of
      variance in retinal status. Lp(a) above 30 mg/dl was related to the risk of
      developing PDR (OR = 8.40, p < 0.05). Lipoprotein(a) appears to be associated
      with the severity of diabetic retinopathy in Type 1 diabetic patients, and
      particular attention should be paid to those with Lp(a) above 30 mg/dl and pre
      proliferative retinopathy.

PMID- 10592865
TI  - Assessment of cardiac arrhythmic risk in diabetic patients using QT dispersion
      abnormalities.
AB  - The purpose of this study was to assess the abnormalities and prevalence of QT
      dispersion in 154 diabetic patients (DP) who underwent a standard 12-lead ECG. QT
      interval was measured from the beginning of the QRS complex until the T wave
      returned to baseline. Atrial fibrillation, pacemakers and the impossibility of
      measuring 6 QT intervals per ECG were reasons for exclusion from the study.
      Diabetic patients were compared with 104 sex- and age-matched controls (C): mean
      age 50.7 +/- 2.3 years (DP) vs 48.4 +/- 10.1 (C) (ns); diabetes duration: 11.6 +/
      7.9 years. Seventy-eight percent of DP were non-insulin-dependent. Mean QT
      duration was 0.383 +/- 0.031 s (DP) vs 0.381 +/- 0.026 (C) (ns); QT dispersion
      (difference between the longest and shortest QT interval measurement) 0.033 +/-
      0.015 s (DP) vs 0.024 +/- 0.011 (C) (p < 0.001); and QT variability 3.003 +/-
      1.23% (DP) vs 2.295 +/- 0.936 (C) (p < 0.001); with a standard deviation of 0.012
      +/- 0.005 s (DP) vs 0.009 +/- 0.004 (C) (ns). QT dispersion indices (dispersion,
      variability) were significantly increased in DP, even for short diabetes
      duration. Future studies should focus on QT dispersion to assess the usefulness
      of such indices in detecting DP at high risk of sudden death and ventricular
      arrhythmias.

PMID- 10592866
TI  - Quality of life in relation to comorbidity among diabetic patients followed for
      three years in Swedish primary health care.
AB  - The aim of this study was to follow health-related quality of life (HRQOL) in
      diabetic subjects over a three-year period in relation to their medical
      situation. Forty-eight subjects 42-81 years of age in 1992 were identified as
      those responding to the HRQOL questionnaire on both occasions from a larger study
      of 341 diabetic patients in 1992 and 413 in 1995 in Stockholm County. Age- and
      sex-matched controls were taken from randomly collected samples of the general
      Swedish population. HRQOL was assessed by the SWED-QUAL (the Swedish Health
      Related Quality of Life Survey). Medical data were extracted from medical records
      at community health centres. Pearson's correlation coefficient for SWED-QUAL
      results over time exceeded 0.60 for seven of the ten scales (p < 0.001). A
      significant difference between 1992 and 1995 was found only for "Physical
      functioning" (p < 0.01). The general deterioration in health seen in medical
      records was accompanied by a decrease in the "Sleep problems" scale. In
      conclusion, worse outcome was noted only for "Physical functioning", while
      deterioration in health according to medical records was related to a worse
      outcome with respect to "Sleep problems". However, as the sample was small and
      not randomly selected, the results should be interpreted with caution and need
      confirmation in further studies.

PMID- 10592868
TI  - [Possible consequences on the follow up of type 2 diabetic patients of a recent
      modification of a glycosylated hemoglobin assay].
AB  - Glycated hemoglobin assay is considered as the gold standard for the follow-up of
      diabetic patients, and the assay must now be calibrated on the results of the
      method used in the DCCT study. It is considered as appropriate to intensify the
      therapy of type 2 diabetic patients when two consecutive values higher than 8%
      are observed. We present herein a case report illustrating the possible
      consequences on the follow up of type 2 diabetic patients of a recent significant
      modification, not reported elsewhere, aimed to eliminate a bias vs the DCCT
      method of a system, DCA 2000, largely used to determine HbA1c level in diabetic
      patients: before this modification, the DCA 2000 method underestimated the
      glycated hemoglobin level by 0.5% for a 8% value. Such is no more the case.

PMID- 10592867
TI  - Insulin autoimmune syndrome: a rare cause of hypoglycaemia not to be overlooked.
AB  - We report the case of a Caucasian patient with insulin autoimmune syndrome (IAS),
      defined as the association of hypoglycaemic attacks with insulin autoantibodies
      in individuals not previously treated with exogenous insulin. This rare syndrome
      (more than 200 published cases) has been reported mainly in Japan. Most affected
      patients present with other autoimmune disorders, most often Graves' disease. In
      most cases, insulin autoantibodies appear a few weeks after the beginning of
      treatment with a drug containing a sulphyldryl group. A significant increase in
      insulin and C-peptide plasma concentrations and the presence of other antiorgan
      antibodies are observed. The susceptibility haplotype is present in the Japanese
      population, which may account for the high frequency of IAS. Spontaneous
      remission is observed in 80% of cases, with cessation of hypoglycaemic attacks
      and disappearance of insulin autoantibodies some months after withdrawal of the
      drug. This rare cause of hypoglycaemia in Caucasian subjects should be considered
      in aetiologic investigation of spontaneous hypoglycaemia.

PMID- 10592869
TI  - [Drug therapy of type 2 diabetes with 1.26g/l fasting blood glucose (see above)].

PMID- 10592870
TI  - [ Absence of evidence of a possible connection vaccination for hepatitis B and
      the development of diabetes type 1. Report of a group of ALFEDIAM experts].

PMID- 10592871
TI  - [Auxiliary liver transplantation: what future?].

PMID- 10592872
TI  - [Prion diseases, the liver and the digestive system].

PMID- 10592873
TI  - [Protective effect of an apoptosis inhibitor in a new model of hepatitis induced
      by interleukin-4 in the rat].
AB  - OBJECTIVES: Interleukin-4 is a cytokine with pleiotropic effects on many cells.
      The effects of its expression on the liver remain unclear. To obtain organ
      localized cytokine expression and analyze its effect on the liver, recombinant
      adenovirus with coding sequences of interleukin-4 were transduced to rat livers.
      METHODS: Adenovirus with coding sequences of rat interleukin-4 were injected into
      the portal vein of Wistar rats. Microscopic examination of the liver was
      performed. The effects of interleukin-4 were confirmed in vitro on primary
      cultured rat hepatocytes. The same analysis was performed after intraperitoneal
      injection of l'YVADcmk, an inhibitor of the interleukin 1 converting enzyme.
      RESULTS: Interleukin-4 expression due to the recombinant adenovirus produced dose
      related, potentially lethal, severe hepatitis. This hepatitis was characterized
      by a leucocyte infiltrate mainly composed of eosinophilic polymorphonuclear and
      mast cells with numerous apoptotic hepatocytes. Intraperitoneal injection of
      YVADcmk decreased hepatocyte apoptosis and biological hepatitis and prevented
      death. CONCLUSION: These results suggested that YVADcmk might be used in
      fulminant hepatitis in which apoptosis is predominant.

PMID- 10592874
TI  - [Endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography
      performed during the same anesthesia session].
AB  - OBJECTIVES: To evaluate the feasibility, results and importance of a diagnostic
      and therapeutic biliary and pancreatic exploration associating endoscopic
      ultrasonography and endoscopic retrograde cholangio-pancreatography during the
      same anaesthesia session. METHODS: From November 1997 to October 1998, 179
      patients (83 males, 96 females), mean age 62 years (range 22 to 95 years), were
      investigated in our gastroenterology unit for biliary or pancreatic disorders.
      Two hundred and sixty two examinations were performed by a single physician for
      patients under general anaesthesia. In 87 cases (42%), endoscopic retrograde
      cholangio-pancreatography was performed immediately without prior endoscopic
      ultrasonography; these patients were not included. When endoscopic retrograde
      cholangio-pancreatography followed endoscopic ultrasonography, it was performed
      during the same anaesthesia session. RESULTS: In 118 cases, endoscopic
      ultrasonography was performed first, followed by endoscopic retrograde cholangio
      pancreatography 57 times (48%). The sensitivity of endoscopic ultrasonography was
      96.5% and the success of therapeutic endoscopic retrograde cholangio
      pancreatography was 100%. Endoscopic retrograde cholangio-pancreatography was
      necessary for 83% of patients with angiocholitis, 60% with cholestasis, 45% with
      acute biliary pancreatitis and only 28% with common bile duct stone migration.
      CONCLUSION: To decrease the number of anaesthesia sessions, endoscopic
      ultrasonography--endoscopic retrograde cholangio-pancreatography during same
      anaesthesia session appears to be particularly interesting for the diagnosis and
      treatment of biliary and pancreatic disorders, in terms of cost, accuracy,
      morbidity and patient comfort.

PMID- 10592875
TI  - [Hepatitis C virus and pregnancy].

PMID- 10592876
TI  - [Estimation of the incidence of digestive tract cancers by region].
AB  - OBJECTIVES: Information about the incidence of cancer in the national territory
      is a necessity for decision makers in public health. The aim of this study was to
      estimate for the first time the incidence of digestive tract cancers in each
      region of France in 1992 as well as trends in incidence between 1985 and 1995.
      METHODS: The incidence/mortality ratio established by sex, by age group and by
      localization in the departments covered by a cancer registry was applied to the
      mortality of each region studied. The mortality data were fit by applying a log
      linear model. RESULTS: The highest incidence rates of esophageal cancer were
      found in the North, in Brittany, Normandy and Picardy. The lowest rates were
      found in the regions of Midi-Pyrenees, Languedoc-Roussillon, Provence-Alpes-Cote
      d'Azur, Aquitaine and Poitou-Charentes. The incidence of this cancer decreased
      slightly between 1985 and 1995. Brittany and Normandy were also high risk regions
      for gastric cancer, while Provence-Alpes-Cote d'Azur, Midi-Pyrenees and Poitou
      Charente were low risk regions. The incidence of gastric cancer also decreased
      more markedly than that of esophageal cancer. Colorectal cancer was more frequent
      in Alsace, Lorraine and in the North, it was less common in Provence-Alpes-Cote
      d'Azur, Midi-Pyrenees and Franche-Comte. The incidence of this cancer increased
      little over the 10 years of the study. CONCLUSION: There are regional disparities
      in the incidence and trends of digestive cancer incidence. These are more marked
      for esophageal cancer and gastric cancer than for colorectal cancer. The data
      supplied are of use both in the planning of health care and in the study of the
      causes or the prevention of digestive cancers.

PMID- 10592877
TI  - [Curative treatment of non-metastatic esophageal cancer: concomitant
      chemoradiotherapy and high-dose-rate endoluminal curietherapy boost].
AB  - OBJECTIVES: The aim of this study was to evaluate the feasibility, toxicity, and
      efficacy of a curative combination of chemo-radiotherapy with high-dose-rate
      brachytherapy (HDRB) in patients with non metastatic esophageal cancer. PATIENTS
      AND METHODS: Fifty-two patients with esophageal carcinoma were treated with > 50
      Gy external irradiation, concomitant chemotherapy (5FU-CDDP) followed by HDRB
      delivering 12.5 Gy (6-20) as a boost. Twelve patients were stage I, 20 stage IIa,
      5 stage IIb, and 13 stage III, 1 Tis, 1 stage N unknown. Surgery was not
      indicated for medical reasons. RESULTS: The response rate was 96%, with complete
      response rate 85%. The 1-, 3-, 5-year overall survival rates were 78%, 33%, and
      22% respectively. A local failure occurred in 32%, and distant metastasis in 16%.
      Severe (grade 3, 4) acute toxicity occurred in 6 cases, severe late toxicity in 2
      cases and there was 1 toxic death. Tumoral length > or = 5 cm and stage IIa, IIb
      and III versus stage 1 indicated poor prognosis. CONCLUSION: This regimen is
      feasible and well tolerated. The 5-year overall survival is 22%, but the local
      failure rate is still very high. These results are encouraging and will be
      prospectively evaluated with currently ongoing randomized trial.

PMID- 10592878
TI  - [Preoperative staging of pancreatic adenocarcinoma: a practice survey of French
      gastroenterologists and digestive surgeons. Ordering of supplemental examinations
      and preoperative criteria of loco-regional spread].
AB  - BACKGROUND: Means used by physicians to perform preoperative staging of
      pancreatic adenocarcinoma are not well known. Therapeutic strategy used relies on
      knowledge of loco-regional spread criteria. AIMS: To assess the frequency of
      prescription of imaging procedures in patients with suspected pancreatic head
      adenocarcinoma; the use by French gastroenterologists (GE) and digestive surgeons
      (S) of criteria which lead to suspect lymph node invasion or vascular
      involvement; the frequency of histological determination in patients with
      unresectable tumor; if there is a difference between GE and S. METHODS: All the
      French GE (n = 3466) and S (n = 687) were sent a survey asking them about their
      habits. RESULTS: 615 answers were received (GE = 426, S = 189). There was no
      significant difference between GE and S for the prescription of ultrasonography
      and CT scan. Endosonography and upper digestive endoscopy were more
      systematically performed by GE than S (44 vs 35% and 50 vs 35%, respectively).
      Celio-mesenteric angiography was less often used by GE (6 vs 13%). Laparoscopy
      was electively used by 35% GE and 52% S. None of vascular involvement criteria
      was used by more than 75% of GE and S. Tumor-vessel interface loss was used by
      46% GE and 16% S (P < 0.001). Intravascular thrombosis and truncular portal
      hypertension signs were used more often by S than GE (84 vs. 71%: P < 0.001; 65
      vs. 51%: P < 0.001). None of nodal involvement criteria was used by more than 50%
      of physicians. All these nodal criteria were used more often by GE than S (P <
      0.001). Percentage of physicians requiring histological confirmation in case of
      unresectable tumor was 41%. CONCLUSION: Preoperative staging of suspected
      pancreatic head adenocarcinoma is performed with grossly the same manner by GE
      and S. Histological proof is searched for in a low percentage of cases. Imaging
      criteria of loco-regional spread of pancreatic adenocarcinoma are heterogeneously
      used by GE and S, the former using them more frequently than the latter. A better
      use of imaging criteria is necessary to optimise the treatment of patients with
      pancreatic adenocarcinoma.

PMID- 10592879
TI  - [Histopathologic diagnosis of the activity of chronic inflammatory bowel disease.
      Evaluation of the effect of drug treatment. Use of histological scores].

PMID- 10592880
TI  - [Auxiliary hepatic transplantation in iproniazid-induced subfulminant hepatitis.
      Should iproniazid still be sold in France?].
AB  - We report a new case of subfulminant hepatitis due to iproniazid, a MAO-inhibitor
      antidepressant, in a 27-year-old man. An auxiliary liver transplantation was
      performed. Liver function returned to normal and the patient was discharged from
      the hospital. However, the patient's native liver did not regenerate, and
      immunosuppressive therapy had to be maintained. Iproniazid hepatotoxicity is
      characterized by jaundice in 1% of cases, with a fulminant or subfulminant course
      in 20% of icteric patients. Although iproniazid is no longer sold in most
      countries, it is still commercialized in France. Because of the frequency and
      severity of hepatic injury, commercialization of iproniazid in France should no
      longer be authorized.

PMID- 10592881
TI  - [Isolated jejunal tuberculosis mimicking Crohn disease. Diagnosis by push video
      enteroscopy].
AB  - Intestinal tuberculosis is relatively unfrequent in Western countries, but
      immigrants and AIDS patients remain groups at particular risk for this disease.
      The diagnosis of intestinal tuberculosis is often difficult to establish because
      of close similarities with other conditions, in particular Crohn's disease. We
      report a case of jejunal tuberculosis in a 33-year-old man with severe weight
      loss and unexplained fever. The diagnosis was obtained on histological
      examination of the distal jejunum biopsies performed during pushed video
      enteroscopy. Interestingly, culture of the biopsies and specific PCR remained
      negative. Dramatic improvement was observed during the first days of
      antituberculous treatment. The main clinical and paraclinical manifestations of
      intestinal tuberculosis are also reviewed, as well as recent epidemiologic
      observations and new developments in diagnosis and treatment.

PMID- 10592882
TI  - [Granular cell tumor of the common bile duct. Contribution of endoscopic
      ultrasonography in 2 cases].
AB  - We report two cases of granular cell tumors involving the common bile duct in
      patients presenting with obstructive jaundice. Pre-operative endoscopic
      ultrasonography showed short asymmetric stricture with small well delimited
      hypoechoic mass in the distal common bile duct wall and proximal dilatation.
      These tumors were misdiagnosed as a bile duct carcinoma in one case and biliary
      metastasis of a melanoma in the other. Histological examination of the resected
      specimen showed granular cell tumors. A review of the previously reported cases
      shows that preoperative diagnosis is uncommon. It should be considered when
      endoscopic ultrasonography performed for biliary obstruction in a young woman
      shows a small and well limited hypoechoic mass.

PMID- 10592883
TI  - [Severe pulmonary embolism after obturation of gastric varices with a butyl
      cyanoacrylate and lipiodol combination].

PMID- 10592884
TI  - [Glimepiride-induced acute hepatitis].

PMID- 10592885
TI  - [Acute hepatitis and destructive cholangitis probably induced by amoxicillin
      clavulanic acid combination].

PMID- 10592886
TI  - [Esophagitis associated with the use of alendronate].

PMID- 10592887
TI  - [Pancreatic lipomatosis revealing Johanson-Blizzard syndrome].

PMID- 10592888
TI  - [Chronic diarrhea and lymphocytic colitis associated with Daflon therapy].

PMID- 10592889
TI  - [Fatal bone marrow aplasia after the 1st injection of methotrexate in a woman
      with Crohn's disease].

PMID- 10592890
TI  - [Primary prevention of esophageal variceal rupture: endoscopic ligation or
      propranolol?].

PMID- 10592891
TI  - [Neoadjuvant treatment of operable esophageal cancers].

PMID- 10592892
TI  - The pathogenesis of Kawasaki disease and superantigens.
AB  - Kawasaki disease (KD) is an acute febrile illness in infants and children with
      systemic clinical symptoms, including coronary artery aneurysms. Findings seen in
      KD patients such as infiltration of T cells into vascular lesions, elevation of
      soluble interleukin 2 receptors in serum, an imbalance of T cell subsets, and
      transient depletion of T cells with CD11/CD18 suggest that the activation of T
      cells is involved in the pathogenesis of KD. In 1992, an interesting mechanism
      was proposed in which T cell activation by a certain superantigen is involved in
      the pathogenesis of KD. Examinations have been undertaken extensively to confirm
      the proposed hypothesis. We, however, still do not have reliable evidence
      supporting the above hypothesis. In the present paper we review the research
      papers which support or rule out the view described above. In addition, we
      discuss the relation between KD and systemic Yersinia pseudotuberculosis
      infection that manifests clinical symptoms quite similar to those in KD.

PMID- 10592893
TI  - Genetic analysis of wild polioviruses towards the eradication of poliomyelitis
      from the Western Pacific Region.
AB  - Since a laboratory network to eradicate poliomyelitis in the Western Pacific
      Region started in 1991, the Department of Virology II, National Institute of
      Infectious Diseases, has been functioning as a Regional Reference Laboratory.
      From 1992 to 1998, we examined 5453 stool samples collected from 3501 patients
      with acute flaccid paralysis in Cambodia, Vietnam, and Laos, and we isolated 392
      type 1 and 10-type 3 wild polioviruses. As a result of the extensive immunization
      during this time in this area, the numbers of poliomyelitis cases by wild
      polioviruses have drastically decreased. In 1997, only nine type 1 wild
      polioviruses were isolated. Eight out of the nine cases were found in Cambodia,
      and one was in mid-Vietnam. Since then no wild polioviruses have been isolated in
      the Western Pacific Region for more than two years. A nucleotide sequence
      analysis of these 1997 isolates indicated that they all belonged to the same
      strain that has been prevailing in the Indochina area, suggesting the complete
      interruption of wild poliovirus transmission in the region.

PMID- 10592894
TI  - Laboratory diagnosis of dengue virus infection by reverse transcriptase
      polymerase chain reaction (RT-PCR) and IgM-capture enzyme-linked immunosorbent
      assay (ELISA).
AB  - Dengue virus infections are a major public health problem in most tropical and
      sub-tropical countries of the world. Dengue is occasionally imported by travelers
      who visit tropical areas and become infected with dengue virus. Laboratory
      diagnosis is essential for confirming the diagnosis of this virus. For purposes
      of confirmation, detection of specific IgM by IgM-capture enzyme-linked
      immunosorbent assay (ELISA) and of dengue virus genome by reverse transcriptase
      polymerase chain reaction (RT-PCR) have recently been used. In the present study,
      we tested serum specimens from dengue-suspected Japanese cases, by IgM-capture
      ELISA, RT-PCR, HI, and virus isolation. Serum samples collected before or on the
      day of defervescence were positive by RT-PCR, though no PCR-positive samples were
      obtained after fever day 1. IgM-capture ELISA was positive as early as disease
      day 4, and all samples but one were IgM-positive when collected on disease day 5
      or later. In light of these findings, we recommend that both RT-PCR and IgM
      capture ELISA be performed, irrespective of the stage of dengue illness.
      Combination of RT-PCR and IgM-capture ELISA increases the ability to diagnose
      dengue virus infection, even in the only that a single serum specimen from the
      patient is available.

PMID- 10592895
TI  - Monoclonal antibodies specific to carbohydrates of Echinococcus multilocularis.
AB  - To investigate the complexity of epitopes presented on Echinococcus
      multilocularis (E.m.) metacestode carbohydrates, a panel of monoclonal antibodies
      (MoAbs) was generated and characterized. Thirty of the clones were obtained and
      classified into three types (types I to III) based on Western blotting (WB) and
      dot-ELISA. One MoAb (type I) appeared to react with one of the carbohydrate
      antigens (C-antigens) located at 30-35 kDa, and was the most effective diagnostic
      antigen for human alveolar hydatid disease (AHD) in Hokkaido, Japan. The second
      group (15 clones) of MoAb (type II) reacted with another C-antigen; one which
      also induced antibody response in AHD patients. The third group (14 clones) of
      MoAb (type III) reacted with other C-antigens both in ELISA and dot-ELISA, but
      did not react in WB. Cross-reaction to the antigens of Echinococcus granulosus
      was faintly observed in only the type I-MoAb by dot-ELISA. In the
      immunohistological studies, all of the MoAbs reacted strongly with the laminated
      layer though not with protoscoleces in metacestode tissue prepared from
      experimentally infected cotton rats. Tissue sections treated with sodium
      periodate lost their immunoreactivity, suggesting that these MoAbs recognized
      carbohydrate epitopes of the E.m. metacestode.

PMID- 10592896
TI  - Phylogenic analysis of echovirus type 30 isolated from a large epidemic of
      aseptic meningitis in Japan during 1997-1998.
AB  - During 1997 to 1998, a nationwide epidemic of aseptic meningitis occurred in
      Japan. More than 4,500 isolates from patients with aseptic meningitis were
      identified as echovirus type 30. To investigate the character of these isolates,
      we examined the nucleotide sequences of thirty-seven geographical representatives
      and compared them with 50 strains isolated during the past 20 years. The
      phylogenic analysis used partial sequences from either the VP1 or VP4-VP2 region
      of the viral capsid. This analysis revealed that the isolates were divided into
      six genomic groups. All isolates identified during 1997-1998 belonged to only two
      genomic groups; these two groups are thought to be the causative viral agents
      involved in the recent epidemic.

PMID- 10592897
TI  - Difference of poliovirus isolation from stool specimens in different cell lines.

PMID- 10592898
TI  - Outbreaks of heat stable enterotoxin-producing Escherichia coli O169 in the Kinki
      district in Japan: epidemiological analysis by pulsed-field gel electrophoresis.

PMID- 10592899
TI  - Increase in heterosexually acquired AIDS among Japanese, 1986 to 1996.

PMID- 10592900
TI  - Sensitivity of cells to poliovirus.

PMID- 10592902
TI  - Measles outbreak in a junior high school in November-December 1998.

PMID- 10592901
TI  - Outbreak of acute gastroenteritis caused by human group C rotavirus in a primary
      school.

PMID- 10592903
TI  - Hepatitis A virus outbreak; a possible indicator of high risk sexual behavior
      among HIV-1 infected homosexual men.

PMID- 10592904
TI  - Two possible pathways for acquisition of mutations related to nelfinavir
      resistance.

PMID- 10592905
TI  - Saquinavir therapy in patients with the advanced HIV infection and liver
      cirrhosis.

PMID- 10592906
TI  - Virus survey in environmental waters in Miyagi Prefecture.

PMID- 10592907
TI  - More beds: more nosocomial infections.

PMID- 10592908
TI  - [Can radiology survive? Must radiology survive? "Chronicle of a death
      announced"].

PMID- 10592909
TI  - [Interventional MRI. Analysis of data and prospects].
AB  - In spite of its many advantages: 3D imaging, improved tissue characterization,
      and lack of ionizing radiation, interventional MRI remains seldom used. Several
      factors are involved. The purpose of this paper is to analyze the factors
      preventing or slowing the development of this technique based on a review of data
      from the literature, work presented at the second symposium on interventional MRI
      (Dusseldorf, 1997), and our own experimental data. The following elements will be
      discussed: difficulties related to image quality and open magnets, control of
      targeted image acquisitions, MR environment and problems related to asepsis, as
      well as advances of other techniques. Finally, short-term and mid-term
      perspectives will be presented. These are related to the goals of the technique:
      open or short bore closed magnets? MR unit installed in a radiology department?
      MR unit dedicated to interventional procedures only or mixed diagnostic
      interventional unit? interventional MR unit placed in a neurosurgery operating
      room? interventional MR unit installed in a general surgery operating room?

PMID- 10592910
TI  - [Web radiology servers: advices for users, their development and evaluation of
      the quality of sites].
AB  - Sites available on the Internet are constantly increasing and over 15,000 medical
      websites covering all medical sub-specialties are now available. Finding relevant
      information on the web may be time consuming and difficult. We suggest that new
      users begin by accessing servers where lists of available sites are grouped under
      headings such as medical sub-specialties. We will list a selection of useful
      radiological websites providing image databases, case reports, radiological
      anatomy and continuing medical education. While surfing on the web, an evaluation
      of the quality of the websites is necessary. We used the quality criteria
      proposed by Darmoni to rate the quality of ten websites. The overall quality was
      good, but the lack of help options and external links were the main pitfalls that
      we noted. All webmasters should pay attention to quality criteria and show the
      Darmoni criteria on their homepage. In order to evaluate which internet options
      should be developed, we evaluated our own website and submitted a questionnaire
      to our users. Clinical cases were the most requested feature, they could be used
      for continuing medical education.

PMID- 10592911
TI  - [RMI of dysfunctional temporomandibular joint (TMJ). Value of gradient-echo T1
      sequences in the evaluation of bony structures].
AB  - PURPOSE: To identify and classify the different types of bony changes of the
      condyles in patients with disorders of the temporomandibular joint (TMJ).
      MATERIALS AND METHODS: Since 1993, we have imaged over 600 patients with 0.5T MR
      unit by using gradient-echo T1-weighted sequences in the sagittal and coronal
      planes. RESULTS: We will first describe the appearance of the normal TMJ. Then,
      we will introduce the concept of "Condylo-diskal disunion" using a three grade
      classification system. We will then describe three patterns of condylar changes:
      adaptive remodeling, either anterior or more frequently posterior, degenerative
      lesions with subchondral sclerosis, erosive lesions due to synovial hyperplasia.
      CONCLUSION: Using a 0.5T MR unit, a GRE T1 sequence is useful to identify lesions
      of the disk and detect bony changes. In addition, the tissues posterior to the
      disk can also be assessed on postcontrast images.

PMID- 10592912
TI  - [Reduction of patient exposure by the use of digital luminescence radiography].
AB  - PURPOSE: To determine the minimum acceptable exposure for an adequate image
      quality using digital luminescence radiography (DLR) instead of screen-film
      system (SFS). MATERIAL AND METHODS: The impact of different physical and
      technical parameters on image quality and exposure was evaluated by obtaining
      radiographs of a test phantom. Conventional and digital radiographs of a humanoid
      phantom, an anatomical preparation or an animal were obtained using variable mAs.
      The image quality was rated by eight experienced radiologists using clinical
      criteria of image quality. The image quality evaluation was analysed using
      graphs. RESULTS: The exposure could be reduced by 60% for skull radiographs, 57%
      for abdominal radiographs, and 25% for chest radiographs of premature infants
      when using DLR instead of conventional SFS. CONCLUSION: DLR provides adequate
      image quality with reasonably low exposure.

PMID- 10592913
TI  - [Characterization of arterial stenosis using 3D imaging. Comparison of 3 imaging
      techniques (MRI, spiral CT and 3D DSA) and 4 display methods (MIP, SR, MPVR, VA)
      by using physical phantoms)].
AB  - INTRODUCTION: Accurate assessment of arterial stenosis is a major public health
      issue for the diagnosis and treatment of cardiovascular diseases. The number of
      imaging techniques and types of software for display of imaging data is
      increasing. Few studies that compare these different techniques are available in
      the literature. MATERIALS AND METHODS: Using phantoms to reproduce the main types
      of arterial stenosis, the authors compared three 3D acquisition techniques (MRA,
      CTA, and 3D DSA) and four types of display methods (MIP, SR, MPVR, and VA). The
      degree, the shape, and the location of different types of stenoses were analyzed
      by three experienced observers during two successive readings. Intra- and inter
      observer reproducibility were assessed. The results of the various acquisition
      techniques and display methods also were compared to the digital reference data
      (CFAO) of the physical phantoms. RESULTS: The degree of intra- and inter-observer
      reproducibility for the assessment of shape and location of the stenoses was
      good. Visual assessment of the degree of stenosis showed significant differences
      between two observers as well as in two readings by one observer. The 3D DSA was
      the most accurate technique for assessing the degree of stenosis. CTA provided
      better results than MRA. MPVR provided an accurate assessment of the degree of
      the stenosis. 3D DSA and CTA assessed stenosis form and localization adequately,
      with no significant difference; both methods appeared to be more accurate than
      MRA. SR provided the best information on the eccentric nature of the stenosis.
      The shape was very well assessed by VA and MPVR. CONCLUSIONS: Even though 3D DSA
      is the most accurate acquisition technique for visualization, the combined use of
      SR and MPVR appears to be the best compromise to describe the morphology and
      degree of stenosis. Further improvements in automatic 3D image processing could
      offer a better understanding and increased possibilities for assessing arterial
      stenosis.

PMID- 10592914
TI  - [US-guided percutaneous drainage of an infected epidermoid cyst of the spleen in
      a child].
AB  - Epidermoid cyst of the spleen is a rare entity (2.5% of all splenic cysts) and
      rarely becomes complicated by hemorrhage, rupture or infection. Classically,
      management consisted of total or partial splenectomy. We report the case of an 8
      year-old boy presenting with a splenic abscess complicating an epidermoid cyst.
      Percutaneous drainage of the abscess was performed under sonographic guidance and
      completed by intravenous antibiotic therapy. Six weeks later, laparoscopic
      surgery was performed and the splenic parenchyma could be preserved.

PMID- 10592915
TI  - [Erroneous diagnosis of subperiosteal osteoid osteoma: value of imaging
      techniques?].
AB  - A case of subperiosteal osteoid osteoma of the tibia misdiagnosed as stress
      fracture based on a history of multiple trauma and the results at MRI and bone
      scintigraphy is described. The nidus was well demonstrated at CT and the
      diagnosis was confirmed at histology. The role of different imaging techniques
      and their pitfalls are discussed.

PMID- 10592916
TI  - [Spinal fractures in ankylosing spondylarthritis. Apropos of 4 cases].
AB  - Fractures of the spine in patients with ankylosing spondylitis may be the result
      of minor trauma. They may lead to severe neurological deficits. They are
      difficult to detect on plain radiographs and CT or MRI often are required for
      diagnosis.

PMID- 10592917
TI  - [Diabetic fibrous mastopathy].
AB  - Diabetic fibrous mastopathy was first described in 1984. This mastopathy usually
      occurs in patients with autoimmune disorders and often occurs in patients with
      insulin-dependent diabetes. Little is known about this benign condition.
      Clinically and radiologically, this entity may simulate malignancy. The presence
      of an underlying auto-immune disorder or diabetes may suggest the correct
      diagnosis. The authors report two cases of fibrous mastopathy and suggest that
      core biopsy could replace surgical biopsy for diagnosis.

PMID- 10592918
TI  - [Quid? Primary bilateral adrenal lymphoma].

PMID- 10592919
TI  - [Spontaneous pneumorachis during sports exertion with a closed glottis].

PMID- 10592920
TI  - [Comments on the technical note, "Scanner-guided biopsy technic with abdominal
      compression"].

PMID- 10592922
TI  - Can dopamine prevent the renal side effects of indomethacin? A prospective
      randomized clinical study.
AB  - BACKGROUND: Indomethacin therapy for closure of a patent ductus arteriosus in
      preterm neonates is responsible for transient renal insufficiency. Dopamine
      theoretically reduces the renal side effects of indomethacin therapy. PATIENTS:
      33 neonates with a mean gestational age of 28.5 weeks who received indomethacin
      for treatment of a symptomatic PDA were included in a prospective randomized
      controlled clinical study. METHOD: 15 patients were treated with indomethacin
      alone (control group), 18 patients with indomethacin and dopamine (study group).
      Indomethacin was given in a dose of 0.2 mg/kg/dose intravenously, all patients
      received three doses with intervall of 12 hours. The dose of dopamine was in all
      patients 4 micrograms/kg per minute commencing 2 hours prior to the first dose of
      indomethacin and continuing for 12 hours after the third dose. RESULTS:
      Indomethacin induced a significant increase in serum creatinin (76.3 mumol/l vs
      99.7 mumol/l for the control group, and 70.7 mumol/l vs 93.0 mumol/l for the
      study group), and weight (1259 g vs 1316 g for the control group, and 1187 g vs
      1221 g for the study group). The increase systolic blood pressure (61 mmHg vs
      65.7 mmHg) in the study group was significant (p < 0.05) but remained unchanged
      in the control group. The changes between the study group and the control group
      were not significant either in serum creatinin, fractional excretion of sodium,
      or weight gain. The failure rate of ductal closure was not different between the
      two groups. CONCLUSION: The additional use of dopamine does not reduce the renal
      side effects of indomethacin.

PMID- 10592921
TI  - [Beta-thalassemia in Germany. Results of cooperative beta-thalassemia study].
AB  - At present, about 300 patients with thalassemia major are living in Germany.
      Starting in 1991, a multicenter study in Germany has concentrated on identifying
      all patients suffering from thalassemia as well as on establishing a uniform
      therapy protocol including follow-up diagnostic procedures. After six years of
      study, the data of 198 patients suffering from thalassaemia major were analysed.
      The majority of these patients originate from endemic regions around the
      Mediterranean Sea. The patient's median age is 13.8 years (range 1-37.5 yrs.). At
      present, about 20% of patients are older than 21 years. Regarding transfusion
      therapy, a shortening of the average transfusion interval to 3 weeks in most
      cases occurred. Throughout the entire period, median baseline haemoglobin
      concentrations of 10.0 g/dl could be observed. The evaluation of serum ferritin
      levels revealed considerable differences depending on patients age. 60% of
      patients in the first decade of life showed good therapeutic results with serum
      ferritin levels below 1800 ng/ml. In contrast, 52% of patients older than ten
      years presented with ferritin levels above 2500 ng/ml. During the observation, a
      decreasing number of patients with ferritin levels above 2500 ng/ml was observed
      in patients aged 15 to 21 years of age. The situation of patients aged 9 to 15
      years proved to be more problematic. More than half of all treated patients
      presented with siderotic complications as cardiac disease in 13%, liver disease
      in 21%, impaired glucose metabolism in 14%, hypothyroidism in 24% and
      hypogonadism in 59% of all patients. These values did not change considerably
      during the observation apart from an increase of cardiac disorders to 20%. Since
      the situation concerning siderosis and the lack of compliance proved to be
      particularly difficult in adolescent patients, further efforts has to concentrate
      on this age group.

PMID- 10592923
TI  - [Language development disorders in childhood: nonverbal intelligence and language
      comprehension].
AB  - 33 children with Specific Language Impairment (F 80, ICD 10) were randomly
      selected and their results regarding nonverbal intelligence, passive vocabulary
      and sentence comprehension were compared with data of 33 control children matched
      by age and sex. Although cognitive performance is average in both groups,
      significant differences regarding nonverbal intelligence are found. Whereas
      nonverbal intelligence is predictable from sentence comprehension to a high
      degree in den SLI-group, it is not predictable in the control group.

PMID- 10592924
TI  - [Verbal and nonverbal intelligence in children with language development
      disorders].
AB  - Difficulties in language acquisition seem to be serious, if there are additional
      problems like intellectual and/or emotional/social impairment, which are often
      reported [10]. These additional problems and the definition of specific language
      impairment as a developmental disorder, restricted to language acquisition seem
      to be contradictory [17]. Aim of that study is to look for specific language
      impaired children with similar cognitive abilities and though to investigate, if
      there are children without additional cognitive problems considering the
      definition of specific language impairment. 93 children, between 4;0 and 6;6
      years old, were diagnostized as specific language impaired (ICD-10) and were
      assessed by the "Hannover Wechsler Intelligenztest fur das Vorschulalter
      (HAWIVA)" [6] (german version of WPPSI). Cluster analysis showed, that 1/3 of the
      specific language impaired children presented no additional cognitive problems
      and 2/3 of them showed cognitive problems regarding nonverbal and verbal
      intelligence indeed. These additional cognitive problems indicate that there may
      be a more basic cognitive defect underlying specific language impairment [15]--at
      least for a group of specific language impaired children. Furthermore the
      nonverbal and verbal intellectual difficulties emphasize to general developmental
      support of specific language impaired children for optimal improvement in
      language acquisition.

PMID- 10592925
TI  - [Prophylaxis of respiratory syncytial virus (RSV) in preterm infants with/without
      bronchopulmonary dysplasia: hyperimmune globulin (RSV-IGIV) and palivizumab (MEDI
      493)].
AB  - Respiratory syncytial virus (RSV) causes seasonal epidemics between December and
      March (April) and remains the main agent that causes severe lower respiratory
      tract infections in young infants. Children with bronchopulmonary dysplasia up to
      24 months of age and preterm infants with a gestational age of 32 weeks and
      below, who are less than six months of age, are at highest risk for severe RSV
      infection. RSV-IGIV has been demonstrated to reduce significantly RSV associated
      hospitalizations, RSV associated hospital days and the incidence of severe RSV
      lower respiratory tract infections. Monthly infusions during RSV season were safe
      and well tolerated. Adverse events related to the hyperimmune globulin infusion
      were generally mild (< 3%) including fluid overload, decreased oxygen saturation
      and fever. Palivizumab, an intramuscularly administered humanized monoclonal
      antibody (RSV-glycoprotein-F antibody), will be preferable for the future because
      of ease of administration and comparable reduction in the risk of
      hospitalization. RSV-IGIV and palivizumab are both cost expansive and prophylaxis
      should be limited to high-risk infants.

PMID- 10592926
TI  - [Suspected SIDS and diagnosis of myocarditis].
AB  - BACKGROUND: During the last years immunohistochemical techniques have improved
      the diagnosis of myocarditis using specific markers for quantification of
      leucocytes and characterization of T-lymphocytes together with the definition of
      MHC class II Antigens (HLA-DP, DQ, DR), known to be enhanced in cases of
      myocarditis. These techniques allow the diagnosis of myocarditis in an early
      stage of the inflammatory process in contrast to the conventional diagnostic with
      hematoxylin-eosin. MATERIALS AND METHODS: 20 autopsy cases were examined in a
      retrospective study with conventional histological and immunohistological
      methods. After routine investigations including toxicological and histological
      examination of internal organs all cases were considered as cases of Sudden
      Infant Death Syndrome (SIDS). RESULTS: Increased number of LCA-positive
      leucocytes and CD-3-positive T-lymphocytes together with enhanced expression of
      inflammatory marker leads to the diagnosis of a lymphomonocytic myocarditis in
      three cases, in one case myocarditis could be diagnosed by conventional
      hematoxylin-eosin staining. In one of these four cases of myocarditis a positive
      immunohistochemical reaction was found using a new antibody against
      enteroviruses. CONCLUSION: Immunohistochemical techniques improve diagnosis of
      myocarditis in cases of suspected sudden infant death syndrome. Further studies
      using immunohistochemical inflammatory markers to control the incidence of acute
      myocarditis are necessary.

PMID- 10592927
TI  - [Polysaccharide specific humoral immunodeficiency in ectodermal dysplasia. Case
      report of a boy with two affected brothers].
AB  - We report a now three year old male patient with ectodermal dysplasia and a
      polysaccharide specific humoral immunodeficiency. Immunological investigations
      showed compromised production of IgA, IgM, and IgG2. Isohaemagglutinins still
      were not detectable at the age of three years. Repeated vaccination with
      polyvalent pneumococcal polysaccharide vaccine did not result in production of
      specific antibodies. Two brothers showed clinical signs of ectodermal dysplasia.
      The elder brother died from pneumococcal sepsis at the age of 3 years. The
      younger brother suffers from chronic inflammatory gastrointestinal disease with
      ulcerations in all parts of the gastrointestinal system. Thus, a possible
      association between polysaccharide specific humoral immunodeficiency and
      ectodermal dysplasia may be considered.

PMID- 10592928
TI  - [Fulminant diphtheria myocarditis in an unvaccinated preschool child].
AB  - We describe a case of a three year old unvaccinated child who developed a
      fulminant diphtheric myocarditis and nephritis four days after the onset of a
      tonsillar diphtheria. Despite of the administration of antitoxin on day three and
      four the child died within 48 hours from the beginning of rhythm disturbances.
      The cardiac involvement rapidly progressed from bradyarrhythmias with the
      necessity of a temporary pacemaker to ventricular rhythm disturbances with
      cardiac failure and final ventricular fibrillation.

PMID- 10592929
TI  - [Ventricular tachycardia after erythromycin administration in a newborn with
      congenital AV-block].
AB  - This report is on a newborn with congenital complete av-block due to a maternal
      collagenosis. The intravenous application of erythromycin produced premature
      ventricular beats and non sustained ventricular tachycardias by prolongation of
      the QT interval. After discontinuation of the erythromycin application, the QT
      interval normalised. CONCLUSION: In atrioventricular conduction disorders with
      severe bradycardia and prolongation of the QT interval, the application of
      erythromycin--if unavoidable--should be managed by slow intravenous infusion and
      with permanent ECG monitoring.

PMID- 10592930
TI  - [Acute erythromelalgia with hypertension in a 5-year old boy].
AB  - BACKGROUND: Burning pain of red and warm hands and/or feet are the classical
      symptoms of erythromelalgia. CASE REPORT: We describe the symptoms of acute
      idiopathic erythromelalgia and arterial hypertension in a five-year-old boy. Five
      days after a gastroenteritis the patient developed burning hands and feet in
      combination with arterial hypertension. Typically continuous cooling of all
      affected limbs was necessary to relieve the pain. Drug therapy with sodium
      nitroprusside only relieved the pain and dropped the blood pressure temporarily.
      Five weeks after onset of the disease all symptoms disappeared and the patient is
      still free of complaints (follow up period: 2 years). In the view of the
      presented case we discuss the differential diagnoses as well as therapeutical
      options.

PMID- 10592931
TI  - [Mamma aberrata in the axilla--case report and review of literature].
AB  - BACKGROUND: Polymastia is a common developmental abnormality of the breast.
      Supernumerary breast tissue usually develops along the mammary line. Polymastia
      in the most woman has been diagnosed by hormonal influence, cancer or other
      pathologic changes. PATIENTS: We report a localisation of polymastia in the
      axilla of a 14 year old girl. The lesion was removed to microscopic examination
      and to eliminate the possibility of a malignancy developing.

PMID- 10592933
TI  - [Primary glomerulonephritis with mesangial IgA deposits: what is new for an old
      disease?].

PMID- 10592932
TI  - [Practice guideline by the German Society for Pediatric Infectious Diseases with
      respect to prevention of RSV infections through immunoglobulin administration].

PMID- 10592934
TI  - [Renal K-ATPases: structure, function and dysfunction].
AB  - Na,K-ATPase and H,K-ATPase consist of two transmembrane proteins, the larger of
      which (catalytic subunit) exchanges extracellular K+ against intracellular Na+ or
      proton, at the expense of ATP hydrolysis. Cloning of four isoforms of Na,K-ATPase
      and two isoforms of H,K-ATPase has provided a molecular basis to the functional
      heterogeneity of these ATPases. Besides its house keeping functions, renal Na,K
      ATPase energizes most solute and water transports along the whole nephron. For
      this purpose, it utilizes about 80% of renal metabolic energy. H,K-ATPase, which
      is restricted to the renal collecting duct, has a more limited role: it energizes
      K+ reabsorption during hypokalemia and, along with H-ATPase, participates to
      acid/base homeostasis. Dysregulation of tubular Na,K-ATPase and H,K-ATPase are
      involved in physiopathological alterations. For examples, results are presented
      which show the relationships that exist between a) Na+ retention during
      experimental nephrotic syndrome and stimulation of collecting duct Na,K-ATPase,
      and b) kaliuretic effect of loop diuretics and inhibition of collecting duct H,K
      ATPase.

PMID- 10592935
TI  - [Tubular hypokalemia of genetic origin].
AB  - Recent progress in molecular genetics have improved our understanding of the
      pathophysiology of several inherited diseases characterized by a renal
      hypokalemia. Some of these diseases result from inactivating mutations on the
      main cotransports involved in the reabsorption of sodium, namely the Gitelman and
      Bartter syndromes, that clinically mimics diuretic abuse with mild hypovolemia
      and low or normal blood pressure. Conversely some affections eventually lead to
      an increase in sodium reabsorption with hypervolemia and arterial hypertension:
      Liddle syndrome, apparent mineralocorticoid excess and dexamethasone suppressible
      hyperaldosteronism.

PMID- 10592936
TI  - Chemokines and renal inflammation.
AB  - The appearance of inflammatory cells at the site of tissue injury is a hallmark
      of almost any renal disease. Infiltrating leukocytes mediate the initiation and
      progression of damage by direct cytotoxicity, the secretion of soluble factors,
      or by the regulation of the immune response. Particularly mononuclear phagocytes
      are present in almost any kidney disease and contribute to the development of
      injury (1, 2). Before leukocytes can exert their effects on renal damage or
      repair, they have to reach the site of injury. In the recent years, it has become
      clear that a group of small proteins called chemokines play a crucial role in the
      regulation of leukocyte trafficking and activation. In this review, we summarize
      the existent evidence that chemokines may act in the initiation of renal
      inflammation.

PMID- 10592937
TI  - [Hemodialysis and strongyloidiasis: a presumed cause of eosinophilia able to mask
      the other].
AB  - The authors report a case of recurrent strongyloidiasis in a former French
      soldier of the Indochina colonial war (1946-54). Strongyloidiasis was associated
      with inaugural renal failure (acute steroid-resistant interstitial-type),
      requiring permanent hemodialysis. Despite antiparasitic treatment, relapse with
      digestive and pulmonary symptoms occurred 10 years later, following chronic
      eosinophilia. This observation emphasises that in dialysed subjects, eosinophilia
      should always stimulate a search for parasitic etiologies before incriminating
      dialysis-material allergy. Strongyloidiasis is a self-perpetuating helminthiasis
      whose distribution area is far greater than the intertropical zone. It can be
      completely asymptomatic, appear as late digestive complications and be
      responsible for bacteraemic peaks with septic visceral localizations. It causes a
      chronic oscillating eosinophilia. Diagnosis is usually performed by iterative
      stool examinations by Baermann technique in order to detect Strongyloides
      stercoralis rhabditoid larvae. In dialysed patients with unexplained eosinophilia
      awaiting renal transplant, the options of systematic thiabendazole (50 mg/kg) or
      ivermectine (0.2 mg/kg) single-dose to overcame the risk of disseminated
      strongyloidiasis induced by immunosuppressive post-transplantation therapy could
      be debated.

PMID- 10592938
TI  - Effect of linear alkylbenzene sulphonate on topical absorption of chromium and
      nickel.
AB  - The effect of the topical applications of linear alkylbenzene sulphonate (LAS),
      or chromium (Cr) + nickel (Ni), or the combination of LAS + Cr + Ni for 30 d were
      investigated. Increased activities of aspartate amino transferase, alanine amino
      transferase, acid phosphatase and gamma glutamyl transpeptidase and decreased
      activity of superoxide dismutase occurred. Increased lipid peroxidation and
      decreased glutathione were observed. Accumulation of Cr and Ni increased in
      tissues. Biochemical alterations and metal accumulations were more marked in the
      Cr + Ni + LAS group.

PMID- 10592939
TI  - Effects of amitraz given by different routes on rats.
AB  - Three-mo-old male Wistar rats were sprayed with 250, 500, 1000 and 2000 ppm
      amitraz 2 w apart or given single doses of 50, 100, or 250 mg/kg p.o, i.m. or
      i.p. No effects were observed in the amitraz-sprayed rats. Single doses of
      amitraz p.o, i.m. or i.p. was non-toxic at 50 mg/kg, toxic at 100 mg/kg and
      lethal at 250 mg/kg within 24 h of dosing. Survivors were killed 48 h post
      dosing. Features of toxicity were depression, incoordination of movement, paresis
      of the limbs, hepatonephrotoxicity, muscular hemorrhage at site of injection and
      peritonitis following i.p. injection. These changes, accompanied by leucopenia,
      were correlated with alterations in serum AST and concentrations of serum
      constituents. Amitraz did not inhibit serum ChE activity.

PMID- 10592940
TI  - Toxicokinetics and oral bioavailability of fumonisin B1.
AB  - The kinetics of fumonisin B1 (FB1) after single doses of 10 mg FB1/kg (po) or 2
      mg FB1/kg (i.v.) were studied in male Wistar rats. Serial blood samples were
      obtained after p.o and i.v. administration. Liver and kidney tissue samples were
      also obtained after p.o administration. Plasma, liver and kidney concentrations
      of FB1 were determined by a reversed-phase high-performance liquid
      chromatographic assay using precolumn 0-phthaldialdehyde derivatisation with
      fluorescence detection. The FB1 plasma profile could be adequately described by a
      2-compartment open model. For FB1, the elimination half-life from plasma was 1.03
      h after i.v. and 3.15 h after p.o administration. The apparent volume of
      distribution and volume of distribution at steady state for FB1 were 0.11 and
      0.072 L, respectively, after i.v. administration. The total plasma clearance of
      FB1 was the same for both the p.o and i.v. routes, 0.072 L/h. After the single
      p.o dose, FB1 was rapidly absorbed with a Tmax of 1.02 h. The maximum plasma
      concentration of FB1 was 0.18 microgram/mL. The p.o bioavailability of FB1 was
      3.5%. The tissue concentration time data for FB1 fit a 1-compartment open model.
      Considerable concentrations of FB1 were found in the liver and kidney tissues.
      The elimination half-lives for FB1 were longer for liver (4.07 h) and kidney
      (7.07 h) than for plasma (3.15 h). Tissue accumulation of FB1 was evidenced by
      the tissue/plasma area under the concentration-time curve (AUC) ratios; the
      AUCtissue/AUCplasma for FB1 was 2.03 in liver and 29.89 in kidney.

PMID- 10592941
TI  - Ammoniated forage poisoning: acute toxicity of newly identified dialkylimidazoles
      to inbred mice.
AB  - The i.p. acute toxicity of the dialkylimidazoles 1,2-dimethylimidazole, 1,4
      dimethylimidazole, 1,5-dimethylimidazole, 2,4-dimethylimidazole and 2-ethyl-4
      methylimidazole was investigated in C57B1 female mice, and compared to the
      toxicity of 4-methylimidazole (4-MI). An approximate median lethal dose protocol
      was applied designed to obtain a qualitative description of the clinical toxic
      effects and an estimate of the acute lethal dose with the use of a minimal number
      of animals. The approximate median lethal dose of the dialkylimidazoles varied
      from slightly above to 3-times greater than that of 4-MI. 1,4-Dimethylimidazole
      and 1,5-dimethylimidazole had tremorogenic and convulsive effects qualitatively
      similar to those of 4-MI. Testing a mixture of alkylimidazoles comparable to the
      composition found in toxic ammoniated forage or milk did not indicate any
      synergistic enhancement of the toxicity to mice.

PMID- 10592942
TI  - Tilapia (Oreochromis niloticus) and rodents exhibit similar patterns of inhibited
      antibody production following exposure to immunotoxic chemicals.
AB  - The hemolytic plaque forming cell assay (PFC), a measure of ability to produce
      specific antibodies following challenge with antigen, is a powerful predictor of
      immunosuppression in chemical-exposed rodents. The efficacy of this assay for
      predicting humoral immunosuppression in non-rodent species remains unknown. In
      the present report, tilapia (Oreochromis niloticus) were exposed to 9 chemical
      agents known to inhibit antibody production in mice (benzo[a]pyrene, 7,12
      dimethylbenzanthracene, 2,3,7,8-tetrachlorodibenzo-p-dioxin, dimethyl
      nitrosamine, cadmium chloride, azathioprine, hexachlorocyclohexane, T2 mycotoxin
      and toluene) and 5 chemical agents which do not inhibit this response
      (oxymethalone, acetonitrile, diethylstilbesterol, t-butylhydroquinone and
      formaldehyde). Eight of 9 agents which inhibit antibody production in rodents
      caused decreased PFC responses in fish. All 5 compounds with negative humoral
      effects in rodents were also negative in fish. Thus, 13/14 chemical agents tested
      gave similar results in tilapia as reported in rodents, suggesting a comparable
      pattern of humoral immunosuppression in chemical-exposed tilapia to that seen in
      laboratory rodent models.

PMID- 10592943
TI  - Mercury concentrations in scalp hair as an environmental contamination index from
      foods in Korea.
AB  - Relationships have been established between the mercury (Hg) levels in human
      scalp hair and environmental or dietary mercury exposures. The average value of
      total mercury (THg) in scalp hair of male residents in Seoul city was 1.66 +/-
      1.10 ppm (+/- SD) and for methylmercury (MeHg) was 1.02 +/- 0.72 ppm (61% of
      total Hg). For females, THg was 1.06 +/- 0.46 ppm and MeHg was 0.51 +/- 0.27 ppm
      (48.8% of total Hg). The levels of Hg in scalp hair of male subjects were
      significantly different according to their occupations and age groups, but in
      females such variation was not detectable. The Hg levels in fishing village
      residents were significantly higher than those of Seoul residents. The
      concentrations of both THg and MeHg of residents in Korean fishing villages were
      similar to those of residents in fishing villages of other countries. Correlation
      between THg and MeHg contents in scalp hair was statistically highly significant.

PMID- 10592944
TI  - Severe uvular angioedema caused by intranasal administration of Ecbalium
      elaterium.
AB  - A 54-y-o woman presented to the Emergency Department with shortness of breath and
      sore throat after intranasal administration of Ecbalium elaterium as a folk
      remedy for her sinusitis. The patient's history included nasal aspiration of the
      juice of the squirting cucumber (Ecbalium elaterium) for acute maxillary
      sinusitis. An airway obstruction due to severe uvular angioedema was detected and
      confirmed by airway X-ray. The patient was treated with 100% oxygen with mask,
      0.3 mg epinephrine s.c., and 80 mg prednisolone i.v. Renal and hepatic function
      tests were normal. After a 24-h observation, the patient was discharged in her
      previous state of health.

PMID- 10592945
TI  - Optic neuropathy in sheep associated with overdosage of closantel.
AB  - This report describes clinical and pathological findings in 2 flocks in Brazil
      where blindness and deaths in sheep occurred after closantel overdosage.
      Depression, weakness, and blindness affected 37 animals and 17 died in 2 flocks
      of 190 animals. Two animals submitted for ophthalmic examination showed no
      inflammation in the anterior segment of both eyes; posterior segment evaluation
      by indirect ophthalmoscopy suggested retinal degeneration. One postmortem
      evaluation local spongy vacuolization was in several regions of the brain and the
      optical nerves had severe axonal degeneration.

PMID- 10592946
TI  - Severe rhabdomyolysis following massive ingestion of oolong tea: caffeine
      intoxication with coexisting hyponatremia.
AB  - A 36-y-o patient with schizophrenia, who had consumed gradually increasing
      quantities of oolong tea that eventually reached 15 L each day, became delirious
      and was admitted to a psychiatric hospital. After abstinence from oolong tea his
      delirium resolved. He was transferred to our hospital when he was discovered to
      have acute renal failure with hyponatremia (118 mEq/L) and severe rhabdomyolysis
      (creatine phosphokinase, 227,200 IU/L). On admission rhabdomyolysis had begun to
      improve despite a worsening of the hyponatremia (113 mEq/L). With aggressive
      supportive therapy, including hypertonic saline administration and hemodialysis,
      the patient fully recovered without detectable sequelae. The clinical course
      suggests that caffeine, which is present in oolong tea, was mainly responsible
      for the rhabdomyolysis as well as the delirium, although severe hyponatremia has
      been reported to cause rhabdomyolysis on rare occasions. We hypothesize that
      caffeine toxicity injured the muscle cells, which were fragile due to the
      potassium depletion induced by the coexisting hyponatremia, to result in
      unusually severe rhabdomyolysis. The possibility of severe rhabdomyolysis should
      be considered in a patient with water intoxication due to massive ingestion of
      caffeine-containing beverages.

PMID- 10592947
TI  - Monensin poisoning in Brazilian horses.
AB  - Three outbreaks of monensin poisoning caused 12 deaths in 16 horses. The
      illnesses were associated with the ingestion of the same batch of a commercial
      ration labeled for feeder calves which contained 180 +/- 20 ppm sodium monensin.
      The morbidity rate was 100% and lethality was 60%, 75%, and 100%. Clinical signs
      were tachycardia and cardiac arrythmia, groaning, incoordination, sudoresis,
      recumbency, and paddling movements with the limbs before death. Two horses had
      dark discolored urine (myoglobinuria). Serum levels of creatine phosphokinase
      activity were increased. Main necropsy findings were in the skeletal muscles and
      myocardium.

PMID- 10592948
TI  - An apparently gluten-induced photosensitivity in horses.
AB  - Primary photosensitization was observed in 3 Appaloosa mares. The skin lesions
      were diffuse erythema followed by edema and subsequently weeping and finally dry
      gangrene and ulceration. The severe photosensitivity dermatitis was apparently
      induced by gluten ingestion. Resolution of lesions occurred after withdrawal of
      the suspected dairy concentrate feed and prevention of exposure to sunlight.
      Neither the ponies nor donkey, which were not fed with the suspected concentrate,
      exhibited similar skin lesions or other clinical abnormalities. Gluten
      metabolites may contain photodynamic agents that cause photosensitization in
      horses.

PMID- 10592949
TI  - Clinical nuances of pediatric methadone intoxication.
AB  - Pediatric methadone intoxication may present with clinically unusual findings
      which could cause confusion to the inexperienced practitioner. We present a case
      of pediatric methadone overdose, address clinical nuances pertinent to these
      overdoses, and discuss measures aimed at limiting these potentially catastrophic
      exposures.

PMID- 10592950
TI  - Fatal privet (Ligustrum amurease) toxicosis in Tennessee cows.
AB  - Five of 24 cows pastured in a 40-acre field in east Tennessee died after they
      consumed leaves from a privet (Ligustrum amurease) hedge. Clinical findings
      included ataxia, recumbency with an inability to stand, depression, greenish
      nasal discharge, cessation of rumination, normal body temperature, and increased
      heart and respiratory rates. Differential diagnoses included grass tetany,
      nitrate toxicosis, and plant toxicosis. Privet toxicosis was confirmed by finding
      privet in ruminal contents, by the presence of a large quantity of privet in the
      field, by observing places where this privet had been eaten by the cows, by the
      immediate cessation of the problem when the cows were removed from the field, and
      by observing no recurrent problems after the privet was destroyed with a
      herbicide and the cows were returned to the field.

PMID- 10592951
TI  - Lead and cadmium concentrations in milk and blood of Indian cows with mastitis.
AB  - Mean milk lead in cows with clinical or subclinical mastitis was 0.35 +/- 0.03 or
      0.42 +/- 0.04 ppm whereas cadmium was 0.16 +/- 0.01 or 0.15 +/- 0.01 ppm.
      Concentrations in blood were 0.45 +/- 0.05 lead or 0.08 +/- 0.05 ppm cadmium in
      clinical and 0.47 +/- 0.06 lead or 0.088 +/- 0.001 ppm cadmium in subclinical
      mastitic cows.

PMID- 10592952
TI  - Should home ipecac-induced emesis be routinely recommended in the management of
      toxic berry ingestions?
AB  - Poison center (PC) management of toxic berry ingestions may include
      recommendations to administer syrup of ipecac (SI) regardless of the number of
      berries ingested. We investigated whether the routine use of SI in the home
      management of asymptomatic single or few (< 6) berry ingestions may be
      unnecessary. A prospective, randomized clinical trial compared SI + home
      observation (HO) to HO alone for management of pediatric toxic berry ingestions.
      Subjects were children 9 mo to 5 y who ingested a small number (< 6) of Taxus sp
      (yew), Solanum americanus (nightshade), Ilex sp (holly) or unknown potentially
      toxic berries. Exclusions were symptomatic subjects, ingestion of more than 1
      type of berry or other plant part, or contraindication to SI. Outcome variables
      consisting of symptom assessment and disposition were assessed 24 h following the
      ingestion. Over a 27-mo period 103 subjects were entered into the study; 45
      received SI/HO and 51 received only HO. While 100% of the SI/HO group experienced
      vomiting, none of the HO group vomited. Diarrhea and sedation were more common in
      the SI/HO group. Use of SI in the home management of young children who ingest
      fewer than 6 toxic berries (yew, nightshade, holly or unknown) and who are
      asymptomatic when the PC is contacted may be responsible for the majority of
      symptoms. Ingestion of small amounts of berries may require no intervention
      beyond observation. Methodological limitations of this study included the lack of
      confirmed identification of the berries and the inability to confirm ingestion
      and absorption.

PMID- 10592953
TI  - Reproducibility of medical information obtained via the telephone vs personal
      interview.
AB  - The Motherisk [corrected] Program, a teratogenic information service, conducts
      patient interviews over the telephone as well as in a clinic setting. In both
      instances, medical information and exposure history is obtained from the patient,
      including such items as pregnancy history, drug exposure, alcohol and smoking
      habits. It occurred on several occasions that the clinic interviewer remarked
      that the same patient had volunteered information to them, that differed from the
      information documented on the intake telephone form. The objective of the study
      was to establish the levels of agreement in the documentation, between these two
      forms of interviews. Two groups of 100 paired telephone and clinic forms were
      randomly selected from our data base, 1990-1991 and 1996-1997. These two groups
      were chosen to assess if there were any differences over a five year time period.
      Statistical calculations were performed using the Kappa statistic, a method that
      measures agreement. Kappa scores indicated high reproducibility for both
      pregnancy and smoking history, good reproducibility for medical history, marginal
      good for exposures (although excellent agreement was found for the primary drug
      of concern) and marginal-good for alcohol information. Overall, agreement was
      superior in the 1990-1991 group. There were marked differences in consistency,
      between the information recorded on the telephone form and the clinic form, most
      specifically relating to secondary exposures and alcohol history. It suggests
      that a person to person interview yields a more complete medical history than a
      telephone interview.

PMID- 10592954
TI  - Role of US poison centers in adverse drug reactions monitoring.
AB  - Poison centers are a valuable source of adverse drug reaction reporting in the US
      based on their ready access, familiarity with adverse events, the training of
      staff health care professionals, and computerized case documentation. During
      1997, 35,563 suspected adverse drug reactions were reported by poison centers to
      their national database. Of these, 71% involved individuals over 19 y of age, 62%
      were treated at a non-health care facility, 64% experienced no effect or a minor
      effect, and 6% were potentially symptomatic but lost to follow-up. There were 18
      fatalities. Although US poison centers currently provide input to reporting
      adverse drug reactions, the data collection system could be better integrated
      with the FDA MedWatch spontaneous adverse drug reactions reporting program on a
      more systematic basis to allow greater input and harmonization of the 2 datasets.

PMID- 10592955
TI  - Ethylene glycol exposures managed by the ASPCA National Animal Poison Control
      Center from July 1995 to December 1997.
AB  - Five-hundred and ten cases of ethylene glycol (EG) exposures in animals were
      compiled by the ASPCA National Animal Poison Control Center from July 1995
      through December 1997. Case distribution was analyzed by species, sex, age,
      weight, seasonality, treatment intervention and final outcome. Dogs and cats were
      most commonly involved (98.0%). The sex distribution was approximately equal.
      Adult animals accounted for the majority of cases. Exposures were commonly
      (57.0%) from container spill, engine flush, or engine leak and were in or around
      the home (66.0%). Cases were reported throughout the year with slight increase
      during March-May. Among cases with a known final outcome, 59.0% did not show
      clinical signs and death/euthanasia, major and minor illness was reported in
      28.0%, 5.0% and 8.0%. In view of the widespread use and potential toxicity of EG,
      the low number of EG exposures reported (510) among the total number of hazardous
      exposures (97,383) to all substances for the same period was remarkable. The EG
      exposures resulting in animal death/euthanasia were lower than previously
      published.

PMID- 10592956
TI  - Suspected Vipera palaestinae envenomation in three cats.

PMID- 10592957
TI  - [About the role of University].

PMID- 10592958
TI  - [Melatonin and time zone transition].

PMID- 10592959
TI  - [Management of terminal cancer patients in Tampere].

PMID- 10592961
TI  - [Datura x candida intoxication].

PMID- 10592960
TI  - [Ocular findings associated to the use of amiodarone].

PMID- 10592962
TI  - [About the hazards concerning over the counter prescription drugs].

PMID- 10592963
TI  - [Abdominal pain and hemorrhagic ascites].

PMID- 10592964
TI  - [Jenner and Pirjo].

PMID- 10592965
TI  - [Finland as a model country for vaccination].

PMID- 10592966
TI  - [How to focus on vaccination, who to vaccinate].

PMID- 10592967
TI  - [Towards Chlamydia Pneumoniae vaccination].

PMID- 10592968
TI  - [Meningococcal vaccine development].

PMID- 10592969
TI  - [Immunogenicity of Haemophilus Influenzae].

PMID- 10592970
TI  - [Clinical evaluation of new vaccines].

PMID- 10592972
TI  - [How to define nosocomial infections?].

PMID- 10592971
TI  - [Vaccine development in developing countries].

PMID- 10592973
TI  - [Who is responsible for hospital infections?].

PMID- 10592974
TI  - [Is the surveillance of hospital-acquired infections adequate in Finland?].

PMID- 10592975
TI  - [Does MRSA invade hospitals in Finland?].

PMID- 10592976
TI  - [Importance and prevention of hospital acquired infections].

PMID- 10592977
TI  - [Outbreak of nosocomial infections].

PMID- 10592978
TI  - [The role of microbiological laboratory in detection and control of nosocomial
      infections].

PMID- 10592979
TI  - [Multiresistance microbes and antimicrobial antibiotic policy in Finland].

PMID- 10592980
TI  - [In what circumstances are nosocomial infections considered malpractice?].

PMID- 10592981
TI  - [Prophylactic administration of antibiotics in surgery].

PMID- 10592982
TI  - [Surgical wound infections].

PMID- 10592983
TI  - [Nosocomial pneumonia].

PMID- 10592984
TI  - [Hospital acquired septicemia].

PMID- 10592985
TI  - [Pediatric nosocomial infections].

PMID- 10592986
TI  - [The future and antimicrobial resistance].

PMID- 10592987
TI  - [Strain variation of morbillivirus, a threat for humans].

PMID- 10592988
TI  - [Applied relaxation in psychiatry and behavioral therapy].

PMID- 10592989
TI  - [Boron neuron capture therapy in the treatment of brain tumors].

PMID- 10592990
TI  - [Neural tube defects and folic acid].

PMID- 10592991
TI  - [Folic acid and neural tube defect].

PMID- 10592992
TI  - [Nutritional status of hemodialysis patients].

PMID- 10592993
TI  - [Guidelines in clinical practice].

PMID- 10592994
TI  - [Portal venous thrombosis as a complication, following appendicitis].

PMID- 10592995
TI  - [Auditory evoked response, monitoring patient during reconstructive surgery of
      aortic dissection].

PMID- 10592996
TI  - [Rhabdomyosarcoma in the middle ear of a three year old male].

PMID- 10592997
TI  - [Relapsing polychondritis].

PMID- 10592998
TI  - [Safe administration of new drugs].

PMID- 10592999
TI  - [Multiple sclerosis with several symptoms of a 48 old female].

PMID- 10593000
TI  - [Debriefing in Finnish].

PMID- 10593001
TI  - [Patients in menopause].

PMID- 10593002
TI  - [Menopausal hormone replacement therapy and quality of life].

PMID- 10593003
TI  - [The cost-effectiveness of hormonal replacement therapy].

PMID- 10593004
TI  - [The endocrinological and physiological changes in menopause].

PMID- 10593005
TI  - [Sexual functions and menopause].

PMID- 10593006
TI  - [The psychiatric aspects in menopause].

PMID- 10593007
TI  - [Who benefits from hormonal therapy in menopause?].

PMID- 10593008
TI  - [The administration of hormonal replacement therapy].

PMID- 10593009
TI  - [How to start and maintain hormonal replacement therapy].

PMID- 10593010
TI  - [Cardiovascular effects of estrogen replacement therapy].

PMID- 10593011
TI  - [The role of progestin in menopausal hormonal replacement therapy].

PMID- 10593013
TI  - [Does menopausal hormonal replacement therapy increase the risk of breast
      cancer?].

PMID- 10593012
TI  - [The use of estrogen in the treatment of menopausal skin and urogenital
      diseases].

PMID- 10593014
TI  - [Alternative therapies in menopause].

PMID- 10593015
TI  - [Do male patients benefit from androgen replacement therapy?].

PMID- 10593016
TI  - [Cloning of human G-CSF genomic gene and its expression in transgenic mice
      mammary gland].
AB  - Human genomic DNA was used as template of PCR. 1.5 kb G-CSF genomic DNA was
      obtained using PCR amplification method. Sequence analysis showed that genomic
      DNA sequence of human G-CSF was correct. The vector of mammary gland expression
      was constructed and contained whey acid protein (WAP) 5' control region directed
      human G-CSF genomic DNA. In order to produce transgenic mice, 1200 fertilized
      eggs were microninjected using WAP-G-CSF fragment. Two male transgenic mice were
      obtained and identified using PCR method and Southern analysis. Integration rate
      of human G-CSF gene was 2.37% in mice. Foreign gene could also be identified in
      F1 and F2 transgenic mice. Expression levels of human G-CSF in transgenic mouse
      milk were 120-250 ng/ml.

PMID- 10593017
TI  - [Cloning and secretory expression of soluble interleukin-6 receptor gene in
      Streptomyces lividans].
AB  - With the total RNA extracted from HeLa cells as templates of retrotranscription,
      the 1,017 bp cDNA fragment of human soluble Interleukin 6 receptor (sIL-6R) was
      amplified by RT-PCR technique. The amplified cDNA fragment was cloned into
      plasmid pUC19 for DNA sequence analysis. The result showed that the cDNA fragment
      is identical to natural sIL-6R encoding sequence reported before. The sIL-6R cDNA
      was fused with melC1 signal peptide encoding sequence. The fusion gene (mel/sIL
      6R) was inserted into Streptomyces plasmid pIJ459. Both Southern blot analysis
      and restriction enzymatic analysis proved that the sIL-6R cDNA has been inserted
      into pIJ459 and the recombinant plasmid was named pIJ459-mel/sIL-6R. pIJ459
      mel/sIL-6R was transformed into S. lividans TK54 and got the recombinant strain
      S. lividans [pIJ459-mel/sIL-6R]. SDS-PAGE and receptor-ligand binding assay show
      that sIL-6R was expressed by this strain and the maximum level is at 72 h. It was
      also proved that the recombinant sIL-6R has biological activity of binding IL-6.

PMID- 10593018
TI  - [HLA-DQ molecules associated with myasthenia gravis in Chinese patients].
AB  - Myasthenia Gravis (MG) is an autoimmune disease which is a neuromuscular disorder
      of autoimmune origin. MG in different races or ethnic groups has different
      genetic susceptibility. To search for the associations of MG in the Chinese
      patients with HLA-DQ molecules, PCR-RFLP method was employed for genotyping HLA
      DQA1 and -DQB1 genes of MG patients and the normal Chinese. The distributions of
      alleles of DQA1 and DQB1 in the normal Chinese and the MG patients were listed.
      The DQB allele, DQB1 * 0302 was positively associated with MG (RR = 2.990, Pc =
      0.0307), and a negative association was found for DQA1 * 0501 (RR = 0.4166, Pc =
      0.0315). DQ haplotype DQA1 * 0301-DQB1 * 0302 was significantly increased in
      patients when compared to controls (RR = 7.727, Pc = 0.0109).

PMID- 10593019
TI  - [A nasopharyngeal carcinoma negatively related EST on 7q32].
AB  - To isolate and clone the tumor suppressor gene on chromosomal region 7q32 that
      corelated with the occurrence of human NPC, we detected the genotype of
      polymorphic microsatellite markers on 7q32 in 24 nasopharyngeal carcinoma
      biopsies and matched normal lymphocyte DNA. LOH was found in 30% biopsies. Using
      differential RT-PCR and Northern hybridization we compared the expression level
      of 20 EST on 7q32 between NPC cell line HNE1 and primary culture of normal
      nasopharyngeal epithelial cell, and found AA070437 EST expressed high in primary
      culture of normal nasopharyngeal epithelial cell, but very low in HNE1.
      Differential RT-PCR (dRT-PCR) analysis showed that the expression level of
      AA070437 was lower in 30.7% NPC biopses than in normal cell. Differential PCR
      (dPCR) showed that allelic loss of AA070437 was observed in 29.1% NPC biopses.
      This EST is a part of sequence of a new gene compared with GeneBank database. Our
      results showed that AA070437 EST negatively related with the occurrence of human
      NPC is a candidate of tumor suppressor gene of NPC on 7q32.

PMID- 10593020
TI  - [Studies of the correlations between DNA fingerprints and meat production traits
      in chickens].
AB  - This study revealed correlations between DNA fingerprints (DFPs) and slaughter
      traits of SR92A male x Xiaoshan female hybrids with EAV (endogenous avian
      retroviral element) as the probe. In the DFP patterns, the band J with molecular
      weight of about 4 kilobasepairs correlated significantly with alive weight,
      dressing weight, semi-eviscerated weight, talon weight, breast muscle weight,
      head weight and thigh weight. The mean alive weight, dressing weight, semi
      eviscerated weight and breast muscle weight are 280 g (28.57%), 225 g (28.87%),
      216 g (28.76%) and 16.71 g (54.00%) higher respectively in individuals without
      band J than in those with band J. With the following formula: delta W = (XJ(-) -
      XJ+) x N x FJ+, it was estimated that an addition of 165.2 kilograms of alive
      weight can be achieved in a hybrid population with size of 1,000 chickens
      established by selecting parents without band J.

PMID- 10593021
TI  - [Binding and interaction of histones and transcription factors on the promoter of
      hAMFR gene].
AB  - In this study, histone H1, core histones H2A-H2B and H3-H4 were purified from
      chicken erythrocytes by hydroxylapatile chromatography. The nuclear extract was
      prepared from HeLa cells. We investigated the binding and interaction of histones
      and transcription factors on the upstream sequence of human autocrine motility
      factor receptor (hAMFR) gene by gel shift mobility assay. We found that the
      binding of H1 on the promoter sequence of hAMFR gene was relatively stable. We
      propose that H1 plays an important role in stablizing chromatosome. We also found
      that histones and HeLa cell extract could form a ternary complex with the DNA
      template.

PMID- 10593022
TI  - [Mitochondrial DNA genetic polymorphism of Drosophila immigrans in China].
AB  - This article uses RFLP to analyze the mitochondrial DNA(mtDNA) variation in
      geographic populations of Drosophila immigrans from 6 regions of mainland of
      China. With the use of fourteen restriction endonucleases, we only discoveried a
      total of 11 mtDNA haplotypes among 46 isofemale lines. The mean value of I is
      0.833, the mean value of J is 0.797, and the estimated Gst value is only 16.8%.
      We recognized that the genetic structures among the geographic populations of D.
      immigrans are highly uniform, and the genetic differentiation rate is low. The
      UPGMA analysis of nucleotide diversity of the 6 populations shows specific
      characteristics of mtDNA variation in population of Huayang, Qinling Mountains
      Regions. From the haplotypes special included in each population, the event that
      the population spread into the high altitute localities of Yunnan perhaps
      happened more recently. Referring other references, we inferred the population of
      D. immigrans distributed in mainland of China is more original than that in
      Chinese Taiwan and Japan.

PMID- 10593023
TI  - [Correlation analysis of (G + C)% of coding sequence and thermostability of
      xylose isomerase of thermophiles].
AB  - Statistical analysis about amino acids and coding sequence of xylose isomerase
      were performed in a number of thermophiles and mesophiles. It was found that
      there are correlations between the (G + C)% of the coding sequence and that of
      1st, 2nd and 3rd position of the code of amino acids. There were also positive
      (for hydrophobic amino acids) and negative (for hydrophilic amino acids)
      correlation between the content of individual amino acids in the enzyme protein
      and the (G + C)% of their respective coding sequence. It speaks for the notion
      that high content of (G + C) in the coding sequence tends to increase the
      thermostability of the corresponding protein. The results in the statistical
      analysis of amino acid substitutions leading to change in thermostability of the
      protein may also be interpreted in the same way. An increase in the (G + C)% of
      DNA of a bacterium can therefore not only increase the thermostability of DNA
      itself but its proteins as well. Evolutionary consequence concerning thermophily
      and coding system are discussed.

PMID- 10593024
TI  - [Cloning and sequences comparison of promoters from Aspergillus niger].
AB  - An Aspergillus niger (A. niger) genomic library was constructed in a promoter
      trap vector, which contains a Hygromycin B (Hy) phosphotransferase-encoding gene
      (hph) and screened for DNA fragments with promoter activity by applying the sib
      selection procedure. A functional promoter PX27 was identified. Both DNA strands
      of this fragment were sequenced and showed no significant homology to the
      sequence already in the database. Comparison of the sequences of all known
      promoters from A. niger revealed a consensus CTTCTC, as a novel motif of the A.
      niger promoters.

PMID- 10593025
TI  - Injection safety: a global challenge.

PMID- 10593026
TI  - Unsafe injections in the developing world and transmission of bloodborne
      pathogens: a review.
AB  - Unsafe injections are suspected to occur routinely in developing countries. We
      carried out a literature review to quantify the prevalence of unsafe injections
      and to assess the disease burden of bloodborne infections attributable to this
      practice. Quantitative information on injection use and unsafe injections
      (defined as the reuse of syringe or needle between patients without
      sterilization) was obtained by reviewing the published literature and unpublished
      WHO reports. The transmissibility of hepatitis B and C viruses and human
      immunodeficiency virus (HIV) was estimated using data from studies of needle
      stick injuries. Finally, all epidemiological studies that linked unsafe
      injections and bloodborne infections were evaluated to assess the attributable
      burden of bloodborne infections. It was estimated that each person in the
      developing world receives 1.5 injections per year on average. However,
      institutionalized children, and children and adults who are ill or hospitalized,
      including those infected with HIV, are often exposed to 10-100 times as many
      injections. An average of 95% of all injections are therapeutic, the majority of
      which were judged to be unnecessary. At least 50% of injections were unsafe in 14
      of 19 countries (representing five developing world regions) for which data were
      available. Eighteen studies reported a convincing link between unsafe injections
      and the transmission of hepatitis B and C, HIV, Ebola and Lassa virus infections
      and malaria. Five studies attributed 20-80% of all new hepatitis B infections to
      unsafe injections, while three implicated unsafe injections as a major mode of
      transmission of hepatitis C. In conclusion, unsafe injections occur routinely in
      most developing world regions, implying a significant potential for the
      transmission of any bloodborne pathogen. Unsafe injections currently account for
      a significant proportion of all new hepatitis B and C infections. This situation
      needs to be addressed immediately, as a political and policy issue, with
      responsibilities clearly defined at the global, country and community levels.

PMID- 10593027
TI  - Transmission of hepatitis B, hepatitis C and human immunodeficiency viruses
      through unsafe injections in the developing world: model-based regional
      estimates.
AB  - Thousands of millions of injections are delivered every year in developing
      countries, many of them unsafe, and the transmission of certain bloodborne
      pathogens via this route is thought to be a major public health problem. In this
      article we report global and regional estimates of the number of hepatitis B
      virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV)
      infections that may occur from unsafe injections in the developing world. The
      estimates were determined using quantitative data on unsafe injection practices,
      transmission efficiency and disease burden of HBV, HCV and HIV and the prevalence
      of injection use obtained from a review of the literature. A simple mass-action
      model was used consisting of a generalized linear equation with variables
      accounting for the prevalence of a pathogen in a population, susceptibility of a
      population, transmission efficiency of the pathogen, proportion of injections
      that are unsafe, and the number of injections received. The model was applied to
      world census data to generate conservative estimates of incidence of transmission
      of bloodborne pathogens that may be attributable to unsafe injections. The model
      suggests that approximately 8-16 million HBV, 2.3-4.7 million HCV and 80,000
      160,000 HIV infections may result every year from unsafe injections. The
      estimated range for HBV infections is in accordance with several epidemiological
      studies that attributed at least 20% of all new HBV infections to unsafe
      injections in developing countries. Our results suggest that unsafe injections
      may lead to a high number of infections with bloodborne pathogens. A major
      initiative is therefore needed to improve injection safety and decrease injection
      overuse in many countries.

PMID- 10593028
TI  - The cost of unsafe injections.
AB  - Unsafe injection practices are associated with substantial morbidity and
      mortality, particularly from hepatitis B and C and human immunodeficiency virus
      (HIV) infections. These inadvertently transmitted bloodborne diseases become
      manifest some considerable time after infection and hence may not be
      appropriately accounted for. Annually more than 1.3 million deaths and US$ 535
      million are estimated to be due to current unsafe injection practices. With the
      global increase in the number of injections for vaccination and medical services,
      safer injecting technologies such as auto-disable syringes must be budgeted for.
      Investment in health education and safer disposal will also reduce infections
      associated with unsafe injecting practices. Safer injecting practices are more
      expensive than current less safe practices, but the additional cost is more than
      offset by the reduction in disease that would result.

PMID- 10593029
TI  - Sterilizable syringes: excessive risk or cost-effective option?
AB  - In recent years, many poorer countries have chosen to use disposable instead of
      sterilizable syringes. Unfortunately, the infrastructure and management systems
      that are vital if disposables are to be used safely do not exist. WHO estimates
      that up to 30% of injections administered are unsafe. The traditional
      sterilizable syringe had many disadvantages, some of which have been minimized
      through better design and the use of modern materials; others have been overcome
      because staff are able to demonstrate that they have performed safely. For
      example, the time-steam saturation-temperature (TST) indicator has enabled staff
      to demonstrate that a sterilizing cycle has been successfully completed. Health
      facility staff must be able to sterilize equipment, and the sterilizable syringe
      remains the least costly means of administering an injection. Data from countries
      that have acceptable systems for processing clinical waste indicate that safe and
      environmentally acceptable disposal, destruction and final containment cost
      nearly as much as the original cost of a disposable syringe. By careful
      supervision of staff behaviour and good management, some countries have
      demonstrated that they are able to administer safe injections with sterilizable
      syringes at a price they can afford.

PMID- 10593030
TI  - Influenza A virus recycling revisited.
AB  - Current textbooks link influenza pandemics to influenza A virus subtypes H2 (1889
      91), H3 (1990), H1 (1918-20), H2 (1957-58) and H3 (1968), a pattern suggesting
      subtype recycling in humans. Since H1 reappeared in 1977, whatever its origin,
      some workers feel that H2 is the next pandemic candidate. This report reviews the
      publications on which the concept of influenza A virus subtype recycling is based
      and concludes that the data are inconsistent with the purported sequence of
      events. The three influenza pandemics prior to 1957-58 were linked with subtypes
      through retrospective studies of sera from the elderly, or through
      seroarchaeology. The pandemic seroarchaeological model for subtype H1 has been
      validated by the recent recovery of swine virus RNA fragments from persons who
      died from influenza in 1918. Application of the model to pre-existing H3 antibody
      among the elderly links the H3 subtype to the pandemic of 1889-91, not that of
      1900 as popularly quoted. Application of the model to pre-existing H2 antibody
      among the elderly fails to confirm that this subtype caused a pandemic in the
      late 1800's, a finding which is consistent with age-related excess mortality
      patterns during the pandemics of 1957 (H2) and 1968 (H3). H2 variants should be
      included in pandemic planning for a number of reasons, but not because of
      evidence of recycling. It is not known when the next pandemic will occur or which
      of the 15 (or more) haemagglutinin subtypes will be involved. Effective global
      surveillance remains the key to influenza preparedness.

PMID- 10593031
TI  - Quantitative bacterial examination of domestic water supplies in the Lesotho
      Highlands: water quality, sanitation, and village health.
AB  - Reported are the results of an examination of domestic water supplies for
      microbial contamination in the Lesotho Highlands, the site of a 20-year-old
      hydroelectric project, as part of a regional epidemiological survey of baseline
      health, nutritional and environmental parameters. The population's hygiene and
      health behaviour were also studied. A total of 72 village water sources were
      classified as unimproved (n = 23), semi-improved (n = 37), or improved (n = 12).
      Based on the estimation of total coliforms, which is a nonspecific bacterial
      indicator of water quality, all unimproved and semi-improved water sources would
      be considered as not potable. Escherichia coli, a more precise indicator of
      faecal pollution, was absent (P < 0.001) in most of the improved water sources.
      Among 588 queried households, only 38% had access to an "improved" water supply.
      Sanitation was a serious problem, e.g. fewer than 5% of villagers used latrines
      and 18% of under-5-year-olds had suffered a recent diarrhoeal illness. The study
      demonstrates that protection of water sources can improve the hygienic quality of
      rural water supplies, where disinfection is not feasible. Our findings support
      the WHO recommendation that E. coli should be the principal microbial indicator
      for portability of untreated water. Strategies for developing safe water and
      sanitation systems must include public health education in hygiene and water
      source protection, practical methods and standards for water quality monitoring,
      and a resource centre for project information to facilitate programme evaluation
      and planning.

PMID- 10593032
TI  - Mass vaccination with a two-dose oral cholera vaccine in a refugee camp.
AB  - In refugee settings, the use of cholera vaccines is controversial since a mass
      vaccination campaign might disrupt other priority interventions. We therefore
      conducted a study to assess the feasibility of such a campaign using a two-dose
      oral cholera vaccine in a refugee camp. The campaign, using killed whole
      cell/recombinant B-subunit cholera vaccine, was carried out in October 1997 among
      44,000 south Sudanese refugees in Uganda. Outcome variables included the number
      of doses administered, the drop-out rate between the two rounds, the proportion
      of vaccine wasted, the speed of administration, the cost of the campaign, and the
      vaccine coverage. Overall, 63,220 doses of vaccine were administered. At best,
      200 vaccine doses were administered per vaccination site and per hour. The direct
      cost of the campaign amounted to US$ 14,655, not including the vaccine itself.
      Vaccine coverage, based on vaccination cards, was 83.0% and 75.9% for the first
      and second rounds, respectively. Mass vaccination of a large refugee population
      with an oral cholera vaccine therefore proved to be feasible. A pre-emptive
      vaccination strategy could be considered in stable refugee settings and in urban
      slums in high-risk areas. However, the potential cost of the vaccine and the
      absence of quickly accessible stockpiles are major drawbacks for its large-scale
      use.

PMID- 10593033
TI  - Infant immunization coverage in Italy: estimates by simultaneous EPI cluster
      surveys of regions. ICONA Study Group.
AB  - In 1998, a series of regional cluster surveys (the ICONA Study) was conducted
      simultaneously in 19 out of the 20 regions in Italy to estimate the mandatory
      immunization coverage of children aged 12-24 months with oral poliovirus (OPV),
      diphtheria-tetanus (DT) and viral hepatitis B (HBV) vaccines, as well as optional
      immunization coverage with pertussis, measles and Haemophilus influenzae b (Hib)
      vaccines. The study children were born in 1996 and selected from birth registries
      using the Expanded Programme of Immunization (EPI) cluster sampling technique.
      Interviews with parents were conducted to determine each child's immunization
      status and the reasons for any missed or delayed vaccinations. The study
      population comprised 4310 children aged 12-24 months. Coverage for both mandatory
      and optional vaccinations differed by region. The overall coverage for mandatory
      vaccines (OPV, DT and HBV) exceeded 94%, but only 79% had been vaccinated in
      accord with the recommended schedule (i.e. during the first year of life).
      Immunization coverage for pertussis increased from 40% (1993 survey) to 88%, but
      measles coverage (56%) remained inadequate for controlling the disease; Hib
      coverage was 20%. These results confirm that in Italy the coverage of only
      mandatory immunizations is satisfactory. Pertussis immunization coverage has
      improved dramatically since the introduction of acellular vaccines. A greater
      effort to educate parents and physicians is still needed to improve the coverage
      of optional vaccinations in all regions.

PMID- 10593035
TI  - Antimicrobial resistance: the importance of developing long-term policy.

PMID- 10593034
TI  - Treatment in Kenyan rural health facilities: projected drug costs using the WHO
      UNICEF integrated management of childhood illness (IMCI) guidelines.
AB  - Guidelines for the integrated management of childhood illness (IMCI) in
      peripheral health facilities have been developed by WHO and UNICEF to improve the
      recognition and treatment of common causes of childhood death. To evaluate the
      impact of the guidelines on treatment costs, we compared the cost of drugs
      actually prescribed to a sample of 747 sick children aged 2-59 months in rural
      health facilities in western Kenya with the cost of drugs had the children been
      managed using the IMCI guidelines. The average cost of drugs actually prescribed
      per child was US$ 0.44 (1996 US$). Antibiotics were the most costly component,
      with phenoxymethylpenicillin syrup accounting for 59% of the cost of all the
      drugs prescribed. Of the 295 prescriptions for phenoxymethylpenicillin syrup, 223
      (76%) were for treatment of colds or cough. The cost of drugs that would have
      been prescribed had the same children been managed with the IMCI guidelines
      ranged from US$ 0.16 per patient (based on a formulary of larger-dose tablets and
      a home remedy for cough) to US$ 0.39 per patient (based on a formulary of syrups
      or paediatric-dose tablets and a commercial cough preparation). Treatment of
      coughs and colds with antibiotics is not recommended in the Kenyan or in the IMCI
      guidelines. Compliance with existing treatment guidelines for the management of
      acute respiratory infections would have halved the cost of the drugs prescribed.
      The estimated cost of the drugs needed to treat children using the IMCI
      guidelines was less than the cost of the drugs actually prescribed, but varied
      considerably depending on the dosage forms and whether a commercial cough
      preparation was used.

PMID- 10593036
TI  - Towards safe management of health care waste in Bangalore City.

PMID- 10593037
TI  - [Developments and prospects of the public health service in Bavaria].
AB  - Public Health Services in Bavaria are presently undergoing basic and complete
      reorganisation. A working group of the Bavarian Ministry of Labour, Social
      Problems, Family, Women and Health is compiling a report and working out a far
      reaching concept of the tasks to be handled by Public Health Offices. The purpose
      of this work is to develop a profile of an update and efficient Public Health
      organisation. This entails not only description and definition of the jobs to be
      handled but also a delineation against other medical disciplines. Closer ties to
      research institutions and intensifying the exchange of expert knowledge with
      universities and other expert institutions is highly essential. Only if all
      professional groups represented in the Public Health organisation are called upon
      to cooperate, will it be possible to translate into reality a profile of tasks
      encompassing both the classical areas of activity such as infection hygiene and
      update requirements of the quality of management and research abilities such as a
      thorough knowledge of epidemiology. The interdisciplinary approach that can be
      realised in Public Health Offices enables teamwork in the development of
      approaches to solving a multitude of problems of a medical but mainly also of a
      social or environmental nature. This potential must be exploited and expanded.
      2.9.99/D1.

PMID- 10593038
TI  - [Definition and requirements of health].
AB  - Health is conceptualized as an ability to cope. Health is dependent on how well
      the personal and the social system are adapted to each other. The person
      environment interaction itself is shaped by culture and social structure and
      their consequences for the living and working conditions.

PMID- 10593039
TI  - [Health objectives--chances for modern health policy].
AB  - If politicians, citizens, decision makers, patients and scientists develop health
      objectives they aim at a specific health outcome in a certain period of time.
      They intend thereby to improve the health of the population, quality of life, and
      quality-adjusted life expectancy as well as to assign resources more effectively
      to achieve a certain outcome. As health goals should be realistic and achievable
      participation and cooperation of citizens, patients, politicians, and scientists
      appears to be of crucial importance. The primary goals should not be mixed up
      with the ways, steps, processes and structures that are only tools to achieve the
      goals. A profound comprehension and valid data of the health status in the
      population and, where possible, projection computations are an important basis
      for the development of health goals. While health policy generally may be a
      defensive business, health objectives offer the chance of shaping future health,
      of acting instead of reacting.

PMID- 10593040
TI  - [Promoting health instead of health education].
AB  - The idea of health education--meaning experts telling laymen how to setup a
      healthy behaviour by applying educational tricks--is an illusion. Humans don't
      act as they should by following the ideas of public health scientists, not even
      after an intensive educational training. They aren't trivial machines. Their way
      of acting ist not predeterminable. A change of strategy from health promotion to
      changing the attitude to health promotion to random circumstances of living has
      been of limited success. Changing these circumstances (top down) improves only a
      part of health influencing factors. It is impossible to exclude that by changing
      these factors others are made worse. But by ethic standards we are titled to
      check decisions relating to living conditions in respect of their health
      relevance. Therefore, health promotion meaning the promotion of more self
      determination of one's own health is inevitable if a sustainable success is
      wanted. The request for a short-time measure of success is understandable from an
      economic point of view but it is not adequate. In the long run this would lead to
      trivilaesation++ of matters that are not trivial.

PMID- 10593041
TI  - [Rate of absenteeism--value and modification by work disability data].
AB  - Data on pre-retirement invalidity and incapacity to work are simple process-data
      gathered from routine procedures within our social system. It is therefore an
      obvious step to use them in describing the prevalent morbidity and relations
      between work and the incidence of illnesses. However, closer examinations have
      shown that the analysis of such secondary data does not provide particularly well
      founded results, especially regarding causal relations between work itself and
      the so-called work-related diseases. All in all, the rate of incapacity for work
      is a product of illness, personal well-being, individual attitude towards work,
      and the social environment. The latter is influenced in particular by the
      management and organisational structures within a company. Therefore, few of the
      programmes designed to reduce the rate of incapacity to work have any great
      effect. They aim at the symptoms without really tackling the real causes. Low
      rates of incapacity to work accompanied by a lasting improvement in the overall
      productivity of the whole staff can only be achieved by a organisational culture
      that is based on raising motivation, personal well-being, and health.

PMID- 10593042
TI  - [Sex-specific drug abuse prevention in adolescence].
AB  - Several studies are discovering differences in how boys and girls use tobacco,
      alcohol, and other drugs. In general, boys and girls differ in the intensity and
      the quality of drug use. Male adolescents report higher usage of drugs than
      female adolescents do (exception: medication). However, there are only few
      prevention programmes with integrated sex-specific strategies. The few existing
      girl-specific and boy-specific prevention programmes focus on strain and
      deficits. Drug consumption is considered a result of inadequate socialisation and
      development of boys and girls. New preventive strategies are therefore based on
      interactional and functional concepts. In this perspective health-related
      behaviour can be regarded in respect of its differential functionality for girls
      and boys. Drug use is considered to be a sex-specific attempt to express
      femininity or masculinity. Sex-specific drug prevention develops different
      strategies for same-sex and opposite-sex groups in order to meet varying needs
      and to take the differential functionality of drug consumption into account.

PMID- 10593043
TI  - [Medical and legal aspects of child abuse].

PMID- 10593044
TI  - [Meningococcal infections: aspects of microbiology, epidemiology and prevention].
AB  - Neisseria meningitidis (meningococcus) is responsible for an average of 40% of
      all cases of bacterial meningitis in Germany. Cerebrospinal fluids, blood
      cultures, throat swabs and scratches, aspirations and biopsies of the skin rash
      are appropriate materials for the diagnosis of meningococcal disease. The
      materials should reach the laboratory without delay. Since 1993, the incidence of
      meningococcal disease in Germany is less than 1 case per 100,000 inhabitants. The
      case fatality rate is about 10%. Most cases of meningococcal disease occur in the
      first quarter of the year. Almost half of all invasive N. meningitidis isolates
      are from children under five years of age. In the period 1990-1998, in Germany an
      average of 74% of cases were caused by serogroup B and 21% by serogroup C. In
      serogroup B disease, isolates of serotype 15, in group C disease strains of
      serotype 2a are predominating. Chemoprophylaxis should be given to all household
      members and all contacts living in institutions with household-like character,
      contacts in institutions for children under six years of age and all persons who
      had contact with the oropharyngeal secretions of the patient. At present, only
      capsular polysaccharide vaccines against serogroups A, C, Y and W135 are
      available for immunoprophylaxis in Germany.

PMID- 10593045
TI  - [New knowledge of the molecular biology of enterohemorrhagic Escherichia coli
      (EHEC) O157].
AB  - Since 1982, enterohaemorrhagic Escherichia coli (EHEC) have been identified as a
      cause of diarrhoea and haemorrhagic colitis. The most serious complication of the
      infection is the haemolytic-uraemic syndrome (HUS) that develops in 5 to 10% of
      children with diarrhoea. Shiga toxins (Stx) are the most important presently
      known virulence factors of EHEC. After reaching the bloodstream, the toxins cause
      damage of endothelial cells but also of tubular cells in the kidneys which may
      result in renal failure. In EHEC O157 isolates from patients, we were able to
      identify seven different combinations of stx genes that occurred with different
      frequency. The genes encoding Stx are located in the genomes of prophages that
      are integrated in EHEC chromosomes. In addition, EHEC O157 strains possess a
      chromosomally located pathogenicity island (pais) termed LEE that contains
      numerous pathogenicity genes including the eae gene encoding intimin. Moreover,
      EHEC O157 strains possess a 93-kb plasmid harbouring genes encoding the EHEC
      hemolysin (EHEC-HlyA), a serin protease (EspP) that cleaves factor V and a
      protein called ToxB that shows homology with the toxin B of Clostridium
      difficile. The EHEC O157 strains exist in two variants, namely non-sorbitol
      fermenting (NSF) O157:H7 and sorbitol-fermenting (SF) O157:H- strains that are
      evolutionary older. Our results obtained up to now demonstrate marked differences
      in epidemiology of the infection caused by the respective EHEC O157 variants.
      EHEC O157:H7 strains occur worldwide, whereas SF strains have been hitherto found
      only in Germany and recently also in the Czech Republic. While the EHEC O157:H7
      strains occur mainly during warm months, the SF strains are more frequent during
      the cold season of the year. In addition, differences exist with regard to the
      resistance to heavy metals, the plasmid structure, and the reservoir. We
      postulate that SF O157:H- strains occur only in the human intestine, whereas NSF
      O157:H7 strains have become adapted to other hosts, such as cattle, promoting a
      more rapid spread of the strains.

PMID- 10593046
TI  - [Indoor air pollution: current aspects].
AB  - Due to the high percentage of time spent indoors, indoor air contributes
      significantly to human exposure via inhalation. Up to now, toxicology-based
      guideline values for indoor air pollutants are very sparse. Examples are the WHO
      Air Quality Guidelines for Europe or guideline values published by an ad-hoc
      group formed from members of the Indoor Air Commission of the Federal German
      Environmental Agency and of the Environmental Hygiene Committee of the Consortium
      of German Health Ministries of the German "Leander" (provincial governments). By
      comparison with recent representative data referring to comparable indoor
      environments, rooms with unusually high concentrations can be identified.
      However, this is not an adequate basis for health risk assessment.

PMID- 10593047
TI  - [Realm and goals of social epidemiology. A contribution to determining current
      status in relation to German language discussion].
AB  - A first approach to the word "social epidemiology" is provided by the two
      components social and epidemiology. They suggest that the social dimension of the
      distribution of morbidity and mortality should be analysed by means of
      epidemiological methods. The interest in this topic has risen considerably in
      recent years, but it is difficult to exactly specify the questions "social
      epidemiologists" are analysing or should be analysing. That is why the "Social
      Epidemiology Working Group" is now reviewing the state of the art of social
      epidemiology discussions in the German-speaking countries. The overview shows the
      broad spectrum of social epidemiology topics, but also the difficulties in
      providing a clear definition. In a brief description of the Anglo-American
      discussion it is pointed out that social epidemiology have to deal with similar
      problems there, and that they classify their work as epidemiology rather than
      social epidemiology. The paper concludes with recommendations by the Working
      Group concerning the main topics and objectives of current socio-epidemiological
      research.

PMID- 10593048
TI  - [Basic principles and justification of drug policy].
AB  - In the international context drug policy is defined as a prohibitive control
      regime equipped with government functions. A possible extension has led to
      conflicts within the member states of the international drug control, resulting
      in two opposite positions: (1) A prohibitive line adhering to a ban of narcotic
      drugs, applying prosecution not only against dealers but also consumers and
      organizing help for drug addicts only to end drug abuse and not for any
      controlled consumption; (2) a permissive line aiming at a more or less controlled
      liberation of the use of narcotic drugs, limiting prosecution at the most to
      organized drug dealing, generally attempting to "decriminalize" the consumption,
      and finally to define heroine as a possible legal help for drug-addicts. The
      conflict concerning a new definition of national politics on drugs finds most
      public attention in Switzerland, where the government (Bundesrat) tries to follow
      a middle-of-the-road policy. Present German policy of the leftist federal
      government favors the Swiss paradigm; but Federal states like Bavaria under a
      conservative government still oppose this attitude.

PMID- 10593049
TI  - [10 years development in the treatment of opiate dependent patients in the
      Kaufbeuren district hospital].
AB  - Discussing drug abuse and the concept of "low-threshold" in the treatment of drug
      addicts, we investigated development of detoxification strategies in the
      Department of Psychiatry at Kaufbeuren during the last 10 years. In the following
      we describe 4 different phases of this development: In 1988 we admitted 34 opiate
      dependent patients treated in general psychiatric units. In 1998 almost, 1,000
      drug addicts were treated in specialised drug detoxification units. In the
      beginning we realised opiate detoxification treatment without medication. In the
      second phase we treated the subjects symptomatically. During the last four years
      we have been offering homologue opiate withdrawal with L-polamidone. Last year we
      extended the opiate detoxification treatment to the day hospital and outpatient
      setting. The comparative examination of patient moods during the so called
      qualified and the homologue splitted opiate withdrawal treatment shows amazing
      similarities regarding the oscillations, leaving out of account that the
      remarkable worsening after one week of drug assisted detoxification was seen one
      week later in the homologue splitted detoxification group.

PMID- 10593050
TI  - [Reduction in malformation-related early mortality--a possibility for modifying
      perinatal mortality].
AB  - From 1980 to 1996 1.8% of all births died as a result of malformations during the
      first week of life. This rate has been declining significantly after 1992.
      Congenital malformations of the heart have increased significantly because of
      improved diagnostic methods. From 1980 to 1996 0.67/1000 of all children died of
      vitium cordis during the first week of life. From 1992 to 1996 this group of
      malformations increased the perinatal mortality rate by 0.4/1000. There is a
      decreased mortality rate of neural tube defects by 0.25/1000 1980 to 1986 and by
      0.08/1000 1992 to 1996. Trisomy 21: the early mortality rate decreased from
      0.07/1000 to 0.03/1000. The number of non-deceased children with Down's syndrome
      remains constant, even though 40 per cent of all cases with trisomy 21 were
      prenatal. 3 per cent of all malformed newborn died during the first week of life
      as a result of their congenital malformations. The possibility of primary
      prevention of malformations with folic acid has not been sufficiently utilised.

PMID- 10593051
TI  - [Real and irrelevant risks of infection by swimming in recreational bodies of
      water].
AB  - Life-threatening infectious diseases associated with recreational water exposure
      are possible but occur very rarely. About eighty per cent of all infections due
      to bathing water produced gastroenteritis, the remaining were spontaneously
      healing infections of ear, nose and throat as well as eye and respiratory
      symptoms. They are caused by endogenic and exogenic agents. The risk, i.e. the
      mean frequency of such commonplace diseases associated with bathing or swimming
      is already doubled by endogenic infectious agents even without any etiological
      agents in the recreational water. The additional risk by exogenic infectious
      agents increases with the concentration of fecal markers. The prescribed limit E
      coli value of 200 CFU per 100 ml of the EU guidelines for bathing waters
      corresponds to a risk increased by the factor 7-8. The Bathing Water Committee of
      the German Federal Environmental Agency issued new recommendations prescribing
      severely lowered limit values. For example, the Committee called for 100 CFU of
      E. coli per 100 ml. However, there are economical and legal objections as well as
      doubts regarding the Committee's scientific competence. The lower limit values
      are associated with high expenses for communities and bathers without
      recognizable returns in terms of efficiency. Furthermore, they offend against the
      legal principle of equality because newly constructed pools are not different
      from bathing water regulated according to EU guidelines. Finally, the Bathing
      Water Committee holds scientifically incorrect views on infectious agents and on
      the risks in recreational waters.

PMID- 10593052
TI  - [Problem-based learning (POL) in environmental medicine].
AB  - "Environmental medicine" is a new sub-discipline in the spectrum of medical
      specialization in Germany. The Berlin Academy of Occupational Medicine and Health
      Protection, now a branch of the Berlin Chamber of Physicians, developed a 200
      lesson curriculum for physicians who want to specialize in this field.
      Coincidentally during the initial courses, the attendants were already highly
      qualified ("Facharzt"-level) and experts in various occupational fields, and
      hence the composition of the classes was highly heterogeneous on the levels of
      practical experience as well as theoretical knowledge. The Academy therefore
      decided to change the teaching method to Problem-Oriented Learning (POL). This
      required training tutors for small learning groups, supervision for these tutors
      and supplying adequate teaching materials and a stimulating environment for the
      student. The "Arbeitsgruppe Reformstudiengang Medizin" (Medicine Curriculum
      Reform Project) at the Berlin Humboldt University as well as the Dutch
      Rijksuniversiteit Limburg in Maastricht helped in the process of
      conceptualization. Participants worked in groups of up to 8 persons under non
      directive tutors. A new "case" was presented every day, and the students
      developed individual learning goals according to the Seven Steps-method, which
      were then researched individually and with the help of outside experts. The
      findings were reported back and discussed in the group. Initially there was
      irritation, but after two or three days participants got used to not being
      lectured. Instead of being passive recipients of expert knowledge they felt that
      the POL method of learning enhanced their competence to act independently.

PMID- 10593053
TI  - ["Managed care in Germany--social rights and economic aspects of possible
      adoption"].

PMID- 10593054
TI  - A developmental perspective of depression--towards a novel formulation.
AB  - A novel conceptualization of depression, analyzed in a developmental frame of
      reference, is based on three major postulates: 1) the distinction between an
      anaclitic type of depression, triggered by the traumatic loss of a need
      satisfying object, and depression of a reflexive (narcissistic) type, caused by
      the loss of a recognizing/mirroring object; 2) in principle, anaclitic object
      loss involves reflexive implications and vice versa; 3) very early breaks of
      object relationships, at the first symbiotic stage of life, are pre-narcissistic
      by nature. These three assumptions form the basis for a systematic juxtaposition
      of two developmental lines--one line from first-stage symbiosis to anaclitic
      object relations, and the second line--from second-stage symbiosis to reflexive
      object relations. Even though the two lines are closely intertwined,
      corresponding distinct forms of depressive reactions can be discerned in each
      line, according to the type of the lost object relationship.

PMID- 10593055
TI  - Deprivation and abstinence in psychoanalytic psychotherapy.
AB  - Freud used the concept of "abstinence" in relation to the patient-therapist
      relationship, and saw "deprivation" as a motivating force in the treatment. Later
      authors related to "deprivation" and "abstinence" in different terms. Kleinians
      tend to emphasize the non-gratifying approach, designed to produce transference
      of all kinds; Bion suggests that an atmosphere of deprivation and abstinence in
      the psychoanalytic treatment allows for an "intuitive" approach to mental events
      and phenomena; Kohut points at abstinence as a structuring aspect in the
      patient's personality; but he also speaks about optimal frustration. Winnicott
      recommends, in the treatment of people who suffered severe "holding" deprivation,
      maximum adjustment of the therapeutic setting to the patient's needs. Deprivation
      and abstinence, in this respect, apply to the therapist; but, on the other hand,
      a state of "holding" in the treatment allows the patient to experience severe
      deprivations and anxieties. This paper also discusses the extent to which wishes
      and needs are satisfied in the treatment as well as the causes for unnecessary
      abstinence and deprivation which are due to the therapist's mistakes or failures.
      Inspired mainly by Winnicott's spirit, this paper also deals with the paradoxes
      all therapists must face in their work.

PMID- 10593056
TI  - Does family therapy need psychiatrists? Do psychiatrists need family therapy?
AB  - BACKGROUND: While many sufferers from mental health problems require a
      therapeutic approach that can see the patient in his systemic context without
      losing sight of pathology that is located in the individual, few in fact receive
      such treatment. DATA: The therapy of an individual and of his family is presented
      by way of illustration of the above point. CONCLUSION: Clinical experience
      suggests that trainees in psychiatry (and other mental health professions) should
      be expected to reach a level of proficiency in family therapy at least equal to
      that expected of them in the various individual approaches; benefits would accrue
      to themselves, to the profession, to family therapy and, most importantly, to
      their patients.

PMID- 10593057
TI  - Manic defences in a mourning process of a group of adolescents.
AB  - This paper describes the central role of manic defences in the process of working
      through mourning in a group of bereaved adolescents. Two factors were found to
      facilitate the effective use of manic defences in working through mourning in the
      group: (a) manic defences were given a legitimate and important place in the
      group, and were regarded as agents of life in the ongoing dealings with death;
      and (b) a certain degree of introspection was always maintained, like a window
      not allowed to be shut completely, to allow an attenuated encounter with
      difficult emotions. The use of manic defences, combined with these two factors,
      allowed flexible two-way movement between the schizoparanoid and the depressive
      positions, hence facilitated the working through of mourning in the group. The
      process described in this paper took place in a group of bereaved adolescents.
      Twenty sessions of one and a half hours were directed by two clinical
      psychologists, as part of the support offered by the Department of Rehabilitation
      of the Israeli Ministry of Defence to bereaved families in Israel.

PMID- 10593058
TI  - Trichotillomania and the mourning process: a case report and review of the
      psychodynamics.
AB  - We present our theory of trichotillomania (hair pulling) as a manic phenomenon,
      complementary to its classic comprehension as a mourning response. Under certain
      conditions, separation or threat of separation can generate sadness or grief,
      while in pathological cases, when the loss is experienced as unbearable, the
      response might be depressive or manic. We suggest that in trichotillomania (TR),
      like in mania, manic defenses are used to cope with separation. We believe hair
      pulling is an expression of primary magical thinking, offering the subject an
      illusion of control and victory over the object. A representative case of a young
      woman suffering from bipolar disorder with TR is described. Based on our case
      analysis, we argue that TR may not necessarily be a variant of OCD, but rather
      classified among the affective disorders.

PMID- 10593059
TI  - Self-envy and the concealment of inner resources.
AB  - Self-envy refers to envy of one's own inner resources. This term is an adjunct to
      the psychodynamic understanding of developmental self-arrest, defined as
      deliberate and defensive impairment of one's own abilities and accomplishments
      and the concealment of inner resources. The article suggests possible
      explanations for the formation of self-envy, emphasizing the formation of envious
      object representations and the construction of a part of the personality based on
      these introjections. The effects of self-envy on patient therapist relations are
      also described, focusing on two particular manifestations: attachment to the
      therapist as a defense against self-envy and attacking the therapeutic contract
      as one of the patient's assets. Excerpts from a case study are included.

PMID- 10593060
TI  - Scanning electron microscope observations on third-instar Gasterophilus nasalis
      (Diptera: Oestridae).
AB  - Scanning electron microscope observations studied the morphology of 3rd-instar
      Gasterophilus nasalis (L.). Distinctive features are illustrated in a sequence of
      16 micrographs, bearing indications of structures considered of special interest.
      The morphology of G. nasalis is compared with that of other larval bot flies.

PMID- 10593061
TI  - Polymerase chain reaction detection efficiency of the human granulocytic
      ehrlichiosis agent (Rickettsiaceae: Ehrlichieae) in ticks (Acari: Ixodidae) is
      dependent on the DNA extraction method.
AB  - Several methods of extracting DNA from ticks were examined to improve the
      efficiency of polymerase chain reaction (PCR) detection of the human granulocytic
      ehrlichiosis (HGE) agent. DNA was extracted from laboratory-reared uninfected and
      HGE-infected ticks using 3 separate methods. In one treatment, unfed nymphs and
      engorged larvae of Ixodes scapularis Say, either individually or in pools of 3,
      were homogenized in 40 microliters of 1x PCR buffer and boiled for 30 min. A 2nd
      group of ticks was extracted using the QiaAmp Tissue kit, a silica column
      separation method. A 3rd group was extracted with DNA-STAT, a guanidinium
      thiocynate method. Five microliters of each extract was used for PCR
      amplification. Pathogen-free tick DNA samples did not amplify a product.
      Laboratory-infected ticks extracted either with the QiaAmp kit or those
      homogenized and boiled in PCR buffer amplified product in 37.5% and 87.5% of the
      samples, respectively. Infected ticks extracted with DNA STAT-60 amplified a
      product in 100% of samples. No differences were observed in detection efficiency
      between ticks tested singly or in pools.

PMID- 10593062
TI  - Comparison of isoenzyme electrophoresis and morphometric analysis for
      phylogenetic reconstruction of the Rhodniini (Hemiptera: Reduviidae:
      Triatominae).
AB  - A phylogenetic reconstruction of the medically important tribe Rhodniini
      (Hemiptera: Reduviidae) based on multilocus isoenzyme electrophoresis is compared
      with phylogenetic patterns derived from a traditional morphometric analysis. Even
      with non-normality in the morphometric data, and some inequalities in population
      variances, discriminant analysis of size-free variables provided broadly similar
      phylogenetic information to that derived from isoenzyme analysis, revealing 3
      main species groups within the genus Rhodnius.

PMID- 10593063
TI  - Experimental and field evaluations of two acaracides for control of I. pacificus
      (Acari: Ixodidae) in northern California.
AB  - Use of acaricides for the control of Ixodes pacificus (Cooley & Kohls), the
      vector of Lyme borreliosis in the western United States, can be a beneficial
      component in a program to reduce the morbidity of Lyme borreliosis in California.
      Three commercially available acaricides, carbaryl, chlorpyrifos, and diazinon,
      were evaluated in laboratory bioassays for their effectiveness against I.
      pacificus adults. Based on bioassay results, chlorpyrifos and carbaryl were
      selected for field evaluations. Chlorpyrifos demonstrated the lowest LD50 in the
      laboratory and the best overall control in the field trials. Chlorpyrifos and
      carbaryl provided effective control with a residual effect on adult ticks up to 7
      wk after a single treatment. A field application timed to coincide with the
      highest period of adult questing activity proved effective in the control of I.
      pacificus in a Sierran foothill habitat. Judicious use of either of the
      acaricides evaluated may help to reduce adult tick densities in a peridomestic
      environment and thereby reduce the risk of human exposure to Lyme borreliosis and
      other tick-borne agents.

PMID- 10593064
TI  - New esterase enzymes involved in organophosphate resistance in Culex pipiens
      (Diptera: Culicidae) from Guang Zhou, China.
AB  - Organophosphate (OP) insecticides have been used widely to control Culex pipiens
      L. populations and this has led to the emergence of OP-resistance. Predominantly,
      resistance in Cx. pipiens is caused by over-production of nonspecific esterases,
      such as Est beta 1(1) and Est alpha 2(1)/beta 2(1). These esterases confer
      multiple resistance to organophosphorus and carbamate insecticides. To define the
      esterases in Chinese Cx. pipiens, restriction fragment-length polymorphism
      analysis was performed at the esterase beta locus. A new esterase haplotype (Est
      beta 8) was found. Starch gel electrophoresis indicated that Est beta 8 was
      coelevated with a novel Est alpha 8. This article reports Est alpha 8/beta 8
      esterase-mediated resistance in Cx. pipiens complex.

PMID- 10593065
TI  - Selection of refractory and permissive strains of Aedes triseriatus (Diptera:
      Culicidae) for transovarial transmission of La Crosse virus.
AB  - The genetic basis of transovarial transmission of La Crosse virus in Aedes
      triseriatus (Say) was investigated through selection experiments on 2 mosquito
      strains. One strain was subject to selection for transovarial transmission
      refractoriness, the other for permissiveness to transovarial transmission.
      Response to selection for a low filial infection rate was rapid, decreasing from
      18 to 3% in 3 generations. However, no response to selection for permissiveness
      was observed in the other strain; the average filial infection rates through 4
      generations fluctuated between 25 and 40%. By contrast, the transovarial
      transmission rate in both strains showed a consistent response to selection in
      both directions. These patterns are consistent with a model in which transovarial
      transmission is controlled by a single genetic locus and permissiveness is
      conditioned by dominant alleles; whereas the filial infection rate is nongenetic
      and influenced by stochastic factors in the mosquito and virus.

PMID- 10593066
TI  - Sequence analysis of the second internal transcribed spacer of ribosomal DNA in
      Anopheles oswaldoi (Diptera: Culicidae).
AB  - Sequence divergence in the second internal transcribed spacer (ITS2) of ribosomal
      DNA was examined for female specimens of Anopheles oswaldoi Peryassu from 7
      localities in South America. The lengths of ITS2 for all mosquitoes ranged from
      348 to 356 nucleotides. After alignment of these sequences, similarity ranged
      from 87 to 100%. Divergence was within the range of inter-specific differences
      for members of anopheline species complexes. Therefore, specimens were placed
      into 4 groups that may correspond to at least 4 cryptic species. One is probably
      related to An. oswaldoi sensu stricto and another to Anopheles konderi Galvao &
      Damasceno. The other 2 groups may correspond to species for which morphological
      identification remains to be clarified. These data provide evidence that An.
      oswaldoi comprise a complex of cryptic species and that DNA identification may
      help to resolve the taxonomic questions related to this group.

PMID- 10593067
TI  - Genetic and morphological characterization of the Aedes (Ochlerotatus) dorsalis
      (Diptera: Culicidae) group in North America.
AB  - An examination of the electrophoretically detectable variation among the North
      American members of the Aedes (Ochlerotatus) dorsalis group revealed large
      genetic differences among all 4 species. At least 9 of 18 loci examined (50%)
      were diagnostic for each species pair. However, morphological variation observed
      among species was low. Only Aedes canadensis (Theobald) was separated readily
      from the other members of this group [Aedes dorsalis (Meigen), Aedes melanimon
      Dyar and Aedes campestris Dyar & Knab] in all life stages. Characters
      traditionally used to separate the remaining 3 species were less reliable. In the
      adult female, Ae. melanimon may be distinguished from Ae. campestris by the
      scaling patterns of the wings and abdomen, but Ae. dorsalis could not be
      distinguished reliably by these characters. Adults of Ae. dorsalis may be
      separated reliably from those of Ae. campestris and Ae. melanimon only by the
      length of the subapical tooth relative to the length of the tarsal claw. Ae.
      melanimon was identified in the larval stage by the short mesothoracic hair 1.
      Eight larval characters differed between Ae. dorsalis and Ae. campestris.
      However, the ranges of these characters overlapped and no character was truly
      diagnostic. Genetic variation within species was low as measured by average
      heterozygosity and Nei's genetic distance coefficients. No allozymes were
      diagnostic for coastal and inland populations of Ae. dorsalis, and the pattern of
      genetic differentiation within this species did not correspond to the geographic
      location of the populations examined. Therefore, the genetic data did not support
      the hypothesis that Ae. dorsalis represents a complex of 2 or more cryptic
      species.

PMID- 10593068
TI  - Observations on the life cycle of Coelomomyces indicus (Blastocladiales:
      Coelomomycetaceae) in anopheline mosquitoes from the Philippines and Thailand.
AB  - The water mold Coelomomyces indicus Iyengar is a widespread pathogen of
      anopheline mosquitoes in Asia and Africa, and it infects the copepod Microcyclops
      varicans Sars as its crustacean alternate host. This was determined by direct
      observation of field-infected copepods, selective meiospore encystment on M.
      varicans, and experimental infections of the copepod with zoospores from both
      thick and thin-walled meiosporangia. The physiological conditions governing
      germination of the 2 sporangial types were determined. The gametothallus in the
      copepod displays a light yellow pigmentation at maturity, and gametogenesis in
      both field and experimentally infected copepods occurs just at night fall, or 24
      h after dark induction. In vivo culture was attained with the mosquito host
      Anopheles culicifacies Giles. Attempts to infect Anopheles stephensi Liston and
      Anopheles gambiae Giles, reported hosts of C. indicus, were unsuccessful.

PMID- 10593069
TI  - Effects of larval density on the size of Aedes polynesiensis adults (Diptera:
      Culicidae).
AB  - Replicated cohorts of a Tahitian laboratory strain of Aedes polynesiensis Marks
      were reared at 3 larval densities with a fixed amount of food. For larvae
      provided with limiting per capita food (i.e., 400 larvae per pan with 500 mg
      liver powder) relative to standard rearing conditions (i.e., 200 larvae per pan),
      mean pupal survival as well as male and female mean adult dry weights were
      significantly reduced and median developmental times were significantly
      prolonged. However, excess per capita food did not allow low density cohorts
      (i.e., 100 larvae per pan) to increase adult production, developmental rate, or
      adult dry weight compared with cohorts reared under standard rearing conditions.
      Male and female pupal wet weights, adult dry weights, and adult wing lengths all
      were correlated for Ae. polynesiensis collected as pupae from natural habitats
      near Papara Commune, Tahiti. Mean adult dry weights of host-seeking females from
      the same and a neighboring location did not differ significantly from weights of
      females emerging from field-collected pupae. The comparison of mean adult dry
      weight of these adults with adults reared at different densities in the
      laboratory indicated that field populations develop under food-limited
      conditions. Aedes polynesiensis responds to intraspecific larval competition by
      producing small adults over elongated developmental periods. Pupal wet weights,
      adult dry weights, and adult wing lengths are equally acceptable measures of
      mosquito size for vector and fecundity studies.

PMID- 10593070
TI  - Host feeding of mosquitoes (Diptera: Culicidae) associated with the recurrence of
      Rift Valley fever in Egypt.
AB  - In 1993, Rift Valley fever (RVF) virus reappeared in Egypt. We determined the
      prevalence and feeding patterns of mosquitoes in 5 villages where the virus was
      active. Of 10 species recovered, Aedes caspius (Pallas), Culex pipiens L., Cx.
      antennatus (Becker), and Cx. perexiguus Theobald constituted 99% of > 35,000
      mosquitoes captured in dry ice-baited CDC light traps. Ae. caspius was most
      prevalent, except at Nag' El Hagar where it was replaced by Cx. perexiguus. Cx.
      pipiens ranked 2nd, except at Nag' El Ghuneimiya, where it was replaced by Cx.
      antennatus. Most blood meals analyzed by an enzyme-linked immunosorbent assay
      reacted to > or = 1 antiserum. Cx. pipiens was mainly anthropophagic, and
      therefore may have been the main vector of RVF virus among humans. Ae. caspius
      feeds were chiefly from humans, bovines, and equines. Cx. antennatus and Cx.
      perexiguus fed generally on bovines. Mixed blood meals from humans and RVF virus
      susceptible animals were identified in the predominant mosquitoes. Prevalence and
      host selection, as well as predicted probability for a blood meal being
      interrupted, indicated that Ae. caspius may have served as a bridge vector
      between humans and bovines in 4 of the villages. Cx. perexiguus may have played
      this role at Nag' El Hagar. Because potential vectors are abundant, susceptible
      domestic animals are associated closely with humans, and surveillance of imported
      livestock is not systematic, we conclude that RVF virus sporadically will recur
      in Egypt.

PMID- 10593071
TI  - Infection rates of Amblyomma americanum (Acari: Ixodidae) by Ehrlichia
      chaffeensis (Rickettsiales: Ehrlichieae) and prevalence of E. chaffeensis
      reactive antibodies in white-tailed deer in southern Indiana, 1997.
AB  - To monitor the percentage and stability of Ehrlichia chaffeensis-infected ticks
      in southern Indiana over time, pools of Amblyomma americanum (L.) ticks were
      screened for infection in southern Indiana for a 2nd time. Nested polymerase
      chain reaction (with 6% DMSO included only in the 2nd reaction) was performed on
      920 ticks in pools of 5 individuals from 9 sites (5 sites previously examined and
      4 new ones) in 6 counties. The average minimum infection rate for all sites for
      1997 was 1.6%, lower than that of 4.9% previously observed for 1995. However,
      when only the 5 sites that were positive for infected ticks in 1995 were
      reexamined, the average minimum infection rate was even more disparate (1.4% in
      1997 and 5.1% in 1995). To correlate the presence of infected ticks with the
      presence of exposed deer, which serve as a reservoir, dried blood samples
      collected from hunter-killed deer at 2 locations in southern Indiana were tested
      for E. chaffeensis-reactive antibodies using an indirect immunofluorescent assay.
      Antibodies were detected in 45 and 47% of 98 samples examined from the 2
      stations. These data provide support to our previous report of a population of E.
      chaffeensis-infected A. americanum in southern Indiana and the high proportion of
      deer previously exposed to E. chaffeensis suggests a stable maintenance of E.
      chaffeensis in this tick-vertebrate zoonotic system.

PMID- 10593072
TI  - Seasonal activity and host associations of Ixodes scapularis (Acari: Ixodidae) in
      southeastern Missouri.
AB  - Based on tick collections recovered from wild vertebrates and by dragging, the
      seasonal occurrence of adult blacklegged ticks, Ixodes scapularis Say, extended
      from October through May in southeastern Missouri. Adult activity was bimodal
      with the higher peak occurring in November followed by a lower peak in February.
      The activity of immature I. scapularis had the general pattern of that found in
      the Northeast where Lyme disease is hyperendemic, with larval activity (July)
      peaking after that of nymphs (May and June). Vertebrates varied in their
      importance as hosts of I. scapularis. White-tailed deer, Odocoileus virginanus
      (Zimmerman), and coyotes, Canis latrans Say, were the primary hosts of adult I.
      scapularis. Broad-headed skinks, Eumeces laticeps (Schneider), and eastern fence
      lizards, Sceloporus undulatus (Latreille), were the primary hosts of nymphal I.
      scapularis. The broad-headed skink, 5-lined skink, Eumeces fasciatus (L.), and
      Carolina wren, Thryothorus ludovicianus (Latham), were the primary hosts of
      larval I. scapularis. Homeotherms were important hosts of immature I. scapularis,
      accounting for 30% of nymphs and 39% of larvae collected. The eastern cottontail
      rabbit, Sylvilagus floridanus (Allen), may play an important role in the
      epidemiology of Lyme disease in Missouri. Isolates of Borrelia burgdorferi
      Johnson, Schmid, Hyde, Steigerwalt & Brenner were made from ticks recovered from
      rabbits, making the cottontail rabbit a key species for further study of the
      epidemiology of Lyme borreliosis in Missouri.

PMID- 10593073
TI  - Efficacy of entomopathogenic nematode strains against engorged Boophilus
      annulatus females (Acari: Ixodidae) under simulated field conditions.
AB  - The biocidal efficacy of entompathogenic nematodes against engorged females of
      Boophilus annulatus (Say) was evaluated in soil-filled buckets in a greenhouse,
      where conditions resemble nature. The 9 tested nematode strains differed markedly
      in their effect upon tick mortality. The Mexican strain of Steinernema
      carpocapsae was most efficient, inducing 100% tick mortality at a concentration
      of 50 nematodes per square centimeter. An increase in the concentration of the S.
      carpocapsae DT strain to > 200 IJ/cm2 failed to kill more ticks. It appears that
      entomopathogenic nematodes show promise as tick control agents.

PMID- 10593074
TI  - Interaction between ticks (Acari: Ixodidae) and pathogenic nematodes (Nematoda):
      susceptibility of tick species at various developmental stages.
AB  - The virulence of entomopathogenic nematodes (Steinernematidae and
      Heterorhabditidae) to tick species under laboratory conditions is reported. The
      susceptibility of larval, nymphal, and adult stages of the ticks Hyalomma
      excavatum (Koch), Rhipicephalus bursa (Canestrini & Fanz), and R. sanguineus
      (Latereille) to 2 strains of Steinernema carpocapsae and 3 strains of
      Heterorhabditis bacteriophora were compared in laboratory assays. Preimaginal
      stages of ticks were found to be more resistant to the nematodes than were adult
      ticks which exhibited 80-100% mortality in a dish containing 5,000 infective
      juveniles of H. bacteriophora IS-3 or IS-5 strains isolated in Israel. These 2
      strains were found to be much more virulent to unfed adult ticks than were the
      other isolates. No marked difference was found between engorged ticks and unfed
      adults of R. sanguineus or H. excavatum in terms of mortality, whereas engorged
      males and unfed females of R. bursa were significantly more susceptible than
      unfed males or engorged females.

PMID- 10593075
TI  - Impact of microclimate on immature tick-rodent host interactions (Acari:
      Ixodidae): implications for parasite transmission.
AB  - Rodents play a significant role in enzootic cycles of tick-borne pathogens,
      notably, in the northern hemisphere, tick-borne encephalitis virus and Lyme
      borreliosis spirochaetes. The relative numbers of nymphal and larval ticks
      feeding on rodents are crucial variables in determining the probability of rodent
      infection and the degree of amplification of infection prevalence in the tick
      population. Manipulation of the microclimate within quasinatural experimental
      arenas revealed that under increasingly dry conditions the numbers of unfed
      nymphal Ixodes ricinus L. questing in upper layers of the herbage decreased,
      whereas the rate of fat use and the numbers of nymphs feeding on small rodents,
      both increased. This is consistent with nymphs descending to the moist lower
      vegetation layers for water replenishment, where they would come into contact
      with small hosts. Very few larvae quested or fed on rodents under the dry
      conditions, but many more did so once the humidity increased, suggesting that
      larvae escape desiccation by becoming quiescent. The ratio of larvae to nymphs
      feeding on rodents thus increases with increasing humidity, contributing to the
      seasonal and geographical variation in disease transmission dynamics.

PMID- 10593076
TI  - Infestation of Peromyscus leucopus and Tamias striatus by Ixodes scapularis
      (Acari: Ixodidae) in relation to the abundance of hosts and parasites.
AB  - The risk of humans acquiring Lyme disease is a function of the local density of
      nymphal and adult ticks that are infected with Lyme disease spirochetes. This in
      turn, will be related to host-use patterns of ticks and to the densities of both
      juvenile ticks and their hosts. At a forested site in Dutchess County, NY, we
      quantified host-use patterns of larval and nymphal Ixodes scapularis Say
      infesting the 2 dominant vertebrate hosts, white-footed mice and eastern
      chipmunks, during a 3-yr period. Larval tick burdens were 2-3 times higher on
      mice than they were on chipmunks, whereas nymphal tick burdens were > 3 times
      higher on chipmunks than they were on mice. We used multiple regression analysis
      to examine juvenile tick and host densities as independent variables influencing
      tick burdens. The density of questing larval ticks was positively correlated with
      larval tick burdens on mice, whereas the density of questing nymphs was weakly
      related to nymphal burdens on either host. Effects of the densities of mice and
      chipmunks on tick burdens were strong in some years, but weak in others.
      Moreover, the sign of the regression coefficients changed from one year to the
      next. We argue that these results are inconsistent with a passive encounter model
      of host selection, and suggest instead that either tick behavior or host
      responses cause strong biases in the distribution of juvenile ticks on their
      hosts.

PMID- 10593077
TI  - Brugia malayi microfilariae (Nematoda: Filaridae) enhance the infectivity of
      Venezuelan equine encephalitis virus to Aedes mosquitoes (Diptera: Culicidae).
AB  - We examined the potentially conflicting effects that microfilarial (MF)
      enhancement of viral infectivity and MF-induced mortality in mosquitoes have on
      the vectorial capacity of Aedes aegypti (L.), Aedes triseriatus (Say), and Aedes
      taeniorhynchus (Wiedemann) for Venezuelan equine encephalitis virus (VEE) when
      mosquitoes feed on gerbils co-infected with Brugia malayi (Buckley). Groups of
      mosquitoes were fed on gerbils that were either dually infected (VEE plus B.
      malayi MF) or singly infected (VEE only). Mosquito mortality was recorded daily,
      and 5-8 d later, surviving mosquitoes were assayed for disseminated viral
      infection. The contrasting effects of MF enhancement and MF-induced mortality
      differed among mosquito species and were determined by the nature and
      consequences of MF penetration through the mosquito midgut, but not to
      differences in mosquito susceptibilities to parenterally introduced virus. In Ae.
      aegypti, MF-induced mortality was high and tended to eliminate any significant
      effect of MF enhancement. In Ae. triseriatus, MF-induced mortality was low, and
      feeding on dually infected hosts resulted in 9 times as many mosquitoes with
      disseminated viral infections as did feeding on singly-infected hosts. In Ae.
      taeniorhynchus, MF-induced mortality was extremely high, yet under our
      experimental conditions, feeding on a dually infected hosts resulted in nearly 30
      times as many disseminated infections as did feeding on singly infected hosts.
      The final outcome on vectorial capacity depended on the specific combination of
      MF, virus, and mosquito species involved. Therefore, future efforts toward
      understanding MF enhancement should be directed toward mosquito-virus-parasite
      species combinations that occur together in nature.

PMID- 10593078
TI  - Cloning and sequencing of a putative acetylcholinesterase cDNA from Boophilus
      microplus (Acari: Ixodidae).
AB  - Using a strategy based on degenerate primers derived from acetylcholinesterase
      (AChE) from other species, we cloned and sequenced a putative AChE cDNA from the
      southern cattle tick, Boophilus microplus (Canestrini). The sequence has a high
      degree of homology to sequences of AChE from other species reported in the
      GenBank. The open reading frame of 1,689 bp, corresponding to a deduced sequence
      of 563 amino acids, has conserved regions and features shared by the AChE family,
      necessary for its catalytic activity. No differences were found in the putative
      cDNA sequences from organophosphorus acaricide (OP) resistant and susceptible
      strains. The results suggest that this putative AChE gene is not involved in
      resistance to OP compounds as a mutated gene in the resistant strain studied.
      However, differences were detected, with a probe derived from this cDNA, in DNA
      fragments after digestion of genomic DNA from different strains with restriction
      nucleases. This indicates polymorphism in this gene in B. microplus.

PMID- 10593079
TI  - First-generation physical map of the Culicoides variipennis (Diptera:
      Ceratopogonidae) genome.
AB  - Recombinant cosmids labeled with biotin-11-dUTP or digoxigenin by nick
      translation were used as in situ hybridization probes to metaphase chromosomes of
      Culicoides variipennis (Coquillett). Paired fluorescent signals were detected on
      each arm of sister chromatids and were ordered along the 3 chromosomes. Thirty
      three unique probes were mapped to the 3 chromosomes of C. variipennis (2n = 6):
      7 to chromosome 1, 20 to chromosome 2, and 6 to chromosome 3. This work
      represents the first stage in generating a physical map of the genome of C.
      variipennis.

PMID- 10593080
TI  - Emergence, survival, and fecundity of adult cat fleas (Siphonaptera: Pulicidae)
      exposed as pupae to juvenile hormone mimics.
AB  - Cat flea, Ctenocephalides felis felis (Bouche), adults exposed to sprays of
      methoprene, pyriproxyfen, or fenoxycarb as cocooned pupae emerged approximately 1
      d earlier than adults from water-treated control pupae. Mortality of adult fleas,
      after exposure to juvenile hormone mimics as pupae, was increased over that of
      controls. Females had higher mortality than males within the first 48 h of
      feeding. Fecundity of females exposed as pupae to juvenile hormone mimics was not
      different from that of controls. Early emergence of preemerged adults from
      treated cocoons is discussed along with reasons for higher female susceptibility
      to juvenile hormone mimics.

PMID- 10593081
TI  - Susceptibility to insect growth regulators and cuticle deposition of the cat flea
      (Siphonaptera: Pulicidae) as a function of age.
AB  - Wandering larval, pharate pupal, pupal, and pharate adult stages of the cat flea,
      Ctenocephalides felis (Bouche), were identified by examination of cuticular cross
      sections via scanning electron microscopy. Visible morphological characteristics
      of each stage were identified and described. Various stages of the flea
      throughout metamorphosis were exposed to juvenile hormone mimics and insect
      developmental inhibitors. Wandering larvae treated with juvenile hormone mimics
      were unable to pupate, whereas treated pharate pupae ecdysed to the pupal stage
      but were unable to enclose. Pupae and pharate adults did not succumb to juvenile
      hormone mimic exposure, even at concentrations 3 orders of magnitude greater than
      those that killed 100% of the wandering larvae and the pharate pupae. Adult
      females were more susceptible to juvenile hormone mimics than males. Possible
      explanations for the variation in tolerance to juvenile hormone mimics of the
      differing stadia are discussed. None of the stages were susceptible to insect
      developmental inhibitor exposure. Analysis of catecholamines that are precursors
      of cuticle sclerotization and melanization were measured in the wandering larval
      through the pharate adult stages of the cat flea. N-acetyldopamine concentration
      was highest in the pupa stage when the flea had a hard, clear cuticle; N-beta
      alanyldopamine concentration was highest during the production of the hard, dark
      cuticle of the pharate adult; and dopamine fluctuated throughout development but
      was highest in the pupal stage.

PMID- 10593082
TI  - An olfactometer for discriminating between attraction, inhibition, and repellency
      in mosquitoes (Diptera: Culicidae).
AB  - We constructed an olfactometer that differentiates and quantifies attraction,
      inhibition, and repellency to mosquitoes. Using this device, 22 formulations of
      various chemicals on gauze pads and 8 dilutions of DEET on skin were tested. Four
      novel formulations were discovered acting as true repellents, whereas DEET did
      not act as a true repellent but as an inhibitor.

PMID- 10593083
TI  - A new mechanism conferring unprecedented high resistance to chlorpyrifos in Culex
      pipiens (Diptera: Culicidae).
AB  - The cause of high resistance to chlorpyrifos observed in Tunisian Culex pipiens
      (L.) was investigated by comparing a Tunisian strain G (> 10,000-fold
      resistance), a French strain T (approximately 50-fold resistance), and a
      susceptible reference strain S. Strains G and T had the same level of propoxur
      resistance (approximately 1,000-fold) and were homozygous for an autosomal
      propoux-insensitive acetylcholinesterase (AChE-1). In G and T strains, as well as
      in the offspring of different F1s and backcrosses using these F1s and the S
      strain, the effect of DEF and Pb synergists on chlorpyrifos resistance was low or
      absent, indicating that increased detoxification by enzymes inhibited by these
      chemicals had a minor role. Chlorpyrifos resistance in the G strain was caused by
      a major gene (or group of genes) tightly linked to the Ace-1 gene (coding AChE-1
      enzyme). The possibility of allelism between this gene and the Ace-1R allele
      present in the T strain was rejected by showing that AChE-1 inhibition by
      chlorpyrifos-oxon was not different between G and T mosquitoes.

PMID- 10593084
TI  - Scanning electron microscopy and comparative morphometrics of eggs from six bot
      fly species (Diptera: Oestridae).
AB  - Scanning electron microscope comparisons were made of the eggs of Cuterebra
      austeni Sabrosky, C. fontinella Coquillet, C. jellisoni Curran, C. lepusculi
      Townsend, C. ruficrus (Austen), and Alouattamyia baeri (Shannon & Greene). Larvae
      of these flies parasitize rodents, lagomorphs, and monkeys. Image analysis of the
      egg length (maximum projection) and width (minimum projection), egg area (in
      dorsal view), operculum area (in dorsal view), and operculum area as a percentage
      of egg area revealed differences among species. The chorion of these eggs is
      sculptured with a distinct pattern of "cells" covering the dorsal, lateral, and
      opercular surfaces. The chorion of A. baeri eggs was distinct with deeply
      sculpted, large, highly polymorphic "cells." C. jellisoni eggs also had large,
      highly polymorphic cells, but the sculpturing was not deep. The chorion of the 4
      remaining species was quite similar. Image analysis of the chorionic sculpturing
      patterns revealed significant differences in the area, perimeter, maximum
      projection, minimum projection and aspect ratio of chorionic "cells" among the
      species examined. The chorionic "cell" parameters of A. baeri and C. jellisoni
      were different from 1 another and from the other species in all parameters. The
      "cell" parameters of C. lepusculi and C. ruficrus were similar. A combination of
      overall egg features in combination with cell features allow the eggs to be
      differentiated from one another. There was no strong association among structural
      features of the eggs and the habitat in which they were found. However, the deep
      sculpturing of the A. baeri eggs might help to prevent drowning in tropical rain
      forests.

PMID- 10593085
TI  - Potential for aging female Aedes aegypti (Diptera: Culicidae) by gas
      chromatographic analysis of cuticular hydrocarbons, including a field evaluation.
AB  - Gas chromatography with flame-ionization detection was used to measure the time
      associated, quantitative changes in the cuticular hydrocarbons of female Aedes
      aegypti (L.). Cohorts of unstressed Ae. aegypti, Rockefeller strain, were reared
      and held at 3 constant temperatures (24, 28, and 30 degrees C). Five females from
      each cohort were taken at 33 degree-day (DD) intervals from 0 to 231 DD (using 17
      degrees C as the threshold temperature). Quantitative changes over time of
      cuticular hydrocarbons associated with gas chromatographic peaks 1 and 5 were
      identified as having promise for age grading. The relative abundance of peak 1
      (pentacosane) decreased linearly from 0 to 132 DD, whereas peak 5 (nonacosane)
      increased linearly over the same period. Suboptimal larval conditions (crowded
      and starved), which resulted in physiological stress (decreased size), had
      negligible effect on the relative abundance of pentacosane and nonacosane.
      Additionally, the rate of change in the relative abundance of pentacosane and
      nonacosane were the same for both a recently colonized Chachoengsao (Thailand)
      strain of Ae. aegypti compared with the long-colonized Rockefeller (Caribbean)
      strain over a 0-99 DD interval. Two linear regression models, one based on the
      relative abundance of pentacosane and the other on the logit transformation of
      these values, were developed for aging female Ae. aegypti. A blind study using
      laboratory-reared mosquitoes and a mark-release-recapture experiment using field
      mosquitoes validated these age-grading models and produced promising results for
      aging females up to 132 DD (19, 12, and 10 calendar days at 24, 28 and 30 degrees
      C, respectively). Therefore the regression models, based on the relative
      abundance of these 2 cuticular hydrocarbons, appeared to be a useful approach for
      age-grading Ae. aegypti up to at least 12 d of age regardless of environmental
      conditions (temperature and stress) and population history (origin and
      colonization time).

PMID- 10593086
TI  - Aedes aegypti (Diptera: Culicidae) age determination by cuticular hydrocarbon
      analysis of female legs.
AB  - We previously described methods for age-grading female Aedes aegypti (L.) by gas
      chromatographic (GC) analysis of whole-body cuticular hydrocarbon patterns. Two
      regression models were developed that were based on the age-dependent, relative
      abundance of 2 cuticular hydrocarbons, pentacosane (GC peak 1) and nonacosane (GC
      peak 5). We have refined this method so that only the legs are required to age
      individual females. Two new regression models were developed that also use the
      relative abundance of a 3rd cuticular hydrocarbon, octacosane (GC peak 4). These
      models improve the overall accuracy of the cuticular hydrocarbon method for aging
      female mosquitoes, especially for older females from 132 to 165 degree-days (DD)
      of age (12-15 calendar days at 28 degrees C). The correlation coefficients (R2)
      for the best-fitted linear regression models for aging females from 0 to 132 and
      0-165 DD were 0.80 and 0.81, respectively (P < 0.001 in all cases). The use of
      leg cuticular hydrocarbons for estimating the age of female Ae. aegypti has a
      significant advantage over whole-body extracts as indicated by the decreased
      variability associated with the relative abundance of pentacosane and the
      expanded range over which the models were able to predict age accurately by the
      addition of the relative abundance of octacosane.

PMID- 10593087
TI  - Three incidents of human myiasis by rodent Cuterebra (Diptera: Cuterebridae)
      larvae in a localized region of western Pennsylvania.
AB  - Three aberrant incidents of human myiasis by Cuterebra larvae (Diptera:
      Cuterebridae) are described. All 3 cases were documented in the fall, on a nearly
      annual basis, and at the same western Pennsylvania hospital. Mature larvae were
      removed from cutaneous warbles of the neck and torso of a small female child and
      adult male, respectively. An early 2nd instar was removed from a warble located
      in the upper anterior quadrant of the left breast of an adult female.

PMID- 10593088
TI  - Decomposition and arthropod succession on exposed rabbit carrion during summer at
      high altitudes in Colorado, USA.
AB  - Six rabbit carcasses were exposed during summer at elevations ranging from 2,713
      to 4,191 m in Colorado to determine decomposition rates and arthropod succession
      patterns. Biomass removal, bloat, and internal and ambient air temperatures were
      measured and the arthropod community was monitored during 51-d succession
      studies. A total of 53 taxa was collected (range, 8-36 taxa), with diversity
      apparently decreasing as a negative function of elevation. Extensive scavenging
      altered decomposition rates and arthropod succession. Rates and duration of
      biomass removal and bloating of carcasses were slowed and prolonged at higher
      elevations.

PMID- 10593089
TI  - Morphometric and phenetic studies of five geographical populations of Lutzomyia
      whitmani (Diptera: Psychodidae) in Brazil.
AB  - A morphometric survey examined adult specimens of Lutzomyia whitmani (Antunes &
      Coutinho) captured at 5 municipalities in southeastern and northeastern Brazil to
      compare the populations. The localities were Ilheus (Bahia), Martinho Campos
      (Minas Gerais), Corte de Pedra (Bahia), Baturite (Ceara), and Amaraji
      (Pernambuco): all are known foci of American cutaneous leishmaniasis. Fifteen
      males and 15 females from each population were analyzed morphometrically for 42
      and 37 characters, respectively. Statistical data alone were insufficient to
      discriminate among the 5 populations. Further analysis generated phenograms that
      indicated there were 2 spatial clusters: the 1st was composed of specimens from
      Ilheus (Bahia) and Baturite (Ceara) and the 2nd of specimens from Martinho Campos
      (Minas Gerais), Corte de Pedra (Bahia), and Amaraji (Pernambuco). Although
      insufficient to define the taxonomic status of the populations studied, the
      results delineated the existence of biogeographical structuring within L.
      whitmani. Complementary studies on the susceptibility to Leishmania braziliensis
      infection in the 5 populations are in progress to clarify the relationship
      between the 2 biogeographical clusters and American cutaneous leishmaniasis
      transmission in those Brazilian regions.

PMID- 10593090
TI  - Calibrated funnel trap for quantifying mosquito (Diptera: Culicidae) abundance in
      wells.
AB  - Our article addresses the problems of sampling and quantifying the abundance of
      immature Aedes aegypti (L.) and other mosquitoes that use subterranean habitats
      such as wells and service manholes. Two versions of the funnel trap, Austrap and
      Vietrap, were extremely sensitive for detecting the presence of Ae. aegypti
      larvae in wells, and the modified version, the Vietrap, sampled on average 20.5%
      of 3rd and 4th instars when set overnight for 12 h. For both models, regression
      analyses between trap catch and absolute abundance indicated high coefficients of
      determination (R2 = 0.932 and 0.992) enabling accurate direct calibration. The
      effects of immature age, mosquito species, well diameter, and trap size on catch
      size were investigated. Because of its simplicity, efficacy, and inexpensiveness,
      the Vietrap will facilitate the comprehensive assessment of key larval habitats
      for Ae. aegypti, data critical for the development of effective control programs.

PMID- 10593091
TI  - Vector competence of mosquitoes (Diptera: Culicidae) from Maroochy Shire,
      Australia, for Barmah Forest virus.
AB  - Mosquitoes were collected in light traps from Maroochy Shire and fed on blood
      containing the sympatric BF1611 strain of Barmah Forest virus (BF). Saltmarsh
      Aedes vigilax (Skuse) and freshwater Aedes procax (Skuse) were highly susceptible
      to infection, with ID50s of 10(1.7) and 10(1.5) African green monkey kidney
      (Vero) cell culture infectious dose, 50% endpoint (CCID50) per mosquito,
      respectively, followed by Aedes multiplex (Theobald) and Aedes funereus
      (Theobald) with 10(2.5) and 10(3.2) CCID50 per mosquito, respectively. Culex
      australicus Dobrotworsky & Drummond and Mansonia uniformis (Theobald) that were
      fed 10(3.6) CCID50 (Vero) BF per mosquito had infection rates of 28 and 60%,
      respectively. Only 8% of freshwater Culex annulirostris Skuse fed the same viral
      dose were infected. Evidence of virus transmission to mice was found with Ae.
      vigilax and Ae. procax, with transmission rates of 65 and 88% at 11-12 d after
      infection, respectively. Based on adult abundance, susceptibility to infection,
      and efficiency of virus transmission, Ae. vigilax would appear to be the most
      important vector of BF in Maroochy Shire.

PMID- 10593092
TI  - Barmah Forest virus epidemic on the south coast of New South Wales, Australia,
      1994-1995: viruses, vectors, human cases, and environmental factors.
AB  - In 1995, the largest recorded outbreak of human disease resulting from infection
      with the mosquito transmitted alphavirus Barmah Forest (BF) virus occurred along
      the south coast of New South Wales, Australia. The virus was first isolated in
      early January from mosquitoes collected at Batemans Bay and predisposed the
      recognition of 135 human clinical cases. The cases of BF virus were identified
      initially from Batemans Bay during late January, and the majority (30%) of all
      cases came from this town. After 5 wk, all major centers on the south coast had
      clinical patients. Aedes vigilax (Skuse) were especially abundant at Batemans
      Bay, with levels up to 8 times greater than normal. This species yielded 111
      isolates and appeared to be the major vector of BF virus. Attempts to examine if
      BF virus was maintained in the field by vertical transmission within Ae. vigilax
      populations were unsuccessful; no evidence of vertical transmission with BF
      virus, nor any other arbovirus, was found in > 17,000 adults emerging from field
      collected larvae from the region following peak virus activity. In addition to BF
      virus, other viruses were recovered from field-collected adult mosquitoes,
      including Ross River (10 isolates), Edge Hill (21), and Stratford (10). Ae.
      vigilax again yielded the majority of these viral isolates. The BF virus outbreak
      appeared to be associated with several factors. A lack of recent BF virus
      activity in the region provided a highly susceptible human population, and
      unusual weather conditions of above average rainfall coupled with high tides
      resulted in extraordinarily large populations of Ae. vigilax.

PMID- 10593093
TI  - Seasonal occurrence of Leptotrombidium deliense (Acari: Trombiculidae) attached
      to sentinel rodents in an orchard near Bangkok, Thailand.
AB  - Leptotrombidium deliense Walch that attached to sentinel laboratory mice and the
      roof rat, Rattus rattus (L.), placed in an orchard habitat near Bangkok,
      Thailand, were studied between April 1993 and April 1995. A single L. deliense
      larva was attached to only 1 of 51 laboratory mice placed in the study area
      between April and September 1993. Overall, 89/202 (44.1%) R. rattus had 1 or more
      L. deliense larvae attached, and Orientia tsutsugamushi (Hayashi), the etiologic
      agent for scrub typhus, was isolated from liver/spleen samples of 2/202 (1.0%)
      rats placed in an endemic area for a single night. A total of 474 L. deliense
      attached to sentinel R. rattus, of which 314 larvae successfully fed to repletion
      and were recovered, and 2 (0.6%) of these were naturally infected with O.
      tsutsugamushi. The occurrence of L. deliense was influenced by rainfall, with
      more chiggers attached to rodents in the wetter months of the year. The study
      showed that the risk of exposure to infection with O. tsutsugamushi is greater
      during the wetter months of the year, and that only a relatively small number of
      chigger attachments are needed to infect potential hosts.

PMID- 10593094
TI  - Action of the saliva of Triatoma infestans (Heteroptera: Reduviidae) on sodium
      channels.
AB  - Saliva of Triatoma infestans (Klug) produced a progressive reduction in the
      amplitude of the compound action potential recorded from rat sciatic nerve. The
      saliva also inhibited the Na+ current on GH3 cells. The data demonstrate that the
      saliva of T. infestans has an inhibitory effect on Na+ channels. We conclude that
      this effect may decrease the generation and conduction of nerve action potential,
      thereby decreasing the sensitivity of the region in which the insect probes, in a
      manner similar to that of local anesthetics. This study demonstrates such
      activity in the saliva of hematophagous insects. The adaptive value of this
      activity is clear, because the quantity of blood obtained by triatomines is
      limited by the irritation caused during the feeding process.

PMID- 10593095
TI  - Black flies (Diptera: Simuliidae) of the Special Province of Aceh, Indonesia.
AB  - The black fly fauna of the Special Province of Aceh, Indonesia, was surveyed in
      24 streams in 5 regencies, from 7 to 13 June 1998. Ten species were identified,
      Simulium (Nevermannia) aureohirtum Brunetti, S. (Gomphostilbia) duolongum Takaoka
      & Davies, S. (G.) sheilae Takaoka & Davies, S. (G.) sundaicum Edwards, S. (S.)
      nobile de Meijere, S. (S.) fenestratum Edwards, S. (S.) argyrocinctum de Meijere,
      S. (S.) nebulicola Edwards, S. (S.) iridescens de Meijere, and S. (S.)
      minangkabaum Takaoka & Sigit. These species are essentially oriental in
      distribution, because they belong to the 3 subgenera that are dominant groups in
      oriental or Palaearctic regions, or both.

PMID- 10593096
TI  - Small-scale field trial of a sensing device for detecting peridomestic
      populations of Triatoma infestans (Hemiptera: Reduviidae) in northwestern
      Argentina.
AB  - Two prototypes of sensing devices for detecting peridomestic populations of
      Triatoma infestans Klug were tested in paired trials with bamboo canes in Amama
      and nearby rural villages under triatomine surveillance. In infested peridomestic
      structures housing domestic animals, 1-2 pairs of numbered devices were placed
      per test site, left for 3-9 nights, and inspected for evidence of infestation.
      Prototype A was a black plastic cylinder 19 cm high and 10 cm diameter, with a
      screw cap on the top, 2 openings in the bottom, and a removable central structure
      made of resistant plastic coated with leather. Prototype B had square leather
      pieces rolled into cylinders instead of the central structure. Prototype A was
      significantly more sensitive than the bamboo cane with pleated paper inside in 13
      test sites in which 20 pairs were tried. In a smaller series involving 7 pairs,
      prototype B also detected infestations more frequently than the cane. Triatomine
      feces were the signs most frequently recorded by both prototypes, whereas the
      bamboo canes recorded no feces. Ten T. infestans and 1 Triatoma guasayana
      Wygodzinsky & Avalos were collected from the prototypes placed on the ground or
      walls, not beneath the thatched roofs of the animal shelters, whereas only 3 T.
      infestans were collected from the canes. This study describes an effective
      sensing device for detecting T. infestans populations in outdoor animal shelters
      and provides quantitative field data on its performance.

PMID- 10593097
TI  - Reservoir competence of Carcinops pumilio for Salmonella enteritidis
      (Eubacteriales: Enterobacteriaceae).
AB  - The histerid beetle Carcinops pumilio (Erichson) occurs naturally in poultry
      house manure and is an important predator of house fly eggs and larvae. Because
      efforts to commercially produce C. pumilio have been unsuccessful, one fly
      control strategy under consideration is the direct transport of adult C. pumilio
      between poultry houses to facilitate their establishment. However, we demonstrate
      that C. pumilio is a competent reservoir of Salmonella enteritidis (Gaertner).
      Adult C. pumilio exposed to S. enteritidis-inoculated house fly eggs harbored the
      bacterium externally and internally for up to 4 and 13 d, respectively, and feces
      were culture-positive for S. enteritidis for at least 14 d. This suggests that C.
      pumilio can be a reservoir of S. enteritidis; therefore its movement between
      poultry facilities should be carefully considered.

PMID- 10593098
TI  - Screening of ten plant species for metaphase chromosome preparation in adult
      mosquitoes (Diptera: Culicidae) using an inoculation technique.
AB  - The screening of 10 plant species (Aloe barbadensis Mill., Asparagus officinalis
      L., As. plumosus Bak., As. racemosus Willd., As. sprengeri Regel, Codyline
      fruticosa Goppert, Dracaena loureiri Gagnep., Gloriosa superba L., Hemerocallis
      flava L., and Sansevieria cylindrica Bojer) for colchicine-like substance(s)
      using a mosquito cytogenetic assay revealed that a 1% solution of dried Gl.
      superba rhizome extracted in 0.85% sodium chloride solution could be used instead
      of a 1% colchicine in Hanks' balanced salt solution. The metaphase rates and
      average number of metaphase chromosomes per positive mosquito of Aedes aegypti
      (L.) after intrathoracic inoculation with 1% Gl. superba-extracted solution were
      100% and 29.80 in females, and 90% and 25.78 in males, whereas the inoculation
      with 1% colchicine solution yielded 100 and 90% metaphase rates, and 20.90 and
      12.22 average number of metaphase chromosomes per positive mosquito in females
      and males, respectively. The application of Gl. superba-extracted solution for
      metaphase chromosome preparation in other mosquito genera and species [e.g.,
      Culex quinquefasciatus Say, Toxorhynchites splendens (Wiedemann), and Anopheles
      vagus (Doenitz)] also has yielded the satisfactory results.

PMID- 10593099
TI  - Honeydew sugars in wild-caught female horse flies (Diptera: Tabanidae).
AB  - Three species of horse fly, Hybomitra illota (Osten Sacken), H. affinis (Kirby),
      and H. zonalis (Kirby), were collected by sweep-netting around human bait at 2
      sites (abandoned airfield and Davies Bog) in Algonquin Provincial Park, Ontario.
      There were 3 times more horse flies collected at Davies Bog than at the abandoned
      airfield. The crop contents of all specimens were identified by thin-layer
      chromatography. Using melezitose and stachyose as honeydew indicator sugars, the
      relative importance of homopteran honeydew and floral nectar as carbohydrate
      sources for these flies was determined. Of flies testing sugar-positive, 42.0% of
      H. illota (n = 50), 52.8% of H. affinis (n = 36), and 100% of H. zonalis (n = 4)
      had recently fed on honeydew. Pooled data for the 3 species showed that 38.9% of
      flies at the abandoned airfield (n = 18) and 51.4% of flies at Davies Bog (n =
      72) were honeydew-fed. There were no significant differences among species or
      between sites. These findings are compared with recent black fly and deer fly
      studies from the same sites.

PMID- 10593100
TI  - Pathogenicity of Bacillus thuringiensis variety kurstaki to Ixodes scapularis
      (Acari: Ixodidae).
AB  - Pathogenicity of the entomopathogenic bacterium Bacillus thuringiensis variety
      kurstaki de Barjac & Lemille was tested against the black-legged tick, Ixodes
      scapularis Say. Engorged larvae dipped in a solution of 10(8) spores per
      milliliter showed 96% mortality 3 wk after infection. The LC50 value for engorged
      larve (concentration required to kill 50% of ticks) was 10(7) spores per
      milliliter. B. thuringiensis shows considerable potential as a microbial control
      agent for the management of I. scapularis.

PMID- 10593101
TI  - Baseline susceptibility of a laboratory strain of Pediculus humanus humanus
      (Anoplura: Pediculidae) using a modified World Health Organization testing
      protocol.
AB  - The World Health Organization (WHO) protocol for determining resistance in body
      lice, Pediculus humanus humanus (L.), requires holding lice for long periods,
      which makes successful execution of the test difficult in field settings. The
      purpose of this study was to modify the WHO test procedure to make the holding
      period of lice shorter and the handling of lice easier. Susceptible lice from a
      laboratory colony were placed in a petri dish containing a paper that had been
      treated with an insecticide solution. After 6 h, the petri dish was turned on its
      side and lightly tapped on the table. Lice that were unable to cling to the paper
      were counted as knocked down. The KD50 in mg (AI)/ml of the insecticide solution
      used to treat the papers was as follows: lindane 0.060, permethrin 0.115, d
      phenothrin 0.554, and malathion 1.008. If the diagnostic dose is set at 2 times
      the KD99, for this test procedure the diagnostic doses and WHO equivalent dose
      would be lindane, 0.368 mg (AI)/ml (WHO 0.132%); permethrin, 0.498 mg (AI)/ml
      (WHO 0.206%); d-phenothrin, 2.680 mg (AI)/ml (WHO 1.107%); and malathion, 5.212
      mg (AI)/ml (WHO 2.020%).

PMID- 10593102
TI  - Ophthalmomyiasis caused by Sarcophaga crassipalpis (Diptera: Sarcophagidae) in a
      hospital patient.
AB  - Nine sarcophagid larvae were found on the right eyelid, cornea, and bulbar
      conjunctiva of a debilitated patient in a hospital in Osaka, Japan. Inflammation
      of the right eyelid and conjunctival congestion, probably initiated or aggravated
      by the larvae, were found. The larvae were removed and reared for accurate
      identification, and, on the basis of the characteristics of the 3rd instar and
      adult flies, the species was identified as Sarcophaga crassipalpis Macquart. This
      is a report of ophthalmomyiasis caused by this facultative parasite in a human.
      Patients with diminished consciousness in hospitals need protection from flies.

PMID- 10593103
TI  - Childhood fever education in a military population: is education enough?
AB  - PURPOSE: Parental knowledge of childhood fever and clinic and emergency room
      utilization were studied in a military pediatric clinic population to determine
      if intervention would improve parental understanding and management of childhood
      fever. METHODS: Multiple choice tests evaluating childhood fever knowledge were
      given to control and intervention groups. Clinic and emergency room utilization
      were tracked for appropriateness of visits based on criteria used in previous
      similar studies. RESULTS: Initial test scores showed no difference between the
      two groups. Subsequent test scores revealed a difference between the two groups
      as reflected by improved test scores. Evaluation of clinic and emergency room
      utilization of the groups did not show an overall improvement except in one
      subgroup analyzed. CONCLUSION: Intervention improved parental knowledge; however,
      intervention did not translate into anticipated improvement in clinic and
      emergency room utilization patterns. Emphasis on education and preventative
      services are important in both civilian and military pediatric practice. Results
      of this study highlight the need to discuss and reinforce fever education as a
      topic in pediatric preventive health care visits.

PMID- 10593104
TI  - Obstetrical outcome in the very young adolescent.
AB  - PURPOSE AND METHODS: To determine the obstetrical outcome in adolescent
      pregnancies younger than 15 years of age. A retrospective multivariant analysis
      from January 1, 1985 to November 2, 1990 was undertaken. Comparison of all data
      sets were structured to analyze groups of patients < 15 years of age (group I) or
      15 years of age (group II) at the time of delivery. RESULTS: No significant
      difference was observed between groups for mode of delivery, incidence of low
      birth weight delivery, or rates of preeclampsia. Group I was less likely to
      obtain adequate prenatal care. The development of preeclampsia and low birth
      weight delivery was positively correlated with late entry into prenatal care.
      Rates of preeclampsia for both groups exceed normal levels for this patient
      population. CONCLUSIONS: Efforts to promote utilization of the health care system
      are of paramount importance in the very young adolescent age group.

PMID- 10593105
TI  - "RU Y2K ready?".

PMID- 10593106
TI  - Services of manipulative therapists, pain.

PMID- 10593107
TI  - Fear of movement/(re)injury, avoidance and pain disability in chronic low back
      pain patients.
AB  - Chronic pain syndromes such as chronic low back pain are responsible for enormous
      costs for health care and society. For these conditions a pure biomedical
      approach often proves insufficient. Numerous studies have shown that there is
      little direct relationship between pain and disability and suggest that the
      biopsychosocial approach offers the foundations for a better insight in how pain
      can become a persistent problem. The main assumption is that pain and pain
      disability are not only influenced by organic pathology, if found, but also by
      psychological and social factors. In this contribution, a behavioural analysis of
      chronic musculoskeletal pain will be discussed, with special attention to the
      role of pain-related fear in the development and maintenance of chronic pain
      disability, and the behavioural rehabilitation perspective of chronic pain
      management.

PMID- 10593108
TI  - Recent concepts in the neurophysiology of pain.
AB  - This paper describes many of the processes that exist for upregulation of the
      nociceptive system in response to tissue injury. The processes of peripheral and
      central sensitization are described. Potential interactions between the
      nociceptive, motor and autonomic systems are considered. The potential for
      psychosocial factors to influence neuroplasticity within the nociceptive system
      is also discussed.

PMID- 10593109
TI  - Psychological aspects of pain.
AB  - Manual therapy is based on a biomedical model of illness and places considerable
      reliance on the patient's report of pain. Reported pain intensity is assumed to
      bear a close relationship with underlying nociception but research has shown that
      the experience of pain is also influenced by a wide range of psychological
      factors. Firstly, response to pain provocation (whether palpation or induction of
      biomechanical stress) can be affected by fear of an adverse outcome (such as
      pain) and fear of injury. Secondly, a patient's global rating of their pain may
      be widely influenced by factors in addition to nociception such as distress, fear
      and mistaken beliefs about the nature of pain and likely outcome of treatment.
      The manual therapist needs, therefore, to conduct and understand biomedical
      assessment within a biopsychosocial framework. In appraising the patient's
      response, the therapist may find it helpful to incorporate specific assessment of
      subjectively reported fear or behavioural indicators of fear such as guarded
      movements or behavioural signs. Therapists need to understand that in manual
      therapy, they are frequently managing the patient's pain behaviour and distress,
      rather than simply the nociceptive component of their pain.

PMID- 10593110
TI  - Assessment of pain perception in clinical practice.
AB  - With pain a frequent precipitant in individuals seeking manual therapy, it is
      important for therapists to adequately assess pain. At one level, pain forms an
      important part of the diagnostic assessment. It is suggested that a simple,
      reliable and quantitative pain measure be used in patients who present with
      routine problems. At another level, when the therapist is presented with clients
      in whom pain does not make sense in terms of its pattern, distribution, history
      or features, it is advisable to go beyond a simple pain intensity measure.

PMID- 10593111
TI  - Complex regional pain syndrome: becoming more or less complex?
AB  - Complex regional pain syndrome (CRPS) is the newest name for the confusing
      conditions of reflex sympathetic dystrophy and causalgia. The epidemiology and
      the signs and symptoms of these conditions are discussed. Although much is only
      poorly understood about the aetiology of CRPS, the roles of neuropathic pain,
      prolonged inflammation and psychological factors are becoming clearer. Physical
      therapies remain the lynchpin of management but the roles of anti-inflammatory
      medication, sympathectomies and a team approach are emphasized.

PMID- 10593112
TI  - A medico-legal report to a solicitor.
AB  - This is an example of the influence that modern pain science can have on medico
      legal reporting. The report has been reproduced with minor changes. These changes
      have been made so as to protect the identities of those involved and to assist
      the reader.

PMID- 10593113
TI  - [Genotoxic effect of the antitumor agent vincristine sulfate on human peripheral
      blood lymphocytes in vitro].
AB  - In consideration of high toxicity of cytostatic drugs and their potential
      mutagenic activity, this work studies the genotoxic effects of the antitumour
      drug Vincristine Sulfate. We analyzed preparations of human peripheral blood
      lymphocytes that have been exposed to different concentrations of Vincristine
      Sulfate in vitro. We have established that this cytostatic stimulates mitotic
      activity of lymphocytes at smaller concentrations (0.05 and 0.1 microgram/ml),
      but at higher concentration (0.5, 1.0 and 20.0 micrograms/ml) decreases
      proliferation of lymphocytes at significant level. It causes the appearance of
      irregular anaphase statuses in form of irregular distribution of chromosomes.
      Vincristine induces of appearance of C-mitosis that are a result of cytostatic
      activity of Vincristine Sulfate that blocks mitosis with prometaphase arrest.
      Cytostatic activity of Vincristine manifests itself as the destruction of
      interphase nuclei, the destruction of prophase nuclei with the destruction of
      chromosome mass and as the presence of chromosome material that is cut up in
      small pieces (chromosome pulverization). Vincristine interferes with the function
      of microtubules that are responsible for this mitosis and cytokinesis, and
      therefore influences itself on the formation of binucleated and multinucleated
      cells. Cytogenetic studies indicate that Vincristine induces the presence of
      micronuclei in lymphocyte's cells, while a higher concentration of Vincristine
      induces the presence of a large number of micronuclei at lymphocyte called
      multimicronuclei. Numerical chromosome aberrations are aneuploidy and poluploidy.

PMID- 10593114
TI  - [Catalytic properties of recombinant pancreatic ribonuclease A-K7H].
AB  - Pancreatic ribonuclease A is an enzyme that binds up ribonucleic acid (RNA) along
      the multiple binding subsites that essentially recognize the negatively charged
      phosphates of the substrate. It is endoribonuclease that catalyse
      depolimerization of single-stranded RNA. This work gives additional support to
      the existence of the phosphate-binding site p2 and confirms the central role of
      Lys-7 in establishing and electrostatic interraction with a phosphate group of
      the substrate. In this work catalytic properties of recombinant ribonuclease K7H
      have been studied. This enzyme is a mutant enzyme which contains histidine
      instead of lysine in a position 7, amino-acid that participates in the main
      catalytic center of RNase A, named p1. It was obtained by site-directed
      mutagenesis. Kinetic parameters of K7H have determined with C > p i poli (C) as
      substrates at pH 5.5 i 7.5. Kinetic parameters of K7H for C > p and as a
      substrate at pH 5.5 have not altered, but at pH 7.5 were significantly increased.
      Value Km was also increased, that indicates decreasing of affinity. Increasing of
      catalysis was double. Results of kinetic parameters of K7H with poli (C) as a
      substrate in pH 5.5 have shown slight difference according to kinetic parameters
      of commercial RNase A with poli (C). Significant decreasing of values of all
      kinetic parameters for K7H were reaction at pH 7.5.

PMID- 10593115
TI  - [Hepatotoxicity of cyclosporine in patients with kidney transplants].
AB  - In this study we have analyzed the liver transaminases levels in the 15 patients
      after kidney transplantation. All these patients have taken immunosuppressive
      cyclosporine therapy. The transaminases levels were determined by using the
      method Bergmayer kinetic ultraviolet test on the apparatus Tehnicon-Opera. The
      well known fact is the liver intoxication the same as kidney intoxication, if
      patients take cyclosporine for a long time. The average of the grafts in these
      patients were 9 years (ages between 1 and 16). The liver transaminases level was
      normal in all of groups of patients except for one who had high liver
      transaminases levels. After the correction cyclosporine therapy in the patient,
      the liver transaminases levels were normal. There was no possibility for
      monitoring of cyclosporine during the war, so the patients were determining the
      dose of cyclosporine on their own without any consulting with doctors. The most
      reliable method of cyclosporine applications is its determination, every day
      monitoring, and dosing by monitoring, which means concentrations in the reference
      values.

PMID- 10593116
TI  - [Ventricular arrhythmias in patients on chronic hemodialysis].
AB  - Prospective, comparative, multifactorial study was undertaken to examine
      occurrence, frequency and type of ventricular arrhythmias (VA) in patients of
      both sexes undergoing chronic haemodialysis using 24-hour method of dynamic
      electrocardiography (Holter). This research considered 100 patients divided into
      Experimental et Control group. 54% of HD patients suffered from PVC (36% Men and
      18% Women). The distribution of VA (PVC) in the Experimental (E) group according
      to Lown was: 0-46%, I-40%, II-6%, III-6%, IVA-16%, IVB-6%, V-2%. 20% of patients
      from the E-group suffered from complex PVC of higher degree simultaneously with
      distribution within the age groups over 40 years of age. The same occurrence was
      not notified in the Control (C) group. Variability of PVC occurrence was higher
      in HD group then in the C-group for all three criteria: a) Average number of
      patients with PVC during 1 hour--E:C group--6.79:4.21, b) Average number of PVC
      during 1 hour--E:C group--106.08:11.16, c) Average number of PVC for a single
      patient during 1 hour--E:C group--14.09:2.72. Occurrence in the E-group was the
      most frequent from 1-6 hrs and in the C-group 3-8 hrs of monitoring. 48% of
      patients from the HD group compared with 18% of patients from the C-group had
      significantly lowered ST-segment. Patients diary indicated dominating silent
      ischaemia. There is a statistically significant difference in the positivity of
      ST-segment with regards to sex M:W-3:1 (Hi2-18,954, p < 0.01). 78% of patients
      from HD group showed pathological ECG results compared to 8% in the C-group. HD
      is potentially arrythmogenic procedure in patients with preexisting cardial
      disease. On the other hand, the value of yearly Holter-monitoring in patients
      with preexisting cardial disease undergoing the programme of intermittent chronic
      HD, is undeniable.

PMID- 10593117
TI  - [Atrial myxomas--echophonocardiographic characteristics].
AB  - Myxomas (MY) of the atria are benign tumors of the heart usually originated from
      the interatrial septum. Moving of these tumors into the blood stream cause
      obstruction of the atrio-ventricular valves and appearance of pathological sounds
      and murmurs. The main goal of this study is analysis of echophonocardiographic
      examinations in 4 patients with left atrial myxomas and in one patient with right
      atrial myxoma. In all the cases, the oval tumor masses with diastolic movements
      from the atrium towards the ventricle and obstruction of the atrial ventricular
      ostium were clearly visualized on two-dimensional echocardiography (2D).
      Simultaneous M-mod echocardilographic and phonocardiographic examinations showed
      individual phases of myxoma movement and occurrence of sounds. In the patients
      with left atrial myxoma, echophonocardiography documented the splitting of the
      first sound (0.05-0.06 sek), protomesosystolic murmur, occurrence of tumor "hit"
      in the early diastole (0.08-0.11 sec after second heart sound) and a presystolic
      murmur above the tricuspid valve were found. In all the patients, surgical
      removal of myxoma was successfully performed followed by disappearance of the
      symptoms and pathological sounds, which was confirmed on both echocardiogram and
      phonocardiograms.

PMID- 10593118
TI  - [Electrocardiography in the detection and prevention of asymptomatic coronary
      heart disease].
AB  - This article presents relevant scientific facts about the role of ECG as a
      screening test in detection and prevention of asymptomatic coronary artery
      disease. The article represents an analytic study of great number of scientific
      publications from this area; only the most significant articles were used as
      references which can be used both as a confirmation of the statements in the
      article and as an initial guideline for those who are interested in more in-depth
      analysis of this problem. According to the conclusions of the majority of
      authors, ECG does not have great practical or medical value as a screening test
      for asymptomatic coronary artery disease because, with its application,
      reductions in morbidity and mortality were proven to be insignificant. ECG
      exercise testing is more sensitive and provides better practical results, but
      considering the costs and difficulties in interpretation (false positive and
      false negative results), its use remains confined to high-risk populations.

PMID- 10593119
TI  - [Relation of laboratory parameters to complications of liver cirrhosis].
AB  - Liver cirrhosis is characterized with alterations in hepatocytic perfusion,
      decreasing in number of hepatocytes and with seriously impared synthetic function
      of liver (hypoalbuminemy, inversion of albumino-globulinic ratio,
      hypoprothrombinemia). In a group of patients, suffered of liver cirrhosis with
      complication, we attempted to establish relationships between some of the typical
      clinical values: body weight in function of ascites evacuation, protein, albumin
      and value of prothrombin time in function of different groups of activity of
      aminotransferase in sera (AspAT, AlaAT) of improved and dead patients. We found a
      positive correlation for different groups of aminotransferase activities and
      laboratory values typical for liver cirrhosis with complications.

PMID- 10593120
TI  - [Organization of emergency care of locomotor injuries in the Canton of Sarajevo].
AB  - The system of the urgent medicine services in Sarajevo is organised on the
      principle of the step by step treatment, i.e. with a clear difference between
      preclinical and clinical levels. The objective of our work is to analyze the
      existing system of organisation of the urgent medical treatment in situations of
      loco-motor apparatus injuries, that is to find out how big discrepancy is between
      diagnostics performed during the pre-clinical period phase and diagnosis which is
      definitely clinically verified. During the above mentioned analyses were used
      patients of the Institute for Urgent medical care who were treated in the period
      of March-June 1999, during the time period from 7 pm-8 am (when surgical
      examination or x-ray diagnostics were not available). The analyses has been
      carried out as a short term survey. During the same time period the patients were
      monitored also by Urgent Medicine Centre of Clinical Centre of Sarajevo
      University, where were available both suitable surgical and x-ray diagnostics.
      For that purpose were controlled 34 patients who were treated by the above
      mentioned institutions with the following monthly frequency: March-13 patient,
      April-11, May-4, June-6. The ratio between male and female patients was 26:8.
      Based on the results, we can conclude that there is a great significant
      discrepancy between the initial diagnosis, verified diagnosis and the final
      treatment. The discrepancy was present in the following months: Marc-incorrect
      initial treatment in even 17.6% (6 patients), April 8.7% (3 patients), May-June
      17.6% (6 patients). The authors are due to complete evaluation of mistakes caused
      by the initial diagnoses and their impact on the final outcome of the treatment,
      including all the consequences caused by them.

PMID- 10593121
TI  - [Incidence of complications in surgical treatment of appendicitis in 1998].
AB  - An analysis of complication of acute appendicitis is given in this paper.
      Patients treated in General Hospital in Tesanj in period from 1.1.1998.
      31.12.1998. has been analysed. 141 patients were included in the study. 72
      (51.7%) out of 141 have had complications, among them 46 (63.8%) with gangrenous
      appendicitis, and 26 (31.1%) with perforations. The result of this study is the
      same, as the result, of the same research, in the literature.

PMID- 10593122
TI  - [Smoking among employees of the Health Center of Novo Sarajevo].
AB  - The survey carried out among 174 employees of the Health center Novo Sarajevo,
      resulted that smoking is a health problem with which BiH is confronted. The
      survey among the employees was carried out anonymously in regards to smoking
      habits, information, attitude and behavior of smokers. Out of 174 persons
      employed with the Health center there were 84 (48.3%) current smokers, 24 (13.8%)
      ex-smokers and 66 (37.9%) non smokers. The highest number of smokers was found
      among heavy smokers (meaning 15 cigarettes per day) compared to light smoker 12
      (13.1%) (meaning 9 cigarettes per day), (p < 0.01). Results of survey among
      smokers showed that knowledge and information about smoking were insufficient, so
      their attitude about smoking as a health problem was not adequate. The inquiry
      showed that level of information about smoking has to be larger and that only
      correct and insufficient informations might change the behaviour of smokers.

PMID- 10593123
TI  - [The role of Islam in the therapeutic rehabilitation process in raped women].
AB  - This paper is based on the author's experience from the psychotherapy group of
      raped women. The paper will present the flow of psychotherapeutic process of the
      group of women who were the victims of the massive rape during the aggression on
      Bosnia and Herzegovina. The rape of the women in B&H by the aggressor was a part
      of the strategy of the genocidal war that occurred recently. The role of Islam in
      our tradition is seen through the whole psychotherapeutic process. The Islam was
      the strongest therapeutic factor in the process of reintegration of the raped
      women's personalities.

PMID- 10593124
TI  - "Hello, I need your help!"--the Lifeline community alarm system for home care.
AB  - In many countries, homes for the elderly are filled to capacity. New technologies
      and technical solutions are available, which support endeavours to care for
      vulnerable people in a community. Home care enables those people to stay in their
      homes as long as possible. So-called "safety alarm systems"--special technical
      aids based on a telephone unit enable immediate contact between a caller and a
      caregiver. The systems are designed to enable people to call for help even if
      they cannot reach the telephone. The calls are directed to a community control
      centre, which is a headquarters for home-based care in a community. It is staffed
      for 24-hours a day accepting calls and arranging or providing adequate help. The
      Lifeline system is described which enables an increased independence to the
      system users and provides them with security and reassurance. The system is
      adaptive to suit requirements of smaller or larger communities.

PMID- 10593125
TI  - [Importance of vertical discrepancy on subgingival position of the crown margin].
AB  - The goal of work was in detecting the existence and the size of vertical
      discrepancy of subgingival positioned edge crown in extracted teeth. Value of the
      vertical discrepancy had been measured on extracted teeth with artificial crowns
      which were founded in the patient's mouth and were extracted with the artificial
      crown. On the teeth that were included in the research was measured the value of
      the vertical discrepancy on the demarked line. The measurement was enabled on the
      specialized measure in the Zavodima za mjerenje Vazduhoplovnog zavoda "ORAO"
      Rajlovac Sarajevo. Value measured vertical discrepancy on the teeth of the
      control group is shown in a table. It was measured if there was any significant
      statistic difference in discrepancy of the teeth in the group measured on the
      same surfaces (B) buccal, (O) oral, (M) mezial, (D) distal. X2 test was measured
      for all the surfaces B, O, M, D on all teeth. On the extracted teeth with the
      artificial crowns appears vertical discrepancy.

PMID- 10593126
TI  - [Materia medica in apothecary shops].
AB  - Even in 15th and 16th century there were people in Bosnia, preparing medicaments
      and selling different kinds of medical herbs. At first, they were Jews, later
      Muslims. They were called "attars"--drugsellers. They were very familiar with
      herbs of medical purpose. They could recognize herb by its colour and outlook.
      The goods were sold in specialized shops--attar shop. When analysing Materia
      Medica from an attar shop--according to the list from the 1911 (dr. Moritz Levy:
      "Sefards in Bosnia"), we can conclude that assortment of medical herbs and some
      medicaments was correct. Some Galen forms used in that time, are still in use
      nowadays. This paper describes all materials encompassed by Materia Medica. They
      are classified as organic and non-organic materials, and their use in therapy was
      also emphasized. Materia Medica of attar shops gives us a lot of material for
      research of non-official medicine and pharmacy from that time.

PMID- 10593127
TI  - [Hermann von Helmholtz--a physicist in medicine].
AB  - Helmholtz left an indelible mark in science. He was a predecessor to the
      multidisciplinary scientific approach, and his contribution to physics (The Law
      on Energy Sustainability, Helmholtz's Free Energy, Gibs-Helmholtz's Equationes,
      Helmholtz Theory of Rotational Liquids Flow, Helmholtz's Oscillatory Cycle,
      Helmholtz's Waves Equation) and to medicine (Ophthalmoscope, Young-Helmholtz's
      Theory of Colours, Sight Theory, Speed of Impulse Transfer, Speech and Tone of
      Voice, The Sound Transfer to Nerves) was indispensable. Helmholtz was surrounded
      by the respect and love of his contemporaries, appreciated and respected by his
      followers for the results he left. As a respectable professor of anatomy,
      physiology and physics at the most eminent universities, "he used to give
      lectures in such a clear and concise way that they could have been, without any
      changes, published in a form of a textbook" (Ostwald).

PMID- 10593128
TI  - Scientific progress versus reduction of animal experiments: weighing human and
      animal interests.

PMID- 10593129
TI  - New drugs for diabetes.

PMID- 10593130
TI  - Dutch university scientists increase research productivity using fewer animals
      per project.
AB  - The proposed general reduction in the number of animals used in research within
      the EU is inappropriate. If a reduction is warranted it should be related to the
      scientific requirements. We show that the numbers of laboratory animals used per
      published paper in the Netherlands has decreased by 23% between 1990 and 1997. A
      further reduction might be detrimental to scientific progress.

PMID- 10593131
TI  - Clinical and biochemical changes following 131I therapy for hyperthyroidism in
      patients not pretreated with antithyroid drugs.
AB  - BACKGROUND: Radioiodine therapy (131I) for the treatment of hyperthyroidism has
      been shown to be effective and safe. Despite the extensive experience with
      radioiodine therapy, the necessity for pretreatment with antithyroid drugs is
      controversial. Pretreatment is partly based on the concept that antithyroid drugs
      deplete the thyroidal hormonal stores, thereby reducing the risk of a radioiodine
      induced aggravation of hyperthyroidism or thyroid storm. Few data are available
      on the frequency of clinically significant exacerbations of hyperthyroidism
      following 131I therapy without prior treatment with antithyroid drugs. The aim of
      the present study was to determine prospectively the early clinical and
      biochemical changes after 131I therapy in patients who were not pretreated with
      antithyroid drugs. METHODS: Patients with Graves' disease (n = 21), toxic
      multinodular goiter (n = 11) or toxic adenoma (n = 2) were studied before and
      after 131I therapy. Clinical and biochemical parameters of thyroid function were
      investigated before and 1, 2, 8, 11, 18 and 25 days after 131I treatment.
      Patients were given no antithyroid drugs prior to 131I therapy, all patients
      received beta-blocking agents for symptomatic relief. RESULTS: In 19 of 34
      patients, a transient increase in thyroid hormone levels was observed,
      predominantly in the first week following 131I therapy. None of these patients
      experienced worsening of thyrotoxic symptoms. This transient increase in thyroid
      hormone levels was demonstrated in all patients with toxic multinodular goiter,
      whereas it was found in only six of 21 patients with Graves' disease. This
      difference could not readily be explained by differences in pretreatment thyroid
      hormone levels, administered dose or effectively absorbed dose of 131I.
      CONCLUSIONS: 131I treatment of hyperthyroidism without pretreatment with
      antithyroid drugs may cause a transient increase in thyroid hormone levels.
      Clinically significant exacerbations of hyperthyroidism were, however, not
      observed in our study population. Increased hormone levels following 131I therapy
      were more often seen in patients with toxic multinodular goiter than in patients
      with Graves' disease.

PMID- 10593132
TI  - Efficacy and tolerance of three different calcium acetate formulations in
      hemodialysis patients.
AB  - BACKGROUND: Calcium acetate (CaAc) is an effective phosphate binder in patients
      with chronic renal failure. However, an important side effect is gastro
      intestinal discomfort. Phos-ex (Cablon, The Netherlands) is the only commercially
      available non-coated CaAc formulation in our country. We developed two new CaAc
      formulations: neutral-coated CaAc (NCCaAc) and enteric-coated CaAc (ECCaAc).
      METHODS: In a randomised double-blinded cross-over trial we compared efficacy and
      tolerance of the three formulations in 19 stable hemodialysis patients, with a
      mean age of 63 years (range, 36-85), who had been on hemodialysis for 19 months
      (range, 6-47). Patients were randomised to receive NCCaAc or ECCaAc, with meals,
      for a period of 10 weeks and after cross-over for another 10 weeks. During a
      third non-blinded period, patients received Phos-ex for 10 weeks. RESULTS: Serum
      phosphate was significantly higher with ECCaAc compared to NCCaAc (1.89 +/- 0.07
      vs. 1.70 +/- 0.08 mmol/l, P < 0.05). Serum Ca was significantly lower with ECCaAc
      compared to NCCaAc or Phos-ex (2.38 +/- 0.04, 2.47 +/- 0.04 and 2.48 +/- 0.04
      mmol/l, P < 0.05). There were less hypercalcemic and more hyperphosphatemic
      events in the ECCaAc period, compared to the other periods. The daily CaAc dose
      and dietary intake of calcium, phosphate, protein and calories were comparable in
      all three periods. With Phos-ex, patients noticed more gastro-intestinal
      complaints than with to NCCaAc and ECCaAc. Two patients stopped taking Phos-ex
      because of side effects. CONCLUSIONS: In hemodialysis patients, phosphate control
      and tolerance were both influenced by the formulation of CaAc. Although phosphate
      control was adequate with all three formulations of CaAc, ECCaAc was less
      effective compared to NCCaAc or Phos-ex. NCCaAc and ECCaAc were better tolerated
      than Phos-ex. Regarding efficacy and tolerance, NCCaAc was the best calcium
      acetate formulation.

PMID- 10593133
TI  - Repaglinide--a new compound for the treatment of patients with type 2 diabetes.
AB  - Repaglinide is a new oral blood glucose lowering agent, a member of the
      carbamoylmethyl benzoic acid (CMBA) family. Its mechanism of action is partly
      similar to that of the sulphonylurea: the release of insulin from the pancreatic
      beta cells is stimulated by closure of ATP-dependent potassium channels. However,
      repaglinide regulates these channels via a different binding site on the beta
      cell than glibenclamide, and the drug does not cause insulin release in the
      absence of glucose, or during voltage-clamping. After oral administration the
      drug is rapidly absorbed and eliminated. It is therefore used in a meal-related
      dosing regimen; repaglinide is taken with each main meal. This meal-related use
      may give a more physiological mimick of daytime insulin requirement than once
      daily or twice-daily use of sulphonylurea. Patients using repaglinide are less
      likely to develop hypoglycaemic symptoms when they miss or postpone a meal in
      comparison with patients on glibenclamide treatment. In long-term comparative
      phase 3 clinical studies it was found that repaglinide is equally effective in
      maintaining glycaemic control as existing sulphonylurea, but it gives
      significantly better control of postprandial blood glucose levels. Repaglinide
      can be used as monotherapy both in obese and non-obese type 2 diabetic patients,
      and is also very effective in combination with drugs like metformin or
      thiazolidines. Because of its excretion through liver and bile it is also an
      attractive drug for diabetic patients with diminished kidney function, especially
      the elderly diabetic. Although the overall incidence of hypoglycaemia was similar
      during use of repaglinide and of sulphonylurea, fewer serious hypoglycaemic
      episodes were observed in repaglinide-treated patients.

PMID- 10593134
TI  - A case of herpes-like Sweet's syndrome in acute myelogenous leukemia during
      treatment with G-CSF.
AB  - A 49-year-old patient with refractory acute myelogenous leukemia (AML) is
      described who developed fever and herpes-like skin lesions during treatment with
      G-CSF. Skin biopsies revealed dermal neutrophilic infiltrates compatible with the
      diagnosis of Sweet's syndrome. The fever and skin lesions disappeared completely
      after treatment with corticosteroids.

PMID- 10593135
TI  - Cardiac arrhythmia as initial presentation of aneurysmal subarachnoid hemorrhage.
AB  - Cardiac arrhythmia and sudden death are most frequently caused by preexisting
      heart disease. Rarely, cardiac arrhythmia is a first symptom of an acute
      neurological event. We describe a patient with asystole and other cardiac
      arrhythmias, as initial symptoms of acute aneurysmal subarachnoid hemorrhage.
      Several aspects of cardiac arrhythmias and acute aneurysmal subarachnoid
      hemorrhage are discussed.

PMID- 10593136
TI  - Cold agglutinins as a fast clue to brucellosis?

PMID- 10593137
TI  - Reply to letter to the editor of J.H. van Loenhout-Rooyackers [published in the
      September issue of The Netherlands Journal of Medicine (1999;55:163)].

PMID- 10593138
TI  - [50th Jubilee Working Meeting of the German Council for Psychosomatic Medicine,
      November 11 to 13, 1999 in Berlin].

PMID- 10593139
TI  - [Melancholia and neurotic depression].
AB  - The author considers the psychopathological distinction between endogenous and
      neurotic depression as one of differing psychodynamics. In so doing he embeds
      both illnesses within psychoanalytic theory while at the same time allowing a
      sharp differentiation. Even the premorbid personalities of patients with
      endogenous and neurotic depression are different. The personalities of those with
      endogenous depression bear a similarity to those with obsessional character and
      betray a pathological super-ego monopolized by defence mechanisms. The
      personalities of patients with neurotic depression show an oral-dependent
      structure characterised by a structural deficit of the ego functions and of an
      autonomous super-ego. These factors are responsible for the greatly differing
      pathodynamics found in these illnesses and point to different etiological factors
      in socialization.

PMID- 10593140
TI  - [Critical review of the categorical structures of the core Conflictual
      Relationship Theme Method (CCRT)].
AB  - The CCRT-method developed by Lester Luborsky is the most widespread and best
      established method to assess relationship structures in the field of
      psychodynamic psychotherapy research. Although its categorical structures are
      criticised in many different ways there have not been any attempts to modify
      them. This article points out the inconsistency of the current categorical system
      and demonstrates first approaches to alternative solutions. For this purpose
      genetic algorithms are used. Their application in psychotherapy research is
      demonstrated here for the first time.

PMID- 10593141
TI  - [Validation of the Inventory for Interpersonal Problems (IIP). Results of a
      representative study in East and West Germany].
AB  - The Inventory of Interpersonal Problems (IIP) was developed in the USA in the
      late 1970s and in the mean time has become a well-established instrument applied
      in numerous clinical studies in German speaking countries under the name
      "Inventar zur Erfassung interpersonaler Probleme". The test manual was published
      in German in 1994, but without the corresponding standardisation for a German
      speaking population. The present study fills this gap. In a representative study
      the IIP was completed by 2025 West Germans and 1022 East Germans aged 14-92
      years. The representative norms are given and the psychometric dimensions of the
      questionnaire adjusted for this sample. As a contribution to testing validity the
      results were also related to the scores of a number of other tests completed by
      the same sample (Giessen Test--GT; Giessener Beschwerdebogen--GBB; Fragebogen zur
      Lebenszufriedenheit--FLZ; Angstbewaltigungsinventar--ABI and the Fragebogen zum
      erinnerten elterlichen Erziehungsverhalten [FEE]). The relevant results will be
      reported.

PMID- 10593142
TI  - [Otto F. Kerberg: psychoanalysis, psychoanalytic psychotherapy and supportive
      psychotherapy: Current controversies. PPmP 49 (1999) 91-99].

PMID- 10593143
TI  - [What is your diagnosis? Cervical aortic arch type D. Combined, calcified aortic
      valve disease with bicuspid abnormality. Mitral valve prolapse].

PMID- 10593144
TI  - [Cerebellar syndrome after varicella infection without virus identification in
      cerebrospinal fluid--an important differential ataxia diagnosis].
AB  - We report on a 35 year old female with a 26 day history of an intermittent
      cerebellar syndrome (dysarthria, ataxia of extremities, gait and trunk,
      nystagmus), mild meningism, cephalgia, recurrent emesis and nausea. Symptoms
      developed after typically chickenpox exanthema. Examination of the liquor showed
      mild pleocytosis, elevated protein and increased albumin quotient. Virus was not
      found by EIA or PCR. There were elevated levels of IgM- and IgG-antibodies to
      VZV. The EEG showed mild general changes, compatible with an encephalitis.
      Neuroradiological examinations were unremarkful. The neurological deficits partly
      regressed in the follow-up of two months. To the best of our knowledge we are the
      first that describe the paradox of an intermittent cerebellar syndrome after
      infection with chickenpox without detection of the virus in the liquor. This
      phenomenon can be related to the unusual combination of cerebellar ataxia and the
      later occurrence of mild encephalitis.

PMID- 10593145
TI  - [Value of invasive preoperative imaging in kidney tumors of malignant or
      uncertain character].
AB  - Preoperative staging of malignant renal tumors or undetermined dignity is mainly
      performed noninvasively using CT or MRI. In cases with vascular invasion or a
      solitary kidney extensive invasive evaluation of the tumor can influence
      preoperative planning. We report two cases of oncocytoma and renal cell carcinoma
      with extensive imaging using DSA or helical CT-cavography.

PMID- 10593146
TI  - [Does early operation of cerebral aneurysms achieve the best outcome?].

PMID- 10593147
TI  - [Ascites].
AB  - A 53 year old Italian with aethylic cirrhosis of the liver was hospitalized
      repeatedly over the last years because of recurrent ascites. During the last
      episode with fever, acute abdominal pain, exsudative ascites and elevated CRP
      spontaneous bacterial peritonitis was suspected and the patient was treated with
      antibiotics. Although the therapy was carried out correctly it had no effects on
      the symptoms. Finally the examination of ascites and matutinal sputum revealed
      mycobacterium tuberculosis and pulmonary and peritoneal tuberculosis was
      diagnosed. Tuberculostatic therapy was initiated with ethambutol, rifampicin and
      isoniacid adapted to impaired hepatic and renal function.

PMID- 10593148
TI  - [Fatal hypercalcemia in tamoxifen. Chief symptom: increasing somnolence in a 68
      year-old patient].

PMID- 10593149
TI  - Application of polymerase chain reaction to the prenatal diagnosis of sickle cell
      anaemia in Nigeria.
AB  - Although sickle-cell disease is very common in Nigeria, control by prenatal
      testing is lacking. The polymerase chain reaction-based technology combined with
      chorionic villi sampling has enabled us to offer prenatal diagnosis of sickle
      cell disease to 50 pregnant women who were at risk of bearing children with
      sickle cell anaemia. DNA was extracted from the villus and subjected to either
      PCR and restriction enzyme (Dde I) analysis (36 samples) or to PCR-ARMS procedure
      (12 samples) or to both procedures when the results by the first procedure were
      equivocal (2 samples). The genotypic distribution was 13AA, 25AS and 11SS. In one
      case, it was not possible to determine the genotype of the villi by both methods.
      A post delivery genotype analysis confirms the correctness of prenatal diagnosis
      in all the 42 subjects that has so far reported. The results clearly demonstrate
      the usefulness of the PCR method in the prenatal diagnosis of sickle-cell anaemia
      in this environment.

PMID- 10593150
TI  - Socio-demographic characteristics and sexual behaviour of adolescents attending
      the STC, UCH, Ibadan: a 5 year review.
AB  - As a continuation of the on-going efforts to prevent and control the spread of
      sexually transmitted diseases (STDs) and the Acquired Immunodeficiency Syndrome
      (AIDS) in adolescents, this retrospective clinic-based study identifies the socio
      demographic characteristics, describes the sexual practices, identifies the
      common STDs, including drug utilization patterns in this risk group at the
      special treatment clinic of the University College Hospital, Ibadan. Results
      reveal that adolescents constituted between 3.3% and 4.8% of the total number of
      patients seen each year. The characteristics of the subjects were as follows: 54
      (38.3%) were aged 19 years, 133 (94.3%) were single, 79 (53.2%) were females and
      103 (73.0%) were students. As regards sexual behaviour, 22 (15.71%) denied
      previous history of sexual intercourse. Vaginal intercourse was reported in all
      the sexually active youth, 2(1.71%) reported oral sex, while 10 (8.41%) admitted
      that they had multiple sexual partners. Gonorrhoea was diagnosed in 23 (21.51%)
      of sexually active youths. Among those who had used drugs before presentation
      ampicillin was the common drug used for treatment by 14 (26.4%). The importance
      of encouraging adolescents to present at STD clinics is highlighted. Health
      workers need to have a sympathetic attitude and assure them of confidentiality.
      The need for more community-based education is shown, including the importance of
      proper and complete documentation of hospital records.

PMID- 10593151
TI  - The effect of anti-hypertensive therapy on urinary albumin excretion in Nigerian
      hypertensives.
AB  - The effect of blood pressure control on urinary protein excretion was assessed in
      24 benign essential hypertensive subjects (12 males and 12 females). There were
      23 controls (11 males and 12 females). Mean ages were 55 and 53 years
      respectively. Twenty-four hours urine was collected from each subject before and
      after control of blood pressure, while the controls had only one 24 h urine
      sample collected. 24 h urinary albumin excretion was assessed using the
      Bromocresol Green Method. Control of blood pressure in the subjects took an
      average of eight weeks. Subjects were either given hydroflumethiazide, alpha
      methyldopa and/or prazosin as required. Blood pressure was measured in the right
      arm at each visit and pill counting was used to assess the compliance with
      therapy. The average urinary albumin excretion was significantly higher in the
      hypertensive subjects than the normotensive controls (P < 0.05). The average
      urinary albumin excretion after control of blood pressure was also significantly
      lower than, before control of blood pressure (P < 0.02). There was no correlation
      between SBP, DBP, MAP, and 24 h urinary albumin excretion in both subjects and
      controls. This study has shown that control of blood pressure can reduce or
      reverse urinary albumin excretion in Nigerian hypertensives.

PMID- 10593152
TI  - Jugular venous access for short-term haemodialysis. Ife experience.
AB  - Nine patients presenting with end stage renal disease needing haemodialysis
      underwent jugular venous access at the Obafemi Awolowo University Teaching
      Hospitals Complex over a two year period. There were 7 males and 2 females with
      age range 22-66 years. All the patients were hypertensive. Frequent complications
      of inadequate flow and inadvertent removal were absent in these cases. There was
      only one patient with catheter thrombosis and in another catheter related
      infection. Haemodialysis was maintained for periods ranging from 3 to 9 months in
      these patients satisfactorily.

PMID- 10593153
TI  - Salivary gland neoplasms: a descriptive analysis of the pattern seen in Enugu.
AB  - The objective of this study is to describe the pattern of salivary gland
      neoplasms as experienced in Enugu-Nigeria. Patients are selected from those
      attending the Otorhinolaryngology units of the author at the University of
      Nigeria Teaching Hospital and Balsam Clinics both in Enugu from January 1992 to
      December 1997, with tumours of salivary gland origin. Non-neoplastic lesions were
      excluded. There were forty-one (41) patients with salivary gland neoplastic
      growths in the following sites: parotids (25) submandibular gland (SMG) (10) and
      minor (6). There were 15 males, 26 females; age range 10-74 year, with mean of 41
      years. Seven of the parotid tumours were recurrent/residual. Salivary gland
      neoplasms are important surgical disease in this region with clinical
      manifestations similar to what obtains in other parts of the world. Surgical
      excision of salivary neoplasms is beneficial, but misadventure is still rampant.

PMID- 10593154
TI  - Erythrocyte osmotic fragility in hypertension and during diuretic therapy.
AB  - To determine the effect of diuretic therapy on osmotic fragility of red blood
      cells of hypertensive patients, 25 hypertensive and 15 normotensive subjects were
      followed up for 12 weeks. Osmotic fragility of erythrocytes of the hypertensive
      subjects were determined before treatment and at 6 weeks and 12 weeks after the
      start of diuretic therapy. The red cell size was larger in hypertensive subjects
      than in normal controls. With treatment, however, the red cell size was similar
      in the two groups of subjects. Osmotic fragility was higher in hypertensive
      subjects than in normotensive subjects. The osmotic fragility also became similar
      in the two groups with control of blood pressure in the hypertensive group.
      Osmotic fragility of red blood cells may be determined as a screening tool for
      hypertensive patients who will benefit from diuretic therapy.

PMID- 10593155
TI  - Comparison of scalar with vectorial electrocardiogram in axis determination.
AB  - Axis deviation is one of the variables most commonly sought for in
      Electrocardiography (ECG). Although no one doubts the superiority of vector
      cardiography (VCG) as the most accurate in axis determination, most clinicians
      adopt the Hexaxial Reference System (HRS) of the 12-Lead ECG (12LS) as the most
      accessible for routine use. The question therefore arises: How accurate is the
      HRS? The 12LS and Orthogonal (Frank Lead) ECG (OLS) were recorded in 664 adult
      Nigerians without heart or metabolic diseases. Their VCG were constructed
      manually for the QRS complexes. On each subject, QRS axis was determined by three
      methods: the HRS for the 12LS, the trigonometric method for the OLS and the
      direction of the maximum deflection vector for the VCG. Axes by the three
      modalities were analysed and compared statistically as applicable to paired
      samples. The frontal plane (FP) QRS axis ranged between O degree and +90 degrees
      in 98.2% of cases by VCG, 96% by the OLS and 93.6% by the 12LS. There was
      excellent correlation between axes obtained by VCG and OLS (r = 0.85; P <
      0.0001). It was lower but highly significant between VCG and the 12LS (r = 0.70;
      P < 0.0001). In the horizontal plane (HP), the 97 per centile distribution ranged
      from 240 degrees through 0 degree to 30 degrees; that is, posteriorly and to the
      left. In the left sagittal plane (LSP), the 95 per centile distribution ranged
      from 60 degrees counter-clockwise to 210 degrees; that is inferiorly and
      posteriorly. In a sample of healthy adult Nigerians, the QRS axis by VCG was
      located posteriorly, inferiorly and to the left. Axis determination by the 12LS
      is limited to the FP only, and it bears a good correlation with VCG. This
      commends the H RS as a condonable tool for estimating wave axis routinely and for
      epidemiologic studies.

PMID- 10593156
TI  - Socio-demographic characteristics of the "unbooked mother".
AB  - In a study to investigate the characteristics of the "Unbooked mother", the
      medical records of 467 patients who presented for delivery with no prenatal care
      at the obstetric unit of the King Khalid University Hospital (KKUH), Riyadh,
      during the period 1991 to 1995 were evaluated. For controls, the records of 415
      mothers who had pre-natal care in the Unit over the same period were also
      evaluated. Data pertaining to their socio-demographic characteristics, previous
      obstetric history, prevalence of pregnancy-related and familial diseases,
      gestation age at delivery and weights of the babies, were extracted and analysed
      using odds ratios and 95% confidence intervals (C.I.). The unbooked mother tended
      to be young (< or = 24 years), unskilled worker, or student. On the other hand,
      the booked ones tended to be primigravid, with pregnancy-related (PET) and
      familial diseases (hypertension and diabetes). However, the level of parity,
      gestation age and birth weights did not appear to significantly influence the
      tendency to be booked or unbooked. These findings highlight the group of women
      who should be targeted for health education counselling regarding the value of
      prenatal care. This way, one can avoid some of the catastrophes often said to be
      associated with deliveries in the unbooked mother.

PMID- 10593157
TI  - Blood pressure patterns in Nigerian adolescents.
AB  - The study was designed to define the mean blood pressure level of adolescents in
      the city of Ibadan and to establish the relationship between blood pressure and
      age, sex, weight, height, skinfold thickness, pulse and parental socio-economic
      class or educational level in an urban adolescent population. All pupils
      attending two schools located in 2 different socio-economic areas of Ibadan, a
      city in Western Nigeria, were recruited into the study. Mean Systolic Blood
      Pressures (SBP) were 111.3 +/- 12.4 mm for males and 112.5 +/- 12.2 mm for
      females (P < 0.04). The Mean Diastolic Blood Pressures (DBP) were 60.2 +/- 9.7 in
      males and 70.7 +/- 10.0 in females (P < 0.003). Mean SBP and DBP increased with
      age in the 2 groups and in both sexes. Adolescents aged 16-19 years had higher
      blood pressures than those aged 12-15 years (P < 0.001). There were positive
      significant correlations between body mass index (BMI), pulse and blood pressure.
      Mean Systolic and Diastolic Pressures were higher in children from the lower
      socio-economic group and the differences were significant in females (P < 0.001).
      Similarly higher percentage prevalences of SBP and DBP above 95th percentile were
      found in adolescents from the lower socio-economic group and the differences were
      statistically significant (P < 0.05 and P < 0.001 respectively). The findings
      confirm that age, sex, body mass and socio-economic background all have an
      influence on the blood pressure levels of Nigerian adolescents.

PMID- 10593158
TI  - The predominance of membranoproliferative glomerulonephritis in childhood
      nephrotic syndrome in Ibadan, Nigeria.
AB  - The histological findings in renal biopsy specimens obtained from 41 children
      with the nephrotic syndrome in Ibadan, Nigeria, between July, 1989 and June, 1996
      are presented. The patients consisted of 26 male and 15 female children and their
      ages ranged from 2-13 years. The predominant histological type was
      membranoproliferative glomerulonephritis (MPGN) which occurred in 21 (51.2%).
      Membranous nephropathy and minimal change nephropathy (MCN) accounted for 4
      (9.8%) patients each. The prevalence of MPGN was 33.3% in children less than 5
      years of age compared with 56.2% amongst children who were > or = 5 years. All
      the three patients with MCN who were treated with a course of prednisolone had
      complete remission of the disease. It is concluded that MPGN is the predominant
      histological lesion seen in childhood nephrotic syndrome in Ibadan and that MCN
      remains an uncommon lesion. Therefore, renal biopsy is recommended as a prelude
      to a trial of steroid therapy in these patients since MCN (which is generally
      associated with steroid-responsiveness) is an uncommon finding among them.

PMID- 10593159
TI  - Post-operative pain control--prescription pattern and patients' experience.
AB  - The prescription pattern for post-operative pain and patients' experience with
      pain relief were studied in 200 adult patients who had anaesthesia and surgery at
      the University College Hospital, Ibadan. Intermittent intramuscular injection of
      analgesics were prescribed for 192 patients (96%) while other routes were
      intravenous injections (2%), intravenous infusion (1%) and intermittent epidural
      injection (1%). Moderate to severe pain was reported by 46% and 49.5% of the
      patients immediately after surgery and before subsequent analgesic doses were due
      respectively. Pain disturbed patients from sleeping, moving in bed and coughing.
      It also made patients cry (20%), feel depressed (23%), anxious (12.5%) and angry
      (14.5%). Despite the high incidence of pain and the associated disturbances, 178
      patients (89%) still found overall pain relief satisfactory.

PMID- 10593160
TI  - Mortality on an ophthalmic ward.
AB  - This study was performed to investigate the causes and prevalence of death on an
      ophthalmic ward. Over a ten-year period, thirteen deaths occurred among 3545
      admitted patients (0.4%) mortality rate). Ten deaths occurred in patients with
      advanced neoplasms or complications of severe orbital infection. Three deaths
      were sudden. They occurred in the post-operative period among apparently healthy
      patients admitted for surgery. The possible causes of such sudden deaths are
      discussed.

PMID- 10593161
TI  - Guinea worm cause of adult onset asthmatic attack, a radiological diagnosis.
AB  - A case report of a fifty years old Hausa male from Sokoto town, Nigeria an
      endemic region of guinea worm infestation, who presented with sudden adult onset
      of asthmatic attack and was evaluated radiologically and the diagnosis of acute
      obstructive airway disease was confirmed. It was noted, that there were
      associated calcified chain of guinea worms in the lung parenchyma. A rare
      association of acute asthmatic attack. Patient responded there-after to an anti
      asthmatic regime of management.

PMID- 10593162
TI  - Outcome of twin pregnancies in patients with haemoglobinopathies--case reports.
AB  - Pregnancy in patients with haemoglobinopathy is associated with increased risk of
      maternal and perinatal morbidities and mortalities. Multiple pregnancy is
      potentially more hazardous than singleton pregnancy. There is a dearth of
      information concerning multiple pregnancies in patients with haemoglobinopathy.
      Four of such patients seen in the obstetric service of the University College
      Hospital, Ibadan are presented here and discussed. Increased surveillance and
      elective caesarean delivery are suggested in the management of these patients.

PMID- 10593163
TI  - Tuberculous osteitis of the cranium: a case report.
AB  - A 3-year old male presented with a 12-month history of painless scalp swellings
      associated with cough, fever and night sweats. Physical examination showed
      tender, fluctuant, pulsatile right frontotemporal and temporoparietal masses.
      Skull radiographs showed osteolytic skull lesions in the frontal and temporal
      bones. Microscopy of drained caseous material and histology of biopsies from the
      affected bone edges confirmed tuberculous osteitis. Though there was an initial
      response to antituberculous agents, the child died after 5 weeks from hepatic
      failure. Tuberculosis of the skull bones though rare, may become more common with
      the recent upsurge of tuberculosis worldwide. A high index of suspicion is
      necessary for early diagnosis and treatment.

PMID- 10593164
TI  - The influence of reproductive phase on lipopolysaccharide stimulation of
      prostacyclin production and cyclooxygenase-2 protein concentrations in
      reproductive and systemic arteries of the sheep.
AB  - Cyclooxygenase, the enzyme that converts arachidonate to prostaglandins, plays a
      regulatory role in vasodilation under normal and pathological conditions. Studies
      were conducted to determine the effects of reproductive phase and
      lipopolysaccharide (LPS) on production of PGI2 and amounts of cyclooxygenase
      protein in uterine, mammary, mesenteric, and renal arteries. Arteries were
      collected from ewes during the follicular (Day 0 = estrus) or luteal (Day 10)
      phase of the estrous cycle and were cultured in the presence of LPS. After 24 h,
      media were collected and analyzed for 6-keto-PGF1alpha, the stable metabolite of
      PGI2. In addition, arteries were collected and homogenized and the relative
      concentration of cyclooxygenase was determined via Western analysis.
      Lipopolysaccharide stimulated PGI2 production in all four-artery types from both
      follicular and luteal phase ewes (p < 0.001). Upon LPS stimulation, uterine and
      mammary arteries produced more PGI2 compared to mesenteric and renal arteries (p
      = 0.04). The phase of estrous cycle did not affect PGI2 production by any of the
      artery populations exposed to LPS (p = 0.35). There was no cyclooxygenase-2 in
      untreated uterine and mammary arteries and no cyclooxygenase-2 was detected in
      untreated or LPS-treated mesenteric and renal arteries. In contrast, LPS-treated
      uterine and mammary arteries from luteal phase ewes had higher (p = 0.064)
      cyclooxygenase-2 concentrations than those from follicular phase ewes. These
      results suggest that the hormone conditions of the follicular (high estrogen) and
      luteal (high progesterone) phases of the ovarian cycle play a role in regulating
      uterine and mammary artery but not mesenteric and renal artery response to LPS.

PMID- 10593165
TI  - In vivo airway eosinophil accumulation does not enhance antigen- or propranolol
      induced bronchoconstriction in guinea pigs.
AB  - BACKGROUND: Chronic airway eosinophil accumulation is characteristic of asthma.
      However, it remains unclear whether airway eosinophils enhance or reduce release
      of chemical mediators and/or action of the released mediators in the airways in
      vivo, because previous investigators have indicated that eosinophil-derived
      factors such as histaminase and arylsulfatase may alter the allergic reaction by
      metabolizing chemical mediators. Recently, we have developed a guinea pig model
      of propranolol-induced bronchoconstriction (PIB), which is mediated by lipid
      mediators such as thromboxane A2 (TxA2), cysteinyl leukotrienes (cLTs) and
      platelet activation factor (PAF). This study was conducted to explain the
      influence of airway eosinophil accumulation on antigen-induced
      bronchoconstriction and the following PIB, both of which are mediated by lipid
      mediators. METHODS: Guinea pigs were transnasally treated with 75 microg/kg of
      polymyxin-B or vehicle twice a week for a total of 3 weeks. Guinea pigs were
      anesthetized and treated with diphenhydramine hydrochloride, and then
      artificially ventilated 24 h after the last administration of polymyxin-B or
      vehicle followed by passive sensitization. Propranolol at a concentration of 10
      mg/ml was inhaled 20 min after an aerosolized antigen challenge. RESULTS: The
      proportion of eosinophils in bronchoalveolar lavage fluid obtained 15 min after
      the propranolol inhalation was significantly increased in guinea pigs treated
      with polymyxin-B compared with the vehicle. The polymyxin-B treatment did not
      affect antigen-induced bronchoconstriction or the following PIB. CONCLUSIONS: We
      conclude that eosinophils accumulated in the airways by polymyxin-B does not
      affect release of chemical mediators induced by antigen or propranolol
      inhalation, or action of released mediators in vivo.

PMID- 10593166
TI  - Insight into prostaglandin, leukotriene, and other eicosanoid functions using
      mice with targeted gene disruptions.
AB  - In recent years, there has been an exponential increase in the number of targeted
      gene disruptions performed in mice. At least 18 different gene knockouts have now
      been reported that have direct relevance to eicosanoid biology. These include
      genes that influence substrate availability (phospholipases), metabolism to
      eicosanoids (e.g., prostaglandin H synthases, lipoxygenases), and eicosanoid
      action (e.g., receptors for various prostaglandins). This minireview will outline
      the phenotype of these knockout mice and what has been learned about eicosanoid
      functions through use of this novel methodology.

PMID- 10593167
TI  - Monitoring of the thromboxane A2/prostacyclin ratio in the urine of patients with
      retinal vascular occlusion through the low-dose-aspirin therapy using the gas
      chromatography/selected ion monitoring method.
AB  - We determined the levels of the stable urinary metabolites of thromboxane A2 and
      prostacyclin, 11-dehydro-thromboxane B2 (11-dehydro-TXB2) and 2,3-dinor-6-keto
      prostaglandin F1alpha (2,3-dinor-6-keto-PGF1alpha) in patients with retinal
      vascular occlusion (RVO) to elucidate the change of the thromboxane
      A2/prostacyclin (TX/PGI) ratio with this disease and the effect of low-dose
      aspirin therapy. 11-Dehydro-TXB2 and 2,3-dinor-6-keto-PGF1alpha were converted to
      1-methyl ester-propylamide-9,12,15-tris-dimethylisopropylsilyl ether derivative
      and 1-methyl ester-6-methoxime-9,12,15-tris-dimethylisopropylsilyl ether
      derivative, respectively, and applied to a gas chromatography/selected ion
      monitoring. The average level of 11-dehydro-TXB2 in 30 patients with RVO was 1038
      +/- 958 pg/mg creatinine. It was significantly higher than that of 27 healthy
      volunteers, which was 616 +/- 294 pg/mg creatinine (p < 0.05 with unpaired t
      test). However, 2,3-dinor-6-keto-PGF1alpha levels were not significantly
      different between these two groups. The average ratio of TX/PGI in the RVO
      patients was 32 +/- 26 and it was significantly higher than that of healthy
      volunteers, 17 +/- 10 (p < 0.01). Patients with central retinal artery occlusion
      or branch retinal artery occlusion showed greatly high 11-dehydro-TXB2 levels and
      TX/PGI ratios, although the number of patients was limited in the current study.
      After the administration of low-dose aspirin (40 mg/day) for about 1 month, the
      TX/PGI ratio decreased to around the normal level. Following the levels for up to
      10 months, they also remained at the normal level. These observations suggested
      that the 11-dehydro-TXB2 levels and the TX/PGI ratio reflect the pathological
      conditions of RVO and are useful markers of the treatment.

PMID- 10593168
TI  - Urinary thromboxane A2/prostacyclin balance reflects the pathological state of a
      diabetic.
AB  - Levels of the stable urinary metabolites of thromboxane A2 and prostacyclin, 11
      dehydro-thromboxane B2 (11-dehydro-TXB2) and 2,3-dinor-6-keto-prostaglandin
      F1alpha (2,3-dinor-6-keto-PGF1alpha) were measured in diabetics to elucidate the
      relation between the thromboxane A2/prostacyclin (TX/PGI) balance and
      pathological states of diabetes mellitus. 11-Dehydro-TXB2 and 2,3-dinor-6-keto
      PGF1alpha were derivatized to methyl ester-propylamide-dimethylisopropylsilyl
      ether and methyl ester-methoxime-dimethylisopropylsilyl ether derivatives,
      respectively, and applied to a gas chromatography/selected ion monitoring. The
      TX/PGI ratios of diabetics were higher than those of healthy volunteers,
      suggesting the hypercoagulative states of this disease. The ratios showed
      positive correlations with the levels of blood glucose. The levels of hemoglobin
      A1c and triglyceride were correlated weakly with the ratio. Some of the patients
      who had relatively low levels of blood glucose also showed high TX/PGI ratios.
      Furthermore, the ratio increased in the order of the groups 1, 2, and 3; group 1
      contained patients who did not take medicine for diabetes, group 2 contained
      those who took oral hypoglycemic agents, and group 3 contained those who received
      insulin therapy. These observations indicate that the TX/PGI ratio reflects the
      pathological conditions of diabetes and is a useful marker, having few different
      features from other markers that are presently used.

PMID- 10593169
TI  - Biochemical changes in prostanoids and cerebral expression of cyclooxygenase
      (COX)-1 and COX-2 during morphine sulfate infusion in the newborn piglet .
AB  - To examine the biochemical regulation of morphine sulfate (MS) on prostanoid
      synthesis, conscious newborn piglets received a bolus dose of 100 microg/kg
      followed by a continuous infusion dose of 100 microg/kg/h. The control group
      received equivalent volume bolus and continuous infusion of 5% dextrose. Blood
      samples were drawn from the femoral artery and sagittal sinus vein before, during
      and after infusion for measurement of prostanoids. The expression of mRNAs
      encoding cyclooxygenases (COX)-1 and -2 in the brainstem, thalamus, cortex, and
      cerebellum of the newborn piglets were also examined. Systemic PGE2 levels
      declined substantially during and post MS infusion (p < 0.01), whereas sagittal
      sinus vein PGE2 levels increased following the bolus dose (p < 0.01) and at 4 h
      of continuous infusion (p < 0.01). MS infusion did not affect systemic 6
      ketoPGF1alpha levels, however, in the cerebral circulation 6-ketoPGF1alpha levels
      increased 146% (p < 0.01) following the bolus dose and remained elevated
      throughout the infusion and post infusion times. Systemic TxB2 levels increased
      transiently at 4 h (p < 0.01) and sagittal sinus vein TxB2 increased at 0.5 and 1
      h (p < 0.01) during continuous infusion. RT-PCR assays revealed a 1.5- (p <
      0.001) to 4-fold (p < 0.001) increased expression of COX-1 mRNA in the MS-infused
      brain samples. In contrast, no differences in COX-2 mRNA were detected between
      the groups. These data imply that MS may have significant effects on prostanoid
      synthesis in the newborn. The data further show that the MS-induced prostanoid
      responses appear to be mediated via COX-1.

PMID- 10593170
TI  - Reduced prostacyclin to thromboxane A2 ratio is correlated with central apneas in
      preterm infants.
AB  - Prostacyclin has a vasodilating effect on pulmonary vessels, whereas thromboxane
      A2 results in vasoconstriction. This study was designed to test the hypothesis
      that recurrent central apneas in preterm infants are correlated with a reduced
      prostacyclin to thromboxane A2 ratio. Twelve preterm infants with clinical events
      of apneas were matched with 12 control infants. Urinary concentration of 2,3
      dinor-6-keto-PGF1alpha and 2,3-dinor-TxB2 was determined, and the ratio
      correlated with the number of central apneas (>20s) measured in overnight
      polygraphy. The number of central apneas >20s/12h was 97.4 (SE 7.8) in the study
      group, and 47.3 (SE 6.6) in the control group (p = 0.001). There was a
      significant correlation between the number of central apneas and the 2,3-dinor-6
      keto-PGF1alpha/2,3-dinor-TxB2-ratio in all infants combined (r = -0.72, p <
      0.0001) as well as in the two subject groups. Central apneas in premature infants
      are correlated with an decreased prostacyclin to thromboxane A2 ratio. The
      underlying pathomechanism may be increased intrapulmonary shunts with reflexive
      central apneas due to reduced pulmonary oxygenation.

PMID- 10593171
TI  - Antigenic and sequence diversity at the C-terminus of the merozoite surface
      protein-1 from rodent malaria isolates, and the binding of protective monoclonal
      antibodies.
AB  - Merozoite surface protein-1 (MSP-1) is a major candidate in the development of a
      vaccine against malaria. Immunisation with a recombinant fusion protein
      containing the two Plasmodium yoelii MSP-1 C-terminal epidermal growth factor
      like domains (MSP-1(19)) can protect mice against homologous but not heterologous
      challenge, and therefore, antigenic differences resulting from sequence diversity
      in MSP-1(19) may be crucial in determining the potential of this protein as a
      vaccine. Representative sequence variants from a number of distinct P. yoelii
      isolates were expressed in Escherichia coli and the resulting recombinant
      proteins were screened for binding to a panel of monoclonal antibodies (Mabs)
      capable of suppressing a P. yoelii YM challenge infection in passive immunisation
      experiments. The sequence polymorphisms affected the binding of the antibodies to
      the recombinant proteins. None of the Mabs recognised MSP-1(19) of P. yoelii
      yoelii 2CL or 33X or P. yoelii nigeriensis N67. The epitopes recognised by the
      Mabs were further distinguished by their reactivity with the other fusion
      proteins. The extent of sequence variation in MSP-1(19) among the isolates was
      extensive, with differences detected at 35 out of the 96 positions compared.
      Using the 3-dimensional structure of the Plasmodium falciparum MSP-1(19) as a
      model, the locations of the amino acid substitutions that may affect Mab binding
      were identified. The DNA sequence of MSP-1(19) from two Plasmodium vinckei
      isolates was also cloned and the deduced amino acid sequence compared with that
      in other species.

PMID- 10593172
TI  - Purification and characterization of recombinant pyruvate phosphate dikinase from
      Giardia.
AB  - The gene encoding pyruvate phosphate dikinase (PPDK) from Giardia duodenalis was
      expressed using a baculovirus system. The recombinant enzyme was purified to
      homogeneity and its enzymological and solution structure properties
      characterized. The catalytic constant for the pyruvate-producing reaction was
      about twice as high (1560 min(-1) at 30 degrees C) as that for the reverse
      reaction (700 min(-1)) and the k(cat)/Km for PPi was about two orders of
      magnitude higher than k(cat)/Km for Pi, indicating that the pyruvate-forming
      reaction is much more efficient than the reverse, phosphoenolpyruvate (PEP)
      forming process. The endogenous substrate levels found for PEP (0.5 mM) and
      pyruvate (< 80 microM) support the assumption that, under physiological
      conditions, the enzyme primarily performs a catabolic function. The molecular
      mass of the purified recombinant PPDK was analyzed by analytical
      ultracentrifugation and size exclusion chromatography using different assay
      conditions that have been reported to affect the quaternary structure of PPDKs in
      other organisms. Both methods clearly indicated a dimeric structure for giardial
      PPDK with a molecular mass of about 197 kDa (monomer mass 97.6 kDa). Several
      compounds, primarily structural analogs of PPi, were tested for their ability to
      inhibit PPDK activity. Most of the bisphosphonates examined showed either no, or
      only a moderate, inhibitory effect on the enzyme. Imidodiphosphate was the only
      competitive inhibitor with respect to PPi (Kic = 0.55 mM), whereas the
      bisphosphonates produced a mixed type of inhibition. The most active compound in
      inhibiting PPDK activity was oxalate, with a Kic value of less than 1 microM with
      respect to PEP.

PMID- 10593173
TI  - Analysis of recombinant merozoite surface protein-1 of Plasmodium falciparum
      expressed in mammalian cells.
AB  - Synthetic chimeric DNA constructs with a reduced A + T content coding for full
      length merozoite surface protein-1 of Plasmodium falciparum (MSP1) and three
      fragments thereof were expressed in HeLa cells. To target the recombinant
      proteins to the surface of the host cell the DNA sequences coding for the N
      terminal signal sequence and for the putative C-terminal recognition/attachment
      signal for the glycosyl-phosphatidyl-inositol (GPI)-anchor of MSP1 were replaced
      by the respective DNA sequences of the human decay-accelerating-factor (DAF). The
      full-length recombinant protein, hu-MSP1-DAF, was stably expressed and recognised
      by monoclonal antibodies that bind to the N-terminus or the C-terminus of the
      native protein, respectively. Its apparent molecular mass is higher as compared
      to the native protein and it is post-translationally modified by attachment of N
      glycans whereas native MSP1 is not glycosylated. Immunofluorescence images of
      intact cells show a clear surface staining. After permeabilization hu-MSP1-DAF
      can be detected in the cytosol as well. As judged by protease treatment of intact
      cells 25% of recombinant MSP1 is located on the surface. This fraction of hu-MSP1
      DAF can be cleaved off the cell membrane by phosphatidylinositol-specific
      phospholipase C indicating that the protein is indeed bound to the cell membrane
      via a GPI-anchor. Human erythrocytes do not adhere to the surface of mammalian
      cells expressing either of the constructs made in this study.

PMID- 10593174
TI  - Mutations in the cytochrome b gene of Plasmodium berghei conferring resistance to
      atovaquone.
AB  - The molecular lesions which underlie the resistance of the malaria parasites to
      atovaquone, a coenzyme Q analogue, were investigated. Resistant clones of
      Plasmodium berghei ANKA strain were isolated following prolonged propagation in
      mice in the presence of increasing doses of the drug, and their cytochrome b gene
      sequenced. Three mutations were detected, T-C substitution at nt 431, G-A at nt
      399 and G-T at nt 850, resulting in amino acid changes in the putative cytochrome
      b product at residues 133, 144 and 284. The V284F amino acid change is in the
      sixth transmembrane helix of the protein and was observed in all resistant
      clones. An additional M133I or L144S amino acid change within the Qo site at an
      extramembranous amphipathic helix significantly increases the resistance to
      atovaquone. Our results (a) provide evidence that the antimalarial activity of
      atovaquone indeed involves an interaction with the cytochrome b; (b) define
      atovaquone as an inhibitor of the ubiquinol oxidase activity of the cytochrome
      bc1 complex; and (c) define amino acid residues in the mammalian cytochrome b
      which might be critical in determining its relative resistance to atovaquone.

PMID- 10593175
TI  - A single-chain antibody fragment specific for the Plasmodium berghei ookinete
      protein Pbs21 confers transmission blockade in the mosquito midgut.
AB  - Mouse monoclonal antibody 13.1 (mAb 13.1) directed against Pbs21, a 21-kDa sexual
      stage surface protein of Plasmodium berghei, is known to inhibit oocyst
      development from gametocytes and ookinetes in the mosquito midgut. To examine the
      properties and potential uses of a single-chain antibody fragment (scFv) for
      blocking transmission of malaria parasites to mosquitoes, we have cloned and
      sequenced the genes encoding variable regions of the immunoglobulin heavy and
      light chains (V(H) and V(L)) of mAb 13.1. The V(H) and V(L) genes were assembled
      as an scFv gene, and expressed in a baculovirus expression system. Following
      purification of 13.1 scFv, Western blotting and inhibition ELISA assays confirmed
      that 13.1 scFv retained the binding specificity of the parent mAb 13.1 for Pbs21.
      Furthermore, 13.1 scFv bound to the surface of P. berghei ookinetes, and blocked
      oocyst development in the mosquito midgut by at least 93%, as assessed by oocyst
      counts in mosquitoes. We suggest that the 13.1 scFv gene could be useful not only
      in studying the mechanism of transmission blockade, but also in generating, by
      mosquito germline transformation, a model system to evaluate the production of
      mosquitoes refractory to malaria.

PMID- 10593176
TI  - Trypanosoma cruzi adenylyl cyclase is encoded by a complex multigene family.
AB  - The parasitic protozoan Trypanosoma cruzi undergoes several differentiation
      events during its life cycle. Some of these transitions are thought to involve
      activation of adenylyl cyclase via the binding of peptide ligands to the cell
      surface. Here we describe the characterisation of the adenylyl cyclase gene
      family of T. cruzi. Two complete genes and one pseudogene have been sequenced.
      The protein products appear to have a large extracellular domain, a single
      transmembrane helix and a cytosolic catalytic domain. The adenylyl cyclase genes
      are present on at least six chromosomes and are scattered rather than clustered.
      They form a large polymorphic family in which the extracellular domain is
      particularly variable. An Escherichia coli adenylyl cyclase mutant could be
      complemented by expression of the catalytic domain of the T. cruzi enzyme. The
      recombinant protein had adenylyl cyclase activity in vitro, which was enhanced by
      increasing concentrations of divalent cations (Mn2+ > Mg2+). This constitutively
      active recombinant protein will be a useful tool for dissecting the catalytic
      mechanism of adenylyl cyclase.

PMID- 10593177
TI  - The evolution of two Trypanosoma cruzi subgroups inferred from rRNA genes can be
      correlated with the interchange of American mammalian faunas in the Cenozoic and
      has implications to pathogenicity and host specificity.
AB  - The agent of Chagas disease, Trypanosoma cruzi, is divided into two highly
      divergent genetic subgroups, lineages 1 and 2, which include all typed strains
      isolated from humans, insect vectors, and sylvatic mammals. The evolutionary
      origin of these two T. cruzi lineages and the clinical importance of their
      identification, have been the subject of intense debate. Here, using molecular
      phylogenetic analysis, we found that the distance between the two T. cruzi
      lineages is equivalent to the distance between genera Leishmania and
      Endotrypanum. Also, we confirmed that T. rangeli is more closely related to T.
      cruzi than to T. brucei using the rDNA sequence from a human strain of T.
      rangeli. Phylogenetic trees based on small subunit rDNA sequences further suggest
      that the two T. cruzi lineages diverged between 88 and 37 million years (Myr)
      ago. We hypothesize that lineage 2 is indigenous to South America while lineage 1
      has been introduced to South America recently, along with North American
      placental mammals, after the connection of the Americas in the Pliocene (5 Myr
      ago) or with caviomorph rodents and primates in the Oligocene (38 Myr ago). This
      would explain the preferential association of T. cruzi lineage 2 with marsupials
      and of lineage 1 with human disease. These two T. cruzi lineages are likely to be
      distinct species, or at least subspecies, because of their different ecological
      and epidemiological traits and estimated long period of independent evolution.

PMID- 10593178
TI  - Developmentally regulated expression of a unique small heat shock protein in
      Brugia malayi.
AB  - A screen of an expression library from the fourth larval stage (L4) of the
      parasitic nematode Brugia malayi resulted in the identification of a 727 bp full
      length cDNA with 29-40% identity to members of the small heat shock family of
      proteins (Bm-hsp-s1). The open reading frame encoded a protein of approximately
      18 kDA (Bm-HSP-s1). An alignment of the Bm-HSP-s1 sequence with the sequences of
      small HSPs from vertebrate and invertebrate species demonstrated that a majority
      of the identity was concentrated in the central alpha-crystallin domain. Bm-HSP
      s1 was constitutively produced by L4 and adult parasites and at low levels by
      third-stage larvae (L3), but not by first-stage larvae (microfilariae). In adult
      parasites, Bm-HSP-s1 was localized to the body wall muscle cells and to the cells
      of the hypodermis/lateral cord. Bm-HSP-s1 production was induced in adult and L3
      incubated at 42 degrees C and in L3s during the developmental transition from
      vector-stage to vertebrate-stage parasites at 37 degrees C. Neither increased nor
      decreased temperatures induced Bm-HSP-s1 production in microfilariae. Nitric
      oxide induced low-level, transient Bm-HSP-s1 synthesis in adults, but not in
      microfilariae. Bm-HSP-s1 did not function as a molecular chaperone to prevent
      heat-induced aggregation of a test substrate. The developmentally regulated
      expression and inducable nature of Bm-HSP-s1 suggests that it may have a stage
      restricted role in maintaining parasite homeostasis.

PMID- 10593179
TI  - Gender-specific gene expression in Brugia malayi.
AB  - Brugia malayi is a mosquito-borne filarial nematode that causes lymphatic
      filariasis and elephantiasis in humans. The purpose of this study was to identify
      and characterize genes that are expressed differentially in male and female B.
      malayi in hopes of gaining new insight into the reproductive biology of the
      parasite. Two approaches were used. A 5' differential display PCR (splice leader
      differential display PCR, SL DD-PCR) was performed by PCR with splice leader and
      random primers on cDNA templates, and electronic subtraction was performed on
      expressed sequence tag (EST) cluster databases developed by the Filarial Genome
      Project (FGP). Gender-specific expression of candidate clones was confirmed by RT
      PCR for six of 22 (27%) clones identified by DD and in seven of 15 (47%) clones
      identified by electronic subtraction. One clone was identified by both methods.
      Several female-specific clones had homology to known nematode genes that encode a
      fatty acid binding protein, a high mobility group protein, an eggshell protein, a
      glutamate-gated ion channel, and a collagen. However, most of the clones have no
      significant homology to known genes or proteins in computer databases. This
      project has confirmed the value of SL DD-PCR and electronic subtraction for
      analysis of gene expression in filariae. These two complimentary techniques may
      be generally applicable to the study of gender-specific (and by analogy stage
      specific) gene expression in other nematodes.

PMID- 10593180
TI  - Characterization of a putative nuclear receptor from Onchocerca volvulus.
AB  - Steroids and retinoids are important regulators of development in invertebrates
      and vertebrates. The central mediators of action of these compounds are their
      cognate receptors, which together form a family of proteins known as the nuclear
      receptor family. Previous studies have demonstrated that the genome of Onchocerca
      volvulus encodes at least three members of the nuclear receptor family. Here, the
      characterization of one member of this family from O. volvulus, designated OvNR
      2, is described. OvNR-2 was found to be most similar to a number of vertebrate
      retinoic acid receptors and to the Drosophila melanogaster EiP78c protein.
      Modeling studies suggest that OvNR-2 forms a boot shaped ligand-binding cavity of
      a shape and size that can bind steroids. Expression of the mRNA corresponding to
      OvNR-2 is tightly regulated in adult parasites, appearing only in the extended
      intrauterine microfilariae. The protein derived from expression of the OvNR-2
      cDNA in a bacterial system is recognized by serum antibodies in a majority of
      individuals infected with O. volvulus.

PMID- 10593181
TI  - Expression and localization of serum resistance associated protein in Trypanosoma
      brucei rhodesiense.
AB  - The trypanosome lytic factor (TLF) is a primate specific innate defense mechanism
      that restricts the host range of African trypanosomes. Trypanosoma brucei
      rhodesiense, the causative agent of the acute form of human sleeping sickness, is
      resistant to the cytolytic action of TLF. By differential display PCR we have
      identified a gene in T. b. rhodesiense that is preferentially expressed in cell
      lines resistant to TLF. The protein sequence predicted from the gene shows
      homology to the trypanosome variable surface glycoprotein (VSG) gene family and
      in particular, to the previously reported human serum resistance associated gene
      (SRA). The amount of SRA mRNA is over 1000-fold higher in TLF resistant cells
      relative to TLF sensitive trypanosomes. Treatment of TLF sensitive trypanosomes
      with increasing concentrations of TLF in mice results in the selection of
      parasites that have reverted back to the TLF resistant phenotype. These
      trypanosomes also showed high levels of SRA mRNA. Antibodies against recombinant
      SRA react with a 59 kDa protein on western blots of total cell protein from TLF
      resistant trypanosomes but not TLF sensitive cells. Indirect immunofluorescence
      revealed that SRA is a cell surface protein present only in TLF resistant
      trypanosomes. These results suggest that TLF resistance in human sleeping
      sickness trypanosomes is a consequence of the selective, high level expression of
      a cell surface molecule(s). In addition, these studies support the role of TLF as
      a major factor in human serum mediated killing of susceptible trypanosomes.

PMID- 10593182
TI  - Caveolae-like structures in the surface membrane of Schistosoma mansoni.
AB  - Specialized regions of cellular membranes termed detergent-insoluble
      glycosphingolipid-enriched membrane domains (DIG) have been identified in
      mammalian cells and shown to contain signalling molecules, cholesterol,
      sphingolipids and caveolae. Here we report that the unusual double surface
      membrane of the tegument of the trematode parasite Schistosoma mansoni possesses
      biochemically distinct domains analogous to DIG. When subjected to sucrose
      density gradient centrifugation, a detergent-extracted tegument from adult
      parasites yielded a low-density fraction consisting of detergent-insoluble
      complexes (DIC). Several tegument proteins were concentrated in DIC and a subset
      of these were labelled when adult schistosomes were biotinylated using a membrane
      impermeant reactive biotin prior to extraction. The GPI-linked proteins alkaline
      phosphatase (SmAP), Sm200, the membrane-bound protein Sm23, and a protein
      recognized by an antibody against human caveolin, co-purified with DIC whereas
      soluble proteins, such as paramyosin and aldolase, were found at the bottom of
      the gradient. Antibodies against DIC immunoprecipitated a subset of worm surface
      proteins and immunolabeled the dorsal tegument of adult worms. Transmission
      electron microscopy of DIC revealed caveolae-like structures in the double
      bilayer surface structure. These results suggest that the tegument of adult S.
      mansoni possesses specialized membrane domains that are resistant to detergent
      extraction, contain a subset of total tegument membrane proteins, and bear
      caveola-like invaginations, and thus are analogous to DIG.

PMID- 10593183
TI  - Atypical post-translational modification and targeting of a Schistosoma mansoni
      surface receptor, a member of the transforming growth factor beta receptor family
      of cell surface receptors.
AB  - The surface membrane of the intravascular parasite Schistosoma mansoni is
      composed of not one but two closely apposed lipid bilayers which overlie a
      syncytial cellular layer, known as the tegument or neodermis. To gain insights
      into how membrane proteins are transported to and displayed on this unusual
      surface structure, we have investigated the post-translational modification and
      targeting of SmRK-1, a receptor and type I membrane protein expressed on the
      parasite surface, using heterologous expression systems. While SmRK-1 enters the
      secretory pathway in these systems, our data indicate that the SmRK-1 N-terminal
      signal peptide is either not cleaved by signal peptidase or is only eleven amino
      acids long or less. Retention of the signal peptide is accompanied by N-linked
      glycosylation of an asparagine residue within the predicted signal peptide. The
      SmRK-1 signal peptide is not capable of directing another cytoplasmic protein to
      the secretory pathway, suggesting that the signal for insertion of the SmRK-1
      extracellular domain into the endoplasmic reticulum resides elsewhere in the
      protein. Further, SmRK-1 is inefficiently transported to the cell surface in
      mammalian cells, suggesting that the schistosome neodermis possesses specialized
      systems for receptor targeting and localization.

PMID- 10593184
TI  - The use of transgenic Trypanosoma brucei to identify compounds inducing the
      differentiation of bloodstream forms to procyclic forms.
AB  - The expression of procyclins is the earliest known marker of differentiation of
      bloodstream forms of Trypanosoma brucei to procyclic forms. We have generated
      transgenic bloodstream and procyclic forms in which the coding region of one
      procyclin gene was replaced by E. coli beta-glucuronidase (GUS). GUS activity can
      be monitored in a simple one-step colour reaction in microtitre plates; this
      assay is potentially suitable for large-scale screening for compounds that
      influence differentiation. GUS was stage-specifically expressed in procyclic
      forms and its synthesis occurred in parallel with that of procyclin when
      bloodstream forms were triggered to differentiate by the addition of cis
      aconitate. GUS could also be induced by brief treatment with the proteases
      trypsin, pronase or thermolysin, but not with pepsin or thrombin. Interestingly,
      a combination of one of the active proteases with cis-aconitate resulted in
      increased GUS activity relative to either trigger alone. In contrast to cis
      aconitate, protease treatment resulted in considerable cell death. Experiments
      with the pleomorphic strain AnTat 1.1 showed that long slender bloodstream forms
      were rapidly killed by proteases, whereas stumpy forms were largely resistant.
      Stumpy forms treated with trypsin differentiated synchronously and expressed
      procyclin with faster kinetics than when they were triggered by cis-aconitate. As
      predicted by the GUS assay, differentiation was even more rapid when both
      inducers were used simultaneously, with all cells expressing maximal levels of
      procyclin within 3 h.

PMID- 10593185
TI  - Upstream regulatory sequences required for expression of the Trichomonas
      vaginalis alpha-succinyl CoA synthetase gene.

PMID- 10593186
TI  - Gametocyte-dominant expression of a novel P-type ATPase in Plasmodium yoelii.

PMID- 10593187
TI  - Gender differences in brain and behavior: hormonal and neural bases.
AB  - This article briefly discusses the difficulties in determining the brain-behavior
      relationship and reviews the literature on some potential mechanisms underlying
      gender differences in behavioral responses. Mechanisms that are discussed include
      genetic effects, organizational effects of gonadal hormones, genomic actions of
      steroids, nongenomic effects of steroids, and environmental influences. The
      review is an introduction to the articles presented in this special volume on
      gender differences in brain and behavior.

PMID- 10593188
TI  - Prenatal exposure to low doses of the estrogenic chemicals diethylstilbestrol and
      o,p'-DDT alters aggressive behavior of male and female house mice.
AB  - Exposure to estrogenic chemicals during critical periods in fetal life can alter
      the development of reproductive organs, the neuroendocrine system, and subsequent
      behavior. We examined the effects of prenatal exposure to the estrogenic
      chemicals, o,p'-DDT (the estrogenic contaminant in commercial DDT) and the drug
      diethystilbestrol (DES), as a positive control, on different forms of aggressive
      behavior in both male and female house mice. We also examined effects of these
      chemicals on male reproductive organs. From gestation days 11-17 female mice were
      fed an average concentration (dissolved in oil) 0.018 and 0.18 ng/g body weight
      of DES. Doses of o,p'-DDT were 18 and 180 ng/g body weight, based on the
      prediction that the in vivo potency of o,p'-DDT would be approximately 1000-times
      lower than DES. We found that prenatal exposure to DES increased the frequency of
      both males and females that responded aggressively to a same-sex conspecific.
      Preputial glands in males exposed to the 0.018 ng/g dose of DES were
      significantly enlarged relative to controls. Males exposed to the 18 ng/g dose of
      DDT had smaller testes than controls. The possible implications of perturbing the
      development of social behaviors, such as aggression, on individuals reproductive
      success and social structure of the population are discussed.

PMID- 10593189
TI  - Sex differences in long-term consequences of prenatal diazepam exposure: possible
      underlying mechanisms.
AB  - Prenatal exposure to diazepam, a benzodiazepine (BZD) compound, leads to
      pronounced effects on responses to stressors in exposed animals when they reach
      adulthood. Many of the responses are sex specific. The mechanisms mediating the
      effects of the exposure on the organism have not been elucidated; however, the
      time course for the appearance of altered function following in utero drug
      exposure indicates that the exposure interfered with neural organization of
      mechanisms mediating responses to stressors. The article discusses possible
      mechanisms that relate to sites of action of the drug in the developing brain:
      the GABA(A) receptor, and the mitochondrial BZD receptor. The mechanisms
      mediating the sex-specific impact of diazepam on the developing brain appear to
      be complex and interactive.

PMID- 10593190
TI  - Neonatal stress alters habituation of exploratory behavior in adult male but not
      female rats.
AB  - The effect of monosodium-L-glutamate (MSG) administration in the neonatal period
      on habituation of exploratory behavior related to gender differences was
      investigated. Rats of both sexes were intraperitoneally treated with MSG (4 mg/g)
      or hypertonic saline (10% NaCl) on postnatal days 2, 4, 6, 8, and 10. On
      postnatal day 65, the animals were tested in an open-field test during 4
      consecutive days, once daily in 6-min sessions. The rapidity of habituation of
      exploratory behavior during repeated exposure to the open field (interrupted
      habituation) and over individual sessions (uninterrupted habituation) was
      evaluated by using the method of linear regression. Compared to intact controls,
      there were no significant differences found in interrupted habituation, neither
      in males nor in females. Uninterrupted habituation in neonatally treated males
      was slowed down in the first 2 days of testing. No differences in adult behavior
      between treated groups (MSG and hypertonic saline) were observed, i.e., there
      were no late effects specific for neonatal MSG administration. In females,
      uninterrupted habituation was not affected. Males proved to be more sensitive to
      neonatal stress associated with injections of MSG or hypertonic saline than
      females, and showed feminine-like habituation in the new environment.

PMID- 10593191
TI  - Perinatal exposure to the estrogenic pollutant bisphenol A affects behavior in
      male and female rats.
AB  - Bisphenol A (BPA) is an environmental estrogen with potentially aversive effects
      on public health. In rats, we studied the effects of perinatal exposure to BPA on
      nonsocial behaviors partly influenced by gonadal hormones. BPA was administered
      orally to one group of mother rats at a concentration within the range of human
      exposure from 10 days before mating until the weaning of the pups. In a second
      group, BPA was given at a higher dosage during a critical period for brain
      organization, i.e., from day 14 of gestation until day 6 after birth. The
      offspring of the treated mothers were tested in the holeboard and the elevated
      plus-maze at 85 days of age. Various aspects of nonsocial behavior were affected
      by BPA, differently in males and females, confirming that exposure to a weak
      environmental estrogen in the period of sexual differentiation of the brain can
      influence adult behavior. However, contrary to our expectation, a clear
      masculinization of females was not observed. In general, the factor analysis
      indicated that in treated males both the motivation to explore and anxiety are
      reduced, while in females, motor activity and motivation to explore are
      depressed. Because there were no substantial differences between the two
      modalities of BPA administration, we suggest that the prolonged treatment with
      the low dosage compensates for the higher dosage given during a shorter steroid
      sensitive period. This may be a cause of concern for public health, given the
      greater incidence of prolonged exposure of humans to low concentrations released
      into the environment.

PMID- 10593192
TI  - Schedule-induced polydipsia: gender-specific effects and consequences of prenatal
      cocaine and postnatal handling.
AB  - The impact of gestational cocaine in conjunction with postnatal handling on
      schedule-induced polydipsia (SIP) was examined. Rat offspring were derived from
      Sprague-Dawley dams injected subcutaneously with 40 mg/kg/3 cc cocaine
      hydrochloride (C40) on gestational days 8-20, dams injected with vehicle and pair
      fed 4 (PF4) days to mimic the acute anorexic effects of cocaine administration,
      and nontreated (NT) control dams. In adulthood, offspring were food deprived and
      given 13 daily 30-min SIP sessions, with water intake recorded during the
      scheduled (fixed time 60 s-FT60) food delivery. For 4 days thereafter, animals
      received saline, 5 or 10 mg/kg of cocaine in counterbalanced order prior to SIP
      testing. Acquisition and maintenance of SIP, but not cocaine-induced suppression
      of SIP performance, were observed to be dependent upon prenatal treatment,
      handling, and gender. Females acquired SIP faster and exhibited notably higher
      levels of polydipsia than males. Early handling increased levels of established
      SIP in NT offspring, while enhancing SIP acquisition in both PF4 and C40
      offspring. In nonhandled animals, NT offspring exhibited less SIP than PF4 and
      C40 offspring, differences that were attenuated by early handling. These effects
      are discussed in relation to previously reported neurohormonal characteristics of
      these gender and treatment variables.

PMID- 10593193
TI  - The maternal separation paradigm and adult emotionality and cognition in male and
      female Wistar rats.
AB  - A single 24-h maternal separation (MS) in the rat during the stress
      hyporesponsive period alters adult behavior and neuroendocrine stress response.
      The age of the animal at MS might be a crucial factor for effects in adulthood.
      We report here on adult behavioral effects of MS performed on postnatal day 4
      (MS4), 9 (MS9), or 18 (MS18) in male and female Wistar rats. Unrelated subjects
      were used to avoid confounding litter effects. Subjects were tested on paradigms
      of unconditioned fear/anxiety, i.e., open field and elevated plus-maze, and on
      paradigms involving learning in an aversive situation, i.e., conditioned
      freezing, active avoidance, and water maze. In line with our predictions we
      obtained (a) sex differences that were consistent with enhanced fear/anxiety in
      males relative to females, (b) evidence that MS4 yielded deficits in active
      avoidance learning and conditioned freezing (trend level), whereas MS9 yielded
      enhanced active avoidance and water maze learning, (c) evidence (at trend level)
      that these effects of MS are greater in males than in females. There was no
      evidence for an effect of MS on paradigms of unconditioned fear/anxiety. We
      conclude that MS, irrespective of the age at separation, does not provide a
      robust environmental model of modified behavior in aversive situations.

PMID- 10593194
TI  - Sex-dependent behavioral effects of the neurosteroid allopregnanolone
      (3alpha,5alpha-THP) in neonatal and adult rats after postnatal stress.
AB  - The neuroactive steroid allopregnanolone (3a-hydroxy-5a-pregnan-20-one,
      3alpha,5alpha-THP) has been shown to be involved in the central nervous system's
      response to stress. This experiment investigated whether response to the
      neuroactive steroid allopregnanolone, a positive modulator of the GABA(A)
      receptor, would be altered in neonatal or adult rats previously exposed to a
      chronic stressor-daily maternal separation during the first week of life.
      Subjects were then tested either as neonates or adults. In neonates,
      allopregnanolone decreased the number of ultrasonic vocalizations after brief
      maternal separation. Previously separated subjects vocalized less and were less
      active than controls, but were not more sensitive to allopregnanolone on either
      measure. In adulthood, subjects with a prior history of maternal separation had a
      greater grooming response to a novel environment after a 10-min cold water swim
      test than nonseparated subjects. Allopregnanolone reduced grooming, but, again,
      there was no difference due to stress history. A significant effect of gender was
      noted in the adult subjects--females were largely responsible for the effects
      reported. These results suggest that early maternal separation stress can produce
      an habituation response in neonates and a long-term sensitization response to
      later novel stress in adults. However, because the behavioral effects of
      allopregnanolone were not differentially influenced by this early stress history,
      the neuroactive steroid/GABA(A) receptor complex may not be the major mediator of
      these early stress sequela. Results indicating that females were more responsive
      to allopregnanolone than males are discussed in light of previous findings.

PMID- 10593195
TI  - Long-lasting effect of early handling on the peripheral benzodiazepine receptor.
AB  - The present study determined the impact of early handling (EH) in rats on
      behavioral response to environmental stress and on peripheral benzodiazepine
      receptor (PBR) binding characteristics (Bmax and Kd) in various organs. The
      behavioral consequences of EH in rats were expressed as increased exploratory
      activity in an open-field paradigm, when compared with nonhandled control rats.
      These findings are interpreted in terms of decreased emotionality. The
      biochemical consequences of EH, in both male and female rats, were expressed as
      the upregulation of PBR in the adrenal and kidney and the downregulation of
      gonadal (testis and ovary) PBR. It is possible that the long-lasting adrenal and
      renal changes in PBR expression in EH rats may enable better regulation of the
      hypothalamic-pituitary-adrenal axis, renin-angiotensin system, and autonomic
      nervous system responses to stress in adulthood. The significance of the EH
      induced reduction in gonadal PBR for gonadal activity in adulthood is as yet
      unclear.

PMID- 10593196
TI  - Factor analysis shows that female rat behaviour is characterized primarily by
      activity, male rats are driven by sex and anxiety.
AB  - This experiment explored sex differences in behaviour using factor analysis to
      describe the relationship between different behavioral variables. A principal
      component solution with an orthogonal rotation of the factor matrix was used,
      ensuring that the extracted factors are independent of one another, and thus
      reflect separate processes. In the elevated plus-maze test of anxiety, in male
      rats factor 1 accounted for 75% of the variance and reflected anxiety, factor 2
      represented activity, and accounted for 24% of the variance. This contrasted with
      the finding in female rats in which factor 1 was activity, accounting for 57% of
      the variance, with the anxiety factor accounting for only 34% of the variance.
      When behaviour in both the plus-maze and holeboard were analysed, a similar sex
      difference was found with anxiety emerging as factor 1 in males and holeboard
      activity as factor 1 in females. Locomotor activity in the inner portion of the
      holeboard loaded on the anxiety factor for males, but on activity for females.
      When behaviours in the plus-maze and sexual orientation tests were analysed,
      anxiety emerged as factor 1 in males, sexual preferences factor 2, and activity
      factor 3. In females, activity was factor 1, sexual preference factor 2, anxiety
      factor 3, and social interest factor 4. These results suggest caution should be
      exercised in interpreting the results from female rats in tests validated on
      males because the primary controlling factor may be different.

PMID- 10593197
TI  - Gender, sex steroids, corticotropin-releasing factor, nitric oxide, and the HPA
      response to stress.
AB  - We used two stresses--exposure to mild electrofoot shocks (a neurogenic stress)
      and acute alcohol injection (a systemic stress)--to investigate the influence of
      gender and circulating sex steroids on ACTH and corticosterone released by adult
      rats. Both types of stresses significantly increased plasma levels of these
      hormones. Following exposure to shocks, intact females secreted significantly
      more ACTH than intact males, a difference that was abolished by ovariectomy.
      Gender differences in corticosterone responses were sometimes, but not always,
      present. In contrast, in this series of experiments males released more ACTH when
      acutely injected with alcohol, while there was no obvious effect of sex on
      corticosterone secretion. Corticotropin-releasing factor (CRF) antagonists were
      more effective at reducing ACTH compared to corticosterone levels. Finally,
      pituitary response to CRF, but much less so to vasopressin (VP), was larger in
      intact females compared to intact males. Blockade of endogenous nitric oxide
      formation slightly enhanced the effect of CRF in males, but not in females, and
      while it produced the expected enhancement of VP-induced ACTH release, this
      effect was more pronounced in females. Collectively, these results provide
      evidence for an influence of circulating sex steroids on pituitary and adrenal
      activity under some, but not all circumstances.

PMID- 10593198
TI  - Effect of sex on fear conditioning is similar for context and discrete CS in
      Wistar, Lewis and Fischer rat strains.
AB  - Enhanced fear in males relative to females, both innate and conditioned, is a
      well-described characteristic of behavior in the laboratory rat. In the case of
      aversive conditioning to foot shock in Long-Evans rats, it has been described
      that conditioning to general (nondiscrete) contextual cues is greater in male
      rats relative to female rats, whereas conditioning to a discrete, predictive
      stimulis (CS) is not. These findings have been combined with evidence for greater
      levels of hippocampal LTP in males in Sprague-Dawley rats to derive a model of
      hippocampal-LTP-mediated contextual and not CS, fear conditioning. The present
      study reports on an analysis of the effect of sex in contextual and discrete CS
      conditioning to foot shock, assessed via measurement of freezing behavior in a
      novel automated paradigm, in three rat strains: Wistar, Fischer, and Lewis. In
      Wistar rats, there was a consistent but nonsignificant tendency for males to
      demonstrate both more contextual and more CS conditioning than females; in
      Fischer rats, males demonstrated both more contextual and more CS conditioning
      than females; in Lewis rats, a markedly enhanced acquisition of freezing in males
      did not translate into a sex difference in either context or CS conditioning at
      expression. Therefore, within each strain the effect of sex was consistent
      between context and CS conditioning. These findings, taken together with the
      hippocampal LTP evidence, suggest that the latter mediates both contextual and
      discrete CS aversive conditioning, and contributes to sex differences in both
      these forms of conditioning, in those strains where these sex differences exist.

PMID- 10593199
TI  - Sex differences in memory performance in the object recognition test. Possible
      role of histamine receptors.
AB  - The mnemonic performances of male and female rats were compared in an object
      recognition test. Females were still able to recognize a previously identified
      object after a 90-min between-trial interval, compared with only 60 min in the
      males. Because histamine (HA) involvement in memory processes has been strongly
      suggested, the effect of H3-HA autoreceptor antagonist thioperamide was
      investigated. This drug was found to produce a dose-dependent promnestic effect
      in both sexes, but it did not influence the time course of memory retrieval.
      These behavioral data were compared to the density of H1-HA, H2-HA, and H3-HA
      receptors in cortical membranes. The densities of H1-HA and H2-HA receptors were
      greater in the females, whereas that of H3-HA was substantially the same in both
      sexes. The behavioral effect of thioperamide was very similar in both sexes, and
      this agrees with a similar H3-HA receptor density; however a better memory
      performance might have been expected in the female after thioperamide treatment
      (in view of different H1-HA and H2-HA receptor density), but this was not found.
      Because thioperamide has also been demonstrated to influence the acetylcholine
      release, its possible role in regulating the cholinergic memory effect was
      investigated. The scopolamine-reduced visual retrieval was antagonized by
      thioperamide in a similar way in both sexes. In conclusion, these data have shown
      a better performance of the female in a visual memory test, but this behavioral
      difference could not be affected by an H3-HA receptor-dependent manipulation of
      histaminergic and cholinergic systems.

PMID- 10593200
TI  - Social learning in animals: sex differences and neurobiological analysis.
AB  - Social learning where an "individual's behavior is influenced by observation of,
      or interaction with, another animal or its products" has been extensively
      documented in a broad variety of species, including humans. Social learning
      occurs within the complex framework of an animal's social interactions that are
      markedly affected by factors such as dominance hierarchies, family bonds, age,
      and sex of the interacting individuals. Moreover, it is clear that social
      learning is influenced not only by important sexually dimorphic social
      constraints but also that it involves attention, motivational, and perceptual
      mechanisms, all of which exhibit substantial male-female differences. Although
      sex differences have been demonstrated in a wide range of cognitive and
      behavioral processes, investigations of male-female differences in social
      learning and its neurobiological substrates have been largely neglected. As such,
      sex differences in social learning and its neurobiological substrates merit
      increased attention. This review briefly considers various aspects of the study
      of social learning in mammals, and indicates where male-female differences have
      either been described, neglected and, or could have a potential impact. It also
      describes the results of neurobiological investigations of social learning and
      considers the relevance of these findings to other sexually dimorphic cognitive
      processes.

PMID- 10593201
TI  - Progesterone in conjunction with estradiol has neuroprotective effects in an
      animal model of neurodegeneration.
AB  - Restorative and neuroprotective effects of the steroid hormones estradiol
      benzoate (EB) and progesterone (P) were investigated in an animal model of
      neurodegeneration. Rats received EB, P, EB + P, or vehicle/cholesterol control
      immediately after (Experiment 1) or prior to (Experiment 2) intrahippocampal
      colchicine infusions, which destroy hippocampal neurons and deplete
      neurotransmitters, such as acetylcholine. Intrahippocampal colchicine produced
      long latencies, distances, and increased wandering in the water maze, in addition
      to hippocampal damage. Chronic administration of hormones immediately after
      colchicine, which produced circulating concentrations within physiological range,
      did not affect water-maze performance compared to cholesterol control (Experiment
      1). When acute EB (10 microg s.c.) + P (500 microg s.c.) was given prior to
      intrahippocampal colchicine, latencies, distances, and wandering in the water
      maze were reduced (Experiment 2). The acutely administered EB + P also were in
      physiological range. Both experiments demonstrate some influence of hormones on
      neuronal integrity and ChAT that warrants further investigation. Together, these
      findings suggest that physiological concentrations of EB + P, when administered
      before hippocampal damage, may have neuroprotective actions on learning and
      memory impairment and hippocampal damage.

PMID- 10593202
TI  - The immunobiology of sexual behavior: gender differences in the suppression of
      sexual activity during illness.
AB  - Following infection or injury, sick individuals experience profound psychological
      and behavioral changes, such as anorexia, depressed activity, and reduced self
      care behavior. In the present review, we present evidence for a gender-difference
      in the behavioral response to sickness. Specifically, following immune
      activation, sexual activity is suppressed in female, but not in male rats. This
      gender difference is specific to sexually related responses, because other
      behaviors, such as locomotion, are equally affected by immune challenges in males
      and estrous females. The suppression of female sexual behavior, induced by either
      endotoxin (lipopolysaccharide), or the cytokine interleukin-1 (IL-1), are
      mediated by central mechanisms that are independent of alterations in ovarian
      hormone secretion. Furthermore, synergistic effects of the cytokines IL-1 and
      tumor necrosis factor alpha (TNF alpha) are involved in modulating sexual
      behavior in sick females, and prostaglandins synthesis is required for the
      effects of IL-1 on female sexual behavior. The gender difference in the
      behavioral response to immune activation may be related to the findings that at
      the same doses and timing in which IL-1 suppressed sexual activity in female but
      not in male rats, females produced more prostaglandin E2 (PGE2) in the brain, and
      less corticosterone than males. Finally, we are suggesting that the suppressive
      effect of cytokines on female reproductive behavior may serve as a mechanism to
      reduce conception during infection, which exposes the mother and the fetus to
      dangers such as spontaneous abortions, preterm labor and maternal mortality.

PMID- 10593203
TI  - Effects of formalin pain on hippocampal c-Fos expression in male and female rats.
AB  - Immediate early genes are crucial intermediates in a cascade linking membrane
      stimulation to long-term alterations of neuronal activity. In the present
      experiment, we performed immunohistochemistry for c-Fos to determine the effects
      of persistent pain on cells of the hippocampus of male and female rats. Animals
      were subcutaneously injected with formalin (50 microl, 10%) and perfused: 2 h
      later, time 2; 24 h later, time 24; 24 h later after 20 min of the open-field
      test, time 24/OF. Controls were left undisturbed. In control, c-Fos was higher in
      females than in males in all hippocampal fields. In males at time 2, formalin
      increased c-Fos in the dentate gyrus (DG) and CA3 fields; at time 24, c-Fos
      returned to the control level; at time 24/OF, c-Fos was higher than in control in
      the DG, but not in the other fields. In the formalin-treated females at time 2
      and at time 24, c-Fos levels were lower, or tended to be lower, than in control
      in all hippocampal fields; at time 24/OF, c-Fos levels in the DG were higher than
      in control and in males. In conclusion, persistent pain had different effects on
      c-Fos in the hippocampal subfields, depending on the time after treatment and the
      sex of the subject.

PMID- 10593204
TI  - Gender differences in dopaminergic function in striatum and nucleus accumbens.
AB  - In female rats the gonadal hormones estrogen and progesterone modulate dopamine
      (DA) activity in the striatum and nucleus accumbens. For example, there is
      estrous cycle-dependent variation in basal extracellular concentration of
      striatal DA, in amphetamine (AMPH)-stimulated DA release, and in striatal DA
      mediated behaviors. Ovariectomy attenuates basal extracellular DA, AMPH-induced
      striatal DA release, and behaviors mediated by the striatal DA system. Estrogen
      rapidly and directly acts on the striatum and accumbens, via a G-protein-coupled
      external membrane receptor, to enhance DA release and DA-mediated behaviors. In
      male rats, estrogen does not affect striatal DA release, and removal of
      testicular hormones is without effect. These effects of estrogen also result in
      gender differences in sensitization to psychomotor stimulants. The effects of the
      gonadal hormones on the striatum and ascending DA systems projecting to the
      striatum and nucleus accumbens are hypothesized to occur as follows: estrogen
      induces a rapid change in neuronal excitability by acting on membrane receptors
      located in intrinsic striatal GABAergic neurons and on DA terminals. The effect
      of these two actions results in enhanced stimulated DA release through modulation
      of terminal excitability. These effects of gonadal hormones are postulated to
      have important implications for gender differences in susceptibility to addiction
      to the psychomotor stimulants. It is suggested that hormonal modulation of the
      striatum may have evolved to facilitate reproductive success in female rats by
      enhancing pacing behavior.

PMID- 10593205
TI  - Sex differences in the effects of neuroleptics on escape-avoidance behavior in
      mice: a review.
AB  - The literature of the effects of dopamine antagonists on escape-avoidance,
      focusing on data obtained in our laboratory with male and female mice, is
      reviewed. The acute administration of haloperidol, raclopride, clozapine, and SCH
      23390 impaired escape-avoidance behavior more in males than in females, and the
      subchronic administration of haloperidol had a similar effect. This appeared to
      be a reliable phenomenon, because it was observed in both kinds of
      administration, in two mouse strains, and with several drugs and doses. The
      observed results were dose dependent, although the dose-effect relationship was
      not the same in all drugs. The sex differences in escape avoidance did not seem
      related to sex differences in the well-known deteriorating effects of these drugs
      on motor activity. In addition, an analysis of all our studies showed that there
      were no sex differences in the variability of responses, reinforcing the idea
      that female subjects should be included in these types of studies.

PMID- 10593206
TI  - The locomotor effects of quinpirole in rats depend on age and gender.
AB  - Periadolescence in the rat [postnatal day (PND) 35-50] is an important but
      understudied period of neurobehavioral development. In this experiment, an
      ongoing survey of the effects of quinpirole in developing rats was completed by
      the addition of periadolescent rats to the range of ages tested. PND40 or 50 rats
      were injected subcutaneously with the dopamine D2/D3 receptor agonist, quinpirole
      (0.0, 0.02, 0.2, or 2.0 mg/kg), and their locomotor activity was recorded.
      Periadolescent rats showed adult-like locomotor responses to either the 0.2 or
      2.0 mg/kg doses of quinpirole, i.e., the responses were biphasic with respect to
      time: early suppression of locomotion followed by later activation within a
      single test session. In younger female rats (PND40) but older male rats (PND50),
      the lowest dose of quinpirole suppressed activity early in the test session but
      did not increase it later. In male rats, the magnitude of locomotor activation
      declined with age. Taken together with previous data from this laboratory, these
      results suggest that periadolescent rats exhibit locomotor responses that fall
      along a continuum from a high level of activation just after weaning to a low
      level of activation in early adulthood.

PMID- 10593207
TI  - Behavioral sensitization following repeated intravenous nicotine administration:
      gender differences and gonadal hormones.
AB  - Repeated intermittent administration of stimulants is well known to produce
      behavioral sensitization in male animals. The present studies explored whether 1)
      behavioral sensitization occurred with the i.v. route of administration, 2)
      sensitization was greater in females than in males, 3) sensitization was
      modulated by gonadectomy, 4) intact adult female rats maintained normal estrous
      cytology patterns in response to repeated nicotine administration, and 5) the
      pharmacokinetics of i.v. nicotine dosing. Adult male, female, castrated, and
      ovariectomized Sprague-Dawley rats (n = 48) were surgically implanted with an
      intravenous access port. Animals received 50 microg/kg i.v. nicotine once/day for
      14 days. Immediately after the initial nicotine injection and the final day 14
      nicotine injection, animals were placed in IR photocell activity chambers for 60
      min. Observational time sampling of behavior was also simultaneously performed by
      an observer blind to treatment condition. An increase in behavioral activity of
      greater than 120% occurred across the 14-day time course of i.v. nicotine
      injections. The magnitude of the increase, however, varied as a function of
      component of activity, gender, and gonadectomy. The behavioral observation data
      further suggested that the females demonstrated an increased sensitivity to
      repeated nicotine, as evidenced in a more rapid response, for example, grooming.
      These behavioral observations were associated with peak arterial levels of
      nicotine (approximately 25 ng/ml) no greater than the average venous levels of
      nicotine commonly maintained by cigarette smokers. Repeated i.v. nicotine, at a
      dose of 50 microg/kg, did not interfere with intact female vaginal cytology or
      body weight; the failure to detect such alterations were not due to inadequate
      statistical power. Moreover, no nicotine-treated animals displayed persistent
      vaginal estrous or were acyclic. Collectively, these data suggest that the i.v.
      nicotine model may be particularly useful in exploring the gender-dependent
      effects of nicotine.

PMID- 10593208
TI  - Gender impacts behavioral and neurochemical adaptations in ethanol-dependent
      rats.
AB  - Previous investigations have found gender differences in the effects of chronic
      ethanol exposure on ethanol withdrawal behaviors as well as GABA(A) receptor gene
      expression. The present investigation extended these studies with additional
      behavioral and neurochemical measures of ethanol dependence and withdrawal. No
      significant gender differences in the elevated plus-maze assessment of ethanol
      withdrawal anxiety behaviors were found. However, the neuroactive steroid,
      3alpha,5alpha-THP, increased exploratory behavior in ethanol withdrawn female,
      but not male, rats. GABA(A) receptor binding assays showed potent competition of
      [35S]TBPS binding by 3alpha,5alpha-THP. Control females displayed a decreased
      affinity for 3alpha,5alpha-THP compared to control males, as evidenced by a
      nearly 30% increase in the IC50 value. There was no significant effect of ethanol
      withdrawal on 3alpha,5alpha-THP modulation of [35S]TBPS binding. However, gender
      differences were observed in the effects of chronic ethanol exposure on GABA(A)
      receptor subunit peptide levels in the hypothalamus. Female rats had a
      significant increase in peptide levels for the alpha2 and alpha3 but not alpha4
      subunit, whereas male rats displayed a significant increase in alpha4 and alpha3
      but not alpha2 subunits compared to pair-fed control levels. Chronic ethanol
      induced alterations in gene expression in the hypothalamus did not coincide with
      previous findings in the cerebral cortex. In particular, male rats showed an
      increase in alpha1 subunit peptide levels in the hypothalamus, whereas
      significant decreases in this subunit have been observed in the cerebral cortex.
      Both female and male rats showed significant increases in the alpha3 subunit in
      the hypothalamus but not the cerebral cortex. Taken together, these studies
      provide additional support for gender-selective effects of chronic ethanol
      elicited adaptations at the molecular level.

PMID- 10593209
TI  - Neonatal naltrindole and handling differently affect morphine antinociception in
      male and female rats.
AB  - The effects of a daily injection of the delta selective opioid antagonist
      naltrindole (1 mg/kg), from birth to postnatal day 19, on antinociceptive
      responses to morphine (2 mg/kg) in 20-day-old rats of both sexes were
      investigated. The effects of postnatal handling were studied by including two
      control groups--one group receiving daily injections of saline, and a naive
      unhandled group. Antinociception was assessed using the tail-immersion test and
      time-response curves (5, 10, 15, and 30 min) were carried out for all
      experimental groups. In all treatment groups females showed greater sensitivity
      to the noxious stimuli compared to males. No significant effect of naltrindole
      treatment on baseline latencies was found. Postnatal handling increased
      sensitivity to thermal pain in both sexes, and reduced the effect of morphine in
      males. No significant effect of chronic naltrindole administration on morphine
      antinociception was found in this sex. Naltrindole-treated females showed an
      increased antinociception when compared to unhandled animals of the same gender.
      The results indicate that preweanling handling stress and chronic naltrindole
      treatment differentially affected morphine antinociception in male and female
      neonatal rats.

PMID- 10593210
TI  - Precipitated withdrawal in the substantia nigra in diazepam-dependent female
      rats.
AB  - Female rats were exposed to diazepam (DZ) implants (90 mg/week) or to empty
      capsules (controls) for 5 weeks. Rats were focally injected (1 microl) into the
      substantia nigra (SNR) with the central (CBR) and peripheral (PBR) benzodiazepine
      receptor antagonists, flumazenil [(FLU) 6.25, 12.5, or 25 microg], and PK 11195
      [(PK) 3.125, 6.25, 12.5, or 25 microg], respectively. Rats were observed for
      behavioral and EEG manifestation of withdrawal syndrome. In female rats, both FLU
      and PK induced a dose-related precipitated abstinence score (PAS), tachypnea, and
      head bobbing. Twitches and jerks tended to increase with increasing dose of both
      FLU and PK. Furthermore, FLU evoked dose-related turning and head and body
      tremors. The FLU- and the PK-induced PAS were accompanied by an increase in total
      power of the EEG in the SNR. The involvement of the CBR and PBR in physical
      dependence on DZ in the SNR is suggested. The present data in female rats are
      discussed with regard to similarities and differences with previous studies in
      male rats.

PMID- 10593211
TI  - The psychological effects of athletic injury.

PMID- 10593212
TI  - Does loss of consciousness predict neuropsychological decrements after
      concussion?
AB  - OBJECTIVE: To investigate the importance of loss of consciousness (LOC) in
      predicting neuropsychological test performance in a large sample of patients with
      head injury. DESIGN: Retrospective comparison of neuropsychological test results
      for patients who suffered traumatic LOC, no LOC, or uncertain LOC. SETTING:
      Allegheny General Hospital, Pittsburgh, Pennsylvania. PATIENTS: The total number
      of patients included in this study was 383. MAIN OUTCOME MEASURES:
      Neuropsychological test measures, including the visual reproduction, digit span,
      and logical memory subtests of the Wechsler memory scale (revised), the Trail
      Making test, Wisconsin Card Sorting test, Hopkins Verbal Learning test,
      Controlled Oral Word Association, and the Galveston Orientation and Amnesia test
      (GOAT). RESULTS: No significant differences were found between the LOC, no LOC,
      or uncertain LOC groups for any of the neuropsychological measures used. Patients
      who had experienced traumatic LOC did not perform more poorly on
      neuropsychological testing than those with no LOC or uncertain LOC. All three
      groups demonstrated mildly decreased performance on formal tests of speed of
      information processing, attentional process, and memory. CONCLUSION: The results
      of this study cast doubt on the importance of LOC as a predictor of
      neuropsychological test performance during the acute phase of recovery from mild
      traumatic brain injury. Neuropsychological testing procedures have been shown to
      be sensitive in measuring cognitive sequelae of mild traumatic brain injury
      (concussion) in athletes. The failure of this study to find any relationship
      between LOC and neuropsychological functioning in a large sample of patients with
      mild head trauma calls into question the assignment of primary importance to LOC
      in grading severity of concussion. This study also does not provide support for
      the use of guidelines that rely heavily on LOC in making return-to-play
      decisions. Continued research is necessary to determine the relative importance
      of markers of concussion in athletes.

PMID- 10593213
TI  - Upper extremity stress fractures in athletes: clinical features of 44 cases.
AB  - PURPOSE: To review the clinical features of a large series of active patients
      with a stress fracture in a non-weight-bearing location of the upper extremity or
      ribs. DESIGN: Multicenter cross-sectional study. SETTING: Multiple academic
      medical centers. PARTICIPANTS: 44 patients with a diagnosis of upper extremity or
      rib stress fracture. MAIN OUTCOME MEASURES: Clinical features according to
      anatomic location, primary sport, and subdivided according to the nature of the
      sport-specific skills involved. RESULTS: A diagnosis of stress fracture was made
      in 44 patients based on history and physical examination, and confirmed by
      radiography, scintigraphy, magnetic resonance imaging (MRI), computed tomography
      (CT), or a combination of imaging techniques. Patients were subjectively divided
      into four categories based on the predominant type of upper extremity activity
      required for participation in their sport: 1) weight lifter (e.g., football,
      weight lifting, wrestling); 2) upper extremity weight bearer (e.g., gymnastics,
      diving, cheerleading); 3) thrower (e.g., pitcher, soccer goalie, javelin); or 4)
      swinger (e.g., golf, tennis). We noted that all fractures in the weight bearers
      occurred distal to the elbow, whereas in the throwers most fractures affected the
      shoulder girdle. Lower rib stress fractures predominated in the swingers group,
      whereas weight lifters had fractures located throughout the upper extremity.
      CONCLUSION: Stress fracture should be considered in the differential diagnosis of
      athletes presenting with upper extremity or rib pain of bony origin that is of
      insidious onset. Further study of the sport-specific patterns of injury described
      here may improve our ability to treat and prevent these injuries.

PMID- 10593214
TI  - Effects of intensified training and detraining on testicular function.
AB  - OBJECTIVE: To examine the effects of an increased training load and period of
      detraining on testicular function in male distance runners. DESIGN: Multiple
      group time-series design using a control group. SETTING: University of Toledo and
      Toledo Hospital. PARTICIPANTS: Eight male runners and eight age-matched sedentary
      control subjects. Subjects were considered fit for participation after a physical
      and genital examination conducted by a physician. INTERVENTION: Subjects provided
      blood and semen samples every 2 weeks for 8 weeks. The training regimen for the
      runners consisted of 2 weeks at normal training (NT), 2 weeks at 143% of NT
      (IT1), 2 weeks at 186% of NT (IT2), and 2 weeks at 50% of NT (RT). These
      percentages represent increases in training distance (volume). MAIN OUTCOME
      MEASURES: Within the context of this investigation, the following hypothesis was
      developed: increases or decreases in training would not significantly alter sperm
      count, density, motility, or morphology, or concentrations of reproductive
      hormones or cortisol in runners. RESULTS: There were no statistically significant
      differences observed between runners and control subjects for any of the
      reproductive hormones or cortisol. In addition, there was no significant
      treatment effect for sperm count, motility, or morphology. The sperm levels in
      two runners in this investigation dropped to oligospermatic levels after IT2;
      however, total sperm count increased in both runners after 2 weeks of RT.
      CONCLUSION: Four weeks of increased training and 2 weeks of reduced training did
      not significantly affect the subjects in this investigation. It is possible that
      a particular level or degree of training must be surpassed before any clinical
      alterations are evident. Future longitudinal studies are necessary to identify
      the extent to which endurance training may alter reproductive hormones and
      testicular function.

PMID- 10593215
TI  - Medical coverage of high school football in Wisconsin in 1997.
AB  - OBJECTIVE: The goals of this study were to assess the health care available to
      Wisconsin high school football players and to assess high schools' compliance
      with safety requirements of the Wisconsin Interscholastic Athletic Association
      (WIAA). DESIGN: The design was a cross-sectional survey-based study. SETTING: The
      setting consisted of WIAA high schools. PARTICIPANTS: Athletic directors of WIAA
      high school football programs participated in the survey. MAIN OUTCOME MEASURES:
      The main outcome measures were the prevalence of medical coverage by physicians,
      certified athletic trainers, and ambulance personnel at football games and
      practice and the prevalence of compliance with WIAA requirements. RESULTS:
      Seventy-seven percent (302/392) of surveys were returned. Thirty-six percent of
      schools had a designated team physician. Eighty-seven percent had a trainer, and
      86% were certified athletic trainers (Athletic Trainer Certified, ATC). At
      practice and scrimmage, 79% had an ambulance available or on call, 52% had a
      trainer present, and 28% had a physician on call. At football games, 71% had an
      ambulance, 67% a certified athletic trainer, 48% an emergency medical technician,
      and 45% a physician present. Regarding WIAA requirements, 9% had no accessible
      phone, 27% had no written emergency plan of action, 92% had gloves, and 92% had
      blood spill kits. Larger schools had better compliance with WIAA requirements
      than did smaller schools. CONCLUSION: Health care coverage was provided mainly by
      trainers and ambulance personnel, although physicians were routinely present at
      almost half of all games. Failure to comply with WIAA medical coverage
      requirements was not infrequent. This study forms the basis for an informational
      intervention, providing an opportunity to correct deficits.

PMID- 10593216
TI  - Musculoskeletal injuries in a six-day track race: ultramarathoner's ankle.
AB  - OBJECTIVE: To document injuries during a 6-day track race (in which direction was
      reversed every 2 hours) and compare these injuries with those incurred during
      other ultra-marathon track and road races, and to investigate a characteristic
      ultra-marathon injury, tendonitis of the ankle dorsiflexors. DESIGN: A
      prospective, cohort study of competitors during a 6-day race. SETTING: 400-m
      grass track in Colac, Victoria. PARTICIPANTS: All 17 competitors (16 men and 1
      woman). MAIN OUTCOME MEASURES: Total numbers and percentages of specific
      musculoskeletal injuries. RESULTS: A total of 36 injuries were recorded in 11
      competitors. The ankle (36%) and the knee (22%) were the regions most frequently
      injured. The four most common diagnoses were: Achilles tendonitis (19%); extensor
      digitorum longus tendonitis (14%); retropatellar pain syndrome (14%); and
      anterior compartment pain (11%). CONCLUSION: Achilles tendonitis, patellofemoral
      pain, and tendonitis of the foot dorsiflexors are the three most common injuries
      in ultra-marathons of 6 days or more. Ankle injuries predominate in track races,
      whereas knee injuries are more common in road races. Road races are associated
      with higher frequency of injury to the leg on the downside of the camber. Track
      races have an even distribution of injury. Confirmation is presented that the
      characteristic ultra-marathon injury is tendonitis of the foot dorsiflexors.

PMID- 10593217
TI  - Stretching before exercise does not reduce the risk of local muscle injury: a
      critical review of the clinical and basic science literature.
AB  - OBJECTIVE: To evaluate the clinical and basic science evidence surrounding the
      hypothesis that stretching immediately before exercise prevents injury. DATA
      SOURCES AND SELECTION: MEDLINE was searched using MEDLINE subject headings (MeSH)
      and textwords for English- and French-language articles related to stretching and
      muscle injury. Additional references were reviewed from the bibliographies, and
      from citation searches on key articles. All articles related to stretching and
      injury or pathophysiology of muscle injury were reviewed. Clinical articles
      without a control group were excluded. RESULTS: Three (all prospective) of the
      four clinical articles that suggested stretching was beneficial included a
      cointervention of warm-up. The fourth study (cross-sectional) found stretching
      was associated with less groin/buttock problems in cyclists, but only in women.
      There were five studies suggesting no difference in injury rates between
      stretchers and nonstretchers (3 prospective, 2 cross-sectional) and three
      suggesting stretching was detrimental (all cross-sectional). The review of the
      basic science literature suggested five reasons why stretching before exercise
      would not prevent injuries. First, in animals, immobilization or heating-induced
      increases in muscle compliance cause tissues to rupture more easily. Second,
      stretching before exercise should have no effect for activities in which
      excessive muscle length is not an issue (e.g., jogging). Third, stretching won't
      affect muscle compliance during eccentric activity, when most strains are
      believed to occur. Fourth, stretching can produce damage at the cytoskeleton
      level. Fifth, stretching appears to mask muscle pain in humans. CONCLUSION: The
      basic science literature supports the epidemiologic evidence that stretching
      before exercise does not reduce the risk of injury.

PMID- 10593218
TI  - Quadratus femoris muscle tear: an uncommon cause for radiating gluteal pain.

PMID- 10593219
TI  - Stress fracture of the ulna in a baseball pitcher.

PMID- 10593220
TI  - Exercise-induced rhabdomyolysis in a woman.

PMID- 10593221
TI  - Renal fracture secondary to blunt trauma in a football player.

PMID- 10593222
TI  - Recurrent epistaxis in a college athlete.

PMID- 10593223
TI  - Guillain-Barre syndrome in sport.

PMID- 10593224
TI  - Smoking, physical activity, and active life expectancy.

PMID- 10593225
TI  - Factors that predict intercollegiate ice hockey injuries.

PMID- 10593226
TI  - The electric resistivity of human tissues (100 Hz-10 MHz): a meta-analysis of
      review studies.
AB  - The electric resistivity of various human tissues has been reported in many
      studies, but on comparison large differences appear between these studies. The
      aim of this study was to investigate systematically the resistivities of human
      tissues as published in review studies (100 Hz-10 MHz). A data set of 103
      resistivities for 21 different human tissues was compiled from six review
      studies. For each kind of tissue the mean and its 95% confidence interval were
      calculated. Moreover, an analysis of covariance showed that the calculated means
      were not statistically different for most tissues, namely skeletal (171 omega cm)
      and cardiac (175 omega cm) muscle, kidney (211 omega cm), liver (342 omega cm),
      lung (157 omega cm) and spleen (405 omega cm), with bone (> 17,583 omega cm), fat
      (3,850 omega cm) and, most likely, the stratum corneum of the skin having higher
      resistivities. The insignificance of differences between various tissue means
      could imply an equality of their resistivities, or, alternatively, could be the
      result of the large confidence intervals which obscured real existing
      differences. In either case, however, the large 95% confidence intervals
      reflected large uncertainties in our knowledge of resistivities of human tissues.
      Applications based on these resistivities in bioimpedance methods, EEG and EKG,
      should be developed and evaluated with these uncertainties in mind.

PMID- 10593227
TI  - Multiple frequency bioelectrical impedance analysis: a cross-validation study of
      the inductor circuit and Cole models.
AB  - It has been proposed that multiple frequency bioelectrical impedance models of
      the human body should include an inductive property for the circulatory system,
      the inductor circuit model (ICM), and that such a model, when coupled with a new
      method of data analysis, can improve the predictive power of multiple frequency
      bioelectrical impedance analysis (MFBIA). This hypothesis was tested using MFBIA
      measurements and gold standard measures of total body and extracellular water
      volumes in a cross-validation study in two subject groups (viz. controls and
      HIV). The MFBIA measurements were analysed using the current, widely accepted
      Cole model and the alternative ICM model which includes an inductive component.
      Correlations in the range 0.75 to 0.92 (for TBW) and 0.46 to 0.79 (for ECW) for
      impedance quotients versus gold standard measures within the subject groups were
      observed. These decreased, to as low as r = 0.50 for TBW and r = 0.29 for ECW,
      when the derived algorithms were applied to the alternative subject group. These
      results suggest that lack of portability of MFBIA algorithms between subject
      groups is not due to an inadequacy of the analogue circuit model per se but is
      possibly due more to fundamental flaws in the principles associated with its
      application. These include assuming a constant proportionality of body segment
      geometries and tissue fluid resistivities. This study has also demonstrated that
      this inadequacy cannot be overcome by simply introducing an inductive component
      into the analogue electrical circuit.

PMID- 10593228
TI  - Sensitivity of multiple frequency bioelectrical impedance analysis to changes in
      ion status.
AB  - Bioelectrical impedance analysis has found extensive application as a simple
      noninvasive method for the assessment of body fluid volumes. The measured
      impedance is, however, not only related to the volume of fluid but also to its
      inherent resistivity. The primary determinant of the resistivities of body fluids
      is the concentration of ions. The aim of this study was to investigate the
      sensitivity of bioelectrical impedance analysis to bodily ion status. Whole body
      impedance over a range of frequencies (4-1012 kHz) of rats was measured during
      infusion of various concentrations of saline into rats concomitant with
      measurement of total body and intracellular water by tracer dilution techniques.
      Extracellular resistance (R0), intracellular resistance (R(i)) and impedance at
      the characteristic frequency (Z(c)) were calculated. R0 and Z(c) were used to
      predict extracellular and total body water respectively using previously
      published formulae. The results showed that whilst R0 and Z(c) decreased
      proportionately to the amount of NaCl infused, R(i) increased only slightly.
      Impedances at the end of infusion predicted increases in TBW and ECW of
      approximately 4-6% despite a volume increase of less than 0.5% in TBW due to the
      volume of fluid infused. These data are discussed in relation to the assumption
      of constant resistivity in the prediction of fluid volumes from impedance data.

PMID- 10593229
TI  - A method for foetal heart rate monitoring during magnetic resonance imaging using
      Doppler ultrasound.
AB  - A means of monitoring foetal heart rate (FHR) during magnetic resonance imaging
      (MRI) is presented. Foetal heart rate was measured using a modified standard
      Doppler ultrasound based monitor. The transducer and lead from the monitor
      required alteration to reduce interference and distortion in the MR images to
      acceptable levels. These changes enabled high quality images to be produced with
      insignificant additional noise and distortion when the foetal heart rate was
      recorded simultaneously.

PMID- 10593230
TI  - Chronodiagnostic acquisition of recovery speed of heart rate under bathing
      stress.
AB  - Cycling on an ergometer is one effective means of measuring cardiovascular
      function while applying stress on the heart. Bathing in a hot water bath applies
      a low stress to the heart. The electrocardiograms of a healthy adult male (aged
      35 at the start of study) were recorded while taking a hot water bath with no
      electrode attached to the body over a period of 2 years (376 days over a 762 day
      period). The recovery speed following the initial overshoot of the heart rate
      (HR) was observed. The bathtub was designed for the automatic acquisition of ECG
      data. Immediately after immersion in the tub, the HR reached a peak within 20 s
      and then exponentially decreased toward the lowest rate in the 120 s of bathing.
      The initial recovery speed of the HR from the stress of bathing had a specific
      rhythm in the subject. Spectrum analysis of the speed series indicated that slow
      recovery speed appeared in cyclic periods of approximately 1 year, 42 days and 17
      days. The methodology may provide a chronodiagnostic index of an exercise test
      for cardiovascular function.

PMID- 10593231
TI  - Electronic nose analysis of urine samples containing blood.
AB  - In this paper the possible application of an electronic nose to the analysis of
      urine is presented. In contrast with the conventional applications of sensors and
      biosensors operating in liquid, the approach discussed here makes use of gas
      sensors performing an analysis of the headspace. The application deals with urine
      samples from patients affected by kidney diseases; some of the samples contained
      traces of blood. Results show the possibility of distinguishing the samples
      containing blood from the others, and a linear correlation between the first
      three principal components and the blood content was found. Furthermore, the
      electronic nose matched with a suitable neural network showed good performance in
      measuring the pH and the specific weight of the samples.

PMID- 10593232
TI  - The application of d.c. electrical stimulation in evoking and recording gustatory
      brain potentials.
AB  - Evidence exists which supports the hypothesis that electrical stimulation of
      appropriate parameters can fulfil the fundamental requirements for an effective
      evoked potential taste stimulus. Nevertheless, it had previously been considered
      that electrical taste stimulation is inadequate for evoking gustatory brain
      potentials. Consequently, the majority of the earlier attempts to record
      gustatory evoked potentials (GEPs) reported in the literature have employed
      chemical stimulus techniques. The design of an electrical taste stimulator and
      its interface to an evoked potential recording unit is described. The first human
      brain potentials recorded with this system are presented, among which are those
      attributable to taste pathway activation. Following future work to unequivocally
      confirm that taste evoked brain potentials are achievable with this system, it
      has potential to become a clinically valuable tool.

PMID- 10593233
TI  - A comparison of neonatal and adult lung impedances derived from EIT images.
AB  - An objective method of extracting respiratory data from lung images is presented,
      together with a technique for automatically generating regions of interest
      delineating the anterior and posterior regions of the lungs. The method is used
      to extract data on the change in lung impedance with frequency, and on calculated
      Cole parameters, from 19 normal neonates (gestational age 32 to 42 weeks) and 8
      normal adults (age 21 to 82 years). A comparison of the impedance properties of
      neonatal and adult lungs was made. The variation of lung impedance with frequency
      in neonates, as derived from EIT images, is significantly different from that
      found for adults. The implications for a model of the electrical impedance of
      lung tissue are discussed.

PMID- 10593234
TI  - Influence of electrode impedance changes on the common-mode rejection ratio in
      bioimpedance measurements.
AB  - Bioelectrical impedance in vivo measurements suffer from many potential sources
      of error due to the patient-instrument interface. The total common-mode rejection
      ratio (CMRR(T)) was investigated experimentally for three measurement channel
      circuit versions, including electrode-skin impedance imbalance. The first version
      was of the 'classical' type. The second one makes use of a differential filter at
      the input of the instrumentation amplifier. The third circuit was a frequency
      converting structure, where the signal was demodulated before being amplified.
      The differential demodulator was based on synchronous sampling using floating
      capacitors. The experiments were accomplished with simulated imbalance of the
      real and imaginary parts of electrode-skin impedances. To reduce unwanted common
      mode voltage, a differential accurately balanced current source was used.
      Considering an application in impedance cardiography, the experiments were
      carried out at a single frequency of 40 kHz. The results showed the advantage of
      the circuits using frequency conversion and differential input filter, rendering
      at least 15 dB higher CMRR(T). The most significant reduction of CMRR(T) resulted
      from imbalance of the capacitance component of voltage-sensing electrode
      impedances. The third circuit showed an unexpected behaviour of CMRR(T)
      improvement with higher imbalance of the electrode-skin impedance resistance
      component.

PMID- 10593235
TI  - Sentinel lymph-node biopsy in breast cancer.

PMID- 10593236
TI  - Reducing arthroplasty costs.

PMID- 10593237
TI  - Soft-tissue images. Choledochal cyst with virtual dochoscopy.

PMID- 10593238
TI  - Musculoskeletal images. Aneurysmal bone cyst of pelvis.

PMID- 10593239
TI  - Soft-tissue case 30. Presentation. Pelvic trauma: detection of active bleeding by
      computed tomography.

PMID- 10593240
TI  - Musculoskeletal case 7. Presentation. Large femoral geode associated with
      osteoarthritis of the hip joint.

PMID- 10593241
TI  - Typhlitis.
AB  - OBJECTIVE: To provide an overview of the pathophysiological features and
      management of the clinical entity typhlitis. DATA SOURCES AND STUDY SELECTION:
      The data presented are derived from a review of the English-language literature
      on typhlitis. The majority of papers analysed were small clinical series. DATA
      EXTRACTION AND SYNTHESIS: Data derived from the literature review were collated.
      The major finding was that typhlitis comprises a number of different diseases
      characterized by the presence of right lower quadrant pain, an immunocompromised
      host and altered function of the mucosal barrier of the right colon. CONCLUSIONS:
      Typhlitis should be suspected in any immunocompromised patient presenting with
      right lower quadrant pain with compatible radiographic findings. Most patients
      can be treated conservatively with intravenously administered fluids and
      antibiotics, although surgery may be necessary if complications arise.

PMID- 10593242
TI  - Frontiers in transplantation of insulin-secreting tissue for diabetes mellitus.
AB  - Transplantation of insulin-secreting tissue represents a physiologic approach to
      reverse diabetes mellitus. Pancreas transplants yield a remarkable enhancement in
      quality of life and appear to modify the devastating neurovascular complications
      of diabetes. A more attractive approach is transplantation of insulin-secreting
      cells, a procedure of low invasiveness with the exciting prospect of modulating
      graft immunogenicity before transplantation, so as to minimize requirements for
      toxic immunosuppressive drugs. The Surgical-Medical Research Institute at the
      University of Alberta in Edmonton, and several others centres throughout the
      world, has demonstrated that islet cell transplants can reverse insulin
      dependence and induce remarkable glycemic stability for several years. However,
      widespread success has been denied because of insufficient donor tissue, early
      failures to reverse insulin dependence and the loss of graft function with time.
      Promising new research approaches to these problems are reviewed, including
      xenogeneic sources of cells, engineering islet cells with genes that induce
      expression of immunoprotective molecules, and neogenesis factors that may sustain
      populations of transplanted beta cells.

PMID- 10593243
TI  - Enzymatic antioxidant defence mechanism in rat intestinal tissue is changed after
      ischemia-reperfusion. Effects of an allopurinol plus antioxidant combination.
AB  - OBJECTIVES: To establish the antioxidant status of rat intestinal tissues after
      ischemia-reperfusion and to determine if pretreatment with an allopurinol and
      antioxidant vitamin combination gives any protection against mucosal injury.
      EXPERIMENTAL ANIMALS: Twenty rats were divided into 4 groups of 5 animals each.
      METHODS: Group 1 (control) rats were not subjected to ischemia-reperfusion and
      received no allopurinol plus vitamin combination; group 2 rats received vitamins
      C (200 mg/kg) and E (100 mg/kg) and allopurinol (50 mg/kg) combination daily for
      3 days preoperatively; group 3 rats were subjected to ischemia-reperfusion only;
      and group 4 rats were subjected to ischemia-reperfusion and received the vitamin
      and allopurinol combination. MAIN OUTCOME MEASURES: Activities of superoxide
      dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) enzymes, the
      level of thiobarbituric acid-reagent substances (TBARS) and histologic grading of
      tissue samples. RESULTS: SOD and GSH-Px activities were decreased, but the CAT
      activity and TBARS level increased. Pretreatment of the rats with the allopurinol
      vitamin C-vitamin E combination did not have any significant effect on the enzyme
      activities. However, it resulted in important reductions in the TBARS tissue
      levels. Histologic investigation revealed significant mucosal injury in group 3
      rats compared with group 4 rats (mean [and standard deviation] for grading, 4.6
      [0.5] versus 1.8 [0.4]). CONCLUSIONS: The enzymatic antioxidant defence system
      was significantly changed after ischemia-reperfusion and intestinal tissue was
      exposed to increased oxidant stress, the results of which were peroxidation of
      some cellular structures and increased concentrations of oxidative products.
      Although antioxidant treatment did not drastically affect the enzyme activities
      or afford complete protection of cellular structures against deformation, it
      apparently could eliminate oxygen radicals and prevent peroxidative reactions.

PMID- 10593244
TI  - A population study in the Province of Ontario of the complications after
      conversion of hip or knee arthrodesis to total joint replacement.
AB  - OBJECTIVE: To evaluate the complication rates after conversion of hip and knee
      fusions to total joint replacements in the Province of Ontario. DESIGN: A
      retrospective cohort study. PATIENTS: Those who had undergone an elective
      conversion of a hip or knee fusion to a total joint replacement during fiscal
      year 1993 through 1996, as captured in the Canadian Institute for Health
      Information and Ontario Health Insurance Plan databases. OUTCOME MEASURES:
      Inhospital complications and length of initial hospital stay, revision,
      infection, amputation and repeat fusion rates within 4 years. RESULTS: Conversion
      of hip and knee fusion to total joint arthroplasty was generally performed by
      high-volume surgeons in high-volume hospital settings. Forty hip and 18 knee
      replacements involved conversion of a previous fusion. Conversion of a hip fusion
      was associated with a 10% infection rate, a 10% revision rate and a 5% resection
      arthroplasty rate due to infection within 4 years of the conversion. Conversion
      of a knee fusion was associated with an 11% infection rate, and a more than 5%
      revision rate at 4 years. Over 16% of patients who underwent conversion of a knee
      fusion required removal of the components (for various reasons) within the first
      4 years. CONCLUSIONS: There is a high rate of complications after conversion of a
      hip or knee fusion to a total joint arthroplasty. These issues must be carefully
      considered and discussed with the patient before any conversion procedure.

PMID- 10593245
TI  - Orthopedic management in autosomal recessive spastic ataxia of Charlevoix
      Saguenay.
AB  - OBJECTIVE: To review the orthopedic management of choice in patients having
      autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). DESIGN: A
      retrospective study from April 1978 to April 1997. SETTING: Centre hospitalier de
      la Sagamie, Chicoutimi, Que. PATIENTS: A review of the records of patients having
      ARSACS who were identified in the registry of the Neuromuscular Diseases Clinic
      at the Centre hospitalier de la Sagamie revealed 26 patients who received
      surgical orthopedic treatment. Initially, the patients were offered conservative
      treatment, which consisted of physiotherapy sessions, the wearing of an ankle
      foot orthosis or serial casting. When this was unsuccessful, foot surgery was
      considered. RESULTS: During the study period, 49 orthopedic procedures were done,
      including 24 triple arthrodeses; of these, 9 were combined with lengthening of
      the Achilles tendon. Most triple arthrodeses were done in patients between the
      ages of 30 and 49 years. The surgical options evolved during the study from
      Lambrinudi arthrodesis through arthrodesis of the ankle to triple arthrodesis
      with lengthening of the Achilles tendon. CONCLUSIONS: As a complement to
      conservative treatment, surgery has a place in the care of patients with ARSACS.
      Clinically, the most effective surgical procedures are triple arthrodesis with
      percutaneous lengthening of the Achilles tendon and adductor and psoas tenotomies
      combined with neurectomy of the obturator nerve for perineal hygiene.

PMID- 10593246
TI  - Reducing arthroplasty costs via vendor contracts.
AB  - OBJECTIVE: To describe a method of reducing the costs of implants in hip and knee
      arthroplasty. DESIGN: Implant costs were compared before and after the
      implementation of a 2-year contract with implant vendors, providing increased
      volume for decreased implant cost. An additional 20% of arthroplasties could be
      done outside the contract for research or special purposes. SETTING: A regional
      health authority involving 2 acute care hospitals. METHOD: Costs were obtained
      for 942 hip and knee arthroplasties performed in 1993/94 and compared with costs
      of 1656 hip and knee arthroplasties performed in 1996/97. OUTCOME MEASURES:
      Implant cost and number of joint arthroplasty procedures performed. RESULTS: A
      40% decrease in the cost per implant for primary knee arthroplasty and an 18%
      decrease in the cost per implant for primary hip arthroplasty were achieved. A
      rebate, calculated as a percentage of volume used, was received from the vendor
      to support general orthopedic research and education. A new contract for 3 years
      has recently been signed with 3 vendors designated as primary vendors for 80% of
      the volume. CONCLUSION: The vendor-contract economic strategy effectively reduced
      the cost of hip and knee arthroplasty and may be useful at other centres looking
      for cost reduction methods that maintain adequate patient care and support
      clinical research and education.

PMID- 10593247
TI  - Role of surgical residents in undergraduate surgical education.
AB  - OBJECTIVES: To identify the role and impact of surgical residents on the various
      activities of a senior (4th year) surgical clerkship, and to explore students'
      perceptions of differences between the teaching behaviours of attending
      physicians and residents. DESIGN: A survey by questionnaire. SETTING: McGill
      University, Montreal. METHOD: A 67-item questionnaire was administered to fourth
      year medical students at the end of their 8-week surgical clerkship. Analysis of
      the data was performed using the Wilcoxon signed-rank test, Dunn's multiple
      comparison test and mean average. MAIN OUTCOME MEASURES: Overall satisfaction
      with the clerkship, teaching behaviours and teaching of clinical skills and basic
      principles. RESULTS: Overall satisfaction with the clerkship was 6.31 out of 10.
      Surgical residents were perceived as being significantly more active than the
      attending staff in 14 out of 15 teaching behaviours. They were also seen as
      important in teaching certain clinical skills such as suturing, assisting in the
      operating room and managing emergency situations. They also contributed
      significantly to teaching the basic principles of surgery such as infections,
      surgical bleeding and fluid and electrolytes. On a 10-point scale, students felt
      that more learning was achieved by independent reading, tutorials and residents'
      teaching than by other teaching modalities, including attending physicians' and
      nurses' teaching. CONCLUSIONS: Medical students perceive surgical residents as
      being significantly more active in their education process than the attending
      staff. Residents appear to be responsible for teaching various technical and
      patient management skills necessary for patient care. Along with independent
      reading and tutorials, resident teaching contributes a significant portion of the
      medical student's acquisition of knowledge and appears to contribute to the
      students' choice of surgery as a career.

PMID- 10593248
TI  - Venous thromboembolism prophylaxis after total hip or knee arthroplasty: a survey
      of Canadian orthopedic surgeons.
AB  - OBJECTIVE: To determine the pharmacologic and physical modalities used by
      orthopedic surgeons in Canada to prevent venous thromboembolism (deep venous
      thrombosis and pulmonary embolism) after total hip or knee arthroplasty. DESIGN:
      Mail survey sent to all members of the Canadian Orthopaedic Association. SETTING:
      A nation-wide study. METHODS: A total of 828 questionnaires, designed to identify
      the type and frequency of prophylaxis against venous thromboembolism that were
      used after hip and knee arthroplasty were mailed to orthopedic surgeons. OUTCOME
      MEASURES: Demographic data and the frequency and type of thromboprophylaxis.
      RESULTS: Of the 828 surveys mailed 445 (54%) were returned, and 397 were included
      in this analysis. Of the respondents, 97% used prophylaxis routinely for patients
      who undergo total hip or knee arthroplasty. Three of the 397 (0.8%) did not use
      any method ofprophylaxis. Warfarin was the most common agent used (46%), followed
      by low-molecular-weight heparin (LMWH) (36%). Combination therapy with both
      mechanical and pharmacologic methods were used in 39% of patients. Objective
      screening tests were not frequently performed before discharge. Extended
      prophylaxis beyond the duration of hospitalization was used by 36% of physicians.
      CONCLUSION: Prophylaxis for venous thromboembolism with warfarin or LMWH has
      become standard care after total hip or knee arthroplasty in Canada.

PMID- 10593249
TI  - Surgically correctable hypertension mistaken for Takayasu's disease: a case
      report.

PMID- 10593250
TI  - Linitis plastica as the first indication of metastatic lobular carcinoma of the
      breast: case report and literature review.

PMID- 10593251
TI  - Evaluating laparoscopic skills.

PMID- 10593252
TI  - Slipped capital femoral epiphysis.

PMID- 10593253
TI  - SESAP questions. Gastroesophageal reflux disease.

PMID- 10593254
TI  - Intracellular localization and trafficking of steroid receptors.

PMID- 10593255
TI  - Understanding the cellular uptake of phosphopeptides.
AB  - Phosphopeptide-cellular uptake has been studied with a unique combination of
      tools designed to quantitate this phenomena and to understand properties that
      contribute to transmembrane penetration. High-affinity src-homology domain (SH2)
      hexapeptides for the phosphatidyl inositol 3-kinase system were used to judge
      cell penetration using red blood cells--a model system for the study of
      transmembrane cellular uptake. Hexapeptides without phosphate groups and devoid
      of charged residues poorly entered cells. N-terminal modification with bulky
      hydrophobic groups enhanced partitioning into octanol, an index of
      hydrophobicity, and allowed certain non-phosphorylated peptides to pass into red
      cells. However, tyrosine phosphorylation of hexapeptides markedly decreased
      octanol-water partitioning and completely eliminated cellular uptake. Inclusion
      of ion-pairing agents that masked the phosphate hydrophilic character enabled
      partitioning of phosphopeptides into octanol and achieved cellular uptake. This
      effect was demonstrated using fluorescent derivatives of phosphopeptides and CV1
      cells in culture. The results validate the concept of facilitating cell entry by
      charge masking and open the way to future refinements of this principle. Various
      penetration techniques are compared and discussed in the context of maximizing
      cellular viability.

PMID- 10593256
TI  - Folding funnels and conformational transitions via hinge-bending motions.
AB  - In this article we focus on presenting a broad range of examples illustrating low
      energy transitions via hinge-bending motions. The examples are divided according
      to the type of hinge-bending involved; namely, motions involving fragments of the
      protein chains, hinge-bending motions involving protein domains, and hinge
      bending motions between the covalently unconnected subunits. We further make a
      distinction between allosterically and nonallosterically regulated proteins.
      These transitions are discussed within the general framework of folding and
      binding funnels. We propose that the conformers manifesting such swiveling
      motions are not the outcome of "induced fit" binding mechanism; instead,
      molecules exist in an ensemble of conformations that are in equilibrium in
      solution. These ensembles, which populate the bottoms of the funnels, a priori
      contain both the "open" and the "closed" conformational isomers. Furthermore, we
      argue that there are no fundamental differences among the physical principles
      behind the folding and binding funnels. Hence, there is no basic difference
      between funnels depicting ensembles of conformers of single molecules with
      fragment, or domain motions, as compared to subunits in multimeric quaternary
      structures, also showing such conformational transitions. The difference relates
      only to the size and complexity of the system. The larger the system, the more
      complex its corresponding fused funnel(s). In particular, funnels associated with
      allosterically regulated proteins are expected to be more complicated, because
      allostery is frequently involved with movements between subunits, and
      consequently is often observed in multichain and multimolecular complexes. This
      review centers on the critical role played by flexibility and conformational
      fluctuations in enzyme activity. Internal motions that extend over different time
      scales and with different amplitudes are known to be essential for the catalytic
      cycle. The conformational change observed in enzyme-substrate complexes as
      compared to the unbound enzyme state, and in particular the hinge-bending motions
      observed in enzymes with two domains, have a substantial effect on the enzymatic
      catalytic activity. The examples we review span the lipolytic enzymes that are
      particularly interesting, owing to their activation at the water-oil interface;
      an allosterically controlled dehydrogenase (lactate dehydrogenase); a DNA
      methyltransferase, with a covalently-bound intermediate; large-scale flexible
      loop motions in a glycolytic enzyme (TIM); domain motion in PGK, an enzyme which
      is essential in most cells, both for ATP generation in aerobes and for
      fermentation in anaerobes; adenylate kinase, showing large conformational
      changes, owing to their need to shield their catalytic centers from water; a
      calcium-binding protein (calmodulin), involved in a wide range of cellular
      calcium-dependent signaling; diphtheria toxin, whose large domain motion has been
      shown to yield "domain swapping;" the hexameric glutamate dehydrogenase, which
      has been studied both in a thermophile and in a mesophile; an allosteric enzyme,
      showing subunit motion between the R and the T states (aspartate
      transcarbamoylase), and the historically well-studied lac repressor.
      Nonallosteric subunit transitions are also addressed, with some examples
      (aspartate receptor and BamHI endonuclease). Hence, using this enzyme-catalysis
      centered discussion, we address energy funnel landscapes of large-scale
      conformational transitions, rather than the faster, quasi-harmonic, thermal
      fluctuations.

PMID- 10593257
TI  - Cloning, sequencing, and characterization of five genes coding for acyl-CoA
      oxidase isozymes in the yeast Yarrowia lipolytica.
AB  - The Acyl-CoA oxidase (AOX) isozymes catalyze the first steps of peroxisomal beta
      oxidation, which is important for the degradation of fatty acids. Using conserved
      blocks in previously identified yeast POX genes encoding AOXs, the authors have
      shown that five POX genes are present in the yeast Yarrowia lipolytica. These
      genes show approx 63% identity among themselves, and 42% identity with the POX
      genes from other yeasts. Mono-disrupted Y. lipolytica strains were constructed
      using a variation of the sticky-end polymerase chain reaction method. AOX
      activity in the mono-disrupted strains revealed that a long-chain oxidase is
      encoded by the POX2 gene and a short-chain oxidase by the POX3 gene.

PMID- 10593258
TI  - Cryo-electron microscopy of GDP-tubulin rings.
AB  - Rings of guanosine diphosphate (GDP)-tubulin formed in the presence of divalent
      cations have been studied using conventional negative stain and cryo-electron
      microscopy. The structure of such rings resembles that of depolymerizing
      microtubule ends and corresponds to an "unconstrained" conformation of tubulin in
      its GDP state. The use of cryo-techniques has allowed us to image the ring
      polymers free from dehydration and flattening artifacts. Preparations of frozen
      hydrated GDP-tubulin rings are generally heterogeneous and contain a mixture of
      double, triple, and incomplete rings, as well as spirals and some rare single
      rings. Images of different polymer types can be identified and classified into
      groups that are then amenable for averaging and single particle reconstruction
      methods. Identifying the differences in tubulin structure, between straight and
      curve protofilaments, will be important to understand the molecular bases of
      dynamic instability in microtubules.

PMID- 10593259
TI  - Quantifying the geometry of micropipets.
AB  - Accurate knowledge of the internal diameter (id) of micropipet tips is important,
      because the ability to study many different aspects of biological membranes is a
      very sensitive function of tip size. The authors examined two methods used to
      characterize pipet tips: the digital manometric method (DMM) and bubble number
      method (BNM). For DMM, the authors compared the ability of Laplace's equation
      (model I) and a modified form of his equation (model II), which accounts for
      adhesion between the test fluid and glass. Pressure measurements were made with a
      digital manometer, and ids at the tip were measured using scanning electron
      microscopy (SEM). The micropipet tips showed a slight asymmetry in id, with a
      approx 5% difference between maximum and minimum id. On average, model I
      overestimates the largest id by 2%. Model II overestimates the smaller id by 2%.
      For micropipet tips ranging from 1.00 to 5.00 microm, the corresponding
      uncertainties range from 20 to 100 nm. Making the normally hydrophilic glass
      surface hydrophobic strongly reduced threshold pressures when tested in water,
      but not 100% methanol. Compared to BNM, DMM was insensitive to changes in
      atmospheric pressure: BNM can be corrected for changes in atmospheric pressure.
      Convergence angle(s) can be determined from measurements of the pressure and the
      axial distance of the meniscus from the tip. The accuracy and precision of
      digital manometry approaches that of SEM. DMM should be particularly useful in
      selecting micropipets for patch clamp studies of small vesicles (< 10 microm),
      and may enable systematic selection of micropipets for many other experiments.

PMID- 10593260
TI  - Inhibitory interneurons in hippocampus.

PMID- 10593261
TI  - Noonan syndrome--then and now.

PMID- 10593262
TI  - The optimal method with which to assess right ventricular function.

PMID- 10593263
TI  - Transthoracic 3-dimensional echocardiography in the assessment of subaortic
      stenosis due to a restrictive ventricular septal defect in double inlet left
      ventricle with discordant ventriculoarterial connections.
AB  - To evaluate the accuracy and clinical utility of three-dimensional
      echocardiography in the assessment of the size and shape of the ventricular
      septal defect in double inlet left ventricle. METHODS: We validated the technique
      in an autopsy study, and then performed a clinical investigation. Six autopsied
      hearts were immersed in a waterbath and examined with 3-dimensional
      echocardiography. We identified the cross-section within the dataset which
      optimally displayed the ventricular septal defect "en face", and compared its
      smallest and largest diameters, as well as its area. The ventricular septal
      defect was then filled with a silicone sealant and a section prepared for direct
      measurement. In patients, we measured the diameters and area of the ventricular
      septal defect in endsystole nad computed the aortic valvar area in endsystole
      from the cross-section showing the aortic valve "en face". Ten patients with
      double inlet left ventricle, aged between 2 and 15 years, were studied using
      rotational or parallel scanning. All patients had undergone banding of the
      pulmonary trunk at a mean age of 7 (3-36) days, usually at the time of repair of
      the coarctation. Two patients had undergone surgical enlargement of the
      ventricular septal defect prior to echocardiographic examination. RESULTS: The
      correlation between the areas of the ventricular septal defect in the specimens
      measured directly and by 3-dimensional echocardiography was r=0.98, with limits
      of agreement between -0.1-0.08 cm2. In the patients, the area of the defect was
      measured as 3.9+/-2 cm2, whereas the aortic valvar area was 2.6+/-0.9 cm2. The
      ratio between the areas was 1.5 (0.5-2.3). Three patients with areas of the
      ventricular septal defect smaller than those of the aortic valve had resting
      Doppler gradients between double inlet left ventricle and the aorta of 16, 20 and
      30 mm Hgs, respectively. CONCLUSIONS: 3-dimensional echocardiography provides
      accurate assessment of the area of the ventricular septal defect in double inlet
      left ventricle, and is helpful in identifying patients with subaortic stenosis
      caused by restrictive defects.

PMID- 10593264
TI  - Normal values of signal-averaged electrocardiographic parameters and QT
      dispersion in infants and children.
AB  - Ventricular late potentials, and dispersion of the QT interval, are markers for
      risk of ventricular arrhythmias. Normal values for these parameters are well
      established in adults, but may not apply for children. This study has
      investigated the age dependency of signal averaged electrocardiographic
      parameters and QT dispersion in 111 normal children aged from 5 days to 16 years.
      The results indicate that parameters change with age: duration of filtered QRS
      and low amplitude (< 40 microV) terminal signal increase with age, especially in
      the younger patients. Filtered QRS is 88.9 +/- 7.87 ms in infants, and increases
      to 108.7 +/- 8.51 in teenagers (p<0.001). Low amplitude terminal signals are 17.0
      +/- 3.44 ms in infants, and 24.5 +/- 5.64 ms in teenagers (p<0.001). Root mean
      square of the last 40 ms decreases with age, but remains stable after the age of
      10 years (122.4 +/- 33.30 microV in infants, 60.9 +/- 31.27 in teenagers,
      p<0.001). QT dispersion, on the other hand, does not change significantly with
      age. The mean value for the whole group is 36 +/- 13.7 ms. A weak but significant
      correlation exists between QT dispersion and filtered QRS. Thus, age must be
      taken into consideration when interpreting signal-averaged electrocardiograms,
      but not when measuring QT dispersion.

PMID- 10593265
TI  - Echocardiographic assessment of interrupted aortic arch.
AB  - BACKGROUND: In patients with interrupted aortic arch echocardiography provides
      detailed information about the anatomy of the aortic arch and the associated
      cardiac anomalies. Only a few reports have evaluated the reliability of this non
      invasive diagnostic procedure by correlation with angiographic and surgical
      findings. METHODS: From 1988 through 1993, 45 infants with interrupted arch
      underwent surgical repair (mean age 13.02 days). Of the patients, 33 had
      interruption of the arch between the left common carotid and subclavian arteries;
      25 patients had a ventricular septal defect, and the remaining 20 had coexisting
      complex congenital heart defects. Preoperative diagnosis was made exclusively by
      echocardiography in 25 of the patients. Accuracy of echocardiographic diagnosis
      was evaluated retrospectively by comparing preoperative studies with angiography
      and surgical reports. We then investigated whether the morphologic features of
      the interrupted arch might influence surgical procedure or outcome. RESULTS:
      Intracardiac anatomy was accurately diagnosed by echocardiography in all cases;
      in 2 patients angiography provided additional information concerning the
      morphology of the aortic arch. Operative notes described differences in
      morphology of the arch in 7 patients, but these did not influence the surgical
      procedure. Direct anastomosis of the interrupted segments was possible in 38
      patients, and 36 patients underwent primary intracardiac repair.
      Echocardiographic measurements revealed that the diameter of the ascending aorta
      was related to the number of vessels originating from the proximal aortic arch.
      The distance between the interrupted segments was significantly different
      according to the site of interruption, but not between cases with an isolated
      ventricular septal defect versus those with complex heart disease. It did not
      influence the method of arch repair, nor was it related to recurrent or residual
      obstruction. CONCLUSION: Preoperative echocardiography offers accurate and
      complete diagnosis in the critically ill neonate with interrupted aortic arch and
      associated intracardiac abnormalities.

PMID- 10593266
TI  - A 5-year experience with surgical repair of atrial septal defect employing
      limited exposure.
AB  - BACKGROUND: There has been a trend in recent years towards less invasive therapy
      for many congenital cardiac malformations. For the past 5 years, we have employed
      a technique of limited surgical exposure when repairing atrial defects within the
      oval fossa. METHODS: Over the 5-year period from July 1992 to August 1997, 115
      consecutive patients underwent surgical repair of an isolated atrial septal
      defect in the region of the oval fossa by a single surgeon. The patients had a
      limited midline skin incision starting at the line of the nipples and extending
      inferiorly across 2 to 3 intercostal spaces. A partial sternotomy was performed,
      sparing the manubrium. Standard instruments and cannulation techniques were used
      for cardiopulmonary bypass and fibrillatory arrest. RESULTS: There were no deaths
      and no major complications. The median time to extubation after leaving the
      operating room was 3 hours (30 minutes to 8 days). Mediastinal drains were
      removed the morning after surgery. The median stay in the intensive care unit was
      7 hours (3 hours to 10 days), and patients were discharged from the hospital a
      median of 4 days postoperatively (2 to 23 days). CONCLUSIONS: This approach using
      limited exposure can be applied safely without any new instruments and without
      peripheral incisions or sites of vascular access, while providing a comfortable
      exposure for the surgeon and achieving a cosmetically superior result for the
      patient.

PMID- 10593267
TI  - Volumetric analysis of the right ventricle in children with congenital heart
      defects: comparison of biplane angiography and transthoracic 3-dimensional
      echocardiography.
AB  - BACKGROUND: Three-dimensional echocardiography is a non-invasive imaging
      technique. The fact that it permits volumetric analyses independently of
      geometrical assumptions makes it a putatively useful method for the precise
      measurement of the volumes of the irregularly shaped right ventricles in
      children. The aim of this study was to assess the feasibility of this method and
      its agreement with angiocardiography based estimates of right ventricular volume
      in children with congenital heart disease. METHODS: We studied 102 children with
      congenital heart disease. The angiocardiographic right ventricular volumetry was
      performed using a biplanar technique using Simpson's rule and corrected with
      Lange's correction factors. The echo data sets were registered trans-thoracically
      with a rotating transmitter. Volumes were calculated after manual planimetry by
      adding the volumes of the individual slices. RESULTS: Calculation of right
      ventricular volume echocardiographically was possible only in 34% of patients,
      mostly infants and toddlers. In comparison to angiocardiography, the measured
      volumes were 1.1 +/- 6.9 ml (19.5 +/- 34.1%) or 6.3 +/- 9.4 ml (42.5 +/- 33.6%)
      smaller during systole or diastole, respectively. The limits of agreement were 
      12.5 and 13.6 ml, or 12.45 and 25.15 ml during systole or diastole, respectively.
      When plotted to a logarithmical scale, the correlation coefficients r2 were 0.70
      for systolic and 0.79 for diastolic measurements. CONCLUSION: Transthoracic 3
      dimensional echocardiography with a rotating transmitter is feasible for
      volumetry only in small children. The volumes measured were significantly smaller
      than the ones calculated from the angiocardiographic images. The correlation
      between the two methods is moderate.

PMID- 10593268
TI  - Long-term follow-up of stents implanted to relieve peripheral pulmonary arterial
      stenosis: hemodynamic findings and results of lung perfusion scanning.
AB  - In recent years, percutaneous placement of stents has been used as an alternative
      to surgery or balloon angioplasty for the treatment of adults with peripheral
      pulmonary arterial stenosis. This therapy has also been proposed for children,
      but questions still remain about its indications in this group of patients. We
      describe here the results of intravascular placement of stents in a group of 29
      patients, with a mean age of 12+/-7 (range 3-31) years and weighing 35+/-19
      (range 11-74) kg. All were affected by postsurgical or congenital isolated
      pulmonary arterial stenosis, and have now been followed for 38+/-19 (range 6-65)
      months. The early hemodynamic results have been excellent, with a significant
      reduction of the pulmonary arterial systolic pressure, the systolic pressure
      gradient, and the ratio of systolic pressures in the pulmonary and systemic
      circuits, and with a significant increase of the diameter of the stented vessels
      in all the patients. Of the 29 patients, 24 have been recatheterized 18+/-10
      months after the procedure, demonstrating the stability of the results, with a
      low incidence of late restenosis, this seen in only 1 patient (2%). Lung
      perfusion scanning, performed in 17 patients each year after the follow-up
      catheterization, has showed that the results are maintained at long-term follow
      up (51+/-9 months).

PMID- 10593269
TI  - Francis Fontan.

PMID- 10593270
TI  - Images in congenital heart disease. Hydropneumopericardium.

PMID- 10593271
TI  - Changes of management in a patient with double outlet left ventricle.
AB  - Double outlet left ventricle is an extremely rare anomaly. Until recently, the
      diagnosis was usually established by angiography or at postmortem. There are only
      a few reports describing the echocardiographic findings in this lesion, and as
      far as we know, no report showing the anatomy as well as the velocity and pattern
      of flow by color Doppler echocardiography. The patient reported here underwent
      surgery at the age of four years, when an aortic homograft was placed between the
      right ventricle and the pulmonary trunk. This biventricular repair had to be
      changed into a Fontan-type procedure, 15 years later since the hypoplastic right
      ventricle did not grow adequately.

PMID- 10593272
TI  - A unique case of ventricular isomerism?
AB  - Isomerism of the atriums has often been described with various complex cardiac
      malformations. As far as is known, a case of 'ventricular isomerism' has never
      been recorded. Described is a specimen where, on the basis of morphological
      criterions, there are two right ventricles.

PMID- 10593273
TI  - Multiple left-sided cardiac lesions in one of Noonan's original patients.
AB  - We describe a complex case of obstruction of the left ventricular outflow tract
      in one of Dr. Noonan's original patients. Intraoperative findings revealed
      pathology at the valvar, subvalvar and supravalvar positions. Patients with
      Noonan syndrome are traditionally described as having right-sided cardiac
      pathology. Review of the literature revealed left-sided lesions to occur in a
      substantial number of these patients. We therefore suggest the routine employment
      of cardiac ultrasonography in all patients with Noonan syndrome with attention
      directed toward left-sided pathology, as well as the frequent pulmonary valvar
      pathology.

PMID- 10593274
TI  - Successful management of a pregnancy at high risk because of Eisenmenger
      reaction.
AB  - Informed medical care, appropriate maternal and fetal monitoring, and cooperation
      among experienced obstetricians, anesthesists cardiologists, particularly during
      delivery and the early puerperium associated with psychological preparation of
      the mother, were the bases of the successful management of a pregnant 28-year-old
      woman at high risk because of the Eisenmenger reaction.

PMID- 10593275
TI  - Common arterial trunk associated with atrioventricular septal defect.
AB  - Described are the clinical, cross-sectional echocardiographic,
      electrocardiographic and angiographic findings, together with the results at
      autopsy, in a 5-month old infant with a common arterial trunk associated with an
      atrioventricular septal defect. As far as is known, this is only the 13th such
      case to be reported in the literature. A particularly unusual feature of this
      case was an intact atrial component of the atrioventricular septal defect.

PMID- 10593276
TI  - Successful radiofrequency ablation in an infant with drug-resistant permanent
      junctional reciprocating tachycardia.
AB  - Over the past decade, the technique of radiofrequency ablation has evolved
      substantially. Currently, most forms of cardiac arrhythmias seen in children can
      be treated with good long-term results and low risk of adverse outcome. Curative
      arrhythmia treatment with this technique, however, is still uncommon in neonates
      and infants. Reported here is our experience in the management of an 8-week-old
      with drug-resistant permanent junctional reciprocating tachycardia.

PMID- 10593277
TI  - Double outlet left ventricle with subpulmonary ventricular septal defect and
      pulmonary hypertension.
AB  - A two-month old male infant with the rare occurrence of double outlet left
      ventricle, subpulmonary ventricular septal defect and pulmonary hypertension is
      presented. The infant was managed temporarily with banding of the pulmonary
      trunk, with a favorable result, and is scheduled for definitive intraventricular
      repair.

PMID- 10593278
TI  - The genetics of hypoplastic left heart syndrome.

PMID- 10593279
TI  - Report of the Coding Committee of the Association for European Paediatric
      Cardiology.

PMID- 10593281
TI  - Outcome for patients with a cavopulmonary shunt.

PMID- 10593280
TI  - The real fate of pulmonary arteries after bidirectional superior cavopulmonary
      anastomosis: is there a real need for concern?

PMID- 10593282
TI  - Ultrasonographic monitoring of high dose rate interstitial implant using template
      technique for oral tongue cancer.
AB  - 192Ir high dose rate (HDR) fractionated interstitial brachytherapy was performed
      on two patients with tongue cancer with the aid of real-time intraoral
      ultrasonographic (US) guidance and the template technique. Blind-ended catheters
      with metallic rods (Obturator, Nucletron, the Netherlands) were inserted into the
      tongue from the submandibular region. This US monitoring allows for detection of
      the accurate location of both tumor and catheters in real-time motion. After
      implantation, we reconfirmed the position of the catheters by CT examination.
      Intraoral US monitoring was thus found to be a useful procedure for accurate
      implantation of brachytherapy for tongue cancer.

PMID- 10593283
TI  - High-resolution MR images of inner ear internal anatomy using a local gradient
      coil at 1.5 Tesla: correlation with histological specimen.
AB  - PURPOSE: To obtain high-resolution MR images of the inner ear at 1.5 Tesla with a
      local gradient coil and to correlate these images with the histological specimen.
      MATERIALS AND METHODS: All studies were performed on a 1.5 Tesla MR unit with a
      local gradient coil (23 mT/m, slew rate of 107 mT/m/ms). The cranio-facial region
      of a cadaver was examined using 3D-fast spin echo (FSE) imaging with the voxel
      size of 0.27 mm x 0.27 mm x 0.5 mm in 9 h 37 min. Two normal volunteers were
      examined with the same system using 3D-FSE imaging with the voxel size of 0.20 mm
      x 0.26 mm x 1.0 mm in 57 min. These images were correlated with the cadaver
      images and histological specimens. RESULTS: On cadaver images, internal
      structures such as the macula utriculi, macula sacculi, crista ampullaris, lamina
      spiralis ossea, ligamentum spirale cochleae, modiolus, scala tympani, scala
      vestibuli, and cochlear aqueduct were visualized. On the images of both
      volunteers, the same structures were visualized as on the cadaver images.
      CONCLUSIONS: This study confirmed that high-resolution MR images obtained at 1.5
      Tesla can visualize inner ear internal anatomy. Knowledge obtained in this study
      may be of significant value for the diagnosis of pathology in the area of the
      inner ear.

PMID- 10593284
TI  - CT findings of BALTOMA.
AB  - OBJECTIVE: To review the CT findings of BALTOMA, a low-grade malignant lymphoma
      originating from bronchus-associated lymphoid tissue (BALT). METHODS: The CT
      findings, symptoms, and clinical courses of BALTOMA in five patients were
      reviewed. The specimens obtained at operation were investigated, and the
      pathological findings were compared with the CT findings. RESULTS: There were no
      symptoms in four patients and normal laboratory data in all patients. One patient
      who complained of general malaise underwent surgery under suspicion of lung
      carcinoma. Four patients were observed from 4 months to 7 years and 1 month under
      the diagnosis of organizing pneumonia or chronic inflammatory processes. On CT
      images a localized lesion was seen in four cases, while multiple lesions were
      seen in one case. Attenuation of the lesions was between 39.15 and 60 HU on
      nonenhanced CT. Lesions were homogeneously enhanced by contrast material. The
      margins of the lesion were clearly demarcated by interlobular septa in one
      portion and were unclear in the other portion in all cases. Air bronchograms were
      seen in four cases. CT angiogram signs were seen in three of four cases in which
      contrast study was performed. There was no lymphadenopathy, pleural changes, or
      invasion to other organs. The pathological investigation revealed small
      lymphocytes that showed monoclonality in all cases. CONCLUSIONS: Awareness of the
      CT findings of BALTOMA can help to avoid misinterpreting BALTOMA as chronic
      inflammation and/or lung carcinoma. When a slowly progressive chronic pneumonia
      is being followed up, transbronchial lung biopsy and immunoglobulin staining of
      lymphocytes should be recommended for the correct diagnosis.

PMID- 10593285
TI  - Intracerebral malignant fibrous histiocytoma in a 5-year-old girl.
AB  - A case of primary intracerebral malignant fibrous histiocytoma (MFH) in 5-year
      old girl is presented, the eighteenth case so described in modern literature. A
      lobulated, heterogenous mass lesion with a haemorragic component was present in
      our case' s MRI. A review of the literature on MFH of the pediatric age group was
      done to establish guidelines for standard treatment modalities in primary
      intracerebral MFH.

PMID- 10593286
TI  - Simultaneous bilateral thalamic hemorrhage: case report.
AB  - A 60-year-old man presented with an extremely rare case of simultaneous
      hypertensive bilateral thalamic hemorrhage manifesting as left hemiparesis with
      headache followed by deterioration in consciousness and tetraparesis. CT scan
      confirmed the bilateral thalamic hemorrhages 17 hours after onset. Magnetic
      resonance imaging showed the bilateral thalamic lesions had similar signal
      intensities, consistent with the simultaneous onset, and had no evidence of
      hemorrhagic reason. Conservative treatment achieved some neurological
      improvement, but he died of pneumonia six months after onset. The prognosis of a
      patient with bilateral hemorrhages is worse than would be indicated by the size
      of the hemorrhages.

PMID- 10593287
TI  - Volar dislocation of the capitate.
AB  - In this report we describe a case of volar dislocation of the capitate associated
      with dislocation of the ulnar side of the carpometacarpal joint. Forced
      dorsiflexion of the wrist caused the rotation and volar displacement of the
      proximal portion of the capitate. Dislocation of the capitate is rare and may be
      seen in more complex injuries. An awareness of this type of injury may contribute
      to prompt diagnosis and treatment.

PMID- 10593289
TI  - A case of Japanese encephalitis: CT and MRI findings in acute and convalescent
      stages.
AB  - We studied the CT and MR images of a patient with Japanese encephalitis. The
      first symptom was general malaise with high fever. The diagnosis of
      meningoencephalitis was made by spinal tap and clinical presentation. CT on the
      third day of illness showed no significant findings. MRI on the fifth day of
      illness demonstrated that the left thalamus and bilateral putamen were
      hyperintense on T2-weighted images. On CT one month later, the density in the
      thalamus and bilateral putamen was normal. MRI two month later showed high signal
      intensity only in the left thalamus. The patient recovered, but was judged to
      have dementia according to the simple dementia scale of Hasegawa. Flaccid
      paralysis was observed during the acute period.

PMID- 10593288
TI  - Imaging features of pancreatoblastoma: a case report.
AB  - We present a patient with pancreatoblastoma along with a discussion of various
      cross-sectional imaging features. The tumor was a large multilocular cystic mass
      with solid components in the left retroperitoneal space. There were fine internal
      echoes on ultrasonography, and the signal intensity was high on both T1- and T2
      weighted MR images in most of the locules, suggesting the presence of hemorrhagic
      debris. Among the various retroperitoneal organs displaced by the tumor, only the
      pancreatic tail was inseparable from the mass, suggesting that the pancreatic
      tail was the origin of the tumor. Pancreatoblastoma should be included in the
      differential diagnosis when a large left upper quadrant mass with these imaging
      features is seen in infants and young children.

PMID- 10593291
TI  - Hepatocellular carcinoma with ring calcification: report of two cases.
AB  - Two cases of hepatocellular carcinoma (HCC) with ring calcification are reported
      together with their CT findings. HCC in both cases showed little early
      enhancement followed by delayed enhancement on dynamic CT. The pathologic
      specimen in one case showed HCC with fairly abundant fibrosis, and calcification
      was noted underneath the thick fibrous capsule, which might explain the
      enhancement pattern on CT.

PMID- 10593290
TI  - A case of moyamoya-like vessels combined with brain anomaly.
AB  - We report here a rare case of moyamoya-like vessels combined with brain anomaly.
      MR imaging revealed a small corpus callosum and stenosis of the internal carotid
      arteries. T2-weighted images revealed multiple hyperintense lesions in the
      cerebral deep white matter, suggesting ischemic or abnormal myelinated tissues.
      Cerebral angiography showed aplastic carotid siphons and anomalous aneurysmal
      dilatation of the petrous portion of the internal carotid arteries. The terminal
      portion of the internal carotid arteries and horizontal portion of the middle
      cerebral artery were stenotic with moyamoya-like vessels.

PMID- 10593292
TI  - Chondromyxoid fibroma of the scapula associated with aneurysmal bone cyst.
AB  - A rare case of chondromyxoid fibroma of the scapula in a 21-year-old man is
      presented. This case is of interest because of its unusual site and association
      of aneurysmal bone cyst. Although chondromyxoid fibroma is uncommon bone tumor of
      the scapula, it should be considered in the differential diagnosis of expansile
      osteolytic lesion of the scapula.

PMID- 10593293
TI  - Local recurrence of breast cancer demonstrated on 99mTc-MIBI scintigraphy.
AB  - We present a postmastectomy patient in whom a mass was palpated in the chest
      wall. It appeared to be difficult to determine whether the chest wall mass was
      local recurrence of breast cancer or granulation induced by mastectomy on
      computed tomography (CT). The mass was successfully demonstrated on 99mTc
      methoxyisobutylisonitrile (99mTc-MIBI) scintigraphy as an area of increased
      accumulation, and was considered to be a recurrent tumor. Surgical resection was
      performed, and the mass was histopathologically proven to be recurrence. 99mTc
      MIBI scintigraphy may contribute to the detection of local recurrence or distant
      metastasis in addition to the diagnosis of primary breast cancer and axillary
      metastasis.

PMID- 10593294
TI  - Clinical application of single shot GRE-EPI as non-enhanced MRA (EPI-MRA) for
      aortic aneurysm and dissection.
AB  - We investigated the usefulness of single shot gradient echo type echo planar
      imaging (GRE-EPI) as magnetic resonance angiography (MRA) for the diagnosis of
      aortic aneurysm and dissection. This technique can detect blood flow signals in
      several tenths of a milliseconds without the need for contrast medium, breath
      holding, or electrocardiographic (ECG) gating. By scanning approximately 20
      frames in the coronal plane, three-dimensional (3D) imaging can be achieved by
      maximum intensity projection (MIP) at different angles. Three radiologists
      evaluated the ability of this single shot GRE-EPI as non-enhanced MRA (EPI-MRA)
      to diagnose aortic aneurysm and dissection. The examined lesions consisted of
      three cases of thoracic aortic aneurysm, seven of abdominal aortic aneurysm and
      eight of aortic dissection with a total of 15 involved aorta. In all patients
      with aortic aneurysm, EPI enabled detection and diagnosis of the aneurysm.
      However, the size of the lesion and relationship with major branches were
      determined only in the abdominal aorta, and could not be determined precisely in
      thoracic lesions. Similar results were obtained for patients with aortic
      dissection. The technique visualized the intimal flap and enabled determination
      of the extent of dissection in the abdominal aorta. In the thoracic aorta,
      serious magnetic susceptibility artifacts caused image distortion, and as a
      result only the dissection could be detected and diagnosed. No entry site was
      detected at either the abdominal or thoracic aorta. These results suggest that
      EPI-MRA may have a clinical potential for screening patients with acute aortic
      disease who cannot undergo physical restraint for scanning.

PMID- 10593295
TI  - Intraluminal brachytherapy using a balloon applicator for superficial esophageal
      carcinoma: importance of applicator confirmation by computed tomography.
AB  - Intraluminal brachytherapy using a balloon applicator has been the treatment of
      choice for superficial esophageal carcinomas. During treatment, the applicator is
      made to expand to be cylindrical as determined from an AP radiograph. However,
      optimal expansion of the applicator is not usually confirmed by computed
      tomography (CT). Therefore, this study was conducted to assess the shape of the
      balloon applicator by CT. Ten patients with superficial esophageal carcinoma were
      treated with intraluminal brachytherapy using a balloon applicator. The
      applicators were expanded properly in all patients as viewed from the AP
      radiograph. In seven of 10 patients, optimal expansion of the applicator was
      observed on CT. However, in the remaining three patients, applicators were found
      to be distorted presumably not only by primary tumor and mediastinal lymph nodes
      but also by neighboring organs. These results indicate that, when treating
      superficial esophageal carcinoma using a balloon applicator, there may be risks
      of applicator distortion in some cases. Assessment by CT should be done to
      precisely confirm the shape of the applicator.

PMID- 10593296
TI  - Dementia associated with Lewy bodies: dilemmas and directions.

PMID- 10593297
TI  - Proton magnetic resonance spectroscopy: an in vivo window to study
      neurodegenerative disorders.

PMID- 10593298
TI  - The role of oxidative stress in Alzheimer disease.

PMID- 10593299
TI  - Single-cell molecular biology: implications for the diagnosis and treatment of
      neurological disease.
AB  - The normal functioning of the central nervous system (CNS) requires complex
      interactions among numerous biological components. The pathophysiology of
      perturbations in this system is as complex as that of neurological disease. Many
      methods exist to examine the biological output of dysfunctional cells from a
      diseased system (e.g., immunohistochemical analysis, electrophysiology, and
      microdialysis), with one goal being to understand the mechanisms of cell death.
      This understanding may allow the design of therapeutic strategies to prevent cell
      death and ensuing behavioral abnormalities. Analysis of messenger RNA (mRNA)
      levels for various genes in CNS tissue may enhance understanding of neurological
      disease, since cells differ in the complement and abundance of genes they
      express. One popular method for detecting changes in gene expression is the
      Northern blot technique, in which total RNA from a sample is extracted and the
      RNA molecules are separated by size on a denaturing gel and transferred or
      "blotted" onto nylon membranes that are then probed with radiolabeled DNA for
      subsequent autoradiograpic detection of gene expression.

PMID- 10593300
TI  - Neurochemical markers do not correlate with cognitive decline in the Lewy body
      variant of Alzheimer disease.
AB  - BACKGROUND: Reductions in neocortical synapses and cholinergic function occur in
      patients with Alzheimer disease (AD) and in patients with the Lewy body variant
      of AD (LBV). The relation between these losses and cognitive decline has been
      reported frequently in patients with AD but remains unclear for patients with
      LBV. OBJECTIVES: To investigate the relation between clinical markers of disease
      progression and choline acetyltransferase activity or synaptic density, measured
      by synaptophysin (Syn) level, in patients with LBV, and to investigate the
      relation of these neurochemical markers with one another. METHODS: Brain
      specimens of 41 patients with autopsy-confirmed (National Institute on Aging
      criteria for AD) LBV were examined. The last Mini-Mental State Examination and
      Blessed Information-Memory-Concentration test scores before death were reviewed.
      Midfrontal synapse counts were quantified by a dot-immunobinding assay for Syn.
      Choline acetyltransferase activity of the midfrontal cortex was assayed by
      established protocols. RESULTS: The last Mini-Mental State Examination score
      before death did not correlate significantly with Syn level (n = 25, r = 0.25, P
      = .24); however, there was a trend toward significance for the relation between
      last Mini-Mental State Examination score and choline acetyltransferase activity
      (n = 39, r = 0.31, P = .05). The last Blessed Information-Memory-Concentration
      test score did not correlate with either Syn level (n = 24, r = -0.17, P = .44)
      or choline acetyltransferase activity (n = 39, r = -0.16, P = .33). Finally,
      there was only a modest correlation between Syn level and choline
      acetyltransferase activity (n = 25, r = 0.38, P = .06), which did not reach
      statistical significance. CONCLUSION: Unlike AD, neurochemical markers do not
      appear to correlate well with cognitive decline in LBV.

PMID- 10593301
TI  - Proton magnetic resonance spectroscopy in Kennedy syndrome.
AB  - OBJECTIVE: To seek regional metabolite abnormalities in patients with Kennedy
      disease (KD) using proton magnetic resonance spectroscopy. DESIGN: Nine patients
      with KD showing the typical phenotype without clinical signs of upper motor
      neuron involvement were compared with 17 male, age-matched, healthy control
      subjects. Relative metabolite concentrations for N-acetyl (NA) groups, choline
      containing groups (Cho), phosphocreatine (Cr), and lactate (Lac) were determined
      in the brainstem and the motor region. RESULTS: Pathologic Lac signals suggesting
      impaired energy metabolism were absent in patients and controls. In the brainstem
      area, patients with KD showed a significant reduction in the NA/Cho metabolite
      ratio (P = .01). In the motor region, NA/Cho (P = .04) and NA/Cr (P = .03) ratios
      were significantly reduced. The reduction of the NA/Cho ratio in the motor region
      mainly resulted from decreased metabolite ratios in 3 patients. Changes in
      metabolite ratios did not correlate with the number of trinucleotide cytosine
      adenine-guanine repeats from leukocytes. Because of the relatively small sample
      size due to the rarity of KD, these results should be considered preliminary.
      CONCLUSIONS: Spectroscopic data fail to provide further evidence for altered
      energy metabolism in KD. Metabolite changes in the brainstem indicate a reduction
      of the neuronal marker NA or elevated Cho. These findings may reflect neuronal
      loss or gliosis consistent with the known pathologic features. In a subset of
      patients, altered metabolite ratios best explained by neuronal loss suggest
      subclinical involvement of the motor region. The extent of metabolite changes
      does not correlate with the trinucleotide repeat length.

PMID- 10593302
TI  - Correlation of basal ganglia magnetic resonance spectroscopy with Apgar score in
      perinatal asphyxia.
AB  - BACKGROUND: Brain metabolite levels are measured by proton magnetic resonance
      spectroscopy (1H MRS) and include N-acetylaspartate (NAA), creatine (Cr), choline
      (Cho), and lactate and the ratios NAA to Cho and Cr (NAA-ChoCr), NAA-Cr, NAA-Cho,
      and Cho-Cr. Brain metabolite levels may correlate with the degree of neonatal
      asphyxia. OBJECTIVE: To determine which brain metabolite ratios have the
      strongest correlation with the Apgar scores in infants with possible asphyxia;
      whether the correlation is stronger with basal ganglia (BG) or anterior border
      zone metabolites; and whether a combined approach using routine MR imaging (MRI),
      diffusion-weighted MRI, and MRS can be used to evaluate the severity of neonatal
      asphyxia. METHODS: Twenty infants with 1-minute Apgar scores of 6 or less were
      studied at 2 to 28 days of age. The MRS variables were compared with routine and
      diffusion-weighted brain MRI. Clinical variables and MRS findings were subjected
      to factor analysis and stepwise multiple regressions to determine
      interrelationships. RESULTS: The BG region NAA-Cho and NAA-ChoCr ratios
      correlated with the 1-minute (P<.001) and 5-minute (P = .01 for NAA-Cho; P = .006
      for NAA-ChoCr). There was no correlation between metabolite levels and the 10
      minute Apgar scores. The stongest predictions exist between the 1-minute Apgar
      scores and the NAA-Cho and NAA-ChoCr ratios. In the anterior border zone, the
      only correlation was between the 1-minute Apgar score and the NAA-Cho ratio, but
      there was a strong age effect in these data. Lactate was found in the BG of 3
      infants, all of whom had 5-minute Apgar scores of 6 or less. Three patients had
      focal lesions on MRI; 2 of these had elevated lactate levels in the abnormal
      region; and the third, who had an intrauterine stroke, had no lactate in the
      region. CONCLUSIONS: Correlations between NAA-Cho and NAA-ChoCr ratios and the 1-
      and 5-minute Apgar scores are stronger in the BG region than in the frontal
      border zone. The presence or absence of lactate may indicate the severity of the
      brain insult, and the combination of MRS, MRI, and diffusion-weighted MRI may
      assist in localizing and predicting a long-term brain injury.

PMID- 10593303
TI  - Preliminary observations on APOE epsilon4 allele and progression of disability in
      multiple sclerosis.
AB  - BACKGROUND: Apolipoprotein E expression is increased in regenerating neural
      tissue and the APOE epsilon4 allele is associated with impaired neuronal repair.
      Since repair is essential for the restoration of central nervous system function
      following multiple sclerosis (MS) relapses, APOE genotype may influence clinical
      progression of the disease. OBJECTIVE: To examine the association of the APOE
      genotype with disease susceptibility and progression in MS. PATIENTS AND METHODS:
      APOE genotyping was determined by polymerase chain reaction and restriction
      enzyme digestion in 47 patients with MS who had been followed up every 3 months
      for 2 years as part of an open-label clinical trial with glatiramer acetate. The
      Expanded Disability Status Scale (EDSS) was used to assess clinical progression.
      RESULTS: Nine patients were heterozygous and 1 patient was homozygous for the
      APOE epsilon4 allele, for a frequency of 12% (11/94), which is similar to that of
      the general Israeli population. The APOE epsilon4 carriers had a mean +/- SE EDSS
      score of 3.10+/-0.45 at entry, which was not significantly different from the
      remaining 37 patients (2.62+/-0.25). During the observation period, the EDSS
      score of the APOE epsilon4 carriers deteriorated to 4.00+/-0.63 while the other
      patients remained stable with an EDSS score of 2.74+/-0.31. The interaction of
      genotype with disability over time was significant (P = .02 by repeated-measures
      analysis of variance). There were no differences in the number of relapses
      occurring in the 2 groups. CONCLUSIONS: These preliminary observations suggest
      that APOE genotype may influence disease progression in MS. The APOE epsilon4
      allele was not associated with an increased risk of MS or relapses.

PMID- 10593305
TI  - Resetting of orthostatic tremor associated with cerebellar cortical atrophy by
      transcranial magnetic stimulation.
AB  - OBJECTIVES: To investigate the resetting effects of transcranial magnetic
      stimulation over motor cortex on orthostatic tremor, characterized by high
      frequency electromyographic discharges in weight-bearing muscles, particularly
      orthostatic tremor (OT) associated with cerebellar cortical atrophy; and to
      compare our results with those obtained in primary OT, for which transcranial
      magnetic stimulation does not reset tremor. DESIGN: Study of 3 patients who
      clinically exhibited a sporadic pancerebellar syndrome associated with isolated
      cerebellar atrophy and features of OT. SETTING: Research hospital. MAIN OUTCOME
      MEASURES: Electromyograms and transcranial magnetic stimulation studies with a
      resetting index calculated on the basis of the timing of measured bursts and
      predicted bursts for a magnetic stimulus given at increasing delays. RESULTS:
      Surface electromyographic recordings in weight-bearing muscles showed tremor with
      a frequency of 14, 15, and 14 Hz in the 3 patients. Transcranial magnetic
      stimulus was able to reset OT. Resetting index was 0.72. CONCLUSIONS:
      Transcranial magnetic stimulus resets OT associated with cerebellar cortical
      atrophy, emphasizing the role of motor cortex in the genesis of OT associated
      with a cerebellar dysfunction. Our results argue in favor of a distinct
      pathophysiological mechanism of primary OT and OT associated with cerebellar
      cortical atrophy.

PMID- 10593304
TI  - The utility of apolipoprotein E genotyping in the diagnosis of Alzheimer disease
      in a community-based case series.
AB  - CONTEXT: A recent collaborative study found that apolipoprotein E (APOE)
      genotype, in conjunction with the clinical diagnosis of Alzheimer disease (AD),
      was useful in improving diagnostic specificity (correctly not diagnosing AD)
      relative to the clinical diagnosis alone. Since these samples are particularly
      enriched with patients with AD and the APOE epsilon4 allele, results may not be
      generalizable to patients seen in the general medical community. OBJECTIVE: To
      evaluate the diagnostic utility of the APOE genotype in diagnosing AD in a
      community-based case series from the largest health maintenance organization in
      an urban area. DESIGN: We examined the effect of including APOE genotype on the
      diagnosis of AD in a community-based case series of patients presenting with
      memory complaints. PATIENTS: Clinical and neuropathologic diagnoses and APOE
      genotype were obtained from 132 patients who underwent evaluation for dementia
      and subsequent autopsy. MAIN OUTCOME MEASURES: Sensitivity, specificity, and
      positive and negative predictive values given various combinations of clinical
      diagnoses and the presence of an APOE epsilon4 allele. RESULTS: Of the 132
      patients, 94 had neuropathologically confirmed AD, yielding a prevalence of 71%.
      The clinical diagnosis alone yielded a sensitivity of 84%, an estimated
      specificity of 50%, and positive and negative predictive values of 81% and 56%,
      respectively. The presence of an epsilon4 allele alone was associated with an
      estimated sensitivity of 59%, specificity of 71%, and positive and negative
      predictive values of 83% and 41%, respectively. Using the presence of clinical AD
      and an epsilon4 allele decreased the sensitivity to 49% and increased the
      specificity to 84%. The positive and negative predictive values were 88% and 40%,
      respectively. Alternatively, the clinical diagnosis of AD or the presence of an
      epsilon4 allele in individuals not meeting clinical criteria for AD increases the
      estimated sensitivity to 94% but decreases the specificity to 37%. The positive
      and negative predictive values were 79% and 70%, respectively. The changes in the
      sensitivity and specificity for the combined tests relative to clinical diagnosis
      alone offset each other. For lower prevalence communities, the positive
      predictive value will be much lower than those observed herein. CONCLUSIONS: Our
      findings do not support the use of APOE genotyping alone in the diagnosis of AD
      in the general medical community. Although the presence of an epsilon4 allele in
      older persons with clinical AD increased the probability of having AD and the
      absence of an epsilon4 allele in this group decreased the probability of having
      AD, the association is not strong enough in the differential diagnosis of non
      Alzheimer dementia and AD.

PMID- 10593306
TI  - Mother with amyotrophic lateral sclerosis and daughter with Creutzfeldt-Jakob
      disease.
AB  - OBJECTIVE: To describe a mother who had autopsy-proved amyotrophic lateral
      sclerosis and her daughter who had clinically diagnosed Creutzfeldt-Jakob
      disease. DESIGN: Case reports with molecular genetic analyses. SETTING: A
      tertiary care center. PATIENTS: The mother had progressive upper and lower motor
      neuron symptoms and signs starting at the age of 54 years. Electrophysiological
      testing supported the diagnosis of amyotrophic lateral sclerosis. Autopsy results
      confirmed the diagnosis. Her daughter had received injections of human growth
      hormone prepared from pooled human pituitary glands as a child. At the age of 31
      years, she experienced the onset of gait ataxia and dysarthria. Cerebrospinal
      fluid showed the 14-3-3 protein. Cognitive difficulties ensued. She progressed to
      a nearly akinetic and mute state. She had overt visible fasciculations and muscle
      atrophy in the legs. MAIN OUTCOME MEASURES AND RESULTS: Neither patient carried a
      mutation in the prion protein gene. Both were homozygous for methionine at the
      polymorphic codon 129. Neither patient carried a deletion of the 5 exons of the
      superoxide dismutase 1 gene. CONCLUSIONS: It is uncertain whether the 2 cases
      occurred in the same family by chance or whether the patients shared genetic risk
      factors for the 2 diseases. The possibility that homozygosity at codon 129 is a
      risk factor for amyotrophic lateral sclerosis is being tested in a case-control
      study.

PMID- 10593308
TI  - One and one-half syndrome with supranuclear facial weakness: magnetic resonance
      imaging localization.
AB  - OBJECTIVE: To provide clinicoanatomical correlation for a small pontine tegmental
      ischemic stroke producing the one and one-half syndrome associated with
      supranuclear facial weakness. DESIGN: Case report. SETTING: Tertiary care center.
      PATIENT: A 70-year-old man developed left-sided facial weakness sparing the
      forehead, a left internuclear ophthalmoplegia, and a complete left horizontal
      gaze palsy immediately after percutaneous transluminal coronary angioplasty.
      Magnetic resonance imaging demonstrated a small lesion in the left paramedian
      aspect of the dorsal pontine tegmentum. MAIN OUTCOME AND RESULTS:
      Electromyographic findings were consistent with supranuclear facial involvement.
      The patient had nearly complete recovery after 1 year. CONCLUSIONS: To our
      knowledge, this is the first report of supranuclear facial weakness in
      association with the one and one-half syndrome. The location of the lesion
      provides evidence of the existence of corticofugal fibers that extend to the
      facial nucleus in the dorsal paramedian pontine tegmentum.

PMID- 10593307
TI  - Accumulation of neurofilaments and SOD1-immunoreactive products in a patient with
      familial amyotrophic lateral sclerosis with I113T SOD1 mutation.
AB  - OBJECTIVE: To report neuropathologic features of argyrophilic inclusions in the
      anterior horn cells, motor cortex Betz cells, and neurons of the medullary
      reticular formation, spinal posterior horn, and Clarke column in a Japanese case
      of familial amyotrophic lateral sclerosis with I113T substitution in exon 4 of
      the copper-zinc superoxide dismutase (SOD1) gene. METHODS AND RESULTS: These
      inclusions were stained pale pink on the hematoxylin-eosin stain and dark on the
      Bielschowsky stain. They were positive for antibodies to phosphorylated
      neurofilaments, ubiquitin, and SOD1. On electron microscopy, they consisted of
      abundant intermediate filaments of 10 to 20 nm in diameter with disordered array
      indicating neurofilaments. CONCLUSION: These findings suggest that the I113T
      mutation induces accumulation of neurofilaments and SOD1 in the central nervous
      system neurons.

PMID- 10593309
TI  - Mild tactile disturbance and a lhermitte phenomenon in a middle-aged man.

PMID- 10593310
TI  - Is cholesterol a risk factor for stroke?: Yes.

PMID- 10593311
TI  - Is cholesterol a risk factor for stroke?: No.

PMID- 10593312
TI  - Restless Legs syndrome.

PMID- 10593313
TI  - Substance abuse, neurobiology, and ideology.

PMID- 10593314
TI  - Hormone replacement therapy and risk of heart disease.

PMID- 10593315
TI  - Comments on flexible sigmoidoscopy.

PMID- 10593316
TI  - Clarification on Strongyloides quiz question.

PMID- 10593317
TI  - Coming face-to-face with social phobia.

PMID- 10593318
TI  - Prevention of recurrent nephrolithiasis.
AB  - The first episode of nephrolithiasis provides an opportunity to advise patients
      about measures for preventing future stones. Low fluid intake and excessive
      intake of protein, salt and oxalate are important modifiable risk factors for
      kidney stones. Calcium restriction is not useful and may potentiate osteoporosis.
      Diseases such as hyperparathyroidism, sarcoidosis and renal tubular acidosis
      should be considered in patients with nephrolithiasis. A 24-hour urine collection
      with measurement of the important analytes is usually reserved for use in
      patients with recurrent stone formation. In these patients, the major urinary
      risk factors include hypercalciuria, hyperoxaluria, hypocitraturia and
      hyperuricosuria. Effective preventive and treatment measures include thiazide
      therapy to lower the urinary calcium level, citrate supplementation to increase
      the urinary citrate level and, sometimes, allopurinol therapy to lower uric acid
      excretion. Uric acid stones are most often treated with citrate supplementation.
      Data now support the cost-effectiveness of evaluation and treatment of patients
      with recurrent stones.

PMID- 10593319
TI  - Obstructive sleep apnea.
AB  - Obstructive sleep apnea is a significant medical problem affecting up to 4
      percent of middle-aged adults. The most common complaints are loud snoring,
      disrupted sleep and excessive daytime sleepiness. Patients with apnea suffer from
      fragmented sleep and may develop cardiovascular abnormalities because of the
      repetitive cycles of snoring, airway collapse and arousal. Although most patients
      are overweight and have a short, thick neck, some are of normal weight but have a
      small, receding jaw. Because many patients are not aware of their heavy snoring
      and nocturnal arousals, obstructive sleep apnea may remain undiagnosed;
      therefore, it is helpful to question the bedroom partner of a patient with
      chronic sleepiness and fatigue. Polysomnography in a sleep laboratory is the gold
      standard for confirming the diagnosis of obstructive sleep apnea; however, the
      test is expensive and not widely available. Home sleep studies are less costly
      but not as diagnostically accurate. Treatments include weight loss, nasal
      continuous positive airway pressure and dental devices that modify the position
      of the tongue or jaw. Upper airway and jaw surgical procedures may also be
      appropriate in selected patients, but invasiveness and expense restrict their
      use.

PMID- 10593320
TI  - Diagnosis of stridor in children.
AB  - Stridor is a sign of upper airway obstruction. In children, laryngomalacia is the
      most common cause of chronic stridor, while croup is the most common cause of
      acute stridor. Generally, an inspiratory stridor suggests airway obstruction
      above the glottis while an expiratory stridor is indicative of obstruction in the
      lower trachea. A biphasic stridor suggests a glottic or subglottic lesion.
      Laryngeal lesions often result in voice changes. A child with extrinsic airway
      obstruction usually hyperextends the neck. The airway should be established
      immediately in children with severe respiratory distress. Treatment of stridor
      should be directed at the underlying cause.

PMID- 10593321
TI  - Assessment and management of acute low back pain.
AB  - Acute low back pain is commonly treated by family physicians. In most cases, only
      conservative therapy is needed. However, the history and physical examination may
      elicit warning signals that indicate the need for further work-up and treatment.
      These "red flags" include a history of trauma, fever, incontinence, unexplained
      weight loss, a cancer history, long-term steroid use, parenteral drug abuse, and
      intense localized pain and an inability to get into a comfortable position.
      Treatment usually consists of nonsteroidal anti-inflammatory agents or
      acetaminophen and a gradual return to usual activities. Surgery is reserved for
      use in patients with severe neurologic deficits and, possibly, those with severe
      symptoms that persist despite adequate conservative treatment.

PMID- 10593322
TI  - Social anxiety disorder: a common, underrecognized mental disorder.
AB  - Social phobia is a highly prevalent yet often overlooked psychiatric disorder
      that can cause severe disability but fortunately has shown responsiveness to
      specific pharmacotherapy and psychotherapy. Recognition of its essential clinical
      features and the use of brief, targeted screening questions can improve detection
      within family practice settings. Cognitive behavioral therapy, with or without
      specific antidepressant therapy, is the evidence-based treatment of choice for
      most patients. Adjunctive use of benzodiazepines can facilitate the treatment
      response of patients who need initial symptom relief. The use of beta blockers as
      needed has been found to be helpful in the treatment of circumscribed social and
      performance phobias. Treatment planning should consider the patient's preference,
      the severity of presenting symptoms, the degree of functional impairment,
      psychiatric and substance-related comorbidity, and long-term treatment goals.

PMID- 10593323
TI  - Preventing stroke in patients with transient ischemic attacks.
AB  - Stroke is the third most common overall cause of death and the leading cause of
      adult disability in the United States. New therapeutic interventions instituted
      in the period immediately after a stroke have revolutionized the approach to
      ischemic cerebrovascular disease. Recognition of a transient ischemic attack
      provides an opportunity to prevent a subsequent stroke. Specific stroke
      prevention treatment depends on the cause of the transient ischemic attack, its
      cerebrovascular localization and the presence of associated coexisting medical
      problems. Modification of stroke risk factors is the principal therapeutic
      approach. Antiplatelet agents and anticoagulants have been shown to be effective
      in reducing the occurrence of stroke in certain populations. Several well
      designed studies have recently demonstrated the effectiveness of carotid
      endarterectomy in preventing strokes related to extracranial carotid artery
      disease.

PMID- 10593324
TI  - Type 1 diabetes mellitus and the use of flexible insulin regimens.
AB  - The management of type 1 diabetes mellitus (formerly known as insulin-dependent
      diabetes) has changed dramatically over the past 30 years. In particular, new
      insulin strategies have improved the ability to maintain near-normal glycemia.
      Factors such as onset, peak and duration of action can influence the ability of a
      particular insulin regimen to help control glucose levels. Patient factors,
      including individual variations in insulin absorption, levels of exercise and
      types of meals consumed, also influence the effectiveness of an insulin regimen.
      Rapid-acting insulin lispro is an ideal mealtime insulin. The premeal dose of
      insulin lispro can be adjusted based on the content of the meal and the patient's
      blood glucose level. Intermediate-acting and long-acting insulins should not be
      given to account for the content of a specific meal. Long-acting insulin can be
      administered once daily at bedtime or, ideally, twice daily in addition to
      another type of insulin. Patients with type 1 diabetes typically require an
      insulin dosage of 0.5 to 1.0 unit per kg per day. Newly diagnosed patients may
      have lower initial requirements because of continued endogenous insulin
      production. Flexible insulin regimens are based on predetermined actions in
      response to self-monitoring of blood glucose levels and carbohydrate intake.

PMID- 10593325
TI  - Task force outlines ways to improve vaccination coverage.

PMID- 10593326
TI  - Analysis of aminoglycosides in the treatment of gram-negative infections in
      surgical patients.
AB  - HYPOTHESIS: Antibiotic regimens containing aminoglycosides result in a similar
      outcome compared with non-aminoglycoside regimens in the treatment of gram
      negative infections in surgical patients. DESIGN: An inception cohort study of
      hospitalized surgical patients from December 1, 1996, through September 30, 1998.
      Patients were observed from the time of diagnosis of infection to discharge.
      SETTING: University hospital. PATIENTS: Two hundred fifty-eight consecutive gram
      negative infections occurring in general surgical and trauma patients and
      patients undergoing transplantation. Sixty-six patients received aminoglycosides
      as a component of their treatment regimen, whereas 192 received other agents.
      RESULTS: Patients treated with aminoglycosides were younger (mean +/- SEM age,
      48+/-2 vs 53+/-1 years; P = .04 by univariate analysis) and had a similar APACHE
      II (Acute Physiology and Chronic Health Evaluation II) score (mean +/- SEM, 17+/
      1 vs 15+/-1; P = .10), yet had a significantly higher mortality vs patients
      treated with other agents (29% vs 14%; P = .02). A larger proportion of patients
      requiring hemodialysis were treated with aminoglycosides (33% vs 13%; P = .001).
      Although there was no difference in the sites of infection between groups,
      surgical patients with gram-negative pneumonia had a higher mortality when
      treated with aminoglycosides (37% vs 18%; P = .04), despite similar APACHE II
      scores (mean +/- SEM, 20+/-1 vs 18+/-1; P = .40). CONCLUSIONS: Despite a younger
      age and similar severity of illness, patients with gram-negative infections
      treated with aminoglycosides were associated with a higher mortality rate,
      although this may be related to selection bias in the use of aminoglycoside
      agents. The mortality rate associated with gram-negative pneumonia was also
      higher in patients treated with aminoglycosides, despite a similar severity of
      illness. Future randomized studies are necessary to reanalyze the role of
      aminoglycosides in treating surgical patients with gram-negative infections,
      particularly pneumonia.

PMID- 10593327
TI  - Waiting for microbiologic data to direct therapy against nosocomial infections in
      febrile surgical patients: are outcomes worsened?
AB  - HYPOTHESIS: Allowing adequate time for laboratory and culture results before
      initial treatment may be associated with a worse outcome in nosocomial
      infections. DESIGN: Cohort study of all episodes of nosocomial infection from
      December 10, 1996, to October 28, 1998. SETTING: Surgical services at a
      university hospital. PATIENTS AND METHODS: In surgical patients presenting with
      fever, 372 episodes of nosocomial infection were evaluated. Nosocomial infections
      were divided by time from fever to intervention (< or =12, 13-24, and >24 hours).
      These groups were subdivided by Acute Physiology and Chronic Health Evaluation II
      (APACHE II) scores into low (< or =10 [n = 114]), moderate (11-20 [n = 169]), and
      high severity of illness (>20 [n = 89]). Pneumonia and bloodstream infections
      were divided by APACHE II scores into low (< or =15 [n = 55 and n = 56,
      respectively]) or high severity of illness (>15 [n = 84 and n = 77,
      respectively]). MAIN OUTCOME MEASURES: Mortality, length of stay. RESULTS: No
      difference in outcome was seen between different time intervals from fever to
      intervention for nosocomial infections in patients with APACHE II scores of no
      more than 10. Patients treated more than 24 hours after fever were significantly
      younger than those treated at no more than 12 and 13 to 24 hours with APACHE II
      scores of 11 to 20 (P<.05) and more than 20 (P<.05). Mortality and length of stay
      for patients treated at later time intervals were comparable with those of
      patients treated earlier with similar APACHE II scores. There was no difference
      in outcome for patients with pneumonia or bloodstream infection. CONCLUSIONS:
      Episodes of infection in which treatment was withheld until initial microbiologic
      data were available (24 hours) did not have worse outcomes compared with those
      treated earlier. Waiting for laboratory and culture results to direct antibiotic
      therapy for nosocomial infections does not appear harmful and may be potentially
      beneficial.

PMID- 10593328
TI  - Outcome and cost-effectiveness of perioperative enteral immunonutrition in
      patients undergoing elective upper gastrointestinal tract surgery: a prospective
      randomized study.
AB  - HYPOTHESIS: Perioperatively administered enteral immunonutrition will improve
      early postoperative morbidity and cost-effectiveness after gastrointestinal tract
      surgery. DESIGN: A prospective, randomized, double-blind, multicenter clinical
      trial. SETTING: Surgical departments in German university and teaching hospitals.
      PATIENTS: One hundred fifty-four patients with upper gastrointestinal tract
      malignant neoplasms who were eligible for analysis. INTERVENTION: Preoperatively,
      patients received 5 days of oral immunonutrition (an arginine-, RNA-, and omega3
      fatty acid-supplemented diet) or an isoenergetic control diet (1 L/d). Early
      postoperative enteral feeding with immunonutrition or an isoenergetic,
      isonitrogenous control diet using a catheter jejunostomy was performed for 10
      days. MAIN OUTCOME MEASURES: Postoperative infectious complications, their
      treatment costs, and cost-effectiveness of immunonutrition were analyzed. Plasma
      levels of the fatty acids eicosapentaenoic acid and docosahexaenoic acid were
      measured. RESULTS: In the immunonutrition group, significantly fewer infectious
      complication events occurred (14 vs 27; P = .05). The number of patients with
      complications was significantly lower in the supplemented diet group after
      postoperative day 3 (7 vs 16; P = .04). The treatment costs of complications in
      the supplemented diet group were suggestively lower than in the control diet
      group (DM 75172 vs DM 204273). Cost-effectiveness was DM 1503 in the experimental
      group vs DM 3587 in the control group, where DM denotes deutsche mark (German
      currency). CONCLUSION: The perioperative administration of an enteral
      immunonutrition significantly (P = .05) decreased the early occurrence of
      postoperative infections and reduced substantially the treatment costs of the
      complications after major upper gastrointestinal tract surgery.

PMID- 10593329
TI  - Protective effects of early interleukin 10 antagonism on injury-induced immune
      dysfunction.
AB  - HYPOTHESIS: Interleukin 10 (IL-10) plays a central role in the development of
      postinjury immune suppression, and early in vivo IL-10 antagonism can be
      protective. DESIGN: Male A/J mice underwent sham or burn injury and were treated
      with monoclonal anti-IL-10 antibody or control antibody at 1 day or 3 days after
      injury. Their ability to survive polymicrobial sepsis induced by the cecum
      ligation and puncture (CLP) technique was then tested. The response of sham- and
      burn-injured mice and burn-injured mice treated with anti-IL-10 to immunization
      with a T-cell-dependent antigen, trinitrophenyl (TNP)-haptenated ovalbumin (TNP
      OVA) was also assessed. MAIN OUTCOME MEASURES: Mortality was monitored for a
      total of 7 days after CLP to assess the effect of anti-IL-10 therapy on the
      survival of burn-injured, immunecompromised mice. Serum antibody isotype
      formation was measured in sham- and burn-injured mice and burn-injured mice
      treated with anti-IL-10 to determine how IL-10 antagonism influenced helper T
      cell responses in vivo. In vitro cytokine production by antigen-stimulated spleen
      cells was assessed to study the effect of blocking IL-10 activity at 1 day vs 3
      days after burn injury. RESULTS: Treating mice with anti-IL-10 at 1 day after
      injury significantly improved CLP survival, whereas delaying treatment 3 days had
      no beneficial effect. The analysis of T-cell function in vivo as determined by
      serum antibody isotype formation indicated that anti-IL-10 treatment at 1 day or
      3 days after injury increased T helper cell 1-type antibody formation to sham
      injury levels by day 10. Moreover, these treatments restored the injury-induced
      reduction of antigen-stimulated IL-2, interferon gamma, and IL-10 production.
      CONCLUSIONS: Interleukin 10 plays an early role in the development of burn injury
      induced immune suppression. Its in vivo inhibition at 1 day after injury may be a
      useful approach toward preventing the development of injury-induced immune
      dysfunction and may do so by restoring T-cell function and cytokine production.

PMID- 10593330
TI  - Proinflammatory mediators stimulate neutrophil-directed angiogenesis.
AB  - BACKGROUND: Vascular endothelial growth factor (VEGF; vascular permeability
      factor) is one of the most potent proangiogenic cytokines, and it plays a central
      role in mediating the process of angiogenesis or new blood vessel formation.
      Neutrophils (PMNs) recently have been shown to produce VEGF. HYPOTHESIS: The
      acute inflammatory response is a potent stimulus for PMN-directed angiogenesis.
      METHODS: Neutrophils were isolated from healthy volunteers and stimulated with
      lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-alpha), interleukin 6
      (IL-6), and anti-human Fas monoclonal antibody. Culture supernatants were assayed
      for VEGF using enzyme-linked immunosorbent assays. Culture supernatants from LPS-
      and TNF-alpha-stimulated PMNs were then added to human umbilical vein endothelial
      cells and human microvessel endothelial cells and assessed for endothelial cell
      proliferation using 5-bromodeoxyuridine labeling. Tubule formation was also
      assessed on MATRIGEL basement membrane matrix. Neutrophils were lysed to measure
      total VEGF release, and VEGF expression was detected using Western blot analysis.
      RESULTS: Lipopolysaccharide and TNF-alpha stimulation resulted in significantly
      increased release of PMN VEGF (532+/-49 and 484+/-80 pg/mL, respectively; for
      all, presented as mean +/- SEM) compared with control experiments (32+/-4 pg/mL).
      Interleukin 6 and Fas had no effect. Culture supernatants from LPS- and TNF-alpha
      stimulated PMNs also resulted in significant increases (P<.005) in macrovascular
      and microvascular endothelial cell proliferation and tubule formation. Adding
      anti-human VEGF-neutralizing polyclonal antibody to stimulated PMN supernatant
      inhibited these effects. Total VEGF release following cell lysis and Western blot
      analysis suggests that the VEGF is released from an intracellular store.
      CONCLUSION: Activated human PMNs are directly angiogenic by releasing VEGF, and
      this has important implications for inflammation, capillary leak syndrome, wound
      healing, and tumor growth.

PMID- 10593331
TI  - Gut-derived mesenteric lymph: a link between burn and lung injury.
AB  - BACKGROUND: Previously, we showed that mesenteric lymph generated following
      hemorrhagic shock increases endothelial cell permeability and contributes to lung
      injury. It has also been shown that lymph produced at the site of burn injury
      plays a role in altering pulmonary vascular hemodynamics. In addition, previous
      experimental work has suggested that organs and tissues distant from the injury
      site may contribute to pulmonary dysfunction. One explanation would be that gut
      derived inflammatory factors (in addition to those produced locally at the site
      of injury) are reaching the pulmonary circulation, where they exert their effects
      via the gut lymphatics. HYPOTHESES: The 2 hypotheses herein were that (1) gut
      derived factors carried in the mesenteric lymph of rats generated following
      thermal injury will contribute to lung injury and (2) intestinal bacterial
      overgrowth will potentiate the degree of burn-induced lung injury. These
      hypotheses were tested by examining the effect of mesenteric lymph flow
      interruption prior to thermal injury on burn-induced lung injury in rats with a
      normal intestinal bacterial flora and in rats with intestinal Escherichia coli
      overgrowth. These rats were termed E. coli-monoassociated rats. METHODS: Normal
      intestinal bacterial flora and monoassociated male Sprague-Dawley rats were
      subjected to sham burn, 40% total body surface area burn, or lymphatic division
      plus burn. After 3 hours, 10 mg of Evans blue was injected to measure lung
      permeability. After the rats were killed, a bronchoalveolar lavage was performed
      and the fluid analyzed spectrophotometrically. Bronchoalveolar lavage fluid
      protein content, pulmonary myeloperoxidase activity, and alveolar apoptosis
      served to further quantitate lung injury. RESULTS: Both normal intestinal
      bacterial flora and monoassociated-burned rats exhibited significant increases in
      lung permeability, bronchoalveolar lavage fluid protein content, myeloperoxidase
      activity, and alveolar apoptosis. The combination of monoassociation and thermal
      injury resulted in even further increases in lung injury over thermal injury
      alone. Lymphatic division prior to thermal injury ameliorated burn-induced
      increases in lung permeability, bronchoalveolar lavage fluid protein content,
      pulmonary myeloperoxidase accumulation, and alveolar apoptosis in both normal
      intestinal bacterial flora and monoassociated rats. CONCLUSIONS: The results of
      this study support the hypothesis that gut-derived factors carried in the
      mesenteric lymph contribute to burn-induced lung injury and may therefore play a
      role in postburn respiratory failure and suggest that intestinal bacterial
      overgrowth primes the host such that when animals are exposed to a second
      stimulus (such as thermal injury) an exaggerated response occurs.

PMID- 10593332
TI  - Gender-based differences in outcome in patients with sepsis.
AB  - HYPOTHESIS: Among factors postulated to affect outcome in sepsis is the gender of
      the patient, with a suggestion that females may have lower mortality. This study
      tested the hypothesis that female patients admitted to the surgical intensive
      care unit with a documented infection have a lower mortality rate. DESIGN:
      Retrospective analysis of a prospectively collected data set. SETTING: Surgical
      intensive care unit of a university hospital medical center. METHODS: Analysis of
      a consecutive series of 1348 patients who had signs of systemic inflammatory
      response syndrome on admission to a surgical intensive care unit. A cohort of 443
      patients (32.9%) admitted with documented infection--and who therefore had
      sepsis, severe sepsis, or septic shock--constituted the study population. For
      each patient, APACHE (Acute Physiology and Chronic Health Evaluation) II and III
      scores, systemic inflammatory response syndrome score, gender, age, and hospital
      mortality were recorded. Chi2 With Fisher exact test was performed to compare
      mortality rates between males and females. Univariate analysis of variance was
      used to compare continuous variables in discrete populations. Multivariate
      analysis of variance was used to determine which factors independently predicted
      mortality. PRIMARY OUTCOME MEASURES: Mortality, intensive care unit length of
      stay, hospital length of stay, and maximal multiple organ dysfunction score.
      Outcomes stratified by gender. RESULTS: Patients had mean +/- SEM age of 67+/-1
      years; mean +/- SEM APACHE II and III scores of 20.1+/-0.4 and 67.7+/-1.0 points,
      respectively. There were no demographic differences between genders. Overall, 104
      (23.5%) of 443 patients with sepsis died. The difference in mortality rates
      between female and male patients was not significant, except in octogenarians (P
      = .05). Multivariate analysis of variance, APACHE III (P<.001), maximal multiple
      organ dysfunction score (P<.001), and female gender (P =.02) predicted mortality.
      In females, APACHE III (P = .03) and maximal multiple organ dysfunction score
      (P<.001) predicted mortality, but age did not. CONCLUSION: Female gender is an
      independent predictor of increased mortality in critically ill surgical patients
      with documented infection.

PMID- 10593333
TI  - Priming interleukin 8 production: role of platelet-activating factor and p38.
AB  - HYPOTHESIS: Platelet-activating factor (PAF) activates p38, an important
      intracellular signal transduction kinase, and primes human mononuclear cells for
      the production of interleukin 8 (IL-8), a potent chemoattractant and activator of
      neutrophils. METHODS: Human mononuclear cells were isolated from healthy adults
      by Ficoll-paque density-gradient centrifugation. Interleukin-8 in the supernatant
      was measured by enzyme-linked immunosorbent assay. Dual phospho-specific p38
      antibody was used to detect activated p38 by Western blotting. RESULTS:
      Lipopolysaccharide (LPS) and PAF activated p38. There was a shorter latency to
      peak p38 activation with PAF vs LPS stimulation, 5 vs 30 minutes. Platelet
      activating factor-induced p38 activation was calcium dependent because it was
      inhibited by ethyleneglycoltetracetic acid. Lipopolysaccharide, 0.01 to 1.00
      ng/mL, induced significant IL-8 production. Although PAF did not induce
      significant IL-8 production, it potentiated LPS-induced IL-8 production.
      Production of IL-8, in response to LPS alone or in combination with PAF, was
      inhibited by SB202190, a specific p38 inhibitor. CONCLUSIONS: Although LPS and
      PAF activated p38, only LPS induced IL-8 production; PAF acted as a priming
      agent. It seems that p38 activation is necessary but not sufficient for IL-8
      production by human mononuclear cells. Identifying and evaluating the activation
      state of inflammatory signal transduction pathways might lead to methods for
      controlling and preventing neutrophil-induced tissue injury without interfering
      with the normal host immune response.

PMID- 10593334
TI  - Effect of diabetes mellitus on endotoxin-induced lung injury.
AB  - OBJECTIVE: To examine the effects of diabetes mellitus on lipopolysaccharide
      (LPS)-induced pulmonary edema and alveolar neutrophil recruitment and activation.
      HYPOTHESIS: Zucker diabetic fatty rats are resistant to the effects of
      intratracheal LPS on the extravasation of plasma proteins into the lungs. DESIGN:
      Zucker diabetic fatty (ZDF) rats (genotype fa/fa) were used as a model of
      diabetes mellitus, while their normoglycemic heterozygous littermates served as
      controls. Lipopolysaccharide (Escherichia coli 0111: B4; 100-200 microg) or
      vehicle (0.25 mL of isotonic sodium chloride solution) was instilled into the
      airways of ZDF and control rats. Four hours later, pulmonary microvascular
      dysfunction was assessed by measuring the extravasation of Evans blue dye into
      the lung. Lipopolysaccharide-induced neutrophil recruitment was assessed by
      counting the number of neutrophils within the bronchoalveolar lavage fluid and
      measuring their expression of CD11b/CD18 by fluorescence-activated cell analysis
      sorting. RESULTS: The LPS (200 microg) induced a 32% increase in Evans blue dye
      extravasation into the lungs of controls (P = .008) but had no such effect in
      diabetic animals. Pulmonary extravasation of Evans blue dye in controls was
      greater than that of ZDF rats both at baseline (P = .002) and in response to 200
      microg of LPS (P<.001). The LPS upregulated neutrophil CD11b/CD18 expression in
      diabetic and nondiabetic groups and induced a greater than 50-fold increase in
      the number of neutrophils within the airways of both control and diabetic groups
      (P<.001). CONCLUSION: Despite the recruitment of a large number of neutrophils
      into the lung, the LPS-induced change in pulmonary microvascular permeability in
      diabetic animals is substantially less than that of nondiabetic controls.

PMID- 10593335
TI  - Chemokine regulation of neutrophil function in surgical inflammation.
AB  - BACKGROUND: Morbidity and even mortality correlate closely with major injury that
      causes a systemic inflammatory response. Cytokines and bioactive molecules
      present at the inflammatory site induce this response and regulate neutrophil
      proinflammatory responses. The CXC chemokines, important for neutrophil
      recruitment and activation, include interleukin 8 (IL-8), granulocyte chemotactic
      protein 2 (GCP-2), and epithelial cell-derived neutrophil attractant 78 (ENA-78).
      They induce neutrophil responses via 2 cell-surface receptors, CXCR-1 and CXCR-2.
      All 3 chemokines bind CXCR-2 with high affinity. Only IL-8 and GCP-2 bind CXCR-1
      with high affinity. HYPOTHESIS: The CXC chemokines regulate neutrophil responses
      differently. METHODS: Pretreatment of neutrophils from healthy volunteers with IL
      8, GCP-2, or ENA-78; measured IL-8-induced migration; and tumor necrosis factor
      alpha (TNF-alpha)-induced peroxide production. RESULTS: Flow cytometry and
      radioligand binding data indicate that IL-8, GCP-2, and ENA-78 equivalently
      reduced CXCR-1 and CXCR-2 cell surface expression by 34% to 54%. All treatments
      decreased affinity of both receptors 1.5- to 2-fold. However, only IL-8
      pretreatment inhibited chemotaxis to 10-nmol/L IL-8 (mean +/- SE inhibition,
      62%+/-6%). Although IL-8 and GCP-2, but not ENA-78, suppressed TNF-alpha-induced
      oxidant production (mean +/- SE inhibition, 42%+/-8% and 40%+/-23%,
      respectively), only GCP-2 inhibited the oxidative response to complement fragment
      C5a, and to the bacterial cell wall peptide N-formyl-methionyl-leucyl
      phenylalanine. CONCLUSIONS: The CXC chemokines regulate neutrophil
      proinflammatory functions differently. A thorough understanding of mechanisms for
      modulating neutrophil responses in inflammation will aid the development of
      interventions that reduce morbidity and mortality associated with severe trauma
      and sepsis.

PMID- 10593336
TI  - Preferential loss of CXCR-2 receptor expression and function in patients who have
      undergone trauma.
AB  - BACKGROUND: In response to traumatic injury or infection, human neutrophils are
      directed to the site of injury or infection by CXC chemokines that signal via 2
      receptors, CXCR-1 and CXCR-2. In vitro studies have shown preferential loss of
      CXCR-2 expression and function after exposure to interleukin 8, N-formyl
      methionyl-leucyl-phenylalanine (fMLP), C5a, and tumor necrosis factor alpha.
      HYPOTHESIS: CXCR-2 expression and function are preferentially down-regulated in
      severely injured patients. METHODS: We studied 20 patients within 24 hours of
      admission to the hospital. Patients with head injuries were excluded. Injury
      Severity Scores (range, 1-50; mean, 35) were calculated for each patient. To
      determine expression of CXCR-1 and CXCR-2, flow cytometry was used. Intracellular
      calcium mobilization and neutrophil migration to 10 nmol of interleukin 8, growth
      related oncogene alpha, and fMLP was measured to determine receptor function.
      RESULTS: Compared with CXCR-1, there is a greater loss of CXCR-2 receptor
      expression in the severely injured group (P = .01). Neutrophils from patients
      with Injury Severity Scores greater than 16 did not mobilize calcium in response
      to growth-related oncogene alpha. However, there was no loss of calcium
      mobilization to interleukin 8 or fMLP. Chemotaxis to various stimulants is
      decreased in all injury groups. CONCLUSIONS: CXCR-2 expression and function are
      preferentially down-regulated in severely injured patients. Our data suggest that
      there are multiple mechanisms, in addition to receptor down-regulation, that play
      a role in the loss of migration and calcium flux in human neutrophils after
      injury.

PMID- 10593337
TI  - Ulcer surgery and highly selective vagotomy--Y2K.

PMID- 10593338
TI  - Statewide variation in the treatment of patients hospitalized with spleen injury.
AB  - HYPOTHESIS: Surgeons' treatment decisions for patients with spleen injuries in
      Washington State from January 1, 1990, through December 31, 1994, were different
      in rural compared with urban communities. DESIGN AND SETTINGS: Retrospective
      cohort analyses using the Death and Illness History Database for the state of
      Washington, which provides a cross-linked record of an individual's sequential
      hospitalizations. Counties were defined as metropolitan, urban, or rural on the
      basis of population density. PATIENTS: A total of 1905 patients (1927
      hospitalizations) with an International Classification of Diseases, Ninth
      Revision, Clinical Modification, discharge diagnosis code of 865. MAIN OUTCOME
      MEASURES: Physician management decisions (perform a celiotomy or repair the
      spleen) were stratified by geographic region. RESULTS: Throughout the state,
      there was substantial variability in the treatment of spleen-injured patients.
      Factors associated with higher odds of splenectomy included older age, overall
      severity of injury, treatment in rural hospitals, and treatment in the earlier
      years of study. While the frequency of splenic salvage increased over time,
      hospital length of stay, rehospitalization, and 30-day mortality did not
      increase. CONCLUSIONS: Injury to the spleen is a common problem for which
      management decisions vary by geographic region, indicating that a single
      management protocol does not universally apply. To evaluate appropriateness of
      care by process measures, such as splenic injury management, will require that
      decision makers grant some latitude in management variability based on factors
      such as practice setting.

PMID- 10593339
TI  - Colostomy vs tube cecostomy for protection of a low anastomosis in rectal cancer.
AB  - BACKGROUND: Symptomatic anastomotic leakage is the most important surgical
      complication following rectal resection with intestinal anastomosis. Therefore,
      the routine use of a protective stoma is suggested by several authors. In our
      department 2 different techniques are performed to protect the anastomosis.
      Patients receive either a loop colostomy/ileostomy (C/I) or a tube cecostomy
      (TC). HYPOTHESIS: No significant difference is noted between C/I and TC for
      protection of a low anastomosis regarding clinical anastomotic leakage rate,
      reoperation rate for anastomotic leaks/fistulas, postoperative mortality, and
      permanent colostomy rate. By avoiding a second operation (for colostomy closure),
      median hospital stay should be significantly reduced. DESIGN: A retrospective
      review during 1985 to 1997. SETTING: Tertiary care center PATIENTS: One hundred
      fifty-eight patients who had undergone anterior resections for rectal cancer were
      studied. Protective C/Is were used in 19 patients; a TC was fashioned in 30
      patients. MAIN OUTCOME MEASURES: Clinical anastomotic leakage rate, reoperation
      rate for anastomotic leaks/fistulas, postoperative mortality, permanent colostomy
      rate, and median hospital stay. RESULTS: The rate of anastomotic leaks (C/I, 16%;
      TC, 17%), fecal peritonitis (C/I, 0%; TC, 10%), reoperation for anastomotic
      leaks/fistulas (C/I, 0%; TC, 13%), permanent colostomies (C/I, 0%; TC, 7%), and
      postoperative mortality (C/I, 5%; TC, 0%) did not differ significantly in both
      groups. Median hospital stay was significantly reduced in patients with TC (C/I,
      28 days; TC, 15 days). CONCLUSION: In our patients with low resections for rectal
      cancer, a C/I for protection of the anastomosis did not improve outcome
      significantly as compared with a TC. With a properly fashioned TC and adequate
      postoperative management a second operation (for colostomy closure) can be
      avoided and the overall hospital stay is significantly reduced.

PMID- 10593340
TI  - Total thyroidectomy for bilateral benign multinodular goiter: effect of changing
      practice.
AB  - HYPOTHESIS: That changing practices in a single institution toward performing
      total thyroidectomy as the preferred option for the treatment of bilateral benign
      multinodular goiter (BMNG) can alter attitudes and practice within an entire
      region (Australia and New Zealand). DESIGN: (1) Single-institution study of
      patients with bilateral BMNG treated by thyroidectomy over a 40-year period,
      examining the changing pattern of use of bilateral subtotal thyroidectomy and
      total thyroidectomy in the initial surgical treatment of nodular goiter. (2) Mail
      survey of all endocrine surgeons (n = 75) in Australia and New Zealand, seeking
      information on their changing practice in the surgical treatment of BMNG.
      SETTING: Tertiary academic referral center. PATIENTS: A group of 3468 patients
      who underwent thyroidectomy for bilateral BMNG during the study period. Of these,
      1838 had a subtotal thyroidectomy performed and 1251 had a total thyroidectomy as
      the primary surgical treatment. MAIN OUTCOME MEASURES: The changing incidence of
      each type of thyroid procedure each year over the study period. RESULTS: Within
      our unit, bilateral subtotal thyroidectomy was the principal procedure performed
      until 1984, when total thyroidectomy became the preferred procedure. Our unit now
      treats 94% of these patients with total thyroidectomy. Secondary thyroidectomy
      for recurrent goiter initially increased over the years (with a lag period of 13
      years), reflecting the numbers of subtotal procedures previously performed, and
      is now declining. This pattern has been reflected throughout Australia and New
      Zealand; 60% of practicing endocrine surgeons now perform total thyroidectomy as
      the preferred treatment for bilateral BMNG. CONCLUSIONS: Total thyroidectomy is a
      safe and effective treatment for bilateral BMNG, and it is now the routine
      procedure throughout Australia and New Zealand. Its use has corresponded to a
      reduction in the need for secondary thyroidectomy for recurrent goiter.

PMID- 10593341
TI  - Five risk factors identify patients with gastroesophageal intussusception.
AB  - HYPOTHESIS: Risk factors in patients with gastroesophageal intussusception who
      have noncardiac chest pain need to be identified and analyzed. DESIGN:
      Prospective consecutive series of 43 patients with gastroesophageal
      intussusception. SETTING: Outpatient gastrointestinal endoscopy suite for 42
      patients; 1 patient sustained gastroesophageal intussusception during labor and
      delivery and underwent an emergency laparotomy. INTERVENTION: Upper
      gastrointestinal tract endoscopy under intravenous sedation with appropriate
      monitoring of vital signs and photographic documentation in most patients.
      RESULTS: Gastroesophageal intussusception was documented endoscopically in 42 of
      43 patients and was found to occur equally in men and women. Five risk factors
      have been identified: eating disorders or alcohol abuse, sudden sustained
      exertion, small-bowel obstruction, acid bile peptic disease, and pregnancy.
      Fifteen (70%) of 22 men were younger than 35 years; precipitating factors
      included sustained athletic effort and binge eating and drinking episodes.
      Fifteen (70%) of the 21 women were older than 35 years and had binge eating,
      peptic disease, and complications of pregnancy as risk factors. CONCLUSIONS: Five
      risk factors identify patients with severe vomiting or retching who are most
      likely to develop gastroesophageal intussusception, the precursor of a Mallory
      Weiss tear. Upper gastrointestinal tract endoscopy with photographic
      documentation is the most accurate method of diagnosis. For most patients,
      medical management can reverse the cause of the vomiting. If vomiting is caused
      by mechanical obstruction or massive hemorrhage, surgical intervention may be
      necessary.

PMID- 10593342
TI  - The case of the common duct stone: cholesterol revisited.

PMID- 10593343
TI  - Surgery in Switzerland.

PMID- 10593344
TI  - Were the people different?

PMID- 10593345
TI  - The Mayo units in World War II.

PMID- 10593346
TI  - Echocardiographic improvement over time after cessation of use of fenfluramine
      and phentermine.
AB  - OBJECTIVE: To determine the echocardiographic changes over time of valvular heart
      lesions in patients who took the weight loss drugs fenfluramine and phentermine.
      SUBJECTS AND METHODS: This prospective cohort study began at the termination of a
      randomized, double-blind, placebo-controlled weight loss trial of 18 obese women
      and 13 obese men (mean age, 42 years; mean body mass index, 33.4 kg/m2) who had
      been assigned randomly to treatment with fenfluramine and phentermine or to
      placebo. Echocardiograms were obtained at termination of the trial when
      fenfluramine was withdrawn from the market and 6 months later. They were
      interpreted independently by 3 cardiologists blinded to treatment assignment and
      temporal sequence of the echocardiograms. The main outcome measure was the change
      in drug-related valvular disease over time. RESULTS: One subject assigned to
      receive the drugs was lost to follow-up, and 3 subjects who did not meet a weight
      loss goal of 10 kg crossed over from placebo to drug treatment. Echocardiograms
      were obtained in 19 subjects who received the drugs and 11 subjects who received
      placebo, and 6-month follow-up echocardiograms were obtained in 15 subjects who
      received the drugs and 3 who received placebo. Subjects had taken fenfluramine
      and phentermine a mean of 41 weeks (range, 8-73 weeks). Five of 19 subjects who
      received the drugs (26%; 95% confidence interval, 7%-46%) and 1 of 11 who
      received placebo (9%) (odds ratio, 3.6; 95% confidence interval, 0.4-35.6) had
      findings that met criteria established for drug-related valvular disease. All 5
      subjects (4 women and 1 man) receiving the drugs had mild aortic regurgitation,
      and 1 also had pulmonary hypertension (estimated pulmonary artery pressure, 59 mm
      Hg). Six months later, the echocardiographic findings had improved in all 5
      subjects (P=.06), and 3 no longer met the criteria for drug-related valvular
      disease. Pulmonary artery pressures decreased to near normal in the subject with
      pulmonary hypertension (37 mm Hg). Overall, the echocardiographic valvular
      features improved in 8 of 15 subjects who received the drugs and had
      echocardiograms performed at both time periods (P=.008). CONCLUSIONS: Valvular
      heart disease did not appear to progress after cessation of use of fenfluramine
      and phentermine, and echocardiographic valvular features appeared to improve over
      time.

PMID- 10593348
TI  - Colorectal cancer screening: a community case-control study of
      proctosigmoidoscopy, barium enema radiography, and fecal occult blood test
      efficacy.
AB  - OBJECTIVE: To examine the effectiveness of screening proctosigmoidoscopy, barium
      enema radiography, and the fecal occult blood test (FOBT) in decreasing
      colorectal cancer mortality in a community setting. PATIENTS AND METHODS: In this
      population-based case-control study, cases comprised 218 Rochester, Minn,
      residents who died of colorectal cancer between 1970 and 1993. Controls were 435
      age- and sex-matched residents who did not have a diagnosis of colorectal cancer.
      Screening proctosigmoidoscopy, barium enema radiography, and FOBT results were
      documented for the 10 years prior to and including the date of diagnosis of fatal
      colorectal cancer in cases and for the same period in matched controls. History
      of general medical examinations and hospitalizations was also recorded. RESULTS:
      Within the 10 years prior to diagnosis, the percentages of cases vs controls with
      at least 1 screening proctosigmoidoscopy were 23 (10.6%) of 218 cases vs 43
      (9.9%) of 435 controls; at least 1 screening barium enema radiographic study was
      done in 12 (5.5%) of 218 vs 25 (5.7%) of 435. Within 3 years prior to diagnosis,
      the percentages of cases vs controls with at least 1 screening FOBT were 27
      (12.4%) of 218 vs 44 (10.1%) of 435. Adjusted odds ratios were 1.04 (95%
      confidence interval [CI], 0.21-5.13) for proctosigmoidoscopy (distal rectosigmoid
      cancers only), 0.67 (95% CI, 0.31-1.48) for barium enema radiography, and 0.83
      (95% CI, 0.45-1.52) for FOBT over the above time periods. CONCLUSION: In this
      case-control study within a community setting, a colorectal cancer-specific
      mortality benefit could not be demonstrated for screening by FOBT,
      proctosigmoidoscopy, or barium enema radiography. Screening frequency was low,
      which may have contributed to the lack of measurable effects.

PMID- 10593349
TI  - Fluorescence in situ hybridization aneuploidy as a predictor of clinical disease
      recurrence and prostate-specific antigen level 3 years after radical
      prostatectomy.
AB  - OBJECTIVE: To determine if fluorescence in situ hybridization (FISH) analysis of
      fresh-tissue biopsy specimens obtained at the time of radical prostatectomy is
      able to predict prospectively clinical disease progression or prostate-specific
      antigen (PSA) level in patients 3 to 4 years after surgery. MATERIALS AND
      METHODS: FISH analysis was performed on fresh-tissue touch preparations obtained
      from 90 randomly selected radical prostatectomy specimens. Cut surface touch
      preparations from 40 specimens resected in 1992 were analyzed with DNA probes for
      chromosomes 4, 6-12, 17, 18, X, and Y. Needle-biopsy specimens were obtained from
      50 tumors resected in 1993, and touch preparations from these specimens were
      studied with DNA probes for chromosomes 7, 8, 11, and 12. Serum PSA levels and
      clinicopathologic data were recorded, and each patient was followed up from the
      time of surgery to determine cancer progression. RESULTS: Of 90 patients
      undergoing radical prostatectomy in 1992 and 1993, 89 returned for follow-up.
      Three patients received preoperative hormonal therapy, and in 2 patients,
      antiandrogen therapy was continued postoperatively. Fifteen patients underwent
      intraoperative orchiectomy immediately after radical prostatectomy, while 9
      patients had postoperative adjuvant hormonal therapy. Six patients underwent
      postoperative radiation therapy. Fourteen patients (15.7%) demonstrated systemic,
      local, or PSA progression. Only 2 (4.7%) of 43 patients with FISH diploid tumors
      demonstrated cancer progression. Conversely, 10 (30.3%) of 33 FISH aneuploid and
      12 (26.1%) of 46 FISH nondiploid tumors demonstrated cancer progression (P=.004
      and P=.006, respectively). Unlike FISH, flow cytometric aneuploidy was not
      associated with early cancer progression. Elevated preoperative PSA
      concentration, increased preoperative and postoperative Gleason score, and
      increased preoperative and postoperative T or N stage were not statistically
      significantly associated with cancer progression. While chromosome 7 and 8
      aneusomies were not statistically associated with cancer progression, 2 of 5
      (P=.04) chromosome 12 aneusomic tumors demonstrated cancer progression.
      CONCLUSION: Early (within 4 years) local, systemic, or PSA progression occurred
      more frequently (P<.05) in radical prostatectomy patients with FISH aneuploid,
      nondiploid, and chromosome 12 aneusomic tumors. Flow cytometric ploidy status,
      preoperative serum PSA concentration, and clinical or pathologic grade or stage,
      including seminal vesicle involvement, margin status, and capsular perforation
      status, were not associated with early prostate cancer progression in this group
      of 89 patients. FISH analysis appears to be a useful preoperative tool for
      predicting aggressive vs indolent prostate cancer.

PMID- 10593347
TI  - Cholesterol-lowering effect of stanol ester in a US population of mildly
      hypercholesterolemic men and women: a randomized controlled trial.
AB  - OBJECTIVE: To determine the efficacy of stanol esters in lowering cholesterol in
      a US population. SUBJECTS AND METHODS: After a run-in phase, 318 subjects were
      randomized to receive one of the following margarine-like spreads containing
      stanol ester or placebo for 8 weeks: EU 3 G: 1 g of stanol (ester form) per 8-g
      serving of a European formula 3 times a day; US 3 G: 1 g of stanol (ester form)
      per 8-g serving of a US reformulation 3 times a day; US 2 G: 0.67 g of stanol
      (ester form) per 8-g serving of a US reformulation 3 times a day; or placebo
      spread. RESULTS: Mean +/- SD baseline total cholesterol (TC) and low-density
      lipoprotein cholesterol (LDL-C) levels were 233+/-20 and 153+21 mg+/-dL,
      respectively. In the US 3 G group, 3 g daily of stanol esters lowered TC and LDL
      C levels by 6.4% and 10.1%, respectively. There was a dose-dependent response
      compared with 2 g daily (US 2 G). Triglyceride and high-density lipoprotein
      cholesterol levels were unchanged. The incidence of adverse effects was not
      different from placebo. Serum vitamin A and 25-hydroxyvitamin D levels were not
      affected. CONCLUSIONS: Stanol esters lowered TC and LDL-C levels in a mildly
      hypercholesterolemic US population without evidence of adverse effects. It may be
      a useful dietary adjunct to lower cholesterol.

PMID- 10593350
TI  - Combined immunosuppression for the treatment of idiopathic giant cell
      myocarditis.
AB  - Giant cell myocarditis (GCM) is a rare and frequently fatal disorder with no
      proven treatment. Case reports and data from a rat model of GCM suggest that
      immunosuppressive therapy directed against T lymphocytes may have clinical
      benefit. We describe a 47-year-old man with severe acute heart failure due to GCM
      in whom the left ventricular ejection fraction normalized and the myocardial
      inflammatory infiltrate resolved rapidly after treatment with muromonab-CD3,
      cyclosporine, azathioprine, and corticosteroids. Three previously published cases
      with less impressive responses to treatment including muromonab-CD3 and a
      critical review of the published data on immunosuppressive therapy are included
      in this report. The response to immunosuppressive therapy is highly variable, and
      direct comparisons between immunosuppressive regimens do not exist. Therefore,
      despite individual reports of dramatic improvement after immunosuppressive
      treatment, firm conclusions cannot be made about the benefit of immunosuppression
      for GCM. The benefits of immunosuppressive therapy must be confirmed in a
      prospective, randomized trial.

PMID- 10593352
TI  - Long-term remission of refractory stiff-man syndrome after treatment with
      intravenous immunoglobulin.
AB  - The stiff-man syndrome is a rare neuromuscular disorder characterized by
      progressive rigidity, stiffness, and intermittent spasm of axial and extremity
      muscles. Its etiology is unknown. Different therapeutic regimens have been used
      with variable success. We present a case of refractory stiff-man syndrome, in
      which the symptoms were successfully controlled by the administration of
      intravenous immunoglobulin (IVIg). This case gives evidence that IVIg can be a
      safe and an efficient treatment of refractory stiff-man syndrome. The exact
      indication for and the cost-effectiveness of IVIg in the treatment of this rare
      entity remain to be determined.

PMID- 10593351
TI  - Staphylococcus lugdunensis endocarditis: a complication of vasectomy?
AB  - Three cases of Staphylococcus lugdunensis endocarditis have been reported in
      patients with a history of vasectomy preceding the development of endocarditis.
      We describe a new case of a 39-year-old man who developed infective endocarditis
      due to S. lugdunensis after vasectomy. He was successfully treated with a 7-week
      course of intravenous antibiotics and subsequently underwent mitral valve
      reconstruction for severe mitral regurgitation. The present case further supports
      an association between vasectomy and S. lugdunensis endocarditis.

PMID- 10593353
TI  - Hypercalcemia complicating leukemic transformation of agnogenic myeloid
      metaplasia-myelofibrosis.
AB  - Hypercalcemia is a common and potentially life-threatening metabolic derangement
      associated with many malignancies, especially solid tumors and multiple myeloma.
      Hypercalcemia has been reported only rarely with acute myelogenous leukemia. We
      describe a patient who developed hypercalcemia in association with transformation
      of agnogenic myeloid metaplasia into M7 acute myelogenous leukemia. Laboratory
      investigation revealed low levels of serum parathyroid hormone, undetectable
      levels of parathyroid hormone-related peptide, and normal levels of 25
      hydroxyvitamin D. These observations suggest that another mediator was
      responsible for hypercalcemia in this patient. Awareness of this rare
      complication of acute myelogenous leukemia is essential for prompt diagnosis and
      management.

PMID- 10593355
TI  - Safe and effective management of the obese patient.
AB  - The prevalence of overweight and obesity has increased dramatically in the recent
      decades, and obesity is now a major public health problem. Obesity negatively
      influences an individual's health by increasing mortality and raising the risk
      for multiple medical conditions such as type 2 diabetes mellitus, hypertension,
      dyslipidemia, and coronary heart disease. In addition, the obese individual is
      often the brunt of social discrimination. Weight loss has been shown to reduce
      the risk for many of these comorbid conditions. A multifaceted approach to the
      obese patient should include identifying potential causes for weight gain,
      outlining medical conditions that would benefit by weight loss, and tailoring a
      weight loss program that is safe and effective for the individual. Components of
      a successful weight loss program include dietary intervention, recommendations
      for physical activity, behavior modification, and, in a select group of patients,
      pharmacologic or surgical intervention.

PMID- 10593354
TI  - Medical treatment of later-stage motor problems of Parkinson disease.
AB  - Parkinson disease progression is associated with the development of levodopa
      short-duration responses and dyskinesias, as well as gait freezing. Levodopa dose
      adjustment and adjunctive treatment with dopamine agonists form the major
      therapeutic strategies. Catechol O-methyltransferase inhibitors are also
      appropriate considerations, whereas other drugs, including selegiline,
      amantadine, anticholinergic agents, and propranolol, have a more minor role.

PMID- 10593356
TI  - 61-year-old man with recurrent spells.

PMID- 10593357
TI  - Antiviral agents for non-human immunodeficiency virus infections.
AB  - Several new agents for treating viral infections have been developed in recent
      years. All available agents are virustatic, inhibiting specific steps in the
      process of viral replication. No agent is active against nonreplicating or latent
      viruses. Acyclovir is useful in the treatment of genital herpes, herpes simplex
      encephalitis, mucocutaneous herpetic infection, varicella infection in the
      immunosuppressed host, and herpes zoster infection in the normal and the
      immunosuppressed host. It can also be used for prevention of herpesvirus
      infection in immunocompromised patients. Ganciclovir is indicated for the
      treatment of cytomegalovirus retinitis in patients with the acquired
      immunodeficiency syndrome and is effective in the treatment and prevention of
      cytomegalovirus infection in other immunocompromised patients. Famciclovir and
      valacyclovir are effective in the management of herpes simplex and varicella
      zoster infection. Amantadine and rimantadine are useful therapeutically and
      prophylactically in the management of influenza A virus infection. Chronic
      hepatitis B infection can respond to lamivudine therapy, and the optimal
      treatment of hepatitis C is the combination of interferon alfa and ribavirin.
      Despite pronounced toxic effects, foscarnet and cidofovir are effective antiviral
      agents in specific settings.

PMID- 10593358
TI  - Antiretrovirals.
AB  - Deaths related to the human immunodeficiency virus (HIV) and the acquired
      immunodeficiency syndrome and the incidence of opportunistic infections have been
      drastically decreased in the industrialized world. These reductions are mainly
      due to recent advances in the management of HIV infection, including the
      availability of new therapies. Until November 1995, the antiretroviral drugs
      available and approved by the Food and Drug Administration for clinical use in
      the United States consisted of only four nucleoside analogue reverse
      transcriptase inhibitors: zidovudine, zalcitabine, didanosine, and stavudine.
      Since then, 2 new classes of agents and 10 new agents have been approved; thus,
      the number of available antiretroviral drugs has more than tripled. Additional
      drugs and newer classes of antiretrovirals are in various stages of development.
      Because of the availability of more drugs, the complexity of HIV treatment has
      increased. Selecting an appropriate antiretroviral therapeutic regimen involves
      addressing multiple interdependent issues, including patient adherence,
      pharmacokinetic properties of the drugs (including food effects and drug-drug
      interactions), drug resistance, and overlapping adverse effects.

PMID- 10593360
TI  - Pulmonary arteriovenous fistulas.

PMID- 10593361
TI  - Sneddon syndrome and dementia.

PMID- 10593359
TI  - The fen-phen controversy: is regression another piece of the puzzle?

PMID- 10593362
TI  - Mary Breckinridge--pioneer nurse brings modern nursing to rural environment.

PMID- 10593363
TI  - Aromatase: a key molecule in the pathophysiology of endometriosis and a
      therapeutic target.
AB  - OBJECTIVE: To provide a clinically useful model illustrating the molecular
      aberrations affecting estrogen biosynthesis and metabolism in endometriosis and
      to discuss the therapeutic role of aromatase inhibitors. DESIGN: Literature
      review. RESULT(S): Several molecular aberrations were found in endometriotic
      lesions (in contrast to eutopic endometrium) that favor increased local
      concentrations of E2. Endometriotic stromal cells aberrantly express aromatase,
      which converts C19, steroids to estrogens. Aromatase activity in these cells is
      stimulated by prostaglandin (PG)E2. Estrogen stimulates cyclooxygenase-2, giving
      rise to increased PGE2 formation. Thus, this positive feedback loop produces
      increasing quantities of E2 and PGE2 in endometriosis. The lack of aromatase
      expression in eutopic endometrium is maintained by binding of an inhibitory
      transcription factor, COUP-TF, to the aromatase promoter. In endometriosis,
      however, an aberrantly expressed factor, SF-1, displaces COUP-TF to bind to this
      same promoter and activates aromatase expression and thus local estrogen
      biosynthesis. Additionally, endometriotic glandular cells are deficient in 17beta
      hydroxysteroid dehydrogenase type 2, which converts E2 to estrone in the eutopic
      endometrium in response to P. Deficiency of this enzyme in endometriosis impairs
      the inactivation of E2 and may be a consequence of insensitivity to P.
      CONCLUSION(S): Molecular aberrations that increase local E2 concentrations may be
      important in the etiology of endometriosis. These molecules may be targeted to
      develop novel therapeutic strategies. The clinical relevance of aromatase
      expression in endometriosis was shown recently by the successful treatment of an
      unusually aggressive case of postmenopausal endometriosis with use of an
      aromatase inhibitor.

PMID- 10593364
TI  - Octuplets and ethics.

PMID- 10593365
TI  - Multifetal prophylaxis--a reality?

PMID- 10593366
TI  - Elevated serum progesterone level on the day of human chorionic gonadotropin
      administration does not adversely affect implantation rates after
      intracytoplasmic sperm injection and embryo transfer.
AB  - OBJECTIVE: To evaluate the association between serum P levels on the day of hCG
      administration and the outcome of intracytoplasmic sperm injection (ICSI).
      DESIGN: Retrospective case study. SETTING: Assisted reproduction unit of a
      tertiary care private hospital. PATIENT(S): Nine hundred eleven ICSI cycles that
      proceeded to ET were studied. INTERVENTION(S): The decision to administer hCG was
      based on serum E2 levels and follicle size. Serum P was measured from frozen sera
      obtained on the day of hCG administration. Cycles were stratified according to
      serum P levels of <0.9 ng/mL (n = 298) or > or =0.9 ng/mL (n = 613). This cutoff
      level was selected because it yielded the highest sensitivity and specificity
      according to a receiver operator characteristic curve. MAIN OUTCOME MEASURE(S):
      Implantation and clinical pregnancy rates. RESULT(S): In cycles with high serum P
      levels, more oocytes were retrieved and more embryos were available for transfer.
      Clinical pregnancy rates per ET in the low and high P groups were 36.9% and
      45.4%, respectively (P<.05). The implantation rate per embryo was similar in the
      two groups (14.9% and 16.4%, respectively, in cycles with P levels <0.9 vs > or
      =0.9 ng/mL). Abortion rates were 22.7 and 25.8%, respectively (P>.05).
      CONCLUSION(S): Our data showed no adverse effect of high serum P levels on the
      day of hCG administration on implantation rates after ICSI and ET.

PMID- 10593367
TI  - Crinone 8% (90 mg) given once daily for progesterone replacement therapy in donor
      egg cycles.
AB  - OBJECTIVE: To determine whether once-daily dosing of Crinone 8% (90-mg
      progesterone vaginal gel; Serono Laboratories, Inc., Norwell, MA) is sufficient
      for normal endometrial development and pregnancy support. DESIGN: Prospective
      cohort study. SETTING: Academic medical center. PATIENT(S): Eighty-six women who
      required complete progesterone replacement for a donor egg cycle.
      INTERVENTION(S): Crinone 8% (90 mg) once daily or IM progesterone (100 mg) once
      daily was administered from day 15 onward. Both groups underwent an endometrial
      biopsy on day 26 of a mock cycle, followed by a second cycle in which ET was
      performed. MAIN OUTCOME MEASURE(S): Endometrial development, serum progesterone
      levels, pregnancy rates, implantation rates, and bleeding patterns. RESULT(S):
      Mean (+/-SD) serum progesterone levels on day 26 were 11.3+/-6.5 ng/mL in the
      Crinone group and 65.2+/-12.5 ng/mL in the IM progesterone group. At histologic
      examination, endometrial biopsy specimens were found to be "in phase" for 100%
      (42/42) of women in the Crinone group and 95.5% (42/44) of women in the IM
      progesterone group. Although 8 of 42 patients had serum progesterone levels of <6
      ng/mL, there was no correlation with endometrial development. Only 1 patient bled
      before the 14th day of progesterone therapy, and she went on to be delivered of
      twins. Clinical pregnancy, ongoing pregnancy, implantation, and miscarriage rates
      were not statistically different for the Crinone and IM progesterone groups:
      45.6% (21/46) versus 52.3% (23/44); 39.1% (18/46) versus 40.9% (18/44); 21.5%
      (34/158) versus 19% (30/158), and 14.3% (3/21) versus 22% (5/23), respectively.
      Power was sufficient to detect a 25% difference in clinical pregnancy rates.
      CONCLUSION(S): Crinone 8% administered once daily appears to produce the same
      endometrial development and pregnancy rates as IM progesterone in women who
      require complete progesterone replacement, and it does not cause early bleeding.

PMID- 10593368
TI  - Effects of metformin on adrenal steroidogenesis in women with polycystic ovary
      syndrome.
AB  - OBJECTIVE: To determine whether the administration of metformin, an insulin
      sensitizing agent, is followed by changes in adrenal steroidogenesis in women
      with polycystic ovary syndrome (PCOS). DESIGN: Prospective trial. SETTING:
      Department of Obstetrics and Gynecology, University of Siena, Siena, Italy.
      PATIENT(S): Fourteen women with PCOS. INTERVENTION(S): Blood samples were
      obtained before (-15 and 0 minutes) and after (15, 30, 45, and 60 minutes) the
      administration of ACTH (250 microg). Metformin then was given at a dosage of 500
      mg three times a day for 30-32 days, at which time the pretreatment study was
      repeated. MAIN OUTCOME MEASURE(S): The adrenal androgen responses to ACTH before
      and after treatment with metformin. RESULT(S): Ovulation occurred in two women
      (14%) in response to metformin treatment. A significant reduction in basal
      concentrations of free testosterone and a significant increase in concentrations
      of sex hormone-binding globulin were observed. The administration of metformin
      was associated with a significant reduction in the response of 17alpha
      hydroxyprogesterone, testosterone, free testosterone, and androstenedione to
      ACTH. The ratio of 17alpha-hydroxyprogesterone to progesterone, which indicates
      17alpha-hydroxylase activity, and the ratio of androstenedione to 17alpha
      hydroxyprogesterone, which indicates 17,20-lyase activity, were significantly
      lower after a month of metformin treatment, indicating a reduction in the
      activities of these enzymes. CONCLUSION(S): The administration of metformin to
      unselected women with PCOS led to a reduction in the adrenal steroidogenesis
      response to ACTH. This finding supports the hypothesis that high insulin levels
      associated with PCOS may cause an increase in plasma levels of adrenal androgens.

PMID- 10593369
TI  - Alterations in low-density lipoprotein and high-density lipoprotein subclasses
      among Hispanic women with polycystic ovary syndrome: influence of insulin and
      genetic factors.
AB  - OBJECTIVE: To examine the influence of hyperandrogenism on low-density
      lipoprotein (LDL) and high-density lipoprotein (HDL) subclass levels as well as
      lipoprotein (a) levels in hyperandrogenic women compared with a control group.
      DESIGN: Case-control study. SETTING: University-based outpatient clinic.
      PATIENT(S): Sixteen Hispanic women with polycystic ovary syndrome were compared
      with 21 controls matched for age, weight, and ethnicity. INTERVENTION(S): None.
      MAIN OUTCOME MEASURE(S): Fasting serum levels of testosterone, insulin, and
      lipoproteins. RESULT(S): Compared with controls, women with polycystic ovary
      syndrome had significantly lower levels of apolipoprotein A-I (95+/-28 mg/dL
      versus 144+/-42 mg/dL) and HDL2a (30.9%+/-4.4% versus 36.6%+/-5.4%) but
      significantly higher levels of HDL3c (5.1%+/-2.2% versus 2.4%+/-1.5%). There were
      no statistically significant differences in LDL subclasses between groups, but
      there was a high incidence (54%) of the atherogenic lipoprotein phenotype B in
      this Hispanic population. As a group, Hispanic women with the abnormal B
      phenotype had significantly higher levels of insulin, HDL, HDL2b, and
      triglycerides. CONCLUSION(S): Hyperandrogenemia may have an adverse effect on
      serum lipoproteins through effects on HDL subclasses. Hispanic women may have a
      higher incidence of the atherogenic lipoprotein phenotype B, which may increase
      their risk for atherosclerosis.

PMID- 10593371
TI  - Pharmacokinetic and pharmacodynamic characteristics of ganirelix
      (Antagon/Orgalutran). Part I. Absolute bioavailability of 0.25 mg of ganirelix
      after a single subcutaneous injection in healthy female volunteers.
AB  - OBJECTIVE: To assess the absolute bioavailability of ganirelix
      (Antagon/Orgalutran; NV Organon, Oss, the Netherlands) after a single SC
      injection. DESIGN: Randomized, crossover, pharmacokinetic study. SETTING: Phase I
      clinical research unit. PATIENT(S): Nineteen healthy female volunteers of
      reproductive age. INTERVENTION(S): Two separate injections of 0.25 mg of
      ganirelix were given, one subcutaneously and one intravenously, with a washout
      period of 1 week between injections. Blood samples were taken for assessment of
      serum ganirelix concentrations, and blood pressure, heart rate, and adverse
      events were monitored. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters.
      RESULT(S): Fifteen subjects were evaluated. The mean concentration-time profile
      after SC administration was comparable to that after IV administration. The mean
      (+/- SD) peak concentration and time of occurrence after SC administration were
      14.8+/-3.2 ng/mL and 1.1+/-0.3 hours, respectively. The mean (+/- SD) half-lives
      after IV administration and SC administration were highly similar (12.7+/-3.7
      hours and 12.8+/-4.3 hours, respectively). Mean (+/- SD) AUC0-infinity (area
      under the concentration-time curve) values of 105+/-11 ng/mL x hours and 96+/-12
      ng/mL x hours were calculated for IV administration and SC administration,
      respectively, resulting in an absolute mean (+/- SD) bioavailability of 91.3%+/
      6.7%. Both treatments were well tolerated. CONCLUSION(S): Ganirelix is absorbed
      rapidly and extensively after SC administration, resulting in a high absolute
      bioavailability of >90%.

PMID- 10593370
TI  - 11beta-hydroxyandrostenedione and delta5-androstenediol as markers of adrenal
      androgen production in patients with 21-hydroxylase-deficient nonclassic adrenal
      hyperplasia.
AB  - OBJECTIVE: To determine the sensitivity of 11beta-hydroxyandrostenedione (11
      OHA4) and delta5-androstenediol (ADIOL) as markers of excessive adrenal androgen
      production. DESIGN: Prospective study. SETTING: Academic medical centers.
      PATIENT(S): Thirteen women with untreated 21-hydroxylase-deficient nonclassic
      adrenal hyperplasia (NCAH) and 18 healthy, eumenorrheic, nonhirsute controls
      matched for age and body mass index. INTERVENTION(S): All subjects were studied
      before and after acute adrenal stimulation with 0.25 mg of IV ACTH-(1-24). MAIN
      OUTCOME MEASURE(S): Basal levels of total testosterone, sex hormone-binding
      globulin, DHEAS, and free testosterone were measured. Levels of androstenedione
      (A4), DHEA, 11-OHA4, and ADIOL were determined before (Steroid0) and 60 minutes
      after (Steroid60) acute ACTH-(1-24) stimulation. RESULT(S): Patients with NCAH
      had higher median basal levels of DHEAS and total and free testosterone than
      controls. Patients with NCAH had higher median A4(0), A460, DHEA(0), DHEA60, 11
      OHA4(0), ADIOL0, and ADIOL60 levels but similar 11-OHA4(60) levels compared with
      controls. Among patients with NCAH, 30%, 54%, 15%, and 85% had 11-OHA4(0),
      ADIOL0, 11-OHA4(60), and ADIOL(60) levels, respectively, above the 95th
      percentile of controls. CONCLUSION(S): Overall, serum levels of 11-OHA4 did not
      appear to be a very sensitive marker of excessive adrenal androgen production, at
      least in patients with NCAH. Although ACTH-stimulated ADIOL levels were elevated
      in 85% of the patients studied, they did not appear to have any advantage over
      the measurement of A4 or DHEA levels.

PMID- 10593372
TI  - Pharmacokinetic and pharmacodynamic characteristics of ganirelix
      (Antagon/Orgalutran). Part II. Dose-proportionality and gonadotropin suppression
      after multiple doses of ganirelix in healthy female volunteers.
AB  - OBJECTIVE: To assess the dose-proportionality and pharmacodynamic properties of
      multiple doses of ganirelix (Antagon/Orgalutran; NV Organon, Oss, the
      Netherlands). DESIGN: Randomized, parallel, pharmacokinetic, and pharmacodynamic
      study. SETTING: Phase I clinical research unit. PATIENT(S): Three groups of 15
      healthy female volunteers of reproductive age. INTERVENTION(S): Subcutaneous
      injections of 0.125 mg, 0.25 mg, or 0.50 mg of ganirelix were given once daily
      for 7 days. Blood samples were taken to assess serum ganirelix, LH, FSH, and E2
      concentrations. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters and hormone
      suppression. RESULT(S): Steady-state levels were reached between days 2 and 3.
      Peak concentrations, which occurred approximately 1 hour after dosing, increased
      in a dose-proportional manner and averaged 5.2 ng/mL, 11.2 ng/mL, and 22.2 ng/mL
      for the 0.125-mg, 0.25-mg, and 0.50-mg doses, respectively. Corresponding mean
      values for the area under the curve over one dosing interval (24 hours) were 33
      ng x h/mL, 77.1 ng x h/mL, and 137.8 ng x h/mL, respectively. After the last 0.25
      mg dose of ganirelix, serum LH, FSH, and E2 concentrations were maximally
      decreased (by 74%, 32%, and 25% at 4 hours, 16 hours, and 16 hours after
      injection, respectively). Serum hormone levels returned to pretreatment values
      within 2 days after the last injection. CONCLUSION(S): The pharmacokinetics of
      ganirelix were dose-proportional within the dose range studied. Multiple
      injections resulted in immediate suppression of gonadotropins, which was rapidly
      reversed after treatment discontinuation.

PMID- 10593373
TI  - Levels of vascular endothelial growth factor are elevated in patients with
      ectopic pregnancy: is this a novel marker?
AB  - OBJECTIVE: To determine serum levels of vascular endothelial growth factor (VEGF)
      and evaluate their capacity to serve as a marker for the diagnosis of ectopic
      pregnancy (EP). DESIGN: Prospective, case-controlled study. SETTING: A tertiary
      care center. PATIENT(S): Twenty women with EP, 10 women with normal intrauterine
      pregnancy, and 10 women with abnormal intrauterine pregnancy, all at comparable
      stages of gestation. INTERVENTION(S): Serum samples were obtained from all women.
      MAIN OUTCOME MEASURE(S): All samples were analyzed for VEGF, progesterone, and
      beta-hCG by specific methods. RESULT(S): Women with EP had higher serum levels of
      VEGF than women with normal intrauterine pregnancy and women with abnormal
      intrauterine pregnancy (median levels, 226.8 pg/mL, 24.4 pg/mL, and 59.4 pg/mL,
      respectively). With a cutoff level of 200 pg/mL, serum VEGF could distinguish
      intrauterine from extrauterine pregnancy with a sensitivity of 60%, specificity
      of 90%, and positive predictive value of 86%. CONCLUSION(S): The increased serum
      VEGF levels in women with EP may facilitate this challenging diagnosis and reduce
      maternal morbidity and mortality.

PMID- 10593374
TI  - Microdose follicular phase gonadotropin-releasing hormone agonist (GnRH-a)
      compared with luteal phase GnRH-a for ovarian stimulation at in vitro
      fertilization.
AB  - OBJECTIVE: To compare an ovarian stimulation protocol using microdose follicular
      phase GnRH agonist (GnRH-a) and oral contraceptive (OC) pills to a luteal phase
      GnRH-a protocol. DESIGN: Retrospective analysis. SETTING: University affiliated
      IVF program. PATIENT(S): One hundred seventy patients who underwent IVF and ET in
      1996. INTERVENTION(S): Patients were assigned to either a midluteal start of
      leuprolide acetate (LA) 1 mg/d, reduced to 0.5 mg/d after addition of
      gonadotropins (LUT), or OC pills until cycle day 0 followed by 20 microg of LA
      every 12 hours on cycle day 3 with addition of gonadotropins on cycle day 5
      (MICRO). MAIN OUTCOME MEASURE(S): Number of FSH ampules, days of stimulation,
      peak E2, and number of oocytes retrieved. RESULT(S): There were no statistically
      significant differences in the main outcome measures between the two groups using
      an age-matched ANOVA. Clinical pregnancy rate per cycle start was not
      statistically different (LUT = 54%, and MICRO = 37%). The cancellation rate was
      significantly higher in the MICRO group (22.5% vs. 8.2%). CONCLUSION(S): Given
      the higher cancellation rate in the microdose group, a randomized clinical trial
      is required to determine the possible benefit of a lower dose of GnRH-a in
      patients with normal ovarian function.

PMID- 10593375
TI  - Vascular endothelial growth factor, nitric oxide, and leptin follicular fluid
      levels correlate negatively with embryo quality in IVF patients.
AB  - OBJECTIVE(S): To measure vascular endothelial growth factor (VEGF), nitric oxide
      (NO) and leptin levels in individual ovarian follicles and to examine their
      relationships with perifollicular blood flow, follicular metabolic indices, and
      the developmental potential of the corresponding oocyte and embryo. DESIGN:
      Prospective study. SETTING: Academic, tertiary care institution. PATIENT(S):
      Unselected IVF patients. INTERVENTION(S): Color-pulsed Doppler analysis of
      perifollicular blood flow; determination of partial pressure of oxygen (pO2),
      partial pressure of carbon dioxide (pCO2), and pH and VEGF, leptin and NO levels
      in follicular fluid. MAIN OUTCOME MEASURE(S): Fertilization and day 3 embryo
      morphology and cleavage. RESULT(S): Fifty-five follicular fluid samples from 16
      patients were studied. Mean follicular fluid levels were as follows: VEGF,
      1,046+/-863.7 pg/mL (range, <63-3,332.7 pg/mL); NO3/NO2, 34.2+/-12 microM (range,
      16.4-76.1 microM); and leptin, 20.1+/-12.1 ng/mL (range, 3.3-52.2 ng/mL).
      Vascular endothelial growth factor had a negative correlation with embryo
      morphology (r = -0.28, P = .01). Leptin demonstrated a negative correlation with
      follicular pO2 (r = -0.42, P = .005) and a positive correlation with follicular
      pCO2 (r = 0.36, P = .02). Follicular leptin levels correlated positively with
      VEGF levels (r = 0.46, P = .008) and with NO3/NO2 levels (r = 0.39, P =.006).
      CONCLUSION(S): Vascular endothelial growth factor, NO and leptin appear to be
      markers of follicular hypoxia and suboptimal embryo development. Whether
      fluctuations of these regulatory factors determine or reflect changes in the
      follicular microenvironment affecting oocyte developmental potential remains to
      be elucidated.

PMID- 10593376
TI  - Superoxide dismutase activity in human follicular fluid after controlled ovarian
      hyperstimulation in women undergoing in vitro fertilization.
AB  - OBJECTIVE: To determine the activity of superoxide dismutase (SOD) and the total
      protein concentration in human preovulatory ovarian follicular fluid (FF) in
      relation to corresponding serum levels and the fertilization capacity of oocytes.
      DESIGN: Prospective, observational study. SETTING: Academic-based center for
      reproductive medicine. PATIENT(S): Twenty-eight female partners of infertile
      couples, 13 of whom were smokers, undergoing controlled ovarian hyperstimulation
      for IVF. INTERVENTION(S): Blood and follicular fluid samples were collected 34-36
      hours after hCG administration. MAIN OUTCOME MEASURE(S): Levels of SOD activity
      and total protein concentrations. RESULT(S): Superoxide dismutase activity was
      present in all the FF studied and mean levels were statistically significantly
      higher than in serum. Total protein concentrations in serum were statistically
      significantly correlated with corresponding concentrations in FF. There was no
      difference in SOD activity between smokers and nonsmokers. Total protein
      concentrations in FF were marginally and statistically significantly lower in
      nonsmokers. Follicular fluid from patients whose oocytes did not become
      fertilized had a statistically significantly higher level of SOD activity than
      that from patients whose oocytes did become fertilized. CONCLUSION(S): Superoxide
      dismutase activity is present in FF and is higher than in serum. The degree of
      SOD activity is variable and seems to be inversely related to the fertilization
      of oocytes.

PMID- 10593377
TI  - Introduction of blastocyst culture and transfer for all patients in an in vitro
      fertilization program.
AB  - OBJECTIVE: To evaluate the nonselective application of extended embryo culture on
      the outcome of IVF. DESIGN: Retrospective analysis. SETTING: Private practice
      assisted reproductive technology center. PATIENT(S): Seven hundred ninety
      nonselected patients undergoing IVF with controlled ovarian stimulation.
      INTERVENTION(S): For day 3 ET, multicell embryos were cultured in human tubal
      fluid medium and 12% synthetic serum substitute. For day 5 ET, embryos were
      cultured for 48 hours in S1 medium and then for 48 hours in S2 medium. MAIN
      OUTCOME MEASURE(S): Implantation rate (determined by total no. of visualized
      gestational sacs), ongoing pregnancy rate, and number of embryos available for
      ET. RESULT(S): Respective day 3 and day 5 implantation rates for patients aged
      <35 years (29.5% and 38.9%), patients aged 35-39 years (20.7% and 28.2%), and all
      patients combined (23.3% and 32.4%) were statistically significantly different.
      Significantly more embryos were transferred on day 3 than on day 5 for patients
      aged <35 years (2.9 vs. 2.4), patients aged 35-39 years (3.1 vs. 2.6), and all
      patients combined (3.0 vs. 2.5). The difference in ongoing pregnancy rates per
      retrieval was statistically significant for day 3 compared with day 5 transfers
      for all patients combined (35.9% vs. 43.8%). Cancellation rates for transfer
      after retrieval increased significantly for day 3 compared with day 5 transfer
      (2.9% vs 6.7%). CONCLUSION(S): These results demonstrate the feasibility of using
      extended embryo culture in a nonselective manner for couples undergoing IVF.
      Overall, extended embryo culture was associated with a significant increase in
      pregnancy rates and implantation rates and a significant decrease in the number
      of embryos transferred. The rate of multiple implantation among patients aged <35
      years warrants consideration of single blastocyst transfers for this group.

PMID- 10593378
TI  - Intracytoplasmic sperm injection overcomes previous fertilization failure with
      conventional in vitro fertilization.
AB  - OBJECTIVE: To evaluate the outcome of intracytoplasmic sperm injection (ICSI) in
      patients with previous idiopathic fertilization failure (< or =20% fertilization
      rate) after conventional IVF. DESIGN: Retrospective analysis. SETTING: IVF
      program at a university medical center. PATIENT(S): Twenty-five patients who
      underwent 38 ICSI cycles after experiencing unexplained fertilization failure
      with conventional IVF (group A) and 87 patients who underwent 118 ICSI cycles for
      male factor indications during the same period (group B). INTERVENTION(S):
      Intracytoplasmic sperm injection was performed in a subsequent cycle after
      fertilization failure with conventional IVF. MAIN OUTCOME MEASURE(S): Outcomes of
      IVF were compared between groups A and B. RESULT(S): Fertilization was achieved
      with ICSI in all patients with previous fertilization failure. The mean (+/- SD)
      fertilization rate (68%+/-21% vs. 64%+/-22%), implantation rate per embryo (22.6%
      vs. 20%), and delivery rate per cycle (47.3% vs. 49.1%) did not differ
      significantly between groups A and B. Overall, 72% of patients with previous
      unexplained fertilization failure had a successful pregnancy after ICSI.
      CONCLUSION(S): Intracytoplasmic sperm injection can overcome unexplained
      fertilization failure caused by a potentially occult gamete abnormality, with the
      same fertilization, implantation, and pregnancy rates as are seen in patients
      with abnormal sperm parameters.

PMID- 10593379
TI  - A comparison of post-thaw results between cryopreserved embryos derived from
      intracytoplasmic sperm injection and those from conventional IVF.
AB  - OBJECTIVE: To study the effect of freezing on early stage embryos derived from
      intracytoplasmic sperm injection (ICSI) or from IVF. DESIGN: Prospective,
      controlled clinical study. SETTING: Private IVF center. PATIENT(S): Sixty-seven
      consecutive patients undergoing frozen-thawed embryo transfer cycles.
      INTERVENTION(S): Early stage embryos were frozen, thawed, and transferred. MAIN
      OUTCOME MEASURE(S): Post-thaw survival, implantation and pregnancy rates.
      RESULT(S): We noted an 88% post-thaw survival rate, an 18% implantation rate, and
      a 52% pregnancy rate in the ICSI group and 81%, 11%, and 25%, respectively, with
      conventional fertilization. CONCLUSION(S): Early stage embryos (either zygote or
      2-4 cells) derived from ICSI can be frozen with confidence and higher post-thaw
      survival and pregnancy rates can be achieved when compared with those from
      conventional IVF.

PMID- 10593380
TI  - Pronuclear stage cryopreservation after intracytoplasmic sperm injection and
      conventional IVF: implications for timing of the freeze.
AB  - OBJECTIVE: To compare clinical outcomes of frozen embryo transfers using
      cryopreserved pronuclear stage oocytes that had undergone either intracytoplasmic
      sperm injection (ICSI) or conventional IVF. DESIGN: Observational. SETTING: A
      tertiary referral reproductive medicine unit. PATIENT(S): Couples undergoing
      either ICSI or conventional IVF from January 1, 1995 to December 31, 1997.
      INTERVENTION(S): Patients underwent a standard controlled ovarian
      hyperstimulation protocol and transvaginal ultrasound-guided oocyte retrieval.
      All normally fertilized (2PN) oocytes exceeding a specified embryo number
      designated for fresh transfer were immediately cryopreserved at the pronuclear
      stage. Our cryopreservation method included timing of the freeze according to
      pronuclear morphology. Subsequent frozen embryo thaw-transfer cycles were usually
      performed by thawing only the intended number of embryos for transfer. MAIN
      OUTCOME MEASURE(S): Thaw survival rate, implantation rate, clinical pregnancy
      rate, delivery rate. RESULT(S): Ninety-six thaw-transfer cycles (n = 72) and 93
      thaw-transfer cycles (n = 67) were undertaken in patients who had previously
      undergone conventional IVF or ICSI, respectively. Embryo thaw survival rates
      (IVF, 90.4%; ICSI, 91.1%) were similar. Clinical pregnancy (IVF, 40.6%; ICSI,
      44.1%) and delivery (IVF, 36.4%; ICSI, 39.8%) rates per transfer, as well as
      implantation (IVF, 19.1%; ICSI, 19.9%) rates, were also similar. There were only
      four clinical pregnancy losses in both groups. CONCLUSION(S): Embryo thaw
      survival is similar for cryopreserved pronuclear stage oocytes derived from ICSI
      and conventional IVF. Clinical pregnancy, implantation and delivery rates were
      also similar for the two groups. In addition, there was no increase in the rate
      of pregnancy loss in ICSI patients after frozen embryo transfers.

PMID- 10593381
TI  - Quality of embryo does not affect the implantation rate of IVF-ET in infertile
      women with antisperm antibody.
AB  - OBJECTIVE: To determine whether low quality score of embryos and advanced
      maternal age affect the implantation rate in infertile women with sperm
      immobilizing antibody. DESIGN: A retrospective study. SETTING: The IVF Unit of
      the Department of Obstetrics and Gynecology at Tokushima University Hospital.
      PATIENT(S): Four infertile groups were studied: 20 women with sperm-immobilizing
      antibodies; 169 with tubal; 129 with male factor; and 72 with unexplained
      etiology. INTERVENTION(S): All women were hyperstimulated with GnRH analogue and
      scheduled ovarian stimulation with FSH and hMG for oocyte retrieval. MAIN OUTCOME
      MEASURE(S): Relationship of quality of transferred embryos, implantation rate and
      maternal age among four groups of infertile couples. RESULT(S): In the antisperm
      group, the fertilization rate (57.6%) and mean (+/- SD) score of transferred
      embryos (5.4+/-1.9) were significantly lower than those in the tubal group (72.4%
      and 6.2+/-1.9, respectively). However, the implantation rate in the antisperm
      group (23.6%) was significantly higher than those in other three groups (tubal,
      8.6%; male factor, 9.5%; unexplained, 7.6%). With advancing maternal age, the
      implantation rate decreased in the three comparative groups. In contrast, the
      implantation rate in the antisperm group did not decrease with advancing maternal
      age. CONCLUSION(S): Women with antisperm antibodies have several disadvantages to
      overcome in order to achieve successful IVF-ET, such as a low fertilization rate
      and poor quality of transferred embryos. However, a high implantation rate was
      observed in this group, even in women at advanced age. The occurrence of a
      cellular or humoral immune reaction against sperm may augment the uterine
      receptivity for the implantation of fertilized ova or blastocyst.

PMID- 10593383
TI  - Analysis of Minnesota Multiphasic Personality Inventory-2 profiles of prospective
      anonymous oocyte donors in relation to the outcome of the donor selection
      process.
AB  - OBJECTIVE: To examine the scores of prospective anonymous oocyte donors on the
      Minnesota Multiphasic Personality Inventory-2 (MMPI-2) in four outcome groups.
      DESIGN: Chart review. SETTING: Academic medical center. PATIENT(S): One hundred
      fifty prospective anonymous oocyte donors who underwent a preliminary screening
      and a 1-hour structured psychological interview and who completed the MMPI-2.
      INTERVENTION(S): Psychological evaluation prior to donation. MAIN OUTCOME
      MEASURE(S): Scores on the MMPI-2 and outcomes of the donor selection process.
      RESULT(S): Seventy (47%) women were accepted as donors and completed one donation
      cycle; 30 (20%) were accepted as donors but did not donate because of medical
      reasons or relocation; 18 (12%) were accepted as donors but were noncompliant;
      and 32 (21%) were rejected as donors because of psychological concerns.
      Statistically significant differences were found between outcome groups on scales
      F, K, 1, 2, 7, 8, and 0. Although these differences were statistically
      significant, all group subscale mean scores were in the average to low-average
      range and differences between group means were small. CONCLUSION(S): The MMPI-2
      differentiates between prospective donor outcome groups, but psychologists need
      to interpret the results of the MMPI-2 carefully in the context of clinical
      interview information.

PMID- 10593382
TI  - Early pregnancy losses in in vitro fertilization and oocyte donation.
AB  - OBJECTIVE: To evaluate prospectively the incidence of early pregnancy losses
      (before menstruation occurs) in IVF and ovum donation cycles. DESIGN: Prospective
      case-control study. SETTING: Tertiary care, university-associated center.
      PATIENT(S): One hundred forty-five patients undergoing IVF and 92 undergoing
      oocyte donation were recruited. The control group for IVF consisted of 15 ovum
      donors who had no ET and were instructed to avoid intercourse. The control group
      for oocyte donation included 10 women undergoing a mock cycle of steroid
      replacement. INTERVENTION(S): Starting on day 6 after ET, the women were
      instructed to collect the first urine sample of the day every 2 days. Each
      patient collected six different specimens of urine (days 6, 8, 10, 12, 14, and 16
      after ET for cases or the same days without ET for controls. MAIN OUTCOME
      MEASURE(S): beta-HCG was measured with a standardized microparticle enzyme
      immunoassay, and IVF reproductive outcome was assessed. RESULT(S): For IVF,
      positive implantation was registered in 88 of 145 cycles of embryo replacement
      (60.7%). Only 30 (20.7%) resulted in viable pregnancies, whereas the remaining 58
      miscarried. Forty-two of these miscarriages (72.4%) were early pregnancy losses
      and 13 (22.4%) were classified as clinical abortions. In ovum donation, positive
      implantation was recorded in 64 of 92 cycles of ET (69.6%). A total of 30 (32.6%)
      ended in viable pregnancies, whereas the remaining 34 (37.0%) were miscarriages.
      Early pregnancy loss accounted for 70.6% of pregnancy losses, whereas biochemical
      pregnancies and clinical abortions accounted for 11.8% and 17.6%, respectively.
      CONCLUSION(S): Our results demonstrate that patients undergoing assisted
      reproductive technology have an increased rate of early pregnancy loss compared
      with fertile patients. In addition, these data indicate that implantation is more
      frequently impaired in IVF than in oocyte donation cycles, resulting in a high
      incidence of early pregnancy loss. This suggests that implantation may be
      subjected to abnormal conditions in assisted reproduction.

PMID- 10593384
TI  - Vitrification of mouse and human blastocysts using a novel cryoloop container
      less technique.
AB  - OBJECTIVE: To vitrify mouse and human blastocysts with use of the cryoloop
      procedure and to assess subsequent development. DESIGN: Controlled study of
      vitrification of mouse and human blastocysts. SETTING: Research department of a
      private assisted reproductive technology unit. PATIENT(S): Blastocysts that were
      not suitable to be frozen were donated from patients. INTERVENTION(S): Culture of
      pronucleate embryos in sequential media to the blastocyst stage. MAIN OUTCOME
      MEASURE(S): Survival of the vitrification procedure was assessed by reexpansion,
      hatching, and outgrowth in culture. In addition, the viability of mouse
      blastocysts was assessed after transfer to pseudopregnant recipients. RESULT(S):
      Vitrification of mouse blastocysts did not affect the ability to reexpand, hatch,
      or outgrow in culture. Furthermore, implantation rates and fetal development were
      equivalent for nonfrozen and vitrified blastocysts. Vitrified human blastocysts
      were able to hatch and outgrow in culture at rates similar to nonfrozen controls.
      CONCLUSION(S): Cryoloop vitrification was able to cryopreserve mouse and human
      blastocysts without any reduction in the ability to reexpand and hatch in
      culture. Furthermore, viability was not reduced by the cryoloop vitrification of
      mouse blastocysts.

PMID- 10593385
TI  - Effects of human follicular fluid on spermatozoa that have been cocultured with
      human oviductal cells.
AB  - OBJECTIVE: To investigate the sequential effects of human oviductal cells and
      human follicular fluid (hFF) on various sperm functions. DESIGN: Laboratory
      experimental study. SETTING: University gynecology unit. PATIENT(S): Fallopian
      tubes were from patients undergoing tubal ligation or hysterectomy. Semen was
      from men attending the subfertility clinics. INTERVENTION(S): Spermatozoa were
      treated with [1] 6 hours in Earle's balanced salt solution (EBSS-BSA; control);
      [2] 5 hours in EBSS-BSA and 1 hour with hFF (hFF); [3] 5 hours with oviductal
      cells and 1 hour in EBSS-BSA (coculture); and [4] 5 hours with oviductal cells
      and 1 hour with hFF (sequential). MAIN OUTCOME MEASURE(S): Motility, acrosome
      reaction, zona binding, and oocyte fusion. RESULT(S): Groups II and III
      spermatozoa had similar motility and were better than that of group I. Group IV
      displayed higher motility parameters than the other groups. Human follicular
      fluid induced acrosome reaction. The incidence of acrosome reaction in group IV
      was significantly lower than that in group II. Group III did not affect the
      acrosome reaction. Spermatozoa in groups II-IV had lower zona binding capacity
      than those in group I. Human follicular fluid stimulated oocyte penetration,
      whereas oviductal cells suppressed this effect of hFF. CONCLUSION(S): Oviductal
      cells maintained the fertilizing capacity of spermatozoa, whereas hFF facilitated
      the fertilization process of oviductal spermatozoa.

PMID- 10593386
TI  - Immunohistochemical localization of insulin-like growth factor-binding protein-3
      in eutopic and ectopic endometrial tissues.
AB  - OBJECTIVE: To evaluate the expression of insulin-like growth factor-binding
      protein-3 (IGFBP-3) in the eutopic endometrium and in endometriotic lesions.
      DESIGN: Retrospective immunohistochemical study. PATIENT(S): Twenty-five normal
      women and 39 women with endometriosis. INTERVENTION(S): Endometrial and
      endometriotic tissue biopsies obtained at laparoscopy. MAIN OUTCOME MEASURE(S):
      Expression of IGFBP-3 assessed by immunohistochemistry. RESULT(S): In the
      endometrium, positive immunostaining of IGFBP-3 was observed both in the stroma
      and the epithelial glands. The intensity of staining in the glands during the
      secretory phase was significantly higher in women with endometriosis compared
      with controls (P = .018). An increased expression of IGFBP-3 over controls was
      found in stages I and II of the disease (P = .018), whereas in stages III and IV,
      the difference between controls and women with endometriosis was not significant
      (P = .300). In endometriotic tissues, a much-marked immunostaining of IGFBP-3 was
      noted in 90% of the glands and 67% of the stroma without apparent differences
      related to cycle phase. CONCLUSION(S): These data show intense staining of IGFBP
      3 in endometriosis lesions and increased expression of the protein in the
      endometrium of patients with endometriosis compared to controls. This marked
      expression of IGFBP-3 could be related to its previous finding in the peritoneal
      fluid and to its potential involvement in the pathophysiology of endometriosis.

PMID- 10593387
TI  - Deglycosylation of a bifunctional lutropin-follitropin agonist reduced its
      follitropin activity more than its lutropin activity.
AB  - OBJECTIVE: To design a drug that blocks the gonadal actions of lutropins and
      follitropins. DESIGN: Controlled in vitro study. SETTING: Academic laboratory.
      PATIENT(S): None. INTERVENTION(S): We removed three glycosylation signals from an
      hCG-hFSH chimera known to have high affinity for LH and FSH receptors, expecting
      this would create a bifunctional antagonist (dgCFC). To offset the inhibition of
      subunit combination caused by deglycosylation of alpha-subunit loop 2, we
      prepared dgCFC as a single-chain fusion protein containing the alpha-subunit
      downstream of the chimeric beta-subunit. MAIN OUTCOME MEASURE(S): Receptor
      binding, cyclic adenosine monophosphate accumulation. RESULT(S): dgCFC bound LH
      or FSH receptors similar to hCG or hFSH. It was a partial agonist and had one
      tenth the efficacy of hFSH and two thirds the efficacy of hCG. CONCLUSION(S): The
      surprising high residual lutropin activity of dgCFC indicated that its FSH
      residues offset the effects of deglycosylation, suggesting this approach to
      preparing a bifunctional antagonist is unlikely to lead to a useful drug. The
      increased lutropin efficacy of dgCFC relative to deglycosylated hCG supports the
      idea that oligosaccharides modulate glycoprotein hormone efficacy through an
      influence on hormone conformation.

PMID- 10593388
TI  - Detection of aromatase cytochrome P-450 in endometrial biopsy specimens as a
      diagnostic test for endometriosis.
AB  - OBJECTIVE: To evaluate the clinical usefulness of examining endometrial biopsy
      specimens for aromatase cytochrome P-450 as a diagnostic test for endometriosis.
      DESIGN: Retrospective, case-controlled study. SETTING: Department of Obstetrics
      and Gynecology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
      PATIENT(S): One hundred five women of reproductive age with normal menstrual
      cycles underwent endometrial biopsy laparotomy or laparoscopy, and examination of
      their tissue revealed endometriosis, adenomyosis, and/or leiomyomas. Patients who
      had cervical carcinoma in situ but no other gynecologic disease were considered
      to be disease-free. INTERVENTION(S): Endometrial biopsy specimens were collected.
      MAIN OUTCOME MEASURE(S): The expression of aromatase cytochrome P-450 was
      examined by reverse transcription-polymerase chain reaction and
      immunohistochemical analysis. The distribution and intensity of the
      immunostaining was assessed using a semiquantitative index designed H-score.
      RESULT(S): Immunostaining for aromatase cytochrome P-450 was detected in biopsy
      specimens obtained from patients with endometriosis, adenomyosis, and/or
      leiomyomas but not in specimens obtained from disease-free patients (H-score
      <20), with a sensitivity and specificity of 91% and 100%, respectively.
      CONCLUSION(S): The expression of aromatase cytochrome P-450 in biopsy specimens
      of eutopic endometrium distinguishes between disease-free women and women with
      endometriosis, adenomyosis, and/or leiomyomas. This technique can be used at
      outpatient infertility clinics as an initial screening procedure to rule out the
      presence of estrogen-dependent disease.

PMID- 10593389
TI  - Patients with stages III and IV endometriosis have a poorer outcome of in vitro
      fertilization-embryo transfer than patients with tubal infertility.
AB  - OBJECTIVE: To evaluate the outcome of IVF in patients with stages III and IV
      endometriosis. DESIGN: Retrospective study. SETTING: The Sara Racine IVF Unit,
      Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Israel. PATIENT(S):
      Fifty-eight patients with stages III and IV endometriosis and 60 patients with
      tubal infertility. INTERVENTION(S): IVF-ET for all couples. MAIN OUTCOME
      MEASURE(S): Fertilization, pregnancy, and birth rates. RESULT(S): The comparison
      between patients with endometriosis and those with tubal infertility indicated
      that the former had a poor IVF outcome in terms of reduced fertilization rate
      (40% vs. 70%), reduced pregnancy rate per cycle (10.6% vs. 22.4%), and reduced
      birth rate per cycle (6.7% vs. 16.6%). The differences were statistically
      significant. CONCLUSION(S): The results show an unfavorable outcome of IVF-ET in
      patients with endometriosis when compared with those who have tubal infertility.

PMID- 10593390
TI  - Are cytokines and growth factors responsible for the detrimental effects of
      hydrosalpingeal fluid on pregnancy rates after in vitro fertilization-embryo
      transfer?
AB  - OBJECTIVE: To characterize the secretion of cytokines and growth factors in
      hydrosalpingeal fluid. DESIGN: Retrospective analysis. SETTING: Hospital-based
      infertility practice. PATIENT(S): Ten infertile women who underwent laparoscopic
      aspiration of their hydrosalpingeal fluid before salpingectomy or
      neosalpingostomy. INTERVENTION(S): Samples were cryopreserved, then thawed and
      centrifuged to remove cellular debris. MAIN OUTCOME MEASURE(S): The supernatants
      were analyzed for the presence of human interferon-gamma, epidermal growth
      factor, transforming growth factor-beta2, and tumor necrosis factor-alpha by
      quantitative enzyme immunoassay kits. RESULT(S): Interferon-gamma and
      transforming growth factor-beta2 were not detected in any of the hydrosalpingeal
      fluid samples. Epidermal growth factor was present in 5 of 10 hydrosalpingeal
      fluid samples, with a mean (+/- SE) concentration of 26.7+/-11.4 pg/mL. Tumor
      necrosis factor-alpha was detected in 7 of 10 samples, with a mean (+/- SE)
      concentration of 6.2+/-3.6 pg/mL. Three of the 10 samples contained both tumor
      necrosis factor-alpha and epidermal growth factor. CONCLUSION(S): For the first
      time, we described the absence of interferon-gamma and transforming growth factor
      beta2, and the presence of epidermal growth factor and tumor necrosis factor
      alpha in human hydrosalpingeal fluid. Because the fundamental role of the human
      fallopian tube is secretory in nature, the alteration in substances secreted from
      the tubal epithelium that reflux into the uterine cavity may explain the
      deleterious effects that hydrosalpingeal fluid has on pregnancy rates after IVF
      ET.

PMID- 10593391
TI  - Sperm quality may adversely affect the chromosome constitution of embryos that
      result from intracytoplasmic sperm injection.
AB  - OBJECTIVE: To determine whether the high rate of chromosomal abnormalities in the
      embryos of an infertile couple were caused by a paternal factor that may have
      involved the sperm centriole. DESIGN: Case report. SETTING: Private IVF program.
      PATIENT(S): An infertile couple who underwent IVF-ET because of severe male
      factor infertility and endometriosis. INTERVENTION(S): Preimplantation genetic
      diagnosis of chromosomal abnormalities in embryos derived from two cycles of ICSI
      in which the husband's sperm was used and one in which donor sperm was used. MAIN
      OUTCOME MEASURE(S): Preimplantation genetic diagnosis with fluorescence in situ
      hybridization using probes for chromosomes X, Y, 13, 16, 18, and 21, and
      determination of hCG levels. RESULT(S): Most of the embryos derived from the
      cycles in which the husband's sperm was used were chromosomally abnormal (82%),
      whereas all the embryos derived from the cycle in which donor sperm was used were
      chromosomally normal. The cycle in which donor sperm was used resulted in an
      ongoing pregnancy. CONCLUSION(S): Paternal factors, which most likely derive from
      the centrosome, can contribute to numerical chromosomal abnormalities, which in
      turn may predispose to implantation failure.

PMID- 10593392
TI  - Blastocyst transfer and monozygotic twinning.
AB  - OBJECTIVE: To report two cases of monozygotic twinning after IVF-blastocyst
      transfer. DESIGN: Case report. SETTING: Private practice in an assisted
      reproductive technology clinic. PATIENT(S): Two women treated with IVF-ET at the
      blastocyst stage. INTERVENTION(S): Pituitary down-regulation with luteal
      leuprolide acetate, ovulation induction with gonadotropins, IVF, sequential
      culture, blastocyst transfer, and P for luteal support. MAIN OUTCOME MEASURE(S):
      Levels of hCG, pelvic ultrasound examination, amniocentesis, obstetric follow-up,
      and cesarean section. RESULT(S): Two intrauterine monozygotic twin pregnancies
      occurred after IVF and blastocyst transfer. One of them was complicated by fetus
      to-fetus transfusion syndrome and was delivered preterm by cesarean section; the
      other woman had a normal pregnancy and vaginal delivery. CONCLUSION(S):
      Monozygotic multiple gestations may be increased in IVF blastocyst transfers. The
      potential obstetric complications of this type of pregnancy should be discussed
      with patients.

PMID- 10593393
TI  - Low-dose human chorionic gonadotropin therapy can improve sensitivity to
      exogenous follicle-stimulating hormone in patients with secondary amenorrhea.
AB  - OBJECTIVE: To assess the effect of supplementing an ovulation induction regimen
      of highly purified FSH with LH activity in the form of low-dose hCG therapy.
      DESIGN: Case report. SETTING: The Reproductive Endocrinology Center at the
      University of Bologna, Bologna, Italy. PATIENT(S): A woman with weight-related
      secondary hypogonadotropic amenorrhea. INTERVENTION(S): The patient was treated
      first with highly purified FSH alone and then received highly purified FSH in
      combination with low-dose hCG therapy (50 IU/d). MAIN OUTCOME MEASURE(S): Pelvic
      ultrasound examinations, serum E2 levels, duration of treatment, total dose of
      highly purified FSH, and outcome of treatment. RESULT(S): The concomitant
      administration of low-dose hCG and highly purified FSH markedly reduced the
      duration of treatment and the dose of highly purified FSH, and resulted in a
      quadruplet pregnancy in a patient in whom several previous ovulation induction
      procedures had been unsuccessful. CONCLUSION(S): Supplementation of an ovulation
      induction regimen with an agent that has LH activity can enhance FSH-induced
      folliculogenesis and markedly reduce costs in women with hypogonadotropic
      hypogonadism. However, this increased response can be associated with
      complications such as multiple gestation.

PMID- 10593395
TI  - A simplified and efficient method for obtaining metaphase chromosomes from
      individual human blastomeres.
AB  - OBJECTIVE: To develop a reliable and cost-effective technique for karyotyping
      single human blastomeres for preimplantation diagnosis of chromosomal
      translocations. DESIGN: Controlled laboratory study. SETTING: Preimplantation
      genetic diagnosis and IVF program, Reproductive Genetics Institute/IVF Illinois,
      Chicago, Illinois. PATIENT(S): Patients undergoing IVF and preimplantation
      genetic diagnosis. INTERVENTION(S): Individual human blastomeres were fused with
      enucleated or intact mouse zygotes. After blastomere-cytoplast fusion,
      heterokaryons were fixed at metaphase of the first cleavage division or treated
      with okadaic acid to induce premature chromosome condensation. MAIN OUTCOME
      MEASURE(S): Percentage of analyzable metaphase plates and ease and reliability of
      the procedure. RESULT(S): The effectiveness of the proposed technique with
      blastomeres from day 3 diploid embryos was 91%. Sixty-three metaphases were
      obtained from 69 blastomeres; 3 blastomeres had not fused, 1 heterokaryon had no
      chromatin (an anucleated cytoplasmic bleb was biopsied and fused), and 2
      heterokaryons cleaved before they were fixed. CONCLUSION(S): Human blastomere
      fusion with an intact mouse zygote is an efficient and technically undemanding
      method for obtaining metaphase chromosome plates from individual human
      blastomeres for preimplantation testing for chromosomal translocations and
      aneuploidy.

PMID- 10593394
TI  - Laparoscopic tubal anastomosis: fertility outcome in 202 cases.
AB  - OBJECTIVE: To evaluate the fertility outcome after laparoscopic tubal anastomosis
      for reversal of sterilization. DESIGN: Retrospective clinical study. SETTING: A
      private practice affiliated with a university medical school. PATIENT(S): Two
      hundred two women who desired reversal of tubal sterilization. INTERVENTION(S):
      Laparoscopic tubal anastomosis. MAIN OUTCOME MEASURE(S): The cumulative pregnancy
      rate (PR) and factors that influenced the fertility outcome. RESULT(S): The
      cumulative PR in the 186 patients for whom follow-up data were available was
      60.3%, 79.4%, and 83.3% at 6, 12, and 18 months after operation, respectively.
      Five patients (3.2%) had ectopic pregnancies; one of these patients subsequently
      conceived normally. There were no statistically significant differences in the PR
      according to the sterilization method used, the site of the tubal anastomosis, or
      the length of the fallopian tube after surgery. The intrauterine PR was 87.1%
      (149/171) with bilateral anastomosis and 60% (9/15) with unilateral anastomosis.
      The PR decreased with increasing patient age (mean [+/- SD], 35+/-3.6 years) but
      was still 70.6% (12/17) in patients aged 40-45 years. CONCLUSION(S): Our findings
      suggest that laparoscopic tubal anastomosis is a highly successful procedure.
      This less invasive approach could be considered the procedure of choice in
      patients who desire reversal of tubal sterilization.

PMID- 10593396
TI  - Pelvic inflammation induced by diagnostic laparoscopy in baboons.
AB  - OBJECTIVE: To test the hypothesis that diagnostic laparoscopy can cause
      pelviperitoneal inflammation. DESIGN: Retrospective analysis of data collected
      during a prospective controlled study in baboons. SETTING: An academic research
      environment. ANIMAL(S): Samples were collected during laparoscopies in female
      baboons at the Institute of Primate Research, Kenya. INTERVENTION(S): In the
      first part of the study, 44 laparoscopies were performed in 16 baboons (5 with a
      normal pelvis, 11 with endometriosis) during the luteal phase, with a time
      interval of 1 month. In the second part of the study, 53 laparoscopies were
      performed in 15 baboons (6 with a normal pelvis, 9 with endometriosis) during the
      late follicular and luteal phases of one cycle, with a median time of 3-4 days
      between each laparoscopy. MAIN OUTCOME MEASURE(S): Peritoneal fluid (PF) was
      measured and analyzed for white blood cell (WBC) concentrations and, in the
      second part of the study, for the distribution of lymphocyte subsets (CD3, CD4,
      CD8, and CD20) and for the presence of cytokines transforming growth factor
      beta1, interleukin (IL)-6, and IL-10. RESULT(S): In the first part of the study,
      PF volumes and WBC concentrations were comparable at the baseline and follow-up
      laparoscopies. In the second part of the study, PF obtained at the second
      laparoscopy showed a 10-fold increase in volume, a 3-fold increase in WBC
      concentration, a 10-fold increase in IL-6 concentration, and a 2-fold increase in
      transforming growth factor-beta1 concentration when compared with PF obtained at
      the first laparoscopy. The PF subset of granulocytes and CD3-positive cells was
      higher and the PF subset of macrophages was lower at follow-up laparoscopies than
      at the baseline laparoscopy. CONCLUSION(S): Diagnostic laparoscopy can cause
      peritoneal inflammation in baboons.

PMID- 10593397
TI  - Clonality analysis of bilateral ovarian endometrial cysts.

PMID- 10593398
TI  - Oral sildenafil may reverse secondary ejaculatory dysfunction during infertility
      treatment.

PMID- 10593399
TI  - "Smart asses"--and spectrum bias.

PMID- 10593400
TI  - "Smart asses"--and spectrum bias.

PMID- 10593401
TI  - A marker locus for fertility?-- Real or spurious?

PMID- 10593402
TI  - A marker locus for fertility?--Real or spurious?

PMID- 10593403
TI  - Advanced sperm analysis--a step in the right direction?

PMID- 10593404
TI  - Exceptions to nature demand a higher level of documentation.

PMID- 10593405
TI  - Exceptions to nature demand a higher level of documentation.

PMID- 10593406
TI  - Evidence for a dense and intimate innervation of the bone tissue, including
      glutamate-containing fibers.
AB  - The recent demonstration in bone cells of receptors for glutamate (Glu), a major
      neuromediator, suggests that Glu may also act as a signaling molecule in bone and
      regulate bone cell metabolism. Although bone is known to be innervated, the
      distribution and characteristics of nerve fibers in this tissue have not been
      well documented. We have studied the anatomical distribution of nerve fibers and
      the presence of glutamate-immunoreactive ones in sections of long bones from
      neonatal, 15-, and 25-day-old rats, using immunocytochemistry with antibodies
      directed against several neuronal markers and Glu. We showed by electron
      microscopy that bone is rich in nerve-like processes running along vessels
      adjacent to bone trabeculae, in the vicinity of hematopoietic cells and bone
      cells. Immunocytochemical studies at the tissue and cellular level confirmed the
      presence of a dense network of thin nerve processes immunolabeled for
      neurofilament 200, tyrosine hydroxylase, and microtubule associated protein-2,
      three markers of nerve fibers. Some of these nerve processes showed local
      dilatations in contact with medullary cells and bone cells that were
      immunolabeled for synaptophysin, a nerve terminal marker. Glu was largely
      expressed in these thin nerve processes in proximity to bone cells. These
      findings show evidence for a dense and intimate network of nerve processes in
      bone, some of which were containing Glu, suggesting glutamatergic innervation in
      bone.

PMID- 10593407
TI  - Functional characterization of N-methyl-D-aspartic acid-gated channels in bone
      cells.
AB  - Our recent identification of glutamate receptors in bone cells suggested a novel
      means of paracrine communication in the skeleton. To determine whether these
      receptors are functional, we investigated the effects of the excitatory amino
      acid, glutamate, and the pharmacological ligand, N-methyl-D-aspartic acid (NMDA),
      on glutamate-like receptors in the human osteoblastic cell lines MG63 and SaOS-2.
      Glutamate binds to osteoblasts, with a Kd of approximately 10(-4) mol/L and the
      NMDA receptor antagonist, D(L)-2-amino-5-phosphonovaleric acid (D-APV), inhibits
      binding. Using the patch-clamp technique, we measured whole-cell currents before
      and after addition of L-glutamate or NMDA and investigated the effects of the
      NMDA channel blockers, dizolcipine maleate (MK801), and Mg2+, and the competitive
      NMDA receptor antagonist, 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphoric
      acid (R-CPP), on agonist-induced currents. Both glutamate and NMDA induced
      significant increases in membrane currents. Application of Mg2+ (200 micromol/L)
      and MK801 (100 micromol/L) caused a significant decrease in inward currents
      elicited in response to agonist stimulation. The competitive NMDA receptor
      antagonist, R-CPP (100 micromol/L), also partially blocked the NMDA-induced
      currents in MG63 cells. This effect was reversed by addition of further NMDA (100
      micromol/L). In Fura-2-loaded osteoblasts, glutamate induced elevation of
      intracellular free calcium, which was blocked by MK801. These results support the
      hypothesis that glutamate plays a role in bone cell signaling and suggest a
      possible role for glutamate agonists/antagonists in the treatment of bone
      diseases.

PMID- 10593408
TI  - Morphological characterization of skeletal cells in Cbfa1-deficient mice.
AB  - To clarify the mechanisms by which core-binding factor-alpha1 (Cbfa1), an
      essential transcription factor in osteogenesis, functions in osteoblast matrix
      formation, as well as in chondrocyte differentiation and osteoclastic bone
      resorption, Cbfa1-deficient embryonic mice were investigated ultrastructurally
      and histocytochemically at 18.5 days postcoitum. In homozygotic mice, both
      endochondral and intramembranous ossification were arrested, although bone tissue
      had already formed at this stage in the wild type. The tibiae of homozygotic mice
      were characterized by calcified cartilage and alkaline phosphatase (ALP)-positive
      perichondrium, whereas membranous structures indicating the presence of ALP
      activity in the lateral portion were observed in the calvariae, rather than the
      bone tissue. Most of the ALP-positive perichondrial cells in homozygotic tibiae
      possessed a spindle-shaped cell contour and small cytoplasm, the extracellular
      matrix of which contained neither type I collagen nor calcifying matrix vesicles.
      In contrast, some perichondrial cells at the very middle part of tibiae became
      flattened. In the vicinity of these cells, a thin layer of type I collagen-based
      calcified matrix, containing osteopontin, bone sialoprotein, or osteocalcin, was
      observed. In the cartilage of mutant mice, we observed a hypoplasic zone of
      proliferative chondrocytes, the flattening of hypertrophic chondrocyte-like
      cells, and calcified chondrocytes which, while not degraded, did display a high
      level of cell function. Mononuclear osteoclastic cells were found in the
      perichondrium, near calcified chondrocytes, in mutant mice. Multinuclear
      osteoclasts possessing H+-ATPase and ruffled borders were also present, although
      only in limited numbers. Neither the development of ruffled borders nor
      intracellular polarization was complete. Because the majority of osteogenic cells
      in Cbfa1-deficient mice can neither form nor calcify the bone matrix, Cbfa1
      principally plays essential roles in osteoblastic differentiation and bone matrix
      formation. Cbfa1 also affects both the proliferation and the differentiation of
      chondrocytes, whereas its absence prevents normal osteoclast formation and
      related functions.

PMID- 10593410
TI  - Inhibiting gap junctional intercellular communication alters expression of
      differentiation markers in osteoblastic cells.
AB  - Gap junctional intercellular communication (GJIC) may contribute to cellular
      differentiation. To examine this possibility in bone cells we examined markers of
      cellular differentiation, including alkaline phosphatase, osteocalcin, and
      osteopontin, in ROS17/2.8 cells (ROS), a rat osteoblastic cell line expressing
      phenotypic characteristics of fully differentiated osteoblasts. We utilized ROS
      rendered communication deficient either by stable transfection with antisense
      cDNA to connexin 43 (Cx43), the predominant gap junction protein in bone (RCx16
      cells), or by overexpression of Cx45, a gap junction protein not normally
      expressed in ROS (ROS/Cx45 cells). Both RCx16 and ROS/Cx45 cells displayed
      reduced dye coupling and Cx43 protein expression relative to ROS, control
      transfectants, and ROS/Cx45tr, ROS cells expressing carboxylterminal truncated
      Cx45. Steady-state mRNA levels for osteocalcin as well as alkaline phosphatase
      activity, two markers of osteoblastic differentiation, were also reduced in
      poorly coupled RCx16 and ROS/Cx45 cells. On the other hand, steady-state mRNA
      levels for osteopontin increased slightly in RCx16 and ROS/Cx45 cells. These
      results suggest that GJIC at least partly contributes to the regulation of
      expression of markers of osteoblastic differentiation.

PMID- 10593409
TI  - Stimulatory effects of phenytoin on osteoblastic differentiation of fetal rat
      calvaria cells in culture.
AB  - Phenytoin (diphenylhydantoin, DPH), an anticonvulsant drug for epileptic
      patients, has several adverse effects, including calvarial thickening and
      coarsening of the facial features, which occur with chronic DPH therapy. While
      previous studies have demonstrated that DPH has an anabolic action on bone cells
      in vivo and in vitro, the basis of these effects is not fully understood. In this
      study, the effect of DPH on osteoblastic differentiation of fetal rat calvaria
      (RC) cells in culture was investigated by measuring bone nodule (BN) formation,
      cell growth, alkaline phosphatase (ALPase) activity, collagen synthesis, and
      expression of osteocalcin (OC) and osteopontin (OP) mRNAs. Continuous treatment
      of RC cells with DPH for 18 days dose-dependently increased the mineralized BN
      number by 1.2-1.7-fold at concentrations of 12.5-200 micromol/L DPH. Cell growth
      was not affected at the same concentrations of DPH. ALPase activity was
      stimulated by DPH (1.1-1.9-fold) dose-dependently and was maintained at higher
      levels in DPH-treated cells throughout the experimental period. DPH increased
      mineralized and unmineralized BN formations both in the presence and the absence
      of 10(-8) mol/L dexamethasone (Dex). Expression of OC and OP mRNAs was markedly
      augmented by DPH on days 12-24 and on days 12-18, respectively. While control
      mRNA levels of OC and OP increased with time, the increases in DPH-treated cells
      were greater than those of the controls and the stimulatory effects were dose
      dependent. Type I collagen was also influenced by DPH; mRNA level was enhanced
      and the percentage of collagen synthesized was increased significantly, by 200
      micromol/L DPH. When DPH was added in three different culture stages, days 1-6
      (growth), days 7-12 (matrix development), and days 13-18 (mineralization), BN
      formation was influenced primarily on days 1-6 and secondarily on days 7-12, but
      not on days 13-18, suggesting that DPH increased BN formation by enhancing not
      only the proportion of osteoprogenitor cells in the early stage but also the
      proportion of functional osteoblasts in the middle stage within mixed-cell
      populations. Moreover, such increases were detected in conditions of both Dex(+)
      and Dex(-). These findings demonstrate that DPH stimulates osteoblast-associated
      markers such as BNs, ALPase, OC, OP, and type I collagen by continuously
      affecting the stages of growth and matrix development in RC cells, and suggests
      that the stimulatory effects by DPH may possibly be induced independent of those
      by Dex.

PMID- 10593411
TI  - Isolation and hormonal responsiveness of primary cultures of human bone-derived
      cells: gender and age differences.
AB  - We present a model for isolating human cell culture derived from biopsies
      obtained during orthopedic surgery. Four donor groups were defined by gender and
      age: pre- and postmenopausal women (<50 and >55 years, respectively), and younger
      (30-55 years) and older (>60 years) men. Bone-derived cells were identified as
      osteoblasts by major osteoblastic characteristics; that is, high alkaline
      phosphatase (ALP) activity, dose-dependent increase of ALP by 1,25(OH)2D3, high
      levels of parathyroid hormone (PTH)-induced cyclic AMP, and 1,25-(OH)2D3-induced
      osteocalcin. In all cells, levels of osteocalcin were significantly elevated (p <
      0.05 and 0.01). In cells derived from men, no significant age differences were
      found in ALP and osteocalcin values of basal activity and in fold stimulation
      1,25(OH)2D3. Cells from postmenopausal women showed a nonsignificant lower basal
      ALP activity than premenopausal cells. In postmenopausal cells, ALP responded
      less to 1,25(OH)2D3 (33% increase, p < 0.05) than the premenopausal cells (100%
      increase, p < 0.05). In cells from either age group, ALP did not respond to the
      gonadal steroids 17beta-estradiol (E2) and dihydrotestosterone (DHT) or
      progesterone. Basal levels of osteocalcin were higher in cells of premenopausal
      origin as compared with postmenopausal cells (p = 0.05), but response to
      1,25(OH)2D3 was the same. PTH significantly stimulated cAMP (p = 0.001) in all
      age and gender groups analyzed. In all groups, no differences were found in
      either basal activity or in PTH response. Unlike men, cells derived from the bone
      of women were more susceptible to age changes. We postulate that the
      postmenopausal cell population had a decreased number of osteoblasts, or cells in
      a lower differentiation stage. These results extend our knowledge of bone biology
      found in animal models and reveal that human osteoblasts from men do not show the
      same age-dependent differences observed in women.

PMID- 10593412
TI  - High-dose estrogen-induced osteogenesis in the mouse is partially suppressed by
      indomethacin.
AB  - We recently found that high-dose estrogen induces the formation of new sites of
      cancellous bone formation within the long bones of intact female mice. To examine
      whether prostaglandins play a role in mediating this response, we studied whether
      this is inhibited by coadministration of the cyclooxygenase inhibitor,
      indomethacin. Eight-week-old intact female mice were divided into four groups of
      ten, and administered vehicle, 17beta-estradiol (E2), at 500 microg/animal per
      week and/or indomethacin at 2 mg/kg per day. Animals were killed after treatment
      for 24 days, and histomorphometric indices subsequently analyzed on longitudinal
      sections of the proximal tibial metaphysis. As found previously, E2 treatment
      caused a striking increase in cancellous bone volume, associated with an
      equivalent increase in the extent of cancellous double-labeled surfaces. In mice
      treated with both indomethacin and E2, significant reductions in cancellous bone
      volume and cancellous double-labeled surfaces were observed as compared with
      animals treated with E2 alone. In contrast, indomethacin did not significantly
      influence these parameters when given alone. Subregional analysis within the
      proximal tibial metaphysis revealed that this inhibitory effect of indomethacin
      was more marked distally as compared with proximally, with the estrogen-induced
      gain in cancellous bone volume at these sites being reduced by 50% and 25%,
      respectively. We conclude that estrogen-induced osteogenesis in female mice is
      partially suppressed by treatment with indomethacin, suggesting that
      prostaglandin synthesis plays a significant role in mediating this response.

PMID- 10593413
TI  - Bone mass changes during pregnancy and lactation in the rat.
AB  - We examined bone mass changes in the total, axial, and appendicular skeleton as
      well as in the different subareas of femur and tibia in rats fed on a normal
      calcium diet. A total of 16 virgin Wistar rats, approximately 5 months of age
      (270+/-30 g), were assigned to two groups of eight rats each. One group was mated
      and, for each pregnant rat, a nonpregnant control rat was studied simultaneously.
      Weaning was performed when the pups reached 38+/-3 g body weight. At the
      beginning (t = 0), on the first day postpartum (t = 22 days), and at weaning (t =
      45 days), total skeleton bone mineral content (BMC), area, and bone mineral
      density (BMD) were determined by dual-energy X-ray absorptiometry (DXA) in vivo
      under anesthesia. Body weight increased significantly during pregnancy (p < 0.05)
      and decreased at weaning, whereas control rats showed a slow, gradual increment
      without reaching a significant difference. During pregnancy, BMC and area of the
      total skeleton increased significantly in pregnant rats, but the changes in BMD
      were not different compared with the control group. A completely different
      pattern was observed between groups during the 23 days of lactation. While the
      skeleton continued to grow in the control group (BMC and area increased), the
      total skeleton of lactating rats showed no change in area (size), small decreases
      in BMC, and a significant decrease in BMD (p < 0.05). Consequently, although BMC
      and BMD of both groups were similar at the time of delivery, BMC was 12.0% lower
      and BMD 4.9% lower at the end of lactation in the lactating rats compared with
      the control group. The contribution of the maternal skeleton to the lactation
      period was not similar; that is, the areas with the highest trabecular component
      showed the greater average differences in BMD at the time of weaning (proximal
      tibia -19.9%, distal femur -12.6%, spine -10.9%) (p < 0.05), compared with
      relatively minor, nonsignificant losses in areas where cortical bone predominates
      (distal tibia -5%, middle tibia -5.2%). Our experimental results demonstrated the
      usefulness of DXA in vivo to visualize changes in BMD during the reproductive
      cycle of the rat. Moreover, the data confirm that normal pregnancy in the rat
      appears to exert little influence on bone, whereas lactation induces significant
      bone loss, mainly in the areas of predominant trabecular bone.

PMID- 10593414
TI  - Trabecular bone turnover, bone marrow cell development, and gene expression of
      bone matrix proteins after low calcium feeding in rats.
AB  - Low-calcium-fed animals have been accepted as one of the experimental models
      showing a reduction in bone mass. However, the effects of short-term low-calcium
      feeding on bone turnover, the development of osteoprogenitor cells, and gene
      expression of bone matrix proteins have not been reported. In this study, we
      examined the effect of a low-calcium diet on rat tibia and analyzed the changes
      in the bone by histomorphometry, bone marrow cell culture, and in situ and
      Northern hybridization of the bone matrix proteins. Rats were fed either a low
      calcium diet (0.05% Ca) or a normal calcium diet (0.5% Ca) using the pair feeding
      technique. They were killed at day 0, 12 h, and days 1, 2, and 3. In the low
      calcium group, the serum parathyroid hormone (PTH) level was temporarily
      increased in 12 h after feeding the low-calcium diet. Bone mineral density in the
      trabecular bone was significantly decreased from 1 day after the low-calcium
      feeding, but cortical bone did not show any changes during the experimental
      period. The bone volume per tissue volume in the proximal tibia also decreased
      from day 1 in the low-calcium group. The number of osteoclasts and osteoblasts on
      the trabecular bone surface was increased in the low-calcium group compared with
      the normal-calcium group. An ex vivo study showed that the number of progenitors
      of osteoclasts and osteoblasts in bone marrow was also increased in the low
      calcium group of rats. The localization of type I collagen mRNA was observed in
      osteoblasts in the low-calcium group. The Northern hybridization study showed
      that the gene expression of type I collagen, osteopontin, and osteocalcin was
      increased at day 3 in the low-calcium group. These results indicated that the
      trabecular bone surface quickly responded to the low-calcium feeding and that
      bone remodeling activity was activated probably by PTH. The changes in bone
      marrow cell populations and the gene expression of bone matrix proteins are
      closely associated with increased bone turnover induced by the low-calcium diet,
      resulting in rapid bone loss of the trabecular bone.

PMID- 10593415
TI  - Anabolic effect of prostaglandin E2 on cortical bone of aged male rats comes
      mainly from modeling-dependent bone gain.
AB  - In this study, prostaglandin E2 (3 mg/kg per day) was administered to 20-month
      old male Wistar rats for 10 and 30 days. Histomorphometric analyses were
      performed on double-fluorescent-labeled undecalcified tibial shaft sections.
      Thirty days of prostaglandin E2 (PGE2) administration increased bone formation
      rate/total bone surface from undetectable levels to 0.6 microm/day at the
      periosteal surface and from 0.5 to 2.1 microm/day at the endocortical surface.
      Endocortical osteoid surface area increased from 2% to 67% at day 10 and
      decreased to 6% at day 30; woven and lamellar bone formation started at day 0,
      but was most obvious at day 30, resulting in a 12% increase of total bone mass.
      The red to yellow marrow ratio was 0.2 in pretreatment controls, and increased to
      1.6 by day 10 and 2.4 by day 30 with PGE2 administration. Intracortical cavity
      number and area increased after 10 days of PGE2 treatment, but with forming
      osteon number and area far exceeding those of resorption cavities at day 30.
      Endocortical modeling surface/endocortical surface was only 1.5%, and remodeling
      was 11.1% in pretreatment controls. PGE2 treatment increased modeling to 24.5% in
      the 10 day group and 93.7% in the 30 day group, whereas remodeling remained
      unchanged at 10 days, and decreased to 6.2% at 30 days. Osteoprogenitor cells and
      osteoblasts could not be detected in pretreatment controls, but increased by day
      10, and returned almost to control levels by 30 days. Our data indicate that PGE2
      induced periosteal and endocortical bone formation mainly by modeling-dependent
      bone gain, accompanied by increases in intracortical remodeling and red bone
      marrow, and a transient increase in the osteoprogenitor cells adjacent to the
      endocortical surface. These findings suggest that 20-month-old male Wistar rats
      were very responsive to the anabolic action of PGE2 in the tibial shaft, a site
      consisting mainly of cortical bone and yellow marrow.

PMID- 10593416
TI  - Advantages of concurrent use of anabolic and antiresorptive agents over single
      use of these agents in increasing trabecular bone volume, connectivity, and
      biomechanical competence of rat vertebrae.
AB  - The purpose of this study was to evaluate the usefulness of a combination regimen
      of anabolic and antiresorptive agents in increasing skeletal quantity and quality
      in comparison to a single-drug regimen with these agents. We examined
      histomorphometrically and biomechanically the effects of separate and combined
      administration of intermittent parathyroid hormone (PTH) and estrogen or
      bisphosphonate on both axial and appendicular skeletons of male Wistar rats,
      which were 4 months old and weighed approximately 300 g at the beginning of the
      treatment. The animals were untreated or injected with vehicle, recombinant human
      PTH(1-84) (PTH; 100 microg/kg daily), 17beta-estradiol (E2, 500 microg/kg every
      other day), incadronate disodium (YM175, 80 microg/kg every other day), combined
      PTH and E2 (PTH + E2), or a combination of PTH and YM175 (PTH + YM175). After 1
      month of treatment, the three groups in which PTH was administered (PTH, PTH +
      E2, and PTH + YM175) had significantly higher trabecular bone volume and
      connectivity in the proximal tibial metaphyses (PTMs) compared with the untreated
      and vehicle-treated groups, whereas only combination groups (PTH + E2 and PTH +
      YM175) showed significant increases in these indices in the lumbar vertebrae.
      This site-related discrepancy was attributed to the fact that PTH significantly
      elevated bone resorption not in the PTMs but in the vertebrae. This increased
      bone resorption in the vertebrae was suppressed by the addition of an
      antiresorptive agent. As a result, trabecular bone mass, connectivity, and
      mechanical strength of the vertebrae were significantly increased from control
      levels only in the concurrent treatment groups (PTH + E2 and PTH + YM175). The
      superior skeletal effects of PTH cotherapy over PTH monotherapy were not seen
      with regard to bone mass, but with increased connectivity and mechanical
      strength. The concurrent use of PTH and an antiresorptive agent has been shown to
      be superior to the single use of PTH for enhancing these properties of rat
      vertebrae, which encourages future research, especially in larger animals.

PMID- 10593417
TI  - Lumbar vertebral body compressive strength evaluated by dual-energy X-ray
      absorptiometry, quantitative computed tomography, and ashing.
AB  - Bone densitometry with DXA (dual energy X-ray absorptiometry) and QCT
      (quantitative computed tomography) techniques are used for in vivo assessment of
      bone strength and thereby prediction of fracture risk. However, only few in vitro
      studies have investigated and compared these techniques' ability to determine
      vertebral compressive strength. The aim of the present study was to (1) assess
      the predictive value of DXA, QCT, and pQCT (peripheral QCT) for vertebral bone
      compressive strength assessed by mechanical testing; (2) describe both linear and
      power relationship between density and strength; and (3) evaluate whether gender
      related differences in the above relations were present. The material comprised
      human lumbar vertebrae L3 from 51 women and 50 men (age range: 18 to 96 years).
      The study showed that both DXA and CT techniques (QCT and pQCT) have a high
      predictive value for vertebral strength. The DXA BMD had a high correlation with
      maximum compressive load (r2 = 0.86). The QCT and pQCT had high correlations with
      maximum compressive stress (r2 = 0.75 and r2 = 0.86, respectively). The
      correlation between ash density of the biomechanically tested specimen and
      maximum compressive stress was r2 = 0.88. There were no differences between
      linear and power fit in the degree of determination between density and strength.
      There was no gender-related difference in the relationship between volumetric
      density and maximum compressive stress. In conclusion, it was demonstrated that
      DXA, QCT, and pQCT are ex situ equally capable of predicting vertebral
      compressive strength with a degree of determination (r2) between 75% and 86%. No
      differences were found between linear and power analysis of the relationship
      between density and strength, and no difference was found in the density strength
      relationship between women and men.

PMID- 10593418
TI  - Bone properties as estimated by mineral density, ultrasound attenuation, and
      velocity.
AB  - Quantitative ultrasound (QUS) analysis of bone has been suggested to have a level
      of performance equal to dual-energy X-ray absorptiometry (DXA) for the assessment
      of fracture risk. In this study, QUS and DXA measurements were conducted on
      bovine trabecular bone in vitro using commercially available clinical
      instruments. The samples were then mechanically tested to obtain Young's modulus
      and ultimate strength. In addition, QUS and DXA parameters of the human calcaneus
      (n = 34) were measured in vivo. The measurements revealed a significant effect of
      bovine bone size on broadband ultrasound attenuation (BUA) and speed of sound
      (SOS) in vitro. By normalizing the DXA and QUS results with bone thickness we
      could systematically improve their ability to predict bone strength. However, in
      bovine trabecular bone, BUA showed no significant linear correlation with either
      bone mineral density (BMD), Young's modulus, or ultimate strength. This finding
      may be typical of only high-density and low-porosity bovine bone. We
      significantly improved prediction of ultimate strength by combining density and
      ultrasound velocity results as compared with assessments of volumetric BMDvol (p
      < 0.05) or SOS (p < 0.001) alone. However, the improvement was not significant if
      BMDvol, instead of wet density, was used. Altogether, 88% of the variation in the
      ultimate strength of bovine bone could be explained by combined density and
      ultrasound velocity. In vivo, SOS showed a weak negative correlation with heel
      width (r = -1.350). The in vivo measurements also showed a close correlation for
      BUA with BMD in the human calcaneus. This suggests that BUA is more suitable for
      quantitative analysis of low-density trabecular bone.

PMID- 10593419
TI  - Computer simulation of trabecular remodeling using a simplified structural model.
AB  - A simplified three-dimensional simulation of trabecular bone remodeling has been
      developed. The model utilizes 441 planar structural units to represent
      approximately 50 mm3 of initial bone volume with 199 basic multicellular units
      (BMUs). The simulation takes into account trabecular perforation in the
      structural model. The cases of male bone remodeling with no menopause and female
      bone remodeling with menopause are examined from the period of simulated age 25
      80 years. Menopause is arbitrarily started at age 45 and extends for 7.5 years.
      Zero-, first-, and second-order BMU activation responses are employed to examine
      how the bone would be affected by the method of increase of BMU activation during
      menopause. At age 80, the female bone remodeling simulation produced a bone
      volume loss of approximately 49% for all three activation responses. This
      compared to a 38% bone volume loss for the case of no menopause. For the
      menopause simulations, an average of about 40% of the total bone loss was due to
      perforation.

PMID- 10593420
TI  - Connectivity and the elastic properties of cancellous bone.

PMID- 10593421
TI  - Effects of tissue viscoelasticity on mechanical loading models using rats.

PMID- 10593422
TI  - A population-based survey of prostate cancer testing in New Mexico.
AB  - Prostate cancer screening has increased dramatically in the past decade, but few
      studies have looked at population-based testing rates and the factors that
      influence testing. The objectives of our study were to estimate prostate cancer
      testing rates for New Mexican men 50 years or older and to identify patient
      factors associated with testing. We surveyed men using random-digit dialing.
      Subjects completed a 32-item questionnaire asking about prostate cancer testing;
      demographics; cancer knowledge, attitudes, and beliefs; health behaviors; and
      risks for prostate cancer. Associations between patient factors and testing were
      analyzed with multivariate logistic regression. Two hundred thirty-nine subjects
      (36% response rate) completed the survey; 95% had heard of prostate cancer and
      nearly 90% felt that testing was important. Forty-eight percent had been tested,
      most within the past year. Significant predictors for testing included receiving
      regular health care (odds ratio = 2.15, 95% CI = 1.07-4.33), being retired (OR =
      2.49, 95 CI = 1.18-5.28), and having been diagnosed with prostatic hyperplasia
      (OR = 3.14, 95% CI = 1.30-7.59). Prostate cancer testing occurred frequently
      among New Mexican men. The study variables that were the most significant
      predictors of testing were all markers for access to health care.

PMID- 10593423
TI  - Between two worlds: the use of traditional and Western health services by Chinese
      immigrants.
AB  - This study examined the use of traditional and Western health services by Chinese
      immigrants, as well as the cultural and socioeconomic factors affecting health
      seeking behaviors and health service utilization patterns among the study
      population from the perspectives of consumers and Chinese health care providers.
      Two instruments were used for data collection. The first, a consumer instrument,
      was designed for interviews of service recipients; the second, a health provider
      instrument, was designed to elicit information from traditional and Western
      providers. A few topics in the former instrument were cross-examined from the
      perspectives of health care providers. The investigation employed a combination
      of qualitative and quantitative research methods for data collection. Qualitative
      ethnographic methods used included: (1) participant-observation, (2) face-to-face
      interview, and (3) case study. To complement the qualitative data, structured
      quantitative survey were conducted with all selected informants. A total of 105
      informants participated in the study: 75 Chinese consumers and 30 Chinese health
      professionals. The latter group was composed of Western physicians and
      traditional practitioners. Results revealed several patterns of health-seeking
      and service utilization behaviors among the Chinese of Houston and Los Angeles.
      These included high rates of self-treatment and home remedies (balanced diets and
      other alternative medicines); medium rates of utilization of integrated Western
      and traditional health services, including travel to country of origin for care;
      and low rates of exclusive utilization of Western or traditional Chinese
      treatments.

PMID- 10593424
TI  - Medium-sized business employees speak out about smoking.
AB  - A health promotion study, funded by a state health department to meet objectives
      3.4 and 3.11 of Healthy People 2000, was designed to: (1) identify tobacco use;
      (2) assess employees' beliefs on one's health and family member's health; and (3)
      assess the type of smoking policies favored. Using the Health Belief Model, it
      was hypothesized that there were differences in the health beliefs of tobacco
      users, former users, and never users. A 34-item questionnaire was administered to
      1090 employees with a return rate of 603 (55%). RESULTS: tobacco users perceived
      weight control and reduction of tension as benefits; they accepted warning label
      as hazardous but reported smokeless not as harmful; they perceived heart disease
      and cancer as related to tobacco use; and 62% had tried to quit smoking. Former
      and never users wanted "total ban policies" while, tobacco users wanted
      "designated areas" for smoking. All perceived their smoking and environmental
      tobacco smoke hazardous to their health and the health of family.

PMID- 10593425
TI  - Training by satellite: planning and evaluating a video conference for injury
      prevention practitioners.
AB  - A non-experimental design was employed to conduct both a process and impact
      evaluation of a video conference for injury control specialists and other
      community members. The video conference was designed to teach participants how to
      conceptualize, develop, and implement community-based injury and violence
      prevention programs. The six-hour event was broadcast to 120 sites all across the
      United States and had a total of 1270 participants. The video conference format
      included a panel of injury control specialists and a moderator, video and audio
      clips that were shown throughout the program, on and off screen activities for
      participants, and an opportunity for participants to ask questions of the panel.
      Three groups were included in the evaluation sample: participants; site
      facilitators; and stakeholders; which included the planning committee members,
      conference speakers, moderator, and audiovisual personnel. Evaluation data were
      collected by telephone and in-person interviews, focus groups, and surveys
      completed at all the viewing sites. Results showed that there was high
      satisfaction among the participants and that the program should be continued as a
      series of video conferences with a changing content. There was lower satisfaction
      with the on-line activities, applicability of material to their work, and the
      opportunity to network with others and to participate in discussion.
      Recommendations made for improving future programs include shortening the video
      conference program, focusing on specific issues within injury and violence
      prevention, training the program presenters on the workings of the satellite
      video conference technology, use of video streaming, and using web-based forms
      for registration and evaluation.

PMID- 10593426
TI  - Knowledge of nutrition and coronary heart disease in Riyadh, Saudi Arabia.
AB  - The purpose of this study was to determine the level of knowledge among adults in
      Riyadh City, Saudi Arabia, concerning dietary fat and the risk of coronary heart
      disease. We assessed the overall knowledge levels among 393 adults who were
      waiting to see their physicians at Primary Health Care Centers (PHCCs). Since the
      overall knowledge levels were high, we conclude that health education should
      concentrate on clarifying areas of misunderstanding shown by this study. Further,
      the importance of addressing perceived barriers is discussed.

PMID- 10593427
TI  - Effect of X-ray contrast media on blood flow properties after coronary
      angiography.
AB  - In vitro studies suggest that ionic and nonionic X-ray contrast media have
      different effects on rheological parameters. The risk of thrombotic complications
      in coronary interventions was reported to be lower using ionic contrast media.
      The aim of the present study was to compare the effects of different types of
      contrast media on rheological parameters after coronary angiography. Sixty
      patients were randomized to four groups: ioxaglate 320 (dimeric, ionic, n = 18),
      iomeprol 400 (monomeric, nonionic, n = 12), iobitridol 350 (monomeric, nonionic,
      n = 12), and iodixanol 320 (dimeric, nonionic, n = 18). Blood samples were
      collected via the side port of the arterial sheath immediately before and at the
      end of coronary angiography. In our study, all types of contrast media caused a
      significant decrease in haematocrit (Hct), plasma viscosity (PV), erythrocyte
      aggregation (EA), and in the platelet reactivity index (PRI). The most pronounced
      decrease in Hct was found using the ionic dimer ioxaglate. There were no
      significant differences between the contrast media with respect to their effects
      on PV, EA, and PRI.

PMID- 10593428
TI  - Effect of cilostazol, a phosphodiesterase III inhibitor, on experimental
      thrombosis in the porcine carotid artery.
AB  - Thrombus formation in the carotid artery is one of the common causes of transient
      ischemic attacks and stroke. Platelet aggregation seems to be an essential
      component in these processes. The present study was conducted to determine the
      ability of cilostazol, a phosphodiesterase III inhibitor, to prevent formation of
      totally occlusive thrombus in a porcine carotid artery, in comparison with
      ticlopidine. Castrated male Yorkshire pigs were allocated to control (n=8),
      cilostazol (30 mg/kg, twice a day [b.i.d] for 2 days, n=8), and ticlopidine (50
      mg/kg, b.i.d. for 3 days, n=7) groups. The endothelium of the right common
      carotid artery was injured with electrical stimulation (150 microA) without
      constriction and blood flow in this region was monitored by Doppler flow probe.
      Arterial blood was sampled during electrical stimulation for the measurement of
      platelet aggregation. Total occlusion rates within 240 minutes were 87.5% (7:8),
      37.5% (3:8), and 85.7% (6:7) in the control, cilostazol, and ticlopidine groups,
      respectively. Compared with the control group, the time to total occlusion was
      significantly prolonged in the cilostazol group, but not in the ticlopidine
      group. Consistently, platelet aggregation was significantly inhibited only in the
      cilostazol group. Because ticlopidine increases blood flow in the intact carotid
      artery before injury to a greater extent than cilostazol, direct antiplatelet
      action is thought to be responsible for cilostazol's beneficial effect in
      preventing thrombotic occlusion. These results suggest that cilostazol may be
      useful for the inhibition of the thrombus formation in the carotid artery and for
      the prevention of cerebral ischemic events.

PMID- 10593429
TI  - Anti-beta2-glycoprotein I antibodies in patients with acute venous
      thromboembolism: prevalence and association with recurrent thromboembolism.
AB  - To establish the prevalence of antibodies against beta2-glycoprotein I (beta2GPI)
      in unselected patients with venous thromboembolism, as well as the association
      with antiphospholipid antibodies (aPL) and a history of previous thromboembolism,
      we investigated the presence of these antibodies in 227 consecutive patients with
      acute deep vein thrombosis or pulmonary embolism, of whom 63 were carriers of aPL
      with or without lupus anticoagulant (LA), and seven were carriers of LA alone.
      The presence of antibodies against beta2GPI was demonstrated in 19 patients
      [8.4%; 95% confidence interval (CI), 4.5-11.3%]. All of them belonged to the
      group of 63 patients with aPL (30.2%). A history of a previous thromboembolism
      was identified in 11 of the 19 patients with anti-beta2GPI antibodies (57.9%) and
      in 45 of the 208 patients without these antibodies [21.6%; odds ratio (OR)=4.98;
      95% CI, 1.89-13.1; p<0.0005]. In the subgroup of patients with aPL and/or LA, the
      rate of recurrent thromboembolism among patients with anti-beta2GPI antibodies
      (11 of 19, 57.9%) was significantly higher than that observed in patients without
      these antibodies (15 of 51, 29.4%; OR=3.3; 95% CI, 1.1-9.83; p=0.28). We conclude
      that in patients with acute venous thromboembolism the prevalence of antibodies
      against beta2GPI is unexpectedly high. The presence of these antibodies seems to
      identify a subgroup of patients with antiphospholipid antibodies who have a
      peculiarly high risk of thrombotic recurrences. Further prospective studies are
      indicated to better define the role of anti-beta2GPI antibodies in the
      development of recurrent thromboembolism.

PMID- 10593430
TI  - Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy.
AB  - Venous thromboembolism remains an important cause of maternal mortality. For
      women at risk during pregnancy, the recommended venous thromboembolismprophylaxis
      is unfractionated heparin. Low molecular weight heparins, such as dalteparin,
      also may be suitable, but randomised trials have not been performed. Pregnant
      women (105) with confirmed previous or current thromboembolism were randomised to
      receive either unfractionated heparin twice daily (mean 20569 IU/day) or
      dalteparin once daily (mean 4631 IU anti-factor Xa units/day) subcutaneously for
      thromboprophylaxis during pregnancy and postpartum period. Recurrence of venous
      thromboembolism and safety of treatments were assessed. Dalteparin administered
      once daily was safe and effective in thromboprophylaxis during pregnancy and
      postpartum.

PMID- 10593431
TI  - Monocyte tissue factor response is decreased in patients with hyperlipidemia.
AB  - Monocytes are potent regulators of blood coagulation through the expression of
      tissue factor (TF) on stimulation and of tissue factor pathway inhibitor (TFPI),
      a selective inhibitor of TF pathway. As hyperlipidemia can modify some monocyte
      functions, we compared the TF and TFPI expression by circulating monocytes and
      the plasma TFPI levels between 65 healthy normolipemic controls and 38 nontreated
      hyperlipemic patients. TF and TFPI relationships with plasma lipoproteins are
      also examined. TF and TFPI expression were evaluated in peripheral mononuclear
      cells after isolation from blood by density gradient centrifugation and after
      short culture with or without lipopolysaccharide (LPS). TF and TFPI activity and
      antigen were measured in mononuclear cell lysates using amidolytic assay and
      enzyme-linked immunosorbent assay, respectively. TFPI activity and antigen were
      measured in plasma using the same methods. Plasma factor VII (FVII) activity and
      antigen were also determined. LPS-stimulated monocyte TF activity and antigen
      were lower in hyperlipidemic patients than in controls (0.0001<p<0.03). This
      decrease of monocyte TF expression in hyperlipidemic patients was not related to
      an increase of monocyte TFPI. Monocyte TF activity was negatively correlated to
      atherogenic fractions and positively correlated to protective fractions,
      specially after ex vivo LPS stimulation. Increased TFPI and FVII plasma levels
      were found in hyperlipidemic patients compared to controls. These results
      indicate an impairment of TF production by circulating monocytes from
      hyperlipidemic subjects, which is linked to the increase of atherogenic
      lipoprotein fractions. Further studies are required to elucidate the mechanism of
      this inhibition.

PMID- 10593432
TI  - Observer dependency of the SimpliRed D-dimer assay in 81 consecutive patients
      with suspected pulmonary embolism.
AB  - The SimpliRed D-dimer assay is a whole blood agglutination test for the exclusion
      of pulmonary embolism (PE) and has been advocated as a reliable rapid bedside
      alternative to more time-consuming quantitative assays. However, widely differing
      negative predictive values (77-100%) are reported. This study assessed the intra-
      and interobserver variability as a possible cause for this wide accuracy range
      and evaluated the accuracy of the SimpliRed test in 81 consecutive patients with
      clinically suspected PE. Absolute D-dimer concentration was measured using the
      Tinaquant (Roche Diagnostics GmbH, Mannheim, Germany) assay. Every assay was
      immediately scored by one observer and then photographed. Photos were randomised
      and read twice by two other independent observers. The intraobserver
      reproducibility was good: kappa=0.81 and 0.73. However, we found poor
      interobserver reproducibility with kappa=0.47. This seems due to the fact that
      the SimpliRed test proved difficult to interpret in the 0.3-1.3 microg/mL plasma
      concentration D-dimer range, which contained 32/81 (40%) patients, 8 of whom had
      PE. Using pulmonary angiograms and ventilation perfusion lung scans with a
      concurrent spiral computed tomography scan as a gold standard (25 patients had
      PE), SimpliRed's accuracy to exclude PE was moderate, with negative predictive
      values of 0.78 and 0.84. In particular, the two observers scored the SimpliRed
      test as normal in 12 of 25 and 5 of 25 patients with proven PE. We conclude that
      SimpliRed is strongly observer-dependent. This explains the varying sensitivities
      for the detection of venous thromboembolism as reported in previous studies.

PMID- 10593433
TI  - Inhibitory mechanisms of dantrolene on platelet aggregation.
AB  - The antiplatelet effect of dantrolene and possible inhibitory mechanisms were
      studied in rabbit platelets. Preincubation of rabbit washed platelets with
      dantrolene (50-300 microM) inhibited the platelet aggregation and adenosine
      triphosphate release induced by arachidonic acid (100 microM), collagen (10
      microg/mL), or thrombin (0.1 U/mL) in a dose-dependent manner. The thromboxane B2
      formation caused by collagen or thrombin was inhibited by dantrolene, while
      formation of thromboxane B2 and prostaglandin D2 induced by arachidonic acid were
      not inhibited. In addition, the formation of phosphoinositide breakdown and the
      rise of intracellular calcium level induced by collagen or thrombin were also
      inhibited in a dose-dependent manner by dantrolene in the presence of
      indomethacin (2 microM). However, the platelets cyclic AMP level was not affected
      by dantrolene. In conclusion, the present study demonstrates that dantrolene
      inhibits platelet activation mainly due to suppression of phosphoinositide
      breakdown.

PMID- 10593434
TI  - Influence of hyperbaric oxygen on leukocyte functions and haemostasis in normal
      volunteer divers.

PMID- 10593435
TI  - Low molecular weight heparin for thromboprophylaxis during caesarean section.

PMID- 10593436
TI  - The prothrombin gene G20210A mutation and the platelet glycoprotein IIIa
      polymorphism PlA2 in patients with central retinal vein occlusion.
AB  - The prothrombin gene G20210A mutation and the platelet glycoprotein IIIa
      polymorphism PlA2 have been shown to be associated with thromboembolic disease.
      We wondered if mutations were overrepresented in patients with central retinal
      vein occlusion. We studied 129 consecutive patients with a history of central
      retinal vein occlusion. We analysed for the prothrombin gene G20210A mutation and
      the platelet glycoprotein IIIa polymorphism PlA2 and compared the results to
      controls with no history of thrombosis. For the platelet glycoprotein IIIa
      polymorphism PlA2, 69% were normal, 26% were heterozygous, and 5% were
      homozygous. For the G20210A prothrombin mutation, 97% were normal and 3% were
      heterozygous. Neither the prothrombin gene G20210A mutation nor the platelet
      glycoprotein IIIa polymorphism PlA2 seem to be associated with central retinal
      vein occlusion.

PMID- 10593437
TI  - A simple method for the isolation, cultivation, and characterization of
      endothelial cells from rabbit coronary circulation.

PMID- 10593438
TI  - Facial changes in extraction and nonextraction patients.

PMID- 10593439
TI  - Craniofacial imaging in orthodontics: historical perspective, current status, and
      future developments.
AB  - Rapid and substantial advances in imaging methods and technology have not always
      been expediently or adequately communicated to the practicing orthodontist. In
      this review we highlight contemporary imaging techniques and innovations in
      imaging that, in the future, are likely to greatly improve the depiction of
      craniofacial structures for use in diagnosis and treatment planning. In order to
      provide an appropriate background for this topic, we first discuss the evolution
      of craniofacial imaging in orthodontics and review the limitations of current
      methods, including the two-dimensional representation of three-dimensional
      anatomy, depiction as a patchwork of site-specific images, associated geometric
      errors, and images that have a limited point of view and are static in space and
      time. Three-dimensional computed tomography can be considered a partial solution
      to these limitations, but imaging costs, radiation exposure, and lack of soft
      tissue representation may make it unacceptable for routine orthodontics. A more
      complete solution might be achieved through digital processing of contemporary
      imaging technologies that would extend their capabilities, overcome many of their
      limitations, and result in an increase in the amount of relevant information
      obtained. Digital processes are currently being developed that create accurate
      multidimensional models that integrate form and function. These models will be
      interactive, linked to knowledge databases, and will provide the clinician with
      answers to pertinent questions. These advances in imaging are likely to enhance
      the accuracy and reliability of orthodontic diagnosis and treatment planning, and
      will be of importance in both clinical practice and research.

PMID- 10593440
TI  - Allometry of the cranial base in prepubertal Korean subjects with class III
      malocclusions: finite element morphometry.
AB  - Sphenoethmoidal allometry could be associated with ethnic heterogeneity of the
      midfacial profile. Thirteen cranial base landmarks were digitized from
      cephalographs of 69 Korean and 73 European American prepubertal children
      exhibiting Class III malocclusion. Average geometries were normalized, and a
      color-coded finite element (FEM) program was used to localize differences in
      morphology. ANOVA indicated that mean Korean and European American cranial base
      configurations differed statistically (p < 0.01); this was also true for seven
      age groups tested (p < 0.001). For size-change, FEM analysis revealed that in the
      anterior cranial base, Korean sphenoethmoidal and sella turcica regions were
      smaller (=12%). Local increases in size were apparent for the posterior region of
      the Korean cranial base (=35%). For shape-change, Korean and European American
      cranial base configurations were isotropic with minor anisotropy in the
      sphenoethmoidal and spheno-occipital regions. A sphenoethmoidal mechanism of
      midfacial retrognathism appears to be implicated in the development of a skeletal
      Class III morphology.

PMID- 10593441
TI  - Effect of appliance reactivation after decay of initial activation on
      osteoclasts, tooth movement, and root resorption.
AB  - Clinical orthodontists frequently reactivate appliances following decay. Studies
      of tooth movement and tissue responses following reactivations indicate that
      linear tooth movement and rapid recruitment of osteoclasts can be achieved if
      reactivation is timed to coincide with the latter part of the bone remodeling
      cycle initiated by the first activation. Both can be delayed if reactivations are
      timed for the early part of the previous cycle. The objective of this study was
      to examine tooth movement, root resorption, and osteoclast recruitment following
      appliance reactivation after the first activation had decayed. Bilateral
      orthodontic appliances were activated with 40 cN in 144 rats to mesially tip the
      maxillary molars. After 16 days, rats were randomized into two groups of 72. In
      group 1, appliances were reactivated in precisely the same manner as the first
      activation. In group 2, appliances were sham-reactivated. Rats were sacrificed at
      1, 3, 5, 7, 10, and 14 days. Orthodontic movement was measured cephalometrically;
      changes in osteoclasts and root resorption were assessed at both compression and
      tension sites histomorphometrically; tartrate-resistant acid phosphatase (TRAP)
      was measured in alveolar bone and serum biochemically. Orthodontic tooth movement
      was linear in group 1, but osteoclasts required 3 to 5 days to appear. There were
      no group- or time-related differences in root resorption. Bone TRAP levels were
      elevated in both groups but dropped significantly (p<0.01) in group 2 at day 7.
      Appliance reactivations that followed decay of the first activation produced
      efficient tooth movement without increased risk of root resorption, but these
      changes were not accompanied by rapid osteoclast recruitment at compression
      sites. Timing appliance reactivations for the latter portion of the previous bone
      remodeling cycle could have significant clinical advantages because the delay
      period seen in tooth movement following a single activation or short-term
      reactivation can be avoided.

PMID- 10593442
TI  - The distribution of clefts of the primary and secondary palates by sex, type, and
      location.
AB  - The frequency and patterns of distribution of cleft lip, cleft lip and alveolus,
      cleft lip and palate, and isolated cleft palate, together with the possible
      association between sex, type of cleft, and affected side were studied from
      records of 278 individuals with clefts. These records were obtained from four
      cleft centers in the New York City area and constituted a racially mixed urban
      sample. The type of the cleft varied between sexes. Males had significantly
      higher rates of cleft lip and palate (p<0.0001), and females had higher rates of
      isolated cleft palate (p<0.0001). No sex differences were found for cleft lip or
      cleft lip and alveolus. Unilateral clefts of both the primary and secondary
      palates were found to occur over three times more frequently than bilateral
      clefts, and left side predominance was demonstrated.

PMID- 10593443
TI  - Standards for permanent tooth emergence in Finnish children.
AB  - Two groups of Finnish children, 1008 from the eastern part of the country and 569
      from the western part, aged 5 to 16 years, were examined to determine the timing
      of permanent tooth emergence and any regional variation therein. The probit
      analysis was used to calculate the median ages of eruption. Permanent teeth in
      the first phase of the mixed dentition erupted earlier and premolars erupted
      later than previously reported for Scandinavian populations. The former finding
      could reflect the secular trend; the latter is probably related to the
      dramatically improved dental health in Finnish children. No regional variation in
      eruption was found. The median ages of eruption of permanent teeth determined in
      the present study are suggested for use as national standards for permanent tooth
      emergence in Finland, separately for girls and boys.

PMID- 10593444
TI  - Dentoalveolar compensation related to variations in sagittal jaw relationships.
AB  - The purpose of this study was to investigate dentoalveolar compensation for
      variations in sagittal jaw relationships in 44 adult females with normal incisor
      relationships and either skeletal Class I or skeletal Class III jaw
      relationships. Cephalometric analysis was performed to evaluate sagittal jaw
      relationship, maxillary and mandibular incisor inclination, and the cant of the
      occlusal plane. Molar relationships were evaluated from study models. Correlation
      analysis was performed between skeletal and dental measurements. The most
      appropriate cephalometric parameters describing dental compensation
      quantitatively were SN-AB as a skeletal measurement and SN-U1, SN-L1, and SN-OP
      as dental measurements. Among the compensatory dentoalveolar changes, lower
      incisor inclination was strongly related to the sagittal jaw relationship and
      played an important role in obtaining a normal incisor relationship. Compensatory
      changes in the occlusal plane angulation were slight when compared with changes
      in the incisor regions. A Class I molar relationship was rare when SN-AB exceeded
      84 degrees, even when incisor relationships were normal.

PMID- 10593445
TI  - C-axis: a growth vector for the maxilla.
AB  - Based on M-point, defined as the center of the largest circle that is tangent to
      the superior, anterior, and palatal outlines of the maxilla in the sagittal view,
      a growth axis and its direction are described for each gender from age 7.4 to
      18.75 years. Growth increments along the C-axis, defined by sella-M-point, are
      described by regression formulas with correlation coefficients of 0.618 for
      females and 0.669 for males. The vector (direction) of the growth axis, defined
      by the angle S-M-C-axis, increases in females from 42.21 degrees at 7.4 years to
      44.47 degrees at 18.75 years, with a standard deviation of 3.55 degrees. In
      males, it increases from a mean of 41.69 degrees at 7.6 years to 45.55 degrees at
      18.6 years, with a standard deviation of 2.74 degrees. This is based on 172
      serial lateral cephalograms of 20 females and 174 serial lateral cephalograms of
      19 males. The C-axis incremental growth change and its vector offer a means of
      quantifying complex maxillary growth in the sagittal plane via cephalometric
      measurements relative to and coordinated with other craniofacial structures.

PMID- 10593446
TI  - Maxillary protraction and chincap appliance treatment effects and long-term
      changes in skeletal class III patients.
AB  - The purpose of this study was to investigate the orthopedic effects of combined
      maxillary protraction appliance (MPA) and chincap therapy on growing Japanese
      girls and the posttreatment changes after growth is complete. To estimate the
      actual effects of treatment and posttreatment changes, we used a series of
      templates that had been constructed from semilongitudinal data of Japanese girls
      with normal occlusion. During treatment, forward movement of the maxilla with
      counterclockwise rotation, and backward and downward movement of the mandible
      with clockwise rotation and growth retardation were observed. The forward
      movement of the maxilla persisted until growth was complete. During the
      posttreatment period, the mandible maintained its improved position but showed
      excessive growth, which could be a rebound change. These results indicate that
      combined MPA and chincap treatment is effective for correcting skeletal Class III
      malocclusion.

PMID- 10593447
TI  - Orthodontics and the millennial mechanical ideal.

PMID- 10593448
TI  - The neuropathological effects of antipsychotic drugs.
AB  - In addition to their neurochemical effects, antipsychotic (neuroleptic) drugs
      produce structural brain changes. This property is relevant not only for
      understanding the drugs' mode of action, but because it complicates morphological
      studies of schizophrenia. Here the histological neuropathological effects of
      antipsychotics are reviewed, together with brief mention of those produced by
      other treatments sometimes used in schizophrenia (electroconvulsive shock,
      lithium and antidepressants). Most data come from drug-treated rats, though there
      are also some human post-mortem studies with broadly congruent findings. The main
      alteration associated with antipsychotic medication concerns the ultrastructure
      and proportion of synaptic subpopulations in the caudate nucleus. In rats,
      synapses and dendrites in lamina VI of the prefrontal cortex are also affected.
      The changes are indicative of a drug-induced synaptic plasticity, although the
      underlying mechanisms are poorly understood. Similarly, it is unclear whether the
      neuropathological features relate primarily to the therapeutic action of
      antipsychotics or, more likely, to their predisposition to cause tardive
      dyskinesia and other motor side-effects. Clozapine seems to cause lesser and
      somewhat different alterations than do typical antipsychotics, albeit based on
      few data. There is no good evidence that antipsychotics cause neuronal loss or
      gliosis, nor that they promote neurofibrillary tangle formation or other features
      of Alzheimer's disease.

PMID- 10593449
TI  - Differential olanzapine plasma concentrations by sex in a fixed-dose study.
AB  - This study examined plasma concentrations of olanzapine by sex (20 males and
      seven females) in an 8-week fixed-dose study. Dosing was 12.5 mg/day for the
      first week, then 25 mg/day. Trough plasma concentrations were drawn at weeks 1,
      3, 5 and 8. Women volunteers were found to have significantly higher plasma
      concentrations than men. This difference was first evident at study week 5. Women
      have higher plasma concentrations of olanzapine, possibly due to differences in
      metabolism of the CYP450 isoenzyme system.

PMID- 10593450
TI  - Measuring neuroleptic-induced akathisia by three-channel actometry.
AB  - Three-channel actometry was used to study neuroleptic-induced akathisia (NIA), a
      common and often serious disorder in association of traditional neuroleptic
      therapy. The aim was to explore the diagnostic possibilities of actometry in NIA
      and to examine in detail the motor phenomenology of the disorder in detail. The
      actometers were attached to the ankles and waists of ten patients, suffering from
      NIA, and to ten matched healthy controls. Five of the patients were changed to
      olanzapine treatment, and these patients were re-examined during the no-NIA
      condition. NIA was associated with manyfold movement activity during controlled
      rest (sitting) but not with increased daily overall motor activity. Movement
      frequencies in NIA seemed to be pathognomonic. Actometry is promising for
      investigation and clinical assessment of NIA. Olanzapine proved to be an adequate
      treatment choice for NIA patients.

PMID- 10593451
TI  - Lack of normal pattern of cerebral asymmetry in familial schizophrenic patients
      and their relatives--The Maudsley Family Study.
AB  - Lack of the normal cerebral asymmetry has been reported in schizophrenia. We
      wished to test the hypothesis that this lack of the normal pattern of asymmetry
      is familial and that it can be found in both schizophrenic and non-schizophrenic
      family members. In particular, we wanted to know whether those relatives who
      appear to be transmitting liability to the illness also demonstrate the loss of
      normal asymmetry. We studied families with several members affected with
      schizophrenia. We carried out volumetric measurements of prefrontal, premotor,
      sensorimotor and occipitoparietal regions in each hemisphere using 3D
      reconstructed MRI images in 29 schizophrenic patients, 55 of their first degree
      relatives, and 39 unrelated control subjects on contiguous thin slices of the
      brain. Nine of the unaffected relatives appeared to be transmitting the liability
      for schizophrenia (e.g. the mother of a schizophrenic patient who, although not
      psychotic herself, had a schizophrenic parent or sibling). We termed them
      presumed obligate carriers and the remaining 46 relatives presumed non-obligate
      carriers. The healthy control subjects showed larger right than left prefrontal
      regions and larger left than right sensorimotor and occipitoparietal regions. The
      schizophrenic patients showed lack of this normal brain asymmetry in the
      prefrontal, sensorimotor and occipitoparietal cortical regions. The presumed
      obligate carriers were similar to the schizophrenic patients in exhibiting lack
      of asymmetries in these cortical regions, while the presumed non-obligate
      relatives showed lack of asymmetry only in the occipitoparietal region. There was
      no overall reduction in total or regional brain volumes among the groups. Our
      findings indicate that lack of the normal pattern of frontal and occipital
      asymmetry is a marker for genetic liability to schizophrenia in families multiply
      affected with schizophrenia.

PMID- 10593452
TI  - Poor perception of nonverbal social-emotional cues in relatives of schizophrenic
      patients.
AB  - The present study compared nonverbal social perception in relatives of
      schizophrenic patients (n = 21) with that of normal controls (n= 19). We
      hypothesized that relatives would display deficits in social perception and we
      sought to determine the skills that are associated with this deficit. Relatives
      performed significantly worse than controls on the Profile of Nonverbal
      Sensitivity Test (PONS), despite comparable performance on skills hypothesized to
      be related to nonverbal social perception: visual perception, nonverbal problem
      solving, facial recognition, facial affect recognition, naming, social judgment,
      and vigilance. To further explore the relationships among these skills, we
      calculated correlations between the PONS score and associated skills separately
      within both the relative and control groups and assessed whether the values of
      these correlations differed between groups. Correlations that differed
      significantly indicated a greater association, within relatives, between slower
      reaction times on vigilance tasks and poor PONS performance. Further research is
      needed to clarify the nature of this relationship, to better characterize social
      perception deficits in relatives, and to determine whether these perceptual
      deficits are part of the genetic diathesis to schizophrenia.

PMID- 10593454
TI  - Enduring negative symptoms in first-episode psychosis: comparison of six methods
      using follow-up data.
AB  - Targeted intervention in the early treatment of enduring positive and negative
      symptoms in first-episode psychosis is contingent on adequate case-identification
      procedures. Six methods of determining enduring negative symptoms in a sample of
      238 individuals with first-episode psychosis who were assessed at three time
      points over a 12-month period are described. Results were examined at each of the
      seven combinations of follow-up points, revealing a highly fluid pattern. The
      percentage of the sample achieving caseness varied dramatically, depending on the
      method used. Compared with non-cases, the enduring negative symptom group had
      significantly lower scores on quality of life, poorer premorbid adjustment, and
      longer durations of prodrome and untreated psychosis. Notwithstanding the 'ebb
      and flow' of negative symptoms in first-episode psychosis, the results suggest
      that early identification of enduring negative symptoms is a feasible goal.

PMID- 10593453
TI  - Intermittent degradation in performance in schizophrenia.
AB  - In a series of repeated trials, schizophrenic patients often fluctuate in
      performance. Our data suggest that it may be useful, not just to report an
      increased variance relative to nonschizophrenics, but to model these fluctuations
      concretely as transitions between a relatively normal and an abnormal cognitive
      state - an intermittent degradation in performance that may be related to
      transient abnormalities in CNS functioning. We define 'dialipsis' as a temporary
      substitution of a less efficient process of task performance. This phenomenon is
      mentioned in the literature, but the descriptions of dialipsis are heuristic
      rather than based on a statistical model. We present a mixture model in which the
      ordinary and degraded states are described by distinct ANOVA structures, each
      with its own task, subject and interaction effects, with transitions between them
      occurring at random times. We discuss ways of detecting dialipsis and comparing
      the mixture model statistically with alternative models.

PMID- 10593455
TI  - An event-related potential study in schizophrenia using Japanese sentences.
AB  - To examine the neurophysiological and cognitive characteristics of language
      disorder in schizophrenia, the N400 component and late positive component (LPC)
      of event-related potentials (ERPs) were investigated in medicated schizophrenic
      patients and health comparison subjects. The subjects were required to indicate
      whether Japanese sentence completions were semantically congruous or incongruous.
      The ERPs for the range of 300-500 ms to the incongruous completions contained a
      more negative component (N400), followed by LPC, which was inversely more
      positive for the incongruous than congruous condition. The N400 effect and the
      mean amplitude of the LPC were reduced in the patients. The attenuated N400
      effect in schizophrenics mainly originated from an enhanced negativity for the
      congruous completions, suggesting that the use of context is poor in
      schizophrenia.

PMID- 10593456
TI  - Lack of association between tryptophan hydroxylase gene and psychotic
      symptomatology in schizophrenia.

PMID- 10593457
TI  - Citation analysis and journal impact factors--is the tail wagging the dog?

PMID- 10593458
TI  - Warming of insufflation gas during laparoscopic hysterectomy: effect on body
      temperature and the autonomic nervous system.
AB  - BACKGROUND: Hypothermia is a known side effect of laparoscopic operations. It may
      increase the sympathetic activity of the autonomic nervous system (ANS), which
      can be evaluated noninvasively by heart rate variability (HRV). We tested the
      hypothesis that warming of the delivered CO2 insufflation gas helps to maintain
      the normal body temperature. METHODS: Thirty-seven healthy women undergoing
      laparoscopic hysterectomy were randomized into heated (37 degrees C, n=18) or
      unheated (24 degrees C, n = 19) gas insufflation groups. Anesthesia was induced
      with propofol and maintained with sevoflurane in O2-air. Tympanic (ttymp)
      temperature was recorded before, during and after the operation. Nasopharyngeal
      (tnaso) temperature was recorded only during operation. Electrocardiograms were
      recorded and stored to evaluate changes in HRV. The individual changes in HRV
      were compared after decibel (dB) transformation. RESULTS: A median decrease in
      tympanic temperatures during the operation was 0.7 degrees C in the heated and
      0.3 degrees C in the unheated group (P = 0.01 between groups), and in
      nasopharyngeal 0.3 degrees C and 0.1 degrees C (P = 0.03), respectively.
      Preanesthetic tympanic values were reached within 90 min after anesthesia. After
      dB transformation, HRV high frequency power differed between the groups. It was
      better preserved in the patients receiving unheated gas. CONCLUSION: The heating
      of insufflation gas does not prevent a decrease in body temperature and is thus
      unnecessary during laparoscopic hysterectomy.

PMID- 10593459
TI  - The effects of two rewarming strategies on heat balance and metabolism after
      coronary artery bypass surgery with moderate hypothermia.
AB  - BACKGROUND: Postoperative hypothermia is common in cardiac surgery with
      hypothermic cardiopulmonary bypass (CPB). This trial was designed to evaluate
      whether rewarming over the normal bladder temperature (over 37 degrees C) at the
      end of hypothermic CPB combined with passive heating methods after CPB might
      result in a better heat balance, lower energy expenditure (EE) and decrease of
      disturbances in oxygen balance compared to only rewarming the patients to a
      bladder temperature of 35-37 degrees C. METHODS: A prospective, randomized
      controlled clinical study was performed in 38 patients scheduled for elective
      coronary artery bypass surgery. Twenty patients (group C) were rewarmed to a
      bladder temperature of 35-37 degrees C at the end of hypothermic (28 degrees C)
      CPB. Eighteen patients (group W) were rewarmed to a bladder temperature of 37
      38.5 degrees C. RESULTS: At the end of CPB, the bladder temperature was 36.2+/
      0.7 degrees C (mean+/-SD) in group C and 37.9+/-0.5 degrees C in group W. After
      half an hour's stay in the ICU, the mean body temperature (MBT) was 35.1+/-0.6
      degrees C in group C and 36.6+/-0.7 degrees C in group W. During the following
      five hours, MBT increased to 37.4+/-0.8 degrees C in group C and to 38.0+/-0.6
      degrees C in the other group. The peak value of EE in the ICU was 1.73+/-0.44
      (group C) vs 1.35+/-0.29 (W/kg) (group W) (P=0.003). EE was significantly
      (P=0.044) higher in group C than in the other group between 1.5 and 5.5 h in the
      ICU. The increased energy expenditure due to heat production was associated with
      an increase in O2 consumption (VO2) 61.6+/-30.4% vs 25.2+/-24.1%, (peak values)
      compared to the basal values of the two groups measured before anesthesia
      (between groups P<0.001). Between 1.5 and 5.5 h in the ICU, group C had
      significantly higher VO2 (P=0.026), CO2 production (P=0.017), venous pCO2
      (P<0.001) and minute ventilation (p=0.014) than group W. Venous pH was lower
      (P<0.001) in group C. The peak value of oxygen extraction was also higher
      (P=0.045) in group C. On the other hand, the lowest value of venous oxygen
      saturation was higher (P=0.04) in group W. CONCLUSION: With rewarming the
      patients at the end of CPB to a bladder temperature of over 37 degrees C combined
      with passive heating methods after CPB, it was possible to decrease EE and VO2
      compared to the control group (rewarmed to bladder temperature of 35-37 degrees
      C) after coronary artery bypass surgery with moderate hypothermia.

PMID- 10593461
TI  - Changes in stroke volume cause change in cardiac output in neonates and infants
      when mean airway pressure is altered.
AB  - BACKGROUND: Based on early studies in the lamb, and in spite of more recent
      studies in humans, it has been the received opinion that neonates and infants can
      not change their stroke volume significantly, but are mainly dependent on changes
      in heart rate, to change cardiac output. To further evaluate the relationship
      between cardiac output and stroke volume during mechanical ventilation of
      neonates and infants, we have studied the effects on cardiac output and stroke
      volume by two different ways of changing mean airway pressure. METHODS: In one
      group, mean airway pressure was decreased by using a patient triggered mode:
      pressure support ventilation; in the other, mean airway pressure was increased by
      increasing positive end-expiratory pressure (PEEP). Changes in cardiac output,
      heart rate and stroke volume were assessed with the Doppler technique, measuring
      blood flow velocity in the ascending aorta. RESULTS: Without a significant change
      in heart rate, we found a significant increase in cardiac output of +16+/-2%
      (P<0.01) with a decrease in mean airway pressure and a decrease in cardiac output
      of -13+/-4%, (P<0.02) with an increase in mean airway pressure, depicting a
      change in stroke volume of +17+/-2% (P<0.02) and -14+/-5%, (P<0.01) respectively.
      CONCLUSIONS: We conclude that neonates and infants are able to regulate cardiac
      output by changing the stroke volume to a greater extent than presumed, at least
      when cardiac output is influenced by changes in the mean airway pressure.

PMID- 10593460
TI  - The interaction of temperature with thiopental and etomidate on extracellular
      dopamine and glutamate levels in Wistar-Kyoto rats subjected to forebrain
      ischemia.
AB  - BACKGROUND: Many studies demonstrate an association between brain damage and the
      extracellular release of catecholamines and amino acids during cerebral ischemia.
      While the clinical value of hypothermia during periods of compromised cerebral
      blood flow and oxygen delivery is well established, the role of anesthetic agents
      is less clear. Furthermore, the interaction between these agents and hypothermia
      remains to be elucidated. The purpose of this study was to examine the
      interactive effects of temperature, sodium thiopental (STP) and etomidate (ETOM)
      on extracellular neurotransmitter accumulation in the rat corpus striatum during
      cerebral ischemia. METHODS: Animals were randomly assigned to one of six
      subgroups: normal saline (NS-norm, pericranial t approximately equal to 37
      degrees C, and NS-hypo, t=30 degrees C), etomidate (ETOM-norm and ETOM-hypo), and
      sodium thiopental (STP-norm and STP-hypo). Microdialysis probes were inserted
      into the corpus striatum. Dopamine (DA), glutamate, 3,4-dihydroxyphenylacetic
      acid (DOPAC) and homovanillic acid (HVA) levels were measured. At zero minutes,
      animals received a 10-min infusion of STP (3 mg x kg(-1) x min(-1)), ETOM (0.6 mg
      x kg(-1) x min(-1)), or NS. Prior to ischemia, animals were given either
      intravenous STP (10 mg x kg(-1)), ETOM (3 mg x kg(-1)), or NS in bolus form. Each
      animal was then subjected to 10 min of forebrain ischemia (Is1) followed by a
      reperfusion interval (Rep1). The entire sequence was then repeated. RESULTS:
      There were significant interactions between temperature and drug for DA (Is1,
      P=0.006, Is2, P=0.032) and its metabolites (DOPAC, Is1 P=0.01, HVA, Is1 P=0.03),
      and for glutamate (Is1, P=0.03, Is2 P=0.06). The nature of this interaction
      differed for DA and glutamate. The reduction in DA accumulation seen during
      hypothermia was offset by the addition of either STP or ETOM, whereas the
      addition of these drugs did not affect the reduced glutamate levels seen with
      hypothermia. During normothermia, STP and ETOM resulted in diminished DA
      accumulation compared to controls, yet they increased the accumulation of
      extracellular glutamate. CONCLUSIONS: Consistent with other studies, hypothermia
      was associated with diminished extracellular DA concentrations during forebrain
      ischemia. However, depending on the temperature condition, the addition of STP or
      ETOM in our forebrain ischemia model led to unexpected findings. The
      administration of these agents during normothermia diminished ischemia-induced DA
      accumulation yet resulted in significantly higher concentrations of extracellular
      glutamate. In contrast, STP and ETOM during hypothermia were noted to
      significantly offset the DA-reducing effects of hypothermia.

PMID- 10593462
TI  - Mild hypothermia does not increase blood loss during total hip arthroplasty.
AB  - BACKGROUND: The effects of mild hypothermia on blood loss are little known.
      METHODS: Patients, undergoing primary prosthetic hip surgery under spinal
      anaesthesia, were randomised to the operative procedure, with (n=25) or without
      (n=25) forced air warming. Core temperature was repeatedly measured from the
      tympanic membrane. The blood loss was calculated by three different methods; the
      intraoperative loss was estimated visually. The loss during and after the
      operation was obtained by determination of lost haemoglobin (the Hb-method). The
      blood loss during hospital stay was also calculated from the haemoglobin balance.
      RESULTS: Among controls, core temperature decreased by 1.3+/-0.6 degrees C
      (mean+/-SD) and in the warmed patients 0.5+/-0.4 degrees C (P<0.0001).
      Preoperative variables and the number of allogeneic units transfused did not
      differ between the groups. In controls, the blood loss during operation was, with
      the visual method, 698+/-314 ml, compared with 665+/-292 ml in warmed patients.
      With the Hb-method, the loss was 662+/-319 and 657+/-348 ml, respectively. With
      this method, the external loss during the entire hospital stay was, in controls,
      1066+/-441 ml and in the warmed group, 1047+/-413 ml. The balance method yielded
      1674+/-646 ml and 1507+/-652 ml, respectively. Indices of blood loss did not
      differ significantly between groups and there was no covariation between those
      variables and the decrease in core temperature. CONCLUSIONS: Forced air warming
      did not decrease the blood loss. Methods for determination of blood loss yielded
      widely differing results.

PMID- 10593463
TI  - Ketamine does not inhibit inflammatory responses of cultured human endothelial
      cells but reduces chemotactic activation of neutrophils.
AB  - BACKGROUND: Ketamine is a widely used general anaesthetic, which has been
      reported to inhibit neutrophil function and neutrophil-endothelial interaction.
      To date, however, it is unknown whether ketamine has any direct effects on
      endothelial cells with respect to inflammation. Therefore, we investigated the
      influence of varying concentrations of ketamine (0.5, 1, and 3 microM) on the
      endothelial expression of cytokines and adhesion molecules with relevance for
      inflammation. METHODS: Cultured human umbilical vein endothelial cells were
      stimulated with tumor necrosis factor alpha (TNFalpha, 2.5 ng/ml) for 4 h in the
      absence or presence of ketamine. The adhesion molecules ICAM-1 and E-selectin on
      the endothelial cells were measured by flow cytometry. Release of the
      proinflammatory cytokines IL-6 and IL-8 by endothelial cells was quantified by
      ELISA. The acute effect of ketamine on leukocyte activation by the supernatant of
      endothelial cells pre-stimulated with TNFalpha (4 h) was tested by flow
      cytometric measurement of CD11b, a leukocyte activation marker, after 15 min of
      coincubation. RESULTS: TNFalpha caused dramatic upregulation of both adhesion
      molecules (15-fold and 5-fold vs. control for ELAM-1 and ICAM-1, respectively)
      and of both cytokines (500-fold and 1.8-fold for IL-6 and IL-8, respectively). No
      concentration of ketamine employed in our study had any effect on these
      inflammatory parameters. However, activation of leukocytes by supernatant of
      TNFalpha-conditioned endothelial cells (70% increase of CD11b) was attenuated by
      coincubation of the PMN with 0.5 and 5 microM ketamine (47% and 44% increase,
      respectively). CONCLUSION: These data suggest that ketamine exerts its
      antiinflammatory actions primarily via inhibition of leukocyte reactivity.
      Indeed, no inhibition of endothelial responses was detectable in our study.

PMID- 10593464
TI  - Passive expiratory flow-volume curve is not an accurate method to measure the
      respiratory time constant in rabbits.
AB  - BACKGROUND: In mechanically ventilated patients, inspiration is forced by an
      externally applied positive pressure whereas expiration remains passive and
      depends on the time constant of the total respiratory system (tau), which
      constitutes an important determinant of mechanical ventilation. The end
      inspiratory occlusion technique is one of the easiest methods to obtain tau
      values in ventilated patients, especially infants, but its accuracy is not well
      established. The aim of this study was to compare in anesthetized, paralyzed
      rabbits tau values given by the end-inspiratory occlusion technique (tau(rs)) to
      tau values obtained by references methods for measurements (i.e. the product of
      static lung compliance by airway resistance: tau(ref)) during carbachol-induced
      bronchospasm eliciting marked modifications of the respiratory mechanics.
      METHODS: Comparisons were made in the basal state and after carbachol-induced
      bronchoconstriction in seven New Zealand adult rabbits. This procedure resulted
      in a wide range of expiratory time constants. A pneumotachograph was used to
      measure expiratory flow and volume before and after end-inspiratory occlusion.
      The slope of the flow volume curve gave tau(rs). Then tau(rs) was compared with
      tau(ref) (which ranged from 0.30 to 1.96 s). RESULTS: Statistical analysis
      revealed a weak correlation between the two methods, and a size-dependent bias of
      tau(rs) measurements. CONCLUSIONS: The end-inspiratory occlusion technique leads
      to a systemic bias in measurements of respiratory time constant, especially when
      the resistance of the respiratory system is elevated.

PMID- 10593465
TI  - Intraarticular, epidural, and intravenous analgesia after total knee
      arthroplasty.
AB  - BACKGROUND: After total knee arthroplasty, patients regularly suffer from severe
      pain. It is unclear whether epidural or systemic pain therapy is superior in
      terms of postoperative pain relief, patients' comfort and side effects. A new
      therapeutic approach, intraarticular opioids, has been suggested with the
      detection of opioid receptors in inflamed tissue. This method has proven suitable
      for clinical use in small operations (e.g. knee arthroscopy). In this study, we
      compared epidural analgesia and intraarticular application of morphine plus "on
      demand" intravenous analgesia to "on-demand" intravenous analgesia alone.
      METHODS: Thirty-seven patients, scheduled for total knee arthroplasty, were
      randomly assigned to three treatment groups: in group 1 (EPI) patients received
      bolus doses of morphine via an epidural catheter; in group 2 (IA) an
      intraarticular bolus of 1 mg of morphine was applied at the end of the operation
      with subsequent use of a patient-controlled analgesia (PCA) pump; group 3
      (Control), in which only PCA was provided, served as control for both analgesic
      procedures. Main outcome measures included visual analogue pain scales, total
      morphine consumption, and stress hormones. RESULTS: No statistically significant
      differences in visual analogue pain scales could be detected between the three
      groups. Application of intraarticular morphine did not reduce the amount of
      analgesics required for postoperative analgesia as compared to intravenous
      analgesia alone. Application of epidural morphine significantly suppressed beta
      endorphine release, but did not significantly influence other stress hormones as
      compared to the control group. CONCLUSION: Epidural and intravenous analgesia
      after total knee arthroplasty are equivalent methods of pain relief. In major
      orthopaedic procedures, application of intraarticular morphine does not reduce
      analgesic requirements.

PMID- 10593466
TI  - Effects of intrathecal morphine, clonidine and baclofen on allodynia after
      partial sciatic nerve injury in the rat.
AB  - BACKGROUND: Increased response to mechanical or cold stimulation of hind paws was
      observed in rats with partial sciatic nerve injury as a result of photochemically
      induced ischemia. The present study examined the effects of intrathecal morphine,
      clonidine and baclofen on the allodynia-like responses. METHODS: The left sciatic
      nerves of rats were irradiated for 2 min with an argon ion laser under chloral
      hydrate anesthesia. The threshold of paw withdrawal to mechanical stimulation was
      determined with a series of monofilaments (von Frey hairs). The response to cold
      stimulation was tested by spraying ethyl chloride on the plantar surface of the
      paw. When rats were exhibiting stable mechanical and cold allodynia-like
      behaviors after nerve injury, the effects of i.t. morphine (1, 2, 7 microg),
      clonidine (1, 2, 7 microg) and baclofen (0.1, 0.2, 0.7, 9 microg) in a cumulative
      dose regime were investigated. RESULTS: Intrathecal morphine dose-dependently
      alleviated the mechanical and cold allodynia without inducing motor impairment or
      sedation. Intrathecal clonidine did not alter the response of hind paws to
      mechanical stimulation, but reduced the cold allodynia. Intrathecal baclofen
      reduced the responses of rats to mechanical stimulation only at doses that also
      induced profound motor deficits. CONCLUSIONS: The present data suggest that
      intrathecal morphine, and to some extent clonidine, but not baclofen, alleviated
      the abnormal pain-related behaviors in this new rat model of partial peripheral
      nerve injury. Differences in the pharmacological profile between the present
      model and other models of peripheral nerve injury are discussed.

PMID- 10593467
TI  - Spinal cord morphology after chronic intrathecal administration of adenosine in
      the rat.
AB  - BACKGROUND: The endogenous compound adenosine is known to have various modulatory
      effects both in the peripheral and central nervous system. Adenosine and its
      analogues induce antinociception in animal models when administrated systemically
      and intrathecally (IT), both in acute and chronic models of pain. Before a new
      drug is introduced for spinal pain treatment in humans, experimental studies of
      neurotoxicity must be undertaken. METHODS: This study was performed in rats in
      order to reveal morphological or morphometric signs of spinal cord damage after
      chronic (two weeks) administration of adenosine. After insertion of IT catheters,
      the animals were injected twice a day during two weeks with adenosine (100
      microg) or saline (controls). Potential spinal neurotoxicity was evaluated
      morphologically by light and electron microscopy supplemented by a morphometric
      analysis. RESULTS: There were no signs of histologic changes indicating
      neurotoxic effects by any of the methods of analysis. The morphological findings
      in the adenosine treated rats did not differ in any case from those of the saline
      treated animals. CONCLUSION: The results suggest that chronic IT administration
      of a high dose of adenosine is not associated with neurotoxicity in the rat
      spinal cord.

PMID- 10593468
TI  - Stereoselective pharmacokinetics of ketorolac in children, adolescents and
      adults.
AB  - BACKGROUND: Previous pharmacokinetic studies on racemic ketorolac using
      nonstereoselective analytical methods have indicated that the plasma clearance of
      ketorolac is higher and the volume of distribution greater in children than in
      adults. The aim of this study was to study the stereoselective pharmacokinetics
      of racemic ketorolac in children, adolescents and adults. METHODS: 18 children (6
      11 yrs), 18 adolescents (12-17 yrs) and 18 adults (18-44 yrs) participated in the
      study. At the end of eye surgery they were given intravenous racemic ketorolac
      tromethamine 0.5 mg/kg. Plasma samples were assayed for (R)- and (S)-ketorolac
      with high-pressure liquid chromatography. Clearance (CL), volume of distribution
      at steady state (Vss) and elimination (Vz) and elimination half-life (t1/2,z)
      were calculated with standard methods. Incidence of side-effects were recorded.
      RESULTS: CL, Vss, Vz and t1/2,z were higher (P<0.05) for (S)-ketorolac than for
      the (R)-enantiomer. Vss of the active (S)-enantiomer was higher in children than
      in adolescents (P<0.05) and adults (P<0.001) but the values for CL were similar.
      Due to the higher volume of distribution, t1/2,z was also higher in children than
      in adults. The pharmacokinetics of the (R)-enantiomer were essentially unaffected
      by age. CONCLUSION: On a pharmacokinetic basis, the maintenance dose requirements
      of ketorolac are similar in children, adolescents and adults.

PMID- 10593469
TI  - Lateral infraclavicular plexus block vs. axillary block for hand and forearm
      surgery.
AB  - BACKGROUND: In the last few years infraclavicular plexus block has become a
      method of increasing interest. However, this block has been associated with high
      complication incidences and without advantage in the quality of blockade over the
      axillary approach. We prospectively studied 40 patients (ASA I-III) undergoing
      surgery of the forearm and hand, and investigated the performance of the lateral
      infraclavicular plexus block against an axillary paravascular block to evaluate
      the success rate as well as the extent and quality of blockade. METHODS: Patients
      were randomized into two groups: group I (lateral infraclavicular approach; n=20)
      and group A (axillary approach; n=20). The lateral infraclavicular approach is a
      technique with the coracoid process (CP) as landmark. Alone the sagittal plane,
      the needle is inserted until contact with the CP. The needle is then withdrawn 2
      3 mm and reinserted directly under the CP, until it contacts the brachial plexus
      sheath. Plexus blockade was performed using 40 ml of mepivacaine 1%. Quality of
      sensory and motor block was recorded selectively for each nerve distribution at
      close intervals for 6 h. RESULTS: Successful block according to Vester-Andersen's
      criteria was achieved in 100% of group I and 85% of group A. In group I, a
      pronounced sensory and motor blockade of the musculocutaneous nerve was observed,
      while patients of group A had a weak block of this nerve. In group I, an
      additional spectrum of nerves (thoracodorsal, axillary and medial brachial
      cutaneous nerves) was involved compared to group A. There was no difference among
      groups in onset and duration of block. CONCLUSION: Based on the safe landmark and
      feasibility of this procedure and the additional spectrum of nerve block
      achieved, the application of lateral infraclavicular technique has to be
      reconsidered in clinical practice.

PMID- 10593470
TI  - The pressor response after laryngeal mask or cuffed oropharyngeal airway
      insertion.
AB  - BACKGROUND: Since the cuffed oropharyngeal airway (COPA) has been suggested to
      cause less pharyngeal trauma than the laryngeal mask airway (LMA), we conducted a
      prospective, randomised study to compare haemodynamic changes after placing
      either the COPA or LMA in healthy anaesthetised adults. METHODS: After standard
      midazolam premedication (0.05 mg kg(-1) IV), general anaesthesia (IV propofol 2
      mg kg(-1)) was induced in 60 ASA physical status I-II, 18-65-yr-old patients, who
      were randomly allocated to receive COPA (n=30) or LMA (n= 30) placement and then
      mechanically ventilated using a 60% nitrous oxide and 1% isoflurane in oxygen
      mixture (TV=8 ml kg(-1), RR=12 b.p.m., I/E=1/2). Haemodynamic variables were
      recorded 20 min after the midazolam premedication (baseline), and then every 1
      min until 10 min after general anaesthesia induction. RESULTS: Nine patients of
      group COPA (30%) required chin lift, jaw thrust or head tilt to maintain adequate
      ventilation, while no problems were observed in the LMA group (P<0.0005);
      however, in no case did the designed extratracheal airway have to be removed due
      to unsuccessful mechanical ventilation, and no signs of gastric insufflation or
      regurgitation were reported. The maximum mean changes in haemodynamic variables
      were more marked after LMA placement (SAP: 12%+/-13%; DAP: 11%+/-18%; HR: 13%+/
      16%) than COPA placement (SAP: -3%+/-18%; DAP: -5%+/-16%; HR: 4%+/-13%) (P<0.005,
      P<0.005, and P<0.01 for SAP, DAP and HR, respectively). Group LMA showed higher
      SAP and DAP values than group COPA only during the first 3 min after airway
      insertion. CONCLUSION: In healthy, anaesthetised patients, placing a cuffed
      oropharyngeal airway is associated with smaller cardiovascular changes after
      airway insertion compared with the laryngeal mask airway.

PMID- 10593471
TI  - A survey of current usage of anticholinergic drugs in paediatric anaesthesia in
      Finland.
AB  - BACKGROUND: The aim of this survey was to obtain information about the current
      use of anticholinergic preanaesthetic medication in children. It was carried out
      as a follow-up study of the previous survey amongst Finnish anaesthesiologists in
      1990. METHODS: A questionnaire was send to all members of the Finnish Society of
      Anaesthesiologists. Data from anaesthesiologists taking care of at least three
      paediatric anaesthesias/week (n= 183) were analyzed. RESULTS: In 1998 only one
      third of the Finnish anaesthesiologists routinely used anticholinergics before
      paediatric anaesthesia. The main indications for routine anticholinergic
      premedication were ENT surgery (66%), eye surgery (71%) and endoscopic procedures
      (67%). Anticholinergic drugs were administered principally via the intravenous
      route (90%) briefly before induction of anaesthesia, and glycopyrrolate was the
      most frequently used (66%). CONCLUSION: During the last eight years in Finland
      the routine use of anticholinergic premedication has decreased. As in 1990 the
      anticholinergic prophylaxis is directed to ENT and eye surgery, endoscopic
      procedures and to children younger than 1 year. Use of glycopyrrolate has gained
      popularity at the expense of atropine and scopolamine.

PMID- 10593472
TI  - Xenon inhalation increases airway pressure in ventilated patients.
AB  - BACKGROUND: The inert gas xenon, known as an anaesthetic for nearly 50 years, is
      also used as a contrast agent during computerised tomography (CT)-scanning. As
      xenon has a higher density and viscosity than air, xenon inhalation may increase
      airway resistance. METHODS: In a retrospective study we investigated the effects
      of 33% xenon/67% oxygen on airway pressure and cardio-respiratory parameters in
      37 long-term mechanically ventilated patients undergoing cerebral blood flow
      (rCBF) measurements by means of stable xenon-enhanced CT. RESULTS: Xenon
      administration caused a significant increase in peak airway pressure from 31.6+/
      8.0 cm H2O to 42.7+/-16.9 cm H2O. This effect was reproducible, did not occur
      after reduction of inspiratory flow rate by 50% from 0.56+/-0.15 L x s(-1) to
      0.28+/-0.08 L x s(-1), and vanished immediately after termination of xenon
      delivery. CONCLUSION: Due to the higher density and viscosity of this gas
      mixture, ventilation with xenon/oxygen produces a higher Reynolds' number than
      oxygen/air when given at the same flow rate. This means that during xenon
      ventilation the zone of transition from turbulent to laminar gas flow may be
      located more peripherally (in smaller airways) than during oxygen/air ventilation
      with a subsequent increase in airway resistance. Our results indicate that xenon
      inhalation may cause a clinically relevant increase of peak airway pressure in
      mechanically ventilated patients.

PMID- 10593473
TI  - Effects of propofol on isolated human pial arteries.
AB  - BACKGROUND: The intravenous anaesthetic propofol has been reported to increase
      cerebral vascular resistance in vivo. The underlying mechanisms are not fully
      understood, but may include effects on metabolism and direct effects on the
      vascular smooth muscle. The present study was designed to evaluate the direct
      effects of propofol on human pial arteries. METHODS: We investigated the direct
      effect of propofol (10(-6)-10(-4) M) on isolated human pial arteries at basal
      tension as well as the influence on contractions induced by 5-hydroxytryptamine,
      prostaglandin F2alpha, noradrenaline and potassium chloride. RESULTS: Propofol
      did not change the basal tension. Propofol at 10(-6) and 10(-5) M did not affect
      the concentration-response curves of any of the contractile agents tested.
      Propofol at the supraclinical concentration 10(-4) M reduced the contractions
      induced by all contractile agents. CONCLUSION: Propofol reduces the tone of human
      pial arteries in vitro at supraclinical concentrations, but has no effect on the
      tone at clinically relevant concentrations.

PMID- 10593475
TI  - Ultrasonographically guided percutaneous dilatational tracheostomy after anterior
      cervical spine fixation.
AB  - Patients with anterior cervical spine fixation (ACSF) after acute spinal cord
      injury often require tracheostomy for prolonged ventilatory support and upper
      respiratory tract clearance. The authors report two patients with ACSF who
      underwent a successful ultrasonographically guided percutaneous tracheostomy with
      dilatation forceps technique. Possible advantages of the ultrasonographically
      guided method with dilatation forceps in patients with ACSF are discussed.

PMID- 10593474
TI  - Effects of desflurane on the pig intestinal circulation during hypotension.
AB  - BACKGROUND: The aim of the present study was to analyze the perfusion pressure
      dependency for the splanchnic vascular effects of desflurane (DES). METHODS: We
      measured portal blood flow (QPORT, perivascular ultrasound) and jejunal mucosal
      perfusion (JMP; laser Doppler) in pentobarbital-anesthetized pigs (n=10).
      Experimentally, decreases in mean arterial pressure (MAP) were produced by
      pericardial infusions of dextran. The protocol included sets of measurements at
      incremental doses of DES (1, 2, 4 and 6%) prior to and during pericardial
      infusions. RESULTS: Although QPORT and JMP decreased significantly during
      pericardial infusions, DES, irrespective of dose, did not reduce QPORT until MAP
      had decreased below 65-70 mm Hg. In higher MAP ranges, vasodilation in pre-portal
      tissues was powerful enough to maintain QPORT in spite of concurrent decreases in
      driving arterial pressure, as produced by either DES or pericardial infusion, or
      by a combination of both. We found no effects of DES on JMP even at very low MAP
      (about 40 mm Hg during pericardial infusion), indicating that the normal
      physiological response of the small intestine to redistribute blood flow from
      deeper to more superficial layers during hypotension was unimpaired by DES.
      CONCLUSIONS: Our data suggest a wide dose-tolerability of DES as regards the
      splanchnic circulation during hypotensive states.

PMID- 10593476
TI  - Nitroglycerin relieves laryngospasm.
AB  - Two young healthy non-asthmatic non-smoking patients developed partial
      laryngospasm directly post-anaesthesia extubation after routine varicocelectomy
      and perianal abscess drainage operations under general anaesthesia. Nitroglycerin
      was administered intravenously in a dose of 4 microg/kg for both cases. The
      laryngospasm was completely relieved within a minute of nitroglycerin
      administration in both cases and the relief was maintained thereafter. The two
      cases suggest that nitroglycerin can be effective in the treatment of post
      extubation partial laryngospasm in ASA (class I) patients.

PMID- 10593477
TI  - Metabolic regulation of cardiac output during inhalation anaesthesia in dogs.

PMID- 10593478
TI  - Ultrasonography and percutaneous dilatational tracheostomy.

PMID- 10593479
TI  - Towards an AIDS vaccine: the role of nonhuman primates.
AB  - Over the last 10 years, about 20 human immunodeficiency virus (HIV) vaccine
      candidates have been tried in humans, with disappointing results as gauged by
      limited immune responses or protection against infection. These difficulties
      suggest that a new strategy is needed to test systematically new vaccine
      candidates. That opportunity is now afforded by nonhuman primate models with SIV,
      which have been shown to provide an excellent mirror of HIV infection in humans.
      The recent introduction of SHIVs, chimeric viruses that carry the HIV envelope
      and are able to infect and cause AIDS in monkeys, also has added an important
      additional research tool. These models can be used to address a series of
      questions, including the following: (1) Can protection be provided by partial
      immunity or is sterilizing immunity required? (2) What are the immune parameters
      that best predict protection against a potentially pathogenic challenge? (3) What
      role does mucosal immunity play and can it be induced by practical modes of
      immunization? (4) Can an attenuated virus be selected that is both protective and
      safe? An orderly strategy for the evaluation of vaccine candidates could be
      adopted that would involve several phases: (a) the selection of a limited set of
      challenge models, ranging from very severe to mild and requiring consideration of
      primate species, age, route of infection, and challenge viruses; (b) the
      assessment of candidate vaccines using comparable virus challenges; and (c)
      accelerated testing in humans of any candidate vaccines that have met a 'proof of
      efficacy' in primates.

PMID- 10593480
TI  - Progress and challenges in therapies for AIDS in nonhuman primate models.
AB  - Efforts to develop animal models for human immunodeficiency virus type-1 (HIV-1)
      vaccine testing have focused on lentivirus infection of nonhuman primates. A long
      term goal of this primate research is to utilize the models to understand the
      mechanisms of pathogenesis leading to AIDS. Because the time to disease is
      compressed relative to HIV infection in humans, therapeutic strategies and
      compounds can be tested in nonhuman primate models in a shorter time frame and
      under more controlled conditions than are possible in many clinical studies.
      Recent interventive studies in primates using antiviral drugs or passive immune
      globulin (IgG) have demonstrated that multiple log reductions in plasma virus can
      be achieved and sustained, with accompanying health benefits. Information gained
      about timing and dosage may be of utility in designing clinical studies. The
      development of reliable and predictable animal models for effective therapies and
      vaccines against AIDS remains a critical priority for primate research.

PMID- 10593481
TI  - In vivo adaptation of SHIV(SF162): chimeric virus expressing a NSI, CCR5-specific
      envelope protein.
AB  - The chemokine receptor CCR5 is known to be a critical determinant of human
      immunodeficiency virus (HIV) transmission and pathogenesis in the human host.
      Towards the development of a macaque model to evaluate the efficacy of vaccines
      and therapeutics against infection with CCR5-specific viruses, and to delineate
      the pathogenic properties of such viruses, we constructed a chimeric simian human
      immunodeficiency virus, SHIV(SF162), containing the env, tat, rev, and vpu genes
      from HIV-1(SF162) (R5, MT/NSI) in the context of the molecular clone simian
      immunodeficiency virus, SIV(mac239). Virus generated from this molecular clone
      was used to intravenously infect two juvenile macaques, followed by three
      consecutive serial blood/bone marrow transfusions. Animals infected with parental
      SHIV(SF162) (P1) had detectable levels of viral replication (as determined by
      p27(gag) production) within days of infection; however, viral set-points fell
      below detection by Week 3. Late passage animals (P3 and P4) had a two-log
      increase in the level of plasma p27(gag) antigen. These results demonstrate that
      in vivo serial passage of the R5-specific SHIV(SF162) enhanced its replicative
      capacity.

PMID- 10593483
TI  - The disruption of macaque CD4+ T-cell repertoires during the early simian
      immunodeficiency virus infection.
AB  - T-cell receptor (TCR) complementarily determining region 3 (CDR3) spetratyping
      analysis was employed to assess the ability of an AIDS virus to disrupt CD4 + T
      cell repertoires during the primary infection. Rhesus and pig-tailed macaques
      infected with simian immunodeficiency virus (SIV)mac 251 and SIVsmmFGb,
      respectively, were evaluated. Following SIV infection, the macaques exhibited an
      apparent decline of CD4 + peripheral blood lymphocyte (PBL) counts, which was
      associated with a change in CDR3 profiles from multiple-length distribution to
      one- or two-length dominance in the selected TCR Vbeta-expressing CD4 + PBL
      subpopulations. Molecular analysis of the perturbed cell subpopulations suggested
      that the CD4 + T cells bearing the dominant CDR3 length were clonally expanded.
      These results indicate that SIV infection can induce a disruption of macaque CD4
      + T-cell repertoires during the primary infection. The finding in this study,
      therefore, suggests that the virus-induced clonal dominance can contribute to the
      disruption of CD4 + T-cell repertoires.

PMID- 10593482
TI  - Natural infection of chimpanzees with new lentiviruses related to HIV-1/SIVcpz.
AB  - To determine newly identified lentiviruses, termed simian immunodeficiency virus
      (SIV)cpz97CG4 and SIVcpz97CG6, from two wild-captured juvenile brother
      chimpanzees in the Republic of Congo, subgenomic pol (integrase, 288 bp),
      5'tat/rev-env Cl (including vpu, 354 bp) and env (C2-C4, 544 bp) gene fragments
      were amplified and sequenced. The analysis revealed significantly discordant
      phylogenetic positions of SIVcpz97CG in each genomic region. In the trees derived
      from partial env sequences (V3), both SIVcpz strains clustered in human
      immunodeficiency virus type 1 (HIV-1) subtype A. However, in the trees derived
      from partial pol (integrase) and 5'tat/rev-env C1 (including vpu) sequences, they
      clustered independently from any of the known HIV-1 subtypes. Especially, in the
      5'tat/rev-vpu tree, they branched before the root of HIV-1 group M. These
      findings suggest that these Congolese SIVcpz genomes are mosaic, probably due to
      a recombinational event in the recent past, and it provides evidence for a rather
      recently occurring cross-species transmission between humans and chimpanzees.

PMID- 10593484
TI  - Antigen-specific cytokine responses in vaccinated Macaca nemestrina.
AB  - We describe a new surrogate assay for CD8 + T lymphocyte activity that has the
      capability of discriminating between cytotoxic T lymphocyte (CTL) activity and
      cytokine-mediated suppressive activity. We applied this approach to two groups of
      Macaca nemestrina vaccinated with a minimally pathogenic strain of human
      immunodeficiency virus type 2 [HIV-2 (HIV-2(KR))] as a model of an attenuated
      virus vaccine. Group 1 was then inoculated with a non-infectious stock of a
      pathogenic strain, HIV-2287. Both groups 1 and 2 were subsequently challenged
      with an infectious stock of HIV-2287. Five out of six group 1 animals were
      protected against CD4 decline, whereas three out of six animals in group 2 were
      protected. Analysis of CTL responses demonstrated strong activity against HIV
      2(KR)-Gag in group 1. It was determined that strong CTL responses correlate with
      antigen-specific T-helper (Th) type 1 responses. This antigen-specific cytokine
      assay has the potential to better elucidate the functional mechanisms of CD8 + T
      cell-mediated protection than traditional methods to date.

PMID- 10593485
TI  - Recombinant human CD40 ligand inhibits simian immunodeficiency virus replication:
      a role for interleukin- 16.
AB  - CD40 ligand (CD40L), expressed on activated T cells, binds its receptor, CD40, on
      dendritic cells, B cells, and monocytes/ macrophages. Human immunodeficiency
      virus (HIV)-infected individuals exhibit normal B-cell CD40 expression but
      diminished expression of CD40L on CD4 + T cells. Thus, we studied recombinant
      human CD40L (huCD40L) in an in vitro rhesus macaque model of acquired
      immunodeficiency syndrome (AIDS). huCD40L induced peripheral blood mononuclear
      cell (PBMC) proliferation independent of mitogenic cytokines and led to a 70%
      reduction in p27 production by simian immunodeficiency virus (SIV) mac239
      infected PBMCs (P < 0.05). Reverse transcriptase-polymerase chain reaction (RT
      PCR) analysis showed reduced expression of SIV gag and increased expression of
      interleukin (IL)-16 mRNA. Supernatants from huCD40L-stimulated PBMC and control
      cultures contained similar amounts of IL-16, suggesting an intracellular
      antiviral effect by IL-16. Phytohemagglutinin (PHA)-stimulated PBMCs similarly
      cultured with huCD40L showed only slight increases in chemokine production (P >
      0.05). These results suggest that huCD40L inhibits replication (antigen and mRNA
      production) of SIVmac239. This response involves huCD40L induction of IL16 mRNA
      expression and appears to be independent of beta-chemokines.

PMID- 10593486
TI  - An anti-HIV strategy combining chemotherapy and therapeutic vaccination.
AB  - Combination chemotherapy using potent anti-retroviral agents has led to
      significant advances in the clinical management of human immunodeficiency virus
      (HIV) disease. However, the emergence of multiple drug-resistant mutants, the
      high need for compliance to adhere to demanding drug-dosing schemes, and the
      remaining toxic side-effects of drugs make the perspective of life-long treatment
      unattractive and possibly unrealistic. Therefore, means must be sought to shorten
      the time span during which treatment is necessary. Such means could be to
      stimulate an efficient immune response during the period of low virus load and
      restored CD4 + cell levels, which might be capable of keeping the virus under
      long-lasting control after treatment is stopped. Here we tested this concept of
      combined chemotherapy/ therapeutic vaccination in a non-human primate model.
      Rhesus macaques chronically infected with the chimeric simian/human
      immunodeficiency virus (SHIV) containing the HIV type 1 (HIV-1) HXBc2 gene for
      reverse transcriptase (RT) in the genomic background of simian immunodeficiency
      virus (SIV)(mac239) (RT-SHIV) were treated with (R)-9-(2
      phosphonylmethoxypropyl)adenine (PMPA), a potent anti-HIV drug. When virus load
      had decreased significantly, we immunized with SIV genes env, gag/pol, rev, tat,
      and nef inserted in two different expression vector systems. Four weeks after the
      second immunization, drug treatment was stopped. Animals were monitored to
      determine if virus load stayed low or if it increased again to the original
      levels and if CD4+ T-cell levels remained stable. Humoral and cellular immune
      responses were also measured. This combined chemotherapy/ therapeutic vaccination
      regimen induced a significant reduction in the steady-state level of viremia in
      one out of two chronically infected rhesus macaques. Chemotherapeutic treatment
      alone did not achieve reduction of viremia in two chronically infected animals.
      The nature of the immune responses assumed to have been induced by vaccination in
      one out of the two monkeys remains to be elucidated.

PMID- 10593487
TI  - Immunization against SIVmne in macaques using multigenic DNA vaccines.
AB  - All structural and regulatory genes of SIVmne were cloned into mammalian
      expression vectors to optimize expression in vitro and immunogenicity in mice.
      Macaca fascicularis were immunized four times with plasmid DNA (n = 4), or two
      DNA priming inoculations followed by two boosts of recombinant gp160 plus Gag-Pol
      particles (n = 4). Following intrarectal challenge with SIVmne, all macaques
      became infected. Three monkeys immunized with DNA alone maintained low plasma
      virus loads by 1 year post-challenge; the fourth exhibited high virus loads and
      significant CD4+ cell decline. Two of the DNA plus boost and three control
      macaques had high virus loads and associated CD4+ cell decline. Both vaccine
      protocols elicited antibodies and comparable helper T-cell proliferative
      responses to gp160. Cytokine mRNA levels in activated peripheral blood
      mononuclear cells (PBMC) taken at time of challenge suggested a dominant T helper
      (Th) 1 state in three DNA-immunized and one protein-boosted macaque, which
      correlated with low virus loads and high CD4+ cell counts post-challenge.

PMID- 10593488
TI  - Antigen-specific humoral and cellular immune responses can be modulated in rhesus
      macaques through the use of IFN-gamma, IL-12, or IL-18 gene adjuvants.
AB  - DNA or nucleic acid immunization has been shown to induce both antigen-specific
      cellular and humoral immune responses in vivo. Moreover, immune responses induced
      by DNA immunization can be enhanced and modulated by the use of molecular
      adjuvants. To engineer the immune response in vivo towards more T-helper (Th)1
      type cellular responses, we investigated the co-delivery of inteferon (IFN)
      gamma, interleukin (IL)-12, and IL-18 genes along with DNA vaccine constructs. We
      observed that both antigen-specific humoral and cellular immune responses can be
      modulated through the use of cytokine adjuvants in mice. Most of this work has
      been performed in rodent models. There has been little confirmation of this
      technology in primates. We also evaluated the immunomodulatory effects of this
      approach in rhesus macaques, since non-human primates represent the most relevant
      animal models for human immunodeficiency virus (HIV) vaccine studies. As in the
      murine studies, we also observed that each Th1 cytokine adjuvant distinctively
      regulated the level of immune responses generated. Co-immunization of IFN-gamma
      and IL-18 in macaques enhanced the level of antigen-specific antibody responses.
      Similarly, co-delivery of IL-12 and IL-18 also enhanced the level of antigen
      specific Th proliferative responses. These results extend this adjuvant strategy
      in a more relevant primate model and support the potential utility of these
      molecular adjuvants in DNA vaccine regimens.

PMID- 10593489
TI  - Efforts to broaden HIV-1-specific immunity by boosting with heterologous peptides
      or envelope protein and the influence of prior exposure to virus.
AB  - In two previous studies, we have demonstrated the successful protection of human
      immunodeficiency virus type 1 (HIV-1)-vaccinated rhesus macaques from challenge
      with SHIV(SF13) with envelop immunogens derived from the closely related HIV
      1(SF2) strain. Here we report on two follow-up studies in which we aimed to
      broaden immunity in order to elicit protection from a more diverse heterologous
      challenge with SHIV(SF33). In the first study, animals were boosted once with HIV
      1(SF33) V2 and V3 peptides that were cross-linked to influenza immune-stimulating
      complexes (ISCOMs). In the second study, monkeys were boosted twice at 12-week
      intervals, using a heterologous recombinant gp120 derived from HIV-1(SF33) that
      was either incorporated into ISCOMs or mixed with the MF59 adjuvant. In both
      studies, the animals were challenged with 50 monkey infectious doses of
      SHIV(SF33) 4 weeks after the final boost. All controls became readily infected
      with the heterologous challenge virus SHIV(SF33). Neither boosting with
      heterologous SF33 peptides or gp120 afforded protection from infection to SF2
      vaccinated animals that had previously resisted SHIV(SF13) challenge. These
      results demonstrate the importance of developing vaccine strategies that are
      capable of generating broad immune responses early in the immunization protocol.
      Furthermore, these findings may illustrate the potential pitfalls of early
      antigenic sin.

PMID- 10593490
TI  - Characterization of SIV-specific CD4+ T-helper proliferative responses in
      macaques immunized with live-attenuated SIV.
AB  - Analysis of immune responses generated by live-attenuated simian immunodeficiency
      virus (SIV) strains may provide clues to the mechanisms of protective immunity
      induced by this approach. We examined SIV-specific T-helper responses in macaques
      immunized with the live-attenuated SIV strains SIVmac239deltanef and
      SIVmac239delta3. Optimization of the concentration and duration of antigenic
      stimulation resulted in the detection of relatively strong SIV-specific
      proliferative responses, with peak stimulation indices of up to 84. SIV-specific
      proliferative responses were mediated by CD4+ T cells and were major
      histocompatibility (MHC) class II restricted. Limiting dilution analysis revealed
      SIV-specific T-helper precursor frequencies of up to 96 per 10(6) peripheral
      blood mononuclear cells (PBMC). Intracellular flow-cytometric analysis
      demonstrated the production of interleukin (IL)-2, interferon (IFN)-gamma, RANTES
      and macrophage inhibitory protein-1alpha (MIP-1alpha) by T lymphocytes from
      SIVmac239deltanef-vaccinated animals following SIV p55 stimulation. Induction of
      strong SIV-specific T-helper responses by live-attenuated SIV vaccines may play a
      role in their ability to induce protective immunity.

PMID- 10593491
TI  - Protective immunity of gene-deleted SHIVs having an HIV-1 Env against challenge
      infection with a gene-intact SHIV.
AB  - We constructed three simian-human immunodeficiency viruses (SHIVs) lacking
      regulatory gene(s) and analyzed their induction of protective immunity against
      challenge infection with gene-intact SHIV in rhesus macaques. Inoculation of SHIV
      dn lacking nef and SHIV-drn lacking nef and vpr induced transient viremia, while
      that of SHIV-dxrn lacking nef, vpr, and vpx induced no viremia. The SHIVs with
      fewer deletions were more effective in inducing neutralizing antibodies and
      cytotoxic T lymphocyte responses. When these macaques were challenged with
      parental gene-intact SHIV-NM-3rN, all the SHIV-dn-vaccinated macaques and two of
      the four SHIV-drn-vaccinated macaques showed complete resistance. The other two
      SHIV-drn-vaccinated macaques and all SHIV-dxrn-vaccinated macaques did not show
      complete resistance, but they did show suppression of replication of the
      challenge virus. These results suggested that as more genes were deleted,
      protective immunity was decreased.

PMID- 10593492
TI  - AIDS preclinical vaccine development: biennial survey of HIV, SIV, and SHIV
      challenge studies in vaccinated nonhuman primates.

PMID- 10593493
TI  - Pressure-controlled high-performance liquid chromatographic study on the
      influence of rim chemistry on partial molar volume differences between free and
      complexed cyclodextrins.
AB  - Pragmatic comparison of pressure dependent retention for differing cyclodextrin
      rim chemistries is assessed using controlled-pressure HPLC. For pressure
      differences of <300 bar, systematic shifts in solute capacity factor are observed
      for both native and methylated beta-cyclodextrin stationary phases. In addition
      to the importance of this observation for the practice of liquid chromatography,
      this technique can also be implemented in the fundamental determination of the
      influence of rim chemistry on the cyclodextrin partial molar volume both with and
      without solute inclusion. That is, pressure-controlled measurements provide a
      direct comparison between the partial molar volumes for native cyclodextrin (CD)
      and methylated cyclodextrin (MCD) in the presence and absence of the complexing
      solute (comp). Surprisingly, direct comparison of the measured partial molar
      volumes for the two rim chemistries indicates that the presence of neutral
      solutes does not contribute significantly to the volumetric component of
      complexation, V(comp,CD) - V(comp,MCD) approximately V(CD) - V(MCD). In contrast,
      their ionized counterparts are shown to exhibit marked rim chemistry differences
      in the partial molar volume of cyclodextrins with and without anion inclusion,
      V(comp(-),CD) - V(comp(-),MCD) < V(CD) - V(MCD). Not previously demonstrated by
      direct chromatographic measurement, these results have interesting implications
      for advancing the fundamental understanding of host-guest solvation properties.

PMID- 10593494
TI  - Cytochrome c unfolding on an anionic surface.
AB  - It is now well accepted that the adsorption of proteins to solid supports
      sometimes involves surface-mediated unfolding. A detailed understanding of the
      adsorption and surface-mediated unfolding process is lacking. We selected a well
      studied protein, horse heart cytochrome c, and a weakly ionic support to examine
      some of the characteristics of protein adsorption under near-physiological
      conditions. We used high-performance liquid chromatography (HPLC) to investigate
      the effect of temperature on surface-mediated unfolding. Samples of cytochrome c
      were introduced to an anionic support, and a NaCl gradient was used to desorb the
      protein at different times and temperatures. The profiles and retention times
      were monitored to examine the adhesive properties of cytochrome c to the anionic
      support. We found that protein retention increased with time at temperatures as
      low as 0 degrees C, and a significant loss of cytochrome c occurred between 55
      degrees C and 70 degrees C. The loss of recovery of cytochrome c indicates
      irreversible surface-mediated unfolding. The changes in retention time may
      indicate more subtle transitions, including reversible surface-mediated unfolding
      of cytochrome c. These results suggest that perturbations in the structure as
      well as unfolding of cytochrome c can be detected at a lower temperature on an
      anionic surface than in solution thereby acting like a catalyst for protein
      unfolding.

PMID- 10593495
TI  - Determination of polar pesticides with atmospheric pressure chemical ionisation
      mass spectrometry-mass spectrometry using methanol and/or acetonitrile for solid
      phase desorption and gradient liquid chromatography.
AB  - Thirty-seven polar pesticides, mainly triazines, phenylurea herbicides and
      phenoxy acids, were determined by LC-atmospheric pressure chemical ionisation MS
      MS with methanol and acetonitrile as the organic modifiers. For most pesticides,
      detection limits were the same irrespective of the modifier. However, for the
      phenylurea herbicides, propachlor, carbetamide, triadimefon, triadimenol,
      triethylcitrate, benzothiazole and metazachlor, the results were much poorer in
      the presence of acetonitrile; in several cases, no meaningful results were
      obtained at all. When carrying out trace enrichment of 100 ml water samples on a
      10x2 mm I.D. solid-phase extraction precolumn containing a polymeric sorbent,
      rapid desorption with a small volume of pure organic solvent and the introduction
      of a T-piece in between the solid-phase extraction precolumn and the analytical
      column was necessary. Aliquots of 300 microl of acetonitrile were optimal for the
      complete desorption of all analytes from the sorbent. With methanol as the
      modifier and when using an identification criterion of three ions, the detection
      limits for most analytes, in the full-scan mode, were 10-100 ng/l. The linearity
      of the procedure, which was tested at the 0.1 and 1 microg/l levels, was
      satisfactory in the positive, but not in the negative ionisation mode. The
      procedures were used to analyse surface water samples.

PMID- 10593496
TI  - Gas chromatography for in situ analysis of a cometary nucleus: characterization
      and optimization of diphenyl/dimethylpolysiloxane stationary phases.
AB  - The development of a gas chromatograph for the cometary sampling and composition
      (COSAC) experiment is described in the context of the preparation for the
      European Space Agency (ESA) Mission Rosetta for investigation of a cometary
      nucleus. COSAC is one out of ten experiments on the Rosetta Lander. Its
      scientific goal is to analyze in situ the chemical composition of the volatile
      constituents of the nucleus of the target comet P/Wirtanen. Constituted of
      several (up to eight) capillary wall-coated and porous-layer open tubular columns
      operating in parallel, the GC system is designed to separate and identify both
      organic and inorganic compounds which evolve from the comet naturally or are
      obtained from cometary samples through stepwise heating in a miniaturized
      pyrolizer. In this first part of our study, dimethylpolysiloxane (DMPS)
      stationary phases with increasing percentages of diphenyl substituted group (DP)
      have been investigated. A coupled experimental and theoretical approach has been
      taken in order to predict chromatographic data. By the use of a four-point
      experimental calibration (0 to 65% diphenyl group) in conjunction with Pro ezGC
      modeling software, results in prediction of multicomponent chromatograms with a
      mean error less than 5% for each compound retention time were obtained,
      irrespective of the stationary phase's diphenyl content and column physical
      parameters. The possibility to associate such phases is illustrated by the
      evolution of coelutions obtained on a non-polar (100% DMPS) and a medium polar
      (65% DP-DMPS) stationary phase, respectively. This study showed that with a small
      number of well tuned DP-DMPS columns, the separation and identification of most
      of the targeted compounds can be achieved with a minimum amount of coelutions and
      within the experiment requirements.

PMID- 10593497
TI  - Selection of methylation procedures for quantitation of short-chain glycerol
      bound compounds formed during thermoxidation.
AB  - Five methylation procedures, including base- and acid-catalyzed methods, were
      tested in thermoxidized methyl linoleate and trilinolein, in order to quantitate
      major oxidation short-chain glycerol-bound compounds by gas chromatography.
      Results indicated that transmethylations using KOH in methanol or CH3ONa-CH3OH in
      tert.-butylmethyl ether were the most appropriate methods, given the excellent
      reproducibility and practically complete recovery obtained for the compounds of
      interest, mainly short-chain fatty acids and aldehydic acids. Also, formation of
      acids from aldehydes during thermoxidation as well as modifications of aldehydic
      functions under acidic conditions, such as conversion to acetals, were checked
      using dodecanal as model aldehyde.

PMID- 10593498
TI  - Automated gas chromatography with cryogenic/sorbent trap for the measurement of
      volatile organic compounds in the atmosphere.
AB  - An automated gas chromatographic system was constructed to easily adapt either
      the cryogenic trap or chemical sorbent trap for preconcentrating ambient levels
      of volatile organic compounds. Remarkable similarity in chromatograms from C3 to
      C10 was found between these two enrichment methods, except that the sorbent trap
      did not quantitatively trap the C2-hydrocarbons. In contrast to cryogenic
      trapping, the chromatographic conditions for more volatile compounds were
      substantially improved using the sorbent trap. Water interference on the porous
      layer open tubular column was also better managed using the sorbent trap for the
      continuous analysis of humid room air. The similarity in peak profiles between
      the GC-flame ionization detection (FID) and a commercial GC-MS system, regardless
      of concentration levels, facilitated compound identification on the FID
      chromatograms based on a field mission involving analysis of 106 air samples.

PMID- 10593499
TI  - Capillary electrophoretic behaviour of humic substances in physical gels.
AB  - We investigated the principles of the capillary electrophoretic behaviour of
      humic substances (HSs) in physical gels. Long chain (Mr 4000, 6000 and 20,000)
      polyethylene glycols (PEGs) at concentrations above their entanglement threshold
      caused the separation of HS fractions according to molecular size differences.
      Close linear relationships between effective mobilities and mean apparent
      molecular masses were observed at PEG concentrations between 2.5 and 15%. The
      efficiency of the separation does not increase in gels of increasing polymer
      concentrations. The possibility of interactions between HSs and gel-forming
      polymers was also investigated. Short chain (Mr 400) PEGs, added to the buffer at
      concentrations from 2.5 to 12.5%, increased the migration times of all HS
      fractions, but no separation was obtained even at large polymer concentrations,
      showing that gel formation was essential for the separation. In 2.5% polyvinyl
      alcohol (PVA) 49 000 all fractions show two unresolved, but well defined peaks.
      This separation is probably artefactual and depends on the relative concentration
      of HSs and PVA, as the relative abundance of the peaks changes with the sample
      concentration.

PMID- 10593500
TI  - 3-Aminobenzamide and 3-aminobenzoic acid, tags for capillary electrophoresis of
      complex carbohydrates with laser-induced fluorescent detection.
AB  - The efficiencies in derivatization of reducing carbohydrates were compared by
      capillary electrophoresis using maltose as a model with nine monoaminobenzene
      derivatives by reductive amination in the presence of sodium cyanoborohydride. We
      found that aminobenzene derivatives substituted at the 3-position showed good
      reactivity with reducing carbohydrates as expected from the reaction mechanism,
      although the fluorescence intensities and molar absorptivities of these
      derivatives were not as high as those of 2- and 4-aminobenzene derivatives. The
      reagents, 3-aminobenzamide and 3-aminobenzoic acid, which showed the highest
      reactivity, were applied to the labeling of carbohydrate chains obtained from
      some sialic acid-containing glycoprotein samples, and also high-mannose and
      hybrid-type oligosaccharides. Capillary electrophoresis of these labeled
      carbohydrate chains in an inner surface-modified capillary with (50%
      phenyl)methylpolysiloxane allowed excellent separation of sialic acid-containing
      carbohydrate chains derived from fetuin and thyroglobulin as well as high mannose
      type and hybrid-type carbohydrates derived from bovine pancreas ribonuclease B,
      soybean agglutinin and hen ovalbumin. The lower limit of calibration was as low
      as the 10(-16) mol (injected amount) with helium-cadmium laser induced detection.

PMID- 10593501
TI  - The unvalidity of Kohlrausch' regulating function for Svensson's isoelectric
      focusing and stationary electrolysis at steady state.
AB  - Kohlrausch' regulating function is of important significance in the field of
      electrophoresis. In this paper, the relative regulating function is defined from
      Kohlrausch' regulating function. The relative values, including the limited
      values, of the regulating function for the stationary electrolysis of salt, on
      which the classic isoelectric focusing (IEF) is based, are computed and compared
      with the computer program of the QBASIC written by us. The results directly
      demonstrate that, (1) in a few cases the regulating function is valid for the
      stationary electrolysis and IEF, whereas (2) the function is, in most of cases,
      not valid for the stationary electrolysis and IEF at steady-state. Those findings
      may be useful for the studies on the relationships between Kohlrausch' regulating
      function and IEF and for the classification of numerous electrophoretic
      techniques.

PMID- 10593502
TI  - High-performance liquid chromatography of methanol released from pectins after
      its oxidation to formaldehyde and condensation with 2,4-dinitrophenylhydrazine.
AB  - A procedure was developed to measure the content of methanol in pectins after the
      base-catalysed hydrolysis of galacturonic acid methyl esters and oxidation of
      released methanol with potassium permanganate followed by condensation of the
      resulting formaldehyde (HCHO) with 2,4-dinitrophenylhydrazine (DNPH) dissolved in
      acetonitrile. The constant yields of resultant formaldehyde 2,4
      dinitrophenylhydrazone (HCHO-DNPH derivative) were obtained at molar ratios of
      DNPH/HCHO higher than 5. The separation of the HCHO-DNPH derivative from DNPH
      reagent was achieved by isocratic reversed-phase HPLC equipped with the
      spectrophotometric detector set at a wavelength of 351 nm. The calibration curve
      was linear in the methanol concentration range between 0.04 and 15 micromol/ml
      (R=0.9995). The total recovery from pectin solutions spiked with methanol was
      equal to 100.6+/-5.1%.

PMID- 10593503
TI  - High-performance liquid chromatographic determination of some anthraquinone and
      naphthoquinone dyes occurring in historical textiles.
AB  - A reversed-phase HPLC method has been developed for identification and
      quantitation of nine natural quinone dyes and applied to historical textile
      fibres. A Purospher RP18e column was used with a convex gradient of methanol in a
      mobile phase of 0.1 M aqueous citrate buffer (pH 2.5) and spectrophotometric
      diode-array detection at 270 nm. For identification of alizarin, purpurin and
      xanthopurpurin, occurring together in the madder plant, an isocratic method was
      used with a methanol-0.2 M acetate buffer (pH 4.3) (75:25) as the mobile phase.
      After an acid extraction of textile fibres and the analysis of the extracts,
      alizarin and purpurin were identified and quantitated in three fibres.

PMID- 10593504
TI  - Pyrolysis-gas-liquid chromatography with atomic emission detection for the
      identification of Corynebacterium species.
AB  - We report here the application of pyrolysis-gas chromatography followed by atomic
      emission detection (AED) for the characterisation of microorganisms. AED measured
      the quantity of carbon, sulfur and nitrogen in the molecules separated
      chromatographically. Twenty-three strains, representing eight Corynebacterium
      species, were tested in this preliminary study. Co-ordinate principal analysis
      grouped 11 strains in their respective species group. Most of the other strains
      appear randomly distributed, perhaps because these strains require additional
      nutrients. These preliminary results show that the method could be used as a tool
      for the taxonomic and perhaps the epidemiologic characterisation of bacteria.

PMID- 10593505
TI  - The role of plasma semicarbazide-sensitive amine oxidase in allylamine and beta
      aminopropionitrile cardiovascular toxicity: mechanisms of myocardial protection
      and aortic medial injury in rats.
AB  - Allylamine (AA; 3-aminopropene) and beta-aminopropionitrile (betaAPN) combined
      treatment (AA + betaAPN) results in myocardial protection from AA-induced
      subendocardial necrosis and a rapid and extensive aortic medial smooth muscle
      injury in rats. To determine the mechanisms of AA + betaAPN-induced vascular
      toxicity, cardiovascular parameters were monitored during a 10-day exposure by
      gavage in male Sprague-Dawley rats (180-200 g). Water intake and urine output
      were measured in rats treated with water, AA (100 mg kg(-1) body weight), betaAPN
      (1 g kg(-1) body weight), and AA + betaAPN for 10 days in metabolic cages. Plasma
      and urine samples were analyzed for blood urea nitrogen, CO2, creatinine,
      hematocrit, electrolytes (Na+, K+, Cl-), and osmolality. Heart and plasma
      semicarbazide-sensitive amine oxidase metabolic capacity (SSAO)was also measured
      following 1, 3 and 10 days of treatment. Following 10 day exposure to control or
      AA + betaAPN treatment, thoracic aortic rings (approximately 3 mm) were removed,
      and aortic reactivity to contractile and relaxant agonists was tested in vitro.
      In addition, cultured rat aorta vascular smooth muscle cells or rat heart beating
      myocytes were exposed to various concentrations of AA and betaAPN or AA
      metabolites and betaAPN to test for synergism in vitro. Several of the changes in
      in vivo cardiovascular parameters were shared, both in direction and magnitude,
      between the AA + betaAPN and the AA alone or the betaAPN alone treatments. This
      suggests that these effects (e.g. increased water intake and urine flow,
      decreased hematocrit, decreased heart and plasma SSAO metabolic capacity) were
      dependent on an AA alone or a betaAPN alone effect and were not AA + betaAPN
      specific effects. Significant inhibition of plasma and heart SSAO metabolic
      capacity occurred in the betaAPN alone and the AA + betaAPN treatments, but not
      in the AA alone treatment. Aortic rings from AA + betaAPN treated rats were
      contracted significantly less than anatomically-matched control rat aortic rings
      by 100 mM potassium chloride or by 10 microM norepinephrine. BetaAPN offered
      substantial protection against AA cytotoxicity in cultured vascular smooth muscle
      cells and beating myocytes, but did not alter the cytotoxicity of AA metabolites
      (i.e. acrolein, H2O2, or ammonia) in vascular smooth muscle cells as determined
      by the MTT viability assay. Overall, these data suggest that myocardial
      protection from AA injury that occurs in the combined AA + betaAPN treatment is
      likely due to inhibition of plasma SSAO. This may result in an increase in the AA
      dose accumulation and metabolism in the aorta leading to the severe aortic medial
      injury.

PMID- 10593506
TI  - Beryllium-stimulated in vitro migration of peripheral blood lymphocytes.
AB  - Inhalation of beryllium (Be) induces both inflammatory and metal antigen-specific
      immune responses in the lungs characterized by mononuclear cell infiltration and
      granuloma formation (chronic beryllium disease, CBD). We tested the hypothesis
      that Be-salts might increase the in vitro migration of peripheral blood
      mononuclear cells (PBMC). PBMC are mixed cells, consisting of lymphocytes and
      monocytes. We compared their responses to populations of both purified blood
      lymphocytes, and purified blood monocytes. Purified blood monocytes and
      lymphocytes, isolated by Percoll gradients and centrifugal elutriation from
      normal human subjects (n = 6), were exposed to graded concentrations (0.01 to 100
      microM) of BeSO4 or to the control metal-salt Al2(SO4)3. Migratory responses of
      stimulated PBMC were measured in Boyden Chambers. As controls, PBMC mixed cells
      or purified lymphocytes or purified monocytes were unstimulated or stimulated
      with a positive chemoattractant, Zymosan-A treated pooled, normal human serum
      (ZAS). The migration index (MI) was defined as the distance (micrometers) that
      cells migrated through a 5 micron filter. The MI for unstimulated PBMC mixed
      cells was 75+/-4 whereas the MI for ZAS-stimulated PBMC mixed cells was 124+/-4
      (P < or = 0.05, Tukey-Kramer). The MI for BeSO4 -stimulated (100 microM) PBMC
      mixed cells was 136+/-4. The observed increase in the BeSO4-stimulated PBMC mixed
      cell migration was significant down to 0.1 microM BeSO4. BeSO4, BeCl2 and BeF2,
      tested at 100 and 10 microM, were equally effective at inducing PBMC mixed cell
      migration. Equimolar concentrations of Al2(SO4)3 were not as effective at
      inducing PBMC mixed cell migration, MI < 100 at 100 microM, and did not induce
      PBMC mixed cell migration at concentrations below 1 microM. The migration of
      purified monocytes through filters was not increased in response to either BeSO4
      or Al2(SO4)3 compared to controls, but did respond to ZAS (MI = 100+/-4).
      Purified lymphocytes migrated in response to stimulation with all concentrations
      of BeSO4 tested (100 microM MI = 133+/-9), and Al2(SO4)3 (100 microM MI = 85+/
      8). There were no significant differences in the MI for PBMC mixed cells or for
      purified lymphocytes at the concentrations of BeSO4 tested. Our data show that Be
      directly induces the in vitro migration of PBMC mixed cells and purified blood
      lymphocytes, and not purified blood monocytes, across a broad range of Be
      concentrations. This induction of migration was independent of the molecular form
      of the Be-salt. Inhaled Be, by promoting lymphocyte emigration to the lung, may
      create a microenvironment that favors a Be-antigen-specific T-lymphocyte
      response, chronic inflammation, and CBD.

PMID- 10593507
TI  - Sodium sulfate potentiates N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and
      N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA) nephrotoxicity in the
      Fischer 344 rat.
AB  - The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) induces
      nephrotoxicity as its major toxicity in rats. Previous studies have shown that
      NDPS induces nephrotoxicity following oxidation of the succinimide ring to form N
      (3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and the hydrolysis product of
      NDHS, N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA). Our recent work
      found that sodium sulfate potentiated NDPS nephrotoxicity, suggesting that
      sulfate conjugation of NDPS metabolites might be a bioactivation step mediating
      NDPS nephrotoxicity. The purpose of this study was to determine if sodium sulfate
      also potentiated the nephrotoxicity of the two nephrotoxic metabolites of NDPS
      and further to see if sodium sulfate potentiated NDHS and 2-NDHSA nephrotoxicity
      to the same degree. Male Fischer 344 rats (4-16 rats/group) received an
      intraperitoneal (ip) injection of sodium sulfate (10 mg/kg) 20 min before a non
      nephrotoxic dose (0.05 mmol/kg, ip) of NDHS or 2-NDHSA, or vehicle (12.5%
      dimethyl sulfoxide in sesame oil). Renal function was then monitored over 48 h.
      Sodium sulfate pretreatment potentiated the renal effects of a non-nephrotoxic
      dose of NDHS and 2-NDHSA to induce nephrotoxicity. Nephrotoxicity was
      characterized by diuresis, increased proteinuria, elevated blood urea nitrogen
      (BUN) concentration, increased kidney weight and proximal tubular necrosis.
      Differences in the potentiation of NDHS and 2-NDHSA nephrotoxicity by sodium
      sulfate were also observed as NDHS nephrotoxicity was potentiated to a lesser
      degree than 2-NDHSA-induced nephrotoxicity. These results support the likelihood
      that one or more sulfate conjugate(s) of NDPS metabolites contribute to NDPS
      nephrotoxicity.

PMID- 10593508
TI  - Alterations of T cell distribution and functions in prenatally cypermethrin
      exposed rats: possible involvement of catecholamines.
AB  - The synthetic pyrethroid insecticide, cypermethrin (50 mg/Kg) was given during
      gestation to pregnant rats by gavage in corn oil. Prenatal cypermethrin-exposure
      induces a marked and long-lasting increase of adrenaline (A) and noradrenaline
      (NA) plasma concentrations. The enhancement of plasma catecholamine levels was
      accompanied by a marked increase of CD5+, CD4+, and CD8+ total T cell numbers in
      the peripheral blood, while in the spleen a reduction of all T cell subsets was
      observed. In addition, peripheral blood lymphocytes (PBL) from rats prenatally
      exposed to cypermethrin showed an enhanced capability to proliferate in response
      to different doses of Concanavalin A (ConA), or human recombinant interleukin-2
      (hrIL-2), whereas an impaired proliferative response was observed in the spleen.
      The percent increase of NA, but not A plasma concentrations paralleles the
      immunomodulatory effects induced by cypermethrin neonatal exposure on T cell
      distribution and mitogen-induced proliferation in the peripheral blood and
      spleen. Collectively, our results suggest that the changes in mitogen-induced
      proliferative responses in the peripheral blood and spleen of prenatally
      cypermethrin-exposed rats may be attributable to pesticide-induced catecholamine
      release, which causes an increased output of CD5+, CD4+, and CD8+ T cells from
      the spleen to the peripheral blood, and a consequent lymphocytosis.

PMID- 10593509
TI  - Dynamics of molecules involved in antigen presentation: effects of fixation.
AB  - Antigen presentation by MHC class II molecules can be enhanced by
      paraformaldehyde fixation of antigen-presenting cells prior to assay. This
      treatment might be expected to aggregate membrane proteins and thus stabilize and
      strengthen transient protein-protein interactions involved in intercellular
      cooperation. Lateral and rotational dynamics of the MHC class II antigen I-Ad on
      A20 cells fixed with various concentrations of paraformaldehyde were examined by
      fluorescence photobleaching recovery and time-resolved phosphorescence
      anisotropy, respectively. Probes were tetramethylrhodamine and erythrosin
      conjugates of MKD6 Fab fragments. Increasing concentrations of paraformaldehyde
      led to a progressive increase in the limiting anisotropy of I-Ad at 4 degrees C
      from the value of 0.042 for untreated cells, indicative of large aggregate
      formation, while leaving the rotational correlation time of 29 micros unchanged,
      a measure of the unperturbed molecule. On the other hand, the translational
      diffusion constants decreased from approximately 2x10(-10) cm2 s(-1), while the
      fractional recovery remained unchanged at about 40-50%. Taken together, these
      results suggest that fixation crosslinks class II molecules to each other or to
      other membrane proteins into structures large enough (>500,000 kDa) to diffuse
      translationally with perceptibly size-dependent rates. The fixation effects on
      both class II rotation and lateral diffusion were half-maximal at
      paraformaldehyde concentrations of approximately 0.2%. Possible relations between
      the biological effector functions of class II and the physical sizes of fixation
      induced aggregates are discussed.

PMID- 10593510
TI  - A single backmutation in the human kIV framework of a previously unsuccessfully
      humanized antibody restores the binding activity and increases the secretion in
      cos cells.
AB  - Humanization of rodent mAbs by CDR-grafting (also called "reshaping") is now a
      standard procedure for reducing immunogenicity and recruiting human effector
      functions. However, the design of the humanized mAb can sometimes prove
      circuitous. Attempts were made to humanize L-25, a mouse antibody against the
      human alpha-4 integrin subunit using the usual protocols. Despite reaching eight
      backmutations in the light chain, it was not possible to recover the binding
      activity to the level of the chimeric. In an effort to restore the binding
      activity, an analysis of the human kappa IV acceptor frameworks was undertaken.
      This analysis highlighted the Asp at position 9 in framework 1, which although a
      common amino acid in human kappa IV frameworks, was an unusual residue in mouse
      kappa frameworks. Backmutating this position to the mouse amino acid completely
      restored the binding of the humanized antibody and as a by-product also increased
      the secretion levels in cos cells. Mutating position 9 to the consensus residue
      for human kappa I also restored the binding and secretion levels although not to
      the same extent. The resulting humanized antibody had a light chain with only a
      single backmutation to the mouse sequence.

PMID- 10593511
TI  - Antibody repertoire against HIV-1 gp120 triggered in nude and normal mice by GM
      CSF/gp120 immunization.
AB  - Granulocyte-macrophage colony stimulating factor (GM-CSF) facilitates the
      induction of primary immune responses by activating and recruiting antigen
      presenting cells (APC), which efficiently present antigen determinants to Th
      cells. We have derived a functional GM-CSF/gp120 chimeric protein that, following
      immunization in soluble, adjuvant-independent form in normal mice, triggers
      highly specific, high affinity anti-gp120 antibodies. In contrast, nude mice
      respond with mutated, polyreactive, low affinity antibodies that mature further
      and increase in affinity in T cell-reconstituted nude mice. Anti-gp120 antibody
      production in nude mice is mediated principally by GM-CSF/gp120-triggered IL-4
      production, since neutralizing anti-IL-4 abrogates the in vivo response. The anti
      gp120 antibody response in normal, nude and T cell-reconstituted nude mice is
      encoded at a remarkably high frequency by the VH81X and VH7183 genes, a family
      used notably during fetal life and, when expressed at the adult stage, associated
      with autoimmune disease. We conclude that HIV gp120 binds and selects a
      subpopulation of developing B cells expressing a set of VH genes associated with
      immunodeficiency and autoimmunity.

PMID- 10593512
TI  - Differential expression of alternative H2-M isoforms in B cells, dendritic cells
      and macrophages by proinflammatory cytokines.
AB  - Major histocompatibility (MHC) class II heterodimers bind peptides generated by
      degradation of endocytosed antigens and display them on the surface of antigen
      presenting cells (APCs) for recognition by CD4+ T cells. Efficient loading of MHC
      class II molecules with peptides is catalyzed by the MHC class II-like molecule
      H2-M. The coordinate regulation of MHC class II and H2-M expression is a
      prerequisite for efficient MHC class II/peptide assembly in APCs determining both
      the generation of the T cell repertoire in the thymus and cellular immune
      responses in the periphery. Here we show that expression of H2-M and MHC class II
      genes is coordinately and cell type-specific regulated in splenic B cells,
      splenic dendritic cells (DCs) and peritoneal macrophages (Mphi) in response to
      proinflammatory and immunoregulatory cytokines, including GM-CSF, IFN-gamma, TGF
      beta2, IL-4, IL-10 and viral IL-10. In addition, ratio-RT-PCR expression analysis
      of the duplicated H2-Mbeta-chain loci demonstrates for the first time that Mbl
      and Mb2 genes are differentially expressed in individual APC types. Mb2 is
      preferentially expressed in IL-4, GM-CSF, IL-10, vIL-10 and IFN-gamma stimulated
      splenic B cells, whereas splenic DCs express both Mb genes at almost equal
      levels. In contrast, peritoneal Mphi express predominantly Mb2 but stimulation
      with IFN-gamma induces a switch towards Mb1 expression. These data suggest a
      common mechanism that regulates coordinate expression of H2-M and MHC class II
      genes in professional APCs. Differential expression of Mb1 and Mb2, and by
      consequence alternative H2-M isoforms (Malphabeta1 or Malphabeta2), may influence
      the nature of the peptide repertoire presented by different APC types.

PMID- 10593513
TI  - A quantitative, single-cell PCR analysis of an antigen-specific TCR repertoire
      selected during an in vivo CD8 response: direct evidence for a wide range of
      clone sizes with uniform tissue distribution.
AB  - The development of T cell effector and memory responses against foreign antigens
      (Ags) involves the activation, differentiation and proliferation of naive T cells
      expressing distinct Ag-specific TCRs. Understanding the complexity of Ag-selected
      TCR repertoires in individual responders in terms of the sequences selected and
      their relative frequencies may provide indications about how a repertoire is
      established and suggest ways to influence the outcome of an immune response. Most
      methods of repertoire analysis are unsuitable for calculating the relative in
      vivo frequencies of Ag-specific clones (expressing distinct TCRs) selected during
      an immune response, whereas sequence data obtained by single-cell PCR analysis
      directly reflect cell frequencies if a sufficiently large number of cells is
      sampled. Using a CD8 T cell response in normal mice in which Ag-selected cells
      are identified by cell surface phenotype and rearranged TCRBV sequences are
      determined by PCR amplification of genomic DNA directly from single cells, we
      have analyzed a large number (>200 per animal) of structurally-related Ag
      specific TCRs to calculate the frequencies of distinct TCRs selected by
      individual mice. We found that each responder selects a unique Ag-specific TCR
      repertoire in which the various TCRBV sequences are present in a wide range of
      frequencies. However, the overall distribution of sequences is quite similar for
      different responder animals. Moreover, an individual's selected TCR repertoire is
      uniformly represented among Ag-specific CD8 cells circulating in the blood or
      localized in the spleen or liver. Relatively few sequences make up the bulk of
      the repertoire and account for the oligoclonality observed in earlier studies. We
      discuss various models that could account for this skewed distribution of an Ag
      selected TCR repertoire.

PMID- 10593514
TI  - Thy-1/CD3 coengagement promotes TCR signaling and enhances particularly tyrosine
      phosphorylation of the raft molecule LAT.
AB  - Clustering of the glycosyl-phosphatidylinositol (GPI)-anchored protein Thy-1 on
      the cell surface leads to T cell activation. However, despite the similarity to
      TCR-mediated events, cell signaling triggered by Thy-1 crosslinking, reportedly
      occurs in a manner independent of the TCR/CD3 complex. To investigate the
      relationship between responses resulting from Thy-1 or TCR engagement, a
      biochemically well defined system employing only affinity purified antibodies was
      used to crosslink these surface molecules and activation was assessed by
      monitoring tyrosine phosphorylation, intracellular calcium influx and IL-2
      production. By these criteria, anti-CD3 mAbs moderately activated EL-4 thymoma or
      2B4 hybridoma cell lines, while costimulation with anti-Thy-1-mAb strongly
      enhanced TCR signaling. Furthermore, a Thy-1 loss mutant cell line, did not
      respond to stimulation through CD3 despite expressing all essential signaling
      molecules. Together these results emphasized the existence of a poorly
      appreciated mutual interdependence between Thy-1 and CD3 for efficient cellular
      signaling. Thy-1/CD3-mediated activation enhanced mostly tyrosine phosphorylation
      of a 40 kDa protein which was identified as a transmembrane protein lacking N
      linked oligosaccharides. These biochemical properties are identical to those
      described for a recently cloned adaptor protein called 'Linker for Activation of
      T cells' (LAT). Indeed, polyclonal Abs raised against a LAT-peptide (amino acids
      103-131) specifically recognized the 40 kDa protein. LAT is present in
      microdomains of the plasma membrane enriched in sphingolipids, cholesterol, GPI
      anchored proteins and a variety of signaling molecules. By contrast, the TCR/CD3
      complex is excluded from these domains at least until stimulation takes place.
      Hence, we propose that Thy-1 promotes TCR/CD3 dependent signaling by facilitating
      LAT phosphorylation on tyrosine and the subsequent recruitment of downstream
      effector molecules.

PMID- 10593515
TI  - The murine clan V(H) III related 7183, J606 and S107 and DNA4 families commonly
      encode for binding to a bacterial B cell superantigen.
AB  - Superantigens, by virtue of their unconventional binding interactions with Ag
      receptors, can simulate a large subset of mature lymphocytes in the repertoire.
      Recent studies have documented that in vivo exposure to the model bacterial B
      cell superantigen, Staphylococcal protein A (SpA), induces large scale effects on
      murine B-cell clonal selection by mechanism(s) that include deletion of supra
      clonal sets. While the structural bases for the immunomodulatory properties of
      several T-cell superantigens have been well characterized, the requirements for
      murine Fab-binding of SpA remain incompletely defined. To investigate these
      structural requirements, a series of direct binding and inhibition studies were
      performed with a large panel of Moabs of diverse variable region gene usage.
      These studies confirm previous reports that superantigen binding is completely
      restricted to the products of clan V(H) III-related families, that include the
      small S107 and J606 families, and we also demonstrated that usage of the related
      small DNA4 family commonly correlates with weaker binding activity. Furthermore,
      our results document that genes from the largest clan V(H) III family, 7183,
      commonly encode for Fab-mediated binding of SpA, while antibodies from five other
      VH families, J558, Q52, Sm7, VH11 and VH12, did not display Fab-mediated SpA
      binding activity. By contributing to the essential foundation for understanding
      of the structural basis for binding interactions, these findings will aid
      interpretation of evolving observations regarding the clonal fates induced by in
      vivo B-cell superantigen exposure.

PMID- 10593516
TI  - Processing of antibodies to the MHC class II antigen by B-cell lymphomas: release
      of Fab-like fragments into the medium.
AB  - Lym-1, an anti-MHC class II Ab, displayed a unique processing pathway after
      binding to the surface of Raji B-lymphoma cells, in which Fab-like fragments were
      gradually released into the medium. The fragments had reduced interchain
      disulfide bonds. Fragmentation was markedly reduced by inhibitors of
      intracellular catabolism, namely ammonium chloride, chloroquine and leupeptin.
      The capacity of the process was high, and fragmentation of approximately 5x10(6)
      Ab molecules per cell per day was measured directly, in what can be considered to
      be a minimum estimate. Five other Abs to the MHC class II antigen were tested
      similarly on Raji and on three other B-cell lymphomas: none showed the same high
      level of fragmentation seen with Lym-1 binding to Raji, but significant
      fragmentation did occur with some of the Abs, particularly EDU-1 and L243. The
      level of fragmentation depended on the cell line as well as on the particular Ab.
      The other 5 Abs were all catabolized, to low molecular weight material, much more
      extensively than Lym-1. Part of the difference between Abs can probably be
      attributed to the fortuitous, preferential labeling of Lym-1 on the light chain,
      since the data suggest that the Fc fragment is fully degraded while the Fab-like
      fragment is released into the supernatant. This pathway of Ab processing is
      likely to be related to the physiology of the MHC class II antigen, which
      recycles into a mildly proteolytic intracellular compartment.

PMID- 10593517
TI  - Critical Lym-1 binding residues on polymorphic HLA-DR molecules.

PMID- 10593518
TI  - Introductory comments for the consensus on physical activity and obesity.

PMID- 10593519
TI  - Physical activity in the prevention and treatment of obesity and its
      comorbidities.

PMID- 10593520
TI  - The obesity epidemic in children and adults: current evidence and research
      issues.
AB  - PURPOSE: The term "epidemic" of obesity implies that obesity is a characteristic
      of populations, not only of individuals. The purpose of this paper is to review
      evidence on obesity in populations and to identify future research issues.
      METHODS: To examine recent increases in the population prevalence of overweight
      or obesity, a literature search was undertaken. RESULTS: Trends in overweight or
      obesity among adults showed considerable variability internationally. Some
      countries, including Canada, Finland (men), New Zealand, the United Kingdom, the
      United States, and Western Samoa showed large increases in prevalence (>5
      percentage points), whereas several other countries showed smaller or no
      increases. Overweight is also increasing among children and adolescents, at least
      in some countries. It is not clear what the expected prevalence of overweight or
      obesity might be in the current environment, and these findings may be most
      usefully viewed as shifts in the distribution of a population characteristic. The
      reasons for these shifts are not clear. The health implications of these shifts
      are also not clear, in part because trends in cardiovascular risk factors do not
      always parallel trends in obesity. Of the classic epidemiologic triad of host,
      agent, and environment, the environment has often received the least attention.
      CONCLUSIONS: The economic, social, and cultural factors that influence the
      distribution of body mass index in a population are not well understood. Future
      research needs include continued monitoring of trends in obesity and in related
      health conditions and observational studies to examine the causes of these
      trends. Public health research should aim at defining realistic goals and
      strategies to improve health in an environment conducive to high levels of
      overweight and obesity.

PMID- 10593521
TI  - Overview of the determinants of overweight and obesity: current evidence and
      research issues.
AB  - PURPOSE: The prevalence of obesity has reached epidemic proportions in many
      countries around the world. However, the genetic and environmental factors
      contributing to obesity are incompletely understood. METHODS: We reviewed studies
      relating to the regulation of energy balance and how these factors may contribute
      to the development of obesity. RESULTS: Although it is widely believed that
      genetics contribute significantly to the variability in body fatness, the
      available data do not support a role for defects in resting metabolic rate,
      substrate metabolism, dietary induced thermogenesis, or the energy cost of
      physical activity as significant causes of obesity. Furthermore, it is safe to
      say that the human genotype has not changed substantially over the past two to
      three decades. Data from several national surveys indicate that over the past few
      decades, there has been either a slight increase or a very modest decline in
      total energy and fat intake. This suggests that decreases in physical activity
      are a major contributing factor. Participation in leisure time physical activity
      is low but has remained relatively constant. However, an increased reliance on
      technology has substantially reduced work-related physical activity and the
      energy expenditure required for daily living. CONCLUSION: The most likely
      environmental factor contributing to the current obesity epidemic is a continued
      decline in daily energy expenditure that has not been matched by an equivalent
      reduction in energy intake. Because daily energy expenditure is decreasing, it is
      difficult for most people to restrict intake to meet energy requirements, and
      more and more people are becoming obese. Thus, increasing physical activity may
      be the strategy of choice for public health efforts to prevent obesity.

PMID- 10593522
TI  - Assessment of physical activity level in relation to obesity: current evidence
      and research issues.
AB  - PURPOSE: Validations of methods for the assessment of physical activity and
      studies on the relation between energy expenditure of activity and obesity were
      reviewed, with suggestions for further research. DESIGN: Validation studies of
      field methods for the assessment of physical activity against doubly labeled
      water were evaluated, studies on the relation between doubly labeled water
      assessed energy expenditure of activity and obesity are discussed. METHODS: Three
      field methods for the assessment of physical activity, validated with doubly
      labeled water as a criterion method, were included: activity questionnaires,
      heart rate monitoring, and motion sensors. RESULTS: The triaxial accelerometer
      came out as the best field method for the assessment of physical activity,
      followed by the Baecke activity questionnaire. The majority of obese subjects are
      moderately active, and an increase in the activity level of obese subjects is
      limited by the ability to perform exercise of higher intensity. CONCLUSIONS:
      Accelerometers are an objective tool for the assessment of physical activity in
      large populations over periods long enough to be representative for normal daily
      life and with minimal discomfort to the subjects. The accelerometer can be used
      to distinguish differences in activity levels between individuals and to assess
      the effect of interventions on physical activity within individuals.

PMID- 10593523
TI  - Levels of physical activity and inactivity in children and adults in the United
      States: current evidence and research issues.
AB  - PURPOSE: The purpose was to describe current levels of physical activity and
      inactivity among adults and young people in the United States. METHODS: Estimates
      of participation in regular physical activity were derived from three national
      surveys for adults (National Health Interview Survey, National Health and
      Nutrition Examination Survey, and the Behavioral Risk Factor Surveillance System)
      and from the Youth Risk Behavior Survey for high school students. RESULTS:
      Overall, 63.8% of high school students surveyed on the 1997 YRBS reported
      participating in vigorous physical activity for at least 20 min on 3 or more days
      per week. Participation in vigorous activity was higher for boys (72.3%) than
      girls (53.5%), whites (66.8%) compared with blacks (53.9%) and Hispanics (60.4%),
      and decreased with advancing grade. Among adults, 27.7% meet recommended levels
      of either moderate or vigorous physical activity, whereas 29.2% report no regular
      physical activity outside of their work. Gender differences in participation in
      physical activity are less pronounced than in youth, and age-related patterns
      were complex. Whites are more active than blacks and Hispanics, and persons with
      higher family incomes and more education report being more physically active.
      There have been only minor changes in reported participation in leisure time
      physical activity over the past 15 yr. CONCLUSION: National estimates of physical
      activity appear to be reliable and valid for adults but may be less so for
      adolescents and are poor measures for children. Research is needed to determine
      the role that objective monitoring with accelerometers may play in surveillance.
      Reliable and valid measures of occupational, household, and transportation
      related physical activity and sedentary behaviors are needed to better
      characterize the range of activity that is associated with health.

PMID- 10593524
TI  - Contribution of a sedentary lifestyle and inactivity to the etiology of
      overweight and obesity: current evidence and research issues.
AB  - PURPOSE: The etiology of overweight and obesity is clearly multifactorial, but
      ultimately it is determined by the long-term balance between energy intake and
      expenditure. This review will consider the effects on body weight and the risk of
      obesity of sedentary lifestyles, within the context of dietary habits. METHODS:
      The data from ecological, cross-sectional, and prospective studies that have
      assessed physical activity and dietary intake and their relationship to body
      weight were reviewed. RESULTS: Ecological analyses imply that the increase in the
      prevalence of obesity is more strongly related to lower levels of physical
      activity than higher energy intakes. However, there is a paucity of pertinent
      data from cross-sectional or prospective studies. There is some evidence that
      both a high proportion of dietary fat and low levels of physical activity may
      increase the likelihood of weight gain. However, even the most comprehensive
      studies are unable to account for more than a small proportion of the
      interindividual variance in weight gain, so it is difficult to usefully assess
      their relative importance. Furthermore, there are insufficient data that pertain
      to "sedentary lifestyles" to segregate any putative effect from a protective
      effect of exercise. All the data in this review is NHLBI Evidence category C.
      CONCLUSIONS: This review provides clear evidence that low levels of physical
      activity are associated with an increased risk of weight gain and obesity. On
      balance, the evidence is suggestive of a causal link, but the experimental
      designs are too weak is provide conclusive evidence. The potential effect of
      interactions between diet and activity have largely been ignored. To make
      progress in this area, a number of key issues need to be resolved with regard to
      the methodology, study design, and statistical analysis of prospective
      epidemiological studies. In the meantime, data need to be drawn from other
      sources, particularly those studies designed to elucidate the mechanism of action
      of diet and physical activity in the etiology of obesity, to establish rational
      interventions to guide public health policies.

PMID- 10593525
TI  - Physical activity in the prevention of obesity: current evidence and research
      issues.
AB  - PURPOSE: The relation between habitual physical activity and the prevention of
      overweight and obesity in adults based on the evidence from the epidemiologic
      literature is described. METHODS: Literature was reviewed of current findings
      from large population-based studies of forward directionality in which physical
      activity was considered as a primary study factor. RESULTS: The longitudinal
      evidence suggests that habitual physical activity plays more of a role in
      attenuating age-related weight gain, rather than in promoting weight loss.
      Moreover, recent data suggest that increasing amounts of physical activity may be
      necessary to effectively maintain a constant body weight with increasing age.
      CONCLUSION: Over decades, small savings in excess weight gain accumulate into net
      savings that may be quite meaningful with regard to minimizing the risk
      associated with obesity-related disorders. The question remains as to how
      important maintaining a constant body weight through middle age and into older
      age is to healthy, already-active people of normal body weight.

PMID- 10593526
TI  - Physical activity in the treatment of the adulthood overweight and obesity:
      current evidence and research issues.
AB  - PURPOSE: The purpose of this paper is to review the evidence on the role of
      physical activity in the treatment of adult overweight and obesity. Three
      specific questions are addressed: (1) Does exercise alone produce weight loss?
      (2) Does exercise in combination with diet produce greater weight loss than diet
      only? and (3) Does exercise in combination with diet produce better maintenance
      of weight loss than diet alone? METHODS: The literature initially identified by
      the Expert Panel on Clinical Guidelines for the Treatment of Obesity, three key
      meta analyses, and additional literature searches were used to identify
      randomized trials related to the three aforementioned topics. These articles were
      reviewed and tabulated. RESULTS: Six of 10 randomized studies found significantly
      greater weight loss in exercise alone versus no treatment controls. The magnitude
      of the effect averaged 1-2 kg. Only 2 of 13 studies found significant differences
      in initial weight loss for diet plus exercise versus diet only, although almost
      all studies pointed in this direction. Six studies were identified with
      maintenance periods of at least 1 yr. In two of the six there were significant
      long term differences favoring diet plus exercise, but in every study considered
      the direction of the difference favored diet plus exercise. Other strong evidence
      showing benefits of exercise for long-term weight loss comes from correlational
      analyses which consistently find that those individuals who report the greatest
      exercise have the best maintenance of weight loss. CONCLUSIONS: Randomized trials
      consistently show benefits of exercise for weight loss, but the effects are often
      modest. This may result from small sample sizes, short study duration, and poor
      adherence to the exercise prescriptions. To better define the doses and types of
      exercise that will promote long-term weight loss, it is necessary to develop
      better ways to measure exercise and promote adherence to exercise.

PMID- 10593527
TI  - Physical activity in the treatment of childhood overweight and obesity: current
      evidence and research issues.
AB  - PURPOSE: This paper reviews the utility of exercise as a treatment for overweight
      and obese children and adolescents. METHODS: Computer database searches
      identified 13 studies that met the following criteria for inclusion: 1) obese
      children or adolescents were provided either different types of exercise programs
      or an exercise program compared with a no-exercise control, 2) subjects were
      randomly assigned to groups or assigned by matching on demographic and
      anthropometric variables, and 3) the exercise program was at least 2 months in
      duration. RESULTS: The only area in which there were a sufficient number of
      studies to make a quantitative analysis was the comparison of diet versus diet
      plus exercise programs, which suggested that exercise adds to the effect of diet
      in the short-term treatment of pediatric obesity. There was not enough research
      to evaluate the effects of exercise alone. The majority of findings indicate
      fitness changes are greater for subjects provided exercise alone or exercise
      combined with diet in comparison with subjects provided no exercise (control) or
      diet alone. CONCLUSIONS: Research on effects of exercise or physical activity in
      pediatric obesity treatments are encouraging and may be important for improving
      treatment outcome for obesity and comorbid conditions. Recommendations for future
      research are presented.

PMID- 10593528
TI  - Physical activity and prevention and treatment of weight gain associated with
      pregnancy: current evidence and research issues.
AB  - PURPOSE: The purpose of this study was to examine the evidence in the literature
      for a relationship between physical activity and weight development during and
      after pregnancy. METHODS: A retrospective analysis of the literature, mainly
      based on an extended MEDLINE search and the Pregnancy and Childbirth Database
      (Cochrane), was conducted. RESULTS: Weight development during pregnancy is the
      result of numerous interacting factors, with physical activity being one
      important determinant of weight outcome and eventually also overweight and
      obesity. Several methodological matters complicate the interpretation of the
      interrelationships: generally body weight and not fat has been measured,
      sociobehavioral confounders have rarely been accounted for, and the time frame to
      determine the effect of pregnancy on later weight development has been highly
      variable. Most studies concentrate on the role of physical activity, such as
      recreational activity and sports, on the safety of the pregnant mother and the
      fetus. The few studies that address the question of exercise and fat deposition
      found slightly a smaller increase in skinfold measures in pregnant women who
      exercised. Factors such as the self-selection of well-educated women under study
      and of normal body weight, as well as the lack of controls, limit the
      possibilities to which these results can be extrapolated. CONCLUSION: Little
      information is available on these issues and the quality of information is at
      most at the evidence type D level, according to the NHLBI classification system.
      Future research priorities include proper prospective control trials of this
      important aspect of an obesity preventing life style tool, as well as studies
      concerning the preventive effects of physical activity on weight retention after
      pregnancy, an issue not as yet addressed in the literature.

PMID- 10593530
TI  - Is abdominal fat preferentially reduced in response to exercise-induced weight
      loss?
AB  - PURPOSE: It is known that a preferential deposition of fat in the abdominal
      region is the obesity phenotype that conveys the greatest health risk. Although
      physical activity is commonly prescribed to reduce obesity, the influence of
      exercise-induced weight loss on abdominal fat is unclear. This review was
      undertaken to clarify whether abdominal fat is preferentially reduced consequent
      to weight loss induced by regular exercise. METHODS: A literature search
      (Medline, 1966-1998) was performed using appropriate keywords to identify studies
      reporting changes in both whole body and abdominal fat in response to exercise.
      RESULTS: At present there are no randomized controlled trails (RCT) wherein it
      was clear that exercise alone induced weight loss. For the four RCT within which
      regular exercise was not associated with weight loss, abdominal fat measured by
      waist circumference was unchanged. A similar trend is observed for the
      nonrandomized studies. Abdominal obesity as measured by waist circumference is
      unchanged for those studies reporting no loss in weight or fat; however, a modest
      reduction (approximately 3 cm) is observed in response to exercise-induced weight
      loss of about 3 kg. Without exception, these studies were not designed to
      determine whether abdominal obesity was preferentially reduced. Absent from the
      literature are RCT that employ imaging techniques (e.g., computerized tomography
      or magnetic resonance imaging) to determine whether exercise-induced weight loss
      is associated with reductions in either visceral or abdominal subcutaneous fat.
      However, the findings from four nonrandomized or controlled studies report that
      exercise with or without weight loss is associated with reductions in both
      visceral and subcutaneous fat. CONCLUSION: There is insufficient evidence to
      determine whether exercise-induced weight loss is associated with reductions in
      abdominal fat. Clearly there is a need for carefully controlled studies wherein
      the primary aim is to determine the influence of regular exercise on total and
      abdominal adiposity.

PMID- 10593531
TI  - Physical activity and regulation of food intake: current evidence.
AB  - OBJECTIVE: The evidence was reviewed on how physical activity could influence the
      regulation of food intake by either adjusting the sensitivity of appetite control
      mechanisms or by generating an energy deficit that could adjust the drive to eat.
      DESIGN: Interventionist and correlational studies that had a significant
      influence on the relationship between physical activity and food intake were
      reviewed. Interventionist studies involve a deliberate imposition of physical
      activity with subsequent monitoring of the eating response. Correlational studies
      make use of naturally occurring differences in the levels of physical activity
      (between and within subjects) with simultaneous assessment of energy expenditure
      and intake. SUBJECTS: Studies using lean, overweight, and obese men and women
      were included. RESULTS: Only 19% of interventionist studies report an increase in
      energy intake after exercise; 65% show no change and 16% show a decrease in
      appetite. Of the correlational studies, approximately half show no relationship
      between energy expenditure and intake. These data indicate a rather loose
      coupling between energy expenditure and intake. A common sense view is that
      exercise is futile as a form of weight control because the energy deficit drives
      a compensatory increase in food intake. However, evidence shows that this is not
      generally true. One positive aspect of this is that raising energy expenditure
      through physical activity (or maintaining an active life style) can cause weight
      loss or prevent weight gain. A negative feature is that when people become
      sedentary after a period of high activity, food intake is not "down-regulated" to
      balance a reduced energy expenditure. CONCLUSION: Evidence suggests that a high
      level of physical activity can aid weight control either by improving the
      matching of food intake to energy expenditure (regulation) or by raising
      expenditure so that it is difficult for people to eat themselves into a positive
      energy balance.

PMID- 10593529
TI  - Physical activity and weight gain and fat distribution changes with menopause:
      current evidence and research issues.
AB  - PURPOSE: At the onset of menopause a woman's body weight reaches its maximum. For
      any given subsequent body weight there is an increase in relative body fat and
      abdominal fatness with advancing age. The increased body fatness and abdominal
      fat distribution are associated with a high incidence of cardiovascular disease
      and certain cancers, particularly breast cancer. The aim of this analysis was to
      assess the role of physical activity for weight gain and changes in fat
      distribution occurring with menopause. METHODS: A systematic review based on a
      Medline search was conducted. RESULTS: According to cross-sectional observational
      studies postmenopausal women with high levels of physical activity have lower
      body fat and abdominal fat. Longitudinal studies show that physically active
      women are less likely to gain body fat and abdominal fat after menopause than
      sedentary women (Evidence category C). There are very few randomized controlled
      trials (RCT) comparing exercise with no intervention, and diet with diet plus
      exercise, and the results do not allow a firm conclusion as to whether physical
      activity may prevent or limit the gain of total fat and abdominal fat after
      menopause, or whether it may be effective as part of an obesity treatment
      program. CONCLUSIONS: There is a need for RCT to evaluate the effect of increased
      physical activity and fitness as a tool for prevention of the changes in body
      composition associated with menopause and aging in normal weight women. The
      efficiency of different programs of exercise training as a treatment option in
      postmenopausal women with existing overweight and obesity should be investigated.
      RCT should have the appropriate design and size and use accurate methods to
      assess exercise compliance, body composition, and intra-abdominal adipose tissue.

PMID- 10593532
TI  - Physical activity and preference for selected macronutrients.
AB  - OBJECTIVE: The impact of physical exercise on macronutrient preferences was
      examined with a perspective to improve preventive and therapeutic strategies of
      obesity. DESIGN: The literature was reviewed pertaining to the acute effects of
      physical activity and the short-term and chronic effects of exercise training on
      macronutrient preferences. RESULTS: The presently available literature does not
      permit to establish a consensus regarding the impact of physical activity, be it
      acute or long-term, on macronutrient selection. However, one observation stands
      out and that is the fact that dietary fat intake needs to be controlled in order
      for exercise to produce a negative energy and fat balance. CONCLUSION: Because
      active individuals do not systematically choose foods that are low in fat
      content, it is important to provide nutritional guidelines in a context where
      physical activity aims at reducing or better controlling body weight.

PMID- 10593533
TI  - Physical activity and the progressive change in body composition with aging:
      current evidence and research issues.
AB  - PURPOSE: The purpose was to review studies that have examined the effect of
      aerobic (AEX) or resistance exercise (REX) on body composition in older
      individuals (>55 yr). Our goal was to examine the effect of these two exercise
      paradigms on fat mass and fat-free mass and to consider those factors that may
      explain variability in findings among studies. METHODS: We conducted a literature
      search (Medline, 1984-1999) for intervention studies (at least 2 months in
      duration) that have examined the independent effect of either REX or AEX on body
      composition in older individuals. RESULTS: AEX decreased fat mass (range: -0.4 to
      -3.2 kg) but had little effect on fat-free mass. The change in fat mass with AEX
      was related to the duration of the exercise program (r = 0.51; P < 0.02) but not
      to body composition methodology. In contrast, REX reduced fat mass (range: -0.9
      to -2.7 kg) and increased fat-free mass (range: 1.1 to 2.1 kg). Changes in body
      composition with REX were not related to body composition methodology or the
      duration of the exercise program. CONCLUSION: Both AEX and REX appear to be
      beneficial in reducing body fat. REX appears to have the additional benefit of
      increasing fat-free mass.

PMID- 10593534
TI  - Overweight and obesity in the mortality rate data: current evidence and research
      issues.
AB  - PURPOSE: The relation between indicators of overweight (body mass index (BMI))
      and all-cause mortality and factors that potentially affect such a relationship
      were reviewed. METHODS: The literature was reviewed. RESULTS: Although there are
      many reports on the relationship between indicators of overweight (such as BMI)
      and all-cause mortality, there are no two studies that have been analyzed
      identically. It is now usually assumed that there is a U- or J-shaped association
      between BMI and mortality, but there are many issues that remain unsolved until
      today. These issues include the effects of: adequate control for cigarette
      smoking; adequate control for (sub)clinical disease at baseline; adequate control
      for intermediate risk factors; adequate measures for exposure to obesity; age,
      period, and cohort effects; adequate control for underlying lifestyle factors;
      adequate control or stratification for ethnicity and socioeconomic status;
      effects of sample size and duration of follow-up; and reliance on self-reported
      body weight and height. CONCLUSION: The literature is dominated by studies in
      young adult and middle-aged white inhabitants of North America and Europe. In
      those populations, it seems well accepted that lowest mortality is in the range
      of BMI between 18.5 and 25 kg.m(-2). When BMI reached values of 30 kg x m(-2) or
      more, mortality is substantially elevated by about 50-150%. These results may not
      be generalizable to other populations, and more studies are needed. All evidence
      is of category C (observational studies).

PMID- 10593535
TI  - Comorbidities of overweight and obesity: current evidence and research issues.
AB  - PURPOSE: The evidence with regard to the relationship of obesity with medical
      comorbidities was assessed and priority research issues identified. METHODS: The
      existing literature in English was surveyed. RESULTS: The evidence is
      overwhelming on the association of obesity to a number of medical conditions.
      These include: insulin resistance, glucose intolerance, diabetes mellitus,
      hypertension, dyslipidemia, sleep apnea, arthritis, hyperuricemia, gall bladder
      disease, and certain types of cancer. The independent association of obesity
      seems also clearly established for coronary artery disease, heart failure,
      cardiac arrhythmia, stroke, and menstrual irregularities. The relationship
      between central (or upper body) obesity and the above conditions is positive for
      most of them but with a lesser number of studies. Most of the fat distribution
      studies have been done using anthropometric measurements rather than the more
      accurate magnetic resonance imaging or computer tomographic scans. Priority
      research issues include the following: more definitive data on the relation of
      central fat to comorbidities; the proportional importance of subcutaneous versus
      visceral fat in producing comorbidities; the relationship between obesity and
      psychiatric disease; the genetics of the relationship between obesity and each of
      the comorbidities; the independent contribution of diet and of sedentariness to
      the development of each of the comorbidities; the impact of gender, race,
      intensity, and duration on these associations. CONCLUSIONS: The evidence for the
      relationship of obesity to a number of comorbidities is strong, though the
      strength of the relationship varies with the condition. Much more research is
      necessary on causation and on what other factors may play an interactive role.

PMID- 10593536
TI  - Physical activity for preventing and treating obesity-related
      dyslipoproteinemias.
AB  - PURPOSE: The clinical trial data were reviewed on effects of physical activity on
      obesity-related dyslipoproteinemias (specifically low HDL-cholesterol (HDL-C),
      elevated triglycerides (TG), and high total and LDL-cholesterol (TC and LDL-C))
      in adult men and women. METHODS: Effort was made to identify all randomized
      clinical trials (RCT), with exercise intervention programs of at least 4 months'
      duration, which had lipoprotein outcomes. Those that had both an exercise only
      intervention and control groups or both a diet plus exercise and identical diet
      only intervention groups were reviewed. Tables were developed of baseline
      characteristics and weight and lipoprotein changes for aerobic exercise trials by
      body mass index: 1) < 25.0 kg x m(-2), 2) 25.0-29.9 kg x m(2), and 3) > or = 30.0
      kg x m(-2)and for studies involving resistance exercise or increased energy
      expenditure from daily activities versus structured exercise programs. RESULTS:
      Very few RCT were found that specifically addressed the role of physical activity
      in preventing or treating obesity-related adverse lipoprotein levels. There was
      essentially no evidence found in lean or overweight men or women to support a
      specific role for exercise in improving undesirable lipoprotein levels; however,
      trial data strongly suggest that the addition of exercise to a hypocaloric,
      reduced-fat diet improves HDL-C and TG in men and women with generally desirable
      initial levels and reduces LDL-C in men and women with initially elevated LDL-C
      levels. The evidence is also reasonably strong that weight loss, including that
      achieved solely by exercise, improves HDL-C and TG in obese men, without reducing
      LDL-C, whereas it remains weak for women. There are also virtually no trial data
      to support a role for resistance exercise or an increase in daily living
      activities for improving obesity-related lipoproteins. CONCLUSIONS: Current
      evidence from RCT is too limited to determine whether physical activity can raise
      low HDL-C or lower high TG or LDL-C levels in overweight and obese individuals.

PMID- 10593537
TI  - Effects of physical activity on insulin action and glucose tolerance in obesity.
AB  - PURPOSE: The purpose of this paper is to examine the effect of physical activity
      on glucose tolerance in relation to obesity. METHODS: We reviewed current
      literature, with particular emphasis on randomized clinical trials, to prepare an
      evidence-based evaluation of the effects of physical activity on glucose
      intolerance in obesity. RESULTS: This literature review indicates that physical
      activity has favorable effects on reducing insulin resistance in obesity and
      among patients with type 2 diabetes mellitus. Improvement in glucose tolerance is
      less consistently observed and is related to intensity of exercise, collateral
      changes in adiposity, the interval between exercise and testing of glucose
      tolerance, and the baseline severity of glucose intolerance. CONCLUSION: A review
      of currently published clinical trial data supports the conclusion that physical
      activity can reduce insulin resistance and improve glucose intolerance in
      obesity.

PMID- 10593538
TI  - Physical activity in the prevention and treatment of hypertension in the obese.
AB  - Physical activity in the prevention and treatment of hypertension in the obese.
      PURPOSE: The purpose of this paper was to assess the value of physical exercise
      in the prevention and treatment of hypertension with particular attention to
      possible interactions with relative weight. METHODS: We describe epidemiological
      studies and report meta-analyses of randomized intervention trials, i.e.,
      randomized controlled trials on dynamic physical training and randomized
      comparative trials of exercise and diet. RESULTS: Epidemiological studies show an
      inverse relationship between physical activity or fitness and the incidence of
      hypertension, which was either independent of body size or more pronounced in the
      overweight. The weighted net reduction of blood pressure in response to dynamic
      physical training averages 3.4/2.4 mm Hg (P < 0.001), which appears to be
      unrelated to the initial body mass index (BMI) and to its training-induced
      changes. Exercise is less effective than diet in lowering blood pressure (P <
      0.02), and adding exercise to diet does not appear to further reduce blood
      pressure. Future studies should observe scientific criteria more strictly,
      address the truly obese (BMI > or = 30 kg x m(-2)) and attempt to resolve the
      blood pressure lowering mechanisms. CONCLUSION: Physical activity contributes to
      the control of blood pressure in overweight as well as in lean subjects.

PMID- 10593539
TI  - Physical activity in the prevention and treatment of a thrombogenic profile in
      the obese: current evidence and research issues.
AB  - PURPOSE: To evaluate the impact of regular physical activity on thrombogenic
      profile in obese individuals. DESIGN: Medline-based literature search with
      emphasis on controlled randomized clinical trials. The focus was on the impact of
      physical activity on platelet aggregation, fibrinogen, and plasminogen activator
      inhibitor-1(PAI-1) in overweight and obese subjects. RESULTS: Physical activity
      increases acutely 1) platelet number and activity, 2) activation of coagulation
      leading to a thrombin generation, and 3) simultaneous activation of fibrinolysis.
      On the other hand, hemostatic changes resulting from regular exercise training
      are limited to few data on platelets and blood coagulation and to some
      indications of increased fibrinolysis. Obesity is a risk factor for
      atherosclerotic cardiovascular diseases, and it is associated with
      hypertriglyceridemia, hyperinsulinemia, and non-insulin-dependent diabetes
      (NIDDM). These states interfere with a balance between blood coagulation and
      fibrinolysis leading to an increased thrombogenesis. Regular physical activity
      reduces platelet aggregability, while the effects on plasma fibrinogen and
      fibrinolytic activity remain unclear. CONCLUSIONS: Although obesity associates
      with several unfavorable derangements in the hemostatic system, data on the
      interactions of regular physical activity with blood coagulation in overweight or
      obese subjects are scarce. Therefore, controlled randomized clinical trials with
      adequate statistical power are needed for the evaluation of physical activity in
      the prevention and treatment of obesity-related atherothrombotic disorders.

PMID- 10593540
TI  - Physical activity in the prevention and treatment of other morbid conditions and
      impairments associated with obesity: current evidence and research issues.
AB  - PURPOSE: To evaluate the current status of knowledge concerning the effects of
      physical activity in the treatment and prevention of obesity- related problems,
      including cancers of the colon, breast, uterus, and prostate; gallstones;
      osteoarthritis; back pain; sleep apnea; reproductive abnormalities; and impaired
      health-related quality of life. DESIGN: A Medline literature search on the
      effects of physical activity in the above conditions was conducted. Only studies
      with some measure of weight and a description of the type of physical activity
      were included. RESULTS: No controlled randomized trials of exercise in the
      treatment of any of the studied conditions in obese patients were identified.
      Most of the epidemiologic studies reviewed were beset with severe methodological
      weaknesses. Most of the 18 studies on physical activity and colon cancer risk
      showed a protective effect that in some studies appeared to be greater than
      expected by weight loss alone. Some but not all studies of hormone-dependent
      cancers and gallstones showed a protective effect for physical activity. There
      were insufficient data on the role of exercise for the other morbid conditions
      studied. CONCLUSION: The scarce data available on the role of physical activity
      in the prevention of obesity-related chronic conditions listed above suggest a
      protective role that needs to be examined further in studies with improved
      methodologies. Well-designed intervention trials are needed to assess the role of
      physical activity in the treatment and long-term outcome of obese patients with
      these co-morbid conditions.

PMID- 10593541
TI  - Effects of physical inactivity and obesity on morbidity and mortality: current
      evidence and research issues.
AB  - PURPOSE: The purpose of this review was to address three specific questions. 1)
      Do higher levels of physical activity attenuate the increased health risk
      normally observed in overweight or obese individuals? 2) Do obese but active
      individuals actually have a lower morbidity and mortality risk than normal weight
      persons who are sedentary? 3) Which is a more important predictor of mortality,
      overweight or inactivity? METHODS: We initially identified more than 700 articles
      that included information on the exposure variables of body habitus (body mass
      index, body composition, or body fat pattern) and physical activity habits, and
      on outcomes such as morbidity or mortality. To be included in the review, we
      required that an article include an analysis of one of our outcomes by strata of
      the two exposure variables. We excluded review articles and reports of cross
      sectional analyses. We used an evidence-based approach to evaluate the quality of
      the published data. RESULTS: We summarized results from 24 articles that met all
      inclusion criteria. Data were available for the outcomes of all-cause mortality,
      cardiovascular disease mortality, coronary heart disease (CHD), hypertension,
      type 2 diabetes mellitus, and cancer. Summary results for all outcomes except
      cancer were generally consistent in showing that active or fit women and men
      appeared to be protected against the hazards of overweight or obesity. This
      apparent protective effect was often stronger in obese individuals than in those
      of normal weight or who were overweight. There were too few data on cancer to
      permit any conclusions. CONCLUSIONS: There are no randomized clinical trials on
      the topics addressed in this review. All studies reviewed were prospective
      observational studies, so all conclusions are based on Evidence Category, C. The
      conclusions for the three questions addressed in the review are: 1) regular
      physical activity clearly attenuates many of the health risks associated with
      overweight or obesity; 2) physical activity appears to not only attenuate the
      health risks of overweight and obesity, but active obese individuals actually
      have lower morbidity and mortality than normal weight individuals who are
      sedentary, and 3) inactivity and low cardiorespiratory fitness are as important
      as overweight and obesity as mortality predictors. Research needs include
      extending current observations to more diverse populations, including more
      studies in women, the elderly, and minority groups, assessment methods need to be
      improved, and randomized clinical trials addressing the questions discussed in
      this review should be undertaken. Owing to size, complexity, and cost, these
      trials will need to be designed with valid noninvasive measures of subclinical
      disease processes as outcomes.

PMID- 10593542
TI  - Economic costs of obesity and inactivity.
AB  - PURPOSE: The purpose of this paper is to assess the economic costs of inactivity
      (including those attributable to obesity). These costs represent one summary of
      the public health impact of increasingly sedentary populations in countries with
      established market economies. Components of the costs of illness include direct
      costs resulting from treatment of morbidity and indirect costs caused by lost
      productivity (work days lost) and forgone earnings caused by premature mortality.
      METHODS: We searched the Medline database for studies reporting the economic
      costs of obesity or inactivity, or cost of illness. From the identified
      references those relating to obesity or conditions attributable to obesity were
      reviewed. Chronic conditions related to inactivity include coronary heart disease
      (CHD), hypertension, Type II diabetes, colon cancer, depression and anxiety,
      osteoporotic hip fractures, and also obesity. Increasing adiposity, or obesity,
      is itself a direct cause of Type II diabetes, hypertension, CHD, gallbladder
      disease, osteoarthritis and cancer of the breast, colon, and endometrium. The
      most up-to-date estimates were extracted. To estimate the proportion of disease
      that could be prevented by eliminating inactivity or obesity we calculated the
      population-attributable risk percent. Prevalence based cost of illness for the
      U.S. is in 1995 dollars. RESULTS: The direct costs of lack of physical activity,
      defined conservatively as absence of leisure-time physical activity, are
      approximately 24 billion dollars or 2.4% of the U.S. health care expenditures.
      Direct costs for obesity defined as body mass index greater than 30, in 1995
      dollars, total 70 billion dollars. These costs are independent of those resulting
      from lack of activity. CONCLUSION: Overall, the direct costs of inactivity and
      obesity account for some 9.4% of the national health care expenditures in the
      United States. Inactivity, with its wide range of health consequences, represents
      a major avoidable contribution to the costs of illness in the United States and
      other countries with modern lifestyles that have replaced physical labor with
      sedentary occupations and motorized transportation.

PMID- 10593543
TI  - Progressive spinal muscular atrophies.
AB  - Spinal muscular atrophy is the most common autosomal-recessive genetic disorder
      lethal to infants. It was first described in the 1890s. Since then our
      understanding of the disorder has progressed significantly. Progression of the
      disease is due to loss of anterior horn cells, thought to be caused by apoptosis.
      Diagnosis is based on the course of the illness, as well as certain changes seen
      on nerve and muscle biopsy and electrodiagnostic studies. More recently, our
      understanding of the genetics of this disorder has provided a noninvasive
      approach to diagnosis. This method of testing has its downside, but the quest for
      a more sensitive analysis is still underway. Even though our knowledge of this
      disease has come a long way since its first recognition, the therapies available
      to these children are still only supportive. Again, researchers eagerly look for
      new therapeutic interventions to allow for improved quality of life and an
      extended life span.

PMID- 10593544
TI  - Treatment of acquired epileptic aphasia with the ketogenic diet.
AB  - Acquired epileptic aphasia remains a poorly understood entity, which is
      frequently difficult to treat. Previously described treatment modalities have
      included antiepileptic drugs, corticosteroids, intravenous immunoglobulin, and
      multiple subpial transections. We describe three patients with acquired epileptic
      aphasia refractory to traditional treatments who were successfully treated with
      the ketogenic diet. All three patients had lasting improvement of their language,
      behavior, and seizures for 26, 24, and 12 months, respectively. This is the first
      reported series of patients with acquired epileptic aphasia successfully treated
      with the ketogenic diet, and suggests a new therapeutic alternative for patients
      with this often difficult-to-treat disorder.

PMID- 10593545
TI  - Multimodality evoked potential findings in infants with congenital heart defects.
AB  - Evoked potentials are sensitive prognostic tools in young infants at risk for
      developmental disability. The objective of this prospective study was to
      determine whether infants with congenital heart defects demonstrate evoked
      potential abnormalities prior to or following open heart surgery, and to examine
      the association between these abnormalities and developmental status 1 year
      following surgery. A consecutive series of newborns (less than 1 month old) and
      infants (1 month to 2 years old) were recruited. Somatosensory and brain stem
      auditory evoked potentials were carried out before or after cardiac surgery, or
      both. One year later, neurologic examination and standardized measures of motor
      performance and functional independence were carried out. Twenty-seven newborns
      and 31 infants underwent perioperative somatosensory evoked potential recordings.
      Results indicate that perioperative somatosensory evoked potential abnormalities
      were common in newborns (41%) but not in infants (13%) with congenital heart
      defects. Brainstem conduction times were within normal limits in all subjects;
      however, 32% presented with mild elevations in hearing thresholds. All newborns
      with abnormal somatosensory evoked potentials had abnormal neurologic
      examinations both perioperatively and again 1 year after open heart surgery.
      Moreover, standardized developmental assessments 1 year following surgery
      indicate that all newborns with somatosensory evoked potential abnormalities had
      developmental deficits in one or more domains. Somatosensory evoked potential
      abnormalities in the perioperative period are common in newborns with congenital
      heart defects, and are strongly predictive of persistent developmental delay
      later.

PMID- 10593546
TI  - Cranial magnetic resonance imaging examination of normal term neonates: a pilot
      study.
AB  - This pilot study's aim was to determine, using magnetic resonance imaging (MRI),
      if and to what extent asymptomatic intracranial hemorrhage occurs in normal term
      neonates after uncomplicated vaginal deliveries. Eight normal, term, vaginally
      delivered infants and three cesarean-section deliveries used as controls
      underwent cranial MRI. No sedation was administered. Small subdural hematomas of
      the falx cerebri or tentorium cerebelli were found in half of those with an
      uneventful vaginal delivery. Pediatric follow-up, on average 3.9 years after the
      MRI study was performed, demonstrated normal growth and development. It appears
      that more data is needed to confirm the observation that the intracranial
      hemorrhages described should not be considered the etiology for neurologic
      abnormalities present in symptomatic neonates.

PMID- 10593547
TI  - Broader clinical spectrum of Fukuyama-type congenital muscular dystrophy
      manifested by haplotype analysis.
AB  - Fukuyama-type congenital muscular dystrophy, Walker-Warburg syndrome, and muscle
      eye-brain disease are clinically similar autosomal-recessive diseases,
      characterized by congenital muscular dystrophy, cobblestone lissencephaly, and
      eye anomalies. The classification of these disorders remains controversial. We
      analyzed five patients with congenital muscular dystrophy from four families who
      had severe eye and brain anomalies, such as retinal dysplasia and hydrocephalus,
      using polymorphic microsatellite markers flanking the Fukuyama-type congenital
      muscular dystrophy locus on chromosome 9q31. All patients were heterozygous for
      the Fukuyama muscular dystrophy founder haplotype with 3-kb insertion. In three
      cases, the other chromosome without the 3-kb insertion exhibited the same
      haplotype with a nonsense mutation on exon 3 of the Fukuyama gene. Thus, these
      three patients were compound heterozygotes for the condition. Severe eye
      anomalies such as retinal dysplasia or detachment and hydrocephalus could be
      included in the clinical spectrum of Fukuyama muscular dystrophy. The clinical
      spectrum of this disease is much broader than previously presumed.

PMID- 10593548
TI  - Cognitive and behavioral effects of carbamazepine in children: data from benign
      rolandic epilepsy.
AB  - The effects of antiepileptic drugs on cognition are difficult to delineate, yet
      of critical importance for children with epilepsy. We investigated the cognitive
      and behavioral effects of carbamazepine in children with benign rolandic
      epilepsy. Ten subjects with benign rolandic epilepsy were evaluated with and
      without carbamazepine treatment. Fourteen unmedicated subjects with migraine
      headache evaluated twice served as a control group. Subjects were 6 to 12 years
      of age, fluent in English, and not mentally retarded. We found that children with
      benign rolandic epilepsy were quicker on a visual-search task and recalled
      stories better when not treated than when treated with carbamazepine. After
      correction for multiple comparisons only the memory finding remained significant.
      Higher carbamazepine serum level was associated with slower performance on the
      same visual-search task. This latter finding did not meet multiple comparison
      criteria. Numerous significant practice effects were found within the control
      group. Comparisons with reliable change indices identified two subjects with
      benign rolandic epilepsy with particularly poor scores while receiving
      carbamazepine. These findings suggest some effects on memory from carbamazepine;
      however, they do not support meaningful dosage-related effects, within the
      recommended range. Significant practice effects confirmed the need to control for
      such effects when evaluating treatments. Finally, identification of two subjects
      who performed more poorly while on carbamazepine suggests that some children
      might experience particular difficulties while receiving this medication and
      highlights the need to investigate individual subject responses to treatment.

PMID- 10593549
TI  - Neurodevelopmental outcome in children with intrauterine growth retardation: a 3
      year follow-up.
AB  - The study was designed to detect early clinical predictors of developmental
      outcome in children with intrauterine growth retardation. Eighty-five children
      with intrauterine growth retardation were followed up prospectively to 3 years of
      age, using biometric parameters, perinatal risk questionnaires, and
      neurodevelopmental evaluations. Forty-two children served as controls. A
      significant difference in neurodevelopmental score at 3 years of age was noted
      between the intrauterine growth retardation and control groups (P < .001). In the
      intrauterine growth retardation group, the clinical parameters that most
      significantly correlated with outcome were cephalization index (head
      circumference:birthweight ratio), neonatal risk score, and birthweight. The best
      predictor of 3-year outcome was the cephalization index (P < .01). The children
      with intrauterine growth retardation with neonatal complications had
      significantly lower IQ scores (P < .05) and a poorer neurodevelopmental outcome
      (P < .01) than those without complications. Children with intrauterine growth
      retardation are at higher risk for developmental disabilities than are controls,
      especially in the presence of neonatal complications and a high cephalization
      index.

PMID- 10593550
TI  - Increased cerebrospinal fluid glycine: a biochemical marker for a
      leukoencephalopathy with vanishing white matter.
AB  - Recently, a new disease entity has been defined: the disease of vanishing white
      matter. This leukoencephalopathy has an autosomal-recessive mode of inheritance.
      No cause or biochemical marker is known. We studied cerebrospinal fluid amino
      acids in five patients with the disease and found a consistent, moderate
      elevation of cerebrospinal fluid glycine in all. The ratio of cerebrospinal fluid
      to plasma glycine was elevated in four patients, in two patients reaching the
      level considered diagnostic for nonketotic hyperglycinemia. The activity of the
      glycine cleavage system was found to be normal in lymphoblasts in two patients.
      The elevation of cerebrospinal fluid glycine in the disease of vanishing white
      matter is either caused by a primary disturbance of glycine metabolism or is
      secondary to excitotoxic brain damage.

PMID- 10593551
TI  - Abnormal visual evoked potentials in children with "Alice in Wonderland" syndrome
      due to infectious mononucleosis.
AB  - Visual illusions characterized by distortion of form, size, reciprocal position
      of objects, movement, or color, labeled as "Alice in Wonderland" syndrome, were
      discussed in children with infectious mononucleosis, as well as in other clinical
      conditions, such as migraine, epilepsy, use of certain hallucinogenic drugs, etc.
      The purpose of our study was to investigate for the first time visual evoked
      potential results in children with "Alice in Wonderland" syndrome associated with
      infectious mononucleosis. Five children with "Alice in Wonderland" syndrome
      associated with infectious mononucleosis underwent visual evoked potential
      studies during and after their clinical symptoms. Visual evoked potential results
      during the disease demonstrated statistically significant high amplitudes of P100
      N145 in all children compared to the control group. A few weeks later, repeated
      studies after the resolution of the complaints were normal. Since the same
      findings can be observed in patients with migraine, we postulate that a common
      pathophysiologic underlying abnormality, which can cause transient focal
      decreased cerebral perfusion, could be involved in the disease process of these
      two conditions.

PMID- 10593552
TI  - Reminiscences of a child neurologist.

PMID- 10593553
TI  - A case of Lafora's disease associated with cardiac arrhythmia.
AB  - Progressive myoclonic epilepsies are rare, genetically transmitted diseases
      characterized by epileptic seizures, myoclonus, and progressive neurologic
      deterioration. Unverricht-Lundborg disease, Lafora's disease, neuronal ceroid
      lipofuscinosis, mitochondrial disorders, and sialidosis are included in this
      group. Lafora's disease is a progressive disorder of the central nervous system
      with onset in the late first or second decade of life and is inherited in an
      autosomal-recessive pattern. The first clinical manifestation is generalized
      tonic-clonic seizures, myoclonus, or both, usually seen between the ages of 11
      and 18 years. The other clinical manifestations are progressive dementia and limb
      ataxia. Diagnosis is based on showing the typical inclusions in the brain, liver,
      skin, or muscle tissue specimens. The case of a 6-year-old male patient, who was
      admitted with the clinical findings of third-degree atrioventricular block and
      dementia and eventually diagnosed with Lafora's disease, is presented.

PMID- 10593554
TI  - Epilepsy with myoclonic absences with early onset: a follow-up study.
AB  - We studied six children (four girls and two boys) suffering from cryptogenic
      myoclonic absence seizures with early onset. The age at onset of the seizures
      ranged between 6 and 27.8 months (mean age +/- SD: 18.5+/-12.4 months). The
      neurologic evaluation was normal in all patients at the first hospital admission.
      After the diagnosis, we followed up all children for at least 5 years. At the end
      of follow-up, two of these patients (a girl and a boy) showed severe mental
      retardation, a high number (from one to three per day) of seizures, and
      persistent pathologic electroencephalograms. The other patients showed normal
      electroencephalograms: all of them were seizure free and without mental
      retardation. The two patients with mental retardation have been treated with
      polytherapy. In all other children we used valproate alone successfully. Our data
      suggest that myoclonic absence seizures with early onset can have a good long
      term prognosis. Valproate is a useful anticonvulsant drug in these patients.
      Mental retardation is present only in patients with poor seizure control.

PMID- 10593555
TI  - Factor V1691 G-A, prothrombin 20210 G-A, and methylenetetrahydrofolate reductase
      677 C-T variants in Turkish children with cerebral infarct.
AB  - Inherited gene defects related to the coagulation system have been reported as
      risk factors for ischemic stroke. These gene defects include a G-A transition at
      nucleotide 1691 in exon 10 of the Factor V gene causing activated protein C
      resistance; a G-A transition in the 3' untranslated region of the prothrombin
      gene at nucleotide position 20210 (G-A), which is associated with increased
      levels of prothrombin activity; and a C-T polymorphism at nucleotide 677 in the
      methylenetetrahydrofolate reductase gene responsible for an alanine to valine
      substitution, resulting in the synthesis of a thermolabile form of
      methylenetetrahydrofolate reductase that causes increased levels of homocysteine.
      The case-control study included 28 patients with cerebral infarction; all were 18
      years of age or younger (range, 10 months to 18 years). Seven (25%) of the 28
      patients were heterozygous for the FV1691 mutation. Five (17.8%) of the patients
      carried the PT20210A mutation. Two (7.1%) of the patients carried both mutations.
      When compared to controls, the difference was significant for both mutations (P =
      .007; .04). The frequency of allele T of methylenetetrahydrofolate reductase 677
      was 0.3214, which was not significant when compared to controls (0.231; P = .3).
      A total of 12 (42.8%) patients carried one or both of the mutations FV1691 G-A
      and PT20210 G-A. From our data, it appears that FV1691 G-A and PT20210 G-A are
      associated with cerebral infarct risk independently. Risk assessment of double
      prothrombotic gene alterations did not reveal synergy between these mutations. In
      conclusion, the presence of FV1691 A and PT20210 A mutations but not the
      methylenetetrahydrofolate reductase 677 TT mutation correlate with the occurrence
      of cerebral infarction in children.

PMID- 10593556
TI  - The effect of carbamazepine and sodium valproate on the blood and serum values of
      children from a third-world environment.
AB  - In third-world countries many children with epilepsy also suffer from
      malnutrition, anemia, liver disease, and immunosuppression. Doctors might have
      reservations about the use of anticonvulsants that could aggravate these
      disorders. The purpose of this study was to establish the prevalence of abnormal
      blood and serum values in children receiving carbamazepine or sodium valproate as
      monotherapy who attended a child neurology clinic serving a third-world community
      in Cape Town, South Africa Blood samples were taken at routine follow-up visits
      from 104 children who had been on carbamazepine or sodium valproate monotherapy
      for at least 6 months. Hematology, serum chemistry, immunoglobulins, and
      anticonvulsant levels were measured by standard laboratory procedures. Very few
      subjects had any values outside accepted normal ranges. When clinically indicated
      and available, carbamazepine and sodium valproate can be prescribed for children
      from a third-world environment. Frequent blood and serum testing is not necessary
      in asymptomatic individuals.

PMID- 10593557
TI  - Agenesis of the corpus callosum associated with DiGeorge-velocardiofacial
      syndrome: a case report and review of the literature.
AB  - We report a patient with clinical and cytogenetic findings consistent with
      DiGeorge-velocardiofacial syndrome and agenesis of the corpus callosum. This
      patient represents the first report of a case of DiGeorge-velocardiofacial
      syndrome associated with such a central nervous system abnormality. This case,
      together with previous reports in the literature, suggests that structural brain
      abnormalities, and in particular abnormalities of the corpus callosum, are part
      of the complex syndrome associated with the chromosomal microdeletion 22q11.2. We
      suggest that the diagnosis of DiGeorge-velocardiofacial syndrome be entertained
      in patients with agenesis of the corpus callosum in the context of other common
      clinical features of this syndrome.

PMID- 10593558
TI  - Interstitial deletion of 14q, 46, XY, del (14) (q24.3q32.1) associated with
      status nonepileptic myoclonia and delayed myelination.
AB  - A Japanese boy with interstitial deletion of the long arm of chromosome 14,
      including band 14q31, is described. The characteristic dysmorphic facial
      features, such as dolichocephaly, bushy eyebrows, horizontal narrow palpebral
      fissures, long philtrum, etc, and mental and motor developmental delay were
      observed. Other characteristic clinical manifestations were anuresis and status
      nonepileptic myoclonia The finding of delayed myelination of the cerebral white
      matter was observed on magnetic resonance examination, suggesting that an unknown
      factor related to myelination in the central nervous system might be localized in
      band 14q31.

PMID- 10593559
TI  - Diagnostic approach to metabolic encephalopathies.

PMID- 10593560
TI  - Automated tandem mass spectrometry for mass newborn screening for disorders in
      fatty acid, organic acid, and amino acid metabolism.
AB  - Development of acylcarnitine and amino acid profiling using tandem mass
      spectrometry, and its application for use with dried blood specimens collected on
      filter-paper cards, has introduced an innovative new technology for detecting
      inborn errors of fatty acid, organic acid, and amino acid metabolism. From
      November 1, 1992 through June 30, 1999 we screened more than 700,000 newborns in
      Pennsylvania, Ohio, North Carolina, and Louisiana. We have prospectively detected
      163 inborn errors of metabolism. Eighty-six patients have amino acid metabolism
      errors. Among them are phenylketonuria, hyperphenylalaninemia, maple syrup urine
      disease, and several urea cycle disorders. Thirty-two have organic acid
      metabolism errors, including glutaric aciduria type 1; 3-methylcrotonyl coenzyme
      A (CoA) carboxylase deficiency, propionic acidemia, methylmalonic acidemia, and 3
      hydroxy-3-methylglutaryl-CoA lyase deficiency; and 45 have fatty acid oxidation
      errors, including 36 with medium-chain acyl-CoA dehydrogenase deficiency. Details
      of the methodology are presented and the potential of this screening technology
      is discussed.

PMID- 10593561
TI  - Value of lumbar puncture in the diagnosis of genetic metabolic encephalopathies.
AB  - Diagnostic testing for genetically determined metabolic disease has for many
      years relied heavily on the use of generalized screening tests that analyze
      groups of related compounds in easily accessible peripheral fluids such as plasma
      and urine. Organic acid profiles in urine and amino acid analysis in plasma are
      two of the most commonly requested tests; these, together with other protocols
      that examine peripheral fluids, have been and continue to be invaluable tools.
      There is, however, an emerging realization that many metabolic encephalopathies
      do not arise secondary to peripheral metabolic changes but rather have their
      origins within the central nervous system. In these cases, testing of peripheral
      fluids might be uninformative. This review is designed to examine the role of
      cerebrospinal fluid analyses in the investigation of infants and children with
      undefined encephalopathies. The aims are to review the conditions in which
      measurement of metabolites in cerebrospinal fluid is critical if a diagnosis is
      to be made, and to emphasize that considerable forethought is often required to
      ensure correct collection and handling of cerebrospinal fluid. Thus, fidelity of
      the diagnostic analytic procedures is maintained. This review will help the
      pediatric neurologist establish practical diagnostic guidelines that in turn will
      help in the recognition of recently described conditions. Those conditions can,
      in general, be identified only after specialized cerebrospinal fluid testing.

PMID- 10593562
TI  - Screening for "prelysosomal disorders": carbohydrate-deficient glycoprotein
      syndromes.
AB  - Physicians have become accustomed to thinking of certain inborn errors of
      metabolism (e.g., lysosomal, peroxisomal, and mitochondrial diseases) as being
      associated with specific subcellular organelles. In recent years, a family of
      disorders of N-glycosylation has been recognized, in which the metabolic defect
      is expressed in the cytosol, endoplasmic reticulum, and Golgi apparatus. These
      could be conveniently thought of as "prelysosomal" disorders. At least six of
      these entities are characterized by hypoglycosylation of many glycoconjugates,
      and have been designated as the carbohydrate-deficient glycoprotein syndromes.
      Given the ubiquity of the products of N-glycosylation in the cellular economy, it
      is not surprising that these defects in metabolism have protean clinical
      manifestations. Delayed development and other neurologic symptoms are wedded to
      variable dysfunctions of the heart, liver, and endocrine and coagulation systems.
      Patients can have dysmorphic features or cerebellar hypoplasia, attesting to the
      antenatal expression of these disorders. The most frequently recognized phenotype
      (several hundred cases worldwide) has been designated carbohydrate-deficient
      glycoprotein syndrome type la, and results from mutations in phosphomannomutase,
      a cytosolic enzyme involved in the synthesis of the lipid-linked oligosaccharide
      that is eventually attached to nascent glycoproteins through the amide group of
      asparagine residues. All forms of carbohydrate-deficient glycoprotein syndrome
      express an excess of hypoglycosylated isoforms of circulating transferrin, which
      serves as a useful screening tool. Physicians should consider screening for
      carbohydrate-deficient glycoprotein syndrome in individuals with delayed
      development, seizures, strokelike episodes, cerebellar hypoplasia, and
      demyelinating neuropathy with or without other signs of multisystem disease.

PMID- 10593563
TI  - Does the patient have a mitochondrial encephalomyopathy?
AB  - The ubiquitous nature of mitochondria, the dual genetic control of the
      respiratory chain, and the peculiar rules of mitochondrial genetics contribute to
      explain the extraordinary clinical heterogeneity of disorders associated with
      defects of oxidative phosphorylation (mitochondrial encephalomyopathies). To
      provide a practical approach to the diagnostic challenge posed by these
      conditions, we critically review the following criteria: (1) clinical
      presentation; (2) family history; (3) laboratory data; (4) neuroradiologic
      patterns; (5) standardized exercise testing; (6) muscle morphology; (7) muscle
      biochemistry; and (8) molecular genetic screening. Judicious sequential
      application of these tools should provide help in recognizing patients with
      mitochondrial disease and define the biochemical and molecular basis of the
      disorder for each patient. This knowledge is indispensable for accurate genetic
      counseling and prenatal diagnosis and is a prerequisite for the development of
      rational therapies, which are still woefully inadequate.

PMID- 10593564
TI  - Diabetes prone BB rats are severely deficient in natural killer T cells.
AB  - Diabetes prone (DP) BB rats develop spontaneous autoimmune hyperglycemia.
      Coisogenic diabetes resistant (DR) BB rats develop diabetes in response to
      immunological and environmental perturbants, but not spontaneously. Both are used
      to model human insulin-dependent diabetes mellitus (IDDM). Deficiencies in
      natural killer (NK) T cells have been implicated in the expression of human IDDM,
      but little is known of their phenotype or function in the rat. We now report that
      the phenotype of NK T cells in the rat is alphabetaTcR+ CD8+ CD4-, comparable to
      the NK T cell phenotype reported for humans, which is alphabetaTcR+ CD4- Valpha24
      JalphaQ, and either CD8- or CD8alphaalpha+. We also report that DP- but not DR-BB
      rats are severely deficient in splenic and intrahepatic NKR-P1+ alphabetaTcR+ (NK
      T) cells. Because RT6+ T cells are deficient in DP-BB rats, and because depletion
      of cells expressing RT6 induces IDDM in DR-BB rats, we studied NK T cells for
      expression of this antigen. We observed that the majority of rat NK T cells
      express RT6+. In addition, injection of cytotoxic anti-RT6.1 monoclonal antibody
      depleted splenic and intrahepatic RT6+ NK T cells, T cells, and NK cells, but
      left intact the RT6- subset of each population. These results suggest that
      deficiencies in NK T cells may play a role in the susceptibility of DP- and DR-BB
      rats, respectively, to spontaneous and induced autoimmune IDDM.

PMID- 10593565
TI  - GAD65 and insulin B chain peptide (9-23) are not primary autoantigens in the type
      1 diabetes syndrome of the BB rat.
AB  - To investigate whether GAD65 whole molecule, GAD65 p35 or insulin B chain peptide
      (amino acids 9-23) play an essential role in the pathogenesis of type 1 diabetes
      in the BioBreeding (BB) rat, we gave serial injections of GAD65, p35 or insulin B
      chain (9-23) to six groups of BB/Worcester rats. The individual antigens were
      administered either intrathymically on day 2 and intraperitoneally in MF 59-0
      adjuvant 5 times during the first 5 weeks, or by intranasal instillation once
      neonatally and 5 days/week for the following 6 weeks. Control groups were
      injected with vehicle only. Age of onset of diabetes and degree of insulitis were
      not different between controls and antigen-treated rats. Rats that received GAD65
      intrathymically and intraperitoneally developed high GAD65-antibody titers
      without altering diabetes development. In GAD65-treated animals, serum antibodies
      recognized epitopes at 3 sites on GAD65 in diabetic animals but only at 1 site in
      non-diabetic animals. GAD65-injected animals also showed a significant reduction
      of IFN-gamma mRNA expression in the thymus. This study provides evidence against
      the hypothesis that GAD65 and insulin B chain peptide (9-23) are primary
      diabetogenic autoantigens in BB rats because immunizations with these antigens
      and GAD65-induced immune deviation did not alter the development of diabetes.

PMID- 10593566
TI  - The B lymphocyte in rheumatoid arthritis: recirculation of B lymphocytes between
      different joints and blood.
AB  - In order to search for further evidence for a pathogenetic role of recirculating,
      antigen-driven B cell clones in rheumatoid arthritis (RA) rearranged VH genes
      were analysed for clonal relationship and somatic mutations from synovial tissue
      and peripheral blood of a patient with RA undergoing synovectomy of several
      finger joints. DNA was prepared from the synovial tissue of two finger joints and
      blood. PCR for the different VH families was performed with one specific
      oligonucleotide for each VH family and a mixture of JH-specific oligonucleotides.
      The PCR products were separated on a high resolution acrylamide gel
      differentiating one base pair difference of length. Transfer of the products onto
      a nylon membrane and hybridization with an oligonucleotide specific for the FR3
      region revealed a polyclonal representation of rearranged VH1, VH3, VH4 and VH5
      genes. The VH6 family, which is encoded by a single germline gene, was
      represented by few distinct bands, with some bands of identical height for both
      joints and blood. DNA from these bands of interest was eluted, reamplified by
      PCR, cloned and sequenced. Sequence analysis of 27 independent bacterial colonies
      allowed distribution of the different VH genes to seven B cell clones (A-G).
      Members of clone A were found in both joints and blood, clones B and C in one
      joint and blood, clone D in both joints, and clones E, F and G only in one joint.
      The VH regions were somatically mutated with characteristic patterns for the
      different clones. In conclusion, our findings confirm the systemic character of
      RA, because they show that not only expansion and affinity maturation of B cells
      occur in synovial membranes but antigen-specific B cells recirculate between
      different joints and blood.

PMID- 10593567
TI  - IDDM12 (CTLA4) on 2q33 and IDDM13 on 2q34 in genetic susceptibility to type 1
      diabetes (insulin-dependent).
AB  - Type 1 diabetes (insulin-dependent) is a multifactorial disease with polygenic
      susceptibility. The major genetic component (IDDM1) resides within the HLA
      region, but several non-HLA loci have been implicated in the genetic
      susceptibility. In the present study, we have analysed two such loci, IDDM12
      (CTLA4) on 2q33 and IDDM13 on 2q34, in Danish (n = 254) and Spanish (n = 39) type
      1 diabetic multiplex families. No significant evidence of linkage of IDDM12 was
      observed in any of the two studied data sets. However, when the present data were
      combined with previously published data, they strengthened the evidence of
      linkage at this locus, p = 0.00002. For the IDDM13 region, we found some positive
      evidence of linkage of the D2S137-D2S164-D2S1471 markers (p-values 0.007, 0.02,
      and 0.007, respectively) using transmission disequilibrium testing (TDT) and the
      Tsp version of the TDT. Importantly, random transmission of all tested alleles
      was observed in unaffected offspring (p > 0.3). Stratification for HLA (high risk
      and non-high risk genotypes) in the Danish families did not reveal heterogeneity
      at IDDM12 or IDDM13. In conclusion, our data on an entirely new family data set
      did not support the existence of IDDM12 as a type 1 diabetes susceptibility locus
      in the Danish population. In addition, we found support for evidence of linkage
      and association of the IDDM13/D2S137-D2S1471 region (approximately 3.5 cM) to
      type 1 diabetes, however, further studies are needed to substantiate this
      observation.

PMID- 10593568
TI  - Immunization in the first month of life may explain decline in incidence of IDDM
      in The Netherlands.
AB  - A low cumulative incidence of IDDM was reported in Dutch males born in 1962
      (Diabetologia 1992: 35: 139-142) compared to males born in previous or later
      years. The cause for the decreased risk has not been previously explained. We
      propose that children born in 1962 during an European smallpox epidemic may have
      received the smallpox vaccine in the first month of life and this may have
      attributed to the decreased risk of IDDM in these children. We have shown that
      immunization with several different vaccines starting in the first month of life
      prevents diabetes in NOD mice and BB rats (Autoimmunity 1996: 24: 137-145) while
      immunization at birth with the BCG vaccine is associated with an decreased risk
      of IDDM in humans (Infectious Diseases in Clinical Practice 1997: 6: 449-454). An
      even bigger decline in diabetes is seen in rodents and associated in humans when
      one compares immunization starting in the first month of life to immunization
      starting after 2 months, since the later has been associated with an increased
      risk of IDDM. Immunization studies in the past have typically followed patients
      for only several weeks to determine any unplanned affects on autoimmune disease.
      Due to the potential benefit of reducing the incidence of diabetes by 50% through
      age 18 we believe clinical trials are warranted to study the effect of timing of
      immunization on IDDM.

PMID- 10593569
TI  - Chromosomal localization and complete genomic sequence of the murine autoimmune
      regulator gene (Aire).
AB  - We have recently cloned the murine autoimmune regulator (Aire) gene, the
      homologue of human AIRE responsible for the autoimmune polyglandular syndrome
      type 1 (APS1) or autoimmune polyendocrinopathy candidiasis ectodermal dystrophy
      (APECED). Here, we report the genomic sequence (18,413 bp) for the entire Aire
      gene and its 5' flanking region, which contains putative regulatory sequences.
      Comparison of the genomic and cDNA sequences indicates that the Aire gene is
      composed of 14 exons and the coding sequence shares high similarities between
      mouse and human. The sizes of the homologous introns in the two species are
      conserved; however, the introns do not share significant sequence homologies
      except the sequences near the splice donor and acceptor sites. Sequence analyses
      of the 5' regulatory region and the complete coding region in three mouse strains
      (B6, NOD and SJL) did not reveal any sequence variation, suggesting sequence
      conservation between different inbred mouse strains. Using one of the six
      microsatellite markers identified by genomic sequencing and a B6 x Cast backcross
      mapping panel, we mapped the mouse Aire gene to chromosome 10, a syntenic region
      containing the Cdl18 and Pfkl genes on human chromosome 21q22.

PMID- 10593570
TI  - Cell-surface expression of lymphocyte activation markers in myasthenia gravis.
AB  - An analysis of the cell-surface expression of activation markers on B- and T
      cells was done to compare patients with myasthenia gravis (MG) and healthy non
      myasthenic controls. Marker expression was determined by immunostaining of
      peripheral blood mononuclear cells (PBMC) isolated from MG patients and from
      controls. The percentage of B-cells in PBMC that expressed CD71, a transferrin
      receptor, was significantly greater in patients compared to controls,
      particularly, in patients who were seropositive for acetylcholine receptor
      specific antibodies. When subgroups of MG patients were studied, our data showed
      that within the first year after disease onset, patients had a significantly
      higher percentage of T-cells in PBMC that were CD25+ (interleukin-2 receptor
      alpha) and CD26+ (dipeptidyl peptidase IV ectoenzyme) in comparison to patients
      with disease symptoms for longer than one year and to healthy controls. Our data
      also showed that patients with generalized MG had significantly lower percentages
      of gamma/delta T-cells in peripheral blood compared to healthy controls. The
      results of this study demonstrate important differences in the cell-surface
      expression of lymphocyte markers between MG patients and healthy non-myasthenic
      controls. In addition, differences between subgroups of patients demonstrate that
      patients with MG are heterogeneous in clinical presentation and in immunological
      parameters.

PMID- 10593571
TI  - Vitamin D binding protein alleles and susceptibility for type 1 diabetes in
      Germans.
AB  - Vitamin D has been shown to modulate the immune system thereby preventing the
      development of diabetes in NOD mice. Since the vitamin D binding protein (DBP) is
      the main transporter for vitamin D and DBP has immunomodulatory properties
      itself, we investigated three polymorphic sites within the DBP gene as candidates
      for type 1 diabetes susceptibility for the first time. 152 Caucasian families
      with at least one affected offspring were genotyped for intron 8 [(TAAA)n repeat]
      and exon 11 (HaeIII, StyI) polymorphisms. Transmission disequilibrium testing was
      used to detect preferential transmission to affected offspring. We found no
      significant transmission disequilibrium for DBP alleles. The strongest deviation
      from expected values was observed for the "10" allele (relative risk = 0.57,
      transmitted 13 of 36 times (corrected p = 0.249)). Although we cannot exclude an
      association of the studied DBP alleles with type 1 diabetes at present, these
      data do not suggest their contribution to this disease in Germans.

PMID- 10593572
TI  - Mediators of nonadrenergic, noncholinergic relaxation in longitudinal muscle of
      the intestine of ICR mice.
AB  - Mediators of nonadrenergic, noncholinergic (NANC) relaxation in longitudinal
      muscle of several regions of ICR mouse intestine were studied. An inhibitor of
      synthesis of nitric oxide, N(G)-nitro-L-arginine (L-NOARG) at 10 microM
      significantly inhibited NANC relaxations induced by electrical field stimulation
      (EFS) in the jejunum, ileum, and the proximal and distal colon. Especially in the
      ileum extent of the inhibition was more than 80%. An antagonist of vasoactive
      intestinal peptide (VIP) receptors, VIP(10-28) at 3 microM partially inhibited
      the EFS induced relaxations in the jejunum and proximal colon, but very slightly
      in the distal colon and had no effect in the ileum. An antagonist of pituitary
      adenylate cyclase activating peptide (PACAP) receptor, PACAP(6-38) at 3 microM
      partially inhibited the EFS-induced relaxations in the proximal and distal colon,
      but not in the jejunum and ileum. Totals of the percentages of relaxant
      components mediated by nitric oxide, VIP and PACAP in every region are roughly
      equal to a hundred percent. In another series of experiments, EFS-induced
      relaxations were almost completely inhibited by the treatment of the segments
      with L-NOARG and VIP(10-28) in the jejunum, with L-NOARG, VIP(10-28) and PACAP(6
      38) in the proximal colon, and with L NOARG and PACAP(6-38) in the distal colon.
      The present results suggest that nitric oxide solely mediates the relaxation of
      longitudinal muscle of the ileum of ICR mice, whereas nitric oxide and VIP co
      mediate it in the jejunum, nitric oxide, VIP and PACAP in the proximal colon, and
      nitric oxide and PACAP in the distal colon.

PMID- 10593573
TI  - Membrane abnormalities of vascular smooth muscle of mesenteric arteries of
      spontaneous diabetic BB rats.
AB  - Mesenteric arteries were isolated from the spontaneous diabetic BB rats, non
      diabetic BB rats and regular Wistar control rats. Gross morphology indicated that
      the mesenteric vascular bed of the control Wistar rats had a normal development
      of mesenteric fat pad around the vessels, while that of the diabetic BB rats
      showed drastically reduced perivascular fat pad, suggesting greater mobilization
      of fat for energy consumption in the hyperglycemic state of diabetes mellitus.
      The perivascular mesenteric fat pad of the non-diabetic BB rats was intermediate
      between those of the Wistar control and diabetic BB rats. The wet weight of the
      mesenteric arteries following removal of fat, vein and connective tissues was
      significantly greater in diabetic BB rats than in the corresponding controls.
      Microsomal membranes isolated from the mesenteric arteries of diabetic BB rats
      showed increased alkaline phosphatase and 5'-nucleotidase activities compared to
      those isolated from the two groups of non-diabetic control rats. Acid phosphatase
      activities were higher in both BB rat groups compared to the Wistar group. The
      total Ca2+ uptake by the microsomes of mesenteric arteries in the presence of ATP
      was not different among three experimental groups, but the ATP dependent active
      transport of Ca2+ was significantly increased and the passive Ca2+ binding was
      significantly reduced in diabetic group compared to the other two non-diabetic
      groups. Our results demonstrate that in the spontaneously diabetic BB rats,
      alterations in both structural and functional parameters may underline the
      vascular complications associated with type I diabetes mellitus in humans.

PMID- 10593575
TI  - Restriction fragment length polymorphism analysis of the F gene of Newcastle
      disease viruses isolated from chickens and an owl in Taiwan.
AB  - To provide information on the epidemiology of Newcastle disease (ND) of poultry
      in Taiwan, ND virus isolates from chickens and an owl were investigated by
      restriction site analysis and sequencing of their gene. A 1,349 base fragment of
      the F (fusion protein) gene was amplified by reverse transcription-polymerase
      chain reaction (RT-PCR). The PCR products were analyzed using restriction
      endonucleases, HinfI, BstOI, and RsaI. Three strains isolated from chickens
      during the 1995 epidemic outbreak had the same restriction sites as that of a
      1994 isolate; the number of the restriction sites of HinfI, BstOI, and RsaI were
      4, 2, and 4, respectively. In the F gene of the strain isolated from an owl
      during the same outbreak an additional restriction site of HinfI was found. The
      1991 isolate had only 3 restriction sites. The F gene of the owl isolate was
      amplified by RT-PCR and followed by direct sequencing. The deduced amino acid
      sequence at the cleavage site of the F protein was of virulent strains, 112R-R-Q
      K-R-F117. The F gene of Ow/Tw/2209/95 was phylogenetically most closely related
      to that of Ck/Tw/2137/95 isolated from the same outbreak. The present results
      indicate that the causative virus of the 1995 ND outbreak had already been
      present in Taiwan.

PMID- 10593574
TI  - Relationship between intracellular Ca2+ store and protein kinase C in agonist
      induced contraction of hypertensive rat aortae.
AB  - The roles of intracellular Ca2+ store and protein kinase C (PKC) in vascular
      contractile responses independent of Ca2+ influx were studied using aortic rings
      from spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat (WKY). The
      functional sizes of agonist-sensitive intracellular Ca2+ store were estimated as
      the peak response to agonist after PKC inhibition with calphostin C (Cal-C), a
      PKC inhibitor. The participation of PKC in 5-hydroxytryptamine-, phenylephrine-,
      and endothelin-1 (ET-1)-induced contractions in aortae of SHR was equal to, or
      greater than that in WKY. In contrast, compared with WKY, SHR aortae possessed a
      greater size of endothelin-1-sensitive Ca2+ store, a similar size of 5
      hydroxytryptamine-sensitive Ca2+ store, and a smaller size of phenylephrine
      sensitive Ca2+ store. Based on these data, both PKC activation and functional
      size of intracellular Ca2+ store differ between SHR and WKY and these differences
      are selective among agosists.

PMID- 10593576
TI  - Regulatory mechanism of polarized membrane transport by glucocorticoid in renal
      proximal tubule cells: involvement of [Ca2+]i.
AB  - We examined the effect of glucocorticoids on brush border membrane transporters
      and, furthermore, the involvement of Ca2+ in its action in the primary cultured
      rabbit renal proximal tubule cells (PTCs). Dexamethasone (DEX, 10(-9) M)
      decreased Pi uptake by 17%; whereas DEX affected neither alpha-methyl
      glucopyranoside (alpha-MG) uptake nor Na+ uptake. The DEX-induced inhibition of
      Pi uptake was due to a decrease of V(max). In contrast, other steroid hormones
      such as progesterone, testosterone, and 17beta-estradiol (10(-9) M) did not
      induce inhibition of Pi uptake. In order to examine the involvement of Ca2+ in
      DEX-induced inhibition of Pi uptake, PTCs were treated with A 23187 (10(-6) M,
      Ca2+ ionophore). A 23187 also inhibited Pi uptake, mimicking DEX action in Pi
      uptake. Treatments with W-7 (10(-4) M, calmodulin dependent kinase inhibitor), KN
      62 (10(-6) M, Ca2+/calmodulin-dependent protein kinase II inhibitor), and
      BAPTA/AM (10(-6) M) or TMB-8 (10(-4) M) (intracellular Ca2+ mobilization
      blockers) blocked the DEX-induced inhibition of Pi uptake. However, nifedifine,
      methoxyverapamil (10(-6) M, L-type Ca2+ channel blockers), and EGTA (1 mM,
      extracellular Ca2+ chelator) did not block it. In conclusion, DEX inhibited Pi
      uptake via, in part, Ca2+/calmodulin pathway mediated by intracellular Ca2+
      mobilization in the PTCs.

PMID- 10593577
TI  - Tumor necrosis factor alpha and gamma interferon are required for the development
      of protective immunity to secondary Corynebacterium pseudotuberculosis infection
      in mice.
AB  - The production and role of endogenous cytokines during the course of secondary
      Corynebacterium (C.) pseudotuberculosis infection were investigated in mice. When
      immunized mice were challenged on day 28 after primary infection, tumor necrosis
      factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) were found to appear at
      3 hr and to reach the maximum at 24 hr after challenge. Spleen cells of mice
      primarily infected from 2 to 8 weeks before produced a significant amount of TNF
      alpha and IFN-gamma when stimulated with formalin-killed bacteria. However, they
      could not produce detectable amounts of IL-4. The administration of anti-TNF
      alpha monoclonal antibody (MAb) and IFN-gamma MAb increased bacterial
      proliferation in the organs of immune mice and exacerbated the secondary
      infection. Injection of anti-CD4 MAb alone or anti-CD4 plus anti-CD8 MAbs
      resulted in significantly increased mortality and a marked suppression of
      bacterial elimination as well as cytokine production of secondarily infected
      mice, while the treatment with anti-CD8 MAb alone showed no effect on either the
      resistance or cytokine production of mice. These results suggest that CD4,
      probably Th1 T cells, play an important role for establishment of protective
      immunity against secondary C. pseudotuberculosis infection by secreting TNF-alpha
      and IFN-gamma.

PMID- 10593578
TI  - Morphological features of the spermatic cord in the musk shrew (Suncus murinus)
      with special reference to extratesticular Leydig cells.
AB  - Morphological features of the testicular artery and vein in the spermatic cord of
      the musk shrew (Suncus murinus) were evaluated by light microscopy, transmission
      electron microscopy, corrosion cast technique combined with scanning electron
      microscopy and immunohistochemistry. The vascular architecture in the spermatic
      cord of the musk shrew was simple. The testicular artery in the musk shrew was
      straight and accompanied by 1 to 3 branches of testicular vein. The testicular
      vein was also straight and anastomosed with each other in some points along its
      length, but it did not form a delicate pampiniform plexus. In the middle and
      distal portions of the spermatic cord, the tunica adventitia of the artery and
      vein was joined together to form a single connective tissue septum. Clusters of
      cells were found in this connective tissue septum in the middle portion of the
      cord. These cells were located close to the arterial wall and nerve endings, but
      they did not appear inside of neurium. They showed several typical
      characteristics similar to Leydig cells, and they were positive for 3beta
      hydroxysteroid dehydrogenase (HSD) antibody. Ultrastructural and
      immunohistochemical studies also indicated that the cells in cluster found in the
      vascular wall of the musk shrew spermatic cord may be equivalent to Leydig cells
      in testes. These extratesticular Leydig cells had characteristics of the active
      steroid-producing cell and seemed to be another source of testosterone.

PMID- 10593580
TI  - Examination of the pathogenesis of diabetic nephropathy in OLETF rats.
AB  - We conducted protein loading to examine the progression and pathogenesis of
      diabetic nephropathy. For this experiment, male OLETF, LETO, F344 and BN rats
      were used. This experiment was performed on rats between 5 and 30 weeks of age.
      Examination parameters included body weight, food intake, oral glucose tolerance
      test (OGTT), urinary protein level (UP), urinary albumin level (UA), glomerular
      filtration rate (GFR), kidney weights, light microscopy (LM) and electron
      microscopy (EM). In the protein-loaded OLETF group, the UP level was markedly
      increased 20 weeks or more after birth. In OLETF control group, GFR were higher
      than those in other strains. Glomerular hypertrophy and kidney weights were
      markedly increased in protein-loaded groups in OLETF rats. Thirty weeks after
      birth, EM showed that the number of polyethyleneimine (PEI) of the glomerular
      basement membrane (GBM) in protein-loaded OLETF group was significantly decreased
      compared to that in control group. These changes in OLETF rats were more marked
      in the protein-loaded group than those in the control group. LM showed that the
      number of exudative lesions with fibrin-cap in the protein-loaded OLETF group was
      significantly increased than those in control group. In OLETF rats, protein
      loading caused deterioration of nephropathy at 30 weeks of age. Therefore, it was
      demonstrated that not only blood sugar control but also protein intake factors
      play important roles in the deterioration of nephropathy in OLETF rats.

PMID- 10593579
TI  - Smooth muscle cell proliferation in the ductus arteriosus and the descending
      aorta, and effects of enalapril on SMC proliferation in perinatal rats.
AB  - This study was carried out to determine the proliferation profile of the smooth
      muscle cells (SMC) in the media of the ductus arteriosus (DA) and the descending
      aorta (Ao), and to examine the effects of the angiotensin-converting enzyme
      inhibitor enalapril on the proliferation of these cells in perinatal rats. The
      proliferating cell nuclear antigen (PCNA) index of the DA peaked in 19-day-old
      fetuses at 75%, and the index significantly declined in 20-day-old fetuses. The
      PCNA index of the Ao showed a similar profile until pups reached 1 day of age;
      however, the index of the Ao then increased in 3-day-old pups. The PCNA indices
      of the DA and Ao decreased significantly after maternal oral treatment with
      enalapril (10 mg/kg for 7 days), with a more marked decline in the DA than in the
      Ao. The PCNA indices of these vessels in 20-day-old fetuses were not altered by
      maternal treatment with enalapril. These results indicate that the SMC
      proliferation rate in the DA was similar to that in the Ao until pups reached the
      age of 1 day, and that the inhibitory effect of enalapril on the SMC
      proliferation was age-dependent and more prominent in the DA than in the Ao.

PMID- 10593581
TI  - Quantitative changes of lung tissue components during perinatal period in rats.
AB  - Quantitative changes of lung tissue components (air spaces lined by PAS-positive
      and PAS-negative epithelium, blood vessels and interstitium) were investigated in
      developing rats from fetal day 18 through neonatal day 1. The volume of the left
      lung increased significantly from fetal day 18 through neonatal day 1. The
      percentage and volume of the air spaces increased strikingly between fetal days
      20 and 21. However, the percentage of the air spaces lined by PAS-positive
      epithelium decreased significantly from fetal days 20 to 21, and that of the
      spaces lined by PAS-negative epithelium increased between the two days. The
      proliferating cell nuclear antigen (PCNA)-positive cells were rich in the
      interstitium and epithelium of the air spaces on fetal days 18 and 19. The
      percentage of the interstitium decreased significantly from fetal day 18 through
      neonatal day 1, showing remarkable decrease between fetal days 20 and 21. From
      fetal day 20 onward, the PCNA-positive cells decreased in number and located in
      the epithelium of the conducting air ways and interstitium. Based upon these
      findings, the present study suggests that the period from fetal days 20 to 21 is
      a critical time for the development of fetal lung: the period before fetal day 20
      is that for proliferation and the period after fetal day 21, functional
      differentiation of the lung.

PMID- 10593582
TI  - Expression of recombinant Toxoplasma gondii P24.
AB  - The gene encoding Toxoplasma gondii P24 has been reported previously. To
      determine the function of P24 against immune systems in the near future, we
      prepared recombinant P24 antigens using Escherichia coli, insect cells infected
      with recombinant baculovirus and mammalian cells infected with recombinant
      vaccinia virus. The P24 antigens derived from E. coli, insect cells and mammalian
      cells were detected with mouse immune sera against P24 or T. gondii homogenates
      by Western blot analysis; these corresponded to the authentic P24 and secreted
      into the supernatants of the insect and mammalian cell cultures. These proteins
      were not effected by tunicamycin treatment in cultured cells, indicating that
      recombinant P24 did not contain N-linked sugars. Recombinant P24 was separated by
      two-dimensional electrophoresis and analyzed by Western blotting. From these
      results, P24 was acidic protein and had identical isoelectric point with the
      authentic P24.

PMID- 10593583
TI  - Cloning of feline cDNA encoding the cytotoxic T lymphocyte-associated antigen 4
      (CTLA-4).
AB  - Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a CD28 homologue which
      down-modulate T cell responses rather than augment them. To investigate its
      biological role in feline immune system, we cloned and sequenced full-length
      feline CTLA-4 (fCTLA-4) cDNA by RT-PCR from pokeweed mitogen stimulated
      peripheral blood lymphocytes. The fCTLA-4 contains an open reading frame of 669
      nucleotides, coding for a polypeptide of 223 amino acids. The predicted fCTLA-4
      amino acids sequence shows the homology of 86.6%, 87.0%, and 76.2% with human,
      bovine, and murine molecules respectively. The hexapeptide motif (MYPPPY) within
      the extra-cellular domain of CTLA-4 molecule, which is believed to be responsible
      for interaction with the B7 family members, is completely conserved in all the
      species.

PMID- 10593584
TI  - Establishment of the PCR system specific to Salmonella spp. and its application
      for the inspection of food and fecal samples.
AB  - We established the PCR detection system specific to Salmonella species using
      Salmonella enterotoxin gene (stn). The detection limit was one bacterial cell per
      one gram of fecal and minced-meat samples using enrichment procedure by
      Tripticase soy broth or Salmonella enrichment broth, respectively. We concluded
      that this PCR system is useful for the practical application in the field of the
      public hygiene.

PMID- 10593585
TI  - Effects of recombinant bovine granulocyte-macrophage colony-stimulating factor on
      bovine peripheral blood neutrophil functions in vitro and in vivo.
AB  - Effects of recombinant bovine granulocyte-macrophage colony-stimulating factor
      (rboGM-CSF) on bactericidal activity of bovine peripheral blood neutrophils in
      vitro and in vivo were studied. In in vitro experiment, bovine blood neutrophils
      were cultured for 9 hr in media containing 0.005, 0.05 or 0.5 microg/ml of rboGM
      CSF. Neutrophils treated with rboGM-CSF showed significantly higher luminol
      dependent chemiluminescence (LDCL) than control cells. In in vivo experiment,
      neutrophils isolated from cows injected 5.0 microg/kg of rboGM-CSF showed
      significantly higher Nitrobluetetrazolium (NBT) reduction value than that from
      control cows 24 hr post injection. Total leukocyte counts of cows injected rboGM
      CSF sharply decreased 6 hr post injection and recovered to normal level 2 days
      post injection. Body temperature of these cows rose 6 hr post injection and back
      to normal level at 24 hr post injection. It was suggested that rboGM-CSF enhanced
      bactericidal activity of bovine neutrophils both in vitro and in vivo.

PMID- 10593586
TI  - Analysis of porcine cytomegalovirus DNA polymerase by consensus primer PCR.
AB  - We used a consensus primer PCR method to amplify a region of herpesviral DNA
      directed DNA polymerase gene using degenerate primers for initial
      characterization of the porcine cytomegalovirus (PCMV) genome. The sequence of
      the PCR product from PCMV DNA template and its alignment with other herpesvirus
      DNA polymerase counterparts showed that both conserved amino acid residues and
      conservative amino acid substitutions are in parallel. Phylogenetic analysis
      revealed that PCMV should be included in the clade comprising human herpesvirus 6
      and 7, rather than human and mouse cytomegaloviruses, in Betaherpesvirus
      subfamily.

PMID- 10593587
TI  - Comparative enzymatic hydrolysis of phytate in various animal feedstuff with two
      different phytases.
AB  - Bacillus amyloliquefaciens DS11 phytase (DS11 phytase) and Aspergillus ficuum
      phytase (AF phytase) activities were investigated by measuring the release of
      phosphate from phytate in animal feedstuff such as wheat bran, corn meal, soybean
      meal and rice flour at pH 5 and 7. In all the tested feedstuff, the enzymatic
      activity of DS11 phytase was more active at pH 7, but that of AF phytase was more
      active at pH 5. From these results, the phytate in the gastrointestinal tract
      could be degraded in the small intestine or stomach by DS11 or AF phytase,
      respectively. In conclusion, the results presented in this paper indicated that
      different combination ratios of DS11 and AF phytase, depending on the kind of
      feedstuff, might effectively induce more enzymatic activity both in the stomach
      and small intestine in terms of the pH of the gastrointestinal tract.

PMID- 10593588
TI  - Identification of a locus for susceptibility to renal cell carcinoma in the Long
      Evans Cinnamon rat.
AB  - The Long-Evans Cinnamon (LEC) mutant rat shows higher incidence of renal cell
      carcinomas induced by a treatment with the chemical carcinogen N
      diethylnitrosamine, as compared to the normal control rat. We performed the first
      genome-wide scan for genes responsible for susceptibility to chemically induced
      renal cell carcinoma in an F2 intercross obtained by mating the LEC and Fischer
      344 (F344) rats. The genotype of 71 (F344 x LEC) F2 progenies was determined with
      the use of 338 simple sequence length polymorphisms (SSLPs) spread over the
      genome. The F2 rats which carried renal cell carcinoma were shown to possess the
      incidence of homozygosity of the LEC allele which is higher than that of the
      other genotypes at SSLP markers on chromosome 5 (chi2 = 17.5 for D5Rat21). Our
      linkage analysis has led to the revelation of a novel gene that influences
      susceptibility to renal cell carcinoma on rat chromosome 5.

PMID- 10593589
TI  - Induction of glutamate-cysteine ligase (gamma-glutamylcysteine synthetase) in the
      brains of adult female mice subchronically exposed to methylmercury.
AB  - Methylmercury (MeHg) is widely known for its potent neurotoxic properties. One
      proposed mechanism of action of MeHg relates to its high affinity for sulfhydryl
      groups, especially those found on glutathione (GSH) and proteins. Previous
      studies have shown that acute MeHg exposure results in an increase in the mRNA
      for the rate-limiting enzyme in GSH synthesis, glutamate-cysteine ligase (GLCL)
      (also known as gamma-glutamylcysteine synthetase). In this study, we evaluated
      the effects of subchronic (12-week) MeHg exposure at 0, 3 or 10 ppm in the
      drinking water on GSH levels, GLCL catalytic (GLCLC) and regulatory subunit mRNA
      and protein levels, and GLCL activity in brain, liver and kidney tissue of
      C57B1/6 female mice. Contrary to previous findings in rats, there were no changes
      in GSH concentration in any of the tissues examined. However, there was an
      increase in GLCLC protein in the brain, which was accompanied by a 30% increase
      in GLCL activity. We conclude that up-regulation of GSH synthetic capacity in the
      brains of mice is a sensitive biomarker of subchronic MeHg exposure.

PMID- 10593590
TI  - Priming effect of benzo[a]pyrene on monocyte oxidative metabolism: possible
      mechanisms.
AB  - Monocytes, separated from human peripheral blood, were preincubated with
      different polycyclic aromatic hydrocarbons (PAHs) for 24 h and the production of
      superoxide ions (O*2-) was then measured using as a stimulating agent phorbol 12
      myristate 13-acetate. A significantly enhanced O*2- production is only observed
      when the cells are treated with benzo[a]pyrene (B[a]P); benzo[e]pyrene,
      benzo[a]anthracene and 3-methylcholanthrene induce a small but not significant
      increase of O*2-. Anthracene has no effect, while phenanthrene slightly inhibits.
      The priming activity of B[a]P is unrelated to variations in intracellular Ca2+
      ([Ca2+]i), as demonstrated by the inability of B[a]P to increase [Ca2+]i
      concentration in both monocytes and the promonocytic cell line U937. Furthermore,
      in monocytes the sarcoplasmic/endoplasmic reticulum Ca2+ -ATPase inhibitor,
      thapsigargin, which can increase [Ca2+]i evokes a differentiation-like event
      associated with a decrease in the production of superoxide ions. These results
      further support that the enhancing activity of B[a]P on monocytes superoxide
      production is not mediated by an increase of [Ca2+]i. In contrast, the role of
      the aryl hydrocarbon receptor (AhR) in B[a]P-induced superoxide ion enhancement
      is suggested by the inhibitory effect of the specific antagonist alpha
      naphthoflavone (alphaNF), while the tumor necrosis factor (TNF-alpha) is not
      involved in the phenomenon. Thus, the interaction of B[a]P with its cytosolic
      receptor and either the metabolism of the compound into reactive intermediates or
      the over-expression of some unknown genes seem to be involved in an essential
      step in this process.

PMID- 10593591
TI  - Cytoprotection and iron mobilization in rat hepatocyte cultures by a new
      synthetic dihydroxamate chelator.
AB  - The cytoprotection and iron mobilization effect of a new dihydroxamate chelator
      1,1 bis [(11-N-hydroxy)-2,5,11-triaza-1,6,10-trioxo dodecanyl] ethane or KD was
      studied in primary rat hepatocyte cultures exposed to iron-citrate. Lactate
      dehydrogenase (LDH) release and malondialdehyde (MDA) production were measured as
      indexes of cytotoxicity. Cell viability was evaluated using the [3-(4,5-dimethyl
      thiazol-2-yl) 2,5-diphenyl tetrazolium bromide] (MTT) reduction test. To
      demonstrate that this chelator was able to decrease iron uptake or increase iron
      release from the hepatocytes, labelled cells were obtained by maintaining the
      cultures in the presence of 0.02 microM 55Fe-citrate. The efficacy of KD was
      compared to desferrioxamine B (DFO) at stoechiometry concentrations. After 24 h
      of exposure to 50 microM of iron-citrate, a significant release of LDH and MDA
      was observed. Cell viability was also significantly decreased. When 100 microM of
      KD were added at the same time as iron, LDH and MDA release was decreased and
      cell viability was improved. In the presence of the same chelator concentration,
      a net decrease of iron uptake by the cells was observed as attested by the low
      intracellular 55Fe level. Moreover, in the 55Fe loaded hepatocytes, the chelator
      increased the iron extracellular level indicating its iron release effect from
      the cells. In all tested experimental conditions, the efficacy of 100 microM of
      the dihydroxamate chelator KD was close to that of 50 microM of the
      trihydroxamate chelator DFO. In conclusion, KD is effective at a level comparable
      to DFO in protecting rat hepatocytes against the toxic effect of iron-citrate by
      decreasing the uptake of the metal and increasing its release from the cells.
      This synthetic compound appears to have some potential therapeutical interest and
      the results obtained encourage the synthesis of new hydroxamate ligands.

PMID- 10593592
TI  - Sulfur mustard upregulates the expression of interleukin-8 in cultured human
      keratinocytes.
AB  - Although the morphological description of sulfur mustard (SM) injury is well
      characterised, little is known of the molecular mediators involved in cutaneous
      toxicity. Since infiltration by lymphocytes and PMNs represents one of the very
      first events observed in vivo upon exposure to SM, this study examined whether SM
      exposure can modify the expression by cultured human keratinocytes of interleukin
      8, one of the most important chemoattractants for polymorphonuclear leukocytes
      (PMNs) in humans. Conditioned medium harvested from control keratinocyte cultures
      showed a gradual accumulation of this cytokine over time followed by a levelling
      off after 12 hours. Upon treatment with 10(-6) and 10(-5) M SM, no significant
      difference compared to the control situation was observed. After 6 h, a
      significantly higher amount of IL-8 was secreted by human keratinocytes treated
      with 10(-4) M SM and the accumulation of the cytokine persisted up to 24 h after
      exposure. The expression of IL-8 mRNA was assessed semi-quantitatively (RT-PCR)
      at the same time points in control and SM-treated (10(-4) M) human keratinocytes.
      When compared to control cultures, a clear upregulation of IL-8 mRNA levels was
      observed 6 and 12 h after SM exposure, which is consistent with the secretion
      pattern of the protein. The present observation indicates that increased
      secretion of IL-8 by human keratinocytes represents an early event of the
      inflammatory reaction following SM which is coherent with the reported delay in
      the recruitment of lymphocytes and PMNs observed in vivo.

PMID- 10593593
TI  - Attenuation of ozone-induced lung injury by interleukin-10.
AB  - Ozone (O3), an oxidant air pollutant, is capable of producing pulmonary
      inflammation and injury. Exposure to O3 results in the release of inflammatory
      cytokines including tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL
      1) by alveolar macrophages. In addition, O3 exposure results in an increased
      expression of the inducible isoform of nitric oxide synthetase (iNOS).
      Interleukin-10 (IL-10) is an anti-inflammatory cytokine which inhibits the
      synthesis of TNF-alpha and IL-1 by macrophages and decreases the expression of
      iNOS. To test the protective properties of IL-10 in vivo, on the pulmonary injury
      induced by O3 exposure, we intratracheally instilled rat recombinant IL-10 1 h
      prior to O3 exposure (0.8 ppm x 3 h). Approximately 10-12 h following exposure,
      the animals were sacrificed and the bronchoalveolar lavage fluid (BALF)
      collected. The quantification of albumin, protein and fibronectin in the BALF
      provided a means of assessing pulmonary injury while the analysis of the BALF
      cells reflected the inflammatory response. Ozone exposure resulted in a
      significant (P<0.05) increase in BALF albumin, protein and fibronectin content as
      compared to air-exposed controls. In addition, significant increases in the
      percentage of BALF polymorphonuclear leukocytes (PMNs) and tissue expression of
      fibronectin mRNA were observed. The intratracheal instillation of IL-10 prior to
      O3 exposure resulted in a significant reduction in BALF albumin, protein and
      fibronectin content, and lung fibronectin mRNA as compared to O3 exposure alone.
      The data shows that IL-10, when given intratracheally, significantly reduces the
      pulmonary injury following O3 exposure in the rat. However, since the PMNs and
      the levels of albumin, protein and fibronectin in the IL-10 treated group did not
      reach baseline values, we conclude that other mediators of inflammation and
      injury not regulated by IL-10 also contribute to the pathophysiology of O3
      induced lung injury.

PMID- 10593594
TI  - Interspecies variations in fatty acid hydroxylations involving cytochromes P450
      2E1 and 4A.
AB  - The liver microsomal fractions of seven mammalian species including rat, dog,
      monkey, hamster, mouse, gerbil and humans, catalyzed the hydroxylation of
      saturated (lauric, myristic and palmitic) and unsaturated (oleic and linoleic)
      fatty acids to the corresponding omega and (omega-1)-hydroxylated derivatives,
      while stearic acid was not metabolized. Lauric acid was the most efficiently
      hydroxylated, and the rank of catalytic activity was lauric > myristic > oleic >
      palmitic > linoleic. Among the mammalian species studied, mouse and hamster
      presented the highest level of fatty acid omega and (omega-1)-hydroxylases, while
      the lowest activity was observed in dog and monkey. In all the animal species,
      the (omega-1)-hydroxylation of fatty acids correlated significantly with the
      immunodetectable content of CYP2E1 and the 4-nitrophenol hydroxylation activity,
      known to be mediated by cytochrome P450 2E1. On the contrary, only the omega
      hydroxylation of lauric acid slighly correlated with the level of cytochrome P450
      4A, while no significant correlation was found with the omega-hydroxylation of
      the other fatty acids. Furthermore, chemical and immuno-inhibitions of the
      hydroxylations of fatty acids led to the conclusion that fatty acid (omega-1)
      hydroxylase activity is catalyzed by P450 2E1 in all the mammalian species, while
      the fatty acid omega-hydroxylase activity may be catalyzed by cytochromes P450
      from the 4A family. Therefore, lauric acid (omega-1)-hydroxylation along with 4
      nitrophenol hydroxylation can be used as a specific and sensitive method to
      measure the level of CYP2E1 induction in humans and various animals.

PMID- 10593595
TI  - Hemolytic drugs aniline and dapsone induce iron release in erythrocytes and
      increase the free iron pool in spleen and liver.
AB  - Incubation of rat erythrocytes with the hydroxylated metabolites of aniline and
      dapsone (4-4'-diaminodiphenylsulfone), phenylhydroxylamine and dapsone
      hydroxylamine, respectively, induced marked release of iron and methemoglobin
      formation. On the contrary, no release of iron nor methemoglobin formation was
      seen when the erythrocytes were incubated with the parent compounds (aniline and
      dapsone). The acute intoxication of rats with aniline or dapsone induced a marked
      increase in the erythrocyte content of free iron and methemoglobin, indicating
      that the xenobiotics are effective only after biotransformation to toxic
      metabolites in vivo. Prolonged administration of aniline or dapsone to rats
      produced continuous release of iron from erythrocytes. Marked iron overload was
      seen in the spleen and in the liver Kupffer cells, as detected histochemically.
      The spleen weight in these subchronically treated animals was significantly
      increased. The free iron pool was markedly increased in the spleen and to a lower
      extent in the liver. The possible relationships between iron release in
      erythrocytes, oxidative damage seen in senescent cells, hemolysis, overwhelmed
      capacity of spleen and liver to keep iron in storage forms and subsequent
      increase in low molecular weight, catalitically active iron is discussed.

PMID- 10593596
TI  - Effects of GSH and WR-2721 on induction of micronuclei by cyclophosphamide.
AB  - The frequency of micronucleated polychromatic erythrocytes (MNPCEs) was assessed
      in the bone marrow and peripheral blood of adult male Swiss mice treated with
      reduced glutathione (GSH) and/or S-2-/3-aminopropylamino/ethyl phosphorothioic
      acid (WR-2721), at a dose of 400 mg/kg body weight, and/or with cyclophosphamide
      (CP), at a dose of 200 mg/kg body weight. GSH was given 60 or 15 min and/or WR
      2721 was applied 30 min before CP administration. The number of MNPCEs was
      determined at 24 h after the drug application. After treatment of mice with CP,
      the frequency of MNPCEs was distinctly increased. The stronger chemoprotective
      effect against CP-induced cytotoxicity was obtained following GSH administration
      than after WR-2721 injection. WR-2721 characterized greater cytotoxicity than
      GSH. The combination of GSH and WR-2721 given alone, or before CP administration
      resulted in the most cytotoxic and chemoprotective effects, compared with the
      respective single-thiol treatment of mice. The most effective protection against
      CP-induced genotoxicity was observed in the case of treatment of mice with WR
      2721and GSH, respectively, 30 and 15 min before CP administration. The most
      cytotoxic effect of the thiols was found when GSH given 30 min prior to WR-2721
      application. The chemoprotection and cytotoxicity caused in the mouse
      erythroblasts by GSH and WR-2721, as indicated by the number of MNPCEs were
      dependent on the thiol(s) given, and the time intervals between the drug
      administration. The modulatory effect of the thiols GSH and WR-2721 on 'delayed
      apoptosis' induced in the erythropoietic system by cyclophosphamide was shown.

PMID- 10593597
TI  - The influence of temperature during alkaline treatment and electrophoresis on
      results obtained with the comet assay.
AB  - The alkaline comet assay (single-cell gel electrophoresis) is becoming
      established as a genotoxicity test with many fold applications in vitro and in
      vivo. While the underlying principles are identical, various modifications of the
      method are in use which clearly affect the sensitivity and resolving power of the
      assay. One variable of potential importance that has been disregarded until now
      is temperature during alkaline treatment and electrophoresis. We therefore
      performed comet assay experiments with human blood and V79 Chinese hamster cells
      using two different temperatures (4 and 20 degrees C, i.e. room temperature)
      during alkaline treatment and electrophoresis. DNA damage was induced by the two
      standard mutagens gamma irradiation and methyl methanesulfonate (MMS). The
      results clearly indicate significant differences in the detection of background
      and mutagen-induced DNA damage at these two temperatures. Under otherwise
      identical test conditions (including the duration of alkaline treatment and
      electrophoresis), increased temperature during alkaline treatment and
      electrophoresis strongly enhances DNA migration. Our findings suggest that the
      comet assay should be performed under strictly controlled and reproducible
      temperature conditions. In any case the temperature during alkaline treatment and
      electrophoresis should be stated in a publication to allow for a critical
      evaluation of results obtained with the comet assay.

PMID- 10593598
TI  - The effects of carbaryl and trichlorphon on differentiating mouse N2a
      neuroblastoma cells.
AB  - The ability of the carbamate pesticide carbaryl (CB) and the organophosphate
      pesticide trichlorphon (TCL) to inhibit the outgrowth of axon-like processes was
      studied using mouse N2a neuroblastoma cells induced to differentiate by serum
      withdrawal. At concentrations of 1 and 2 microg/ml (4.97 and 9.94 microM), CB did
      not cause cell death but inhibited the outgrowth of axon-like processes from N2a
      cells. This effect was noted as early as 24 h after exposure of the cells to CB.
      A similar effect was observed with TCL at concentrations of 1 and 2 microg/ml
      (3.89 and 7.78 microM). Western blot analysis of cell extracts treated with the
      pesticides showed decreased cross reactivities with the monoclonal antibody RMd09
      compared to control extracts. The results indicate that CB and TCL are both able
      to inhibit axon development and that this effect is associated with reduced
      levels of the neurofilament high molecular weight protein subunit (NFH).

PMID- 10593599
TI  - Cytochrome P450 isoforms catalyzing benzo[a]pyrene metabolism in the Chinese
      hamster liver.
AB  - Cytochrome P450 isoforms involved in the benzo[a]pyrene metabolism in the Chinese
      hamster liver were characterized. The activity of benzo[a]pyrene hydroxylase in
      male hamster livers increased markedly by treatment with 3-methylcholanthrene (25
      mg/kg per day, i.p., 3 days) and moderately with phenobarbital (60 mg/kg per day)
      and dexamethasone (100 mg/kg per day). In contrast, the ability for the mutagenic
      activation of benzo[a]pyrene determined by the mutagenicity test was increased
      most markedly by treatment with phenobarbital and significantly with 3
      methylcholanthrene, but not with dexamethasone. These observations are similar to
      those in the rat rather than in the Syrian hamster. Western blot analysis and
      assay of the enzymes associated with cytochrome P450 isoforms showed that the 3
      methylcholanthrene treatment elevated markedly the level of CYP1A2, but not that
      of CYP1A1, while the phenobarbital treatment elevated markedly the level of CYP2A
      and CYP3A, but not that of CYP2B. Further, immunoinhibition study demonstrated
      that, in Chinese hamster livers, CYP2A and CYP1A2 were mainly involved in the
      mutagenic activation of benzo[a]pyrene and CYP3A in the benzo[a]pyrene
      hydroxylase activity, respectively.

PMID- 10593600
TI  - Prevention and recovery of CuSO4-induced inhibition of Na+/K+ -ATPase and Mg2+ 
      ATPase in rat brain synaptosomes by EDTA.
AB  - Enzymatic activities of Na+/K+-ATPase and Mg2+ -ATPase from rat brain synaptic
      plasma membrane were studied in the absence and presence of EDTA. The aim of the
      study was to examine the ability of this strong chelator to prevent and recover
      the CuSO4-induced inhibition. The influence of experimentally added CuSO4 and
      EDTA on MgATP2- complex and 'free' Cu2+ concentrations in the reaction mixture
      was calculated and discussed. CuSO4 induced dose-dependent inhibition of both
      enzymes in the absence and presence of 1 mM EDTA. In the absence of EDTA, the
      IC50 values of Cu2+, as calculated from the experimental curves, were 5.9x10(-7)
      M for Na+/K+ -ATPase and 3.6x10(-6) M for Mg2+ -ATPase. One millimolar EDTA
      prevented the enzyme inhibition induced by CuSO4, but also reversed the inhibited
      activity, in a concentration-dependent manner, following exposure of the enzymes
      to the metal ion, by lowering 'free' Cu2+ concentration. Kinetic analysis showed
      that CuSO4 inhibits both the Na+/K+ -ATPase and Mg2+ -ATPase, by reducing their
      maximum enzymatic velocities (Vmax), rather than apparent affinity for substrate
      MgATP2- (K0.5), implying the noncompetitive nature of enzyme inhibition induced
      by the metal. The kinetic analysis also confirmed two distinct Mg2+ -ATPase
      subtypes activated in the presence of low and high MgATP2- concentrations. K0.5
      and Vmax were calculated using a computer-based program. The results of
      calculation showed that MgATP2- concentration in the kinetic experiments exceeded
      three times the apparent K0.5 value for the enzyme activation.

PMID- 10593601
TI  - The occurrence of ochratoxin A in blood in general population of Croatia.
AB  - The exposure of general population in Croatia to mycotoxin ochratoxin A (OTA) was
      investigated in five cities: Split, Rijeka, Varazdin, Osijek, and Zagreb. In June
      1997, blood donors from each of these cities gave 50 samples of 3 ml plasma each.
      The mean concentration of OTA, determined using high-pressure liquid
      chromatography (HPLC), was 0.39 ng/ml of plasma. The highest frequency of OTA
      positive samples (>0.2 ng/ml plasma), and the highest number of samples with the
      concentration exceeding 1.0 ng/ml, were found in Osijek. This difference is
      probably due to the higher consumption of fresh and dried pork by population of
      Osijek. The calculated daily intake of OTA, estimated from the mean OTA
      concentration of all samples in each town (in the range from 0.24 to 0.91 ng/kg
      b.w. found in Rijeka and Osijek, respectively) is lower than the tolerable daily
      intake proposed by Joint FAO/WHO Expert Committee on Food Additives (1995) of
      16.0 ng OTA/kg b.w.

PMID- 10593602
TI  - Alveolar lesions induced by systemic administration of cocaine to rats.
AB  - In this work, alveolar lesions induced after systemic administration of cocaine
      (30 mg/kg per day, i.p.) to rats were evaluated both by light microscope analysis
      for morphological assessment as well as by measurement of the alveolar area as a
      quantitative index of the alveolar damage. Rats were examined after different
      times of exposure: 7, 15, 30, 45, 60 and 75 days. The histopathological
      evaluation of cocaine-treated rats revealed a remarkable thickening in some
      interalveolar septa, with interstitial hemorrhages, progressive thrombosis and
      transformation of reticular and elastic fibers into diffuse fibrosis. A
      significant decrease of the alveolar area was also observed. These findings are
      indicative of severe changes in capillaries, alveoli and bronchiole after cocaine
      exposure, which in turn may progressively disrupt the general function of the
      lungs. Differential mechanisms of systemic toxicity after cocaine exposure are
      discussed.

PMID- 10593603
TI  - Species differences in sequence and activity of the peroxisome proliferator
      response element (PPRE) within the acyl CoA oxidase gene promoter.
AB  - In rats and mice, peroxisome proliferators (PP) cause liver enlargement,
      hepatocarcinogenesis and peroxisome proliferation associated with induction of
      enzymes such as acyl CoA oxidase (ACO). However, humans appear to be non
      responsive to the adverse effects of PPs such as ACO induction. PPs activate the
      peroxisome proliferator activated receptor alpha (PPARalpha) that binds to DNA at
      peroxisome proliferator response elements (PPREs) within the promoters of PP
      responsive genes. When the human ACO promoter was cloned previously (Varanasi et
      al., 1996. Journal of Biological Chemistry, 271, 2147-2155), it was reported to
      contain a PPRE (5' AGGTCA C TGGTCA 3') that bound PPARalpha and could be
      activated in vitro by Wyeth-14,643 (at >1 mM) or DEHP (at > 1.5 mM). In contrast,
      when we cloned the ACO gene promoter from a human liver biopsy, it was non
      responsive to PPs and differed at three positions (5' AGGTCA G CTGTCA 3') from
      that reported previously (Woodyatt et al., 1999. Carcinogenesis, 20, 369-375).
      Subsequent to this, Varanasi et al. re-sequenced their constructs and obtained
      the same sequence as we have described (Varanasi et al., 1998. Journal of
      Biological Chemistry, 273, 30832). However, the observation that the errant
      sequence (5' AGGTCA C TGGTCA 3') was able to bind PPARalpha still remained since
      it appears that this sequence was used by Varanasi et al. (1996) to design
      oligonucleotides for their DNA binding analyses. Thus, if the 5' AGGTCA C TGGTCA
      3' sequence did exist in some individuals, it could be active. To address this,
      we used site-directed mutagenesis to create a promoter fragment that contained
      the errant sequence. This reporter gene was transfected into NIH3T3 cells
      together with a plasmid expressing mPPARalpha, and assessed for its ability to
      drive PP-mediated gene transcription using a non-toxic concentration of Wyeth
      14,643 (100 microM). This human ACO promoter was also inactive, unlike the
      equivalent rat ACO promoter fragment used as a positive control. Next, we used
      site directed mutagenesis to convert the PPRE found in the active rat ACO
      promoter (3' AGGACA A AGGTCA 5') to our inactive human sequence (AGGTCA G
      CTGTCA). This human PPRE was unable to drive PP-induced gene transcription even
      in the context of the rat ACO promoter suggesting that the activity of the rat
      promoter is conferred principally by the PPRE sequence, even though it may be
      enhanced by flanking sequences. These data confirm that neither the native nor
      the errant human ACO gene PPRE can respond to PPs. The absence of a responsive
      PPRE contributes to our understanding of the lack of response of humans to some
      of the adverse effects of the PP class of non-genotoxic hepatocarcinogens.

PMID- 10593604
TI  - Differences in phosphatase modulation of alpha4beta1 and alpha5beta1 integrin
      mediated adhesion and migration of B16F1 cells.
AB  - It is well established that a biphasic relationship exists between the adhesive
      strength of beta1 integrins and their ability to mediate cell movement. Thus,
      cell movement increases progressively with adhesive strength, but beyond a
      certain point of optimal interaction, cell movement is reduced with further
      increases in adhesive function. The interplay between the various kinase and
      phosphatase activities provides the balance in beta1 integrin-mediated cell
      adhesion and migration. In the present study, the significance of protein
      tyrosine phosphatases (PTP) and ser/thr protein phosphatases (PP) in alpha4beta1
      and alpha5beta1 integrin-mediated mouse melanoma B16F1 cell anchorage and
      migration on fibronectin was characterized using phosphatase inhibitors. At low
      fibronectin concentration, alpha5beta1 functioned as the predominant receptor for
      cell movement; a role for alpha4beta1 in B16F1 cell migration increased
      progressively with fibronectin concentration. Treatment of B16F1 cells with PTP
      inhibitors, sodium orthovanadate (Na3VO4) and phenylarsine oxide (PAO), or PP
      1/2A inhibitor, okadaic acid (OA), abolished cell movement. Inhibition of cell
      movement by PAO and OA was associated by a reduction in the adhesive strength of
      alpha4beta1 and alpha5beta1. In contrast, treatment of B16F1 cells with Na3VO4
      resulted in selective stimulation of the adhesive function of alpha5beta1, but
      not alpha4beta1. Therefore, our results demonstrate that (i) both PTP and PP-1/2A
      have roles in cell movement, (ii) modulation of cell movement by PTP and PP-1/2A
      may involve either a stimulation or reduction of beta1 integrin adhesive
      strength, and (iii) distinct phosphatase-mediated signaling pathways for
      differential regulation of the various beta1 integrins exist.

PMID- 10593605
TI  - Cloning of a Schizosaccharomyces pombe homologue of elongation factor 1 alpha by
      two-hybrid selection of calmodulin-binding proteins.
AB  - This study reports the cloning and characterization of a cDNA encoding elongation
      factor 1-alpha (EF1alpha) from the yeast Schizosaccharomyces pombe. The cDNA was
      cloned from an Schizosaccharomyces pombe expression library by a two-hybrid
      selection for clones encoding calmodulin (CaM)-binding proteins. The predicted
      protein is highly homologous to mammalian EF1alpha, indicating a strong tendency
      towards conservation of the primary amino acid sequence. The protein was
      expressed as a glutathione S-transferase fusion in both bacteria and in
      Schizosaccharomyces pombe. The bacterial protein was shown by solution assay to
      compete with CaM kinase II for CaM. The CaM binding domain was localized to the C
      terminus of the protein by this method. Expression of full-length EF1alpha in
      vivo caused an increase in cell cycle length and a decreased rate of growth as
      evidenced by a lack of elongated cells in slowly dividing cultures. This effect
      appears to involve CaM binding because a truncation mutant version of EF1alpha
      lacking the CaM binding domain did not cause cell cycle delay.

PMID- 10593606
TI  - Analysis of transcription factors binding to the human 7SL RNA gene promoter.
AB  - Transcription of the human 7SL RNA gene by RNA polymerase III depends on the
      concerted action of transcription factors binding to the gene-internal and gene
      external parts of its promoter. Here, we investigated which transcription factors
      interact with the human 7SL RNA gene promoter and which are required for
      transcription of the human 7SL RNA gene. A-box/B-box elements were previously
      identified in 5S RNA, tRNA, and virus associated RNA genes and are recognized by
      transcription factor IIIC (TFIIIC). The gene-internal promoter region of the
      human 7SL RNA gene shows only limited similarity to those elements. Nevertheless,
      competition experiments and the use of highly enriched factor preparations
      demonstrate that TFIIIC is required for human 7SL transcription. The gene
      external part of the promoter includes an authentic cAMP-responsive element
      previously identified in various RNA polymerase II promoters. Here we demonstrate
      that members of the activating transcription factor/cyclic AMP-responsive element
      binding protein (ATF/CREB) transcription factor family bind specifically to this
      element in vitro. However, the human 7SL RNA gene is not regulated by cAMP in
      vivo. Furthermore, in vitro transcription of the gene does not depend on ATF/CREB
      transcription factors. It rather appears that a transcription factor with DNA
      binding characteristics like ATF/CREB proteins but otherwise different properties
      is required for human 7SL RNA transcription.

PMID- 10593607
TI  - Free clathrin triskelions are required for the stability of clathrin-associated
      adaptor protein (AP-2) coated pit nucleation sites.
AB  - In this study image correlation spectroscopy was used to demonstrate the presence
      of two populations of clathrin in situ, on intact cells. In the periphery of the
      cell approximately 35% of the clathrin triskelions are free within the cytosol
      while approximately 65% are in large aggregates, presumably coated pits. Although
      endocytosis is inhibited at low temperature, free clathrin triskelions are still
      present and small AP-2 aggregates (of approximately 20 proteins), or coated pit
      nucleation sites, are still observed. Following hypertonic treatment, or
      cytoplasmic acidification, free clathrin triskelions within the cytosol are
      depleted and all of the clathrin becomes associated with the membrane. Under
      these conditions coated pit associated AP-2 remains while the smaller AP-2
      aggregates, or coated pit nucleation sites, dissociate. This indicates that the
      stabilization of AP-2 coated pit nucleation sites requires the presence of free
      clathrin triskelions within the cytosol. Furthermore, this indicates that free
      clathrin is required for the early stages of coated pit formation and presumably
      the continuation of the clathrin-mediated endocytic process. We also provide
      indirect evidence that AP-2 binding to the membrane in coated pit nucleation
      sites may be regulated in part by binding to internalization-competent membrane
      receptors.

PMID- 10593608
TI  - Kinetics of oxidation of serotonin by myeloperoxidase compounds I and II.
AB  - The oxidation of serotonin (5-hydroxytryptamine) by the myeloperoxidase
      intermediates compounds I and II was investigated by using transient-state
      spectral and kinetic measurements at 25.0 +/- 0.1 degrees C. Rapid scan spectra
      demonstrated that both compound I and compound II oxidize serotonin via one
      electron processes. Rate constants for these reactions were determined using both
      sequential-mixing and single-mixing stopped-flow techniques. The second order
      rate constant obtained for the one-electron reduction of compound I to compound
      II by serotonin is (1.7 +/- 0.1) x 10(7) M(-1) x s(-1), and that for compound II
      reduction to native enzyme is (1.4 +/- 0.1) x 10(6) M(-1) x s(-1) at pH 7.0. The
      maximum pH of the compound I reaction with serotonin occurs in the pH range 7.0
      7.5. At neutral pH, the rate constant for myeloperoxidase compound I reacting
      with serotonin is an order of magnitude larger than for its reaction with
      chloride, (2.2 +/- 0.2) x 10(6) M(-1) x s(-1). A direct competition of serotonin
      with chloride for myeloperoxidase compound I oxidation was observed. Our results
      suggest that serotonin may have a role to protect lipoproteins from oxidation and
      to prevent enzymes from inactivation caused by the potent oxidants HOCl and
      active oxygen species.

PMID- 10593609
TI  - Differential transmission of G1 cell cycle arrest and mating signals by
      Saccharomyces cerevisiae Ste5 mutants in the pheromone pathway.
AB  - Saccharomyces cerevisiae Ste5 is a scaffold protein that recruits many pheromone
      signaling molecules to sequester the pheromone pathway from other homologous
      mitogen-activated protein kinase pathways. G1 cell cycle arrest and mating are
      two different physiological consequences of pheromone signal transduction and
      Ste5 is required for both processes. However, the roles of Ste5 in G1 arrest and
      mating are not fully understood. To understand the roles of Ste5 better, we
      isolated 150 G1 cell cycle arrest defective STE5 mutants by chemical mutagenesis
      of the gene. Here, we found that two G1 cell cycle arrest defective STE5 mutants
      (ste5M(D248V) and ste5(delta-776)) retained mating capacity. When overproduced in
      a wild-type strain, several ste5 mutants also showed different dominant
      phenotypes for G1 arrest and mating. Isolation and characterization of the
      mutants suggested separable roles of Ste5 in G1 arrest and mating of S.
      cerevisiae. In addition, the roles of Asp-248 and Tyr-421, which are important
      for pheromone signal transduction were further characterized by site-directed
      mutagenesis studies.

PMID- 10593610
TI  - Structure, modelling, and molecular dynamics studies of the inhibition of protein
      tyrosine phosphatase 1B by sulfotyrosine peptides.
AB  - The protein tyrosine phosphatases comprise a class of enzymes that are crucial
      for the regulation of a number of cellular processes. Because of this, they are
      attracting increasing attention, not only as legitimate therapeutic targets, but
      also because of their relationship to many fundamental cellular processes.
      Certain sulfotyrosine peptides derived from casein are known to be good
      inhibitors of the protein tyrosine phosphatase, PTP1B. In this study, NMR
      transfer nuclear Overhauser effect studies have been used to ascertain the bound
      state conformation adopted by the 12-amino acid residue casein-derived peptide,
      CAS200 (NANEEE(sY)SIGSA) and N-terminal truncated forms of this peptide, CAS203
      and CAS205. Each of the peptides were found to bind in an extended beta-strand
      conformation. Extensive molecular modelling and molecular dynamics simulations of
      the PTP1B/peptide complexes, in a fully hydrated model, allowed a detailed
      description of the potential sources of the binding interactions to be developed.
      In agreement with the NMR studies, the modelling provided a picture of binding of
      CAS200 in which only the central (E203-I208) residues contributed significantly
      to the binding while the 3 N-terminal and 3 C-terminal residues were quite
      fluxional. Critical cationic surface residues, lying near to, but outside the
      active site pocket were the source of strong stabilizing forces that complemented
      the stabilizing interactions of the active site pocket. Electrostatic,
      hydrophobic, and hydrogen bonding interactions, in a residue specific manner,
      were all found to make significant contributions to the binding of these
      inhibitors.

PMID- 10593611
TI  - Mechanisms of oligodendrocyte commitment in the vertebrate CNS.

PMID- 10593612
TI  - Dehydroepiandrosterone selectively inhibits production of tumor necrosis factor
      alpha and interleukin-6 [correction of interlukin-6] in astrocytes.
AB  - Dehydroepiandrosterone (DHEA) is a native neurosteroid with immunomodulating
      activity. DHEA effectively protects animals from several viral, bacterial and
      parasitic infections and it was suggested that its age-associated decline is
      related with immunosenescence. In the present study we examined the ability of
      DHEA to inhibit the production of inflammatory mediators by mycoplasma-stimulated
      glial cells and to change the course of acute central nervous system (CNS)
      inflammatory disease in vivo. Addition of DHEA (10 microg/ml) markedly inhibited
      tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production (98
      and 95%, respectively), whereas nitric oxide (NO) and prostaglandin E2 (PGE2)
      production was not affected. However, daily administration of 0.5 mg DHEA to mice
      or 5 mg to rats did not change the clinical outcome of experimental autoimmune
      encephalomyelitis (EAE).

PMID- 10593613
TI  - Correlation between lead-induced changes in cerebral ornithine decarboxylase and
      protein kinase C activities during development and in cultured PC 12 cells.
AB  - Exposure to lead (Pb) interferes with neurodevelopment and disturbs ornithine
      decarboxylase (ODC) activity. ODC the key regulatory enzyme of the polyamine
      pathway, is a potential substrate for protein kinase C (PKC). Therefore, we
      examined developmental changes in PKC activity and its relationship to ODC
      activity. Male rats were lactationally exposed to 0.2% Pb-acetate from birth to
      weaning. PKC and ODC activity were measured on postnatal days (PND) 3, 5, 10, 20
      and 30. We found that the basal patterns of ODC and PKC activities resembled each
      other in both the neocortex and cerebellum and Pb-exposure attenuated both
      enzymes in a similar manner. To determine whether any link existed between these
      enzymes, ODC and PKC activities were induced to increase using nerve growth
      factor (NGF) in the presence and/or absence of ODC (difluoromethylornithine,
      DFMO) and PKC (staurosporine) inhibitors, in control and Pb-exposed
      Pheochromocytoma (PC-12) cells. Staurosporine decreased both ODC activity and PKC
      activity, while DFMO had no effect on PKC activity. These data suggest that ODC
      may be regulated by PKC and that Pb-induced developmental alterations in ODC
      activity may be secondary to changes in the integrity of PKC.

PMID- 10593614
TI  - Role of acetylcholinesterase in the development of axon tracts within the
      embryonic vertebrate brain.
AB  - In the developing vertebrate brain, acetylcholinesterase (AChE) expression
      coincides temporally with axon tract formation. Although AChE promotes neurite
      outgrowth in vitro, the role of this molecule in the development of axon tracts
      in vivo is unknown. To address this question, we examined the effects of the AChE
      inhibitor, BW284C51, on the formation of the early scaffold of axon tracts in the
      embryonic Xenopus brain. In exposed Xenopus brain preparations, axons elongate
      and establish a normal topography of axon tracts. However, when brains were
      exposed to BW284C51, the thickness of the major longitudinal axon tract, the
      tract of the post-optic commissure decreased in a dose-dependent manner. When
      BW284C51 was removed from the culture media axon tract development returned to
      normal within 5 h. These findings provide the first evidence for a non-classical
      role of AChE in the initial formation of axon tracts within the developing
      vertebrate brain.

PMID- 10593615
TI  - Ontogeny of cholinergic amacrine cells in the oppossum (Didelphis aurita) retina.
AB  - Immunocytochemistry for choline acetyltransferase (ChAT), the synthesizing enzyme
      for acetylcholine, was used to determine the onset and to follow the maturation
      of the cholinergic cells in the retina of a marsupial, the South American opossum
      (Didelphis aurita). ChAT-immunoreactivity was first detected in amacrine cells in
      the ganglion cell layer by postnatal day 15 (P15) and in the inner nuclear layer
      by P35. Much later, at P50 a second sub-population of ChAT-immunoreactive cell
      bodies was evident in the inner nuclear layer. Processes from ChAT-immunoreactive
      amacrine cells were detected in the two bands of the inner plexiform layer before
      synaptogenesis. In the adult retina, these two bands correspond to sublamina 2
      and 4 of the inner plexiform layer. In flat whole-mounted preparations,
      cholinergic cell density was 263 +/- 13 cells/mm2 in the ganglion cell layer and
      it was estimated a total of 24,000 cholinergic neurons. ChAT-immunoreactive
      somata showed a random pattern of distribution.

PMID- 10593616
TI  - Increased basal activity of the HPA axis and renin-angiotensin system in
      congenital learned helpless rats exposed to stress early in development.
AB  - Learned helpless behavior has been successfully bred in rats and designated as a
      genetic animal model of human depression and/or anxiety. Since congenital learned
      helpless animals have an impaired stress response in adulthood, we examined the
      effects of early stressors (at postnatal day 7, 14 or 21) on the hypothalamic
      pituitary-adrenal axis and the renin-angiotensin system. The functioning of the
      hypothalamic-pituitary-adrenal axis was monitored through changes in
      corticosterone plasma levels in the adult animals after acute exposure to cold
      stress and maternal deprivation early in development. Renin-angiotensin system
      functioning was assessed by plasma renin activity. Unstressed congenital learned
      helpless rats had corticosterone levels that were similar to control animals
      (congenital non-learned helpless rats not stressed during development), but
      unstressed plasma renin activity levels of congenital learned helpless rats were
      lower than congenital non-learned helpless rats. There was a step-wise increase
      in corticosterone plasma levels in the congenital learned helpless rats with age
      of acute presentation of either cold stress or maternal deprivation stress (day
      7, 49%; day 14, 84%; and day 21, 543% for cold stress). However, these baseline
      corticosterone levels were significantly lower in congenital learned helpless
      rats compared to congenital non-learned helpless controls. Similarly, in response
      to early exposure to cold stress and maternal deprivation, there was an increase
      in plasma renin activity levels of congenital learned helpless rats with age of
      presentation to either stressors. However, this increase in plasma renin activity
      levels was not evident in congenital non-learned helpless controls. Taken
      together, these results suggest that exposure to stress early in development has
      long-term effects on both the hypothalamic pituitary-adrenal axis and the renin
      angiotensin system, two neuroendocrine indicators of stress responsivity.

PMID- 10593617
TI  - IL-1beta increases intracellular calcium through an IL-1 type 1 receptor mediated
      mechanism in C6 astrocytic cells.
AB  - Interleukin-1beta (IL-1beta) is a cytokine that regulates a variety of biological
      processes. In addition to its traditional role in the immune system, IL-1beta
      plays an integral role in neural-immune and developmental processes in the
      nervous system. The pleiotropic ability of IL-1beta may be due to the activation
      of different signal transduction mechanisms in specific cell types or under
      certain cellular conditions. We have previously demonstrated that IL- regulates
      healing and repair in the developing, mammalian nervous system. In the damaged
      perinatal mouse brain, IL-1beta is expressed in astrocytes that change from a
      stellate to a spindle-shaped morphology. The spindle-shaped astrocytes enclose
      the wound, separating the healthy from damaged neural tissue. The shape change
      and subsequent repair processes are IL-1beta activity-dependent, acting through
      the IL-1 type 1 receptor (IL-1R1), as co-application of the IL-1type 1 receptor
      antagonist protein (IL-1ra) blocks IL-1beta induced effects. In the C6 astrocytic
      cell line, IL-1beta induced similar shape changes and upregulated expression of
      the cytoskeletal protein, glial fibrillary acidic protein (GFAP). Since
      cytoskeletal changes, as well as specific signal transduction mechanisms, are
      associated with increases in intracellular calcium ([Ca2+]i), studies were
      carried out to determine if increases in [Ca2+]i induced by IL-1beta occurred
      through activation of the IL-1R1 in C6 cells. Cells were treated with IL-1beta
      and/or IL-1ra, followed by measurement of relative changes in [Ca2+]i using fura
      2 fluorescence imaging methods. IL-1beta increased [Ca2+]i levels in a dose and
      time dependent manner. Treatment with IL-1ra blocked IL-1beta induced increases
      in [Ca2+]i, indicating that IL-1beta acts through the IL-1R1. Immunocytochemistry
      experiments showed that untreated C6 cells normally express IL-1beta, IL-1ra, and
      IL-1RI. Thus, IL-1 system molecules may play a role in normal C6 astrocyte
      physiology.

PMID- 10593618
TI  - GFAP gene methylation in different neural cell types from rat brain.
AB  - It is generally believed that specific demethylation processes take place in the
      promoter of tissue-specific genes during development. It has been suggested that
      hypomethylation of the -1500/-1100 domain of the 5' flanking regulatory region of
      the rat glial fibrillary acidic protein gene may be specific for neuroectodermal
      derivatives such as neurons and astrocytes. In the present work the methylation
      status of one of those seven CG sites (the -1176) of the 'neuroectoderm-specific
      domain' was analyzed. In agreement with the neuroectoderm hypothesis, the -1176
      site is highly demethylated in astroglial, oligodendroglial and neuronal cells,
      but heavily methylated in microglial and fibroblast cells. The three different
      glial population are derived from the same tissue (cerebral hemispheres of
      newborn rats) but have a different embryological origin: oligodendrocytes and
      astrocytes originate from neuroectoderm, while microglia is of mesodermal origin.
      It is not clear if GFAP-negative neuronal cells maintain such demethylation in
      the advanced stage of maturation or if they undergo a second phase of de novo
      methylation. In order to clarify this point we used a subcellular fractionation
      method which allowed us to separate two different nuclear populations from adult
      rat cerebral hemispheres: one enriched in neuronal nuclei (called N1) and the
      other enriched in glial nuclei (N2). A higher methylation level of the -1176 site
      was detected in the N1 fraction, suggesting the GFAP gene undergo a de novo
      methylation process during neuronal maturation. This observation is in agreement
      with recent results showing a de novo methylation of the -1176 site during
      postnatal brain development. We hypothesize that a DNA demethylation process
      takes place in neuroectodermal precursor cells and that the -1176 site persists
      demethylated at the earlier stages of neuronal differentiation (immature neurons)
      and becomes fully methylated at more advanced stages of differentiation.

PMID- 10593619
TI  - Neurofilament proteins are constitutively expressed in F9 teratocarcinoma cells.
AB  - We examined neuronal differentiation of F9 teratocarcinoma cells using retinoic
      acid (RA) and cyclic AMP (cAMP) as inducing agents. Neuronal differentiation was
      monitored using (1) cDNA probes for the rat 68-kDa neurofilament gene, (2) RT-PCR
      for neurofilament genes and (3) antibodies against several neuronal
      differentiation markers. We found by Northern blotting that the uninduced F9
      cells, grown in 10% serum, expressed mRNA for the 68-kDa neurofilament protein
      whereas the control cells, grown in 3% serum, failed to express detectable levels
      of the 68-kDa neurofilament transcripts. However, RT-PCR allowed detection of
      both the 68- and 200-kDa neurofilament gene transcripts in F9 cells with or
      without the inducing agents. Under serum deprivation, a prolonged (> 10-15 days)
      cultivation of the F9 cells in the presence of RA and cAMP was required for the
      expression of detectable levels of the 68-kDa neurofilament transcripts and
      immunocytochemically detectable neurofilament proteins. Treatment of the F9 cells
      with RA and cAMP was also required for induction of their neuronal phenotype.
      Immunocytochemically, the uninduced F9 cells expressed several neuronal antigens
      including the 68-kDa neurofilament protein, the 200-kDa neurofilament protein,
      neural cell adhesion molecule (N-CAM) and a neuronal specific tubulin isoform
      (TUJI). The control cells expressed N-CAM and TUJI, but failed to express the
      neurofilament proteins. A subclone, D9L2, derived from a single F9 parent cell,
      expressed both TUJI and neurofilament proteins, but no N-CAM molecule. The
      present results indicate that both the 68- and the 200-kDa neurofilament genes
      are constitutively active in uninduced F9 teratocarcinoma cells. Under serum
      deprivation both RA and cAMP are required for expression of detectable levels of
      neurofilament mRNA and protein. Thus, serum deprivation of the F9 cells either
      down-regulates the NF gene expression, stability of mRNA or degradation of the NF
      proteins. Importantly, expression of a neuronal phenotype by a subpopulation of
      F9 cells appears to require administration of RA and cAMP, although expression of
      neuronal marker proteins is not dependent on these agents. Lastly, we demonstrate
      cloning of a novel cell line (D9L2), derived from a single F9 parent cells,
      capable of extending neurites and expressing several neuronal antigens under
      serum deprivation without the requirement of RA and cAMP. We propose that the
      D9L2 cell line may offer a simplified F9 cell model system to investigate the
      mechanisms of neuronal differentiation.

PMID- 10593620
TI  - Functional and biochemical criteria for investigation of brain development
      disorders.
AB  - Functional state and creatine kinase (CK) activity in the amniotic fluid and
      blood of anencephalic fetuses was studied in the second trimester of pregnancy
      with the following pathomorphological investigation of the state of their CNS to
      reveal possible markers of development disorders. The extent of neurological
      disorders in newborn infants was retrospectively compared with data from
      functional studies of components of a biophysical profile (motor-cardiac reflex,
      heart rhythm oscillations, respiratory movements) and with CK activity in the
      amniotic fluid and blood of fetuses with hemolytic disease and fetuses of
      diabetic mothers and normal mothers in the third trimester of pregnancy. The
      results revealed informative indices of fetal CNS developmental disorders in the
      prenatal period that are of importance for predicting a prognosis of the extent
      of neurological disorders in newborn infants. These results will allow the
      establishment of criteria for evaluation of fetuses to reveal possible disorders
      in the formation of the CNS.

PMID- 10593621
TI  - Depression and risk of sudden cardiac death after acute myocardial infarction:
      testing for the confounding effects of fatigue.
AB  - OBJECTIVES: This study examined the impact of depressive symptoms and social
      support on 2-year sudden cardiac death (SCD) risk, controlling for fatigue
      symptoms. METHODS: Myocardial infarction (MI) patients (N = 671) participating in
      the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial completed measures
      of depression, hostility, and social support. RESULTS: After controlling for
      significant biological predictors, psychosocial predictors of increased SCD risk
      in the survival analysis were greater social network contacts (RR = 1.04; 95% CI
      = 1.01-1.06; p < .007), lower social participation (RR = 0.98; 95% CI = 0.96
      1.00; p < .05), and, in placebo-treated patients, elevated depressive symptoms
      (RR = 2.45; 95% CI = 1.14-5.35; p < .02). Fatigue was associated with SCD (RR =
      1.31; 95% CI = 1.11-1.53; p < .001), and, when included in the model, diminished
      the influence of depression (RR = 1.73; 95% CI = 0.75-3.98; p = .20). When the
      cognitive-affective depressive symptoms were examined separately from somatic
      symptoms, there was a trend for an association between cognitive-affective
      symptoms and SCD in placebo-treated patients after controlling for fatigue (RR =
      1.09; 95% CI = 0.99-1.19, p < .06). CONCLUSIONS: Symptoms of depression and
      fatigue overlap in patients with MI. The trend for the cognitive-affective
      symptoms of depression to be associated with SCD risk, even after controlling for
      dyspnea/fatigue, suggests that the association between depression and mortality
      after AMI cannot be entirely explained as a confound of cardiac-related fatigue.
      The independent contribution of social participation suggests a role of both
      depressive symptomatology and social factors in influencing mortality risk after
      MI.

PMID- 10593622
TI  - Depression and social support in recovery from myocardial infarction: confounding
      and confusion.

PMID- 10593623
TI  - Exposure to New York City as a risk factor for heart attack mortality.
AB  - OBJECTIVE: If New York City (NYC) residents' unusually high rate of ischemic
      heart disease (IHD) results from chronic exposure to that city, there might also
      be an effect of acute exposure among visitors to NYC. We explored this
      possibility and also whether IHD is reduced among NYC residents dying away from
      the city. METHODS: Using all US death certificates for 1985-1994, we examined
      (correcting for age, race, and sex) IHD deaths in three groups: NYC residents who
      died in the city, non-NYC residents visiting the city, and NYC residents
      traveling out of the city. RESULTS: IHD deaths among NYC residents dying in the
      city were 155% of the expected proportion (p < .0001). Among visitors to the
      city, such deaths were 134% of the expected proportion (p < .0001). The
      proportion of IHD deaths among NYC residents dying out of the city was only 80%
      of the expected value (p <.0001). These effects are not due to nearby commuters,
      recent immigrants, local classification practices, or socioeconomic status, and
      they do not appear in other US cities. CONCLUSIONS: With both chronic and acute
      effects of exposure to NYC, these data are consistent with the hypothesis that
      the stress of NYC is linked to the high rate of IHD.

PMID- 10593624
TI  - Location, location, location.

PMID- 10593625
TI  - An 18-month longitudinal study of posttraumatic disorders in children who were
      taken hostage in their school.
AB  - OBJECTIVE: The objective of our investigation was to study the course of direct
      and indirect posttraumatic disorders over 18 months in children after they were
      taken hostage in their school. METHODS: Twenty-six young hostages were evaluated
      by using standardized clinical interviews and self-administered questionnaires
      (State and Trait Anxiety Inventory for Children [STAIC]and Revised Impact of
      Event Scale [IES]) 2, 4, 7, and 18 months after the event. They were compared
      with 21 children from the same school who were not taken hostage (indirect
      exposure). RESULTS: Symptoms of acute stress were observed in 25 (96%) of the
      children who were directly involved in the traumatic event. After 2 months, 18
      children had developed disorders according to criteria of the Diagnostic and
      Statistical Manual of Mental Disorders, fourth edition, including 7 cases of full
      posttraumatic stress disorder (PTSD), 11 cases of subclinical PTSD, 3 cases of
      separation anxiety, 1 case of specific phobia, and 2 cases of major depressive
      disorder. Anxiety scores (STAIC) decreased between 2 and 4 months and then
      stabilized, whereas symptoms of avoidance (IES-avoidance) decreased gradually
      throughout the follow-up period, and symptoms of repetition (IES-intrusion)
      decreased less markedly. Children who were indirectly exposed to the trauma also
      manifested protracted posttraumatic symptomatology (two full cases of PTSD and
      six cases of subclinical PTSD), but their IES-intrusion scores were significantly
      lower at 7 months than those of children who were directly exposed, and the
      severity of their symptoms diminished over time. Girls tended to show a higher
      level of anxiety and more features of intrusion than boys. Psychological
      debriefing did not prevent occurrence of the disorders, but children who were not
      debriefed had the worst outcomes. CONCLUSIONS: Even after a short event and even
      if they are not directly exposed, children under the age of 9 years can develop
      high rates of posttraumatic disorders that follow a protracted course despite
      early intervention and careful monitoring.

PMID- 10593626
TI  - Persistence of depressive symptoms and cardiovascular death among patients with
      affective disorder.
AB  - OBJECTIVE: Studies of both community and clinical samples have associated
      depressive symptoms with risks for subsequent cardiovascular morbidity and
      mortality. Because the physiological mechanisms thought to underlie this link
      would be cumulative in their effects, the following analyses tested the
      prediction that risks for cardiovascular death would increase in proportion to
      the persistence of depressive symptoms in a long-term follow-up. METHODS:
      Baseline assessment was performed as patients sought treatment for major
      depressive disorder, mania, or schizo-affective disorder. Follow-up evaluations
      occurred semiannually for the next 5 years and annually thereafter. The 903
      patients described, observed for a mean of 11.0 years (SD = 5.2 years), were
      divided into thirds according to the proportion of follow-up weeks in episodes of
      major depressive disorder, schizoaffective disorder, or intermittent depressive
      disorder. The resulting groups were then compared by cumulative risks of
      cardiovascular death. RESULTS: Patients whose depressive symptoms were the most
      persistent were no more likely to die of cardiovascular causes than were those
      with the fewest weeks ill. A regression analysis showed that older age and the
      presence of cardiovascular disease at baseline, but not the subsequent chronicity
      of depressive symptoms, predicted cardiovascular death. CONCLUSIONS: The
      physiological concomitants of depressive illness apparently do not promote
      cardiovascular mortality in a cumulative manner. Efforts should be directed
      toward identification of risk factors common to both lifetime depressive symptoms
      and cardiovascular morbidity.

PMID- 10593627
TI  - Childhood sexual abuse, psychological distress, and medical use among women.
AB  - OBJECTIVE: This study examined the relationships between reported history of
      childhood sexual abuse (CSA), psychological distress, and medical utilization
      among women in a health maintenance organization (HMO) setting. METHODS:
      Participants were 206 women aged 20 to 63 years who were recruited from an HMO
      primary care clinic waiting area. Participants were classified, using screening
      questionnaires and the revised Symptom Checklist 90, as 1) CSA-distressed, 2)
      distressed only, 3) CSA only, or 4) control participants. Medical utilization
      rates were generated from the computerized database of the HMO for 1)
      nonpsychiatric outpatient, 2) psychiatric outpatient, 3) emergency room (ER), and
      4) inpatient admissions. RESULTS: CSA-distressed and distressed only groups both
      used significantly more nonpsychiatric outpatient visits than CSA only and
      control participants but were not different from one another. CSA only and
      control participants did not differ on nonpsychiatric outpatient utilization. CSA
      distressed participants used significantly more ER visits and were more likely to
      visit the ER for pain-related complaints than other participants. Among CSA
      distressed participants, those who met criteria for physical abuse had
      significantly more ER visits than those who did not. There were no differences
      among the four groups in inpatient utilization rates. CONCLUSIONS: Psychological
      distress is associated with higher outpatient medical utilization, independent of
      CSA history. History of CSA with concomitant psychological distress is associated
      with significantly higher ER visits, particularly for those with a history of
      physical abuse. History of CSA without distress is not associated with elevated
      rates of medical utilization. Screening for psychological distress, CSA, and
      physical abuse may help to identify distinct subgroups with unique utilization
      patterns.

PMID- 10593628
TI  - Comparison of generalized and localized hyperalgesia in patients with recurrent
      headache and fibromyalgia.
AB  - OBJECTIVES: Research suggests that dysregulated pain modulation may play an
      important role in recurrent headaches and fibromyalgia syndrome (FMS). The
      primary objective of this study was to investigate algesic responses in localized
      cervical and pericranial regions (ie, headache-specific areas) and distal
      locations (ie, trochanter and gluteal) in patients with primary headaches
      (tension-type and migraine). The headache patients' algesic responses were
      compared with those of a sample of patients with musculoskeletal pain who report
      generalized hyperalgesia, or FMS. METHODS: Seventy patients with mixed headache
      diagnoses and 66 patients with FMS underwent a standardized examination of
      generalized hyperalgesia based on American College of Rheumatology criteria.
      RESULTS: Twenty-eight of the 70 headache patients reported the presence of
      widespread TP pain, suggesting generalized hyperalgesia. Headache diagnosis was
      unrelated to the presence or absence of generalized hyperalgesia. The subset of
      headache patients with generalized hyperalgesia did not differ from the FMS
      patients in pain sensitivity in the cervical and pericranial areas. Regression
      analyses revealed that pressure pain sensitivity was significantly related to
      self-reported pain only in the headache patients with generalized hyperalgesia.
      CONCLUSIONS: These results suggest that extensive dysregulation in pain
      modulation is important for a substantial minority of recurrent headache
      patients, who seem to be quite similar to FMS patients. Differential treatment
      planning targeting generalized hyperalgesia may be useful in treating headache
      patients exhibiting generalized hyperalgesia more effectively.

PMID- 10593629
TI  - Core mental state in irritable bowel syndrome.
AB  - OBJECTIVE: Psychiatric illness is higher among patients with irritable bowel
      syndrome (IBS) who seek medical care; however, a specific psychopathology that
      differentiates patients with IBS from patients with other organic
      gastrointestinal disorders has not been found. In the study described here, we
      investigated the predominant psychiatric symptoms in women with IBS. METHODS: The
      criteria of Manning et al., as modified by Thompson et al., were used to make the
      diagnoses of IBS. Psychiatric assessment was performed by using a structured
      interview in 64 women, aged 20 to 70 years, 36 with IBS and 28 with chronic
      cholelithiasis. Diagnosis of chronic cholelithiasis was made by histopathological
      examination. The final diagnoses were confirmed by interview after 1 year. The
      diagnostic system based on the fourth edition of the Diagnostic and Statistical
      Manual of Mental Disorders (DSM-IV) was used to make the current diagnoses. The
      Present State Examination (PSE)-Index of Definition (ID) computer program
      (CATEGO) was used to define total psychopathology (total PSE score), current
      clinical severity (ID), and clusters of psychiatric symptoms. RESULTS: No
      difference in the specific DSM-IV diagnostic categories was found, but there were
      more total depressive disorders in the IBS group. The ID and total PSE score were
      high among patients with IBS. Multiple logistic regression analysis showed that
      duration of gastrointestinal pain, and the symptoms of general anxiety, and
      hypochondriasis significantly predicted a diagnosis of IBS. CONCLUSIONS: Female
      patients with IBS are categorized into the general DSM-IV category of depressive
      disorder, their current psychiatric severity is high compared with that of women
      with chronic cholelithiasis, and patients with IBS are characterized by the
      psychiatric syndromes of general anxiety and hypochondriasis. The implications of
      these findings and areas for future research are discussed.

PMID- 10593630
TI  - Coping style of individuals with functional dyspepsia.
AB  - OBJECTIVES: The objectives of the study described here were to 1) examine the
      coping style of patients with functional dyspepsia (FD) and 2) adopt a new
      interview questionnaire to examine the extent of discriminativeness in the use of
      coping strategies across different stressful situations. METHODS: A matched case
      control design was adopted to compare differences among a target group of 30
      patients with FD, a pain control group of 30 patients with rheumatism, and a
      control group of 30 healthy persons. A new interview questionnaire, the Coping
      Flexibility Interview Schedule, was used to assess subjects' experience of
      stressful life events, use of coping strategies, and perceived severity of major
      FD symptoms. RESULTS: Subjects with FD perceived their experienced stressors as
      more uncontrollable and as having a greater impact (p < .05). They also used more
      direct-action strategies but fewer divert attention, acceptance, social support,
      and relaxation strategies when handling stressful life events (p < .05). A
      significant group-by-controllability interaction effect was found (p < .001),
      indicating that FD subjects tended to use coping strategies nondiscriminatively,
      whereas both rheumatic and healthy subjects tended to use coping strategies more
      discriminatively across stressful life events of different extents of
      controllability. CONCLUSIONS: These results indicate that FD patients are
      characterized by a nondiscriminative, action-oriented coping style. The
      implications of this finding for the extant body of research and the advantages
      of using our interview questionnaire, which has a more flexible format, are
      discussed.

PMID- 10593631
TI  - Work stress and metabolic and hemostatic risk factors.
AB  - OBJECTIVE: A high level of work stress has been associated with cardiovascular
      disease. However, the pathophysiological mechanisms underlying this association
      remain unclear. This study examined the effect of work stress on a cluster of
      metabolic and hemostatic risk factors. METHODS: Blood was collected three times,
      on the first, third, and fifth day of a work week, from 124 middle-aged, white
      collar workers. Metabolic measures were insulin, glucose, triglycerides, low
      density lipoprotein cholesterol, high-density lipoprotein cholesterol, and total
      cholesterol. Hemostatic measures were fibrinogen, tissue-type plasminogen
      activator activity, tissue-type plasminogen activator antigen, and type 1
      plasminogen activator inhibitor antigen. Chronic work stress was defined
      according to Siegrist's model as 1) a combination of high effort and low reward
      at work (effort-reward imbalance) or 2) high overcommitment (an exhaustive work
      related coping style). RESULTS: Overcommitment, but not imbalance or the
      imbalance-overcommitment interaction, was associated with an impaired
      fibrinolytic system, as reflected in decreased tissue-type plasminogen activator
      activity levels and increased type 1 plasminogen activator inhibitor antigen
      levels on all three measurement occasions. After controlling for body mass index,
      total cholesterol, triglycerides, high-density lipoprotein/low-density
      lipoprotein cholesterol ratio, glucose, and insulin, the relation between overcom
      mitment and the fibrinolytic factors was attenuated but remained significant.
      CONCLUSIONS: The results suggest that individuals with an exhaustive coping style
      at work have an impaired fibrinolytic capacity that is possibly due to the
      effects of chronic stress on insulin resistance.

PMID- 10593632
TI  - Ambulatory blood pressure monitoring is associated with reduced physical activity
      during everyday life.
AB  - OBJECTIVE: The objective of this study was to assess the impact on noninvasive
      ambulatory blood pressure monitoring on physical activity measured objectively by
      use of triaxial accelerometers. METHODS: Twenty-four working men and women
      performed ambulatory blood pressure plus activity monitoring for 1 working day
      and evening and activity monitoring alone for a separate day and evening. Blood
      pressure measures were taken at 20-minute intervals during the day and 30-minute
      intervals in the evening and were accompanied by diary assessments of mood,
      location, and posture. Comparisons were made of energy expenditure on the 2 days
      and of activity levels during the minutes surrounding each blood pressure reading
      and diary completion. RESULTS: Energy expenditure assessed in terms of activity
      calories per hour was significantly lower during blood pressure plus activity
      monitoring compared with activity monitoring alone (mean 37.3, SD = 16.3 vs. mean
      = 43.0, SD = 18.7 kcal, respectively: p = .02). Energy expenditure was lower
      during the 4 minutes surrounding each blood pressure reading than in the
      intervals between blood pressure readings. However, energy expenditure was also
      lower in the intervals between blood pressure readings than during comparable
      times on the activity only monitoring day. Blood pressure, heart rate, and
      physical activity were moderately correlated within individuals. CONCLUSIONS:
      Ambulatory blood pressure recording using automated sphygmomanometers is
      associated with reduced physical activity during the monitoring day. This is due
      partly to regular periods of immobility during cuff inflation and deflation and
      diary completion and partly to more general self-imposed restrictions on
      activity. This pattern has implications for the representativeness of ambulatory
      blood pressure monitoring, and the construction of ambulatory monitoring diaries.

PMID- 10593633
TI  - Zazen and cardiac variability.
AB  - OBJECTIVE: This study examined the effects of "tanden breathing" by Zen
      practitioners on cardiac variability. Tanden breathing involves slow breathing
      into the lower abdomen. METHODS: Eleven Zen practitioners, six Rinzai and five
      Soto, were each studied during 20 minutes of tanden breathing, preceded and
      followed by 5-minute periods of quiet sitting. During this time, we measured
      heart rate and respiration rate. RESULTS: For most subjects, respiration rates
      fell to within the frequency range of 0.05 to 0.15 Hz during tanden breathing.
      Heart rate variability significantly increased within this low-frequency range
      but decreased in the high-frequency range (0.14-0.4 Hz), reflecting a shift of
      respiratory sinus arrhythmia from high-frequency to slower waves. Rinzai
      practitioners breathed at a slower rate and showed a higher amplitude of low
      frequency heart rate waves than observed among Soto Zen participants. One Rinzai
      master breathed approximately once per minute and showed an increase in very-low
      frequency waves (<0.05 Hz). Total amplitude of heart rate oscillations (across
      frequency spectra) also increased. More experienced Zen practitioners had
      frequent heart rhythm irregularities during and after the nadir of heart rate
      oscillations (ie, during inhalation). CONCLUSIONS: These data are consistent with
      the theory that increased oscillation amplitude during slow breathing is caused
      by resonance between cardiac variability caused by respiration and that produced
      by physiological processes underlying slower rhythms. The rhythm irregularities
      during inhalation may be related to inhibition of vagal modulation during the
      cardioacceleratory phase. It is not known whether they reflect cardiopathology.

PMID- 10593634
TI  - Relationship between clinical pain complaints and pain sensitivity in patients
      with depression and panic disorder.
AB  - OBJECTIVE: There is evidence that depression and panic disorder are both
      associated with an increased frequency of clinical pain complaints. A change in
      pain sensitivity is alleged to be involved in this phenomenon. However, few
      studies have assessed clinical pain complaints and pain sensitivity in the same
      group of patients. METHODS: Thirteen patients with a major depressive disorder,
      13 patients with a panic disorder (diagnoses based on the Diagnostic and
      Statistical Manual of Mental Disorders, fourth edition), and 13 healthy control
      subjects were investigated. None of the subjects were taking medications. Body
      maps were used to measure the number of painful sites as well as the intensity
      and unpleasantness of pain complaints in the previous 6 months. Furthermore, pain
      thresholds for pressure, cold, and heat were assessed at the forearm or hand.
      RESULTS: Patients with depression and panic disorder had significantly more
      frequent, more intense, and more unpleasant pain complaints than healthy control
      subjects. Despite this similarity, patients with depression had significantly
      higher pain thresholds than patients with panic disorder in two (pressure and
      cold) of three stimulus modalities and significantly higher pressure pain
      thresholds than the healthy control subjects. There were no differences between
      the pain thresholds of patients with panic disorder and healthy control subjects.
      The correlations between clinical pain measures and pain thresholds were
      generally weak. CONCLUSIONS: These findings suggest that the clinical pain
      complaints of patients with depression and panic disorder cannot simply be
      explained by changes in pain sensitivity.

PMID- 10593635
TI  - Association between burnout at work and leukocyte adhesiveness/aggregation.
AB  - OBJECTIVE: This study examined whether burnout at work is associated with
      leukocyte adhesiveness/aggregation (LAA), a phenomenon known to be affected by
      stress. METHODS: The LAA levels of 179 employees (68 men and 111 women) of Tel
      Aviv University were determined when the employees underwent their annual routine
      medical checkup. Blood pressure and toxic chemical exposure were also measured,
      and background data were retrieved from medical records. Information on burnout
      and somatic complaints (known to be a general marker of stress) was collected
      through a self-report questionnaire. RESULTS: Total burnout and each of its
      subcomponents, emotional exhaustion, chronic fatigue, and cognitive weariness,
      was significantly associated with LAA levels, even after controlling for age,
      sex, and educational level. Burnout and somatic complaints intercorrelated
      positively, but somatic complaints were not significantly associated with LAA
      levels before or after controlling for the above possible confounders.
      CONCLUSIONS: Burnout was positively associated with LAA levels. This finding is
      consistent with the growing evidence of the negative impact of burnout on
      physical health. The lack of an association between somatic complaints and LAA
      levels reinforces the claim that burnout and stress are two different concepts.

PMID- 10593636
TI  - Psychological risk factors may moderate pharmacological treatment effects among
      ischemic heart disease patients. Canadian Amlodipine/Atenolol in Silent Ischemia
      Study (CASIS) Investigators.
AB  - BACKGROUND: Numerous research findings support the proposed connection between
      such psychological characteristics as stress and hostility and the manifestation
      of disease. However, less evidence is available concerning the role(s)
      psychological factors might play in the process of disease recovery. METHODS:
      Eighty patients with known coronary disease and exercise-induced ischemia
      underwent treadmill exercise testing and 48-hour ambulatory electrocardiographic
      monitoring and completed a battery of standardized psychological tests assessing
      hostility, depression, and daily stress on four occasions during a 12-week
      pharmacological treatment study. After withdrawal of antiischemic drugs at
      baseline, patients returned for subsequent tests at 3-week intervals. During the
      second and third intervals, patients were prescribed one of two antiischemic
      medications, atenolol or amlodipine, or given a placebo. All patients were then
      placed on a combination treatment protocol for the 3 weeks before the final
      testing date. RESULTS: The combination treatment produced highly significant
      benefits across all measured cardiac variables (20.3% improvement in exercise
      performance, 13% reduction in reported angina, 64.0% reduction in the frequency
      of ischemic episodes; for all, p < .01). However, results showed that high
      baseline levels of daily stress were associated with reliably smaller treatment
      effects on measures of ischemia frequency and treadmill exercise time and with a
      significantly greater likelihood of reporting angina after treatment (r = -0.24, 
      0.25, and -0.33, respectively; p <.05). In addition, high baseline hostility
      predicted significantly smaller diastolic blood pressure improvements (r = -0.29,
      p < .05). CONCLUSIONS: These results indicate that psychological risk factors may
      have globally negative effects on the course of treatment and suggest particular
      factors that may warrant attention in trials targeting cardiac symptom reduction.

PMID- 10593637
TI  - Do episodes of anger trigger myocardial infarction? A case-crossover analysis in
      the Stockholm Heart Epidemiology Program (SHEEP).
AB  - OBJECTIVE: Our objectives were to study anger as a trigger of acute myocardial
      infarction (MI) and to explore potential effect modification by usual behavioral
      patterns related to hostility. METHODS: This study was a case-crossover study
      within the Stockholm Heart Epidemiology Program. Exposure in the period
      immediately preceding MI was compared with exposure during a control period for
      each case. From April 1993 to December 1994, 699 patients admitted to coronary
      care units in Stockholm County were interviewed. RESULTS: During a period of 1
      hour after an episode of anger, with an intensity of at least "very angry," the
      relative risk of MI was 9.0 (95% CI, 4.4-18.2). In patients with premonitory
      symptoms, the time of disease initiation may be misclassified. When restricting
      the analyses to those without such symptoms, the trigger risk was 15.7 (95% CI,
      7.6-32.4). The possibility of examining effect modification was limited by a lack
      of statistical power (eight exposed cases). Results of the analyses suggested,
      however, an increased trigger effect among subjects reporting nonhostile usual
      behavior patterns, nonovert strategies of coping with aggressive situations (not
      protesting when being treated unfairly), and nonuse of beta-blockers.
      CONCLUSIONS: The hypothesis that anger may trigger MI is further supported, with
      an increased risk lasting for approximately 1 hour after an outburst of anger. It
      is suggested that the trigger risk may be modified by personal behavior patterns.

PMID- 10593638
TI  - Pathways linking major depression and immunity in ambulatory female patients.
AB  - OBJECTIVES: The goals of this study were to investigate whether depression is
      associated with cellular immunity in ambulatory patients and to identify
      neuroendocrine and behavioral pathways that might account for this relationship.
      METHODS: We studied 32 women who met Diagnostic and Statistical Manual of Mental
      Disorder, fourth edition, criteria for major depressive disorder and 32 healthy
      female control subjects. The groups were matched for age and ethnicity. None were
      taking medication, and all were free of disease involving the immune system.
      RESULTS: Depressed subjects had reduced proliferative responses to the mitogens
      concanavalin A and phytohemagglutinin compared with control subjects. Natural
      killer cell activity was reduced among older depressed subjects but enhanced
      among younger depressed subjects. Although depression was associated with
      elevated circulating levels of norepinephrine and estradiol, these hormones could
      not account for the immunologic differences between depressed and control
      subjects. Depression was also associated with greater tobacco and caffeine
      consumption, less physical activity, and poorer sleep quality. Mediational
      analyses were consistent with physical activity acting as a pathway through which
      depression was associated with reduced lymphocyte proliferation. CONCLUSIONS:
      Ambulatory patients with mild to moderately severe depression exhibit reduced
      mitogen-stimulated lymphocyte proliferative responses and altered natural killer
      cell cytotoxicity. The relationship between depression and proliferative
      responses may be mediated by physical activity.

PMID- 10593639
TI  - Psychosocial and developmental antecedents of chest pain in young adults.
AB  - OBJECTIVE: The objective of this study was to assess the relationships among
      chest pain, psychiatric disorder, and early experience of ill health. METHODS:
      The Medical Research Council National Survey of Health and Development is a
      population-based birth cohort study established in 1946 (N = 5362). During
      childhood, several informants (parents, teachers, and school physicians) were
      interviewed or completed questionnaires. Data were available on the subjects'
      health, the health of their parents, and subjects' personalities. At the age of
      36 years, subjects were asked about chest pain using the Rose Angina
      Questionnaire and completed the Present State Examination, a semistructured
      psychiatric interview. Subjects were followed for another 7 years (to age 43
      years) to determine the outcome of those with chest pain. RESULTS: Chest pain was
      reported in 17.2% (95% CI = 15.9-18.5%) of respondents at 36 years. The
      prevalence of exertional chest pain was 1.0% (95% CI = 0.7-1.3%). There was
      little evidence of coronary heart disease in those with exertional pain at age 36
      years when followed for 7 years. However, there was a powerful cross-sectional
      relationship between psychiatric disorder and chest pain (OR for psychiatric
      disorder and all chest pain = 3.55, 95% CI = 2.34-5.37; OR for psychiatric
      disorder and exertional chest pain = 29.08, 95% CI = 6.65-127.15). Childhood risk
      factors, including poor health reported in parents at age 15 years and fatigue
      during childhood, were also associated with chest pain. CONCLUSIONS: Chest pain
      (especially exertional chest pain) is strongly associated with psychiatric
      disorders in young adults. Childhood experiences, including illness in parents,
      are associated with subsequent chest pain.

PMID- 10593640
TI  - Attitudes toward menopause and aging across ethnic/racial groups.
AB  - OBJECTIVE: Attitudes have a potential role to play in the experience of
      menopause. The objective of this study was to examine the degree to which
      attitudes toward menopause and aging vary across ethnic groups and menopausal
      status (ie, premenopausal through postmenopausal). METHODS: More than 16,000
      women were interviewed by telephone as part of the Study of Women's Health Across
      the Nation. They represented five ethnic/racial groups (African American, white,
      Chinese American, Japanese American, and Hispanic) from seven geographical sites
      (Boston, MA; Pittsburgh, PA; Chicago, IL; Michigan; New Jersey; and northern and
      southern California). RESULTS: African American women were significantly more
      positive in attitude. The least positive groups were the less acculturated
      Chinese American and Japanese American women. Menopausal status was not a
      consistent predictor of attitude across ethnic groups. CONCLUSIONS: In general,
      women's attitudes toward menopause range from neutral to positive. Ethnic groups
      within the United States vary slightly, but reliably, in their attitudes toward
      menopause and aging. Factors other than those directly associated with menopausal
      status seem to play a role in attitude.

PMID- 10593641
TI  - Daily psychosocial stressors interfere with the dynamics of urine neopterin in a
      patient with systemic lupus erythematosus: an integrative single-case study.
AB  - OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease
      characterized by flare-ups, the causes of which are not known. In accordance with
      new concepts in stress research, this study investigated whether daily
      psychosocial stressors interfere with immunological processes in SLE. Because
      such processes are unique to each individual, single-case design using time
      series analysis (Box and Jenkins) was applied. METHODS: A 40-year-old woman with
      SLE (last flare-up September 1995) was interviewed initially to determine major
      life events and difficulties (using the Life Events and Difficulties Schedule) in
      the previous 2 years. She was then observed for 63 days. Urine neopterin, an
      immunological parameter demonstrated to parallel disease activity in SLE
      patients, was measured in daily overnight urine. Daily incidents were identified
      weekly by the Incidents and Hassles Inventory and independently rated.
      Intervening factors, including infections, medication, and lifestyle, were
      controlled. RESULTS: Retrospectively, data obtained from the Life Events and
      Difficulties Schedule indicated that major life events and difficulties had
      preceded the patient's last flare-up in 1995. Although there were no clinical
      signs of SLE during this prospective study of 63 days, cross-correlational
      analyses revealed that "moderately" stressful incidents associated with higher
      levels of emotional irritation (lag 0: +0.271, p < .05) predicted an increase in
      urine neopterin the following day (lag 1: +0.441, p < .05). Moreover, a 7-day
      cyclicity in neopterin levels that corresponded to the weekly examinations and
      interviews was found. CONCLUSIONS: This study showed a causal relationship
      between psychosocial stressors and urine neopterin concentrations that may be
      related to SLE disease activity. Furthermore, the workability of an integrative
      approach using single-case design and time-series analysis in
      psychoneuroimmunology was demonstrated for the first time.

PMID- 10593642
TI  - Biochemical assessment of individual sports for improved performance.
AB  - Biomechanists are able to offer a scientific service which aids the process of
      achieving improved sports performance. They are able to provide measurement tools
      to quantify key mechanical variables related to performance. Biomechanists use
      different methods to define these key variables, although there is no generally
      accepted approach on how this should be done. The process of intervention should
      be undertaken using information gained from a biomechanical assessment. This is
      often not conducted by the biomechanist and is usually left to other specialists.
      The success of this intervention is rarely evaluated so as to provide evidence to
      validate the earlier stages of the assessment. Biomechanists who have
      considerable experience and have conducted applied research programmes with
      specific sports seem to be able to demonstrate success. It is concluded that
      biomechanists need to support their claim to be able to influence performance
      outcome with more evidence based practice.

PMID- 10593643
TI  - Physical activity and high density lipoprotein cholesterol levels: what is the
      relationship?
AB  - High density lipoprotein cholesterol (HDL-C) levels are strongly, inversely and
      independently associated with coronary heart disease (CHD). Increased physical
      activity is associated with reduced CHD mortality. This protection against CHD
      may partially be explained by the increase in HDL-C levels observed following
      aerobic exercise training. Many also agree that an exercise threshold needs to be
      met before such favourable changes in HDL-C metabolism can occur. Most likely,
      the exercise-induced changes in HDL-C are the result of the interaction amongst
      exercise intensity, frequency, duration of each exercise session and length of
      the exercise training period. Although a relative contribution of each exercise
      component (intensity, duration and frequency) is also likely, it has not been
      established. There is also substantial support for a dose-response relationship.
      Favourable changes in HDL-C appear to occur incrementally and reach statistical
      significance at approximately 7-10 miles per week or 1200 to 1600kcal. Exercise
      induced changes in HDL-C may also be gender dependent. The volume of exercise
      required to increase HDL-C levels appears to be substantially more for women than
      men. This perhaps is due to higher HDL-C levels in women at baseline compared
      with men. However, the many other health benefits derived from increased physical
      activity should encourage women to participate in regular exercise regardless of
      the exercise effects on HDL-C levels. A practical approach in prescribing
      exercise for patients is to use moderate intensity exercises (70 to 80% of
      predicted maximal heart rate), 3 to 5 times per week, for a total of 7 to 14
      miles per week. This is equivalent to approximately 1200 to 1600kcal per week.
      Moderate to low intensity exercise should be preferred because such exercise
      carries a lower risk for cardiac complications. In addition, patients are more
      likely to participate and sustain a lower than higher intensity exercise
      programme. It is also important to recognise that other modes of physical
      activity can also be encouraged for patients. Such activities should be
      associated with similar increases in HDL-C levels as long as they meet or exceed
      the caloric expenditure of 1200 to 1600kcal (7 to 14 miles per week of jogging).

PMID- 10593644
TI  - Physical activity, cardiometabolic health and older adults: recent findings.
AB  - Cardiometabolic disease is a major cause of disability and death among older
      people. The scientific evidence purporting the cardiometabolic health benefits of
      moderate intensity, habitual physical activity among older adults has grown in
      recent years. Regular, moderate intensity physical activity is associated with
      lower resting blood pressure, less abdominal adiposity, improved blood lipids
      lipoproteins and glucose homeostasis and reduced mortality and morbidity from
      coronary heart disease. Although more vigorous intensity exercise confers similar
      cardiometabolic health benefits, it predisposes older people to increased risk of
      injury and sudden death. Older adults prefer to engage in light to moderate
      intensity physical activities such as walking and activities of daily living. For
      these reasons, a cardiometabolic approach to exercise prescription is presented
      emphasising daily accumulated, familiar and enjoyable light to moderate
      intensity, aerobic physical activity supplemented by resistive exercise for the
      functionally able older adult.

PMID- 10593645
TI  - Preventing in-line skating injuries: how effective are the countermeasures?
AB  - There was a six-fold growth in participation in in-line skating in the US from
      1989 to 1996 and a concomitant increase in injuries. Similar trends have been
      reported in Canada, the UK, Denmark and Australia. Falls, mostly from loss of
      balance, are a common cause of injury. Falling skaters typically put one or both
      hands out to break their fall and land on a hard surface with the upper limb
      sustaining the injury. Approximately one-quarter of all in-line skating injuries
      are wrist fractures. Hospital emergency department data shows that skaters aged
      10 to 14 years are most at risk for injury. First-time skaters, inexperienced
      skaters and experienced skaters trying new tricks are also at risk for injury. In
      line skating injuries can be severe, with several deaths reported. Measures to
      prevent in-line skating injury include: wearing personal protective equipment
      (wrist guards, helmets, knee and elbow pads); improving environmental conditions
      for skaters; providing lessons, particularly for novice skaters; certification
      for skating instructors; encouraging physical preparation; educating skaters
      about safety; improving equipment design and standards; and refining government
      policy and regulation in consultation with skating groups. Few of these measures
      have been formally proven to reduce injury. Controlled evaluations of the
      currently advocated methods are needed to establish their efficacy. More
      biomechanical and epidemiological research is needed, particularly in the area of
      wrist/forearm injury prevention. Given the rapid increase in popularity of in
      line skating and the potential for a related epidemic of moderate to serious
      injuries, research into in-line skating injury prevention should be a priority.

PMID- 10593647
TI  - Treating lateral epicondylitis.
AB  - Lateral epicondylitis is a common problem among physically active individuals.
      One of the most important roles of the clinician is to provide the most effective
      rehabilitation intervention for the injured athlete and the physically active
      individual. Over 40 different treatment methods for lateral epicondylitis have
      been reported in the literature. Initially, lateral epicondylitis can be treated
      with rest, ice, tennis brace and/or injections. Injections are one of the most
      popular methods utilised, with a high success rate. However, when the condition
      is chronic or not responding to initial treatment, physical therapy is initiated.
      Common rehabilitation modalities utilised are ultrasound, phonophoresis,
      electrical stimulation, manipulation, soft tissue mobilisation, neural tension,
      friction massage, augmented soft tissue mobilisation (ASTM) and stretching and
      strengthening exercise. ASTM is becoming a more popular modality due to the
      detection of changes in the soft tissue texture as the patient progresses through
      the rehabilitation process. Other new modalities include laser and acupuncture.
      As a last resort for chronic or resistant cases, lateral epicondylitis may
      undergo surgery. Scientific research has found that all these methods have been
      inconsistently effective in treating lateral epicondylitis. Therefore, further
      research efforts are needed to determine which method is more effective.

PMID- 10593646
TI  - Acute aerobic exercise and affect: current status, problems and prospects
      regarding dose-response.
AB  - One of the assumptions underlying recent physical activity recommendations is
      that lower doses of activity (i.e. intensity and duration) are more enjoyable for
      the average person, thus leading to higher involvement and adherence rates.
      However, the veracity of this hypothesis can be questioned, since little is
      actually known regarding the association between activity doses and affective
      responses. The few preliminary attempts at the conceptual delineation of the dose
      response relationship, all centred around an 'inverted-U' notion, are reviewed
      and criticised as lacking empirical foundation. Available meta-analyses, as well
      as the empirical literature on the role of exercise intensity and duration, are
      examined. Increased intensity appears to be associated with reduced positivity of
      affect during and immediately following an exercise bout. Intensity effects
      appear to be attenuated during recovery. Fitness and training status appear to
      become significant mediators of the exercise-affect relationship only at high
      intensities. With intensity being kept constant, different exercise bout
      durations have not been shown to have a differential impact on pre- to post
      exercise affective changes. Recommendations for future research include: (i) a
      shift from categorical to dimensional conceptualisations and operationalisations
      of affect; (ii) the examination of psychological theories on the association
      between activation and affect (e.g. extraversion-introversion, sensation seeking,
      type A behaviour pattern and related self-evaluative tendencies, reversal theory,
      optimal stimulation theory, multidimensional activation theory and self
      efficacy); (iii) the systematic and theory-based examination of in-task and post
      exercise affective responses; (iv) the incorporation of the parameter of fitness
      and/or activity status in research designs; and (v) the re-evaluation of methods
      for selecting exercise intensity levels.

PMID- 10593648
TI  - Loss of insulin-like growth factor I receptor-dependent expression of p107 and
      cyclin A in cells that lack the extracellular matrix protein secreted protein
      acidic and rich in cysteine.
AB  - The extracellular matrix-associated glycoprotein secreted protein acidic and rich
      in cysteine (SPARC) has been implicated in the control of cell proliferation
      during tissue remodeling, wound healing, and malignant development. Here, we
      describe a novel mechanism through which SPARC influences cell cycle progression
      in embryonic fibroblasts derived from Sparc-nullizygous (-/-) mice. SPARC
      deficient cells were indistinguishable from wild-type cells in their ability to
      initiate DNA synthesis after treatment with either fetal bovine serum or platelet
      derived growth factor. In contrast, Sparc -/- cells responded poorly to
      activation of the insulin-like growth factor receptor (IGFI-R) by insulin. This
      defect was traced to reduced expression of the IGFI-R in Sparc -/- cells.
      Consistent with impaired cell cycle progression through S-phase, insulin
      stimulated Sparc -/- cells also revealed reduced expression of two key regulators
      of S phase progression (cyclin A and thymidine kinase), whereas expression of the
      G1 phase progression regulators cmyc or cyclin D1 was unaffected. An examination
      of the status of retinoblastoma family pocket proteins in Sparc -/- cells
      revealed a selective and dramatic reduction in levels of the retinoblastoma
      related protein p107. Exogenous platelet-derived growth factor restored
      expression of the IGFI-R and IGFI-R dependent DNA synthesis as well as induction
      of cyclin A, thymidine kinase, and p107 in insulin-stimulated Sparc -/- cells.
      These results suggest that SPARC-dependent matrix to cell interactions contribute
      to the regulation of p107 and cyclin A through IGFI-R dependent pathway(s).

PMID- 10593649
TI  - Stabilization and reactivation of the p53 tumor suppressor protein in
      nontumorigenic revertants of HeLa cervical cancer cells.
AB  - We demonstrated previously that loss of in vitro transformation and in vivo
      tumorigenicity in two independent revertant clones of HeLa cells (designated HA
      and HF) resulted from dominant-acting genetic changes. Analysis of the p53 tumor
      suppressor gene revealed stabilization and at least partial restoration of wild
      type p53 transactivation properties pathways in both revertants of HPV-induced
      cell transformation. The half-lives of the p53 protein and both of the HA and HF
      clones were increased approximately 4 fold compared with the parental HeLa cells
      (16, 17, and 4 min, respectively). The levels of E6 viral protein expression were
      similar in the three cell lines, whereas the levels of the ubiquitin ligase
      protein, E6 associated protein (E6-AP), were elevated in the revertants. Western
      blot analysis of immunoaffinity-purified p53 demonstrated that stabilization of
      p53 in the revertants was correlated with a reduction in the in vivo formation of
      complexes involving the E6 oncoprotein and p53. Stabilization of p53 function in
      the revertants did not result from mutations in either the p53 or E6-AP genes.
      Despite the observed stabilization and restoration of p53 transactivation
      function in the revertants, exposure of the revertants to DNA-damaging agents did
      not result in elevated levels of p21(waf-1) protein and failed to induce growth
      arrest in the G1 phase of the cell cycle. However, p53-independent induction of
      p21(waf-1) protein also failed to induce the G1 phase of the cell cycle. Thus,
      restoration of wild-type p53 transactivation activity in the HA and HF revertants
      is insufficient to induce G1 arrest and reversion from HPV-induced cell
      transformation in our model system.

PMID- 10593650
TI  - Effect of elevated levels of ornithine decarboxylase on cell cycle progression in
      skin.
AB  - By crossing TG.AC v-Ha-ras and K6/ODC transgenic mice, we found previously that
      an activated ras and follicular ornithine decarboxylase (ODC) overexpression
      cooperate to generate spontaneous tumors in the skin. Cellular proliferation was
      dramatically increased in the K6/ODC transgenic skin, as evidenced by elevated
      proliferating cell nuclear antigen and Ki67 expression compared with
      nontransgenic littermates. Keratinocytes isolated from transgenic skin also
      displayed increased clonal growth. Paradoxically, expression of the growth
      inhibition-associated proteins p53, p21Waf1, p27Klp1, and Bax was increased with
      ODC overexpression in the skin. ODC overexpression did not affect cyclin D/cyclin
      dependent kinase 4 (Cdk4)-dependent phosphorylation of retinoblastoma protein but
      stimulated cyclin E/Cdk2 and cyclin A/Cdk2-associated kinase activity, with
      minimal effect on the levels of these proteins. Thus, ODC/polyamine-induced
      activation of cyclin E/Cdk2 and cyclin A/Cdk2-associated kinase activity may
      cooperate with the ras induction of cyclin D/Cdk4/6-associated retinoblastoma
      protein phosphorylation to not only stimulate proliferation but ultimately
      contribute to tumor development.

PMID- 10593651
TI  - Relationship between DNA adduct levels, repair enzyme, and apoptosis as a
      function of DNA methylation by azoxymethane.
AB  - DNA alkylating agent exposure results in the formation of a number of DNA
      adducts, with O6-methyl-deoxyguanosine (O6-medG) being the major mutagenic and
      cytotoxic DNA lesion. Critical to the prevention of colon cancer is the removal
      of O6-medG DNA adducts, either through repair, for example, by O6-alkylguanine
      DNA alkyltransferase (ATase) or targeted apoptosis. We report how rat colonocytes
      respond to administration of azoxymethane (a well-characterized experimental
      colon carcinogen and DNA-methylating agent) in terms of O6-medG DNA adduct
      formation and adduct removal by ATase and apoptosis. Our results are: (a) DNA
      damage is greater in actively proliferating cells than in the differentiated cell
      compartment; (b) expression of the DNA repair enzyme ATase was not targeted to
      the proliferating cells or stem cells but rather is confined primarily to the
      upper portion of the crypt; (c) apoptosis is primarily targeted to the stem cell
      and proliferative compartments; and (d) the increase in DNA repair enzyme
      expression over time in the bottom one-third of the crypt corresponds with the
      decrease in apoptosis in this same crypt region.

PMID- 10593652
TI  - Proteolysis of heat shock transcription factor is associated with apoptosis in
      rat Nb2 lymphoma cells.
AB  - Previously, we reported that prolactin (PRL)-dependent Nb2 lymphoma cells exhibit
      an aberrant heat shock response because of cysteine protease-mediated
      fragmentation of the heat shock transcription factor (HSF). Moreover, exposure of
      the cells to PRL abrogated heat-induced HSF proteolysis. The present study was
      conducted to investigate whether HSF proteolysis is a component of the apoptotic
      process in this model. Initially, the effect of heat stress (41 degrees C for 1
      h) on apoptosis, determined by agarose gel electrophoresis and flow cytometric
      analysis, was evaluated in PRL-dependent Nb2-11 cells and in an autonomous
      subline (Nb2-SFJCD1). Heat was found to induce HSF proteolysis concomitant with
      activation of apoptosis in each cell line; treatment with PRL blocked these
      effects. To determine whether HSF proteolysis occurred as a generalized
      phenomenon associated with apoptosis, the effects of other activators of this
      process were evaluated. Vinblastine, cycloheximide, and thapsigargin stimulated
      fragmentation of HSF and hydrolysis of DNA in each cell line. The addition of PRL
      blocked the effects of vinblastine but was ineffective in cells treated with
      either cycloheximide or thapsigargin. Iodoacetamide, a cysteine protease
      inhibitor that blocks HSF fragmentation, also inhibited apoptosis. In addition, Z
      VAD, a general caspase antagonist, blocked vinblastine-induced fragmentation of
      HSF and DNA, suggesting that the enzyme responsible for proteolysis of the
      transcription factor was likely a caspase family member. The results suggest that
      proteolysis of HSF reflects the action of one or more caspases activated as a
      consequence of stimulation of cell death. It is concluded that HSF may represent
      a previously unrecognized substrate for caspases or other cysteine proteases
      activated during apoptosis.

PMID- 10593653
TI  - BUBR1 phosphorylation is regulated during mitotic checkpoint activation.
AB  - Eukaryotic cells have evolved a mechanism that delays the progression of mitosis
      until condensed chromosomes are properly positioned on the mitotic spindle. To
      understand the molecular basis of such monitoring mechanism in human cells, we
      have been studying genes that regulate the mitotic checkpoint. Our early studies
      have led to the cloning of a full-length cDNA encoding MAD3-like protein (also
      termed BUBR1/MAD3/SSK1). Dot blot analyses show that BUBR1 mRNA is expressed in
      tissues with a high mitotic index but not in differentiated tissues. Western blot
      analyses show that in asynchronous cells, BUBR1 protein primarily exhibits a
      molecular mass of 120 kDa, and its expression is detected in most cell lines
      examined. In addition, BUBR1 is present during various stages of the cell cycle.
      As cells enter later S and G2, BUBR1 levels are increased significantly.
      Nocodazole-arrested mitotic cells obtained by mechanical shake-off contain BUBR1
      antigen with a slower mobility on denaturing SDS gels. Phosphatase treatment
      restores the slowly migrating band to the interphase state, indicating that the
      slow mobility of the BUBR1 antigen is attributable to phosphorylation.
      Furthermore, purified recombinant His6-BUBR1 is capable of autophosphorylation.
      Our studies indicate that BUBR1 phosphorylation status is regulated during
      spindle disruption. Considering its strong homology to BUB1 protein kinase, BUBR1
      may also play an important role in mitotic checkpoint control by phosphorylation
      of a critical cellular component(s) of the mitotic checkpoint pathway.

PMID- 10593654
TI  - An intragastric amino acid mixture influences extracellular amino acid profiles
      in the lateral hypothalamic area of freely moving rats.
AB  - We tested the effect of equicaloric loads of glucose (0.89 g) or a balanced amino
      acid mixture (0.85 g) on extracellular amino acid concentrations in the brains of
      freely moving rats. At 15:30 hours, the microdialysis probe was inserted into the
      lateral hypothalamic area of ambulatory rats, and food and water were removed.
      Dialysates were collected every 20 min from 1 h prior to gavage (18:00 hours) and
      until 3 h after the gavage. Amino acid concentrations in the dialysate were
      determined by reverse-phase HPLC. Following the amino acid gavage, extracellular
      amino acid concentrations significantly increased from baseline for alanine,
      isoleucine, leucine, methionine, threonine, tyrosine, and valine. Those
      elevations occurred within 20-40 min following the amino acid load, and lasted up
      to 100 min. After the glucose and water treatments, amino acid concentrations
      were either not affected or gradually diminished from baseline. We conclude that
      extracellular amino acid concentration in the lateral hypothalamus is influenced
      by the composition of food consumed.

PMID- 10593655
TI  - K+ transport in resting rat hind-limb skeletal muscle in response to
      paraxanthine, a caffeine metabolite.
AB  - This study tested the hypothesis that paraxanthine, a caffeine metabolite,
      stimulates skeletal muscle potassium (K+) transport by an increase in Na+ -K+
      ATPase activity. The unidirectional transport of K+ into muscle (J(in)K) was
      studied using a perfused rat hind limb technique. Using 12 hind limbs, we
      examined the response to 20 min of paraxanthine perfusion (0.1 mM), followed by
      20 min perfusion with 0.1 mM paraxanthine and 5 mM ouabain (n = 5) to
      irreversibly inhibit Na+ -K+ ATPase activity. Paraxanthine stimulated J(in)K by
      23+/-5% within 20 min. Ouabain abolished the paraxanthine-induced stimulation of
      J(in)K, suggesting the increase in K+ uptake was due to activation of the Na+ -K+
      ATPase. To confirm the role of the Na+ -K+ ATPase, 14 hind limbs were perfused
      for 20 min with 5 mM ouabain prior to 20 min perfusion with 0.1 mM paraxanthine
      and 5 mM ouabain (n = 6). Ouabain alone resulted in a 41+/-7% decrease in J(in)K
      within 15 min. Inhibition of ouabain-sensitive J(in)K prevented the paraxanthine
      induced increase in J(in)K. Hind limbs (n = 3) were also perfused with 0.1 mM
      paraxanthine for 60 min to examine the response to longer duration paraxanthine
      perfusion. The paraxanthine-induced increase in J(in)K continued for the entire
      60 min. In another series, hind limbs were perfused with 0.01 (n = 9), 0.1 (n =
      9), or 0.5 (n = 6) mM paraxanthine for 15 min. There was no concentration
      dependent relationship between J(in)K and paraxanthine concentration, and 0.01,
      0.1, and 0.5 mM paraxanthine increased J(in)K similarly (25+/-5, 22+/-4, and 27+/
      6%, respectively). The effect of paraxanthine on J(in)K could not be reversed by
      subsequent perfusion with paraxanthine-free perfusate. Caffeine (0.05-1.0 mM) had
      no effect on K+ transport. It is concluded that paraxanthine increases J(in)K in
      resting skeletal muscle by stimulating ouabain-sensitive Na+ -K+ ATPase activity.

PMID- 10593656
TI  - Central benzodiazepine involvement in clonidine cardiovascular actions.
AB  - It is well known that the GABAergic and noradrenergic systems play an important
      role in blood pressure and heart rate regulation. Benzodiazepines and beta
      carbolines, respectively, increase or decrease the probability of chloride
      channel opening induced by GABA. The aim of this study was to determine, in
      conscious rats, the interaction existing between the central alpha2-adrenoceptor
      stimulation induced by clonidine and the facilitation or impairment of
      benzodiazepine receptor activity through the administration of either diazepam, a
      benzodiazepine receptor agonist, or methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3
      carboxylate (DMCM), an inverse benzodiazepine agonist. Clonidine (5-10 microg,
      intracerebroventricularly) reduced heart rate and increased mean blood pressure
      by activation of central alpha2-adrenoceptors. Diazepam (2 mg/kg, intravenously
      (i.v.)) induced an increase in heart rate, while DMCM (0.3 mg/kg, i.v.) elicited
      a bradycardic effect. The bradycardic effects induced by both clonidine and DMCM
      were antagonized by the prior administration of methylatropine (1.5 mg/kg, i.v.).
      DMCM (0.3 mg/kg, i.v.) prevented the clonidine effects on heart rate and mean
      blood pressure, while diazepam (2 mg/kg, i.v.) failed to modify these effects.
      Our results suggest that the bradycardic effects of clonidine are mediated by a
      vagal stimulation and are related to the activation of a GABAergic pathway.

PMID- 10593657
TI  - Modulation of liver cell membrane NHE-1, Na+-K+ ATPase, and GLUT-2 protein
      content after cold preservation and rewarming.
AB  - Liver cell pH and volume regulation are perturbed by prolonged cold storage in
      University of Wisconsin solution and subsequent rewarming, but the molecular
      basis of this effect remains unknown. We prepared membranes from hepatocytes
      subjected to variable periods of cold preservation with or without subsequent
      rewarming and probed them by Western blotting with specific antibodies against
      the Na+ -H+ exchanger isoform NHE-1 and the Na+ -K+ ATPase alpha subunit. Results
      were compared with the content of GLUT-2, an abundant basolateral protein. NHE-1
      decreased significantly as cold preservation times exceeded 10 h. Subsequent
      rewarming by short-term culture at 37 degrees C did not further reduce this
      parameter. On the other hand, expression of Na+ -K+ ATPase remained stable during
      cold storage times lasting up to 48 h, whereas rewarming resulted in a dramatic
      reduction in cells cold preserved beyond 10 h. In contrast, the membrane content
      of GLUT-2 was unaffected by cold preservation with or without subsequent
      rewarming. The results indicate that cold storage and rewarming respectively and
      selectively modulate the expression of specific hepatocellular membrane transport
      proteins.

PMID- 10593658
TI  - Parathyroid hypertensive factor inhibits voltage-gated K+ channels in vascular
      smooth muscle cells.
AB  - Parathyroid hypertensive factor (PHF) has been implicated in regulation of
      vascular smooth muscle tone and pathogenesis of several forms of hypertension.
      Earlier studies have suggested that PHF enhances the actions of other
      vasoconstrictors, while it has no in vitro vasoconstrictor property of its own.
      PHF was previously found to enhance the L-type Ca channel currents and
      intracellular Ca responses to depolarization in vascular smooth muscle cells
      (VSMCs). The present study examined whether PHF might act on K channels in the
      plasma membrane of VSMCs. Primary cultured VSMCs from rat tail artery were used.
      The whole-cell version of the patch-clamp technique was used under conditions in
      which there was no contribution of Ca-activated K channels to the outward
      current. Both purified and semipurified PHF inhibited the delayed rectifier type
      potassium current in a dose-dependent manner. The effect was time dependent and
      was first significantly different from the control current after 30 min. The
      inhibition of the delayed rectifier K channel was associated with a time
      dependent decrease in the resting membrane potential. Therefore, PHF may alter
      VSMC cellular Ca responses by reducing the membrane potential to a level closer
      to the activation potential of Ca channels.

PMID- 10593659
TI  - Class I antiarrhythmic drug effects on ouabain binding to guinea pig cardiac Na+ 
      K+ ATPase.
AB  - The notion that the inhibition of the Mg2+ -dependent ATP-hydrolytic function of
      the myocardial Na+ -K+ ATPase by class I antiarrhythmic agents occurs as a result
      of their binding to the same receptor sites as the digitalis glycosides was
      tested by performing competitive binding assays of [3H]ouabain (OUA) with eight
      drugs: disopyramide, encainide, lidocaine, lorcainide, phenytoin, procainamide,
      quinidine, and tocainide in guinea pig heart microsomal preparations. In the
      first set of experiments, 10-200 microM concentrations of the drugs were
      preincubated with the enzyme and displacement assays performed with 250 nM OUA.
      The drugs showed receptor occupancy of 19-32% at 50 microM, 25-44% at 100 microM,
      and 37-56% at 200 microM. Then, 10-500 nM concentrations of OUA were preincubated
      with the enzyme, and competitive assays were performed using 200 microM
      concentrations of the drugs. OUA occupied 39-51% of the receptor sites at 100 nM,
      44-67% at 250 nM, and 62-82% at 500 nM, displacing the drugs in a concentration
      dependent fashion. The results show that antiarrhythmic drugs interact with the
      same or similar receptor sites as ouabain on the Na+ -K+ ATPase, pointing to a
      possible contribution of these interactions to the mechanism for their inhibitory
      actions on the enzyme, and perhaps their arrhythmogenic effects.

PMID- 10593660
TI  - Methionine sulfoximine shows excitotoxic actions in rat cortical slices.
AB  - Methionine sulfoximine (MSO) is a rare amino acid. It occurs in nature or as a by
      product of some forms of food processing. A notable example of the latter was a
      former method for bleaching wheat flour, using nitrogen trichloride, the "agene
      process," in use for most of the first 50 years of this century. "Agenized" flour
      was found to be responsible for various neurological disorders in animals, and
      MSO was identified as the toxic factor. The agene process was subsequently
      discontinued in the United States and the United Kingdom circa 1950. MSO inhibits
      the synthesis of both glutathione and glutamine, and it is possible that its
      actions on the nervous system arise from alterations in the amount or
      distribution of these molecules. Structurally, MSO resembles glutamate, an
      observation that has also raised the possibility that it might have more direct
      glutamate-like actions on neurons. In the present investigation, we report
      excitatory and toxic actions of MSO in an in vitro preparation of adult rat
      cortex. Field potential recordings in this preparation show that MSO application
      evokes a sustained depolarization, which can be blocked by the N-methyl-D
      aspartate (NMDA) antagonist L-(+)-2-amino-5-phosphonovalerate (AP5). However,
      competition assays using MSO on [3H]CGP-39653 (DL-(E)-2-amino-4-propyl-1
      phosphono-3-pentenoate) binding in rat cortical homogenates show only 20%
      displacement of total binding, suggesting that MSO is acting indirectly, perhaps
      by releasing glutamate. To investigate this possibility, we measured glutamate
      release during MSO application. Time course and dose-response experiments with
      MSO showed significant [3H]glutamate release, which was partially attenuated by
      AP5. To assess cellular toxicity, we measured lactate dehydrogenase (LDH) release
      from cortical sections exposed to MSO. MSO treatment led to a rapid increase in
      LDH activity, which could be blocked by AP5. These data suggest that MSO acts by
      increasing glutamate release, which then activates NMDA receptors, leading to
      excitotoxic cell death. These data suggest the possibility that MSO in processed
      flour had excitotoxic actions that may have been contributing factors to some
      human neuronal disorders.

PMID- 10593661
TI  - Functional role of local angiotensin-converting enzyme (ACE) in adrenal
      catecholamine secretion in vivo.
AB  - The aim of the present study was to investigate whether exogenous angiotensin I
      (AngI) is locally converted to angiotensin II (AngII), which in turn results in
      an increase in the adrenal catecholamine (CA) secretion in the adrenal gland in
      anesthetized dogs. Plasma CA concentrations in adrenal venous and aortic blood
      were determined by an HPLC-electrochemical method. Adrenal venous blood flow was
      measured by gravimetry. Local administration of AngI (0.0062 to 6.2 microg,
      0.0096 to 9.6 microM) to the left adrenal gland resulted in significant increases
      in CA output in a dose-dependent manner. Following administration of 0.62 microg
      (0.96 microM) of AngI, adrenal epinephrine and norepinephrine outputs increased
      from 20.8+/-13.6 to 250.9+/-96.4 ng x min(-1) x g(-1) (p<0.05, n = 5) and from
      2.8+/-1.7 to 29.6+/-11.1 ng x min(-1) x g(-1) (p<0.05, n = 5), respectively. From
      the same left adrenal gland, the output of AngII increased from -0.02+/-0.04 to
      26.39+/-11.38 ng x min(-1) x g(-1) (p<0.05, n = 5), while plasma concentrations
      of AngII in aortic blood remained unchanged. In dogs receiving captopril (12.5
      microg, 0.5 mM) 10 min prior to AngI, the net amounts of CA and AngII secreted
      during the first 3 min after AngI were diminished by about 80% (p<0.05, n = 5)
      compared with those obtained from the control group. There was a close
      correlation (r2 = 0.91, n = 6) between the net increases in AngII and CA outputs
      induced by AngI. The results indicate that the local angiotensin converting
      enzyme is functionally involved in regional AngII formation in the canine adrenal
      gland in vivo. The study suggests that AngII thus generated may play a role in
      the local regulation of adrenal CA secretion.

PMID- 10593662
TI  - The human renin infused rat: use as an in vivo model for the biological
      evaluation of human renin inhibitors.
AB  - The human renin infused rat model (HRIRM) was used as an in vivo small-animal
      model for evaluating the efficacy of a collection of inhibitors of human renin.
      The intravenous infusion of recombinant human renin (2.4 microg x kg(-1) x min(
      1)) in the ganglion-blocked, nephrectomized rat produced a mean blood pressor
      response of 47+/-3 mm Hg (1 mm Hg = 133.3 Pa), which was reduced by captopril,
      enalkiren, and losartan in a dose-dependent manner following oral administration,
      with ED50 values of 0.3+/-0.1, 2.5+/-0.9, and 5.2+/-1.6 mg/kg, respectively. A
      series of peptidomimetic P2-P3 butanediamide renin inhibitors inhibited purified
      recombinant human renin in vitro in a concentration-dependent manner, with IC50
      values ranging from 0.4 to 20 nM at pH 6.0, with a higher range of IC50 values
      (0.8-80 nM) observed at pH 7.4. Following i.v. administration of renin
      inhibitors, the pressor response to infused human renin in the HRIRM was
      inhibited in a dose-dependent manner, with ED50 values ranging from 4 to 600
      microg/kg. The in vivo inhibition of human renin following i.v. administration in
      the rat correlated significantly better with the in vitro inhibition of human
      renin at pH 7.4 (r = 0.8) compared with pH 6.0 (r = 0.5). Oral administration of
      renin inhibitors also resulted in a dose-dependent inhibition of the pressor
      response to infused human renin, with ED50 values ranging from 0.4 to 6.0 mg/kg
      and the identification of six renin inhibitors with an oral potency of <1 mg/kg.
      The ED50 of renin inhibitors for inhibition of angiotensin I formation in vivo
      was highly correlated (r = 0.9) with the ED50 for inhibition of the pressor
      response. These results demonstrate the high potency, dose dependence, and
      availability following oral administration of the butanediamide series of renin
      inhibitors.

PMID- 10593663
TI  - Cytosolic fatty acid binding protein enhances rat hepatocyte [3H]palmitate
      uptake.
AB  - Liver cytosolic fatty acid binding protein (FABP) represents the intracellular
      equivalent to extracellular serum albumin, participating in the intracellular
      transport of long-chain fatty acids. In this study we observed the effect of
      increasing and decreasing FABP levels on hepatocyte [3H]palmitate uptake in male
      Sprague-Dawley rats. We also were interested to determine whether uptake, from
      either the unbound or unbound and protein-bound fractions, was fundamentally
      different at the different FABP levels. FABP levels were modified by
      hypophysectomy and clofibrate treatment (50 mg/100 g body weight for 10 days).
      Results showed that the [3H]palmitate clearance rates paralleled the 54% decrease
      and 73% increase in FABP levels in hypophysectomy and clofibrate-treated animals,
      respectively. In the presence of 2 and 20 microM albumin, hepatocyte clearance
      rates of unbound [3H]palmitate from hypophysectomized animals (0.16+/-0.01 and
      0.64+/-0.01 mL x s(-1) x 10(-6) cells, respectively) were significantly lower
      (p<0.01) than those of the sham group (0.30+/-0.02 and 1.00+/-0.06 mL x s(-1) x
      10(-6) cells, respectively). However, the unbound [3H]palmitate clearance rates
      from the clofibrate-treated group (0.39+/-0.04 and 1.18+/-0.12 mL x s(-1) x 10(
      6) cells) were significantly higher (p<0.01) than the control group (0.29+/-0.02
      and 0.81+/-0.05 mL x s(-1) x 10(-6) cells) for 2 and 20 microM albumin,
      respectively. To investigate whether uptake was fundamentally different between
      the hypophysectomized and clofibrate-treated groups, we expressed the clearance
      rates as enhancement factors, i.e., EF = CL20 microM/CL2microM. No statistical
      difference was observed between EF of the hypophsectomized (3.8+/-0.4) and EF of
      the clofibrate-treated (3.1+/-0.3) groups, suggesting that the extracted ligand
      originated from similar fractions.

PMID- 10593664
TI  - Myocardial blood flow regulation relative to left ventricle pressure and volume
      in anesthetized dogs.
AB  - The influence of left ventricle pressure and volume changes on coronary blood
      flow was investigated in eight anesthetized dogs. Coronary artery pressure-flow
      relationships were determined at two levels of left ventricular pressure and
      volume. The distribution of blood flow within the myocardium was also determined
      when these relationships varied. Reducing left ventricle pressures and volumes
      increased heart rate. Rate-pressure product, diastolic coronary pressure,
      myocardial O2 consumption, total, subendocardial and subepicardial flow
      decreased. Hematocrit and blood gas data were unchanged. The pressure-flow
      relationships were shifted leftward (p = 0.001) but the range of autoregulation
      was not altered. At low left ventricle pressures and volumes, the lower coronary
      artery pressure limit was shifted leftward (from 75 to 45 mm Hg (1 mm Hg = 133.3
      Pa)), while total, subendocardial, and subepicardial blood flow did not change
      compared with the control. Below the lower coronary artery pressure limit,
      subendocardial but not subepicardial flow decreased, resulting in maldistribution
      of flow across the left ventricular wall. When coronary pressure was reset
      between control and the lower coronary artery pressure limit, subendocardial flow
      was restored. These results show that the lower coronary artery pressure limit
      can be shifted leftward while the distribution of blood flow across the left
      ventricular wall is preserved.

PMID- 10593665
TI  - Effects of pregnancy and chronic exercise on maternal cardiac structure and
      function.
AB  - This study examined the interactive effects of pregnancy and aerobic conditioning
      on maternal cardiac structure and function. Effects of closely monitored cycle
      ergometer conditioning were studied during the second (TM2) and third trimesters
      (TM3) in 22 previously sedentary pregnant women (exercised group, EG) and a
      nonexercising pregnant control group with similar characteristics (CG, n = 19).
      Subjects were studied in the resting state by two-dimensional echocardiography
      and during cycle ergometer exercise at three steady-state power outputs at the
      start of TM2 (ENTRY), at the end of TM2 and TM3 (postconditioning), and 3-4
      months postpartum (NPR, nonpregnant reference, CG only). Aerobic conditioning did
      not increase left ventricular dimensions beyond those attributable to pregnancy
      itself. In addition, in contrast with previous studies of nonpregnant women,
      physical conditioning during pregnancy did not reduce heart rate (HR) in the
      resting state. During exercise, the slope of the HR versus oxygen uptake (VO2)
      regression decreased significantly between preconditioning and the end of TM3 in
      the EG, suggesting that training-induced reductions in HR become more evident
      with increasing exercise intensity. Also, significant reductions in oxygen pulse
      (VO2/HR) were observed at all three work rates in the CG, but not in the EG.
      These findings support the hypothesis that the cardiovascular effects of aerobic
      conditioning are obscured by more powerful effects of pregnancy in the resting
      state but become "unmasked" during strenuous exercise.

PMID- 10593666
TI  - Neonatal neurologic prognostication: the asphyxiated term newborn.
AB  - The pediatric neurologist is often requested to predict the neurologic outcome in
      an uncertain situation. A common and problematic clinical setting in which this
      occurs is the asphyxiated term newborn. This report reviews the predictive tools
      available for prognostication in this situation and formulates a practical
      paradigm that the authors hope will improve predictive accuracy and lessen
      uncertainty in this setting.

PMID- 10593667
TI  - Early prediction of neurologic outcome after perinatal depression.
AB  - Evaluation is presented of whether or not a detailed neuromotor examination at 3
      months of age could predict later neurologic abnormalities among term infants
      with perinatal depression. In a prospective cohort, infants were neurologically
      evaluated at 3 and 12 months. Infants were scored from 0 to 5 according to a new
      neuromotor scoring system. The neuromotor score at 3 months (NMS-3) was compared
      with the NMS at 12 months (NMS-12). Seventy-four infants were enrolled in the
      study; nine were lost to follow-up, and five died before reaching 1 year. Sixty
      infants were examined (neurologic abnormalities = 52%, normal = 48% at 1 year).
      The NMS-3 correlated strongly with the NMS-12 and the results of the 12-month
      neurologic examination. All infants with a NMS-3 of 5 had neurologic
      abnormalities at 1 year. Infants with neonatal seizures had a significantly
      increased risk of developmental abnormalities at 1 year. Eighteen infants
      exhibited transient abnormalities. Using a simple scoring system, the results of
      the early neurologic examinations correlated strongly with outcome among term
      infants with perinatal depression. A subgroup of infants had transient
      abnormalities. These findings suggest that in term high-risk infants, the 1-year
      neurologic outcome can be predicted at 3 months of age using these parameters.

PMID- 10593668
TI  - Absence of glutamic acid decarboxylase antibodies in childhood epilepsies.
AB  - Glutamic acid decarboxylase antibodies are present in some patients with therapy
      resistant epilepsy. The authors measured glutamic acid decarboxylase antibodies
      in an unselected population of 114 children with different types of epilepsy.
      Three children with temporal lobe epilepsy and six children with various other
      types of epilepsy had intractable epilepsy. None of the children tested positive
      for glutamic acid decarboxylase antibodies. The study suggests that glutamic acid
      decarboxylase antibody testing cannot be recommended in unselected cases of
      childhood epilepsy.

PMID- 10593669
TI  - Transient periventricular echodensities and developmental outcome in preterm
      infants.
AB  - The outcome of very low-birth-weight infants is reported in relation to neonatal
      cerebral ultrasound findings. Routine cerebral ultrasound scans were performed in
      all 147 very low-birth-weight infants admitted to the authors' neonatal intensive
      care unit from January 1995 to June 1997. Group 1 consisted of 22 infants without
      ultrasound abnormalities, group 2 consisted of 32 infants with transient
      periventricular echodensities, and group 3 consisted of 15 infants with
      intraventricular hemorrhage. Neurologic status was recorded at follow-up visits
      at the corrected age of 6 and 12 months, and the infants were evaluated further
      using the Bayley Scales of Infant Development II. More infants in groups 2 and 3
      appeared to have significant and mild motor developmental delays than infants in
      the control group (group 1) at the corrected age of 1 year (P = 0.001).
      Furthermore, more infants in group 3 appeared to have significant motor
      developmental delays than did infants in group 2 at the corrected age of 1 year
      (15% vs 3%). Infants with transient periventricular echodensities and
      intraventricular hemorrhage have an increased risk of delayed developmental
      outcome. Infants with transient periventricular echodensities have a more
      favorable prognosis than do the infants with intraventricular hemorrhage.

PMID- 10593670
TI  - Efficacy of lamotrigine and vigabatrin in drug-resistant epilepsies of childhood.
AB  - It was the purpose of this study to compare the efficacy and side effects of
      lamotrigine (LTG) and vigabatrin (VGB) as add-on therapy in epilepsies of
      childhood resistant to conventional drugs. Retrospective analysis of the medical
      charts and electroencephalograms of 134 children (LTG 57, VGB 77) was performed
      considering the various epileptic seizures and syndromes. In general, LTG and VGB
      had similar efficacy, with 30-40 % of patients demonstrating significant
      improvement. Few differences according to seizure type and epileptic syndrome
      were observed. Primary generalized tonic-clonic seizures more frequently improved
      and less frequently worsened with LTG than with VGB. In tonic seizures the
      treatment results were significantly more favorable with VGB. Only
      insignificantly better results occurred with LTG in the generalized group and
      with VGB in the localization-related group. VGB was significantly more effective
      in symptomatic than in idiopathic and cryptogenic syndromes. The frequency of
      adverse reactions with both drugs was close to 60%. However, treatment had to be
      discontinued because of severe rashes in only a few patients taking LTG or
      because of behavior disturbances in patients taking VGB.

PMID- 10593671
TI  - Jervell and Lange-Nielsen syndrome: neurologic and cardiologic evaluation.
AB  - Recurrent syncope, malignant ventricular arrhythmias, and sudden death are
      complications of the long QT syndrome (LQTS). Two well-known syndromes with long
      QT intervals are known. The Jervell and Lange-Nielsen syndrome (JLNS) is
      characterized by prolongation of the QT interval, deafness, and autosomal
      recessive inheritance, and the Romano-Ward syndrome is characterized by a
      prolonged QT interval, autosomal-dominant inheritance, and no deafness. In the
      present study assessment was performed of the diagnostic importance of the
      ventricular derepolarization parameters, clinical features, and prevalence of
      JLNS among 132 children with congenital hearing loss (CHL). In the CHL group the
      mean QT, QTc, JT, and JTc intervals and the dispersion values (QT-d, JT-d, QTc-d,
      and JTc-d) were significantly longer than those of control subjects (n = 96) (P <
      0.05). Patients with CHL and JLNS (n = 5) had significantly longer mean values of
      QT, QTc, JT, and JTc intervals and dispersion values than those of CHL without
      JLNS (n = 127) and control subjects (P < 0.05). The results suggest that
      assessment of ventricular derepolarization parameters in children with CHL will
      be helpful in the early detection of JLNS because infants with CHL cannot
      accurately describe the symptoms of syncope.

PMID- 10593672
TI  - Corticosteroid treatment of childhood Bell's palsy.
AB  - The therapeutic effect of corticosteroids in acute idiopathic peripheral nerve
      paralysis (Bell's palsy) in children is controversial. The authors evaluated the
      effect of steroids on the early and late outcome of children with Bell's palsy in
      a prospective randomized controlled setting. Forty-two patients (21 females, 21
      males) with complete paralysis were enrolled in the study. Group 1 (n = 21)
      received methylprednisolone (1 mg/kg daily for 10 days orally); Group 2 (n = 21)
      did not. All patients were observed in the first 3 days of the disease and at 4,
      6, and 12 months of follow-up. The mean age of Group 1 was 52.4 +/- 4.3 months,
      not significantly different from that of Group 2. In Group 1, 86% and 100%
      exhibited normal nerve function at 4 and 6 months of follow-up, respectively; in
      Group 2, 72% and 86% demonstrated complete recovery at 4 and 6 months,
      respectively, with improvement in all patients by 12 months. The improvement
      rates between the treated and untreated groups did not differ significantly. No
      side effects necessitated steroid withdrawal. The results of this study indicate
      that steroid therapy initiated at an early stage of childhood Bell's palsy does
      not significantly improve the outcome.

PMID- 10593673
TI  - Hereditary neuropathy with liability to pressure palsies in children.
AB  - The clinical and neurophysiologic findings of two children presenting with focal
      weakness and atrophy in unusual nerve distributions and no apparent antecedent
      injuries are reported. Patient 1 presented with a droopy left shoulder that was
      initially attributed to scoliosis. Patient 2 presented with right biceps brachii
      atrophy that was first brought to his parent's attention during a routine
      physical examination. In addition to documenting focal spinal accessory and
      musculocutaneous mononeuropathies as the cause of weakness in Patients 1 and 2,
      respectively, nerve conduction studies also revealed evidence of superimposed
      diffuse demyelinating polyneuropathy in both children. The latter findings
      suggested the diagnosis of hereditary neuropathy with liability to pressure
      palsies and led to definitive DNA diagnoses.

PMID- 10593674
TI  - Mycoplasma pneumoniae: a cause of coma in the absence of meningoencephalitis.
AB  - Mycoplasma pneumoniae encephalitis is a recognized cause of reversible coma in
      children. As an etiology of infectious encephalitis, it yields a relatively
      poorer prognosis than most other causes of infectious encephalopathies.
      Encephalitis is generally diagnosed by a constellation of clinical symptoms and
      confirmed by a cerebrospinal fluid (CSF) examination revealing cell pleocytosis
      and elevated protein. That Mycoplasma pneumoniae encephalopathy can occur in the
      presence of a normal CSF examination is less well appreciated. The authors report
      two children who presented with coma and normal CSF findings in whom a diagnosis
      of acute Mycoplasma pneumoniae infection was made. The two children both had
      rapid and complete recovery over several days. These cases exemplify that coma
      can result from acute infection with Mycoplasma pneumoniae in the absence of an
      inflammatory CSF response and that a normal CSF may herald a more favorable
      prognosis.

PMID- 10593675
TI  - Hyperpipecolic acidemia: clinical, biochemical, and radiologic observations.
AB  - Pipecolic acid is a biochemical marker frequently detected in group 1 peroxisomal
      disorders (peroxisomal biogenesis disorders). Its presence, in addition to the
      constellation of particular phenotypic manifestations and pathologic findings,
      has led to its recent classification under disorders of peroxisomal biogenesis as
      a separate disease entity (hyperpipecolic acidemia or hyperpipecolatemia). The
      clinical, biochemical, and radiologic findings observed in three patients
      diagnosed with hyperpipecolic acidemia are reported.

PMID- 10593676
TI  - Unusual presentation of Kearns-Sayre syndrome in early childhood.
AB  - Congenital glaucoma and insulin-dependent diabetes mellitus were the predominant
      presenting signs in a patient with Kearns-Sayre syndrome. Thereafter, he
      developed short stature, pigmentary retinopathy, progressive external
      ophthalmoplegia, and ataxia. The diagnosis was confirmed by detecting a deletion
      of mitochondrial DNA in muscle, thus demonstrating that Kearns-Sayre syndrome can
      have the unusual presenting signs described above.

PMID- 10593677
TI  - Bilateral hippocampal encephalitis caused by enteroviral infection.
AB  - Nonpolio enteroviral encephalitis usually presents as a diffuse, generalized
      encephalitis. Focal cerebral involvement by nonpolioviruses is uncommon, and
      neuroradiologic studies in these cases are usually normal. The authors present a
      case of a 5-year-old male with an acute encephalitic illness and bilateral
      lesions of the hippocampi on magnetic resonance imaging. Enteroviral nucleic
      acids were detected in the cerebrospinal fluid by the reverse transcription
      polymerase chain reaction. The findings suggest that enteroviral infection should
      be considered in the differential diagnosis of acute bilateral hippocampal
      encephalitis in patients in whom polymerase chain reaction fails to demonstrate
      the presence of herpes simplex virus.

PMID- 10593678
TI  - Unusual presentation and MRI findings in Rasmussen's syndrome.
AB  - Rasmussen's syndrome is a chronic disorder characterized by uncontrollable focal
      seizures and eventually epilepsia partialis continua, ipsilateral hemiparesis,
      developmental arrest, and cerebral inflammation. Viral and autoimmune etiologies
      have been postulated. A patient is presented who illustrates the wide variability
      of clinical and radiographic presentations in this disorder. The patient is an 8
      year-old female who developed intermittent facial twitching at 2 years of age
      that eventually progressed to epilepsia partialis continua.
      Electroencephalography demonstrated clinical seizures that emanated from the
      right parasagittal area. Cranial magnetic resonance imaging revealed pronounced
      atrophy of the right caudate nucleus, globus pallidus, and putamen, with mild
      increased T2-weighted signal in the right striatum, without accompanying cortical
      atrophy. Ictal single-photon emission computed tomography revealed markedly
      reduced uptake in the right hemisphere that was maximum in the right basal
      ganglia. Cerebrospinal fluid, blood, and urine collected for metabolic and
      immunologic screening and DNA testing for a wide variety of disorders were all
      unremarkable. Neuropsychologic testing demonstrated difficulties in memory,
      attention, and calculation. Brain biopsy revealed mild microglial activation,
      rare glial nodules, and collections of lymphocytes and histiocytes, consistent
      with the clinical diagnosis of Rasmussen's syndrome. After a modified
      hemispherectomy, she demonstrated marked clinical improvement.

PMID- 10593679
TI  - Neurophysiology and MRI in late-infantile metachromatic leukodystrophy.
AB  - We present serial clinical, radiologic, and neurophysiologic findings of a
      patient with late-infantile metachromatic leukodystrophy who was first admitted
      at 30 months of age because of gait disturbance. The neurologic findings were
      consistent with mild spastic diplegia (occasionally with toe walking). Magnetic
      resonance imaging disclosed diffuse high intensity in the cerebral white matter
      on T2-weighted images. Nerve conduction velocity studies and evoked-potential
      studies were markedly abnormal. Assay of arylsulfatase A activity in leukocyte
      culture disclosed a marked deficiency of the enzyme, confirming the diagnosis of
      late-infantile metachromatic leukodystrophy. Serial neurophysiologic studies
      demonstrated a marked decrease of nerve conduction velocities, both motor and
      sensory, as well as prolongation or disappearance of brainstem auditory-, visual
      , and somatosensory-evoked potential latencies. Magnetic resonance imaging
      studies revealed initially diffuse increased signal intensity of periventricular
      and subcortical white matter on T2-weighted images, progressing to cortical
      atrophy with involvement of the arcuate fibers and the cerebellar white matter,
      correlating with the clinical deterioration (severe spastic tetraplegia with
      optic atrophy and epilepsy).

PMID- 10593680
TI  - Use of breathing pacemakers to suppress intractable hiccups of up to thirteen
      years duration.
AB  - To suppress intractable neurologic hiccups that were unresponsive to
      pharmacologic management, seven patients have been implanted with modern
      breathing pacemakers of our design and manufacture. These devices control
      excursions of the diaphragm by electrical stimulation of the phrenic nerve. The
      first five patients have been able to control their hiccups by electrical
      stimulation after periods of up to 13 years. Two additional patients have been
      recently implanted and results are still pending.

PMID- 10593681
TI  - Mortality in peritoneal dialysis patients.
AB  - The incidence of end-stage renal disease is growing. Mortality remains high,
      despite improvements in care. Much of this can be explained by the presence of
      cardiovascular disease and other co-morbid conditions that are present at the
      start of dialysis. However, the dialysis treatment itself may exacerbate these
      conditions, and dialysis related factors such as adequacy, cytokine production,
      and dialysis-related infections are important factors in survival. Early studies
      reported similar or better survival on peritoneal dialysis (compared with
      hemodialysis), although more recent studies have questioned this finding. This
      review summarizes the information on mortality in peritoneal dialysis patients.

PMID- 10593682
TI  - A novel percutaneous barrier device that permits safe subcutaneous access.
AB  - Successful subcutaneous access is important for optimal management of internal
      artificial organs and treatment of many diseases. However, skin downgrowth and
      tissue infection are still significant problems in the use of devices that
      require long-term subcutaneous access. The authors developed a new percutaneous
      device that provides a unique biologic boundary with surrounding connective
      tissue while minimizing the risk of complications. This new percutaneous device
      is made of a circumferential, strong, thin, and flexible mesh collar with
      millimeter size holes for connecting the structure. It has two distinct
      functional portions: a connecting zone and a sealing line. The most important
      features of the structure are: 1) Connective tissue grows through the millimeter
      size pores of the connecting zone to form a strong bond between the device and
      healthy tissue. 2) The millimeter size pores of the connecting zone allow
      capillaries to grow through its entire surface, ensuring sufficient blood supply.
      3) The tissue of the connecting zone and the device surface form a biosealed
      junction (sealing line). This sealing line is protected by the connecting zone
      and is free from external forces acting on local skin. 4) The device is generally
      functional immediately after surgical implantation. The subcutaneous perimeter of
      the functional dome contains extruded rigid rings of millimeter size holes
      permitting growth of subcutaneous tissue through the device. This functions as
      the minor connecting structure of the device. Four of five implanted rabbits have
      remained healthy 8 months postimplantation without antibiotic administration. The
      fifth rabbit died 4 months postimplantation for reasons unrelated to the device.
      Gross or histopathologic inspection revealed no signs of tissue injury or
      inflammation. Growth of healthy connective tissue was clearly observed. These
      results indicate this percutaneous device can provide a strong, stable, and
      effective connection to internal organs without bioboundary damage, skin
      downgrowth, or tissue infection.

PMID- 10593683
TI  - Development of a hydraulic model of the human systemic circulation.
AB  - Physical and numeric models of the human circulation are constructed for a number
      of objectives, including studies and training in physiologic control,
      interpretation of clinical observations, and testing of prosthetic cardiovascular
      devices. For many of these purposes it is important to quantitatively validate
      the dynamic response of the models in terms of the input impedance (Z =
      oscillatory pressure/oscillatory flow). To address this need, the authors
      developed an improved physical model. Using a computer study, the authors first
      identified the configuration of lumped parameter elements in a model of the
      systemic circulation; the result was a good match with human aortic input
      impedance with a minimum number of elements. Design, construction, and testing of
      a hydraulic model analogous to the computer model followed. Numeric results
      showed that a three element model with two resistors and one compliance produced
      reasonable matching without undue complication. The subsequent analogous
      hydraulic model included adjustable resistors incorporating a sliding plate to
      vary the flow area through a porous material and an adjustable compliance
      consisting of a variable-volume air chamber. The response of the hydraulic model
      compared favorably with other circulation models.

PMID- 10593685
TI  - Effect of nitric oxide upon gas transfer and structural integrity of a
      polypropylene membrane oxygenator.
AB  - Gaseous nitric oxide (NO) may act as a membrane passivator during cardiopulmonary
      bypass by inhibition of platelet and leukocyte adhesion, activation, and
      aggregation. However, NO and its by-product nitrogen dioxide (NO2) are potently
      reactive and may be capable of degradation of membrane oxygenator constituents in
      an oxygen-rich environment. To test these concepts, nine polypropylene hollow
      fiber membrane oxygenators received 224 +/- 10 ppm NO and 6.7 +/- 1.7 ppm NO2 in
      73% oxygen (O2), and six oxygenators received 73% O2, while being perfused with
      heparinized thrombocytopenic bovine blood for 6 hours. Oxygenators were used for
      measurement of O2 and carbon dioxide (CO2) transfer rates, structural integrity
      by pulsing with 22 psi water at 0.5 Hz for 6 hours, and scanning electron
      microscopic (SEM) examination of structural integrity. Transfer rates between
      groups at 0, 1, 3, and 6 hours revealed no differences in O2 or CO2. No
      oxygenator failed hydraulic tests of structural integrity or exhibited "wet-out"
      during bypass. No evidence of material degradation was shown in the SEM
      appearance of oxygenators. There were no differences in hematologic values. These
      data support the safety of gaseous NO in polypropylene membrane oxygenators for
      limited-term cardiopulmonary bypass.

PMID- 10593684
TI  - Determination of the in vivo cavitation nuclei characteristics of blood.
AB  - Cavitation has been documented in the in vitro testing of blood-handling devices.
      To predict whether cavitation will occur clinically, the nuclei content of blood
      and the threshold pressure for activation of the in situ nuclei must be
      characterized. A single-pass flow apparatus is described for determining the
      nuclei characteristics of blood. The flow apparatus consists of a syringe pump
      and a venturi-geometry hydrodynamic device, called a cavitation susceptibility
      meter (CSM). Blood is accelerated through the throat of the CSM, thus exposing
      the nuclei in the blood to a well-defined pressure profile. The apparatus was
      used in an ex vivo sheep model for the determination of the in vivo nuclei
      characteristics of blood. The active nuclei concentration of in vivo blood was
      measured to be at most 2.7 nuclei per liter of plasma at a minimum throat
      pressure of -1610 mm Hg gauge (i.e., tension of 900 mm Hg). At this pressure,
      bubble stability theory predicts the active nuclei to have a radius on the order
      of 0.3 microm. Based on these results, in vitro studies to determine the
      cavitation potential of blood-handling devices must utilize test fluids that
      contain a minimum nuclei size distribution and concentration. It cannot be
      assumed that in vivo blood is nuclei rich, such that it will cavitate at or near
      vapor pressure.

PMID- 10593687
TI  - Modeling the postdialysis rebound: the reconciliation of current formulas.
AB  - Three approaches are currently used in kinetic models (UKMs) to account for the
      postdialysis rebound in urea concentration, and thereby accurately measure the
      hemodialysis dose, KT/V (where K, T, V denote dialyzer clearance, dialysis
      duration, and urea distribution volume, respectively). The approach developed by
      Smye uses an intradialytic sample to predict the postdialysis equilibrium
      concentration, Ce, which is then used in a single pool UKM to give KT/V. A second
      approach developed by Tattersall introduces a patient clearance time, tp. The
      true dialysis dose is then given by T/(T + tp) x apparent dose, and tp is
      estimated to be 36 minutes. The Daugirdas analysis uses an empiric regression
      equation to give the true dose; KT/V)true from the single pool value, KT/V)sp;
      KT/V)true = KT/V)sp - (36/T)(KT/V)sp + 0.03. The analysis confirms the
      equivalence of all three formulas, which arises from the observation that during
      the later stages of dialysis, the urea concentration decreases as a single
      exponential. The formulas are independent of whether a flow or diffusion model is
      used to describe the kinetics of urea removal. The original analysis assumed
      constant volumes, but the effect of ultrafiltration volume u on C(e) may be
      accounted for by multiplying by (1 + u/V). The Smye equation is more vulnerable
      to error in practice, because small errors in the intradialytic sample give
      larger errors in the equilibrium concentration estimate, whereas dose estimates
      based on the Tattersall and Daugirdas equations are less affected by sampling
      errors. However, unlike the Smye approach, these two formulas would need
      adaptation for use with other solutes. The advent of continuous urea monitoring
      should permit more accurate, prospective estimates of equilibrium concentrations
      and dialysis dose.

PMID- 10593686
TI  - Assessment of chronically implanted subcutaneous glucose sensors in dogs: the
      effect of surrounding fluid masses.
AB  - We developed a continuous, distributed-anode glucose sensor and now report on its
      use during subcutaneous implantation in dogs without diabetes. Using telemetry,
      we monitored sensor response to weekly administration of intravenous glucose. In
      a preliminary attempt to reduce fibrosis around the sensor, some sensors were
      designed to slowly release dexamethasone (DEX). Before implantation, in vitro
      sensor sensitivity was similar to values obtained after explantation (0.66 +/-
      0.09 vs 1.07 +/- 0.19 nA/mM, n = 9, p = ns). Sensitivity in individual animals
      varied substantially over time. Average longevity of sensors was 32.1 +/- 8.6
      days. Device failure was caused by leakage of fluid into, or interruption of,
      circuitry. Lag time during glucose ascent averaged 5.8 +/- 1.0 min. In devices
      that became surrounded by fluid masses, lag time during descent was greater than
      in devices without fluid (33.7 +/- 4.5 vs 10.7 +/- 1.6 min, p < 0.001). There was
      a nonsignificant tendency for longevity of the six sensors that contained DEX to
      be greater than the eight sensors without DEX (47.2 +/- 18.7 vs 20.8 +/- 3.6
      days, p = ns). The development of fluid masses surrounding electrochemical
      glucose sensors prolongs lag time and probably contributes to the commonly
      observed instability of sensitivity over time. In future long-term implant
      studies, it is likely that avoidance of fluid masses will improve sensor
      function.

PMID- 10593688
TI  - Impact of peritoneal membrane transport on technique failure and patient survival
      in a population on automated peritoneal dialysis.
AB  - The peritoneal equilibration test (PET) is well established as a tool for
      classifying patients as low (L), low average (LA), high average (HA), or high (H)
      peritoneal transporters. We performed this retrospective 6 year cohort survey to
      evaluate the impact of different types of PET results on technique survival and
      patient survival on automated peritoneal dialysis (APD) therapy. From March 1992
      to May 1998, 50 patients (20 men, 30 women) receiving APD were enrolled. The mean
      follow-up period was 25.2 +/- 9.2 months. Basic data and PET results of each
      patient at the initiation of APD therapy were retrospectively obtained for
      analysis. Adequacy of dialysis was estimated by measurement of total weekly urea
      clearance (Kt) normalized to total body water (V) and total weekly creatinine
      clearance (Ccr) per 1.73 m2 body surface area. The clinical outcomes evaluated
      were technique survival and patient survival. For statistical analyses we used
      the Kruskal-Wallis test, Friedman test, Kaplan-Meier life table analysis, and
      Cox's proportional hazards regression model. There were no differences in age,
      gender, prevalence of diabetes mellitus (DM), duration of APD, or the initial
      value of serum albumin between the four subgroups (H, HA, LA, and L). There were
      11 (22%) deaths and 8 (16%) technique failures. The 2 year patient survival
      probability was significantly higher (100%) in the L subgroup than in the LA
      (62.6%), HA (48.4%), or H (46.2%) subgroups. Patients with DM had a lower patient
      survival rate than patients without DM; however, there was no statistical
      significance in technique survival rate between them. Diabetes mellitus (RR =
      2.898) and the final albumin value (RR = 0.2099 per increase of 1 gm/dl) had a
      significant influence on patient survival. By stepwise regression analysis of
      final serum albumin levels, we found that patients with lower serum albumin
      values (< or = 3.0 gm/dl vs. >3.0 gm/dl) had a significantly lower probability of
      patient survival (p = 0.0156). We conclusively demonstrate four important
      findings in this work: 1) patients with H peritoneal transport had a lower
      probability of patient survival, but not a decreased rate of technique survival;
      2) patients with L peritoneal transport can tolerate APD well; 3) there was no
      significant difference in technique survival rate between the different PET
      subgroups; and 4) DM and a lower serum albumin, implicating malnutrition, may
      contribute to the lower probability of patient survival among H peritoneal
      transporters.

PMID- 10593689
TI  - Dialysis catheter infection related peritonitis: incidence and time dependent
      risk.
AB  - The aim of this study was to conduct an in-depth analysis of the relationship of
      exit site and tunnel infection (ES/TI) to peritonitis and catheter loss in
      peritoneal dialysis patients, with emphasis on the incidence and risk of
      infection over time. Bacterial epidemiologies of 63 consecutively implanted
      catheters were studied for a combined total of 1,248 dialysis months. Analyses of
      bacterial profiles, infection rates, probabilities of time to first infection,
      and catheter survival were performed. The probability of first ES/TI and
      peritonitis was greatest during the first postimplant year. The earlier in
      dialysis history that patients developed an infection, the more infection prone
      they continued to be during the course of their dialysis experience.
      Staphylococcus aureus was the predominant organism for both ES/TI and
      peritonitis. The incidence of S. aureus infection was greatest during the first
      year and decreased over time on dialysis. S. aureus ES/TI caused significant risk
      for subsequent development of peritonitis, and 93% of ES/TI related peritonitis
      episodes were caused by this organism. Half of all ES/TIs that led to related
      peritonitis occurred by 3.5 months, and 100% by 12.8 months postimplant. S.
      aureus ES/TI related peritonitis led to catheter loss in 85% of cases. Our study
      identified a high risk period for infection for as long as 12 months postimplant.
      The inherent characteristics of ES/TI related peritonitis suggest that prevention
      should focus on both the organism and time period at risk. These findings are
      important in considering issues regarding S. aureus prophylaxis regimens versus
      nasal carrier treatment protocols.

PMID- 10593690
TI  - Application of an unstructured grid algorithm to artificial heart valve
      simulations.
AB  - The time varying flow pattern in the vicinity of mechanical heart valves (MHV) is
      fairly complex: it involves multiple passages and moving leaflets. The numeric
      simulation of unsteady flows in these multiple passages with moving boundaries
      presents a major challenge to computational fluid dynamics (CFD). Two major
      difficulties in the numeric simulation of MHV flows are 1) the generation of a
      body fitted grid within the multipassage device and 2) moving leaflets. The
      conventional finite difference and finite volume scheme obtained by using a
      structured grid have serious deficiencies in these applications. To fit the grid
      lines with the various angles of the moving MHV, the grid may often become too
      skewed for accurate numeric solution. To overcome these deficiencies, significant
      effort and attention should be placed on the grid generation and moving grid
      scheme. We present an unstructured moving grid finite volume method for heart
      valve simulations. The Navier-Stokes equations are discretized on a general
      tetrahedral mesh by using a finite volume scheme. With this scheme, the mesh can
      be automatically generated with any commercial software. The method is applied to
      a tilting disk (Medtronic Hall 29mm, Medtronic, Inc., Minneapolis, MN) heart
      valve, and results are compared with that of the steady flow solutions.
      Significant differences between steady and unsteady flow solutions are observed.

PMID- 10593692
TI  - Reliability model from the in vitro durability tests of a left ventricular assist
      system.
AB  - A reliability test of the Novacor N100PC left ventricular assist system (LVAS)
      with valved conduits, including a pump/drive unit with compact controller and
      LVAS monitor was performed. The initial test objective was to demonstrate
      sufficient reliability for clinical use as a long-term circulatory support
      system. The subsequent objective, a test to failure, was intended to provide an
      assessment of the durability of the design and to determine the LVAS wearout
      modes. Testing began in April 1993 and was performed with 12 systems on gravity
      feed mock circulatory loops. The pump/ drive units were submersed in body
      temperature saline for the duration of the test. Each of the LVAS units was
      operated at nominal afterloads of 75, 90, and 105 mm Hg, with test conditions
      varied to yield nominal pump outputs of 5.6, 7.1, and 8.3 L/min. Failure was
      defined as the inability of the LVAS to maintain an average pump output of 4
      L/min or an average output pressure of 60 mm Hg. After 3 years, all systems
      remained on test, with durations of 2.3 to 3.0 years. Analysis of the testing to
      that date, using a constant hazard rate model, indicated a minimum demonstrated
      reliability of 94% at a 60% confidence level, or 86% at a 90% confidence level,
      for a 2 year mission time. This greatly surpasses the reliability level included
      in the STS-ASAIO Long-Term Mechanical Circulatory Support System Reliability
      Recommendation (80% reliability, 60% confidence level for a 1 year mission time).
      In the subsequent test-to-failure protocol, all systems ran failure-free for at
      least 3 years. System failures occurring at longer durations were caused by a
      single common cause: wear of the energy converter's armature support bearings and
      shafts. The wearout mode was gradual and could be diagnosed noninvasively before
      failure. An analysis using a Weibull model was performed, using the test
      durations of those devices that failed, those that were electively removed from
      test for analysis of the wear mode, and those that continued on test. As of April
      1998, the test results showed a reliability, at a 60% confidence level, of >99.9%
      for a 1 year mission time, 99.5% for a 2 year mission, and 92.0% for a 3 year
      mission (>99.9%, 98.3%, and 85.9% for equivalent mission times, at a 90%
      confidence level). Systems continue on test after as long as 4.9 years.

PMID- 10593691
TI  - Feedback control of mean aortic pressure in a dynamic model of the cardiovascular
      system.
AB  - Orbital measurements of the cardiac function of Space Shuttle crew members have
      shown an initial increase in cardiac stroke volume upon entry into
      weightlessness, followed by a gradual reduction in stroke volume to a level
      approximately 15% less than preflight values. In an effort to explain this
      response, it was hypothesized that gravity plays a role in cardiac filling. A
      mock circulatory system was designed to investigate this effect. Preliminary
      studies carried out with this system on the NASA KC-135 aircraft, which provides
      brief periods of weightlessness, showed a strong correlation between cardiac
      filling, stroke volume, and the presence or absence of gravity. The need for
      extended periods of high quality zero gravity was identified to verify this
      observation. To accomplish this, the aircraft version of the experiment was
      reduced in size and fully automated for eventual integration into a Get Away
      Special canister to conduct an orbital version of the experiment. This article
      describes the automated system, as well as the development and implementation of
      a control algorithm for the servoregulation of the mean aortic pressure in the
      orbital experiment. Three nonlinearities that influence the ability of the
      apparatus to regulate to a mean aortic pressure of 95 mm Hg were identified and
      minimized. In preparation for a Space Shuttle flight, the successful function of
      the servoregulatory scheme was demonstrated during ground tests and additional
      test flights aboard the KC-135. The control algorithm was successful in carrying
      out the experimental protocol, including regulation of mean aortic pressure. The
      algorithm could also be used for the automated operation of long-term tests of
      circulatory support systems, which may require a scheduled cycling of the pumping
      conditions on a daily basis.

PMID- 10593693
TI  - Myocardial mechanics, energetics, and hemodynamics during intraaortic balloon and
      transvalvular axial flow hemopump support with a bovine model of ischemic cardiac
      dysfunction.
AB  - Unlike the mechanisms of intraaortic balloon pump (IABP) support, the mechanisms
      by which transvalvular axial flow Hemopump (HP) support benefit dysfunctional
      myocardium are less clearly understood. To help elucidate these mechanisms,
      hemodynamic, metabolic, and mechanical indexes of left ventricular function were
      measured during conditions of control, ischemic dysfunction, IABP support, and HP
      support. A large animal (calf) model of left ventricular dysfunction was created
      with multiple coronary ligations. Peak intraventricular pressure increased with
      HP support and decreased with IABP support. Intramyocardial pressure (an
      indicator of intramyocardial stress), time rate of pressure change (an indicator
      of contractility), and left ventricular myocardial oxygen consumption decreased
      with IABP and HP support. Left ventricular work decreased with HP support and
      increased with IABP support. During HP support, indexes of wall stress, work, and
      contractility, all primary determinants of oxygen consumption, were reduced.
      During IABP support, indexes of wall stress and contractility were reduced and
      external work increased. These changes were attributed primarily to changes in
      ventricular preload, and geometry for HP support, and to a reduction in afterload
      for IABP support. These findings support the hypothesis that both HP and IABP
      support reduce intramyocardial stress development and the corresponding oxygen
      consumption, although via different mechanisms.

PMID- 10593694
TI  - Pulsatile and nonpulsatile flows can be quantified in terms of energy equivalent
      pressure during cardiopulmonary bypass for direct comparisons.
AB  - The purpose of this study was to quantify and compare pulsatile and nonpulsatile
      pressure and flow waveforms in terms of energy equivalent pressure (EEP) during
      cardiopulmonary bypass in a neonatal piglet model. EEP is the ratio of the area
      under the hemodynamic power curve and the flow curve. Piglets, mean weight of 3
      kg, were used in physiologic pulsatile pump (n = 7), pulsatile roller pump (n =
      6), and nonpulsatile roller pump (n = 7) groups. Data (waveforms of the femoral
      artery pressure, pump flow, and preaortic cannula extracorporeal circuit
      pressure) were collected during normothermic cardiopulmonary bypass at 35 degrees
      C (15 minutes on-pump), before deep hypothermic circulatory arrest (pre-DHCA) at
      18 degrees C, and after cold reperfusion and rewarming (post-DHCA) at 36 degrees
      C. The pump flow rate was 150 ml/kg/min in all three groups. During pulsatile
      perfusion, the pump rate was 150 bpm in both pulsatile groups. Although there was
      no difference in mean pressures in all groups, EEP and the percentage increase of
      pressure (from mean pressure to EEP) of mean arterial pressure and preaortic
      cannula extracorporeal circuit pressure were higher with pulsatile perfusion
      compared with nonpulsatile perfusion (p < 0.001). In particular, the physiologic
      pulsatile pump group produced significantly higher hemodynamic energy compared
      with the other groups (p < 0.001). These results suggest that pulsatile and
      nonpulsatile flows can be quantified in terms of EEP for direct comparisons, and
      pulsatile flow generates higher energy, which may be beneficial for vital organ
      perfusion during cardiopulmonary bypass.

PMID- 10593695
TI  - Long-term survival with use of percutaneous extracorporeal life support in
      patients presenting with acute myocardial infarction and cardiovascular collapse.
AB  - Up to 10% of patients who arrive at the hospital with acute myocardial infarction
      (AMI) present with or develop cardiogenic shock. Some patients, despite inotropes
      and intra-aortic balloon pump (IABP) placement, are not hemodynamically stable
      enough to undergo emergent revascularization. The use of percutaneous
      extracorporeal life support (ECLS) can stabilize patients to allow effective
      therapy. In a retrospective review of the first 100 patients emergently placed on
      ECLS by a nurse-supported physician insertion technique at Sharp Memorial
      Hospital, 10 patients underwent placement of ECLS after out-of hospital AMI. All
      AMI patients required intubation for respiratory failure and temporary CPR for
      cardiovascular collapse before initiation of ECLS. Of the 10 AMI patients placed
      on ECLS, four (40%) are currently long-term survivors (5.1 +/- 4.2 years; range,
      6 months to 11 years). All survivors underwent successful revascularization after
      placement on ECLS. The cause of death in the other six patients was neurologic
      insufficiency in two, ineffective ECLS in two, and recurrent cardiovascular
      collapse after weaning from bypass in two. Total CPR time before initiation of
      cardiopulmonary bypass was 17 +/- 10.3 minutes for the survivors and 54.2 +/-11.1
      minutes for the nonsurvivors (p < 0.001). The average time on ECLS was 29 +/- 26
      hours for the survivors and 30 +/-67 hours for the nonsurvivors (p = NS). Leg
      complications were common among long-term survivors, associated with the use of
      ECLS (three ischemia, one infection). After AMI and cardiovascular collapse,
      insertion of ECLS may permit long-term patient survival.

PMID- 10593696
TI  - Successful repair of a ventricular assist system percutaneous lead.
AB  - A patient with an implanted, electrically powered, ventricular assist device
      (Thermo Cardiosystems VE HeartMate) experienced a partial break of the
      percutaneous lead 5 months after implantation. The break (limited to the Silicone
      rubber tube) occurred at the junction of the lead with the Y-connector to the
      controller and vent, leaving approximately 5 cm of exposed lead from the skin
      exit site to the connector. Electronic and pumping functions of the pump
      continued, but the opening in the lead (which went more that half way around the
      circumference) prevented the use of pneumatic actuation as a back-up mode for
      pump operation, and placed the pump at risk for contamination. Repair of the lead
      without surgical intervention was desirable, with ease of repair and minimal risk
      to the patient being the top priorities. The use of multiple layers of heat
      shrink tubing or external metal stents was ruled out in favor of a three stage
      repair procedure. The first stage involved the removal of the Dacron velour in
      growth material from the lead to expose the underlying Silicone rubber tube.
      While the opening in the tube was held shut, a coating of medical grade Silicone
      rubber adhesive was applied to the tube, then wrapped with a woven Dacron mesh,
      followed by two layers of plastic wrapping material to protect the adhesive. This
      initial layer was secured by an external stent of tubing with cable ties. After
      several days to allow for complete curing of the adhesive, the adhesive coating
      with mesh was repeated. The final step involved a double layer wrap of a 1 mm
      thick Silicone rubber sheeting with mesh incorporation and adhesive secured in
      place with cable ties. After completion of the repair and verification of the
      ability to operate the device with pneumatic actuation, the patient was
      discharged with no recurrence of the problem after 8 months of weekly follow-up.
      This experience demonstrates the need to clinically anticipate component repair
      or replacement without total device replacement in future implantable blood pump
      systems.

PMID- 10593697
TI  - Neuroimaging as a probe of brain function in late-life psychiatric illness: old
      paradigms, new challenges.

PMID- 10593698
TI  - Neuroanatomic substrates of late-life mental disorders.
AB  - Advances in magnetic resonance imaging (MRI) techniques have made it possible to
      quantify anatomic brain abnormalities in neuropsychiatric disorders. This review
      focuses on controlled, quantitative MRI studies in depression, degenerative
      disorders, and psychosis in the elderly. Although many of the anatomic
      abnormalities detected are observed across disorders, the patterns of regional
      involvement may be more selective and disorder specific. We integrate MRI
      findings with relevant clinical and neurobiologic observations in an attempt to
      develop a cohesive model of late-life psychiatric illness. Although the model
      primarily alludes to the pathophysiology of late-life depression, it may have
      broader biologic implications for other mental disorders in the elderly.

PMID- 10593699
TI  - Brain biochemistry using magnetic resonance spectroscopy: relevance to
      psychiatric illness in the elderly.
AB  - Magnetic resonance spectroscopy (MRS) allows for the noninvasive study of
      cerebral biochemistry. It has been used to investigate cerebral metabolic changes
      associated with mental illness in vivo and in vitro. In this review, we will
      discuss the application of MRS to psychiatric illness in the elderly. Following a
      brief description of the basic principles of MRS, the use of phosphorus (31P) and
      proton (1H) MRS to enable a better understanding of normal brain aging, dementia
      (Alzheimer's disease, multiple subcortical infarct dementia, Down syndrome,
      frontotemporal dementia, vascular dementia, age-associated memory impairment, and
      other dementias), major depression, and electroconvulsive therapy is detailed.

PMID- 10593700
TI  - Cerebral blood flow and metabolism in late-life depression and dementia.
AB  - Late-life depression (LLD) is characterized by abnormalities in cerebral blood
      flow (CBF) and cerebral metabolic rate (CMR) for glucose. Unlike younger adults
      with major depression, global cortical CBF and CMR reductions have been reported
      in LLD. Patients with LLD are also characterized by topographic abnormalities,
      most commonly involving selective prefrontal, superior temporal, and anterior
      parietal cortex. The fate of these abnormalities with response to antidepressant
      treatment is highly uncertain, and heterogeneous findings have been reported in
      younger samples with major depression. The limited data in LLD suggest that
      response to electroconvulsive therapy or antidepressant medications does not
      involve reversal of baseline abnormalities but rather accentuation of prefrontal
      deficits. At minimum, these paradoxical findings suggest that abnormalities in
      CBF and CMR may be persistent in LLD and a trait characteristic. Characteristic
      profiles of CBF and CMR abnormalities have also been demonstrated in samples with
      Alzheimer's disease (AD) and other types of dementia. Functional imaging has
      shown sensitivity to disease severity and progression. Nonetheless, there is
      limited information regarding the sensitivity and specificity of the functional
      imaging modalities in the differential diagnosis of dementias. At present, the
      evidence does not support the use of functional imaging in isolation as a
      diagnostic tool. Rather, these imaging modalities may be considered as an adjunct
      to careful clinical assessment, either to improve diagnosis in early cases or to
      assist in subtyping difficult cases.

PMID- 10593701
TI  - Pathophysiology of secondary depressions in the elderly.
AB  - Although the pathophysiology of depression is not fully understood in either
      primary depression (i.e., no known neuropathology related to depression) or
      secondary depression (i.e., neuropathologic disorder that leads to depression), a
      number of studies have begun to identify aspects of the pathophysiology of both
      primary and secondary depression. This article reviews the findings of studies
      examining the pathophysiology of depression following stroke, Parkinson's
      disease, or Huntington's disease and compares them to findings in primary
      depression. Studies examining glucose metabolic rates or blood flow changes in
      regional brain areas found that stroke, Parkinson's disease, and Huntington's
      disease, as well as primary depression, were all associated with decreased
      activity or brain lesions in the orbital frontal cortex and basal ganglia. There
      were also abnormalities noted in the basal temporal lobes, cingulate cortex, and
      thalamus in some but not all disorders. Studies in stroke have also noted
      depletions of serotonin receptors in left temporal cortex associated with
      depression. These findings are consistent with the hypothesis that the
      pathophysiology of secondary and primary depression involves the dysfunction of
      one or more of the cortical-basal ganglia-thalamic neuronal loops. This
      dysfunction may be mediated by decreased serotonin release. These studies may
      ultimately lead to more focused and specific treatments.

PMID- 10593702
TI  - Neuropharmacology and receptor studies in the elderly.
AB  - Functional brain imaging has provided unique and exciting opportunities to
      strengthen our knowledge of the biologic substrate of the aging brain and
      neuropsychiatric disorders. Positron emission tomography (PET) is a particularly
      powerful tool for quantifying the neurobiologic correlates of cognition, mood,
      and behavior. Initial PET studies of aging, psychiatric disorders, and
      neurodegenerative disease focused primarily on generalized physiologic parameters
      such as cerebral blood flow and metabolism, and early neuroreceptor imaging
      studies relied on relatively nonselective markers. New, selective receptor
      radioligands now offer a previously inaccessible means to investigate the dynamic
      relationships among neurochemistry, aging, and psychopathology in vivo. This
      approach has substantial advantages over peripheral (platelet and cerebrospinal
      fluid) markers, neuroendocrine challenge studies, animal models, and postmortem
      receptor binding assays. Advances in tracer kinetic modeling, magnetic resonance
      imaging facilitated PET image analysis, radiochemistry techniques,
      instrumentation, and image processing have helped pave the way for increased
      emphasis on functional imaging studies of neuropsychiatric disorders. The
      capability to correct PET image data for the confounding effect of cerebral
      atrophy permits relationships among age-related brain changes and neurobiologic
      disease mechanisms to be more accurately examined in the elderly.

PMID- 10593703
TI  - Clinical neurophysiology using electroencephalography in geriatric psychiatry:
      neurobiologic implications and clinical utility.
AB  - Electroencephalography (EEG) offers a unique contribution to the armamentarium of
      imaging technologies used in the evaluation of brain function. The primary
      clinical application of EEG is in the diagnosis of delirium, dementia, and
      epilepsy, which are frequently encountered in the practice of geropsychiatry.
      This review summarizes the principles behind generation of the EEG signal, its
      strengths and limitations as a technology, clinical indications for performing an
      EEG, the principles underlying quantitative EEG (QEEG), and how QEEG is allowing
      us to probe brain function and connectivity in new ways.

PMID- 10593704
TI  - Assuring bioavailability of fixed-dose combinations of anti-tuberculosis
      medications. A joint statement of the International Union Against Tuberculosis
      and Lung Diseases and the World Health Organization.

PMID- 10593706
TI  - Fixed-dose combination formulations for tuberculosis treatment.

PMID- 10593705
TI  - Quality assurance: protocol for assessing the rifampicin bioavailability of
      combined formulations in healthy volunteers.

PMID- 10593707
TI  - Review of the Indian market of anti-tuberculosis drugs: focus on the utilisation
      of rifampicin-based products.
AB  - SETTING: There is a need to better understand the extent of the utilisation of
      rifampicin in the market, particularly in fixed-dose combinations (FDC).
      OBJECTIVE: To review the Indian market of antituberculosis drugs, as this is the
      largest single market in the world of this therapeutic class. DESIGN: Review and
      analysis of the sales data proffered by the Indian market audit. Estimated data
      relating to public sector product usage were utilised in order to obtain a more
      complete scenario. RESULTS: The use of rifampicin-based products is very
      important in the Indian market of anti-tuberculosis drugs. Particularly common is
      the use of FDCs, which represent 62% of anti-tuberculosis drugs sold in the
      private market. CONCLUSIONS: The Indian market for anti-tuberculosis drugs is
      very large and well integrated. FDCs are widely used. In addition to double- and
      triple-drug FDCs, four-drug combinations have recently been introduced into the
      market. The Indian industry also exports raw materials and pharmaceutical
      specialities.

PMID- 10593709
TI  - Rifampicin bioavailability: a review of its pharmacology and the chemotherapeutic
      necessity for ensuring optimal absorption.
AB  - The World Health Organization encourages the use of fixed dose combinations
      (FDCs) of rifampicin (RMP) and isoniazid together with pyrazinamide or
      pyrazinamide plus ethambutol for the treatment of tuberculosis. The main
      advantages of such FDCs are the simplification of procurement and prescribing
      practices and the protection they afford against the potential selection of RMP
      resistant strains of Mycobacterium tuberculosis. There is convincing evidence,
      however, that the rifampicin absorption from FDCs manufactured under suboptimal
      conditions may be significantly impaired, and this appears to be especially
      problematic with combined formulations of rifampicin, isoniazid and pyrazinamide.
      In view of the marked dose-dependence of rifampicin's bacterial sterilizing
      action, it is therefore essential that tuberculosis control programmes only use
      rifampicin-containing FDCs with proven rifampicin bioavailability. The
      comprehensive literature on the pharmacology of rifampicin is reviewed, together
      with the methods employed for determining it and its most important metabolite,
      desacetyl-rifampicin, in either serum or urine. By contrast, published
      information concerning the absorption of rifampicin from currently marketed
      combined formulations and on laboratory methods for precisely assessing their
      bioavailability is very sparse. There is therefore a crucial need to establish
      the quality of currently marketed rifampicin-containing FDCs in studies using
      adequate numbers of volunteers, precise analytical techniques and sophisticated
      statistical techniques.

PMID- 10593708
TI  - Estimate of the global market for rifampicin-containing fixed-dose combination
      tablets.
AB  - SETTING: Despite WHO and IUATLD recommendations to use fixed-dose combination
      (FDC) tablets for treatment of tuberculosis, more than 75% of all rifampicin used
      in the public sector globally is administered as single drug tablets. OBJECTIVE:
      To estimate the potential global market for rifampicin-containing FDCs in the
      public and private sectors. DESIGN: The public sector market for FDCs was
      calculated from the number of tuberculosis cases notified to WHO for 1996 and
      from information on treatment regimens currently used in each country. The
      private sector market was calculated from the estimated number of treated
      tuberculosis cases and the treatment regimens presumed to be used in the private
      sector. RESULTS: The potential global market for the four-drug FDC tablet
      (rifampicin 150 mg, isoniazid 75 mg, pyrazinamide 400 mg and ethambutol 275 mg)
      is 305 (90%CI 145-505) million tablets per year, 105 (90%CI 50-160) and 200
      (90%CI 95-345) million of which would be distributed in the public and private
      sectors, respectively. The uncertainty of the estimate remains considerable, as
      shown by the 90% confidence intervals. CONCLUSION: The study demonstrated a large
      potential global market for FDCs that should encourage pharmaceutical
      manufacturers to produce WHO-recommended dosages of FDCs at affordable prices.

PMID- 10593710
TI  - Recent bioequivalence studies on fixed-dose combination anti-tuberculosis drug
      formulations available on the global market.
AB  - SETTING: Concern has been expressed about the bioavailability of rifampicin in
      some fixed-dose combination (FDC) anti-tuberculosis formulations. OBJECTIVE: To
      evaluate the relative bioavailability of rifampicin in various FDC formulations
      currently in use in tuberculosis control programmes in the global market. DESIGN:
      A two-period randomised crossover bioequivalence study in healthy male
      volunteers, with a 1 week washout period between treatments. Plasma rifampicin
      concentrations were measured at 0, 1, 2, 4, 6, 8 and 12 hours after each drug
      administration. RESULTS: The AUC0-8, AUC0-12 and Cmax for rifampicin in seven of
      10 FDC formulations was not found to be bioequivalent to the reference
      administered as loose (separate) formulations. This was confirmed using
      parametric and non-parametric statistical methods. CONCLUSIONS: The poor relative
      bioavailability of rifampicin from some FDCs has been documented. The
      implications for tuberculosis programmes are extremely serious and warrant urgent
      attention.

PMID- 10593711
TI  - The evaluation of rifampicin bioavailabilities of fixed-dose combinations of anti
      tuberculosis drugs: procedures for ensuring laboratory proficiency.
AB  - SETTING: The perceived need to demonstrate whether or not the rifampicin
      bioavailability of commercially manufactured fixed-dose combinations is
      satisfactory. OBJECTIVE: To establish an international laboratory network to
      assess rifampicin bioavailability. DESIGN: Convenient assay kits were devised to
      evaluate the ability of laboratories in China, India, Italy, South Africa,
      Thailand and the USA to determine plasma and urinary concentrations of rifampicin
      and desacetyl-rifampicin. RESULTS: Five laboratories, all of whom used high
      pressure liquid chromatographic methods, were shown to be able to accurately and
      precisely determine the two compounds. CONCLUSION: Such a procedure is simple,
      convenient and objective and could be further employed to enlarge the intended
      international laboratory network.

PMID- 10593712
TI  - Determination of rifampicin, isoniazid and pyrazinamide by high performance
      liquid chromatography after their simultaneous extraction from plasma.
AB  - SETTING: Isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA) are first-line
      antituberculosis drugs. Due to difficulties in producing effective combined
      formulations of these three drugs, the bioavailability of new combination
      formulations needs to be assessed prior to registration. OBJECTIVE: To develop a
      rapid, simple and sensitive high performance liquid chromatography (HPLC) assay
      method suitable for assaying RIF, INH and PZA in large numbers of plasma samples
      generated in bioavailability studies. METHOD: RIF, desacetyl-rifampicin (DRIF),
      INH and PZA were extracted simultaneously from plasma using a solid phase
      extraction column. RIF and DRIF were quantitated by HPLC using an 80%
      acetonitrile/0.1% trifluoroacetic acid (TFA) mobile phase and a C8 reversed phase
      column. INH and PZA were also quantitated on a C8 reversed phase column, but a 3%
      acetonitrile/0.6% TFA mobile phase was used. RESULTS: Mean recovery of RIF, DRIF
      and PZA from plasma was well over 90%, and over 70% for INH. Calibration graphs
      were linear for all the drugs in their therapeutic range. Correlation
      coefficients were all above 0.9995, and between- and within-run coefficients of
      variation below 10%. CONCLUSION: A simple, accurate, sensitive and cost effective
      assay for first-line antituberculosis drugs has been developed.

PMID- 10593713
TI  - The development of a standardised screening protocol for the in vivo assessment
      of rifampicin bioavailability.
AB  - SETTING: The prerequisite for in vivo bioavailability testing of rifampicin in
      fixed-dose combination (FDC) formulations is widely accepted. However, many
      smaller drug regulatory authorities and drug manufacturers have difficulty
      implementing costly and cumbersome testing procedures. OBJECTIVE: To test whether
      a simplified blood sampling schedule can be used for the determination of drug
      bioequivalence in randomised, single dose, crossover studies of FDCs and
      appropriate reference formulations. METHOD: The results of three bioavailability
      and bioequivalence studies of different rifampicin-containing FDCs were analysed.
      The relationship between the number of time points employed and precision of
      estimated relative bioavailability was explored. The relative bioavailabilities
      of the drug components in the test FDCs were calculated using maximal
      concentration and area under the curve estimates based on an extended blood
      sampling schedule of up to 15 time points over 48 hours, and a contracted
      sampling scheme with only six blood samples over 8 hours. RESULTS: Estimates of
      relative bioavailability calculated using the contracted blood sampling protocol
      were closely similar to those derived using the extended sampling schedules.
      CONCLUSION: Considerable cost and convenience benefits can be gained by using the
      contracted sampling schedule with only a minor reduction in the precision of the
      estimation of relative rifampicin bioavailability.

PMID- 10593714
TI  - The WHO simplified study protocol in practice: investigation of combined
      formulations supplied by the WHO.
AB  - SETTING: The benefits of fixed-dose combination (FDC) formulations of rifampicin,
      isoniazid and pyrazinamide over individual formulations are well recognised.
      OBJECTIVES: To evaluate the comparative bioavailability of antituberculosis drugs
      in FDC formulations and the same doses in separate formulations of
      antituberculosis drugs, using a simplified protocol developed by the World Health
      Organization (WHO). METHODS: Twenty healthy volunteers were included in the study
      and evaluated for bioequivalence of rifampicin in a cross-over experimental
      design. After administration of drugs the plasma concentration of rifampicin and
      desacetyl-rifampicin was measured repeatedly up to 8 hours in both plasma and
      urine. Various pharmacokinetic parameters of rifampicin, such as Cmax, Tmax,
      elimination rate constant, area under the curve (AUC) up to 8 hours and
      absorption efficiency were calculated. RESULTS: No significant differences were
      observed between the FDCs and separate formulations when Cmax, Tmax, AUC and
      absorption efficiencies were compared by parametric test and Hauschke's analysis.
      CONCLUSION: The WHO simplified protocol is suitable for evaluating bioequivalence
      of antituberculosis drugs.

PMID- 10593715
TI  - The colorimetric analysis of anti-tuberculosis fixed-dose combination tablets and
      capsules.
AB  - SETTING: The perceived need to demonstrate whether or not the actual amounts of
      rifampicin, isoniazid and pyrazinamide in fixed-dose combination tablets or
      capsules correspond to their stated drug contents. OBJECTIVE: To adapt specific,
      robust and simple colorimetric methods that have been previously applied to
      measuring plasma and urinary rifampicin, isoniazid, pyrazinamide and ethambutol
      concentrations to estimate tablet and capsule drug contents. DESIGN: The methods
      were applied to the analysis of 14 commercially manufactured fixed-dose
      combinations: two capsule and three tablet formulations containing rifampicin and
      isoniazid; seven tablet formulations containing rifampicin, isoniazid and
      pyrazinamide; and two tablet formulations containing rifampicin, isoniazid,
      pyrazinamide and ethambutol. RESULTS: All the combined formulations contained
      near to their stated drug contents. Replicate analyses confirmed the excellent
      precision of the drug analyses. CONCLUSION: Such methods are not only rapid to
      perform but should be practical in many Third World situations with relatively
      modest laboratory facilities.

PMID- 10593716
TI  - Detection of substandard fixed-dose combination tuberculosis drugs using thin
      layer chromatography.
AB  - SETTING: A convenience sample of 13 fixed-dose combination (FDC) tuberculosis
      (TB) drugs from 'The Fixed Dose Combination Project' was analysed in laboratories
      at the University of Botswana and the US Food and Drug Administration (FDA).
      OBJECTIVE: To determine actual versus stated content of drugs in these FDCs.
      DESIGN: Chemical analysis was performed using thin-layer chromatography (TLC) as
      a screening method, and ultraviolet (UV) spectrophotometry or liquid
      chromatography (LC) as confirmation. FDCs with content outside of 85-115% of
      stated concentration were defined as substandard. RESULTS: All 13 FDCs contained
      the stated drugs. However, four (31%) were substandard, including two (15%) with
      low rifampicin content, one (8%) with excessive rifampicin, and one (8%) with
      excessive pyrazinamide. Both FDCs with low rifampicin contained four drugs and
      failed TLC screening. The FDC with excessive rifampicin was not detected by TLC
      screening. Using UV as the gold standard, the sensitivity of TLC for low
      rifampicin was 2/2 (100%), and the specificity was 9/10 (90%). CONCLUSION: This
      study found that 31% of the FDCs in 'The Fixed Dose Combination Project' had
      substandard content, irrespective of bioavailability. Low rifampicin content,
      which can be reliably detected by TLC screening, was identified in both four-drug
      FDC products and is particularly worrisome. TB drugs should be screened for
      quality using TLC to optimise treatment outcomes and to prevent increases in
      acquired drug resistance.

PMID- 10593717
TI  - Implementation of fixed-dose combinations in tuberculosis control: outline of
      responsibilities.
AB  - Fixed-dose combinations (FDCs) of antituberculosis drugs have been available on
      the world market for more than forty years. For more than twenty years rifampicin
      containing FDCs have become increasingly visible on the market in combinations of
      two, three and even four fixed-dose combinations, but in different dosages
      depending on the country and the region. As a result, instead of simplifying
      tuberculosis treatment and the application of standardised chemotherapy regimens,
      the situation has become progressively more complicated, and at the same time
      neither bioavailability nor patients' safety is guaranteed. It is time to
      rationalise and extend the use of FDCs in national tuberculosis programmes.
      International, supranational and national responsibilities must be clearly
      defined in this process.

PMID- 10593718
TI  - Requirements for anti-tuberculosis drug tender requests.
AB  - As more and more institutions and experts push for the use of fixed-dose
      combinations (FDC) of anti-tuberculosis drugs, the market will most probably
      change dramatically in the next few years. Prices should go down, but quality
      must remain an essential goal for managers in charge of the procurement process.
      General essential requirements for suppliers submitting for competitive bidding
      are reviewed, and in particular the WHO certification scheme. Even though the
      scheme does not dispense with the need to submit drugs to the quality control
      procedures required in the importing country, it is a very useful tool which
      should be encouraged in the supply process. Specific requirements for FDCs are
      discussed, particularly interpretation of the bioavailability tests which are
      compulsory for rifampicin-containing FDCs.

PMID- 10593719
TI  - Proposed minimum registration requirements for fixed-dose combination anti
      tuberculosis drugs.
AB  - Registration requirements for combined pharmaceutical preparations have been
      published before, but not specifically for fixed-dose combination (FDC) anti
      tuberculosis preparations. With tuberculosis being a high priority disease world
      wide and concerns being raised over substandard FDC anti-tuberculosis
      preparations being marketed on a wide scale, specific guidelines for industry
      seem to be indicated. This is predominantly necessitated by the fact that
      rifampicin bioavailability can be adversely affected when put in combination with
      isoniazid and pyrazinamide, and by the need for standardisation of the
      formulations to only a few essential combinations in order to better control
      quality. This paper proposes certain minimum requirements to be met when
      standardising dose in the combinations and when ensuring bioavailability of the
      preparations. Nine rifampicin-containing combinations are listed as essential.
      Furthermore, bioavailability testing of the rifampicin component only by a
      restricted assay protocol of six sample times over 8 hours is advocated, whilst
      in vitro procedures for other actives in the combination would suffice for
      registration purposes.

PMID- 10593720
TI  - Structures required, roles and responsibilities in maintaining laboratories for
      quality assurance of anti-tuberculosis fixed-dose combinations in accordance with
      the IUATLD/WHO statement.
AB  - Combining rifampicin in the same tablet with isoniazid, with or without
      pyrazinamide, is known to affect the bioavailability of the drug. It is also
      known that many fixed-dose combination (FDC) preparations exist in the market
      which are of inferior quality, but are unknowingly used extensively in
      tuberculosis treatment programmes in low-income countries with high tuberculosis
      caseloads. This has led to joint statements by the International Union Against
      Tuberculosis and Lung Disease and the World Health Organization (WHO) pointing
      out that anti-tuberculosis FDCs should only be used in National Tuberculosis
      Programmes if the bioavailability of at least the rifampicin component has been
      demonstrated. Through the FDC Quality Assurance Project launched by the WHO in
      1997, a strategy was proposed which aimed to provide specific guidance to ensure
      the improved quality of such preparations, and in particular the bioavailability
      of the rifampicin component. A crucial component of drug quality assurance is to
      ensure that the infrastructure and logistics required to carry out the
      operational aspects of quality assurance are adequate and sustainable. This paper
      describes the structures and management responsibilities required to meet this
      objective, based on general WHO guidelines for the quality assurance of
      pharmaceuticals.

PMID- 10593722
TI  - Sons or Sonnets. Nature and Culture in a Shakespearean Anthropology.

PMID- 10593723
TI  - Ghost Dancing the Grand Canyon. Southern Paiute Rock Art, Ceremony, and Cultural
      Landscapes.
AB  - Combining rock art studies with ethnohistory, contemporary ethnographic analysis,
      and the interpretations of people who share the cultural traditions being
      studied, this paper documents a rock art site in Kanab Creek Canyon that appears
      to have been the location of a Ghost Dance ceremony performed by Southern Paiute
      and perhaps Hualapai people in the late 1800s. Using the site as a point of
      departure, it focuses on the way in which synergistic associations among place,
      artifact, resources, events, and historic and contemporary Indian people
      contribute to the construction of a contextual cultural landscape.

PMID- 10593721
TI  - Availability of quality fixed-dose combinations for the treatment of
      tuberculosis: what can we learn from studying the World Health Organization's
      vaccine model?
AB  - SETTING: In efforts to promote the use of fixed-dose combinations (FDCs) for the
      treatment of tuberculosis (TB), the World Health Organization (WHO) and partners
      address the issue of quality assurance. OBJECTIVE: To provide guidance for the
      development of strategies for quality assurance of FDCs. DESIGN: This review
      examines the WHO strategies for and experience with quality assurance and supply
      of vaccines. RESULTS: Several elements in the strategies for quality assurance
      and supply of vaccines may be applicable for FDCs. At national level, the
      important strategies are to strengthen National Regulatory Authorities (NRA) and
      procurement systems and develop planning activities. Stressing quality assurance
      of FDCs in training activities for regulatory personnel and recommending that aid
      agencies require adherence to quality assurance policies as conditions for
      support would promote the implementation of quality assurance of FDCs at country
      level. At the global level, pre-qualification of manufacturers of FDCs should be
      explored as a mechanism to assure quality. The pre-qualification process should
      include evaluation of product files, initial testing for compliance and
      consistency of specifications, and site visits to producers and NRAs. The vaccine
      model defines criteria for reassessment that can be used for FDCs.

PMID- 10593724
TI  - The Tortoise and the Hare. Small-Game Use, the Broad-Spectrum Revolution, and
      Paleolithic Demography.
AB  - This study illustrates the potential of small-game data for identifying and
      dating Paleolithic demographic pulses such as those associated with modern human
      origins and the later evolution of food-producing economies. Archaeofaunal series
      from Israel and Italy serve as our examples. Three important implications of this
      study are that (1) early Middle Paleolithic populations were exceptionally small
      and highly dispersed, (2) the first major population growth pulse in the eastern
      Mediterranean probably occurred before the end of the Middle Paleolithic, and (3)
      subsequent demographic pulses in the Upper and Epi-Paleolithic greatly reshaped
      the conditions of selection that operated on human subsistence ecology,
      technology, and society. The findings of this study are consistent with the main
      premise of Flannery's broad-spectrum-revolution hypothesis. However, ranking
      small prey in terms of work of capture (in the absence of special harvesting
      tools) proved far more effective in this investigation of human diet breadth than
      have the taxonomic-diversity analyses published previously.

PMID- 10593725
TI  - Reconciliation and Revenge in Post-Apartheid South Africa. Rethinking Legal
      Pluralism and Human Rights.
AB  - Human rights are a central element in the new governmental project in the new
      South Africa, and this article traces some of the specific forms of connection
      and disconnection between notions of justice found in townships of the Vaal and
      rights discourses as articulated by the Truth and Reconciliation Commission. The
      introduction of human rights in post-apartheid South Africa has had varied social
      effects. Religious values and human rights discourse have converged on the notion
      of reconciliation on the basis of shared value orientations and institutional
      structures. There are clear divergences, however, between human rights ideas and
      the notions of justice expressed in local lekgotla, or township courts, which
      emphasize punishment and retribution. The article concludes that the plurality of
      legal orders in South Africa results not from systemic relations between law and
      society but from multiple forms of social action seeking to alter the direction
      of social change in the area of justice within the context of the nation-building
      project of the post-apartheid state.

PMID- 10593726
TI  - Representations of Race and Racism in American Anthropology.

PMID- 10593728
TI  - On Animism.

PMID- 10593727
TI  - On an Antiessential Political Ecology.

PMID- 10593729
TI  - On the Nile Corridor and the Out-of-Africa Model.

PMID- 10593730
TI  - On Territoriality and Sedentism.

PMID- 10593731
TI  - Egypt and Syro-Mesopotamia in the 4th Millennium: Implications of the New
      Chronology.

PMID- 10593732
TI  - A Test of the "Showing-Off" Hypothesis with Ache Hunters.

PMID- 10593734
TI  - Guanxi: A Nesting of Groups.

PMID- 10593733
TI  - Structure of the Prehistoric Population of San Pedro de Atacama.

PMID- 10593765
TI  - CHEST at the new millennium.

PMID- 10593764
TI  - Treatment of sleep apnea: unmet needs.

PMID- 10593766
TI  - Why the upper airway is not like a gall bladder.

PMID- 10593767
TI  - Bloody pericardial effusion: clinically significant without intrinsic diagnostic
      specificity.

PMID- 10593768
TI  - Improvements in lung and respiratory muscle function following lung volume
      reduction surgery: smaller may be better, but how long does It last?

PMID- 10593769
TI  - Asthma: we need to do better!

PMID- 10593770
TI  - Evaluation of variable mandibular advancement appliance for treatment of snoring
      and sleep apnea.
AB  - OBJECTIVE: To evaluate an adjustable mandibular positioning appliance for
      treatment of snoring and sleep apnea. METHODS: One hundred thirty-four patients
      with baseline apnea/hypopnea index (AHI) of 37 +/- 28 events/h (mean +/- SD)
      received the appliance. The efficacy of the appliance was assessed by the
      following investigations, performed at baseline and with the appliance:
      polysomnography, Epworth sleepiness scale, bedpartners' assessment of snoring
      severity, patients' assessment of side effects, and overall satisfaction.
      RESULTS: Thirteen patients were lost to follow-up. An additional 46 patients had
      no follow-up polysomnography, but answered the questionnaires. A total of 75
      patients had polysomnography at baseline and with the appliance. We found a
      significant reduction in AHI from 44 +/- 28 events/h to 12 +/- 15 events/h (p <
      0.0005) and a reduction in the arousal index from 37 +/- 27 events/h to 16 +/- 13
      events/h (p < 0.05). Epworth scores fell from 11 +/- 5 to 7 +/- 3 (p < 0.0005).
      Bedpartners' assessment revealed marked improvement in snoring. For example, at
      baseline 96% of patients were judged to snore loudly "often" or "always" by their
      bedpartners, whereas only 2% were judged so while using dental appliance. The
      most frequent side effect was teeth discomfort, present "sometimes" or "often" in
      up to 32% of patients. Follow-up clinical assessment in 121 patients conducted on
      the average 350 days after the insertion of the appliance revealed that 86% of
      patients continued to use the appliance nightly; 60% were very satisfied with the
      appliance, 27% were moderately satisfied, 11% were moderately dissatisfied, and
      2% were very dissatisfied. CONCLUSION: We conclude that the adjustable mandibular
      positioning appliance is an effective treatment alternative for some patients
      with snoring and sleep apnea.

PMID- 10593771
TI  - Maxillomandibular advancement surgery in a site-specific treatment approach for
      obstructive sleep apnea in 50 consecutive patients.
AB  - OBJECTIVE: To report the efficacy of maxillomandibular advancement (MMA) surgery,
      with a description of several innovations, as a site-specific treatment of
      obstructive sleep apnea syndrome (OSAS) in selected cases with disproportionate
      velo-orohypopharyngeal anatomy. DESIGN: Clinical series of 50 consecutive cases.
      SETTING: Surgery was performed in a hospital operating room, and perioperative
      management was provided in an intensive care environment. Except for
      polysomnography (PSG), which was performed and interpreted by independent sleep
      facilities/physicians, all pre- and postoperative evaluations were accomplished
      in a solo office private practice setting. PATIENTS: Patients were referred for
      MMA evaluation when applicable conservative therapies such as nasal continuous
      positive airway pressure (nCPAP) were not tolerated, refused, or unsuccessful.
      Case selection was based primarily on the sites of disproportionate upper airway
      anatomy. INTERVENTIONS: MMA consisted of a Lefort I osteotomy, bilateral sagittal
      split ramus osteotomies, and a new modified procedure called an anterior inferior
      mandibular osteotomy with indirect hyoid suspension. Some patients also received
      concomitant adjunctive nonpharyngeal procedures. MEASUREMENTS AND RESULTS:
      Obtained at a mean of 5.2 months postoperatively, revealed significant
      improvement in all cases. Mean BPs (n = 50) were lowered, subjective symptoms
      were ameliorated, and mean body mass index (n = 50) was reduced. Cephalometric
      analysis (n = 50), with several new modifications including standardization for
      phases of respiration, quantified structural changes in soft-tissue and bony
      landmarks. Postoperative PSG results (n = 50) showed dramatic improvement over
      preoperative data (n = 50), with therapeutic values similar to nCPAP (n = 42).
      Mean values improved from preoperative to postoperative vs nCPAP for apnea index
      (34.5 to 1.0 vs 2.0, respectively), apnea-hypopnea index (59.2 to 4.7 vs 5.4,
      respectively), lowest arterial oxyhemoglobin desaturations (72.7% to 88.6% vs
      88.6%, respectively), and number of desaturations < 90% (118.8 to 6.6 vs 2.4,
      respectively). The success rate was 100%. CONCLUSION: MMA is highly successful
      and safe and may be a definitive primary single-staged surgical treatment of
      selected OSAS cases with diffusely complex or multiple sites of disproportionate
      velo-orohypopharyngeal anatomy.

PMID- 10593772
TI  - Prevalence of snoring and sleep-disordered breathing in a student population.
AB  - INTRODUCTION: The prevalence of snoring and sleep-disordered breathing (SDB) in
      young adults in Southeast Asian countries is unknown. We aim to determine the
      symptoms and prevalence of SDB in a university student population using a
      questionnaire survey followed by home sleep monitoring. METHODS: The Sleep and
      Health Questionnaire (a modified version of the Specialized Centers of Research
      Sleep Questionnaire, translated into Chinese) was distributed to all first-year
      students (1,306 male and 1,757 female) enrolled in the Chinese University of Hong
      Kong. Subsequently, those students who returned the questionnaires were randomly
      chosen to undergo portable home sleep monitoring using the MESAM IV device
      (Madaus Medizin-Elektronik; Freiburg, Germany). RESULTS: A total of 1,910 replies
      were obtained from 3,063 questionnaires sent by mail (response rate, 62.4%). The
      female to male ratio was 1.8:1, with mean age of 19.4 years (SD, 1.3 years) and
      mean body mass index (BMI) of 20.0 (SD, 2.5). Overall, 25.7% of subjects reported
      snoring; 10.7% and 42.1% reported impaired performance ability and daytime
      sleepiness, respectively. Of the 88 subjects who underwent overnight sleep
      monitoring, 66 subjects (75%) were snorers and 8 subjects (9%) snored > 10% of
      the night. Male subjects had a higher BMI (p < 0.001) and tended to snore more
      often than female subjects (p = 0.06). Subjects with an oxygen desaturation index
      (ODI) > or = 3 had a BMI > 22 (p < 0.05). On sleep study, nine subjects (10.2%)
      and two subjects (2.3%) had a respiratory disturbance index (RDI) > or = 3 and an
      RDI > or = 5, respectively, associated with self-reported sleepiness, giving a
      minimum estimated prevalence of SDB as 0.1% (RDI > or = 5) in the study
      population. There was no correlation between recorded snoring with either RDI or
      self-reported sleepiness. Questionnaire responses, neck circumference, and
      alcohol consumption did not predict the occurrence of SDB. CONCLUSION: Snoring
      was prevalent, while SDB was uncommon in this student population. However,
      snoring and self-reported symptoms by questionnaire were poor predictors for SDB.
      Male gender showed a trend as an independent predictor for snoring, but not for
      SDB.

PMID- 10593773
TI  - Value of clinical, functional, and oximetric data for the prediction of
      obstructive sleep apnea in obese patients.
AB  - OBJECTIVE: To evaluate the diagnostic value of clinical features, pulmonary
      function testing, blood gas tensions, and oximetric data for case finding of
      obstructive sleep apnea (OSA) before polysomnography (PSG) in a series of
      consecutive overweight patients. METHODS: We studied a population of 102
      consecutive patients referred by an obesity clinic for suspected OSA, in whom
      body mass index was > or = 25 kg/m(2). The following tests were performed:
      clinical score (CS), pulmonary function tests (PFTs), measurement of arterial
      blood gas tensions, nocturnal oximetry, and full-night PSG. RESULTS: Six of 34
      women and 34 of 68 men had OSA, defined by an apnea-hypopnea index > or = 15. CS
      and the cumulative time spent below 80% arterial oxygen saturation (SaO(2)) were
      higher, and PaO(2), minimal SaO(2), and mean nocturnal SaO(2) (mSaO(2)) were
      lower in OSA patients than in non-OSA patients. Logistic regression showed that
      sex, CS, and the ratio of FEV(1) over forced expiratory volume in 0.5 s (an index
      of upper airway obstruction on flow-volume curves) and mSaO(2), expressed as
      categorical variables, were independent predictors of OSA. None of these
      individual variables had a satisfactory diagnostic value for the diagnosis of
      OSA. A logistic regression model including sex and all continuous variables would
      have allowed us to predict the presence or absence of OSA confidently in 72.5% of
      the population, in whom the positive predictive value of the model was 94% and
      the negative predictive value was 90%. CONCLUSION: In obese patients referred to
      a respiratory sleep laboratory and evaluated by CS, PFTs, arterial blood gases,
      and oximetry, no individual sign or symptom may accurately predict the presence
      or absence of OSA. Provided that it is validated in prospective studies, a
      logistic regression model using these variables may be useful for the prediction
      of OSA.

PMID- 10593774
TI  - Effect of continuous positive airway pressure vs placebo continuous positive
      airway pressure on sleep quality in obstructive sleep apnea.
AB  - STUDY OBJECTIVES: Continuous positive airway pressure (CPAP) therapy has become
      the treatment of choice for obstructive sleep apnea (OSA). However, the efficacy
      of CPAP therapy has not been evaluated against a suitable control. We
      investigated the effectiveness of CPAP therapy in improving sleep quality in
      patients with OSA. We hypothesized that CPAP improves sleep quality. PATIENTS:
      Forty-eight CPAP-naive OSA patients were evaluated. None were receiving
      antihypertensive medications, and none had major medical illnesses. DESIGN:
      Patients were randomized to receive either CPAP or placebo CPAP (CPAP at an
      ineffective pressure) for 7 days in a double-blind fashion. Forty-one patients
      completed the protocol. Sleep quality variables, arousals, sleep arterial oxygen
      saturation (SaO(2)), and respiratory disturbance index (RDI) were assessed at
      baseline, after 1 day of treatment, and after 7 days of treatment. Repeated
      measures analysis of variance was used to evaluate the effects of treatment,
      time, and the interaction of the two. RESULTS: As expected, CPAP lowered RDI and
      number of arousals, and increased SaO(2) over time (p = 0.001). Contrary to
      expectations, both CPAP and placebo CPAP had comparable effects on sleep quality
      as assessed by sleep architecture, sleep efficiency, total sleep time, and wake
      after sleep onset time. CONCLUSIONS: This study confirms the effectiveness of
      CPAP in lowering the number of arousals and the RDI, and in raising SaO(2).
      However, our data suggest that short-term CPAP is no different than placebo in
      improving sleep architecture. Further evaluation of the effectiveness of CPAP
      using a suitable placebo CPAP in prospective randomized studies is needed

PMID- 10593775
TI  - Comparison of oxygen therapy with nasal continuous positive airway pressure on
      Cheyne-Stokes respiration during sleep in congestive heart failure.
AB  - STUDY OBJECTIVES: Both oxygen therapy and nasal continuous positive airway
      pressure (CPAP) therapy have independently been shown to be effective in the
      treatment of Cheyne-Stokes respiration (CSR) in patients with congestive heart
      failure (CHF). The purpose of this study was to compare the short-term effects of
      oxygen therapy and nasal CPAP therapy on CSR in a group of stable patients with
      severe CHF. DESIGN: Prospective, randomized, controlled trial. SETTING:
      University hospital. PATIENTS: Twenty-five stable patients (mean [+/- SD] age, 56
      +/- 9) with CHF and a mean left ventricular ejection fraction (LVEF) of 17 +/-
      0.8%. INTERVENTIONS AND MEASUREMENTS: All patients had a right heart
      catheterization prior to the study and an echocardiogram performed to measure
      LVEF. In addition, all patients had an initial sleep study to identify the
      presence of CSR. Sleep studies included continuous recordings of breathing
      pattern, pulse oximetry, and EEG. Those patients identified as having CSR were
      randomized to a night on oxygen therapy (2 L/min by nasal cannula) and another
      night on nasal CPAP therapy (9 +/- 0.3 cm H(2)O). RESULTS: Fourteen of the 25
      patients (56%) studied had CSR (apnea hypopnea index [AHI], 36 +/- 7 events per
      hour) during their initial sleep study. Nine of the 14 patients with CSR
      completed the study. When compared with baseline measurements, both oxygen
      therapy and nasal CPAP therapy significantly decreased the AHI (from 44 +/- 9 to
      18 +/- 5 and 15 +/- 8 events per hour, respectively; p < 0.05), with no
      significant difference between the two modalities. The mean oxygen saturation
      increased significantly and to a similar extent with oxygen therapy and nasal
      CPAP therapy (from 93 +/- 0.7% to 96 +/- 0.8% and 95 +/- 0. 7%, respectively; p <
      0.05), as did the lowest oxygen saturation during the night (from 80 +/- 2% to 85
      +/- 3% and 88 +/- 2%, respectively; p < 0.05). In addition, the mean percent time
      the oxygen saturation was < 90% also improved with both interventions (from a
      baseline of 17 +/- 5 to 6 +/- 3% with oxygen therapy and 5 +/- 2% with nasal CPAP
      therapy; p < 0.05). When compared with baseline measurements, the apnea-hypopnea
      length, cycle length, circulation time, and heart rate did not significantly
      change with either oxygen therapy or nasal CPAP therapy. Total sleep time and
      sleep efficiency decreased only with nasal CPAP therapy (from 324 +/- 20 to 257
      +/- 14 min, and from 82 +/- 3 to 72 +/- 2%, respectively; p < 0.05). The arousal
      index, when compared with baseline, remained unchanged with both oxygen therapy
      and nasal CPAP therapy. CONCLUSION: CSR occurs frequently in stable patients with
      severe CHF. In addition, oxygen therapy and nasal CPAP therapy are equally
      effective in decreasing the AHI in those CHF patients with CSR.

PMID- 10593776
TI  - Performance of sleep histories in an ambulatory medicine clinic: impact of simple
      chart reminders.
AB  - BACKGROUND: The sleep history is essential to recognizing clinically important
      sleep disorders, but little is documented about its performance in the primary
      care setting. STUDY OBJECTIVES: To estimate the frequency of documented sleep
      histories by medical house officers (HOs) in an ambulatory medicine clinic and to
      assess whether a chart reminder influences their performance. DESIGN: We reviewed
      the performance of medical HOs after introduction of a medical record form that
      included a simple sleep history prompt among reminders relating to health
      promotion. For each of 108 HOs, we randomly selected a chart with a sleep history
      prompt and one without. RESULTS: Any sleep history was documented in only 37 of
      216 medical records (17%), including 21 of 122 patients (17%) with risk factors
      for obstructive sleep apnea (OSA). Use of chart reminders was associated with
      nearly a fivefold increase of sleep histories (29% vs 6%, p < 0.001), and charts
      with prompts had more notations about specific sleep complaints (2.6 +/- 0.9 vs
      1.0 +/- 0.0 notes per patient, p < 0.0001). Sleep histories were recorded less
      often (p < 0.001) than histories of cigarette smoking or alcohol use. Although
      24% of physicians appeared to be influenced by the prompt, sleep problems were
      included on problem lists of only six patients (3%). Overall, the frequencies of
      diagnostic studies (1% of all patients, 6% of those with sleep histories) or
      documented therapeutic recommendations (0%) relating to sleep were low, whether
      or not chart reminders were used, with sleep testing obtained in only one
      patient. Sleep interventions were documented less often than smoking cessation or
      weight loss (p < 0.002). CONCLUSIONS: Sleep histories are seldom documented by
      medical HOs, even in patients at risk for OSA. Use of a simple chart reminder was
      associated with an increased frequency of recorded sleep histories, but had no
      clear impact on diagnosis or treatment. If sleep problems and their management
      are to be prioritized appropriately, then the obstacles to obtaining sleep
      histories and to following up cues to sleep disorders must be clarified and
      overcome.

PMID- 10593777
TI  - Bloody pericardial effusion in patients with cardiac tamponade: is the cause
      cancerous, tuberculous, or iatrogenic in the 1990s?
AB  - STUDY OBJECTIVES: The decrease in incidence of tuberculosis, along with the
      increase in invasive cardiovascular procedures, may have changed the frequency of
      causes of bloody pericardial effusion associated with cardiac tamponade, although
      this is not yet recognized by medical textbooks. We analyzed the causes of bloody
      pericardial effusion in the clinical setting of cardiac tamponade in the 1990s;
      patients' survival; the effect of laboratory results on discharge diagnosis; and
      how often bloody pericardial effusion is a presenting manifestation of a new
      malignancy or tuberculosis. DESIGN: Retrospective, observational, single-center
      study. SETTING: A community hospital. PATIENTS: The charts of all patients who
      underwent pericardiocentesis for cardiac tamponade and had bloody pericardial
      effusion were retrospectively reviewed. RESULTS: Of 150 patients who had
      pericardiocentesis for relieving cardiac tamponade, 96 patients (64%) had a
      bloody pericardial effusion. The most common cause of bloody pericardial effusion
      was iatrogenic disease (31%), namely, secondary to invasive cardiac procedures.
      The other common causes were malignancy (26%), complications of atherosclerotic
      heart disease (11%), and idiopathic disease (10%). Tuberculosis was detected as a
      cause of bloody pericardial effusion in one patient and presumed to be the cause
      in another patient. Bloody pericardial effusion was found to be a presenting
      manifestation of a newly diagnosed malignancy in two patients. The patients in
      the idiopathic and iatrogenic groups were all alive and had no recurrence of
      pericardial effusion at 24 +/- 27 and 33 +/- 21 months after hospital discharge,
      respectively, whereas 80% of patients with malignancy-related bloody effusions
      died within 8 +/- 6 months. CONCLUSIONS: In a patient population that is
      reasonably representative of that in most community hospitals in the United
      States, the most common cause of bloody pericardial effusion in patients with
      signs or symptoms of cardiac tamponade is now iatrogenic disease. Of the
      noniatrogenic causes, malignancy, complications of acute myocardial infarction,
      and idiopathic disease predominated. Hemorrhagic tuberculous pericardial
      effusions are uncommon and may likely reflect a low incidence of cardiac
      tuberculosis in community hospitals in the United States.

PMID- 10593778
TI  - Factors associated with health indicators in patients undergoing coronary artery
      bypass surgery.
AB  - BACKGROUND: The main goals of coronary artery bypass graft (CABG) surgery for
      most patients are to relieve angina, to improve functional capacity, to return to
      work, and to improve health. A limited amount of information is available
      regarding the various attributes that are associated with achieving these goals.
      STUDY OBJECTIVES: To investigate different patient attributes affecting these
      outcomes. DESIGN: Prospective data collection. SETTING: Fourteen medical centers
      that perform CABG surgery in Israel. PATIENTS: The 4,012 patients who underwent
      CABG surgery during 1994. MEASUREMENTS: Trained nurses collected data using
      structured questionnaires prior to and 4 to 5 months after the operation. Using
      logistic regression, four risk models were created to the following health
      indicators: recurrence of angina, functional capacity, return to work, and
      perception of health. Candidate variables were sociodemographic details, major
      comorbidities, risk factors for cardiac disease, and severity of cardiac disease.
      RESULTS: The mean age of the patients was 63.8 years old, 79.3% were men, 59.9%
      were elective operations, and left main disease was found in 17.3%. Multivariate
      logistic regression revealed that the variables that significantly contributed to
      three or more of the models were Sephardic Jewish origin, female gender, left
      ventricular dysfunction, and diabetes mellitus. CONCLUSIONS: There is a
      similarity between risk factors of various health indicators in CABG surgery
      patients. Thus, it is possible to define a population at high risk that may not
      benefit from the procedure.

PMID- 10593779
TI  - Abnormality of left ventricular sympathetic nervous function assessed by (123)I
      metaiodobenzylguanidine imaging in patients with COPD.
AB  - BACKGROUND: Cardiac and systemic autonomic nervous function may be impaired in
      patients with COPD. Few reports, however, have described sympathetic nervous
      function of the left ventricle (LV) in COPD patients. STUDY OBJECTIVE: To assess
      the LV sympathetic nervous function in patients with COPD using (123)I
      metaiodobenzylguanidine (MIBG) imaging of the heart. DESIGN: Prospective
      comparison of (123)I-MIBG imaging results in COPD patients and normal subjects.
      PARTICIPANTS: Twenty-eight patients with COPD without manifest right ventricular
      overload and 7 volunteers without cardiopulmonary disease (control subjects).
      MEASUREMENTS: (123)I-MIBG imaging results and plasma norepinephrine concentration
      were compared between the COPD and control groups. In the COPD group, pulmonary
      function tests were performed and all subjects were interviewed about their
      symptoms. RESULTS: (123)I-MIBG uptake, assessed as the cardiac to mediastinal
      activity ratio in the delayed image, was significantly lower in the COPD group
      than in the control group (p < 0.05). (123)I-MIBG turnover, expressed as the
      washout rate (WR) of (123)I-MIBG from 15 to 240 min, was significantly higher in
      the COPD group than in the control group (p < 0.01). In the COPD group, patients
      with dyspnea showed lower cardiac to mediastinal activity ratios and higher WRs
      compared with patients who had mild dyspnea. The WR correlated negatively with
      the vital capacity/predicted value ratio, correlated negatively with the maximal
      voluntary ventilation volume/predicted value ratio, and correlated positively
      with the residual volume/total lung capacity ratio in the COPD group. The plasma
      norepinephrine concentration in COPD patients was higher than that in the control
      subjects. CONCLUSION: Patients with COPD have significant sympathetic nervous
      impairment of the LV myocardium as a result of generalized sympathetic
      overactivity.

PMID- 10593780
TI  - Bronchial hyperreactivity in patients with mitral stenosis before and after
      successful percutaneous mitral balloon valvulotomy.
AB  - OBJECTIVES: We aimed to identify the bronchial response to inhaled methacholine
      in patients with mitral stenosis (MS) and to clarify whether or not the bronchial
      hyperreactivity (BHR) is reversible after percutaneous mitral balloon valvulotomy
      (PBMV). PATIENTS AND SETTING: Thirty patients with MS and 28 age-matched healthy
      control subjects were prospectively evaluated with pulmonary function tests and
      methacholine challenge. The productive concentration of methacholine causing 20%
      decrease in FEV(1) (PC(20)) was calculated and used as a parameter of bronchial
      responsiveness. BHR was defined as a PC(20) < 8 mg/mL. Mean pulmonary artery
      pressure (PAP) and mean pulmonary capillary wedge pressure (PCWP) were recorded
      in all patients through a Swan-Ganz balloon-tipped catheter. Sixteen patients
      underwent PMBV, and a methacholine test was repeated after each procedure.
      RESULTS: Bronchial response to methacholine was significantly increased in
      patients with MS, so that 53% of them had BHR, whereas all control subjects were
      nonresponders. The PC(20) was closely correlated with the PAP (r = - 0.777; p <
      0.001), PCWP (r = - 0.723; p < 0.001), and mitral valve area (MVA; r = 0.676; p <
      0. 001). Balloon valvulotomy was successfully performed in all of the 16
      patients, and the cardiac parameters (MVA, PAP, and PCWP) significantly improved
      after the procedure. In contrast, no significant changes were shown in pulmonary
      function test variables (total lung capacity, vital capacity [VC], FEV(1), and
      FEV(1)/VC). Although significant improvement was observed in the mean PC(20)
      values (from 4.97 +/- 5.24 to 7.47 +/- 6.96 mg/mL; p = 0.0006), BHR was
      completely eliminated in only one patient. CONCLUSIONS: Our data shows that BHR
      is fairly common among patients with MS, and severity of bronchial responsiveness
      is significantly correlated with the severity of MS. Moreover, PMBV leads to
      significant reduction in pulmonary congestion and a consequent improvement in
      BHR.

PMID- 10593781
TI  - Safety profile and hemodynamic responses to beta-adrenergic stimulation by
      dobutamine in heart transplant patients.
AB  - STUDY OBJECTIVE: Dobutamine stress echocardiography (DSE) has been used as a
      screening tool for coronary artery disease after heart transplantation and in the
      identification of patients at risk for development of cardiac events. However,
      the safety profile of high-dose dobutamine in heart transplant patients has not
      been systematically examined. Accordingly, we studied the safety profile and
      hemodynamic responses to escalating doses of dobutamine to determine the
      influence of denervation. DESIGN: We assessed the hemodynamic responses, heart
      rate (HR), and arterial BP indexes (mean arterial pressure, systolic BP [SBP],
      diastolic BP [DBP], and pulse pressure) to dobutamine in 87 heart transplant
      patients ([mean +/- SD] age, 51 +/- 1 years) and compared the results with 97
      nontransplant patients (age, 63.0 +/- 1 years) who served as innervated control
      subjects. MEASUREMENTS AND RESULTS: The baseline HR (84 +/- 2 vs 69 +/- 1
      beats/minute, respectively; p < 0.001) and peak HR response (144 +/- 2 vs 117 +/-
      2 beats/minute, respectively; p < 0.001) were significantly higher in heart
      transplant patients than in the nontransplant patients. SBP was lower in heart
      transplant patients than in nontransplant patients at baseline (131 +/- 2 vs 138
      +/- 2 mm Hg, respectively; p < 0.02) and at peak (150 +/- 3 vs 158 +/- 3 mm Hg,
      respectively; p < 0.03). However, baseline DBP was higher in transplant patients
      than in nontransplant patients (86 +/- 1 vs 77 +/- 1 mm Hg, respectively; p <
      0.001). The decrease in DBP was similar in both groups (15 mm Hg). The dose
      response curve for HR was shifted leftward in heart transplant patients. Heart
      transplant patients attained a higher absolute HR at each infusion stage and
      higher rates of increase, but the decrease in DBP was not significantly different
      in the two groups. CONCLUSIONS: These results show that there is augmented
      chronotropic response and expected decline in DBP in response to dobutamine
      infusion in heart transplant patients. This increase in myocardial oxygen demand
      and a decrease in coronary perfusion pressure may be important mechanisms in the
      development of ischemic abnormalities that are detectable as regional dysynergy
      on echocardiography.

PMID- 10593782
TI  - Neural drive to the diaphragm after lung volume reduction surgery.
AB  - STUDY OBJECTIVES: The aim of this study was to investigate prospectively the
      changes in neural drive to the diaphragm in the first year after lung volume
      reduction surgery (LVRS) in patients with COPD. PATIENTS AND METHODS: In 14
      patients with severe emphysema (mean +/- SD; age, 53.7 +/- 8.3 years; FEV(1),
      0.64 +/- 0. 18 L; residual volume [RV], 5.33 +/- 1.25 L; PaO(2), 62.3 +/- 9.0 mm
      Hg; PaCO(2), 39.0 +/- 6.0 mm Hg), we assessed lung function, arterial blood
      gases, maximal exercise capacity (Wmax), and oxygen uptake (f1.gif"
      BORDER="0">O(2)max); intrinsic positive end-expiratory pressure (PEEPi);
      diaphragmatic strength (transdiaphragmatic pressure, Pdisniff) and endurance
      capacity (tlim); central diaphragmatic drive assessed by root mean square
      analysis of the esophageal electromyogram (rmsdia); and isotime dyspnea during
      loaded breathing tests (BS). RESULTS: Despite a significant increase (expressed
      as a percentage of baseline) in FEV(1) (40.6%) and a decrease in RV (30.0%) and
      PEEPi (75.7%) 1 month after LVRS, the improvements in Wmax (31.2%) and f1.gif"
      BORDER="0">O(2)max (13.7%); Pdisniff (25.4%) and tlim (64.9%); rmsdia (34.6%);
      and BS (21.7%) did not reach statistical significance (p < 0.05) until 6 months
      after LVRS. Arterial blood gases did not change significantly. Significant
      correlations were found between decrease in rmsdia and changes in PEEPi (r =
      0.69), Wmax (r = -0.56), Pdisniff (r = -0.65), tlim (r = -0.59), and BS (r =
      0.71) 6 months after LVRS. CONCLUSIONS: Our results show that LVRS is able to
      increase the efficacy of the respiratory pump and by this way reduce ventilatory
      drive and respiratory effort sensation.

PMID- 10593783
TI  - Weight gain after lung volume reduction surgery is not correlated with
      improvement in pulmonary mechanics.
AB  - STUDY OBJECTIVES: Malnutrition and low body weight are common in patients with
      emphysema. Previous work has demonstrated correlation between severity of airflow
      obstruction and body weight. Lung volume reduction surgery (LVRS) is a recent
      advance in the treatment of patients with severe emphysema that results in
      improved pulmonary function. We formed the hypothesis that improved lung
      mechanics after LVRS would result in body weight gain. DESIGN: Retrospective
      chart review. PATIENTS: All patients who underwent bilateral LVRS for severe
      emphysema at the University of Michigan between January 1995 and April 1996 were
      eligible for the study. MEASUREMENTS AND RESULTS: Pulmonary function and body
      weight were measured preoperatively and at 3, 6, and 12 months postoperatively
      for patients who underwent bilateral LVRS between January 1995 and April 1996.
      The average weight gain in 38 patients returning for 12 months of follow-up was
      3.8 +/- 0.9 kg, or 6.2% of the preoperative weight. Women gained significantly
      more weight than men (9.2 vs 2.2%, respectively) at 1 year. Interestingly, there
      was no correlation between change in weight and postoperative change in FEV(1),
      FVC, residual volume (RV), total lung capacity (TLC), or RV/TLC at 12 months.
      However, there was a statistically significant correlation between weight gained
      and improvement in diffusion of carbon monoxide measured 12 months
      postoperatively. CONCLUSIONS: This study shows that patients with severe
      emphysema gain weight after LVRS. These changes were independent of changes in
      pulmonary mechanics but may be a result of improved gas exchange. These findings
      provide further information about benefits of LVRS in patients with advance
      emphysema that are beyond simple changes in pulmonary function.

PMID- 10593784
TI  - Lung function 4 years after lung volume reduction surgery for emphysema.
AB  - STUDY OBJECTIVES: Current data for patients > 2 years after lung volume reduction
      surgery (LVRS) for emphysema is limited. This prospective study evaluates pre
      LVRS baseline data and provides long-term results in 26 patients. INTERVENTION:
      Bilateral targeted upper lobe stapled LVRS using video thoracoscopy was performed
      in 26 symptomatic patients (18 men) aged 67 +/- 6 years (mean +/- SD) with severe
      and heterogenous distribution of emphysema on lung CT. Lung function studies were
      measured before and up to 4 years after LVRS unless death intervened. RESULTS: No
      patients were lost to follow-up. Baseline FEV(1) was 0.7 +/- 0.2 L, 29 +/- 10%
      predicted; FVC, 2.1 +/- 0.6 L, 58 +/- 14% predicted (mean +/- SD); maximum oxygen
      consumption, 5.7 +/- 3.8 mL/min/kg (normal, > 18 mL/min/kg); dyspneic class > or
      = 3 (able to walk < or = 100 yards) and oxygen dependence part- or full-time in
      18 patients. Following LVRS, mortality due to respiratory failure at 1, 2, 3, and
      4 years was 4%, 19%, 31%, and 46%, respectively. At 1, 2, 3, and 4 years after
      LVRS, an increase above baseline for FEV(1) > 200 mL and/or FVC > 400 mL was
      noted in 73%, 46%, 35%, and 27% of patients, respectively; a decrease in dyspnea
      grade > or = 1 in 88%, 69%, 46%, and 27% of patients, respectively; and
      elimination of oxygen dependence in 78%, 50%, 33%, and 22% of patients,
      respectively. The mechanism for expiratory airflow improvement was accounted for
      by the increase in both lung elastic recoil and small airway intraluminal caliber
      and reduction in hyperinflation. Only FVC and vital capacity (VC) of all
      preoperative lung function studies could identify the 9 patients with significant
      physiologic improvement at > 3 years after LVRS, respectively, from 10 patients
      who responded < or = 2 years and died within 4 years (p < 0.01). CONCLUSIONS:
      Bilateral LVRS provides clinical and physiologic improvement for > 3 years in 9
      of 26 patients with emphysema primarily due to both increased lung elastic recoil
      and small airway caliber and decreased hyperinflation. The 9 patients had VC and
      FVC greater at baseline (p < 0.01) when compared to 10 short-term responders who
      died < 4 years after LVRS.

PMID- 10593785
TI  - Declining bone mass in men with chronic pulmonary disease: contribution of
      glucocorticoid treatment, body mass index, and gonadal function.
AB  - BACKGROUND: Men with chronic lung disease (CLD) are at risk for osteoporosis, but
      the relative contributions of their chronic pulmonary disease, glucocorticoid
      therapy, and other factors toward loss of bone has not been established.
      Understanding the relative importance of these factors would assist in selecting
      patients for bone densitometry screening and in policy decisions regarding
      Medicare reimbursement. OBJECTIVE: To identify patients with CLD who are most
      likely to benefit from bone densitometry screening based on clinical and
      biochemical measures. DESIGN: Cross-sectional medical survey. PATIENTS: Patients
      with CLD who were treated with either oral, inhaled, or no glucocorticoid
      therapy. A control group without lung disease was recruited from the same clinic
      population. MEASUREMENTS: Dual-energy X-ray absorptiometry was obtained for each
      group, and the association between bone mass and clinical variables,
      glucocorticoid use, gonadal hormones, and biochemical markers of bone metabolism
      was determined. RESULTS: Osteoporosis (a T score < -2.5 at the hip or spine) was
      five times as likely in patients with CLD as in control subjects. Although the
      prevalence of osteoporosis was higher (ninefold) after chronic glucocorticoid
      therapy, patients with CLD who had never been treated with glucocorticoids had a
      substantial (fourfold) risk of osteoporosis. Chronic inhaled glucocorticoid
      therapy offered no protection from bone loss compared to treatment with oral
      glucocorticoids. Of the clinical and biochemical measures that were obtained,
      bone mass was weakly correlated with body mass index (BMI), serum estradiol
      17beta, and N-telopeptide, but not with testosterone, alkaline phosphatase, bone
      specific alkaline phosphatase, or osteocalcin. CONCLUSION: Patients with CLD
      should be considered for bone densitometry screening regardless of glucocorticoid
      use. Those patients with a low BMI and/or decreased serum estradiol-17beta
      comprise a subgroup with increased risk for osteoporosis.

PMID- 10593786
TI  - Delayed type of hypersensitivity and late allergic reactions in patients with
      stable COPD.
AB  - BACKGROUND: Malnutrition, a common feature among patients with COPD, has adverse
      effects on the immune system. Delayed type of hypersensitivity (DTH) tests have
      been used to evaluate the nutritional and immune status of patients and to
      predict outcome in various conditions. DTH is known to be and late allergic
      reaction (LAR) has been suggested to be dependent on T-lymphocyte function. STUDY
      OBJECTIVES: To compare DTH and LAR tests in COPD patients and healthy controls,
      to investigate whether skin tests have any value in estimating nutritional status
      and outcome in COPD patients, and to see whether there is any relationship
      between DTH and LAR. METHODS: Twenty-five patients with stable COPD and 20
      healthy controls were tested for DTH and LAR. The patients were investigated with
      spirometry and anthropometric measurements and were followed for 1 year. RESULTS:
      Both the LAR and DTH reactions were diminished in the patient group (p < 0.001)
      compared with controls. The skin tests did not correlate with anthropometric
      parameters. DTH correlated to lung function, which was expressed as FEV(1)
      (percent predicted) (r = 0.56; p < 0.01), and LAR correlated to the number of
      exacerbations (at 3 months, r = - 0.61; p < 0.01). No correlation was found
      between LAR and DTH reactions. CONCLUSIONS: We conclude that patients with COPD
      in stable condition have diminished DTHs and LARs. Our results indicate that the
      magnitude of the LAR may be a prognostic marker in patients with COPD.

PMID- 10593787
TI  - A comparison of the level of dyspnea vs disease severity in indicating the health
      related quality of life of patients with COPD.
AB  - STUDY OBJECTIVES: To compare categorizations of the level of dyspnea with the
      staging of disease severity as defined by the FEV(1) in representing how the
      health-related quality of life (HRQOL) is distributed in patients with COPD.
      DESIGN: Cross-sectional study. SETTING: Outpatient clinic at the respiratory
      department of a university hospital. PATIENTS: A total of 194 consecutive male
      patients with stable, mild-to-severe COPD. MEASUREMENTS: The score distributions
      for the components of the St. George's respiratory questionnaire (SGRQ) were used
      as disease-specific HRQOL measures, and the scores from the Medical Outcomes
      Study Short Form 36-item questionnaire (SF-36) were used as generic HRQOL
      measures. These scores were stratified according to the level of dyspnea, as
      defined by the Medical Research Council (MRC) dyspnea scale, and the stage of
      disease severity, as defined by the American Thoracic Society (ATS). Differences
      in the HRQOL scores among the subgroups were compared by an analysis of variance
      (ANOVA). Multiple pairwise comparisons were made with Fisher's least significant
      difference (LSD) method, with the overall alpha-level set at 0.05. RESULTS: In
      those groups classified according to the level of dyspnea, significant
      differences were observed for the scores on the SGRQ and SF-36 (ANOVA, p < 0.05).
      The scores for activity and impact, and the total scores of the SGRQ and all
      scales, except for bodily pain and general health on the SF-36, were
      significantly worse for patients with severe dyspnea (MRC scale grades, 3, 4, and
      5, respectively) than for those with moderate dyspnea (MRC grade level, 2;
      Fisher's LSD method, p < 0.05). Significant differences were recognized among the
      different stages of disease severity with respect to the scores from all scales
      of the SF-36, except for bodily pain, and all scores from the SGRQ (ANOVA, p <
      0.05). However, differences in the scores on the SGRQ and SF-36 between patients
      with ATS stage II disease (FEV(1), 35 to 49% predicted) and stage III disease
      (FEV(1), < 35% predicted) were not statistically significant. CONCLUSIONS: Using
      the SGRQ and SF-36, the HRQOL of patients with COPD was more clearly separated by
      the level of dyspnea than by the ATS disease staging. In addition to the ATS
      disease staging, categorizations based on the level of dyspnea may be useful to
      clinicians in terms of the HRQOL of COPD patients.

PMID- 10593788
TI  - Current outpatient management of asthma shows poor compliance with International
      Consensus Guidelines.
AB  - STUDY OBJECTIVE: This study aimed to establish whether the outpatient management
      of patients presenting with an asthma exacerbation to the emergency department
      (ED) was in compliance with the 1992 guidelines of the "International Consensus
      Report on the Diagnosis and Management of Asthma." DESIGN: Prospective,
      observational study using a researcher-administered questionnaire. SETTING:
      University tertiary referral ED. PATIENTS: Convenience sample of asthmatics (aged
      18 to 54 years) presenting for asthma treatment between July 1, 1997, and June
      30, 1998. RESULTS: Eighty-five asthmatic patients were enrolled. Of these, 34
      patients (40%) smoked, 53 patients (62%) were undertreated with medication when
      compared to the consensus guidelines, and 74 patients (87%) had no written "plan
      of action." During an asthma attack, 9 patients (11%) did not use a
      bronchodilator as first-line action and 76 patients (89%) did not commence or
      increase the use of an inhaled steroid. Forty-nine patients (58%) did not know
      that bronchospasm occurred in asthma, and 53 patients (62%) did not know that
      bronchial swelling occurred. Twenty-six patients (31%) thought short-acting
      bronchodilator drugs were asthma preventers. Sixty-two patients (73%) could not
      adequately define peak expiratory flow (PF), 41 patients (48%) did not own a PF
      meter, and only 8 patients (9%) determined their PF daily. Fifty-three patients
      (62%) were reviewed by a physician once a year or less, and 18 patients (21%)
      noted family and friends as their only source of asthma education. CONCLUSIONS:
      The outpatient management of most asthma patients presenting to the ED did not
      comply with the consensus guidelines, and asthma knowledge was poor.

PMID- 10593789
TI  - Route of breathing in patients with asthma.
AB  - STUDY OBJECTIVES: To measure route of breathing in chronic asthmatic patients
      during and after an acute severe exacerbation. PATIENTS OR PARTICIPANTS: Thirteen
      asthmatic patients were studied during hospital admission for acute asthma and,
      in 9 patients, again when asymptomatic. Nine healthy subjects were also studied.
      INTERVENTIONS: Spontaneous route of breathing was qualitatively assessed using
      oral and nasal thermistor probes, and was then quantified using a dual
      compartment face mask with attached pneumotachographs. MEASUREMENTS AND RESULTS:
      All asthmatic patients had severe bronchoconstriction initially (FEV(1), 46 +/-
      3% of predicted) that had resolved at follow-up (FEV(1), 91 +/- 6% of predicted).
      No healthy subject had evidence of bronchoconstriction (FEV(1), 102 +/- 5% of
      predicted). During acute asthma, 11 asthmatics were spontaneously breathing
      oronasally, as assessed using thermistor probes, while all 13 breathed oronasally
      via face mask. When assessed using thermistor probes, seven of nine asymptomatic
      asthmatic patients studied were breathing exclusively via the nose; however, all
      breathed oronasally via face mask. In contrast, while eight of nine healthy
      subjects were also breathing exclusively via the nose when assessed using
      thermistor probes, all breathed nasally only via face mask. CONCLUSIONS: Thus,
      when asymptomatic and at rest, asthmatic patients breathe exclusively via the
      nose. However, during acute exacerbations of asthma, these patients switch to
      oronasal breathing. Unlike healthy subjects, chronic asthmatic patients also
      switch to oronasal breathing when wearing a face mask, irrespective of the degree
      of bronchoconstriction. We speculate that asthmatics may have an increased
      tendency to switch to oral breathing, a factor that may contribute to the
      pathogenesis of their asthma.

PMID- 10593790
TI  - Effect of mild hypoxia on airway responsiveness to methacholine in subjects with
      airway hyperresponsiveness.
AB  - STUDY OBJECTIVES: The inhalation of hypoxic gas has been reported to enhance the
      airway responsiveness to methacholine in some animal models. However, the data on
      humans have so far been conflicting. We attempted to examine the effect of
      hypoxic gas inhalation on the airway responsiveness to methacholine. DESIGN: We
      evaluated the airway responsiveness to methacholine by continuously measuring
      respiratory conductance with the forced oscillation method under normoxia or
      hypoxia in a single-blind, randomized, crossover fashion (2 days for each).
      PARTICIPANTS: Twelve asymptomatic male volunteers (mean +/- SD age, 27 +/- 4
      years) with airway hyperresponsiveness to methacholine. Two of the 12 volunteers
      had a history of bronchial asthma. SETTING: The participants inhaled either
      normoxic or hypoxic gas with continuous inhalation of aerosolized methacholine in
      incremental doses with a sustained respiratory rate of 15 breaths/min. The
      arterial oxygen saturation was kept to 90% on the hypoxic days. RESULTS: There
      were no significant differences in any indexes of airway responsiveness to
      methacholine (the cumulative dose of methacholine at the threshold and the point
      of 35% decrease of the respiratory conductance, and the slope factor of the dose
      response curve) between the hypoxic days and the normoxic days. CONCLUSION: The
      inhalation of mildly hypoxic gas does not enhance the airway responsiveness to
      methacholine in humans with airway hyperresponsiveness.

PMID- 10593791
TI  - Airway hyperresponsiveness and symptoms of asthma in a six-year follow-up study
      of childhood asthma.
AB  - BACKGROUND AND AIM: In an inception cohort study of 457 asthmatic children
      diagnosed at the age of 3 to 4 years, airway hyperresponsiveness (AHR) was
      assessed 6 years after first diagnosis in a subgroup of 84 children. Our
      objective was to associate the level of AHR with the symptomatic asthma status at
      follow-up. METHODS: Information on respiratory symptoms and medication use for
      the previous 6 years was obtained. Children with reported wheezing episodes
      during the previous year (n = 169) or for > or = 2 years at any time during the
      follow-up period (n = 85) were eligible for the challenge test. RESULTS: Among
      the 254 eligible children, 166 were randomly selected. The parents of 88 of them
      consented to have their child participate. At the time of assessment of AHR, 19
      children (22%) were asymptomatic and 24 others (29%) had symptoms but did not use
      any medication. Forty-one children (49%) were symptomatic and required
      medication, including antiinflammatory preparations in 26 instances (31%). All
      but two children had significant AHR. There was no significant association
      between the level of AHR and graded symptomatic and medication score. Twenty-four
      of the 70 children (34%) with greatly enhanced AHR used no medication.
      CONCLUSIONS: This study shows that (1) almost all children first diagnosed with
      asthma 6 years ago and with persisting but not necessarily current symptoms of
      asthma have increased AHR, which satisfies a proposed epidemiologic definition of
      asthma; (2) AHR was present in 95% of the 20 currently asymptomatic children; and
      (3) one third of children with greatly enhanced AHR did not use any treatment.

PMID- 10593792
TI  - Effects of itraconazole therapy in allergic bronchopulmonary aspergillosis.
AB  - STUDY OBJECTIVES: Allergic bronchopulmonary aspergillosis (ABPA) is the result of
      an immune reaction to antigens of Aspergillus fumigatus, which colonizes the
      bronchial lumen of affected individuals. Presently, the recommended treatment of
      ABPA, mainly for acute episodes of exacerbations, is administration of
      glucocorticoids. We initiated this study to analyze the effects of itraconazole
      on the clinical, biological, and functional parameters in patients with ABPA.
      PATIENTS: in this report, we describe the follow-up of 14 asthmatic patients who
      presented with ABPA. During the 2-year reference period (a 2-year period before
      the introduction of itraconazole), 14 patients were treated with inhaled
      corticosteroids and 12 of the 14 received oral glucocorticoids. During the
      itraconazole treatment period, the patients were treated with oral itraconazole,
      200 mg/d, for at least 12 months. RESULTS: During the 2-year reference period, no
      significant clinical, immunologic, and functional improvement was observed on a
      long-term basis. During the itraconazole treatment period, a clinical improvement
      was observed. Blood eosinophilia, serum total IgE levels, and serum precipitating
      antibodies against A fumigatus antigen significantly decreased. No decrease of
      specific IgE against A fumigatus spp was observed. All patients experienced a
      partial improvement in pulmonary function tests: FEV(1) significantly increased
      from 1,433 +/- 185 to 1,785 +/- 246 mL/s (p < 0.01). All patients successfully
      lowered oral glucocorticoid dose when receiving itraconazole. In 7 of 14 patients
      receiving itraconazole, the removal of oral glucocorticoids was possible.
      CONCLUSION: These results demonstrate the efficacy of itraconazole in ABPA in
      reducing or eliminating the need for glucocorticoid therapy, along with clinical,
      biological, and functional improvement.

PMID- 10593793
TI  - Management of airway manifestations of relapsing polychondritis: case reports and
      review of literature.
AB  - STUDY OBJECTIVE: To report the first series of patients with severe airway
      manifestations of relapsing polychondritis (RP) that were managed successfully
      with self-expandable metallic stents, and to review the literature. DESIGN:
      Retrospective review of medical records, and current clinical follow-up. SETTING:
      Tertiary care referral hospital. PATIENTS: All patients with airway
      manifestations of RP that were managed with self-expandable metallic stents at
      our institution. RESULTS: All five patients (four women and one man; age, 40 to
      69 years old) had severe airway manifestations, and three of them required
      mechanical ventilation. Spirometry with flow-volume curves showed severe combined
      obstructive and restrictive ventilatory defects. Bronchoscopy revealed dynamic
      collapse of the proximal airways. Diagnosis was made 8 months to 13 years after
      the first symptom of the disease. Pharmacotherapy included prednisone,
      methotrexate, cyclosporine, and dapsone. A total of 17 self-expandable metallic
      stents of varying sizes were placed using flexible bronchoscope from 4 to 19
      years after the first symptom. The overall outcome was favorable in four
      patients. Three patients have survived without ventilatory support 16 to 18
      months following the first stent placement, and the fourth patient survived for
      20 months without ventilatory support before she died. The fifth patient, who was
      receiving mechanical ventilation, died in 1 week probably due to persistent
      dynamic collapse of the airways distal to the stents. CONCLUSION: Self-expandable
      metallic tracheobronchial stents should be considered in the management of airway
      manifestations of RP, especially in patients who require mechanical ventilation.

PMID- 10593794
TI  - Vocal cord dysfunction in patients with exertional dyspnea.
AB  - STUDY OBJECTIVES: To evaluate patients for vocal cord dysfunction (VCD) in a
      military population presenting with symptoms of exertional dyspnea. DESIGN: Cross
      sectional, controlled study. SETTING: Pulmonary disease clinic at an army
      tertiary care center. PATIENTS: Forty military patients with complaints of
      exertional dyspnea and 12 military asymptomatic control subjects. INTERVENTION:
      Patients underwent direct visualization of vocal cords with flexible laryngoscopy
      before and after exercise to evaluate for presence of inspiratory vocal cord
      adduction. MEASUREMENTS AND RESULTS: Complete evaluation for all patients
      consisted of spirometry with flow-volume loops, lung volumes, diffusing capacity,
      and maximum voluntary ventilation at rest; chest radiograph; methacholine
      bronchoprovocation testing; and a maximal cardiopulmonary exercise test with
      expiratory gas analysis. Fifteen percent of patients studied prospectively were
      found to have VCD, whereas all control subjects were negative for VCD. There was
      minimal difference in pulmonary function testing between VCD-positive and VCD
      negative patients, whereas control subjects had higher spirometric values. Twenty
      percent of VCD-positive patients had abnormal flow-volume loops compared with 14%
      of patients without VCD, but after methacholine, 60% of VCD-positive patients
      developed abnormal flow-volume loops. In the VCD-positive group, 60% had a
      positive methacholine response, but there was less decrease in FEV(1)/FVC ratio
      compared with either VCD-negative patients or control subjects. CONCLUSIONS:
      Paradoxical inspiratory vocal cord closure is a frequent occurrence in patients
      with symptoms of exertional dyspnea and should be strongly considered in their
      evaluation.

PMID- 10593795
TI  - Recovery from blast lung injury: one-year follow-up.
AB  - BACKGROUND: Blast injury to the lung is one of the devastating threats facing
      victims of an explosion. Although the pathogenesis of blast injury has been
      studied, little is known about the long-term effects on lung function in
      survivors. OBJECTIVE: To examine the pulmonary function of survivors 1 year after
      sustaining a blast injury. DESIGN: Prospective study. SETTING: Pulmonary function
      test laboratory at Hadassah Medical Center, Jerusalem. PARTICIPANTS: Eleven
      surviving victims of a blast injury sustained during a bus terrorist explosion.
      MEASUREMENTS: Twelve months after the injury, physical examinations, lung
      function tests, and progressive cardiopulmonary exercise examinations were
      conducted, and chest radiographs were obtained. RESULTS: The average age was 28
      +/- 9.8 years. Most of the victims had multiple injuries in addition to the lung
      injury. Ten patients received mechanical ventilation, and 6 patients required
      chest drainage. All patients were treated in the ICU, with an average stay of
      11.8 +/- 9 days. The patients were discharged to their homes or to a
      rehabilitation center 32.4 +/- 27. 3 days after the explosion. One year later,
      none had any pulmonary-related complaints. Physical examination of the lungs was
      normal. Most of the patients demonstrated normal lung function tests and complete
      resolution of the chest radiograph findings. CONCLUSION: Most patients who
      survive lung blast injury will regain good lung function within a year.

PMID- 10593796
TI  - Percutaneous transtracheal jet ventilation: a safe, quick, and temporary way to
      provide oxygenation and ventilation when conventional methods are unsuccessful.
AB  - INTRODUCTION: Percutaneous transtracheal jet ventilation (PTJV) with a large-bore
      angiocath that is inserted through the cricothyroid membrane can provide
      immediate oxygenation from a high-pressure (50 lb per square inch) oxygen wall
      outlet, as well as ventilation by means of manual triggering. The objective of
      this retrospective study is to highlight the potential benefit of PTJV as a
      temporary lifesaving procedure during difficult situations when oral endotracheal
      intubation is unsuccessful and bag-valve-mask ventilation is ineffective for
      oxygenation during acute respiratory failure. METHODS: The medical records of 29
      consecutive patients who required emergent PTJV within the past 4 years were
      reviewed. PTJV was required because the pulse O(2) saturation could not be
      maintained at > 90% with bag-mask-valve ventilation and because the airway could
      not be secured quickly with direct laryngoscopy. RESULTS: The cricothyroid
      membrane was cannulated successfully in 23 patients. In these patients, pulse
      O(2) saturation was raised to > 90% and was maintained with PTJV until the airway
      was secured. All but 3 of the 23 patients were subsequently intubated orally. In
      one patient, PTJV maintained adequate gas exchange until an emergent tracheostomy
      was performed. In two patients, airway exchange catheters were inserted into the
      trachea due to a small glottic aperture. The endotracheal tube was slid over the
      catheter. In 6 of the 29 patients, there was difficulty inserting a catheter
      through the cricothyroid membrane or there was inability to insufflate the oxygen
      with a jet ventilator. There were no immediate fatalities from the use of PTJV.
      CONCLUSION: Based on the subsequent insertion of an endotracheal tube into the
      trachea, there were two important benefits in the patients who underwent PTJV
      successfully. First, PTJV provided effective oxygenation, while allowing adequate
      time for upper airway visualization and possible suctioning of oropharyngeal
      secretions. Second, tracheal intubation was subsequently easier, possibly because
      the high tracheal pressure from the gas insufflation opened the collapsed
      glottis, making visualization of the glottic aperture better. PTJV is safe and
      quick in providing immediate oxygenation, and therefore should be considered as
      an alternative to insistent, multiple intubation attempts, when neither bag-mask
      valve ventilation nor endotracheal intubation is feasible in providing adequate
      gas exchange.

PMID- 10593797
TI  - Electrical impedance tomography in the assessment of extravascular lung water in
      noncardiogenic acute respiratory failure.
AB  - STUDY OBJECTIVES: To establish the value of electrical impedance tomography (EIT)
      in assessing pulmonary edema in noncardiogenic acute respiratory failure (ARF),
      as compared to the thermal dye double indicator dilution technique (TDD). DESIGN:
      Prospective clinical study. SETTING: ICU of a general hospital. PATIENTS:
      Fourteen ARF patients. INTERVENTIONS: In order to use the TDD to determine the
      amount of extravascular lung water (EVLW), a fiberoptic catheter was placed in
      the femoral artery. MEASUREMENTS AND MAIN RESULTS: Fourteen consecutive ARF
      patients receiving mechanical ventilation were measured by EIT and TDD. EIT
      visualizes the impedance changes caused by the ventilation in two-dimensional
      image planes. An impedance ratio (IR) of the ventilation-induced impedance
      changes of a posterior and an anterior part of the lungs was used to indicate the
      amount of EVLW. For the 29 measurements in 14 patients, a significant correlation
      between EIT and TDD (r = 0. 85; p < 0.001) was found. The EIT reproducibility was
      good. The diagnostic value of the method was tested by receiver operator
      characteristic analysis, with 10 mL/kg of EVLW considered as the upper limit of
      normal. At a cutoff level of the IR of 0.64, the IR had a sensitivity of 93%, a
      specificity of 87%, and a positive predictive value of 87% for a supranormal
      amount of EVLW. Follow-up measurements were performed in 11 patients. A
      significant correlation was found between the changes in EVLW measured with EIT
      and TDD (r = 0.85; p < 0.005). CONCLUSION: We conclude that EIT is a noninvasive
      technique for reasonably estimating the amount of EVLW in noncardiogenic ARF.

PMID- 10593798
TI  - The utility of daily therapeutic thoracentesis for the treatment of early
      empyema.
AB  - STUDY OBJECTIVES: To determine if therapeutic thoracentesis is as effective as
      early chest tube placement or no drainage procedure in the treatment of early
      empyema in rabbits. DESIGN AND INTERVENTIONS: An empyema, as evidenced by gross
      pleural pus and a decreased pleural fluid pH and glucose level, was induced in 49
      rabbits. The rabbits were divided into three groups: 16 underwent daily
      therapeutic thoracentesis starting at 48 h, 14 underwent chest tube placement at
      48 h, and 19 served as controls. RESULTS: The mortality rate in the therapeutic
      thoracentesis group (0/16) did not differ significantly from that in the chest
      tube group (3/14) or that in the control group (6/19). At autopsy at 10 days, the
      gross empyema score in the therapeutic thoracentesis group (2.1 +/- 0.3) was
      significantly lower (p < 0.05) than that in the chest tube group (2. 8 +/- 0.3)
      or the control group (3.5 +/- 0.2). The mean pleural peel score of 5.8 +/- 1.1 in
      the therapeutic thoracentesis group was significantly less (p < 0.05) than the
      score for the nonintervention control group (13.4 +/- 1.6). CONCLUSIONS: From
      this study, we conclude that therapeutic thoracentesis is at least as effective
      as early chest tube placement for the treatment of early empyema using our rabbit
      model of empyema.

PMID- 10593799
TI  - Pulmonary neutrophil accumulation following human endotoxemia.
AB  - OBJECTIVE: To elucidate the role of pulmonary neutrophil accumulation in the
      pathogenesis of human acute lung injury (ALI) following endotoxemia. DESIGN:
      Retrospective study. SETTING: Surgical unit in a tertiary-care university
      hospital. PATIENTS: Thirty-three patients who died of intra-abdominal sepsis and
      received an autopsy. MEASUREMENTS: Just before each patient's death, (1) plasma
      endotoxin was determined by the limulus gelation test, and (2) the severity of
      ALI was estimated by the Murray lung injury score. (3) Neutrophil accumulation in
      the pulmonary microcirculation was evaluated in the autopsy specimens using a
      computerized picture analysis method. RESULTS: (1) Endotoxin-positive patients
      were more likely to fall into the severe lung injury group (endotoxin-positive
      patients, 38% vs endotoxin-negative patients, 0%; p < 0.01). (2) The endotoxin
      positive patients exhibited significantly higher neutrophil accumulation in the
      pulmonary microcirculation than endotoxin-negative patients (8,349 +/- 984/mm(2)
      vs 4,047 +/- 447/mm(2), respectively; p < 0.01). (3) Severe lung injury patients
      with endotoxemia had almost the same degree of neutrophil accumulation in the
      pulmonary microcirculation as mild-to-moderate lung injury patients with
      endotoxemia (8,338 +/- 1,622/mm(2) vs 8, 359 +/- 1,290/mm(2), respectively),
      showing a significant higher neutrophil accumulation compared to no lung injury
      patients without endotoxemia (5,102 +/- 410/mm(2); p < 0.01). CONCLUSION:
      Endotoxemia might cause ALI and pulmonary neutrophil accumulation. Pulmonary
      neutrophil accumulation might not be enough to cause severe lung injury (ARDS),
      although it is necessary to cause ALI, because the degree of pulmonary neutrophil
      accumulation did not correlate with the severity of ALI.

PMID- 10593800
TI  - The value and complications of percutaneous transthoracic lung aspiration for the
      etiologic diagnosis of community-acquired pneumonia.

PMID- 10593802
TI  - Rationale and design of The National Emphysema Treatment Trial: a prospective
      randomized trial of lung volume reduction surgery. The National Emphysema
      Treatment Trial Research Group.
AB  - The National Emphysema Treatment Trial is a multicenter, randomized clinical
      trial of medical therapy vs medical therapy plus lung volume reduction surgery
      (LVRS) for the treatment of patients with severe bilateral emphysema. LVRS will
      be accomplished by bilateral stapled excision via median sternotomy or video
      assisted thoracoscopic surgery. Every patient will complete 6 to 10 weeks of
      pulmonary rehabilitation prior to randomization and will participate in a
      maintenance program of pulmonary rehabilitation after randomization. The primary
      outcome to be assessed by the trial is survival. Additional outcomes to be
      assessed are maximum exercise capacity, pulmonary function, oxygen requirement,
      distance walked in 6 min, quality of life, respiratory symptoms, and health-care
      utilization and costs. In addition, selected clinics will evaluate lung mechanics
      and respiratory muscle function, partial and maximal flow-volume curves, gas
      exchange during maximal exercise, and right heart function. The trial is targeted
      to enroll patients with severe emphysema who have no significant comorbid
      conditions; each patient will be randomized to one of the two treatment groups.
      The study duration is 4.5 years with a close-out period of 6 months.

PMID- 10593801
TI  - Chronic glucocorticoid therapy-induced osteoporosis in patients with obstructive
      lung disease.
AB  - Long-term glucocorticoid (GC) therapy has been instrumental in decreasing
      morbidity and mortality in a variety of chronic inflammatory diseases, including
      persistent asthma. Long-term GC therapy is also widely prescribed for COPD. One
      of the important and often unrecognized side effects of chronic GC therapy is
      secondary osteoporosis. The risk of GC-induced bone loss is roughly correlated
      with daily dose, duration, and total cumulative lifetime dose of GC treatment.
      Oral prednisone increases the risk of bone loss and fracture. High doses of
      inhaled GCs may also increase the risk of osteopenia/osteoporosis, but the risk
      appears to be less than that associated with oral GCs. Hormone replacement
      therapy, oral and parenteral bisphosphonates, supplemental calcium and vitamin D,
      calcitonin, and fluoride compounds have been used, experimentally, in the
      management of GC-induced bone loss. Asthma and COPD specialists are key
      prescribers of oral and inhaled steroids and are likely to encounter patients
      with significant bone loss. Despite known risk factors and the availability of
      reliable diagnostic tools to recognize bone loss, the opportunity to slow,
      reverse, and treat bone loss is often missed. We present a review of the current
      literature regarding the incidence, treatment, and prevention of
      osteopenia/osteoporosis secondary to chronic GC therapy in adult asthma and COPD
      patients. Guidelines are presented regarding the identification of patients at
      risk for developing GC-induced secondary bone loss, and therapeutic alternatives
      are discussed.

PMID- 10593803
TI  - A pilot study of expiratory flow limitation and lung volume reduction surgery.
AB  - STUDY OBJECTIVES: To examine the relationships between changes in expiratory flow
      limitation (FL) during anesthesia and postoperative responses to lung volume
      reduction surgery (LVRS). DESIGN: Prospective consecutive case comparison.
      SETTING: University medical center. PATIENTS: Eight patients with severe
      emphysema. INTERVENTIONS: General anesthesia with muscle paralysis and thoracic
      epidural analgesia were provided for LVRS via median sternotomy. MEASUREMENTS:
      FEV(1), functional residual capacity (FRC), and total lung capacity (TLC) were
      measured preoperatively and 3 months postoperatively. Tidal volume (VT)
      flow/volume (F/V) curves were obtained with a Pitot-type spirometer. VT,
      expiratory flow rate at 0. 25 x VT (V'VT,25% ), and peak expiratory flow rate
      (V'VT,MAX) were obtained from VT F/V curves to derive V'VT,25%/V'VT,MAX ratio as
      a measure of FL. RESULTS: Closed chest VT F/V curves during anesthesia pre-LVRS
      showed four patients with FL (group A) whose V'VT,25%/V'VT, MAX ratio was 0.38 +/
      0.06 (mean +/- SD) and four patients without FL (group B) whose
      V'VT,25%/V'VT,MAX ratio was 0.82 +/- 0.06 (p = 0. 0001). Closed chest post-LVRS
      V'VT,25%/V'VT,MAX ratio during anesthesia increased by 0.48 +/- 0.08 in group A,
      compared with a 0. 19 +/- 0.16 reduction in group B (p = 0.0001). Preoperative
      FEV(1) was 0.57 +/- 0.10 L for group A vs 0.82 +/- 0.13 L for group B (p = 0.02).
      Postoperative FEV(1) increased by 67 +/- 40% for group A (p = 0.03) vs 29 +/- 21%
      for group B (not significant). FRC decreased by 33 +/- 3% for group A vs 17 +/-
      5% for group B (p = 0.0007), and FRC/TLC decreased by 0.14 +/- 0.05 for group A
      vs 0.01 +/- 0.07 for group B (p = 0.026). Post-LVRS V'VT,25%/V'VT,MAX ratio
      change during anesthesia correlated with postoperative reduction in FRC (r(2) =
      0. 89, p = 0.0004) and FRC/TLC (r(2) = 0.52, p = 0.045). CONCLUSION: Post-LVRS
      change in V'VT,25%/V'VT,MAX ratio during anesthesia showed a linear relationship
      with 3-month postoperative improvement in dynamic hyperinflation. Thus,
      V'VT,25%/V'VT,MAX ratio may help provide valuable insights into the interactions
      between chest wall recoil, dynamic hyperinflation, and VT flow rates in patients
      with severe COPD and LVRS.

PMID- 10593804
TI  - Transesophageal echocardiography in the diagnosis of diseases of the thoracic
      aorta: part 1. Aortic dissection, aortic intramural hematoma, and penetrating
      atherosclerotic ulcer of the aorta.

PMID- 10593805
TI  - The outcome of asthma related to workplace irritant exposures: a comparison of
      irritant-induced asthma and irritant aggravation of asthma.
AB  - STUDY OBJECTIVES: (1) To characterize workers' compensation claims accepted on
      the basis of new-onset asthma associated with accidental high respiratory
      irritant exposure at work; (2) to compare the frequency, characteristics, and
      outcomes in this group of workers to workers who were compensated for an
      exacerbation of preexisting asthma associated with accidental high respiratory
      irritant exposure at work. DESIGN: A retrospective review was performed of 469
      asthma claims accepted by the Ontario Workers' Compensation Board (WCB) between
      1984 and 1988. Among these, claims attributed to an accidental high respiratory
      irritant exposure at work were classified into two groups: one group with
      reported preexisting asthma prior to the exposure (accidental aggravation of
      asthma [AAA]) and another group with no previous history of asthma (irritant
      induced asthma [IIA]). RESULTS: Of the 469 claims, 89 subjects (19%) had symptoms
      related to accidental high respiratory irritant exposure in the workplace; of
      these, 68 subjects (76%) had AAA, 12 subjects (13%) had IIA, and 9 subjects (10%)
      had possible IIA but were excluded from the analysis because of insufficient
      data. Those with IIA had a longer duration of work-attributed symptoms (mean, 219
      +/- 208 days) than the subjects with AAA (mean, 32 +/- 38 days; p < 0.001). Nine
      subjects (75%) with IIA were no longer in the same work environment, while 47
      subjects in the AAA group (71%) were still in the same work environment (p <
      0.001). The most common triggering agent for subjects with IIA was an isocyanate
      spill; for those with AAA, the most common triggering agent was paint.
      CONCLUSIONS: The WCB-accepted claims related to accidental, high respiratory
      irritant exposure at work are more commonly assigned to the category of AAA than
      to IIA. IIA patients in this claimant group had a longer mean duration of work
      attributed respiratory symptoms, perhaps due to a need for a larger (and thus
      less common) irritant exposure to induce asthma in previously normal subjects.

PMID- 10593806
TI  - Clinical conference on management dilemmas: obstructive sleep apnea and
      respiratory failure.

PMID- 10593807
TI  - New pulmonary lesions during therapy for extrapulmonary tuberculosis.

PMID- 10593808
TI  - A 74-year-old man with chronic lymphocytic leukemia, cough, and a lung mass.

PMID- 10593809
TI  - Amnestic agents in pediatric bronchoscopy.
AB  - STUDY OBJECTIVE: To assess the risk for complications with the use of sedation
      and analgesia techniques in pediatric fiberoptic bronchoscopy. DESIGN: A
      retrospective case series. SETTING: The ICU of a 325-bed tertiary care research
      hospital. PATIENTS: Patients from 1 to 18 years of age who underwent fiberoptic
      bronchoscopy with BAL or transbronchial biopsy between June 1991 and December
      1995 and received IV sedation and analgesia. INTERVENTIONS: None. METHODS: A
      retrospective chart review was performed. Extracted data included anesthetics and
      sedatives used and their per kilogram dosages, procedure durations, and
      complications including oxygen desaturations < 90%, vital sign alterations that
      required intervention, and emergence reactions to ketamine. RESULTS: A total of
      103 bronchoscopies were performed on 64 patients. Ketamine was used as the
      primary anesthetic in 60 procedures (58%). A combination of fentanyl and
      midazolam was used in 38 of the 43 remaining procedures. A variety of
      combinations were used in the five remaining procedures. Complications occurred
      in 13 procedures and included oxygen desaturations, stridor, cough, apnea, and
      nasal bleeding. Twelve of the 13 complications occurred in patients with a
      diagnosis of HIV infection. Eight of the13 complications involved children < or =
      3 years of age. CONCLUSIONS: Pediatric bronchoscopy is a safe and valuable
      procedure. However, in this study, anesthetic selection was shown to adversely
      affect the complication rate in the subsets of children < or = 3 years of age and
      with an underlying diagnosis of HIV infection.

PMID- 10593810
TI  - Development of a giant bulla after lung volume reduction surgery.
AB  - Lung volume reduction surgery (LVRS) is being evaluated in the treatment of
      emphysema. The proposed mechanisms of improvement are increased elastic recoil of
      the lung and improved mechanical efficiency of the muscles of respiration. We
      report a unique patient with emphysema who developed a giant bulla 3 years
      subsequent to LVRS. The patient underwent extensive evaluation, including
      measurements of lung mechanics. Bullectomy was performed, but it was
      unsuccessful. Although the mechanisms behind the development of giant bullous
      disease remain speculative, heterogeneous improvement in elastic recoil following
      LVRS may be one of the responsible mechanisms.

PMID- 10593811
TI  - Endobronchial metastasis from osteosarcoma of bone: treatment with intraluminal
      radiotherapy.
AB  - Lung parenchymal metastases are common manifestations in patients with
      osteosarcoma; however, spread to the major airway itself is extremely rare. We
      present a young man who had been previously treated with surgical resection
      following preoperative chemotherapy and immediate postsurgical adjuvant
      chemotherapy for proximal tibial osteosarcoma. He developed metastasis to the
      major airways. The patient was treated with intraluminal radiotherapy (ILT) for
      the endobronchial metastasis. This is the first report of an endobronchial
      osteosarcoma that was treated with ILT with a complete endoscopic response. ILT
      provided excellent palliation in this particular case.

PMID- 10593812
TI  - Extensive mediastinal lymphadenopathy in an adult immunocompetent woman caused by
      Mycobacterium avium complex.
AB  - We report a case of extensive mediastinal lymphadenopathy in a 29-year-old
      immunocompetent woman, which was thought to be caused by Mycobacterium
      tuberculosis (MTB). Chest radiographs showed deterioration while the patient was
      receiving antituberculous medication for 8 months. After isolation of
      Mycobacterium avium complex (MAC) from a lymph node aspiration biopsy and switch
      to a MAC-specific therapeutic regimen, the lesion almost completely disappeared
      within 1 year. To our knowledge, this is the first report of an extensive
      mediastinal lymphadenopathy caused by MAC in an immunocompetent adult.

PMID- 10593813
TI  - Saphenous vein graft infection: a fatal complication of postoperative
      mediastinitis.
AB  - Infection and erosion of the saphenous vein graft with mediastinal hemorrhage is
      a rare but highly lethal complication of cardiac surgery. This is associated with
      a mortality rate of 50%. We present a patient who died during the postoperative
      period due to this complication.

PMID- 10593814
TI  - Successful treatment of prosthetic aortic valve mucormycosis.
AB  - Mucor endocarditis after cardiovascular surgery is rare and usually fatal. We
      report the first known case of prosthetic aortic valve mucormycosis in a patient
      without predisposing risk factors who was successfully treated using a
      combination of early antifungal drug therapy and surgical removal of infected
      material.

PMID- 10593815
TI  - Can pleural effusions cause cardiac tamponade?
AB  - Pleural effusion(s) can increase the pressure of an otherwise insignificant
      pericardial effusion to a degree that can result in cardiac tamponade. The case
      histories presented here illustrate the importance of recognizing this phenomenon
      and altering our treatment algorithm to drain the pleural effusions instead of
      the pericardial collections.

PMID- 10593816
TI  - Pine oil ingestion: a common cause of poisoning.
AB  - Pine oil is a common component of household cleaning solutions. We present the
      case of an elderly woman with dementia who ingested a household cleaning solution
      that contained pine oil and review the treatment of pine oil ingestion. The
      patient developed CNS depression and respiratory failure that required intubation
      and mechanical ventilation. A chest radiograph revealed diffuse alveolar
      interstitial infiltrates consistent with pneumonitis. The patient improved with
      supportive care. However, she developed nosocomial pneumonia, sepsis, and
      multiple organ failure and subsequently died. This case is illustrative of the
      increased risk for ingestion of toxic household compounds in the growing
      population of elderly and demented individuals, who are being cared for in the
      home. Pine oil ingestions are one of the most common accidental ingestions
      encountered in clinical practice. Clinical features of ingestion include
      depressed mentation, respiratory failure, and GI dysfunction. The treatment is
      supportive, and the ingestions are rarely fatal.

PMID- 10593817
TI  - Exacerbation of acute pulmonary edema during assisted mechanical ventilation
      using a low-tidal volume, lung-protective ventilator strategy.
AB  - STUDY OBJECTIVES: To assess the magnitude of negative intrathoracic pressure
      development in a patient whose pulmonary edema acutely worsened immediately
      following the institution of a low-tidal volume (VT) strategy. DESIGN: Mechanical
      lung modeling of patient-ventilator interactions based on data from a case
      report. SETTING: Medical ICU and laboratory. PATIENT: A patient with suspected
      ARDS and frank pulmonary edema. INTERVENTIONS: The patient's pulmonary mechanics
      and spontaneous breathing pattern were measured. Samples of arterial blood and
      pulmonary edema fluid were obtained. MEASUREMENTS: A standard work-of-breathing
      lung model was used to mimic the ventilator settings, pulmonary mechanics, and
      spontaneous breathing pattern observed when pulmonary edema worsened. Comparison
      of the pulmonary edema fluid-to-plasma total protein concentration ratio was
      made. RESULTS: The patient's spontaneous VT demand was greater than preset. The
      lung model revealed simulated intrathoracic pressure changes consistent with
      levels believed necessary to produce pulmonary edema during obstructed breathing.
      A high degree of imposed circuit-resistive work was found. The pulmonary edema
      fluid-to-plasma total protein concentration ratio was 0.47, which suggested a
      hydrostatic mechanism. CONCLUSION: Ventilator adjustments that greatly increase
      negative intrathoracic pressure during the acute phase of ARDS may worsen
      pulmonary edema by increasing the transvascular pressure gradient. Therefore,
      whenever sedation cannot adequately suppress spontaneous breathing (and muscle
      relaxants are contraindicated), a low-VT strategy should be modified by using a
      pressure-regulated mode of ventilation, so that imposed circuit-resistive work
      does not contribute to the deterioration of the patient's hemodynamic and
      respiratory status.

PMID- 10593818
TI  - Low-molecular-weight heparin for unstable angina.

PMID- 10593820
TI  - A voice from a modern hospital

PMID- 10593819
TI  - Classic, abbreviated, and modified Light's criteria: the end of the story?

PMID- 10593821
TI  - Should a cytologic study be ordered in transudative pleural effusions?

PMID- 10593822
TI  - Substitution of arm span for standing height is important for the assessment of
      predicted value of lung volumes in elderly people with osteoporosis.

PMID- 10593823
TI  - Chronic diaphragmatic hernia.

PMID- 10593824
TI  - Carcinoid-related intrapulmonary shunting may be associated with increased
      production of nitric oxide.

PMID- 10593825
TI  - Monitoring of tissue pH: the critical measurement.

PMID- 10593826
TI  - Screening of tuberculosis: is it a real prediction model?

PMID- 10593827
TI  - Bacteremic community-acquired pneumonia in an immunocompetent adult due to
      Burkholderia cepacia.

PMID- 10593828
TI  - Catamenial pneumothorax and its relation to the peritoneal stomata of the
      diaphragm.

PMID- 10593829
TI  - Safety of neuraxial anesthesia in patients receiving perioperative low-molecular
      weight heparin for thromboprophylaxis.

PMID- 10593830
TI  - Perioperative cardiopulmonary evaluation and management: are we ignoring
      obstructive sleep apnea syndrome?

PMID- 10593831
TI  - Allergic bronchopulmonary aspergillosis or bronchopulmonary aspergillosis with
      asthma: which one is more appropriate?

PMID- 10593857
TI  - Studies of the molecular mechanisms in the regulation of telomerase activity.
AB  - Telomerase, a specialized RNA-directed DNA polymerase that extends telomeres of
      eukaryotic chromosomes, is repressed in normal human somatic cells but is
      activated during development and upon neoplasia. Whereas activation is involved
      in immortalization of neoplastic cells, repression of telomerase permits
      consecutive shortening of telomeres in a chromosome replication-dependent
      fashion. This cell cycle-dependent, unidirectional catabolism of telomeres
      constitutes a mechanism for cells to record the extent of DNA loss and cell
      division number; when telomeres become critically short, the cells terminate
      chromosome replication and enter cellular senescence. Although neither the
      telomere signaling mechanisms nor the mechanisms whereby telomerase is repressed
      in normal cells and activated in neoplastic cells have been established,
      inhibition of telomerase has been shown to compromise the growth of cancer cells
      in culture; conversely, forced expression of the enzyme in senescent human cells
      extends their life span to one typical of young cells. Thus, to switch telomerase
      on and off has potentially important implications in anti-aging and anti-cancer
      therapy. There is abundant evidence that the regulation of telomerase is
      multifactorial in mammalian cells, involving telomerase gene expression, post
      translational protein-protein interactions, and protein phosphorylation. Several
      proto-oncogenes and tumor suppressor genes have been implicated in the regulation
      of telomerase activity, both directly and indirectly; these include c-Myc, Bcl-2,
      p21(WAF1), Rb, p53, PKC, Akt/PKB, and protein phosphatase 2A. These findings are
      evidence for the complexity of telomerase control mechanisms and constitute a
      point of departure for piecing together an integrated picture of telomerase
      structure, function, and regulation in aging and tumor development-Liu, J.-P.
      Studies of the molecular mechanisms in the regulation of telomerase activity.

PMID- 10593858
TI  - Specificity, diversity, and regulation in TGF-beta superfamily signaling.
AB  - Transforming growth factor-beta (TGF-beta) superfamily members are
      multifunctional cell-cell signaling proteins that play pivotal roles in tissue
      homeostasis and development of multicellular animals. They mediate their
      pleiotropic effects from membrane to nucleus through distinct combinations of
      type I and type II serine/threonine kinase receptors and their downstream
      effectors, known as Smad proteins. Certain Smads, termed receptor-regulated
      Smads, become phosphorylated by activated type I receptors and form heteromeric
      complexes with a common-partner Smad4, which translocates into the nucleus to
      control gene transcription. In addition to these signal transducing Smads,
      inhibitory Smads have been identified that inhibit the activation of receptor
      regulated Smads. In contrast to the still growing TGF-beta superfamily (with
      approximately 30 members in mammals), relatively few type I and type II receptors
      as well as Smads have been identified. We will focus on recent insights into the
      molecular mechanisms by which signaling specificity between different TGF-beta
      superfamily members is achieved and regulated, and how a single family member can
      elicit a broad scala of biological responses.-Piek, E., Heldin, C.-H., ten Dijke,
      P. Specificity, diversity, and regulation in TGF-beta superfamily signaling.

PMID- 10593859
TI  - Regulation of the expression of the inflammatory nitric oxide synthase (NOS2) by
      cyclic AMP.
AB  - The enzyme nitric oxide synthase 2 (NOS2), often called inducible NOS, plays a
      central role in the inflammatory reactions that follow infection or tissue
      damage. NOS2 has been detected in virtually every cell type, and the NO it
      produces can perform both beneficial and detrimental actions. It is thus
      conceivable that regulatory mechanisms exist which control the timing and
      intensity of NO production by NOS2 in order to outweigh protective effects
      against detrimental ones. Since cyclic AMP inhibits numerous immunological
      reactions, studies have been carried out to determine whether cAMP-dependent
      pathways could inhibit NOS2 expression as well. Pharmacological studies in
      cultured cells show that, depending on the cell type examined, increased cAMP can
      exert opposite effects on the endotoxin- or cytokine-induced expression of NOS2,
      being either stimulatory or inhibitory in macrophages, stimulatory in adipocytes,
      smooth muscle, skeletal muscle, and brain endothelial cells, and inhibitory in
      pancreatic, liver, and brain glial cells. Regulation of NOS2 gene transcription
      appears to be the primary mechanism of action of cAMP, and whether it is
      stimulatory or inhibitory hinges on the cell-specific regulation of transcription
      factors including CREB, NF-kappaB, and C/EBP. Cyclic AMP must therefore be
      considered a modulator rather than a suppressor of NOS2 expression. This review
      summarizes evidence derived from in vitro studies, considers regulation of NOS2
      by cAMP in vivo, and discusses possible therapeutic applications of cAMP
      treatment.-Galea, E., Feinstein, D. L. Regulation of the expression of the
      inflammatory nitric oxide synthase (NOS2) by cyclic AMP.

PMID- 10593860
TI  - The effect of increased intakes of polyunsaturated fatty acids and vitamin E on
      DNA damage in human lymphocytes.
AB  - The effect of increasing dietary intakes of polyunsaturated fatty acids (PUFAs)
      and vitamin E on indices of oxidative DNA damage was investigated. Twenty-one
      healthy male, nonsmokers aged 28.9 +/- 1.3 years participated in a free-living,
      split plot/change over trial in which half the volunteers consumed diets
      containing 5% PUFA as food energy for 4 wk and, after a 10 wk washout period,
      consumed a 15% PUFA diet for another 4 wk. The other volunteers followed an
      identical protocol, except that they consumed the 15% PUFA diet first. The diets
      were provided to volunteers either with or without an additional 80 mg dalpha
      tocopherol acetate/day; otherwise total fat, carbohydrates, protein, and basal
      vitamin E contents remained unchanged. DNA damage induced by 200 microM H(2)O(2)
      in lymphocytes from volunteers as well as endogenous DNA damage in the form of
      oxidized pyrimidines, measured by alkaline single-cell gel electrophoresis (the
      comet assay), significantly decreased after consumption of the 5% PUFA diet
      (P<0.001 and P=0.01, respectively), but significantly increased after consumption
      of the 15% PUFA diet when alpha-tocopherol levels were in the range of 5-7 mg/day
      (P=0. 008 and P=0.03, respectively). These changes were abolished by an
      additional 80 mg dalpha-tocopherol/day. This study indicates that increasing
      dietary levels of PUFA to 15% may adversely affect some indices of DNA stability.
      However, increasing the dietary intake of vitamin E by 80 mg/day ameliorates the
      damaging effects of PUFA. -Jenkinson, A. McE., Collins, A. R., Duthie, S. J.,
      Wahle, K. W. J., Duthie, G. G. The effect of increased intakes of polyunsaturated
      fatty acids and vitamin E on DNA damage in human lymphocytes.

PMID- 10593862
TI  - Increased glucose disposal induced by adenovirus-mediated transfer of glucokinase
      to skeletal muscle in vivo.
AB  - In non-insulin-dependent diabetes mellitus, insulin-stimulated glucose uptake is
      impaired in muscle, contributing in a major way to development of hyperglycemia.
      We previously showed that expression of the glucose phosphorylating enzyme
      glucokinase (GK) in cultured human myocytes improved glucose storage and
      disposal, suggesting that GK delivery to muscle in situ could potentially enhance
      glucose clearance. Here we have tested this idea directly by intramuscular
      delivery of an adenovirus containing the liver GK cDNA (AdCMV-GKL) into one hind
      limb. We injected an adenovirus containing the beta-galactosidase gene (AdCMV
      lacZ) into the hind limb of newborn rats. beta-Galactosidase activity was
      localized in muscle for as long as 1 month after delivery, with a large
      percentage of fibers staining positive in the gastrocnemius. Using the same
      approach with AdCMV-GKL, GK protein content was increased from zero to 50-400% of
      the GK in normal liver sample, and total glucose phosphorylating activity was
      increased in GK-expressing muscles relative to the counterpart uninfected muscle.
      Expression of GK in muscle improved glucose tolerance rather than changing basal
      glycemic control. Glucose levels were reduced by approximately 35% 10 min after
      administration of a glucose bolus to fed animals treated with AdCMV-GKL relative
      to AdCMV-lacZ-treated controls. The enhanced rate of glucose clearance was
      reflected in increases in muscle 2-deoxy glucose uptake and blood lactate levels.
      We conclude that restricted expression of GK in muscle leads to an enhanced
      capacity for muscle glucose disposal and whole body glucose tolerance under
      conditions of maximal glucose-insulin stimulation, suggesting that under these
      conditions glucose phosphorylation becomes rate-limiting. Our findings also show
      that gene delivery to a fraction of the whole body is sufficient to improve
      glucose disposal, providing a rationale for the development of new therapeutic
      strategies for treatment of diabetes.-Jimenez-Chillaron, J. C., Newgard, C. B.,
      Gomez-Foix, A. M. Increased glucose disposal induced by adenovirus-mediated
      transfer of glucokinase to skeletal muscle in vivo.

PMID- 10593861
TI  - Nitric oxide and cGMP regulate gene expression in neuronal and glial cells by
      activating type II cGMP-dependent protein kinase.
AB  - Nitric oxide (NO) and cGMP have been implicated in many neuronal functions,
      including regulation of gene expression, but little is known about the downstream
      targets of NO/cGMP in the nervous system. We found that type II cGMP-dependent
      protein kinase (G-kinase), which is widely expressed in the brain, mediated NO-
      and cGMP-induced activation of the fos promoter in cells of neuronal and glial
      origin; the enzyme was ineffective in regulating gene expression in fibroblast
      like cells. The effect of G-kinase II on gene expression did not require calcium
      uptake but was synergistically enhanced by calcium. G-kinase II was membrane
      associated and did not translocate to the nucleus; however, a soluble G-kinase II
      mutant translocated to the nucleus and regulated gene expression in fibroblast
      like cells. Soluble G-kinase I also regulates fos promoter activity, but membrane
      targeting of G-kinase I prevented the enzyme from translocating to the nucleus
      and regulating transcription in multiple cell types, including glioma cells; this
      suggests that cell type-specific factor(s) that mediate the transcriptional
      effects of extranuclear G-kinase II are not regulated by G-kinase I. Our results
      suggest that G-kinase I and II control gene expression by different mechanisms
      and that NO effects on neuronal plasticity may involve G-kinase II regulation of
      gene expression.-Gudi, T., Hong, G. K.-P., Vaandrager, A. B., Lohmann, S. M.,
      Pilz, R. B. Nitric oxide and cGMP regulate gene expression in neuronal and glial
      cells by activating type II cGMP-dependent protein kinase.

PMID- 10593863
TI  - Signaling from beta-adrenoceptor to L-type calcium channel: identification of a
      novel cardiac protein kinase A target possessing similarities to AHNAK.
AB  - A novel calcium channel-associated protein of approximately 700 kDa has been
      identified in mammalian cardiomyocytes that undergoes substantial cAMP-dependent
      protein kinase (PKA) phosphorylation. It was therefore designated as
      phosphoprotein 700 (pp700). The pp700 interacts specifically with the beta(2)
      subunit of cardiac L-type calcium channels as revealed by coprecipitation
      experiments using affinity-purified antibodies against different calcium channel
      subunits. It is surprising that amino acid sequence analysis of pig pp700
      revealed homology to AHNAK-encoded protein, which was originally identified in
      human cell lines of neural crest origin as 700-kDa phosphoprotein. Cardiac AHNAK
      expression was assessed on mRNA level by reverse transcriptase-polymerase chain
      reaction. Sequence-directed antibodies raised against human AHNAK recognized
      pp700 in immunoblotting and immunoprecipitation experiments, confirming the
      homology between both proteins. Anti-AHNAK antibodies labeled preferentially the
      plasma membrane of cardiomyocytes in cryosections of rat cardiac tissue and
      isolated cardiomyocytes. Sarcolemmal pp700/AHNAK localization was not influenced
      by stimulation of either the PKA or the protein kinase C pathway. In back
      phosphorylation studies with cardiac biopsies, we identified distinct pp700
      pools. The membrane-associated fraction of pp700 underwent substantial in vivo
      phosphorylation on beta-adrenergic receptor stimulation by isoproterenol, whereas
      the cytoplasmic fraction of pp700 was not accessible to endogenous PKA. It is
      important that in vivo phosphorylation occurred in that pp700 fraction which
      coprecipitated with the calcium channel beta subunit. We hypothesize that both
      phosphorylation of pp700 and its coupling to the beta subunit play a
      physiological role in cardiac beta-adrenergic signal transduction. Haase, H.,
      Podzuweit, T., Lutsch, G., Hohaus, A., Kostka, S., Lindschau, C., Kott, M.,
      Kraft, R., Morano, I. Signaling from beta-adrenoceptor to L-type calcium channel:
      identification of a novel cardiac protein kinase A target that has similarities
      to AHNAK.

PMID- 10593864
TI  - Low cellular IRS 1 gene and protein expression predict insulin resistance and
      NIDDM.
AB  - We examined the gene and protein expression of IRS 1 (insulin receptor substrate
      1) in adipocytes from two groups of healthy individuals with an increased
      propensity for non-insulin-dependent diabetes mellitus (NIDDM): those with two
      first-degree relatives with diabetes and another group with massive obesity. A
      low expression of IRS 1 (</=50% of the matched control group) was seen in
      approximately 30% of both groups and these individuals were characterized by
      insulin resistance and its hallmarks: higher levels of insulin, glucose, and
      triglycerides. Two individuals with previously unknown NIDDM were diagnosed and
      both had low IRS 1 expression. Low IRS 1 protein expression was associated with
      low mRNA levels but not with the common Gly972Arg polymorphism of the IRS 1 gene.
      Taken together, our present and previous findings show that a low expression of
      IRS 1 in fat cells predicts insulin resistance and NIDDM. Furthermore, they
      support the likelihood that an impaired transcriptional activation may play a key
      role in the pathogenesis of NIDDM.-Carvalho, E., Jansson, P.-A., Axelsen, M.,
      Eriksson, J. W., Huang, X., Groop, L., Rondinone, C., Sjostrom, L., Smith, U. Low
      cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM.

PMID- 10593865
TI  - The glutamate receptor antagonist MK801 modulates bone resorption in vitro by a
      mechanism predominantly involving osteoclast differentiation.
AB  - Recent identification in bone of transporters, receptors, and components of
      synaptic signaling suggests a role for glutamate in the skeleton. We investigated
      effects of glutamate and its antagonist MK801 on osteoclasts in vitro. Glutamate
      applied to patch clamped osteoclasts induced significant increases in whole-cell
      membrane currents (P<0.01) in the presence of the coagonist glycine. Agonist
      elicited currents were significantly decreased after application of MK801 (100
      microM, P<0.01), but MK801 had no effect on actin ring formation necessary for
      osteoclast polarization, attachment, and resorption. In cocultures of bone marrow
      cells and osteoblasts in which osteoclasts develop, MK801 inhibited osteoclast
      differentiation and reduced resorption of pits in dentine (3 to 100 microM;
      P<0.001). MK801 added early in the culture (for as little as 2-4 days) was as
      effective as addition for the entire culture period. Addition of MK801 for any
      time after day 7 of culture was ineffective in reducing osteoclast activity.
      Using rat and rabbit mature osteoclasts cultured on dentine or explants of mouse
      calvariae prelabeled with (45)Ca, we could not detect significant effects of
      MK801 on osteoclastic resorption. These data show clearly that glutamate receptor
      function is critical during osteoclastogenesis and suggest that glutamate is less
      important in regulating mature osteoclast activity.-Peet, N. M., Grabowski, P.
      S., Laketic-Ljubojevic, I., Skerry, T. M. The glutamate receptor antagonist MK801
      modulates bone resorption in vitro by a mechanism predominantly involving
      osteoclast differentiation.

PMID- 10593866
TI  - HGF triggers activation of the COX-2 gene in rat gastric epithelial cells: action
      mediated through the ERK2 signaling pathway.
AB  - Although it is established that growth factors and prostaglandins function in the
      maintenance of gastric mucosal integrity and in the healing of gastric mucosal
      injury and ulceration, the regulatory relationship between growth factors and
      prostaglandins in the gastric mucosa is not well characterized. Therefore, we
      investigated whether hepatocyte growth factor (HGF) affects expression of COX-2
      (the inducible form of the prostaglandin synthesizing enzyme, cyclooxygenase) in
      gastric epithelial cells and whether this action is mediated through the MAP
      (ERK) kinase signaling pathway. In RGM1 cells (an epithelial cell line derived
      from normal rat gastric mucosa), HGF caused an increase in COX-2 mRNA and protein
      by 236% and 175%, respectively (both P<0.05). This induction of COX-2 expression
      was abolished by pretreatment with the MAPK kinase (MEK) inhibitor PD98059. HGF
      also triggered a 13-fold increase in c-Met/HGF receptor phosphorylation (P<0.005)
      and increased ERK2 activity by 684% (P<0.01). Pretreatment with PD98059 abolished
      the HGF-induced increase in ERK2 activity, but not c-Met/HGF receptor
      phosphorylation. The specific inhibitor of p38 MAP kinase, SB203580, had no
      effect on HGF-induced COX-2 expression. Thus, HGF triggers activation of the COX
      2 gene in gastric epithelial cells through phosphorylation of c-Met/HGF receptor
      and activation of the ERK2 signaling pathway.-Jones, M. K., Sasaki, E., Halter,
      F., Pai, R., Nakamura, T., Arakawa, T., Kuroki, T., Tarnawski, A. S. HGF triggers
      activation of the COX-2 gene in rat gastric epithelial cells: action mediated
      through the ERK2 signaling pathway.

PMID- 10593867
TI  - Interleukin-18 acts as an angiogenesis and tumor suppressor.
AB  - Interleukin-18 (IL-18), also called interferon-gamma (IFN-gamma)-inducing factor,
      has recently been characterized as a potent IFN-gamma-inducing cytokine. We now
      report that IL-18 is a novel antiangiogenic and antitumor cytokine. In vitro, IL
      18 specifically inhibits fibroblast growth factor-2-stimulated proliferation of
      capillary endothelial cells. In vivo, IL-18 is sufficiently potent to suppress
      the fibroblast growth factor-induced corneal neovascularization by systemic
      administration in mice. This cytokine also inhibits embryonic angiogenesis in the
      chick chorioallantoic membrane assay. Systemic and intralesional administrations
      of IL-18 produce a significant suppression of the growth of murine T241
      fibrosarcoma in syngeneic C57Bl6/J and immunodeficient SCID mice. The antitumor
      effect appears to be potent because an average of >75% inhibition of primary
      tumor growth was observed at a dose of 50 microg/kg/day. In cell culture, murine
      T241 fibrosarcoma cells are insensitive to recombinant IL-18 at concentrations
      that significantly inhibit endothelial cell proliferation. Immunohistochemical
      studies of tumor tissues reveal hypovascularization of the IL-18-treated tumors.
      These results suggest that IL-18 may participate in the regulation of a switch of
      tumor angiogenesis.-Cao, R., Farnebo, J., Kurimoto, M., Cao, Y. Interleukin-18
      acts as an angiogenesis and tumor suppressor.

PMID- 10593868
TI  - Epstein-Barr virus envelope glycoprotein gp350 induces NF-kappaB activation and
      IL-1beta synthesis in human monocytes-macrophages involving PKC and PI3-K.
AB  - Epstein-Barr virus (EBV) is a highly immunotropic human herpesvirus with
      oncogenic potential and is involved in numerous pathologies. EBV utilizes its
      major envelope glycoprotein gp350 to bind to its receptor CR2/CD21 on target
      cells for initiating the infection. We have previously shown that EBV is able to
      modulate transcription and translation of a number of cytokine genes via its
      gp350-mediated binding to this receptor. However, the effects of the binding of
      purified gp350 to CR2/CD21 on plastic-adherent monocyte-macrophages (AMM) have
      not been investigated. These cells are a rich source of potent proinflammatory
      and immune-modulating cytokines, and express low levels of CR2/CD21. We show here
      for the first time that recombinant gp350 (rgp350) causes production of the
      potent proinflammatory cytokine IL-1beta in human AMM. Surprisingly, rgp350 is
      comparable in this capacity to the phorbol ester 12-0-tetradecanoylphorbol 13
      acetate. This induction of IL-1beta production was accompanied by increased
      steady-state levels of its mRNA in gp350-treated AMM, and was dependent on the
      specific binding of rgp350 to the EBV receptor CR2/CD21. We also show that the
      signaling pathways resulting in the induction of IL-1beta synthesis by rgp350
      required protein kinase C and phosphatidylinositol 3,4,5 triphosphate kinase
      activities and occurred via activation of the NF-kappaB family of transcription
      factors.-D'Addario, M., Ahmad, A., Xu, J. W., Menezes, J. Epstein-Barr virus
      envelope glycoprotein gp350 induces NF-kappaB activation and IL-1beta synthesis
      in human monocytes-macrophages involving PKC and PI3-K.

PMID- 10593869
TI  - Incorporation of heparin-binding peptides into fibrin gels enhances neurite
      extension: an example of designer matrices in tissue engineering.
AB  - The goal of this work was to improve the potential of fibrin to promote nerve
      regeneration by enzymatically incorporating exogenous neurite-promoting heparin
      binding peptides. The effects on neurite extension of four different heparin
      binding peptides, derived from the heparin-binding domains of antithrombin III,
      neural cell adhesion molecule and platelet factor 4, were determined. These
      exogenous peptides were synthesized as bi-domain peptide chimeras, with the
      second domain being a substrate for factor XIIIa. This coagulation
      transglutaminase covalently bound the peptides within the fibrin gel during
      coagulation. The heparin-binding peptides enhanced the degree of neurite
      extension from embryonic chick dorsal root ganglia through 3-dimensional fibrin
      gels, and the extent of enhancement was found to correlate positively with the
      heparin-binding affinity of the individual domains. The enhancement could be
      inhibited by competition with soluble heparin, by degradation of cell-surface
      proteoglycans, and by inhibition of the covalent immobilization of the peptide.
      These results demonstrate an important potential role for proteoglycan-binding
      components of the extracellular matrix in neurite extension and suggest that
      fibrin gels modified with covalently bound heparin-binding peptides could serve
      as a therapeutic agent to enhance peripheral nerve regeneration through nerve
      guide tubes. More generally, the results demonstrate that the biological
      responses to fibrin, the body's natural wound healing matrix, can be dramatically
      improved by the addition of exogenous bioactive peptides in a manner such that
      they become immobilized during coagulation.-Sakiyama, S. E., Schense, J. C.,
      Hubbell, J. A. Incorporation of heparin-binding peptides into fibrin gels
      enhances neurite extension: an example of designer matrices in tissue
      engineering.

PMID- 10593870
TI  - Mitotic signaling by beta-amyloid causes neuronal death.
AB  - Aggregates of beta-amyloid peptide (betaAP), the main constituent of amyloid
      plaques in Alzheimer's brain, kill neurons by a not yet defined mechanism,
      leading to apoptotic death. Here, we report that both full-length betaAP((1-40))
      or ((1-42)) and its active fragment betaAP((25-35)) act as proliferative signals
      for differentiated cortical neurons, driving them into the cell cycle. The cycle
      followed some of the steps observed in proliferating cells, including induction
      of cyclin D1, phosphorylation of retinoblastoma, and induction of cyclin E and A,
      but did not progress beyond S phase. Inactivation of cyclin-dependent protein
      kinase-4 or -2 prevented both the entry into S phase and the development of
      apoptosis in betaAP((25-35))-treated neurons. We conclude that neurons must cross
      the G1/S transition before succumbing to betaAP signaling, and therefore multiple
      steps within this pathway may be targets for neuroprotective agents.-Copani, A.,
      Condorelli, F., Caruso, A., Vancheri, C., Sala, A., Giuffrida Stella, A. M.,
      Canonico, P. L., Nicoletti, F., Sortino, M. A. Mitotic signaling by beta-amyloid
      causes neuronal death.

PMID- 10593871
TI  - Annexin I modulates cell functions by controlling intracellular calcium release.
AB  - Annexin I is an intracellular protein in search of a function. Ex vivo it has
      calcium- and phospholipid-binding properties. To evaluate its role in vivo, MCF-7
      cells were stably transfected with annexin I in sense or antisense orientations.
      In cells overexpressing annexin I, calcium release was abrogated on stimulation
      of purinergic or bradykinin receptors, whereas non-transfected cells or cells
      with down-regulated annexin I released calcium within seconds. Basal calcium and
      calcium stores were not affected. The impaired calcium release was paralleled by
      a down-regulation of the activities of phospholipase C, group II phospholipase
      A2, and E-cadherin with altered adhesion and enhanced tumor growth on soft agar.
      Significantly smaller tumors, with the histologically most differentiated cells,
      were observed in nude mice inoculated with cells transfected with the antisense
      rather than with the sense plasmid. These observations indicate that annexin I
      modulates cell functions by controlling intracellular calcium release. Frey, B.
      M., Reber, B. F. X., Vishwanath, B. S., Escher, G., Frey, F. J. Annexin I
      modulates cell functions by controlling intracellular calcium release.

PMID- 10593872
TI  - Postexercise glucose uptake and glycogen synthesis in skeletal muscle from GLUT4
      deficient mice.
AB  - To determine the role of GLUT4 on postexercise glucose transport and glycogen
      resynthesis in skeletal muscle, GLUT4-deficient and wild-type mice were studied
      after a 3 h swim exercise. In wild-type mice, insulin and swimming each increased
      2-deoxyglucose uptake by twofold in extensor digitorum longus muscle. In
      contrast, insulin did not increase 2-deoxyglucose glucose uptake in muscle from
      GLUT4-null mice. Swimming increased glucose transport twofold in muscle from fed
      GLUT4-null mice, with no effect noted in fasted GLUT4-null mice. This exercise
      associated 2-deoxyglucose glucose uptake was not accompanied by increased cell
      surface GLUT1 content. Glucose transport in GLUT4-null muscle was increased 1.6
      fold over basal levels after electrical stimulation. Contraction-induced glucose
      transport activity was fourfold greater in wild-type vs. GLUT4-null muscle.
      Glycogen content in gastrocnemius muscle was similar between wild-type and GLUT4
      null mice and was reduced approximately 50% after exercise. After 5 h
      carbohydrate refeeding, muscle glycogen content was fully restored in wild-type,
      with no change in GLUT4-null mice. After 24 h carbohydrate refeeding, muscle
      glycogen in GLUT4-null mice was restored to fed levels. In conclusion, GLUT4 is
      the major transporter responsible for exercise-induced glucose transport. Also,
      postexercise glycogen resynthesis in muscle was greatly delayed; unlike wild-type
      mice, glycogen supercompensation was not found. GLUT4 it is not essential for
      glycogen repletion since muscle glycogen levels in previously exercised GLUT4
      null mice were totally restored after 24 h carbohydrate refeeding.-Ryder, J. W.,
      Kawano, Y., Galuska, D., Fahlman, R., Wallberg-Henriksson, H., Charron, M. J.,
      Zierath, J. R. Postexercise glucose uptake and glycogen synthesis in skeletal
      muscle from GLUT4-deficient mice.

PMID- 10593873
TI  - Degradation of Id proteins by the ubiquitin-proteasome pathway.
AB  - Id proteins act as negative regulators of bHLH transcription factors by forming
      transcriptionally inactive protein complexes. The proposed function of these
      proteins includes promotion of cell growth and cell cycle progression, induction
      of apoptosis, and inhibition of cellular differentiation. We investigated the
      role of the ubiquitin-mediated proteolytic pathway in the degradation of the Id3
      protein. We found Id3 to be a short-lived protein and estimated the half-life to
      be approximately 20 min in 293 cells. Using specific inhibitors of the 26S
      proteasome and mutant fibroblast cells with a temperature-sensitive defect in the
      essential E1 ubiquitin-activating enzyme, we show that Id3 and the related Id1
      and Id2 proteins are degraded through the ubiquitin-proteasome pathway. We found
      the Id4 protein to be much less sensitive to inhibitors of the 26S proteasome,
      but its degradation was dependent on the E1 enzyme. In addition, we observed that
      coexpression of the bHLH protein E47 with Id3 significantly reduced the rate of
      degradation of Id3, suggesting that Id3 is less susceptible to degradation by the
      26S proteasome when complexed to a bHLH protein. -Bounpheng, M. A., Dimas, J. J.,
      Dodds, S. G., Christy, B. A. Degradation of Id proteins by the ubiquitin
      proteasome pathway.

PMID- 10593874
TI  - Effects of the human CD38 glycoprotein on the early stages of the HIV-1
      replication cycle.
AB  - CD38 displays lateral association with the HIV-1 receptor CD4. This association
      is potentiated by the HIV-1 envelope glycoprotein gp120. The aim of this work was
      to evaluate the CD38 role in T cell susceptibility to HIV-1 infection. Using
      laboratory X4 HIV-1 strains and X4 and X4/R5 primary isolates, we found that CD38
      expression was negatively correlated to cell susceptibility to infection,
      evaluated as percentage of infected cells, release of HIV p24 in the
      supernatants, and cytopathogenicity. This correlation was at first suggested by
      results obtained in a panel of human CD4(+) T cell lines expressing different
      CD38 levels (MT-4, MT-2, C8166, CEMx174, Supt-1, and H9) and then demonstrated
      using CD38 transfectants of MT-4 cells (the line with the lowest CD38
      expression). To address whether CD38 affected viral binding, we used mouse T
      cells that are non-permissive for productive infection. Gene transfection in
      mouse SR.D10.CD4(-).F1 T cells produced four lines expressing human CD4 and/or
      CD38. Ability of CD4(+)CD38(+)cells to bind HIV-1 or purified recombinant gp120
      was significantly lower than that of CD4(+)CD38(-) cells. These data suggest that
      CD38 expression inhibits lymphocyte susceptibility to HIV infection, probably by
      inhibiting gp120/CD4-dependent viral binding to target cells.-Savarino, A.,
      Bottarel, F., Calosso, L., Feito, M. J., Bensi, T., Bragardo, M., Rojo, J. M.,
      Pugliese, A., Abbate, I., Capobianchi, M. R., Dianzani, F., Malavasi, F., and
      Dianzani, U. Effects of the human CD38 glycoprotein on the early stages of theHIV
      1 replication cycle.

PMID- 10593875
TI  - Protein homocysteinylation: possible mechanism underlying pathological
      consequences of elevated homocysteine levels.
AB  - Homocysteine thiolactone, a cyclic thioester, is synthesized by certain aminoacyl
      tRNA synthetases in editing or proofreading reactions that prevent translational
      incorporation of homocysteine into proteins. Although homocysteine thiolactone is
      expected to acylate amino groups in proteins, virtually nothing is known
      regarding reactivity of the thiolactone. Here it is shown that reactions of the
      thiolactone with protein lysine residues were robust under physiological
      conditions. In human serum incubated with homocysteine thiolactone, protein
      homocysteinylation was a major reaction that could be observed with as little as
      10 nM thiolactone. Individual proteins were homocysteinylated at rates
      proportional to their lysine contents. Homocysteinylation led to protein damage,
      manifested as multimerization and precipitation of extensively modified proteins.
      Model enzymes, such as methionyl-tRNA synthetase and trypsin, were inactivated by
      homocysteinylation. Metabolic conversion of homocysteine to the thiolactone,
      protein homocysteinylation, and resulting protein damage may underlie involvement
      of Hcy in the pathology of vascular disease.-Jakubowski, H. Protein
      homocysteinylation: possible mechanism underlying pathological consequences of
      elevated homocysteine levels.

PMID- 10593876
TI  - Cyclin B-dependent kinase and caspase-1 activation precedes mitochondrial
      dysfunction in fumarylacetoacetate-induced apoptosis.
AB  - Hereditary tyrosinemia type I is the most severe metabolic disease of the
      tyrosine catabolic pathway mainly affecting the liver. It is caused by deficiency
      of fumarylacetoacetate hydrolase, which prevents degradation of the toxic
      metabolite fumarylacetoacetate (FAA). We report here that FAA induces common
      effects (i.e., cell cycle arrest and apoptosis) in both human (HepG2) and rodent
      (Chinese hamster V79) cells, effects that seem to be temporally related. Both the
      antiproliferative and apoptosis-inducing activities of FAA are dose dependent and
      enhanced by glutathione (GSH) depletion with L-buthionine-(S,R)-sulfoximine
      (BSO). Short treatment (2 h) with 35 microM FAA/+BSO or 100 microM FAA/-BSO
      induced a transient cell cycle arrest at the G2/M transition (20% and 37%,
      respectively) 24 h post-treatment. In cells treated with 100 microM FAA/-BSO, an
      inactivation, followed by a rapid over-induction of cyclin B-dependent kinase
      occurred, which peaked 24 h post-treatment. Maximum levels of caspase-1 and
      caspase-3 activation were detected at 3 h and 32 h, respectively, whereas release
      of mitochondrial cytochrome c was maximal at 24-32 h post-treatment. The G2/M
      peak declined 24 h later, concomitantly with the appearance of a sub-G1,
      apoptotic population showing typical nucleosomal-sized DNA fragmentation and
      reduced mitochondrial transmembrane potential (Deltapsi(m)). These events were
      prevented by the general caspase inhibitor z-VAD-fmk, whereas G2/M arrest and
      subsequent apoptosis were abolished by GSH-monoethylester or N-acetylcysteine.
      Other tyrosine metabolites, maleylacetoacetate and succinylacetone, had no
      antiproliferative effects and induced only very low levels of apoptosis. These
      results suggest a modulator role of GSH in FAA-induced cell cycle disturbance and
      apoptosis where activation of cyclin B-dependent kinase and caspase-1 are early
      events preceding mitochondrial cytochrome c release, caspase-3 activation, and
      Deltapsi(m) loss. -Jorquera, R., Tanguay, R. M. Cyclin B-dependent kinase and
      caspase-1 activation precedes mitochondrial dysfunction in fumarylacetoacetate
      induced apoptosis.

PMID- 10593877
TI  - Increase in nuclear phosphatidylinositol 3-kinase activity and
      phosphatidylinositol (3,4,5) trisphosphate synthesis precede PKC-zeta
      translocation to the nucleus of NGF-treated PC12 cells.
AB  - We and others have previously demonstrated the existence of an autonomous nuclear
      polyphosphoinositide cycle that generates second messengers such as
      diacylglycerol (DAG), capable of attracting to the nucleus specific protein
      kinase C (PKC) isoforms (Neri et al. (1998) J. Biol. Chem. 273, 29738-29744).
      Recently, however, nuclei have also been shown to contain the enzymes responsible
      for the synthesis of the non-canonical 3-phosphorylated inositides. To clarify a
      possible role of this peculiar class of inositol lipids we have examined the
      question of whether nerve growth factor (NGF) induces PKC-zeta nuclear
      translocation in PC12 cells and whether this translocation is dependent on
      nuclear phosphatidylinositol 3-kinase (PI 3-K) activity and its product,
      phosphatidylinositol 3,4, 5-trisphosphate [PtdIns(3,4,5)P(3)]. NGF increased both
      the amount and the enzyme activity of immunoprecipitable PI 3-K in PC12 cell
      nuclei. Activation of the enzyme, but not its translocation, was blocked by PI 3
      K inhibitors wortmannin and LY294002. Treatment of PC12 cells for 9 min with NGF
      led to an increase in the nuclear levels of PtdIns(3,4,5)P(3). Maximal
      translocation of PKC-zeta from the cytoplasm to the nucleus (as evaluated by
      immunoblotting, enzyme activity, and confocal microscopy) occurred after 12 min
      of exposure to NGF and was completely abrogated by either wortmannin or LY294002.
      In contrast, these two inhibitors did not block nuclear translocation of the
      conventional, DAG-sensitive, PKC-alpha. On the other hand, the specific
      phosphatidylinositol phospholipase C inhibitor, 1-O-octadeyl-2-O-methyl-sn
      glycero-3-phosphocholine, was unable to abrogate nuclear translocation of the DAG
      insensitive PKC-zeta. These data suggest that a nuclear increase in PI 3-K
      activity and PtdIns(3,4,5)P(3) production are necessary for the subsequent
      nuclear translocation of PKC-zeta. Furthermore, they point to the likelihood that
      PKC-zeta is a putative nuclear downstream target of PI 3-K during NGF-promoted
      neural differentiation.-Neri, L. M., Martelli, A. M., Borgatti, P., Colamussi, M.
      L., Marchisio, M., Capitani, S. Increase in nuclear phosphatidylinositol 3-kinase
      activity and phosphatidylinositol (3,4, 5) trisphosphate synthesis precede PKC
      zeta translocation to the nucleus of NGF-treated PC12 cells.

PMID- 10593878
TI  - Nitric oxide induces tyrosine nitration and release of cytochrome c preceding an
      increase of mitochondrial transmembrane potential in macrophages.
AB  - Treatment of elicited peritoneal macrophages or the macrophage cell line RAW
      264.7 with high concentrations of nitric oxide donors is followed by apoptotic
      cell death. Analysis of the changes in the mitochondrial transmembrane potential
      (DeltaPsi(m)) with specific fluorescent probes showed a rapid and persistent
      increase of DeltaPsi(m), a potential that usually decreases in cells undergoing
      apoptosis through mitochondrial-dependent mechanisms. Using confocal microscopy,
      the release of cytochrome c from the mitochondria to the cytosol was
      characterized as an early event preceding the rise of DeltaPsi(m). The cytochrome
      c from cells treated with nitric oxide donors was modified chemically, probably
      through the formation of nitrotyrosine residues, suggesting the synthesis of
      peroxynitrite in the mitochondria. These results indicate that nitric oxide
      dependent apoptosis in macrophages occurs in the presence of a sustained increase
      of DeltaPsi(m), and that the chemical modification and release of cytochrome c
      from the mitochondria precede the changes of DeltaPsi(m).-Hortelano, S., Alvarez,
      A. M., Bosca, L. Nitric oxide induces tyrosine nitration and release of
      cytochrome c preceding an increase of mitochondrial transmembrane potential in
      macrophages.

PMID- 10593879
TI  - The roles of free radicals in amyotrophic lateral sclerosis: reactive oxygen
      species and elevated oxidation of protein, DNA, and membrane phospholipids.
AB  - To explore whether reactive oxygen species (ROS) play a role in the pathogenesis
      of amyotrophic lateral sclerosis (ALS), a unique microdialysis or microcannula
      sampling technique was used in mice transfected with a mutant Cu,Zn-superoxide
      dismutase (SOD1) gene from humans with familial ALS, mice transfected with the
      normal human SOD1 gene, and normal mice. We demonstrate for the first time that
      the levels of hydrogen peroxide (H(2)O(2)) and the hydroxyl radical ((.)OH) are
      significantly higher, and the level of the superoxide anion (O(2)(.-)) is
      significantly lower in ALS mutant mice than in controls, supporting by in vivo
      evidence the hypothesis that the mutant enzyme catalyzes (.)OH formation by the
      sequence: O(2)(.-) --> H(2)O(2) --> (.)OH. This removes doubts regarding the
      relevance of elevated ROS in FALS raised by in vitro experiments. The levels of
      oxidation products are also significantly higher in the mutant mice than in
      controls, consistent with some previous reports. Only the superoxide
      concentration differs between two controls among all the measurements. Our
      findings correlate in vivo a gene mutation to both elevated H(2)O(2) and (.)OH
      and increased oxidation of cellular constituents. The elevated H(2)O(2) in mutant
      mice indicates impairment of its detoxification pathways, perhaps by changed
      interactions between SOD1 and H(2)O(2) detoxification enzymes.-Liu, D., Wen, J.,
      Liu, J., Li, L. The roles of free radicals in amyotrophic lateral sclerosis:
      reactive oxygen species and elevated oxidation of protein, DNA, and membrane
      phospholipids.

PMID- 10593880
TI  - Overexpression of core 2 N-acetylglycosaminyltransferase enhances cytokine
      actions and induces hypertrophic myocardium in transgenic mice.
AB  - Elevated levels of glycocojugates, commonly observed in the myocardium of
      diabetic animals and patients, are postulated to contribute to the myocardial
      dysfunction in diabetes. Previously, we reported that UDP-GlcNAc: Galbeta1
      3GalNAcalphaRbeta1-6-N-acetylglucosaminyltransferas e (core 2 GlcNAc-T), a
      developmentally regulated enzyme of O-linked glycans biosynthesis pathway, is
      specifically increased in the heart of diabetic animals and is regulated by
      hyperglycemia and insulin. In this study, transgenic mice overexpressing core 2
      GlcNAc-T with severe increase in cardiac core 2 GlcNAc-T activities were normal
      at birth but showed progressive and significant cardiac hypertrophy at 6 months
      of age. The heart of transgenic mice showed elevation of sialylated O-glycan and
      increases of c-fos gene expression and AP-1 activity, which are characteristics
      of cardiac stress. Furthermore, transfection of PC12 cells with core 2 GlcNAc-T
      also induced c-fos promoter activation, mitogen activated-protein kinase (MAPK)
      phosphorylation, Trk receptor glycosylation, and cell differentiation. These
      results suggested a novel role for core 2 GlcNAc-T in the development of diabetic
      cardiomyopathy and modulation of the MAP kinase pathway in the heart.-Koya, D.,
      Dennis, J. W., Warren, C. E., Takahara, N., Schoen, F. J., Nishio, Y., Nakajima,
      T., Lipes, M. A., King, G. L. Overexpression of core 2 N
      acetylglycosaminyltransferase enhances cytokine actions and induces hypertrophic
      myocardium in transgenic mice.

PMID- 10593881
TI  - Porcine relaxin, a 500 million-year-old hormone?

PMID- 10593882
TI  - Regulation of the p53 tumor suppressor protein.

PMID- 10593883
TI  - MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated
      protein kinase 1 (BMK1) signaling pathway.
AB  - Big mitogen-activated protein (MAP) kinase (BMK1), also known as ERK5, is a
      member of the MAP kinase family whose cellular activity is elevated in response
      to growth factors, oxidative stress, and hyperosmolar conditions. Previous
      studies have identified MEK5 as a cellular kinase directly regulating BMK1
      activity; however, signaling molecules that directly regulate MEK5 activity have
      not yet been defined. Through utilization of a yeast two-hybrid screen, we have
      identified MEKK3 as a molecule that physically interacts with MEK5. This
      interaction appears to take place in mammalian cells as evidenced by the fact
      that cellular MEK5 and MEKK3 co-immunoprecipitate. In addition, we show that a
      dominant active form of MEKK3 stimulates BMK1 activity through MEK5. Moreover, we
      demonstrate that MEKK3 activity is required for growth factor mediated cellular
      activation of endogenous BMK1. Taken together, these results identify MEKK3 as a
      kinase that regulates the activity of MEK5 and BMK1 during growth factor-induced
      cellular stimulation.

PMID- 10593884
TI  - Reactivity of glutaredoxins 1, 2, and 3 from Escherichia coli shows that
      glutaredoxin 2 is the primary hydrogen donor to ArsC-catalyzed arsenate
      reduction.
AB  - In Escherichia coli ArsC catalyzes the reduction of arsenate to arsenite using
      GSH with glutaredoxin as electron donors. E. coli has three glutaredoxins: 1, 2,
      and 3, each with a classical -Cys-Pro-Tyr-Cys- active site. Glutaredoxin 2 is the
      major glutathione disulfide oxidoreductase in E. coli, but its function remains
      unknown. In this report glutaredoxin 2 is shown to be the most effective hydrogen
      donor for the reduction of arsenate by ArsC. Analysis of single or double
      cysteine-to-serine substitutions in the active site of the three glutaredoxins
      indicated that only the N-terminal cysteine residue is essential for activity.
      This suggests that, during the catalytic cycle, ArsC forms a mixed disulfide with
      GSH before being reduced by glutaredoxin to regenerate the active ArsC reductase.

PMID- 10593885
TI  - Mammalian mitochondrial ribosomal proteins (2). Amino acid sequencing,
      characterization, and identification of corresponding gene sequences.
AB  - Four different classes of mammalian mitochondrial ribosomal proteins were
      identified and characterized. Mature proteins were purified from bovine liver and
      subjected to N-terminal or matrix-assisted laser-desorption mass spectroscopic
      amino acid sequencing after tryptic in-gel digestion and high pressure liquid
      chromatography separation of the resulting peptides. Peptide sequences obtained
      were used to virtually screen expressed sequence tag data bases from human,
      mouse, and rat. Consensus cDNAs were assembled in silico from various expressed
      sequence tag sequences identified. Deduced mammalian protein sequences were
      characterized and compared with ribosomal protein sequences of Escherichia coli
      and yeast mitochondria. Significant sequence similarities to ribosomal proteins
      of other sources were detected for three out of four different mammalian protein
      classes determined. However, the sequence conservation between mitochondrial
      ribosomal proteins of mammalian and yeast origin is much less than the sequence
      conservation between cytoplasmic ribosomal proteins of the same species. In
      particular, this is shown for the mammalian counterparts of the E. coli EcoL2
      ribosomal protein (MRP-L14), that do not conserve the specific and functional
      highly important His(229) residue of E. coli and the corresponding yeast
      mitochondrial Rml2p.

PMID- 10593886
TI  - Direct activation of the fission yeast PAK Shk1 by the novel SH3 domain protein,
      Skb5.
AB  - The p21-activated kinase (PAK) homolog Shk1 is essential for cell viability in
      the fission yeast Schizosaccharomyces pombe. Roles have been established for Shk1
      in the regulation of cell morphology, sexual differentiation, and mitosis in S.
      pombe. In this report, we describe the genetic and molecular characterization of
      a novel SH3 domain protein, Skb5, identified as a result of a two-hybrid screen
      for Shk1 interacting proteins. S. pombe cells carrying a deletion of the skb5
      gene exhibit no discernible phenotypic defects under normal growth conditions,
      but when subjected to hypertonic stress, become spheroidal in shape and growth
      impaired. Both of these defects can be suppressed by overexpression of the Shk1
      modulator, Skb1. The growth inhibition that results from overexpression of Shk1
      in S. pombe cells is markedly suppressed by a null mutation in the skb5 gene,
      suggesting that Skb5 contributes positively to the function of Shk1 in vivo.
      Consistent with this notion, we show that Skb5 stimulates Shk1 catalytic function
      in S. pombe cells. Furthermore, and perhaps most significantly, we show that
      bacterially expressed recombinant Skb5 protein directly stimulates the catalytic
      activity of recombinant Shk1 kinase in vitro. These and additional data described
      herein demonstrate that Skb5 is a direct activator of Shk1 in fission yeast.

PMID- 10593887
TI  - The role of external loop regions in serotonin transport. Loop scanning
      mutagenesis of the serotonin transporter external domain.
AB  - Chimeric transporters were constructed in which the predicted external loops of
      the serotonin transporter (SERT) were replaced one at a time with a corresponding
      sequence from the norepinephrine transporter (NET). All of the chimeric
      transporters were expressed at levels equal to or greater than those of wild type
      SERT, but the transport and binding activity of the mutants varied greatly. In
      particular, mutants in which the NET sequence replaced external loops 4 or 6 of
      SERT had transport activity 5% or less than that of wild type, and the loop 5
      replacement was essentially inactive. In some of these mutants, binding of a high
      affinity cocaine analog was less affected than transport, suggesting that the
      mutation had less effect on the initial binding steps in transport than on
      subsequent conformational changes. The more severely affected mutants also
      displayed an altered response to Na(+). In contrast to the dramatic reduction in
      transport and binding, the specificity of ligand binding was essentially
      unchanged. Chimeric transporters did not gain affinity for dopamine, a NET
      substrate, or desipramine, an inhibitor, at the expense of affinity for serotonin
      or paroxetine, a selective SERT inhibitor. The results suggest that external
      loops are not the primary determinants of substrate and inhibitor binding sites.
      However, they are not merely passive structures connecting transmembrane segments
      but rather active elements responsible for maintaining the stability and
      conformational flexibility of the transporter.

PMID- 10593888
TI  - Distinct specificities of inwardly rectifying K(+) channels for
      phosphoinositides.
AB  - Activation of several inwardly rectifying K(+) channels (Kir) requires the
      presence of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)). The
      constitutively active Kir2.1 (IRK1) channels interact with PtdIns(4,5)P(2)
      strongly, whereas the G-protein activated Kir3.1/3.4 channels (GIRK1/GIRK4), show
      only weak interactions with PtdIns(4,5)P(2). We investigated whether these
      inwardly rectifying K(+) channels displayed distinct specificities for different
      phosphoinositides. IRK1, but not GIRK1/GIRK4 channels, showed a marked
      specificity toward phosphates in the 4,5 head group positions. GIRK1/GIRK4
      channels were activated with a similar efficacy by PtdIns(3,4)P(2),
      PtdIns(3,5)P(2), PtdIns(4,5)P(2), and PtdIns(3,4,5)P(3). In contrast, IRK1
      channels were not activated by PtdIns(3,4)P(2) and only marginally by high
      concentrations of PtdIns(3,5)P(2). Similarly, high concentrations of
      PtdIns(3,4,5)P(3) were required to activate IRK1 channels. For either channel,
      PtdIns(4)P was much less effective than PtdIns(4,5)P(2), whereas PtdIns was
      inactive. In contrast to the dependence on the position of phosphates of the
      phospholipid head group, GIRK1/GIRK4, but not IRK1 channel activation, showed a
      remarkable dependence on the phospholipid acyl chains. GIRK1/GIRK4 channels were
      activated most effectively by the natural arachidonyl stearyl PtdIns(4,5)P(2) and
      much less by the synthetic dipalmitoyl analog, whereas IRK1 channels were
      activated equally by dipalmitoyl and arachidonyl stearyl PtdIns(4,5)P(2).
      Incorporation of PtdInsP(2) into the membrane is necessary for activation, as the
      short chain water soluble diC(4) PtdIns(4,5)P(2) did not activate either channel,
      whereas activation by diC(8) PtdIns(4, 5)P(2) required high concentrations.

PMID- 10593889
TI  - Sec-independent protein translocation in Escherichia coli. A distinct and pivotal
      role for the TatB protein.
AB  - In Escherichia coli, transmembrane translocation of proteins can proceed by a
      number of routes. A subset of periplasmic proteins are exported via the Tat
      pathway to which proteins are directed by N-terminal "transfer peptides" bearing
      the consensus (S/T)RRXFLK "twin-arginine" motif. The Tat system involves the
      integral membrane proteins TatA, TatB, TatC, and TatE. Of these, TatA, TatB, and
      TatE are homologues of the Hcf106 component of the DeltapH-dependent protein
      import system of plant thylakoids. Deletion of the tatB gene alone is sufficient
      to block the export of seven endogenous Tat substrates, including hydrogenase-2.
      Complementation analysis indicates that while TatA and TatE are functionally
      interchangeable, the TatB protein is functionally distinct. This conclusion is
      supported by the observation that Helicobacter pylori tatA will complement an E.
      coli tatA mutant, but not a tatB mutant. Analysis of Tat component stability in
      various tat deletion backgrounds shows that TatC is rapidly degraded in the
      absence of TatB suggesting that TatC complexes, and is stabilized by, TatB.

PMID- 10593890
TI  - Does the triple helical domain of type I collagen encode molecular recognition
      and fiber assembly while telopeptides serve as catalytic domains? Effect of
      proteolytic cleavage on fibrillogenesis and on collagen-collagen interaction in
      fibers.
AB  - Over the last several decades, it has been established that proteolytic removal
      of short, non-helical terminal peptides (telopeptides) from type I collagen
      significantly alters the kinetics of in vitro fibrillogenesis. However, it has
      also been observed that the protein is still capable of forming fibers even after
      complete removal of telopeptides. This study focuses on the characterization of
      this fibrillogenesis competency of collagen. We have combined traditional kinetic
      and thermodynamic assays of fibrillogenesis efficacy with direct measurements of
      interaction between collagen molecules in fibers by osmotic stress and x-ray
      diffraction. We found that telopeptide cleavage by pepsin or by up to 20 h of
      Pronase treatment altered fiber assembly kinetics, but the same fraction of the
      protein still assembled into fibers. Small-angle x-ray diffraction showed that
      these fibers have normal, native-like D-stagger. Force measurements indicated
      that collagen-collagen interactions in fibers were not affected by either pepsin
      or Pronase treatment. In contrast, prolonged (>20 h) Pronase treatment resulted
      in cleavage of the triple helical domain as indicated by SDS-polyacrylamide gel
      electrophoresis. The triple-helix cleavage correlated with the observed decrease
      in the fraction of protein capable of forming fibers and with the measured loss
      of attraction between helices in fibers. These data suggest that telopeptides
      play a catalytic role, whereas the information necessary for proper molecular
      recognition and fiber assembly is encoded in the triple helical domain of
      collagen.

PMID- 10593891
TI  - Isolation, characterization, and functional expression of cDNAs encoding NADH
      dependent methylenetetrahydrofolate reductase from higher plants.
AB  - Methylenetetrahydrofolate reductase (MTHFR) is the least understood enzyme of
      folate-mediated one-carbon metabolism in plants. Genomics-based approaches were
      used to identify one maize and two Arabidopsis cDNAs specifying proteins
      homologous to MTHFRs from other organisms. These cDNAs encode functional MTHFRs,
      as evidenced by their ability to complement a yeast met12 met13 mutant, and by
      the presence of MTHFR activity in extracts of complemented yeast cells. Deduced
      sequence analysis shows that the plant MTHFR polypeptides are of similar size (66
      kDa) and domain structure to other eukaryotic MTHFRs, and lack obvious targeting
      sequences. Southern analyses and genomic evidence indicate that Arabidopsis has
      two MTHFR genes and that maize has at least two. A carboxyl-terminal
      polyhistidine tag was added to one Arabidopsis MTHFR, and used to purify the
      enzyme 640-fold to apparent homogeneity. Size exclusion chromatography and
      denaturing gel electrophoresis of the recombinant enzyme indicate that it exists
      as a dimer of approximately 66-kDa subunits. Unlike mammalian MTHFR, the plant
      enzymes strongly prefer NADH to NADPH, and are not inhibited by S
      adenosylmethionine. An NADH-dependent MTHFR reaction could be reversible in plant
      cytosol, where the NADH/NAD ratio is 10(-3). Consistent with this, leaf tissues
      metabolized [methyl-(14)C]methyltetrahydrofolate to serine, sugars, and starch. A
      reversible MTHFR reaction would obviate the need for inhibition by S
      adenosylmethionine to prevent excessive conversion of methylene- to
      methyltetrahydrofolate.

PMID- 10593892
TI  - The FMN to heme electron transfer in cytochrome P450BM-3. Effect of chemical
      modification of cysteines engineered at the FMN-heme domain interaction site.
AB  - The crystal structure of the complex between the heme and FMN-containing domains
      of Bacillus megaterium cytochrome P450BM-3 (Sevrioukova, I. F., Li, H., Zhang,
      H., Peterson, J. A., and Poulos, T. L. (1999) Proc. Natl. Acad. Sci. U. S. A. 96,
      1863-1868) indicates that the proximal side of the heme domain molecule is the
      docking site for the FMN domain and that the Pro(382)-Gln(387) peptide may
      provide an electron transfer (ET) path from the FMN to the heme iron. In order to
      evaluate whether ET complexes formed in solution by the heme and FMN domains are
      structurally relevant to that seen in the crystal structure, we utilized site
      directed mutagenesis to introduce Cys residues at positions 104 and 387, which
      are sites of close contact between the domains in the crystal structure and at
      position 372 as a control. Cys residues were modified with a bulky sulfhydryl
      reagent, 1-dimethylaminonaphthalene-5-sulfonate-L-cystine (dansylcystine (DC)),
      to prevent the FMN domain from binding at the site seen in the crystal structure.
      The DC modification of Cys(372) and Cys(387) resulted in a 2-fold decrease in the
      rates of interdomain ET in the reconstituted system consisting of the separate
      heme and FMN domains and had no effect on heme reduction in the intact heme/FMN
      binding fragment of P450BM-3. DC modification of Cys(104) caused a 10-20-fold
      decrease in the interdomain ET reaction rate in both the reconstituted system and
      the intact heme/FMN domain. This indicates that the proximal side of the heme
      domain molecule represents the FMN domain binding site in both the crystallized
      and solution complexes, with the area around residue 104 being the most critical
      for the redox partner docking.

PMID- 10593893
TI  - The cytoplasmic, transmembrane, and stem regions of glycosyltransferases specify
      their in vivo functional sublocalization and stability in the Golgi.
AB  - We provide evidence for the presence of targeting signals in the cytoplasmic,
      transmembrane, and stem (CTS) regions of Golgi glycosyltransferases that mediate
      sorting of their intracellular catalytic activity into different functional
      subcompartmental areas of the Golgi. We have constructed chimeras of human
      alpha1, 3-fucosyltransferase VI (FT6) by replacement of its CTS region with those
      of late and early acting Golgi glycosyltransferases and have stably coexpressed
      these constructs in BHK-21 cells together with the secretory reporter
      glycoprotein human beta-trace protein. The sialyl Lewis X:Lewis X ratios detected
      in beta-trace protein indicate that the CTS regions of the early acting GlcNAc
      transferases I (GnT-I) and III (GnT-III) specify backward targeting of the FT6
      catalytic domain, whereas the CTS region of the late acting human alpha1,3
      fucosyltransferase VII (FT7) causes forward targeting of the FT6 in vivo activity
      in the biosynthetic glycosylation pathway. The analysis of the in vivo functional
      activity of nine different CTS chimeras toward beta-trace protein allowed for a
      mapping of the CTS donor glycosyltransferases within the Golgi/trans-Golgi
      network: GnT-I < (ST6Gal I, ST3Gal III) < GnT-III < ST8Sia IV < GalT-I < (FT3,
      FT6) < ST3Gal IV < FT7. The sensitivity or resistance of the donor
      glycosyltransferases toward intracellular proteolysis is transferred to the
      chimeric enzymes together with their CTS regions. Apparently, there are at least
      three different signals contained in the CTS regions of glycosyltransferases
      mediating: first, their Golgi retention; second, their targeting to specific in
      vivo functional areas; and third, their susceptibility toward intracellular
      proteolysis as a tool for the regulation of the intracellular turnover.

PMID- 10593894
TI  - Characterization of ATP and DNA binding activities of TrwB, the coupling protein
      essential in plasmid R388 conjugation.
AB  - TrwB is the conjugative coupling protein of plasmid R388. TrwBDeltaN70 contains
      the soluble domain of TrwB. It was constructed by deletion of trwB sequences
      containing TrwB N-proximal transmembrane segments. Purified TrwBDeltaN70 protein
      bound tightly the fluorescent ATP analogue TNP-ATP (K(s) = 8.7 microM) but did
      not show measurable ATPase or GTPase activity. A single ATP binding site was
      found per TrwB monomer. An intact ATP-binding site was essential for R388
      conjugation, since a TrwB mutant with a single amino acid alteration in the ATP
      binding signature (K136T) was transfer-deficient. TrwBDeltaN70 also bound DNA
      nonspecifically. DNA binding enhanced TrwC nic cleavage, providing the first
      evidence that directly links TrwB with conjugative DNA processing. Since DNA
      bound by TrwBDeltaN70 also showed increased negative superhelicity (as shown by
      increased sensitivity to topoisomerase I), nic cleavage enhancement was assumed
      to be a consequence of the increased single-stranded nature of DNA around nic.
      The mutant protein TrwB(K136T)DeltaN70 was indistinguishable from TrwBDeltaN70
      with respect to the above properties, indicating that TrwB ATP binding activity
      is not required for them. The reported properties of TrwB suggest potential
      functions for conjugative coupling proteins, both as triggers of conjugative DNA
      processing and as motors in the transport process.

PMID- 10593895
TI  - Inhibition of calcineurin phosphatase activity by a calcineurin B homologous
      protein.
AB  - Calcineurin, a Ca(2+)/calmodulin-stimulated protein phosphatase, plays a key role
      in T-cell activation by regulating the activity of NFAT (nuclear factor of
      activated T cells), a family of transcription factors required for the synthesis
      of several cytokine genes. Calcineurin is the target of the immunosuppressive
      drugs cyclosporin A and FK506 complexed with their cytoplasmic receptors
      cyclophilin and FKBP12, respectively. In this study we report that calcineurin is
      also the target of a recently identified Ca(2+)-binding protein, CHP (for
      calcineurin homologous protein), which shares a high degree of homology with the
      regulatory B subunit of calcineurin and with calmodulin. In Jurkat and HeLa
      cells, overexpression of CHP specifically impaired the nuclear translocation and
      transcriptional activity of NFAT but had no effect on AP-1 transcriptional
      activity and only a small (<25%) inhibitory effect on the transcriptional
      activity of NFkappaB. Further study indicated that CHP inhibits calcineurin
      activity. In cells overexpressing CHP, the phosphatase activity of
      immunoprecipitated calcineurin was inhibited by approximately 50%; and in a
      reconstituted assay, the activity of purified calcineurin was inhibited up to 97%
      by the addition of purified recombinant CHP in a dose-dependent manner. Moreover,
      prolonged activation of Jurkat cells was associated with a decreased abundance of
      CHP, suggesting a possible regulatory mechanism allowing activation of
      calcineurin. CHP, therefore, is a previously unrecognized endogenous inhibitor of
      calcineurin activity.

PMID- 10593896
TI  - Similarities and differences between the effects of heparin and glypican-1 on the
      bioactivity of acidic fibroblast growth factor and the keratinocyte growth
      factor.
AB  - The keratinocyte growth factor (KGF or FGF-7) is unique among its family members
      both in its target cell specificity and its inhibition by the addition of heparin
      and the native heparan-sulfate proteoglycan (HSPG), glypican-1 in cells
      expressing endogenous HSPGs. FGF-1, which binds the FGF-7 receptor with a similar
      affinity as FGF-7, is stimulated by both molecules. In the present study, we
      investigated the modulation of FGF-7 activities by heparin and glypican-1 in HS
      free background utilizing either HS-deficient cells expressing the FGF-7 receptor
      (designated BaF/KGFR cells) or soluble extracellular domain of the receptor. At
      physiological concentrations of FGF-7, heparin was required for high affinity
      receptor binding and for signaling in BaF/KGFR cells. In contrast, binding of FGF
      7 to the soluble form of the receptor did not require heparin. However, high
      concentrations of heparin inhibited the binding of FGF-7 to both the cell surface
      and the soluble receptor, similar to the reported effect of heparin in cells
      expressing endogenous HSPGs. The difference in heparin dependence for high
      affinity interaction between the cell surface and soluble receptor may be due to
      other molecule(s) present on cell surfaces. Glypican-1 differed from heparin in
      that it stimulated FGF-1 but not FGF-7 activities in BaF/KGFR cells. Glypican-1
      abrogated the stimulatory effect of heparin, and heparin reversed the inhibitory
      effect of glypican-1, indicating that this HSPG inhibits FGF-7 activities by
      acting, most likely, as a competitive inhibitor of stimulatory HSPG species for
      FGF-7. The regulatory effect of glypican-1 is mediated at the level of
      interaction with the growth factor as glypican-1 did not bind the KGFR. The
      effect of heparin and glypican-1 on FGF-1 and FGF-7 oligomerization was studied
      employing high and physiological concentrations of growth factors. We did not
      find a correlation between the effects of these glycosaminoglycans on FGFs
      biological activity and oligomerization. Altogether, our findings argue against
      the heparin-linked dimer presentation model as key in FGFR activation, and
      support the notion that HSPGs primarily affect high affinity interaction of FGFs
      with their receptors.

PMID- 10593897
TI  - Human acyl-CoA:cholesterol acyltransferase-1 is a homotetrameric enzyme in intact
      cells and in vitro.
AB  - Acyl-CoA:cholesterol acyltransferase (ACAT) is a key enzyme in cellular
      cholesterol homeostasis and in atherosclerosis. ACAT-1 may function as an
      allosteric enzyme. We took a multifaceted approach to investigate the subunit
      composition of ACAT-1. When ACAT-1 with two different tags were co-expressed in
      the same Chinese hamster ovary cells, antibody specific to one tag caused co
      immunoprecipitation of both types of ACAT-1 proteins. Radioimmunoprecipitations
      of cells expressing the untagged ACAT-1 or the 6-histidine-tagged ACAT-1 yielded
      a single radiolabeled band of predicted size on SDS-polyacrylamide gel
      electrophoresis. These results show that ACAT-1 exists as homo-oligomers in
      intact Chinese hamster ovary cells. We solubilized HisACAT-1 with the detergent
      deoxycholate or CHAPS (3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonic
      acid), performed gel filtration chromatography and sucrose density gradient
      centrifugations in H(2)O and D(2)O, and determined the Stokes radii and
      sedimentation coefficients of the HisACAT1-detergent complexes. The estimated
      molecular mass of HisACAT-1 is 263 kDa, which is 4 times that of the HisACAT-1
      monomer (69 kDa). Finally, cross-linking experiments in intact cells and in vitro
      show that the increase in cross-linker concentrations causes an increase in size
      of the HisACAT-1-positive signals, forming material(s) 4 times the size of the
      monomer, supporting the conclusion that ACAT-1 is a homotetrameric enzyme.

PMID- 10593898
TI  - Peptides corresponding to the N and C termini of IkappaB-alpha, -beta, and 
      epsilon as probes of the two catalytic subunits of IkappaB kinase, IKK-1 and IKK
      2.
AB  - The signal-inducible phosphorylation of serines 32 and 36 of IkappaB-alpha is the
      key step in regulating the subsequent ubiquitination and proteolysis of IkappaB
      alpha, which then releases NF-kappaB to promote gene transcription. The
      multisubunit IkappaB kinase (msIKK) responsible for this phosphorylation contains
      two catalytic subunits, termed IKK-1 and IKK-2. Using recombinant IKK-2, a
      kinetic pattern consistent with a random, sequential binding mechanism was
      observed with the use of a peptide corresponding to amino acids 26-42 of IkappaB
      alpha. Values of 313 microM, 15.5 microM, and 1.7 min(-1) were obtained for
      K(peptide), K(ATP), and k(cat), respectively. The value of alpha, a factor by
      which binding of one substrate changes the dissociation constant for the other
      substrate, was determined to be 0.2. Interestingly, the recombinant IKK-1 subunit
      gave similar values for alpha and K(ATP), but values of 1950 microM and 0.016
      min(-1) were calculated for K(peptide) and k(cat), respectively. This suggests
      that the IKK-2 catalytic subunit provides nearly all of the catalytic activity of
      the msIKK complex with the IKK-1 subunit providing little contribution to
      catalysis. Using peptides corresponding to different regions of IkappaB-alpha
      within amino acids 21-47, it was shown that amino acids 31-37 provide most
      binding interactions (-4.7 kcal/mol of binding free energy) of the full-length
      IkappaB-alpha (-7.9 kcal/mol) with the IKK-2. This is consistent with the
      observation that IKK-2 is able to phosphorylate the IkappaB-beta and IkappaB
      epsilon proteins, which have consensus phosphorylation sites nearly identical to
      that of amino acids 31-37 of IkappaB-alpha. A peptide corresponding to amino
      acids 279-303 in the C-terminal domain of IkappaB-alpha was unable to activate
      IKK-2 to phosphorylate an N-terminal peptide, which is in contrast to the results
      observed with the msIKK. Moreover, the IKK-2 catalyzes the phosphorylation of the
      full-length IkappaB-alpha and the amino acid 26-42 peptide with nearly equal
      efficiency, while the msIKK catalyzes the phosphorylation of the full-length
      IkappaB-alpha 25,000 times more efficiently than the 26-42 peptide. Therefore,
      the C terminus of IkappaB-alpha is important in activating the msIKK through
      interactions with subunits other than the IKK-2.

PMID- 10593899
TI  - The leucine-based sorting motifs in the cytoplasmic domain of the invariant chain
      are recognized by the clathrin adaptors AP1 and AP2 and their medium chains.
AB  - Recognition of sorting signals within the cytoplasmic tail of membrane proteins
      by adaptor protein complexes is a crucial step in membrane protein sorting. The
      three known adaptor complexes, AP1, AP2, and AP3, have all been shown to
      recognize tyrosine- and leucine-based sorting signals, which are the most common
      sorting signals within membrane protein cytoplasmic tails. Although tyrosine
      based signals are recognized by the micro-chains of adaptor complexes, the
      subunit recognizing leucine-based sorting signals is less clear. In this report
      we show by surface plasmon resonance that the two leucine-based sorting signals
      within the cytoplasmic tail of the invariant chain bind independently from each
      other to AP1 and AP2 but not to AP3. We also show that both motifs can be
      recognized by the micro-chains of AP1 and AP2. Moreover, by using monomeric as
      well as trimeric invariant chain constructs, we show that adaptor binding does
      not require trimerization of the invariant chain.

PMID- 10593900
TI  - MRG1 binds to the LIM domain of Lhx2 and may function as a coactivator to
      stimulate glycoprotein hormone alpha-subunit gene expression.
AB  - Tissue-specific expression of the alpha-subunit gene of glycoprotein hormones
      involves an enhancer element designated the pituitary glycoprotein basal element,
      which interacts with the LIM homeodomain transcription factor, Lhx2. In the
      present studies we have explored the function of the LIM domain of Lhx2 in
      stimulating alpha-subunit transcription. When fused to the GAL4 DNA-binding
      domain, the LIM domain of Lhx2 was shown to contain a transcriptional activation
      domain. Furthermore, in the context of an alpha-subunit reporter gene in which a
      GAL4-binding site replaced the pituitary glycoprotein basal element, the LIM
      domain enhanced both basal and Ras-mediated transcription. In addition, a
      synergistic response to Ras activation was observed when the Lhx2 LIM domain and
      the transactivation domain of Elk1 are directed to a minimal reporter gene. A
      yeast two-hybrid screen identified the recently described melanocyte-specific
      gene-related gene 1 (MRG1) as an Lhx2 LIM-interacting protein. MRG1 was shown to
      bind Lhx2 in vitro, and a co-immunoprecipitation assay provided evidence that
      endogenous MRG1 forms a complex with Lhx2 in alphaT3-1 cells. Expression of MRG1
      in alphaT3-1 cells enhanced alpha-subunit reporter gene activity. MRG1 was also
      shown to bind in vitro to the TATA-binding protein and the transcriptional
      coactivator, p300. These data suggest a model in which the Lhx2 LIM domain
      activates transcription through interaction with MRG1 leading to recruitment of
      p300/CBP and the TATA-binding protein.

PMID- 10593901
TI  - Leucine, glutamine, and tyrosine reciprocally modulate the translation initiation
      factors eIF4F and eIF2B in perfused rat liver.
AB  - Leucine, glutamine, and tyrosine, three amino acids playing key modulatory roles
      in hepatic proteolysis, were evaluated for activation of signaling pathways
      involved in regulation of liver protein synthesis. Furthermore, because leucine
      signals to effectors that lie distal to the mammalian target of rapamycin, these
      downstream factors were selected for study as candidate mediators of amino acid
      signaling. Using the perfused rat liver as a model system, we observed a 25%
      stimulation of protein synthesis in response to balanced hyperaminoacidemia,
      whereas amino acid imbalance due to elevated concentrations of leucine,
      glutamine, and tyrosine resulted in a protein synthetic depression of roughly 50%
      compared with normoaminoacidemic controls. The reduction in protein synthesis
      accompanying amino acid imbalance became manifest at high physiologic
      concentrations and was dictated by the guanine nucleotide exchange activity of
      translation initiation factor eIF2B. Paradoxically, this phenomenon occurred
      concomitantly with assembly of the mRNA cap recognition complex, eIF4F as well as
      activation of the 70-kDa ribosomal S6 kinase, p70(S6k). Dual and reciprocal
      modulation of eIF4F and eIF2B was leucine-specific because isoleucine, a
      structural analog, was ineffective in these regards. Thus, we conclude that amino
      acid imbalance, heralded by leucine, initiates a liver-specific translational
      fail-safe mechanism that deters protein synthesis under unfavorable circumstances
      despite promotion of the eIF4F complex.

PMID- 10593902
TI  - Cysteine-scanning mutagenesis of transmembrane segment 7 of the GLUT1 glucose
      transporter.
AB  - The human erythrocyte facilitative glucose transporter (Glut1) is predicted to
      contain 12 transmembrane spanning alpha-helices based upon hydropathy plot
      analysis of the primary sequence. Five of these helices (3, 5, 7, 8, and 11) are
      capable of forming amphipathic structures. A model of GLUT1 tertiary structure
      has therefore been proposed in which the hydrophilic faces of several amphipathic
      helices are arranged to form a central aqueous channel through which glucose
      traverses the hydrophobic lipid bilayer. In order to test this model, we
      individually mutated each of the amino acid residues in transmembrane segment 7
      to cysteine in an engineered GLUT1 molecule devoid of all native cysteines (C
      less). Measurement of 2-deoxyglucose uptake in a Xenopus oocyte expression system
      revealed that nearly all of these mutants retain measurable transport activity.
      Over one-half of the cysteine mutants had significantly reduced specific activity
      relative to the C-less protein. The solvent accessibility and relative
      orientation of the residues within the helix was investigated by determining the
      sensitivity of the mutant transporters to inhibition by the sulfhydryl directed
      reagent p-chloromercuribenzene sulfonate (pCMBS). Cysteine replacement at six
      positions (Gln(282), Gln(283), Ile(287), Ala(289), Val(290), and Phe(291)), all
      near the exofacial side of the cell membrane, produced transporters that were
      inhibited by incubation with extracellular pCMBS. Residues predicted to be near
      the cytoplasmic side of the cell membrane were minimally affected by pCMBS. These
      data demonstrate that the exofacial portion of transmembrane segment 7 is
      accessible to the external solvent and provide evidence for the positioning of
      this alpha-helix within the glucose permeation pathway.

PMID- 10593903
TI  - Diacylglycerol kinase epsilon, but not zeta, selectively removes polyunsaturated
      diacylglycerol, inducing altered protein kinase C distribution in vivo.
AB  - Porcine aortic endothelial cells have previously been shown to contain
      particularly high basal levels of polyunsaturated diacylglycerol (DAG) together
      with a very high degree of membrane-associated protein kinase C (PKC), which is
      largely insensitive to further activation (Pettitt, T. R., Martin, A., Horton,
      T., Liossis, C., Lord, J. M., and Wakelam, M. J. O. (1997) J. Biol. Chem. 272,
      17354-17359). To investigate the possibility that the high polyunsaturated DAG
      levels were constitutively activating PKC, we transfected porcine aortic
      endothelial cells with two different forms of human diacylglycerol kinase,
      epsilon and zeta. In vitro, the former is specific for polyunsaturated
      structures, whereas the latter shows no apparent selectivity. Overexpression of
      DAGKepsilon specifically reduced the level of polyunsaturated DAG in the
      transfected cells while having little effect on the more saturated structures. It
      also caused the redistribution of PKCalpha and epsilon from the membrane to the
      cytosol. Overexpression of DAGKzeta caused a general reduction in DAG levels but
      had little effect on PKC distribution. These results for the first time show that
      DAGKepsilon specifically phosphorylates polyunsaturated DAG in vivo and that in
      so doing it regulates PKC localization and activity. This provides support for
      the proposal that it is the polyunsaturated DAGs that function as messengers and
      convincing evidence for DAGKepsilon being a physiological terminator of DAG
      second messenger signaling.

PMID- 10593904
TI  - C-terminal residues 621-635 of protein S are essential for binding to factor Va.
AB  - Protein S is anticoagulant in the absence of activated protein C because of
      direct interactions with coagulation Factors Xa and Va. Synthetic peptides
      corresponding to amino acid sequences of protein S were tested for their ability
      to inhibit prothrombinase activity. The peptide containing the C-terminal
      sequence of protein S, residues 621-635 (PSP14), reversibly inhibited
      prothrombinase activity in the presence but not in the absence of Factor Va (K(i)
      approximately 2 microM). PSP14 inhibition of prothrombinase was independent of
      phospholipids but could be competitively overcome by increasing Factor Xa
      concentrations, suggesting that the C-terminal region of protein S may compete
      for a Factor Xa binding site on Factor Va. Studies using peptides with amino acid
      substitutions suggested that lysines 630, 631, and 633 were critical residues.
      PSP14 inhibited Factor Va activity in Factor Xa-one-stage clotting assays. PSP14
      inhibited protein S binding to immobilized Factor Va. When preincubated with
      protein S, antibodies raised against PSP14 inhibited binding of protein S to
      Factor Va and blocked inhibition of prothrombinase activity by protein S. These
      results show that the C-terminal region of protein S containing residues 621-635
      is essential for binding of protein S to Factor Va and that this interaction
      contributes to anticoagulant action.

PMID- 10593905
TI  - Correction of aberrant splicing of the cystic fibrosis transmembrane conductance
      regulator (CFTR) gene by antisense oligonucleotides.
AB  - The CFTR splicing mutation 3849 + 10 kb C --> T creates a novel donor site 10
      kilobases (kb) into intron 19 of the gene and is one of the more common splicing
      mutations that causes cystic fibrosis (CF). It has an elevated prevalence among
      patients with atypically mild disease and normal sweat electrolytes and is
      especially prominent in Ashkenazi Jews. This class of splicing mutations,
      reported in several genes, involves novel splice sites activated deep within
      introns while leaving wild-type splice elements intact. CFTR cDNA constructs that
      modeled the 3849 + 10 kb C --> T mutation were expressed in 3T3 mouse fibroblasts
      and in CFT1 human tracheal and C127 mouse mammary epithelial cells. In all three
      cell types, aberrant splicing of CFTR pre-mRNA was comparable to that reported in
      vivo in CF patients. Treatment of the cells with 2'-O-methyl phosphorothioate
      oligoribonucleotides antisense toward the aberrant donor and acceptor splice
      sites or to the retained exon-like sequence, disfavored aberrant splicing and
      enhanced normal processing of CFTR pre-mRNA. This antisense-mediated correction
      of splicing was dose- and sequence-dependent and was accompanied by increased
      production of CFTR protein that was appropriately glycosylated. Antisense
      mediated correction of splicing in a mutation-specific context represents a
      potential gene therapy modality with applicability to many inherited disorders.

PMID- 10593906
TI  - Both p38alpha(MAPK) and JNK/SAPK pathways are important for induction of nitric
      oxide synthase by interleukin-1beta in rat glomerular mesangial cells.
AB  - Interleukin 1beta (IL-1beta) induces expression of the inducible nitric-oxide
      synthase (iNOS) with concomitant release of nitric oxide (NO) from glomerular
      mesangial cells. These events are preceded by activation of the c-Jun NH(2)
      terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38(MAPK). Our
      current study demonstrates that overexpression of the dominant negative form of
      JNK1 or p54 SAPKbeta/JNK2 significantly reduces the iNOS protein expression and
      NO production induced by IL-1beta. Similarly, overexpression of the kinase-dead
      mutant form of p38alpha(MAPK) also inhibits IL-1beta-induced iNOS expression and
      NO production. In previous studies we demonstrated that IL-1beta can activate
      MKK4/SEK1, MKK3, and MKK6 in renal mesangial cells; therefore, we examined the
      role of these MAPK kinases in the modulation of iNOS induced by IL-1beta.
      Overexpression of the dominant negative form of MKK4/SEK1 decreases IL-1beta
      induced iNOS expression and NO production with inhibition of both SAPK/JNK and
      p38(MAPK) phosphorylation. Overexpression of the kinase-dead mutant form of MKK3
      or MKK6 demonstrated that either of these two mutant kinase inhibited IL-1beta
      induced p38(MAPK) (but not JNK/SAPK) phosphorylation and iNOS expression.
      Interestingly overexpression of wild type MKK3/6 was associated with
      phosphorylation of p38(MAPK); however, in the absence of IL-1beta, iNOS
      expression was not enhanced. This study suggests that the activation of both
      SAPK/JNK and p38alpha(MAPK) signaling cascades are necessary for the IL-1beta
      induced expression of iNOS and production of NO in renal mesangial cells.

PMID- 10593907
TI  - Chromium(VI) inhibits the transcriptional activity of nuclear factor-kappaB by
      decreasing the interaction of p65 with cAMP-responsive element-binding protein
      binding protein.
AB  - Chromium(VI) regulation of gene expression has been attributed to the generation
      of reactive chromium and oxygen species, DNA damage, and alterations in mRNA
      stability. However, the effects of Cr(VI) on signal transduction leading to gene
      expression are not resolved. Therefore, this study investigated the effects of
      Cr(VI) on basal and tumor necrosis factor-alpha (TNF-alpha)-induced
      transcriptional competence of nuclear factor-kappaB (NF-kappaB) in A549 human
      lung carcinoma cells. Pretreatment of A549 cells with nontoxic levels of Cr(VI)
      inhibited TNF-alpha-stimulated expression of the endogenous gene for interleukin
      8 and of an NF-kappaB-driven luciferase gene construct, but not expression of
      urokinase, a gene with a more complex promoter. Chromium did not inhibit TNF
      alpha-stimulated IkappaBalpha degradation or translocation of NF-kappaB-binding
      proteins to the nucleus. However, Cr(VI) pretreatments prevented TNF-alpha
      stimulated interactions between the p65 subunit of NF-kappaB and the
      transcriptional cofactor cAMP-responsive element-binding protein-binding protein
      (CBP). This inhibition was not the result of an effect of chromium on the protein
      kinase A catalytic activity required for p65/CBP interactions. In contrast,
      Cr(VI) caused concentration-dependent increases in c-Jun/CBP interactions. These
      data indicate that nontoxic levels of hexavalent chromium selectively inhibit NF
      kappaB transcriptional competence by inhibiting interactions with coactivators of
      transcription rather than DNA binding.

PMID- 10593908
TI  - A point mutation in a plant calmodulin is responsible for its inhibition of
      nitric-oxide synthase.
AB  - The calcium/calmodulin-dependent activation of nitric-oxide synthase (NOS) and
      its production of nitric oxide (NO) play a key regulatory role in plant and
      animal cell function. SCaM-1 is a plant calmodulin (CaM) isoform that is 91%
      identical to mammalian CaM (wild type CaM (wtCaM)) and a selective competitive
      antagonist of NOS (Cho, M. J., Vaghy, P. L., Kondo, R., Lee, S. H., Davis, J. P.,
      Rehl, R., Heo, W. D., and Johnson, J. D. (1998) Biochemistry 37, 15593-15597). We
      have used site-directed mutagenesis to show that a point mutation, involving the
      substitution of valine for methionine at position 144, is responsible for SCaM
      1's inhibition of mammalian NOS. An M144V mutation in wild type CaM produced a
      mutant (M144V) which exhibited nearly identical inhibition of NOS's NO production
      and NADPH oxidation, with a similar K(i) (approximately 15 nM) as SCaM-1. A V144M
      back mutation in SCaM-1 significantly restored its ability to activate NOS's
      catalytic functions. The length of the hydrophobic amino acid side chain at
      position 144 appears to be critical for NOS activation, since M144L and M144F
      activated NOS while M144V and M144C did not. Despite their competitive antagonism
      of NOS, M144V, like SCaM-1, exhibited a similar dose-dependent activation of
      phosphodiesterase and calcineurin as wtCaM. SCaM-1 and M144V produced greater
      inhibition of NOS's oxygenase domain function (NO production) than its reductase
      domain functions (NADPH oxidation and cytochrome c reduction). Thus, CaM's
      methionine 144 plays a critical role the activation of NOS, presumably by
      influencing the function of NOS's oxygenase domain.

PMID- 10593909
TI  - Acylation stimulating protein (ASP) deficiency alters postprandial and adipose
      tissue metabolism in male mice.
AB  - Acylation stimulating protein (ASP) is a potent stimulator of triglyceride
      synthesis in adipocytes. In the present study, we have examined the effect of an
      ASP functional knockout (ASP(-/-)) on lipid metabolism in male mice. In both
      young (14 weeks) and older (26 weeks) mice there were marked delays in
      postprandial triglyceride clearance (80% increase at 14 weeks and 120% increase
      at 26 weeks versus wild type (+/+)). Postprandial nonesterified fatty acids were
      also increased in ASP(-/-) mice versus ASP(+/+) mice by 37% (low fat 10% Kcal)
      and by 73% (high fat 40% Kcal) diets, although there were no differences in
      fasting lipid levels. The ASP(-/-) mice had moderately increased energy intake
      (16% +/- 2% p < 0.0001) and reduced feed efficiency (33% increase in calories/g
      of body weight gained on low fat diet) versus wild type. The ASP(-/-) mice also
      had modest changes in insulin/glucose metabolism (30% to 40% decrease in
      insulin.glucose product), implying increased insulin sensitivity. As well, there
      were decreases in leptin (29% shift in leptin to body weight ratio) and up to a
      26% decrease in specific adipose tissue depots versus the wild type mice on both
      low fat and high fat diets. These results demonstrate that ASP plays an important
      role in adipose tissue metabolism and fat partitioning.

PMID- 10593910
TI  - Identification of catalytic residues in glyoxal oxidase by targeted mutagenesis.
AB  - Glyoxal oxidase is a copper metalloenzyme produced by the wood-rot fungus
      Phanerochaete chrysosporium as an essential component of its extracellular lignin
      degradation pathways. Previous spectroscopic studies on glyoxal oxidase have
      demonstrated that it contains a free radical-coupled copper active site
      remarkably similar to that found in another fungal metalloenzyme, galactose
      oxidase. Alignment of primary structures has allowed four catalytic residues of
      glyoxal oxidase to be targeted for site-directed mutagenesis in the recombinant
      protein. Three glyoxal oxidase mutants have been heterologously expressed in both
      a filamentous fungus (Aspergillus nidulans) and in a methylotrophic yeast (Pichia
      pastoris), the latter expression system producing as much as 2 g of protein per
      liter of culture medium under conditions of high density methanol-induced
      fermentation. Biochemical and spectroscopic characterization of the mutant
      enzymes supports structural correlations between galactose oxidase and glyoxal
      oxidase, clearly identifying the catalytically important residues in glyoxal
      oxidase and demonstrating the functions of each of these residues.

PMID- 10593911
TI  - Studies on the reaction mechanism of Rhodotorula gracilis D-amino-acid oxidase.
      Role of the highly conserved Tyr-223 on substrate binding and catalysis.
AB  - We have studied D-amino-acid oxidase from Rhodotorula gracilis by site-directed
      mutagenesis for the purpose of determining the presence or absence of residues
      having a possible role in acid/base catalysis. Tyr-223, one of the very few
      conserved residues among D-amino-acid oxidases, has been mutated to phenylalanine
      and to serine. Both mutants are active catalysts in turnover with D-alanine, and
      they are reduced by D-alanine slightly faster than wild-type enzyme. The Tyr-223 
      -> Phe mutant is virtually identical to the wild-type enzyme, whereas the Tyr-223
      --> Ser mutant exhibits 60-fold slower substrate binding and at least 800-fold
      slower rate of product release relative to wild-type. These data eliminate Tyr
      223 as an active-site acid/base catalyst. These results underline the importance
      of Tyr-223 for substrate binding and exemplify the importance of steric
      interactions in RgDAAO catalysis.

PMID- 10593912
TI  - The von Willebrand factor-glycoprotein Ib/V/IX interaction induces actin
      polymerization and cytoskeletal reorganization in rolling platelets and
      glycoprotein Ib/V/IX-transfected cells.
AB  - Platelet adhesion to sites of vascular injury is initiated by the binding of the
      platelet glycoprotein (GP) Ib-V-IX complex to matrix-bound von Willebrand factor
      (vWf). This receptor-ligand interaction is characterized by a rapid on-off rate
      that enables efficient platelet tethering and rolling under conditions of rapid
      blood flow. We demonstrate here that platelets adhering to immobilized vWf under
      flow conditions undergo rapid morphological conversion from flat discs to spiny
      spheres during surface translocation. Studies of Glanzmann thrombasthenic
      platelets (lacking integrin alpha(IIb)beta(3)) and Chinese hamster ovary (CHO)
      cells transfected with GPIb/IX (CHO-Ib/IX) confirmed that vWf binding to GPIb/IX
      was sufficient to induce actin polymerization and cytoskeletal reorganization
      independent of integrin alpha(IIb)beta(3). vWf-induced cytoskeletal
      reorganization occurred independently of several well characterized signaling
      processes linked to platelet activation, including calcium influx, prostaglandin
      metabolism, protein tyrosine phosphorylation, activation of protein kinase C or
      phosphatidylinositol 3-kinase but was critically dependent on the mobilization of
      intracellular calcium. Studies of Oregon Green 488 1, 2-bis(o-amino-5
      fluorophenoxy)ethane-N,N,N',N-tetraacetic acid tetraacetoxymethyl ester-loaded
      platelets and CHO-Ib/IX cells demonstrated that these cells mobilize
      intracellular calcium in a shear-dependent manner during surface translocation on
      vWf. Taken together, these studies suggest that the vWf-GPIb interaction
      stimulates actin polymerization and cytoskeletal reorganization in rolling
      platelets via a shear-sensitive signaling pathway linked to intracellular calcium
      mobilization.

PMID- 10593913
TI  - A copper-sensing transcription factor regulates iron uptake genes in
      Schizosaccharomyces pombe.
AB  - Copper and iron serve essential functions as catalytic co-factors in a wide
      variety of critical cellular enzymes. Studies in yeast have demonstrated an
      absolute dependence upon copper acquisition for proper assembly and function of
      the iron transport machinery. We have cloned genes for a high affinity copper
      transporter (Ctr4) and copper-sensing transcription factor (Cuf1) from
      Schizosaccharomyces pombe. Interestingly, the primary structure of Ctr4 and a
      putative human high affinity copper transport protein, hCtr1, suggests that they
      are derived from a fusion of the functionally redundant but structurally distinct
      Ctr1 and Ctr3 copper transporters from Saccharomyces cerevisiae. Furthermore,
      although Cuf1 activates ctr4(+) gene expression under copper starvation
      conditions, under these same conditions Cuf1 directly represses expression of
      genes encoding components of the iron transport machinery. These studies have
      identified an evolutionary step in which copper transport modules have been
      fused, and describe a mechanism by which a copper-sensing factor directly
      represses expression of the iron uptake genes under conditions in which the
      essential copper co-factor is scarce.

PMID- 10593914
TI  - Lengthening the second stalk of F(1)F(0) ATP synthase in Escherichia coli.
AB  - In Escherichia coli F(1)F(0) ATP synthase, the two b subunits dimerize forming
      the peripheral second stalk linking the membrane F(0) sector to F(1). Previously,
      we have demonstrated that the enzyme could accommodate relatively large deletions
      in the b subunits while retaining function (Sorgen, P. L., Caviston, T. L.,
      Perry, R. C., and Cain, B. D. (1998) J. Biol. Chem. 273, 27873-27878). The
      manipulations of b subunit length have been extended by construction of insertion
      mutations into the uncF(b) gene adding amino acids to the second stalk. Mutants
      with insertions of seven amino acids were essentially identical to wild type
      strains, and mutants with insertions of up to 14 amino acids retained
      biologically significant levels of activity. Membranes prepared from these
      strains had readily detectable levels of F(1)F(0)-ATPase activity and proton
      pumping activity. However, the larger insertions resulted in decreasing levels of
      activity, and immunoblot analysis indicated that these reductions in activity
      correlated with reduced levels of b subunit in the membranes. Addition of 18
      amino acids was sufficient to result in the loss of F(1)F(0) ATP synthase
      function. Assuming the predicted alpha-helical structure for this area of the b
      subunit, the 14-amino acid insertion would result in the addition of enough
      material to lengthen the b subunit by as much as 20 A. The results of both
      insertion and deletion experiments support a model in which the second stalk is a
      flexible feature of the enzyme rather than a rigid rod-like structure.

PMID- 10593915
TI  - Selective effects of sodium chlorate treatment on the sulfation of heparan
      sulfate.
AB  - We have analyzed the effect of sodium chlorate treatment of Madin-Darby canine
      kidney cells on the structure of heparan sulfate (HS), to assess how the various
      sulfation reactions during HS biosynthesis are affected by decreased availability
      of the sulfate donor 3'-phosphoadenosine 5'-phosphosulfate. Metabolically
      [(3)H]glucosamine-labeled HS was isolated from chlorate-treated and untreated
      Madin-Darby canine kidney cells and subjected to low pH nitrous acid cleavage.
      Saccharides representing (i) the N-sulfated domains, (ii) the domains of
      alternating N-acetylated and N-sulfated disaccharide units, and (iii) the N
      acetylated domains were recovered and subjected to compositional disaccharide
      analysis. Upon treatment with 50 mM chlorate, overall O-sulfation of HS was
      inhibited by approximately 70%, whereas N-sulfation remained essentially
      unchanged. Low chlorate concentrations (5 or 20 mM) selectively reduced the 6-O
      sulfation of HS, whereas treatment with 50 mM chlorate reduced both 2-O- and 6-O
      sulfation. Analysis of saccharides representing the different domain types
      indicated that 6-O-sulfation was preferentially inhibited in the alternating
      domains. These data suggest that reduced 3'-phosphoadenosine 5'-phosphosulfate
      availability has distinct effects on the N- and O-sulfation of HS and that O
      sulfation is affected in a domain-specific fashion.

PMID- 10593916
TI  - Genetically encoded and post-translationally modified forms of a major
      histocompatibility complex class I-restricted antigen bearing a glycosylation
      motif are independently processed and co-presented to cytotoxic T lymphocytes.
AB  - The mechanisms by which antigenic peptides bearing a glycosylation site may be
      processed from viral glycoproteins, post-translationally modified, and presented
      by major histocompatibility complex class I molecules remain poorly understood.
      With the aim of exploring these processes, we have dissected the structural and
      functional properties of the MHC-restricted peptide GP92-101 (CSANNSHHYI)
      generated from the lymphocytic choriomeningitis virus (LCMV) GP1 glycoprotein.
      LCMV GP92-101 bears a glycosylation motif -NXS- that is naturally N-glycosylated
      in the mature viral glycoprotein, displays high affinity for H-2D(b) molecules,
      and elicits a CD8(+) cytotoxic T lymphocyte response. By analyzing the functional
      properties of natural and synthetic peptides and by identifying the viral
      sequence(s) from the pool of naturally occurring peptides, we demonstrated that
      multiple forms of LCMV GP92-101 were generated from the viral glycoprotein and co
      presented at the surface of LCMV-infected cells. They corresponded to non
      glycosylated and post-translationally modified sequences (conversion of Asn-95 to
      Asp or alteration of Cys-92). The glycosylated form, despite its potential
      immunogenicity, was not detected. These data illustrate that distinct, non
      mutually exclusive antigen presentation pathways may occur simultaneously within
      a cell to generate structurally and functionally different peptides from a single
      genetically encoded sequence, thus contributing to increasing the diversity of
      the T cell repertoire.

PMID- 10593917
TI  - Mutation of the RIIbeta subunit of protein kinase A differentially affects
      lipolysis but not gene induction in white adipose tissue.
AB  - Targeted disruption of the RIIbeta subunit of protein kinase A (PKA) produces
      lean mice that resist diet-induced obesity. In this report we examine the effects
      of the RIIbeta knockout on white adipose tissue physiology. Loss of RIIbeta is
      compensated by an increase in the RIalpha isoform, generating an isoform switch
      from a type II to a type I PKA. Type I holoenzyme binds cAMP more avidly and is
      more easily activated than the type II enzyme. These alterations are associated
      with increases in both basal kinase activity and the basal rate of lipolysis,
      possibly contributing to the lean phenotype. However, the ability of both beta(3)
      selective and nonspecific beta-adrenergic agonists to stimulate lipolysis is
      markedly compromised in mutant white adipose tissue. This defect was found in
      vitro and in vivo and does not result from reduced expression of beta-adrenergic
      receptor or hormone-sensitive lipase genes. In contrast, beta-adrenergic
      stimulated gene transcription remains intact, and the expression of key genes
      involved in lipid metabolism is normal under both fasted and fed conditions. We
      suggest that the R subunit isoform switch disrupts the subcellular localization
      of PKA that is required for efficient transduction of signals that modulate
      lipolysis but not for those that mediate gene expression.

PMID- 10593918
TI  - MIR is a novel ERM-like protein that interacts with myosin regulatory light chain
      and inhibits neurite outgrowth.
AB  - The ERM protein family members ezrin, radixin, and moesin are cytoskeletal
      effector proteins linking actin to membrane-bound proteins at the cell surface.
      Here we report on the cloning of myosin regulatory light chain interacting
      protein (MIR), a protein with an ERM-homology domain and a carboxyl-terminal RING
      finger, that is expressed, among other tissues, in brain. MIR is distributed in
      cultured COS cells, in a punctuated manner as shown using enhanced green
      fluorescent protein (EGFP)-tagged MIR and by staining with a specific antibody
      for MIR. In the yeast two-hybrid system and in transfected COS cells, MIR
      interacts with myosin regulatory light chain B, which in turn regulates the
      activity of the actomyosin complex. Overexpression of MIR cDNA in PC12 cells
      abrogated neurite outgrowth induced by nerve growth factor (NGF) without
      affecting TrkA signaling. The results show that MIR, a novel ERM-like protein,
      affects cytoskeleton interactions regulating cell motility, such as neurite
      outgrowth.

PMID- 10593919
TI  - Regulation of glucose transport and glycogen synthesis in L6 muscle cells during
      oxidative stress. Evidence for cross-talk between the insulin and SAPK2/p38
      mitogen-activated protein kinase signaling pathways.
AB  - We have investigated the cellular mechanisms that participate in reducing insulin
      sensitivity in response to increased oxidant stress in skeletal muscle.
      Measurement of glucose transport and glycogen synthesis in L6 myotubes showed
      that insulin stimulated both processes, by 2- and 5-fold, respectively. Acute (30
      min) exposure of muscle cells to hydrogen peroxide (H(2)O(2)) blocked the
      hormonal activation of both these processes. Immunoblot analyses of cell lysates
      prepared after an acute oxidant challenge using phospho-specific antibodies
      against c-Jun N-terminal kinase (JNK), p38, protein kinase B (PKB), and p42 and
      p44 mitogen-activated protein (MAP) kinases established that H(2)O(2) induced a
      dose-dependent activation of all five protein kinases. In vitro kinase analyses
      revealed that 1 mM H(2)O(2) stimulated the activity of JNK by approximately 8
      fold, MAPKAP-K2 (the downstream target of p38 MAP kinase) by approximately 12
      fold and that of PKB by up to 34-fold. PKB activation was associated with a
      concomitant inactivation of glycogen synthase kinase-3. Stimulation of the p38
      pathway, but not that of JNK, was blocked by SB 202190 or SB203580, while that of
      p42/p44 MAP kinases and PKB was inhibited by PD 98059 and wortmannin
      respectively. However, of the kinases assayed, only p38 MAP kinase was activated
      at H(2)O(2) concentrations (50 microM) that caused an inhibition of insulin
      stimulated glucose transport and glycogen synthesis. Strikingly, inhibiting the
      activation of p38 MAP kinase using either SB 202190 or SB 203580 prevented the
      loss in insulin-stimulated glucose transport, but not that of glycogen synthesis,
      by oxidative stress. Our data indicate that activation of the p38 MAP kinase
      pathway plays a central role in the oxidant-induced inhibition of insulin
      regulated glucose transport, and unveils an important biochemical link between
      the classical stress-activated and insulin signaling pathways in skeletal muscle.

PMID- 10593920
TI  - The fatty acid transport protein (FATP1) is a very long chain acyl-CoA
      synthetase.
AB  - The primary sequence of the murine fatty acid transport protein (FATP1) is very
      similar to the multigene family of very long chain (C20-C26) acyl-CoA
      synthetases. To determine if FATP1 is a long chain acyl coenzyme A synthetase,
      FATP1-Myc/His fusion protein was expressed in COS1 cells, and its enzymatic
      activity was analyzed. In addition, mutations were generated in two domains
      conserved in acyl-CoA synthetases: a 6- amino acid substitution into the putative
      active site (amino acids 249-254) generating mutant M1 and a 59-amino acid
      deletion into a conserved C-terminal domain (amino acids 464-523) generating
      mutant M2. Immunolocalization revealed that the FATP1-Myc/His forms were
      distributed between the COS1 cell plasma membrane and intracellular membranes.
      COS1 cells expressing wild type FATP1-Myc/His exhibited a 3-fold increase in the
      ratio of lignoceroyl-CoA synthetase activity (C24:0) to palmitoyl-CoA synthetase
      activity (C16:0), characteristic of very long chain acyl-CoA synthetases, whereas
      both mutant M1 and M2 were catalytically inactive. Detergent-solubilized FATP1
      Myc/His was partially purified using nickel-based affinity chromatography and
      demonstrated a 10-fold increase in very long chain acyl-CoA specific activity
      (C24:0/C16:0). These results indicate that FATP1 is a very long chain acyl-CoA
      synthetase and suggest that a potential mechanism for facilitating mammalian
      fatty acid uptake is via esterification coupled influx.

PMID- 10593921
TI  - Structural determinants of aldosterone binding selectivity in the
      mineralocorticoid receptor.
AB  - The structural determinants of aldosterone binding specificity in the
      mineralocorticoid receptor (MR) have not been determined. The MR has greatest
      sequence identity with the better characterized glucocorticoid receptor (GR),
      which is reflected in their overlapping ligand binding specificities. There must
      be subtle sequence differences that can account for the MR-specific binding of
      aldosterone and the shared binding of cortisol. To characterize ligand binding
      specificity, chimeras were made between the human MR and GR ligand-binding
      domains (LBDs). Three points were chosen as break points to generate a total of
      16 different constructs. These chimeric LBDs were placed in a human GR expression
      vector containing the GR DNA-binding and N-terminal domains and assayed by co
      transfection into CV-1 cells with the mouse mammary tumor virus-luciferase
      reporter plasmid. Binding of [(3)H]aldosterone and [(3)H]dexamethasone was also
      measured. All of the constructs that are potently activated by aldosterone
      contain amino acids 804-874 of the MR. The results of the ligand binding
      experiments using [(3)H]aldosterone were consistent with the transactivation
      assay. Cortisol activation of the chimeras was surprisingly complex. Constructs
      that are activated by cortisol contain either amino acids 804-874 and 932-984 of
      the MR or amino acids 598-668 and 726-777 of the GR. However, all of the chimeras
      retained the ability to bind the synthetic glucocorticoid [(3)H]dexamethasone,
      and cortisol was able to displace [(3)H]dexamethasone binding, suggesting that
      the differential effects of cortisol on transcriptional activation are caused by
      an effect that occurs downstream of ligand binding. These results identify a
      subregion of the MR LBD that confers specificity of aldosterone binding, which
      contrasts with cortisol binding where differential effects between chimeras
      appear to be mediated by interactions distal to ligand binding.

PMID- 10593922
TI  - Biosynthesis of a neo-epi-verrucosane diterpene in the liverwort Fossombronia
      alaskana. A retrobiosynthetic NMR study.
AB  - The biosynthesis of the diterpene 8alpha-acetoxy-13alpha-hydroxy-5-oxo-13-epi-
      neoverrucosane in the arctic liverwort Fossombronia alaskana was studied by
      incorporation experiments using [1-(13)C]- and [U-(13)C(6)]glucose as precursors.
      The (13)C-labeling patterns of acetyl-CoA, pyruvate, and phosphoenolpyruvate in
      intermediary metabolism were reconstructed from the (13)C NMR data of
      biosynthetic amino acids (leucine, alanine, phenylalanine) and were used to
      predict hypothetical labeling patterns for isopentenyl pyrophosphate formed via
      the mevalonate pathway and the deoxyxylulose pathway. The labeling patterns
      observed for the neoverrucosane diterpene were consistent with the intermediate
      formation of geranyllinaloyl pyrophosphate assembled from dimethylallyl
      pyrophosphate and three molecules of isopentenyl pyrophosphate generated
      predominantly or entirely via 1-deoxyxylulose 5-phosphate. The experimental data
      can be integrated into a detailed biosynthetic scheme involving a 1,5-hydride
      shift. The postulated involvement of the 1,5-hydride shift was confirmed by an
      incorporation experiment with [6,6-(2)H(2)]glucose.

PMID- 10593924
TI  - The integrin alpha(9)beta(1) binds to a novel recognition sequence (SVVYGLR) in
      the thrombin-cleaved amino-terminal fragment of osteopontin.
AB  - The integrin alpha(9)beta(1) mediates cell adhesion to tenascin-C and VCAM-1 by
      binding to sequences distinct from the common integrin-recognition sequence,
      arginine-glycine-aspartic acid (RGD). A thrombin-cleaved NH(2)-terminal fragment
      of osteopontin containing the RGD sequence has recently been shown to also be a
      ligand for alpha(9)beta(1). In this report, we used site-directed mutagenesis and
      synthetic peptides to identify the alpha(9)beta(1) recognition sequence in
      osteopontin. alpha(9)-transfected SW480, Chinese hamster ovary, and L-cells
      adhered to a recombinant NH(2)-terminal osteopontin fragment in which the RGD
      site was mutated to RAA (nOPN-RAA). Adhesion was completely inhibited by anti
      alpha(9) monoclonal antibody Y9A2, indicating the presence of a non-RGD
      alpha(9)beta(1) recognition sequence within this fragment. Alanine substitution
      mutagenesis of 13 additional conserved negatively charged amino acid residues in
      this fragment had no effect on alpha(9)beta(1)-mediated adhesion, but adhesion
      was dramatically inhibited by either alanine substitution or deletion of tyrosine
      165. A synthetic peptide, SVVYGLR, corresponding to the sequence surrounding
      Tyr(165), blocked alpha(9)beta(1)-mediated adhesion to nOPN-RAA and exposed a
      ligand-binding-dependent epitope on the integrin beta(1) subunit on alpha(9)
      transfected, but not on mock-transfected cells. These results demonstrate that
      the linear sequence SVVYGLR directly binds to alpha(9)beta(1) and is responsible
      for alpha(9)beta(1)-mediated cell adhesion to the NH(2)-terminal fragment of
      osteopontin.

PMID- 10593925
TI  - Advantages of using same species enzyme for replacement therapy in a feline model
      of mucopolysaccharidosis type VI.
AB  - In a feline model of mucopolysaccharidosis type VI (MPS VI), recombinant feline N
      acetylgalactosamine-4-sulfatase (rf4S) administered at a dose of 1 mg/kg of body
      weight, altered the clinical course of the disease in two affected cats treated
      from birth. After 170 days of therapy, both cats were physically
      indistinguishable from normal cats with the exception of mild corneal clouding.
      Feline N-acetylgalactosamine-4-sulfatase was effective in reducing urinary
      glycosaminoglycan levels and lysosomal storage in all cell types examined except
      for corneal keratocytes and cartilage chondrocytes. In addition, skeletal
      pathology was nearly normalized as assessed by radiographic evidence and bone
      morphometric analysis. Comparison of results with a previous study in which
      recombinant human 4S (rh4S) was used at an equivalent dose and one 5 times higher
      indicated that rf4S had a more pronounced effect on reducing pathology than the
      same dose of rh4S, and in some instances such as bone pathology and lysosomal
      storage in aorta smooth muscle cells, it was as good as, or better than, the
      higher dose of rh4S. We conclude that in the feline MPS VI model the use of
      native or same species enzyme for enzyme replacement therapy has significant
      benefits.

PMID- 10593923
TI  - Inhibition of calpain blocks platelet secretion, aggregation, and spreading.
AB  - Previous studies have indicated that the Ca(2+)-dependent protease, calpain, is
      activated in platelets within 30-60 s of thrombin stimulation, but specific roles
      of calpain in platelets remain to be identified. To directly test the functions
      of calpain during platelet activation, a novel strategy was developed for
      introducing calpain's specific biological inhibitor, calpastatin, into platelets
      prior to activation. This method involves treatment of platelets with a fusion
      peptide, calpastat, consisting of the cell-penetrating signal sequence from
      Kaposi's fibroblast growth factor connected to a calpain-inhibiting consensus
      sequence derived from calpastatin. Calpastat specifically inhibits thrombin
      peptide (SFLLR)-induced alpha-granule secretion (IC(50) = 20 microM) during the
      first 30 s of activation, thrombin-induced platelet aggregation (IC(50) = 50
      microM), and platelet spreading on glass surfaces (IC(50) = 34 microM). Calpastat
      Ala, a mutant peptide in which alanine is substituted at conserved calpastatin
      residues, lacks calpain inhibitory activity and fails to inhibit secretion,
      aggregation, or spreading. The peptidyl calpain inhibitors calpeptin, MDL 28,170
      (MDL) and E64d also inhibit secretion, aggregation and spreading, but require 3
      10-fold higher concentrations than calpastat for biological activity. Together,
      these findings demonstrate that calpain regulates platelet secretion,
      aggregation, and spreading and indicate that calpain plays an earlier role in
      platelet activation following thrombin receptor stimulation than had been
      previously detected.

PMID- 10593926
TI  - Mlx, a novel Max-like BHLHZip protein that interacts with the Max network of
      transcription factors.
AB  - Mad:Max heterodimers oppose the growth-promoting action of Myc:Max heterodimers
      by recruiting the mSin3-histone deacetylase (mSin3. HDAC) complex to DNA and
      functioning as potent transcriptional repressors. There are four known members of
      the Mad family that are indistinguishable in their abilities to interact with
      Max, bind DNA, repress transcription, and block Myc + Ras co-transformation. To
      investigate functional differences between Mad family proteins, we have
      identified additional proteins that interact with this family. Here we present
      the identification and characterization of the novel basic-helix-loop-helix
      zipper protein Mlx (Max-like protein x), which is structurally and functionally
      related to Max. The similarities between Mlx and Max include 1) broad expression
      in many tissues, 2) long protein half-life, and 3) formation of heterodimers with
      Mad family proteins that are capable of specific CACGTG binding. We show that
      transcriptional repression by Mad1:Mlx heterodimers is dependent on dimerization,
      DNA binding, and recruitment of the mSin3A.HDAC corepressor complex. In contrast
      with Max, Mlx interacts only with Mad1 and Mad4. Together, these findings suggest
      that Mlx may act to diversify Mad family function by its restricted association
      with a subset of the Mad family of transcriptional repressors.

PMID- 10593927
TI  - Degradation of the basic helix-loop-helix/Per-ARNT-Sim homology domain dioxin
      receptor via the ubiquitin/proteasome pathway.
AB  - The basic helix-loop-helix/Per-ARNT-Sim homology domain dioxin receptor (DR)
      translocates to the nucleus upon binding of aromatic hydrocarbon ligands typified
      by dioxin, whereupon it partners the Ah receptor nuclear translocator and
      initiates transcription. Concurrently, ligand binding down-regulates receptor
      levels via an unknown mechanism. In this study we show that receptor levels are
      dependent upon cellular compartmentalization, with entry into the nucleus leading
      to the rapid destruction of the DR. Ligand-induced DR translocation was bypassed
      by adding a heterologous nuclear localization signal to the DR, creating a
      constitutively nuclear form of the dioxin receptor (DRNLS). The DRNLS protein was
      shown to be unstable with a half-life of </=1 h whether partnering ARNT or HSP90.
      Thus, the structural changes induced by ligand binding have no inherent effect on
      DR stability but are critical in transporting the receptor prior to degradation.
      The proteolytic pathway that degrades the nuclear receptor is suggested to
      involve ubiquitination as it was inhibited by the proteasome inhibitor MG132 or
      co-expression of DRNLS with the ubiquitin mutant UbK48R. Incubation of cells
      expressing DRNLS with the phosphatase inhibitor calyculin resulted in the rapid
      phosphorylation and ubiquitination of DRNLS, suggesting that a nuclear kinase is
      required to trigger receptor proteolysis. Overall, this study demonstrates a
      novel mechanism of proteolysis whereby the simple relocation of a transcription
      factor from cytoplasm to nucleus initiates its rapid destruction.

PMID- 10593928
TI  - Tandem B1 elements located in a mouse methylation center provide a target for de
      novo DNA methylation.
AB  - A cis-acting methylation center that signals de novo DNA methylation is located
      upstream of the mouse Aprt gene. In the current study, two approaches were taken
      to determine if tandem B1 repetitive elements found at the 3' end of the
      methylation center contribute to the methylation signal. First, bisulfite genomic
      sequencing demonstrated that CpG sites within the B1 elements were methylated at
      relative levels of 43% in embryonal stem cells deficient for the maintenance DNA
      methyltransferase when compared with wild type embryonal stem cells. Second, the
      ability of the B1 elements to signal de novo methylation upon stable transfection
      into mouse embryonal carcinoma cells was examined. This approach demonstrated
      that the B1 elements were methylated de novo to a high level in the embryonal
      carcinoma cells and that the B1 elements acted synergistically. The results from
      these experiments provide strong evidence that the tandem B1 repetitive elements
      provide a significant fraction of the methylation center signal. By extension,
      they also support the hypothesis that one role for DNA methylation in mammals is
      to protect the genome from expression and transposition of parasitic elements.

PMID- 10593929
TI  - Activated ERK2 interacts with and phosphorylates the docking protein GAB1.
AB  - Grb2-associated binder 1 (GAB1) is a docking protein found to associate with the
      activated c-MET receptor via the MET-binding domain (MBD) and appears to be
      critical for the tubulogenic actions of this receptor. Pull-down experiments with
      bacterially expressed MBD and full-length GAB1 revealed the presence of c-MET as
      well as phosphorylated ERK2 (pERK2). By using purified pERK2 and non-pERK2, we
      found that GAB1 associates exclusively with the phosphorylated form of the enzyme
      and that this association does not require mediation by a third protein. When
      epitope-tagged GAB1 was co-transfected with constitutively active MEK1 into A293
      cells, co-immunoprecipitation of GAB1 and pERK2 was observed, demonstrating that
      this interaction can occur in intact cells. In vitro, both the MBD and full
      length GAB1 were found to be substrates for activated ERK2. In intact cells,
      epitope-tagged GAB1 was found to be basally phosphorylated on serine with an
      increase following co-transfection with constitutively active MEK1 and the
      appearance of novel phosphorylation sites detected by phosphopeptide mapping.
      Thus, it appears that GAB1 can associate directly with phosphorylated ERK2 via
      the MET-binding domain and that GAB1 then acts as a substrate for the enzyme.

PMID- 10593930
TI  - The N-terminal domain of Pseudomonas aeruginosa exoenzyme S is a GTPase
      activating protein for Rho GTPases.
AB  - Pseudomonas aeruginosa exoenzyme S (ExoS) is a bifunctional cytotoxin. The ADP
      ribosyltransferase domain is located within the C terminus part of ExoS. Recent
      studies showed that the N terminus part of ExoS (amino acid residues 1-234,
      ExoS(1-234)), which does not possess ADP-ribosyltransferase activity, stimulates
      cell rounding when transfected or microinjected into eukaryotic cells. Here we
      studied the effects of ExoS(1-234) on nucleotide binding and hydrolysis by Rho
      GTPases. ExoS(1-234) (100-500 nM) did not influence nucleotide exchange of Rho,
      Rac, and Cdc42 but increased GTP hydrolysis. A similar increase in GTPase
      activity was stimulated by full-length ExoS. Half-maximal stimulation of GTP
      hydrolysis by Rho, Rac, and Cdc42 was observed at 10-11 nM ExoS(1-234),
      respectively. We identified arginine 146 of ExoS to be essential for the
      stimulation of GTPase activity of Rho proteins. These data identify ExoS as a
      GTPase-activating protein for Rho GTPases.

PMID- 10593931
TI  - Identification of amino acids in the factor XI apple 3 domain required for
      activation of factor IX.
AB  - Activated coagulation factor XI (factor XIa) proteolytically cleaves its
      substrate, factor IX, in an interaction requiring the factor XI A3 domain (Sun,
      Y., and Gailani, D. (1996) J. Biol. Chem. 271, 29023-29028). To identify key
      amino acids involved in factor IX activation, recombinant factor XIa proteins
      containing alanine substitutions for wild-type sequence were expressed in 293
      fibroblasts and tested in a plasma clotting assay. Substitutions for Ile(183)
      Val(191) and Ser(195)-Ile(197) at the N terminus and for Ser(258)-Ser(264) at the
      C terminus of the A3 domain markedly decreased factor XI coagulant activity. The
      plasma protease prekallikrein is structurally homologous to factor XI, but
      activated factor IX poorly. A chimeric factor XIa molecule with the A3 domain
      replaced with A3 from prekallikrein (FXI/PKA3) activated factor IX with a K(m) 35
      fold greater than that of wild-type factor XI. FXI/PKA3 was used as a template
      for a series of proteins in which prekallikrein A3 sequence was replaced with
      factor XI sequence to restore factor IX activation. Clotting and kinetics studies
      using these chimeras confirmed the results obtained with alanine mutants. Amino
      acids between Ile(183) and Val(191) are necessary for proper factor IX
      activation, but additional sequence between Ser(195) and Ile(197) or between
      Phe(260) and Ser(265) is required for complete restoration of activation.

PMID- 10593932
TI  - Reactions of type II restriction endonucleases with 8-base pair recognition
      sites.
AB  - Type II restriction endonucleases usually recognize 4-6-base pair (bp) sites on
      DNA and cleave each site in a separate reaction. A few type II endonucleases have
      8-bp recognition sites, but these seem unsuited for restriction, since their
      sites are rare on most DNA. Moreover, only one endonuclease that recognizes a
      target containing 8 bp has been examined to date, and this enzyme, SfiI, needs
      two copies of this site for its DNA cleavage reaction. In this study, several
      endonucleases with 8-bp sites were tested on plasmids that have either one or two
      copies of the relevant sequence to determine if they also need two sites. SgfI,
      SrfI, FseI, PacI, PmeI, Sse8781I, and SdaI all acted through equal and
      independent reactions at each site. AscI cleaved the DNA with one site at the
      same rate as that with two sites but acted processively on the latter. In
      contrast, SgrAI showed a marked preference for the plasmid with two sites and
      cleaved both sites on this DNA in a concerted manner, like SfiI. Endonucleases
      that require two copies of an 8-bp sequence may be widespread in nature, where,
      despite this seemingly inappropriate requirement, they may function in DNA
      restriction.

PMID- 10593933
TI  - Feedback phosphorylation of an RGS protein by MAP kinase in yeast.
AB  - Regulators of G protein signaling (RGS proteins) are well known to accelerate G
      protein GTPase activity in vitro and to promote G protein desensitization in
      vivo. Less is known about how RGS proteins are themselves regulated. To address
      this question we purified the RGS in yeast, Sst2, and used electrospray
      ionization mass spectrometry to identify post-translational modifications. This
      analysis revealed that Sst2 is phosphorylated at Ser-539 and that phosphorylation
      occurs in response to pheromone stimulation. Ser-539 lies within a consensus
      mitogen-activated protein (MAP) kinase phosphorylation site, Pro-X-Ser-Pro.
      Phosphorylation is blocked by mutations in the MAP kinase genes (FUS3, KSS1), as
      well as by mutations in components needed for MAP kinase activation (STE11, STE7,
      STE4, STE18). Phosphorylation is also blocked by replacing Ser-539 with Ala, Asp,
      or Glu (but not Thr). These point mutations do not alter pheromone sensitivity,
      as determined by growth arrest and reporter transcription assays. However,
      phosphorylation appears to slow the rate of Sst2 degradation. These findings
      indicate that the G protein-regulated MAP kinase in yeast can act as a feedback
      regulator of Sst2, itself a regulator of G protein signaling.

PMID- 10593934
TI  - Identification of a UDP-GlcNAc:Skp1-hydroxyproline GlcNAc-transferase in the
      cytoplasm of Dictyostelium.
AB  - Skp1 is a cytoplasmic and nuclear protein required for the ubiquitination of cell
      cycle regulatory proteins and transcriptional factors. In Dictyostelium, Skp1 is
      modified by a linear pentasaccharide, Galalpha1-6Galalpha1-Fucalpha1-2Galbeta1
      3Glc NAc, attached to a hydroxyproline (HyPro) residue at position 143. To study
      the formation of the GlcNAc-HyPro linkage, an assay was developed for the
      transfer of [(3)H]GlcNAc from UDP-[(3)H]GlcNAc to Skp1-HyPro-143 or a synthetic
      Skp1 4-HyPro peptide. The cytosolic but not the particulate fraction of the cell
      mediated transfer in a time-, concentration-, and HyPro-dependent fashion.
      Incorporated radioactivity was alkali-resistant and was recovered as GlcNH(2)
      after acid hydrolysis, consistent with linkage of GlcNAc to HyPro. The GlcNAc
      transferase activity was purified 130,000-fold as a single component with a
      recovery of 5%. Key to the purification was the synthesis of a novel affinity
      resin linking UDP-GlcNAc at its 5-uridyl position. The purified activity had an
      apparent M(r) of approximately 45,000 by gel filtration, required dithiothreitol
      and a divalent cation, and consisted predominantly of a M(r) 51,000 band after
      SDS-polyacrylamide gel electrophoresis that was photoaffinity labeled with 5
      (125)I-[3-(p-azidosalicylamido)-1-propenyl-UDP-GlcNAc in a UDP-GlcNAc-sensitive
      fashion. Its apparent K(m) values for UDP-GlcNAc and Skp1 were submicromolar. The
      presence of the enzyme in the cytosolic fraction, its dependence on a reducing
      environment, and its high affinity for UDP-GlcNAc strongly suggest that Skp1 is
      glycosylated by a HyPro GlcNAc-transferase that resides in the cytoplasm.

PMID- 10593935
TI  - Perlecan mediates the antiproliferative effect of apolipoprotein E on smooth
      muscle cells. An underlying mechanism for the modulation of smooth muscle cell
      growth?
AB  - Apolipoprotein E (apoE) is known to inhibit cell proliferation; however, the
      mechanism of this inhibition is not clear. We recently showed that apoE
      stimulates endothelial production of heparan sulfate (HS) enriched in heparin
      like sequences. Because heparin and HS are potent inhibitors of smooth muscle
      cell (SMC) proliferation, in this study we determined apoE effects on SMC HS
      production and cell growth. In confluent SMCs, apoE (10 microg/ml) increased
      (35)SO(4) incorporation into PG in media by 25-30%. The increase in the medium
      was exclusively due to an increase in HSPGs (2.2-fold), and apoE did not alter
      chondroitin and dermatan sulfate proteoglycans. In proliferating SMCs, apoE
      inhibited [(3)H]thymidine incorporation into DNA by 50%; however, despite
      decreasing cell number, apoE increased the ratio of (35)SO(4) to [(3)H]thymidine
      from 2 to 3.6, suggesting increased HS per cell. Purified HSPGs from apoE
      stimulated cells inhibited cell proliferation in the absence of apoE. ApoE did
      not inhibit proliferation of endothelial cells, which are resistant to heparin
      inhibition. Analysis of the conditioned medium from apoE-stimulated cells
      revealed that the HSPG increase was in perlecan and that apoE also stimulated
      perlecan mRNA expression by >2-fold. The ability of apoE isoforms to inhibit cell
      proliferation correlated with their ability to stimulate perlecan expression. An
      anti-perlecan antibody completely abrogated the antiproliferative effect of apoE.
      Thus, these data show that perlecan is a potent inhibitor of SMC proliferation
      and is required to mediate the antiproliferative effect of apoE. Because other
      growth modulators also regulate perlecan expression, this may be a key pathway in
      the regulation of SMC growth.

PMID- 10593936
TI  - Novel physiological function of sphingomyelin in plasma. Inhibition of lipid
      peroxidation in low density lipoproteins.
AB  - Although sphingomyelin (SPH) is a major constituent of all lipoproteins, its
      physiological function in plasma is not known. In this study, we tested the
      hypothesis that SPH inhibits lipid peroxidation in low density lipoproteins (LDL)
      because of its effects on surface fluidity and packing density and that the
      relative resistance of the buoyant LDL to oxidation, compared with the dense LDL,
      is partly due to their higher SPH content. Depletion of SPH by treatment with
      SPHase resulted in shortened lag times and increased rates of oxidation in both
      LDL subfractions, as measured by the conjugated diene formation in the presence
      of Cu(2+). Oxidation of LDL by soybean lipoxygenase was similarly stimulated by
      the degradation of SPH. Oxidation-induced fluorescence decay of
      diphenylhexatriene-labeled phosphatidylcholine (PC), equilibrated with LDL-PC,
      was accelerated significantly by the enzymatic depletion of SPH from the
      lipoprotein. Oxidation of 16:0-18:2 PC in the proteoliposomes was inhibited
      progressively by the incorporation of increasing amounts of egg SPH into the
      liposomes. Treatment of SPH-containing proteoliposomes with SPHase reversed the
      effect of SPH, showing that the presence of intact SPH is necessary for the
      inhibition of oxidation. Although the incorporation of SPH into the same liposome
      as the PC (intrinsic SPH) protected the PC against oxidation, the addition of SPH
      liposomes to PC liposomes (extrinsic SPH) was not effective. Oxidation of 16:0
      18:2 PC in liposomes was also inhibited by the incorporation of dipalmitoyl-PC,
      but not by free cholesterol. These results suggest that SPH acts as a
      physiological inhibitor of lipoprotein oxidation, possibly by modifying the
      fluidity of the phospholipid monolayer and thereby inhibiting the lateral
      propagation of the lipid peroxy radicals.

PMID- 10593937
TI  - The second hydrophobic domain contributes to the kinetic properties of epithelial
      sodium channels.
AB  - The epithelial sodium channel (ENaC) is the prototype of a new class of ion
      channels known as the ENaC/Deg family. The hallmarks of ENaC are a high
      selectivity for Na(+), block by amiloride, small conductance, and slow kinetics
      that are voltage-independent. We have investigated the contribution of the second
      hydrophobic domain of each of the homologous subunits alpha, beta, and gamma to
      the kinetic properties of ENaC. Chimeric subunits were constructed between alpha
      and beta subunits (alpha-beta) and between gamma and beta subunits (gamma-beta).
      Chimeric and wild-type subunits were expressed in various combinations in Xenopus
      oocytes. Analysis of whole-cell and unitary currents made it possible to
      correlate functional properties with specific sequences in the subunits.
      Functional channels were generated without the second transmembrane domain from
      alpha subunits, indicating that it is not essential to form functional pores. The
      open probability and kinetics varied with the different channels and were
      influenced by the second hydrophobic domains. Amiloride affinity, Li(+)/Na(+)
      selectivity, and single channel conductance were also affected by this segment.

PMID- 10593938
TI  - Poor binding of a HER-2/neu epitope (GP2) to HLA-A2.1 is due to a lack of
      interactions with the center of the peptide.
AB  - Class I major histocompatibility complex (MHC) molecules bind short peptides
      derived from proteins synthesized within the cell. These complexes of peptide and
      class I MHC (pMHC) are transported from the endoplasmic reticulum to the cell
      surface. If a clonotypic T cell receptor expressed on a circulating T cell binds
      to the pMHC complex, the cell presenting the pMHC is killed. In this manner, some
      tumor cells expressing aberrant proteins are recognized and removed by the immune
      system. However, not all tumors are recognized efficiently. One reason
      hypothesized for poor T cell recognition of tumor-associated peptides is poor
      binding of those peptides to class I MHC molecules. Many peptides, derived from
      the proto-oncogene HER-2/neu have been shown to be recognized by cytotoxic T
      cells derived from HLA-A2(+) patients with breast cancer and other
      adenocarcinomas. Seven of these peptides were found to bind with intermediate to
      poor affinity. In particular, GP2 (HER-2/neu residues 654-662) binds very poorly
      even though it is predicted to bind well based upon the presence of the correct
      HLA-A2.1 peptide-binding motif. Altering the anchor residues to those most
      favored by HLA-A2.1 did not significantly improve binding affinity. The
      crystallographic structure shows that unlike other class I-peptide structures,
      the center of the peptide does not assume one specific conformation and does not
      make stabilizing contacts with the peptide-binding cleft.

PMID- 10593939
TI  - An SC35-like protein and a novel serine/arginine-rich protein interact with
      Arabidopsis U1-70K protein.
AB  - The U1 small nuclear ribonucleoprotein 70-kDa protein, a U1 small nuclear
      ribonucleoprotein-specific protein, has been shown to have multiple roles in
      nuclear precursor mRNA processing in animals. By using the C-terminal arginine
      rich region of Arabidopsis U1-70K protein in the yeast two-hybrid system, we have
      identified an SC35-like (SR33) and a novel plant serine/arginine-rich (SR)
      protein (SR45) that interact with the plant U1-70K. The SR33 and SR45 proteins
      share several features with SR proteins including modular domains typical of
      splicing factors in the SR family of proteins. However, both plant SR proteins
      are rich in proline, and SR45, unlike most animal SR proteins, has two distinct
      arginine/serine-rich domains separated by an RNA recognition motif. By using
      coprecipitation assays we confirmed the interaction of plant U1-70K with SR33 and
      SR45 proteins. Furthermore, in vivo and in vitro protein-protein interaction
      experiments have shown that SR33 protein interacts with itself and with SR45
      protein but not with two other members (SRZ21 and SRZ22) of the SR family that
      are known to interact with the Arabidopsis full-length U-70K only. A Clk/Sty
      protein kinase (AFC-2) from Arabidopsis phosphorylated four SR proteins (SR33,
      SR45, SRZ21, and SRZ22). Coprecipitation studies have confirmed the interaction
      of SR proteins with AFC2 kinase, and the interaction between AFC2 and SR33 is
      modulated by the phosphorylation status of these proteins. These and our previous
      results suggest that the plant U1-70K interacts with at least four distinct
      members of the SR family including SR45 with its two arginine/serine-rich
      domains, and the interaction between the SR proteins and AFC2 is modulated by
      phosphorylation. The interaction of plant U1-70K with a novel set of proteins
      suggests the early stages of spliceosome assembly, and intron recognition in
      plants is likely to be different from animals.

PMID- 10593940
TI  - Structure and function of the tryptophan synthase alpha(2)beta(2) complex. Roles
      of beta subunit histidine 86.
AB  - To probe the structural and functional roles of active-site residues in the
      tryptophan synthase alpha(2)beta(2) complex from Salmonella typhimurium, we have
      determined the effects of mutation of His(86) in the beta subunit. His(86) is
      located adjacent to beta subunit Lys(87), which forms an internal aldimine with
      the pyridoxal phosphate and catalyzes the abstraction of the alpha-proton of L
      serine. The replacement of His(86) by leucine (H86L) weakened pyridoxal phosphate
      binding approximately 20-fold and abolished the circular dichroism signals of the
      bound coenzyme and of a reaction intermediate. Correlation of these results with
      previous crystal structures indicates that beta-His(86) plays a structural role
      in binding pyridoxal phosphate and in stabilizing the correct orientation of
      pyridoxal phosphate in the active site of the beta subunit. The H86L mutation
      also altered the pH profiles of absorbance and fluorescence signals and shifted
      the pH optimum for the synthesis of L-tryptophan from pH 7.5 to 8.8. We propose
      that the interaction of His(86) with the phosphate of pyridoxal phosphate and
      with Lys(87) lowers the pK(a) of Lys(87) in the wild-type alpha(2)beta(2) complex
      and thereby facilitates catalysis by Lys(87) in the physiological pH range.

PMID- 10593941
TI  - Involvement of lipoxygenase-dependent production of fatty acid hydroperoxides in
      the development of the hypersensitive cell death induced by cryptogein on tobacco
      leaves.
AB  - Lipid peroxidation was investigated in relation with the hypersensitive reaction
      in cryptogein-elicited tobacco leaves. A massive production of free
      polyunsaturated fatty acid (PUFA) hydroperoxides dependent on a 9-lipoxygenase
      (LOX) activity was characterized during the development of leaf necrosis. The
      process occurred after a lag phase of 12 h, was accompanied by the concomitant
      increase of 9-LOX activity, and preceded by a transient accumulation of LOX
      transcripts. Free radical-mediated lipid peroxidation represented 10% of the
      process. Inhibition and activation of the LOX pathway was shown to inhibit or to
      activate cell death, and evidence was provided that fatty acid hydroperoxides are
      able to mimic leaf necrotic symptoms. Within 24 h, about 50% of leaf PUFAs were
      consumed, chloroplast lipids being the major source of PUFAs. The results
      minimize the direct participation of active oxygen species from the oxidative
      burst in membrane lipid peroxidation. They suggest, furthermore, the involvement
      of lipase activity to provide the free PUFA substrates for LOX. The LOX-dependent
      peroxidative pathway, responsible for tissue necrosis, appears as being one of
      the features of hypersensitive programmed cell death.

PMID- 10593942
TI  - Molecular cloning of a zinc finger autoantigen transiently associated with
      interphase nucleolus and mitotic centromeres and midbodies. Orthologous proteins
      with nine CXXC motifs highly conserved from nematodes to humans.
AB  - We have cloned a novel human autoimmune antigen in a patient suffering from
      rheumatoid arthritis with high levels of antibodies to the nucleolus organizer
      regions. Initially the human autoimmune serum was used to select a cDNA of 317
      amino acids from a hamster expression library. Using the hamster DNA as a probe,
      we isolated the human homologous cDNA of 320 amino acids. Human and hamster
      polypeptides share a 95% amino acid homology. The deduced 36-kDa protein contains
      a putative amino-terminal NLS signal, nine cysteine-X-X-cysteine motifs highly
      conserved, and a carboxyl-terminal poly acidic region. Several homologous
      expressed sequence tags have been identified in data bases suggesting that
      orthologous proteins are present throughout evolution from worms to humans. A
      Drosophila expressed sequence tag was further completely sequenced for a full
      length protein with 60% amino acid identity to the human homologue. Northern blot
      analysis revealed that this novel protein is widely distributed in human tissues
      with significantly higher expression levels in heart and skeletal muscle.
      Specific antibodies to the recombinant protein and transfection experiments
      demonstrated by immunofluorescence the localization of the protein predominantly
      but not exclusively to the nucleolus of interphase mammalian cells. In
      actinomycin D-treated cells the protein remains associated with the nucleolus but
      is not segregated, like other ribosomal factors such as upstream binding factor.
      In mitosis the protein was found to be associated with centromeres and
      concentrated at the midbody in cytokinesis. Transient distribution of this
      evolutionarily conserved zinc finger nucleolar autoantigen to the mitotic
      centromeres may provide the means for several aspects of cell cycle control and
      transcriptional regulation.

PMID- 10593943
TI  - Crystal structure of beta-ketoacyl-acyl carrier protein synthase III. A key
      condensing enzyme in bacterial fatty acid biosynthesis.
AB  - Beta-ketoacyl-acyl carrier protein synthase III (FabH), the most divergent member
      of the family of condensing enzymes, is a key catalyst in bacterial fatty acid
      biosynthesis and a promising target for novel antibiotics. We report here the
      crystal structures of FabH determined in the presence and absence of acetyl-CoA.
      These structures display a fold that is common for condensing enzymes. The
      observed acetylation of Cys(112) proves its catalytic role and clearly defines
      the primer binding pocket. Modeling based on a bound CoA molecule suggests
      catalytic roles for His(244) and Asn(274). The structures provide the molecular
      basis for FabH substrate specificity and reaction mechanism and are important for
      structure-based design of novel antibiotics.

PMID- 10593944
TI  - Phosphorylation-dependent conformational changes induce a switch in the actin
      binding function of MARCKS.
AB  - Phosphorylation of myristoylated alanine-rich protein kinase C substrate (MARCKS)
      by protein kinase C eliminates actin filament cross-linking activity, but
      residual filament binding activity docks phosphorylated MARCKS on filamentous
      actin. The postulated actin-binding region of MARCKS, which includes a Ca(2+)
      calmodulin-binding site, has been portrayed with alpha-helical structure,
      analogous to other calmodulin-binding domains. Previous speculation suggested
      that MARCKS may dimerize to form the two functional actin-binding sites requisite
      for cross-linking activity. Contrary to these hypotheses, we show that MARCKS
      peptide with actin-cross-linking activity has an extended structure in aqueous
      solution but assumes a more compact structure upon phosphorylation. We
      hypothesize that structural changes in the MARCKS peptide induced by
      phosphorylation create a dynamic structure that, on average, has only one actin
      binding site. Moreover, independent of the state of phosphorylation, this peptide
      is monomeric rather than dimeric, implying that two distinct actin-binding sites
      are responsible for the actin-cross-linking activity of unphosphorylated MARCKS.
      These studies uniquely elucidate the mechanism by which phosphorylation of MARCKS
      induces structural changes and suggest how these structural changes determine
      biological activity.

PMID- 10593945
TI  - Alteration of the reduction potential of the [4Fe-4S](2+/+) cluster of
      Azotobacter vinelandii ferredoxin I.
AB  - The [4Fe-4S](2+/+) cluster of Azotobacter vinelandii ferredoxin I (FdI) has an
      unusually low reduction potential (E(0')) relative to other structurally similar
      ferredoxins. Previous attempts to raise that E(0') by modification of surface
      charged residues were unsuccessful. In this study mutants were designed to alter
      the E(0') by substitution of polar residues for nonpolar residues near the
      cluster and by modification of backbone amides. Three FdI variants, P21G, I40N,
      and I40Q, were purified and characterized, and electrochemical E(0') measurements
      show that all had altered E(0') relative to native FdI. For P21G FdI and I40Q
      FdI, the E(0') increased by +42 and +53 mV, respectively validating the
      importance of dipole orientation in control of E(0'). Protein Dipole Langevin
      Dipole calculations based on models for those variants accurately predicted the
      direction of the change in E(0') while overestimating the magnitude. For I40N
      FdI, initial calculations based on the model predicted a +168 mV change in E(0')
      while a -33 mV change was observed. The x-ray structure of that variant, which
      was determined to 2.8 A, revealed a number of changes in backbone and side chain
      dipole orientation and in solvent accessibility, that were not predicted by the
      model and that were likely to influence E(0'). Subsequent Protein Dipole Langevin
      Dipole calculations (using the actual I40N x-ray structures) did quite accurately
      predict the observed change in E(0').

PMID- 10593946
TI  - p53 and tumor necrosis factor alpha regulate the expression of a mitochondrial
      chloride channel protein.
AB  - A novel chloride intracellular channel (CLIC) gene, clone mc3s5/mtCLIC, has been
      identified from differential display analysis of differentiating mouse
      keratinocytes from p53+/+ and p53-/- mice. The 4.2-kilobase pair cDNA contains an
      open reading frame of 762 base pairs encoding a 253-amino acid protein with two
      putative transmembrane domains. mc3s5/mtCLIC protein shares extensive homology
      with a family of intracellular organelle chloride channels but is the first shown
      to be differentially regulated. mc3s5/mtCLIC mRNA is expressed to the greatest
      extent in vivo in heart, lung, liver, kidney, and skin, with reduced levels in
      some organs from p53-/- mice. mc3s5/mtCLIC mRNA and protein are higher in p53+/+
      compared with p53-/- basal keratinocytes in culture, and both increase in
      differentiating keratinocytes independent of genotype. Overexpression of p53 in
      keratinocytes induces mc3s5/mtCLIC mRNA and protein. Exogenous human recombinant
      tumor necrosis factor alpha also up-regulates mc3s5/mtCLIC mRNA and protein in
      keratinocytes. Subcellular fractionation of keratinocytes indicates that both the
      green fluorescent protein-mc3s5 fusion protein and the endogenous mc3s5/mtCLIC
      are localized to the cytoplasm and mitochondria. Similarly, mc3s5/mtCLIC was
      localized to mitochondria and cytoplasmic fractions of rat liver homogenates.
      Furthermore, mc3s5/mtCLIC colocalized with cytochrome oxidase in keratinocyte
      mitochondria by immunofluorescence and was also detected in the cytoplasmic
      compartment. Sucrose gradient-purified mitochondria from rat liver confirmed this
      mitochondrial localization. This represents the first report of localization of a
      CLIC type chloride channel in mitochondria and the first indication that
      expression of an organellular chloride channel can be regulated by p53 and tumor
      necrosis factor alpha.

PMID- 10593947
TI  - Interdomain signaling in glutamine phosphoribosylpyrophosphate amidotransferase.
AB  - The glutamine phosphoribosylpyrophosphate (PRPP) amidotransferase-catalyzed
      synthesis of phosphoribosylamine from PRPP and glutamine is the sum of two half
      reactions at separated catalytic sites in different domains. Binding of PRPP to a
      C-terminal phosphoribosyltransferase domain is required to activate the reaction
      at the N-terminal glutaminase domain. Interdomain signaling was monitored by
      intrinsic tryptophan fluorescence and by measurements of glutamine binding and
      glutamine site catalysis. Enzymes were engineered to contain a single tryptophan
      fluorescence reporter in key positions in the glutaminase domain. Trp(83) in the
      glutamine loop (residues 73-84) and Trp(482) in the C-terminal helix (residues
      471-492) reported fluorescence changes in the glutaminase domain upon binding of
      PRPP and glutamine. The fluorescence changes were perturbed by Ile(335) and
      Tyr(74) mutations that disrupt interdomain signaling. Fluoresence titrations of
      PRPP and glutamine binding indicated that signaling defects increased the K(d)
      for glutamine but had little or no effect on PRPP binding. It was concluded that
      the contact between Ile(335) in the phosphoribosyltransferase domain and Tyr(74)
      in the glutamine site is a primary molecular interaction for interdomain
      signaling. Analysis of enzymes with mutations in the glutaminase domain C
      terminal helix and a 404-420 peptide point to additional signaling interactions
      that activate the glutamine site when PRPP binds.

PMID- 10593948
TI  - Fibroblast activation protein, a dual specificity serine protease expressed in
      reactive human tumor stromal fibroblasts.
AB  - Proteolytic degradation of extracellular matrix (ECM) components during tissue
      remodeling plays a pivotal role in normal and pathological processes including
      wound healing, inflammation, tumor invasion, and metastasis. Proteolytic enzymes
      in tumors may activate or release growth factors from the ECM or act directly on
      the ECM itself, thereby facilitating angiogenesis or tumor cell migration.
      Fibroblast activation protein (FAP) is a cell surface antigen of reactive tumor
      stromal fibroblasts found in epithelial cancers and in granulation tissue during
      wound healing. It is absent from most normal adult human tissues. FAP is
      conserved throughout chordate evolution, with homologues in mouse and Xenopus
      laevis, whose expression correlates with tissue remodeling events. Using
      recombinant and purified natural FAP, we show that FAP has both dipeptidyl
      peptidase activity and a collagenolytic activity capable of degrading gelatin and
      type I collagen; by sequence, FAP belongs to the serine protease family rather
      than the matrix metalloprotease family. Mutation of the putative catalytic serine
      residue of FAP to alanine abolishes both enzymatic activities. Consistent with
      its in vivo expression pattern determined by immunohistochemistry, FAP enzyme
      activity was detected by an immunocapture assay in human cancerous tissues but
      not in matched normal tissues. This study demonstrates that FAP is present as an
      active cell surface-bound collagenase in epithelial tumor stroma and opens up
      investigation into physiological substrates of its novel, tumor-associated
      dipeptidyl peptidase activity.

PMID- 10593949
TI  - Association of two nuclear proteins, Npw38 and NpwBP, via the interaction between
      the WW domain and a novel proline-rich motif containing glycine and arginine.
AB  - We have previously reported a nuclear protein possessing a WW domain, Npw38
      (Komuro, A., Saeki, M., and Kato, S. (1999) Nucleic Acids Res. 27, 1957-1965).
      Here we report a Npw38-binding protein, NpwBP, isolated from HeLa cell nuclear
      extracts and its characterization using a cloned cDNA. NpwBP contains two proline
      rich regions that are capable of binding to the WW domain of Npw38. The binding
      analysis using an oligopeptide-immobilized membrane revealed that the WW domain
      of Npw38 preferentially recognizes a short proline-rich sequence, PPGPPP,
      surrounded by an arginine residue, so we named it a PGR motif. Localization
      analysis using green fluorescent protein fusion protein and immunostaining showed
      that Npw38 and NpwBP are colocalized in the same subnuclear region.
      Coimmunoprecipitation experiments confirmed the association between Npw38 and
      NpwBP, which were expressed as epitope-tagged forms in COS7 cells. Furthermore,
      the N-terminal region of NpwBP has binding ability for poly(rG) and G-rich single
      stranded DNA. These results suggest that NpwBP is a physiological ligand of Npw38
      and that the Npw38-NpwBP complex may function as a component of an mRNA factory
      in the nucleus.

PMID- 10593950
TI  - Presence of WT1, the Wilm's tumor suppressor gene product, in nuclear poly(A)(+)
      ribonucleoprotein.
AB  - The tumor suppressor gene WT1 encodes a zinc finger protein, which consists of
      four C-terminal C(2)-H(2) zinc fingers of the Kruppel type, and at the N terminus
      a Q/P-rich trans-regulatory domain, both characteristic of transcription factors.
      However, recent findings suggest that WT1 may also be involved in a post
      transcriptional process. Specifically, WT1 isoforms containing the alternatively
      spliced exon 9 (+lysine-threonine-serine (KTS)) preferentially associate with
      nuclear speckles and co-immunoprecipitate splicing antigens (Larsson, S. H.,
      Charlieu, J.-P., Miyagawa, K., Engelkamp, D., Rassoulzadegan, M., Ross, A.,
      Cuzin, F., van Heyningen, V., and Hastie, N. D. (1995) Cell 81, 391-401);
      furthermore, WT1 has been shown to interact with the ubiquitous splicing factor
      U2AF65 (Davies, R. C., Calvo, C., Larsson, S. H., Lamond, A. I., and Hastie, N.
      D. (1998) Genes Dev. 12, 3217-3225) and binds to RNA in vitro (Caricasole, A.,
      Duarte, A., Larsson, S. H., Hastie, N. D., Little, M., Holmes, G., Todorov, I.,
      and Ward, A. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 7562-7566; Bardeesy, N.,
      and Pelletier, J. (1998) Nucleic Acids Res. 26, 1784-1792). To extend these
      findings, we have fractionated nuclear extracts to see if particles containing
      WT1 have the properties of ribonucleoprotein (RNP). In summary, WT1 is enriched
      by oligo(dT) chromatography, as are U2AF65, the U5 small nuclear RNP-associated
      protein p116 and hnRNP A1. Gel filtration and sedimentation profiles suggest that
      WT1 is present in RNase-sensitive particles, >2 MDa in size, peaking at
      approximately 60 S, and approximately 1.27 g/cm(3) on Nycodenz. Similar results
      were obtained from two cell lines expressing WT1, fetal kidneys (day E17), and
      transiently transfected cells, suggesting that the presence of WT1 protein in
      nuclear poly(A)(+) RNP is a general aspect of WT1 function.

PMID- 10593951
TI  - The seven amino acids (547-553) of rat glucocorticoid receptor required for
      steroid and hsp90 binding contain a functionally independent LXXLL motif that is
      critical for steroid binding.
AB  - Hsp90 association with glucocorticoid receptors (GRs) is required for steroid
      binding. We recently reported that seven amino acids (547-553) overlapping the
      amino-terminal end of the rat GR ligand-binding domain are necessary for hsp90
      binding, and consequently steroid binding. The role of a LXXLL motif at the COOH
      terminus of this sequence has now been analyzed by determining the properties of
      Leu to Ser mutations in full-length GR and glutathione S-transferase chimeras.
      Surprisingly, these mutations decreased steroid binding capacity without altering
      receptor levels, steroid binding affinity, or hsp90 binding. Single mutations in
      the context of the full-length receptor did not affect the transcriptional
      activity but the double mutant (L550S/L553S) was virtually inactive. This
      biological inactivity was found to be due to an increased rate of steroid
      dissociation from the activated mutant complex. These results, coupled with those
      from trypsin digestion studies, suggest a model in which the GR ligand-binding
      domain is viewed as having a "hinged pocket," with the hinge being in the region
      of the trypsin digestion site at Arg(651). The pocket would normally be kept shut
      via the intramolecular interactions of the LXXLL motif at amino acids 550-554
      acting as a hydrophobic clasp.

PMID- 10593952
TI  - The growth-related gene product beta induces sphingomyelin hydrolysis and
      activation of c-Jun N-terminal kinase in rat cerebellar granule neurones.
AB  - The growth-related gene product beta (GRObeta) is a small chemoattractant
      cytokine that belongs to the CXC chemokine family, and GRObeta receptors are
      expressed in the brain, including the cerebellum. We demonstrate that rat
      cerebellar granule neurones express the GRObeta receptor CXCR2. We also show
      that, in addition to the known stimulation of a phosphoinositide-specific
      phospholipase C, GRObeta activates both neutral (N-) and acidic (A-)
      sphingomyelinases (SMase) and the stress-activated c-Jun N-terminal kinase 1
      (JNK1). Although both exogenous ceramide and bacterial SMase stimulate JNK1,
      GRObeta-induced JNK1 activation is an event probably independent of ceramide
      generated by A-SMase, since it is maintained in the presence of compounds that
      block A-SMase activity. This is the first report on the activation of the SMase
      pathway by chemokines.

PMID- 10593953
TI  - HRad17 colocalizes with NHP2L1 in the nucleolus and redistributes after UV
      irradiation.
AB  - The rad17 gene of Schizosaccharomyces pombe plays an important role as a
      checkpoint protein following DNA damage and during DNA replication. The human
      homologue of S. pombe rad17, Hrad17, was recently identified, but its function
      has not yet been established. Using the yeast two-hybrid system, we determined
      that HRad17 can interact with a nucleolar protein, NHP2L1. This interaction was
      also demonstrated biochemically, in human cells. Immunofluorescence studies
      revealed that HRad17 and NHP2L1 colocalize to the nucleolus, and immunogold
      labeling further resolved the location of NHP2L1 to the dense fibrillar component
      of the nucleolus. Interestingly, the localization of HRad17 in the nucleolus was
      altered in response to UV irradiation. These results provide some insight into
      the DNA damage and replication checkpoint mechanisms of HRad17.

PMID- 10593954
TI  - Structural and immunochemical characterization of a Neisseria gonorrhoeae epitope
      defined by a monoclonal antibody 2C7; the antibody recognizes a conserved epitope
      on specific lipo-oligosaccharides in spite of the presence of human carbohydrate
      epitopes.
AB  - Lipo-oligosaccharides (LOS) produced by Neisseria gonorrhoeae are important
      antigenic and immunogenic components of the outer membrane complex. Previously,
      we showed that murine monoclonal antibody (mAb) 2C7 did not cross-react with
      human glycosphingolipids but identified the LOS epitope that is widely expressed
      in vivo and in vitro (Gulati, S., McQuillen, D. P., Mandrell, R. E., Jani, D. B.,
      and Rice, P. A. (1996) J. Infect. Dis. 174, 1223-1237). In the present study, we
      analyzed the structure of gonococcal strain WG LOS containing the 2C7 epitope and
      investigated the structural requirements for expression of the epitope. We
      determined that the WG LOS components are Hep[1]-elongated forms of 15253 LOS
      that have a lactose on both Hep[1] and Hep[2] (Yamasaki, R., Kerwood, D. E.,
      Schneider, H., Quinn, K. P., Griffiss, J. M., and Mandrell, R. E. (1994) J. Biol.
      Chem. 269, 30345-30351). In addition, we found that expression of the 2C7 epitope
      within the LOS is blocked when the Hep[2]-lactose is elongated. Based on the
      structural data of these LOS and the results obtained from immunochemical
      analyses, we conclude the following: 1) mAb 2C7 requires both the 15253 OS
      minimum structure and the N-linked fatty acids in the lipoidal moiety for
      expression of the epitope; 2) mAb 2C7 binds to the LOS that elongates the lactose
      on Hep[1] of the 15253 OS, but not the one on Hep[2]; and 3) the 2C7 epitope is
      expressed on gonococcal LOS despite the presence of human carbohydrate epitopes
      such as a lactosamine or its N-acetylgalactosaminylated (globo) form. Our study
      shows that the conserved epitope defined by mAb 2C7 could potentially be used as
      a safe site for the development of a vaccine candidate.

PMID- 10593955
TI  - Single amino acid substitutions in alpha-conotoxin PnIA shift selectivity for
      subtypes of the mammalian neuronal nicotinic acetylcholine receptor.
AB  - The alpha-conotoxins, a class of nicotinic acetylcholine receptor (nAChR)
      antagonists, are emerging as important probes of the role played by different
      nAChR subtypes in cell function and communication. In this study, the native
      alpha-conotoxins PnIA and PnIB were found to cause concentration-dependent
      inhibition of the ACh-induced current in all rat parasympathetic neurons
      examined, with IC(50) values of 14 and 33 nM, and a maximal reduction in current
      amplitude of 87% and 71%, respectively. The modified alpha-conotoxin [N11S]PnIA
      reduced the ACh-induced current with an IC(50) value of 375 nM and a maximally
      effective concentration caused 91% block. [A10L]PnIA was the most potent
      inhibitor, reducing the ACh-induced current in approximately 80% of neurons, with
      an IC(50) value of 1.4 nM and 46% maximal block of the total current. The
      residual current was not inhibited further by alpha-bungarotoxin, but was further
      reduced by the alpha-conotoxins PnIA or PnIB, and by mecamylamine. (1)H NMR
      studies indicate that PnIA, PnIB, and the analogues, [A10L]PnIA and [N11S]PnIA,
      have identical backbone structures. We propose that positions 10 and 11 of PnIA
      and PnIB influence potency and determine selectivity among alpha7 and other nAChR
      subtypes, including alpha3beta2 and alpha3beta4. Four distinct components of the
      nicotinic ACh-induced current in mammalian parasympathetic neurons have been
      dissected with these conopeptides.

PMID- 10593956
TI  - Cell surface stability of gamma-aminobutyric acid type A receptors. Dependence on
      protein kinase C activity and subunit composition.
AB  - Type A gamma-aminobutyric acid receptors (GABA(A)), the major sites of fast
      synaptic inhibition in the brain, are believed to be composed predominantly of
      alpha, beta, and gamma subunits. Although cell surface expression is essential
      for GABA(A) receptor function, little is known regarding its regulation. To
      address this issue, the membrane stability of recombinant alpha(1)beta(2) or
      alpha(1)beta(2)gamma(2) receptors was analyzed in human embryonic kidney cells.
      Alpha(1)beta(2)gamma(2) but not alpha(1)beta(2) receptors were found to recycle
      constitutively between the cell surface and a microtubule-dependent, perinuclear
      endosomal compartment. Similar GABA(A) receptor endocytosis was also seen in
      cultured hippocampal and cortical neurons. GABA(A) receptor surface levels were
      reduced upon protein kinase C (PKC) activation. Like basal endocytosis, this
      response required the gamma(2) subunit but not receptor phosphorylation. Although
      inhibiting PKC activity did not block alpha(1)beta(2)gamma(2) receptor
      endocytosis, it did prevent receptor down-regulation, suggesting that PKC
      activity may block alpha(1)beta(2)gamma(2) receptor recycling to the cell
      surface. In agreement with this observation, blocking recycling from endosomes
      with wortmannin selectively reduced surface levels of gamma(2)-containing
      receptors. Together, our results demonstrate that the surface stability of
      GABA(A) receptors can be dynamically and specifically regulated, enabling neurons
      to modulate cell surface receptor number upon the appropriate cues.

PMID- 10593957
TI  - Electron crystallography of human blood coagulation factor VIII bound to
      phospholipid monolayers.
AB  - Coagulation factor VIII binds to negatively charged platelets prior to assembly
      with the serine protease, factor IXa, to form the factor X-activating enzyme (FX
      ase) complex. The macromolecular organization of membrane-bound factor VIII has
      been studied by electron crystallography for the first time. For this purpose two
      dimensional crystals of human factor VIII were grown onto phosphatidylserine
      containing phospholipid monolayers, under near to physiological conditions (pH
      and salt concentration). Electron crystallographic analysis revealed that the
      factor VIII molecules were organized as monomers onto the lipid layer, with unit
      cell dimensions: a = 81.5A, b = 67.2 A, gamma = 66.5 degrees, P1 symmetry. Based
      on a homology-derived molecular model of the factor VIII (FVIII) A domains, the
      FVIII projection structure solved at 15-A resolution presents the A1, A2, and A3
      domain heterotrimer tilted approximately 65 degrees relative to the membrane
      plane. The A1 domain is projecting on top of the A3, C1, and C2 domains and with
      the A2 domain protruding partially between A1 and A3. This organization of factor
      VIII allows the factor IXa protease and epidermal growth factor-like domain
      binding sites (localized in the A2 and A3 domains, respectively) to be situated
      at the appropriate position for the binding of factor IXa. The conformation of
      the lipid-bound FVIII is therefore very close to that for the activated factor
      VIIIa predicted in the FX-ase complex.

PMID- 10593958
TI  - Deacylation of lipopolysaccharide in whole Escherichia coli during destruction by
      cellular and extracellular components of a rabbit peritoneal inflammatory
      exudate.
AB  - Deacylation of purified lipopolysaccharides (LPS) markedly reduces its toxicity
      toward mammals. However, the biological significance of LPS deacylation during
      infection of the mammalian host is uncertain, particularly because the ability of
      acyloxyacyl hydrolase, the leukocyte enzyme that deacylates purified LPS, to
      attack LPS residing in the bacterial cell envelope has not been established. We
      recently showed that the cellular and extracellular components of a rabbit
      sterile inflammatory exudate are capable of extensive and selective removal of
      secondary acyl chains from purified LPS. We now report that LPS as a constituent
      of the bacterial envelope is also subject to deacylation in the same inflammatory
      setting. Using Escherichia coli LCD25, a strain that exclusively incorporates
      radiolabeled acetate into fatty acids, we quantitated LPS deacylation as the loss
      of radiolabeled secondary (laurate and myristate) and primary fatty acids (3
      hydroxymyristate) from the LPS backbone. Isolated mononuclear cells and
      neutrophils removed 50% and 20-30%, respectively, of the secondary acyl chains of
      the LPS of ingested whole bacteria. When bacteria were killed extracellularly
      during incubation with ascitic fluid, no LPS deacylation occurred. In this
      setting, the addition of neutrophils had no effect, but addition of mononuclear
      cells resulted in removal of >40% of the secondary acyl chains by 20 h.
      Deacylation of LPS was always restricted to the secondary acyl chains. Thus, in
      an inflammatory exudate, primarily in mononuclear phagocytes, the LPS in whole
      bacteria undergoes substantial and selective acyloxyacyl hydrolase-like
      deacylation, both after phagocytosis of intact bacteria and after uptake of LPS
      shed from extracellularly killed bacteria. This study demonstrates for the first
      time that the destruction of Gram-negative bacteria by a mammalian host is not
      restricted to degradation of phospholipids, protein, and RNA, but also includes
      extensive deacylation of the envelope LPS.

PMID- 10593959
TI  - Efficient integration of short interspersed element-flanked foreign DNA via
      homologous recombination.
AB  - We investigated whether mouse short interspersed elements (SINEs) could influence
      the recombination frequency of foreign DNA. Vectors harboring a reporter gene in
      combinations of SINEs B1 and/or B2 or a portion of long interspersed element-1
      were prepared and tested in vitro by a colony assay using HC11 murine mammary
      epithelial cells and in vivo by microinjection into fertilized mouse eggs. In
      transfected HC11 cells, the number of colonies surviving G418 selection increased
      by 3.5-fold compared with control when the reporter was flanked by fused B1-B2
      sequences. Similar results were obtained from microinjection study; in fetuses
      11.5 days post coitum, transgene positives in control and SINE-flanked vectors
      were 16 and 53%, respectively. Individual B1- and B2-harboring vectors showed
      equivalent activities with each other, as determined by the colony assay (2.8
      fold versus 3.2-fold compared with control). We determined the contribution of
      homologous recombination to the SINE-mediated increase in integration frequency
      through a polymerase chain reaction-based strategy; in more than half of embryos
      transgenes underwent homologous recombinations involving B1 sequences. These
      results demonstrate that the SINE sequences can increase the integration rate of
      foreign DNA and that such an increase is most likely due to the enhancement of
      homologous recombination.

PMID- 10593960
TI  - Identification and characterization of cvHsp. A novel human small stress protein
      selectively expressed in cardiovascular and insulin-sensitive tissues.
AB  - Starting with computational tools that search for tissue-selective expression of
      assembled expressed sequenced tags, we have identified by focusing on heart
      libraries a novel small stress protein of 170 amino acids that we named cvHsp.
      cvHsp was found as being computationally selectively and highly (0.3% of the
      total RNA) expressed in human heart. The cvHsp gene mapped to 1p36.23-p34.3
      between markers D1S434 and D1S507. The expression of cvHsp was analyzed with RNA
      dot, Northern blots, or reverse transcription-polymerase chain reaction:
      expression was high in heart, medium in skeletal muscle, and low in aorta or
      adipose tissues. In the heart of rat models of cardiac pathologies, cvHsp mRNA
      expression was either unchanged (spontaneous hypertension), up-regulated (right
      ventricular hypertrophy induced by monocrotaline treatment), or down-regulated
      (left ventricular hypertrophy following aortic banding). In obese Zucker rats,
      cvHsp mRNA was increased in skeletal muscle, brown, and white adipose tissues but
      remained unchanged in the heart. Western blot analysis using antipeptide
      polyclonal antibodies revealed two specific bands at 23 and 25 kDa for cvHsp in
      human heart. cvHsp interacted in both yeast two-hybrid and immunoprecipitation
      experiments with alpha-filamin or actin-binding protein 280. Within cvHsp, amino
      acid residues 56-119 were shown to be important for its specific interaction with
      the C-terminal tail of alpha-filamin.

PMID- 10593961
TI  - A phosphatidic acid-activated protein kinase and conventional protein kinase C
      isoforms phosphorylate p22(phox), an NADPH oxidase component.
AB  - Using a phosphorylation-dependent cell-free system to study NADPH oxidase
      activation (McPhail, L. C., Qualliotine-Mann, D., and Waite, K. A. (1995) Proc.
      Natl. Acad. Sci. U. S. A. 92, 7931-7935), we previously showed that p47(phox), a
      cytosolic NADPH oxidase component, is phosphorylated. Now, we show that
      p22(phox), a subunit of the NADPH oxidase component flavocytochrome b(558), also
      is phosphorylated. Phosphorylation is selectively activated by phosphatidic acid
      (PA) versus other lipids and occurs on a threonine residue in p22(phox). We
      identified two protein kinase families capable of phosphorylating p22(phox): 1) a
      potentially novel, partially purified PA-activated protein kinase(s) known to
      phosphorylate p47(phox) and postulated to mediate the phosphorylation-dependent
      activation of NADPH oxidase by PA and 2) conventional, but not novel or atypical,
      isoforms of protein kinase C (PKC). In contrast, all classes of PKC isoforms
      could phosphorylate p47(phox). In a gel retardation assay both the phosphatidic
      acid-dependent kinase and conventional PKC isoforms phosphorylated all molecules
      of p22(phox). These findings suggest that phosphorylation of p22(phox) by
      conventional PKC and/or a novel PA-activated protein kinase regulates the
      activation/assembly of NADPH oxidase.

PMID- 10593962
TI  - Identification of arfophilin, a target protein for GTP-bound class II ADP
      ribosylation factors.
AB  - Yeast two-hybrid screening of a human kidney cDNA library using the GTP-bound
      form of a class II ADP-ribosylation factor (ARF5) identified a novel ARF5-binding
      protein with a calculated molecular mass of 82.4 kDa, which was named arfophilin.
      Northern hybridization analysis showed high level arfophilin mRNA expression in
      human heart and skeletal muscle. Arfophilin bound only to the active, GTP-bound
      form of ARF5 and did not bind to GTP-ARF3, which is a class I ARF. The N terminus
      of ARF5 (1-17 amino acids) was essential for binding to arfophilin. The GTP-bound
      form of ARF5 with amino acid residues in the N terminus mutated to those in ARF4
      (another class II ARF) also bound to arfophilin, suggesting it is a target
      protein for GTP-bound forms of class II ARFs. The binding site for ARF on
      arfophilin was localized to the C terminus (residues 612-756), which contains
      putative coiled-coil structures. Recombinant arfophilin overexpressed in CHO-K1
      cells was localized in the cytosol and translocated to a membrane fraction in
      association with GTP-bound ARF5. ARF5 containing the N terminus of ARF3 did not
      promote translocation indicating that class II ARFs are specific carriers for
      arfophilin.

PMID- 10593963
TI  - Molecular cloning, sequencing, and expression of the gene encoding alkaline
      ceramidase from Pseudomonas aeruginosa. Cloning of a ceramidase homologue from
      Mycobacterium tuberculosis.
AB  - We previously reported the purification and characterization of a novel type of
      alkaline ceramidase from Pseudomonas aeruginosa strain AN17 (Okino, N., Tani, M.,
      Imayama, S., and Ito, M. (1998) J. Biol. Chem. 273, 14368-14373). Here, we report
      the molecular cloning, sequencing, and expression of the gene encoding the
      ceramidase of this strain. Specific oligonucleotide primers were synthesized
      using the peptide sequences of the purified ceramidase obtained by digestion with
      lysylendopeptidase and used for polymerase chain reaction. DNA fragments thus
      amplified were used as probes to clone the gene encoding the ceramidase from a
      genomic library of strain AN17. The open reading frame of 2,010 nucleotides
      encoded a polypeptide of 670 amino acids including a signal sequence of 24
      residues, 64 residues of which matched the amino acid sequence determined for the
      purified enzyme. The molecular weight of the mature enzyme was estimated to be
      70,767 from the deduced amino acid sequence. Expression of the ceramidase gene in
      Escherichia coli, resulted in production of a soluble enzyme with the identical N
      terminal amino acid sequence. Recombinant ceramidase was purified to homogeneity
      from the lysate of E. coli cells and confirmed to be identical to the Pseudomonas
      enzyme in its specificity and other enzymatic properties. No significant sequence
      similarities were found in other known functional proteins including human acid
      ceramidase. However, we found a sequence homologous to the ceramidase in
      hypothetical proteins encoded in Mycobacterium tuberculosis, Dictyostelium
      discoideum, and Arabidopsis thaliana. The homologue of the ceramidase gene was
      thus cloned from an M. tuberculosis cosmid and expressed in E. coli, and the gene
      was demonstrated to encode an alkaline ceramidase. This is the first report for
      the cloning of an alkaline ceramidase.

PMID- 10593964
TI  - Structural determinants for signal sequence function in the mammalian endoplasmic
      reticulum.
AB  - Signal sequences function in protein targeting to and translocation across the
      endoplasmic reticulum membrane. To investigate the structural requirements for
      signal sequence function, chimeras of the Escherichia coli LamB signal peptide
      and prolactin were prepared. The LamB signal peptide was chosen by virtue of the
      extensive biophysical and biological characterization of its activity. In vitro,
      nascent prolactin chains bearing the LamB signal peptide (LamB) were targeted in
      a signal recognition particle (SRP)-dependent manner to rough microsomes but
      remained protease- and salt-sensitive and translocated at low efficiency. Full
      translocation activity was obtained in a gain of function mutant (LamB*) in which
      three hydrophobic residues in the LamB hydrophobic core were converted to leucine
      residues. Cross-linking studies demonstrated that the LamB* signal sequence
      displayed markedly enhanced interactions with SRP and integral membrane proteins.
      In contrast, chemically denatured LamB and LamB*-precursors bound with identical
      efficiencies and in a salt-resistant manner to rough microsomes, suggesting that
      during de novo synthesis the signal sequence of LamB-bearing precursors assumes a
      conformation refractory to translocation. These data indicate that a leucine-rich
      signal sequence is necessary for optimal interaction with SRP and suggest that
      SRP, by maintaining the signal sequence in a conformation suitable for membrane
      binding, performs a chaperone function.

PMID- 10593965
TI  - Aminosalicylic acid inhibits IkappaB kinase alpha phosphorylation of IkappaBalpha
      in mouse intestinal epithelial cells.
AB  - Tumor necrosis factor alpha (TNFalpha)-stimulated nuclear factor (NF) kappaB
      activation plays a key role in the pathogenesis of inflammatory bowel disease
      (IBD). Phosphorylation of NFkappaB inhibitory protein (IkappaB) leading to its
      degradation and NFkappaB activation, is regulated by the multimeric IkappaB
      kinase complex, including IKKalpha and IKKbeta. We recently reported that 5
      aminosalicylic acid (5-ASA) inhibits TNFalpha-regulated IkappaB degradation and
      NFkappaB activation. To determine the mechanism of 5-ASA inhibition of IkappaB
      degradation, we studied young adult mouse colon (YAMC) cells by immunodetection
      and in vitro kinase assays. We show 5-ASA inhibits TNFalpha-stimulated
      phosphorylation of IkappaBalpha in intact YAMC cells. Phosphorylation of a
      glutathione S-transferase-IkappaBalpha fusion protein by cellular extracts or
      immunoprecipitated IKKalpha isolated from cells treated with TNFalpha is
      inhibited by 5-ASA. Recombinant IKKalpha and IKKbeta autophosphorylation and
      their phosphorylation of glutathione S-transferase-IkappaBalpha are inhibited by
      5-ASA. However, IKKalpha serine phosphorylation by its upstream kinase in either
      intact cells or cellular extracts is not blocked by 5-ASA. Surprisingly,
      immunodepletion of cellular extracts suggests IKKalpha is predominantly
      responsible for IkappaBalpha phosphorylation in intestinal epithelial cells. In
      summary, 5-ASA inhibits TNFalpha-stimulated IKKalpha kinase activity toward
      IkappaBalpha in intestinal epithelial cells. These findings suggest a novel role
      for 5-ASA in the management of IBD by disrupting TNFalpha activation of NFkappaB.

PMID- 10593966
TI  - Purification, cloning, and expression of a pathogen inducible UDP
      glucose:Salicylic acid glucosyltransferase from tobacco.
AB  - Salicylic acid (SA) plays an important role in plant disease resistance.
      Inoculation of tobacco leaves with incompatible pathogens triggers the
      biosynthesis of SA which accumulates primarily as the SA 2-O-beta-D-glucoside
      (SAG) and glucosyl salicylate (GS). The tobacco UDP-glucose:salicylic acid
      glucosyltransferase (SA GTase) capable of forming both SAG and GS was purified,
      characterized, and partially sequenced. It has an apparent molecular mass of 48
      kDa, a pH optimum of 7.0, and an isoelectric point at pH 4.4. UDP-glucose was the
      sole sugar donor for the enzyme. However, SA and several phenolics served as
      glucose acceptors. The apparent K(m) values for UDP-glucose and SA were 0.27 and
      1-2 mM, respectively. Zn(2+) and UDP inhibited its activity. The corresponding
      cDNA clone which encoded a protein of 459 amino acids was isolated from an SA
      induced tobacco cDNA library and overexpressed in Escherichia coli. The
      recombinant protein catalyzed the formation of SAG and GS, and exhibited a broad
      specificity to simple phenolics, similar to that of the purified enzyme. Northern
      blot analysis showed that the SA GTase mRNA was induced both by SA and
      incompatible pathogens. The rapid induction timing of the mRNA by SA indicates
      that it belongs to the early SA response genes.

PMID- 10593967
TI  - Characterization of active reverse transcriptase and nucleoprotein complexes of
      the yeast retrotransposon Ty3 in vitro.
AB  - Human immunodeficiency virus (HIV) and the distantly related yeast Ty3
      retrotransposon encode reverse transcriptase (RT) and a nucleic acid-binding
      protein designated nucleocapsid protein (NCp) with either one or two zinc
      fingers, required for HIV-1 replication and Ty3 transposition, respectively. In
      vitro binding of HIV-1 NCp7 to viral 5' RNA and primer tRNA(3)(Lys) catalyzes
      formation of nucleoprotein complexes resembling the virion nucleocapsid.
      Nucleocapsid complex formation functions in viral RNA dimerization and tRNA
      annealing to the primer binding site (PBS). RT is recruited in these
      nucleoprotein complexes and synthesizes minus-strand cDNA initiated at the PBS.
      Recent results on yeast Ty3 have shown that the homologous NCp9 promotes
      annealing of primer tRNA(i)(Met) to a 5'-3' bipartite PBS, allowing RNA:tRNA
      dimer formation and initiation of cDNA synthesis at the 5' PBS (). To compare
      specific cDNA synthesis in a retrotransposon and HIV-1, we have established a Ty3
      model system comprising Ty3 RNA with the 5'-3' PBS, primer tRNA(i)(Met), NCp9,
      and for the first time, highly purified Ty3 RT. Here we report that Ty3 RT is as
      active as retroviral HIV-1 or murine leukemia virus RT using a synthetic template
      primer system. Moreover, and in contrast to what was found with retroviral RTs,
      retrotransposon Ty3 RT was unable to direct cDNA synthesis by self-priming. We
      also show that Ty3 nucleoprotein complexes were formed in vitro and that the N
      terminus of NCp9, but not the zinc finger, is required for complex formation,
      tRNA annealing to the PBS, RNA dimerization, and primer tRNA-directed cDNA
      synthesis by Ty3 RT. These results indicate that NCp9 chaperones bona fide cDNA
      synthesis by RT in the yeast Ty3 retrotransposon, as illustrated for NCp7 in HIV
      1, reinforcing the notion that Ty3 NCp9 is an ancestor of HIV-1 NCp7.

PMID- 10593968
TI  - A methylation-responsive MDBP/RFX site is in the first exon of the collagen
      alpha2(I) promoter.
AB  - DNA methylation inhibits transcription driven by the collagen alpha2(I) promoter
      and the 5' end of the gene in transient transfection and in vitro transcription
      assays. DNA-binding proteins in a unique family of ubiquitously expressed
      proteins, methylated DNA-binding protein (MDBP)/regulatory factor for X box
      (RFX), form specific complexes with a sequence overlapping the transcription
      start site of the collagen alpha2(I) gene. Complex formation increased when the
      CpG site at +7 base pairs from the transcription start site was methylated. The
      identity of the protein was demonstrated by co-migration and cross-competition
      for a characteristic slowly migrating doublet complex formed on MDBP/RFX
      recognition sequences and the collagen sequences by band shift assays. A RFX1
      specific antibody supershifted the collagen DNA-protein complexes. Furthermore,
      in vitro translated RFX1 protein formed a specific complex with the collagen
      sequence that was also supershifted with the RFX1 antibody. MDBP/RFX displayed a
      higher affinity binding to the collagen sequence if the CpG at +7 was mutated in
      a manner similar to TpG. This same mutation within reporter constructs inhibited
      transcription in transfection and in vitro transcription assay. These results
      support the hypothesis that DNA methylation-induced inactivation of collagen
      alpha2(I) gene transcription is mediated, in part, by increased binding of
      MDBP/RFX to the first exon in response to methylation in this region.

PMID- 10593969
TI  - Characterization and properties of dominant-negative mutants of the ras-specific
      guanine nucleotide exchange factor CDC25(Mm).
AB  - Ras proteins are small GTPases playing a pivotal role in cell proliferation and
      differentiation. Their activation depends on the competing action of GTPase
      activating proteins and guanine nucleotide exchange factors (GEF). The properties
      of two dominant-negative mutants within the catalytic domains of the ras-specific
      GEF, CDC25(Mm), are described. In vitro, the mutant GEF(W1056E) and GEF(T1184E)
      proteins are catalytically inactive, are able to efficiently displace wild-type
      GEF from p21(ras), and strongly reduce affinity of the nucleotide-free ras x GEF
      complex for the incoming nucleotide, thus resulting in the formation of a stable
      ras.GEF binary complex. Consistent with their in vitro properties, the two mutant
      GEFs bring about a dramatic reduction in ras-dependent fos-luciferase activity in
      mouse fibroblasts. The stable ectopic expression of the GEF(W1056E) mutant in
      smooth muscle cells effectively reduced growth rate and DNA synthesis with no
      detectable morphological changes.

PMID- 10593970
TI  - Functional interaction between Galpha(z) and Rap1GAP suggests a novel form of
      cellular cross-talk.
AB  - G(z) is a member of the G(i) family of trimeric G proteins whose primary role in
      cell physiology is still unknown. In an ongoing effort to elucidate the cellular
      functions of G(z), the yeast two-hybrid system was employed to identify proteins
      that specifically interact with a mutationally activated form of Galpha(z). One
      of the molecules uncovered in this screen was Rap1GAP, a previously identified
      protein that specifically stimulates GTP hydrolytic activity of the monomeric G
      protein Rap1 and thus is believed to function as a down-regulator of Rap1
      signaling. Like G(z), the precise role of Rap1 in cell physiology is poorly
      understood. Biochemical analysis using purified recombinant proteins revealed
      that the physical interaction between Galpha(z) and Rap1GAP blocks the ability of
      RGSs (regulators of G protein signaling) to stimulate GTP hydrolysis of the alpha
      subunit, and also attenuates the ability of activated Galpha(z) to inhibit
      adenylyl cyclase. Structure-function analyses indicate that the first 74 amino
      terminal residues of Rap1GAP, a region distinct from the catalytic core domain
      responsible for the GAP activity toward Rap1, is required for this interaction.
      Co-precipitation assays revealed that Galpha(z), Rap1GAP, and Rap1 can form a
      stable complex. These data suggest that Rap1GAP acts as a signal integrator to
      somehow coordinate and/or integrate G(z) signaling and Rap1 signaling in cells.

PMID- 10593971
TI  - Inferences concerning the ATPase properties of DnaK and other HSP70s are affected
      by the ADP kinase activity of copurifying nucleoside-diphosphate kinase.
AB  - Preparations of Escherichia coli DnaK from our lab as well as preparations of
      DnaK and other HSP70 proteins from several major labs in the field produce a
      stoichiometric initial burst of [alpha-(32)P]ADP when incubated with [alpha
      (32)P]ATP and contain an ADP kinase activity. We determined that the initial
      burst activity results from the transfer of gamma-phosphate from the radiolabeled
      substrate [alpha-(32)P]ATP to unlabeled ADP bound by the DnaK and is the same
      activity that results in ADP phosphorylation. The purification of DnaK from E.
      coli cells that carry a disrupted ndk gene, ndk::km, results in preparations with
      greatly reduced ADP kinase activities compared with preparations of DnaK purified
      from ndk(+) cells. The reduction in the amount of ADP kinase activity in
      preparations of DnaK purified from ndk::km cells shows that nucleoside
      diphosphate kinase (NDP kinase) is responsible for most of the ADP kinase
      activity present in DnaK preparations isolated from ndk(+) cells. The remaining
      ADP kinase activity in preparations from ndk::km cells, which varies between
      preparations, is also a property of NDP kinase, which is most likely expressed
      because of a low frequency reversion of the disrupted ndk gene. A weak, but
      measurable physical interaction exists between DnaK and NDP kinase and may be at
      least partially responsible for the co-purification of NDP kinase with DnaK. The
      presence of contaminating NDP kinase can explain the range of k(cat) values
      reported for the ATPase activity of DnaK as well as recent reports of initial
      burst kinetics by DnaK (Banecki, B., and Zylicz, M. (1996) J. Biol. Chem. 271,
      6137-6143) and an ADP-ATP exchange activity of DnaK (Hiromura, M., Yano, M.,
      Mori, H., Inoue, M., and Kido, H. (1998) J. Biol. Chem. 273, 5435-5438).

PMID- 10593972
TI  - Yeast Sml1, a protein inhibitor of ribonucleotide reductase.
AB  - Ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides to
      deoxyribonucleotides; this step is rate-limiting in DNA precursor synthesis. A
      number of regulatory mechanisms ensure optimal deoxyribonucleotide pools, which
      are essential for cell viability. The best studied mechanisms are transcriptional
      regulation of the RNR genes during the cell cycle and in the response to DNA
      damage, and the allosteric regulation of ribonucleotide reductase by nucleoside
      triphosphates. Recently, another mode of RNR regulation has been hypothesized in
      yeast. A novel protein, Sml1, was shown to bind to the Rnr1 protein of the yeast
      ribonucleotide reductase; this interaction was proposed to inhibit ribonucleotide
      reductase activity when DNA synthesis is not required (Zhao, X., Muller, E.G.D.,
      and Rothstein, R. (1998) Mol. Cell 2, 329-340). Here, we use highly purified
      recombinant proteins to directly demonstrate that the Sml1 protein is a strong
      inhibitor of yeast RNR. The Sml1p specifically binds to the yeast Rnr1p in a 1:1
      ratio with a dissociation constant of 0.4 microM. Interestingly, Sml1p also
      specifically binds to the mouse ribonucleotide reductase R1 protein. However, the
      inhibition observed in an in vitro mouse ribonucleotide reductase assay is less
      pronounced than the inhibition in yeast and probably occurs via a different
      mechanism.

PMID- 10593973
TI  - The role of focal adhesion kinase binding in the regulation of tyrosine
      phosphorylation of paxillin.
AB  - Focal adhesion kinase (FAK) and paxillin are focal adhesion-associated,
      phosphotyrosine-containing proteins that physically interact. A previous study
      has demonstrated that paxillin contains two binding sites for FAK. We have
      further characterized these two binding sites and have demonstrated that the
      binding affinity of the carboxyl-terminal domain of FAK is the same for each of
      the two binding sites. The presence of both binding sites increases the affinity
      for FAK by 5-10-fold. A conserved paxillin sequence called the LD motif has been
      implicated in FAK binding. We show that mutations in the LD motifs in both FAK
      binding sites are required to dramatically impair FAK binding in vitro. A
      paxillin mutant containing point mutations in both FAK-binding sites was
      characterized. The mutant exhibited reduced levels of phosphotyrosine relative to
      wild type paxillin in subconfluent cells growing in culture, following cell
      adhesion to fibronectin and in src-transformed fibroblasts. These results suggest
      that paxillin must bind FAK for maximal phosphorylation in response to cell
      adhesion and that FAK may function to direct tyrosine phosphorylation of paxillin
      in the process of transformation by the src oncogene.

PMID- 10593974
TI  - Activation of Helicobacter pylori VacA toxin by alkaline or acid conditions
      increases its binding to a 250-kDa receptor protein-tyrosine phosphatase beta.
AB  - Helicobacter pylori, a Gram-negative gastric bacterium, secretes VacA, a
      cytotoxin that causes vacuolar degeneration of susceptible cells. Velocity
      sedimentation analysis showed that treatment of VacA at alkaline pH led to
      disassembly of VacA oligomers, an observation reported previously for acid
      treated VacA. Exposure of VacA to acid or alkali increased its binding to AZ-521
      cells, as shown by indirect immunofluorescence and flow cytometry. Moreover,
      immunoprecipitates with polyclonal antibodies against VacA from AZ-521 cells
      previously exposed to acid- or alkali-treated VacA had a 250-kDa glycoprotein
      containing galactose-beta(1-3)-N-acetylgalactosamine and galactose-beta(1-4)-N
      acetylglucosamine. p250, purified by chromatography on peanut agglutinin affinity
      and Superose 6 columns, contained N-terminal and internal amino acid sequences of
      YRQQRKLVEEIGWSYT and LIIQDHILEATQDDY, respectively. These sequences are identical
      to those of a receptor protein-tyrosine phosphatase (RPTPbeta/PTPzeta); in
      agreement, p250 reacted with anti-human RPTPbeta monoclonal antibody.
      Immunoprecipitation with anti-human RPTPbeta antibody of solubilized membrane
      preparations previously incubated with VacA or heat-inactivated VacA demonstrated
      that RPTPbeta bound native, but not denatured, VacA. Acidic and alkaline
      treatments were associated with activation of VacA and increased binding to the
      cell surface RPTPbeta.

PMID- 10593975
TI  - Phosphorylation uncouples the gastrin-releasing peptide receptor from G(q).
AB  - Previous work on the desensitization of G protein-coupled receptors has focused
      on the role of arrestin binding following receptor phosphorylation. We have
      examined the hypothesis that phosphorylation alone contributes to
      desensitization. In this study we demonstrate that for the G(q)-coupled gastrin
      releasing peptide receptor (GRP-R), phosphorylation by GRK2 to a stoichiometry of
      approximately 1 mol PO(4)/mol GRP-R is sufficient in the absence of arrestin to
      reduce the rate of receptor catalyzed G protein activation by approximately 80%.
      Furthermore, GRP-Rs exposed in vivo to agonist are rapidly phosphorylated to a
      similar stoichiometry and are desensitized to a similar degree. Finally, the
      molecular mechanism for both in vitro GRK2-induced and in vivo agonist-induced
      desensitization is primarily a decrease in the maximum velocity (V(max)) for the
      catalysis of guanine nucleotide exchange by the GRP-R rather than a change in the
      affinity of the receptor for the alpha(q) or betagamma subunits. Based on these
      results, we suggest that, for some G protein-coupled receptors, phosphorylation
      has a role in desensitization that is independent of arrestin.

PMID- 10593976
TI  - Nerve growth factor signaling in caveolae-like domains at the plasma membrane.
AB  - Nerve growth factor (NGF) binding to its receptors TrkA and p75(NTR) enhances the
      survival, differentiation, and maintenance of neurons. Recent studies have
      suggested that NGF receptor activation may occur in caveolae or caveolae-like
      membranes (CLM). This is an intriguing possibility because caveolae have been
      shown to contain many of the signaling intermediates in the TrkA signaling
      cascade. To examine the membrane localization of TrkA and p75(NTR), we isolated
      caveolae from 3T3-TrkA-p75 cells and CLM from PC12 cells. Immunoblot analysis
      showed that TrkA and p75(NTR) were enriched about 13- and 25-fold, respectively,
      in caveolae and CLM. Binding and cross-linking studies demonstrated that the NGF
      binding to both TrkA and p75(NTR) was considerably enriched in CLM and that about
      90% of high affinity binding to TrkA was present in CLM. When PC12 cells were
      treated with NGF, virtually all activated (i.e. tyrosine phosphorylated) TrkA was
      found in the CLM. Remarkably, in NGF-treated cells, it was only in CLM that
      activated TrkA was coimmunoprecipitated with phosphorylated Shc and PLCgamma.
      These results document a signaling role for TrkA in CLM and suggest that both
      TrkA and p75(NTR) signaling are initiated from these membranes.

PMID- 10593977
TI  - Identification and characterization of a novel ferric reductase from the
      hyperthermophilic Archaeon Archaeoglobus fulgidus.
AB  - Archaeoglobus fulgidus, a hyperthermophilic sulfate-reducing Archaeon, contains
      high Fe(3+)-EDTA reductase activity in its soluble protein fraction. The
      corresponding enzyme, which constitutes about 0.75% of the soluble protein, was
      purified 175-fold to homogeneity. Based on SDS-polyacrylamide gel
      electrophoresis, the ferric reductase consists of a single subunit with a M(r) of
      18,000. The M(r) of the native enzyme was determined by size exclusion
      chromatography to be 40,000 suggesting that the native ferric reductase is a
      homodimer. The enzyme uses both NADH and NADPH as electron donors to reduce
      Fe(3+)-EDTA. Other Fe(3+) complexes and dichlorophenolindophenol serve as
      alternative electron acceptors, but uncomplexed Fe(3+) is not utilized. The
      purified enzyme strictly requires FMN or FAD as a catalytic intermediate for
      Fe(3+) reduction. Ferric reductase also reduces FMN and FAD, but not riboflavin,
      with NAD(P)H which classifies the enzyme as a NAD(P)H:flavin oxidoreductase. The
      enzyme exhibits a temperature optimum of 88 degrees C. When incubated at 85
      degrees C, the enzyme activity half-life was 2 h. N-terminal sequence analysis of
      the purified ferric reductase resulted in the identification of the hypothetical
      gene, AF0830, of the A. fulgidus genomic sequence. The A. fulgidus ferric
      reductase shares amino acid sequence similarity with a family of NAD(P)H:FMN
      oxidoreductases but not with any ferric reductases suggesting that the A.
      fulgidus ferric reductase is a novel enzyme.

PMID- 10593978
TI  - Increased stability upon heptamerization of the pore-forming toxin aerolysin.
AB  - Aerolysin is a bacterial pore-forming toxin that is secreted as an inactive
      precursor, which is then processed at its COOH terminus and finally forms a
      circular heptameric ring which inserts into membranes to form a pore. We have
      analyzed the stability of the precursor proaerolysin and the heptameric complex.
      Equilibrium unfolding induced by urea and guanidinium hydrochloride was monitored
      by measuring the intrinsic tryptophan fluorescence of the protein. Proaerolysin
      was found to unfold in two steps corresponding to the unfolding of the large COOH
      terminal lobe followed by the unfolding of the small NH(2)-terminal domain. We
      show that proaerolysin contains two disulfide bridges which strongly contribute
      to the stability of the toxin and protect it from proteolytic attack. The
      stability of aerolysin was greatly enhanced by polymerization into a heptamer.
      Two regions of the protein, corresponding to amino acids 180-307 and 401-427,
      were identified, by limited proteolysis, NH(2)-terminal sequencing and matrix
      assisted laser desorption ionization-time of flight, as being responsible for
      stability and maintenance of the heptamer. These regions are presumably involved
      in monomer/monomer interactions in the heptameric protein and are exclusively
      composed of beta structure. The stability of the aerolysin heptamer is
      reminiscent of that of pathogenic, fimbrial protein aggregates found in a variety
      of neurodegenerative diseases.

PMID- 10593979
TI  - Localization of nitric-oxide synthase in plant peroxisomes.
AB  - The presence of nitric-oxide synthase (NOS) in peroxisomes from leaves of pea
      plants (Pisum sativum L.) was studied. Plant organelles were purified by
      differential and sucrose density gradient centrifugation. In purified intact
      peroxisomes a Ca(2+)-dependent NOS activity of 5.61 nmol of L-[(3)H]citrulline
      mg(-1) protein min(-1) was measured while no activity was detected in
      mitochondria. The peroxisomal NOS activity was clearly inhibited (60-90%) by
      different well characterized inhibitors of mammalian NO synthases. The immunoblot
      analysis of peroxisomes with a polyclonal antibody against the C terminus region
      of murine iNOS revealed an immunoreactive protein of 130 kDa. Electron microscopy
      immunogold-labeling confirmed the subcellular localization of NOS in the matrix
      of peroxisomes as well as in chloroplasts. The presence of NOS in peroxisomes
      suggests that these oxidative organelles are a cellular source of nitric oxide
      (NO) and implies new roles for peroxisomes in the cellular signal transduction
      mechanisms.

PMID- 10593980
TI  - Regulation of E-cadherin/Catenin association by tyrosine phosphorylation.
AB  - Alteration of cadherin-mediated cell-cell adhesion is frequently associated to
      tyrosine phosphorylation of p120- and beta-catenins. We have examined the role of
      this modification in these proteins in the control of beta-catenin/E-cadherin
      binding using in vitro assays with recombinant proteins. Recombinant pp60(c-src)
      efficiently phosphorylated both catenins in vitro, with stoichiometries of 1.5
      and 2.0 mol of phosphate/mol of protein for beta-catenin and p120-catenin,
      respectively. pp60(c-src) phosphorylation had opposing effects on the affinities
      of beta-catenin and p120 for the cytosolic domain of E-cadherin; it decreased (in
      the case of beta-catenin) or increased (for p120) catenin/E-cadherin binding.
      However, a role for p120-catenin in the modulation of beta-catenin/E-cadherin
      binding was not observed, since addition of phosphorylated p120-catenin did not
      modify the affinity of phosphorylated (or unphosphorylated) beta-catenin for E
      cadherin. The phosphorylated Tyr residues were identified as Tyr-86 and Tyr-654.
      Experiments using point mutants in these two residues indicated that, although
      Tyr-86 was a better substrate for pp60(c-src), only modification of Tyr-654 was
      relevant for the interaction with E-cadherin. Transient transfections of
      different mutants demonstrated that Tyr-654 is phosphorylated in conditions in
      which adherens junctions are disrupted and evidenced that binding of beta-catenin
      to E-cadherin in vivo is controlled by phosphorylation of beta-catenin Tyr-654.

PMID- 10593981
TI  - Phosphorylation of B-Myb regulates its transactivation potential and DNA binding.
AB  - The transcription factor B-Myb is a cell cycle-regulated phosphoprotein and a
      potent regulator of cell cycle progression. Previous studies demonstrated that B
      Myb was phosphorylated at the onset of S phase, suggesting that it could be due
      to cyclin-dependent kinases. We identified 10 B-Myb phosphorylation sites by
      automated peptide radiosequencing of tryptic phosphopeptides derived from in vivo
      (32)P-labeled B-Myb. Each B-Myb phosphorylation site contained a phosphoserine or
      phosphothreonine followed by a proline, suggesting that this phosphorylation is
      due to a proline-directed kinase. Cyclin A-Cdk2 and cyclin E-Cdk2 complexes each
      phosphorylated B-Myb in a cell-free system on the same sites as in intact cells.
      Furthermore, the ability of B-Myb to activate a reporter plasmid was enhanced by
      the cotransfection of cyclin A, whereas mutagenesis of the 10 identified
      phosphorylation sites from B-Myb blocked the effect of cyclin A coexpression.
      Additional analysis revealed that the effect of phosphorylation on B-Myb
      transactivation potential was enhanced by phosphorylation sites in its carboxyl
      terminal half. One phosphorylation site (Ser(581)) appeared to negatively
      regulate DNA binding, as mutation of this site enhanced the ability of B-Myb to
      bind a Myb-binding sequence. These data suggest that B-Myb is a target for
      phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its
      transcriptional activity.

PMID- 10593982
TI  - Rubisco small and large subunit N-methyltransferases. Bi- and mono-functional
      methyltransferases that methylate the small and large subunits of Rubisco.
AB  - Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco)is methylated at the
      alpha-amino group of the N-terminal methionine of the processed form of the small
      subunit (SS), and at the epsilon-amino group of lysine-14 of the large subunit
      (LS) in some species. The Rubisco LS methyltransferase (LSMT) gene has been
      cloned and expressed from pea and specifically methylates lysine-14 of the LS of
      Rubisco. We determine here that both pea and tobacco Rubisco LSMT also exhibit
      (alpha)N-methyltransferase activity toward the SS of Rubisco, suggesting that a
      single gene product can produce a bifunctional protein methyltransferase capable
      of catalyzing both (alpha)N-methylation of the SS and (epsilon)N-methylation of
      the LS. A homologue of the Rubisco LSMT gene (rbcMT-S) has also been identified
      in spinach that is closely related to Rubisco LSMT sequences from pea and
      tobacco. Two mRNAs are produced from rbcMT-S, and both long and short forms of
      the spinach cDNAs were expressed in Escherichia coli cells and shown to catalyze
      methylation of the alpha-amino group of the N-terminal methionine of the SS of
      Rubisco. Thus, the absence of lysine-14 methylation in species like spinach is
      apparently a consequence of a monofunctional protein methyltransferase incapable
      of methylating Lys-14, with activity limited to methylation of the SS.

PMID- 10593983
TI  - Heat shock protein (Hsp) 40 mutants inhibit Hsp70 in mammalian cells.
AB  - Heat shock protein (Hsp) 70 and Hsp40 expressed in mammalian cells had been
      previously shown to cooperate in accelerating the reactivation of heat-denatured
      firefly luciferase (Michels, A. A., Kanon, B., Konings, A. W. T., Ohtsuka, K.,
      Bensaude, O., and Kampinga, H. H. (1997) J. Biol. Chem. 272, 33283-33289). We now
      provide further evidence for a functional interaction between Hsp70 and the J
      domain of Hsp40 with denatured luciferase resulting in reactivation of heat
      denatured luciferase within living mammalian cells. The stimulating effect of
      Hsp40 on the Hsp70-mediated refolding is lost when the proteins cannot interact
      as accomplished by their expression in different intracellular compartments.
      Likewise, the cooperation between Hsp40 and Hsp70 is lost by introduction of a
      point mutation in the conserved HPD motif of the Hsp40 J-domain or by deletion of
      the four C-terminal amino acids of Hsp70 (EEVD motif). Most strikingly, co
      expression of a truncated protein restricted to the J-domain of Hsp40 had a
      dominant negative effect on Hsp70-facilitated luciferase reactivation. Taken
      together, these experiments indicate for the first time that the Hsp70/Hsp40
      chaperones functionally interact with a heat-denatured protein within mammalian
      cells. The dominant negative effect of the Hsp40 J-domain on the activity of
      Hsp70 demonstrates the importance of J-domain-containing proteins in Hsp70
      dependent processes.

PMID- 10593984
TI  - Regulation of arachidonic acid mobilization in lipopolysaccharide-activated
      P388D(1) macrophages by adenosine triphosphate.
AB  - Murine P388D(1) macrophages exhibit a delayed prostaglandin biosynthetic response
      when exposed to bacterial lipopolysaccharide (LPS) for prolonged periods of time
      that is dependent on induction of the genes coding for Group V secretory
      phospholipase A(2) and cyclooxygenase-2. We herein report that LPS-induced
      arachidonic acid (AA) metabolite release in P388D(1) macrophages is strongly
      attenuated by the P2X(7) purinergic receptor antagonists periodate-oxidized ATP
      and pyridoxal-phosphate-6-azophenyl-2', 4'-disulfonic acid, and this is
      accompanied by suppression of the expression of both Group V secretory
      phospholipase A(2) and cyclooxygenase-2. The effect appears to be specific for
      LPS, because the P2 purinergic receptor antagonists do not affect P388D(1) cell
      stimulation by other stimuli such as platelet-activating factor or the Ca(2+)
      ionophore A23187. Moreover, extracellular nucleotides are found to stimulate
      macrophage AA mobilization with a pharmacological profile that implicates the
      participation of the P2X(7) receptor and that is inhibited by periodate-oxidized
      ATP. Collectively these results demonstrate coupling of the P2X(7) receptor to
      the AA cascade in P388D(1) macrophages and implicate the participation of this
      type of receptor in LPS-induced AA mobilization.

PMID- 10593985
TI  - Baculovirus-based genetic screen for antiapoptotic genes identifies a novel IAP.
AB  - The prototype baculovirus, Autographa californica multiple nuclear polyhedrosis
      virus (AcMNPV) expresses p35, a potent anti cell-death gene that promotes the
      propagation of the virus by blocking host cell apoptosis. Infection of insect Sf
      21 cells with AcMNPV lacking p35 induces apoptosis. We have used this pro
      apoptotic property of the p35 null virus to screen for genes encoding inhibitors
      of apoptosis that rescue cells infected with the p35 defective virus. We report
      here the identification of Tn-IAP1, a novel member of the IAP family of cell
      death inhibitors. Tn-IAP1 blocks cell death induced by p35 null AcMNPV,
      actinomycin D, and Drosophila cell-death inducers HID and GRIM. Given the
      conserved nature of the cell death pathway, this genetic screen can be used for
      rapid identification of novel inhibitors of apoptosis from diverse sources.

PMID- 10593986
TI  - Binding of 14-3-3 protein to the plasma membrane H(+)-ATPase AHA2 involves the
      three C-terminal residues Tyr(946)-Thr-Val and requires phosphorylation of
      Thr(947).
AB  - 14-3-3 proteins play a regulatory role in a diverse array of cellular functions
      such as apoptosis, regulation of the cell cycle, and regulation of gene
      transcription. The phytotoxin fusicoccin specifically induces association of
      virtually any 14-3-3 protein to plant plasma membrane H(+)-ATPase. The 14-3-3
      binding site in the Arabidopsis plasma membrane H(+)-ATPase AHA2 was localized to
      the three C-terminal residues of the enzyme (Tyr(946)-Thr-Val). Binding of 14-3-3
      protein to this target was induced by phosphorylation of Thr(947) (K(D) = 88 nM)
      and was in practice irreversible in the presence of fusicoccin (K(D) = 7 nM).
      Mass spectrometry analysis demonstrated that AHA2 expressed in yeast was
      phosphorylated at Thr(947). We conclude that the extreme end of AHA2 contains an
      unusual high-affinity binding site for 14-3-3 protein.

PMID- 10593987
TI  - Recycling of furin from the plasma membrane. Functional importance of the
      cytoplasmic tail sorting signals and interaction with the AP-2 adaptor medium
      chain subunit.
AB  - The predominant intracellular localization of the eukaryotic subtilisin-like
      endoprotease furin is the trans-Golgi network (TGN), but a small fraction is also
      found on the cell surface. Furin on the cell surface is internalized and
      delivered to the TGN. The identification of three endocytosis motifs, a tyrosine
      (YKGL(765)) motif, a leucine-isoleucine (LI(760)) motif, and a phenylalanine
      (Phe(790)) signal, in the furin cytoplasmic domain suggested that endocytosis of
      furin occurs via an AP-2/clathrin-dependent pathway. Since little is known about
      proteins containing multiple sorting components in their cytoplasmic domain, the
      combination of diverse internalization signals in the furin tail raised the
      question of their individual role. Here we present data showing that the furin
      tail interacts with the medium (micro2) subunit of the AP-2 plasma membrane
      specific adaptor complex in vitro and that this interaction primarily depends on
      recognition of the tyrosine-based sorting signal and to less extent on the
      leucine-isoleucine motif. We further provide evidence that the three endocytosis
      signals are of different functional importance for furin internalization and
      retrieval to the TGN in vivo, with the tyrosine-based motif being the major
      determinant, followed by the phenylalanine signal, whereas the leucine-isoleucine
      motif is only a minor component. Finally, we report that phosphorylation of the
      furin tail by casein kinase II is not only important for efficient interaction
      with micro2 and internalization from the plasma membrane but also determines fast
      retrieval of the protein from the plasma membrane to the TGN.

PMID- 10593988
TI  - Novel inositol polyphosphate 5-phosphatase localizes at membrane ruffles.
AB  - We have cloned a novel inositol polyphosphate 5-phosphatase from the rat brain
      cDNA library. It contains two highly conserved 5-phosphatase motifs, both of
      which are essential for its enzymatic activity. Interestingly, the proline
      content of this protein is high and concentrated in its N- and C-terminal
      regions. One putative SH3-binding motif and six 14-3-3 zeta-binding motifs were
      found in the amino acid sequence. This enzyme hydrolyzed phosphate at the D-5
      position of inositol 1,4,5-trisphosphate, inositol 1,3,4, 5-tetrakisphosphate,
      and phosphatidylinositol 4,5-bisphosphate, consistent with the substrate
      specificity of type II 5-phosphatase, OCRL, synaptojanin and synaptojanin 2,
      already characterized 5-phosphatases. When the Myc-epitope-tagged enzyme was
      expressed in COS-7 cells and stained with anti-Myc polyclonal antibody, a signal
      was observed at ruffling membranes and in the cytoplasm. We prepared several
      deletion mutants and demonstrated that the 123 N-terminal amino acids (311-433)
      and a C-terminal proline-rich region containing 277 amino acids (725-1001) were
      essential for its localization to ruffling membranes. This enzyme might regulate
      the level of inositol and phosphatidylinositol polyphosphates at membrane
      ruffles.

PMID- 10593989
TI  - Identification of COUP-TF as a transcriptional repressor of the c-mos proto
      oncogene.
AB  - The c-mos proto-oncogene is specifically expressed in the male and female germ
      cells of the mouse and other vertebrates. We previously identified a 15-base pair
      sequence element (B2) as the binding site of a candidate repressor of c-mos
      transcription in somatic cells. In the present study, we used the yeast one
      hybrid system to isolate HeLa cell cDNAs encoding proteins that specifically
      bound to the c-mos B2 element. Nucleotide sequencing identified several of the
      clones isolated in this screen as the orphan nuclear receptors COUP-TFI and COUP
      TFII. A COUP-TF-binding site was then identified within the B2 sequence.
      Complexes formed between purified COUP-TFs and the c-mos B2 probe comigrated in
      electrophoretic mobility shift assays with those formed using whole nuclear
      extracts of NIH 3T3 or HeLa cells. Moreover, the complexes formed with NIH 3T3
      nuclear extracts and B2 probe were supershifted with antibody against COUP-TF,
      identifying COUP-TF as the candidate repressor previously detected in these
      somatic cell extracts. Substitution of a consensus COUP-TF-binding site for the c
      mos negative regulatory element suppressed expression from the c-mos promoter in
      transfected somatic cells, demonstrating the functional activity of COUP-TF as a
      repressor of c-mos transcription.

PMID- 10593990
TI  - Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of
      Notch.
AB  - Presenilin-1 (PS1), a polytopic membrane protein primarily localized to the
      endoplasmic reticulum, is required for efficient proteolysis of both Notch and
      beta-amyloid precursor protein (APP) within their trans- membrane domains. The
      activity that cleaves APP (called gamma-secretase) has properties of an aspartyl
      protease, and mutation of either of the two aspartate residues located in
      adjacent transmembrane domains of PS1 inhibits gamma-secretase processing of APP.
      We show here that these aspartates are required for Notch processing, since
      mutation of these residues prevents PS1 from inducing the gamma-secretase-like
      proteolysis of a Notch1 derivative. Thus PS1 might function in Notch cleavage as
      an aspartyl protease or di-aspartyl protease cofactor. However, the ER
      localization of PS1 is inconsistent with that hypothesis, since Notch cleavage
      occurs near the cell surface. Using pulse-chase and biotinylation assays, we
      provide evidence that PS1 binds Notch in the ER/Golgi and is then co-transported
      to the plasma membrane as a complex. PS1 aspartate mutants were indistinguishable
      from wild-type PS1 in their ability to bind Notch or traffic with it to the cell
      surface, and did not alter the secretion of Notch. Thus, PS1 appears to function
      specifically in Notch proteolysis near the plasma membrane as an aspartyl
      protease or cofactor.

PMID- 10593991
TI  - The processing of ligands by the class A scavenger receptor is dependent on
      signal information located in the cytoplasmic domain.
AB  - The mechanisms that regulate the transport of the macrophage class A scavenger
      receptor during ligand uptake were investigated. Kinetic analysis of the changes
      in receptor phosphorylation demonstrated that serine phosphorylation increased
      during the internalization of acetyl-low density lipoproteins (LDL) by
      macrophages. The increase was maximal at about 2.5 min after the initiation of
      ligand uptake. Oxidized LDL also stimulated serine phosphorylation, but the
      relative increase was smaller and the time to maximum was shorter. Receptor
      mutants expressed in Chinese hamster ovary and COS cells showed that elimination
      of the potential phosphorylation site at Ser(21) increased acetyl-LDL metabolism,
      whereas inactivation of the site at Ser(49) reduced acetyl-LDL uptake. The
      increase in uptake by the Ser(21) mutant was due to an increase in surface
      receptor expression. In contrast, elimination of the site at Ser(49) did not
      affect receptor expression but slowed receptor internalization. To identify
      potential internalization signal sequences, beta-turn structure in the cytosolic
      domain was targeted for mutagenesis. Disruption of one region near Asp(25)
      inhibited receptor activity. The studies support a model whereby receptor
      internalization requires the presence of an internalization signal motif but that
      the rate of receptor internalization is governed by the pattern of receptor
      phosphorylation induced by the ligand.

PMID- 10593992
TI  - Resistance to the cytotoxic effects of tumor necrosis factor alpha can be
      overcome by inhibition of a FADD/caspase-dependent signaling pathway.
AB  - Tumor necrosis factor (TNF) alpha initiates the activation of a pro-apoptotic
      pathway involving the recruitment of the death domain containing protein FADD and
      the subsequent activation of specific proteases (caspases). Many cells are
      resistant, however, to the cytotoxic effects of TNFalpha due to the concurrent
      activation of pro-survival pathways involving the transcription factor NFkappaB
      and TRAF2. Here we show that the TNFalpha-activated FADD/caspase pathway can also
      exert an unexpected pro-survival effect. Inhibition of this pathway in NIH3T3
      fibroblasts or U937 leukemic cells by peptide caspase inhibitors or expression of
      dominant-negative FADD leads to rapid death following treatment with TNFalpha,
      whereas control cells are TNFalpha-resistant. FADD/caspase-inhibited cells die by
      a non-apoptotic mechanism caused by increased production of reactive oxygen
      species which precedes loss of the mitochondrial membrane potential. Cytotoxicity
      can be prevented by preincubation with antioxidants including reduced glutathione
      or by expression of a dominant-negative Rac GTP-binding protein. These results
      indicate that caspase activation in response to TNFalpha has anti-necrotic as
      well as pro-apoptotic effects and extend our understanding of the biological role
      of these proteases.

PMID- 10593993
TI  - Familial gastric cancer: overview and guidelines for management.
AB  - Families with autosomal dominant inherited predisposition to gastric cancer have
      been described. More recently, germline E-cadherin/CDH1 mutations have been
      identified in hereditary diffuse gastric cancer kindred. The need to have
      protocols to manage and counsel these families in the clinic led a group of
      geneticists, gastroenterologists, surgeons, oncologists, pathologists, and
      molecular biologists to convene a workshop to produce consensus statements and
      guidelines for familial gastric cancer. Review of the available cancer pathology
      from people belonging to families with documented germline E-cadherin/CDH1
      mutations confirmed that the gastric cancers were all of the diffuse type.
      Criteria to define the different types of familial gastric cancer syndromes were
      agreed. Foremost among these criteria was that review of histopathology should be
      part of the evaluation of any family with aggregation of gastric cancer cases.
      Guidelines for genetic testing and counselling in hereditary diffuse gastric
      cancer were produced. Finally, a proposed strategy for clinical management in
      families with high penetrance autosomal dominant predisposition to gastric cancer
      was defined.

PMID- 10593994
TI  - Mutations of the cathepsin C gene are responsible for Papillon-Lefevre syndrome.
AB  - Papillon-Lefevre syndrome (PLS) is an autosomal recessive disorder characterised
      by palmoplantar hyperkeratosis and severe early onset periodontitis that results
      in the premature loss of the primary and secondary dentitions. A major gene locus
      for PLS has been mapped to a 2.8 cM interval on chromosome 11q14. Correlation of
      physical and genetic maps of this interval indicate it includes at least 40 ESTs
      and six known genes including the lysosomal protease cathepsin C gene (CTSC). The
      CTSC message is expressed at high levels in a variety of immune cells including
      polymorphonuclear leucocytes, macrophages, and their precursors. By RT-PCR, we
      found CTSC is also expressed in epithelial regions commonly affected by PLS,
      including the palms, soles, knees, and oral keratinised gingiva. The 4.7 kb CTSC
      gene consists of two exons. Sequence analysis of CTSC from subjects affected with
      PLS from five consanguineous Turkish families identified four different
      mutations. An exon 1 nonsense mutation (856C-->T) introduces a premature stop
      codon at amino acid 286. Three exon 2 mutations were identified, including a
      single nucleotide deletion (2692delA) of codon 349 introducing a frameshift and
      premature termination codon, a 2 bp deletion (2673-2674delCT) that results in
      introduction of a stop codon at amino acid 343, and a G-->A substitution in codon
      429 (2931G-->A) introducing a premature termination codon. All PLS patients were
      homozygous for cathepsin C mutations inherited from a common ancestor. Parents
      and sibs heterozygous for cathepsin C mutations do not show either the
      palmoplantar hyperkeratosis or severe early onset periodontitis characteristic of
      PLS. A more complete understanding of the functional physiology of cathepsin C
      carries significant implications for understanding normal and abnormal skin
      development and periodontal disease susceptibility.

PMID- 10593995
TI  - Popliteal pterygium syndrome: a clinical study of three families and report of
      linkage to the Van der Woude syndrome locus on 1q32.
AB  - Popliteal pterygium syndrome (PPS) is a rare autosomal dominant disorder, thought
      to occur with an incidence of approximately 1 in 300 000 live births. The main
      clinical manifestations are popliteal webbing, cleft lip, cleft palate, lower lip
      pits, syndactyly, and genital and nail anomalies. This report describes the
      clinical features in two families with PPS and one isolated case, showing the
      range of anomalies found both within and between the families. PPS has some
      features in common with Van der Woude syndrome (VWS), also inherited as an
      autosomal dominant condition, with cleft lip/palate and, more distinctively,
      lower lip pits. Although the gene for VWS has not yet been identified, it has
      been localised to within 1.6 cM in the region 1q32-41. To determine whether PPS
      and VWS represent allelic forms of the same gene, three families were genotyped
      for markers flanking and within the critical region. A multipoint lod score of
      2.7 was obtained, with no evidence of recombination, supporting the hypothesis
      that these two disorders are allelic.

PMID- 10593996
TI  - Unusual clustering of brain tumours in a family with NF1 and variable expression
      of cutaneous features.
AB  - Neurofibromatosis type 1 (NF1) is one of the commonest autosomal dominant
      disorders in man. It is characterised by cafe au lait spots, peripheral
      neurofibromas, Lisch nodules, axillary freckling, skeletal dysplasia, and optic
      glioma. Symptomatic brain tumours occur in 1.5-2.2% of patients with NF1. We
      report here a family where seven members developed brain tumours. Of these, three
      have a clinical history strongly suggestive of NF1, while two do not fulfil
      diagnostic criteria for the disorder. A splice site mutation in exon 29 of the
      NF1 gene was found in these two subjects. This lesion is thought to be disease
      causative since it creates a frameshift and a premature termination of the
      neurofibromin protein. Different hypotheses to explain the unusual recurrence of
      brain tumours in this family, such as the nature of the mutation or cosegregation
      of other predisposing genes, are discussed.

PMID- 10593997
TI  - Psychological functioning before predictive testing for Huntington's disease: the
      role of the parental disease, risk perception, and subjective proximity of the
      disease.
AB  - BACKGROUND: Psychometric testing of participants in predictive DNA testing for
      Huntington's disease (HD) has shown that 15% of the subjects at risk for HD had
      at least mild depression or a high score for general anxiety or both in the pre
      test period. The main aim of the study was the delineation of variables
      associated with pre-test distress of applicants for predictive testing for HD.
      Based on theoretical considerations, four specific hypotheses were tested
      regarding the role of (1) the test participant's age at the (perceived) parental
      onset of HD, (2) the affected parent's sex, (3) the perception of the risk for
      HD, and (4) the subjective proximity of the disease. Secondly, these four
      variables were used in multiple regression analyses to select the best predictors
      of pre- and post-test psychological functioning (one year after the test).
      Increasing the understanding of pre- and post-test distress is important for
      developing better counselling and support strategies for test applicants.
      METHODS: Data were collected by means of clinical interviews and psychometric
      questionnaires during the pre- and post-test (one year after the test)
      counselling sessions for predictive testing for HD. RESULTS: We found significant
      associations of the participant's age at the parental onset, the subjective
      proximity of the disease onset, and the perceived risk with pre-test psychometric
      measures of psychological functioning. Multiple regression analyses showed that
      the best predictors of pre-test functioning were the perceived proximity of the
      disease onset and its interaction with risk perception. Regarding post-test
      functioning, none of the proposed variables had a unique contribution beyond that
      accounted for by pre-test psychological functioning. CONCLUSIONS: Test
      participants who are close to the perceived age of onset of HD and who have a
      pessimistic risk perception should be given special attention during pre-test
      counselling because of their possible negative affective condition at that time.
      Pre-test psychological measures were the best predictors of post-test distress,
      irrespective of the test result. Suggestions for future longitudinal research are
      formulated. This kind of research should enable clinical geneticists and mental
      health professionals to refine the pre- and post-test counselling strategies for
      predictive DNA testing, not only for HD, but also for other incurable late onset
      disorders.

PMID- 10593998
TI  - Presymptomatic testing for BRCA1 and BRCA2: how distressing are the pre-test
      weeks? Rotterdam/Leiden Genetics Working Group.
AB  - Presymptomatic DNA testing for autosomal dominant hereditary breast/ovarian
      cancer (HBOC) became an option after the identification of the BRCA1 and BRCA2
      genes in 1994-1995. Healthy female mutation carriers have a high lifetime risk
      for breast cancer (56-87%) or ovarian cancer (10-60%) and may opt for intensive
      breast and ovary surveillance or prophylactic surgery (mastectomy/oophorectomy).
      We studied general and cancer related distress in 85 healthy women with a 25% or
      50% risk of being carrier of a BRCA1/BRCA2 gene mutation and 66 partners in the
      six to eight week period between genetic counselling/blood sampling and
      disclosure of the test result. Questionnaire and interview data are analysed.
      Associations are explored between levels of distress and (1) expected
      consequences of being identified as a mutation carrier, (2) personality traits,
      (3) sociodemographic variables, and (4) experiences related to HBOC. Mean pre
      test anxiety and depression levels in women at risk of being a carrier and
      partners were similar to those of a normal Dutch population. In about 25% of
      those at risk of being a carrier and 10% of the partners, increased to high
      levels of general and cancer related distress were found. Increased levels of
      distress were reported by women who (1) anticipated an increase in problems after
      an unfavourable test outcome, (2) considered prophylactic mastectomy if found to
      be mutation carrier, (3) had an unoptimistic personality, (4) tended to suppress
      their emotions, (5) were younger than 40 years, and (6) were more familiar with
      the serious consequences of HBOC. Recently obtained awareness of the genetic
      nature of cancer in the family was not predictive of distress.The majority of the
      women and their partners experienced a relatively calm period before the
      disclosure of the test result and seemed to postpone distressing thoughts until
      the week of disclosure of the result. The low distress levels may partly be
      explained by the use of strategies to minimise the emotional impact of a possibly
      unfavourable test outcome. However, a minority reported feeling very distressed.
      Several factors were found to be predictive for increased distress levels.

PMID- 10593999
TI  - Neocentromere formation in a stable ring 1p32-p36.1 chromosome.
AB  - Neocentromeres are functional centromeres formed in chromosome regions outside
      the normal centromere domains and are found in an increasing number of
      mitotically stable human marker chromosomes in both neoplastic and non-neoplastic
      cells. We describe here the formation of a neocentromere in a previously
      undescribed chromosomal region at 1p32-->p36.1 in an oligospermic patient.
      Cytogenetic GTL banding analysis and the absence of detectable fluorescence in
      situ hybridisation (FISH) signals using telomeric probes indicate the marker to
      be a ring chromosome. The chromosome is negative for CBG banding and is devoid of
      detectable centromeric alpha satellite and its associated centromere protein CENP
      B, suggesting activation of a neocentromere within the 1p32-36.1 region.
      Functional activity of the neocentromere is shown by the retention of the ring
      chromosome in 97% of the patient's lymphocytes and 100% of his cultured
      fibroblasts, as well as by the presence of key centromere binding proteins CENP
      E, CENP-F, and INCENP. These results indicate that in addition to CENP-A, CENP-C,
      and CENP-E described in earlier studies, neocentromere activity can further be
      defined by CENP-F and INCENP binding. Our evidence suggests that neocentromere
      formation constitutes a viable mechanism for the mitotic stabilisation of
      acentric ring chromosomes.

PMID- 10594000
TI  - A proven de novo germline mutation in HNPCC.
AB  - Hereditary non-polyposis colon cancer (HNPCC) is a heterogeneous group of tumour
      predisposition syndromes caused by germline mutations in at least four different
      mismatch repair genes. HNPCC patients are prone to the development of carcinomas
      of the intestinal tract and other specific sites. Identification of presumptive
      HNPCC patients is primarily based on a positive family history of colorectal
      cancer in at least two generations. In the course of mutation screening of the
      MLH1 and MSH2 genes in patients manifesting a carcinoma of the HNPCC tumour
      spectrum before the age of 45 years, we identified a germline MSH2 344delA
      frameshift mutation in a male proband. This index patient, at the age of 25
      years, initially developed a large rectal adenoma that was removed by
      polypectomy. Ten years later he was operated on for an invasive right sided colon
      carcinoma in the caecum (International Union Against Cancer (UICC) stage III).
      The mother and father, aged 61 and 66 years, respectively, were healthy and had
      no family history of colorectal cancer. Subsequent molecular analyses excluded
      the germinal MSH2 344delA alteration identified in their son and at the same time
      paternity was confirmed with a set of informative polymorphic markers. Thus, the
      genetic alteration identified in our patient definitely represented a de novo
      germline mutation in one of the major HNPCC genes. This case report of a patient
      with colorectal cancer at a relatively young age with no family history is
      intended to encourage mutation screening of the MSH2 and MLH1 genes in similar
      cases to find out whether this group of patients contains an increased proportion
      of de novo mutations in mismatch repair genes.

PMID- 10594001
TI  - Mutational analysis of the HGO gene in Finnish alkaptonuria patients.
AB  - Alkaptonuria (AKU), the prototypic inborn error of metabolism, has recently been
      shown to be caused by loss of function mutations in the homogentisate-1,2
      dioxygenase gene (HGO). So far 17 mutations have been characterised in AKU
      patients of different ethnic origin. We describe three novel mutations (R58fs,
      R330S, and H371R) and one common AKU mutation (M368V), detected by mutational and
      polymorphism analysis of the HGO gene in five Finnish AKU pedigrees. The three
      novel AKU mutations are most likely specific for the Finnish population and have
      originated recently.

PMID- 10594002
TI  - Skewed sex ratios in familial holoprosencephaly and in people with isolated
      single maxillary central incisor.
AB  - Autosomal dominant holoprosencephaly is a rare but well documented entity and it
      can be the result of mutations in the Sonic Hedgehog gene (SHH). The transmitting
      parent may be normal or have a single maxillary central incisor. We describe a
      skewed sex ratio among the transmitting parents with SHH mutations, with more
      mothers than fathers having the mutation (p=0.002). The mechanism underlying this
      skewed sex ratio is not clear; the SHH mutations do not involve triplet repeats,
      imprinting is plausible but untested, and there is no evidence that the risk of
      holoprosencephaly is greater among males carrying such a mutation (p=0.15). We
      considered the possibility that males with such a mutation are at greater risk of
      other malformations outside the central nervous system, which could reduce their
      reproductive fitness. To avoid ascertainment bias in identifying children with
      various malformations in kindreds with familial holoprosencephaly, we reviewed
      the reports of people with single maxillary central incisor and no other
      congenital malformations. Of the 16 cases identified, 13 were female (p=0.0085).
      We suggest that boys with mutations associated with autosomal dominant
      holoprosencephaly may be at greater risk of major malformations outside the
      central nervous system than girls.

PMID- 10594003
TI  - Scanning mutagenesis of Mcm1: residues required for DNA binding, DNA bending, and
      transcriptional activation by a MADS-box protein.
AB  - MCM1 is an essential gene in the yeast Saccharomyces cerevisiae and is a member
      of the MADS-box family of transcriptional regulatory factors. To understand the
      nature of the protein-DNA interactions of this class of proteins, we have made a
      series of alanine substitutions in the DNA-binding domain of Mcm1 and examined
      the effects of these mutations in vivo and in vitro. Our results indicate which
      residues of Mcm1 are important for viability, transcriptional activation, and DNA
      binding and bending. Substitution of residues in Mcm1 which are highly conserved
      among the MADS-box proteins are lethal to the cell and abolish DNA binding in
      vitro. These positions have almost identical interactions with DNA in both the
      serum response factor-DNA and alpha2-Mcm1-DNA crystal structures, suggesting that
      these residues make up a conserved core of protein-DNA interactions responsible
      for docking MADS-box proteins to DNA. Substitution of residues which are not as
      well conserved among members of the MADS-box family play important roles in
      contributing to the specificity of DNA binding. These results suggest a general
      model of how MADS-box proteins recognize and bind DNA. We also provide evidence
      that the N-terminal extension of Mcm1 may have considerable conformational
      freedom, possibly to allow binding to different DNA sites. Finally, we have
      identified two mutants at positions which are critical for Mcm1-mediated DNA
      bending that have a slow-growth phenotype. This finding is consistent with our
      earlier results, indicating that DNA bending may have a role in Mcm1 function in
      the cell.

PMID- 10594004
TI  - Pan1p, End3p, and S1a1p, three yeast proteins required for normal cortical actin
      cytoskeleton organization, associate with each other and play essential roles in
      cell wall morphogenesis.
AB  - The EH domain proteins Pan1p and End3p of budding yeast have been known to form a
      complex in vivo and play important roles in organization of the actin
      cytoskeleton and endocytosis. In this report, we describe new findings concerning
      the function of the Pan1p-End3p complex. First, we found that the Pan1p-End3p
      complex associates with Sla1p, another protein known to be required for the
      assembly of cortical actin structures. Sla1p interacts with the first long repeat
      region of Pan1p and the N-terminal EH domain of End3p, thus leaving the Pan1p
      End3p interaction, which requires the second long repeat of Pan1p and the C
      terminal repeat region of End3p, undisturbed. Second, Pan1p, End3p, and Sla1p are
      also required for normal cell wall morphogenesis. Each of the Pan1-4, sla1Delta,
      and end3Delta mutants displays the abnormal cell wall morphology previously
      reported for the act1-1 mutant. These cell wall defects are also exhibited by
      wild-type cells overproducing the C-terminal region of Sla1p that is responsible
      for interactions with Pan1p and End3p. These results indicate that the functions
      of Pan1p, End3p, and Sla1p in cell wall morphogenesis may depend on the formation
      of a heterotrimeric complex. Interestingly, the cell wall abnormalities exhibited
      by these cells are independent of the actin cytoskeleton organization on the cell
      cortex, as they manifest despite the presence of apparently normal cortical actin
      cytoskeleton. Examination of several act1 mutants also supports this conclusion.
      These observations suggest that the Pan1p-End3p-Sla1p complex is required not
      only for normal actin cytoskeleton organization but also for normal cell wall
      morphogenesis in yeast.

PMID- 10594005
TI  - Association of yeast adenylyl cyclase with cyclase-associated protein CAP forms a
      second Ras-binding site which mediates its Ras-dependent activation.
AB  - Posttranslational modification, in particular farnesylation, of Ras is crucial
      for activation of Saccharomyces cerevisiae adenylyl cyclase (CYR1). Based on the
      previous observation that association of CYR1 with cyclase-associated protein
      (CAP) is essential for its activation by posttranslationally modified Ras, we
      postulated that the associated CAP might contribute to the formation of a Ras
      binding site of CYR1, which mediates CYR1 activation, other than the primary Ras
      binding site, the leucine-rich repeat domain. Here, we observed a
      posttranslational modification-dependent association of Ras with a complex
      between CAP and CYR1 C-terminal region. When CAP mutants defective in Ras
      signaling but retaining the CYR1-binding activity were isolated by screening of a
      pool of randomly mutagenized CAP, CYR1 complexed with two of the obtained three
      mutants failed to be activated efficiently by modified Ras and exhibited a
      severely impaired ability to bind Ras, providing a genetic evidence for the
      importance of the physical association with Ras at the second Ras-binding site.
      On the other hand, CYR1, complexed with the other CAP mutant, failed to be
      activated by Ras but exhibited a greatly enhanced binding to Ras. Conversely, a
      Ras mutant E31K, which exhibits a greatly enhanced binding to the CYR1-CAP
      complex, failed to activate CYR1 efficiently. Thus, the strength of interaction
      at the second Ras-binding site appears to be a critical determinant of CYR1
      regulation by Ras: too-weak and too-strong interactions are both detrimental to
      CYR1 activation. These results, taken together with those obtained with mammalian
      Raf, suggest the importance of the second Ras-binding site in effector
      regulation.

PMID- 10594006
TI  - Large T-antigen double hexamers imaged at the simian virus 40 origin of
      replication.
AB  - The initial step of simian virus 40 (SV40) DNA replication is the binding of the
      large tumor antigen (T-Ag) to the SV40 core origin. In the presence of Mg(2+) and
      ATP, T-Ag forms a double-hexamer complex covering the complete core origin. By
      using electron microscopy and negative staining, we visualized for the first time
      T-Ag double hexamers bound to the SV40 origin. Image processing of side views of
      these nucleoprotein complexes revealed bilobed particles 24 nm long and 8 to 12
      nm wide, which indicates that the two T-Ag hexamers are oriented head to head.
      Taking into account all of the biochemical data known on the T-Ag-DNA
      interactions at the replication origin, we present a model in which the DNA
      passes through the inner channel of both hexamers. In addition, we describe a
      previously undetected structural domain of the T-Ag hexamer and thereby amend the
      previously published dimensions of the T-Ag hexamer. This domain we have
      determined to be the DNA-binding domain of T-Ag.

PMID- 10594007
TI  - Definition of a T-cell receptor beta gene core enhancer of V(D)J recombination by
      transgenic mapping.
AB  - V(D)J recombination in differentiating lymphocytes is a highly regulated process
      in terms of both cell lineage and the stage of cell development. Transgenic and
      knockout mouse studies have demonstrated that transcriptional enhancers from
      antigen receptor genes play an important role in this regulation by activating
      cis-recombination events. A striking example is the T-cell receptor beta-chain
      (TCRbeta) gene enhancer (Ebeta), which in the mouse consists of at least seven
      nuclear factor binding motifs (betaE1 to betaE7). Here, using a well
      characterized transgenic recombination substrate approach, we define the
      sequences within Ebeta required for recombination enhancer activity. The Ebeta
      core is comprised of a limited set of motifs (betaE3 and betaE4) and an
      additional previously uncharacterized 20-bp sequence 3' of the betaE4 motif. This
      core element confers cell lineage- and stage-specific recombination within the
      transgenic substrates, although it cannot bypass the suppressive effects
      resulting from transgene integration in heterochromatic centromeres. Strikingly,
      the core enhancer is heavily occupied by nuclear factors in immature thymocytes,
      as shown by in vivo footprinting analyses. A larger enhancer fragment including
      the betaE1 through betaE4 motifs but not the 3' sequences, although active in
      inducing germ line transcription within the transgenic array, did not retain the
      Ebeta recombinational activity. Our results emphasize the multifunctionality of
      the TCRbeta enhancer and shed some light on the molecular mechanisms by which
      transcriptional enhancers and associated nuclear factors may impact on cis
      recombination, gene expression, and lymphoid cell differentiation.

PMID- 10594008
TI  - A double-strand break in a chromosomal LINE element can be repaired by gene
      conversion with various endogenous LINE elements in mouse cells.
AB  - A double-strand break (DSB) in the mammalian genome has been shown to be a very
      potent signal for the cell to activate repair processes. Two different types of
      repair have been identified in mammalian cells. Broken ends can be rejoined with
      or without loss or addition of DNA or, alternatively, a homologous template can
      be used to repair the break. For most genomic sequences the latter event would
      involve allelic sequences present on the sister chromatid or homologous
      chromosome. However, since more than 30% of our genome consists of repetitive
      sequences, these would have the option of using nonallelic sequences for
      homologous repair. This could have an impact on the evolution of these sequences
      and of the genome itself. We have designed an assay to look at the repair of DSBs
      in LINE-1 (L1) elements which number 10(5) copies distributed throughout the
      genome of all mammals. We introduced into the genome of mouse epithelial cells an
      L1 element with an I-SceI endonuclease site. We induced DSBs at the I-SceI site
      and determined their mechanism of repair. We found that in over 95% of cases, the
      DSBs were repaired by an end-joining process. However, in almost 1% of cases, we
      found strong evidence for repair involving gene conversion with various
      endogenous L1 elements, with some being used preferentially. In particular, the
      T(F) family and the L1Md-A2 subfamily, which are the most active in
      retrotransposition, appeared to be contributing the most in this process. The
      degree of homology did not seem to be a determining factor in the selection of
      the endogenous elements used for repair but may be based instead on
      accessibility. Considering their abundance and dispersion, gene conversion
      between repetitive elements may be occurring frequently enough to be playing a
      role in their evolution.

PMID- 10594009
TI  - Histone H1 is dispensable for methylation-associated gene silencing in Ascobolus
      immersus and essential for long life span.
AB  - A gene encoding a protein that shows sequence similarity with the histone H1
      family only was cloned in Ascobolus immersus. The deduced peptide sequence
      presents the characteristic three-domain structure of metazoan linker histones,
      with a central globular region, an N-terminal tail, and a long positively charged
      C-terminal tail. By constructing an artificial duplication of this gene, named
      H1, it was possible to methylate and silence it by the MIP (methylation induced
      premeiotically) process. This resulted in the complete loss of the Ascobolus H1
      histone. Mutant strains lacking H1 displayed normal methylation-associated gene
      silencing, underwent MIP, and showed the same methylation-associated chromatin
      modifications as did wild-type strains. However, they displayed an increased
      accessibility of micrococcal nuclease to chromatin, whether DNA was methylated or
      not, and exhibited a hypermethylation of the methylated genome compartment. These
      features are taken to imply that Ascobolus H1 histone is a ubiquitous component
      of chromatin which plays no role in methylation-associated gene silencing. Mutant
      strains lacking histone H1 reproduced normally through sexual crosses and
      displayed normal early vegetative growth. However, between 6 and 13 days after
      germination, they abruptly and consistently stopped growing, indicating that
      Ascobolus H1 histone is necessary for long life span. This constitutes the first
      observation of a physiologically important phenotype associated with the loss of
      H1.

PMID- 10594010
TI  - A model system for activation-induced alternative splicing of CD45 pre-mRNA in T
      cells implicates protein kinase C and Ras.
AB  - Multiple isoforms of the protein tyrosine phosphatase CD45 are expressed on the
      surface of human T cells. Interestingly, the expression of these isoforms has
      been shown to vary significantly upon T-cell activation. In this report, we
      describe a novel cell line-based model system in which we can mimic the
      activation-induced alternative splicing of CD45 observed in primary T cells. Of
      the many proximal signaling events induced by T-cell stimulation, we show that
      activation of protein kinase C and activation of Ras are important for the switch
      toward the exclusion of CD45 variable exons, whereas events related to Ca(2+)
      flux are not. In addition, the ability of cycloheximide to block the activation
      induced alternative splicing of CD45 suggests a requirement for de novo protein
      synthesis. We further demonstrate that sequences which have previously been
      implicated in the tissue-specific regulation of CD45 variable exons are likewise
      necessary and sufficient for activation-induced splicing. These results provide
      an initial understanding of the requirements for CD45 alternative splicing upon T
      cell activation, and they confirm the importance of this novel cell line in
      facilitating a more detailed analysis of the activation-induced regulation of
      CD45 than has been previously possible.

PMID- 10594011
TI  - Auto-inhibition of Ets-1 is counteracted by DNA binding cooperativity with core
      binding factor alpha2.
AB  - Auto-inhibition is a common transcriptional control mechanism that is well
      characterized in the regulatory transcription factor Ets-1. Autoinhibition of Ets
      1 DNA binding works through an inhibitory module that exists in two
      conformations. DNA binding requires a change in the inhibitory module from the
      packed to disrupted conformation. This structural switch provides a mechanism to
      tightly regulate Ets-1 DNA binding. We report that the Ets-1 partner protein core
      binding factor alpha2 (CBFalpha2; also known as AML1 or PEBP2) stimulates Ets-1
      DNA binding and counteracts auto-inhibition. Support for this conclusion came
      from three observations. First, the level of cooperative DNA binding (10-fold)
      was similar to the level of repression by auto-inhibition (10- to 20-fold). Next,
      a region necessary for cooperative DNA binding mapped to the inhibitory module.
      Third, an Ets-1 mutant with a constitutively disrupted inhibitory module did not
      bind DNA cooperatively with CBFalpha2. Furthermore, two additional lines of
      evidence indicated that CBFalpha2 affects the structural switch by direct
      interactions with Ets-1. First, the retention of cooperative DNA binding on
      nicked duplexes eliminated a potential role of through-DNA effects. Second,
      cooperative DNA binding was observed on composite sites with altered spacing or
      reversed orientation. We suggest that only protein interactions can accommodate
      this observed flexibility. These findings provide a mechanism by which CBF
      relieves the auto-inhibition of Ets-1 and illustrates one strategy for the
      synergistic activity of regulatory transcription factors.

PMID- 10594012
TI  - Auto-inhibition and partner proteins, core-binding factor beta (CBFbeta) and Ets
      1, modulate DNA binding by CBFalpha2 (AML1).
AB  - Core-binding factor alpha2 (CBFalpha2; otherwise known as AML1 or PEBP2alphaB) is
      a DNA-binding subunit in the family of core-binding factors (CBFs), heterodimeric
      transcription factors that play pivotal roles in multiple developmental processes
      in mammals, including hematopoiesis and bone development. The Runt domain in
      CBFalpha2 (amino acids 51 to 178) mediates DNA binding and heterodimerization
      with the non-DNA-binding CBFbeta subunit. Both the CBFbeta subunit and the DNA
      binding protein Ets-1 stimulate DNA binding by the CBFalpha2 protein. Here we
      quantify and compare the extent of cooperativity between CBFalpha2, CBFbeta, and
      Ets-1. We also identify auto-inhibitory sequences within CBFalpha2 and sequences
      that modulate its interactions with CBFbeta and Ets-1. We show that sequences in
      the CBFalpha2 Runt domain and sequences C terminal to amino acid 214 inhibit DNA
      binding. Sequences C terminal to amino acid 214 also inhibit heterodimerization
      with the non-DNA-binding CBFbeta subunit, particularly heterodimerization off
      DNA. CBFbeta rescinds the intramolecular inhibition of CBFalpha2, stimulating DNA
      binding approximately 40-fold. In comparison, Ets-1 stimulates CBFalpha2 DNA
      binding 7- to 10-fold. Although the Runt domain alone is sufficient for
      heterodimerization with CBFbeta, sequences N terminal to amino acid 41 and
      between amino acids 190 and 214 are required for cooperative DNA binding with Ets
      1. Cooperative DNA binding with Ets-1 is less pronounced with the CBFalpha2
      CBFbeta heterodimer than with CBFalpha2 alone. These analyses demonstrate that
      CBFalpha2 is subject to both negative regulation by intramolecular interactions,
      and positive regulation by two alternative partnerships.

PMID- 10594013
TI  - Kin28, the TFIIH-associated carboxy-terminal domain kinase, facilitates the
      recruitment of mRNA processing machinery to RNA polymerase II.
AB  - The cotranscriptional placement of the 7-methylguanosine cap on pre-mRNA is
      mediated by recruitment of capping enzyme to the phosphorylated carboxy-terminal
      domain (CTD) of RNA polymerase II. Immunoblotting suggests that the capping
      enzyme guanylyltransferase (Ceg1) is stabilized in vivo by its interaction with
      the CTD and that serine 5, the major site of phosphorylation within the CTD
      heptamer consensus YSPTSPS, is particularly important. We sought to identify the
      CTD kinase responsible for capping enzyme targeting. The candidate kinases Kin28
      Ccl1, CTDK1, and Srb10-Srb11 can each phosphorylate a glutathione S-transferase
      CTD fusion protein such that capping enzyme can bind in vitro. However, kin28
      mutant alleles cause reduced Ceg1 levels in vivo and exhibit genetic interactions
      with a mutant ceg1 allele, while srb10 or ctk1 deletions do not. Therefore, only
      the TFIIH-associated CTD kinase Kin28 appears necessary for proper capping enzyme
      targeting in vivo. Interestingly, levels of the polyadenylation factor Pta1 are
      also reduced in kin28 mutants, while several other polyadenylation factors remain
      stable. Pta1 in yeast extracts binds specifically to the phosphorylated CTD,
      suggesting that this interaction may mediate coupling of polyadenylation and
      transcription.

PMID- 10594014
TI  - Alleviation of human papillomavirus E2-mediated transcriptional repression via
      formation of a TATA binding protein (or TFIID)-TFIIB-RNA polymerase II-TFIIF
      preinitiation complex.
AB  - Transcription in human papillomaviruses (HPVs) is mainly regulated by cellular
      transcription factors and virus-encoded E2 proteins that act as sequence-specific
      DNA-binding proteins. Although the functions of E2 as a transcriptional activator
      and a repressor have been well documented, the role of cellular factors involved
      in E2-mediated regulation of the HPV promoters and the mechanism by which E2
      modulates viral gene expression remain unclear. Using reconstituted cell-free
      transcription systems, we found that cellular enhancer-binding factors and
      general cofactors, such as TAF(II)s, TFIIA, Mediator, and PC4, are not required
      for E2-mediated repression. Unlike other transcriptional repressors that function
      through recruitment of histone deacetylase or corepressor complexes, HPV E2 is
      able to directly target components of the general transcription machinery to
      exert its repressor activity on the natural HPV E6 promoter. Interestingly,
      preincubation of TATA binding protein (TBP) or TFIID with HPV template is not
      sufficient to overcome E2-mediated repression, which can be alleviated only via
      formation of a minimal TBP (or TFIID)-TFIIB-RNA polymerase II-TFIIF preinitiation
      complex. Our data therefore indicate that E2 does not simply work by displacing
      TBP or TFIID from binding to the adjacent TATA box. Instead, E2 appears to
      function as an active repressor that directly inhibits HPV transcription at steps
      after TATA recognition by TBP or TFIID.

PMID- 10594015
TI  - IRS-4 mediates protein kinase B signaling during insulin stimulation without
      promoting antiapoptosis.
AB  - Insulin receptor substrate (IRS) proteins are tyrosine phosphorylated and mediate
      multiple signals during activation of the receptors for insulin, insulin-like
      growth factor 1 (IGF-1), and various cytokines. In order to distinguish common
      and unique functions of IRS-1, IRS-2, and IRS-4, we expressed them individually
      in 32D myeloid progenitor cells containing the human insulin receptor (32D(IR)).
      Insulin promoted the association of Grb-2 with IRS-1 and IRS-4, whereas IRS-2
      weakly bound Grb-2; consequently, IRS-1 and IRS-4 enhanced insulin-stimulated
      mitogen-activated protein kinase activity. During insulin stimulation, IRS-1 and
      IRS-2 strongly bound p85alpha/beta, which activated phosphatidylinositol (PI) 3
      kinase, protein kinase B (PKB)/Akt, and p70(s6k), and promoted the
      phosphorylation of BAD. IRS-4 also promoted the activation of PKB/Akt and BAD
      phosphorylation during insulin stimulation; however, it weakly bound or activated
      p85-associated PI 3-kinase and failed to mediate the activation of p70(s6k).
      Insulin strongly inhibited apoptosis of interleukin-3 (IL-3)-deprived 32D(IR)
      cells expressing IRS-1 or IRS-2 but failed to inhibit apoptosis of cells
      expressing IRS-4. Consequently, 32D(IR) cells expressing IRS-4 proliferated
      slowly during insulin stimulation. Thus, the activation of PKB/Akt and BAD
      phosphorylation might not be sufficient to inhibit the apoptosis of IL-3-deprived
      32D(IR) cells unless p85-associated PI 3-kinase or p70(s6k) are strongly
      activated.

PMID- 10594016
TI  - The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for
      farnesyltransferase inhibitor-induced apoptosis.
AB  - Farnesyltransferase inhibitors (FTIs) represent a novel class of anticancer drugs
      that exhibit a remarkable ability to inhibit malignant transformation without
      toxicity to normal cells. However, the mechanism by which FTIs inhibit tumor
      growth is not well understood. Here, we demonstrate that FTI-277 inhibits
      phosphatidylinositol 3-OH kinase (PI 3-kinase)/AKT2-mediated growth factor- and
      adhesion-dependent survival pathways and induces apoptosis in human cancer cells
      that overexpress AKT2. Furthermore, overexpression of AKT2, but not oncogenic H
      Ras, sensitizes NIH 3T3 cells to FTI-277, and a high serum level prevents FTI-277
      induced apoptosis in H-Ras- but not AKT2-transformed NIH 3T3 cells. A
      constitutively active form of AKT2 rescues human cancer cells from FTI-277
      induced apoptosis. FTI-277 inhibits insulin-like growth factor 1-induced PI 3
      kinase and AKT2 activation and subsequent phosphorylation of the proapoptotic
      protein BAD. Integrin-dependent activation of AKT2 is also blocked by FTI-277.
      Thus, a mechanism for FTI inhibition of human tumor growth is by inducing
      apoptosis through inhibition of PI 3-kinase/AKT2-mediated cell survival and
      adhesion pathway.

PMID- 10594017
TI  - Genetic analysis of mouse embryonic stem cells bearing Msh3 and Msh2 single and
      compound mutations.
AB  - We have previously described the use of homologous recombination and CRE-loxP
      mediated marker recycling to generate mouse embryonic stem (ES) cell lines
      homozygous for mutations at the Msh3, Msh2, and both Msh3 and Msh2 loci (2). In
      this study, we describe the analysis of these ES cells with respect to processes
      known to be affected by DNA mismatch repair. ES cells homozygous for the Msh2
      mutation displayed increased resistance to killing by the cytotoxic drug 6
      thioguanine (6TG), indicating that the 6TG cytotoxic mechanism is mediated by
      Msh2. The mutation rate of the herpes simplex virus thymidine kinase 1 (HSV-tk1)
      gene was unchanged in Msh3-deficient ES cell lines but markedly elevated in Msh2
      deficient and Msh3 Msh2 double-mutant cells. Notably, the HSV-tk1 mutation rate
      was 11-fold higher, on average, than that of the hypoxanthine-guanine
      phosphoribosyl transferase (Hprt) locus in Msh2-deficient cells. Sequence
      analysis of HSV-tk1 mutants from these cells indicated the presence of a
      frameshift hotspot within the HSV-tk1 coding region. Msh3-deficient cells
      displayed a modest (16-fold) elevation in the instability of a dinucleotide
      repeat, whereas Msh2-deficient and Msh2 Msh3 double-mutant cells displayed
      markedly increased levels of repeat instability. Targeting frequencies of
      nonisogenic vectors were elevated in Msh2-deficient ES cell lines, confirming the
      role of Msh2 in blocking recombination between diverged sequences (homeologous
      recombination) in mammalian cells. These results are consistent with accumulating
      data from other laboratories and support the current model of DNA mismatch repair
      in mammalian cells.

PMID- 10594019
TI  - Stabilizing effects of interruptions on trinucleotide repeat expansions in
      Saccharomyces cerevisiae.
AB  - In most trinucleotide repeat (TNR) diseases, the primary factor determining the
      likelihood of expansions is the length of the TNR. In some diseases, however,
      stable alleles contain one to three base pair substitutions that interrupt the
      TNR tract. The unexpected stability of these alleles compared to the frequent
      expansions of perfect TNRs suggested that interruptions somehow block expansions
      and that expansions occur only upon loss of at least one interruption. The work
      in this study uses a yeast genetic assay to examine the mechanism of
      stabilization conferred by two interruptions of a 25-repeat tract. Expansion
      rates are reduced up to 90-fold compared to an uninterrupted allele.
      Stabilization is greatest when the interruption is replicated early on the
      lagging strand, relative to the rest of the TNR. Although expansions are
      infrequent, they are often polar, gaining new DNA within the largest available
      stretch of perfect repeats. Surprisingly, interruptions are always retained and
      sometimes even duplicated, suggesting that expansion in yeast cells can proceed
      without loss of the interruption. These findings support a stabilization model in
      which interruptions contribute in cis to reduce hairpin formation during TNR
      replication and thus inhibit expansion rates.

PMID- 10594018
TI  - Phosphatidylinositol 3-kinase, Cdc42, and Rac1 act downstream of Ras in integrin
      dependent neurite outgrowth in N1E-115 neuroblastoma cells.
AB  - Ras and Rho family GTPases have been ascribed important roles in signalling
      pathways determining cellular morphology and growth. Here we investigated the
      roles of the GTPases Ras, Cdc42, Rac1, and Rho and that of phosphatidylinositol 3
      kinase (PI 3-kinase) in the pathway leading from serum starvation to neurite
      outgrowth in N1E-115 neuroblastoma cells. Serum-starved cells grown on a laminin
      matrix exhibited integrin-dependent neurite outgrowth. Expression of dominant
      negative mutants of Ras, PI 3-kinase, Cdc42, or Rac1 all blocked this neurite
      outgrowth, while constitutively activated mutants of Ras, PI 3-kinase, or Cdc42
      were each sufficient to promote outgrowth even in the presence of serum. A
      Ras(H40C;G12V) double mutant which binds preferentially to PI 3-kinase also
      promoted neurite formation. Activated Ras(G12V)-induced outgrowth required PI 3
      kinase activity, but activated PI 3-kinase-induced outgrowth did not require Ras
      activity. Although activated Rac1 by itself did not induce neurites, neurite
      outgrowth induced by activated Cdc42(G12V) was Rac1 dependent. Cdc42(G12V)
      induced neurites appeared to lose their normal polarization, almost doubling the
      average number of neurites produced by a single cell. Outgrowth induced by
      activated Ras or PI 3-kinase required both Cdc42 and Rac1 activity, but
      Cdc42(G12V)-induced outgrowth did not need Ras or PI 3-kinase activity. Active
      Rho(G14V) reduced outgrowth promoted by Ras(G12V). Finally, expression of
      dominant negative Jun N-terminal kinase or extracellular signal-regulated kinase
      did not inhibit outgrowth, suggesting these pathways are not essential for this
      process. Our results suggest a hierarchy of signalling where Ras signals through
      PI 3-kinase to Cdc42 and Rac1 activation (and Rho inactivation), culminating in
      neurite outgrowth. Thus, in the absence of serum factors, Ras may initiate cell
      cycle arrest and terminal differentiation in N1E-115 neuroblastoma cells.

PMID- 10594020
TI  - Pre-mRNA splicing by the essential Drosophila protein B52: tissue and target
      specificity.
AB  - B52, an essential SR protein of Drosophila melanogaster, stimulates pre-mRNA
      splicing in splicing-deficient mammalian S100 extracts. Surprisingly, mutant
      larvae depleted of B52 were found to be capable of splicing at least several pre
      mRNAs tested (H. Z. Ring and J. T. Lis, Mol. Cell. Biol. 14:7499-7506, 1994). In
      a homologous in vitro system, we demonstrated that B52 complements a Drosophila
      S100 extract to allow splicing of a Drosophila fushi tarazu (ftz) mini-pre-mRNA.
      Moreover, Kc cell nuclear extracts that were immunodepleted of B52 lost their
      ability to splice this ftz pre-mRNA. In contrast, splicing of this same ftz pre
      mRNA occurred in whole larvae homozygous for the B52 deletion. Other SR protein
      family members isolated from these larvae could substitute for B52 splicing
      activity in vitro. We also observed that SR proteins are expressed variably in
      different larval tissues. B52 is the predominant SR protein in specific tissues,
      including the brain. Tissues in which B52 is normally the major SR protein, such
      as larval brain tissue, failed to produce ftz mRNA in the B52 deletion line.
      These observations support a model in which the lethality of the B52 deletion
      strain is a consequence of splicing defects in tissues in which B52 is normally
      the major SR protein.

PMID- 10594021
TI  - The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid
      X receptor transactivation: two mechanisms for repression.
AB  - The orphan nuclear hormone receptor SHP interacts with a number of other nuclear
      hormone receptors and inhibits their transcriptional activity. Several mechanisms
      have been suggested to account for this inhibition. Here we show that SHP
      inhibits transactivation by the orphan receptor hepatocyte nuclear factor 4 (HNF
      4) and the retinoid X receptor (RXR) by at least two mechanisms. SHP interacts
      with the same HNF-4 surface recognized by transcriptional coactivators and
      competes with them for binding in vivo. The minimal SHP sequences previously
      found to be required for interaction with other receptors are sufficient for
      interaction with HNF-4, although deletion results indicate that additional C
      terminal sequences are necessary for full binding and coactivator competition.
      These additional sequences include those associated with direct transcriptional
      repressor activity of SHP. SHP also competes with coactivators for binding to
      ligand-activated RXR, and based on the ligand-dependent interaction with other
      nuclear receptors, it is likely that coactivator competition is a general feature
      of SHP-mediated repression. The minimal receptor interaction domain of SHP is
      sufficient for full interaction with RXR, as previously described. This domain is
      also sufficient for full coactivator competition. Functionally, however, full
      inhibition of RXR transactivation requires the presence of the C-terminal
      repressor domain, with only weak inhibition associated with this receptor
      interaction domain. Overall, these results suggest that SHP represses nuclear
      hormone receptor-mediated transactivation via two separate steps: first by
      competition with coactivators and then by direct effects of its transcriptional
      repressor function.

PMID- 10594022
TI  - Role of apoptosis signal-regulating kinase in regulation of the c-Jun N-terminal
      kinase pathway and apoptosis in sympathetic neurons.
AB  - We have previously shown that nerve growth factor (NGF) withdrawal-induced death
      requires the activity of the small GTP-binding protein Cdc42 and that
      overexpression of an active form of Cdc42 is sufficient to mediate neuronal
      apoptosis via activation of the c-Jun pathway. Recently, a new mitogen-activated
      protein (MAP) kinase kinase kinase, apoptosis signal-regulating kinase 1 (ASK1)
      which activates both the c-Jun N-terminal kinase (JNK) and p38 MAP kinase
      pathways and plays pivotal roles in tumor necrosis factor- and Fas-induced
      apoptosis, has been identified. Therefore, we investigated the role of ASK1 in
      neuronal apoptosis by using rat pheochromocytoma (PC12) neuronal cells and
      primary rat sympathetic neurons (SCGs). Overexpression of ASK1-DeltaN, a
      constitutively active mutant of ASK1, activated JNK and induced apoptosis in
      differentiated PC12 cells and SCG neurons. Moreover, in differentiated PC12
      cells, NGF withdrawal induced a four- to fivefold increase in the activity of
      endogenous ASK1. Finally, expression of a kinase-inactive ASK1 significantly
      blocked both NGF withdrawal- and Cdc42-induced death and activation of c-jun.
      Taken together, these results demonstrate that ASK1 is a crucial element of NGF
      withdrawal-induced activation of the Cdc42-c-Jun pathway and neuronal apoptosis.

PMID- 10594023
TI  - Increased expression of death receptors 4 and 5 synergizes the apoptosis response
      to combined treatment with etoposide and TRAIL.
AB  - Chemotherapeutic genotoxins induce apoptosis in epithelial-cell-derived cancer
      cells. The death receptor ligand TRAIL also induces apoptosis in epithelial-cell
      derived cancer cells but generally fails to induce apoptosis in nontransformed
      cells. We show here that the treatment of four different epithelial cell lines
      with the topoisomerase II inhibitor etoposide in combination with TRAIL (tumor
      necrosis factor [TNF]-related apoptosis-inducing ligand) induces a synergistic
      apoptotic response. The mechanism of the synergistic effect results from the
      etoposide-mediated increase in the expression of the death receptors 4 (DR4) and
      5 (DR5). Inhibition of NF-kappaB activation by expression of kinase-inactive MEK
      kinase 1(MEKK1) or dominant-negative IkappaB (DeltaIkappaB) blocked the increase
      in DR4 and DR5 expression following etoposide treatment. Addition of a soluble
      decoy DR4 fusion protein (DR4:Fc) to cell cultures reduced the amount of
      etoposide-induced apoptosis in a dose-dependent manner. The addition of a soluble
      TNF decoy receptor (TNFR:Fc) was without effect, demonstrating the specificity of
      DR4 binding ligands in the etoposide-induced apoptosis response. Thus, genotoxin
      treatment in combination with TRAIL is an effective inducer of epithelial-cell
      derived tumor cell apoptosis relative to either treatment alone.

PMID- 10594024
TI  - Integration of Bombyx mori R2 sequences into the 28S ribosomal RNA genes of
      Drosophila melanogaster.
AB  - R2 non-long-terminal-repeat retrotransposable elements integrate into a precise
      location in the 28S rRNA genes of arthropods. The purified protein encoded by R2
      can cleave the 28S gene target site and use the 3' hydroxyl group generated by
      this cleavage to prime reverse transcription of its own RNA, a process called
      target-primed reverse transcription. An integration system is described here in
      which components from the R2 element of the silkmoth, Bombyx mori, are injected
      into the preblastoderm embryo of Drosophila melanogaster. Silkmoth R2 sequences
      were readily detected in the 28S rRNA genes of the surviving adults as well as in
      the genes of their progeny. The 3' junctions of these insertions were similar to
      those seen in our in vitro assays, as well as those from endogenous R2
      retrotransposition events. The 5' junctions of the insertions originally
      contained major deletions of both R2 and 28S gene sequences, a problem overcome
      by the inclusion of upstream 28S gene sequences at the 5' end of the injected
      RNA. The resulting 5' junctions suggested a recombination event between the cDNA
      and the upstream target sequences. This in vivo integration system should help
      determine the mechanism of R2 retrotransposition and be useful as a delivery
      system to integrate defined DNA sequences into the rRNA genes of organisms.

PMID- 10594025
TI  - Rsp5, a ubiquitin-protein ligase, is involved in degradation of the single
      stranded-DNA binding protein rfa1 in Saccharomyces cerevisiae.
AB  - In Saccharomyces cerevisiae, RAD1 and RAD52 are required for alternate pathways
      of mitotic recombination. Double-mutant strains exhibit a synergistic interaction
      that decreases direct repeat recombination rates dramatically. A mutation in
      RFA1, the largest subunit of a single-stranded DNA-binding protein complex (RP
      A), suppresses the recombination deficiency of rad1 rad52 strains (J. Smith and
      R. Rothstein, Mol. Cell. Biol. 15:1632-1641, 1995). Previously, we hypothesized
      that this mutation, rfa1-D228Y, causes an increase in recombinogenic lesions as
      well as the activation of a RAD52-independent recombination pathway. To identify
      gene(s) acting in this pathway, temperature-sensitive (ts) mutations were
      screened for those that decrease recombination levels in a rad1 rad52 rfa1-D228Y
      strain. Three mutants were isolated. Each segregates as a single recessive gene.
      Two are allelic to RSP5, which encodes an essential ubiquitin-protein ligase. One
      allele, rsp5-25, contains two mutations within its open reading frame. The first
      mutation does not alter the amino acid sequence of Rsp5, but it decreases the
      amount of full-length protein in vivo. The second mutation results in the
      substitution of a tryptophan with a leucine residue in the ubiquitination domain.
      In rsp5-25 mutants, the UV sensitivity of rfa1-D228Y is suppressed to the same
      level as in strains overexpressing Rfa1-D228Y. Measurement of the relative rate
      of protein turnover demonstrated that the half-life of Rfa1-D228Y in rsp5-25
      mutants was extended to 65 min compared to a 35-min half-life in wild-type
      strains. We propose that Rsp5 is involved in the degradation of Rfa1 linking
      ubiquitination with the replication-recombination machinery.

PMID- 10594026
TI  - ei24, a p53 response gene involved in growth suppression and apoptosis.
AB  - DNA damage and/or hyperproliferative signals activate the wild-type p53 tumor
      suppressor protein, which induces a G(1) cell cycle arrest or apoptosis. Although
      the mechanism of p53-mediated cell cycle arrest is fairly well defined, the p53
      dependent pathway regulating apoptosis is poorly understood. Here we report the
      functional characterization of murine ei24 (also known as PIG8), a gene directly
      regulated by p53, whose overexpression negatively controls cell growth and
      induces apoptotic cell death. Ectopic ei24 expression markedly inhibits cell
      colony formation, induces the morphological features of apoptosis, and reduces
      the number of beta-galactosidase-marked cells, which is efficiently blocked by
      coexpression of Bcl-X(L). The ei24/PIG8 gene is localized on human chromosome
      11q23, a region frequently altered in human cancers. These results suggest that
      ei24 may play an important role in negative cell growth control by functioning as
      an apoptotic effector of p53 tumor suppressor activities.

PMID- 10594027
TI  - Dbf4p, an essential S phase-promoting factor, is targeted for degradation by the
      anaphase-promoting complex.
AB  - The Dbf4p/Cdc7p protein kinase is essential for the activation of replication
      origins during S phase. The catalytic subunit, Cdc7p, is present at constant
      levels throughout the cell cycle. In contrast, we show here that the levels of
      the regulatory subunit, Dbf4p, oscillate during the cell cycle. Dbf4p is absent
      from cells during G(1) and accumulates during the S and G(2) phases. Dbf4p is
      rapidly degraded at the time of chromosome segregation and remains highly
      unstable during pre-Start G(1) phase. The rapid degradation of Dbf4p during G(1)
      requires a functional anaphase-promoting complex (APC). Mutation of a sequence in
      the N terminus of Dbf4p which resembles the cyclin destruction box eliminates
      this APC-dependent degradation of Dbf4p. We suggest that the coupling of Dbf4p
      degradation to chromosome separation may play a redundant role in ensuring that
      prereplicative complexes, which assemble after chromosome segregation, do not
      immediately refire.

PMID- 10594028
TI  - The Rous sarcoma virus Env glycoprotein contains a highly conserved motif
      homologous to tyrosine-based endocytosis signals and displays an unusual
      internalization phenotype.
AB  - The cytoplasmic domains of retroviral transmembrane (TM) glycoproteins contain
      conserved sequence motifs that resemble tyrosine-based (YXXO-type) endocytosis
      signals. We have previously described a mutant Rous sarcoma virus (RSV) Env
      protein, Env-mu26, with an L165R mutation in the membrane-spanning domain (MSD)
      of TM, that exhibited dramatically decreased steady-state surface expression (G.
      L. Davis and E. Hunter, J. Cell Biol. 105:1191-1203, 1987; P. B. Johnston, J. Y.
      Dong, and E. Hunter, Virology 206:353-361, 1995). We now demonstrate that the
      tyrosine of the Y(190)RKM motif in the RSV TM cytoplasmic domain is crucial for
      the mu26 phenotype and is part of an efficient internalization signal in the
      context of a mutant MSD. In contrast, despite the presence of the Y(190)RKM
      motif, wild-type RSV Env is constitutively internalized at a slow rate (1.1%/min)
      more characteristic of bulk uptake during membrane turnover than of active
      clustering into endocytic vesicles. The mu26 mutation and two MSD mutations that
      abrogate palmitoylation of TM resulted in enhanced Env endocytosis indicative of
      active concentration into coated pits. Surprisingly, an Env-Y190A mutant was
      apparently excluded from coated pits since its uptake rate of 0.3%/min was
      significantly below that expected for the bulk rate. We suggest that in RSV Env
      an inherently functional endocytosis motif is silenced by a counteracting
      determinant in the MSD that acts to prevent clustering of Env into endocytic
      vesicles. Mutations in either the cytoplasmic tail or the MSD that inactivate one
      of the two counteracting signals would thus render the remaining determinant
      dominant.

PMID- 10594029
TI  - Establishment of distinct MyoD, E2A, and twist DNA binding specificities by
      different basic region-DNA conformations.
AB  - Basic helix-loop-helix (bHLH) proteins perform a wide variety of biological
      functions. Most bHLH proteins recognize the consensus DNA sequence CAN NTG (the E
      box consensus sequence is underlined) but acquire further functional specificity
      by preferring distinct internal and flanking bases. In addition, induction of
      myogenesis by MyoD-related bHLH proteins depends on myogenic basic region (BR)
      and BR-HLH junction residues that are not essential for binding to a muscle
      specific site, implying that their BRs may be involved in other critical
      interactions. We have investigated whether the myogenic residues influence DNA
      sequence recognition and how MyoD, Twist, and their E2A partner proteins prefer
      distinct CAN NTG sites. In MyoD, the myogenic BR residues establish specificity
      for particular CAN NTG sites indirectly, by influencing the conformation through
      which the BR helix binds DNA. An analysis of DNA binding by BR and junction
      mutants suggests that an appropriate BR-DNA conformation is necessary but not
      sufficient for myogenesis, supporting the model that additional interactions with
      this region are important. The sequence specificities of E2A and Twist proteins
      require the corresponding BR residues. In addition, mechanisms that position the
      BR allow E2A to prefer distinct half-sites as a heterodimer with MyoD or Twist,
      indicating that the E2A BR can be directed toward different targets by
      dimerization with different partners. Our findings indicate that E2A and its
      partner bHLH proteins bind to CAN NTG sites by adopting particular preferred BR
      DNA conformations, from which they derive differences in sequence recognition
      that can be important for functional specificity.

PMID- 10594030
TI  - Regulation of a senescence checkpoint response by the E2F1 transcription factor
      and p14(ARF) tumor suppressor.
AB  - Normal cells do not divide indefinitely due to a process known as replicative
      senescence. Human cells arrest growth with a senescent phenotype when they
      acquire one or more critically short telomeres as a consequence of cell division.
      Recent evidence suggests that certain types of DNA damage, chromatin remodeling,
      and oncogenic forms of Ras or Raf can also elicit a senescence response. We show
      here that E2F1, a multifunctional transcription factor that binds the
      retinoblastoma (pRb) tumor suppressor and that can either promote or suppress
      tumorigenesis, induces a senescent phenotype when overexpressed in normal human
      fibroblasts. Normal human cells stably arrested proliferation and expressed
      several markers of replicative senescence in response to E2F1. This activity of
      E2F1 was independent of its pRb binding activity but dependent on its ability to
      stimulate gene expression. The E2F1 target gene critical for the senescence
      response appeared to be the p14(ARF) tumor suppressor. Replicatively senescent
      human fibroblasts overexpressed p14(ARF), and ectopic expression of p14(ARF) in
      presenescent cells induced a phenotype similar to that induced by E2F1.
      Consistent with a critical role for p14(ARF), cells with compromised p53 function
      were immune to senescence induction by E2F1, as were cells deficient in p14(ARF).
      Our findings support the idea that the senescence response is a critical tumor
      suppressive mechanism, provide an explanation for the apparently paradoxical
      roles of E2F1 in oncogenesis, and identify p14(ARF) as a potentially important
      mediator of the senescent phenotype.

PMID- 10594031
TI  - Essential function of the polo box of Cdc5 in subcellular localization and
      induction of cytokinetic structures.
AB  - Members of the polo subfamily of protein kinases play pivotal roles in cell
      proliferation. In addition to the kinase domain, polo kinases have a strikingly
      conserved sequence in the noncatalytic C-terminal domain, termed the polo box.
      Here we show that the budding-yeast polo kinase Cdc5, when fused to green
      fluorescent protein and expressed under its endogenous promoter, localizes at
      spindle poles and the mother bud neck. Overexpression of Cdc5 can induce a class
      of cells with abnormally elongated buds in a polo box- and kinase activity
      dependent manner. In addition to localizing at the spindle poles and cytokinetic
      neck filaments, Cdc5 induces and localizes to additional septin ring structures
      within the elongated buds. Without impairing kinase activity, conservative
      mutations in the polo box abolish the ability of Cdc5 to functionally complement
      the defect associated with a cdc5-1 temperature-sensitive mutation, to localize
      to the spindle poles and cytokinetic neck filaments, and to induce elongated
      cells with ectopic septin ring structures. Consistent with the polo box-dependent
      subcellular localization, the C-terminal domain of Cdc5, but not its polo box
      mutant, is sufficient for subcellular localization, and its overexpression
      appears to inhibit cytokinesis. These data provide evidence that the polo box is
      required to direct Cdc5 to specific subcellular locations and induce or organize
      cytokinetic structures.

PMID- 10594032
TI  - Activated mutants of SHP-2 preferentially induce elongation of Xenopus animal
      caps.
AB  - In Xenopus ectodermal explants (animal caps), fibroblast growth factor (FGF)
      evokes two major events: induction of ventrolateral mesodermal tissues and
      elongation. The Xenopus FGF receptor (XFGFR) and certain downstream components of
      the XFGFR signal transduction pathway (e.g., members of the Ras/Raf/MEK/mitogen
      activated protein kinase [MAPK] cascade) are required for both of these
      processes. Likewise, activated versions of these signaling components induce
      mesoderm and promote animal cap elongation. Previously, using a dominant negative
      mutant approach, we showed that the protein-tyrosine phosphatase SHP-2 is
      necessary for FGF-induced MAPK activation, mesoderm induction, and elongation of
      animal caps. Taking advantage of recent structural information, we now have
      generated novel, activated mutants of SHP-2. Here, we show that expression of
      these mutants induces animal cap elongation to an extent comparable to that
      evoked by FGF. Surprisingly, however, activated mutant-induced elongation can
      occur without mesodermal cytodifferentiation and is accompanied by minimal
      activation of the MAPK pathway and mesodermal marker expression. Our results
      implicate SHP-2 in a pathway(s) directing cell movements in vivo and identify
      potential downstream components of this pathway. Our activated mutants also may
      be useful for determining the specific functions of SHP-2 in other signaling
      systems.

PMID- 10594033
TI  - The drosophila MSL complex acetylates histone H4 at lysine 16, a chromatin
      modification linked to dosage compensation.
AB  - In Drosophila, dosage compensation-the equalization of most X-linked gene
      products in males and females-is achieved by a twofold enhancement of the level
      of transcription of the X chromosome in males relative to each X chromosome in
      females. A complex consisting of at least five gene products preferentially binds
      the X chromosome at numerous sites in males and results in a significant increase
      in the presence of a specific histone isoform, histone 4 acetylated at lysine 16.
      Recently, RNA transcripts (roX1 and roX2) encoded by two different genes have
      also been found associated with the X chromosome in males. We have partially
      purified a complex containing MSL1, -2, and -3, MOF, MLE, and roX2 RNA and
      demonstrated that it exclusively acetylates H4 at lysine 16 on nucleosomal
      substrates. These results demonstrate that the MSL complex is responsible for the
      specific chromatin modification characteristic of the X chromosome in Drosophila
      males.

PMID- 10594035
TI  - Characterization of a Ustilago maydis gene specifically induced during the
      biotrophic phase: evidence for negative as well as positive regulation.
AB  - The phytopathogenic basidiomycete Ustilago maydis requires its host plant, maize,
      for completion of its sexual cycle. To investigate the molecular events during
      infection, we used differential display to identify plant-induced U. maydis
      genes. We describe the U. maydis gene mig1 (for "maize-induced gene"), which is
      not expressed during yeast-like growth of the fungus, is weakly expressed during
      filamentous growth in axenic culture, but is extensively upregulated during plant
      infection. mig1 encodes a small, highly charged protein of unknown function which
      contains a functional N-terminal secretion sequence and is not essential for
      pathogenic development. Adjacent to mig1 is a second gene (mdu1) related to mig1,
      which appears to result from a gene duplication. mig1 gene expression during the
      infection cycle was assessed by fusing the promoter to eGFP. Expression of mig1
      was absent in hyphae growing on the leaf surface but was detected after
      penetration and remained high during subsequent proliferation of the fungus until
      teliospore formation. Successive deletions as well as certain internal deletions
      in the mig1 promoter conferred elevated levels of reporter gene expression during
      growth in axenic culture, indicative of negative regulation. During fungal growth
      in planta, sequence elements between positions -148 and -519 in the mig1 promoter
      were specifically required for high levels of induction, illustrating additional
      positive control. We discuss the potential applications of mig1 for the
      identification of inducing compounds and the respective regulatory genes.

PMID- 10594034
TI  - Biological characteristics of the leukemia-associated transcriptional factor AML1
      disclosed by hematopoietic rescue of AML1-deficient embryonic stem cells by using
      a knock-in strategy.
AB  - AML1 is one of the most frequently mutated genes associated with human acute
      leukemia and encodes the DNA-binding subunit of the heterodimering
      transcriptional factor complex, core-binding factor (CBF) (or polyoma enhancer
      binding protein 2 [PEBP2]). A null mutation in either AML1 or its dimerizing
      partner, CBFbeta, results in embryonic lethality secondary to a complete block in
      fetal liver hematopoiesis, indicating an essential role of this transcription
      complex in the development of definitive hematopoiesis. The hematopoietic
      phenotype that results from the loss of AML1 can be replicated in vitro with a
      two-step culture system of murine embryonic stem (ES) cells. Using this
      experimental system, we now demonstrate that this hematopoietic defect can be
      rescued by expressing the PEBP2alphaB1 (AML1b) isoform under the endogenous AML1
      regulatory sequences through a knock-in (targeted insertion) approach. Moreover,
      we demonstrate that the rescued AML1(-/-) ES cell clones contribute to
      lymphohematopoiesis within the context of chimeric animals. Rescue requires the
      transcription activation domain of AML1 but does not require the C-terminal VWRPY
      motif, which is conserved in all AML1 family members and has been shown to
      interact with the transcriptional corepressor, Groucho/transducin-like Enhancer
      of split. Taken together, these data provide compelling evidence that the
      phenotype seen in AML1-deficient mice is due solely to the loss of
      transcriptionally active AML1.

PMID- 10594036
TI  - The human TFIID components TAF(II)135 and TAF(II)20 and the yeast SAGA components
      ADA1 and TAF(II)68 heterodimerize to form histone-like pairs.
AB  - It has been previously proposed that the transcription complexes TFIID and SAGA
      comprise a histone octamer-like substructure formed from a heterotetramer of H4
      like human hTAF(II)80 (or its Drosophila melanogaster dTAF(II)60 and yeast
      [Saccharomyces cerevisiae] yTAF(II)60 homologues) and H3-like hTAF(II)31
      (dTAF(II)40 and yTAF(II)17) along with two homodimers of H2B-like hTAF(II)20
      (dTAF(II)30alpha and yTAF(II)61/68). However, it has not been formally shown that
      hTAF(II)20 heterodimerizes via its histone fold. By two-hybrid analysis with
      yeast and biochemical characterization of complexes formed by coexpression in
      Escherichia coli, we showed that hTAF(II)20 does not homodimerize but
      heterodimerizes with hTAF(II)135. Heterodimerization requires the alpha2 and
      alpha3 helices of the hTAF(II)20 histone fold and is abolished by mutations in
      the hydrophobic face of the hTAF(II)20 alpha2 helix. Interaction with hTAF(II)20
      requires a domain of hTAF(II)135 which shows sequence homology to H2A. This
      domain also shows homology to the yeast SAGA component ADA1, and we show that
      yADA1 heterodimerizes with the histone fold region of yTAF(II)61/68, the yeast
      hTAF(II)20 homologue. These results are indicative of a histone fold type of
      interaction between hTAF(II)20-hTAF(II)135 and yTAF(II)68-yADA1, which therefore
      constitute novel histone-like pairs in the TFIID and SAGA complexes.

PMID- 10594038
TI  - E2F is required to prevent inappropriate S-phase entry of mammalian cells.
AB  - E2F is a family of transcription factors that regulates the cell cycle. It is
      widely accepted that E2F-mediated transactivation of a set of genes is the
      critical activity that governs cellular progression through G(1) into S phase. In
      contrast to this hypothesis, we demonstrate that E2F actually suppresses the
      onset of S phase in two cell types when the cells are arrested by gamma
      irradiation. Our findings indicate that in these cells, the critical event
      triggering progression from G(0)/G(1) arrest into S phase is the release of E2F
      mediated transrepression of cell cycle genes, not transactivation by E2F.
      Furthermore, our data suggest that E2F-mediated transactivation is not necessary
      for the G(1)/S-phase transition in these cells.

PMID- 10594037
TI  - The G-protein beta subunit GPB1 is required for mating and haploid fruiting in
      Cryptococcus neoformans.
AB  - Cryptococcus neoformans is an opportunistic fungal pathogen with a defined sexual
      cycle. The gene encoding a heterotrimeric G-protein beta subunit, GPB1, was
      cloned and disrupted. gpb1 mutant strains are sterile, indicating a role for this
      gene in mating. GPB1 plays an active role in mediating responses to pheromones in
      early mating steps (conjugation tube formation and cell fusion) and signals via a
      mitogen-activated protein (MAP) kinase cascade in both MATalpha and MATa cells.
      The functions of GPB1 are distinct from those of the Galpha protein GPA1, which
      functions in a nutrient-sensing cyclic AMP (cAMP) pathway required for mating,
      virulence factor induction, and virulence. gpb1 mutant strains are also defective
      in monokaryotic fruiting in response to nitrogen starvation. We show that MATa
      cells stimulate monokaryotic fruiting of MATalpha cells, possibly in response to
      mating pheromone, which may serve to disperse cells and spores to locate mating
      partners. In summary, the Gbeta subunit GPB1 and the Galpha subunit GPA1 function
      in distinct signaling pathways: one (GPB1) senses pheromones and regulates mating
      and haploid fruiting via a MAP kinase cascade, and the other (GPA1) senses
      nutrients and regulates mating, virulence factors, and pathogenicity via a cAMP
      cascade.

PMID- 10594039
TI  - INK4d-deficient mice are fertile despite testicular atrophy.
AB  - The INK4 family of cyclin-dependent kinase (CDK) inhibitors includes four 15- to
      19-kDa polypeptides (p16(INK4a), p15(INK4b), p18(INK4c), and p19(INK4d)) that
      bind to CDK4 and CDK6. By disrupting cyclin D-dependent holoenzymes, INK4
      proteins prevent phosphorylation of the retinoblastoma protein and block entry
      into the DNA-synthetic phase of the cell division cycle. The founding family
      member, p16(INK4a), is a potent tumor suppressor in humans, whereas involvement,
      if any, of other INK4 proteins in tumor surveillance is less well documented.
      INK4c and INK4d are expressed during mouse embryogenesis in stereotypic tissue
      specific patterns and are also detected, together with INK4b, in tissues of young
      mice. INK4a is expressed neither before birth nor at readily appreciable levels
      in young animals, but its increased expression later in life suggests that it
      plays some checkpoint function in response to cell stress, genotoxic damage, or
      aging per se. We used targeted gene disruption to generate mice lacking INK4d.
      These animals developed into adulthood, had a normal life span, and did not
      spontaneously develop tumors. Tumors did not arise at increased frequency in
      animals neonatally exposed to ionizing radiation or the carcinogen
      dimethylbenzanthrene. Mouse embryo fibroblasts, bone marrow-derived macrophages,
      and lymphoid T and B cells isolated from these animals proliferated normally and
      displayed typical lineage-specific differentiation markers. Males exhibited
      marked testicular atrophy associated with increased apoptosis of germ cells,
      although they remained fertile. The absence of tumors in INK4d-deficient animals
      demonstrates that, unlike INK4a, INK4d is not a tumor suppressor but is instead
      involved in spermatogenesis.

PMID- 10594040
TI  - Munc18c function is required for insulin-stimulated plasma membrane fusion of
      GLUT4 and insulin-responsive amino peptidase storage vesicles.
AB  - To examine the functional role of the interaction between Munc18c and syntaxin 4
      in the regulation of GLUT4 translocation in 3T3L1 adipocytes, we assessed the
      effects of introducing three different peptide fragments (20 to 24 amino acids)
      of Munc18c from evolutionarily conserved regions of the Sec1 protein family
      predicted to be solvent exposed. One peptide, termed 18c/pep3, inhibited the
      binding of full-length Munc18c to syntaxin 4, whereas expression of the other two
      peptides had no effect. In parallel, microinjection of 18c/pep3 but not a control
      peptide inhibited the insulin-stimulated translocation of endogenous GLUT4 and
      insulin-responsive amino peptidase (IRAP) to the plasma membrane. In addition,
      expression of 18c/pep3 prevented the insulin-stimulated fusion of endogenous and
      enhanced green fluorescent protein epitope-tagged GLUT4- and IRAP-containing
      vesicles into the plasma membrane, as assessed by intact cell immunofluorescence.
      However, unlike the pattern of inhibition seen with full-length Munc18c
      expression, cells expressing 18c/pep3 displayed discrete clusters of GLUT4 abd
      IRAP storage vesicles at the cell surface which were not contiguous with the
      plasma membrane. Together, these data suggest that the interaction between
      Munc18c and syntaxin 4 is required for the integration of GLUT4 and IRAP storage
      vesicles into the plasma membrane but is not necessary for the insulin-stimulated
      trafficking to and association with the cell surface.

PMID- 10594041
TI  - DNA binding site selection of dimeric and tetrameric Stat5 proteins reveals a
      large repertoire of divergent tetrameric Stat5a binding sites.
AB  - We have defined the optimal binding sites for Stat5a and Stat5b homodimers and
      found that they share similar core TTC(T/C)N(G/A)GAA interferon gamma-activated
      sequence (GAS) motifs. Stat5a tetramers can bind to tandemly linked GAS motifs,
      but the binding site selection revealed that tetrameric binding also can be seen
      with a wide range of nonconsensus motifs, which in many cases did not allow
      Stat5a binding as a dimer. This indicates a greater degree of flexibility in the
      DNA sequences that allow binding of Stat5a tetramers than dimers. Indeed, in an
      oligonucleotide that could bind both dimers and tetramers, it was possible to
      design mutants that affected dimer binding without affecting tetramer binding. A
      spacing of 6 bp between the GAS sites was most frequently selected, demonstrating
      that this distance is favorable for Stat5a tetramer binding. These data provide
      insights into tetramer formation by Stat5a and indicate that the repertoire of
      potential binding sites for this transcription factor is broader than expected.

PMID- 10594042
TI  - Redox-regulated recruitment of the transcriptional coactivators CREB-binding
      protein and SRC-1 to hypoxia-inducible factor 1alpha.
AB  - Hypoxia-inducible factor 1alpha (HIF-1alpha) functions as a transcription factor
      that is activated by decreased cellular oxygen concentrations to induce
      expression of a network of genes involved in angiogenesis, erythropoiesis, and
      glucose homeostasis. Here we demonstrate that two members of the SRC-1/p160
      family of transcriptional coactivators harboring histone acetyltransferase
      activity, SRC-1 and transcription intermediary factor 2 (TIF2), are able to
      interact with HIF-1alpha and enhance its transactivation potential in a hypoxia
      dependent manner. HIF-1alpha contains within its C terminus two transactivation
      domains. The hypoxia-inducible activity of both these domains was enhanced by
      either SRC-1 or the CREB-binding protein (CBP)/p300 coactivator. Moreover, at
      limiting concentrations, SRC-1 produced this effect in synergy with CBP.
      Interestingly, this effect was strongly potentiated by the redox regulatory
      protein Ref-1, a dual-function protein harboring DNA repair endonuclease and
      cysteine reducing activities. These data indicate that all three proteins, CBP,
      SRC-1, and Ref-1, are important components of the hypoxia signaling pathway and
      have a common function in regulation of HIF-1alpha function in hypoxic cells.
      Given the absence of cysteine residues in one of the Ref-1-regulated
      transactivation domains of HIF-1alpha, it is thus possible that Ref-1 functions
      in hypoxic cells by targeting critical steps in the recruitment of the CBP-SRC-1
      coactivator complex.

PMID- 10594043
TI  - Characterization of insulin-responsive GLUT4 storage vesicles isolated from 3T3
      L1 adipocytes.
AB  - Insulin regulates glucose transport in muscle and adipose tissue by triggering
      the translocation of a facilitative glucose transporter, GLUT4, from an
      intracellular compartment to the cell surface. It has previously been suggested
      that GLUT4 is segregated between endosomes, the trans-Golgi network (TGN), and a
      postendosomal storage compartment. The aim of the present study was to isolate
      the GLUT4 storage compartment in order to determine the relationship of this
      compartment to other organelles, its components, and its presence in different
      cell types. A crude intracellular membrane fraction was prepared from 3T3-L1
      adipocytes and subjected to iodixanol equilibrium sedimentation analysis. Two
      distinct GLUT4-containing vesicle peaks were resolved by this procedure. The
      lighter of the two peaks (peak 2) was comprised of two overlapping peaks: peak 2b
      contained recycling endosomal markers such as the transferrin receptor (TfR),
      cellubrevin, and Rab4, and peak 2a was enriched in TGN markers (syntaxin 6, the
      cation-dependent mannose 6-phosphate receptor, sortilin, and sialyltransferase).
      Peak 1 contained a significant proportion of GLUT4 with a smaller but significant
      amount of cellubrevin and relatively little TfR. In agreement with these data,
      internalized transferrin (Tf) accumulated in peak 2 but not peak 1. There was a
      quantitatively greater loss of GLUT4 from peak 1 than from peak 2 in response to
      insulin stimulation. These data, combined with the observation that GLUT4 became
      more sensitive to ablation with Tf-horseradish peroxidase following insulin
      treatment, suggest that the vesicles enriched in peak 1 are highly insulin
      responsive. Iodixanol gradient analysis of membranes isolated from other cell
      types indicated that a substantial proportion of GLUT4 was targeted to peak 1 in
      skeletal muscle, whereas in CHO cells most of the GLUT4 was targeted to peak 2.
      These results indicate that in insulin-sensitive cells GLUT4 is targeted to a
      subpopulation of vesicles that appear, based on their protein composition, to be
      a derivative of the endosome. We suggest that the biogenesis of this compartment
      may mediate withdrawal of GLUT4 from the recycling system and provide the basis
      for the marked insulin responsiveness of GLUT4 that is unique to muscle and
      adipocytes.

PMID- 10594045
TI  - Probing of NMDA channels with fast blockers.
AB  - Using whole-cell patch-clamp techniques, we studied the interaction of open NMDA
      channels with tetraalkylammonium compounds: tetraethylammonium (TEA),
      tetrapropylammonium (TPA), tetrabutylammonium (TBA), and tetrapentylammonium
      (TPentA). Analysis of the blocking kinetics, concentration, and agonist
      dependencies using a set of kinetic models allowed us to create the criteria
      distinguishing the effects of these blockers on the channel closure,
      desensitization, and agonist dissociation. Thus, it was found that TPentA
      prohibited, TBA partly prevented, and TPA and TEA did not prevent either the
      channel closure or the agonist dissociation. TPentA and TBA prohibited, TPA
      slightly prevented, and TEA did not affect the channel desensitization. These
      data along with the voltage dependence of the stationary current inhibition led
      us to hypothesize that: (1) there are activation and desensitization gates in the
      NMDA channel; (2) these gates are distinct structures located in the external
      channel vestibule, the desensitization gate being located deeper than the
      activation gate. The size of the blocker plays a key role in its interaction with
      the NMDA channel gating machinery: small blockers (TEA and TPA) bind in the depth
      of the channel pore and permit the closure of both gates, whereas larger blockers
      (TBA) allow the closure of the activation gate but prohibit the closure of the
      desensitization gate; finally, the largest blockers (TPentA) prohibit the closure
      of both activation and desensitization gates. The mean diameter of the NMDA
      channel pore in the region of the activation gate localization was estimated to
      be approximately 11 A.

PMID- 10594044
TI  - Distinct synaptic and extrasynaptic NMDA receptors in developing cerebellar
      granule neurons.
AB  - In rat cerebellar granule neurons, mRNA and protein levels of the NR2A and NR2C
      subunits of the NMDA receptor increase during the second postnatal week. At this
      time, mRNA and protein levels of the NR2B subunit begin to fall. To investigate
      targeting of NMDA receptor subunits, we performed whole-cell recordings from rat
      cerebellar granule neurons at different times during development and investigated
      the pharmacological and biophysical properties of mossy fiber-evoked NMDA EPSCs.
      Isolated NMDA EPSCs from newly formed synapses in the first postnatal week
      exhibited partial block by the NR2B subunit-specific antagonist (1S, 2S)-1-(4
      hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP 101,606). By the
      end of the second postnatal week, NMDA EPSCs were virtually unaffected by the
      NR2B antagonist. In parallel, NMDA EPSC decay times decreased over a similar
      developmental time course. We compared properties of synaptic NMDA receptors with
      extrasynaptic receptors that are present on the cell body with rapid application
      of glutamate to excised nucleated patches. Deactivation of patch responses
      accelerated with development and closely resembled evoked NMDA EPSCs in rats of
      the same age. However, patch responses were highly sensitive to CP 101,606
      through the second postnatal week, and sensitivity was seen in some neurons up to
      the fourth postnatal week. Spermine potentiated peak NMDA patch responses from
      postnatal days 10-14 rats but had little effect on evoked NMDA EPSCs. Our data
      suggest selective targeting of a distinct NMDA receptor subtype to synaptic
      receptor populations in cerebellar granule neurons. Later in development, similar
      changes occur in the extrasynaptic receptor population.

PMID- 10594046
TI  - C terminus of presenilin is required for overproduction of amyloidogenic Abeta42
      through stabilization and endoproteolysis of presenilin.
AB  - Mutations in presenilin (PS) genes cause early onset familial Alzheimer's disease
      (FAD) by increasing production of the amyloidogenic form of amyloid beta peptides
      ending at residue 42 (Abeta42). To identify a PS subdomain responsible for
      overproduction of Abeta42, we analyzed neuro2a cell lines expressing modified
      forms of PS2 that harbor an N141I FAD mutation. Deletion or addition of amino
      acids at the C terminus and Ile448 substitution in PS2 with the N141I FAD
      mutation abrogated the increase in Abeta42 secretion, and Abeta42 overproduction
      was dependent on the stabilization and endoproteolysis of PS2. The same C
      terminal modifications in PS1 produced similar effects. Hence, we suggest that
      the C terminus of PS plays a crucial role in the overproduction of Abeta42
      through stabilization of endoproteolytic PS derivatives and that these
      derivatives may be the pathologically active species of PS that cause FAD.

PMID- 10594047
TI  - The general anesthetic propofol slows deactivation and desensitization of GABA(A)
      receptors.
AB  - Propofol (2,6-di-isopropylphenol) has multiple actions on GABA(A) receptor
      function that act in concert to potentiate GABA-evoked currents. To understand
      how propofol influences inhibitory IPSCs, we examined the effects of propofol on
      responses to brief applications of saturating concentrations of GABA (1-30 mM).
      GABA was applied using a fast perfusion system to nucleated patches excised from
      hippocampal neurons. In this preparation, propofol (10 microM) had no detectable
      agonist effect but slowed the decay, increased the charge transfer (62%), and
      enhanced the peak amplitude (8%) of currents induced by brief pulses (3 msec) of
      GABA. Longer pulses (500 msec) of GABA induced responses that desensitized with
      fast (tau(f) = 1.5-4.5 msec) and slow (tau(s) = 1-3 sec) components and, after
      the removal of GABA, deactivated exponentially (tau(d) = 151 msec). Propofol
      prolonged this deactivation (tau(d) = 255 msec) and reduced the development of
      both fast and slow desensitization. Recovery from fast desensitization, assessed
      using pairs of brief pulses of GABA, paralleled the time course of deactivation,
      indicating that fast desensitization traps GABA on the receptor. With repetitive
      applications of pulses of GABA (0.33 Hz), the charge transfer per pulse declined
      exponentially (tau approximately 15 sec) to a steady-state value equal to
      approximately 40% of the initial response. Despite the increased charge transfer
      per pulse with propofol, the time course of the decline was unchanged. These
      experimental data were interpreted using computer simulations and a kinetic model
      that assumed fast and slow desensitization, as well as channel opening developed
      in parallel from a pre-open state. Our results suggest that propofol stabilizes
      the doubly liganded pre-open state without affecting the isomerization rate
      constants to and from the open state. Also, the rate constants for agonist
      dissociation and entry into the fast and slow desensitization states were reduced
      by propofol. The recovery rate constant from fast desensitization was slowed,
      whereas that from slow desensitization appeared to be unchanged. Taken together,
      the effects of propofol on GABA(A) receptors enhance channel opening,
      particularly under conditions that promote desensitization.

PMID- 10594048
TI  - Similarities and differences between the responses of rat sensory neurons to
      noxious heat and capsaicin.
AB  - We have compared the membrane response of rat primary sensory neurons to
      capsaicin and noxious heat, using electrophysiological and ion flux measurements.
      Our aim was to determine whether, as recently proposed, the same molecular entity
      accounts for excitation by both types of stimulus. The properties of the ion
      channels activated by heat and capsaicin show many similarities but also
      important differences. The calcium permeability of heat-activated channels is
      lower than that of capsaicin-activated channels. Distinct single channels respond
      to heat or capsaicin, and only a few show dual sensitivity. At the whole-cell
      level, individual cells invariably show dual sensitivity, but the amplitudes of
      the responses show little correlation. We conclude that distinct molecular
      entities, which are both likely to be derived from the VR1 gene product, account
      for the membrane responses to heat and capsaicin.

PMID- 10594049
TI  - Long-term depression of excitatory synaptic transmission in the rat amygdala.
AB  - In view of the fact that both kindling and fear-potentiated startle are expressed
      by long-term enhancement of synaptic transmission in the amygdala, synaptic
      plasticity in this area of the brain is of particular importance. Here, we show
      for the first time that low-frequency stimulation of the lateral nucleus at 1 Hz
      for 15 min elicited a long-term depression (LTD) in the basolateral amygdala
      (BLA) neurons. LTD is expressed specifically at the lateral-BLA synapses but not
      at ventral endopyriform nucleus-BLA synapses. The induction of LTD requires
      activation of both NMDA and metabotropic glutamate receptors. Loading cells with
      a Ca(2+) chelator BAPTA or extracellular superfusion with protein phosphatase
      inhibitors prevents LTD, suggesting that LTD may result from dephosphorylation of
      AMPA receptors. The same stimulating protocol could not elicit LTD in neurons
      from kindled animals, whereas neurons from sham-operated or age-matched control
      rats were able to exhibit LTD. Together, this study characterizes the properties
      of LTD in the naive amygdala slices for the first time and demonstrates that
      epileptogenesis in vivo induces disruption of LTD in the in vitro preparation.

PMID- 10594050
TI  - Heterogeneity of synaptic plasticity at unitary CA3-CA1 and CA3-CA3 connections
      in rat hippocampal slice cultures.
AB  - Long-term potentiation (LTP) of unitary EPSPs, generated by pairs of
      monosynaptically connected CA3 and CA1 pyramidal cells, was compared with LTP of
      extracellularly evoked, multi-unitary EPSPs in rat hippocampal slice cultures.
      LTP was induced by repeated, synchronous pairing of low-frequency presynaptic and
      postsynaptic activity. Three differences were observed. First, LTP of multi
      unitary EPSPs displayed two phases: transient (<5 min) and sustained.
      Potentiation of unitary EPSPs displayed both phases in 42% of experiments; the
      remainder showed sustained potentiation only. Unitary EPSPs displaying transient
      sustained and only sustained potentiation could be recorded from single
      postsynaptic cells, indicating that excitatory synapses on a given cell are
      heterogeneous with respect to short-term plasticity. Second, whereas LTP of multi
      unitary EPSPs never resulted in greater than twofold increases in amplitude (mean
      potentiation of 175% of control), maximal LTP of unitary EPSPs was as great as 13
      fold (mean potentiation of 250%). Third, LTP could not be induced in 24% of
      unitary EPSPs. We provide here the first evidence for the coexistence of
      potentiatable and nonpotentiatable synapses on individual postsynaptic neurons.
      Thirty-seven percent of connections not displaying LTP exhibited long-term
      depression (LTD), suggesting that the connections were already maximally
      potentiated. In the remaining 63% of these pairs, neither LTP nor LTD could be
      induced, despite the existence of a pharmacologically identified, NMDA receptor
      mediated EPSP component. In conclusion, there is considerable heterogeneity in
      the amplitude and time course of LTP expression at different synaptic
      connections. A substantial proportion of apparently nonplastic synapses probably
      accounts for the weaker potentiation displayed by compound EPSPs.

PMID- 10594051
TI  - Differences in expression of acetylcholinesterase and collagen Q control the
      distribution and oligomerization of the collagen-tailed forms in fast and slow
      muscles.
AB  - The collagen-tailed forms of acetylcholinesterase (AChE) are accumulated at
      mammalian neuromuscular junctions. The A(4), A(8), and A(12) forms are expressed
      differently in the rat fast and slow muscles; the sternomastoid muscle contains
      essentially the A(12) form at end plates, whereas the soleus muscle also contains
      extrajunctional A(4) and A(8) forms. We show that collagen Q (ColQ) transcripts
      become exclusively junctional in the adult sternomastoid but remain uniformly
      expressed in the soleus. By coinjecting Xenopus oocytes with AChE(T) and ColQ
      mRNAs, we reproduced the muscle patterns of collagen-tailed forms. The soleus
      contains transcripts ColQ1 and ColQ1a, whereas the sternomastoid only contains
      ColQ1a. Collagen-tailed AChE represents the first evidence that synaptic
      components involved in cholinergic transmission may be differently regulated in
      fast and slow muscles.

PMID- 10594052
TI  - A Kv1.5 to Kv1.3 switch in endogenous hippocampal microglia and a role in
      proliferation.
AB  - The proliferation of microglia is a normal process in CNS development and in the
      defense against pathological insults, although, paradoxically, it contributes to
      several brain diseases. We have examined the types of voltage-activated K(+)
      currents (Kv) and their roles in microglial proliferation. Microglia were tissue
      printed directly from the hippocampal region using brain slices from 5- to 14-d
      old rats. Immediately after tissue prints were prepared, unipolar and bipolar
      microglia expressed a large Kv current, and the cells were not proliferating.
      Surprisingly, this current was biophysically and pharmacologically distinct from
      Kv1.3, which has been found in dissociated, cultured microglia, but it was very
      similar to Kv1.5. After several days in culture the microglia became highly
      proliferative, and although the Kv prevalence and current density decreased, many
      cells exhibited a prominent Kv that was indistinguishable from Kv1.3. The Kv1.5
      like current was present in nonproliferating cells, whereas proliferating cells
      expressed the Kv1.3-like current. Immunocytochemical staining showed a dramatic
      shift in expression and localization of Kv1.3 and Kv1.5 proteins in microglia:
      Kv1.5 moving away from the surface and Kv1.3 moving to the surface as the cells
      were cultured. K(+) channel blockers inhibited proliferation, and the
      pharmacology of this inhibition correlated with the type of Kv current expressed.
      Our study, which introduces a method for the physiological examination of
      microglia from identified brain regions, demonstrates the differential expression
      of two functional Kv subunits and shows that a functional delayed rectifier
      current is necessary for microglia proliferation.

PMID- 10594053
TI  - The organization of the Golgi complex and microtubules in skeletal muscle is
      fiber type-dependent.
AB  - Skeletal muscle has a nonconventional Golgi complex (GC), the organization of
      which has been a subject of controversy in the past. We have now examined the
      distribution of the GC by immunofluorescence and immunogold electron microscopy
      in whole fibers from different rat muscles, both innervated and experimentally
      denervated. The total number of GC elements, small polarized stacks of cisternae,
      is quite similar in all fibers, but their intracellular distribution is fiber
      type-dependent. Thus, in slow-twitch, type I fibers, approximately 75% of all GC
      elements are located within 1 micrometer from the plasma membrane, and each
      nucleus is surrounded by a belt of GC elements. In contrast, in the fast-twitch
      type IIB fibers, most GC elements are in the fiber core, and most nuclei only
      have GC elements at their poles. Intermediate, type IIA fibers also have an
      intermediate distribution of GC elements. Interestingly, the distribution of
      microtubules, with which GC elements colocalize, is fiber type-dependent as well.
      At the neuromuscular junction, the distribution of GC elements and microtubules
      is independent of fiber type, and junctional nuclei are surrounded by GC elements
      in all fibers. After denervation of the hindlimb muscles, GC elements as well as
      microtubules converge toward a common pattern, that of the slow-twitch fibers, in
      all fibers. Our data suggest that innervation regulates the distribution of
      microtubules, which in turn organize the Golgi complex according to muscle fiber
      type.

PMID- 10594054
TI  - Xenopus embryonic spinal neurons express potassium channel Kvbeta subunits.
AB  - Developmental regulation of voltage-dependent delayed rectifier potassium current
      (I(Kv)) of Xenopus primary spinal neurons regulates the waveform of the action
      potential. I(Kv) undergoes a tripling in density and acceleration of it
      activation kinetics during the initial day of its appearance. Another voltage
      dependent potassium current, the A current, is acquired during the subsequent day
      and contributes to further shortening of the impulse duration. To decipher the
      molecular mechanisms underlying this functional differentiation, we are
      identifying potassium channel genes expressed in the embryonic amphibian nervous
      system. Potassium channels consist of pore-forming (alpha) as well as auxiliary
      (beta) subunits. Here, we report the primary sequence, developmental
      localization, and functional properties of two Xenopus Kvbeta genes. On the basis
      of primary sequence, one of these (xKvbeta2) is highly conserved with Kvbeta2
      genes identified in other species, whereas the other (xKvbeta4) appears to
      identify a new member of the Kvbeta family. Both are expressed in developing
      spinal neurons during the period of impulse maturation but in different neuronal
      populations. In a heterologous system, coexpression of xKvbeta subunits modulates
      properties of potassium current that are developmentally regulated in the
      endogenous I(Kv). Consistent with xKvbeta4's unique primary sequence, the
      repertoire of functional effects it has on coexpressed Kv1alpha subunits is
      novel. Taken together, the results implicate auxiliary subunits in regulation of
      potassium current function and action potential waveforms in subpopulations of
      embryonic primary spinal neurons.

PMID- 10594055
TI  - Blue- and green-absorbing visual pigments of Drosophila: ectopic expression and
      physiological characterization of the R8 photoreceptor cell-specific Rh5 and Rh6
      rhodopsins.
AB  - Color discrimination requires the input of different photoreceptor cells that are
      sensitive to different wavelengths of light. The Drosophila visual system
      contains multiple classes of photoreceptor cells that differ in anatomical
      location, synaptic connections, and spectral sensitivity. The Rh5 and Rh6 opsins
      are expressed in nonoverlapping sets of R8 cells and are the only Drosophila
      visual pigments that remain uncharacterized. In this study, we ectopically
      expressed Rh5 and Rh6 in the major class of photoreceptor cells (R1-R6) and show
      them to be biologically active in their new environment. The expression of either
      Rh5 or Rh6 in "blind" ninaE(17) mutant flies, which lack the gene encoding the
      visual pigment of the R1-R6 cells, fully rescues the light response.
      Electrophysiological analysis showed that the maximal spectral sensitivity of the
      R1-R6 cells is shifted to 437 or 508 nm when Rh5 or Rh6, respectively, is
      expressed in these cells. These spectral sensitivities are in excellent agreement
      with intracellular recordings of the R8p and R8y cells measured in Calliphora and
      Musca. Spectrophotometric analyses of Rh5 and Rh6 in vivo by
      microspectrophotometry, and of detergent-extracted pigments in vitro, showed that
      Rh5 is reversibly photoconverted to a stable metarhodopsin (lambda(max) = 494
      nm), whereas Rh6 appears to be photoconverted to a metarhodopsin (lambda(max) =
      468 nm) that is less thermally stable. Phylogenetically, Rh5 belongs to a group
      of short-wavelength-absorbing invertebrate visual pigments, whereas Rh6 is
      related to a group of long-wavelength-absorbing pigments and is the first member
      of this class to be functionally characterized.

PMID- 10594056
TI  - Control of action potential timing by intrinsic subthreshold oscillations in
      olfactory bulb output neurons.
AB  - Rhythmic patterns of neuronal activity have been found at multiple levels of
      various sensory systems. In the olfactory bulb or the antennal lobe, oscillatory
      activity exhibits a broad range of frequencies and has been proposed to encode
      sensory information. However, the neural mechanisms underlying these oscillations
      are unknown. Bulbar oscillations might be an emergent network property arising
      from neuronal interactions and/or resulting from intrinsic oscillations in
      individual neurons. Here we show that mitral cells (output neurons of the
      olfactory bulb) display subthreshold oscillations of their membrane potential.
      These oscillations are mediated by tetrodotoxin-sensitive sodium currents and
      range in frequency from 10 to 50 Hz as a function of resting membrane potential.
      Because the voltage dependency of oscillation frequency was found to be similar
      to that for action potential generation, we studied how subthreshold oscillations
      could influence the timing of action potentials elicited by synaptic inputs.
      Indeed, we found that subthreshold oscillatory activity can trigger the precise
      occurrence of action potentials generated in response to EPSPs. Furthermore,
      IPSPs were found to set the phase of subthreshold oscillations and can lead to
      "rebound" spikes with a constant latency. Because intrinsic oscillations of
      membrane potential enable very precise temporal control of neuronal firing, we
      propose that these oscillations provide an effective means to synchronize mitral
      cell subpopulations during the processing of olfactory information.

PMID- 10594057
TI  - Sustained plateau activity precedes and can generate ictal-like discharges in low
      Cl(-) medium in slices from rat piriform cortex.
AB  - Interictal and ictal discharges represent two different forms of abnormal brain
      activity associated with epilepsy. Ictal discharges closely parallel seizure
      activity, but depending on the form of epilepsy, interictal discharges may or may
      not be correlated with the frequency, severity, and location of seizures. Recent
      voltage-imaging studies in slices of piriform cortex indicated that interictal
      like discharges are generated in a two-stage process. The first stage consists of
      a sustained, low-amplitude depolarization (plateau activity) lasting the entire
      latent period prior to discharge onset. Plateau activity takes place at a site
      distinct from the site of discharge onset and serves to sustain and amplify
      activity initiated by an electrical stimulus. In the second stage a rapidly
      accelerating depolarization begins at the onset site and then spreads over a wide
      region. Here, we asked whether ictal-like discharges can be generated in a
      similar two-stage process. As with interictal-like activity, the first sign of an
      impending ictal-like discharge is a sustained depolarization with a plateau-like
      time course. The rapidly accelerating depolarization that signals the start of
      the actual discharge develops later at a separate onset site. As found previously
      with interictal-like discharges, local application of kynurenic acid to the
      plateau site blocked ictal-like discharges throughout the entire slice. However,
      in marked contrast to interictal-like activity, blockade of synaptic transmission
      at the onset site failed to block the ictal-like discharge. This indicates that
      interictal- and ictal-like discharges share a common pathway in the earliest
      stage of their generation and that their mechanisms subsequently diverge.

PMID- 10594058
TI  - Protein 4.1N binding to nuclear mitotic apparatus protein in PC12 cells mediates
      the antiproliferative actions of nerve growth factor.
AB  - Protein 4.1N is a neuronal selective isoform of the erythrocyte membrane
      cytoskeleton protein 4.1R. In the present study, we demonstrate an interaction
      between 4.1N and nuclear mitotic apparatus protein (NuMA), a nuclear protein
      required for mitosis. The binding involves the C-terminal domain of 4.1N. In PC12
      cells treatment with nerve growth factor (NGF) elicits translocation of 4. 1N to
      the nucleus and promotes its association with NuMA. Specific targeting of 4.1N to
      the nucleus arrests PC12 cells at the G1 phase and produces an aberrant nuclear
      morphology. Inhibition of 4.1N nuclear translocation prevents the NGF-mediated
      arrest of cell division, which can be reversed by overexpression of 4.1N. Thus,
      nuclear 4.1N appears to mediate the antiproliferative actions of NGF by
      antagonizing the role of NuMA in mitosis.

PMID- 10594059
TI  - Neuregulin induces GABA(A) receptor subunit expression and neurite outgrowth in
      cerebellar granule cells.
AB  - Neuregulin (NRG), a growth and differentiation factor that signals via erbB
      receptor tyrosine kinases, has been shown to have biological effects in both the
      CNS and the peripheral nervous system. We report here that erbB4 is expressed in
      mature cerebellar granule cells, where it appears to be concentrated at the
      granule cell postsynaptic terminals. We also show that one form of NRG, Ig-NRG,
      plays a crucial role in aspects of cerebellar granule cell development in vitro.
      First, Ig-NRG treatment of granule cells in culture selectively induces the
      expression of the GABA(A) receptor beta2 subunit. This increase in subunit
      expression is paralleled by an increase in functional GABA(A) receptors. In
      contrast to its effects on GABA(A) receptor subunit expression, Ig-NRG does not
      upregulate NMDA receptor N2B and N2C subunit expression. Second, we demonstrate
      that Ig-NRG also enhances neurite outgrowth from cultured granule cells. Ig-NRG
      does not, however, act as a survival factor for the granule cells. We have
      compared the effect of Ig-NRG with the effects of brain-derived neurotrophic
      factor (BDNF), a neurotrophin that exerts specific effects on granule cells in
      culture, and found that BDNF does not mimic the effects of Ig-NRG on GABA(A)
      receptor subunit expression. Our results show that Ig-NRG has specific effects on
      granule cell development and maturation and may regulate these processes in vivo.

PMID- 10594060
TI  - Compromised glutamate transport in human glioma cells: reduction-mislocalization
      of sodium-dependent glutamate transporters and enhanced activity of cystine
      glutamate exchange.
AB  - Elevated levels of extracellular glutamate ([Glu](o)) can induce seizures and
      cause excitotoxic neuronal cell death. This is normally prevented by astrocytic
      glutamate uptake. Neoplastic transformation of human astrocytes causes malignant
      gliomas, which are often associated with seizures and neuronal necrosis. Here, we
      show that Na(+)-dependent glutamate uptake in glioma cell lines derived from
      human tumors (STTG-1, D-54MG, D-65MG, U-373MG, U-251MG, U-138MG, and CH-235MG) is
      up to 100-fold lower than in astrocytes. Immunohistochemistry and subcellular
      fractionation show very low expression levels of the astrocytic glutamate
      transporter GLT-1 but normal expression levels of another glial glutamate
      transporter, GLAST. However, in glioma cells, essentially all GLAST protein was
      found in cell nuclei rather than the plasma membrane. Similarly, brain tissues
      from glioblastoma patients also display reduction of GLT-1 and mislocalization of
      GLAST. In glioma cell lines, over 50% of glutamate transport was Na(+)
      independent and mediated by a cystine-glutamate exchanger (system x(c)(-)).
      Extracellular L-cystine dose-dependently induced glutamate release from glioma
      cells. Glutamate release was enhanced by extracellular glutamine and inhibited by
      (S)-4-carboxyphenylglycine, which blocked cystine-glutamate exchange. These data
      suggest that the unusual release of glutamate from glioma cells is caused by
      reduction-mislocalization of Na(+)-dependent glutamate transporters in
      conjunction with upregulation of cystine-glutamate exchange. The resulting
      glutamate release from glioma cells may contribute to tumor-associated necrosis
      and possibly to seizures in peritumoral brain tissue.

PMID- 10594061
TI  - The chondroitin sulfate proteoglycans neurocan and phosphacan are expressed by
      reactive astrocytes in the chronic CNS glial scar.
AB  - Chondroitin sulfate proteoglycans (CS-PGs) expressed by reactive astrocytes may
      contribute to the axon growth-inhibitory environment of the injured CNS. The
      specific potentially inhibitory CS-PGs present in areas of reactive gliosis,
      however, have yet to be thoroughly examined. In this study, we used
      immunohistochemistry, combined immunohistochemistry-in situ hybridization,
      immunoblot analysis, and reverse transcription-PCR to examine the expression of
      specific CS-PGs by reactive astrocytes in an in vivo model of reactive gliosis:
      that is, the glial scar, after cortical injury. Neurocan and phosphacan can be
      localized to reactive astrocytes 30 d after CNS injury, whereas brevican and
      versican are not expressed in the chronic glial scar. Neurocan is also expressed
      by astrocytes in primary cell culture. Relative to the amount present in cultured
      astrocytes or uninjured cortex, neurocan expression increases significantly in
      the glial scar resulting from cortical injury, including the re-expression of the
      neonatal isoform of neurocan. In contrast, phosphacan protein levels are
      decreased in the glial scar compared with the uninjured brain. Because these CS
      PGs are capable of inhibiting neurite outgrowth in vitro, our data suggest that
      phosphacan and neurocan in areas of reactive gliosis may contribute to axonal
      regenerative failure after CNS injury.

PMID- 10594062
TI  - Cloning of components of a novel subthreshold-activating K(+) channel with a
      unique pattern of expression in the cerebral cortex.
AB  - Potassium channels that are open at very negative membrane potentials govern the
      subthreshold behavior of neurons. These channels contribute to the resting
      potential and help regulate the degree of excitability of a neuron by affecting
      the impact of synaptic inputs and the threshold for action potential generation.
      They can have large influences on cell behavior even when present at low
      concentrations because few conductances are active at these voltages. We report
      the identification of a new K(+) channel pore-forming subunit of the ether-a-go
      go (Eag) family, named Eag2, that expresses voltage-gated K(+) channels that have
      significant activation at voltages around -100 mV. Eag2 expresses outward
      rectifying, non-inactivating voltage-dependent K(+) currents resembling those of
      Eag1, including a strong dependence of activation kinetics on prepulse potential.
      However, Eag2 currents start activating at subthreshold potentials that are 40-50
      mV more negative than those reported for Eag1. Because they activate at such
      negative voltages and do not inactivate, Eag2 channels will contribute sustained
      outward currents down to the most negative membrane potentials known in neurons.
      Although Eag2 mRNA levels in whole brain appear to be low, they are highly
      concentrated in a few neuronal populations, most prominently in layer IV of the
      cerebral cortex. This highly restricted pattern of cortical expression is unlike
      that of any other potassium channel cloned to date and may indicate specific
      roles for this channel in cortical processing. Layer IV neurons are the main
      recipient of the thalamocortical input. Given their functional properties and
      specific distribution, Eag2 channels may play roles in the regulation of the
      behavioral state-dependent entry of sensory information to the cerebral cortex.

PMID- 10594063
TI  - Opposing effects of excitatory amino acids on chick embryo spinal cord
      motoneurons: excitotoxic degeneration or prevention of programmed cell death.
AB  - Acute administration of a single dose of NMDA on embryonic day (E) 7 or later
      induces a marked excitotoxic injury in the chick spinal cord, including massive
      necrotic motoneuron (MN) death. When the same treatment was performed before E7,
      little, if any, excitotoxic response was observed. Chronic treatment with NMDA
      starting on E5 prevents the excitotoxic response produced by a later "acute"
      administration of NMDA. Additionally, chronic NMDA treatment also prevents the
      later excitotoxic injury induced by non-NMDA glutamate receptor agonists, such as
      kainate or AMPA. Chronic NMDA treatment also reduces normal MN death when
      treatment is maintained during the period of naturally occurring programmed cell
      death (PCD) of MNs and rescues MNs from PCD induced by early peripheral target
      deprivation. The trophic action of chronic NMDA treatment appears to involve a
      downregulation of glutamate receptors as shown by both a reduction in the
      obligatory NR1 subunit protein of the NMDA receptor and a decrease in the kainate
      induced Co(2+) uptake in MNs. Both tolerance to excitotoxicity and trophic
      effects of chronic NMDA treatment are prevented by the NMDA receptor antagonist
      MK-801. Additionally, administration of MK-801 alone results in an increase in MN
      PCD. These data indicate for the first time that early activation of NMDA
      receptors in developing avian MNs in vivo has a trophic, survival-promoting
      effect, inhibiting PCD by a target-independent mechanism that involves NMDA
      receptor downregulation.

PMID- 10594064
TI  - Gap junctional coupling and patterns of connexin expression among neonatal rat
      lumbar spinal motor neurons.
AB  - Interneuronal gap junctional coupling is a hallmark of neural development whose
      functional significance is poorly understood. We have characterized the extent of
      electrical coupling and dye coupling and patterns of gap junction protein
      expression in lumbar spinal motor neurons of neonatal rats. Intracellular
      recordings showed that neonatal motor neurons are transiently electrically
      coupled and that electrical coupling is reversibly abolished by halothane, a gap
      junction blocker. Iontophoretic injection of Neurobiotin, a low molecular weight
      compound that passes across most gap junctions, into single motor neurons
      resulted in clusters of many labeled motor neurons at postnatal day 0 (P0)-P2,
      and single labeled motor neurons after P7. The compact distribution of dye
      labeled motor neurons suggested that, after birth, gap junctional coupling is
      spatially restricted. RT-PCR, in situ hybridization, and immunostaining showed
      that motor neurons express five connexins, Cx36, Cx37, Cx40, Cx43, and Cx45, a
      repertoire distinct from that expressed by other neurons or glia. Although all
      five connexins are widely expressed among motor neurons in embryonic and neonatal
      life, Cx36, Cx37, and Cx43 continue to be expressed in many adult motor neurons,
      and expression of Cx45, and in particular Cx40, decreases after birth. The
      disappearance of electrical and dye coupling despite the persistent expression of
      several gap junction proteins suggests that gap junctional communication among
      motor neurons may be modulated by mechanisms that affect gap junction assembly,
      permeability, or open state.

PMID- 10594066
TI  - Thrombin-induced growth cone collapse: involvement of phospholipase A(2) and
      eicosanoid generation.
AB  - The studies presented here explore intracellular signals resulting from the
      action of repellents on growth cones. Growth cone challenge with thrombin or
      thrombin receptor-activating peptide (TRAP) triggers collapse via a receptor
      mediated process. The results indicate that this involves activation of cytosolic
      phospholipase A(2) (PLA(2)) and eicosanoid synthesis. The collapse response to
      repellents targets at least two functional units of the growth cone, the actin
      cytoskeleton and substratum adhesion sites. We show in a cell-free assay that
      thrombin and TRAP cause the detachment of isolated growth cones from laminin.
      Biochemical analyses of isolated growth cones reveal that thrombin and TRAP
      stimulate cytosolic PLA(2) but not phospholipase C. In addition, thrombin
      stimulates synthesis of 12- and 15-hydroxyeicosatetraenoic acid (HETE) from the
      released arachidonic acid via a lipoxygenase (LO) pathway. A selective LO
      inhibitor blocks 12/15-HETE synthesis in growth cones and inhibits thrombin
      induced growth cone collapse. Exogenously applied 12(S)-HETE mimics the thrombin
      effect and induces growth cone collapse in culture. These observations indicate
      that thrombin-induced growth cone collapse occurs by a mechanism that involves
      the activation of cytosolic PLA(2) and the generation of 12/15-HETE.

PMID- 10594065
TI  - Synaptic density in geniculocortical afferents remains constant after monocular
      deprivation in the cat.
AB  - Monocular eyelid closure in cats during a critical period in development produces
      both physiological plasticity, as indicated by a loss of responsiveness of
      primary visual cortical neurons to deprived eye stimulation, and morphological
      plasticity, as demonstrated by a decrease in the total length of individual
      geniculocortical arbors representing the deprived eye. Although the physiological
      plasticity appears maximal after 2 d of monocular deprivation (MD), the shrinkage
      of deprived-eye geniculocortical arbors is less than half-maximal at 4 d and is
      not maximal until 7 d of deprivation, at which time the deprived arbors are
      approximately half their previous size. To study this form of plasticity at the
      level of individual thalamocortical synapses rather than arbors, we developed a
      new double-label colocalization technique. First, geniculocortical afferent
      arbors serving either the deprived or nondeprived eye were labeled by injection
      of the anterograde tracer Phaseolus vulgaris leucoagglutinin into lamina A of the
      lateral geniculate nucleus. Then, using antibodies to synaptic vesicle proteins,
      we identified presynaptic terminals within the labeled arbors in layer IV of the
      primary visual cortex. Analysis of serial optical sections obtained using
      confocal microscopy allowed measurement of the numerical density of presynaptic
      sites and the relative amounts of synaptic vesicle protein in geniculocortical
      afferents after both 2 and 7 d of MD. We found that the density of synapses in
      geniculocortical axons was similar for deprived and nondeprived afferents,
      suggesting that this feature of the afferents is conserved even during periods in
      which synapse number is reduced by half in deprived-eye arbors. These results are
      not consistent with the hypothesis that a rapid loss of deprived-eye
      geniculocortical presynaptic sites is responsible for the prompt physiological
      effects of MD.

PMID- 10594067
TI  - Involvement of cajal-retzius neurons in spontaneous correlated activity of
      embryonic and postnatal layer 1 from wild-type and reeler mice.
AB  - Cajal-Retzius (CR) cells are a transient population of neurons in developing
      cortical layer 1 that secrete reelin, a protein necessary for cortical
      lamination. Combining calcium imaging of cortical hemispheres and cross
      correlation analysis, we previously found spontaneous correlated activity among
      non-CR neurons in postnatal rat layer 1. This correlated activity was blocked by
      GABAergic and glutamatergic antagonists, and we postulated that it was controlled
      by CR cells. We now investigate the correlated activity of embryonic and
      postnatal layer 1 in wild-type and reeler mice, mutant in the production of
      reelin. We find that mouse layer 1 also sustains patterned spontaneous activity
      and that CR cells participate in correlated networks. These networks are present
      in embryonic marginal zone and are blocked by GABAergic and glutamatergic
      antagonists. Surprisingly, network activity in reeler mice displays similar
      characteristics and pharmacological profile as in wild-type mice, although small
      differences are detected. Our results demonstrate that the embryonic marginal
      zone has correlated spontaneous activity that could serve as the scaffold for the
      development of intracortical connections. Our data also suggest that reelin does
      not have a major impact in the development of specific synaptic circuits in layer
      1.

PMID- 10594069
TI  - Graded and areal expression patterns of regulatory genes and cadherins in
      embryonic neocortex independent of thalamocortical input.
AB  - The differentiation of areas of the mammalian neocortex has been hypothesized to
      be controlled by intrinsic genetic programs and extrinsic influences such as
      those mediated by thalamocortical afferents (TCAs). To address the interplay
      between these intrinsic and extrinsic mechanisms in the process of arealization,
      we have analyzed the requirement of TCAs in establishing or maintaining graded or
      areal patterns of gene expression in the developing mouse neocortex. We describe
      the differential expression of Lhx2, SCIP, and Emx1, representatives of three
      different classes of transcription factors, and the type II classical cadherins
      Cad6, Cad8, and Cad11, which are expressed in graded or areal patterns, as well
      as layer-specific patterns, in the cortical plate. The differential expression of
      Lhx2, SCIP, Emx1, and Cad8 in the cortical plate is not evident until after TCAs
      reach the cortex, whereas Cad6 and Cad11 show subtle graded patterns of
      expression before the arrival of TCAs, which later become stronger. We find that
      these genes exhibit normal-appearing graded or areal expression patterns in Mash
      1 mutant mice that fail to develop a TCA projection. These findings show that
      TCAs are not required for the establishment or maintenance of the graded and
      areal expression patterns of these genes and strongly suggest that their
      regulation is intrinsic to the developing neocortex.

PMID- 10594068
TI  - Amygdala-hippocampal involvement in human aversive trace conditioning revealed
      through event-related functional magnetic resonance imaging.
AB  - Previous functional neuroimaging studies have characterized brain systems
      mediating associative learning using classical delay conditioning paradigms. In
      the present study, we used event-related functional magnetic resonance imaging to
      characterize neuronal responses mediating aversive trace conditioning. During
      conditioning, neutral auditory tones were paired with an aversive sound
      [unconditioned stimulus (US)]. We compared neuronal responses evoked by
      conditioned (CS+) and nonconditioned (CS-) stimuli in which a 50% pairing of CS+
      and the US enabled us to limit our analysis to responses evoked by the CS+ alone.
      Differential responses (CS+ vs CS-), related to conditioning, were observed in
      anterior cingulate and anterior insula, regions previously implicated in delay
      fear conditioning. Differential responses were also observed in the amygdala and
      hippocampus that were best characterized with a time x stimulus interaction,
      indicating rapid adaptation of CS+-specific responses in medial temporal lobe.
      These results are strikingly similar to those obtained with a previous delay
      conditioning experiment and are in accord with a preferential role for medial
      temporal lobe structures during the early phase of conditioning. However, an
      additional activation of anterior hippocampus in the present experiment supports
      a view that its role in trace conditioning is to maintain a memory trace between
      the offset of the CS+ and the delayed onset of the US to enable associative
      learning in trace conditioning.

PMID- 10594070
TI  - Neurochemical and cellular reorganization of the spinal cord in a murine model of
      bone cancer pain.
AB  - The cancer-related event that is most disruptive to the cancer patient's quality
      of life is pain. To begin to define the mechanisms that give rise to cancer pain,
      we examined the neurochemical changes that occur in the spinal cord and
      associated dorsal root ganglia in a murine model of bone cancer. Twenty-one days
      after intramedullary injection of osteolytic sarcoma cells into the femur, there
      was extensive bone destruction and invasion of the tumor into the periosteum,
      similar to that found in patients with osteolytic bone cancer. In the spinal
      cord, ipsilateral to the cancerous bone, there was a massive astrocyte
      hypertrophy without neuronal loss, an expression of dynorphin and c-Fos protein
      in neurons in the deep laminae of the dorsal horn. Additionally, normally non
      noxious palpation of the bone with cancer induced behaviors indicative of pain,
      the internalization of the substance P receptor, and c-Fos expression in lamina I
      neurons. The alterations in the neurochemistry of the spinal cord and the
      sensitization of primary afferents were positively correlated with the extent of
      bone destruction and the growth of the tumor. This "neurochemical signature" of
      bone cancer pain appears unique when compared to changes that occur in persistent
      inflammatory or neuropathic pain states. Understanding the mechanisms by which
      the cancer cells induce this neurochemical reorganization may provide insight
      into peripheral factors that drive spinal cord plasticity and in the development
      of more effective treatments for cancer pain.

PMID- 10594071
TI  - Cerebral microvascular obstruction by fibrin is associated with upregulation of
      PAI-1 acutely after onset of focal embolic ischemia in rats.
AB  - The mechanisms underlying cerebral microvascular perfusion deficit resulting from
      occlusion of the middle cerebral artery (MCA) require elucidation. We, therefore,
      tested the hypothesis that intravascular fibrin deposition in situ directly
      obstructs cerebral microcirculation and that local changes in type 1 plasminogen
      activator inhibitor (PAI-1) gene expression contribute to intravascular fibrin
      deposition after embolic MCA occlusion. Using laser-scanning confocal microscopy
      (LSCM) in combination with immunofluorescent staining, we simultaneously measured
      in three dimensions the distribution of microvascular plasma perfusion deficit
      and fibrin(ogen) immunoreactivity in a rat model of focal cerebral embolic
      ischemia (n = 12). In addition, using in situ hybridization and immunostaining,
      we analyzed expression of PAI-1 in ischemic brain (n = 13). A significant (p <
      0.05) reduction of cerebral microvascular plasma perfusion accompanied a
      significant (p < 0.05) increase of intravascular and extravascular fibrin
      deposition in the ischemic lesion. Microvascular plasma perfusion deficit and
      fibrin deposition expanded concomitantly from the subcortex to the cortex during
      1 and 4 hr of embolic MCA occlusion. Three-dimensional analysis revealed that
      intravascular fibrin deposition directly blocks microvascular plasma perfusion.
      Vascular plugs contained erythrocytes, polymorphonuclear leukocytes, and
      platelets enmeshed in fibrin. In situ hybridization demonstrated induction of PAI
      1 mRNA in vascular endothelial cells in the ischemic region at 1 hr of ischemia.
      PAI-1 mRNA significantly increased at 4 hr of ischemia. Immunohistochemical
      staining showed the same pattern of increased PAI-1 antigen in the endothelial
      cells. These data demonstrate, for the first time, that progressive intravascular
      fibrin deposition directly blocks cerebral microvascular plasma perfusion in the
      ischemic region during acute focal cerebral embolic ischemia, and upregulation of
      the PAI-1 gene in the ischemic lesion may foster fibrin deposition through
      suppression of fibrinolysis.

PMID- 10594072
TI  - Corticostriatal projections from rat barrel cortex have an anisotropic
      organization that correlates with vibrissal whisking behavior.
AB  - To elucidate the detailed organization of corticostriatal projections from rodent
      somatosensory cortex, the anterograde tracers biotinylated dextran amine (BDA)
      and fluoro-ruby (FR) were injected into separate parts of the whisker "barrel"
      representation. In one group of rats, the two tracers were injected into
      different barrel columns residing in the same row; in the other group of rats,
      the tracers were deposited into barrel columns residing in different rows.
      Reconstructions of labeled axonal varicosities in the neostriatum and ventrobasal
      thalamus were analyzed quantitatively to compare the extent of overlapping
      projections to these subcortical structures. For both groups of animals,
      corticostriatal projections terminated in densely packed clusters that occupied
      curved lamellar-shaped regions along the dorsolateral edge of the neostriatum.
      When the tracers were injected into different whisker barrel rows, the
      distribution of BDA- and FR-labeled terminals in the neostriatum followed a crude
      somatotopic organization in which the amount of overlap was approximately the
      same as in the ventrobasal thalamus. When both tracers were injected into the
      same whisker barrel row, however, the amount of corticostriatal overlap was
      significantly higher than the amount of overlap observed in the ventrobasal
      thalamus. These results indicate that corticostriatal projections from whisker
      barrel cortex have an anisotropic organization that correlates with the pattern
      of vibrissal movements during whisking behavior.

PMID- 10594073
TI  - An essential role of interleukin-1beta in mediating NF-kappaB activity and COX-2
      transcription in cells of the blood-brain barrier in response to a systemic and
      localized inflammation but not during endotoxemia.
AB  - When released into the bloodstream, proinflammatory cytokines have the ability to
      trigger the transcription of different genes in cells of the blood-brain barrier
      (BBB), including members of the nuclear factor kappa B (NF-kappaB) family and
      cyclooxygenase-2 (COX-2), the limiting enzyme for the formation of prostaglandins
      (PGs). The present study investigated the possibility that interleukin-1beta (IL
      1beta) plays an essential role in these events during a systemic inflammatory
      response. Both wild-type and IL-1beta-deficient mice were killed at different
      times after two different immunogenic stimuli, i.e., intraperitoneal
      lipopolysaccharide (LPS) injection and intramuscular turpentine injection, used
      here as a model of systemic localized inflammatory insult. The inhibitory factor
      kappaBalpha (IkappaBalpha, index of NF-kappaB activity) and COX-2 transcripts
      were detected throughout the brain by means of in situ hybridization. Systemic
      LPS injection caused a strong and rapid expression of IkappaBalpha in endothelial
      cells lining the BBB of large and small blood vessels and thereafter within
      parenchymal microglia across the brain. This treatment also provoked a transient
      expression of COX-2 along cells of the vascular system, and the expression
      pattern and intensity of the signal for both transcripts were essentially the
      same in wild-type and IL-1beta-deficient animals. In contrast, the induction of
      these genes that was quite selective to the cells of the BBB in response to
      intramuscularly turpentine insult was completely abolished in IL-1beta-deficient
      mice. Indeed, a late and prolonged expression of IkappaBalpha and COX-2 mRNAs was
      found along the cerebral blood vessels in response to the sterile and localized
      inflammation in wild-type mice, whereas such induction was absent in the brain of
      IL-1beta-deficient animals. These results indicate that IL-1beta has an
      obligatory role in the activation of NF-kappaB molecules and PGs within
      endothelial cells of the BBB in an experimental model of intramuscularly
      turpentine-induced inflammation but not during endotoxemia.

PMID- 10594074
TI  - Saccadic dysmetria and adaptation after lesions of the cerebellar cortex.
AB  - We studied the effects of small lesions of the oculomotor vermis of the
      cerebellar cortex on the ability of monkeys to execute and adapt saccadic eye
      movements. For saccades in one horizontal direction, the lesions led to an
      initial gross hypometria and a permanent abolition of the capacity for rapid
      adaptation. Mean saccade amplitude recovered from the initial hypometria,
      although variability remained high. A series of hundreds of repetitive saccades
      in the same direction resulted in gradual decrement of amplitude. Saccades in
      other directions were less strongly affected by the lesions. We suggest the
      following. (1) The cerebellar cortex is constantly recalibrating the saccadic
      system, thus compensating for rapid biomechanical changes such as might be caused
      by muscle fatigue. (2) A mechanism capable of slow recovery from dysmetria is
      revealed despite the permanent absence of rapid adaptation.

PMID- 10594075
TI  - Cerebellar cortex lesions prevent acquisition of conditioned eyelid responses.
AB  - We have used aspiration and electrolytic lesions to investigate the contributions
      of cerebellar cortex to the acquisition and expression of conditioned eyelid
      responses. We show that lesions of the anterior lobe of rabbit cerebellar cortex
      disrupt the timing of previously learned conditioned eyelid responses. These
      short-latency responses were used as an indication that the cerebellar cortex was
      sufficiently damaged and that the underlying pathways necessary for the
      expression of responses were sufficiently intact to support responses. Rabbits
      were subsequently trained for 15 daily sessions using a new conditioned stimulus.
      Whereas rabbits in which lesions had no significant effect on response timing
      showed rapid acquisition of appropriately timed eyelid responses to the new
      conditioned stimulus, animals with lesions that disrupt timing showed no
      significant increases in either amplitude or probability of responses.
      Histological analysis suggests that damage to the anterior lobe of the cerebellar
      cortex is necessary and sufficient to abolish timing and prevent acquisition.
      These data indicate that the cerebellar cortex is necessary for the acquisition
      of conditioned eyelid responses and are consistent with the hypotheses that (1)
      eyelid conditioning results in plasticity in both the anterior lobe of the
      cerebellar cortex and in the anterior interpositus nucleus and (2) induction of
      plasticity in the interpositus requires intact input from the cerebellar cortex.

PMID- 10594076
TI  - Cytomegalovirus cell tropism, replication, and gene transfer in brain.
AB  - Cytomegalovirus (CMV) infects a majority of adult humans. During early
      development and in the immunocompromised adult, CMV causes neurological deficits.
      We used recombinant murine cytomegalovirus (mCMV) expressing either green
      fluorescent protein (GFP) or beta-galactosidase under control of human elongation
      factor 1 promoter or CMV immediate early-1 promoter as reporter genes for
      infected brain cells. In vivo and in vitro studies revealed that neurons and
      glial cells supported strong reporter gene expression after CMV exposure. Brain
      cultures selectively enriched in either glia or neurons supported viral
      replication, leading to process degeneration and cell death within 2 d of viral
      exposure. In addition, endothelial cells, tanycytes, radial glia, ependymal
      cells, microglia, and cells from the meninges and choroid were infected. Although
      mCMV showed no absolute brain cell preference, relative cell preferences were
      detected. Radial glia cells play an important role in guiding migrating neurons;
      these were viral targets in the developing brain, suggesting that cortical
      problems including microgyria that are a consequence of CMV may be caused by
      compromised radial glia. Although CMV is a species-specific virus, recombinant
      mCMV entered and expressed reporter genes in both rat and human brain cells,
      suggesting that mCMV might serve as a vector for gene transfer into brain cells
      of non-murine species. GFP expression was sufficiently strong that long axons,
      dendrites, and their associated spines were readily detected in both living and
      fixed tissue, indicating that mCMV reporter gene constructs may be useful for
      labeling neurons and their pathways.

PMID- 10594077
TI  - Proprioceptive control of extensor activity during fictive scratching and weight
      support compared to fictive locomotion.
AB  - At rest, extensor group I afferents produce oligosynaptic inhibition of extensor
      motoneurons. During locomotor activity, however, such inhibition is replaced by
      oligosynaptic excitation. Oligosynaptic excitation from extensor group I
      afferents plays a crucial role in the regulation of extensor activity during
      walking. In this study we investigate the possibility that this mechanism also
      regulates extensor muscle activity during other motor tasks. We show that the
      reflex pathways responsible for extensor group I oligosynaptic excitation during
      fictive locomotion can be activated during both fictive scratching and fictive
      weight support (tonic motor activity induced by contralateral scratching). These
      observations suggest that the excitatory group I oligosynaptic reflex pathways
      are open for transmission during several forms of motor activities. We also show
      that extensor group I input during fictive scratching can affect the amplitude
      and the timing of extensor activity in a pattern similar to that observed during
      locomotion. Most likely these effects involve the activation of the excitatory
      group I oligosynaptic reflex pathways. Accordingly, it is suggested that extensor
      group I oligosynaptic excitation during motor activities other than locomotion is
      also used to regulate extensor muscle activity. Furthermore, the similarity of
      effects from extensor group I input on the rhythmicity during scratching and
      locomotion supports the hypothesis that both rhythms are generated by a common
      network.

PMID- 10594078
TI  - Upregulation of GABA neurotransmission suppresses hippocampal excitability and
      prevents long-term potentiation in transgenic superoxide dismutase-overexpressing
      mice.
AB  - Cu/Zn superoxide dismutase (SOD-1) is a key enzyme in oxygen metabolism in the
      brain. Overexpression of SOD-1 in transgenic (Tg) mice has been used to study the
      functional roles of this enzyme in oxidative stress, lipid peroxidation, and
      neurotoxicity. We found that Tg-SOD-1 mice are strikingly less sensitive to
      kainic acid-induced behavioral seizures than control mice. Furthermore, the
      hippocampus of Tg-SOD-1 mice was far less sensitive to local application of
      bicuculline, a GABA-A antagonist, than the hippocampus of control mice. GABAergic
      functions, expressed in extracellular paired-pulse depression, and in IPSCs
      recorded in dentate granular cells were enhanced in Tg-SOD-1 mice. Finally, long
      term potentiation (LTP), not found in the dentate gyrus of Tg-SOD-1 mice, could
      be restored by local blockade of inhibition and could be blocked in control mice
      by injection of diazepam, which amplifies inhibition. These results indicate that
      constitutive elevation of SOD-1 activity exerts a major effect on neuronal
      excitability in the hippocampus, which, in turn, controls hippocampal ability to
      express LTP.

PMID- 10594079
TI  - Norepinephrine-deficient mice have increased susceptibility to seizure-inducing
      stimuli.
AB  - Several lines of evidence suggest that norepinephrine (NE) can modulate seizure
      activity. However, the experimental methods used in the past cannot exclude the
      possible role of other neurotransmitters coreleased with NE from noradrenergic
      terminals. We have assessed the seizure susceptibility of genetically engineered
      mice that lack NE. Seizure susceptibility was determined in the dopamine beta
      hydroxylase null mutant (Dbh -/-) mouse using four different convulsant stimuli:
      2,2,2-trifluroethyl ether (flurothyl), pentylenetetrazol (PTZ), kainic acid, and
      high-decibel sound. Dbh -/- mice demonstrated enhanced susceptibility (i.e.,
      lower threshold) compared with littermate heterozygous (Dbh +/-) controls to
      flurothyl, PTZ, kainic acid, and audiogenic seizures and enhanced sensitivity
      (i.e., seizure severity and mortality) to flurothyl, PTZ, and kainic acid. c-Fos
      mRNA expression in the cortex, hippocampus (CA1 and CA3), and amygdala was
      increased in Dbh -/- mice in association with flurothyl-induced seizures.
      Enhanced seizure susceptibility to flurothyl and increased seizure-induced c-fos
      mRNA expression were reversed by pretreatment with L-threo-3, 4
      dihydroxyphenylserine, which partially restores the NE content in Dbh -/- mice.
      These genetically engineered mice confirm unambiguously the potent effects of the
      noradrenergic system in modulating epileptogenicity and illustrate the unique
      opportunity offered by Dbh -/- mice for elucidating the pathways through which NE
      can regulate seizure activity.

PMID- 10594080
TI  - Effect of enriched environment rearing on impairments in cortical excitability
      and plasticity after prenatal alcohol exposure.
AB  - The daily ingestion of alcohol by pregnant mammals exposes the fetal brain to
      varying levels of alcohol through the placental circulation. Here we focus on the
      lingering impact on cortical function of 6.5% alcohol administered in a liquid
      diet to pregnant rats throughout gestation, followed by 3 alcohol-free months
      before brain function was analyzed in the offspring. Both spontaneous activity of
      the neurons in the barrel cortex and the level of response to test stimuli
      applied to the whiskers remained reduced by >75% after alcohol exposure. Whisker
      pairing, a type of cortical plasticity induced by trimming all but two whiskers
      in adult rats, occurred in <1 d in controls, but required 14 d to reach
      significance after alcohol exposure. These long-term neuronal deficits are
      present in all layers of cortex and affect neurons with both fast and slow action
      potentials. Plasticity is first seen in the total sample of neurons at 14 d;
      however, by 7 d, neurons in layer II/III already show plasticity, with no change
      in layer IV neurons, and a reverse shift occurs toward the inactive whisker in
      layer V neurons. Analysis of NMDA receptor subunits shows a persistent,
      approximately 30-50% reduction of NR1, NR2A, and NR2B subunits at postnatal day
      90 in the barrel field cortex. Exposing the prenatal alcohol-exposed rats to
      enriched rearing conditions significantly improves all measured cortical
      functions but does not restore normal values. The results predict that
      combinations of interventions will be necessary to completely restore cortical
      function after exposure of the fetal brain to alcohol.

PMID- 10594081
TI  - Factors contributing to preferential motor reinnervation in the primate
      peripheral nervous system.
AB  - Functional recovery after nerve lesions in the peripheral nervous system requires
      the accurate regeneration of axons to their original target end organs. This
      paper examines axonal regeneration of the primate median nerve lesioned at the
      wrist over nerve gap distances of up to 50 mm. Nerve gaps were bridged by either
      a sural nerve graft or a biodegradable collagen nerve guide tube, and recovery
      was followed for up to 1100 d. Nondestructive physiological methods were used to
      serially examine the number of regenerated motor units, and binomial statistics
      were used to compare the observed number of regenerated motor units with that
      expected if axonal regeneration of motor neurons were random. We found up to
      twice the number of motor units expected by random regeneration in direct suture
      and sural cable graft groups but not in nerve guide repairs of 20 or 50 mm. In
      all repaired nerves, aberrant motor axon collaterals were detected in digital
      sensory nerve territory. The results support the contention that the aberrant
      fibers represent collaterals of an alpha-motor axon, which also innervates
      muscle. Although the aberrant motor axon collaterals remained in digital sensory
      nerve territory for long periods, they remained relatively immature compared with
      their sibling collateral projecting to muscle, or sensory axons within the
      digital nerve. The number of such aberrant motor axon collaterals decreased over
      time in some repair groups, suggesting a selective pruning of the inappropriate
      collateral under certain conditions.

PMID- 10594082
TI  - Role of adenosine A2 receptors in brain stimulation reward under baseline
      conditions and during cocaine withdrawal in rats.
AB  - The present experiments tested the hypothesis that adenosine A2 receptors are
      involved in central reward function. Adenosine receptor agonists or antagonists
      were administered to animals that had been trained to self-stimulate in a rate
      free brain stimulation reward (BSR) task that provides current thresholds as a
      measure of reward. The adenosine A(2A) receptor-selective agonists 2-p-(2
      carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride (CGS
      21680) (0.1-1.0 mg/kg) and 2-[(2-aminoethylamino)carbonylethyl phenylethylamino]
      5'-N-ethylcarboxamido adenosine (APEC) (0.003-0.03 mg/kg) elevated reward
      thresholds without increasing response latencies, a measure of performance.
      Specifically, CGS 21680 had no effect on response latency, whereas APEC shortened
      latencies. Bilateral infusion of CGS 21680 (3, 10, and 30 ng/side), directly into
      the nucleus accumbens, elevated thresholds but shortened latencies. The highly
      selective A(2A) antagonist 8-(3-chlorostyryl)caffeine (0.01-10.0 mg/kg) and the
      A2-preferring antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) (0.3-10.0 mg/kg)
      did not alter thresholds or latencies, but DMPX (1.0, 10.0 mg/kg) blocked the
      threshold-elevating effect of APEC (0.03 mg/kg). In another study, repeated
      administration of cocaine (eight cocaine injections of 15 mg/kg, i.p.,
      administered over 9 hr) produced elevations in thresholds at 4, 8, and 12 hr
      after cocaine. DMPX (3 and 10 mg/kg), administered before both the 8 and 12 hr
      post-cocaine self-stimulation tests, reversed the threshold elevation produced by
      cocaine withdrawal. These results indicate that stimulating adenosine A(2A)
      receptors diminishes BSR without producing performance deficits, whereas blocking
      adenosine receptors reverses the reward impairment produced by cocaine withdrawal
      or by an A(2A) agonist. These findings indicate that adenosine, via A(2A)
      receptors, may inhibit central reward processes, particularly during the
      neuroadaptations associated with chronic drug-induced neuronal activation.

PMID- 10594083
TI  - Modulation of basolateral amygdala neuronal firing and afferent drive by dopamine
      receptor activation in vivo.
AB  - The basolateral amygdala (BLA) is implicated in responding to affective stimuli.
      Dopamine (DA) is released in the BLA during numerous conditions; however, the
      neurophysiological effects of DA in the BLA have not been examined in depth. In
      this study, the effects of DA receptor manipulation on spontaneous and afferent
      driven neuronal firing were examined using in vivo extracellular single-unit
      recordings in parallel with systemic and iontophoretic drug application, and
      stimulation of the substantia nigra/ventral tegmental area in the rat. The
      effects of DA receptor activation in the BLA were found to depend on the
      characteristics of the BLA neuron examined, causing an increase in the firing
      rate of putative interneurons and a decrease in the firing of identified
      projection neurons. Additionally, DA receptor activation attenuated short-latency
      spikes evoked by electrical stimulation of prefrontal cortical and mediodorsal
      thalamic inputs to the BLA while potentiating the responses evoked by electrical
      stimulation of sensory association cortex. DA receptor activation can thus
      attenuate BLA projection neuron firing via two mechanisms: (1) by a direct
      inhibition, and (2) by indirect actions mediated via activation of BLA
      interneurons. This is hypothesized to lead to a global filtration of weaker
      inputs. Moreover, DA potentiates sensory inputs and attenuates medial prefrontal
      cortex inputs to the BLA. Conditions in which DA is released in the BLA, such as
      during the presentation of an affective stimulus, will lead to a potentiation of
      the strongest sensory input and a dampening of cortical inhibition over the BLA,
      thus augmenting the response to affective sensory stimuli.

PMID- 10594084
TI  - Evidence of a functional relationship between the nucleus accumbens shell and
      lateral hypothalamus subserving the control of feeding behavior.
AB  - Inhibition of neurons in the nucleus accumbens shell (AcbSh) with local
      injections of GABA agonists or glutamate antagonists elicits an intense, but
      specific, feeding response resembling that seen after stimulation of the lateral
      hypothalamus (LH). To help characterize the contribution of the LH to the
      expression of AcbSh-mediated feeding, we used the immunohistochemical detection
      of the nuclear protein Fos to determine whether inhibition of AcbSh cells results
      in an activation of LH neurons. Injections of the GABA(A) agonist muscimol into
      the AcbSh greatly increased the number of cells exhibiting Fos-like
      immunoreactivity in the LH, as well as in the lateral septum, paraventricular
      hypothalamic nucleus, ventral tegmental area, substantia nigra pars compacta, and
      nucleus of the solitary tract. Blocking activation of LH neurons with the
      selective NMDA receptor blocker D(-)-AP-5 is known to suppress deprivation
      induced feeding. We found that injections of D(-)-AP5 into the LH also dose
      dependently suppressed AcbSh-mediated feeding. It is likely that inhibition of
      GABAergic neurons in the AcbSh is responsible for eliciting this feeding. If a
      behaviorally relevant GABAergic projection terminates in the LH, we should be
      able to mimic the effects seen after inhibition of the projection neurons by
      applying a GABA receptor blocker to the area. However, injections of the GABA(A)
      receptor blocker bicuculline or the GABA(B) receptor blocker saclofen did not
      significantly affect food intake. Thus, it appears that the expression of the
      feeding response depends on an NMDA-preferring receptor-mediated activation of LH
      neurons and is not the result of disinhibiting LH cells by disrupting
      transmission at GABA synapses.

PMID- 10594085
TI  - Dopamine terminals in the rat prefrontal cortex synapse on pyramidal cells that
      project to the nucleus accumbens.
AB  - Afferents to the prefrontal cortex (PFC) from dopamine neurons in the ventral
      tegmental area have been implicated in working memory processes and in the
      pathogenesis of schizophrenia. Previous anatomical investigations have
      demonstrated that dopamine terminals synapse on dendritic spines and shafts of
      pyramidal cells in the PFC. Moreover, neurochemical and physiological studies
      suggest that dopamine modulates the activity of PFC neurons that project to the
      nucleus accumbens. However, whether this modulation involves direct synaptic
      input to cortico-accumbens projection neurons has not been determined. To address
      this question, retrograde transport of an attenuated strain of pseudorabies virus
      (PRV) from the nucleus accumbens was combined with immunoperoxidase labeling of
      tyrosine hydroxylase (TH) to identify dopamine terminals in the PFC. At survival
      times <48 hr, extensive dendritic distribution of immunogold labeling for PRV was
      observed in cortico-accumbens neurons. However, evidence consistent with trans
      synaptic passage of PRV within this timeframe was observed only rarely. When
      examined at the electron microscopic level, immunogold labeling for PRV was
      localized to neuronal somata, proximal and distal dendrites, and dendritic
      spines. Some of these dendritic processes received symmetric synaptic input from
      TH-immunoreactive terminals. These data represent the first demonstration of
      dopamine synaptic contacts onto an identified population of pyramidal cells in
      the PFC. The findings have important implications for understanding how dopamine
      modulates cortical outflow to limbic regions in normal brain and pathological
      states such as schizophrenia.

PMID- 10594086
TI  - Thalamic-cortical-striatal circuitry subserves working memory during delayed
      responding on a radial arm maze.
AB  - The medial dorsal nuclei of the thalamus (MDNt), the prefrontal cortex, and the
      ventral striatum form an interconnected neural circuit that may subserve certain
      types of working memory. The present series of experiments investigated
      functional interactions between these brain regions in rats during the
      performance of delayed and nondelayed spatially cued radial-arm maze tasks. In
      Experiment 1, transient inactivation of the MDNt by a bilateral injection of
      lidocaine selectively disrupted performance on a delayed task but not on a
      nondelayed random foraging version of the radial arm maze task. In Experiment 2,
      asymmetrical lidocaine injections into the MDNt on one side of the brain and the
      prefrontal cortex on the other transiently disconnected these two brain regions
      and significantly impaired foraging during the delayed task. Similarly,
      disconnections between the prefrontal cortex and the nucleus accumbens also
      disrupted foraging on this task, whereas disconnections between the MDNt and the
      nucleus accumbens had no effect. These data suggest that serial transmission of
      information among the MDNt, the prefrontal cortex, and the nucleus accumbens is
      required when trial-unique, short-term spatial memory is used to guide
      prospective search behavior. The results are discussed with respect to a
      distributed neural network linking limbic, thalamic, cortical, and striatal
      regions, which mediates executive functions of working memory.

PMID- 10594087
TI  - A novel persistent tetrodotoxin-resistant sodium current in SNS-null and wild
      type small primary sensory neurons.
AB  - TTX-resistant (TTX-R) sodium currents are preferentially expressed in small C
      type dorsal root ganglion (DRG) neurons, which include nociceptive neurons. Two
      mRNAs that are predicted to encode TTX-R sodium channels, SNS and NaN, are
      preferentially expressed in C-type DRG cells. To determine whether there are
      multiple TTX-R currents in these cells, we used patch-clamp recordings to study
      sodium currents in SNS-null mice and found a novel persistent voltage-dependent
      sodium current in small DRG neurons of both SNS-null and wild-type mice. Like SNS
      currents, this current is highly resistant to TTX (Ki = 39+/-9 microM). In
      contrast to SNS currents, the threshold for activation of this current is near 70
      mV, the midpoint of steady-state inactivation is -44 +/- 1 mV, and the time
      constant for inactivation is 43+/-4 msec at 20 mV. The presence of this current
      in SNS-null and wild-type mice demonstrates that a distinct sodium channel
      isoform, which we suggest to be NaN, underlies this persistent TTX-R current.
      Importantly, the hyperpolarized voltage-dependence of this current, the
      substantial overlap of its activation and steady-state inactivation curves and
      its persistent nature suggest that this current is active near resting potential,
      where it may play an important role in regulating excitability of primary sensory
      neurons.

PMID- 10594088
TI  - Organization of intracortical circuits in relation to direction preference maps
      in ferret visual cortex.
AB  - Neurons in the primary visual cortex are selective for the direction of movement
      of a visual stimulus. Like other stimulus features, direction preference is
      mapped on the cortical surface in a systematic manner. Intracortical synaptic
      circuits, in particular inhibitory connections, have been implicated in the
      emergence of direction selectivity. Whether intracortical inhibition specifically
      suppresses responses to the nonpreferred direction or has a nonspecific
      "thresholding" effect is still controversial. To address these questions we
      investigated the relationship between patterns of intracortical synaptic
      connections and direction domains in ferret primary visual cortex (area 17) using
      a combined in vivo-in vitro approach. Excitatory synaptic inputs were iso
      direction-tuned. The majority of local inhibitory inputs were also iso-direction
      tuned. However, approximately 40% of inhibitory connections originated in regions
      preferring the opposite direction. These findings indicate that specific
      inhibitory interactions between cortical regions of opposite direction preference
      may contribute to the emergence and sharpening of direction selectivity.

PMID- 10594089
TI  - Cerebellar cortical AMPA-kainate receptor blockade prevents performance of
      classically conditioned nictitating membrane responses.
AB  - Classical conditioning of the nictitating membrane-eye blink response of rabbits
      is a simple form of associative motor learning. Lesion studies have shown that
      performance of learned responses is dependent on the cerebellum, but they have
      not shown whether there is storage of memories within the cerebellum or
      distinguished the roles of the cerebellar cortex and nuclei. Reversible
      inactivations of the cerebellar nuclei have directly implicated the cerebellum in
      the acquisition of nictitating membrane conditioning, but previously the
      cerebellar cortex has not been reversibly inactivated to assess its contribution
      to the performance or acquisition of conditioned responses. Here we use the water
      soluble disodium salt of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) reversibly
      to block cerebellar cortical AMPA-kainate receptors in lobule HVI and
      quantitative autoradiography to map its distribution. Conditioned responses are
      completely, but reversibly, abolished for 10-60 min depending on the
      concentration of the CNQX infusion and its location within HVI. Zebrin
      immunohistochemistry was used to define the optimal cortical infusion site that,
      we suggest, corresponds to the location of the eye blink control regions. We
      confirm that areas in HVI are essential for the expression of classically
      conditioned nictitating membrane responses, and we establish a method to analyze
      the role of cerebellar cortex in the acquisition of this form of motor learning.

PMID- 10594090
TI  - Regulation of terminal Schwann cell number at the adult neuromuscular junction.
AB  - Terminal Schwann cells (TSCs), neuroglia that cover motoneuron terminals, play a
      role in regulating the structure and function of the neuromuscular junction. In
      rats, the number of TSCs at each junction increases rapidly in early postnatal
      life and more slowly in young adults. It is possible that TSC number increases to
      match increasing endplate area. Alternatively, the increase in TSC number may
      reflect a developmental process independent of endplate size or terminal
      function. To experimentally test the relationship between endplate size and TSC
      number, we manipulated endplate area in an androgen-sensitive muscle of the rat,
      the levator ani (LA), by castration and by androgen replacement. We found that
      TSC number not only increased as endplates enlarged but also decreased when
      endplates shrank. Ninety days after castration, TSC number decreased by
      approximately 20% (one cell per junction) as endplate size decreased by 30%.
      These effects were reversed by testosterone. Testosterone levels did not affect
      TSC number in the extensor digitorum longus (EDL) muscle, where endplate area was
      unaffected by castration or testosterone treatment. TSC number was, however,
      significantly correlated with endplate area in both LA and EDL muscles.
      Furthermore, the relationship between endplate size and TSC number, as defined by
      the slope of the regression line, was the same in LA and EDL muscles, indicating
      that this relationship is not a unique feature of the LA muscle. These data
      suggest that TSC number is a dynamic property of the neuromuscular synapse that
      is actively regulated throughout life.

PMID- 10594091
TI  - Phenotypic interaction between temperature-sensitive paralytic mutants comatose
      and paralytic suggests a role for N-ethylmaleimide-sensitive fusion factor in
      synaptic vesicle cycling in Drosophila.
AB  - The temperature-induced paralysis of comatose (comt) mutants of Drosophila is
      suggestive of a function for N-ethylmaleimide-sensitive fusion factor (NSF) in
      the CNS. Mutations in the para gene encoding the subunit of the voltage-gated
      sodium channel also result in a similar phenotype. We show that paralysis in comt
      flies is activity-dependent, and in the doubly mutant comt para flies comt-like
      paralysis does not set in until the effects of para are reversed by shifting to
      permissive temperatures. During recording from the thoracic flight muscles, we
      observed that comt flies showed a burst of spontaneous activity at restrictive
      temperature. This has been reported earlier as a unique characteristic of comt
      paralysis. The comt para double mutant showed this burst of activity not at
      restrictive but only on shifting back to permissive temperature. The unusual
      behavior and electrophysiology of the doubly mutant flies reported here indicates
      a role for NSF in synaptic vesicle cycling.

PMID- 10594092
TI  - Functional inactivation of the amygdala before but not after auditory fear
      conditioning prevents memory formation.
AB  - Two competing theories predict different effects on memory consolidation when the
      amygdala is inactivated after fear conditioning. One theory, based on studies
      using inhibitory avoidance training, proposes that the amygdala modulates the
      strength of fear learning, and post-training amygdala manipulations interfere
      with memory consolidation. The other, based on studies using Pavlovian fear
      conditioning, hypothesizes that fear learning occurs in the amygdala, and post
      training manipulations after acquisition will not affect memory consolidation. We
      infused the GABAA agonist muscimol (4.4 nmol/side) or vehicle into lateral and
      basal amygdala (LBA) of rats either before or immediately after tone-foot shock
      Pavlovian fear conditioning. Pre-training infusions eliminated acquisition,
      whereas post-training infusions had no effect. These findings indicate that
      synaptic activity in LBA is necessary during learning, but that amygdala
      inactivation directly after training does not affect memory consolidation.
      Results suggest that essential aspects of plasticity underlying auditory fear
      conditioning take place within LBA during learning.

PMID- 10594093
TI  - Pretraining prevents spatial learning impairment after saturation of hippocampal
      long-term potentiation.
AB  - Spatial learning is impaired by NMDA receptor antagonists at doses that block
      hippocampal long-term potentiation (LTP). The deficit is not observed in animals
      that have received spatial or nonspatial pretraining in a different water maze.
      To determine whether this conditional impairment reflects debilitating
      sensorimotor effects of NMDA receptor antagonists in na?ve animals, we compared
      spatial learning in na?ve and pretrained animals in which induction of LTP was
      blocked by a saturation procedure with no obvious effects on sensorimotor
      functions. Rats with unilateral hippocampal lesions were implanted with multiple
      bipolar stimulation electrodes in the angular bundle and a recording electrode in
      the dentate gyrus of the intact hemisphere. Half of the rats were pretrained to
      find a hidden platform in a water maze. A week later, pretrained and na?ve rats
      received either high-frequency (HF) or low-frequency (LF) stimulation at 2 hr
      intervals, until no further LTP could be induced. The stimulation did not
      interefere with performance on a balance task or a visual platform task. After
      stimulation, all rats were trained in a second water maze. Whereas na?ve HF
      animals were impaired, pretrained HF animals acquired the new task rapidly and
      searched as extensively around the platform as LF control animals. These results
      suggest that pretraining prevents disruption of spatial learning after saturation
      of LTP in the absence of sensorimotor impairment, that hippocampal LTP might not
      be crucial for spatial representation per se, and that LTP may be involved only
      when spatial and contextual or procedural learning take place simultaneously.

PMID- 10594094
TI  - Prokaryotes and phytochrome. The connection to chromophores and signaling

PMID- 10594095
TI  - Apoplastic pH and Fe(3+) reduction in intact sunflower leaves
AB  - It has been hypothesized that under NO(3)(-) nutrition a high apoplastic pH in
      leaves depresses Fe(3+) reductase activity and thus the subsequent Fe(2+)
      transport across the plasmalemma, inducing Fe chlorosis. The apoplastic pH in
      young green leaves of sunflower (Helianthus annuus L.) was measured by
      fluorescence ratio after xylem sap infiltration. It was shown that NO(3)(-)
      nutrition significantly increased apoplastic pH at distinct interveinal sites (pH
      >/= 6.3) and was confined to about 10% of the whole interveinal leaf apoplast.
      These apoplastic pH increases presumably derive from NO(3)(-)/proton cotransport
      and are supposed to be related to growing cells of a young leaf; they were not
      found in the case of sole NH(4)(+) or NH(4)NO(3) nutrition. Complementary to pH
      measurements, the formation of Fe(2+)-ferrozine from Fe(3+)-citrate was monitored
      in the xylem apoplast of intact leaves in the presence of buffers at different
      xylem apoplastic pH by means of image analysis. This analysis revealed that
      Fe(3+) reduction increased with decreasing apoplastic pH, with the highest rates
      at around pH 5. 0. In analogy to the monitoring of Fe(3+) reduction in the leaf
      xylem, we suggest that under alkaline nutritional conditions at interveinal
      microsites of increased apoplastic pH, Fe(3+) reduction is depressed, inducing
      leaf chlorosis. The apoplastic pH in the xylem vessels remained low in the still
      green veins of leaves with intercostal chlorosis.

PMID- 10594096
TI  - Characterization and expression of four proline-rich cell wall protein genes in
      Arabidopsis encoding two distinct subsets of multiple domain proteins.
AB  - We have characterized the molecular organization and expression of four proline
      rich protein genes from Arabidopsis (AtPRPs). These genes predict two classes of
      cell wall proteins based on DNA sequence identity, repetitive motifs, and domain
      organization. AtPRP1 and AtPRP3 encode proteins containing an N-terminal PRP-like
      domain followed by a C-terminal domain that is biased toward P, T, Y, and K.
      AtPRP2 and AtPRP4 represent a second, novel group of PRP genes that encode two
      domain proteins containing a non-repetitive N-terminal domain followed by a PRP
      like region rich in P, V, K, and C. Northern hybridization analysis indicated
      that AtPRP1 and AtPRP3 are exclusively expressed in roots, while transcripts
      encoding AtPRP2 and AtPRP4 were most abundant in aerial organs of the plant.
      Histochemical analyses of promoter/beta-glucuronidase fusions localized AtPRP3
      expression to regions of the root containing root hairs. AtPRP2 and AtPRP4
      expression was detected in expanding leaves, stems, flowers, and siliques. In
      addition, AtPRP4 expression was detected in stipules and during the early stages
      of lateral root formation. These studies support a model for involvement of PRPs
      in specifying cell-type-specific wall structures, and provide the basis for a
      genetic approach to dissect the function of PRPs during growth and development.

PMID- 10594097
TI  - Requirement of functional ethylene-insensitive 2 gene for efficient resistance of
      Arabidopsis to infection by Botrytis cinerea.
AB  - Inoculation of wild-type Arabidopsis plants with the fungus Alternaria
      brassicicola results in systemic induction of genes encoding a plant defensin
      (PDF1.2), a basic chitinase (PR-3), and an acidic hevein-like protein (PR-4).
      Pathogen-induced induction of these three genes is almost completely abolished in
      the ethylene-insensitive Arabidopsis mutant ein2-1. This indicates that a
      functional ethylene signal transduction component (EIN2) is required in this
      response. The ein2-1 mutants were found to be markedly more susceptible than wild
      type plants to infection by two different strains of the gray mold fungus
      Botrytis cinerea. In contrast, no increased fungal colonization of ein2-1 mutants
      was observed after challenge with avirulent strains of either Peronospora
      parasitica or A. brassicicola. Our data support the conclusion that ethylene
      controlled responses play a role in resistance of Arabidopsis to some but not all
      types of pathogens.

PMID- 10594098
TI  - Genes expressed in Pinus radiata male cones include homologs to anther-specific
      and pathogenesis response genes.
AB  - We describe the isolation and characterization of 13 cDNA clones that are
      differentially expressed in male cones of Pinus radiata (D. Don). The transcripts
      of the 13 genes are expressed at different times between meiosis and microspore
      mitosis, timing that corresponds to a burst in tapetal activity in the developing
      anthers. In situ hybridization showed that four of the genes are expressed in the
      tapetum, while a fifth is expressed in tetrads during a brief developmental
      window. Six of the seven cDNAs identified in database searches have striking
      similarity to genes expressed in angiosperm anthers. Seven cDNAs are homologs of
      defense and pathogen response genes. The cDNAs identified are predicted to encode
      a chalcone-synthase-like protein, a thaumatin-like protein, a serine hydrolase
      thought to be a putative regulator of programmed cell death, two lipid-transfer
      proteins, and two homologs of the anther-specific A9 genes from Brassica napus
      and Arabidopsis. Overall, our results support the hypothesis that many of the
      reproductive processes in the angiosperms and gymnosperms were inherited from a
      common ancestor.

PMID- 10594099
TI  - Molecular dissection of the role of histidine in nickel hyperaccumulation in
      Thlaspi goesingense (Halacsy).
AB  - To understand the role of free histidine (His) in Ni hyperaccumulation in Thlaspi
      goesingense, we investigated the regulation of His biosynthesis at both the
      molecular and biochemical levels. Three T. goesingense cDNAs encoding the
      following His biosynthetic enzymes, ATP phosphoribosyltransferase (THG1, GenBank
      accession no. AF003347), imidazoleglycerol phosphate dehydratase (THB1, GenBank
      accession no. AF023140), and histidinol dehydrogenase (THD1, GenBank accession
      no. AF023141) were isolated by functional complementation of Escherichia coli His
      auxotrophs. Northern analysis of THG1, THD1, and THB1 gene expression revealed
      that each gene is expressed in both roots and shoots, but at the concentrations
      and dosage times of Ni treatment used in this study, these genes failed to show
      any regulation by Ni. We were also unable to observe any increases in the
      concentration of free His in root, shoot, or xylem sap of T. goesingense in
      response to Ni exposure. X-ray absorption spectroscopy of root and shoot tissue
      from T. goesingense and the non-accumulator species Thlaspi arvense revealed no
      major differences in the coordination of Ni by His in these tissues. We therefore
      conclude that the Ni hyperaccumulation phenotype in T. goesingense is not
      determined by the overproduction of His in response to Ni.

PMID- 10594100
TI  - Stop-and-go movements of plant Golgi stacks are mediated by the acto-myosin
      system.
AB  - The Golgi apparatus in plant cells consists of a large number of independent
      Golgi stack/trans-Golgi network/Golgi matrix units that appear to be randomly
      distributed throughout the cytoplasm. To study the dynamic behavior of these
      Golgi units in living plant cells, we have cloned a cDNA from soybean (Glycine
      max), GmMan1, encoding the resident Golgi protein alpha-1,2 mannosidase I. The
      predicted protein of approximately 65 kD shows similarity of general structure
      and sequence (45% identity) to class I animal and fungal alpha-1,2 mannosidases.
      Expression of a GmMan1::green fluorescent protein fusion construct in tobacco
      (Nicotiana tabacum) Bright Yellow 2 suspension-cultured cells revealed the
      presence of several hundred to thousands of fluorescent spots. Immuno-electron
      microscopy demonstrates that these spots correspond to individual Golgi stacks
      and that the fusion protein is largely confined to the cis-side of the stacks. In
      living cells, the stacks carry out stop-and-go movements, oscillating rapidly
      between directed movement and random "wiggling." Directed movement (maximal
      velocity 4.2 microm/s) is related to cytoplasmic streaming, occurs along straight
      trajectories, and is dependent upon intact actin microfilaments and myosin
      motors, since treatment with cytochalasin D or butanedione monoxime blocks the
      streaming motion. In contrast, microtubule-disrupting drugs appear to have a
      small but reproducible stimulatory effect on streaming behavior. We present a
      model that postulates that the stop-and-go motion of Golgi-trans-Golgi network
      units is regulated by "stop signals" produced by endoplasmic reticulum export
      sites and locally expanding cell wall domains to optimize endoplasmic reticulum
      to Golgi and Golgi to cell wall trafficking.

PMID- 10594101
TI  - Identification of a promoter sequence from the BETL1 gene cluster able to confer
      transfer-cell-specific expression in transgenic maize
AB  - The maize (Zea mays L.) betl1 locus, encoding a basal endosperm transfer layer
      specific protein, has been mapped and molecularly cloned in its entirety. The
      locus is shown to consist of three gene copies in the maize inbred line A69Y. To
      distinguish the three transcription units from the locus name, we have termed
      them BETL1a, BETL1b, and BETL1c. Two of the copies are expressed, whereas one is
      inactive and contains retrotransposon-like insertions in both promoter and intron
      regions. Based on this information, and a restriction site map covering 17 kb
      around the BETL1 locus, a DNA fragment putatively containing an active promoter
      sequence was identified. This fragment was tested for its ability to confer
      transfer-cell-specific expression in transient and stably transformed maize
      tissues. The transgenic maize plants obtained showed the predicted cell-type
      specificity of expression restricted to the basal endosperm transfer cells,
      although there were minor deviations in promoter strength and timing and
      accumulation of the transgene product from the corresponding BETL-1 endogene
      expression pattern.

PMID- 10594102
TI  - Developmental and wound-, cold-, desiccation-, ultraviolet-B-stress-induced
      modulations in the expression of the petunia zinc finger transcription factor
      gene ZPT2-2
AB  - The ZPT2-2 gene belongs to the EPF gene family in petunia (Petunia hybrida),
      which encodes proteins with TFIIIA-type zinc-finger DNA-binding motifs. To
      elucidate a possible function for ZPT2-2, we analyzed its pattern of expression
      in relation to different developmental and physiological stress signals. The
      activity of the ZPT2-2 promoter was analyzed using a firefly luciferase (LUC)
      reporter gene, allowing for continuous measurements of transgene activity in
      planta. We show that ZPT2-2::LUC is active in all plant tissues, but is strongly
      modulated in cotyledons upon germination, in leaves in response to desiccation,
      cold treatment, wounding, or ultraviolet-B light, and in petal tissue in response
      to pollination of the stigma. Analysis of mRNA levels indicated that the
      modulations in ZPT2-2::LUC expression reflect modulations in endogenous ZPT2-2
      gene expression. The change in ZPT2-2::LUC activity by cold treatment, wounding,
      desiccation, and ultraviolet-B light suggest that the phytohormones ethylene and
      jasmonic acid are involved in regulating the expression of ZPT2-2. Although up
      regulation of expression of ZPT2-2 can be blocked by inhibitors of ethylene
      perception, expression in plants is not induced by exogenously applied ethylene.
      The application of jasmonic acid does result in an up-regulation of gene activity
      and, thus, ZPT2-2 may play a role in the realization of the jasmonic acid
      hormonal responses in petunia.

PMID- 10594103
TI  - Disruption of auxin transport is associated with aberrant leaf development in
      maize
AB  - Despite recent progress, the mechanisms governing shoot morphogenesis in higher
      plants are only partially understood. Classical physiological studies have
      suggested that gradients of the plant growth regulator auxin may play a role in
      controlling tissue differentiation in shoots. More recent molecular genetic
      studies have also identified knotted1 like homeobox (knox) genes as important
      regulators of shoot development. The maize (Zea mays L.) mutant rough sheath2
      (rs2) displays ectopic expression of at least three knox genes and consequently
      conditions a range of shoot and leaf phenotypes, including aberrant vascular
      development, ligular displacements, and dwarfism (R. Schneeberger, M. Tsiantis,
      M. Freeling, J.A. Langdale [1998] Development 125: 2857-2865). In this report, we
      show that rs2 mutants also display decreased polar auxin transport in the shoot.
      We also demonstrate that germination of wild-type maize seedlings on agents known
      to inhibit polar auxin transport mimics aspects of the rs2 mutant phenotype. The
      phenotype elaborated in inhibitor-treated plants is not correlated with ectopic
      KNOX protein accumulation.

PMID- 10594104
TI  - Cadmium tolerance and accumulation in Indian mustard is enhanced by
      overexpressing gamma-glutamylcysteine synthetase.
AB  - To investigate rate-limiting factors for glutathione and phytochelatin (PC)
      production and the importance of these compounds for heavy metal tolerance,
      Indian mustard (Brassica juncea) was genetically engineered to overexpress the
      Escherichia coli gshI gene encoding gamma-glutamylcysteine synthetase (gamma
      ECS), targeted to the plastids. The gamma-ECS transgenic seedlings showed
      increased tolerance to Cd and had higher concentrations of PCs, gamma-GluCys,
      glutathione, and total non-protein thiols compared with wild-type (WT) seedlings.
      When tested in a hydroponic system, gamma-ECS mature plants accumulated more Cd
      than WT plants: shoot Cd concentrations were 40% to 90% higher. In spite of their
      higher tissue Cd concentration, the gamma-ECS plants grew better in the presence
      of Cd than WT. We conclude that overexpression of gamma-ECS increases
      biosynthesis of glutathione and PCs, which in turn enhances Cd tolerance and
      accumulation. Thus, overexpression of gamma-ECS appears to be a promising
      strategy for the production of plants with superior heavy metal phytoremediation
      capacity.

PMID- 10594105
TI  - Auxin is required for leaf vein pattern in Arabidopsis.
AB  - To investigate possible roles of polar auxin transport in vein patterning,
      cotyledon and leaf vein patterns were compared for plants grown in medium
      containing polar auxin transport inhibitors (N-1-naphthylphthalamic acid, 9
      hydroxyfluorene-9-carboxylic acid, and 2,3,5-triiodobenzoic acid) and in medium
      containing a less well-characterized inhibitor of auxin-mediated processes, 2-(p
      chlorophynoxy)-2-methylpropionic acid. Cotyledon vein pattern was not affected by
      any inhibitor treatments, although vein morphology was altered. In contrast, leaf
      vein pattern was affected by inhibitor treatments. Growth in polar auxin
      transport inhibitors resulted in leaves that lacked vascular continuity through
      the petiole and had broad, loosely organized midveins, an increased number of
      secondary veins, and a dense band of misshapen tracheary elements adjacent to the
      leaf margin. Analysis of leaf vein pattern developmental time courses suggested
      that the primary vein did not develop in polar auxin transport inhibitor-grown
      plants, and that the broad midvein observed in these seedlings resulted from the
      coalescence of proximal regions of secondary veins. Possible models for leaf vein
      patterning that could account for these observations are discussed.

PMID- 10594106
TI  - Direct measurement of xylem pressure in leaves of intact maize plants. A test of
      the cohesion-tension theory taking hydraulic architecture into consideration
AB  - The water relations of maize (Zea mays L. cv Helix) were documented in terms of
      hydraulic architecture and xylem pressure. A high-pressure flowmeter was used to
      characterize the hydraulic resistances of the root, stalk, and leaves. Xylem
      pressure measurements were made with a Scholander-Hammel pressure bomb and with a
      cell pressure probe. Evaporation rates were measured by gas exchange and by
      gravimetric measurements. Xylem pressure was altered by changing the light
      intensity, by controlling irrigation, or by gas pressure applied to the soil mass
      (using a root pressure bomb). Xylem pressure measured by the cell pressure probe
      and by the pressure bomb agreed over the entire measured range of 0 to -0.7 MPa.
      Experiments were consistent with the cohesion-tension theory. Xylem pressure
      changed rapidly and reversibly with changes in light intensity and root-bomb
      pressure. Increasing the root-bomb pressure increased the evaporation rate
      slightly when xylem pressure was negative and increased water flow rate through
      the shoots dramatically when xylem pressure was positive and guttation was
      observed. The hydraulic architecture model could predict all observed changes in
      water flow rate and xylem. We measured the cavitation threshold for oil- and
      water-filled pressure probes and provide some suggestions for improvement.

PMID- 10594107
TI  - Both phyA and phyB mediate light-imposed repression of PHYA gene expression in
      Arabidopsis.
AB  - The negatively photoregulated PHYA gene has a complex promoter structure in
      Arabidopsis, with three active transcription start sites. To identify the
      photoreceptors responsible for regulation of this gene, and to assess the
      relative roles of the three transcription start sites, we analyzed the changes in
      PHYA transcript levels in wild-type and photoreceptor mutant seedlings under
      various irradiation conditions. Continuous far-red or red light exposures each
      induced a significant decline in transcript levels in wild-type etiolated
      seedlings. Analysis of mutants specifically lacking either phyA or phyB protein
      demonstrated that these phytochromes are required for the negative regulation
      induced by far-red and red light, respectively. Ribonuclease protection
      experiments showed further that this negative regulation is confined almost
      exclusively to the shortest, most abundant PHYA transcript, and occurs
      predominantly in shoots. By contrast, both of the other minor transcripts in
      shoots, and all three transcripts in roots, exhibit near constitutive expression.
      This complex expression pattern indicates that the PHYA gene is subject to
      regulation by multiple signals, including environmental, developmental, and organ
      specific signals.

PMID- 10594108
TI  - Testing models of fatty acid transfer and lipid synthesis in spinach leaf using
      in vivo oxygen-18 labeling.
AB  - Oxygen-18 labeling has been applied to the study of plant lipid biosynthesis for
      the first time. [(13)C(2)(18)O(2)]Acetate was incubated with spinach (Spinacia
      oleracea) leaves and the (18)O content in fatty acid methyl esters isolated from
      different lipid classes measured by gas chromatography-mass spectometry. Fatty
      acids isolated from lipids synthesized within the plastid, such as
      monogalactosyldiacylglycerol, show an (18)O content consistent with the exogenous
      acetate undergoing a single activation step and with the direct utilization of
      acyl-acyl carrier protein by the acyl transferases of the chloroplast. In
      contrast, fatty acids isolated from lipids assembled in the cytosol, such as
      phosphatidylcholine, show a 50% reduction in the (18)O content. This is
      indicative of export of the fatty acyl groups from the plastid via a free
      carboxylate anion, and is consistent with the acyl-acyl carrier protein
      thioesterase:acyl-coenzyme A (CoA) synthetase mediated export mechanism. If this
      were not the case and the acyl group was transferred directly from acyl-acyl
      carrier protein to an acyl acceptor on the cytosolic side, there would be either
      complete retention of (18)O or, less likely, complete loss of (18)O, but not a
      50% loss of (18)O. Thus, existing models for fatty acid transfer from the plastid
      and for spatially separate synthesis of "prokaryotic" and "eukaryotic" lipids
      have both been confirmed.

PMID- 10594109
TI  - Soil compaction. A role for ethylene in regulating leaf expansion and shoot
      growth in tomato?
AB  - The role of ethylene in regulating growth in tomato (Lycopersicon esculentum
      Mill.) during compaction stress was examined using wild-type (cv Ailsa Craig) and
      transgenic (ACO1(AS)) genotypes; the latter has a reduced capacity to produce
      ethylene. Ethephon or silver ions were applied to increase ethylene production or
      block its action. Shoot growth in both genotypes was comparable in uncompacted
      (1.1 g cm(-3)) and uniformly compacted soil (1.5 g cm(-3)). However, a 1.1/1.5-g
      cm(-3) split-pot treatment invoked marked genotypic differences: growth was
      reduced in cv Ailsa Craig but was comparable to uncompacted control plants in
      ACO1(AS). As xylem sap abscisic acid levels were similar, abscisic acid was not
      responsible for inhibiting growth in cv Ailsa Craig. These genotypic differences
      in growth were accompanied by increased ethylene evolution in cv Ailsa Craig,
      suggesting that the ability of ACO1(AS) to maintain growth in the split-pot
      treatment reflected its lower ethylene levels, a view supported by the
      observation that excising the roots in the compacted compartment reduced ethylene
      evolution and restored shoot growth in cv Ailsa Craig. Treatment with silver
      restored shoot growth in cv Ailsa Craig, whereas treatment with ethephon reduced
      growth in ACO1(AS). Thus, ethylene apparently has a key role in determining
      growth when tomato plants encounter differential soil compaction.

PMID- 10594110
TI  - Wound-induced expression of the FAD7 gene is mediated by different regulatory
      domains of its promoter in leaves/stems and roots.
AB  - The FAD7 gene is expressed preferentially in the chlorophyllous tissues of
      unwounded plants. Wounding activates the expression of the FAD7 gene not only in
      chlorophyllous tissues, but also in nonchlorophyllous tissues of stems and roots.
      Our previous study suggested that wound-responsive transcriptional activation by
      the FAD7 promoter in leaves/stems and roots is brought about by a jasmonic acid
      (JA)-independent and JA-dependent signaling pathway, respectively. In this paper,
      we show that a specific region (from -259 to -198) in the FAD7 promoter is
      required for wound-activated expression of this gene in leaves and stems, while
      another region (from -521 to -363) is necessary not only for wound-activated but
      also for JA-responsive expression of this gene in roots. Thus, different
      regulatory regions of the FAD7 promoter mediate distinct wound-induced expression
      of this gene in leaves/stems and roots. Gel mobility shift assays revealed the
      wound-inducible DNA-binding activity to the -242/-223 region in both stem and
      leaf nuclear extracts. In fact, deletion of this region abolished wound response
      of the FAD7 promoter, suggesting the in vivo role of this site. Furthermore, we
      detected root nuclear factors interacting with the region from -433 to -363 of
      this promoter. Wounding and methyl jasmonate treatments induced differently these
      DNA-binding activities. These results suggest that different regulatory
      mechanisms mediate the wound-induced expression of the FAD7 gene in aerial and
      subterranean organs.

PMID- 10594111
TI  - Evidence for an inorganic carbon-concentrating mechanism in the symbiotic
      dinoflagellate Symbiodinium sp.
AB  - The presence of a carbon-concentrating mechanism in the symbiotic dinoflagellate
      Symbiodinium sp. was investigated. Its existence was postulated to explain how
      these algae fix inorganic carbon (C(i)) efficiently despite the presence of a
      form II Rubisco. When the dinoflagellates were isolated from their host, the
      giant clam (Tridacna gigas), CO(2) uptake was found to support the majority of
      net photosynthesis (45%-80%) at pH 8.0; however, 2 d after isolation this
      decreased to 5% to 65%, with HCO(3)(-) uptake supporting 35% to 95% of net
      photosynthesis. Measurements of intracellular C(i) concentrations showed that
      levels inside the cell were between two and seven times what would be expected
      from passive diffusion of C(i) into the cell. Symbiodinium also exhibits a
      distinct light-activated intracellular carbonic anhydrase activity. This, coupled
      with elevated intracellular C(i) and the ability to utilize both CO(2) and
      HCO(3)(-) from the medium, suggests that Symbiodinium sp. does possess a carbon
      concentrating mechanism. However, intracellular C(i) levels are not as large as
      might be expected of an alga utilizing a form II Rubisco with a poor affinity for
      CO(2).

PMID- 10594112
TI  - Characterization of ethylene biosynthesis associated with ripening in banana
      fruit.
AB  - We investigated the characteristics of ethylene biosynthesis associated with
      ripening in banana (Musa sp. [AAA group, Cavendish subgroup] cv Grand Nain)
      fruit. MA-ACS1 encoding 1-aminocyclopropane-1-carboxylic acid (ACC) synthase in
      banana fruit was the gene related to the ripening process and was inducible by
      exogenous ethylene. At the onset of the climacteric period in naturally ripened
      fruit, ethylene production increased greatly, with a sharp peak concomitant with
      an increase in the accumulation of MA-ACS1 mRNA, and then decreased rapidly. At
      the onset of ripening, the in vivo ACC oxidase activity was enhanced greatly,
      followed by an immediate and rapid decrease. Expression of the MA-ACO1 gene
      encoding banana ACC oxidase was detectable at the preclimacteric stage, increased
      when ripening commenced, and then remained high throughout the later ripening
      stage despite of a rapid reduction in the ACC oxidase activity. This discrepancy
      between enzyme activity and gene expression of ACC oxidase could be, at least in
      part, due to reduced contents of ascorbate and iron, cofactors for the enzyme,
      during ripening. Addition of these cofactors to the incubation medium greatly
      stimulated the in vivo ACC oxidase activity during late ripening stages. The
      results suggest that ethylene production in banana fruit is regulated by
      transcription of MA-ACS1 until climacteric rise and by reduction of ACC oxidase
      activity possibly through limited in situ availability of its cofactors once
      ripening has commenced, which in turn characterizes the sharp peak of ethylene
      production.

PMID- 10594113
TI  - The PsbY protein is not essential for oxygenic photosynthesis in the
      cyanobacterium Synechocystis sp. PCC 6803.
AB  - A tetra-manganese cluster in the photosystem II (PSII) pigment-protein complex
      plays a critical role in the photosynthetic oxygen evolution process. PsbY, a
      small membrane-spanning polypeptide, has recently been suggested to provide a
      ligand for manganese in PSII (A.E. Gau, H.H. Thole, A. Sokolenko, L. Altschmied,
      R.G. Herrmann, E.K. Pistorius [1998] Mol Gen Genet 260: 56-68). We have
      constructed a mutant strain of the cyanobacterium Synechocystis sp. PCC 6803 with
      an inactivated psbY gene (sml0007). Southern-blot and polymerase chain reaction
      analysis showed that the mutant had completely segregated. However, the DeltapsbY
      mutant cells grew normally under photoautotrophic conditions. Moreover, growth of
      the wild-type and mutant cells were similar under high-light photoinhibition
      conditions, as well as in media without any added manganese, calcium, or
      chloride, three required inorganic cofactors for the oxygen-evolving complex of
      PSII. Analysis of steady-state and flash-induced oxygen evolution, fluorescence
      induction, and decay kinetics, and thermoluminescence profiles demonstrated that
      the DeltapsbY mutant cells have normal photosynthetic activities. We conclude
      that the PsbY protein in Synechocystis 6803 is not essential for oxygenic
      photosynthesis and does not provide an important binding site for manganese in
      the oxygen-evolving complex of PSII.

PMID- 10594114
TI  - An expansin gene expressed in ripening strawberry fruit.
AB  - Tissue softening accompanies the ripening of many fruit and initiates the
      processes of irreversible deterioration. Expansins are plant cell wall proteins
      proposed to disrupt hydrogen bonds within the cell wall polymer matrix.
      Expression of specific expansin genes has been observed in tomato (Lycopersicon
      esculentum) meristems, expanding tissues, and ripening fruit. It has been
      proposed that a tomato ripening-regulated expansin might contribute to cell wall
      polymer disassembly and fruit softening by increasing the accessibility of
      specific cell wall polymers to hydrolase action. To assess whether ripening
      regulated expansins are present in all ripening fruit, we examined expansin gene
      expression in strawberry (Fragaria x ananassa Duch.). Strawberry differs
      significantly from tomato in that the fruit is derived from receptacle rather
      than ovary tissue and strawberry is non-climacteric. A full-length cDNA encoding
      a ripening-regulated expansin, FaExp2, was isolated from strawberry fruit. The
      deduced amino acid sequence of FaExp2 is most closely related to an expansin
      expressed in early tomato development and to expansins expressed in apricot fruit
      rather than the previously identified tomato ripening-regulated expansin, LeExp1.
      Nearly all previously identified ripening-regulated genes in strawberry are
      negatively regulated by auxin. Surprisingly, FaExp2 expression was largely
      unaffected by auxin. Overall, our results suggest that expansins are a common
      component of ripening and that non-climacteric signals other than auxin may
      coordinate the onset of ripening in strawberry.

PMID- 10594115
TI  - Proline metabolism in the wild-type and in a salt-tolerant mutant of nicotiana
      plumbaginifolia studied by (13)C-nuclear magnetic resonance imaging
AB  - To obtain insight into the link between proline (Pro) accumulation and the
      increase in osmotolerance in higher plants, we investigated the biochemical basis
      for the NaCl tolerance of a Nicotiana plumbaginifolia mutant (RNa) that
      accumulates Pro. Pro biosynthesis and catabolism were investigated in both wild
      type and mutant lines. (13)C-Nuclear magnetic resonance with [5-(13)C]glutamate
      (Glu) as the Pro precursor was used to provide insight into the mechanism of Pro
      accumulation via the Glu pathway. After 24 h under 200 mM NaCl stress in the
      presence of [5-(13)C]Glu, a significant enrichment in [5-(13)C]Pro was observed
      compared with non-stress conditions in both the wild type (P2) and the mutant
      (RNa). Moreover, under the same conditions, [5-(13)C]Pro was clearly synthesized
      in higher amounts in RNa than in P2. On the other hand, measurements of enzyme
      activities indicate that neither the biosynthesis via the ornithine pathway, nor
      the catabolism via the Pro oxidation pathway were affected in the RNa mutant.
      Finally, the regulatory effect exerted by Pro on its biosynthesis was evaluated.
      In P2 plantlets, exogenous Pro markedly reduced the conversion of [5-(13)C]Glu
      into [5-(13)C]Pro, whereas Pro feedback inhibition was not detected in the RNa
      plantlets. It is proposed that the origin of tolerance in the RNa mutant is due
      to a mutation leading to a substantial reduction of the feedback inhibition
      normally exerted in a wild-type (P2) plant by Pro at the level of the Delta
      pyrroline-5-carboxylate synthetase enzyme.

PMID- 10594116
TI  - Changes in cytosolic pH within Arabidopsis root columella cells play a key role
      in the early signaling pathway for root gravitropism.
AB  - Ratiometric wide-field fluorescence microscopy with 1',7'- bis-(2-carboxyethyl)-5
      (and-6)-carboxyfluorescein (BCECF)-dextran demonstrated that gravistimulation
      leads to rapid changes in cytoplasmic pH (pHc) in columella cells of Arabidopsis
      roots. The pHc of unstimulated columella cells in tiers 2 and 3, known sites of
      graviperception (E.B. Blancaflor, J.B. Fasano, S. Gilroy [1998] Plant Physiol
      116: 213-222), was 7.22 +/- 0.02 pH units. Following gravistimulation, the
      magnitude and direction of pHc changes in these cells depended on their location
      in the columella. Cells in the lower side of tier 2 became more alkaline by 0.4
      unit within 55 s of gravistimulation, whereas alkalinization of the cells on the
      upper side was slower (100 s). In contrast, all cells in tier 3 acidified by 0.4
      pH unit within 480 s after gravistimulation. Disrupting these pHc changes in the
      columella cells using pHc modifiers at concentrations that do not affect root
      growth altered the gravitropic response. Acidifying agents, including bafilomycin
      A1, enhanced curvature, whereas alkalinizing agents disrupted gravitropic
      bending. These results imply that pHc changes in the gravisensing cells and the
      resultant pH gradients across the root cap are important at an early stage in the
      signal cascade leading to the gravitropic response.

PMID- 10594117
TI  - N-Acylethanolamines in signal transduction of elicitor perception. Attenuation Of
      alkalinization response and activation of defense gene expression
AB  - In a recent study of N-acylphosphatidylethanolamine (NAPE) metabolism in elicitor
      treated tobacco (Nicotiana tabacum L.) cells, we identified a rapid release and
      accumulation of medium-chain N-acylethanolamines (NAEs) (e.g. N
      myristoylethanolamine or NAE 14:0) and a compensatory decrease in cellular NAPE
      (K.D. Chapman, S. Tripathy, B. Venables, A.D. Desouza [1998] Plant Physiol 116:
      1163-1168). In the present study, we extend this observation and report a 10- to
      50-fold increase in NAE 14:0 content in leaves of tobacco (cv Xanthi) plants
      treated with xylanase or cryptogein elicitors. Exogenously supplied synthetic NAE
      species affected characteristic elicitor-induced and short- and long-term defense
      responses in cell suspensions of tobacco and long-term defense responses in
      leaves of intact tobacco plants. In general, synthetic NAEs inhibited elicitor
      induced medium alkalinization by tobacco cells in a time- and concentration
      dependent manner. Exogenous NAE 14:0 induced expression of phenylalanine ammonia
      lyase in a manner similar to fungal elicitors in both cell suspensions and leaves
      of tobacco. NAE 14:0, but not myristic acid, activated phenylalanine ammonia
      lyase expression at submicromolar concentrations, well within the range of NAE
      14:0 levels measured in elicitor-treated plants. Collectively, these results
      suggest that NAPE metabolism, specifically, the accumulation of NAE 14:0, are
      part of a signal transduction pathway that modulates cellular defense responses
      following the perception of fungal elicitors.

PMID- 10594118
TI  - Increased respiratory restriction during phosphate-limited growth in transgenic
      tobacco cells lacking alternative oxidase.
AB  - We found that mitochondrial alternative oxidase (AOX) protein and the capacity
      for CN-resistant respiration are dramatically increased in wild-type tobacco
      (Nicotiana tabacum) suspension-cultured cells in response to growth under P
      limitation, and antisense (AS8) tobacco cells unable to induce AOX under these
      conditions have altered growth and metabolism. Specifically, we found that the
      respiration of AS8 cells was restricted during P-limited growth, when the
      potential for severe adenylate control of respiration (at the level of C supply
      to the mitochondrion and/or at the level of oxidative phosphorylation) is high
      due to the low cellular levels of ADP and/or inorganic P. As a result of this
      respiratory restriction, AS8 cells had altered growth, morphology, cellular
      composition, and patterns of respiratory C flow to amino acid synthesis compared
      with wild-type cells with abundant AOX protein. Also, AS8 cells under P
      limitation displayed high in vivo rates of generation of active oxygen species
      compared with wild-type cells. This difference could be abolished by an uncoupler
      of mitochondrial oxidative phosphorylation. Our results suggest that induction of
      non-phosphorylating AOX respiration (like induction of adenylate and inorganic P
      independent pathways in glycolysis) is an important plant metabolic adaptation to
      P limitation. By preventing severe respiratory restriction, AOX acts to prevent
      both redirections in C metabolism and the excessive generation of harmful active
      oxygen species in the mitochondrion.

PMID- 10594119
TI  - The activity of the maize Opaque2 transcriptional activator is regulated
      diurnally.
AB  - The maize (Zea mays L.) Opaque2 (O2) protein is an endosperm-specific
      transcriptional activator whose DNA-binding activity is regulated diurnally by a
      phosphorylation/dephosphorylation mechanism. We show that the O2 transcript
      undergoes pronounced oscillations during the day-night cycle. The highest level
      of the O2 message is present at midday and the lowest level at midnight. The
      level of O2 transcript follows a diurnal rhythm that appears controlled by the
      circadian clock. Two different endosperm-expressed DNA-binding proteins, PBF
      (prolamin box-binding factor) and OHP1 (O2-heterodimerizing protein 1), were also
      analyzed. While the PBF message levels oscillate diurnally, the steady-state
      levels of OHP1 transcript were constant through the day and night. We present
      data showing that the seed is not directly involved in the perception of the
      light signal, but presumably responds to diurnal fluxes of nutrients into the
      endosperm. Moreover, we show that the O2 protein is not involved in the
      regulation of its own transcript levels. These data indicate that O2 activity is
      down-regulated at night by both a reduction in O2 transcript and by
      hyperphosphorylation of residual O2 protein, and suggest that regulatory gene
      activity during endosperm development may be acutely sensitive to a diurnal
      signal(s) emanating from the plant and passing into the developing seeds.

PMID- 10594120
TI  - CO(2)-responsive transcriptional regulation of CAH1 encoding carbonic anhydrase
      is mediated by enhancer and silencer regions in Chlamydomonas reinhardtii.
AB  - Chlamydomonas reinhardtii adapts to the stress of CO(2)-limiting conditions
      through the induction of a set of genes including CAH1, which encodes a
      periplasmic carbonic anhydrase. CAH1 is up-regulated under low-CO(2) conditions
      (air containing 0.04% [v/v] CO(2)) in the presence of light, whereas it is down
      regulated under high-CO(2) conditions (5% [v/v] CO(2)) or in the dark. In an
      effort to identify cis-elements involved in the transcriptional regulation of
      CAH1, a series of 5'-nested deletions of the region upstream of CAH1 were fused
      to a promoterless arylsulfatase reporter gene (ARS). The upstream region from 
      651 to +41 relative to the transcription start site was sufficient to regulate
      the expression of ARS with kinetics similar to those of endogenous CAH1. Deletion
      of the region between -651 and -294 resulted in a significant decrease in the
      level of arylsulfatase activity expressed under low-CO(2) conditions. The 543-bp
      upstream region from -651 to -109, without any promoter elements, CAAT-box, or
      TATA-box, could confer CO(2) and light responsiveness on the beta(2)-tubulin
      minimal promoter. This 543-bp region was divided into two parts: a 358-bp
      silencer region from -651 to -294, which represses the minimal promoter activity
      under high-CO(2) conditions, and a 185-bp enhancer region from -293 to -109,
      which activates the promoter under low-CO(2) conditions in the presence of light.

PMID- 10594121
TI  - Vacuolar H(+)-ATPase is expressed in response to gibberellin during tomato seed
      germination.
AB  - Completion of germination (radicle emergence) by gibberellin (GA)-deficient (gib
      1) mutant tomato (Lycopersicon esculentum Mill.) seeds is dependent upon
      exogenous GA, because weakening of the endosperm tissue enclosing the radicle tip
      requires GA. To investigate genes that may be involved in endosperm weakening or
      embryo growth, differential cDNA display was used to identify mRNAs
      differentially expressed in gib-1 seeds imbibed in the presence or absence of
      GA(4+7). Among these was a GA-responsive mRNA encoding the 16-kD hydrophobic
      subunit c of the V(0) membrane sector of vacuolar H(+)-translocating ATPases (V
      ATPase), which we termed LVA-P1. LVA-P1 mRNA expression in gib-1 seeds was
      dependent on GA and was particularly abundant in the micropylar region prior to
      radicle emergence. Both GA dependence and tissue localization of LVA-P1 mRNA
      expression were confirmed directly in individual gib-1 seeds using tissue
      printing. LVA-P1 mRNA was also expressed in wild-type seeds during development
      and germination, independent of exogenous GA. Specific antisera detected protein
      subunits A and B of the cytoplasmic V(1) sector of the V-ATPase holoenzyme
      complex in gib-1 seeds only in the presence of GA, and expression was localized
      to the micropylar region. The results suggest that V-ATPase plays a role in GA
      regulated germination of tomato seeds.

PMID- 10594122
TI  - Effects of solar ultraviolet radiation on the potential efficiency of photosystem
      II in leaves of tropical plants
AB  - The effects of solar ultraviolet (UV)-B and UV-A radiation on the potential
      efficiency of photosystem II (PSII) in leaves of tropical plants were
      investigated in Panama (9 degrees N). Shade-grown tree seedlings or detached sun
      leaves from the outer crown of mature trees were exposed for short periods (up to
      75 min) to direct sunlight filtered through plastic or glass filters that
      absorbed either UV-B or UV-A+B radiation, or transmitted the complete solar
      spectrum. Persistent changes in potential PSII efficiency were monitored by means
      of the dark-adapted ratio of variable to maximum chlorophyll a fluorescence. In
      leaves of shade-grown tree seedlings, exposure to the complete solar spectrum
      resulted in a strong decrease in potential PSII efficiency, probably involving
      protein damage. A substantially smaller decline in the dark-adapted ratio of
      variable to maximum chlorophyll a fluorescence was observed when UV-B irradiation
      was excluded. The loss in PSII efficiency was further reduced by excluding both
      UV-B and UV-A light. The photoinactivation of PSII was reversible under shade
      conditions, but restoration of nearly full activity required at least 10 d.
      Repeated exposure to direct sunlight induced an increase in the pool size of
      xanthophyll cycle pigments and in the content of UV-absorbing vacuolar compounds.
      In sun leaves of mature trees, which contained high levels of UV-absorbing
      compounds, effects of UV-B on PSII efficiency were observed in several cases and
      varied with developmental age and acclimation state of the leaves. The results
      show that natural UV-B and UV-A radiation in the tropics may significantly
      contribute to photoinhibition of PSII during sun exposure in situ, particularly
      in shade leaves exposed to full sunlight.

PMID- 10594123
TI  - Increased flow of fatty acids toward beta-oxidation in developing seeds of
      Arabidopsis deficient in diacylglycerol acyltransferase activity or synthesizing
      medium-chain-length fatty acids.
AB  - Synthesis of polyhydroxyalkanoates (PHAs) from intermediates of fatty acid beta
      oxidation was used as a tool to study fatty acid degradation in developing seeds
      of Arabidopsis. Transgenic plants expressing a peroxisomal PHA synthase under the
      control of a napin promoter accumulated PHA in developing seeds to a final level
      of 0. 06 mg g(-1) dry weight. In plants co-expressing a plastidial acyl-acyl
      carrier protein thioesterase from Cuphea lanceolata and a peroxisomal PHA
      synthase, approximately 18-fold more PHA accumulated in developing seeds. The
      proportion of 3-hydroxydecanoic acid monomer in the PHA was strongly increased,
      indicating a large flow of capric acid toward beta-oxidation. Furthermore,
      expression of the peroxisomal PHA synthase in an Arabidopsis mutant deficient in
      the enzyme diacylglycerol acyltransferase resulted in a 10-fold increase in PHA
      accumulation in developing seeds. These data indicate that plants can respond to
      the inadequate incorporation of fatty acids into triacylglycerides by recycling
      the fatty acids via beta-oxidation and that a considerable flow toward beta
      oxidation can occur even in a plant tissue primarily devoted to the accumulation
      of storage lipids.

PMID- 10594124
TI  - The redox state regulates RNA degradation in the chloroplast of Chlamydomonas
      reinhardtii.
AB  - A Chlamydomonas reinhardtii chloroplast transformant, designated MU7, carrying a
      chimeric (rbcL promoter: beta-glucuronidase [GUS]: psaB 3' end) gene whose
      transcripts have been found previously to be unstable in light (half-life of 20
      min in light as opposed to a half-life of 5 h in the dark), was used to study the
      role of electron transport and of the redox state in the degradation of
      chloroplast transcripts in the light. Blocking photosynthetic electron transport
      with 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) prevented the light-dependent
      breakdown of the pool of GUS transcripts in MU7 cells. Diamide, an oxidizing
      agent, caused a measurable delay in the degradation of GUS transcripts in the
      light. The addition of dithiothreitol (DTT), a dithiol reductant, to MU7 cells in
      which GUS transcript levels were stabilized by DCMU induced degradation of GUS
      transcripts. Similarly, DTT induced a decrease in the levels of GUS transcripts
      when added to MU7 cells in the dark period of the light/dark cycle, a period in
      which GUS transcript levels normally increase. The levels of transcripts of
      endogenous chloroplast genes were affected by DCMU and DTT in the same direction
      as levels of GUS transcripts. The results suggest a regulatory role of the redox
      state in the degradation of chloroplast transcripts in C. reinhardtii.

PMID- 10594125
TI  - Early copper-induced leakage of K(+) from Arabidopsis seedlings is mediated by
      ion channels and coupled to citrate efflux.
AB  - Copper tolerance among Arabidopsis ecotypes is inversely correlated with long
      term K(+) leakage and positively correlated with short-term K(+) leakage (A.
      Murphy, L. Taiz [1997] New Phytol 136: 211-222). To probe the mechanism of the
      early phase of K(+) efflux, we tested various channel blockers on copper and
      peroxide-induced K(+) efflux from seedling roots. The K(+) channel blockers
      tetraethyl ammonium chloride and 4-aminopyridine (4-AP) both inhibited short-term
      copper-induced K(+) efflux. In contrast, peroxide-induced K(+) efflux was
      insensitive to both tetraethyl ammonium chloride and 4-AP. Copper-induced lipid
      peroxidation exhibited a lag time of 4 h, while peroxide-induced lipid
      peroxidation began immediately. These results suggest that short-term copper
      induced K(+) efflux is mediated by channels, while peroxide-induced K(+) efflux
      represents leakage through nonspecific lesions in the lipid bilayer. Tracer
      studies with (86)Rb(+) confirmed that copper promotes K(+) efflux rather than
      inhibiting K(+) uptake. Short-term K(+) release is electroneutral, since
      electrophysiological measurements indicated that copper does not cause membrane
      depolarization. Short-term K(+) efflux was accompanied by citrate release, and
      copper increased total citrate levels. Since citrate efflux was blocked by 4-AP,
      K(+) appears to serve as a counterion during copper-induced citrate efflux. As
      copper but not aluminum selectively induces citrate production and release, it is
      proposed that copper may inhibit a cytosolic form of aconitase.

PMID- 10594126
TI  - The electronic plant gene register.

PMID- 10594128
TI  - Morphometric analysis of preterm fetal pulmonary development in the sheep model
      of congenital diaphragmatic hernia.
AB  - Congenital diaphragmatic hernia (CDH) in humans carries high mortality/morbidity
      attributed to associated pulmonary hypoplasia. An understanding of the effects of
      CDH on fetal lung growth is important for development of successful treatments.
      This study aimed to quantitate structural differences between normal and CDH
      affected preterm lamb lungs. We hypothesized that (a) pulmonary hypoplasia is
      present in preterm CDH-affected lungs; (b) the relative degree of pulmonary
      hypoplasia increases with gestation; and (c) the left upper lobe (LUL) is
      affected most. Fetal lambs were allocated to two groups. One group underwent
      surgery (72-74 days gestation) inducing CDH. Both groups (n = 7, n = 7) were
      delivered by cesarean section at 129 days (term: 145-149). Lungs were obtained at
      autopsy, were inflation-fixed, processed for histology, and morphometry was
      performed. Preterm lungs of CDH-affected lambs in comparison to those of normal
      lambs demonstrated a reduction in the following: lung weight (37.7 g vs. 116.3
      g); lung weight:body weight (0.012 vs. 0.040); fixed lung volume (33.6 ml vs.
      96.9 ml); gas-exchange surface area (4.56 m(2) vs. 13.70 m(2));
      parenchyma:nonparenchyma (59:41 vs. 72:28); and parenchymal airspace:tissue
      (16:84 vs. 35:65). Non-parenchyma connective tissue was increased (58%),
      airspaces were more numerous (1077/mm(2)) and smaller (perimeter 76.6 microm),
      gas-exchange surface density (2394 cm(-1)) was greater and capillary loading
      (0.04 ml/m(2)) was reduced compared to preterm normal lung (49%; 778/mm(2); 108.7
      microm; 2003 cm(-1), 0.11 ml/m(2), respectively). The LUL was affected most.
      These data quantitate pulmonary hypoplasia in preterm CDH-affected lambs.
      Comparisons with published data indicate increasing relative hypoplasia as
      gestation proceeds. Fetal interventions will affect lung development, depending
      on timing, with intervention still likely to be worthwhile during late gestation.

PMID- 10594127
TI  - Bile acid synthetic defects and liver disease.

PMID- 10594129
TI  - Project Pro-natal: population-based study of perinatal and infant mortality in
      natal, Northeast Brazil.
AB  - The Pro-Natal project is a collaborative initiative that aims to improve maternal
      and infant health in a deprived community in Natal, Northeast Brazil. To assess
      the perinatal and infant mortality in this population of 40,000, we have
      collected over a 2-year period a consecutive series of 39 autopsy examinations on
      deaths under 1 year of age. During this period there were 2212 live births in the
      study population. The 14 perinatal deaths are described using the Wrigglesworth
      classification, and the 25 infant deaths, using a clinicopathological system. The
      contribution of normally formed stillbirths was small (14%), which probably
      reflects the underreporting of stillbirths in this community. The most common
      cause of death in the live births was complications of prematurity (43%).
      Specific causes (22%) of perinatal deaths were predominantly infections,
      including one case of congenital syphilis. Perinatal asphyxia was diagnosed in
      14%, and there was one case (7%) of a chromosome abnormality. Infant deaths were
      predominantly due to respiratory (45%) and gastrointestinal infections (28%),
      with chronic malnutrition as an underlying cause in 80% of cases. Prenatal care
      could theoretically have prevented three of the perinatal deaths, and a further
      six deaths could have been avoided by improved management of labor and the
      immediate neonatal period. Prevention of malnutrition and improved treatment of
      acute infections would contribute to a reduction in infant mortality in this
      population. The Pro-Natal project will use these data to design preventative
      interventions to reduce perinatal and infant mortality in this community.

PMID- 10594130
TI  - Immunohistochemical detection of myocardial necrosis in stillbirth and neonatal
      death.
AB  - The aims of this study were to determine whether immunohistochemical staining for
      C9 can demonstrate myocardial necrosis in the fetus and neonate. Hearts from
      cases of stillbirth or neonatal death with confirmed myocardial necrosis (in
      neonates) or with ischemic lesions outside the heart (in neonates and stillborns)
      were stained immunohistochemically with antibodies to C9. All five cases with
      confirmed myocardial infarction showed positive immunohistochemical staining for
      C9, largely localized to the infarcted areas. The youngest subject was born at 24
      weeks gestation and died at 4 days of age. One of two neonates without myocardial
      necrosis on H&E staining but with pathological evidence of ischemic lesions
      elsewhere showed staining of scattered fibers. Six out of ten hearts from
      macerated stillborn infants showed varying degrees of positive staining.
      Immunohistochemical staining for C9 detects myocardial necrosis in neonates of a
      gestational age of 24 weeks or more. C9 is also demonstrable
      immunohistochemically in macerated stillborns, and this is likely to represent
      myocardial necrosis. The method is of great potential value in the investigation
      of cardiac ischemia in the fetal and perinatal period.

PMID- 10594131
TI  - Beta-cell hyperplasia in macrosomic infants and fetuses of nondiabetic mothers.
AB  - The objective of this study was to test the hypothesis that macrosomic infants of
      nondiabetic mothers have beta-cell hyperplasia in their pancreases. Pancreatic
      tissues were examined from 10 macrosomic fetuses and liveborn infants and from 10
      comparison cases matched for gestational age and gender. None of the mothers had
      a history of diabetes and all had normal glucose screening during pregnancy.
      Tissues were stained with hematoxylin and eosin and a monoclonal antibody against
      beta cells and were analyzed using an image analysis program to evaluate the size
      and surface area of beta-cell clusters. Brain/liver weight ratios were calculated
      and compared. The total surface area and cluster size of beta cells in the
      pancreases of macrosomic subjects were significantly larger than in the
      comparison pancreases. The study subjects lacked macroscopic and histopathologic
      findings expected in infants of diabetic mothers. We conclude that some
      macrosomic fetuses and infants of nondiabetic mothers manifest beta-cell
      hyperplasia. This corresponds to the higher insulin levels in macrosomic infants
      of nondiabetic mothers described in previous clinical studies. In macrosomic
      fetuses the stimulus for beta-cell hyperplasia may not involve aberrant maternal
      glucose levels.

PMID- 10594132
TI  - Prognostic value of pre- and postoperative cardiac troponin I measurement in
      children having cardiac surgery.
AB  - The objective of this study was to determine if perioperative elevation of
      cardiac troponin I (cTnI) predicts mortality in infants and children after
      surgical correction of congenital heart defects. One hundred infants and children
      having open heart surgery were studied. Blood samples for cTnI analysis were
      collected before cardiopulmonary bypass (CPB) and at 4, 8, 12, and 24 h after
      initiation of CPB. Demographic information, cardiac defect, repair performed,
      duration of CPB, complications, and outcome were recorded. Cardiac defects were
      categorized as atrial septal defect (ASD), ventricular septal defect (VSD),
      hypoplastic left heart syndrome (HLHS), complex, and "other." Baseline cTnI was
      significantly lower in survivors (mean 0.42 ng/ml, median 0.35 ng/ml) than in
      nonsurvivors (mean 1.89, median 1.30), p = 0.0001. Baseline cTnI was
      significantly higher in the HLHS group (mean 1.47, median 1.10) than in all other
      subgroups (mean 0.62, median 0.35), p </= 0.009. There were no significant
      differences between survivors and nonsurvivors at the remaining sampling times.
      Children who died from cardiac failure (n = 2) were more likely to have 4 h cTnI
      >125 ng/ml compared to survivors (2 of 90). Within cardiac defect subgroups, 4 h
      cTnI was significantly higher in the complex group (mean = 53.51, median = 32.30)
      than in the ASD (mean = 23.84, median = 19.85) and other (mean = 21.59, median
      21.50) subgroups. Perioperative measurement of cTnI identifies children within
      specific cardiac defect subgroups at risk of mortality after cardiac surgery. We
      speculate that detection of myocardial injury may decrease mortality and
      morbidity in children with complicated congenital cardiac lesions by leading to
      improvements in perioperative management.

PMID- 10594133
TI  - Phosphaturic mesenchymal tumor-induced rickets.
AB  - We describe two prepubertal girls with oncogenic rickets. The first patient, 9
      years of age, presented with recent-onset lower-extremity pain. The second girl,
      presented at 4 years of age following a 9-month period of muscle weakness, bone
      pain, and poor linear growth. Laboratory analyses in both patients revealed
      hypophosphatemia and hyperphosphaturia; elevated circulating alkaline phosphatase
      activity was present in one of them. Radiographic evidence of a generalized
      rachitic process was evident in both cases. Computerized tomography of the
      paranasal sinuses and facial bones in patient 1 revealed a small lesion eroding
      through the inner table of the left mandibular ramus. Microscopic examination of
      this mass revealed a spindle cell neoplasm with chondroid material, dystrophic
      calcification, and both osteoclast-like and fibroblast-like cells. Prominent
      vascularity and marked atypia were present. These features are consistent with a
      phosphaturic mesenchymal tumor of the mixed connective tissue variant. In the
      second patient, computerized tomography revealed a lytic lesion located in the
      right proximal tibia, with histologic features consistent with a phosphaturic
      mesenchymal tumor of the nonossifying fibroma-like variant. Resection of each
      tumor resulted in rapid correction of the phosphaturia and healing of the
      rachitic abnormalities. A careful search for small or occult tumors should be
      carried out in cases of acquired phosphaturic rickets.

PMID- 10594134
TI  - Normal hepatic growth: study of the proliferative capacity and apoptosis of the
      normal liver during childhood.
AB  - We explored the mechanism of normal hepatic growth in children by evaluating the
      proliferation index (with Ki-67 antibody) and apoptosis index (with the ApopTag
      kit). The proliferative index is almost constant, but the level of apoptosis is
      very low in childhood and increases with age. Thus the growth of the liver in
      children is not due to a high proliferation index, but to a very low apoptosis
      index.

PMID- 10594135
TI  - Infantile G(M1) gangliosidosis: complete morphology and histochemistry of two
      autopsy cases, with particular reference to delayed central nervous system
      myelination.
AB  - Inborn metabolic errors causing lysosomal storage, such as beta-galactosidase
      deficiency (G(M1) gangliosidosis [G(M1)]), have well-recognized effects on
      cellular function and morphology. In some classically "neuronal" storage
      diseases, including G(M1), neuroradiologic observations of infants have suggested
      a delay in myelination on the basis of persistently "immature" signal intensities
      monitored over time. We sought to evaluate in a semiquantitative fashion the
      pattern and degree of myelination in two infantile G(M1) patients, one boy and
      one girl, autopsied at 15 months of age. We assigned myelination degrees for
      defined sites on an ordinal scale of 0 to 4, and compared them to published
      population-based values for autopsied infants. In both patients, earlier
      myelinating structures were comparable in development to that expected for
      postconceptional age, whereas later-myelinating structures were delayed. These
      data correlate well with the neuroradiologic diagnosis of myelination delay in
      these infants and suggest that the metabolic defect has a primary influence on
      myelin development, in addition to effects related to neuronal storage.
      Furthermore, our analysis by light and electron microscopy and lectin
      histochemistry of both CNS and systemic tissues, several of which had not been
      described, add to the understanding of the stored material in different cell
      types.

PMID- 10594136
TI  - Occult pulmonary synovial sarcoma confirmed by molecular techniques.
AB  - We report a unique case of a minute, occult synovial sarcoma of the lung detected
      intraoperatively during a pneumothorax repair in a 17-year-old boy. No
      alternative primary site could be detected upon complete body imaging studies and
      physical examinations. The diagnosis was confirmed by demonstration of the
      characteristic SYT/SSX gene fusion by reverse transcriptase polymerase chain
      reaction (RT-PCR) performed upon RNA extracted from the paraffin block of the
      biopsy. This case demonstrates the utility of this technique in diagnostic
      pathology.

PMID- 10594137
TI  - Juxtaposed cystic nephroma and Wilms' tumor.
AB  - We report a case of juxtaposed Wilms' tumor (WT) and cystic nephroma (CN) in a 21
      month-old girl which gave rise to radiological diagnostic difficulty.
      Preoperative chemotherapy was given, resulting in marked tumor necrosis but the
      cystic nephroma remained untouched. Histological examination showed
      characteristic features of a triphasic WT and a CN; the two lesions were
      separated by a thick fibrous capsule. While everybody agrees that WT and cystic
      partially differentiated nephroblastoma (CPDN) are closely related, there are two
      opposite views about their relationship to CN. One is that CN may represent the
      final step in maturation of WT and CPDN. Other authors argue that there is no
      evidence to support this theory but believe CN might have something in common
      with nephrogenic rests. We suggest that the two lesions in the present case may
      have originated from two intralobar nephrogenic rests, which would strengthen the
      latter view.

PMID- 10594138
TI  - Partial molar transformation of the placenta of presumably monozygotic twins.
AB  - A pregnancy with one normal female fetus and a placenta that was divided into
      halves, one normal the other molar, is described. Genetic analysis shows the
      molar component to be hyperdiploid/tetraploid but having an identical DNA
      composition as the normal twin. Because there was no trophoblastic proliferation
      and the hyperdiploid cells were confined to the villous stroma, and because the
      molar component was still being perfused by diploid vessels from the normal twin,
      we believe the mole is derived from polyploidization of the mesenchymal epiblast
      in a monozygotic twin pregnancy.

PMID- 10594139
TI  - Light microscopic, immunophenotypic, and molecular genetic study of autoimmune
      lymphoproliferative syndrome caused by fas mutation.
AB  - This case provides a complete light microscopic, immunophenotypic, and molecular
      genetic analysis of autoimmune lymphoproliferative syndrome (ALPS), a rare benign
      cause of dramatic lymphadenopathy with atypical histology and phenotype that may
      be mistaken for malignancy. The patient is 3-year-old child who was first
      clinically evaluated at the age of 16 months because of marked generalized
      lymphadenopathy and hepatosplenomegaly. Histologic sections of a cervical lymph
      node demonstrated a marked paracortical proliferation of occasional small and
      intermediate-sized lymphocytes and numerous large immunoblasts, the majority of
      which displayed a CD3(+), CD43(+), CD45RO(-) (OPD4, UCHL1) CD4(-), CD8(-)
      phenotype on paraffin sections, and which had a CD2(+), CD3(+), CD5(+), CD56(-),
      Tdelta1(-), [CD4(-), CD8(-)] double negative profile on flow cytometric analysis.
      Southern blot analysis did not identify a clonal T or B cell population, and
      sequencing of the fas gene identified a mutation that caused a single amino acid
      substitution in the intracytoplasmic death domain of this protein. An enriched
      population of CD45RO-negative naive T cells in the paracortex may explain the
      atypical histologic and immunophenotypic features of this case. Greater awareness
      of this heritable lymphoproliferative disorder will facilitate its recognition
      and minimize the possibility of misdiagnosis.

PMID- 10594140
TI  - "Teratomas" in the Currarino triad: a misnomer.

PMID- 10594141
TI  - New artificial sediment for Chironomus riparius toxicity testing.

PMID- 10594142
TI  - Potential application of elemental analysis of fish otoliths as pollution
      indicator.

PMID- 10594143
TI  - Heavy metals and methylmercury in tissues of Risso's dolphin (Grampus griseus)
      and Cuvier's beaked whale (Ziphius cavirostris) stranded in italy (South Adriatic
      sea).

PMID- 10594144
TI  - Content of cadmium in carrots compared with rice in Japan.

PMID- 10594145
TI  - Cadmium-99 transfer between water and sediments studied in laboratory experiments
      and with a computer model.

PMID- 10594146
TI  - PAH contamination levels in air particles and sediments of Ho Chi Minh City,
      vietnam.

PMID- 10594147
TI  - Chlorinated aromatic hydrocarbons in the brains and lipids of sparrows (Passer
      domesticus and Passer montanus) from rural and suburban areas near Warsaw.

PMID- 10594148
TI  - Chromium tolerant yeast strains isolated from industrial effluents and their
      possible use in environmental clean-up.

PMID- 10594149
TI  - Relationship between the structure of some humic compounds and their inhibitory
      effects on carp catalase.

PMID- 10594150
TI  - Interactions between dibutyl phthalate and aquatic organisms.

PMID- 10594151
TI  - Effects of sucrose and dried alum sludge on the growth of Rudbeckia and leaching
      of nitrogen and phosphorus from potting media containing biosolids compost.

PMID- 10594152
TI  - Metabolic effects of sulfur dioxide fumigation on Mangifera indica plants.

PMID- 10594153
TI  - Growth of kerosene-biodegrading microorganisms in the presence of alpha-amino
      acid.

PMID- 10594154
TI  - Evaluation of detoxification enzyme levels in Egyptian catfish, Clarias lazera,
      exposed to dimethoate.

PMID- 10594155
TI  - Toxicity and differential tissue accumulation of copper in the tropical
      freshwater fish, Prochilodus scrofa (Prochilodontidae).

PMID- 10594156
TI  - Short-term ecotoxicity of a mixture of five metals to the zebra mussel Dreissena
      polymorpha.

PMID- 10594157
TI  - Evaluation by HPLC-UV of polar pesticides in rice fields.

PMID- 10594158
TI  - Bone mineral density and androgen levels in elderly males.
AB  - To clarify the relationship of sex male hormones and bone in men, we studied in
      140 healthy elderly men (aged 55-90 years) the relation between serum levels of
      androgens and related sex hormones, bone mineral density (BMD) at different
      sites, and other parameters related to bone metabolism. Our results show a slight
      decrease of serum-free testosterone with age, with an increase of follicle
      stimulating hormone (FSH) and luteinizing hormone (LH) in a third of the elderly
      subjects studied. BMD decreased significantly with age in all regions studied,
      except in the lumbar spine. We found a positive correlation between body mass
      index (BMI) and BMD at the lumbar spine and femoral neck (P < 0.001). No
      relationship was found (uni- and multivariate regression analysis) between serum
      androgens or sex hormone-binding globulin (SHBG) and BMD. We found a positive
      correlation of vitamin D binding protein (DBP) and osteocalcin with lumbar spine
      BMD and with BMI, DBP, IGF-1, and PTH with femoral neck BMD. In conclusion, there
      is a slight decline in free testosterone and BMD in the healthy elderly males.
      However, sex male hormones are not correlated to the decrease in hip BMD. Other
      age-related factors must be associated with bone loss in elderly males.

PMID- 10594159
TI  - Factor of risk for hip fracture in normal Chinese men and women in Taiwan.
AB  - We have investigated the age-related change in factor of risk (Phi) for the
      proximal femoral load during free fall in 548 females and 240 males aged 21-79
      years. These individuals were divided into either young (age <50 years) or old
      group (age >/=50 years). Another 26 females with hip fractures were included for
      comparison. The bone mineral density (BMD) of proximal femoral neck was measured
      by a Norland XR-26 dual-energy X-ray absorptiometer (DXA). The estimated fracture
      load (L) of femoral neck was calculated from the BMD with the regression equation
      derived by Courtney et al. [2,3] and estimated fall force (F) by body weight and
      height according to the regression equation derived by Nakamura et al. [6]
      respectively. Phi was defined as the quotient of F/L. The results showed an age
      related decrease of BMD (P < 0.001) in both genders corrected for weight and
      height. By multiple linear regression analysis, the F decreased significantly
      with aging corrected for BMD in old males (partial r = -0.255, P < 0.01) and
      increased with aging in all females (young, partial r=0.287, p < 0.001; old,
      partial r = 0.252, P < 0.001). L decreased significantly with aging corrected for
      height and weight in males (young, partial r = -0.401, P < 0.01; old, partial r =
      -0.178, P < 0.05) and females (young, partial r = -0. 168, P < 0.05; old, partial
      r = -0.459, P < 0.001). However Phi decreased with aging in young males (P <
      0.01) and females (young: P < 0.001, old: P < 0.001). Phi increased in old women
      but not in old men, and was higher in old women compared with old men. The 26
      patients with hip fractures had a significantly higher Phi value than 85 age
      matched women. In conclusion, Phi may provide a comprehensive comparison of the
      risk of hip fracture in the elderly population.

PMID- 10594160
TI  - Thirty cases of concurrent Paget's disease and primary hyperparathyroidism: sex
      distribution, histomorphometry, and prediction of the skeletal response to
      parathyroidectomy.
AB  - Studies of the effect of parathyroidectomy (PTX) on bone turnover in patients
      with the combination of primary hyperparathyroidism (PHPT) and Paget's disease
      (PD) are largely limited to case reports. The etiology of the combination is
      disputed. We report 30 patients and their biochemical (n = 17) and
      histomorphometric (n = 4) responses to PTX in 18. All 18 patients except one had
      a post-PTX fall in plasma alkaline phosphatase (pAP). There was a significant
      positive correlation between the degree of post-PTX fall in pAP and both the
      preoperative plasma total corrected calcium (CaC) (P < 0.01) and serum ionized
      calcium (P < 0.05). For the patients with CaC levels >3.0 mmol/liter, the mean %
      fall in pAP was 68% of pretreatment (to 32%). For those with CaC levels >/=2.68
      mmol/liter the fall in pAP was >18%. Of 12 literature cases treated by PTX and
      followed up, 11 had a postoperative fall in pAP (range 6-83%). Pretreatment bone
      biopsies (n = 6) could not be distinguished from uncomplicated PD. No significant
      histomorphometric changes were documented postoperatively in the four patients
      studied; however, % fibrotic surfaces declined in each of the four. Of the 18
      patients, only one had radiologic subperiosteal erosions preoperatively; none had
      clinical tetany postoperatively-thus distinguishing this combination of diseases
      from severe PHPT bone disease-a situation easily biochemically confused with this
      combination. The sex distribution of 2.75:1 F/M in this series resembles reported
      ratios in pure PHPT of 2.37:1, unlike the ratios found in pure PD (0.49-1.01:1).
      The prevalence of PHPT in PD is 2.2-6.0% (mean 4.4%) in 1836 patients. In our
      series, 73% of patients with both diseases were females >60 years of age. In
      population studies >60 years, PHPT was present in 3% of women and 1% of men.
      Hypercalcemia in PD is frequently attributed to immobilization. As part of this
      study, we examined 184 patients referred with PD for the existence of, and cause
      of hypercalcemia. Of this group, 21 were hypercalcemic, 19 (90%) of whom had
      PHPT; none had immobilization hypercalcemia. In patients with both disorders, the
      indications for PTX should include the potential post-PTX improvement in pagetic
      biochemistry and symptoms. The sex distribution (resembling pure PHPT) and the
      similar prevalence of PHPT in Paget's, and in the elderly population, support the
      likelihood, in most cases, that these two common diseases are associated by
      chance.

PMID- 10594161
TI  - Ultrasound densitometry of the os calcis in patients with hemiparesis following a
      cerebrovascular accident.
AB  - Ultrasound densitometry has been measured in the os calcis of 31 stroke patients
      (14 women, 17 men), ages 46-87 years, to determine whether bone density is lower
      than expected for normal subjects at this site, and to investigate whether or not
      the stroke side has lower values than the nonstroke side. We have also measured a
      large control group of 268(39 men, 228 women) subjects who showed similar values
      to other published data. Immobility is a known precursor to bone loss and so we
      also compared ultrasound Stiffness Index with an index of mobility in 22 of the
      stroke patients. In healthy subjects, ultrasound densitometry (measured as
      Stiffness) fell by 25% in females from 48-52 to 68-72 years. Stiffness (expressed
      as z-score) in patients with stroke was low in females (P < 0.02) but not in
      males, but both stroke side and nonstroke side were equally low. Stiffness did
      not decline with time since stroke, but did correlate with mobility after stroke,
      on the stroke (r = 0.73) and nonstroke (r = 0.62) side. The data suggest that
      stroke patients, particularly females, have low bone density before the stroke
      event. The greater ultrasound Stiffness with increasing mobility after stroke may
      suggest that active rehabilitation after stroke may produce denser bone.

PMID- 10594162
TI  - Circulating beta(2) microglobulin in relation to bone metabolism: implications
      for bone loss with aging.
AB  - The aim of this cross-sectional study was to evaluate the relationships between
      circulating beta(2) microglobulin (beta(2) m) and bone mineral density (BMD),
      parameters of bone remodeling, vitamin D metabolites, parathyroid hormone (PTH),
      estradiol levels, and age in a group of 165 clinically healthy or osteoporotic,
      but otherwise normal untreated women. In this group of women, systemic beta(2) m
      correlated with BMD (g/cm(2)) levels for total hip and Ward's triangle (r = 
      0.298, P < 0.0001; and r = -0.299, P < 0.0001, respectively), but only at the
      borderline level with BMD at the spine (r = -0.145, P = 0.0604). Serum beta(2)
      microglobulin markedly correlated with age (r = 0.512, P = 0.0001). beta(2) m
      levels correlated with indices of bone remodeling, as well as with serum
      creatinine and estradiol levels. However, after stratification of all analyses by
      age, body mass index, and serum 25OHD(3), 1, 25(OH)(2)D(3), PTH, or estradiol
      levels (using standard multiple regression and stepwise forward regression
      models), only 25OHD(3) was found to be an independent predictor of BMD at the
      hip, including Ward's triangle, as estradiol of BMD at the spine. On the other
      hand, beta(2) m was not associated with BMD at any of the measured regions. Also,
      no association was found between serum PTH and BMD values. Therefore, systemic
      beta(2) m seems to be an indicator of bone remodeling in the course of natural
      skeletal aging rather than a variable independently predicting bone loss.

PMID- 10594163
TI  - Peripheral quantitative computed tomography of the femoral neck in 60 Japanese
      women.
AB  - Peripheral quantitative computed tomography (pQCT) is able to evaluate trabecular
      and cortical bone separately, and to determine geometric properties from cross
      sectional images for noninvasive assessments of mechanical strength. In order to
      assess the diagnostic value of pQCT of the femoral neck, 60 healthy women were
      examined with a new pQCT machine, XCT-3000 (Norland-Stratec, Germany), which is
      suitable for direct measurement of the hip. The region of interest chosen was the
      center of the femoral neck. pQCT of the distal radius and dual energy X-ray
      absorptiometry (DXA) of the lumbar spine and femoral neck were also performed.
      The study demonstrated that total bone mineral density (BMD) (femoral MD) and
      trabecular BMD (femoral-TBD) decreased with advancing age. Percent cortical area
      showed a small but significant decrease with advancing age and % trabecular area
      increased slightly. Both the endosteal perimeter and the periosteal perimeter
      were relatively constant with aging. Bone strength index (BSI) and stress-strain
      index (SSI), which reflect the mechanical strength of bone, declined with
      advancing age, especially after menopause. Femoral TBD correlated strongly with
      femoral neck BMD by DXA and L2-L4 BMD by DXA but femoral-CBD did not correlate
      with femoral neck BMD by DXA. Volumetric BMD of the femoral neck and distal
      radius were closely correlated. It is concluded that (1) cortical thinning occurs
      with aging by endocortical resorption and loss of femoral-TBD; (2) loss of
      femoral-CBD occurred at a slower rate than radial CBD, perhaps due to the weight
      bearing effect; (3) biomechanical parameters such as the BSI and SSI may reflect
      increasing fragility of the femoral neck in pre- and postmenopausal women; (4)
      pQCT of the femoral neck had diagnostic value at least equivalent to that of DXA
      or pQCT of the distal radius.

PMID- 10594164
TI  - Increase in the potential of osteoblasts to support bone resorption by
      osteoclasts in vitro in response to roughness of bone surface.
AB  - The development of the potential of osteoblasts to support bone resorption by
      osteoclasts in response to roughness on bone slices was examined in the co
      incubation cell system of immature osteoclasts and osteoblastic cells. The
      immature osteoclasts, which need alkaline phosphatase (ALP)-positive osteoblastic
      cells for bone resorption, were generated in mouse spleen cultures with 1, 25
      dihydroxyvitamin D(3) and prostaglandin E(2). ALP-negative osteoblastic cells
      from mouse calvaria were incubated on rough surfaced bone slices for 3 days. The
      number of ALP-positive cells increased greatly on the rough surface, but little
      on the smooth surface. When immature osteoclasts were added and incubated for 1
      more day, the resorption pit number and the total pit areas on the smooth surface
      were not much different from those before incubation but were approximately four
      times higher on the rough surface.

PMID- 10594165
TI  - A comparative infrared spectroscopic study of hydroxide and carbonate absorption
      bands in spectra of shark enameloid, shark dentin, and a geological apatite.
AB  - The purpose of the present work was to investigate the infrared (IR) spectrum of
      shark enameloid, especially with regard to hydroxide and carbonate bands. With
      thin sections placed directly in the IR beam it was possible to get high
      concentrations of ions without interfering effects from a dispersion medium
      (e.g., alkali halides). For comparison, spectra of shark dentin and a geo-apatite
      were also recorded. In spectra of shark enameloid and geo-apatite medium strong
      hydroxide absorption bands were found around 3535 cm(-1), and in shark dentin and
      geo-apatite spectra weak shoulders were observed at about 3570 cm(-1). Hydroxide
      libration bands at about 740 cm(-1) were found in shark enameloid and geo-apatite
      spectra; in the latter, also a band at 680 cm(-1). Carbonate bands were found in
      shark enameloid spectra at 1480 (weak shoulder), 1453, 1423, and 868 cm(-1). In
      shark dentin spectra there were carbonate bands at 1452, 1417, and 875 cm(-1),
      and probably also a carbonate band at about 1530 cm(-1) overlapped by an amide II
      band. Weak carbonate bands were also found in the spectra of the geo-apatite at
      1452 cm(-1), and at about 1425 and 880 cm(-1). The relative intensities of the
      bands at 1453 cm(-1) (contributed from A and B sites) and around 1420 cm(-1) (B
      sites) changed from shark enameloid to shark dentin, and also from shark
      enameloid to the geo-apatite. More A sites seem to be occupied by carbonate in
      shark dentin than in shark enameloid, supposedly owing to fluoride occupation of
      A sites in shark enameloid. In geo-apatite and shark enameloid there are
      hydroxide ions hydrogen bonded to fluoride. Both shark enameloid and the geo
      apatite are fluoride rich, and geo-apatite seems to have the highest fluoride
      concentration. There are, however, indications that the hydroxide concentration
      is also higher in the geo-apatite than in shark enameloid. This can be explained
      by the much higher carbonate content, and partly also by the higher water content
      in shark enameloid. There are A sites in geo-apatite and probably also in shark
      enameloid which are occupied by carbonate, but the proportion of occupied A sites
      relative to occupied B sites is greater in geo-apatite than in shark enameloid.
      This difference can be explained by the preference of A sites when the carbonate
      concentration is very low. On the other hand, for greater amounts of carbonate
      such as we have in shark enameloid, B sites are preferred.

PMID- 10594166
TI  - Toward a mathematical description of bone biology: the principle of cellular
      accommodation.
AB  - Mathematical theories for bone biology or more specifically, bone mass
      regulation, should be viewed with considerable interest because they provide
      powerful tools for prediction of bone mass changes in response to mechanical or
      humeral stimuli. Frost [1] put forward one such theory when he postulated that
      bone mass is a controlled mechanical feedback system called the "mechanostat." He
      suggested that certain hormones and biochemical agents act on bone biology by
      changing the thresholds (or minimum effective strains) of the mechanostat.
      Critical examination of the mechanostat theory indicates that it does not conform
      well with certain experimental observations. In the present paper, a new theory
      is presented that addresses some of the flaws in the mechanostat. The new theory
      is based upon the assumption that bone cells react strongly to transients in
      their environment, but eventually "accommodate" to steady state signals. This
      cellular accommodation, represented by a relaxation function, forms the basis for
      mathematical rate equations that describe bone mass changes in response to
      external stimuli. Importantly, the cellular accommodation theory can have the
      property of "path dependence," meaning that final bone mass will be dependent
      upon the temporal sequence of preceding mechanical loading/hormonal events. Bone
      tissue demonstrates path dependence in its responses to mechanical loading and
      anabolic agents. Theoretically, it is possible to exploit the nonlinear character
      of path dependence to maximize the osteogenic effect of various therapeutic
      regimens. An experimental approach to test this possibility is described.

PMID- 10594167
TI  - C-Type natriuretic peptide/guanylate cyclase B system in rat osteogenic ROB-C26
      cells and its down-regulation by dexamethazone.
AB  - There is recent evidence that natriuretic peptides are important regulators of
      bone and cartilage, although they were originally identified as the cardiac
      hormones causing natriuresis and hypotension. Three members of natriuretic
      peptide family are known: atrial natriuretic peptide (ANP), brain natriuretic
      peptide (BNP), and C-type natriuretic peptide (CNP). The biologically active
      receptors for these peptides are particulate guanylate cyclases; the two known
      types are GC-A and GC-B. ANP and BNP have high affinities for GC-A, and CNP is
      the preferred ligand for GC-B. In this paper we report the results of our study
      of the expression and possible role(s) of natriuretic peptides in the ROB-C26
      cell, which is an osteogenic cell line with multiple potentials for
      differentiating into myoblast, osteoblast, and adipocyte. ROB-C26 cells produced
      cGMP in response to natriuretic peptides at both their basal state and after
      enhanced differentiation into osteoblast which was induced by bone morphogenetic
      protein [(BMP)-2]. CNP was far more potent than ANP in cGMP production. In
      contrast, enhanced differentiation into adipocyte by dexamethasone resulted in
      the marked decrease in their responsiveness to natriuretic peptides. Although the
      messages for GC-A and GC-B were demonstrated by Northern blot analysis at both
      the basal stage and after BMP treatment, they were down-regulated after
      dexamethasone treatment. The presence of CNP was shown by RT-PCR and
      immunohistochemistry in ROB-C26 cells. C3H10T1/2, which is another and more
      primitive mesenchymal cell line, also produced cGMP in response to CNP, and less
      potently to ANP. Culturing ROB-C26 cells with CNP or 8-bromo cGMP decreased
      [(3)H]thymidine uptake and slightly increased the message for alkaline
      phosphatase, which is a marker for osteoblast differentiation. These results
      suggest that the CNP/GC-B system is preferentially expressed in the cells of
      osteogenic lineage and their expression is down-regulated with differentiation
      into adipocyte lineage. The CNP/GC-B system is likely to be an
      autocrine/paracrine regulator of osteoblast growth and differentiation.

PMID- 10594168
TI  - Interference of lead with the calcium release activated calcium flux of
      osteoblast-like cells.
AB  - Lead (Pb(2+)) tends to accumulate in bone from where it is released during bone
      resorption, thus leading to high local concentrations of Pb(2+) with the risk of
      cellular toxicity. We investigated the interference of Pb(2+) with the calcium
      release activated calcium influx (CRAC) of osteoblast-like (OBL) cells. CRAC was
      elicited by depletion of intracellular Ca(2+) stores with thapsigargin and/or
      A23187 under Ca(2+)-free conditions and re-addition of extracellular Ca(2+). The
      fura-2 excitation ratio (R) was used to monitor changes of the free intracellular
      concentration of Ca(2+) and Pb(2+), the latter being reversible by the heavy
      metal chelator TPEN. Five or 12. 5 microM Pb(2+) applied simultaneously with re
      added Ca(2+) reduced the immediate CRAC of OBL cells to 70% or 37% of control
      value, respectively. An enlarged influx of Pb(2+) occurred during CRAC, which led
      to a 2.7-fold faster increase of R. When 1 microM Pb(2+) was added during ongoing
      CRAC, the Pb(2+)-mediated increase of R correlated with the degree of CRAC (r =
      0.83). Inhibitory effects of Pb(2+) on Ca(2+) ATPase activity did not contribute
      to the aforementioned findings. Our results demonstrated that CRAC channels of
      OBL cells are blocked as well as permeated by Pb(2+).

PMID- 10594169
TI  - Characterization of matrix-induced osteogenesis in rat calvarial bone defects:
      II. Origins of bone-forming cells.
AB  - Two experimental models that separated demineralized bone matrix (DBM) implants
      from the host bone were utilized to identify the origins of bone-forming cells in
      the repair of calvarial defects in rats. Rat DBM, Guanadine-HCl (Gdn-HCl)
      extracted insoluble residue of DBM, and Gdn-HCl extracted insoluble DBM to which
      the dialyzed Gdn-HCl extract was added back, were implanted in the two models
      which prevented cells of the adjacent host bone from participating in the repair.
      In addition, cells in the dura and in the subcutaneous tissue overlying the
      calvarial defect were locally labeled with (3)H-thymidine to identify the origins
      of those cells that were stimulated to divide and differentiate to osteoblasts.
      Histological studies of the temporal events that occurred during the healing
      process in these defect models, combined with (3)H-thymidine labeling
      demonstrated that the osteoblasts induced by DBM were initially derived from
      undifferentiated mesenchymal stem cells of the dura and later augmented by cells
      in the overlying connective tissue covering the defect, and not from cells in the
      cranial bone surrounding the circular defect. The cells of both dura and
      subcutaneous tissue were stimulated to proliferate and differentiate principally
      to osteoblasts and to a very much lesser extent to chondroblasts by DBM and by
      reconstituted components of DBM after Gdn-HCl extraction. Gdn-HCl-extracted
      insoluble DBM failed to induce bone or cartilage. These results indicate that the
      cytokines or other factors present in DBM are required to induce bone-forming
      cells derived from the dura and the overlying connective tissue for the repair of
      the calvarial defect.

PMID- 10594170
TI  - Activity strongly affects heel ultrasound.

PMID- 10594171
TI  - An attempt to pinpoint the phylogenetic introduction of glutaminyl-tRNA
      synthetase among bacteria.
AB  - Until recently it was believed that most Bacteria form Gln-tRNA(GLN) by the
      amidation of Glu-tRNA(GLN), only a few members of the gamma subdivision of
      Proteobacteria being able to charge tRNA(GLN) directly. We undertook a
      phylogenetic study in an attempt to determine at what point the changeover to the
      direct system may have occurred. To this end, we selected a number of
      representative Proteobacteria to see if we could find a division point. We
      constructed degenerate primers and conducted PCR analysis to identify which
      Bacteria had Gln-tRNA synthetase, on the one hand, and which had the
      amidotransferase system, on the other. At the same time, we surveyed data banks
      of completely sequenced microbial genomes, as well as those for genomes in the
      process of being sequenced. These combined efforts revealed four Proteobacteria
      in a phylogenetically intermediate position which have the genetic potential for
      both mechanisms. Perplexingly, however, three distantly related bacteria were
      also found to have both enzymes.

PMID- 10594172
TI  - Exploring nonnatural evolutionary pathways by saturation mutagenesis: rapid
      improvement of protein function.
AB  - Random point mutagenesis does not access a large fraction of protein sequence
      space corresponding to primarily nonconservative amino acid substitutions. The
      cost of this limitation during directed evolution is unknown. Random point
      mutagenesis over the entire gene encoding the psychrophilic protease subtilisin
      S41 identified a pair of residues (Lys211 and Arg212) where mutations provided
      significant increases in thermostability. These were subjected to saturation
      mutagenesis to test whether the amino acids not easily accessible by point
      mutagenesis provide even better "solutions" to the thermostabilization challenge.
      A significant fraction of these variants surpassed the stability of the variants
      with point mutations. DNA sequencing revealed highly hydrophobic residues in the
      four most stable variants (Pro/Ala, Pro/Val, Leu/Val, and Trp/Ser). These
      nonconservative replacements, accessible only by multiple (two to three) base
      substitutions in a single codon, would be extremely rare in a point mutation
      library. Such replacements are also extremely rare in natural evolution.
      Saturation mutagenesis may be used advantageously during directed evolution to
      explore nonnatural evolution pathways and enable rapid improvement in protein
      traits.

PMID- 10594173
TI  - Rapid evolution of the ribonuclease A superfamily: adaptive expansion of
      independent gene clusters in rats and mice.
AB  - The two eosinophil ribonucleases, eosinophil-derived neurotoxin (EDN/RNase 2) and
      eosinophil cationic protein (ECP/RNase 3), are among the most rapidly evolving
      coding sequences known among primates. The eight mouse genes identified as
      orthologs of EDN and ECP form a highly divergent, species-limited cluster. We
      present here the rat ribonuclease cluster, a group of eight distinct ribonuclease
      A superfamily genes that are more closely related to one another than they are to
      their murine counterparts. The existence of independent gene clusters suggests
      that numerous duplications and diversification events have occurred at these loci
      recently, sometime after the divergence of these two rodent species (
      approximately 10-15 million years ago). Nonsynonymous substitutions per site
      (d(N)) calculated for the 64 mouse/rat gene pairs indicate that these
      ribonucleases are incorporating nonsilent mutations at accelerated rates, and
      comparisons of nonsynonymous to synonymous substitution (d(N) / d(S)) suggest
      that diversity in the mouse ribonuclease cluster is promoted by positive
      (Darwinian) selection. Although the pressures promoting similar but clearly
      independent styles of rapid diversification among these primate and rodent genes
      remain uncertain, our recent findings regarding the function of human EDN suggest
      a role for these ribonucleases in antiviral host defense.

PMID- 10594174
TI  - Monophyly of lampreys and hagfishes supported by nuclear DNA-coded genes.
AB  - The phylogenetic position of hagfishes in vertebrate evolution is currently
      controversial. The 18S and 28S rRNA trees support the monophyly of hagfishes and
      lampreys. In contrast, the mitochondrial DNAs suggest the close association of
      lampreys and gnathostomes. To clarify this controversial issue, we have conducted
      cloning and sequencing of the four nuclear DNA-coded single-copy genes encoding
      the triose phosphate isomerase, calreticulin, and the largest subunit of RNA
      polymerase II and III. Based on these proteins, together with the Mn superoxide
      dismutase for which hagfish and lamprey sequences are available in database,
      phylogenetic trees have been inferred by the maximum likelihood (ML) method of
      protein phylogeny. It was shown that all the five proteins prefer the
      monophyletic tree of cyclostomes, and the total log-likelihood of the five
      proteins significantly supports the cyclostome monophyly at the level of +/-1 SE.
      The ML trees of aldolase family comprising three nonallelic isoforms and the
      complement component group comprising C3, C4, and C5, both of which diverged
      during vertebrate evolution by gene duplications, also suggest the cyclostome
      monophyly.

PMID- 10594175
TI  - Functional analyses of natural variation in Sp1 binding sites of a TATA-less
      promoter.
AB  - Within the lactate dehydrogenase-B (LdhB) proximal promoter is a region with
      multiple in vivo footprinted sites that resembles the binding site for the
      transcription factor SP1. Like many sequences that regulate transcription rate,
      these Sp1 binding sites are well conserved among species of the teleost fish
      Fundulus. The only exception is in the northern population of F. heteroclitus,
      where there are many changes in the Sp1 binding sites. These changes affect
      footprinting patterns, measures of promoter strength, and are associated with the
      adaptive increase in Ldh-B transcription rates. Reported here is data that
      demonstrates that Fundulus hepatocyctes have an SP1-like protein; in comparison
      to human SP1 protein, it has similar specificity and size and a greater affinity
      for the consensus Sp1 site. This Fundulus hepatocyte SP1-like protein as well as
      the human SP1 protein binds the Ldh-B Sp1 sites. Sequence variation in the
      northern Sp1 region eliminates the "preferred" Sp1 binding site, yet these
      northern Sp1 sites have significantly greater affinity for the SP1 protein than
      either the Sp1 sites from southern F. heteroclitus ( approximately 1.6-fold) or
      the consensus Sp1 site (GGGCGG; approximately 1.8-fold). Furthermore, the Ldh-B
      Sp1 sites also bind non-SP1 proteins, and the extent of binding is affected by
      the sequence variation in the proximal promoter. These data suggest that natural
      variation in Sp1 sites affect binding of transcription factors and may effect a
      modest change in transcription rates.

PMID- 10594176
TI  - Male-driven evolution among Eoaves? A test of the replicative division hypothesis
      in a heterogametic female (ZW) system.
AB  - Because avian females are heterogametic, the reverse of mammals, avian sex
      chromosomes undergo significantly different patterns and numbers of DNA
      replications than do those in mammals. This makes the W (female-specific) and the
      Z chromosomes an excellent model system for the study of the replicative division
      hypothesis, which purports that DNA substitution rate is determined by the number
      of germline replications. The sex-specific chromosome in birds (the W) is
      predicted to change at the slowest rate of all avian chromosomes because it
      undergoes the fewest rounds of replication per unit of evolutionary time. Using
      published data on gametogenesis from a variety of sources, we estimated the ratio
      of male-to-female germline replications (c) in galliforms and anseriforms to be
      approximately 4.4. The value of c should predict the value of the ratio of male
      to-female mutation rates (alpha(m)) if the replicative division hypothesis is
      true. Homologous DNA sequences including an intron and parts of two exons of the
      CHD gene were obtained from the W and the Z chromosomes in ostrich, sage grouse,
      canvasback duck, tundra swan, and snow goose. The exons show significantly
      different nucleotide composition from the introns, and the W-linked exons show
      evidence of relaxed constraint. The Z-linked intron is diverging approximately
      3.1 times faster than the W-linked intron. From this, alpha(m) was calculated to
      be approximately 4.1, with a confidence interval of 3.1 to 5.1. The data support
      the idea that the number of replicative divisions is a major determinant of
      substitution rate in the Eoavian genome.

PMID- 10594177
TI  - Phylogenetic analysis of Mos1-like transposable elements in the Drosophilidae.
AB  - We have performed a phylogenetic analysis of 59 mariner elements in 14
      Drosophilidae species that are related to the active Drosophila mauritiana Mos1
      element. This includes 38 previously described sequences and 21 new sequences
      amplified by PCR from 10 species. Most of the elements detected are nonfunctional
      due to several frameshifts and deletions. They have been subdivided into four
      groups according to specific signatures in the nucleotidic and amino acid
      sequences. The mean nucleotide diversity is 4.8 +/- 0.1% and reflects mainly the
      divergence of inactive elements over different periods. Although this probably
      gives rise to occasional homoplasies between distantly related taxa, the elements
      of each species remain grouped together. Horizontal transfer, reported previously
      between D. mauritiana and Zaprionus tuberculatus, can be extended to Z. verruca,
      while the Mos1-like element of Z. indianus belongs to another group.
      Interpretation of the phylogeny leads to a comparison of the influence of common
      ancestral sequences and putative horizontal transfers.

PMID- 10594178
TI  - Gene conversion and evolution of daphniid hemoglobins (Crustacea, cladocera).
AB  - The extracellular hemoglobins of cladocerans derive from the aggregation of 12
      two-domain globin subunits that are apparently encoded by four genes. This study
      establishes that at least some of these genes occur as a tandem array in both
      Daphnia magna and Daphnia exilis. The genes share a uniform structure; a bridge
      intron separates two globin domains which each include three exons and two
      introns. Introns are small, averaging just 77 bp, but a longer sequence (2.2-3.2
      kb) separates adjacent globin genes. A survey of structural diversity in globin
      genes from other daphniids revealed three independent cases of intron loss, but
      exon lengths were identical, excepting a 3-bp insertion in exon 5 of
      Simocephalus. Heterogeneity in the extent of nucleotide divergence was marked
      among exons, largely as a result of the pronounced diversification of the
      terminal exon. This variation reflected, in part, varying exposure to concerted
      evolution. Conversion events were frequent in exons 1-4 but were absent from
      exons 5 and 6. Because of this difference, the results of phylogenetic analyses
      were strongly affected by the sequences employed in this construction.
      Phylogenies based on total nucleotide divergence in exons 1-4 revealed affinities
      among all genes isolated from a single species, reflecting the impact of gene
      conversion events. In contrast, phylogenies based on total nucleotide divergence
      in exons 5 and 6 revealed affinities among orthologous genes from different taxa.

PMID- 10594179
TI  - Preserved close linkage between the genes encoding troponin I and troponin T,
      reflecting an evolution of adapter proteins coupling the Ca(2+) signaling of
      contractility.
AB  - Ca(2+)-regulated motility is essential to numerous cellular functions, including
      muscle contraction. Systems with troponin C, myosin light chain, or calmodulin as
      the Ca(2+) receptor have evolved in striated muscle and other types of cells to
      transduce the cytoplasm Ca(2+) signals into allosteric conformational changes of
      contractile proteins. While these Ca(2+) receptors are homologous proteins, their
      coupling to the responding elements is quite different in various cell types. The
      Ca(2+) regulatory system in vertebrate striated muscle represents a highly
      specialized such signal transduction pathway consisting of the troponin complex
      and tropomyosin associated with the actin filament. To understand the molecular
      mechanism in the Ca(2+) regulation of muscle contraction and cell motility, we
      have revealed a preserved ancestral close linkage between the genes encoding two
      of the troponin subunits, troponin I and troponin T, in the genome of mouse. The
      data suggest that the troponin I and troponin T genes may have originated from a
      single locus and evolved in parallel to encode a striated muscle-specific adapter
      to couple the Ca(2+) receptor, troponin C, to the actin-myosin contractile
      machinery. This hypothesis views the three troponin subunits as two structure
      function domains: the Ca(2+) receptor and the signal transducing adapter. This
      model may help to further our understanding of the Ca(2+) regulation of muscle
      contraction and the structure-function relationship of other potential adapter
      proteins which are converged to constitute the Ca(2+) signal transduction
      pathways governing nonmuscle cell motility.

PMID- 10594180
TI  - Amino acid reiterations in yeast are overrepresented in particular classes of
      proteins and show evidence of a slippage-like mutational process.
AB  - Long amino acid repeats are often observed in eukaryotic proteins. In humans,
      several neurological disorders are caused by proteins containing abnormally long
      polyglutamines. However, no systematic analysis has attempted to investigate the
      relationship between reiterations of particular amino acids and protein function,
      the possible mechanisms involved in the generation of these regions, or the
      contribution of selection in restricting their genomic distribution, in a large
      collection of wild-type proteins. We have used baker's yeast open reading frames
      to study these questions. The most abundant amino acid repeats found in yeast
      proteins are repeats of glutamine, asparagine, aspartic acid, glutamic acid, and
      serine. Different amino acid repeats are concentrated in different classes of
      proteins. Acidic and polar amino acid repeats are significantly associated with
      transcription factors and protein kinases, while serine repeats are significantly
      associated with membrane transporter proteins. In most cases the codon structures
      encoding the repeats at the gene level show a significant bias toward long tracts
      of one of the possible codons, suggesting that trinucleotide slippage has played
      an important role in generating these reiterations. However, many, particularly
      those encoding serine repeats, do not show evidence of slippage. The
      distributions of codon repeats within proteins and between coding and noncoding
      regions of the genome, and of amino acids between proteins with different
      functions, suggest that repeats of these kinds are subject to strong selection.

PMID- 10594181
TI  - Analysis of the primary sequence and secondary structure of the unusually long
      SSU rRNA of the soil bug, Armadillidium vulgare.
AB  - The complete nucleotide sequence of the SSU rRNA gene from the soil bug,
      Armadillidium vulgare (Crustacea, Isopoda), was determined. It is 3214 bp long,
      with a GC content of 56.3%. It is not only the longest SSU rRNA gene among
      Crustacea but also longer than any other SSU rRNA gene except that of the
      strepsipteran insect, Xenos vesparum (3316 bp). The unusually long sequence of
      this species is explained by the long sequences of variable regions V4 and V7,
      which make up more than half of the total length. RT-PCR analysis of these two
      regions showed that the long sequences also exist in the mature rRNA and sequence
      simplicity analysis revealed the presence of slippage motifs in these two
      regions. The putative secondary structure of the rRNA is typical for eukaryotes
      except for the length and shape variations of the V2, V4, V7, and V9 regions.
      Each of the V2, V4, and V7 regions was elongated, while the V9 region was
      shortened. In V2, two bulges, located between helix 8 and helix 9 and between
      helix 9 and helix 10, were elongated. In V4, stem E23-3 was dramatically
      expanded, with several small branched stems. In V7, stem 43 was branched and
      expanded. Comparisons with the unusually long SSU rRNAs of other organisms imply
      that the increase in total length of SSU rRNA is due mainly to expansion in the
      V4 and V7 regions.

PMID- 10594182
TI  - Ribosomal DNA intergenic spacer of the swimming crab, Charybdis japonica.
AB  - We have determined the full sequence of the ribosomal DNA intergenic spacer (IGS)
      of the swimming crab, Charybdis japonica, by long PCR for the first time in
      crustacean decapods. The IGS is 5376 bp long and contains two nonrepetitive
      regions separated by one long repetitive region, which is composed mainly of four
      subrepeats (subrepeats I, II, III, and IV). Subrepeat I contains nine copies of a
      60-bp repeat unit, in which two similar repeat types (60 bp-a and 60 bp-b) occur
      alternatively. Subrepeat II consists of nine successive repeat units with a
      consensus sequence length of 142 bp. Subrepeat III consists of seven copies of
      another 60-bp repeat unit (60 bp-c) whose sequence is complementary to that of
      subrepeat I. Immediately downstream of subrepeat III is subrepeat IV, consisting
      of three copies of a 391-bp repeat unit. Based on comparative analysis among the
      subrepeats and repeat units, a possible evolutionary process responsible for the
      formation of the repetitive region is inferred, which involves the duplication of
      a 60-bp subrepeat unit (60 bp-c) as a prototype.

PMID- 10594183
TI  - The appearance of a different DNA sequence may decrease nucleotide diversity.
AB  - Nucleotide diversity may be decreased when a different DNA sequence type appears
      in a population. This undesirable property in a genetic diversity index is
      demonstrated by mathematical examples. The possibility of this phenomenon in
      natural populations is briefly discussed.

PMID- 10594184
TI  - Ancient species flocks and recent speciation events: what can rockfish teach us
      about cichlids (and vice versa)?

PMID- 10594185
TI  - Papaya (Carica papaya) lysozyme is a member of the family 19 (basic, class II)
      chitinases.
AB  - The most comprehensive studies on a plant lysozyme (EC 3.2.1.17) are those on the
      enzyme from papaya (Carica papaya) latex, published in 1967 and 1969. However,
      the N-terminal amino acid sequence of five amino acid sequence of this enzyme,
      determined by manual Edman degradation, did not allow assignment to any of the
      much later-classified families of glycosyl hydrolases. N-Terminal sequence
      analysis of 22 residues of papaya lysozyme now shows unambiguously that the
      enzyme belongs to the family 19 chitinases. It has properties similar to those of
      basic class I chitinases with lysozyme activity, such as cleavage specificity at
      the C-1 of N-acetylmuramic acid with inversion of configuration, but as it lacks
      an N-terminal hevein domain, it should be classified as a class II chitinase.

PMID- 10594186
TI  - FORUM: Reinventing Environmental Regulation from the Grassroots Up: Explaining
      and Expanding the Success of the Toxics Release Inventory.
AB  - / The success of the Toxics Release Inventory (TRI) stands in stark contrast to
      most other environmental regulations in the United States. Between its inception
      in 1988 and 1995, releases of chemicals listed on the TRI have declined by 45%.
      We argue the TRI has achieved this regulatory success by creating a mechanism of
      "populist maxi-min regulation." This style of regulation differs from traditional
      command-and-control in several ways. First, the majorrole of public agencies is
      not to set and enforce standards, but to establish an information-rich context
      for private citizens, interest groups, and firms to solve environmental problems.
      Second, environmental "standards" are not determined by expert analysis of
      acceptable risk, but are effectively set at the levels informed citizens will
      accept. Third, firms adopt pollution prevention and abatement measures in
      response to a dynamic range of public pressures rather than to formalized agency
      standards or governmental sanction. Finally, public pressure ruthlessly focuses
      on the worst polluters-maximum attention to minimum performers-to induce them to
      adopt more effective environmental practices. TRI has inadvertently set in motion
      this alternative style of regulation that has, in turn, dramatically reduced
      toxics emissions in the United States. By properly understanding the mechanisms
      that drive TRI's accomplishments, more intentional public policy designs can
      expand the system of populist maxi-min regulation and achieve even more rapid
      toxics reduction.

PMID- 10594187
TI  - PROFILE: Examining Hazard Mitigation Within the Context of Public Goods.
AB  - / This paper presents a case study of an American barrier island devastated by a
      hurricane to show how it is addressing the free-riding problem and protecting its
      public goods, thereby contributing to hazard mitigation. It examines hazard
      mitigation and the free-riding problem within the public goods framework. Free
      riding is a term used in the public choice theory and common pool resource
      literature. It is a term used for describing the actions of rational individuals
      who freely exploit a collective or public good at the expense of others. Free
      riding is a major problem faced by public goods. The problem very frequently
      occurs in the context of hazard mitigation and coastal resource management. Very
      little is known about the factors that contribute to the promotion of hazard
      mitigation. This paper identifies some of the important factors that help local
      institutions provide and sustain hazard mitigation measures. Theoretical and
      practical implications for hazards research and disaster management policy are
      presented.

PMID- 10594188
TI  - Land Evaluation in a Salt-Affected Irrigated District Using an Index of
      Productive Potential.
AB  - / The indiscriminate allocation of funds supporting agricultural policies can
      lead to land misuse, with undesirable effects either on the shorter to mid-term
      productivity or on the environment. This article proposes a methodology, based on
      land rating, that can be useful to land-use planning or to decide about
      environmental protection measures. The methodology is applied to the land
      evaluation of a 260-km(2) semiarid irrigated area with salt-affected soils. The
      available soil map is at 1:100,000 scale and its mapping units are used for the
      land evaluation with the FAO framework. These data are then elaborated using the
      index value method. This procedure gives a map of land evaluation units and a
      table that rates the productive potential of these units for six crops: alfalfa,
      barley, maize, rice, sunflower, and wheat.

PMID- 10594189
TI  - RESEARCH: Motives as Predictors of the Public's Attitudes Toward Solid Waste
      Issues.
AB  - / Surveys focusing on solid-waste-related issues, conducted over a period of
      several years, provided data from independent samples of residents of a
      Midwestern, USA, community. The collection of these data yielded useful
      information about the relationship between residents' recycling motives and their
      attitudes toward solid waste management in light of several changes in the solid
      waste infrastructure of the community over that time. The initial survey assessed
      baseline beliefs and attitudes, while later surveys were conducted after the
      implementation of a community educational program and a curbside recycling
      program. The findings indicated that for recyclers and nonrecyclers, different
      motives predicted endorsement of solid waste programs and policies. Although a
      similar percentage of recyclers and nonrecyclers were in support of various
      proposed programs and policies, concern for the environment was found to be
      positively related to nonrecyclers' support of proposed programs, particularly
      before these programs were implemented. Prior to program implementation, motives
      other than environmental altruism were found to be related to recyclers' support
      of the programs. Additional findings support the idea that educational programs
      and increased accessibility to recycling opportunities affect the relationship
      between people's attitudes toward solid waste management and their recycling
      motives.

PMID- 10594190
TI  - Estimation of Nitrous Oxide Emissions from US Grasslands.
AB  - / Nitrous oxide (N(2)O) emissions from temperate grasslands are poorly quantified
      and may be an important part of the atmospheric N(2)O budget. In this study N(2)O
      emissions were simulated for 1052 grassland sites in the United States using the
      NGAS model of Parton and others (1996) coupled with an organic matter
      decomposition model. N(2)O flux was calculated for each site using soil and land
      use data obtained from the National Resource Inventory (NRI) database and weather
      data obtained from NASA. The estimates were regionalized based upon temperature
      and moisture isotherms. Annual N(2)O emissions for each region were based on the
      grassland area of each region and the mean estimated annual N(2)O flux from NRI
      grassland sites in the region. The regional fluxes ranged from 0.18 to 1.02 kg
      N(2)O N/ha/yr with the mean flux for all regions being 0.28 kg N(2)O N/ha/yr.
      Even though fluxes from the western regions were relatively low, these regions
      made the largest contribution to total emissions due to their large grassland
      area. Total US grassland N(2)O emissions were estimated to be about 67 Gg N(2)O
      N/yr. Emissions from the Great Plains states, which contain the largest expanse
      of natural grassland in the United States, were estimated to average 0.24 kg
      N(2)O N/ha/yr. Using the annual flux estimate for the temperate Great Plains, we
      estimate that temperate grasslands worldwide may potentially produce 0.27 Tg
      N(2)O N/yr. Even though our estimate for global temperate grassland N(2)O
      emissions is less than published estimates for other major temperate and tropical
      biomes, our results indicate that temperate grasslands are a significant part of
      both United States and global atmospheric N(2)O budgets. This study demonstrates
      the utility of models for regional N(2)O flux estimation although additional data
      from carefully designed field studies is needed to further validate model
      results.

PMID- 10594191
TI  - The ISO 14001 EMS Implementation Process and Its Implications: A Case Study of
      Central Japan.
AB  - / This study aims to investigate the ISO 14001 implementation process and its
      implications for regional environmental management. The region of Central Japan
      (known as Chubu in Japanese, which literally means center) was chosen for this
      case study. The study focuses on selected issues such as the: (1) trends and
      motives of private firms in the implementation of an ISO 14001-based
      environmental management system (EMS); (2) obstacles during system
      implementation; (3) role of the system in enhancing environmental performance
      within the certified organization; and (4) relation between the major
      stakeholders, local citizens, governments, and firms after adopting the system.
      To achieve these objectives, a questionnaire survey was mailed to all certified
      firms in the region. A 58% response was achieved overall. The results show that
      the main aims behind the adoption of ISO 14001 by firms in the Chubu region are
      to improve the environmental aspects within the enterprises and to enhance the
      employees' environmental awareness and capacity. The results have also shown that
      the ISO 14001-based EMS has had a great effect on a firm's environmental status
      as certified firms have claimed that natural resources such as fuel, water, and
      paper consumption have been more efficiently managed after adopting the system.
      Implementation of the system causes the firms to consider the role of the local
      people and the government in more effectively involving the local people in the
      firm's daily environmental activities. It also helps to enhance the environmental
      awareness among the local people. Adopting the system also promotes a better
      relation within the enterprises affiliated to the same group, such as more
      attention given by the parent firms (head offices) towards other firms working
      for the same group, or branches-mainly small and medium sized enterprises (SMEs)
      in the field of EMS. Finally, the results show that firms give serious
      consideration to their final products' impacts on the environment. In other
      words, attention is given to life cycle analysis (LCA) among certified firms.

PMID- 10594192
TI  - Manatee Mortality in Puerto Rico.
AB  - / The most pressing problem in the effective management of the West Indian
      manatee (Trichechus manatus) in Puerto Rico is mortality due to human activities.
      We assessed 90 cases of manatee strandings in Puerto Rico based on historical
      data and a coordinated carcass salvage effort from 1990 through 1995. We
      determined patterns of mortality, including type of event, condition of
      carcasses, spatial and temporal distribution, gender, size/age class, and the
      cause of death. The spatial distribution of stranding events was not uniform,
      with the north, northeast, and south coasts having the highest numbers. Six
      clusters representing the highest incidence included the areas of Fajardo and
      Ceiba, Bahia de Jobos, Toa Baja, Guayanilla, Cabo Rojo, and Rio Grande to
      Luquillo. The number of reported cases has increased at an average rate of
      9.6%/yr since 1990. The seasonality of stranding events showed a bimodal pattern,
      from February through April and in August and September. Most identified causes
      of death were due to human interaction, especially captures and watercraft
      collisions. Natural causes usually involved dependent calves. From 1990 through
      1995, most deaths were attributed to watercraft collisions. A reduction in
      anthropogenic mortality of this endangered species can be accomplished only
      through education and a proactive management and conservation plan that includes
      law enforcement, mortality assessment, scientific research, rescue and
      rehabilitation, and inter- and intraagency cooperation.

PMID- 10594193
TI  - Water-Quality Monitoring and Biological Integrity Assessment in the Indian River
      Lagoon, Florida: Status, Trends, and Loadings (1988-1994).
AB  - / The Indian River Lagoon (IRL) system that extends from Ponce DeLeon Inlet to
      Jupiter Inlet is comprised of three interconnected estuarine lagoons: the
      Mosquito Lagoon (ML), the Banana River Lagoon (BRL), and the Indian River Lagoon
      (subdivided into North Indian River Lagoon, NIRL and the South Indian River
      Lagoon, SIRL). The declines in both the areal coverage and species diversity of
      seagrass communities within the IRL system are believed to be due in part to
      continued degradation of water quality. Large inflows of phosphorus (P) and
      nitrogen (N) -laden storm-water from urban areas and agricultural land have been
      correlated with higher chlorophyll a production in the central, south central,
      and the south segments of the lagoon. In a system as large and complex as the
      lagoon, N and P limitations are potentially subject to significant spatial and
      temporal variability. Total Kjeldahl nitrogen (TN) was higher in the north (1.25
      mg/liter) and lower in the south (0.89 mg/liter). The reverse pattern was
      observed for total P (TP), i.e., lowest in the north (0.03 mg/liter) and highest
      at the south (0.14 mg/liter) ends of the IRL. This increased P concentration in
      the SIRL appears to have a significantly large effect on chlorophyll a production
      compared with the other segments, as indicated by stepwise regression statistics.
      This relationship can be expressed as follows: South IRL [chlorophyll a] = -8.52
      + 162.41 [orthophosphate] + 7.86 [total nitrogen] + 0.38 [turbidity]; R(2) =
      0.98**.

PMID- 10594194
TI  - ENVIRONMENTAL AUDITING: A Vegetation-Based Method for Ecological Diagnosis of
      Riverine Wetlands.
AB  - / The management of riverine wetlands, recognized as a major component of
      biodiversity in fluvial hydrosystems, is problematic. Preservation or restoration
      of such ecosystems requires a method to assess the major ecological processes
      operating in the wetlands, the sustainability of the aquatic stage, and the
      restoration potential of each riverine wetland. We propose a method of diagnosis
      based on aquatic macrophytes and helophytes. Plant communities are used because
      they are easy to survey and provide information about (1) the origin of a water
      supply (i.e., groundwater, seepage, or surface river water) and its nutrient
      content, (2) effects of flood disturbances, and (3) terrestrialization processes.
      The novelty of the method is that, in contrast to available typologies, it is
      based on the interference of gradients resulting from several processes, which
      makes it possible to predict wetland sustainability and restoration potential.
      These predictions result from knowledge of the processes involved in
      terrestrialization, i.e., the influence of flood disturbances, occurrence of
      groundwater supplies, trophic degree, and water permanency of the habitat during
      a yearly cycle. The method is demonstrated on five different river systems.

PMID- 10594195
TI  - History of the International Society of Surgery/Societe International de
      Chirurgie (ISS/SIC). I. Short story of Theodor Kocher's life and relationship to
      the International Society of Surgery.
AB  - With the aim of promoting progress in surgery through the friendly exchange of
      views and experience, the International Society of Surgery was founded in
      Brussels in 1902, thereby helping to overcome the narrow boundaries of that
      time's nationalism. At its first congress, the International Society of Surgery
      (ISS), otherwise known by its French name, Societe Internationale de Chirurgie
      (SIC), already numbered 638 members, among them the most important surgeons from
      all over the world. Theodor Kocher (1841-1917) was the president of the first
      congress, held in Brussels in 1905, and was also responsible for the choice of
      topics. His presidential address clearly reflected the high aims the Society set
      for itself. Kocher's personal and professional authority, his surgical skill,
      which he liked so much to communicate to his colleagues, and his international
      thinking shaped the young Society. He remained on the international committee of
      the ISS until his death. Renowned surgeons from all over the globe traveled to
      Bern to see Kocher at work, among whom were many distinguished leaders of U.S.
      surgery. Thus Kocher's contribution had a great impact on the developing surgery,
      in particular in the United States. A short curriculum outlines the personality
      of this outstanding surgeon.

PMID- 10594196
TI  - Activation of monocytes and endothelial cells depends on the severity of surgical
      stress.
AB  - Surgical injury not only induces a systemic endocrine-metabolic response but also
      influences the function of the leukocytes and endothelial cells leading to
      various systemic responses. These responses appear to depend on the severity of
      surgical stress, which differs according to the surgical procedures. In this
      study, we investigated the response of monocytes and endothelial cells, and the
      development of systemic inflammatory response syndrome (SIRS) in relation to the
      severity of surgical stress. The postoperative clinical course was evaluated
      between patients undergoing an esophagectomy (ER group) and a distal gastrectomy
      (DG group). The tumor necrosis factor alpha (TNF-alpha) production of monocytes,
      the serum interleukin 6 (IL-6) levels, the CD11b expression on either monocytes
      or granulocytes, and the intercellular adhesion molecule-1 (ICAM-1) expression on
      human umbilical vein endothelial cells (HUVECs) stimulated with culture
      supernatants of monocytes were compared between the 2 groups. The development of
      SIRS was observed in all patients in the ER group, whereas no patients
      demonstrated SIRS in the DG group. The serum IL-6 levels, TNF-alpha production of
      monocytes, and CD11b intensity on monocytes or granulocytes in the ER group were
      higher than those in the DG group. In the ER group, the ICAM-1 intensity on
      HUVECs with monocytes immediately after operation significantly increased
      compared with before the operation. In conclusion, both the CD11b expression on
      monocytes and the TNF-alpha production of monocytes are considered to reflect the
      degree of surgical stress, and the activation of endothelial cells stimulated
      with these activated leukocytes may therefore lead to both tissue and organ
      injury.

PMID- 10594197
TI  - Altered bile composition in the gallbladder and common bile duct of patients with
      anomalous pancreaticobiliary ductal junction.
AB  - The high incidence of biliary tract carcinoma in patients with anomalous
      pancreaticobiliary ductal junction (APBDJ) has been well documented. Elevation of
      the secondary and free bile acid (FBA) concentrations is considered a risk factor
      for biliary carcinogenesis in these patients. Bile from the gallbladder and
      common bile duct in 12 patients with APBDJ was analyzed and compared with
      gallbladder bile from 19 patients with gastric cancer and a normal hepatobiliary
      tract. The concentrations of secondary bile acids were significantly lower in the
      APBDJ group than in the control group, and FBA concentrations were not detected
      in the gallbladder in either group. The lysolecithin (LL) in the phospholipid,
      which is produced from lecithin by activated phospholipase A(2) in refluxing
      pancreatic juice, was significantly elevated in the APBDJ group. Elevation of the
      LL concentration in the bile is one of the factors for the development of biliary
      tract carcinoma in patients with APBDJ.

PMID- 10594198
TI  - Tauroursodeoxycholate and cholestyramine enhance biliary carcinogenesis in
      hamsters.
AB  - The aim of this study was to examine whether tauroursodeoxycholate (TUDC) and
      cholestyramine resin (CR) enhance biliary carcinogenesis in the hamster model. A
      cholecystoduodenostomy with dissection of the extrahepatic bile duct on the
      distal end of the common duct was performed on Syrian hamsters. The hamsters were
      then divided randomly into 3 groups: control group, TUDC-treated group, and CR
      treated group. All animals received N-nitrosobis(2-oxopropyl)amine (BOP) to
      initiate pancreaticobiliary cancer. The experiment was terminated at week 16 and
      the number of neoplastic lesions was counted microscopically. In the TUDC group,
      the intrahepatic biliary carcinogenesis was more accelerated than that observed
      in the control group, but no promoting effect was seen in the pancreas,
      gallbladder, or extrahepatic bile duct. In the CR group, both the intrahepatic
      biliary and the gallbladder carcinogenesis were inhibited compared with that
      observed in the control group and the TUDC group. TUDC enhanced the intrahepatic
      bile duct carcinogenesis, whereas CR inhibited both the intrahepatic bile duct
      and the gallbladder carcinoma. Bile acids were suggested to promote biliary
      carcinoma in the hamster model.

PMID- 10594199
TI  - Video-assisted thoracoscopic lobectomy achieves a satisfactory long-term
      prognosis in patients with clinical stage IA lung cancer.
AB  - We designed a prospective trial to determine the long-term prognosis of video
      assisted thoracoscopic (VATS) lobectomy versus conventional lobectomy for
      patients with clinical stage IA (T1N0M0) lung cancer. Between January 1993 and
      June 1994, 100 consecutive patients with clinical stage IA non-small cell lung
      carcinoma underwent either conventional lobectomy through an open thoracotomy
      (open group; n = 52) or VATS lobectomy (VATS group; n = 48). Lymph node
      dissections were performed in a similar manner in both groups. No significant
      differences were observed in the number of dissected lymph nodes between the 2
      groups. Pathologic N1 and N2 disease was found in 3 and 1 patients, respectively,
      from the open group, and in 2 and 1 patients, respectively, from the VATS group.
      During the follow-up period, distant metastases and local or regional recurrences
      developed in 7 and 3 of the open group patients, respectively, and in 2 and 3 of
      the VATS group patients, respectively. Two and one of the open and VATS group
      patients developed second primary cancers, respectively. The overall survival
      rates 5 years after surgery were 85% and 90% in the open and VATS groups,
      respectively (log-rank test, p = 0.74; generalized Wilcoxon test, p = 0.91). VATS
      lobectomy with lymph node dissection achieved an excellent 5-year survival,
      similar to that achieved by the conventional approach.

PMID- 10594200
TI  - Relaparotomy in peritonitis: prognosis and treatment of patients with persisting
      intraabdominal infection.
AB  - Some patients are prone to persisting intraabdominal infection regardless of
      initial eradication of the source of infection. Our aim was to characterize
      patients who had to undergo relaparotomy for persisting abdominal sepsis using
      simple clinical parameters and to define those patients who are susceptible to
      benefit of aggressive surgical treatment by early and repeated reoperations to
      control multiple organ dysfunction syndrome (MODS) caused by ongoing
      intraabdominal infection. Persisting abdominal sepsis was the cause of death in
      all of our patients who had to undergo relaparotomy. Controlling persisting
      abdominal sepsis should achieve a reduction in the tremendously high mortality
      rate. Performing a case-control study, we retrospectively reviewed 523
      consecutive patients with secondary peritonitis treated from 1986 to 1996 and
      focused our attention on 105 patients, in whom standard surgical treatment of
      secondary peritonitis failed and who had to undergo relaparotomy for persisting
      abdominal sepsis (study group). Overall, there was no significant difference in
      the postoperative mortality rate between "planned relaparotomy" and "relaparotomy
      on demand" (54.5% versus 50. 6%). Equally clear risk estimations were given
      preoperatively by both the Acute Physiology and Chronic Health Evaluation
      (APACHE) II and the Goris scores. There was a significant difference between
      patients of the control group and patients of the study group with regard to
      preoperative APACHE II score, Goris score, age >70 years, albumin <30 g/L, extent
      of peritonitis, and outcome (p = 0.0001). Reexploration performed more than 48 hr
      after the initial operation resulted in a significantly higher mortality rate
      (76.5% versus 28%; p = 0.0001). However, the time of reoperation had no
      significant impact on survival in patients with an APACHE II score of > or = 26,
      because physiologic derangement is such that only a few patients could benefit
      from reoperation. The lowest mortality rate (9%) was achieved in patients who
      underwent reoperation on demand within 48 hr. We conclude that patients >70 years
      of age with secondary peritonitis extending over the entire abdomen and a greater
      degree of physiologic compromise (serum albumin levels <30 g/L, preoperative
      APACHE II scores >20, and existing organ failure measured by the Goris score) are
      at high risk for developing persistent intraabdominal infection. Our data show
      that timely relaparotomy provides the only surgical option that significantly
      improves outcome. However, aggressive surgical treatment has reached its limit in
      patients whose source of infection could not be controlled at the initial
      operation. To improve overall survival the decision to perform a relaparotomy on
      demand after an initially successful eradication of the source of infection must
      be made within 48 hr, at least before MODS emerges.

PMID- 10594201
TI  - Syringe pressure irrigation of subdermic tissue after appendectomy to decrease
      the incidence of postoperative wound infection.
AB  - To evaluate syringe pressure irrigation of the surgical wound to decrease its
      infection after appendectomy, we designed a randomized control trial at the
      Emergency Department of Mexico City General Hospital, including 350 patients with
      acute abdomen suggestive of appendicitis, without any other infection clinically
      evident. The trial was randomized into 2 groups. Group I patients received
      prophylactic systemic antibiotics before surgery. Group II patients received the
      same prophylactic systemic antibiotics plus syringe pressure irrigation of the
      surgical wound with 300 ml of saline solution using a 20-ml syringe with 19-gauge
      intravenous (IV) catheter to measure the incidence of postoperative wound
      infection. In our results, 283 patients had appendicitis. Of these, 188 were
      uncomplicated (66.4%) and 95 (33.6%) were complicated. Of the complicated cases,
      40 were assigned to group I, and of these, 29 (72. 5%) developed wound infection.
      In group II there were 55 patients and only 9 (16.3%) developed wound infection
      after syringe pressure irrigation [p = 0.000001; 95% confidence interval (CI) =
      0.02-0.22]. We conclude that syringe pressure irrigation of the surgical wound
      after appendectomy contributes significantly to decrease the incidence of
      postoperative wound infection in complicated cases. It is a cheap, safe, and
      accessible method in any surgical room.

PMID- 10594202
TI  - Intraoperative ultrasonography versus helical computed tomography and computed
      tomography with arterioportography in diagnosing colorectal liver metastases:
      lesion-by-lesion analysis.
AB  - Helical computed tomography with arterioportography (CTAP) and intraoperative
      sonography (IOUS) are both recognized to be extremely sensitive in the detection
      of liver metastases measuring <2 cm in diameter. As sensitivity and specificity
      values for both techniques differ significantly in the literature and in default
      of sufficient published data regarding this subject, a lesion-by-lesion analysis
      was considered necessary. Accuracy of IOUS was compared with helical computed
      tomography (CT) and portal-phase contrast enhancement (CTAP) in the preoperative
      detection of liver metastases from colorectal carcinoma projected as a
      prospective blinded study. Cost efficiency should be determined. Liver CTAP and
      IOUS were evaluated in 33 patients with colorectal carcinoma. Metastases were
      resected in 10 cases, and the remaining 23 patients were observed for follow-up
      with CT investigations every 3 months for a period of 1 year. CTAP and IOUS
      detected all 13 lesions measuring 5-10 mm (13/13). One metastasis measuring >10
      mm was missed by IOUS. CTAP presented an ideal sensitivity of 100%, but
      specificity was as low as 68%. IOUS sensitivity was 98% and specificity was 95%.
      IOUS and CTAP are of comparable value regarding the detection of liver metastases
      <10 mm. Both techniques may be used if resections of synchronous or metachronous
      metastases are planned in order not to miss limiting small lesions and to prevent
      superfluous liver surgery. Helical CT scan with dynamic intravenous contrast
      enhancement is considered the most cost-effective preoperative staging method,
      although local staging may not be achieved because of insufficient intraabdominal
      survey.

PMID- 10594203
TI  - Lidocaine-metabolizing activity after warm ischemia and reperfusion of the rat
      liver in vivo.
AB  - The effect of warm ischemia on lidocaine-metabolizing activity was examined in
      vivo. Total liver ischemia was produced for 1 hr in Sprague-Dawley rats by
      clamping the portal vein and hepatic artery at the hilum. Livers were then
      reperfused, and liver microsomes were prepared before and 0, 2, 6, and 24 hr, and
      3, 6, and 10 days after reperfusion. Microsomal lidocaine-metabolizing activity
      and cytochrome P-450 content were examined. Lidocaine N-deethylase activity was
      decreased from 2.25 +/- 0.33 to 0.97 +/- 0.21 nmol/mg protein/min (mean +/- SD)
      24 hr after reperfusion. This inhibition was prolonged, and activity gradually
      recovered after 10 days. The cytochrome P-450 content showed the same tendency.
      On the other hand, serum levels of alanine aminotransferase increased
      significantly 2 hr after reperfusion and returned to control levels 3 days after
      reperfusion. Liver blood flow recovered rapidly after unclamping and reached
      baseline levels within 6 hr. Our results suggest that after warm ischemia,
      prolonged hepatic dysfunction in drug metabolism, which cannot be detected by
      evaluating serum enzymes or liver blood flow, exists at the microsomal level.

PMID- 10594204
TI  - Clinicopathologic correlation of p53 protein overexpression in adenoma and
      carcinoma of the ampulla of Vater.
AB  - It has been well documented that ampullary carcinoma arises from a precancerous
      lesion, but there have been few studies concerning changes at the molecular level
      during the adenoma-carcinoma sequence. In this study, p53 overexpression during
      the progression of carcinoma was compared and the relation between p53 expression
      and prognosis was analyzed. Ninety-four cases of adenocarcinoma of the ampulla of
      Vater were reviewed histopathologically and examined for overexpression of p53
      protein using the DO-7 (mouse monoclonal; DAKO, Glostrup, Denmark) antibody. The
      correlation of p53 overexpression with the existence of adenoma, clinical stage,
      histologic grade, and overall survival was investigated. The proportion of p53
      positive cases among normal mucosa, adenoma, early stage carcinoma (I and II),
      advanced stage carcinoma (III and IV), and metastatic lesion was 0% (0/94), 14.3%
      (6/42), 32.3% (20/62), 53.1% (17/32), and 63.3% (19/30), respectively. The
      existence of adenoma or histologic grade of carcinoma did not correlate with p53
      overexpression. The carcinoma having adenomatous component was more common in
      early stages (54.8% in stages I and II, 25% in stages III and IV; p = 0. 006) and
      in well-differentiated carcinoma (p = 0.001). The existence of adenoma or p53
      overexpression did not independently correlate with prognosis. In contrast, the
      p53 overexpressed group without adenoma showed a worse prognosis than the
      remaining patients (p = 0. 0006) and this trend was still demonstrable when the
      groups were compared stage by stage. In ampullary carcinoma, p53 abnormality
      occurs during malignant transformation from the adenoma and continues during the
      tumor progression in carcinoma. The clinical prognosis of de novo carcinomas with
      p53 overexpression was worse than that of the remaining patients.

PMID- 10594205
TI  - Prospective study of gastric outlet obstruction in unresectable periampullary
      adenocarcinoma.
AB  - Controversy persists regarding the role of prophylactic gastrojejunostomy in
      patients with unresectable periampullary adenocarcinoma. In review of the
      retrospective series, presence of gastric outlet obstruction (GOO) has been
      claimed to be a bad prognostic sign. This prospective study aimed to clarify the
      necessity of routine prophylactic gastrojejunostomy in patients with unresectable
      periampullary adenocarcinoma. The incidence and prognostic significance of GOO
      were also evaluated. Sixty-six patients with unresectable periampullary
      adenocarcinoma were enrolled. They were divided into 2 groups to receive either a
      single biliary bypass or a double bypass (concomitant gastric and biliary
      bypasses) if they had GOO. The single bypass group was followed up to assess the
      incidence of GOO and subsequent need of a gastric bypass. Prognostic factors were
      evaluated by univariate and multivariate analyses. Forty-four (67%) of the
      overall 66 patients presented with GOO at the time of diagnosis. There was no
      statistical difference regarding the morbidity and mortality between the 2
      groups, except longer (7 days) hospital stay in the double bypass group. Seven
      (31.8%) of the 22 patients in the single bypass group subsequently developed GOO
      an average of 6.2 +/- 1.0 months after their initial biliary bypass. By
      univariate analysis, significant prognostic factors for unresectable
      periampullary adenocarcinoma were: GOO (p = 0.0379), pancreatic head origin (p =
      0. 0146 by univariate analysis), and distant metastasis (p < 0.0001). After
      multivariate analysis, only pancreatic head origin and distant metastasis
      remained significant independent factors of poor prognosis. In conclusion,
      gastrojejunostomy should be performed prophylactically in addition to a biliary
      bypass in patients with unresectable periampullary adenocarcinoma. The presence
      of GOO is not an independent factor of poor prognosis, but a reflection of the
      aggressive biologic behavior of pancreatic head adenocarcinoma.

PMID- 10594206
TI  - Pylorus-preserving total pancreatectomy for pancreatic cancer.
AB  - Standard total pancreatectomy (TP) combined with gastric resection often results
      in uncontrollable diabetes and malnutrition. Pylorus-preserving total
      pancreatectomy (PPTP) and standard TP for pancreatic cancer were compared in
      terms of operative outcomes, nutritional recovery, and long-term survival. Twenty
      four patients with pancreatic ductal adenocarcinoma (n = 14) or intraductal
      papillary mucinous carcinoma (N = 10) underwent PPTP (n = 10) or standard TP (n =
      14). There were no significant differences in age, gender, or tumor type or stage
      between the PPTP and standard TP groups. Early (within 30 days of surgery)
      morbidity and mortality rates were 20% and 0% for PPTP and 29% and 7% for
      standard TP, respectively. Delayed gastric emptying occurred in 2 patients in
      each group. The incidence of late complications, including uncontrollable
      diabetes, diarrhea, and malnutrition, tended to be lower after PPTP (30%) than
      after standard TP (69%). Serum albumin and body weight at 6 months after surgery
      were significantly higher in the PPTP than in the standard TP group. Regardless
      of the tumor type, long-term survival did not differ significantly between
      patients receiving PPTP and those with standard TP. PPTP for pancreatic cancer
      improves nutritional recovery, without compromising long-term survival, compared
      with standard TP.

PMID- 10594207
TI  - DNA ploidy status and proliferative activity as markers of malignant potential in
      Barrett's esophagus: flow cytometric study using routinely paraffin-embedded
      tissue.
AB  - Regular endoscopic surveillance is recommended for patients with Barrett's
      esophagus to detect dysplasia and to diagnose carcinoma while it is in an early
      and possibly treatable stage. However, there are numerous unknown aspects
      regarding the natural history of dysplasia in this disease, and there is still a
      need for more accurate markers of risk of a malignant change. The aim of this
      study was to investigate the usefulness of DNA flow cytometry in Barrett's
      esophagus to define subgroups of patients showing similar histologic findings but
      with a different malignancy potential. Routinely formalin-fixed and paraffin
      embedded tissues of 43 patients with Barrett's esophagus were processed for flow
      cytometric measurements (ploidy, proliferative index) and the results were
      compared with the histologic evolution observed in these patients. Only in the
      group of patients with "indefinite" dysplasia did we find statistically
      significant differences between the samples from patients with and without
      progression to more severe lesions (mean proliferative index of stable patients:
      5.2% versus 8.3% in patients with progression, p = 0.001, Student's t-test). The
      presence in the flow cytometric analysis of a DNA aneuploid cell line is closely
      related to the presence of severe histologic alterations (i.e., high-grade
      dysplasia: p < 0.001, Fisher's exact test). Our results suggest that this
      procedure is at least capable of distinguishing between a real, although
      incipient, neoplastic process and morphologic changes of a reactive or reparative
      type. The increment in the tissue proliferative index could be an indicator of an
      early genomic instability which, with time, will develop into lesions with a more
      altered DNA content: aneuploidy.

PMID- 10594208
TI  - Anastomotic diameters and strictures following esophagectomy and total
      gastrectomy in 256 patients.
AB  - The prevalence of anastomotic strictures in esophageal anastomoses provides us
      with limited information about the anastomotic healing process. This prospective
      study evaluates the exact esophageal anastomotic diameters in 256 patients who
      underwent esophagectomy and esophagogastrostomy without pyloroplasty (n = 107) or
      total gastrectomy and Roux reconstruction (n = 149). No perioperative
      chemoradiotherapy was given. Anastomotic strictures and diameters were assessed
      during endoscopy by a separately inserted (inflated to the anastomotic width)
      balloon catheter. The anastomotic diameters increased significantly during the
      first postoperative year in the esophagectomy (p = 0.001) and gastrectomy (p <
      0.001) groups. The anastomoses in the gastrectomy group were significantly wider
      than those in the esophagectomy group 3 (25.7 versus 19.9 mm), 6 (28.5 versus
      22.0 mm), and 12 (30.5 versus 23.3 mm) months after surgery (p < 0.001). Neither
      the anastomotic site (neck or chest) in the esophagectomy group (p = 0.176) nor
      that in the gastrectomy group (abdomen or chest) (p = 0.577) influenced the
      anastomotic diameter. Benign anastomotic strictures were most frequently found
      after 3 months and after esophagectomy. Esophagojejunostomies performed with 2
      linear stapling devices or cartridge size 28 mm showed the widest anastomoses
      with only 1 stricture. Esophagogastric anastomoses following esophagectomy are
      narrower and develop more strictures than esophagojejunal anastomoses after total
      gastrectomy, but both dilate during the first year.

PMID- 10594209
TI  - Gastric acidity following pancreaticogastrostomy with pylorus-preserving
      pancreaticoduodenectomy.
AB  - Pancreaticogastrostomy (PG) has been reintroduced and employed occasionally as a
      useful alternative to pancreaticojejunostomy (PJ) after Whipple resection or
      pylorus-preserving pancreaticoduodenectomy (PPPD). Although the physiologic
      alteration in the stomach is important for the correlation between gastric and
      pancreatic functions, the actual intragastric pH profile after PG is still
      unclear. This study was conducted to investigate the physiologic changes in
      gastric pH and serum gastrin and secretin levels before and after PPPD
      reconstructed with PG (PPPD-PG) in humans. Twenty-four hour continuous
      intragastric pH and serum gastrin and secretin levels in the fasting state were
      examined in 25 patients who had undergone PPPD-PG. No peptic ulcer was detected
      after the operation. After PG, serum gastrin and secretin levels were unchanged.
      Twenty-four hour gastric pH monitoring revealed two distinct patterns during the
      nocturnal period before the operation: patients with acid-type secretion (n = 11)
      exhibited a persistent acid pH, whereas those with alkaline-type secretion (n =
      14) had cyclic variations between an acid and an alkaline pH value. After PG, in
      both acid- and alkaline-type patients, median pH and percentages of time that the
      gastric pH was less than 4 (% pH < 4) and more than 6 (% pH > 6) did not change,
      and circadian pH patterns also remained unchanged. These results suggest that
      PPPD-PG has little influence on gastric acidity, and the neurohumoral relation
      between the stomach, duodenum, and pancreas is preserved after PG. Therefore,
      physiologically, PG can be recommended as a reconstructive procedure after PPPD.

PMID- 10594210
TI  - Therapeutic splenectomy in immune thrombocytopenic purpura.
AB  - The effects of splenectomy in 41 patients managed from 1982 to 1995 at Sher-i
      Kashmir Institute of Medical Sciences, Srinagar (Jammu and Kashmir), India, were
      studied. Immune thrombocytopenic purpura (ITP) was the main indication for
      therapeutic splenectomy among all the hematologic disorders. The mean age was 30
      years (range 7-64), and the male to female ratio was 1.05:1. The mean platelet
      count in the preoperative period was 31,751/mm(3) (range 4000-85,000). All
      patients presented with thrombocytopenia, i.e., platelet count of <100,000/mm(3).
      In addition, 5 patients presented with anemia, i.e., Hb <10 g%. Among the
      patients with thrombocytopenia, 30 patients presented with counts <50,000/mm(3)
      and 11 patients presented with counts between 50,000-100,000/mm(3). None of the
      patients presented with leukopenia. The morbidity observed was 15% and mortality
      was 2%. The response to splenectomy was complete for thrombocytopenia in 3
      patients and partial in 5 patients; 4 patients failed to show any response. In
      anemic patients, 4 patients showed complete response and 1 patient showed no
      response. The prognosis was excellent in patients with platelet count
      >50,000/mm(3), age <50 years, no concomitant disease, and disease of shorter
      duration.

PMID- 10594211
TI  - Factors affecting recurrence following incisional herniorrhaphy.
AB  - The purpose of this study was to determine the influence of chronic illness,
      obesity, and type of repair on the likelihood of recurrence following incisional
      herniorrhaphy. The medical records of 77 patients who underwent elective repair
      of a midline incisional hernia at the Dallas Veterans Affairs Medical Center
      between 1991 and 1995 were reviewed. Demographic data, presence of chronic
      illnesses, type of repair, and presence of recurrence were noted. Ninety-six
      percent of the patients were men, with an average age of 59 years. More than 50%
      of the patients had chronic lung or cardiac diseases and more than 40% weighed >
      or = 120% of their ideal body weight and had a body mass index (BMI) > or = 30.
      Sixty-two percent of the patients underwent primary reapproximation of the fascia
      (tissue repair), whereas 38% underwent repair with prosthetic material
      (prosthetic repair). The overall recurrence rate was 45%, with a median follow-up
      of 45 months (range 6-73). Seventy-four percent of the recurrences presented
      within 3 years of repair. The recurrence rate for those patients undergoing a
      tissue repair was 54%, whereas the recurrence rate following prosthetic repair
      was 29%. The incidence of recurrence for patients with pulmonary or cardiac
      disease or diabetes mellitus was similar to that of patients without these
      illnesses. The percent ideal body weight and BMI of patients who developed a
      recurrent hernia, particularly following a prosthetic repair, were significantly
      greater than those of patients whose repairs remained intact. These data strongly
      support the use of prosthetic repairs for incisional hernias, particularly in
      patients who are overweight.

PMID- 10594212
TI  - Muscular performance and fatigue in primary hyperparathyroidism.
AB  - The purpose of this study was to evaluate changes in muscular strength and
      endurance, work capacity, and subjective fatigue following surgical treatment of
      primary hyperparathyroidism (pHPT), and to assess whether changes in muscular
      function were due to changes in activation of the muscles. A prospective
      consecutive study design was used, and patients surgically treated for nontoxic
      goiter served as controls. Nineteen female patients with mild to moderate pHPT
      and 20 controls were included. Maximal isometric handgrip and quadriceps
      strength, quadriceps endurance (intermittent stimulation), and quadriceps
      activation (superimposed twitch technique) were used for evaluation of muscular
      function. All patients were operated on successfully. Knee extension strength
      increased by 17 +/- 17% (mean +/- SD; p = 0.0004) in the patients, whereas no
      change was observed in the controls. The relative strength increase correlated
      positively to patient age at operation (r = 0.52, p = 0.02). Handgrip strength,
      quadriceps endurance, and general work capacity did not change in any group after
      operation. Subjective fatigue was preoperatively higher in patients than in
      controls (p = 0.01), and decreased postoperatively to the level of controls. In
      conclusion, women with pHPT increase knee extension force after parathyroidectomy
      as a result of increased force generation capacity of the muscle. If change in
      physical performance is a determinant for change in subjective fatigue in pHPT
      after operation, then change in strength of the quadriceps muscle seems to be of
      primary importance, whereas handgrip strength, muscular endurance, and work
      capacity do not seem to be important. The cause of the increasing strength
      benefit with increasing age at operation as found in this study needs further
      investigation.

PMID- 10594213
TI  - Long-term results of total adrenalectomy for Cushing's disease.
AB  - The objective of this study was to present the long-term results of total
      adrenalectomy for Cushing's disease. Forty-four patients undergoing total
      adrenalectomy for Cushing's disease between 1953 and 1989 at Leiden University
      Medical Center, The Netherlands, were studied retrospectively. Remission was
      achieved in 42 patients (95%), with a mean duration of 19 years. Adrenal remnants
      were observed in 12 patients (27%), and were without clinical consequence in the
      majority of patients, but caused early recurrent disease in 2 patients. Nine
      patients (20%) experienced Addisonian crises up to 30 years following treatment.
      Nelson's syndrome developed in 10 patients (23%) 7-24 years following total
      adrenalectomy. Prior pituitary irradiation was a protective factor against
      Nelson's syndrome as it delayed its onset (p = 0.025). On the other hand,
      subnormal dose or noncontinuous glucocorticoid replacement therapy was associated
      with increased risk of development of Nelson's syndrome (p = 0.047). The
      incidence of Nelson's syndrome increased with prolonged follow-up, and female
      patients seemed to be at increased risk. Quality-of-life assessment showed less
      favorable scores on mental health and health perception scales, for which no
      explanation can be found except the long-lasting metabolic effects of Cushing's
      disease, even when successfully treated. In conclusion, total adrenalectomy
      remains the final treatment for Cushing's disease. The presence of adrenal
      remnants which can cause recurrent disease and the development of Nelson's
      syndrome during prolonged follow-up enhance the need for continued regular follow
      up. Pituitary irradiation prior to total adrenalectomy delays the onset of
      Nelson's syndrome.

PMID- 10594214
TI  - Operative management of civilian rectal gunshot wounds: simpler is better.
AB  - Extraperitoneal rectal gunshot wounds have been managed with a variety of methods
      from simple diverting colostomy to combinations of rectal repair, proximal
      diversion, transperitoneal or presacral drainage, and distal bowel irrigation
      techniques. Treatment methodology is chosen based on anecdotal experience, and
      there is no clear evidence that any technique is superior to the others. The
      objective of this study was to compare 3 methods of managing civilian
      extraperitoneal gunshot wounds. Retrospective analysis of 30 consecutive patients
      with extraperitoneal rectal gunshot wounds was undertaken. Patients were treated
      with 1 of these 3 techniques: (1) simple diverting colostomy without rectal
      repair (group A, 12 patients); (2) diverting colostomy and rectal repair (group
      B, 12 patients); and (3) diverting colostomy and presacral drainage without
      repair (group C, 6 patients). Injury, hospital course, and outcome data were
      compared. The 3 groups were similar in age, injury severity, admission
      hemodynamics, preoperative and intraoperative time, blood loss, fecal
      contamination, and associated injuries. The overall incidence of complications
      was 27% (8/27): 25% (3/12) in group A, 33% (4/12) in group B, and 17% (1/6) in
      group C (p = NS). Complications directly associated with the rectal injury were
      found in 2 cases (7%): 1 group A patient developed a vesicorectal fistula and 1
      group B patient developed a rectocutaneous fistula. For 10 patients with both
      rectal and bladder injuries, the complication rates for groups A, B, and C were
      50%, 20%, and 0%, respectively (p = NS). No patient died. In conclusion,
      diverting colostomy without rectal repair or drainage appears to be safe for the
      management of most civilian retroperitoneal rectal gunshot wounds. Additional
      surgical maneuvers may be required for combined rectal and urinary trauma or
      other complex rectal injuries. Sound surgical principles, tailored to the
      individual case, should overrule any unproven dogmas.

PMID- 10594215
TI  - Changes in intestinal transit time after proctocolectomy assessed by the
      lactulose breath test.
AB  - After proctocolectomy with ileal pouch-anal anastomosis (IPAA) patients have
      increased stool frequency and intermittently use antidiarrheal medication. In
      addition to other factors, gastrointestinal transit time (MTT) could influence
      stool frequency. The aim of this study was to investigate how MTT changes after
      IPAA and to study whether MTT has an influence on daily stool frequency. In a
      prospective trial MTT was investigated with the lactulose breath test in 12
      patients undergoing surgery for chronic ulcerative colitis (CUC) or familial
      adenomatous polyposis coli (FAPC) at different stages: before proctocolectomy,
      after IPAA with loop ileostomy, and 3 months and 1 year after ileostomy closure.
      MTT was also measured in 12 patients with IPAA, 12 patients with subtotal
      colectomy and ileorectal anastomosis (IRA), and 8 patients with conventional
      proctocolectomy and Brooke ileostomy (CPC) several years after surgery. Twelve
      healthy volunteers served as controls. Before IPAA, MTT was prolonged in CUC
      versus FAPC and controls. After restoration of gut continuity MTT was markedly
      accelerated. After 1 year MTT was slowed again, though values before
      proctocolectomy and those in controls were not reached. Several years after
      surgery MTT was significantly prolonged in IPAA and IRA versus controls. In CPC,
      MTT could not be determined by lactulose breath test. Stool frequency showed an
      inverse correlation to MTT in IPAA. In conclusion, this study shows that orocecal
      and oropouch transit are accelerated in the early postoperative period after
      (procto)colectomy but prolonged in the long-term course. Adaptation of the small
      bowel takes longer than 1 year. Impairment of stool frequency may be partly due
      to this adaptation.

PMID- 10594216
TI  - Fate of the rectum and ileal recurrence rates after total colectomy for Crohn's
      disease.
AB  - The aim of this study was to examine the fate of the rectum and ileal recurrence
      rates after total colectomy for Crohn's disease. One hundred thirty patients who
      underwent total colectomy between 1970 and 1997 were reviewed; 65 patients
      underwent end ileostomy with an oversewn rectal stump (TC+I) and 65 had
      ileorectal anastomosis (IRA). Patients treated by TC+I had significantly more
      rectal involvement (93%) than those having IRA (43%) (p < 0.0001). The incidence
      of ileal disease at the time of colectomy was similar (TC+I 34% versus IRA 32%; p
      = 0.99). Rectal recurrence requiring proctectomy was significantly more common
      after TC+I (51%) than after IRA (26%) (p = 0.01), whereas ileal recurrence
      requiring resection was significantly more common after IRA (45%) than after TC+I
      (18%) (p = 0.002). Using Kaplan-Meier methods, the 10-year cumulative probability
      of proctectomy was significantly higher after TC+I than IRA (58% versus 22%; p =
      0.0001), whereas the 10-year cumulative probability of ileal resection was
      significantly higher after IRA than TC+I (37% versus 18%; p = 0.03). In
      conclusion, the proctectomy rate is higher after colectomy and ileostomy probably
      due to a higher incidence of preoperative rectal involvement. By contrast, the
      ileal recurrence rate is higher after colectomy and IRA.

PMID- 10594217
TI  - Anal surgical techniques in early Ottoman period performed by Serefeddin
      Sabuncuoglu.

PMID- 10594218
TI  - Phototrophic biofilms on ancient Mayan buildings in Yucatan, Mexico.
AB  - Buildings at the important archaeological sites of Uxmal and Kabah, Mexico, are
      being degraded by microbial biofilms. Phospholipid fatty acid (PLFA) and
      chlorophyll a analyses indicated that phototrophs were the major epilithic
      microorganisms and were more prevalent on interior walls than exterior walls.
      Culture and microscopical techniques showed that Xenococcus formed the major
      biomass on interior surfaces, but the stone-degrading genera Gloeocapsa and
      Synechocystis were also present in high numbers. Relatively few filamentous algae
      and cyanobacteria were detected. The fatty acid analysis also showed that complex
      biofilms colonize these buildings. Circular depressions observed by scanning
      electron microscopy (SEM) on stone and stucco surfaces beneath the biofilm
      corresponded in shape and size to coccoid cyanobacteria. SEM images also
      demonstrated the presence of calcareous deposits on some coccoid cells in the
      biofilm. Phototrophic biofilms may contribute to biodegradation by (1) providing
      nutrients that support growth of acid-producing fungi and bacteria and (2) active
      "boring" behavior, the solubilized calcium being reprecipitated as calcium
      carbonate.

PMID- 10594220
TI  - Expression of marker RNAs in Pseudomonas putida.
AB  - A broad-host-range vector that expresses a unique artificial RNA in Pseudomonas
      putida has been developed. This vector was derived from the plasmid pBBR1MCS and
      incorporates regulatory regions from the Escherichia coli ribosomal operon, rrnB.
      These include the promoters P1 and P2, and the terminators T1 and T2. The gene
      for the artificial RNA was derived from Vibrio proteolyticus 5S rRNA. The
      artificial RNA product accumulates to a level that is 10-20% of the total 5S rRNA
      in P. putida. The RNA product is not incorporated into ribosomes and has a
      minimal effect on cell growth rate. In contrast, when wild-type V. proteolyticus
      5S rRNA was expressed from the vector, it was incorporated into ribosomes. It is
      expected that this new vector system will allow artificial RNA expression systems
      to be readily developed for a large variety of species.

PMID- 10594221
TI  - Clarithromycin and amoxicillin susceptibility of Helicobacter pylori strains
      isolated from adult patients with gastric or duodenal ulcer in Italy.
AB  - Helicobacter pylori strains, isolated from 100 gastric biopsies from 49
      previously untreated adult patients with endoscopy and histology-confirmed
      gastric or duodenal ulcer, were tested for in vitro antimicrobial susceptibility.
      Strains were isolated from biopsies of 75.5% (37 of 49) patients before therapy
      and of 13.5% after therapy. Clarithromycin and amoxicillin susceptibility testing
      was performed on pretreatment and posttreatment strains by using the agar disk
      diffusion method and E-test, a quantitative technique for the minimal inhibitory
      concentration (MIC) determination. All strains (n = 53) were susceptible to
      amoxicillin by the two methods. Three strains of 34 (8.8%) patients were
      resistant to clarithromycin: two by both methods and one by E-test (MIC > 2
      microg/ml). E-test, although more expensive than the disk diffusion method, is
      easy to perform and is a reliable method for testing H. pylori susceptibility to
      antimicrobial agents in the clinical microbiology laboratory.

PMID- 10594222
TI  - Double cell bulk acoustic wave sensor for ion chromatographic study of the
      relation between magnesium and growth of organisms.
AB  - An ion chromatography (IC) method with a double cell bulk acoustic wave (DCBAW)
      detector was used for the detection of magnesium concentration decrease during
      the culture of whole cells. The detector parameters were optimized according to
      its theoretical equation, including the cell constants and the background
      conductance of the adjusting cell. A low temperature coefficient and thus high
      sensitivity were obtained by this method. The detection limit is 0.01 ppm, and
      the linear range is 0.05-50 ppm. A new mathematical model was developed to
      describe the growth of the cell. The baseline for this model is the concept that
      a noninteractive growth process occurs among perfectly substitutable nutrients if
      the locus of points of the substrate concentrations producing equal growth rate
      is linear. The monitoring results agreed well with the calculated results.

PMID- 10594223
TI  - Production of 10-ketostearic acid and 10-hydroxystearic acid by strains of
      Sphingobacterium thalpophilum isolated from composted manure.
AB  - Six strains of Sphingobacterium thalpophilum were isolated from a compost mixture
      enriched with oleic acid. These strains converted oleic acid to 10-ketostearic
      acid (10-KSA; 87-94% of the total conversion product) and to 10-hydroxystearic
      acid (10-HSA; 6-13%) exhibiting three levels of total product yields. The
      predominant production of 10-KSA by these new S. thalpophilum isolates is in
      contrast to strain 142b (NRRL B-14797) previously isolated from a commercial
      compost, which produces exclusively 10-HSA. The production yield of greater than
      75% 10-KSA was achieved in 36 h, acting on 0.26 g of oleic acid in 30-ml
      fermentation broth incubated with agitation at 28 degrees C. For easy
      maintenance, fast-growth, and high bioreactivity, these S. thalpophilum strains
      are suited for developing a large-scale production of 10-KSA and 10-HSA.

PMID- 10594224
TI  - Morphology and general characteristics of phages specific for Astragalus cicer
      rhizobia.
AB  - Three newly isolated phages, K1, K2, and C1, specific for A. cicer rhizobia were
      characterized by their morphology, host range, rate of adsorption, restriction
      endonuclease patterns, and DNA molecular weights. All three phages were
      classified to the morphological group B of Bradley's (Siphoviridae family) on the
      basis of presence of hexagonal in outline heads and long noncontractile tails.
      Phages K1, K2, and C1 are related by host range and restriction endonuclease
      patterns. The molecular weights of phage DNAs estimated from restriction enzyme
      digests were in the range from 64.6 kb to 68.5 kb.

PMID- 10594225
TI  - Nucleotide sequence of the gene encoding the BstLVI DNA methyltransferase:
      comparison with other amino-DNA methyltransferases.
AB  - The nucleotide sequence of a 2837-base pairs (bp) EcoRI-PvuI fragment of Bacillus
      stearothermophilus LV chromosomal DNA encoding the bstLVIM gene was determined.
      It revealed a large open reading frame (ORF) of 1737 bp specifying a methylase of
      579 amino acid (aa) residues and Mr 66,831. This was in agreement with the size
      estimated for the M. BstLVI ( approximately 67 kDa) purified from Escherichia
      coli cells harboring a recombinant plasmid containing the bstLVIM gene and with
      results of transcription-translation experiments performed in vitro. Upstream the
      bstLVIM gene and in the opposite transcriptional orientation, there is a 81-aa
      ORF that showed great homology with the regulatory C proteins identified in other
      type II restriction and modification (R-M) systems. This 81-aa ORF precedes a
      truncated ORF of 86 aa which in turn may represent the structural gene for the
      BstLVI restriction endonuclease.

PMID- 10594226
TI  - Overexpression of the cat-86 gene is associated with thermosensitivity in
      Bacillus subtilis.
AB  - Bacillus subtilis harboring the cat-86 constitutive plasmid pPL708C2 with an
      ochre mutation at the 9th codon (terc 9) was sensitive to chloramphenicol (Cm(s))
      and exhibited relative thermostability when heated at 47 degrees C. Reversion to
      chloramphenicol resistance (Cm(r)) occurred at a frequency of 5.4 x 10(-8). All
      of the plasmid Cm(r) revertants tested were thermosensitive. Similarly, wild-type
      pPL708C2 present in B. subtilis also rendered the bacterium thermosensitive. When
      a nonsense mutation is introduced at codon 141, however, this terc 141 variant of
      pPL708C2 failed to thermosensitize B. subtilis. Another variant of pPL708C2 that
      produces intact yet catalytically inactive CAT-86 has both His-16 and His-17 at
      the active site replaced by Pro. Nevertheless, cells of B. subtilis carrying this
      variant were thermosensitive. Plasmid-free and pPL708C2-bearing strains did not
      exhibit differences in major heat shock proteins. Electron micrographs revealed a
      threefold increase of inclusion bodies present in a strain harboring pPL708C2
      when compared with those in an isogenic plasmid-free strain.

PMID- 10594227
TI  - A replication origin of Bacillus thuringiensis.
AB  - A replication origin of Bacillus thuringiensis (Bt) was found in a Bacillus
      thuringiensis-Escherichia coli shuttle vector of pHT3101. Deletion analysis
      showed that the replication origin was segregationally stable at suitable
      temperature for Bt growth. The fragment containing the replication origin was
      cloned in pUC18 and sequenced. It was 261 base pairs in length, located in the
      open reading frame 2 (ORF2) of BTSPB sequence. The 261-bp fragment was cloned in
      pBR322, creating an improved Bt-E. coli shuttle vector pBR261, which contained
      two resistance genes responsible for ampicillin and tetracycline. Our study
      showed that the replication origin structure could be recognized by replication
      protein of host cells.

PMID- 10594228
TI  - Spherical parasporal inclusions of the lepidoptera-specific and coleoptera
      specific Bacillus thuringiensis strains: a comparative electron microscopic
      study.
AB  - Four Lepidoptera-specific Bacillus thuringiensis strains that belong to the four
      H serogroups (serovars sumiyoshiensis, fukuokaensis, darmstadiensis, and
      japonensis) and a Coleoptera (Scarabaeidae)-specific strain belonging to serovar
      japonensis were examined for comparative ultrastructure of spherical parasporal
      inclusions. The prominent feature of the inclusions of the Lepidoptera-specific
      strains was the existence of thick, highly electron-dense envelopes surrounding a
      homogeneous protein matrix. The envelopes were 15.0-66.7 nm thick and consisted
      of 5-12 layers of membrane. This is also the case with inclusions of a Coleoptera
      specific strain. The ultrastructure of inclusions from the five strains was in
      marked contrast to that of the bipyramidal parasporal inclusions produced by a
      Lepidoptera-specific serovar sotto strain.

PMID- 10594229
TI  - Isolation of intracytoplasmic membrane from the methanotrophic bacterium
      Methylomicrobium album BG8.
AB  - Methane-oxidizing bacteria, including Methylomicrobium album BG8, form an
      intracytoplasmic membrane in addition to the cytoplasmic and outer membranes of
      the cell envelope. Techniques to isolate the intracytoplasmic membrane of M.
      album BG8 were developed. An intracytoplasmic membrane fraction was separated
      from a cell envelope fraction on the basis of sedimentation velocity in sucrose
      density gradients. Proteins associated with the particulate methane monooxygenase
      were found in both membrane fractions.

PMID- 10594230
TI  - News & notes: detection of microorganisms with overall cellulolytic activity.
AB  - A modification is described of the plate method for the detection of
      microorganisms with overall cellulolytic activity, including those like
      Cytophaga, in which the activity is cell bound. Within a few days of incubation
      colonies of cellulose-degrading bacteria formed holes in discs of lens paper
      placed on freshly inoculated agar plates.

PMID- 10594231
TI  - Genetic characterization of a new thermotolerant Bacillus licheniformis strain.
AB  - A potentially new thermotolerant B. licheniformis strain (code name I89),
      producer of an antibiotic active against Gram-positive bacteria, was genetically
      characterized and compared with the type strain B. licheniformis ATCC 10716,
      producer of bacitracin. Studies on DNA base composition (G + C content) and DNA
      reassociation revealed that the two strains show around 76% homology.
      Nevertheless, results obtained by rRNA hybridization, with a heterologous probe
      coding for most of the 16S region of the rRNA operon of Bacillus subtilis,
      revealed differences in the number of copies for that gene and in the
      hybridization pattern. Additionally, a different restriction digestion pattern
      was obtained when DNA was digested with the enzymes NotI, SmaI and analyzed by
      PFGE. The I89 strain holds a 7.6-kb plasmid not present in the reference strain.
      The existence of various unique restriction sites and also the stability of this
      plasmid make it ideal for the future development of a cloning and expression
      vector.

PMID- 10594232
TI  - Organization and sequence of histidine biosynthesis genes hisH, -A, -F, and -IE
      in Thermoanaerobacter ethanolicus.
AB  - Nucleotide sequence analysis of a 3.5-kb chromosomal fragment from the low G + C
      Gram-positive bacterium Thermoanaerobacter ethanolicus revealed a cluster of five
      contiguous open reading frames (ORFs) designated hisH, hisA, hisF, hisIE, and
      ORF5. The first four ORFs showed homology to genes of the histidine biosynthesis
      pathway, and ORF5 encoded a product with no significant similarities to
      polypeptides presently known. The hisH ORF was partial (truncated by cloning) and
      ORF5 was adjacent to xylF, which codes for a xylose-binding periplasmic protein.
      The five genes encoded putative proteins of >104, 237, 254, 216, and 169 amino
      acids, respectively. Amino acid sequence comparison of the four his gene products
      indicated closely related homologs in prokaryotes, varying from low G + C Gram
      positive bacteria to archaea. This is the first report of his anabolic genes in a
      thermophilic anaerobic bacterium.

PMID- 10594233
TI  - Completion of the mouse aggrecan gene structure and identification of the defect
      in the cmd-Bc mouse as a near complete deletion of the murine aggrecan gene.
AB  - Mouse cartilage matrix deficiency (cmd), an autosomal recessive phenotype caused
      by absence of aggrecan, maps to Chromosome (Chr) 7 and is caused by a 7-bp
      deletion in exon 5 generating a premature stop codon (Watanabe et al. 1994).
      Another spontaneous mutation with the same locus and phenotype, cmd-Bc, has now
      been defined as the complete loss of exons 2 to 18, resulting in a significantly
      shortened mRNA (1.2 kb). The upstream breakpoint is in intron 1, 18. 8 kb 3' of
      exon 1; the downstream breakpoint lies 10.5 kb past the final aggrecan exon 18.
      The deletion is flanked by sequences homologous to topoisomerase I and II
      cleavage sites and a 7-bp direct repeat, suggesting the defect resulted from a
      nonhomologous recombination event. Additionally, the size of the first intron and
      the intron-exon structure between exons 12 and 14 were determined, establishing
      the length of the murine aggrecan gene as 68.6 kb. This report completes the
      structural analysis of the murine aggrecan gene, defines a second null mutation,
      and reinforces the importance of aggrecan in development.

PMID- 10594234
TI  - Identification of novel non-insulin-dependent diabetes mellitus susceptibility
      loci in the Otsuka Long-Evans Tokushima fatty rat by MQM-mapping method.
AB  - The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese
      type, non-insulin-dependent diabetes mellitus (NIDDM) in humans. We have
      previously identified 11 quantitative trait loci (QTLs) responsible for NIDDM
      susceptibility on Chromosomes (Chrs) 1, 5, 7, 8, 9, 11, 12, 14, and 16 (Nidd1
      11/of for Non-insulin-dependent diabetes 1-11/oletf) by using the interval
      mapping method in 160 F(2) progenies obtained by mating the OLETF and the Fischer
      344 (F344) rats. MQM-mapping, which was applied for QTL analysis based on
      multiple-QTL models, is reported to be more powerful than interval mapping,
      because in the process of mapping one QTL the genetic background, which contains
      the other QTLs, is controlled. Application of MQM-mapping in the F(2)
      intercrosses has led to a revelation of three novel QTLs on rat Chrs 5
      (Nidd12/of), 7 (Nidd13/of), and 17 (Nidd14/of), in addition to Nidd1-11/of loci.
      The three QTLs, together with the Nidd1-11/of, account for a total of
      approximately 70% and approximately 85% of the genetic variance of the fasting
      and postprandial glucose levels, respectively, in the F(2). While the OLETF
      allele corresponds with increased glucose levels as expected for Nidd12 and
      14/of, the Nidd13/of exhibits heterosis: heterozygotes showing significantly
      higher glucose levels than OLETF or F344 homozygotes. There is epistatic
      interaction between Nidd2 and 14/of. Additionally, our results indicated that the
      novel QTLs could show no linkage with body weight, but Nidd12/of has an
      interaction with body weight.

PMID- 10594235
TI  - The Belt mutation in pigs is an allele at the Dominant white (I/KIT) locus.
AB  - A white belt is a common coat color phenotype in pigs and is determined by a
      dominant allele (Be). Here we present the result of a genome scan performed using
      a Hampshire (Belt)/Pietrain (non-Belt) backcross segregating for the white belt
      trait. We demonstrate that Belt maps to the centromeric region of pig Chromosome
      (Chr) 8 harboring the Dominant white (I/KIT) locus. Complete cosegregation
      between Belt and a single nucleotide polymorphism in the KIT gene was observed.
      Another potential candidate gene, the endothelin receptor type A gene (EDNRA),
      was excluded as it was assigned to a different region (SSC8q21) by FISH analysis.
      We argue that Belt is a regulatory KIT mutation on the basis of comparative data
      on mouse KIT mutants and our previous sequence analysis of the KIT coding
      sequence from a Hampshire pig. Quantitative PCR analysis revealed that Belt is
      not associated with a KIT duplication, as is the case for the Patch and Dominant
      white alleles. Thus, Belt is a fourth allele at the Dominant white locus, and we
      suggest that it is denoted I(Be).

PMID- 10594236
TI  - Identification of a bovine beta-mannosidosis mutation and detection of two beta
      mannosidase pseudogenes.
AB  - Beta-mannosidase deficiency results in beta-mannosidosis, a severe
      neurodegenerative lysosomal storage disease identified in cattle, goats, and
      humans. To more fully understand the molecular pathology of this disease, the
      mutation associated with bovine beta-mannosidosis was identified by sequence
      analysis of cDNA from an affected calf. A transition mutation of G to A at
      position 2574 of the cDNA coding sequence creates a premature stop codon near the
      3' end of the protein coding region. To aid commercial breeders of Salers cattle,
      a PCR-based test was developed to detect the mutation for beta-mannosidosis
      carrier screening. Application of this test also revealed the presence of two
      beta-mannosidase pseudogenes. Portions of the pseudogenes were amplified with
      allele-specific primers and then sequenced. One pseudogene was highly homologous
      (>99% sequence identity) to the expressed cDNA sequence over the 1292 bp that
      were sequenced, while the other showed more divergence (83% sequence identity) in
      the 477 bp that were sequenced. Both are processed pseudogenes that are not
      expressed. The severity of the bovine beta-mannosidosis phenotype suggests that
      the 22 C-terminal amino acids of beta-mannosidase play an important role in the
      function of this enzyme.

PMID- 10594237
TI  - Re-sequencing of DNA from a diverse panel of cattle reveals a high level of
      polymorphism in both intron and exon.
AB  - In order to assess the extent of DNA sequence variation in cattle, introns and
      exons from both the leptin and Amyloid Precursor Protein (APP) genes have been
      sequenced in a panel of DNAs derived from 22 diverse animals. Direct DNA
      sequencing of PCR products was used; thus, 44 chromosomes were studied.
      Polymorphisms were identified by manual scanning of sequence chromatograms and
      computerized sequence analysis. Twenty Single Nucleotide Polymorphisms (SNPs)
      were detected in 1788 bp sequenced from the leptin gene, giving a frequency of 1
      SNP per 89 bp. Twenty-four SNPs were detected in a 458-bp fragment of the APP
      gene; 23 of the polymorphisms were contained in a 302-bp intron 16 fragment. This
      equates to an SNP frequency of 1 per 13 bp for the intron. We can thus conclude
      that this portion of the bovine APP gene constitutes a hypermutable region.
      Nucleotide sequence diversity values of 0.019 and 0.0026 were obtained for APP
      and leptin respectively.

PMID- 10594238
TI  - Cloning of bovine LYST gene and identification of a missense mutation associated
      with Chediak-Higashi syndrome of cattle.
AB  - An inheritable bleeding disorder with light coat color caused by an autosomal
      recessive gene has been reported in a population of Japanese black cattle. The
      disease has been diagnosed as Chediak-Higashi Syndrome (CHS) of cattle which
      correspond to a human inheritable disorder caused by mutation in LYST gene. To
      characterize the molecular lesion causing CHS in cattle, cDNAs encoding bovine
      LYST were isolated from a bovine brain cDNA library. The nucleotide and deduced
      amino acid sequences of bovine LYST had 89.6 and 90.2% identity with those of the
      human LYST gene, respectively. In order to identify the mutation within the LYST
      gene causing CHS in cattle, cDNA fragments of the LYST gene were amplified from
      an affected animal by RT-PCR and their nucleotide sequences were completely
      determined. Notably, a nucleotide substitution of A to G transition, resulting in
      an amino acid substitution of histidine to arginine (H2015R) was identified in
      the affected animal. The presence of the substitution was completely
      corresponding with the occurrence of the CHS phenotype among 105 members of
      pedigrees of the Japanese black cattle and no cattle of other populations had
      this substitution. These findings strongly suggested that H2015R is the causative
      mutation in CHS of Japanese black cattle.

PMID- 10594239
TI  - A novel pleckstrin homology-related gene family defined by Ipl/Tssc3, TDAG51, and
      Tih1: tissue-specific expression, chromosomal location, and parental imprinting.
AB  - We previously described a gene, Ipl (Tssc3), that is expressed selectively from
      the maternal allele in placenta, yolk sac, and fetal liver and that maps within
      the imprinted domain of mouse distal Chromosome (Chr) 7/human Chr 11p15.5 (Hum
      Mol Genet 6, 2021, 1997). Ipl is similar to TDAG51, a gene that is involved in
      FAS/CD95 expression. Here we describe another gene, Tih1 (TDAG/Ipl homologue 1),
      with equivalent sequence similarity to Ipl. Structural prediction indicates that
      the products of these three genes share a central motif resembling a pleckstrin
      homology (PH) domain, and TIH1 protein has weak sequence similarity to the PH
      domain protein SEC7/CYTOHESIN. Like Ipl, Tih1 is a small gene with a single small
      intron. Tih1 maps to distal mouse Chr 1 and human Chr 1q31, chromosomal regions
      that have not shown evidence for imprinting and, in contrast to Ipl, Tih1 is
      expressed equally from both parental alleles. Ipl, Tih1, and TDAG51 have
      overlapping but distinct patterns of expression. Tih1 and TDAG51 are expressed in
      multiple fetal and adult tissues. In contrast, during early mouse development Ipl
      mRNA and protein are highly specific for two tissues involved in maternal/fetal
      exchange: visceral endoderm of the yolk sac and labyrinthine trophoblast of the
      placenta. These findings highlight the dominance of chromosomal context over gene
      structure in some examples of parental imprinting and extend previous evidence
      for placenta-specific expression of imprinted genes. The data also define a new
      subfamily of PH domain genes.

PMID- 10594241
TI  - The mouse silver locus encodes a single transcript truncated by the silver
      mutation.

PMID- 10594240
TI  - Alternative splicing, gene localization, and binding of SH2-B to the insulin
      receptor kinase domain.
AB  - The SH2-B protein is an SH2-domain-containing molecule that interacts with a
      number of phosphorylated kinase and receptor molecules including the insulin
      receptor. Two isoforms of the SH2-B have been identified and have been proposed
      to arise through alternate splicing. Here we have identified a third isoform of
      the SH2-B protein, SH2-Bgamma, that interacts specifically with the insulin
      receptor. This interaction required phosphorylation of residue Y1146 in the
      triple tyrosine motif within the activation loop of the IR kinase and is one of
      only two signaling molecules shown to interact directly with this residue of the
      insulin receptor kinase domain. The intron/exon structure of the SH2-B gene was
      determined. Alternate splice sites utilized to generate the different isoforms of
      the SH2-B protein were identified in the 3' end of the SH2-B gene immediately
      downstream of the exon encoding the core of the SH2 domain. Additionally, the
      chromosomal location of the SH2-B gene was determined to be the distal arm of
      mouse Chromosome (Chr) 7 in a region linked to obesity in mice.

PMID- 10594242
TI  - Sequence and chromosomal localization of the mouse ortholog of the human
      olfactory receptor gene 912-93.

PMID- 10594243
TI  - Genomic organization of the KIAA0057 gene that encodes a TRAM-like protein and
      its exclusion as a polycystic kidney and hepatic disease 1 (PKHD1) candidate
      gene.

PMID- 10594244
TI  - Hybrid Weakness in Phaseolus vulgaris L. I. Disruption of Development and
      Hormonal Allocation.
AB  - A reduced concentration of cytokinins may cause the abnormal growth and
      development found in F1 hybrids between Andean and Mesoamerican races of
      Phaseolus vulgaris L. In this study, concentrations of the transportable
      cytokinin zeatin riboside (ZR) were measured by ELISA for ZR (cross reactivities
      dihydrozeatin, 14%, zeatin 7.6%) in roots, stems, and leaves of a Phaseolus
      Mesoamerican landrace (P. vulgaris L. cv. Redkloud), an Andean landrace (P.
      vulgaris L. cv. Batt), and their F1 hybrids. Concentrations of ZR in roots and
      leaves of F1 hybrids were significantly less than that found in roots and leaves
      of parental cultivars. Approximately 90% of the ZR found in F1 hybrids was found
      sequestered in the stems, whereas cytokinins of the parental cultivars were
      distributed throughout the plant (roots: Batt 37%, Redkloud, 44%; stems: Batt
      35%, Redkloud 42%; leaves: Batt 28%, Redkloud 14%). These results suggest that
      abnormal growth and development of F1 hybrids may involve interruption of the
      regulation of cytokinin allocation, thereby disrupting the root-shoot feedback
      loop between root-sourced cytokinins and putative shoot-produced factors.

PMID- 10594245
TI  - Hybrid Weakness in Phaseolus vulgaris L. II. Disruption of Root-Shoot
      Integration.
AB  - We have been examining the importance of the root system on shoot growth and
      development using a developmentally disabled hybrid of the common bean Phaseolus
      vulgaris L. Parental cultivars (P. Vulgaris cv. Redkloud of Mesoamerican origin,
      and P. vulgaris cv. Batt of Andean origin) grow normally, but crosses produce F1
      hybrids exhibiting hybrid weakness associated with reduced root and shoot growth.
      In this study, applications of benzylaminopurine (BAP) to roots of F1 hybrids
      increased the number of root tips and leaves. Reciprocal grafting was used to
      study the effects of the root system on shoots. Grafting of roots of the
      Mesoamerican cultivar onto shoots of F1 hybrids increased the cytokinin
      concentrations in leaves of F1 hybrids and removed the characteristics associated
      with hybrid weakness. To determine whether factors in the xylem sap enhanced leaf
      growth, leaf discs were incubated on sap collected from Mesoamerican and Andean
      cultivars. Sap from Mesoamerican plants enhanced the growth of leaf discs excised
      from F1 hybrids more than sap collected from Andean cultivars. Estimates of the
      transport of zeatin riboside (ZR)-type cytokinins from roots of F1 hybrids
      indicated that transport out of hybrid roots was reduced compared with those
      transported out of Mesoamerican or Andean roots. Results suggest that ZR-type
      cytokinins are involved in hormonal integration between roots and shoots of P.
      vulgaris and that one of the barriers to hybridization between Andean and
      Mesoamerican landraces is related to hormone transport.

PMID- 10594246
TI  - The Effect of Gibberellins on Flowering in Roses.
AB  - The gibberellins A(1), A(3), A(5), A(8), A(19), A(20), and A(29) were identified
      in vegetative shoot tips of Rosa canina by comparing their mass spectra and
      Kovats retention indices with those of standards. Most wild roses have a short
      flowering season of 2-4 weeks in spring, whereas most modern cultivars flower
      recurrently. 'Felicite et Perpetue' is a short-season hybrid from a cross between
      a wild rose and a recurrent-flowering rose, whereas its sport, 'Little White
      Pet,' flowers recurrently. The concentrations of gibberellins (GAs) were measured
      in shoot apices of both cultivars. In March (before floral initiation in spring)
      the concentrations of GA(1) and GA(3) were respectively threefold and twofold
      higher in 'Felicite et Perpetue' than in 'Little White Pet.' In April (after
      floral initiation) the concentrations of both gibberellins were substantially
      greater than in March, and concentrations of GA(1) and GA(3) were, respectively,
      17-fold and 12-fold greater in 'Felicite et Perpetue' than in 'Little White Pet.'
      It is postulated that, in 'Felicite et Perpetue,' floral initiation occurs when
      concentrations of GAs are low and is inhibited when concentrations of GAs are
      high, whereas in 'Little White Pet' concentrations of GAs remain at permissive
      levels throughout the growing season. Applications of GA(1) and GA(3) to axillary
      shoots in March inhibited floral development in 'Felicite et Perpetue' but not in
      'Little White Pet.' This suggests that the combined concentration of exogenous
      and endogenous gibberellins might have been raised to inhibitory levels in the
      former but not in the latter cultivar.

PMID- 10594247
TI  - Alteration of Hormonal Levels in a Rootless Epiphytic Bromeliad in Different
      Phenological Phases.
AB  - Major changes in indole-3-acetic acid (IAA) and cytokinin (CK) levels occur at
      different phenological phases of Tillandsia recurvata shoots. This epiphytic
      rootless bromeliad was chosen as suitable material for hormonal analysis because
      CK synthesis is restricted to the shoots, thus avoiding problems in the
      interpretation of results caused by translocation and interconversion of CK forms
      between roots and leaves encountered in plants with both organs. Young plants of
      T. recurvata have weak apical dominance because side shoots appeared early in
      development, and branch growth was correlated with a strong increase in the level
      of zeatin. The flowering phase was characterized by a significant increase in
      free base CKs, zeatin, and isopentenyladenine compared with the levels found in
      adult vegetative shoots. In contrast, both free-base CKs declined in the fruiting
      phenological phase, and the IAA level increased dramatically. It was concluded
      that in phases characterized by intense organ formation, such as in the juvenile
      and flowering stages, there was an enhancement of CK content, mainly caused by
      zeatin, leading to a lower IAA/CK ratio. Higher ratios were correlated with
      phases that showed no organogenesis, such as adult and fruiting phenologies.

PMID- 10594248
TI  - Methyl Jasmonate Reduces Water Stress in Strawberry.
AB  - The effect of methyl jasmonate (MJ) on changes of oxygen-scavenging enzyme
      activities and membrane lipid composition was studied in strawberry leaves under
      water stress. Under water stress, MJ treatment reduced the increase of peroxidase
      (EC 1.11.1.7; POD) activity, maintained higher catalase (EC 1.11.1.6; CAT) and
      superoxide dismutase (EC 1.15.1.1; SOD) activities, and ascorbic acid content. In
      addition, MJ treatment reduced transpiration and membrane-lipid peroxidation as
      expressed by malondialdehyde (MDA) content, lessened the reduction of membrane
      lipids, glycolipids [monogalactosyl diglyceride (MGDG), digalactosyl diglyceride
      (DGDG)], and phospholipids [phosphatidylcholine (PC), phosphatidylethanolamine
      (PE), phosphatidylglycerol (PG), and phosphatidylinositol (PI)]. In water-deficit
      conditions, MJ treatment also alleviated the decline in the degree of fatty acid
      unsaturation and the ratio of linolenic (18:3) to linoleic acid (18:2). These
      results indicate that MJ treatment appears to alter the metabolism of strawberry
      plants rendering the tissue better able to withstand water stress.

PMID- 10594250
TI  - Comments: the old and new brigade, passing on the baton

PMID- 10594249
TI  - The Role of Abscisic Acid in Induction of Androgenesis: A Comparative Study
      Between Hordeum vulgare L. Cvs. Igri and Digger.
AB  - Under the same mannitol pretreatment and culture conditions, regeneration
      efficiency in the barley cultivar (cv.) Igri was about 10 times higher than in
      the cv. Digger, a difference only partially reflected by a difference in viable
      microspores after anther pretreatment. Therefore, a comparative study between
      cvs. Igri and Digger was carried out under various pretreatment conditions. For
      both cultivars, under water, CPW buffer and mannitol pretreatment conditions,
      there was a positive correlation between microspore viability and regeneration
      efficiency in that mannitol > CPW buffer >> water. Mannitol pretreatment of cv.
      Igri produced a much higher endogenous abscisic acid (ABA) level than as to
      Digger. Addition of ABA stimulated both percentages of viability and regeneration
      efficiency except in the case of mannitol pretreatment. Under CPW buffer
      pretreatment conditions, addition of ABA significantly stimulated regeneration
      efficiency and was ABA concentration dependent. However, cv. Digger was less
      responsive to ABA than cv. Igri. In both cultivars, under less optimal
      pretreatment conditions (e.g., water and CPW buffer), the effect of ABA was to
      stimulate increased percentages of viability and/or to reduce the number of
      binucleate microspores. Moreover, in cv. Igri, direct culture of anthers for 4
      days without pretreatment caused an increased number of binucleate microspores
      compared with microspores with pretreatment for 4 days. These binucleate
      microspores showed DNA degradation in the nuclei. However, with mannitol
      pretreatment binucleate microspores and DNA fragmentation in the nuclei of
      microspores was rarely observed. On the basis of our observations, we suggest
      that the difference in regeneration efficiency in cv. Igri and cv. Digger is
      related to the differences in endogenous ABA production levels under mannitol
      pretreatment and responsiveness to ABA. One of the effects of ABA is likely due
      to an inhibition of cell death.

PMID- 10594251
TI  - Comparison ratings of pureed versus molded fruits: preliminary results.
AB  - Food molds change the appearance of pureed items to resemble typically prepared
      food. The present study examined the perceptions of 12 adults with normal
      swallowing and two adults with impaired swallowing for typical pureed versus
      molded pureed fruits (peach and pear). Results are presented for ratings of
      overall liking, taste, texture, appearance, and ease of chewing and swallowing.
      The present findings indicated that the pureed food molds did not positively
      influence attribute ratings. For both groups of adults, the typical method of
      pureed food presentation was rated higher or very similar to the molded pureed
      fruit. Results are discussed in terms of scaling methods, criteria applied for
      ratings, and implication of altering the viscosity of pureed foods.

PMID- 10594252
TI  - Interrater and intrarrater reliability of the exeter dysphagia assessment
      technique applied to healthy elderly adults.
AB  - The purpose of this study was to evaluate the inter- and intrarater reliabilities
      of the Exeter Dysphagia Assessment Technique in a sample of elderly adults. This
      procedure uses noninvasive methods to record aspects of oral motor efficiency and
      synchronization of respiration during swallowing with the aid of specially
      developed equipment. Changes in the direction of nasal air flow, time of lip or
      tongue/spoon contact, and the time/frequency of swallow sounds are monitored and
      analyzed. Seventy records were evaluated independently by three trained assessors
      on three consecutive occasions. Interrater reliability was found to be good to
      very good for five of the respiratory variables assessed and moderate for the
      sixth. Interrater agreement was also very good for three of the timed
      oropharyngeal events assessed and moderate for the fourth. Intrarater reliability
      was very good for the same five respiratory variables and moderate for the sixth.
      Intrarater agreement was also very good for three of the timed oropharyngeal
      events and moderate for the fourth. Repeat evaluations of these records showed
      that agreement between and within raters concerning the sixth respiratory
      variable was improved substantially when the charts were examined in an enlarged
      form that provided improved resolution. We conclude that the majority of
      variables monitored by the Exeter Dysphagia Assessment Technique can be evaluated
      very reliably.

PMID- 10594253
TI  - Learning about the dynamic swallowing process using an interactive multimedia
      program.
AB  - The management of dysphagia is the largest recognized subspecialty in the field
      of speech-language pathology. Practicing speech-language pathologists require a
      comprehensive theoretical and functional knowledge base to underpin the safe and
      effective management of people with dysphagia. Students need to develop an
      understanding of the normal integrated swallow and how it can be affected to
      appreciate the assessment or treatment of dysphagia. Although students are well
      motivated to learn this material, assimilating knowledge of the dynamic nature of
      the swallow has typically been problematic because of its complex character. The
      limitations of currently available teaching resources have been addressed by the
      production of an interactive multimedia program that includes integrated
      presentation of text, graphics, voice-overs, and video and animation sequences to
      highlight various aspects of the swallowing process. Students can selectively
      manipulate parts of this process to understand the normal swallow and to simulate
      different aspects of dysfunction and the consequent effects on swallow safety and
      efficiency. Feedback from students, faculty, and experts has demonstrated that
      The Dynamic Swallow would be a valued tool in the teaching of dysphagia.

PMID- 10594254
TI  - CT study of closure of the hemipharynx with head rotation in a case of lateral
      medullary syndrome.
AB  - In a patient with unilateral pharyngeal paralysis, rotation of the head to the
      paralyzed side can effectively close the hemipharynx on that side. However, the
      exact level or place of closure is unknown. Serial computed tomography of the
      pharynx in a patient with lateral medullary syndrome showed that hemipharyngeal
      closing occurred at the level of the hyoid bone, or the hypopharyngeal cavity
      above the pyriform sinus, and that the entire space of the bilateral pyriform
      sinuses remained open despite the head rotation.

PMID- 10594255
TI  - Screening for oropharyngeal dysphagia in stroke: insufficient evidence for
      guidelines.
AB  - There is no evaluation of the evidence for the screening of oropharyngeal
      dysphagia in stroke. We reviewed the literature on clinical screening for
      oropharyngeal dysphagia in adults with stroke to determine (a) the accuracy of
      different screening tests used to detect dysphagia defined by abnormal
      oropharyngeal physiology on videofluoroscopy and (b) the health outcomes reported
      and whether screening alters those outcomes. Peer-reviewed English-language and
      human studies were sought through Medline (from 1966 to July 1997) by using the
      key words cerebrovascular disorders and deglutition disorders, relevant Internet
      addresses, and extensive hand searching of bibliographies of identified articles.
      Of the 154 sources identified, 89 articles were original, peer-reviewed, and
      focused on oropharyngeal dysphagia in stroke patients. To evaluate the evidence,
      the next selection identified 10 articles on the comparison of screening and
      videofluoroscopic findings and three articles on screening and health outcomes.
      Evidence was rated according to the level of study design by using the values of
      the Canadian Task Force on Periodic Health Examination. From the identified
      screening tests, most of the screenings were related to laryngeal signs (63%) and
      most of the outcomes were related to physiology (74%). Evidence for screening
      accuracy was limited because of poor study design and the predominant use of
      aspiration as the diagnostic reference. Only two screening tests were identified
      as accurate: failure on the 50-ml water test (likelihood ratio = 5.7, 95%
      confidence interval = 2.5-12.9) and impaired pharyngeal sensation (likelihood
      ratio = 2.5, 95% confidence interval = 1.7-3.7). Limited evidence for screening
      benefit suggested a reduction in pneumonia, length of hospital stay, personnel
      costs, and patient charges. In conclusion, screening accuracy needs to be
      assessed by using both abnormal physiology and aspiration as diagnostic markers
      for dysphagia. Large well-designed trials are needed for more conclusive evidence
      of screening benefit.

PMID- 10594256
TI  - The interdependency of protein-energy malnutrition, aging, and dysphagia.
AB  - Advancing age is increasingly associated with confounding chronic and acute
      ailments, predisposing elderly individuals to conditions such as malnutrition and
      swallowing dysfunction. This enhanced susceptibility to malnutrition and
      dysphagia in this aging demographic lends itself to exacerbating, disabling
      conditions that may result in increased morbidity and mortality in the event of
      an aspiration episode. Early identification of substandard nutritional status and
      subsequent interventiion in the elderly dysphagic population may circumvent the
      deleterious effects of malnutrition.

PMID- 10594257
TI  - The safety of flexible endoscopic evaluation of swallowing with sensory testing
      (FEESST): an analysis of 500 consecutive evaluations.
AB  - We assessed the safety of a new office or bedside method of evaluating both the
      motor and sensory components of swallowing called flexible endoscopic evaluation
      of swallowing with sensory testing (FEESST). FEESST combines the established
      endoscopic evaluation of swallowing with a technique that determines
      laryngopharyngeal sensory discrimination thresholds by endoscopically delivering
      air-pulse stimuli to the mucosa innervated by the superior laryngeal nerve.
      Endoscopic assessment of laryngopharyngeal sensory capacity followed by
      endoscopic visualization of deglutition was prospectively performed 500 times in
      253 patients with dysphagia over a 2.5-year period in a tertiary care center. The
      patients had a variety of underlying diagnoses, with stroke and chronic
      neurological disease predominating (n = 155). To determine the safety of FEESST,
      the presence of epistaxis, airway compromise, and significant changes in heart
      rate before and after the evaluation were assessed. Patients were also asked to
      rate the level of discomfort of the examination; 498 evaluations were completed.
      There were three instances of epistaxis that were self-limited. There were no
      cases of airway compromise. There were no significant differences in heart rate
      between pre- and posttest measurements (p > 0.05). Eighty-one percent of patients
      noted either no discomfort or mild discomfort as a result of the examination. In
      conclusion, FEESST is a safe method of evaluating dysphagia in the tertiary care
      setting and may also have application for the chronic care setting.

PMID- 10594259
TI  - There is a need for a regular review of swallowing ability in patients after PEG
      insertion to identify patients with delayed recovery of swallowing.

PMID- 10594260
TI  - Surgical endoscopy enters the era of electronic publication

PMID- 10594261
TI  - Factors predictive of dysphagia after laparoscopic Nissen fundoplication.
AB  - BACKGROUND: Persistent postoperative dysphagia occurs in up to 24% of patients
      who undergo a laparoscopic Nissen fundoplication for reflux disease [7]. We
      hypothesized that patient history, pH testing, and esophageal manometry could be
      used to preoperatively identify patients at risk for this complication. METHODS:
      Of 156 laparoscopic Nissen fundoplications performed over a 27-month period, we
      identified 19 patients (12%) who suffered from postoperative dysphagia longer
      than 3 months. The presenting complaint of preoperative swallowing difficulty was
      noted as was the presence of a known esophageal stricture. Preoperative pH
      testing and esophageal manometry were performed for all subjects. We compared the
      following parameters to an age and gender-matched control group: history of
      esophageal stricture, presence of preoperative dysphagia, DeMeester reflux score,
      upper esophageal sphincter pressure and relaxation, esophageal body motility,
      location of respiratory inversion point, and lower esophageal sphincter length,
      resting pressure, and relaxation. Data were compared via t-test and Fisher's
      exact test. RESULTS: Patients who presented before surgery with complaints of
      difficulty swallowing were more likely to suffer from postoperative dysphagia (p
      = 0.029). Incidence of stricture, DeMeester score, and manometric measurements
      did not differ between the dysphagia and control groups (p > 0.05 for all
      parameters). CONCLUSIONS: Although preoperative studies are not helpful in
      identifying patients at risk for persistent dysphagia after laparoscopic Nissen
      fundoplication, patients presenting with the preoperative complaint of difficulty
      swallowing are at increased risk for this complication.

PMID- 10594262
TI  - Endoscopic grading of the gastroesophageal valve in patients with symptoms of
      gastroesophageal reflux disease (GERD).
AB  - BACKGROUND: It has been suggested that endoscopic grading of the gastroesophageal
      flap valve is a good predictor of the reflux status. METHODS: To test this
      hypothesis, 268 symptomatic patients underwent endoscopic grading of the
      gastroesophageal valve using Hill's classification, with grades I through IV.
      Esophageal acid exposure, lower esophageal sphincter characteristics, and the
      degree of esophageal mucosal injury were compared among the groups. RESULTS: The
      prevalence of a mechanically defective sphincter, abnormal esophageal acid
      exposure, erosive esophagitis, and Barrett's esophagus increased with increasing
      alteration of the gastroesophageal valve. The presence of a grade IV valve
      indicated increased esophageal acid exposure in 75% of patients. As a predictor,
      this is similar to lower esophageal sphincter pressure but not as good as the
      presence of esophageal mucosal injury. CONCLUSIONS: Endoscopic grading of the
      gastroesophageal valve provides useful information about the reflux status but is
      less useful as an indicator of gastroesophageal reflux disease (GERD) than the
      presence of esophageal mucosal injury.

PMID- 10594263
TI  - Patterns of success and failure with laparoscopic Toupet fundoplication.
AB  - BACKGROUND: Advocates of the Toupet partial fundoplication claim that the
      procedure has a lower rate of the side effects of dysphagia and gas bloat than a
      complete Nissen fundoplication. However, there is increasing recognition that
      reflux control is not always as good with the Toupet procedure as with the
      Nissen. Therefore, we set out to evaluate the factors contributing to success and
      failure in patients who underwent laparoscopic modified Toupet fundoplication
      (LTF). METHODS: A total of 143 patients undergoing LTF for documented
      gastroesophageal reflux disease (GERD) were evaluated prospectively in regard to
      their outcomes over a 4-year period. All patients had preoperative
      esophagogastroduodenoscopy (EGD) and manometry; 24-h pH testing was used
      selectively. Esophageal manometry was requested of all patients 6 weeks
      postoperatively. Clinical follow-up was by office visit or questionnaire every 6
      months after surgery; patients with significant problems were investigated
      further. Failure was defined as the development of recurrent reflux documented by
      endoscopy, 24-h pH test, or wrap disruption on barium swallow, or severe
      dysphagia persisting >3 months and requiring surgical revision. RESULTS: At a
      mean follow-up of 30 months (range, 3-51), 21 of 143 patients failed LTF; two had
      dysphagia and 19 had recurrent reflux. Failure was associated with preoperative
      findings of a defective lower esophageal sphincter (LES) (14/21), complicated
      esophagitis (13/21), and failure to divide short gastric vessels (12/19) (chi
      square p < 0.05). Defective esophageal body peristalsis, present in 14 patients,
      resulted in failure in six cases. Presence of either complicated esophagitis or a
      defective LES was associated with a 3-year 50% success rate, whereas presence of
      mild esophagitis and a normal LES was reflected in a 96% 3-year success rate.
      CONCLUSION: Laparoscopic Toupet fundoplication should be reserved for milder
      cases of GERD, as assessed by manometry and endoscopy.

PMID- 10594264
TI  - Gasless vs gaseous laparoscopy in the treatment of hepatic hydatid disease.
AB  - BACKGROUND: Despite the reduced rate of occurrence, the hydatidosis of the liver
      is still taking an important place in surgical practice in Asia Minor and the
      Middle East. Traditional techniques for performing liver cyst surgery seem to be
      comparatively traumatic. In this clinical study, we present our experience with
      laparoscopic treatment of hydatid cyst of the liver and discuss the validity of
      the gasless technique as a solution to carbon dioxide (CO(2)) ensufflation
      problems. METHODS: All patients were prepared by administering albendazole for 21
      days preoperatively. Surgery was performed on 87 patients under general
      anesthesia. Working space was obtained in 51 operations by using an abdominal
      wall lifting device, Laparolift (Origin Med Systems, Menlo Park, California, USA)
      (group 1). In 36 patients, the abdominal cavity was insufflated with CO(2) gas
      (group 2). In all cases, hydatid cysts were identified, and gauze soaked in
      germicide solution were placed around them. The cysts were punctured and
      aspirated. Then germisid solution was injected into the cysts. The cysts walls
      were opened, and germinative membranes were evacuated. RESULTS: The median
      operation time was 50.49 +/- 10.9 min (range, 30-75 min) in group 1 and 70.8 +/-
      16 min (ranges 40-120 min) in group 2. The difference in the operative times of
      the two groups was significant (p < 0.01). There was no significant difference
      between the minor complications of the two groups. There were no deaths and no
      major complications or conversions to open surgery in any of the groups. There
      were no recurrences during follow-up time. CONCLUSIONS: The use of gasless
      technique for the laparoscopic treatment of liver cyst is a safe, time-saving,
      and promising procedure that can be applied in selected cases.

PMID- 10594265
TI  - Experience with percutaneous transhepatic cholangioscopy (PTCS) in the management
      of biliary tract disease.
AB  - BACKGROUND: Biliary tract disorders often present significant management
      difficulties, particularly in patients who are poor surgical candidates.
      Percutaneous transhepatic cholangioscopy (PTCS) is an infrequently utilized
      alternative that might offer significant therapeutic benefit. We reviewed our
      experience with the use of this modality as a definitive therapy for biliary
      tract disorders. METHODS: Patient records at the Atlanta VAMC and Emory
      University hospitals were reviewed. We identified 17 patients who had undergone
      25 PTCS interventions between August 1994 and December 1998. The indications for
      PTCS included dilatation of biliary-enteric anastomoses in four patients, biliary
      stone removal (with or without lithotripsy) in eight patients, stricturoplasty in
      four patients, biopsy of suspected biliary neoplasms in seven patients, and
      removal of obstructing clot in one patient. Most procedures (n = 17) were
      performed through percutaneous transhepatic tracts (12-18 Fr) that were <1 week
      old. All tracts were dilated to operating size on the day of the procedure. All
      patients received periprocedural antibiotics. RESULTS: The interventions were
      successful in seven of eight stone removals, four of five stricturoplasties,
      three of four anastomotic dilatations, seven of seven biopsies, and the single
      clot removal. The only complication involved one episode of hemobilia, requiring
      angio-embolization of a small branch of the right hepatic artery. CONCLUSIONS:
      PTCS is a safe, useful, and well-tolerated adjunct to the more common endoscopic
      and surgical techniques for managing complicated biliary tract disorders. Our
      experience suggests that PTCS can be performed early, without prolonged
      sequential dilatation of the percutaneous transhepatic tract, and may allow
      avoidance of operation in high-risk surgical candidates.

PMID- 10594266
TI  - Experimental studies of thermal therapy for severe nonvariceal bleeding in dogs.
AB  - BACKGROUND: There are several methods of achieving endoscopic hemostasis for
      nonvariceal hemorrhage, including use of a heater probe, bipolar
      electrocoagulation, use of a Gold probe, and injection therapy with epinephrine
      or ethyl alcohol. However, due to clinical variations, clinical studies comparing
      thermal with injection therapy have yielded conflicting results. Therefore, we
      used a canine model of acute bleeding from gastric serosal vessels to examine the
      efficacy of the heater probe and the Gold probe in achieving hemostasis and to
      compare the injurious effects of these methods with injection therapy. METHODS:
      Seven mongrel dogs were used in the study. Four were assigned to acute
      experiments in which transected blood vessels were allowed to bleed profusely.
      Two dogs of this group were treated with either a large or small Gold probe,
      while the other two were treated with either a large or small heater probe. In
      the other three dogs, we tested the chronic effects of the heater probe, the Gold
      probe, and injection therapy with dilute epinephrine. RESULTS: Complete
      hemostasis was achieved for all four dogs in the acute experiments. Dogs treated
      with either a large or small heater probe had coagulation necrosis that extended
      to the serosa and muscularis but not to the mucosa. The large Gold probe had
      similar results, but the small Gold probe caused tissue damage to the serosa,
      muscularis, submucosa, and mucosa at several of the application sites. Both
      probes caused scarring of the gastric wall. In the chronic experiments, we found
      that the Gold probe caused larger mucosal ulcers than the heater probe. All
      ulcers healed in 3 weeks. The epinephrine injection caused localized swelling and
      discoloration, but after 1 week the tissue returned to normal. CONCLUSIONS: Both
      the heater probe and the Gold probe are effective in achieving hemostasis in a
      canine model of nonvariceal hemorrhage, and both methods are superior to
      injection therapy. For active bleeding ulcers, we currently recommend a
      combination therapy, using first injection therapy and then a heater or Gold
      probe. However, clinicians should be aware of the potential for tissue damage.

PMID- 10594267
TI  - A cost-effective thoracoscopic treatment strategy for pediatric spontaneous
      pneumothorax.
AB  - BACKGROUND: Recent data suggest that children have a higher incidence of
      recurrence than adults after nonoperative treatment of primary spontaneous
      pneumothorax (PSP). Video-assisted thoracoscopic surgery (VATS) allows
      efficacious therapy with significantly less morbidity. We attempt to define the
      most cost-effective clinically efficacious strategy using VATS to manage
      pediatric PSP. METHODS: We retrospectively reviewed all admissions to a tertiary
      care children's hospital for PSP between January 1, 1991 and June 30, 1996.
      RESULTS: Fifteen children had 29 primary or recurrent PSPs. Mean patient age was
      14.8 +/- 1.1 years, boy-girl ratio 4:1, median body mass index 18 (normal, 20
      25), and 67% of pneumothoraces left sided. All patients were managed initially
      nonoperatively: 14 with tube thoracostomy drainage and 1 with oxygen alone. Of
      the children initially managed nonoperatively, 57% had a recurrent pneumothorax,
      and 50% of these patients eventually developed contralateral pneumothoraces.
      Nonoperative treatment for recurrence resulted in a 75% second recurrence rate.
      In contrast, eight children who underwent operative management had a 9% incidence
      of recurrence. The total for charges accrued in treating 29 pneumothoraces in
      these 15 patients was approximately $315,000. In the same population, the
      estimated charges for initial nonoperative therapy followed by bilateral
      thoracoscopy after a single recurrence would be $230,000. CONCLUSIONS: A cost
      effective treatment strategy for pediatric primary spontaneous pneumothorax is
      tube thoracostomy at first presentation, followed by VATS with thoracoscopic bleb
      resection and pleurodesis for patients who experience recurrent pneumothorax.

PMID- 10594268
TI  - Endoscopic placement of nasojejunal feeding tubes in ICU patients.
AB  - BACKGROUND: Enteral nutrition is an important component in the management of
      critically ill patients, but it may be limited by gastric ileus and unreliable
      positioning of standard feeding tubes. The purpose of this study was to determine
      the risk, utility, and outcome of endoscopically placed nasojejunal feeding tubes
      (NJT) in intensive care unit (ICU) patients. METHODS: We reviewed the records of
      all ICU patients who underwent endoscopic NJT placement from May 1995 to May
      1997. A through-the-scope method was used with placement of either an 8-Fr or 10
      Fr 240-cm tube. Comparison was made between tubes secured to a nasopharyngeal
      bridle and tubes secured without bridling. RESULTS: A total of 66 NJT were placed
      in 56 patients. Previous gastric feeds had been attempted in 39 patients (70%) an
      average of 8.4 days prior to placing the NJT. Fifty tubes (76%) were placed in
      the ICU and 16 (34%) in the OR at the time of additional procedures. Procedure
      time ranged from 7 to 28 mins (mean, 15.2), and bridling was used in 24 of 66
      placements (36%). Full caloric goal rates were achieved via 56 of 66 tubes (85%)
      at an average of 26.1 h after placement (range, 1-144). Goal rates were not
      achieved in 10 cases due to inadequate tube positioning in six, ileus in three,
      and early dislodgement in one. A procedure complication, consisting of
      aspiration, occurred in one case (1.5%). Length of tube use averaged 18.5 days
      (range, 1-74). Accidental tube dislodgement or migration occurred in 16 of 42
      (38%) nonbridled tubes vs one of 24 (4%) bridled tubes (p <.05). CONCLUSIONS:
      Endoscopic placement of nasojejunal feeding tubes in critically ill patients is a
      safe, quick, and reliable option for enteral nutrition. Full caloric goal rates
      can be achieved rapidly in a high percentage of patients, even in cases where
      previous gastric feeds have not been tolerated. Use of a nasopharyngeal bridling
      system for tube security significantly decreases the risk of migration or
      accidental tube dislodgement.

PMID- 10594269
TI  - First clinical experience with an endoscopic retroperitoneal approach for
      anterior fusion of lumbar spine fractures from levels T12 to L5.
AB  - BACKGROUND: Recent experience indicates that unstable spine fractures should be
      stabilized dorsoventrally. To avoid the high morbidity associated with the common
      anterior approach-i.e., thoraco-phreno-lumbotomy-we developed a technique that
      allows the anterior fusion of lumbar spine fractures using an endoscopic
      retroperitoneal (lumboscopic) approach. METHODS: Lumboscopic anterior fusion was
      performed a few days after the initial dorsal stabilization. The retroperitoneal
      space was accessed endoscopically via a suprailic incision and enlarged using a
      balloon spacer and CO(2) insufflation. The peritoneum and the kidney were gently
      pushed ventrally. Mobilization of the psoas muscle dorsally then allowed exposure
      of the fractured spine bodies. Via two additional trocars placed opposite the
      fractured level, the damaged disc and bone were removed, and anterior
      spondylodesis was performed with an iliac crest bone block and a titanium plate.
      RESULTS: The technique was applied successfully in 12 patients with fractures of
      L1 (n = 6), L2 (n = 4), L3 (n = 1), and L4 (n = 1) as a mono- or bisegmental
      fusion, requiring instrumentation from T12 to L5. No major complications
      (including neurological problems) were encountered. Blood loss was minimal. None
      of the patients required conversion to open surgery. Patients were mobilized
      early, starting regularly at the second postoperative day. CONCLUSIONS:
      Lumboscopic instrumentation of the lumbar spine is a safe, minimally invasive
      method for the treatment of spine fractures. The patients benefit from reduced
      pain, low morbidity, and excellent cosmetic results.

PMID- 10594270
TI  - Laparoscopic vs open splenectomy in the management of hematologic diseases.
AB  - BACKGROUND: Laparoscopic splenectomy (LS) is becoming the gold standard in the
      treatment of several splenic diseases. Shorter postoperative stay and more rapid
      return to full activity are the primary advantages of LS. METHODS: Prospective
      data collection of 44 consecutive LS (group 1) and comparison with a historical
      control group of 56 consecutive open splenectomies (OS) (group 2) were performed
      for hematologic diseases. RESULTS: The LS patients started earlier on an oral
      diet (p < 0.0001) and left the hospital sooner (p < 0.0002) than OS patients.
      Less blood transfusion (p < 0.004) and pain medication (p < 0.0001) was required
      by LS patients. They also had fewer postoperative complications (p < 0.03).
      Compared by diagnosis, patients with laparoscopic idiopathic thrombocytopenic
      purpura or Hodgkin's disease started to eat earlier (p < 0.0001) and left the
      hospital sooner (p < 0.01). Multivariate analysis showed that time to oral diet
      and postoperative stay was related to operative technique and age. Morbidity and
      pain medications were related, respectively, to transfusion requirements and type
      of surgical approach. CONCLUSIONS: Used to manage hematologic diseases, LS is
      feasible, effective, and safe. It offers several advantages over the open
      approach. The type of surgical approach seems to be the crucial factor in
      determining the length of the postoperative course.

PMID- 10594271
TI  - Endoscopic axillary lymphadenectomy without prior liposuction. Development of a
      technique and initial experience.
AB  - BACKGROUND: A new technique of endoscopic axillary lymphadenectomy without prior
      liposuction was developed by our group. METHOD: A total of 33 patients with early
      stage breast cancer were treated by breast-conserving therapy and endoscopic
      axillary lymphadenectomy. RESULTS: The median duration of the operation was 74.9
      min (range, 30-130). Operation time was significantly shorter for the last 17
      patients (p < 0.05) than for the first 16 patients. There were no intraoperative
      complications. The median number of removed lymph nodes was 14.5 (range, 2-28).
      Postoperatively three patients developed a seroma, one of which required
      evacuation. At postoperative day 5, arm mobility was unrestricted in 26 patients
      (78.7%); nine patients (27.2%) reported a loss of sensation in the outer side of
      the upper arm related to dermatome C5. One patient developed a temporary alar
      scapula, and one patient developed an axillary abscess 9 weeks after axillary
      lymphadenectomy during radiation therapy. After a median follow-up of 4.6 months
      seven patients reported persistent impairment of sensation, but all patients had
      regained full shoulder mobility. CONCLUSION: Endoscopic axillary lymphadenectomy
      can be done safely without prior liposuction.

PMID- 10594272
TI  - Iliac vascular injuries during elective laparoscopic surgery.
AB  - Although it is extremely uncommon, iliac vascular injury is a serious
      complication of laparoscopic surgery. We performed a retrospective review of five
      patients who sustained injury to the iliac vessels during elective laparoscopic
      surgery. We reviewed the mechanism and location of injury for each case and
      examined ways in which such complications can be prevented. There were four women
      and one man; their mean age was 32 years. Three patients were undergoing
      laparoscopy at our institution, and two patients were transferred from outlying
      facilities soon after the injuries occurred. There were a total of seven iliac
      vascular injuries among our five patients. Three cases involved injury caused by
      the insufflation needle; the other two were injured by trocar introduction.
      Postoperative sequelae included decreased lower-extremity pulses in two patients
      and lower-extremity edema in three patients. The incidence of iliac vascular
      injury can be significantly reduced by proper insertion technique, the use of an
      open (Hasson) approach rather than the percutaneous insufflation needle, and a
      thorough knowledge of the vascular anatomy in the pelvic region.

PMID- 10594273
TI  - Intestinal obstruction from midgut volvulus after laparoscopic cholecystectomy. A
      report of an unusual complication.
AB  - Congenital midgut malrotation, a rare anatomic anomaly that can lead to duodenal
      or small bowel obstruction, rarely is recognized beyond the first year of life.
      We report a case of unrecognized congenital midgut malrotation that resulted in
      midgut volvulus, causing intestinal obstruction and requiring emergent
      reoperation after laparoscopic cholecystectomy. This unusual complication, first
      reported in 1994, involved a 56-year-old man and resulted in cecal infarction
      recognized and treated on the second postoperative day. This second case
      describes a less acute postoperative course, with multiple bouts of partial bowel
      obstruction leading to two readmissions and finally resulting in a reexploration
      and definitive treatment on the 19th postoperative day.

PMID- 10594274
TI  - Mucinous cystadenoma of the cecum missed at laparoscopic appendectomy. Pitfalls
      in laparoscopy.
AB  - We report an unusual case of acute appendicitis caused by a mucinous cystadenoma
      of the cecum obstructing the lumen of the appendix. At laparoscopic appendectomy,
      an inflamed appendix was identified and resected. Subsequent histologic
      evaluation of the appendiceal base revealed mucin lakes. After discovery of a
      cecal mass at colonoscopy, the patient underwent definitive right hemicolectomy
      for treatment of a benign mucinous cystadenoma of the appendix.

PMID- 10594275
TI  - Use of the Hasson cannula producing major vascular injury at laparoscopy.
AB  - Despite the recent demonstration that vascular lesions occur significantly more
      frequently in patients having closed rather than "open" laparoscopy, there never
      has been a published case report of injury to the great vessels associated with
      the open technique of initial access to the peritoneal cavity at laparoscopy. We
      present the first two such cases reported, along with a brief review of the
      literature related to such major vascular injuries (MVI) sustained at
      laparoscopy. Lacking appreciation of aortic anatomy and intraoperative technical
      factors contribute to the occurrence of these injuries. Delayed diagnosis and
      management contribute to poor outcomes. Secondary injury frequently is associated
      with MVI at laparoscopy.

PMID- 10594276
TI  - Laparoscopic management of a large posttraumatic splenic cyst in a child.
AB  - Splenic cysts are rare in pediatric surgery. Nowadays management consists of
      partial splenectomy or decapsulation of the cystic wall. The case reported in
      this article describes the successful laparoscopic decapsulation of the cystic
      wall in an 11-year-old child.

PMID- 10594277
TI  - Laparoscopic extraperitoneal inguinal hernia repair. A safe approach based on the
      understanding of rectus sheath anatomy.
AB  - We have devised a reproducible approach to the preperitoneal space for
      laparoscopic repair of inguinal hernias that is based on an understanding of the
      abdominal wall anatomy. Laparoscopic totally extraperitoneal herniorrhaphy was
      performed on 99 hernias in 90 patients at the Los Angeles County-University of
      Southern California Medical Center, using a standardized approach to the
      preperitoneal space. Operative times, morbidity, and recurrence rates were
      recorded prospectively. The median operative time was 37 min (range, 28-60) for
      unilateral hernias and 46 min (range, 35-73) for bilateral hernias. There were no
      conversions to open repair, and there was only one conversion to a laparoscopic
      transabdominal approach. Complications were limited to urinary retention in two
      patients, pneumoscrotum in one patient, and postoperative pain requiring a large
      dose of analgesics in one patient. All patients were discharged within 23 h.
      There were no recurrences or neuralgias on follow-up at 2 years. A standardized
      approach to the preperitoneal space based on a thorough understanding of the
      abdominal wall anatomy is essential to a satisfactory outcome in hernia repair.

PMID- 10594278
TI  - The "LAP-LOOP". A substitute for the fourth trocar in laparoscopic
      cholecystectomy.
AB  - The "LAP-LOOP," a device used to avoid the fourth trocar in the laparoscopic
      cholecystectomy, has been successfully applied by the author over more than 200
      patients, even in the cases of acute cholecystitis.

PMID- 10594279
TI  - A simple technique for trocar site closure after laparoscopic surgery.
AB  - Hernias have been reported to occur at trocar sites and small anterior wall
      defect has been casually identified during laparoscopic surgery. The aim of this
      article is to describe a simple, fast, and cheap technique for the safe closure
      of trocar sites in laparoscopic surgery. Closure is accomplished with a #0#
      absorbable suture, which is applied in a pursestring manner using 15 gauge spinal
      cord needle. This procedure is also suitable for the laparoscopic repair of
      uncomplicated small hernias or fascial defects of the anterior abdominal wall; a
      mesh prosthesis in case the defect is > cm(2). This technique allows a secure
      closure of umbilical or fascial defects of the anterior abdominal wall. It is a
      useful method for large trocar sites closure and is recommended for small
      uncomplicated hernias or fascial defects of the anterior abdominal wall. In case
      of > cm(2) defects the technique could be an optimal laparoscopic alternative for
      patch tension free repair.

PMID- 10594280
TI  - A new retraction technique to allow better visualization of Calot's triangle
      during laparoscopic cholecystectomy.

PMID- 10594281
TI  - Guidelines for teleconsultation in surgery. The German experience.

PMID- 10594283
TI  - News and notices

PMID- 10594282
TI  - Laparoscopic cholecystectomy by harmonic dissection.

PMID- 10594284
TI  - Thyroid pathologic findings in patients with Cowden disease.
AB  - We describe the histologic findings in thyroid glands from six female and five
      male patients with Cowden disease. The patients were aged 9 to 43 years (mean
      age, 26 years). The salient thyroid lesions in this syndrome were multicentric
      follicular adenomas and adenomatous (parenchymatous, hyperplastic) nodules
      showing a wide range of nonspecific cytoarchitectural patterns. Multiple tiny
      cellular foci, so-called microadenomas, were also a feature. Specific lesions
      composed of oxyphil or clear cells, a tumor with features of hyalinizing
      trabecular adenoma, and an adenolipoma also occurred. Two cases showed a
      follicular carcinoma in addition to multiple benign follicular cell
      proliferations. The follicular carcinomas occurred at an older age and were
      larger in size than the clinically significant benign nodular lesions, suggesting
      tumor progression. All tumors showed thyroglobulin immunoreactivity and were
      negative for calcitonin. The histologic findings of a multiple adenomatous goiter
      or multiple follicular adenomas, particularly in children and young adults,
      should alert the pathologist and physician to the possibility of an inherited
      trait, such as Cowden disease, with its implications for family screening. The
      tumors are usually benign and well demarcated, but, because of multicentricity
      and increased risk of recurrence or progression to carcinoma, total thyroidectomy
      should be advocated.

PMID- 10594285
TI  - Embryonal "Botryoid" rhabdomyosarcoma of the larynx: a clinicopathologic and
      immunohistochemical study of two cases.
AB  - Two cases of embryonal rhabdomyosarcoma of the larynx are reported. The tumors
      occurred in a 16-year-old boy and in a 66-year-old man. They manifested
      clinically with nonspecific symptoms, including voice hoarseness and sense of
      throat fullness. Treatment consisted of total and partial laryngectomy,
      respectively. Grossly, both lesions had an exophytic growth pattern and
      microscopically featured a proliferation of small round to oval cells. Cell
      cytoplasms were occasionally stainable and fibrillary. Quite often, tumor
      cellularity was denser beneath the covering mucosa, recalling a "cambium layer"
      pattern. Tumor cells immunoreacted for desmin, actins, myoglobin, and sarcomeric
      actin; no immunostaining was noted for epithelial markers. No further antitumoral
      treatment was administered after surgery. There has been no recurrence of tumor
      at 2 and 10 years, respectively. Based on our series and the available
      literature, it seems that rhabdomyosarcoma of the larynx pursues a less
      aggressive course than that seen in the homonimic juvenile or adult soft tissue
      lesion. Surgery alone appears to be a valid treatment option, especially when a
      polypoid, or "botryoid" gross pattern, coupled with the embryonal small cell
      histotype is encountered. In light of these findings, it is suggested that
      botryoid rhabdomyosarcoma of the larynx may deserve a specific consideration
      among the various laryngeal mesenchymal malignancies.

PMID- 10594286
TI  - Patterns of distribution of cytokeratins 20 and 7 in special types of invasive
      breast carcinoma: a study of 123 cases.
AB  - Metastatic adenocarcinomas of unknown primary site are a common clinical problem.
      Invasive ductal carcinomas of the breast and some special types of invasive
      breast carcinoma are common sources of metastases. Immunohistochemical
      algorithms, such as a combination of cytokeratins 20 and 7, can be helpful in
      this situation. Detailed phenotyping of the different types and subtypes of
      primary invasive carcinomas and their metastases is an essential prerequisite for
      a successful search for an unknown primary tumor. A series of 123 primary
      invasive breast adenocarcinomas of special type and of 27 lymph node metastases
      was analyzed. Sections of selected blocks were stained with two monoclonal
      cytokeratin antibodies (CK20 and CK7) and evaluated as negative (no staining),
      focally positive or diffusely positive. Of the 123 carcinomas, 113 (92%) proved
      to be CK20 negative. Three of 82 (4%) invasive lobular carcinomas, three of 11
      (27%) mucinous carcinomas, one of 10 (10%) tubular carcinomas, and one invasive
      papillary carcinoma stained diffusely with CK20. Additionally, a tubulolobular
      carcinoma and a medullary carcinoma showed focal CK20 positivity. One hundred
      twenty (98%) of the 123 tumors were CK7 positive, five of them only focally. One
      of the four solid invasive lobular carcinomas, one medually carcinoma, and one
      invasive papillary carcinoma were completely negative for CK7. Only two cases,
      one mucinous and one invasive papillary carcinoma, exhibited the CK20(+)/CK7(-)
      ("colorectal") pattern. One of the lymph node metastases was CK20(+); another was
      CK7(-). Like their ductal counterparts, invasive breast carcinomas of special
      type are usually CK20(-)/CK7(+); they generally retain this phenotype in their
      metastases. However, there are CK20-positive special-type breast carcinomas that
      can be confused with gastrointestinal or pancreaticobiliary carcinoma in
      metastases, especially if they are mucinous or invasive lobular.

PMID- 10594287
TI  - Human herpesvirus-8 in lymphomatous and nonlymphomatous body cavity effusions
      developing in Kaposi's sarcoma and multicentric Castleman's disease.
AB  - Human herpesvirus-8 (HHV-8) has been associated with Kaposi's sarcoma,
      multicentric Castleman's disease and primary effusion lymphoma. Kaposi's sarcoma
      and multicentric Castleman's disease patients may develop body cavity effusions
      that, unlike primary effusion lymphoma, are poorly characterized. To better
      define these effusions, pleural and peritoneal fluids derived from 12 human
      immunodeficiency virus-seropositive and one seronegative patients affected by
      Kaposi's sarcoma or multicentric Castleman's disease were analyzed by a
      combination of morphologic, immunophenotypic, and DNA analyses, including
      polymerase chain reaction amplification of HHV-8, Epstein-Barr virus, and
      immunoglobulin heavy-chain (IgH) gene sequences. In addition, HHV-8 serologic
      status was assessed by using an immunofluorescence assay. All patients were adult
      men with high antibody titers to HHV-8; 11 of the 13 patients were
      homosexual/bisexual. Effusions revealed monocyte/macrophage-rich infiltration (10
      patients) or large-cell lymphoma with CD45(+)/non-T/non-B phenotype (three of 13
      patients); polymerase chain reaction analysis showed the presence of HHV-8
      sequences (nine of 13 patients), germline IgH (seven of 12 patients) or clonal
      IgH rearrangements (four of 12 patients), and rarely Epstein-Barr virus sequences
      (two of 12 patients). In the setting of HHV-8 infection, two effusion types may
      occur. One fulfills the criteria for HHV-8-positive PEL (lymphoma-morphology, HHV
      8-DNA(+), IgH rearrangement). The other seems more reminiscent of an HHV-8
      associated nonneoplastic process (monocyte-macrophage morphology, HHV-8-DNA(+/-),
      germline IgH). Interestingly, a single case of the latter effusion type harbored
      a B-cell monoclonal proliferation, which suggests the hypothesis that a
      prelymphomatous effusion may precede overt body cavity lymphoma.

PMID- 10594288
TI  - Examination of tumor and tumor-like conditions of bone.
AB  - Surgical pathology specimens composed of bone, ranging from core biopsy to limb
      amputation specimens, require special attention, processing, and often unique
      equipment. This readily translates into additional handling steps and time,
      especially when one factors in clinical correlation with the surgeon and
      radiologic review of all images with a knowledgeable musculoskeletal radiologist.
      When these factors are superimposed on the rarity of these lesions in routine
      practice, it is not surprising that most trainees, as well as seasoned
      pathologists, are wary of these lesions. In this report, we use a case of
      osteofibrous dysplasia (Campanacci's disease) to demonstrate the dissection of
      such a surgical specimen and complete the report with a brief discussion of the
      entity.

PMID- 10594289
TI  - Angiosarcoma arising in a bone infarct.
AB  - A primary angiosarcoma of the femur arose in continuity with a bone infarct in a
      74-year-old man. The tumor, resected by amputation, had pleomorphic polygonal and
      spindle cells in solid and cystic patterns with focal vasoformative features. The
      immunohistochemical stains CD31, CD34, factor VIII-related antigen, and Ulex
      europeus corroborated the endothelial differentiation of the tumor. The patient
      died after developing pulmonary metastases. This is the oldest reported patient
      with a well-documented angiosarcoma associated with a bone infarct.

PMID- 10594290
TI  - Nasopharyngeal carcinoma.
AB  - Nasopharyngeal carcinoma represents a morphologic spectrum of neoplasms localized
      to the nasopharynx and arising from nasopharyngeal epithelium. Nasopharyngeal
      carcinomas have rather unique clinical, epidemiologic, pathologic, and biologic
      features. The morphologic spectrum of nasopharyngeal carcinoma includes
      keratinizing, nonkeratinizing, and undifferentiated subtypes. The separation of
      these morphologic types is not an academic exercise, but has practical importance
      relative to differential diagnosis, management, and prognosis. A similar
      morphologic classification applies to carcinomas arising in the palatine tonsils
      and the base of tongue. The nasopharynx, palatine tonsils, and base of tongue are
      collectively designated as Waldeyer's tonsillar tissues. Awareness of the
      morphologic spectrum of Waldeyer's ring carcinomas may assist in suggesting the
      primary tumor site in the face of an occult metastatic carcinoma to cervical neck
      lymph nodes.

PMID- 10594291
TI  - The original illustrations of Hodgkin's disease.
AB  - In this report, the illustrations from the original papers on Hodgkin's disease
      are used to trace its early history. Thomas Hodgkin's report included six cases
      of his own and a seventh given to him by Robert Carswell, whose beautiful colored
      pictures of the latter case accompanied Hodgkin's presentation. Early clinical
      pictures are also presented. The histologic definition of the disease, with its
      characteristic cell, is traced with drawings from the reports of Greenfield,
      Sternberg, Reed, and Andrews. Modern histologic and immunocytochemical
      confirmation (Leu-M1 reactivity) of some of Hodgkin's original cases, preserved
      at Guy's Hospital, London, UK, are also illustrated. It is concluded that not
      only did Hodgkin describe cases of Hodgkin's disease that meet present-day
      criteria, he also included at least one case of non-Hodgkin's lymphoma, a term
      that now might be considered a misnomer.

PMID- 10594292
TI  - A whole-glove method for the evaluation of surgical gloves as barriers to
      viruses.
AB  - BACKGROUND: Today, because of the wide variety of infectious agents encountered
      in the health care environment, clinicians must be particularly concerned about
      the potential for small-sized virus penetration through glove defects. OBJECTIVE:
      To describe a method for testing gloves that evaluates the entire glove and
      allows for detection of low levels of virus penetration. Ten sets of 10 different
      gloves from 4 manufacturers were evaluated using this method. METHODS: Barrier
      properties were evaluated using the bacteriophage, phiX174. Gloves were filled
      with surfactant solution placed in flasks containing 10(6) viruses per mL. Flasks
      were agitated at 37 degrees C +/- 2 degrees C and assayed for 180 minutes.
      RESULTS: Virus penetration was detected in 8% of the 100 gloves tested using the
      quantitative assay. The qualitative assay determined that 14% of the gloves
      tested allowed penetration.

PMID- 10594293
TI  - Assessment of the ability of the topical skin protectant (TSP) to protect against
      contact dermatitis to urushiol (Rhus) antigen.
AB  - BACKGROUND: Military personnel have a need for effective protection against
      cutaneous exposure to chemical warfare agents (CWA). Topical Skin Protectant
      (TSP) is being developed to supplement chemical warfare protective garments. TSP
      protects against CWA exposure in animals, but does it work for humans? Because
      humans should not be tested with live CWA, urushiol (poison ivy) extract was used
      as a surrogate substance in place of CWA for human efficacy testing of TSP.
      OBJECTIVE: Determine whether TSP protects human skin against experimentally
      induced urushiol dermatitis. METHODS: Open urushiol patch testing of 50 rhus
      sensitive subjects comparing the 96-hour dermatitis severity scores between TSP
      protected and TSP unprotected sites. There were 4 paired sites (i.e., protected
      versus unprotected) per subject. Test sites were scored using a 9-point
      dermatitis scale of 0.0 to 4.0 (using 0.5 increments). RESULTS: Analysis of
      variance of the dermatitis scores from 192 paired sites on 48 evaluable subjects
      showed that TSP protected sites had mean dermatitis scores about 2 points lower
      than TSP unprotected sites (P <.001). CONCLUSION: Although this study does not
      provide direct scientific evidence that TSP protects humans against the
      percutaneous absorption of CWA, it does provide circumstantial evidence that this
      is the case. The fact that TSP is so highly effective against a lipophilic
      substance like urushiol and that most common vesicant CWAs are lipophilic and are
      weaponized in oleaginous vehicles, makes the effectiveness of TSP in preventing
      absorption and dermatitis from CWA seem likely.

PMID- 10594294
TI  - Cheilitis: analysis of 75 cases referred to a contact dermatitis clinic.
AB  - BACKGROUND: Cheilitis is a common problem, the cause of which is often obscure.
      OBJECTIVE: Data on 75 cases of recalcitrant cheilitis were analyzed. These had
      been referred to a tertiary care center. METHODS: Each of the 75 patients had
      undergone a detailed history, physical examination, and patch tests. RESULTS: Of
      the patients, 53 were female (67%), and the age range was 9 to 79 years. Of the
      cases, 36% included irritant contact dermatitis (ICD), 25% included allergic
      contact dermatitis (ACD), 19% were attributed to atopic eczema, and in 9% the
      dermatitis was of unknown cause. Nine percent were noneczematous. The materials
      causing ACD were medicaments applied to the lips, lipstick ingredients, sunscreen
      agents, toothpaste ingredients, colophony in dental floss and toothpicks, nail
      varnish, cosmetics, and nickel in the mouthpiece of a flute. CONCLUSION: The most
      common cause of cheilitis was irritation, frequently caused by liplicking. About
      one quarter was caused by ACD. Medicaments, lipsticks, sunscreens, and toothpaste
      were the most common allergens. Atopic eczema is a commonly overlooked cause of
      cheilitis. However, there is a troublesome group of patients, 9% in this series,
      who are often severely affected, but the cause of their cheilitis remains
      obscure.

PMID- 10594295
TI  - Prevalence of gold sensitivity in asymptomatic individuals with gold dental
      restorations.
AB  - BACKGROUND: The clinical relevance of positive patch test reactions to gold
      sodium thiosulfate in asymptomatic individuals with gold dental restorations is
      often unclear. Knowledge of the prevalence of gold sensitivity in individuals
      with and without gold dental restorations is required to better understand the
      relevance of these reactions. OBJECTIVE: To determine the prevalence of positive
      patch test reactions to gold in asymptomatic individuals with gold dental
      restorations (gold patients) compared with similar individuals without gold
      dental appliances (nongold patients). METHODS: One hundred thirty-six healthy,
      asymptomatic patients were patch tested to gold sodium thiosulfate, nickel
      sulfate and palladium chloride. Readings occurred after 2 days and 7 days.
      RESULTS: Of the patients tested, 24 of 71 (33.8%) gold patients had a positive
      reaction to gold versus 7 of 65 (10.8%) of the nongold patients, P <.001. Of
      those with a positive gold reaction, 12 of 31 (38.7%) also had a positive nickel
      reaction. Nickel alone was positive in 18 of 71 (25. 4%) of gold patients versus
      11 of 65 (16.9%) of nongold patients. 19 of 29 (65.5%) of those with a positive
      nickel reaction also reacted to palladium and 19 of 22 (86.4%) of those with a
      palladium reaction also reacted to nickel. The rate of allergy to gold computed
      over a 3-year period for patients patch tested in the Oregon Health Sciences
      University (OHSU) Contact Dermatitis Clinic was 13.5% (46/342). CONCLUSIONS: The
      prevalence of gold sensitivity in individuals with gold dental restorations is
      approximately 33.8%. This is significantly greater than the 10.8% prevalence seen
      in individuals without gold dental appliances, as well as greater than the 3-year
      rate from the OHSU Contact Dermatitis Clinic. This data should help shed light on
      issues of clinical relevance.

PMID- 10594296
TI  - Identification of metal allergens in the local lymph node assay.
AB  - BACKGROUND: The murine local lymph node assay (LLNA) has recently been endorsed
      as a validated alternative to guinea pig methods for the identification of skin
      sensitization hazard. Nevertheless, there has been some debate regarding the
      utility of this method for the detection of metal contact allergens. OBJECTIVE:
      In these investigations, we have used the LLNA to determine the skin
      sensitization potential of 13 metal salts, 8 of which were considered to possess
      a significant ability to sensitize man, whereas the remaining 5 were judged to
      lack such potential. RESULTS: The predictions from the LLNA were correct for 7 of
      the 8 (88%) sensitizing metals and for 4 of the 5 (80%) nonsensitizers when
      considered against the experience of these metals as human skin sensitizers.
      Thus, the overall predictive accuracy of the LLNA in relation to metals was 11/13
      (85%), which is very similar to the accuracy of approximately 88% in relation to
      a much larger number of low-molecular-weight organic chemicals, as reported
      previously. CONCLUSION: These data provide support for the potential utility of
      the LLNA in hazard identification of metal contact allergens.

PMID- 10594297
TI  - The impact of vehicle on assessment of relative skin sensitization potency of 1,4
      dihydroquinone in the local lymph node assay.
AB  - BACKGROUND: The murine local lymph node assay (LLNA) has been validated as an
      alternative method for the identification of skin sensitization hazards. Contact
      allergens are identified as a function of proliferative responses induced in
      draining lymph nodes. The quantitative nature of the LLNA data also provides the
      opportunity of assessing relative potency by reference to dose response analyses.
      OBJECTIVE: In the current investigations, the influence of vehicle on the skin
      sensitization potency of a known skin sensitizer (1,4-dihydroquinone) was
      assessed. METHODS: 1, 4-dihydroquinone was tested in the LLNA using 7 different
      vehicle systems in each of 2 independent laboratories. RESULTS: Results from the
      2 laboratories were almost identical. LLNA dose response data were interpolated
      to derive the estimated concentration (EC) of 1, 4-dihydroquinone necessary to
      cause a three-fold stimulation of proliferation compared with controls, the EC3
      value. The vehicles used and mean EC3 values obtained were: methyl ethyl ketone
      0.07%, acetone 0.08%, acetone/olive oil (80/20 v/v) 0.15%, dimethyl formamide
      0.22%, dimethyl sulfoxide 0.4%, and propylene glycol and acetone/saline (50/50
      v/v) vehicles gave negative results. However, when tested at higher
      concentrations, positive results were obtained in these vehicles. CONCLUSION:
      These data reveal that the vehicle in which a chemical is encountered in the skin
      can have a significant impact on a quantitative measure of skin sensitization
      potency. The implication is that accurate assessment of risk to humans will
      require an understanding of the matrix in which skin exposure is likely to occur.

PMID- 10594298
TI  - Concomitant positive reactions to allergens in a patch testing standard series
      from 1988-1997.
AB  - BACKGROUND: Patch testing is a useful diagnostic technique in patients with
      suspected allergic contact dermatitis (ACD). Concomitant reactions may reflect
      associations between tested allergens. OBJECTIVE: This study was performed to
      identify positive correlations between reactions to test substances in a standard
      screening series. The results of patch testing in patients seen from 1988 to 1997
      are described. METHODS: Data were collected from chart review for patients who
      underwent patch testing to the full standard screening series at the
      Massachusetts General Hospital Contact Dermatitis Clinic. The Fisher exact test
      was used to evaluate associations between allergens. RESULTS: A total of 927
      patients were patch tested to 22 allergens included in a screening tray. The mean
      age was 43.9 years, and 68.6% were women. Two or more positive reactions occurred
      in 36.5% of patients. Reactions to 13 pairs of allergens were found to be
      significantly correlated: balsam of Peru/fragrance mix, carba mix/thiuram mix,
      carba mix/paraben mix, cobalt chloride/potassium dichromate, cobalt
      chloride/nickel sulfate, ethylenediamine/neomycin sulfate,
      formaldehyde/imidazolidinyl urea, formaldehyde/paraben mix,
      formaldehyde/quaternium-15, imidazolidinyl urea/quaternium-15, neomycin
      sulfate/potassium dichromate, paraben mix/quaternium-15, and potassium
      dichromate/thimerosal. CONCLUSION: Concomitant reactions to 13 pairs of allergens
      in a standard series occurred at a rate greater than would be predicted by
      chance. Such associations may reflect cross-sensitization or cosensitization.

PMID- 10594299
TI  - Late patch test reaction to acrylates in a dental worker.
AB  - A dental technician developed eyelid and hand dermatitis. She had been previously
      patch-tested elsewhere with a sample of an acrylic material from a nail salon
      that reportedly was positive only after 1 month. Repeat testing with ethyl
      acrylate and methyl methacrylate gave no reaction at 48 or 96 hours, but became
      positive 5 weeks later. This very late reaction is probably a true allergic
      manifestation and not a case of active sensitization.

PMID- 10594300
TI  - Allergic contact dermatitis to polyethylene glycol and nitrofurazone.
AB  - We report a case of worsening dermatitis after the application of an antibiotic
      ointment (Furacin) containing furazone and polyethylene glycol. Patch tests to
      nickel sulfate, potassium dischromate, chloride cobalt, Furacin, nitrofurazone 1%
      petrolatum, polyethylene glycol mix 4% petrolatum, polyethylene glycol (PEG) 300
      4% petrolatum, and PEG 400 as is (ai) were positive. The use of topical agents
      containing nitrofurazone or polyethylene glycol on damaged skin may predispose to
      contact allergy. We discuss the sensitizing properties of nitrofurazone and
      polyethylene glycol.

PMID- 10594301
TI  - Allergic contact dermatitis to benzyl alcohol in a hearing aid impression
      material.
AB  - A patient with allergic contact dermatitis caused by benzyl alcohol in a hearing
      aid impression material and in topical medications is described. In addition, the
      patient had topical and probably systemic corticosteroid allergy. Benzyl alcohol
      allergy is reviewed. allergic contact dermatitis is the most commonly reported
      allergic reaction to benzyl alcohol. There is also 1 report of contact urticaria.
      Balsam of Peru patch tests are frequently positive. Reported allergic reactions
      to injected benzyl alcohol include generalized urticarial reactions, 1
      generalized maculopapular reaction and 1 delayed localized reaction.

PMID- 10594302
TI  - Allergic contact dermatitis to Fraxinus americanus and Macherium acutifolium.
AB  - Contact allergy to tropical hardwoods and domestic woods are well documented in
      the literature. The authors document a case of contact allergy to both types of
      wood in a woodworking artisan.

PMID- 10594303
TI  - Evaluation and management of the "red face". Interview by K. Watsky and M. Rothe.
AB  - Patients presenting with a "red face" challenge clinicians to consider a broad
      differential diagnosis that includes contact dermatitis. The diagnosis may be
      obscured or complicated by underlying actinic damage or rosacea. Unraveling this
      Gordian knot to arrive at a precise and accurate diagnosis takes patience and
      practice. The collective experience of our invited group of expert clinicians
      sheds light on this process.

PMID- 10594304
TI  - Proceedings of the first meeting of the experimental contact dermatitis research
      group.

PMID- 10594305
TI  - Toxicological aspects of allergic contact dermatitis: report on selected
      proceedings of the society of toxicology meeting, New Orleans, LA, USA, March 14
      18, 1999.

PMID- 10594308
TI  - Skill acquisition in music performance: relations between planning and temporal
      control.
AB  - We investigated the acquisition of music performance skills in novice and expert
      pianists. Temporal disruptions in novice performances coincided with constraints
      in planning capacities. Child and adult pianists ranging in age (9-26 years),
      training (3-15 years) and sight-reading ability learned to perform a novel
      musical piece in eleven practice trials. Computer-detected pitch and timing
      errors revealed: (1) gradual improvements in performance tempo and pitch accuracy
      with skill level and practice, generally fitting a power function; (2) a relative
      timing/pitch accuracy trade-off and high incidence of simultaneous pitch/time
      errors; (3) improvements in relative timing (temporal continuity, underlying
      beat, metrical structure) with skill and practice; and (4) increased anticipatory
      behavior and a greater range of planning with skill and practice. A strong
      positive relationship between the mastery of temporal constraints and planning
      abilities within performance suggests that these two cognitive indicators are
      closely related and may arise from segmentation processes during performance.
      Examination of sequence timing may explicate planning abilities that underlie
      many complex skills.

PMID- 10594309
TI  - Thinking ahead: the case for motor imagery in prospective judgements of
      prehension.
AB  - How similar are judgements concerning how we expect to perform an action, to how
      we actually behave? The veracity of such prospective action judgements, and the
      mechanisms by which they are computed, was explored in a series of tasks that
      involved either grasping (MC conditions) or thinking about grasping (PJ
      conditions) a dowel presented in various orientations. PJs concerning limits of
      comfortable hand supination and pronation when turning a dowel in the picture
      plane were highly consistent with values obtained during actual hand rotation
      (Exp. 1). The same was true for judgements regarding the level of awkwardness
      involved in adopting a prescribed grip (e.g. overhand with right hand) for dowels
      in various picture plane orientations (Exp. 2). When allowed to select the most
      natural grip (overhand versus underhand) or hand (left versus right) for engaging
      dowels in these orientations, subjects preferred virtually identical responses in
      both PJ and MC conditions. In both instances, they consistently chose the least
      awkward response options. As would be expected for actual movements, PJs
      involving awkward hand postures had longer response times (RTs), and were less
      accurate. Likewise, latencies for both grip and hand judgements tended to
      increase as a function of the angular distance between the current positions of
      subjects' hands, and the orientation of the chosen posture. Together, these
      findings are consistent with a the hypothesis that PJs involve mentally simulated
      actions, or motor imagery. These results suggest that motor imagery does not
      depend on the existence of a completed premotor plan (Jeannerod, 1994), but may
      instead be involved in the planning process itself. A provisional model for the
      involvement of imagery in motor planning is outlined, as are a set of criteria
      for evaluating claims of the involvement of motor imagery in problem solving.

PMID- 10594310
TI  - Representation of the cardinality principle: early conception of error in a
      counterfactual test.
AB  - There is debate over how the integration of non-verbal quantifying and verbal
      counting relates to the representation of number principles. A stringent
      representational test would be one in which a child obeyed a number principle
      where it ran counter to a characteristic procedure. We devised a test relying on
      the uniqueness principle for using evidence from a miscount in inferring a
      counterfactual cardinal number. All the 5-year-olds passed, as did half the
      preschoolers. Subtests probed associated number-skills. We suggest that a crucial
      preschool step is to start conceptualising error by categorising relations
      between counting and miscounting. That step is taken at a similar age to passing
      a representational theory of mind test but the two were uncorrelated.

PMID- 10594311
TI  - Attractor dynamics in word recognition: converging evidence from errors by normal
      subjects, dyslexic patients and a connectionist model.
AB  - People make both semantic and visual errors when trying to recognise the meaning
      of degraded words. This result mirrors the finding that deep dyslexic patients
      make both semantic and visual errors when reading aloud. We link the results with
      the demonstration that a recurrent connectionist network which produces the
      meaning of words in response to their spelling pattern produces this distinctive
      combination of errors both when its input is degraded and when it is lesioned.
      The reason why the network can simulate the errors of both normal subjects and
      patients lies in the nature of the attractors which it develops as it learns to
      map orthography to semantics. The key role of attractor structure in the
      successful simulation suggests that the normal adult semantic reading route may
      involve attractor dynamics.

PMID- 10594312
TI  - Large number discrimination in 6-month-old infants.
AB  - Six-month-old infants discriminate between large sets of objects on the basis of
      numerosity when other extraneous variables are controlled, provided that the sets
      to be discriminated differ by a large ratio (8 vs. 16 but not 8 vs. 12). The
      capacities to represent approximate numerosity found in adult animals and humans
      evidently develop in human infants prior to language and symbolic counting.

PMID- 10594313
TI  - Effect of subchronic lithium carbonate treatment on anxiolytic-like effect of
      citalopram and MKC-242 in conditioned fear stress in the rat.
AB  - We investigated the effect of citalopram [selective serotonin (5-HT) reuptake
      inhibitor] and MKC-242 (5-[3-?(2S)-(1, 4-Benzodioxan-2-ylmethyl) amino?propoxy]
      1, 3-benzo-dioxol hydrochloride; a selective 5-HT(1A) receptor agonist) on the
      expression of conditioned freezing, an index of anxiety, following treatment with
      subchronic lithium carbonate (LiCO(3)). Male Sprague-Dawley rats were used in
      these experiments. Acute administration of citalopram (subcutaneously, s.c.)
      reduced freezing significantly at a high dose (30 mg/kg), while showing no effect
      at lower doses (3 and 10 mg/kg). Acute administration of MKC-242 (s.c.; 0.1-10
      mg/kg) dose dependently reduced freezing. Subchronic LiCO(3) treatment (1 week;
      0.05% or 0.2% LiCO(3) in diet; p.o.) showed no effect on freezing behavior. Acute
      treatment with both citalopram (3 and 30 mg/kg) and MKC-242 (1 mg/kg) after
      subchronic treatment with the higher, but not the lower concentration of LiCO(3)
      (1 week), reduced freezing markedly and significantly, as compared with either
      drug alone. These results suggest that subchronic LiCO(3) treatment enhanced the
      anxiolytic-like effects of these serotonergic drugs by facilitating central 5-HT
      neurotransmission at clinically therapeutic plasma lithium levels.

PMID- 10594314
TI  - Effect of rivastigmine on scopolamine-induced memory impairment in rats.
AB  - The effect of rivastigmine on memory impairments induced in rats by scopolamine
      (0.5 mg/kg) was assessed in the Morris water maze and passive avoidance tests and
      compared with that of tacrine (2.5-17.7 mg/kg). Rivastigmine, (0.5-2.5 mg/kg)
      inhibited cholinesterase in the cortex and hippocampus by 21-60% and antagonised
      the deficits in working and reference memory. Tacrine (12.5 and 17.7 mg/kg)
      produced significantly less inhibition of cholinesterase in the hippocampus but
      more in the striatum than rivastigmine (0.75 and 1.5 mg/kg) and only antagonised
      the deficit in reference memory. Rivastigmine (1.5 and 2.5 mg/kg) or tacrine
      (12.5 mg/kg), injected immediately after completion of the acquisition trial in
      the passive avoidance test, antagonised the deficit induced by scopolamine (1
      mg/kg) in memory retention. The inability of higher doses of the cholinesterase
      inhibitors to antagonise memory deficits induced by scopolamine may be related to
      excessive cholinergic stimulation in the central nervous system.

PMID- 10594315
TI  - The modulatory effect of (+)-TAN-67 on the antinociceptive effects of the
      nociceptin/orphanin FQ in mice.
AB  - To clarify the pharmacological properties of (+)2-Methyl-4aalpha-(3
      hydroxyphenyl)-1, 2, 3, 4, 4a, 5, 12, 12aalpha-octahydro-quinolino[2, 3, 3
      g]isoquinoline ((+)-TAN-67), the effect of (+)-TAN-67 on the antinociception
      induced by the intrathecal (i.t.) administration of nociceptin/orphanin FQ was
      studied in mice using the tail-flick test and the formalin test. I.t.
      administration of (+)-TAN-67, at doses of 1 to 10 ng, facilitated the tail-flick
      response in a dose-dependent manner in mice. In addition, i.t. administration of
      (+)-TAN-67 (1 to 10 ng) in mice produced a marked pain-like aversive responses.
      I.t. pretreatment with D-Pro(9)-[spiro-gamma-lactam]-Leu(10)-Trp(11)
      physalaemin(1-11) (GR82334, 0.1-1.0 nmol), a potent and selective tachykinin
      NK(1) receptor antagonist, dose-dependently blocked the reduction of the tail
      flick response induced by (+)-TAN-67. Furthermore, (+)-TAN-67-induced
      facilitation of the tail-flick response was abolished in capsaicin-treated mice.
      On the other hand, (+)-TAN-67-induced flinching responses were dose-dependently
      and significantly reduced by i.t. pretreatment with GR82334 (0.1-1.0 nmol). The
      duration of i.t. (+)-TAN-67-induced flinching responses was significantly reduced
      in capsaicin-treated mice as compared with naive mice. I.t. administration of
      nociceptin/orphanin FQ (1-10 nmol) dose-dependently increased the tail-flick
      latency. I.t. administration of nociceptin/orphanin FQ (0.1-1.0 nmol)
      significantly and dose-dependently reduced the first-phase nociceptive response,
      but not the second-phase nociceptive response. I.t. pretreatment with (+)-TAN-67
      (0.3-3.0 microg) for 30 min dose-dependently attenuated the antinociception
      induced by i.t. nociceptin (10 nmol) in the tail-flick test. Furthermore, the
      antinociceptive effect of nociceptin/orphanin FQ (1 nmol, i.t.) on the first
      phase response in the formalin test was dose-dependently attenuated by s.c.
      pretreatment with (+)-TAN-67 (0.3-3.0 microg). (+)-TAN-67 (0.3-3.0 microg, i.t.),
      by itself, did not facilitate the tail-flick response or produce apparent
      behavioral changes. It is possible that (+)-TAN-67 has an antagonistic effect on
      nociceptin/orphanin FQ-induced antinociception.

PMID- 10594316
TI  - Trazodone increases extracellular serotonin levels in the frontal cortex of rats.
AB  - The effects of the antidepressant drug, trazodone, on the extracellular 5
      hydroxytryptamine (5-HT) levels in the frontal cortex of freely moving rats was
      investigated using microdialysis coupled to a high performance liquid
      chromatography (HPLC) detection method. Systemic administration of 1.25 and 2.5
      mg/kg s.c. of trazodone was followed by a rise in the 5-HT level which reached a
      5-fold peak over the basal level 5 h after injection, and a 3-fold peak after 1
      h. Higher doses had no effect. The increase was prevented by pretreatment with
      fluoxetine (10 mg/kg s.c.), a 5-HT uptake inhibitor. Direct administration of
      trazodone (0.03, 0.1, 1, 2 microg/microl), by reverse dialysis into the frontal
      cortex, elicited a dose-dependent large increase in 5-HT levels. The increase was
      not prevented by systemic fluoxetine administration but was reduced by local
      perfusion of ketanserin (0.1 microg/microl) a 5-HT(2A/C) receptor antagonist.
      Trazodone s.c. administration for 7 days did not increase 5-HT basal levels but
      enhanced the effects of challenge doses of 2.5 and 5 mg/kg s.c. The present work
      demonstrated that trazodone increases the 5-HT extracellular level through a
      double mechanism which involves the 5-HT transporter and 5-HT(2A/C) receptors.
      This increase may trigger the chain of events which lead to the therapeutic
      effects, similar to the case of many other antidepressant drugs.

PMID- 10594317
TI  - Age-dependence of the anticonvulsant effects of the GABA uptake inhibitor
      tiagabine in vitro.
AB  - Epileptic syndromes frequently start at childhood and therefore it is crucial to
      test new anticonvulsants at immature stages of the nervous system. We compared
      the effects of the gamma-aminobutyric acid (GABA) uptake inhibitor tiagabine [(R)
      N-(4, 4-bis(3-methyl-2-thienyl)but)3-en-1-yl nipecotic acid] on low-Mg(2+)
      induced epileptic discharges in brain slices from rat pups (p 5-8) and juvenile
      animals (p 15-20). In tissue from rat pups, tiagabine slightly reduced
      epileptiform activity in hippocampal area CA1 but had no effect in the entorhinal
      cortex. In juvenile rats, epileptiform discharges were unaffected in CA1 but
      suppressed by 60% in the entorhinal cortex. While tiagabine increases its
      efficacy with age, in-situ hybridisation and PCR analysis show that mRNA coding
      for the neuronal GABA-transporter GAT-1 is already present at p 5. We therefore
      conclude that the increasing efficacy of tiagabine during ontogenesis is due to
      functional maturation of GABAergic synapses rather than to up-regulation of GAT-1
      expression.

PMID- 10594318
TI  - Nicergoline enhances glutamate re-uptake and protects against brain damage in rat
      global brain ischemia.
AB  - Whereas a 2-3 degrees C decrease in intraischemic brain temperature can be
      neuroprotective, mild brain hyperthermia significantly worsens outcome. Our
      previous study suggested that an ischemic injury mechanism which is sensitive to
      temperature may not actually increase the extracellular glutamate concentration
      ([Glu](e)) during the intraischemic period, but rather impairs the Glu re-uptake
      system, which has been suggested to be involved in the reversed uptake of Glu. We
      speculated that enhancing Glu re-uptake, pharmacologically or hypothermically,
      may shorten exposure to high [Glu](e) in the postischemic period and thereby
      decrease its deleterious excitotoxic effect on neuronal cells. In the present
      study, rats treated with nicergoline (32 mg/kg, i.p.), an ergot alkaloid
      derivative, showed minimal inhibition of the [Glu](e) elevation which
      characteristically occurs during the 10-min intraischemic period, while Glu re
      uptake was dramatically improved in the postischemic period, when severe
      transient global ischemia was caused by mild hyperthermia. Moreover, the
      nicergoline (32 mg/kg, i.p.) treated rats showed reduced cell death
      morphologically and clearly had a far lower mortality. The present study suggests
      that the development of therapeutic strategies aimed at inhibition or prevention
      of the reversed uptake of glutamate release during ischemia, i.e., activation of
      the glutamate uptake mechanism, is a promising approach to reduce neural damage
      occurring in response to brain ischemia.

PMID- 10594319
TI  - Local application of SCH 39166 reversibly and dose-dependently decreases
      acetylcholine release in the rat striatum.
AB  - The effect of local application by reverse dialysis of the dopamine D(1) receptor
      antagonist (-)-trans-6,7,7a,8,9, 13b-exahydro-3-chloro-2-hydroxy-N-methyl-5H
      benzo-[d]-nap hto-[2, 1b]-azepine hydrochloride (SCH 39166) on acetylcholine
      release was studied in awake, freely moving rats implanted with concentric
      microdialysis probes in the dorsal striatum. In these experiments, the reversible
      acetylcholine esterase inhibitor, neostigmine, was added to the perfusion
      solution at two different concentrations, 0.01 and 0.1 microM. SCH 39166 (1, 5
      and 10 microM), in the presence of 0.01 microM neostigmine, reversibly decreased
      striatal acetylcholine release (1 microM SCH 39166 by 8+/-4%; 5 microM SCH 39166
      by 24+/-5%; 10 microM SCH 39166 by 27+/-7%, from basal). Similarly, SCH 39166,
      applied in the presence of a higher neostigmine concentration (0.1 microM),
      decreased striatal acetylcholine release by 14+/-4% at 1 microM, by 28+/-8% at 5
      microM and by 30+/-5% at 10 microM, in a dose-dependent and time-dependent
      manner. These results are consistent with the existence of a facilitatory tone of
      dopamine on striatal acetylcholine transmission mediated by dopamine D(1)
      receptors located on striatal cholinergic interneurons.

PMID- 10594320
TI  - Localization of the 5-HT(4) receptor in the human and the guinea pig colon.
AB  - The functions of the 5-HT(4) receptor in the gastrointestinal tract are complex,
      depending on the species and anatomical regions, and localization of the receptor
      was not clear. The present study attempted to examine the localization of the 5
      HT(4) receptor in the colon of human for comparison with that in guinea pig
      colon. Human specimens of sigmoid colon and the distal colon of guinea pig were
      used for in vitro receptor autoradiography using [125I]SB207710, (1-n-butyl-4
      piperidinyl) methyl-8-amino-7-iodo-1, 4-benzodioxane-5-carboxylate, as a ligand.
      [125I]SB207710 binding sites were distributed over the muscle layer of human
      colon, in the myenteric plexus and in the muscle. In the guinea pig colon, a much
      higher density was detected in the myenteric plexus than in the muscle.
      Therefore, in the human and guinea pig colon, the 5-HT(4) receptor was located
      both in the myenteric plexus and in the muscle, and in the guinea pig colon, the
      receptor was located more predominantly in the myenteric plexus of the muscle
      than it is in the human colon.

PMID- 10594321
TI  - Vasopressin V2 (SR121463A) and V1a (SR49059) receptor antagonists both inhibit
      desmopressin vasorelaxing activity.
AB  - Although [Arg(8)]vasopressin is a potent vasoconstrictor, it possesses
      vasorelaxant properties manifested either after vasopressin V1 receptor blockade
      or directly in some vascular beds. The nature of the receptor involved in the
      vasorelaxant effect of [deamino-Cys(1) D-Arg(8)]vasopressin (desmopressin), a
      vasopressin V2 receptor agonist, was studied on rat precontracted aortic rings by
      the use of highly selective new non-peptide vasopressin receptor antagonists. The
      present study demonstrates for the first time that desmopressin relaxant effect
      is antagonized by the vasopressin V2 receptor antagonist SR121463A, but also by
      the vasopressin V1A receptor antagonist SR49059, suggesting that desmopressin
      induced relaxation is mediated by a receptor subtype sharing both V1A and V2
      pharmacological profiles.

PMID- 10594322
TI  - Role of MaxiK channels in vasoactive intestinal peptide-induced relaxation of rat
      mesenteric artery.
AB  - We investigated the functional relevance of large conductance voltage-dependent
      and Ca(2+)-sensitive K(+)(MaxiK) channels in vasoactive intestinal peptide (VIP)
      induced relaxation of rat mesenteric artery. VIP, which is known to increase cAMP
      levels, produced a concentration-dependent relaxation in endothelium-denuded
      arteries. Iberiotoxin, a MaxiK channel blocker, greatly diminished the VIP
      induced relaxation. In a similar manner, a significant portion of the relaxant
      response to dibutyryl-cAMP (DBcAMP), a membrane-permeable analog of cAMP, was
      inhibited by iberiotoxin. These results suggest that activation of MaxiK channels
      significantly contributes to the relaxant response of rat mesenteric artery to
      VIP, possibly via cAMP-mediated pathways.

PMID- 10594323
TI  - Effects of TAK-637, a tachykinin receptor antagonist, on lower urinary tract
      function in the guinea pig.
AB  - The effects of TAK-637 ((aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8, 9,10,11
      tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2 , 1
      g][1,7]naphthyridine-6,13-dione), a novel tachykinin NK(1) receptor antagonist,
      on the micturition reflex in guinea pigs were studied in comparison with those of
      anti-pollakiuria agents. Cystometry was performed under urethane anesthesia. TAK
      637 increased the volume threshold with a minimum effective dose of 0.03 mg/kg,
      i.v. without affecting voiding pressure. Oxybutynin, tolterodine, propiverine and
      inaperisone also increased the volume threshold in urethane-anesthetized guinea
      pigs, but they decreased voiding pressure, although the effect of propiverine was
      not statistically significant. A structurally unique tachykinin NK(1) receptor
      antagonist, (+/-)-CP-99,994 ((+/-)-(2S, 3S)-3-(2-methoxybenzylamino)-2
      phenylpiperidine), increased the volume threshold with a minimum effective dose
      of 0.3 mg/kg, i.v. TAK-637 increased the volume threshold with a minimum
      effective dose of 0.01 mg/kg, p.o. in unanesthetized guinea pigs. These results
      indicate that TAK-637 may be useful as pharmacotherapy for detrusor overactivity
      without decreasing voiding pressure or causing voiding difficulties.

PMID- 10594324
TI  - Apparent efficacy of kappa-opioid receptor ligands on serum prolactin levels in
      rhesus monkeys.
AB  - These studies investigated whether serum prolactin levels could be a quantitative
      marker of the apparent efficacy of kappa-opioid receptor ligands in primates. The
      effects of s.c. bremazocine and U50,488 (trans-(+/-)-3, 4-Dichloro-N-methyl-N-[2
      (1-pyrrolidinyl)-cyclohexyl]-benzeneacetamid e; agonists), nalorphine (partial
      agonist) and nalmefene (antagonist) on prolactin levels were studied in intact
      female rhesus monkeys. The above compounds, except nalmefene, increased prolactin
      levels, and their actions conformed to sigmoidal dose-effect curves. The rank
      order of the compounds' maximum effects in this neuroendocrine endpoint is
      similar to that in cloned kappa-receptors in vitro, and in a presently studied
      thermal antinociception assay in vivo. Prolactin may therefore be a quantitative
      marker of the apparent efficacy of kappa-opioid receptor ligands in primates.

PMID- 10594325
TI  - Agonist-induced GTPgamma35S binding mediated by human 5-HT(2C) receptors
      expressed in human embryonic kidney 293 cells.
AB  - The 5-HT(2C) receptor as heterologously expressed in various mammalian cells
      mediates inositol 1,4,5-triphosphate (IP(3)) signal by activating G(q/11)
      subtypes of G proteins, but minimally promotes agonist-induced GTPgamma35S
      binding in membranes due to slow GTP turnover rates of the G proteins. Here we
      discovered robust (over 200%) agonist-induced GTPgamma35S binding mediated by the
      human receptor expressed in human embryonic kidney (HEK) 293 cells, and
      investigated its pharmacology. Agonists concentration-dependently increased
      GTPgamma35S binding in isolated membranes, which was competitively blocked by
      antagonists. Intrinsic efficacies of agonists from GTPgamma35S binding were
      comparable to those from IP(3) measurement. Pertussis toxin treatment largely
      blocked serotonin-induced GTPgamma35S binding, serotonin high affinity sites by
      70% without altering the total binding sites, and reduced IP(3) release by 40%.
      GTPgamma35S-bound Galpha subunits from serotonin-activated membranes were mainly
      Galpha(i), judging from immobilization studies with various Galpha-specific
      antibodies. Inhibition of forskolin-stimulated cAMP formation, however, was not
      observed. Apparently, the 5-HT(2C) receptor-mediated GTPgamma35S binding is a
      unique phenotype observed in HEK293 cells, reflecting its coupling to pertussis
      toxin-sensitive G(i) subtypes, which contribute to the IP(3) signal, along with
      pertussis toxin-insensitive G(q/11) subtypes.

PMID- 10594326
TI  - On the mechanism underlying calcein-induced cytotoxicity.
AB  - The cellular pharmacology of calcein acetoxymethyl ester (calcein/AM)-induced
      cytotoxicity was investigated in human tumor cell lines in order to identify
      tentative mechanisms of action. The activity profile in 10 cell lines with known
      mechanisms of resistance was compared with the activity profiles of standard
      drugs and experimental substances. The activity of calcein correlated with that
      of different topo II inhibitor/intercalating compounds and mitochondrial
      accumulating compounds, such as Rhodamine 123, Mito Fluor Green and Acridine
      Orange-10. Using U-937 GTB as a model cell line, calcein was found to distribute
      throughout the whole cell, nuclei and mitochondria included. In addition, studies
      of mitochondrial dehydrogenase activity and extracellular acidification rate
      showed an almost complete lack of dehydrogenase activity and extracellular
      acidification at 12 and 24 h, respectively. The results indicate that calcein/AM
      may induce cytotoxicity through interference with both mitochondrial and nuclear
      DNA.

PMID- 10594327
TI  - Reactive oxygen species are involved in the apoptosis induced by nonsteroidal
      anti-inflammatory drugs in cultured gastric cells.
AB  - We previously reported the induction of apoptotic DNA fragmentation by
      nonsteroidal anti-inflammatory drugs (NSAIDs) in cultured rat gastric cells, and
      indicated that prostaglandin-synthesis is only marginally involved in the
      apoptotic process. In the present study, we examined whether the generation of
      reactive oxygen species is critically involved in NSAID-induced apoptosis.
      Indomethacin, sodium diclofenac, flurbiprofen, zaltoprofen, etodolac, but not
      mofezolac, enhanced apoptotic DNA fragmentation and mRNA expression for
      cyclooxygenase-2 in AGS cells, a cell line derived from human gastric epithelium.
      The apoptotic effect of indomethacin was then confirmed by fluorescent staining
      of the cells with annexin V. Apoptotic DNA fragmentation induced by indomethacin
      and flurbiprofen was suppressed by incubation of the cells with the anti-oxidants
      pyrrolidine dithiocarbamate, diphenyleneiodonium chloride, and N-acetyl-L
      cysteine. These two NSAIDs also enhanced release from the cells of 8-isoprostane,
      a nonenzymatic product by free-radical-mediated peroxidation of arachidonic acid.
      Further, lucigenin chemiluminescence showed that the intracellular production of
      reactive oxygen species increased in cells treated with indomethacin. The present
      data thus indicate a crucial association between the generation of reactive
      oxygen species and NSAID-induced apoptosis in gastric epithelial cells.

PMID- 10594328
TI  - Contrasting roles of leu(356) in the human CCK(1) receptor for antagonist SR
      27897 and agonist SR 146131 binding.
AB  - A new highly specific, potent non-peptide agonist for the cholecystokinin subtype
      1 receptor (CCK(1)), SR 146131 (2-[4-(4-chloro-2, 5-dimethoxyphenyl)-5-(2
      cyclohexyl-ethyl)-thiazol-2-ylcarbamoyl ]-5, 7-dimethyl-indol-1-yl-1-acetic acid)
      was recently described [Bignon, E., Bachy, A., Boigegrain, R., Brodin, R.,
      Cottineau, M., Gully, D., Herbert, J.-M., Keane, P., Labie, C., Molimard, J.-C.,
      Olliero, D., Oury-Donat, F., Petereau, C., Prabonneaud, V., Rockstroh, M.-P.,
      Schaeffer, P., Servant, O.Thurneyssen, O., Soubrie, P., Pascal, M., Maffrand, J.
      P., Le Fur, G., 1999. SR 146131: a new, potent, orally active and selective non
      peptide cholecystokinin subtype I receptor agonist: I. In vitro studies. J.
      Pharmacol. Exp. Ther. 289, 742-751]. From binding and activity assays with
      chimeric constructs of human CCK(1) and the cholecystokinin subtype 2 receptor
      (CCK(2)) and receptors carrying point mutations, we show that Leu(356), situated
      in transmembrane domain seven in the CCK(1) receptor, is a putative contact point
      for SR 146131. In contrast, Leu(356) is probably not in contact with the CCK(1)
      receptor specific antagonist SR 27897 (1-[2-(4-(2-chlorophenyl)thiazol-2
      yl)aminocarbonyl indoyl]acetic acid), a compound structurally related to SR
      146131, since its replacement by alanine, histidine or asparagine gave receptors
      having wild-type CCK(1) receptor SR 27897 binding affinity. Previous mutational
      analysis of His(381), the cognate position in the rat CCK(2) receptor, had
      implicated it as being involved in subtype specificity for SR 27897, results
      which we confirm with corresponding mutations in the human CCK(2) receptor.
      Moreover, binding and activity assays with the natural CCK receptor agonist, CCK
      8S, show that CCK-8S is more susceptible to the mutations in that position in the
      CCK(1) receptor than in the CCK(2) receptor. The results suggest different
      binding modes for SR 27897, SR 146131 and CCK-8S in each CCK receptor subtype.

PMID- 10594329
TI  - Agonist activation and alpha-bungarotoxin inhibition of wild type and mutant
      alpha7 nicotinic acetylcholine receptors.
AB  - The properties of wild type and mutant rat nicotinic alpha7 receptors expressed
      in Xenopus oocytes were investigated using electrophysiology and site-directed
      mutagenesis. When compared at individual agonist concentrations, neither the
      normalised nicotinic, nor acetylcholine, responses of the wild type receptors
      were significantly different from the corresponding responses obtained from a
      first extracellular domain mutant, phenylalanine(189)tyrosine (P0.05). The
      dissociation constants (K(D)) of the wild type (4.7 nM) and Phe(189)Tyr mutant
      (5.2 nM) receptors for alpha-bungarotoxin were estimated by an
      electrophysiological approach. The similarity of the results suggests that the
      mutation did not lead to a widespread disruption of structure-function
      relationships, although a slight change in nicotine sensitivity may have
      occurred. In contrast, the mutations (Tyr(190)Gln, first extracellular domain),
      (Glu(261)Ala, M2 region) severely compromised receptor function. An additional
      mutation was made in a negatively charged motif of the second extracellular
      domain which is conserved in homomeric nicotinic receptors. This mutation,
      Asp(268)Ala, also caused a loss of function. Thus the structure-function
      relationships in nicotinic alpha7 receptors have parallels with heteromeric
      nicotinic receptors, but there may also be some marked differences.

PMID- 10594330
TI  - Electropharmacological effects of UK-1745, a novel cardiotonic drug, in guinea
      pig ventricular myocytes.
AB  - Effects of (2RS, 3SR)-2-aminomethyl-2,3,7,8-tetrahydro-2,3,5,8, 8-pentamethyl-6H
      furo-[2,3-e] indol-7-one hydrochloride (UK-1745), a novel cardiotonic drug with
      beta-adrenoceptor blocking property and antiarrhythmic activity, on the action
      potentials of isolated papillary muscles and the membrane currents of single
      ventricular myocytes of guinea pigs were examined and compared with those of
      milrinone using conventional microelectrode and patch-clamp techniques. In
      papillary muscles, UK-1745 (3-100 microM) produced a mild positive inotropic
      response and depressed the maximum upstroke velocity of the action potential
      (V(max)) at 100 microM. Milrinone, a phosphodiesterase III inhibitor, markedly
      shortened the action potential duration with a significant increase in developed
      tension. In enzymatically-dissociated ventricular myocytes, UK-1745 failed to
      increase the L-type Ca(2+) current (I(Ca)) at 10 and 30 microM and rather
      decreased I(Ca) at 100 microM. The high concentration of UK-1745 slightly
      inhibited the delayed rectifier K(+) current (I(K)). Although UK-1745 antagonized
      the isoproterenol-induced increase in I(Ca), it potentiated the histamine-induced
      increase in I(Ca). On the other hand, milrinone per se significantly increased
      I(Ca) and markedly enhanced the isoproterenol-induced increase in I(Ca). It can
      be concluded that UK-1745 is a unique cardiotonic drug possessing beta
      adrenoceptor blocking and weak phosphodiesterase-inhibitory actions in addition
      to direct inhibitory actions on the Na(+), Ca(2+) and K(+) channels with its high
      concentrations.

PMID- 10594331
TI  - SKP-450 inhibits migration and DNA synthesis stimulated by oxidized low density
      lipoprotein in smooth muscle cells.
AB  - This study was carried out to examine the inhibitory effects of SKP-450 (2
      [2"(1", 3"-dioxolone)-2-methyl]-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro-2H-1-be nzo
      pyran), a potassium channel opener, on the proliferation and migration stimulated
      by oxidized low density lipoprotein (LDL) of cultured smooth muscle cells of
      Wistar Kyoto rat aorta. SKP-450 (10(-7) and 10(-6) M) as well as probucol (10(-7)
      10(-5) M) reduced the production of thiobarbituric acid reactive substances from
      LDL submitted to CuSO(4) (10 microM). The increased [3H]thymidine incorporation
      and migration (chemotactic and wound-edge) of the cultured smooth muscle cells in
      association with increased production of platelet-derived growth factor (PDGF)-BB
      like immunoreactivity stimulated by oxidized LDL were significantly reduced by
      SKP-450 (10(-7)-10(-6) M). Inhibition by SKP-450 of the oxidized LDL-stimulated
      [3H]thymidine incorporation was antagonized by iberiotoxin (10(-7) M), but not by
      glibenclamide (10(-6) M), suggestive of mediation of Ca(2+)-activated K(+)
      channel opening in the action of SKP-450. Taken together, SKP-450 inhibited the
      proliferation and migration of the smooth muscle cells as well as PDGF production
      stimulated by oxidized LDL, accompanying with its antiperoxidative action.

PMID- 10594332
TI  - Modulation of actomyosin ATPase by thiotetromycin is mediated through
      conformational change of actin.
AB  - Thiotetromycin isolated from the culture broth of Streptomyces sp. strain OM-674
      slightly enhanced the superprecipitation and the ATPase activity of myosin B from
      skeletal muscle. The ATPase activity of troponin-tropomyosin-free myosin B was
      inhibited by thiotetromycin. The inhibitory effect of thiotetromycin was
      significantly attenuated by troponin-tropomyosin complex. The ATPase activity of
      actomyosin reconstituted from actin and myosin was inhibited by pretreatment of
      actin with thiotetromycin. Thiotetromycin induced a concentration-dependent
      decrease in the fluorescence intensity of actin and pyrenyl-F-actin. By using
      surface plasmon resonance (SPR), it was proved that thiotetromycin bound to
      actin. Thiotetromycin caused a concentration-dependent decrease in sedimentation
      of F-actin by hard centrifugation. This was a cross-correlation among the
      concentration-inhibition curves for thiotetromycin in the activity of actomyosin
      ATPase and the fluorescence intensity. These results suggest that thiotetromycin
      binds to actin to cause a conformational change, resulting in modulation of the
      interaction between actin and myosin, and in depolymerization of F-actin.

PMID- 10594333
TI  - Effects of nicotine on cultured cells suggest that it can influence the formation
      and resorption of bone.
AB  - The acute effects of nicotine [1-methyl-2-(3-pyridyl)pyrrolidine] on the
      formation and resorption of bone were examined in cultures of clonal rat
      calvarial osteogenic cells (ROB-C26) and clonal mouse calvarial preosteoblastic
      cells (MC3T3-E1), as well as in osteoclast-like cells formed during coculture of
      mouse bone marrow cells and clonal stromal cells from mouse bone marrow, ST2
      cells, at concentrations that occur in the saliva of smokeless tobacco users.
      Nicotine stimulated the rate of deposition of Ca(2+) by ROB-C26 cells, as well as
      the alkaline phosphatase activity of these cells, in a dose-dependent manner.
      However, both activities decreased in MC3T3-E1 cells that had been exposed to
      nicotine. These results indicate that nicotine affected osteoblastic
      differentiation in osteoblast-like cells. By contrast, nicotine reduced, in a
      dose-dependent manner, the formation of tartrate-resistant acid phosphatase
      (TRAP)-positive multinucleated cells (MNCs) and the formation of pits on slices
      of dentine, both of which are typical characteristics of osteoclasts. Our results
      suggest that nicotine might have critical effects on bone metabolism.

PMID- 10594334
TI  - ZM 241385, an adenosine A(2A) receptor antagonist, inhibits hippocampal A(1)
      receptor responses.
AB  - 4-(2-[7-amino-2-(2-furyl?1,2,4?-triazolo?2,3a?-?1,3, 5?triazin-5-yl
      amino]ethyl)phenol (ZM 241385) has been used as an antagonist of adenosine A(2A)
      receptors, exhibiting high selectivity over adenosine A(1) receptors. We now
      report that ZM 241385 (10-50 nM) attenuated the inhibitory action of N(6)
      cyclopentyladenosine (10 nM) and R(-)-N(6)-phenylisopropyladenosine (R-PIA, 20
      nM), two selective adenosine A(1) receptor agonists, on hippocampal population
      spike amplitude. This effect is unlikely to be a direct antagonism of adenosine
      A(1) receptor since the K(i) of ZM 241385 to displace [3H]PIA (2 nM) binding,
      from hippocampal membranes ranged from 0.8 to 1.9 microM. These results question
      the usefulness of ZM 241385 to define adenosine A(2A) receptors actions in
      functional studies.

PMID- 10594335
TI  - Induction of pulmonary cytochrome P4501A1: interactive effects of nicotine and
      mecamylamine.
AB  - The effect of the nicotinic receptor antagonist mecamylamine on nicotine-mediated
      convulsions and induction of pulmonary cytochrome P4501A1 (CYP1A1) was examined
      in the rat. Mecamylamine blocked the convulsions and inhibited CYP1A1 induction
      by nicotine at the level of CYP1A1 activity (93%) and protein (97%), but
      independently induced the enzyme also at the level of activity and protein. The
      results show that mecamylamine antagonizes both the CYP1A1 induction and
      convulsions by nicotine but, independently, is an inducer of the enzyme. The
      results indicate that CYP1A1 induction is not a consequence of the convulsant
      effects of nicotine.

PMID- 10594336
TI  - Corrigendum to: Effects of L-arginine on endothelial and cardiac function in rats
      with heart failure

PMID- 10594337
TI  - Lack of morphine-induced dopamine release in the nucleus accumbens of cannabinoid
      CB(1) receptor knockout mice.
AB  - Morphine (10 and 20 mg/kg, s.c.) does not modify dopamine release in the nucleus
      accumbens of cannabinoid CB(1) knock-out mice under conditions where it dose
      dependently stimulates the release of dopamine in the corresponding wild-type
      mice. These results demonstrate that cannabinoid CB(1) receptors, regulate
      mesolimbic dopaminergic transmission in brain areas known to be involved in the
      reinforcing effects of morphine.

PMID- 10594338
TI  - Acute low doses of melatonin stimulate rat sex behavior: the role of serotonin
      neurotransmission.
AB  - Melatonin is known to inhibit male and female sex behavior, but this effect has
      been reported only after repeated administration of sustained doses of the
      hormone. The present experiments were performed in order to study the effects of
      acute treatment with low doses of melatonin on rat male and female sex behavior
      in a dose-response paradigm. After four mating tests with a receptive female,
      sexually active male rats of the Wistar strain were injected intraperitoneally
      (i.p.) with small doses of melatonin (10, 50 and 100 microg/kg) administered
      acutely 1 h before a 30-min mating test. Melatonin (50 and 100 ng/2 microl) or
      its analogs, 6-chloromelatonin (2 and 4 ng/2 microl) and 2-iodomelatonin (5 and
      10 ng/2 microl) were also injected intracerebroventricularly (i.c.v.) 30 min
      before mating. Either treatments caused a reduction of the latency to the first
      mount, intromission and ejaculation. An increase in the frequency of mounts,
      intromissions and ejaculations was also observed. Inhibition of sexual activity
      was observed when a greater dose (1 mg/kg) of melatonin was repeatedly injected
      for 14 days. Female sex behavior, measured by the lordosis quotient in Wistar
      female rats, was not affected by acute treatment with the hormone, while it
      appeared to be inhibited by the repeated injection. The facilitating effect of
      acute i.p. or i.c.v. melatonin low doses on sexual activity of male rats was
      partially abolished by the pre-treatment with the non-selective melatonin
      antagonist, luzindole (0.25 mg/kg, injected subcutaneously), and totally
      suppressed by the injection of small quantities of serotonin or the 5H(2A)-5H(2C)
      receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane into the
      amygdala. These results suggest that melatonin may exert opposite effects on male
      and female sex behavior depending on the dose and duration of treatment.

PMID- 10594339
TI  - Focal bicuculline increases extracellular dopamine concentration in the nucleus
      accumbens of freely moving rats as measured by in vivo microdialysis.
AB  - This study was designed to assess the involvement of GABA(A) receptors in the
      regulation of in vivo dopamine release in the nucleus accumbens. Extracellular
      dopamine in the nucleus accumbens was measured using intracerebral microdialysis
      coupled with a high-performance liquid chromatography with electrochemical
      detection (HPLC-EC) system in freely moving Sprague-Dawley rats. Bicuculline, a
      GABA(A) receptor antagonist, and muscimol, a GABA(A) receptor agonist, were
      administered via a dialysis probe into the nucleus accumbens, respectively. The
      results showed that perfusion with bicuculline at concentrations of 25, 50, and
      100 microM elicited a significant and concentration-dependent increase in
      extracellular dopamine in the nucleus accumbens. Dopamine levels returned to
      control values within 40-60 min after the termination of bicuculline perfusion.
      The increased dopamine produced by perfusion with 100 microM bicuculline was
      sensitive to sodium channel blockade with tetrodotoxin, and antagonized by co
      perfusion with muscimol (25 and 50 microM) in a concentration-related fashion.
      Perfusion with 25 or 50 microM muscimol alone failed to alter basal levels of
      dopamine. The results suggest that local application of bicuculline increases
      dopamine release in the nucleus accumbens via a receptor-mediated process, and
      are consistent with the concept that basal dopamine release in the nucleus
      accumbens is under tonic inhibitory control by GABA(A) receptors within this
      structure.

PMID- 10594340
TI  - Effect of N-methyl-D-aspartate on motor activity and in vivo adenosine striatal
      outflow in the rat.
AB  - It has been previously found that the systemic administration of low doses of N
      methyl-D-aspartate (NMDA) in mice induces motor depression. The effects of the
      systemic administration of different doses of NMDA (10, 30 and 60 mg/kg s.c.) on
      the motor activity and on the in vivo extracellular levels of adenosine in the
      striatum was studied in Sprague-Dawley rats. The adenosine concentration in
      samples of perfusate was determined 24 h after implantation of a transverse
      microdialysis probe. At 30 and 60 mg/kg, but not 10 mg/kg, NMDA induced both a
      significant motor depression (motility and rearing) and a significant increase in
      the striatal extracellular levels of adenosine. Both the motor depression and the
      changes in the extracellular levels of adenosine were only evident during the
      first 30 min after NMDA administration. The non-competitive NMDA receptor
      antagonist MK-801 (0.1 mg/kg s.c.) completely counteracted the effects of NMDA
      (30 mg/kg s.c.) on motor activity (motility) and on the striatal extracellular
      levels of adenosine. The correlation between the behavioural and the biochemical
      data strongly support the hypothesis that adenosine release in the striatum is a
      main mechanism responsible for the motor depressant effects produced by the
      systemic administration of NMDA.

PMID- 10594341
TI  - Nitric oxide modulates captopril-mediated angiotensin-converting enzyme
      inhibition in porcine iliac arteries.
AB  - The influence of the angiotensin-converting enzyme inhibitor captopril on
      bradykinin-and angiotensin I-induced responses with special regard to nitric
      oxide (NO) was studied. Auxometric tension and angiotensin-converting enzyme
      activity was studied in isolated porcine iliac arteries. Captopril potentiated
      bradykinin-induced contraction of preparations with intact endothelium; this
      potentiation was not seen with the kininase I inhibitor mergepta or a bradykinin
      B(1)-receptor antagonist. Captopril did not affect bradykinin-induced relaxation.
      The captopril-mediated increase of bradykinin-induced contraction was only seen
      in preparations with intact endothelium, while captopril did not affect arterial
      strips treated with Nomega-nitro-L-arginine. Angiotensin I-induced contractions
      was less reduced by captopril when the strips were pretreated with Nomega-nitro-L
      arginine. Both captopril and the NO donor S-nitroso-N-acetyl-penicillamine
      inhibited angiotensin-converting enzyme activity. An additional reduction in
      angiotensin-converting enzyme activity was seen when S-nitroso-N-acetyl
      penicillamine was added to captopril-treated preparations. In conclusion,
      captopril increased bradykinin-induced contraction in a NO-dependent manner. This
      potentiation is probably mediated by the increased metabolism of bradykinin by
      kininase I, and the additive angiotensin-converting enzyme inhibitory effect of
      captopril and NO.

PMID- 10594342
TI  - Chronic exposure to hypoxia attenuates contractile responses in rat airways in
      vitro: a possible role for nitric oxide.
AB  - We investigated the effect of chronic hypoxia (10% O(2) for 14 days) on airway
      responsiveness in rats. Chronic hypoxia significantly (P<0. 05, P<0.01, P<0.01,
      respectively) attenuated contractions evoked by methacholine (10(-9)-3x10(-4) M),
      endothelin-1 (10(-10)-3x10(-7) M) and potassium chloride (10(-3)-7x10(-2) M) in
      rat isolated trachea. To investigate this attenuation, we studied the effect of
      epithelial removal, indomethacin (3x10(-6) M), and L-nitro arginine methyl ester
      (L-NAME, 10(-4) M), on contractile responses in control and chronically hypoxic
      rat trachea. Indomethacin did not alter contractions evoked by methacholine or
      endothelin-1 in control or hypoxic rats. In contrast, epithelial removal and L
      NAME both significantly potentiated responses to methacholine and endothelin-1 in
      trachea from control and chronically hypoxic rats. In separate experiments,
      tracheal rings were first contracted with methacholine (10(-6) M) and then
      relaxed, either by the nitric oxide donor sodium nitroprusside or by the beta(2)
      adrenoceptor agonist, salbutamol. Sodium nitroprusside was significantly
      (P<0.001) more effective at reversing induced tone in tracheal rings from
      chronically hypoxic than control rats. Salbutamol, however, was equally effective
      in chronically hypoxic and control rats. These results suggest that, in trachea
      from both control and chronically hypoxic rats, contractile responses to
      methacholine and endothelin-1 are inhibited by nitric oxide, probably released
      from the epithelium. The attenuation of contractile responses in airways from
      chronically hypoxic rats may be due to an enhanced guanylyl cyclase activity and
      hence, an increased response to nitric oxide.

PMID- 10594343
TI  - Efficacy of pramipexole, a new dopamine receptor agonist, to relieve the
      parkinsonian-like muscle rigidity in rats.
AB  - The aim of the present study was to assess the efficacy of pramipexole (2-amino
      4,5,6, 7-tetrahydro-6-propyl-amino-benzthiazole-dihydrochloride), a new dopamine
      D(2)/D(3) receptor agonist, to attenuate parkinsonian-like muscle rigidity in
      rats. Muscle tone was examined using a combined mechano- and electromyographic
      (EMG) method, which simultaneously measured the muscle resistance of a rat's
      hindlimb to passive extension and flexion at the ankle joint, and the EMG
      acitivity of the antagonistic muscles of that joint: gastrocnemius and tibialis
      anterior. Muscle rigidity was produced by reserpine (5 mg/kg) injected in
      combination with alpha-methyl-p-tyrosine (250 mg/kg) or by haloperidol (0.5
      mg/kg). Pramipexole in doses of 0.5-5 mg/kg antagonized both reserpine+alpha
      methyl-p-tyrosine- and haloperidol-induced muscle rigidity. Pramipexole also
      reduced reserpine-enhanced tonic and reflex EMG activities in the gastrocnemius
      muscle. The present results suggest that stimulation of the postsynaptic dopamine
      receptor may be chiefly responsible for the antiparkinsonian action of
      pramipexole. The ability of pramipexole to diminish the parkinsonian-like muscle
      rigidity seems to indicate a therapeutic value of this compound in the treatment
      of Parkinson's disease.

PMID- 10594344
TI  - Role of prostaglandins generated by cyclooxygenase-1 and cyclooxygenase-2 in
      healing of ischemia-reperfusion-induced gastric lesions.
AB  - In this study, ischemia-reperfusion produced in rats by clamping the celiac
      artery for 0.5 h followed by 1 h of reperfusion was used to develop a new model
      of superficial gastric erosions progressing to deeper ulcers. Ischemia alone
      resulted in an immediate fall in gastric blood flow but no gross mucosal lesions
      were observed. When ischemia was followed by reperfusion, gastric erosive lesions
      occurred, reached a maximum at 12 h and then declined after 24 h. These acute
      erosions progressed into deeper lesions 24 h after ischemia-reperfusion and
      reached a peak after 3 days. Gastric blood flow and the mucosal generation of
      prostaglandin E(2) were significantly suppressed immediately following ischemia
      reperfusion, but with the healing of deeper gastric ulcers, both gastric blood
      flow and prostaglandin E(2) generation were gradually restored. Cyclooxygenase-1
      mRNA was detected by reverse transcription-polymerase chain reaction in intact
      gastric mucosa and throughout the recovery of the mucosa from acute ischemia
      reperfusion lesions, whereas cyclooxygenase-2 mRNA, was recorded only after
      ischemia-reperfusion. NS-398 and rofecoxib, selective inhibitors of
      cyclooxyganase-2, failed to affect prostaglandin E(2) generation in the non
      ulcerated gastric mucosa but inhibited it significantly in the ulcer area. The
      two cyclooxygenase-2 inhibitors as well as resveratrol, a specific cyclooxygenase
      1 inhibitor and indomethacin and meloxicam, non-specific inhibitors of
      cyclooxygenase, augmented acute gastric erosions induced by ischemia-reperfusion
      and delayed significantly the progression of these lesions into deeper ulcers at
      each time interval after ischemia-reperfusion. We conclude that prostaglandins
      generated by both cyclooxygenase-1 and cyclooxygenase-2 contribute to the healing
      of gastric lesions induced by ischemia-reperfusion.

PMID- 10594345
TI  - Phosphorylation of extracellular signal-regulated kinases 1 and 2 in 3T3-L1
      adipocytes by stimulation of beta(3)-adrenoceptor.
AB  - Recent studies have revealed that activated extracellular signal-regulated
      kinases (ERKs) 1 and 2 by the stimulation of beta(3)-adrenoceptors played a
      critical role in cell survival in brown adipocytes. On the other hand,
      phosphorylation of ERK1/2 via beta(3)-adrenoceptors and its physiological and
      pathological significance in white adipocyte has remained uncertain despite the
      increasing significance of functioning white adipocytes. Accordingly, we here
      studied phosphorylation of ERK1/2 caused by the stimulation of beta(3)
      adrenoceptors in 3T3-L1 adipocytes, and the roles of phosphorylated ERK1/2 in
      lipolysis. Phosphorylation of ERK1/2 was induced by a selective beta(3)
      adrenoceptor agonist, DL-4-[2'-?2-hydroxy-2-(3-chlorophenyl)ethylamino?propyl]
      phenoxyacetic acid sodium salt sesquihydrate (BRL37344), in 3T3-L1 adipocytes in
      a time- and dose-dependent manner. The phosphorylation of ERK1/2 by BRL37344 was
      sensitive to the cyclic AMP (cAMP)-dependent protein kinase inhibitor, N-[2-((p
      bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide (H89). To elucidate the
      roles of phosphorylated ERK1/2 in lipolysis, the effect of a selective inhibitor
      of ERK1/2 phosphorylation, 2'-amino-3'-methoxyflavone (PD98059), was examined.
      This inhibitor did not alter the lipolytic action caused by BRL37344, even at
      concentrations sufficient to block phosphorylation of ERK1/2, suggesting that
      ERK1/2 play no role in the lipolysis caused by BRL37344 in 3T3-L1 adipocytes.

PMID- 10594346
TI  - Auranofin inhibits interleukin-1beta-induced transcript of cyclooxygenase-2 on
      cultured human synoviocytes.
AB  - The aim of this study was to characterize the effects of auranofin (2,3,4,6-tetra
      O-acetyl-l-thio-beta-D-gluco-pyranosato-S) on cyclooxygenase expression and
      prostaglandin E(2) synthesis on cultured human synovial fibroblast-like cells
      (synoviocytes). Synoviocytes were treated with auranofin in the presence or
      absence of interleukin-1beta. Cultured supernatants were harvested for
      prostaglandin E(2) synthesis. Cyclooxygenase-1 and -2 expression was analyzed
      with Western and Northern blotting. Translocation of nuclear factor-kappa B p65
      was determined by immunostaining. Cytotoxicity was measured with 51Cr release
      assay. Auranofin attenuated interleukin-1beta-induced prostaglandin E(2)
      production of the cells in a dose-dependent fashion. Auranofin selectively
      suppressed interleukin-1beta-induced cyclooxygenase-2 mRNA and protein expression
      of the cells without alteration of cyclooxygenase-1 expression. Also, auranofin
      interfered with interleukin-1beta-induced translocation of nuclear factor-kappa
      B. These inhibitory effects did not originate in the cytotoxicity of the agent.
      Our data indicate that auranofin inhibits interleukin-1beta-induced prostaglandin
      E(2) synthesis and cyclooxygenase-2 expression via suppression of nuclear factor
      kappa B activation on synoviocytes.

PMID- 10594347
TI  - Effects of CP-060S, a novel Ca(2+) channel blocker, on oxidative stress in
      cultured cardiac myocytes.
AB  - The effect of (-)-(S)-2-[3,5-bis(1, 1-dimethylethyl)-4-hydroxyphenyl]-3-[3-[N
      methyl-N-[2-(3, 4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thiazolidin- 4
      one hydrogen fumarate (CP-060S), a novel Ca(2+) channel blocker, on hydrogen
      peroxide (H(2)O(2))-induced cytotoxicity was studied in cultured rat cardiac
      myocytes. The CP-060S effect was compared with that of CP-060R, an optical isomer
      of CP-060S with a less potent Ca(2+) channel blocking action than CP-060S.
      H(2)O(2) increased the release of lactate dehydrogenase from cardiac myocytes and
      decreased the formation of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium
      bromide) (MTT) formazan in cardiac myocytes (i.e., cytotoxic action). Both CP
      060S (1 microM) and CP-060R (1 microM) attenuated to a similar extent the
      foregoing alterations induced by H(2)O(2). On the other hand, 1,3-dimethyl-2
      thiourea (10 mM), a scavenger of both H(2)O(2) and hydroxyl radical, also
      attenuated the H(2)O(2)-induced cytotoxicity whereas diltiazem (10 microM) did
      not. In an experiment using electron spin resonance (ESR) with 5, 5-dimethyl-1
      pyrroline N-oxide (DMPO), a spin-trapping agent, both CP-060S and CP-060R
      decreased the intensity of DMPO-hydroxyl radical signal concentration
      dependently. These results suggest that CP-060S protects cardiac myocytes from
      oxidative stress through its radical scavenging action.

PMID- 10594348
TI  - An efficient method for simultaneous isolation of biologically active
      transcription factors and DNA.
AB  - Transcription factors play a crucial role in gene regulation during different
      stages of eukaryotic development as well as in controlling various cellular
      disorders involving the immune system. In order to study the role of cellular
      DNAs and the effects of certain biologically active regulatory proteins, which
      can affect gene expression, we have developed a rapid and efficient method for
      preparing highly purified DNAs as well as nuclear and cytoplasmic proteins,
      simultaneously. These DNAs and proteins can be effectively analyzed to determine
      their genetic integrity and binding motifs to specific DNA sequences,
      respectively. This protocol avoids the drastic use of mechanical shearing of
      cells, aggressive use of detergents or high speed ultracentrifugation steps, as
      well as facilitating the ease of collecting samples in a sequential and effective
      manner with minimal time lapse during processing. Such an approach permits the
      analysis of a large number of samples in a short time. The current technique uses
      a non-ionic detergent to isolate nuclei, and obtain the cytosolic extract, a low
      ionic strength buffer to wash off the detergent and a high-salt buffer to extract
      nuclear proteins including transcription factors. The remainder of the cellular
      products are processed for DNA extraction. This method will be particularly
      useful to evaluate the time course effects of various cell signal transducing
      biological modifiers such as cytokines or mitogens, as well as drugs used in
      therapy, especially in infectious diseases and also in immunological or
      neoplastic disorders, with minimal physical contact to the laboratory personnel.
      This rapid DNA and protein isolation method can be widely used in various systems
      to analyze the modulation of DNA characteristics and transcriptionally active
      proteins as biomarkers in different human diseases.

PMID- 10594349
TI  - 96-Well plates providing high optical resolution for high-throughput,
      immunofluorescence-based screening of monoclonal antibodies against Toxoplasma
      gondii.
AB  - We have developed a method for high resolution, high magnification
      immunofluorescence-based screening in a multi-well format, using a recently
      introduced 96-well plate specifically developed for fluorescence microscopy. We
      report here on the use of these plates to screen hybridoma supernatants for
      reactivity with specific subcellular compartments of the protozoan parasite
      Toxoplasma gondii. This has proven to be a powerful screening strategy,
      particularly when combined with high-throughput immunoblotting, and has enabled
      us to generate nine different monoclonal antibodies (MAbs) against either the
      periphery or structures within the apical end of T. gondii. The availability of a
      disposable, inexpensive, 96-well plate with optical properties suitable for high
      magnification imaging could lead to applications in a variety of fluorescence
      based screening protocols.

PMID- 10594350
TI  - A fluorimeter-based RT-PCR method for the detection and quantitation of porcine
      cytokines.
AB  - In this paper, we describe a fluorimeter-based, closed-tube, polymerase chain
      reaction (PCR) assay for the detection and quantification of the mRNA of porcine
      interleukin 1alpha (IL1alpha) and interleukin 2 (IL2) cytokines in peripheral
      blood leukocytes (PBLs) using melting curve analysis and compare it to a standard
      PCR performed in a block-based thermocycler.

PMID- 10594351
TI  - Detection of IgM to hepatitis B core antigen in a reductant containing,
      chemiluminescence assay.
AB  - The Abbott PRISM(R) hepatitis B core (HBc) antigen assay is an automatic in vitro
      competitive chemiluminescence immunoassay for the detection of total antibody to
      HBc (anti-HBc) antigen in human serum or plasma. The assay utilizes cysteine
      solution as a reducing reagent in order to maximize specificity. To help
      understand the effect of cysteine on detection of anti-HBc antigen, we separated
      and purified anti-HBc IgM and IgG from human plasma using size exclusion, protein
      A/G, and affinity chromatography techniques. We showed that cysteine affected the
      reactivity of anti-HBc IgM with recombinant HBc (rHBc) antigen but not the
      reactivity of anti-HBc IgG. Anti-HBc IgM treated with cysteine yielded byproducts
      which were reactive in the PRISM HBcore assay. Reduction-sensitive factor (RSF) -
      IgM fraction from serum known to be non-specific for anti-HBc activity, similarly
      treated with cysteine, was no longer reactive in the PRISM HBcore assay. We
      showed that cysteine treatment is effective against non-specific IgM in human
      blood. Also, the inclusion of cysteine in the PRISM HBcore assay does not
      compromise the detection of HBc specific antibodies.

PMID- 10594352
TI  - Beta galactosidase release as an alternative to chromium release in cytotoxic T
      cell assays.
AB  - In the present report, we describe a beta galactosidase release (BGR) assay to
      evaluate cytotoxic T lymphocyte (CTL) activity against specific targets.
      Transient expression of beta galactosidase (beta gal) was obtained by infection
      with recombinant beta gal vaccinia virus. Incubation of target cells with
      effector cells resulted in the release of beta gal depending on the infection
      time and the effector/target cell ratio. BGR was evaluated using the
      chemiluminescent substrate, AMPGD (3-?4-Methoxyspiro[1,2-dioxetane-3, 2'
      tricyclo(3.3.1.1(3,7))decan]-yl?phenyl-b-D-galactopyra nos ide), a
      phenylgalactose-substituted 1,2-dioxetane compound. The use of a digenic vector
      carrying two genes coding for the beta gal gene and the antigen, respectively,
      permits expression of the two proteins in the same cell. Coinfection of target
      cells with two different vectors, carrying beta gal and antigen genes,
      respectively, was demonstrated to be as efficient as digenic vector when using
      high multiplicity of infection (MOI). The BGR assay was compared to the standard
      4 h 51chromium (51Cr) release assay both in mouse and human models and showed
      comparable sensitivity. The BGR assay, therefore, provides a simple, specific and
      responsive method for measuring cell-mediated cytotoxic activity.

PMID- 10594353
TI  - Use of herpesvirus saimiri-immortalized macaque CD4(+) T cell clones as
      stimulators and targets for assessment of CTL responses in macaque/AIDS models.
AB  - Herpesvirus saimiri (HVS), a nonhuman primate gamma herpes virus, was used to
      immortalize pig-tailed macaque CD4(+) T lymphocytes. The HVS-immortalized T cell
      lines were used to develop CD4(+) T cell clones from two animals. Three CD4(+) T
      cell clones were further characterized for the expression of cell surface
      markers. All expressed CD2, CD4, CD58, CD69 and CD80 and therefore resembled
      activated T cells. These clones required exogenous IL-2 for efficient growth and
      were found to be highly susceptible to infection by the challenge virus, Chimeric
      simian/human immunodeficiency virus (SHIV(KU-1)). They could also be productively
      infected not only by the quasispecies of the challenge virus (SHIV(KU-1/PDJ) and
      SHIV(KU-1/PNA), isolated from macaque PDj and PNa, respectively) but also by a
      different chimeric simian/human immunodeficiency virus (SHIV(89.6P)) and simian
      immunodeficiency virus (SIV(MAC239)). The virus-infected CD4(+) T cell clones
      were also used as stimulators for generation of CTL effectors. These effectors
      exhibited excellent virus-specific lysis in chromium-release assays when syngenic
      SHIV(KU-1) infected autologous CD4(+) T cell clones were used as targets. The
      target cell lysis was virus specific, as uninfected control cells showed no or
      minimal lysis.

PMID- 10594354
TI  - Efficient laboratory-scale production of monoclonal antibodies using membrane
      based high-density cell culture technology.
AB  - Monoclonal antibodies (MAbs) are important tools used in basic research as well
      as in the imaging and therapy of cancer. Many countries have limited the use of
      animals for large-scale production of MAbs, obliging laboratories to find
      efficient in vitro alternatives to ascites production. In this report we describe
      a protocol for laboratory-scale production of MAbs by culturing hybridoma cells
      in the two-chamber cell culture device CELLine 1000. This culture flask supports
      high cell densities (10(7)-10(8) cells/ml) and generates high concentrations of
      MAbs (0.7-2.5 mg/ml). Two hybridomas producing MAbs directed against the
      gastrointestinal antigen GA733-2, GA733 MAb and CO17-1A MAb, were evaluated over
      culture periods of up to two months using several alternative conditions. Two
      different sets of conditions are reported; the first using serum-supplemented
      medium (20% v/v) and the second using serum-free medium (SFM). Average weekly
      yields of the purified MAbs in serum-supplemented medium were 24 mg and 33 mg,
      and in SFM were 21 mg and 17 mg for GA733 MAb and CO17-1A MAb, respectively.
      Experimental variables that can affect antibody production and economy include:
      nutrient medium and cell compartment medium compositions (cell line dependent),
      the proportion of the cell compartment medium harvested every 3 days (50% to 80%
      with 80% optimal) and the frequency of nutrient medium changes (3 to 9 days with
      6 days as most cost effective). Protein-A Sepharose purification followed by
      antigen-specific affinity purification showed that MAbs obtained from serum
      supplemented cultures contain less than 0.6% of bovine IgG contamination, while
      MAbs obtained from serum-free cultures contained no extraneous IgG. In addition,
      MAbs from both culture media were fully active (essentially 100%) as measured by
      their ability to bind to an antigen column. In contrast, the same MAbs purified
      from ascites using Protein-A-Sepharose typically contained a major portion of
      inactive IgG. This in vitro method for laboratory-scale production of MAbs (10 to
      500 mg) proved to be simple, reproducible and cost effective. It represents a
      useful alternative to the in vivo production of MAbs in mice.

PMID- 10594355
TI  - A novel signal amplification technology for ELISA based on catalyzed reporter
      deposition. Demonstration of its applicability for measuring aflatoxin B(1).
AB  - In an earlier communication we have described a novel signal amplification
      technology termed Super-CARD, which is able to significantly improve antigen
      detection sensitivity in conventional Dot-ELISA by approximately 10(5)-fold. The
      method utilizes hitherto unreported synthesized electron rich proteins containing
      multiple phenolic groups which, when immobilized over a solid phase as blocking
      agent, markedly increases the signal amplification capability of the existing
      CARD method (Bhattacharya, R., Bhattacharya, D., Dhar, T.K., 1999. A novel signal
      amplification technology based on catalyzed reporter deposition and its
      application in a Dot-ELISA with ultra high sensitivity. J. Immunol. Methods 227,
      31.). In this paper we describe the utilization of this Super-CARD amplification
      technique in ELISA and its applicability for the rapid determination of aflatoxin
      B(1) (AFB(1)) in infected seeds. Using this method under identical conditions,
      the increase in absorbance over the CARD method was approximately 400%. The limit
      of detection of AFB(1) by this method was 0.1 pg/well, the sensitivity
      enhancement being 5-fold over the optimized CARD ELISA. Furthermore, the total
      incubation time was reduced to 16 min compared to 50 min for the CARD method.
      Assay specificity was not adversely affected and the amount of AFB(1) measured in
      seed extracts correlated well with the values obtained by conventional ELISA.

PMID- 10594356
TI  - Characterization of a peptide-loading compartment by monoclonal antibodies.
AB  - Whether or not peptide-loading compartments are classical or specialized
      compartments of the endocytic pathway of antigen presenting cells is still a
      matter of debate. One way to solve this discrepancy would be to characterize
      specific markers for the peptide-loading compartment. We chose to generate
      monoclonal antibodies against the peptide-loading compartment that we previously
      characterized as lysozyme loading compartment (LLC) [Escola, J.M., Grivel, J.C.,
      Chavrier, P., Gorvel, J.P., 1995. Different endocytic compartments are involved
      in the tight association of class II molecules with processed hen egg lysozyme
      and ribonuclease A in B cells. J. Cell Sci. 108, 2337; Escola, J.M., Deleuil, F.,
      Stang, E., Boretto, J., Chavrier, P., Gorvel, J.P., 1996. Characterization of a
      lysozyme-major histocompatibility complex class II molecule-loading compartment
      as a specialized recycling endosome in murine B lymphocytes. J. Biol Chem. 271,
      27360]. A preliminary screening by dot blot enabled us to identify several
      monoclonal antibodies recognizing the LLC and not early and late endosomes. One
      of these antibodies, the 20C4, was then characterized. It is directed against
      mature class II molecules of all murine haplotypes. By electron microscopy, 20C4
      labeling was restricted to both the plasma membrane and the LLC. These reagents
      may be useful in the further characterization of the specialized function of
      these intracellular organelles.

PMID- 10594357
TI  - A flow cytometric method to estimate the precursor frequencies of cells
      proliferating in response to specific antigens.
AB  - Fluorescent dyes that stain cell membranes or cytoplasm and then partition
      between daughter cells at division have been used in conjunction with flow
      cytometry to measure the proliferation of cells. In this paper, using peripheral
      blood mononuclear cells responding to tetanus toxoid, we describe an extension of
      this dye methodology to calculate the precursor frequency of antigen-specific T
      cells. With mathematical deconvolution of the fluorescence histograms providing
      information about the proportion of cells in each of the daughter generations,
      information can be derived about the precursor frequency of cells in the original
      population that responded to the specific stimulus. Data from a model system with
      different proportions of fixed and viable cells indicate that the flow method
      returns accurate values for precursor frequency. Based on the characteristics of
      flow cytometric data acquisition, it is estimated that the flow method could
      detect proliferation of cells that represented, before addition of the stimulus,
      approximately 1/10(5) of the population. When comparing results to those from the
      limiting dilution technique, the flow cytometric method returns values that
      indicate higher precursor frequencies. Possible reasons for this discrepancy are
      discussed. The flow cytometric method offers the advantage of simplicity as well
      as the additional ability to phenotype the responding cells and determine their
      rate of proliferation. The flow method may find use as a simple, routine assay in
      the fields of allergy, transplant rejection, and autoimmunity and for
      quantitating responses to vaccination and cancer immunotherapy.

PMID- 10594358
TI  - Enzymatic signal amplification for sensitive detection of intracellular antigens
      by flow cytometry.
AB  - Flow cytometry is the method of choice for the analysis of single cells with
      respect to the expression of specific antigens. Antigens can be detected with
      specific antibodies either on the cell surface or within the cells, after
      fixation and permeabilization of the cell membrane. Using conventional
      fluorochrome-labeled antibodies several thousand antigens are required for clear
      cut separation of positive and negative cells. More sensitive reagents, e.g.,
      magnetofluorescent liposomes conjugated to specific antibodies permit the
      detection of less than 200 molecules per cell but cannot be used for the
      detection of intracellular antigens. Here, we describe an enzymatic amplification
      technique (intracellular tyramine-based signal amplification, ITSA) for the
      sensitive cytometric analysis of intracellular cytokines by immunofluorescence.
      This approach results in a 10 to 15-fold improvement of the signal-to-noise ratio
      compared to conventional fluorochrome labeled antibodies and permits the
      detection of as few as 300-400 intracellular antigens per cell.

PMID- 10594359
TI  - Fluobodies: green fluorescent single-chain Fv fusion proteins.
AB  - An expression system (pSKGFP), which permits the expression of single-chain
      variable fragments as fusion proteins with modified green fluorescent proteins,
      was designed. This expression system is comparable to frequently used phage
      display vectors and allows single-step characterization of the selected
      recombinant antibodies by flow cytometry or fluorescent cell staining. Two
      different single-chain variable fragment antibodies, both directed against the
      lipopolysaccharide of the bacterium Ralstonia solanacearum have been genetically
      fused to a red-shifted green fluorescent protein and the produced fusion protein
      tested for usefulness. These fluobodies can be produced in cultures of bacterial
      cells and purified using immobilized metal affinity chromatography. They function
      well in flow cytometry and immunofluorescent cell staining, are specific for
      their target antigens and, unlike FITC-conjugated antibodies, they do not fade
      upon illumination.

PMID- 10594360
TI  - Evaluation of single- and dual antigen delayed fluorescence immunoassay in
      comparison to an ELISA and the in vivo toxin neutralisation test for detection of
      diphtheria toxin antibodies.
AB  - An evaluation of the delayed fluorescence immunoassay (Delfia) against an ELISA
      method for determination of diphtheria antitoxin levels in serum was performed.
      The Delfia was also validated in the in vivo toxin neutralisation test (Txn) in
      rabbits. Two variants of the Delfia were studied, a single-antigen Delfia
      (sDelfia) with only the diphtheria toxin included and a dual-antigen Delfia
      (dDelfia) with tetanus toxoid included for simultaneous detection of antibodies
      against two antigens. The diphtheria antitoxin cut-off levels in the sDelfia and
      the dDelfia were 0.004 and 0.002 AU/ml, respectively, which is lower than the
      internationally accepted level showing any protection against diphtheria (0.01
      IU/ml). Both Delfia variants showed good correlation with the ELISA procedure
      above the ELISA cut-off level of 0.02 AU/ml. Results from samples assayed in the
      in vivo Txn assay indicated that the low antitoxin levels detected by the Delfia
      were valid. These results show that the Delfia could be considered as an in vitro
      reference method for detection of diphtheria antitoxin in seroepidemiological
      surveys and vaccine studies.

PMID- 10594361
TI  - Improved cell line development by a high throughput affinity capture surface
      display technique to select for high secretors.
AB  - A novel process is described which permits rapid and objective selection of rare
      cells from a heterogeneous population based on quantity of secreted target
      protein. The process involves construction of an immobilised affinity surface
      display matrix that specifically binds secreted target product which is then
      detected using a fluorescent labelled ligand. Cells with the highest fluorescence
      can then be sorted using conventional flow cytometric technology. Overall, the
      whole process can be completed in less than 4 h during which time in the region
      of five million cells can be analysed. Cells are rapidly selected for in a
      quantitative manner compared to traditional methods which can take several months
      and have a reduced probability of finding low abundance high secretors due to
      practical limitations imposed on the number of cells which can be screened.

PMID- 10594362
TI  - Quantification of substance P mRNA in human mononuclear phagocytes and
      lymphocytes using a mimic-based RT-PCR.
AB  - We have recently demonstrated that human monocytes and lymphocytes express the
      substance P (SP) gene at both the mRNA and protein level [Ho, W.Z., Lai, J.P.,
      Zhu, X.H., Uvaydova, M., Douglas S.D., 1997. Human monocytes and macrophages
      express substance P and neurokinin-1 receptor. Journal of Immunology, 159, p.
      5654; Lai, J.P., Douglas, S. D., Ho, W.Z., 1998. Human lymphocytes express
      substance P and its receptor. Journal of Neuroimmunology, 86, p. 80; Lai, J.-P.,
      Douglas, S.D., Rappaport, E., Wu, J., Ho, W.-Z., 1998. Identification of a delta
      isoform of preprotachykinin mRNA in human mononuclear phagocytes and lymphocytes.
      Journal of Neuroimmunology, 91, p. 121]. Using RT-PCR assay with several specific
      human SP primer pairs, we were able to differentiate four isoforms of
      preprotachykinin (PPT-A, the SP precursor) mRNA transcripts on ethidium bromide
      stained agarose gels and clone the PCR amplified cDNA of the four isoforms
      (alpha, beta, gamma, and delta) of the PPT-A gene. In an effort to quantitatively
      measure PPT-A mRNA levels, we have developed a mimic-based RT-PCR assay to
      analyze total PPT-A mRNA levels in human monocytes and lymphocytes. We designed a
      specific human SP primer pair (HSP4/HSP3) to amplify a single fragment of cDNA
      derived from all four isoforms of PPT-A mRNA transcripts, with a sensitivity of
      120 molecules per reaction. Thus the PPT-A mRNA transcripts in an unknown sample
      can be quantitatively analyzed using the mimic-based RT-PCR. The accuracy and
      reproducibility of this assay were confirmed by the plasmids containing alpha,
      beta, gamma and delta cDNA inserts and by in vitro synthesized mRNA from a
      plasmid containing beta isoform cDNA insert. Our data indicate that the SP mimic
      based RT-PCR assay has potential advantages in studies of SP levels in a variety
      of human cells as well as in clinical specimens.

PMID- 10594363
TI  - Acquired antagonistic activity of a bispecific diabody directed against two
      different epitopes on vascular endothelial growth factor receptor 2.
AB  - Bispecific antibody (BsAb) technology has been successfully used as a means to
      construct novel antibody (Ab) molecules with increased avidity for binding, by
      combining two Ab or their fragments directed against different epitopes within
      the same antigen. Using two single chain antibodies (scFv) isolated from a phage
      display library, we have constructed a bispecific diabody directed against two
      different epitopes on the extracellular domain (ECD) of human vascular
      endothelial growth factor receptor 2 (VEGFR2), the kinase-insert domain
      containing receptor (KDR). Neither of the parent scFv blocks KDR/VEGF
      interactions or inhibits VEGF-induced receptor activation. The diabody binds to
      KDR with an affinity that is 1.5- to 3-fold higher than its parent scFv, mainly
      due to a much slower dissociation rate (k(off)), which is approximately 17- to 26
      fold slower than that of the individual scFv. In addition, the diabody binds
      simultaneously to, and thus cross-links, the two epitopes on the receptor(s). It
      is rather unexpected that the diabody effectively blocked KDR/VEGF interactions,
      and inhibited both VEGF-induced activation of the receptor and mitogenesis of
      human endothelial cells. Taken together, our results suggest that the diabody is
      most likely to exert its effect through steric hindrance and/or causing major
      conformational changes of the receptor. This is the first report on the
      construction of a bispecific diabody with acquired novel antagonistic activity.

PMID- 10594364
TI  - The presence of an endogenous endo-D-arabinase in Mycobacterium smegmatis and
      characterization of its oligoarabinoside product.
AB  - Endogenous mycobacterial endo-D-arabinase activity, which degrades cell wall
      polysaccharide arabinogalactan, was found in Mycobacterium smegmatis. The
      arabinan product contains 20-30 arabinosyl residues but no galactofuranosyl
      residues. Recognition of this endogenous activity results in the possibility of
      developing antituberculosis drugs that do not require bacterial growth for
      activity.

PMID- 10594365
TI  - The dolichol pathway in the retina and its involvement in the glycosylation of
      rhodopsin.

PMID- 10594366
TI  - Platelet aggregation may not be a prerequisite for collagen-stimulated platelet
      generation of nitric oxide.
AB  - By determining the sum of the supernatant concentrations of nitrite and nitrate
      the stimulated generation of nitric oxide (NO) by human washed platelets induced
      by a range of fibrillar collagen concentrations (0.0156-25 microg ml(-1)) was
      investigated. Platelet serotonin (5-hydroxytryptamine, 5-HT) efflux and platelet
      aggregation were also measured. Under resting conditions (0 microg ml(-1)
      collagen) platelet NO release was equivalent to 1.06+/-0.17 nmol per 10(8)
      platelets. Maximal NO release, equivalent to 2.1+/-0. 37 nmol per 10(8)
      platelets, was observed with only 0.0625 microg ml(-1) collagen (P<0.02,
      stimulated vs. resting release), higher collagen concentrations producing no
      further increases in platelet NO output. By contrast, maximal platelet
      aggregation and 5-HT efflux did not occur until collagen concentrations of 2.5
      microg ml(-1) and 10-25 microg ml-1), respectively, had been achieved. L-NAME (1
      mmol l(-1)) and L-NMMA (1 mmol l(-1)) inhibited stimulated platelet NO generation
      by 78+/-6% and 72%, respectively. Contrasting with fibrillar collagen, fibrillar
      beta-amyloid protein had no effect on platelet NO generation, or on 5-HT efflux
      or aggregation. These data perhaps indicate that NO generation by human platelets
      is stimulated by concentrations of fibrillar collagen insufficient to elicit an
      aggregatory response. Such a mechanism could operate in vivo to inhibit platelet
      aggregation which might otherwise be induced by low concentrations of circulating
      agonists.

PMID- 10594367
TI  - Extracellular nuclease from Rhizopus stolonifer: purification and characteristics
      of - single strand preferential - deoxyribonuclease activity.
AB  - An extracellular nuclease from Rhizopus stolonifer (designated as nuclease Rsn)
      was purified to homogeneity by chromatography on DEAE-cellulose followed by Blue
      Sepharose. The M(r) of the purified enzyme determined by native PAGE was 67?
      omitted?000 and it is a tetramer and each protomer consists of two unidentical
      subunits of M(r) 21? omitted?000 and 13? omitted?000. It is an acidic protein
      with a pI of 4.2 and is not a glycoprotein. The purified enzyme showed an
      obligate requirement of divalent cations like Mg(2+), Mn(2+) and Co(2+) for its
      activity but is not a metalloprotein. The optimum pH of the enzyme was 7.0 and
      was not influenced by the type of metal ion used. Although, the optimum
      temperature of the enzyme for single stranded (ss) DNA hydrolysis in presence of
      all three metal ions and for double stranded (ds) DNA hydrolysis in presence of
      Mg(2+) was 40 degrees C, it showed higher optimum temperature (45 degrees C) for
      dsDNA hydrolysis in presence of Mn(2+) and Co(2+). Nuclease Rsn was inhibited by
      divalent cations like Zn(2+), Cu(2+) and Hg(2+), inorganic phosphate and
      pyrophosphate, low concentrations of SDS, guanidine hydrochloride and urea,
      organic solvents like dimethyl sulphoxide, dimethyl formamide and formamide but
      not by 3'- or 5'-mononucleotides. The studies on mode and mechanism of action
      showed that nuclease Rsn is an endonuclease and cleaves dsDNA through a single
      hit mechanism. The end products of both ssDNA and dsDNA hydrolysis were
      predominantly oligonucleotides ending in 3'-hydroxyl and 5'-phosphoryl termini.
      Moreover, the type of metal ion used did not influence the mode and mechanism of
      action of the enzyme.

PMID- 10594368
TI  - Mitochondrial impact on nerve growth factor production in vascular smooth muscle
      derived cells.
AB  - Ht30</=Ht10>/=Ht5). Cells with reduced mitochondrial activity also showed
      abnormal responses to the stimulation of NGF output. Thrombin and phorbol ester
      elevated NGF production from Ht100, Ht30 and Ht10 cells, but not from Ht5 cells.
      Ht30 cells, despite secreting less NGF basally than Ht100 cells, reached a
      similar or greater NGF output upon stimulation. Mitogens increased NGF output and
      NGF mRNA levels with the largest effect on NGF protein in Ht30 cells. Free
      radical production and the ability of cells to respond to NGF-inducing agents
      were related. These data suggest that chronic impairment of mitochondrial
      function associates with disturbances in cellular production of a signaling
      protein.

PMID- 10594369
TI  - Studies of in vivo electropermeabilization by gamma camera measurements of
      (99m)Tc-DTPA.
AB  - A protocol was developed to study the drug uptake from in vivo
      electropermeabilization at different settings of parameters influencing the
      uptake efficiency. Radiolabelled diethylenetriaminepentaacetic acid (DTPA) was
      used to trace the distribution and internalization of a hydrophilic drug after in
      vivo electropermeabilization. Skeletal muscle tissue in rat was treated with
      permeabilizing electric pulses before or after intravenous administration of
      (99m)Tc-DTPA. The drug accumulation in the treated volume was subsequently
      evaluated with a scintillation camera. The dependence of uptake on field strength
      and duration of the applied electric pulses was investigated for exponentially
      decaying pulses and square wave pulses. Further, the uptake dependence on time
      interval between injection and pulsation was studied as well as the uptake
      dependence on the number of pulses applied in a single electropermeabilization
      treatment. Dynamic gamma camera studies were performed to quantify the time scale
      of the drug uptake in electropermeabilized tissue.

PMID- 10594370
TI  - Inhibitory effect of bilirubin on complement-mediated hemolysis.
AB  - We investigated the in vitro action of the bile pigments, unconjugated bilirubin
      (UB) and bilirubin monoglucuronide (BMG) on complement (C) cascade reaction. Both
      UB and BMG inhibited hemolysis in the classical pathway (CP) in a dose-dependent
      manner at low micromolar concentrations, UB showing a stronger effect than BMG.
      The analysis of the action of UB on the hemolytic activity of the C1, C4, C2 and
      C-EDTA components of the C cascade revealed that the C1 step was the most
      inhibited. An enzyme immunoassay was developed to evaluate the effect of UB on
      the binding of C1q, one of the subcomponents of C1, to human IgM and IgG. The
      study demonstrated that the unconjugated pigment interferes both the C1q-IgM and 
      IgG interactions, thus tentatively explaining the inhibitory action of UB on
      hemolytic activity of C1. We conclude that the anti-complement effect of UB is
      mainly exerted on the C1 component, the recognition unit of CP. The potential
      clinical implication of the reported effects in hyperbilirubinemia is discussed.

PMID- 10594371
TI  - Combined effects of trehalose and cations on the thermal resistance of beta
      galactosidase in freeze-dried systems.
AB  - The purpose of this study was to investigate the combined effects of trehalose
      and cations on the preservation of beta-galactosidase in freeze-dried systems and
      their relationship to physical properties. Differential scanning calorimetry was
      employed to measure the glass transition temperature (T(g)) and the endothermal
      peak area, related to the amount of crystalline trehalose dihydrate present in
      the samples. In systems in which the trehalose matrix was humidified to
      conditions which allowed a high proportion of trehalose to crystallize, the
      enzyme was rapidly inactivated upon heating at 70 degrees C. In these conditions
      the addition of CsCl, NaCl and particularly KCl or MgCl(2), improved the enzyme
      stability with respect to that observed in matrices containing only trehalose.
      For a given moisture content, addition of salts produced very little change on
      the glass transition temperature; therefore the protective effect could not be
      attributed to a higher T(g) value. The crystallization of trehalose dihydrate in
      the humidified samples was delayed in the trehalose/salt systems (principally in
      the presence of Mg(2+)) and a parallel improvement of enzyme stability was
      observed.

PMID- 10594372
TI  - Calmodulin activates intramolecular electron transfer between the two flavins of
      neuronal nitric oxide synthase flavin domain.
AB  - The neuronal NO synthase (nNOS) flavin domain, which has similar redox properties
      to those of NADPH-cytochrome P450 reductase (P450R), contains binding sites for
      calmodulin, FAD, FMN, and NADPH. The aim of this study is to elucidate the
      mechanism of activation of the flavin domain by calcium/calmodulin (Ca(2+)/CaM).
      In this study, we used the recombinant nNOS flavin domains, which include or
      delete the calmodulin (CaM)-binding site. The air-stable semiquinone of the nNOS
      flavin domains showed similar redox properties to the corresponding FAD
      FMNH(&z.ccirf;) of P450R. In the absence or presence of Ca(2+)/CaM, the rates of
      reduction of an FAD-FMN pair by NADPH have been investigated at different
      wavelengths, 457, 504 and 590 nm by using a stopped-flow technique and a rapid
      scan spectrophotometry. The reduction of the oxidized enzyme (FAD-FMN) by NADPH
      proceeds by both one-electron equivalent and two-electron equivalent mechanisms,
      and the formation of semiquinone (increase of absorbance at 590 nm) was
      significantly increased in the presence of Ca(2+)/CaM. The air-stable semiquinone
      form of the enzyme was also rapidly reduced by NADPH. The results suggest that an
      intramolecular one-electron transfer between the two flavins is activated by the
      binding of Ca(2+)/CaM. The F(1)H(2), which is the fully reduced form of the air
      stable semiquinone, can donate one electron to the electron acceptor, cytochrome
      c. The proposed mechanism of activation by Ca(2+)/CaM complex is discussed on the
      basis of that provided by P450R.

PMID- 10594373
TI  - A single base substitution in the variable pocket of yeast tRNA(Arg) eliminates
      species-specific aminoacylation.
AB  - Early biochemical data showed that aminoacyl-tRNA synthetases often displayed
      species-specific recognition of tRNA. We compared the ability of purified
      Saccharomyces cerevisiae and Escherichia coli arginyl-tRNA synthetases to
      aminoacylate native and transcribed yeast tRNA(Arg) as well as E. coli tRNA(Arg).
      The kinetic data revealed that yeast ArgRS could charge E. coli tRNA(Arg), but at
      a lower efficiency than it charged either the transcribed or native yeast
      tRNA(Arg). E. coli ArgRS can acylate only its cognate E. coli tRNA. Strikingly, a
      single base change from C to A at position 20 in yeast tRNA(3)(Arg) altered the
      species specificity. The transcript of yeast tRNA(3)(Arg)CA20 mutant was
      aminoacylated by E. coli ArgRS with a 10(6) increase in k(cat)/K(m) over that for
      aminoacylation of yeast tRNA(3)(Arg) transcript. This indicates that A20 is not
      only an important identity of E. coli tRNA(Arg), but is also the key to altering
      species-specific aminoacylation of yeast tRNA(Arg).

PMID- 10594374
TI  - Analysis of the nifHDK operon and structure of the NifH protein from the
      unicellular, diazotrophic cyanobacterium, Cyanothece strain sp. ATCC 51142(1).
AB  - Cyanothece sp. ATCC 51142 is a unicellular, diazotrophic cyanobacterium that
      demonstrates diurnal rhythms for photosynthesis and N(2) fixation, with peaks of
      O(2) evolution and nitrogenase activity approximately 12 h out of phase. We
      cloned and sequenced the nifHDK operon, and determined that the amino acid
      sequences of all three proteins were highly conserved relative to those of other
      cyanobacteria and bacteria. However, the Fe-protein, encoded by the nifH gene,
      demonstrated two differences from the related protein in Azotobacter vinelandii,
      for which a 3-D structure has been determined. First, the Cyanothece Fe-protein
      contained a 37 amino acid extension at the N-terminus. This approximately 4 kDa
      addition to the protein appeared to fold as a separate domain, but remained a
      part of the active protein, as was verified by migration on acrylamide gels. In
      addition, the Cyanothece Fe-protein had amino acid differences at positions
      involved in formation of the Fe-protein dimer-dimer contacts in A. vinelandii
      nitrogenase. There were also changes in residues involved with interaction
      between the Fe-protein and the MoFe-protein when compared with A. vinelandii.
      Since the Cyanothece Fe-protein is quickly degraded after activity, it is
      suggested that the extension and the amino acid alterations were somehow involved
      in this degradative process.

PMID- 10594375
TI  - 5'-Nucleotidase in Dictyostelium: protein purification, cloning, and
      developmental expression.
AB  - 5'-Nucleotidase (5NU) in Dictyostelium discoideum is an enzyme that shows high
      substrate specificity to 5'-AMP. The enzyme has received considerable attention
      in the past because of the critical role played by cyclic AMP in cell
      differentiation in this organism. Degradation of cAMP by cAMP phosphodiesterase
      (PDE) produces 5'-AMP, the substrate of 5NU. During the time course of
      development, the enzyme activity of 5NU increases and becomes restricted to a
      narrow band of cells that form the interface between the prestalk/prespore zones.
      We have purified a polypeptide associated with 5NU enzyme activity. Protein
      sequence of this peptide was obtained from mass spectrometry and Edman
      degradation. Polymerase chain reaction PCR amplification of genomic DNA using
      degenerate oligonucleotides and a search of sequences of a cDNA project yielded
      DNA fragments with sequence corresponding to the peptide sequence of 5NU. In
      addition, a clone was found that corresponded to the classical 'alkaline
      phosphatase' (AP) as described in several organisms. The sequences of the 5NU and
      AP cDNAs were not similar, indicating they are the products of separate genes and
      that both genes exist in Dictyostelium. Analysis of the expression of 5nu during
      Dictyostelium development by Northern blotting determined that the gene is
      developmentally regulated. Southern blot analysis showed a single form of the 5nu
      gene. Targeted gene disruption and knockout mutagenesis using the 5nu sequences
      suggested that a 5nu mutation may be lethal.

PMID- 10594376
TI  - Peptide mapping of proteins in cerebrospinal fluid utilizing a rapid preparative
      two-dimensional electrophoretic procedure and matrix-assisted laser
      desorption/ionization mass spectrometry.
AB  - A quick two-step procedure involving liquid phase isoelectric focusing in the
      Rotofor cell in combination with electroelution in the Mini whole cell gel eluter
      has been used for purification of proteins from human cerebrospinal fluid (CSF).
      Fractions, each highly enriched in a single protein band and virtually free of
      other proteins, were selected for characterization by matrix-assisted laser
      desorption/ionization mass spectrometry (MALDI-TOFMS). Six CSF proteins,
      transferrin, alpha1-acid-glycoprotein, Zn-alpha2-glycoprotein, apolipoprotein A1,
      apolipoprotein E and beta-trace were identified by MALDI-TOFMS analysis of the
      tryptic digests. These results demonstrate that the combination of liquid phase
      IEF and electroelution is a rapid preparative two-dimensional separation which
      can provide single proteins of high purity, in yields sufficient for
      characterization by MALDI-TOFMS. Characterization of such brain-specific proteins
      in CSF will be useful in the investigation of the pathophysiology of different
      brain disorders.

PMID- 10594377
TI  - Reduction of ultraviolet light-induced oxidative stress by amino acid-based iron
      chelators.
AB  - The generation of free radicals by ultraviolet (UV) light accelerates skin aging,
      which is known as photoaging. Cutaneous iron catalyzes the generation of free
      radicals. We designed novel antioxidants that suppressed the iron-catalyzed free
      radical generation and the ensuing UV-induced damage by mimicking the binding
      site of iron sequestering proteins. These antioxidants, N-(2-hydroxybenzyl)amino
      acids, were prepared by condensation of amino acids such as glycine and L-serine
      with salicylaldehyde and followed by catalytic reduction. The compounds formed a
      2:1 complex to iron ion. These amino acid derivatives inhibited the iron-induced
      hydroxyl radical generation (the Fenton reaction). The compounds also suppressed
      UV-induced lipid peroxidation in murine dermal fibroblast homogenates. In
      addition, N-(2-hydroxybenzyl)-L-serine showed protective activity against UV
      induced cytotoxicity in murine dermal fibroblasts. Desferrioxamine, a strong iron
      sequestering compound, was effective in inhibiting the Fenton reaction and the
      lipid peroxidation, but it was ineffective in protecting against UV-induced
      cytotoxicity. The results suggest that UV-induced oxidative stress can be reduced
      by these amino acid derivatives.

PMID- 10594378
TI  - Microchemical analysis of retina layers in pigmented and albino rats by Fourier
      transform infrared microspectroscopy.
AB  - Fourier transform infrared (FT-IR) microspectroscopy is a powerful technique that
      can be used to collect infrared spectra from microscopic regions of tissue
      sections. The infrared spectra are evaluated to chemically characterize the
      absorbing molecules. This technique can be applied to normal or diseased tissues.
      In the latter case, FT-IR microspectroscopy can reveal chemical changes that are
      associated with discrete regions of lesion sites, which can provide insights into
      the chemical mechanisms of disease processes. In the present study, FT-IR
      microspectroscopy was used to analyze sections of retina from normal (pigmented)
      and albino rats. The outer segments of retinas from pigmented animals were found
      to have unusually strong absorption values for C&z.dbnd6;C-H unsaturation and
      carbonyl functional groups. Docosahexaenoic acid (DHA), a major constituent of
      lipids in the outer segments, also had particularly high absorption values for
      these functional groups, which suggests that it is responsible for those enhanced
      absorption values. Absorbance values for the unsaturation and carbonyl functional
      groups were substantially reduced in the outer segments of retinas from albino
      animals. This finding, together with data from other studies on light-induced
      oxidative events in the retina, indicates a loss of DHA by a light-induced
      mechanism in albino animals. The outer nuclear layer had strong absorbance values
      for H-C-OH and P&z. dbnd6;O functional groups, which is likely due to the sugar
      phosphate backbone of DNA. The outer and inner plexiform layers were found to
      contain greater concentrations of CH(2) and C&z.dbnd6;O functional groups than
      the outer and inner nuclear layers, which is due to the high concentration of
      synaptic connections in the former layers. In summary, FT-IR microspectroscopy
      revealed a unique chemical profile in the outer segments compared to other
      retinal layers, and this profile was altered in albino animals.

PMID- 10594379
TI  - The effect of pH on the structure, binding and model membrane lysis by cecropin B
      and analogs.
AB  - Cecropins are a group of anti-bacterial, cationic peptides that have an
      amphipathic N-terminal segment, and a largely hydrophobic C-terminal segment and
      normally form a helix-hinge-helix structure. In this study, the ability of
      cecropin B (CB) and two analogs to lyse phospholipid bilayers, which have two
      levels of anionic content, has been examined by dye-leakage measurements over the
      pH range 2. 0-12.0. The two analogs differ from the natural peptide by having
      either two amphipathic segments (CB1) or two hydrophobic segments (CB3). All
      these peptides (except CB3 on low anionic content bilayers where it is not
      active) have maximal lytic activity on both types of bilayers at high pH.
      However, the pattern of secondary structure formation on these bilayers by the
      peptides, as measured by circular dichroism (CD), and the pattern of their
      ability to bind lipid monolayers, as measured using a biosensor, do not directly
      correlate with the pattern of their lytic ability. CB and CB1 with low anionic
      content bilayers have secondary structures as measured by CD with a similar
      pattern to membrane lysis, but binding is maximal near neutral, not high, pH. CB3
      has some secondary structures on low anionic content bilayers at low pH and this
      becomes maximal over the basic range, but CB3 neither binds to nor lyses with
      these lipid layers. On high anionic content lipid layers, all peptides show high
      levels of secondary structures over most of the pH range and maximal binding at
      neutral pH (except for CB3, which does not bind). All three peptides lyse with
      high anionic content bilayers, but show no activity at neutral pH and reach
      maximal activity at very high pH. This work shows that pH is a major factor in
      the capability of antibacterial peptides to lyse with liposomes and that
      secondary structure and binding ability may not be the main determinants.

PMID- 10594380
TI  - Stability of SUV liposomes in the presence of cholate salts and pancreatic
      lipases: effect of lipid composition.
AB  - The effect of bile salts (sodium cholate and sodium taurocholate), and pancreatic
      lipases on the structural integrity of SUV liposomes of different lipid
      compositions was studied. Liposomal membrane integrity was judged by bile salt or
      pancreatin-induced release of vesicle encapsulated 5,6-carboxyfluorescein, and
      vesicle size distribution before and after incubations. Bile salt concentration
      was 10 mM, while a saturated solution of pancreatin (mixed with equal volume of
      liposomes) was utilized. Results agree with earlier studies, demonstrating the
      instability of liposomes composed of lipids with low transition temperatures (PC
      and DMPC) in presence of cholates. Addition of cholesterol (1:1 lipid:chol molar
      ratio) does not substantially increase the encapsulated molecule retention.
      Nevertheless, liposomes composed of lipids with high transition temperatures
      (DPPC, DSPC and SM), retain significantly higher amounts of encapsulated
      material, under all conditions studied. Furthermore, the vesicles formed by
      mixing cholesterol with these lipids will possibly be sufficiently stable in the
      gastrointestinal tract for long periods of time. Sizing results reveal that in
      most cases release of encapsulated molecules is mainly caused by their leakage
      through holes formed on the lipid bilayer. However, in stearylamine containing
      DPPC and DSPC vesicles, the cholate-induced drastic decrease in vesicle size
      suggests total liposome disruption as the possible mechanism of encapsulated
      material immediate release.

PMID- 10594381
TI  - Systemic delivery of the GnRH antagonist cetrorelix by intratracheal instillation
      in anesthetized rats.
AB  - Pulmonary absorption of the decapeptide cetrorelix acetate was studied in rats by
      a non-surgical intratracheal instillation method. The pharmacological effect
      (decrease of testosterone plasma concentration) following intratracheal (i.t.)
      instillation was determined in four groups of seven rats each at three different
      concentrations (0.5, 1.0 and 2.5 mg/kg body weight). The applied doses reduced
      testosterone plasma concentration to subnormal level (</=1 ng/ml), for 24, 34 and
      72 h, respectively. Pharmacokinetic data of cetrorelix were determined in two
      additional groups of ten and nine rats, respectively, at doses of 0.5 and 1 mg/kg
      body. After i.t. administration the mean terminal t(1/2) was 12.94+/-1.74 (0.5
      mg/kg) and 13.03+/-3.15 h (1 mg/kg); mean residence time (MRT) was 6. 85+/-3.01
      and 8.72+/-2.33 h; the C(max) (277.72+/-252.11 and 274. 23+/-113.49 ng/ml) were
      observed in the first or the second plasma sample, suggesting that the drug was
      rapidly absorbed (t=1 and 2 h). Comparing the plasma concentration after i.t.
      administration with data after i.v. administration from a previous study
      undertaken in the same laboratory, the mean i.t. bioavailability was calculated
      as 75.80+/-45.42 and 58.97+/-18.25%. The data from the group of 0.5 mg/kg were
      confirmed in a subsequent experiment. Our studies show that intratracheal
      instillation via the adopted method of non-surgical cannulation provides
      reproducible results. In addition, we demonstrated that pharmacologically active
      amounts of cetrorelix were absorbed from the lungs.

PMID- 10594382
TI  - Stability study of a new antidote drug combination (Atropine-HI-6-Prodiazepam)
      for treatment of organophosphate poisoning.
AB  - The main purpose of this study was to investigate the chemical stability of a new
      antidote combination for the treatment of organophosphate poisoning. The antidote
      combination was packed (enclosed) in two plastic compartments separated by a
      barrier film. One of them contained a powder oxime cholinesterase reactivator (HI
      6-monohydrate 1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydro
      xyimino)meth yl]-pyridinium dichloride). The other contained an anticholinergic
      (Atropine) and an anticonvulsant (Prodiazepam or Avizafone (L-lysyl-N-(2-benzoyl
      4-chlorophenyl)-N-methyl-glycinamide dihydrochloride) drug in a liquid mixture.
      The plastic compartments were mounted in an autoinjector device to study the
      dissolution of HI-6 by ejection of the solution. Drug analysis was performed by
      high-performance liquid chromatography. The results obtained after 6 months show
      that this new antidote combination is stable. The amount of each antidote is
      unchanged during the study. Some known degradation products can be detected in
      small amounts. The autoinjector mechanism used, gives a complete dissolution of
      HI-6 powder in the liquid mixture throughout the study.

PMID- 10594383
TI  - Enzymatic and permeation barrier of [D-Ala(2)]-Met-enkephalinamide in the
      anterior membranes of the albino rabbit eye.
AB  - Enzymatic and physical barrier properties of anterior ocular membranes were
      characterized. The permeation and metabolic degradation of [D-Ala(2)]-methionine
      enkephalinamide (DAMEA) in the albino rabbit cornea, conjunctiva and sclera were
      studied in vitro. DAMEA was administered with and without peptidase inhibitors
      bestatin (aminopeptidase inhibitor) and SCH 39370 (enkephalinase inhibitor). The
      modified Ussing chambers were used to study the peptide permeation and the
      samples were analyzed with a novel HPLC method using UV and EC detectors. Sclera
      was the most permeable membrane to DAMEA, while cornea was almost impermeable to
      DAMEA. Without inhibitors, the permeability coefficients of DAMEA were 2. 7x10(
      8) cm/s, 3.1x10(-6) cm/s and 12.5x10(-6) cm/s in the cornea, conjunctiva and
      sclera, respectively. DAMEA was partly metabolized to tyrosine (Tyr) and tyrosine
      D-alanine-glycine (Tyr-D-Ala-Gly). When inhibitors were co-administered with
      DAMEA, the corneal permeability of intact DAMEA increased 15 times, while
      conjunctival permeability increased 5.5 times and scleral permeability remained
      practically unaltered. The formation of metabolites decreased markedly, when the
      inhibitors were used. Interestingly, when the permeability of DAMEA was compared
      to permeabilities of polyethylene glycols in different membranes, the permeation
      was in the same range suggesting that DAMEA permeates through cornea via a
      paracellular pathway. Both enzymatic and physical barriers were more prominent in
      the cornea than in the conjunctiva and sclera. Non-corneal pathway of absorption
      and combined with inhibition of peptidases may be the most viable pathway for
      ocular peptide administration.

PMID- 10594384
TI  - An exploration of inter-relationships between contact angle, inverse phase gas
      chromatography and triboelectric charging data.
AB  - Surfaces of pharmaceutical powders have been assessed using contact angle,
      inverse phase gas chromatography (IGC) and triboelectric (electrostatic) charging
      techniques. The suitability of the Dynamic Angle Tester (DAT), an instrument
      based on the sessile drop technique, in determining contact angles and then the
      surface energy of pharmaceutical powders was assessed. The dispersive components
      of the surface energy of powders determined from the DAT and IGC method ranked
      the powders in the same order. The dispersive component values obtained by IGC
      were, as expected, higher than those from the DAT, due to IGC probing the highest
      energy sites on the powder surface. IGC and triboelectric studies allow materials
      to be characterised in terms of their electron donating-accepting tendencies, so
      inter-relationships between the data from the two techniques were explored.
      Although the data set was limited, there appeared to be a correlation between the
      charges developed by the powders on contact with stainless steel and the ratio of
      the electron-donating to electron-accepting tendencies of the materials as
      obtained from IGC.

PMID- 10594385
TI  - Mechanical property predictions for polymorphs of sulphathiazole and
      carbamazepine.
AB  - The mechanical properties of polymorphs of sulphathiazole and carbamazepine have
      been determined experimentally by three-point beam bending. It is shown that the
      mechanical properties of sulphathiazole and carbamazepine polymorphs can be
      predicted using the atom-atom potential model applied to lattice dynamics, as
      long as account is taken of crystal morphology when considering the experimental
      results.

PMID- 10594386
TI  - Lipid emulsions as a novel system to reduce the hemolytic activity of lytic
      agents: mechanism of the protective effect.
AB  - The hemolytic activity of sodium oleate, a high lytic agent, was investigated in
      different surfactant solutions and lipid emulsion formulations. A new explanation
      of the protective function of these systems is proposed. It was found that the
      hemolytic activity of the lytic agent was greatly decreased in solutions and/or
      dispersions with the surfactant Cremophor EL, Solutol H16 and phospholipids,
      which can usually build a micellar or liposomal structure. In the case of F68,
      where the micelle formation is still controversial, the hemolytic activity of the
      lytic agent was practically not affected and complete hemolysis was observed. In
      contrast to this, all emulsion formulations, independent of the emulsifier type,
      showed a stable erythrocyte behavior. Additionally, in the case of lipid
      emulsions only, a larger amount of the lytic agent could be added without any
      remarkable increase in the hemolytic activity. As an explanation for these
      effects it is proposed that the lytic agent is either incorporated into the
      lipophilic core or intercalates between the emulsifier molecules at the
      interface. This decreases the direct contact of the lytic agent with the
      erythrocyte membrane. As a result, the erythrocytes will effectively be protected
      from hemolytic damage, which can otherwise be induced by such substances.

PMID- 10594387
TI  - Influence of surfactants (present in the dissolution media) on the release
      behaviour of tolbutamide from its inclusion complex with beta-cyclodextrin.
AB  - The possible competitive displacement of a drug from its cyclodextrin-based
      inclusion complex by a third substance was investigated by studying the
      dissolution behaviour of tolbutamide-beta-cyclodextrin inclusion complex in
      demineralised water and in aqueous solution of different surfactants. Physical
      mixtures and kneaded systems were prepared in 1:1 and 1:2 drug-beta-cyclodextrin
      mol/mol ratios and they were characterised by hot-stage microscopy, differential
      scanning calorimetry, and X-ray powder diffractometry. The release behaviour of
      tolbutamide from its inclusion complex was studied by studying the dissolution of
      the binary systems in water and in aqueous solutions of three surfactants:
      polysorbate 20, poloxyl 23-lauryl ether, and sodium lauryl sulphate. When
      demineralised water was used as the dissolution media, the fastest dissolution of
      tolbutamide was obtained from 1:2 kneaded system followed by 1:1 kneaded system.
      The presence of poloxyl 23-lauryl ether and sodium lauryl sulphate in the media
      caused a decrement in the rate and extent of dissolution of the drug from both
      kneaded systems in comparison with that obtained from the same systems in water.
      However, the release of tolbutamide from the kneaded systems remains unaffected
      when polysorbate 20 was present in the dissolution media. Results of this study
      suggest that the simultaneous presence of beta-cyclodextrin and surfactants of
      proper molecular structure in a pharmaceutical formulation can give rise to an
      unexpected dissolution of the drug.

PMID- 10594388
TI  - Evaluation of mucoadhesion for two polyelectrolyte gels in simulated
      physiological conditions using a rheological method.
AB  - A rheological method to measure mucoadhesion was evaluated for two ion-sensitive
      polymers, Carbopol 934 and Gelrite((R)) (deacetylated gellan gum), in a simulated
      physiological environment using two commercially available mucins. The method
      simulates the interpenetration layer in the mucoadhesion process. The elastic
      modulus for a polymer/mucin mixture is compared with the elastic modulus for the
      polymer alone, and an increase in the elastic modulus for the mixture compared to
      the polymer is interpreted as a positive interaction caused by mucoadhesion. In
      this study the influence of polymer concentration, type of mucin and experimental
      rheological factors, such as gap width, were examined. The choice of polymer
      concentration was crucial, especially with the porcine gastric mucin. We found
      that one is more likely to obtain positive interactions with weak gels. It was
      also shown that the choice of mucin has a large influence on the results
      obtained. Carbopol 934 interacted more strongly with the bovine submaxillary
      gland mucin than with the porcine gastric mucin, whereas the gel structure of
      Gelrite((R)) was destroyed when mixed with the bovine mucin. Furthermore, it was
      concluded that with hydrogels consisting of gel particles (such as Carbopol 934),
      rheological measurements can give highly varying results, depending on, for
      example, the concentration and ion-sensitivity of the polymer, the quantity of
      ions present, as well as the gap width of the measuring system.

PMID- 10594389
TI  - Spectrophotometric methods for determining meloxicam in pharmaceuticals using
      batch and flow-injection procedures.
AB  - Two sensitive and fast spectrophotometric methods using batch and flow-injection
      procedures for the determination of meloxicam (MX) are proposed. The methods are
      based on the formation of a green complex between this drug and Fe(III)
      [2MX/Fe(III)] in a methanolic medium. The calibration graphs resulting from
      measuring the absorbance at 570 nm are linear over the ranges 2.0-200 and 5.00
      250 mg l(-1) with detection limits of 0.47 and 0.72 mg l(-1), respectively.
      Furthermore, a flow-injection spectrophotometric method involving measurement of
      the absorbance of the drug at 362 nm in 0.1 M NaOH is presented. The calibration
      graph is linear over the range 0.5-20 mg l(-1) with a detection limit of 0.04 mg
      l(-1). The methods are applied to the routine analysis of MX in pharmaceuticals.

PMID- 10594390
TI  - Influence of temperature and storage time after light exposure on the quinine
      monohydrochloride chemical actinometric system.
AB  - The ICH guideline on photostability has proposed quinine monohydrochloride
      chemical actinometric system as a standard method for measuring light exposure
      during photostability testing. A change in the absorption at 400 nm of quinine
      monohydrochloride after light exposure corresponds to a defined dose of light.
      The present work investigated the effect of temperature, light exposure level and
      the dark reactions following light exposure on the change of absorbance obtained.
      The change in the absorbance was linear with respect to time, the rate increased
      threefold in the temperature range of 25-52 degrees C, and the calculated
      activation energy was 30 kJ/mol as calculated by the Arrhenius equation. For the
      dark reactions the change in absorbance was non-linear with respect to time. The
      rate of the dark reactions was smaller than during light exposure and dependent
      on the light exposure level prior to the dark reactions. The calculated
      activation energy of the dark reactions was 18 kJ/mol when calculated by the
      Arrhenius equation on the initial reaction rates. The different activation energy
      of the light reaction and the dark reactions indicated different degradation
      patterns of the two reactions. The present study shows that the absorbance change
      of quinine monohydrochloride chemical actinometric system is dependent on
      temperature during light exposure and on storage time and storage temperature
      after light exposure. The method proposed in the ICH guideline should therefore
      be optimized in terms of definition of temperature and limitations in storage
      time after light exposure.

PMID- 10594391
TI  - Review article: acid suppression in non-variceal acute upper gastrointestinal
      bleeding.
AB  - Despite a decreased incidence of ulcer disease and improvements in the management
      of acute upper gastrointestinal (GI) bleeding, mortality remains at about 6-7%.
      Although endoscopic haemostatic therapy has been demonstrated to be the mainstay
      of management, the search continues for less invasive medical modalities that
      might also improve patient outcome. In vitro data have indicated the important
      role of acid in impairing haemostasis and causing clot digestion. Therefore,
      theoretically, maintenance of a high intragastric pH (above 6.0) during
      management of upper GI bleeding is warranted. Until recently, available agents
      did not permit such a sustained elevation in gastric pH. Early studies with H2
      receptor antagonists have not demonstrated significant improvements in important
      patient outcomes, such as rebleeding, surgery or mortality. With the availability
      of intravenous formulations of proton pump inhibitors, it is now possible to aim
      at maintaining gastric pH above 6.0 for 24 h per day. Recent clinical trial data
      would appear to support the use of proton pump inhibitors to decrease the rate of
      rebleeding and the need for surgery. This paper provides a review of non-variceal
      acute GI bleeding, with special reference to the role of proton pump inhibitors
      in this clinical setting.

PMID- 10594392
TI  - Review article: cardiac adverse effects of gastrointestinal prokinetics.
AB  - Gastrointestinal prokinetics, such as metoclopramide, cisapride and
      levosulpiride, are widely used for the management of functional gut disorders.
      Recently, several studies have shown that cisapride (a partial 5-HT4 receptor
      agonist) can induce dose-dependent cardiac adverse effects, including lengthening
      of the electrocardiographic QT interval, syncopal episodes and ventricular
      dysrhythmias. Until recently, it was not clear whether these effects were
      dependent on 5-HT4 receptor activation or related to peculiar characteristics in
      the molecular structure of single agents within the benzamide class. Experimental
      evidence now favours the second hypothesis: cisapride possesses Class III
      antiarrhythmic properties and prolongs the action potential duration through
      blockade of distinct voltage-dependent K+ channels, thus delaying cardiac
      repolarization and prolonging the QT interval. Patients at risk of cardiac
      adverse effects are children, subjects with idiopathic, congenital or acquired
      long QT syndrome and, in particular, those receiving concomitant medication with
      Class III antiarrhythmic agents, some H1-receptor antagonists (e.g. terfenadine),
      or drugs such as azole antifungals (e.g. ketoconazole, itraconazole, miconazole
      and fluconazole) and macrolide antibacterials (e.g. erythromycin, clarithrod
      mycin and troleandomycin), which can inhibit cisapride metabolism by interfering
      with the CYP3A4 isoenzyme.

PMID- 10594393
TI  - Ursodeoxycholic acid has no influence on function after restorative
      proctocolectomy in ulcerative colitis.
AB  - BACKGROUND: Poor pouch function is associated with impaired bile acid absorption
      and increased faecal loss of bile acids. Bile acid replacement therapy might
      therefore be of clinical benefit, provided that diarrhoea is not aggravated by
      therapy. AIM: To investigate the role of exogenous bile acid therapy in patients
      with poor pouch function after restorative proctocolectomy for ulcerative
      colitis. PATIENTS AND METHODS: Twenty ulcerative colitis patients with poor pouch
      function (score > 4 on a 12-point score) were recruited for inclusion to a
      prospective, randomized, double-blind crossover, placebo-controlled trial of
      ursodeoxycholic acid (10 mg/kg per day in two divided doses for 1 month).
      RESULTS: A total of 16 patients completed the study. There was no significant
      difference in the functional score or bowel frequency following treatment
      irrespective of whether the active treatment was given before or after placebo.
      CONCLUSIONS: We conclude that ursodeoxycholic acid given over 4 weeks had no
      influence on functional score or bowel frequency after restorative
      proctocolectomy for U.C.

PMID- 10594394
TI  - A randomized dose-response and pharmacokinetic study of methotrexate for
      refractory inflammatory Crohn's disease and ulcerative colitis.
AB  - BACKGROUND AND AIMS: The optimum initial dose of methotrexate for steroid
      requiring inflammatory bowel disease is not known. AIM: To compare directly the
      efficacy and toxicity of methotrexate 15 and 25 mg/week, and to explore the value
      of methotrexate blood levels as predictors of outcome. METHODS: A 16-week
      randomized single-blind comparison of subcutaneous methotrexate 15 or 25 mg/week
      was performed in 32 patients with steroid-requiring Crohn's disease or ulcerative
      colitis. Patients who did not respond to methotrexate 15 mg/week were further
      studied for an additional 16 weeks on methotrexate 25 mg/week. Blood was drawn
      every 2 weeks for methotrexate levels. RESULTS: After 16 weeks, 17% of patients
      in each group achieved remission; 39% of patients randomized to 15 mg/week and
      33% of patients randomized to 25 mg/week improved (P=N.S. ). Clinical status
      improved in four out of 11 patients after methotrexate dose escalation from 15 to
      25 mg/week. Toxicity was not different between the treatment groups. Methotrexate
      blood levels did not predict efficacy or toxicity. CONCLUSIONS: For induction of
      remission in steroid-requiring inflammatory bowel disease, subcutaneous
      methotrexate at initial doses of 15 and 25 mg/week are equally efficacious. At
      these doses, response is not associated with blood methotrexate concentrations.

PMID- 10594395
TI  - Onset of action during on-demand treatment with maalox suspension or low-dose
      ranitidine for heartburn.
AB  - AIM: To compare the onset of action of the local antacid Maalox and the systemic
      H2-antagonist ranitidine, during 'on demand' ambulant treatment of a single
      heartburn episode, using a randomized, parallel group, double-blind, double-dummy
      design. METHODS: Subjects with self-perceived heartburn without known
      gastrointestinal disease or interfering treatments were selected with
      questionnaires. The study was performed unsupervised, whenever heartburn required
      medication. An electronic patient diary gave instructions when to take study
      medication, and provided visual analogue scales and five-item relief ratings for
      heartburn, at frequent time intervals activated by an alarm-clock. RESULTS: After
      a study of the natural history of heartburn and the feasibility of the study
      procedures in 23 patients, 49 subjects took Maalox and 45 ranitidine. Half of
      these experienced meaningful heartburn relief within 19 min after Maalox, and
      within 70 min after ranitidine. One hour after intake, the average heartburn
      relief score was 3.43 in the Maalox group and 3.04 in the ranitidine group (3
      means 'slight improvement' and 4 'strong improvement'). Heartburn was similar in
      both groups after 3 h. CONCLUSIONS: Maalox provides faster relief of heartburn
      than ranitidine. Heartburn can be assessed frequently and reliably under ambulant
      conditions using an electronic patient diary.

PMID- 10594396
TI  - Standard-dose lansoprazole is more effective than high-dose ranitidine in
      achieving endoscopic healing and symptom relief in patients with moderately
      severe reflux oesophagitis. The Dutch Lansoprazole Study Group.
AB  - BACKGROUND: In the treatment of reflux oesophagitis, H2-receptor antagonists are
      still widely used in spite of the apparent higher efficacy of proton pump
      inhibitors. In an attempt to compensate for the lower efficacy, H2-receptor
      antagonists are now increasingly being used at a higher dose. OBJECTIVE: To
      assess whether or not standard-dose lansoprazole (30 mg o.d.) is more effective
      than high-dose ranitidine (300 mg b.d.) in moderately severe reflux oesophagitis
      (grades II-III). METHODS: Lansoprazole or ranitidine was given to 133 patients
      for 4-8 weeks in a double-blind, randomized, parallel group, multicentre trial.
      RESULTS: The percentage of patients with endoscopically-verified healing was
      significantly higher on lansoprazole than on ranitidine both after 4 weeks (79%
      vs. 42%) and 8 weeks (91% vs. 66%), though smoking had a negative impact on
      oesophagitis healing with lansoprazole. Heartburn, retrosternal pain and belching
      improved significantly better with lansoprazole than with ranitidine, as did the
      patient-rated overall symptom severity. Relief of heartburn appeared somewhat
      faster with ranitidine, but was more pronounced with lansoprazole. The number of
      patients with adverse events was similar in both treatment groups. CONCLUSION:
      Standard-dose lansoprazole is better than high-dose ranitidine in moderately
      severe reflux oesophagitis.

PMID- 10594397
TI  - Complete resolution of heartburn symptoms and health-related quality of life in
      patients with gastro-oesophageal reflux disease.
AB  - BACKGROUND: Medical treatments for gastro-oesophageal reflux disease (GERD) vary
      in their ability to completely resolve heartburn and other symptoms. Although
      GERD reduces health-related quality of life (HRQL) little is known about the
      relationship between resolution of heartburn symptoms with medical therapy and
      HRQL. We evaluated the association between complete resolution of heartburn
      symptoms and functioning and well-being in three samples of patients with GERD.
      METHODS: We analysed baseline and follow-up assessments of heartburn symptoms and
      HRQL scores from three clinical trials (total n=1351) comparing omeprazole and
      ranitidine for acute symptomatic treatment of GERD. Heartburn symptoms were
      measured using patient diaries and/or patient self-report. HRQL was assessed
      using the Psychological General Well-Being Index (PGWB) in all three clinical
      trials and the SF-36 Health Survey in two clinical trials. Resolution of
      heartburn symptoms was defined as no heartburn reported during the assessment
      period. RESULTS: We observed statistically significant differences favouring
      patients with no heartburn symptoms on the PGWB total score (P=0.018 to P <
      0.0001) and anxiety (P=0.002 to P < 0.0001), general health (P=0.05 to P < 0.
      0001), positive well-being (P=0.028 to P < 0.0001) and vitality (P=0. 05 to P <
      0.0001) sub-scale scores at 4-14 weeks. Patients with no heartburn reported
      better SF-36 pain (P=0.005 to P < 0.0001) and general health perceptions (P=0.032
      to P < 0.0001) compared with patients still experiencing heartburn symptoms at 4
      24 weeks. SF-36 physical component summary scores were significantly better in
      patients with no heartburn symptoms compared with patients with heartburn
      symptoms at 4-24 weeks (P=0.013 to P=0.009), while mental component summary
      scores were only significantly different at 24 weeks (P=0.0005) in one of the two
      studies where the SF-36 was utilized. CONCLUSIONS: Complete resolution of
      heartburn symptoms was consistently associated with improvement in HRQL; the
      greatest impact was observed on measures of psychological well-being and physical
      functioning and well-being. Effective treatment of GERD that completely resolves
      heartburn results in clinically significant improvement in patient HRQL.

PMID- 10594398
TI  - Impact of advertisement and clinic populations in symptoms and perception of
      irritable bowel syndrome.
AB  - BACKGROUND: This study assessed the impact of recruitment on irritable bowel
      syndrome clinical trials, by determining whether irritable bowel syndrome
      patients recruited from advertisement or a specialty clinic differ in clinical
      and physiologic measures. METHODS: We prospectively surveyed 657 irritable bowel
      syndrome patients who either: (i) were referred from a functional bowel disease
      clinic (52%); or (ii) responded to advertisement for clinical trials (48%), using
      questionnaires about bowel and psychological symptoms, and quality of life. In a
      subset of 42 irritable bowel syndrome patients (29 advertisement and 15 clinic
      patients), rectal discomfort thresholds were measured before and after repetitive
      sigmoid stimulation. RESULTS: While the advertisement population more commonly
      consulted primary care physicians, the clinic population more commonly consulted
      gastroenterologists. The clinic population reported more prevalent and severe
      abdominal pain, and higher psychological symptom scores, while the advertisement
      population had greater quality of life. In the visceral perception studies, both
      subgroups were hypersensitive to rectal distension. CONCLUSION: Compared to the
      clinic population, the advertisement population had less severe abdominal pain
      and psychological symptoms, better quality of life but similar visceral
      perception. The differences in clinical self-reports may have consequences for
      enrolment of these different patient populations into clinical trials.

PMID- 10594399
TI  - Efficacy of two different dosage regimens of omeprazole, amoxycillin and
      metronidazole for the cure of Helicobacter pylori infection.
AB  - BACKGROUND: While addition of metronidazole to the omeprazole-amoxycillin
      combination has been shown to be advantageous, the optimal dosage and drug
      distribution of the antimicrobials has not been sufficiently evaluated. AIM: To
      investigate the efficacy of two different regimens of omeprazole, amoxycillin and
      metronidazole for the cure of Helicobacter pylori infection. METHODS: Two hundred
      and fifty-five patients with H. pylori associated duodenal ulcers were randomly
      treated with either a 1-week regimen of omeprazole 20 mg b.d., amoxycillin 1000
      mg b.d. and metronidazole 800 mg b.d. (OAM b.d.) or a combination of omeprazole
      40 mg o.d., amoxycillin 500 mg t.d.s. and metronidazole 400 mg t.d.s. (OAM
      t.d.s.). All patients subsequently received omeprazole 20 mg o.d. for an
      additional 3 weeks. H. pylori status was assessed by histology and 13C-UBT prior
      to treatment and 8 weeks after randomization. Additional biopsies were obtained
      for H. pylori culture to determine primary and secondary resistance to
      metronidazole by agar dilution. RESULTS: Two hundred and thirty-seven patients
      were included in the intention-to-treat analysis and 198 patients in the per
      protocol analysis. With intention-to-treat analysis, the cure rate was 77% after
      treatment with OAM b.d. (95% CI, 69%-85%) and 76% after OAM t. d.s. therapy (95%
      CI, 67%-83%). Ulcer healing (intention-to-treat analysis) was documented in 95%
      of patients in the OAM b.d. group (n=122) and in 97% of patients in the OAM
      t.d.s. group (n=115). Adverse events were reported in 26 (20%) and in 18 (14%)
      patients in the OAM b.d. and OAM t.d.s. groups, respectively. None resulted in
      discontinuation of treatment. Overall primary resistance of H. pylori against
      metronidazole was found in 22 of 116 strains (19%). CONCLUSIONS: The combination
      of omeprazole, amoxycillin and metronidazole achieves about an 80% cure rate of
      H. pylori infection even in active ulcers. The total daily dose, and the choice
      of twice or three times daily dosing does not seem critical with this regimen.

PMID- 10594400
TI  - Omeprazole, clarithromycin and furazolidone for the eradication of Helicobacter
      pylori in patients with duodenal ulcer.
AB  - AIM: To evaluate the efficacy of omeprazole plus clarithromycin and furazolidone
      in Helicobacter pylori eradication and duodenal ulcer healing in Brazilian
      patients. METHODS: Forty H. pylori-positive patients with duodenal ulcer were
      randomized to receive 20 mg omeprazole o.m. or b.d. for 1 month plus 500 mg
      clarithromycin (b.d. ) and 200 mg furazolidone (b.d.) for 1 week. RESULTS: Three
      months after the end of the treatment the eradication rates were 90% by intention
      to-treat analysis, and 97% by per protocol analysis. Mild side-effects were
      observed in 25 patients, none of whom abandoned the protocol. No difference was
      observed between the 20 mg and 40 mg omeprazole daily doses. Cure or significant
      improvement of the symptoms and of the histological alterations were observed
      after H. pylori eradication. CONCLUSION: Our results demonstrate that
      clarithromycin and furazolidone in combination with omeprazole are a good
      alternative for H. pylori eradication in Brazilian patients with duodenal ulcer.

PMID- 10594401
TI  - Non-steroidal anti-inflammatory drugs inhibit Helicobacter pylori-induced human
      neutrophil reactive oxygen metabolite production in vitro.
AB  - BACKGROUND: Helicobacter pylori infection is associated with increased production
      of gastric mucosal reactive oxygen metabolites which have been implicated in
      mucosal damage and carcinogenesis. In vitro, neutrophils produce reactive oxygen
      metabolites following activation by H. pylori. Non-steroidal anti-inflammatory
      drugs (NSAIDs) inhibit neutrophil activation by several factors, e.g. N-formyl
      methionyl-leucyl-phenyalanine (f-MLP). AIM: To examine the effect of NSAIDs on H.
      pylori-induced reactive oxygen metabolite production by human peripheral blood
      neutrophils. METHODS: Neutrophils were stimulated by H. pylori (NCTC 11637) water
      extract or f-MLP in the presence or absence of NSAIDs. Reactive oxygen metabolite
      activity was measured by luminol-enhanced chemiluminescence. RESULTS: H. pylori
      water extract stimulated a sevenfold increase in chemiluminescence which was
      inhibited dose-dependently by diclofenac. All six NSAIDs studied (at 10-4 M)
      significantly inhibited H. pylori-and f-MLP-stimulated neutrophil reactive oxygen
      metabolite production. Meclofenamic acid and diclofenac had the greatest
      inhibitory effects on both H. pylori and f-MLP-stimulated neutrophil reactive
      oxygen metabolite production. The inhibitory effects of other NSAIDs varied with
      the activation stimulus. NSAIDs did not quench reactive oxygen metabolites
      generated in a cell-free xanthine:xanthine oxidase assay. CONCLUSION: Several
      NSAIDs attenuate H. pylori-induced neutrophil reactive oxygen metabolites
      production in vitro. This may be relevant to a potential chemopreventative role
      in gastric cancer and to a possible lack of synergy between H. pylori and NSAID
      use regarding peptic ulceration.

PMID- 10594402
TI  - Behaviour of Saccharomyces boulardii in recurrent Clostridium difficile disease
      patients.
AB  - BACKGROUND: Despite recent interest in therapeutic microorganisms taken orally,
      little is known about the pharmacodynamics of these agents in a target population
      of patients with disease. The present study reports the stool concentrations of
      Saccharomyces boulardii in a patient population with Clostridium difficile
      disease (CDD) and correlates stool concentrations with efficacy. METHODS:
      Patients with recurrent CDD all received a 10-day standard antibiotic regimen
      together with 28 days of S. boulardii or placebo. Stool samples were collected
      from patients at various time points and assayed for S. boulardii. RESULTS: The
      mean concentration of S. boulardii of patients who recurred was 2.5 x 104 CFU/g
      compared to 1 x 106 CFU/g in patients that did not recur (P=0.02). Patients with
      low yeast concentrations in their stools (<104/g) recurred more often (14/15,
      93%) compared with patients with higher levels (19/35, 54%, P=0.007). Clearance
      of S. boulardii was rapid; only 4% had positive stools 3 days after stopping
      dosing. CONCLUSIONS: After chronic dosing of S. boulardii, patients with low
      stool concentrations had a higher likelihood of recurrence of CDD. Stool
      concentrations were also lower during periods of diarrhoea. These results show
      the importance of characterizing the dynamics of a therapeutic microorganism in
      patients with disease, as kinetic studies in healthy volunteers may not give a
      true reflection of the disturbed microecology in the disease state.

PMID- 10594403
TI  - Nalpha-methyl histamine and histamine stimulate gastrin release from rabbit G
      cells via histamine H2-receptors.
AB  - BACKGROUND: Gastrin release by Helicobacter pylori may be an important step in
      the pathway leading to duodenal ulceration. A histamine H3-receptor agonist was
      found to release gastrin from antral mucosal fragments; this was interpreted as
      being due to suppression of somatostatin release. H. pylori is reported to
      produce Nalpha-methyl histamine (NalphaMH), which is an agonist of H3 as well as
      other histamine receptors. H. pylori infection also recruits mast cells, which
      release histamine. AIM: To determine the direct effects of histamine receptor
      agonists on isolated gastrin cells. METHODS: Rabbit G-cells were prepared by
      countercurrent elutriation and cultured on 24-well plates. RESULTS: NalphaMH (10
      6-10-4 M) caused a dose-dependent increase in gastrin release from a basal level
      of 2.3 +/- 0.2% total cell content (TCC; mean +/- S.E.M.) to a maximum of 5.1 +/-
      0.7%, an increase of 117% (P < 0. 005) above basal. This was abolished by the H2
      antagonist ranitidine (10-5 M), but not by immunoblockade with anti-somatostatin
      antibody, the H1-antagonist chlorpheniramine (10-5 M) or the H3-antagonist
      thioperamide (10-4 M). The histamine H2-receptor agonist dimaprit (10-6-10-4 M)
      increased gastrin release from 2.4 +/- 0.2% to 3.6 +/- 0.2% TCC (P < 0.001).
      Gastrin release was also stimulated by histamine (10-7-10-4 M) from a basal value
      of 3.0 +/- 0.3% to 5.4 +/- 0.5% TCC (P < 0.001). This also was inhibited by
      ranitidine (10-5 M) (P < 0.01). CONCLUSION: NalphaMH and histamine release
      gastrin from G-cells via H2-receptors; this might contribute to H. pylori
      associated hypergastrinaemia.

PMID- 10594404
TI  - N-bisphosphonates cause gastric epithelial injury independent of effects on the
      microcirculation.
AB  - BACKGROUND: Nitrogen-containing bisphosphonates have been shown to be effective
      for the treatment of osteoporosis and Paget's disease of bone. Unfortunately,
      these drugs also have the capacity to irritate the upper gastrointestinal mucosa.
      In this study we investigated the ability of alendronate and pamidronate to
      directly damage the gastric epithelium and attempted to determine whether these
      drugs caused injury through gastric microcirculatory alterations. METHODS: An ex
      vivo gastric chamber model was used. Effects of topically applied alendronate and
      pamidronate on transmucosal potential difference and epithelial integrity
      (histology) were determined. Also, the effects of agents capable of preventing
      microvascular injury in the stomach (PGE2 and two nitric oxide donors) were
      examined for their ability to prevent gastric injury induced by the two N
      bisphosphonates. RESULTS: Alendronate and pamidronate caused a concentration
      dependent decrease in transmucosal potential difference, widespread epithelial
      injury and infiltration of neutrophils into the mucosa. PGE2 and the two nitric
      oxide donors did not prevent the changes in potential difference or the
      epithelial injury, but did reduce neutrophil infiltration. Significant release of
      PGE2 into the lumen was observed following application of the two
      bisphosphonates, but neither drug altered mucosal blood flow. CONCLUSIONS: These
      results suggest that these N-bis- phosphonates directly damage the gastric
      epithelium independent of actions on the microvasculature.

PMID- 10594405
TI  - Endogenous nitric oxide in the regulation of gastric secretory and motor activity
      in humans.
AB  - BACKGROUND: Studies in animals have shown that nitric oxide (NO) affects gastric
      secretory and motor functions. However, little information is available about the
      involvement of this substance in the control of gastric secretory and motor
      activity in man. METHODS: This study, performed on 18 healthy, Helicobacter
      pylori-negative volunteers, was designed to evaluate the role of NO in the
      control of gastric acid secretion and of gastrin and somatostatin release in
      response to ordinary feeding (group A) and on gastric motor and electrical
      activity (group B). Gastric acid secretion was determined by means of
      intragastric pH-metry before and after feeding with a semi-liquid meal. Plasma
      levels of gastrin and somatostatin were measured using specific
      radioimmunoassays. Gastric emptying rate was measured using the 13C-acetate
      breath test, antral motor activity using a manometric catheter and myoelectric
      activity using cutaneous electrogastrography. Studies were repeated following pre
      treatment with NG-monomethyl-L-Arginine (L-NMMA), L-Arginine (L-Arg) or their
      combination. RESULTS: L-NMMA delayed the recovery of intragastric pH to the pre
      meal value, and suppressed postprandial gastrin release while increasing the
      plasma somatostatin level. L-Arg did not affect postprandial pH and plasma
      hormones, but reversed L-NMMA-induced alterations in intragastric pH and in
      plasma gastrin and somatostatin levels. Both postprandial antral motor activity
      (motility index) and gastric emptying significantly increased in tests with L
      NMMA, but this was not observed when L-NMMA was given in combination with L-Arg
      or when L-Arg alone was used. The gastric electrical pattern, as measured by
      cutaneous electrogastrography, was not affected by L-NMMA, L-Arg or their
      combination. CONCLUSIONS: (1) Endogenous NO appears to be involved in the
      regulation of postprandial gastric acid secretion. This effect may be mediated by
      the changes in release of gastrin and somatostatin. (2) Endogenous NO delays
      gastric emptying and antral motor activity without affecting gastric
      myoelectrical activity.

PMID- 10594406
TI  - The importance of clarithromycin dose in the management of H. pylori infection: a
      meta-analysis of triple therapies with a proton pump inhibitor, clarithromycin
      and amoxycillin or metronidazole.

PMID- 10594408
TI  - Burns treatment in the 21st century: a challenge for British anaesthesia.

PMID- 10594409
TI  - Preliminary UK experience of dexmedetomidine, a novel agent for postoperative
      sedation in the intensive care unit.
AB  - Dexmedetomidine, a highly selective and potent alpha2-adrenergic agonist, has a
      potentially useful role as a sedative agent in patients requiring intensive care.
      As part of a larger European multicentre trial, a total of 119 postoperative
      cardiac and general surgical patients requiring ventilation and sedation in an
      intensive care unit were enrolled in four centres in the United Kingdom. One
      hundred and five patients were randomly allocated to receive either
      dexmedetomidine or placebo with rescue sedation and analgesia provided by
      midazolam and morphine, respectively. Compared with the control group, intubated
      patients receiving dexmedetomidine required 80% less midazolam [mean 4.9 (5.8)
      microg.kg-1.h-1 vs. 23.7 (27.5) microg.kg-1.h-1, p < 0.0001], and 50% less
      morphine [11.2 (13.4) microg.kg-1.h-1 vs. 21.5 (19.4) microg.kg-1.h-1,p =
      0.0006]. Cardiovascular effects and adverse events could be predicted from the
      known properties of alpha-2 agonists. In conclusion, dexmedetomidine is a useful
      agent for the provision of postoperative analgesia and sedation.

PMID- 10594410
TI  - Clinical indicators and other complications in the recovery room or
      postanaesthetic care unit.
AB  - Clinical indicators and complications occurring in the recovery room or post
      anaesthetic care unit were recorded for patients who had an anaesthetic procedure
      during 1995, 1996 and 1997 (n = 13 266). Clinical indicators measured were those
      developed by the Australian Council on Healthcare Standards in conjunction with
      the Australian and New Zealand College of Anaesthetists, and three other
      indicators. All patients were assessed and positive data were collected by
      nursing staff on a standardised form which was checked and collated by the
      anaesthetist responsible for the recovery room (the author). The rates for some
      indicators were higher than the Australian Council on Healthcare Standards 1997
      rates, but the overall rates of complications were comparable with, or lower
      than, those in published series. Clinical indicator data are seen as a valuable
      quantitative tool for quality assurance, particularly if collected as part of a
      more comprehensive programme.

PMID- 10594411
TI  - Electroencephalographic arousal response during tracheal intubation and laryngeal
      mask airway insertion after induction of anaesthesia with propofol.
AB  - Laryngoscopy and tracheal intubation, or insertion of a laryngeal mask airway may
      lead to an arousal response on the electroencephalogram. We studied whether more
      intense stimulation (laryngoscopy and tracheal intubation) causes a greater
      arousal response than less intense stimulation (laryngeal mask airway insertion).
      Thirty-four patients (ASA I-II) were anaesthetised with propofol 3 mg.kg-1,
      followed by vecuronium 0.15 mg.kg-1 and a propofol infusion of 10 mg.kg-1.h-1.
      Three minutes after induction of anaesthesia, either laryngoscopy and tracheal
      intubation (n = 18), or laryngeal mask airway insertion (n = 16) was performed.
      Laryngoscopy and tracheal intubation caused a significantly greater increase in
      blood pressure (but not heart rate) than laryngeal mask airway insertion (p <
      0.05). Electroencephalogram responses were not different. More intense
      stimulation does not cause a greater arousal response during propofol
      anaesthesia.

PMID- 10594412
TI  - Minimum alveolar sevoflurane concentrations required for insertion of the cuffed
      oropharyngeal airway and the laryngeal mask airway: a comparative study.
AB  - Both the cuffed oropharyngeal airway and the laryngeal mask airway share a
      similar property of being less stimulating to the upper airway than the tracheal
      tube. This study was conducted to compare sevoflurane concentrations required for
      insertion of the cuffed oropharyngeal airway and the laryngeal mask airway in
      elderly and young adult patients. Forty-one elderly (65-90 years) and 34 young
      adult (18-50 years) patients, scheduled for elective surgery during spontaneous
      breathing anaesthesia were randomly assigned to either the cuffed oropharyngeal
      airway or the laryngeal mask airway group. After a predetermined end-tidal
      concentration of sevoflurane had been established and maintained for at least 20
      min, insertion of the device was attempted without neuromuscular relaxants or
      other adjuvants. Each concentration at which insertion of the device was
      attempted was predetermined by modification of Dixon's up-and-down method with
      0.5% as the step size. Sevoflurane MACCOPA [mean 1.17 (SD 0.38)%, 0.77-1.56% (95%
      CI)] was significantly less than MACLMA [2.00 (0.52)%, 1.45-2.55%, p < 0.05] for
      elderly patients. Similarly, sevoflurane MACCOPA [1.33 (0.38)%, 0.94-1.73%] was
      significantly less than MACLMA [2.00 (0.42)%, 1.56-2.44%, p < 0.05] for young
      adult patients. There were no significant differences in either MACCOPA or MACLMA
      between the elderly and the young adult patients. We conclude that the insertion
      of the cuffed oropharyngeal airway can be accomplished at a lower sevoflurane
      concentration, and hence, is less stimulating to the upper airway than that of
      the laryngeal mask airway.

PMID- 10594413
TI  - Complications following the use of the Combitube, tracheal tube and laryngeal
      mask airway.
AB  - In a prospective, randomised trial, 75 patients scheduled for routine surgery
      were randomly allocated to one of three groups to evaluate trauma and
      postoperative complications after insertion of the Combitube, tracheal tube or
      laryngeal mask airway. Insertion of the Combitube was associated with a higher
      incidence of sore throat (48% vs. 16% vs. 12% [p < 0.01]) and dysphagia (68% vs.
      12% vs. 8% [p < 0.01]) compared with tracheal intubation or insertion of the
      laryngeal mask airway, respectively. Hoarseness was significantly less common in
      both the Combitube and the laryngeal mask groups (both 12%) than in the tracheal
      tube group (44%; p < 0.01). Haematoma occurred in 36% of the Combitube group
      compared with 4% in both the laryngeal mask and the tracheal tube groups (p <
      0.01). The higher incidence of complications should be considered when using the
      Combitube.

PMID- 10594414
TI  - The use of 0.25% isoflurane premixed in 50% nitrous oxide and oxygen for pain
      relief in labour.
AB  - The addition of 0.25% isoflurane to 50% nitrous oxide in oxygen provides more
      effective pain relief in labour than 50% nitrous oxide alone. This study was
      carried out to determine whether self-administration by demand valve of 0.25%
      isoflurane in 50% nitrous oxide in oxygen premixed in cylinders at 13.7 MPa
      (IN2O) was practical and safe during labour. Two hundred and twenty-one mothers
      used IN2O in labour after 50% nitrous oxide had become inadequate for pain
      relief. Data on IN2O use was recorded during labour and details of the course of
      labour and opioid usage were taken from the clinical notes. The duration of IN2O
      use was 0.1-12.35 h (median 2.3). Thirty-two mothers (14.5%) required an epidural
      and intolerance to IN2O was seen in a maximum of 17 cases (7.7%). One hundred and
      twenty-six cases were primiparous and 93 parous with 151 deliveries being
      spontaneous and 70 interventional, of which 12 were by Caesarean section.
      Maternal blood loss was 20-1500 ml (median 200 ml). Apgar scores at 1 and 5 min
      were unaffected by IN2O use although a positive correlation was found between the
      use of opioids and the number of neonates with a 1-min score below 8 and the
      number requiring resuscitation. Six neonates had an Apgar score below 8 at 5 min,
      but their condition was adequately explained by factors other than the sedative
      technique used. Self-administered IN2O was found to be a safe and practical
      technique for sedation in labour when 50% nitrous oxide alone had become
      inadequate.

PMID- 10594415
TI  - Extending low-dose epidural analgesia for emergency Caesarean section. A
      comparison of three solutions.
AB  - We conducted a prospective double-blind randomised trial to compare bupivacaine
      0.5%; a 50 : 50 mixture of bupivacaine 0.5%/lignocaine 2% with 1 : 200 000
      adrenaline (final concentration); and lignocaine 2% with 1 : 200 000 adrenaline
      for converting a low-dose labour epidural into a block adequate for emergency
      Caesarean section. Ninety patients were studied, 30 in each group. There was no
      difference between the groups in the time taken for bilateral loss of cold
      sensation to reach T4. Onset time was unaffected by the existing sensory level
      pre-Caesarean section top-up; the number of low-dose top-ups in labour; the total
      dose of bupivacaine in labour; or maternal weight or height. Three patients in
      the lignocaine with adrenaline group had blocks that reached the cervical
      dermatomes and three in the same group required general anaesthesia for
      inadequate anaesthesia, compared with none in the other groups (both p = 0.04).

PMID- 10594416
TI  - A comparison of 1% ropivacaine with a mixture of 0.75% bupivacaine and 2%
      lignocaine for peribulbar anaesthesia.
AB  - In a single centre, randomised, double-blind study, 54 patients underwent
      intraocular surgery under peribulbar anaesthesia with either ropivacaine 1% or a
      mixture of bupivacaine 0.75% and lignocaine 2%, both with hyaluronidase 7.5 iu.ml
      1. There were no significant differences in volume of anaesthetic required, time
      to onset of block, peri-operative pain scores or frequency of adverse events
      between the ropivacaine group and the lignocaine and bupivacaine group.

PMID- 10594417
TI  - Ventilator-associated pneumonia. Diagnosis, pathogenesis and prevention.
AB  - Ventilator-associated pneumonia is common, difficult to diagnose, affects the
      most vulnerable of patients and carries a high mortality. During prolonged
      mechanical ventilation the oropharynx, sinuses, dentition and stomach of
      critically ill patients become colonised with pathogenic bacteria. Colonised
      secretions pool in the oropharynx and subglottic space. These secretions
      repeatedly gain access to the lower airways by leakage past the tracheal tube
      cuff. If host defence mechanisms are overwhelmed, multiplication occurs in the
      lower respiratory tract producing an inflammatory response in the bronchioles and
      alveoli. The inflammatory response is characterised by capillary congestion,
      leucocyte and macrophage infiltration and fibrinous exudation into the alveolar
      spaces. If this inflammatory response occurs more than 48 h after intubation, it
      is called ventilator-associated pneumonia. Prevention depends on reducing upper
      airway and gastrointestinal reservoirs of bacteria, reducing or abolishing
      aspiration of these bacteria past the tracheal tube cuff and enhancing bacterial
      clearance from the lower airways.

PMID- 10594418
TI  - A comparison of two silicone-reinforced tracheal tubes with different bevels for
      use with the intubating laryngeal mask.
AB  - Seventy consecutive patients were randomly allocated for intubation through the
      intubating laryngeal mask airway using a straight reinforced silicone tracheal
      tube with either a conventional or a modified bevel. The conventional bevel was
      firm, wedge-shaped and with a leading edge at the side. The modified bevel was
      soft, hemispherical and with a leading edge in the midline. The intubating
      laryngeal mask position was adjusted until optimal ventilation was obtained and
      intubation was attempted using the randomised device. If tactile resistance was
      felt, a predetermined sequence of adjusting manoeuvres were utilised before a
      subsequent attempt. The first-attempt successful intubation rate with the
      conventional bevel was 23/37 (62%) and with the modified bevel was 28/33 (85%).
      The second-attempt successful intubation rate for the conventional bevel was
      12/37 (32%) and for the modified bevel was 4/33 (12%). Intubation failed after
      three attempts for one patient in each group. Fewer overall intubation attempts
      were required with the modified bevel (p = 0.033). We conclude that intubation
      success rates through the intubating laryngeal mask with a straight silicone
      reinforced tube are higher with a soft, hemispherical bevel with a leading edge
      in the midline compared with the firm, wedge-shaped bevel with a leading edge at
      the side.

PMID- 10594419
TI  - 'Speaking in tongues'. Paradoxical fixation on a non-native language following
      anaesthesia.
AB  - An intriguing case of transient language disturbance following anaesthesia is
      described which may throw some light on the way languages are stored in the
      brain. A review of the existing literature and its relevance to this unique case
      is discussed.

PMID- 10594420
TI  - The effect of pre-emptive acupuncture treatment on analgesic requirements after
      day-case knee arthroscopy.
AB  - The role of acupuncture analgesia in the management of postoperative pain is yet
      to be clearly evaluated. We conducted a prospective, double-blind, randomised
      controlled study to evaluate the effect of acupuncture pretreatment on the
      analgesic requirement after knee arthroscopy. Forty-two patients presenting for
      unilateral knee arthroscopy were randomly allocated to receive a standard
      anaesthetic with or without acupuncture (given after the induction of
      anaesthesia). Visual analogue pain scores, time to first postoperative analgesia
      and total analgesia requirement in the first 24 h were recorded. There was no
      significant difference between the two groups in any of the outcome measures. We
      conclude that acupuncture analgesia has no additional effect when given under
      anaesthesia to patients undergoing knee arthroscopy.

PMID- 10594421
TI  - Comparison of the effects of desflurane and isoflurane anaesthesia on
      hepatocellular function assessed by alpha glutathione S-transferase.
AB  - The purpose of this study was to investigate the influence of isoflurane and
      desflurane on hepatocellular function. Twenty male patients undergoing elective
      surgery were randomly assigned to receive either isoflurane or desflurane
      anaesthesia. Alpha glutathione S-transferase concentrations and aminotransferase
      activities were measured at induction of anaesthesia (t0), 15 min (t1), 90 min
      after induction (t2), end of surgery (t3) and 2 h thereafter (t4). A significant
      increase in alpha glutathione S-transferase concentration was observed only in
      the isoflurane group. Alpha glutathione S-transferase levels increased
      significantly from 2.3 microg.l-1 at t0 to 6.1 (1.9) microg.l-1 at t2 and to 7.8
      (2.1) microg.l-1 at t3. A significant difference in alpha glutathione S
      transferase concentration between the two groups was found at t2 and t3. The
      significant increases in alpha glutathione S-transferase concentrations in
      patients receiving isoflurane suggest a transient disturbance of hepatocellular
      function.

PMID- 10594422
TI  - A comparison of the effect of rocuronium and vecuronium on heart rate during
      gynaecological laparoscopy.
AB  - The effect on intra-operative heart rate of two nondepolarising muscle relaxants,
      rocuronium and vecuronium, was compared in 116 fit out-patients undergoing
      gynaecological laparoscopic procedures. Both groups received an anaesthetic
      technique which differed only in the choice of muscle relaxant. Intra-operatively
      it was noted that patients given rocuronium (20 mg) had significantly fewer
      episodes of bradycardia (heart rate < 50 beat.min-1) than patients given
      vecuronium 4 mg (p < 0.05). Profound bradycardias (heart rate < 30 beat.min-1)
      did not occur in any of the patients in the rocuronium study group, whereas 5% of
      patients receiving vecuronium had a period of transient asystole. We conclude
      that, at the doses stated, rocuronium results in significantly fewer episodes of
      bradycardia than vecuronium when used as a muscle relaxant for laparoscopic
      gynaecological procedures.

PMID- 10594423
TI  - A survey of pre-operative fasting regimens before regional ophthalmic anaesthesia
      in three regions of the United Kingdom.
AB  - A postal and telephone survey of the practice of fasting before regional
      ophthalmic anaesthesia with and without sedation was sent to 50 hospitals in
      three regions of the United Kingdom. Responses were received from 100% of
      hospitals. In most hospitals (58%), local anaesthetic blocks were performed by
      both surgeons and anaesthetists, with surgeons alone providing ophthalmic
      anaesthesia in only 14%. Eighty-six per cent of hospitals surveyed had a formal
      policy regarding pre-operative fasting, with 44% allowing patients to eat and
      drink freely until their operation. In those hospitals where a fast was imposed,
      the most common fasting periods were 6 h for food and 2 h for fluids. Twenty-six
      per cent of respondents would be prepared to give intravenous sedation to a non
      fasted patient during eye surgery: small doses of benzodiazepine were the most
      frequently suggested method. National evidence-based guidelines for ophthalmic
      regional anaesthesia are needed.

PMID- 10594425
TI  - What's new for the millennium?

PMID- 10594424
TI  - 'Would they be proud of us?'.

PMID- 10594426
TI  - Systemic stress response during operations for acute abdominal pain performed via
      laparoscopy or laparotomy in children.
AB  - We compared the endocrine and metabolic changes during acute emergency abdominal
      surgery performed using either laparoscopy or laparotomy in children. Twenty-nine
      children aged 1.5-14 years were assigned to undergo laparoscopy (n = 15) or
      laparotomy (n = 14) with a standard anaesthesia technique. Arterial blood gases
      and blood prolactin, cortisol, interleukin-6, glucose, insulin, lactic acid and
      epinephrine levels were determined 5 min after the induction of anaesthesia, 30
      min into surgery and at the end of surgery. Intra-operative heart rate and mean
      arterial pressure were stable in both groups. In the laparoscopy group, slight
      respiratory acidosis occurred during surgery (p < 0.01) but there were no changes
      in the laparotomy group. Insulin, cortisol, prolactin, epinephrine, lactate and
      blood glucose levels increased in both groups (p < 0.05) although there was no
      difference between the groups. The surgical stress and trauma imposed by
      laparoscopy seems similar to that caused by laparotomy in children undergoing
      emergency abdominal surgery.

PMID- 10594427
TI  - Haemodynamic changes during thoracoscopic surgery the effects of one-lung
      ventilation compared with carbon dioxide insufflation.
AB  - We investigated the haemodynamic and respiratory effects of one-lung ventilation
      and carbon dioxide insufflation in 13 adult patients undergoing video-assisted
      thoracoscopy. Cardiorespiratory variables were determined during carbon dioxide
      insufflation at intrahemithoracic pressures of 5, 10 and 15 mmHg, and after 5 and
      15 min of one-lung ventilation. Carbon dioxide insufflation was associated with a
      clear deterioration in circulatory function. The cardiac index decreased
      subsequent to increasing intrathoracic pressures. The mean cardiac index (SD) at
      pressures of 10 and 15 mmHg was 1.86 (0.39) and 1.52 (0.46), respectively, and
      may be compared with the reduced venous return consistent with tension
      pneumothorax. One-lung ventilation did not affect haemodynamic variables but
      reduced arterial oxygenation indices (PaO2/FIO2) from 424.29 (160.79) after
      induction of anaesthesia, to 207.72 (125.50) after 5 min and 172.04 (72.03) after
      15 min of one-lung ventilation, respectively. The oxygenation index was not
      influenced by intrahemithoracic carbon dioxide insufflation. One-lung ventilation
      via a double-lumen endobronchial tube is safe and convenient for video-assisted
      thoracoscopic surgery. It has no further consequences on haemodynamic variables,
      whereas the compression of the lung by carbon dioxide insufflation may cause
      circulatory dysfunction.

PMID- 10594428
TI  - Speed of onset of regional analgesia in labour: a comparison of the epidural and
      spinal routes.
AB  - This study compares the speed of onset of effective analgesia in two randomly
      assigned groups of patients requesting analgesia in labour. Patients in the
      combined spinal-epidural group (n = 69) were given a subarachnoid injection of
      1.5 ml containing bupivacaine 2.5 mg and fentanyl 25 microg for initiation of
      analgesia. Patients in the epidural group (n = 73) were given an epidural
      injection of 10 ml containing bupivacaine 12.5 mg and fentanyl 50 microg. Mean
      (SD) onset times to the first pain-free contraction were 10.0 (5.7) min in the
      combined spinal-epidural group and 12.1 (6.5) min in the epidural group (p =
      0.054). Patients in the combined spinal-epidural group suffered a higher
      incidence of motor weakness and proprioceptive deficit than those in the epidural
      group (p = 0.01). The incidence of technique failure and side-effects was similar
      in the two groups. It is our contention that the statistically nonsignificant
      difference in onset times does not justify the additional potential for side
      effects and the extra cost of the equipment involved in the combined spinal
      epidural technique.

PMID- 10594429
TI  - Tourniquet pain in a volunteer study: effect of changes in cuff width and
      pressure.
AB  - This study examines the relationship between pneumatic tourniquet cuff size,
      occlusion pressure and the resulting pain. Two tourniquet cuff widths were used,
      a wide (14 cm) and a narrow cuff (7 cm). Twenty volunteers were divided into two
      groups for tourniquet application: a pressure group in which the tourniquet was
      inflated to a pressure equal to the systolic pressure + 100 mmHg, and a
      saturation group in which the tourniquet was inflated to 10 mmHg above the loss
      of arterial pulse, as indicated by cessation of pulse waveform on an oximeter.
      According to a randomised cross-over protocol, subjects were studied using wide
      and narrow cuffs simultaneously and/or successively on both arms. Pain was
      assessed by subjects by means of a visual analogue score (0-10 cm). Occlusion
      pressures were similar for all volunteers in the pressure group and significantly
      higher than those in the saturation group with both the wide and narrow
      tourniquets. The wide cuff data turned out to be significantly lower than the
      narrow cuff results. Subjects in the pressure group could tolerate pain with the
      narrow cuff for significantly longer than with the wide cuff. However, in the
      saturation group, volunteers tolerated the wide cuff for longer. Pain intensity
      increased more rapidly in those in the pressure group with the wide cuff than
      with the narrow cuff. In contrast, volunteers in the saturation group found the
      narrow cuff to be more painful than the wide cuff. In conclusion, this study has
      shown that a wide tourniquet cuff is less painful than a narrow cuff if inflated
      at lower pressures and at these lower pressures it is still effective at
      occluding blood flow.

PMID- 10594430
TI  - The use of a blood conservation pressure transducer system in critically ill
      patients.
AB  - We tried to determine if a blood conservation pressure transducer system reduced
      blood transfusions, increased haemoglobin concentration or reduced line
      infections in critically ill patients. One hundred patients were randomly
      allocated to conventional or blood conserving systems attached to systemic and
      pulmonary arterial catheters. Intravascular lines were cultured after removal.
      There were no significant differences in transfusions or haemoglobin
      concentration. Blood conservation: median units transfused, 2 (range 0-19); mean
      haemoglobin at 7 days, 11.2 g.dl-1 (SD, 1.0). Conventional: median units, 2
      (range 0-34); mean haemoglobin at 7 days, 11.1 g.dl-1 (SD 1.0). Thirty-seven of
      99 arterial lines were colonised in the controls compared with 29 of 96 in the
      blood conservation group. Patients who required haemofiltration in both groups
      had significantly increased transfusion requirements. Haemofiltration: median 6
      units (range 0-34) vs. non-haemofiltered: median 1 (range 0-14; p < 0.001). There
      were no significant differences in transfusions, haemoglobin concentration or
      line colonisation with the blood conservation system. There is considerable
      potential for blood conservation during haemofiltration.

PMID- 10594432
TI  - Combined spinal-epidural techniques.
AB  - The combined spinal-epidural technique has been used increasingly over the last
      decade. Combined spinal-epidural may achieve rapid onset, profound regional
      blockade with the facility to modify or prolong the block. A variety of
      techniques and devices have been proposed. The technique cannot be considered
      simply as an isolated spinal block followed by an isolated epidural block as
      combining the techniques may alter each block. This review concentrates on
      technical and procedural aspects of combined spinal-epidural. Needle-through
      needle, separate-needle and combined-needle techniques are described and
      modifications discussed. Failure rates and causes are reviewed. The problems of
      performing a spinal block before epidural blockade (potential for unrecognised
      placement of an epidural catheter, inability to detect paraesthesia during
      epidural placement, difficulty in testing the epidural, delay in positioning the
      patient) are described and evaluated. Problems of performing spinal block after
      epidural blockade (risk of catheter or spinal needle damage) are considered.
      Mechanisms of modification of spinal blockade by subsequent epidural drug
      administration are discussed. The review considers choice of technique, needle
      type, patient positioning and paramedian vs. midline approach. Finally,
      complications associated with combined spinal-epidural are reviewed.

PMID- 10594431
TI  - Anaesthesia and pain management in cerebral palsy.
AB  - Cerebral palsy is the result of an injury to the developing brain during the
      antenatal, perinatal or postnatal period. Clinical manifestations relate to the
      area affected. Some of the conditions associated with cerebral palsy require
      surgical intervention. Problems during the peri-operative period may include
      hypothermia, nausea and vomiting and muscle spasm. Peri-operative seizure
      control, respiratory function and gastro-oesophageal reflux also require
      consideration. Intellectual disability is common and, in those affected, may
      range from mild to severe. These children should be handled with sensitivity as
      communication disorders and sensory deficits may mask mild or normal intellect.
      They should be accompanied by their carers at induction and in the recovery room
      as they usually know how best to communicate with them. Postoperative pain
      management and the prevention of muscle spasm is important and some of the drugs
      used in the management of spasm such as baclofen and botulinum toxin are
      discussed. Epidural analgesia is particularly valuable when major orthopaedic
      procedures are performed.

PMID- 10594433
TI  - Performance of the radiometer OSM3 and ABL505 blood gas analysers for
      determination of sodium, potassium and haemoglobin concentrations.
AB  - We have compared results obtained from two widely used ward-based blood gas
      analysers, the Radiometer OSM3 and ABL505, with standard laboratory analysers,
      for haemoglobin, sodium and potassium measurement in critically ill adult
      patients. During the study, paired samples for analysis were obtained from 81
      patients for haemoglobin, 115 patients for sodium and 95 patients for potassium.
      There was good agreement between the ward and the laboratory analysers in terms
      of the mean results for each test. However, the limits of agreement for the ward
      based analysers were wide, suggesting that their results should be used with
      caution.

PMID- 10594434
TI  - Awake tracheal intubation with the intubating laryngeal mask in a patient with
      diffuse idiopathic skeletal hyperostosis.
AB  - Diffuse idiopathic skeletal hyperostosis, otherwise known as Forestier's disease
      or ankylosing hyperostosis, is a relatively common condition that is
      distinguished from ankylosing spondylitis by the relative preservation of spinal
      function and the characteristic 'candle flame' lipping of the vertebrae. We
      report a patient with this condition and a well-recorded history of impossible
      intubation who presented for emergency laparotomy. The patient was intubated
      awake using the intubating laryngeal mask and sedation and anaesthesia were
      provided by a target-controlled infusion of propofol.

PMID- 10594435
TI  - Postoperative pseudostatus: not everything that shakes is epilepsy.
AB  - Postoperative epileptic seizures are recognised but rare. Psychogenic seizures
      and pseudostatus epilepticus are relatively common, particularly in the peri
      operative period. Our series of five cases of postoperative pseudostatus
      epilepticus demonstrates that the failure to recognise the psychogenic nature of
      this condition may cause anaesthetists to give inappropriate and potentially
      harmful treatment. Psychogenic 'status' is easy to diagnose once it has been
      considered. Convulsive episodes lasting longer than 90 s, closed eyes during a
      'tonic-clonic' attack, retained pupillary response and resistance to eye opening
      are useful signs. Often there is a history of multiple admissions with 'status
      epilepticus' and of previous postoperative 'status'.

PMID- 10594436
TI  - Heat loss during induction of anaesthesia for elective aortic surgery.
AB  - We have studied core temperature changes occurring during induction of general
      anaesthesia and surgery in 18 patients undergoing elective aortic aneurysm
      repair. In the operating theatre, all patients were warmed with a forced-air
      warmer and a warming mattress, and received warmed (37 degrees C) intravenous
      fluids. Despite this, mean (SD) [range] core temperatures in the anaesthetic room
      decreased by 1.5 (0.3)[1.1-2.2] degrees C, while intravascular lines, epidural
      and urinary catheters were inserted before the introduction of warming methods in
      theatre. In one-third of patients, the core temperature was still below 36
      degrees C at the end of surgery. The overall temperature decrease correlated
      significantly with the duration of time between induction of general anaesthesia
      and surgical incision (R2 = 0.6912), when the patients were not being warmed.
      Hypothermia may thus be prevented by minimising the period that the patient is
      anaesthetised without being warmed. Vascular lines, urinary and epidural
      catheters should be inserted before the induction of general anaesthesia or,
      alternatively, warming methods should be introduced in the anaesthetic room.

PMID- 10594437
TI  - Ease of tracheal intubation through the intubating laryngeal mask during manual
      in-line head and neck stabilisation.
AB  - We studied 40 anaesthetised and paralysed patients, in a randomised manner, to
      compare the ease of tracheal intubation either using a Macintosh laryngoscope and
      gum elastic bougie (group C) with the ease of tracheal intubation through the
      intubating laryngeal mask using a fibreoptic bronchoscope (group L), during
      manual in-line stabilisation of the patient's head and neck. In both groups, a
      maximum of 120 s was allowed for attempts at tracheal intubation. The ease of
      placement of the intubating laryngeal mask or tracheal intubation was assessed
      using a 100-mm visual analogue scale (VAS). In patients in whom tracheal
      intubation succeeded, time for intubation was measured. The intubating laryngeal
      mask was placed successfully in 19 of 20 patients, with the median VAS of 18 mm
      (95% CI: 13-32 mm). The success rate of tracheal intubation in group L (17
      patients) was significantly higher than in group C (nine patients) (p < 0.01),
      tracheal intubation in group L was significantly easier than intubation in group
      C (p < 0.001; 95% CI for difference in VAS: 18-68 mm) and time taken for tracheal
      intubation was significantly shorter in group L than in group C (95% CI for
      difference: 8-50 s).

PMID- 10594438
TI  - Rapid sequence induction: suxamethonium or rocuronium?

PMID- 10594440
TI  - Use of the airway exchange catheter for the patient with a partially obstructed
      airway.

PMID- 10594441
TI  - The use of an oxygen source attached to the nonventilated lung during one-lung
      anaesthesia.

PMID- 10594442
TI  - Death in the dental chair.

PMID- 10594443
TI  - Target-controlled infusions.

PMID- 10594444
TI  - In defence of target-controlled infusion.

PMID- 10594445
TI  - Simple remifentanil infusions.

PMID- 10594446
TI  - Iatrogenic postoperative peripheral neuropathy is more common than generally
      realised.

PMID- 10594447
TI  - Combined spinal-epidural techniques and the awake/asleep debate.

PMID- 10594448
TI  - Profound motor blockade with epidural ropivacaine.

PMID- 10594449
TI  - A new method of identifying the epidural space.

PMID- 10594450
TI  - Postanaesthetic shivering.

PMID- 10594451
TI  - Hyperchloraemia causes metabolic acidosis by reducing strong ion difference.

PMID- 10594452
TI  - Self reports of postoperative cognitive dysfunction.

PMID- 10594453
TI  - Hemispheric-synchronisation for nociception control.

PMID- 10594454
TI  - Carbon dioxide narcosis caused by midazolam in a patient with myotonic dystrophy.

PMID- 10594455
TI  - Anaesthesia for MRI angiography in a patient with Williams syndrome.

PMID- 10594456
TI  - Latex allergy - further comment.

PMID- 10594457
TI  - Knotting of a nasogastric tube.

PMID- 10594458
TI  - Training in fiberoptic intubation.

PMID- 10594459
TI  - Multiple choice examinations.

PMID- 10594460
TI  - Side-effects of cardiac output measurement.

PMID- 10594461
TI  - Harmless herbs: a cause for concern?

PMID- 10594462
TI  - Removal of the laryngeal mouse airway.

PMID- 10594463
TI  - Peanuts or paranoia?

PMID- 10594464
TI  - The UK prospective diabetes study (UKPDS): clinical and therapeutic implications
      for type 2 diabetes.

PMID- 10594465
TI  - Therapeutic drug monitoring in a developing country: an overview.
AB  - Therapeutic Drug Monitoring (TDM) was introduced in India in the mid and late
      1980s and the last 10 years have seen it grow, together with the growth of
      separate Clinical Pharmacology departments. The TDM service in the country is
      broadly of two types: in large teaching hospitals where the service is available
      through departments of Clinical Pharmacology, and in the private sector, where
      drug estimations are done by clinical biochemistry departments with minimal
      interpretation. This article is based on literature review and our own
      experiences over a 10 year period in a department of Clinical Pharmacology. It
      focuses on the evolution of TDM, its problems such as lack of funding, special
      aspects such as the impact of ethnic differences, nutritional deficiencies,
      quality of medicines and availability of generic products; its utility as a
      research tool and its future.

PMID- 10594466
TI  - Effect of chronic magnesium supplementation on magnesium distribution in healthy
      volunteers evaluated by 31P-NMRS and ion selective electrodes.
AB  - AIMS: The role of magnesium (Mg) intake in the prevention and treatment of
      diseases is greatly debated. Mg biodistribution after chronic Mg supplementation
      was investigated, using state-of-the-art technology to detect changes in free
      ionized Mg, both at extra- and intracellular levels. METHODS: Thirty young
      healthy male volunteers participated in a randomised, placebo (P)-controlled,
      double-blind trial. The treated group (MgS) took 12 mmol magnesium lactate daily
      for 1 month. Subjects underwent in vivo 31P-NMR spectroscopy and complete
      clinical and biological examinations, on the first and last day of the trial.
      Total Mg was measured in plasma, red blood cells and 24 h urine ([Mg]U ). Plasma
      ionized Mg was measured by ion-selective electrodes. Intracellular free Mg
      concentrations of skeletal muscle and brain tissues were determined noninvasively
      by in vivo 31P-NMR at 3T. NMR data were automatically processed with the
      dedicated software MAGAN. RESULTS: Only [Mg]U changed significantly after
      treatment (in mmol/24 h, for P, from 4.2+/-1.4 before to 4.1+/-1.3 after and, for
      MgS, from 3.9+/-1.1 before to 5. 1+/-1.1 after, t=2.15, P=0.04). The two groups
      did not differ, either before or after the trial, in any other parameter, whether
      clinical, biological or in relation with the Mg status. CONCLUSIONS: Chronic oral
      administration of Mg tablets to young healthy male volunteers at usual
      pharmaceutical doses does not alter Mg biodistribution. This study shows that an
      adequate and very complete noninvasive methodology is now available and
      compatible with the organization of clinical protocols which aim at a thorough
      evaluation of Mg biodistribution.

PMID- 10594467
TI  - Tacrine is not an ideal probe drug for measuring CYP1A2 activity in vivo.
AB  - AIMS: The aim of the present study was to examine the CYP1A2 substrate tacrine as
      a possible alternative to caffeine for assessing CYP1A2 activity in vivo.
      METHODS: Eighteen, healthy, nonsmoking men participated. Each volunteer was
      tested by caffeine (200 mg orally), and caffeine metabolic ratios were
      calculated. Subsequently, on two occasions, separated by at least 4 weeks, each
      volunteer was tested with tacrine (40 mg orally). The apparent oral clearance,
      partial clearances and different metabolic ratios of tacrine were determined.
      RESULTS: The median oral clearances of tacrine in the two study periods were 1893
      l h-1 (range: 736-3098) and 1890 l h-1 (range: 438-4175), respectively. The
      interindividual coefficient of variation was 42% and 49%, respectively. The
      intraindividual coefficients of variation ranged from 0.28% to 64% (median: 13%).
      In both study periods, the oral clearance of tacrine correlated with the caffeine
      urinary metabolic ratio. However, only modest magnitudes of correlation were
      observed (rs: 0.64-0.66, P<0. 01). No tacrine metabolic ratio correlating with
      the oral clearance of tacrine was found. Conclusion The applicability of tacrine
      as a probe drug for measuring CYP1A2 activity in vivo appears limited.

PMID- 10594468
TI  - A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction
      in breast cancer patients.
AB  - AIMS: This study investigated the pharmacokinetics of cyclophosphamide (CP) and
      its main metabolite 4-hydroxycyclophosphamide (4-OH-CP) in patients with breast
      cancer undergoing high dose chemotherapy prior to autologous stem cell
      transplantation. An enzyme turn-over model was also developed to study the time
      course of cyclophosphamide induction. METHODS: Fourteen patients received a
      combination of CP (6 g m-2 ), thiotepum (500 mg m-2 ) and carboplatin (800 mg m-2
      ) as a 96 h infusion. Plasma concentrations of CP and 4-OH-CP were determined
      with h.p.l.c. and a pharmacokinetic and enzyme turn-over model applied to data
      using NONMEM. RESULTS: CP plasma concentrations were described by a two
      compartment model with a noninducible and an inducible pathway, the latter
      forming 4-OH-CP. In the final enzyme model, CP affects the amount of enzymes by
      increasing the enzyme production rate. CP concentrations decreased during the
      infusion with no subsequent change in 4-OH-CP concentrations. CP inducible and
      noninducible clearance were estimated to 1.76 l h-1 (90% C.I. 0.92-2.58) and 1.14
      l h-1 (0.31-1.85), respectively. The induction resulted in an approximately
      doubled CP clearance through the inducible pathway at the end of treatment. The
      model predicted the enzyme turn-over half-life to be 24 h. CONCLUSIONS: The
      presented mechanism-based enzyme induction model where the pharmacokinetics of
      the inducer and the enzyme pool counterbalance each other successfully described
      CP autoinduction. It is reasonable to believe that CP affects its own elimination
      by increasing the enzyme production rate and thereby increasing the amount of
      enzyme by which CP is eliminated.

PMID- 10594469
TI  - Clinical pharmacokinetics of doxazosin in a controlled-release gastrointestinal
      therapeutic system (GITS) formulation.
AB  - AIMS: A controlled-release gastrointestinal therapeutic system (GITS) formulation
      of doxazosin mesylate, a long-acting selective alpha1-adrenoceptor antagonist,
      was developed to enhance the pharmacokinetic profile and simplify the titration
      schedule by precisely controlling drug delivery rate, permitting an initial dose
      of 4 mg once daily, compared with standard doxazosin, which is initiated at 1 mg
      day-1 and titrated to a higher therapeutically effective dose. The aim of the
      present work was to evaluate the pharmacokinetics and bioavailability of
      doxazosin GITS with respect to the effect of food, age and gender, and multiple
      dosing. In addition, in vitro performance was assessed in conditions simulating
      the gastrointestinal environment. METHODS: A three-way crossover study in 24
      subjects assessed the comparative bioavailability of doxazosin GITS under fed and
      fasting conditions and doxazosin standard under fasting condition. A multiple
      dose, two-way crossover study in 35 subjects assessed the comparative
      pharmacokinetics and bioavailability of doxazosin GITS and doxazosin standard 4
      and 8 mg upon multiple dosing. A multiple-dose, four-parallel-group study was
      conducted to determine the steady-state pharmacokinetics and bioavailability of
      doxazosin GITS 4 mg in 41 young and elderly male and female subjects. The release
      rate profiles of doxazosin GITS were determined in artificial gastric fluid
      (pH=1.2), intestinal fluid (pH=7.5), and water. The effect of agitation on the
      dissolution characteristics of doxazosin GITS in artificial gastric fluid was
      studied at stirring rates of 50, 75, and 100 rev min-1. RESULTS: In vitro studies
      demonstrated that release rates for the GITS tablet are independent of pH in the
      range of 1.2 (gastric) to 7. 5 (intestinal), and of stirring rates simulating
      gastrointestinal motility. Clinical pharmacology studies showed that doxazosin
      GITS had a lower maximum plasma concentration, prolonged time to reach maximum
      plasma concentration, and a higher minimum plasma concentration compared with
      doxazosin standard. Thus, the GITS formulation results in a more gradual
      absorption of doxazosin, and a reduced plasma doxazosin concentration peak-to
      trough fluctuation ratio. The relative bioavailability of doxazosin GITS is
      approximately 60%. With a high-fat meal, the maximum plasma concentration and
      area under the concentration-time curve were 31% and 18% higher, respectively
      (P<0.05). Bioequivalence was established between the dose strengths of two 4 mg
      doxazosin GITS tablets and one 8 mg doxazosin GITS tablet. For both young adult
      and elderly subjects, and males and females, the pharmacokinetics of doxazosin
      GITS once daily for 7 days were comparable. Doxazosin GITS was well tolerated in
      the subjects studied, including young and elderly males and females. CONCLUSIONS:
      The GITS formulation of doxazosin enhances the pharmacokinetic profile compared
      with doxazosin standard, allowing more gradual absorption of doxazosin, and a
      reduced plasma doxazosin peak-to-trough concentration ratio. Thus, doxazosin GITS
      therapy can be initiated at a therapeutic dose of 4 mg with reduced haemodynamic
      side-effects.

PMID- 10594470
TI  - Population pharmacokinetics of enterally administered cisapride in young infants
      with gastro-oesophageal reflux disease.
AB  - AIMS: To investigate the pharmacokinetics of enterally administered cisapride
      suspension in young infants being treated for gastro-oesophageal reflux disease.
      METHODS: Plasma cisapride concentrations in 49 subjects (weight: 825-5010 g;
      n=108 samples, median two per patient; concentration: 14.8-170 ng ml-1 ) were
      fitted to a one-compartment model with first-order absorption and elimination in
      the NONMEM program using a logarithmic transformation of the observed and
      predicted concentrations. Fitting was achieved using the first order conditional
      estimation (FOCE) method with interaction between the interpatient and
      intrapatient variabilities. The interpatient variance of clearance (CL/F ) and
      volume of distribution (V /F ) and their covariance were estimated using an
      exponential error model. Intrapatient (residual) variance was estimated using an
      additive model. RESULTS: The clearance of cisapride was shown to be linearly
      related to current body weight, slope: 0.538. The typical population values of
      CL/F, V /F and Ka (absorption rate constant) were 0.538 l h-1 kg-1, 21.9 l, and
      2.58 h-1, respectively. The population coefficients of variation (CV%) for CL/F
      and V/F were 34.4% and 84.3%, respectively. The squared coefficient of
      correlation between random effects for CL/F and V /F was 0.45. The intrapatient
      variance was 0.15. V /F and Ka were not influenced significantly by any patient
      characteristic. CONCLUSIONS: Cisapride pharmacokinetics in infants with reflux
      disease were satisfactorily described by a one-compartment model. Current weight
      should be taken into account when calculating maintenance cisapride doses in
      these infants.

PMID- 10594471
TI  - Entry-into-human study with the novel immunosuppressant SDZ RAD in stable renal
      transplant recipients.
AB  - AIMS: To evaluate the tolerability of single oral SDZ RAD doses in stable renal
      transplant recipients and the pharmacokinetics of ascending SDZ RAD doses when
      coadministered with steady-state cyclosporin A microemulsion (Neoral). METHODS:
      This randomized, double-blind, placebo-controlled, sequential study involved 54
      patients in six treatment groups; a different SDZ RAD dose (0.25, 0. 75, 2.5,
      7.5, 15, 25 mg) was assessed in each group. Patients received a single oral dose
      of SDZ RAD (n=6) or placebo (n=3) with their usual Neoral dose. SDZ RAD and
      cyclosporin A pharmacokinetic parameters were determined. RESULTS: All SDZ RAD
      doses were well tolerated, with no discontinuations due to adverse events,
      serious adverse events, or deaths. Similar proportions of patients receiving SDZ
      RAD and placebo had at least one adverse event (44% and 50%, respectively). Mean
      changes in laboratory variables (baseline to endpoint) showed no clinically
      meaningful differences between SDZ RAD and placebo groups. SDZ RAD was absorbed
      rapidly and showed dose-proportional pharmacokinetics (dose: 2.5-25 mg), based on
      systemic exposure. Multiple postabsorptive phases in the pharmacokinetic profile
      indicate tissue distribution. The elimination half-life ranged from 24 to 35 h
      across the five highest dose groups. Pharmacokinetics were similar in men and
      women. Co-administration of escalating single oral SDZ RAD doses did not affect
      steady-state cyclosporin A pharmacokinetics. CONCLUSIONS: SDZ RAD was well
      tolerated; safety profiles of SDZ RAD and placebo were similar. SDZ RAD
      pharmacokinetics were dose-proportional across the range 2.5-25 mg in conjunction
      with cyclosporin A-based therapy, according to systemic exposure. Cyclosporin A
      pharmacokinetics were not affected by coadministration of single oral doses of
      0.25-25 mg SDZ RAD.

PMID- 10594472
TI  - Pharmacokinetics of rifabutin in HIV-infected patients with or without wasting
      syndrome.
AB  - AIMS: The purpose of the study was to compare the pharmacokinetic parameters of
      rifabutin obtained in a group of patients without wasting syndrome (NWS) with
      those obtained in a group with wasting syndrome (WS). METHODS: A single dose of
      300 mg rifabutin was administered in the fasting state to the patients in both
      study groups and blood samples were scheduled to be collected at the following
      times: 0 (predose), 0.5, 1, 2, 3, 4, 6, 8, 24, 48, 72 and 96 h following
      administration. Data were analysed using noncompartmental methods. The
      pharmacokinetic parameters of rifabutin in patients with and without wasting
      syndrome were compared using the Mann-Whitney U-test. RESULTS: Cmax was 0.34+/-0.
      14 mg l-1 in NWS patients and 0.55+/-0.16 mg l-1 (P=0.01) in patients with WS.
      tmax was 4.2+/-1.5 and 3.3+/-2.3 h (P=0.17) in NWS and WS patients, respectively.
      The AUCs were similar in the two study groups. V/F was 2905+/-1646 l in NWS
      patients and 1701+/-492 l (P=0.07) for the WS group. These differences are less
      pronounced following normalization of V/F to patients body weight (43.7+/-20.1 vs
      35.4+/-10.3 l kg-1 ). t1/2,lambdaz tended to be shorter in patients with WS
      (31.4+/-12.9 vs 46.0+/-23.5 h, P=0.12). CONCLUSIONS: Our study suggests that the
      pharmacokinetics of rifabutin in patients with wasting syndrome are not altered
      to a degree that is clinically important.

PMID- 10594473
TI  - Pharmacokinetics of efavirenz (EFV) alone and in combination therapy with
      nelfinavir (NFV) in HIV-1 infected patients.
AB  - AIMS: To define the pharmacokinetic profile of efavirenz (EFV) in HIV-1 infected
      patients, when administered alone or with nelfinavir (NFV). METHODS: Eleven HIV
      positive patients, in steady-state treatment with EFV and 11 patients in steady
      state treatment with EFV+NFV, were evaluated. Blood samples for pharmacokinetic
      analysis were obtained during a dosage interval. Plasma concentrations of EFV
      were determined by h.p.l.c. RESULTS: No significant difference was found between
      the principal pharmacokinetic parameters of EFV when administered alone or in
      combination with NFV (mean AUC: 57.1-7727.3 vs 60.9+/-12.3 microg ml-1 h; mean
      CL/F: 0.18+/-0.072 vs 0.16+/-0.04 l h-1 kg-1; mean Cmax: 4.0+/-1.7 vs 4.3+/-1.2
      microg ml-1, and mean tmax: 4.1+/-1.7 vs 3.5+/-0.5 h) Mean trough plasma
      concentrations (C0) of EFV were 1.64+/-0.93 microg ml-1, with and without NFV. A
      good correlation was found between C0 and AUC(0,24h) (r=0.96; P<0. 01).
      CONCLUSIONS: Despite the common metabolic pathway, there was no significant
      influence of NFV on the pharmacokinetics of EFV. EFV exhibits a relatively low
      interindividual variability and a dosing regimen of 600 mg day-1 assures plasma
      concentrations that are adequate for inhibition of viral replication.

PMID- 10594474
TI  - CYP3A4 drug interactions: correlation of 10 in vitro probe substrates.
AB  - AIMS: Many substrates of cytochrome P450 (CYP) 3A4 are used for in vitro
      investigations of drug metabolism and potential drug-drug interactions. The aim
      of the present study was to determine the relationship between 10 commonly used
      CYP3A4 probes using modifiers with a range of inhibitory potency. METHODS: The
      effects of 34 compounds on CYP3A4-mediated metabolism were investigated in a
      recombinant CYP3A4 expression system. Inhibition of erythromycin,
      dextromethorphan and diazepam N-demethylation, testosterone 6beta-hydroxylation,
      midazolam 1-hydroxylation, triazolam 4-hydroxylation, nifedipine oxidation,
      cyclosporin oxidation, terfenadine C-hydroxylation and N-dealkylation and
      benzyloxyresorufin O-dealkylation was evaluated at the apparent Km or S50 (for
      substrates showing sigmoidicity) value for each substrate and at an inhibitor
      concentration of 30 microM. RESULTS: While all CYP3A4 probe substrates
      demonstrate some degree of similarity, examination of the coefficients of
      determination, together with difference and cluster analysis highlighted that
      seven substrates can be categorized into two distinct substrate groups.
      Erythromycin, cyclosporin and testosterone form the most closely related group
      and dextromethorphan, diazepam, midazolam and triazolam form a second group.
      Terfenadine can be equally well placed in either group, while nifedipine shows a
      distinctly different relationship. Benzyloxyresorufin shows the weakest
      correlation with all the other CYP3A4 probes. Modifiers that caused negligible
      inhibition or potent inhibition are generally comparable in all assays, however,
      the greatest variability is apparent with compounds causing, on average,
      intermediate inhibition. Modifiers of this type may cause substantial inhibition,
      no effect or even activation depending on the substrate employed. CONCLUSIONS: It
      is recommended that multiple CYP3A4 probes, representing each substrate group,
      are used for the in vitro assessment of CYP3A4-mediated drug interactions.

PMID- 10594475
TI  - Impact of gastric emptying on the pharmacokinetics of ethanol as influenced by
      cisapride.
AB  - AIMS: To examine the influence of cisapride on the pharmacokinetics of ethanol
      and the impact of gastric emptying monitored by the paracetamol absorption test.
      METHODS: Ten healthy male volunteers took part in a cross-over design experiment.
      They drank a moderate dose of ethanol 0.30 g kg-1 body weight exactly 1 h after
      eating breakfast either without any prior drug treatment or after taking
      cisapride (10 mg three times daily) for 4 consecutive days. In a separate study,
      the same dose of ethanol was ingested on an empty stomach (overnight fast).
      Paracetamol (1.5 g) was administered before consumption of ethanol to monitor
      gastric emptying. Venous blood was obtained at 5-10 min intervals for
      determination of ethanol by headspace gas chromatography and paracetamol was
      analysed in serum by high performance liquid chromatography (h.p.l.c.). Results
      The maximum blood-ethanol concentration (Cmax ) increased from 3.8+/-1.7 to 5.6+/
      2.3 mmol l-1 (+/-s.d.) after treatment with cisapride (95% confidence interval CI
      on mean difference 0.28-3.28 mmol l-1 ). The area under the blood-ethanol curve
      (AUC) increased from 6.3+/-3.5 to 7.9+/-2.6 mmol l-1 h after cisapride (95% CI 
      0. 74-3.9 mmol l-1 h). The mean blood ethanol curves in the cisapride and no-drug
      sessions converged at approximately 2 h after the start of drinking. Both Cmax
      and AUC were highest when the ethanol was ingested on an empty stomach (Cmax
      9.5+/-1.7 mmol l-1 and AUC 14. 6+/-1.9 mmol l-1 h), compared with drinking 1 h
      after a meal and regardless of pretreatment with cisapride. CONCLUSIONS: A small
      but statistically significant increase in Cmax occurred after treatment with
      cisapride owing to faster gastric emptying rate as shown by the paracetamol
      absorption test. However, the rate of absorption of ethanol, as reflected in Cmax
      and AUC, was greatest after drinking the alcohol on an empty stomach. The
      cisapride-ethanol interaction probably lacks any clinical or forensic
      significance.

PMID- 10594476
TI  - Effects of cytochrome P450 inducers on 17alpha-ethinyloestradiol (EE2)
      conjugation by primary human hepatocytes.
AB  - AIMS: Our objective was to elucidate further the underlying mechanism responsible
      for therapeutic failures observed with concomitant administration of the oral
      contraceptive 17alpha-ethinyloestradiol (EE2 ) and rifampicin. METHODS: We
      investigated both oxidative and direct conjugative [3H]-EE2 metabolism by human
      liver S9 fraction and the effect of known enzyme-inducing drugs using a human
      hepatocyte induction model in vitro. RESULTS: Cofactor dependent [3H]-EE2
      metabolism by human liver S9 fraction produced 2-hydroxy-[3H]-EE2, 2-methoxy-[3H]
      EE2, and direct [3H]-EE2 sulphate and glucuronide conjugates. Only two detectable
      metabolites of [3H]-EE2 were produced by the S9 fraction in the presence of all
      cofactors: [3H]-EE2-3-sulphate (75.7+/-7.6% s. d.) and 2-methoxy-3H-EE2 (2.6%+/
      0.5% s.d.). Human hepatocytes extensively metabolized [3H]-EE2 to its glucuronide
      and sulphate conjugates. Small amounts of a 2-methoxy-[3H]-EE2 3-conjugate, < or
      = 10%, was observed but no. 2-hydroxy-[3H]-EE2 was detected. An unexpected
      finding in our study was increased [3H]-EE2-3-sulphate production (1.5-3.3 fold,
      n=3 donor livers) by hepatocytes pretreated with rifampicin compared to control
      hepatocytes. No statistically significant increase in [3H]-EE2-3-sulphation was
      observed in hepatocytes pretreated with 3-methylcholanthrene, phenobarbitone,
      dexamethasone, or omeprazole over nontreated hepatocytes. To our knowledge, this
      is the first observation of sulphotransferase induction by rifampicin in human
      hepatocytes in vitro resulting in increased [3H]-EE2 sulphation. CONCLUSIONS: Our
      data indicate that the major EE2 metabolic products formed by human hepatocytes
      in vitro are direct EE2 conjugates with EE2 oxidation representing minor
      pathways. Further studies are required to establish the mechanism of
      sulphotransferase induction and the clinical relevance of our findings.

PMID- 10594477
TI  - Myocardial region (right or left ventricle) and aetiology of heart failure can
      influence the inotropic effect of ouabain in failing human myocardium.
AB  - AIMS: To investigate whether the inotropic effect of ouabain in failing human
      myocardium varies according to the heart chamber tested (right or left ventricle)
      or the aetiology of the heart disease, i.e. ischaemic or idiopathic. METHODS: The
      inotropic effect of ouabain was measured, as the percentage change in baseline
      tension, in myocardial strips isolated from right (RV; n=21) and left ventricles
      (LV; n=21) of hearts explanted from patients with idiopathic (IDC; n=11) and
      ischaemic cardiomyopathy (CAD; n=10). Concentration-effect curves obtained with
      ouabain (0.05-1.6 micromol l-1 ) were analysed using the Emax sigmoidal model,
      and the following parameters were calculated: Emax, EC50, n and EC10 (threshold
      concentration). The influence of ventricular chamber and heart failure aetiology
      on these parameters was evaluated by means of a two-way anova. RESULTS: Age and
      baseline haemodynamic parameters did not differ between IDC and CAD patients.
      Baseline strip contractility was highly variable (range: 0.48-10.0 mN), but
      neither ventricular chamber nor aetiology could explain such variability. A two
      way anova showed that EC10 was greater in CAD than in IDC preparations (0.097+/
      0.013 micromol l-1 vs 0.059+/-0. 009 micromol l-1; 95% C.I. for difference 0.043,
      0.071) and Emax was lower in RV than in LV (121+/-21% vs 250+/-38%; 95% C.I. 
      221, -36), while EC50 and n were not significantly different between groups.
      CONCLUSIONS: The inotropic effect of ouabain in human myocardium may vary
      according to aetiology of heart failure and the ventricle being tested. Although
      our results do not support the hypothesis of increased sensitivity to cardiac
      glycosides in CAD patients, they may explain the diminished effect observed in
      patients with RV failure.

PMID- 10594478
TI  - Rapid development of tolerance to dipyridamole-associated headaches.
AB  - AIMS: In the Second European Stroke Prevention Study headaches associated with
      dipyridamole frequently (8% of patients taking dipyridamole or dipyridamole plus
      acetylsalicylic acid (ASA) vs 2% of patients taking ASA or placebo) led to
      discontinuation of therapy. We have now used data from a recent trial comparing
      the bioequivalence of two formulations of the fixed combination of 200 mg
      dipyridamole in an extended release formulation and 25 mg ASA to explore
      predicting factors for headaches associated with this drug combination. METHODS:
      The bioequivalence trial employed a two-way crossover, randomised, open design.
      Trial medication was given for two periods of five days separated by a 72 h
      washout period. Statistical methods were employed to explore the prevalence, the
      time course, and the relation to individual pharmacokinetic parameters of
      treatment associated headaches. RESULTS: Headache episodes, being mostly mild and
      transient, rapidly declined from 67% of the volunteers on the first day of
      treatment to 3% on the final days of treatment (days 4-5 of the second period).
      During the first days the prevalence of the headaches peaked 2-3 h after the
      morning administration, which coincided with the peak of the plasma
      concentrations of dipyridamole. The occurrence of headaches was not related to
      interindividual differences of the pharmacokinetic parameters. CONCLUSIONS: The
      rapid decrease in the incidence of headaches over time implies that most patients
      quickly develop tolerance to dipyridamole-associated headaches. Appropriate
      information given to the patient when prescribing and dispensing dipyridamole/ASA
      may reduce early withdrawals from treatment and increase compliance.

PMID- 10594479
TI  - Raised aldosterone to renin ratio predicts antihypertensive efficacy of
      spironolactone: a prospective cohort follow-up study.
AB  - AIMS: Aldosterone/renin ratio is an index for inappropriate aldosterone activity,
      and it is increasingly being used to screen for primary aldosteronism within the
      hypertensive population. It may also be a good index to help predict the response
      to spironolactone. To assess the blood pressure response to oral spironolactone
      in hypertensive patients with primary aldosteronism identified with raised
      aldosterone to renin ratio. METHODS: We conducted a prospective cohort study of
      hypertensive patients with raised aldosterone/renin ratio, who failed to suppress
      plasma aldosterone with salt loading and fludrocortisone suppression test. These
      patients were treated with spironolactone and were followed-up for a period of up
      to 3 years. RESULTS: We studied 28 (12 male) subjects with a mean age of 55 (s.d.
      10) years who were followed up for a mean period of 12.9 (7) months. At baseline,
      the patients were taking a mean of 2.1 (1.2) antihypertensive drugs, but despite
      this 16/28 (57%) had diastolic BP >90 mmHg, 39% with systolic BP >160 mmHg. After
      commencing spironolactone, three patients complained of breast tenderness but
      continued treatment and one patient was intolerant of spironolactone and had to
      stop treatment. Of the remaining 27 patients, the mean number of antihypertensive
      drugs used dropped to spironolactone plus 0.7 (s.d. 0.9). All but one patient
      (96%) achieved a diastolic BP</=90 mmHg and 78% achieved a systolic BP</=160
      mmHg. In total 48% had BP</=140/90 mmHg and 13/27 (48%) were treated with
      spironolactone monotherapy. Assessing only patients on drug treatment at baseline
      (n=24), spironolactone significantly reduced the need for antihypertensive drugs
      by -0.5 (CI 0.1-1.0), P=0.02, as well as reducing blood pressure [systolic BP -15
      mmHg (CI 5-25), P=0.007 and diastolic BP (mmHg) by -8 mmHg (CI 4-13), P=0.001].
      CONCLUSIONS: Spironolactone was a highly effective antihypertensive agent in
      hypertensive patients who had a raised aldosterone/renin ratio. As a raised ratio
      was highly predictive of nonsuppression of plasma aldosterone suggesting primary
      aldosteronism, it might be worthwhile using spironolactone in this subgroup of
      hypertensive patients with raised aldosterone/renin ratios, provided that adrenal
      adenomas are excluded with imaging techniques.

PMID- 10594480
TI  - Population frequency, mutation linkage and analytical methodology for the
      Arg16Gly, Gln27Glu and Thr164Ile polymorphisms in the beta2-adrenergic receptor
      among Turks.
AB  - AIMS: Inherited polymorphisms of codons 16, 27, and 164 of the beta2-adrenergic
      receptor (B2AR) gene may result in significantly changed functions of this
      receptor. The aim of the present study was to investigate the frequencies of the
      main mutations of the B2AR gene in Turks. METHODS: A group of 104 unrelated
      Turkish subjects were analysed for the Arg16Gly, Gln27Glu, and Thr164Leu
      polymorphisms of B2AR by a newly designed polymerase chain reaction-restriction
      fragment length polymorphism (PCR-RFLP) assay. A 242-bp amplicon including the
      Arg16Gly and Gln27Glu polymorphisms was generated including an arbitrary
      restriction site, allowing the cleavage with Eco130I or Fnu4HI for analysis of
      the two polymorphic sites, respectively. For the amino acid polymorphism at codon
      164 a 280-bp fragment was generated and digested by MnlI. RESULTS: The allelic
      frequencies of mutated Gly16, Glu27, and Ile164 alleles were found as 59.6%,
      31.7%, and 0.5%, respectively. Although, the frequencies of the polymorphisms at
      codon 16 and 164 were found similar as in various Caucasian populations, the
      frequency of the Glu27 variant was found significantly lower than these
      populations. CONCLUSIONS: Obviously there are interethnic differences in
      functionally relevant B2AR variants which may have implications for drug
      treatment and disease susceptibility.

PMID- 10594481
TI  - The selective oestrogen receptor modulation: evolution and clinical applications.

PMID- 10594482
TI  - Thiopurine methyltransferase activity and its relationship to the occurrence of
      rejection episodes in paediatric renal transplant recipients treated with
      azathioprine.
AB  - AIMS: Azathioprine is a prodrug commonly used in combination therapy to prevent
      allograft rejection after renal transplantation. After conversion to 6
      mercaptopurine, the drug is metabolized into 6-thioguanine nucleotides (6-TGN)
      and catabolized by thiopurine methyltransferase (TPMT), an enzyme under monogenic
      control. The aim of this study was to evaluate the inter- and intraindividual
      variability of red blood cell thiopurine methyltransferase and 6-TGN
      concentrations and their relationship to the clinical effects of azathioprine in
      paediatric patients. METHODS: In the present study, the inter- and
      intraindividual variations in red blood cell TPMT activity and 6-TGN
      concentrations and their relationship to the actions of azathioprine were
      evaluated during the first year after renal transplantation in 22 paediatric
      patients. RESULTS: 6-TGN concentration reached steady-state values after 6 months
      and correlated negatively with TPMT activity (P=0.004). Initial TPMT activity
      (median: 20.8 nmol h-1 ml-1, range 7.8-34.6) and 6-TGN concentration at steady
      state (median: 80 pmol 8 x 10(8-1) cells, range not detected to 366) were not
      related to the occurrence of rejection episodes during the period of the study.
      In contrast, TPMT activity and the percentage difference in TPMT activity from
      the day of transplantation determined at month 1 were higher in the patients with
      rejection episodes by comparison with those that did not reject during the first
      3 months or the first year following transplantation (P<0.005). CONCLUSIONS: We
      report a relationship between TPMT activity and occurrence of rejection in
      paediatric kidney transplant patients undergoing azathioprine therapy. These data
      suggest a link between high red blood cell TPMT activity and poor clinical
      outcome probably caused by rapid azathioprine catabolism.

PMID- 10594483
TI  - Pharmacokinetic-pharmacodynamic model for fantofarone cardiac and brachial
      haemodynamic effects in healthy volunteers.
AB  - AIMS: To investigate the pharmacokinetics of SR 33671, the main active metabolite
      of the calcium antagonist fantofarone, and the relationships between its
      concentrations and pharmacodynamic effects after a single oral administration of
      two doses (100 and 300 mg) of fantofarone. METHODS: A placebo-controlled,
      randomized, double-blind and crossover study was performed in six healthy
      volunteers. SR 33671 plasma concentrations (C, ng ml-1 ) and effects (E) on heart
      rate (HR, beats min-1 ), PR interval duration (ms), brachial artery flow (BAF, ml
      min-1 ) and brachial vascular resistance (BVR, mmHg s ml-1 ) were determined
      repeatedly after drug intake. Haemodynamic effects were expressed as percent
      changes from initial values. Bi-exponential (pharmacokinetics), and linear
      [E=S.C+E0, for cardiac effects] or sigmoid [E=Emax.Cgamma/(CEgamma50+Cgamma ),
      for haemodynamic effects] models were fitted to individual data. RESULTS: Peak
      plasma concentrations and areas under the curve up to 24 h were (mean+/-s.d.)
      16+/-10 ng ml-1 and 157.50+/-89.13 ng ml-1 h, and 63+/-11 ng ml-1 and 535.50+/
      135.11 ng ml-1 h, after 100 and 300 mg, respectively. Terminal half-life was
      approximately 4 h. For pharmacodynamics, we obtained: S=-0.201+/-0.057 beats min
      1/ng ml-1 for HR, S=0.526+/-0.114 ms/ng ml-1 for PR interval duration, Emax=42+/
      6%, CE50=8.8+/-7.2 ng ml-1 and gamma=2.2+/-1.5 for BAF, and Emax=-28+/-4%,
      CE50=5.8+/-5.1 ng ml-1 and gamma=3.4+/-1.8 for BVR. At a SR 33671 concentration
      of 15 ng ml-1, BVR is decreased by 27% whereas HR is reduced by less than 3 beats
      min-1 and PR interval duration is increased by less than 8 ms. CONCLUSIONS:
      Fantofarone is able to induce submaximal peripheral vasodilating effects at doses
      that are devoid of any clinically significant cardiac effect.

PMID- 10594484
TI  - Glucuronidation and sulphation of paracetamol in HIV-positive patients and
      patients with AIDS.
AB  - AIMS: To gauge the effect of disease state and disease progression on the
      glucuronidation and sulphation of paracetamol (APAP) among HIV-positive patients
      and patients with AIDS. METHODS: The extent of APAP glucuronidation and APAP
      sulphation was assessed using a spot urine sample collected 4 h after the oral
      administration of 500 mg of APAP to 108 patients with AIDS or HIV infection. The
      molar concentrations of APAP and its glucuronide and sulphate metabolites were
      determined using a validated h.p.l.c. method and glucuronidation and sulphation
      indices were constructed using APAP metabolite/APAP molar concentration ratios.
      RESULTS: No effect of disease state, AIDS vs asymptomatic HIV positive vs
      control, on APAP glucuronidation or sulphation was observed. The patient
      population was studied over time and disease progression also did not
      significantly alter the calculated glucuronidation and sulphation indices. The
      effect of the concomitant administration of other therapeutic agents was assessed
      and in the cross sectional portion of the study dapsone appeared to significantly
      decrease APAP sulphation as did lamivudine. In the longitudinal portion of the
      study the latter effect was not observed but zidovudine was seen to increase APAP
      glucuronidation. The data also indicates that APAP glucuronidation may be reduced
      in patients who are >10% below their ideal body weight.

PMID- 10594485
TI  - Lack of interaction between thioctic acid, glibenclamide and acarbose.
AB  - AIMS: Thioctic acid (TA), glibenclamide and acarbose are widely used to either
      alone or concomitantly treat patients suffering from noninsulin-dependent
      diabetes (NIDDM). This study systematically investigated drug-drug interactions
      between TA and glibenclamide and TA and acarbose. METHODS: Fourteen male and 10
      female healthy volunteers participated a randomized, open three period cross over
      trial (treatments A-C) followed by a fourth period (treatment D). A baseline
      profile for plasma insulin and glucose concentrations, variables which served as
      pharmacodynamic measures, was assessed before entering the trial. Treatments were
      A=600 mg TA orally, B=3.5 mg glibenclamide orally, C=600 mg TA+3.5 mg
      glibenclamide, D=600 mg TA+50 mg acarbose. Time courses of R(+)-TA and S(-)-TA as
      well as glibenclamide concentrations were measured with specific analytical
      methods. RESULTS: There was no clinically relevant change of TA enantiomer
      pharmacokinetics by glibenclamide or acarbose. Also, glibenclamide
      pharmacokinetics were not altered by TA to a clinically meaningful extent. Plasma
      insulin and glucose concentrations did not indicate an interaction between TA and
      glibenclamide or TA and acarbose. Glibenclamide had the expected effect on
      insulin and glucose levels independent of comedication. There were only minor and
      short lasting adverse events with the majority being (expected) hypoglycaemic
      symptoms occurring during the treatments with glibenclamide. CONCLUSIONS:
      Coadministration of single doses of TA and glibenclamide or TA and acarbose does
      not appear to cause drug-drug interactions.

PMID- 10594486
TI  - Effects of bupivacaine on human erythrocytes submitted to stress and evidence for
      an interaction between bupivacaine and flumazenil.
AB  - AIMS: To examine the effects of bupivacaine on erythrocytes submitted to an
      oxidative stress (AAPH) and to provide evidence for an in vitro interaction
      between bupivacaine and flumazenil. METHODS: Human erythrocytes were studied with
      or without AAPH in the presence of different concentrations of bupivacaine (0.15,
      0.3, 0.9 and 1.8 mmol l-1 ), or flumazenil (0.16 mmol l-1 ) and with the
      association of flumazenil and two doses of bupivacaine (0.15 and 0.3 mmol l-1 ).
      Potassium efflux was measured by flame photometry at T0, and every 30 min for 2
      h. RESULTS: In the absence of AAPH, extracellular potassium remained unchanged.
      Oxidative stress induced a significant increase in extracellular potassium, which
      was not modified by incubation with flumazenil. Bupivacaine significantly lowered
      the increase in extracellular potassium in a dose-related fashion. The
      association with flumazenil blunted the effects of bupivacaine. Discussion In
      this model, bupivacaine proved effective in protecting erythrocytes against
      oxidative stress. Flumazenil interacted with bupivacaine and blunted its
      protective effects.

PMID- 10594487
TI  - Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin
      on the pharmacokinetics of quinidine.
AB  - AIMS: In vitro studies suggest that the oxidation of quinidine to 3
      hydroxyquinidine is a specific marker reaction for CYP3A4 activity. To assess the
      possible use of this reaction as an in vivo marker of CYP3A4 activity, we studied
      the involvement of cytochromes CYP2C9, CYP2E1 and CYP3A4 in the in vivo oxidative
      metabolism of quinidine. METHODS: An open study of 30 healthy young male
      volunteers was performed. The pharmacokinetics of a 200 mg single oral dose of
      quinidine was studied before and during daily administration of 100 mg
      diclofenac, a CYP2C9 substrate (n=6); 200 mg disulfiram, an inhibitor of CYP2E1
      (n=6); 100 mg itraconazole, an inhibitor of CYP3A4 (n=6); 250 ml single strength
      grapefruit juice twice daily, an inhibitor of CYP3A4 (n=6); 250 mg of
      erythromycin 4 times daily, an inhibitor of CYP3A4 (n=6). Probes of other enzyme
      activities, caffeine (CYP1A2), sparteine (CYP2D6), mephenytoin (CYP2C19),
      tolbutamide (CYP2C9) and cortisol (CYP3A4) were also studied. RESULTS:
      Concomitant administration of diclofenac reduced the partial clearance of
      quinidine by N-oxidation by 27%, while no effect was found for other
      pharmacokinetic parameters of quinidine. Concomitant administration of disulfiram
      did not alter any of the pharmacokinetic parameters of quinidine. Concomitant
      administration of itraconazole reduced quinidine total clearance, partial
      clearance by 3-hydroxylation and partial clearance by N-oxidation by 61, 84 and
      73%, respectively. The renal clearance was reduced by 60% and the elimination
      half-life increased by 35%. Concomitant administration of grapefruit juice
      reduced the total clearance of quinidine and its partial clearance by 3
      hydroxylation and N-oxidation by 15, 19 and 27%, respectively. The elimination
      half-life of quinidine was increased by 19%. The caffeine metabolic index was
      reduced by 25%. Concomitant administration of erythromycin reduced the total
      clearance of quinidine and its partial clearance by 3-hydroxylation and N
      oxidation by 34, 50 and 33%, respectively. Cmax was increased by 39%.
      CONCLUSIONS: The results confirm an important role for CYP3A4 in the oxidation of
      quinidine in vivo, and this applies particularly to the formation of 3
      hydroxyquinidine. While a minor contribution of CYP2C9 to the N-oxidation of
      quinidine is possible, a major involvement of the CYP2C9 or CYP2E1 enzymes in the
      oxidation of quinidine in vivo is unlikely.

PMID- 10594488
TI  - Cutaneous reactions to drugs. An analysis of spontaneous reports in four Italian
      regions.
AB  - AIMS: Cutaneous manifestations are frequently reported in association with drug
      use. The aim of this study was to analyse the skin reactions reported to the
      spontaneous surveillance systems of four Italian regions (Friuli Venezia Giulia,
      Lombardy, Sicily and the Veneto), and correlate the reports with estimated drug
      consumption during the same period, paying particular attention to the reactions
      to antimicrobial agents and nonsteroidal anti-inflammatory drugs (NSAIDs).
      METHODS: All of the adverse drug reactions (ADRs) reported spontaneously between
      January 1996 and December 1997 to the surveillance systems of four Italian
      regions (a total population of about 20 million people) were analysed by a panel
      of experts including dermatologists. On the basis of the Critical Term List of
      the World Health Organization (WHO), the reactions were classified as either
      serious or nonserious events. Drug consumption was expressed as a daily defined
      dose (DDD)/1000 inhabitants/day. RESULTS: A total of 2224 adverse skin reaction
      reports (44.7% of all of the reported ADRs) were identified, making a reporting
      rate of about 5.5 per 100 000 inhabitants/year. The female/male ratio was 1.58,
      and the reporting rate progressively increased with age. The drug categories with
      the highest number of cutaneous reactions were antimicrobials, followed by
      NSAIDs, analgesics and radiology contrast media. There was a total of 372 (16.9%)
      serious reaction reports, the most frequent being angioedema (171 cases),
      erythema multiforme (68 cases) and photosensitivity (37 cases). Co-trimoxazole,
      followed by the cephalosporins and fluoroquinolones, were associated with the
      highest consumption-related reporting rate among the antimicrobials, and aspirin
      and dipyrone among the NSAIDs and analgesics. CONCLUSIONS: Spontaneous reports
      from four Italian regions revealed that the skin was the organ most frequently
      affected by ADRs. The paper shows the validity of a regional decentralized system
      in Italy.

PMID- 10594489
TI  - A cohort study on the risk of acute liver injury among users of ketoconazole and
      other antifungal drugs.
AB  - AIMS: The aim of this cohort study was to estimate the risk of clinical acute
      liver injury among users of oral antifungals identified in the general population
      of the General Practice Research Database in UK. METHODS: The cohort included 69
      830 patients, 20-79 years old, free of liver and systemic disease, who had
      received at least one prescription for either oral fluconazole, griseofulvin,
      itraconazole, ketoconazole, or terbinafine between 1991 and 1996. RESULTS:
      Sixteen cases of acute liver injury were identified and validated. Ten cases
      occurred during nonuse of oral antifungals with a background rate of 0.6 per
      100,000 person-months (95% confidence interval 0.3,1.1). Five cases occurred
      during current use of oral antifungals. Two were using ketoconazole, another two
      itraconazole, and one terbinafine. Incidence rates of acute liver injury were
      134.1 per 100 000 person-months (36.8,488.0) for ketoconazole, 10.4 (2.9-38.1)
      for itraconazole, and 2.5 (0.4,13. 9) for terbinafine. The remaining case was
      associated with past use of fluconazole. Ketoconazole was the antifungal
      associated with the highest relative risk, 228.0 (95% confidence interval
      33.9,933.0), when compared with the risk among nonusers, followed by itraconazole
      and terbinafine with relative risks of 17.7 (2.6,72.6) and 4.2 (0.2, 24.9),
      respectively. CONCLUSIONS: Ketoconazole and itraconazole were the two oral
      antifungal associated with a marked increase of clinical acute liver injury. The
      risk associated with ketoconazole should be taken into account when prescribing
      it as initial treatment for uncomplicated fungal infections.

PMID- 10594490
TI  - Placebo effect in the treatment of duodenal ulcer.
AB  - AIMS: To assess whether frequency of placebo administration is associated with
      duodenal ulcer healing. METHODS: A systematic literature review of randomized
      clinical trials was undertaken. 79 of 80 trials that met the inclusion criteria.
      The pooled 4 week placebo healing rate of all duodenal ulcer trials that employed
      a four times a day regimen was compared with the rate obtained from trials with a
      twice a day regimen. RESULTS: The pooled 4 week healing rate of the 51 trials
      with a four times a day regimen was 44. 2% (805 of 1821 patients) compared with
      36.2% (545 of 1504 patients) in the 28 trials with a twice a day regimen
      (difference, 8.0% [equal effects model]; 95% confidence interval, 4.6% to 11.3%).
      Depending on the statistical analysis, the rate difference ranged from 6.0%
      (multivariable random effects model) to 8.0% (equal effects model). A number of
      sensitivity analyses showed comparable differences between the two regimens. Most
      of these sensitivity analyses were not significant, probably because a number of
      trials were excluded resulting in a loss of power. CONCLUSIONS: We found a
      relation between frequency of placebo administration and healing of duodenal
      ulcer. We realize that the comparison was based on nonrandomized data. However,
      we speculate that the difference between regimens was induced by the difference
      in frequency of placebo administration. A better knowledge of various placebo
      effects is required in order to make clinically relevant assessments of treatment
      effects derived from placebo-controlled trials.

PMID- 10594491
TI  - Angioedema due to ACE inhibitors: increased risk in patients of African origin.
AB  - AIMS: To determine patterns in presentation, risk factors, management and outcome
      of patients with ACE inhibitor associated angioedema in one British teaching
      hospital. METHODS: Cases of ACE inhibitor associated angioedema in patients
      presenting to the City Hospital, Birmingham between 1993 and 1999 were collected
      and entered prospectively onto a computerised register. RESULTS: A total of 20
      cases (mean age 60 years, range 42-82 years) of ACE inhibitor associated
      angioedema were reported (11 female and 9 male) with 65% (n=13) of patients being
      black/Afro-Caribbean. In 70% of cases (n=14), angioedema occurred within 4 weeks
      of starting therapy, although three patients presented following long-term
      treatment (24-48 months). ACE inhibitors were continued in 50% (n=10) patients,
      despite at least one documented episode of angioedema. Admission to hospital was
      necessary in 40% (n=8) patients, with three of these admitted to the intensive
      care unit, and one of these died as a result of severe laryngeal obstruction.
      CONCLUSIONS: ACE inhibitor related angioedema is a serious and potentially fatal
      complication which is relatively rare in the general population, but is more
      common amongst black/Afro-Caribbean patients. ACE inhibitors are frequently
      continued following an episode of angioedema and it is important that these
      episodes are minimised by prompt cessation of the drug, careful patient
      counselling and heightened awareness in all clinicians who prescribe this common
      group of drugs.

PMID- 10594492
TI  - Pharmacokinetics of chlorofluorocarbon and hydrofluoroalkane metered-dose inhaler
      formulations of beclomethasone dipropionate.
AB  - AIMS: To compare the pharmacokinetic profile of Beclazone (beclomethasone
      dipropionate) in its chlorofluorocarbon (CFC)-based and CFC-free formulations.
      METHODS: Ten healthy adults received a single 1,000 microg nominal dose (ex
      valve) of beclomethasone dipropionate from a CFC inhaler (BEC-CFC) or from a CFC
      free inhaler containing hydrofluoroalkane (HFA)-134a (BEC-HFA) in an open-label,
      randomized, two-way, crossover study. Blood samples were collected predose and
      over 12 h after inhalation. Comparisons were made of maximum plasma concentration
      of beclomethasone 17-monopropionate (17-BMP) (Cmax), and area under the plasma
      concentration vs time curve (AUC). RESULTS: The tmax was significantly (P<0.05)
      earlier with BEC-HFA and plasma levels were significantly higher following
      administration of BEC-HFA than BEC-CFC. Geometric mean values for AUC were 1.5
      fold greater (90% CI 1.3-1.9) and for Cmax were 1.9 fold greater (90% CI 1.6-2.6)
      following BEC-HFA than BEC-CFC. CONCLUSIONS: Our data in healthy volunteers would
      not be consistent with the manufacturers' recommendation for a microgram
      equivalent (1:1) nominal dose switch between these HFA and CFC formulations.
      Further well designed trials are required in asthmatic patients to properly
      define their respective dose-response relationships for antiasthmatic and
      systemic adverse effects.

PMID- 10594493
TI  - Flat adenomas.

PMID- 10594494
TI  - A patient declines mastectomy.

PMID- 10594495
TI  - Combined inguinal and pelvic lymph node dissection for stage III melanoma.
AB  - BACKGROUND: The incidence of melanoma is increasing in the UK and a significant
      number of patients are still presenting with primary lesions of poor prognosis.
      As a consequence there is likely to be an increasing number of patients with
      lymph node metastases for whom the appropriate extent of groin dissection remains
      controversial. This review summarizes the evidence to enable surgeons to make an
      informed decision about the management of patients with melanoma metastases to
      the groin lymph nodes. METHODS: A Medline search was performed to identify all
      English language articles about melanoma containing the words lymphadenectomy,
      lymph nodes, inguinal or lymphoedema. Eighty-seven relevant articles were
      selected from 3904 abstracts retrieved; 34 were related directly to the aim of
      this review. RESULTS: There are no randomized controlled trials comparing the
      outcome of combined inguinal and pelvic lymph node dissection (CLND) and
      superficial inguinal lymph node dissection (SLND). Excision of pelvic lymph node
      metastases is reported to yield a 5-year survival rate of 0-35 per cent.
      Recurrence within the pelvis occurs in 9-18 per cent of patients after SLND and
      in less than 5 per cent after CLND. Morbidity following either CLND or SLND is
      poorly reported. Major long-term lymphoedema limiting patient activity affects 6
      20 per cent of patients after groin dissection. Cloquet's node was demonstrated
      in one study to be a useful predictor of pelvic lymph node involvement. Patients
      may be selected for pelvic node dissection on the basis of clinical findings, the
      results of pelvic computed tomography and the status of Cloquet's node.
      CONCLUSION: The controversy surrounding the appropriate management of
      cytologically positive inguinal nodes in melanoma can be resolved only by a
      prospective randomized trial comparing CLND with SLND. Morbidity and local
      disease control must be measured as outcomes in addition to disease-free and
      overall survival.

PMID- 10594496
TI  - Xenotransplantation.
AB  - BACKGROUND: Over the past 10 years xenotransplantation has generated much
      interest in the hope that it will enable us to overcome the current lack of human
      organ donors. This review examines the evolution and current therapeutic
      strategies that have been developed to overcome the predominant problem of graft
      rejection. METHODS: A literature review was undertaken using a Medline search
      from January 1966 to August 1999. RESULTS AND CONCLUSION: Despite the
      considerable advances that have been made in molecular biological techniques,
      xenograft rejection cannot be prevented without significant immunosuppression and
      toxic side-effects. The problem of delayed rejection, in particular, will
      probably be very difficult to overcome, although some of the difficulties
      associated with hyperacute rejection have been resolved. The potential risk of
      porcine endogenous retrovirus transmission has generated much debate recently,
      but it is likely that some of the important issues relating to
      xenotransplantation will never be resolved until carefully regulated clinical
      trials are allowed to begin.

PMID- 10594497
TI  - Training opportunities in liver transplantation surgery.
AB  - BACKGROUND: Liver transplantation surgery is carried out in only a few selected
      centres in the UK. This study was performed with a view to identifying potential
      training opportunities available for the general and specialist higher surgical
      trainee, and also to assess the outcome following liver transplant surgery
      according to the grade of the surgeon performing the procedure. METHODS: Data on
      111 liver transplants with caval preservation undertaken consecutively in a
      single unit during a 32-month period were collected and analysed. The transplant
      procedures were grouped into those performed by consultants and those performed
      by supervised trainees. Survival was estimated by the Kaplan-Meier method. The
      Cox regression model was used to examine the influence of grade of the surgeon on
      survival. chi2 and independent sample t tests were used to identify significant
      preoperative, intraoperative and postoperative variables. RESULTS: Trainees
      carried out 34 recipient hepatectomies (31 per cent), 47 implant procedures (42
      per cent) and all 143 retrieval operations. The mean time taken by a supervised
      trainee to carry out a recipient hepatectomy and implantation was 183 and 44 min
      compared with 165 and 46 min for a consultant (P = 0. 22 and P = 0.44
      respectively). The mean intraoperative red cell requirement was 8 units for both
      consultants and trainees (P = 0.85). The overall patient survival rate was 88 per
      cent at 3 years and the grade of the surgeon made no difference to survival or
      the occurrence of complications (P > 0.05). CONCLUSION: The outcome following
      liver transplantation with caval preservation did not differ according to the
      grade of the surgeon performing the procedure. Extensive training opportunities
      are available to learn hepatobiliary and vascular surgical techniques in liver
      transplantation surgery.

PMID- 10594498
TI  - Emergency cholecystostomy and subsequent cholecystectomy for acute gallstone
      cholecystitis in the elderly.
AB  - BACKGROUND: The morbidity and mortality rates associated with acute cholecystitis
      are higher in the elderly. This study reports the results of treatment of acute
      cholecystitis in the elderly with emergency ultrasonographically guided
      percutaneous cholecystostomy followed by elective cholecystectomy after
      endoscopic treatment of any common bile duct stones diagnosed by percutaneous
      cholangiography. METHODS: From January 1989 to December 1998, 92 patients aged
      over 70 years were treated for acute gallstone cholecystitis. A group of 84
      patients with ultrasonographic signs of severe cholecystitis or an American
      Society of Anesthesiologists score of II to IV were submitted to
      ultrasonographically guided percutaneous cholecystostomy. Transcatheter
      cholangiography was performed in all patients and endoscopic sphincterotomy was
      performed before operation in patients with common bile duct stones. After
      resolution of the acute phase and treatment of any associated diseases, patients
      were submitted to cholecystectomy. RESULTS: Cholecystostomy was performed
      successfully in 83 patients and permitted resolution of the acute attack in all
      after a mean period of 1.8 days. Cholangiography yielded a diagnosis of non
      gallstone obstruction in one patient and common bile duct stones in 19 patients;
      preoperative endoscopic sphincterotomy and stone extraction was performed in 18
      patients. Elective cholecystectomy was then performed in 70 patients with no
      deaths and a morbidity rate of 24 per cent. CONCLUSION: Combining emergency
      ultrasonographically guided percutaneous cholecystostomy, preoperative endoscopic
      treatment of common bile duct stones and subsequent elective cholecystectomy
      constitutes an optimal treatment regimen for acute gallstone cholecystitis in
      selected elderly patients with a mortality rate of zero in the authors'
      experience.

PMID- 10594499
TI  - Gallbladder ascariasis: presentation and management.
AB  - BACKGROUND: As many as 1.5 billion people around the world harbour Ascaris
      lumbricoides in the digestive tract. Gallbladder ascariasis, although less common
      than bile duct ascariasis, is quite often seen in endemic areas. METHODS: Some
      1300 patients with hepatobiliary ascariasis, admitted between October 1992 and
      June 1998, were analysed prospectively. The clinical features and outcome of 56
      cases of gallbladder ascariasis are presented. RESULTS: Forty-seven patients were
      diagnosed by ultrasonography and nine were diagnosed at laparotomy. Only ten
      patients diagnosed by ultrasonography expelled the worms spontaneously, with
      resolution of symptoms and signs. The remaining 37 patients underwent
      cholecystectomy. CONCLUSION: Gallbladder ascariasis is a significant entity in
      endemic areas which usually requires cholecystectomy.

PMID- 10594500
TI  - Prospective study of chronic pain after groin hernia repair.
AB  - BACKGROUND: The aim was to provide a detailed description of any residual pain 1
      year after elective day-case open groin hernia repair under local anaesthesia.
      METHODS: This was a prospective consecutive case series study by questionnaire of
      500 consecutive operations in 466 unselected adult patients 1 year after surgery.
      Pain was scored (none, mild, moderate or severe) at rest, while coughing and
      during mobilization, and compared with similar data collected 1 and 4 weeks after
      operation. RESULTS: Some 419 questionnaires were returned (response rate 93 per
      cent); 20 patients had died within the year and 30 data sets from patients who
      had a subsequent operation during the study were excluded. Eighty patients (19
      per cent) reported some degree of pain, and 25 (6 per cent) had moderate or
      severe pain. Pain restricted daily function in 24 patients (6 per cent). The
      incidence of moderate or severe pain was higher after repair of recurrent than
      primary hernias (14 versus 3 per cent; P < 0.001). The risk of developing
      moderate or severe pain was increased in patients who had a high pain score 1
      week after operation (9 versus 3 per cent; P < 0.05) and also in patients who had
      moderate or severe pain 4 weeks after operation (24 versus 3 per cent; P <
      0.001). CONCLUSION: Chronic pain is a significant problem after open groin hernia
      repair. It may be worse after surgery for a recurrent hernia and may be predicted
      by the intensity of early postoperative pain.

PMID- 10594501
TI  - Clinicopathological study of intrapelvic cancer spread to the iliac area in lower
      rectal adenocarcinoma by serial sectioning.
AB  - BACKGROUND: The role of iliac lymphadenectomy in surgery for rectal cancer
      remains unknown. Detailed clinicopathological data on lateral cancer extension
      may be needed to determine the true role of this procedure. METHODS: Seventy
      consecutive patients with low rectal cancer who underwent systematic iliac
      lymphadenectomy between 1991 and 1995 were reviewed. The iliac area was divided
      into five regions: (1) middle rectal root, (2) internal iliac, (3) obturator, (4)
      common iliac and (5) external iliac. Iliac lymph nodes that were cancer-free
      based on conventional pathological examination were serially sectioned at 100
      microm intervals and re-examined for occult microscopic involvement. RESULTS:
      Occult microscopic foci were detected in five (7 per cent) of the 70 patients,
      and the overall incidence of lateral cancer spread was 24 per cent (17 of 70).
      Among patients without other sites of distant metastasis or circumferential
      involvement of the margin, the 5-year survival rate of those with lateral spread
      was 35 per cent. Although the prognosis of patients with cancer involving
      multiple iliac regions was poor, three of six patients with metastasis to only a
      single region were alive without disease at 3 years. CONCLUSION: Surgeons should
      be aware of the possibility of localized lateral spread, including microscopic
      metastasis, when determining the optimum procedure for iliac lymphadenectomy in
      patients with rectal cancer.

PMID- 10594502
TI  - Nitric oxide synthetase and Helicobacter pylori in patients undergoing
      appendicectomy.
AB  - BACKGROUND: This study was designed to determine whether Helicobacter pylori
      forms part of the normal microenvironment of the appendix, whether it plays a
      role in the pathogenesis of acute appendicitis, and whether it is associated with
      increased expression of inducible nitric oxide synthetase (iNOS) in appendicular
      macrophages. METHODS: Serology for H. pylori was performed on 51 consecutive
      patients undergoing emergency appendicectomy. Appendix samples were tested for
      urease activity, cultured and stained for H. pylori, graded according to the
      degree of inflammatory infiltrate, and probed immunohistochemically for iNOS
      expression. RESULTS: The mean age of the patients was 21 (range 7-51) years.
      Seventeen patients (33 per cent) were seropositive for H. pylori but no evidence
      of H. pylori was found in any appendix specimen. However, an enhanced
      inflammatory cell infiltration was observed in seropositive patients (P < 0.04)
      and the expression of macrophage iNOS in the mucosa of normal and inflamed
      appendix specimens was increased (P < 0.01). CONCLUSION: H. pylori does not
      colonize the appendix and is unlikely to be a pathogenic stimulus for
      appendicitis. Priming effects on mucosal immunology downstream from the foregut
      may occur after infection with H. pylori.

PMID- 10594503
TI  - Preliminary results of a multicentre trial of the electrically stimulated
      gracilis neoanal sphincter.
AB  - BACKGROUND: The electrically stimulated gracilis neoanal sphincter was initially
      developed to treat refractory incontinence. Good early results were reported from
      the two centres that pioneered the technique. The aim of this study was to assess
      the operation in a prospective multicentre setting. METHODS: The procedure was
      performed on 64 patients from seven centres worldwide and was performed in
      stages. All patients were evaluated clinically and manometrically before and
      after operation. RESULTS: There was a high incidence of infective and hardware
      related complications. At a median of 10 months following closure of the
      defunctioning stoma 56 per cent had experienced a good functional result. The
      major functional problems comprised evacuatory difficulties experienced by 25 per
      cent. CONCLUSION: The technique is effective in treating otherwise refractory
      incontinence. It is, however, a complex procedure and the morbidity rate may be
      high, particularly during the learning curve, factors that necessitate careful
      patient selection. Presented to the Association of Surgeons of Great Britain and
      Ireland in Bournemouth, UK, April 1997 and the European Council of Coloproctology
      in Edinburgh, UK, June 1997; and published in abstract form as Br J Surg 1997;
      88(Suppl): 39 and Int J Colorectal Dis 1997; 12: 144

PMID- 10594504
TI  - Patients' perception of surgical services in a district general hospital.
AB  - BACKGROUND: In addition to studying the outcomes of surgery in terms of mortality
      and morbidity rates and performance, it is also important to consider how
      patients perceive the delivery of the service given to them. METHODS: A patient
      satisfaction survey was carried out by the Surgical Epidemiology and Audit Unit
      of the Royal College of Surgeons of England, on patients undergoing surgical
      procedures by the Department of Surgery at Wrexham Maelor Hospital. No day cases
      were included in the study. Two hospitals in southern England (undergoing the
      same survey) designated X and Y were used for comparison. RESULTS: Some 2000
      questionnaires were sent out twice; 1666 subjects (83 per cent) responded to the
      first questionnaire and 1445 (87 per cent) of these responded to a second
      questionnaire 6 weeks later (overall response 72 per cent). A total of 35 per
      cent of patients were older than 65 years of age. Some 76 per cent of patients
      with a malignant condition were seen within 4 weeks of referral compared with 38
      per cent of those with a benign condition (P < 0.0001). A total of 78 per cent of
      patients with cancer were admitted within 4 weeks compared with 84 and 88 per
      cent in hospitals X and Y. Some 23 per cent of patients were admitted as an
      emergency. Eighteen per cent of patients did not know who presented a consent
      form to them before surgery compared with 13 and 17 per cent in hospitals X and Y
      (P < 0.0001). Some 26 per cent of patients perceived that they had complications
      after surgery compared with 27 and 25 per cent for hospitals X and Y. A total of
      35 per cent of patients did not receive a follow-up appointment and 20 per cent
      of these patients were unhappy about this. Two areas of major concern revealed by
      the responses were the lack of written information and the overall poor scores
      generally attained by the emergency admission ward. However, 94 per cent of
      patients said that they would return to the same consultant. CONCLUSION: Patients
      were generally happy with their surgical care and there was little difference
      between the three hospitals studied. Lower scores were given when patients were
      admitted to emergency admission wards. Higher scores were given when patients
      received printed information.

PMID- 10594505
TI  - Prognosis after breast recurrence following conservative surgery and radiotherapy
      in patients with node-negative breast cancer.
AB  - BACKGROUND: Breast conservation surgery with radiotherapy is a safe and effective
      alternative to mastectomy for early-stage breast cancer. This retrospective study
      examined the outcome of patients with isolated local recurrence following
      conservative surgery and radiotherapy in node-negative breast cancer. METHODS:
      Between November 1979 and December 1994, 503 women with node-negative breast
      cancer were treated by conservation surgery and radiotherapy without adjuvant
      systemic therapy. RESULTS: After a median follow-up of 73 months the 5-year rate
      of freedom from local recurrence was 94 per cent. Thirty-five patients developed
      an isolated local recurrence within the breast as a first event. Thirty-three
      patients were treated with salvage mastectomy and two patients were treated with
      systemic therapy alone. The 5-year rate of freedom from second relapse was 46 per
      cent and the overall 5-year survival rate was 59 per cent for patients who had
      salvage mastectomy. Patients who developed breast recurrence as a first event had
      a 3.25 greater risk of developing distant metastasis (P < 0.001) than those who
      did not have breast recurrence as a first event. CONCLUSION: Salvage mastectomy
      after local recurrence was an appropriate treatment if there was no evidence of
      distant metastasis. Breast recurrence after conservative surgery and radiotherapy
      in node-negative breast cancer predicted an increased risk of distant relapse.

PMID- 10594506
TI  - Endoscopically assisted, minimally invasive parathyroidectomy.
AB  - BACKGROUND: Despite the success of open parathyroid exploration, minimally
      invasive alternatives have been emerging. This study reports an experience with
      endoscopically assisted, minimally invasive parathyroidectomy and evaluates its
      current role in patients undergoing surgery for hyperparathyroidism. METHODS: One
      hundred consecutive patients requiring surgery for hyperparathyroidism were
      evaluated. Endoscopic parathyroidectomy was offered based on the absence of
      coexisting nodular thyroid disease, previous neck surgery or irradiation,
      suspicion of parathyroid hyperplasia, or other anatomical or medical
      contraindications. Some 24 of 100 patients fulfilled the criteria and underwent
      endoscopic parathyroidectomy. Unequivocal localization to a single site by a
      technetium-99m-radiolabelled sestamibi scan allowed removal of the adenoma
      through a 25-mm suprasternal incision while being guided by a surgical telescope.
      RESULTS: There were no statistically significant differences in operating time or
      the mean size of resected adenomas between patients undergoing endoscopic and
      open parathyroidectomy. Four patients required conversion to an open procedure.
      Two patients developed temporary recurrent laryngeal nerve paresis and one had
      persistent hyperparathyroidism. CONCLUSION: Although endoscopic parathyroidectomy
      is technically feasible, its applicability is limited to a minority of patients
      undergoing operation for hyperparathyroidism. The potential for higher
      complication and failure rates makes optimism for the procedure appropriately
      guarded.

PMID- 10594507
TI  - Complexity- and risk-adjusted model for measuring surgical outcome.
AB  - BACKGROUND: Although currently available surgical scoring systems have good
      outcome predictive power, their use is often limited by complexity and their non
      dynamic nature. The aim of this study was to develop and test a risk adjustment
      for general surgical audit which is both simple and dynamic, while preserving a
      high predictive power for surgical morbidity. METHODS: Twelve easily measured,
      well defined prognostic variables for morbidity were identified from the Otago
      Surgical Audit data collection form and stratified into suitable categories.
      Logistic regression was used to adjust for confounding between factors,
      identifying risk factors with the strongest prognostic value for the outcome of
      severe and intermediate complications. The resulting model was tested by back
      validation and validation. RESULTS: The derived risk adjustment included all 12
      variables. Adjusted odds ratios for all variables were markedly lower than
      unadjusted values. After logistic regression, the strongest predictors of
      postoperative morbidity were duration of operation, operation category, inpatient
      status and organ system in which the procedure was carried out. The area under
      the receiver operating characteristic curve was 0.86. CONCLUSION: A simple
      dynamic model for surgical morbidity has been developed which is comparable to
      previously published surgical scoring systems in terms of predictive power. This
      risk adjustment tool can be incorporated into the existing audit system, enabling
      comparison of surgical unit performance.

PMID- 10594508
TI  - Fatal and life-threatening complications in antireflux surgery: analysis of 5,502
      operations.
AB  - BACKGROUND: There have been few comprehensive studies relating to the life
      threatening or fatal complications of antireflux surgery. METHODS: Some 5502
      antireflux operations were performed in Finland between January 1987 and January
      1996 (population approximately 5 million); 3993 procedures (72.6 per cent) were
      open fundoplications, 1162 (21.1 per cent) laparoscopic fundoplications and 347
      (6.3 per cent) other anti-reflux procedures. RESULTS: There were 43 fatal or life
      threatening complications (prevalence 0.8 per cent). Twenty-two followed primary
      open fundoplication (prevalence 0.6 per cent), 15 laparoscopic fundoplication
      (prevalence 1.3 per cent) (P < 0.05), one refundoplication and five other
      antireflux procedures. The overall mortality rate was 0.3 per cent. Nine patients
      (0.2 per cent) died after open fundoplication, one (0.1 per cent) following
      laparoscopic fundoplication (P = 0.43), one following refundoplication and four
      after other antireflux procedures. Laparoscopic fundoplication was followed by 14
      non-fatal life-threatening complications (prevalence 1.2 per cent), open
      fundoplication by 13 (prevalence 0.3 per cent) (P < 0.01) and other antireflux
      procedures by one life-threatening complication (0.3 per cent). CONCLUSION:
      Laparoscopic fundoplication was associated with more life-threatening
      complications than open fundoplication. This may compromise the advantages of the
      laparoscopic technique.

PMID- 10594509
TI  - Value of a surgical high-dependency unit.
AB  - BACKGROUND: A minority of hospitals in the UK have a high-dependency unit (HDU).
      One reason for this is a lack of evidence supporting its benefit. This study
      sought to compare the outcomes of patients undergoing major abdominal surgery
      with regard to HDU utilization. METHODS: Data were collected prospectively from
      two groups of patients over 10 months. Patients in the no-HDU group underwent
      major abdominal surgery in a hospital without an HDU and returned to a general
      surgical ward. The other group was managed initially in an HDU. Data collected
      included Physiological and Operative Severity Score for enUmeration of Mortality
      and morbidity (POSSUM) scores, complications, deaths and length of stay. RESULTS:
      Physiological and operative scores as calculated on the RAJIS POSSUM software
      were similar in both groups. The HDU group comprised 121 patients. Sixty-four
      developed a complication whereas 58.81 were expected to, giving an observed :
      expected (O : E) ratio of 1.09. Sixteen deaths occurred and 14.54 were expected
      (O : E ratio 1.10). Some 50 per cent stayed in hospital longer than was
      predicted. The no-HDU group comprised 71 patients. Fifty-nine developed a
      complication compared with 33.82 expected (O : E ratio 1.74). Ten deaths
      occurred, whereas 8.88 were expected, giving an O : E ratio of 1.13. Some 63 per
      cent stayed longer than predicted. The O : E ratios for morbidity were
      significantly different (P < 0.0005). The complications that occurred more
      frequently in the absence of an HDU were chest infection, arrhythmias and
      hypotension. CONCLUSION: Postoperative management on an HDU was associated with
      fewer cardiorespiratory complications. There was no difference in mortality rate
      but there was a trend towards shorter hospital stay.

PMID- 10594510
TI  - Vocal cord paralysis after subtotal oesophagectomy.
AB  - BACKGROUND: Although vocal cord paralysis is a well known complication of
      subtotal oesophagectomy, precise data concerning origin, incidence and associated
      morbidity are lacking. METHODS: A retrospective study was performed of 241
      patients who underwent transhiatal oesophagectomy for carcinoma of the mid/distal
      oesophagus between 1994 and 1998. Preoperative and postoperative laryngoscopy
      results were available for 140 patients. RESULTS: There were 109 men and 31
      women, of mean age 63 years. Thirty-one patients (22 per cent) with recurrent
      laryngeal nerve paralysis were identified, three with bilateral and 28 with
      unilateral dysfunction. Paralysis occurred ipsilateral to the side of the
      cervical incision in 22 of 28 patients. It was permanent in six patients. The
      associated morbidity was substantial: pulmonary complications were more common in
      patients with vocal cord paralysis (12 of 31 versus 26 (24 per cent) of 109),
      leading to significantly more reintubations, and a significantly prolonged
      ventilation time and stay in the intensive care unit. CONCLUSION: Although mostly
      transient, vocal cord paralysis is a frequent complication with significant
      associated morbidity. In an extended transthoracic resection (including a
      lymphadenectomy in the aortopulmonary window where the left recurrent laryngeal
      nerve is at risk) the cervical anastomosis should be made on the left side, to
      minimize the risk of bilateral vocal cord paralysis.

PMID- 10594511
TI  - Scientific surgery

PMID- 10594512
TI  - Aetiology-specific effect of premature ovarian failure on bone mass - is residual
      ovarian function important?

PMID- 10594513
TI  - Relationship between ovarian cortisol:cortisone ratios and the clinical outcome
      of in vitro fertilization and embryo transfer (IVF-ET).
AB  - OBJECTIVE: Previously, we have reported an association between low levels of
      intraovarian cortisol metabolism, mediated by 11beta-hydroxysteroid dehydrogenase
      (11betaHSD), and the establishment of pregnancies by in vitro fertilization and
      embryo transfer (IVF-ET). The objective of the present study was to investigate
      the relationship between the clinical outcome of IVF-ET and the intraovarian
      concentrations of cortisol and cortisone and the cortisol:cortisone ratios in
      random samples of ovarian follicular fluid (FF). DESIGN: Retrospective, double
      blind correlation analyses. PATIENTS: FF samples (n = 41) were obtained from 23
      women undergoing gonadotrophin-stimulated IVF-ET cycles at the Cardiff Assisted
      Reproduction Unit. MEASUREMENTS: Clinical pregnancy was confirmed by
      ultrasonography. Intrafollicular steroid concentrations were measured by
      radioimmunoassays. RESULTS: Concentrations of both cortisol and cortisone were
      significantly lower in FF samples obtained from 6 patients that conceived than in
      samples obtained from 17 patients that did not achieve pregnancy (cortisol (mean
      +/- SEM) = 304 +/- 29 vs. 407 +/- 26 nmol/l, P = 0. 0411; cortisone = 32 +/- 3
      vs. 65 +/- 7 nmol/l, P = 0.0002). Intrafollicular cortisol:cortisone ratios were
      significantly higher in samples from conception cycles than in those samples
      obtained from nonconception cycles (9.7 +/- 0.7 vs. 6.9 +/- 0.5, respectively, P
      = 0.0060). Whereas 5 of 10 women with intrafollicular cortisol:cortisone ratios
      greater than the outcome-independent mean of 7.7 became pregnant, only 1 of the
      13 patients with intrafollicular cortisol:cortisone ratios < 7.7 conceived (chi2
      = 5. 247, P = 0.0220). CONCLUSIONS: Concentrations of both cortisol and cortisone
      were significantly lower in FF samples obtained from patients that conceived by
      IVF-ET than in those obtained from nonconception cycles. Conception by
      gonadotrophin-stimulated IVF-ET was associated with an elevated intrafollicular
      ratio of cortisol:cortisone, consistent with a low level of intraovarian cortisol
      oxidation by 11betaHSD.

PMID- 10594514
TI  - In vitro and in vivo responses to short-term recombinant human insulin-like
      growth factor-1 (IGF-I) in a severely growth-retarded girl with ring chromosome
      15 and deletion of a single allele for the type 1 IGF receptor gene.
AB  - OBJECTIVES: Patients with single allele defects in the gene encoding the type 1
      IGF receptor have been reported to have growth failure, but fibroblasts from
      affected patients have not exhibited insensitivity to the effects of IGF-I in
      vitro. The in vitro and in vivo responses to short-term recombinant human IGF-I
      (rhIGF-I) in a severely growth-retarded girl with ring chromosome 15 and deletion
      of a single allele for the type 1 IGF receptor gene have been investigated.
      DESIGN AND PATIENT: The child exhibited prenatal and severe post-natal growth
      failure, and delayed psychomotor development. Southern blotting revealed a 50%
      reduction in IGF-I receptor DNA, and in an RNase protection assay (RPA), a
      quantitatively similar reduction in steady-state mRNA for type 1 IGF receptor.
      rhIGF-I was administered in graded doses of 40, 60 and 80 microg/kg twice daily
      by subcutaneous injection for periods of 2-2.5 days each. RESULTS: During rhIGF-I
      treatment, mean urinary nitrogen excretion was unchanged and urinary calcium rose
      to 60% greater than in the pre-treatment period. rhIGF-I injections produced only
      a modest decrease in indices of GH secretion, assessed by frequent (every 20 min)
      sampling over periods of 12 h. There was no significant difference between the
      mean GH concentrations during rhIGF-I treatment (5.32 +/- 6.2 mU/l) compared with
      that before rhIGF-I treatment (8.46 +/- 10.2 mU/l). Mean IGFBP-3-values were
      increased (4.5 mg/l before vs. 5.4 mg/l during rhIGF-I). TSH values after
      injection of TRH were not significantly reduced by IGF-I (mean of all values,
      18.6 mU/l vs. 15.5 mU/l during rhIGF-I treatment). In vitro binding of
      radiolabelled IGF-I to the patient's fibroblasts was less than that bound by
      control fibroblasts (patient, 0.69% binding by 248 000 cells, vs. 1.41% binding
      by 260 000 fibroblasts from an age-matched control). However, the patient's
      fibroblasts exhibited a growth response in vitro to the addition of IGF-I in a
      fashion similar to that of control fibroblasts. CONCLUSIONS: These studies show
      evidence in each of the indices examined of in vivo resistance to IGF-I and
      suggest that the growth retardation observed in such patients may be the direct
      result of the absence of one of the alleles encoding the type 1 IGF receptor.

PMID- 10594515
TI  - How many tests are required to diagnose growth hormone (GH) deficiency in adults?
AB  - OBJECTIVE: The diagnosis of GH deficiency in adults relies on the results of GH
      provocative testing. Whilst in some patients the testing strategy is clear, this
      is not the case in all patients. The objective of this study was to further
      examine the concordance between the GH responses to two different provocative
      stimuli, to correlate this with the number of additional pituitary hormone
      deficits, and to produce guidelines as to which patients require two GH
      provocative tests and which require only one. STUDY DESIGN AND PATIENTS: The
      results of GH provocative tests were reviewed in 103 patients (mean age 28 years,
      48 male), with documented or potential hypothalamic-pituitary disease and 35
      normal volunteers (mean age 21 years, 18 male). All patients and normal
      volunteers underwent an insulin tolerance test (ITT) and an arginine stimulation
      test (AST). Severe GH deficiency was defined as a GH response to an ITT of < 5
      mU/l and a GH response to an AST of < 2 mU/l, utilizing data from previous
      studies in this unit. Patients were divided into four groups according to the
      number of anterior pituitary hormone deficits present other than possible GH
      deficiency: no other pituitary hormone deficits (GHD0) or one, two or three other
      hormone deficits (GHD1, GHD2 or GHD3). RESULTS: The 103 patients were divided
      between the four groups as follows: 69 (67%) in GHD0, 15 (14. 6%) in GHD1, six
      (5.8%) in GHD2, and 13 (12.6%) in GHD3. There was a significant decline in the
      median GH peak to both the ITT and the AST with increasing numbers of other
      pituitary hormone deficits (P < 0.0001). If the magnitude of the difference
      between each individual's GH response to the ITT and AST is plotted against the
      mean GH value a clear trend is seen (Spearmans rank correlation = 0. 88, P <
      0.0001) indicating that the magnitude of the difference between the GH responses
      to an ITT and AST increases with the underlying mean GH value. These data allow
      the estimation of the median ITT/AST ratio as 1.17 (CI 0.98, 1.39). None of the
      control subjects and 14.1% (10), 26.7% (four), 83% (five) and 92.3% (12) of
      groups GHD0, 1, 2 and 3, respectively, had severe GHD. The concordance between
      the AST and ITT (percent of patients in whom both tests confirmed or refuted the
      biochemical diagnosis of severe GHD) was 100%, 76.8%, 66.6%, 83.3%, and 92.3% in
      the controls, GHD0, 1, 2, and 3, respectively. Thus, 16/69 GHD0, 5/15 GHD1, 1/6
      GHD2 and 1/13 GHD3 patients were misclassified by one or other test. CONCLUSION:
      We have demonstrated that a constant ratio links the GH response to an ITT and
      AST in an individual, rather than a constant difference, and that the difference
      between the GH responses to two provocative stimuli is greater in those patients
      with milder degrees of GH deficiency or insufficiency. These patients tend to
      have one or no additional pituitary hormone deficits and may be misclassified if
      a single GH provocative test is performed. We suggest that whilst a single GH
      provocative test can be used with confidence in patients with two or three
      additional pituitary hormone deficits, in patients with suspected isolated GH
      deficiency or with only one additional pituitary hormone deficit, two GH
      provocative tests should be performed.

PMID- 10594516
TI  - Serum leptin and body composition in children with familial GH deficiency (GHD)
      due to a mutation in the growth hormone-releasing hormone (GHRH) receptor.
AB  - OBJECTIVE: The relationship between GH, body composition and leptin in children
      remains ill-defined. We have therefore examined the impact of severe GH
      deficiency (GHD) due to a mutation in the GHRH receptor on serum leptin
      concentrations and body composition in childhood. PATIENTS: 12 affected children
      and young people (GHD) (4 M:8F, age 5.4-20.1 years, 8 Tanner stage (TS) 1-2, 4 TS
      3-5) and 40 healthy controls (C) from the same region (13 M:27F, age 5.3-18.4
      years, 20 TS 1-2, 20 TS 3-5). METHODS: Percent body fat was determined by infra
      red interactance, from which the amounts of fat mass (FM, kg) and fat free mass
      (FFM, kg) were derived. Serum leptin concentrations were measured in a single
      fasted, morning serum sample and results expressed as a concentration and as
      leptin per unit fat mass (L/FM, ng/ml/kg). To control for differences in sex and
      pubertal maturation, leptin standard deviation scores (leptin SDS) were
      calculated using normative data from UK children. RESULTS: FFM was significantly
      lower in GHD children than in controls (TS 1-2 P < 0.05, TS 3-5 P < 0.001). FM
      did not differ significantly between the two groups. Serum leptin concentrations,
      leptin per unit fat mass and leptin SDS were significantly elevated in GHD
      children both peripubertal and pubertal compared with controls. Using all
      subjects, stepwise multiple linear regression with FM, FFM, age, puberty and sex
      as explanatory variables and leptin concentration as the dependent variable
      indicated that 59% of the variability in leptin could be accounted for by FM (+,
      45%), FFM (-, 9%) and sex (+, 5%) (P < 0.001). However on inclusion of GH
      deficiency (coded GHD = 1, control = 2) as an explanatory variable 73% of the
      variability in leptin was explained by FM (+, 45%), GHD (-, 22%) and sex (+, 6%)
      (P < 0.001). CONCLUSIONS: These data indicate that severe GH deficiency in
      children is associated with elevated leptin concentrations, irrespective of sex
      or pubertal stage. This increase is not associated with differences in fat mass
      but is related to reduced fat free mass in GH deficiency. Furthermore in this
      population there may be an additional effect of GH deficiency on leptin,
      independent of the influences of sex and body composition.

PMID- 10594517
TI  - Influences on quality of life in GH deficient adults and their effect on response
      to treatment.
AB  - OBJECTIVE: Studies of the effect of GH on quality of life (QOL) in growth hormone
      deficient (GHD) adults have reported conflicting results. Recently, however, we
      have demonstrated that by selecting only those patients with impaired QOL the
      efficacy of GH replacement on QOL can be greatly improved. The improvement in QOL
      was observed to correlate significantly with that recorded before commencing GH
      therapy. This study aims to assess if demographic variables affect QOL in
      untreated GHD adults or the improvement in QOL following GH therapy. DESIGN: An
      open study of GH replacement, initiating treatment with a dose of 0.8 IU/day and
      titrating the dose by 0.4 IU increments to normalize the IGF-I SDS between - 2.0
      and + 2.0 SD of the age related normal range. PATIENTS: 65 severely GHD patients
      (peak GH < 9 mU/l to provocative testing), mean age 38.7 (range 17-72) years.
      Inclusion criterion was that of subjectively poor quality of life on clinical
      interview. MEASUREMENTS: Blood was taken for insulin-like growth factor 1 (IGF
      I). The Psychological General Well-Being Schedule (PGWB) and Adult Growth Hormone
      Deficiency Assessment (AGHDA) self-rating questionnaires were used to assess
      quality of life at baseline, three and eight months after commencing GH. RESULTS:
      The patients were subgrouped on the basis of gender, age of onset of GHD,
      pathology and presence of additional pituitary hormone deficits. The cohort
      consisted of 40 females and 25 males, 45 of adult-onset (AO) and 20 of childhood
      onset (CO). GH deficiency resulted from a hypothalamo-pituitary pathology, or
      treatment thereof, in 36 patients and as a result of cranial irradiation for a
      primary brain tumour or prophylaxis in acute lymphoblastic leukaemia in 29
      patients. Isolated GH deficiency (IGHD) was present in 25 patients, and 32
      patients were demonstrated to have at least two additional pituitary hormone
      deficits (MPHD). No significant difference was detected between baseline PGWB
      scores of the subgroups. Multiple linear regression analysis revealed the age of
      onset of GHD to be a significant determinant of both the baseline PGWB (P = 0.05)
      and AGHDA (P = 0.025) scores, AO patients perceiving the greater distress. A
      significant improvement, from baseline, in both QOL scores was observed in all
      subgroups at three months, and in all subgroups at eight months except IGHD,
      where a trend towards improvement in the AGHDA score was observed but failed to
      reach significance. The mean improvement in the PGWB following GH therapy was not
      significantly different between subgroups. Multiple linear regression analysis
      confirmed baseline PGWB and AGHDA scores to be the most important variable in
      prediction of the level of improvement in respective scores following GH therapy.
      Age of onset was also observed to be a significant determinant of the PGWB scores
      following GH therapy (P = 0.02), the CO cohort experiencing the greater
      improvement. A similar relationship between age of onset and AGHDA scores was not
      observed (P = 0.22). CONCLUSIONS: Baseline QOL as assessed by self-rating
      questionnaires is influenced by the age of onset of the GH deficiency, adult
      onset patients expressing the greater distress. Improvements in QOL scores are
      influenced by both baseline score and to a lesser extent the age of onset of GHD,
      the greater improvement being observed in childhood onset patients. The degree of
      improvement was observed to be independent of gender, pathology and number of
      pituitary hormone deficits. In a cohort selected by subjectively impaired QOL, we
      have demonstrated childhood onset GHD patients perceive themselves to have less
      impairment of QOL pretreatment. In contrast to previous data in unselected
      cohorts, however, we have shown that those childhood onset GHD patients in whom
      QOL is significantly reduced, show a capacity for improvement that is equal to,
      if not greater, than that seen in adult onset-GHD patients.

PMID- 10594518
TI  - The relative roles of continuous growth hormone-releasing hormone (GHRH(1-29)NH2)
      and intermittent somatostatin(1-14)(SS) in growth hormone (GH) pulse generation:
      studies in normal and post cranial irradiated individuals.
AB  - OBJECTIVES: Pulsatile GH release in humans is thought to involve the coordinated
      interaction of growth hormone-releasing hormone (GHRH) and somatostatin (SS).
      Disordered GH secretion is seen in most patients following high dose (> 30 Gy)
      cranial irradiation in childhood and could result from dysregulation of these
      hypothalamic hormones or reflect direct pituitary damage. We have used a peptide
      'clamp' to assess the relative roles of continuous GHRH and intermittent SS in GH
      pulse generation in healthy volunteers and short-and long-term survivors of
      childhood brain tumours. DESIGN: Randomized controlled study. PATIENTS: 12 adult
      male long-term survivors of childhood brain tumours (median age 17.0 years (15.2
      19. 7); 12.2 years (5.8-14.0) postradiotherapy, > 30Gy whole brain irradiation)
      with 9 matched control volunteers and 6 short-term survivors of childhood brain
      tumours (median age 6.4 years (5.9-7. 7); 2.5 years (1.7-3.6) post radiotherapy,
      > 30Gy whole brain irradiation) with 6 matched controls (studies of spontaneous
      GH release alone). MEASUREMENTS: Serum GH concentrations in 24 h spontaneous GH
      profiles and during three 'clamp' studies: continuous GHRH(1-29)NH2 (60
      ng/kg/minutes, subcutaneous infusion, 24 h); intermittent SS(1-14) withdrawal
      (20microg/m2/hour, intravenous infusion, 3 h on/1 h off, 2-3 cycles over 8-12 h);
      intermittent SS and continuous GHRH combined (2-3 cycles over 8-12 h). Data were
      analysed by spectral analysis, 'peak' and 'trough' determination and serial array
      averaging. RESULTS: In normal adults, discrete pulsatility was seen in all
      profiles of spontaneous GH secretion. Continuous GHRH amplified peak GH
      concentrations (median basal peak 21.1 mU/l vs. GHRH 62.0 mU/l, P = 0.008) whilst
      pulse timing remained unaffected. Rebound GH release following SS withdrawal
      alone was variable. Combining continuous GHRH with intermittent SS produced
      regular GH responses upon SS withdrawal (20.3 mU/l; range 2. 3-105.4).
      Heterogeneous patterns of spontaneous GH release were seen in the irradiated
      subjects. Spontaneous peak GH release was reduced in the children following
      irradiation (Irradiation 14.9 mU/l vs. Control 25.1 mU/l, P = 0.007). Peak GH
      concentrations were significantly amplified by GHRH in half of them. Adult long
      term survivors had lower spontaneous GH concentrations and continuous GHRH
      amplified GH release in most subjects (Spontaneous 4.2 mU/l vs. GHRH 6.5 mU/l, P
      = 0.008) but peak concentrations remained far less than those of controls.
      Combining intermittent SS with continuous GHRH regularized GH release in many
      patients but the GH responses remained attenuated (4.6 mU/l; 2.5-17.5).
      CONCLUSION: GH pulsatility can be generated in normal volunteers by the
      combination of continuous GHRH and intermittent SS and provides indirect evidence
      for a role for GHRH in GH synthesis and replenishment of stored GH pools at times
      of high SS tone. Patterns of GH release in short-and long-term survivors of
      childhood brain tumours are heterogeneous suggesting that combined hypothalamic
      deficiencies of GHRH and SS occur following high dose radiotherapy. The
      attenuated GH release seen in long-term survivors compared to controls suggests
      that GH secretory dysfunction does not simply reflect reduced GHRH and SS
      secretion, and that trophic effects or pituitary damage may be important with
      time.

PMID- 10594519
TI  - Evaluation of the components of insulin-like growth factor (IGF)-IGF binding
      protein (IGFBP) system in adolescents with type 1 diabetes and persistent
      microalbuminuria: relationship with increased urinary excretion of IGFBP-3 18 kD
      N-terminal fragment.
AB  - OBJECTIVE: IGFs and their binding proteins (IGFBPs) have an important role in
      controlling glucose homeostasis and there is evidence to support their
      involvement in complications related to type I diabetes. The aim of this study
      was to evaluate the components of the IGF-IGFBP system in adolescents with type 1
      diabetes that had developed persistent microalbuminuria (MA). DESIGN AND
      PATIENTS: A cohort of 49 adolescents with type 1 diabetes were enrolled in the
      study. Patients were evaluated at baseline and 1 year later (follow-up). Twenty
      six patients with persistent urinary albumin excretion (UAE) of more than 20
      microg/min/1.73 m2 (21.6-109. 4 microg/min/1.73 m2) in three different nocturnal
      urinary collections within 6 months were considered to have MA (baseline mean:
      41.9 +/- 22.3 microg/min/1.73 m2; follow-up: 55.9 +/- 24.8 microg/min/1.73 m2).
      Twenty-three patients with UAE of less than 20 microg/min/1.73 m2 were assigned
      to the group without MA (baseline mean: 8.6 +/- 3.7 microg/min/1.73 m2; follow
      up: 11.8 +/- 4.2 microg/min/1.73 m2). Fasting serum levels of IGFBP-1, IGFBP-2,
      IGFBP-3, IGF-I and free-IGF-I were determined using appropriate immunoenzymatic,
      radioimmuno- or immunoradiometric assays. Overnight 12-h urinary collections were
      obtained and assessed for IGFBP-3 levels, determined by immunoradiometric assay.
      Urinary and circulating immunoreactive IGFBP-3 forms were determined by Western
      immunoblotting (WIB) analysis using a specific polyclonal antibody and monoclonal
      antibodies directed against N-terminal and C-terminal epitopes of IGFBP-3. IGFBP
      3 protease activity was determined using protease assay and by analysis of the
      intact over the fragmented immunoreactive forms of IGFBP-3 determined by WIB
      analysis. RESULTS: Patients with MA showed higher levels of urinary IGFBP-3 (649
      +/- 440 ng/h/m2) than patients without MA (398 +/- 229 ng/h/m2; P < 0.05).
      Urinary levels of IGFBP-3 were directly correlated to UAE (P < 0.001). WIB
      analysis, using monoclonal antibodies directed against characterized N-terminal
      and C-terminal IGFBP-3 epitopes, determined that the immunoreactive form of IGFBP
      3 found in urine from patients with diabetes was an N-terminal 18 kD fragment.
      Serum IGFBP-3 levels were lower in patients with MA (baseline: 3613 +/- 598
      microg/l; one year follow-up: 3347 +/- 624 microg/l) compared with patients
      without MA (baseline: 4701 +/- 1484 microg/l; follow-up: 4177 +/- 703 microg/l; P
      < 0.001). In serum from patients with MA, intact IGFBP-3 was decreased, as
      indicated by WIB analysis. Conversely, IGFBP-3 proteolysis was increased in
      patients with MA (baseline: 131 +/- 21% of control; follow-up: 130 +/- 23% of
      control), compared to patients with normal UAE (baseline: 96 +/- 23% of control;
      follow-up: 96 +/- 14% of control; P < 0.001). Serum IGFBP-3 protease activity was
      directly correlated to urinary IGFBP-3 levels (P < 0.001). Serum IGFBP-1 levels
      were increased in patients with MA (baseline: 36 +/- 20 microg/l; follow-up: 36
      +/- 17 microg/l) compared with patients without MA (baseline: 17 +/- 11 microg/l;
      follow-up: 18 +/- microg/l; P < 0.05). Serum IGFBP-2 levels were also
      persistently increased in patients with MA (baseline: 503 +/- 134 microg/l;
      follow-up: 484 +/- 166 microg/l) compared with patients without MA (baseline: 375
      +/- 83 microg/l; follow-up: 390 +/- 85 microg/l; P < 0.05). On the other hand,
      free IGF-I levels were decreased in patients with MA (baseline: 2.3 +/- 1. 5
      microg/l; follow-up: 2.5 +/- 1. (ABSTRACT TRUNCATED)

PMID- 10594520
TI  - Quantitative growth hormone secretion and final adult height.
AB  - OBJECTIVE: The relationship of quantitative GH secretion to height, growth
      velocity and puberty is complex and has been the subject of extensive study in
      children. This study was designed to relate quantitative GH secretion to final
      height. SUBJECTS: Twenty tall (> 183 cm, 90th centile for adult height) and 20
      short (< 166 cm, 10th centile) postpubertal men who had recently completed linear
      growth (age range 18-27 years). MEASUREMENTS: GH dynamics were studied on four
      occasions; insulin (0.15 units/kg, iv)-induced hypoglycaemia and GHRH (100 mg,
      iv) with and without the anticholinesterase, pyridostigmine (120 mg orally).
      Spontaneous nocturnal GH secretion was assessed by 20 minute sampling from 2100 h
      until 0600 h. GH was measured by IRMA. Analysis was by comparison of peak GH
      response and area under the curve (AUC). GH profiles were further analysed using
      the 'pulsar' programme. RESULTS: The mean height in the tall group was 187.7 cm
      (range 183-197) compared to 163.5 cm (range 160-166) for the short group. No
      difference existed between groups in the GH response to hypoglycaemia or GHRH
      with and without pyridostigmine. Area under the curve, pulse number, length and
      amplitude for spontaneous nocturnal GH secretion showed no significant difference
      between the tall and short subjects. Serum IGF-I (mean 230.5 +/- 15. 4 vs. 230.6
      +/- 18.9 microg/l) did not differ between the groups. CONCLUSIONS: Quantitative
      GH secretion does not appear to be an important determinant of final height in
      healthy individuals.

PMID- 10594521
TI  - High serum leptin levels in children with type 1 diabetes mellitus: contribution
      of age, BMI, pubertal development and metabolic status.
AB  - OBJECTIVE: Children with diabetes mellitus are prone to develop obesity and to
      experience a delay in onset of the pubertal process. In order to understand the
      role of leptin in these abnormalities, serum leptin levels were analysed in
      children with type 1 diabetes mellitus. SUBJECTS: Twenty diabetic girls, 23
      diabetic boys and 66 healthy children (selected from a reference population of
      706 normal children), age-, sex- and BMI-matched with diabetic patients, were
      studied. MEASURMENTS: Standing height, weight and BMI were determined in each
      child. Serum testosterone, oestradiol and leptin were measured by specific
      radioimmunoassays, and HBA1c by high performance liquid chromatography. RESULTS:
      Both diabetic girls and boys showed higher leptin levels than the normative
      healthy population and a group of age-, sex- and BMI-matched normal children. In
      an age-related analysis, leptin levels in diabetic girls rose from 7.4 +/- 1.2
      and 8.1 +/- 2.1 microg/l for the 5-7.99 and 8-10.99 year groups, to 12.6 +/- 2.4
      microg/l for the 11-13.99 year group, and to 15.6 +/- 4.0 microg/l in the 14
      15.99 year group in parallel with body weight. Leptin concentrations were
      parallel but higher (P < 0.05) than those of healthy girls. Diabetic boys had
      lower leptin levels than girls and, in contrast with normal boys, did not show a
      drop after the 10-year period. Leptin levels were 4.9 +/- 2.2, 3.9 +/- 0.2, 5.5
      +/- 0.6 and 5.1 +/- 0.9 microg/l for the 5-7.99, 8-10. 99, 11-13.99 and 14-15.99
      year groups, respectively. When divided by pubertal stage, leptin levels in the
      prepuberty stage of diabetic girls (8.6 +/- 1.0 microg/l) were higher (P < 0.05)
      than those in the controls (4.1 +/- 0.4 microg/l). In overt puberty girls, leptin
      was higher (P < 0.05) for diabetic (15.9 +/- 2.9 microg/l) than for healthy girls
      (9.2 +/- 1.1 microg/l). In prepubertal boys, differences were observed in leptin
      levels (4.9 +/- 0.5 microg/l for diabetic boys and 3.4 +/- 0.6 microg/l for
      healthy boys). In the overt puberty stage, diabetic boys showed higher (P < 0.05)
      levels of leptin (5.2 +/- 0.7 microg/l) than the healthy matched controls (2.1 +/
      0.2 microg/l). A multiple step regression analysis in the diabetic children
      revealed no associations between leptin and other relevant variables such as
      glycosylated haemoglobin, daily insulin dose, or years of suffering from the
      disease. CONCLUSION: Serum leptin levels were higher in diabetic than in healthy
      children. These differences were not attributable to age, adiposity or stage of
      pubertal development, and were probably conditioned by the metabolic perturbation
      intrinsic to the diabetic state, or the chronic hyperinsulinemia.

PMID- 10594522
TI  - Ultrasonographic evidence of joint thickening reversibility in acromegalic
      patients treated with lanreotide for 12 months.
AB  - BACKGROUND: A major cause of morbidity and functional disability in acromegaly is
      represented by axial and peripheral arthropathy. OBJECTIVE: The effect of a 12
      month treatment with lanreotide (LAN) on arthropathy in 12 untreated acromegalic
      patients has been evaluated. Twelve healthy subjects served as controls. STUDY
      DESIGN: Open prospective. STUDY PROTOCOL: Articular cartilage thickness of
      shoulder, wrist and knee, as well as the size of the heel tendons, was measured
      by ultrasonic (USG) examination before, monthly for the first 3 months and
      quarterly thereafter, during treatment with 60-90 mg/month of LAN. The
      achievement of safe GH and IGF-I levels was considered when fasting GH was below
      5 mU/l and IGF-I levels were normalized for age. RESULTS: Before treatment,
      thickening of shoulder, wrist and knee cartilages, and of heel tendons, was found
      in all patients compared with controls (P < 0.01). During the first 3 months of
      LAN treatment, a significant decrease in circulating GH (from 86.8 +/- 19.8 to
      25.6 +/- 9.8 mU/l) and IGF-I levels (from 624 +/- 47.8 to 412.2 +/- 44.5
      microg/l) was observed. Overall, a slight decrease was noted in all the articular
      sites examined, but it reached statistical significance only at the right
      shoulder (P < 0. 001). However, a notable improvement of joint pain and active
      and passive articular mobility were recorded in all patients, as well as of
      weakness, soft tissue swelling, hyperhydrosis and headache. After 6 months of LAN
      treatment, a further significant decrease was observed at the level of the right
      shoulder (P < 0.01) and the right knee (P < 0.01). Eight patients achieved safe
      GH and IGF-I levels. After 12 months of LAN treatment, a significant decrease was
      observed at the level of all the articular sites examined (P < 0.01), as well as
      at the level of both heel tendons (P < 0.01). Safe GH and IGF-I levels were
      achieved in all but one of the patients who, similarly, had a significant
      decrease in shoulder, wrist and both heel tendon thicknesses. The thickness
      reduction of right shoulder cartilage, a non-weight-bearing joint, was
      significantly greater than that observed at the level of the right and left knee
      cartilages and heel tendons (37.4 +/- 4.4% vs. 18 +/- 6.1%, 19.3 +/- 4.4%, 16.5
      +/- 4.2%, and 13.7 +/- 5.5%, respectively, P < 0.01). No difference was found in
      thickness decrease of all sites examined between the eight patients achieving
      safe GH levels after 3-6 months, and the remaining four patients, or between
      patients with estimated disease duration below (n = 6) or above 10 years (n = 6).
      CONCLUSIONS: Improvement in articular and periarticular soft tissue hypertrophy
      of the shoulder and wrist, two non-weight-bearing joints, but also of the knees,
      two weight-bearing joints, and heel tendons, was obtained by suppressing GH and
      IGF-I levels for 12 months with LAN treatment, although complete reversal of
      joint thickening was not achieved. Since no difference in the response to
      treatment, in terms of joint size decrease, was found between patients with short
      or long disease duration, treatment longer than 12 months may be needed to
      reverse the acromegalic arthropathy completely.

PMID- 10594523
TI  - Long-term results of octreotide-therapy in severe dumping syndrome.
AB  - OBJECTIVE: Little is known about the long-term results of octreotide therapy in
      dumping syndrome. We report the results of an open study including 20 patients
      with severe dumping symptoms after gastric surgery treated with octreotide
      between 1987 and 1997 at the Leiden University Medical Centre. DESIGN: Patient
      selection was based on (1) the results of a dumping provocation test and (2)
      symptoms that were refractory to other therapeutic measures. At regular intervals
      the presence of dumping symptoms was evaluated together with measurement of body
      weight and faecal fat excretion. RESULTS: Mean follow-up was 37 +/- 9 months
      (range 1-107 months). Doses of octreotide ranged from 25 to 200 microg/day.
      Initial relief of symptoms was achieved in all subjects, but after three months
      of therapy symptom relief persisted in 80% of patients. Mean body weight
      increased by 2.4 +/- 1.2 kg despite a significant increase in faecal fat
      excretion from 10 +/- 2 g/24 h to 24 +/- 3 g/24 h. Reasons for discontinuation of
      therapy were diminished efficacy in the longer term in 4 patients and side
      effects in 7 patients. Biliary complications were encountered in 3 patients.
      CONCLUSIONS: Self-administration of octreotide proves an effective symptomatic
      treatment of severe dumping, even on the long-term. Its use is frequently limited
      by the occurrence of side-effects.

PMID- 10594524
TI  - The 1microg short Synacthen test in chronic fatigue syndrome.
AB  - OBJECTIVE: Many studies suggest mild hypocortisolism in chronic fatigue syndrome
      (CFS), usually assumed to be due to reduced suprahypothalamic drive to the
      hypothalamo-pituitary-adrenal (HPA) axis. We wished to explore further the state
      of the HPA axis in CFS using the 1 microg low dose short Synacthen test. DESIGN:
      Subjects received an intravenous bolus of 1 microg Synacthen; samples for
      cortisol estimation were taken at baseline and 2, 10, 20, 30, 40 and 60 minutes
      after injection. PATIENTS: We tested 20 subjects suffering from CFS according to
      the criteria of the Center for Diseases Control without psychiatric comorbidity
      and 20 matched healthy controls. All subjects were drug free for at least 1
      month. MEASUREMENTS: We calculated the cortisol responses to the test as the
      maximum cortisol attained, the incremental rise in cortisol over baseline
      (Deltavalue) and as the integrated area under the curve. RESULTS: There were no
      significant differences in baseline cortisol or cortisol responses between
      patients and controls. However, responses generally were low, and many subjects'
      peak responses were prior to the standard 30 minute sampling time., CONCLUSIONS
      These results do not lend support to the theory that patients with chronic
      fatigue syndrome have a low adrenal reserve. However, results from studies
      assessing the HPA axis are proving to be inconsistent. We suggest that many other
      factors may be contributing to HPA axis alterations in chronic fatigue syndrome,
      including sleep disturbance, inactivity, altered circadian rhythmicity, illness
      chronicity, concomitant medication and comorbid psychiatric disturbance. These
      sources of heterogeneity need to be considered in future studies, and may explain
      the inconsistent findings to date.

PMID- 10594525
TI  - Malignant human renin producing paraganglionoma-localization with 123I-MIBG and
      treatment with 131I-MIBG.
AB  - A 22-year-old woman presenting severe hypertension and hypokalaemia is described.
      Initial evaluation showed a large tumour localized at the position of the left
      adrenal gland. Subsequent surgery temporarily relieved all signs and symptoms
      caused by the tumour. The symptoms relapsed after a 2-year disease-free interval.
      At re-evaluation, the tumour was shown to produce an uncontrolled secretion of
      renin, thus triggering aldosterone-dependent hypertension. This report describes
      the diagnosis, treatment and clinical course of this unique patient with a
      malignant paraganglionoma of adrenal origin.

PMID- 10594526
TI  - The effect of melatonin administration on pituitary hormone secretion in man.
AB  - OBJECTIVE: Evidence is accumulating that the nocturnal increase in melatonin may
      influence pituitary hormone secretion. The aim of this study was to determine the
      effect of exogenous melatonin, in concencetrations spanning the physiological
      range, on the release of pituitary hormones in man during daylight hours. DESIGN:
      A double blind, randomized, crossover study. SUBJECTS: Eight healthy male
      volunteers with a mean age of 21 +/- 0.5 years were studied on four occasions,
      observations being made after the adminstration of melatonin in doses of 0.05,
      0.5 or 5.0 mg or placebo. They refrained from taking heavy exercise, alcohol and
      from smoking for 24 h prior to the study. MEASUREMENTS: Serum cortisol, growth
      hormone, prolactin and plasma oxytocin, vasopressin, sodium, osmolality and
      packed cell volume were measured in samples taken at 30 minutes intervals for 150
      minutes after the administration of melatonin. RESULTS: Melatonin produced dose
      dependent changes in circulating concentrations of oxytocin and vasopressin, the
      0.5 mg dose being stimulatory, while 5.0 mg was inhibitory. These two doses
      stimulated growth hormone release, while there was no significant effect on
      prolactin or cortisol release. CONCLUSIONS: These results confirm that the
      nocturnal increase in melatonin could contribute to the patterns of oxytocin,
      vasopressin and growth hormone release seen over 24 h.

PMID- 10594527
TI  - The effects of six months of treatment with a low-dose of conjugated oestrogens
      in menopausal women.
AB  - OBJECTIVE: Hormone replacement therapy (HRT) is usually prescribed as medium- to
      high-dose formulations. Little is known, however, about dose-dependency of
      oestrogen effects on plasma hormone levels, markers of cardiovascular risk in
      lipid metabolism and the haemostatic system, or markers of bone turnover.
      SUBJECTS AND DESIGN: In an open trial, three groups of 12 or 13 healthy, non
      obese postmenopausal women received conjugated equine oestrogens (CEE) for 6
      months at doses of 0.3 mg/day (group 1), 0.6 mg/day (group 2) or 1.25 mg/day
      (group 3). From day 1 to day 10, CEE was administered alone, and from day 11 to
      day 21, in combination with 5 mg of medrogestone. Each treatment cycle was
      followed by a pause of 7 days. Fasting blood samples were obtained before
      treatment as well as on days 10, 21 and 28 of the first, third and sixth months
      on treatment. All results obtained on day 10 were grouped together as phase A, on
      day 21 as phase B, and on day 28 as phase C. MEASUREMENTS: Plasma concentrations
      of oestradiol (E), dehydroepiandrosterone sulphate (DHEA-S), total testosterone
      (T), FSH, PRL, sex hormone binding globulin (SHBG), type I procollagen propeptide
      (PICP) and the cross-linked carboxyterminal telopeptide of type I collagen
      (ICTP), total cholesterol, HDL-cholesterol, triglycerides (TG), apolipoprotein
      (apo) A-1, apo B, lipoprotein(a)[Lp (a)], fibrinogen, factor VIIc and plasminogen
      activator inhibitor 1 (PAI-1) were evaluated with commercially available kits.
      RESULTS: Dose-dependently, the three regimens increased E, SHBG and factor VIIc
      activity and decreased FSH, DHEAS, cholesterol, LDL-cholesterol and apoB. HDL
      cholesterol and apoA-1 were slightly decreased in group 1 but increased in groups
      2 and 3. The high CEE dosage in group 3 resulted in a significant increase of TG
      and decrease of Lp(a) and PAI-1. Markers of bone turnover were not significantly
      changed by any CEE dosage. CONCLUSIONS: Six months of treatment with 0.3 mg/day
      of conjugated equine oestrogen significantly lowers serum levels of total
      cholesterol and LDL-cholesterol without causing the adverse increases of
      triglycerides or factor VIIc, which were observed at higher doses. However, this
      low-dose treatment did not yield the maximal LDL-cholesterol lowering effect.
      Moreover, the positive effects of HRT on HDL-cholesterol, apolipoprotein A-I,
      lipoprotein (a) and plasminogen activator inhibitor-1 required at least the
      medium dose of 0.6 mg conjugated equine oestrogens per day. Therefore, further
      studies are needed to determine which dose of conjugated equine oestrogens has
      the optimal effect on cardiovascular risk and bone turnover.

PMID- 10594528
TI  - ACTH and cortisol release following intravenous desmopressin: a dose-response
      study.
AB  - OBJECTIVE: Desmopressin (DDAVP) is a synthetic analogue of AVP, the companion
      regulator of corticotrophin-releasing hormone (CRH) in the control of ACTH
      synthesis and release from the pituitary corticotrophs. The body of evidence from
      human studies suggests that DDAVP alone, unlike AVP, does not bring about ACTH
      release, although recent evidence suggests idiosyncracies of response in healthy
      subjects. We examined whether DDAVP exerted any consistent effect on ACTH and
      cortisol release, and also if this occurred in a dose-dependant manner. DESIGN
      AND SUBJECTS: A total of 18 subjects participated in the study. Saline, 5 microg,
      10 microg and 15 microg DDAVP were administered as an intravenous bolus at 1300
      h; 5, 7, 18 and 8 subjects, respectively, participated in each arm of the study.
      Plasma ACTH and cortisol responses were measured over a 120-minutes period.
      RESULTS: Significant between group comparisons were demonstrated for both ACTH (P
      < 0.05) and cortisol responses (P < 0. 005) measured as maximum increment from
      baseline. The ACTH response to 5, 10 and 15 microg DDAVP was significantly
      greater than saline at all three doses, whilst maximal responses were seen at 10
      microg. The cortisol responses to 10 and 15 microg DDAVP doses, but not 5 microg,
      were significantly greater than following saline. 11/18 subjects were deemed
      'responders' following 10microg DDAVP on the basis of both ACTH and cortisol
      output. CONCLUSIONS: This data suggests that DDAVP is capable of stimulating ACTH
      and cortisol release when administered alone as a bolus in over 50% of healthy
      subjects. This is in contrast to much of the extant literature. The mode of
      administration may be pertinent to this effect. This finding has implications for
      the recent focus on DDAVP as a diagnostic tool in disorders such as Cushing's
      Disease.

PMID- 10594529
TI  - The relationship between insulin, IGF-I and weight gain in cystic fibrosis.
AB  - OBJECTIVE: In cystic fibrosis, reduced body mass is related to low levels of IGF
      I and changes in the IGF binding proteins. Our aim was to determine whether these
      abnormalities are linked to pancreatic endocrine dysfunction. PATIENTS AND
      DESIGN: We measured serum levels of insulin, IGF-I, IGFBP-I, IGFBP-3 and IGF
      bioactivity in 77 fasting subjects (43 male) mean age 9.6 years (range 2.99-17.98
      years). Data were analysed with respect of body mass, puberty and stature and
      compared with control data established in the same laboratory. RESULTS: The mean
      height standard deviation score (SDS (SD)) was -0.54 (0.97) and the body mass
      index SDS -0.24 (1.09). Both body mass index SDS (r = -0.40, P = 0.0003) and IGF
      I SDS (r = - 0.32, P = 0.009) declined with age. Insulin levels were also low and
      correlated with IGF-I and IGFBP-3 (r = 0.42, P = 0.0004, and r = 0.45, P =
      0.0002, respectively) whereas levels of IGFBP-I were inversely related to those
      of IGF-I and insulin (r = - 0.43, P = 0. 0004, r = - 0.52, P < 0.0001). IGF
      bioactivity was reduced and inversely related to IGFBP-I (r = - 0.31, P = 0.009).
      In multiple regression analysis, body mass index SDS was negatively related to
      age (P < 0.0001) and positively related to insulin and IGF-I (P = 0. 04, P =
      0.03, respectively). Height SDS was correlated with IGF bioactivity (P = 0.003)
      and negatively with IGFBP-I (P = 0.01). CONCLUSIONS: We conclude that progressive
      insulin deficiency may result in reduced IGF-I levels and IGF-bioactivity and may
      determine weight gain and statural growth in cystic fibrosis.

PMID- 10594530
TI  - Acute pancreatitis and parotitis induced by methimazole in a patient with Graves'
      disease.
AB  - A wide variety of adverse effects of methimazole (MMI) have been reported. Here
      we report a new MMI-induced disorder, acute pancreatitis and parotitis. Three
      weeks after a woman started MMI treatment for Graves' disease, she developed a
      high fever, painful parotid swelling and dull pain in the upper abdomen with
      elevation of the serum levels of salivary and pancreatic enzymes. These
      abnormalities disappeared soon after the withdrawal of MMI. However, the same
      abnormalities were rapidly provoked when MMI was reintroduced. Marked increases
      in the leucocyte count and CRP were also observed during these episodes. The
      possible mechanisms of MMI-induced pancreatitis/parotitis are discussed.

PMID- 10594532
TI  - Allergen isoforms for immunotherapy: diversity, degeneracy and promiscuity.

PMID- 10594531
TI  - Towards defining the full spectrum of important house dust mite allergens.

PMID- 10594533
TI  - The influence of beliefs on the quality of life of patients with allergic
      diseases.

PMID- 10594534
TI  - Anti-inflammatory actions of new antihistamines.

PMID- 10594535
TI  - Could the airway epithelium play an important role in mucosal immunoglobulin A
      production?
AB  - Immunoglobulin (Ig) A is the major immunoglobulin of the healthy respiratory
      tract and is thought to be the most important immunoglobulin for lung defence.
      The basis for the preferential generation of IgA-secreting cells in the airway
      mucosa remains unclear. Given the half-life of 5 days for the majority of IgA
      plasma cells, many IgA plasma cells must develop daily from B cells to guarantee
      a continuous supply of IgA antibodies in the airway mucosa. For this, the
      surrounding cells must provide a constant supply of cytokines necessary for B
      cell isotype switch, growth and differentiation into IgA-secreting plasma cells.
      Studies with CD4+ T-cell knockout mice, T-cell receptor knockout mice and mice
      made transgenic for CTLA4-Ig demonstrate normal mucosal IgA isotype switch,
      differentiation and IgA production, thereby suggesting that T cells are not
      critical for mucosal IgA production, and that other cell sources may be more
      important. Also, the bronchus-associated lymphoid tissue (BALT), which is
      believed to be the major site where IgA isotype switch and differentiation of B
      cells into plasma cells occur with the help of cytokines released by T cells, is
      not a constitutive feature of the normal human lung. This indicates that other
      parts of the respiratory tract must carry out the BALT function. We have recently
      demonstrated that healthy human airway epithelial cells constitutively produce IL
      5, a major cytokine implicated in the growth and differentiation of post-switch
      mIgA+ B cells to IgA-producing plasma cells. Several studies have recently
      reported that the human airway epithelium also constitutively produces IL-2,
      TGFbeta, IL-6 and IL-10, factors which are essential for B-cell clonal
      proliferation, IgA isotype switch and differentiation into IgA-producing plasma
      cells. The close proximity of B cells to the airway epithelium probably ensures a
      constant supply of growth and differentiation factors necessary for mucosal IgA
      production. In addition, the epithelial cells produce a glycoprotein, called the
      secretory component, which not only confers increased stability to S-IgA, but is
      also quantitatively the most important receptor of the mucosal immune system,
      since it is responsible for the external transport of locally produced polymeric
      IgA and IgM. Recent studies also suggest a possible role for epithelial cells in
      antigen presentation. Dendritic cells situated within the airway epithelium could
      directly present antigens to B cells and direct their isotype switch towards IgA1
      and IgA2 with the help of cytokines produced by epithelial cells. Airway
      epithelial cells could therefore play a major role in the production of mucosal
      IgA antibodies which are essential for airway mucosal defence.

PMID- 10594536
TI  - Sequence analysis and expression of a cDNA clone encoding a 98-kDa allergen in
      Dermatophagoides farinae.
AB  - BACKGROUND: The important dust mite allergens identified to date are of molecular
      weights ranging from 14 to 60 kDa. Our previous protein study indicated that the
      98-kDa native paramyosin in Dermatophagoides farinae mite showed IgE reactivity
      with 82% of the mite-sensitive asthmatic patients suggesting that it is a novel
      major mite allergen. This study described the isolation and characterization of
      the cDNA clone encoding the 98-kDa mite allergen. METHODS: A Dermatophagoides
      farinae cDNA library was constructed in lambda ZAPII vector and the library was
      immunoscreened with a monoclonal antibody 642. The cDNA insert was sub-cloned
      into M13 sequencing vector for single-stranded sequencing. The whole cDNA insert
      was expressed in pGEX-2T Escherichia coli expression system as a fusion protein
      with GST. The allergenicity of the recombinant peptides was tested by skin tests
      and IgE immunoassay. The IgE and IgG immunoassays were performed with sera from
      20 mite-allergic patients. RESULTS: The cDNA clone Df642 was 2134 bp long, coding
      for a polypeptide of 711 amino acid residues. Protein sequence analysis and
      alignment confirmed that the deduced polypeptide is a mite paramyosin which is
      truncated slightly at the N- and C-terminuses. In vivo skin tests and in vitro
      IgE-binding study showed that 62% (13/21) and 50% (10/20) of the mite-sensitive
      asthmatic patients reacted positively with the recombinant Dermatophagoides
      farinae paramyosin, respectively. CONCLUSION: The study indicated that 98-kDa
      mite paramyosin is an important allergen.

PMID- 10594538
TI  - Debilitating beliefs, emotional distress and quality of life in patients given
      immunotherapy for insect sting allergy.
AB  - BACKGROUND: Patients who receive immunotherapy for systemic reaction to insect
      stings are told that once they reach maintenance dose they are almost 100%
      protected against future systemic reactions. However, we have observed that some
      patients continued to perceive themselves as highly debilitated by the allergy,
      and this perception had a significant impact on their quality of life. OBJECTIVE:
      To validate this clinical observation and to explore possible reasons for such an
      undesired psychological reaction. METHODS: The study group consisted of 97
      patients who regularly attended an allergy outpatient clinic for venom
      immunotherapy, and who had been under medical surveillance for up to 8 years.
      They completed a questionnaire measuring debilitating beliefs, preoccupation with
      the systemic reaction event, emotional distress, perceived restriction by
      allergy, and perceived quality of life. We also recorded the duration of
      immunotherapy, physician-graded severity of the systemic reaction and the
      frequency at which immunotherapy was administered. The reference group consisted
      of patients who had not reached maintenance dose and were still at risk of
      recurrent systemic reactions. RESULTS: As many as one-third of the patients held
      self-imposed debilitating beliefs, were preoccupied with the systemic reaction
      event, perceived a moderate to severe impairment in their quality of life, and
      manifested symptoms of emotional distress. These psychological responses did not
      correlate with the immunotherapy dosage that had been reached. Patients who
      reached a full maintenance dose were doing no better psychologically than those
      in the reference group. Moreover, the length of time on immunotherapy did not
      result in attenuation of the psychological responses. CONCLUSION: This study
      demonstrates for the first time, the long-lasting psychological impact of a
      threatening systemic reaction. It suggests a need for intervention aimed at
      dispelling patients' unfounded and persisting debilitating beliefs.

PMID- 10594537
TI  - Identification of isoform-specific T-cell epitopes in the major timothy grass
      pollen allergen, Phl p 5.
AB  - BACKGROUND: The involvement of CD4+ T cells in the pathophysiology of atopic
      disease is well established. OBJECTIVE: To gain further insight into the
      activation requirements for allergen-specific T cells, we characterized epitope
      specificity, HLA restriction and T-cell receptor (TCR) usage for T cells specific
      to Phl p 5, the group 5 major allergen of the grass Phleum pratense. METHODS: To
      identify the T-cell epitopes of Phl p 5, three Phl p 5-specific T-cell lines
      (TCLs) and 15 T-cell clones (TCCs) generated from the peripheral blood of three
      grass-allergic patients were tested with recombinant truncated Phl p 5a fragments
      and synthetic Phl p 5b peptides representing these two different recombinant Phl
      p 5 isoallergens. Additional activation experiments with HLA-subtyped antigen
      presenting cells and flow cytometry analysis with TCR V-specific mAb were
      performed to further characterize the activation requirements for Phl p 5
      specific TCCs. RESULTS: At least nine distinct T-cell specificities were
      identified and the T-cell epitopes recognized differed considerably among the
      three patients. Most of the epitopes found were isoform-specific, whereas three
      epitopes were shared between Phl p 5a and 5b. Several human leucocyte antigen
      (HLA) class II molecules were involved in the recognition of Phl p 5. Different
      HLA restriction specificities were even found among TCCs specific to the same
      epitope region. All TCCs were TCR-alpha/beta positive, and an overrepresentation
      of TCR Vbeta 3.1+ clones among TCCs specific to Phl p 5 appear to exists as 31%
      (4/13) of the TCCs expressed TCR Vbeta 3.1 (compared with 5% TCR Vbeta 3.1+ T
      cells in human peripheral blood) with no correlation with epitope specificity or
      HLA restriction. CONCLUSION: The T-cell reactivity of the three grass-allergic
      patients investigated shows that isoallergen-specific T-cell epitopes are found
      throughout the peptide backbone of Phl p 5a and Phl p 5b, and dominant T-cell
      epitopes of Phl p 5 were not identified. This indicates that a mixture of at
      least full-length rPhl p 5a and rPhl p 5b may be required to target the total Phl
      p 5-specific T-cell response of atopic patients.

PMID- 10594539
TI  - Airway inflammation and altered alveolar macrophage phenotype pattern after
      repeated low-dose allergen exposure of atopic asthmatic subjects.
AB  - BACKGROUND: The alveolar macrophage (AM) constitutes an important link between
      pulmonary innate and adaptive immunity due to its antigen-presenting capacity and
      ability to express different immunomodulating mediators. The role of AMs in the
      pathogenesis of allergic inflammation has yet to be fully determined. OBJECTIVE:
      To investigate clinical effects and any change in the AM phenotype pattern after
      inhalation of sub-clinical doses of allergen by asthmatic patients. METHODS:
      Eight subjects with allergic asthma underwent repeated low-dose allergen
      provocations equivalent to 10% of PD20. AMs recovered with bronchoalveolar lavage
      (BAL) were characterized by flow cytometric analysis of adhesion molecules, co
      stimulatory molecules and markers for AM population activation and heterogeneity.
      RESULTS: An allergic airway inflammation, sub-clinical in six out of eight
      subjects, was obtained after low-dose allergen provocations, as determined by
      increased airway methacholine reactivity, increased BAL fluid total cell and
      eosinophil counts and increased serum ECP levels. The AMs showed a post-challenge
      altered phenotype pattern with a decreased expression of CD11a, CD16, CD71 and
      HLA class I and an increased expression of CD11b and CD14. The AMs were positive
      for CD83 and a weak post-challenge increase in the CD83 expression was found.
      CONCLUSION: Repeated low-dose allergen exposure induces an allergic airway
      inflammation in asthmatic subjects. The inflammation is associated with an
      altered AM phenotype pattern, consistent with an influx of monocytes and a
      hypothetical increased accessory cell function in the airways, possibly
      contributing to the development and sustenance of airway inflammation in asthma.

PMID- 10594540
TI  - Immunohistochemical investigation of the cellular infiltrates at the sites of
      allergoid-induced late-phase cutaneous reactions associated with pollen allergen
      specific immunotherapy.
AB  - BACKGROUND: Reduction in the size of the allergen-induced late-phase reaction
      (LPR) is seen as a consequence of successful allergen specific immunotherapy.
      OBJECTIVE: It was the aim of this study to characterize the cellular infiltrate
      at the sites of cutaneous LPR that may occur following injection of a depot
      pollen allergoid (Allergovit(R)) during immunotherapy and thereby determine the
      immunological nature of the response. METHODS: Punch biopsies were taken 24 h
      after subcutaneous injection of a depot pollen allergoid from eight patients that
      showed LPR and a further five patients that did not. Additional biopsies taken 24
      h after injection of allergoid-free depot in the same patients served as
      controls. Immunoenzymatic labelling of the cryostat sections with different
      antibodies was performed with the APAAP technique. Results were expressed as
      cells/field (400 x magnification). RESULTS: Similar dermal cellular infiltrations
      were seen following depot allergoid injections in patients both with and without
      LPR. Patients with LPR showed statistically significant increases in total cells,
      CD4+ cells, CD11c+ cells, CD45RO+ cells, CD45RB+ cells and activated eosinophils
      at the reactions sites as compared with control sites. In patients without LPR
      CD11c+ cells, HLA-DR+ cells and CD45RA+ T cells increased significantly. CD8+,
      CD1a+, NP57+, CD23+ and CD25+ cells did not differ significantly in either group.
      CONCLUSION: These results indicate that activation of T cells,
      monocytes/macrophages and eosinophils at the sites of LPR following injection of
      depot allergoid are comparable with those following injection of allergen. Even
      in the absence of a cutaneous LPR, subsets of T cells and monocytes/macrophages
      increased. These cell activations may reflect events associated with the
      mechanisms of allergoid-based specific immunotherapy, and suggest that at least
      part of the late-phase reaction may be independent of IgE.

PMID- 10594541
TI  - Increased mast cell tryptase in sudden infant death - anaphylaxis, hypoxia or
      artefact?
AB  - BACKGROUND: Increased concentrations of mast cell tryptase in post mortem blood
      have frequently been observed in sudden infant deaths but the cause of this has
      not yet been clarified. OBJECTIVE: The aim was to evaluate factors
      (immunological, morphological and anamnestic data) behind the observed increase
      in mast cell tryptase in sudden infant deaths with elevated tryptase. METHODS:
      Mast cell tryptase and total immunoglobulin (Ig) E were measured in post mortem
      sera from 44 infants younger than 1.5 years. Radioallergosorbent tests were
      performed for possible allergens (mixture for relevant food allergens, Phadiatop
      and latex). IgG subclasses, IgM, and complement factors (C3, C4 and factor B)
      were measured with radial immunodiffusion. Mast cells, labelled with antibodies
      against mast cell tryptase, were counted in the lungs and heart. The
      circumstances of death and medical history of the deceased infant and family were
      obtained through police and hospital records. RESULTS: In 40% of the SIDS cases
      tryptase was elevated (>10 microg/L). Total IgE in serum was increased in 33%
      compared with clinical reference values but showed no association with mast cell
      tryptase. RAST tests were positive in three cases. In one of these cases both
      tryptase and total IgE were elevated. The only variable that was associated with
      high tryptase values was prone position at death (P < or = 0.05 ). Allergy or
      asthma in the family were alleged in 50% of the cases, but was not associated
      with elevated tryptase or IgE. Children with elevated total IgE also displayed
      high concentrations of IgG1 and IgG2. Infants who died in the spring had
      significantly higher IgE than the others (P < or = 0.05). CONCLUSION: The results
      do not support the hypothesis that the elevated tryptase concentrations in sudden
      infant death are caused by allergy. The association between prone position at
      death and elevated tryptase could hypothetically be explained by mast cell
      degranulation due to, for example, a hypoxic stimulus in these infants.

PMID- 10594542
TI  - Exposure to systemic prednisolone for 4 hours reduces ex vivo synthesis of GM-CSF
      by bronchoalveolar lavage cells and blood mononuclear cells of mild allergic
      asthmatics.
AB  - BACKGROUND: In acute severe asthma, the earliest clinical effects of
      glucocorticosteroids occur from 4 to 5 h after systemic administration, but the
      mechanisms are unclear. In persistent asthma, corticosteroids are thought to
      suppress airway inflammation by modulating the expression of adhesion molecules,
      enzymes, and leucotactic cytokines, including granulocyte-macrophage colony
      stimulating factor (GM-CSF). GM-CSF is also overexpressed in the airways of
      symptomatic asthmatics. OBJECTIVES: To examine the early effects of systemic
      corticosteroids on cytokine expression, we investigated whether ex vivo synthesis
      of GM-CSF is suppressed in the bronchoalveolar lavage (BAL) cells and peripheral
      blood mononuclear cells (PBMCs) of normal and mild allergic asthmatic subjects
      obtained 4 h after a single intravenous dose of prednisolone. METHODS: In a
      randomized, double-blind, placebo-controlled study, BAL cells and PBMCs were
      obtained from mild atopic asthmatic patients (n = 9) and normal subjects (n = 9)
      4 h after an intravenous bolus dose of 80 mg prednisolone, and cultured for 0-18
      h in the presence or absence of lipopolysaccharide (LPS; 10 microg/mL). Enzyme
      immunoassay was used to assess GM-CSF levels in BAL cell and PBMC culture
      supernatants, and in BAL fluid. RESULTS: After placebo, GM-CSF synthesis tended
      to be higher in BAL cells from asthmatics than in normals. LPS stimulation
      significantly increased median (interquartile range) GM-CSF synthesis by BAL
      cells ex vivo from 16.4 (23 to 74) to 35.8 (3-148) pg/106 cells in normals (P <
      0.05), and from 59 (9 to 204) to 134 (24-288) pg/106 cells in asthmatics (P <
      0.01). After intravenous prednisolone, the rise in GM-CSF production induced in
      BAL cells by LPS was completely abolished in both subject groups. In PBMCs of
      placebo-treated asthmatics (but not normals), LPS stimulated median GM-CSF
      synthesis from 164 (110 to 300) to 314 (235-485) pg/106 cells (P = 0.02), and
      this was blocked by intravenous prednisolone. CONCLUSIONS: LPS-stimulated GM-CSF
      synthesis ex vivo is abolished in BAL cells of mild asthmatic and normal
      subjects, and in PBMCs of asthmatics, obtained 4 h after a single intravenous
      dose of prednisolone. Suppression of GM-CSF synthesis in airway and blood
      leucocytes may contribute to the early clinical efficacy of systemic
      glucocorticoids in acute allergic asthma.

PMID- 10594543
TI  - Value of immunoglobulin E density in predicting nasal and bronchial response to
      inhaled allergens in rhinitic and asthmatic subjects with multiple
      sensitizations.
AB  - BACKGROUND: In atopic subjects with multiple sensitizations to inhalant allergens
      the relationship between the specific serum immunoglobulin (Ig) E and the in vivo
      response to each allergen is not well established. OBJECTIVE: To investigate the
      relationship between the specific serum IgE expressed as amount (kU/L) or density
      (specific IgE/total IgE percentage) with the in vivo response to inhaled
      allergens in rhinitic and asthmatic subjects with multiple sensitization.
      METHODS: By means of Reverse Enzyme AllergoSorbent Test (REAST) the absolute
      values and the density of specific IgE for each sensitizing allergen was
      determined. Rhinitics (n = 12) underwent nasal and asthmatics (n = 11) bronchial
      allergen challenges with the two to three sensitizing allergens for a total of 33
      nasal and 32 bronchial challenges. Correlations and degree of concordance between
      specific serum IgE and results of challenges were calculated. RESULTS: IgE
      density significantly correlated with nasal challenge score (rs = 0.72, P <
      0.001), bronchial challenge score (rs = 0.56, P < 0.001) and late asthmatic
      response (rp = 0.53, P < 0.005). Among subjects with three sensitizations,
      comparison of values of IgE density with the results of challenges showed
      significant concordance in graduation (chi2 = 11.3, P < 0.005). CONCLUSIONS: In
      subjects with multiple sensitizations, the nasal and bronchial response to the
      different sensitizing allergens may be predicted, at least in part, by the IgE
      density. A satisfactory agreement between graduation of the IgE density to the
      different allergens and the in vivo response to the same allergens has been found
      within subject.

PMID- 10594544
TI  - Studies of differential gene expression in clinically derived eosinophil
      populations.
AB  - BACKGROUND: Influx of eosinophils into the post-capillary bronchial epithelium
      and the subsequent release of inflammatory mediators is characteristic of the
      late phase of asthmatic attacks. The genes that serve to predispose the
      peripheral blood eosinophils of asthmatics to undergo this process are poorly
      defined. The aim of this report is to describe the differential gene expression
      of both the known pro-inflammatory genes 5-lipoxygenase and 5-lipoxygenase
      activating protein (FLAP) and novel cDNA sequences in eosinophils derived from
      clinical samples. METHODS: Novel cDNA sequences representing genes upregulated in
      peripheral blood eosinophils of asthmatic as compared with nonasthmatic patients
      were identified by differential display polymerase chain reaction (DDPCR). The
      differential expression of these sequences, in addition to known pro-inflammatory
      genes, were then studied by reverse dot blotting of amplified RNA generated from
      the eosinophils of nonasthmatic donors, asthmatic donors, asthmatic donors taking
      steroids, interleukin (IL) -3, IL-5, granulocyte-macrophage colony stimulating
      factor- (GM-CSF) treated eosinophils from asthmatic donors and the eosinophilic
      cell line AML14. RESULTS: Four unique DDPCR-generated 3'UTR DNA fragments were
      identified that showed differing patterns of expression between the eosinophil
      populations of interest. Expression of each of the novel clones was increased in
      the peripheral blood eosinophils of asthmatics and downregulated in those donors
      taking steroids. Expression of 5-lipoxygenase was not found to vary between the
      different eosinophil populations, whereas FLAP was induced by treatment with the
      cytokine cocktail in both primary eosinophils and the eosinophilic cell line
      AML14. CONCLUSION: The differential regulation of the novel cDNA sequences and
      FLAP in the range of eosinophil populations studied suggest that they may provide
      clinically relevant therapeutic targets. Moreover, the procedures used in these
      studies may provide a general approach to the study of differential gene
      expression in small numbers of cells such as those obtained from clinical
      samples.

PMID- 10594545
TI  - Cetirizine counter-regulates interleukin-8 release from human epithelial cells
      (A549)
AB  - BACKGROUND: Cetirizine, a H1-receptor antagonist, exerts besides its well-known
      anti-allergic potential an array of anti-inflammatory activities. In particular
      epithelial cells activated in the presence of cetirizine showed a reduced ICAM-1
      cell surface expression and a diminished release of sICAM-1. OBJECTIVE: We
      wondered whether cetirizine might influence the release of interleukin-8 (IL-8)
      from human epithelial cells activated with agonists distinct from histamine.
      METHODS: We used the human lung epithelial cell line A549 for our in vitro
      studies. IL-8 release was determined by IL-8 enzyme immunoassay, the
      intracellular staining for IL-8 and NF-kB was analysed by FACS analysis and IL-8
      mRNA steady state level was studied by Northern blot analysis. Confluent
      epithelial cell monolayer were pre-incubated with cetirizine (0.01 -1.0
      micromol/L) for 30 min and afterwards activated with pro-inflammatory cytokines
      (TNF-alpha IL-1beta, IL-6, IFN-gamma) or different agonists (PMA, NaF,
      respiratory syncytial virus [RSV]) for 24 h. RESULTS: Epithelial cells stimulated
      with TNF-alpha IL-1beta, PMA and RSV, respectively, showed a significantly
      increased release of IL-8. Pre-incubation with cetirizine diminished the IL-8
      release from cells activated with TNF-alpha or PMA in a significant manner. The
      reduced IL-8 release coincided with a diminished percentage of cells expressing
      IL-8. Northern blot analysis revealed a reduced steady state level of IL-8 mRNA
      in cells pretreated with cetirizine and stimulated with TNF-alpha. Furthermore, a
      decreased amount of accessible DNA-binding sites of the nuclear factor kappa B
      (NF-kB) was determined by FACS analysis. CONCLUSIONS: These results suggest that
      cetirizine reduced the release of IL-8 from A549 cells stimulated with PMA and
      TNF-alpha, respectively, by lowering IL-8 gene expression. Therefore, cetirizine
      might exert anti-inflammatory effects beyond its H1-receptor antagonistic
      activity in the course of inflammatory respiratory tract disorders such as
      bronchial asthma and allergic rhinitis.

PMID- 10594546
TI  - Sensitization to grass, ragweed, mugwort pollen allergens in Japanese monkeys
      (Macaca fuscata): preliminary report.
AB  - BACKGROUND: The natural occurrence of Japanese cedar (CJ, Cryptomeria japonica)
      pollinosis has been reported in Japanese monkeys (Macaca fuscata). Furthermore,
      most of these monkeys with CJ pollinosis have immunoglobulin (Ig) E sensitization
      to Japanese cypress (Chamaecyparis obtusa) pollen. However, specific IgE to other
      pollens has not yet been reported. OBJECTIVES: The present study was designed to
      investigate IgE sensitization of Japanese monkeys to grass, ragweed, and mugwort
      pollen. METHODS: Serum samples from 47 monkeys as a general population in one
      troop were collected at random. We measured specific IgE to grass, ragweed and
      mugwort pollen. Next, 10 monkeys with CJ pollinosis from the same troop were also
      examined for their IgE sensitization to grass, ragweed, and mugwort pollen.
      RESULTS: Of 47 monkeys, 13 (28%) had specific IgE to CJ pollen, 15 (32%) to grass
      pollen, five (11%) to ragweed pollen, and three (6%) to mugwort pollen.
      Furthermore, CJ pollinosis monkeys seemed to be sensitized to these pollen
      allergens with higher frequency; of 10 monkeys, 10 (100%) had specific IgE to CJ
      pollen, six (60%) to grass pollen, four (40%) to ragweed pollen, and two (20%) to
      mugwort pollen. CONCLUSION: Japanese monkeys had specific IgE to grass, ragweed,
      and mugwort pollen in addition to CJ pollen.

PMID- 10594547
TI  - Allergy to bovine beta-lactoglobulin: specificity of immunoglobulin E generated
      in the Brown Norway rat to tryptic and synthetic peptides.
AB  - BACKGROUND: Animal models which reflect the induction and development of food
      allergic reactions are important in the identification of allergenic potential of
      food proteins and peptides. A number of rat strains, including PVG, Hooded Lister
      and Brown Norway have been shown to produce immunoglobulin (Ig) E antibodies to
      food proteins as well as to inhaled allergens. Previous work in our laboratory
      using the Brown Norway (BN) rat has shown that specific IgE is produced following
      administration of ovalbumin and milk products via both enteral and parenteral
      route; this has allowed us to rank ovalbumin, lactoferrin and bovine serum
      albumin in terms of their inherent allergenic potential and has enabled us to
      demonstrate that milk protein allergens recognized by the systemically-sensitized
      animal are consistent with those recognized by sera from cow's milk-allergic
      patients (the most common allergens recognized were beta-lactoglobulin and the
      alpha, beta and kappa-caseins). OBJECTIVE: To demonstrate that the BN rat model
      can be used to identify the major IgE-binding peptides from beta-lactoglobulin, a
      known human food allergen, and that those IgE-binding peptides are similar to
      those recently identified using sera from cow's milk-allergic patients. METHODS:
      BN rats were exposed to beta-lactoglobulin or to semiskimmed milk via the
      intraperitoneal route in the presence of the adjuvant carrageenan. Specific IgE
      raised against beta-lactoglobulin was determined by a direct enzyme immunoassay
      using acetyl-cholinesterase substrate; specific IgG responses were also
      monitored. Overlapping synthetic peptides and tryptic peptides were used within
      the ELISA to identify the major and minor IgE-binding immunoreactive sequences.
      RESULTS: In terms of comparative immunogenicity, there appeared to be sequences
      that were predominantly IgE- or IgG-reactive. IgE-dominant regions were amino
      acid sequences 21-40, 41-60, 107-117 and 148-168 whereas sequences 1-24, 67-77,
      82-92, 85-95 and 117-127 appeared more selective for IgG antibody recognition. An
      increased capacity to induce specific IgE was observed when the allergen was
      present in the context of whole food. CONCLUSIONS: These studies provide evidence
      that the immune system of the BN rat and humans - at least in the case of milk
      allergens - is recognizing similar protein allergens and indeed, at the molecular
      level, similar peptide epitopes.

PMID- 10594548
TI  - Cytokines in experimental colitis.

PMID- 10594549
TI  - Role of JAK2 signal transductional pathway in activation and survival of human
      peripheral eosinophils by interferon-gamma (IFN-gamma).
AB  - The purpose of this study was to determine whether the JAK pathway is involved in
      eosinophil activation and survival through IFN-gamma receptor signalling in human
      peripheral eosinophils. Eosinophils were purified from the blood of six atopic
      disease patients by anti-CD16 magnetic bead-negative selection. IFN-gamma
      significantly up-regulated survival and CD69 expression in 24-48 h cultured
      eosinophils. Further, IFN-gamma induced tyrosine phosphorylation of JAK2 in
      eosinophils, as indicated by Western blot analysis. Finally, the specific JAK2
      inhibitor AG-490 inhibited the tyrosine phosphorylation of JAK2, IFN-gamma
      induced survival and CD69 expression in eosinophils. In conclusion, these results
      indicate that IFN-gamma induces eosinophil survival and CD69 expression through
      the activation of JAK2 in peripheral eosinophils, suggesting that JAK2 may play a
      significant role in eosinophil regulation by IFN-gamma-IFN-gammaR interaction.

PMID- 10594550
TI  - Structural relationship of kappa-type light chains with AL amyloidosis: multiple
      deletions found in a VkappaIV protein.
AB  - Two amyloidogenic Bence Jones proteins (Am37 VkappaIV and NIG1 VkappaI) and one
      non-amyloidogenic protein (NIG26 VkappaIII) were characterized. The protein Am37
      had four deletions when compared with the translated germ-line gene sequence: two
      Ser residues following position 27 (27e, 27f) in CDR1 and two amino acids Pro-44,
      and Tyr-49 in FR2 were deleted. A strictly conserved salt-bridge-forming amino
      acid, Asp-82, was replaced by the hydrophobic residue Leu. In a comparative study
      of amyloidogenic and non-amyloidogenic proteins, five amino acids (Ser-10, Ala
      13, Ser-65, Gln-90, and Ile-106) were found to be unique to NIG1 and several
      other amyloidogenic proteins. Additional substitutions also occur within these
      proteins. These substitutions might be significant in altering protein folding as
      well as in contributing to their aggregation as amyloid fibrils.

PMID- 10594551
TI  - Comparative analysis of epitope recognition of glutamic acid decarboxylase (GAD)
      by autoantibodies from different autoimmune disorders.
AB  - Autoantibodies to GAD, an important marker of the autoimmune process in type I or
      insulin-dependent diabetes mellitus (IDDM), are also found in non-diabetic
      individuals with autoimmune polyendocrine syndrome type 1 (APS1), APS2, and stiff
      man syndrome (SMS). Most IDDM sera contain two distinct GAD antibody
      specificities, one of which targets an epitope region in the middle-third of
      GAD65 (IDDM-E1; amino acids 221-359) and one of which targets the carboxy-third
      of GAD65 (IDDM-E2; amino acids 453-569). Using 11 chimeric GAD65/GAD67 proteins
      to maintain conformation-dependent epitopes of GAD65, we compared the humoral
      repertoire of IgG antibodies from an individual with APS2-like disease (b35, b78,
      and b96) and MoAbs from an IDDM patient (MICA-2, MICA-3, and MICA-4). Neither the
      APS2 IgG antibodies nor the IDDM MoAbs bind the amino-terminal third of GAD65,
      but instead target the carboxy-terminal two-thirds of GAD65. Amino acids 270-359
      (IDDM-E1) are targeted by one APS2 IgG antibody and MICA-4, while two other APS2
      IgG antibodies, MICA-2 and MICA-3, target amino acids 443-585 (IDDM-E2). Using
      GAD65/67 chimera that span the IDDM-E2 region, we found that MICA-2 binds amino
      acids 514-528 of GAD65, but two APS2 IgG antibodies require this region and amino
      acids 529-570. In contrast, the binding of MICA-3 requires two discontinuous
      amino acid segments of GAD65 (452-513 and 528-569), but not amino acids 514-528.
      These results indicate that there are both similarities and differences in the
      humoral response to GAD65 in APS2 and IDDM.

PMID- 10594552
TI  - Apoptosis of CD4+ T cells occurs in experimental autoimmune anterior uveitis
      (EAAU).
AB  - To investigate the spontaneous turning off mechanism of endogenous uveitis, EAAU
      was induced in Lewis rats. Immunohistochemical and terminal deoxynucleotidyl
      transferase-mediated dUTP nick end labelling (TUNEL) stains revealed that CD4+ T
      cells were predominant in the uveal tissue of EAAU and that the apoptosis of
      these cells had occurred and progressed throughout the inflammatory period in
      EAAU eyes. The immunohistochemistry and in situ hybridization for Fas ligand
      (FasL) expression showed that the expression of Fas ligand was increased in the
      EAAU eyes compared with control eyes. These results suggest that the apoptosis of
      CD4+ T cells may play a key role in the spontaneous turning off mechanism of
      intra-ocular inflammation and that the induction of apoptosis may be mediated by
      the Fas-FasL system in EAAU.

PMID- 10594553
TI  - The matrix metalloproteinase inhibitor BB-1101 prevents experimental autoimmune
      uveoretinitis (EAU).
AB  - EAU is characterized by breakdown of the blood-retinal barrier and extravasation
      of leucocytes into retinal tissue leading to destruction of photoreceptor cells.
      Matrix metalloproteinases (MMP) have been implicated in trafficking of cells into
      tissues, but their role in inflammatory eye disease is unclear. A synthetic MMP
      inhibitor, BB-1101, was administered subcutaneously, from either day 0 or day 7,
      to Lewis rats challenged with bovine S-antigen to induce EAU. When given up to
      day 14, BB-1101 reduced the incidence of disease and delayed the day of onset of
      clinical disease. When administered from day 7 until day 21, EAU was completely
      abrogated. A quantitative polymerase chain reaction (PCR) assay showed an
      increase of both matrilysin (MMP-7), neutrophil collagenase (MMP-8) and
      macrophage metalloproteinase (MMP-12) in retinas from EAU animals compared with
      naive controls. These enzymes are produced by activated leucocytes and act on
      components of the basement membrane. These results therefore implicate these MMP
      as integral to the development of pathology in EAU.

PMID- 10594554
TI  - Transglutaminase and coeliac disease: endomysial reactivity and small bowel
      expression.
AB  - This study was aimed at verifying whether tissue transglutaminase (tTG) is the
      sole autoantigen eliciting anti-endomysial antibodies in coeliac disease (CoD)
      and investigating tTG expression in normal and coeliac mucosa. Twelve anti
      endomysial-positive coeliac sera and 12 anti-endomysial-negative control sera (10
      microl, diluted 1:5-1:400 in PBS pH 7.3) were preincubated with 10, 20 or 50
      microg guinea pig liver tTG at 4 degrees C overnight. Monkey oesophagus tissue
      slides were then tested with tTG-preincubated and non-preincubated sera to search
      for IgA anti-endomysial reactivity by indirect immunofluorescence. Moreover, six
      sections of monkey oesophagus were incubated with an anti-tTG mouse MoAb, six
      sections with an anti-cytokeratin mouse MoAb and six sections with only 3% bovine
      serum albumin. Finally, endoscopic duodenal biopsy sections obtained from 12
      patients affected by untreated CoD, six patients affected by treated CoD and 10
      biopsied controls were immunohistochemically stained with a peroxidase-conjugated
      anti-tTG MoAb. Our results show that (i) preincubation with tTG abolished
      endomysial immunofluorescence in most, but not in all, coeliac sera; (ii) the
      incubation of anti-tTG MoAb with sections of monkey oesophagus resulted in an
      immunofluorescence staining pattern similar but not identical to that of anti
      endomysial-positive coeliac sera; (iii) although tTG expression was present at
      muscularis mucosae and pericryptal fibroblast in both normal and coeliac mucosa,
      it was slightly more marked and evident in the latter. Although our absorption
      experiment was performed with guinea pig liver tTG, we confirm that tTG is the
      predominant antigen of endomysial antibodies, but we speculate that, at least in
      some patients, it is not the only one.

PMID- 10594555
TI  - The inhibitory effect of dexamethasone on lymphocyte adhesion molecule expression
      and intercellular aggregation is not mediated by lipocortin 1.
AB  - Glucocorticoids exert their anti-inflammatory activity through multiple pathways
      which include the inhibition of cell adhesion events. The glucocorticoid-induced
      protein lipocortin 1 (LC1) has reported anti-inflammatory properties and has been
      proposed as a putative mediator of the anti-inflammatory effects of
      glucocorticoids. The role of LC1 in mediating the glucocorticoid inhibition of
      lymphocyte adhesion and cell adhesion molecule (CAM) expression was investigated
      in vitro using a microaggregation assay, flow cytometry and confocal microscopy.
      Lymphocytes stimulated for 96 h with plastic-bound OKT3 antibody showed
      significant increases in LFA-1 and CD2 expression. Dexamethasone (DEX; 10(-6) M)
      inhibited this increase but the neutralizing anti-LC1 MoAb 1A (5 microg/ml)
      failed to reverse the DEX effect; neither was purified human LC1 (50 x 10(-9) M)
      able to inhibit CAM expression. The biological activity of the LC1 was confirmed
      by its ability to suppress monocyte phagocytosis and respiratory burst in
      response to bovine serum albumin (BSA)-anti-BSA complexes. OKT3 stimulation of
      cultured mononuclear cells resulted in intercellular aggregation, scored
      microscopically using a visual index. This aggregation was completely reversed by
      10-6 M DEX but unaffected by LC1 (50 x 10(-9) M). Significant intracellular
      expression of lymphocyte LC1 was observed using the anti-LC1 MoAb 1B in saponin
      permeabilized cells. Distribution of LC1 had a diffuse, cytoplasmic pattern. LC1
      expression was reduced following 3 h treatment with 10(-6) M DEX. These findings
      indicate that the DEX effects on lymphocyte adhesion and CAM expression are not
      mediated by LC1. Thus the reported in vivo effects of LC1 on leucocyte adhesion
      and transmigration probably occur through functional/conformation changes of
      surface CAM, rather than by alteration in expression.

PMID- 10594556
TI  - Naive human T cells can be a source of IL-4 during primary immune responses.
AB  - IL-4 plays a key role in driving the differentiation of CD4+ Th precursors into
      Th2 cells, both in mice and in humans. The source of IL-4 during primary immune
      responses is, however, still debated. When IL-4 consumption in in vitro T cell
      cultures was blocked with a MoAb to the IL-4 receptor alpha-chain (IL-4Ralpha),
      it became evident that freshly isolated naive (CD45RO-) CD4+ T cells from adults
      or cord blood produce IL-4 upon activation with anti-CD3 and CD80. IL-4
      production by naive T cells is strictly IL-2-dependent. Endogenous IL-4 activity
      in naive CD4+ T cell cultures modulates the production of interferon-gamma (IFN
      gamma) on the one hand and IL-5 and IL-13 on the other hand in opposite
      directions, and it is partly responsible for the low IFN-gamma production by cord
      blood T cells. Comparison of the ratio of IL-4/IFN-gamma in supernatants of T
      cell cultures reveals a skewing towards IL-4 production by cord blood T cells,
      while naive T cells from (non-atopic) adults predominantly produce IFN-gamma. We
      conclude that CD4+ naive T cells can produce IL-4 without the need for Th2
      differentiation, and therefore that they can be the initial source of IL-4
      required at the time of priming for T cell differentiation into Th2 cells.

PMID- 10594557
TI  - Extensive characterization of the immunophenotype and pattern of cytokine
      production by distinct subpopulations of normal human peripheral blood MHC
      II+/lineage- cells.
AB  - Dendritic cells (DC) represent the most powerful professional antigen-presenting
      cells (APC) in the immune system. The aim of the present study was to analyse, on
      a single-cell basis by multiparametric flow cytometry with simultaneous four
      colour staining and a two-step acquisition procedure, the immunophenotypic
      profile and cytokine production of DC from 67 normal whole peripheral blood (PB)
      samples. Two clearly different subsets of HLA-II+/lineage- were identified on the
      basis of their distinct phenotypic characteristics: one DC subset was CD33strong+
      and CD123dim+ (0.16 +/- 0.06% of the PB nucleated cells and 55.9 +/- 11. 9% of
      all PB DC) and the other, CD33dim+ and CD123strong+ (0.12 +/- 0.04% of PB
      nucleated cells and 44.53 +/- 11.5% of all PB DC). Moreover, the former DC
      subpopulation clearly showed higher expression of the CD13 myeloid-associated
      antigen, the CD29 and CD58 adhesion molecules, the CD2, CD5 and CD86
      costimulatory molecules, the CD32 IgG receptor and the CD11c complement receptor.
      In addition, these cells showed stronger HLA-DR and HLA-DQ expression and a
      higher reactivity for the IL-6 receptor alpha-chain (CD126) and for CD38. In
      contrast, the CD123strong+/CD33dim+ DC showed a stronger reactivity for the CD4
      and CD45RA molecules, whereas they did not express the CD58, CD5, CD11c and CD13
      antigens. Regarding cytokine production, our results show that while the
      CD33strong+/CD123dim+ DC are able to produce significant amounts of inflammatory
      cytokines, such as IL-1beta (97 +/- 5% of positive cells), IL-6 (96 +/- 1.1% of
      positive cells), IL-12 (81.5 +/- 15.5% of positive cells) and tumour necrosis
      factor-alpha (TNF-alpha) (84 +/- 22.1% of positive cells) as well as chemokines
      such as IL-8 (99 +/- 1% of positive cells), the functional ability of the
      CD123strong+/CD33dim+ DC subset to produce cytokines under the same conditions
      was almost null. Our results therefore clearly show the presence of two distinct
      subsets of DC in normal human PB, which differ not only in their immunophenotype
      but also in their functionality, as regards cytokine production.

PMID- 10594558
TI  - Contribution of serotype-specific IgG concentration, IgG subclasses and relative
      antibody avidity to opsonophagocytic activity against Streptococcus pneumoniae.
AB  - The contribution of serotype-specific IgG concentration, subclasses, and avidity
      to opsonophagocytic activity (OPA) against Streptococcus pneumoniae (Pnc) was
      evaluated in sera of adults and infants immunized with different pneumococcal
      vaccines. Antibody concentrations and avidities were measured by enzyme
      immunoassay (EIA) and OPAs by killing assay of Pnc. The most important factor
      contributing positively to OPA was the specific IgG level. In infants, a tendency
      to negative correlation was found between the concentration needed for killing of
      bacteria and avidity, suggesting that less antibodies of high rather than low
      avidity were required for killing. No such correlation was seen in adults.
      However, in adults the avidity was high already before vaccination and the
      variation was narrow. Thus, avidity was probably not a limiting factor
      influencing OPA. The effect of IgG2/IgG1 ratio on OPA was mostly negative but
      insignificant.

PMID- 10594559
TI  - Adhesion molecules (E-selectin, intercellular adhesion molecule-1 (ICAM-1) and
      vascular cell adhesion molecule-1 (VCAM-1)) in sera from patients with
      Staphylococcus aureus bacteraemia with or without endocarditis.
AB  - The aim of this prospective study was to evaluate if patients with endocarditis
      display a more extensive endothelial activation than those with bacteraemia but
      without endocarditis. Sixty-five patients with blood culture-verified
      Staphylococcus aureus bacteraemia were included and serum samples collected on
      admission were analysed by enzyme immunoassays. Elevated serum concentrations of
      adhesion molecules were found in most of the patients with S. aureus bacteraemia.
      Patients with endocarditis (n = 15) showed significantly higher serum E-selectin
      (median 156 ng/ml) and VCAM-1 (median 1745 ng/ml) concentrations compared with
      those with S. aureus bacteraemia but without endocarditis (80 ng/ml and 1172
      ng/ml, respectively; P = 0.01 and P = 0.003). No significant difference was found
      between the groups concerning ICAM-1 (median 451 ng/ml versus 522 ng/ml). In
      addition, serum tumour necrosis factor-alpha (TNF-alpha) concentrations were
      significantly correlated (P < 0.002) to serum levels of E-selectin, ICAM-1 and
      VCAM-1.

PMID- 10594560
TI  - Highly active anti-retroviral therapy (HAART) is associated with a lower level of
      CD4+ T cell apoptosis in HIV-infected patients.
AB  - HAART may increase CD4+ T cell counts despite a persistently detectable HIV load.
      The impact of HAART on apoptosis, which may play a role in the disease process in
      HIV-infected patients, has not been extensively studied. We performed a study to
      compare the level of spontaneous T cell apoptosis and anti-retroviral treatments
      in a cohort of HIV-1-infected patients. Data were obtained from a computerized
      medical record. Quantification of apoptotic cells was by cytofluorometric
      technique. From November 1995 to December 1997 we studied T cell apoptosis in 112
      HIV-infected patients. Forty patients were classified A, 36 B and 36 C. Thirty
      patients were naive and 82 received an anti-retroviral treatment, 49 including a
      protease inhibitor (PI). The median plasma viraemia determined in 63 patients was
      3.6 (range 1.3-5.6) log10. The median apoptotic cell count was 22% (range 2-73%)
      and 12% (range 2-60%) for CD4+ and CD8+ T cells, respectively. We did not observe
      any correlation between the HIV viraemia and the level of apoptosis of T cell
      subsets. Patients with HAART showed a lower percentage of apoptotic CD4+ T cells
      only: 16% (range 2-61%) versus 25% (range 5-73%) for patients receiving two
      nucleoside analogues (P = 0.02). This effect was significant in stage A patients
      and remained observable during the whole course of HIV disease. In conclusion,
      HAART, without any relation to plasma viraemia, is able to reduce apoptosis of
      CD4+ T cells.

PMID- 10594561
TI  - Elevated levels of beta-chemokines in bronchoalveolar lavage fluid (BALF) of
      individuals infected with human T lymphotropic virus type-1 (HTLV-1).
AB  - Pulmonary complications are known to develop in HTLV-1 carriers, including T
      lymphocytic alveolitis, and increased IL-2 receptor alpha (CD25)-bearing T cells
      have been found in BALF. Several chemokines may contribute to accumulation of T
      lymphocytes in the lungs of HTLV-1 carriers. Here, we compared the distribution
      of T lymphocyte subsets and beta-chemokines, such as macrophage inflammatory
      peptide-1alpha (MIP-1alpha), regulated on activation normal T expressed and
      secreted (RANTES), and macrophage chemoattractant protein-1 (MCP-1), in BALF and
      peripheral blood between HTLV-1 carriers and non-infected healthy normal
      subjects. Flow cytometric analysis with MoAbs to cell surface antigens was used
      to identify T lymphocyte subsets in BALF samples from HTLV-1 carriers (n = 13)
      and non-infected healthy controls (n = 10). The levels of different beta
      chemokines were estimated by ELISA. High percentages of CD3+ cells, CD3
      expressing HLA-DR antigen and CD3+CD25+ cells were detected in BALF of HTLV-1
      carriers compared with non-infected controls. The concentration of MIP-1alpha in
      BALF of patients was significantly higher than in non-infected healthy controls
      and correlated well with the percentage of CD3+CD25+ cells. The level of RANTES
      in BALF was also significantly high in HTLV-1 carriers, but did not correlate
      with the percentage of CD3+CD25+ cells. On the other hand, the level of MCP-1 in
      BALF of HTLV-1 carriers was not different from that of controls. Our results
      suggest a possible interaction between activated T cells bearing CD25 and beta
      chemokines, especially MIP-1alpha, which may contribute to the pulmonary
      involvement in HTLV-1 carriers.

PMID- 10594562
TI  - Soluble platelet selectin (sP-selectin) and soluble vascular cell adhesion
      molecule-1 (sVCAM-1) decrease during therapy with benznidazole in children with
      indeterminate form of Chagas' disease.
AB  - The immune response against Trypanosoma cruzi infection has been associated with
      both protection and pathogenesis. Central events in host defence system- and
      immune-mediated damage are tightly regulated by cell adhesion molecules (CAM).
      Levels of sP-selectin and sVCAM-1 were measured in sera from 41 children with the
      indeterminate phase of Chagas' disease. Simultaneously, levels of soluble
      adhesion molecule were also quantified in Chagas' disease children undergoing
      specific chemotherapy with benznidazole. Levels of sP-selectin and sVCAM-1 were
      found to be elevated in children with indeterminate Chagas' disease before
      aetiologic therapy was started. However, a small group of patients showed sP
      selectin and sVCAM-1 levels comparable to those of non-infected children. A
      positive correlation between levels of sVCAM-1 and sP-selectin in sera from
      Chagas' disease patients was found. There was a significantly greater decrease in
      the titres of sP-selectin and sVCAM-1 in those children receiving benznidazole
      therapy compared with those children receiving placebo. Measurement of soluble
      adhesion molecules revealed differences in the activation of the immune system in
      children with the indeterminate form of Chagas' disease. The early decrease of sP
      selectin and sVCAM-1 levels after anti-parasitic treatment suggests that these
      molecules might be valuable indicators of effective parasitologic clearance.

PMID- 10594563
TI  - Effects of cocaine administration to influenza virus-immunized mice on cytokine
      profiles of individual splenic CD4+ and CD8+ T cells.
AB  - We have analysed the effects of cocaine, administered to mice during the in vivo
      differentiation of effector T cells stimulated by antigen (influenza virus)
      recognition, on the frequency of IL-2-, IL-4- and interferon-gamma (IFN-gamma)
      expressing CD4+ and CD8+ T cells. Each animal was injected intraperitoneally with
      10 mg/kg of cocaine 6, 24, 48 and 72 h after immunization with A/PR8 influenza
      virus (PR8). This enabled the determination of the pharmacological effects of
      cocaine on T cells during the initial step of the immune response, which is
      characterized by the production of large amounts of immunoregulatory cytokines.
      The distribution of IL-2-, IL-4- and IFN-gamma-producing CD4+ and CD8+ T cells
      was assayed on unseparated PR8-immune spleen cells, obtained from mice treated
      with cocaine or vehicle, and restimulated in vitro with UV-inactivated PR8 virus.
      The frequency of T cells singly or co-expressing the above three cytokines was
      determined at single-cell level by simultaneous flow cytometric analysis of
      intracellular cytokines and surface antigen expression. In parallel, the levels
      of IL-2, IL-4 and IFN-gamma in the culture supernatants were quantified by ELISA.
      The results showed that cocaine, administered during the in vivo virus-induced
      differentiation of T cells, caused an increase of both the frequencies of CD8+ T
      cells singly and co-expressing IL-2 and IFN-gamma and the levels of these
      cytokines in virus-restimulated spleen cell culture supernatants, compared with
      those of untreated controls. In contrast, no effect was found on IL-4-positive
      CD8+ T cells and on IL-2-, IFN-gamma- and IL-4-positive CD4+ T cells. Our
      findings suggest that the immunomodulatory effects of cocaine may be due to the
      up-regulation of the production of IL-2 and IFN-gamma by CD8+ T cells with a type
      0 cytokine profile.

PMID- 10594564
TI  - Neopterin-induced expression of intercellular adhesion molecule-1 (ICAM-1) in
      type II-like alveolar epithelial cells.
AB  - Production and release of proinflammatory mediators such as tumour necrosis
      factor-alpha and neopterin are common events following the activation of the
      cellular immune system. Concerning inflammatory disorders of the lung, e.g.
      sepsis or sarcoidosis, high serum neopterin levels have been reported to
      correlate well with the severity of the disease. These situations are often
      associated with an increased expression of ICAM-1 reported to be induced in type
      II alveolar epithelial cells. In our study we investigated the potential effects
      of neopterin on ICAM-1 synthesis in the type II-like pneumocyte cell line L2.
      Detection of ICAM-1 gene expression by reverse transcriptase-polymerase chain
      reaction revealed a dose-dependent effect of neopterin, with maximum impact
      following 12-h incubations. Comparable results were obtained when ICAM-1 protein
      synthesis was measured via a cell-based ELISA. In a second set of experiments we
      were able to show that coincubation of L2 cells with pyrrolidine dithiocarbamate
      (PDTC) significantly suppressed neopterin-induced ICAM-1 synthesis. Since PDTC is
      known to be a potent inhibitor of NF-kappaB, the stimulating effects of neopterin
      on ICAM-1 gene expression and protein generation may be mediated by activation of
      this transcription factor. From these data we conclude that neopterin stimulates
      ICAM-1 production in L2 cells. In vivo, these effects may contribute to the
      prolongation of the inflammatory response, including cytotoxic cell host defence
      mechanisms that impair the functions of the airway epithelium.

PMID- 10594565
TI  - Serum levels of soluble Fas ligand in patients with silicosis.
AB  - Certain patients with silicosis have been reported to exhibit immunological
      abnormalities such as the appearance of antinuclear antibodies and the occurrence
      of autoimmune diseases. Fas ligand (FasL) is a type II membrane protein which
      induces apoptosis by binding to its membrane receptor, Fas. FasL is converted to
      a soluble form by a metalloproteinase-like enzyme. We have already found serum
      soluble Fas (sFas) levels in silicosis patients as well as in patients with
      systemic lupus erythematosus (SLE) to be significantly higher than those in
      healthy volunteers. To examine further the role of the Fas/FasL system in silica
      induced immunological abnormalities, we investigated serum soluble FasL (sFasL)
      levels in silicosis patients with no clinical symptoms of autoimmune diseases,
      using ELISA for sFasL. Although the serum sFasL levels in patients with SLE were
      significantly higher than those in healthy volunteers and showed a slight
      positive correlation with serum sFas levels, those in silicosis patients
      exhibited no significant difference from those in healthy volunteers, and there
      was no correlation with serum sFas levels. However, sFasL levels were elevated in
      silicosis patients with slight dyspnoea or normal PCO2 among various clinical
      parameters of silicosis. It may be speculated that the immunological disturbances
      presented by the abnormalities of apoptosis-related molecules in silicosis
      patients do not occur with a similar degree of respiratory involvement. Further
      studies are required to clarify which kinds of factors are involved in silicosis
      patients who exhibit immunological abnormalities.

PMID- 10594566
TI  - Circulating antibodies against alpha-enolase in patients with primary membranous
      nephropathy (MN).
AB  - MN is characterized by the glomerular deposition of IgG4 immune complexes. This
      suggests that nephritogenic immune responses in MN are of the Th2 T helper cell
      type; however, the pathogenesis of MN is still unknown. In this study we examined
      sera from patients with primary MN for antibodies to renal proteins. A 47-kD
      protein in both human and porcine renal extracts was found by immunoblotting to
      react specifically with serum IgG from some patients. This protein was purified
      from porcine kidney and identified as alpha-enolase on the basis of its partial
      amino acid sequences. Sera from 87 patients with primary MN, 24 patients with
      secondary MN (15 rheumatoid arthritis patients, nine systemic lupus erythematosus
      patients), and 16 healthy subjects were examined by ELISA using purified alpha
      enolase. In 60 (69%) patients with primary MN and 14 (58%) patients with
      secondary MN, the measured optical density values, and hence serum anti-alpha
      enolase antibody levels, were greater than the mean + 2 s.d. of healthy subjects.
      Immunoblot analysis showed that IgG1 or IgG3 was the predominant subclass (Th1 T
      helper cell type subclass) of antibodies against alpha-enolase in patients with
      primary and secondary MN. Since circulating antibodies against alpha-enolase have
      recently been reported in patients with various autoimmune disorders, our results
      suggest that a number of patients with presumed primary MN may also have
      abnormalities in Th1 T helper cell-mediated immune responses.

PMID- 10594567
TI  - Gammadelta T cells in Behcet's disease (BD) and recurrent aphthous stomatitis
      (RAS).
AB  - The immunopathogenesis of BD is believed to be T cell-mediated. The objective of
      this study was to characterize the activation stage and cytokine profile of
      peripheral blood lymphocytes (PBL), with particular emphasis on gammadelta T
      cells. Venous blood was collected from 20 patients with BD, and for comparison,
      from 11 patients with RAS and from 15 healthy controls. Both the expression of
      activation markers (CD25, CD29, CD40 ligand, CD69 and HLA-DR) on freshly isolated
      PBL and T cell subsets, and the expression of intracellular cytokines (IL-4, IL
      10, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha)) on
      mitogen-stimulated PBL and T cell subsets were analysed by double
      immunofluorescent staining and flow cytometry. Significantly decreased proportion
      of alphabeta T cells and increased proportion of gammadelta T cells, CD56+ cells
      and CD8+ gammadelta T cells were found in BD patients compared with healthy
      controls. This was also seen to a lesser extent in patients with RAS.
      Furthermore, in BD a significantly increased proportion of the gammadelta T cell
      population expressed CD69 and high levels of CD29 and were induced to produce IFN
      gamma and TNF-alpha compared with healthy controls. In contrast, an increased
      percentage of gammadelta T cells from RAS patients was induced to produce IFN
      gamma, but not TNF-alpha. These results indicate that in BD, activated gammadelta
      T cells, capable of producing IFN-gamma and TNF-alpha, are present in peripheral
      blood, suggesting that gammadelta T cells are dynamic and may be regulating
      immunopathogenic events.

PMID- 10594568
TI  - Effect of plasmapheresis on ligand binding capacity and expression of erythrocyte
      complement receptor type 1 (CR1) of patients with systemic lupus erythematosus
      (SLE).
AB  - The functional activity and the expression of CR1 on the erythrocytes (E) of
      patients with SLE were, respectively, determined by measuring the binding to E of
      either complement-opsonized bovine serum albumin (BSA)-anti-BSA immune complexes
      (ICC) or specific anti-ECR1 MoAbs. We found that both the functional activity and
      levels of ECR1 in SLE patients homozygous for ECR1 high density allele were
      significantly lowered compared with healthy controls having the same allele. Soon
      after plasmapheresis there was a significant increase in E ICC binding activity,
      and this increased functional activity was stable. Moreover, plasmapheresis
      reduced the level of immune complexes demonstrable in the circulation of the
      patients. The expression of ECR1 determined with several different anti-CR1 MoAbs
      was also elevated as a consequence of plasmapheresis. This elevation was observed
      for both MoAb 1B4, which competes for the ICC binding site of ECR1, and for MoAb
      HB8592, which does not, but the time course for the increase in binding of the
      two MoAbs was different, in that the epitope recognized by MoAb 1B4 increased
      more rapidly. The present results, considered in the context of previous
      findings, suggest that more than one mechanism may be operative with respect to
      the effects of the plasmapheresis in increasing ECR1 levels defined by different
      epitopes on the molecule.

PMID- 10594569
TI  - Oligo-monoclonal immunoglobulins frequently develop during concurrent
      cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections in patients after
      renal transplantation.
AB  - In the present study we report that the appearance of oligo-monoclonal
      immunoglobulins (oligoM-Igs) in the sera of transplanted individuals is
      concurrent with the detection of coincident active CMV infection and EBV
      replication. Eighty-four renal allograft patients were monitored with respect to
      CMV isolation, to CMV conventional serology and humoral response against the EBV
      trans-activator ZEBRA (an immediate-early antigen also called BZLF1). Titration
      of anti-ZEBRA antibodies (IgG and IgM) and amount of EBV DNA in serum were
      evaluated. Using the combination of four techniques (agarose gel electrophoresis,
      analytical isoelectric focusing, high resolution immunoelectrophoresis,
      immunofixation electrophoresis), oligoM-Igs were found in 25% of patients after
      allografting and significantly associated with rejection episodes (P < 0.001).
      Twenty out of 23 (86%) concurrent CMV/EBV infections were associated with serum
      oligoM-Igs (P < 0.001). One can thus reasonably assume that a sustained EBV
      replication following iatrogenic immunosuppression can promote the immunoglobulin
      heavy chain expression in EBV-infected B lymphocytes. The proliferation of
      immunoglobulin-secreting clones might occur after active CMV infection, through a
      transient over-immunosuppression or via immune subversion.

PMID- 10594570
TI  - T helper frequencies in peripheral blood reflect donor-directed reactivity in the
      graft after clinical heart transplantation.
AB  - We describe the usefulness of a fast (48-h) limiting dilution assay (LDA) for the
      enumeration of human alloreactive helper T lymphocytes (HTL) in the peripheral
      blood, in relation to histologically defined rejection grades after heart
      transplantation. HTL frequencies (HTLf) in pretransplant samples varied from
      patient to patient, ranging from 106 to 625 HTL/106 peripheral blood mononuclear
      cells (PBMC). In the first week after heart transplantation (HTx), when
      immunosuppression was instituted, HTLf were significant lower (range 30-190
      HTL/106). The level of HTL in the first week after HTx when rejection grade was 0
      or 1A (ISHLT score) was considered to be the baseline frequency. This frequency
      did not correlate with the number of subsequent rejection episodes. During
      rejection (grade 3), donor-specific HTLf were increased above their baseline
      frequencies (P = 0.01). Expressed as percentage of baseline frequencies, HTLf
      increased significantly during acute rejection (AR) compared with 1-2 weeks
      before rejection (P = 0.003). The increase was specific, since viral infections
      did not result in a rise of donor-specific HTL, while also HTLf specific for
      third party HLA antigens were not elevated during rejection. Monitoring HTLf in
      peripheral blood with a shortened (48-h) assay may serve as a non-invasive method
      for detecting intragraft immunological reactivity. Demonstrating absence of donor
      specific reactivity may limit the number of invasive endomyocardial biopsy (EMB)
      procedures and allow tapering of immunosuppressive treatment.

PMID- 10594572
TI  - Characterization of monoclonal antibodies to proteinase 3 (PR3) as candidate
      tools for epitope mapping of human anti-PR3 autoantibodies.
AB  - Anti-neutrophil cytoplasmic antibodies directed against PR3 (PR3-ANCA) in
      patients with Wegener's granulomatosis are supposedly involved in the
      pathophysiology of this disease as different functional characteristics of the
      autoantibodies correlate with disease activity. However, little is known about
      the epitopes of PR3 that are recognized by PR3-ANCA and how epitope specificity
      may relate to functional characteristics of PR3-ANCA. As candidate tools for
      epitope mapping we studied 13 anti-PR3 MoAbs, including nine widely used and four
      newly raised MoAbs, for their mutual binding characteristics to PR3 using
      biosensor technology. Antigen specificity was confirmed by indirect
      immunofluorescence, immunoblotting, FACS analysis and antigen-specific ELISA.
      Competition between anti-PR3 MoAbs in binding to PR3 was investigated in a
      capture system set up in a BIAcore. In this system grouping of 12 of the 13 anti
      PR3 MoAbs based on their mutual recognition patterns was achieved. Four MoAbs,
      from different research groups, namely 12.8, PR3G-2, 6A6 and Hz1F12, recognized
      comparable epitopes (group 1). Group 2 MoAbs including PR3G-4 and PR3G-6 bound to
      overlapping regions on PR3. The MoAbs PR3G-3, 4A5 and WGM2 recognized similar
      epitopes as they inhibited binding of each other (group 3). The fourth group of
      related MoAbs consisted of MC-PR3-2, 4A3 and WGM3. Because of its binding
      characteristics MoAb WGM1 could not be grouped. These results demonstrate that
      eight well-established anti-PR3 MoAbs produced by different research groups and
      four newly produced anti-PR3 MoAbs recognize four separate epitope areas on PR3,
      including one area detected with newly raised MoAbs only.

PMID- 10594573
TI  - Residual thermal damage resulting from pulsed and scanned resurfacing lasers.
AB  - BACKGROUND: Laser resurfacing with rapidly scanned or pulsed carbon dioxide (CO2)
      lasers has evolved rapidly in recent years. These lasers vaporize small amounts
      of tissue, while leaving minimal residual thermal damage. OBJECTIVE: To compare
      the depth of residual thermal damage of two of the most commonly used CO2 laser
      systems. A rapidly scanned laser was compared to a short-pulse laser system.
      METHODS: Laser treatment was performed on abdominoplasty specimens prior to
      removal in four subjects. One, two, or three passes of the two most commonly used
      energies were administered using each laser system. RESULTS: The depth of thermal
      damage increased with a greater number of passes with each laser system. Higher
      energies resulted in greater residual thermal damage with each system after the
      first pass up to three passes, which was the maximum number of passes
      administered. Combining the second and third passes, residual thermal damage was
      remarkably similar when comparing the pulsed and scanned lasers. CONCLUSIONS: The
      most commonly used energy settings of two lasers with very different modes of
      action resulted in remarkably similar depths of thermal damage, suggesting that
      the zone of thermal damage may correlate with clinical outcome. In addition, the
      zone of thermal damage enlarges as the number of passes increases from one to
      three.

PMID- 10594571
TI  - Binding properties of antibodies to prothrombin and beta2-glycoprotein I (beta2
      GPI) assayed by ELISA and dot blot.
AB  - Most anti-phospholipid antibodies (aPL) associated with the anti-phospholipid
      syndrome are autoantibodies with specificity towards beta2-GPI (anti-beta2-GPI)
      or prothrombin (anti-II). They are mainly screened by ELISA using polyoxygenated
      plates. However, some authors have claimed that immunoblotting can also be used.
      Exposure of cryptic epitopes or increase of antigen density on its binding to
      either phospholipids or suitable plastic surfaces are the two hypotheses proposed
      for the interaction of beta2-GPI or prothrombin with their antibodies. Forty-five
      patients with aPL were studied: 25 with lupus anti-coagulant (LA) and anti
      cardiolipin antibodies (aCL), 10 with LA alone and 10 with aCL but negative LA.
      All patients with LA and aCL were positive for anti-beta2-GPI by ELISA and dot
      blot, while 15/25 had anti-IIELISA and 14 of them also had anti-II by dot blot
      assay. No patient with LA alone tested positive for anti-beta2-GPI by ELISA or
      dot blot, whereas 6/10 had anti-IIELISA (five of them were also positive by dot
      blot). Four out of 10 aCL-positive patients had anti-beta2-GPI by ELISA and dot
      blot, while none of this group had anti-II by ELISA or dot blot. Antibody binding
      to beta2-GPI or prothrombin in both ELISA and dot blot was significantly reduced
      by phospholipid liposomes mixed together with beta2-GPI or prothrombin, whereas
      liposomal eluants retained it in both assays. Parallel fluid-phase inhibition
      experiments using increasing concentrations (up to 200 microg/ml) of beta2-GPI or
      prothrombin demonstrated that antibody binding reduction was more evident on dot
      blot than on ELISA. It was almost completely abolished on dot blot, while on
      ELISA a moderate inhibition was achieved even at the highest protein
      concentration. However, antibody binding on ELISA was virtually abolished when
      diluted sera were incubated with high protein concentrations applied to
      nitrocellulose membranes. We could infer that ELISA and dot blot detect
      antibodies with some differences in avidity but directed against native epitopes
      on beta2-GPI and prothrombin.

PMID- 10594574
TI  - Neck rejuvenation by combining Jessner/TCA peel, dermasanding, and CO2 laser
      resurfacing.
AB  - BACKGROUND: One of the greatest challenges facing facial cosmetic surgeons today
      is the simultaneous rejuvenation of the neck and face. Laser resurfacing of the
      face using the carbon dioxide (CO2) laser or the erbium:yttrium-aluminum-garnet
      (Er:YAG) laser has enjoyed widespread popularity, but the neck and chest are
      often avoided. It would be quite helpful to rejuvenate the neck at the same time
      the face is being resurfaced. This would diminish lines of demarcation and help
      reduce the signs of aging of the neck. There would be a better match between the
      new skin of the neck and face. OBJECTIVE: To develop a safe and effective method
      to rejuvenate the neck. METHOD: A step-by-step skin care program was instituted.
      The patients preconditioned their face and neck skin with vitamin A/glycolic skin
      conditioning lotions for 6-8 weeks prior to surgery. Following this the chest and
      neck area was treated with the Jessner-trichloroacetic acid (TCA) peel. Then the
      middle section of the neck was sanded with 150 grit sandscreen. Finally, the
      central area was resurfaced with the UltraPulse CO2 laser using reduced power
      settings. Usually two passes was adequate to shrink the skin of this central
      section of the neck. A petrolatum-based ointment was applied during the initial 7
      day postoperative period. After reepithelialization a sunscreen-moisturizer was
      used during the day and hydrocortisone moisturizer was applied at night. RESULTS:
      The neck skin was able to tolerate this step-by-step skin rejuvenation. The
      blending from the decollete area to the hairline produced a rejuvenation without
      a line of demarcation. There were no examples of scarring in the 12 cases that
      were evaluated for 6 months. Two cases developed persistent erythema that
      responded to silicone gel sheeting. Although no patients complained of
      hypopigmentation, a decrease in pigment was found using special UV photography.
      CONCLUSION: It is possible with this gradient, step-by-step method to produce a
      rejuvenation of the neck. An improved texture of the neck developed without
      visible scarring.

PMID- 10594575
TI  - Treatment of cutaneous lesions of xanthoma disseminatum with a CO2 laser.
AB  - We describe a case of a 15-year-old African American girl with widespread
      papulonodular lesions of xanthoma disseminatum especially in the periorbital area
      and on the flexural surfaces of the neck, axillae, arms, and legs. There were no
      mucosal lesions. An initial trial in the distant past of liquid nitrogen
      cryotherapy resulted in partial shrinking of cutaneous lesions but was too
      painful for the patient. She then underwent surgical excision of bilateral eyelid
      lesions with improvement, but additional procedures were deemed impractical when
      considering the great number and size of the lesions. Consequently we treated the
      patient with a carbon dioxide (CO2) laser with excellent results. The relatively
      great speed at which the CO2 laser procedure can be performed has made the
      removal of multiple lesions in each session possible. Additional advantages
      included precise vaporization of lesions, hemostasis during the operative
      procedure, and minimal postoperative pain and edema.

PMID- 10594576
TI  - Modified tumescent liposuction.
AB  - BACKGROUND: Tumescent liposuction has been found to be safe and effective.
      However, there are still many refinements that may be possible, such as varying
      the size and tips of the cannulas, varying the types of infiltrate and associated
      anesthesia, and the method of compression. OBJECTIVE: To examine possible
      variables in tumescent liposuction techniques such as the most efficient
      liposuction cannulas, to determine an effective tumescent fluid, and to examine
      the extent of compression provided by different garments. METHODS: Patient
      markings, tumescent fluid formulas, methods of infiltration, types of cannulas,
      skin incisions, and compression garments were compared between the pure tumescent
      technique and modified tumescent liposuction. RESULTS: The most efficient
      cannulas were those with three staggered ports, such as the Mercedes, Cobra-keel,
      Giorgio Fischer, and Accelerator II tips. When these are combined with modified
      tumescent fluids and sedation, it is possible to perform total body liposuction
      in a safe and efficient manner. Multiple ports and compression garments are
      beneficial to reduce bruising and focal areas of inflammation. CONCLUSION: The
      tumescent liposuction technique will continue to be improved. So far, with more
      efficient cannulas and more efficient tumescent fluids, combined with sedation,
      it has been possible to increase the yield and decrease the required time for the
      technique. We call this modified tumescent liposuction.

PMID- 10594577
TI  - Cryogen spray cooling and higher fluence pulsed dye laser treatment improve port
      wine stain clearance while minimizing epidermal damage.
AB  - BACKGROUND: When a cryogen spurt is applied to the skin surface for an
      appropriately short period of time (on the order of tens of milliseconds), the
      cooling remains localized in the epidermis, while leaving the temperature of the
      deeper port-wine stain (PWS) blood vessels unchanged. OBJECTIVE: The objective of
      this study was to compare the efficacy and safety of noncooled laser treatment
      (NC-LT), and cryogen spray cooled laser treatment (CSC-LT) of PWS birthmarks in a
      large series of patients. METHODS: A retrospective review was conducted of 196
      patients with head or neck PWS birthmarks treated with the pulsed dye laser
      (lambda = 585 nm; taup = 450 microseconds) over a 7-year period. Subjects' ages
      ranged between 2 months and 62 years; there were 109 females and 87 males, all of
      whom were Asian. Ninety-eight patients received NC-LT using light dosages of 5-7
      J/cm2. Subsequently, 98 patients received CSC-LT using light dosages of 8-10
      J/cm2. The primary efficacy measure was the quantitative assessment of the
      blanching response scores of NC-LT PWSs as compared, on a blinded basis, to CSC
      LT PWSs. RESULTS: Based on chi-squared analysis, there were clinical, and
      statistically significant, differences in the blanching response scores favoring
      PWS receiving CSC-LT as compared to the NC-LT group (P <.001). Permanent scarring
      was noted in 3.1% (n = 3) of the patients in the NC-LT group. Permanent scarring
      was not observed in the CSC-LT treatment group. Transient hyperpigmentation was
      noted in 57% (n = 56) and 48% (n = 47) of the patients in the NC-LT and CSC-LT
      groups, respectively. In both groups, the transient hyperpigmentation resolved in
      all patients within 1 year. Two patients in the NC-LT group developed delayed
      permanent hypopigmentation. Permanent hypopigmentation was not observed in the
      CSC-LT group. CONCLUSION: CSC permitted the use of higher incident light dosages
      leading to improved PWS clearance without producing complications such as
      permanent scarring or dyspigmentation.

PMID- 10594578
TI  - TCA-based blue peel: a standardized procedure with depth control.
AB  - BACKGROUND: Trichloroacetic acid (TCA) peels are popular, well known, and widely
      utilized to correct a variety of skin problems. Different methods exist, ranging
      from the use of plain TCA to augmented or modified TCA at concentrations ranging
      from 30% to 50%. However, peel results vary depending upon the physician skill
      level, patient selection, and patient management. OBJECTIVES: The purpose of this
      article is to fill the gap for a peel that is deeper than superficial exfoliative
      procedures yet lighter than a medium-depth peel, to simplify and standardize the
      TCA peel, to define depth properly based on intraoperative clinical signs, to
      implement a color guide that facilitates even application of TCA and avoids skip
      areas, and to identify and minimize variables that may contribute to inconsistent
      outcomes. METHODS: A coating system for TCA application is created by selecting a
      specific TCA concentration (15% or 20%), TCA volume (4 or 6 ml, respectively),
      and a standardized body surface area to be peeled (5%), taking into consideration
      skin thickness and fragility. Multiple coats of TCA are applied to reach the
      desired endpoints: papillary dermis (light Blue Peel) or the immediate upper
      reticular dermis (light/medium Blue Peel). Clinical signs guide the depth
      achieved (frost quality, even blue, pink sign, epidermal sliding) and correlate
      retrospectively with healing time (7-10 days). RESULTS: The TCA Blue Peel was
      found to be a simple and consistent treatment approach for problems related to
      the epidermis, papillary dermis, and immediate upper reticular dermis. An
      unexpected benefit was the appearance of skin tightening and a reduction of skin
      laxity in many cases. This suggests that the papillary dermis and the immediate
      upper reticular dermis play a significant role in skin tightness. CONCLUSION: A
      simple coating system for achieving depth-controlled TCA peels is presented with
      correlation to intraoperative clinical signs. This method makes it easier to peel
      skin of all racial backgrounds, including nonfacial skin. This is especially
      useful for many patients previously excluded from having procedures that
      penetrate beneath the papillary dermis. Commonly encountered variables in
      chemical peels are presented which may affect outcome.

PMID- 10594579
TI  - Prolonged erythema after facial laser resurfacing or phenol peel secondary to
      corticosteroid addiction.
AB  - BACKGROUND: Prolonged persistent erythema postprocedure using phenol or carbon
      dioxide (CO2) lasers occurs frequently and the reasons have not been fully
      ascertained. OBJECTIVE: To describe patients whose postoperative care consisted
      of prolonged use of topical corticosteroids and to assess the outcome of
      cessation of this medicine. METHODS: Twelve patients who underwent CO2 laser
      resurfacing or phenol peels to their face are presented. All patients were seen
      between 3 and 30 months after the procedures were performed. All dressings, wound
      care, and other medicaments had been stopped prior to being seen. Most were patch
      tested to a wide variety of chemicals including corticosteroids, topical
      medications, and preservatives. They were observed during the poststeroid
      cessation period and the clinical response is described. RESULTS: All patch
      testing showed insignificant results. All postpeel patients cleared within 6
      months of steroid cessation, experiencing several flares of erythema before the
      end result. Three of the six laser resurfacing patients cleared fully within 12
      months and three are still being followed. The erythema and severe burning in the
      patients that cleared stayed clear during long-term follow-up. No scars or
      atrophy were seen. CONCLUSION: The use of topical corticosteroid preparations
      postoperatively in peel and resurfacing patients is believed to be a major cause
      of prolonged erythema, dermatitis, burning, and telangiectasias in these
      patients. The mechanism is believed to be one of vasoconstriction/vasodilatation
      secondary to the corticosteroids through a nonintact barrier.

PMID- 10594580
TI  - The multilayer technique: A new and fast approach for flashlamp-pumped pulsed
      (FLPP) dye laser treatment of port-wine stains (preliminary reports).
AB  - BACKGROUND: The 585 nm flashlamp-pumped pulsed (FLPP) dye laser is an effective
      and established treatment for port-wine stains (PWSs) during childhood.
      Unfortunately, PWSs tend to darken in color and may thicken or develop nodules as
      the lesions age, thereby making treatment difficult in adult patients since they
      may require several laser sessions producing unpredictable results. The aim of
      this article is to present and discuss the results obtained in four adult
      patients with PWS by use of a new approach in FLPP dye laser treatment.
      OBJECTIVE: The goal of this technique was to damage, during the same treatment,
      the lesions at both deep and superficial levels and to reduce the number of laser
      sessions required to obtain the most effective eradication of hypertrophied PWSs.
      METHODS: Four patients (two men and two women aged 54, 57, 49, and 61,
      respectively) were referred for treatment of congenital hypertrophied PWS of the
      face. Every dye laser session consisted of two laser passes. During the first
      pass the wavelength ranged from 590 to 600 nm with a long pulse (1.500
      microseconds), while the second pass was performed utilizing the classic short
      pulse (450 microseconds) and wavelength (585 nm). Successive treatments were
      performed at 6- to 8-week intervals. RESULTS: All four patients had a complete
      clearing of their PWS after a number of treatments, ranging from three to five
      sessions. Three of them (one man and the two women) experienced extremely mild
      blistering in a limited small area that healed in approximately 10 days without
      scarring. The laser sessions were well tolerated by all patients. None of the
      patients developed atrophic or hypertrophied scars or dyschromia. CONCLUSIONS:
      Our results show an excellent response in all patients with just a few treatments
      (three to five sessions) and, in spite of two passes, only mild side effects that
      are probably limited due to cooling of the skin. We also observed a flattening
      and reduction of the nodules.

PMID- 10594581
TI  - Preserved particulate fascia lata for injection: a new alternative.
AB  - BACKGROUND: Preserved particulate fascia lata, derived from screened human
      cadavers, has recently become available. This injectable form of the material can
      be injected when soft tissue augmentation is desired. Historically, preserved
      fascia grafts have proven efficacy and an excellent safety record over the past
      73 years. OBJECTIVE: To examine the clinical response to preserved fascia lata
      injections in human subjects. METHODS: Clinical subjects (N = 81; 74 women, 7
      men, age range 19-56 years) requiring deep, soft tissue augmentation to repair
      various cosmetic deficiencies were injected with a total of 109 syringes of
      preserved particulate fascia lata. Three different preparations-<2.0 mm, <0.5 mm,
      and <0.25 mm particle sizes-were hydrated in 3-5 cc of 0.3% lidocaine solution
      and injected with needles ranging in size from 16 to 25 gauge. RESULTS: The
      patients were followed for 6-9 months after implantation without incidence of
      infections, allergic reactions, or acute rejection. After the treatment day,
      patients experienced no further discomfort. No dermal inflammation was evident
      and the local echymosis associated with injections was typically minor. Soft
      tissue augmentation was evident 3-4 months after grafting or longer in most
      cases. CONCLUSIONS: This patient series indicates that injectable preparations of
      preserved fascia lata have the same high biocompatibility as experienced with
      whole-tissue implants. The safety record of preserved fascia lata implants is
      reviewed.

PMID- 10594582
TI  - Subcutaneous fistulectomy in bridging hidradenitis suppurativa.
AB  - BACKGROUND: The treatment of chronic lesions in hidradenitis suppurativa remains
      a challenge. For some clinical types surgical management is an excellent
      alternative. OBJECTIVE: This study evaluates an alternative surgical approach for
      the treatment of hidradenitis suppurativa of specific bridging lesions by
      subcutaneous resection of the tubular fibrotic tissue. METHODS: Periorificial
      fusiform skin incisions were made around the orifices parallel to the axillary or
      inguinal folds and the subcutaneous tubular fibrotic tissue was removed en bloc
      before skin suturing. RESULTS: The outcome was evaluated as satisfactory due to
      lower morbidity, minimizing the excised skin areas, prevention of bridles or
      adherences, shorter incisions, no healing difficulties, and less dehiscence or
      wound exposure. CONCLUSION: The subcutaneous fistulectomy is a surgical option in
      bridging hidradenitis suppurativa.

PMID- 10594583
TI  - Ropivacaine: an important anesthetic agent for slow infusion and other forms of
      tumescent anesthesia.
AB  - BACKGROUND: Reliable, long-acting local anesthetics reduce postoperative pain and
      make it easier to plan surgery. This is especially true when slow infusion
      tumescent anesthesia (SITA) is used. The anesthetic agent ropivacaine appears to
      meet the requirements of SITA especially well. OBJECTIVE: This study examined the
      clinical effectiveness and tolerance of ropivacaine in healthy volunteers and in
      a large number of patients. METHODS: Ropivacaine's clinical action was
      investigated as follows: Thirty healthy volunteers received 30 ml of three
      solutions of lidocaine alone, lidocaine mixed with ropivacaine, and ropivacaine
      alone, all containing epinephrine 1:1,000,000. The local anesthetic effects were
      studied. Ropivacaine was used clinically both alone and with different mixtures
      of ropivacaine and prilocaine, containing epinephrine 1:1,000,000, in a total of
      5220 surgical procedures of all kinds in 3270 patients. The maximum dose of
      ropivacaine was 300 mg. No patient was excluded from this kind of anesthesia.
      Patient ages ranged from 5 to 95 years (median 54). No suprarenin was added for
      nerve blocks of the fingers and penis. RESULTS: Ropivacaine acted more than twice
      as long as lidocaine. Clinical application was completely free of side effects
      and complications and involved a very low rate of postoperative bleeding. The
      patients remained free of pain as a rule for many hours. CONCLUSION: We regard
      ropivacaine as a major step forward in the use of local anesthesia.

PMID- 10594584
TI  - The surgical treatment of traumatic hematoma of the auricle.
AB  - BACKGROUND: The auricular hematoma occurs secondary to trauma and can present a
      therapeutic dilemma for clinicians. Early intervention can be limited to simple
      incision and drainage. Delay in treatment may allow the growth of ectopic
      fibroneocartilage derived from the damaged perichondrium. Removal of this
      abnormal tissue is imperative to avoid permanent ear deformity. OBJECTIVE:
      Surgical intervention was utilized to treat auricular hematomas in two teenage
      boys. METHODS: The auricular hematomas were treated by raising a cutaneous flap
      over the injury site. The clot and serosanguinous fluid were drained and, because
      the injuries were 1 month old, the developing plate of fibroneocartilage and
      associated perichondrium was extirpated. The exposed cartilage was fenestrated
      prior to repairing the cutaneous flap. RESULTS: Both auricles healed without
      evidence of fibrosis or distortion. CONCLUSION: Appropriate surgical intervention
      can avoid the cosmetic deformity associated with an auricular hematoma (ie,
      cauliflower ear).

PMID- 10594585
TI  - Current issues in dermatologic office-based surgery. The American Academy of
      Dermatology Joint AAD/ASDS Liaison Committee.
AB  - Dermatologists and dermatologic surgeons have played major roles in the
      development and refinement of many office-based cutaneous surgical procedures.
      The comprehensive scientific education in the structure and function of skin that
      dermatologists receive during formal residency training programs has contributed
      directly to these advances. This long tradition of comprehensive training and
      strong basic research activities in skin biology has supported a scholarly
      approach to cutaneous surgery. As a result, many pioneering cutaneous surgical
      techniques have been created by dermatologists and dermatologic surgeons. One
      example of this creativity can be seen in the field of laser surgery where
      techniques to effectively treat tattoos, benign pigmented lesions, port-wine
      stains and other vascular conditions, premalignant and malignant skin lesions,
      wrinkles and sun-damaged skin, and excess or unwanted hair were developed by
      dermatologists. Some of the most innovative procedures, like tumescent
      liposuction, have focused primarily on improving patient safety while preserving
      the highest standards of care. Virtually every aspect of cutaneous surgery,
      including Mohs micrographic surgery for the treatment of skin cancers, hair
      replacement surgery, sclerotherapy of leg veins, the correction of scars and sun
      damaged skin with the injection of filler materials, dermabrasion or chemical
      peels, and new anesthesia techniques, have been favorably impacted by the unique
      education and skills of many dermatologists and dermatologic surgeons. This
      article reviews the important historic role that has been played by
      dermatologists and dermatologic surgeons in developing and improving outpatient
      cutaneous surgical procedures and examines current issues and future directions
      in credentialing, privileging, and accreditation.

PMID- 10594586
TI  - High-energy pulsed light source hair removal device used to evaluate the onset of
      action of a new topical anesthetic.
AB  - BACKGROUND: Topical anesthetic agents are widely used to mitigate the pain
      associated with laser and high-energy pulsed light source hair removal.
      OBJECTIVE: To evaluate the relative efficacy and onset of action of a new topical
      anesthetic agent, ELA-Max cream (lidocaine 4%), relative to a widely used agent,
      EMLA cream (lidocaine 2.5%/prilocaine 2.5%). METHODS: ELA-Max and EMLA were
      applied to the forearms of 10 unblinded test subjects. The EMLA-treated sites
      were occluded for 1.5 hours prior to testing. The ELA-Max-treated sites were
      unoccluded and the cream was applied immediately prior to testing. Pulses from an
      Epilight high-energy pulsed light source were then administered 1.5 hours after
      occlusion with EMLA and in 5-minute intervals after application of ELA-Max. Pain
      scores were recorded on a visual analog scale (VAS). RESULTS: Six of 10 patients
      reported some anesthetic effect from ELA-Max after 5 minutes of unoccluded skin
      contact. Seven of 10 subjects reported maximal pain control 20 minutes after
      application of unoccluded ELA-Max, roughly equivalent to EMLA after 1.5 hours of
      occlusion. CONCLUSION: ELA-Max is an effective topical anesthetic agent
      comparable to EMLA under occlusion. It appears to be faster acting than EMLA, and
      along with its effectiveness without occlusion, may be an easier agent to use.

PMID- 10594587
TI  - Treatment of multiple eruptive hair cysts with erbium:YAG laser.
AB  - BACKGROUND: Eruptive vellus hair cysts (EVHC) frequently resist a variety of
      treatment modalities. While pulsed carbon dioxide (CO2) laser has been used
      effectively for facial EVHC, this laser presents significant risks for
      hypertrophic scarring when used on truncal sites. Due to absorption of 2940 nm
      energy by both tissue water and protein, the erbium:yttrium-aluminum-garnet
      (Er:YAG) laser ablates more cleanly and creates less residual thermal injury in
      the wound bed. This laser might prove efficacious and safe in treating nonfacial
      EVHC. OBJECTIVE: To assess treatment efficacy and wound healing after Er:YAG
      laser ablation of EVHC. METHODS: Two patients with 32 truncal EVHC were treated
      with pulsed Er:YAG laser using a drilling technique followed by second intention
      healing. RESULTS: Laser treatment sites healed without permanent dyspigmentation
      or hypertrophic scarring. No lesion recurrence was observed. CONCLUSION: Er:YAG
      laser ablation is an effective method for treating EVHC at anatomic sites prone
      to hypertrophic scar formation.

PMID- 10594589
TI  - Regarding pulse durations.

PMID- 10594588
TI  - Invasion of the lacrimal system by basal cell carcinoma.
AB  - BACKGROUND: The rate of recurrence of basal cell carcinoma (BCC) in the
      periorbital region is higher than that in other areas because of the spread of
      the tumor along barrier structures. OBJECTIVE: A better understanding of the
      biological behavior of BCC in this area, in particular as it relates to the
      lacrimal system, should improve the outcome of surgery. METHODS: A study was made
      of two cases of BCC that developed in the periorbital region and invaded the
      lacrimal system. RESULTS: The tumors were found to have invaded the lacrimal
      system along the mucosal epithelium. Magnetic resonance imaging (MRI) did not
      suggest any abnormalities in this area. In one patient, the tumor had infiltrated
      the nasal cavity without destruction of the periorbital bone and nasal cartilage.
      A preoperative fiberscopic examination clearly demonstrated the involvement of
      the nasal cavity in this case. CONCLUSION: The lacrimal system is often invaded
      by BCC that originates from the periorbital region. Physicians and surgeons need
      to be well aware of the possibility of such aggressive infiltration by BCC.

PMID- 10594591
TI  - Mathematical note on wound tension and healing of surgical wounds.

PMID- 10594590
TI  - Regarding d-alpha-tocopherol.

PMID- 10594592
TI  - Never, ever a twinkle from billboard advertising-nor from advertising budgets.

PMID- 10594593
TI  - Erbium:YAG laser resurfacing of the hands, arms, and neck.
AB  - BACKGROUND: Resurfacing procedures to improve photodamage, rhytides, and scars
      have been developed and refined over the last century. Laser resurfacing is a
      relatively new procedure in the resurfacing spectrum. It has been appreciated
      that resurfacing of nonfacial skin by dermabrasion, chemical peels, or carbon
      dioxide (CO2) laser carries an unacceptably high risk of scarring. More recently,
      the erbium:YAG (Er:YAG) laser has been developed and marketed for facial and
      nonfacial resurfacing. Specifically, manufacturers have promoted Er:YAG lasers as
      safe for resurfacing photodamaged skin on the hands, forearms, and neck.
      Surprisingly, there is little evidence to support these claims. OBJECTIVE: To
      evaluate the safety and efficacy of resurfacing photodamaged skin on the dorsum
      of the hands, forearms, and neck with an Er:YAG laser. METHODS: Twelve patients
      with photodamage of the neck or of the hands and forearms participated in this
      study. Seven patients received laser resurfacing of the hands and forearms
      utilizing the Er:YAG laser with a 5 mm spot size at an energy of 1 J (5 J/cm2).
      These patients received 2 to 3 passes. Five patients received resurfacing of
      photodamaged neck skin with a 5 mm spot size at 1 J (5 J/cm2). These patients
      received one to 2 passes. Patients were evaluated for time to healing, cosmetic
      improvement, and satisfaction with the procedure. RESULTS: Several observations
      of note are reported in patients receiving nonfacial resurfacing. Despite
      previous reports of patients receiving Er:YAG laser treatment with topical
      anesthesia alone, all patients required some intralesional anesthesia during the
      procedure for some areas. All patients required significantly longer to heal as
      compared to the face. Both the hands and forearms and the neck require 2-3 weeks
      to heal. Two of 7 hand and forearm patients developed bacterial infections during
      healing. One of 5 neck resurfacing patients developed transitory
      hyperpigmentation. Cosmetic improvement was mild, with 6 of 7 hand and forearm
      patients showing poor (0-25%) cosmetic improvement and one of 7 showing fair (25
      50%) improvement. In the neck resurfacing group, 3 of 5 had poor (0-25%)
      improvement, one of 5 had fair (25-50%) improvement, and one of 5 had good (50
      75%) results. CONCLUSION: Er:YAG laser resurfacing of the hands, forearms, and
      neck may be safely performed. Topical anesthesia alone is inadequate, healing
      takes up to 3 weeks, and cosmetic improvement is minimal with the parameters used
      in this study.

PMID- 10594594
TI  - The "facelift" flap for reconstruction of cheek, lateral orbit, and temple
      defects.
AB  - BACKGROUND: Large defects of the cheek, lateral orbit, zygomatic arch, or the
      lower temple pose challenges for reconstruction. These defects can be elegantly
      reconstructed using the "facelift" flap. OBJECTIVE: The facelift flap is a large
      advancement flap with a rotational component based on rhytidectomy principles.
      METHODS: Redundant skin from the lower cheek is used as the donor tissue, which
      is advanced cephalad and posteriorly. Flap design varies slightly for men and
      women depending on characteristics of the external ear and ear lobe as well as
      the position and density of the preauricular hairline. Extensive undermining is
      critical to reduce tension on the flap and allow for complete closure. Traction
      provided by an assistant aids in the undermining. Specialized instruments are
      helpful when performing this flap. Rhytidectomy scissors, multipronged skin
      rakes, hand-held fiberoptic lighted retractor, and insulated forceps are
      particularly useful. Correct trimming of the flap and ear lobe placement without
      tension on the lobe are essential for a good cosmetic result. A large standing
      cone is excised retroauricularly such that the scar is hidden primarily behind
      the ear. RESULTS AND CONCLUSION: The facelift flap gives superior and elegant
      results for reconstruction of large cutaneous defects involving the cheek,
      lateral orbit, zygomatic arch, and lower temple.

PMID- 10594595
TI  - Hair removal using topical suspension-assisted Q-switched Nd:YAG and long-pulsed
      alexandrite lasers: A comparative study.
AB  - BACKGROUND: The use of lasers for removal of unwanted hair has been shown to be
      effective in temporarily controlling hair growth. Several lasers are currently
      utilized for this purpose. OBJECTIVE: This study evaluates the short-term
      effectiveness and discomfort levels of the long-pulsed alexandrite laser and the
      topical suspension-assisted Q-switched Nd:YAG laser in a side-by-side comparison.
      METHODS: Fifteen subjects were treated in the bilateral hair-bearing axilla,
      using one treatment with the alexandrite laser for the right and two treatments
      with the topical suspension-assisted Nd:YAG laser for the left. Reduction in hair
      regrowth was measured at 2 and 3 months following the first treatment by
      comparing the terminal hair count to the baseline values. Patients rated their
      pain on a scale of 0-10 immediately following the first treatment at each site.
      RESULTS: The mean percentage reduction in hair regrowth 2 months following
      alexandrite laser treatment was 55% and 73% for the Nd:YAG laser-treated regions.
      After 3 months, alexandrite laser-treated patients showed a reduction of 19%,
      while Nd:YAG laser-treated patients showed a 27% reduction. Patients reported
      average pain values of 8 and 4 for the long-pulsed alexandrite and Nd:YAG laser
      sites, respectively. All differences were significant. CONCLUSION: While the
      design of this study makes it difficult to compare the relative effectiveness of
      the lasers, both systems evaluated were shown to delay hair growth and provide
      patients with a satisfactory treatment.

PMID- 10594596
TI  - A pilot study of in vivo immediate tissue contraction with CO2 skin laser
      resurfacing in a live farm pig.
AB  - BACKGROUND: It has been suggested that tissue ablation, collagen shrinkage, and
      new collagen deposition contribute to the clinical outcome of laser skin
      resurfacing. OBJECTIVE: To study the effects of fluence and pass number on
      thermal damage and tissue shrinkage, we performed experiments in an in vivo farm
      pig model. METHODS: A CO2 laser was used to treat the flank skin of a farm pig.
      There were nine treatment sites based on number of passes and fluence per pass.
      Wound surface areas were measured pretreatment and immediately posttreatment.
      Biopsies were performed immediately after irradiation. RESULTS: Surface area
      measurements showed that immediate contraction tended to increase with increasing
      fluence and pass number up to a maximum of approximately 38% shrinkage, after
      which the percent contraction remained constant. Thermal damage increased with
      pass number for low and moderate fluence groups; however, in high fluence groups
      the thermal damage remained constant with an increasing number of passes.
      CONCLUSIONS: Our results suggest that CO2 laser resurfacing produces immediate
      tissue contraction and residual thermal damage that is saturable for multiple
      passes and high fluences. For small fluences, however, there is an almost linear
      increase in thermal damage and shrinkage with an increasing number of passes.

PMID- 10594597
TI  - Cutaneous CO2 laser resurfacing infection rate with and without prophylactic
      antibiotics.
AB  - BACKGROUND: Cutaneous laser resurfacing is a well-accepted modality, with
      excellent clinical outcomes and low morbidity rates, for the treatment of a
      variety of epidermal and dermal lesions. The use of antibiotic prophylaxis
      continues to be an area of controversy, with laser practitioners divided in their
      approach. OBJECTIVE: To identify the rate of postoperative bacterial infection
      following full-face carbon dioxide (CO2) laser resurfacing with and without
      antibiotic prophylaxis. METHODS: A retrospective chart review of 133 consecutive
      patients following full-face CO2 laser resurfacing was performed. The rate,
      severity, duration, and subsequent treatment of bacterial infections observed in
      four treatment categories were recorded: (1) no antibiotic prophylaxis; (2)
      intraoperative single-dose intravenous cephalexin (1 g); (3) postoperative oral
      azithromycin (1.5 g over 5 days); (4) intraoperative IV cephalexin (1 g) and
      postoperative oral azithromycin (1.5 g). RESULTS: A significantly higher rate of
      infection occurred in patients receiving combination intraoperative and/or
      postoperative antibiotic prophylaxis. The most frequently cultured organisms
      included Enterobacter and Pseudomonas species. CONCLUSION: The rate of
      postoperative bacterial infections after full-face CO2 laser resurfacing in this
      retrospective study was not significantly reduced with the use of prophylactic
      antibiotics.

PMID- 10594598
TI  - Mohs micrographic surgery referral patterns: the University of Missouri
      experience.
AB  - BACKGROUND: Mohs micrographic surgery (MMS) provides a higher cure rate for
      nonmelanoma skin cancer (NMSC) than other forms of therapy. The American Academy
      of Dermatology has published recommended guidelines for MMS referral. However,
      factors other than the location, size, and type of NMSC may often affect the
      referral process. OBJECTIVE: To tabulate and analyze the rates of referral of
      NMSC for MMS by the dermatology clinics within the University of Missouri system.
      Data obtained for every biopsy-proven basal cell carcinoma (BCC) and squamous
      cell carcinoma (SCC) diagnosed at each of our four dermatology clinics during the
      3-year period of October 1993-September 1996 were cross-referenced with our Mohs
      surgery clinic logbook to identify which patients had been referred for MMS.
      RESULTS: During the study period, 19.2% of NMSC patients diagnosed were referred
      for MMS. However, there was significant disparity in referral rates among our
      four clinics. When the skewed data from our Veterans Administration Hospital
      clinic were discounted, the overall referral rate from the other clinics was
      found to be 30.8%. CONCLUSION: Our finding of a 30.8% referral rate of NMSC for
      MMS (27. 4% for SCC and 32.9% for BCC) within our university dermatology system
      is similar to the rates found in previous studies by the Mayo Clinic and Brooke
      Army Medical Center. MMS referral patterns are affected by many factors besides
      whether the NMSC meets MMS criteria, including the preference of each individual
      referring physician, patient, and involved insurance carrier.

PMID- 10594599
TI  - Skin surgery under local anesthesia leads to stress-induced alterations of
      psychological, physical, and immune functions.
AB  - BACKGROUND: Although excision of nevi under local anesthesia is a frequent and
      harmless operation, it apparently causes increased stress in many patients.
      However, thus far no studies have focused on the question of whether there are
      measurable effects on psychological, physiological, and immunological parameters.
      OBJECTIVE: To assess the perioperative stress reactions of patients undergoing
      skin surgery under local anesthesia for nevocellular nevi. METHODS: Fifty
      consecutive patients with pigmented nevi were examined at five points of
      measurement: 1 week and 30 minutes before the operation, during the operation, 30
      minutes and 1 week after the operation. Somatic parameters included blood
      pressure, pulse, respiratory rate, and the level of pain. Lymphocyte
      subpopulations, white blood cell count, and cortisol in saliva were determined.
      Anxiety and general psychological distress were evaluated with validated
      questionnaires. RESULTS: There was a significant increase in anxiety at the time
      of surgery. In parallel, the physiological parameters as well as the CD56+
      lymphocytes changed significantly. Preoperation anxiety and intraoperation pain
      were significantly higher in women (P <.001), but did not depend on age.
      CONCLUSION: There appears to be an interaction between physiological and
      emotional components in the operative stress reaction under local anesthesia. In
      patients with skin cancer, the perioperative stress may lead to transient
      impairment of immune function.

PMID- 10594600
TI  - Malar fat pad elevation: An aid to closure.
AB  - BACKGROUND: In closure of defects inferior to the eye, it is important to avoid
      inducing lower lid ectropion. OBJECTIVE: To describe a new technique for closure
      of defects inferior and lateral to the eye. METHODS: A case of malar fat pad
      elevation to close a post-Mohs surgical defect is described and the procedure is
      detailed. RESULTS: This technique enabled good wound closure with minimal tension
      and avoided the complication of ectropion. A transient asymmetry was manifest
      postoperatively. CONCLUSION: Malar fat pad elevation is an effective and elegant
      means of closing defects inferior and lateral to the eye. This technique
      minimizes extensive tissue undermining and movement with its consequences of
      postoperative tissue swelling, bruising, and hematoma formation. The side effect
      of ectropion is prevented.

PMID- 10594601
TI  - Minimally invasive surgery for axillary osmidrosis: combined operation with CO2
      laser and subcutaneous tissue remover.
AB  - BACKGROUND: Axillary osmidrosis is a distressing problem characterized by
      unpleasant odor, profuse sweating, and occasionally staining of clothes that may
      handicap those affected both socially and psychologically. Various types of
      surgical procedures have been developed for the treatment of axillary
      hyperhidrosis and osmidrosis. OBJECTIVE: To introduce a new odor measurement
      method and minimally invasive surgery technique for axillary osmidrosis. METHODS:
      Eighty-eight patients with axillary osmidrosis were treated by combined operation
      using a carbon dioxide (CO2) laser and subcutaneous tissue remover. Measurement
      of axillary odor was done with the cotton-roll method. RESULTS: Eighty-seven of
      the 88 patients (98.8%) had good to fair results; only one patient (1.2%) had
      poor results. Complications such as ecchymosis and partial skin necrosis with
      delayed wound healing occurred in four patients (4.6%). CONCLUSION: A combined
      technique using a CO2 laser and subcutaneous tissue remover has the advantages of
      a high success rate, low complication rate, no admission treatment, less
      scarring, and rapid recovery. This combined approach should become the preferred
      technique for the treatment of axillary osmidrosis.

PMID- 10594602
TI  - Pathophysiology of venous ulcers: surgical implications, review, and update.
AB  - BACKGROUND: Ambulatory venous hypertension has long been accepted as the
      principal and sole factor underlying the development of venous ulcers of the leg.
      This concept is now being seriously challenged as other factors emerge as
      important in the pathophysiology of venous ulcers. OBJECTIVE: This study was
      undertaken in order to review and update the current thinking concerning the
      pathophysiology of venous ulcers of the leg. METHOD: A review of the current
      medical literature. RESULTS: The prevailing current thinking about the
      pathophysiology of venous ulcers of the leg reveals that ambulatory venous
      pressure is the initiating factor. Over time this causes endothelial damage by
      the activation of leukocytes with subsequent release of proteolytic enzymes along
      with free oxygen radicals, leading to tissue damage which over time may cause
      ulceration. CONCLUSIONS: The production of venous ulcers of the leg is more
      complex than what was first thought. Although it is most likely that inflammatory
      factors are involved in its production, the cascade of inflammatory events
      postulated to occur need further investigation and clarification.

PMID- 10594603
TI  - Cosmetic surgery in the United States: its past and present.

PMID- 10594604
TI  - Another method of tie-over dressing for surgical wounds of hair-bearing areas.
AB  - BACKGROUND: We describe a modified tie-over dressing for any kind of surgical
      wound in the hair-bearing areas. METHODS: The long ends of the sutures are tied
      over the gauze pad to secure it. CONCLUSIONS: This modified technique of tie-over
      dressing can be utilized for the majority of surgical wounds in hair-bearing
      areas, such as the scalp. The dressing can be removed 1 or 2 days postoperatively
      by the patients, and the wound can be washed thereafter. The dressing helps
      ensure hemostasis, is simple to perform, looks tidy, and is well accepted by the
      patients.

PMID- 10594605
TI  - Elder care and the dermatologic surgeon.
AB  - BACKGROUND: The elderly are an increasing percentage of the population and
      dermatologic surgeons will be caring for more senior citizens. OBJECTIVE:
      Understanding issues in geriatric care will help both surgeons and patients have
      productive and rewarding encounters. METHODS: Approaches to the care of elders
      are detailed in this article. Surgical tips for the senior patient are
      prescribed. RESULTS: Older patients need more time and may need special
      assistance. Multiplicity of disease increases with age. A third-party interview
      can be helpful in gathering information. The elderly have sensory loss and
      benefit from extra attention, follow-up telephone calls, and therapeutic touch.
      Written handouts and instructions printed in large type are excellent.
      Dermatologic care should be kept as simple as possible with surgical closures
      designed to require minimal attention. Be cognizant of the social services
      available for the elderly and watch for dermatologic signs of internal disease. A
      skin care program for the elderly is helpful and cosmetic procedures are of
      interest to seniors. CONCLUSIONS: Dermatologic surgeons can provide excellent
      care to elders. An understanding of gerontologic issues and surgical tips can
      help the dermatologic surgeon care for the older patient.

PMID- 10594606
TI  - Epidermal maturation arrest.
AB  - BACKGROUND: Cutaneous wound repair involves a complex and temporal integration of
      cytokines, formed blood components, extracellular matrix, and parenchymal cells.
      The normal healing process can be impeded at any step along its path by a variety
      of factors. OBJECTIVE: We present four cases of abnormal wound repair in patients
      whose defects were left to heal by second intention following Mohs micrographic
      surgery. In particular, these patients experienced an unusual delay in healing
      with an apparent arrest of epidermal maturation. RESULTS: Each appeared to
      respond to a topical steroid and/or ibuprofen. The intent of this therapy was to
      inhibit products of the arachadonic acid cascade or other cytokines that may have
      been hindering normal epidermal differentiation. CONCLUSION: We present four case
      reports, a brief review of epidermal reconstitution in wounds, and a possible
      explanation for why our therapy may have hastened wound repair in our patients.

PMID- 10594607
TI  - Extensive periocular defect reconstruction with local flaps and conchal cartilage
      graft.
AB  - BACKGROUND: Advanced, histologically aggressive basal cell carcinomas (BCCs) of
      eyelids are difficult to eradicate. OBJECTIVE: To describe a case of BCC of both
      eyelids and lateral canthus and the reconstruction procedures used. METHODS: A
      two-stage reconstruction procedure was used. First, only mobilization of the
      forniceal conjunctiva and the musculocutaneous flap technique were used. The
      because of shortage and insufficiency of the upper eyelid the flap/graft
      technique was performed. A conchal complex cartilage-perichondrial graft was
      selected. RESULTS: The described procedure resulted in a very good functional and
      aesthetic outcome.

PMID- 10594608
TI  - Palmar basal cell carcinoma: case report and literature review.
AB  - BACKGROUND: Although basal cell carcinoma (BCC) is the most common tumor of the
      skin, its occurrence on the palm is very rare. Only eight cases not associated
      with the basal cell nevus syndrome having been reported in the world literature
      so far. Among these eight cases, one was associated with epidermolysis bullosa
      dystrophica and another with previous trauma to the site of the appearance of the
      lesion. OBJECTIVE: The authors report a case of palmar BCC due to its rare
      occurrence on that site. The case is not associated with any predisposing factors
      such as basal cell nevus syndrome, trauma, or preexistent dermatosis. METHODS: An
      incisional biopsy was performed into the border of the palmar ulcer. The
      histopathologic findings of the fragment, stained by hematoxylin and eosin, were
      characteristic of BCC. RESULTS: Following surgical removal of the lesion, there
      was complete healing and the patient has presented no signs of relapse after 3
      years of clinical follow-up. CONCLUSION: Palmar BCC not associated with the basal
      cell nevus syndrome or any other predisposing condition is very rare.
      Nevertheless, when facing an ulcerated lesion on the palm, BCC should be
      considered as a diagnostic possibility.

PMID- 10594609
TI  - Eccrine porocarcinoma treated with Mohs micrographic surgery: A report of five
      cases.
AB  - BACKGROUND: Eccrine porocarcinoma is a rare, locally aggressive, potentially
      fatal neoplasm. While wide local excision has traditionally been the treatment of
      choice, recurrences following excision are common. OBJECTIVE: The purpose of this
      study was to review the traditional treatments of eccrine porocarcinoma as well
      as to introduce Mohs micrographic surgery as an alternative to wide local
      excision. METHODS: We reviewed all cases of eccrine porocarcinoma seen at Emory
      University between 1985 and 1999. All cases were treated definitively with Mohs
      micrographic surgery. The clinical characteristics and outcome of each case are
      summarized. RESULTS: Five patients with eccrine porocarcinoma were treated with
      Mohs micrographic surgery. There have been no recurrences to date, with an
      average follow-up of 2.1 years (ranging from 5 months to 4 years). CONCLUSION:
      Follow-up of five patients supports the view that Mohs micrographic surgery may
      be an effective treatment for eccrine porocarcinoma.

PMID- 10594610
TI  - Regarding the scalp biopsy: making it more efficient.

PMID- 10594611
TI  - Regarding freezing in dermabrasion.

PMID- 10594613
TI  - Regarding silicone injections: response

PMID- 10594612
TI  - Regarding silicone injections.

PMID- 10594614
TI  - Commentary on the bipedicle nasalis musculocutaneous flap.

PMID- 10594615
TI  - Regarding corporate affiliation.

PMID- 10594616
TI  - Treatment of idiopathic guttate hypomelanosis by localized superficial
      dermabrasion.

PMID- 10594617
TI  - Regarding amelanotic melanomas.

PMID- 10594618
TI  - Regarding venous leg ulcers.

PMID- 10594619
TI  - Regarding dermabrasion for acne scars.

PMID- 10594620
TI  - Regarding inappropriate training for unqualified professionals.

PMID- 10594621
TI  - Dermatologists, surgery, and anesthesia: who is speaking to/for us?

PMID- 10594622
TI  - Laser resurfacing of the neck with the combined CO2/Er:YAG laser.
AB  - BACKGROUND: Several clinical studies on laser resurfacing on the neck have
      yielded variable results with adverse sequelae of hypopigmentation and scarring
      using the CO2 laser. The Er:YAG laser on the neck resulted in an improved
      appearance with no adverse sequelae. The combined CO2/Er:YAG laser is a laser
      that combines a low fluence CO2 laser with the Er:YAG laser in a near
      simultaneous beam. OBJECTIVE: To study the effects of the CO2/Er:YAG laser on the
      neck. The decreased nonspecific thermal damage of the CO2/Er:YAG laser should
      result in decreased postoperative erythema and improved wound healing. METHODS:
      Eleven patients were treated with the CO2/Er:YAG laser on the neck as well as the
      face at identical settings. The face was treated with four passes while the neck
      was treated with two passes. The patients were evaluated for the first 2 weeks
      then 3-6 months postoperatively. Patients were asked about treatment satisfaction
      and improvement in skin texture and color using a 25% scale. Skin texture and
      color, as well as improvement in wrinkling and adverse results were judged by a
      dermatologist using a 0-4 scale. RESULTS: Moderate improvement was seen in skin
      color while a higher degree of improvement was seen in skin texture and wrinkling
      in all 11 patients. No adverse sequelae, including hypopigmentation or scarring,
      were observed. The majority of patients had a 75-100% improvement in skin texture
      and color in addition to a 75-100% overall satisfaction rating. CONCLUSIONS:
      There is a higher degree of overall patient satisfaction, as well as improvement
      in skin texture and skin color, compared to patients treated with the Er:YAG
      laser alone. The CO2/Er:YAG laser is a highly effective laser for neck
      resurfacing with no adverse sequelae to date.

PMID- 10594623
TI  - Prolonged clinical and histologic effects from CO2 laser resurfacing of atrophic
      acne scars.
AB  - BACKGROUND: The recent development of high-energy pulsed CO2 lasers that minimize
      thermal injury to uninvolved adjacent structures has revolutionized the manner in
      which atrophic facial scars are recontoured. Significant improvement of atrophic
      scars with laser resurfacing has clearly been demonstrated; however, the exact
      timing for assessment of skin for further treatment has varied due to the unknown
      amount of time needed after laser scar resurfacing to effect maximal collagen
      formation and remodeling. OBJECTIVE: The aim of this study was to determine the
      immediate and long-term (12-18 months) histologic and clinical effects of
      atrophic acne scars after CO2 laser resurfacing in order to provide physician
      guidelines for postoperative clinical assessment for retreatment. METHODS: Sixty
      patients (50 women, 10 men, mean age 38 years, skin types I-V) with moderate to
      severe atrophic facial scars were evaluated. Nineteen patients received regional
      cheek treatment and 41 patients received full-face resurfacing with a high-energy
      pulsed CO2 laser. Independent clinical assessments of treated scars were
      performed at 1, 6, 12, and 18 months and blinded histologic analyses were made of
      skin biopsies immediately prior to and after laser resurfacing, and at 1, 6, 12,
      and 18 months postoperatively in six patients. RESULTS: Significant immediate and
      prolonged clinical improvement in skin tone, texture, and appearance of CO2 laser
      irradiated scars was seen in all patients. Average clinical improvement scores
      were 2.22 (69%) at 1 month, 2.1 (67%) at 6 months, 2.37 (73%) at 12 months, and
      2.5 (75%) at 18 months. Continued collagenesis and subsequent dermal remodeling
      were observed on histologic examination of biopsied tissue up to 18 months after
      surgery. CONCLUSION: Continued clinical improvement was observed as long as 18
      months after CO2 laser resurfacing of atrophic scars, with an 11% increase in
      improvement observed between 6 and 18 months postoperatively. We propose that a
      longer postoperative interval (12-18 months) prior to assessment for re-treatment
      be advocated in order to permit optimal tissue recovery and an opportunity for
      collagen remodeling.

PMID- 10594625
TI  - Hair removal using an 810 nm gallium aluminum arsenide semiconductor diode laser:
      A preliminary study.
AB  - BACKGROUND: Laser hair removal is a popular treatment method for removing
      unwanted hair. Several laser systems are available for laser hair removal. The
      gallium aluminum arsenide semiconductor diode (GAASD) laser is one of the newer
      laser modalities to be studied. OBJECTIVE: To evaluate the efficacy of the GAASD
      laser system in removing unwanted hair. METHODS: Twenty-six patients with brown
      or black hair growth were treated with the GAASD laser at fluences of 20-80
      J/cm2. Hair regrowth was measured 4 weeks after the first treatment, 4 weeks
      after the second treatment, 4 weeks after the third treatment, and 4 weeks, 8
      weeks, and 8 months after the fourth treatment. CONCLUSION: GAASD laser treatment
      resulted in hair growth delay in all treated regions. Repeated laser treatments
      did not produce an increased number of vellus hairs. The percentage of hair
      reduction fluctuated between 5% and 13% with the second or third treatment
      averaging the highest percent reduction. In all cases, the percentage of hair
      reduction of the treatment sites evaluated at 8 months after the fourth treatment
      was less than both the second and third treatments (highest average percent
      reduction) and the fourth (last) treatment.

PMID- 10594624
TI  - Analysis of pressure achieved by various materials used for pressure dressings.
AB  - BACKGROUND: To minimize the risk of complications, pressure dressings are
      frequently applied to wounds. The actual pressures yielded by different dressing
      materials and application techniques have not been documented. OBJECTIVE: To
      measure and compare pressures produced using various types of dressing tapes with
      and without a gauze roll. METHODS: An infant blood pressure cuff was adapted for
      use in a pressure dressing model. Investigators independently applied four strips
      of each of five different types of tape to the cuff when it was located in three
      settings: a hard inanimate surface, a subject's distal volar forearm, and the
      subject's forehead. RESULTS: Foam and plastic tapes produced more pressure under
      a simple dressing than three other commonly used tapes. Higher, more consistent
      pressures were achieved on the forearm than the forehead. Adding a gauze roll to
      the dressing consistently increased the pressure. CONCLUSION: The experimental
      model demonstrated substantial differences in pressures yielded by various
      pressure dressing materials.

PMID- 10594626
TI  - Q-Switched ruby laser therapy of acquired bilateral nevus of Ota-like macules.
AB  - BACKGROUND: Acquired bilateral nevus of Ota-like macules (ABNLM), also called
      nevus fuscoceruleus zygomaticus or nevus of Hori, is a relatively common disease
      in Asia. It is refractory to all medical treatment. OBJECTIVE: To present the
      first report on the use of Q-switched ruby laser to treat ABNLM. METHODS: One
      hundred and forty female patients, ages 19-62 years (mean 39 years), were
      included in the study. The laser fluence employed was 7-10 J/cm2, at a repetition
      rate of 1 Hz, and with a spot size of 2-4 mm. The number of treatment sessions
      ranged from 1 to 6 (mean 2.3). RESULTS: Nine patients were lost to follow-up
      before complete clearance of the lesions, while in the remaining 131 patients
      complete clearance was obtained. The only complication was a long-term
      hypopigmentation, observed in three patients. There was no recurrence at 6 months
      4.3 years (mean 2.5 years) of follow-up. CONCLUSION: Q-switched ruby laser is an
      effective and less invasive tool to eradicate ABNLM.

PMID- 10594627
TI  - Effects of topical vitamin K and retinol on laser-induced purpura on nonlesional
      skin.
AB  - BACKGROUND: Pulsed dye laser treatments usually result in purpura. Any topical
      application that eliminates or shortens the duration of purpura would be
      extremely useful. OBJECTIVE: The purpose of this prospective study was to
      determine the safety and efficacy of topical vitamin K cream in shortening the
      duration of laser-induced purpura. METHODS: Twenty adult subjects were enrolled.
      Each subject had five 1.5 cm sites treated with a pulsed dye laser at 585 nm, 450
      nsec, 7 mm spot size at each subject's respective threshold fluence. Each subject
      had a control site where no topical application was used and four other sites
      where a different formulation was applied to each for 2 weeks before and for 2
      weeks after laser irradiation. Five vitamin K formulations with or without
      retinol were studied: 3% vitamin K in acrylates copolymer cream, 5% vitamin K in
      acrylates copolymer cream, 1% vitamin K and 0.3% retinol in acrylates copolymer
      cream, 1% vitamin K and 0.15% retinol in acrylates copolymer cream, 1% free
      vitamin K cream. Purpuric discoloration at each site was rated on days 0, 1, 3,
      7, 10, and 14 after laser treatment on a quartile scale. Each site was assigned
      100% discoloration on day 0 after laser irradiation. RESULTS: Laser-induced
      purpuric discoloration resolved faster with 1% vitamin K and 0.3% retinol in
      acrylates copolymer cream than with no topical application. The difference is
      statistically significant from day 3 onward. CONCLUSION: A combination of 1%
      vitamin K and 0.3% retinol in acrylates copolymer cream hastened the resolution
      of laser-induced purpura.

PMID- 10594628
TI  - Stromal progenitor cells present within liposuction and reduction abdominoplasty
      fat for autologous transfer to aged skin.
AB  - BACKGROUND: Autologous fat is used for direct transfer to locally replace fat, as
      well as for use intradermally in the treatment of rhytids in aged skin.
      OBJECTIVE: To determine if the components of the autologous fat could be
      separated to produce a better agent for the treatment of rhytids. METHODS:
      Liposuction material from four patients and fat from abdominoplasty from five
      patients was processed by homogenization and centrifugation to separate mature
      lipocytes from other stromal cell populations in its associated extracellular
      matrix, and then to separate this from the blood and cellular debris. The
      cellular layer was evaluated histologically and with the immunohistochemical
      antibodies for CD34, SM-actin, S-100 protein, MIB-1, Bcl-2, and factor XIIIa.
      RESULTS: The cellular layer showed spindle cells, some small vascular structures,
      a small amount of mature fat, and extracellular matrix. CD34 showed diffuse
      staining of most spindle and endothelial cells in all sections, factor XIIIa
      showed only focal staining of spindle and dendritic cells, and Bcl-2 showed light
      to moderate staining in scattered cells within the cellular component. S-100
      protein, SM-actin, and MIB-1 were negative. CONCLUSION: Processed liposuction and
      abdominoplasty processed fat may be ideal for the treatment of wrinkles in aged
      skin because it contains progenitor stromal cells that are known to be present
      within the fat and which may be concentrated by processing methods.

PMID- 10594629
TI  - Comparative study of the efficacy of four topical anesthetics.
AB  - BACKGROUND: With the emergence of new laser and dermatologic procedures, the need
      for more effective topical anesthesia continues to grow. There are now several
      topical anesthetics that are being used prior to laser and surgical procedures.
      OBJECTIVE: To compare the degree and duration of anesthesia produced by four
      commonly used topical anesthetics, we performed a prospective study investigating
      the efficacy of EMLA (eutectic mixture of local anesthetics), ELA-Max, 4%
      tetracaine gel, and betacaine-LA ointment (formerly eutectic-LA). METHODS: Equal
      amounts of the above topical anesthetics plus a control (eucerin cream) were
      applied to 10 test sites under occlusion on the volar forearms of 12 adult
      volunteers. After a 60-minute application time, the degree of anesthesia was
      assessed immediately by a Q-switched Nd:YAG laser at 1064 nm. Pain testing was
      also performed 30 minutes after the 60-minute application period. Volunteer
      responses to pain stimuli were recorded using an ordinal scale of 0 (no pain) to
      4 (maximal pain). The mean scores for the time intervals were obtained. Analysis
      of the data was performed using analysis of variance (ANOVA), Newman-Keuls test,
      Friedman rank order test, and paired t-tests. RESULTS: ELA-Max, EMLA, and
      tetracaine were statistically superior to control after the 60-minute application
      period. Thirty minutes later, ELA-Max, EMLA, tetracaine, and betacaine-LA were
      all statistically superior to the control. Comparing individual anesthetics, ELA
      Max and EMLA were the superior anesthetics at both time intervals. Although the
      mean pain scores for each anesthetic were lower 30 minutes after their removal,
      the differences did not reach statistical significance. CONCLUSION: This is the
      first prospective study comparing the efficacy of several new topical anesthetic
      agents. Using the methodology of this study, in which the anesthetics were
      applied under occlusion, ELA-Max and EMLA were the superior anesthetics after a
      60-minute application time and 30 minutes later. In addition, there was a
      clinical increase in efficacy suggested with all of the anesthetics 30 minutes
      after their removal.

PMID- 10594630
TI  - Suction blister epidermal grafting versus punch skin grafting in recalcitrant and
      stable vitiligo.
AB  - BACKGROUND: Among various surgical therapies for replenishment of melanocytes in
      recalcitrant and stable vitiligo, punch skin grafting (PSG) and suction blister
      epidermal grafting (SBEG) are the simplest ones. Literature is lacking on a
      comparison of both. OBJECTIVE: We compared the results of both techniques in
      small patches of vitiligo. METHODS: Fifty stable vitiligo (focal, segmental, and
      generalized) patients were selected for study. One patient was lost to follow-up
      and excluded. PSG was done in 48 patches of 25 patients and SBEG was done in 38
      patches of 24 patients. All patients were kept on psoralen ultraviolet-A
      (PUVA)/psoralen sunrays (PUVASOL). Results were evaluated after a follow-up of 4
      7 months. RESULTS: Thirty-two (67%) patches of the PSG group and 31 (82%) patches
      of the SBEG group showed greater than 75% pigmentation. The difference in both
      groups was not statistically significant. Cobblestone appearance (23%) over the
      recipient area (RA) and superficial scarring of the donor area (DA) (100%) were
      seen in PSG. No serious complications were seen in both groups. CONCLUSION: Both
      techniques are simple and effective, however, SBEG gives cosmetically better and
      rapid results.

PMID- 10594631
TI  - Treatment of atrophic facial scars with combined use of high-energy pulsed CO2
      laser and Er:YAG laser: a practical guide of the laser techniques for the Er:YAG
      laser.
AB  - BACKGROUND: Although CO2 laser resurfacing provides substantial clinical
      improvement for atrophic facial scars, the CO2 laser often results in excessive
      thermal damage to the skin. It increases complications postoperatively. The
      Er:YAG laser ablates thinner layers of tissue than the CO2 laser with minimal
      thermal damage to the surrounding skin. OBJECTIVE: To determine the efficacy of
      combined treatment of atrophic facial scars with high-energy pulsed CO2 laser and
      Er:YAG laser. METHODS: One hundred fifty-eight patients were treated with a
      combination of high-energy pulsed CO2 laser and Er:YAG laser for atrophic facial
      scars. All patients were evaluated after 3 months of treatment. RESULTS: The
      scars improved 80-89% in 65 patients, 70-79% in 56 patients, more than 90% in 32
      patients, 60-69% in 2 patients, and less than 60% in 3 patients after laser
      treatment. CONCLUSION: Treatment of atrophic facial scars with combined use of
      high-energy pulsed CO2 laser and Er:YAG laser is a very effective and useful
      method.

PMID- 10594632
TI  - Basal cell carcinoma arising from surgical scars: a case and review of the
      literature.
AB  - BACKGROUND: Scar malignancies are generally known as Marjolin's ulcer and the
      majority of them are epidermoid carcinomas. In addition to epidermoid carcinomas,
      Basal cell carcinoma (BCC) also can grow in various scars. Basal cell carcinoma
      cases developing in surgical scars are extremely rare; only 5 cases have been
      encountered in available English literature. METHOD: A 68-year-old woman who has
      a BCC originating from a surgical scar due to a previous inguinal hernia
      operation was presented. CONCLUSION: Trauma has been suggested as one of the
      etiologic factors for BCC; but the role of trauma or resulting scar in BCC
      pathogenesis is not known. This unresolved issue can be explained with advanced
      studies revealing biochemical tissue changes occurring during wound healing and
      trauma.

PMID- 10594633
TI  - Pili bigeminy induced by low fluence therapy with hair removal alexandrite and
      ruby lasers.
AB  - BACKGROUND: Lasers are being widely used for the hair removal. Several
      complications including hyperpigmentation, erythma, hypopigmentation, and burns
      have been reported. OBJECTIVE: To study laser hair removal complications.
      METHODS: Pubic hairs were treated with alexandrite and ruby lasers. RESULTS: Pili
      Bigeminy can be induced by low fluence therapy with hair removal Alexandrite and
      Ruby lasers as a complication. CONCLUSION: To our knowledge, this is the first
      report of pili bigminy as a complication of laser-assisted hair removal.

PMID- 10594634
TI  - Resurfacing of facial angiofibromas in tuberous sclerosis patients using CO2
      laser with flashscanner.
AB  - BACKGROUND: Angiofibromas are a common presentation of tuberous sclerosis. They
      cause considerable cosmetic and hygienic morbidity for patients. Treatments of
      angiofibromas have included curettage, cryosurgery, chemical peel, dermabrasion,
      shave excision, and 13-cis retinoic acid. Results from these modalities in many
      cases were not satisfactory from a cosmetic standpoint. Copper vapor, argon,
      pulsed dye, and CO2 lasers have been used with success in isolated cases.
      OBJECTIVE: The purpose of this study was to evaluate the efficacy of CO2 laser
      resurfacing with flashscanner in the treatment of facial angiofibromas. METHODS:
      Two patients with angiofibromas on the face were treated with a CO2 laser with
      flashscanner. The cheek and nose were treated in one patient, and entire face was
      done in the other. RESULTS: Both patients showed remarkable cosmetic improvements
      without scarring. Mild hyperpigmentation was found in both patients, which
      disappeared in 1 month with the application of topical agents. Facial erythema
      persisted about 2 months in both patients. CONCLUSION: A CO2 laser equipped with
      flashscanner causes less residual thermal damage than conventional CO2 lasers and
      enables controlled depth vaporization for more precise and regular removal of
      angiofibromas. In whole-face resurfacing, more cosmetically acceptable results
      are possible because localized treatment leaves marginal prominences. Laser
      resurfacing is an effective alternative in the treatment of multiple protuberant
      angiofibromas even though we cannot permanently clear these lesions due to their
      nature.

PMID- 10594635
TI  - Regarding propofol-ketamine and propofol-fentanyl sedation technique.

PMID- 10594636
TI  - Regarding the death of density debate.

PMID- 10594637
TI  - Letter to the editor etiquette.

PMID- 10594638
TI  - The first congress of the French Society for Dermatologic Surgery-Paris, May
      1999.

PMID- 10594639
TI  - A nationwide dermatologic surgical training program in Indonesia.

PMID- 10594640
TI  - Distinct kinetics of cloned T-type Ca2 + channels lead to differential Ca2 +
      entry and frequency-dependence during mock action potentials.
AB  - Voltage-dependent activity around the resting potential is determinant in
      neuronal physiology and participates in the definition of the firing pattern. Low
      voltage-activated T-type Ca2 + channels directly affect the membrane potential
      and control a number of secondary Ca2 + -dependent permeabilities. We have
      studied the ability of the cloned T-type channels (alpha1G,H,I) to carry Ca2 +
      currents in response to mock action potentials. The relationship between the
      spike duration and the current amplitude is specific for each of the T-type
      channels, reflecting their individual kinetic properties. Typically the charge
      transfer increases with spike broadening, but the total Ca2 + entry saturates at
      different spike durations according to the channel type: 4 ms for alpha1G; 7 ms
      for alpha1H; and > 10 ms for alpha1I channels. During bursts, currents are
      inhibited and/or transiently potentiated according to the alpha1 channel type,
      with larger effects at higher frequency. The inhibition may be induced by voltage
      independent transitions toward inactivated states and/or channel inactivation
      through intermediate closed states. The potentiation is explained by an
      acceleration in the channel activation kinetics. Relatively fast inactivation and
      slow recovery limit the ability of alpha1G and alpha1H channels to respond to
      high frequency stimulation ( > 20 Hz). In contrast, the slow inactivation of
      alpha1I subunits allows these channels to continue participating in high
      frequency bursts (100 Hz). The biophysical properties of alpha1G, H and I
      channels will therefore dramatically modulate the effect of neuronal activities
      on Ca2 + signalling.

PMID- 10594641
TI  - Induction of hypoxia-inducible factor-1 (HIF-1) and its target genes following
      focal ischaemia in rat brain.
AB  - HIF-1 is a heterodimeric transcription factor, induced by hypoxia, that is
      composed of HIF-1alpha and HIF-1beta protein subunits. It binds to
      promoter/enhancer elements and stimulates the transcription of hypoxia-inducible
      target genes, including glucose transporter-1 and the glycolytic enzymes. Because
      HIF-1 activation might promote cell survival in hypoxic tissues, we studied the
      effect of permanent middle cerebral artery occlusion on the expression of HIF
      1alpha, HIF-1beta and several HIF-1 target genes in adult rat brain. After focal
      ischaemia, mRNAs encoding HIF-1alpha, glucose transporter-1 and several
      glycolytic enzymes were up-regulated in the peri-infarct penumbra. This was
      observed by 7.5 h after the onset of ischaemia and increased further at 19 and 24
      h. Regional cerebral blood flow was moderately decreased at 1 and 24 h after the
      ischaemia in areas of HIF-1 and HIF-1 target gene induction. Because hypoxia
      induces HIF-1 in other tissues, systemic hypoxia (6% O2 for 4.5 h) was also shown
      to increase HIF-1alpha protein expression in the adult rat brain. It is proposed
      that decreased blood flow to the penumbra decreases the supply of oxygen and that
      this induces HIF-1 and its target genes. This is the first study to show
      induction of HIF-1 after focal ischaemia in brain. Increased expression of HIF-1
      target genes as a result of HIF-1 activation by hypoxia may contribute to tissue
      viability in the hypoxic/ischaemic penumbra by increasing glucose transport and
      glycolysis.

PMID- 10594642
TI  - Comparison of the Ca2 + currents induced by expression of three cloned alpha1
      subunits, alpha1G, alpha1H and alpha1I, of low-voltage-activated T-type Ca2 +
      channels.
AB  - Expression of rat alpha1G, human alpha1H and rat alpha1I subunits of voltage
      activated Ca2 + channels in HEK-293 cells yields robust Ca2 + inward currents
      with 1.25 mM Ca2 + as the charge carrier. Both similarities and marked
      differences are found between their biophysical properties. Currents induced by
      expression of alpha1G show the fastest activation and inactivation kinetics. The
      alpha1H and alpha1I currents activate and inactivate up to 1.5- and 5-fold
      slower, respectively. No differences in the voltage dependence of steady state
      inactivation are detected. Currents induced by expression of alpha1G and alpha1H
      deactivate with time constants of up to 6 ms at a test potential of - 80 mV, but
      currents induced by alpha1I deactivate about three-fold faster. Recovery from
      short-term inactivation is more than three-fold slower for currents induced by
      alpha1H and alpha1I in comparison to alpha1G. In contrast to these
      characteristics, reactivation after long-term inactivation was fastest for
      currents arising from expression of alpha1I and slowest in cells expressing
      alpha1H calcium channels. The calcium inward current induced by expression of
      alpha1I is increased by positive prepulses while currents induced by alpha1H and
      alpha1G show little ( < 5%) or no facilitation. The data thus provide a
      characteristic fingerprint of each channel's activity, which may allow
      correlation of the alpha1G, alpha1H and alpha1I induced currents with their in
      vivo counterparts.

PMID- 10594644
TI  - Expression, distribution and ultrastructural localization of the synapse
      organizing molecule agrin in the mature avian retina.
AB  - At the vertebrate neuromuscular junction the extracellular matrix molecule agrin
      is responsible for the formation, maintenance and regeneration of most if not all
      postsynaptic specializations. Several agrin isoforms are generated by alternative
      splicing which differ in their function and which are all expressed in the CNS.
      To analyse the role of agrin in the CNS, we investigated the expression and
      ultrastructural localization of agrin in the posthatched chick retina. In situ
      hybridization revealed the presence of agrin mRNA in all cellular layers of the
      mature retina, indicating that most if not all major retinal cell types
      synthesize agrin. Pan-specific as well as isoform-specific antiagrin antisera
      stained the optic fibre layer and the outer plexiform layer. However, only the
      pan-specific antiserum additionally stained the inner limiting membrane.
      Immunoelectron microscopy showed that in the optic fibre layer agrin was
      associated with ganglion cell axons and that at least part of this agrin
      corresponds to a neuronal isoform of agrin. In the outer plexiform layer, agrin
      was localized in the cleft between the photoreceptor terminals and the
      invaginating horizontal and bipolar cell dendrites. In the synapse-containing
      inner plexiform layer both antisera revealed punctate immunoreactivity. This
      staining corresponded to agrin concentrated in the synaptic cleft of conventional
      synapses as determined by preembedding immunoelectron microscopy. Agrin is thus
      concentrated at mature interneuronal synapses as it is at the neuromuscular
      junction, consistent with a role of agrin during formation and/or maintenance of
      synapses in the CNS.

PMID- 10594643
TI  - A mouse model of familial amyotrophic lateral sclerosis expressing a mutant
      superoxide dismutase 1 shows evidence of disordered transport in the vasopressin
      hypothalamo-neurohypophysial axis.
AB  - Amyotrophic lateral sclerosis (ALS) is a fatal, paralytic disorder that primarily
      affects motoneurons. By combining physiological and morphological approaches, we
      examined the effect of a murine superoxide dismutase 1 (SOD1) mutation (G86R),
      which induces neurological disorders resembling human familial ALS (FALS), on the
      arginine vasopressin (AVP) hypothalamo-neurohypophysial axis, an unmyelinated
      tract poor in neurofilaments. First, we observed that G86R mice progressively
      consumed more water than wild-type littermates. Furthermore, levels of plasma AVP
      and neurohypophysial AVP content were decreased in the SOD1 mutant mice, whereas
      the amount of hypothalamic AVP increased in an age-dependent manner. However,
      hypothalamic AVP mRNA levels were not significantly modified in these animals. At
      the ultrastructural level, we found that the neurohypophysis of G86R mice had a
      decreased number of neurosecretory axons. Conversely, the presence of large axon
      swellings was more pronounced in the SOD1 mutant mice. In addition, the size of
      neurosecretory granules was higher in G86R than in wild-type animals. All these
      findings strongly suggest that the FALS-associated SOD1 mutation injures the
      hypothalamo-neurohypophysial axis by provoking early, progressive disturbances in
      the axonal transport of neurosecretory products from neuronal perikarya to nerve
      terminals. This blockade could ultimately result in degeneration of the tract, as
      proposed for the myelinated, neurofilament-enriched motor axons affected by ALS.

PMID- 10594645
TI  - Neurochemical gradients along monkey sensory cortical pathways: calbindin
      immunoreactive pyramidal neurons in layers II and III.
AB  - We examined the distribution of neurons containing immunoreactivity for three
      calcium-binding proteins, calbindin, parvalbumin and calretinin, as well as
      nonphosphorylated neurofilament protein, in cortical areas along the ventral and
      dorsal cortical visual pathways, and in ventrally-directed somatosensory and
      auditory cortical pathways. Calbindin-immunoreactive pyramidal neurons showed the
      most prominent regional differences. They were largely restricted to layers II
      and III and their number monotonically increased from the primary sensory areas
      to the anteroventral areas along the ventral visual pathway and along the
      ventrally-directed somatosensory and auditory pathways. The number of calbindin
      immunoreactive pyramidal neurons in layers II and III also increased along the
      dorsal visual pathway, but the number in the last recognized stage of the dorsal
      visual pathway (area 7a) was significantly smaller than that at the corresponding
      stage in the ventral visual pathway (TE). The number of calbindin-immunoreactive
      pyramidal neurons was highest in layers II and III of areas 35/36, TG, and TF/TH,
      which represent terminal cortical regions of the pathways. These results show
      neurochemical differences between cortical areas located at early and late stages
      along serial corticocortical pathways, as well as confirming differences between
      pyramidal neurons in the supragranular and infragranular layers.

PMID- 10594646
TI  - Apoptosis in Ca2 + reperfusion injury of cultured astrocytes: roles of reactive
      oxygen species and NF-kappaB activation.
AB  - We previously reported that incubation of cultured astrocytes in Ca2 + 
      containing medium after exposure to Ca2 + -free medium caused Ca2 + influx
      followed by delayed cell death. Here, we studied the mechanisms underlying the
      Ca2 + -mediated injury of cultured astrocytes. Our results show that Ca2 +
      reperfusion injury of astrocytes appears to be mediated by apoptosis, as
      demonstrated by DNA fragmentation and prevention of death by caspase-3
      inhibitors. Paradoxical Ca2 + challenge stimulated rapidly reactive oxygen
      species (ROS) production. Ca2 + reperfusion injury of astrocytes was influenced
      by several reagents which modified ROS production. When astrocytes were exposed
      to hydrogen peroxide (H2O2) for 30 min and then incubated without H2O2 for 1-5
      days, cell toxicity including apoptosis was observed. Ca2 + reperfusion injury
      induced by Ca2 + depletion or H2O2 exposure was blocked by the iron chelator 1,
      10-phenanthroline, the NF-kappaB inhibitor pyrrolidinedithiocarbamate and the
      calcineurin inhibitor FK506. Incubation in normal medium after H2O2 exposure
      rapidly increased the level of nuclear NF-kappaB p65 subunit, and the effect was
      blocked by 1,10-phenanthroline, pyrrolidinedithiocarbamate and FK506. These
      findings indicate that Ca2 + reperfusion-induced apoptosis is mediated at least
      partly by ROS production and ROS cause NF-kappaB activation in cultured
      astrocytes.

PMID- 10594647
TI  - Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in
      the adult mouse forebrain.
AB  - Cannabinoids can modulate motor behaviour, learning and memory, cognition and
      pain perception. These effects correlate with the expression of the cannabinoid
      receptor 1 (CB1) and with the presence of endogenous cannabinoids in the brain.
      In trying to obtain further insights into the mechanisms underlying the
      modulatory effects of cannabinoids, CB1-positive neurons were determined in the
      murine forebrain at a single cell resolution. We performed a double in situ
      hybridization study to detect mRNA of CB1 in combination with mRNA of glutamic
      acid decarboxylase 65k, neuropeptide cholecystokinin (CCK), parvalbumin,
      calretinin and calbindin D28k, respectively. Our results revealed that CB1
      expressing cells can be divided into distinct neuronal subpopulations. There is a
      clear distinction between neurons containing CB1 mRNA either at high levels or
      low levels. The majority of high CB1-expressing cells are GABAergic (gamma
      aminobutyric acid) neurons belonging mainly to the cholecystokinin-positive and
      parvalbumin-negative type of interneurons (basket cells) and, to a lower extent,
      to the calbindin D28k-positive mid-proximal dendritic inhibitory interneurons.
      Only a fraction of low CB1-expressing cells is GABAergic. In the hippocampus,
      amygdala and entorhinal cortex area, CB1 mRNA is present at low but significant
      levels in many non-GABAergic cells that can be considered as projecting principal
      neurons. Thus, a complex mechanism appears to underlie the modulatory effects of
      cannabinoids. They might act on principal glutamatergic circuits as well as
      modulate local GABAergic inhibitory circuits. CB1 is very highly coexpressed with
      CCK. It is known that cannabinoids and CCK often have opposite effects on
      behaviour and physiology. Therefore, we suggest that a putative cross-talk
      between cannabinoids and CCK might exist and will be relevant to better
      understanding of physiology and pharmacology of the cannabinoid system.

PMID- 10594648
TI  - Ulip/CRMP proteins are recognized by autoantibodies in paraneoplastic
      neurological syndromes.
AB  - Anti-CV2 autoantibodies have recently been discovered in patients with
      paraneoplastic neurological diseases (PND). These disorders are associated with
      neuronal degeneration, mediated by autoimmune processes, in patients with
      systemic cancer. Anti-CV2 autoantibodies recognize a brain protein of 66 kDa
      developmentally regulated and specifically expressed by a subpopulation of
      oligodendrocytes in the adult brain. Here, we demonstrate that anti-CV2 sera
      recognize several post-translationally modified forms of Ulip4/CRMP3, a member of
      a protein family related to the axonal guidance and homologous to the Unc-33 gene
      product in Caenorhabditis elegans. The sequence of the human Ulip4/CRMP3 was
      determined and the gene localized to chromosome 10q25.2-q26, a region mutated in
      glioblastomas and containing tumour suppressor genes. The identification of the
      Ulip/CRMP proteins as recognized by anti-CV2 sera should provide new insights
      into the role of Ulip/CRMPs in oligodendrocytes and into pathophysiology of PND.

PMID- 10594649
TI  - Characterization of AMPA receptors on isolated amacrine-like cells in carp
      retina.
AB  - In amacrine-like cells freshly dissociated from crucian carp (Carassius auratus)
      retina, we recorded whole-cell responses to rapid application of glutamate and
      kainate. Currents induced by glutamate, but not kainate, usually showed extremely
      rapid desensitization, and the mean time constant for the decay of the responses
      to 10 mM glutamate was 2.77 ms. N-methyl-D-aspartate (NMDA) failed to induce any
      current even with coapplication of glycine and removal of extracellular Mg2 +. 1
      (4-aminophenyl)-3-Methylcarbamyl-4-methyl-7,8-methylenedioxy-3, 4-dihydro-5H-2,3
      benzodiazepine (GYKI 53655), a selective alpha-amino-3-hydroxy-5-methylisoxazole
      4-propionic acid (AMPA) receptor antagonist, was found to completely block
      glutamate-induced currents, suggesting that the glutamate receptors on these
      cells are AMPA preferring. The value of EC50 for glutamate and kainate was
      determined to be 2.73 mM and 97.5 microM, respectively. Noise analysis of
      fluctuation of whole-cell currents induced by kainate of different concentrations
      indicated that the mean conductance of the AMPA receptor channels was 5.70 pS.
      Splice variant analysis of the AMPA receptors was also conducted by comparing the
      effects of cyclothiazide, a flip receptor-preferring modulator and 4-[2
      (phenylsulphonylamino)ethylthio]-2,6-difluoro-phenoxyaceta mide (PEPA), a flop
      receptor-preferring modulator, on glutamate-induced responses. PEPA was much more
      potent than cyclothiazide at these receptors with a EC50 of 17.3 microM. The mean
      ratio of the potentiation by PEPA versus cyclothiazide (P/C ratio) was 4.39.
      These modulatory effects of cyclothiazide and PEPA were rather similar to those
      obtained at AMPA receptors assembled from flop variants expressed in Xenopus
      oocytes, suggesting that the AMPA receptor of the carp amacrine cells may
      predominantly consist of the flop splice variants.

PMID- 10594650
TI  - Activity-dependent formation of perforated synapses in cultured hippocampal
      neurons.
AB  - The study investigated the formation of perforated synapses in rat hippocampal
      cell cultures. Perforated synapses are defined by their discontinuous
      postsynaptic densities (PSDs) and are believed to occur in parallel with changes
      in synaptic activity and possibly also synaptic efficacy. Several in vivo studies
      have demonstrated an increase in the frequency of perforated synapses induced by
      development and environmental stimulation as well as long-term potentiation
      (LTP). Also in in vitro brain slices, LTP was associated with an elevated number
      of perforated spine synapses. Our study demonstrated for the first time that the
      formation of perforated synapses can be induced by a short-term increase in
      spontaneous neural activity in a hippocampal cell culture model. Stimulation with
      the GABAA-antagonist picrotoxin (PTX) induced a significant increase in the
      percentage of perforated synapses. This strong increase was blocked when APV was
      added together with PTX, indicating that the formation of perforated synapses
      depended on the activation of NMDA receptors. We also showed that inhibition of
      the tissue type plasminogen activator (tPA-stop/PAI-1) significantly interfered
      with the activity-induced increase in perforated synapses. This implies that the
      proteolytic activities of tPA might be involved in steps which are downstream
      from the NMDA receptor-mediated synaptic plasticity leading to structural changes
      at synaptic contacts. In contrast, even long-term inhibition of electrical
      network activity by tetrodotoxin had no effect on the number of perforated
      synapses, but almost completely abolished the formation of spine synapses. These
      results indicate that a short-term increase in neural activity via NMDA receptors
      and a proteolytic cascade involving tPA lead to the formation of perforated
      synapses.

PMID- 10594651
TI  - Morphological, immunophenotypical and electrophysiological properties of resting
      microglia in vitro.
AB  - Morphological, immunophenotypical and electrophysiological properties were
      investigated in isolated cultured murine microglia before and after exposure to
      astrocyte-conditioned medium (ACM). Following application of ACM, microglial
      cells underwent a dramatic shape transformation from an amoeboid appearance to a
      ramified morphology. In parallel to morphological changes, a downregulation of
      macrophage surface antigens was observed in microglia exposed to ACM. Staining
      intensities for major histocompatibility complex (MHC) class II molecules and for
      the adhesion molecules leukocyte function-associated antigen-1 (LFA-1) and
      intercellular adhesion molecule-1 (ICAM-1) were significantly decreased in
      ramified microglia 5 days after exposure to ACM. In microglial cells treated
      daily with ACM over a period of 5 days, the smallest staining intensities for all
      surface antigens as well as the smallest ramification index as a measure for the
      highest degree of ramification were determined. In addition, upregulation of
      delayed rectifier K + currents was observed in microglia exposed to ACM for 1 day
      or treated daily with ACM for 5 days. In contrast, untreated amoeboid microglia
      or ramified microglia analysed 5 days after exposure to ACM did not express
      delayed rectifier K + currents. Analyses of the resting membrane potential and
      expression levels and properties of inward rectifier K + currents did not reveal
      any differences between untreated and ACM-treated microglia. It is suggested that
      electrophysiological properties of microglia do not strongly correlate with the
      morphology or the immunophenotype of microglial cells.

PMID- 10594652
TI  - Doc2alpha is an activity-dependent modulator of excitatory synaptic transmission.
AB  - Doc2alpha is a synaptic vesicle-associated Ca2 + -binding protein. To study the
      role of Doc2alpha in synaptic transmission and modulation, we generated
      homozygous null Doc2alpha mutant mice. In the CA1 region of hippocampal slices in
      the mutant mice, excitatory synaptic responses evoked with prolonged 5 Hz
      stimulation showed a significantly larger frequency facilitation followed by a
      steeper depression than those in wild-type mice, whereas there was no difference
      in synaptic transmission at lower frequencies or in paired-pulse facilitation.
      These results suggest that Doc2alpha regulates synaptic transmission when high
      Ca2 + concentrations in the presynaptic terminal are sustained. Furthermore, the
      mutant mice showed impairment in long-term potentiation and passive avoidance
      task. Thus, Doc2alpha may regulate transmitter release during repetitive synaptic
      activation, thereby contributing to memory formation.

PMID- 10594653
TI  - Activity-dependent neurotransmitter release kinetics: correlation with changes in
      morphological distributions of small and large vesicles in central nerve
      terminals.
AB  - In central nerve terminals transmitter release is tightly regulated and thought
      to occur in a number of steps. These steps include vesicle mobilization and
      docking prior to neurotransmitter release. Intrasynaptic changes in vesicle
      distribution were determined by electron microscopical analysis and
      neurotransmitter release was monitored by biochemical measurements. We correlated
      K + -induced changes in distribution of small and large vesicles with the release
      of their transmitters. For small synaptic vesicles, amino acid release as well as
      recruitment to and docking at the active zone were activated within 1 s of
      depolarization. In contrast, the disappearance of large dense-cored vesicles and
      the release of the neuropeptide cholecystokinin were much slower, and no docking
      was observed. Studies with diverse Ca2 + channel blockers indicated that
      mobilization and neurotransmitter release from both vesicle types were regulated
      by multiple Ca2 + channels, although in different ways. Neurotransmitter release
      from small synaptic vesicles was predominantly regulated by P-type Ca2 +
      channels, whereas primarily Q-type Ca2 + channels regulated neurotransmitter
      release from large dense-cored vesicles. The different Ca2 + channnel types
      directly regulated mobilization of and neurotransmitter release from small
      synaptic vesicles whereas, by their cooperativity in raising the intracellular
      Ca2 + concentration above release threshold, they more indirectly regulated large
      dense-cored vesicle exocytosis.

PMID- 10594654
TI  - Hippocampal Cajal-Retzius cells project to the entorhinal cortex: retrograde
      tracing and intracellular labelling studies.
AB  - Cajal-Retzius (CR) cells are characteristic horizontally orientated, early
      generated transient neurons in the marginal zones of the neocortex and
      hippocampus that synthesize the extracellular matrix protein reelin. They have
      been implicated in the pathfinding of entorhino-hippocampal axons, but their role
      in this process remained unclear. Here we have studied the axonal projection of
      hippocampal CR cells. Following injection of the carbocyanine dye DiI into the
      entorhinal cortex of aldehyde-fixed rat embryos and young postnatal rats, neurons
      in the outer molecular layer of the dentate gyrus and stratum lacunosum
      moleculare of the hippocampus proper with morphological characteristics of CR
      cells were retrogradely labelled. In a time course analysis, the first
      retrogradely labelled CR cells were observed on embryonic day 17. This projection
      of hippocampal CR cells to the entorhinal cortex was confirmed by retrograde
      tracing with Fast Blue in new-born rats and by intracellular biocytin filling of
      CR cells in acute slices from young postnatal rat hippocampus/entorhinal cortex
      and in entorhino-hippocampal slice cocultures using infrared videomicroscopy in
      combination with the patch-clamp technique. In double-labelling experiments CR
      cells were identified by their immunocytochemical staining for reelin or
      calretinin, and their interaction with entorhino-hippocampal axons labelled by
      anterograde tracers was analysed. Future studies need to investigate whether this
      early transient projection of hippocampal CR cells to the entorhinal cortex is
      used as a template by the entorhinal axons growing to their target layers in the
      hippocampus.

PMID- 10594655
TI  - Orientation topography of layer 4 lateral networks revealed by optical imaging in
      cat visual cortex (area 18).
AB  - The functional specificity of corticocortical connections with respect to the
      topography of orientation selectivity was studied by optical imaging of intrinsic
      signals and bulk injections of fluorescent latex beads (green and red) and
      biocytin into layer 4. The distributions of retrogradely labelled cells and
      anterogradely labelled axon terminals were histologically reconstructed from all
      cortical laminae, and the resulting anatomical maps compared with the optically
      imaged functional maps. Layer 4 injections produced extensive horizontal
      labelling up to 2-3 mm from the injection centres albeit without the clear patchy
      pattern described after layer 2/3 injections (Gilbert & Wiesel 1989, J.
      Neurosci., 9, 2432-2442; Kisvarday et al. 1997, Cerebral Cortex, 7, 605-618). The
      functional (orientation) distribution of the labelled projections was analysed
      according to laminar location and lateral spread. With regard to the former, no
      major difference in the orientation topography between supragranular- (upper
      tier), granular- (middle tier) and infragranular (lower tier) layers was seen.
      Laterally, proximal and distal projections were distinguished and further
      dissected into three orientation categories, iso- (+/- 30 degrees ), oblique- (+/
      30-60 degrees ) and cross-orientations (+/- 60-90 degrees ) with respect to the
      orientation preference at the injection sites. The majority of distal connections
      (retrograde and anterograde) was equally distributed across orientations (35.4%
      iso-, 33.7% oblique-, and 30.9% cross-orientations) that are equivalent with a
      preponderance to dissimilar orientations (oblique- and cross-orientations,
      64.6%). In one case, distal excitatory and inhibitory connections could be
      morphologically distinguished. For both categories, a marked bias to dissimilar
      orientations was found (excitatory, 63.7%; inhibitory, 86.6%). Taken together,
      these results suggest that the long-range layer 4 circuitry has a different
      functional role from that of the iso-orientation biased (52.9%, Kisvarday et al.
      1997, Cerebral Cortex, 7, 605-618) layer 2/3 circuitry, and is perhaps involved
      in feature difference-based mechanisms, e.g. figure ground segregation.

PMID- 10594656
TI  - Cortically driven Fos induction in the striatum is amplified by local dopamine D2
      class receptor blockade.
AB  - Dopamine D2-class receptors have been shown to control the excitability of
      striatal neurons in response to cortical activation. It has been unclear,
      however, whether such receptors could regulate the number of striatal neurons
      activated by cortical stimulation, and thus affect the population response of the
      striatum to its cortical inputs. We used Fos induction as a readout to measure
      the ensemble response of striatal neurons to localized stimulation of the frontal
      cortex and tested for the effects of D2-class dopamine receptor blockade on this
      response. In freely moving rats, we stimulated the frontal cortex by local
      epidural application of a dose of a GABAA receptor antagonist (picrotoxin) just
      threshold for inducing Fos in the striatum. We combined this treatment with D2
      class dopamine receptor antagonist treatments at dose levels also just threshold
      for inducing Fos, using either (i) systemic haloperidol or (ii) intrastriatal (
      )sulpiride. Both systemic and intrastriatal blockade of D2-class receptors
      sharply increased the numbers of striatal neurons exhibiting cortically evoked
      Fos induction. These findings suggest that local activation of intrastriatal D2
      class dopamine receptors can regulate the number of striatal neurons responsive
      to cortical inputs, thus dynamically shaping the flow of information through the
      striatum.

PMID- 10594657
TI  - Genetic and epigenetic regulation of NMDA receptor expression in the rat visual
      cortex.
AB  - The susceptibility of cortical networks to use-dependent modifications declines
      with age (critical period) and this decline of neuronal plasticity during
      development is paralleled by the shortening of NMDA receptor EPSCs. We showed
      previously in the somatosensory cortex that the shortening of NMDA receptor
      kinetics correlates with a developmentally-regulated increase in the NR2A subunit
      expression. Here we examine whether this developmental regulation of NR2A
      expression is related to the duration of critical periods and whether it is
      influenced by experience. Functional NMDA receptors and their molecular
      characteristics are studied in identified layer IV neurons of rat visual cortex.
      In this structure the time course of the critical period differs from that in the
      somatosensory cortex and can be changed by sensory deprivation, thus permitting
      examination of correlations between the time course of receptor expression and
      the duration of the critical period. We find that the developmental expression of
      the NR2A subunit is delayed compared with the somatosensory cortex, in agreement
      with the prolonged critical period in the visual cortex. Moreover, sensory
      deprivation further delays the developmental change in the NMDA receptor subunit
      composition, demonstrating the activity dependence of this process and
      strengthening the correlation between changes in subunit composition and the time
      course of the critical period.

PMID- 10594658
TI  - Sensorimotor transformation in cat nociceptive withdrawal reflex system.
AB  - The withdrawal reflex system of higher vertebrates has been extensively used as a
      model for spinal sensorimotor integration, nociceptive processing and plasticity.
      In the rat, the nociceptive withdrawal reflex system appears to have a modular
      organization. Each reflex module controls a single muscle or a few synergistic
      muscles, and its cutaneous receptive field corresponds to the skin area withdrawn
      upon contraction of the effector muscle(s) when the limb is in the standing
      position. This organization principle is at odds with the 'flexion reflex'
      concept postulated from cat studies. To assess the generality of the modular
      organization principle we have therefore re-examined the cutaneous input to the
      withdrawal reflex system of the cat. The cutaneous receptive fields of hindlimb
      and forelimb muscles were mapped using calibrated noxious pinch stimulation and
      electromyographic recording technique in barbiturate anaesthetized animals. The
      investigated muscles had specific cutaneous receptive fields that appeared to
      correspond to the area of the skin withdrawn upon contraction of the muscle when
      the limb is in the standing position. The spatial organization of receptive
      fields in the cat was similar to that in the rat. However, differences in gain
      properties of reflexes to some anatomically equivalent muscles in the two species
      were observed, possibly reflecting adaptations to the biomechanics characteristic
      of the digitigrade and plantigrade stance in cats and rats, respectively.
      Implications of the findings for the generality of the modular organization of
      the withdrawal reflex system and for its adaptive properties are discussed.

PMID- 10594659
TI  - Short-lasting conditioned stimulus applied to the middle cerebellar peduncle
      elicits delayed conditioned eye blink responses in the decerebrate ferret.
AB  - In delay eye blink conditioning, the conditioned stimulus (CS) ends at the time
      of the unconditioned stimulus (US). If the CS duration is decreased, there will
      be a 'trace' period with no ongoing CS before the onset of the US. During this
      period some neural activity has to continue after the CS offset to: (i) permit
      association between the CS and the US; and (ii) elicit a conditioned response
      appearing after the CS offset. In this study we test the role of the cerebellum
      in maintaining CS activity required for eliciting a conditioned response after
      the CS offset. Decerebrate ferrets were trained in a delay conditioning paradigm
      with an electrical stimulation of the forelimb as CS and of the periorbital area
      as US. The conditioned responses in the upper eyelid were monitored with
      electromyographical techniques. In well-trained animals, test CSs of short
      duration down to 0.2 ms were applied to the forelimb or the middle cerebellar
      peduncle, while the interstimulus interval between CS onset and US onset was kept
      constant at 300 ms. Test CSs of short duration applied to the forelimb elicited
      conditioned responses. More importantly, also a short-lasting CS to the middle
      cerebellar peduncle could elicit conditioned responses. The results indicate that
      precerebellar CS pathways are not required for maintaining the neural activity
      that elicits conditioned responses after the CS offset. It is suggested that
      neurons maintaining such activity are located in the cerebellum, either the
      cortex alone or the cortex and the deep nuclei.

PMID- 10594660
TI  - Dopamine cells in nigral grafts differentiate prior to implantation.
AB  - The yield of surviving dopamine cells in nigral grafts is typically low. It is
      unclear whether the dopamine neurons that do survive are postmitotic at the time
      of implantation, or are precursor cells that differentiate into dopamine neurons
      following transplantation in the host brain. We have therefore compared the
      survival of dopamine neurons in grafts that have been labelled with BrdU at
      different times prior to or following implantation in order to identify those
      cells that undergo final cell division at each stage of the procedure. Seven
      groups of rats were prepared with unilateral nigrostriatal lesions. Three groups
      received nigral grafts derived from E14 embryos labelled with BrdU in utero on
      either E12, E13 or E14 days of embryonic age (the E14 injection made 2 h prior to
      preparation of the graft cell suspension). Three further groups received nigral
      grafts from untreated E14 embryos, and then dividing cells within the grafts were
      labelled by injection of BrdU into the host lateral ventricle, 2 h, 1 day or 2
      days after implantation (equivalent to E14, E15 and E16 days of embryonic age).
      The control group received standard (unlabelled) E14 grafts. Five weeks after the
      transplantation surgery, the host brains were processed using double
      immunohistochemical techniques to detect tyrosine hydroxylase (TH)-positive
      neurons which had incorporated BrdU. In the grafts labelled with BrdU prior to
      implantation, there was an increasing proportion of double-labelled cells (out of
      the total TH-positive cells surviving in the grafts) with birth dates on E12, E13
      and E14 (1%, 12% and 10% per day, respectively). By contrast, grafts labelled
      following implantation, although containing many dividing neurons, had very few
      of these BrdU-labelled cells expressing a dopaminergic phenotype; < 1% surviving
      TH-positive cells were double-labelled from the 2 h post-transplant injection,
      and < 0.1% from each subsequent injection. This suggests not only that the great
      majority of TH-positive neurons in nigral grafts were already differentiated at
      the time of implantation, but also that transplantation of E14 ventral
      mesencephalic tissue either kills dopaminergic precursors or (more likely in our
      opinion) prevents their differentiation into a dopaminergic phenotype. Precursor
      cells that would differentiate into dopaminergic neurons beyond E14 if left in
      situ in the intact ventral mesencephalon do not readily differentiate into mature
      dopamine neurons following transplantation. If we are to enhance yields of
      functional dopamine-rich transplants, then we must identify strategies both to
      protect predifferentiated dopamine neurons in the grafts and to promote
      differentiation of a dopaminergic phenotype in precursor cells that continue to
      divide within the grafts following transplantation into an adult host
      environment.

PMID- 10594661
TI  - Selective sensitivity of early postmitotic retinal cells to apoptosis induced by
      inhibition of protein synthesis.
AB  - In previous work we showed that apoptosis in retinal tissue from developing rats
      can be induced by inhibition of protein synthesis (Rehen et al. 1996,
      Development, 122, 1439-1448). Here we show that recent postmitotic cells are the
      cells sensitive to apoptosis triggered by blockade of protein synthesis. To label
      all proliferating cells in the retina, a series of injections of the nucleotide
      analogue, bromo-deoxy-uridine (BrdU, 60 mg/kg b.w.), was given in rat pups. Then,
      explants of the retina were incubated in vitro with the inhibitor of protein
      synthesis anisomycin (1.0-3.2 microg/mL) for 1 day to induce apoptosis. Detection
      of apoptotic bodies under differential interference contrast microscopy was
      combined with immunocytochemistry for BrdU, proliferating cell nuclear antigen
      (PCNA) or for various markers of retinal cell differentiation. Despite the large
      number of BrdU- and PCNA-labelled cells in the tissue, the vast majority of the
      cells that underwent apoptosis were postmitotic cells which have left the mitotic
      cycle 3-4 days before. However, these cells were not labelled with antibodies to
      calretinin, calbindin, rhodopsin or to a Muller glial cell marker, suggesting
      that these are early postmitotic neurons. We suggest that during migration and
      initial differentiation, the apoptotic machinery is blocked by suppressor
      proteins, thus allowing recent postmitotic cells to find their final positions
      and differentiate while protected from apoptosis.

PMID- 10594662
TI  - Progenitor cells of the adult mouse subventricular zone proliferate, migrate and
      differentiate into oligodendrocytes after demyelination.
AB  - Identifying a source of cells with the capacity to generate oligodendrocytes in
      the adult CNS would help in the development of strategies to promote
      remyelination. In the present study, we examined the ability of the precursor
      cells of the adult mouse subventricular zone (SVZ) to differentiate into
      remyelinating oligodendrocytes. After lysolecithin-induced demyelination of the
      corpus callosum, progenitors of the rostral SVZ (SVZa) and the rostral migratory
      pathway (RMS), expressing the embryonic polysialylated form of the neural cell
      adhesion molecule (PSA-NCAM), increased progressively with a maximal expansion
      occurring after 2 weeks. This observation correlated with an increase in the
      proliferation activity of the neural progenitors located in the SVZa and RMS.
      Moreover, polysialic acid (PSA)-NCAM-immunoreactive cells arizing from the SVZa
      were detected in the lesioned corpus callosum and within the lesion. Tracing of
      the constitutively cycling cells of the adult SVZ and RMS with 3H-thymidine
      labelling showed their migration toward the lesion and their differentiation into
      oligodendrocytes and astrocytes but not neurons. These data indicate that, in
      addition to the resident population of quiescent oligodendrocyte progenitors of
      the adult CNS, neural precursors from the adult SVZ constitute a source of
      oligodendrocytes for myelin repair.

PMID- 10594663
TI  - Nitric oxide stimulates cGMP formation in rat optic nerve axons, providing a
      specific marker of axon viability.
AB  - A major transduction pathway for nitric oxide (NO) is stimulation of soluble
      guanylyl cyclase and the generation of cyclic GMP (cGMP). In the central nervous
      system, the NO-cGMP pathway has previously been associated primarily with
      synapses, particularly glutamatergic synapses. We report here that NO caused a
      large increase in the levels of cGMP in a central white matter tract devoid of
      synapses, namely in the rat isolated optic nerve. Cyclic GMP immunohistochemistry
      indicated that this response was confined to the axons. Accordingly, nerves
      previously subjected to 1 h of oxygen/glucose deprivation, which leads to
      irreversible axonal damage, displayed an 80% reduction in their subsequent
      capacity to generate cGMP in response to NO and a corresponding reduction in the
      numbers of cGMP-immunostained axons. Protection of the axon cGMP response against
      this insult was achieved by omission of Ca2 + or Na + from the incubation medium,
      and by the pharmacological agents tetrodotoxin, lamotrigine, BW619C89 and
      BW1003C87, all of which protect axonal structure from oxygen/glucose deprivation
      induced damage. The results suggest that the NO-cGMP pathway has a hitherto
      unsuspected function in the optic nerve. Additionally, the expression of NO
      stimulated guanylyl cyclase in optic nerve axons provides a simple, sensitive and
      specific marker of their functional integrity that is likely to be valuable in
      investigating the mechanisms responsible for axon degeneration in ischaemia and
      other conditions.

PMID- 10594664
TI  - Firing rate and theta-phase coding by hippocampal pyramidal neurons during 'space
      clamping'.
AB  - In the hippocampus, spatial representation of the environment has been suggested
      to be coded by either the firing rate of pyramidal cell assemblies or the
      relative timing of the action potentials during the theta EEG cycle. Here, we
      used a behavioural 'space clamp' method, which involved the confinement of the
      actively running animal in a defined position in space (running wheel) to examine
      how 'spatial' and other inputs affect firing rate and timing of hippocampal CA1
      pyramidal cells and interneurons. Nineteen per cent of the recorded CA1 pyramidal
      cells were selectively active while the rat was running in the wheel in a given
      direction ('wheel' cells). Spatial rotation of the apparatus showed that
      selective discharge of pyramidal cells in the wheel was under the combined
      influence of distal and apparatus cues. During steady running, both discharge
      rate and theta phase were constant. Rotation of the wheel apparatus resulted in a
      shift of both firing rate and preferred theta phase. The discharge frequency of
      'wheel' cells increased threefold (on average) with increasing running velocity.
      In contrast, change in running speed had relatively little effect on the theta
      phase-related discharge of 'wheel' cells. Our findings indicate that mechanisms
      that regulate rate and phase of spikes are overlapping but not necessarily
      identical.

PMID- 10594665
TI  - Hippocampal neuronal position selectivity remains fixed to room cues only in rats
      alternating between place navigation and beacon approach tasks.
AB  - To study the relationship between brain representations and behaviour, we
      recorded hippocampal neuronal activity in rats repeatedly alternating between two
      different tasks on a circular platform with four reward boxes along the edge. In
      the beacon approach task, rewards were provided only at the pair of diametrically
      opposite boxes that was illuminated. In the place navigation task, rewards were
      available only at the boxes positioned near the north-east and south-west corners
      of the room. Performance levels were high and rats rapidly reoriented to changes
      in lamp cues in the beacon approach task. Neuropsychological studies show that
      rats with hippocampal lesions readily employ beacon approach strategies, while
      place navigation is severely impaired. Previous studies suggested that the
      neurons might change their behavioural correlates as the rat performed the
      respective tasks. However, of 34 hippocampal 'place cells' recorded, all showed
      position selectivity fixed with respect to room cues, even in the beacon approach
      task where coding the position of the rat in the room was of no use for locating
      rewards. Whether or not hippocampal signals are actually employed for ongoing
      behaviour would then be decided by structures downstream from the hippocampus. If
      this is the case, then the 'counterproductive' room referred place-related
      discharges in the beacon approach task would be a background representation. This
      would provide support for proposals of multiple memory systems underlying
      different types of information processing and contrasts with the popular notion
      that local neuronal activity levels are selectively increased to the degree that
      the brain region is required for the ongoing function.

PMID- 10594666
TI  - Modulation of feeding-induced activation of mesolimbic dopamine transmission by
      appetitive stimuli and its relation to motivational state.
AB  - We have previously shown in non-deprived rats that feeding of an unfamiliar
      palatable food (Fonzies(R)) phasically stimulates in vivo dopamine (DA)
      transmission in the medial nucleus accumbens (NAc) and this effect undergoes
      habituation after a previous (24 h) Fonzies meal (Bassareo & Di Chiara 1997, J.
      Neurosci., 17, 851-861). The present study shows that an unfamiliar food
      (Kinder(R)) with a taste and composition (milk chocolate) different from that of
      Fonzies, also induces a release of DA in the NAc subjected to one-trial
      habituation. Habituation was taste specific as no cross-habituation was observed
      between Fonzies and Kinder. In undeprived rats, a 40-min exposure to an intrinsic
      appetitive stimulus (food smell arising from a Fonzies-filled plastic box) also
      prevented the increase in dialysate DA associated with Fonzies feeding, and this
      effect was partially reversed by food deprivation. Food deprivation also
      prevented habituation of Fonzies-induced increase of dialysate DA in the NAc.
      Predictive association of an empty plastic box to Fonzies feeding resulted in the
      acquisition of appetitive properties by the box and in facilitation (rather than
      inhibition) of the phasic responsiveness of DA transmission to Fonzies feeding. A
      10-min pre-exposure to appetitive olfactory stimuli intrinsic to Fonzies still
      prevented, like a 40-min pre-exposure, the NAc DA response to Fonzies feeding;
      however, a 5-min pre-exposure to these appetitive stimuli did not prevent the DA
      response in the NAc. These results show that the phasic responsiveness of NAc DA
      transmission to an unfamiliar palatable food is under strong modulatory control
      by primary (consummatory) and secondary (appetitive) stimuli, and that the sign
      and extent of this control depends on the nature of the appetitive stimulus,
      delay of reward and motivational state (deprivation).

PMID- 10594667
TI  - Age-related behavioural deficits in transgenic mice expressing the HIV-1 coat
      protein gp120.
AB  - Transgenic mice expressing HIV-1 coat glycoprotein gp120 in brain glial cells
      were previously shown to display AIDS dementia-like neuropathological changes and
      reduced hippocampal long-term potentiation. In this report, neuromotor and
      cognitive performance in 3- and 12-month-old gp120-expressing mice was compared
      with wildtype controls. Rotarod and cage activity measures showed no significant
      differences between transgenic animals and controls of either age. Open field
      activity was slightly altered in 12-month-old gp120 animals (reduced corner
      crossings and dwell in centre), but not in the 3-month-olds. Cognitive assessment
      using the Morris water maze showed unimpaired performance in 3-month-old mice
      during acquisition and (no-platform) probe trials. In 12-month-old gp120 animals,
      escape latency and swimming velocity during the acquisition trials were
      significantly reduced, but performance improved at roughly the same rate as in
      control animals. However, the probe trials revealed a highly significant
      reduction in spatial retention in transgenic mice of this age. This demonstration
      of age-dependent impairments in open field activity and spatial reference memory
      may relate to cognitive and neuromotor deficits seen in a proportion of HIV-1
      infected individuals.

PMID- 10594668
TI  - Effects of aspiration versus neurotoxic lesions of the amygdala on emotional
      responses in monkeys.
AB  - All previous reports describing alterations in emotional reactivity after
      amygdala damage in monkeys were based on aspiration or radiofrequency lesions
      which likely disrupted fibres of passage coursing to and from adjacent ventral
      and medial temporal cortical areas. To determine whether this associated indirect
      damage was responsible for some or all of the changes described earlier, we
      compared the changes induced by aspiration of the amygdala with those induced by
      fibre-sparing neurotoxic lesions. Four different stimuli, two with and two
      without a social component, were used to evaluate the expression of defence,
      aggression, submission and approach responses. In unoperated controls, defence
      and approach behaviours were elicited by all four stimuli, 'social' and inanimate
      alike, whereas aggression and submission responses occurred only in the presence
      of the two 'social' stimuli. Furthermore, all defence reactions were reduced with
      an attractive inanimate item, while freezing was selectively increased with an
      aversive one. Relative to controls, monkeys with neurotoxic amygdala lesions
      showed the same array of behavioural changes as those with aspiration lesions,
      i.e. reduced fear and aggression, increased submission, and excessive manual and
      oral exploration. Even partial neurotoxic lesions involving less than two-thirds
      of the amygdala significantly altered fear and manual exploration. These findings
      convincingly demonstrate that the amygdala is crucial for the normal regulation
      of emotions in monkeys. Nevertheless, because some of the symptoms observed after
      neurotoxic lesions were less marked than those seen after aspiration lesions, the
      emotional disorders described earlier after amygdalectomy in monkeys were likely
      exacerbated by the attendant fibre damage.

PMID- 10594669
TI  - Contrasting mechanisms of action and sensitivity to antipsychotics of
      phencyclidine versus amphetamine: importance of nucleus accumbens 5-HT2A sites
      for PCP-induced locomotion in the rat.
AB  - In the present study, the comparative mechanisms of action of phencyclidine (PCP)
      and amphetamine were addressed employing the parameter of locomotion in rats. PCP
      induced locomotion (PLOC) was potently blocked by the selective serotonin (5
      HT)2A vs. D2 antagonists, SR46349, MDL100,907, ritanserin and fananserin, which
      barely affected amphetamine-induced locomotion (ALOC). In contrast, the selective
      D2 vs. 5-HT2A antagonists, eticlopride, raclopride and amisulpride,
      preferentially inhibited ALOC vs. PLOC. The potency of these drugs and 12
      multireceptorial antipsychotics in inhibiting PLOC vs. ALOC correlated
      significantly with affinities at 5-HT2A vs. D2 receptors, respectively.
      Amphetamine and PCP both dose dependently increased dialysate levels of dopamine
      (DA) and 5-HT in the nucleus accumbens, striatum and frontal cortex (FCX) of
      freely moving rats, but PCP was proportionally more effective than amphetamine in
      elevating levels of 5-HT vs. DA in the accumbens. Further, whereas microinjection
      of PCP into the accumbens elicited locomotion, its introduction into the striatum
      or FCX was ineffective. The action of intra-accumbens PCP, but not intra
      accumbens amphetamine, was abolished by SR46349 and clozapine.
      Parachloroamphetamine, which depleted accumbens pools of 5-HT but not DA,
      likewise abolished PLOC without affecting ALOC. In contrast, intra-accumbens 6
      hydroxydopamine (6-OHDA), which depleted DA but not 5-HT, abolished ALOC but only
      partially attenuated PLOC. In conclusion, PLOC involves (indirect) activation of
      accumbens-localized 5-HT2A receptors by 5-HT. PLOC is, correspondingly, more
      potently blocked than ALOC by antipsychotics displaying marked affinity at 5-HT2A
      receptors.

PMID- 10594670
TI  - Encoding of target direction and speed during visual instruction and arm tracking
      in dorsal premotor and primary motor cortical neurons.
AB  - The encoding of direction and speed in the discharge of dorsal premotor (PMd) and
      primary motor (MI) neurons was studied during two-dimensional visually-instructed
      pursuit arm movements in which eight directions and four constant speeds were
      independently manipulated. Each trial consisted of equal durations of visual
      observation of target movement without hand movement (cue) and visual pursuit
      tracking of the target with the hand (track). A total of 240 neurons was recorded
      from PMd and MI in two Macaca mulatta monkeys. Two classes of regression analyses
      were used to relate neuronal firing during the cue and track periods to direction
      and speed. First, the average firing from each period was fitted to target
      direction or speed. Period-averaged firing significantly correlated with
      direction more frequently in the track than in the cue period. Conversely,
      correlations with speed (with or without direction) were more common in the cue
      than in the track period. Secondly, a binwise regression evaluated the temporal
      evolution of firing correlations with direction and speed. Supporting the period
      based results, significant binwise correlations of the discharge with speed
      occurred preferentially during the cue period when there was no hand movement.
      Prior to movement, correlations of the firing with direction became significant
      and continued through the movement. Both analyses demonstrated a distinct
      tendency for neurons to be modulated by speed information early and by direction
      information later. This temporal parcellation reflects both the sequential
      demands of the task and constraints placed on the neural computations. The early
      representation of target speed is hypothesized to reflect the need to calculate a
      'go signal' for the initiation of movement.

PMID- 10594671
TI  - Adenosine suppresses protein kinase A- and C-induced enhancement of glutamate
      release in the hippocampus.
AB  - Cultured hippocampal neurons from neonatal rats were used to investigate the
      effect of adenosine on the release of glutamate. Spontaneous tetrodotoxin
      resistant miniature excitatory postsynaptic currents (mEPSCs) through AMPA
      receptor channels were recorded by means of the whole-cell patch-clamp technique.
      Adenosine (50 microM) reversibly reduced the frequency of mEPSCs by approximately
      50-60%, but did not change their amplitudes. The protein kinase A inhibitor Rp
      cyclic adenosine monophosphate (100-150 microM) did not block the adenosine
      dependent reduction of the mEPSC frequency, showing that adenosine is not
      depressing synaptic transmission via a protein kinase A (PKA)-dependent
      mechanism. The D1 dopamine agonist SKF-38393 (250 microM), forskolin (5 microM)
      and 8Br-cAMP (2 mM), known to activate the cAMP/PKA-dependent signalling pathway,
      all enhanced the mEPSC frequency. A subsequent application of adenosine (50
      microM) strongly reduced the potentiation produced by any one of these three
      drugs. It also reversed protein kinase C (PKC)-dependent stimulation of glutamate
      release induced by phorbol myristate acetate (100 nM). Taken together, adenosine
      not only inhibits the spontaneous release of glutamate independently of protein
      kinases A and C but also reverses the enhancement of exocytosis produced by
      protein kinases A and C activators.

PMID- 10594672
TI  - Short communication: mapping of somatosensory cortices with functional magnetic
      resonance imaging in anaesthetized macaque monkeys.
AB  - Functional magnetic resonance imaging (fMRI) in macaque monkeys is emerging as a
      potent candidate to bridge the gap between data from human fMRI studies and data
      from anatomy, electrophysiology and lesion studies in monkeys. The primary (SI)
      and secondary (SII) somatosensory cortices are the principal regions for
      somatosensory information processing and contain systematic representations of
      the body surface map (somatotopy). To examine the functional organization of the
      somatosensory cortices in anaesthetized macaque monkeys with fMRI, we asked
      whether focal and differential activation could be observed in SI and SII in
      response to tactile stimulation with two parameters: body sides (right and left)
      and body regions (hand and face). We found that changes in stimulus parameters
      elicited differential focal activation in both SI and SII in two ways. First, the
      hand and face stimulation activated SI and SII in the contralateral, but not in
      the ipsilateral, hemisphere. Second, the hand and face stimulation differentially
      activated two adjacent regions in both SI and SII. These fMRI results appear to
      correlate with previous mapping studies by other methods in the macaque
      somatosensory cortices. This study shows the feasibility of fMRI studies in
      mapping multiple sensory areas in monkeys by which we can distinguish between
      adjacent functionally distinct regions.

PMID- 10594673
TI  - Short communication: altered synaptic clustering of GABAA receptors in mice
      lacking dystrophin (mdx mice).
AB  - Dystrophin is selectively localized in the postsynaptic density of neurons in
      cerebral cortex, hippocampus and cerebellum. Here, we show by double
      immunofluorescence staining that dystrophin is extensively colocalized with GABAA
      receptor subunit clusters in these brain regions. To determine the relevance of
      this observation, we investigated in mdx mice, which provide a model of Duchenne
      muscular dystrophy, whether the absence of dystrophin affects the synaptic
      clustering of GABAA receptors. A marked reduction in the number of clusters
      immunoreactive for the alpha1 and alpha2 subunits was observed in, respectively,
      cerebellum and hippocampus of mdx mice, but not in striatum, which is normally
      devoid of dystrophin. Furthermore, these alterations were not accompanied by a
      change in gephyrin staining, although gephyrin is colocalized with the majority
      of GABAA receptor clusters in these regions. These results indicate that
      dystrophin may play an important role in the clustering or stabilization of GABAA
      receptors in a subset of central inhibitory synapses. These deficits may underlie
      the cognitive impairment seen in Duchenne patients.

PMID- 10594674
TI  - Molecular characterization and in situ localization of a full-length cyclic
      nucleotide-gated channel in rat brain.
AB  - Ion channels gated directly by cyclic nucleotides are required for the
      transduction of sensory signals in photoreceptor cells and olfactory cells.
      Cyclic nucleotide-gated (CNG) channels may also be expressed in the central
      nervous system because partial transcripts that share homology with CNG channels
      have been found therein. We have now isolated and cloned a full-length CNG
      channel cDNA from adult rat brain. The sequence is identical to that of the alpha
      subunit originally found in the olfactory epithelium (CNCalpha3). In situ
      hybridization, using probes specific for the CNCalpha3 mRNA, suggest that this
      channel is expressed widely in the rat brain, albeit mostly at relatively low
      levels. Certain neuronal populations, however, such as deep cerebellar nuclei,
      olfactory bulb mitral cells and cerebellar Purkinje neurons, appeared specially
      enriched. The study demonstrates for the first time that a full-length CNG
      channel mRNA is expressed in the brain, supporting the possibility that CNG
      channels are involved in central neural communication and plasticity. The
      sequence reported in this paper has been deposited in the GenBank data base
      (accession no. AF126808).

PMID- 10594675
TI  - Expression of nonclassical MHC class I (RT1-U) in certain neuronal populations of
      the central nervous system.
AB  - Major histocompatibility complex (MHC) class I genes consist of classical (Ia)
      and nonclassical (Ib) types. Recently, a set of structurally similar MHC class Ib
      genes in the rat, denoted RT1-U, was described. We here demonstrate expression of
      RT1-U mRNA using highly stringent oligonucleotide in situ hybridization in
      several different neuronal populations, including different motor nuclei and the
      substantia nigra in the rat MHC (c) and (n) haplotypes under normal conditions.
      The expression pattern for beta2-microglobulin mRNA was almost identical. In
      contrast, neuronal expression of classical MHC class I (RT1-A) was low.
      Interestingly, after mechanical nerve injury, glial cells predominantely
      upregulated expression of RT1-A, whereas neuronal expression of RT1-U remained
      unchanged. Neuronal expression of nonclassical MHC class I may thus be important
      for immune surveillance in the nervous system.

PMID- 10594676
TI  - alpha-Gustducin expression in the vomeronasal organ of the mouse.
AB  - The expression of alpha-gustducin, a G protein alpha subunit involved in bitter
      and sweet taste transduction, was investigated in chemosensory tissues of adult
      mice. By immunohistochemistry, alpha gustducin was absent in the olfactory
      neuroepithelium. Instead, alpha gustducin was expressed in a subset of bipolar
      cells in the proliferative zone of the vomeronasal neuroepithelium as well as in
      taste buds. Northern blot analysis confirmed the presence of alpha gustducin in
      isolated vomeronasal organs. Moreover, immunohisto- chemistry revealed the
      expression of alpha gustducin in scattered cells of the nasal respiratory
      epithelium. These results show for the first time that alpha gustducin is
      expressed in chemosensory tissue outside the alimentary tract, suggesting that
      common transduction mechanisms could be shared by apparently unrelated
      chemosensory tissues.

PMID- 10594677
TI  - Cyclical changes in endogenous levels of oestrogen modulate the induction of LTD
      and LTP in the hippocampal CA1 region.
AB  - The present study investigated the effects of naturally fluctuating endogenous
      levels of oestrogen on the induction and maintenance of long-term potentiation
      (LTP) and long-term depression (LTD) in the CA1 region of the hippocampus. Using
      an anaesthetized in vivo preparation, the results showed that the induction of
      LTP was augmented during the pro-oestrous stage of the oestrous cycle. In
      contrast to LTP, however, the induction of paired-pulse LTD was severely
      attenuated during pro-oestrous, but was clearly manifested by rats during
      met/dioestrous and oestrous stages of the cycle. These findings are discussed
      with reference to: (i) the modulatory effects of oestrogen on N-methyl-D
      aspartate (NMDA) receptor function and gamma-aminobutyric acid (GABA)
      neurotransmission in the hippocampus; and (ii) the functional implications that
      such cyclical changes in synaptic plasticity have for learning and memory
      processes supported by the hippocampus.

PMID- 10594678
TI  - Simple chemicals can induce maturation and apoptosis of dendritic cells.
AB  - As is well known in the case of Langerhans cells, dendritic cells (DCs) play a
      crucial role in the initiation of immunity to simple chemicals such as noted in
      the contact hypersensitivity. Because DCs are scattered in non-lymphoid organs as
      immature cells, they must be activated to initiate primary antigen-specific
      immune reactions. Therefore, we hypothesized that some simple chemicals must
      affect the function of DCs. In this paper, we first demonstrated that human
      monocyte-derived DCs responded to such simple chemicals as 2, 4
      dinitrochlorobenzene (DNCB), 2,4,6-trinitrochlorobenzene (TNCB), 2, 4
      dinitrofluorobenzene (DNFB), NiCl2, MnCl2, CoCl2, SnCl2, and CdSO4 by augmenting
      their expression of CD86 or human leucocyte antigen-DR (HLA-DR), down-regulating
      c-Fms expression or increasing their production of tumour necrosis factor-alpha
      (TNF-alpha). In addition, the DCs stimulated with the chemicals demonstrated
      increased allogeneic T-cell stimulatory function. Next, we found that, among
      these chemicals, only NiCl2 and CoCl2 induced apoptosis in them. Finally, we
      examined the effects of these chemicals on CD86 expression by three different
      macrophage subsets and DCs induced from the cultures of human peripheral blood
      monocytes in the presence of macrophage colony-stimulating factor (M-CSF), M-CSF
      + interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor (GM
      CSF), and GM-CSF + IL-4, respectively. Among them, only DCs dramatically
      augmented their expression of CD86. These observations have revealed unique
      characteristics of DCs, which convert chemical stimuli to augmentation of their
      antigen presenting function, although their responses to different chemicals were
      not necessarily uniform in the phenotypic changes, cytokine production or in the
      induction of apoptosis.

PMID- 10594679
TI  - Granulocyte-macrophage colony-stimulating factor modulates lipopolysaccharide
      (LPS)-binding and LPS-response of human macrophages: inverse regulation of tumour
      necrosis factor-alpha and interleukin-10.
AB  - Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a well-known
      stimulus for the activation, differentiation and survival of monocytes (MO). Up
      to now most investigations focused on the short-term effects of GM-CSF. In this
      study we investigated the effects of GM-CSF on the long-term differentiation of
      human MO in the presence of serum. We found that MO-derived macrophages (Mphi)
      cultured with serum plus GM-CSF (GM-Mphi) were different from control Mphi (SER
      Mphi) in terms of lipopolysaccharide (LPS)-stimulated cytokine release: GM-Mphi
      showed an increased tumour necrosis factor-alpha (TNF-alpha) and interleukin-6
      (IL-6) production, especially at lower LPS concentrations, but the secretion of
      IL-10 was diminished. In addition, GM-Mphi secreted TNF-alpha but not IL-6 and IL
      10, spontaneously. The spontaneous TNF-alpha production was not due to LPS
      contamination as it could not be blocked by anti-CD14 antibody. Flow cytometry
      revealed, however, that the receptor for LPS, CD14, was up-regulated on GM-Mphi
      and those Mphi released twice as much soluble CD14 into the supernatant as
      compared with SER-Mphi. The higher CD14 expression also resulted in an enhanced
      LPS-binding capacity of GM-Mphi. Furthermore, the LPS-response of GM-Mphi could
      only be blocked by about fourfold higher concentration of anti-CD14 antibody
      compared with SER-Mphi. In summary, GM-CSF promotes the generation of a pro
      inflammatory type of Mphi in two different ways: first, the down-regulation of
      autocrine IL-10 production increases the release of cytokines such as IL-6 and
      TNF-alpha and second, the up-regulation of membrane and soluble CD14 expression
      leads to a higher sensitivity towards LPS-stimulation.

PMID- 10594680
TI  - Differential expression of inducible nitric oxide synthase gene by alveolar and
      peritoneal macrophages in lipopolysaccharide-hyporesponsive C3H/HeJ mice.
AB  - In lipopolysaccharide (LPS)-hyporesponsive C3H/HeJ mice, alveolar macrophages
      (AMphi) produce much more tumour necrosis factor-alpha than peritoneal
      macrophages (PMphi) when stimulated with LPS (10 microgram/ml), but the induction
      of inducible nitric oxide synthase (iNOS) gene expression and production of
      nitric oxide (NO) in AMphi are not found. In the present study, we determined the
      induction of iNOS gene expression, using semi-quantitative reverse transcription
      polymerase chain reaction, and the release of NO in AMphi and PMphi from C3H/HeJ
      and C3H/HeN mice. The results showed the induction of iNOS mRNA accumulation in a
      dose-dependent manner by LPS alone or in combination with interferon-gamma in
      both macrophages. The effects of the stimuli on iNOS gene expression and NO
      production were significantly higher in AMphi than in the PMphi of C3H/HeJ mice.
      The response of macrophages from C3H/HeN mice was similar to those from C3H/HeJ
      mice, but the difference of iNOS gene expression between AMphi and PMphi in
      C3H/HeN mice was not as striking as in C3H/HeJ mice. The results show that the
      iNOS gene expression and NO production were activated differently in AMphi and
      PMphi and suggest that the functional properties of macrophages isolated from
      distinct origins are different.

PMID- 10594681
TI  - Interleukin-15 strongly inhibits interleukin-8 and monocyte chemoattractant
      protein-1 production in human colonic epithelial cells.
AB  - Interleukin-15 (IL-15) is a novel cytokine with actions similar to IL-2 because
      of common receptor components. Although IL-15 is expressed in colonic epithelial
      cells and may regulate epithelial cell function, its effects on these cells are
      not fully defined. We explored the regulatory effects of IL-15 on IL-8 and
      monocyte-chemoattractant protein-1 (MCP-1) production in the colonic epithelial
      cell line Caco-2 as well as in freshly isolated human colonic epithelial cells.
      IL-15 was added to intestinal epithelial cells under various culture conditions.
      Levels of chemokines were determined by enzyme-linked immunosorbent assay. To
      determine the elements of the IL-2/IL-15R complex involved we used neutralizing
      antibodies specific for individual receptor chains. IL-15 down-regulates IL-8 and
      MCP-1 production in Caco-2 cells as well as in freshly isolated human colonic
      epithelial cells in a dose-dependent manner. Intestinal epithelial cells became
      more responsive to IL-15-induced suppression when activated with greater IL-1
      doses. Strong chemokine suppression was seen when IL-15 was given prior to,
      simultaneous with, or after stimulatory agent. Anti-IL-2Rgamma antibodies
      efficiently blocked (82% inhibition) the suppression induced by IL-15, while anti
      IL-2Rbeta antibodies were less effective. The involvement of beta-chain was
      further suggested by the finding that a mixture of both monoclonal antibodies
      (mAb) at a suboptimal concentration (1 microgram/ml of each mAb) produced a
      synergistic inhibitory effect on down-regulation of epithelial chemokine
      production. These results show that IL-15 can suppress IL-8 and MCP-1 secretion
      by intestinal epithelial cells. A microenvironment containing high concentrations
      of IL-15 may alter the recruitment of neutrophils to enterocytes at least partly
      by inhibiting IL-8 and MCP-1 production.

PMID- 10594682
TI  - The intercellular adhesion molecule type-1 is required for rapid activation of T
      helper type 1 lymphocytes that control early acute phase of genital chlamydial
      infection in mice.
AB  - Recent studies in animal models of genital chlamydial disease revealed that early
      recruitment of dendritic cells and specific T helper type-1 (Th1) cells into the
      genital mucosae is crucial for reducing the severity of the acute phase of a
      cervico-vaginal infection and arresting ascending disease. These immune effectors
      are therefore important for preventing major complications of genital chlamydial
      infection. Other in vitro studies showed that intercellular adhesion molecule-1
      (ICAM-1) plays a role in the antichlamydial action of specific CD4+ and CD8+ T
      cells. In the present study, we investigated the clinicopathological consequences
      of ICAM-1 deficiency during chlamydial genital infection in ICAM-1 knockout (ICAM
      1KO) mice, and analysed the cellular and molecular immunological bases for any
      observed pathology or complication. Following a primary genital infection of
      female ICAM-l-/- and ICAM-1+/+ mice, the intensity of the disease during the
      first 3 weeks (as assessed by shedding of chlamydiae in the genital tract) was
      significantly greater in ICAM-1KO mice than in ICAM-1+/+ mice (P < 0.0001),
      although both ICAM-l-/- and ICAM-1+/+ mice subsequently cleared the primary
      infection. There was greater ascending disease during the initial stage of the
      infection, and a higher incidence of tubal disease (hydrosalpinx formation) after
      multiple infections in ICAM-l-/- mice. Analysis of the cellular and molecular
      bases for the increased acute and ascending disease in ICAM-l-/- mice revealed
      that the high affinity of ICAM-1 for leucocyte function antigen type-1 is a
      property that promotes rapid activation of specific Th1 cells, as well as their
      early recruitment into the genital mucosa. Moreover, ICAM-1 was more important
      for naive T-cell activation than primed Th1 cells, although its absence delayed
      or suppressed immune T-cell activation by at least 50%. Taken together, these
      results indicated that ICAM-1 is crucial for rapid T-cell activation, early
      recruitment and control of genitally acquired Chlamydia trachomatis.

PMID- 10594683
TI  - Contribution of mast cells to the T helper 2 response induced by simultaneous
      subcutaneous and oral immunization.
AB  - This work examines the contribution of mast cells to the synergistic enhancement
      of the T helper 2 (Th2) immune response elicited following simultaneous oral and
      subcutaneous (s.c.) immunization. The s.c. route induced a Th1-biased immune
      response, characterized by increased interferon-gamma (IFN-gamma) and
      immunoglobulin G2a (IgG2a) antibody production. In contrast, oral immunization
      stimulated a primarily Th2-type response in which interleukin-4 (IL-4) and IgG1
      antibody production were dominant. Simultaneous immunization also triggered a Th2
      biased response, the magnitude of which exceeded the additive effects of s.c. and
      oral immunization alone by greater than threefold. To analyse whether mast cells
      in gut-associated lymphoid tissue contributed to this synergistic response, mast
      cell-deficient mice WBB6F1-w/wv were studied. Whereas the primary response
      following simultaneously antigen administration was reduced only twofold in these
      animals compared with wild type controls WBB6F1-+/+ (suggesting that mast cells
      were not needed to initiate Th2 immunity), reconstitution with bone-marrow
      derived mast cells from WBB6F1-+/+ mice resulted in a superoptimal response
      (suggesting that mast cells contribute to the magnitude and perpetuation of these
      Th2-biased responses).

PMID- 10594684
TI  - Schistosomal egg antigen-responsive CD8 T-cell population in Schistosoma mansoni
      infected BALB/c mice.
AB  - We demonstrated here that schistosomal egg antigen (SEA) is able to stimulate an
      antigen-specific, cytotoxic CD8+ T-cell response in mice. Indeed, a single i.p.
      immunization with SEA resulted in the in vivo induction of significant cytotoxic
      T lymphocyte (CTL) activity in the spleen within 20 days. Effector cells were
      classic class I major histocompatibility complex (MHC)-restricted CD8+
      lymphocytes producing interferon-gamma (IFN-gamma) and interleukin-2 (IL-2),
      suggesting a type 1 response to SEA. We therefore investigated the relevance of
      these observations in the context of the Schistosoma mansoni parasite infection.
      CTL activity against SEA-pulsed target cells was evidenced throughout the
      infection after in vitro stimulation of recovered splenic cells with SEA
      demonstrating that SEA-specific CD8+ T cells with cytotoxic potentialities are
      present during infection. This activity was strongly increased after immunization
      of mice with SEA like the production of IFN-gamma in the sera. A marked reduction
      in the number of granulomas and of fibrosis with the presence of cells producing
      IFN-gamma in the liver was also observed leading to the survival of SEA-immunized
      mice.

PMID- 10594685
TI  - In vivo selective expansion of a tumour-specific cytotoxic T-cell clone derived
      from peripheral blood of a melanoma patient after vaccination with gene-modified
      autologous tumour cells.
AB  - Melanoma-specific cytotoxic T lymphocytes (CTL) can be generated from peripheral
      blood lymphocytes (PBL) by mixed lymphocyte-tumour cell cultures. Analysis of CTL
      precursor frequencies in peripheral blood of melanoma patients is generally used
      for immunomonitoring purposes to evaluate vaccination efficacy. At present, it is
      unclear whether PBL-derived CTL generated in vitro are indicative of an anti
      tumour immune response in vivo. Three tumour-specific human leucocyte antigen
      (HLA)-B/C-restricted CTL clones were derived from peripheral blood of a melanoma
      patient immunized with interleukin-7 (IL-7) gene-modified tumour cells. CTL
      clones differing in their T-cell receptor-gamma (TCRgamma) rearrangement produced
      interferon-gamma, IL-4 and/or IL-10. On the basis of their unique TCRgamma gene
      rearrangements clone-specific primers were generated for detection of clone
      specific DNA by polymerase chain reaction. One CTL clone (E5) of the three was
      found to be selectively expanded in one of seven metastases obtained at autopsy,
      as determined by Southern blot hybridization. However, the presence of E5 in only
      one of seven metastases at death indicates that the in vivo accumulation of the
      specific CTL clone was not sufficient to contain tumour progression.
      Nevertheless, our data support the proposition that analysis of anti-tumour
      activity of PBL-derived CTLs may reflect an anti-tumour immune response in vivo.

PMID- 10594686
TI  - Human antigen-presenting cell/tumour cell hybrids stimulate strong allogeneic
      responses and present tumour-associated antigens to cytotoxic T cells in vitro.
AB  - Most tumours do not stimulate effective antitumour immune responses in vivo. In
      order to enhance the immunogenicity of human tumour cells, we fused a variety of
      tumour cell lines with an Epstein-Barr virus transformed B-lymphoblastoid cell
      line (EBV B-LCL) in vitro, to produce stable hybrid cells. Hybrid cell lines
      showed a marked increase in their ability to stimulate primary allogeneic T-cell
      responses in vitro, as compared with the parent tumour cells. The hybrid cells
      induced proliferation of naive (CD45RA+) as well as memory (CD45RO+) T
      lymphocytes, and both CD4+ and CD8+ subpopulations of T cells were directly
      stimulated. The stimulatory hybrids expressed human leucocyte antigen (HLA) class
      I and II, and a wide range of surface accessory molecules, including the T-cell
      co-stimulatory ligand molecules CD40, CD80 (B7.1) and CD86 (B7.2), the expression
      of which was required for optimal stimulation of T-cell responses. Fusion of the
      EBVB-LCL with a melanoma cell line (518.A2) yielded hybrid cells that expressed
      the melanoma-associated antigens MAGE-1 and MAGE-3, and presented these antigens
      to antigen-specific, HLA class I-restricted cytotoxic T-lymphocyte clones with
      greater efficiency than the parent melanoma cell line. These findings suggest
      that the generation of human antigen-presenting cell/tumour cell hybrids offers
      promise as an approach to cancer immunotherapy.

PMID- 10594687
TI  - Suppression of the reactive oxygen intermediates production of human macrophages
      by colorectal adenocarcinoma cell lines.
AB  - Although some in vitro studies indicate that macrophages exert cytotoxic
      responses against tumour cells by production of reactive oxygen intermediates
      (ROI), no obvious impairment of tumour cell growth is visible in various human
      malignant tumours, which contain a large number of tumour-associated macrophages
      (TAM). We made use of an in vivo-like co-culture model of multicellular tumour
      spheroids of three colon carcinoma cell lines (HRT-18, HT-29, CX-2) and three
      functionally different phenotypes of human macrophages (27E10, RM3/1, 25F9) to
      investigate if tumour cells deactivate macrophage cytotoxicity. The production of
      ROI was measured by a lucigenin-amplified chemiluminescence assay in a 96-well
      microplate luminometer. Different capabilities to produce ROI by different
      macrophage phenotypes were observed. However, independent of the macrophage
      phenotype and the tumour cell type a significant inhibition of ROI formation was
      found in co-cultures after 1 hr, 1 and 2 days. Macrophages were also suppressed
      by tumour cell supernatants, which contained anti-inflammatory cytokines
      transforming growth factor-beta1 (TGF-beta1) and negligible levels of interleukin
      4 (IL-4) and IL-10 as shown by enzyme-linked immunosorbent assay (ELISA).
      Although recombinant human cytokines TGF-beta1, IL-10 and IL-4 inhibited the
      production of ROI in freshly isolated monocytes, these cytokines had no effect on
      differentiated macrophage phenotypes, indicating that these cytokines are not
      involved in mediating tumour-induced suppression of ROI production by human
      macrophages.

PMID- 10594688
TI  - Effects of alpha-galactosylceramide (KRN7000), interleukin-12 and interleukin-7
      on phenotype and cytokine profile of human Valpha24+ Vbeta11+ T cells.
AB  - The alpha-galactosylceramide KRN7000 was reported to be presented by CD1d to
      natural killer (NK) T cells, cells that are thought to play an important role in
      the rejection of malignant tumours and in the regulation of several autoimmune
      diseases. Here we analysed human peripheral blood (PB) NK T cells (Valpha24+
      Vbeta11+ T cells) before and after a short-term culture in the presence of
      KRN7000. KRN7000 strongly activated PB Valpha24+ Vbeta11+ T cells and, when
      stimulated, the vast majority of these cells expressed interferon-gamma (IFN
      gamma). Exposure of these KRN7000-cultured Valpha24+ Vbeta11+ T cells to
      interleukin-12 (IL-12), but not to IL-7, resulted in a relative increase in IFN
      gamma-expressing Valpha24+ Vbeta11+ T cells, compared with IL-4-expressing
      Valpha24+ Vbeta11+ T cells, indicating a shift towards a T-helper type 1 (Th1)
      phenotype. KRN7000 strongly up-regulated the expression of the cytotoxic molecule
      granzyme B (GrB) in Valpha24+ Vbeta11+ T cells. Although IL-7 resulted in a
      decrease in GrB levels in KRN7000-cultured Valpha24+ Vbeta11+ T cells, IL-12
      increased GrB levels in both Valpha24+ Vbeta11+ T cells and in Valpha24+ Vbeta11+
      T-cell clones and increased cytotoxicity against hCD1d-transfected HeLa cells.
      Our data provide further insight into the characteristics of human Valpha24+
      Vbeta11+ T cells and indicate that KRN7000 is a potent activator of Valpha24+
      Vbeta11+ T cells. Combined with the established anti-tumour effects of KRN7000 in
      mouse models, these results may support the use of KRN7000 as an anti-tumour
      agent in man.

PMID- 10594689
TI  - Adhesion to fibronectin promotes the activation of the p125(FAK)/Zap-70complex in
      human T cells.
AB  - The beta1 integrins are a family of heterodimeric adhesion receptors involved in
      cell-to-cell contacts and cell-to-extracellular matrix interactions. Through
      their adhesive role, integrins participate in transduction of outside/inside
      signals and contribute to trigger a multitude of cellular events such as
      differentiation, cell activation, and motility. The fibronectin integrin
      receptors, alpha4beta1 and alpha5beta1, can function as costimulatory molecules
      in T-cell receptor (TCR)-dependent T-cell activation. In the current study the
      Jurkat T-cell line was used as a model system to investigate the TCR-independent
      role of cell adhesion to fibronectin in the activation of Zap-70, a central
      molecule in the signalling events in T cells. Upon adhesion to plastic
      immobilized fibronectin but not to bovine serum albumin (BSA) the phosphorylation
      of p125FAK, a protein kinase that localizes to focal adhesion sites, was induced.
      Moreover, clustering of fibronectin receptors led to the detection of a
      p125FAK/Zap-70 complex. Finally, while the complex between fak-B, another protein
      kinase localized to focal adhesion sites, and Zap-70 was detected in cells plated
      either on BSA or on fibronectin, the formation of the p125FAK/Zap-70 complex
      appeared specifically induced following fibronectin-mediated integrin clustering.
      These data suggest the existence of a high degree of specificity when the members
      of the beta1 integrin family mediate signalling pathways in T cells.

PMID- 10594690
TI  - Lack of activation induced cell death in human T blasts despite CD95L up
      regulation: protection from apoptosis by MEK signalling.
AB  - The generation of effective immunity requires that antigen-specific T cells are
      activated, clonally expanded and ultimately eliminated by apoptosis. The
      involvement of CD95-mediated apoptosis in T-cell elimination is well established,
      but the conditions which regulate the death pathway under normal circumstances
      are still emerging. Using superantigen-activated human T cells, we found that
      whilst T-cell receptor (TCR) signalling triggered up-regulation of CD95 ligand
      (CD95L), the majority of T cells were resistant to apoptosis induction, despite
      co-expressing high levels of CD95. Resistance was maintained following direct
      antibody-mediated cross-linking of CD95 and was not confined to early time
      periods following activation. Our data implicate TCR-derived signals in
      protection from apoptosis and reveal a role for the mitogen-activated protein
      (MAP) kinase pathway by use of a MAP kinase kinase (MEK) inhibitor. Collectively
      these data demonstrate that resistance to activation-induced cell death in human
      T cells is prolonged rather than transient, is not attributable to a lack of
      CD95L up-regulation and is due, at least in part, to signalling via the MEK
      pathway.

PMID- 10594691
TI  - Anterior chamber-associated immune deviation-inducing cells activate T cells, and
      rescue them from antigen-induced apoptosis.
AB  - Immune responses to antigens injected into the anterior chamber of the eye are
      devoid of T helper 1 (Th1)-type responses of the delayed hypersensitivity type,
      which has been termed anterior chamber-associated immune deviation (ACAID).
      Recently, it has been found that peritoneal exudate cells (PEC) from normal mice
      can be made to acquire the capacity to induce ACAID in vivo when the cells are
      pulsed with antigen in vitro in the presence of transforming growth factor-beta2
      (TGF-beta2), a major cytokine in the ocular microenvironment. We now report that
      when ovalbumin (OVA)-specific T cells from DO11.10 transgenic mice, or from OVA
      primed normal mice, were activated in vitro by normal (untreated) PEC pulsed with
      OVA, the responding T cells were induced to undergo apoptosis. However, when PEC
      were first treated with TGF-beta2 and then used to stimulate DO11.10 T cells in
      the presence of OVA, T-cell proliferation occurred without evidence of increased
      apoptosis. The ability of TGF-beta2 to rescue responding T cells from apoptosis
      rested with the capacity of this cytokine to inhibit interleukin-12 (IL-12)
      production by PEC. Untreated PEC produced large amounts of IL-12 upon interaction
      with responding T cells. Under these conditions, tumour necrosis factor-alpha
      (TNF-alpha) production was up-regulated, and this cytokine, in turn, triggered
      apoptosis among T cells stimulated with OVA-pulsed PEC. From these results, we
      conclude that TGF-beta2-treated APC promote ACAID by rescuing antigen-activated T
      cells from apoptosis, and by conferring upon these cells the capacity to down
      regulate delayed hypersensitivity.

PMID- 10594692
TI  - Some Bence-Jones proteins enter cultured renal tubular cells, reach nuclei and
      induce cell death.
AB  - Eighteen monoclonal Bence-Jones proteins (BJPs) were examined for their effects
      on cultured LLC-PK1 (porcine kidney proximal tubule) cells as well as for their
      amidase and DNase activities. Five proteins were found to enter the cell and to
      gain access to the nucleus without degradation of epitopes. Intranuclear BJPs
      ultimately induced DNA fragmentation and cell death. BJPs with relatively high
      amidase activity were cytotoxic. On the other hand, three of four BJPs with DNase
      activity had a cytocidal effect on cultured cells; the remaining BJP, which had a
      relatively high DNase activity but a very low amidase activity, failed to enter
      the cell and was not cytotoxic in vitro. These results suggest that catalytic and
      cytotoxic activities of some BJPs may make a significant contribution, in a
      substantial proportion of myeloma patients, to the development and/or
      deterioration of the disease.

PMID- 10594693
TI  - Elevated apoptosis of peripheral T lymphocytes in diabetic BB rats.
AB  - Thymocytes and peripheral lymphocytes of BioBreeding (BB) diabetes-prone (BBDP)
      and diabetes-resistant (BBDR) rat were analysed by fluorescence-activated cell
      sorter (FACS). The number of CD4- CD8-, CD4+ CD8-, CD4- CD8+ and CD4+ CD8+
      subsets was not different between BBDP and BBDR rat thymocytes, whereas spleen
      and lymph nodes in BBDP rats undergo severe T-cell lymphopenia. Notably, mature
      CD4- CD8+ [T-cell receptor (TCR)-alphabeta+ and CD5+] cells are certainly present
      in the BBDP rat thymus, unlike some previous reports, suggesting that the
      differentiation of CD4- CD8+ from CD4+ CD8+ cells occurs normally in the BBDP rat
      thymus. As a cause of peripheral T-cell lymphopenia we suspected apoptosis of
      recent thymic emigrants. By FACS analysis with fluorescein isothiocyanate
      labelled annexin V, elevated apoptosis was evident in BBDP rat peripheral
      lymphocytes. Furthermore, terminal deoxynucleotidyl transferase-mediated dUTP
      biotin nick end labelling (TUNEL) staining in BBDP rat splenic sections revealed
      that a number of TUNEL-positive cells were observed in the T-lymphocyte-rich
      area. From these results, we postulate that an abnormally elevated apoptosis of
      peripheral T lymphocytes, but not impaired thymocyte differentiation, is a cause
      of the peripheral T-cell lymphopenia in BBDP rats.

PMID- 10594694
TI  - Regulation of B-1 cell activation and its autoantibody production by Lyn kinase
      regulated signallings.
AB  - The src-family protein tyrosine kinase, Lyn, has been reported to play a crucial
      role in the regulation of B-cell antigen receptor (BCR)-mediated signalling. To
      elucidate the role of Lyn in the maintenance of immunological tolerance and the
      prevention of B-1 cell activation and its autoantibody production, Lyn-deficient
      mice were crossed with transgenic mice carrying the immunoglobulin heavy and
      light chain genes encoding an autoantibody against mouse red blood cells. In the
      transgenic mice, most peripheral B cells expressed the B-1 cell phenotype. When
      the transgenic mice were bred in specific pathogen-free (SPF) conditions, B-1
      cells were anergic and did not produce any autoantibody. In contrast, Lyn
      deficient transgenic mice kept in the same SPF conditions revealed markedly
      increased numbers of activated B-1 cells and developed severe autoimmune
      haemolytic anaemia. Moreover, the mice had a huge splenomegaly containing a
      remarkable accumulation of erythroblasts, resulted from extramedullary
      erythropoiesis, in addition to the increased numbers of lymphoblast-like cells of
      the B-1 cell lineages. The present study demonstrates a crucial role of Lyn
      kinase in the regulation of B-1 cell activation and maintenance of tolerance.

PMID- 10594695
TI  - Pregnancies modulate B lymphopoiesis and myelopoiesis during murine ageing.
AB  - We recently reported that pregnancy affects age-related changes in the
      distribution of lymphoid and macrophage populations in the spleen of C57Bl/6
      mice. In the present study, we examined the influence of pregnancies on the
      generation of various developmental B-cell subsets and granulocyte/macrophage
      lineage cells during murine ageing. Using flow cytometry, changes in lymphoid
      (mature and early B-cell precursors: B220high, B220low, surface immunoglobulin M
      (sIgM) mu chain +/-) and myeloid (monocyte/macrophage Mac-1/CD11b, granulocyte Gr
      1/Ly-6G) compartments were monitored in the bone marrow of young (2 months) and
      15- and 23-month-old mice including male, multiparous and virgin female mice.
      Pregnancies delayed the age-related decline in murine B lymphopoiesis and
      maintained B-cell reserve capacity during ageing. We also found an increased
      production of myeloid cells induced by pregnancies at middle (15 months) and
      advanced (23 months) ages. This comparative study provides new information on
      changes in marrow lymphopoiesis and myelopoiesis with age. Our data emphasizes
      that the onset, magnitude and kinetics of age-related changes in the
      haematopoietic marrow are parity dependent. These changes could influence the
      incidence of age-related diseases and may account for the greater longevity of
      females.

PMID- 10594696
TI  - Systematic characterization of porcine ileal Peyer's patch, I. apoptosis
      sensitive immature B cells are the predominant cell type.
AB  - It is now apparent that the Peyer's patches of some species exhibit structural,
      functional and developmental heterogeneity. In sheep, for example, the ileal
      Peyer's patch (IPP) is the primary, antigen-independent site for the generation
      of the primary immunoglobulin repertoire and consequent production of the
      systemic B-cell pool. The pig has three distinct Peyer's patches, including an
      IPP, but the functional status of this organ, as primary or secondary lymphoid
      tissue, is not clear. Here, we have systematically characterized pig IPP
      follicular lymphocytes and show that about 90% B cells that are positive for
      surface immunoglobulin G (sIgM+) and express an immature phenotype characterized
      by expression of myeloid marker sWC3 (74-22-15) and two molecules recognized by
      IPP B-cell-specific monoclonal antibodies (F10/4, F12/35). Extensive apoptosis in
      vivo and in vitro was demonstrated by electron microscopy, immunohistology with
      TdT-mediated dUTP nick end labelling, DNA analysis and fluorescence-activated
      cell sorter analysis. Thus, when isolated IPP follicular cells were incubated at
      37 degrees in vitro, the majority of them became apoptotic. The few that
      survived, however, had lost their expression of sWC3, F10/4, F12/35, but showed
      an increased expression of sIgM and major histocompatibility complex class II
      indicating that such surviving cells were of a more mature phenotype. Although
      more T cells were observed in porcine IPP follicles than in sheep IPP, CD3+ cells
      comprised less than 5% of the IPP follicular lymphocytes. Thus, the results
      clearly indicate that pig IPP is equivalent to sheep IPP.

PMID- 10594697
TI  - Systematic characterization of porcine ileal Peyer's patch, II. A role for CD154
      on T cells in the positive selection of immature porcine ileal Peyer's patch B
      cells.
AB  - We previously demonstrated that the majority (>/= 90%) of porcine ileal Peyer's
      patch (IPP) follicular cells are immature B cells destined to die by apoptosis,
      when incubated at 37 degrees. In this paper we approached the mechanisms
      responsible for positive selection of porcine IPP follicular immature B-cell
      selection, by screening for various cell types, cytokines and polyclonal and
      monoclonal antibodies for promoting the survival of IPP B cells. Of these
      reagents, only CD3 cross-linked purified T cells from mesenteric lymph nodes were
      able to rescue IPP follicular B cells from apoptosis, although polyclonal anti
      IPP lymphocyte antibodies delayed apoptosis. This survival effect could be
      reproduced simply by incubating IPP follicular B cells with soluble and cell
      membrane-expressed CD154, an observation consistent with the demonstrated
      presence of CD40 and CD154 on porcine IPP follicular B cells and activated T
      cells, respectively. The IPP follicular B cells rescued in this manner expressed
      a more mature surface marker phenotype. Immunohistology and fluorescence
      activated cell sorter analysis demonstrated that subpopulations of IPP follicular
      T cells (less than 0.5%) express CD154. Thus, perhaps unexpectedly, CD154 on T
      cells may play a role in the positive selection of immature B cells in the
      porcine IPP. The origin and control of the activated T cells identified within
      the porcine IPP remains to be investigated.

PMID- 10594698
TI  - Mice transgenic for a soluble form of murine cytotoxic T lymphocyte antigen 4 are
      refractory to murine acquired immune deficiency sydrome development.
AB  - Interactions between B and CD4+ T cells are central to the pathogenesis of
      retrovirus-induced murine acquired immune deficiency virus (MAIDS). Prompted by
      previous work showing that treatment with cytotoxic T lymphocyte antigen 4
      immunoglobulin (CTLA4Ig) partly inhibited the disease, we studied the course of
      infection in mice deficient for CD28-B7 interactions (mCTLA4-Hgamma1 transgenic
      mice). Despite a relative viral load identical to that of non-transgenic mice,
      the transgenic mice did not develop any of the major MAIDS symptoms (i.e.
      lymphoproliferation and immune anergy). The mCTLA4-Hgamma1 did not however,
      completely inhibit B-cell activation as indicated by a slight
      hypergammaglobulinaemia and microscopic blastic transformation. Absence of MAIDS
      in transgenic mice was associated with much lower levels of both interleukin-4
      and interferon-gamma transcripts following viral infection. These results support
      the theory that the CD28/B7 costimulatory pathway is a critical determinant to
      MAIDS development.

PMID- 10594699
TI  - Immune responses and protection against vaginal infection after nasal or vaginal
      immunization with attenuated herpes simplex virus type-2.
AB  - We compared nasal and vaginal immunizations using attenuated herpes simplex virus
      type-2 (HSV-2) for protection against vaginal infection with wild-type HSV-2.
      Mice were immunized once intranasally, intravaginally after progestin (DP)
      treatment, or intravaginally with scarification after oestradiol treatment.
      Compared with vaginal immunizations, nasal immunization did not increase
      immunoglobulin A (IgA) plasma cell numbers in the vagina or elicit a higher
      antiviral IgA titre in vaginal secretions. Both types of vaginal immunizations
      increased the number of immunoglobulin G (IgG) plasma cells in the vagina and the
      secretion/serum titre ratio of IgG antiviral antibody, indicating local
      production of virus-specific IgG in these groups. Cell-mediated immunity in the
      vagina, as indicated by memory T-cell secretion of interferon-gamma (IFN-gamma)
      in situ 20 hr after HSV-2 challenge, was essentially equivalent in the vaginally
      immunized groups but significantly lower in the nasal group, while lymphocyte
      recruitment to the vagina was similar in all three groups. All three
      immunizations protected all mice from neurological disease after challenge, but
      vaginal DP immunization induced the greatest immunity against reinfection of the
      vaginal epithelium.

PMID- 10594700
TI  - Analysis of immunoglobulin E VH transcripts in a bronchial biopsy of an asthmatic
      patient confirms bias towards VH5, and indicates local clonal expansion, somatic
      mutation and isotype switch events.
AB  - Immunoglobulin E (IgE)-dependent mechanisms play a pivotal role in mediating
      allergic disease. Previously, VH-Cepsilon transcripts from blood or spleen of
      atopic asthmatics have been analysed for VH gene usage and patterns of somatic
      mutation. An over-representation of the minor VH5 family has been observed,
      consistent with a superantigen drive. As local mucosal events in IgE production
      may be more significant in the disease process, we have analysed VH-Cepsilon
      transcripts from a bronchial biopsy of a patient with severe asthma. VH5
      predominance was confirmed with 10 of 30 unique clones derived from this family.
      Repeated sequences, some with intraclonal variation, revealed clonal expansion
      and continuing mutational activity at the site. Unexpectedly, three unmutated VH
      Cepsilon sequences were found, indicating that isotype switching to IgE can occur
      without mutation. Detection of a sister clone with extensive mutations was again
      consistent with local mutational activity. Evidence for local isotype switching
      was obtained by identification of clonally related immunoglobulin M (IgM),
      immunoglobulin G (IgG) and immunoglobulin E (IgE) sequences. However, in contrast
      to findings in blood, no IgG4 transcripts clonally related to IgE were detected,
      suggesting that the balance between synthesis of IgG4 and IgE may differ between
      systemic and local sites. These data confirm a VH5 bias in IgE, and support the
      concept that IgE-synthesizing B cells arise via local differentiation.

PMID- 10594702
TI  - The protective effects of high amylose maize (amylomaize) starch granules on the
      survival of Bifidobacterium spp. in the mouse intestinal tract.
AB  - The possibility of using high amylose maize starch granules as a delivery system
      for probiotic bacteria has been investigated using Bifidobacterium spp. LaftiTM
      8B and LaftiTM 13B which were isolated from a healthy human. The Bifidobacterium
      cells were able to adhere to the amylomaize starch granules and were also able to
      hydrolyse the starch during growth. Initially, in vitro studies were carried out
      by studying the survival of strains Bifidobacterium LaftiTM 8B and LaftiTM 13B
      when exposed to pH 2.3, 3.5 and 6.5 as well as 0.03 and 0.05% w/v bile acids.
      Both strains were grown either in the absence or presence of high amylose maize
      starch granules, then mixed with the high amylose maize starch granules and
      exposed to acidic buffers or bile acid solutions. It was shown that growth in and
      the presence of high amylose maize starch granules led to enhanced survival of
      strains LaftiTM 8B and LaftiTM 13B. Subsequently, survival in vivo was monitored
      by measuring the faecal level of Bifidobacterium LaftiTM 8B after oral
      administration of the strain to mice. A sixfold better recovery of strain LaftiTM
      8B from mice faeces after oral dosage was noted for cells grown in amylose
      containing medium compared with controls. It was concluded that high amylose
      maize starch granules contributed to enhanced survival of Bifidobacterium sp.
      LaftiTM 8B and LaftiTM 13B.

PMID- 10594703
TI  - Identification and characterization of the new bacillus thuringiensis serovars
      pirenaica (serotype H57) and iberica (serotype H59)
AB  - Two new Bacillus thuringiensis strains have been classified by the H antigen of
      the cells and differentiated by their morphological, biochemical and molecular
      characteristics. The flagellar agglutination showed that both strains bore
      specific H antigens which allowed their classification as the new serotypes H57
      and H59. The serovar names proposed for the type strains characterized in this
      work are B. thuringiensis ser. pirenaica, for the H serotype 57, and B.
      thuringiensis ser. iberica, for the H serotype 59. Further characterization of
      these strains, by means of SDS-PAGE, Western inmunodetection, plasmid profile and
      cry-gene identification by polymerase chain reaction, confirmed the originality
      of the two novel serotypes. Toxicity tests carried out against several insect
      species, belonging to the orders Lepidoptera, Diptera and Coleoptera, showed no
      detectable insecticidal activity for either of the B. thuringiensis strains.

PMID- 10594701
TI  - Identification of cation-independent mannose 6-phosphate receptor/insulin-like
      growth factor type-2 receptor as a novel target of autoantibodies.
AB  - Two human monoclonal autoantibodies, B-33 and B-24, were generated from the B
      cells of a patient with scleroderma. Both monoclonal antibodies (mAbs) were
      composed of mu and lambda chains, and recognized cytoplasmic vesicular structures
      by indirect immunofluorescence on Hep-2 cell line slides, although mAb B-24
      showed an additional diffuse cytoplasmic staining pattern. By Western blot, mAb B
      24 exhibited a polyreactive-like binding pattern, whereas mAb B-33 failed to
      recognize any electroblotted Hep-2 antigen. The polyreactive versus monospecific
      behaviour of mAbs B-24 and B-33 was further confirmed by enzyme-linked
      immunosorbent assay (ELISA) with a variety of foreign and autoantigens. The N
      terminal sequence of a protein band isolated by affinity chromatography with mAb
      B-33 was identical to that of cation-independent mannose 6-phosphate receptor (CI
      MPR), also known as the insulin-like growth factor type-2 receptor (IGF-2R).
      Immunofluorescence experiments on Hep-2 cell line slides demonstrated a striking
      co-localization between the staining pattern exhibited by these mAbs and the
      pattern obtained using a goat anti-CI-MPR serum, indicating the recognition by B
      24 and B-33 of a structure located predominantly in late endosomes. Sequence
      analysis of the V-region gene segments of B-33 and B-24 showed both to be
      identical, except for the existence of a point mutation in B-33 located in the H
      complementarity-determining region 3 (H-CDR3) (position 100D), which produces a
      non-conservative replacement of Gly by Ser. This single replacement appears to be
      responsible for the dramatic change in reactivity of human mAb B-33. The data
      shown here provide new evidence of the critical role played by the H-CDR3 region
      in distinguishing a polyspecific from a monospecific antibody. A population study
      demonstrated the existence of immunoglobulin G (IgG) reactivity against CI
      MPR/IGF-2R in serum specimens from five individuals with different pathological
      conditions, thus indicating that this molecule is a potential target for the
      human autoimmune response.

PMID- 10594704
TI  - A gene involved in quinate metabolism is specific to one DNA homology group of
      Xanthomonas campestris.
AB  - A gene involved in quinate metabolism was cloned from Xanthomonas campestris pv.
      juglandis strain C5. The gene, qumA, located on a 4. 2-kb KpnI-EcoRV fragment in
      plasmid pQM38, conferred quinate metabolic activity to X. c. pv. celebensis. Tn3
      spice insertional analyses further located the qumA gene on a region of about 3.0
      kb within pQM38. Nucleotide sequencing of this 3.0-kb fragment reveals that the
      coding region of qumA is 2373 bp, the deduced amino acid sequence of which
      closely resembles a pyrrolo-quinoline quinone-dependent quinate dehydrogenase of
      Acinetobacter calcoaceticus. A 0.7 kb SalI-PstI fragment internal to qumA was
      used as a probe to hybridize against total genomic DNA from 43 pathovars of X.
      campestris. The fragment hybridized only to total genomic DNA from the four
      pathovars of DNA homology group 6, X. c. pv. celebensis, X. c. pv. corylina, X.
      c. pv. juglandis and X. c. pv. pruni, and from X. c. pv. carotae, which belongs
      to DNA homology group 5. This 0.7 kb fragment was also used as a probe to
      hybridize BamHI-digested total genomic DNAs from the four pathovars of DNA
      homology group 6 and X. c. pv. carotae. The restriction fragment length
      polymorphism pattern of DNA homology group 6 was different from that of X. c. pv.
      carotae. The probe hybridized to a 5.7-kb BamHI fragment in all four pathovars of
      group 6 and to a 6.1-kb BamHI fragment in three of four pathovars. It hybridized
      only to a 9. 9-kb BamHI fragment in X. c. pv. carotae. Quinate metabolism has
      previously been reported as a phenotypic property specific to X. campestris DNA
      homology group 6. Accordingly, a combination of the quinate metabolism phenotypic
      test and Southern hybridization using a qumA-derived probe will be very useful in
      the identification of pathovars in DNA homology group 6.

PMID- 10594705
TI  - Phenotypic characterization and antibiotic resistance of Acinetobacter spp.
      isolated from aquatic sources.
AB  - A total of 99 Acinetobacter isolates from sewage, freshwater aquaculture
      habitats, trout intestinal contents and frozen shrimps was characterized
      phenotypically and antibiotic susceptibility patterns determined. One group of
      genomic species, including Ac. johnsonii, Ac. lwoffi and spp. 15TU, was detected
      in all sample types and represented the majority of the isolates (n = 54).
      Isolates belonging to the Acb complex (Ac. calcoaceticus, Ac. baumannii and
      genomic species 3) were detected in sewage (n = 6) and frozen shrimps (n = 1),
      Ac. haemolyticus in frozen shrimps (n = 6) and trout intestinal contents (n = 2)
      and genomic species 11 in freshwater aquaculture habitats (n = 6) and trout
      intestinal contents (n = 1). Acinetobacter junii (n = 5), genomic species 10 (n =
      2), 14BJ (n = 8) and 16BJ (n = 4) were only isolated from sewage. Acinetobacter
      isolates from sewage were generally more biochemically reactive and resistant to
      antimicrobial agents compared with isolates from other sample types. Different
      strains, often belonging to different genomic species, were isolated from sites
      situated upstream and downstream of the discharge point of a pharmaceutical
      plant. This finding supported the hypothesis that the waste effluent from the
      pharmaceutical plant was likely to cause a change in the distribution of
      Acinetobacter spp. by selecting and/or introducing antibiotic-resistant strains
      into the recipient sewers.

PMID- 10594706
TI  - Amine borate catabolism by bacteria isolated from contaminated metal-working
      fluids
AB  - Four bacterial strains (tentatively identified as strains of Aeromonas,
      Pseudomonas, Flavobacterium and Bacillus) isolated from contaminated metal
      working fluids were assayed for the capacity to utilize the borate derivatives of
      monoethanolamine (MEA), diethanolamine (DEA) and triethanolamine (TEA). Two of
      these strains, isolates AV1 (Flavobacterium) and CL1 (Bacillus) were capable of
      growth on each of the borate esters with cell yields of 0.6 gl - 1 for AV1
      cultured on DEA- and TEA-borate, 0.3-0.4 gl - 1 for CL1 cultured on DEA- and TEA
      borate and approximately 1.4 gl - 1 for AV1 and CL1 cultured on MEA-borate. In
      the case of strain CL1, growth yields on TEA- or DEA-borate as substrates were
      doubled by the addition of potassium ions. Lower ethanolamines, glycolaldehyde,
      acetaldehyde and ammonia were identified as breakdown products. The enzymes
      produced during growth upon the alkanolamine borates were shown to possess
      similar properties to those seen for cells cultured upon alkanolamine
      hydrochlorides.

PMID- 10594707
TI  - Water quality and public health in northern Sudan: a study of rural and peri
      urban communities.
AB  - Access to adequate supplies of good quality drinking water continues to be
      limited among many rural and peri-urban communities in Africa, despite several
      decades of water improvement programmes. The present study investigated water
      quality at the source and point of consumption among rural and peri-urban
      communities in northern Sudan. Faecal coliform counts were determined by the
      membrane filtration technique and geometric mean counts compared in different
      seasons and among the different communities. Among nomadic pastoralists and
      riverine villages, both water sources and water stored for consumption had faecal
      coliform counts grossly in excess of WHO standards, with higher counts at the end
      of the rainy season. In the peri-urban community on the outskirts of Omdurman,
      while water quality from the distribution system had faecal coliform counts
      generally below 10 dl - 1, after storage, water was of considerably lower
      quality, with faecal coliform counts up to 1000 d1 - 1. The highest counts again
      occurred in the rainy season. Rates of diarrhoeal disease for Khartoum province
      were also greatest towards the end of the rainy season. The study has shown that
      poor quality water continues to be a major risk factor for public health in these
      communities.

PMID- 10594708
TI  - Prevalence of mycobacteria in a swimming pool environment.
AB  - A study was performed to evaluate the prevalence of non-tubercular mycobacteria
      in swimming pool environments. The bacteria in question were found in 88.2% of
      pool water samples. The most frequent species were Mycobacterium gordonae (73.5%
      of samples; range 1-840 cfu 100 ml - 1), M. chelonei (38.2% 2-360 cfu 100 ml - 1)
      and M. fortuitum (35.3% 2-250 cfu 100 ml - 1). The same species were also
      recovered from the water at the different phases of the treatment cycle, with
      relative percentages similar to those of the pool water. Shower floors and pool
      edges also presented high concentrations of the mycobacteria (100% of samples)
      and M. marinum was isolated from the surfaces of pool edges on two occasions
      (4.5% of samples). The swimming pool environment provides a suitable habitat for
      the survival and reproduction of mycobacteria. Although mycobacteria are common
      in swimming pools, human mycobacterial disease associated with their use is rare.
      Apart from superficial infections with M. marinum, the risk of more serious
      diseases in subjects with weakened immune systems should not be underestimated,
      given the widespread presence of mycobacteria that are possible opportunistic
      pathogens and the direct contact bathers have with the water and aerosol.

PMID- 10594709
TI  - Complement-mediated bactericidal activity of human milk to a serum-susceptible
      strain of E. coli 0111.
AB  - There has been a lot of controversy concerning the physiological significance of
      the complement system in human breast-milk. This is mainly due to the observation
      that human milk contains predominantly non-inflammatory and many anti
      inflammatory factors, while simultaneously protecting the infant against a wide
      range of infectious and other diseases. The present study was carried out to
      assess the contribution of the complement system to the bactericidal activity of
      the human colostrum and early lactational milk. Using a serum-sensitive strain of
      Escherichia coli, different fractions of human breast-milk were assessed for
      their ability to kill the bacteria, with and without inactivation of their
      complement components, in comparison to another strain of the bacteria species.
      Deposition of activated C3 fragments on the killed bacteria, using an established
      ELISA technique, was demonstrated, further proving that the human milk complement
      could be activated in vitro. The bactericidal activities of human milk were
      almost completely abolished by complement heat inactivation at 56 degrees C or by
      the addition of EDTA.

PMID- 10594710
TI  - Occurrence of Helicobacter pylori in surface water in the United States.
AB  - The primary mode of transmission of the human pathogen Helicobacter pylori is
      unresolved. This study examined the possibility that H. pylori is water-borne.
      Because methods for the direct culture of H. pylori from water samples remain
      elusive, a microscopic technique was used for detection of this organism.
      Actively respiring micro-organisms binding monoclonal anti-H. pylori antibody
      were found in the majority of surface and shallow groundwater samples tested (n =
      62), indicating that H. pylori may be present in aquatic environments in the US
      and supporting a water-borne route of transmission for this organism. There was
      no significant correlation between the occurrence of either total coliforms or
      Escherichia coli in the water and the presence of H. pylori. Our results indicate
      that routine screening of water supplies for the presence of traditional
      indicator organisms may fail to protect the consumer from exposure to H. pylori.

PMID- 10594711
TI  - Studies on the mechanisms of the antibacterial action of ortho-phthalaldehyde.
AB  - The reaction of ortho-phthalaldehyde (OPA) with amino acids and proteins was
      investigated as a possible mode of action. Bacterial pellets (obtained by
      centrifugation) changed colour after exposure to OPA. These colours were more
      intense at alkaline than acidic pH. Acidic and alkaline OPA reacted with primary
      amino acids to form coloured products. The reaction rate accelerated with
      increasing pH. OPA increased the optical density of bacterial cell suspensions
      (an indication of protein coagulation or microbial surface or other changes in
      the opacity of cell constituents). The inhibition of ethylenediaminetetraacetic
      acid- and sodium lauryl sulphate-induced lysis was not as great as for
      glutaraldehyde (GTA), possibly indicating less cross-linking of amines.
      Interactions with primary amino groups of the outer envelope or cell wall
      probably play a part in the action of OPA but the level of cross-linking
      associated with the outer membrane does not appear to be as extensive as that of
      GTA. The aromatic component might allow OPA to penetrate the outer layers of
      cells, thus helping to explain the very high activity of OPA against Gram
      negative vegetative organisms even though the degree of cross-linking seems to be
      less than that seen with GTA. Thus, OPA reacts strongly with primary amines and
      stabilizes, to some extent, the outer membrane and cell walls of vegetative
      organisms and this probably accounts for part, but not necessarily all, of its
      lethal action.

PMID- 10594713
TI  - A comparison of the bactericidal efficacy of 18 disinfectants used in the food
      industry against Escherichia coli O157:H7 and Pseudomonas aeruginosa at 10 and 20
      degrees C.
AB  - A number of proprietary disinfectant products (18) used in the food industry were
      tested for their bactericidal efficacy against Pseudomonas aeruginosa and
      Escherichia coli O157:H7 at 20 and 10 degrees C according to the BS EN 1276
      (1997) quantitative suspension test for the evaluation of bactericidal activity
      of chemical disinfectants and antiseptics used in food, industrial, domestic and
      institutional areas. At 20 degrees C, 13 products passed at their in-use
      concentration (under clean and dirty conditions) against Ps. aeruginosa and 15
      passed against E. coli O157:H7. The number of products passing the test at 10
      degrees C was 11 and 14 for Ps. aeruginosa and E. coli O157:H7, respectively. The
      products exhibiting reduced efficacy at the lower temperature were amphoterics
      and quaternary ammonium compounds although some of these types of products were
      effective at both temperatures. Products that passed against Ps. aeruginosa
      generally also passed against E. coli O157:H7. Taking all the results together,
      only 11 of the total of 18 products achieved a pass result under all the
      parameters tested. This work demonstrates the need for final verification of
      disinfectant efficacy by undertaking field trials in the food-processing
      environment in which the product is intended for use.

PMID- 10594712
TI  - An approach to obtain specific polyclonal antisera to Xanthomonas campestris pv.
      cyamopsidis and its potential application in indexing of infected seeds of guar.
AB  - Clusterbean seed health testing is warranted since the pathogen (Xanthomonas
      campestris pv. cyamopsidis (Xccy)) is seed-borne and seed-transmitted. A
      polyclonal antibody was developed in rabbit via subcutaneous and intramuscular
      injections and characterized for sensitivity, specificity and its applicability
      to ELISA which: (i) was sensitive in detecting as few as 102 cells ml - 1 at a
      titre of 1: 4000; (ii) was specific, since it reacted only with Xccy and not with
      other xanthomonads; (iii) reacted both with Xccy cells and culture filtrate,
      indicating that the antigenic determinant is a secretory component; (iv) was
      applicable and reliable in seed health testing since it reacted only with
      infected seeds and plant materials and not with healthy seeds and (v) a purified
      fraction of antibody was virulent-specific since heat-denatured and avirulent
      isolates were not detected. The ELISA thus developed is highly reproducible and
      therefore suitable for the evaluation of the potential disease status of seeds
      and plant health, which is appropriate for routine seed health testing.

PMID- 10594714
TI  - Characterization of pentocin TV35b, a bacteriocin-like peptide isolated from
      Lactobacillus pentosus with a fungistatic effect on Candida albicans.
AB  - Lactobacillus pentosus TV35b, isolated from the posterior fornix secretions of
      the vagina of a prenatal patient, produced a bacteriocin-like peptide (pentocin
      TV35b), which is inhibitory to Clostridium sporogenes, Cl. tyrobutyricum, Lact.
      curvatus, Lact. fermentum, Lact. sake, Listeria innocua, Propionibacterium
      acidipropionici, Propionibacterium sp. and Candida albicans. The mechanism of
      activity of pentocin TV35b is bactericidal, as shown by a decrease in the viable
      cell numbers of Lact. sake from approximately 4 x 108 to less than 10 cfu ml - 1
      over a period of 4 h. Pentocin TV35b added to the growth medium of C. albicans
      stimulated the formation of pseudohyphae during the first 36 h, followed by a
      slight repression in cell growth. Production of pentocin TV35b was at its maximum
      towards the end of the logarithmic growth phase of strain TV35b. The peptide was
      purified by ammonium sulphate precipitation, followed by SP-Sepharose cation
      exchange chromatography. The molecular size of pentocin TV35b was estimated to be
      between 2.35 and 3.4 kDa, according to tricine-SDS PAGE. However, results
      obtained by electrospray ionization mass spectroscopy indicated that the peptide
      is 3930.2 Da in size. Amino acid analysis performed by using the Pico-Tag(R)
      method and a Nova-Pak C18 HPLC column indicated that pentocin TV35b consists of
      33 amino acids with a total mass of 3929.63 Da. Pentocin TV35b is inactivated
      when treated with papain and Proteinase K, but remains active after incubation at
      pH 1-10 for 2 h at 25 degrees C, and when heat-treated for 30 min at 100 degrees
      C.

PMID- 10594715
TI  - Specific variations of fatty acid composition of Pseudomonas aeruginosa ATCC
      15442 induced by quaternary ammonium compounds and relation with resistance to
      bactericidal activity.
AB  - The role of membrane fatty acid composition in the resistance of Pseudomonas
      aeruginosa ATCC 15442 to the bactericidal activity of Quaternary Ammonium
      Compounds (QACs) was investigated. The strain was grown in a medium with
      increasing concentrations of a QAC, benzyldimethyltetradecylammonium chloride
      (C14) and two non-QACs, sodium dichloroisocyanurate and tri-sodium phosphate. In
      the presence of C14 only, the strain was able to grow in concentrations higher
      than the minimal inhibitory concentration. As the strain adapted to C14,
      resistance to bactericidal activity of the same biocide increased. For the non
      QACs, no change was noted when cells were grown in the presence of biocides. The
      C14-adapted cells showed variations in membrane fatty acid composition. A
      hierarchical clustering analysis was used to compare all fatty acid compositions
      of cultures in the presence, or not, of the three biocides used here and another
      QAC studied previously. The clusters obtained underlined specific variations of
      membrane fatty acids in response to the presence of QACs. Furthermore, with a
      simple linear regression analysis, a relationship was shown between the membrane
      fatty acids and the resistance developed by the strain against the bactericidal
      activity of C14.

PMID- 10594716
TI  - Differentiation of Lactobacillus isolates from infant faeces by SDS-PAGE and rRNA
      targeted oligonucleotide probes.
AB  - Isolates of lactobacilli from infant faeces phenotypically characterized as
      Lactobacillus paracasei subsp. paracasei (six strains), Lact. rhamnosus (six
      strains), Lact. gasseri (three strains), Lact. acidophilus (one strain) and Lact.
      fermentum/reuteri (three strains) according to recent classification systems were
      subjected to SDS-PAGE of whole cell proteins and rRNA-targeted oligonucleotide
      probe hybridization, in order to confirm the phenotypic characterization and
      elucidate the exact taxonomic position of the three strains that had properties
      between fermentum and reuteri. Results suggested a good agreement between the
      phenotypic characterization, SDS-PAGE and rRNA-targeted oligonucleotide probe
      hybridization for strains of all species except for the Lact. fermentum/reuteri
      strains. Results obtained by rRNA probes suggested a possible phylogenetic
      relatedness of the strains to Lact. reuteri. Isolates from infant faeces with
      interesting probiotic properties could be used as components of fermented milk
      products.

PMID- 10594717
TI  - Antimicrobial activity of a 14-residue peptide against Escherichia coli O157:H7.
AB  - An amphiphilic, cationic peptide composed of eight leucines and six lysines was
      synthesized by solid phase peptide synthesis (SPPS). The synthetic peptide was
      bactericidal within 10 min at concentrations as low as 3 microg ml - 1 against
      mid-exponential Escherichia coli O157:H7 suspended in buffer. Concentrations of
      25 microg ml - 1 caused up to 7 log10 cfu ml - 1 reductions. When tested against
      E. coli O157:H7 grown in TSB, the peptide was bactericidal and bacteriostatic at
      concentrations of 50 and 25 microg ml - 1, respectively. An inhibitory effect was
      also observed against stationary phase cells. The synthetic peptide caused the
      release of u.v.-absorbing materials from the E. coli O157:H7 as well as an
      increase in its O.D.600 nm. Intracellular K+ and ATP depletion were also
      observed. These results suggest that the peptide increased the cell membrane
      permeability but it did not lyse the cells.

PMID- 10594718
TI  - Pathogenicity of vibrio splendidus strains associated with turbot larvae,
      scophthalmus maximus
AB  - Turbot larvae were challenged with eight strains of Vibrio splendidus isolated
      from diseased larvae, plus a ninth strain pathogenic to scallop larvae (A515;
      Nicolas et al. 1996). Six strains caused heavy mortality but the scallop pathogen
      and the other two strains did not. All the strains shared a large number of
      phenotypic traits, and an attempt was made to relate virulence to genotype and
      phenotype. Five of the six pathogenic strains were very similar, as shown by RAPD
      fingerprinting and phenotypic characteristics. The relatedness of the other
      strains was intermediate between the main pathogenic group and V. splendidus ATCC
      33125, but the DNA-DNA homology between the pathogenic group and the reference
      strain was still high (78% of reassociation rate). The non-pathogenic isolates
      may be a useful tool for determining the possible virulence factors, as all the
      isolates differed by few characteristics.

PMID- 10594719
TI  - The survival and growth of an environmental Klebsiella isolate in detergent
      solutions.
AB  - A Klebsiella isolate (G1) was capable of survival and growth in an environment
      containing high levels of anionic (15.6%) and non-ionic detergent (7.8%). Cell
      numbers were monitored by traditional viable plate counts (culturability), and by
      staining with Rhodamine 123 (vital counts) and Acridine Orange (total counts). On
      inoculation into detergent solutions, only 10% of cells retained vitality
      (rhodamine 123) after 24 h. Of those, only 1% were able to form colonies on
      artificial culture media. Under low nutrient conditions (TOC < 0.89 mg l - 1), no
      recovery was observed over a 96 h period, but addition of nutrients (TOC 3.84 mg
      l - 1) allowed recovery within 48 h. Such cells were initially (24 h) elongated,
      but subsequently (144 h) returned to their normal size. In the presence of
      detergent without added nutrient, cell size was reduced after 144 h. After
      adaptation to the detergent environment (24 - 48 h), cell numbers in detergent
      with added nutrient broth (vital, viable and total) rose, until levels equivalent
      to those of a detergent-free control were attained. Detergent solutions provide a
      stressful environment. Nutrient levels in the detergent solutions affected cell
      size and the ability of the Klebsiella (G1) to survive and grow.

PMID- 10594720
TI  - Evaluation of phenotypic and molecular typing techniques for determining
      diversity in Erwinia carotovora subspp. atroseptica.
AB  - A number of phenotypic and molecular fingerprinting techniques, including
      physiological profiling (Biolog), restriction fragment length polymorphism
      (RFLP), enterobacterial repetitive intergenic consensus (ERIC) and a phage typing
      system, were evaluated for their ability to differentiate between 60 strains of
      Erwinia carotovora ssp. atroseptica (Eca) from eight west European countries.
      These techniques were compared with other fingerprinting techniques, random
      amplified polymorphic DNA (RAPD) and Ouchterlony double diffusion (ODD),
      previously used to type this pathogen. Where possible, data were represented as
      dendrograms and groups/subgroups of strains identified. Simpson's index of
      diversity (Simpson's D) was used to compare groupings obtained with the different
      techniques which, with the exception of Biolog, gave values of 0.46 (RFLP), 0. 39
      (ERIC), 0.83 (phage typing), 0.82 (RAPD) and 0.26 (ODD). Of the techniques
      tested, phage typing showed the highest level of diversity within Eca, and this
      technique will now form the basis of studies into the epidemiology of blackleg
      disease.

PMID- 10594721
TI  - A kinetic study of the effect of hydrogen peroxide and peracetic acid against
      Staphylococcus aureus and Pseudomonas aeruginosa using the bioscreen disinfection
      method.
AB  - Hydrogen peroxide and peracetic acid at pH 4 were examined against Staphylococcus
      aureus and Pseudomonas aeruginosa using the published 'Bioscreen' technique of
      biocide analysis. The data were examined using either classical Chick-Watson (CW)
      log-linear disinfection kinetics or the empirical, non-linear time Hom model. In
      some cases, modelling the data with the classical CW method gave good linear
      correlations, in others, however, deviations from this model were observed. In
      such cases the Hom model proved an adequate descriptor of the data. The Bioscreen
      technique therefore gives data which can be analysed using the normal mechanistic
      and empirical models currently available.

PMID- 10594722
TI  - In this issue

PMID- 10594724
TI  - Differences in hair follicle dermal papilla volume are due to extracellular
      matrix volume and cell number: implications for the control of hair follicle size
      and androgen responses.
AB  - The size of a hair follicle is thought to be determined by the volume of its
      dermal papilla. The volume of the dermal papilla depends on the number of cells
      it contains and on the volume of the extracellular matrix. To establish which of
      these two variables is related to differences in hair follicle size we performed
      a stereologic study on 235 hair follicles from different sites, including male
      facial skin (beard), female facial skin, and scalp. In facial follicles there was
      a strong correlation between the area of the hair cortex and the volume of the
      dermal papilla. The area of the hair cortex also correlated with the number of
      cells in the dermal papilla and with the volume of dermal papilla per cell. In
      scalp hair follicles, where there was a smaller range of sizes, the correlations
      between these variables were weaker. In large male facial follicles the mean
      total dermal papilla volume was almost 40-fold higher than in vellus follicles
      from female facial skin. This difference was associated with a mean 17-fold
      greater number of cells in the dermal papilla and a 2.4-fold greater volume
      associated with each cell. Intermediate results were obtained in scalp follicles.
      In many regions of the skin hair follicles enlarge in response to androgens
      during adult life hair. Our results imply that the increase in the volume of the
      dermal papilla in these follicles is due to an increase in the number of cells,
      either through proliferation or through the migration of cells from the
      follicular dermal sheath, and to an increase in the amount of extracellular
      matrix per cell. As androgens are thought to act primarily on the dermal papilla,
      these changes may have a direct bearing on the mechanism of androgen-mediated
      alterations in hair follicle size.

PMID- 10594723
TI  - Identification of differentially expressed genes during a wool follicle growth
      cycle induced by prolactin.
AB  - The wool follicles of New Zealand Wiltshire sheep can be induced to undergo
      growth cycles by manipulating circulating prolactin levels. Altered patterns of
      gene expression through this cycle were examined using differential display, and
      nine sequence tags for differentially expressed genes were isolated. Four of
      these tags were identified as fragments of known genes, encoding a wool keratin,
      KRTAP3.2, a desmosome component, desmoglein 1, an epithelial cell marker,
      stratifin, and a protein kinase, Clk3. All four genes were shown to be
      downregulated in telogen skin compared with anagen. In situ hybridization showed
      that all had localization patterns which included cells that are absent in
      telogen. The stratifin tag was used to clone a cDNA that incorporated a complete
      open-reading frame for ovine stratifin. Ovine stratifin is similar to the human
      form, showing only six single residue differences in the predicted amino acid
      sequence. Stratifin probably acts as a regulator of other proteins involved in
      trichocyte cell cycling and differentiation. Clk3 is involved in regulating RNA
      splicing. KRTAP3.2 and Dsg1 both play structural roles in hair follicles. The
      other five tags, including two representing genes that were upregulated during
      catagen, could not be identified by homology. Differential display is an
      effective means of identifying genes involved in follicle function and,
      potentially, of genes controlling the growth cycle.

PMID- 10594725
TI  - Hair cycle-dependent changes in adrenergic skin innervation, and hair growth
      modulation by adrenergic drugs.
AB  - Skin nerves may exert "trophic" functions during hair follicle development,
      growth, and/or cycling. Here, we demonstrate hair cycle-related plasticity in the
      sympathetic innervation of skin and hair follicle in C57BL/6 mice. Compared with
      telogen skin, the number of nerve fibers containing norepinephrine or
      immunoreactive for tyrosine hydroxylase increased during the early growth phase
      of the hair cycle (anagen) in dermis and subcutis. The number of these fibers
      declined again during late anagen. beta2-adrenoreceptor-positive keratinocytes
      were transiently detectable in the noncycling hair follicle epithelium,
      especially in the isthmus and bulge region, but only during early anagen. In
      early anagen skin organ culture, the beta2-adrenoreceptor agonist isoproterenol
      promoted hair cycle progression from anagen III to anagen IV. The observed hair
      cycle-dependent changes in adrenergic skin innervation on the one hand, and hair
      growth modulation by isoproterenol, accompanied by changes in beta2
      adrenoreceptor expression of selected regions of the hair follicle epithelium on
      the other, further support the concept that bi-directional interactions between
      the hair follicle and its innervation play a part in hair growth control. This
      invites one to systematically explore the neuropharmacologic manipulation of
      follicular neuroepithelial interactions as a novel therapeutic strategy for
      managing hair growth disorders.

PMID- 10594726
TI  - Free hapten molecules are dispersed by way of the bloodstream during contact
      sensitization to fluorescein isothiocyanate.
AB  - The fate of the contact sensitizer fluorescein isothiocyanate was traced by means
      of fluorescence spectrophotometry and flow cytometry. The hapten applied to one
      ear rapidly entered the circulation by way of local lymphatics and blood vessels.
      It was dispersed for several hours essentially as free hapten, released from a
      reservoir left behind at the site. Hapten molecules coupled to plasma proteins
      while circulating and reacted with white blood cells. Total cells of regional
      lymph nodes, spleen, and distant lymph nodes became fluorescent in successive
      order. Fluorescence of CD11c-positive dendritic cells exceeded significantly that
      of lymphoid cells. Total spleen cells and total nonregional lymph node cells were
      shown in vitro to drive committed lymph node cells to proliferation. The
      mechanism disclosed is proposed to counterbalance the action of epidermal
      Langerhans cells for regulation of contact hypersensitivity.

PMID- 10594727
TI  - Two ceramide subfractions detectable in Cer(AS) position by HPTLC in skin surface
      lipids of non-lesional skin of atopic eczema.
AB  - The non-involved skin of atopic eczema (NEAE) is characterized by severe dryness
      and an impaired barrier function of the stratum corneum as indicated by an
      increased transepidermal water loss. Previous studies have demonstrated that this
      barrier impairment coincides with marked alterations in the amount and
      composition of stratum corneum ceramides. The aim of this study was to identify
      specific alterations in NEAE that may be used in the diagnosis of the atopic
      eczema. Using a classical procedure for high performance thin layer
      chromatography we could confirm earlier results: apart from Cer(EOH), which
      contains omega-hydroxy fatty acid (O) ester-linked to linoleic acid (E) and amide
      linked to 6-hydroxy-4-sphingenine (H), the quantities of all ceramide fractions
      were significantly decreased. Furthermore, Cer(EOH)/Certotal was significantly
      increased, whereas the percentage of Cer(EOS), which contains sphingosine (S),
      and Cer(NP), which contains non-hydroxy fatty acid (N) amide-linked to
      phytosphingosine (P), were significantly decreased. Using a modified procedure
      for high performance thin layer chromatography we could demonstrate the formation
      of a double peak in the position of Cer(AS), which contains alpha-hydroxy fatty
      acid (A), in lipids of NEAE. The subfractions of the double peak comprised 15%
      and 12% of Certotal. MALDITOF mass spectrometry suggested that the double peak
      was formed by a homologous series of mono-hydroxylated and mono-unsaturated
      ceramides of different chain length, e.g., Cer(AS) subfractions containing either
      (C16,18) or (C22,24,26) alpha-hydroxy fatty acids. In contrast, in normal skin a
      single peak in Cer(AS) position, which comprised 22% of Certotal, was mainly
      formed by the long chain subfraction. In some cases this single peak displayed a
      small shoulder at its right flank, but never showed a clear peak separation when
      developed with NEAE samples. Furthermore, even in senile xerosis, or in either
      non-involved skin of psoriasis or seborrhoic eczema, only a single peak occurred
      in Cer(AS) position. Accordingly, the double peak might be specific for NEAE and
      turn out to be a marker for atopic eczema.

PMID- 10594728
TI  - Microsatellite instability in benign skin lesions in hereditary non-polyposis
      colorectal cancer syndrome.
AB  - The coexistence of cutaneous and extra-cutaneous malignancies within one family
      could be explained by shared genetic mechanisms such as common tumor suppressor
      gene mutations or oncogene activation, as well as mutations in DNA repair genes.
      Hereditary non-polyposis colorectal cancer syndrome (HNPCC) and its variant Muir
      Torre syndrome (MTS) are caused by germline DNA mismatch repair gene mutations.
      Colonic and endometrial tumors from HNPCC patients exhibit microsatellite
      instability (MSI), as do sebaceous lesions in MTS. We recruited individuals from
      cancer prone families to determine if MSI is found in benign and malignant skin
      lesions and to assess whether MSI in the skin is predictive of genomic
      instability with susceptibility to tumors characteristic of HNPCC. One hundred
      and fifteen benign, dysplastic, and malignant skin lesions from 39 cancer prone
      families were analyzed. Thirteen benign skin lesions from three individuals
      belonging to two HNPCC pedigrees showed MSI. No mutations in hMSH2 and hMLH1 were
      found in two of the three individuals with RER + skin lesions. We found MSI in
      non-sebaceous non-dysplastic skin lesions in HNPCC pedigrees. MSI was not found
      in skin lesions within other family cancer syndromes. These results have
      important clinical implications as the detection of MSI in prevalent readily
      accessible skin lesions could form the basis of noninvasive screening for HNPCC
      families. It may also be a valuable tool in the search for new mismatch repair
      genes.

PMID- 10594729
TI  - Spatiotemporal changes of fibronectin, tenascin-C, fibulin-1, and fibulin-2 in
      the skin during the development of chronic contact dermatitis.
AB  - In order to elucidate how chronic inflammation affects the organization of the
      extracellular matrix in the skin, a prolonged allergic contact dermatitis was
      induced in a mouse by repeated application to the ear of 2,4-dinitrofluorobenzene
      every 3 d for 66 d. Subsequently, the spatiotemporal changes of fibronectin,
      tenascin-C, fibulin-1, and fibulin-2 in the skin were examined. In the acute
      phase of inflammation (day 3-day 12), the amount of fibronectin and tenascin-C
      increased markedly and were degraded, whereas the amount of fibulin-2 changed
      slightly. Abundant deposition of tenascin-C was observed in the connective
      tissue. Fibulin-1 and fibulin-2 distributed as fine fibrils. In contrast, the
      amounts of fibronectin and tenascin-C decreased and their degradation was
      suppressed in the chronic phase (day 15-day 66), but the amount of fibulin-2
      increased. Tenascin-C was observed mainly at and underneath the epidermal
      basement membrane. In the subepidermal region, many fibulin-2-positive
      microfibrils were distributed. The amount and distribution of fibulin-1 did not
      change markedly in either phase. MMP-like enzymes of 62 kDa, probably activated
      MMP-2, were upregulated in the chronic phase, whereas components of 92, 85, or 67
      kDa were highly induced in the acute phase. These results suggest that chronic
      inflammation in allergic contact dermatitis is associated with temporal changes
      in the expression, deposition, and degradation of inducible extracellular matrix
      components.

PMID- 10594730
TI  - Fibrin and collagen differentially regulate human dermal microvascular
      endothelial cell integrins: stabilization of alphav/beta3 mRNA by fibrin1.
AB  - Integrin alphavbeta3 is specifically but transiently expressed on the tips of
      capillary sprouts as they invade the fibrin clot during angiogenesis of cutaneous
      wound repair. Specific blocking of alphavbeta3 function inhibits granulation
      tissue formation in cutaneous wounds. The mechanisms of regulation of alphavbeta3
      expression on human dermal microvascular endothelial cells, however, have not
      been fully delineated. As alphavbeta3 was highly expressed on capillary sprouts
      in 5 d wounds rich in fibrin, but was almost undetectable on blood vessels in 7 d
      wounds rich in collagen, we hypothesized that the extracellular matrix
      environment could regulate human dermal micro- vascular endothelial cell
      alphavbeta3 expression. To address this, human dermal microvascular endothelial
      cells were cultured on surfaces coated with collagen, fibronectin, and gelatin,
      and mRNA levels of integrin alphav/beta3 were determined. Compared with human
      dermal microvascular endothelial cells on collagen, mRNA levels of alphav/beta3
      were higher in human dermal microvascular endothelial cells on fibronectin and on
      gelatin. To simulate the in vivo environment better, human dermal microvascular
      endothelial cells cultured on collagen were overlaid by fibrin or collagen gels
      prior to assessment of alphav/beta3 mRNA levels. alphav/beta3 mRNA levels were
      higher in human dermal microvascular endothelial cells surrounded by a three
      dimensional fibrin gel compared with a collagen gel, whether angiogenic factors
      were present or absent. As modulation of mRNA stability is a potential regulatory
      mechanism for integrin expression, integrin subunit mRNA stability was assessed.
      beta3 mRNA decayed much faster than alphav, alpha2, and beta1 mRNA. Three
      dimensional fibrin gels enhanced alphav/beta3 mRNA stability compared with
      collagen gels. We propose that the provisional matrix molecules in the wound clot
      regulate angiogenesis associated with cutaneous wound repair through their
      modulation of integrin receptor expression.

PMID- 10594731
TI  - Nerve growth factor protects human keratinocytes from ultraviolet-B-induced
      apoptosis.
AB  - Ultraviolet radiation is a potent inducer of apoptosis, whereas autocrine nerve
      growth factor protects human keratinocytes from programmed cell death. To
      evaluate the role of nerve growth factor in the mechanisms of ultraviolet B
      induced apoptosis, cultured human keratinocytes were ultraviolet B irradiated
      following pretreatment with K252, a specific inhibitor of the tyrosine kinase
      high-affinity nerve growth factor receptor. Here we report that the addition of
      K252 significantly enhanced keratinocyte apoptosis. We then transfected normal
      human keratinocytes with pNUT-hNGF. Nerve growth factor overexpressing
      keratinocytes secreted the highest amounts of nerve growth factor in culture
      supernatants, were more viable, and had a higher rate of proliferation than mock
      transfected cells. Whereas ultraviolet B radiation downregulated nerve growth
      factor mRNA and protein as well as the tyrosine kinase high-affinity nerve growth
      factor receptor in normal keratinocytes, it failed to do so in nerve growth
      factor-transfected cells. Moreover, nerve growth factor overexpressing
      keratinocytes were partially resistant to apoptosis induced by increasing doses
      of ultraviolet B at 24 and 48 h. These results indicate that downregulation of
      nerve growth factor function plays an important part in the mechanisms of
      ultraviolet B-induced apoptosis in human keratinocytes. In addition, ultraviolet
      B caused a decrease in BCL-2 and BCL-xL expression in mock-transfected
      keratinocytes, but not in nerve growth factor overexpressing cells. Finally,
      nerve growth factor prevented the cleavage of the enzyme poly(ADP-ribose)
      polymerase induced in human keratinocytes by ultraviolet B. These results are
      consistent with a model whereby the autocrine nerve growth factor protects human
      keratinocytes from ultraviolet B-induced apoptosis by maintaining constant levels
      of BCL-2 and BCL-xL, which in turn might block caspase activation.

PMID- 10594732
TI  - Selective incorporation and specific cytocidal effect as the cellular basis for
      the antimelanoma action of sulphur containing tyrosine analogs.
AB  - Tyrosine analogs are good candidates for developing melanoma chemotherapy because
      melanogenesis is inherently toxic and uniquely expressed in melanocytic cells.
      Sulphur containing substrate (tyrosine) analogs, N-acetyl-4-S-cysteaminylphenol
      (NAcCAP) and N-propionyl-4-S-cysteaminylphenol (NPrCAP), have been shown to have
      potent antimelanoma activity in mice bearing melanoma. Both NAcCAP and NPrCAP
      show selective cytotoxicity towards melanoma cell lines. But the mechanism
      leading to selectivity is not clear as these drugs are also toxic to other cell
      lines to a lesser extent. Here we show that these drugs have both cytostatic and
      cytocidal effects, which could account for this. Cytostatic effect is suggested
      by DNA flow cytometry. The drug causes cell cycle changes in four human cell
      lines (normal skin fibroblasts, HeLa cells, and melanoma cell lines, C32 and SK
      MEL-23) in a dose-dependent manner blocking cells in S phase with concomitant
      decrease in the number of cells in G1 phase. There is also a gradual decrease in
      cells in G2 + M phases. The dose-concentration curves give IC50 values in the
      range of 50-400 microM and the melanotic melanoma cell line SK-MEL-23 has the
      lowest IC50 value consistent with our hypothesis that these drugs are selective
      towards melanoma cells. The concentration-dependent accumulation of cells in S
      phase suggest a cytostatic effect as a consequence of inhibition of DNA synthesis
      in agreement with [3H] thymidine incorporation assay. There is a highly specific
      uptake of [14C]NAcCAP and irreversible damage to DNA synthesis machinery in SK
      MEL-23 cells, indicating a melanotic-specific cytocidal effect as well. Trypan
      blue exclusion study and competitive inhibition assay indicated that visible
      cytocidal effect occurs slowly and oxidative stress resulting from tyrosinase
      mediated oxidation of the drug appears to be the underlying mechanism. The
      primary antimelanoma effect of cysteaminylphenols derives from a selective
      cytostatic effect, but is followed by a specific cytocidal action rendering the
      drugs useful for targeted melanoma chemotherapy.

PMID- 10594733
TI  - Increased synthesis of hyaluronate enhances motility of human melanoma cells.
AB  - Hyaluronate plays a unique role in the cancer cell microenvironment. In
      particular, melanoma is the tumor type in which hyaluronate and hyaluronate
      recognition have been most closely linked to malignancy. In this study we show
      that a human melanoma cell line stably transfected with hyaluronate synthase cDNA
      displays enhanced motility. We used a fixed erythrocyte exclusion assay to
      isolate subsets of the WM793 human melanoma cell line that expressed either high
      or low amounts of hyaluronate. A cell line with a high level of hyaluronate on
      its surface (WM793H) displayed significantly higher cell motility on colloidal
      gold-coated coverslips than did a line with a low level (WM793L). Next, in order
      to directly investigate the effects of hyaluronate on melanoma cell migration, we
      transfected cDNA encoding mouse hyaluronate synthase HAS1 or HAS2 into the re
      cloned human melanoma cell line that produced a low amount of hyaluronate
      (WM793L) by the lipofection method. Several clonal transfectants differentially
      producing hyaluronate were obtained. There was a positive correlation between
      total hyaluronate synthesis and formation of the pericellular hyaluronate-rich
      matrix. We observed an increase in the migration ability of hyaluronate cDNA
      (HAS1 or HAS2)-transfected cells compared with control cells on glass plates
      covered with colloidal gold particles. A migration-inhibition assay with anti
      CD44 monoclonal antibody showed blocking of the cell motility. It is speculated
      that the tumor cells might migrate through a hyaluronate-rich extracellular
      environment when they invade nearby host tissues and that hyaluronate production
      by the tumor cells could increase this migration. These results suggest that
      hyaluronate may play a role in the aggressiveness of human melanoma cells.

PMID- 10594734
TI  - Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency.
AB  - Recently, the first example of a human mutation in the gene encoding the
      desmosomal plaque protein, desmoplakin, has been described in a patient with
      autosomal dominant striate palmoplantar kerato-derma. We now report a further
      case of a desmoplakin mutation in a proband with striate palmoplantar keratoderma
      that also results in a null allele and haploinsufficiency. The mutation was a
      heterozygous G > A transition at the donor + 1 site of intron 7 of the
      desmoplakin gene (939 + 1 G > A; Genbank M77830). The aberrant splicing leads to
      retention of the entire intron 7, which contains a premature termination codon
      within the N-terminal domain of the peptide. Because the mutant null allele could
      not be identified on cDNA sequencing, we determined by polymerase chain reaction
      the exon-intron organization of the desmoplakin gene to facilitate analysis of
      genomic DNA. The gene spans approximately 45 kb of chromosome 6 and comprises 24
      exons ranging in size from 51 bp to 3922 bp. We have also characterized fully the
      3'UTR of the desmoplakin cDNA. This study demonstrates the relevance of
      haploinsufficiency for desmoplakin in the pathogenesis of this genodermatosis.
      Assessment of family members bearing the mutant allele also emphasizes the
      significance of an individual's age and exposure to skin trauma in manifesting
      full phenotypic expression of the disorder.

PMID- 10594736
TI  - Novel Hairless mutations in two kindreds with autosomal recessive papular
      atrichia.
AB  - Papular atrichia is an autosomal recessive disorder characterized clinically by
      the occurrence of universal congenital alopecia and disseminated papular lesions.
      Recently, mutations in the human hairless (HR) gene have been reported in Irish
      and Arab Palestinian families with papular atrichia. We have studied two further
      kindreds with this clinical phenotype from other ethnic backgrounds. For mutation
      detection the complete coding region as well as exon-intron boundaries of the HR
      gene were sequenced. The first family is a Mexican family with clinically typical
      papular atrichia. Sequencing identified a homozygous deletion of 4 bp in exon 7
      (2001delCCAG) leading to a premature stop codon in exon 8. The second family is a
      South Tyrolian family with affected individuals showing papular atrichia and
      retardation of bone age during childhood. All affected individuals were
      identified as homozygous for an A-->G transition at nucleotide position 2909
      (exon 14) leading to an amino acid change of asparagine to serine in codon 970
      (Asn970Ser). These data provide further evidence for the involvement of hairless
      mutations in papular atrichia. In addition, these findings suggest that the
      hairless protein is not only involved in hair development but also in the process
      of ossification during development.

PMID- 10594735
TI  - Autoantibodies in a subgroup of patients with linear IgA disease react with the
      NC16A domain of BP1801.
AB  - Linear IgA disease is an autoimmune subepidermal blistering disease characterized
      by IgA deposits at the cutaneous basement membrane zone. IgA antibodies from
      linear IgA disease sera react with antigens of 97 kDa (LABD97) and 120 kDa (LAD
      1), both of which appear to be fragments of the extracellular domain of bullous
      pemphigoid 180 (type XVII collagen). The aim of this study was to determine
      whether linear IgA disease sera react with the immunodominant region of BP180
      (NC16A domain), which is a major target of IgG autoantibodies produced by
      patients with bullous pemphigoid. Indeed, 11 of 50 linear IgA disease sera were
      found to contain IgA autoantibodies that recognized a recombinant form of NC16A
      by immunoblotting. The same sera also reacted with NC16A by enzyme-linked
      immunosorbent assay. An epitope mapping analysis uncovered four linear IgA
      disease-associated epitopes located within the 45 amino acid N-terminal stretch
      of NC16A, all of which were previously identified as antigenic sites targeted by
      bullous pemphigoid autoantibodies. Eight of the linear IgA disease sera that were
      reactive with NC16A also recognized LAD-1 secreted by the SCC-25 cell line, and
      five sera recognized BP180 extracted from keratinocytes. Linear IgA disease sera
      depleted of reactivity to NC16A by immunoadsorption continued to react with both
      the LAD-1 antigen and BP180 by immunoblotting and with the basement membrane zone
      by indirect immunofluorescence microscopy. Our results demonstrate that IgA
      autoantibodies from a subset of linear IgA disease patients react with the same
      sites on BP180 that are targeted by IgG autoantibodies in bullous pemphigoid.

PMID- 10594737
TI  - Water disrupts stratum corneum lipid lamellae: damage is similar to surfactants.
AB  - Using electron microscopy, we investigated the effect of (i) a dilute surfactant
      and of water alone on the ultrastructure of stratum corneum lipids in pig skin
      exposed in vitro at 46 degrees C, and (ii) of water alone on human skin exposed
      in vivo at ambient temperature. For pig skin, the surfactant sodium dodecyl
      sulfate disrupts stratum corneum intercellular lamellar bilayers, leading to
      bilayer delamination and "roll-up" in a water milieu after 1 h, extensive bilayer
      disruption after 6 h, and nearly complete dissociation of corneocytes after 24 h.
      Corneodesmosomes show progressive degradation with exposure time. Water alone
      also disrupts the stratum corneum, but with a slower onset. Alterations in
      intercellular lamellar bilayers, but not intercellular lamellar bilayer roll-up,
      are detected after 2 h. Intercellular lamellar bilayer roll-up occurs after 6 h.
      Extensive dissociation of corneocytes occurs after 24 h of water exposure. Unlike
      sodium dodecyl sulfate, water exposure results in the formation of amorphous
      intercellular lipid. Corneodesmosome degradation parallels intercellular lamellar
      bilayer disruption; calcium appears to offer some protection. Similar disruption
      of intercellular lamellar bilayers occurs in human skin in vivo at ambient
      temperature. Our studies show that water can directly disrupt the barrier lipids
      and are consistent with surfactant-induced intercellular lamellar bilayer
      disruption being due at least in part to the deleterious action of water.
      Intercellular lamellar bilayer disruption by water would be expected to enhance
      permeability and susceptibility to irritants; accordingly, increased attention
      should be given to the potential dangers of prolonged water contact. For common
      in vitro procedures, such as skin permeation studies or isolation of stratum
      corneum sheets, exposure to water should also be minimized.

PMID- 10594738
TI  - Overgrowth of skin in growth hormone transgenic mice depends on the presence of
      male gonads.
AB  - Growth hormone has been shown to possess stimulatory effects on various
      connective tissues. We observed that skin growth in male rat phosphoenolpyruvate
      carboxykinase-bovine growth hormone transgenic mice (serum growth hormone levels:
      740-1940 ng per ml) is progressive with age, resulting in an "oversized coat"
      phenotype with a marked increase in absolute and relative skin weight and surface
      area, and in thickness of the dermis. Histologic changes include severe dermal
      fibrosis and replacement of subdermal adipose tissue by fibrous tissue. Apart
      from an increase in skin surface area, these changes were not noted in female
      transgenic mice, arguing for a specific interaction of growth hormone with male
      sex hormones. To clarify this point, 6 wk old male transgenic mice and control
      mice were castrated and compared with their noncastrated counterparts in
      parameters of skin growth at an age of 8 mo. The skin weight of castrated
      transgenic mice was smaller (p < 0.01) than that of intact transgenic mice both
      absolutely and relative to body weight. The relative skin weight of castrated
      transgenic mice was in the same range as in intact and castrated control mice.
      Absolute and relative skin area of castrated transgenic mice was greater (p < 0.
      001 and p < 0.05) than in controls but lower than in intact transgenic mice (p <
      0.001 and p < 0.05). When compared with control mice, intact transgenic mice
      displayed an increase (p < 0.01) in the thickness of dermis. In castrated
      transgenic mice the thickness of the dermis was in the same range as in control
      mice. Our findings demonstrate a specific interaction of growth hormone with male
      sex hormones resulting in a marked stimulation of skin growth.

PMID- 10594739
TI  - Low frequency of genetic change in p53 immunopositive clones in human epidermis.
AB  - Sun-exposed skin of Caucasians harbors thousands of p53-mutated clones, which are
      clinically invisible. Using whole mount immunostaining for p53 or Ki67 antigens,
      p53 sequencing, and loss of heterozygosity analysis, we have further
      characterised these clones. Loss of heterozygosity for the alleles examined is
      uncommon with the exception of 9q, which occurred in 28.3% of the samples. P53
      clones are more common and larger in individuals with basal cell carcinoma than
      in control subjects (p < 0.03). Loss of heterozygosity is also more common in
      clones from individuals with basal cell carcinoma than in clones from subjects
      without a history of basal cell carcinoma, as would be expected if both relate to
      ultraviolet radiation exposure. p53 sequencing of clones is in keeping with the
      mutagenic role of ultraviolet radiation. Surprisingly, skin found to harbor p53
      clones showed no clusters of Ki67 positive cells, unlike the situation for
      actinic keratoses or basal cell carcinomas. These results show that in human skin
      p53 mutation is not directly associated with genomic instability or abnormal cell
      cycling; that the p53 immunopositive clones are either genetically distinct or
      precursors to other squamous cell lesions of skin; and that p53 immunopositive
      clones are early lesions, in that gross disturbance of proliferation has not
      already occurred.

PMID- 10594740
TI  - The in vivo fluorescence of tryptophan moieties in human skin increases with UV
      exposure and is a marker for epidermal proliferation.
AB  - We have investigated the in vivo fluorescence of human skin with UV excitation
      and the effect of UV irradiation on the UV fluorescence. A particular chromophore
      was found to be very sensitive to suberythemogenic UV radiation. This chromophore
      has the spectral characteristics of tryptophan residues in proteins and is
      characterized by a fluorescence excitation maximum at 295 nm. The fluorescence of
      this chromophore in human epidermis has an excitation maximum that is coincident
      with the maximum of the action spectrum of most UV-induced photobiologic
      responses to human skin. The fluorescence of the chromophore was found to
      increase with UV exposure. The action spectrum was determined by following the
      increase of the emission at 345 nm with excitation at 295 nm as a function of
      skin exposure to a number of wavelengths in the UV region of the spectrum. The
      results show that irradiation in the UVB (290-320 nm) is more effective in
      producing the change in the fluorescence of tryptophan. Irradiation in the UVA
      (320-380 nm) was found to be capable of producing the increase but to a smaller
      extent. Whereas tryptophan fluorescence is found in both the epidermis and the
      dermis, it is only the epidermal component that increases with UV exposure. The
      change in 295 nm fluorescence with UV exposure was determined to be oxygen
      dependent. The fluorescence of tryptophan moieties measured in situ was found to
      increase when epidermal proliferation increases. This was verified by inducing
      epidermal repair after mechanical insult (tape stripping). The results suggest
      two possible scenarios for the UV-induced increase of the fluorescence: a prompt
      photooxidation of tryptophan moieties or a fast proliferation response to the
      insult created by UV irradiation.

PMID- 10594741
TI  - Local ultraviolet B irradiation impairs contact hypersensitivity induction by
      triggering release of tumor necrosis factor-alpha from mast cells. Involvement of
      mast cells and Langerhans cells in susceptibility to ultraviolet B.
AB  - Our laboratory has previously demonstrated that ultraviolet B radiation impairs
      contact hypersensitivity induction in ultraviolet B susceptible mice through a
      tumor necrosis factor-alpha-dependent mechanism, involving calcitonin gene
      related peptide and cutaneous mast cells. This study was designed to test
      directly whether mast cells are the source of tumor necrosis factor-alpha, to
      account for the ultra-violet B-susceptible phenotype. As dermal mast cells seem
      to release tumor necrosis factor-alpha following exposure to ultraviolet B, we
      investigated whether tumor necrosis factor-alpha released by mast cells could
      mediate impairment of contact hypersensitivity in a manner similar to that found
      with ultraviolet B radiation treatment. First, we loaded Fcepsilon receptors of
      mast cells of ultraviolet B-susceptible (C3H/HeN), ultraviolet B-resistant
      (C3H/HeJ), and mast-cell deficient (Sl/Sld) mice by intradermal injections of
      anti-dinitrophenyl immunoglobulin E antibodies. Twenty-four hours later,
      dinitrophenyl was injected intravenously, and within 30 min oxazolone was painted
      on injected skin sites. Contact hypersensitivity induction was impaired in
      ultraviolet B-susceptible mice, but not in ultraviolet B-resistant or Sl/Sld
      mice, and treatment with anti-tumor necrosis factor-alpha antibodies was able to
      reverse this impairment of contact hypersensitivity. Second, we have found that
      ultraviolet B radiation did not impair contact hypersensitivity induction when
      haptens were painted on irradiated skin of mast cell deficient mice. As
      ultraviolet B radiation impairs contact hypersensitivity induction through a
      tumor necrosis factor-alpha-dependent mechanism, we conclude that ultraviolet B
      radiation triggers the prompt release of tumor necrosis factor-alpha from dermal
      mast cells, and that mast cell-derived tumor necrosis factor-alpha interferes
      with generation of the hapten-specific signal required for contact
      hypersensitivity induction. In addition, we are providing data that indicate that
      tumor necrosis factor-alpha levels released from mast cells as well as
      sensitivity of Langerhans cells to tumor necrosis factor-alpha contribute in
      defining the phenotypes of resistance versus sensitivity to ultra-violet B
      radiation.

PMID- 10594742
TI  - Mouse langerhans cells differentially express an activated T cell-attracting CC
      chemokine.
AB  - Epidermal Langerhans cells represent an immature population of dendritic cells,
      not yet able to prime naive T cells. Following in vitro culture Langerhans cells
      mature into potent immunostimulatory cells. We constructed a representative cDNA
      library of in vitro matured murine Langerhans cells. Applying a differential
      screening procedure 112 differentially expressed cDNA clones were isolated.
      Thirty-six clones represented cDNA fragments of the same gene, identifying it to
      be the most actively expressed gene induced in maturing Langerhans cells. A full
      length cDNA was sequenced completely. The open reading frame codes for a protein
      of 92 amino acids containing a leader peptide of 24 amino acids, yielding a
      mature protein of 7.8 kDa molecular weight. Database searches revealed 99.4%
      sequence identity on the nucleotide level to the recently described mouse CC
      chemokine ABCD-1, as well as 74% sequence identity to the human CC chemokine, the
      macrophage-derived chemokine/stimulated T cell chemotactic protein. Expression
      was analyzed by reverse transcriptase-polymerase chain reaction on a large panel
      of cell types. Unlike the macrophage-derived chemokine, expression was not
      detected in macrophages stimulated by various cytokines. Expression is restricted
      to cultured Langerhans cells, in vitro cultured dendritic cells, and
      lipopolysaccharide-activated B cells. Recombinant protein was expressed in the
      yeast Pichia pastoris and purified to homogeneity. Whereas no chemotactic
      activity was observed in chemotaxis assays for naive T cells, B cells, cultured
      dendritic cells, and Langerhans cells, a strong chemoattractant activity was
      exerted on activated T cells. Thus, production of this chemokine by dendritic
      cells may be essential for the establishment and amplification of T cell
      responses.

PMID- 10594743
TI  - Granulocyte-macrophage colony-stimulating factor gene transfer to dendritic cells
      or epidermal cells augments their antigen-presenting function including induction
      of anti-tumor immunity.
AB  - Dendritic antigen-presenting cells derived from epidermis (Langerhans cells),
      bone marrow, and peripheral blood can present a wide variety of antigens,
      including tumor-associated antigens, for various immune responses. The
      development and function of dendritic cells is dependent upon a number of
      cytokines including granulocyte-macrophage-colony-stimulating factor. For
      example, Langerhans cells can present tumor-associated antigens for the induction
      of substantial in vivo anti-tumor immunity but only after activation in vitro by
      granulocyte-macrophage-colony-stimulating factor. Thus, we reasoned that
      insertion of a cDNA for granulocyte-macrophage-colony-stimulating factor into
      dendritic antigen-presenting cells may allow for autocrine stimulation and
      increased antigen-presenting capability. To test this possibility, we utilized an
      adenovirus vector to insert a cDNA for murine granulocyte-macrophage-colony
      stimulating factor into the dendritic cell lines XS52-4D and XS106 (derived from
      neonatal mouse epidermis), bone marrow-derived dendritic cells, and epidermal
      cells that contain Langerhans cells. Infection of each of these cell types
      resulted in release of abundant quantities of granulocyte-macrophage-colony
      stimulating factor. XS52-4D and XS106 cells infected with adenovirus granulocyte
      macrophage-colony-stimulating factor exhibited prolonged dendrites and greater
      expression of major histocompatibility complex class II molecules and CD86
      compared with cells infected with a null vector. Granulocyte-macrophage-colony
      stimulating factor cDNA-containing XS cells, bone marrow-derived dendritic cells,
      and epidermal cells had more potent alloantigen presenting capability than cells
      infected with a null vector. Most importantly, granulocyte-macrophage-colony
      stimulating factor gene-transferred epidermal cells were able to present tumor
      associated antigens for in vivo anti-tumor immunity against challenge with the
      S1509a spindle-cell tumor whereas null vector-infected cells were unable to prime
      for immunity. These results suggest that introduction of a cDNA for granulocyte
      macrophage-colony-stimulating factor into dendritic cells may be an effective
      means to augment their antigen-presenting capability and that granulocyte
      macrophage-colony-stimulating factor gene-transfer- red epidermal cells may be
      useful in tumor vaccination strategies.

PMID- 10594744
TI  - Sebaceous gland secretion is a major physiologic route of vitamin E delivery to
      skin.
AB  - Skin plays an important part in the protection against oxidative stressors, such
      as ultraviolet radiation, ozone, and chemicals. This study was based on the
      observation that upper facial stratum corneum contained significantly higher
      levels of the antioxidant alpha-tocopherol than corresponding layers of arm
      stratum corneum. We hypothesized that the underlying mechanism involves sebaceous
      gland secretion of vitamin E. To test this, we examined in eight human
      volunteers: (i) stratum corneum levels and distribution profiles of vitamin E in
      sites with a different sebaceous gland density (arm versus cheek); (ii) whether
      vitamin E is a significant constituent of human sebum; and (iii) if there is a
      correlation between levels of vitamin E and squalene, a marker of sebum
      secretion, in skin surface lipids. Using standardized techniques for stratum
      corneum tape stripping and sebum collection, followed by high-performance liquid
      chromatography analysis of tocopherols and squalene, we found that: (i) the ratio
      of cheek versus upper arm alpha-tocopherol levels was 20 : 1 for the upper
      stratum corneum and decreased gradually with stratum corneum depth; (ii) vitamin
      E (alpha- and gamma-tocopherol forms) is a significant constituent of human sebum
      and is continuously secreted at cheek and forehead sites during a test period of
      135 min; and (iii) vitamin E correlates well with levels of cosecreted squalene
      (r2 = 0.86, p < 0.001). In conclusion, sebaceous gland secretion is a relevant
      physiologic pathway for the delivery of vitamin E to upper layers of facial skin.
      This mechanism may serve to protect skin surface lipids and the upper stratum
      corneum from harmful oxidation.

PMID- 10594745
TI  - Establishment and characterization of an immortalized human sebaceous gland cell
      line (SZ95).
AB  - Human facial sebaceous gland cells were transfected with a PBR-322-based plasmid
      containing the coding region for the Simian virus-40 large T antigen. The
      resulting proliferating cell cultures have been passaged over 50 times to date,
      have been cloned, and show no signs of senescence after 4&DF;1 2 y in vitro,
      whereas normal human sebocytes can only be grown for three to six passages. The
      immortalized transfected cells, termed SZ95, expressed the Simian virus-40 large
      T antigen and presented an hyper-diploid-aneuploid karyotype with a modal
      chromosome number of 64.5. The SZ95 cell line exhibited epithelial, polymorphous
      characteristics with different cell sizes of up to 3.25-fold during proliferation
      and 6-fold at confluence, showing numerous cytoplasmic lipid droplets. The cells
      showed large cytoplasm profiles with abundant organelles, including vacuoles and
      myelin figures which indicated lipid synthesis. Lack of or only few desmosomal
      areas were observed. SZ95 cells expressed molecules typically associated with
      human sebocytes, such as keratins 7, 13, and 19, and several proteins of the
      polymorphous epithelial mucin family. Functional studies revealed synthesis of
      the sebaceous lipids squalene and wax esters as well as of triglycerides and free
      fatty acids, even after 25-40 passages; active lipid secretion; population
      doubling times of 52.4 +/- 1.6 h; reduced growth but maintenance of lipid
      synthesis under serum-free conditions; and retrieval of cell proliferation after
      addition of 5alpha-dihydrotestosterone. Retinoids significantly inhibited
      proliferation of certain SZ95 cell clones in the expected magnitude 13-cis
      retinoic acid > all-trans-retinoic acid > > acitretin. Thus SZ95 is an
      immortalized human sebaceous gland cell line that shows the morphologic,
      phenotypic and functional characteristics of normal human sebocytes.

PMID- 10594746
TI  - Differential effects of cytokines and immunosuppressive drugs on CD40, B7-1, and
      B7-2 expression on purified epidermal Langerhans cells1.
AB  - Langerhans cells are MHC class II antigen-positive antigen-presenting cells in
      the epidermis. Recent studies have revealed that Langerhans cells express
      costimulatory molecules like B7-1 and B7-2 and the accessory molecule CD40.
      Although these molecules are important for the antigen-presenting function of
      Langerhans cells, little is known about the precise regulation of their
      expression on purified Langerhans cells. Using a panning technique, we purified
      epidermal Langerhans cells to around 95% purity. Freshly prepared Langerhans
      cells (fLC) expressed the mRNA for receptors for M-CSF (cfms), GM-CSF (GM-CSFR),
      and TNF-alpha (TNFRII). TNF-alpha markedly upregulated CD40 and B7-1 expression
      on Langerhans cells, but not B7-2 expression. GM-CSF moderately upregulated B7-1
      and B7-2 expression, and slightly upregulated CD40 expression. M-CSF moderately
      upregulated B7-1 expression, but did not modulate CD40 or B7-2 expression.
      Dexamethasone (DEX) markedly inhibited CD40, B7-1, and B7-2 expression on
      Langerhans cells. Cyclosporin A (CsA) and FK506 slightly inhibited CD40 and B7-1
      expression on Langerhans cells, but not B7-2. Furthermore, TNF-alpha restored the
      DEX-induced inhibition of CD40 expression on Langerhans cells, but not the
      inhibition of B7-1 or B7-2 expression. GM-CSF restored DEX-induced inhibition of
      CD40, B7-1, and B7-2 expression. M-CSF did not affect the DEX-induced inhibition
      of these molecule expressions. These data provide a better understanding of the
      role of selective cytokines and immunosupressive drugs in the modulation of the
      antigen-presenting capacity of Langerhans cells.

PMID- 10594747
TI  - Differential regulation of epidermal and dermal dendritic cells by IL-12 and Flt3
      ligand.
AB  - An abrogation of the decline in epidermal Langerhans cell numbers above melanoma
      might significantly improve the efficacy of immunotherapy for melanoma treatment.
      Systemic Flt3 ligand (FL) administration in mice induced a significant increase
      in mature dendritic cells (DC) within the skin, preferentially in the dermis,
      whereas IL-12 promoted a significant increase of immature DC preferentially in
      the epidermis. Both effects were abrogated in IL-12 knockout mice. Thus, IL-12
      could promote FL-induced accumulation of skin DC. The involvement of FL and IL-12
      in the regulation of DC accumulation within the skin may contribute, at least in
      part, to the stimulation of antimelanoma immunity by FL- and IL-12-based
      immunotherapies. Moreover, FL and IL-12 could be used for selective in vivo
      generation of DC in either epidermis or dermis for experimental and clinical
      purposes.

PMID- 10594748
TI  - Accumulation of identical T cells in melanoma and vitiligo-like leukoderma.
AB  - The cloning of genes encoding melanoma antigens has opened new possibilities for
      the treatment of patients with cancer; however, most tumor rejection antigens
      recognized by tumor infiltrating lymphocytes are the products of genes that are
      also expressed by normal melanocytes. Hence, a large set of antigenic
      determinants of the self have not induced self-tolerance and these peptide
      determinants furnish target structures for immune responses directed against
      tumors. The notion that the immunotherapeutic targets involved in cancer
      regression comprise normal differentiation antigens is stressed by the
      association between vitiligo-like leukoderma, due to destruction of normal
      melanocytes, and melanoma regression, due to destruction of cancer cells.
      Nevertheless, this is the first report to demonstrate by means of a new technique
      based on reverse transcription polymerase chain reaction and denaturing gradient
      gel electrophoresis, the presence of clonally expanded T cells with identical BV
      regions in areas of destruction of both normal and neoplastic cells.

PMID- 10594749
TI  - High levels of expression of p27KIP1 and cyclin E in invasive primary malignant
      melanomas.
AB  - Cancer cells have abnormal cell cycle regulation which favors accelerated
      proliferation, chromosomal instability, and resistance to the senescence
      response. Although the p16INK4a locus is the most prominent susceptibility locus
      for familial melanomas, the low frequency of p16 mutations in sporadic melanomas
      suggests additional alterations in other cell cycle regulatory genes. Here we
      used primary melanoma tumors to reveal early cell cycle alterations that could be
      masked in advanced metastatic lesions due to their inherently high genetic
      instability. Unexpectedly, the cyclin-dependent kinase inhibitors p27KIP1 and/or
      p21Waf-1/SDI-1 were found to be expressed in 13 of 18 (72%) of the primary
      melanomas with a Breslow thickness greater than 0.076 mm. In general, p27 and/or
      p21 staining in the primary tumors correlated with low Ki-67 index. Importantly,
      most of the p21- and p27-positive tumors expressed high levels of cyclin D1 and
      cyclin E. In proliferating cells p27 is predominantly associated with cyclin D
      CDK4 complexes, but does not inhibit the kinase activity, whereas in quiescent
      cells p27 is found associated with inactive CDK2 complexes. p27 was also
      expressed at high levels in proliferating primary melanomas in culture, and found
      to be associated with active cyclin E-CDK2 complexes containing high levels of
      cyclin E. It is thus likely that accumulation of cyclin E overcomes the potent
      inhibitory activity of p27 and p21 in CDK2 complexes. Of the primary melanomas
      with no indication of invasiveness, only three of 15 (20%) were positive for p27
      and/or p21. We propose that high levels of p27 and p21 may confer upon melanoma
      tumors their characteristic resistance to conventional therapies. In turn, high
      levels of cyclins E and D1 may contribute to unlimited proliferation in primary
      melanomas that express the tumor suppressor p16INK4. J Invest Dermatol 113:1039
      1046 1999

PMID- 10594750
TI  - Vascular endothelial growth factor-C (VEGF-C) and its receptors KDR and flt-4 are
      expressed in AIDS-associated Kaposi's sarcoma.
AB  - Kaposi's sarcoma is characterized by clusters of spindle-shaped cells that are
      considered to be tumor cells and by prominent vasculature. Whereas spindle cells
      are most likely endothelial in origin, it remains controversial whether they are
      of lymphatic or blood vascular derivation. To test the hypothesis that the
      lymphangiogenesis factor vascular endothelial growth factor-C and its receptors,
      KDR and flt-4, are involved in the pathogenesis of Kaposi's sarcoma, we performed
      in situ hybridizations and immunofluorescent stainings on human immunodeficiency
      virus-associated Kaposi's sarcoma. Spindle-shaped tumor cells strongly expressed
      KDR and flt-4 mRNA. Immunofluorescent staining confirmed expression of the flt-4
      receptor in Kaposi's sarcoma cells, and double labeling revealed its
      colocalization with the endothelial cell marker CD31. Vascular endothelial growth
      factor-C was strongly expressed in blood vessels associated with Kaposi's
      sarcoma. In vitro, human dermal microvascular endothelial cells also expressed
      vascular endothelial growth factor-C mRNA that was further upregulated by
      vascular permeability factor/vascular endothelial growth factor. Vascular
      endothelial growth factor-C potently stimulated the proliferation of Kaposi's
      sarcoma tumor cells in vitro. These results demonstrate important paracrine
      functions of vascular endothelial growth factor-C, produced by blood vessels, in
      the pathogenesis of cutaneous Kaposi's sarcoma, and suggest a lymphatic origin
      and/or differentiation of Kaposi's sarcoma tumor cells.

PMID- 10594751
TI  - Antibodies against hair follicles are associated with alopecia totalis in
      autoimmune polyendocrine syndrome type I.
AB  - In the autosomal recessively inherited autoimmune polyendocrine syndrome type I
      (APS I) patients have autoantibodies directed against several endocrine and
      nonendocrine organs. Alopecia areata is present in about one-third of the
      patients and usually in the more severe forms, alopecia universalis or totalis.
      Sera from 39 patients with APS I, diluted 1:150, were used in indirect
      immunofluorescence staining of cryo-sections from normal human scalp. Two hair
      follicle staining patterns were observed. A cytoplasmic staining of the
      differentiating matrix, cuticle, and cortex keratinocytes in the anagen hair
      follicle was seen in five (13%) APS I sera. All these five patients had alopecia
      totalis, representing 63% of the eight patients with alopecia totalis (p <
      0.0001). Furthermore, four (10%) of the APS I sera stained the nuclei of the
      melanocytes in the hair follicle. Two of these patients had vitiligo. None of 20
      healthy control sera stained the keratinocyte cells or the melanocyte nuclei.
      These data show that many patients with APS I have high-titer autoantibodies
      directed against the anagen matrix, cuticle, and cortex keratinocytes and a
      melanocyte nuclear antigen, and also that the hair follicle keratinocyte staining
      is associated with alopecia, especially alopecia totalis. This study emphasizes
      the role of the differentiating anagen keratinocytes as an important structure in
      the autoimmune etiology of alopecia, both in APS I and at least in a subgroup of
      patients with alopecia areata unrelated to APS I.

PMID- 10594752
TI  - Modulation of IL-10, IL-12, and IFN-gamma in the epidermis of hairless mice by
      UVA (320-400 nm) and UVB (280-320 nm) radiation.
AB  - We have observed recently that the suppression of contact hypersensitivity (CHS)
      induced in mice by UVB irradiation may be prevented by suberythemal exposure to
      UVA radiation. Because the UVB-immunosuppressed state is associated with an
      upregulation of the Th2-associated cytokines IL-10 and IL-4, and a deficiency in
      Th1-associated IL-2, IL-12, and IFN-gamma, and because UVA photoimmunoprotection
      appeared to be IFN-gamma- dependent, we tested the hypothesis that UVA
      immunoprotection results from an ability to prevent the UVB-induced cytokine
      disarray. This study describes changes in epidermal IL-10, IL-12 and IFN-gamma
      for 5 d following irradiation of hairless mice with the CHS-modulating doses of
      UVB, UVA, or UVA + UVB, using immuno-histochemical detection in paraffin embedded
      skin sections, followed by image analysis quantitation. We found that UVB, but
      not UVA exposure, caused an increase in epidermal IL-10 expression, peaking at 3
      d. UVA irradiation, but not UVB, resulted in increased epidermal IL-12
      expression, peaking at 3 d, and increased epidermal IFN-gamma expression peaking
      earlier at 1 d. Irradiation with UVA + UVB abrogated the UVB-enhanced expression
      of IL-10, and caused small but significant increases in IL-12 and IFN-gamma at 3
      d and 1 d, respectively. These findings suggest that UVA photoimmunoprotection is
      mediated via prevention of IL-10 release, and thus the maintenance of the Th1/Th2
      balance, probably by upregulation of IL-12 and IFN-gamma, which are known to
      antagonize IL-10 in numerous models. The time course suggests that IFN-gamma
      responds initially to UVA radiation, and may stimulate the increased expression
      of IL-12.

PMID- 10594753
TI  - Molecular cytogenetic analysis of Spitz nevi shows clear differences to melanoma.
AB  - Spitz nevus is a benign neoplasm of melanocytes that can be difficult or
      impossible to distinguish from melanoma by clinical and histopathologic
      examination. We studied genomic DNA from 17 Spitz nevi by comparative genomic
      hybridization (CGH). Thirteen lesions showed no chromosomal aberrations, three
      cases had a gain involving the entire p-arm of chromosome 11, and one case showed
      a gain of chromosome 7q21-qter. Fluorescence in situ hybridization (FISH) on
      lesional tissue with a probe for the p-arm of chromosome 11 showed 6-10 p-arm
      signals per nucleus in those cases with a CGH-detected gain of chromosome 11p.
      One case with a normal CGH profile also showed increased copy number of 11p by
      FISH. Thus, the majority of Spitz nevi have a normal chromosomal complement at
      the level of CGH resolution; however some may contain gains, with 11p apparently
      being the most frequently involved location. These findings differ significantly
      from the previously reported changes in primary cutaneous melanoma, which show
      frequent deletions of chromosomes 9p (82%), 10q (63%), 6q (28%), and 8p (22%), as
      well as gains of chromosomes 7 (50%), 8 (34%), 6p (28%), 1q (25%) by CGH
      analysis. These clear differences in the location and frequencies of chromosomal
      aberrations in Spitz nevi and primary cutaneous melanomas could represent a basis
      for developing adjunctive techniques for refining accuracy in the difficult
      differential diagnosis of spitzoid melanocytic neoplasms.

PMID- 10594754
TI  - Green tea protects against psoralen plus ultraviolet A-induced photochemical
      damage to skin.
AB  - The use of psoralens combined with exposure to ultraviolet A radiation is a major
      form of treatment for psoriasis and a number of other common skin diseases.
      Although psoralen plus ultraviolet A treatment is highly effective, careful
      follow-up cohort studies have shown that it greatly increases risk for the
      development of cutaneous squamous cell carcinoma and melanoma. Strategies to
      reduce the risk of cancer development in psoralen plus ultraviolet A-treated
      populations are highly desirable. In prior studies, we demonstrated that green
      tea and constituent polyphenols protect against ultraviolet B-induced
      carcinogenesis and reduce the growth rate of established tumors in skin. In this
      study, we show that pre- and post-treatment with standardized green tea extract
      in psoralen plus ultraviolet A treatment populations abrogates the psoralen plus
      ultraviolet A-induced photochemical damage to skin. Intact mouse and human skin
      and reconstituted human skin were employed to assess the effect of both topical
      and oral administration of standardized green tea extract against psoralen plus
      ultraviolet A-induced photodamage. Oral administration of standardized green tea
      extract prior to and during multiple psoralen plus ultraviolet A treatments
      reduced hyperplasia and hyperkeratosis in murine skin. Standardized green tea
      extract treatment also inhibited accumulation of c-fos and p53 protein induction
      following a single exposure to psoralen plus ultraviolet A. c-fos and p53
      positive cells in psoralen plus ultraviolet A-treated skin were found to be
      increased by 55.4 +/- 13. 6% and 62.3 +/- 10.5%, respectively, compared with
      saline-treated unexposed control skin. Oral administration of 0.4 or 0.8%
      standardized green tea extract inhibited c-fos protein accumulation by 18.5% and
      46.2% (p < 0.05), respectively, and p53 protein accumulation by 26.1% and 54.3%
      (p < 0.05), respectively. Similarly proliferating cell nuclear antigen staining,
      a marker of cell proliferation was induced (73.7%) in psoralen plus ultraviolet A
      treated skin. Oral administration of 0.4% or 0.8% standardized green tea extract
      1 d after psoralen plus ultraviolet A treatment was effective in reducing
      psoralen plus ultraviolet A-induced inflammatory responses including erythema and
      edema formation. When standardized green tea extract was applied to EpiDerm, a
      reconstituted human skin equivalent, psoralen plus ultraviolet A-induced 8
      methoxypsoralen-DNA adduct formation and p53 protein accumulation were inhibited.
      Topical application of 0.2 mg 8-methoxypsoralen per cm2 followed by exposure to
      ultraviolet A (2.5 J per cm2) resulted in delayed erythema formation in human
      subjects. Pretreatment of human skin with topical application of 0.2 mg
      standardized green tea extract per cm2 30 min prior to psoralen plus ultraviolet
      A treatment resulted in an almost complete abrogation of psoralen plus
      ultraviolet A-induced erythema. In summary, these data demonstrate that
      standardized green tea extract protects against psoralen plus ultraviolet A
      induced phototoxicity by inhibiting DNA damage and diminishing the inflammatory
      effects of this modality.

PMID- 10594755
TI  - Expression and targeting of the apoptosis inhibitor, survivin, in human melanoma.
AB  - The newly described apoptosis inhibitor survivin is expressed in many human
      cancers and appears to play a critical part in both apoptosis regulation and cell
      cycle progression. Its potential role in malignant melanoma is unknown. In a
      panel of 30 malignant melanomas, survivin was strongly expressed in all cases (15
      of 15) of metastatic malignant melanomas and 13 of 15 cases of invasive malignant
      melanomas by immunohistochemistry. In invasive malignant melanomas, survivin was
      also expressed in the in-situ component of the lesion. Survivin expression was
      found in all cases (11 of 11) of nevi, but not in melanocytes in sections of
      normal skin. The apoptosis inhibitor bcl-2 was expressed in 26 of 30 cases, but
      generally at lower levels than that of infiltrating lymphocytes. The mitotic
      index, as assessed by MIB-1 staining, was consistently higher in metastatic than
      invasive malignant melanomas. Assessment of apoptotic index by in situ end
      labeling revealed extremely low rates of apoptosis in most malignant melanomas.
      Survivin expression by western blotting was detected in four human metastatic
      malignant melanoma cell lines but not in cultured normal human melanocytes.
      Transfection of both YUSAC-2 and LOX malignant melanoma cells with green
      fluorescence protein-conjugated survivin anti-sense or green fluorescence protein
      conjugated survivin dominant negative mutant (Cys84Ala) [corrected] resulted in
      increased apoptosis in the absence of other genotoxic stimuli. Two-color flow
      cytometry confirmed that YUSAC-2 cells transfected with survivin anti-sense
      expressed less endogenous survivin and exhibited an increased fraction of cells
      with sub-G1 DNA content. These data demonstrate that apoptosis inhibition by
      survivin may participate in the onset and progression of malignant melanomas, and
      suggest that therapeutic targeting of survivin may be beneficial in patients with
      recurrent or metastatic disease.

PMID- 10594756
TI  - 1alpha,25-dihydroxycholecalciferol and cyclosporine suppress induction and
      promote resolution of psoriasis in human skin grafts transplanted on to SCID
      mice.
AB  - Accumulating evidence has emphasized the importance of immunocompetent cells in
      determining the psoriatic phenotype. We have investigated the effect of 1alpha,25
      dihydroxycholecalciferol, the naturally occurring active form of vitamin D3,
      cyclosporine A, and interleukin-10 on the phenotype of human psoriatic skin
      xenotransplants. First, psoriatic skin transplants were injected with either
      1alpha,25-dihydroxy- cholecalciferol, cyclosporine A, or interleukin-10. Second,
      we determined the ability of autologous lymphocytes, activated in vitro using
      staphylococcal enterotoxin B and interleukin-2 and then exposed to either 1alpha,
      25-dihydroxycholecalciferol or cyclosporine A, to induce psoriatic lesions if
      they were injected into the dermis of uninvolved skin grafts. We found that
      injections into transplanted psoriatic plaques of either 1alpha,25
      dihydroxycholecalciferol or cyclosporine A, but not interleukin-10, resulted in a
      consistent reduction in the clinical and histologic score of psoriasis with
      remission towards uninvolved psoriatic skin. Injection of activated immunocytes
      into symptomless psoriatic skin grafts, changed the grafts towards plaque-type
      psoriasis with silvery scale, parakeratosis, elongated rete pegs, acanthosis, and
      dermal angiogenic reaction. In contrast, if activated immunocytes were exposed to
      1alpha, 25-dihydroxycholecalciferol or cyclosporine A prior to injection, only
      minimal changes occurred. It was determined that neither staphylococcal
      enterotoxin B and interleukin-2 activation by itself, nor the drugs investigated,
      changed the CD4/CD8 ratio of activated (CD25 + ) cells. Our results are
      consistent with the hypothesis that psoriasis may be induced by activated T
      lymphocytes, and indicate that novel immunomodulatory drugs can serve to inhibit
      the pathogenetic ability of immunocytes in psoriasis.

PMID- 10594757
TI  - The function of nitric oxide in wound repair: inhibition of inducible nitric
      oxide-synthase severely impairs wound reepithelialization.
AB  - Recently, we demonstrated a large induction of inducible nitric oxide synthase
      (iNOS) during cutaneous wound repair. In this study, we established an in vivo
      model in mice to investigate the role of NO during the wound healing process.
      During excisional repair, mice were treated with L-N6-(1-iminoethyl)lysine (L
      NIL), a selective inhibitor of iNOS enzymatic activity. Compared with control
      mice, L-NIL-treated animals were characterized by a severely impaired
      reepithelialization process, as the hyperproliferative epithelia at the wound
      edges appeared to be delayed and characterized by an atrophied morphology.
      Immunohistochemical labeling for detection of proliferating cells (BrdU-, Ki67
      staining) revealed a strong reduction in proliferating keratinocyte cell numbers
      during the process of re-epithelialization after inhibition of iNOS activity
      during repair. Western blot analysis of total wound lysates from PBS- and L-NIL
      treated mice clearly demonstrated a reduction in proliferating cell nuclear
      antigen, representing a marker for cell proliferation, in lysates isolated from L
      NIL-treated mice. The dependency between keratinocyte proliferation and NO
      availability observed during wound repair in vivo is further supported by the
      observation that proliferation of the keratinocyte cell line (HaCaT) is
      stimulated by low concentrations of NO-donors also in vitro. In summary, our data
      demonstrate that the presence of a functionally active iNOS is a crucial
      prerequisite for normal wound reepithelialization.

PMID- 10594758
TI  - Association of p63 with proliferative potential in normal and neoplastic human
      keratinocytes.
AB  - p63, a recently identified member of the p53 gene family, encodes multiple
      products with transactivating, death-inducing, and dominant-negative activities.
      We show that in normal human epidermis, in hair follicles, and in stratified
      epidermal cultures, p63 protein is principally restricted to cells with high
      proliferative potential and is absent from the cells that are undergoing terminal
      differentiation. In normal human epidermis and in hair follicles, basal cells
      with abundant p63 are interspersed with cells with little or no p63. Whenever p63
      mRNA is present, it encodes mainly truncated, potentially dominant-negative
      isotypes. In squamous cell carcinomas, the number of cells containing p63 and
      their distribution depends on the degree of anaplasia. In highly differentiated
      tumors, p63 is confined to a ring of basal-like cells surrounding, but at a
      distance from, centers of terminal differentiation. In less differentiated
      tumors, most cells contain p63 and their distribution is chaotic with respect to
      centers of terminal differentiation. p63 appears to be a valuable diagnostic
      marker for anaplastic keratinocytes.

PMID- 10594759
TI  - Barrier formation in the human fetus is patterned.
AB  - We recently demonstrated patterned stratum corneum maturation and skin barrier
      formation during fetal development in rodents and rabbit. The presence of skin
      patterning in these mammals led us to predict patterned barrier formation during
      human infant development. Here we extend our mammalian study and demonstrate
      patterned stratum corneum development and skin barrier formation in the pre-term
      human infant. Surprisingly, we show initiation of human barrier regionally as
      early as 20-24 wk gestational age (22-26 wk menstrual age), bringing barrier
      formation close to the time of periderm disaggregation. We use the mouse model to
      show that patterns of periderm disaggregation mirrors barrier formation. Periderm
      disaggregation follows and recapitulates barrier pattern, suggesting a
      relationship between the processes. This work reveals regional patterning in skin
      maturation and barrier formation in the human infant and demonstrates that
      initiation of human skin barrier formation in utero coincides with the current
      lower limit of viability of the pre-term infant.

PMID- 10594760
TI  - Identification of a novel mutation R42P in the gap junction protein beta-3
      associated with autosomal dominant erythrokeratoderma variabilis.
AB  - We report a missense mutation in the gap junction protein beta-3 (encoding
      Connexin 31), which was detected in only the affected members of a family in
      which the autosomal dominant skin disease erythrokeratoderma variabilis was
      segregating. The nucleotide change results in an arginine to proline substitution
      in codon 42. This residue is positioned on the first transmembrane/first
      extracellular domain of the gap junction protein with the mutation replacing a
      negatively charged residue with a nonpolar residue. This change may disrupt the
      conformation of the protein and voltage gating polarity leading to impaired
      channel function.

PMID- 10594761
TI  - Two different mutations in the same codon of a type II hair keratin (hHb6) in
      patients with monilethrix.
AB  - Monilethrix is an autosomal dominant hair disorder characterized by a beaded
      appearance of the hair due to periodic thinning of the shaft. The phenotype shows
      variable penetrance and results in hair fragility and patchy dystrophic alopecia.
      Mutations of the helix-encoding region in two hair-specific keratins (hHb1 and
      hHb6) have been identified. We have now investigated two unrelated monilethrix
      patients and identified two different novel heterozygous point mutations of the
      same codon in exon 7 of the hHb6 gene. Dystrophic hair samples obtained from both
      patients showed the typical beaded appearance by scanning electron microscopy.
      Both mutations affected the first base of codon 402 (glutamic acid). In patient
      A, a G to C transition occurred causing a glutamine substitution (GAG to CAG:
      E402Q) whereas in patient B, the transition was G to A yielding a lysine
      substitution (GAG to AAG: E402K). The sequence of the 1A helical regions of hHb1
      and hHb6 as well as the 2B helical region of hHb1, were normal. Unaffected
      relatives did not have the hHb6 mutation and this codon was found to be highly
      conserved showing no alteration in the normal population (100 alleles examined).
      Both mutations disrupted a Taq I restriction site and restriction fragment length
      polymorphism analysis showed that a diagnostic 361 bp fragment could confirm the
      mutation. Thus, two new point mutations of the hair-specific keratin gene hHb6
      have been identified in this genetic disease.

PMID- 10594762
TI  - Vitamin C, uric acid, and glutathione gradients in murine stratum corneum and
      their susceptibility to ozone exposure.
AB  - The stratum corneum has been recognized as the main cutaneous oxidation target of
      atmospheric ozone (O3), a major part of photochemical smog. This study reports
      the presence and distribution of vitamin C, glutathione, and uric acid in murine
      stratum corneum, and evaluates their susceptibility to acute environmental
      exposure to O3. Based on tape stripping and a modified extraction method with
      high performance liquid chromatography electrochemical analysis, we detected
      vitamin C (208.0 +/- 82.5 pmol per 10 consecutive pooled tapes), glutathione
      (283.7 +/-96.3), and uric acid (286.4 +/-47.1) in murine stratum corneum as
      compared with only 16.5 +/- 1.4 pmol alpha-tocopherol. Vitamin C, glutathione
      (both p < 00.001), and urate (p < 0.01) were found to exhibit a gradient with the
      lowest concentrations in the outer layers and a steep increase in the deeper
      layers. To investigate the effect of O3 exposure on hydrophilic antioxidants, we
      exposed SKH-1 hairless mice to O3 concentrations of 0, 0.8, 1, and 10 p.p.m., and
      stratum corneum was analyzed before and after exposure. Whereas mock exposure
      with 0 p.p. m. for 2 h had no significant effect, O3 doses of 1 p.p.m. for 2 h
      and above showed depletion of all three antioxidants. Vitamin C was decreased to
      80% +/- 15% of its pretreatment content (p < 0.05), GSH to 41% +/- 24% (p <
      0.01), and uric acid to 44% +/- 28% (p < 0.01). This report demonstrates the
      previously unrecognized role of hydrophilic antioxidants in the stratum corneum
      and provides further evidence that O3 induces oxidative stress in this outer skin
      layer.

PMID- 10594763
TI  - Induction of melanogenic abnormalities in NF1+/- mutant mice by DMBA.

PMID- 10594764
TI  - 001: hepatocyte growth factor/scatter factor inhibits UVB induced apoptosis of
      human keratinocytes via the PI-3-kinase pathway
AB  - UVB-irradiation induces apoptosis in primary keratinocytes (KC) and KC-derived
      cell-lines A431 and HaCaT. Here we report on the inhibition of UV induced KC
      apoptosis by hepatocyte growth factor/scatter factor (HGF/SF). The protective
      effect of HGF/SF for UVB-irradiated primary KC was observed at concentrations as
      low as 1 ng/ml HGF and was confirmed by demonstration of the inhibition of
      nucleosome-release and the activation of caspase-3. In contrast to the
      observation with primary KC HGF/SF had no effect on the survival of A431 and
      HaCaT cells after UVB-irradiation, despite the fact that we could demonstrate
      that these cells functionally express the HGF/SF receptor c-met. When blocking
      signalling pathways initiated by c-met, we found that the inhibition of the
      phosphatidylinositol-3-OH (PI-3) kinase by wortmannin or LY294002 led to a total
      inhibition of the anti-apoptotic effect of HGF/SF, whereas the blockade of the
      MAP-kinase pathway by PD90859 had no effect. This represents the first
      demonstration of an involvement of the PI-3 kinase pathway in the anti-apoptotic
      effect of HGF/SF. In conclusion, our data demonstrate that HGF/SF is able to
      rescue KC but not autonomously growing KC cell lines from apoptosis induced by
      UVB. Since in vivo HGF/SF is produced by mesenchymal cells, this mechanism may
      represent an important paracrine loop in the skin supporting the survival of KC
      after UV-injury.

PMID- 10594765
TI  - Editor's report for 1998

PMID- 10594766
TI  - Corporate supporting members of the european society for dermatological research

PMID- 10594767
TI  - Celloidin-wax sandwich microtomy: a novel and rapid method for producing serial
      semithin sections.
AB  - A method is described that allows rapid and reliable serial sectioning down to
      thicknesses of 1 micron. The tissue is first embedded in celloidin and then in
      wax and trimmed so that the block is sandwiched between two layers of wax. This
      combines the virtues of both media. The celloidin gives greater support to tissue
      than wax and enables the cutting of semithin sections. The wax allows ribbons of
      serial sections to be produced as in conventional wax microtomy. This makes it
      easy to produce serial semithin sections as a matter of routine.

PMID- 10594768
TI  - Biological ultrastructure as revealed by high resolution cryo-SEM of block faces
      after cryo-sectioning.
AB  - Ultrastructural information was obtained by imaging the block face of high
      pressure-frozen cryo-sectioned biological samples in a high-resolution cryo-SEM.
      Cryo-sectioning leads to a well-defined flat artificial surface in contrast to
      cryo-fracturing. Typical artefacts of cryo-sections such as compression and
      crevasses were not visible on the block face. The ultrastructural features known
      from resin sections and from freeze-fractures could also be found on the block
      faces. The cytoplasms show particles of different size which most likely
      represent proteins. The effects of radiation damage could be reduced considerably
      by applying the double layer coating technique and backscattered electron
      imaging. High quality cryo-sections are only obtained from vitrified material.
      Reasonably flat block faces were, however, also obtained from adequately frozen
      microcrystalline samples, thereby facilitating ultrastructural studies in the
      frozen hydrated state.

PMID- 10594769
TI  - High resolution transmission soft X-ray microscopy of deterioration products
      developed in large concrete dams
AB  - In concrete structures, the reaction of certain siliceous aggregates with the
      highly alkaline concrete pore solution produces an alkali-silicate gel that can
      absorb water and expand. This reaction can lead to expansion, cracking, increased
      permeability, and decreased strength of the concrete. Massive concrete
      structures, such as dams, are particularly susceptible to the damage caused by
      the alkali-silica reaction because of the availability of water and because
      massive gravity dams usually do not contain steel reinforcement to restrain the
      expansion. Both the cement hydration products and alkali-silica reaction products
      are extremely sensitive to humidity. Consequently, characterization techniques
      that require high vacuum or drying, as many existing techniques do, are not
      particularly appropriate for the study of the alkali-silica reaction because
      artefacts are introduced. Environmental scanning electron micrographs and
      scanning electron micrographs with energy dispersive X-ray analysis results
      demonstrate the effect of drying on the morphology and chemical composition of
      the alkali-silicate reaction gel. Thus, the impetus for this research was the
      need to observe and characterize the alkali-silica reaction and its gel product
      on a microscopic level in a wet environment (i.e. without introducing artefacts
      due to drying). Only soft X-ray transmission microscopy provides the required
      high spatial resolution needed to observe the reaction process in situ. The
      alkali-silica reaction can be observed over time, in a wet condition, and at
      normal pressures, features unavailable with most other high resolution
      techniques. Soft X-rays also reveal information on the internal structure of the
      sample. The purpose of this paper is to present research, obtained using
      transmission soft X-ray microscopy, on the effect of concrete pore solution
      cations, namely sodium and calcium, on the product formed as a result of alkali
      attack. Alkali-silicate reaction (ASR) gel was obtained from the FURNAS Dam in
      Minas Gerais, Brazil. Images of the ASR gel in sodium hydroxide indicated
      dissolution and repolymerization of the silicate into a less dense form,
      demonstrating the expansive nature of the gel when exposed to alkalis. In the
      calcium hydroxide solution, ASR gel, silica fume, and chemical grade silica gel
      each reacted with the calcium ions in solution to produce a calcium silicate
      hydrate precursor with a lathlike, branching morphology. The distinctive
      spherulitic microstructure formed during this reaction was identified as the
      'sheaf of wheat' morphology, previously described in the literature. In addition,
      the development of the sheaf of wheat morphology was documented over time. These
      results suggest that of the cations studied in this investigation, it is the
      alkalis in concrete pore solution that produce the expansive ASR gel, while
      reaction with calcium ions does not result in expansion or damage to the concrete
      structure. More broadly, these results demonstrate the advantage of transmission
      soft X-ray microscopy for the study of the alkali-silica reaction, indicating the
      value of this technique for further studies in concrete technology.

PMID- 10594770
TI  - Adaptation of a super-sensitive epitope detection technique for the
      immunoelectron microscopy of titin filaments in vertebrate striated muscle.
AB  - A super-sensitive epitope-detection technique based on gold-silver
      intensification was adapted for pre-embedding immunolabelling of titin filaments
      in vertebrate striated muscle. Indirect immunoelectron microscopy of titin
      filaments was performed with monoclonal titin antibodies as primary antibodies
      and Fab anti-mouse IgG conjugated with 1.4 nm gold particles as secondary
      antibodies. The secondary antibodies penetrated easily into the tissue owing to
      their reduced size and the very small gold particles. After the labelling
      procedure, the tissue was fixed in glutaraldehyde. Since the gold particles were
      not visible by conventional transmission electron microscopy, they were
      intensified with a silver developing system. Although the particle size varied
      nonlinearly with the developing time, very fine grain size was achievable. The
      technique provided super-sensitive detection with excellent contrast and
      demonstrated epitopes with both strong and weak affinities.

PMID- 10594771
TI  - Membrane ion channels as physiological targets for local Ca2+ signalling.
AB  - Ionized calcium plays a central role as a second messenger in a number of
      physiologically important processes determining smooth muscle function. To
      regulate a wide range of cellular activities the mechanisms of subcellular
      calcium signalling should be very diverse. Recent progress in development of
      visible light-excitable fluorescent dyes with high affinity for Ca2+ (such as
      oregon green 488 BAPTA indicators, fluo-3 and fura red) and confocal laser
      scanning microscopy provides an opportunity for direct visualization of
      subcellular Ca2+ signalling and reveals that many cell function are regulated by
      the microenvironment within small regions of the cytoplasm ('local control'
      concept). Here confocal imaging is used to measure and locate changes in [Ca2+]i
      on a subcellular level in response to receptor stimulation in visceral myocytes.
      We show that stimulation of muscarinic receptors in ileal myocytes with carbachol
      leading to activation of inositol 1,4,5-trisphosphate receptors (IP3Rs)
      accelerates the frequency of spontaneous calcium sparks (discharged via ryanodine
      receptors, RyRs) and gives rise to periodic propagating Ca2+ waves oscillating
      with a frequency similar to that of carbachol-activated cationic current
      oscillations. Furthermore, by combining the whole-cell patch clamp technique with
      simultaneous confocal imaging of [Ca2+]i in voltage-clamped vascular myocytes we
      demonstrate that calcium sparks may lead to the opening of either Ca2+-activated
      Cl- channels or Ca2+-activated K+ channels, and the discharge of a spontaneous
      transient inward current (STIC) or a spontaneous transient outward current
      (STOC), respectively.

PMID- 10594772
TI  - An optical sectioning programmable array microscope implemented with a digital
      micromirror device.
AB  - The defining feature of a programmable array microscope (PAM) is the presence of
      a spatial light modulator in the image plane. A spatial light modulator used
      singly or as a matched pair for both illumination and detection can be used to
      generate an optical section. Under most conditions, the basic optical properties
      of an optically sectioning PAM are similar to those of rotating Nipkow discs. The
      method of pattern generation, however, is fundamentally different and allows
      arbitrary illumination patterns to be generated under programmable control, and
      sectioning strategies to be changed rapidly in response to specific experimental
      conditions. We report the features of a PAM incorporating a digital micromirror
      device, including the axial sectioning response to fluorescent thin films and the
      imaging of biological specimens. Three axial sectioning strategies were compared:
      line scans, dot lattice scans and pseudo-random sequence scans. The three
      strategies varied widely in light throughput, sectioning strength and robustness
      when used on real biological samples. The axial response to thin fluorescent
      films demonstrated a consistent decrease in the full width at half maximum
      (FWHM), accompanied by an increase in offset, as the unit cells defining the
      patterns grew smaller. Experimental axial response curves represent the sum of
      the response from a given point of illumination and cross-talk from neighbouring
      points. Cross-talk is minimized in the plane of best focus and when measured
      together with the single point response produces a decrease in FWHM. In patterns
      having constant throughput, there appears to be tradeoff between the FWHM and the
      size of the offset. The PAM was compared to a confocal laser scanning microscope
      using biological samples. The PAM demonstrated higher signal levels and dynamic
      range despite a shorter acquisition time. It also revealed more structures in x-z
      sections and less intensity drop-off with scanning depth.

PMID- 10594773
TI  - The shape of field emitters and the ion trajectories in three-dimensional atom
      probes
AB  - The lateral resolution of three-dimensional atom probes is mainly controlled by
      the aberrations of the ion trajectories near the specimen surface. For the first
      time, a simulation program has been developed to reconstruct the ion trajectories
      near a sharp hemispherical electrode defined at the atomic scale. Surface atoms
      submitted to the highest field were removed one by one. The consecutive gradual
      change of the surface topology was taken into account in the calculation of ion
      trajectories. As the tip was 'field evaporated', the initial spherical shape of
      the emitter was observed to transform gradually into a polygonal shape. When the
      tip reached its equilibrium shape, the field distribution at the tip surface was
      found to be much more uniform compared to the initial distribution. The
      calculated distribution of ion impacts on the detector exhibits the presence of
      depleted zones both at the centre of low index poles and along <001> zone axes.
      These predictions are in excellent agreement with experiments.

PMID- 10594774
TI  - Flat-bed scanning as a tool for quantitative neuroimaging.
AB  - The aim of this study was to compare three different imaging techniques which are
      used to provide data on the laminar structure of the human cerebral cortex.
      Region V1 of Brodmann's area 17 stained with cresyl violet was investigated, and
      a conventional semi-automatic morphometric evaluation, the videomicroscropic
      procedure and a new transparent flat-bed scanning technique were compared. The
      results of each digitizing method were converted into normalized profiles which
      allow the laminae in the striate cortex to be displayed. It was found that major
      laminar patterns can be detected by the scanning technique, but that subsidiary
      laminations are more clearly displayed by morphometry and videomicroscopy. For
      magnifications up to x 400 a high resolution transparent flat-bed scanner may be
      used in place of the videomicroscopy technique.

PMID- 10594775
TI  - Stereoscopic display of atomic force microscope images using anaglyph techniques.
AB  - This paper describes the use of a standard stereo-pair image display method for
      presenting the three-dimensional relief information found in atomic force
      microscope (AFM) images. The method makes use of commercially available image
      processing software packages. The techniques are illustrated on AFM images of the
      cuticle structure of a human hair fibre.

PMID- 10594776
TI  - Effect of membrane composition and structure on solute removal and
      biocompatibility in hemodialysis.
AB  - Effect of membrane composition and structure on solute removal and
      biocompatibility in hemodialysis. Significant changes in extracorporeal membranes
      have occurred over the past five decades in which hemodialysis (HD) has been
      available as a therapy for both acute renal failure (ARF) and end-stage renal
      disease (ESRD). For cellulosic membranes, these changes have included a reduction
      in thickness, hydroxyl group substitution, and an increase in pore size. These
      modifications have resulted in enhanced efficiency of small solute removal, a
      broader spectrum of overall solute removal, and an attenuation of complement
      activation in comparison to the thick, unsubstituted cellulosic membranes of low
      permeability used in the early days of HD therapy. Synthetic membranes,
      originally developed specifically for use in high-flux HD and hemofiltration,
      have also evolved during this same time period. In fact, the initially clear
      distinction between low-flux regenerated cellulosic and high-flux synthetic
      membranes has become blurred, as membrane formulators have developed products
      designed to appeal to enthusiasts for both membrane formats. The purpose of this
      review is to characterize both the solute removal and biocompatibility
      characteristics of dialysis membranes according to their composition (that is,
      polymeric makeup) and structure. In this regard, the manner in which membrane
      biocompatibility interacts with flux is highlighted.

PMID- 10594777
TI  - Renal basement membrane components.
AB  - Renal basement membrane components. Basement membranes are specialized
      extracellular matrices found throughout the body. They surround all epithelia,
      endothelia, peripheral nerves, muscle cells, and fat cells. They play
      particularly important roles in the kidney, as demonstrated by the fact that
      defects in renal basement membranes are associated with kidney malfunction. The
      major components of all basement membranes are laminin, collagen IV,
      entactin/nidogen, and sulfated proteoglycans. Each of these describes a family of
      related proteins that assemble with each other in the extracellular space to form
      the basement membrane. Over the last few years, new basement membrane components
      that are expressed in the kidney have been discovered. Here, the major components
      and their localization in mature and developing renal basement membranes are
      described. In addition, the phenotypes of basement membrane component gene
      mutations, both naturally occurring and experimental, are discussed, as is the
      aberrant deposition of basement membrane proteins in the extracellular matrix in
      several renal diseases.

PMID- 10594778
TI  - Expression and localization of fibroblast growth factors and fibroblast growth
      factor receptors in the developing rat kidney.
AB  - Expression and localization of fibroblast growth factors and fibroblast growth
      factor receptors in the developing rat kidney. BACKGROUND: The permanent kidney,
      or metanephros, develops through a complex series of reciprocal inductive events
      and involves branching morphogenesis, tubulogenesis, angiogenesis, and tissue
      remodeling. Fibroblast growth factors (FGFs) are a family of growth and
      differentiation factors that have been implicated in metanephric development.
      FGFs exert their actions through tyrosine kinase receptors, FGFRs, which are
      encoded by four FGFR genes (FGFR1 through FGFR4). METHODS: Reverse transcriptase
      polymerase chain reaction was used to detect the expression of FGFs and FGFRs in
      rat metanephroi from embryonic day (E) 14 to E21. Nonradioactive in situ
      hybridization was used to localize FGF1 mRNA in E20 rat metanephroi, and
      immunohistochemistry was used to localize FGFRs in E15 and E20 rat metanephroi.
      RESULTS: We detected the expression of mRNAs for FGF1 through FGF5, FGF7 through
      FGF10, and FGFR1 through FGFR4 (IIIb and IIIc splice variants) in rat metanephroi
      from E14 to E21. By in situ hybridization, FGF1 mRNA was detected in the
      nephrogenic zone, ureteric epithelium, and developing nephron elements. FGFR
      proteins were localized in a distinct pattern that altered with maturation. FGFR1
      was widely distributed in developing metanephric epithelia and mesenchyme, but
      not in developing interstitium. FGFR2 was also widely distributed in nephron
      epithelia, particularly in proximal convoluted tubules, but was not detected in
      metanephric mesenchyme, mesenchymal condensates, or developing interstitium.
      FGFR3 was localized to mesenchymal condensates, nephron elements, and medullary
      interstitium but not proximal convoluted tubules. FGFR4 was localized mostly to
      maturing nephron structures and was not detected in nephrogenic mesenchyme,
      mesenchymal condensates, or developing interstitium. CONCLUSIONS: These results
      indicate that FGFs and FGFRs are expressed in the developing rat metanephros from
      at least E14 and that they likely play important roles in metanephric development
      and maturation.

PMID- 10594779
TI  - 22-Oxacalcitriol ameliorates high-turnover bone and marked osteitis fibrosa in
      rats with slowly progressive nephritis.
AB  - 22-Oxacalcitriol ameliorates high-turnover bone and marked osteitis fibrosa in
      rats with slowly progressive nephritis. BACKGROUND: 22-Oxacalcitriol (OCT) is a
      unique vitamin D analogue with less calcemic activity than calcitriol, and it
      effectively suppresses parathyroid hormone (PTH) secretion in uremic rats. This
      study was performed to examine the long-term effect of intravenously administered
      OCT on high-turnover bone disease in model rats of slowly progressive renal
      failure. METHODS: Slowly progressive renal failure rats were made by a single
      injection of glycopeptide isolated from rat renal cortical tissues. At 250 days,
      glycopeptide-induced nephritis (GN) rats were divided into three groups with the
      same levels of serum creatinine and PTH, and they received either OCT (0.03 or
      0.15 microg/kg body wt) or vehicle given intravenously three times per week for
      15 weeks. RESULTS: Renal function of GN rats deteriorated very slowly but
      progressively, as assessed by the increase of serum creatinine concentration. At
      sacrifice, serum PTH levels, bone formation markers, bone resorption markers, and
      fibrosis volume were significantly elevated in vehicle-treated GN rats compared
      with those of sham-operated rats, suggesting the development of high-turnover
      bone disease with osteitis fibrosa. In contrast, in the GN-OCT 0.15 microg/kg
      group, these high PTH levels and high-turnover bone and fibrosis were
      significantly decreased. Such amelioration of bone abnormalities by OCT was not
      accompanied by either hypercalcemia or further deterioration of renal function.
      CONCLUSIONS: These data indicate that OCT may be a useful and safe agent not only
      for the suppression of PTH, but also for the amelioration of osteitis fibrosa and
      high-turnover bone without causing hypercalcemia in chronic dialysis patients.

PMID- 10594780
TI  - Compensatory renal growth in uninephrectomized adult mice is growth hormone
      dependent.
AB  - Compensatory renal growth in uninephrectomized adult mice is growth hormone
      dependent. BACKGROUND: Growth hormone (GH) and insulin-like growth factors (IGFs)
      have been implicated as pathogenic factors in compensatory renal growth (CRG)
      following unilateral nephrectomy in rodents. CRG in adult rats has been suggested
      to be GH dependent and GH independent in immature rats. However, the exact role
      of GH as a regulating or permissive factor in CRG in adult rodents has not been
      fully resolved to date. METHODS: To elucidate a possible direct, permissive role
      of GH in CRG, we examined the effect of a newly developed specific GH receptor
      (GHR) antagonist (G120K-PEG) on kidney IGF-I accumulation and renal/glomerular
      hypertrophy over seven days after uninephrectomy in adult mice. RESULTS: Placebo
      treated uninephrectomized mice were characterized by a transient increase in
      kidney IGF-I concentration preceding CRG and an increase in glomerular volume. In
      G120K-PEG-treated uninephrectomized animals, increased kidney IGF-I levels,
      kidney weight, and glomerular volume were fully abolished. No differences were
      seen between the two uninephrectomized groups with respect to body weight, food
      intake, blood glucose, serum GH, IGF-I, or IGFBP-3 levels. CONCLUSIONS: The
      administration of a GHR antagonist in uninephrectomized adult mice has renal
      effects without affecting circulating levels of GH/IGFs, indicating that the
      effect of G120K-PEG may be mediated through a direct inhibitory effect on renal
      IGF-I accumulation through the renal GHR. This study shows, to our knowledge for
      the first time, that CRG in adult mice is strictly GH dependent.

PMID- 10594781
TI  - Vascular endothelial growth factor activates MAP kinase and enhances collagen
      synthesis in human mesangial cells.
AB  - Vascular endothelial growth factor activates MAP kinase and enhances collagen
      synthesis in human mesangial cells. BACKGROUND: Vascular endothelial growth
      factor (VEGF) is an endothelial mitogen that is constitutively expressed in
      normal human glomeruli, but its role in the kidney is still unclear. In this
      study, we examined the effects of VEGF on human mesangial cells (HMCs). Methods
      and Results. Reverse transcription-polymerase chain reaction analysis
      demonstrated the presence of VEGF receptor mRNA (flt-1 and KDR) in HMCs. The
      treatment of HMCs with VEGF did not cause a change in 3H-thymidine incorporation
      or cell numbers. In contrast, VEGF caused a dose- and time-dependent increase in
      collagen synthesis, with threefold to fivefold increases in both cell-associated
      and secreted collagen synthesis seen after treatment with 200 ng/ml VEGF. The
      effects of VEGF were attenuated by treatment of HMCs with the tyrosine kinase
      inhibitor herbimycin A or the MEK inhibitor PD 98059, but not with the protein
      kinase C (PKC) inhibitor chelerythrine. VEGF treatment also caused a marked
      increase in p42/p44 mitogen-activated protein kinase (MAPK) activity, but had no
      significant effect on HMC superoxide production. Finally, an increase in collagen
      synthesis was also seen in rat mesangial cells treated with VEGF. CONCLUSIONS:
      These results suggest that VEGF is not a mitogenic signal in HMCs, but may be
      involved in the regulation of the mesangial matrix in humans by a MAPK-dependent
      mechanism.

PMID- 10594782
TI  - Lysophosphatidic acid-induced proliferation in opossum kidney proximal tubular
      cells: role of PI 3-kinase and ERK.
AB  - Lysophosphatidic acid-induced proliferation in opossum kidney proximal tubular
      cells: Role of PI 3-kinase and ERK. BACKGROUND: Lysophosphatidic acid (LPA) is a
      mitogenic lipid bound to albumin in the circulation and implicated in the
      induction of proximal tubular cell (PTC) injury in proteinuric states. In this
      study, we investigated the effect of LPA on proliferation of opossum kidney (OK)
      cells and the roles of the p85/p110 phosphatidylinositol 3-kinase (PI 3-kinase)
      and extracellular signal-regulated kinases (ERKs) ERK-1 and ERK-2 in LPA-induced
      proliferation. METHODS: [3H]-thymidine incorporation was used as an index of OK
      cell proliferation. PI 3-kinase and ERK activities were measured by in vitro
      kinase assays of immunoprecipitates from both wild-type OK cells and OK cells
      expressing a dominant negative p85 (Deltap85) subunit of PI 3-kinase in an
      inducible vector. RESULTS: LPA stimulated a marked increase in [3H]-thymidine
      uptake in wild-type and Deltap85 OK cells. OK cell PI 3-kinase activity was
      stimulated by LPA and was inhibited by expression of Deltap85. LPA-induced
      proliferation was inhibited by wortmannin and the induction of Deltap85
      expression. These data suggest that LPA stimulates PI 3-kinase activity, which is
      essential for signaling the induction of proliferation. LPA also stimulated ERK
      activity (peak at 5 min, return to baseline by 60 min) maximally at a dose of 100
      microM LPA. This increase was approximately 600% above basal and was similar to
      the effects of 10% fetal calf serum. The proliferative effect of LPA was
      decreased by the ERK-kinase (MEK) inhibitor PD98059 (5 microM), therefore
      suggesting that ERK as well as PI 3-kinase activation is important for
      proliferation. ERK activation by LPA was not affected by pretreatment with
      wortmannin or by the expression of Deltap85. PI 3-kinase activation by LPA was
      not affected by pretreatment with PD98059. CONCLUSIONS: We conclude that
      activation of PI 3-kinase is essential for the LPA-induced proliferation of OK
      cells and that ERK activation is also important. Therefore, they are both vital
      elements in separate signaling pathways leading to cell proliferation. LPA
      filtered into the proximal tubule in proteinuric states is likely to have
      profound effects on PTC growth.

PMID- 10594783
TI  - Serum-free insulin-like growth factor I correlates with clearance in patients
      with chronic renal failure.
AB  - Serum-free insulin-like growth factor I correlates with clearance in patients
      with chronic renal failure. BACKGROUND: Chronic renal failure (CRF) results in
      major changes in the circulating growth hormone (GH)/insulin-like growth factor
      (IGF) system. However, there are only limited data on changes in free IGF-I in
      CRF. METHODS: Matched groups of nondiabetic, nondialyzed patients with CRF (N =
      25) and healthy controls (N = 13) were compared. The creatinine clearance (CCr)
      based on a 24-hour urine collection ranged from 3 to 59 and 89 to 148 ml/min/1.73
      m2 in patients and controls, respectively. Overnight fasting serum samples were
      analyzed for free and total IGF-I and -II, and IGF-binding protein (IGFBP)-1, -2,
      and -3. Additionally, intact as well as proteolyzed IGFBP-3 was determined.
      RESULTS: The patients had reduced serum-free IGF-I (-53%) and increased levels of
      total IGF-II (40%), IGFBP-1 (546%), and IGFBP-2 (270%, P < 0.05). Serum total IGF
      I and free IGF-II were normal. Also, serum levels of immunoreactive IGFBP-3 were
      elevated (33%, P < 0.05), but this could be explained by an increased abundance
      of IGFBP-3 fragments, as ligand blotting showed no difference in levels of intact
      IGFBP-3. Accordingly, patients had an increased proteolysis of IGFBP-3 in vivo
      (17%) and in vitro (7%, P < 0.05). In patients, free IGF-I levels correlated
      positively with CCr (r2 = 0.38, P < 0.002) and inversely with IGFBP-1 (r2 = 0.69,
      P < 0. 0001) and IGFBP-2 (r2 = 0.41, P < 0.0007), whereas CCr was inversely
      correlated with levels of IGFBP-1 (r2 = 0.48, P < 0.0001) and IGFBP-2 (r2 = 0.63,
      P < 0.0001). CONCLUSIONS: These data strongly support the hypothesis that CRF
      related growth failure and tissue catabolism are caused by an increased
      concentration of circulating IGFBP-1 and -2, resulting in low serum levels of
      free IGF-I and thus IGF-I bioactivity. In addition, low levels of free IGF-I may
      explain the increased secretion of GH in CRF.

PMID- 10594784
TI  - Roles of E2F1 in mesangial cell proliferation in vitro.
AB  - Roles of E2F1 in mesangial cell proliferation in vitro. BACKGROUND: The
      proliferation of mesangial cells is a common feature of many glomerular diseases.
      E2F transcription factors play an important role in the regulation of the cell
      cycle. However, the regulation of the mesangial cell cycle and the participation
      of the E2F family (E2F1 through E2F5) in mesangial cells have not been clarified.
      Therefore, we investigated the roles of the E2F family in the mesangial cell
      cycle. METHODS: To elucidate the importance of the E2F family, we investigated
      the mesangial cell cycle by examining the cell count and thymidine incorporation,
      and compared it with the protein expression of E2F. Using adenovirus-mediated
      gene transfer, the cell cycle and apoptosis were examined by measurement of
      thymidine incorporation, flow cytometry, and caspase 3 activity. We also studied
      the interaction between E2F1 and G1 cyclins by promoter assay, Western blotting,
      and CDK kinase assay. RESULTS: E2F1 increased 20-fold in G1/S phase transition.
      E2F1 overexpression facilitated the mesangial cell cycle and later induced
      apoptosis. Furthermore, E2F1 overexpression increased the promoter activities and
      protein expressions of G1 cyclins, cyclin D1, cyclin E, cyclin A. The up
      regulation of G1 cyclins contributed to the activation of CDK4 and CDK2.
      CONCLUSIONS: In mesangial cells, we conclude that E2F1 plays an important role in
      G1/S phase transition and in apoptosis. E2F1 regulates the mesangial cell cycle
      through two distinct pathways. First, E2F1 directly transcribes genes that are
      necessary for DNA synthesis, and second, it promotes cell cycle progression via
      the induction of G1 cyclins.

PMID- 10594785
TI  - Crry, a complement regulatory protein, modulates renal interstitial disease
      induced by proteinuria.
AB  - Crry, a complement regulatory protein, modulates renal interstitial disease
      induced by proteinuria. BACKGROUND: Recent studies have suggested a role for
      urinary complement components in mediating tubulointerstitial damage, which is
      known to have a good correlation with progression of chronic renal diseases.
      Although accumulating evidence suggests that complement regulatory proteins play
      an important protective role in glomeruli, their role in renal tubules remains
      unclear. In order to establish the role of a complement regulatory protein, Crry,
      in renal tubular injury, we employed a molecular biological approach to block the
      expression of Crry in tubules of animals with proteinuria induced with puromycin
      aminonucleoside nephritis (PAN). Methods and Results. Two different antisense
      oligodeoxynucleotides (ODNs) against Crry were designed and applied to cultured
      rat mesangial cells in vitro in order to establish their efficacy. Antisense ODN
      treatment resulted in decreased expression of Crry protein associated with
      increased sensitivity to complement attack in cell lysis assays compared with
      control ODN treatment or no treatment (44.7, 1.50, and 1.34%, respectively).
      Antisense ODNs did not affect the expression of Thy1 as a control, confirming the
      specificity of our ODNs. In vivo, we performed selective right renal artery
      perfusion to administer antisense ODNs to the kidney and showed prominent uptake
      of ODNs by proximal tubular cells. Reduced expression of Crry protein was
      demonstrated in proximal tubular cells in antisense ODNs-treated kidneys. Normal
      rats treated with the antisense ODNs did not show any pathological changes.
      However, in PAN, rats with massive proteinuria showed increased deposition of C3
      and C5b-9 in tubules in antisense-treated kidneys, and histological assessment
      revealed more severe tubulointerstitial injury in antisense-treated animals
      compared with controls. CONCLUSION: These results establish a pathogenic role for
      complement in leading to tubulointerstitial injury during proteinuria and, to our
      knowledge for the first time, show a protective role of a complement regulatory
      protein, Crry, in renal interstitial disease.

PMID- 10594786
TI  - The chemokine receptor antagonist AOP-RANTES reduces monocyte infiltration in
      experimental glomerulonephritis.
AB  - The chemokine receptor antagonist AOP-RANTES reduces monocyte infiltration in
      experimental glomerulonephritis. BACKGROUND: This study was designed to evaluate
      the role of the novel chemokine receptor antagonist amino-oxypentane RANTES (AOP
      RANTES), which blocks the binding of macrophage inflammatory protein-1alpha (MIP
      1alpha), MIP-1beta, and RANTES to the chemokine receptor-5 (CCR-5) on the
      infiltration of monocytes in experimental glomerulonephritis. METHODS: Rats were
      treated twice daily with 12.5 microg AOP-RANTES following an induction of anti
      rat-thymocyte antibody-mediated glomerulonephritis. The white blood cell count,
      glomerular monocyte infiltration, chemokine expression, and collagen type IV
      deposition were assessed. RESULTS: The induction of glomerulonephritis increased
      glomerular monocyte/macrophage (M/M) infiltration at 24 hours and at 5 days was
      still higher than in controls. AOP-RANTES prevented glomerular M/M infiltration
      at 24 hours and at 5 days. This was paralleled by reduced glomerular collagen
      type IV deposition as a fibrotic marker in nephritic animals. CONCLUSION: These
      data show that the CCR-5 chemokine receptor antagonist AOP-RANTES ameliorates M/M
      infiltration and improves glomerular pathology in experimental
      glomerulonephritis. The use of chemokine receptor antagonists may offer a new
      therapeutic option in inflammatory renal injuries.

PMID- 10594787
TI  - Interferon-gamma inhibits experimental renal fibrosis.
AB  - Interferon-gamma inhibits experimental renal fibrosis. BACKGROUND: Recent
      evidence has implicated myofibroblasts as a cell type responsible for the laying
      down of extracellular matrix components during fibrosis in a number of organs. In
      this study, we examined the capacity of interferon-gamma (IFN-gamma) to inhibit
      the activation of fibroblasts to the myofibroblastic phenotype and hence reduce
      the extent of renal scarring in the rat subtotal nephrectomy (SNx) model using a
      novel method of intrarenal delivery. METHODS: Rats were divided into four groups:
      sham, SNx (group 1), SNx + drug vehicle (group 2) and SNx + IFN-gamma (400
      units/day; group 3) for 30 days. Rats were sacrificed on days 15, 30, 45, and 90
      following SNx. RESULTS: Clinical data showed a marked reduction in proteinuria in
      the group treated with IFN-gamma (161 vs. 280 mg/24 hr by day 45, P < 0.01) and a
      preservation of the creatinine clearance (1.16 vs. 0. 84 ml/min by day 45, P <
      0.05) when compared to the SNx or SNx + vehicle groups throughout the time
      course. Immunohistochemical staining for alpha-smooth muscle actin (alpha-SMA)
      revealed a reduction in myofibroblastic cell types (6.5 +/- 3.1% glomerular alpha
      SMA in group 3 compared with 14.8 +/- 4.2% glomerular alpha-SMA in group 2, P <
      0.05, 3.8 +/- 1.4% tubulointerstitial alpha-SMA in group 3 compared with 8.8 +/-
      2.0% tubulointerstitial alpha-SMA in group 2 on day 45, P < 0.05). There was also
      a reduction in immunostaining for collagens III and IV in the IFN-gamma-treated
      group. Scoring for both glomerulosclerosis and tubulointerstitial fibrosis in the
      IFN-gamma group (group 3) was lower than the other two operated groups.
      CONCLUSIONS: We conclude that IFN-gamma, administered at a dose of 400 units/day,
      has a strong inhibitory effect on myofibroblasts and that as a possible result of
      this action, renal fibrosis is reduced and renal function is preserved in the rat
      SNx model. The IFN-gamma renoprotective effect lasted only for the extent of its
      administration and subsided when discontinued.

PMID- 10594788
TI  - Role of organic anion transporter 1 (OAT1) in cephaloridine (CER)-induced
      nephrotoxicity.
AB  - Role of organic anion transporter 1 (OAT1) in cephaloridine (CER)-induced
      nephrotoxicity. BACKGROUND: Cephaloridine (CER) has been used to elucidate the
      mechanisms of cephalosporin antibiotic-induced nephrotoxicity. Organic anion
      transporters have been thought to mediate CER uptake by the proximal tubule. The
      purpose of this study was to elucidate the possible involvement of organic anion
      transporter 1 (OAT1) in CER-induced nephrotoxicity. METHODS: A mouse terminal
      proximal straight tubule (S3) cell line stably expressing rat OAT1 (S3 rOAT1) was
      established and used in this study. The cellular uptake of [14C]-para
      aminohippuric acid (PAH), a prototype organic anion, and that of [14C]-CER were
      measured. The effects of CER on the viability of the cells and the amount of
      lipid peroxidation were estimated. RESULTS: S3 rOAT1 expressed a functional
      organic anion transporter in the cytoplasmic membrane, and exhibited CER uptake
      activity. CER treatment resulted in a more significant decrease in the viability
      and a more significant increase in the amount of lipid peroxidation in S3 rOAT1
      than in S3 cells transfected with an expression vector lacking the rOAT1 insert.
      Probenecid, an inhibitor of organic anion transport, and probucol, an
      antioxidant, significantly suppressed the decrease in viability and increase in
      the amount of lipid peroxidation in S3 rOAT1 treated with CER. The effects of
      various cephalosporin antibiotics on the uptake of [14C]PAH were correlated
      significantly with the effects of these drugs on cell viability. CONCLUSIONS:
      These results suggest that rOAT1 is, at least in part, responsible for the
      cellular uptake of CER and therefore CER-induced nephrotoxicity.

PMID- 10594789
TI  - Increased expression of TGF-beta1 but not of its receptors contributes to human
      obstructive nephropathy.
AB  - Increased expression of TGF-beta1 but not of its receptors contributes to human
      obstructive nephropathy. BACKGROUND: Previous studies have revealed an increased
      expression of transforming growth factor-beta1 (TGF-beta1) and deposition of
      extracellular matrix in the kidney of animals with ureteral obstruction. However,
      these relationships have not been elucidated in the hydronephrotic kidney of
      humans. METHODS: We analyzed the tissue expression of extracellular matrix
      proteins, TGF-beta1, and its receptors in the human kidney with ureteral
      obstruction by immunohistochemistry and reverse transcription-polymerase chain
      reaction (RT-PCR). Obstructed kidneys (OBKs) were obtained from patients with
      ureteral tumors. A kidney specimen from patients with a renal tumor was used as
      control (CNKs). RESULTS: The interstitial volume was significantly increased in
      OBKs in comparison with CNKs. OBKs showed increased deposition of collagen types
      I and IV and fibronectin in the renal interstitium. RT-PCR revealed
      overexpression of collagen alpha1(IV) mRNA and fibronectin mRNA in OBKs. OBKs
      showed a significantly increased mRNA expression of TGF-beta1 in comparison with
      CNKs. The immunoreactivity for TGF-beta1 increased markedly in the interstitium
      of OBKs. There was a significant correlation between the TGF-beta1 mRNA level and
      the interstitial volume. However, there was no significant difference between
      OBKs and CNKs in the relative mRNA level nor in immunoreactivity for TGF-beta
      receptors. CONCLUSIONS: These data suggest that TGF-beta1 may contribute to the
      interstitial fibrosis found in the human kidney with ureteral obstruction, mainly
      because of an increase in the expression of this cytokine without significant
      changes to its receptors.

PMID- 10594790
TI  - Expression of apoptosis regulatory genes in chronic cyclosporine nephrotoxicity
      favors apoptosis.
AB  - Expression of apoptosis regulatory genes in chronic cyclosporine nephrotoxicity
      favors apoptosis. BACKGROUND: Chronic cyclosporine (CsA) nephrotoxicity is
      characterized by interstitial fibrosis, tubular dropout, and loss of cellularity
      in areas of fibrosis. Apoptosis was found to play a role in CsA-induced fibrosis.
      We evaluated the role of the death genes p53, Bax, and Fas-L (ligand), survival
      gene Bcl-2, interleukin-converting enzyme (ICE), and caspase-3. METHODS: Salt
      depleted rats were administered CsA 15 mg/kg/day or vehicle (VH) and were
      sacrificed at 7 or 28 days. Apoptosis was detected by TdT-mediated dUTP-biotin
      nick end labeling assay. p53 and Bax expressions were evaluated by Northern and
      Western blot analysis. Fas-L and Bcl-2 expressions were evaluated by
      immunofluorescence. In addition to ICE mRNA, caspase-3 enzymatic activity was
      assayed. RESULTS: Although no differences were seen at one week, apoptosis
      positive cells increased with CsA at four weeks (P < 0.05) and correlated with
      tubular atrophy and interstitial fibrosis (r = 0.8, P < 0.05). CsA induced the
      expression of p53 (P < 0.05) and Bax (P < 0.01) and decreased that of Bcl-2 (P <
      0.05). CsA up-regulated Fas-L expression (P < 0.001). ICE mRNA and caspase-3
      activity were also increased (P < 0.01). The changes occurred as early as one
      week and remained statistically significant at four weeks. CONCLUSIONS: Specific
      apoptotic genes are increased in chronic CsA nephrotoxicity. The balance favors
      the induction of apoptosis. Increased apoptosis could explain the tubular dropout
      and loss of cellularity with fibrosis. This then may impair the ability of the
      tubulointerstitium to remodel. Apoptosis could also contribute to some of CsA
      immunosuppressive effects on activated lymphocytes.

PMID- 10594791
TI  - NH4+ secretion in inner medullary collecting duct in potassium deprivation: role
      of colonic H+-K+-ATPase.
AB  - NH4+ secretion in inner medullary collecting duct in potassium deprivation: Role
      of colonic H+-K+-ATPase. BACKGROUND: In K+ deprivation (KD), gastric (g) H+-K+
      ATPase (HKA) is suppressed, whereas colonic (c) HKA is induced in the terminal
      inner medullary collecting duct (IMCD). We hypothesized that in KD, cHKA is
      induced and can mediate the secretion of NH4+. METHODS: Rats were sacrificed
      after 2, 3, 6, or 14 days on regular (NML) or K+-free (KD) diet. mRNA expression
      of HKA isoforms in terminal inner medulla was examined and correlated with NH4+
      secretion in perfused IMCD in vitro. RESULTS: Urinary NH4+ excretion increased
      after K+-free diet for six days. In terminal inner medulla, cHKA expression was
      strongly induced, whereas gHKA expression was decreased. NH4+ secretion increased
      by 62% in KD (JtNH4+ 0.57 vs. 0.92 pmol/min/mm tubule length, P < 0.001). Ouabain
      (1 mM) in perfusate inhibited NH4+ secretion in KD by 45% (P < 0.002) but not in
      NML. At luminal pH 7.7, which inhibits NH3 diffusion, NH4+ secretion in IMCD was
      140% higher in KD (0.36 vs. 0.15, P < 0.03) and was sensitive to ouabain. ROMK-1
      mRNA expression was induced in parallel with cHKA in inner medulla. CONCLUSIONS:
      These data suggest that in KD, cHKA replaces gHKA and mediates enhanced secretion
      of NH4+ (and H+) into the lumen facilitated by K+ recycling through ROMK-1.

PMID- 10594792
TI  - Phenylalanine hydroxylation across the kidney in humans rapid communication.
AB  - Phenylalanine hydroxylation across the kidney in humans. BACKGROUND: Although
      phenylalanine hydroxylase activity is detectable in in vitro renal tissue
      preparations, no data on in vivo phenylalanine hydroxylation across the human
      kidney, as well as on its possible contribution to whole-body hydroxylation,
      currently exist. METHODS: To this aim, we have measured whole-body, renal, and
      splanchnic phenylalanine hydroxylation to tyrosine, as well as phenylalanine and
      tyrosine rates of appearance (Ra) and disposal (Rd), in postabsorptive subjects
      by means of renal and splanchnic arteriovenous catheterization combined with
      phenylalanine and tyrosine isotope infusions. RESULTS: In the kidney, a relevant
      phenylalanine hydroxylation activity was detected (3.51 +/- 0.97 micromol/min x
      1.73 m2 of body surface), whereas it was 2.48 +/- 1. 35 micromol/min x 1.73 m2
      across the splanchnic area. These two sites together accounted for virtually the
      entire whole-body phenylalanine hydroxylation. Renal production of tyrosine from
      phenylalanine hydroxylation accounted for approximately 13% of whole-body
      tyrosine Ra, whereas renal total tyrosine Ra accounted for approximately 34% of
      whole-body tyrosine Ra. In the splanchnic area, these figures were approximately
      9 and 40%, respectively. Hydroxylation accounted for approximately 70% of
      phenylalanine Rd in the kidney, as opposed to approximately 8% in the splanchnic
      area. CONCLUSIONS: These data indicate that hydroxylation represents the major
      route of phenylalanine disposal within the kidney. The kidney and the splanchnic
      bed together account for all of the whole-body phenylalanine hydroxylation. These
      data also provide a further explanation for the reduced tyrosine pools occurring
      in uremia.

PMID- 10594793
TI  - Angiotensin II type 1 receptor gene polymorphism predicts response to losartan
      and angiotensin II.
AB  - Angiotensin II type 1 receptor gene polymorphism predicts response to losartan
      and angiotensin II. BACKGROUND: Most of the known actions of angiotensin II (Ang
      II) are mediated by the Ang II type 1 receptor (AGT1R). A noncoding polymorphism
      of the AGT1R gene has been described in which there is either an adenine (A) or
      cytosine (C) base at position 1166. The functional significance of this
      polymorphism is unknown, prompting us to examine the relationship between this
      polymorphism and the systemic and renal responses to AGT1R blockade and
      subpressor Ang II infusion. METHODS: Sixty-six healthy Caucasian men and women,
      genotyped for the AGT1R polymorphism by polymerase chain reaction, were chosen to
      form two homogeneous groups: AA and AC/CC. Renal hemodynamic function was
      assessed with inulin and para-aminohippurate clearance before and after AGT1R
      receptor blockade with losartan and Ang II infusion. RESULTS: The mean values at
      baseline for glomerular filtration rate (GFR), renal plasma flow (ERPF), and
      renal blood flow (RBF) were significantly lower in the AC/CC group compared with
      the AA group. Losartan increased the GFR and decreased the mean arterial pressure
      (MAP) in the AC/CC group, but did not influence these parameters in the AA group.
      The aldosterone responses to losartan were blunted in the AA subgroup. During Ang
      II infusion, AC/CC subjects maintained GFR despite equivalent declines in RBF,
      suggesting an enhanced efferent arteriolar constrictive response. CONCLUSIONS:
      Taken together, these results suggest that there is a relationship between the
      AGT1R A1166-->C polymorphism and the humoral and renal hemodynamic responses to
      AGT1R blockade and to Ang II infusion in the sodium-replete state, and that the C
      allele is associated with enhanced intrarenal and peripheral Ang II activity.
      Further studies are required to determine the genetic locus for this effect.

PMID- 10594794
TI  - Hypertension and renal injury in experimental polycystic kidney disease.
AB  - Hypertension and renal injury in experimental polycystic kidney disease.
      BACKGROUND: Hypertension accelerates renal failure in autosomal dominant
      polycystic kidney disease (ADPKD), and evidence suggests a role for the renin
      angiotensin system (RAS) in the functional and structural changes. To explore the
      hypothesis that RAS adaptations contribute to disease progression, we examined
      RAS activity and the long-term consequences of antihypertensive drugs, which
      suppress (enalapril) or stimulate (hydralazine) the RAS, in experimental
      polycystic kidney disease. METHODS: Studies were conducted in male heterozygous
      cystic Han:SPRD rats (Cy/+) and in unaffected littermates (controls). In protocol
      1, either angiotensin II (Ang II), enalaprilat, or saline vehicle was acutely
      infused into cystic and control rats, which were aged 10 to 12 weeks. The mean
      arterial pressure (MAP), glomerular filtration rate (GFR), and renal plasma flow
      (RPF) were measured at baseline and after an infusion of test substances. In
      protocol 2, cystic rats received chronic therapy with either enalapril,
      hydralazine, or no therapy for 10 to 12 weeks of age and then underwent renal
      function and RAS studies. In protocol 3, similar cohorts were followed for 40
      weeks to assess the effects of therapy on blood pressure, proteinuria, serum
      creatinine, RAS parameters, and renal morphology. RESULTS: In protocol 1, cystic
      rats had massive kidneys, slightly elevated blood pressure, and profound renal
      vasoconstriction and reduced GFR. Ang II induced similar changes in MAP and renal
      function in control and cystic rats. Enalaprilat induced little effect on MAP but
      more striking increases in GFR and RPF in cystic rats. In protocol 2, at 10 weeks
      of age, enalapril was superior in preserving renal function, but neither drug
      limited the expansion of the tubulointerstitium. In protocol 3, at 40 weeks of
      age, both drugs ameliorated the increase in serum creatinine, although only
      enalapril reduced proteinuria and kidney size. CONCLUSIONS: In polycystic rats,
      acute RAS suppression markedly ameliorates renal dysfunction. However, although
      chronic enalapril and hydralazine protect against the loss of renal function,
      only enalapril limits renal growth and proteinuria, and neither significantly
      limits tubulointerstitial fibrosis. The long-term studies give clear support to
      the importance of blood pressure control, per se, but only partial support to the
      importance of the particular agent used. As in clinical studies, angiotensin
      converting enzyme inhibition may be less beneficial in ADPKD than in renal
      diseases characterized by predominant glomerular injury.

PMID- 10594795
TI  - Increased nitric oxide synthase mRNA expression in the renal medulla of water
      deprived rats.
AB  - Increased nitric oxide synthase mRNA expression in the renal medulla of water
      deprived rats. BACKGROUND: Experiments were performed to investigate whether
      renal nitric oxide synthase (NOS) mRNA and protein expression are responsive to
      the alteration of body volume. METHODS: Four days of water deprivation (WD) was
      initiated in 16 male Wistar rats, and 16 normal rats (NC) served as the control
      group. Neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS)
      mRNAs and immunoreactivity were measured by reverse transcription-polymerase
      chain reaction (RT-PCR) followed by Southern blot hybridization and
      immunohistochemistry, respectively. Plasma angiotensin II, vasopressin, and
      atrial natriuretic peptide (ANP) concentrations were measured by
      radioimmunoassay. RESULTS: The four-day WD increased plasma sodium and osmolality
      levels, but severely decreased daily urine sodium excretion and urine volume.
      Plasma angiotensin II and vasopressin concentrations were increased, but the
      plasma ANP level was significantly decreased in WD rats. nNOS, eNOS, and iNOS
      mRNA levels were increased by 5.2-, 3.3-, and 3. 4-fold in the outer medulla and
      1.7-, 1.5-, and 1.8-fold in the inner medulla, whereas no significant difference
      was found in the renal cortex of WD rats as compared with NC rats. Additionally,
      immunohistochemistry revealed that the immunostaining intensity of nNOS, eNOS,
      and iNOS was clearly enhanced in the medullary thick ascending limb, proximal
      straight tubule, inner medullary collecting duct, and proximal convoluted tubule
      in WD rats. Kidney angiotensin II content as well as renin mRNA levels in renal
      cortex, outer medulla, and inner medulla in WD rats were apparently increased.
      CONCLUSIONS: Our results indicate that the increases of nNOS, eNOS, and iNOS
      synthesis in the kidney, particularly in the renal medulla, may have a role in
      the adaptation of renal function to volume depletion in the face of an increase
      of systemic and intrarenal vasoconstrictive substances.

PMID- 10594796
TI  - Collapsing glomerulopathy in HIV and non-HIV patients: a clinicopathological and
      follow-up study.
AB  - Collapsing glomerulopathy in HIV and non-HIV patients: A clinicopathological and
      follow-up study. BACKGROUND: Collapsing glomerulopathy (CG) is a pattern of renal
      injury that is seen in association with HIV infection and that is increasingly
      recognized in non-HIV patients. METHODS: A review of native kidney biopsies with
      CG that were diagnosed between 1979 and 1997 in 18 HIV and 42 non-HIV patients is
      provided. RESULTS: HIV and non-HIV patients with CG were similar in terms of age,
      sex ratio, serum creatinine, proteinuria, the extent of collapsing and sclerosing
      glomerular lesions, and interstitial damage. A slight female predominance was
      found in both groups. In contrast to non-HIV patients, the HIV group was
      characterized by a high prevalence of blacks (94 vs. 57%), frequent
      tubuloreticular inclusions (76 vs. 29%), and microcystic tubular changes (72 vs.
      40%). In 13 non-HIV patients, CG was associated with a systemic lupus
      erythematosus (SLE)-like disease (5), hepatitis C virus (HCV) infection (3), HTLV
      I infection, MCTD, acute monoblastic leukemia, multiple myeloma, and cerebral
      arteritis. Overall, the renal survival of human immunodeficiency virus (HIV) and
      non-HIV patients with CG was not significantly different. Cox regression revealed
      that HIV infection had an adverse effect on short-term renal survival, with other
      significant risk factors being extensive interstitial fibrosis, high serum
      creatinine, proteinuria, and a low percentage of glomeruli with collapse. The
      slope of reciprocal creatinine was best predicted by the degree of proteinuria.
      Serum creatinine correlated with the extent of interstitial fibrosis, the male
      gender, and the percentage of glomeruli with collapse. Proteinuria was best
      predicted by the extent of effacement of podocyte foot processes. CONCLUSIONS: CG
      shares many clinicopathological similarities in HIV and non-HIV patients. In some
      non-HIV patients, CG was associated with autoimmune diseases, lymphoproliferative
      disorders, and viral infections.

PMID- 10594797
TI  - Cardiovascular disease and mortality in a community-based cohort with mild renal
      insufficiency.
AB  - Cardiovascular disease and mortality in a community-based cohort with mild renal
      insufficiency. BACKGROUND: Little is known about the prevalence of cardiovascular
      disease (CVD) and associated risk factors in individuals with mild renal
      insufficiency (RI). Furthermore, the long-term outcomes associated with mild RI
      in the community have not been described. METHODS: Serum creatinine (SCr) was
      measured in 6233 adult participants of the Framingham Heart Study (mean age 54
      years, 54% women). Mild RI was defined as SCr 136 to 265 micromol/liter (1.5 to
      3.0 mg/dl) in men and 120 to 265 micromol/liter (1.4 to 3.0 mg/dl) in women. The
      lower limits for mild RI were defined by the sex-specific 95th percentile SCr
      values in a healthy subgroup of our sample. The upper limit for mild RI was
      chosen to exclude those subjects with more advanced renal failure. Cox
      proportional hazards analyses were used to determine the relationship of baseline
      RI to CVD and all-cause mortality. RESULTS: At baseline, 8.7% of men (N = 246)
      and 8.0% of women (N = 270) had mild RI. Nineteen percent of the subjects with
      mild RI had prevalent CVD. During 15 years of follow-up, there were 1000 CVD
      events and 1406 deaths. In women, mild RI was not associated with increased risk
      for CVD events [hazards ratio (HR) 1.04, 95% CI, 0.79 to 1.37] or all-cause
      mortality (HR 1.08, 95% CI, 0.87 to 1.34). In men, mild RI showed no significant
      associations with CVD events (HR 1.17, 95% CI, 0.88 to 1.57), but it was
      associated with all-cause mortality in age-adjusted (HR 1.42, 95% CI, 1.12 to
      1.79) and multivariable adjusted (HR 1.31, 95% CI, 1.02 to 1.67) analyses.
      CONCLUSION: Mild RI in the community is common and is associated with a high
      prevalence of CVD. The association of RI with risk for adverse outcomes is
      strongly related to coexisting CVD and CVD risk factors.

PMID- 10594798
TI  - A randomized trial of cyclosporine in patients with steroid-resistant focal
      segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group.
AB  - A randomized trial of cyclosporine in patients with steroid-resistant focal
      segmental glomerulosclerosis. BACKGROUND: A clinical trial of cyclosporine in
      patients with steroid-resistant focal segmental glomerulosclerosis (FSGS) was
      conducted. Despite the fact that it is the most common primary glomerulonephritis
      to progress to renal failure, treatment trials have been very limited. METHODS:
      We conducted a randomized controlled trial in 49 cases of steroid-resistant FSGS
      comparing 26 weeks of cyclosporine treatment plus low-dose prednisone to placebo
      plus prednisone. All patients were followed for an average of 200 weeks, and the
      short- and long-term effects on renal function were assessed. RESULTS: Seventy
      percent of the treatment group versus 4% of the placebo group (P < 0. 001) had a
      partial or complete remission of their proteinuria by 26 weeks. Relapse occurred
      in 40% of the remitters by 52 weeks and 60% by week 78, but the remainder stayed
      in remission to the end of the observation period. Renal function was better
      preserved in the cyclosporine group. There was a decrease of 50% in baseline
      creatinine clearance in 25% of the treated group compared with 52% of controls (P
      < 0.05). This was a reduction in risk of 70% (95% CI, 9 to 93) independent of
      other baseline demographic and laboratory variables. CONCLUSIONS: These results
      suggest that cyclosporine is an effective therapeutic agent in the treatment of
      steroid-resistant cases of FSGS. Although a high relapse rate does occur, a long
      term decrease in proteinuria and preservation of filtration function were
      observed in a significant proportion of treated patients.

PMID- 10594799
TI  - Level of renal function at the initiation of dialysis in the U.S. end-stage renal
      disease population.
AB  - Level of renal function at the initiation of dialysis in the U.S. end-stage renal
      disease population. BACKGROUND: More than 285,000 individuals in the United
      States suffer from end-stage renal disease (ESRD) and are treated predominantly
      by dialysis. Despite the high cost and poor outcomes of dialysis treatment for
      ESRD, there are few data about the level of renal function at the onset of ESRD
      and no established medical criteria for the initiation of dialysis. METHODS: We
      report the level of serum creatinine and glomerular filtration rate (GFR) in
      90,897 patients who began dialysis in the U. S. between April 1995 through
      September 1997. Data were obtained from the U.S. Renal Data System. GFR was
      predicted by an equation developed from the Modification of Diet in Renal Disease
      Study. RESULTS: The mean (SD) serum creatinine was 8.5 (3.8) mg/dl. The mean (SD)
      predicted GFR was 7.1 (3.1) ml/min/1.73 m2, with a range from 1 to 42 ml/min/1.73
      m2. The proportion of patients with predicted GFR of > 10, 5 to 10, and <5
      ml/min/1.73 m2 was 14, 63, and 23%, respectively. The mean predicted GFR was
      significantly lower among younger patients, women, African Americans, patients
      with a higher body weight, patients with ESRD because of diseases other than
      diabetes, uninsured patients, patients who were employed, homemakers or students,
      and patients selecting hemodialysis. CONCLUSIONS: There is wide variation in
      renal function at the initiation of dialysis in the U.S. ESRD population, and a
      substantial fraction of patients start dialysis at very low levels of predicted
      GFR. Further analyses are needed to examine the factors associated with late
      initiation of dialysis and its impact on the cost and outcomes of ESRD.

PMID- 10594800
TI  - Predicting renal survival in primary focal glomerulosclerosis from the time of
      presentation.
AB  - Predicting renal survival in primary focal glomerulosclerosis from the time of
      presentation. BACKGROUND: To predict the risk of developing chronic renal failure
      in patients with primary focal glomerulosclerosis (FGS) using predictors
      available at the time of presentation, a retrospective analysis was performed on
      111 patients who were diagnosed at Christchurch Hospital from 1965 to 1998.
      METHODS: The predictors of outcome included age, gender, systolic and diastolic
      blood pressure, serum albumin, plasma creatinine, presence of hematuria, and
      amount of proteinuria (all at the time of presentation). An injury score
      (combination of percentage of sclerosed glomeruli and proportion of
      tubulointerstitial fibrosis) was derived from a review of the initial kidney
      biopsy. Log-logistic accelerated failure time parametric models were used.
      RESULTS: The median renal survival was 16.4 years (Kaplan-Meier estimate). The
      best single variable model was that using the proportion of tubulointerstitial
      fibrosis (global chi-square 55.99, P < 0.0001). However, inclusion of plasma
      creatinine significantly improved the fit of the model (global chi-square 65.04,
      P < 0.0001). This joint model was superior to the single-variable model. Both of
      the models were validated using jackknifing. CONCLUSION: For a patient with
      primary FGS, these models can be used to predict the risk of developing chronic
      renal failure at any time and the median renal survival, given the proportion of
      tubulointerstitial fibrosis and plasma creatinine at the time of presentation.

PMID- 10594801
TI  - Prescription of hormone replacement therapy in postmenopausal women with renal
      failure.
AB  - Prescription of hormone replacement therapy in postmenopausal women with renal
      failure. BACKGROUND: Although patients with end-stage renal disease (ESRD) are at
      increased risk for early menopause, osteoporosis, cognitive dysfunction, and
      cardiovascular disease, few postmenopausal women are prescribed hormone
      replacement therapy (HRT). The reasons for the low prescription rate are not
      known. This study uses data from the United States Renal Data System (USRDS) to
      assess the prevalence and predictors of HRT use in postmenopausal women with
      ESRD. METHODS: Data were obtained from the USRDS Dialysis Morbidity and Mortality
      Study Wave 2. All women who were at least 45 years of age were considered
      postmenopausal and were selected for our analysis. Demographics, behavior and
      medical characteristics were abstracted from the database. Logistic regression
      was used to estimate the independent contribution of population characteristics
      in predicting the use of HRT. Linear regression models were used to estimate the
      relationship between HRT use and both triglycerides and total cholesterol.
      RESULTS: The overall prevalence of HRT prescription was 10.8%. Important
      predictors of HRT use included age (aOR = 0.74, 95% CI 0.13 to 0.88, P < 0.001),
      black ethnicity (aOR = 0.50, 95% CI, 0.31 to 0.78, P < 0.002), college education
      (aOR = 3. 00, 95% CI, 1.70 to 5.24, P < 0.001), and the ability to ambulate (aOR
      = 1.99, 95% CI, 1.01 to 3.91, P = 0.05). Serum triglyceride and total cholesterol
      levels were higher among women treated with HRT than among those not treated with
      HRT (264 +/- 155 vs. 217 +/- 159 mg/dl, P = 0.001 and 220 +/- 62 vs. 209 +/- 55
      mg/dl, P = 0.02, respectively). CONCLUSIONS: HRT is prescribed less frequently in
      postmenopausal ESRD patients than in the general population. Younger age, higher
      education levels, white race, and the ability to ambulate were important
      predictors of HRT use. Targeting populations of patients who are likely to
      benefit from but less likely to be prescribed HRT may increase the prescription
      of HRT.

PMID- 10594802
TI  - Echocardiography overestimates left ventricular mass in hemodialysis patients
      relative to magnetic resonance imaging.
AB  - Echocardiography overestimates left ventricular mass in hemodialysis patients
      relative to magnetic resonance imaging. BACKGROUND: Left ventricular hypertrophy
      (LVH) is a common finding and a strong adverse prognostic factor in patients with
      chronic renal failure. An accurate method of measuring left ventricular mass (LV
      mass) is therefore a prerequisite in the management of these patients. Recent
      evidence has suggested that echocardiography overestimates LV mass in patients
      with essential hypertension, and this error increases with increasing LV mass.
      METHODS: We studied 35 patients on maintenance hemodialysis within 24 hours of
      their last dialysis. LV mass was measured by both echocardiography and magnetic
      resonance imaging (MRI) performed less than three hours apart. Clinic and
      ambulatory blood pressure (ABPM), resting echocardiogram, and blood sampling were
      performed at the same visit. RESULTS: Thirty-two patients had results from both
      methods. Clinic blood pressure, ABPM, and QT dispersion all correlated with LV
      mass, with a stronger correlation observed for MRI values. Intraobserver and
      interobserver variability were significantly greater for echocardiography
      (although similar to other published data). Comparing the two methods, the
      difference in LV mass values (echo minus magnetic resonance) increased in a
      linear fashion with an increasing mean mass and chamber diameter. CONCLUSIONS:
      Echocardiography significantly overestimates LV mass relative to MRI in the
      presence of LVH and dilation. This overestimation is the result of assumptions
      made in the calculation of mass from echocardiography M-mode images, which are
      invalid when LV geometry is abnormal. This error is therefore amplified in
      dialysis patients, the majority of whom have LVH and in whom intravascular volume
      is constantly changing.

PMID- 10594803
TI  - Impact of lower delivered Kt/V on the survival of overweight patients on
      hemodialysis.
AB  - Impact of lower delivered Kt/V on the survival of overweight patients on
      hemodialysis. BACKGROUND: A recent study suggests that overweight (OW) patients
      on hemodialysis are more likely to receive inadequate doses of dialysis. Because
      underdialysis is associated with higher mortality, OW patients might be at risk
      for higher mortality. This is in contrast with our recent observation in which
      survival was better in OW patients on hemodialysis. The objective of this study
      was to verify whether being OW was associated with underdialysis and to determine
      the influence of underdialysis on the survival of OW patients. METHOD: Kt/V
      measurements were obtained in 1151 patients on hemodialysis for two consecutive
      months, and their survival was prospectively followed for nine months. Body
      weights were defined by body mass index (BMI): OW if BMI was> 27.5, underweight
      (UW) if BMI was <20, and normal weight (NW) if BMI was 20 to 27.5. RESULTS: The
      Kt/V was inversely related to BMI (r = -0. 30, P < 0.0001). Kt/V in the OW
      patients was significantly lower than Kt/V in the NW or UW patients. By using a
      Kt/V threshold of 1.2, more patients were underdialyzed in the OW group (24%)
      than in the NW (15%) or UW (7%) groups. Underdialysis in the whole study group
      was associated with a 1.6-fold increase in the relative risk (RR) for mortality.
      The risk was more pronounced (RR, 2.6) in the underdialyzed OW patients compared
      with adequately dialyzed OW patients. In multivariate analysis, underdialysis in
      OW patients (RR, 4.3), but not in UW or NW patients, was a significant and
      independent risk factor for mortality. CONCLUSION: Our results verify that in the
      current practice of dialysis prescription, OW patients are less likely to receive
      adequate dialysis, and, to our knowledge for the first time, suggest that such
      underdialysis in OW patients might exert a negative influence on their survival.
      Prospective studies are required to test whether ensuring adequate delivery of
      dialysis in the OW patients might further improve their survival.

PMID- 10594804
TI  - Rise in serum albumin and creatinine in the first half year on hemodialysis.
AB  - Rise in serum albumin and creatinine in the first half year on hemodialysis.
      BACKGROUND: Serum albumin and creatinine have been reported to rise in new
      hemodialysis patients; however, these trends have not been quantitated in a
      stable cohort, and their determinants and prognostic value are unknown. METHODS:
      This study examined the changes in monthly values of serum albumin and creatinine
      over the first half year of hemodialysis in 115 patients who survived to the
      start of the sixth month. After verifying that the trends were approximately
      linear, we calculated the rates of rise (slope) of six predialysis values of
      serum albumin (months 1 through 6) and of creatinine (months 2 through 7) and
      examined their associations with age, diabetes, race, baseline 24-hour urine
      protein and creatinine excretion, and survival during the latter half of the
      first year. RESULTS: Serum albumin rose by 13% over months 1 through 6 [0.08 +/-
      0.12 (SD) g/dl/month, P < 10-9 vs. zero slope]. Patients who survived the entire
      year had higher mean values for both serum albumin (month 1, P < 0.003; months 3
      through 6, P < 10-3) and rate of rise of albumin (0.09 +/- 0.11 g/dl/month vs.
      0.01 +/- 0.13 g/dl/month, P < 0.005) than patients who died during months 6
      through 12, but the slope was not an independent predictor of survival after
      adjusting for serum albumin concentration. Baseline proteinuria correlated
      inversely with serum albumin measured at the first and second months (P < 0.005)
      and directly with the albumin slope (r = 0.49, P < 10-5). Serum creatinine rose
      by 12% between months 2 through 7 (0.12 +/- 0.47 mg/dl/month, P < 0.02).
      Survivors had a significantly higher mean baseline creatinine excretion (P < 0.
      03) and serum creatinine (month 2, P < 0.03; months 3 through 7, P < 0.01) but
      only a marginally higher rate of rise of serum creatinine (0.16 +/- 0.47
      mg/dl/month vs. -0.07 +/- 0.48 mg/dl/month, P < 0.06) than patients who died
      during the second half of the year. Baseline urinary creatinine excretion
      correlated directly with serum creatinine at month 2 (P < 0.01) and more strongly
      at months 3 through 7 (P < 10-3), as well as correlating with the creatinine
      slope (r = 0.26, P < 0.03). CONCLUSIONS: Serum albumin and creatinine rose by 12
      to 13% during the first half year of hemodialysis in a stable cohort. The slope
      of serum albumin versus time predicted survival, but it was not as predictive as
      the absolute albumin concentration. The pattern of correlations of baseline
      urinary protein and creatinine excretion with the respective monthly serum values
      of albumin and creatinine and their slopes is consistent with the hypothesis that
      as residual renal function declines, progressive retention of protein and
      creatinine contributes to the respective rises in serum albumin and creatinine.

PMID- 10594805
TI  - Twenty-five years of experience with out-center hemodialysis.
AB  - Twenty-five years of experience with out-center hemodialysis. BACKGROUND: Out
      center hemodialysis (HD) offers patients a better quality of life, a greater
      independence, and a better rehabilitation opportunity. A lower mortality than
      with other modalities of dialysis has been reported. In addition, in France the
      charges paid depend on the modality of dialysis, out-center HD being the less
      expensive, and savings are also accomplished through fewer patient transports,
      which are additionally reimbursed. We present a 25-year experience of out-center
      HD. METHODS: We retrospectively studied the clinical records of 471 patients
      treated between 1974 and 1997 in a single nonprofit organization operating
      regional home HD (H-HD) and facilities for self-care HD (SC-HD). Survival results
      were analyzed according to: (a) causes of end-stage renal disease, (b) age at the
      start of HD, (c) period of start of HD, (d) modality of HD (H-HD, SC-HD), and (e)
      a subgroup of 174 patients defined at risk because they were contraindicated for
      transplantation. RESULTS: The mean age at the start of HD increased from 31.2 +/-
      9.7 (mean +/- SD) years in 1974 to 52.6 +/- 13.5 years in 1997. Causes of the end
      of treatment were: (a) transplantation (63%), (b) transfer (20%), and (c) death
      (17%). The overall survival was 90% at 5 years, 77% at 10 years, 62% at 15 years,
      and 45% at 20 years, and, for the group at risk, 78%, 62%, 46%, and 31%,
      respectively. Cox proportional hazard analyses showed that risk factors were
      older age, diabetes, and renal vascular diseases. CONCLUSION: If adequate choice
      is given, out-center HD offers a reliable and safe modality of dialysis with
      better survival results than survival in full-care in-center HD. In addition, out
      center HD ensures a striking financial benefit as compared with the higher costs
      if the same patients were treated with full-care in-center HD. These modalities
      should be encouraged for all HD patients who are able to be treated by out-center
      modalities.

PMID- 10594806
TI  - Plasma and Lp(a)-associated PAF-acetylhydrolase activity in uremic patients
      undergoing different dialysis procedures.
AB  - Plasma and Lp(a)-associated PAF-acetylhydrolase activity in uremic patients
      undergoing different dialysis procedures. BACKGROUND: Platelet-activating factor
      (PAF) is a potent inflammatory mediator associated with several
      physiopathological conditions, including renal diseases. PAF is degraded to the
      inactive metabolite lyso-PAF by PAF-acetylhydrolase (PAF-AH), which is considered
      as a potent anti-inflammatory and anti-atherogenic enzyme associated with
      lipoproteins. In this study, we evaluated the plasma- and lipoprotein(a) [Lp(a)]
      associated PAF-AH activity in relationship to plasma lipid parameters and Lp(a)
      isoform size in patients with mild/moderate chronic renal failure (CRF), as well
      as in hemodialysis (HD) and chronic ambulatory peritoneal dialysis (CAPD)
      patients. METHODS: We studied 74 patients undergoing maintenance HD, 44 patients
      undergoing CAPD, 56 patients with mild/moderate CRF, and 98 healthy subjects
      whose lipid profile, as well as plasma and high-density lipoprotein (HDL)
      associated PAF-AH activity, was determined. Moreover, the effect of Lp(a) plasma
      levels on the distribution of PAF-AH among plasma lipoproteins, as well as the
      specific activity and kinetic properties of PAF-AH on two different Lp(a)
      isoforms, was measured in each studied group. RESULTS: The plasma PAF-AH activity
      in all studied groups was significantly higher than in controls, and the increase
      was more profound in CAPD patients. The HDL-associated PAF-AH activity, expressed
      per milliliter of plasma, was similar among all studied groups; however, when it
      was expressed as either per milligrams of HDL cholesterol or per milligrams of
      plasma apolipoprotein (apo) AI, the PAF-AH activity was significantly higher in
      all patient groups compared with controls. All patient groups had significantly
      elevated plasma Lp(a) levels, which altered the distribution of PAF-AH among the
      plasma lipoproteins compared with that observed in subjects with very low plasma
      Lp(a) levels (<8 mg/dl). Additionally, in each studied group, the specific
      activity as well as the apparent Km and Vmax values of the 19K4 apo(a) isoform
      were significantly higher (P < 0.01) compared with the values of the 23K4
      isoform. However, the specific activity, as well as the Km and Vmax values on
      either the 19K4 apo(a) isoform or the 23K4 isoform, was significantly higher in
      CAPD patients compared with the other three groups. CONCLUSIONS: Plasma PAF-AH
      activity is increased in uremic patients. This elevation is more profound in CAPD
      patients, who also exhibit a more atherogenic lipid profile and more pronounced
      alterations in the specific activity and the kinetic constants of Lp(a)
      associated PAF-AH.

PMID- 10594807
TI  - Hemodialysis prevents liver disease caused by hepatitis C virus: role of
      hepatocyte growth factor.
AB  - Hemodialysis prevents liver disease caused by hepatitis C virus: Role of
      hepatocyte growth factor. BACKGROUND: Hemodialysis increases markedly the serum
      levels of hepatocyte growth factor (HGF) so that regular dialysis treatment (RDT)
      mimics the regular administration of HGF as a drug. Therefore, we have studied
      the effects of dialysis-associated HGF production on the severity of liver damage
      caused by hepatitis C virus (HCV). METHODS: Biochemical tests of liver function
      and liver biopsy were performed in 10 patients on RDT and in 11 patients without
      renal disease (WRD) converted to anti-HCV serum-positive test for the same time
      (48 +/- 4 months). The HGF serum concentration was measured by enzyme
      immunoassay. In patients on RDT, HGF was measured just before starting a dialysis
      session (T0), at 15 and 240 minutes of dialysis (T15 and T240), and 24 hours
      later (T24 hr). RESULTS: Serum HGF was similar in WRD (average 0.17 ng/ml) as in
      RDT at T0 (0.25 ng/ml). In RDT serum HGF increased markedly at T15 and T240 (5.51
      and 2.67 ng/ml, respectively, P < 0. 001 vs. WRD and T0) and was still higher
      than baseline at T24 hr (0. 41 ng/ml, P < 0.05). Both grade of necroinflammatory
      activity and stage of fibrosis were significantly lower in RDT than in WRD (both,
      P < 0.001). The number of apoptotic hepatocytes was also significantly reduced in
      patients on RDT compared with patients WRD. CONCLUSION: These results show that
      HCV-related liver disease is more benign in patients on RDT. The phenomenon may
      depend on the marked and prolonged HGF release caused by dialysis.

PMID- 10594808
TI  - Effective correction of hyperhomocysteinemia in hemodialysis patients by
      intravenous folinic acid and pyridoxine therapy.
AB  - Effective correction of hyperhomocysteinemia in hemodialysis patients by
      intravenous folinic acid and pyridoxine therapy. BACKGROUND: Folic acid
      supplementation is only partially efficacious in correcting moderate elevation of
      plasma total homocysteine (tHcy) concentrations observed in hemodialysis (HD)
      patients. Experimental and clinical data have suggested that this partial
      efficacy may be due to impairment of folic acid metabolism to 5
      methyltetrahydrofolate (MTHF) and of MTHF transmembrane transport as well. To
      bypass these difficulties, we assessed the efficacy of intravenous (i.v.) folinic
      acid, a ready precursor of MTHF, on reducing plasma tHcy concentrations in HD
      patients. METHODS: In a cohort of 37 patients on intermittent HD treatment,
      plasma tHcy concentrations were determined before and during i.v. supplementation
      of folinic acid (50 mg once per week), together with i.v. pyridoxine (250 mg 3
      times per week), to prevent vitamin deficiency, particularly in those treated by
      recombinant erythropoietin. RESULTS: Folinic acid and pyridoxine i.v.
      supplementation was given for 11.2 +/- 2.45 months (range 7.5 to 17 months). The
      mean plasma tHcy levels decreased significantly from 37. 3 +/- 5.8 microM at
      baseline to 12.3 +/- 5.4 microM on folinic acid treatment (P < 0.001). Moreover,
      29 of the 37 patients (78%) had normal plasma tHcy levels at the end of follow-up
      (that is, <14.1 microM, mean 9.8 microM, range 6.2 to 13 microM). No adverse
      effects attributable to folinic acid treatment were observed during this time.
      CONCLUSIONS: Intravenous folinic acid therapy (50 mg) once per week associated
      with pyridoxine supplementation appears to be an effective and safe strategy to
      normalize plasma tHcy levels in the majority of chronic HD patients.

PMID- 10594809
TI  - Measuring total body water in peritoneal dialysis patients using an ethanol
      dilution technique.
AB  - Measuring total body water in peritoneal dialysis patients using an ethanol
      dilution technique. BACKGROUND: The accuracy with which total body water (TBW) is
      estimated is a direct determinant of the reliability of Kt/V urea measurements in
      peritoneal dialysis (PD) patients. Ethanol dilution has been previously shown to
      be a reliable measure of TBW. Advances in breath alcohol technology make this a
      feasible clinical tool. METHODS: We gave 19 fasting chronic PD patients 0.3 g/kg
      of ethanol (EtOH) orally on two separate occasions. Breath alcohol concentrations
      (BrACs), determined by dual-beam infrared analysis, were recorded at baseline and
      periodically thereafter until BrACs were less than 0.01%. The TBW was then
      determined by standard pharmacokinetic techniques. RESULTS: TBW measurements were
      reproducible, with a mean between-run difference of -0.004 liter/kg (95% limits
      of agreement -0.040 to 0. 032 by Bland-Altman). The Watson equations tended to
      underestimate TBW, with a mean difference (EtOH - Watson) of +3.0 liters (SD 4.0
      liters, P = 0.004) and a mean absolute difference of 4.1 liters (SD 2.7 liters,
      range -4.4 to 9.5 liters). Kt/V was calculated from dialysate and urine
      collection, using V as determined from TBW estimates from EtOH and Watson. The
      mean Kt/V(EtOH) was 2.31 (SD 0. 50) compared with 2.46 (SD 0.52) using Watson.
      The mean absolute difference between the two Kt/V estimates was 0.26 (SD 0.20,
      range -0.87 to 0.57), with Kt/V overestimated by Watson in 14 patients. EtOH was
      well tolerated, and the procedure was completed in about four hours. CONCLUSIONS:
      Measuring V by the BrAC technique does not require blood sampling, is reliable,
      and is reproducible. It is a potentially useful method for a periodic
      determination of volume that may allow for more accurate Kt/V measurement in PD
      patients.

PMID- 10594810
TI  - The paracellular permeability of opossum kidney cells, a proximal tubule cell
      line.
AB  - The paracellular permeability of opossum kidney cells, a proximal tubule cell
      line. BACKGROUND: The regulation of the unusually leaky paracellular pathway of
      the proximal tubule is poorly understood partially because of the lack of an
      appropriate in vitro cell model. In this study, we determined whether the
      paracellular permeability of opossum kidney (OK) cells would resemble that of the
      in vivo proximal tubule epithelium. METHODS: The parental and subclonal OK cells
      and, for comparison, LLC-PK1 cells were cultured on permeable Transwell supports.
      The apparent paracellular permeability coefficient (Papp) for the extracellular
      marker 3H-mannitol was determined. RESULTS: The Papp of OK cell sheets (12.17 x10
      6 cm/sec) was remarkably close to the previously reported Papp of rat proximal
      tubules. The Papp of LLC-PK1 cells, another proximal tubule cell line, however,
      was approximately 20-fold lower than that of both OK cells and the in vivo
      proximal tubule. Phorbol 12-myristate 13-acetate, a protein kinase C activator,
      enhanced the Papp of OK cell sheets. The characteristic response of paracellular
      permeability to Ca2+ switch was demonstrated in OK cell sheets. Slight variations
      of Papp among several OK subclones were observed. Basal to apical Papp was
      uniformly higher than apical to basal Papp, independent of cell subtype. This
      rectification was attenuated by inhibition of active transport. CONCLUSIONS: OK
      cell sheets cultured on Transwell supports possess a leaky paracellular pathway
      resembling that of the proximal tubule epithelium in vivo.

PMID- 10594811
TI  - We need to inhibit complement in glomerular proteinuria.

PMID- 10594812
TI  - Why are some people more receptive to angiotension II?

PMID- 10594813
TI  - Disorders of the epithelial sodium channel: insights into the regulation of
      extracellular volume and blood pressure.

PMID- 10594814
TI  - Helicase motifs: the engine that powers DNA unwinding.
AB  - Helicases play essential roles in nearly all DNA metabolic transactions and have
      been implicated in a variety of human genetic disorders. A hallmark of these
      enzymes is the existence of a set of highly conserved amino acid sequences termed
      the 'helicase motifs' that were hypothesized to be critical for helicase
      function. These motifs are shared by another group of enzymes involved in
      chromatin remodelling. Numerous structure-function studies, targeting highly
      conserved residues within the helicase motifs, have been instrumental in
      uncovering the functional significance of these regions. Recently, the results of
      these mutational studies were augmented by the solution of the three-dimensional
      crystal structure of three different helicases. The structural model for each
      helicase revealed that the conserved motifs are clustered together, forming a
      nucleotide-binding pocket and a portion of the nucleic acid binding site. This
      result is gratifying, as it is consistent with structure-function studies
      suggesting that all the conserved motifs are involved in the nucleotide
      hydrolysis reaction. Here, we review helicase structure-function studies in the
      light of the recent crystal structure reports. The current data support a model
      for helicase action in which the conserved motifs define an engine that powers
      the unwinding of duplex nucleic acids, using energy derived from nucleotide
      hydrolysis and conformational changes that allow the transduction of energy
      between the nucleotide and nucleic acid binding sites. In addition, this ATP
      hydrolysing engine is apparently also associated with proteins involved in
      chromatin remodelling and provides the energy required to alter protein-DNA
      structure, rather than duplex DNA or RNA structure.

PMID- 10594815
TI  - Time-lapsed confocal microscopy reveals temporal and spatial expression of the
      lysine epsilon-aminotransferase gene in Streptomyces clavuligerus.
AB  - To investigate the temporal and spatial expression patterns of the gene (lat )
      encoding lysine epsilon-aminotransferase (LAT) for cephamycin C biosynthesis, a
      mutant form of green fluorescent protein (mut1GFP) was integrated into the
      Streptomyces clavuligerus chromosome (strain LH369), resulting in a translational
      fusion with lat. LAT activity and fluorescence profiles of the recombinant
      protein paralleled the native LAT enzyme activity profile in wild-type S.
      clavuligerus, which peaked during exponential growth phase and decreased slowly
      towards stationary phase. These results indicate that the LAT-Mut1GFP fusion
      protein retains both LAT and GFP functionality in S. clavuligerus LH369. LH369
      produced wild-type levels of cephamycin C in minimal medium culture conditions
      supplemented with lysine. Time-lapsed confocal microscopy of the S. clavuligerus
      LH369 strain revealed the temporal and spatial characteristics of lat gene
      expression and demonstrated that physiological development of S. clavuligerus
      colonies leading to cephamycin C biosynthesis is limited to the substrate
      mycelia.

PMID- 10594816
TI  - An ordered reaction mechanism for bacterial toxin acylation by the specialized
      acyltransferase HlyC: formation of a ternary complex with acylACP and protoxin
      substrates.
AB  - The 110 kDa haemolysin protoxin (proHlyA) is activated in the Escherichia coli
      cytosol by acyl carrier protein-dependent fatty acylation of two internal lysine
      residues, directed by the co-synthesized protein HlyC. Using an in vitro
      maturation reaction containing purified protoxin peptides and acylACP, we show
      unambiguously that HlyC possesses an apparently unique acyltransferase activity
      fully described by Michaelis-Menten analysis. The Vmax of HlyC at saturating
      levels of both substrates was approximately 115 nmol acyl group min-1 mg-1 with
      KMacylACP of 260 nM and KMproHlyA of 27 nM, kinetic parameters sufficient to
      explain why in vivo HlyC is required at a concentration equimolar to proHlyA.
      HlyC bound the fatty acyl group from acylACP to generate an acylated HlyC
      intermediate that was depleted in the presence of proHlyA, but enriched in the
      presence of proHlyA derivatives lacking acylation target sites. HlyC was also
      able to bind in vivo 4'-phosphopantetheine. Substitution of conserved amino acids
      that could act as putative covalent attachment sites did not prevent binding of
      the fatty acyl or 4'-phosphopantetheine groups. These data and substrate
      variation analyses suggest that the unique acylation reaction does not involve
      covalent attachment of fatty acid to the acyltransferase, but rather that it
      proceeds via a sequential ordered Bi-Bi reaction mechanism, requiring the
      formation of a non-covalent ternary acylACP-HlyC-proHlyA complex.

PMID- 10594817
TI  - Interaction between the protein InlB of Listeria monocytogenes and lipoteichoic
      acid: a novel mechanism of protein association at the surface of gram-positive
      bacteria.
AB  - InlB is a Listeria monocytogenes protein that is sufficient to promote entry in a
      variety of mammalian cells. The last 232-amino-acid domain (Csa) of InlB has been
      shown to mediate attachment on the listerial surface, although its sequence does
      not suggest any known mechanism of association to the bacterial surface. InlB is
      present both on the bacterial surface and in culture supernatants. As has been
      recently demonstrated, both forms of InlB, soluble and surface-bound, can trigger
      signalling in host cells. To elucidate the specific role of each of the two
      forms, it was important to understand how InlB associates with the bacterial
      surface. Using microscopy, we find evidence that InlB is partially buried in the
      cell wall layer, and using fractionation experiments we demonstrate that InlB
      associates with the bacterial cytoplasmic membrane. Moreover, using purified
      lipoteichoic acid (LTA) and the three polypeptides InlB, Csa, or InlBDeltaCsa
      (InlB lacking the last 232 amino acids), we demonstrate that LTA is a ligand for
      the Csa domain of InlB. These results provide the first evidence of an
      interaction between lipoteichoic acids and a bacterial protein involved in
      adhesion and signalling, and highlight a new mechanism of protein association on
      the surface of Gram-positive bacteria.

PMID- 10594818
TI  - Activation of CheY mutant D57N by phosphorylation at an alternative site, Ser-56.
AB  - The site of phosphorylation of the chemotaxis response regulator CheY is
      aspartate 57. When Asp-57 is replaced with an asparagine, the resultant protein
      can be phosphorylated at an alternative site. We report here that phosphorylation
      of this mutant protein, CheY D57N, at the alternative site affords the protein
      activity in vivo in the absence of CheZ. Using a direct phosphopeptide mapping
      approach, we identified the alternate phosphorylation site as serine 56.
      Introduction of a Ser-->Ala substitution at this position in wild-type CheY had
      no effect on function. However, replacement of Ser-56 with Ala in CheY D57N
      abrogated the activity seen in vivo for the CheY D57N single mutant protein, and
      no phosphorylation of the CheY S56A/D57N double mutant protein was observed in
      vitro. Construction and analysis of double mutants CheY D57N/T87A and CheY
      D57N/K109R, which were both inactive, suggested that phosphorylation at Ser-56 or
      Asp-57 may activate the protein by similar mechanisms. In contrast to CheY D57N,
      mutant CheY D57E displayed no activity in vivo, despite its ability to be
      phosphorylated in vitro. Acid-base stability analysis indicated that CheY D57E
      phosphorylates on an acidic residue, presumably Glu-57. These data suggest that a
      key determinant of the ability of a phosphoryl group to activate CheY is
      proximity to the hydrophobic core of the protein, with consequent opportunity to
      reposition key residues, irrespective of the chemical nature of the linkage
      attaching the phosphoryl group to CheY.

PMID- 10594819
TI  - Characterization of a candidate Borrelia burgdorferi beta3-chain integrin ligand
      identified using a phage display library.
AB  - The spirochaetal agents of Lyme disease, Borrelia burgdorferi (sensu lato) bind
      to integrins alphaIIbbeta3, alphavbeta3 and alpha5beta1 in purified form and on
      the surfaces of human cells. Using a phage display library of B. burgdorferi
      (sensu stricto) DNA, a candidate ligand for beta3-chain integrins was identified.
      The native B. burgdorferi protein, termed p66, is known to be recognized by human
      Lyme disease patient sera and to be expressed on the surface of the spirochaete.
      We show here that recombinant p66 binds specifically to beta3-chain integrins and
      inhibits attachment of intact B. burgdorferi to the same integrins. When
      expressed on the surface of Escherichia coli, this protein increases the
      attachment of E. coli to a transfected cell line that expresses alphavbeta3, but
      not to the parental cell line, which expresses no beta3-chain integrins.
      Localization of p66 on the surface of B. burgdorferi, the ability of recombinant
      forms of the protein to bind to beta3-chain integrins and the fact that p66 and
      B. burgdorferi bind to beta3-chain integrins in a mutually exclusive manner make
      p66 an attractive candidate bacterial ligand for integrins alphaIIbbeta3 and
      alphavbeta3.

PMID- 10594820
TI  - Hierarchy in the expression of the locus of enterocyte effacement genes of
      enteropathogenic Escherichia coli.
AB  - Enteropathogenic Escherichia coli (EPEC) elicit changes in host cell morphology
      and cause actin rearrangement, a phenotype that has commonly been referred to as
      attaching/effacing (AE) lesions. The ability of EPEC to induce AE lesions is
      dependent upon a type III protein secretion/translocation system that is encoded
      by genes clustered in a 35.6 kb DNA segment, named the locus of enterocyte
      effacement (LEE). We used transcriptional fusions between the green fluorescent
      protein (gfp) reporter gene and LEE genes rorf2, orf3, orf5, escJ, escV and eae,
      together with immunoblot analysis with antibodies against Tir, intimin, EspB and
      EspF, to analyse the genetic regulation of the LEE. The expression of all these
      LEE genes was strictly dependent upon the presence of a functional integration
      host factor (IHF). IHF binds specifically upstream from the ler (orf1) promoter
      and appears to activate expression of ler, orf3, orf5 and rorf2 directly. The ler
      encoded Ler protein was involved in activating the expression of escJ, escV, tir,
      eae, espB and espF. Expression of both IHF and Ler was needed to elicit actin
      rearrangement associated with AE lesions. In conclusion, IHF directly activates
      the expression of the ler and rorf2 transcriptional units, and Ler in turn
      mediates the expression of the other LEE genes.

PMID- 10594821
TI  - A DNA architectural protein couples cellular physiology and DNA topology in
      Escherichia coli.
AB  - In Escherichia coli, the transcriptional activity of many promoters is strongly
      dependent on the negative superhelical density of chromosomal DNA. This, in turn,
      varies with the growth phase, and is correlated with the overall activity of DNA
      gyrase, the major topoisomerase involved in the elevation of negative
      superhelicity. The DNA architectural protein FIS is a regulator of the metabolic
      reorganization of the cell during early exponential growth phase. We have
      previously shown that FIS modulates the superhelical density of plasmid DNA in
      vivo, and on binding reshapes the supercoiled DNA in vitro. Here, we show that,
      in addition, FIS represses the gyrA and gyrB promoters and reduces DNA gyrase
      activity. Our results indicate that FIS determines DNA topology both by
      regulation of topoisomerase activity and, as previously inferred, by directly
      reshaping DNA. We propose that FIS is involved in coupling cellular physiology to
      the topology of the bacterial chromosome.

PMID- 10594822
TI  - Functional analysis of the FimE integrase of Escherichia coli K-12: isolation of
      mutant derivatives with altered DNA inversion preferences.
AB  - Phase variable expression of type 1 fimbriae in Escherichia coli arises from a
      site-specific recombination event that inverts a short segment of chromosomal DNA
      carrying the promoter for transcription of the gene encoding the fimbrial subunit
      protein. Two integrase-like recombinases are involved in switching. The FimB
      recombinase inverts the DNA segment in either orientation, whereas the FimE
      protein inverts it predominantly in the ON-to-OFF direction. In this paper, we
      report the isolation of a FimE mutant protein that has enhanced bidirectional
      switching activity. This protein has an arginine-to-lysine substitution at
      position 59, and this confers a FimB-like switching character on FimE without
      altering its ability to bind to DNA. The arginine was not a member of the
      arginine-histidine-arginine-tyrosine catalytic tetrad that is common to all
      integrase-like recombinases. The catalytic tetrad members of FimE were identified
      at positions 41, 136, 139 and 171 and shown to be essential for FimE function. In
      addition, other amino acid residues that make important contributions to the DNA
      binding activity of FimE or its ON-to-OFF inversion efficiency were identified.

PMID- 10594823
TI  - The anti-immunity system of phage-plasmid N15: identification of the
      antirepressor gene and its control by a small processed RNA.
AB  - N15 is a temperate virus of Escherichia coli related to lambdoid phages. However,
      unlike all other known phages, the N15 prophage is maintained as a low copy
      number linear DNA molecule with covalently closed ends. The primary immunity
      system at the immB locus is structurally and functionally comparable to that of
      lambdoid phages, and encodes the immunity repressor CB. We have characterized a
      second locus, immA, in which clear plaque mutations were mapped, and found that
      it encodes an anti-immunity system involved in the choice between the lytic and
      the lysogenic cycle. Three open reading frames at the immA locus encode an
      inhibitor of cell division (icd ), an antirepressor (antA) and a gene that may
      play an ancillary role in anti-immunity (antB ). These genes may be transcribed
      from two promoters: the upstream promoter Pa is repressed by the immunity
      repressor CB, whereas the downstream promoter Pb is constitutive. Full repression
      of the anti-immunity system is achieved by premature transcription termination
      elicited by a small RNA (CA RNA) produced by processing of the leader transcript
      of the anti-immunity operon. The N15 anti-immunity system is structurally and
      functionally similar to the anti-immunity system of bacteriophage P1 and to the
      immunity system of satellite phage P4.

PMID- 10594824
TI  - The synthesis of Rhodobacter capsulatus HupSL hydrogenase is regulated by the two
      component HupT/HupR system.
AB  - The synthesis of the membrane-bound [NiFe]hydrogenase of Rhodobacter capsulatus
      (HupSL) is regulated negatively by the protein histidine kinase, HupT, and
      positively by the response regulator, HupR. It is demonstrated in this work that
      HupT and HupR are partners in a two-component signal transduction system. The
      binding of HupR protein to the hupS promoter regulatory region (phupS ) was
      studied using gel retardation and footprinting assays. HupR protected a 50 bp
      region localized upstream from the binding site of the histone-like integration
      host factor (IHF) regulator. HupR, which belongs to the NtrC subfamily, binds to
      an enhancer site (TTG-N5-CAA) localized at -162/-152 nt. However, the enhancer
      binding HupR protein does not require the RpoN sigma factor for transcriptional
      activation, as is the case for NtrC from enteric bacteria, but functions with
      sigma70-RNA polymerase, as is the case for R. capsulatus NtrC. Besides, unlike
      NtrC from Escherichia coli, HupR activates transcription in the unphosphorylated
      form and becomes inactive by phosphorylation. This was demonstrated by replacing
      the putative phosphorylation site (D54) of the HupR protein with various amino
      acids or by deleting it using site-directed mutagenesis. Strains expressing
      mutated hupR genes showed high hydrogenase activities even in the absence of H2,
      indicating that hupSL transcription is activated by the binding of
      unphosphorylated HupR protein. Strains producing mutated HupRD54 proteins were
      derepressed for hupSL expression as were HupT- mutants. It is shown that the
      phosphorylated form of HupT was able to transfer phosphate to wild-type HupR
      protein but not to mutated D54 HupR proteins. Thus, it is concluded that HupT and
      HupR are the partners of a two-component regulatory system that regulates hupSL
      gene transcription.

PMID- 10594825
TI  - The MAP kinase kpp2 regulates mating and pathogenic development in Ustilago
      maydis.
AB  - In the phytopathogenic fungus Ustilago maydis, fusion of compatible haploid cells
      is a prerequisite for infection. This process is genetically controlled by the
      biallelic a locus, encoding pheromone precursors and receptors. These are
      presumed to be coupled to a heterotrimeric G protein and a MAP kinase cascade,
      leading to activation of the HMG domain transcription factor Prf1. Here, we have
      demonstrated that putative MAP kinase sites in Prf1 are required for its activity
      during mating. In addition, we have identified a gene, kpp2, which encodes a
      putative MAP kinase related to Pmk1 of Magnaporthe grisea and Fus3p of
      Saccharomyces cerevisiae. kpp2 deletion mutants are attenuated in several steps
      of development: cell fusion, induction of pheromone-responsive genes and
      pathogenicity. Epistasis analysis shows that kpp2 does not affect pheromone gene
      expression through the cAMP signalling cascade. Pathogenicity of kpp2 mutants can
      be partially restored by overexpressing the b genes, indicating a regulation of
      Prf1 by Kpp2. These data support the hypothesis that the MAP kinase Kpp2
      transmits the pheromone signal.

PMID- 10594826
TI  - The NADH oxidase of Streptococcus pneumoniae: its involvement in competence and
      virulence.
AB  - A soluble flavoprotein that reoxidizes NADH and reduces molecular oxygen to water
      was purified from the facultative anaerobic human pathogen Streptococcus
      pneumoniae. The nucleotide sequence of nox, the gene which encodes it, has been
      determined and was characterized at the functional and physiological level.
      Several nox mutants were obtained by insertion, nonsense or missense mutation. In
      extracts from these strains, no NADH oxidase activity could be measured,
      suggesting that a single enzyme encoded by nox, having a C44 in its active site,
      was utilizing O2 to oxidize NADH in S. pneumoniae. The growth rate and yield of
      the NADH oxidase-deficient strains were not changed under aerobic or anaerobic
      conditions, but the efficiency of development of competence for genetic
      transformation during growth was markedly altered. Conditions that triggered
      competence induction did not affect the amount of Nox, as measured using Western
      blotting, indicating that nox does not belong to the competence-regulated genetic
      network. The decrease in competence efficiency due to the nox mutations was
      similar to that due to the absence of oxygen in the nox+ strain, suggesting that
      input of oxygen into the metabolism via NADH oxidase was important for
      controlling competence development throughout growth. This was not related to
      regulation of nox expression by O2. Interestingly, the virulence and persistence
      in mice of a blood isolate was attenuated by a nox insertion mutation. Global
      cellular responses of S. pneumoniae, such as competence for genetic exchange or
      virulence in a mammalian host, could thus be modulated by oxygen via the NADH
      oxidase activity of the bacteria, although the bacterial energetic metabolism is
      essentially anaerobic. The enzymatic activity of the NADH oxidase coded by nox
      was probably involved in transducing the external signal, corresponding to O2
      availability, to the cell metabolism and physiology; thus, this enzyme may
      function as an oxygen sensor. This work establishes, for the first time, the role
      of O2 in the regulation of pneumococcal transformability and virulence.

PMID- 10594827
TI  - Hyperosmotic shock induces the sigma32 and sigmaE stress regulons of Escherichia
      coli.
AB  - The rise in the levels of sigmaS that accompanies hyperosmotic shock plays an
      important role in Escherichia coli survival by increasing the transcription of
      genes involved in the synthesis and transport of osmoprotectants. To determine if
      other stress regulons collaborate with sigmaS in dealing with high osmolality, we
      used single copy fusions of lacZ to representative promoters induced by protein
      misfolding in the cytoplasm (dnaK and ibp ), extracytoplasmic stress [P3rpoH and
      htrA(degP )] and cold shock (cspA). Both the sigma32-dependent, dnaK and ibp,
      promoters, and the sigmaE-dependent, P3rpoH and htrA, promoters were rapidly but
      transiently induced when mid-exponential phase cells were treated with 0.464 M
      sucrose. The cspA promoter, however, did not respond to the same treatment.
      Overproduction of the cytoplasmic domain of the sigmaE anti-sigma factor, RseA,
      reduced the magnitude of osmotic induction in lambdaphi(P3rpoH:lacZ ) lysogens,
      but had no effect on the activation of the dnaK and ibp promoters. Similarly,
      induction of the dnaK:lacZ and ibp:lacZ fusions was not altered in either rpoS or
      ompR genetic backgrounds. Osmotic upshift led to a twofold increase in the
      enzymatic activity of the lambdaTLF247 rpoH:lacZ translational fusion whether or
      not the cells were treated with rifampicin, indicating that both heat shock and
      exposure to high osmolality trigger a transient increase in rpoH translation. Our
      results suggest that the sigma32, sigmaE and sigmaS regulons closely co-operate
      in the managment of hyperosmotic stress. Induction of the sigma32 and sigmaE
      regulons appears to be an emergency response required to repair protein
      misfolding and facilitate the proper folding of proteins that are rapidly
      synthesized following loss of turgor, while providing a mechanism to increase the
      activity of sigmaS, the primary stress factor in osmoadaptation.

PMID- 10594828
TI  - Interspecies complementation in Saccharopolyspora erythraea : elucidation of the
      function of oleP1, oleG1 and oleG2 from the oleandomycin biosynthetic gene
      cluster of Streptomyces antibioticus and generation of new erythromycin
      derivatives.
AB  - Two glycosyltransferase genes, oleG1 and oleG2, and a putative isomerase gene,
      oleP1, have previously been identified in the oleandomycin biosynthetic gene
      cluster of Streptomyces antibioticus. In order to identify which of these two
      glycosyltransferases encodes the desosaminyltransferase and which the
      oleandrosyltransferase, interspecies complementation has been carried out, using
      two mutant strains of Saccharopolyspora erythraea, one strain carrying an
      internal deletion in the eryCIII (desosaminyltransferase) gene and the other an
      internal deletion in the eryBV (mycarosyltransferase) gene. Expression of the
      oleG1 gene in the eryCIII deletion mutant restored the production of erythromycin
      A (although at a low level), demonstrating that oleG1 encodes the
      desosaminyltransferase required for the biosynthesis of oleandomycin and
      indicating that, as in erythromycin biosynthesis, the neutral sugar is
      transferred before the aminosugar onto the macrocyclic ring. Significantly, when
      an intact oleG2 gene (presumed to encode the oleandrosyltransferase) was
      expressed in the eryBV deletion mutant, antibiotic activity was also restored
      and, in addition to erythromycin A, new bioactive compounds were produced with a
      good yield. The neutral sugar residue present in these compounds was identified
      as L-rhamnose attached at position C-3 of an erythronolide B or a 6
      deoxyerythronolide B lactone ring, thus indicating a relaxed specificity of the
      oleandrosyltransferase, OleG2, for both the activated sugar and the macrolactone
      substrate. The oleP1 gene located immediately upstream of oleG1 was likewise
      introduced into an eryCII deletion mutant of Sac. erythraea, and production of
      erythromycin A was again restored, demonstrating that the function of OleP1 is
      identical to that of EryCII in the biosynthesis of dTDP-D-desosamine, which we
      have previously proposed to be a dTDP-4-keto-6-deoxy-D-glucose 3, 4-isomerase.

PMID- 10594829
TI  - Genome-wide analysis of gene expression regulated by the yeast cell wall
      integrity signalling pathway.
AB  - The cell integrity pathway of Saccharomyces cerevisiae monitors cell wall
      remodelling during growth and differentiation. Additionally, this pathway
      responds to environmental stresses that challenge the integrity of the cell wall.
      We conducted a genome-wide survey of genes whose expression was altered in
      response to activation of Mpk1/Slt2, the MAP kinase, under the control of cell
      integrity signalling. We identified 25 genes whose regulation was altered by Mpk1
      activity. Among these, 20 were positively regulated by Mpk1, and five were
      negatively regulated. Most of the genes identified encode either known or
      suspected cell wall proteins or enzymes involved in cell wall biogenesis. These
      include glycosyl-phosphatidylinositol (GPI) proteins, members of the Pir family
      of cell wall proteins, Mpk1 itself and others. All of the regulation detected was
      mediated by the Rlm1 transcription factor, a MADS-box protein that is
      phosphorylated and activated by Mpk1, but for which no transcriptional targets
      had been identified. A similar pattern of regulation was observed when cell
      integrity signalling was induced by environmental stress (i.e. temperature
      upshift).

PMID- 10594830
TI  - Spontaneous tandem amplification and deletion of the shiga toxin operon in
      Shigella dysenteriae 1.
AB  - Only one species of Shigella, Shigella dysenteriae 1, has been demonstrated to
      produce Shiga toxin (Stx). Stx is closely related to the toxins produced by Shiga
      toxin-producing Escherichia coli (STEC). In STEC, these toxins are often encoded
      on lambdoid bacteriophages and are major virulence factors for these organisms.
      Although the bacteriophage-encoded stx genes of STEC are highly mobile, the stx
      genes in S. dysenteriae 1 have been believed to be chromosomally encoded and not
      transmissible. We have located the toxin genes of S. dysenteriae 1 to a region
      homologous to minute 30 of the E. coli chromosome, within a 22.4 kbp putative
      composite transposon bracketed by IS600 insertion sequences. This region is
      present in all the S. dysenteriae 1 strains examined. Tandem amplification occurs
      via the flanking insertion sequences, leading to increased toxin production. The
      global regulatory gene, fnr, is located within the stx region, allowing deletions
      of the toxin genes to be created by anaerobic growth on chlorate-containing
      medium. Deletions occur by recombination between the flanking IS600 elements.
      Lambdoid bacteriophage genes are found both upstream and within the region, and
      we demonstrate the lysogeny of Shigella species with STEC bacteriophages. These
      observations suggest that S. dysenteriae 1 originally carried a Stx-encoding
      lambdoid prophage, which became defective due to loss of bacteriophage sequences
      after IS element insertions and rearrangements. These insertion sequences have
      subsequently allowed the amplification and deletion of the stx region.

PMID- 10594831
TI  - Identification of dipeptide repeats and a cell wall sorting signal in the
      fimbriae-associated adhesin, Fap1, of Streptococcus parasanguis.
AB  - Fap1, a fimbriae-associated protein, is involved in fimbriae assembly and
      adhesion of Streptococcus parasanguis FW213 (Wu et al., 1998). In this study, the
      sequence of the fap1 gene was resolved using a primer island transposition
      system. Sequence analysis indicated that fap1 was composed of 7659 nucleotides.
      The predicted Fap1 protein contains an unusually long signal sequence (50 amino
      acid residues), a cell wall sorting signal and two repeat regions. Repeat regions
      I and II have a similar dipeptide composition (E/V/I)S, composed of 28 and 1000
      repeats respectively. The two regions combined accounted for 80% of the Fap1
      coding region. The experimental amino acid composition and isoelectric point (pI)
      of Fap1 were similar to that predicted from the deduced Fap1 protein. Results of
      Northern analyses revealed that the fap1 open reading frame (ORF) was transcribed
      as a 7.8 kb monocistronic message. Insertional inactivation at the 3' end,
      downstream of the fap1 ORF, did not affect Fap1, fimbrial expression or bacterial
      adhesion. Insertional inactivation of fap1 immediately upstream of the repeat
      region II abolished expression of Fap1 and fimbriae, and was concurrent with a
      diminution in adhesion of FW213. Inactivation of the cell wall sorting signal of
      fap1 also eliminated long fimbrial formation and reduced the ability of FW213 to
      bind to SHA. Fap1 was no longer anchored on the cell surface. Large quantities of
      truncated Fap1 were found in the growth medium instead. These results suggest
      that the fap1 ORF alone is sufficient to support Fap1 expression and adhesion,
      and demonstrate that anchorage of Fap1 on the cell surface is required for long
      fimbriae formation. These data further document the role of long fimbriae in
      adhesion of S. parasanguis FW213 to SHA.

PMID- 10594832
TI  - Quorum sensing in Pseudomonas aeruginosa controls expression of catalase and
      superoxide dismutase genes and mediates biofilm susceptibility to hydrogen
      peroxide.
AB  - Quorum sensing (QS) governs the production of virulence factors and the
      architecture and sodium dodecyl sulphate (SDS) resistance of biofilm-grown
      Pseudomonas aeruginosa. P. aeruginosa QS requires two transcriptional activator
      proteins known as LasR and RhlR and their cognate autoinducers PAI-1 (N-(3
      oxododecanoyl)-L-homoserine lactone) and PAI-2 (N-butyryl-L-homoserine lactone)
      respectively. This study provides evidence of QS control of genes essential for
      relieving oxidative stress. Mutants devoid of one or both autoinducers were more
      sensitive to hydrogen peroxide and phenazine methosulphate, and some PAI mutant
      strains also demonstrated decreased expression of two superoxide dismutases
      (SODs), Mn-SOD and Fe-SOD, and the major catalase, KatA. The expression of sodA
      (encoding Mn-SOD) was particularly dependent on PAI-1, whereas the influence of
      autoinducers on Fe-SOD and KatA levels was also apparent but not to the degree
      observed with Mn-SOD. beta-Galactosidase reporter fusion results were in
      agreement with these findings. Also, the addition of both PAIs to suspensions of
      the PAI-1/2-deficient double mutant partially restored KatA activity, while the
      addition of PAI-1 only was sufficient for full restoration of Mn-SOD activity. In
      biofilm studies, catalase activity in wild-type bacteria was significantly
      reduced relative to planktonic bacteria; catalase activity in the PAI mutants was
      reduced even further and consistent with relative differences observed between
      each strain grown planktonically. While wild-type and mutant biofilms contained
      less catalase activity, they were more resistant to hydrogen peroxide treatment
      than their respective planktonic counterparts. Also, while catalase was
      implicated as an important factor in biofilm resistance to hydrogen peroxide
      insult, other unknown factors seemed potentially important, as PAI mutant biofilm
      sensitivity appeared not to be incrementally correlated to catalase levels.

PMID- 10594833
TI  - Analysis of the function of Escherichia coli poly(A) polymerase I in RNA
      metabolism.
AB  - To help understand the role of polyadenylation in Escherichia coli RNA
      metabolism, we constructed an IPTG-inducible pcnB [poly(A) polymerase I, PAP I]
      containing plasmid that permitted us to vary poly(A) levels without affecting
      cell growth or viability. Increased polyadenylation led to a decrease in the half
      life of total pulse-labelled RNA along with decreased half-lives of the rpsO,
      trxA, lpp and ompA transcripts. In contrast, the transcripts for rne (RNase E)
      and pnp (polynucleotide phosphorylase, PNPase), enzymes involved in mRNA decay,
      were stabilized. rnb (RNase II) and rnc (RNase III) transcript levels were
      unaffected in the presence of increased polyadenylation. Long-term overproduction
      of PAP I led to slower growth and irreversible cell death. Differential display
      analysis showed that new RNA species were being polyadenylated after PAP I
      induction, including the mature 3'-terminus of 23S rRNA, a site that was not
      tailed in wild-type cells. Quantitative reverse transcriptase-polymerase chain
      reaction (RT-PCR) demonstrated an almost 20-fold variation in the level of
      polyadenylation among three different transcripts and that PAP I accounted for
      between 94% and 98.6% of their poly(A) tails. Cloning and sequencing of cDNAs
      derived from lpp, 23S and 16S rRNA revealed that, during exponential growth, C
      and U residues were polymerized into poly(A) tails in a transcript-dependent
      manner.

PMID- 10594834
TI  - Residual polyadenylation in poly(A) polymerase I (pcnB ) mutants of Escherichia
      coli does not result from the activity encoded by the f310 gene.
AB  - As extracts of poly(A) polymerase I (PAP I) deficient strains of Escherichia coli
      appeared to contain considerable residual polyadenylating activity, efforts were
      undertaken to identify a second poly(A) polymerase. Recently, a gene (f310 )
      encoding the putative second poly(A) polymerase was cloned and sequenced. Here we
      have tested the ability of the F310 protein to add poly(A) tails in vivo by
      measuring total poly(A) levels in both f310 mutants and strains that overproduce
      F310. In addition, we have visualized poly(A) tails and examined ColE1 plasmid
      copy number in various genetic backgrounds. We also carried out direct
      biochemical measurements of AMP incorporation, using cell extracts after
      amplification of F310. All the data obtained indicate that F310 is not a poly(A)
      polymerase. Although the presence of two potential ATP binding domains in the
      F310 protein may account for its apparent ATP binding activity, its true
      biochemical function remains to be identified. In addition, we show that the f310
      gene is transcribed, almost exclusively, during stationary phase from a sigmas
      promoter.

PMID- 10594835
TI  - Extensive interplasmidic duplications change the virulence phenotype of the
      relapsing fever agent Borrelia turicatae.
AB  - The relapsing fever agent Borrelia turicatae has two antigenically distinct
      serotypes, A and B, which differ in their variable small proteins (Vsps) and in
      their degree of virulence and neurotropism in mice. Each Vsp gene (vspA or vspB)
      had an expression-linked copy that was unique to the serotype expressing it. This
      was located on one linear plasmid, which was defined by the upstream sequence.
      The archived copies of vspA and vspB were each located on different linear
      plasmids that were the same in both serotypes. In this feature, the mechanism of
      antigenic variation is similar to that of another relapsing fever agent, B.
      hermsii. However, in other features, the mechanisms of the two organisms differ.
      The expressed and archived loci for vspA and vspB of B. turicatae were near the
      centre of linear plasmids instead of near the telomeres. The vspA and vspB
      expression loci were duplicate copies of their respective silent loci: from the
      vsp itself to at least 13-14 kb downstream. Despite the extensive interplasmidic
      duplications and the internal position of the expression locus, the only
      detectable difference between serotypes A and B was in whether they expressed
      VspA or VspB.

PMID- 10594836
TI  - A molecular switch in SecA protein couples ATP hydrolysis to protein
      translocation.
AB  - SecA, the dimeric ATPase subunit of bacterial protein translocase, catalyses
      translocation during ATP-driven membrane cycling at SecYEG. We now show that the
      SecA protomer comprises two structural modules: the ATPase N-domain, containing
      the nucleotide binding sites NBD1 and NBD2, and the regulatory C-domain. The C
      domain binds to the N-domain in each protomer and to the C-domain of another
      protomer to form SecA dimers. NBD1 is sufficient for single rounds of SecA ATP
      hydrolysis. Multiple ATP turnovers at NBD1 require both the NBD2 site acting in
      cis and a conserved C-domain sequence operating in trans. This intramolecular
      regulator of ATP hydrolysis (IRA) mediates N-/C-domain binding and acts as a
      molecular switch: it suppresses ATP hydrolysis in cytoplasmic SecA while it
      releases hydrolysis in SecY-bound SecA during translocation. We propose that the
      IRA switch couples ATP binding and hydrolysis to SecA membrane
      insertion/deinsertion and substrate translocation by controlling nucleotide
      regulated relative motions between the N-domain and the C-domain. The IRA switch
      is a novel essential component of the protein translocation catalytic pathway.

PMID- 10594837
TI  - Conservation of xer site-specific recombination genes in bacteria.

PMID- 10594838
TI  - Choline acetyltransferase: the structure, distribution and pathologic changes in
      the central nervous system.
AB  - Choline acetyltransferase (ChAT), the enzyme responsible for the biosynthesis of
      acetylcholine, is presently the most specific indicator for monitoring the
      functional state of cholinergic neurones in the central and peripheral nervous
      systems. ChAT is a single-strand globular protein. The enzyme is synthesized in
      the perikaryon of cholinergic neurones and transported to the nerve terminals
      probably by both slow and rapid axoplasmic flows. ChAT exists in at least two
      forms in cholinergic nerve terminals: (i) soluble; and (ii) non-ionically
      membrane-bound forms. Multiple mRNA species of ChAT (R-, N-and M-types) are
      transcribed from different promoter regions and produced by different splicing in
      the mouse, rat, and human. All transcripts encode the same ChAT protein in
      rodents, while in human M-type mRNA has the capability to generate both large and
      small forms of ChAT proteins and R-and N-types ChAT mRNA generate a small form,
      which corresponds to the rodent ChAT. The genomic structure of ChAT is unique
      compared with other enzymes for neurotransmitters. The first intron of the ChAT
      gene encompasses the open reading frame encoding another protein, vesicular
      acetylcholine transporter (VAChT), which is responsible for the transportation of
      acetylcholine from the cytoplasm into the synaptic vesicles. The expressions of
      ChAT and VAChT appear to be coordinately regulated by multiple regulatory
      elements in cholinergic neurones. Immunohistochemical and in situ hybridization
      studies have revealed the localization of cholinergic neurones in the central
      nervous system: the medial septal nucleus, the nucleus of the diagonal band of
      Broca, the basal nucleus of Meynert, the caudate nucleus, the putamen, the
      nucleus accumbens, the pedunculopontine tegmental nucleus, the laterodorsal
      tegmental nucleus, the medial habenular nucleus, the parabigeminal nucleus, some
      cranial nerve nuclei, and the anterior horn of the spinal cord. Focally
      distributed cholinergic neurones project fibers to many areas in the central
      nervous system and construct a complicated cholinergic network, playing an
      important role in neuropsychic activities, such as learning, memory, arousal,
      sleep and movement. Central cholinergic neurones are involved in several
      neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral
      sclerosis, in which disturbance of the central cholinergic system does not appear
      to be closely related to the etiology, but rather to the development of clinical
      symptoms. In addition, abnormalities of ChAT in the brain have been recently
      demonstrated in schizophrenia and sudden infant death syndrome.

PMID- 10594839
TI  - An immunohistochemical study of the mesenchymal and epithelial components of
      pulmonary chondromatous hamartomas.
AB  - Twenty-five cases of solitary pulmonary chondromatous hamartomas (PCH) were
      examined by immunohistochemistry to evaluate the mesenchymal and epithelial
      components. PCH composed of predominantly mature cartilage were designated as C
      type, those predominantly composed of fibromyxoid tissue as FM type, and those
      predominantly composed of adipose tissue as A type. FM type PCH revealed various
      amounts of cartilage in various developmental stages, adipose tissue and
      fibromyxoid tissue, compared with a uniform pattern of cartilage tissue in C
      type. The cells of transitional form between spindle cells, stellate cells and
      chondrocytes were present in FM type. Epithelial components in PCH were
      bronchial, bronchiolar and cuboidal cells, mostly at the periphery of PCH. S-100
      protein consistently stained chondrocytes, stellate and spindle cells in the
      fibromyxoid tissue of solitary PCH. Fibroblast growth factor was immunolocalized
      to chondrocytes, spindle and stellate cells in the fibromyxoid tissue. The
      collagen type was associated with differentiation from primitive mesenchymal
      cells to chondrocytes (i. e. type I and III collagen appeared in fibromyxoid
      matrix and type II collagen in the cartilaginous matrix). Fibronectin
      coordinately appeared with type I and III collagens. The proliferating cell
      nuclear antigen labeling index of epithelial cells was comparable to those of
      neoplastic mesenchymal cells, but it was not significantly different between C
      type and FM type PCH. The primitive mesenchymal cells in the bronchial walls of
      the control premature neonates were also observed. This immunohistochemical study
      showed that the progenitor mesenchymal cells in the bronchial and bronchiolar
      walls may differentiate along chondrocytes, lipocytes, and smooth muscle cells in
      PCH and that epithelial proliferation is reactive and closely associated with
      neoplastic proliferation of the mesenchymal component.

PMID- 10594840
TI  - Mucinous carcinoma of the breast: a multifaceted study with special reference to
      histogenesis and neuroendocrine differentiation.
AB  - Although mucinous carcinoma (MC) of the breast is considered to originate from
      ductal carcinoma, it is not known whether mucinous growth begins in the
      intraductal carcinoma or later in the invasive carcinoma. In this study, 33 MC
      (16 pure without any ductal components, 10 mixed Type I with an intraductal
      component, seven mixed Type II with a common invasive ductal carcinoma (IDC)
      component)) were examined to clarify the time when mucinous growth begins.
      Histochemical and immunohistochemical examinations of mucin revealed that
      mucinous growth can begin in the intraductal carcinoma and in the common IDC.
      Histological transition and clonality analysis using microsatellite markers
      supported that some MC originate from common IDC. The pure type of MC probably
      originates from the intraductal carcinoma, showing a micropapillary feature.
      Neuroendocrine differentiation, known to be associated with MC, seemed to create
      the main progress in the typical MC. Moreover, we analyzed the factors of a worse
      prognosis of mixed MC Type II, which was strongly suggested by the lymph node
      status. However, no explainable differences on the cell proliferating ability, or
      c-erbB-2 and p53 protein overexpression were found.

PMID- 10594841
TI  - Mammary Paget's disease: evidence of diverse origin of the disease with a
      subgroup of Paget's disease developing from the superficial portion of
      lactiferous duct and a discontinuous pattern of tumor spread.
AB  - The pattern of spread of intraductal carcinoma associated with mammary Paget's
      disease has not been well studied. The purpose of this study was to examine the
      site of origin and the pattern of tumor spread with a three-dimensional view by
      serial sectioning of the tissue blocks from 19 cases of Paget's disease.
      Intraductal carcinoma in the superficial portion of the lactiferous ducts was
      seen in continuity with the overlying epidermis with Paget's disease in all 19
      cases. In seven cases that had adequate tissue sampling, five showed a continuous
      pattern of the intraductal carcinoma within the superficial as well as the deep
      breast tissue. In the remaining two cases, a portion of benign duct was
      identified between the intraductal carcinoma in the superficial lactiferous duct
      and the deep breast tissue. This discontinuous pattern of spread of the
      intraductal carcinoma was also identified in the foci of carcinoma in deep
      tissue. In the five cases in which the tumor involved the skin and only the
      superficial portions of the lactiferous duct, the leading edge of the intraductal
      carcinoma was seen orientated in the direction of the nipple towards the deep
      breast tissue. Our study of Paget's disease demonstrated that in addition to
      tumor spread along the lactiferous ducts from intraductal carcinoma in the deep
      tissue towards the nipple, there was a group of Paget's disease arising from the
      nipple. These lesions included: (i) lesions limited to the areolar tissue; and
      (ii) lesions with intraductal carcinoma involving the duct system in both
      superficial and deep breast tissue with and, possibly, without skip areas pattern
      of spread. Although certain cases of Paget's disease may appear superficial, an
      independent associated carcinoma in deep breast tissue has to be ruled out.

PMID- 10594842
TI  - Fusion of intussusceptum and intussuscipiens in intrauterine intussusception: a
      rare type of intestinal atresia.
AB  - Intrauterine intussusception is well known as one of the rare causes of
      intestinal atresia. Although the polypoid intussusceptum is usually observed at
      the obstructed end on the distal side, a few cases with the polypoid lesion
      located apart from the blind end have been reported. To elucidate the etiology of
      separated polypoid intussusceptum, we reviewed 42 surgical cases of jejunal or
      ileal atresia over the last 12 years at Kobe Children's Hospital, Kobe, Japan. Of
      the 42 cases, 11 were intrauterine intussusception. Two of the 11 cases were
      associated with polypoid intussusceptums separated from the obstructed ends; the
      intestinal portion between the polypoid intussusceptum and the obstructed end
      showed a partial two-fold proper muscle wall and a mesenteric structure
      invaginated between the two walls. Another case showed linear ulcers facing each
      other on both the intussusceptum and intussuscipiens. Linear ulceration and
      subsequent fusion of the intussusceptum and intussuscipiens are suggested to be
      the pathogenesis of the first two cases.

PMID- 10594843
TI  - MEN1 gene mutations in sporadic neuroendocrine tumors of foregut derivation.
AB  - Foregut-derived neuroendocrine (NE) tumors occur sporadically or in association
      with multiple endocrine neoplasia type 1 (MEN1) syndrome. Thirty-nine sporadic NE
      tumors of foregut derivation (six thymic, 21 bronchial, three gastric, and nine
      pancreatic tumors) as well as two hindgut-derived rectal carcinoids for somatic
      MEN1 gene mutation were analyzed by direct sequencing analysis. Five tumors
      showed mutations: nonsense mutations (Q393X and R98X) in thymic and pancreatic NE
      tumors, respectively, a 4 b.p. deletion (357del4) in a gastric NE carcinoma, and
      missense mutations (D172Y and S178Y) in pancreatic NE tumors. No mutation was
      identified in pulmonary or rectal NE tumors. In a patient with a pancreatic NE
      tumor (D172Y), the corresponding germline DNA showed the same mutation,
      suggesting that sporadic MEN1 syndrome was masked in this case. Somatic MEN1 gene
      mutations and deletions may play a crucial role in the tumorigenesis of a subset
      of foregut-derived NE tumors. Sporadic MEN1 syndrome may occur as a sporadic NE
      tumor of the pancreas.

PMID- 10594844
TI  - Genetic dissection of the complex pathological manifestations of collagen disease
      in MRL/lpr mice.
AB  - An MRL strain of mice bearing a Fas-deletion mutant gene, lpr, MRL/MpJ-lpr/lpr
      (MRL/lpr) develops collagen disease involving vasculitis, glomerulonephritis,
      arthritis and sialoadenitis, each of which has been studied as a model for
      polyarteritis, lupus nephritis, rheumatoid arthritis and Sjogren's syndrome,
      respectively. Development of such lesions seems dependent on host genetic
      background since the congenic C3H/HeJ-lpr/lpr (C3H/lpr) mice rarely develop them.
      To identify the gene loci affecting each lesion, a genetic dissection of these
      complex pathological manifestations was carried out. First, histopathological
      features in MRL/lpr, C3H/lpr, (MRL/lpr x C3H/lpr) F1 intercross, and MRL/lpr x
      (MRL/lpr x C3H/lpr) F1 backcross mice were analyzed. Genomic DNA of the backcross
      mice were subjected to association studies by Chi-squared analysis for
      determining which polymorphic microsatellite locus occurs at higher frequency
      among affected compared to unaffected individuals for each lesion. As a result,
      gene loci recessively associated with each lesion were mapped on different
      chromosomal positions. We concluded that each of these lesions in MRL/lpr mice is
      under the control of a different set of genes, suggesting that the complex
      pathological manifestations of collagen disease result from polygenic
      inheritance.

PMID- 10594845
TI  - Expression of scavenger receptor class A and CD14 in lipopolysaccharide-induced
      lung injury.
AB  - CD14 and macrophage scavenger receptor class A type I and II (MSR-A) are
      receptors for lipopolysaccharide (LPS). In this study, the expressions of both
      receptors in the lung after administration of LPS in aerosol to mice with a
      nebulizer were observed. Bronchiolar epithelial cells and alveolar macrophages
      immediately incorporated LPS and expressed CD14. CD14-positive neutrophils then
      appeared in the alveolar space followed by the appearance of MSR-A-expressing
      cells in the vascular lumen, pulmonary interstitium, and alveolar space. Numbers
      of apoptotic cells increased after 1 day, and MSR-A-expressing macrophages
      actively incorporated apoptotic bodies. Daily administration of macrophage colony
      stimulating factor (M-CSF) to the mice resulted in increased levels of MSR-A
      expression and reduced levels of CD14 as well as several cytokine expressions,
      leading to shortening of the inflammatory process. The numbers of apoptotic cells
      were reduced in M-CSF injected mice. These findings imply that CD14 acts as an
      immediate expressing receptor for LPS and MSR-A exerts a protective function by
      scavenging LPS and apoptotic cells in LPS-induced lung injury.

PMID- 10594846
TI  - An immunohistochemical study of bizarre neoplastic cells in pleomorphic adenoma:
      its cytological nature and proliferative activity.
AB  - The cytological nature and proliferative activity of bizarre neoplastic cells,
      widely scattered in pleomorphic adenomas of salivary gland origin were studied.
      Pleomorphic adenomas containing numerous bizarre neoplastic cells were found in
      four cases, and were equal to 2.9% of all pleomorphic adenomas examined. All four
      cases presented as well-circumscribed, firm masses measuring less than 1.5 cm in
      size, located in the palate, and were of 7 months to 4 years duration.
      Histopathologically, these pleomorphic adenomas were cell rich type, and were
      well demarcated from surrounding tissues, although their fibrous capsules were
      partially defective. In addition to characteristic histopathological findings of
      pleomorphic adenoma, numerous neoplastic cells with bizarre appearance were
      scattered throughout the lesion, excepting for tubuloductal structures. These
      bizarre neoplastic cells had irregular-shaped and large nuclei with or without
      hyperchromatism, although their nucleoli were small and mitotic figures were few.
      Furthermore, there were many multinucleated giant cells, some of which showed
      multilobulated nuclei. Neither necrosis nor infarct was seen in the tumors.
      Immunohistochemically, bizarre neoplastic cells scattered in solid-proliferating
      areas and myxoid areas were neoplastic myoepithelial cells in nature. There was
      no statistical significance of MIB-1 labeling indices between pleomorphic
      adenomas with bizarre neoplastic cells and usual pleomorphic adenomas. The p53
      labeling indices were quite low. Although the benign nature of pleomorphic
      adenomas with numerous bizarre neoplastic cells and hypercellularity,
      distinguishing such pleomorphic adenomas from various stages of malignant
      transformation in pleomorphic adenomas and other carcinomas should be made by
      histological section of submitted biopsy specimen or aspirated content for
      cytological diagnosis. The present paper suggests that the term 'bizarre cell
      pleomorphic adenoma' is an appropriate name for this neoplasm, in that it is
      distinguished from the usual benign pleomorphic adenoma which is easily diagnosed
      by routinely prepared histological or cytological stainings.

PMID- 10594847
TI  - The histological spectrum of subperiosteal fibrocartilaginous pseudotumor of long
      bone (focal fibrocartilaginous dysplasia).
AB  - Clinicopathological features in six cases of focal fibrocartilaginous dysplasia
      (FFCD) which involved either the tibia (n = 4) or the femur (n = 2) were
      reviewed. All cases presented clinical and radiological characteristic features,
      and histopathological findings were analyzed in five of the six cases. The
      subject group comprised three boys and three girls, ages ranged from 12 to 18
      months. Histologically, the individual lesions showed regional variation in
      cellularity, amount of fibrous and cartilaginous components. Paucicellular areas
      were mainly composed of dense fibrous tissue while more cellular areas contained
      foci of fibrocartilaginous element. The chondrocytes and stellate cells around
      cartilaginous area were positive for S-100 protein. One case contained both
      hyaline and fibrocartilage, and architecturally mimicked normal tendinous
      insertion. One case, which involved proximal tibia, was purely composed of
      fibrous tissue without fibrocartilage. All cases formed undulating and irregular
      borders against underlying cortical bone. Histopathologically variable spectrum
      suggests a strong possibility of undergoing transition from initial cellular and
      cartilagnous to late paucicellular, fibrous phase. Although any evidence that can
      explain basic pathogenesis or prognostic histological parameter is lacking, we
      believe that the term FFCD is not relevant because the presence of fibrocartilage
      is not an essential feature, and it can cause confusion with other pathological
      processes. We propose the term 'subperiosteal fibrocartilaginous pseudotumor of
      long bone' for this unique clinicopathological entity with which heterologous
      cartilaginous element can be associated.

PMID- 10594848
TI  - Lipoma of the adrenal gland.
AB  - A rare case of a lipoma of the adrenal gland is reported with a review of the
      literature. The tumor was incidentally found at autopsy in a 50-year-old man who
      died from severe head trauma after a traffic injury. At autopsy, an oval-shaped,
      soft yellow nodule measuring 1.1 cm in diameter was found in the right adrenal
      cortex. Histological examination revealed a lesion consisting of mature adipose
      tissue partially surrounded by a thin fibrous capsule. On serial sections there
      was no evidence of hematopoiesis nor of adrenal medulla cells. To the best of our
      knowledge, this is the eighth case described in the English literature. With the
      increasing use and the high resolution of modern imaging techniques, these
      unsuspected adrenal masses may become more prevalent.

PMID- 10594849
TI  - An immunohistochemical study on a case of granulocyte-colony stimulating factor
      producing gall-bladder carcinoma.
AB  - Primary gall-bladder carcinoma producing granulocyte-colony stimulating factor
      (GCSF) is extremely rare. Only four cases, histologically investigated, have been
      reported to date in the English literature. We report a case of a 48-year-old
      female with primary gall-bladder carcinoma, associating with leukocytosis (15
      700/mm3) and a high level of serum GCSF (54.0 pg/mL). The tumor was,
      histologically, a poorly differentiated adenocarcinoma with marked interspersed
      neutrophils invading into the primary tumor itself and the right lobe of the
      liver. Tumor cells distinctly showed positive immunoreaction in the cytoplasm
      with anti-GCSF antibody, and in the nucleus for anti-p53 antibody. After surgery,
      the leukocytosis and serum level of GCSF began to decrease. These findings
      confirmed the present case of GCSF-producing gall-bladder carcinoma, exhibiting
      leukocytosis. A total of five cases, including our case, reported as a GCSF
      producing gall-bladder carcinoma were clinicopathologically reviewed.

PMID- 10594850
TI  - So-called 'hybrid' lesion of desmoplastic and conventional ameloblastoma: report
      of a case and review of the literature.
AB  - So-called 'hybrid' lesion of ameloblastoma, which is composed of desmoplastic
      ameloblastoma and conventional follicular/plexiform ameloblastoma, is an unusual
      variant of ameloblastoma and only eight cases of 'hybrid' lesion have been
      published in the English literature. To enhance knowledge of this interesting
      tumor, we add a case of 'hybrid' lesion that occurred in the right mandible of a
      48-year-old Japanese male. Radiographic examination disclosed a honeycomb
      appearance at the anterior alveolar region, combined with a unicystic
      radiolucency in the molar region of the mandibular body. Histologically, the
      former showed microscopic features of desmoplastic ameloblastoma and the latter
      those of follicular ameloblastoma with focal granular cell transformation. The
      lesion was enucleated with curettage of surrounding bone and the lesional cavity
      was marsupialized. Although tumor tissues reappeared at 3, 5, 7 and 14 months
      after the surgery, the patient has remained disease free for 11 years after the
      last vaporization by CO2 laser of the recurred tumor. Many more cases of 'hybrid'
      lesion are needed to clarify the clinicopathological, histopathological and
      biological characteristics of this interesting variant of ameloblastoma.

PMID- 10594851
TI  - Uterine adenomyoma of endocervical type.
AB  - A uterine adenomyoma of endocervical type was presented histopathologically in a
      44-year-old woman. She had a mural tumor of the uterine endocervix, which showed
      a well-circumscribed margin and multiple cysts filled with mucin. Histologically,
      the tumor was composed of a proliferation of endocervical glands and smooth
      muscle. The glandular epithelial components were cystic and occasionally
      papillary, but neither component showed cytological atypia. A differential
      diagnosis of the uterine endocervical tumor should include adenomyoma of
      endocervical type.

PMID- 10594852
TI  - Minimal solid tumor involvement of regional and distant sites: when is a
      metastasis not a metastasis?

PMID- 10594853
TI  - The ongoing evolution of dendritic cell therapy.

PMID- 10594854
TI  - Expression of cyclin E in dysplasia, carcinoma, and nonmalignant lesions of
      Barrett esophagus.
AB  - BACKGROUND: Barrett esophagus (BE) is a condition in which the normal squamous
      epithelium of the esophagus is replaced by metaplastic columnar epithelium. BE is
      a premalignant lesion because it is the initiating factor in a metaplasia
      dysplasia-carcinoma sequence. METHODS: Expression of the proliferation-associated
      molecule cyclin E was immunohistochemically determined in metaplastic specialized
      epithelium (SE; n = 24), low grade dysplasia (LGD; n = 21), high grade dysplasia
      (HGD; n = 17), and invasive adenocarcinoma (CA; n = 35) from 36 esophagectomy
      specimens. In addition, endoscopically obtained samples of SE with minimal
      inflammatory changes (n = 11) and SE adjacent to erosions or ulcerations were
      tested for cyclin E expression. RESULTS: In the surgical specimens, expression of
      cyclin E was found in 0 of 24 SE (0%), 2 of 21 LGD (9.5%), 3 of 17 HGD (17.6%),
      and 5 of 35 CA (14. 3%). In the biopsy specimens, expression of cyclin E was
      found in all samples adjacent to erosions or ulcerations, whereas SE with minimal
      inflammatory changes was invariably negative for cyclin E. CONCLUSIONS:
      Accumulation of cyclin E can be found by means of immunohistochemistry in
      premalignant and malignant lesions in BE as well as in regenerative metaplastic
      epithelium. The determination of cyclin E expression is therefore not useful in
      the identification of BE patients with an increased risk for the development of
      carcinoma.

PMID- 10594855
TI  - Larger and more invasive colorectal carcinoma contains larger amounts of
      plasminogen activator inhibitor type 1 and its relative ratio over urokinase
      receptor correlates well with tumor size.
AB  - BACKGROUND: Considering recent findings that both urokinase plasminogen activator
      receptor (uPAR) and plasminogen activator inhibitors (PAIs) are involved in tumor
      growth through an urokinase-type plasminogen activator (uPA) activity-independent
      mechanism, the relation between the presence of these factors in tumor tissue and
      the clinicopathologic variables in colorectal carcinoma was reevaluated. METHODS:
      In 100 colorectal carcinoma patients, antigen levels of u-PA, uPAR, and PAI-1 and
      PAI-2 were assayed in both tumor tissues and their normal counterparts. Plasma
      levels of soluble uPAR also were determined. RESULTS: All uPAR, uPA, PAI-1, and
      PAI-2 antigen levels in tumor tissue were significantly higher than those in
      normal tissue. Levels of both uPAR and PAI-1 were significantly higher (3.09 +/-
      1.37 and 6.63 +/- 7.49, respectively) in large tumors (>/=50 mm in greatest
      dimension) than those in smaller tumors (< 50 mm) (2.50 +/- 1.07 and 2.72 +/-
      2.70, respectively) (P < 0.05). Significant positive correlation coefficients (r)
      were obtained between tumor size and the calculated ratios of PAI-1/uPAR (r =
      0.490; P < 0.0001) and PAI-1/uPA (r = 0. 469; P < 0.0001). In addition to liver
      metastases (P = 0.004) and lymph node involvement (P = 0.04), high levels of uPAR
      (P = 0.05) also were found to be of independent prognostic value by multivariate
      analysis. CONCLUSIONS: Higher expression of uPAR was related to poor prognosis of
      patients with colorectal carcinoma and excess amounts of PAI-1 over uPAR or uPAR
      bound uPA appeared to play an important role in tumor progression.

PMID- 10594856
TI  - Chemoradiation with or without intraoperative radiation therapy in patients with
      locally recurrent rectal carcinoma: prognostic factors and long term outcome.
AB  - BACKGROUND: Rectal carcinoma patients with local recurrence are reported to have
      a dismal prognosis. The purpose of this study was to evaluate the effect of
      combined modality therapy on clinical outcome and to determine the prognostic
      impact of a "presurgical" staging system. METHODS: Between September 1989 and
      June 1997, 47 patients (with a median follow-up of 80 months) with locally
      recurrent, nonmetastatic rectal carcinoma were classified according to the extent
      of pelvic sidewall involvement as determined by pretreatment computed tomography
      (CT) scan. They received preoperative external beam radiation (45-47 grays [Gy]
      in 34 patients; 23.4 Gy in 13 preirradiated patients) plus concomitant 5
      fluorouracil (1000 mg/m(2)/day as a 96-hour continuous infusion on Days 1-4 + 29
      32) and mitomycin C (10 mg/m(2) as a bolus intravenously on Day 1 + 29). After 4
      6 weeks, the patients were evaluated for surgical resection and intraoperative
      radiation therapy (IORT) procedure (10-15 Gy) or, in unresectable patients, a
      boost dose was planned by chemoradiation (23.4 Gy) or brachytherapy. Thereafter,
      adjuvant chemotherapy (5-fluorouracil and leucovorin for a total of six to nine
      courses) was prescribed. RESULTS: During chemoradiation, 2 patients (4.3%)
      developed Radiation Therapy Oncology Group Grade 3-4 acute toxicity. Twenty-five
      patients (53. 2%) had an objective response after chemoradiation. Twenty-one
      patients (45%) underwent radical surgical resection. The overall 5-year survival
      and local control rates were 22% and 32%, respectively. The classification system
      significantly predicted survival (P = 0.008). Radically resected patients had
      better local control and survival (P < 0.0001); in patients treated with IORT,
      the 5-year local control and survival rates were 79% and 41%, respectively.
      CONCLUSIONS: The data from the current study suggest that combined modality
      therapy was well tolerated and improved resectability, local control, and
      survival. The classification system appears to be a reliable tool with which to
      predict clinical outcome in patients with locally recurrent rectal carcinoma.

PMID- 10594857
TI  - Pyloric gland metaplasia with perineural invasion of the gallbladder: A lesion
      that can be confused with adenocarcinoma.
AB  - BACKGROUND: Metaplastic pyloric glands have been described in a variety of organs
      including the gallbladder, in which they can extend into the muscular wall and
      serosa. METHODS: Clinical, histologic, and immunohistochemical features of four
      cases of gallbladder florid pyloric gland metaplasia with perineural and
      intraneural invasion are analyzed. RESULTS: The patients with pyloric gland
      metaplasia and perineural and intraneural invasion were all females ages 57-72
      years. A preoperative diagnosis of chronic cholecystitis and cholelithiasis was
      made for all four patients, but a histologic diagnosis of adenocarcinoma was made
      for two patients and entertained in two others. Macroscopically the gallbladders
      showed changes usually associated with chronic cholecystitis. No intraluminal
      masses were observed in any of the gallbladders. The characteristic microscopic
      features included florid pyloric gland metaplasia, proliferation of medium-sized
      nerve trunks more prominent in the muscular layer and serosa, and perineural and
      intraneural invasion by the metaplastic glands lined by cytologically bland
      cuboidal or columnar mucin-containing cells. At last follow-up all patients were
      alive and symptom free 1-7 years after laparoscopic cholecystectomy. CONCLUSIONS:
      Pyloric gland metaplasia of the gallbladder should be added to the long and
      increasing list of benign epithelial proliferations that are associated with
      perineural and intraneural invasion. This lesion should not be mistaken for
      adenocarcinoma of the gallbladder, a misinterpretation that may have serious
      therapeutic implications. The pathogenesis of this phenomenon is unknown.

PMID- 10594858
TI  - Chronic myelogenous leukemia in nonlymphoid blastic phase: analysis of the
      results of first salvage therapy with three different treatment approaches for
      162 patients.
AB  - BACKGROUND: The prognoses of patients with chronic myelogenous leukemia in
      blastic phase (CML-BP) are extremely poor. Treatment of patients with nonlymphoid
      CML-BP is associated with very low response rates, a median survival of 2-3
      months, and significant toxicities. The aim of this study was to evaluate the
      results of therapy in CML-BP with different treatments in relation to response
      rate, survival, and toxicity. METHODS: A total of 162 adults patients with a
      diagnosis of nonlymphoid CML-BP referred from 1986 to 1997 were included in this
      analysis. Only first salvage therapy was considered for the purpose of this
      analysis. The blastic phase of CML was defined by the presence of 30% or more
      blasts in the blood or bone marrow, or extramedullary disease. Ninety patients
      were treated with intensive chemotherapy, 31 with decitabine, and 41 with other
      single agents. RESULTS: Thirty-six patients (22%) had an objective response.
      Response rates were similar among patients treated with intensive chemotherapy
      (28%) or with decitabine (26%). In aggregate, other single agents showed
      objective response rates of 7%. The median duration of remission for all patients
      was 29 weeks and the median overall survival 22 weeks. Patients treated with
      decitabine showed a trend toward better survival, despite a higher percentage of
      older patients (P < 0.004). The median survival times were 29 weeks with
      decitabine, 21 weeks with intensive chemotherapy, and 22 weeks with other agents.
      When only older patients were considered, survival was significantly better with
      decitabine versus other treatments (P < 0.01). A multivariate analysis of
      prognostic factors for survival confirmed the independent, significant favorable
      effect of decitabine therapy (P = 0.047). In all groups complications of
      myelosuppression were the most significant side effects. Severe nonhematologic
      toxicities were not observed in patients treated with decitabine; they occurred
      in 20% and 17% of patients treated with intensive chemotherapy or other single
      agents, respectively. CONCLUSIONS: Compared with intensive chemotherapy,
      decitabine showed favorable results, with similar objective response rates, a
      better nonhematologic toxicity profile, and a trend for better survival,
      particularly among older patients. Studies will now attempt to combine decitabine
      with other promising approaches, such as homoharringtonine, low dose cytarabine,
      and interferon-alpha, in all CML phases.

PMID- 10594859
TI  - Alternative medicine use in patients with localized prostate carcinoma treated
      with curative intent.
AB  - BACKGROUND: Alternative medicine therapies are estimated to be used by 7-64% of
      cancer patients but up to 72% do not inform their physician. To the authors'
      knowledge little useful information is available regarding the prevalence of
      alternative medicine use by patients with prostate carcinoma. Thus, the authors
      attempted to evaluate the prevalence of alternative medicine use by prostate
      carcinoma patients treated with curative intent by either radical prostatectomy,
      brachytherapy alone, or a combination of brachytherapy and external radiation
      therapy. METHODS: Between January 1997 and May 1998, 234 men with clinically
      localized prostate carcinoma underwent radical prostatectomy (54 patients) or
      brachytherapy (180 patients) with (74 patients) or without (106 patients)
      external beam radiation therapy. In July 1998 a questionnaire was mailed to all
      patients comprised of multiple questions regarding alternative medicine use to
      which 190 patients (81%) responded. The overall prevalence and types of
      alternative medicine therapies used were assessed and the relation between age at
      procedure, pretreatment prostate specific antigen level, clinical stage,
      pretreatment Gleason score, and type of treatment with the use of alternative
      medicine therapies was evaluated using univariate and multivariate analysis.
      RESULTS: The prevalence of alternative medicine use by prostate carcinoma
      patients responding to the survey was 43% (81 of 190 patients). No significant
      differences in alternative medicine use were observed between the patients who
      received brachytherapy alone (38%), those who underwent radical prostatectomy
      (40%), and those treated with combined brachytherapy and external beam radiation
      therapy (51%). Vitamins, prayer or other religious practices, and herbal
      medicines were the most commonly used therapies in these patients. Higher
      pretreatment Gleason scores were associated with a greater use of alternative
      medicine therapies on both multivariate and univariate analyses. Finally, using
      multivariate analysis, younger prostate carcinoma patients were more likely to
      use alternative medicine therapies than older patients. CONCLUSIONS: Alternative
      medicine use is very prevalent among patients treated for localized prostate
      carcinoma. Because some of these treatments may have a potential biologic impact
      on tumor behavior and, consequently, on definitive or surrogate therapeutic
      endpoints, patients should be questioned carefully regarding alternative medicine
      use during routine tumor follow-up.

PMID- 10594860
TI  - Expression of beta1 and beta4 integrins in normal arachnoid membrane and
      meningiomas.
AB  - BACKGROUND: The aim of this work was to study the expression of alpha, beta1, and
      beta4 integrin subunits in meningiomas. METHODS: Seventeen atypical or anaplastic
      meningiomas were retrieved from the files of Hopital de Bellevue, Saint-Etienne,
      France. They were compared with 17 benign meningiomas consecutively examined in
      1997 and 6 schwannomas. The tumors were classified according to standard
      histologic criteria. Frozen sections were immunostained for alpha1, alpha2,
      alpha3, alpha4, alpha5, alpha6, beta1, and beta4 integrin subunits; collagen;
      laminin and fibronectin; cytokeratin; vimentin; neural cell adhesion molecule
      (NCAM); and MIB-1. RESULTS: The study included 7 fibrous meningiomas, 6
      transitional meningiomas, 19 syncytial meningiomas, and 2 secretory meningiomas.
      The expression of alpha1, alpha3, alpha5, alpha6, and beta1 was constant. The
      expression of alpha1 was higher in fibrous meningiomas than in syncytial
      meningiomas. Only in transitional, syncytial, and secretory meningiomas was the
      expression of alpha2 detected. The expression of alpha2 and beta4 was associated
      with the expression of cytokeratin in the glandular structures of secretory
      meningiomas, whereas it was associated with NCAM expression in the whorls of
      meningothelial meningiomas. The expression of integrin receptors by tumor cells
      was strongly correlated with that of their respective ligands in the
      extracellular matrix. In invasive meningiomas, the expression of alpha3 and
      alpha6 by tumor cells was significantly lower. The higher the MIB-1 proliferation
      index, the lower the expression of alpha3. The 6 schwannomas expressed only
      alpha2, alpha3, alpha6, beta1, and beta4 integrins. CONCLUSIONS: Each histologic
      subtype of meningioma has a specific spectrum of integrin expression. The study
      of alpha3 and alpha6 may have prognostic value in the assessment of meningiomas.
      The study of the integrin profile is valuable for the differential diagnosis of
      fibrous meningiomas and schwannomas.

PMID- 10594861
TI  - A single-visit cervical carcinoma prevention program offered at an inner city
      church: A pilot project.
AB  - BACKGROUND: A single-visit cervical carcinoma prevention program was implemented,
      integrating screening, diagnosis, treatment, and health education in the familiar
      environment of the community church. METHODS: Nonpregnant women age 18 years or
      older, who had not received cervical carcinoma screening in the preceding year
      were eligible. Subjects provided information on personal demographics, health,
      and knowledge regarding cervical carcinoma prevention. Thereafter, cervical
      cytology was collected, processed, and interpreted on site. Participants attended
      small-group instruction on cervical carcinoma prevention. Screening results were
      given to each subject individually. Patients with abnormal cytology underwent
      immediate colposcopy with biopsies or loop electrosurgical excision procedure as
      indicated. Participant satisfaction and educational impact were evaluated.
      RESULTS: Ninety of the 98 participants reported that Spanish was their native
      language; 59 did not speak English. Fifty-four had had fewer than 6 years of
      education and 55 were unemployed. Seventy-eight did not have a regular physician
      or health insurance. Twenty-four either had never undergone cervical carcinoma
      screening or had let more than 5 years elapse since their previous examination.
      None of nine potential barriers assessed correlated with past compliance with
      cervical carcinoma screening. The mean time for processing and on-site
      interpretation of cervical cytology smears was 22.6 +/- 5.3 minutes. The median
      time patients spent in the program was 75 minutes. There was a significant
      improvement in the subjects' knowledge regarding cervical carcinoma prevention.
      All participants were highly satisfied. CONCLUSIONS: This parish-based,
      integrated, single-visit program for the prevention of cervical carcinoma was
      easily implemented and provided care to a substantial proportion of underserved
      patients.

PMID- 10594862
TI  - International Union Against Cancer. Classification of isolated tumor cells and
      micrometastasis.
AB  - BACKGROUND: Findings of isolated (disseminated or circulating) tumor cells (ITC)
      by immunocytochemistry and molecular pathology methods have led to varied
      interpretations and different applications of the TNM system. METHODS: An
      analysis of the relevant literature was undertaken. In addition, optional
      proposals for the classification of ITC, micrometastasis, and cytologic results
      in pleural and peritoneal washings are presented. RESULTS: Immunocytochemistry
      has a lower false-positive rate than nonmorphologic methods such as flow
      cytometry or the polymerase chain reaction; therefore the method(s) used always
      should be recorded. At the current time, the independent prognostic significance
      of ITC in regional lymph nodes and in the general circulation (blood, bone
      marrow, and other distant sites) is difficult to assess. To enable comparisons of
      treatment results and to avoid variation in staging, a finding of ITC should not
      be considered in the TNM and residual tumor (R) classifications, at least not at
      the current time. However, for future evaluation of their prognostic
      significance, the respective findings should be documented according to uniform
      criteria. CONCLUSIONS: ITC should be distinguished from micrometastasis. To
      investigate the independent prognostic significance of ITC and of positive lavage
      cytology, uniform data collection according to the proposed coding schema is
      recommended.

PMID- 10594863
TI  - Report from the International Union Against Cancer (UICC) Tumor Biology
      Committee: UICC workshop on the use of dendritic cells in cancer clinical trials.

PMID- 10594864
TI  - The American College of Surgeons Commission on Cancer and the American Cancer
      Society. The National Cancer Data Base report on age, gender, treatment, and
      outcomes of patients with chronic lymphocytic leukemia.
AB  - BACKGROUND: The natural history of chronic lymphocytic leukemia (CLL) is
      changing, although the reasons (potential changes in the disease's biology or in
      patterns in patient characteristics, treatment, or referral) are unclear.
      METHODS: This report uses National Cancer Data Base (NCDB) data, which reflect a
      hospital-based patient population from a broad spectrum of hospitals in the
      United States. Age, gender, race/ethnicity, income, treatment, overall survival,
      and relative survival were evaluated according to time period (1985-1990 and 1991
      1995). Comparisons were made with U. S. population figures for 1990 and with
      series published over the last 70 years. RESULTS: CLL comprised 22.6% of the
      108,396 cases of leukemia in the data base. The risk of developing CLL increased
      progressively with age and did not plateau; the average age was 69.6 years. At
      the time of initial diagnosis, 60.5% of patients received no treatment (this
      proportion increased from 58.1% to 62.7% between the 2 time periods). Overall
      survival was 48.2% at 5 years and 22.5% at 10 years. The 5-year relative survival
      was 69.5%, 72.2%, 63.1%, and 41.7% for age groups <40, 40-59, 60-79, and 80+
      years, respectively; these rates indicated that CLL, and not comorbid disease,
      caused the greatest percentage of deaths. CONCLUSIONS: The risk of developing CLL
      increases progressively with age without plateauing and is 2.8 times higher for
      older men than for older women. There is an increasing trend toward no treatment
      at the time of initial diagnosis. Long term overall survival of CLL patients is
      poor. CLL is a more fatal disease among older individuals because of the disease
      itself, not because of comorbid conditions.

PMID- 10594865
TI  - The American College of Surgeons Commission on Cancer and the American Cancer
      Society. Adenocarcinoma of the small bowel: review of the National Cancer Data
      Base, 1985-1995.
AB  - BACKGROUND: Small bowel adenocarcinoma (SBA) accounts for 2% of gastrointestinal
      (GI) tumors and 1% of GI cancer deaths. The objective of this study was to review
      the National Cancer Data Base (NCDB) to identify case-mix characteristics,
      patterns of treatment, and factors influencing survival of patients with SBA.
      METHODS: NCDB data from patients diagnosed with primary SBA between 1985-1995
      were analyzed. Chi-square statistics were used to compare differences between
      groups. Disease specific survival (DSS) was calculated using the life table
      method for patients diagnosed between 1985-1990; univariate differences in
      survival were compared using the Wilcoxon statistic, and multivariate analyses
      were performed using a Cox regression model. RESULTS: There were 4995 SBA cases
      reported to the NCDB between 1985-1995, 55% of which occurred in the duodenum,
      18% in the jejunum, 13% in the ileum, and 14% in nonspecified sites. The overall
      5-year DSS was 30.5%, with a median survival of 19.7 months. By multivariate
      analysis, factors significantly correlated with DSS included patient age, tumor
      site, disease stage, and whether cancer-directed surgery was performed.
      CONCLUSIONS: SBA is found most commonly in the duodenum, and patient DSS is
      reduced at this site compared with those patients with jejunal or ileal tumors.
      This reduction in survival was associated with a lower percentage of cancer
      directed surgery. Patients age > 75 years had a reduced DSS and more duodenal
      tumors, and were less frequently treated by cancer-directed surgery than their
      younger counterparts. This study reflects the experience with SBA from a large
      cross-section of U.S. hospitals, allowing for the identification of prognostic
      factors and providing a reference with which results from single institutions may
      be compared.

PMID- 10594867
TI  - Population estimation of valproic acid clearance in adult patients using routine
      clinical pharmacokinetic data.
AB  - The aim of the present study was to estimate valproic acid (VPA) clearance values
      for adult patients with epilepsy, using serum concentrations gathered during
      their routine clinical care. Retrospective steady state serum concentrations data
      (n=534) collected from 208 adult patients receiving VPA were studied. Data were
      analysed according to a one-compartment model using the NONMEM program. The
      influence of VPA daily dose (Dose), gender, age, total body weight (TBW), and
      comedication with carbamazepine (CBZ), phenytoin (PHT) and phenobarbital (PB)
      were investigated. The results of the population pharmacokinetics analysis were
      validated in a group of 30 epileptic patients. The final regression model for VPA
      clearance (Cl) was: $?rm Cl?left (?rm L/h ?right )=0?rm. 004?times TBW?times Dose
      ?0.304??rm ?times 1.363?,?rm CBZ?times 1. 541?,?rm PHT?times 1.397?,?rm PB.$ The
      inter-individual variability in VPA clearance, described by a proportional error
      model, had a variation coefficient (CV) of 23.4% and the residual variability,
      described using an additive model, was 11.4 mg/L. These results show that VPA
      clearance increased linearly with TBW, but increases nonlinearly with increasing
      VPA daily dose. Concomitant administration of CBZ, PHT and PB led to a
      significant increase in VPA clearance. The model predictions in the validation
      group were found to have satisfactory precision and bias. In conclusion, inter
      individual variability in VPA clearance can be partly explained by TBW, daily
      dose and bitherapy with CBZ, DPH or PB. Inclusion of these factors allows this
      variability to be reduced by 37.23% which may be very useful for clinicians when
      establishing the initial VPA dosage regimen. However, the magnitude of inter
      individual plus residual variabilities, remaining in the final model, render
      these dosage predictions imprecise and justify the need for VPA serum level
      monitoring in order to individualize dosage regimens more accurately.

PMID- 10594868
TI  - Pharmacokinetic interactions between HIV-protease inhibitors in rats.
AB  - The interactions of four HIV-protease inhibitors, ritonavir (RIT), saquinavir
      (SAQ), indinavir (IND) and nelfinavir (NEL), were examined by in vitro metabolic
      studies using rat liver microsomal fractions. The substrate concentrations
      employed were 0.75 approximately 12 microM, and the inhibitor concentrations were
      2.5 approximately 60 microM. The metabolic clearance rates of SAQ, NEL and IND as
      determined by V(max)/K(m) were 170.9+/-10.9, 126.0+/-4.4 and 73.0+/-2.0
      microL/min/mg protein, respectively. RIT was a potent inhibitor of the other
      three protease inhibitors, and the inhibition constants (K(i)) were 1.64 microM
      for SAQ, 0.95 microM for IND and 1. 01 microM for NEL. NEL was the second
      strongest inhibitor with a K(i) for NEL inhibition of IND metabolism of 2.14
      microM. IND was the third strongest inhibitor with K(i)s of 2.76 microM for
      inhibition of NEL and 3.55 microM for inhibition of SAQ. As SAQ has the highest
      metabolic clearance rate, the K(i) for the SAQ inhibition of IND metabolism was
      high, 9.50 microM. Based on these in vitro results, drug interactions between NEL
      and IND or RIT were studied after oral administration to rats where the dose of
      each drug was 20 mg/kg. The C(max) and AUC of NEL were increased 3.6- and 8.5
      fold by the co-administration with RIT. However, in contrast to co-administration
      of NEL and RIT, the effect of IND on the pharmacokinetics of NEL was negligible
      and the t(1/2) of NEL was not significantly increased by IND. Therefore, the
      combination of NEL and IND is recommended as a combination therapy for AIDS
      patients.

PMID- 10594869
TI  - Conversion from liquid to solid rapamycin formulations in stable renal allograft
      transplant recipients.
AB  - Sirolimus (rapamycin, RAPA, Rapamunetrade mark) is a potent immunosuppressive
      agent currently being investigated for prophylaxis against acute rejection
      episodes in renal transplant recipients. In the present study, stable renal
      allograft recipients under maintenance therapy with RAPA and cyclosporine (CsA)
      were converted from the original oil-based liquid RAPA to a solid tablet
      formulation on a milligram-to-milligram basis, in order to evaluate the
      pharmacokinetics and safety of this new dosage form. Twelve-hour pharmacokinetic
      (PK) profiles of both RAPA and CsA were conducted with the final liquid RAPA
      dose, and at 2, 4, and 8 weeks postconversion to the solid tablet. In addition,
      the parameters of the PK profiles for the solid formulation were compared with
      those for liquid RAPA, which were performed prior to this study. Area under the
      concentration-time curve (AUC) values for the liquid formulation and for the
      solid tablet at 2, 4, and 8 weeks postconversion were 256.5, 205.8, 226.1, and
      224.4 ng.h/mL, respectively (p=NS). Time to maximum RAPA concentration was longer
      at 4 weeks postconversion, but similar at 2 and 8 weeks. There were no
      differences observed between the liquid and solid tablet trough concentrations.
      The only significant differences observed among the PK parameters of the solid
      tablet versus those of the liquid formulation were the lower C(max) values of the
      solid, namely 25.3, 24.9, and 26.7 ng/mL versus 37.1 ng/mL (p<0.05). In addition,
      the dose corrected C(max) was lower in the solid tablet PK profiles compared with
      the prior PK profiles for the liquid (7.7 versus 10.2 ng/mL, p<0.02).
      Cyclosporine AUC values did not change appreciably during the study. Conversion
      from the liquid to the solid formulation was neither associated with episodes of
      acute rejection, nor changes in laboratory values, during the 8-week study. In
      summary, conversion from the liquid to the solid RAPA formulation resulted in
      similar PK profiles and appears to be both safe and well-tolerated in renal
      transplant recipients.

PMID- 10594870
TI  - Immunodynamics of methylprednisolone induced T-cell trafficking and deactivation
      using whole blood lymphocyte proliferation techniques in the rat.
AB  - Glucocorticoids have diverse effects on various components of the immune system
      and assessment of such activities in vivo often involves complex techniques and
      numerous animals. We developed a whole blood technique for determining
      proliferation rate of lymphocytes in minute amounts of rat blood (5 microL as
      opposed to a whole rat spleen) (Fasanmade AA, Jusko WJ. J Immunol Methods 1995;
      184: 163-167). This method was used in assessment of in vivo T-cell deactivation
      by methylprednisolone (MP). The blockade of this process by the anti
      glucocorticoid, RU 40555, also allows measurement of T-lymphocyte trafficking
      between vascular and extravascular pools. Blood samples were taken over several
      hours after iv MP administration to adrenalectomized rats, MP concentrations and
      lympho-proliferative activities were determined ex vivo after mitogen activation
      with and without blocking MP with RU 40555. MP disposition was mono-exponential
      with a t(1/2) of 34 min. The pharmacodynamics (PD) of T-cell trafficking was
      modeled with a physiological indirect model to generate the IC(50) (0.4 ng/mL)
      for the inhibitory action of MP on return of T-cells to blood as well as cell
      trafficking rate constants. The overall suppression of blood T-cells was modeled
      with an equation which accounts directly for inhibition of the proliferation
      activity of available blood T-cells with an DC(50) of 0.37 ng/mL. MP produced an
      initial influx of T-cells to blood within 1 h of infusion, a later marked T-cell
      depletion with a nadir at 4 h, and return to baseline by 9 h. Lymphocyte
      deactivation occurred within minutes of MP infusion and returned to baseline in 9
      h. MP action was prolonged owing to the low IC(50). This approach for assessing
      dual features of corticosteroid effects on T-cell trafficking and deactivation
      allows quantitative PK/PD modeling in small animals such as the rat.

PMID- 10594871
TI  - Metabolic kinetics of p-aminobenzoic acid in rabbits.
AB  - The metabolic kinetics of p-aminobenzoic acid (PABA) in rabbits was studied. PABA
      is predominantly metabolized by acetylation and glycine conjugation to form p
      acetamidobenzoic acid (PAABA), p-aminohippuric acid (PAHA), and p
      acetamidohippuric acid (PAAHA). After PABA IV administration (20 mg/kg) to rapid
      (n=16) and slow (n=8) acetylation rabbits, PABA was eliminated rapidly. The half
      lives of PABA were 7.01+/-0.32 min in rapid acetylation rabbits and 7.08+/-0.78
      min in slow acetylation rabbits. Significant differences were obtained in
      formation of PAABA and PAHA formed from PABA in both acetylation phenotype
      rabbits. The formation fraction of PAABA, formed by acetylation of PABA, was
      0.8029+/-0.0267 in rapid acetylators and 0.2385+/-0.0428 in slow acetylators
      (p<0.001). PAHA formed from PABA was 0.0462+/-0.0102 in rapid acetylators and 0.
      6652+/-0.0562 in slow acetylators (p<0.001). Only 0.0156+/-0.0030 of PABA could
      be detected as PAAHA in rapid acetylation rabbits which was obtained by
      acetylation of PAHA. After individual IV injection of PAHA, PAAHA, and PAABA to
      both phenotypes of rabbits, PAABA and PAAHA were eliminated in their unchanged
      forms whereas PAHA was further acetylated to form PAAHA. The formation fraction
      of PAAHA formed from the acetylation of PAHA was 0.4408+/-0.0570 in rapid
      acetylators and 0.0539+/-0.0084 in slow acetylators (p=0.002). From the results
      obtained, metabolic pathways of PABA show significant differences in both
      acetylation phenotypes of rabbits. Acetylation is the major metabolic route of
      PABA in rapid acetylation rabbits, while glycine conjugation is more predominant
      in slow acetylation rabbits.

PMID- 10594872
TI  - Mechanism of the uricosuric action of E3040, a drug used to treat inflammatory
      bowel disease II: study using DBA/2N mice.
AB  - In the initial phase of clinical studies, it was shown that E3040, a new type of
      anti-inflammatory drug, reduced plasma uric acid levels. The present study
      describes a comparison of the excretion of uric acid in the proximal tubules of
      the kidney after administration of E3040 and its conjugates, sulphate and
      glucuronide, with that of other general uricosuric agents in DBA/2N mice. The aim
      of this investigation was to elucidate the mechanism for the uricosuric action of
      E3040. It was found that E3040 increased the excretion rate of uric acid in a
      dose-dependent manner, and the excretion rates following 10 and 50 mg/kg doses
      were significantly greater than that of the control group. The paradoxical effect
      observed with probenecid was not seen in the E3040 dose-response curve for the
      uric acid excretion rate. Neither E3040-sulphate nor E3040-glucuronide increased
      the excretion rate of uric acid significantly, even at a high dose, such as 200
      mg/kg. In the pyrazinoic acid suppression test, the uric acid excretion rate
      after concomitant administration of E3040 and pyrazinoic acid was significantly
      higher than that after administration of pyrazinoic acid alone, and the rate
      after concomitant administration was 30% of the level after administration of
      E3040 alone. The change in the excretion rate of uric acid after concomitant
      administration of E3040 and pyrazinoic acid was similar to that of AA193, a
      selective inhibitor of the presecretory reabsorption of uric acid. From these
      results, it appears that E3040 may exert its uricosuric action by reducing the
      presecretory reabsorption of uric acid rather than increasing its secretion.

PMID- 10594873
TI  - Mosaic trisomy 7 in a patient with pigmentary abnormalities.
AB  - Somatic chromosomal mosaicism may present as isolated pigmentary abnormalities or
      multiple congenital anomalies with mental retardation. Pigmentary lesions are
      visually dramatic and are differentiated based on appearance when the underlying
      pathogenesis is not known. It is now clear that mosaicism is responsible for the
      pigmentary findings in hypomelanosis of Ito (HI) and linear and whorled nevoid
      hypermelanosis (LWH). Both hypopigmentation and hyperpigmentation have been noted
      in the same individual, and both LWH and HI can be caused by similar chromosomal
      abnormalities. Both of these conditions exhibit similar systemic involvement. We
      present a case of LWH associated with mosaic trisomy 7 and review the relevant
      literature.

PMID- 10594874
TI  - Blaschkolinear malformation syndrome in complex trisomy-7 mosaicism.
AB  - Results of repeated peripheral blood chromosome studies were normal in a boy with
      intrauterine growth retardation, short stature, moderate mental retardation, and
      multiple minor anomalies. At age 9 years it was recognized that the swirls of
      pigmentation/depigmentation on his trunk, linear streaks on his limbs, and body
      asymmetry were suggestive of chromosomal mosaicism. Four skin biopsies were
      obtained under anesthesia during a dental procedure. All showed mosaicism for a
      normal cell line, a line with an extra chromosome 7, and a cell line with an
      extra small ring. In one biopsy, there was a fourth cell line with an extra
      chromosome 7 and the ring. Fluorescence in situ hybridization (FISH) with a
      chromosome 7 paint confirmed trisomy 7 and the chromosome 7 derivation of the
      ring. This young man's intra-uterine and postnatal growth retardation is an
      aneuploidy effect, whereas his asymmetry reflects a mosaicism effect that should
      have aroused suspicion of tissue-limited mosaicism before the development of
      obvious Blaschkolinear skin pigmentary dysplasia.

PMID- 10594875
TI  - Clinical, cytogenetic, and fluorescence in situ hybridization findings in two
      cases of "complete ring" syndrome.
AB  - The term "ring syndrome" was proposed to describe a phenotype of growth failure
      without major malformations due to a ring autosome. The growth failure is thought
      to be caused by instability of the ring chromosome leading to aneusomy and cell
      death. Most previous studies of ring chromosomes were based on standard
      cytogenetic banding techniques and were limited to microscopically detectable
      deletions in the ring chromosomes. We report on two patients with complete ring
      (4) and ring (9) chromosomes, respectively. The first was a 15-month-old girl and
      the second was a 16-month-old boy. They both presented with severe, symmetrical
      growth failure and normal psychomotor development in the absence of
      malformations. Their parents had a normal phenotype. The first case had a whorled
      pattern of hyperpigmentation and hypopigmentation on part of the face and chest,
      and the second case had a patchy hyperpigmented rash on the trunk. Peripheral
      blood karyotype of the first patient was 46,XX, r(4)(p16.3q35.2) and of the
      second 45,XY,-9/46,XY,r(9)(p24q34.3). G-band analysis suggested no loss of
      material in the ring chromosomes. These findings were confirmed by fluorescence
      in situ hybridization (FISH) analysis using chromosome-specific subtelomeric
      probes. The common human telomeric sequences were intact in the first patient but
      absent in the second patient. The cytogenetic and FISH data in our two cases
      provide further evidence for the existence of a "complete ring" phenotype
      independent of the autosome involved. Pigmentary skin changes are a useful
      clinical sign of mosaicism caused by the ring instability.

PMID- 10594876
TI  - Partial duplication of the long arm of chromosome 15: confirmation of a causative
      role in craniosynostosis and definition of a 15q25-qter trisomy syndrome.
AB  - A syndrome of mental retardation and multiple congenital anomalies, including
      craniosynostosis and overgrowth, was observed in two related individuals from a
      large kindred. Both of them carried a 15q25.1-qter trisomy associated with a
      subtle 13qter monosomy resulting from unbalanced segregation of a familial
      t(13;15)(q34;q25.1) translocation. Reportedly, a further individual in this
      kindred has the same condition. The present report confirms previous claims that
      gene(s) in the distal 15q region play a role in suture formation. At the same
      time it adds new data to the delineation of a 15q25-qter trisomy syndrome.

PMID- 10594877
TI  - De novo direct duplication of 15q15-->q24 in a newborn boy with mild
      manifestations.
AB  - Duplication of distal 15q results in a recognizable clinical phenotype. We report
      here on a 25-day-old boy with a de novo interstitial duplication of chromosome
      region 15q15-q24. The manifestations in this patient are milder than those of
      previously described patients and include minor facial anomalies, velopharyngeal
      insufficiency, branchial cleft cyst, and hydronephrosis. Fluorescence in situ
      hybridization (FISH) using a chromosome 15 painting probe confirmed that the
      extra material is of chromosome 15 origin. Further analysis with the SNRPN probe
      demonstrated that the duplication is telomeric to the Prader-Willi/Angelman
      syndrome critical region. This case delineates a broader spectrum for patients
      with duplication 15q syndrome.

PMID- 10594878
TI  - Phenotypic variability of triphalangeal thumb-polysyndactyly syndrome linked to
      chromosome 7q36.
AB  - Triphalangeal thumb-polysyndactyly (TPT-PS) is an isolated limb malformation
      consisting of pre- and postaxial polysyndactyly of hands and feet. The only
      family reported so far is of Dutch origin, and the genetic mapping study
      localized the TPT-PS locus at chromosome region 7q36 where the isolated
      triphalangeal thumb (TPT) anomaly has also been mapped. It was suggested that TPT
      PS is a phenotypic variation of isolated TPT, and the same ancestral mutation may
      produce both phenotypes. Here we report on the second family with this
      malformation from the Turkish population. The characteristic findings in this
      family are triphalangeal thumb, webbing between 3rd, 4th, and 5th fingers
      associated with bony synostosis in the distal phalanges of the same fingers, and
      pre- and postaxial polysyndactyly of feet. Some individuals show a more severe
      phenotype with a complete syndactyly of all fingers giving a "cup-like"
      appearance to the hands. Genetic linkage study with DNA markers D7S1823, D7S550,
      D7S559, and D7S2423 demonstrated that this family is also linked to chromosome
      band 7q36. Identification of a second family from a distinct ethnic background
      suggests that TPT-PS and isolated TPT are not caused by the same ancestral
      mutation as it was originally anticipated.

PMID- 10594879
TI  - Distribution of alleles of the methylenetetrahydrofolate reductase (MTHFR) C677T
      gene polymorphism in familial spina bifida.
AB  - Spina bifida cystica (SB) is one of the most common and disabling of birth
      defects. Folic acid supplementation in mothers during the periconceptional period
      has been shown to prevent more than 70% of neural tube defects (NTD) including
      SB. However, the mechanism is unknown. We tested a series of multicase SB
      families in which 224 individuals were genotyped and a group of 215 unrelated
      unaffected (external) control individuals for association of SB with the T allele
      of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism that produces a
      heat-labile enzyme protein. The data were analyzed using first the
      transmission/disequilibrium test (TDT) and second a modified case-control study
      design with Monte Carlo sampling methods. No association of SB with the MTHFR T
      allele was found by either method. Presently, association between SB and the T
      allele has been found in four studies, a Dutch study, an Irish study, a North
      American study, and an Italian study. But no association was found in four other
      studies, a British study, a French study, a Turkish study, and a German study. A
      California population-based study found only modestly increased risk of SB with
      this allele that was not significant at the P < 0.05 level. The present study
      finds no evidence of the association. Only one other study, the German study, has
      used TDT analysis. The present study is the first to use a modified case-control
      study design with Monte Carlo sampling methods to test this association. Thus, it
      appears that the MTHFR T allele is a risk factor for SB in some populations but
      not others. Major genetic risk factors for folate-related SB remain to be found.

PMID- 10594880
TI  - Never again joy without sorrow: the effect on parents of a child with ataxia
      telangiectasia.
AB  - The purpose of this study was to explore the impact of having a child with ataxia
      telangiectasia (A-T) as well as to assess parental understanding of the genetics
      of A-T and attitudes toward carrier testing. Sixty-eight parents of individuals
      with A-T were interviewed. Ninety percent of the parents correctly believed if
      there is a child with A-T, both are obligate heterozygotes. Only 9% knew each
      well sib had a two-thirds chance of being a carrier. Eighty-four percent would
      have their unaffected child tested for carrier status prior to age 18 years.
      Eighty-two percent believed heterozygosity is associated with increased health
      risks. We offer the following recommendations. 1) Physicians must realize that
      communicating the possibility of early death is difficult; parents need
      guidelines so they know what to expect, but diagnosis should not be a death
      sentence. Clinicians should stress individual variations in expression of the
      disorder and offer hope for future progress in treatment. 2) Parents
      underestimated carrier risks for the well sib and the frequency of carrier status
      in the general population. Although these distortions are self-protective, they
      interfere with transmission of accurate genetic information to their children.
      Parents should be referred to genetic counseling. 3) Psychological counseling
      should be offered to families at the time of diagnosis so parents can support
      each other, the affected, and unaffected offspring.

PMID- 10594881
TI  - "My crooked vision": the well sib views ataxia-telangiectasia.
AB  - The ataxia-telangiectasia gene (designated ATM) has been identified by positional
      cloning. Retrospective studies in cystic fibrosis (CF) have shown that the
      illness and death of a sib have far-reaching ramifications on the surviving sib's
      life. However, there have been no studies on sibs of children and adults with
      ataxia-telangiectasia (A-T). Thirty-five sibs from 24 families, including 26
      adults and 9 adolescents, were drawn from the University of California, Los
      Angeles; the A-T Clinical Center at the Johns Hopkins University School of
      Medicine; and the A-T Children's Project Interviews indicated that, unlike CF,
      the visibility of A-T caused less resentment of time or attention given to the
      affected, less guilt, and less identification or idealization of the affected,
      but more embarrassment and shame. It may be said that, unlike CF, the dynamic is
      one of burden rather than trauma. The specific phenotypic expression of a genetic
      illness predisposes the way in which the well sib will encounter problems. In A-T
      affected families, one must help families locate caregiving resources so they
      will not burden their well children; sibs need help with managing feelings of
      embarrassment and shame. Geneticists must be alert to understanding
      characteristic differences of disorders they encounter in order to offer the most
      appropriate support to affected families.

PMID- 10594882
TI  - Postaxial polydactyly, ulnar ray dysgenesis, and renal cystic dysplasia in sibs.
AB  - We describe two brothers with variable expression of a unique syndrome. One sib
      has postaxial polydactyly of the right hand and feet, two digits on the left hand
      (a thumb and first digit), bilateral ulnar ray dysgenesis, ectrodactyly of one
      hand, and ultrasonic evidence of cystic kidneys. His brother has postaxial
      polydactyly and small kidneys. The parents and a third sib are normal. They do
      not have the Pallister ulnar-mammary syndrome but may have an unusual form of the
      Weyers oligodactyly syndrome. This appears to be the first report of an acro
      renal syndrome with ulnar dysgenesis, oligodactyly, polydactyly, and dysplastic
      kidneys.

PMID- 10594883
TI  - The Richieri-Costa and Pereira form of acrofacial dysostosis: first case in a non
      Brazilian infant.
AB  - We report on a French boy with cleft mandible, pre/postaxial hand anomalies, and
      clubfoot born to consanguineous parents. These findings are comparable to those
      of previous cases of the autosomal recessive Richieri-Costa and Pereira syndrome
      of short stature, Robin sequence, cleft mandible, pre/postaxial hand anomalies,
      and clubfoot. This is the first case in a non-Brazilian infant.

PMID- 10594884
TI  - Apple-peel intestinal atresia associated with balanced reciprocal translocation
      t(2;3)(q31.3;p24.2) mat.
AB  - Apple peel intestinal atresia is an apple-peel-appearing bowel obstruction of
      unknown cause. We describe a Japanese girl with the apple-peel jejunal atresia
      associated with apparently balanced reciprocal translocation between chromosomes
      2 and 3, t(2;3)(q31. 3;p24.2)mat. The translocation breakpoints in the patient
      may become candidate regions for the putative gene causing apple-peel atresia.
      Alternatively, the association of the two abnormalities in the patient is
      coincidental because her phenotypically normal mother had the same chromosome
      translocation.

PMID- 10594885
TI  - Longitudinal course of behavioral and emotional problems in fragile X syndrome.
AB  - We describe a follow-up of a study of behavior and emotional problems in a cohort
      of young people with Fragile X syndrome over 7 years. The study demonstrates that
      there is substantial persistence of the overall level of behavior and emotional
      problems. However, there are changes in certain types of behavior. Scores on the
      "disruptive" subscale of the Developmental Behavior Checklist decline
      significantly, whereas those on the "antisocial" subscale increase significantly.
      These changes parallel those seen in a large epidemiological control sample of
      young people with intellectual disability due to other causes. Further, two
      individual behaviors that distinguished the Fragile X individuals from the
      control individuals in the original study, namely "shy" and "avoids eye contact,"
      continue to do so 7 years later.

PMID- 10594886
TI  - Familial lissencephaly with cleft palate and severe cerebellar hypoplasia.
AB  - Lissencephaly is a brain malformation characterized by absence of gyral
      formation, resulting in a smooth brain surface. Histologic study shows severe
      anomalies of cerebral cortical development. Several lissencephaly syndromes have
      been described. Here we report a familial syndrome of lissencephaly, cleft
      palate, diffuse agyria, and severe cerebellar hypoplasia. Microscopic examination
      of the abnormally thick cerebral cortex showed absence of cortical layering, with
      preservation of the pia-glial barrier. This is the first report of recurrent
      lissencephaly with cleft palate and severe cerebellar hypoplasia in which these
      unique neuropathology findings are described. Autosomal recessive inheritance is
      suggested by recurrence in sibs within the same family, but germ cell mosaicism
      for a dominant mutation is not excluded.

PMID- 10594887
TI  - W syndrome: report of three cases and review.
AB  - Only three cases of W syndrome have been reported. These patients have a typical
      "pugilistic" face, incomplete oral cleft, absent upper incisors, mental
      retardation, spasticity, seizures, and acne scars. Two of them had additional
      skeletal anomalies. Here we report on three male patients with findings
      compatible with the W syndrome. We emphasize the importance of some constant
      findings and describe additional signs. Familial history supports X-linked
      dominant heredity, as postulated previously.

PMID- 10594889
TI  - Diagnosis of progeria syndrome is the only one possible

PMID- 10594888
TI  - Can Hutchinson-Gilford progeria syndrome be a neonatal condition?

PMID- 10594890
TI  - Preface

PMID- 10594891
TI  - Promising new approaches for treatment of botulinum intoxication.

PMID- 10594892
TI  - Evaluation of phosphoramidon and three synthetic phosphonates for inhibition of
      botulinum neurotoxin B catalytic activity.
AB  - Three putative metalloprotease inhibitors were synthesized and tested for their
      ability to inhibit the catalytic activity of botulinum neurotoxin B light chain
      (BoNT/B LC). The compounds were designed to emulate the naturally occurring
      metalloprotease inhibitor phosphoramidon, which has been reported to be a weak
      antagonist of BoNT/B action. All three analogs contained the dipeptide Phe-Glu in
      place of Leu-Trp of phosphoramidon and possessed a phenyl, ethyl or methyl group
      in place of the rhamnose sugar of the parent compound. The inhibitors were
      evaluated in a cell-free assay based on the detection of a fluorescent product
      following cleavage of a 50-mer synaptobrevin peptide ([Pya(88)] S 39-88) by
      BoNT/B LC. This peptide corresponds to the hydrophilic core of synaptobrevin-2
      and contains a fluorescent analog L-pyrenylalanine (Pya) in place of Tyr(88).
      Cleavage of [Pya(88)] S 39-88 by BoNT/B LC gives rise to fragments of 38 and 12
      amino acid residues. Quantification of BoNT/B-mediated substrate cleavage was
      achieved by separating the 12-mer fragment (FETSAAKLKRK-Pya) that contains the C
      terminal fluorophore and measuring fluorescence at 377 nm. The results indicate
      that the phenyl-substituted synthetic compound ICD 2821 was slightly more active
      than phosphoramidon, but analogs with methyl or ethyl substitutions were
      relatively inactive. These findings suggest that phosphonate monoesters may be
      useful for providing insights into the structural requirement of BoNT/B protease
      inhibitors.

PMID- 10594893
TI  - Rapid microplate assay for monitoring botulinum neurotoxin B catalytic activity.
AB  - The binding activity of a rabbit polyclonal antiserum raised against a 51-residue
      peptide (P51) homologous to human VAMP2 (residues 44-94) was examined. Human
      VAMP2 is an 18-kDa protein located on the external membrane of small synaptic
      vesicles and is targeted by four of the seven botulinum neurotoxin (BoNT)
      serotypes (B, D, F and G). The antiserum, designated anti-P51, recognized P51 but
      exhibited little cross-reactivity with the two cleavage products that result from
      BoNT/B-mediated proteolysis of P51. The larger of these fragments, designated as
      P33 (residues 44-76), exhibited a weak but measurable interaction with the
      antiserum. The smaller cleavage product, designated as P18 (residues 77-94), was
      not recognized by the antiserum. Anti-P51 was used to monitor BoNT/B light chain
      (LC)-mediated cleavage of P51 using an indirect ELISA. The serine protease
      inhibitor phenylmethylsulfonyl fluoride did not inhibit BoNT/B activity, but the
      zinc chelator N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine (TPEN) and the
      elastase inhibitor 7- N -phenylcarbamoylamino-4-chloro-3-propyloxyisocoumarin
      (ICD 1578) produced complete blockade of BoNT/B LC action. Under ideal
      conditions, it will be possible to evaluate up to seven candidate anti-BoNT/B
      drugs in triplicate at four concentrations using a single 96-well microtiter
      plate. These findings indicate that the ELISA will be suitable for rapid
      screening of BoNT/B inhibitors.

PMID- 10594894
TI  - Buforin I, a natural peptide, inhibits botulinum neurotoxin B activity in vitro.
AB  - Botulinum neurotoxin B (BoNT/B) serotype specifically cleaves between the amino
      acids glutamine and phenylalanine (Q and F bond) in position 76-77 of
      synaptobrevin (VAMP2). We evaluated peptides that contain the QF cleavage site
      but are not identical in primary structure to the VAMP2 sequence surrounding the
      QF site for both inhibition of BoNT/B proteolytic activity and as substrates for
      BoNT/B. A reverse-phase high-performance liquid chromatography (RP-HPLC) method
      was used to measure digested peptides. A dose as high as 600 microM of substance
      P, and 11-amino acid peptide containing the QF bond, was neither a substrate nor
      inhibitor of BoNT/B in our assay, suggesting that more than the QF bond is
      required to be recognized by BoNT/B. Buforin I (B-I, QF site 24-25) is 39 amino
      acids in length, and sequence comparison of B-I and VAMP2 indicated a similarity
      of 18% for conserved amino acids around the QF site. Furthermore, computer-aided
      secondary structure computations predict alpha-helical structures flanking the QF
      site for VAMP2 and for the upstream sequence of B-I. Although predictions for the
      downstream sequence give nearly equal tendencies for alpha-helical and beta-sheet
      structures, Yi et al. showed that the downstream sequence is likely to be the
      alpha-helix based on their examination of buforin II (B-II, a 21-amino acid
      subset of B-I (16-36)), which includes the QF site and the downstream sequence of
      B-I. Buforin I was found not to be a substrate for BoNT/B; however, B-I dose
      dependently and competitively inhibited BoNT/B activity, yielding IC(50) = 1 x
      10(-6) M. In contrast, B-II was not a substrate for BoNT/B and exhibited only 25%
      of the B-I inhibition of BoNT/B. Two additional B-I deletion peptides were tested
      for inhibition of BoNT/B proteolysis: peptide 36 (36 mer; containing B-I amino
      acids 1-36) and peptide 24 (24 mer; B-I amino acids 16-39). Peptide 24 had a
      similar inhibitory effect to B-II (ca. 25% of B-I) but peptide 36 was almost 50%
      as potent as B-I. These findings suggest that the buforin tertiary structure is
      important for the inhibitory activity of these peptides for BoNT/B.

PMID- 10594895
TI  - Peptides that mimic the carboxy-terminal domain of SNAP-25 block acetylcholine
      release at an Aplysia synapse.
AB  - Botulinum neurotoxin serotypes A and E (BoNT/A and BoNT/E) block neurotransmitter
      release, presumably by cleaving SNAP-25, a protein involved in docking of
      synaptic vesicles with the presynaptic plasma membrane. Three excitation
      secretion uncoupling peptides (ESUPs), which mimic the carboxy-terminal domain of
      SNAP-25 and span or adjoin the cleavage sites for BoNT/A and BoNT/E, also inhibit
      transmitter release from permeabilized bovine chromaffin cells. In this study,
      these peptides were tested for effects on acetylcholine (ACh) release at an
      identified cholinergic synapse in isolated buccal ganglia of Aplysia californica.
      The presynaptic neuron was stimulated electrically to elicit action potentials.
      The postsynaptic neuron was voltage-clamped, and evoked inhibitory postsynaptic
      currents (IPSCs) were recorded. The ESUPs were pressure-injected into the
      presynaptic neuron, and their effects on the amplitude of the IPSCs were studied.
      Acetylcholine release from presynaptic cells, as measured by IPSC amplitudes, was
      gradually inhibited by the ESUPs. All three peptides caused ca. 40% reduction in
      IPSC amplitude in 2 h. Random-sequence peptides of the same amino acid
      composition had no effect. Injection of BoNT/E, in contrast, caused ca. 50%
      reduction in IPSC amplitude in 30 min and almost complete inhibition in 2 h.
      These results are the first demonstration that ESUPs block neuronal cholinergic
      synaptic transmission. They are consistent with the concept that ESUPs compete
      with the intact SNAP-25 for binding with other fusion proteins, thus inhibiting
      stimulus-evoked exocytosis of neurotransmitter.

PMID- 10594896
TI  - Phospholipaise A2 and arachidonic acid-mediated mechanism of neuroexocytosis: a
      possible target of botidinum neurotoxin A other then SNAP-25.
AB  - The vesicular neuroexocytosis process consists of two important steps: fusion of
      transmitter-loaded vesicles at release sites on the presynaptic nerve terminal
      membrane; followed by the release of transmitter molecules into the synaptic
      cleft. We previously reported that in nerve growth factor (NGF)-differentiated
      PC12 cells, arachidonic acid (AA) release is associated with acetylcholine (ACh)
      release, botulinum neurotoxin A (BoNT/A) inhibits both processes and AA itself or
      a phospholipase A(2) (PLA(2)) activator can cause ACh release in BoNT/A-poisoned
      cells in which SNAP-25 has supposedly been hydrolyzed. In the present study, we
      examined the roles of two endogenous intraterminal components in neuroexocytosis:
      the membrane fusogenic agent AA; and the vesicle fusion protein SNAP-25. A PLA(2)
      activator, mastoparan, was used to induce the release of AA and ACh from NGF
      differentiated PC12 cells. Release depended upon the mastoparan concentration, as
      well as Ca(2+) influx via the neuronal-type voltage-sensitive Ca(2+) channels.
      Release of ACh followed a rise in intracellular free Ca(2+) concentration; the
      increased Ca(2+) activated PLA(2) and, thereby, increased the AA level. Scanning
      and transmission electron microscopy confirmed that mastoparan-induced ACh and AA
      release were not due to simple diffusion through damaged plasma membranes.
      Treatment of PC12 cells with appropriate antisense oligonucleotides blocked SNAP
      25 expression, as judged by Western blot protein analysis with a specific
      monoclonal antibody. Despite apparent elimination of SNAP-25, treatment of
      differentiated PC12 cells with mastoparan and high (80 mM) K(+) induced ACh
      exocytosis. The results support the conclusion that PLA(2) and AA have important
      roles in neuroexocytosis that are independent of SNAP-25. Both PLA(2) and AA have
      been shown to be involved in actin cytoskeletal organization related to vesicle
      fusion and exocytosis. This mechanism may be an alternative target of BoNT/A
      other than SNAP-25.

PMID- 10594897
TI  - Comparison of in vivo and in vitro mouse bioassays for botulinum toxin
      antagonists.
AB  - Measurements of the efficacy of novel botulinum toxin antagonists can be based on
      classical bioassays of toxin concentration. However, the relative sensitivities
      of in vivo and in vitro assays to the effects of antagonists are not necessarily
      correlated with the sensitivities of the assays to toxin. Comparisons of the
      sensitivity of an in vitro mouse muscle contraction assay with an in vivo mouse
      survival assay indicated that the in vivo assay was more sensitive to botulinum
      toxin serotype A by more than one order of magnitude at equivalent molar
      concentrations. However, in studies of toxin neutralization with equine antisera,
      the in vitro muscle assay was more than three times more sensitive to the
      presence of antisera than the equivalent mouse survival assay. For the
      development of new drugs to treat botulism, antagonist sensitivity is a primary
      consideration in determining relative efficacy during structure-activity studies.
      Thus, in studies of toxin antagonists, the in vitro assay appears to be superior
      for initial testing.

PMID- 10594898
TI  - Protection against botulinum toxins provided by passive immunization with
      botulinum human immune globulin: evaluation using an inhalation model.
AB  - Pentavalent botulinum toxoid adsorbed (ABCDE) vaccine is intended to protect
      military personnel from battlefield exposures to botulinum serotypes A-E. To
      determine the neutralizing antibody levels in serum that are indicative of
      protection against aerosolized botulinum toxins, a guinea pig model of passive
      antibody transfer was developed. Botulinum immune globulin (BIG), derived from
      plasma of vaccinated volunteers, was administered to guinea pigs by
      intraperitoneal injection to attain neutralizing antibody levels in serum of ca.
      0.25 U ml(-1). Control groups were treated with vaccinia immune globulin (VIG),
      with dosages normalized to antibody content. Neutralizing antibody levels were
      determined by a mouse bioassay. Twenty-four hours after BIG treatment, animals
      were challenged with lethal levels (target of 25 x LCt(50)) of botulinum toxins
      by an inhalation route. Protection was defined as 80% or greater survival for BIG
      treated animals. If protective, additional groups were treated with progressively
      smaller BIG dosages (75% decreases per iteration) and challenged with 25 x
      LCt(50) until protection was no longer afforded. Greater than 80% survival was
      observed at target levels of 0.25 U ml(-1) for all five serotypes. Breakthrough
      mortality (>20%) was observed at test levels of 0.05, 0. 004, 0.015, 0.014 and
      0.003 U ml(-1) for serotypes A-E, respectively. These results, along with
      neutralizing antibody measurements from clinical trials, can be used to predict
      human efficacy following vaccination with pentavalent botulinum toxoid adsorbed
      (ABCDE) vaccine.

PMID- 10594899
TI  - Historical overview of topical skin protectant development.

PMID- 10594901
TI  - Development of a reactive topical skin protectant.
AB  - The use of a topical skin protectant (TSP) as a means of protecting troops from
      percutaneous chemical warfare agent (CWA) exposure has been proposed since these
      weapons were first used during World War I. The TSP is applied to vulnerable skin
      surfaces prior to entry into a chemical combat area. In 1990, the US Army Medical
      Research Institute of Chemical Defense transferred two non-reactive TSPs into
      advanced development. Following US Food and Drug Administration approval, the
      final product is expected to be available to soldiers in 1999. A continuing
      research effort is designed to develop a second-generation TSP that will increase
      effectiveness and also decontaminate CWAs into non-toxic products. We identified
      a list of 29 reactive moieties as potential additives to the TSP formulation. All
      candidate formulations are evaluated in a decision tree network, consisting of a
      series of 11 efficacy testing models. A prototype formulation (ICD 2701)
      containing the reactive ingredient S-330 has dramatically improved the protection
      against saturated sulfur mustard vapor. In addition, we have discovered a
      compound (ICD 2837) that significantly increases the skin's natural resistance to
      CWA penetration. Our goal is to transfer a significantly improved TSP formulation
      into advanced development by 1999.

PMID- 10594900
TI  - Efficacy of the topical skin protectant in advanced development.
AB  - A topical skin protectant (TSP) (ICD 2289) is being developed to protect service
      members from exposure to chemical warfare agents (CWA). The TSP is designed for
      use on the skin at the overgarment closures and other vulnerable areas to enhance
      protection. The TSP, which is in phase II clinical studies, is a cream containing
      two chemically inert substances: perfluoroalkylpolyether and
      polytetrafluoroethylene. Animal data showed that the TSP was effective against
      percutaneous penetration of a blister agent, sulfur mustard (HD), by reducing the
      size of skin lesions and against T-2 mycotoxin by preventing the development of
      erythema and edema. The insect repellent N,N-diethyl-m-toluamide (DEET) reduced
      the TSP protection against HD regardless of the order of application on rabbit
      skin prior to dosing of HD. The protection was sustained when DEET was removed
      with a dry gauze prior to TSP application. The TSP was also effective against
      percutaneous exposure of nerve agents-thickened (with 5% methyl methacrylamide)
      soman (TGD) and VX (O-ethyl-S-[2-(diisopropylamino)ethyl]methylphosphonothioate )
      by reducing the mortality rate and protecting the red blood cell
      acetylcholinesterase activity. The TSP was effective against VX when DEET was
      applied prior to TSP application. Because human efficacy studies using CWA cannot
      be conducted, the efficacy will be demonstrated by the level of protection
      against poison ivy (urushiol) contact dermatitis in humans.

PMID- 10594902
TI  - Model for assessing efficacy of topical skin protectants against sulfur mustard
      vapor using hairless guinea pigs.
AB  - Sulfur mustard (HD; 2,2'-dichlorodiethyl sulfide) can produce incapacitating
      blisters in humans following dermal exposure. Most non-human animal models,
      however, do not form the large fluid-filled blisters observed in humans. Many
      models, nevertheless, do produce similar damage at the dermal/epidermal junction
      when evaluated by histopathology. In this study, it was observed that the
      hairless guinea pig (HGP) exhibits similar histopathological responses following
      exposure to HD vapor. Two sets of HGPs were exposed percutaneously for various
      lengths of time to HD vapor. In one set, the HGPs were sacrificed 24 h after
      exposure, and skin specimens were collected and processed for histopathology. In
      the other set, light reflectance was measured at skin test sites 4, 5, 6 and 24 h
      after exposure, to assess erythema. The Nikolsky's sign test was also performed
      24 h after exposure by rotating a metal disk glued to the skin test site and
      inspecting the skin for loss of epidermis. Probit analysis of data indicated that
      the exposure durations that produced a 50% incidence of microblisters and
      Nikolsky's sign were ca. 7.5 and 4.5 min, respectively. Maximum erythema was
      observed 6 h following a 6 min exposure. Operating parameters for assessing the
      efficacies of skin protectants have been characterized.

PMID- 10594903
TI  - Development of reactive topical skin protectants against sulfur mustard and nerve
      agents.
AB  - The potential for highly reactive nanoparticles (RNP) to absorb destructively,
      i.e. to neutralize highly toxic substances such as the warfare agents GA, GB, HD
      and VX, has been demonstrated in the laboratory. Reactive nanoparticles represent
      a new class of nanoscale particles of metals and metal oxides that differ from
      other nanoparticles in reactivity and crystalline morphology. The potential for
      incorporating RNP into a protective barrier skin cream also has been
      demonstrated. Preliminary studies indicate that RNP are physically and chemically
      compatible with a base cream provided by the Army Medical Research Office and,
      importantly, remain reactive with chemical agents while promising to be
      compatible with skin contact.

PMID- 10594904
TI  - Polyoxometalate oxidation of chemical warfare agent simulants in fluorinated
      media.
AB  - The aim of this research is to determine if appropriate polyoxometalates (POMs)
      could be added to perfluoropolyether topical skin protectants (TSPs) currently
      available or under development to give these TSPs the additional capability of
      detecting and in some cases catalytically decontaminating sulfur mustard (HD) and
      perhaps other chemical warfare agents (CWAs) at ambient temperatures. Detection
      would be based on significant color changes in the POM upon reduction by the CWA
      whereas catalytic decontamination would be based on the ability of some families
      of POMs to catalyze O(2)-based oxidations by more than one mechanism. Five POMs
      (10-25% by weight) were each suspended in ca. 5 g of the perfluoropolyether
      (PFPE, CF(3)O[-CF(CF(3))CF(2)O-](x)(-CF(2)O-)(y)CF(3)) 'barrier' cream. A
      stoichiometric amount of HD sulfide simulant was layered on top of each POM-cream
      mixture. The short reaction times were recorded for each system. Mechanistic
      studies were conducted using an PFPE oil analog of the barrier cream in a
      microemulsion with the sulfide simulant, POM, PFPE surfactant and 2,2,2
      trifluoroethanol co-surfactant.

PMID- 10594905
TI  - Development of an in vitro screening method for evaluating decontamination of
      sulfur mustard by reactive dermal formulations.
AB  - New barrier creams known as topical skin protectants (TSPs) recently have been
      formulated and demonstrated to be effective in delaying skin penetration of the
      blistering warfare agent sulfur mustard (HD). To further inactivate or neutralize
      HD, compounds that react with the toxic agent must be incorporated in the
      formulations, which then become reactive topical skin protectants (rTSPs).
      Specific and fast screening methods are necessary to assess the decontaminating
      activity of rTSPs. A headspace sampling technique in conjunction with thermal
      desorption and gas chromatography-mass spectrometry was evaluated as a potential
      screening method. A lower detection limit of 1 ng and a coefficient of variation
      of <20% were observed for the repetitive measurements of residual HD. Using this
      method, we evaluated a candidate rTSP. The percentage recovery of HD applied to
      the rTSP decreased by 35% over a 20-min time period compared with a non-rTSP. The
      candidate formulation showed an instant decontamination of the HD simulant
      dibutyl sulfide (decontamination was achieved in 2 s). The instrument set-up has
      the potential to accommodate multiple samples and can be automated. The method
      can be extended also to test reactive dermal formulations with toxic
      organophosphorus compounds.

PMID- 10594906
TI  - Reactions of sulfides with S-330, a potential decontaminant of sulfur mustard in
      formulations.
AB  - Because the vesicant sulfur mustard (HD) remains a major chemical threat from
      either domestic terrorists or countries in conflict, topical preparations are
      being evaluated as protectants from HD exposure. The objective of this study was
      to evaluate the effectiveness of chloroamide S-330 as a potential reactive
      component in topical formulations. Therefore, the rate, mechanism and by-products
      of the oxidation reactions of sulfides by S-330 in solvent media or specific
      formulation vehicles were investigated. Using NMR, LC, LC-MS and GC-MS, the
      reactions of S-330 with HD, dibutyl sulfide (DBS) and methyl phenyl sulfide (MPS)
      were studied in acetonitrile, chloroform and perfluoropolyether (PFPE) oil. The
      oxidation of the three sulfides with S-330 was very rapid and completed in <4 min
      in acetonitrile-water or PFPE oil, but the rates of reaction in chloroform were
      significantly slower. In a large excess of S-330, the major products resulted
      from chlorination of the side chains. At a high HD/S-330 ratio, the major product
      was HD sulfoxide. Under both conditions, only a trace of HD sulfone, also a
      blistering agent, was observed. Reactions with DBS and MPS primarily gave
      sulfoxides and sulfones, with less side-chain chlorination. The chloroamide S-330
      appeared to be a rapid and effective decontaminant of HD in either polar media or
      in a PFPE oil. The two alkyl and aryl sulfides are suitable simulants of HD for
      the initial screening and evaluation of S-330 or other similar oxidizing agents.

PMID- 10594907
TI  - Analysis and stability of the candidate sulfur mustard decontaminant S-330.
AB  - The chloroamide compound 1,3,4,6-tetrachloro-7,8-diphenyl-2, 5-diiminoglycoluril
      (S-330) was found to be a strong reactant in dermal formulations for the
      decontamination of sulfur mustard (HD). In this report, we present analytical
      methodologies applicable to the characterization, purity determination and
      quantitation of S-330 in bulk material or formulations. High-performance liquid
      chromatography-mass spectrometry (LC-MS) coupled with atmospheric pressure
      chemical ionization (APCI) interface or ultraviolet detector and nuclear magnetic
      spectroscopy (NMR) were used to identify and characterize S-330 and impurities in
      the synthetic lots or degradation products in formulations. Bulk synthesis using
      a chlorination process has yielded a product of 90% purity. The major impurity
      has been separated and identified structurally as the trichloro analog of S-330.
      Higher purity S-330 can be made using column chromatography, but this does not
      appear to be economical for large-scale production. Factors affecting the
      stability of S-330 in topical formulations include water content, pH, alcohols
      and UV light. Chloroamide S-330 decomposes at 50-60 degrees C and is not amenable
      for GC analysis. The HPLC technique is superior to NMR or active chlorine assay
      in the purity determination for S-330 in bulk material or formulations. In
      topical formulations containing S-330, 5-10% of water can be tolerated, but
      alcohols and acidic and basic conditions should be avoided.

PMID- 10594908
TI  - Surgical approach and histoanatomical aspects of the oculomotor nerve in rats.
AB  - The surgical approach and some histoanatomical characteristics of the
      intracavernous portion of the oculomotor nerve are described. Moreover, some
      perioperative precautions for intracranial surgical procedures in the rat are
      reported and the suitability of the rat as a model for studying intracranial
      nerve regeneration is discussed. With the data provided, this model of oculomotor
      nerve approach can be used to study various aspects of intracranial nerve
      regeneration.

PMID- 10594909
TI  - Viability of cultured nerve grafts: An assessment of proliferation of Schwann
      cells and fibroblasts.
AB  - Previous studies demonstrated that the viability of nerve grafts had a positive
      effect on nerve regeneration, while the cold storage of nerve grafts obtained few
      viable cells at the later stage. The purpose of this study was to examine the
      cellular activities of Schwann cells and fibroblasts in cultured nerve grafts
      prior to transplantation. 2.5-cm long sciatic nerve grafts were harvested from 75
      male Lewis rats. Two different media were utilized to culture the nerve grafts up
      to 3 weeks: Dulbecco's modified eagle medium (DMEM) only or DMEM supplemented
      with 2 microM forskolin and 10 microg/ml pituitary exact (mitogen medium for
      Schwann cells). In vivo predegenerated and normal nerve grafts were used as
      positive and negative controls, respectively. We employed a 5-bromo-2'
      deoxyuridine (BrdU) incorporation method to evaluate the proliferating cells in
      the cultured nerve grafts. S-100 and vimentin immunostaining were used to
      estimate the presence of Schwann cells and fibroblasts in all nerve grafts at
      different intervals. The results showed that the proliferating cells increased
      progressively under culture conditions. The proliferating cells distributed
      evenly in small fascicles (average diameter 251 +/- 71.5 microm), whereas they
      appeared mainly in the margin of large fascicles (average diameter 624 +/- 87.3
      microm). The mitogen medium stimulated Schwann cell multiplication more
      significantly in comparison with DMEM after 3 days of culture (P < 0.01),
      however, there were fewer fibroblasts present in the mitogen medium than in DMEM
      after 2 days of culture (P < 0.01). It is suggested that the viability of nerve
      grafts can be preserved under culture conditions. Furthermore, the cellular
      activity of the Schwann cells and fibroblasts in nerve grafts can be manipulated
      in in vitro Wallerian degeneration.

PMID- 10594910
TI  - Arterial crush injury causes decrease in tissue perfusion at the level of the
      microcirculation in skeletal muscle flap.
AB  - This study was designed to evaluate the effects of crush injuries to the feeding
      arteries of a muscle flap on microcirculatory haemodynamics. Eighteen male
      Sprague-Dawley rats were divided into three experimental groups for intravital
      microscopy of the cremaster muscle flap. Group 1 served as control. In group 2
      the common iliac artery and in group 3 additionally the lower abdominal aorta was
      crushed with a Kocher clamp (17.4 N) over 5 min. Microcirculatory parameters (red
      blood cell velocity, vessel diameter, and capillary perfusion) were monitored
      before and 2 h after crush. In the one-level crush group, red blood cell
      velocities significantly decreased by 39.17% (P=0.046) in first order arterioles
      and by 32. 91% (P=0.0106) in second order arterioles. In capillary perfusion, a
      drop of 48.02% (P=0.0039) was noted. In the two-level crush group, red blood cell
      velocities significantly dropped over 32.06% (P=0. 0250) in first order
      arterioles, 35.91% (P=0.0065) in second order arterioles, and 45.69% (P=0.0782)
      in first order venules. Capillary perfusion was reduced by 20.16% (P=0.374).
      Arterial crush injuries as possible thrombogenic insults may result in a
      significant decrease in skeletal muscle perfusion although the blood supply
      through the crushed supplying vessel is maintained.

PMID- 10594911
TI  - Local application of FFR-rFVIIa reduces thrombus formation at arterial
      anastomosis in rats.
AB  - Thrombosis is still a significant problem in microvascular surgery. The aim of
      this study was to evaluate the antithrombotic effect of topically applied active
      site-inhibited recombinant human factor VIIa (FFR-rFVIIa) in a rat model with
      microvascular thrombosis. Forty-five male rats were allocated to one of three
      groups: local treatment with vehicle only, local treatment with 0.035 mg of FFR
      rFVIIa, or local treatment with 0.35 mg of FFR-rFVIIa. An arteriotomy was made in
      the right femoral artery. Ten minutes following topical application, a
      thrombogenic anastomosis was performed. Using a transilluminator, thrombus
      formation and anastomotic bleeding episodes were observed and registered for 40
      min. Local application of FFR-rFVIIa resulted in a 85-90% reduction of thrombus
      formation in both treated groups compared to the control group, but the reduction
      was only statistically significant in the group treated with 0.035 mg of FFR
      rFVIIa. An increased occurrence and duration of anastomotic bleeding episodes
      were observed in both FFR-rFVIIa-treated groups.

PMID- 10594912
TI  - Ischaemia-reperfusion injury of the peripheral nerve: An experimental study.
AB  - Although the neuropathology of ischaemic fibre degeneration is relatively well
      known, its pathogenesis is poorly understood. One of the presumed mechanisms is
      oxidative stress, causing the breakdown of the blood-nerve barrier (BNB) and
      ending in lipid peroxidation. We evaluated the effect of ischaemia and
      reperfusion on the sciatic-tibial nerve of the rat and investigated the
      biochemical, pathological, and functional evidence of BNB disruption and lipid
      peroxidation. The distal portion and trifurcation of the sciatic nerve were
      rendered ischaemic by clamping the femoral vessels for 3 h and followed by
      varying durations of reperfusion. Reperfusion resulted in an increase in lipid
      peroxidation beginning from the first hour and increasing until the seventh day,
      followed by a gradual decline over the following weeks. Nerve oedema and
      ischaemic fibre degeneration (IFD) consistently became more severe and prominent
      with reperfusion, indicating that oxidative stress damages the BNB and causes
      IFD. Results of functional testing by the sciatic function index correlated with
      other parameters as walking track analysis results got worse as reperfusion
      periods increased. Impairment of walking patterns was more striking after the
      first day and continued up to the third week. These data indicate that severe
      ischaemia of the peripheral nerve results in reperfusion injury, functional
      impairment, and disruption of the BNB. Microvascular events, which may occur
      during reperfusion, may be important in amplifying the nerve fibre degeneration
      that initiated during ischaemia.

PMID- 10594913
TI  - Functional assessment of sciatic nerve reconstruction: biodegradable poly (DLLA
      epsilon-CL) nerve guides versus autologous nerve grafts.
AB  - The aim of this study was to compare functional nerve recovery after
      reconstruction with a biodegradable p(DLLA-epsilon-CL) nerve guide filled with
      modified denatured muscle tissue (MDMT), or an autologous nerve graft. We
      evaluated nerve recovery using walking track analysis (measurement of the sciatic
      function index [SFI]) and electrostimulation tests. Functional nerve recovery
      after reconstruction with a biodegradable p(DLLA-epsilon-CL) nerve guide filled
      with MDMT was faster when compared with nerve reconstruction using an autologous
      nerve graft. We conclude that in case of a short nerve gap in the rat,
      reconstruction can best be carried out using a p(DLLA-epsilon-CL) biodegradable
      nerve guide filled with MDMT.

PMID- 10594914
TI  - Isolated cremaster flap: A modified model in intravital microscopy.
AB  - Inspection of the microcirculation in living tissues has been accomplished using
      various models. The rat cremaster muscle has been used for this purpose for more
      than 20 years. In our study, for the first time, the pedicle of the cremaster
      muscle has been catheterised indirectly in order to perfuse and drain the muscle
      and to obtain blood samples. The assessment of the effects of a variety of
      perfusants on the microcirculation after reperfusion injury can be carried out by
      using this model.

PMID- 10594915
TI  - End-to-end versus peripheral nerve graft repair of the oculomotor nerve in rats:
      A comparative histological and morphometric study.
AB  - A comparative study was undertaken to evaluate end-to-end versus peripheral nerve
      graft repair in cranial nerve reconstruction. In 14 rats, the oculomotor nerve
      was sharply transected in the cavernous sinus and repaired either by end-to-end
      coaptation (n = 7) or by interposition of a peripheral nerve graft (n = 7). The
      results were evaluated 16 weeks after surgery by light and transmission electron
      microsurgery and by morphometric analysis. The degree of neuroma formation,
      fibrosis, and axonal disorganisation at the repair site was the same for both
      groups. Histologically, both end-to-end and graft repair groups revealed various
      degrees of axonal regeneration with myelinated nerve fibres in the distal nerve
      segments. In both groups, the number of nerve fibres distal to the repair site
      was increased compared to proximal to the repair (P < 0.001) but myelinated axon
      diameter was significantly less than that of control nerves (P < 0.001). No
      difference existed between the two repair groups in terms of mean myelinated
      axonal diameter. However, the number and density of myelinated axons was
      statistically greater in the graft group (P < 0.05). In conclusion, despite the
      disadvantage of two repair sites, peripheral nerve grafting results in equal or
      slightly superior axonal regeneration compared to an end-to-end repair in the
      rodent model of intracranial oculomotor nerve reconstruction. We speculate that
      this may be due to the structure of the peripheral nerve graft.

PMID- 10594916
TI  - Failure in developing a model for complete vascular thrombosis in the common
      iliac artery in the rat.
AB  - The purpose of this study was to develop a model for complete arterial thrombosis
      proximal to the rat cremaster flap for subsequent fibrinolytic studies at the
      microcirculatory level. We divided 20 male Sprague-Dawley rats into four
      experimental groups of five animals each. We assigned each group to an
      established thrombosis model using crush and standard microsurgical anastomosis,
      crush and intimal abrasion, inverted arterial suture, and intravascular silk
      sutures combined with microsurgical anastomosis at the common iliac artery.
      Vessel patency was examined using the milking test 30, 60, 90, and 120 min after
      the thrombogenic insults. The model of perpendicular silk sutures and anastomosis
      caused complete arterial thrombosis in one animal over 120 min. The other models
      failed in all animals. In conclusion, the thrombogenic models used in this study
      are not capable of creating a reliable complete arterial thrombosis in the common
      iliac artery of the rat.

PMID- 10594917
TI  - Split median nerve.
AB  - Carpal tunnel syndrome is encountered frequently in the every day practice for
      many orthopaedic surgeons and neurosurgeons. However, the rate of recurrence or
      incomplete relief is high and difficult to treat. This may be related to the high
      percent of anomalies of the median nerve and its surrounding tissues. A case of a
      split median nerve entrapped by an abnormally inserted palmaris longus muscle is
      presented. The case is discussed and a conclusion of safer standard surgical
      release is recommended, especially in doubtful cases.

PMID- 10594918
TI  - Production of nitric oxide by glial cells: regulation and potential roles in the
      CNS.
AB  - Roles proposed for nitric oxide (NO) in CNS pathophysiology are increasingly
      diverse and range from intercellular signaling, through necrotic killing of cells
      and invading pathogens, to the involvement of NO in apoptosis and tissue
      remodeling. In vitro evidence and observations from experimental animal models of
      a variety of human neuropathologies, including stroke, indicate that glial cells
      can produce NO. Regulation of at least one of the NO synthase genes (NOS-2) in
      glia has been well described; however, apart from hints emerging out of co
      culture studies and extrapolation based upon the reactivity of NO, we are a long
      way from identifying functions for glial-derived NO in the CNS. Although the
      assumption is that NO is very often cytotoxic, it is evident that NO production
      does not always equate with tissue damage, and that both the cellular source of
      NO and the timing of NO production are important factors in terms of its effects.
      With the development of strategies to transfer or manipulate expression of the
      NOS genes in specific cells in situ, the ability to deliver NO into the CNS via
      long-lived chemical donors, and the emergence of more selective NOS inhibitors,
      an appreciation of the significance of glial-derived NO will change.

PMID- 10594919
TI  - Neurosteroid progesterone is up-regulated in the brain of jimpy and shiverer
      mice.
AB  - Concentrations of neurosteroids have been measured in the brains of postnatal
      myelin mutants jimpy (jp) and shiverer (shi) mice and of their normal controls.
      Progesterone (PROG) concentrations were increased more than threefold in the
      brains of mutant mice. Marked astroglial reaction occurs in the brains of jp mice
      and to a much smaller extent in shi ones. Whereas the mitochondrial
      benzodiazepine/diazepam binding inhibitor (DBI) receptor (MBR) was below the
      immunohistochemical detection limit in normal mice (except in the choroid plexus
      and ependyma cells), it was significantly expressed in many reactive astrocytes
      of jp and shi mice brains. DBI-like peptides, investigated either by
      immunohistochemistry or by radioimmunoassay, were expressed to similar extents in
      mutant and control mice. Reversed-phase HPLC indicated that DBI-like peptides
      were almost exclusively of the triakontatetraneuropeptide size. It was concluded
      that the increased expression of MBR (involved in the intramitochondrial delivery
      of cholesterol to P450scc) likely accounts for the large PROG content in mutant
      mice brain. The role of PROG in myelin repair is discussed.

PMID- 10594920
TI  - Cellular distribution of superoxide dismutases in the rat CNS.
AB  - Superoxide dismutase (SOD) is considered to be a major factor in protection of
      nervous tissue against excitotoxic and ischemic/hypoxic lesion. Controversial
      reports about the localization of SOD after such an insult prompted us to re
      investigate immunocytochemically the localization of the enzyme in the brain and
      spinal cord using specific antibodies against the manganese (Mn-SOD) and
      copper/zinc (Cu/Zn-SOD) containing isoenzyme in combination with cell type
      specific markers. CNS tissue sections were analyzed by confocal laser scanning
      microscopy and digital photo imaging. Cu/Zn-SOD immunoreactivity was found to be
      located predominantly in astrocytes throughout the CNS. The staining was found in
      the cytoplasm, in cellular processes and, less intensive, in the nucleus sparing
      the nucleolus. At a lower level the enzyme was also detectable in neuronal
      perikarya and in structures of the neuropil. Motoneurons of the spinal cord
      displayed an enhanced Cu/Zn-SOD staining intensity, when compared to brain
      neurons. In contrast the Mn-containing isoenzyme was predominantly localized to
      neurons and their processes throughout the brain and the spinal cord. Confirming
      the mitochondrial localization of the enzyme, a granular staining pattern sparing
      the nucleus was observed. Mn-SOD stained mitochondria were also seen in
      astroglial cells but the staining intensity was, on the whole, much lower
      compared to neurons, and often hardly detectable. It seems reasonable to conclude
      that differences in the basal content of SOD-isoenzymes may contribute to
      different cellular susceptibilities in neurodegenerative processes that are
      accompanied by oxidative stress.

PMID- 10594921
TI  - Role of glial K(+) channels in ontogeny and gliosis: a hypothesis based upon
      studies on Muller cells.
AB  - The electrophysiological properties of Muller cells, the principal glial cells of
      the retina, are determined by several types of K(+) conductances. Both the
      absolute and the relative activities of the individual types of K(+) channels
      undergo important changes in the course of ontogenetic development and during
      gliosis. Although immature Muller cells express inwardly rectifying K(+) (K(IR))
      currents at a very low density, the membrane of normal mature Muller cells is
      predominated by the K(IR) conductance. The K(IR) channels mediate spatial
      buffering K(+) currents and maintain a stable hyperpolarized membrane potential
      necessary for various glial-neuronal interactions. During "conservative" (i.e.,
      non-proliferative) reactive gliosis, the K(IR) conductance of Muller cells is
      moderately reduced and the cell membrane is slightly depolarized; however, when
      gliotic Muller cells become proliferative, their K(IR) conductances are
      dramatically down-regulated; this is accompanied by an increased activity of
      Ca(2+)-activated K(+) channels and by a conspicuous unstability of their membrane
      potential. The resultant variations of the membrane potential may increase the
      activity of depolarization-activated K(+), Na(+) and Ca(2+) channels. It is
      concluded that in respect to their K(+) current pattern, mature Muller cells pass
      through a process of dedifferentiation before proliferative activity is
      initiated.

PMID- 10594922
TI  - Muller glia cells reorganize reaggregating chicken retinal cells into correctly
      laminated in vitro retinae.
AB  - Muller cells, that belong to the family of radial glia cells, have central
      functions during retinogenesis. They form a stabilizing scaffold, they are
      candidate targets for the mediation of extraneous retinogenetic factors, and they
      are an important source for retina-borne retinogenetic factors. Reaggregate
      cultures allow the analysis of retinogenesis from dispersed cells to fully
      laminated tissues. Reaggregating cells from the embryonic chick retina reassemble
      to reversed laminated cellular spheres including constituents of all retinal
      layers, yet the outer nuclear layer is represented by internal rosettes. Using
      spheroids, we tested whether Muller cells have a decisive function in
      establishing retinal polarity and in determining the lamination pattern. To this
      end, we established confluent monolayers of highly enriched Muller cells derived
      from E6 or E13 chicken retinas, and then let dispersed E5.5 retinal cells
      reaggregate either in the absence of these monolayers or on top of them. In the
      presence of Muller cells, the reversed lamina polarity of rosetted spheroids
      progressively transformed within a week into correctly laminated retinal spheres,
      whereas all initial rosettes vanished. Moreover, photoreceptors formed a regular
      outer nuclear layer, as visualized by the rod-specific CERN901 antibody. In
      correctly laminated spheroids, staining for vimentin and glutamine synthetase was
      much more pronounced than in rosetted spheroids; in particular, a well
      established inner limiting membrane stood out wherever the retinal lamination was
      complete. Because these effects can be similarly achieved by supernatants derived
      from Muller cells, direct cell-cell contacts or cellular replenishment from the
      monolayer do not account for these effects. We conclude that Muller cells are
      involved in the establishment of a correct retinal lamination and in the
      arrangement of the cells in the reaggregate cultures. In particular, rosette
      formation is counteracted and the formation of an inner limiting membrane is
      induced. Because rosettes are objects of concern in several ophthalmological
      defects, these results are highly relevant, both biomedically and also for normal
      retinogenesis.

PMID- 10594923
TI  - Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial
      cells.
AB  - The effect of cannabinoids on the induction of cytokine mRNA by rat microglial
      cells was examined. Exposure of neonatal rat cortical microglial cells to the
      exogenous cannabinoid delta(9)-tetrahydrocannabinol (THC) resulted in reduced
      amounts of lipopolysaccharide (LPS)-induced mRNAs for IL-1alpha, IL-1beta, IL-6,
      and TNF-alpha. Of these cytokine mRNAs, the response of that for IL-6 was
      exquisitely sensitive to THC. Similarly, exposure of microglial cells to the
      putative endogenous cannabinoid anandamide before LPS treatment resulted in a
      decrease in cytokine mRNA levels, but not to the same extent as that caused by
      THC; however, when methanandamide, the non-hydrolyzable analog of anandamide was
      tested, its ability to inhibit cytokine mRNA expression was comparable to that of
      THC. Exposure of microglial cells to either of the paired enantiomers CP55,940 or
      CP56,667 resulted in similar inhibition of LPS-induced cytokine mRNA expression.
      A comparable inhibitory outcome was obtained when the paired enantiomers
      levonantradol and dextronantradol were employed. Neither the CB(1)-selective
      antagonist SR141716A nor the CB(2)-selective antagonist SR144528 was able to
      reverse the inhibition of cytokine mRNA expression by levonantradol. The CB(2)
      antagonist, however, when administered alone augmented the production of cytokine
      mRNAs. Collectively, these studies demonstrate that cannabinoids can modulate
      levels of cytokine mRNA in rat microglial cells; however, the inhibition of
      cytokine mRNA expression is apparently not mediated through either the CB(1) or
      CB(2) cannabinoid receptors.

PMID- 10594924
TI  - Metabotropic glutamate receptors in acutely isolated hippocampal astrocytes:
      developmental changes of mGluR5 mRNA and functional expression.
AB  - We previously found that 82% of glial fibrillary acidic protein (GFAP)-positive
      hippocampal astrocytes acutely isolated from P1-10 rats responded to glutamate
      (Glu) with transient intracellular calcium increases via activation of a Group I
      metabotropic glutamate receptor (mGluR). Fewer cells responded to ATP and none to
      serotonin (5-HT). In this study we asked the question whether hippocampal
      astrocytes in older animals retain this relative pattern of expression. We have
      found that 77% of GFAP (+) cells from P11-20 rats responded to 50 microM Glu, 43%
      to ATP, and none to 5-HT. Thirty-three percent of GFAP (+) cells from P25-35 rats
      responded to Glu, 12% to ATP and 3% to 5-HT. In the case of the responses to Glu,
      pharmacological characterization and single-cell RT-PCR data confirmed that these
      responses were mediated by the mGluR5 subtype of group I mGluRs. Also, fewer
      (36%) GFAP mRNA (+) cells from P25-35 rats expressed detectable mGluR5 mRNA than
      those from P11-20 rats (77%). This number essentially corresponds to the number
      of GFAP(+) showing a Ca(2+) response to Glu. Both mGluR5a and b were expressed
      with equal frequency in cells from P11-20 rats, but the b form predominated in
      cells from older animals. Overall, our studies show that expression of mGluR5 in
      hippocampal astrocytes decreases with increasing age and the "a" splice variant
      declines to a greater extent than the "b" splice variant, corresponding to the
      developmental changes shown in total tissue for mGluR5.

PMID- 10594925
TI  - Myelin basic protein (MBP) and MBP peptides are mitogens for cultured astrocytes.
AB  - After CNS demyelination, astrogliosis interferes with axonal regeneration and
      remyelination. We now provide evidence that myelin basic protein (MBP) can
      contribute to this observed astrocyte proliferation. We found that astrocytes
      grown in either serum-containing or serum-free medium proliferate in response to
      MBP. The mitogenic regions of MBP in both media were MBP(1-44), MBP(88-151) and
      MBP(152-167). The mitogenic effect of these individual peptides was potentiated
      by simultaneous treatment with microglia conditioned media (CM). MBP-induced
      proliferation was inhibited by suramin at concentrations known to block the
      fibroblast growth factor receptor (FGFR), whereas neither MBP(1-44), MBP(88-151)
      nor MBP(152-167) were affected. Cholera toxin B, that binds to ganglioside GM(1),
      inhibited the mitogenicity of MBP(1-44) and had no significant effect on the
      mitogenicity of MBP, MBP(88-151) or MBP(152-167). Treatment of astrocytes with
      MBP and MBP(152-167) caused a modest and transitory elevation of intracellular
      calcium, whereas treatment with MBP(1-44) resulted in a substantial and sustained
      increase in intracellular calcium. These results suggest that for cultured
      astrocytes 1) FGFR and extracellular calcium play a major role in MBP
      mitogenicity; 2) MBP(1-44), MBP(88-151) and MBP(152-167) are the mitogenic
      regions of MBP; 3) MBP(1-44) and MBP(152-167) interact with ganglioside GM(1) and
      FGFR, respectively; 4) Component(s) present in microglial CM potentiate the
      mitogenicity of MBP(1-44), MBP(88-151) and MBP(152-167). These data support the
      hypothesis that MBP related peptides in conjunction with microglial secreted
      factors may stimulate astrogliosis after demyelination in vivo.

PMID- 10594926
TI  - Pro-inflammatory cytokines induce the transcription factors C/EBPbeta and
      C/EBPdelta in astrocytes.
AB  - The transcription factors CCAAT/enhancer binding protein (C/EBP)-beta and -delta
      are key regulators for the expression of the acute phase genes in the liver, such
      as complement component C3 and antichymotrypsin. In the brain, these acute phase
      proteins are produced in response to pro-inflammatory cytokines by the reactive
      astrocytes, in particular those surrounding the amyloid plaques of Alzheimer's
      disease brains. Here we show that lipopolysaccharides (LPS), IL-1beta, and
      TNFalpha induce the expression of the c/ebpbeta and -delta genes in mouse primary
      astrocytes. This induction precedes the expression of the acute phase genes
      coding for the complement component C3 and the mouse homologue of
      antichymotrypsin. The induction of these two acute phase genes by LPS is blocked
      by cycloheximide, whereas this protein synthesis inhibitor does not affect the
      expression of the c/ebp genes. Altogether, our data support a role as immediate
      early genes for c/ebpbeta and -delta, whose expression is induced by pro
      inflammatory cytokines in mouse cortical astrocytes. In the liver, these
      transcription factors are known to play an important role in inflammation and
      energy metabolism regulation. Therefore, C/EBPbeta and -delta could be pivotal
      transcription factors involved in brain inflammation, in addition to their
      previously demonstrated role in brain glycogen metabolism regulation (Cardinaux
      and Magistretti. J Neurosci 16:919-929, 1996).

PMID- 10594927
TI  - Induction of nitric oxide synthesis lowers intracellular glutathione in microglia
      of primary glial cultures.
AB  - Glutathione (GSH) is one of the most important antioxidants involved in
      detoxification of reactive oxygen and nitrogen species. We investigated the
      changes in intracellular GSH in primary glial cultures stimulated to produce
      inducible nitric oxide synthase and subsequently nitric oxide by bacterial
      lipopolysaccharide and gamma interferon treatment. Intracellular GSH content was
      measured by both the monochlorobimane fluorescence microscopy method and the GSH
      reductase recycling assay (Tietze. Anal Biochem 27:502-522, 1969.). Our results
      show that irrespective of the assay used the GSH content in stimulated cultures
      decreased to almost half that of control cultures. This decrease in GSH content
      was accompanied by an increase in S-nitrosoglutathione in the stimulated
      cultures. Analysis of the GSH related fluorescence images showed that the
      fluorescence intensity was lowered exclusively in microglial cells whereas that
      of astrocytes remained almost unchanged. The present study in conjunction with
      our previous investigation (Chatterjee et al. Glia 27:152-161, 1999) can be
      interpreted to imply that the higher GSH levels in untreated microglia are a
      mechanism to withstand nitric oxide synthase induced oxidative and nitrosative
      stress and therefore the GSH levels in microglia drop to astrocyte levels after
      induction.

PMID- 10594928
TI  - Thapsigargin induces microglial transformation from amoeboid- to ramified- type
      in vivo
AB  - Yagi R, Tanaka S, Koike T. 1999. Thapsigargin induces microglial transformation
      from amoeboid- to ramified- type in vivo. Glia 28:49-52. The article referenced
      above was published as an Original Article instead of a Short Communication. The
      publisher regrets this error.

PMID- 10594929
TI  - Remyelination occurs as extensively but more slowly in old rats compared to young
      rats following fliotoxin-induced CNS demyelination
AB  - Shields SA, Gilson JM, Blakemore W, Franklin RJ. 1999. Remyelination occurs as
      extensively but more slowly in old rats compared to young rats following
      fliotoxin-induced CNS demyelination. Glia 28:77-83. The article referenced above
      was published as a Short Communication instead of an Original Article. The
      publisher regrets this error.

PMID- 10594930
TI  - Transcriptional activation of Cu/Zn superoxide dismutase and catalase genes by
      panaxadiol ginsenosides extracted from Panax ginseng.
AB  - Superoxide dismutase (SOD) converts superoxide radical to H(2)O(2), which is in
      turn broken down to water and oxygen by catalase. Thus, SOD and catalase
      constitute the first coordinated unit of defence against reactive oxygen species.
      A wide variety of chemical and environmental factors are known to induce these
      antioxidant enzymes. Here, we examined the effect of ginseng saponins on the
      induction of SOD and catalase gene expression. To explore this possibility, the
      upstream regulatory promoter region of Cu/Zn superoxide dismutase (SOD1) and
      catalase genes were linked to the chloramphenicol acetyltransferase (CAT)
      structural gene and introduced into human hepatoma HepG2 cells. Total saponin and
      panaxatriol did not activate the transcription of SOD1 and catalase genes but
      panaxadiol increased the transcription of these genes about 2-3 fold. Among the
      panaxadiol ginsenosides, the Rb(2) subfraction appeared to be a major inducer of
      SOD1 and catalase genes. The specificity of the Rb(2) effect was further
      confirmed by time course- and dose-dependent induction experiments. These results
      suggest that the panaxadiol fraction and its ginsenosides could induce the
      antioxidant enzymes which are important for maintaining cell viability by
      lowering the level of oxygen radical generated from intracellular metabolism.

PMID- 10594931
TI  - Vascular effects of aqueous crude extracts of Artemisia verlotorum Lamotte
      (Compositae): in vivo and in vitro pharmacological studies in rats.
AB  - Artemisia verlotorum Lamotte (Compositae), growing in almost all the northern
      hemisphere, is used in folk medicine of some countries of Tuscany, Italy, as a
      remedy for hypertension. The pharmacological evaluation of the responses evoked
      by an aqueous dried extract of Artemisia verlotorum on the blood pressure of
      anaesthetized rats and on in vitro rat isolated aortae showed a marked, but
      transient, hypotensive activity. This effect was mediated by a strong vasodilator
      action, closely linked to the release of endothelial nitric oxide and to the
      nitric oxide-guanosine 3'-5'-cyclic monophosphate (cGMP) pathway, caused by a
      muscarinic receptor agonism.

PMID- 10594932
TI  - Effect of active molluscicidal component of spices on different enzyme activities
      and biogenic amine levels in the nervous tissue of Lymnaea acuminata.
AB  - In vivo exposure of Lymnaea acuminata to thymol and [6]-gingerol (active
      molluscicidal components of Trachyspermum ammi and Zingiber officinale,
      respectively) indicates that they significantly alter acetylcholinesterase,
      lactic dehydrogenase, succinic dehydrogenase and cyto-oxidase activity in the
      nervous -tissue of snails. In vitro exposure showed that, except for
      acetylcholinesterase and lactic dehydrogenase, no significant changes were
      observed in cyto-oxidase and succinic dehydrogenase activity in the nervous
      tissue of L. acuminata. Sublethal exposure to thymol and [6]-gingerol reduced the
      levels of 5-hydroxytryptamine (5-HT) and dopamine (DA) in the nervous tissue of
      L. acuminata. There was, however, no significant change in the level of 5-hydroxy
      indol acetic acid (5-HIAA). Thymol and [6]-gingerol thus affects all the known
      neurotransmission mechanisms in the snail either separately or through a complex
      interaction between the different neurotransmitters. This may account for their
      toxicity to snails.

PMID- 10594933
TI  - Effects of mistletoe lectin I and ionizing radiation on the glucose and thymidine
      uptake in tumour cells in vitro.
AB  - The increased uptake of hexose by mammalian cells is considered to be a general
      response to stress. Nowadays, mistletoe lectin separated from the extracts of the
      European mistletoe (Viscum album L.) is often used in adjuvant cancer therapy.
      The present work studies the effect of the lectin on unirradiated and x
      irradiated tumour cells. The response of cultured human lung carcinoma cells
      (Calu-1) was followed by radioactive glucose uptake as well as by tritiated
      thymidine incorporation. The cells were maintained either in a complete or a so
      called restrictive medium. Slight metabolic changes were found in the restrictive
      medium but not in the complete one. Mistletoe lectin I at a very low
      concentration (0.001 ng/mL) increased the glucose uptake and thymidine
      incorporation. Ionizing radiation (1 Gy) did not influence the hexose uptake but
      it enhanced the incorporation of thymidine. It seems that the actions of two
      different factors (mistletoe lectin I and radiation) proved to be rather
      provoking stress effects for the tumour cells as detected in the restrictive
      medium.

PMID- 10594934
TI  - Molluscicidal activity of the diterpenoids jatrophone and jatropholones A and B
      isolated from Jatropha elliptica (Pohl) Muell. Arg.
AB  - In the search for new molluscicidal natural products, the activity of the crude
      ethanol extract of the rhizome of Jatropha elliptica (Pohl.) Muell. Arg. was
      tested. The LC(50) was 13.07 ppm. The fractionation and purification of the
      extract furnished jatrophone and a mixture of jatropholones A and B, as the main
      compounds. They were tested against the snail Biomphalaria glabrata. Jatrophone
      showed an LC(50) of 1.16 ppm as a molluscicide and an LC(50) of 1.14 ppm for the
      assay of egg mass, while the mixture of jatropholones A and B presented an LC(50)
      of 58.04 ppm as a molluscicide and was not active against the second assay at a
      concentration up to 100 ppm.

PMID- 10594935
TI  - Studies on antihypertensive and antispasmodic activities of methanol extract of
      Acacia nilotica pods.
AB  - A methanol extract of Acacia nilotica pods (AN) caused a dose-dependent (3-30
      mg/kg) fall in arterial blood pressure. Treatment of animals with atropine
      abolished the vasodilator response of acetylcholine (ACh), whereas the
      antihypertensive effect of the plant extract remained unaltered. Phentolamine (an
      alpha-adrenergic blocker) abolished the vasoconstrictor effect of norepinephrine
      (NE), whereas pretreatment of the animal with AN, did not modify the NE response.
      These results indicate that the antihypertensive effect of plant extract is
      independent of muscarinic receptor stimulation or adrenoceptor blockade. In the
      in vitro studies, AN produced a dose-dependent (0.3-3.0 mg/mL) inhibitory effect
      on force and rate of spontaneous contractions in guinea-pig paired atria.
      Similarly, it inhibited the spontaneous contraction of rabbit jejunum in a
      concentration-dependent (0.1-3.0 mg/mL) manner. AN also inhibited K(+)-induced
      contractions in rabbit jejunum at a similar concentration range, which suggests
      that the antispasmodic action of AN is mediated through calcium channel blockade,
      and this may also be responsible for the blood pressure lowering effect of AN,
      observed in the in vivo studies.

PMID- 10594937
TI  - Antibacterial activities of extracts from Nigerian chewing sticks.
AB  - Ten aqueous extracts from wooden chewing sticks widely used in Nigeria for teeth
      cleaning were studied for antibacterial activities against 25 different bacteria
      using an agar diffusion assay. The extracts from five sticks, namely Garcinia
      kola, Anogeissus leiocarpus, Terminalia glaucescens, Sorindeia warneckei and
      Vitex doniana, exhibited strong activities against a wide spectrum of bacteria
      including medically and dentally relevant bacteria. Notably, these five chewing
      stick extracts showed potent activities against methicillin-resistant
      Staphylococcus aureus, vancomycin-resistant Enterococcus, and multidrug-resistant
      Burkholderia cepacia and Pseudomonas aeruginosa. Extracts from Vernonia
      amygdalina, Fagara zanthoxyloides and Massularia acuminata also showed activities
      against bacteria significant to periodontal disease. Methanol extracts prepared
      from G. kola, A. leiocarpus and V. doniana were further fractionated by solvent
      extraction. Results showed that the antibacterial activities were distributed
      into different fractions suggesting that the sticks contain different active
      antibacterial principles. In conclusion, the results showed that most of the
      Nigerian chewing sticks do contain antibacterial activities which may contribute
      to the reported anticaries effect of chewing sticks. These sticks may be sources
      for new lead antibacterial agents for therapeutic or preventive applications.

PMID- 10594936
TI  - Isolation of a muscarinic alkaloid with ocular hypotensive action from Trophis
      racemosa.
AB  - A muscarinic alkaloid with a quaternary nitrogen was isolated from Trophis
      racemosa. Aqueous solutions (0.5%-2%) of the chloride salt of the alkaloid
      produced dose-dependent reductions of intra-ocular pressure ranging from 6.6 +/-
      0.7 mmHg to 15.7 +/- 0.3 mmHg, (p < 0. 001, n = 5) in dogs. Atropine (0.1 mL of a
      1% solution) and pirenzepine at a non selective antagonist dose (0.1 mL of 0.5%
      solution) for M(1) and M(3) receptors blocked the reduction of intra-ocular
      pressure, but alpha-adrenoceptor blockade with phenoxybenzamine (0.1 mL of a 1%
      solution) did not block the reduction of intra-ocular pressure. On the isolated
      guinea-pig ileum and trachea, the alkaloid produced contractions which were
      inhibited by atropine (6 x 10(-7) M or 0.4 microg/mL) and by pirenzepine at a non
      selective antagonist dose (3.1 x 10(-6) M or 1.3 microg/mL) for M(1) and M(3)
      receptors. But neither selective blockade of M(2) receptors with gallamine (1.7 x
      10(-6) M or 1.5 microg/mL) nor selective blockade of M(1) receptors with
      pirenzepine (7 x 10(-9) M or 3 ng/mL) inhibited the alkaloid-induced
      contractions. There was also no inhibition of the alkaloid-induced contractions
      in the presence of ganglionic nicotinic receptor blockade with pentolinium (5.6 x
      10(-7) M or 0.3 microg/mL) and hexamethonium (1.7 x 10(-6) M or 0.6 microg/mL),
      but nicotine-induced contractions were inhibited by these ganglionic blockers.
      These results suggest that a muscarinic alkaloid from Trophis racemosa produced
      ocular hypotension via M(3) receptor stimulation in dogs.

PMID- 10594938
TI  - Screening of Korean plants against human immunodeficiency virus type 1 protease.
AB  - With the aim of finding novel anti-human immunodeficiency virus agents from
      natural products, 93 MeOH extracts of Korean plants were screened for their
      inhibitory activities against HIV-1 protease. The most potent inhibition was
      shown by the root of Rodiola rosea with 70.4% inhibition at a concentration of
      100 microg/mL.

PMID- 10594939
TI  - The pharmacological effects of an aqueous extract from Acacia nilotica seeds.
AB  - An aqueous extract of the seed of Acacia nilotica was investigated for its
      pharmacological profile. On the isolated guinea-pig ileum, the extract displayed
      sustained dose-related contractile activity. The contractions which were reduced
      by hexamethonium, promethazine or atropine were completely abolished by
      nifedipine. The intravenous (i.v.) administration of the extract (11, 22, 44, 55
      microg/kg) to anaesthetized cats produced a dose-related significant elevation of
      blood pressure. The mechanisms of the spasmogenic and vasoconstrictor actions of
      the extract have not been determined, however, the results suggest the
      involvement of calcium.

PMID- 10594940
TI  - Acute and subchronic evaluation of Indigofera arrecta: absence of both toxicity
      and modulation of selected cytochrome P450 isozymes in ddY mice.
AB  - Indigofera arrecta, an anti diabetic plant was investigated in ddY mice to
      determine its acute and subchronic effects, and whether it modulated hepatic
      cytochrome P450 (CYP) isozymes and glutathione (GSH). No mortality was observed
      in the acute (up to 10 g I. arrecta/kg body wt, p.o.) and subchronic (2 g I.
      arrecta/kg body wt, p.o. daily for 30 days) studies. The extract did not alter
      haematological indices, serum and tissue lipids and glutathione but lowered serum
      bile acids. The latter phenomenon is under further investigation. Neither the
      duration of pentobarbital (PB) and zoxazolamine (ZA) effects in vivo, nor CYP
      dependent 7-ethoxyresorufin-O-deethylase (EROD), 7-pentoxyresorufin-O-depentylase
      (PROD) and p-nitrophenol hydroxylase (PNPH) activities in vitro were altered by
      I. arrecta. The extract was thus devoid of overt acute and subchronic toxic
      effects, and did not affect CYPs and GSH whose modulation may cause interactions
      of components in a multiple drug therapy.

PMID- 10594941
TI  - Antioestrogenic effect of trans-dehydrocrotonin, a nor-clerodane diterpene from
      Croton cajucara Benth. in rats.
AB  - This study examined trans-dehydrocrotonin (t-DCTN), a nor-clerodane diterpene
      isolated from the Brazilian medicinal plant Croton cajucara Benth., for a
      possible antioestrogenic activity using immature rats as a model system for
      bioassay of oestrogen, and for an antiimplantation effect in regularly cycling
      rats of proven fertility. In the antioestrogen test, t-DCTN (25 and 50 mg/kg)
      effectively prevented oestrogen-induced increases of uterine wet weights. In
      addition, the vaginal openings provoked by oestrogen were completely prevented by
      t-DCTN. However, blastocyst-implantation was only insignificantly affected in t
      DCTN pretreated animals. These results suggest that t-DCTN may be an
      antioestrogen and warrants further studies with regard to its mechanism of
      action.

PMID- 10594942
TI  - Changes in immunomodulatory activity of human mononuclear cells after cultivation
      with leaf decoctions from the genus Ligustrum L.
AB  - Leaf decoctions from Ligustrum vulgare (LV) and Ligustrum delavayanum (LD) were
      studied for candidacidal activity, phagocytic activity studied on human
      mononuclear cells (MO) and complement activated by the classical pathway.
      Candidacidal activity was studied on Candida albicans SC 1539 incubated with MO.
      The decoction of LD increased the candidacidal activity of MO, whereas LV did not
      show any effect. The phagocytic activity of MO was decreased by the decoction of
      LV, whereas LD did not change the activity. The phagocytic index of MO incubated
      with LD decoction was increased, but use of the LV decoction did not show
      significant changes. Decoctions from LD and LV significantly decreased the
      haemolytic activity of complement activated by the classical pathway (conc. 0.78
      mg/mL).

PMID- 10594943
TI  - Bioassay-directed isolation of oxytocic principles from the methanol extract of
      Monechma ciliatum.
AB  - The hot methanol extract (HME) of Monechma ciliatum which has been reported to
      have potent oxytocic activity was purified by fractionation in an attempt to
      isolate the oxytocic principle. Thin layer analysis indicated that the oxytocic
      fraction was very polar. A positive reaction with ninhydrin-spray suggested that
      it is an amino acid/protein. Repeated column chromatography (CC) on silica gel
      followed by sephadex LH-20 column, accompanied by bioassay of the fractions on
      the rat isolated uterus enabled partial isolation of the oxytocic principle (P3)
      to be achieved. Although the exact structure of P3 could not be identified from
      the present study, various spectral analyses suggest that it is a small peptide
      made up of tyrosine, leucine and a third component which is probably serine. It
      is interesting to note that the parent compound, oxytocin, is also a peptide with
      tyrosine and leucine in its structure.

PMID- 10594944
TI  - Patents alert

PMID- 10594945
TI  - Selected bibliography

PMID- 10594946
TI  - Star Trek reality.

PMID- 10594947
TI  - New horizons for cardiovascular drugs.

PMID- 10594948
TI  - Heart surgery by robots.

PMID- 10594949
TI  - Ask the doctor. Are the rumors that grape juice can help prevent heart disease
      true?

PMID- 10594950
TI  - Ask the doctor. My legs get terribly swollen during the day. I asked my doctor
      for a water pill, but he seems reluctant to prescribe one. Do you think this type
      of medication will help me?

PMID- 10594952
TI  - Paying for the golden age of medicine.

PMID- 10594953
TI  - Infectious disease. Here to stay.

PMID- 10594954
TI  - Heart disease. Incredible shrinking surgical incisions.

PMID- 10594955
TI  - Cancer. Genotyping treatments.

PMID- 10594956
TI  - Alzheimer's disease. The secret may be secretase.

PMID- 10594957
TI  - Nutrition. Superpower, heavyweight.

PMID- 10594958
TI  - Genetics. Speed reading the book of life.

PMID- 10594959
TI  - Alternative medicine. Wedding bells or divorce papers?

PMID- 10594960
TI  - General review: violence and mental health - part I.

PMID- 10594961
TI  - Suicide, assisted suicide, and medical illness.

PMID- 10594962
TI  - Who seeks alternative treatment?

PMID- 10594963
TI  - Do antidepressants lose their efficacy?

PMID- 10594964
TI  - Cardiovascular disease at the millennium: a progress report.

PMID- 10594965
TI  - Viagra and the heart: an update.

PMID- 10594966
TI  - Creatine and andro: muscle-builders or health-breakers?

PMID- 10594967
TI  - On call. I am a 49-year-old man with diabetes. I take Glucophage and I'm careful
      with my diet. I also walk three miles almost every day. My blood sugar is always
      below 150, usually in the 130s. My problem is tingling in my fingers and pain in
      my feet, which often keeps me up at night. Is there anything I can do?

PMID- 10594968
TI  - Twenty suggestions for 2000.

PMID- 10594969
TI  - The future of women's health.

PMID- 10594970
TI  - Essential tremor. Don't get shaken by this manageable disease.

PMID- 10594971
TI  - By the way, doctor. I am 59 years old, in good health, and have been on HRT
      (estrogen and progesterone) for about 10 years. I have tried several different
      preparations, but despite this, have developed a uterine fibroid, experienced
      indigestion, gained 20 pounds, and had one abnormal mammogram (with, thankfully,
      a negative biopsy). Because there is heart disease in my family, my doctor wants
      me to stay on HRT for the rest of my life. Can you suggest any alternatives?

PMID- 10594972
TI  - DNA vaccines for viral diseases.
AB  - DNA vaccines, with which the antigen is synthesized in vivo after direct
      introduction of its encoding sequences, offer a unique method of immunization
      that may overcome many of the deficits of traditional antigen-based vaccines. By
      virtue of the sustained in vivo antigen synthesis and the comprised stimulatory
      CpG motifs, plasmid DNA vaccines appear to induce strong and long-lasting humoral
      (antibodies) and cell-mediated (T-help, other cytokine functions and cytotoxic T
      cells) immune responses without the risk of infection and without boost. Other
      advantages over traditional antigen-containing vaccines are their low cost, the
      relative ease with which they are manufactured, their heat stability, the
      possibility of obtaining multivalent vaccines and the rapid development of new
      vaccines in response to new strains of pathogens. The antigen-encoding DNA may be
      in different forms and formulations, and may be introduced into cells of the body
      by numerous methods. To date, animal models have shown the possibility of
      producing effective prophylactic DNA vaccines against numerous viruses as well as
      other infectious pathogens. The strong cellular responses also open up the
      possibility of effective therapeutic DNA vaccines to treat chronic viral
      infections.

PMID- 10594973
TI  - The natural resistance-associated macrophage protein and susceptibility to
      intracellular pathogens.
AB  - Over 20 years ago it was recognised that murine susceptibility to several
      antigenically unrelated pathogens was influenced by a host genetic factor.
      Linkage studies suggested that Lsh, Ity, and Bcg, the leishmania-, salmonella-,
      and mycobacteria-susceptibility genes, may be one gene, located on mouse
      chromosome 1. A reverse genetics strategy identified a candidate gene, Nramp1,
      which was expressed only in reticuloendothelial cells. A single nonconservative
      amino acid substitution was found to correlate with the susceptibility genotype
      in 27 inbred mouse strains. The production of an Nramp1 gene-disrupted mouse and
      a transgenic mouse, which restored the resistance genotype, conclusively proved
      that Nramp1 is the Bcg/Lsh/Ity gene. The Nramp family includes genes expressed in
      both prokaryotic and eukaryotic species. These genes have provided clues to the
      possible function of Nramp1. The ubiquitously expressed gene Nramp2 is an Fe(2+)
      transporter and a mutation in this gene causes microcytic anaemia in mice and
      rats. The functions of Nramp1 and its human homologue, NRAMP1, remain unknown,
      though it is hypothesised that they may regulate the intraphagosomal
      concentration of Fe(2+) and/or other cations. The identification of polymorphisms
      in the human NRAMP1 gene has facilitated studies on the relevance of this gene to
      human mycobacterial susceptibility. NRAMP1 variant alleles are strongly
      associated with tuberculosis, indicating that this is an important mycobacterial
      susceptibility gene in humans and confirming the usefulness of this mouse model
      in the study of human infectious disease susceptibility.

PMID- 10594974
TI  - Legal challenges posed by the use of antimicrobials in food animal production.
AB  - This review article provides a general analysis of the legal challenges presented
      by antimicrobial use in food animal production and the emerging public health
      responses to such use. The article stresses the importance of national and
      international law to the public health strategies and the interdependence between
      national and international law. The article argues that antimicrobial use in food
      animal production poses a challenge to the development of global health
      jurisprudence.

PMID- 10594975
TI  - Introduction of protein or DNA delivered via recombinant Salmonella typhimurium
      into the major histocompatibility complex class I presentation pathway of
      macrophages.
AB  - Recombinant (r) Salmonella typhimurium aroA strains which display the hen egg
      ovalbumin OVA(257-264) peptide SIINFEKL in secreted form were constructed. In
      addition, attenuated rS. typhimurium pcDNA-OVA constructs harbouring a eukaryotic
      expression plasmid encoding complete OVA were used to introduce the
      immunodominant OVA(257-264) epitope into the major histocompatibility complex
      (MHC) class I presentation pathway. Both modes of antigen delivery (DNA and
      protein) by Salmonella vaccine carriers stimulated OVA(257-264)-specific CD8 T
      cell hybridomas. An in vitro infection system was established that allowed both
      rSalmonella carrier devices to facilitate MHC class I delivery of OVA(257-264) by
      coexpression of listeriolysin (Hly) or by coinfection with rS. typhimurium Hlys
      (Hess J., Gentschev I., Miko D., Welzel M., Ladel C., Goebel W., Kaufmann S.H.E.,
      Proc. Natl. Acad. Sci. USA 93 (1996) 1458-1463). Coexpression of Hly and
      coinfection with rS. typhimurium Hlys slightly improved MHC class I processing of
      OVA. Our data provide further evidence for the feasibility of attenuated, Hly
      expressing rS. typhimurium carriers secreting heterologous antigens or harbouring
      heterologous DNA as effective vaccines for stimulating CD8 T cells in addition to
      CD4 T cells.

PMID- 10594976
TI  - Antimicrobial properties of allicin from garlic.
AB  - Allicin, one of the active principles of freshly crushed garlic homogenates, has
      a variety of antimicrobial activities. Allicin in its pure form was found to
      exhibit i) antibacterial activity against a wide range of Gram-negative and Gram
      positive bacteria, including multidrug-resistant enterotoxicogenic strains of
      Escherichia coli; ii) antifungal activity, particularly against Candida albicans;
      iii) antiparasitic activity, including some major human intestinal protozoan
      parasites such as Entamoeba histolytica and Giardia lamblia; and iv) antiviral
      activity. The main antimicrobial effect of allicin is due to its chemical
      reaction with thiol groups of various enzymes, e.g. alcohol dehydrogenase,
      thioredoxin reductase, and RNA polymerase, which can affect essential metabolism
      of cysteine proteinase activity involved in the virulence of E. histolytica.

PMID- 10594977
TI  - Molecular pathogenesis of Bacillus anthracis infection.
AB  - This review summarizes the current knowledge pertaining to the pathogenesis of
      infection with Bacillus anthracis relative to the two exotoxins and the capsule.
      Emphasis is given to the structure and activities of the individual components of
      the exotoxins, their interaction with cells, and the response of macrophages to
      lethal toxin. Finally, results from vaccination studies are reviewed.

PMID- 10594978
TI  - Pathogenesis of Cryptosporidium parvum infection.
AB  - Cryptosporidium parvum can be regarded as a minimally invasive mucosal pathogen,
      since it invades surface epithelial cells that line the intestinal tract but does
      not invade deeper layers of the intestinal mucosa. Nonetheless, infection can be
      associated with diarrhea and marked mucosal inflammation. This article briefly
      reviews in vitro and in vivo models useful for studying the pathogenesis of C.
      parvum infection and explores the role of innate and acquired immune responses in
      host defense against this protozoan parasite.

PMID- 10594979
TI  - The flagellated parasite Trichomonas vaginalis: new insights into
      cytopathogenicity mechanisms.
AB  - Our knowledge concerning cytopathogenicity of Trichomonas vaginalis has been
      enriched in the past by numerous findings. In this paper, we review the latest
      advances in the field and discuss the different mechanisms and molecules
      responsible for the parasite's virulence.

PMID- 10594980
TI  - Current studies on the pathogenesis of melioidosis.
AB  - Burkholderia pseudomallei is a major cause of bacterial septicemias in many parts
      of the world, particularly Thailand; the known geographic range of the organism
      appears to be enlarging as awareness of the organism and the disease it causes-
      melioidosis--increases. B. pseudomallei is intrinsically resistant to most
      antibiotics, and our knowledge of B. pseudomallei pathogenesis is lacking. Thus,
      the long-term objective of our research is to define at a molecular level the
      pathogenesis by combining genetic, immunologic, and biochemical approaches with
      animal model studies. Basic studies on B. pseudomallei pathogenesis are acutely
      needed to provide a knowledge base to rationally design new modes of therapy
      directed against this organism.

PMID- 10594981
TI  - Recognition of nonpeptide prenyl pyrophosphate antigens by human gammadelta T
      cells

PMID- 10594982
TI  - Ask the doctor. I have had dizzy spells every few weeks for years. My doctor has
      done a lot of tests, including a Holter monitor, but nothing has turned up. I am
      most concerned about whether I could be having heart-rhythm problems, but my
      Holter was apparently normal. Should I be undergoing other tests?

PMID- 10594983
TI  - Unremembered depression.

PMID- 10594984
TI  - By the way, doctor. I am 47 and have been taking Loestrin 1/20 for the past seven
      months. After the first month, I ceased having periods, which my gynecologist
      says is typical. Could you comment on why this happens and whether I am putting
      myself at increased risk for uterine cancer?

PMID- 10594985
TI  - Do-not-resuscitate orders and informed consent.

PMID- 10594986
TI  - RNs working in extended practice--how should they be judged competent to
      practise.

PMID- 10594987
TI  - My battle with obsessive compulsive disorder.

PMID- 10594988
TI  - Review of telephone consults to the practice area--Part 2.
AB  - The overall volume and complexity of calls in this review reflects the pace and
      stresses of most current health care settings in Alberta. This synopsis only
      highlights some areas of concern and does not encompass the nature of every call.
      The consulting services are available to all registered nurses and all Albertans-
      and it is clear from this review that callers are contacting the AARN in record
      numbers with a wide range of practice questions and concerns.

PMID- 10594989
TI  - Informed decision-making and hospital report cards.

PMID- 10594990
TI  - The painful (and costly) facts about children's tonsillectomy day surgery.

PMID- 10594991
TI  - Confidentiality.

PMID- 10594992
TI  - RN registration--answers to commonly asked questions to guide you through the
      registration renewal ritual.

PMID- 10594993
TI  - A continued competence framework for Alberta's registered nurses.

PMID- 10594994
TI  - Nursing week 1998

PMID- 10594995
TI  - Review of telephone consults to the AARN practice consultants--Part 1.

PMID- 10594996
TI  - Individual moral responsibility in nursing.

PMID- 10594997
TI  - The politics of women's health.

PMID- 10594998
TI  - The history of the CCCN: a collection of the presidents' memories.

PMID- 10594999
TI  - The evolution of the CCCN's scientific sessions--we've come a long way!

PMID- 10595000
TI  - Saskatchewan Registered Nurses' Association. Staff & council telephone directory.

PMID- 10595001
TI  - Questions and answers on Grotsky decision.

PMID- 10595002
TI  - Policy statement. Educational support for competent nursing practice. Canadian
      Nurses Association.

PMID- 10595003
TI  - Self-regulation and the SRNA: nurse knowledge and attitudes.

PMID- 10595004
TI  - Vicarious liability.

PMID- 10595005
TI  - Nurses in independent practice.

PMID- 10595006
TI  - Parish nursing in Saskatchewan.

PMID- 10595007
TI  - Solving professional practice issues. A guide for registered nurses. Saskatchewan
      Registered Nurses' Assocation.

PMID- 10595008
TI  - Competence assurance for registered nurses: an update by SRNA Ad Hoc Committee on
      competence assurance.

PMID- 10595009
TI  - Competence assurance for registered nurses. Fact sheet.

PMID- 10595010
TI  - Enhancing the health of the "well".

PMID- 10595011
TI  - Primary health care and new life.

PMID- 10595012
TI  - Facilitating an integrated approach to primary health care in Saskatchewan.
AB  - It is unlikely that truly integrated primary health care will become a reality
      unless health professionals actively strive to foster integration. Dialogue about
      integration barriers and opportunities has begun between the nursing, pharmacy,
      social work, emergency medical services, and medical professions. This dialogue
      should be expanded to include all of the professions with a potential role in an
      integrated system. The dialogue will also need to include government leaders as
      key public policy decisions will significantly influence the success or failure
      of integrated primary health service delivery strategies. As well, dialogue needs
      to occur with communities so that citizens can understand, value and help shape
      and maintain this kind of service delivery. Public education needs to emphasize
      that an integrated approach to primary health care in Saskatchewan is the best
      kind of service that can be provided. The Integrated Primary Health Care Working
      Group believes that the principles of primary health care require health
      professionals in Saskatchewan to develop an integrated approach to health
      services delivery in Saskatchewan. An exploration of possible barriers to this
      integrated approach is an important first step in eliminating barriers and
      facilitating effective health care service delivery to meet population health
      needs.

PMID- 10595013
TI  - A survey of nursing students in Saskatchewan.

PMID- 10595014
TI  - Nurse perceptions of changes impacting nursing practice.

PMID- 10595015
TI  - Shiftwork and CNE: a commentary.

PMID- 10595016
TI  - Nurses raise their voice about the quiet crisis.

PMID- 10595017
TI  - Streptococcal necrotizing fasciitis: treating a hidden killer.

PMID- 10595018
TI  - International study looks at nursing and patient care.

PMID- 10595019
TI  - Outcomes of hospital staffing research project: a preliminary report.

PMID- 10595020
TI  - Standards and foundation competencies for the practice of registered nurses,
      effective year 2000. A new document.

PMID- 10595021
TI  - Complementary and alternative therapies: role and responsibilities of the
      registered nurse. Saskatchewan Registered Nurses' Association.

PMID- 10595022
TI  - Primary health care from think tank to reality.

PMID- 10595023
TI  - Managing health information in continuing care: CIHI data set pilot achieves
      successful results.

PMID- 10595024
TI  - Students probe gaps in health research.

PMID- 10595025
TI  - Abstract world of expertise.

PMID- 10595026
TI  - RCN (Royal College of Nursing) A&E Nursing Association. Adolescent's in A&E. A
      position statement.

PMID- 10595027
TI  - Managing epistaxis in A&E.
AB  - The emergency nurse should never underestimate the volume of blood that can be
      lost from epistaxis. It is important to be alert for respiratory obstruction or
      distress and vigilant for shock like symptoms. Examine for underlying disorders
      and seek advice from ENT specialists, monitoring vital signs. Finally, a patient
      with a nasal pack in situ must be admitted to hospital.

PMID- 10595028
TI  - Pesticide poisoning: insecticides.

PMID- 10595029
TI  - Declaring a major incident.

PMID- 10595030
TI  - Nurse practitioners. Are we being true to the spirit of nursing?

PMID- 10595031
TI  - Honesty in what we do.

PMID- 10595032
TI  - Total eclipse of the sun.

PMID- 10595033
TI  - Co-ordinating major incident trauma care: international responses.

PMID- 10595034
TI  - Anti hypertensive drug overdose.

PMID- 10595035
TI  - What's wrong with triage?

PMID- 10595036
TI  - Emergency nurses and their perceptions of caring.

PMID- 10595037
TI  - From Star Wars to 'turf wars'.

PMID- 10595038
TI  - Putting the nurse back into triage.

PMID- 10595039
TI  - Towards a faculty of emergency nursing.

PMID- 10595040
TI  - Acute iron overdose: clinical features and management.

PMID- 10595041
TI  - Health promotion as an ENP: is it possible.

PMID- 10595042
TI  - Problems of telemedicine.

PMID- 10595043
TI  - Spiritual care: a challenge in multicultural critical care.

PMID- 10595044
TI  - Revealing higher levels of nursing practice.
AB  - The following discussion describes the early findings of a doctoral study, due
      for completion in 2001. The findings represent data collected in the USA,
      Australia, New Zealand and the UK, from nurses deemed to be engaged in advanced
      nursing practice. The paper will review the need for the study and provide a
      brief overview of the methodology employed. The current status of the findings,
      utilizing open coding, is presented. Major categories identified thus far are
      enhancing patient stay, improving patient outcome, promoting the role,
      trustworthiness, tenacity and survival in the role. The categories identified
      clarify current understanding of the concept, advanced nursing practice.

PMID- 10595045
TI  - Immediate effects of a five-minute foot massage on patients in critical care.
AB  - Critical care can be considered to be a stressful environment at both
      physiological and psychological levels for patients. In this article, a research
      study in which a five-minute foot massage was offered to 25 patients (68 sessions
      in total) as a stress-reduction intervention is described. A quasi-experimental
      repeated measures design was used to collect data before, during and after the
      intervention. Physiological data (heart rate, mean arterial blood pressure,
      respirations and peripheral oxygen saturation) were obtained from the patient
      bedside monitoring system. Repeated measures analysis of variance indicated there
      was no significant effect from the intervention on peripheral oxygen saturation.
      However, a significant decrease in heart rate, blood pressure and respirations
      was observed during the foot massage intervention. Results indicated foot massage
      had the potential effect of increasing relaxation as evidenced by physiological
      changes during the brief intervention administered to critically ill patients in
      intensive care.

PMID- 10595047
TI  - Iatrogenic drug dependence--a problem in intensive care? Case study and
      literature review.
AB  - Use of sedative and analgesic pharmacological agents is a widespread practice in
      intensive care units (ICUs). Mainly, this involves opioid and benzodiazepine
      analogues, both known to induce dependence/tolerance states. This paper is based
      on a clinical scenario in which a patient treated with these agents developed
      problems when they had been discontinued, and exploration of the extent of such
      problems generally. The problems range across a wide range of domains and may
      include physical discomfort, difficulty weaning from respiratory assistance and
      the drugs, and the problems of short- and long-term psychological distress.
      Although there may be a recognition that these drugs can typically cause
      dependence problems, little emphasis has traditionally been given to assessing
      these problems in ICUs. Yet the ICU may be an area where these drugs are used in
      high volumes. The recognition, physiology, management and prevention of
      iatrogenic drug dependence/tolerance in critical care environments is elucidated,
      with reference to relevant literature.

PMID- 10595046
TI  - Taiwanese nurses' appraisal of a lecture on spiritual care for patients in
      critical care units.
AB  - The purpose of this study is to develop a lecture on spiritual care for adult
      critical care trainees, and to evaluate the trainees' appraisal of the
      effectiveness of this lecture in preparing them to provide spiritual care for
      their clients in a critical care setting. A between-method triangulation research
      design encompassing a questionnaire and descriptive qualitative content analysis
      was used. A convenience sample consisting of 64 registered nurses who attended an
      adult critical care nurse training programme in a leading medical centre in
      northern Taiwan were invited to participate in this study. A total of 64 female
      participants completed the questionnaire. Ninety-two per cent (59) of the
      subjects considered the lecture on spiritual care to be helpful in assisting them
      to provide holistic care for critically ill patients in the Intensive Care Unit
      (ICU). Three types of help were identified by the subjects: (1) help in
      clarifying the abstract concepts related to spiritual care (86%); (2) help in
      self-disclosing the nurses' personal beliefs and values regarding life goals,
      nursing, and spiritual needs (67%); (3) help in learning how to provide spiritual
      care to patients in a critical care setting (34%). Twenty per cent of the
      subjects thought that inclusion of the following content in the lecture would
      have been helpful to provide a more comprehensive picture of spiritual care:
      religious practices and rituals (11%); the culturally bonded nursing care plan
      (9%); the development of human spirituality (3%); patients' families' spiritual
      needs in the ICU (3%); and resources for nurses in providing spiritual care (2%).
      Thirteen per cent of the subjects suggested that the instructor might employ the
      following strategies to improve the quality of teaching: providing more empirical
      examples (5%); discussion with the students in classes of smaller size following
      the lecture or extending the instruction time (5%); and providing a syllabus with
      detailed information (3%).

PMID- 10595048
TI  - The challenge of breaking bad news.
AB  - Critical care nurses will be involved in supporting patients and their families
      who are receiving, or who have received 'bad news'. This paper will identify the
      specific challenges faced by critical care staff involved in imparting bad news
      within an intensive care setting. A framework for practice is shared which might
      assist them to meet successfully the challenges posed.

PMID- 10595049
TI  - The development of Pulse Points, a unit-based journal review magazine.
AB  - This article details the development of a project conceived by the author to
      assist colleagues in fulfilling the professional development requirements of the
      UKCC.

PMID- 10595050
TI  - Treatment of hepatitis C infection.
AB  - There is growing awareness of the health risk posed by hepatitis C virus and
      fears that an epidemic of 'AIDS proportions' may be just around the corner. As
      our understanding of the disease increases, it is likely that substantial
      resources will be spent on developing newer and more effective treatments for
      hepatitis C infection in the years ahead.

PMID- 10595051
TI  - Chest X-ray quiz. Pneumothorax and effusion.

PMID- 10595052
TI  - History and development of coronary care.
AB  - The first coronary care units (CCUs) were opened in the 1960s in an attempt to
      reduce mortality from acute myocardial infarction (AMI). Nurses were closely
      involved in the development and success of these early units. This paper will
      provide an overview of the history and development of the CCU, including nurses'
      crucial involvement in pioneering the first CCUs in the 1960s through to the
      emerging role of nurses in the care of cardiac patients in the late 1990's.

PMID- 10595054
TI  - Exploring the expanded role of nurses in critical care.
AB  - This paper reports on a small research study that explored the perceptions of
      staff in an intensive/coronary/high-dependency care unit on the expanded role of
      nurses in critical care. The research was undertaken in two phases. In the first
      phase, focus groups and interviews of nursing and medical staff were used as
      methods to explore their perceptions. Data were analysed by thematic content
      analysis and generated four categories: specialized skills; maintaining
      competence; how far nurses can go; and training and education. Using verbatim
      examples from the participants, these categories are described. In summary, it
      was found that both doctors and nurses were in favour of nursing role
      developments, and for the nurses this was driven by their desire to meet the
      patients' needs. In a smaller second phase, a questionnaire was developed based
      on information gained in the first phase. It was utilized to seek the views of
      all the nursing staff on specific role-expansion activities. Findings revealed
      substantial support for developing the role of critical care nurses in a number
      of activities: cannulation; venepuncture; ordering blood tests and X-rays;
      performing physiotherapy; inserting arterial lines; performing elective
      cardioversion; thrombolysis treatment and intubation. This research study has
      yielded important information. However, it is recognized that, whilst these roles
      may be new to this particular critical care unit, there are many other units
      where they may already be common practice. Whenever new roles are developed, it
      is important to evaluate their effectiveness in measurable terms and regular
      audit is advisable. Further research is therefore recommended on both the
      development and evaluation of new roles in critical care.

PMID- 10595053
TI  - Telephone support in the early post-discharge period following elective cardiac
      surgery: does it reduce anxiety and depression levels?
AB  - Over the last decade, much has been published concerning the information needs of
      patients and their families on and after discharge from hospital. With ever
      decreasing lengths of stay in hospital following cardiac surgery as a result of
      technological improvements and the relentless pressure for beds, the time
      available for nurses to attend to these needs has been reduced dramatically, thus
      presenting new challenges to nurses. This study examines the levels of anxiety
      and depression in 78 elective cardiac surgery patients on discharge and at five
      weeks after, but before their recall to the outpatient department. The study
      tests the hypothesis that telephone follow-up from the ward will reduce patients'
      anxiety and depression levels in the early post-discharge period. The findings
      indicated that patients found follow-up calls beneficial and helpful, but follow
      up calls did not reduce anxiety and depression levels in the early post-discharge
      period.

PMID- 10595055
TI  - Cost considerations for the use of low-air-loss bed therapy in adult intensive
      care.
AB  - The aim of this study was to consider the costs of low-air-loss bed therapy in
      the adult intensive care unit (ICU). A retrospective cost analysis was performed
      on 269 consecutive patients, 63 of whom had received low-air-loss bed therapy.
      Patients' APACHE II scores, length of stay (LOS), average daily TISS and ICU
      outcomes were also collected. Patients' APACHE II and LOS were further studied
      using odds ratios to test for an association between these factors and likelihood
      of receiving bed therapy. A prospective 10-week study to identify the amount of
      nursing time spent repositioning patients was also performed. The results of this
      study found the bed therapy to represent approximately 3% of the total average
      cost of care per patient. Patients requiring the bed therapy had higher APACHE II
      scores on admission, higher average daily TISS points and a longer length of ICU
      stay. Study of the odds ratios would suggest that the likelihood of patients
      receiving low-air-loss bed therapy increases if their APACHE II score on
      admission is between 11 and 20 and they stay > 4.5 days in the ICU. The results
      of the prospective study found the daily cost of repositioning patients to be
      172.80 Pounds per patient.

PMID- 10595056
TI  - Cardiac rehabilitation into the new millennium.
AB  - Coronary heart disease remains the commonest cause of death in Western society
      and the highest rates in the world are found in the British Isles. It is a major
      cause of death in Ireland, claiming approximately 7000 lives each year. Cardiac
      rehabilitation aims to restore the patient to an optimum level of recovery, and
      where possible to prevent coronary heart disease from progressing. Hospitalized
      patients with coronary heart disease who require rehabilitation are often
      provided with in-hospital cardiac teaching programmes, comprising health
      education aimed at lifestyle modification. The focus of education is mainly
      concerned with moderation of risk factors which, if adequately controlled, can
      assist in reducing patients' morbidity and mortality. These include smoking,
      hypertension, diabetes, elevated serum cholesterol, hypertension and obesity. The
      intended outcome of education in the area of risk factor management is to produce
      observable sustainable changes in patients' behaviour. Changes in lifestyle
      behaviour are aimed at reducing their risk of worsening disease, and improving
      their overall quality of life. However, the extent to which these programmes
      actually elicit behavioural changes is uncertain. Studies have demonstrated that
      patients' knowledge level increased following the implementation of a structured
      teaching programme, but this did not necessarily produce the changes required in
      lifestyle. Where behavioural changes have been observed, these are usually
      confined to one area, and is not sustained over time. The failure of current
      cardiac teaching programmes to elicit behavioural changes may be due to lack of
      individualized approach, and inappropriate timing of information. In addition,
      programmes often have not been structured to suit patients' individual needs. In
      hospital education is essential for all cardiac patients. This needs to be
      structured, systematic and easily adaptable to suit individual requirements.

PMID- 10595057
TI  - The revised Jackson/Cubbin Pressure Area Risk Calculator.

PMID- 10595058
TI  - Sildenafil citrate (Viagra).
AB  - Sildenafil is the first of a series of orally active treatments for MED which has
      resulted in unprecedented demand for treatment and potentially high cost to the
      NHS. Further oral therapies are likely to follow in the next year or so. In
      clinical trials, sildenafil produced an erection (sufficient to achieve
      intercourse) lasting up to 4 h on around 70% of occasions. This was reduced to
      50% in 'high-risk' groups (e.g. diabetics) and a placebo response in as many as
      10-20% has been reported. Whether or not sildenafil should be prescribed at NHS
      expense has been more a matter for political, than clinical, debate. A clearer
      picture is now emerging with treatment available to those considered the 'most
      deserving' cases. The bigger picture is of impotence in large numbers of men with
      hypertension who are on antihypertensive therapy and have obvious small vessel
      disease. One option is to consign sildenafil to Schedule 10 (Black List) so that
      it is only available on private prescription. This would allay fears of the cost
      of treatment for those merely seeking to 'boost' already adequate sexual
      performance.

PMID- 10595059
TI  - Trends, bandwagons and academic standards.

PMID- 10595060
TI  - Experienced nurses learning with medical students: a case study.
AB  - Although there are successful examples of interdisciplinary education this
      generally relates to pre-registration health-care professionals. Post
      registration projects are usually confined to skills workshops or social science
      subjects, which rarely include medical staff. This project was unusual in its
      attempt to combine the needs of experienced practitioners with those of medical
      students. There are practical issues for this form of learning such as, the
      organization of modules into 'systems' when health-care professionals (as part of
      a parallel project) indicated their interests lay in courses that related to
      clinical practice organized around disease processes/conditions. This case study
      demonstrates that concerns related to the potential mismatch of clinical
      expertise, maturity and scientific background are not insurmountable problems,
      and that clear benefits can be gained. It could be argued that until pre- and
      post-graduate medical staff are integrated with other disciplines, the real
      benefits of shared understanding, enhanced team work and mutual respect will
      remain illusive. It is not anticipated that this form of learning would be
      suitable for the majority of practitioners, whose core needs are generally met by
      existing opportunities. However, there is a need for a greater depth of academic
      understanding particularly for those in senior positions or in specific
      specialized areas (also identified in the parallel study) and for those whose
      roles are expanding. These practitioners are more likely to have the ability to
      apply their new knowledge to clinical practice, using reflective techniques with
      minimal facilitation to enhance their established clinical expertise. For them
      this model of learning offers the opportunity to tailor education to the
      individual needs of the practitioner without the costly establishment of complete
      new programmes of learning. This case study proved particularly successful for
      the participants as they enhanced understanding and confidence in the knowledge
      underpinning their practice. This enabled them to better anticipate patients
      needs, to identify complications and initiate action at an earlier stage. Their
      appreciation of rationale underpinning medical treatment has enabled them to
      support junior medical staff, and to promote the continuity of appropriate care.
      They are more active in the education of patients, relatives and staff, and have
      identified specific developments which will be informed by the knowledge they
      have gained. It also proved beneficial to junior medical staff with whom
      interdisciplinary working has improved. Each organization involved in
      facilitating the initiative also benefited by gaining mutual understanding and
      appreciation of systems, constraints and opportunities. Equally, relationships
      among them have been strengthened and key issues with practical solutions have
      been identified to inform future joint ventures. Indications suggest that there
      would be value in using this case study to inform a structured pilot project
      involving other modules of learning and potentially other disciplines. If
      successful it could benefit all health-care professionals, particularly those
      senior staff who are expanding their roles and have educational needs unmet by
      existing provision. In addition to providing complementary opportunities this
      format provides a mechanism to enhance the mutual understanding essential to
      effective teamwork.

PMID- 10595061
TI  - The way forward for practice education.

PMID- 10595062
TI  - ASSET: a model for actioning spirituality and spiritual care education and
      training in nursing.
AB  - This paper presents a model of spiritual care education. A definition of
      spirituality is offered, this is followed by a review of empirical studies on
      spirituality and nurse education which conclude that nurses' knowledge and skills
      related to spiritual care are impoverished because of a poor role preparation in
      this dimension of care. The asset model (actioning spirituality and spiritual
      Care education and training in Nursing) is recommended as a possible option for
      improving spiritual care education in nursing. It should prove to be a useful
      framework and catalyst in effecting change in nurses' knowledge and understanding
      of the spiritual care requirements of patients. Extensive details of this model
      are provided in this paper.

PMID- 10595063
TI  - Seven years on: distance learning courses for first level registered nurses and
      midwives.
AB  - There is a recognized need to increase the accessibility and flexibility of post
      registration course provision for first level registered nurses and midwives.
      Distance learning courses were developed and implemented at the University of
      Dundee in response to this need. The courses provide a range of learning
      opportunities from single module certificate courses to Bachelor, Honours and
      Masters level studies. The courses are well received by nurses and midwives and
      experience, over the last 7 years, has highlighted important aspects for distance
      learning education for both professional groups. Different educational strategies
      such as Work-based Learning and Problem-based Learning are incorporated into
      distance learning course design to facilitate the integration of theory and
      practice and develop cognitive and meta-cognitive skills. The relationship
      between course assessment and clinical environment is also a key feature of
      course design, with assessment methods built around work-based learning
      opportunities in clinical practice. Experience has shown that students require
      support throughout the learning process. This is achieved through text-based
      study guides and a range of other support strategies. It is concluded that
      distance learning can be individualized to meet the professional and personal
      needs of students and provide quality, flexible learning opportunities for nurses
      and midwives, facilitating practice development and benefiting patient care.

PMID- 10595064
TI  - Rewriting myself.

PMID- 10595065
TI  - Knowledge in health visiting practice.
AB  - Health visiting is a practical discipline, hence knowledge in health visiting
      practice cannot be thought of as inert, that is merely as items of information
      merely; rather, it must be thought of in terms of a dynamic interplay among the
      individuality of the knower (the practitioner), the sources whereby knowledge may
      be acquired, and the contexts in which it must be applied. This discussion is an
      exploration of that interplay. Thus, in the discussion, the distinctive demands
      on the practitioner (and the kinds of personal qualities these entail) in
      acquiring and applying knowledge are highlighted, as are the sources of knowledge
      and the constraints of context. Three sources of knowledge are noted: authority,
      personal experience, and intuition. Context is conceived both in terms of the
      macro, sociopolitical, level and in terms of the micro level, i.e. the individual
      homes and interpersonal relationships in and through which health visiting is
      typically practised. Conclusions are drawn relating to the education of health
      visitors. The discussion draws on a distinction between three kinds of knowledge:
      factual or propositional knowledge, knowledge by acquaintance, and practical
      knowledge, or know-how.

PMID- 10595066
TI  - Improving care requires leadership in nursing.
AB  - The purpose of this paper is to provide a model of leadership in nursing. The
      model outlines factors that influence leadership styles, discusses approaches to
      leadership and the impact of the leadership style on nursing care. The model is
      based on a critical examination of the current leadership themes from nursing
      literature in the UK, USA and Australia, between 1992 and 1997, and the findings
      from semi-structured interviews with five leaders in nursing. These findings help
      support the proposed leadership model as a basis for further exploration and as a
      framework for thinking about leadership and leadership preparation.

PMID- 10595067
TI  - A taxonomy for developing cultural competence.
AB  - This paper proposes a taxonomy to develop culturally competent practitioners.
      Arguments about what this might mean and how this could be achieved are discussed
      first, identifying problems with multicultural and antiracist approaches. The
      model follows the cognitive, emotional and behavioural levels of Steinaker and
      Bell's experiential taxonomy. Five elements are proposed: cultural awareness,
      cultural knowledge, cultural understanding, cultural sensitivity and cultural
      competence. These could address, in increasingly sophisticated and increasingly
      praxis-oriented ways, issues of power and the construction of meanings and
      identities which go beyond essentialist notions of ethnicity.

PMID- 10595068
TI  - Ability and attitudes to mathematics of post-registration health-care
      professionals.
AB  - A small study was conducted to investigate the mathematical abilities and
      attitudes to mathematics teaching of a sample of students embarking upon post
      registration courses in health care. Mathematical ability showed a number of
      deficiencies of some concern. Expressed attitudes to mathematics teaching led to
      a discussion of the nature of mathematics teaching and some recommendations for
      remedial action.

PMID- 10595069
TI  - Student nurse satisfaction: implications for the common foundation programme.
AB  - This decade has seen a major restructuring of pre-registration nurse education
      within the higher education system that was costly and initially largely
      unpopular with qualified nurses and students. Major flaws have been identified in
      the common foundation programme (CFP) and student attrition rates remain too
      high. Our detailed survey of student satisfaction within the CFP shows that
      clinical placement is the most popular course component and that poor
      organization remains the worst aspect of the course. Teaching was more highly
      regarded than the organizational component of the course, although students found
      room for improvement. Core teaching modules such as bioscience and nursing
      interventions achieved better ratings than supporting modules, for example social
      policy or research and reflection on practice. The establishment of contact
      between personal tutors and students appeared to be slow. The described
      deficiencies have since been addressed in curriculum planning and the development
      of new course structure.

PMID- 10595070
TI  - Monitoring the quality of pre-registration education: development, validation and
      piloting of competency based performance indicators for newly qualified nurses.
AB  - The clinical competence or 'fitness for purpose' of newly qualified nurses
      continues to be an important professional and corporate issue that as yet has no
      objective means of assessment. A mixed group of managers, clinicians and
      educationalists was commissioned to develop a method for the measurement and
      evaluation of performance during the first year of employment of newly qualified
      nurses. Two instruments were developed and the results of the initial pilot study
      are demonstrated in this article. The results are preceded by a review of the
      relevant literature. The initial pilot study results indicate that in the case of
      both instruments the tests designed do give clear results on the small numbers
      used. A complete picture of the validity of the audit tool will not be seen until
      the results of the full validation study, including the above exercise, are
      known. However, the results to date indicate that the instruments have the
      potential to demonstrate the clinical competency of newly qualified staff on
      employment in their first post and their development over the first year of
      employment.

PMID- 10595071
TI  - Reaping the rewards.

PMID- 10595072
TI  - Fighting back against superbugs.

PMID- 10595073
TI  - What are super-bugs and why do they matter?

PMID- 10595074
TI  - Streptococcal necrotizing fasciitis: recognizing and treating a hidden killer.

PMID- 10595076
TI  - RNABC's continuing competence program.

PMID- 10595075
TI  - Perinatal care for survivors of sexual abuse.
AB  - Some pregnant women with a history of sexual abuse tend to have high anxiety
      during labor, often causing labor to be extended and making delivery more
      physically as well as emotionally painful. Now, thanks to the collaborative
      effort of a unique community health perinatal program and nurses at Vernon
      Jubilee Hospital, these women are receiving additional nursing support to help
      reduce their anxiety and make their deliveries less difficult.

PMID- 10595077
TI  - When can you call yourself a nurse?

PMID- 10595078
TI  - Library services on the Internet.

PMID- 10595079
TI  - The power to decide.

PMID- 10595080
TI  - Standards for nursing practice in British Columbia. Registered Nurses Association
      of British Columbia.

PMID- 10595081
TI  - Invisible nursing made visible.

PMID- 10595082
TI  - Tyleen Katz: advocate of the year. Interview by Helen Griffiths.

PMID- 10595084
TI  - Nursing and the law: who's liable, who pays?

PMID- 10595083
TI  - Providing nursing services on the Net.

PMID- 10595085
TI  - Regulating nursing: a new chapter begins.

PMID- 10595086
TI  - Overview of the Nurses (Registered) Act, rules and RNABC constitution and bylaws.
      Registered Nurses Association of British Columbia.

PMID- 10595087
TI  - Overview of legislation relevant to nursing practice.

PMID- 10595088
TI  - Pain management.

PMID- 10595089
TI  - Showcasing nursing to the public.

PMID- 10595090
TI  - B.C.'s last hospital-based nursing school leaves. A lasting legacy.

PMID- 10595091
TI  - VGH School of Nursing remembered.

PMID- 10595092
TI  - Managing conflict.

PMID- 10595093
TI  - Choosing boldly, deciding wisely.

PMID- 10595094
TI  - Meet RNABC's new executive director Laurel Brunke.

PMID- 10595095
TI  - Commonly asked questions about continuing competence.

PMID- 10595096
TI  - Developing a path to sustainable performance standards.

PMID- 10595098
TI  - Creating your own web page.

PMID- 10595097
TI  - Evacuation.
AB  - What happens to your patients when a forest fire burning out of control threatens
      your community and forces a major evacuation? This summer, nurses in Salmon Arm
      found they had a lot of support from their colleagues in the region.

PMID- 10595099
TI  - Bladder management post catheter.

PMID- 10595101
TI  - Lessons for the future.

PMID- 10595100
TI  - Talking to others about standards for nursing practice.

PMID- 10595102
TI  - Nursing practice guideline documentation.

PMID- 10595103
TI  - Nursing practice guideline Freedom of Information and Protection of Privacy Act.

PMID- 10595104
TI  - Caring for clients with end-stage AIDS.

PMID- 10595105
TI  - Using your title.
AB  - The Nursing Practice Guideline: Use of Title included as an insert in this issue
      of Nursing BC was developed by RNABC to increase nurses' awareness of when it is
      appropriate and not appropriate to use the titles "registered nurse" and "RN,"
      "licensed graduate nurse" and "LGN," or "nurse" in their practice. Be sure to
      pull it out and keep it as a reference along with your Standards for Nursing
      Practice in British Columbia and other practice guides that have been sent to you
      as inserts in Nursing BC. The scenarios in this article will help you to
      understand RNABC's policy on use of title outlined in the insert.

PMID- 10595106
TI  - Getting started on your personal practice review requirements.

PMID- 10595107
TI  - Emergency nursing care of injection drug users: a positive approach.

PMID- 10595108
TI  - Health promotion: when the client is the community.

PMID- 10595109
TI  - Where is primary health care in health care reform?

PMID- 10595110
TI  - Taking the first step.

PMID- 10595111
TI  - Nursing practice guideline. Pronouncement of death. Registered Nurses Association
      of British Columbia.

PMID- 10595112
TI  - Nursing practice guideline. Use of title. Registered Nurses Association of
      British Columbia.

PMID- 10595113
TI  - Web sites for evidence-based practice.

PMID- 10595114
TI  - Dispelling the myths about continuing competence.

PMID- 10595115
TI  - Finding support through RNABC's Agency Consultation Program.

PMID- 10595116
TI  - Self-regulation for solo nurses.

PMID- 10595117
TI  - Managing aggressive behavior.
AB  - Staff often have excellent approaches to reduce, defuse or even eliminate
      aggressive responses to caregiving. However, unless these ideas are pulled
      together in an organized way to produce consistent care, the problem of
      aggression will continue (Banazak, 1996). Once the care plan is in place, it is
      important to evaluate and fine tune it regularly through team meetings. All
      members of the team should be considered as resources in managing this most
      difficult care dilemma.

PMID- 10595118
TI  - Perspectives from the RNABC new graduate nursing survey.

PMID- 10595119
TI  - RNABC position. Education requirements for future nurses. Registered Nurses
      Assocation of British Columbia.

PMID- 10595120
TI  - RNABC position. Informed consent. Registered Nurses Association of British
      Columbia.

PMID- 10595121
TI  - Opportunity knocks.

PMID- 10595122
TI  - The explosion of complementary and alternative therapies.

PMID- 10595123
TI  - You make the diagnosis. Case study: the role of nurses in the protection of
      children and the importance of naming the phenomena of nursing concern.

PMID- 10595124
TI  - Toward an unequivocal definition and classification of patient outcomes.
AB  - PURPOSE: To determine the extent possible of developing an unequivocal
      formulation of a conceptual, structural, and contextual definition of "patient
      outcomes," and the possibility of coming to an agreement on the criteria for
      classification of patient outcomes. METHODS: An international Delphi survey of 33
      experts. FINDINGS: A conceptual, structural, and contextual definition of patient
      outcomes and priorities for the characteristics of patient outcome
      classification. CONCLUSIONS: The authors recommend the unequivocalness of nursing
      terminology, not only for reasons of effectiveness and efficiency, but also to
      clarify the nursing vocabulary for epistemological reasons.

PMID- 10595125
TI  - Fear and anxiety: a simultaneous concept analysis.
AB  - TOPIC: A simultaneous concept analysis of fear and anxiety. PURPOSE: To develop a
      process model that reflects distinct characteristics of fear and anxiety.
      SOURCES: Existing biopsychology empirics and theory from peer review with and
      external to nursing literature. CONCLUSIONS: Fear and anxiety are distinct
      diagnoses guided by separate brain mechanisms. The author offers a process model
      for further critique by peers and clinical populations.

PMID- 10595126
TI  - Utilization of nursing diagnoses in Iowa Child Health Specialty Clinics.
AB  - PURPOSE: To determine nursing diagnoses utilization in the Iowa Child Health
      Specialty Clinics (CHSC). METHODS: A review of charts of 631 children seen in
      CHSC's Integrated Evaluation and Planning Clinic (IEPC) and of 108 children
      served in the CHSC Home and Community Care (HCC) programs. FINDINGS: For the 21
      patients in the HCC group, 12 (57%) had at least one documented nursing
      diagnosis. Forty-six different nursing diagnoses were documented, with a range of
      2 to 8 nursing diagnoses (average 3.75) per patient. Of the 46 nursing diagnoses,
      12 (26%) were exact matches, 25 (54%) were close matches, and 9 (20%) were no
      matches to NANDA. For the IEPC group, 126 children (46%) had at least one
      documented nursing diagnosis. Ninety different nursing diagnoses were used 157
      times, with a range of 1 to 8 diagnoses (average 2.6) per patient. Nineteen (21%)
      different nursing diagnoses used 27 times were considered to be exact matches to
      NANDA diagnoses. Fifteen (17%) different diagnoses used 28 times were considered
      to be close NANDA matches. Fifty-six (62%) different nursing diagnoses used 102
      times were considered to be no matches. CONCLUSIONS: The documentation of nursing
      diagnoses for select groups of CHSC patients has provided information about the
      patient phenomena of concern addressed by CHSC nurses.

PMID- 10595127
TI  - Diagnoses for community nursing.

PMID- 10595129
TI  - Growing pains in nursing.

PMID- 10595128
TI  - One practice week at a glance.

PMID- 10595130
TI  - Workplace violence in healthcare environments.
AB  - Violence in the workplace is making headlines across the United States.
      Healthcare workers are not immune to violent encounters. Many healthcare workers
      will experience workplace violence at least once during their professional
      careers. Nurses are in a unique position to develop and provide assistance to
      implement prevention programs that can decrease the incidence and prevalence of
      violence in healthcare environments. This article reviews the definition of
      violence and its elements, and outlines a plan to reduce violence in healthcare
      environments.

PMID- 10595131
TI  - Nurse practitioners' role in complementary and alternative medicine: active or
      passive?
AB  - Complementary and alternative medical (CAM) therapies are emerging as a
      significant force that is shaping the delivery of health care in the United
      States. The physician-scientists of conventional medicine are slowly easing into
      the process of evaluating and integrating CAM therapies. After all factors are
      considered, should the role of NPs in this process be active or passive? This
      article explores reasons why NPs should or should not take an active role in
      evaluating and integrating CAM therapies. It proposes a role that NPs could have
      in determining the influence of complementary and alternative medicine on their
      clinical practice.

PMID- 10595132
TI  - Caregiver distress: what nurses in rural settings can do to help.
AB  - Caregivers in rural settings experience unmet needs. Some family caregivers in
      rural areas, either willingly or grudgingly, take on the role of caregiving as
      one of many responsibilities. A review of the literature reveals that the burden
      of the added responsibility results in physiological and psychological caregiver
      distress. The authors suggest some strategies to meet caregiver needs and outline
      areas where research is needed.

PMID- 10595133
TI  - Nurse-doctor relationships. 1966.

PMID- 10595134
TI  - Issue: what are important skills for RNs who specialize in home care?

PMID- 10595135
TI  - Ohio Council on Nursing: "retaining experienced nurses in all practice settings".

PMID- 10595136
TI  - Under oath: what a nurse witness must know.

PMID- 10595137
TI  - Senate Bill 240 introduced. Patient safety bill in the hands of legislators.

PMID- 10595138
TI  - Registered nurses as good samaritans: legal protection in Ohio.

PMID- 10595139
TI  - Issue: what guidelines does the Joint Commission on Accreditation of Healthcare
      Organizations use to determine if a hospital has adequate staffing for patient
      care?

PMID- 10595140
TI  - Nurses who become abusers: what can be done?

PMID- 10595141
TI  - Pain management--an overview.

PMID- 10595142
TI  - Understanding organizations which regulate or influence nursing practice.

PMID- 10595143
TI  - Special treatment for skin tears.

PMID- 10595144
TI  - On the precipice of the future: licensure stirs emotions.

PMID- 10595145
TI  - Latex allergies: registered nurses can sue for compensation.

PMID- 10595146
TI  - "Alzheimer's disease".

PMID- 10595147
TI  - Multi-state licensure. The pros and cons.

PMID- 10595148
TI  - Arthritis--rheumatoid and osteo.

PMID- 10595149
TI  - Issue: is it appropriate for a nurse to accompany a patient to dinner from an
      extended care facility?

PMID- 10595150
TI  - Profiling reduces boundaries.

PMID- 10595151
TI  - 'Someone to watch over me'. Covert surveillance and the difficulties of a public
      debate.

PMID- 10595152
TI  - Growing pains.

PMID- 10595153
TI  - Minor head injury: a cause for concern.

PMID- 10595154
TI  - The iron cage and the spider's web: children's spirituality and the hospital
      environment.

PMID- 10595155
TI  - Hypnosis in the management of eczema in children.

PMID- 10595156
TI  - Pain, nausea and vomiting: a day surgery audit.

PMID- 10595157
TI  - Who's the boss? Children's perception of hospital hierarchy.
AB  - Young people in an in-patient mental health unit seemed to recognise that a
      hierarchy existed within the multidisciplinary team and that it had an effect
      upon their care and treatment. A literature review suggested that the prevailing
      culture perpetuated a hierarchy and those who get things done ('the bosses') have
      power while nurses have 'relational' power (Souminen et al 1997). The views of 35
      in-patients aged between 13 and 17 years were obtained using a questionnaire and
      discussion. These young people believed that doctors (and possibly psychologists)
      make the important decisions, with nurses perceived as being 'all rounders' with
      no particular authority. Other professionals had distinct roles but were also
      subordinate. The findings of this exploratory study are relevant for the
      multidisciplinary team but further studies are needed to identify more specific
      implications for practice.

PMID- 10595158
TI  - Wound management in children.
AB  - This article explains the physiological events in wound healing in children, the
      rationale for dressing selection and the importance of taking a holistic approach
      to wound management.

PMID- 10595159
TI  - Scientific evidence and emotional care.

PMID- 10595160
TI  - Cleft lip and palate: reflections on a Nepali experience.

PMID- 10595161
TI  - Recording tympanic temperature.

PMID- 10595162
TI  - Philosophy of care: recognition and assessment of pain in children.

PMID- 10595163
TI  - Clinical guideline for the recognition and assessment of acute pain in children.

PMID- 10595164
TI  - Personal held records: encouraging partnership with children and parents.

PMID- 10595165
TI  - Child abuse and HIV: a discussion.

PMID- 10595166
TI  - Nursing roles: advice, counselling or therapy.

PMID- 10595167
TI  - Hypnosis in the treatment of enuresis.

PMID- 10595168
TI  - Phenomenology: understanding the life experience of long-term ventilated
      adolescents.
AB  - To care effectively for young people requires insight into how the children think
      about their care and how they want to live their lives. A phenomenological
      approach was used to gain new understandings into the thoughts and experiences of
      two teenage boys who were on long-term ventilation. The method included use of
      dialogue, observation and a reflective diary. Five themes emerged which helped
      the team caring for the boys to plan and prioritise care. Phenomenology is
      recommended as one way for nurses to become more thoughtfully aware of their
      practice.

PMID- 10595169
TI  - Traumatic events in the lives of adolescents.

PMID- 10595170
TI  - Pain management for children with special needs: a neglected area?

PMID- 10595171
TI  - Effects of postnatal depression.

PMID- 10595172
TI  - Essential skills for life.

PMID- 10595173
TI  - Piloting a higher level of practice.

PMID- 10595174
TI  - Providing psychological support to cancer patients.
AB  - Nurses may lack the confidence to deal with the psychological problems of
      patients with cancer. A nurse specialist in psychological support can help staff
      improve patient assessment. The specialist nurse can also undertake skilled
      psychological interventions.

PMID- 10595175
TI  - Improving the detection of postnatal depression.
AB  - Women are at risk of developing mental health problems in the postnatal period.
      Health visitors play an important role in the detection of postnatal depression.
      The Edinburgh Postnatal Depression Scale can be used to screen all new mothers.

PMID- 10595176
TI  - Community nurses' views of leg ulcer treatment.
AB  - Healing rates have been found to be higher among patients with a leg ulcer
      attending specialist clinics than those cared for at home. Understanding the
      experience of delivering care in the home and the clinic will help improve
      practice in both areas.

PMID- 10595177
TI  - The patient's perception of chronic pain.
AB  - Chronic pain is common among hospital inpatients. Patients with chronic pain have
      low expectations of pain relief. The patient's need for information is frequently
      not met.

PMID- 10595178
TI  - Continence assessment in long-term care.
AB  - Many continence problems are curable. Elderly people living in long-term care
      should have their continence assessed. Inappropriately managed incontinence can
      be unnecessarily costly.

PMID- 10595179
TI  - Basic life support techniques in adults.
AB  - Cardiac arrest in adults requires prompt resuscitation measures. Individuals can
      help to reduce premature deaths from cardiac arrests if they are skilled in
      rescue breathing and chest compression, and regularly update their knowledge.

PMID- 10595180
TI  - Emollients for managing dry skin conditions.
AB  - Emollients are essential in the management of dry skin conditions, but are often
      underused in general practice. Selection depends on the knowledge and experience
      of the practitioner and patient preference. Careful explanation of the use and
      variety of emollients will assist successful management of dry skin conditions.

PMID- 10595181
TI  - Colorectal cancer. Part 2: Treatment.
AB  - Treatment choice for patients with colorectal cancer will depend on the stage of
      disease and the patient's prognosis at the time of presentation. The primary
      treatment for potentially curable cancer is surgical resection. Radiotherapy is
      often used in conjunction with surgery, while chemotherapy may be used in all
      stages of the disease.

PMID- 10595182
TI  - Peri-operative nursing.

PMID- 10595183
TI  - Adolescence to adulthood--a journey or a struggle?

PMID- 10595184
TI  - Australian Labor Party (ALP) nursing policy.

PMID- 10595185
TI  - Queensland's new Health Minister. Interview by John Moran.

PMID- 10595186
TI  - Rendering assistance in an emergency.

PMID- 10595187
TI  - No use-by date.

PMID- 10595188
TI  - Nurse in profile. Heather Ward.

PMID- 10595189
TI  - The rise of charities and their legal protections.

PMID- 10595190
TI  - Nurse in profile. Peter Conaghan.

PMID- 10595191
TI  - [An education in science for activism].

PMID- 10595192
TI  - [Creating a local collection of professional reports. A stake in the engineering
      of diploma education and research in continuing education].
AB  - The question of the dissertation written during the training is tackled through
      the entry key offered by the professional dissertations written during the
      training courses leading to qualification in the framework of a university
      department of vocational training. 72 professional dissertations, defended
      between 1993 and 1996, were analysed on the basis of observation sheets filled
      out by the directors. In reference to the semiotic approach which provides
      relevant theoretical and methodological materials for the problem posed, we shall
      show the interest of considering that these documents are, above all, "object
      speeches" and must therefore be studied as such. According to the demands to be
      determined, related to the types of speeches to deliver, the professional
      dissertations considered as written traces reconstituting the practices and
      praxis which found them, as well on the professional as on the scientific level,
      can provide indications for training, in the area of research as well as in the
      one of praxeology. The written document is thought of as an object of transition
      from practice to professional praxis, rallying the scientific praxis which is
      expressed particularly in the writing work.

PMID- 10595194
TI  - [The temptation of classification ... or how an apprenticeship that does not
      reflect scientific knowledge can create an epistemological problem].

PMID- 10595193
TI  - [The end-of-study dissertations in nursing schools. Pedagogic and methodologic
      considerations].
AB  - The writing of the study end dissertation, in the degree course of the student
      nurses poses pedagogical as well as methodological problems. The goal of the
      study end dissertation, if this latter takes the form of a research, is not a
      production of knowledge, but a methodological and conceptual learning. The
      critical analysis of 142 study end dissertations highlights a level
      heterogeneousness, a total lack of research problematics and unsuitable
      methodologies. The study end dissertation does not take the form of a research
      but of a reflection work, chosen by the student.

PMID- 10595195
TI  - [Reduction of blood-exposure accidents: utopia or reality].

PMID- 10595196
TI  - ["The nurse ought to be convinced that she is irreplaceable"] [In Process
      Citation]

PMID- 10595197
TI  - [Taking care of oneself].

PMID- 10595198
TI  - [Emotions of the nurse, emotions of the patient].

PMID- 10595199
TI  - [Plea for touch-massage].

PMID- 10595200
TI  - [Taking care of the human being. A perspective for nursing in the XXI century].

PMID- 10595201
TI  - ["If you want to travel, take care of your mount"].

PMID- 10595202
TI  - [The educational role of the nurse in insulin therapy (part 1)].

PMID- 10595203
TI  - [Following protocols from the nurse's viewpoint].

PMID- 10595204
TI  - [Health determinants and inequalities].

PMID- 10595205
TI  - [Correct use of drugs. Oral drug administration].

PMID- 10595206
TI  - [Nursing responsibilities. 3/12: the responsibility of the private health
      facility].

PMID- 10595207
TI  - [What to do in case of a traffic accident].

PMID- 10595208
TI  - [Attention to the health of the skin. 2].

PMID- 10595209
TI  - [There should be a law to develop palliative care. Interview by Marie Hetier].

PMID- 10595210
TI  - [For a global approach to oncologic care. Cancer patients are speaking out].

PMID- 10595211
TI  - ["Learning to live with cancer"].

PMID- 10595212
TI  - [A guide book for the care of cancer patients].

PMID- 10595213
TI  - [Sexuality and cancer].

PMID- 10595214
TI  - [Forty years of progress in chemotherapy].

PMID- 10595216
TI  - [When the nurse becomes a patient...].

PMID- 10595215
TI  - [Chemically induced nausea and vomiting].

PMID- 10595217
TI  - [A nurse's view of ovarian pathology].

PMID- 10595218
TI  - [Possibilities and limits of treating fatigue].

PMID- 10595219
TI  - [Living with the uncertainty of developing cancer].

PMID- 10595220
TI  - [Harmonizing nursing practices with the preservation of the French identity].

PMID- 10595221
TI  - [2001 ... accreditation].

PMID- 10595222
TI  - [Patient education. The nurse's role as an educator in insulin therapy. 2].

PMID- 10595223
TI  - [The proper handling of drugs. Administration by nasogastric tube].

PMID- 10595224
TI  - [Nurses' responsibility. 4/13--responsibility of personnel in private
      establishments].

PMID- 10595225
TI  - [What to do about the inhalation of a foreign body by a child].

PMID- 10595227
TI  - [Experiencing ones death is the ultimate moment of personal freedom] [In Process
      Citation]

PMID- 10595226
TI  - [Changes in sleep habits].

PMID- 10595228
TI  - [Sports with honor] [In Process Citation]

PMID- 10595229
TI  - [Bedsores and clinical approach].

PMID- 10595230
TI  - [Scales for the evaluation of risk of bedsores].

PMID- 10595231
TI  - [Local treatment of the existing bedsore].

PMID- 10595232
TI  - [European recommendations on prevention of bedsores].

PMID- 10595233
TI  - [Prevention of bedsores, a shared task].

PMID- 10595234
TI  - [Home nursing and prevention of bedsores].

PMID- 10595235
TI  - [The point of view of a private duty nurse. Nutrition and hydration are essential
      for the prevention of bedsores].

PMID- 10595236
TI  - [Promoting a policy of decubitus ulcer prevention].

PMID- 10595238
TI  - [Risks of medication].

PMID- 10595237
TI  - [Let us stop for a short moment...].

PMID- 10595239
TI  - [Public health. The nurse and the avoidable medication risk].

PMID- 10595240
TI  - [Patient education. The role of the nurse in the education of patients with non
      insulin-dependent diabetes mellitus].

PMID- 10595241
TI  - [Correct usage of drugs. 3/12: Oral administration and nutrition].

PMID- 10595242
TI  - [The nursing responsibility. 5/13: responsibility of the state diploma nurse].

PMID- 10595243
TI  - [What to do in case of a severe trauma to the upper extremity].

PMID- 10595244
TI  - [Risk in trauma].

PMID- 10595245
TI  - Cancer genetics services in Europe.

PMID- 10595246
TI  - Four years analysis of cancer genetic clinics activity in France from 1994 to
      1997: a survey on 801 patients. French Cooperative Network/Groupe Genetique et
      Cancer de la Federation Nationale des Centres de Lutte Contre le Cancer.
AB  - AIM: In order to evaluate the characteristics and the evolution of cancer
      genetics activity in France, a survey was conducted at the national level during
      a period of 4 years from 1994 to 1997 through the French Cooperative Network, a
      multidisciplinary group formed to investigate inherited tumors. METHOD: A
      questionnaire was sent to all the 29 French non-specialized cancer genetic
      clinics to evaluate activity during a period of 4 consecutive weeks each year
      from 1994 to 1997. Items concerning the cancer genetic clinics, the consultees
      and the types of consultation were explored. RESULTS: A total number of 801
      consultees were seen during the period of analysis. Some prominent
      characteristics of patients attending cancer genetic clinics were found. The
      majority of these are women (88%), and the mean age of consultees is 48 years.
      Fifty five percent of consultees are affected with cancer, and breast (personal
      and/or family history) is the most frequent site involved (63%). A genetic
      predisposition is certain or likely in about 53% of cases and unlikely in only
      13% of consultations. The majority of consultations are devoted to new families
      (71%). The mean duration of consultations is 50 minutes, but 40% have a duration
      of at least 1 hour. Variations of several parameters during the 4 years period
      were observed and analyzed. Finally, since duration of consultations (more or
      equal to 1 hour) and personal or family history of breast/ovarian cancer appeared
      as pivotal elements in our study and consequently may affect the organization of
      clinics and the structuring as well as the evolution of cancer genetic activity
      in France, we analyzed more precisely the factors significantly associated with
      these 2 elements. CONCLUSION: Study compliance was fair (60% of centers) and
      these results give a good measure of cancer genetic activity in France. The
      variation of parameters from one year to another may reflect modifications in
      medical practice (medical orientation rather than research focus and content of
      cancer genetic clinics) and/or scientific breakthroughs in cancer genetics such
      as identification of genes predisposing to cancer.

PMID- 10595247
TI  - Familial breast cancer: clinical services in The Netherlands.

PMID- 10595248
TI  - Breast cancer screening in high-risk women. Rotterdam Committee of Medical and
      Genetic Counseling.

PMID- 10595249
TI  - Cancer genetics services in Northern Ireland.

PMID- 10595251
TI  - Cancer genetics services in the UK.

PMID- 10595250
TI  - Familial breast and ovarian cancer: genetic counseling and clinical management in
      Italy.

PMID- 10595252
TI  - Clinical genetic services for familial breast cancer in Poland.

PMID- 10595254
TI  - Genetic testing for breast cancer predisposition in 1999: which molecular
      strategy and which family criteria?

PMID- 10595253
TI  - Risk estimation as a decision-making tool for genetic analysis of the breast
      cancer susceptibility genes. EC Demonstration Project on Familial Breast Cancer.
AB  - For genetic counselling of a woman on familial breast cancer, an accurate
      evaluation of the probability that she carries a germ-line mutation is needed to
      assist in making decisions about genetic-testing. We used data from eight
      collaborating centres comprising 618 families (346 breast cancer only, 239 breast
      or ovarian cancer) recruited as research families or counselled for familial
      breast cancer, representing a broad range of family structures. Screening was
      performed in affected women from 618 families for germ-line mutations in BRCA1
      and in 176 families for BRCA2 mutations, using different methods including SSCP,
      CSGE, DGGE, FAMA and PTT analysis followed by direct sequencing. Germ-line BRCA1
      mutations were detected in 132 families and BRCA2 mutations in 16 families. The
      probability of being a carrier of a dominant breast cancer gene was calculated
      for the screened individual under the established genetic model for breast cancer
      susceptibility, first, with parameters for age-specific penetrances for breast
      cancer only [7] and, second, with age-specific penetrances for ovarian cancer in
      addition [20]. Our results indicate that the estimated probability of carrying a
      dominant breast cancer gene gives a direct measure of the likelihood of detecting
      mutations in BRCA1 and BRCA2. For breast/ovarian cancer families, the genetic
      model according to Narod et al. [20] is preferable for calculating the proband's
      genetic risk, and gives detection rates that indicate a 50% sensitivity of the
      gene test. Due to the incomplete BRCA2 screening of the families, we cannot yet
      draw any conclusions with respect to the breast cancer only families.

PMID- 10595255
TI  - Mutation analysis of the BRCA1 and BRCA2 genes in the Belgian patient population
      and identification of a Belgian founder mutation BRCA1 IVS5 + 3A > G.
AB  - Since the identification of the BRCA1 and BRCA2 genes, several hundred different
      germline mutations in both genes have been reported. Recurrent mutations are rare
      and mainly due to founder effects. As the mutational spectrum of the BRCA1 and
      BRCA2 genes in the Belgian patient population is largely unknown, we initiated
      mutation analysis for the complete coding sequence of both genes in Belgian
      families with multiple breast and/or ovarian cancer patients and in "sporadic"
      patients with early onset disease. We completed the analysis in 49 families and
      in 19 "sporadic" female patients with early onset breast and/or ovarian cancer.
      In 15 families we identified a mutation (12 mutations in BRCA1 and 3 mutations in
      BRCA2). In 5 apparently unrelated families the same splice site mutation was
      identified (BRCA1 IVS5 + 3A > G). Haplotype analysis revealed a common haplotype
      immediately flanking the mutation in all families suggesting that disease alleles
      are identical by descent. In none of the 19 sporadic patients was a mutation
      found.

PMID- 10595256
TI  - Molecular cancer genetics in eastern and central Europe.

PMID- 10595257
TI  - BRCA1 1675delA and 1135insA account for one third of Norwegian familial breast
      ovarian cancer and are associated with later disease onset than less frequent
      mutations.
AB  - A total of 845 women from breast-ovarian cancer kindreds were enrolled in a
      clinical follow-up program for early disease diagnosis; 35 women were
      prospectively identified with cancer. In order to estimate the role of genetic
      factors for cancer predisposition in this well-defined set of patients,
      considered as representative for familial breast-ovarian cancer in the Norwegian
      population, the BRCA1 gene was investigated for germline mutations. The entire
      coding region of BRCA1 was analysed using a protein truncation test, direct
      sequencing and a screen for known large genomic deletions and insertions. Twenty
      one (60%) of the 35 patients were identified as carriers of 11 distinct BRCA1
      mutations. Two previously described founder mutations, 1675delA and 1135insA,
      were found to account for more than half (11/21) of all BRCA1 cases and for
      almost one third (11/35) of all breast and ovarian cancers. Supported by a
      previous population-based analysis of these founder mutations in ovarian cancer,
      our findings suggest that a significant proportion of women at risk for
      developing inherited breast and ovarian cancer can be identified. This is
      particularly obvious in certain geographic regions where these founder mutations
      are prevalent. Women carrying the two founder mutations had a significantly older
      age of disease onset as compared to women with other BRCA1 mutations. This
      observation indicates that BRCA mutation penetrance estimates from populations
      with strong founder effects may be biased. One reason why some deleterious
      mutations are allowed to prevail in a population may be coupled to penetrance and
      the fact that they seldom induce disease in women in child-bearing ages. Eleven
      out of 12 (92%) breast cancers in BRCA1 mutation carriers were estrogen receptor
      negative, versus 4 out of 9 (44%) in mutation negative patients (p = 0.03).
      Histopathological characteristics of the prospectively detected cancers indicated
      an unfavourable prognosis in mutation carriers.

PMID- 10595258
TI  - Familial cancer in women from the Gomel region of Belarus.

PMID- 10595259
TI  - Hereditary susceptibility to breast cancer: significance of age of onset in
      family history and contribution of BRCA1 and BRCA2.
AB  - OBJECTIVE: To correlate mutations in BRCA1 and BRCA2 with family history of
      breast cancer in a first-degree relative for women diagnosed with breast cancer
      before age 45 who do not have a personal or family history of ovarian cancer.
      METHODS: Family history for women with breast cancer diagnosed before age 45 was
      provided by ordering physicians via a test requisition form designed for this
      purpose. Gene analysis was performed by dye primer sequencing for the entire
      coding regions of BRCA1 and BRCA2. Because a personal and family history of
      ovarian cancer are known to be significantly associated with mutations, women
      with either were excluded from analysis. RESULTS: Overall, deleterious mutations
      in BRCA1 or BRCA2 were identified in 85 of 440 women (19%) with breast cancer
      under 45. Mutations were identified in 73 of 276 women (26%) with a first degree
      family history of breast cancer compared to 12 of 164 without (7%) (P < .0001).
      When results were analyzed by the age of diagnosis in first degree relatives,
      mutations were identified in 56 of 185 women (30%) with at least one first degree
      relative with breast cancer diagnosed before age 50 compared with 17 of 91 women
      (19%), where the first degree family history of breast cancer was at or over age
      50 (P = .042). CONCLUSION: Among women with breast cancer diagnosed before age
      45, a first-degree relative diagnosed with the disease under age 50 is an
      indicator of a mutation in BRCA1 or BRCA2 even in the absence of a family history
      of ovarian cancer. Therefore, women diagnosed with early-onset breast cancer
      should be asked about the age of onset in any first-degree relative diagnosed
      with the disease, as well as about any family history of ovarian cancer.
      Mutations in BRCA2 account for a substantial proportion of hereditary breast
      cancer. Therefore, studies that are limited to BRCA1 or that do not analyze by
      age of onset of breast cancer in relatives may underestimate the contribution of
      mutations in BRCA1 and BRCA2 to women with early onset breast cancer.

PMID- 10595260
TI  - The future of DNA diagnostics.

PMID- 10595261
TI  - The future of DNA diagnostics.

PMID- 10595262
TI  - The pathology of hereditary breast cancer.

PMID- 10595263
TI  - New screening techniques for breast cancer (MRI).

PMID- 10595264
TI  - A second family with probable CRAC (colorectal adenomata and carcinoma) syndrome-
      a new familial cancer.

PMID- 10595266
TI  - A patient's perspective on breast cancer and the implications of genetic testing.

PMID- 10595265
TI  - Ethical, social and economic issues in familial breast cancer: a compilation of
      views from the E.C. Biomed II Demonstration Project.
AB  - Demand for clinical services for familial breast cancer is continuing to rise
      across Europe. Service provision is far from uniform and, in most centres, its
      evolution has been determined by local conditions, specifically by local research
      interests, rather than by central planning. However, in a number of countries
      there is evidence of progress towards co-ordinated development and audit of
      clinics providing risk assessment, counselling, screening and, in some cases,
      prophylactic intervention. Much important information should emerge from
      continued observation and comparative assessment of these developments. In most
      countries for which relevant data are available, there is a distinct bias towards
      higher social class among those who avail themselves of clinic facilities (in
      line with findings from many other health-promotion initiatives). This should be
      addressed when considering future organisation of clinical services. Molecular
      genetic studies designed to identify the underlying mutations responsible for
      familial breast cancer are not generally regarded as part of the clinical service
      and are funded through research grants (if at all). Economic considerations
      suggest that there is a case for keeping this policy under review. Familial
      cancers throw into sharp relief certain ethical and legal issues that have
      received much recent attention from government advisory bodies, patients'
      representatives, professional commentators and the popular media. Two are of
      particular importance; first, the right to gain access to medical records of
      relatives, in order to provide accurate risk assessment for a given family
      member, versus the right to privacy in respect of personal medical information
      and, second, the obligation (or otherwise) to inform family members of their risk
      status if they have not actively sought that knowledge. The legal position seems
      to vary from country to country and, in many cases, is unclear. In view of
      pressures to establish uniform approaches to medical confidentiality across the
      EC, it is important to evaluate the experience of participants in this
      Demonstration Programme and to apply the principle of "non-malfeasance" in
      formulating regulations that should govern future practice in this field. Data on
      economic aspects of familial breast cancer are remarkably sparse and outdated. As
      evidence accrues on the influence of screening and intervention programmes on
      morbidity and mortality, there is a strong case for evaluating the cost
      effectiveness of different models of service provision.

PMID- 10595267
TI  - Genetic testing for familial breast cancer--ethical questions concerning
      individual rights and social responsibility.

PMID- 10595268
TI  - Uptake of genetic testing and pre-test levels of mental distress in Norwegian
      families with known BRCA1 mutations.
AB  - 232 family members from 27 Norwegian families with BRCA1 mutations were offered
      genetic testing. 180/232 (78%) chose to be tested, 14/232 (6%) have not yet
      decided and 38/232 (16%) declined. All 232 persons were invited to fill in the
      following questionnaires when offered testing: Impact of Event Scale (IES),
      Hospital Anxiety and Depression Scale (HADS), General Health Questionnaire (GHQ
      28) and Beck Hopelessness Scale (BHS). 207/232 (89%) responded to the
      questionnaires. Of those declining to be tested 23/38 (61%) answered the
      questionnaires compared to 170/180 (94%) of those wanting the test (p < 0.0001).
      A higher proportion of females with a history of cancer than females without such
      a history had abnormal scores on the IES-intrusion and GHQ questionnaires (p <
      0.001). Healthy females who were deciding on predictive testing had the same or
      lower prevalence of mental distress compared to the general population, between
      4.3% and 18.0% as measured by the different questionnaires. Males did not differ
      from healthy females on any of the measures. According to their HADS scores,
      women without a history of cancer deciding on predictive testing for breast
      ovarian cancer had lower or equal levels of mental distress compared to the
      general population. The high uptake of genetic testing combined with the lower
      than normal prevalence of mental distress indicates that the activity may
      continue as practised, awaiting longitudinal data concerning the levels of mental
      distress after genetic testing.

PMID- 10595269
TI  - Genetic nurses and counsellors--preparation for practice with families at risk of
      familial cancer.

PMID- 10595270
TI  - Utilisation of prophylactic mastectomy in 10 European centres.
AB  - Increasingly women at high risk of breast cancer are opting for prophylactic
      surgery to reduce their risks. Data from 10 European centres that offer a risk
      counselling and screening service to women at risk show different approaches to
      the option of preventive surgery, although most centres adhere to a protocol
      including at least two risk counselling sessions and a psychological assessment.
      Thus far the combined centres have data on 174 women who have undergone
      prophylactic mastectomy with in excess of 400 women years of follow up.
      Operations were carried out on women with lifetime risks of 25-80%, with an
      average annual expected incidence rate of 1% per women. No breast cancers have
      occurred in this cohort. Long term follow up on an extended group of women will
      be necessary to truly address the risk of subsequent breast cancer and the
      psychological sequelae.

PMID- 10595271
TI  - Psychosocial aspects of familial breast and ovarian cancer: psychological
      guidelines for genetic testing.

PMID- 10595272
TI  - Insurance implications for individuals with a high risk of breast and ovarian
      cancer in Europe.

PMID- 10595273
TI  - Costs and benefits of diagnosing familial breast cancer.
AB  - Based on results from our surveillance program for women at risk for inherited
      breast cancer, we have calculated cost per year earned. Norwegian National
      Insurance Service reimbursement fees were used in the calculations. The
      calculated costs are based on empirical figures for expanding already established
      medical genetic departments and diagnostic outpatient clinics to undertake the
      work described. Cost per year earned was estimated at Euro 753 using our current
      practice of identifying the high-risk women through a traditional cancer family
      clinic. A strategy of identifying the high-risk families through genetic testing
      of all incident breast and ovarian cancers for founder mutations in BRCA1, will
      increase the cost to Euro 832. Costs related more to genetic counseling and
      clinical follow-up than to laboratory procedures. This potential economic
      limiting factor coincides with a shortage of personnel trained in genetic
      counseling. The number of relatives counseled to identify one healthy female
      mutation carrier (i.e. the uptake of genetic testing) is more important to cost
      effectiveness than family size. Costs will vary depending upon the penetrance of
      the mutations detected and the prevalence of founder mutations in the population
      examined. Prevalences of BRCA1 founder mutations in some high incidence areas of
      Norway may be sufficiently high to consider population screening. Unlike mutation
      screening of cancer genes, founder mutation analysis will not identify DNA
      variants of uncertain clinical significance. Identification of high-risk families
      through founder mutation analysis of BRCA1 ensures that families with maximum
      risks are given first access to the limited resources of the high-risk clinics.
      This may be the greatest contribution to increased cost effectiveness of such a
      strategy. The assumptions underlying the calculations are discussed. The
      conclusion is that inherited breast cancer may be managed effectively for the
      cost of Euro 750-1,600 per year earned.

PMID- 10595274
TI  - Economics of genetics from a health commissioning point of view.

PMID- 10595275
TI  - Efficacy of early diagnosis and treatment in women with a family history of
      breast cancer. European Familial Breast Cancer Collaborative Group.
AB  - BACKGROUND: Surveillance programmes for women at increased genetic risk of breast
      cancer are being established worldwide but little is known of their efficacy in
      early detection of cancers and hence reduction in mortality. METHODS: Data were
      contributed from seven centres participating in the EU Demonstration Programme on
      Clinical Services for Familial Breast Cancer. All breast tumours (n = 161)
      detected prospectively, from the time of enrolment of women in a screening
      programme, were recorded. Analysis took account of age at diagnosis, whether
      tumours were screen-detected or not, their pathological stage and outcome by
      Kaplan-Meier survival plots. RESULTS: Mean age at diagnosis was 48.6 years.
      Overall, 75% of tumours were detected in the course of planned examinations. For
      women under age 50 at diagnosis, this figure was 68%. Eighteen percent were
      mammographically negative, (23% in patients under age 50). At first
      ("prevalence") round and at follow-up screening, 16% and 22% of tumours
      respectively were carcinoma in situ (CIS) while 27% and 22% respectively had
      evidence of nodal or distant spread (CaN+). Comparison of screen-detected and
      other tumours showed that the latter were more frequently mammogram-negative and
      CaN+. Overall five-year survival was 89% and five-year event-free survival 86%.
      Five-year event-free survival was 100% for CIS, 88% for invasive cancer without
      nodal or distant spread and 67% for CaN+. CONCLUSIONS: The majority of cancers
      arising in women at increased genetic risk of breast cancer can be detected by
      planned screening, even in those under age 50. Surveillance should include
      regular expert clinical examination and teaching of "breast awareness" as well as
      mammography. Attention to the logistics of screening programmes may improve still
      further the proportion of tumours that are screen-detected. The trend towards
      earlier pathological stage in tumours detected during follow-up rounds and the
      preliminary findings on survival analysis suggest that this approach will prove
      to be of long-term benefit for breast cancer families.

PMID- 10595276
TI  - Management of hereditary breast cancer. European Familial Breast Cancer
      Collaborative Group.

PMID- 10595277
TI  - Genetic counselling and testing for hereditary breast and ovarian cancer: the
      gent(le) approach.
AB  - The counselling experience with 50 Flemish families in whom mutation analysis of
      the total coding region of the BRCA1 and BRCA2 gene has been initiated, is
      presented. Genetic testing for breast-ovarian cancer susceptibility is offered by
      a multidisciplinary team. During the counselling sessions, special attention is
      given to comprehensible and emotionally acceptable communication of genetic
      information and to the psychosocial evaluation of the counselee. The limitations
      of molecular testing and the controversy surrounding cancer prevention strategies
      are also discussed. The overall acceptance of mutation testing is high. Some of
      the problems encountered are inaccuracy of the reported family history, poor
      retrieval of the medical records of affected family members and the reluctance of
      many patients to inform their relatives about the possibility of being tested.

PMID- 10595278
TI  - The role of bilateral prophylactic mastectomy (BPMX) in women at high risk of
      breast cancer.

PMID- 10595279
TI  - Audit of women attending the Aberdeen Genetic Clinic with a family history of
      breast cancer who subsequently develop cancer.

PMID- 10595281
TI  - Joint hypermobility and headache.

PMID- 10595280
TI  - Guidelines for follow-up of women at high risk for inherited breast cancer:
      consensus statement from the Biomed 2 Demonstration Programme on Inherited Breast
      Cancer.

PMID- 10595282
TI  - Evidence linking magnesium deficiency to migraines.

PMID- 10595283
TI  - Nitric oxide pathway, Ca2+ and serotonin.

PMID- 10595284
TI  - Reliability of cervicogenic headache diagnosis.

PMID- 10595285
TI  - Sumatriptan nasal spray in the acute treatment of migraine: a review of clinical
      studies.
AB  - Sumatriptan nasal spray is a single-dose device that delivers 5 mg, 10 mg, or 20
      mg of sumatriptan (dosage availability dependent upon country) in a 0.1 ml
      aqueous solution to one nostril. The efficacy and tolerability of sumatriptan
      nasal spray have been assessed in a number of studies. It has been demonstrated
      that administering sumatriptan as a divided dose in both nostrils confers no
      advantage over administration in a single nostril. It appears from these studies
      that sumatriptan nasal spray is rapidly effective (with an onset of efficacy as
      early as 15 min postdose). The 20 mg dose is superior to the lower doses (5 mg,
      10 mg) in terms of both time to onset of efficacy and the extent of migraine
      symptom relief. Sumatriptan nasal spray is consistently effective in the
      treatment of multiple migraine attacks (with 67% of patients treated with the 20
      mg dose responding in at least two of three treated attacks) and with long-term
      use for up to 1 year. Apart from a bitter taste, the adverse event profile of
      sumatriptan nasal spray is comparable to that of placebo.

PMID- 10595286
TI  - Acupuncture for recurrent headaches: a systematic review of randomized controlled
      trials.
AB  - OBJECTIVE: To assess whether there is evidence that acupuncture is effective in
      the treatment of recurrent headaches. DESIGN: Systematic review. STUDY SELECTION:
      Randomized or quasi-randomized clinical trials comparing acupuncture with any
      type of control intervention for the treatment of recurrent headaches. DATA
      SOURCES: Electronic databases (Medline, Embase, Cochrane Field for Complementary
      Medicine, Cochrane Controlled Trials Register), personal communications and
      bibliographies. DATA COLLECTION AND ANALYSIS: Information on patients,
      interventions, methods, and results were extracted by at least two independent
      reviewers using a pretested form. A pooled estimate of the responder rate ratio
      (responder rate in treatment group/responder rate in control group) was
      calculated as a crude indicator of trial results as meta-analysis of more
      specific outcome data was impossible due to heterogeneity and insufficient
      reporting. RESULTS: Twenty-two trials, including a total of 1042 patients (median
      36, range 10-150), met the inclusion criteria. Fifteen trials were in migraine
      patients, six in tension-headache patients, and in one trial patients with
      various headaches were included. The majority of the 14 trials comparing true and
      sham acupuncture showed at least a trend in favor of true acupuncture. The pooled
      responder rate ratio was 1.53 (95% confidence interval 1.11 to 2.11). The eight
      trials comparing acupuncture and other treatment forms had contradictory results.
      CONCLUSIONS: Overall, the existing evidence suggests that acupuncture has a role
      in the treatment of recurrent headaches. However, the quality and amount of
      evidence is not fully convincing. There is urgent need for well-planned, large
      scale studies to assess effectiveness and efficiency of acupuncture under real
      life conditions.

PMID- 10595287
TI  - Headache in intracranial tumors.
AB  - The clinical data of 279 consecutive patients with brain tumors were analyzed pre
      and postoperatively in the period of 1994-95. No headache had been recorded in
      the history of 115 patients, neither pre- nor postoperatively. Only in 139 of the
      remaining 164 headache patients was there a probable connection between headache
      and intracranial neoplasm. In the headache group the most frequent findings were
      metastatic brain tumors and different astrocytomas. Hypophysis adenomas and
      glioblastoma multiforme were frequent in the no-headache group. Progressive
      headache was found in 110 patients (67% of the headache group). The progressive
      character of the headache showed a close relationship with the prevailing edema,
      but not with the size of the tumor. Infratentorial and intraventricular tumors
      were more frequently accompanied by headache than those located supratentorially,
      probably due to the disturbance of CSF circulation and midline dislocation with
      increased intracranial pressure. Only in one-third of the patients did the site
      of the tumor coincide with the lateralization of headache. In half of the
      headache patients, pain was the first complaint. Headaches caused by tumor were
      characterized by pain lasting for hours, developing for weeks or months. The
      headache was never permanent and there was no regular daily recurrence.

PMID- 10595288
TI  - Headache in Ehlers-Danlos syndrome.
AB  - OBJECTIVE: Ehlers-Danlos Syndrome (EDS) is a complex hereditary connective tissue
      disorder with neurologic manifestations that include cerebrovascular disorders
      and chronic pain. The clinical data collected on 18 patients with EDS and chronic
      headaches is reported. PROCEDURE: Clinical history, neurologic examination,
      computerized tomography of the head, magnetic resonance imaging (MRI) of the
      brain, and electroencephalogram (EEG). Headaches were classified according to the
      International Headache Society and the patients were followed by the author for a
      minimum of 2 years. FINDINGS: Four patients had migraine with aura, four had
      migraine without aura, four had tension headaches, four had a combination of
      migraine and tension headaches, and two had post-traumatic headaches. Nine
      patients exhibited blepharoclonus but none had history of seizures and their EEGs
      were normal, ruling out eye closure epilepsy. Although one patient had a small
      right frontal angioma, a second had Arnold Chiari malformation type I, and a
      third had an old stroke, headaches did not clinically correlate with their
      central nervous system (CNS) lesions. CONCLUSION: Chronic recurrent headaches may
      constitute the neurologic presentation of EDS in the absence of structural,
      congenital, or acquired CNS lesions that correlate with their symptoms.
      Individuals with EDS may be prone to migraine due to an inherent disorder of
      cerebrovascular reactivity or cortical excitability. Additional studies are
      needed to elucidate the pathogenesis of headaches in EDS.

PMID- 10595289
TI  - Migraine-related seizures in an epileptic population.
AB  - A relationship between epilepsy and migraine has long been postulated, but the
      nature of this interaction is still debated. We studied adult patients with
      epilepsy and investigated the relationship between migraine and epilepsy.
      Fourteen percent (n = 412) of adult patients with seizures were identified with a
      diagnosis of migraine. We also found a direct relationship between migraine and
      epilepsy (a migraine-induced epilepsy) in 1.7% (seven patients) of the patients
      with seizures. Patients were at increased risk for both conditions if they had
      migraine with aura and catamenial epilepsy. The seizure began during or shortly
      after the migraine aura in all of the cases and preceded the headache. Three of
      four patients who were refractory to management with antiepileptic drugs using
      either mono or combination therapy improved seizure control with combination
      antimigraine and antiepileptic drugs.

PMID- 10595290
TI  - Intracellular Mg++ concentration and electromyographical ischemic test in
      juvenile headache.
AB  - One-hundred-and-twenty-eight young headache outpatients underwent an
      electromyographical (EMG) ischemic test and determination of Mg++ levels in red
      and mononuclear blood cells. In migraine patients, with and without aura (MwA and
      MwoA), Mg++ concentration in the erythrocytes and in mononuclear cells was
      significantly reduced compared to tension-type headache (TTH) patients and
      healthy controls (p < 0.0001). The EMG ischemic test was positive in 71% of
      migraineurs, but only in 9.5% of TTH patients. Low intra-erythrocyte and
      mononuclear cell levels were evident in 84.3% and 81.2% of migraine patients,
      respectively; those whose ischemic tests were positive had intra-erythrocyte and
      mononuclear cell levels of Mg++ below the norm, respectively. However, reduced
      levels of Mg++ in erythrocytes were found in only two patients with TTH, and in
      mononuclear cells in one patient with TTH. These data provide further
      confirmation of the role of Mg++ in determining the status of neuromuscular
      hyperexcitability in about two-thirds of migraine patients, including childhood
      and adolescence. They also support the validity of carrying out EMG ischemic
      testing for distinguishing this condition, which can be corrected with adequate
      oral Mg++ supplementation and with a possible positive impact on headache.

PMID- 10595291
TI  - Nitric oxide pathway, Ca2+, and serotonin content in platelets from patients
      suffering from chronic daily headache.
AB  - An alteration in serotonin concentration has been found in patients with chronic
      headache caused by abuse of analgesic substances as well as an up-regulation of
      5HT2 platelet receptors, which has been correlated with chronicization of the
      headache. In a previous study we demonstrated an increase in L-arginine/nitric
      oxide (NO) pathway activity in platelets from patients affected by migraine with
      or without aura, particularly during attacks. In the present research we assessed
      the variations in platelet L-arginine/NO pathway and cyclic guanosine
      monophosphate (cGMP) levels in 32 patients affected by chronic daily headache
      (CDH) (8 M, 24 F, age range 34-50 years) both during and between attacks. In
      these same patients, the platelet aggregation to different collagen
      concentrations (0.3, 1, 3 micrograms/ml) was determined as well as the
      intracellular platelet calcium concentration using fluorescence polarization
      spectrometry. These parameters were compared with those of an age- and sex
      matched control group (n = 25; n = 10, n = 15, age range 35-51 years). A
      reduction found in platelet aggregation response to each collagen concentration
      used (p < 0.001) was coupled with an increased NO and cGMP production (NO: p <
      0.0001; cGMP: p < 0.001). This was accompanied by a significant increase in
      intracytosolic Ca2+ (p < 0.0001) concentration and a reduced platelet serotonin
      content compared to those in control individuals (p < 0.0002). Changes in the
      above platelet parameters were accentuated more in patients with analgesic abuse
      than in CDH patients with no drug abuse. These findings suggest the occurrence of
      an activation of cGMP-Ca2+ mediated events in CDH patients with analgesic abuse.
      This physiologic compensatory mechanism, which intervenes in overcoming the
      increase in cytosolic Ca2+ levels, is not as efficient at limiting serotonin
      depletion by platelet dense bodies. A similar depletion in the central
      serotoninergic pathway can be assumed in the same patients.

PMID- 10595292
TI  - Interobserver reliability of diagnostic criteria for cervicogenic headache.
AB  - To assess the interobserver reliability in distinguishing cervicogenic headache
      (CEH) from migraine without aura and tension-type headache we conducted a study
      keeping as closely as possible to daily clinical practice. In contrast to other
      reliability studies, which use data from clinical patient records or semi
      structured interviews recorded on videotape ('in vitro' design), we examined
      'live' patients ('in vivo' design). Twenty-four headache patients participated in
      our 'in vivo' design experiment. During a session, each physician performed a
      physical examination and queried six patients in succession using a semi
      structured interview. Diagnosis was carried out in accordance with the
      International Headache Society (IHS) criteria and the criteria from Sjaastad and
      co-workers. Kappa statistics were used: 0.83 between the expert headache
      neurologists; 0.74/0.73 between the expert anesthesiologist in (head) pain
      treatment and both expert neurologists respectively; kappa ranged from 0.43 to
      0.62 between the other physicians. The results of our 'in vivo' design study show
      that the reliability in diagnosing CEH, when strictly applying the criteria from
      Sjaastad and co-workers, is similar to the reliability in diagnosing migraine and
      tension-type headache according the IHS criteria.

PMID- 10595293
TI  - Possible predictive factors in the prognosis of migraine with aura.
AB  - In order to identify possible predictive factors in the prognosis of migraine
      with aura (MA), we conducted a review at 10 to 20 years from referral on a sample
      of 77 MA patients (51 F, 26 M) consecutively seen for the first time at the
      University of Parma Headache Center. Based on the date of the last MA attack
      reported by these patients, we divided them into two study groups: a group of 22
      patients "with remission of the disease," i.e. attack-free for at least 2 years
      at the end of the follow-up study; and a group of 55 patients "without remission
      of the disease," i.e. still having attacks in the last 2 years of the follow-up
      study. A comparative analysis of the MA clinical features observed in the two
      groups at the time of the patients' first visit to our Center enabled us to
      identify a number of favorable prognostic indicators, namely: a family history of
      parents with MA, the absence of other associated forms of primary headache, and
      the absence of both natural and artificial light stimulation as trigger factors.

PMID- 10595295
TI  - Loss of topographic memory and prosopagnosia during migraine aura.
AB  - We report the case of a 28-year-old woman with a past history of acephalalgic
      migraine. She had a complex migraine aura with left-sided scintillating scotomas,
      hemianopia, left-sided paresthesias, a loss of topographic and procedural memory,
      and prosopagnosia. The rarity of right hemisphere cognitive dysfunction during
      the aura, its diagnostic difficulties, and differential diagnosis are discussed.

PMID- 10595294
TI  - Migraine consultation patterns in primary care. Results from the PCAOM study 1994
      96.
AB  - In order to establish a basis for the planning of improved medical care of
      migraine in Germany, we report on the proportion of migraine patients under
      primary care and the continuity of consultations for migraine as determined by
      age, gender, and history of migraine and nonmigraine practice contact (Primary
      Care of Migraine, PCAOM Study). A primary-care-physician-based migraineurs'
      sample of 16,573 women and 4,636 men (MediPlus, IMS Health) was placed in
      relation to cases expected according to International Headache Society criteria
      in the base population, and was followed for up to 3 years for repeat
      consultations. Overall, no more than 51% and 37%, respectively, of female and
      male statutory health-insured migraine headache sufferers had a migraine
      diagnosis mentioned at least once a year in primary care. At younger ages,
      substantially less advantage was taken of available primary healthcare for
      migraine; 79% of the women and 74% of the men were estimated to present again to
      the same primary-care physician within 3 years because of migraine, the
      corresponding figures for patients with no history of migraine in the practice
      concerned being 41% and 31%, respectively. Following first migraine contacts,
      time to recontact and quarterly recontact prevalences for migraine did not
      differ, whether on the basis of an established nonmigraine primary care
      relationship or a first encounter with a medical practice. Trust evidenced by an
      existing nonmigraine doctor-patient relationship apparently did not carry over to
      migraine. Results indicate that one of the greatest challenges in relation to the
      care of migraine patients in Germany is to establish and maintain solid doctor
      patient relationships.

PMID- 10595296
TI  - Escherichia coli O157:H7 as an emerging foodborne pathogen: a literature review.

PMID- 10595297
TI  - On modeling the irregular fluctuations in microbial counts.
AB  - Daily or other periodic microbial counts in many foods, particularly ground
      meats, poultry, and raw milk, show an irregular fluctuating pattern. The cause of
      the fluctuations is the interplay of many random factors that tend to promote or
      inhibit microbial growth. Therefore, the actual size of a microbial population
      can vary randomly around a typical level or around a trend determined, for
      example, by seasonal variations or changing sanitary conditions. Fluctuations
      around a fixed level can often be modeled as a sequence of independent counts
      having a lognormal or other parametric distribution. The independence of the
      counts and the type of distribution can be established by standard statistical
      tests. Once selected, the distribution function can be used to estimate the
      probability of encountering a population in any given size range. The model can
      be modified to describe sequences that include zero counts, which are the result
      of the organisms' absence, or of the failure of the method to detect them. In the
      case of fluctuations around a trend, a modified version of the model can be used
      to estimate the probability of deviations from the trend. A more thorough
      modification is required in order to account for fluctuating patterns that
      include outbursts of appreciable duration, like those caused by massive
      contamination of a water reservoir.

PMID- 10595298
TI  - Current trends in immunoassay-based kits for pesticide analysis.
AB  - Detection of pesticides and their metabolites in food and environmental samples
      in real time is the goal of many industries. Immunoassay technology has several
      attributes that make it a useful tool for screening purposes (e.g., selectivity,
      sensitivity, portability, and rapid turnaround time). Approximately 90% of the
      developed immunoassays for the pesticide residue analysis use the ELISA
      technique. Commercial kits are tailored to target different analytes, thus
      eliminating in some cases the need for clean-up steps. The manageability of the
      immunoassay test kit, together with its accuracy and speed of analysis, allows
      the rapid determination in situ of many samples simultaneously. This article
      gives an overview on the applications of the immunokits for pesticide analysis in
      drinking water and foods, as well as examples of different immunoassay formats
      commonly used. Special attention is given to sample extraction and clean-up
      procedures. Application to the determination of common pesticides and their
      detection limit are summarized. Immunoassay kits offer many practical advantages,
      and the acceptance of these methods depends on several factors, including the
      demonstration of quality and validity compared with reference methods. Although
      the advantages of the technique and their applications to food industry quality
      control are scarcely referred to in the literature.

PMID- 10595299
TI  - Food safety control in the Republic of Korea.
AB  - With the increased globalization of the food trade, the work of the World Trade
      Organization has led to the greater recognition and use of the concept of
      equivalence. Use of this concept, however, requires countries to be aware of the
      national controls applied in other countries. This article provides an overview
      of the current system in use in the Republic of Korea. It outlines the
      administrative systems employed to maintain food safety that includes the recent
      establishment of the Korea Food and Drug Administration. It provides details of
      the legislative structure, including the Food Sanitation Act of 1986 (and its
      recent amendment) and related regulations. Certain nongovernmental bodies are
      also described. The article concludes by recognizing that modern food safety
      problems require concerted action, both nationally and internationally.

PMID- 10595300
TI  - Early events of somitogenesis in higher vertebrates: allocation of precursor
      cells during gastrulation and the organization of a meristic pattern in the
      paraxial mesoderm.

PMID- 10595301
TI  - Retrospective tracing of the developmental lineage of the mouse myotome.

PMID- 10595302
TI  - Segmentation of the paraxial mesoderm and vertebrate somitogenesis.
AB  - Somites are the most obviously segmented features of the vertebrate embryo.
      Although the way segmentation is achieved in the fly is now well described,
      little was known about the molecular mechanisms underlying vertebrate
      somitogenesis. Through the recent identification of genes important for
      vertebrate somitogenesis and the analysis of their function, several theoretical
      models accounting for somitogenesis such as the clock and wavefront model, which
      have been proposed over the past 20 years, are now starting to receive
      experimental support. A molecular clock linked to somitogenesis has been
      identified which might act as a periodicity generator in the presomitic cells.
      This temporal periodicity is then translated into a tightly controlled spatial
      periodicity which is revealed by the expression of several genes. Analysis of
      mouse mutants in the Notch-Delta pathway suggest that this signaling mechanism
      might play an important role at this level. The final step of the cascade is to
      translate these genetically specified segments into morphological units: the
      somites. Importantly, these studies have helped in dissociating the segmentation
      and the somitogenesis processes in vertebrates. In addition, although
      segmentation was classically thought to have arisen independently in protostomes
      and deuterostomes, recent evidence suggests that part of the segmentation
      machinery might actually have been conserved. The conservation of segmentation
      mechanisms reported in the fly such as the pair-rule pattern, however, remain a
      subject of controversy.

PMID- 10595303
TI  - Segmentation: a view from the border.
AB  - Segmentation, or metamerism, consists of the subdivision of the body into
      discrete units that subsequently acquire regional specializations. In
      vertebrates, the most obvious manifestation of this phenomenon is seen during the
      formation of the mesodermal somites and their derivatives. This review surveys
      three different models for how somites form, and how they relate to recent
      molecular data suggesting the involvement of transcription factors and cell
      surface molecules. A new model (the "Morse code" model) is proposed to convey
      positional information to somitogenic cells. Finally, the molecular events of
      boundary formation (during the initial epithelialization of somites) and boundary
      maintenance (between adjacent somite halves as well as in resegmentation) are
      discussed.

PMID- 10595304
TI  - Genetic regulation of somite formation.
AB  - Segmentation of the paraxial mesoderm into somites requires a strategy distinct
      from the division of a preexisting field of cells, as seen in the segmentation of
      the vertebrate hindbrain into rhombomeres and the formation of the body plan of
      invertebrates. Each new somite forms from the anterior end of the segmental
      plate; therefore, the conditions for establishing the anterior-posterior boundary
      must be re-created prior to the formation of the next somite. It has been
      established that regulation of this process is native to the anterior end of the
      segmental plate, however, the components of a genetic pathway are poorly
      understood. A growing library of candidate genes has been generated from
      hybridization screens and sequence homology searches, which include cell adhesion
      molecules, cell surface receptors, growth factors, and transcription factors.
      With the increasing accessibility of gene knockout technology, many of these
      genes have been tested for their role in regulating somitogenesis. In this
      chapter, we will review the significant advances in our understanding of
      segmentation based on these experiments.

PMID- 10595305
TI  - Hox genes and the global patterning of the somitic mesoderm.

PMID- 10595306
TI  - The origin and morphogenesis of amphibian somites.
AB  - The origin and development of the amphibian somitic mesoderm is summarized and
      reviewed with the goal of identifying issues most profitably pursued in these
      organisms. The location of the prospective somitic mesoderm as well as the cell
      movements bringing this tissue into its definitive position varies among
      amphibians. These variations have implications for the tissue interactions
      patterning the embryo, the design of the gastrulation movements, the role of the
      somitic mesoderm in early patterning and morphogenic processes, and the nature of
      the developmental pathway leading to somites. The presegmentation morphogenesis,
      the process of segmentation, and the subsequent, postsegmentation morphogenesis
      of the somitic mesoderm also varies considerably among amphibians. Although
      segmentation in amphibians shares what may be highly conserved and general
      patterning mechanisms with other vertebrates, the somitic developmental pathway
      as a whole is not conservative and has been capable of accommodating the use of a
      number of quite different morphogenic processes, all leading to very similar
      ends. The major challenges in studying amphibian somitogenesis are to develop
      molecular markers for major components of the somite, to determine the
      derivatives of the somite with better cell tracing experiments, and learning to
      work with the small dermatomal and sclerotomal cell populations found in most
      species. A potential advantage is that the diversity of somitogenesis among the
      amphibians makes this group ideal for studying the evolution of developmental
      processes. In addition, many amphibians allow direct observation of somitogenesis
      with great resolution and permit biomechanical analysis of tissues participating
      in morphogenesis, thus making it possible to analyze cellular mechanisms of
      morphogenesis in ways not possible in most other systems.

PMID- 10595307
TI  - Somitogenesis in zebrafish.
AB  - Both genetic and embryological studies in the zebrafish, Danio rerio, have
      contributed to our general understanding of how somites form and differentiate.
      In the zebrafish, mutants have been isolated that have specific effects on
      virtually every aspect of somite development. The fss-type mutants, defining 5
      genes, affect somite segmentation and epithelialization. The you-type mutants,
      comprising 7 genes, and mutants in another 13 genes defective in notochord
      formation, have somites with abnormal pattern and morphology. Eighteen genes have
      been identified that are required for the differentiation and maintenance of the
      somitic musculature, and 2 genes have been identified that are involved in the
      development of motoneurons that innervate the somitic musculature. The true
      utility of the zebrafish lies in the ability to combine genetic analysis with
      embryological experimentation. Such analysis of somite segmentation suggests that
      homologues of both the Drosophila pair-rule and segment polarity genes, her1 and
      Sonic hedge-hog, respectively, are involved generating periodicity during
      somitogenesis. The Sonic hedge-hog protein secreted from the notochord also
      induces the formation of specific muscle types including the slow muscle fibers
      which are initially induced in the medial somite and undergo a series of
      morphological transitions including migration through the somite to the lateral
      surface where they complete their differentiation. The role of the notochord in
      patterning the somite is also demonstrated by its involvement in regulating the
      permissiveness of the somite to the extension of axons of primary motoneurons.

PMID- 10595308
TI  - Rostrocaudal differences within the somites confer segmental pattern to trunk
      neural crest migration.

PMID- 10595309
TI  - Signaling through Gp130: toward a general scenario of cytokine action.
AB  - Cytokines play roles in a wide range of responses such as immune response,
      hematopoiesis and inflammation. A large volume of studies revealed that cytokines
      show functional pleiotropy and redundancy. Gp130 is a receptor subunit shared by
      the interleukin-6 family of cytokines. We describe and discuss signaling through
      gp130 in relation to a general scenario for cytokine signaling regulating cell
      growth, differentiation and survival.

PMID- 10595310
TI  - Distinct regulation of myoblast differentiation by intracellular and
      extracellular fibroblast growth factor-1.
AB  - We studied the role of fibroblast growth factor (FGF)-1 in the physiology of
      myoblast differentiation. We found that, while endogenous FGF-1 in L6-10 rat
      myoblasts did not suppress the progress of differentiation, the addition of FGF-1
      to the culture medium suppressed it. Moreover, L6-10 cells stably transfected
      with full length FGF-1 undergo enhanced differentiation. The latter was well
      correlated with myogenin expression and myotube formation. Constitutive
      expression of a mutant FGF-1 (FGF-1U) that lacked a nuclear localization signal,
      promoted the differentiation of the myoblasts even more strongly. Furthermore,
      the expression of FGF-1U in an inducible expression system enhanced myogenin
      expression promptly. In L6-10 transfectants expressing a dominant-negative mutant
      of FGF receptor, stable transfection of FGF-1 promoted differentiation as it did
      in parent cells. Studies with FGF receptors and MAP kinase suggest that both are
      involved in the effect of FGF-1 when it is supplemented to culture medium but not
      during the effect of endogenous FGF-1 synthesized in cells. We conclude that
      intracellular (endogenous) and extracellular (exogenous) FGF-1 have differential
      effects on the regulation of myogenic differentiation of L6-10 cells.

PMID- 10595311
TI  - Immunohistochemical localization of connective tissue growth factor (CTGF) in the
      mouse embryo between days 7.5 and 14.5 of gestation.
AB  - Connective tissue growth factor (CTGF) is a 38 kDa modular protein that is
      involved in processes such as cell proliferation, survival, migration, adhesion
      and extracellular matrix production. Target cells for CTGF include fibroblasts,
      smooth muscle cells and endothelial cells. Using a specific peptide antibody,
      CTGF was localized in tissue sections obtained from mouse embryos between days
      7.5 and 14.5 of gestation. On day 7.5, CTGF was present at high levels in the
      embryonic ectoderm, mesoderm, and chorion, with weaker levels in the squamous
      endoderm. No CTGF was detected in Reichert's membrane, parietal endoderm, and
      visceral endoderm. Decidual cells of the maternal uterus stained strongly for
      CTGF. There was no specific staining for CTGF on day 11.5 but by day 13.5, the
      protein was detectable in a limited number of structures, most notably the liver,
      thymus, lung, and intestine. By day 14.5, staining for CTGF had become extensive
      and was present at high or moderate levels in the thymus, aorta, trachea, liver,
      lung, adrenal gland, kidney, iliac sinus, olfactory region, tongue, pharynx,
      esophagus, thyroglossal duct, choroid plexi, Rathke's pouch, stomach, pancreas,
      and midgut. Relatively weak staining was present in the heart and dorsal root
      ganglia. There was no staining in the vitelline duct or in the outer cortical or
      medullary regions of the brain. Among specific cell types, CTGF was localized at
      high levels in secretory and absorptive epithelial cells and liver parenchyma
      cells, at moderate levels in vascular endothelial cells and myoblasts and at low
      levels in mesenchymal and connective tissue cells. These data show that various
      tissues and organ systems produce CTGF in a specific temporo-spatial pattern
      during embryogenesis and support a role for CTGF in cellular differentiation and
      development during prenatal life.

PMID- 10595312
TI  - mAngiogenin-3, a target gene of oncoprotein E2a-Pbx1, encodes a new angiogenic
      member of the angiogenin family.
AB  - Angiogenins are proteins in the pancreatic ribonuclease superfamily that utilize
      their ribonuclease activity to induce formation of new blood vessels. Recently we
      identified a new member of the angiogenin gene family, mouse angiogenin-3, by
      virtue of its transcriptional activation in NIH3T3 fibroblasts coincident with
      transformation by the chimeric leukemia oncogene, E2a-Pbx1. Here we have isolated
      the cDNA encoding mouse angiogenin-3 and used it to produce the protein in E.
      coli. We demonstrate that mouse angiogenin-3 is a ribonuclease whose activity and
      specificity towards tRNA and dinucleotide substrates differ from those of mouse
      angiogenin or of mouse angiogenin-related protein, a non-angiogenic factor. Mouse
      angiogenin-3 induced angiogenesis in both the chicken embryo chorioallantoic
      membrane assay and the rat cremaster muscle. Electron microscopy revealed that
      endothelial cells within vessels induced by both mouse angiogenin-3 and mouse
      angiogenin contain fenestrations similar to those observed in endothelial cells
      from neovasculature induced by vascular endothelial growth factor and basic
      fibroblast growth factor. Mouse angiogenin-3 also induced other molecular events
      typical of rapidly proliferating endothelial cells, such as increases in rough
      endoplasmic reticulum, polysomes, and mitochondria.

PMID- 10595314
TI  - Confirmation of pleisiomorphic daily torpor in mammals: the round-eared elephant
      shrew Macroscelides proboscideus (Macroscelidea).
AB  - The characteristics of daily torpor were measured in the round-eared elephant
      shrew Macroscelides proboscideus (Macroscelidea) in response to ambient
      temperature and food deprivation. Elephant shrews are an ancient mammal order
      within a superordinal African clade including hyraxes, elephants, dugongs and the
      aardvark. M. proboscideus only employed torpor when deprived of food; torpor did
      not occur under an ad libitum diet at ambient temperatures of 10, 15 and 25
      degrees C. Torpor bout duration ranged from < 1 h to ca. 18 h. The times of entry
      into torpor were restricted to the scotophase, despite normothermic body
      temperature patterns indicating a rest phase coincident with the photophase. Full
      arousal was always achieved within the first 3 h of the photophase. When food
      deprived, the onset of the rest phase, and hence torpor, advanced with respect to
      the experimental photoperiod. The lowest torpor body temperature measured was
      9.41 degrees C. Daily torpor in M. proboscideus confirms a pleisiomorphic origin
      of daily heterothermy. Torpor facilitates risk-averse foraging behaviour in these
      small omnivores by overcoming long-term energy shortfalls generated by the
      inherent variability of food availability in their semiarid, El Nino-afflicted
      habitats.

PMID- 10595313
TI  - The dynamic expression of the epidermal growth factor receptor and epidermal
      growth factor ligand family in a differentiating intestinal epithelial cell line.
AB  - The Caco-2 intestinal epithelial cell line differentiates when cultured on
      plastic or permeable filters, and offers a valuable system to study events
      associated with enterocytic differentiation in vitro. Little is known as to
      whether the expression of the epidermal growth factor receptor (EGFR) and its
      ligands changes as intestinal epithelial cells differentiate. We found that total
      cellular EGFR protein and mRNA transcript levels were relatively unchanged during
      Caco-2 cell differentiation, but the expression of surface EGFR and patterns of
      steady state epidermal growth factor (EGF)-family ligand expression changed
      significantly. EGFR affinity, surface EGFR expression levels, and the repertoire
      of expressed EGF-family ligands, were different between Caco-2 cells cultured on
      plastic and filters. Functionally, EGFR-mediated cell proliferation and tyrosine
      phosphorylation of the signal transduction protein SHC could be inhibited in Caco
      2 cells cultured on filters, but not on plastic. Thus, the substrate on which the
      cells were grown and the degree of cell differentiation strongly modulate EGFR
      affinity, EGFR surface expression, the steady state expression of EGF-family
      ligands, as well as, EGFR-mediated cellular responses. Our results suggest that
      the EGFR system is regulated during intestinal epithelial cell differentiation
      primarily at the level of ligand expression.

PMID- 10595316
TI  - Seasonal cycles of mitochondrial ADP sensitivity and oxidative capacities in
      trout oxidative muscle.
AB  - Mitochondria from red myotomal muscle of rainbow trout, Oncorhynchus mykiss,
      showed seasonal cycles of their maximal rates of substrate oxidation (nmol.min-1
      mg-1 mitochondrial protein) and their apparent ADP affinity (Kmapp), as well as
      in the thermal sensitivity of these properties. Increases in the maximal capacity
      of pyruvate oxidation were sufficient to compensate for seasonal changes in
      temperature, except during the winter months when rates at habitat temperature
      were depressed relative to other periods. The ADP affinity of isolated
      mitochondria was highest during cold months. Thus, the Kmapp for ADP at habitat
      temperature showed less seasonal variation than the ADP Kmapp at a given
      temperature. A loss in ADP affinity with decreasing temperature occurred through
      much of the year, and only was definitively suppressed in December and July. Both
      the ADP affinity and the maximal oxidative capacities of muscle mitochondria seem
      to be regulated parameters.

PMID- 10595315
TI  - Physiology of acute silver toxicity in the starry flounder (Platichthys
      stellatus) in seawater.
AB  - Physiological effects of exposure to silver (AgClnn-1; 250 micrograms Ag l-1 or
      1000 micrograms Ag l-1) in seawater fish were investigated using adult starry
      flounders. While all fish survived up to 10 days in 250 micrograms Ag l-1,
      flounders started to die after day 4 in 1000 micrograms l-1. Dose-dependent
      increases in plasma and hepatic silver concentrations showed that silver was
      available for uptake. There were minimal negative effects on hematological
      parameters, acid-base status, and blood gases. Plasma ammonia showed a pronounced
      (three- to four-fold), but transient increase in flounders exposed to either 250
      micrograms Ag l-1 or 1000 micrograms Ag l-1. Whole body ammonia and acid
      equivalent efflux measurements indicated that ammonia retention was due to a
      combination of stimulated production and inhibited excretion. In the 1000
      microgram Ag l-1 group there was a similar transient increase in plasma
      [magnesium], which was restored by day 4. In contrast, plasma chloride and sodium
      levels increased gradually towards the point when fish began to die. At 250
      micrograms Ag l-1, the Na+/K(+)-ATPase activity of the intestine was unaffected
      but there was a two-fold increase in branchial Na+/K(+)-ATPase activity. The
      latter effect was interpreted as compensation for an elevated chloride and sodium
      load. The increases in plasma chloride and sodium concentrations were accompanied
      by a marked suppression of drinking, thereby indicating that acute silver
      toxicity was likely caused by a combination of elevated electrolyte
      concentrations and dehydration.

PMID- 10595317
TI  - Active transport of calcium ions in the skin of the salamander Ambystoma
      tigrinum.
AB  - We measured Ca2+ exchanges across the skin of larval and adult Ambystoma tigrinum
      using the radio-isotope influx method. We found that the skin of both morphs
      takes up Ca2+ in a manner that is proportional to external [Ca2+], saturable and
      oriented against the electrochemical gradient for Ca2+. We conclude that this
      uptake occurs by active transport. Kinetic analysis yields affinities for calcium
      ions that are similar to the affinities for both Ca2+ and Na+ in the skin of
      other amphibians. The capacity for calcium is similar to Ca2+ capacity in other
      amphibians. The capacity for Ca2+ is lower than the capacity for Na+. Cutaneous
      Ca2+ deposits are lower in this urodele than found in anurans. Adults tend to
      have higher levels of Ca in their skin than do larvae.

PMID- 10595318
TI  - In vitro studies on active calcium absorption from ovine rumen.
AB  - From various in vivo and in vitro studies it has been shown that the rumen
      represents a significant site of Ca2+ absorption in sheep and goats. It was the
      aim of the present study to further characterize the underlying mechanisms.
      Unidirectional flux rates of Ca2+ across rumen wall epithelia of sheep were
      measured in vitro by applying the Ussing-chamber technique in the absence of
      electrochemical gradients. Under these conditions, significant Ca2+ net flux
      rates (Jnet) clearly indicate the presence of active mechanisms for Ca2+
      transport. Short chain fatty acids (SCFAs) caused highest stimulation of Ca2+
      Jnet (6.3 +/- 1.9 nmol.cm-2.h-1) when used as a mixture of acetate, proprionate
      and butyrate in physiological proportions (36, 15, 9 mmol.l-1, respectively). The
      effect of 30 mmol.l-1 butyrate (3.2 +/- 0.6 nmol.cm-2.h-1) was higher than
      respective amounts of propionate and acetate (0.6 +/- 0.8 nmol.cm-2.h-1 and 0.9
      +/- 0.8 nmol.cm-2.h-1, respectively). Eliminating SCFAs resulted in Ca2+ Jnet of
      0.4 +/- 1.1 nmol.cm-2.h-1. Addition of Ca channel blocker verapamil (mucosal 1
      mmol.l-1) had no significant effect on SCFA-stimulated Jnet of Ca2+, whereas
      application of Na+/H- inhibitor amiloride (mucosal 1 mmol.l-1) further enhanced
      the Ca2+ Jnet by > 65%. The Ca(2+)-pump inhibitor vanadate had no significant
      effect on Jnet of Ca2+. Dietary Ca depletion enhanced calcitriol plasma
      concentrations but had no effect on active Ca2+ absorption across the rumen wall
      of sheep. In addition, no effect on active Ca2+ absorption could be observed
      during early lactation. In conclusion, there is clear evidence for the rumen as a
      main site for active Ca2+ absorption in sheep. Our results suggest the presence
      of a Ca2+/H+ exchange mechanism in the apical membrane of rumen epithelial cells
      which depends on SCFA absorption and which does not seem to be under the control
      of calcitriol. Basolateral Ca2+ extrusion occurs independently from Ca(2+)-pump
      activity and may be accomplished via Na+/Ca2+ exchange.

PMID- 10595319
TI  - Characteristics of dipeptide transport in pig jejunum in vitro.
AB  - Characteristics of dipeptide transport in pig jejunum were investigated in vitro
      by applying the Ussing-chamber technique and mucosal uptake studies. Addition of
      both glycyl-L-glutamine and glycyl-L-sarcosine (20 mmol.l-1) to the mucosal
      buffer solution significantly increased the short-circuit current by 2.60 +/-
      0.15 and 1.57 +/- 0.20 mu eq.cm-2.h-1, respectively. Concentration-dependent
      changes in short-circuit current followed Michaelis-Menten kinetics with similar
      affinity constants for both dipeptides. From unidirectional flux rates for
      radiolabelled glycyl-L-sarcosine, a net flux rate for glycyl-L-sarcosine of 49.8
      +/- 6.7 nmol.cm-2.h-1 was calculated. In mucosal uptake experiments, the apical
      influx of 14C-labelled glycyl-L-sarcosine into isolated porcine mucosa was pH
      dependent and significantly inhibited by glycyl-L-glutamine. Moreover, RT-PCR
      studies with primers derived from rabbit PepT1 identified two PCR fragments of
      identical size to rabbit PepT1 from pig intestinal mRNA preparations. In
      conclusion, our studies revealed key features of mammalian intestinal peptide
      transporters and give evidence for a PepT1-like transporter in the pig jejunum
      that could significantly contribute to the overall amino acid absorption from the
      gut.

PMID- 10595320
TI  - Natriuretic peptides and the acclimation of aglomerular toadfish to hypo-osmotic
      media.
AB  - Since the aglomerular toadfish (Opsanus tau) experiences a natriuresis following
      transfer to 10% seawater, we examined the role of natriuretic peptides in the
      acclimation of toadfish to hypo-osmotic media. Gel filtration chromatography of
      acid extracts of toadfish heart and kidney identified a broad peak of atrial
      natriuretic peptide-like immunoreactivity in both tissues, with maximal
      immunoreactivity in fractions coeluting with human alpha-atrial natriuretic
      peptide. Using a homologous bioassay to measure changes in aortic ring tension,
      both vasorelaxing and, surprisingly, vasoconstricting bioactivities were
      identified in gel fractions of heart extract. No significant vasorelaxing
      activity was identified in kidney extract or fractions. Instead, a potent
      vasoconstricting activity was observed, with maximal activity in gel fractions
      with an estimated MW greater than 1000 Da. Levels of atrial natriuretic peptide
      immunoreactivity in plasma from the caudal vein were very low in seawater
      toadfish and were unchanged 12 h after transfer of toadfish to 10% seawater. We
      conclude, that natriuretic peptides are present in the heart and kidney of
      toadfish. However, atrial natriuretic peptide-like peptides of cardiac origin
      circulating to the kidney via the caudal vein do not appear responsible for the
      natriuresis that ensues upon the transfer of toadfish to 10% seawater. In the
      absence of glomeruli, this tubular natriuresis may be regulated by natriuretic
      peptides present in the kidney.

PMID- 10595321
TI  - Differences in fuel utilization between trout and human thrombocytes in
      physiological media.
AB  - Cell culture preparations now play a significant and essential role in
      physiological and biochemical studies of cell biology. However, the fuels offered
      in cell culture media are only glucose and glutamine, plus whatever might be in
      the added sera. It is currently difficult to find a rational way forward on this
      problem, as there are few data on what fuels cells use in vivo or even in an in
      vitro physiological situation. A recent study on human platelets redressed the
      situation somewhat by finding that 75% of ATP turnover could be accounted for by
      aerobic glycolysis, and by the oxidation of glucose, hydroxybutyrate, acetate,
      glutamine, palmitate and oleate. In the present study we used a similar strategy
      to investigate fuel choices by trout thymocytes, cells with a similar function
      but from a different phylogenetic group. When these cells were presented with a
      physiological medium, we found that aerobic glycolysis accounted for 9% of total
      ATP turnover, glucose and glutamine oxidation made a combined contribution of
      2.3%, oleate and palmitate oxidation accounted for 15%, and 74% was unaccounted
      for. These patterns of fuel use are very different from that in human platelets.
      They demonstrate the cell- and animal-specific nature of cellular metabolism and
      again expose the inadequacy of the fuel component in culture media.

PMID- 10595322
TI  - Discordant responses of mitogen-activated protein kinases to anoxia and freezing
      exposures in hatchling turtles.
AB  - The role of two vertebrate mitogen-activated protein kinases (MAPKs) in mediating
      responses to in vivo anoxia or freezing exposures was examined in four organs
      (liver, heart, kidney and brain) of hatchling red-eared turtles, Trachemys
      scripta elegans, which are naturally tolerant of these stresses. The
      extracellular signal-regulated kinases were not stress-activated except in brain
      of frozen turtles. The c-Jun NH2-terminal kinases (JNKs) were transiently
      activated by anoxia exposure in all four organs (after 1 h in brain or 5 h in
      other organs) but activity was suppressed during freezing except in brain which
      showed a transient activation of JNK after 1 h. Changes in the concentrations of
      the transcription factors, c-Fos and c-Myc, were also stress- and organ-specific.
      The patterns of MAPK activation in a stress-tolerant animal suggest the relative
      importance of these kinase pathways in cellular adaptation to oxygen deprivation
      or freezing and identify novel natural activators of MAPKs in vivo. The
      specificity of the signaling pathways is also emphasized here as the general
      whole-body stresses, anoxia and freezing, activated individual MAPKs in a tissue
      , time-, and stress-dependent manner.

PMID- 10595323
TI  - A spotlight on autoimmune diseases: the need for an NIH autoimmune diseases
      office.

PMID- 10595324
TI  - The tolls cancer takes on women.

PMID- 10595325
TI  - Developing maternal and child health epidemiology capacity in state and local
      health departments.

PMID- 10595326
TI  - Toward optimal health: the experts respond to depression. Interview by Jodi
      Godfrey Meisler.

PMID- 10595327
TI  - Medical family: a new view of the relationship between chronic dialysis patients
      and staff arising from discussions about advance directives.

PMID- 10595328
TI  - Estrogen replacement therapy and colon cancer: a clinical review.
AB  - Colorectal cancer is the third leading cause of cancer death in women. Studies on
      the potential protective effect of postmenopausal hormone replacement on the
      incidence of colon cancer have been contradictory. To attempt to clarify the
      potential protective effect of hormone replacement therapy (HRT), an English
      language key word (KW) search of MEDLINE, up to August 1999, was performed for KW
      colon cancer or colorectal adenoma or colon adenoma or adenomatous polyp and KW
      estrogen replacement or hormone replacement. Additional references were obtained
      from reading of the reference lists. Thirty-five studies, including 3 meta
      analyses, were found. Of these, 23 suggested any degree of protective effect of
      HRT, 11 reported neutral results, and 1 reported negative impact of hormone
      replacement. The single prospective randomized controlled trial included small
      numbers of inpatients taking high-dose estrogen. However, studies did not
      uniformly specify hormone type, dose, duration, and potential differential
      effects on right and left colon. Estrogen and progesterone effects were not often
      considered separately. Many studies had inadequate control of confounders, for
      example, family history of colon cancer or indication for endoscopy. Therefore,
      although the majority of studies, especially more rigorously designed recent
      studies, support the conclusion that postmenopausal estrogen replacement therapy
      (ERT) has a protective effect against colon adenomas and colon cancer,
      methodological limitations preclude practical application of study results at
      present. Prospective studies are needed to confirm the existence and degree of
      protective effect, as well as to specify the mechanism of protection.

PMID- 10595329
TI  - Plasma homocysteine in women taking hormone replacement therapy: the
      Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.
AB  - Elevated plasma homocysteine levels have been associated with increased
      atherosclerotic disease risk. Estrogen and estrogen/progestin replacement therapy
      have been suggested to lower plasma homocysteine levels in postmenopausal women.
      To assess the impact of hormone replacement therapy (HRT) on plasma homocysteine,
      levels were measured in samples from adherent women randomized to placebo (n =
      34), conjugated equine estrogens (n = 36), or continuous conjugated equine
      estrogens + progestin (n = 33) in the Postmenopausal Estrogen/Progestin
      Interventions (PEPI) Trial. Homocysteine levels decreased between baseline and
      follow-up (12 and 36 months) in all treatment groups. The magnitude of the
      reduction was greater in the conjugated estrogens group at 12 months compared
      with placebo (p = 0.036), even when adjusted for folate and B vitamin
      consumption, but this difference did not persist at 36 months. These data suggest
      that estrogen therapy has a modest, but transient, impact on plasma homocysteine
      levels in women with normal homocysteine at baseline.

PMID- 10595330
TI  - The associations between health and domestic violence in older women: results of
      a pilot study.
AB  - This study examined the association of domestic violence (DV) with the general
      physical and mental health of older women. This pilot cross-sectional survey
      studied 257 women, aged 50-79, who came for screening visits to the Observational
      Study arm of the Women's Health Initiative's (WHI) Newark, NJ, site between June
      1995 and August 1996. A 27-item, interviewer-administered questionnaire was used
      to detect DV. To measure overall health status, we used questions from the
      Medical Outcomes Study Short Form 36. Of the 257 women interviewed, 82 (31.9%)
      had experienced DV at some point in their life; 51 (22.6%) had been threatened,
      and 31 (15%) had experienced physical assault. Women who were either physically
      assaulted or threatened had lower mental component summary (MCS) scores (50.0
      versus 53.7). Women who had only been threatened had a mean MCS score of 49.7
      compared with 53.8 for nonthreatened women. Both of these MCS scores indicate
      poorer mental health. DV, which about 1 in 4 women experience over their
      lifetime, has a negative relationship to health status. Women who have
      experienced DV have lower MCS scores than those who have not. They also tend to
      have lower physical component summary scores. These findings suggest the
      importance that detection and prevention of DV have for women's health.

PMID- 10595331
TI  - Prevalence of mood and anxiety disorders in women who seek treatment for
      premenstrual syndrome.
AB  - Many women experience symptoms of premenstrual irritability, reactivity of mood,
      anxiety, and change in appetite and sleep. Whereas some women experience these
      symptoms exclusively during the premenstrual phase of the menstrual cycle, others
      may have premenstrual complaints but actually suffer from mood and anxiety
      symptoms across the entire menstrual cycle. We sought to determine the extent to
      which women who seek treatment for premenstrual syndrome (PMS) actually suffer
      from symptoms of sufficient severity and duration to meet formal criteria for
      mood or anxiety disorders. Two hundred six women who responded to advertisements
      for a treatment study of premenstrual dysphoric disorder (PMDD) and who were
      screened by telephone for study eligibility were included in the current
      investigation. A telephone questionnaire keyed to the Structured Clinical
      Interview for Diagnosis (SCID-I/P) was used to screen for the presence of current
      mood and anxiety disorders. Approximately 39% (n = 80) of respondents met
      criteria for mood or anxiety disorders or both. Mood disorders were noted almost
      twice as commonly as anxiety disorders. The high prevalence of mood disorders in
      the sample underscores the need for clinicians to be aware of the overlap between
      reported PMS symptoms and underlying depressive disorder. Given that early
      identification and treatment of mood disorder can increase the likelihood of
      recovery and lower risk for recurrent illness, clinicians should have a low
      threshold for ruling out mood and anxiety disorders in women with complaints of
      premenstrual symptoms.

PMID- 10595332
TI  - The association of behavior and lifestyle factors with menstrual symptoms.
AB  - The present study examines the association of obesity, cigarette smoking, alcohol
      consumption, and exercise with the prevalence of menstrual cycle disorders among
      2912 women aboard U.S. Navy ships. Self-administered surveys obtained information
      on weight, height, cigarette smoking, alcohol consumption, and exercise.
      Participants also indicated whether they experienced cramps or pain during their
      period requiring medication or time off work, bleeding between periods, excessive
      frequency of periods, heavy periods, periods lasting for longer than a week,
      scanty menstrual flow, and irregular periods during the past 90 days. Women
      ranged in age from 18 to 49 years, with an average of 26 years. After adjustment
      for age, race, and pay grade, current cigarette smoking was associated with
      increased risk of all menstrual symptoms and cycle disorders. As compared with
      nonsmokers, current smokers were at increased risk of cramps or pain requiring
      medication or time off work (odds ratio [OR] = 1.13, 95% confidence interval [CI]
      = 1.03, 1.25), bleeding between periods (OR = 1.22, CI = 1.09, 1.38), excessive
      frequency of periods (OR = 1.33, CI = 1.17, 1.51), heavy periods (OR = 1.17, CI =
      1.06, 1.29), periods lasting longer than a week (OR = 1.31, CI = 1.16, 1.48),
      scanty flow (OR = 1.13, CI = 1.01, 1.29), and irregular periods (OR = 1.14, CI =
      1.05, 1.24). Obesity, exercise, and alcohol consumption did not show consistent
      associations with menstrual symptoms or cycle disorders. Logistic regression
      models that included age, race, pay grade, and all behavioral and lifestyle
      variables indicated only cigarette smoking was associated with an increased risk
      of bleeding between periods (OR = 1.33, CI = 1.05, 1.68), excessive frequency of
      periods (OR = 1.38, CI = 1.21, 1.58), periods lasting longer than a week (OR =
      1.45, CI = 1.13, 1.84), and irregular periods (OR = 1.25, CI = 1.05, 1.47).
      Although the lifestyle factors are all potentially modifiable, results suggest
      that only interventions targeted at smoking cessation might be useful in reducing
      the prevalence of menstrual symptoms, cycle disorders, and time lost from work.

PMID- 10595333
TI  - Assessing the need for faculty development in women's health among internal
      medicine and family practice teaching faculty. The Women's Health Education
      Working Group (WHEWG).
AB  - Women's health education is an emerging interdisciplinary field that has recently
      received national attention. The American Board of Internal Medicine and the
      American Academy of Family Practice recently have published competencies in
      women's health for their residents, with increased attention to gynecological and
      mental health issues. Increasing women's health in the curricula of internal
      medicine (IM) and family practice (FP) residents will certainly require faculty
      development among IM and FP teaching faculty. We report a multiinstitution needs
      assessment among IM and FP teaching faculty for continuing medical education
      (CME) in multidisciplinary women's health topics. The survey (n = 100) asked
      whether faculty desired CME in 30 women's health topics. It also requested rates
      of referral to specialists for breast and menstrual problems and performance of
      tests commonly carried out in the care of women (e.g., endometrial biopsy,
      colposcopy, skin biopsy, and sigmoidoscopy) as measures of possible need for CME.
      Of the 69 respondents, 37% were IM physicians and 63% were FP physicians. Among
      the 30 women's health topics listed, breast cancer treatment alternatives,
      infertility for primary care providers, cervical dysplasia, medical treatment in
      pregnancy, vulvar disease, indications for pelvic ultrasound/endometrial biopsy,
      and menstrual disorders were of highest interest. The ranking of desirability of
      topics by IM and FP faculty correlated by .54 (Spearman rank, df = 28, p < 0.01).
      Analysis of variance revealed a significantly higher interest overall by IM than
      FP physicians, 58% vs. 42% (F = 4.1, df = 1, 50, p < 0.05). None of the IM
      teaching faculty performed endometrial biopsy or colposcopy compared with 57% of
      FP physicians, and only 12.5% of internists performed skin biopsy and
      sigmoidoscopy compared with 70% of FP physicians (F = 33, df = 1, 38, p < 0.001).
      We conclude that faculty development in women's health would benefit resident
      training in IM and FP, and topics of interest are identifiable. The correlation
      in interests between the IM and FP teaching faculty might make joint programs
      successful, although gynecological skills and knowledge clearly are needed more
      by IM teaching faculty. Obstetrics and gynecology (OB/GYN) faculty could be
      instrumental in improving women's health education among their IM and FP
      colleagues.

PMID- 10595334
TI  - The role of personal health concerns and knowledge of the health effects of
      hormone replacement therapy (HRT) on the ever use of HRT by menopausal women,
      aged 50-54 years.
AB  - Previous studies of factors important in a woman's decision to use hormone
      replacement therapy (HRT) infrequently have simultaneously considered the effects
      of personal concern for chronic medical disorders that begin at the time of the
      menopause (such as osteoporosis and heart disease) and knowledge of the
      beneficial and adverse effects of HRT on these conditions (increased risk of
      uterine and breast cancers). Moreover, few studies have been performed in broad
      based populations that have included black women. This study was undertaken to
      determine the cross-sectional association of concern for chronic medical
      disorders that begin at the time of the menopause and knowledge of the effects of
      HRT on these disorders on the ever use of HRT in a biracial cohort of
      postmenopausal women. Two hundred eight-eight women, aged 50-54 years, who were
      members of an HMO, who reported their last menstrual period to be more than 1
      year ago, and who were aware of HRT, were examined by questionnaire. Of the
      cohort, 21.2% were black. Concern for chronic medical disorders that begin at the
      time of the menopause was modest (approximately 50%). Knowledge of the effects of
      HRT on breast cancer, uterine cancer, and heart disease was low (approximately
      30%). Only for osteoporosis was knowledge high (approximately 65%). On adjusted
      analysis, concern for heart disease was weakly associated with ever use of HRT,
      but only for white women. The factors most strongly associated with initiating
      HRT were a doctor's recommendation to use HRT and satisfaction with a doctor's
      counseling. Having menopausal symptoms was associated with ever use of HRT in
      black women. Black women were only 30% as likely as white women to ever use HRT
      after adjustment for baseline differences. CONCLUSION: In this study, personal
      concerns for medical conditions that begin at the time of the menopause and
      knowledge of the effects of HRT on these conditions were low. Only personal
      concern for heart disease among white women was independently, but weakly,
      associated with ever use of HRT. Black women were less likely than white women to
      ever use HRT, even after adjustment for baseline differences between them.

PMID- 10595335
TI  - Women's Health Literature Watch.

PMID- 10595336
TI  - [Complications of cochlear implant surgery in children and adults].
AB  - BACKGROUND: In a retrospective analysis we evaluated the complication rate in 697
      patients after cochlear implantation between 1985 and 1995 (366 children, 331
      adults; 604 Nucleus, 50 Clarion and 42 other implants). RESULTS: Intraoperatively
      in 74 cases (10.6%) total or partial cochlear obliteration was found, a CSF
      gusher occurred in 7 cases. Minor complications such as seroma (8 adults), wound
      infections (14 patients), emphysema, and swelling were successfully treated with
      conservative methods and drugs. Seven (2.1%) adults showed facial nerve palsy
      postoperatively with incomplete recovery only in 2 of them (0.6%). No permanent
      facial nerve palsy was observed in children. Cholesteatoma developed in 18 adults
      (5.4%), which was treated by revision surgery. CONCLUSIONS: In conclusion,
      cochlear implant surgery is a safe procedure with a low complication rate.
      However, Cochlear implantation should be performed by well experienced ear
      surgeons who can properly handle intraoperative and postoperative problems. The
      patients should be informed about the typical risks of ear surgery including
      implant removal due to infection or technical defects, facial nerve palsy,
      vertigo and, especially in adults, increased tinnitus.

PMID- 10595337
TI  - [Surgical treatment of auditory canal exostoses].
AB  - BACKGROUND: Although complications of surgical removal of external auditory canal
      exostoses are rare, reported surgical complications include tympanic membrane
      perforation, postoperative hearing loss, canal stenosis, and facial nerve
      injuries. PATIENTS AND METHODS: We report on our experience in exostosis surgery,
      consisting of 59 procedures in 48 patients. Preoperative and postoperative
      complaints and findings, intraoperative complications, and audiologic results are
      described and discussed. There has been a minimum of one year of follow-up in
      every case. RESULTS: Postoperative canal stenosis was seen in 2 cases of
      preoperative severe persistent external otitis. Temporary threshold shift was
      recorded in 6 patients. Persistent sensorineural hearing loss occurred in 4
      patients. Six of the 10 patients with temporary or persistent hearing loss had
      already shown preoperative sensorineural hearing loss. Intraoperatively tympanic
      membrane perforation occurred in 3 cases, accidental opening of the mastoid in 1
      case. CONCLUSIONS: Exostosis surgery should be reserved for uninfected ear
      canals. Meatal skin preservation without circular meatal flap incision is
      recommended to avoid postoperative canal stenosis. Especially in cases of
      preexisting sensorineural hearing loss, attention should be focused on the
      intraoperative noise reduction by tympanic membrane protection and pauses of
      noise exposition.

PMID- 10595338
TI  - [Laryngeal manifestations in patients with Parkinson disease].
AB  - BACKGROUND: Impairments of articulation, respiration, and phonation are a common
      symptom of Parkinson's disease and may result in reduced communication. Previous
      observations have shown a high incidence of laryngeal abnormalities. However, no
      relevant data were available for gender differences of laryngeal abnormalities in
      Parkinson's disease. METHOD: Thirty-nine female and 61 male patients with
      Parkinson's disease were examined. The laryngeal function was explored by
      laryngoendoscopy and laryngostroboscopy in respiration and production of [i:]
      during normal pitch and normal loudness. RESULTS: Abnormal function of vocal cord
      abduction and adduction were observed in 54% of the women and 39% of the men;
      more patients had reduced abduction. Bilateral vocal fold atrophy was seen in 36%
      of the women and 56% of the men, while 41% of the women and 57% of the men had a
      bilateral hypertrophy ventricular fold. Phase closure incompetence was found in
      60.5% of the women and 49% of the men. Abnormal amplitude and mucosal waveform
      were seen in more male patients, while 30.7% of the women and 25% of the men had
      a laryngeal tremor. Gender differences were observed with respect to common
      laryngeal symptoms. CONCLUSION: This study concludes that laryngeal abnormalities
      in Parkinson's disease show a high degree of gender differences. The percentage
      of patients with abnormal abduction of the vocal cord was higher than has been
      reported in other studies. Vocal-fold bowing appear to be related to vocal fold
      atrophy. Although patients with Parkinson's disease frequently exhibit vocal fold
      atrophy, other mechanisms and causes should be discussed. Patients with tremor
      and common laryngeal symptoms were observed. These findings were not expected and
      further studies of this phenomena would be useful.

PMID- 10595339
TI  - [Possible one-dimensional determination of cortical representative fields of
      mimetic lower lip muscles by transcranial magnetic stimulation].
AB  - BACKGROUND: Recent reports as well as results from animal studies indicate
      changes of cortical organization in patients with facial palsy with a decrease in
      size of the face-associated cortical representation area. With regard to these
      alterations, there are no detailed reports in the literature about the
      possibility of a cortical mapping of mimetic muscles by TMS. METHOD: In 21
      healthy volunteers we investigated the amplitude and the onset latency of motor
      evoked potentials (MEPs) from the depressor anguli oris and depressor labii
      inferioris muscles during cortical transcranial magnetic stimulation by use of a
      figure-8-shaped coil (double 70 mm coil) as a function of the scalp positions
      stimulated in order to establish a reproducible representation area along the
      interaural line. RESULTS: Cortical evoked MEPs characterized by onset latencies
      of 6-30 ms were elicited by contralateral and ipsilateral stimulation from coil
      positions between 4 and 13 cm lateral to the vertex. Maximal responses (mean
      amplitude 1.5 +/- 0.8 mV contralateral, 0.8 +/- 0.5 mV ipsilateral) with shortest
      mean onset latencies (11.5 +/- 1.5 ms contralateral, 12.2 +/- 2.8 ms ipsilatral)
      were observed at a coil position of 10 cm latral to the vertex. CONCLUSION: TMS
      offers a noninvasive method of one dimensional quantification of the cortical
      representation area of lower lip mimetic muscles.

PMID- 10595340
TI  - [Rapidly progressing course of cutaneous angiosarcoma in the area of the head
      neck].
AB  - INTRODUCTION: Angiosarcomas are rare, aggressive tumors of vascular origin, most
      commonly affecting older males. An optimum treatment strategy has not yet been
      defined. CASE REPORT: We report on a 68-year-old male patient who initially
      presented with a small, bruise-like macule of the cheek. He was treated with
      different antibiotics and steroids for a few weeks. Due to failure of any
      clinical improvement, a biopsy was taken revealing an undifferentiated malignant
      tumor. Subsequently, the patient was referred to our department, where the lesion
      was excised. Histology showed an extensive, well-differentiated angiosarcoma.
      According to oncological protocols, the patient underwent 5 cycles of
      chemotherapy with etoposid, ifosphamid and adriamycine. Despite therapy, tumor
      size remained unchanged. After therapy was discontinued, tumor growth rapidly
      proceeded with semicircular infiltration of the right face and neck. A few weeks
      later the patient died. DISCUSSION: About 50 percent of cutaneous angiosarcomas
      are found in the head and neck region of the elderly. No clear etiology has been
      implicated with respect to the origin of this tumor. Traumatic bruises,
      infections, and allergic reaction may be confused clinically with angiosarcoma.
      Differential diagnosis also comprises other vascular neoplastic diseases, i.e.
      lymphangioma, hemangiopericytoma and Kaposi's sarcoma. If complete excision is
      possible, radical surgery is the treatment of choice. The effectiveness of
      chemotherapy is unclear. The role of radiation therapy is also under discussion
      due to the technical problems of administering radiotherapy to the extensive
      volume at risk. As the late diagnosis adversely affects the prognosis, the
      importance of early biopsy in suspicious lesions is mandatory.

PMID- 10595341
TI  - [Value of B-image ultrasound in patients with carcinomas of the upper
      aerodigestive tract and N0 lymph node stage].
AB  - BACKGROUND: The wait-and-see policy in patients with a N0 neck stage is not
      common. PATIENTS AND METHOD: One hundred twenty-one patients with a pT1 or pT2
      carcinoma of the upper aerodigestive tract and a N0 neck stage in ultrasound
      studies underwent transoral laser microsurgery without neck dissection or
      radiation therapy. In these patients the probability of survival and local or
      regionals recurrence were analyzed in a follow-up period of 18 to 36 months.
      RESULTS: Thirty patients in whom cervical lymph nodes were detected in ultrasound
      studies, underwent a curative neck dissection procedure. In 8 of these 30
      patients, lymph node metastases were histologically demonstrated, and 6 patients
      showed a local recurrence. The probability of survival was 1.0 and the
      probability of being free of local or regional recurrence was between 0.95 and
      0.6 depending on the tumor location. CONCLUSIONS: A wait-and-see policy will not
      necessarily alter the prognosis, which depends on the location of the tumor.
      Ultrasound follow-up studies should be performed at regular intervals.

PMID- 10595342
TI  - [Ultrasound evaluation of characteristics of cervical lymph nodes with special
      reference to color Doppler ultrasound. A contribution to differentiating reactive
      from metastatic lymph node involvement in the neck].
AB  - BACKGROUND: Cervical mass due to lymphadenopathy is a common cause for
      consultation of an ENT specialist by patients. In many cases exact
      differentiation without biopsy between reactive and metastatic lymphnodes is
      difficult but crucial and necessary for each patient. Ultrasound is the imaging
      system with the highest sensitivity for the evaluation of pathological lymph
      nodes. However, differentiating benign and malignant lesions remains a problem.
      PATIENTS: In a prospective study, 138 cervical lymph nodes of 62 patients were
      evaluated according to conventional ultrasound criteria such as size, shape,
      brightness, demarcation, etc., and according to parameters of color doppler
      sonography such as intensity and localization of perfusion. The so called
      Pourcelot or resistance index, an objective parameter, was measured in order to
      examine a possible improvement of specificity in differential diagnosis of both
      entities. All lymph nodes were surgically removed and histologically examined
      after ultrasonography. RESULTS: 133 lymph nodes were evaluated in the study.
      Lymphadenitis was demonstrated in 72 cases, whereas 61 of the lumps showed
      metastases of squamous cell carcinoma of the head and neck region. Three patients
      with primary malignant lymphoma were excluded from the study. The conventional
      ultrasound parameters such as size, homogenity, shape and brightness did not
      reveal any substantial difference between the two groups. However, lymph node
      metastases significantly showed higher Doppler signals than the reactive ones.
      Most of the metastases were perfused in the periphery or had a diffuse spread of
      blood flow. The most valuable parameter from the prognostical point of view
      proved to be the Pourcelot Index with a threshold value less than 0.6 for
      metastases, which increased the specificity to 92% with a probability of p =
      0.001. CONCLUSIONS: The results of this study demonstrate an increase of the
      ultrasound specificity in differentiation of pathological cervical lymph nodes
      using color flow imaging. Unfortunately, this method does not enable the
      physician to correctly diagnose the findings in all patients. Therefore
      histological evaluation is mandatory in all doubtful cases.

PMID- 10595344
TI  - [A punch for enlarging the frontal ostium].
AB  - BACKGROUND: The opening of the frontal sinus represents a challenge in primary
      and revision surgery of the paranasal sinuses. RESULTS: Newly developed frontal
      sinus punches were used in 35 cases of primary or secondary surgery of the
      frontal sinus, with a post operative follow-up period of up to 18 months. So far,
      the results are promising. CONCLUSIONS: Forward-cutting angled punches adapted to
      the anterior skull base have been developed to reduce the risk of trauma to
      mucosal structures when broadly exposing the frontal sinus through an anterior
      approach.

PMID- 10595345
TI  - [Interesting case no. 29. Schwannoma without signs of malignancy].

PMID- 10595343
TI  - [Clinical significance of allergic reactions in glucocorticoid therapy].
AB  - BACKGROUND: Glucocorticoids are widely used in medicine. Within the last few
      years, however, patients have become very suspicious of corticoids. The attending
      physicians frequently has to use a great deal of persuasion prior to applying
      this very effective and often indispensable group of medication. PATIENTS: We
      report on four patients who developed allergic reactions (i.e. erythema in face
      and on body, itching, flushing, drop in blood pressure, respiratory distress,
      cold sweats, etc.) immediately after intravenous administration of prednisolone
      21 hydrogen succinate (Solu-Decortin H, SDH). RESULTS: Three out of four patients
      had a positive reaction to an intracutaneous test with SDH, but no reaction to
      the additive sodium succinate. The prick test was negative in all patients. No
      specific IgE antibodies were detected in the serum of these patients. However
      allergic reaction to SDH must be presumed in at least three cases as it is
      difficult to detect glucocorticoid antibodies in serum and standardizes
      techniques are lacking. One female patient had a cross-reaction to prednisolon
      and dexamethasone. A renewed application of SDH was tolerated well by all
      patients when H1- and H2-receptors were blocked and calcium was administered to
      stabilize membranes. CONCLUSIONS: Allergic reactions after glucocorticosteroid
      therapy are only occasionally mentioned in literature, appear more often when the
      agent is applied topically, and may lead to dangerous complications in patients
      if administered intravenously. Therefore, when allergic reactions result from
      glucocorticoid therapy (immediate reactions should be suspect), corticosteroid
      allergy should be considered as a differential diagnosis.

PMID- 10595346
TI  - [Surgery of malignant and benign diseases of the hypopharynx. II].

PMID- 10595347
TI  - Progress in antisense technology: the end of the beginning.

PMID- 10595348
TI  - Basic principles of using antisense oligonucleotides in vivo.

PMID- 10595349
TI  - Polyethyleneimine-mediated transfection to improve antisense activity of 3'
      capped phosphodiester oligonucleotides.

PMID- 10595350
TI  - Design of antisense and triplex-forming oligonucleotides.

PMID- 10595351
TI  - Chimeric oligodeoxynucleotide analogs: chemical synthesis, purification, and
      molecular and cellular biology protocols.

PMID- 10595352
TI  - Evaluation of antisense mechanisms of action.

PMID- 10595353
TI  - Physiology and molecular biology brought to single-cell level.

PMID- 10595354
TI  - Antisense properties of peptide nucleic acid.

PMID- 10595355
TI  - Synthesis of oligonucleotide conjugates in anhydrous dimethyl sulfoxide.

PMID- 10595356
TI  - Gene switching: analyzing a broad range of mutations using steric block antisense
      oligonucleotides.

PMID- 10595357
TI  - Vesicular stomatitis virus as model system for studies of antisense
      oligonucleotide translation arrest.

PMID- 10595358
TI  - Purification of antisense oligonucleotides.
AB  - Chromatography is an effective tool for obtaining high-purity synthetic
      oligonucleotides for a variety of end uses, including antisense drug therapy.
      Reversed-phase and anion-exchange chromatographies are widely used techniques for
      this application. While selectivity of these techniques can be modified by
      methods such as ion-pair RP-HPLC or affinity chromatography, these are presently
      used only at small scales. RP chromatography makes use of terminal hydrophobic
      protecting groups to increase retention and selectivity. The main advantages of
      the RP method are its utility for the purification of a wide variety of modified
      oligonucleotide structures, its applicability across a range of terminal
      hydrophobic groups, such as fluorescein, and its ready use from small scale to
      very large scale with a minimal requirement for process development. AX-HPLC can
      also give high-purity products at generally higher media capacities. A more
      extensive method development effort is typically required for the AX-HPLC
      purification of AO. The AX yield per unit operation can be lower, but the
      isolated yield of DMT-off desalted oligonucleotide can be equal to or higher than
      that from RP-HPLC. As additional AO drugs enter and mature in the market, there
      will be a potential need for ton-scale purification processes. AX provides a way
      to scale up production on somewhat less expensive equipment with reduced organic
      solvent requirements.

PMID- 10595359
TI  - Boranophosphate backbone: a mimic of phosphodiesters, phosphorothioates, and
      methyl phosphonates.
AB  - Nucleoside boranophosphates are distinctive in that one of the non-bridging
      oxygens in the phosphate diester 1 is replaced by a borane moiety (BH3). Although
      they retain the same net charge, BH3(-)-ODN have unique chemical and biochemical
      characteristics relative to other analogs. The change in polarity, lipophilicity,
      nuclease resistance, and the activation of RNase H cleavage of RNA in RNA:
      boranophosphate hybrids make boranophosphates very attractive for applications in
      enzymology and molecular biology and as potential antisense agents.

PMID- 10595360
TI  - Intracellular distribution of digoxigenin-labeled phosphorothioate
      oligonucleotides.

PMID- 10595361
TI  - Use of minimally modified antisense oligonucleotides for specific inhibition of
      gene expression.

PMID- 10595362
TI  - Determination of cellular internalization of fluoresceinated oligonucleotides.

PMID- 10595363
TI  - Intrabody tissue-specific delivery of antisense conjugates in animals: ligand
      linker-antisense oligomer conjugates.

PMID- 10595364
TI  - Lipid-based formulations of antisense oligonucleotides for systemic delivery
      applications.

PMID- 10595365
TI  - In vitro transport and delivery of antisense oligonucleotides.
AB  - A variety of techniques are currently available to enhance the cellular uptake
      and pharmacological effectiveness of antisense oligonucleotides in the in vitro
      setting. The choice of technique will depend on the context of investigation, the
      likelihood of cytotoxity due to the delivery agents, and the ease and convenience
      of the approach. The considerations for the delivery of antisense molecules in
      the in vivo setting are likely to be quite different from the cell culture
      situation emphasized in this article.

PMID- 10595366
TI  - In vitro and in vivo delivery of antisense oligodeoxynucleotides using
      lipofection: application of antisense technique to growth suppression of
      experimental glioma.

PMID- 10595368
TI  - Cell-specific optimization of phosphorothioate antisense oligodeoxynucleotide
      delivery by cationic lipids.

PMID- 10595367
TI  - Preparation and application of liposome-incorporated oligodeoxynucleotides.

PMID- 10595369
TI  - Intracellular expression and function of antisense catalytic RNAs.

PMID- 10595370
TI  - Selective degradation of targeted mRNAs using partially modified
      oligonucleotides.

PMID- 10595371
TI  - Reversible depletion of specific RNAs by antisense oligodeoxynucleotide-targeted
      degradation in frog oocytes.

PMID- 10595372
TI  - Inactivation of gene expression using ribonuclease P and external guide
      sequences.

PMID- 10595373
TI  - Disruption of mRNA-RNP formation and sorting to dendritic synapses by antisense
      oligodeoxynucleotides.

PMID- 10595374
TI  - Antisense RNA and DNA in Escherichia coli.

PMID- 10595375
TI  - Utilization of properties of natural catalytic RNA to design and synthesize
      functional ribozymes.

PMID- 10595376
TI  - Antisense oligonucleotides and RNAs as modulators of pre-mRNA splicing.

PMID- 10595377
TI  - Selective RNA cleavage by isolated RNase L activated with 2-5A antisense chimeric
      oligonucleotides.

PMID- 10595378
TI  - To stent or not to stent.
AB  - Coronary artery stenting has definitely been proven to improve results of
      percutaneous revascularisation in a large number of patients. Stenting reduces
      restenosis in large vessels above 3 mm diameter. Stenting has not solved the
      problem of restenosis but in spite of the inevitable in-stent restenosis due to
      neointimal proliferation seems to yield better long-term results than
      conventional PTCA. Adjunctive pharmacological treatment with aspirin and
      clopidogrel in combination with improved stent deployment techniques has reduced
      the incidence of subacute stent thrombosis. GP IIb/IIIa inhibition is a promising
      mean for the reduction of procedure related ischaemic events and complications
      not only with stent implantation but also with conventional PTCA. Other new
      devices may further influence the treatment choices of stenting versus
      conventional PTCA in the future. Novel approaches such as brachytherapy and
      molecular genetic approaches to reduce in-stent restenosis are currently being
      investigated but to date no conclusions can be drawn as to their future place in
      clinical practice. From a mechanistic standpoint it seems obvious to give all our
      efforts to protect patients with coronary atherosclerosis from loss of myocardium
      either with coronary artery bypass grafting or percutaneous revascularisation. As
      both approaches are palliative in nature, it may be useful to attempt
      percutaneous revascularisation in patients amenable to this therapy and thus
      obviate or delay the need for definitive revascularisation by coronary artery
      bypass grafting. At the end of this discussion we would like to remind that
      medical therapy for coronary artery disease is of utmost importance as all
      revascularisation procedures do not influence the underlying disease. Besides
      symptomatic relief of angina, treatment of heart failure, and other beneficial
      strategies to improve endothelial function, medical therapy with lipid lowering
      compounds together with risk factor control offers the possibility to delay
      progression of coronary artery disease.

PMID- 10595379
TI  - Dialogue with a patient with coronary artery disease.
AB  - A fictive dialogue between an internist and a patient with acute myocardial
      infarction is used to highlight the role of drug therapy in coronary artery
      disease.

PMID- 10595380
TI  - Medical economic considerations of coronary stenting.
AB  - Elective coronary stenting has been shown to reduce restenosis and improve
      clinical outcomes compared with balloon angioplasty. Despite the availability of
      numerous large-scale randomised and controlled clinical trials, few economic
      appraisals have been performed and reported. The majority of these were conducted
      in the US. Nonetheless, early studies have suggested that medical care costs
      remain higher with stenting, in part due to the prolonged length of stay and
      frequent vascular complications related to early periprocedural anticoagulation
      regimens. Recent long-term follow-up studies have demonstrated that initial costs
      are often recovered by avoiding complications. Some studies mainly built on
      modelling techniques even suggest that stenting is more cost-effective than
      balloon angioplasty, chiefly in single-vessel disease. If advances in newer
      stenting techniques can be confirmed by large randomised controlled studies, the
      additional procedural costs and health care resource consumption might be even
      more justified. This paper reviews and summarises the major economic evaluations
      comparing intracoronary stenting and angioplasty.

PMID- 10595381
TI  - [Vascular endothelial cells: an interesting immunological barrier].

PMID- 10595382
TI  - [Medical ethics directives concerning somatic gene therapy applied to human
      beings. Swiss Academy of Medical Sciences (ASSM)].

PMID- 10595383
TI  - Balanced type of double aortic arch.

PMID- 10595384
TI  - [Ultrasound screening of malformations in pregnancy--a high forensic risk?].

PMID- 10595385
TI  - [Prenatal diagnosis of heart defects and associated chromosomal aberrations].
AB  - AIM: According to epidemiological studies on newborns, the association of
      congenital heart defects with chromosomal anomalies varies between 4 and 12%.
      Prenatally this rate is probably higher, due to antenatal death occurring in
      fetuses with chromosomal aberrations. The aim of the study was therefore to
      determine the rate and the distribution of chromosomal aberrations in prenatally
      detected heart defects. PATIENTS AND METHOD: Within a period of 7 years fetal
      echocardiography was performed on 2716 fetuses at high risk for CHD. The analysis
      of the fetal heart was achieved by the visualization of different planes. Once a
      heart defect was detected, karyotyping was performed after amniocentesis,
      cordocentesis or chorion villous sampling, or in a few cases postnatally from
      cord blood. Prenatal ultrasound findings were confirmed postnatally by ultrasound
      examination or, in case of abortion, stillbirth or neonatal death, by autopsy.
      RESULTS: A total of 203 fetal heart malformations were detected and 46 of them
      (22%) had associated chromosomal anomalies. 60% of all cases and 80% of the study
      group had extracardiac anomalies. Only eight out of the 46 pregnant women (17.5%)
      were older than 35 years. Eight out of the 15 fetuses with trisomy 18 had a
      ventricular septal defect, 9/13 fetuses with trisomy 21 had an atrioventricular
      septal defect and all 5 fetuses with monosomy X had a left heart outflow
      obstruction. No typical cardiac defects were found in the remaining 13 fetuses (5
      trisomy 13, 2 triploidies, 6 miscellaneous). Of the 13 live births (23
      terminations of pregnancy and 10 intrauterine deaths) 6 children survived (46%
      and overall survival rate 13%). The following rates of associations with
      aneuploidies were found: atrioventricular septal defect 55%, ventricular septal
      defect and aortic coaction both 43%, tetralogy of Fallot and double outlet right
      ventricle both 36%. In comparison, fetuses with isomerism, transposition of the
      great arteries and pulmonary atresia or stenosis had normal chromosomes.
      CONCLUSION: We conclude that the rate of association of heart defects and
      chromosomal abnormalities is higher prenatally than in the neonatal period and is
      approximately 22%. After detecting a fetal cardiac malformation, karyotyping is
      mandatory for the further management of pregnancy. The likelihood of detection of
      an aneuploidy increases when some typical heart defects are detected or when an
      association with extracardiac anomalies is found.

PMID- 10595386
TI  - [Improved assessment of the left ventricular endocardial border by intravenous
      injection of a left heart contrast agent].
AB  - PURPOSE: The purpose of this study was to find out whether intravenous injection
      of a phospholipid-based left heart echo contrast agent improves the delineation
      of the left ventricular endocardial border. The influence of echo contrast on the
      quantification of left ventricular volumes, ejection fraction, regional wall
      function and interobserver variability was also assessed. METHOD: Prospectively,
      the apical 4-chamber view was recorded in 20 adult patients before and after
      intravenous injection of the contrast agent. Left ventricular endocardial border
      resolution was assessed in 5 segments and left ventricular volumes, ejection
      fraction, regional wall motion and interobserver variability were measured.
      RESULTS: After contrast injection a diagnostically useful left ventricular
      opacification was present in 18 patients (90%) and an optimal opacification in 14
      patients (70%). Without contrast 1.05 endocardial segments could be delineated at
      end diastole and 1.8 segments at end systole. After contrast injection 3.65
      endocardial segments were recognizable at end diastole (p < 0.01), 2.5 segments
      at end systole (p < 0.02). Left heart contrast improves interobserver-variability
      of end diastolic volume (p < 0.006), end systolic volume (p < 0.004), ejection
      fraction (p < 0.0002) and regional wall motion assessment (p < 0.03). Side
      effects did not occur. CONCLUSIONS: The intravenous injection of the investigated
      phospholipid-based echo contrast agent improves left ventricular endocardial
      border delineation and reproducibility of left ventricular volumes, ejection
      fraction and regional wall motion assessment.

PMID- 10595387
TI  - [Duplex ultrasonography-controlled Nd:Yag laser therapy of vascular
      malformations].
AB  - AIM: Vascular malformations can be studied in detail by colour Doppler
      sonography. These lesions are best treated by Nd:YAG laser therapy. The aim of
      the study was to improve the quality of therapy by the use of colour Doppler
      sonography guided Nd-YAG laser application. PATIENTS AND METHOD: 17 vascular
      malformations/haemangiomas in 16 patients were treated by colour Doppler
      sonography guided Nd:YAG laser therapy. 5 children were less than one year of
      age, 4 children were between one and five years of age, the other patients were
      adults (age 22-57 years). The size of the vascular malformations (largest
      diameter) were 1.5-3 cm (8 cases), all others were larger than 3 cm. RESULTS:
      When using laser therapy in combination with colour Doppler sonography it is
      possible to adjust the treatment variables (dose, duration and energy of the
      laser pulse as well as the precise intralesional positioning) individually. As a
      result more than 80% of cases can be treated successfully during a single
      session. Larger lesions may be divided into functional units which can be treated
      subsequently. CONCLUSION: Through colour Doppler sonography it is possible to
      monitor the effects of laser treatment in vascular malformations. The development
      of smaller ultrasound probes has facilitated the application of laser therapy
      guided by Doppler sonography in the region of the head and neck. Colour Doppler
      sonography guided laser therapy increases efficiency and selectivity of the laser
      treatment. Early interventions prevent growth of the lesions and reduce long-term
      disfigurement particularly in children.

PMID- 10595388
TI  - [Preoperative sonographic diagnosis of melanoma--comparison of 7.5- and 20-MHz
      sonography].
AB  - AIM: High-frequency sonography has become extremely helpful for the preoperative
      assessment of malignant melanoma. The purpose of this study was to compare the
      preoperative vertical tumour thickness as assessed by 7.5 MHz as well as 20 MHz
      ultrasound probes to the postoperative tumour thickness as determined
      histomorphometrically. METHODS: 249 patients with malignant melanoma were studied
      using a conventional 7.5 MHz ultrasound machine (since 1987) or a high-frequency
      20 MHz ultrasound imaging system (since 1991). RESULTS: The correspondence of the
      sonographically assessed tumour thickness with the thickness assessed by
      histomorphometry was significantly better for high-frequency sonography (r =
      0.94) as compared to conventional sonography (r = 0.76). For stages pT3 and pT4,
      however, this difference was not significant. CONCLUSION: Based on these data,
      high-frequency sonography should be given preference in the preoperative
      assessment of malignant melanoma over conventional 7.5 MHz ultrasound. However,
      for stages pT3 and pT4 both methods offer similarly reliable results.

PMID- 10595389
TI  - [Sonographic course of systemic echinococcosis in a 10 year old girl (with
      cardiac, hepatic, renal and muscular involvement)].
AB  - PURPOSE: To present the predominantly ultrasonographic (initial and follow-up)
      imaging in a disease that is rare among the Central European paediatric
      population--and to evaluate the role of ultrasound for initial staging and follow
      up under antihelmintic therapy. METHOD: The imaging documents as well as the
      clinical record of a 10-year old Armenian girl with systemic hydatid disease
      (cystic echinococcosis) were analysed retrospectively. RESULTS: By means of
      ultrasound, the complete initial systemic spread of the disease with at least 11
      cysts within the liver, 1 cyst in the left kidney, 1 peri-/2 intracardiac cysts,
      and 1 cyst in the dorsal musculature was detected. Repeated sonographic
      examinations allowed the estimation of successful medical treatment by the
      following criteria: size reduction of all cysts with changing internal structures
      from an initially echo-free to an increasingly homogeneous echodense character;
      no developing new cysts. In addition, CT and MRI enabled a more complete
      demonstration of especially the intra- and pericardiac lesions (preoperatively)
      and the exclusion of further intracranial cysts. CONCLUSION: In paediatric
      hydatid disease, ultrasonography yields important information not only with
      regard to the initial staging, but also to the antihelmintic therapeutic effects
      and thus helps to determine when to discontinue medical treatment.

PMID- 10595390
TI  - [Epignathus: prenatal diagnosis by sonography and magnetic resonance imaging].
AB  - Prenatal diagnosis of a teratoma of the oral cavity (epignathus) is presented
      using ultrasonography and magnetic resonance imaging as complementary techniques.
      Chromosome analysis from amniotic fluid revealed an inverted duplication of
      chromosome 1 that was confined to the tumour, whereas the constitutional
      karyotype was normal. The development of polyhydramnios, presumably reflecting
      impaired fetal swallowing, led to premature rupture of membranes and spontaneous
      delivery at 23 + 4 weeks of pregnancy. The premature neonate succumbed to acute
      respiratory distress secondary to airway obstruction by the tumour, and died
      immediately after birth.

PMID- 10595391
TI  - [Third-party risks in prenatal diagnosis].

PMID- 10595392
TI  - Aneurysmal portosystemic venous shunt: a case report.
AB  - A case of an aneurysmal portosystemic venous shunt detected by colour Doppler
      ultrasound (CDUS) is presented. A young female patient complained of postprandial
      fatigue and had paroxysmal tachycardia. A direct vascular communication between
      right portal vein and right hepatic vein was found at CDUS and confirmed by
      direct portal angiogram. Using detachable coils a complete occlusion of the
      intrahepatic shunt was obtained. Reports from the literature regarding
      portovenous aneurysms are reviewed.

PMID- 10595393
TI  - [Sonographic diagnosis of metastatic renal cell carcinoma to the head and neck
      region].
AB  - In the area of the head and neck metastases from distant primary tumours are rare
      in comparison to the common squamous cell carcinomas of the upper respiratory and
      digestive tract. Thus correct preoperative diagnosis may be difficult. Two cases
      with distant metastases of renal cell carcinoma to the head and neck region are
      presented in this report. In a 60-year-old male patient, diagnostic evaluation of
      unilateral epistaxis revealed a radioopacity of the maxillary sinus, six months
      after removal of a renal cell carcinoma. In the second case a slowly progressive
      indolent swelling of the left neck developed in a 56-year-old man six years after
      resection of a renal cell carcinoma and two years after surgical treatment of a
      pancreatic carcinoma. Following clinical examination, modern imaging techniques
      with special emphasis on colour Doppler sonography with a Siemens Quantum 2000
      were used for diagnostic evaluation in both patients. Sonography of metastatic
      renal cell carcinoma to the maxillary sinus revealed complete opacity of the
      antrum. The cervical mass proved to the inhomogeneous and hypoechogenic and was
      difficult to distinguish from the lower parotid lobe and the vessel sheath. A
      common feature of both tumours was a high degree of perfusion which could be
      confirmed by superselective angiography. The histological examination of the
      surgical specimen showed an isolated metastasis of a renal cell carcinoma in both
      cases. In patients with a history of renal cell carcinoma the possibility of
      distant spread to the head and neck region should be taken into account even
      after a long period of complete remission. Colour Doppler sonography facilitates
      the distinction between the normally well perfused secondary tumours and squamous
      cell carcinomas which usually only have a minimal blood supply. Because of the
      high risk of profuse bleeding a biopsy should only be performed in the operating
      theatre.

PMID- 10595394
TI  - The gammaPE complex contains both SATB1 and HOXB2 and has positive and negative
      roles in human gamma-globin gene regulation.
AB  - A large nuclear protein complex, termed gammaPE (for gamma-globin promoter and
      enhancer binding factor), binds to five sites located 5' and 3' of the human y
      globin gene. Two proteins, SATB1 (special A-T-rich binding protein 1) and HOXB2,
      can bind to yPE binding sites. SATB1 binds to nuclear matrix-attachment sites,
      and HOXB2 is a homeodomain protein important in neural development that is also
      expressed during erythropoiesis. The present work showed that antisera directed
      against either SATB1 or HOXB2 reacted specifically with the entire gammaPE
      complex in electrophoretic mobility shift assays (EMSAs), suggesting that the two
      proteins can bind to the gammaPE binding site simultaneously. When SATB1 or HOXB2
      was expressed in vitro, they could bind independently to gammaPE binding sites in
      EMSA. Interestingly, the proteins expressed in vitro competed effectively with
      each other for the gammaPE binding site, suggesting that this may occur under
      certain conditions in vivo. Transient cotransfections of a HOXB2 cDNA and a y
      globin-luciferase reporter gene construct into cells expressing SATB1 suggested
      that SATB1 has a positive and HOXB2 a negative regulatory effect on
      transcription. Taking into account their potentially opposing effects and binding
      activities, SATB1 and HOXB2 may modulate the amount of gamma-globin mRNA
      expressed during development and differentiation.

PMID- 10595395
TI  - The synthetic CD4 exocyclic CDR3.AME(82-89) inhibits NF-kappaB nuclear
      translocation, HIV-1 promoter activation, and viral gene expression.
AB  - We have previously shown that the synthetic aromatically modified exocyclic (AME)
      analog (CDR3.AME(82-89), derived from the CDR3 (residues 82-89) region of CD4
      domain 1, inhibits replication of human immunodeficiency virus type 1 (HIV-1) in
      infected cells. In this work, we investigated the mechanism by which this
      inhibition is achieved. Although cells exposed to HIV-1 and treated with the
      CDR3.AME(82-89) peptide did not release viral particles for more than a week and
      kept surface expression of CD4, viral DNA was found in those cells 24 h after
      virus exposure, indicating that the CDR3.AME(82-89) analog does not prevent virus
      entry. However, virus transcription remained extremely low in infected cells, as
      demonstrated by the study of spliced HIV-1 mRNA in cultures treated with
      CDR3.AME(82-89) 72 h postinfection. Finally, the CDR3.AME(82-89) peptide was
      found to be a potent inhibitor of HIV-1 promoter activity and nuclear factor
      kappaB translocation, indicating that the antiviral property of this peptide is,
      at least in part, linked with the ability of the molecule to prevent HIV-1
      transcription.

PMID- 10595396
TI  - Application of an improved cDNA competition technique to identify prostate cancer
      associated gene.
AB  - A technique to improve cDNA library screening was developed by using mixed probes
      derived from two closely related cDNA populations of high-metastatic MAT-LyLu and
      low-metastatic AT-1 Dunning R3227 rat prostate cancer sublines. The technique
      required the generation of a cDNA library from each subline followed by
      polymerase chain reaction (PCR) amplification of the cDNA insert population. The
      PCR products derived from the first library were radiolabeled and mixed with an
      excess amount of PCR products from the second library. The mixture and an excess
      amount of both the lambda and pBluescript DNA were used as a probe to screen the
      first cDNA library. This mixed probe (designated the competition probe)
      differentially cross-hybridized with the plaque lift of the screened first cDNA
      library. Weak radioactive signals indicated the cross-hybridization of cDNA
      sequences common to the competition probe mixture and the first cDNA library,
      whereas strong signals implied unhybridized unique or abundant cDNA sequences in
      the first cDNA library. The reproducibility of this technique was confirmed by
      showing that the full-length cDNA clones were associated with the phenotype of
      the screened first cell line. The isolated clones were characterized as rat
      nucleolar protein, rat mitochondrial genes coding for 16S and 12S rRNAs, and rat
      tRNAs specific for valine and phenyl-alanine. This result is consistent with the
      fact that the first cell line, MAT-LyLu, is metabolically more active than are AT
      1 cells because of higher gene dosage or amplification of nucleolar and
      mitochondrial RNA and its associated genes. Another clone which had a strong
      signal represented a novel gene associated with the MAT-LyLu cancer phenotype.

PMID- 10595397
TI  - Infection with vaccinia virus alters regulation of cell cycle progression.
AB  - The effect of vaccinia virus (VV) on cell cycle progression and its regulators
      was studied. Infected cultures showed significantly increased transit through G1,
      decreasing the percentage of cells in G1 and increasing the percentage in S
      phase. The numbers of cells in G2/M were not affected. Because of the increased S
      phase fraction at the expense of G1, expression of cyclins and cyclin-dependent
      kinases (Cdks) that regulate cell cycle checkpoints was examined. Transcripts for
      cyclins A and B, Cdk2, and Cdc2 were decreased in VV-infected cells as infection
      progressed. The amounts of p53 and p27 proteins decreased after 12 and 24 h of
      infection, respectively. The Cdc2 and Cdk2 protein levels were decreased with
      increasing time after infection. Taken together, these findings would be expected
      to lead to more cells in S phase and G2/M, as was observed. Therefore, VV
      actively modulates expression of cellular regulators of the cell cycle and alters
      cell cycle progression.

PMID- 10595398
TI  - Expression and characterization of bioactive human thrombopoietin in the milk of
      transgenic mice.
AB  - Human thrombopoietin (hTPO) is the primary physiological regulator of platelet
      production and plays a pivotal role in promoting the proliferation and maturation
      of megakaryocytic progenitor cells and megakaryocytes. In this study, transgenic
      mice were produced harboring either full-length or the erythropoietin (EPO)-like
      amino-terminal domain of hTPO cDNA sequences fused to the regulatory elements of
      the bovine beta-casein gene. The transgene RNA was expressed exclusively in the
      mammary glands of eight transgenic mice, and a trace amount of the transgene was
      also found in the lungs of one mouse. The full-length form induced efficient
      expression of the protein with the highest expression level of 1500 microg/ml;
      however, the EPO-like domain alone expressed the protein at <0.1 microg/ml. The
      proteins from the two recombinant cDNAs have apparent molecular weights of about
      74 and 17 kDa, due to glycosylation in the case of the full-length cDNA. Cell
      proliferation assay in vitro indicated that both of the recombinant forms
      stimulated proliferation of the TPO-dependent BaF3-Mpl cells. A positive
      correlation appeared between the amount of TPO in the milk of lactating animals
      and their blood platelet levels. About a twofold increase in platelet numbers in
      the blood was observed after direct subcutaneous injection of the recombinant
      hTPO at the level of 30 microg/kg of body weight. On the basis of these results,
      we anticipate that the recombinant hTPO produced efficiently in milk of
      transgenic mice will have the same activities as the native hTPO in a few in vivo
      as well as in vitro biochemical aspects.

PMID- 10595399
TI  - Calnexin from Pisum sativum: cloning of the cDNA and characterization of the
      encoded protein.
AB  - A full-length cDNA of 1951 bp encoding a calnexin (CNX) protein was cloned from a
      Pisum sativum expression library. The open reading frame (ORF) within this cDNA
      encodes a 551-amino acid protein with a calculated molecular mass of 62.47 kDa
      that exhibits extensive homology with the CNX proteins from soybean (80%),
      Arabidopsis thaliana (70%), maize (70%), and dog (39%). The characteristic CNX
      signature motifs, KPEDWDE and GXW, generally found in molecular chaperones, are
      present in pea CNX (PsCNX), along with putative sites for Ca2+ binding and
      phosphorylation. In PsCNX, a signal sequence and a single transmembrane domain
      are also present at the N- and C-terminal ends, respectively. The PsCNX protein
      is expressed constitutively at the RNA level in vegetative and flowering tissues,
      as was evident from Northern analysis. Expression of PsCNX was light independent.
      In vitro translation of PsCNX cDNA yielded a 75-kDa precursor, which, in the
      presence of canine microsomal membranes, was cotranslationally processed into a
      72.5-kDa product and was imported and localized to the endoplasmic reticulum.
      Trypsin treatment of the in vitro translated PsCNX in the presence of canine
      microsomes generated a further processed 67-kDa intraluminal form. The results
      with PsCNX also showed that the plant protein is a phosphoprotein containing
      phosphoserine residues, as evidenced by immunoprecipitation of PsCNX with anti
      phosphoserine antibody. The PsCNX protein was also phosphorylated by endogenous
      kinases of pea microsomes.

PMID- 10595400
TI  - Transforming growth factor-beta1 inhibits rat prolactin promoter activity in GH4
      neuroendocrine cells.
AB  - The prototypic member of the transforming growth factor beta family is TGFbeta1,
      which is known to be important in extracellular matrix production, cell
      proliferation, and cell differentiation. Specifically in the pituitary
      lactotroph, TGFbeta1 inhibits prolactin (PRL) peptide secretion, PRL mRNA levels,
      and PRL gene transcription. To further elucidate the molecular details by which
      TGFbeta1 modulates PRL gene transcription, we used a transient transfection
      approach to characterize and to map the TGFbeta1 inhibitory response element of
      the rat (r) PRL promoter. Here, we show that TGFbeta1 selectively inhibits basal
      rPRL promoter activity in GH4 cells in a dose-responsive fashion, with an IC50 of
      6 pM, and that this inhibition occurs within 6 h after TGFbeta1 addition. Using a
      series of 5' deletion promoter mutants, the TGFbeta1 inhibitory response was
      found to be unaffected by deletion to position -116 and was abrogated by further
      deletion to -54 in the rPRL promoter. However, on the basis of data from site
      specific and linker-scanning mutants of the rPRL promoter, it appears that no
      single element is sufficient to mediate the TGFbeta1 inhibitory effect. Sequence
      analysis of the -116/-54 region failed to reveal any sequence homology to
      previously characterized TGFbeta response elements. Finally, TGFbeta1 failed to
      alter significantly the endogenous levels of the cell-specific activator protein
      GHF-1/Pit-1, indicating that the TGFbeta1 inhibitory effect is not attributable
      to diminished levels of GHF-1/Pit-1. Taken together, these data indicate that the
      TGFbeta1 inhibitory response is more complex than previously appreciated,
      requiring more than one cis-acting element and not always acting via TTGG or
      GTCTAGAC sites.

PMID- 10595401
TI  - Validation of an accurate method for three-dimensional reconstruction and
      quantitative assessment of volumes, lengths and diameters of coronary vascular
      branches and segments from biplane angiographic projections.
AB  - The goal of the study was the validation of an accurate method for three
      dimensional reconstruction and quantitative assessment of volumes, lengths and
      diameters of coronary vascular branches and segments from biplane angiographic
      projections. METHODS: The accuracy was tested in a complex phantom. In vivo,
      inter- and intraobserver agreement were assessed by analysis of routine
      angiograms. The sensitivity was evaluated using angiograms of patients having
      diagnostic vasoactive pharmacological intervention. Two-dimensional quantitative
      coronary angiography (2-D QCA) and 3-D QCA were compared concerning the accuracy
      of diameter evaluation. RESULTS: 3-D QCA yields accurate results (< 3% error)
      even based on nonorthogonal views, provided that projections parallel to the
      object are avoided. The inter- and intraobserver variability is < or = 5%.
      Significant (p < 0.01) changes of the volume (36-39%) and the diameter (19-21%)
      are detected following pharmacological intervention. 2-D QCA and 3-D QCA agree in
      short matched segments without foreshortening. 2-D QCA is rather sensitive to
      foreshortening and not suitable for evaluation of diameters of longer branches or
      total coronaries. CONCLUSION: 3-D QCA permits an accurate, reproducible and
      sensitive comprehensive three-dimensional geometric analysis of the coronaries
      and is superior to 2-D QCA with respect to extended diameter evaluation.

PMID- 10595403
TI  - Rest-redistribution thallium-201 myocardial scintigraphic study in cardiac
      amyloidosis.
AB  - BACKGROUND: Histopathological study in amyloid heart demonstrates that myocyte
      destructed by the extracellular deposition of amyloid protein together with
      viable myocyte is present. We hypothesized that rapid thallium washout may be
      found in amyloid heart as in regions which have a mixture of viable myocyte and
      scar tissue in patients with myocardial infarction. Thus, the purpose of this
      study was to evaluate the extent and severity of myocardial damage due to amyloid
      deposits using the washout rate of the tracer on rest-redistribution thallium-201
      (201Tl) myocardial scans in cardiac amyloidosis patients. METHODS: Rest
      redistribution 201Tl myocardial scintigraphy was performed in 5 patients with
      biopsy-proved systemic amyloidosis with cardiac involvement (amyloidosis group).
      The initial and delayed images were obtained 15 min and 4 h, respectively, after
      intravenous injection of the tracer of 111 MBq. Washout rate of the tracer was
      calculated. Twelve patients with no apparent heart disease served as controls
      (control group). RESULTS: Mean washout rate of the whole heart was higher in the
      amyloidosis group than in the control group (56 +/- 9% vs 36 +/- 6%, p < 0.001).
      Particularly, 4 of the 5 patients in the amyloidosis group presented a very high
      rate of thallium clearance which ranged from 57 to 61%, and died in less than a
      year. In the remaining 1 patient who had a normal washout rate of the tracer in
      the first study, it changed from 40 to 53% during the 5-year follow-up period.
      CONCLUSIONS: Washout rate in the setting of rest and delayed 201Tl images may
      represent the severity of amyloid depositions in the myocardium and may provide
      prognostic information.

PMID- 10595402
TI  - Fusion imaging: combined visualization of 3D reconstructed coronary artery tree
      and 3D myocardial scintigraphic image in coronary artery disease.
AB  - BACKGROUND: In patients with coronary artery disease, coronary angiography is
      performed for assessment of epicardial coronary artery stenoses. In addition,
      myocardial scintigraphy is commonly used to evaluate regional myocardial
      perfusion. These two-dimensional (2D) imaging modalities are typically reviewed
      through a subjective, visual observation by a physician. Even though on the
      analysis of 2D display scintigraphic myocardial perfusion segments are
      arbitrarily assigned to three major coronary artery systems, the standard
      myocardial distribution territories of the coronary tree correspond only in 50
      60% of patients. On the other hand, the mental integration of both 2D images of
      coronary angiography and myocardial scintigraphy does not allow an accurate
      assignment of particular myocardial perfusion regions to the corresponding
      vessels. To achieve an objective assignment of each vessel segment of the
      coronary artery tree to the corresponding myocardial regions, we have developed a
      3D 'fusion image' technique and applied it to patients with coronary artery
      disease. The morphological data (coronary angiography) and perfusion data
      (myocardial scintigraphy) are displayed in a 3D format, and these two 3D data
      sets are merged into one 3D image. RESULTS: Seventy-eight patients with coronary
      artery disease were studied with this new 3D fusion technique. Of 162 significant
      coronary lesions, 120 (74%) showed good coincidence with regional myocardial
      perfusion abnormality on 3D fusion image. No regional myocardial perfusion
      abnormality was found in 44 (26%) lesions. Furthermore, the 3D fusion image
      revealed 24 ischemic myocardial regions that could not be related to
      angiographically significant coronary artery lesions. CONCLUSION: The results of
      this study demonstrate that our newly developed 3D fusion technique is useful for
      an accurate assignment of coronary vessel segments to the corresponding
      myocardial perfusion regions, and suggest that it may be helpful to improve the
      interpretative and decision-making process in the treatment of patients with
      coronary artery disease.

PMID- 10595404
TI  - Tissue Doppler imaging (TDI) for on-line detection of regional early diastolic
      ventricular asynchrony in patients with coronary artery disease.
AB  - Diastolic filling of the left ventricle is often impaired in patients with
      coronary artery disease (CAD) in the absence of systolic wall motion
      abnormalities or previous myocardial infarction. The current study was designed
      to assess the ability of tissue Doppler imaging (TDI) for on-line detection of
      regional diastolic wall motion abnormalities to identify CAD in patients with
      preserved systolic function. 20 normal subjects (age 51 +/- 13 years) and 17 CAD
      patients with normal systolic function and > or = 70% luminal narrowing of the
      LAD (age 56 +/- 11 years) were included. Coronary anatomy was unknown to the
      echocardiographer. In the parasternal short axis and the apical 4-chamber-view,
      peak tissue velocities of the anterior/inferior and the midseptal/midlateral LV
      segments during rapid ejection (RE), isovolumic relaxation (IR), rapid filling
      (RF) and atrial contraction (AC) were analyzed by color-M-Mode-TDI. In the apical
      view, in 13 of 35 (37%) patients with adequate recordings, myocardial asynchrony
      was detected during IR: while the septum was moving inwards (red color-coding),
      the lateral wall was moving outwards (blue/green coding). In the remaining 22
      patients (63%) a slow, synchronous outward motion of septum and lateral wall with
      homogeneous color-coding (blue/green) was seen. Unblinding of the coronary status
      revealed a critical LAD stenosis in all 13 patients (100%) with myocardial
      asynchrony. Analysis of midseptal peak velocities during IR revealed positive
      velocities (1.22 +/- 1.64 cm/s) in CAD patients and negative velocities (-1.39 +/
      0.81 cm/s) in normal subjects. Thus, TDI allowed for the on-line detection of
      early diastolic asynchrony in 13 of 16 (82%) patients with critical LAD
      narrowing. Due to the rapid assessment of regional wall motion abnormalities, TDI
      might help to identify CAD in patients with normal systolic function.

PMID- 10595405
TI  - Ultrasonic tissue characterization in patients with dilated cardiomyopathy:
      comparison with findings from right ventricular endomyocardial biopsy.
AB  - AIM: The clinical usefulness of integrated backscatter (IB) imaging was compared
      with right ventricular endomyocardial biopsy for assessing myocardial damage in
      patients with dilated cardiomyopathy (DCM). METHODS: We examined 15 patients with
      DCM and 20 healthy controls. In addition to the conventional M-mode
      echocardiographic parameters, we determined the cyclic variation in IB values (CV
      IB) obtained from parasternal short axis views of the left ventricle just under
      the transducer for both the interventricular septum (IVS) and the left
      ventricular posterior wall (PW). The per cent fibrosis area (%) and the
      transverse diameter of myocytes (microm) were measured in right ventricular
      endomyocardial biopsy specimens by computer image analysis. To analyze the
      relationship between pathological findings and CV-IB, we divided patients into
      four subgroups on the basis of the pathological characteristics of endomyocardial
      biopsy specimens as follows: degeneration dominant group (n = 5), fibrosis
      dominant group (n = 5), dilated phase hypertrophic cardiomyopathy (n = 2), and
      mixed type (n = 3). RESULTS: CV-IB in the IVS and the PW was lower in patients
      with DCM (8.8 +/- 2.9, 8.3 +/- 2.7 dB, respectively) than in normal subjects
      (14.4 +/- 2.9, 13.6 +/- 2.6 dB, respectively). Biopsy findings showed a mean per
      cent fibrosis area of 24.0 +/- 12.3%, and a mean myocyte diameter of 14.3 +/- 2.9
      microm in patients with DCM. CV-IB was correlated with both of these findings:
      per cent fibrosis area (r = -0.56 in IVS, r = -0.56 in PW) and myocyte diameter
      (r = 0.67 in IVS, r = 0.71 in PW). CV-IB was decreased in all DCM subgroups
      compared with normal subjects, but there was no significant difference between
      subgroups. CONCLUSIONS: CV-IB was correlated with both the extent of fibrosis in
      myocardial tissue and the myocyte diameter. These findings suggest that
      ultrasonic tissue characterization is a good indicator of the severity of
      fibrosis and myocyte atrophy in patients with DCM.

PMID- 10595406
TI  - Left atrial volumes assessed by three- and two-dimensional echocardiography
      compared to MRI estimates.
AB  - OBJECTIVES: The aim of the present study was to establish the accuracy and
      reproducibility of left atrial volume measurements by three-dimensional (3D)
      echocardiography compared to 2D biplane and monoplane measurements. BACKGROUND:
      No echocardiographic technique is generally accepted as optimal for estimation of
      left atrial size. METHODS: Left atrial volumes of 18 unselected cardiac patients
      were obtained with magnetic resonance imaging (MRI) (volumes 145 +/- 58 ml).
      These volumes were compared with those obtained with different echocardiographic
      methods: a multiplane 3D method based on 90 images acquired by apical probe
      rotation, a simplified 3D method using only the three standard apical views, and
      2D biplane and monoplane methods based on area-length, disc summation and
      spherical formulas. RESULTS: The echocardiographic methods significantly
      underestimated maximum left atrial volumes as obtained by MRI by 14-37% (p <
      0.001). Accuracy, expressed as 1 SD of individual estimates around this
      systematic underestimation, was 25 to 27% for all methods, except for the 2D 2
      chamber monoplane method (37%). Interobserver coefficient of variation was
      between 14 and 20% for all methods (n.s.). CONCLUSION: All echocardiographic
      methods significantly underestimated left atrial volumes as obtained by MRI. A
      minor non-significant improvement in individual echocardiographic estimates by
      the 3D methods was obtained at the cost of more time consumption. In unselected
      patients ultrasound image quality precludes significant improvement of left
      atrial volume measurements by the applied 3D methods.

PMID- 10595407
TI  - MRI-derived left ventricular function parameters and mass in healthy young
      adults: relation with gender and body size.
AB  - PURPOSE: To obtain normal values of left ventricular (LV) end-diastolic volume
      (EDV), stroke volume (SV), cardiac output (CO) and LV mass, in relation to
      gender, weight (W), length (L) and body surface area (BSA). METHODS: Sixty-one
      healthy volunteers (32 male, 22.4 +/- 2.2 years) were examined, weight was 70.9
      +/- 12.2 kg, length was 1.78 +/- 0.09 m, BSA was 1.88 +/- 0.19 m2. Segmented k
      space breathhold cine MRI was used to obtain a stack of parallel short-axis
      images, from which LV volumes and end-diastolic mass were derived by slice
      summation. Four different body size indices were studied: W, L, L2 and BSA.
      RESULTS: After indexing for L, L2 and BSA, the gender differences in all LV
      parameters are still persisting. After indexing for W, gender differences persist
      for EDV and EDM, but are no longer observed for SV and CO. Separate regression
      analyses for males and females were performed. EDV, SV, CO and EDM correlated
      significantly with each body size index, both in males and in females. L or BSA
      were in general better predictors for LV parameters than W. Linear regression
      equations of EDV (ml) vs. L(m) were for males: EDV = 275 x L - 359 and for
      females: EDV = 190 x L - 215. Equations of SV(ml) vs. L were for males: SV = 186
      x L - 237 and for females: SV = 118 x L - 121. Equations of LV mass(g) vs. L were
      for males: Mass = 175 x L - 179 and for females: Mass = 65.8 x L - 10.9.
      CONCLUSION: Most gender differences in LV parameters remain even after correction
      for body size indices. Normal reference values for LV parameters are given in
      relation to body size indices, by calculating regression coefficients separately
      for males and females. These normal values serve to obtain more accurate
      reference values for a patient with given gender, weight and length, and thus to
      improve the differentiation between normal and abnormal LV parameters.

PMID- 10595408
TI  - Genetical and immunological analysis of recent Asian type A and O foot-and-mouth
      disease virus isolates.
AB  - This report extends the knowledge on the epizootical situation of foot-and-mouth
      disease in Asia. RNA from six samples of type A and five of type O virus,
      isolated between 1987 and 1997 in Bangladesh, Iran, Malaysia and Turkey, was
      subjected to reverse transcription-dependent polymerase chain reactions that
      amplify large parts of the capsid protein VP1 encoding genome region. The
      amplification products were sequenced, and the sequences aligned to each other
      and to published sequences. This showed the type O isolates of 1987-1997 from
      Bangladesh to be of same genotype and closely related to isolates of 1988 and
      later from Saudi Arabia, 1990 from India, 1996 from Greece and Bulgaria, and 1997
      from Iran. Among the analyzed type A isolates, those of 1992 and 1996 from Turkey
      were of same genotype and related to previously described isolates of 1987 from
      Iran and of 1992 from Saudi Arabia. The isolate of 1997 from Malaysia was found
      to be related to isolates from Thailand of 1993 and 1996. The isolates of 1987
      from Bangladesh and 1997 from Iran, however, represent different so far not
      described genotypes. Monoclonal antibodies, raised against the vaccine production
      strains A22 Iraq, Asial Shamir, O1 Kaufbeuren and O1 Manisa, and the recent type
      A field isolates Saudi Arabia/92 and Albania/96, were used in an ELISA to compare
      the reaction patterns of many of the field isolates. The monoclonal antibodies
      were further characterized for virus-neutralizing activity and binding to
      trypsinized homologous virus. The failure of neutralizing antibodies in binding
      to trypsinized homologous as well as to heterologous virus suggested the epitopes
      to reside at the major antigenic component of the virus, which is the capsid
      protein VP1. Two non-neutralizing antibodies that bind to trypsin-sensitive
      epitopes cross-reacted, however, with heterologous virus. This indicates the
      existence of a trypsin-sensitive antigenic site outside of VP1. In summary, the
      results obtained by ELISA confirm the observed sequence differences, but indicate
      further sequence differences at minor antigenic sites that do not reside on VP1.

PMID- 10595409
TI  - Recombinant expression of late genes agno-2a and agno-2b of avian polyomavirus
      BFDV.
AB  - Budgerigar fledgling disease virus (BFDV) genome contains two times two (two
      pairs) open reading frames (agnogenes) at the 5' end of the late coding region.
      Recombinant influenza A viruses were constructed to express the second pair of
      BFDV agnoproteins, agno-2a and agno-2b, with a fusion of a histidine-tag at their
      carboxy-termini, respectively. Specific proteins were detected in Western blot
      analysis using anti histidine-tag monoclonal antibody. By indirect
      immunofluorescence experiments agno-2a and agno-2b were shown to be located on
      the surface and in the perinuclear and cytoplasmic areas of infected cells.
      Comparisons of the expression patterns of BFDV agno-2a and agno-2b with that of
      simian virus 40 agnoprotein reveal high similarity, suggesting that they might
      have the same function(s) in polyomavirus infectious cycle.

PMID- 10595410
TI  - Phylogenetic comparison and molecular epidemiology of classical swine fever
      virus.
AB  - The genetic diversity of classical swine fever virus (CSFV) was studied by RT-PCR
      amplification and sequencing of a 409 bp fragment of the NS5B polymerase region.
      A total of 106 viruses isolated from 20 countries over a period of 52 years (1945
      1997) were included in the phylogenetic study. The results showed that the
      viruses could be divided into two main groups. Group 1 consisted of Asian and
      South American isolates from the 1980s, as well as of old European and American
      isolates. Group 2 consisted mostly of recent European viruses from the 1980s and
      1990s, and was further divided into three subgroups largely according to
      geographic origin and/or year of isolation. Five 1997 CSFV isolates from Germany,
      Netherlands and Italy clustered together indicating a common origin for these
      outbreaks, but two other 1997 isolations in different regions of Germany are
      likely due to different epidemiological events. The results show that the NSSB
      region of the genome gives a good resolution for phylogenetic studies of CSFV.
      Molecular epidemiology based on nucleotide sequence diversity is a useful tool
      for tracing virus spread and for developing disease control strategies.

PMID- 10595411
TI  - Bovine herpesvirus type 2 is closely related to the primate alphaherpesviruses.
AB  - Bovine herpesvirus type 2 (BoHV-2), also known as bovine mammillitis virus, is
      classified in the Family Herpesviridae, Subfamily Alphaherpesvirinae, and Genus
      Simplexvirus along with herpes simplex viruses type 1 and 2 (HSV-1 and HSV-2) and
      other primate simplexviruses on the basis of similarities in 4 genes within the
      15 kb U(L) 23-29 cluster. This could be explained either by a global similarity
      or a recombination event that brought primate herpesviral sequences into a bovine
      virus. Our sequences for DNA polymerase (U(L)30), a large gene adjacent to the
      previously identified conserved cluster, and glycoprotein G (U(S)4), a gene as
      distant from the cluster as possible on the circularized genome, confirm the
      close relationship between BoHV-2 and the primate simplexviruses, and argue for a
      global similarity and probably a close evolutionary relationship. Thus one can
      speculate that BoHV-2 may represent a greater hazard to humans than has been
      appreciated previously.

PMID- 10595412
TI  - Molecular characterization of the guinea pig cytomegalovirus UL83 (pp65) protein
      homolog.
AB  - The tegument phosphoproteins of human cytomegalovirus (HCMV) elicit cytotoxic T
      lymphocyte (CTL) responses and are hence candidates for subunit vaccine
      development. Little is known, however, about the tegument proteins of nonhuman
      cytomegaloviruses, such as guinea pig CMV (GPCMV). DNA sequence analysis of the
      Eco R I "C" fragment of the GPCMV genome identified an open reading frame (ORF)
      which is colinear with that of the HCMV tegument phosphoprotein, UL83 (pp65).
      This ORF was found to have identity to HCMV UL83 and was predicted to encode a
      565-amino-acid (aa) protein with a molecular mass of 62.3 kDa. Transcriptional
      analyses revealed that a GPCMV UL83 probe hybridized with both 2.2 kb and 4.2 kb
      mRNA species at 48 h post-infection (p.i.); synthesis of these messages was
      blocked by phosphonoacetic acid (PAA), defining these as "late" gene transcripts.
      In vitro translation of the UL83 ORF in reticulocyte lysate resulted in synthesis
      of a 65 kDa protein. Immunofluorescence experiments revealed that the putative
      GPCMV UL83 homolog exhibited a predominantly nuclear localization pattern.
      Polyclonal antisera were raised against a UL83/glutathione-S-transferase (GST)
      fusion protein. This antibody identified a 70-kDa virion-associated protein, the
      putative GPCMV UL83 homolog, in immunoblot and radioimmunoprecipitation
      experiments. Labeling experiments with 32P-orthophosphate indicated that the
      GPCMV UL83 protein is phosphorylated. Western blot analysis of glycerol tartrate
      gradient-purified virions and dense bodies confirmed that the putative GPCMV UL83
      homolog was a constituent of both fractions.

PMID- 10595413
TI  - Matrix protein of Chandipura virus inhibits transcription from an RNA polymerase
      II promoter.
AB  - Chandipura virus (CHPV) is a Vesiculovirus, related to, but phylogenetically
      distinct from, vesicular stomatitis virus (VSV). The matrix protein of VSV, as
      well as its role in virus assembly, inhibits the transcription from promoters for
      host RNA polymerases I and II. Cloning and expression of the matrix protein of
      CHPV in human cells showed that this protein is also functional in its inhibitory
      effect on transcription of a reporter gene from the cytomegalovirus immediate
      early promoter, despite sharing only 28% amino acid sequence identity with the
      matrix protein of VSV.

PMID- 10595414
TI  - Characterization of the structural-protein-coding region of SAT 2 type foot-and
      mouth disease virus.
AB  - The South African Territories (SAT) types of foot-and-mouth disease (FMD) virus
      show marked genomic and antigenic variation in sub-Saharan Africa that is to a
      large extent geographically determined. This has implications for selection of
      appropriate vaccine strains as well as the accuracy of laboratory diagnosis.
      However, adaptation of field isolates as vaccine strains is cumbersome, time
      consuming and expensive. We propose the construction of recombinant viruses in
      which specific antigenic determinants can be manipulated. To achieve this goal,
      the structural-protein-coding region of a SAT 2 vaccine strain, ZIM 7/83/2, was
      determined and compared with two other known SAT 2 P1 regions. Five hypervariable
      regions were identified of which four are situated within VP1. The cleavage sites
      for proteolytic processing differs from serotype A, while the junction between
      P1/2A is variable within the SAT 2 serotype. These differences could influence
      the construction of recombinant vaccines.

PMID- 10595415
TI  - Infectious RNA transcripts from grapevine virus A cDNA clone.
AB  - A full length cDNA clone of grapevine virus A (GVA) was constructed downstream
      from the bacteriophage T7 RNA polymerase promoter. Capped in vitro-transcribed
      RNA was infectious in Nicotiana benthamiana and N. clevelandii plants. Symptoms
      induced by the RNA transcripts or by the parental virus were indistinguishable.
      The infectivity of the in vitro-transcribed RNA was confirmed by serological
      detection of the virus coat and movement proteins and by observation of virions
      by electron microscopy. This is the first report of infectious RNA transcripts
      derived from a full-length cDNA clone of a member of the Vitivirus genus.

PMID- 10595416
TI  - Genetic analysis of the bovine herpesvirus type 4 gene locus for the putative
      terminase.
AB  - The complete DNA sequence of the 10-45 kbp HindIII B fragment of bovine
      herpesvirus type 4 (BoHV-4) was determined. This fragment contains nine complete
      and two incomplete open reading frames (ORFs), all of which are homologous to
      herpesvirus saimiri (HVS), Kaposi's Sarcoma-associated herpesvirus (HHV-8) and
      Epstein-Barr virus (EBV). Particularly, the arrangement of the gene for the
      terminase-related protein with the two coding exons 29a/29b is conserved among
      all herpesviruses sequenced to date. The intron carries the ORFs 30 to 33 in the
      opposite direction. Analysis by reverse transcription and polymerase chain
      reaction (PCR) of the transcript across the proposed splice junction of the ORF
      29a/29b and subsequent sequence determination of the amplified product revealed
      the precise structure of the splice junction. Furthermore, the phylogenetic
      analysis of the 29a/29b protein and its counterparts in other herpesviruses
      revealed that BoHV-4 clustered in the genus Rhadinovirus of the subfamily
      Gammaherpesvirinae.

PMID- 10595417
TI  - A selective genetic analysis of the Syracuse high- and low-avoidance (SHA/Bru and
      SLA/Bru) strains of rats (Rattus norvegicus).
AB  - Selective breeding of Long-Evans rats for good and poor avoidance learning in a
      two-way shuttle box resulted in the Syracuse strains that differ markedly in the
      selected phenotypes. These phenotypes have many associated traits, five of which
      are studied here: emotionality (open-field defecation), Pavlovian fear
      conditioning (CER suppression), passive avoidance training (punishment), size
      (weight) of the adrenal glands and adrenal concentration of corticosterone.
      Specifically, animals of the low-avoidance strain are more emotional, show
      greater fear conditioning, exhibit faster passive avoidance learning, and have
      larger adrenal glands in which adrenal corticosterone levels are lower than those
      of the high-avoidance strain. A reciprocal dihybrid cross of the two strains
      produced F1 hybrids, which were used to produce the segregating second filial and
      high and low backcross generations from which animals displaying the extreme high
      and low-avoidance phenotypes were selected for study of the associated traits.
      Measurement of the five traits in these high and low phenotypic animals indicated
      that all five remain significantly associated with the avoidance phenotypes, in
      the expected direction, and comparably in all three segregating generations. The
      results indicate that the hypothesis of a major gene controlling avoidance
      learning must be rejected and that the few (2-3) genetic units thought to be
      involved may be closely linked to those that mediate these five associated
      characters, or express all five pleiotropically.

PMID- 10595418
TI  - Medial prefrontal and neostriatal lesions disrupt performance in an operant
      delayed alternation task in rats.
AB  - An operant version of the classical delayed alternation task is presented and
      applied to evaluate the effects of bilateral prefrontal and striatal lesions in
      rats. Retractable levers in a conventional operant chamber control discrete trial
      opportunities for making sequential choice responses to the two sides, and the
      rats are required to maintain repeated nose poke responses to a central panel
      during the delay interval, which is randomly varied. The operant task provides
      measures of the speed and accuracy of response alternation and side bias;
      analysis at different delay intervals provides an index of the memory demands of
      accurate performance; and analysis of accuracy depending on the response on
      preceding trials provides measures of proactive interference and perseveration.
      Following pretraining in the task contingencies, both striatal and prefrontal
      lesions induced profound deficits in task accuracy, with no change in side bias
      and only small changes in movement times. The deficit in the prefrontal lesion
      group recovered more rapidly, neither group showed any change in sensitivity to
      proactive interference, while the rats with striatal lesions alone exhibited an
      increased tendency to perseverate incorrect responses on either side. We conclude
      that the operant delayed alternation task should assist analysis of fronto
      striatal function in rats as well as be useful for the analysis of strategies for
      fronto-striatal repair.

PMID- 10595419
TI  - Behavioural correlates of conditioned ventilatory responses to hypoxia in rats.
AB  - To examine the possible contribution of behavioural arousal to ventilatory
      conditioning, we performed a differential conditioning experiment using two
      odours as the paired conditioned stimulus (CS + ) and unpaired conditioned
      stimulus (CS-) and a hypoxic mixture (7.5% O2) as the unconditioned stimulus (US)
      in 24 adult male rats. Vanillin was the CS + and rose the CS - in half the rats,
      and vice versa in the other half. Each rat underwent 26 paired CS + /hypoxia
      trials and 26 CS - trials in alternation, followed by two CS + only and two CS -
      trials to test for conditioning. Analysis of breathing variables and behavioural
      scores during the test showed two qualitatively different conditioned responses.
      The initial conditioned response was characterised by short breath durations
      (TT), frequent sniffing episodes, and arousal responses. Following this, a
      specific, conditioned increase in tidal volume (VT) and levelling off of sniffing
      and motor activities occurred. The early TT-response and late VT-response to CS +
      both contributed to an increase in ventilation (VI). The present data show that
      the association of an odour and hypoxia elicits a biphasic ventilatory
      conditioned response, of which the first component is integrated into conditioned
      arousal.

PMID- 10595420
TI  - Memory dissociation: the approach to the study of retrieval processes.
AB  - The phenomenon of dissociated memory retrieval is observed when some influences
      (for example, pharmacological) on the brain result in specific changes of long
      term memory. The purpose of present paper is to reveal possibilities of the
      phenomenon for study of long-term memory retrieval. Pharmacologically-induced
      dissociated states could be identified when the retrieval of responses learned
      before treatment is temporarily blocked by the drug influence, but the ability of
      the animals to learn new tasks is intact. Furthermore, memory traces that were
      formed in drugged state are not accessible for the retrieval in normal state and
      only the same drug treatment allows retrieving them. In the present work,
      dissociated learning of food-motivated tasks was carried out in Wistar rats with
      cholinesterase inhibitor physostigmine (0.5 mg/kg, intraperitonealy) or general
      anaesthetic sodium pentobarbital (15 mg/kg, intraperitonealy.). The retrieval of
      dissociated responses was studied under the influence of various doses of the
      same drugs. The results revealed the asymmetry of memory dissociation with
      physostigmine in contrast to pentobarbital-induced memory dissociation. Gradual
      access for the retrieval of dissociated memory traces after pharmacological
      modulation of cholinergic and GABA-ergic brain systems was shown. It was
      suggested an important role of hippocampus in memory dissociation, as a structure
      performing match-mismatch operations between different retrieved memory traces.

PMID- 10595421
TI  - Proximal versus distal control in proprioceptively guided movements of motor
      impaired children.
AB  - Two groups of 7-year-old children diagnosed as motor-impaired (N = 6) or as
      controls (N = 6) were required to perform a task that involved locating targets
      under a table-top with one hand while attempting to match the position of the
      target with the other, on the table-top (intra-modal matching), always without
      visual control. The experimental design involved three different conditions:
      proximal control (P), distal control (D) or both (PD). Target distance errors
      were analysed in terms of absolute (AE) and variable error. When the scores for
      each hand were combined, the motor-impaired group showed inferior mean
      performance (AE scores) on all three conditions as compared with the control
      children and were also more variable in their behaviour. Analyses of scores
      achieved with the right and the left hand separately, however, demonstrated that
      the difference could largely be attributed to the scores obtained when matching
      with the right hand in conditions P and PD, and matching with the left hand in
      condition D. Possible explanations of these findings are discussed in the context
      of 'delay' (developmental lag) and/or 'deviancy' (neurological
      lesion/disconnection).

PMID- 10595422
TI  - The effects of posterior parietal and posterior temporal cortical lesions on
      multimodal spatial and nonspatial competencies in rats.
AB  - The functional consequences of posterior parietal (PPC) and posterior temporal
      (Te2/3) cortical lesions on rat spatial and nonspatial multimodal learning, and
      memory were assessed using three behavioral paradigms. In the first, a stimulus
      elicited object-place recognition task, PPC-lesioned animals were found to
      habituate to repeated presentation and dishabituate to changes in the visual and
      auditory properties of the objects but they fail to respond to changes in their
      location. The Te2/3-lesioned animals recognized changes in spatial location, but
      not changes in auditory or visual characteristics of the objects. Sham controls
      recognized both. In water maze-based auditory and visual place object conditional
      learning tasks, Te2/3 and Sham controls learned both discriminations, whereas the
      performance of PPC animals was significantly retarded. In the third paradigm, all
      three groups learned the visual discriminations. Although PPC-lesioned animals
      subsequently demonstrated recognition of the amodal property of duration in a
      visual/auditory cross-modal transfer (CMT) test, they were unable to do so on two
      CMT tasks involving the property of space. In all three tests, the Sham controls
      consistently displayed CMT and the Te2/3-lesioned animals did not. The present
      study extends the description of somewhat distinctive roles played by two
      association cortical regions (PPC and Te2/3) in the perceptual/cognitive
      functioning, particularly with respect to auditory stimuli and correspondences
      between auditory and visual events.

PMID- 10595423
TI  - Postural adjustments during spontaneous and goal-directed arm movements in the
      first half year of life.
AB  - We studied the development of postural control during goal-directed reaching and
      spontaneous arm movements in early infancy. Two groups of infants participated.
      The first group consisted of 10 healthy infants, who were assessed four times at
      the ages of 3, 4, 5 and 6 months. Each assessment consisted of simultaneous
      recording of video-data and surface EMGs of arm, neck, trunk, and leg muscles in
      various lying and sitting positions. Additionally, postural adjustments during
      spontaneous arm movements were studied in a second group of five infants aged 1-3
      months. Already before the onset of successful reaching, which occurred at 4 5
      months, both spontaneous and goal-directed arm movements were accompanied by a
      high amount of postural activity. During the goal-directed arm movements a
      preference for neck muscle activation and a direction specific organisation
      (dorsal postural muscles activated before the ventral antagonists) prevailed,
      whereas during spontaneous arm movements such a specific postural organisation
      was absent. With increasing age and concurrent with successful reaching, the
      amount of postural activity decreased. Still, the persisting postural activity
      continued to become more organised with increasing age. Position affected the
      postural adjustments accompanying goal-directed arm movements at all ages.

PMID- 10595424
TI  - Modulatory role of 5-HT3 receptors in mediation of apomorphine-induced aggressive
      behaviour in male rats.
AB  - We have studied the effects of serotonin (5-HT) 5-HT3 receptor agonists 1
      phenylbiguanide (1-PBG) and 1-(m-chlorophenyl)biguanide (mCPBG), and antagonists
      3-tropanyl-3,5-dichlorobenzoate (MDL-72222) and tropisetron (3-tropanyl-indole-3
      carboxylate HCl; ICS-205930) on apomorphine-induced aggressive behaviour in
      normal or DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] pre
      treated male Wistar rats. DSP-4 (50 mg/kg) pre-treatment significantly
      accelerated the development of apomorphine-induced aggressive behaviour. mCPBG
      (1.0 and 10 mg/kg) did not modify the aggressiveness, but 1-PBG (3.0 and 30
      mg/kg) attenuated the aggressiveness in normal but not DSP-4 pre-treated rats.
      MDL-72222 (0.4 and 4.0 mg/kg) attenuated the aggressive behaviour in normal rats,
      tropisetron (0.3 mg/kg) had an antiaggressive effect only by citalopram (10
      mg/kg) challenge. MDL-72222 and tropisetron were ineffective in DSP-4 pre-treated
      rats. In conclusion, our results indicate that the 5-HT3 receptors modulate the
      apomorphine-induced aggressive behaviour and the 5-HT3 receptor antagonists have
      moderate antiaggressive effect in this test.

PMID- 10595425
TI  - Retrograde amnesia and selective damage to the hippocampal formation: memory for
      places and object discriminations.
AB  - Using a within-subjects design, rats were trained on two place-memory problems
      and five object-discrimination problems at different intervals prior to receiving
      either ibotenate lesions of the hippocampal formation or sham surgery. Places # 1
      and 2 were fixed-platform water-maze tasks that were run in different rooms and
      they were learned during the 14th and 2nd week before surgery, respectively.
      Object-discrimination problems # 1-5 were learned during the 13th, 10th, 7th,
      4th, and 1st week before surgery, respectively. Rats with hippocampal lesions
      displayed impaired retention of both Place problems with no evidence of a
      temporal gradient to the impairment. In contrast to their retrograde place-memory
      deficits, the hippocampal rats displayed normal retention of the five object
      discriminations that were learned before surgery. Hippocampal lesions had similar
      consequences for anterograde learning, as the lesioned rats were impaired in
      acquisition of a new water-maze problem that was run in a third room (Place #3),
      whereas they showed normal acquisition of two new object-discriminations. The
      findings indicate that the hippocampal formation is not required for long-term
      consolidation of information underlying accurate performance of object
      discriminations, and that its critical role in memory for places persists for at
      least 14 weeks, and probably for as long as those memories exist.

PMID- 10595426
TI  - Role of interleukin-1 beta in impairment of contextual fear conditioning caused
      by social isolation.
AB  - Isolating rats immediately after conditioning impairs contextual but not auditory
      cue fear conditioning. The reported experiments examine the involvement of brain
      interleukin-1beta (IL-1beta) in the impairment in contextual fear conditioning
      caused by social isolation. As measured by the conditioned freezing response, 5 h
      of social isolation after conditioning, impaired contextual but not auditory-cue
      fear conditioning in adult male Sprague-Dawley rats. Social isolation for 1 or 3
      h after conditioning also increased IL-1beta protein in the hippocampus and
      cerebral cortex. No differences in IL-1beta protein levels were found in the
      pituitary or the hypothalamus. Intracerebroventricular (ICV) IL-1 receptor
      antagonist (IL-1ra) given after conditioning prevented the impairment in
      contextual fear conditioning caused by isolation. ICV IL-1ra had no effect on
      auditory-cue fear conditioning in these same animals, nor did it affect the level
      of contextual fear conditioning displayed by home cage controls. Like isolation,
      ICV IL-1beta (10 or 20 ng) after conditioning also impaired contextual but not
      auditory-cue fear conditioning. These results suggest that increased levels of
      brain IL-1beta play a role in producing the impairment in contextual fear
      conditioning produced by social isolation. These findings also add to the
      generality of the idea that stressors induce IL-1beta activity in the brain and
      that IL-1beta may play physiological roles in the uninjured brain.

PMID- 10595427
TI  - The amygdala mediates the anxiolytic-like effect of the neurosteroid
      allopregnanolone in rat.
AB  - The neurosteroid allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one)
      possesses clear anxiolytic-like effects. Other neurosteroids namely pregnenolone
      sulfate (PREG-S) and dehydroepiandrosterone sulfate (DHEA-S) influence anxiety
      related behavior differently. In the present study, the implication of the
      amygdala, a key structure in mechanisms of fear and anxiety, was investigated as
      a potential neural substrate for the effects of neurosteroids on anxiety-like
      behavior in rat. Animals implanted with bilateral cannulae aimed at the central
      nucleus of the amygdala (CeA) and infused with neurosteroids, were tested in two
      animal models of anxiety. Allopregnanolone (8 microg/side) produced a significant
      increase in responding suppressed by punishment in the conflict test. In the
      elevated plus maze, allopregnanolone (8 microg/side) induced a significant
      increase in the time spent and the number of entries in open arms compared with
      the vehicle-infused controls. No significant changes in punished and unpunished
      responding of the conflict test were observed with PREG-S (0.001-8 microg/side)
      and DHEA-S (2-8 microg/side) administered into the CeA or into the lateral
      ventricle (1-20 microg). The results reveal the lack of activity of PREG-S and
      DHEA-S in the operant conflict test, but suggest that the central nucleus of the
      amygdala is a key region involved in the mechanisms underlying the anxiolytic
      like action of allopregnanolone.

PMID- 10595428
TI  - Cortical injury impairs contralateral forelimb immobility during swimming: a
      simple test for loss of inhibitory motor control.
AB  - Most animal models of focal injury to the sensorimotor cortex have been aimed at
      detecting non-use or impairment of the limbs in specific tasks or during
      spontaneous exploratory behaviors. However, the inability to hold a limb still
      can be an equally disabling movement disorder. The present study investigated the
      loss of control of limb immobility that occurs following damage to the forelimb
      region of the rat sensorimotor cortex (FL-SMC). When swimming forward in a tank
      of water, adult rats typically hold both forepaws mostly motionless underneath
      the chin, using primarily the hindlimbs for stroking movements. Following a
      unilateral FL-SMC lesion, rats hold only the non-impaired forelimb immobile under
      the chin, and make 'immature' stroking movements with the impaired forelimb. We
      have devised a simple means of assessing and quantifying this deficit. While the
      criterion for most tests of motor recovery involves appropriate movement of an
      impaired limb, this test depends on adequate inhibition of movement as the norm,
      and may be a useful way to assess the loss of inhibitory motor control and the
      efficacy of potential restorative interventions.

PMID- 10595429
TI  - Isolation changes the incentive value of sucrose and social behaviour in juvenile
      and adult rats.
AB  - The present study was undertaken to assess the motivational aspects of social
      behaviour in juvenile and adult rats using the conditioned place preference (CPP)
      test and anticipatory behaviour for social contact. In addition, the consequences
      of social isolation during different periods of age on the motivational
      properties of sucrose-drinking and adult social behaviour were studied. Social
      play and adult social contact could be used as incentives for place preference
      conditioning and for inducing conditioned hyperactivity (anticipation) in rats.
      Both social activities have motivational properties for individually housed rats,
      whereas group-housing dramatically reduced the motivational aspects of adult
      social contact. In contrast, sucrose-drinking appears to have motivational
      aspects independent of the housing condition. Adult social behaviour could not
      induce a CPP in juvenile isolated rats, suggesting that juvenile isolation during
      4 5 weeks reduced the motivational aspects of adult social contact. It seems
      likely that no CPP was established as a result of the reduced level of social
      behaviour during the conditioning sessions. Additionally, juvenile isolation
      during 4-5 weeks appeared to also decrease the motivational properties of sucrose
      drinking in maturity, because the intensity of anticipation in response to
      sucrose was significantly suppressed. Thus, the data suggest that juvenile
      isolation during 4-5 weeks decreases the motivational properties of both social
      contact and sucrose-drinking in later life.

PMID- 10595430
TI  - Dopamine D1 or D2 receptor blockade in the globus pallidus produces akinesia in
      the rat.
AB  - In the present study, the involvement of dopamine D1 and D2 receptors in the
      dorsal globus pallidus (GP) in motor control was investigated in rats. Results
      show that bilateral microinfusions of the dopamine D1 receptor antagonist
      SCH23390 or the dopamine D2 antagonist S( - )-sulpiride into the GP induced
      akinesia determined by means of the catalepsy test. These findings indicate that
      pallidal dopamine D1 and D2 receptors are critically involved in the control of
      motor behaviour. The findings further imply that defective dopaminergic
      transmission in the GP might contribute to akinesia due to lesion- or drug
      induced dopamine hypofunction in experimental animals and in neurodegenerative
      diseases, e.g. Parkinson's disease, affecting the nigrostriatal dopamine system.

PMID- 10595431
TI  - Excitotoxic hippocampal lesions disrupt allocentric spatial learning in mice:
      effects of strain and task demands.
AB  - Spatial discrimination of ibotenic acid-lesioned C57BL/6 (B6) and DBA/2 (D2) mice
      was tested in two-choice water maze and plus maze tasks. B6 but not D2 mice
      learned the spatial discrimination in the water maze, but strains did not differ
      in learning a spatial discrimination in the plus maze paradigm. Ibotenic acid
      lesions of the hippocampus impaired percentage correct choices in the water maze
      spatial discrimination task in B6 but not in D2 mice, the latter of which may
      have been due to a floor effect. Furthermore, lesioned mice were more
      thigmotaxic, the distance travelled until a choice was made was longer and
      animals made more errors of omission. Despite the poor performance during water
      maze acquisition, lesioned animals, as well as sham-lesioned D2 mice, eventually
      acquired some place response in the water maze, as was evident when the location
      of the platform was reversed. However, hippocampus-lesioned mice of both strains
      were impaired when tested in the plus maze spatial discrimination task. Thus,
      ibotenic acid-induced lesions of the hippocampus impair acquisition of spatial
      discrimination in mice. These deficits were strain-dependent and likely comprise
      impaired accuracy as well as changes in non-mnemonic types of behaviour.
      Importantly, lesions in both strains impaired spatial learning, and whether a
      deficit was seen in mice of the D2 strain seemed to depend on the demands of the
      task.

PMID- 10595432
TI  - Altered adaptive behaviour expressed in an open-field paradigm in experimental
      hepatic encephalopathy.
AB  - Chronic hepatic encephalopathy (HE) encounters a neuropsychiatric syndrome
      arising as a complication to liver dysfunction. Patients with chronic HE display
      a great variety of neuropsychiatric symptoms including such mental derangements
      as adaptational difficulty, and deteriorated learning and memory capacity. The
      portacaval shunt (PCS) in the rat is a widely used model for experimental chronic
      HE. In the present study, the adaptive capacity of unhabituated PCS rats and sham
      operated control rats were studied by measuring two exploratory behaviours
      (locomotion and rearing) during 5 or 60 min, at four consecutive days or nights
      with 24 h between sessions. The results revealed that PCS and sham-operated
      control rats showed parallel behavioural outcome over the four sessions in the 5
      min trial. However, at the four consecutive test sessions in the 60-min trials,
      the sham-controls displayed a continuing decrease in overall activity between
      sessions whereas the PCS rats evidenced a repeated and stable activity level.
      These results indicate a presence of a long-term habituation deficiency as
      exhibited by the PCS rats. Additionally, the results indicate that differences in
      normal open-field motor behaviour between PCS rats and controls may not be found
      if such tests are conducted repeatedly during night-time but may emerge when
      tested repeatedly during daytime. The results may also be interpreted as a
      possible impaired learning/memory capacity in PCS rats. However, further
      investigations of how the PCS procedure affects entities of adaptation and
      learning ability are needed before any conclusions may be drawn since this is the
      first report of such an impairment in experimental chronic HE when represented by
      the PCS rat.

PMID- 10595433
TI  - Roots of brain specializations: preferential left-eye use during mirror-image
      inspection in six species of teleost fish.
AB  - It has recently been reported that predator inspection is more likely to occur
      when a companion (i.e. the mirror image of the test animal) is visible on the
      left rather than on the right side of mosquitofish Gambusia holbrooki. This very
      unexpected outcome could be consistent with the hypothesis of a preferential use
      of the right eye during sustained fixation of a predator as well as of a
      preferential use of the left eye during fixation of conspecifics. We measured the
      time spent in monocular viewing during inspection of their own mirror images in
      females of six species of fish, belonging to different families-G. holbrooki,
      Xenotoca eiseni, Phoxinus phoxinus, Pterophyllum scalare, Xenopoecilus
      sarasinorun, and Trichogaster trichopterus. Results revealed a consistent left
      eye preference during sustained fixation in all of the five species. Males of G.
      holbrooki, which do not normally show any social behaviour, did not exhibit any
      eye preferences during mirror-image inspection. We found, however, that they
      could be induced to manifest a left-eye preference, likewise females, if tested
      soon after capture, when some affiliative tendencies can be observed. These
      findings add to current evidence in a variety of vertebrate species for
      preferential involvement of structures located in the right side of the brain in
      response to the viewing of conspecifics.

PMID- 10595434
TI  - Early postnatal treatment with ACTH4-9 analog ORG 2766 improves adult spatial
      learning but does not affect behavioural stress reactivity.
AB  - Studies on adult animals and humans have shown that the ACTH4-9 analog ORG 2766
      influences cognitive performance and possibly has neurotrophic effects. For this
      reason we studied the effect of ORG 2766 applied in early postnatal life when
      brain structures and neuronal pathways are still developing. Our aim was to see
      whether such treatment during development would result in permanent changes in
      adult behavioural performance. Pups received subcutaneous injections of 1
      microg/g bodyweight ACTH4-9 analog ORG 2766 on day 1, 3 and 5 after birth.
      Control animals in the same nest received saline injections. When the animals had
      reached an adult age of 3 months they were subjected to a series of tests to
      measure their behavioural performance. In the first experiment, behavioural
      stress responses and anxiety were measured by subjecting the rats to the
      following tests: open field, defensive burying, elevated plus maze, and
      conditioned fear test. In a second experiment, adult cognitive function was
      measured in the Morris water-maze, a hippocampus-related spatial learning test,
      and in the active avoidance test, a more amygdala-related nonspatial test. The
      results showed that animals treated with ORG 2766 during early postnatal life
      learned faster in the spatial Morris water-maze. The treatment had a positive
      effect on performance during the acquisition phase of the learning task, while
      memory retrieval was not affected. Learning in the nonspatial active avoidance
      task did not change due to the postnatal ACTH4-9 treatment. In addition, there
      were no differences in the open field test, the defensive burying test, elevated
      plus maze and the conditioned fear test. The latter supports the conclusion that
      the differences in water-maze performance was due to a difference in learning
      speed, rather than a difference in anxiety or behavioural stress reactivity.
      Analysis of [3H]CORT binding capacity measured after the learning tests revealed
      no differences in the hippocampal MR and GR concentration between non-treated and
      treated animals.

PMID- 10595435
TI  - Effects of neurotensin administered into the ventral tegmental area on prepulse
      inhibition of startle.
AB  - Prepulse inhibition (PPI) of the acoustic startle reflex is an operational
      measure of sensorimotor gating. Both locomotor activity and PPI are regulated by
      mesolimbic dopamine activity. Neurotensin is a neuropeptide, which coexists with
      dopamine in mesolimbic neurons. Neurotensin receptors have been identified in the
      nucleus accumbens (NAC) and ventral tegmental area (VTA). Previous studies have
      shown that neurotensin administered into the NAC differentially modulates PPI and
      locomotor activity. In this study we tested the effects of neurotensin
      administered into the VTA on PPI and locomotor activity. Consistent with previous
      studies, intra-VTA administered neurotensin significantly increased spontaneous
      locomotor activity. However, intra-VTA administered neurotensin did not have any
      significant effect on PPI. These results suggest that PPI and locomotor activity
      may have dissociable mesolimbic substrates and that neurotensin in the VTA does
      not play an important role in regulating PPI.

PMID- 10595436
TI  - Degumming of crude palm oil by membrane filtration.
AB  - The application of membrane separation in palm oil refining process has potential
      for energy and cost savings. The conventional refining of crude palm oil results
      in loss of oil and a contaminated effluent. Degumming of crude palm oil by
      membrane technology is conducted in this study. The objective of this research is
      to study the feasibility of membrane filtration for the removal of phospholipids
      in the degumming of crude palm oil, including analyses of phosphorus content,
      carotene content free fatty acids (as palmitic acid), colour and volatile matter.
      A PCI membrane module was used which was equipped with polyethersulfone membranes
      having a molecular weight cut off of 9,000 (type ES209). In this study,
      phosphorus content was the most important parameter monitored. The membrane
      effectively removed phospholipids resulting in a permeate with a phosphorus
      content of less than 0.3 ppm The percentage removal of phosphorus was 96.4% and
      was considered as a good removal. Lovibond colour was reduced from 27R 50Y to 20R
      30Y. The percentage removal of carotene was 15.8%. The removal of colour was
      considered good but the removal of carotene was considered insignificant by the
      membrane. Free fatty acids and volatile matter were not removed. Typical of
      membrane operations, the permeate flux decreased with time and must be improved
      in order to be adopted on an industrial scale. Membrane technology was found to
      have good potential in crude palm oil degumming. However, an appropriate method
      has to be developed to clean the membranes for reuse.

PMID- 10595437
TI  - Recovery of coal fines from washery and power plant effluents by integrated
      technique of oil agglomeration and biofilm formation.
AB  - The possibility of applying an integrated technique of oil agglomeration and
      biofilm formation for recovery of coal fines from coal washeries and power plants
      effluents has been explored. Laboratory experiments with simulated slurries of
      different Indian coal fines demonstrate that vegetable oils are satisfactory
      agglomerating agents for recovery of most of the coal fines depending on the
      nature of coal and type of oil. The agglomeration behaviour of coal fines was
      assessed in terms of % yield, % organic matter recovery and % ash rejections.
      Maximum 85% agglomerate recovery was obtained in the agglomeration stage.
      Residual oil concentrations in some cases were found to exceed the permissible
      limit. Recovery of residual coal fines and reduction in residual oil
      concentration in the resultant slurry after oil agglomeration have been attempted
      using biofilm formation. A laboratory scale treatment reactor was put under
      complete recirculation to facilitate attached microbial growth on coal particles
      as carrier under aerobic conditions. The influence of various parameters on
      attached growth and stable biofilm formation were studied. The growth patterns of
      attached cell in suspension and consumption pattern of carbon substrate (oil)
      have been investigated. Steady decline in residual substrate concentration in the
      slurry with corresponding increase in the growth of attached and free cell mass
      is observed. The growth process was favoured in pH range of 6.5-7.0. The attached
      growth was found to be expanded in size in due course of time ultimately leading
      to the formation of stable biofilm in the treatment reactor which was subjected
      to the influent total suspended solids loading resulting from oil agglomeration
      step. Performance of the biofilm reactor in terms of % reduction in total
      suspended solids and residual oil concentration in the influent slurry was
      assessed in continuous mode. Complete recovery of coal fines and 60% degradation
      of oil was observed in the final effluent discharged from the treatment reactor.

PMID- 10595438
TI  - Studies on the kinetics of Isopropyl Palmitate synthesis in packed bed bioreactor
      using immobilized lipase.
AB  - The objective of this research was to study the kinetics of synthesis of a
      commercially important ester - Isopropyl Palmitate (IPP) using immobilized lipase
      (Lipozyme IM). It was studied in a packed bed differential reactor. In order to
      establish the kinetics of the reaction, parameters such as linear velocity of the
      fluid through the reactor, particle size, substrate concentration, substrate
      molar ratio, temperature and water activity were studied. Operational and storage
      stability of the enzyme were also assessed. The reaction followed Michaelis
      Menton kinetics as observed from the relationship of initial rate of the reaction
      as a function of substrate concentration. It was found that the optimum substrate
      concentration was 0.15M palmitic acid and isopropyl alcohol in 1:1 stoichiometric
      ratio. Inhibition by excess of isopropyl alcohol has been identified. The optimum
      temperature for the esterification reaction was found to be around 50 degrees C.
      The activation energy of this process was determined to be 43.67 kJ/mol. The
      optimum water content was 0.50%. The reaction rates were measured in the absence
      of any significant external diffusional limitations. Since internal diffusional
      limitations could not be eliminated, the kinetics observed is only apparent.

PMID- 10595439
TI  - Production of urokinase by HT 1080 human kidney cell line.
AB  - Studies were carried out in T-flasks and bioreactor to produce urokinase enzyme
      using HT 1080 human kidney cell line. While growing the cell line it has been
      observed that the lag phase is reduced considerably in the bioreactor as compared
      to T-flask culture. The HT 1080 cell adhesion rate and urokinase production were
      observed to be the function of serum concentration in the medium. The maximum
      urokinase activity of 3.1 x 10(-4) unit ml(-1) was achieved in the bioreactor at
      around 65 h of batch culture. Since HT 1080 is an anchorage dependent cell line,
      therefore, the hydrodynamic effects on the cell line were investigated.

PMID- 10595440
TI  - An empirical model on extractive lactic acid bioconversion.
AB  - The commercial production of lactic acid through fermentation process has always
      been in competition with its chemical synthesis process (Kirk Othmer, 1995).
      Lactic acid produced through the fermentation process has to cope with the
      problems of purification to meet the required quality standards. An attempt to
      improve the fermentative production is possible by proper design of an industrial
      process involving low capital cost for the plant. Also, the low energy costs both
      in its fermentation and purification, are required. In the commercial interest,
      the investment cost should be minimised, which is possible only when the cell
      density in fermenter is high. It means that the inhibitory effect of the product
      on process kinetics must be minimised. Based on these requirements, the
      extractive bioconversion technique is one of the approaches to achieve the
      commercially viable lactic acid production. Extractive lactic acid bioconversion
      using ion-exchange resin process has already been described in our earlier
      publications (Srivastava e al., 1992: Roychoudhury et al., 1995) It is always an
      advantage to develop a process model, thus opening an area of biotechnological
      improvements to the process. In the present paper, an empirical mathematical
      model has been described to explain this extractive bioconversion using ion
      exchange resin process. It was based on generalised Monod's growth model and
      Leudeking and Piret equation. The system was defined with the assumption that the
      microbial growth can be represented as a single reaction; only a very little part
      of the substrate is utilised for the maintenance of the cells. The effect of end
      product inhibition on growth and product formation kinetics has also been
      considered in this model. A non-linear regression technique was used for
      evaluation of bioconversion kinetic parameters. The fourth order Runge Kutta
      method was used for solving the differential equations. The results of this
      process simulation are also discussed in the present paper. It indicates that the
      use of present technique has minimised the effect of lactic acid inhibition on
      process kinetics and hence higher productivity and least substrate utilisation
      for maintenance of cells. A statistical F-test has been performed for determining
      the validity of the model for a given set of experimental data with a level of
      significance alpha = 0.05 selected for this extractive batch recycle
      bioconversion process using ion-exchange resin.

PMID- 10595441
TI  - Feasibility study on the utilization of rubber latex effluent for producing
      bacterial biopolymers.
AB  - Rubber latex effluent is a polluting source that has a high biochemical oxygen
      demand (BOD). It is estimated that about 100 million liters of effluent are
      discharged daily from rubber processing factories. Utilization of this effluent
      such as the use of a coupled system not only can reduce the cost of treatment but
      also yield a fermentation feedstock for the production of bioplastic. This study
      initially was carried out to increase the production of organic acids by
      anaerobic treatment of rubber latex effluent. It was found that through anaerobic
      treatment the concentration of organic acids did not increase. Consequently,
      separation of organic acids from rubber latex effluent by anion exchange resin
      was examined as a preliminary study of recovering acetic and propionic acids.
      However, the suspended solids (SS) content in the raw effluent was rather high
      which partially blocked the ion-exchange columns. Lime was used to remove the SS
      in the rubber latex effluent. After the lime precipitation process, organic acids
      were found to adsorb strongly onto the anion exchange resin. Less adsorption of
      organic acids onto the resin was observed before the lime precipitation. This was
      probably due to more sites being occupied by colloidal particles on the resin
      thus inhibiting the adsorption of organic acids. The initial concentration of
      organic acids in the raw effluent was 3.9 g/L. After ion exchange, the
      concentration of the organic acids increased to 27 g/L, which could be utilized
      for production of polyhydroxyalkanoates (PHA). For PHA accumulation stage,
      concentrated rubber latex effluent obtained from ion exchange resins and
      synthetic acetic acid were used as the carbon source. Quantitative analyses from
      fed batch culture via HPLC showed that the accumulation of PHA in Alcaligenes
      eutrophus was maximum with a concentration of 1.182 g/L when cultivated on
      synthetic acetic acid, corresponding to a yield of 87% based on its cell dry
      weight. The dry cell weight increased from 0.71 to 1.67 g/L. On the other hand,
      using concentrated rubber latex effluent containing acetic and propionic acids
      resulted in reduced PHA content by dry weight (14%) but the dry cell weight
      increased from 0.49 to 1.30 g/L. The results clearly indicated that the cells
      grow well in rubber latex effluent but no PHA was accumulated. This could be due
      to the high concentration of propionic acid in culture broth or other factors
      such as heavy metals. Thus further work is required before rubber latex effluent
      can be utilized as a substrate for PHA production industrially.

PMID- 10595442
TI  - Kinetics study of palm oil hydrolysis using immobilized lipase Candida rugosa in
      packed bed reactor.
AB  - Continuous hydrolysis of palm oil triglyceride in organic solvent using
      immobilized Candida rugosa on the Amberlite MB-1 as a source of immobilized
      lipase was studied in packed bed reactor. The enzymatic kinetics of hydrolysis
      reaction was studied by changing the substrate concentration, reaction
      temperature and residence time(tau) in the reactor. At 55 degrees C, the optimum
      water concentration was found to be 15 % weight per volume of solution (%w/v).
      The Michaelis-Menten kinetic model was used to obtain the reaction parameters,
      Km(app) and V max(app). The activation energies were found to be quite low
      indicating that the lipase-catalyzed process is controlled by diffusion of
      substrates. The Michaelis-Menten kinetic model was found to be suitable at low
      water concentration 10-15 %w/v of solution. At higher water concentration,
      substrate inhibition model was used for data analysis. Reactor operation was
      found to play an important role in the palm oil hydrolysis kinetic.

PMID- 10595443
TI  - Pilot scale study on retrofitting conventional activated sludge plant for
      biological nutrient removal.
AB  - Eutrophication of receiving waters due to the discharge of nitrogen and
      phosphorus through the wastewater effluent has received much interest in recent
      years. Numerous techniques have been proposed and aimed at retrofitting the
      existing conventional activated sludge process for nutrient removal. A pilot
      scale research program was conducted to evaluate the effectiveness of a
      biological nutrient process for this purpose. The results indicated that creating
      an anoxic/anaerobic zone before aeration basin significantly enhances total
      phosphorus (TP) and total nitrogen (TN) removal. Without internal cycle, about 80
      percent TP and TN removal were respectively achieved under their optimal
      conditions. However, adverse trends for phosphorus and nitrogen removal were
      observed when the ratio of return sludge to the influent was varied in the range
      between 0.5 and 3.0. The total phosphorus removal decreased as the concentration
      of BOD5 in the mixture of influent and return sludge decreased. Improved sludge
      settling properties and reduced foaming problems were also observed during the
      pilot plant operation. Based upon experimental results, the strategies to modify
      an existing conventional activated sludge plant into a biological nutrient
      removal (BNR) system are discussed.

PMID- 10595444
TI  - Ability of Pycnoporus sanguineus to remove copper ions from aqueous solution.
AB  - The equilibrium sorption capacity of a macro-fungi, Pycnoporus sanguineus biomass
      was studied using a single-metal system comprising copper ions. The rate and
      extent for the removal of copper were subjected to environmental parameters such
      as pH, biomass loading, temperature, and contact time. Results showed that the
      uptake of copper increased as the pH increased. However, as the biomass loading
      increased, the amount of metal uptake decreased. Instead, temperature does not
      have a significant effect on the metal uptake, especially between 30 to 40
      degrees C. A maximum adsorption of copper ions was also observed within 15
      minutes of reaction time for the entire sample tested. Furthermore, pre-treatment
      with sodium bicarbonate and boiling water significantly improved the sorption
      capacity of copper by Pycnoporus sanguineus.

PMID- 10595445
TI  - Modeling and simulation of an enzymatic reactor for hydrolysis of palm oil.
AB  - Hydrolysis of palm oil has become an important process in Oleochemical
      industries. Therefore, an investigation was carried out for hydrolysis of palm
      oil to fatty acid and glycerol using immobilized lipase in packed bed reactor.
      The conversion vs. residence time data were used in Michaelis-Menten rate
      equation to evaluate the kinetic parameters. A mathematical model for the rate of
      palm oil hydrolysis was proposed incorporating role of external mass transfer and
      pore diffusion. The model was simulated for steady-state isothermal operation of
      immobilized lipase packed bed reactor. The experimental data were compared with
      the simulated results. External mass transfer was found to affect the rate of
      palm oil hydrolysis at higher residence time.

PMID- 10595446
TI  - Binding mechanism of heavy metals biosorption by Pycnoporus sanguineus.
AB  - Non-living biomass of Pycnoporus sanguineus has an ability to take up lead,copper
      and cadmium ions from an aqueous solution. The role played by various functional
      groups in the cell wall and the mechanism uptake of lead, copper and cadmium by
      Pycnoporus sanguineus were investigated. Modification of the functional groups
      such as lipids, carboxylic and amino was done through chemical pretreatment in
      order to study their role in biosorption of metal ions. Results showed that the
      chemical modification of these functional groups has modified the ability of
      biomass to remove lead, copper and cadmium ions from the solution. Scanning
      electron microscopy was also used to study the morphological structure of the
      biomass before and after adsorption. The electron micrograph indicated that the
      structure of biomass changed due to the adsorption of the metals onto the cell
      walls. Furthermore, the X-ray energy dispersion analysis (EDAX) showed that the
      calcium ion present in the cell wall of biomass was released and replaced by lead
      ions. This implied that an ion exchange is one of the principal mechanisms for
      metal biosorption.

PMID- 10595447
TI  - Cross flow ultrafiltration studies on solutions of pectin with pulsatile flow in
      situ cleaning.
AB  - A study was conducted to evaluate the cross flow tubular ultrafiltration behavior
      of aqueous solutions of pectin. The effectiveness of pulsatile flow as a cleaning
      in-place (CIP) technique to improve permeate flux was undertaken on the above
      mentioned solution. This investigation is part of a study to apply membrane
      filtration in the clarification of tropical fruit juice. The main variables,
      which were investigated, include the concentration of pectin, pulse frequency and
      amplitude. It was found that the amount of pectin in the solution significantly
      affects its ultrafiltration behavior. From the observed profiles, it is evident
      that the formation of gel layer on the membrane surface is responsible for the
      leveling of flux at high pressures. The presence of pectin was found to affect
      the properties of the solution such as viscosity, pH and the size of pectin
      colloid. Improvements in the permeate flux for pectin solution were obtained by
      employing pulsatile flow cleaning-in-place technique. Both pulse frequency and
      amplitude are important parameters that can improve the improvement of in-situ
      cleaning method. Similar to several findings reported in the literature,
      pulsatile flow showed significant effectiveness of about 60% higher flux when the
      ultrafiltration process is operated under laminar condition.

PMID- 10595448
TI  - Production of organic acids from kitchen wastes.
AB  - This study involves the production of short-chain organic acids from kitchen
      wastes as intermediates for the production of biodegradable plastics. Flasks,
      without mixing were used for the anaerobic conversion of the organic fraction of
      kitchen wastes into short-chain organic acids. The influence of pH, temperature
      and addition of sludge cake on the rate of organic acids production and yield
      were evaluated. Fermentations were carried out in an incubator at different
      temperatures controlled at 30 degrees C. 40 degrees C, 50 degrees C, 60 degrees C
      and uncontrolled at room temperature. The pH was also varied at pH 5, 6, 7, and
      uncontrolled pH. 1.0 M phosphate buffer was used for pH control, and 1.0 M HCl
      and 1.0 M NaOH were added when necessary. Sludge cake addition enhanced the rate
      of maximum acids production from 4 days to 1 day. The organic acids produced were
      maximum at pH 7 and 50 degrees C i.e., 39.84 g/l on the fourth day of
      fermentation with a yield of 0.87 g/g soluble COD consumed, and 0.84 g/g TVS. The
      main organic acid produced was lactic acid (65-85%), with small amounts of acetic
      (10-30%), propionic (5-10%), and butyric (5-20%) acids. The results of this study
      showed that kitchen wastes could be fermented to high concentration of organic
      acids, which could be used as substrates for the production of biodegradable
      plastics.

PMID- 10595449
TI  - Biphasic biomethanation of wood-hydrolysate effluent.
AB  - The dissolving pulp industry, spread throughout the world, is the principal
      source of wood-hydrolysate effluent rich in hemicelluloses. This effluent is the
      major source of pollution in the industry. COD and BOD5 values of the effluent
      range from 60,000 to 103,000 and 42,000 to 78,000 mg/l respectively.
      Biomethanation of this effluent is the best possible treatment option for
      reducing the COD load and recovering the bioenergy embedded in the effluent. This
      paper deals with the study on the biphasic biomethanation of the wood-hydrolysate
      in upflow acidogenic reactor coupled with anaerobic filter methanogenic reactor.
      The two reactors were operated at organic loading rates of 69.6 and 30.1 g
      COD/l/d respectively. The overall COD, hemicelluloses and lignin reductions, and
      methane generation were observed to be 88%, 92%, 82% and 6.5 l/l reactor volume/d
      respectively. The relative size of the biphasic, anaerobic filter (mono-phasic)
      and upflow anaerobic sludge blanket (mono-phasic) reactors is found to be
      1:1.6:2.03 respectively.

PMID- 10595450
TI  - The performance and kinetic study of membrane anaerobic system in treating POME.
      Palm oil mill effluent.
AB  - The application of the three known kinetic models on MAS (membrane anaerobic
      system) process treating the POME and the overall MAS treatment efficiency were
      investigated. The MAS consists of a cross-flow ultrafiltration membrane (Model
      Micro 240) for solid-liquid separation. Six steady states were attained over a
      range of mixed liquor suspended solids of 12,681 - 30,460 mg/l. The study showed
      a good fitting of the Monod Model (91.1%), Contois Model (98.5%) and Chen and
      Hashimoto Model (95%) for the MAS treating raw POME at organic loadings between
      1.5 kgCOD/m3/d to 6.5 kgCOD/m3/d. The growth yield coefficient, Y, was found to
      be 0,604 kg VSS/kgCOD while the specific microorganism decay rate was 0.099 day(
      1). The k values were in the range of 0,242 to 0.425 mg COD/mg VSS.d and the
      microm values were between 0.145 to 0.257 day(-1). Throughout the study, the
      removal efficiency of COD was 83.2 to 97.97%. The methane production rate was
      between 0.262 to 0.473 l/g-COD-utilised/d. The MAS treatment efficiency was
      greatly affected by SRT and OLRs. In the study, membrane fouling and polarization
      at the membrane surface played a significant role in the formation of the
      strongly attached cake layer limiting membrane permeability

PMID- 10595451
TI  - Artificial cell microcapsules containing genetically engineered E. coli DH5 cells
      for in-vitro lowering of plasma potassium, phosphate, magnesium, sodium,
      chloride, uric acid, cholesterol, and creatinine: a preliminary report.
AB  - Lowering of plasma Mg, P, Na, Cl, uric acid, cholesterol, and creatinine is
      required in renal failure and other diseases. In this preliminary report, we
      studied the ability of artificial cells microencapsulated genetically engineered
      E. coli DH5 cells in lower K, Mg, P, Na, Cl, uric acid, cholestrol, creatinine,
      and billirubin from plasma in-vitro. Result shows that this novel approach has
      the ability to significantly lower these metabolites from the plasma in-vitro.

PMID- 10595452
TI  - A direct binding assay for thyrotropin receptor autoantibodies.
AB  - There is, at present, no assay in clinical use for the direct assay of
      autoantibody binding to the thyrotropin receptor (TSHR). We now describe a direct
      thyrotropin receptor autoantibody binding assay (DTAb) using a secreted form of
      the TSHR ectodomain (TSHR-289) without the need for antigen purification. The
      assay compensates for the low TSHR autoantibody concentration in serum by
      capturing a relatively large amount of patient immunoglobulin G (IgG) on high
      capacity beads, a reversal of standard methods that typically first immobilize
      antigen. TSHR-289 captured by Graves' IgG was detected in a colorimetric reaction
      using a biotinylated murine monoclonal antibody to the poly-histidine tail
      engineered into the antigen. By this approach, sera from 11 normal individuals
      provided a mean optical density (OD) value of 0.20 +/- 0.08 SD (range 0.06-0.33).
      Of 38 sera from unselected patients with a history of Graves' disease (untreated
      and treated), 29 (76%) generated OD values > 0.37 (2 SD above the mean for the
      normal sera), the highest being OD 1.38. Surprisingly, 3 of 13 (23%) sera from
      TPO autoantibody-positive patients with Hashimoto's thyroiditis also provided
      values > 2 SD above the normal sera. The extent of direct autoantibody binding to
      the TSHR correlated closely with the thyrotropin binding inhibition (TBI) values
      (r = 0.881; p < 0.001). One serum was clearly positive in only the direct binding
      assay and another in only the TBI assay. The data obtained with the direct
      binding assay correlated less well with the thyroid-stimulating antibody (TSAb)
      assay (r = 0.582; p < 0.001). In summary, we describe a new direct DTAb assay
      that correlates more closely with the TBI than with the TSI assays. Future
      studies in a large series of clinically defined patients will be needed to
      evaluate the clinical utility of the DTAb assay.

PMID- 10595453
TI  - Thyrotropin receptor mutations in hyperfunctioning thyroid adenomas from Brazil.
AB  - Constitutively activating mutations in the thyrotropin (TSH) receptor have been
      identified as a major molecular cause of hyperfunctioning thyroid adenomas. A
      smaller subset of these benign tumors is caused by constitutive activation of the
      adenylyl cyclase cascade by somatic mutations in the Gsalpha gene. In this study,
      we analyzed hyperfunctioning thyroid adenomas from seven Brazilian patients for
      TSH receptor and G(s)alpha gene mutations. Solitary autonomous thyroid adenomas
      were identified by ultrasound and scintigraphy, and DNA was extracted from
      adenomatous and periadenomatous tissue. Exons 9 and 10 of the TSH receptor gene,
      and exons 8 and 9 of the G(s)alpha gene, were amplified by polymerase chain
      reaction (PCR) and subjected to direct sequence analysis. Six of seven adenomas
      harbored heterozygous mutations known to confer constitutive activity to the TSH
      receptor. In one case, aspartate 619 was substituted by glycine (D619G). In four
      adenomas, alanine 623 was replaced by valine (A623V). Both residues are located
      in the third intracellular loop. In one instance, aspartate 633 located in the
      sixth transmembrane domain was replaced by tyrosine (D633Y). In this patient, one
      allele also contained a change of aspartate 727 to glutamate (D727E). This
      substitution is thought to be a polymorphic variant of the wild-type but it has
      also been associated with toxic multinodular goiters. Functional comparison of
      D727 with E727 did not reveal differences in basal or TSH-stimulated cyclic
      adenosine monophosphate (cAMP)-dependent luciferase activity in transiently
      transfected cells. These results demonstrate a high prevalence of activating TSH
      receptor mutations in toxic adenomas in this small series from Brazil
      (approximately 86%). These findings are in agreement with reports from other
      countries with a marginal iodine intake but contrast with studies from regions
      with a high iodine intake where these mutations appear to be less prevalent.

PMID- 10595454
TI  - Validation of ultrasonography of the thyroid gland for epidemiological purposes.
AB  - Ultrasonography of the thyroid is often used in epidemiological surveys, thus
      thorough characterization of the interobserver variation of the different
      parameters obtained is important. Various methods have been used for measuring
      thyroid volume, and different formulas have been used for calculation of thyroid
      volume from the measured dimensions. In this article, two principles of thyroid
      volume measurement are described in detail: the wellknown method based on the
      three axes of each lobe and a new principle based on planimetry in two planes.
      The interobserver variation of the examination and the measuring procedure in
      itself were tested on 25 participants in a population study. A comparison of
      postmortem ultrasonography of the thyroid and results of an autopsy was
      performed. Good correlation and agreement between observers was found for thyroid
      volume (r = 0.98) and prevalence of thyroid nodules (kappa = 0.72), whereas
      echogenecity and echopattern showed little agreement. The correlation of thyroid
      volume by ultrasonography to autopsy results was satisfactory (r = 0.93), but the
      volume tended to be slightly underestimated even when using the formula pi/6(=
      0.52)*length*width*depth. No major differences were found between the performance
      of the two principles of volume calculation. We conclude that when the measuring
      procedure is well defined, results of ultrasonography are comparable between
      observers for thyroid volume and prevalence of thyroid nodules, but not for
      echogenecity or echopattern. The formula of length*depth*width*pi/6 is suitable
      for thyroid volume measurement.

PMID- 10595455
TI  - Thyroid hemiagenesis in an endemic goiter area diagnosed by ultrasonography:
      report of sixteen patients.
AB  - During a period of 9 years, 71,500 patients underwent thyroid investigations at
      our department. Sixteen patients with thyroid hemiagenesis, 13 women and 3 men,
      were seen during this period. Fifteen had no left lobe and only 1 had no right
      lobe, the isthmus was present in 5 patients. Associated thyroid diseases of the
      lobe that was present could be observed in 11 patients (9 diffuse or nodular
      goiters, 2 thyroid autoimmune diseases). One patient was hyperthyroid and 7 were
      hypothyroid. Hypothyroidism associated with hemiagenesis has rarely been reported
      in the literature. In our survey, the high percentage of hypothyroidism may be
      explained by coexisting iodine deficiency, which could be verified in 4
      hypothyroid patients. Ultrasonography is the key investigation to diagnose
      thyroid hemiagenesis. Fine-needle aspiration biopsies, laboratory tests, and
      scintigraphies are useful to diagnose other diseases within the remaining lobe or
      to visualize ectopic thyroid tissue. Review of the literature, including our
      cases, presented a total of 256 patients with thyroid hemiagenesis. Its
      prevalence can be estimated between 1:1900 and 1:2675. Left to right ratio of
      thyroid hemiagenesis is 3.6:1 with an isthmus present in 44%. The female-to-male
      ratio is 3:1; however, the larger number of females is probably based on a bias
      due to a female predominance of the populations investigated. On the basis of an
      equal distribution of both sexes, the female-to-male ratio of thyroid
      hemiagenesis would be only 1.3:1 in our survey.

PMID- 10595456
TI  - Increase in serum concentrations of thyroxine-binding globulin and of cortisol
      binding globulin after the induction of normal thyroid function in previously
      hyperthyroid patients.
AB  - Serum concentrations of thyroxine-binding globulin (TBG) were determined in 36
      female patients with hyperthyroidism due to either Graves' disease (n = 33), or
      autonomous thyroid adenomas (n = 3). After the induction of euthyroidism by
      antithyroid drugs, serum concentrations of TBG rose from 13.7 +/- 2.4 ng/mL to
      17.1 +/- 2.8 ng/mL (p < 0.001) whereas those of sex hormone-binding globulin
      (SHBG) fell from 142.2 +/- 66.4 nmol/L to 53.6 +/- 21.8 nmol/L (p < 0.001). Serum
      concentrations of cortisol-binding globulin (CBG) rose to 42.9 +/- 10.3 microg/mL
      (basal: 36.8 +/- 9.4 microg/mL; p < 0.001) but serum concentrations of total and
      of free cortisol remained unchanged. Thus, thyroid hormones exert different
      effects on the production of various carrier proteins in vivo. Whereas they
      stimulate the production of SHBG, they suppress the level of CBG and of their own
      carrier protein, TBG.

PMID- 10595457
TI  - Effect of iodine supplementation on a pediatric population with mild iodine
      deficiency.
AB  - A cross-sectional study in two stages consisted of healthy children to assess the
      effect of iodine supplementation on a pediatric population with mild iodine
      deficiency in an ongoing program in the Province of Pontevedra, northwestern
      Spain. In the first survey (1984), 1565 schoolchildren and in the second survey
      (1995) 907 schoolchildren were randomly selected from the population. In January
      1985, a mandatory consumption of iodized salt in our region was begun. In both
      surveys we studied prevalence of goiter, urinary iodine excretion, and prevalence
      of thyroid dysfunction. Similar prevalences of goiter were observed in both
      surveys, 3.7% versus 3.9%; however, significantly lower prevalence of Ib and II
      degree goiters were observed in the second survey. The mean iodine excretion was
      88.6 +/- 73 microg/L (median 66.3) and 146.4 +/- 99 microg/L (median 115.7), p <
      0.01 for the first and second surveys, respectively. Finally, the overall
      prevalence of thyroid dysfunction was similar in both surveys, 9.2% versus 7.0%;
      however, significantly lower prevalence of suppressed serum thyrotropin (TSH),
      considered as a marker of subclinical hyperthyroidism, was observed in the second
      survey when compared to the first, 0.1% versus 2%, p < 0.01. Our results are in
      agreement with the recent data from Denmark, where the prevention of subclinical
      hyperthyroidism occurring in the elderly as a consequence of longstanding mild
      iodine deficiency is the reason that the Danish finally started iodine
      supplementation on a national basis. In conclusion, long-term correction of mild
      iodine deficiency in a pediatric population has beneficial effects on the
      prevalence of high-degree goiters, and this correction reduces significantly the
      prevalence of subclinical hyperthyroidism. The present observation constitutes a
      strong argument for correcting even mild iodine deficiency.

PMID- 10595458
TI  - Expression of the cadherin-catenin complex in well-differentiated human thyroid
      neoplastic tissue.
AB  - E-cadherin is a member of the cadherin family that plays a major role in
      epithelial integrity and tumorigenesis. Catenins are a group of cytoplasmic
      proteins that regulate the intracellular anchorage of cadherin and are required
      for the linkage between cadherin and the actin cytoskeleton. Loss of E-cadherin
      contributes to the pathogenesis in tumor invasion and gives a poor prognosis. In
      order to investigate the adhesion property of intercellular junctions in thyroid
      tumors, expression of alpha-,beta, and gamma-catenin should also be studied. A
      correlation between these molecular markers and malignancy would be useful as a
      preoperative diagnostic test for thyroid neoplasms. The expression of E-cadherin,
      alpha-, beta-, and gamma-catenin were studied in normal and neoplastic thyroid
      tissue by immunofluorescence microscopy and Western blot analysis. In the normal
      thyroid and in nodular goiter, and follicular adenoma, staining for E-cadherin,
      alpha-, beta-, and gamma-catenin was seen mainly at the lateral surface of
      epithelial cells in the follicle and the presence of these molecules was
      confirmed by Western blot analysis. Follicular carcinoma tissue stained positive
      for E-cadherin and alpha-catenin, but the results of beta- and gamma-catenin
      immunostaining were highly variable, with beta-catenin being absent in most
      follicular carcinomas (8/10) and gamma-catenin being absent in some follicular
      carcinomas (3/10). These results suggest that E-cadherin expression was not
      reduced during the pathogenesis of differentiated thyroid malignancies.
      Impairment of the cadherin-catenin complex at the cell junction may contribute to
      the malignant progression of differentiated thyroid neoplastic tissue.

PMID- 10595459
TI  - Gender, clinical findings, and serum thyrotropin measurements in the prediction
      of thyroid neoplasia in 1005 patients presenting with thyroid enlargement and
      investigated by fine-needle aspiration cytology.
AB  - One thousand five euthyroid patients (870 females and 135 males, mean age 47
      years), who presented with thyroid enlargement were evaluated by fine-needle
      aspiration cytology (FNAC) of the thyroid as the first-line investigation. The
      final cytological or histological diagnosis was determined after surgery (n =
      312) or clinical follow-up for a minimum period of 2 years (range 2-14 years,
      mean 6.7 years). Goiter type was assessed clinically and was classified as
      diffuse in 147, multinodular in 247, or solitary nodule in 611. The overall
      sensitivity and specificity of the procedure in the detection of thyroid
      neoplasia was 88% and 89%, respectively. Males who presented with thyroid
      enlargement had significantly higher rates of malignancy (p = 0.007) and
      neoplasia (benign + malignant) (p = 0.002) than females, as did subjects with
      solitary nodule compared with diffuse or multinodular goiters (malignancy p =
      0.001, neoplasia p < 0.001). Subjects with normal thyrotropin (TSH) (>0.4 mU/L)
      at presentation had a nonsignificantly increased risk of thyroid neoplasia (p =
      0.07) and malignancy, in contrast to those with low TSH (<0.4 mU/L). We confirmed
      FNAC of the thyroid to be an accurate test in the detection of thyroid neoplasia.
      Gender and goiter type at presentation both contribute significantly to the
      prediction of the diagnosis of thyroid neoplasia.

PMID- 10595460
TI  - Resolution of fetal goiter after discontinuation of propylthiouracil in a
      pregnant woman with Graves' hyperthyroidism.
AB  - We report a case of Graves' hyperthyroidism in a 34-year-old pregnant woman
      treated with propylthiouracil (PTU) complicated by the development of a fetal
      goiter. Because of the fetal goiter and normal maternal thyroid function tests,
      the PTU was discontinued. Over the next 10 weeks, there was a progressive
      decrease in the fetal thyroid volume as documented by ultrasonography. The fetal
      neck returned to a normal flexed position, fetal growth and amniotic fluid
      remained normal, and the patient remained asymptomatic. A normal infant was
      delivered at term. This is the first report to demonstrate that noninvasive
      management may be appropriate for fetuses with goiter caused by antithyroid drug
      therapy.

PMID- 10595461
TI  - Severe thyroid eye disease associated with primary hypothyroidism and thyroid
      associated dermopathy.
AB  - Four unusual cases of patients are described with severe thyroid eye disease
      (TED) who presented with primary hypothyroidism and thyroid-associated dermopathy
      (TAD). All four patients had moderate or severe TED and elevated circulating
      thyrotropin (TSH) receptor antibodies.

PMID- 10595462
TI  - Invasive aspergillosis diagnosed by fine-needle aspiration of the thyroid gland.
AB  - Invasive aspergillosis has been increasingly recognized as causing significant
      morbidity and mortality in immunocompromised patients but has never been
      diagnosed by fine-needle thyroid aspiration. A 24-year-old female with systemic
      lupus erythematosus presented with cough, shortness of breath, and fever of
      unknown origin unresponsive to broad-spectrum antibiotics. History and physical
      examination failed to indicate a source of infection. An 111In white blood cell
      scan showed thyroid localization. Physical examination revealed a multinodular
      goiter with a left dominant nodule. Fine-needle aspiration biopsy of a thyroid
      nodule revealed branching hyphae suggestive of Aspergillus sp. Despite immediate
      and aggressive treatment with amphotericin B and fluconazole, the patient died of
      overwhelming infection.

PMID- 10595463
TI  - Brain metastases from medullary thyroid carcinoma in a patient with multiple
      endocrine neoplasia type 2A.
AB  - Medullary thyroid carcinoma (MTC) is an uncommon thyroid cancer occurring in less
      than 10% of patients with thyroid cancer. Brain metastasis from MTC is
      exceedingly rare. Only six cases of brain metastasis from MTC have been reported
      in the literature and none had MTC as a part of multiple endocrine neoplasia
      (MEN) syndrome. We report a 42-year-old Caucasian male with MEN 2A who presented
      with neurological symptoms 25 years after total thyroidectomy with
      lymphadenectomy for MTC metastatic to local lymph nodes. A brain magnetic
      resonance imaging (MRI) showed a 4-cm cystic mass and a 1-cm nodule in the left
      frontal-parietal lobe in addition to a 0.8-cm cystic mass in the left frontal
      lobe and multiple tiny cerebellar metastatic lesions. Partial resection of the
      cerebral metastasis followed by whole brain radiotherapy resulted in resolution
      of the neurological symptoms. However, the patient had multiple systemic
      metastasis from the MTC and he died of systemic complications due to metastatic
      MTC. To our knowledge this is the first report of brain metastases from MTC in a
      patient with MEN 2A.

PMID- 10595464
TI  - Thyrotoxicosis due to the simultaneous occurrence of silent thyroiditis and
      Graves' disease.
AB  - Silent thyroiditis (ST) and Graves' disease (GD) are two clinical entities
      belonging to the wide spectrum of autoimmune thyroid diseases (AITD). The two
      diseases are closely linked because sequential development of GD followed by ST,
      or the reverse course of events, ie, ST followed by GD, have been documented.
      However, the pathogenetic basis of the above association remains unknown. Some
      authors have suggested that the concomitant existence of ST and activation of GD
      can occur in thyrotoxic postpartum women with normal radioiodoine uptake. The
      simultaneous occurrence of the two diseases in different parts of the same
      thyroid gland has, however, to our knowledge, not been documented. We report the
      case of a 40-year-old thyrotoxic female with atypical presentation of GD. The
      titers of the antithyrotropin receptor antibodies were elevated and her initial
      99mTc-pertechnetate thyroid scan showed the coexistence of ST and GD in different
      parts of the thyroid gland. Through serial thyroid scans, we document the
      recovery from ST in parts of the gland and demonstrate the progression to Graves'
      hyperthyroidism in the entire gland.

PMID- 10595465
TI  - Transient diffuse low thyroid echogenicity in painless postpartum thyroiditis:
      report of two cases.
AB  - We report two cases of chronic autoimmune thyroiditis, one patient with recurrent
      painless thyroiditis and another with recurrent postpartum thyroiditis. In these
      two patients, the episode of subacute thyroiditis seemed to be immune mediated.
      Thyroid ultrasonography showed a diffuse, markedly hypoechogenic gland,
      coinciding with each of the episodes of transient thyroid dysfunction that
      reverted to a normal echographic appearance with recovery of normal thyroid
      function. These two cases show that a diffuse low echogenicity of the thyroid,
      frequently seen in autoimmune thyroid disorders, can be a reversible event and
      suggest that the transient nature of certain forms of hypothyroidism may be
      predicted by a follow-up echographic examination. Further studies with a larger
      number of patients are required to confirm this observation.

PMID- 10595466
TI  - Expression of the mutant thyroid hormone receptor PV in the pituitary of
      transgenic mice leads to weight reduction.
AB  - Resistance to thyroid hormone (RTH) is a genetic disease caused by mutations of
      the thyroid hormone receptor beta gene (TRbeta). One of the symptoms in some
      affected individuals is growth retardation. To understand the molecular basis of
      growth retardation in these patients with RTH, a transgenic mouse was prepared in
      which the expression of the TRbeta1 mutant PV was targeted to the pituitary using
      the promoter of the glycoprotein hormone alpha-subunit. The PV mutant was
      originally identified in a patient with severe growth impairment. The PV mutation
      is a C-insertion at codon 448 of the TRbeta gene and leads to a frame-shift of
      the carboxyl-terminal 14 amino acids of TRbeta1, resulting in total loss of
      triiodothyronine (T3) binding and transcriptional activation. PV was selectively
      expressed in the pituitary of the transgenic mouse and not in other tissues
      examined. The transgenic mice showed a significant impairment in weight gain.
      However, no changes in the serum level of thyroid-stimulating hormone were seen,
      and no elevation of thyroid hormones was detected in the transgenic mice. The
      circulating levels of growth hormone and insulin-like growth factor I were not
      affected in the transgenic mice, suggesting that the growth impairment in RTH is
      complex and is mediated by pathways that are yet to be elucidated.

PMID- 10595467
TI  - Scintigraphic patterns of injury in amateur weight lifters.
AB  - PURPOSE: Weight lifting is now a standard part of training in most sports. An
      increasing number of amateur athletes are doing strength training, mostly in
      unsupervised situations. A series of injuries in amateur weight lifters was
      analyzed by bone scintigraphy, with the aim of depicting specific patterns that
      would accurately identify the primary lesions. METHODS: Twelve patients (10 men
      and 2 women) were studied whose ages ranged from 18 to 35 years. Patients were
      referred for bone scintigraphy with clinical diagnoses based on history, physical
      examination, and appropriate radiologic investigations. Diagnoses were confirmed
      by surgery, arthroscopy, arthrography, local steroid injection, and outcome.
      RESULTS: Most of the injuries were in athletes undertaking free-weight training.
      Most injuries were in the upper limbs, particularly around the shoulder.
      Scintigraphic patterns of supraspinatus and bicipital tendons and also rotator
      cuff lesions were identified. Clavicular osteolysis, avulsion injuries, muscle
      damage, and vertebral lesions were also noted. Several abnormalities revealed by
      scintigraphy were clinically unsuspected. CONCLUSIONS: Scintigraphic
      manifestations of several injuries, particularly around the shoulder, have a
      specific pattern. Recognition of these patterns can enhance the performance of
      bone scintigraphy. Scintigraphy also has the potential to detect clinically
      unsuspected disease.

PMID- 10595468
TI  - Gated Tc-99m sestamibi SPECT versus stress-rest SPECT in detecting coronary
      artery disease: correlation with coronary angiography in patients without
      myocardial infarction.
AB  - PURPOSE: It is possible to simultaneously evaluate wall thickening and perfusion
      abnormalities with radionuclide techniques that use tracers such as Tc-99m MIBI.
      We presumed that detection of wall thickening by gated MIBI SPECT imaging in the
      presence of a stress-induced perfusion defect correlates with reversibility of
      that defect on resting images. Therefore, the aim of our study was to analyze, in
      patients without myocardial infarction, resting wall thickening and stress
      perfusion imaging as an alternative to conventional stress-rest imaging. METHODS
      AND RESULTS: The patients (n = 44) underwent an exercise (n = 37) or
      pharmacologic (n = 7) stress protocol. All patients had previous coronary
      angiography within 3 months. Stress-rest MIBI SPECT and gated MIBI SPECT studies
      were analyzed by visual scoring. The sensitivity and specificity of segmental
      analysis of both stress-rest MIBI SPECT perfusion and gated MIBI SPECT studies
      for the overall detection of coronary artery disease were, respectively, 71% and
      96%. For patient evaluation for detection of coronary artery disease, stress-rest
      MIBI SPECT perfusion and gated MIBI SPECT studies showed a sensitivity rate of
      96% for both and specificity rates of 84% and 79%, respectively. CONCLUSIONS: Our
      data revealed close agreement between reversible perfusion defects on stress-rest
      MIBI SPECT scans and significant wall thickening on gated MIBI SPECT stress
      images in patients without previous myocardial infarction (95%). Gated MIBI SPECT
      stress, without resting studies, which provide an assessment of wall motion and
      wall thickening, potentially allows stress defect reversibility to be evaluated
      in patients without previous myocardial infarction.

PMID- 10595469
TI  - Biliary sepsis as a cause of appearance of endoluminal Tc-99m HMPAO-labeled
      leukocytes: a case report.
AB  - A case is presented that shows the abnormal early appearance of Tc-99m HMPAO
      labeled leukocytes within the small bowel lumen as a result of septic
      cholangitis. It is essential to perform early images with Tc-99m HMPAO-labeled
      leukocytes to differentiate between the appearance of abnormal uptake in the
      bowel and normal physiologic excretion, which occurs later in the renal and
      biliary tracts. Endoluminal radiolabeled leukocytes have been described in
      several clinical settings unrelated to bowel disease, such as swallowed activity
      from sinus or pulmonary infection, and it is important to differentiate this from
      primary gastrointestinal disease. To our knowledge, acute pyogenic cholangitis
      has not been shown previously as a cause of these appearances and should be
      included in the differential diagnosis for the early appearance of mobile
      radiolabeled leukocytes in the lumen of the gastrointestinal tract.

PMID- 10595470
TI  - Tc-99m DMSA renal scan in first-time versus recurrent urinary tract infection
      yield and patterns of abnormalities.
AB  - PURPOSE: To determine the yield and patterns of abnormalities noted by Tc-99m
      DMSA renal imaging in cases of first-time versus recurrent urinary tract
      infections (UTIs) in children. MATERIALS AND METHODS: We reviewed 101 Tc-99m DMSA
      studies performed for 52 first-time and 49 recurrent UTIs in 99 children during a
      period of 1 year. The average age of the patients was 4.4 years, and the
      female:male ratio was 7:1. Static images of the kidneys were acquired 2 hours
      after injection of Tc-99m DMSA in anterior, posterior, and right and left
      posterior oblique views. SPECT was performed in 9% of the cases. The studies were
      scored as normal or abnormal. RESULTS: The yield of abnormal scans in first-time
      UTIs was 22 (42%) and in recurrent UTI 27 (55%). Three categories of
      abnormalities were noted: 1) renal cortical defects (55% of the abnormal scans in
      first-time UTIs and 59% of the abnormal scans in recurrent UTIs; P = 0.40); 2)
      dilated pelvicalyceal system (27% of the abnormal studies in first-time UTIs and
      63% of the abnormal studies in recurrent UTIs; P < 0.01); and 3) renal swelling
      showing disproportionate function with size (41% of the abnormal scans in first
      time UTIs and 22% of the abnormal scans in recurrent UTIs; P = 0.21).
      CONCLUSIONS: The high yield of renal abnormalities by Tc-99m DMSA scanning
      emphasizes the importance of testing all cases of UTI, including patients with a
      first-time infection. Documentation of the pattern of abnormalities may help in
      planning for subsequent management of UTIs in these patients.

PMID- 10595471
TI  - Radionuclide renal scan findings in rupture of the ureter: a case report.
AB  - Radionuclide renal scan findings in a patient with iatrogenic rupture of the
      ureter are reported. Although the literature contains reports of the radionuclide
      scan in rupture of the ureter from other causes, this, to our knowledge is the
      first description of the scan findings in iatrogenic rupture.

PMID- 10595472
TI  - Value of Ga-67 SPECT in monitoring the effects of therapy in invasive
      aspergillosis of the sphenoid sinus.
AB  - PURPOSE: We report a case of invasive sphenoid sinus aspergillosis clinically
      presenting as a pituitary mass. METHODS: After exploration via the trans
      sphenoidal approach and subsequent treatment with amphotericin-B, Ga-67 brain
      SPECT was performed twice to monitor the therapeutic effect. RESULTS: Three
      months after antifungal treatment, Ga-67 brain SPECT showed partial resolution of
      the lesion in the sella turcica region. The patient continued with fluconazole
      treatment for another 2 months and received another Ga-67 brain SPECT, which
      showed complete clearing of the previous lesion. CONCLUSION: Ga-67 brain SPECT
      may play a potentially useful role in monitoring the therapeutic effect of
      treatment of invasive sphenoid sinus aspergillosis.

PMID- 10595473
TI  - Retropharyngeal abscess on a Ga-67 scan: a case report.
AB  - A retropharyngeal abscess is a potentially fatal deep neck infection. Classical
      symptoms include fever, neck swelling, sore throat, dysphagia, and cervical
      rigidity. Sometimes small children present with nonspecific symptoms. We report a
      rare case whereby the Ga-67 citrate scan was the first investigation to reveal an
      inflammatory process in the retropharyngeal or submastoid region of a 3-year-old
      child with sepsis. This directed the line of investigation to a more precise
      anatomic imaging modality, CT scanning, to localize the abscess. With prompt
      administration of intravenous antibiotics, the child recovered quickly and did
      not require surgery. The Ga-67 scan is thus a useful screening test to detect
      inflammatory foci because of its high sensitivity. It is also valuable in the
      follow-up of the patient's response to therapy.

PMID- 10595474
TI  - The clinical usefulness of F-18 FDG coincidence PET without attenuation
      correction and without whole-body scanning mode in pulmonary lesions comparison
      with CT, MRI, and clinical findings.
AB  - PURPOSE: This study was undertaken to assess the clinical usefulness of fluorine
      18 flurodeoxyglucose (F-18 FDG) coincidence detection (CoDe) positron emission
      tomography (PET) of various lung lesions by comparing it with CT, MRI, and
      clinical findings. MATERIALS AND METHODS: Forty-two patients with pulmonary
      lesions underwent CoDe PET using a dual-head gamma camera equipped with a 5/8
      inch thick NaI (Tl) crystals. The patients were prepared for the study by
      overnight fasting. Data was acquired at approximately 1 hour after the
      intravenous injection of 111 to 370 MBq (3 to 10 mCi) of F-18 FDG. A spinal scan
      of the thorax was performed using a slip ring gantry for 30 minutes. After
      rebinning, routine tomographic slices were reconstructed without attenuation
      correction and the images were analyzed visually. RESULTS: Pathologic diagnoses
      and staging were obtained at surgery in nine patients; in the remaining 33
      patients, aspiration cytology was available. CoDe PET detected all 35
      pathologically proved malignant lesions. In nine patients who underwent surgery,
      seven CoDe PET studies corresponded with pathologic staging, whereas in six of
      the nine patients, CT and MRI corresponded with the pathologic findings. Seven
      patients also had benign lesions that showed FDG uptake. CONCLUSIONS: F-18 FDG
      CoDe PET was sensitive in the evaluation of lung lesions but was not specific for
      malignancy. F-18 FDG CoDe PET was more sensitive than CT and MRI in nodal staging
      in the limited number of patients studied thus far.

PMID- 10595475
TI  - FDG positron emission tomography in head and neck cancer: pitfall or pathology?
AB  - PURPOSE: Fluorodeoxyglucose (FDG) positron emission tomography (PET) is a
      functional imaging technique used for imaging and staging malignant diseases. In
      many oncologic situations, however, abnormal changes seen on the PET studies are
      not caused by tumor, which is especially true in the head and neck region. The
      authors present an overview of the phenomena that may confound the interpretation
      of the images in head and neck cancer. MATERIALS AND METHODS: FDG PET studies
      were performed in patients with primary head and neck cancer and in patients in
      whom recurrent disease was likely. The results were correlated with clinical
      findings. Eight solitary cases were selected from a total of 180 patients
      studied. RESULTS AND CONCLUSIONS: Benign lesions and iatrogenic and physiologic
      changes may show increased FDG uptake. Therefore, clinical information on
      previous surgical interventions and optimal patient preparation are necessary for
      adequate interpretation. If these prerequisites can be met, benign lesions appear
      to be the only lesions that may interfere with the specificity of FDG PET.

PMID- 10595476
TI  - In-111 octreotide scan in a case of a neuroendocrine tumor of unknown origin.
AB  - Major neuroendocrine tumors contain many somatostatin receptors. This feature
      allows for the localization of primary tumors and tumor metastases by
      scintigraphy with the radiolabeled somatostatin analog octreotide. We describe a
      patient with nonspecific clinical data and ultrasonography and CT that showed an
      isolated focal lesion in the liver. In-111 octreotide scintigraphy was essential
      in establishing the diagnosis of liver metastasis from a neuroendocrine tumor
      confirmed by pathologic findings. Because clinical symptoms recurred,
      ultrasonography and CT were performed a few months after surgery. Both were
      negative. However, In-111 octreotide scintigraphy suggested multiple bone
      metastases and established the diagnosis of bone metastases from a neuroendocrine
      tumor, which was confirmed by Tc-99m MDP bone scans and MRI.

PMID- 10595477
TI  - The usefulness of Tc-99m tetrofosmin scintigraphy in the diagnosis and
      localization of hyperfunctioning parathyroid glands.
AB  - PURPOSE: The aim of the work was to study the diagnostic value of Tc-99m
      tetrofosmin to localize anomalous parathyroid glands in patients with
      hyperparathyroid disease. METHODS: We studied 31 patients, 19 with primary and 12
      with secondary hyperparathyroid disease. Five of these patients were renal graft
      recipients. All patients underwent surgery. Each patient was injected with 555 to
      740 MBq (15 to 20 mCi) Tc-99m tetrofosmin. Subsequently, radionuclide images were
      acquired 15 and 120 minutes after injection using a low-energy, all-purpose,
      parallel-hole collimator. Pertechnetate thyroid scintigraphy was obtained in nine
      cases (24 to 48 h later) when the thyroid activity made it difficult to identify
      the parathyroid glands. RESULTS: All cases showed tracer uptake as early as 15
      minutes after injection. In the group of patients with primary hyperparathyroid
      disease, 15 showed focal uptake in a parathyroid gland, and surgery revealed an
      adenoma in the same location. In one patient with hyperplasia, scintigraphy
      identified only two of four diseased glands. In the three remaining cases,
      scintigraphy showed focal uptake in the lower parathyroid gland, whereas at
      surgery the abnormal gland was located in the upper pole. In the secondary
      hyperparathyroidism group, seven patients showed diffuse tracer uptake in two or
      more glands, and histologic analysis confirmed hyperplasia in all of them. Five
      cases showed focal uptake, with three evaluated after surgery (uptake in the only
      remaining gland); one of them was a renal graft recipient, and the remaining
      patient had chronic renal failure and was receiving hemodialysis. CONCLUSIONS:
      Our results suggest that Tc-99m tetrofosmin may be a suitable tracer for
      preoperative detection and screening of anomalous parathyroid glands. The earlier
      images at 15 minutes were better than those at 120 minutes. Tc-99m tetrofosmin is
      cleared more slowly from the normal thyroid than is Tc-99m sestamibi, and both of
      these tracers may give better results than the old pertechnetate TI-201
      subtraction technique.

PMID- 10595478
TI  - Effect of atropine and sincalide on the intestinal uptake of F-18
      fluorodeoxyglucose.
AB  - PURPOSE: Variable diffuse intestinal uptake of F-18 fluorodeoxyglucose (FDG) is
      commonly seen in patients undergoing positron emission tomography (PET) imaging.
      Diffuse high uptake can obscure a lesion, whereas occasional high focal uptake
      can mimic a lesion. The cause of intestinal FDG uptake and the parameters that
      influence the level of uptake are unknown. METHODS: We hypothesized that
      intestinal FDG uptake may result from smooth muscle peristalsis. We tested our
      hypothesis by comparing FDG uptake at baseline and after administration of two
      drugs (atropine and sincalide) that are known to affect intestinal motility. We
      performed FDG PET scans in random order in five healthy male volunteers without
      medication, after intramuscular administration of atropine, and after intravenous
      administration of sincalide. RESULTS: Qualitative comparison of the images before
      and after both medications did not show any significant difference in the level
      of intestinal FDG uptake. CONCLUSIONS: We conclude that intestinal FDG uptake is
      probably not caused by peristalsis. Mucosal uptake may be an alternative
      explanation.

PMID- 10595479
TI  - Tc-99m sestamibi scintimammography in the mammographically dense breast.
AB  - PURPOSE: The mammographically dense breast or the "difficult-to-interpret
      mammogram" poses significant clinical and diagnostic imaging concerns. From our
      experience using Tc-99m sestamibi mammography in more than 650 patients, we share
      our experience in a pictorial manner and include suggested indications and
      limitations of this exciting new technique. Examples of Tc-99m sestamibi imaging
      in six patients with mammographically dense breasts are presented. MATERIALS AND
      METHODS: All patient examinations were ordered clinically for various
      indications. Comparison radiographic mammography and, when available,
      confirmatory pathologic analysis were also done. The examples were chosen from
      our experience with more than 650 patients at two university hospitals and one
      outpatient imaging center. RESULTS: Of the six examples presented, four had
      cancer, one had fibrosis after chemotherapy for ductal cell carcinoma, and one
      had no evidence of cancer. Tc-99m sestamibi imaging showed no increased uptake in
      the one patient with no tumor and various degrees of uptake in the other five
      patients. CONCLUSIONS: Six examples from our clinical experience show the
      usefulness of Tc-99m sestamibi imaging in patients with mammographically dense
      breasts. The ability to identify a malignancy or its absence supports the
      continued use of this procedure in these patients.

PMID- 10595480
TI  - Metastatic melanoma detected by Tc-99m sestamibi during routine cardiac imaging.

PMID- 10595481
TI  - Detection and follow-up of metastatic melanoma before and after high-dose
      regional chemotherapy by isolated limb perfusion with Tc-99m tetrofosmin.

PMID- 10595482
TI  - Incidental detection of carcinoid with Tc-99m-labeled carcinoembryonic antigen
      monoclonal antibody scintigraphy during evaluation of metastatic colon cancer.

PMID- 10595483
TI  - Hot-to-cold transition of intrasplenic lymphoma after chemotherapy.

PMID- 10595484
TI  - Prostatic bone metastases associated with multifocal Paget's disease.

PMID- 10595485
TI  - Indium-111 capromab pendetide (ProstaScint) images before and after salvage
      radiation therapy.

PMID- 10595486
TI  - Possible false-positive metastatic prostate cancer on an In-111 capromab
      pendetide scan as a result of a pelvic kidney.

PMID- 10595487
TI  - Subarachnoid-pleural fistula complicating thoracoscopy: value of In-111 DTPA
      myeloscintigraphy.

PMID- 10595488
TI  - Cerebrospinal fluid fistula in a congenital lumbar meningocele revealed by
      radionuclide cisternography.

PMID- 10595489
TI  - Healed rib fractures presenting as linear foci of increased tracer uptake on bone
      scintigraphy.

PMID- 10595490
TI  - Extensive rhabdomyolysis after streptokinase therapy for acute myocardial
      infarction demonstrated by Tc-99m PYP scintigraphy.

PMID- 10595491
TI  - Altered biodistribution of Tc-99m MDP in a uremic and severely malnourished
      patient supported with enteral nutritional feeding.

PMID- 10595492
TI  - F-18 FDG uptake in benign esophageal disease.

PMID- 10595493
TI  - A retroesophageal parathyroid adenoma detected with Tc-99m sestamibi and MRI.

PMID- 10595494
TI  - Incidental detection of a vertebral body hemangioma on three-phase bone
      scintigraphy.

PMID- 10595495
TI  - Multicentric epithelioidal hemangioendothelioma of bone: diagnostic imaging.

PMID- 10595496
TI  - Current readings in nuclear medicine.

PMID- 10595497
TI  - TrkB works at postsynaptic sites.

PMID- 10595498
TI  - Whisking away space in the brain.

PMID- 10595499
TI  - Retinal waves: stirring up a storm.

PMID- 10595500
TI  - Calcium on the up: supralinear calcium signaling in central neurons.

PMID- 10595501
TI  - Expanding our understanding of polyglutamine diseases through mouse models.

PMID- 10595502
TI  - Prion protein and the transmissible spongiform encephalopathy diseases.

PMID- 10595503
TI  - Neurodegenerative tauopathies: human disease and transgenic mouse models.

PMID- 10595504
TI  - Assessment of animal models for MS and demyelinating disease in the design of
      rational therapy.

PMID- 10595505
TI  - From Charcot to SOD1: mechanisms of selective motor neuron death in ALS.

PMID- 10595506
TI  - Neuroplasticity failure in Alzheimer's disease: bridging the gap between plaques
      and tangles.

PMID- 10595507
TI  - Serotonergic neurons transiently require a midline-derived FGF signal.
AB  - In the grasshopper CNS, serotonergic growth cones cross the midline early in
      development and initiate expression of serotonin uptake activity, or SERT. To
      test if the midline contains an activity that induces SERT, cuts were made that
      separated serotonergic cell bodies from the midline. SERT activity is completely
      lost when the midline is separated but is then rescued by bath-applied FGF2
      (fibroblast growth factor 2), which can activate the heartless FGF receptor.
      heartless is expressed specifically in serotonergic neurons. A candidate FGF-like
      molecule was identified that is expressed in a subset of midline glia. SERT
      expressing severed growth cones continue to migrate to their correct targets,
      which indicates that by the time SERT is activated, the serotonergic growth cones
      are committed to target-directed growth.

PMID- 10595508
TI  - Misexpression of the Emx-related homeobox genes cVax and mVax2 ventralizes the
      retina and perturbs the retinotectal map.
AB  - The mechanisms that establish the dorsal-ventral (D-V) axis of the eye are poorly
      understood. We isolated two homeobox genes from mouse and chicken, mVax2 and
      cVax, whose expression during early eye development is restricted to the ventral
      retina. In chick, ectopic expression of either Vax leads to ventralization of the
      early retina, as assayed by expression of the transcription factors Pax2 and
      Tbx5, and the Eph family members EphB2, EphB3, ephrinB1, and ephrinB2, all of
      which are normally dorsally or ventrally restricted. Moreover, the projections of
      dorsal but not ventral ganglion cell axons onto the optic tectum showed profound
      targeting errors following cVax misexpression. mVax2/cVax thus specify positional
      identity along the D-V axis of the retina and influence retinotectal mapping.

PMID- 10595509
TI  - Development of noradrenergic neurons in the zebrafish hindbrain requires BMP,
      FGF8, and the homeodomain protein soulless/Phox2a.
AB  - We report that the zebrafish mutation soulless, in which the development of locus
      coeruleus (LC) noradrenergic (NA) neurons failed to occur, disrupts the
      homeodomain protein Phox2a. Phox2a is not only necessary but also sufficient to
      induce Phox2b+ dopamine-beta-hydroxylase+ and tyrosine hydroxylase+ NA neurons in
      ectopic locations. Phox2a is first detected in LC progenitors in the dorsal
      anterior hindbrain, and its expression there is dependent on FGF8 from the
      mid/hindbrain boundary and on optimal concentrations of BMP signal from the
      epidermal ectoderm/future dorsal neural plate junction. These findings suggest
      that Phox2a coordinates the specification of LC in part through the induction of
      Phox2b and in response to cooperating signals that operate along the mediolateral
      and anteroposterior axes of the neural plate.

PMID- 10595510
TI  - Disruption of Trkb-mediated signaling induces disassembly of postsynaptic
      receptor clusters at neuromuscular junctions.
AB  - Neurotrophins and tyrosine receptor kinase (Trk) receptors are expressed in
      skeletal muscle, but it is unclear what functional role Trk-mediated signaling
      plays during postnatal life. Full-length TrkB (trkB.FL) as well as truncated TrkB
      (trkB.t1) were found to be localized primarily to the postsynaptic acetylcholine
      receptor- (AChR-) rich membrane at neuromuscular junctions. In vivo, dominant
      negative manipulation of TrkB signaling using adenovirus to overexpress trkB.t1
      in mouse sternomastoid muscle fibers resulted in the disassembly of postsynaptic
      AChR clusters at neuromuscular junctions, similar to that observed in mutant
      trkB+/- mice. When TrkB-mediated signaling was disrupted in cultured myotubes in
      the absence of motor nerve terminals and Schwann cells, agrin-induced AChR
      clusters were also disassembled. These results demonstrate a novel role for
      neurotrophin signaling through TrkB receptors on muscle fibers in the ongoing
      maintenance of postsynaptic AChR regions.

PMID- 10595511
TI  - Neurotrophin binding to the p75 receptor modulates Rho activity and axonal
      outgrowth.
AB  - While the neurotrophin receptor p75NTR is expressed by many developing neurons,
      its function in cells escaping elimination by programmed cell death remains
      unclear. The lack of intrinsic enzymatic activity of p75NTR prompted a search for
      protein interactors expressed in the developing retina, which resulted in the
      identification of the GTPase RhoA. In transfected cells, p75NTR activated RhoA,
      and neurotrophin binding abolished RhoA activation. In cultured neurons,
      inactivation of Rho proteins mimicked the effect of neurotrophins by increasing
      the rate of neurite elongation. In vivo, axonal outgrowth was retarded in mice
      carrying a mutation in the p75NTR gene. These results indicate that p75NTR
      modulates in a ligand-dependent fashion the activity of intracellular proteins
      known to regulate actin assembly.

PMID- 10595512
TI  - The SH2/SH3 adaptor protein dock interacts with the Ste20-like kinase misshapen
      in controlling growth cone motility.
AB  - Recent studies suggest that the SH2/SH3 adaptor Dock/Nck transduces tyrosine
      phosphorylation signals to the actin cytoskeleton in regulating growth cone
      motility. The signaling cascade linking the action of Dock/Nck to the
      reorganization of cytoskeleton is poorly understood. We now demonstrate that Dock
      interacts with the Ste20-like kinase Misshapen (Msn) in the Drosophila
      photoreceptor (R cell) growth cones. Loss of msn causes a failure of growth cones
      to stop at the target, a phenotype similar to loss of dock, whereas
      overexpression of msn induces pretarget growth cone termination. Physical and
      genetic interactions between Msn and Dock indicate a role for Msn in the Dock
      signaling pathway. We propose that Msn functions as a key controller of growth
      cone cytoskeleton in response to Dock-mediated signals.

PMID- 10595513
TI  - Extension of long leading processes and neuronal migration in the mammalian brain
      directed by the chemoattractant netrin-1.
AB  - Long distance cell migration occurs throughout the developing CNS, but the
      underlying cellular and molecular mechanisms are poorly understood. We show that
      the directed circumferential migration of basilar pontine neurons from their
      origin in the neuroepithelium of the dorsal hindbrain to the ventral midline
      involves the extension of long (>1 mm) leading processes, which marker analyses
      suggest are molecularly distinct from axons. In vivo analysis of knockout mice
      implicates the axonal chemoattractant netrin-1, functioning via its receptor
      Deleted in Colorectal Cancer (DCC), in attracting the leading process to the
      ventral midline. Direct evidence for this chemoattractant mechanism is provided,
      using explant cultures and time-lapse analysis in vitro. Our results demonstrate
      the attraction of migrating neurons in the mammalian brain by an axon guidance
      molecule and the chemotactic responsiveness of their leading processes.

PMID- 10595514
TI  - Two directions of plasticity in the sensory-deprived adult cortex.
AB  - Damage or deprivation of a localized region of the skin surface has been shown to
      induce a selective expansion of adjacent skin surface representations in the
      adult somatosensory cortex. Here, we use repeated optical imaging in conjunction
      with single unit recordings to assess the plasticity of a single whisker's
      functional representation in the adult rat. We observed a large-scale expansion
      of a single whisker's functional representation following innocuous removal of
      all neighboring whiskers. Surprisingly, the same manipulation can also induce a
      large-scale contraction of the representation if the animal is removed from its
      home cage and given a brief opportunity to use its whiskers for active
      exploration of a different environment. Both the expansion and contraction
      reverse upon regrowth of the deprived whiskers. Thus, allowing the animal to use
      its deprived receptor organ in active exploration can determine the direction of
      plasticity in the adult cortex.

PMID- 10595515
TI  - A therapeutic vaccine approach to stimulate axon regeneration in the adult
      mammalian spinal cord.
AB  - Axon growth inhibitors associated with myelin play an important role in the
      failure of axon regeneration in the adult mammalian central nervous system (CNS).
      Several inhibitors are present in the mature CNS. We now present a novel
      therapeutic vaccine approach in which the animals' own immune system is
      stimulated to produce polyclonal antibodies that block myelin-associated
      inhibitors without producing any detrimental cellular inflammatory responses.
      Adult mice immunized in this manner showed extensive regeneration of large
      numbers of axons of the corticospinal tracts after dorsal hemisection of the
      spinal cord. The anatomical regeneration led to recovery of certain hind limb
      motor functions. Furthermore, antisera from immunized mice were able to block
      myelin-derived inhibitors and promote neurite growth on myelin in vitro.

PMID- 10595516
TI  - Role of AMPA receptor cycling in synaptic transmission and plasticity.
AB  - Compounds known to disrupt exocytosis or endocytosis were introduced into CA1
      pyramidal cells while monitoring excitatory postsynaptic currents (EPSCs).
      Disrupting exocytosis or the interaction of GluR2 with NSF caused a gradual
      reduction in the AMPAR EPSC, while inhibition of endocytosis caused a gradual
      increase in the AMPAR EPSC. These manipulations had no effect on the NMDAR EPSC
      but prevented the subsequent induction of LTD. These results suggest that AMPARs,
      but not NMDARs, cycle into and out of the synaptic membrane at a rapid rate and
      that certain forms of synaptic plasticity may utilize this dynamic process.

PMID- 10595518
TI  - Dynamics of retinal waves are controlled by cyclic AMP.
AB  - Waves of spontaneous activity sweep across the developing mammalian retina and
      influence the pattern of central connections made by ganglion cell axons. These
      waves are driven by synaptic input from amacrine cells. We show that cholinergic
      synaptic transmission during waves is not blocked by TTX, indicating that release
      from starburst amacrine cells is independent of sodium action potentials. The
      spatiotemporal properties of the waves are regulated by endogenous release of
      adenosine, which sets intracellular cAMP levels through activation of A2
      receptors present on developing amacrine and ganglion cells. Increasing cAMP
      levels increase the size, speed, and frequency of the waves. Conversely,
      inhibiting adenylate cyclase or PKA prevents wave activity. Together, these
      results imply a novel mechanism in which levels of cAMP within an immature
      retinal circuit regulate the precise spatial and temporal patterns of spontaneous
      neural activity.

PMID- 10595517
TI  - Cypin: a cytosolic regulator of PSD-95 postsynaptic targeting.
AB  - Postsynaptic density 95 (PSD-95/SAP-90) is a membrane associated guanylate kinase
      (GK) PDZ protein that scaffolds glutamate receptors and associated signaling
      networks at excitatory synapses. Affinity chromatography identifies cypin as a
      major PSD-95-binding protein in brain extracts. Cypin is homologous to a family
      of hydrolytic bacterial enzymes and shares some similarity with collapsin
      response mediator protein (CRMP), a cytoplasmic mediator of semaphorin III
      signalling. Cypin is discretely expressed in neurons and is polarized to basal
      membranes in intestinal epithelial cells. Overexpression of cypin in hippocampal
      neurons specifically perturbs postsynaptic trafficking of PSD-95 and SAP-102, an
      effect not produced by overexpression of other PDZ ligands. In fact, PSD-95 can
      induce postsynaptic clustering of an otherwise diffusely localized K+ channel,
      Kv1.4. By regulating postsynaptic protein sorting, cypin may influence synaptic
      development and plasticity.

PMID- 10595519
TI  - Essential roles in synaptic plasticity for synaptogyrin I and synaptophysin I.
AB  - We have generated mice lacking synaptogyrin I and synaptophysin I to explore the
      functions of these abundant tyrosine-phosphorylated proteins of synaptic
      vesicles. Single and double knockout mice were alive and fertile without
      significant morphological or biochemical changes. Electrophysiological recordings
      in the hippocampal CA1 region revealed that short-term and long-term synaptic
      plasticity were severely reduced in the synaptophysin/synaptogyrin double
      knockout mice. LTP was decreased independent of the induction protocol,
      suggesting that the defect in LTP was not caused by insufficient induction. Our
      data show that synaptogyrin I and synaptophysin I perform redundant and essential
      functions in synaptic plasticity without being required for neurotransmitter
      release itself.

PMID- 10595520
TI  - Facilitation of NMDAR-independent LTP and spatial learning in mutant mice lacking
      ryanodine receptor type 3.
AB  - To evaluate the role in synaptic plasticity of ryanodine receptor type 3 (RyR3),
      which is normally enriched in hippocampal area CA1, we generated RyR3-deficient
      mice. Mutant mice exhibited facilitated CA1 long-term potentiation (LTP) induced
      by short tetanus (100 Hz, 100 ms) stimulation. Unlike LTP in wild-type mice, this
      LTP was not blocked bythe NMDA receptor antagonist D-AP5 but was partially
      dependent on L-type voltage-dependent Ca2+ channels (VDCCs) and metabotropic
      glutamate receptors (mGluRs). Long-term depression (LTD) was not induced in RyR3
      deficient mice. RyR3-deficient mice also exhibited improved spatial learning on a
      Morris water maze task. These results suggest that in wild-type mice, in contrast
      to the excitatory role of Ca2+ influx, RyR3-mediated intracellular Ca2+ ([Ca2+]i)
      release from endoplasmic reticulum (ER) may inhibit hippocampal LTP and spatial
      learning.

PMID- 10595521
TI  - ERK plays a regulatory role in induction of LTP by theta frequency stimulation
      and its modulation by beta-adrenergic receptors.
AB  - MAP kinase (ERK) translates cell surface signals into alterations in
      transcription. We have found that ERK also regulates hippocampal neuronal
      excitability during 5 Hz stimulation and thereby regulates forms of long-term
      potentiation (LTP) that do not require macromolecular synthesis. Moreover, ERK
      mediated changes in excitability are selectively required for some forms of LTP
      but not others. ERK is required for the early phase of LTP elicited by brief 5 Hz
      stimulation, as well as for LTP elicited by more prolonged 5 Hz stimulation when
      paired with beta1-adrenergic receptor activation. By contrast, ERK plays no role
      in LTP elicited by a single 1 s 100 Hz train. Consistent with these results, we
      find that ERK is activated by beta-adrenergic receptors in CA1 pyramidal cell
      somas and dendrites.

PMID- 10595522
TI  - Synergistic release of Ca2+ from IP3-sensitive stores evoked by synaptic
      activation of mGluRs paired with backpropagating action potentials.
AB  - Increases in postsynaptic [Ca2+]i can result from Ca2+ entry through ligand-gated
      channels or voltage-gated Ca2+ channels, or through release from intracellular
      stores. Most attention has focused on entry through the N-methyl-D-aspartate
      (NMDA) receptor in causing [Ca2+]i increases since this pathway requires both
      presynaptic stimulation and postsynaptic depolarization, making it a central
      component in models of synaptic plasticity. Here, we report that repetitive
      synaptic activation of metabotropic glutamate receptors (mGluRs), paired with
      backpropagating action potentials, causes large, wave-like increases in [Ca2+]i
      predominantly in restricted regions of the proximal apical dendrites and soma of
      hippocampal CA1 pyramidal neurons. [Ca2+]i changes of several micromolars can be
      reached by regenerative release caused by the synergistic effect of mGluR
      generated inositol 1,4,5-trisphosphate (IP3) and spike-evoked Ca2+ entry acting
      on the IP3 receptor.

PMID- 10595523
TI  - Ataxia and abnormal cerebellar microorganization in mice with ablated contactin
      gene expression.
AB  - Axon guidance and target recognition depend on neuronal cell surface receptors
      that recognize and elicit selective growth cone responses to guidance cues in the
      environment. Contactin, a cell adhesion/recognition molecule of the
      immunoglobulin gene superfamily, regulates axon growth and fasciculation in
      vitro, but its role in vivo is unknown. To assess its function in the developing
      nervous system, we have ablated contactin gene expression in mice. Contactin-/-
      mutants displayed a severe ataxic phenotype consistent with defects in the
      cerebellum and survived only until postnatal day 18. Analysis of the contactin-/-
      mutant cerebellum revealed defects in granule cell axon guidance and in dendritic
      projections from granule and Golgi cells. These results demonstrate that
      contactin controls axonal and dendritic interactions of cerebellar interneurons
      and contributes to cerebellar microorganization.

PMID- 10595524
TI  - Age-dependent emergence and progression of a tauopathy in transgenic mice
      overexpressing the shortest human tau isoform.
AB  - Filamentous tau aggregates are hallmarks of tauopathies, e.g., frontotemporal
      dementia with parkinsonism linked to chromosome 17 (FTDP-17) and amyotrophic
      lateral sclerosis/parkinsonism-dementia complex (ALS/PDC). Since FTDP-17 tau gene
      mutations alter levels/functions of tau, we overexpressed the smallest human tau
      isoform in the CNS of transgenic (Tg) mice to model tauopathies. These mice
      acquired age-dependent CNS pathology similarto FTDP-17 and ALS/PDC, including
      insoluble, hyperphosphorylated tau and argyrophilic intraneuronal inclusions
      formed by tau-immunoreactive filaments. Inclusions were present in cortical and
      brainstem neurons but were most abundant in spinal cord neurons, where they were
      associated with axon degeneration, diminished microtubules (MTs), and reduced
      axonal transport in ventral roots, as well as spinal cord gliosis and motor
      weakness. These Tg mice recapitulate key features of tauopathies and provide
      models for elucidating mechanisms underlying diverse tauopathies, including
      Alzheimer's disease (AD).

PMID- 10595525
TI  - The interaction of neurotrophins with the p75NTR common neurotrophin receptor: a
      comprehensive molecular modeling study.
AB  - Neurotrophins are a family of proteins with pleiotropic effects mediated by two
      distinct receptor types, namely the Trk family, and the common neurotrophin
      receptor p75NTR. Binding of four mammalian neurotrophins, nerve growth factor
      (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and
      neurotrophin-4/5 (NT-4/5), to p75NTR is studied by molecular modeling based on X
      ray structures of the neurotrophins and the extracellular domain of p55TNFR, a
      homologue of p75NTR. The model of neurotrophin/receptor interactions suggests
      that the receptor binding domains of neurotrophins (loops I and IV) are
      geometrically and electrostatically complementary to a putative binding site of
      p75NTR, formed by the second and part of the third cysteine-rich domains.
      Geometric match of neurotrophin/receptor binding domains in the complexes, as
      characterized by shape complementarity statistic Sc, is comparable to known
      protein/protein complexes. All charged residues within the loops I and IV of the
      neurotrophins, previously determined as being critical for p75NTR binding,
      directly participate in receptor binding in the framework of the model. Principal
      residues of the binding site of p75NTR include Asp47, Lys56, Asp75, Asp76, Asp88,
      and Glu89. The additional involvement of Arg80 and Glu53 is specific for NGF and
      BDNF, respectively, and Glu73 participates in binding with NT-3 and NT-4/5.
      Neurotrophins are likely to induce similar, but not identical, conformational
      changes within the p75NTR binding site.

PMID- 10595526
TI  - The turn sequence directs beta-strand alignment in designed beta-hairpins.
AB  - A previous NMR investigation of model decapeptides with identical beta-strand
      sequences and different turn sequences demonstrated that, in these peptide
      systems, the turn residues played a more predominant role in defining the type of
      beta-hairpin adopted than cross-strand side-chain interactions. This result
      needed to be tested in longer beta-hairpin forming peptides, containing more
      potentially stabilizing cross-strand hydrogen bonds and side-chain interactions
      that might counterbalance the influence of the turn sequence. In that direction,
      we report here on the design and 1H NMR conformational study of three beta
      hairpin forming pentadecapeptides. The design consists of adding two and three
      residues at the N- and C-termini, respectively, of the previously studied
      decapeptides. One of the designed pentadecapeptides includes a potentially
      stabilizing R-E salt bridge to investigate the influence of this interaction on
      beta-hairpin stability. We suggest that this peptide self-associates by forming
      intermolecular salt bridges. The other two pentadecapeptides behave as monomers.
      A conformational analysis of their 1H NMR spectra reveals that they adopt
      different types of beta-hairpin structure despite having identical strand
      sequences. Hence, the beta-turn sequence drives beta-hairpin formation in the
      investigated pentadecapeptides that adopt beta-hairpins that are longer than the
      average protein beta-hairpins. These results reinforce our previous suggestion
      concerning the key role played by the turn sequence in directing the kind of beta
      hairpin formed by designed peptides.

PMID- 10595527
TI  - Intrabody construction and expression III: engineering hyperstable V(H) domains.
AB  - The folding of immunoglobulin domains requires the formation of a conserved
      structural disulfide. Therefore, as a general rule, they cannot be functionally
      expressed in the reducing environment of the cellular cytoplasm. We have
      previously reported that stability engineering can lead to the cytoplasmic
      expression of functional immunoglobulin V(L) domains. Here we apply rational
      stability engineering by consensus sequence analysis to V(H) domains. Isolated
      V(H) domains tend to aggregate more easily than V(L) domains; they do not refold
      quantitatively and are generally more difficult to handle in vitro. To overcome
      these problems, we successfully predicted and experimentally verified several
      stabilizing point mutations in the V(H) domain of a designed, catalytic Fv
      fragment. The effect of single mutations was additive, and they could be combined
      in a prototype domain with significantly improved stability against chemical
      denaturation and a 20-fold increased half time of irreversible thermal
      denaturation, at physiological temperature. This stabilized, isolated V(H) domain
      could be expressed solubly in the reducing cellular cytoplasm of Escherichia
      coli, at a yield of approximately 1.2 mg/L of shake flask culture. It remains
      fully functional, as evidenced by the successful reconstitution of an esterolytic
      Fv fragment with the V(L) domain. This success provides further evidence that
      consensus sequence engineering is a rational, plannable route to the construction
      of intrabodies.

PMID- 10595528
TI  - Folding of an isolated ribonuclease H core fragment.
AB  - Based on results from both equilibrium and kinetic hydrogen exchange studies of
      Escherichia coli ribonuclease HI (RNase H), a fragment of RNase H (eABCD) was
      designed. The sequence of eABCD contains less than half of the protein's primary
      sequence and includes the regions that were shown to be the most protected from
      hydrogen exchange in all previous studies of RNase H. This core fragment of RNase
      H encodes a well-ordered protein with native-like properties. When isolated from
      the full-length monomeric protein, the eABCD fragment forms a stable dimer.
      However, we show indirectly that the monomeric form of eABCD is folded and has an
      overall secondary structure similar to the dimeric form.

PMID- 10595529
TI  - Crystal structure of brain-type creatine kinase at 1.41 A resolution.
AB  - Excitable cells and tissues like muscle or brain show a highly fluctuating
      consumption of ATP, which is efficiently regenerated from a large pool of
      phosphocreatine by the enzyme creatine kinase (CK). The enzyme exists in tissue-
      as well as compartment-specific isoforms. Numerous pathologies are related to the
      CK system: CK is found to be overexpressed in a wide range of solid tumors,
      whereas functional impairment of CK leads to a deterioration in energy
      metabolism, which is phenotypic for many neurodegenerative and age-related
      diseases. The crystal structure of chicken cytosolic brain-type creatine kinase
      (BB-CK) has been solved to 1.41 A resolution by molecular replacement. It
      represents the most accurately determined structure in the family of guanidino
      kinases. Except for the N-terminal region (2-12), the structures of both monomers
      in the biological dimer are very similar and closely resemble those of the other
      known structures in the family. Specific Ca2+-mediated interactions, found
      between two dimers in the asymmetric unit, result in structurally independent
      heterodimers differing in their N-terminal conformation and secondary structure.
      The high-resolution structure of BB-CK presented in this work will assist in
      designing new experiments to reveal the molecular basis of the multiple isoform
      specific properties of CK, especially regarding different subcellular locations
      and functional interactions with other proteins. The rather similar fold shared
      by all known guanidino kinase structures suggests a model for the transition
      state complex of BB-CK analogous to the one of arginine kinase (AK). Accordingly,
      we have modeled a putative conformation of CK in the transition state that
      requires a rigid body movement of the entire N-terminal domain by rms 4 A from
      the structure without substrates.

PMID- 10595531
TI  - Molecular dynamics investigation of the effect of an antiviral compound on human
      rhinovirus.
AB  - The factors that influence the enhanced stability observed experimentally of
      human rhinovirus 14 (HRV14) upon binding a hydrophobic antiviral drug have been
      investigated by molecular dynamics. Simulations centered about the HRV14 drug
      binding pocket allow the reliable assessment of differences in capsid protein
      motions of HRV14 and drug-bound HRV14. We propose that the experimentally
      observed stabilization of the ligated virus arises from higher entropy, rather
      than enthalpy. Time-averaged interaction energies between the viral protein and
      molecules occupying the pocket are less favorable in the presence of the drug,
      consistent with the proposal that the observed stability arises from entropic
      effects. Interaction energies characterizing subunit-subunit contacts within one
      viral protomer are found to be substantially stronger than those between two
      protomers. Such distinction in subunit interaction would have clear implications
      on assembly and disassembly. Drug binding is found to affect large-scale,
      collective properties, while leaving local atomic properties unperturbed.
      Specifically, the simulations reveal a weakening of long-range correlations in
      atomic motions upon drug binding. On the other hand, neither the fast time scale
      RMS fluctuations of individual atomic positions nor the fluctuation build-up
      curves from the capsid beta-sandwich forming the drug-binding pocket show a
      consistent distinction between the drug-bound and drug-free viral simulations.
      Collectively, the detailed description available from the simulations provides an
      understanding of the experimental observations on the drug-induced changes in
      thermal stability and protease sensitivity reported for picornaviruses. The
      predicted significance of binding entropy can be explored experimentally and
      should be considered in the design of new antiviral compounds.

PMID- 10595530
TI  - The solution structure of the anti-HIV chemokine vMIP-II.
AB  - We report the solution structure of the chemotactic cytokine (chemokine) vMIP-II.
      This protein has unique biological activities in that it blocks infection by
      several different human immunodeficiency virus type 1 (HIV-1) strains. This
      occurs because vMIP-II binds to a wide range of chemokine receptors, some of
      which are used by HJV to gain cell entry. vMIP-II is a monomeric protein, unlike
      most members of the chemokine family, and its structure consists of a disordered
      N-terminus, followed by a helical turn (Gln25-Leu27), which leads into the first
      strand of a three-stranded antiparallel beta-sheet (Ser29-Thr34; Gly42-Thr47;
      Gln52-Asp56). Following the sheet is a C-terminal alpha-helix, which extends from
      residue Asp60 until Gln68. The final five residues beyond the C-terminal helix
      (Pro70-Arg74) are in an extended conformation, but several of these C-terminal
      residues contact the first beta-strand. The structure of vMIP-II is compared to
      other chemokines that also block infection by HIV-1, and the structural basis of
      its lack of ability to form a dimer is discussed.

PMID- 10595532
TI  - Limited proteolysis of bovine alpha-lactalbumin: isolation and characterization
      of protein domains.
AB  - The partly folded states of alpha-lactalbumin (alpha-LA) exposed to acid solution
      at pH 2.0 (A-state) or at neutral pH upon EDTA-mediated removal of the single
      protein-bound calcium ion (apo form) have been probed by limited proteolysis
      experiments. These states are nowadays commonly considered to be molten globules
      and thus protein-folding intermediates. Pepsin was used for proteolysis at acid
      pH, while proteinase K and chymotrypsin at neutral pH. The expectations were that
      these proteolytic probes would detect sites and/or chain regions in the partly
      folded states of alpha-LA sufficiently dynamic, or even unfolded, capable of
      binding and adaptation to the specific stereochemistry of the protease's active
      site. A time-course analysis of the proteolytic events revealed that the fast,
      initial proteolytic cuts of the 123-residue chain of alpha-LA in its A-state or
      apo form by the three proteases occur at the same chain region 39-54, the actual
      site(s) of cleavage depending upon the protease employed. This region in native
      alpha-LA encompasses the beta-sheets of the protein. Subsequent cleavages occur
      mostly at chain regions 31-35 and 95-105. Four fragment species of alpha-LA have
      been isolated by reverse-phase high-performance liquid chromatography, and their
      conformational properties examined by circular dichroism and fluorescence
      emission spectroscopy. The single chain fragment 53-103, containing all the
      binding sites for calcium in native alpha-LA and cross-linked by two disulfide
      bridges, maintains in aqueous buffer and in the presence of calcium ions a folded
      structure characterized by the same content of alpha-helix of the corresponding
      chain segment in native alpha-LA. Evidence for some structure was also obtained
      for the two-chain species 1-40 and 104-123, as well as 1-31 and 105-123, both
      systems being covalently linked by two disulfide bonds. In contrast, the protein
      species given by fragment 1-34 connected to fragment 54-123 or 57-123 via four
      disulfide bridges adopts in solution a folded structure with the helical content
      expected for a native-like conformation. Of interest, the proteolytic fragment
      species herewith isolated correspond to the structural domains and subdomains of
      alpha-LA that can be identified by computational analysis of the three
      dimensional structure of native alpha-LA (Siddiqui AS, Barton GI, 1995, Protein
      Sci 4:872-884). The fast, initial cleavages at the level of the beta-sheet region
      of native alpha-LA indicate that this region is highly mobile or even unfolded in
      the alpha-LA molten globule(s), while the rest of the protein chain maintains
      sufficient structure and rigidity to prevent extensive proteolysis. The
      subsequent cleavages at chain segment 95-105 indicate that also this region is
      somewhat mobile in the A-state or apo form of the protein. It is concluded that
      the overall domain topology of native alpha-LA is maintained in acid or at
      neutral pH upon calcium depletion. Moreover, the molecular properties of the
      partly folded states of alpha-LA deduced here from proteolysis experiments do
      correlate with those derived from previous NMR and other physicochemical
      measurements.

PMID- 10595533
TI  - Identification of ligand effector binding sites in transmembrane regions of the
      human G protein-coupled C3a receptor.
AB  - The human C3a anaphylatoxin receptor (C3aR) is a G protein-coupled receptor
      (GPCR) composed of seven transmembrane alpha-helices connected by hydrophilic
      loops. Previous studies of chimeric C3aR/C5aR and loop deletions in C3aR
      demonstrated that the large extracellular loop2 plays an important role in
      noneffector ligand binding; however, the effector binding site for C3a has not
      been identified. In this study, selected charged residues in the transmembrane
      regions of C3aR were replaced by Ala using site-directed mutagenesis, and mutant
      receptors were stably expressed in the RBL-2H3 cell line. Ligand binding studies
      demonstrated that R161A (helix IV), R340A (helix V), and D417A (helix VII) showed
      no binding activity, although full expression of these receptors was established
      by flow cytometric analysis. C3a induced very weak intracellular calcium flux in
      cells expressing these three mutant receptors. H81A (helix II) and K96A (helix
      III) showed decreased ligand binding activity. The calcium flux induced by C3a in
      H81A and K96A cells was also consistently reduced. These findings suggest that
      the charged transmembrane residues Arg161, Arg340, and Asp417 in C3aR are
      essential for ligand effector binding and/or signal coupling, and that residues
      His81 and Lys96 may contribute less directly to the overall free energy of ligand
      binding. These transmembrane residues in C3aR identify specific molecular
      contacts for ligand interactions that account for C3a-induced receptor
      activation.

PMID- 10595534
TI  - The role of position a in determining the stability and oligomerization state of
      alpha-helical coiled coils: 20 amino acid stability coefficients in the
      hydrophobic core of proteins.
AB  - We describe here a systematic investigation into the role of position a in the
      hydrophobic core of a model coiled-coil protein in determining coiled-coil
      stability and oligomerization state. We employed a model coiled coil that allowed
      the formation of an extended three-stranded trimeric oligomerization state for
      some of the analogs; however, due to the presence of a Cys-Gly-Gly linker,
      unfolding occurred from the same two-stranded monomeric oligomerization state for
      all of the analogs. Denaturation from a two-stranded state allowed us to measure
      the relative contribution of 20 different amino acid side chains to coiled-coil
      stability from chemical denaturation profiles. In addition, the relative
      hydrophobicity of the substituted amino acid side chains was assessed by reversed
      phase high-performance liquid chromatography and found to correlate very highly
      (R = 0.95) with coiled-coil stability. We also determined the effect of position
      a in specifying the oligomerization state using ultracentrifugation as well as
      high-performance size-exclusion chromatography. We found that nine of the analogs
      populated one oligomerization state exclusively at peptide concentrations of 50
      microM under benign buffer conditions. The Leu-, Tyr-, Gln-, and His-substituted
      analogs were found to be exclusively three-stranded trimers, while the Asn-, Lys
      , Orn-, Arg-, and Trp-substituted analogs formed exclusively two-stranded
      monomers. Modeling results for the Leu-substituted analog showed that a three
      stranded oligomerization state is preferred due to increased side-chain burial,
      while a two-stranded oligomerization state was observed for the Trp analog due to
      unfavorable cavity formation in the three-stranded state.

PMID- 10595535
TI  - The complexed structure and antimicrobial activity of a non-beta-lactam inhibitor
      of AmpC beta-lactamase.
AB  - Beta-lactamases are the major resistance mechanism to beta-lactam antibiotics and
      pose a growing threat to public health. Recently, bacteria have become resistant
      to beta-lactamase inhibitors, making this problem pressing. In an effort to
      overcome this resistance, non-beta-lactam inhibitors of beta-lactamases were
      investigated for complementarity to the structure of AmpC beta-lactamase from
      Escherichia coli. This led to the discovery of an inhibitor, benzo(b)thiophene-2
      boronic acid (BZBTH2B), which inhibited AmpC with a Ki of 27 nM. This inhibitor
      is chemically dissimilar to beta-lactams, raising the question of what specific
      interactions are responsible for its activity. To answer this question, the X-ray
      crystallographic structure of BZBTH2B in complex with AmpC was determined to 2.25
      A resolution. The structure reveals several unexpected interactions. The
      inhibitor appears to complement the conserved, R1-amide binding region of AmpC,
      despite lacking an amide group. Interactions between one of the boronic acid
      oxygen atoms, Tyr150, and an ordered water molecule suggest a mechanism for
      acid/base catalysis and a direction for hydrolytic attack in the enzyme catalyzed
      reaction. To investigate how a non-beta-lactam inhibitor would perform against
      resistant bacteria, BZBTH2B was tested in antimicrobial assays. BZBTH2B
      significantly potentiated the activity of a third-generation cephalosporin
      against AmpC-producing resistant bacteria. This inhibitor was unaffected by two
      common resistance mechanisms that often arise against beta-lactams in conjunction
      with beta-lactamases. Porin channel mutations did not decrease the efficacy of
      BZBTH2B against cells expressing AmpC. Also, this inhibitor did not induce
      expression of AmpC, a problem with many beta-lactams. The structure of the
      BZBTH2B/AmpC complex provides a starting point for the structure-based
      elaboration of this class of non-beta-lactam inhibitors.

PMID- 10595536
TI  - Mutations of endo-beta-N-acetylglucosaminidase H active site residueAs sp130 anG
      glu132: activities and conformations.
AB  - Endo-beta-N-acetylglucosaminidase H hydrolyzes the beta-(1-4)-glycosidic link of
      the N,N'-diacetylchitobiose core of high-mannose and hybrid asparagine-linked
      oligosaccharides. Seven mutants of the active site residues, Asp130 and Glu132,
      have been prepared, assayed, and crystallized. They include single site mutants
      of each residue to the corresponding amide, to Ala and to the alternate acidic
      residue, and to the double amide mutant. The mutants of Asp130 are more active
      than the corresponding Glu132 mutants, consistent with the assignment of the
      latter residue as the primary catalytic residue. The amide mutants are more
      active than the alternate acidic residue mutants, which in turn are more active
      than the Ala mutants. The structures of the Asn mutant of Asp130 and the double
      mutant are very similar to that of the wild-type enzyme. Several residues
      surrounding the mutated residues, including some that form part of the core of
      the beta-barrel and especially Tyr168 and Tyr244, adopt a very different
      conformation in the structures of the other two mutants of Asp130 and in the Asp
      mutant of Glu132. The results show that the residues in the upper layers of the
      beta-barrel can organize into two very distinct packing arrangements that depend
      on subtle electrostatic and steric differences and that greatly affect the
      geometry of the substrate-binding cleft. Consequently, the relative activities of
      several of the mutants are defined by structural changes, leading to impaired
      substrate binding, in addition to changes in functionality.

PMID- 10595537
TI  - Arginine 197 of the cholecystokinin-A receptor binding site interacts with the
      sulfate of the peptide agonist cholecystokinin.
AB  - The knowledge of the binding sites of G protein-coupled cholecystokinin receptors
      represents important insights that may serve to understand their activation
      processes and to design or optimize ligands. Our aim was to identify the amino
      acid of the cholecystokinin-A receptor (CCK-AR) binding site in an interaction
      with the sulfate of CCK, which is crucial for CCK binding and activity. A three
      dimensional model of the [CCK-AR-CCK] complex was built. In this model, Arg197
      was the best candidate residue for a ionic interaction with the sulfate of CCK.
      Arg197 was exchanged for a methionine by site-directed mutagenesis. Wild-type and
      mutated CCK-AR were transiently expressed in COS-7 cells for pharmacological and
      functional analysis. The mutated receptor on Arg197 did not bind the agonist
      radioligand 125I-BH-[Thr, Nle]-CCK-9; however, it bound the nonpeptide antagonist
      [3H]-SR27,897 as the wild-type receptor. The mutant was approximately 1,470- and
      3,200-fold less potent than the wild-type CCK-AR to activate G proteins and to
      induce inositol phosphate production, respectively. This is consistent with the
      500-fold lower potency and 800-fold lower affinity of nonsulfated CCK relative to
      sulfated CCK on the wild-type receptor. These data, together with those showing
      that the mutated receptor failed to discriminate nonsulfated and sulfated CCK
      while it retained other pharmacological features of the CCK-AR, strongly support
      an interaction between Arg197 of the CCK-AR binding site and the sulfate of CCK.
      In addition, the mutated CCK-AR resembled the low affinity state of the wild-type
      CCK-AR, suggesting that Arg197-sulfate interaction regulates conformational
      changes of the CCK-AR that are required for its physiological activation.

PMID- 10595538
TI  - Crystal structure analysis of a pentameric fungal and an icosahedral plant
      lumazine synthase reveals the structural basis for differences in assembly.
AB  - Lumazine synthase catalyzes the penultimate step in the synthesis of riboflavin
      in plants, fungi, and microorganisms. The enzyme displays two quaternary
      structures, the pentameric forms in yeast and fungi and the 60-meric icosahedral
      capsids in plants and bacteria. To elucidate the structural features that might
      be responsible for differences in assembly, we have determined the crystal
      structures of lumazine synthase, complexed with the inhibitor 5-nitroso-6
      ribitylamino-2,4-pyrimidinedione, from spinach and the fungus Magnaporthe grisea
      to 3.3 and 3.1 A resolution, respectively. The overall structure of the subunit
      and the mode of inhibitor binding are very similar in these enzyme species. The
      core of the subunit consists of a four-stranded parallel beta-sheet sandwiched
      between two helices on one side and three helices on the other. The packing of
      the five subunits in the pentameric M. grisea lumazine synthase is very similar
      to the packing in the pentameric substructures in the icosahedral capsid of the
      plant enzyme. Two structural features can be correlated to the differences in
      assembly. In the plant enzyme, the N-terminal beta-strand interacts with the beta
      sheet of the adjacent subunit, thus extending the sheet from four to five
      strands. In fungal lumazine synthase, an insertion of two residues after strand
      beta1 results in a completely different orientation of this part of the
      polypeptide chain and this conformational difference prevents proper packing of
      the subunits at the trimer interface in the icosahedron. In the spinach enzyme,
      the beta-hairpin connecting helices alpha4 and alpha5 participates in the packing
      at the trimer interface of the icosahedron. Another insertion of two residues at
      this position of the polypeptide chain in the fungal enzyme disrupts the hydrogen
      bonding in the hairpin, and the resulting change in conformation of this loop
      also interferes with proper intrasubunit contacts at the trimer interface.

PMID- 10595539
TI  - Crystal structure of reduced thioredoxin reductase from Escherichia coli:
      structural flexibility in the isoalloxazine ring of the flavin adenine
      dinucleotide cofactor.
AB  - Catalysis by thioredoxin reductase (TrxR) from Escherichia coli requires
      alternation between two domain arrangements. One of these conformations has been
      observed by X-ray crystallography (Waksman G, Krishna TSR, Williams CH Jr,
      Kuriyan J, 1994, J Mol Biol 236:800-816). This form of TrxR, denoted FO, permits
      the reaction of enzyme-bound reduced FAD with a redox-active disulfide on TrxR.
      As part of an investigation of conformational changes and intermediates in
      catalysis by TrxR, an X-ray structure of the FO form of TrxR with both the FAD
      and active site disulfide reduced has been determined. Reduction after
      crystallization resulted in significant local conformation changes. The
      isoalloxazine ring of the FAD cofactor, which is essentially planar in the
      oxidized enzyme, assumes a 34 degree "butterfly" bend about the N(5)-N(10) axis
      in reduced TrxR. Theoretical calculations reported by others predict ring bending
      of 15-28 degrees for reduced isoalloxazines protonated at N(1). The large bending
      in reduced TrxR is attributed in part to steric interactions between the
      isoalloxazine ring and the sulfur of Cys138, formed by reduction of the active
      site disulfide, and is accompanied by changes in the positions and interactions
      of several of the ribityl side-chain atoms of FAD. The bending angle in reduced
      TrxR is larger than that for any flavoprotein in the Protein Data Bank.
      Distributions of bending angles in published oxidized and reduced flavoenzyme
      structures are different from those found in studies of free flavins, indicating
      that the protein environment has a significant effect on bending.

PMID- 10595540
TI  - Mapping of ATP binding regions in poly(A) polymerases by photoaffinity labeling
      and by mutational analysis identifies a domain conserved in many
      nucleotidyltransferases.
AB  - We have identified regions in poly(A) polymerases that interact with ATP.
      Conditions were established for efficient cross-linking of recombinant bovine and
      yeast poly(A) polymerases to 8-azido-ATP. Mn2+ strongly stimulated this reaction
      due to a 50-fold lower Ki for 8-azido-ATP in the presence of Mn2+. Mutations of
      the highly conserved Asp residues 113, 115, and 167, critical for metal binding
      in the catalytic domain of bovine poly(A) polymerase, led to a strong reduction
      of cross-linking efficiency, and Mn2+ no longer stimulated the reaction. Sites of
      8-azido-ATP cross-linking were mapped in different poly(A) polymerases by CNBr
      cleavage and analysis of tryptic peptides by mass spectroscopy. The main cross
      link in Schizosaccharomyces pombe poly(A) polymerase could be assigned to the
      peptide DLELSDNNLLK (amino acids 167-177). Database searches with sequences
      surrounding the cross-link site detected significant homologies to other
      nucleotidyltransferase families, suggesting a conservation of the nucleotide
      binding fold among these families of enzymes. Mutations in the region of the
      "helical turn motif" (a domain binding the triphosphate moiety of the nucleotide)
      and in the suspected nucleotide-binding helix of bovine poly(A) polymerase
      impaired ATP binding and catalysis. The results indicate that ATP is bound in
      part by the helical turn motif and in part by a region that may be a structural
      analog to the fingers domain found in many polymerases.

PMID- 10595541
TI  - Immunochemical evidence that cholesteryl ester transfer protein and
      bactericidal/permeability-increasing protein share a similar tertiary structure.
AB  - Cholesteryl ester transfer protein (CETP) plays an important role in plasma
      lipoprotein metabolism through its ability to transfer cholesteryl ester,
      triglyceride, and phospholipid between lipoproteins. CETP is a member of a gene
      family that also includes bactericidal/permeability-increasing protein (BPI). The
      crystal structure of BPI shows it to be composed of two domains that share a
      similar structural fold that includes an apolar ligand-binding pocket. As
      structurally important residues are conserved between BPI and CETP, it is thought
      that CETP and BPI may have a similar overall conformation. We have previously
      proposed a model of CETP structure based on the binding characteristics of anti
      CETP monoclonal antibodies (mAbs). We now present a refined epitope map of CETP
      that has been adapted to a structural model of CETP that uses the atomic
      coordinates of BPI. Four epitopes composed of CETP residues 215-219, 219-223, 223
      227, and 444-450, respectively, are predicted to be situated on the external
      surface of the central beta-sheet and a fifth epitope (residues 225-258) on an
      extended linker that connects the two domains of the molecule. Three other
      epitopes, residues 317-331, 360-366, and 393-410, would form part of the putative
      carboxy-terminal beta-barrel. The ability of the corresponding mAbs to compete
      for binding to CETP is consistent with the proximity of the respective epitopes
      in the model. These results thus provide experimental evidence that is consistent
      with CETP and BPI having similar surface topologies.

PMID- 10595542
TI  - X-ray crystallographic analysis of the structural basis for the interaction of
      pokeweed antiviral protein with guanine residues of ribosomal RNA.
AB  - Pokeweed antiviral protein (PAP) is a ribosome-inactivating protein (RIP), which
      enzymatically removes a single adenine base from a conserved, surface exposed
      loop sequence of ribosomal rRNA. We now present unprecedented experimental
      evidence that PAP can release not only adenine but guanine as well from
      Escherichia coli rRNA, albeit at a rate 20 times slower than for adenine. We also
      report X-ray structure analysis and supporting modeling studies for the
      interactions of PAP with guanine. Our modeling studies indicated that PAP can
      accommodate a guanine base in the active site pocket without large conformational
      changes. This prediction was experimentally confirmed, since a guanine base was
      visible in the active site pocket of the crystal structure of the PAP-guanine
      complex.

PMID- 10595543
TI  - Crystal structure of Trypanosoma cruzi tyrosine aminotransferase: substrate
      specificity is influenced by cofactor binding mode.
AB  - The crystal structure of tyrosine aminotransferase (TAT) from the parasitic
      protozoan Trypanosoma cruzi, which belongs to the aminotransferase subfamily
      Igamma, has been determined at 2.5 A resolution with the R-value R = 15.1%. T.
      cruzi TAT shares less than 15% sequence identity with aminotransferases of
      subfamily Ialpha but shows only two larger topological differences to the
      aspartate aminotransferases (AspATs). First, TAT contains a loop protruding from
      the enzyme surface in the larger cofactor-binding domain, where the AspATs have a
      kinked alpha-helix. Second, in the smaller substrate-binding domain, TAT has a
      four-stranded antiparallel beta-sheet instead of the two-stranded beta-sheet in
      the AspATs. The position of the aromatic ring of the pyridoxal-5'-phosphate
      cofactor is very similar to the AspATs but the phosphate group, in contrast, is
      closer to the substrate-binding site with one of its oxygen atoms pointing toward
      the substrate. Differences in substrate specificities of T. cruzi TAT and
      subfamily Ialpha aminotransferases can be attributed by modeling of substrate
      complexes mainly to this different position of the cofactor-phosphate group.
      Absence of the arginine, which in the AspATs fixes the substrate side-chain
      carboxylate group by a salt bridge, contributes to the inability of T. cruzi TAT
      to transaminate acidic amino acids. The preference of TAT for tyrosine is
      probably related to the ability of Asn17 in TAT to form a hydrogen bond to the
      tyrosine side-chain hydroxyl group.

PMID- 10595544
TI  - Production of soluble alphabeta T-cell receptor heterodimers suitable for
      biophysical analysis of ligand binding.
AB  - A method to produce alphabeta T-cell receptors (TCRs) in a soluble form suitable
      for biophysical analysis was devised involving in vitro refolding of a TCR fusion
      protein. Polypeptides corresponding to the variable and constant domains of each
      chain of a human and a murine receptor, fused to a coiled coil heterodimerization
      motif from either c-Jun (alpha) or v-Fos (beta), were overexpressed separately in
      Escherichia coli. Following recovery from inclusion bodies, the two chains of
      each receptor were denatured, and then refolded together in the presence of
      denaturants. For the human receptor, which is specific for the immunodominant
      influenza A HLA-A2-restricted matrix epitope (M58-66), a heterodimeric protein
      was purified in milligram yields and found to be homogeneous, monomeric, antibody
      reactive, and stable at concentrations lower than 1 microM. Using similar
      procedures, analogous results were obtained with a murine receptor specific for
      an influenza nucleoprotein epitope (366-374) restricted by H2-Db. Production of
      these receptors has facilitated a detailed analysis of viral peptide-Major
      Histocompatibility Complex (peptide-MHC) engagement by the TCR using both surface
      plasmon resonance (SPR) and, in the case of the human TCR, isothermal titration
      calorimetry (ITC) (Willcox et al., 1999). The recombinant methods described
      should enable a wide range of TCR-peptide-MHC interactions to be studied and may
      also have implications for the production of other heterodimeric receptor
      molecules.

PMID- 10595545
TI  - Using genomic information to investigate the function of ThiI, an enzyme shared
      between thiamin and 4-thiouridine biosynthesis.
AB  - The gene thiI encodes a protein (ThiI) that plays a role in the transfer of
      sulfur from cysteine to both thiamin and 4-thiouridine, but the reaction
      catalyzed by ThiI remains undetermined. Based upon sequence alignments, ThiI
      shares a unique "P-loop" motif with the PPi synthetase family, four enzymes that
      catalyze adenylation and subsequent substitution of carbonyl oxygens. To test
      whether or not this motif is critical for ThiI function, the Asp in the motif was
      converted to Ala (D189A), and a screen for in vivo 4-thiouridine production
      revealed the altered enzyme to be inactive. Further scrutiny of sequence data and
      the crystal structures of two members of the PPi synthetase family implicated
      Lys321 in the proposed adenylation function of ThiI, and the critical nature of
      Lys321 has been demonstrated by site-directed mutagenesis and genetic screening.
      Our results, then, indicate that ThiI catalyzes the adenylation of a substrate at
      the expense of ATP, a narrowing of possible reactions that provides a strong new
      basis for deducing the early steps in the transfer of sulfur from cysteine to
      both thiamin and 4-thiouridine.

PMID- 10595546
TI  - A test case for structure-based functional assignment: the 1.2 A crystal
      structure of the yjgF gene product from Escherichia coli.
AB  - The YER057c/YIL051c/YjgF protein family is a set of 24 full-length homologs, each
      approximately 130 residues in length, and each with no known function or
      relationship to proteins of known structure. To determine the function of this
      family, the structure of one member--the YjgF protein from Escherichia coli--was
      solved and refined at a resolution of 1.2 A. The YjgF molecule is a homotrimer
      with exact threefold symmetry. Its tertiary and quaternary structures are related
      to that of Bacillus subtilis chorismate mutase, although their active sites are
      completely different. The YjgF protein has an active site curiously similar to
      protein tyrosine phosphatases, including a covalently modified cysteine, but it
      is unlikely to be functionally related. The lessons learned from this attempt to
      deduce function from structure may be useful to future projects in structural
      genomics.

PMID- 10595547
TI  - Probing the location and function of the conserved histidine residue of
      phosphoglucose isomerase by using an active site directed inhibitor N
      bromoacetylethanolamine phosphate.
AB  - Phosphoglucose isomerase (EC 5.3.1.9) catalyzes the interconversion of D
      glucopyranose-6-phosphate and D-fructofuranose-6-phosphate by promoting an
      intrahydrogen transfer between C1 and C2. A conserved histidine exists throughout
      all phosphoglucose isomerases and was hypothesized to be the base catalyzing the
      isomerization reaction. In the present study, this conserved histidine, His311,
      of the enzyme from Bacillus stearothermophilus was subjected to mutational
      analysis, and the mutational effect on the inactivation kinetics by N
      bromoacetylethanolamine phosphate was investigated. The substitution of His311
      with alanine, asparagine, or glutamine resulted in the decrease of activity, in
      k(cat)/K(M), by a factor of 10(3), indicating the importance of this residue. N
      bromoacetylethanolamine phosphate inactivated irreversibly the activity of wild
      type phosphoglucose isomerase; however, His311 --> Ala became resistant to this
      inhibitor, indicating that His311 is located in the active site and is
      responsible for the inactivation of the enzyme by this active site-directed
      inhibitor. The pKa of His311 was estimated to be 6.31 according to the pH
      dependence of the inactivation. The proximity of this value with the pKa value of
      6.35, determined from the pH dependence of k(cat)/K(M), supports a role of His311
      as a general base in the catalysis.

PMID- 10595548
TI  - Conformational and metal-binding properties of androcam, a testis-specific,
      calmodulin-related protein from Drosophila.
AB  - Androcam is a testis-specific protein of Drosophila melanogaster, with 67%
      sequence identity to calmodulin and four potential EF-hand calcium-binding sites.
      Spectroscopic monitoring of the thermal unfolding of recombinant calcium-free
      androcam shows a biphasic process characteristic of a two-domain protein, with
      the apo-N-domain less stable than the apo-C-domain. The two EF hands of the C
      domain of androcam bind calcium cooperatively with 40-fold higher average
      affinity than the corresponding calmodulin sites. Magnesium competes with calcium
      binding [Ka(Mg) approximately 3 x 10(3) M(-1)]. Weak calcium binding is also
      detected at one or more N-domain sites. Compared to apo-calmodulin, apo-androcam
      has a smaller conformational response to calcium and a lower alpha-helical
      content over a range of experimental conditions. Unlike calmodulin, a tryptic
      cleavage site in the N-domain of apo-androcam remains trypsin sensitive in the
      presence of calcium, suggesting an altered calcium-dependent conformational
      change in this domain. The affinity of model target peptides for androcam is
      10(3)-10(5) times lower than for calmodulin, and interaction of the N-domain of
      androcam with these peptides is significantly reduced. Thus, androcam shows
      calcium-induced conformational responses typical of a calcium sensor, but its
      properties indicate calcium sensitivity and target interactions significantly
      different from those of calmodulin. From the sequence differences and the altered
      calcium-binding properties it is likely that androcam differs from calmodulin in
      the conformation of residues in the second calcium-binding loop. Molecular
      modeling supports the deduction that there are significant conformational
      differences in the N-domain of androcam compared to calmodulin, and that these
      could affect the surface, conferring a different specificity on androcam in
      target interactions related to testis-specific calcium signaling functions.

PMID- 10595549
TI  - Thermodynamics of replacing an alpha-helical Pro residue in the P40S mutant of
      Escherichia coli thioredoxin.
AB  - Escherichia coli thioredoxin is a 108 amino acid oxidoreductase and contains a
      single Met residue at position 37. The protein contains a long alpha-helical
      stretch between residues 32 and 49. The central residue of this helix, Pro40, has
      been replaced by Ser. The stabilities of the oxidized states of two proteins, the
      single mutant M37L and the double mutant M37L,P40S, have been characterized by
      differential scanning calorimetry (DSC) and also by a series of isothermal
      guanidine hydrochloride (GuHCl) melts in the temperature range of 277 to 333 K.
      The P40S mutation was found to stabilize the protein at all temperatures upto 340
      K though both proteins had similar Tm values of about 356 K. At 298 K, the
      M37L,P40S mutant was found to be more stable than M37L by 1.5 kcal/mol. A
      combined analysis of GuHCl and calorimetric data was carried out to determine the
      enthalpy, entropy, and heat capacity change upon unfolding. At 298 K there was a
      large, stabilizing enthalpic effect in P40S though significant enthalpy-entropy
      compensation was observed and the two proteins had similar values of deltaCp.
      Thus, replacement of a Pro in the interior of an alpha helix can have substantial
      effects on protein stability.

PMID- 10595550
TI  - Real-time measurements of dark substrate catalysis.
AB  - We have developed a novel procedure to monitor the real-time cleavage of natural
      unmodified peptides (dark substrates). In the competition-based assay, the
      initial cleavage rate of a fluorogenic peptide substrate is measured in the
      presence of a second substrate that is not required to exhibit any optical
      property change upon cleavage. Using a unique experimental design and steady
      state enzyme kinetics for a two-substrate system, we were able to determine both
      Km and k(cat) values for cleavage of the dark substrate. The method was applied
      to HIV-1 protease and to the V82F/I84V drug resistant mutant enzyme. Using two
      different substrates, we showed that the kinetic parameters derived from the
      competition assay are in good agreement with those determined independently using
      standard direct assay. This method can be applied to other enzyme systems as long
      as they have one substrate for which catalysis can be conveniently monitored in
      real time.

PMID- 10595551
TI  - Structures of yeast vesicle trafficking proteins.
AB  - In protein transport between organelles, interactions of v- and t-SNARE proteins
      are required for fusion of protein-containing vesicles with appropriate target
      compartments. Mammalian SNARE proteins have been observed to interact with NSF
      and SNAP, and yeast SNAREs with yeast homologues of NSF and SNAP proteins. This
      observation led to the hypothesis that, despite low sequence homology, SNARE
      proteins are structurally similar among eukaryotes. SNARE proteins can be
      classified into two groups depending on whether they interact with SNARE binding
      partners via conserved glutamine (Q-SNAREs) or arginine (R-SNAREs). Much of the
      published structural data available is for SNAREs involved in exocytosis (either
      in yeast or synaptic vesicles). This paper describes circular dichroism, Fourier
      transform infrared spectroscopy, and dynamic light scattering data for a set of
      yeast v- and t-SNARE proteins, Vti1p and Pep12p, that are Q-SNAREs involved in
      intracellular trafficking. Our results suggest that the secondary structure of
      Vti1p is highly alpha-helical and that Vti1p forms multimers under a variety of
      solution conditions. In these respects, Vti1p appears to be distinct from R-SNARE
      proteins characterized previously. The alpha-helicity of Vti1p is similar to that
      of Q-SNARE proteins characterized previously. Pep12p, a Q-SNARE, is highly alpha
      helical. It is distinct from other Q-SNAREs in that it forms dimers under many of
      the solution conditions tested in our experiments. The results presented in this
      paper are among the first to suggest heterogeneity in the functioning of SNARE
      complexes.

PMID- 10595552
TI  - Purification and characterization of a cobalt-activated carboxypeptidase from the
      hyperthermophilic archaeon Pyrococcus furiosus.
AB  - A novel metallocarboxypeptidase (PfuCP) has been purified to homogeneity from the
      hyperthermophilic archaeon, Pyrococcus furiosus, with its intended use in C
      terminal ladder sequencing of proteins and peptides at elevated temperatures.
      PfuCP was purified in its inactive state by the addition of
      ethylenediaminetetraacetic acid (EDTA) and dithiothreitol (DTT) to purification
      buffers, and the activity was restored by the addition of divalent cobalt (K, =
      24 +/- 4 microM at 80 degrees C). The serine protease inhibitor
      phenylmethylsulfonyl fluoride (PMSF) had no effect on the activity. The molecular
      mass of monomeric PfuCP is 59 kDa as determined by matrix-assisted laser
      desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) and 58 kDa
      by SDS-PAGE analysis. In solution, PfuCP exists as a homodimer of approximately
      128 kDa as determined by gel filtration chromatography. The activity of PfuCP
      exhibits a temperature optimum exceeding 90 degrees C under ambient pressure, and
      a narrow pH optimum of 6.2-6.6. Addition of Co2+ to the apoPfuCP at room
      temperature does not alter its far-UV circular dichroism (CD) or its intrinsic
      fluorescence spectrum. Even when the CoPfuCP is heated to 80 degrees C, its far
      UV CD shows a minimal change in the global conformation and the intrinsic
      fluorescence of aromatic residues shows only a partial quenching. Changes in the
      intrinsic fluorescence appear essentially reversible with temperature. Finally,
      the far-UV CD and intrinsic fluorescence data suggest that the overall structure
      of the holoenzyme is extremely thermostable. However, the activities of both the
      apo and holo enzyme exhibit a similar second-order decay over time, with 50%
      activity remaining after approximately 40 min at 80 degrees C. The N-blocked
      synthetic dipeptide, N-carbobenzoxy-Ala-Arg (ZAR), was used in the purification
      assay. The kinetic parameters at 80 degrees C with 0.4 mM CoCl2 were: Km, 0.9 +/-
      0.1 mM; Vmax, 2,300 +/- 70 U mg(-1); and turn over number, 600 +/- 20 s(-1).
      Activity against other ZAX substrates (X = V, L, I, M, W, Y, F, N, A, S, H, K)
      revealed a broad specificity for neutral, aromatic, polar, and basic C-terminal
      residues. This broad specificity was confirmed by the C-terminal ladder
      sequencing of several synthetic and natural peptides, including porcine N-acetyl
      renin substrate, for which we have observed (by MALDI-TOF MS) stepwise hydrolysis
      by PfuCP of up to seven residues from the C-terminus: Ac-Asp-Arg-Val-Tyr-Ile-His
      Pro-Phe-His-Leu-Leu-Val-Tyr-Ser.

PMID- 10595553
TI  - Locating and identifying posttranslational modifications by in-source decay
      during MALDI-TOF mass spectrometry.
AB  - A technique is described for identifying and locating posttranslational
      modifications (PTMs) in peptides and proteins of known sequence by interpretation
      of c(n) ion signals generated by in-source decay during delayed ion extraction in
      matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
      Sites of phosphorylation in seven synthetic peptides were determined, as was the
      location of both the heme group and N,N,N-trimethyllysine in yeast cytochrome c.
      A semi-automated data analysis process facilitates the identification of segments
      of the sequence on each side of the PTM, permitting its placement at the junction
      of the segments and definition of the added mass. A graphical display facilitates
      illustration of both the location and mass of the PTM.

PMID- 10595554
TI  - NikR is a ribbon-helix-helix DNA-binding protein.
AB  - Escherichia coli NikR, a repressor with homologs in other bacteria and archaea,
      was identified as a potential new member of the ribbon-helix-helix (beta-alpha
      alpha) family of transcription factors in profile based sequence searches and in
      structure prediction experiments. Biophysical and biochemical characterization of
      the N-terminal domain of NikR show that it has many features expected of a beta
      alpha-alpha protein including alpha-helical content, dimeric solution form,
      concentration dependent thermal stability, and ability to bind DNA in sequence
      specific manner. Mutation of a residue predicted to be important for DNA-binding
      reduces operator affinity but does not affect the secondary structure or
      stability of the protein.

PMID- 10595555
TI  - The relationship between effector binding and inhibition of activity in D-3
      phosphoglycerate dehydrogenase.
AB  - The binding of L-serine to phosphoglycerate dehydrogenase from Escherichia coli
      displays elements of both positive and negative cooperativity. At pH 7.5,
      approximately 2 mol of serine are bound per mole of tetrameric enzyme. A
      substantial degree of positive cooperativity is seen for the binding of the
      second ligand, but the binding of the third and fourth ligand display substantial
      negative cooperativity. The data indicate a state of approximately 50% inhibition
      when only one serine is bound and approximately 80-90% inhibition when two
      serines are bound. This is consistent with the tethered domain hypothesis that
      has been presented previously. Comparison of the data derived directly from
      binding stoichiometry to the binding constants determined from the best fit to
      the Adair equation, produce a close agreement, and reinforce the general validity
      of the derived binding constants. The data also support the conclusion that the
      positive cooperativity between the binding to the first and second site involves
      binding sites at opposite interfaces over 110 A apart. Thus, an order of binding
      can be envisioned where the binding of the first ligand initiates a
      conformational transition that allows the second ligand to bind with much higher
      affinity at the opposite interface. This is followed by the third ligand, which
      binds with lesser affinity to one of the two already occupied interfaces, and in
      so doing, completes a global conformational transition that produces maximum
      inhibition of activity and an even lower affinity for the fourth ligand,
      excluding it completely. Thus, maximal inhibition is accomplished with less than
      maximal occupancy of effector sites through a mechanism that displays strong
      elements of both positive and negative cooperativity.

PMID- 10595556
TI  - Methionine sulfoxidation of the chloroplast small heat shock protein and
      conformational changes in the oligomer.
AB  - The small heat shock proteins (sHsps), which counteract heat and oxidative stress
      in an unknown way, belong to a protein family of sHsps and alpha-crystallins
      whose members form large oligomeric complexes. The chloroplast-localized sHsp,
      Hsp21, contains a conserved methionine-rich sequence, predicted to form an
      amphipatic helix with the methionines situated along one of its sides. Here, we
      report how methionine sulfoxidation was detected by mass spectrometry in
      proteolytically cleaved peptides that were produced from recombinant Arabidopsis
      thaliana Hsp21, which had been treated with varying concentrations of hydrogen
      peroxide. Sulfoxidation of the methionine residues in the conserved amphipatic
      helix coincided with a significant conformational change in the Hsp21 protein
      oligomer.

PMID- 10595557
TI  - A common mechanism for recombinant human NGF, BDNF, NT-3, and murine NGF slow
      unfolding.
AB  - The recombinant human nerve growth factor (hNGF), brain-derived neurotrophic
      factor (BDNF), neurotrophin-3 (NT-3), neurotrophin 4/5 (NT4/5), and murine NGF
      (mNGF) dimers all undergo rapid unfolding and dissociation to monomer in GdnHCl.
      Fluorescence spectroscopy, reversed-phase high-performance liquid chromatography,
      and size-exclusion chromatography were used to show that this monomer M1 converts
      slowly to a more fully unfolded monomer, M2, by a first order process with half
      lives of 22, 2.5, 1.6, and 0.73 h for hNGF, mNGF, NT-3, and BDNF, respectively,
      at 25 degrees C. Linear Arrhenius plots for the conversion of M1 to M2 yielded
      activation energies of 27, 22, 24, and 24 kcal/mol for hNGF, mNGF, NT-3, and
      BDNF, respectively. The refolding of these neurotrophins from 5 M GdnHCl was also
      first order with NT-3 the slowest to refold and BDNF the fastest. Threading of
      the N-terminus out through the cystine-knot loop present in each of these
      proteins is proposed as the slow step in unfolding. The number of amino acids in
      the cystine-knot loop (14 for hNGF, mNGF, NT-3, and BDNF; 21 for NT4/5), and the
      number and position of the proline residues in this loop (2 for hNGF; 1 for mNGF,
      NT-3, BDNF, and NT4/5) correlate with the relative rates of unfolding. The
      smaller the loop and the greater the number of prolines, the more hindered and
      slower the unfolding.

PMID- 10595558
TI  - The effects of alpha-helix on the stability of Asn residues: deamidation rates in
      peptides of varying helicity.
AB  - Asn deamidation was monitored in Ala-based octadecapeptides of varying alpha
      helicity. Gly was substituted for Ala residues at positions 6 and 16 to create a
      peptide with less helicity. Ala --> Gly substitutions were made at three or more
      residues from the Asn to negate known primary sequence effects on deamidation
      rates. The extent of helicity and rate of Asn deamidation for alkaline aqueous
      solutions of each peptide was measured as a function of temperature by circular
      dichroism and reversed-phase high-performance liquid chromatography,
      respectively. The rate of deamidation in the peptides was inversely proportional
      to the extent of alpha-helicity. The results support the conclusion that Asn
      deamidation only occurs in the nonhelical population of conformers.

PMID- 10595559
TI  - 2'Halo-ATP and -GTP analogues: rational phasing tools for protein
      crystallography.
AB  - The solution of the crystallographic macromolecular phase problem requires
      incorporation of heavy atoms into protein crystals. Several 2'-halogenated
      nucleotides have been reported as potential universal phasing tools for
      nucleotide binding proteins. However, only limited data are available dealing
      with the effect of 2'-substitution on recognition by the protein. We have
      determined equilibrium dissociation constants of 2'-halogenated ATP analogues for
      the ATP binding proteins UMP/CMP kinase and the molecular chaperone DnaK. Whereas
      the affinities to UMP/CMP kinase are of the same order of magnitude as for
      unsubstituted ATP, the affinities to DnaK are drastically decreased to
      undetectable levels. For 2'-halogenated GTP analogues, the kinetics of
      interaction were determined for the small GTPases p21ras(Y32W) (fluorescent
      mutant) and RabS. The rates of association were found to be within about one
      order of magnitude of those for the nonsubstituted nucleotides, whereas the rates
      of dissociation were accelerated by factors of approximately 100 (p21ras) or
      approximately 10(5) (Rab5), and the resulting equilibrium dissociation constants
      are in the nm or microM range, respectively. The data demonstrate that 2'halo-ATP
      and -GTP are substrates or ligands for all proteins tested except the chaperone
      DnaK. Due to the very high affinities of a large number of GTP binding proteins
      to guanine nucleotides, even a 10(5)-fold decrease in affinity as observed for
      Rab5 places the equilibrium dissociation constant in the microM range, so that
      they are still well suited for crystallization of the G-protein:nucleotide
      complex.

PMID- 10595560
TI  - Molecular basis for triclosan activity involves a flipping loop in the active
      site.
AB  - The crystal structure of the Escherichia coli enoyl reductase-NAD+-triclosan
      complex has been determined at 2.5 A resolution. The Ile192-Ser198 loop is either
      disordered or in an open conformation in the previously reported structures of
      the enzyme. This loop adopts a closed conformation in our structure, forming van
      der Waals interactions with the inhibitor and hydrogen bonds with the bound NAD+
      cofactor. The opening and closing of this flipping loop is likely an important
      factor in substrate or ligand recognition. The closed conformation of the loop
      appears to be a critical feature for the enhanced binding potency of triclosan,
      and a key component in future structure-based inhibitor design.

PMID- 10595561
TI  - Common protein architecture and binding sites in proteases utilizing a Ser/Lys
      dyad mechanism.
AB  - Escherichia coli signal peptidase (SPase) and E. coli UmuD protease are members
      of an evolutionary clan of serine proteases that apparently utilize a serine
      lysine catalytic dyad mechanism. Recently, the crystallographic structure of a
      SPase inhibitor complex was solved elucidating the catalytic residues and the
      substrate binding subsites. Here we show a detailed comparison of the E. coli
      SPase structure to the native E. coli UmuD' structure. The comparison reveals
      that despite a very low sequence identity these functionally diverse enzymes
      share the same protein fold within their catalytic core and allows by analogy for
      the assignment of the cleavage-site orientation and substrate binding subsites in
      the UmuD(D') protease. The structural alignment of SPase and UmuD' predicts
      important mechanistic and structural similarities and differences within these
      newly characterized families of serine proteases.

PMID- 10595562
TI  - Thermolysin and mitochondrial processing peptidase: how far structure-functional
      convergence goes.
AB  - The structure-functional convergence between two Zn-dependent proteases, namely
      thermolysin and mitochondrial processing peptidase (MPP), is described. These two
      families of nonhomologous enzymes show not only functional convergence of several
      active site residues as in chymotrypsin and subtilisin, but also structural
      convergence of overall molecular architectures including the beta-sheet
      arrangement and packing of the surrounding alpha-helices. The major functionally
      important structural elements are present in both enzymes with different
      topological connections and often in reverse main-chain orientation, but display
      similar packing. The structural comparison helps to rationalize sequence
      "inversion" of the HEXXH thermolysin consensus present as HXXEH in MPP. The
      described structural convergence may be due to a limited number of alternatives
      to build a Zn-protease that utilizes hydrogen bonding between a substrate main
      chain and the enzyme beta-sheet for substrate binding.

PMID- 10595563
TI  - Solution structure and dynamics of bovine beta-lactoglobulin A.
AB  - Using heteronuclear NMR spectroscopy, we studied the solution structure and
      dynamics of bovine beta-lactoglobulin A at pH 2.0 and 45 degrees C, where the
      protein exists as a monomeric native state. The monomeric NMR structure,
      comprising an eight-stranded continuous antiparallel beta-barrel and one major
      alpha-helix, is similar to the X-ray dimeric structure obtained at pH 6.2,
      including betaI-strand that forms the dimer interface and loop EF that serves as
      a lid of the interior hydrophobic hole. [1H]-15N NOE revealed that betaF, betaG,
      and betaH strands buried under the major alpha-helix are rigid on a pico- to
      nanosecond time scale and also emphasized rapid fluctuations of loops and the N-
      and C-terminal regions.

PMID- 10595564
TI  - The extracellular regions of PSMA and the transferrin receptor contain an
      aminopeptidase domain: implications for drug design.
AB  - The Aeromonas proteolytica aminopeptidase (AMP), Pseudomonas sp. (RS-16)
      carboxypeptidase G2 (CPG2), and Streptomyces griseus aminopeptidase (SGAP) are
      zinc dependent proteolytic enzymes with cocatalytic zinc ion centers and a
      conserved aminopeptidase fold. A BLAST search with the sequence of the solved AMP
      structure indicated that a similar domain could be found in prostate-specific
      membrane antigen (PSMA) and the transferrin receptor (TfR). When the PSMA or TfR
      sequence was input into the THREADER program, the top structural matches were
      SGAP and AMP confirming that these are structurally conserved domains. Optimal
      sequence alignment of PSMA and TfR using the known three-dimensional structures
      of AMP, CPG2, and SGAP shows that the critical amino acids involved in forming
      the catalytic pocket are conserved in PSMA but absent in the TfR. The specificity
      pocket in AMP is formed from four aromatic side chains and the equivalent region
      in CPG2/PSMA has a changed sequence pattern. Since CPG2 and PSMA are folate
      hydrolases, the changed specificity pocket leaves space to accommodate the large
      pteroate moiety of folic acid. In contrast, no enzyme function has been ascribed
      to the TfR.

PMID- 10595565
TI  - Cost considerations in the evaluation of new therapies for gram-positive
      bacteria.
AB  - The rapid emergence of antibiotic resistance in hospitals and the community,
      particularly amongst Gram-positive cocci, has not been paralleled by adequate
      understanding of the true clinical and economic impact of infection with
      resistant pathogens. Furthermore, the development of novel compounds to combat
      this threat has been slow until recently when a number of new agents, some with a
      unique structure and mode of action (e.g. linezolid), are now being developed for
      clinical use. This paper aims to outline (1) the costs associated with infection
      by a resistant organism (2) the pharmacoeconomic arguments when considering a new
      drug and (3) the key decisions when evaluating a new drug such as linezolid, for
      inclusion in a formulary or policy with particular reference to the treatment of
      serious Gram-positive infections.

PMID- 10595566
TI  - New developments in the treatment of infective endocarditis infective
      cardiovasculitis.
AB  - The natural history of infective endocarditis has undergone remarkable changes
      over the past 100 years as regards both the demographic characteristics of the
      disease and changes in the incidence of the so-called diagnostic signs. Alongside
      these changes and the development of new and better diagnostic tools and
      criteria, we are also facing new problems with the precise definition of
      cardiovascular infections and calculation of the incidence of the disease.
      Nosocomial endocarditis presents an emerging problem of diagnosis and treatment
      after heart valve surgery, with pace-maker catheters, defibrillators and a very
      large variety of foreign materials used in connection with heart valve surgery.
      New technological progress including new types of prosthetic valves and use of
      homografts or the Ross operation will give a greater possibility of choosing the
      best solution in a particular case. Antimicrobial chemotherapy is mainly based on
      our understanding of the pathophysiology of the disease and efficacy of the
      antibiotics achieved in an experimental animal model of endocarditis. Important
      recommendations of single or combined drug therapy or the dosing regimens of
      antibiotics are still an expression of expert opinion not always supported by
      experimental or clinical proof. A typical example is the recommendation of two
      divided doses of gentamicin for treatment of streptococcal endocarditis.
      Nevertheless, it is the author's opinion that the development of uncomplicated,
      easy to handle diagnostic and treatment regimens are justified in order to
      achieve better compliance with these recommendations.

PMID- 10595567
TI  - Drug-resistant and multidrug-resistant tubercle bacilli.
AB  - Drug resistant (DR) and multidrug resistant (MDR) tuberculosis (TB) is a
      consequence of human activity and did not exist before chemotherapeutic drugs
      were introduced. Monotherapy with various drugs in sequence or other inadequate
      drug regimens have strongly contributed to the creation of MDR-TB. Such TB
      strains are mainly prevalent in regions with weak national TB programmes or poor
      socio-economic environments. Strains may also spread in some communities such as
      poorly administered prisons. From these and other sources, MDR-TB may spread in
      the population from which travellers might transfer strains between countries and
      continents. Therefore an effective surveillance of the resistance pattern of TB
      bacilli is a demanding task in all countries. In this review some aspects of
      epidemiology, diagnosis and mechanisms of DR in TB are discussed. MDR-TB is an
      important international problem of increasing significance for the whole global
      community.

PMID- 10595568
TI  - A 1997-1998 national surveillance study: Moraxella catarrhalis and Haemophilus
      influenzae antimicrobial resistance in 34 US institutions.
AB  - From November 1, 1997 to April 30, 1998, 726 Moraxella catarrhalis isolates and
      1529 Haemophilus influenzae isolates were obtained from 34 medical centres
      throughout the United States. Rates of beta-lactamase production were 94.6% among
      M. catarrhalis and 31.1% among H. influenzae strains. Susceptibility rates of M.
      catarrhalis isolates to selected antimicrobial agents were greater than 99% for
      amoxycillin-clavulanate, cefixime, cefpodoxime, cefuroxime, cefaclor, loracarbef,
      clarithromycin, azithromycin, chloramphenicol and tetracycline, 97.8% for
      cefprozil, 50.4% for trimethoprim-sulphamethoxazole and 28.1% for ampicillin. Of
      the antimicrobials tested against H. influenzae, the only agents with
      susceptibility rates below 96% were loracarbef (87.6%), cefprozil (83.4%),
      cefaclor (82.7%), trimethoprim-sulphamethoxazole (67.3%) and ampicillin (64.7%).
      The clarithromycin susceptibility rate was 67.4% but this agent was not tested in
      the presence of its 14-OH metabolite.

PMID- 10595569
TI  - A 1-year study of antibiotic resistance among paediatric pneumococcal isolates in
      1995 from four regions of France.
AB  - The main object of this study was to describe the features of antibiotic
      resistance in pneumococci from children in four regions of France in 1995.
      Despite the high prevalence (40%) of pneumococci with diminished susceptibilty to
      penicillin (PDSP), resistance to amoxycillin (0.8%) and cefotaxime (0.4%) was
      rare; 16% of pneumococci were resistant to penicillin G (PRP, MIC > 1 mg/l). PDSP
      showed the expected resistance to macrolides (67%) and cotrimoxazole (57%) and
      were predominantly serotypes 23F, 14, 9 and 6. This study by the Regional
      Pneumococcal Observatories confirms the high prevalence and the main
      characteristics of antibiotic resistance among pneumococci isolated from
      children. Nevertheless, the resistance to all antibiotics was lower than that
      found in French multicentre, nationwide surveys, possibly because of differences
      in the mode of strain collection and geographic origin.

PMID- 10595570
TI  - The MYSTIC (meropenem yearly susceptibility test information collection)
      programme.
AB  - The primary objective of the MYSTIC study is to monitor the performance of
      meropenem over a period of at least 3 years during which this carbapenem is
      prescribed in different hospital units thus allowing profiles to be established
      within individual hospitals. Monitoring is being carried out by assessing the
      antibiotic susceptibility of bacterial pathogens isolated from patients with a
      predominate problem of intraabdominal infections (IAI) and/or lower respiratory
      tract infections (LRTI), treated in specialist centres (haematology wards, the
      Intensive Care Unit [ICU], cystic fibrosis units) and non-specialised centres.
      Samples will be collected over each year and tested against meropenem and a set
      of comparators. The data obtained from the first year of the study (1997) come
      from 33 centres spread mainly throughout Europe but also in Israel and Mexico.
      The results shows that meropenem retains its broad spectrum and potency whilst
      there is evidence that the activity of comparator antibiotics is being eroded by
      a variety of resistance mechanisms. Data from subsequent years of the programme
      will determine whether these trends continue and will allow a series of
      individual centre profiles to be compiled and presented.

PMID- 10595571
TI  - Empiric antimicrobial therapy of febrile neutropenic patients undergoing
      haematopoietic stem cell transplantation.
AB  - This study was conducted to assess the efficacy and toxicity of intravenous
      (i.v.) ceftazidime and ciprofloxacin in neutropenic febrile patients undergoing
      high dose myeloablative therapy and hematopoietic stem cell transplantation
      (HSCT). All patients undergoing HSCT for leukaemia, lymphoma, multiple myeloma
      and solid tumours received open-label ceftazidime 2 g i.v. every 8 h and
      ciprofloxacin 400 mg i.v. every 12 h if they developed fever while they were
      neutropenic. Success with or without modification of this regimen was defined as
      survival through the neutropenic period; failure was defined as death secondary
      to infection. Of 106 patients treated with this regimen, the success rate was
      99%. Sixty-one of the patients (57.5%) defervesced within 48-72 h and remained
      afebrile without regimen modification. In 41.5% of the cases (44/106), the
      regimen was modified because of persistent fever. One patient died secondary to
      sepsis. The combination of ceftazidime and ciprofloxacin as initial empiric
      antibacterial therapy in febrile neutropenic patients undergoing myeloablative
      therapy and HSCT is highly effective and is associated with minimal toxicity.

PMID- 10595572
TI  - Salmonella meningitis and multiple cerebral abscesses in an infant.
AB  - The history of a 4-week-old infant with meningitis and multiple cerebral
      abscesses caused by Salmonella enteritidis is reported. Management included
      successful treatment with a prolonged course of antibiotics, including
      ciprofloxacin, neurosurgical drainage and long-term immunoglobulin supplements.
      No adverse effects of joint toxicity were detected.

PMID- 10595573
TI  - Bactericidal action of ampicillin/sulbactam against intracellular mycobacteria.
AB  - The resistance of mycobacteria to beta-lactam antibiotics is attributed to their
      ability to synthesize beta-lactamase. In our previous studies, beta-lactam/beta
      lactamase-inhibitor combinations suppressed the growth of several mycobacteria in
      axenic cultures and ampicillin/sulbactam was bactericidal to Mycobacterium
      tuberculosis H37Rv in vitro, and to Mycobacterium leprae multiplying in mouse
      foot-pads. Since both these organisms multiply in phagocytic cells in the host,
      it is important to know whether the drug combination is active against
      mycobacteria multiplying in macrophages. We tested the action of
      ampicillin/sulbactam against four potentially pathogenic (to humans or to
      animals) mycobacteria, M. simiae, M. haemophilum, M. avium, M. microti, when
      phagocytosed by mouse macrophages. Bacteria were exposed to monolayers of
      peritoneal macrophages harvested from BALB/c mice. Unphagocytosed bacilli were
      removed and three concentrations of ampicillin/sulbactam were tested. Optimum
      activity was observed at 100 mg/l which killed 58-97% of the mycobacteria within
      macrophages, as determined by the CFU. beta-Lactam/beta-lactamase-inhibitors,
      especially ampicillin/sulbactam, might provide an effective alternative therapy
      against infections caused by mycobacteria resistant to other drugs.

PMID- 10595574
TI  - Macrolide resistance phenotypes and mechanisms of resistance in Streptococcus
      pyogenes in La Rioja, Spain.
AB  - One hundred and thirty seven consecutive clinical Streptococcus pyogenes isolates
      were evaluated for macrolide-lincosamide-streptogramin resistance (MLS). Forty of
      these isolates were resistant to erythromycin (29.2%), 36 of them showed the new
      M resistance phenotype (erythromycin resistant and clindamycin susceptible) and
      four isolates had the MLS(B) resistance phenotype (erythromycin and clindamycin
      resistant). In all 36 isolates with the M resistance phenotype, the mef gene was
      identified by polymerase chain reaction (PCR). In two of the four S. pyogenes
      isolates with the MLS(B) phenotype, both ermB and ermTR genes were found;
      negative results were obtained with the other two isolates which might possess a
      new mechanism of high level resistance against erythromycin not previously
      described. In summary, a high rate of erythromycin resistance was found in S.
      pyogenes isolates and the active efflux pump mediated by the mef gene was the
      mechanism most frequently involved.

PMID- 10595575
TI  - Walter Neupert: spellbound by mitochondria.

PMID- 10595576
TI  - Posttranslational protein translocation across the membrane of the endoplasmic
      reticulum.
AB  - Posttranslational protein translocation across the membrane of the endoplasmic
      reticulum is mediated by the Sec complex. This complex includes a transmembrane
      channel formed by multiple copies of the Sec61 protein. Translocation of a
      polypeptide begins when the signal sequence binds at a specific site within the
      channel. Binding results in the insertion of the substrate into the channel,
      possibly as a loop with a small segment exposed to the lumen. While bound, the
      signal sequence is in contact with both protein components of the channel and the
      lipid of the membrane. Subsequent movement of the polypeptide through the channel
      occurs when BiP molecules interact transiently with a luminal domain of the Sec
      complex, hydrolyze ATP, and bind to the substrate. Bound BiP promotes
      translocation by preventing the substrate from diffusing backwards through the
      channel, and thus acts as a molecular ratchet.

PMID- 10595577
TI  - Import of carrier proteins into mitochondria.
AB  - Carrier proteins located in the inner membrane of mitochondria are responsible
      for the exchange of metabolites between the intermembrane space and the matrix of
      this organelle. All members of this family are nuclear-encoded and depend on
      translocation machineries for their import into mitochondria. Recently many new
      translocation components responsible for the import of carrier proteins were
      identified. It is now possible to describe a detailed import pathway for this
      class of proteins. This review highlights the contribution made by translocation
      components to the process of carrier protein import into mitochondria.

PMID- 10595578
TI  - The essential role of mitochondria in the biogenesis of cellular iron-sulfur
      proteins.
AB  - Iron-sulfur (Fe/S) proteins play an important role in electron transfer processes
      and in various enzymatic reactions. In eukaryotic cells, known Fe/S proteins are
      localised in mitochondria, the cytosol and the nucleus. The biogenesis of these
      proteins has only recently become the focus of investigations. Mitochondria are
      the major site of Fe/S cluster biosynthesis in the cell. The organelles contain
      an Fe/S cluster biosynthesis apparatus that resembles that of prokaryotic cells.
      This apparatus consists of some ten proteins including a cysteine desulfurase
      producing elemental sulfur for biogenesis, a ferredoxin involved in reduction,
      and two chaperones. The mitochondrial Fe/S cluster synthesis apparatus not only
      assembles mitochondrial Fe/S proteins, but also initiates formation of extra
      mitochondrial Fe/S proteins. This involves the export of sulfur and possibly iron
      from mitochondria to the cytosol, a reaction performed by the ABC transporter
      Atm1p of the mitochondrial inner membrane. A possible substrate of Atm1p is an
      Fe/S cluster that may be stabilised for transport. Constituents of the cytosol
      involved in the incorporation of the Fe/S cluster into apoproteins have not been
      described yet. Many of the mitochondrial proteins involved in Fe/S cluster
      formation are essential, illustrating the central importance of Fe/S proteins for
      life. Defects in Fe/S protein biogenesis are associated with the abnormal
      accumulation of iron within mitochondria and are the cause of an iron storage
      disease.

PMID- 10595579
TI  - Mitochondrial iron metabolism in the yeast Saccharomyces cerevisiae.
AB  - Iron is fundamental to many biological processes, but is also detrimental as it
      fosters the synthesis of destructive oxygen radicals. Recent experiments have
      increased our knowledge of the critical process of regulation of mitochondrial
      iron metabolism. A number of genes directly involved in iron homeostasis in this
      organelle have been identified. Intriguingly, a minor Hsp70 molecular chaperone
      of the mitochondrial matrix has been implicated as a player in this process as
      well.

PMID- 10595580
TI  - A Scj1p homolog and folding catalysts present in dog pancreas microsomes.
AB  - Dog pancreas microsomes represent the key components of the established model
      system for the analysis of protein transport into the mammalian endoplasmic
      reticulum. More recently, these microsomes were also employed in cell-free
      systems which address questions related to protein folding and protein
      degradation in the mammalian endoplasmic reticulum. In order to get at a complete
      picture of these undoubtedly related processes in the in vitro system we need to
      know all the proteins we are dealing with, and their respective stoichiometries.
      Here we give a progress report on our attempts to identify and to quantify the
      soluble molecular chaperones and folding catalysts which are present in the lumen
      of dog pancreas microsomes. Eventually, we will need to know how the in vitro
      system compares with the situation in intact pancreatic cells as well as in other
      cells.

PMID- 10595581
TI  - The import pathway of human and Thermoplasma 20S proteasomes into HeLa cell
      nuclei is different from that of classical NLS-bearing proteins.
AB  - Wild-type proteasomes of human erythrocytes and the archaeon Thermoplasma
      acidophilum compete with each other for transport into nuclei of digitonin
      permeabilized HeLa cells in the presence of an energy-regenerating system and
      rabbit reticulocyte lysate. 'NLS'-mutated Thermoplasma proteasomes were also able
      to compete with human proteasomes in the same assay, although with lower
      efficiency. Furthermore, in contrast to the other archaeal and bacterial cell
      lysates tested, the Thermoplasma cytosol efficiently supported nuclear import of
      human and Thermoplasma proteasomes. However, the same lysate could barely direct
      the nuclear transport of BSA-NLSsv40 peptide conjugates or the classical NLS
      bearing protein, nucleoplasmin. Finally, additional importin alpha/beta
      significantly decreased the import efficiency of both human and Thermoplasma
      proteasomes. Taken together, these results suggest that nuclear import of
      proteasomes may use a novel pathway that is different from that of classical NLS
      bearing proteins.

PMID- 10595582
TI  - Role of p52 (NF-kappaB2) in LPS tolerance in a human B cell line.
AB  - Cells of the weakly CD14 positive human B cell line RPMI 8226, clone 1, will
      mobilize NF-kappaB (p50/p65 and p50/p50) proteins and produce TNF mRNA when
      stimulated with lipopolysaccharide (LPS). When such cells are precultured with a
      low amount of LPS (50-250 ng/ml) for 3 - 4 days followed by a secondary
      stimulation with a high dose of LPS (1 microg/ml) then the cytokine expression is
      strongly reduced, i. e. the cells have become tolerant. Western blot analysis of
      proteins of the NF-kappaB/rel family demonstrates cytoplasmic p50 and p65 for
      naive B cells plus a low level of p52. While with tolerance induction the pattern
      of p50 and p65 proteins remains essentially unchanged, the LPS tolerant 8226
      cells show a dramatic increase of both p52 protein and its p100 precursor in the
      cytosol. This p52 is found strongly upregulated in Western blots of extracts from
      purified nuclei of tolerant cells. Also, gelshift analysis with the -605 kappaB
      motif of the human TNF 5'-region shows an additional high mobility complex in LPS
      tolerant cells -a complex that is supershifted with an anti-p52 antibody.
      Functional analysis with the -1064 TNF 5'-region in front of the luciferase
      reporter gene demonstrates that transactivation of the TNF promoter is strongly
      reduced in tolerant cells. Also, overexpression of p52 will suppress activity of
      TNF promoter reporter gene constructs. Taken together these data show that
      tolerance to LPS in the human RPMI 8226 B cell line involves upregulation of the
      p52 (NF-kappaB2) gene, which appears to be instrumental in the blockade of TNF
      gene expression.

PMID- 10595583
TI  - SHP1 protein tyrosine phosphatase negatively modulates erythroid differentiation
      and suppression of apoptosis in J2E erythroleukemic cells.
AB  - The SH2 domain-containing tyrosine phosphatase SHP1 is known to play a crucial
      role in the regulation of hematopoiesis. It has been shown previously that SHP1
      associates with the activated erythropoietin receptor (EPOR) and negatively
      regulates mitogenic signaling. To further elucidate the role of SHP1 in
      erythropoietin (EPO)-induced cellular responses we employed J2E erythroleukemic
      cells as a model for erythroid maturation and cytokine-triggered suppression of
      apoptosis. Our data indicate that overexpressed SHP1 inhibits both EPO-induced
      differentiation as well as prevention of apoptosis. The specific signaling
      pathways responsible are not unraveled so far. Therefore, we analyzed the
      involvement of SHP1 in two established EPO-stimulated pathways, the JAK/STAT and
      the MAP kinase cascades, by transient coexpression of reporter constructs
      containing binding sites for transcription factors targeted by these pathways and
      a SHP1 cDNA. Both pathways are inhibited by SHP1 as indicated by the lower
      induction of reporter gene activity. In conclusion, SHP1 regulates the
      transcriptional activity stimulated by the EPO-induced JAK/STAT and MAPK pathways
      and is involved in the signaling machinery responsible for erythroid
      differentiation and suppression of apoptosis.

PMID- 10595584
TI  - Comparative cleavage sites within the reactive-site loop of native and oxidized
      alpha1-proteinase inhibitor by selected bacterial proteinases.
AB  - Human alpha1-proteinase inhibitor (alpha1-PI) is responsible for the tight
      control of neutrophil elastase activity which, if down regulated, may cause local
      excessive tissue degradation. Many bacterial proteinases can inactivate alpha1-PI
      by hydrolytic cleavage within its reactive site, resulting in the down regulation
      of elastase, and this mechanism is likely to contribute to the connective tissue
      damage often associated with bacterial infections. Another pathway of the
      inactivation of alpha1-PI is reversible and involves oxidation of a critical
      active-site methionine residue that may influence inhibitor susceptibility to
      proteolytic inactivation. Hence, the aim of this work was to determine whether
      this oxidation event might affectthe rate and pattern of the cleavage of the
      alpha1-PI reactive-site loop by selected bacterial proteinases, including
      thermolysin, aureolysin, serralysin, pseudolysin, Staphylococcus aureus serine
      proteinase, streptopain, and periodontain. A shift of cleavage specificity was
      observed after alpha1-PI oxidation, with a preference for the Glu354-Ala355 bond
      by most of the proteinases tested. Only aureolysin and serralysin cleave the
      oxidized form of alpha1-PI faster than the native inhibitor, suggesting that
      bacteria which secrete these metalloproteinases may specifically take advantage
      of the host defense oxidative mechanism to accelerate elimination of alpha1-PI
      and, consequently, tissue degradation by neutrophil elastase.

PMID- 10595585
TI  - A high affinity binding site for the polypyrimidine tract binding protein (PTB)
      is located in the 5'-untranslated region of the rat proteinase alpha1-inhibitor 3
      variant I gene.
AB  - As a first step towards understanding the mechanism underlying the differential
      gene expression of the two variants of the rat proteinase-inhibitor alpha1
      inhibitor 3 (alpha1-I3) corresponding genomic clones were isolated. The 100%
      similarity between the sequence of one genomic clone and that of the alpha1-13
      variant I cDNA strongly suggested that its 5'-sequence represented the upstream
      region of the corresponding gene. Several putative cis-regulatory elements were
      identified as well as a polypyrimidine tract located between the transcription
      start site of the alpha1-I3 variant I mRNA and the AUG codon. The polypyrimidine
      tract functions as a positive cis-element in a heterologous promoter. By
      electrophoretic mobility shift assays (EMSA) we have shown that a GST
      (glutathione S-transferase) fusion of the rat polypyrimidine tract binding
      protein (PTB) has a high affinity for the pyrimidine-rich sense strand but not
      for the complementary sequence of the 5'-untranslated region of the alpha1-I3
      variant I gene.

PMID- 10595586
TI  - Defining the location and function of domains of McrB by deletion mutagenesis.
AB  - The GTP-dependent restriction endonuclease McrBC of E. coli K12, which recognizes
      cytosine-methylated DNA, consists of two protein subunits, McrB and McrC. We have
      investigated the structural assignment and interdependence of the McrB subunit
      functions, namely (i) specific DNA recognition and (ii) GTP binding and
      hydrolysis. Extending earlier work, we have produced McrB variants comprising N-
      and C-terminal fragments. The variants McrB1-162 and McrB1-170 are still capable
      of specific DNA binding. McrB169-465 shows GTP binding and hydrolysis
      characteristics indistinguishable from full-length McrB as well as wild-type like
      interaction with McrC. Thus, DNA and GTP binding are spatially separated on the
      McrB molecule, and the respective domains function quite independently.

PMID- 10595587
TI  - Disruption of the gene for Hsp30, an alpha-crystallin-related heat shock protein
      of Neurospora crassa, causes defects in import of proteins into mitochondria.
AB  - The gene for Hsp30, the only known alpha-crystallin-related heat shock protein of
      Neurospora crassa, was disrupted by repeat-induced point mutagenesis, leading to
      loss of cell survival at high temperature. Hsp30, which is not synthesized at 30
      degrees C, associates reversibly with the mitochondria at high temperature (45
      degrees C). In this study, we found that import of selected proteins into
      internal compartments of mitochondria, following their synthesis in the cytosol,
      was severely impaired at high temperature in a strain mutant in Hsp30. After 70
      min of cell incubation at 45 degrees C, most matrix, inner membrane, and
      intermembrane-space proteins tested were reduced in import by about 50-70% in the
      mutant, as compared to wild-type cells. In contrast, assembly of selected
      proteins into the outer mitochondrial membrane was not reduced, except for one
      component of the preprotein translocase complex of the mitochondrial outer
      membrane. Three proteins of this complex co-immunoprecipitated with Hsp30 of wild
      type cells incubated at 45 degrees C. We propose that Hsp30 interacts with the
      preprotein translocase of the mitochondrial outer membrane and that it chaperones
      the activity of one or more components of this translocase complex at high
      temperature.

PMID- 10595588
TI  - Cloning, purification and characterisation of cystathionine gamma-synthase from
      Nicotiana tabacum.
AB  - Cystathionine gamma-synthase, the enzyme catalysing the first reaction specific
      for methionine biosynthesis, has been cloned from Nicotiana tabacum,
      overexpressed in Escherichia coli and purified to homogeneity. The recombinant
      cystathionine gamma-synthase catalyses the pyridoxal 5'-phosphate dependent
      formation of L-cystathionine from L-homoserine phosphate and L-cysteine with
      apparent Km-values of 7.1+/-3.1 mM and of 0.23+/-0.07 mM, respectively. The
      enzyme was irreversibly inhibited by DL-propargylglycine (Ki = 18 microM,
      k(inact) = 0.56 min(-1)), while the homoserine phosphate analogues 3
      (phosphonomethyl)pyridine-2-carboxylic acid, 4-(phosphonomethyl)pyridine-2
      carboxylic acid, Z-3-(2-phosphonoethen-1-yl)pyridine-2-carboxylic acid, and DL-E
      2-amino-5-phosphono-3-pentenoic acid acted as reversible competitive inhibitors
      with Ki values of 0.20, 0.30, 0.45, and 0.027 mM, respectively. In combination
      these results suggest a ping-pong mechanism for the cystathionine gamma-synthase
      reaction, with homoserine phosphate binding to the enzyme first. Large single
      crystals of cystathionine gamma-synthase diffracting to beyond 2.7 A resolution
      were obtained by the sitting drop vapour diffusion method. The crystals belong to
      the orthorhombic space group P2(1)2(1)2(1) with unit cell constants a = 120.0 A,
      b = 129.5 A, c = 309.8 A, corresponding to two tetramers per asymmetric unit.

PMID- 10595589
TI  - Isolation and characterization of viridin, a new 65 kDa antifungal protein from
      the mould Trichoderma viride.
AB  - A new extracellular antifungal protein with a yield of 10 mg per liter was
      isolated from the culture medium of the mould Trichoderma viride. The protein,
      which we named viridin, was purified by carboxymethyl-cellulose cation-exchange
      chromatography and Superose 12 HR 10/30 high-performance liquid chromatography.
      Viridin, a basic protein of approximately 65 kDa as determined by SDS-PAGE,
      inhibits the growth of the cotton pathogen Verticillum dahliae, the IC50 being 6
      microM.

PMID- 10595590
TI  - The T-knot motif revisited.
AB  - The T-knot scaffold, a disulphide-reinforced structural motif shared by several
      proteins with very different biological functions, has been defined as 'a stretch
      of the protein chain which comprises two strands of a beta-sheet and three loops,
      knotted by two disulphides into the shape of the letter T'. In this communication
      we show that the presence of a central beta-sheet is not a required structural
      feature for proteins sharing the T-knot topology. Moreover, superposition of the
      three-dimensional structures of representative members of the T-knot family
      highlights a common and structurally well-defined core, formed by the two knotted
      disulphides, substituting for a larger residue-based hydrophobic core. These
      results suggest that folding and stability of the T-knot scaffold mainly depend
      on the geometry of the two knotted disulphides and on the loop length, and that
      the secondary structure elements are not a prerequisite for motif formation.
      Accordingly, a redefinition of the T-knot motif is proposed.

PMID- 10595591
TI  - A desktop guide to Type 2 diabetes mellitus. European Diabetes Policy Group 1998
      1999 International Diabetes Federation European Region.

PMID- 10595592
TI  - Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current
      evidence from clinical trials.
AB  - Diabetic neuropathy represents a major health problem, as it is responsible for
      substantial morbidity, increased mortality, and impaired quality of life. Near
      normoglycaemia is now generally accepted as the primary approach to prevention of
      diabetic neuropathy, but is not achievable in a considerable number of patients.
      In the past two decades several medical treatments that exert their effects
      despite hyperglycaemia have been derived from the experimental pathogenetic
      concepts of diabetic neuropathy. Such compounds have been designed to improve or
      slow the progression of the neuropathic process and are being evaluated in
      clinical trials, but with the exception of alpha-lipoic acid (thioctic acid)
      which is available in Germany, none of these drugs is currently available in
      clinical practice. Here we review the current evidence from the clinical trials
      that assessed the therapeutic efficacy and safety of thioctic acid in diabetic
      polyneuropathy. Thus far, 15 clinical trials have been completed using different
      study designs, durations of treatment, doses, sample sizes, and patient
      populations. Within this variety of clinical trials, those with beneficial
      effects of thioctic acid on either neuropathic symptoms and deficits due to
      polyneuropathy or reduced heart rate variability resulting from cardiac autonomic
      neuropathy used doses of at least 600 mg per day. The following conclusions can
      be drawn from the recent controlled clinical trials. 1.) Short-term treatment for
      3 weeks using 600 mg of thioctic acid i.v. per day appears to reduce the chief
      symptoms of diabetic polyneuropathy. A 3-week pilot study of 1800 mg per day
      given orally indicates that the therapeutic effect may be independent of the
      route of administration, but this needs to be confirmed in a larger sample size.
      2.) The effect on symptoms is accompanied by an improvement of neuropathic
      deficits. 3.) Oral treatment for 4-7 months tends to reduce neuropathic deficits
      and improves cardiac autonomic neuropathy. 4.) Preliminary data over 2 years
      indicate possible long-term improvement in motor and sensory nerve conduction in
      the lower limbs. 5.) Clinical and postmarketing surveillance studies have
      revealed a highly favourable safety profile of the drug. Based on these findings,
      a pivotal long-term multicenter trial of oral treatment with thioctic acid
      (NATHAN I Study) is being conducted in North America and Europe aimed at slowing
      the progression of diabetic polyneuropathy using a clinically meaningful and
      reliable primary outcome measure that combines clinical and neurophysiological
      assessment.

PMID- 10595593
TI  - Reduction of leptin precedes fat loss from running exercise in insulin-resistant
      rats.
AB  - Serum concentrations of leptin, a hormone secreted into the circulation by
      adipocytes, correlate with body mass index. Circulating of leptin is thought to
      signal the brain in patients with hyperinsulinemia, a condition reported to be
      preventable and testable by exercise training. In the present experiments,
      sucrose-fed rats had reduced concentrations of leptin in portal venous blood
      after 4 weeks of nonforced wheel-running exercise (1.1 +/- 0.1 vs. 6.2 +/- 1.8
      ng/mL, in nonexercised sucrose-fed rats, P < 0.05). Mesenteric and subcutaneous
      fat stores were similar between groups. After 12 weeks of exercise, portal vein
      levels of leptin concentrations (5.2 +/- 2.1 vs. 9.9 +/- 0.8 ng/mL, P < 0.05) and
      mesenteric and subcutaneous fat all were reduced in the exercise group. These
      results suggest that short-term running exercise reduces circulating leptin
      before any reduction of adipose mass, and this reduction in the concentration of
      leptin available to its receptors has beneficial effects on the metabolism of fat
      and carbohydrates.

PMID- 10595594
TI  - The KID Study VI: diabetic complications and associated diseases in younger type
      2 diabetics still performing a profession. Prevalence and correlation with
      duration of diabetic state, BMI and C-peptide.
AB  - A sub-study evaluated 698 younger (54.5 +/- 6.9 years) type 2 diabetics of the
      KID Study participants to establish the prevalence of diabetic complications and
      associated diseases and their correlation with body mass index (BMI), duration of
      disease and to C-peptide levels. Only 19.8% of the type 2 diabetics had a normal
      weight. In all weight subgroups, the average age of diabetes manifestation were
      around age 45. In 46.6% of all type 2 diabetics we could already demonstrate
      microangiopathic complications. Strikingly, 15.9% of the patients already had
      proliferative retinopathies and 12.6% had albuminuria of more than 1000 mg/dl.
      74.7% of our type 2 diabetics presented with the well-known risk cluster of the
      metabolic syndrome: In every other patient, we found hypertension and/or
      hyperlipoproteinaemia. Accordingly, the prevalence of the macroangiopathic
      diabetic complications, coronary artery disease and peripheral vascular disease
      was 17.8%, which is high for a relatively young population with a mean age of
      53.9 years and goes conform with recent literature (Lowel et al., 1999). An
      increase in BMI correlated significantly with deterioration of HbA1, a decrease
      in HDL cholesterol, an increase in triglycerides and with a higher prevalence of
      hypertension. The frequency of nephropathy increase significantly up to a BMI of
      30-35 kg/m2. Retinopathies and polyneuropathies were associated with BMI but
      increased significantly with the duration of the diabetic state. In contrast to
      microangiopathic diabetic complications, there was already a high prevalence of
      nephropathy after a comparatively short duration of disease. The prevalence of
      hyperlipoproteinaemia and hypertension did not depend from the duration of
      diabetes. These concomitant diseases already were frequent early in the disease
      and did not increase with the duration of disease. However, there was a strong
      correlation between increasing hyperlipoproteinaemia and hypertension and higher
      C-peptide levels. We found no coincidence between C-peptide levels and
      microangiopathic diabetic complications.

PMID- 10595595
TI  - Lack of effects of the beta3-adrenoreceptor agonist UL-TG 307 on insulin
      sensitivity and insulin secretion in Type 2 diabetic patients.
AB  - The effects of a novel beta3-adrenoreceptor agonist, UL-TG 307, on insulin
      sensitivity and insulin secretion, lipid metabolism, and body weight were
      investigated. Thirteen diet treated male Type 2 diabetic patients participated in
      a randomized, double-blind, placebo controlled cross-over trial with two 14 day
      administration periods with placebo and UL-TG 307 (24 mg daily). After each
      administration period insulin secretion was assessed by means of an OGTT and
      insulin sensitivity was measured by an hyperinsulinaemic euglycaemic glucose
      clamp. Lipid metabolism was evaluated by measuring non-esterified fatty acid,
      glycerol, and triglyceride serum concentrations at the end of each administration
      period. Treatment with UL-TG 307 did not improve insulin sensitivity (insulin
      sensitivity index (S(I)): UL-TG 307 2.5 -/+ 0.6 (mean +/- SD) vs. placebo 2.2 +/-
      0.8 ml/min*m2 per microU/ml) nor increased insulin secretion (area under the
      serum insulin profile AUC0-240/plasma glucose AUC0-240: UL-TG 307 8.8 +/- 7.4 vs.
      placebo 8.3 +/- 6.4 microU/ ml/mmol/l). No differences in lipid metabolism,
      metabolic control, and body weight were observed. We conclude that two weeks'
      administration of the beta3-adrenoreceptor agonist UL-TG 307 in a daily dose of
      24 mg did not lead to any significant effect in diet treated type 2 diabetic
      patients.

PMID- 10595596
TI  - Proinsulin in pregnant women with normal glucose tolerance or mild gestational
      diabetes mellitus.
AB  - Pregnancy is characterized by peripheral insulin resistance, which is
      physiologically compensated by an increase in insulin secretion. Type 2 diabetes
      and impaired glucose tolerance (IGT) have been associated with an inappropriate
      increase in insulin precursors, namely proinsulin. The aim of this study was to
      determine levels of proinsulin (PI), specific insulin (SI) and the proinsulin-to
      specific insulin (PI/SI) ratio in consecutive pregnant women (n = 209) with
      normal glucose tolerance (NGT), as assessed by a 2h oral glucose tolerance test,
      and with mild gestational diabetes (GDM), in comparison to 32 healthy, non
      pregnant women. Furthermore, we related these variables to surrogate markers of
      insulin resistance and insulin secretion. We found no significant differences in
      the levels of PI and the PI/ SI ratio between pregnant and non-pregnant women
      (PI: 5.0 +/- 3.6 vs. 4.8 +/- 3.5 pmol/L, p = NS), and between pregnant women with
      mild GDM and NGT (PI: 5.4 +/- 2.4 vs. 4.9 +/- 3.9 pmol/L, p = NS). SI was
      elevated in women with mild GDM (112.2 +/- 47.3 vs. 94.8 +/- 43.0 pmol/L in NGT,
      p=0.02). PI was related to fasting glucose (r = 0.17, p < 0.02), but not post
      load glucose levels, and to fasting insulin [specific insulin: r = 0.67, p =
      0.0001; total immunoreactive insulin (IRI): r = 0.69, p = 0.0001], as well as
      post-load insulin levels (IRI at 120 min: r = 0.18, p < 0.03). The PI/SI ratio
      showed no association with fasting or post-load glucose or insulin levels.
      Pregnant women presented with a metabolic pattern suggestive of enhanced insulin
      resistance, namely increased fasting and post-load insulin levels. In women with
      mild GDM, fasting and post-load hyperglycemia, as well as an additional increase
      in insulin resistance was found. Group differences weakened when accounting for
      differences in body weight. The data of the present study suggest that in normal
      pregnancy as well as mild GDM metabolic alterations including enhanced insulin
      resistance and hyperglycemia do not result in an increase in circulating levels
      of proinsulin, both in absolute terms and relative to levels of specific insulin,
      as indicated by the proinsulin-to-specific insulin ratio.

PMID- 10595597
TI  - Glucosaminyl N-deacetylase mRNA expression in diabetic rats.
AB  - Glucosaminyl N-deacetylase is a key enzyme in the synthesis of heparan sulphate.
      N-deacetylase activity is inhibited in experimental diabetes. The mechanism by
      which diabetes influences N-deacetylase activity is unknown. Using reverse
      transcription PCR we quantified hepatic N-deacetylase mRNA in normal and
      streptozotocin diabetic rats. A negative correlation was found between final
      blood glucose and N-deacetylase mRNA expression in diabetic rats, r = -0.44, p <
      0.05. N-deacetylase mRNA expression was also correlated to N-deacetylase activity
      (r = 0.48, p < 0.05). N-deacetylase:cyclophilin mRNA ratio was not significantly
      affected by diabetes, 0.26 (0.2-0.35) vs 0.31 (0.16-0.5), p =0.48, in 10 weeks
      and 0.21 (0.15-0.37) vs 0.27 (0.19-0.32), p = 0.65, in 8 months rats, diabetic
      and normal rats respectively, median (interquartile range). The negative
      correlation between blood glucose and N-deacetylase mRNA in diabetic rats
      suggests however that altered gene expression may contribute to the altered N
      deacetylase activity seen in experimental diabetes.

PMID- 10595598
TI  - Prevalence of primary hyperparathyroidism in 13387 patients with thyroid
      diseases, newly diagnosed by screening of serum calcium.
AB  - Primary Hyperparathyroidism (PHP) often goes unrecognised. Evidence of the
      influence of thyroid diseases on parathyroid activity exists. In order to
      determine the prevalence of primary hyperparathyroidism (PHP) in patients with
      thyroid diseases, a series of patients referred to an outpatient department for
      patients with thyroid diseases were examined for additional PHP. In addition to
      screening for thyroid diseases, serum calcium concentration (S-Ca) was measured
      in a series of persons who came to our outpatients' service for patients with
      thyroid diseases during the period 1992 to 1998. 13387 persons, median age 48 y,
      m = 2367, f = 11020, among them 9017 patients with thyroid diseases and 4370
      persons without thyroid dysfunction, were studied. In patients with S-Ca outside
      the normal range, further diagnostic tests relating to PHP were performed.
      106/13387 persons showed S-Ca > or = 2.6 mmol/L, in 31 cases due to PHP. In
      comparison to persons without thyroid diseases, the occurrence of PHP was
      significantly higher in patients with thyroid diseases (4/4370 = 0.09% vs.
      26/9017 = 0.29%). Furthermore, 2 patients with normal S-Ca were diagnosed as
      having PHP in addition to another endocrine disease (acromegaly, multiple
      endocrine neoplasia type IIa, resp.). 31 of the 54 persons with S-Ca > 2.6mmol/L
      and who showed no other reasons for hypercalcaemia were found to be in a
      hyperthyroid state. The prevalence of PHP was significantly higher in patients
      with euthyroid goitre (p < 0.05) and in patients with thyroid carcinoma (p =
      0.01) as compared to other persons with thyroid diseases. The groups of patients
      did not differ with regard to age. However, patients without thyroid diseases
      were significantly younger (median age 38y). Above the age of 50, the prevalence
      of PHP became higher in patients with euthyroid goitre or thyroid carcinoma than
      in those with a healthy thyroid gland. In contrast, in persons of under 50 y,
      there was no difference between these groups. The percentage of males with PHP
      was higher than in the total population studied (30% vs. 21.5%). In conclusion, a
      high occurence of PHP could be demonstrated in patients with thyroid diseases
      (0.29%) as compared to persons without thyroid dysfunction (0.09%), the highest
      prevalence being in patients with thyroid carcinoma. A clinically not relevant
      influence of thyroid function on S-Ca was seen in some patients with
      hyperthyroidism. Determination of S-Ca is recommended for each patient referred
      to a thyroid outpatients' department because of the high number of PHP cases in
      this context.

PMID- 10595599
TI  - Naloxone and vitamin E block stress-induced reduction of locomotor activity and
      elevation of plasma corticosterone.
AB  - Normal rats, on being repetitively stressed by being restrained in a tight
      container for two hours, had higher levels of plasma corticosterone compared to
      pre stress values. These rats also reacted to the stress by a behavioral response
      in which there was marked decrease in locomotor activity assessed by the open
      field test (pre stress: 71.3 +/- 2.6 squares crossed versus post stress: 14.3 +/-
      2.5 squares crossed) by counting the number of squares entered by the rat over 5
      minutes. By the 6th to 7th exposures to the repetitive stress, the rats adapted
      to the stress and had normal plasma corticosterone levels and locomotor activity
      scores comparable to the pre stress values. These responses to stress were
      completely blocked by the administration of 0.32 microg/100 g BW of naloxone i.p
      at 10 minutes prior to the stress. In rats fed with rat chow supplemented with 90
      mg/kg rat chow or 150 mg/kg rat chow of vitamin E, there was significant
      reduction of the plasma corticosterone levels and improvement in the locomotor
      activity. Stress thus caused opioid mediated increase in plasma corticosterone
      and reduction in locomotor activity which could be blocked by naloxone. These
      stress responses probably also involved generation of oxygen free radicals which
      were scavenged by the vitamin E, thus reducing the effects of repetitive stress
      on locomotor activity and serum corticosterone levels.

PMID- 10595600
TI  - Thyroidectomy in iodine induced thyrotoxic storm.
AB  - Between January 1996 and September 1997 we treated 4 patients with iodine-induced
      thyrotoxic storm (2 females, 2 men; age 54-77 years). Iodine contamination was
      due to iodine-containing contrast media in 3 patients and iodine-containing
      disinfectant in 1 patient. Thyroid storm with tachycardia, hypertension,
      sweating, tremor, weight loss and coma occured 3-10 weeks after iodine
      contamination. These symptoms were accompanied by raised fT4- and fT3-values. All
      4 patients were initially treated with antithyroid drugs for 7 days, whereas 2
      patients with coronary artery disease, demonstrated by coronary angio-graphy,
      were treated with antithyroid drugs for 2 weeks. Because of unsuccessful
      antithyroid drug treatment, all 4 patients underwent subtotal thyroidectomy.
      There were no perioperative complications. We conclude that early thyroidectomy
      is the appropriate treatment for iodine-induced thyrotoxicosis even in patients
      with severe accompanying diseases.

PMID- 10595601
TI  - Plasma leptin levels do not change in healthy humans shortly after a
      hydrocortisone challenge.
AB  - The acute response of plasma leptin levels to a hydrocortisone challenge was
      measured in 16 healthy volunteers. We additionally asessed insulin which is known
      to play a regulatory role in the leptin system. While plasma cortisol levels
      increased significantly after the administration of hydrocortisone, this rise was
      not associated with any change in leptin and insulin concentrations during the
      3.5-hour experimental period. This result corroborates the assumption that
      glucocorticoid-induced increases in leptin levels, as described in the
      literature, occur delayed and are due rather to an activation of leptin synthesis
      than to a mere leptin release.

PMID- 10595602
TI  - The role of cytokines, coagulation, and fibrinolysis in peritoneal tissue repair.
AB  - Peritoneal tissue repair is a distinct entity. Regardless of the type of injury,
      a common series of events follows, culminating in inflammation and restoration.
      Molecular actors interact in a series of events in which the balance of fibrin
      deposition and degradation is vital. Although the complexity of the repair is
      illustrated by the multitude of effects and the overlap of molecular mediators
      involved, a framework is emerging. In this context, the overall role of cytokines
      is to shift the balance of fibrin deposition and degradation in favour of fibrin
      residues. Coagulation, as well as generating fibrin, is probably of importance in
      stimulating remesothelialisation, and fibrinolysis is instrumental in the
      degradation of fibrin deposits. As far as wound healing in concerned, we propose
      that the ultimate goal may not be to prevent adhesions, but rather to control
      their formation. To attain this, site-specific modulation of the repair process
      is essential. The new insights in mediators and modulators reviewed in this paper
      may provide means for site-specific modulation of peritoneal tissue repair as
      well as constituting molecular markers of the repair process.

PMID- 10595604
TI  - Local inflammatory peritoneal response to operative trauma: studies on cell
      activity, cytokine expression, and adhesion molecules.
AB  - OBJECTIVE: To test the hypothesis that different surgical procedures may lead to
      different degrees of activation of the human peritoneal response. DESIGN:
      Clinical laboratory study. SETTING: University Hospital, Germany. MATERIAL:
      Peritoneal specimens taken from the incision or parietal resection margins at the
      beginning and end of laparoscopic or open cholecystectomy, or other conventional
      open operations (n = 5 in each group). MAIN OUTCOME MEASURES: Detection of
      indicators of the inflammatory response: interleukin 1 (IL-1), interleukin 6 (IL
      6), intercellular adhesion molecule- (ICAM-1), antibacterial protein (defensin 3
      that reflects the activation of granulocytes), the antibody clone HAM 56 (for
      detection of local macrophages), and antibodies against macrophage inhibiting
      factor (MIF)-related proteins 8 and 14 (MRP 8 and 14). RESULTS: The rise between
      preoperative and postoperative evaluations was significant for each variable (p <
      0.05). With one single exception (IL-6 between laparoscopic cholecystectomy and
      other operations), the one way analysis of variance (ANOVA) showed no significant
      differences among the three groups in the detectable increases in staining.
      Linear regression analysis showed no correlation between length of operation and
      increases in immunohistochemically detected inflammatory variables. CONCLUSION:
      Minimally invasive surgery does not necessarily mean minimal peritoneal damage.
      The immunohistochemical evaluation of the local cellular response may provide
      additional objective criteria for the grading of operative trauma.

PMID- 10595603
TI  - Detection of T cell apoptosis after major operations.
AB  - OBJECTIVE: To detect T cell apoptosis in reduced peripheral lymphocyte counts in
      patients having major operations. DESIGN: Prospective study. SETTING: University
      hospital, Japan. SUBJECTS: 11 patients having oesophagectomy and 5 having
      laparoscopic cholecystectomy. INTERVENTIONS: To investigate T cell apoptosis we
      detected DNA fragmentation using electrophoresis, and T-cell receptor-gamma (TCR
      gamma) gene amplification using polymerase chain reaction (PCR) in serum. MAIN
      OUTCOME MEASURES: Peripheral lymphocyte count and DNA extracted from the serum
      preoperatively and on postoperative days 1, 3, 5, and 7. RESULTS: The lymphocyte
      count decreased significantly until day 5 and then increased in the patients who
      had had oesophagectomy. DNA fragmentation and PCR products for the TCRgamma
      variable region gene were found in the serum DNA of 10 patients until day 5. No
      DNA fragmentation or PCR products were found in the serum of patients who had had
      laparoscopic cholecystectomy. CONCLUSION: These results suggest that transient T
      cell apoptosis occurs after major operations.

PMID- 10595605
TI  - Comparison of one-lung ventilation and high-frequency ventilation in
      thoracoscopic surgery.
AB  - OBJECTIVE: To report our experience of the use of high frequency ventilation
      (HFV) in thoracoscopic surgery. DESIGN: Retrospective study. SETTING: University
      Hospital Rotterdam, The Netherlands. SUBJECTS: 31 patients (18 men and 13 women,
      mean age 42 years, range 26-67 years) who underwent 46 thoracoscopic procedures
      between January 1992 and December 1997. INTERVENTIONS: Until October 1994
      patients had conventional mechanical ventilation with a double-lumen tube. Since
      then HFV has been used. MAIN OUTCOME MEASURES: Duration of induction, oxygen
      saturation, and end-tidal carbon dioxide tension. RESULTS: 25 procedures were
      done with a double-lumen endotracheal tube for one-lung ventilation and in 21 HFV
      was used. Induction of anaesthesia took significantly less time in the HFV group
      (median 14 minutes) compared with one-lung ventilation group (median 31 minutes)
      (p < 0.05). There were no significant differences between the groups in either
      SaO2 or end-tidal CO2. CONCLUSION: HFV is both safe and simple for use in
      thoracoscopic surgery.

PMID- 10595606
TI  - Postoperative downregulation of MHC class II antigen on monocytes does not differ
      between open and endovascular repair of aortic aneurysms.
AB  - OBJECTIVES: To study immune cell response and histocompability class II (HLA-DR)
      expression after aortic aneurysm repair. SETTING: University hospital, Sweden.
      SUBJECTS: 42 patients operated on for aortic aneurysm, 26 by an endovascular and
      16 by an open technique. MAIN OUTCOME MEASURES: Analysis of HLA-DR expression and
      concentrations of blood mononuclear cells by flow cytometry. Splanchnic pH
      analysed by tonometry and interleukin-6 and tumour necrosis factor-alpha measured
      by enzyme-linked immunosorbent assay. RESULTS: The HLA-DR expression on
      lymphocytes did not change, whereas total HLA-DR expression on monocytes was
      downregulated, and more pronounced in five patients who developed severe
      postoperative complications. There were no differences in cell or HLA-DR
      responses between the two operations. CONCLUSIONS: Both endovascular and open
      repair of aortic aneurysm produced similar downregulation of monocyte HLA-DR
      expression and similar responses in circulating mononuclear blood cells. There
      was pronounced downregulation of monocyte HLA-DR expression in patients with
      severe postoperative complications.

PMID- 10595607
TI  - Effect of hypertonic saline and alcohol on viability of daughter cysts in hepatic
      hydatid disease.
AB  - OBJECTIVE: To test the efficacy of hypertonic saline (20%) and absolute alcohol
      on the integrity of daughter cysts and the viability of the protoscoleces
      contained in these cysts. DESIGN: Experimental study. SETTING: Teaching hospital,
      Turkey. MATERIAL: 80 daughter cysts obtained from two patients with Gharbi type
      III hydatid cysts of the liver. INTERVENTIONS: The cysts were divided into two
      groups, in the first of which cysts were placed into hypertonic saline and in the
      second into absolute alcohol; they were kept there for 5, 15, 30 or 60 minutes.
      MAIN OUTCOME MEASURES: Integrity of the cyst wall and viability of the contents
      were evaluated using a vital staining technique with 0.1% eosin. RESULTS: Neither
      hypertonic saline nor absolute alcohol solution had any effect on the integrity
      of the daughter cysts or the viability of the protoscoleces. CONCLUSION:
      Percutaneous drainage of type III hydatid cysts can lead to high recurrence
      rates.

PMID- 10595608
TI  - Effect of trypsin inhibitor on reflux oesophagitis after total gastrectomy in
      rats.
AB  - OBJECTIVE: To characterise alkaline reflux oesophagitis after total gastrectomy
      in rats from the standpoints of cell proliferation and apoptosis and from its
      macroscopic and microscopic findings, and to evaluate the preventive and curative
      effects of camostat mesilate, a trypsin inhibitor. DESIGN: Open laboratory study.
      SETTING: University hospital, Japan. ANIMALS: 70 male Wistar rats. INTERVENTIONS:
      Total gastrectomy with Billroth II anastomosis (n = 30) and with Roux-en-Y
      anastomosis (n = 30) were used to establish reflux oesophagitis. Camostat
      mesilate was given for prevention and cure. The remaining 10 animals had a sham
      operation. MAIN OUTCOME MEASURES: Trypsin activity of the oesophagus, macroscopic
      and microscopic findings, bromodeoxyuridine (BrdU) and apoptotic cell labelling
      indices. RESULTS: Reflux oesophagitis was more common and extensive after
      Billroth II than Roux-en Y anastomosis. The BrdU labelling index was increased in
      oesophagitis, while the apoptotic index did not change. Camostat mesilate was
      effective in both preventing and treating oesophagitis. CONCLUSION: Trypsin has
      an important role in the development of reflux oesophagitis after total
      gastrectomy.

PMID- 10595609
TI  - Manual compared with mechanical cervical oesophagogastric anastomosis: a
      randomised trial.
AB  - OBJECTIVE: To compare the short and medium term result of hand-sewn and stapled
      anastomoses after oesophagectomy. DESIGN: Randomised study. SETTING: Teaching
      hospital, Italy. SUBJECTS: 41 patients who required oesophagectomy between
      February 1993 and December 1996. INTERVENTIONS: Oesophagectomy and left cervical
      gastroplasty. MAIN OUTCOME MEASURES: Mortality and morbidity. RESULT: 21 patients
      were randomised to have the anastomosis hand-sewn, and 20 to have it stapled. The
      two groups were comparable. 3 patients died in hospital (2 in the hand-sewn and 1
      in the stapled group), and the remainder were followed up a mean of 21 months
      (range 6-34). There was one clinical leak in the hand-sewn group compared with 3
      in the stapled group, and 1 further radiological leak in the stapled group. 2
      patients in the hand-sewn and 3 in the stapled group developed strictures.
      CONCLUSION: Though the numbers are too small to be assessed statistically, we
      think that these result are sufficient to persuade us that oesophagogastric
      anastomoses should be hand-sewn rather than stapled.

PMID- 10595610
TI  - Clinical experience of feeding through a needle catheter jejunostomy after major
      abdominal operations.
AB  - OBJECTIVE: To report our incidence of local and systemic complications after
      needle-catheter jejunostomy. DESIGN: Retrospective analysis. SETTING: University
      hospital, Switzerland. RESULTS: 100 patients (70 men and 30 women; mean age 65
      years, range 42-90) had needle-catheter jejunostomy for postoperative enteral
      feeding. 26 developed catheter-related and 18 nutrition-related complications.
      Most of the complications were minor (lumenal obstruction of the catheter or
      local cellulitis) and only 3 patients needed reoperation, 2 because the catheter
      broke with extravasation of the nutrition formula into the subcutaneous tissue,
      and the other because of a small bowel obstruction. There was no small bowel
      necrosis and no patient died as a direct result of the jejunostomy. Overall, 92
      patients were fed enterally according to the protocol, and 8 required removal of
      the catheter. CONCLUSION: Needle-catheter jejunostomy gives a safe and effective
      access for postoperative enteral feeding. Minor technical complications are
      common and can be reduced by a meticulous insertion technique and careful
      postoperative management. Regular clinical surveillance may reduce the incidence
      of nutrition-related complications.

PMID- 10595611
TI  - Surgical treatment of sacrococcygeal pilonidal sinus disease by excision and skin
      flaps: the Toulouse experience.
AB  - OBJECTIVE: To compare various techniques for the treatment of pilonidal sinus.
      DESIGN: Retrospective study SETTING: University Hospital of Toulouse, France.
      SUBJECTS: 246 consecutive patients who presented between 1979 and 1996. The
      male:female ratio was 2:1, and the mean age 26 years (range 18-69).
      INTERVENTIONS: 218 one or two stage excision and rotation skin flaps, and 28
      simple incisions. RESULTS: 16 sinuses recurred, and no flaps necrosed.
      CONCLUSION: Excision and rotation skin flaps offers an effective and elegant
      alternative to the more classic operations for pilonidal sinus as it causes less
      postoperative pain and shortens convalescence.

PMID- 10595612
TI  - Influence of peroperative lavage solutions on peritoneal defence mechanisms in
      vitro.
AB  - OBJECTIVE: To find out the in vitro reaction of mesothelial cells and
      polymorphonuclear leucocytes (PMN) to incubation with seven commonly-used lavage
      solutions. DESIGN: Experimental study. SETTING: Laboratories, The Netherlands.
      MATERIAL: Cultured human peritoneal mesothelial cells and isolated PMN.
      INTERVENTION: Incubation of cells with clinically used lavage solutions (sodium
      chloride, Hartmann's solution, povidone-iodine, Dakin's solution, taurolidine,
      chlorhexidine, and hydrogen peroxide). MAIN OUTCOME MEASURES: Activation of
      monolayers of mesothelial cells and PMN measured by release of oxygen free
      radicals (chemiluminescence) and interleukin (IL)-8 concentrations and toxic
      effects measured by morphology, release of lactate dehydrogenase, failure of the
      restriction of the passage of inulin, and incorporation of propidium iodide.
      RESULTS: All solutions activated and killed mesothelial cells and PMN to some
      extent; the more concentrated the solution the greater the effect on these cells.
      CONCLUSION: Lavage solutions both poison and stimulate mesothelial cells and
      neutrophils, and some solutions are more potent than others.

PMID- 10595613
TI  - Local treatment of generalised peritonitis in rats; effects on bacteria,
      endotoxin and mortality.
AB  - OBJECTIVE: To assess the effect of debridement, intraoperative lavage with
      saline, and additional instillation of taurolidine or imipenem/cilastatin in rats
      with faecal peritonitis. DESIGN: Laboratory study. SETTING: University hospital,
      The Netherlands. MATERIAL: 60 male Wistar rats. INTERVENTIONS: Rats were given an
      intraperitoneal injection of a faecal suspension containing Escherichia coli and
      Bacteroides fragilis. Six groups of 10: sham operation, debridement, debridement
      with saline lavage, debridement with saline lavage with intraperitoneal
      instillation of saline or taurolidine, or imipenem/cilastatin, were studied. MAIN
      OUTCOME MEASURES: Bacterial growth and endotoxin concentration in abdominal
      exudate and plasma, abscess formation, and mortality. RESULTS: Debridement
      temporarily reduced bacterial growth and the concentration of endotoxin in
      abdominal exudate, and delayed mortality. Lavage with saline further reduced
      bacterial growth and the endotoxin concentration. It also reduced the plasma
      endotoxin concentration, and mortality. Additional instillation of taurolidine
      did not reduce bacterial growth, but did initially reduce the endotoxin
      concentration in abdominal exudate and plasma. Instillation of
      imipenem/cilastatin, after debridement and lavage, significantly reduced all
      variables measured. CONCLUSION: In rats with faecal peritonitis, debridement,
      lavage with saline, and additional instillation of imipenem/cilastatin, all have
      cumulatively reducing effect on bacterial growth, endotoxin concentrations,
      abscess formation, and mortality. Instillation of taurolidine reduces only the
      amount of endotoxin.

PMID- 10595614
TI  - Autologous skin graft, human dura mater and polypropylene mesh for the repair of
      ventral abdominal hernias: an experimental study.
AB  - OBJECTIVE: To compare primary repair and grafting with one of two materials (one
      biological human dura mater, and one synthetic polypropylene mesh) or autologous
      skin, with primary repair alone in abdominal wall hernias in rats. DESIGN:
      Randomised experiment. SETTING: Teaching hospital, Turkey. ANIMALS: 72 male
      Wistar albino rats randomised into 4 groups of 18 rats each. These were further
      randomly divided into subgroups of 6 each that were killed on days 15, 30,and 45
      postoperatively. INTERVENTIONS: Each test material was sutured to the abdominal
      wall by an onlay technique. MAIN OUTCOME MEASURES: Macroscopic and microscopic
      appearance, and strength of the abdominal wall. RESULTS: Macroscopically, dura
      mater grafts lost their original shape, but polypropylene and skin did not. When
      completely incorporated the skin grafts had developed a new fascia. Dura mater
      and polypropylene induced a pronounced inflammatory reaction at all three times
      postoperatively, and there were significantly more fibroblasts in the dura mater
      group on days 15 and 30, and in the skin graft group on day 45, than in the other
      groups (p < 0.05). Mechanical resistance and mean breaking strength were
      significantly greater in the skin graft group than in the other groups at all
      times tested (p < 0.05). CONCLUSION: Full thickness autologous skin grafts were
      stronger than both human dura mater and polypropylene mesh when used to reinforce
      primary repairs of abdominal wall hernias in rats.

PMID- 10595616
TI  - Appendicectomy under local anaesthesia.
AB  - OBJECTIVE: To analyse our results of appendicetomy under local anaesthesia.
      DESIGN: Prospective study. SETTING: University hospital, India. SUBJECTS: 165
      patients who presented with appendicitis between January 1996 and December 1997.
      INTERVENTION AND MAIN OUTCOME MEASURES: Appendicectomy after infiltration of
      local anaesthetic. No patient required general or spinal anaesthesia. RESULT:
      Five patients (3%) developed postoperative wound infections. Mean operating time
      was 20 minutes (range 15-30) and median hospital stay 2 days (range 1-3).
      CONCLUSION: Appendicectomy under local anaesthesia is quick, cost-effective and
      carries little morbidity. It can be safely used for all age groups.

PMID- 10595615
TI  - Properties of endothelium and smooth muscle cells in canine femoral arteries
      after lumbar sympathectomy.
AB  - OBJECTIVE: To find out whether the lumbar sympathectomy modulated the endothelial
      function (as measured by nitric oxide (NO) and prostacyclin (PGI2), and blood
      flow in the canine femoral artery. DESIGN: Laboratory experiments. SETTING:
      Teaching hospital, Japan. ANIMALS: 16 mongrel dogs. INTERVENTION: Unilateral
      sympathectomy from L3 to L6. MAIN OUTCOME MEASURES: Five weeks later, the changes
      in blood flow, the endothelium-dependent responses and the PGI2 production in the
      canine femoral arteries were measured. RESULTS: The median (range) blood flow of
      left (denervated) and right (innervated) femoral arteries was 162 ml/min (122
      330) and 65 ml/min (40-92), respectively. There was a significant difference
      between the two groups (p < 0.01). The endothelium-dependent relaxations to
      acetylcholine, adenosine diphosphate (ADP) and A23187 were comparable. The
      amounts of PGI2 produced in the two groups were similar. Direct relaxation in
      response to sodium nitroprusside was also similar in the two groups. CONCLUSIONS:
      Lumbar sympathectomy did not alter the endothelial function, although the median
      blood flow in the denervated femoral arteries was significantly higher than in
      the innervated ones. The continuous vasodilatation after sympathectomy may be a
      more potent factor in the regulation of vascular tonus than the physiological
      regulation of NO and PGI2.

PMID- 10595617
TI  - Primary hydatid cysts of the common bile duct and hepatoduodenal ligament.

PMID- 10595618
TI  - Horseshoe appendicitis.

PMID- 10595619
TI  - Late complication associated with the use of non-absorbable clips in laparoscopic
      cholecystectomy.

PMID- 10595620
TI  - Histologically invaded intramammary sentinel node, but no metastases found on
      axillary dissection.

PMID- 10595621
TI  - Thrombotic thrombocytopenic purpura: a simpler diagnosis at last?

PMID- 10595622
TI  - Estimation of the von Willebrand factor-cleaving protease in plasma using
      monoclonal antibodies to vWF.
AB  - A protease present in plasma cleaves von Willebrand factor (vWF) at the peptide
      bond 842Tyr-843Met of the mature subunit. To quantify this vWF-cleaving protease
      activity in plasma we have developed a simple method based on the estimation by
      IRMA of the degradation of a constant amount of wild type recombinant vWF used as
      substrate, by serial dilutions of test plasma used as protease provider. vWFAg
      was estimated by two-site IRMA using as first coating antibody a monoclonal
      antibody (MoAb) whose epitope is localized on the C-terminal side of the cleavage
      site, and as second labeled antibody a pool of MoAbs specific for the N-terminal
      side. Because the proteolytic process leads to the progressive separation of the
      C- and N-terminal portions of the vWF subunit such an IRMA also shows a
      progressive apparent loss of vWFAg. In contrast, the levels of vWFAg estimated
      after proteolysis by regular IRMA remained essentially constant. Results obtained
      with this new method were compared with the analysis by SDS-agarose gel
      electrophoresis of the multimeric pattern of proteolyzed WT-rvWF and no
      significant difference was noted testing a series of 28 plasmas. As compared with
      normal pooled plasma, 14 normal individuals and 13 patients with various types of
      vWD had normal levels of protease activity (44-178%) by both methods. The
      validity of the method was confirmed by showing a lack of detectable protease
      activity in a patient with chronic relapsing thrombotic thrombocytopenic purpura.
      In conclusion our method appears as a useful tool for the quantification of the
      vWF-cleaving protease activity in plasma. Its sensitivity and specificity are
      similar to those of SDS-gel electrophoresis. However, this new IRMA has the major
      advantages of being much simpler and faster, and open to most research
      laboratories in the field.

PMID- 10595623
TI  - Assay of von Willebrand factor (vWF)-cleaving protease based on decreased
      collagen binding affinity of degraded vWF: a tool for the diagnosis of thrombotic
      thrombocytopenic purpura (TTP)
AB  - Patients with thrombotic thrombocytopenic purpura (TTP) have a deficiency of von
      Willebrand factor (vWF)-cleaving protease, whereas patients with hemolytic-uremic
      syndrome (HUS) show normal activity of this protease. Present methods for
      assaying vWF-cleaving protease by immunoblotting are time-intensive and
      cumbersome. We therefore developed a new functional assay based on the
      preferential binding of high-molecular-weight forms of vWF to collagen. In this
      assay, the diluted plasma sample to be tested is added to normal human plasma in
      which protease activity had been abolished. The vWF present in the protease
      depleted plasma is digested by the vWF-cleaving protease in the test plasma. The
      proteolytic degradation leads to low-molecular-weight forms of vWF, which show
      impaired binding to microtiter plates coated with human collagen type III. The
      collagen-bound vWF is quantified using a peroxidase-conjugated rabbit antibody
      against human vWF. The values of vWF-cleaving protease activity in tested plasma
      samples are read from a calibration curve achieved by incubating the vWF
      substrate with dilutions of a normal human plasma pool (NHP). Testing of plasma
      from patients with TTP and HUS showed that the assay can be used to distinguish
      between these two syndromes. The presence of an inhibitor can be detected by
      carrying out the test after incubation of NHP with the patient plasma sample,
      thus enabling differentiation of patients with familial TTP from those with
      nonfamilial TTP.

PMID- 10595624
TI  - Atorvastatin increases ecNOS levels in human platelets of hyperlipidemic
      subjects.
AB  - BACKGROUND: The purpose of this study was to probe the pleiotrophic effects of
      Atorvastatin on intraplatelet-nitric oxide metabolism. METHODS AND RESULTS:
      Hyperlipidemic subjects (n = 19) were treated for 1 month (following a 3-week
      washout) with either Atorvastatin or placebo in a double-blinded randomized (n =
      2, crossover), placebo-controlled study. Changes in the levels of intraplatelet
      nitric oxide synthase, nitrotyrosine were correlated with cholesterol, LDL-C, HDL
      C and triglyceride levels. These studies indicate that with atrovastatin ecNOS
      levels increased on average by approximately approximately 1.7-fold (paired t
      test p = 0.009). Interestingly, levels of nitrotyrosylated platelet proteins, an
      indication of peroxynitrite damage, decreased as ecNOS levels increased in
      presence of the drug (paired t-test p = 0.33). Atorvastatin, at 10 mg per day,
      lowered cholesterol and LDL-C levels in all patients with the average lowering of
      approximately 21% and approximately 17% respectively. The effect on HDL was not
      significant whilst triglyceride levels were lowered by an average of
      approximately 18%. CONCLUSIONS: This study adds to the volume of evidence that
      statins have beneficial effects other than lipid lowering. Here, Atorvastatin is
      shown to significantly elevate intraplatelet ecNOS levels in hyperlipidemic
      subjects without affecting iNOS expression. The net result of this would be the
      elevation of NO production which would promote platelet deaggregation and
      vasodilation.

PMID- 10595625
TI  - The VITA project: prothrombin G20210A mutation and venous thromboembolism in the
      general population.
AB  - Recently a new identified genetic variant in the 3'-untranslated region of the
      prothrombin gene (G20210A allele) associated with increased plasma prothrombin
      levels has been linked to an increased risk of venous thromboembolism (VTE). Most
      of our knowledge on the G20210A allele as a risk factor for VTE derives from a
      population-based case-control study and from studies on selected series of VTE
      patients. To determine the importance of the G20210A allele as a causative risk
      factor for VTE in the general population, we analyzed the cross-sectional data of
      the Vicenza Thrombophilia and Atherosclerosis (VITA) Project. One hundred sixteen
      cases of VTE, ascertained in a random fashion within the general population aged
      18-65, were age and sex-matched with 232 healthy subjects. Heterozygosity for the
      G20210A allele was present in 4.3% of VTE cases and in 3.4% of controls,
      indicating a marginal increase of VTE risk in carriers of the allele (odds ratio:
      1.26; 95% CI 0.4-3.9). However, the VTE risk was substantially higher in subjects
      with idiopathic VTE before age 45 or with recurrent, idiopathic VTE (odds ratio:
      2.8; 95% CI 0.6-13.8) or in subjects with a family history of VTE (odds ratio:
      7.6; 95% CI 1.8-32.8). Accordingly, our results suggest that the G20210A allele
      associates with VTE only in selected cases, and that screening for this genetic
      variant is not warranted for all patients with VTE.

PMID- 10595626
TI  - Local versus central assessment of venographies in a multicenter trial on the
      prevention of deep vein thrombosis in neurosurgery.
AB  - Venography is the diagnostic method of choice for end-point measurement in
      multicenter trials on the prevention of postoperative deep vein thrombosis (DVT).
      The aim of the study was to determine the inter-observer agreement between the
      local and central assessment of venographies in a multicenter trial comparing
      enoxaparin and placebo in the prevention of DVT after elective neurosurgery. The
      study was run in seven centers experienced in venography trials on DVT
      prevention. The central and local adjudication panels were both blind with
      respect to the assigned treatment. The central panel was unaware of the local
      adjudication. Venographies were adjudicated as positive, negative or inadequate
      for adjudication and positive venographies as proximal or distal DVT. Inter
      observer agreement was assessed according to the Cohen's inter-observer
      variability index (K index). All 266 venographies (8 monolateral) were considered
      adequate for adjudication by both the central and local panels. A disagreement
      was found in 25 cases; K index = 0.75. Fourteen venographies adjudicated as
      negative centrally were considered positive locally (3 were proximal DVT). Eleven
      venographies adjudicated as positive centrally (1 was a proximal DVT) were
      considered negative locally. Enoxaparin was found to be more effective than
      placebo according to both the central and local adjudication: 16.9% versus 32.6%
      (Relative risk, RR = 0.52; CI 95% 0.33-0.82) according to central adjudication;
      18.5% versus 33.3% (RR = 0.56; CI 95% 0.36-0.87) according to local adjudication.
      We conclude that a good inter-observer agreement in the assessment of venography
      was observed between the central and local adjudication in a study on DVT
      prevention run in a restricted experienced study framework. The cost and work
      overloading of central assessment of venographies in this study framework seems
      not to be justified.

PMID- 10595627
TI  - Elevated high molecular weight fibrinogen in plasma is predictive of coronary
      ischemic events after acute myocardial infarction.
AB  - This study investigates the association between the concentration and function of
      plasma fibrinogen molecules measured at the time of hospital admission in
      patients with acute myocardial infarction (AMI), with reference to the risk of
      new coronary ischemic events during a three-day follow-up period of. Before
      starting fibrinolytic and anticoagulant treatment plasma fibrinogen, high
      molecular weight fibrinogen (HMW-fibrinogen), fibrin formation rate (FbFR) and
      phosphorous content in fibrinogen were determined in 90 AMI patients. During a
      three-day follow-up period 12 patients suffered new ischemic events. The 12
      patients with coronary ischemia had higher concentrations of plasma fibrinogen
      (312+/-23 vs. 270+/-73 mg/dl, p<0.05) and HMW-fibrinogen (246+/-35 vs. 189+/-23
      mg/dl, p<0.001) and a higher FbFR (65+/-30 vs. 40+/-25, p<0.001) than patients
      without these events. No association was found between the phosphorous content in
      fibrinogen and new coronary ischemic events. We conclude that after myocardial
      infarction an elevated plasma level of HMW-fibrinogen and a high FbFR value at
      the time of hospital admission are associated with new coronary ischemic events
      during a three-day follow-up period.

PMID- 10595628
TI  - Contribution of the -455G/A polymorphism at the beta-fibrinogen gene to
      erythrocyte aggregation in patients with coronary artery disease.
AB  - BACKGROUND: A high level of red blood cell (RBC) aggregation has been
      consistently found in patients with coronary artery disease (CAD) in case-control
      studies. Plasma fibrinogen has been shown to promote RBC aggregability. The
      purpose of this study was to investigate the influence of the genetic variability
      of the beta-fibrinogen gene on RBC aggregation in patients with CAD. METHODS AND
      RESULTS: The genotype of the beta-fibrinogen gene locus was determined by
      polymerase chain reaction using the restriction enzyme HaeIII for a G to A
      substitution at position -455 upstream from the transcriptional start site in 135
      French Canadians with premature CAD (age: 51+/-7 years). Indices measuring the
      RBC aggregation kinetics (S10) and shear resistance of the aggregates (gammaS)
      were obtained by laser reflectometry. Patients were separated into groups by
      using the medians of S10 and gammaS. Using chi2 analyses, the distribution of the
      -455GG, -455GA, and -455AA genotypes in the groups with high levels of S10 (0.43,
      0.49, and 0.08) and gammaS (0.45, 0.49, and 0.06) were found to be significantly
      distinct from those in the groups with low levels of S10 (0.67, 0.27, and 0.06;
      p<0.05) and gammaS (0.70, 0.23, and 0.07; p<0.01). High levels of RBC aggregation
      were closely associated with the rare -455A allele. Multivariate linear
      regression analyses showed that S10 was positively correlated with the linear
      combination of the fibrinogen concentration, age, and the -455G/A genotype
      (adjusted r = 0.63, p<0.0001). Fibrinogen and age were positive determinants, and
      HDL-cholesterol was a negative predictor of gammaS (adjusted r = 0.51, p<0.0001).
      CONCLUSION: These findings support the hypothesis that RBC hyperaggregation in
      premature CAD may be associated with the beta-fibrinogen -455G/A polymorphism.
      This association may be explained by a change in the concentration and/or the
      functional properties of the fibrinogen protein.

PMID- 10595629
TI  - Automated latex agglutination and ELISA testing yield equivalent D-dimer results
      in patients with recent myocardial infarction. THROMBO Research Investigators.
AB  - Our previous prospective study of post-infarction patients described a strong and
      significant association of increased plasma D-dimer concentrations in those who
      experienced a subsequent coronary death or non-fatal myocardial infarction. In
      the present study, we compare results on stored plasma obtained two months after
      the index myocardial infarction from 1,038 patients of this trial, using a simple
      automated latex agglutination (LA) assay in parallel with the standard ELISA
      test. Results show a somewhat higher mean value for the LA assay (702+/-1092 vs.
      638+/-986 ng/ml, p = 0.0002), a strong linear correlation of the two assays (r =
      0.86) and 88% agreement for values below 500 ng/ml by the ELISA test. D-dimer
      concentrations determined by each assay were highly correlated in patients with
      subsequent coronary artery events (p = 0.93) and quartile values for both the LA
      and ELISA were equally predictive of such events (p = 0.003 and p = 0.001,
      respectively). This is the first demonstration that a latex agglutination assay
      for D-dimer can be used to assess the prognostic risk of recurrent coronary
      thrombotic disease after myocardial infarction

PMID- 10595630
TI  - Antiplatelet activity of clopidogrel in coronary artery bypass graft surgery
      patients.
AB  - Clopidogrel is a recently introduced platelet ADP receptor antagonist, belonging
      to the thienopyridine derivatives, like its analogue ticlopidine. Its potential
      advantage is to be safer than ticlopidine. At 75 mg/od clopidogrel significantly
      inhibits platelet aggregation in ambulatory patients with symptomatic
      atherosclerotic disease and it prevents the recurrence of ischemic events more
      efficiently than aspirin. Its adequate dose in more acute situations remained to
      be determined. Therefore, sixty two patients with coronary artery disease were
      randomly assigned in four groups treated, within 24 h after coronary artery
      bypass graft, by clopidogrel 50 mg/od, 75 mg/od or 100 mg/od or by ticlopidine
      250 mg/bid which was considered as the reference. The tolerance of clopidogrel
      was fairly good during the whole period of the study. Bleeding time and ex-vivo
      platelet aggregation induced by ADP 2 microM and 5 microM were performed at day 
      1, +9 and +28 after surgery. Like ticlopidine, the three dose levels of
      clopidogrel significantly inhibited ex-vivo platelet activity and prolonged the
      bleeding time at day 28. However, unlike ticlopidine, the inhibitory effects of
      clopidogrel were not significant at day 9, especially with 75 mg/od, a dose which
      was found to significantly protect patients in a chronic situation. Hence,
      although the clinical outcome for patients included in this limited study was the
      same in the four groups, these results suggest that the dose regime of
      clopidogrel should be more extensively investigated during the early period
      following coronary artery bypass graft, facing an overproduction of young and
      hyperreactive platelets. By analogy, the dose regime should be also investigated
      in other situations with an acute risk of arterial thrombotic occlusion.

PMID- 10595631
TI  - Haematological abnormalities in early abstinent alcoholics are closely associated
      with alterations in thrombopoietin and erythropoietin serum profiles.
AB  - Numerous reports exist on haematological pathology in alcoholism. However, no
      data are available regarding a potential involvement of haematopoietic growth
      factors in the recovery from alcohol-induced haematological abnormalities upon
      abstinence. Therefore, thrombopoietin (TPO) and erythropoietin (EPO) serum levels
      along with haematological and other routine laboratory parameters were closely
      followed in 14 thoroughly characterized male alcoholic patients over one to five
      months of controlled abstention from alcohol. Haematological changes in these
      early abstinent alcoholics consisted predominantly of (a) the well known rebound
      surge of platelets, (b) an early reticulocyte peak, and (c) persistently low
      haematocrit levels over months without signs of recovery. Observations on EPO and
      TPO during early abstinence can be summarized as follows: (1) Increased TPO
      levels precede the rebound thrombocytosis by several days, (2) both EPO and TPO
      concentrations are higher in anaemic than in nonanaemic alcoholics, with (3)
      nonanaemic subjects exhibiting levels of TPO in the range of healthy controls but
      levels of EPO below controls and (4) TPO concentrations show a stronger
      correlation with initial haematocrit values than with thrombocyte counts. To
      conclude, haematological recovery in early alcohol abstinence appears to be, at
      least in part, growth factor-driven, involving both TPO and EPO, and may reflect
      an intense interaction of erythro- and thrombopoiesis.

PMID- 10595632
TI  - Parallel reduction of plasma levels of high and low molecular weight kininogen in
      patients with cirrhosis.
AB  - Little is known about the regulation of high-molecular-weight-kininogen (HK) and
      low-molecular-weight-kininogen (LK) or the relationship of each to the degree of
      liver function impairment in patients with cirrhosis. In this study, we evaluated
      HK and LK quantitatively by a recently described particle concentration
      fluorescence immunoassay (PCFIA) and qualitatively by SDS PAGE and immunoblotting
      analyses in plasma from 33 patients with cirrhosis presenting various degrees of
      impairment of liver function. Thirty-three healthy subjects served as normal
      controls. Patients with cirrhosis had significantly lower plasma levels of HK
      (median 49 microg/ml [range 22-99 microg/ml]) and LK (58 microg/ml [15-100
      microg/ml]) than normal subjects (HK 83 microg/ml [65-115 microg/ml]; LK 80
      microg/ml [45-120 microg/ml]) (p<0.0001). The plasma concentrations of HK and LK
      were directly related to plasma levels of cholinesterase (P<0.0001) and albumin
      (P<0.0001 and P<0.001) and inversely to the Child-Pugh score (P<0.0001) and to
      prothrombin time ratio (P<0.0001) (reflecting the clinical and laboratory
      abnormalities in liver disease). Similar to normal individuals, in patients with
      cirrhosis, plasma HK and LK levels paralleled one another, suggesting that a
      coordinate regulation of those proteins persists in liver disease. SDS PAGE and
      immunoblotting analyses of kininogens in cirrhotic plasma showed a pattern
      similar to that observed in normal controls for LK (a single band at 66 kDa) with
      some lower molecular weight forms noted in cirrhotic plasma. A slight increase of
      cleavage of HK (a major band at 130 kDa and a faint but increased band at 107
      kDa) was evident. The increased cleavage of HK was confirmed by the lower cleaved
      kininogen index (CKI), as compared to normal controls. These data suggest a
      defect in hepatic synthesis as well as increased destructive cleavage of both
      kininogens in plasma from patients with cirrhosis. The decrease of important
      regulatory proteins like kininogens may contribute to the imbalance in
      coagulation and fibrinolytic systems, which frequently occurs in cirrhotic
      patients.

PMID- 10595633
TI  - Elevated levels of sE-selectin in post-menopausal females are decreased by
      hormone replacement therapy to levels observed in pre-menopausal females.
AB  - Observational epidemiological studies have shown that mortality from coronary
      heart disease is reduced in post-menopausal women by hormone replacement therapy
      (HRT). The aim of this study was to measure sE-selectin levels in post-menopausal
      females before and after HRT and to compare these with pre-menopausal females and
      aged matched males. Post-menopausal females (n = 70) were given HRT or no
      treatment to act as a control group. sE-selectin levels were significantly lower
      in the pre-menopausal (n = 36) when compared with the post-menopausal females (n
      = 70) (p = 0.027), whereas no difference between two age matched male groups was
      found (n = 40). Oral and transdermal HRT significantly decreased sE-selectin
      levels (p<0.0001 and p = 0.0005 respectively) with no change in the control
      group. The reduction in the levels of this marker of endothelial activation after
      HRT, may reflect a decrease in leucocyte/endothelial interaction which may reduce
      atherosclerotic risk in post-menopausal females.

PMID- 10595635
TI  - An inhibitory anti-factor IX antibody effectively reduces thrombus formation in a
      rat model of venous thrombosis.
AB  - An inhibitory anti-factor IX/IXa antibody (BC2) has been investigated as an anti
      thrombotic agent in a rat venous thrombosis model. The treatment of rats post
      injury with a single bolus dose of BC2 (3 mg/kg, i.v.) resulted in an
      approximately 4 fold reduction in venous thrombus mass (P = 0.043). This efficacy
      was matched by a minimal (<2.5 fold) prolongation of the aPTT and had no effect
      on the prothrombin time (PT). Heparin by comparison, given as a bolus followed by
      continuous infusion, at doses comparable in efficacy at reducing thrombus
      formation, prolonged the aPTT >50 fold. These results demonstrate that the anti
      factor IX/IXa antibody (BC2), when compared to heparin, can effectively reduce
      venous thrombosis with less disruptive consequences on blood clotting.

PMID- 10595634
TI  - Factor IX gene analysis in 70 unrelated patients with haemophilia B: description
      of 13 new mutations.
AB  - Seventy unrelated patients suffering from haemophilia B have been screened for
      determining the molecular defect and for evaluating the spectrum of factor IX
      mutations in the Rhone Alpes region in France. Most patients were characterized
      with respect to factor IX antigen and factor IX coagulant activity. We have used
      denaturing gradient gel electrophoresis to obtain a full scanning of the whole
      coding, promoter, and exon flanking sequences of the factor IX gene. This
      technique enabled us to determine the molecular defect in 68 out of 70 families
      (97%), and the mutation was further identified in the two last patients with a
      direct sequencing of the gene. A total of 2 complete gene deletions in patients
      with antifactor IX inhibitor, 6 small insertions/deletions and 62 point mutations
      were found. Two of these nucleotide substitutions (Arg145His and Ala233Thr) were
      detected in 21 patients (30%) suggesting the existence of a local founder effect.
      Thirteen mutations were previously undescribed, including 7 missense mutations.
      The detection of mutations in patients affected with haemophilia B may shed some
      light in the structure-function relationship of factor IX molecule within the
      coagulation system.

PMID- 10595636
TI  - Mutations in von Willebrand factor multimerization domains are not a common cause
      of classical type 1 von Willebrand disease.
AB  - Type 1 von Willebrand disease (vWD) is an autosomal dominant bleeding disorder of
      variable penetrance. It is characterised by a mild to moderate bleeding tendency
      and a quantitative deficiency of von Willebrand factor (vWF) with the full range
      of vWF multimers. Few mutations have been described which account for the mode of
      inheritance in dominant vWD type 1. We screened the vWF multimerization domains
      (regions D1-D3 of the vWF gene) of 12 unrelated patients with dominant vWD type 1
      to investigate the hypothesis that multimerization of vWF sub-units may be
      inhibited or reduced by a "dominant negative" mechanism. Platelet-derived RNA was
      reverse transcribed and the resulting vWF cDNA amplified by the polymerase chain
      reaction (PCR) in a series of overlapping fragments. These were subjected to a
      combination of single-strand conformation polymorphism (SSCP) and heteroduplex
      analysis. This approach identified mobility shifts on acrylamide gels that
      represented 12 distinct SSCP and/or heteroduplex patterns in our patient group.
      DNA sequencing of the region encompassing each mobility shift showed these
      variants to represent previously described polymorphisms within the vWF coding
      sequence. Examination in all 12 patients for the previously described G3389T and
      T3445C mutations proved negative. The molecular pathology of classical type 1 vWD
      remains enigmatic, mutations having been identified in only a small minority of
      patients. A common mechanism underlying this disease state has still to be
      elucidated.

PMID- 10595637
TI  - Multicenter evaluation of lyophilized and deep-frozen plasmas for assignment of
      the International Normalized Ratio.
AB  - The interlaboratory variation of the International Normalized Ratio (INR) in
      various external quality assessment schemes is still relatively high. This is
      partly caused by inaccuracy of manufacturers' stated International Sensitivity
      Index (ISI) and/or local instrumentation effects. The interlaboratory variation
      and accuracy of INR determinations may be improved by a local calibration
      procedure based on lyophilized plasmas with assigned INRs. The purpose of the
      present study was to determine INR values for different types of lyophilized
      plasmas to be used for local calibration. A total of 13 lyophilized plasmas (one
      normal, six from coumarin-treated patients, six artificially depleted) were
      analyzed by 10 laboratories, each using five calibrated prothrombin time (PT)
      systems. INRs were calculated for each plasma using each laboratory's specific
      ISI and mean normal prothrombin time values. In the same way, five deep-frozen
      pooled plasmas from coumarin-treated patients were analyzed. There were
      significant INR differences for the lyophilized plasmas between the prothrombin
      time systems. The differences were relatively small for the deep-frozen coumarin
      plasmas (CV 2.6-3.3%) and three lyophilized coumarin plasmas from one
      manufacturer (CV 3.7-4.8%). Important INR differences were observed for three
      lyophilized coumarin plasmas from another manufacturer (CV 9.5-14.1%) and several
      artificially depleted plasmas (CV 5.3-12.8%). The citrate concentrations in the
      artificially depleted plasmas were lower than those in the normal and coumarin
      plasmas. These differences should be considered in the selection and
      certification of plasmas as calibrants for local calibration of PT systems. The
      lyophilized plasmas' INR values obtained in the present study will be used for a
      field study of local PT calibration to assess their efficacy.

PMID- 10595638
TI  - Variations in coagulation factors in women: effects of age, ethnicity, menstrual
      cycle and combined oral contraceptive.
AB  - To assess variations of coagulation factors in women, 123 women were included in
      a cross-sectional study of the effect of age, ethnic origin, blood group and
      menstrual cycle on surface induced coagulation time (activated partial
      thromboplastin time) and plasma levels of Factor VIII clotting assay, von
      Willebrand factor antigen, von Willebrand factor activity and factor XI. The
      effect of menstrual cycle was further assessed in a longitudinal study including
      39 Caucasian women, 20 of whom were using combined oral contraceptives. Activated
      partial thromboplastin time was longer in women with blood groups B or O, and
      plasma levels of factor VIII clotting assay, von Willebrand factor antigen and
      von Willebrand factor activity were significantly higher in black women.
      Fibrinogen, von Willebrand factor antigen and von Willebrand factor activity
      concentrations showed strong cyclic variations with peak values in the luteal
      phase. This pattern was dampened for von Willebrand factor antigen and von
      Willebrand factor activity but completely disappeared for fibrinogen with the use
      of combined oral contraceptives. There was a cyclical pattern for factor VIII
      clotting assay in pill users, evidence of which was not evident in non-pill
      users. There were strong associations between the levels of von Willebrand factor
      antigen and von Willebrand factor activity and age, with levels rising by an
      average of 0.17 and 0.15 U/ml, respectively, for each 10 year increase in age. In
      conclusion, there are great inter- and intraindividual variations in coagulation
      markers in women due to different physiological conditions such as age,
      ethnicity, blood group and phases of the menstrual cycle. However, there were no
      significant associations between coagulation markers and weight, alcohol
      consumption or smoking status.

PMID- 10595639
TI  - Dermatan sulfate and LMW heparin enhance the anticoagulant action of activated
      protein C.
AB  - Unfractionated heparin potentiates the anticoagulant action of activated protein
      C (APC) through several mechanisms, including the recently described enhancement
      of proteolytic inactivation of factor V. Possible anticoagulant synergism between
      APC and physiologic glycosaminoglycans, pharmacologic low molecular weight
      heparins (LMWHs), and other heparin derivatives was studied. Dermatan sulfate
      showed potent APC-enhancing effect. Commercial LMWHs showed differing abilities
      to promote APC activity, and the molecular weight of LMWHs correlated with
      enhancement of APC activity. Degree of sulfation of the glycosaminoglycans
      influenced APC enhancement. However, because dextran sulfates did not potentiate
      APC action, the presence of sulfate groups per se on a polysaccharide is not
      sufficient for APC enhancement. As previously for unfractionated heparin, APC
      anticoagulant activity was enhanced by glycosaminoglycans when factor V but not
      factor Va was the substrate. Thus, dermatan sulfate and LMWHs exhibit APC
      enhancing activity in vitro that could be of physiologic and pharmacologic
      significance.

PMID- 10595640
TI  - A new factor Xa inhibitor (lefaxin) from the Haementeria depressa leech.
AB  - The salivary complex of the leech Haementeria depressa produces potent
      anticoagulant components. Among them, a protein named lefaxin inhibits factor Xa
      (FXa). Lefaxin was purified to homogeneity from dissected salivary complexes by
      gel filtration in Sephadex G-150 followed by two ion exchange chromatography
      steps in Mono-Q. Inhibition of FXa by lefaxin was demonstrated by the inhibition
      of its amidolytic activity, measured with chromogenic substrate S-2765 (apparent
      K(I) of 4 nM), and of its ability to inhibit thrombin generation in the
      prothrombinase complex (EC50 of 40 nM). Lefaxin has a molecular weight of 30 kDa
      and an isoelectric point of 5.7. It is made of a polypeptide chain whose N
      terminal sequence shows no similarity with that of other FXa inhibitors
      (antistasin and ghilianten) isolated from leech saliva. On the other hand, the N
      terminal sequence of lefaxin presents significant sequence similarity with nitric
      oxide carrier proteins myohemerythrin from the annelid Nereis diversicolor and
      prolixin S from the triatoma Rhodnius prolixus. Interestingly, prolixin S also
      proved to be an anticoagulant protein acting on FXa.

PMID- 10595641
TI  - Recombinant Kunitz protease inhibitory domain of the amyloid beta-protein
      precursor as an anticoagulant in venovenous extracorporeal circulation in
      rabbits.
AB  - Investigations were performed to characterize a recombinant Kunitz protease
      inhibitory domain of the amyloid beta-protein precursor (rKPI) as anticoagulants.
      After a single intravenous infusion of wild type rKPI into dogs, its elimination
      fit a two compartment model with a t1/2alpha and t1/2beta of 5 and 77 min,
      respectively. Further investigations determined if a variant form of rKPI with
      178-fold more potent anti-factor Xa activity (rKPI-DD135, Ki = 0.9 nM) could
      serve as an anticoagulant in a rabbit model of extracorporeal circulation using a
      venovenous shunt. A prospective investigation was initiated to compare standard
      heparin (n = 8) at 400 U/kg with different infusion concentrations of rKPI-DD135.
      After a single intravenous infusion of 1.89 mg/kg of rKPI-DD135 followed by a
      constant infusion at 0.003 (n = 3), 0.03 (n = 7), or 0.3 (n = 5) mg/kg/min, the
      anti-factor Xa activity of the animals' plasma rapidly reaches a steady state for
      the two lower infusion concentrations of the agent. All infusions of rKPI-DD135
      prolong the activated clotting time with less variation than that seen with
      heparin administration. rKPI-DD135 anticoagulation does not prevent a drop in the
      platelet counts. Fibrinogen levels decrease only slightly when the circuit is
      anticoagulated with rKPI-DD135. rKPI-DD135 markedly prolongs the APTT, has little
      effect on the PT, and reduces plasma prekallikrein and plasminogen activation.
      The 0.3 mg/kg/min infusion concentration of rKPI-DD135 results in reduced
      deposition of 111Indium-labeled platelets on the circuit when compared to
      heparin. Last, after a steady state level is achieved, 60% of the plasma anti
      factor Xa activity of rKPI-DD135 is eliminated within 60 min after stopping the
      infusion. These data show the rKPI-DD135 can provide single agent anticoagulation
      in a rabbit extracorporeal circuit. Development of short acting factor Xa
      inhibitors may be useful anticoagulants for cardiopulmonary bypass.

PMID- 10595642
TI  - Abnormal fibrin clot architecture in nephrotic patients is related to
      hypofibrinolysis: influence of plasma biochemical modifications: a possible
      mechanism for the high thrombotic tendency?
AB  - Porosity, viscoelasticity and morphological properties of plasma fibrin from 16
      nephrotic patients and 16 healthy volunteers were compared. Nephrotic patients
      were characterized by formation of tight and rigid plasma fibrin gels which
      resulted in a slower rate of fibrin lysis studied either under pressure-driven
      permeation or diffusional transport of fibrinolytic agents. These latter findings
      indicated that both abnormal fibrin network conformation and abnormal fibrin
      fiber structure were involved in hypofibrinolysis. Albumin supplementation up to
      40 mg/ml partially restored normal fibrin architecture and increased the rate of
      fibrinolysis in these patients. Multiparametric analysis showed that nephrotic
      patients were mainly characterized by a low plasma albumin level (R = -0.85), a
      low albumin to fibrinogen ratio (R = -0.89) and a high resistance to lysis (R = 
      0.82). High triglycerides level was the only plasma modification related to the
      slower fibrin lysis rate (R = -0.54). High fibrin rigidity (G') was the only
      fibrin parameter simultaneously related to the nephrotic state (R = 0.75) and the
      lysis resistance (R = -0.71). After eliminating the effects of age, albumin and
      fibrinogen levels, low fibrin porosity (Ks) and low fiber mass-length ratio (mu)
      were the main features of the nephrotic state. These findings are discussed in
      relation to both the pathophysiology of thrombotic complications in nephrotic
      syndrome and their pharmacological prevention.

PMID- 10595643
TI  - Relationship between visceral fat and PAI-1 in overweight men and women before
      and after weight loss.
AB  - This study was aimed at evaluating the relationship between visceral fat
      accumulation and plasma plasminogen activator inhibitor-1 (PAI-1) levels in
      healthy, obese men and women undergoing weight loss therapy. The subjects, 25 men
      and 25 premenopausal women, aged between 26 and 49 years, with an initial body
      mass index between 28 and 38 kg/m2, received a controlled diet for 13 weeks
      providing a 4.2 MJ/day energy deficit. Magnetic resonance imaging was used to
      measure visceral and subcutaneous abdominal fat. Our results show that before
      weight loss visceral fat was significantly correlated with PAI-1 in men (r =
      0.45; p<0.05), but not in women (r = -0.15; ns). The association between visceral
      fat and PAI-1 in men remained significant after adjustment for age and total fat
      mass, and multiple linear regression analysis showed a significant independent
      contribution of visceral fat to plasma PAI-1 levels. Both visceral fat areas and
      PAI-1 levels decreased significantly with weight loss in both men and women.
      Changes in visceral fat area were related to changes in PAI-1 in women (r = 
      0.43; p = 0.05) but not in men (r = -0.01; ns); however, this association in
      women disappeared after adjustment for total fat mass. We conclude that there is
      a relationship between visceral fat and PAI-1 in obese men but not in obese
      women, and that PAI-1 levels decrease substantially (52%) by weight loss, but
      this change is not related to changes in visceral fat mass per se.

PMID- 10595644
TI  - Natriuretic peptides regulate the expression of tissue factor and PAI-1 in
      endothelial cells.
AB  - In the present study, we demonstrate that brain natriuretic peptide (BNP) and C
      type natriuretic peptide (CNP) interact with angiotensin II (Ang II) in
      regulative blood coagulation and fibrinolysis by suppressing the expressions of
      both tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) induced by
      Ang II. The expressions of TF and PAI-1 mRNA were analyzed by northern blotting
      methods, and the activities of TF on the surface of rat aortic endothelial cells
      (RAECs) and PAI-1 in the culture media were respectively measured by chromogenic
      assay. Both BNP and CNP suppressed the expressions of TF and PAI-1 mRNA induced
      by Ang II in a time- and concentration-dependent manner via cGMP cascade, which
      suppressions were accompanied by respective decrease in activities of TF and PAI
      1. However, neither the expression of tissue factor pathway inhibitor (TFPI) nor
      tissue-type plasminogen activator (TPA) mRNA was affected by the treatment of BNP
      and CNP.

PMID- 10595645
TI  - Expression of plasminogen activator inhibitor type I in genotyped human
      endothelial cell cultures: genotype-specific regulation by insulin.
AB  - Patients with non-insulin-dependent diabetes mellitus frequently have been
      associated with elevation in plasma levels of PAI-1. Part of the variations in
      individual plasma PAI-1 levels have been attributed to variations in the PAI-1
      gene. In order to determine whether insulin regulates PAI-1 expression in a
      genotype-specific manner, individual human umbilical vein ECs (HUVECs) were
      genotyped using a Hind III RFLP and incubated in the absence/presence of insulin.
      Treatment of 1/1 PAI-1 genotype HUVECs with insulin increased secretion of PAI-1
      antigen approximately 1.7 to 2.2-fold and mRNA levels were increased
      approximately 1.8 to 2.8-fold. Treatment of HUVECs with actinomycin D or
      puromycin completely abolished the induction of PAI-1 by insulin. The nuclear run
      on assays indicated approximately 3-4 fold increase in PAI-1 transcription rates.
      These in vitro studies with the 1/1 PAI-1 genotyped cultured HUVECs, suggests
      that hyperinsulinemia may be expected to increase EC PAI-1 synthesis in those
      patients with the responsive 1/1 genotype.

PMID- 10595646
TI  - Immunological quantitation of rabbit plasminogen activator inhibitor-1 in
      biological samples: evidence that rabbit platelets do not contain PAI-1.
AB  - Two immunoassays for the specific quantitation of rabbit plasminogen activator
      inhibitor-1 (PAI-1) antigen and activity in biological samples were developed and
      applied for the evaluation of PAI-1 in rabbits. Levels of PAI-1 antigen in rabbit
      plasma were 9.8+/-4.6 ng/ml (mean +/- SD, n = 6), with a corresponding value of
      20.5+/-13.5 ng/ml for PAI-1 activity. In rabbit serum PAI-1 antigen was 11.8+/
      4.9 ng/ml (n = 6) and PAI-1 activity was 2.9+/-2.0 ng/ml (n = 6). Endotoxin
      injection (20 microg/kg, i.v.) induced a time-dependent increase of both PAI-1
      antigen and PAI-1 activity levels in rabbit plasma, eventually resulting in a 40-
      to 90-fold increase (p<0.0001 vs. baseline). A linear correlation was found
      between PAI-1 antigen and activity levels in normal plasma (r = 0.90, n = 6,
      p<0.05) and in plasma from endotoxin-treated rabbits (r = 0.98, n = 20, p<0.001).
      Analysis of PAI-1 antigen and activity in lysates of washed rabbit platelets
      revealed the absence of PAI-1 (i.e. <0.03 ng/10(8) platelets). In conclusion,
      development of specific immunological assays allowed the quantitation of PAI-1 in
      rabbit samples. In striking contrast to other species (human, rat, mouse, pig)
      rabbit platelets lack detectable amounts of PAI-1 (i.e. >100-1000 fold lower vs
      other species studied). This observation may have important implications for the
      use of experimental rabbit models especially in studies on the role of platelets
      in various pathological conditions including thrombosis and atherosclerosis.

PMID- 10595647
TI  - The effects of angiotensin metabolites on the regulation of coagulation and
      fibrinolysis in cultured rat aortic endothelial cells.
AB  - Not only angiotensin II (Ang II) but also other angiotensin metabolites such as
      angiotensin I (Ang I), angiotensin III (Ang III), angiotensin IV, or angiotensin
      1-7 have recently been reported to have various activities. Few data, however,
      are available on the regulation of thrombus formation. In this study, we
      investigated the effects of angiotensin metabolites on the mRNA expression of
      tissue factor (TF), tissue factor pathway inhibitor (TFPI), plasminogen activator
      inhibitor-1 (PAI-1), and tissue type plasminogen activator (TPA) in cultured rat
      aortic endothelial cells. None of the used angiotensin metabolites altered TFPI
      or TPA mRNA expression levels. Ang I, Ang II, and Ang III made TF and PAI-1 mRNA
      inductions which were inhibited by an selective antagonist of angiotensin II type
      1 receptors. These metabolites made TF predominant to TFPI or PAI-1 to TPA, and
      could render endothelial cells thrombogenic.

PMID- 10595648
TI  - Differential effects of dietary supplementation with fish oil or soy lecithin on
      human platelet adhesion.
AB  - To investigate the possible regulating role of omega-6 and of omega-3 fatty acids
      on platelet adhesiveness, we randomised 60 volunteers into three groups to take
      20 ml (equivalent to 0.3 g omega-6, 3.6 g omega-3; omega-6/omega-3 ratio 0.1) per
      day of a fish oil supplement, or to take 25 g (equivalent to 1.5 g omega-6, 0.5 g
      omega-3; omega-6/omega-3 ratio 3) per day of a soy lecithin supplement, or to
      continue on their usual diet without any supplement (control group) for a period
      of 15 days. Platelet adhesion on fibrinogen-coated 96-well microtitre plates was
      evaluated in the resting condition and after stimulation with 2 microM ADP or
      0.02 U/ml thrombin. Compared to the values before the experimental period, the
      fish oil group showed a significant reduction in stimulated adhesion (with ADP:
      from 18.8% to 15.6%, p<0.01; with thrombin: from 24.4% to 20.8%, p<0.005),
      whereas no difference was noted in the resting condition (from 3.6% to 3.5%, NS).
      In the soy lecithin group, platelet adhesion was increased in all test conditions
      (with ADP: from 18.7% to 23.2%, p<0.001; with thrombin: from 24.0% to 29.9%
      p<0.001; resting: from 3.5% to 6.6%, p<0.001). No significant changes were
      observed in the control group. A good correlation was found between platelet
      adhesion data and the changes in the platelet fatty acid omega-6/omega-3 ratio
      caused by the different supplementations. Our results indicate an inhibitory
      effect of fish oil rich in omega-3 fatty acids on stimulated human platelet
      adhesiveness and a stimulatory effect of soy lecithin rich in omega-6 fatty acids
      on resting and stimulated adhesion. They suggest moreover that the omega-6/omega
      3 ratio is a determinant of platelet adhesion.

PMID- 10595649
TI  - Mutations of the platelet thromboxane A2 (TXA2) receptor in patients
      characterized by the absence of TXA2-induced platelet aggregation despite normal
      TXA2 binding activity.
AB  - Previously, we reported five cases of platelet dysfunction characterized by the
      absence of thromboxane A2 (TXA2) - induced platelet aggregation despite normal
      TXA2 binding activity. In this platelet disorder, patients were divided into two
      groups; i.e. those whose platelets lacked or did not lack phospholipase C (PLC)
      activation (Group A and Group B, respectively) (Thromb Haemost 1996; 76: 1080).
      Furthermore, in one of the patients, we showed that a single amino acid
      substitution (Arg60 to Leu) in the first cytoplasmic loop of the TXA2 receptor
      (TXR) was responsible for this platelet disorder. However, mutational analysis of
      the TXR in the remaining patients has not been performed. Based on this
      background, we investigated the mutations of the TXR in these patients, and found
      that all of the patients have the same abnormality of the TXR (Arg60-->Leu),
      although the Group A patients were homozygous and the Group B patients were
      heterozygous for this mutation. This mutation is the only abnormality which has
      been found in this platelet disorder, and in patients heterozygous for this
      mutation, the mutant type TXR suppresses wild-type receptor-mediated platelet
      aggregation by a mechanism independent of PLC activation.

PMID- 10595650
TI  - Lysophosphatidic acid activates nuclear factor kappa B and induces
      proinflammatory gene expression in endothelial cells.
AB  - The cellular phospholipid, lysophosphatidic acid (LPA), released by activated
      platelets and fibroblasts or, at high levels, from ovarian and cervical
      carcinomas is a powerful serum mitogen that may modulate several signaling
      pathways in endothelial cells (EC). Hence, LPA could function in a paracrine
      manner during EC-platelet interactions at sites of vascular injury. Here, we
      demonstrate activation of the transcription factor nuclear factor kappa B (NF
      kappaB) in EC following exposure to LPA. EC activation was further characterized
      by increased levels of mRNA transcripts encoding E-selectin, Intercellular
      Adhesion Molecule-1, Interleukin-8 and Monocyte Chemoattractant Protein-1. These
      effects were inhibited by preincubating EC either in the presence of mepacrine
      (to block phospholipase A2) or of pertussis toxin (to increase ADP-ribosylation
      of Gi proteins). No inhibition was observed in the presence of putative LPA
      receptor antagonists suramin or thrombospondin. LPA induces a proinflammatory
      activation of endothelial cells that (i) involves Gi proteins; (ii) depends on
      phospholipase A2 activity; (iii) is associated with the activation of NF-kappaB
      and (iv) results in increased expression of proinflammatory genes. We propose
      that LPA release by activated platelets may directly modulate vascular
      inflammatory responses.

PMID- 10595651
TI  - Analysis of CD39/ATP diphosphohydrolase (ATPDase) expression in endothelial
      cells, platelets and leukocytes.
AB  - Purinergic signaling may influence hemostasis, inflammatory responses and
      apoptosis. Therefore, hydrolysis of extracellular ATP and ADP by the ATP
      diphosphohydrolase (ATPDase) could regulate these processes. We have previously
      demonstrated the identity between the vascular ATPDase and CD39. Here we show
      that levels of CD39 expression correlate with ATPDase activity in human
      endothelial cells (EC), platelets and selected monocyte, NK, and megakaryocyte
      cell lines. Western blotting revealed one to three isoforms of CD39/ATPDase:
      mobility variations of major protein resulted from post-translational
      modifications. Northern blotting and primer extension indicated two major mRNA
      transcripts and one transcription start point, respectively. In addition, mRNAs
      specific for purinergic P2 receptors were detected in all of the investigated
      cells, suggesting that the coexpressed CD39/ATPDase may regulate purinergic
      signaling. Thrombotic and inflammatory responses may be modulated by the
      expression of CD39/ATPDase.

PMID- 10595652
TI  - Comparative study of vanadate- and phorbol ester-induced cyclo-oxygenase-2
      expression in human endothelial cells.
AB  - Our previous study showed that vanadate, an inhibitor of protein tyrosine
      phosphatases, induced the expression of cyclo-oxygenase (COX)-2 in a protein
      tyrosine-kinase (PTK)-dependent manner in human umbilical vein endothelial cells
      (HUVEC). Here, we further compared the actions of vanadate and phorbol 12
      myristate 13-acetate (PMA), an activator of protein kinase C (PKC), on induction
      of COX-2 with special reference to mitogen-activated protein kinases (MAPKs) in
      HUVEC. Vanadate induced activation of three families of MAPKs, extracellular
      signal-regulated kinases 1 and 2 (ERK1/2), p38, and c-Jun amino-terminal kinase
      (JNK) 1, while activation of ERK 1/2 alone was induced by PMA. The former
      activation by vanadate and the latter one by PMA were inhibited by tyrphostin-47,
      an inhibitor of PTKs, and by Ro31-8220, a PKC inhibitor, respectively. Either
      tyrphostin-47, PD98059, a specific inhibitor of the upstream kinase toward
      ERK1/2, or SB203580, a specific inhibitor of p38, completely suppressed vanadate
      induction of COX-2 mRNA and protein. On the other hand, PMA-induction of COX-2
      mRNA and protein was abolished by Ro31-8220 or PD98059 but not by SB203580. These
      data indicate that PMA-induced and PKC-dependent expression of COX-2 requires
      mainly activation of ERK 1/2 among MAPKs, while activation of both ERK1/2 and p38
      or possibly of all three families of MAPKs is necessary for vanadate-induced and
      PTK-dependent expression of COX-2.

PMID- 10595653
TI  - A Thai patient with the mutation of Arg306 of FV gene identical to the Hong Kong
      but not to the Cambridge type.

PMID- 10595654
TI  - Prevalence of the prothrombin gene 20210A mutation in thrombophilic and healthy
      Algerian subjects.

PMID- 10595655
TI  - High frequency of factor V Leiden mutation and prothrombin 20210A variant in
      Romanies of Eastern Hungary.

PMID- 10595656
TI  - A UK National External Quality Assessment scheme (UK Neqas) for molecular genetic
      testing for the diagnosis of familial thrombophilia.

PMID- 10595657
TI  - Type 2B von Willebrand's disease and angiodysplasia.

PMID- 10595658
TI  - A case of type 2B von Willebrand disease reverse to normal when treated with high
      doses of protease inhibitor.

PMID- 10595659
TI  - Evidence for antiphospholipid antibodies in hemophilic children with factor VIII
      inhibitors. Recombinate PUP Study Group.

PMID- 10595660
TI  - The importance of differentiating ReoPro (c7E3 abciximab) induced
      thrombocytopenia from heparin-induced thrombocytopenia.

PMID- 10595661
TI  - Compared study of optokinetic and caloric nystagmus in children with unilateral
      hyporeflexia and other vestibular disorders.
AB  - The authors compare the nystagmus evoked by the caloric test and by two slow and
      fast optokinetic 'look' stimulations performed in 78 subjects subdivided into two
      groups and recorded by ENG: group 1 composed of 22 subjects with 'significative'
      unilateral hyporeflexia and group 2 composed of 56 subjects with important
      anomalies at the vestibular caloric test. The results can be summarized as
      follows: 1. the presence of unilateral vestibular hyporeflexia is not exceptional
      in the child: 22 over 140 cases (15.7%); 2. the comparison between the caloric
      test and the OKN test in the 22 subjects with significant unilateral hyporeflexia
      shows: slow and fast TAP homolateral to the side with labyrinthine deficit
      prevails in ten subjects (45.4%); TAP is inconsistency with respect to the
      hyporeflexic side (i.e. homolateral in one test and contralateral in the other)
      in seven cases (31.8%); TAP is contralateral in five cases (22.7%). Within the
      same group, STAP varies according to cases. 3. In group II, TAP values at the OKN
      test overlap considerably with respect to the caloric test (18 cases with a total
      TAP prevailing on the right side, 32.2%; 19 cases with divergent TAP, 33.9%; 19
      cases with total TAP prevailing on the left side, 33.9%). 4. The data shown in
      group 1 with significant vestibular hyporeflexia can be correlated to the time
      elapsed between the last electronystagmography and that performed soon after
      disease onset. Since for ENG performed some days after vertigo onset (even though
      clinical examination is negative) shows a concordance of OKN TAP and the
      hyporeflexic side (as the mechanisms of central compensation are still being
      developed) and then when these mechanisms improve with time, an inconsistency of
      OKN TAP and hyporeflexic side and finally a contralaterality. We might rely on
      the comparison between OKN TAP and caloric test as a finding of the time distance
      from the vertigo onset (when unknown) and a rough prognostic sign. The only case
      of vestibular neuritis by us followed in time seems to confirm our assumption.

PMID- 10595662
TI  - The air caloric test in children: subdivision and statistical analysis of the
      response.
AB  - Among a population of 200 children, suffering by dizziness that we examined in
      the ENT department of the G. Gaslini Institute of Genoa, we acquired and checked,
      through the statistical analysis, the data of an air caloric test (according to
      the standard stimulation method) performed in 20 children (resulted normal to
      neurological, ophtalmological and audiovestibuler examinations which included
      audiometry, tympanometry, spontaneous, positional and positioning nystagmus
      research, OKN and caloric tests) and subdivided into 10 s sequences. The
      statistical analysis of the results obtained showed the following: (1) in both
      cold and warm air caloric test, the response can be obtained already in the
      stimulation phase, requiring ENG recording to start at the beginning of
      stimulation; (2) even in children, response culmination occurs in a period
      ranging from 60 to 90 s from stimulation onset; therefore the Visual Suppression
      Test should be performed in this period to obtain more significant data; (3) in
      cold and warm test, considering SSCs, the response is constant and intense up to
      130 and 110 s, respectively, from beginning of ENG recording. After these time
      ranges, the response is less intense and homogeneous, becoming poor and variable.
      In our opinion, this allows suspension of recording immediately after these
      periods without the risk of the excluding significant aspects of the response.

PMID- 10595663
TI  - Otoacoustic emissions--an approach for monitoring aminoglycoside induced
      ototoxicity in children.
AB  - OBJECTIVES: The early detection of hearing impairment caused by ototoxic drugs,
      such as aminoglycosides, has been the aim of research world-wide.
      Histopathological studies have shown that the outer hair cells are the most
      susceptible cochlear components to injury from ototoxic drugs like
      aminoglycosides. Otoacoustic emissions reflect the functional status of the outer
      hair cells and constitute the only non-invasive means of objective cochlear
      investigation. The aim of this study was to evaluate the potential of otoacoustic
      emissions in early identification of aminoglycoside-induced cochlear dysfunction.
      In addition, a comparison with pure-tone audiometry or auditory brainstem
      responses was performed in order to determine if this test might provide a more
      reliable method of monitoring early ototoxic insults to the cochlea. METHODS:
      Twenty four children receiving gentamicin (4 mg/kg once daily) for 6-29 days were
      included in the study. Eleven children received gentamicin for up to 7 days
      (group A), while 13 underwent longer-term therapy lasting 8-29 days (group B).
      Hearing was serially monitored using transient evoked otoacoustic emissions and
      pure-tone audiometry (0.25-12 kHz) or auditory brainstem responses for younger or
      uncooperative children. Transient evoked otoacoustic emissions data were analysed
      in terms of emission amplitude and response reproducibility as a function of
      frequency. RESULTS: All patients yielded a normal baseline audiometric assessment
      upon hospital admission. For group A patients no significant changes in hearing
      levels were observed either by pure-tone audiometry (P = 0.2), auditory brainstem
      responses (P = 0.3) or transient evoked otoacoustic emissions (mean response: P =
      0.06, reproducibility by frequency: P > 0.05). For group B patients no
      significant changes in hearing levels measured by pure-tone audiometry (P = 0.1)
      or auditory brainstem responses (P = 0.4) were observed. Transient evoked
      otoacoustic emissions however revealed a statistically significant decrease in
      the mean response level (P = 0.017) and in the reproducibility over the whole
      frequency spectrum (1 kHz: P = 0.0057, 2 kHz: P = 0.0247, 3 kHz: P = 0.0134, 4
      kHz: P = 0.0049, 5 kHz: P = 0.0019). CONCLUSIONS: The findings suggest that
      transient evoked otoacoustic emissions are an extremely sensitive measure of the
      early effects of aminoglycoside-induced injury to the peripheral auditory system.
      Therefore, their use is recommended for regular monitoring of cochlear function,
      in the presence of potentially toxic factors, aiming at prevention of permanent
      damage.

PMID- 10595664
TI  - The cochlear nuclei in two patients with Usher syndrome type I.
AB  - HYPOTHESIS: Does long-term sound deprivation lead to degeneration of the cochlear
      nuclei in two Usher type I patients? METHODS: The cochlear nuclei of these
      patients were morphometrically analyzed and compared with two age-matched
      controls. Routine autopsy of the brainstems was performed before the design of
      this study was known. During this procedure, the ventral cochlear nucleus (VCN)
      can easily be damaged. Five partially damaged VCN could nevertheless be analyzed
      for this study, including the right VCN of Usher patient 1 and both VCN of Usher
      patient 2. Using 15 microm thick serial paraffine sections of the cochlear
      nuclei, estimates of volume, neuronal densities, number of cells and mean cell
      diameter of the dorsal cochlear nucleus (DCN) and VCN were obtained. RESULTS:
      This study presents unique material of the cochlear nuclei in two patients with
      Usher syndrome type I. Data regarding volume and total cell number of the VCN are
      influenced by the absence of a part of the VCN. Results suggest a decrease in
      mean cell diameter of the VCN in Usher patients. Other parameters of the VCN and
      DCN, however, showed no major differences between Usher type I patients and
      controls. CONCLUSION: Only minor degenerative changes are apparent in the
      cochlear nuclei of two patients with Usher type I, who were deprived of acoustic
      stimuli since birth.

PMID- 10595665
TI  - Passy-Muir valve in children with tracheotomy.
AB  - INTRODUCTION: Early vocalization and speech production remains a goal in children
      who require tracheotomy for airway obstruction or chronic ventilation. Although
      studies document the efficacy of the Passy-Muir valve (PMV) in adults, none have
      reviewed its efficacy in children. We performed this study to better understand
      the clinical complexity of its use in children. MATERIALS AND METHODS:
      Retrospective evaluation of 55 consecutive cases of children with tracheotomy
      using the PMV. RESULTS: The children ranged in age from 3 days to 18 years at the
      time of their tracheotomies, and nearly half were 12 months old or younger.
      Successful use often requires patient and family conditioning. Overall, 52
      children out of the 55 who were evaluated as candidates for the PMV tolerated its
      use. Many required two or more trials prior to the patient and family being
      comfortable with its use. CONCLUSIONS: The PMV may be used successfully in
      children with a variety of airway pathologies as well as diverse medical
      problems. Discussed is the current protocol for the evaluation of the patient and
      the introduction of the valve.

PMID- 10595666
TI  - A retrospective study of hearing, speech and language function in children with
      clefts following palatoplasty and veloplasty procedures at 18-24 months of age.
AB  - Many cleft palate teams currently schedule palatoplasty and veloplasty within the
      child's first year of life. At Hannover Medical School, palatoplasty and
      veloplasty are performed at approximately 18-24 months of age. It was questioned
      which speech and language outcome was achieved and whether it may be influenced
      by: (1) type and extent of the clefts; (2) velopharyngeal inadequacy; and (3)
      hearing disorders. A retrospective evaluation of data collected from 1985 to 1993
      was performed summarizing receptive and expressive speech and language skills of
      370 children aged 4.5 years. Cleft types were unilateral cleft lip and palate
      (UCLP, 30.0%), bilateral cleft lip and palate (BCLP, 28.7%), cleft hard and soft
      palate (CP, 21.6%), cleft soft palate (cleft velum, CV, 10.8%), cleft lip and
      alveolus (CLA, 5.8%) and submucous clefts (SUB, 3.2%). n = 86 had constant normal
      hearing, and n = 284 had conductive hearing loss > 20 dB (500-4000 Hz). Severe
      developmental phonology errors were found in 30-50% of children with repaired
      cleft palate and in less than 8% of patients with CLA and SUB. Posterior
      compensatory misarticulation was below 15% in the groups UCLP, BCLP, CP, CV and
      SUB. Nasal resonance and air emission was nearly normal in CLA, but was increased
      in 27% to 38% of the other cleft types. Children with conductive hearing loss had
      significantly more and severely affected phonology, morphology, syntax,
      vocabulary, language comprehension, and auditory perception than normal hearing
      children. Findings indicated that speech and language function in CLP patients
      were predominantly related to the hearing status.

PMID- 10595667
TI  - Isolated primary unilateral stenosis of the internal auditory canal.
AB  - Congenital primary stenosis of the internal auditory canal (IAC) may exist in
      isolation or along with a number of other osseous anomalies of the temporal bone.
      Most of the literature on IAC stenosis is concerned with its effect on the
      outcome of cochlear implantation (i.e. patients with profound bilateral hearing
      loss). In addition, some degree of canal asymmetry has been noted in patients
      with normal hearing, questioning the causal relationship of this finding to
      deafness. We describe two children with computed tomography (CT) documented
      severe primary unilateral narrowing of the IAC and an associated ipsilateral
      sensorineural hearing loss. Typical radiographic findings are described, and the
      relevant developmental pathology is discussed. The ipsilateral association of
      stenosis and hearing loss strengthens the link between narrowing of the IAC and
      deafness.

PMID- 10595668
TI  - Use of mediastinoscopy for foreign body removal.
AB  - Foreign body removal from the aerodigestive tract can be a challenging endeavor
      despite improvements in technology. Rigid bronchoscopy has been demonstrated to
      be a safe and effective means of airway foreign body removal with appropriate
      training and expertise. However, potential complications exist and include
      extraluminal impaction of a penetrating foreign body during removal. This report
      details such a complication and the first known use of mediastinoscopy to remove
      the impacted foreign body to avoid the need for thoracotomy.

PMID- 10595669
TI  - Menkes disease and Wilson disease: two sides of the same copper coin. Part II:
      Wilson disease.

PMID- 10595670
TI  - Cerebral infarction in the newborn infant: review of the literature and personal
      experience.

PMID- 10595671
TI  - Is the International League against Epilepsy classification of epileptic
      syndromes applicable to children in Estonia?
AB  - The concept of the epileptic syndrome has had a practical and research impact on
      the management of patients with epilepsy. The aim of the present study was to
      verify the applicability of the International Classification of Epilepsies and
      Epileptic Syndromes in children and adolescents in Estonia. A population-based
      study was performed between January 1995 and December 1997 in seven counties.
      Only cases involving children between the ages of 1 month and 19 years with at
      least two unprovoked seizures were included. In all, 560 children and adolescents
      were referred to the Children's Hospital of the University of Tartu. A syndrome
      diagnosis was made in 550 (98.2%) cases: (49.4%) were localization-related (6.4%
      idiopathic, 18.9% symptomatic, 24.1% cryptogenic). Benign childhood epilepsy with
      centrotemporal spikes was present in 33 (5.9%) and childhood epilepsy with
      occipital paroxysms in three (0.5%); 48.4% were generalized (28.8% idiopathic,
      5.7% cryptogenic or symptomatic, 14% symptomatic). Childhood absence epilepsy was
      present in 6.4%, juvenile absence in 2.0%, juvenile myoclonic in 0.7% and
      epilepsy with generalized tonic-clonic seizures on awakening in 17.7%. West
      syndrome was diagnosed in 1.4%, Lennox-Gastaut syndrome in 2.9% of the cases. In
      0.4% of the cases it was undetermined whether seizures were focal or generalized.
      In 8.8% of the cases there were atypical features so they were classified as
      'other symptomatic generalized epileptic syndromes not defined above' and 1.8% of
      the cases were unclassified. Specific neurological diseases were diagnosed in
      5.0% of cases. Thus, the International Classification of Epilepsies and Epileptic
      Syndromes was very applicable to children and adolescents in Estonia.

PMID- 10595672
TI  - Influence of infant-walkers on motor development: mimicking spastic diplegia?
AB  - We discuss two patients, who used an infant walker during the period in which
      they learned to walk. The influence on qualitative and quantitative motor
      development is illustrated in this report. A disharmonic and delayed motor
      development, contractures of the calf-muscles and motor development mimicking
      spastic diplegia are considered to be caused by the early use of infant walkers.
      As illustrated by the literature, infant walkers do not have any positive effect
      on improving motor development. Vulnerability of infants with regards to
      accidents is increased. In our opinion, the use of infant-walkers should be
      discouraged.

PMID- 10595673
TI  - Acute sensory neuropathy in an adolescent girl following BCG vaccination.
AB  - A 13-year-old girl developed a sensory neuropathy following bacille Calmette
      Guerin (BCG) vaccination, consistent with acute inflammatory demyelinating
      polyradiculoneuropathy or acute sensory axonal neuropathy.

PMID- 10595674
TI  - Cauda equina syndrome due to lumbosacral arachnoid cysts in children.
AB  - We describe the clinical, neuroradiological and surgical aspects of two children
      in whom symptoms attributable to cauda equina compression were caused by spinal
      arachnoid cysts. The first patient presented with recurrent urinary tract
      infections due to neurogenic bladder dysfunction, absent deep tendon reflexes and
      sensory deficit in the lower limbs. The second child presented with unstable gait
      as a result of weakness and diminished sensation in the lower extremities. Spinal
      magnetic resonance imaging revealed a lumbosacral arachnoid cyst in both
      patients. During surgery the cysts were identified and excised. Two years after
      surgery, the sensory deficits of the first patient have disappeared and patellar
      and ankle reflexes can be elicited, but there is no improvement in bladder
      function. Neurological examination of the second patient was normal. We conclude
      that the diagnosis of cauda equina syndrome should prompt a vigorous search for
      its aetiology. Lumbosacral arachnoid cysts are a rare cause of cauda equina
      syndrome in children.

PMID- 10595675
TI  - Cerebral tuberculomas in Northern Ireland.
AB  - Two children presenting with very different clinical pictures were both found to
      have intracranial tuberculomas. This condition, although rare in developed
      countries, should be suspected in any child with enhancing cerebral lesions or
      cranial computed tomography.

PMID- 10595676
TI  - Central nervous system malformations: locations of known human mutations.

PMID- 10595677
TI  - Transcranial magnetic stimulation in the treatment of psychiatric disorders.
AB  - Transcranial magnetic stimulation (TMS) is a new technology that applies the
      principles of electromagnetism to deliver an electrical field to the cerebral
      cortices. Well established in diagnostic electrophysiology, TMS is now being
      studied as a treatment for psychiatric disorders. Evidence suggests this
      technique is safe and acceptable to patients. The future may see the application
      of TMS in obsessive-compulsive disorder, post-traumatic stress disorder and
      mania. There is strong evidence that it will become an accepted treatment of
      depression.

PMID- 10595678
TI  - Physiognomic perception, vitality affect and delusional perception in autism.
AB  - The relationship between autism and schizophrenia has been denied from the
      symptomatological and epidemiological standpoints. However, the mechanism whereby
      psychotic symptoms appear in association with autism has not been investigated at
      any length. Therefore, an investigation was conducted on how the unique modes of
      perception in autism are related to the psychotic symptoms observed. Through the
      therapy of one case of adolescent autism, the author points out the existence of
      physiognomic perception and vitality affect as characteristic modes of perception
      in autism. It was inferred that should autistics be placed under circumstances
      forcing them to withdraw from open communalism, their unique interpretation of
      the environmental world could give rise to psychopathological phenomena which
      would be considered delusional perception.

PMID- 10595679
TI  - Add-on polytherapy with antidepressants and its significance in inpatients with
      major depression.
AB  - Add-on polytherapy with antidepressant agents was reviewed in 42 inpatients with
      major depression diagnosed according to the ICD-10 criteria. Twenty-eight (67.7%)
      patients were treated with two or more antidepressants. The most frequent
      combination consisted of a tricyclic antidepressant and a non-tricyclic
      antidepressant. Nineteen (67.8%) patients of the polytherapy group were treated
      with a dosage equivalent to 150 mg/day of tricyclic antidepressant. Clinically,
      not every patient with major depression can tolerate the adverse side effects
      induced by an effective dose of a single tricyclic antidepressant. From this
      viewpoint, add-on polytherapy with antidepressants could be one of the treatment
      options, especially for such intolerant patients.

PMID- 10595680
TI  - Cognitive therapy for a major depressive episode in residual schizophrenia.
AB  - The present paper describes cognitive approaches to the treatment of a major
      depressive episode in a patient with residual schizophrenia. The goal of therapy
      was to increase and stabilize the patient's physical activity through decreasing
      dysfunctional cognition pertinent to inertia. A therapeutic strategy of
      'scheduling activities' was first selected, but to no effect. The vicious circle
      of alternating excessive activity and total inertia remained unchanged. Based on
      a revised cognitive case conceptualization, a second strategy, 'scheduling
      inertia', was then introduced, in which the patient was asked to stay in bed or
      take a rest for planned periods of time every day. This intervention helped the
      patient to counteract her perfectionist beliefs. The results suggest that
      'scheduling inertia' may be a useful strategy for improving inactivity in a major
      depressive episode during the residual phase of schizophrenia.

PMID- 10595681
TI  - Suicidal thoughts in cancer patients: clinical experience in psycho-oncology.
AB  - Because cancer is a life-threatening illness, its impact on the patient's
      emotional well-being, such as suicidal thoughts, has become a significant problem
      in public health as well as in clinical oncology. Factors such as the pain and
      hopelessness are suggested as making cancer patients more vulnerable to suicide.
      On the other hand, euthanasia and physician-assisted suicide are now important
      medical and social issues all over the world. However, little is known about the
      relationship between the characteristics of cancer patients and suicidal
      thoughts. The present study investigated the characteristics of patients who were
      referred to the Psychiatry Division, National Cancer Center Hospital East, due to
      risk of suicide or suicide attempts. Fourteen patients were referred,
      representing 3.9% of all consultations. Most of these patients suffered from
      advanced cancer and poor physical functioning. The most frequent psychiatric
      diagnosis was mood disorder (57%), and the next was delirium (29%). In patients
      with mood disorders (8 cases), suicidal thoughts disappeared after psychiatric
      treatment in 5 cases, but not in 3 cases. Those three patients survived a
      significantly shorter time than the others after psychiatric consultation. These
      empirical data might indicate that most suicidal thoughts experienced by cancer
      patients are not rational, and a careful evaluation, including psychiatric
      assessment, should be conducted in such patients.

PMID- 10595682
TI  - Progressive myoclonic epilepsies syndrome (Ramsay Hunt syndrome) with mental
      disorder: report of two cases.
AB  - Ramsay Hunt syndrome (RHS) is a rare condition within the progressive myoclonic
      epilepsies syndrome (PME), with a triad of action myoclonus, grand mal seizure
      and severe cerebellar ataxia. There are few reports about the psychiatric
      disturbances associated with PME or RHS. The present study examines the evidence
      that RHS may accompany an organic mental syndrome, ethanol's effective
      suppression of myoclonus, and the possible resultant problem of alcohol
      dependence in RHS patients. Two brothers with the previous long-standing
      diagnosis of RHS and their mental symptoms of persecutory delusion and depression
      are reported, as well as the additional problem of alcohol dependence in one of
      them. The cerebellar dysfunction found in RHS may be associated with an
      underlying organic condition. Determination of the relationship between
      cerebellar dysfunction and psychosis in RHS will require further study. Although
      the mechanism of the suppression of myoclonus by alcohol remains unclear,
      patients should be allowed to drink socially, and alcohol consumption should not
      be totally prohibited. However, effective treatment of the problems of alcohol
      tolerance, abuse, or dependence requires the cooperation of both neurologists and
      psychiatrists.

PMID- 10595683
TI  - Novel intronic polymorphisms in the presenilin-2 gene and a case-control
      association study of Alzheimer's disease.
AB  - Several alleles of introns or untranslated regions in the presenilin-1 (PS-1) and
      presenilin-2 (PS-2) genes have been reported to behave as risk factors for senile
      Alzheimer's disease (AD). On the other hand, mutations in the three presenile AD
      genes also have been identified in a small number of sporadic presenile AD and
      senile AD cases. The present study evaluated the genetic contributions of PS-2
      exons and introns to 56 senile and 18 Japanese cases of presenile AD using
      polymerase chain reaction single-strand conformation polymorphism analysis. In
      the PS-2 gene, one exonic polymorphic site without amino acid substitution, 9
      intronic polymorphic sites, and 2 intronic variant sites were detected. However,
      in all cases, amino acid substitutions in exons between 4 and 12 of the PS-2 gene
      were not observed. The risk factors of senile and presenile AD were evaluated
      using a population-based study of restriction cleavages between patients and
      controls in introns 3, 4, 10 and 11. Regarding PS-2, there was no association
      between AD and intronic polymorphisms.

PMID- 10595684
TI  - Quantitative analysis of neurofilament proteins in Alzheimer brain by enzyme
      linked immunosorbent assay system.
AB  - The abnormality of cytoskeletal proteins is related to Alzheimer's disease.
      Because neurofilament proteins (NF) are major cytoskeletal components of
      neurones, abnormality of NF may be involved in the pathology of disease. In this
      study, insoluble NF in the grey matter of temporal lobes of Alzheimer and control
      brains were dissolved in a urea buffer and quantitatively measured by an enzyme
      linked immunosorbent assay system. No apparent quantitative changes of NF-L and
      NF-H were found between the Alzheimer and control brains, and there were also no
      significant differences in the mean molar ratio of NF-L to NF-H between them.
      However, the relative amount of phosphorylated NF-H in Alzheimer brains was
      increased in comparison with that in control brains. These results suggest that
      the increase of phosphorylated NF-H might be accompanied with Alzheimer's
      disease.

PMID- 10595685
TI  - The effect of cytochrome P450 2D6 genotypes on haloperidol metabolism: a
      preliminary study in a psychiatric population.
AB  - We investigated the effect of cytochrome P450 (CYP2D6) genotypes on plasma levels
      of haloperidol (HAL) and reduced haloperidol (RHAL) in 47 Japanese male
      schizophrenic inpatients being treated with HAL. Mutation-specific polymerase
      chain reaction (PCR) analysis was used to detect CYP2D6*10 as the C188C1T
      mutation in exon 1. A long-PCR analysis method was used to detect CYP2D6*5.
      Allele frequencies of CYP2D6*5 and CYP2D6*10 were 4.3% and 34.0%, respectively.
      Plasma concentrations of HAL and RHAL were measured using high-performance liquid
      chromatography. The ranges of the plasma concentration of HAL and RHAL corrected
      to the dose were 0.28-1.60 (mean +/- SD, 0.66+/-0.25, n = 47) ng/mL/mg and 0.03
      3.00 (mean+/-SD, 0.36+/-0.46, n = 47) ng/mL, respectively. Plasma RHAL/HAL ratios
      (R/H ratios) ranged from 0.06 to 1.88 (mean +/- SD, 0.48+/-0.32, n = 47). The
      analysis was performed among the four genotype groups: CYP2D6*1/CYP2D6*1 (n =
      11), CYP2D6*1/CYP2D6*10 (n = 11), CYP2D6*10/CYP2D6*10 (n = 6) and those who have
      CYP2D6*5 allele (CYP2D6*1/ CYP2D6*5 or CYP2D6*5/CYP2D6*10 (n = 4). We observed
      significant tendency in effects of CYP2D6 genotypes on plasma concentration of
      HAL and significant effects on plasma concentration of RHAL, and R/H ratio. These
      results we obtained suggested that the plasma concentration of HAL and RHAL were
      determined partly by CYP2D6 polymorphic activity.

PMID- 10595686
TI  - A case of small cerebral cyst and pericentric inversion of chromosome 9 that
      developed schizophrenia-like psychosis.
AB  - A case of schizophrenia-like psychosis (psychotic disorder not otherwise
      specified according to the DSM-IV criteria) with pericentric inversion on
      chromosome 9 [inv.(9) (p11; q13)] is reported. In this case, a minor brain
      anomaly, a small cyst in the left subcortex, was observed on magnetic resonance
      imaging of the brain. In the clinical course, prominent chronic hallucinations
      were observed; however, there was no evidence of the disorganization of
      personality, delusion, and deterioration in level of functioning that are usually
      seen in schizophrenia. This case and a review of the literature indicate that the
      pericentric region of chromosome 9 might be a potential areas of interest for the
      aetiology of psychiatric disorders. The phenotype-karyotype relationship of
      pericentric inversion on chromosome 9 and its relationship to psychosis are
      discussed.

PMID- 10595687
TI  - A case of psychotic disorder associated with a right temporal lesion: a special
      reference to magnetic resonance imaging and single photon emission computed
      tomography findings.
AB  - A case of psychotic disorder with a right temporal lesion was reported. The
      patient, a 19 year old male, who underwent a brain surgery to remove the
      trigeminal Schwannoma, occupying from the right cerebellopontine angle to the
      right middle cranial fossa. One year postoperatively, he presented with a
      psychotic disorder, including auditory hallucinations, delusions of persecution
      and reference, thought hearing, thought insertion and passive experiences. T1
      weighted images on magnetic resonance imaging (MRI) demonstrated a low intensity
      signal area in the right temporal cortex and white matter. T2-weighted images
      demonstrated a high intensity signal within the same region. Single photon
      emission computed tomograghy (SPECT) demonstrated a severe low perfusion
      corresponding to the region in which the MRI demonstrated the abnormalities. The
      clinical and neuroimaging studies of this case suggest that psychotic disorder
      may occur in association with a right temporal lesion and MRI and SPECT are
      useful to evaluate an organic basis for the psychotic disorder.

PMID- 10595688
TI  - Bipolar II disorder is common among depressed outpatients.
AB  - The aim of this study was to find the prevalence of bipolar II disorder among
      major depressive episode private practice outpatients. Consecutive 578 unipolar
      and bipolar outpatients were interviewed with Comprehensive Assessment of
      Symptoms and History structured interview, Montgomery Asberg Depression Rating
      Scale, and the Global Assessment of Functioning Scale. The prevalence of bipolar
      II disorder was 43.4%. Bipolar II disorder is common among depressed outpatients.

PMID- 10595689
TI  - Blood pressure and coronary heart disease.

PMID- 10595690
TI  - White coat hypertension and carotid atherosclerosis.
AB  - To investigate further the relationship between atherosclerotic vascular disease
      and blood pressure, and the phenomenon of white coat hypertension, we performed a
      cross-sectional study of patients referred for carotid Doppler scanning, to
      determine the relationship between ambulatory blood pressure monitoring (ABPM)
      and carotid atherosclerosis. We studied 79 patients (51 men, 28 women) undergoing
      Doppler ultrasound examination of the carotid arteries: 44 (56%) had evidence of
      carotid atherosclerosis on Doppler ultrasound examination ("disease group"),
      whilst 35 (44%) had normal carotid arteries ("controls"). "Adequate" ABPM
      recordings, defined by > 90% of recordings over the 24 h, were available in 51
      patients (30 positive, 21 negative). There were no significant differences in
      mean daytime, mean night-time or mean 24 h ABPM recordings between those with and
      without carotid atherosclerosis. Mean manual clinic systolic blood pressure was
      significantly greater in those with carotid atherosclerosis than in controls
      (146.7 +/- 25.2 vs 131.1 +/- 35 mmHg, p < 0.005). In patients with carotid
      atherosclerosis, the first systolic blood pressure ABPM recording was not
      significantly different from the mean manual clinic recording (mean difference 
      1.5 mmHg, 95% confidence interval (CI) -7.9 to 4.8 mmHg). The initial diastolic
      blood pressure ABPM recording was significantly higher than the mean manual
      recording. Carotid atherosclerosis was identified in 53% of normotensive controls
      compared with 56% of white coat hypertensives and 75% of persistent
      hypertensives. One-third (9/27) of the patients with normal carotid arteries did
      not have nocturnal dipping ("non-dippers") compared with 50% (12/24) of the
      atherosclerotic patients. This study suggests that carotid atherosclerosis may be
      associated with white coat hypertension. Our study adds to the body of evidence
      that white coat hypertension is associated with end-organ damage and is not
      simply a benign disease. Such patients should be screened for other
      cardiovascular risk factors and should be monitored for the development of
      persistent hypertension.

PMID- 10595691
TI  - Effects of the correction of renal artery stenosis on blood pressure, renal
      function and left ventricular morphology.
AB  - The aim of this study was to evaluate the effect of renal artery stenosis (RAS)
      correction in hypertensive patients on 24 h SBP, 24 h DBP, creatinine clearance
      (GFR), urinary albumin excretion (UAE) and LV morphology and mass (LVMI). A total
      of 61 hypertensive patients with RAS undergoing PTRA and/or surgical treatment
      entered the prospective study. The final analysis was done in 44 patients (age
      range 45.8 +/- 16.2 years) with RAS (atherosclerosis (ASC) 31 patients,
      fibromuscular dysplasia (FMD) 12 patients, arteritis 1 patient) who underwent
      PTRA (34 patients) or surgical treatment (10 patients) and presented no Doppler
      signs of restenosis (or a new stenosis) during 1-year observation. The pre
      interventional assessment repeated after 6 and 12 months included ABPM, GFR, UAE
      and echocardiography. The results were analysed in the combined group (CG) and in
      according aetiology. 24 h SBP and 24 h DBP decreased in all groups 6 months post
      intervention and did not change further. Cure of HT was observed in 35% and 29%
      of ASC patients at 6 and 12 months respectively; and in 58% of FMD patients.
      Failure rate at 12 months was 48% in ASC against 25% in FMD. The mean GFR in CG
      was higher 12 months after intervention. The increase in GFR was noted in 45% of
      patients, the decrease in 25% of patients at 12 months. Normal values of UAE were
      found in 71% of patients, pre- and post-intervention alike. Mean LVMI and number
      of patients with LVH in CG decreased already during the initial 6 months post
      intervention and did not change further. In conclusion, correction of RAS leads
      to cure of or improved control of hypertension in the majority of the patients
      with FMD, but in the ASC group in about half of cases no BP cure or improvement
      was seen. The renal function was improved or stable in two-thirds of patients
      after revascularization. Successful renal revascularization was followed by
      regression of LVH, which was evident within 6 months post-intervention.

PMID- 10595692
TI  - Evaluation of patients referred for possible coronary revascularization among
      patients with and without a history of hypertension. Swedish Coronary Artery
      Revascularization/Swedish Council on Technology Assessment in Health Care
      (SECOR/SBU) Project Group.
AB  - Patients with and without a history of hypertension referred for eventual
      coronary revascularization were compared on the basis of a national survey
      including previous history, indications for coronary angiography, use of
      medication, findings at exercise test and cardioangiography, and long-term
      prognosis. As part of a national study of the appropriateness of coronary
      revascularization, data were prospectively collected on patients referred for
      possible coronary revascularization to 7/8 public Swedish heart centers that
      performed approximately 92% of all bypass operations in Sweden in 1994. The study
      included 2764 patients of whom 986 (36%) had a history of hypertension.
      Indications for coronary angiography were similar in patients with and without a
      history of hypertension. Triple therapy (a combination of beta-blockers, long
      acting nitrates and calcium channel-blockers) was more frequently used among
      patients with hypertension (32.6% as compared with 21.4% among patients without
      hypertension; p < 0.001). With the exception of ST depression > 6 min after
      discontinuation of exercise test, which was more frequent among hypertensive
      patients (30.9% vs 25.7%; p < 0.05), the various indicators of myocardial
      ischemia were similar in the two groups during exercise. Patients with
      hypertension had a somewhat lower exercise capacity (mean of 109.6 w) than
      patients without hypertension (113.7; p < 0.05). The extent of coronary artery
      disease was more severe among hypertensives (p < 0.001). Overall mortality during
      the subsequent 21 months was 5.6% for patients with hypertension and 3.1% for
      patients without hypertension (p < 0.01). This was caused mainly by a difference
      in cardiovascular mortality (3.9% vs 2.5%; p < 0.05) and cerebrovascular
      mortality (1.0% vs 0.3%; p < 0.05). Among patients referred for possible coronary
      revascularization, those with a history of hypertension differed from those
      without such a history, in that they more frequently had ST depression at
      exercise test, a lower exercise capacity, more severe coronary artery disease, a
      higher frequency of triple-therapy use and a higher mortality rate.

PMID- 10595693
TI  - Endothelium-dependent vasodilatation in treated and untreated hypertensive
      subjects.
AB  - It has repeatedly been shown that endothelium-dependent vasodilatation (EDV) is
      impaired in patients with untreated hypertension. The effect of antihypertensive
      treatment on EDV has, however, not been extensively investigated. In the present
      study, EDV and endothelium-independent vasodilatation (EIDV) were studied in 20
      untreated and 41 treated hypertensive subjects and in 26 matched, normotensive
      controls by means of infusion of methacholine (MCh), 2 and 4 microg/min,
      evaluating EDV, and nitroprusside (SNP), 5 and 10 microg/min, evaluating EIDV, in
      the brachial artery. Forearm blood flow (FBF) was measured by venous occlusion
      plethysmography. The vasodilatory action of MCh was impaired in untreated
      hypertensives compared with controls, with the response in the treated
      hypertensives in between the other two groups (p < 0.01 vs both of the other
      groups). EIDV, on the other hand, was enhanced in the treated hypertensives (p <
      0.01), so that the MCh to SNP FBF ratio, an index of endothelial function, was
      attenuated in both treated and untreated hypertensives (0.97 +/- 0.24 and 0.96 +/
      0.15, respectively), compared with controls (1.27 +/- 0.29, p < 0.001). Both EDV
      and EIDV declined with increasing number of antihypertensive drugs used in the
      treated hypertensives (p < 0.05). In conclusion, the endothelial function index
      was found to be similarly depressed in both treated and untreated hypertensive
      subjects compared with normotensive controls. Antihypertensive therapy seems to
      improve the vasodilatory capacity in general rather than enhancing endothelial
      function.

PMID- 10595694
TI  - Loss of nocturnal decline of blood pressure in patients with nasal polyposis.
AB  - The objective of this study was to assess the blood pressure pattern in patients
      with nasal polyposis. Twenty-seven patients with nasal polyposis (18 males and 9
      females), ranging in age from 15 to 72 years (mean 37.1 years) were eligible for
      inclusion in the study. All patients were hospitalized overnight before surgery.
      After the basal blood pressure measurements were taken, non-invasive ambulatory
      blood pressure monitoring was carried out. Oxygen saturation was measured via a
      finger probe and venous blood sampling was taken for catecholamine level during
      the full night. All measurements were repeated 4 months after nasal surgery. Mean
      values for nocturnal decline in blood pressure and heart rate before surgery were
      less marked than those measured after surgery. Mean decline values (+/- SD) were;
      4.6 +/- 2.4 mmHg for systolic blood pressure, 5.8 +/- 3.8 mmHg for diastolic
      blood pressure, and 7.9 +/- 3.9 beats/min for heart rate before surgery, 9.3 +/-
      2.8 mmHg, 8.5 +/- 4.1 mmHg and 10.4 +/- 4.3 beats/min after surgery (p < 0.01),
      respectively. Whereas mean and minimum SaO2 (%) significantly increased (p <
      0.01), catecholamine levels decreased (p < 0.05 for adrenaline, p < 0.01 for
      noradrenaline) after surgery. A correlation was found between BMI and blood
      pressure as well as between duration of obstruction and blood pressure. Patients
      who snored had higher blood pressure values than those who did not. Our data show
      that in cases of nasal polyposis, hypoxia, hypercapnia, snoring, and sleep
      disorders may develop and persons with nasal polyposis and snoring have an
      increased risk of hypertension and loss of nocturnal decline in blood pressure.

PMID- 10595695
TI  - Influence of cuff size on blood pressure among schoolchildren.
AB  - In 236 schoolchildren aged 7-15 years arm blood pressure was measured using a
      semiautomatic technique. Three different cuffs were chosen among four cuffs with
      bladder sizes of either 6 x 20 cm, 9 x 27 cm, 12 x 35 cm or 15 x 43 cm. Ideal
      cuff size in each pupil was defined as the one in which the width of the bladder
      was closest to 40% of arm circumference. In all subjects ideal cuffs were tested
      along with two cuffs bigger or smaller than the ideal one. The study showed that
      "normal blood pressure" in relation to age depended on the cuff used. Using the
      ideal one, systolic blood pressure increased from 105 mmHg at 7 years of age to
      117-119 mmHg at age 11, with no further increase at higher ages, while diastolic
      blood pressure was almost unchanged in the different age groups. Normal blood
      pressure curves constructed using the same cuff in all children showed a steeper
      increase in both systolic and diastolic blood pressure in relation to age
      compared to the curve based on the ideal cuff in all children. It is strongly
      recommended that future studies should take the best-suited cuff problem into
      consideration when planning studies among children. Some of the differences
      between previous published studies may be explained by the differences introduced
      by different cuff sizes.

PMID- 10595696
TI  - Study on COgnition and Prognosis in the Elderly (SCOPE).
AB  - The Study on COgnition and Prognosis in the Elderly (SCOPE) is a multicentre,
      prospective, randomized, double-blind, parallel-group study designed to compare
      the effects of candesartan cilexetil and placebo in elderly patients with mild
      hypertension. The primary objective of the study is to assess the effect of
      candesartan cilexetil on major cardiovascular events. The secondary objectives of
      the study are to assess the effect of candesartan cilexetil on cognitive function
      and on total mortality, cardiovascular mortality, myocardial infarction, stroke,
      renal function, hospitalization, quality of life and health economics. Male and
      female patients aged between 70 and 89 years, with a sitting systolic blood
      pressure (SBP) of 160-179 mmHg and/or diastolic blood pressure (DBP) of 90-99
      mmHg, and a Mini-Mental State Examination (MMSE) score of 24 or above, are
      eligible for the study. The overall target study population is 4000 patients, at
      least 1000 of whom are also to be assessed for quality of life and health
      economics data. After an open run-in period lasting 1-3 months, during which
      patients are assessed for eligibility and those who are already on
      antihypertensive therapy at enrolment are switched to hydrochlorothiazide 12.5 mg
      o.d., patients are randomized to receive either candesartan cilexetil 8 mg once
      daily (o.d.) or matching placebo o.d. At subsequent study visits, if SBP remains
      >160 mmHg, or has decreased by <10 mmHg since the randomization visit, or DBP is
      >85 mmHg, study treatment is doubled to candesartan cilexetil 16 mg o.d. or two
      placebo tablets o.d. Recruitment was completed in January 1999. At that time 4964
      patients had been randomized. All randomized patients will be followed for an
      additional 2 years. If the event rate is lower than anticipated, the follow-up
      will be prolonged.

PMID- 10595697
TI  - Doxazosin GITS compared with doxazosin standard and placebo in patients with mild
      hypertension.
AB  - Doxazosin, an effective treatment for mild-to-moderate hypertension and benign
      prostatic hyperplasia, in its standard formulation requires a multiple-step
      titration regimen to minimize the potential for first-dose effects. A new
      controlled-release gastrointestinal therapeutic system (GITS) formulation of
      doxazosin was developed to enhance the pharmacokinetic profile, significantly
      reducing serum peak-to-trough ratios, thereby minimizing the need for titration.
      We assessed the efficacy and tolerability of doxazosin GITS compared with
      doxazosin standard and placebo in a prospective, randomized, double-blind,
      parallel-group, dose-titration, multicenter study of 392 patients with mild
      hypertension (blood pressure [BP] < or = 180/95-105 mmHg). Patients were
      randomized to doxazosin GITS, doxazosin standard, or placebo in 2:2:1 manner. The
      primary outcome measure was the proportion of patients in the per-protocol
      analysis (PPA) who achieved goal BP response (sitting BP < or = 90 mmg or 10 mmHg
      decrease from baseline at 24 h postdose at the final evaluable visit). Goal BP
      response in the intention-to-treat (ITT) population and prespecified BP and/or
      heart rate changes in the PPA and/or ITT population were also analyzed.
      Tolerability was assessed throughout the study. Doxazosin GITS and doxazosin
      standard produced comparable goal BP responses superior to that of placebo, with
      92 of 156 patients (59.0%) on doxazosin GITS and 86 of 152 patients (56.6%) on
      doxazosin standard in the PPA population achieving goal BP response 24 hours
      postdose on the final visit, compared with 25 of 70 patients (35.7%) on placebo.
      Both active treatments produced mean significant BP reductions compared with
      baseline and placebo (p < 0.001). The most commonly reported side effects were
      headache, dizziness, and asthenia. No syncope was reported in the doxazosin GITS
      group; two cases were observed in the doxazosin standard group and one case in
      the placebo group. Doxazosin GITS was well tolerated and as effective as
      doxazosin standard in patients with mild hypertension, producing well-tolerated,
      comparable BP reductions with minimal need for titration. Both active treatments
      were clinically and statistically superior to placebo.

PMID- 10595698
TI  - Conditions providing enhanced transfection efficiency in rat pheochromocytoma
      PC12 cells permit analysis of the activity of the far-upstream and proximal
      promoter of the brain creatine kinase gene.
AB  - While brain creatine kinase (CKB) is expressed at highest levels in the brain,
      where it functions in regenerating ATP, the gene elements and protein factors
      regulating CKB transcription in neuronal and glial cells have not been
      identified. To investigate the regulation of CKB in neuronal cells, we examined
      the expression of the promoter proximal and 5' far-upstream regions of the rat
      CKB gene transiently transfected into rat PC12 pheochromocytoma cells. Initially,
      these experiments were hampered by the extremely low transfection efficiency of
      PC12 cells. We increased efficiency by greater than 200-fold by employing CaPO4
      precipitated DNA transfection into PC12 cells which were optimized for transient
      transfection by: (i) culturing cells in polylysine-coated dishes to insure
      attachment throughout transfection; (ii) exposing cells to transfected DNA for an
      optimal time and employing a glycerol shock; and, most importantly, (iii)
      dissociating the characteristic self-adhesive clumps of PC12 into mostly single
      cells. Use of the plasmid expressing green fluorescent protein allowed
      identification of the transfected cells that averaged 10-20% of the total.
      Analyses of CKB promoter-CAT gene constructs showed that in PC12 cells expression
      of the proximal (0.2 kb) CKB promoter was low while expression of the 1.4 kb
      promoter was three fold higher and the 2.9 kb promoter was ten fold higher,
      suggesting the presence of at least two upstream cis-acting, positive regulatory
      elements. In agreement, the steady-state CKB mRNA level was higher in PC12 than
      in other neuronal cell lines examined, possibly reflecting the effects of
      positive upstream factors. The results are discussed in relation to how this
      economical and straightforward transfection procedure may be useful in identify
      factors regulating the transcription of CKB and other genes expressed in neuronal
      cells.

PMID- 10595699
TI  - Measurement of some small-molecule and peptide neurotransmitters in-vitro using a
      fiber-optic probe with pulsed ultraviolet resonance Raman spectroscopy.
AB  - Many techniques have been developed to investigate the chemistry associated with
      brain activity. These techniques generally fall into two categories: fast
      techniques with species-limited sensitivity; and generally slower techniques with
      broader species sensitivity. Therefore, a need exists for a fast, minimally
      invasive technique that is sensitive to a wide array of biologically relevant
      compounds in order to measure chemical brain events in real time. The work
      presented here describes the development of a novel spectroscopic
      neurotransmitter probe for the rapid and simultaneous detection of a variety of
      neurotransmitters. A fiber-optic-linked Raman and tunable ultraviolet resonance
      Raman system was assembled with custom designed optical fiber probes. Using this
      system, the ultraviolet resonance Raman spectra of some small-molecule and
      peptide neurotransmitters were measured in-vitro with a fiber-optic probe and are
      reported here for the first time. The probe has furthermore been used to measure
      neurotransmitter secretions obtained from depolarized rat pheochromocytoma (PC12)
      cells. These results demonstrate the general utility of this approach which, due
      to the fiber-optic implementation, could potentially also be applied to in-vivo
      neurotransmitter determinations.

PMID- 10595700
TI  - Microwave-stimulated recovery of myosin-V immunoreactivity from formalin-fixed,
      paraffin-embedded human CNS.
AB  - The lability of brain myosin-V (BM-V) to aldehyde-fixation has hindered
      immunohistochemical (IH) studies of this actin-based motor. We show here that BM
      V immunoreactivity (IR) can be retrieved from formalin-fixed, paraffin-embedded
      human tissue. BM-V IR was optimally retrieved by boiling 5 microm cerebellar
      tissue sections in 10 mM sodium citrate buffer, pH 6, for 15 min, using a
      microwave oven set at 900 W and 2.45 GHz. A polyclonal, affinity purified anti-BM
      V antibody, raised in rabbits against the tail domain of chicken BM-V, was shown
      here to recognize a single band in Western blots of human cortical homogenates.
      The combined use of this monospecific antibody and of the antigen retrieval (AR)
      method above allowed us to verify that BM-V IR is strongly expressed in human
      Purkinje cell bodies and dendrites, and in granule cells. The same pattern of BM
      V IR expression was consistently and maximally detected in tissues stored in 10%
      formalin from 1 week to 2.5 months. The AR protocol for BM-V described here
      permits its IH study in formaldehyde-fixed tissues. It is a valuable tool to
      study BM-V in well fixed tissues, as occurs with the large collection of human
      archival tissue available.

PMID- 10595701
TI  - Electrophysiological characterization of rat and mouse olfactory receptor neurons
      from an intact epithelial preparation.
AB  - To understand the coding mechanisms underlying olfactory discrimination, it is
      necessary to characterize odor response properties of olfactory receptor neurons
      (ORNs). In contrast with rapid progress in molecular biology, there is little
      physiological data from ORNs in rodent. To facilitate acquisition of such data,
      we have developed an intact olfactory epithelial preparation from both rat and
      mouse. We have carried out initial studies of this preparation by monitoring odor
      responses by patch-clamping directly on the ORN dendritic knobs, a subcellular
      site very close to the locus of olfactory signal transduction. Our results show
      that rat and mouse ORNs have similar intrinsic membrane properties. Most cells
      fired spontaneously at a low frequency (f) and about one half fired repetitively
      in response to current (I) injection with a linear f/I relation. About one third
      of rat and mouse ORNs responded to a mixture of four odors in a dose-dependent
      manner and about 60% of them responded to IBMX, a potent inhibitor of
      phosphodiesterase. The results suggest that this intact preparation offers the
      advantage of approximating in vivo physiological conditions, while furnishing an
      opportunity to map single neuron responses in the epithelium in a spatially
      defined manner, using electrophysiological or cell imaging methods.

PMID- 10595702
TI  - The measurement of tremor using a velocity transducer: comparison to simultaneous
      recordings using transducers of displacement, acceleration and muscle activity.
AB  - Precise kinematic measurements of tremor have historically been obtained using
      accelerometers. However, current technology permits precise measurements in
      velocity and displacement. The primary advantage of velocity recording is that
      only one step of integration or differentiation is required for either
      displacement or acceleration. A method is presented of measuring finger tremor
      using a laser system that transduces velocity precisely. Measurements of postural
      finger tremor thus obtained were compared to those simultaneously obtained from a
      laser system that transduces displacement, from an accelerometer and from surface
      electromyography (EMG) of the extensor digitorum communis. A range of amplitude
      and frequency content was obtained by testing control subjects and subjects with
      Parkinson's disease. The velocity transducer showed excellent correspondence of
      amplitude and frequency measurement with the displacement transducer. Measures of
      absolute and relative amplitude correlated well (r > or = 0.96 in amplitude
      measures in displacement, velocity and acceleration), and high coherence was
      found throughout the frequency range of interest. Measurements by the
      accelerometer generally showed poorer correspondence with those of the other
      instruments. EMG measurements showed good correspondence in some trials but
      poorer correspondence in others, attributed to the low level of muscle activity
      required in the task. Precise kinematic measurements appear to be highly
      sensitive to neuromotor impairment.

PMID- 10595703
TI  - Optimized protocol for biolistic transfection of brain slices and dissociated
      cultured neurons with a hand-held gene gun.
AB  - DNA-transfer into postmitotic neurons or neuronal tissues has been a major
      problem in neurobiology. For this aim different methods have been used such as
      viral infection, microinjection, lipofection or calcium phosphate precipitation.
      However, using these techniques, very poor transfection efficiency was achieved
      except for virus-mediated gene transfer. Though viral infections are very
      efficient, this method is expensive and labor-intensive, especially when
      recombination is used to prepare viral vectors. Biolistic gene transfer of
      neurons represents another promising transfection technique. This technique was
      originally used to transfect plant cells and has been further developed for gene
      transfer into neurons or neuronal tissues. Up to now, only a few reports are
      available where successful biolistic gene transfer into neurons or neuronal
      tissues could be shown. Transfection efficiencies were only about 2%. Most of the
      previously published experiments were carried out under vacuum conditions using
      in-chamber gene gun types. Here we describe an improved method for efficient
      neuronal cell transfection using a hand-held gene gun. Expression vectors could
      be successfully transferred into dissociated cultured hippocampal neurons, PC12
      cells, cultured cerebellar granule cells and cerebellar brain slices. In
      cerebellar granule cells and hippocampal neurons, transfection efficiencies of
      about 10% were reached.

PMID- 10595704
TI  - Automatic detection, characterization, and discrimination of kinetically distinct
      spontaneous synaptic events.
AB  - Rapid and reliable detection of randomly occurring small amplitude synaptic
      events resulting from activation of different classes of ligand-gated receptors
      is a difficult task. Here, we describe and characterize an amplitude threshold
      algorithm, written as an IGOR Pro procedure, which detects events as well as
      characterizes their amplitudes and kinetics. The program was developed to analyze
      recording traces that each contained both excitatory (glutamate-mediated) and
      inhibitory (GABA and glycine-mediated) events. By using differences in kinetics,
      the program could discriminate between the two different classes of events. In
      summary, the program has the following strengths: (1) it is generally applicable
      to circumstances in which different populations of elementary events occur
      concurrently, a drawback of methods that employ matched filtering techniques, (2)
      it is relatively insensitive to drifts in baseline, and (3) it generates user
      accessible arrays of the timing, amplitude and kinetic parameters of the detected
      events, making customized statistical analysis of event characteristics easily
      executable.

PMID- 10595705
TI  - A rapid method for semi-quantitative analysis of neurite outgrowth from chick DRG
      explants using image analysis.
AB  - Neurite outgrowth from dorsal root ganglion (DRG) explants is a method of
      evaluating neurotrophic activity of growth factors and neurotrophin mimetics. The
      drawbacks to this approach are the difficulties in quantifying the response.
      Neurite counts are time consuming and labour intensive, and the accuracy is often
      questionable due to branching and fasciculation of the neurites. We report here a
      method of semi-quantitative analysis of neurite outgrowth from chick DRG
      explants, using image analysis to quantify the area occupied by neurites
      emanating from the ganglion. This method is rapid, takes into account both the
      length and number of neurites, and is unaffected by neurite fasciculation or
      branching. Primary explants of chick DRGs were treated with the neurotrophins
      nerve growth factor (NGF) or neurotrophin-3 (NT-3) and with the compound K252a.
      K252b was tested for potentiation of the response to NT-3. The results show a
      dose dependent outgrowth of neurites from explants treated with NGF, NT-3 and
      K252a, and potentiation of the NT-3 response by K252b. These responses were
      quantified by neurite area quantification using image analysis. We conclude that
      neurite area measurement using image analysis provides a robust means of
      evaluating neurotrophic activity of growth factors and neurotrophin mimetics in
      vitro.

PMID- 10595706
TI  - A low cost, high precision subminiature microdrive for extracellular unit
      recording in behaving animals.
AB  - A new design for an inexpensive and reliable subminiature microdrive for unit
      recording in the freely moving animal is presented. The 'Scribe' microdrive is
      (a) of a small size and low weight, (b) allows for precise advancement of the
      electrodes, (c) permits stable unit recordings over time, (d) is simple to
      install, and (e) is economical to construct. These advantages are a result of its
      simple, single screw-based drive system and the ready availability of component
      parts. The Scribe microdrive is a small diameter device suitable for multi-site,
      multi-electrode applications.

PMID- 10595707
TI  - Evaluation of quantal neurosecretion from evoked and miniature postsynaptic
      responses by deconvolution method.
AB  - A new deconvolution algorithm has been developed for evaluation of quantal
      content and its variability at high-output synapses. The algorithm derives the
      distribution of the number of neurosecretory quanta released in a trial (M) from
      the measured sizes of evoked postsynaptic responses. The deconvolution employs
      the distribution of quantal sizes obtained by measuring sizes of miniature
      postsynaptic responses. The distribution of quantal content M is derived by ridge
      regression method from the distributions of sizes of the responses and of quantal
      sizes. The deconvolution method was applied to postsynaptic responses from the
      excitory innervation of lobster dactyl opener muscle obtained by focal
      extracellular recordings. The obtained solution (distribution of M) had six to
      eight components and was stable. The method was tested by the analysis of
      simulated multiquantal responses. For the simulated responses, the ridge
      regression solution reproduced the imposed distribution of M within the limits of
      the calculated confidence intervals. To further test the algorithm, the
      distribution of M at a low-output synapse was obtained both by deconvolution
      method and by the method of direct quantal counts. The results of these two
      methods were found to be in a very good agreement.

PMID- 10595708
TI  - Bio-imaging of nitric oxide-producing neurones in slices of rat brain using 4,5
      diaminofluorescein.
AB  - 4,5-Diaminofluorescein (DAF-2) was used to identify individual nitric oxide (NO)
      producing neurones in brain slices in vitro. Coronal slices of midbrain or
      hippocampus, 300 microm thick from young adult rats, were incubated for 30 min in
      1 microM DAF-2 diacetate (DAF-2 DA) and maintained in ACSF at 33 degrees C.
      Illumination at 450-490 nm revealed punctate fluorescence in neurones in the
      lateral tegmental nucleus, dorsal raphe nucleus, dorsolateral periaqueductal grey
      matter, deep collicular layers and cortical areas. Neurones in the hippocampal
      pyramidal cell layer, molecular layer of the dentate gyrus and the hilus
      fluoresced also. The fluorescence was abolished by pre-incubation of slices with
      L-NAME (100 microM-1 mM), the inhibitor of constitutive nitric oxide synthase
      (NOS), but not by D-NAME (100 microM) or L-NIL (5-50 microM), an inhibitor of
      inducible NOS. In some superficially located arterioles, there were small regions
      of bright fluorescence close to the outer smooth muscle wall and diffuse
      fluorescence within the adjacent smooth muscle cells. A diffuse fluorescence was
      also seen in some superficially located capillaries. Basal production of NO was
      not seen within deeper blood vessels. DAF-2 DA offers a sensitive indicator for
      visualising basal production of NO with high spatial resolution and could provide
      a means of identifying NOS-containing neurones in brain slices in vitro prior to
      neurophysiological study.

PMID- 10595709
TI  - Control of brain temperature during experimental global ischemia in rats.
AB  - Temperature control during experimental ischemia continues to be of major
      interest. However, if exposure of brain tissue is necessary during the
      experiment, regional heat loss may occur even when the core temperature is
      maintained. Furthermore, valid non-invasive brain temperature monitoring is
      difficult in small rodents. This paper describes a method for both monitoring and
      maintenance of brain temperature during small animal preparations in a
      stereotaxic frame. The device used includes an ear-bar thermocouple probe and a
      small near-infrared radiator. The new equipment permitted to maintain peri
      ischemic brain temperature at a desired level while carrying out non-invasive
      continuous recordings of cerebral blood flow (laser Doppler-flowmetry) and of
      electrical brain function (EEG). In contrast, without extracranial heat
      application, superficial and basal brain temperatures decreased during global
      cerebral ischemia by 4.1 +/- 0.1 and 4.6 +/- 0.4 degrees C (mean +/- SEM),
      respectively, returning to baseline values at 15-30 min of reperfusion while
      rectal (core) temperature remained stable at baseline values. The ear-bar
      thermocouple probe (tympanic membrane) reliably reflected basal brain
      temperature, and temperature in superficial brain areas correlated well with that
      in the temporal muscle. Our data show that the new system allows to exclude
      unwanted hypothermic neuroprotection, and does not interfere with optical and
      electrical measurement techniques.

PMID- 10595710
TI  - Fast scanning and efficient photodetection in a simple two-photon microscope.
AB  - Two-photon laser scan microscopy carries many advantages for work on brain slices
      and bulk tissue. However, it has very low signal levels compared to conventional
      fluorescence microscopy. This is disadvantageous in fast imaging applications
      when photon shot noise is limiting. Working on brain slices with excitation
      powers of 8-10 mW at the specimen plane, the resting signal from cerebellar
      Purkinje cell somas loaded with 10 microM Oregon Green 488 BAPTA-1 averaged 4
      detected photons/micros; axons of interneurons loaded with 200 microM of this
      indicator yielded about 1 photon/micros. To obtain satisfactory images at high
      time resolution, long pixel dwell times are required and data collection should
      be restricted to as few pixels as necessary. Furthermore, a large proportion of
      total measurement time (duty cycle) should be available for data collection. We
      therefore developed a method for scanning small regions of interest with line
      repetition rates two to four times higher than conventional ones and a duty cycle
      of 70%. We also compared the performance of several photodetectors and found the
      optimum choice to depend strongly on the photon flux during a given application.
      For fluxes smaller than 5 photons/micros, the photon counting avalanche
      photodiode shows the best signal to noise ratio. At larger fluxes,
      photomultipliers or intensified photodiodes are superior.

PMID- 10595711
TI  - A polyclonal goat antiserum against the calcium-binding protein calretinin is a
      versatile tool for various immunochemical techniques.
AB  - Specific antibodies are useful tools to label particular neurons and at times to
      delineate neuronal circuits--a task not easily achieved by other techniques.
      Human recombinant calretinin, a protein belonging to the EF-hand family of Ca2+
      binding proteins, was used to produce an antiserum in goat. The specificity of
      the antiserum to recognize calretinin was demonstrated in brain extracts from
      mouse, rat, and chick and in extracts from human tumor cell lines known to
      express this protein. Immunohistochemically, the antiserum-stained specific
      neurons in human, rhesus monkey, mouse, and rat brain. The goat anti-calretinin
      antiserum is an appropriate tool for double- or triple-immunolabeling studies
      along with previously-established rabbit and mouse antibodies. Thus, it allows
      for the concomitant staining with antibodies directed against other EF-hand
      calcium-binding proteins including calbindin-D28k and parvalbumin. The antiserum
      can further be used for the quantification of calretinin in different tissues or
      cell lines in a sandwich ELISA. Additionally, it is well suited for the detection
      of calretinin in certain cell lines or malignant pleural mesotheliomas.
      Immunostaining of these samples is comparable to that with the well-characterized
      calretinin-specific polyclonal rabbit antiserum 7696.

PMID- 10595712
TI  - Improved lipid-mediated gene transfer in C6 glioma cells and primary glial cells
      using FuGene.
AB  - Gene therapy is a potent method to counteract neurodegeneration by introducing
      genetic information encoding neuroprotective factors. In this study cationic
      lipids were used to transfer DNA into C6 glioma cells and primary glial cells.
      When comparing the novel compound FuGene with other commercially-available
      lipids, it was found that FuGene markedly enhanced gene transfer of a beta
      galactosidase reporter plasmid into C6 glioma cells. FuGene had several
      advantages compared to other lipids, such as a very low toxicity and the
      capability of transfection under serum conditions. When optimizing, a DNA-lipid
      ratio of 150 ng DNA/1 microl FuGene and a concentration of 3 microl FuGene/1 ml
      medium was found to be optimal. The incubation time peaked after 8 h and the
      expression time reached an optimum between 2 and 6 days. When cells were
      transfected on 3 consecutive days for 6 h each ('boosting'), the transfection
      efficiency was markedly enhanced in primary glial cells. When using endotoxin
      free DNA the transfection efficiency could be enhanced up to 3 times. The optimal
      transfection efficiency in C6 glioma cells and in primary glial cells was found
      to be 16.3 +/- 0.3% and 5.1 +/- 0.37% of total cells, respectively. In conclusion
      this study shows that the novel compound FuGene has a very high potential to
      transfer DNA into cells of glial origin, and it might be an interesting canditate
      for ex vivo and in vivo gene therapeutic approaches.

PMID- 10595713
TI  - A rapid method for the evaluation of compounds with mitochondria-protective
      properties.
AB  - Mitochondrial dysfunction has been implicated in a number of neurodegenerative
      diseases, such as ischemia and Parkinson's disease. We present here a method that
      allows the rapid quantification of interventions, aimed at inhibiting the effect
      of mitochondrial membrane potential uncouplers, based on the ratioing properties
      of the fluorescent probe 5,5',6,6'-tetrachloro-1,1',3,3'
      tetraethylbenzimidazolcarbocyanine iodide (JC-1), by using currently available 96
      well fluorescent plate readers. A method is presented for evaluation of cross
      talk between the two excitation/emission channels. Further characterization of
      the probe shows that the effect of plasma membrane potential changes on JC-1
      fluorescence ratio are negligible, but that the signal is very sensitive to pH.
      One of the most exciting applications is the possibility to perform end-point
      measurements, thanks to the ratioing properties of the probe. The system is
      tested in different culture types with different mitochondrial uncouplers. As an
      example of a quantitative evaluation, we show that flunarizine is able to
      inhibit, dose-dependently, FCCP mediated JC-1 signal increase. The procedure is
      simple and allows for the fast screening of mitochondria-protective compounds.

PMID- 10595715
TI  - A combined electrophysiological and video data acquisition system using a single
      computer.
AB  - Numerous experimental paradigms in behavioral electrophysiology and neuroethology
      require simultaneous recording of neural signals and behavior. A computer fitted
      with an analog to digital converter and a frame grabber was configured to perform
      both tasks. The analog to digital converter collected electrophysiological data
      while the frame grabber recorded video images. Since spike and image information
      were present in one computer, arbitrary combinations of electrophysiological and
      behavioral parameters could be used as the basis of an operant conditioning
      paradigm. The system was used to record subicular cell firing in rats performing
      a place search task. The computer monitored the output of the analog to digital
      converter for supra-threshold events. When one was detected, a block of samples
      (pre- and post-trigger) was stored in memory. The same computer also scanned
      every video frame to find the rat, and recorded a image of its behavior. The
      location of the rat was then quickly calculated. If it satisfied the task
      conditions, a brain reward pathway (medial forebrain bundle) was stimulated. The
      recording of neural and image data was monitored in real-time by writing spike
      waveforms and location data directly to video card RAM.

PMID- 10595714
TI  - Pretreatment methods to improve nerve immunostaining in corneas from long-term
      fixed embryonic quail eyes.
AB  - Pretreatment methods were used to improve neurofilament immunostaining in corneas
      from embryonic day 16 Japanese quail corneas that had been stored in fixative
      solution for several months. A sequential combination of the following three
      pretreatments: brief microwave heating in saline, followed by extraction with
      sodium dodecyl sulfate (SDS) at 37 degrees C, followed by digestion with
      hyaluronidase at 37 degrees C, produced significantly increased antibody staining
      of corneal neurofilament proteins, compared with embryonic corneas subjected to
      no prior pretreatments or to single or two-step protocols. After applying the
      sequence of all three pretreatments, darkest nerve staining and increased numbers
      of fine branches were observed, together with lower background staining. Thus,
      the result of applying the three-step pretreatment sequence is better than that
      of applying any of its component single pretreatments or even combinations of any
      two of them. These findings therefore suggest that each of these three
      pretreatments causes a unique effect, beneficial to immunostaining of
      neurofilament proteins, and that their individual effects are independent and
      additive. In addition to embryonic corneas, the three-step procedure also may be
      useful for immunostaining of nerves in other very delicate, highly-hydrated
      tissues containing an abundance of extracellular matrix.

PMID- 10595716
TI  - Comparison of sensitivity between gas chromatography-low-resolution mass
      spectrometry and gas chromatography-high-resolution mass spectrometry for
      determining metandienone metabolites in urine.
AB  - In doping control laboratories the misuse of anabolic androgenic steroids is
      commonly investigated in urine by gas chromatography-low-resolution mass
      spectrometry with selected ion monitoring (GC-LRMS-SIM). By using high-resolution
      mass spectrometry (HRMS) detection sensitivity is improved due to reduction of
      biological background. In our study HRMS and LRMS methods were compared to each
      other. Two different sets were measured both with HRMS and LRMS. In the first set
      metandienone (I) metabolites 17alpha-methyl-5beta-androstan-3alpha,17beta-dio l
      (II), 17-epimetandienone (III), 17beta-methyl-5beta-androst-1-ene-3alpha,17alpha
      diol (IV) and 6beta-hydroxymetandienone (V) were spiked in urine extract prepared
      by solid-phase extraction, hydrolysis with beta-glucuronidase from Escherichia
      coli and liquid-liquid extraction. In the second set the metabolites were first
      spiked in blank urine samples of four male persons before pretreatment.
      Concentration range of the spiked metabolites was 0.1-10 ng/ml in both sets. With
      HRMS (resolution of 5000) detection limits were 2-10 times lower than with LRMS.
      However, also with the HRMS method the biological background hampered detection
      and compounds from matrix were coeluted with some metabolites. For this reason
      the S/N values of the metabolites spiked had to be first compared to S/N values
      of coeluted matrix compounds to get any idea of detection limits. At trace
      concentrations selective isolation procedures should be implemented in order to
      confirm a positive result. The results suggest that metandienone misuse can be
      detected by HRMS for a prolonged period after stopping the intake of
      metandienone.

PMID- 10595717
TI  - Determination of the enantiomers of omeprazole in blood plasma by normal-phase
      liquid chromatography and detection by atmospheric pressure ionization tandem
      mass spectrometry.
AB  - An enantioselective assay of omeprazole in blood plasma using normal-phase liquid
      chromatography on a Chiralpak AD column and detection by mass spectrometry is
      described. Omeprazole is extracted by a mixture of dichloromethane and hexane
      and, after evaporation, redissolution and injection, separated into its
      enantiomers on the chiral stationary phase. Detection is made by a triple
      quadrupole mass spectrometer, using deuterated analogues as internal standards.
      The method enables determination in plasma down to 10 nmol/l (LOQ) and shows
      excellent consistency suited for pharmacokinetic studies in man.

PMID- 10595718
TI  - Quantitative determination of thalidomide in human serum with high-performance
      liquid chromatography using protein precipitation with trichloroacetic acid and
      ultraviolet detection.
AB  - A validated and precise reversed-phase high-performance liquid chromatographic
      method for the determination of thalidomide in serum, with phenacetin as an
      internal standard, is described. Protein precipitation, using trichloroacetic
      acid, was used for clean-up. The aliquot was chromatographed on a octadecyl
      column, using an eluent composed of 250 ml 0.01 M potassium dihydrogenphosphate,
      adjusted to a pH of 3.0 with a 43% phosphoric acid solution, mixed with 750 ml
      methanol. Ultraviolet detection was used at an operation wavelength of 220 nm.
      Hydrolytic degradation was prevented during analysis by acidification of samples
      with the precipitation reagent. Thalidomide and phenacetin were found to have
      retention times of 7.9 and 15.0 min, respectively. Recoveries ranging from 79 to
      84% were found for both components, with reproducibility relative standard
      deviations of 0.8-3% and repeatability coefficients of 1.2-3%. A mean correlation
      coefficient of 0.9995 was found for the linear calibration curve (n=2) of
      thalidomide with limits of quantitation of 0.222-21 mg/l. The method appeared to
      be feasible for pharmacokinetic studies with thalidomide.

PMID- 10595719
TI  - Assay of 2-naphthol in human urine by high-performance liquid chromatography.
AB  - This paper describes a novel liquid chromatographic method for the quantitation
      of 2-naphthol in human urine. Urine samples were extracted after enzymatic
      hydrolysis of glucuronides and sulfates; 2-naphthol was then separated using
      reversed-phase high-performance liquid chromatography. The corresponding
      detection limits were 0.04 ng/ml for the standard sample in acetonitrile and 0.13
      ng/ml for urine samples. The level of urinary 2-naphthol in 100 Korean shipyard
      workers was analyzed using this new method. The level ranged from 0.21 ng/ml
      (0.26 micromol/mol creatinine) to 34.19 ng/ml (59.11 micromol/mol creatinine),
      and the mean+/-standard deviation was 5.08 ng/ml (6.60 micromol/mol creatinine)+/
      5.75 ng/ml (9.22 micromol/mol creatinine). The mean+/-standard deviation of
      urinary 2-naphthol level of smokers, 7.03 ng/ml (8.49 micromol/mol creatinine)+/
      6.16 ng/ml (10.23 micromol/mol creatinine), was significantly higher than that of
      non-smokers, 2.49 ng/ml (4.10 micromol/mol creatinine)+/-3.92 ng/ml (7.03
      micromol/mol creatinine).

PMID- 10595720
TI  - Determination of polychlorinated biphenyls in human blood by solid-phase
      extraction including on-column lipid decomposition.
AB  - A method for the isolation of polychlorinated biphenyls (PCBs) from human blood
      using solid-phase extraction (SPE) has been developed. The procedure incorporates
      decomposition of lipids by concentrated sulphuric acid directly on the SPE
      column. Conditions for transferring PCBs onto the SPE column and washing the
      decomposed blood components from the SPE column were optimised. After clean-up
      the extracts were analysed using gas chromatography with electron capture
      detection. An average recovery of PCBs from spiked blood samples was about 78+/
      8% and an average precision was about 109+/-7%. Quantitation has been done using
      four internal standards and calibration curves based on five concentration
      levels. Low procedural blanks made it possible to determine PCBs in blood
      quantitatively at a level down to 2-10 pg g(-1). The integrated method for blood
      is fast, less laborious than methods using liquid-liquid extraction and has a low
      consumption of organic solvents.

PMID- 10595721
TI  - Simultaneous determination of citalopram, fluoxetine, paroxetine and their
      metabolites in plasma and whole blood by high-performance liquid chromatography
      with ultraviolet and fluorescence detection.
AB  - A method for the simultaneous determination of the three selective serotonin
      reuptake inhibitors (SSRIs) citalopram, fluoxetine, paroxetine and their
      metabolites in whole blood and plasma was developed. Sample clean-up and
      separation were achieved using a solid-phase extraction method with C8 non
      endcapped columns followed by reversed-phase high-performance liquid
      chromatography with fluorescence and ultraviolet detection. The robustness of the
      solid-phase extraction method was tested for citalopram, fluoxetine, paroxetine,
      Cl-citalopram and the internal standard, protriptyline, using a fractional
      factorial design with nine factors at two levels. The fractional factorial design
      showed two significant effects for paroxetine in whole blood. The robustness
      testing for citalopram, fluoxetine, Cl-citalopram and the internal standard
      revealed no significant main effects in whole blood and plasma. The optimization
      and the robustness of the high-performance liquid chromatographic separation were
      investigated with regard to pH and relative amount of acetonitrile in the mobile
      phase by a central composite design circumscribed. No alteration in the elution
      order and no significant change in resolution for a deviation of +/-1%
      acetonitrile and +/-0.3 pH units from the specified conditions were observed. The
      method was validated for the concentration range 0.050-5.0 micromol/l with
      fluorescence detection and 0.12-5.0 micromol/l with ultraviolet detection. The
      limits of quantitation were 0.025 micromol/l for citalopram and paroxetine, 0.050
      micromol/l for desmethyl citalopram, di-desmethyl citalopram and citalopram-N
      oxide, 0.12 micromol/l for the paroxetine metabolites by fluorescence detection,
      and 0.10 micromol/l for fluoxetine and norfluoxetine by ultraviolet detection.
      Relative standard deviations for the within-day and between-day precision were in
      the ranges 1.4-10.6% and 3.1-20.3%, respectively. Recoveries were in the 63-114%
      range for citalopram, fluoxetine and paroxetine, and in the 38-95% range for the
      metabolites. The method has been used for the analysis of whole blood and plasma
      samples from SSRI-exposed patients and forensic cases.

PMID- 10595722
TI  - Determination of norgestimate and its metabolites in human serum using high
      performance liquid chromatography with tandem mass spectrometric detection.
AB  - A rapid and reliable analytical method is described for the simultaneous
      determination of a synthetic progestin norgestimate (NGM), and its metabolites,
      17-deacetylnorgestimate (17-DA-NGM), 3-ketonorgestimate (3-keto-NGM) and
      norgestrel (NGL) in human serum using reversed phase high-performance liquid
      chromatography (HPLC) with tandem mass spectrometric (MS-MS) detection. The assay
      was linear over the concentration ranges of 0.1-5.0 ng/ml for 17-DA-NGM and NGL
      and 0.5-5.0 ng/ml for NGM and 3-keto-NGM. The inter-assay reproducibility was
      consistently less than 10%. The overall recovery of the analytes ranged from 72
      to 92%. Serum profiles following oral administration of norgestimate to female
      volunteers are presented.

PMID- 10595723
TI  - Automated protein precipitation by filtration in the 96-well format.
AB  - The use of automated protein precipitation by filtration in the 96-well format as
      a rapid sample preparation technique for high throughput bioanalysis using liquid
      chromatography tandem mass spectrometry is reported. A robotic sample processor
      is used to aspirate sequentially a plasma sample and acetonitrile separated by
      air gaps. These are then mixed by being dispensed into individual channels of a
      96-well filter block. The resulting supernatant is separated from the
      precipitated plasma proteins by the application of gentle vacuum using a custom
      manifold. The filtered supernatants are collected into a deep well microtitre
      plate, evaporated to dryness using a heated 96-well dry down station and
      reconstituted in water prior to analysis. The efficiency of the extraction
      procedure is measured by the Lowry method for determining protein concentration.
      This method was used to optimise both the volume and the order of reagent
      addition, and to compare several prototype 96-well filter blocks. Using the
      optimised procedure a specific, precise and accurate method was developed for the
      beta-agonist salbutamol in rabbit plasma with a calibration range of 1 to 100
      ng/ml from 100 microl of sample.

PMID- 10595724
TI  - Assay method for the perfluorooctyl bromide (perflubron) in rat blood by gas
      chromatography-mass spectrometry.
AB  - This paper describes a GC-MS method (SIM mode) for the analysis of perfluorooctyl
      bromide (perflubron, I) in rat blood. The chromatographic separation was
      performed by injection in the split mode using a CP-select 624 CB capillary
      column. Following destruction of the emulsion by addition of ethanol, the
      analytical procedure involves a liquid-liquid extraction with 1,1,2
      trichlorotrifluoroethane. The bis(F-butyl)ethene (II) was used as internal
      standard. Observed retention times were 3.22 min for I and 2.32 min for II. Two
      calibration curves were used; linear detection responses were obtained for
      concentrations ranging from 0.009 to 0.9 mg/ml and from 0.9 to 13.5 mg/ml. The
      extraction efficiency averaged 50% for I and 93% for II. Precision ranged from
      0.7 to 14%, and accuracy was between 91 and 109%. The limit of quantification was
      9 microg/ml. The method validation results indicate that the performance
      characteristics of the method fulfilled the requirements for assay method for use
      in pharmacokinetic studies.

PMID- 10595725
TI  - Measurement of hydroxyl radical in rat blood vessel by microbore liquid
      chromatography and electrochemical detection: an on-line microdialysis study.
AB  - Salicylic acid (0.5 mM) is used as a trapping reagent of hydroxyl radical, and
      the formed 2,3- and 2,5-dihydroxybenzoic acids were collected via an on-line
      microdialysis device from the blood vessels. This study revealed the use of a
      sensitive liquid chromatographic system with electrochemical detection for the
      determination of 2,3- and 2,5-dihydroxybenzoic acids. Mobile phase consisted of
      0.1 M monochloroacetic acid, 10 mM EDTA, 0.5 mM sodium octylsulfate, 20%
      acetonitrile and 5% tetrahydrofuran in 1 l (pH 3.0 adjusted with 1 M NaOH), and
      the flow-rate of 0.05 ml/min were found to be optimum. Isocratic separation of
      these adducts on a microbore column (reversed-phase C18, 150x1 mm I.D., 5 microm)
      was achieved within 10 min. The optimal applied potential of dihydroxybenzoic
      acids was set at 750 mV based on a hydrodynamic study. This method has the
      detection limits of 1.3 pmol/ml (or 0.2 ng/ml) for 2,3- and 2,5-dihydroxybenzoic
      acids in Ringer solution (at signal-to-noise ratio=3).

PMID- 10595726
TI  - Simultaneous determination of two human urinary metabolites of N,N
      dimethylformamide using gas chromatography-thermionic sensitive detection with
      mass spectrometric confirmation.
AB  - Two human urinary metabolites of the industrial solvent N,N-dimethylformamide
      (DMF), N-hydroxymethyl-N-methylformamide (HMMF) and N-acetyl-S-(N
      methylcarbamoyl)cysteine (AMCC), were assayed using a new analytical method (gas
      chromatography and thermionic sensitive detection). Clean-up of urine samples
      includes a liquid-liquid extraction step followed by a solid-phase extraction
      step to separate HMMF and AMCC from other urine components. During clean-up, AMCC
      is converted into ethyl-N-methylcarbamate (EMC), and during gas chromatography,
      HMMF is degraded in the injector to N-methylformamide (NMF). All the validation
      data necessary for a quantitative procedure are given. The method was applied to
      urine samples from workers exposed to DMF and from the general population. The
      results were confirmed by mass spectrometric determination. For this purpose a
      further liquid-liquid extraction step was introduced in the clean-up procedure.
      Background levels of AMCC in the general population were identified.

PMID- 10595727
TI  - Determination of zolpidem in serum microsamples by high-performance liquid
      chromatography and its application to pharmacokinetics in rats.
AB  - A single-solvent extraction step high-performance liquid chromatographic method
      is described for quantitating zolpidem in rat serum microsamples (50 microl). The
      separation used a 2.1 mm I.D. reversed-phase OD-5-100 C18 column, 5 microm
      particle size with an isocratic mobile phase consisting of methanol-acetonitrile
      26 mM sodium acetate buffer (adjusted to pH 2.0 with 40% phosphoric acid)
      containing 0.26 mM tetrabutylammonium phosphate (13:10:77, v/v/v). The detection
      limit was 3 ng/ml for zolpidem using an ultraviolet detector operated at 240 nm.
      The recovery was greater than 87% with analysis performed in 12 min. The method
      is simple, rapid, and applicable to pharmacokinetic studies of zolpidem after
      administering two intravenous bolus doses (1 and 4 mg/kg) in rats.

PMID- 10595728
TI  - Simultaneous determination of seven penicillins in muscle, liver and kidney
      tissues from cattle and pigs by a multiresidue high-performance liquid
      chromatographic method.
AB  - A high-performance liquid chromatographic (HPLC) method based on solid-phase
      extraction (SPE) was developed for determination of amoxicillin, penicillin G
      (benzylpenicillin), ampicillin, oxacillin, cloxacillin, nafcillin and
      dicloxacillin in muscle, liver and kidney tissues of pigs and cattle. The
      compounds were extracted in aqueous solution by precipitation of organic
      materials with a mixture of sulphuric acid and sodium tungstate. The extract was
      cleaned up by SPE on a divinylbenzene-co-N-vinylpyrrolidone polymeric sorbent.
      Further clean-up was performed by liquid-liquid partition with diethyl ether. The
      extract was derivatised with benzoic anhydride and 1,2,4-triazole mercury (II)
      reagent. Chromatography was performed by reversed-phase gradient HPLC on a C18
      column with ultraviolet detection at 323 nm. The limits of detection estimated by
      a conservative model were in the range 8.9-11.1 microg/kg for amoxicillin,
      penicillin G, ampicillin, oxacillin, cloxacillin and nafcillin and 18.3-20.9
      microg/kg for dicloxacillin. The mean recovery range was 66-77% for amoxicillin,
      73-75% for penicillin G, 81-82% for ampicillin, 73-76% for oxacillin, 74-75% for
      cloxacillin, 66-72% for nafcillin and 58-65% for dicloxacillin.

PMID- 10595729
TI  - Sensitive assay of trimethylamine N-oxide in liver microsomes by headspace gas
      chromatography with flame thermionic detection.
AB  - To compare the trimethylamine N-oxygenase activity of liver microsomes from house
      musk shrew (Suncus murinus) and rat, a sensitive method for the quantitation of
      trimethylamine (TMA) N-oxide was developed using gas chromatography with flame
      thermionic detection. The limit of quantification was 0.5 microM and the
      calibration curve was linear at least up to 5 microM in incubations containing
      liver microsomal preparations from Suncus. The intra-day RSD values ranged from
      10.4 to 12.8 at 0.5 microM and from 3.5 to 6.7 at 5 microM. The inter-day RSD
      values were 11.6 and 6.5 at 0.5 and 5 microM, respectively. This method provides
      a sensitive assay for TMA N-oxygenase activity in liver microsomes. Using this
      method we found that Suncus was capable of N-oxidizing trimethylamine at a very
      slow rate.

PMID- 10595730
TI  - Method for the simultaneous determination of losartan and its major metabolite,
      EXP-3174, in human plasma by liquid chromatography-electrospray ionization tandem
      mass spectrometry.
AB  - A liquid chromatography-electrospray ionization tandem mass spectrometric method
      was developed for the simultaneous determination of losartan and its major active
      metabolite, EXP-3174, in human plasma. The two analytes and the internal standard
      (DuP-167) were extracted from plasma under acidic conditions by using solid-phase
      extraction cartridges containing a sorbent of copolymer, poly(divinylbenzene-co-N
      vinylpyrrolidone). The analytes were separated by LC equipped with a reversed
      phase C18 column, and introduced into the mass spectrometer via the electrospray
      ion source with pneumatically-assisted nebulization. For LC-MS-MS samples, an
      isocratic mobile phase consisting of [0.1% triethylamine-0.1% acetic acid (pH
      7.1)]-acetonitorile (65:35, v/v) was used, and the assay was monitored for the
      negative fragment ions of the analytes. The method demonstrated linearity from 1
      to 1000 ng/ml for both losartan and EXP-3174. The limit of quantification for
      both compounds in plasma was 1 ng/ml. This assay method may be useful for the
      measurement of levels of the two compounds in clinical studies of losartan.

PMID- 10595731
TI  - Viral hepatitis and hepatocellular carcinoma prevention strategy in Japan.
AB  - The study of human hepatitis, particularly in Asia, where the incidence rate has
      been the highest in the world, has contributed greatly to the understanding of
      carcinogenesis of the liver and related diseases. In this article, the history of
      research on hepatitis viruses and hepatocellular carcinoma (HCC) and the
      successful prevention of vertical transmission of hepatitis B virus (HBV) in
      Japan are reviewed, focusing on the studies that resulted in the identification
      of vertical transmission of HBV infection and the association of HBV-sustained
      infection and HCC. The vaccination trials for preventing HBV vertical
      transmission and the fruitful outcome of the nationwide vaccination strategy in
      Japan, on the basis of "selective" immunization by using anti-HBs immunoglobulin
      (HBIG) and HB vaccine, are highlighted. Ongoing studies on the mechanisms
      underlying hepatocarcinogenesis induced by viruses, e.g., the roles of viral
      proteins and inflammation, are also reviewed, and prospects for the control of
      HCC are discussed.

PMID- 10595732
TI  - Chemoprevention by the oxygenated carotenoid beta-cryptoxanthin of N
      methylnitrosourea-induced colon carcinogenesis in F344 rats.
AB  - Beta-cryptoxanthin (betaCx), one of 4 major carotenoids in the blood, was
      investigated for anticarcinogenic activity in F344 rats. Four groups of 25 rats
      each received an intrarectal dose of 2 mg of N-methylnitrosourea 3 times a week
      for 5 weeks, and were fed the diet supplemented with 0 ppm (control), 25 ppm, 5
      ppm or 1 ppm betaCx throughout the experiment. The colon cancer incidence at week
      30 was significantly lower in the betaCx (25 ppm) diet group, but not in the
      betaCx (5 ppm) and betaCx (1 ppm) diet groups, than in the control diet group:
      68%, 84%, 80% vs. 96%. The results suggested that dietary betaCx may affect colon
      carcinogenesis after accumulation in the colonic mucosa, perhaps due to
      absorption from the colon as well as the small intestine.

PMID- 10595733
TI  - Chronic active desease refext cancer riski in ulcreative collitis.
AB  - There is an increased risk of developing colorectal neoplasia in ulcerative
      colitis (UC) and surveillance colonoscopy is recommended for early detection. We
      investigated the precise features of UC retrospectively to identify a subgroup
      with longstanding extensive UC at increased risk of neoplasia. From 1985 to
      August 1997, we experienced eight UC patients with colorectal cancer and eight
      with definite dysplasia. All 16 had extensive disease of seven years or more in
      duration. During the same period, 61 of 334 UC patients without colorectal
      neoplasia were available for detailed study, allowing evaluation of non-surgical
      patients with extensive colitis of seven years or more in duration. Basic
      clinical factors including family history of cancer, expressions of disease
      activity and durations of pharmacotherapy were investigated. Univariate analysis
      revealed four significant factors: intractability (P=0.001), periods of
      inflammation persisting for 3 months or more (P<0.01) and total durations of
      diarrhea (P<0.01) and hematochezia (P<0.05). The number of admissions and the
      duration of systemic steroid administration were higher in the neoplasia group
      but without statistical significance. Multivariate analysis revealed two
      significant factors: duration of diarrhea (P<0.001) and age at onset (P<0.01).
      Chronic active disease is a risk factor for colorectal cancer or dysplasia in
      extensive and longstanding UC.

PMID- 10595734
TI  - Screening for nicotine dependence among smoking-related cancer patients.
AB  - To identify lung and head-and-neck cancer patients who will have difficulty
      stopping smoking it is necessary to measure the severity of their nicotine
      dependence. In this study, we compiled a Japanese version of the Fagerstrom test
      for nicotine dependence (FTND) and examined its reliability and validity. One
      hundred and fifty-one cancer patients participated in this study and took our
      Japanese version of the FTND. Socio-demographic and medical data and information
      about smoking habits were obtained from a semi-structured interview, and the
      patients' nicotine dependence was evaluated according to the Diagnostic and
      Statistical Manual of Mental Disorders, 3rd Ed., Rev. (DSM-III-R). The mean FTND
      scores+/-SD of the group with nicotine dependence and the group without nicotine
      dependence were 6.85+/-2.00 and 3.70+/-2.13 respectively, and the difference was
      significant (P<0.001, Mann-Whitney's U-test). The test-retest correlation was
      0.75. Cronbach's alpha of the FTND was 0.66. The FTND score correlated
      significantly with the number of satisfied criteria of nicotine dependence
      (r=0.70; P<0.001, Pearson's correlation). By using a receiver-operating
      characteristic curve, we determined a score of 5/6 as a suitable cut-off point
      for nicotine dependence; this point gave high sensitivity and specificity (0.75
      and 0.80, respectively). These results suggest that our Japanese version of FTND
      is a reliable and valid measure of nicotine dependence in patients with smoking
      related cancers.

PMID- 10595735
TI  - Relationship between multicentric occurrence of hepatocellular carcinoma and
      histology of noncancerous hepatic tissue in patients with chronic hepatitis C.
AB  - The relationship between multicentric occurrence of hepatocellular carcinoma
      (HCC) and the histology of noncancerous hepatic tissue was investigated in 252
      patients infected with hepatitis C virus (HCV) and surgically treated for HCC.
      One type of multicentric HCC had at least one tumor consisting of well
      differentiated HCC, together with moderately or poorly differentiated HCC located
      in a separate region. The other type had an area of well-differentiated component
      around HCC with less differentiation in all occurrences. Noncancerous hepatic
      tissues were assessed using a histologic activity index score. Serum alanine
      aminotransferase (ALT) activity, the concentration of type 4 collagen, the
      grading score (severity of active hepatitis), and the staging score (degree of
      fibrosis) were significantly higher in patients with multicentric HCCs than in
      those without them. Platelet count was significantly lower in patients with
      multicentric HCCs. The prevalence of multicentric HCCs increased as the grading
      score and staging score increased. On univariate analysis, a low platelet count
      and high grading and staging scores were risk factors for multicentric HCCs. A
      high ALT activity and a high concentration of type 4 collagen tended to be risk
      factors. On multivariate analysis, high grading score and high staging score were
      independent risk factors. These findings indicate that active hepatitis and
      extensive fibrosis are responsible for the development of multicentric HCCs.
      Measurement of platelet count, ALT activity, and the concentration of type 4
      collagen, and histologic assessment of noncancerous hepatic tissue provide
      information useful for estimation of the potential for multicentric
      carcinogenesis.

PMID- 10595736
TI  - Genetic alterations in ulcerative colitis-associated neoplasia focusing on APC, K
      ras gene and microsatellite instability.
AB  - The status of genetic alterations in ulcerative colitis (UC)-associated neoplasia
      (UCAN) was investigated focusing on microsatellite instability (MSI) which is
      seen in a certain fraction of colorectal carcinomas, and adenomatous polyposis
      coli (APC) gene and K-ras gene, in which mutations occur in the early stage of
      sporadic colorectal tumorigenesis. Thirty-one UCAN from 15 UC patients who had
      undergone colorectal resection at our institution were investigated. There were 8
      lesions of invasive carcinoma, 15 high-grade dysplasia (HGD) and 8 low-grade
      dysplasia (LGD). DNA was extracted from each neoplastic lesion and corresponding
      non-neoplastic tissue by a microdissection method. MSI status at 9 microsatellite
      loci, loss of heterozygosity (LOH) at the APC locus, and K-ras codon 12 point
      mutation were examined. As for MSI, 4/31 (13%) UCAN (carcinoma: 1/8 (13%), HGD:
      2/15 (13%), LGD: 1/8 (13%)) were MSI-high (3 or more unstable loci) and 12/31
      (39%) UCAN (carcinoma: 3/8 (38%), HGD: 6/15 (40%), LGD: 3/8 (38%)) were MSI-low
      (1 or 2 unstable loci). LOH at the APC locus was not found in 9 UCAN from 6
      informative (heterozygous) cases. The K-ras mutation rate of UCAN was 3/31 (9.7%)
      (carcinoma: 2/8 (25%), HGD: 1/15 (7%) and LGD: 0/8). MSI is relatively common in
      UCAN and is present at the early stage of tumorigenesis of UCAN, while the
      involvement of genetic alterations of the APC gene and K-ras gene is small. MSI
      may be one of the mechanisms of the increased neoplastic risk in UC, and UCAN may
      develop through a different carcinogenic pathway from sporadic carcinomas.

PMID- 10595737
TI  - Characterization of the MEN1 gene product, menin, by site-specific polyclonal
      antibodies.
AB  - The gene associated with multiple endocrine neoplasia type 1 (MEN 1), designated
      MEN1, has recently been identified. This gene shows no homology to other known
      genes, and its expression is not restricted to endocrine organs as estimated by
      northern blotting. Expression of the MEN1 gene product, menin, has been studied
      only in a few tissues. In this report, expression of menin in various cells and
      mouse tissues was studied using two polyclonal antibodies against menin.
      Expression of menin as a 76 kDa single protein was observed in all cell lines
      examined, regardless of origin. Two nuclear localization signals of the menin
      have been reported, but through the study of mutant menin in lymphocytes from
      subjects with MEN 1, impaired nuclear localization of the mutant menin was
      observed even though the mutant retained one of the two nuclear localization
      signals (NLSs). Menin was stable in vitro with a half-life of over 24 h at 37
      degrees C. In the cell, the half-life of wild-type menin was about 10 h, while
      that of the mutant was about 2 h. The mutant rapidly disappeared from the
      nucleus.

PMID- 10595738
TI  - Epidermal growth factor-dependent dissociation of CrkII proto-oncogene product
      from the epidermal growth factor receptor in human glioma cells.
AB  - Human glioma cells frequently overexpress epidermal growth factor receptor
      (EGFR). We found that the CrkII proto-oncogene product was associated with the
      EGFR in human glioma cells in the absence of epidermal growth factor (EGF). EGF
      stimulation of glioma cells induced the phosphorylation of tyrosine 221 of the
      CrkII protein, which correlates with its dissociation from the EGFR. By contrast,
      Shc and Grb2 were inducibly associated with the EGFR in response to EGF
      stimulation of glioma cells. In A431 cells, epidermoid carcinoma cells which
      overexpress EGFR, CrkII was tyrosine-phosphorylated and associated with the EGFR
      in an EGF-dependent manner. Therefore, the dissociation of CrkII from the EGFR
      upon stimulation with EGF appears to be specific to glioma cells. The Cbl
      oncogene product was also tyrosine-phosphorylated in U87MG glioma cells upon EGF
      stimulation. However, unlike in other cell lines, CrkII was not inducibly bound
      to Cbl in U87MG glioma cells. Thus, EGF-dependent binding of CrkII to
      phosphotyrosine-containing proteins appears to be suppressed in glioma cells. To
      evaluate the physiological role of dissociation of CrkII from EGFR, we expressed
      the CrkII-23 mutant in glioma cells. CrkII-23 mutant, which was isolated as a
      suppressor gene of the EGF-dependent transformation of NRK cells, binds
      constitutively to EGFR. We found that expression of CrkII-23 inhibited the
      anchorage-independent growth of the glioma cells in the presence of EGF. Taken
      together, these data implicate EGF-dependent dissociation of CrkII from EGFR in
      the oncogenicity of human glioma cells.

PMID- 10595739
TI  - Detection of methylation damage in DNA of gastric cancer tissues using 32P
      postlabelling assay.
AB  - Gastric cancer is the most common cancer in Korea. The causes are still unknown
      but it has been speculated that gastric cancer is associated with consumption of
      foods rich in nitrates/nitrites or a high dietary intake of salt or pickled food.
      In the present study, we studied the level of alkylated DNA adducts formed in
      gastric cancer tissues in comparison with that in normal gastric mucosa. DNA was
      extracted from surgically removed gastric cancer tissues and patient-matched
      normal gastric mucosa. The level of N7-methyldeoxyguanosine was measured by 32P
      postlabelling assay after high performance liquid chromatography (HPLC)
      enrichment. We found that the level of N7-methyldeoxyguanosine of gastric
      cancerous tissues was significantly higher than that of normal gastric mucosa
      (P=0.01685).

PMID- 10595740
TI  - Morphology, proliferation and apoptosis of mouse liver epithelial cells cultured
      as spheroids.
AB  - The MLEC10 is an epithelial cell line derived from an untreated, normal C3H/HeN
      mouse liver. We previously demonstrated that tumorigenic variants from this cell
      line produced moderately differentiated hepatocellular carcinomas in nude mice.
      However, it has remained unclear whether the parental MLEC10 cells represent
      immortalized hepatocytes or so-called oval cells, both of which may serve as
      precursors for hepatocellular neoplasms. In this study, we performed 3
      dimensional, spheroid culture of the MLEC100 cells in order to facilitate
      histological assessment of their lineage. Spheroidal aggregates were formalin
      fixed and embedded in paraffin for routine light-microscopic observation of
      hematoxylin and eosin-stained sections. Histopathologically, the MLEC10 cells
      were indistinguishable from immature hepatocytes and distinct from oval cells. At
      the electron-microscopic level, their hepatocytic nature was evidenced by bile
      canaliculus structures and glycogen storage. Intriguingly, the spheroids
      contained fragmentary material reminiscent of Councilman bodies, implying
      apoptosis of the hepatocytes. Although the cells significantly proliferated
      during the first three days of culture, apoptotic death then resulted in a 75 %
      decrease in viable cell number. Thereafter, both apoptosis and cell division
      appeared silent, the numbers being unchanged. Expression of the p53 tumor
      suppressor gene became gradually elevated, correlating positively with growth
      arrest, but negatively with apoptosis, suggesting that the cell death occurred
      independently of p53. Our results indicate that at least some liver epithelial
      cell lines derived from untreated murine livers exhibit a hepatocytic morphology
      in spheroid culture. Also, the present culture system provides a useful tool for
      investigating biological phenomena, e.g. apoptosis, specifically involving liver
      cells, under 3-dimensional conditions.

PMID- 10595741
TI  - Analysis of a chronic myelogenous leukemia patient vaccinated with leukemic
      dendritic cells following autologous peripheral blood stem cell transplantation.
AB  - Dendritic cells (DCs) are believed to be the most potent antigen-presenting cells
      and may be important in the induction of anti-leukemia specific T cell responses.
      In this preliminary clinical study, a patient with chronic phase chronic
      myelogenous leukemia (CML) was vaccinated with autologous leukemic DCs following
      autologous peripheral blood stem cell transplantation (PBSCT). In an in vitro
      study, leukemic DCs were generated using granulocyte-macrophage colony
      stimulating factor (GM-CSF), tumor necrosis factor-alpha, and interleukin-4 from
      granulocyte colony-stimulating factor (G-CSF)-mobilized PBSC fraction of this
      patient, and were found to be Ph1+, and to possess the morphologic and phenotypic
      characteristics of mature DCs. These cells could also elicit antigen specific
      immune responses, including a vigorous cytotoxicity specific to CML cells. In the
      clinical experiment, we obtained evidence that infused leukemic DCs could induce
      T cell clones expressing the same T cell receptor usage as a cytotoxic T cell
      line, suggesting that the immune repertoire includes tumor-reactive T cells.
      These cytotoxic T lymphocytes are activated in vivo. The vaccination of leukemic
      DC caused a decrease in the number of Ph1+ cells in the peripheral blood and bone
      marrow. These results indicate that the activity is an immunologically mediated
      phenomenon and vaccination therapy with leukemic DC following autologous PBSCT
      may be effective in treating CML.

PMID- 10595742
TI  - Effectiveness of a simply designed tumor vaccine in prevention of malignant
      melanoma development.
AB  - We investigated the efficacy of a simple syngeneic tumor vaccine to induce
      specific antitumor immunity in female C57Bl/6 mice. Tumor vaccine was prepared by
      mixing irradiated B-16 melanoma tumor cells with the pleiotropic biological
      response modifier-maleic anhydride divinyl ether (MVE-2). Experimental animals
      were pretreated with the vaccine in order to prevent the development of
      intraperitoneal (i.p.) B-16 melanoma tumors after inoculation of viable tumor
      cells. More than 40% of prevaccinated animals challenged i.p. with 5 x 10(5)
      viable tumor cells were completely protected from tumor development and remained
      tumor-free 100 days after tumor cell inoculation. The percentage of tumor-free
      animals (survivors) rose to as much as 90% when the application of tumor vaccine
      was repeated two weeks after the first vaccination (i.e. one week after the
      inoculation of viable tumor cells). The induced antitumor response depended
      predominantly upon macrophage function, since vaccinated animals which were
      depleted of peritoneal macrophages died within the same time range as animals in
      the control group. Also, tumor-type specificity of the vaccine was confirmed by
      the fact that the animals vaccinated with B-16 melanoma vaccine were not
      protected from the development of another type of tumor. In conclusion,
      comparison of the experimental data with the data from the literature suggests
      that our simple tumor vaccine may be as effective as genetically engineered tumor
      vaccines. At the same time, this kind of vaccine is easier to control and thus
      safer to apply in humans when compared to genetically engineered vaccines.

PMID- 10595744
TI  - Enhanced sonodynamic antitumor effect of ultrasound in the presence of
      nonsteroidal anti-inflammatory drugs.
AB  - The antitumor effects of non-steroidal anti-inflammatory drugs, tenoxicam and
      piroxicam, against sarcoma 180 cells cultured in 7-week-old male mice were
      examined in vitro under ultrasonic irradiation. The survival rate of tumor cells
      when tenoxicam or piroxicam was added to sarcoma 180 suspension under ultrasonic
      irradiation was significantly lower than that when ultrasound alone was applied.
      Furthermore, when L-histidine, a scavenger of singlet oxygen and hydroxyl
      radical, or D-mannitol, a scavenger of hydroxyl radical, was used concurrently,
      the survival rate of tumor cells was significantly higher with L-histidine. From
      the above findings, it is surmised that tenoxicam and piroxicam increase the
      antitumor effects of ultrasound by increasing the production of singlet oxygen
      and other active oxygen species.

PMID- 10595743
TI  - Antitumor efficacy of hypothemycin, a new Ras-signaling inhibitor.
AB  - We have devised a new drug screening assay to discover anti-cancer drugs which
      inhibit Ras-mediated cellular signals, by utilizing a Ras-responsive element
      (RRE)-driven reporter gene system. We found that hypothemycin, an anti-bacterial,
      reduces RRE-dependent transcription. Treatment of tumor cells with hypothemycin
      resulted in reduced expression of Ras-inducible genes, including MMP (matrix
      metalloproteinase)-1, MMP-9, transforming growth factor-beta (TGF-beta), and
      vascular endothelial growth factor (VEGF), but not that of the constitutively
      expressed gene, MMP-2. The results of zymography demonstrated that hypothemycin
      reduced the production of MMP-9 and MMP-3, another Ras-inducible MMP, in the
      culture medium. Hypothemycin selectively inhibits anchorage-independent growth of
      Ras-transformed cells in comparison with anchorage-dependent growth. These
      findings suggest that hypothemycin inhibits Ras-mediated cellular signaling.
      Daily treatment of tumor-bearing mice with hypothemycin resulted in significant
      inhibition of tumor growth. Since MMP-1, MMP-3 and MMP-9 play important roles in
      tumor invasion and TGF-beta and VEGF are involved in tumor angiogenesis,
      hypothemycin is considered to be an example of a new class of antitumor drugs,
      whose antitumor efficacy can be at least partly attributed to inhibition of Ras
      inducible genes.

PMID- 10595745
TI  - A selective cyclooxygenase-2 inhibitor suppresses tumor growth in nude mouse
      xenografted with human head and neck squamous carcinoma cells.
AB  - The anti-tumor effect of a selective cyclooxygenase (COX)-2 inhibitor, JTE-522,
      was examined with the human head and neck squamous cell carcinoma cell line KB.
      KB cells do not produce prostaglandin (PG)-E2. In vitro, JTE-522 induced an
      increase of G1 phase-arrested cells, suppression of platelet-derived growth
      factor (PDGF) production and inhibition of telomerase activity. No cytotoxic
      effect was detected. In vivo, the growth of the tumor xenografted into nude mice
      was significantly suppressed by JTE-522. Suppression of angiogenesis at the
      periphery of the tumor, increase of G1-arrested cells and suppression of
      telomerase activity were observed, together with an increase of apoptotic cell
      death in the tumor. Immunological enhancement did not play a role. We concluded
      that the anti-tumor effect of JTE-522 was caused by anti-angiogenesis action,
      cell cycle arrest and inhibition of telomerase activity of the tumor cells. These
      combined effects might induce apoptosis.

PMID- 10595746
TI  - In vivo anti-tumor activity of a novel indolocarbazole compound, J-107088, on
      murine and human tumors transplanted into mice.
AB  - J-107088 (6-N-(1-hydroxymethyl-2-hydroxy)ethylamino-12,13-dihydro-2,10-dihydroxy-
      13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo [3,4-c]carbazole-5,7(6H)
      dione) is a derivative of NB-506, an indolocarbazole compound previously reported
      as an anti-tumor agent targeting topoisomerase I. The optimal administration
      schedule of J-107088 was found to be intermittent injections. The GID75 (75%
      growth inhibiting total dose) values of J-107088 against LX-1 lung cancer and PC
      3 prostate cancer when given by intermittent injection (twice a week for 2
      consecutive weeks) were 200 and 15 mg/m2, respectively, whereas the 10% lethal
      dose (LD10) values of J-107088 against LX-1- and PC-3-bearing mice were 578 and
      1200 mg/m2. The ratio of LD10/GID75 indicates the therapeutic window of an anti
      tumor agent. Although the ratios of doxorubicin, paclitaxel and cisplatin against
      PC-3 were <0.3, <0.5 and <0.2, J-107088 showed the widest therapeutic window
      among the anti-tumor drugs tested. J-107088 was also effective on cells that had
      acquired resistance related to P-glycoprotein. Furthermore, J-107088 was found to
      be highly effective in inhibiting proliferation of micro-metastases of tumors to
      the liver in mice. Therefore, J-107088 is considered to be a promising candidate
      as an anti-tumor drug for treatment of solid tumors in humans.

PMID- 10595747
TI  - In vivo cisplatin resistance depending upon canalicular multispecific organic
      anion transporter (cMOAT).
AB  - The in vitro sensitivities to cisplatin of AH66 and AH66F cells, a variant
      obtained from AH66 cells, were very similar, when assayed in a medium containing
      5% fetal bovine serum (FBS), whereas in the in vivo experiments AH66F cells were
      sensitive and AH66 cells were highly resistant to cisplatin. In this study, we
      examined the mechanism of the in vivo cisplatin resistance of AH66 cells. The in
      vitro cisplatin sensitivity of AH66 cells was lowered by changing FBS to 5%
      ascites fluid (ASF) in the assay medium and the sensitivity in FBS by treatment
      with buthioninesulfoximine (BSO). The sensitivity of AH66F cells was not changed
      by these treatments. Moreover, after culture in 5% ASF for 48 h, the accumulation
      of cisplatin in AH66 cells was decreased and the efflux of cisplatin from the
      cells was accelerated. The accumulation of cisplatin in AH66 cells in ASF was
      increased by pretreatment with BSO, sodium azide or probenecid. Then, we examined
      the expression of the glutathione (GSH) conjugate efflux pump family. Among them,
      only the expression of canalicular multispecific organic anion transporter
      (cMOAT) in AH66 cells was decreased by culture in FBS and enhanced by ASF. These
      results suggest that some substances contained in ASF enhanced the expression of
      cMOAT in the plasma membrane of AH66 cells and this transporter actively extruded
      cisplatin-GSH conjugate from the cells. Consequently, AH66 cells afford a
      cisplatin-resistant tumor in the host.

PMID- 10595749
TI  - Achievements in hematology in the twentieth century: an introduction.

PMID- 10595748
TI  - Preoperative clinical radioimmunodetection of pancreatic cancer by 111 In-labeled
      chimeric monoclonal antibody Nd2.
AB  - The present study was carried out with the purpose of evaluating the clinical
      usefulness of radioimmunodetection (RAID) with 111In-labeled murine/human
      chimeric monoclonal antibody, Nd2 (c-Nd2) in patients with pancreatic cancer.
      Nineteen patients suspected to have pancreatic cancer were administered
      intravenously 74 MBq/2 mg 111In-labeled c-Nd2 in 100 ml of saline containing 2%
      albumin over 30 min. A scintigram was obtained on the 3rd day after infusion by
      using single photon emission computed tomography (SPECT) imaging. Of the 14
      patients finally diagnosed as having pancreatic cancer on the basis of surgical
      specimens or progress of disease, specific focal uptake at the site of the tumor
      was detected in 12 (true positive cases), representing a sensitivity of 85.7%
      (12/14), and liver metastasis was found in one case with metastasis. Of the 5
      patients diagnosed with tumor-forming pancreatitis (TFP), 4 patients demonstrated
      true negative imaging, but one patient whose tumor demonstrated interesting
      findings in histology and immunostaining, showed false positive imaging. Of
      patients investigated for human anti-chimeric antibody (HACA) response, none
      showed HACA response, and no allergic reaction was seen in any of the patients
      administered c-Nd2. These results suggest that RAID with 11In-labeled c-Nd2 is
      useful for differential preoperative diagnosis between invasive pancreatic cancer
      and TFP.

PMID- 10595750
TI  - Cellular hematopoiesis in the twentieth century.
AB  - From work particularly In the last two decades of the century, the cell
      populations forming blood cells can now be purified and cultured clonally so that
      blood cell formation can be analyzed in vitro. A large number of specific
      regulators of this process have been identified and mass-produced in recombinant
      form. Three of these, erythropoletin, granulocyte colony-stimulating factor (G
      CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) are in
      extensive clinical use to stimulate hematopoiesis. Similar advances have
      characterized the processes by which T lymphocytes, B lymphocytes, and dendritic
      cells are formed and interact to mediate immune responses. In the last decade
      most research on blood cell formation has involved the generation of animals with
      inactivation of specific genes involved in hematopolesis. Major unsolved problems
      are the molecular control of differentiation commitment and maturation in
      hematopoietic cells, processes that need to be better understood to allow
      improvements in the management of leukemia and other disorders of hematopoiesis.

PMID- 10595751
TI  - Nutritional anemias.
AB  - Folate, vitamin B12, and iron are the subjects of active biochemical and
      molecular research so that further understanding of their metabolism in health
      and in a wide variety of Inherited and acquired diseases can be achieved. The
      roles of folate and vitamin B12 in cardiovascular and neurologic diseases and in
      neural tube defects (NTDs) will be further explored in the next decade. The
      effects of prophylactic therapy and of food fortification with the vitamins on
      these diseases remain to be established. Iron deficiency is a public health
      problem in all countries and prevention or treatment, particularly in children in
      developing countries, are major goals. The increased recent understanding of iron
      metabolism and absorption may clarify the etiology of diseases of iron metabolism
      and of dietary iron overload. Improved iron chelation therapy for transfusion
      dependent patients with refractory anemias will continue to be actively
      researched over the next decades.

PMID- 10595752
TI  - Genetic disorders of hemoglobin.
AB  - The inherited disorders of hemoglobin, the most common monogenic diseases, are
      now well understood at the molecular and cellular level, knowledge which has led
      to considerable Improvements in their control and management. Because of their
      particularly high gene frequencies in sub-Saharan Africa, the Indian
      subcontinent, and throughout Southeast Asia, the organization of their control
      and treatment provides a major challenge for the new millennium.

PMID- 10595753
TI  - Hemolytic anemia.
AB  - We entered the 20th century with only meager understanding of the erythrocyte. We
      leave this century with a relatively detailed understanding of the metabolism of
      the erythrocyte, the structure of its membrane, and the basis of genetic
      disorders that lead to its early demise in hemolytic anemia. Among the immune
      hemolytic disorders, the conquest of Rh hemolytic disease is one of the important
      clinical achievements of this century. Hereditary disorders of the membrane
      generally cause shape changes, such as spherocytosis or ovalocytosis. Paroxysmal
      nocturnal hemoglobinuria is the result of an acquired (somatic) mutation of PIG
      A, an X-linked component of the glycosylphosphatidylinositol (GPI) anchor. Red
      cell enzyme deficiencies cause hereditary nonspherocytic hemolytic anemia. The
      mutations that cause the more common of these deficiencies are now well
      understood at the DNA level. Although much progress has been made, much is still
      to be learned. In particular, management of both acquired and hereditary
      hemolytic anemias is still very unsatisfactory. Often the only decision that can
      be made is whether to perform a splenectomy. In the future it is to be hoped that
      the knowledge that has been gained about these disorders in this century will
      make available better therapy to our patients in the next.

PMID- 10595754
TI  - Blood transfusion.
AB  - Blood transfusion became a relatively safe and practicable procedure following
      the discovery in 1900 of blood groups and the realization early in the first
      World War that citrate was a safe and effective anticoagulant. Transfusion may
      elicit the formation of antibodies in the recipient due to "foreign" antigens on
      the donor's red cells, white cells, or platelets. Application of the methods of
      molecular biology has characterized the antigens concerned and the genes that
      determine them. The concept of transfusing whole blood to remedy a deficiency of
      any constituent, for example, platelets, has been superseded by the idea of
      transfusing only that component of blood which is needed. Many viruses, for
      example, hepatitis viruses and human immunodeficiency viruses, can be transmitted
      by transfusion. The high degree of success in preventing their transmission is a
      scientific triumph.

PMID- 10595755
TI  - The role of chromosome translocations in leukemogenesis.
AB  - Certain chromosome abnormalities, especially translocations, are specifically
      associated with particular subtypes of leukemia, lymphoma, and sarcomas. This
      review describes the translocations involving the AML1(CBFA2) gene on 21q22, the
      MLL gene on 11q23, and the TEL(ETV6) gene on 12p13. Abnormalities of these genes
      account for a large proportion of patients with acute lymphoblastic leukemia
      (ALL) and acute myeloid leukemia (AML). Cloning of translocation breakpoints
      results in unique diagnostic tools for fluorescence in situ hybridization (FISH)
      and molecular analysis of leukemic cells. Recent advances in understanding the
      alterations in the function of the fusion genes as compared with normal genes
      provide insights regarding new therapeutic strategies, which should lead to
      improved clinical responses with less toxicity.

PMID- 10595756
TI  - Cure of leukemia.
AB  - This century has seen remarkable progress towards the understanding and treatment
      of leukemia. The development of combination therapies of cytotoxic drugs with or
      without stem-cell transplantation has increased the cure rate of childhood acute
      lymphoblastic leukemia (ALL) to greater than 70% in many centers. However, major
      problems remain, with cure rates for adults with ALL and for other types of
      leukemia remaining much lower. Moveover, the complexity and expense of current
      therapies makes them unavailable to most individuals worldwide, while their
      toxicity makes them universally undesirable. Our challenge for the next century
      is to build on our increasing understanding of the molecular basis of leukemia to
      devise safe, cheap, and effective approaches to prevent or treat this group of
      diseases.

PMID- 10595757
TI  - The lymphomas.
AB  - The history of therapeutic advances in the lymphomas is reviewed. The initial
      studies that led to the cure of Hodgkin's disease and diffuse large B-cell
      lymphomas set a paradigm of cancer treatment broadly applicable to a number of
      malignancies. In recent times our knowledge of the biology of the Immune system
      has clarified the origin of subsets of lymphomas and provided specific targets of
      future therapeutic approaches.

PMID- 10595758
TI  - Bone marrow transplantation: a review.
AB  - Bone marrow transplantation has evolved over a period of 50 years. Laboratory
      observations and animal studies defined the essentials of transplantation
      biology. The first attempts to transfer these studies to patients met with little
      success. The definition of the complexities of the human leukocyte antigen (HLA)
      system made it possible to select compatible sibling donors and more recently
      unrelated donors. Transplantation of stem cells from marrow, blood, or cord blood
      is now the treatment of choice for a variety of hematological and genetic
      diseases. Transplantation using less toxic preparative regimens to induce mixed
      chimerism makes possible an application to autoimmune diseases. Laboratory and
      clinical research directed toward induction of tolerance and elimination of
      malignant cells point the way to a wider application of hematopoietic cell
      transplantation in the next decade.

PMID- 10595759
TI  - The hemophilias: progress and problems.
AB  - Known since the beginning of the first millenium, the hemophilias are among the
      most frequent inherited disorders of blood coagulation and definitely the most
      severe. In the 1970s, with the availability of concentrated preparations of the
      deficient coagulation factors VIII and IX and with the large-scale adoption of
      home treatment, hemophilia care became one of the most gratifying examples of
      successful secondary prevention of a chronic disease. Unfortunately, in the early
      1980s It was recognized that factor concentrates prepared from plasma pooled from
      thousands of donors transmitted the hepatitis and the human immunodeficiency
      viruses. The scientific community reacted promptly to the devastation brought
      about by hepatitis and AIDS. The last 15 years of the second millenium have
      witnessed the development of methods that applied during concentrate
      manufacturing inactivate viruses escaping the screening procedures. The adoption
      of these measures has reduced dramatically the risk of transmission of bloodborne
      infections. The production of recombinant factors and their availability for
      patient treatment epitomize progress in hemophilia care through DNA technology.
      Methods based on the polymerase chain reaction (PCR) have unraveled an array of
      gene lesions associated with hemophilia, permitting improved secondary control of
      the disease through carrier detection in women from affected families and
      prenatal termination of their affected male infants. This article will review the
      aforementioned areas of progress and discuss unresolved problems (such as
      treatment of patients with antibodies, the risk of new infectious complications,
      and the issue of secondary tumors). Hopes and expectations for further
      improvement in the third millenium and particularly the prospects of hemophilia
      cure through gene replacement therapy will also be mentioned.

PMID- 10595760
TI  - Thrombosis and anticoagulation.
AB  - Most of the major advances in thrombosis research have occurred in the last 50
      years, reflecting progress in biomedical sciences and clinical trials
      methodology. Improved understanding of the mechanisms of thrombogenesis has led
      to the discovery of a plethora of new antithrombotic agents that target many of
      the key steps in blood coagulation and platelet activation. Although most of
      these compounds are still under development, low-molecular-weight heparins
      (LMWH), glycoprotein (GP) IIb/IIIa receptor antagonists, and inhibitors of the
      adenosine diphosphate (ADP) receptor on platelets have already established their
      niche in the clinic. The vessel wall has emerged as a major player, both in
      protecting against and in promoting thrombosis, and as we approach the new
      millennium, compounds are being developed that have the potential to prevent and
      treat thrombosis by modulating vessel wall function.

PMID- 10595761
TI  - Gram-negative bacillary meningitis in adult post-neurosurgical patients.
AB  - BACKGROUND: To assess the clinical features and therapeutic outcomes of gram
      negative bacillary meningitis (GNBM) in adult postneurosurgical patients.
      METHODS: Thirty adult patients with GNBM were included in this study. Their
      clinical features, laboratory data, prognostic factors, and therapeutic outcome
      were analyzed. The patients were 22 males and 8 females, aged 17-72 years. Seven
      had community-acquired infections and 23 had nosocomial infections. Two patients
      were associated with brain abscess. RESULTS: The pathogens found in the 30 GNBM
      patients were Pseudomonas aeruginosa, Klebsiella species, Escherichia coli,
      Acinetobacter baumannii, and some rare pathogens including Citrobacter freundii,
      Serratia marcescens, Enterobacter cloacae, and Proteus mirabilis. Among these 30
      patients, 8 patients with third-generation cephalosporin-resistant GNBM were
      identified since 1994; all infections were nosocomially acquired. Appropriate
      antibiotics were given to 22 patients. Eight patients did not receive appropriate
      antibiotic therapy. All eight died. The mortality rate in those treated with
      appropriate antibiotics was 14%. CONCLUSIONS: There has been an increase of GNBM
      in postneurosurgical patients in recent years. In addition, the emergence of
      strains resistant to third-generation cephalosporins in this specific group of
      patients has also been noted in recent years, and has become a great therapeutic
      challenge. We noted many prognostic factors in postneurosurgical patients in this
      study; however, appropriate antibiotic therapy and initial consciousness level
      are the most significant ones. Therefore, in cases of postneurosurgical patients
      with nosocomially acquired GNBM, the possibility of third-generation
      cephalosporin resistance should be strongly suspected. Early initiation of
      appropriate antibiotic therapy is needed in this potentially fatal disease.

PMID- 10595762
TI  - Successful treatment of brainstem abscess with stereotactic aspiration.
AB  - BACKGROUND: Brainstem abscess is an uncommon condition associated with a high
      mortality. We report a case of brainstem abscess in a 51-year-old female with a
      pulmonary arteriovenous fistula that was cured after appropriate antibiotic
      therapy following stereotactic aspiration. The value of stereotactic aspiration
      in the management of brainstem abscess is documented with a review of the
      relevant literature. CASE REPORT: A 51-year-old female with a pulmonary
      arteriovenous fistula suffered fever, diplopia and weakness on the right side.
      Magnetic resonance (MR) imaging of the brain showed a large cystic mass with ring
      like enhancement in the brainstem. A diagnosis of brainstem abscess as a
      complication of pulmonary arteriovenous fistula was made. MR imaging-guided
      stereotactic exploration was carried out via the suboccipital transcerebellar
      approach and the pathogen of the brainstem abscess was identified. The brainstem
      abscess was cured after treatment employing antibiotics to which the pathogen was
      sensitive. CONCLUSIONS: Stereotactic aspiration is an effective procedure for
      brainstem abscesses. This procedure is less invasive than open surgery and can be
      performed even in patients in poor general condition.

PMID- 10595763
TI  - Neurosurgery of the peripheral nervous system: entrapment syndromes of the lower
      extremity.

PMID- 10595764
TI  - Transthoracic endoscopic sympathectomy in the treatment of palmar hyperhidrosis-
      with emphasis on perioperative management (1,360 case analyses).
AB  - BACKGROUND: Primary palmar hyperhidrosis (PH) is very common, and can be
      disabling. Various surgical methods for endoscopic sympathectomy have been
      advocated. We present a simple and effective method of treating PH by means of
      transthoracic endoscopic sympathectomy (TES). METHODS: From July 1994 to May
      1998, a total of 1,360 patients with hyperhidrosis palmaris underwent TES. There
      were 544 males and 816 females with a mean age of 23.1 years old (range, 5 to 60
      years). All patients were placed in a half-sitting position under single-lumen
      intubational anesthesia. We performed the ablation of the T2 ganglion using
      either a 6- or 8-mm, 0-degree thoracoscope (Karl Storz Company, Germany) RESULTS:
      In these 1,360 patients, 2,715 sympathectomies were performed. TES was usually
      accomplished within 15 min. Surgical complications were minimal: six cases of
      pneumothorax (0.44%), four cases of segmental collapse of lung (0.29%), and two
      wound infections (0.15%). There was no surgical mortality. The mean postoperative
      follow-up period was 27.8 months. A total of 1,292 patients (95%) had highly
      satisfactory results, although 1,140 patients (84%) have developed compensatory
      sweating of the trunk and lower limbs. The affected area was the axillae, back,
      abdomen, lower limbs (16%, 82%, 52%, and 78%, respectively). The recurrence rates
      of PH were 0.4% in the first year, 0.6% in the second year, and 1.1% in the third
      year. CONCLUSIONS: TES is a simple, safe, and effective method of treating PH.

PMID- 10595765
TI  - Hypertrophic inflammatory neuropathy involving bilateral brachial plexus.
AB  - BACKGROUND: The present case is an example of hypertrophic inflammatory
      neuropathy (HIN). This entity is a rare tumor-like, chronic inflammatory, focal
      or multifocal, mainly demyelinating neuropathy of unknown origin, most frequently
      involving the brachial plexus. CASE DESCRIPTION: The authors describe a 67-year
      old man presenting with a nodular mass in his right supraclavicular fossa. A
      nodular mass grossly resembling a schwannoma originating from a single nerve
      fascicle was surgically removed from the right C6 spinal nerve. Histologically,
      endoneurial edema, fibrosis, focal chronic inflammation, and extensive "onion
      bulb" formation were seen. Electron microscopy studies and immunohistochemistry
      proved that the onion bulb-forming cells were schwannian in nature and that the
      whorls of onion bulbs surrounded a generally demyelinated axon. Three months
      following surgery the patient developed acute painless paralysis of his right
      biceps brachii muscle that rapidly reversed; after that he remained
      neurologically asymptomatic. MRI revealed multiple fusiform mass lesions
      involving the brachial plexus bilaterally. Electrophysiologic studies
      demonstrated a bilateral, asymmetrical, mainly demyelinating neuropathy involving
      the brachial plexus; they failed to reveal any abnormality suggestive of
      generalized neuropathy. CONCLUSION: HIN is different from other focal tumor-like
      neuropathies and in particular from localized hypertrophic neuropathy (LHN).

PMID- 10595766
TI  - Intraoperative microdoppler monitoring for spinal dural arteriovenous fistulae.
AB  - BACKGROUND: One of the most important goals in the surgical treatment of spinal
      dural arteriovenous fistulae is complete interruption of the flow in the fistula.
      To confirm complete interruption, we use intraoperative microdoppler monitoring.
      METHODS: Three patients with spinal dural arteriovenous fistulae with
      perimedullary venous drainage underwent surgical treatment using microdoppler
      monitoring. All of them suffered from congestive myelopathy before treatment.
      Microdoppler monitoring was performed on the perimedullary draining vein to
      detect the arterial spectrum before and after the interruption of the
      arteriovenous shunt. RESULTS: In all patients, an arterial spectrum was detected
      on the dorsal perimedullary vein. Sequential monitoring demonstrated the effects
      of each surgical procedure, which included epidural coagulation of the fistulae
      or intradural ligation of the retrogradely draining radiculomedullary veins.
      After complete interruption of the fistula, the arterial spectrum disappeared
      completely. In a patient with duplicated dural arteriovenous fistulae, the
      direction of the flow of the second arteriovenous shunt could be demonstrated by
      microdoppler monitoring combined with temporary clipping. This is especially
      useful in a complex case with duplicated fistulae. In all patients, postoperative
      angiography demonstrated complete disappearance of the arteriovenous fistulae.
      The patients all showed remarkable improvement with no therapeutic morbidity.
      CONCLUSION: Intraoperative microdoppler monitoring is an easily available and
      useful technique to safely confirm complete obliteration of spinal dural
      arteriovenous fistulae.

PMID- 10595767
TI  - Cavernous hemangiomas in the cavernous sinus. Case reports.
AB  - BACKGROUND: Extra-axial cavernous hemangiomas are rare and have a propensity to
      develop within the cavernous sinus. Total removal of these vascular tumors is
      difficult due to the risk of severe intraoperative bleeding and the complicated
      neurovascular structures of the cavernous sinus. Only a small number of cases
      have been reported to be successfully totally removed. METHODS: Retrospective
      studies were done in three cases of extraaxial cavernous hemangiomas located in
      the cavernous sinus. All three patients presented with clinical symptoms common
      to other tumors located in the region, such as headache and impairment of cranial
      nerve function. Their preoperative MRI results showed significant hyperintensity
      on T2-weighted images and marked enhancement with gadolinium-DTPA that delineated
      a sharp tumor margin. RESULTS: All three patients underwent total tumor removal,
      with an uneventful postoperative course. There was no postoperative neurological
      deficit in one patient, and a complete ophthalmoplegia and diminished sensation
      in the V1 distribution in two patients. Three months after operation, follow-up
      MRI or CT scan showed no residual tumor. CONCLUSION: Surgical resection of these
      lesions was possible but difficult because of severe bleeding. Avoiding piecemeal
      removal before the main feeding arteries are interrupted can minimize
      intraoperative bleeding.

PMID- 10595768
TI  - Late hemorrhage from persistent pseudoaneurysm in vertebral artery dissection
      presenting with ischemia: case report.
AB  - BACKGROUND: Vertebral artery dissection lesions tend to resolve spontaneously,
      but abnormal findings such as aneurysmal-dilatation occasionally persist.
      However, the clinical features and pathological findings in such cases have never
      been verified. CASE DESCRIPTION: A 62-year-old man presented with left cerebellar
      infarction. Angiography showed the "pearl and string sign" in the left vertebral
      artery, and he was diagnosed as having left vertebral artery dissection. Repeated
      angiography showed persistent aneurysmal dilatation with irregular stenosis.
      Eleven years after the cerebellar infarction, the patient presented with a
      subarachnoid hemorrhage from an aneurysm of the left vertebral artery, and the
      lesion was explored via the left suboccipital approach. The vertebral artery was
      firm, making the placement of a clip impossible, so the lesion was treated by
      coating of the bleeding point. The patient died of pneumonia and hyperglycemia on
      postoperative day 15. Postmortem examination revealed an organized intramural
      hematoma, thickening of the intima, and fibrous degeneration of the media of the
      vertebral artery, a fusiform, distended thin arterial wall with intimal
      disruption at the aneurysmal dilatation, and arteriosclerosis of all cerebral
      arteries. CONCLUSION: This case indicates that persistent aneurysmal dilatation
      of a dissection is a pseudoaneurysm prone to rupture, and that healing of the
      affected vessels might be severely compromised in the presence of pathological
      conditions such as arteriosclerosis and disturbed intraluminal blood flow in the
      dissected lesions.

PMID- 10595769
TI  - An unusual fatal complication of low basilar trunk aneurysm surgery: isolated
      prepontine tension pneumocephalus.
AB  - OBJECTIVE: A case of postoperative tension pneumocephalus after low basilar trunk
      aneurysm clipping is presented. To our knowledge, this is the first case of
      isolated prepontine tension pneumocephalus. BACKGROUND: A 63-year-old woman was
      admitted for repair of a basilar aneurysm that had caused a subarachnoid
      hemorrhage. She was cooperative and partially oriented. According to Hunt & Hess
      classification, she was considered Grade III. METHOD: The aneurysm was clipped,
      using a right lateral suboccipital craniectomy with the patient in the sitting
      position. In the early postoperative period, she had no new neurological deficit.
      However, 2 hours later the patient became lethargic and unresponsive to verbal
      commands. Emergency CT scan revealed an isolated prepontine tension
      pneumocephalus with prominent posterior displacement of the pons. She was
      immediately taken back to surgery. Upon incision of the dura mater, air could be
      heard escaping under pressure from the posterior fossa cavity. The clip was in
      its proper position and all arteries were patent. Spontaneous respiration and
      pupil reflexes returned soon after surgery, but she remained unconscious and died
      3 days later. CONCLUSION: We believe that this death was directly attributable to
      the tension pneumocephalus and the distortion of the pons. Postoperative
      prepontine tension pneumocephalus, although this is an extremely rare condition,
      should be considered if a patient deteriorates after basilar aneurysm surgery in
      the sitting position.

PMID- 10595771
TI  - Subcranial fronto-orbito-nasal approach for ethmoidal cancers surgical techniques
      and results.
AB  - BACKGROUND: The authors report their experience with the subfronto-orbito-nasal
      approach (SFON) for the treatment of 30 patients suffering from ethmoidal cancers
      over the past 3 years. The advantages and pitfalls of this technique are
      described and compared with other classic approaches. METHODS: Among 156 patients
      suffering from ethmoidal cancers and treated between January 1984 and January
      1998, 30 patients were operated on using the SFON approach during the past 3
      years. There were 27 males and 3 females, ranging in age from 15 to 77 years.
      Histologic composition of the lesions was as follows: 15 adenocarcinomas, 6
      esthesioneuroblastomas, 3 melanomas, 2 epidermoid carcinomas, 1 nondifferentiated
      carcinoma, 1 neuroendocrine carcinoma, 1 villous carcinoma, and 1 cystic adenoid
      carcinoma (cylindroma). According to the authors' classification, 7% were T1, 6%
      T2, 22% T3, 38.5% T4a, and 26.5% T4b. All patients were operated on through a
      SFON approach, followed by removal of the tumor and reconstruction of the skull
      base with a pericranial flap. RESULTS: Since the mean follow-up was of short
      duration (12 months, ranging from 3 to 29 months), significant carcinologic
      results could not be obtained. However, a detailed analysis of the surgical
      procedure was performed. No patient died or had major complications related to
      the SFON approach. One cerebrospinal fluid (CSF) fistula and four oculomotricity
      dysfunctions were observed. Definitive anosmia was reported in all cases.
      CONCLUSION: The advantages of the procedure include a wide exposure of the
      anterior skull base through a limited approach, the possibility of modifying the
      approach according to the size and location of the lesion, total resection of
      tumors, simplified skull base reconstruction technique, and reduction of
      postoperative confusion and hospital stay.

PMID- 10595770
TI  - Cerebrovascular biomodelling: a technical note.
AB  - BACKGROUND: Recently computed tomographic angiography (CTA) and MR angiography
      (MRA) have been used to image cerebrovascular structures. Although CTA and MRA
      are accurate and sensitive imaging modalities, limitations have been identified
      in relation to image interpretation. Stereolithographic (SL) biomodelling is a
      new technology that allows three-dimensional (3D) CT and MR data to be used to
      accurately manufacture solid plastic replicas of anatomical structures. A
      prospective trial of SL biomodelling in cerebrovascular surgery has been
      performed to investigate the feasibility and clinical utility of this new display
      medium. METHODS: Fifteen patients with cerebral aneurysms and 1 patient with a
      cerebral arteriovenous malformation (AVM) were selected. 3D CT and/or MR
      angiograms were acquired and 19 solid anatomical biomodels manufactured using the
      rapid prototyping technology of stereolithography. The biomodels were used for
      patient education, diagnosis, operative planning and surgical navigation.
      RESULTS: The biomodels replicated the CTA and MRA source data. The accuracy of
      one biomodel was verified by comparison with a post mortem specimen, which
      corresponded exactly in the x and y planes but differed by 2 mm in the z plane.
      The ability to closely study an overview of complex cerebrovascular anatomy from
      any perspective on a solid biomodel was reported to enhance the surgeon's
      understanding, particularly when conventional images were equivocal.
      Cerebrovascular biomodels were found to be useful when positioning the patient's
      head for surgery, for selecting the best aneurysm clip and for the simulation of
      clipping. Patient informed consent was anecdotally improved. Disadvantages of the
      technology were the cost and manufacturing time. CONCLUSIONS: Cerebrovascular
      biomodelling may have utility in complex cases or when the standard imaging is
      felt to be equivocal.

PMID- 10595772
TI  - Anterior cervical micro-dural repair of cerebrospinal fluid fistula after surgery
      for ossification of the posterior longitudinal ligament. Technical note.
AB  - BACKGROUND: Cerebrospinal fluid (CSF) fistulas may occur during anterior cervical
      surgery performed for the resection of ossification of the posterior longitudinal
      ligament (OPLL), as OPLL occasionally erodes to and through the dura. These
      fistulas have been variously managed with gelfoam, dural substitutes sutured in
      place, fibrin glue, lumbar drains, and lumboperitoneal shunts. However, more
      adequate dural repair is now feasible with the 1.4-mm microdural titanium
      stapler. METHODS: A 59-year-old female with OPLL and moderate to severe
      myelopathy (Nurick Grade IV) had a C3-C7 anterior corpectomy with fusion using
      Orion plates followed by a C3-T1 posterior wiring and fusion with halo
      application. During the anterior approach, a 5-mm CSF fistula at C4-C5 was
      directly repaired under the operating microscope using a 1.4-mm microdural
      stapler, bovine pericardial graft, and fibrin glue. Immediately postoperatively,
      a lumboperitoneal shunt was also placed. RESULTS: Postoperatively, her myelopathy
      improved to a mild to moderate level (Nurick Grade II). Her acute left deltoid
      plegia resolved within 3 months. CONCLUSIONS: The 1.4-mm microdural stapler makes
      "watertight" closure of anterior cervical CSF fistulas more feasible.

PMID- 10595773
TI  - The stereotactic volumetric information: its role in two-step resection of
      brainstem and thalamic giant tumor. Report of three cases and technical note.
AB  - BACKGROUND: A compact intracerebral tumoral lesion is usually considered to be
      completely resectable. Nevertheless, radical resection of a huge lesion located
      in a critical area may damage the surrounding compressed brain tissue. In cases
      with a good prognosis, a two-step removal appears to be a safer strategy.
      METHODS: In three cases, two with huge brain stem lesions and one with a thalamic
      lesion, a two-step volumetric stereotactic resection was planned. This strategy
      allowed us to evaluate the amount of tumor to be removed during the first
      procedure and to have, during the second operation, an exact definition of the
      reduced mass with regard to the scar tissue and postoperative adhesions.
      Furthermore, we avoided significant shifting of the cerebral structures during
      both procedures. RESULTS: There was a very good final recovery in the cases with
      brain stem lesions and a minimal deficit in the patient with the thalamic lesion.
      The patient with a mesencephalic lesion remained comatose for almost 2 days after
      the first procedure, confirming our fears about too radical a one-step resection.
      CONCLUSIONS: We think that by using current techniques, it is possible to remove
      a well circumscribed lesion regardless of its position. This is probably easier
      with giant lesions where a safe trajectory can be planned. In these cases, with
      lesions located in very critical areas but with a good prognosis, a two-step
      resection appears to be a good option.

PMID- 10595774
TI  - Reconstruction of the temporalis muscle for pterional and cranio-orbital
      craniotomies.
AB  - BACKGROUND: Atrophy of the temporalis muscle can result after dissection and
      reattachment with pterional and cranio-orbital craniotomies. To prevent this
      sequel, a number of surgical modifications have been used to preserve the deep
      temporal nerve and artery, and also to allow for reconstruction of the temporalis
      muscle with minimal damage. In this report another surgical modification for
      reconstruction of the temporalis muscle is described that can be used in both
      pterional and cranio-orbital craniotomies. METHODS: The subperiosteum of the
      temporalis muscle is dissected sharply away from the temporal fossa preserving
      the deep temporal arteries and nerves. After the intracranial procedure, the bone
      flap is resecured and attached to the bone, and then several small holes are made
      along the superior temporal line, to which the temporalis muscle is directly
      reattached with sutures. RESULTS: We have used the technique described in over
      100 cases without related cosmetic or temporalis atrophy. With this technique,
      muscle tension has been maintained with good stabilization and cosmetic
      appearance. CONCLUSION: In our technique, the temporalis muscle is anatomically
      reconstructed to the bone with easy attachment to the superior temporal line. The
      muscle tension is maintained with good stabilization and cosmetic appearance.

PMID- 10595775
TI  - A quick, simple, and inexpensive method of surgical navigation for superficial
      intracranial targets.

PMID- 10595777
TI  - Lessons from Romania.

PMID- 10595776
TI  - Sudden headache with pituitary infarction.

PMID- 10595778
TI  - Relationship of cerebral aneurysms and medial raphes.

PMID- 10595779
TI  - Omental transposition.

PMID- 10595780
TI  - Nevoid basal cell carcinoma (Gorlin) syndrome: unanswered issues.

PMID- 10595781
TI  - Role of carbohydrate on angiostatin in the treatment of cancer.

PMID- 10595782
TI  - Prothrombotic mechanisms in primary pulmonary hypertension.
AB  - Pulmonary hypertensive states are associated with an increased propensity for
      thrombosis. This prothrombotic state appears to be a result of pulmonary
      hypertension promoting endothelial dysfunction and altered hemodynamic status. In
      some patients with primary pulmonary hypertension, however, a primary
      prothrombotic state directly induces the pulmonary hypertensive state. This
      review focuses on the evidence for the association between prothrombotic states,
      especially increased platelet activation, and the development of pulmonary
      hypertension.

PMID- 10595783
TI  - Use of the plasminogen activation system by microorganisms.
AB  - The use of host-derived PAS components by invasive bacteria is an increasingly
      recognized mechanism for acquisition of extracellular proteolytic activity. This
      overview summarizes the pertinent contributions to this field and is divided into
      three parts: (1) the PAS, (2) the interaction of bacteria that produce their own
      plasminogen activators with the host's PAS, and (3) the interaction of bacteria
      that do not produce their own plasminogen activators but use plasminogen
      activators supplied by the host. The significance of these mechanisms in relation
      to the invasive potentials of the various organisms is discussed.

PMID- 10595784
TI  - Novel biologic approaches for the treatment of AIDS.

PMID- 10595785
TI  - Increase in nucleoli after x-radiation of fibroblasts of patients with Gorlin
      syndrome.
AB  - Gorlin syndrome (GS) is an autosomal dominant disorder in which patients are
      abnormally susceptible to ionizing radiation with radiotherapeutic doses.
      Radiogenic basal cell carcinomas may develop with a short latent period in
      patients. The mechanisms underlying the abnormal radiosusceptibility of cells in
      patients with GS has not been well characterized. In this study we report an
      increase in the number of nucleoli in fibroblast cells from 3 patients with GS
      after x-radiation. In GS fibroblasts, the increase in nucleolus number
      concomitant with the increase of ribonucleoprotein immunoreactive aggregates
      within the nucleus was observed after x-radiation, whereas significant change was
      not found in normal fibroblasts derived from healthy donors. This increase
      disappeared when cells were cultured with the RNA synthesis inhibitor actinomycin
      D after x-radiation but not when they were cultured with cycloheximide or
      aphydicolin, which are protein and DNA synthesis inhibitors, respectively.
      Ultraviolet exposure did not induce remarkable changes in the GS nucleoli. Thus
      the increase in nucleoli was induced after x-radiation of GS fibroblasts, and
      this increase seemed to be related to RNA synthesis metabolism.

PMID- 10595786
TI  - Beta-carotene and lycopene, but not lutein, supplementation changes the plasma
      fatty acid profile of healthy male non-smokers.
AB  - Polyunsaturated fatty acids (PUFAs) are highly susceptible to free radical
      attack. In vitro studies of carotenoids--including beta-carotene, lycopene, and
      lutein--have shown them to be effective quenchers of singlet oxygen, to have good
      radical-trapping properties, or to be effective peroxyl radical scavengers (or to
      have a combination of these qualities). If carotenoids act as antioxidants in
      vivo, then arguably, plasma PUFA should be conserved. The objective of the
      current study was to answer the question "Does supplementation with beta
      carotene, lycopene, or lutein, at dietarily achievable levels, over a time period
      known to significantly increase circulating carote concentrations, lead to an
      observable increase in fasting plasma PUFA?" The normal diets of human volunteers
      were supplemented with either 15 mg/day beta-carotene (n = 25), lycopene (n =
      23), or lutein (n = 21) for 26 days in three independent double-blind, placebo
      controlled supplementation studies. Supplementation with beta-carotene increased
      plasma linoleic acid but left the polyunsaturated:saturated (P:S) fatty acid
      ratio unaltered. In contrast, supplementation with lycopene reduced linoleic
      acid, which resulted in a large decrease in the P:S ratio. Lutein supplementation
      had no effect. It was concluded that neither beta-carotene, lycopene, nor lutein
      supplementation engender antioxidant effects that lead to the widespread general
      conservation of plasma PUFAs. Beta-carotene and lycopene supplementation appear
      to interact with the metabolism of linoleic acid, the "essential" fatty acid,
      resulting in either an increase (beta-carotene) or decrease (lycopene) in its
      plasma concentration. Alterations in plasma 18:2 or P:S ratios could ultimately
      lead to changes in tissue cellular membrane composition and hence to alterations
      in membrane fluidity and cell-surface protein expression.

PMID- 10595787
TI  - Detection of soluble alpha1 integrin in human serum.
AB  - An enzyme-linked immunosorbent assay (ELISA) for the detection and quantitation
      of soluble alpha1beta1 integrins (salpha1) in human serum samples was developed.
      Solid phase-bound anti-alpha1 integrin monoclonal antibody (mAb) TS2/7 was used
      to capture salpha1, and mAb 1B3.1 was used to detect the immobilized integrin. An
      extract of human placenta (PE) containing 340 ng/mL of VLA-1 molecules served as
      a positive control, and serum samples from normal donors and patients were
      assayed. Optimal binding of anti-alpha1 integrin mAb 1B3.1, expressed as specific
      optical density (OD), was obtained when a 5 microng/mL solution of anti-alpha1
      integrin "capture" mAb TS2/7 was immobilized to the wells and the PE was added.
      Solutions of albumin or collagen, in contrast, did not result in binding,
      confirming the specificity of the assay for sal. Furthermore, the specific OD of
      the wells correlated directly with the concentration of PE. A concentration of
      salpha1 above that of a 1:100 dilution of PE--that is, >3.4 ng/mL of integrin, in
      which the intra-assay correlation of variance was <5.7%, was found in 5 of 8, 3
      of 8, and 6 of 9 serum samples from normal individuals, patients with connective
      tissue diseases (CTD), and patients with liver diseases (LD), respectively. These
      results suggest, for the first time, that salpha1 are present in healthy and
      diseased human serum.

PMID- 10595788
TI  - Preoperative screening for von Willebrand disease type 1: low yield and limited
      ability to predict bleeding.
AB  - Type 1 von Willebrand disease (vWd) is the most common hereditary bleeding
      disorder. The objective of this study was to measure the von Willebrand factor
      antigen (vWf:Ag) in a large cohort of patients who underwent surgery to assess
      the role of a new rapid immunoassay in a screening procedure for vWd in
      preoperative conditions. We studied 832 consecutive patients (540 children, 292
      adults) referred to the surgical departments. For each patient we determined the
      vWf:Ag level with two different assays, an enzyme-linked immunosorbent assay
      (ELISA)(Asserachrom vWf:Ag; Diagnostica Stago, France) and a rapid immunoassay
      (Liatest vWf:Ag; Diagnostica Stago). Using the reference test, we found 30 of 832
      patients with a vWf:Ag value below the lower limits (21 U/dL to 46 U/dL). The
      coefficient of correlation between the two tests was 0.77 (P = .001). When
      receiver operating characteristic curves were used, the cutoff value calculated
      to detect vWf:Ag defect with the rapid assay was 68.5 U/dL, leading to 0.36%
      false negatives and 9.7% false positives. Thus the rapid immunoassay appears to
      be a useful and easy method that is adaptable to urgent situations. Among the 30
      patients with low values in ELISA, 8 had personal or familial bleeding history.
      Repeat blood samples confirmed the diagnosis of vWd in 5 cases, leading to a
      prevalence of vWd type 1 of 0.6%. However, in our series the absence of severe
      bleeding complications raises the question of the screening and the management of
      patients bearing a type 1 Willebrand disease during surgery.

PMID- 10595789
TI  - Occurrence of anti-prothrombin and anti-beta2-glycoprotein I antibodies in
      patients with history of thrombosis.
AB  - New evidence indicates that antibodies to beta2-glycoprotein I (anti-beta2GPI) or
      to human prothrombin (anti-II)(or to both of these) are specific markers of the
      antiphospholipid syndrome (APS). They have been mainly associated with thrombotic
      complications in patients with APS. However, some studies have reported that
      elevated levels of anti-II, but not of anfi-beta2GPI, imply a risk of venous
      thrombosis (VT) or arterial thrombosis (AT) in subjects with no previous
      thrombosis and no antiphospholipid antibodies (aPL) by ELISA. The present study
      Included 180 patients with a history of thrombosis, 83 of them without aPL (group
      I) and the remaining 97 diagnosed as having APS (group II). Anti-beta2GPI was
      found in only 1 of the 83 patients from group I but was found in approximately
      50% of those from group II (P < .0001). In contrast, positive anti-II was
      detected with a high prevalence in patients from group I (VT, 22.6%; AT, 26.7%)
      and in those from group II (VT, 37.5%; AT, 14.6%). No statistical differences
      were found in the prevalence of anti-II between the two groups of patients. On
      the other hand, such a difference was significant when compared with results in a
      normal group (1/67, 1.4%, P < .0001). These data Indicate that anti-II occurs
      frequently in patients with previous thrombosis either with or without lupus
      anticoagulant activity. Accordingly, testing of anti-II might be clinically
      useful in the evaluation for thrombophilla.

PMID- 10595790
TI  - Dopamine enhances the phosphaturic effect of PTH during acute respiratory
      alkalosis.
AB  - The phosphaturic response to parathyroid hormone (PTH) is blunted during acute
      respiratory alkalosis. The objective of the present study was to determine the
      effect of dopamine on the blunted phosphaturic response to PTH during acute
      respiratory alkalosis. The phosphaturic response to PTH was determined in
      thyroparathyroidectomized (TPTX) normocapnic and respiratory alkalotic rats in
      the absence and presence of the infusion of exogenous dopamine (25 microg/kg/min)
      or of 3,4-dihydroxyphenylalanine (L-DOPA, 250 microg/kg/min) to increase
      endogenous dopamine synthesis. In normocapnic rats, PTH infusion (33 U/kg plus 1
      U/kg/min) significantly increased the fractional excretion of phosphate (FE(Pi)),
      from 1.5%+/-0.5% to 28.4%+/-4.0%, (deltaFE(Pi) 26.9%+/-4.1%, n = 11, P<.05); in
      respiratory alkalotic rats, the increase was from 0.4%+/-0.1% to 11.4%+/-1.7%
      (deltaFE(Pi) 11.0%+/-1.8%, n = 13, P<.05). However, the phosphaturic response to
      PTH was attenuated in respiratory alkalotic rats (deltaFE(Pi) 26.9%+/-4.1% vs
      11.0%+/-1.9%, P<.05). In normocapnic rats, in the presence of dopamine or L-DOPA
      infusions, PTH infusion significantly increased the FE(Pi) from 6.1%+/-2.3% to
      33.4%+/-8.0% (deltaFE(Pi) 27.3%+/-7.0%, n = 5) and from 3.2%+/-0.6% to 32.5%+/
      3.3% (deltaFE(Pi) 29.3%+/-3.2%, n = 7), respectively. In respiratory alkalotic
      rats, in the presence of dopamine infusion, PTH significantly increased the
      FE(Pi), from 0.6%+/-0.2% to 19.3%+/-3.3% (deltaFE(Pi) 18.7%+/-3.3%, n = 6); in
      the presence of L-DOPA infusion it increased from 1.0%+/-0.3% to 20.5%+/-2.8%
      (deltaFE(Pi) 19.5%+/-2.9%, n = 8, P<.05 as compared with PTH alone). Thus the
      phosphaturic effect of PTH that was attenuated in respiratory alkalotic rats was
      enhanced by stimulation of endogenous dopamine synthesis by the infusion of L
      DOPA.

PMID- 10595791
TI  - Interleukin-6 production by endothelial cells after infection with influenza
      virus and cytomegalovirus.
AB  - Inflammation plays a role in the pathogenesis of cardiovascular diseases. Viruses
      may be a cause of chronic inflammation, and both influenza virus and CMV have
      been associated with cardiovascular diseases. IL-6, a proinflammatory cytokine
      with antiviral effects, has a pivotal role in the immune response, and under
      pathologic conditions, prohemostatic effects of IL-6 could lead to pathologic
      thrombosis and vascular plaque instability. To investigate this role of IL-6, we
      measured the production of IL-6 by human endothelial cells after infection with
      influenza virus and CMV. After infection with influenza virus or CMV, IL-6
      release into the medium increased (1756.5+/-156.9 pg/mL vs 284.4+/-55.3 pg/mL; P
      < .001) for influenza-Infected compared with uninfected cells after 36 hours'
      incubation. Ultracentrifuged influenza virus supernatants, heat-inactivated
      virus, and purified hemagglutinin were not able to elicit IL-6 synthesis by human
      endothelial cells. These findings show that CMV and influenza virus are capable
      of modulating the in vitro production of IL-6, a cytokine involved in vascular
      inflammation, by human endothelial cells.

PMID- 10595792
TI  - Estimation of cumulative lead releases (lead flux) from the maternal skeleton
      during pregnancy and lactation.
AB  - Recent longitudinal studies with human subjects and nonhuman primates using high
      precision stable lead isotopes show that lead is mobilized from the maternal
      skeleton during pregnancy and the postpartum period. We have now calculated the
      cumulative lead release (lead flux in micrograms) mobilized from the skeleton
      during these periods by means of analysis of monthly PbB samples from recent
      immigrants to Australia. Results included a statistically significant inverse
      relationship (P = .006) between the lead flux and the time of conception after
      the arrival of the subjects in Australia. By using an area-under-the-curve
      approach to determine the added lead inputs to blood during pregnancy and nursing
      versus a baseline value, the net lead release to blood varied from 0.9 to 10.1
      microg/d, which is equivalent to 0.3 to 4.03 mg of lead. With group PbB
      concentrations usually less than 3 microg/dL, the observed releases imply a high
      skeletal turnover of greater than 10% and possibly greater than 30% in some
      subjects during pregnancy and the postpartum period. These elevated rates in some
      subjects may partly arise from low daily calcium intakes, being one half to two
      thirds of that of recommended daily requirements. The lead flux calculated from a
      cumulative approach was compared with other approaches: first-order kinetics,
      bone turnover, bone x-ray fluorescence measurements, and the International
      Commission for Radiological Protection lead pharmacokinetic model. Calculated
      lead releases and remaining bone lead concentrations would likely not be
      detectable by current x-ray fluorescence methods.

PMID- 10595793
TI  - Hemorrhage and renal ischemia-reperfusion upregulates the epidermal growth factor
      receptor in rabbit duodenum.
AB  - To study the role of EGF-R in small intestinal adaptation to hemorrhage and I/R,
      anesthetized rabbits were implanted aseptically with arterial and venous
      catheters and bilateral renal artery Doppler flow probes and silastic occluders
      and allowed to recover. Rabbits were then randomly assigned to one of six groups:
      time control; hemorrhage (22.5 mL/kg) and 2.5 hours of renal occlusion
      (hemorrhage plus I/R); hemorrhage plus I/R and 2:1 LRS resuscitation; hemorrhage
      plus I/R and 3:1 LRS resuscitation; hemorrhage alone; or I/R alone. Rabbits were
      killed 48 hours after hemorrhage, and a section of duodenum was collected for
      analysis. Hemorrhage plus I/R induced a 2.5-fold increase in EGF-R tyrosine
      kinase activity compared with that found in the control group (P < .05), and this
      effect was not modified by either LRS resuscitation regimen. This increased
      activity was associated with similar Increases in EGF-R protein concentrations
      and approximately a 50% increase in EGF-R messenger (m)RNA levels compared with
      levels found in the control group. Further analysis of possible regulatory
      mechanisms for the increased EGF-R expression after hemorrhage plus I/R detected
      higher levels of EGF-R phosphorylation compared with those found in the control
      group but no significant increases in transforming growth factor-alpha mRNA
      levels. These data, coupled with a significant increase in duodenal
      thlobarbituric acid-reactive substance concentrations from rabbits in the
      hemorrhage plus I/R group, support the hypothesis that tyrosine kinase signal
      transduction pathways involving the EGF-R are activated in the small intestine
      after hemorrhage, renal I/R, or both, and this process may be mediated, at least
      in part, by oxidant stress.

PMID- 10595794
TI  - Attenuation of cisplatin-induced acute renal failure is associated with less
      apoptotic cell death.
AB  - To clarify the pathophysiologic role of apoptosis in acute renal failure (ARF),
      we examined whether the attenuation of cisplatin-induced ARF is associated with
      the change in the degree of apoptotic cell death. The administration of cisplatin
      (CDDP) (6 mg/kg body weight) in rats induced ARF at day 5, as manifested by a
      significant increase in serum creatinine (Scr) and tubular damage. CDDP-induced
      apoptotic cell death was confirmed by electron microscopic examination, agarose
      gel electrophoresis, and increased cells positive for TaT-mediated deoxyuridine
      triphosphate nick-end labeling (TUNEL) in the outer medulla of the kidney.
      Treatment with dimethylthiourea (DMTU)--a scavenger of hydroxyl radicals--or
      glycine abrogated CDDP-induced increases in Scr, the tubular damage score, and
      the number of TUNEL-positive cells. Pretreatment with uranyl acetate (UA) induced
      a significant expression of Bcl-2 in the kidney and ameliorated CDDP-induced
      increases in Scr, the tubular damage score, and TUNEL-positive cells in the outer
      stripe of the outer medulla. Our findings indicate (1) that the attenuation of
      CDDP-induced ARF was associated with less apoptotic cell death and (2) that the
      induction of the anti-apoptotic protein Bcl-2 attenuated apoptosis and tubular
      damage. Our results suggest that apoptotic cell death may play an important role
      in the development of cisplatin-induced ARF.

PMID- 10595796
TI  - A rack of bifid ribs.

PMID- 10595795
TI  - Synergy between thrombin and serotonin in inducing vascular smooth muscle cell
      proliferation.
AB  - Previous studies have indicated that apart from playing an important role in
      hemostasis and thrombosis, thrombin may also contribute to the development of
      postangioplasty restenosis caused by the stimulation of vascular smooth muscle
      cell (VSMC) proliferation. Because thrombin generation in vivo is accompanied by
      platelet activation and release of smooth muscle cell (SMC) growth factors such
      as serotonin, we examined the possible interaction between these two compounds on
      VSMC proliferation. Thrombin (0.01 to 100 nmol/L), thrombin receptor-activating
      peptide (0.1 to 1000 micromol/L), and serotonin (5HT; 0.1 to 1000 micromol/L)
      increased tritiated thymidine incorporation into the DNA of canine aortic VSMCs
      in a dose-dependent manner. When thrombin and 5HT were added together at sub
      threshold concentrations, they acted synergistically in inducing tritiated
      thymidine incorporation. These findings were paralleled by a 90%+/-5% increase in
      the cell number at 48 hours, as compared with a 37%+/-2% increase with 50
      micromol/L serotonin and a 13%+/-3% increase with 0.1 nmol/L thrombin. We also
      demonstrated that a brief exposure to thrombin (1 hour) is sufficient to show its
      potentiating effect on serotonin. The mitogenic effect of serotonin and its
      synergistic interaction with thrombin on VSMC proliferation was abolished by
      serotonin type 2 receptor antagonist LY281067. Similarly, gamma-hirudin--a direct
      thrombin inhibitor--blocked the mitogenic effect of thrombin and its synergistic
      interaction with serotonin. When LY281067 and gamma-hirudin were used together,
      they abolished the mitogenic effects of both the agonists. Because clot-bound
      active thrombin can escape inactivation by anti-thrombin, this thrombin may
      potentiate the mitogenic effect of serotonin and keep the SMCs in a proliferative
      state for a long period of time. These findings support the use of 5HT2 receptor
      antagonists in combination with thrombin inhibitors in the prevention of SMC
      proliferation after coronary angioplasty.

PMID- 10595797
TI  - Use of meningococcal vaccine in college freshmen reconsidered.

PMID- 10595798
TI  - Communicating with plan members by e-mail.

PMID- 10595799
TI  - Developing an immunization program.

PMID- 10595800
TI  - New drug overview. Doxercalciferol.

PMID- 10595801
TI  - Importance of documenting your services.

PMID- 10595802
TI  - Novel oral fluoropyrimidines in the treatment of metastatic colorectal cancer.
AB  - The evolution of and rationale for fluorouracil-based strategies in the treatment
      of metastatic colorectal cancer are discussed, and the role of the new oral
      fluoropyrimidines is described. Although fluorouracil is one of the most widely
      used drugs in the United States for colorectal, head and neck, bladder, and
      breast cancer, response rates and survival times have been disappointing.
      Dihydropyrimidine dehydrogenase (DPD), a rate-limiting enzyme in the catabolism
      of fluorouracil, indirectly determines the drug's anticancer efficacy by
      regulating the availability of fluorouracil for anabolism. Recently,
      investigators have identified at least five compounds -capecitabine, UFT (tegafur
      plus uracil), eniluracil, S-1, and BOF-A2-that inhibit, destroy, inactivate, or
      bypass DPD's activity. Capecitabine, a prodrug of fluorouracil, circumvents DPD.
      UFT, S-1, and BOF-A2 contain prodrugs of fluorouracil in combination with
      compounds that alter DPD's activity. Fluorouracil must be administered in
      combination with eniluracil, an inactivator of DPD. These compounds, classified
      as fluoropyrimidines, can be administered orally. Oral fluoropyrimidines appear
      to be at least as active against metastatic colorectal cancer as conventionally
      administered intravenous fluorouracil, with significantly less toxicity, improved
      quality of life, and less expense. New oral fluoropyrimidines may ultimately
      provide enhanced antitumor activity to fluorouracil-containing regimens for
      advanced colorectal cancer.

PMID- 10595803
TI  - ASHP survey of ambulatory care responsibilities of pharmacists in managed care
      and integrated health systems--1999.
AB  - The results of a 1999 national survey of the ambulatory care responsibilities of
      pharmacists in managed care organizations (MCOs) and integrated health systems
      are reported and compared with the results of a similar survey conducted in 1997.
      Four hundred MCOs and integrated health systems participated in the telephone
      survey. The survey elicited data about organizational structure and pharmacist
      functions in the ambulatory care environment. Survey recipients were asked about
      24 specific ambulatory pharmacist functions. The performance of functions was
      related to five "enabling" factors: pharmacists on interdisciplinary teams,
      automated dispensing systems, integrated electronic medical records, and "very
      supportive" medical staff and senior management. Thirteen functions were reported
      to be routine activities for more than 50% of the respondents, compared with nine
      functions in 1997. The top four functions-using pharmacoeconomic data to make
      formulary decisions, conducting medication management programs, tracking adverse
      drug reactions, and providing written information with each new prescription-were
      performed in 75% or more of organizations. Some 15-18% of respondents indicated
      they would add specialized pharmacy-managed clinics, services to determine
      patient use of herbal products and dietary supplements, and Internet prescription
      services within 12 months, suggesting this expansion is likely to continue.
      Enabling factors supported expansion. Two clusters of functions were identified
      that related to either population-focused or patient-focused activities, and
      these were supported differentially by enabling factors. Group-model and staff
      model HMOs had the most enabling factors and the greatest scope of pharmacist
      functions. Independent practice associations had fewer enabling factors and a
      different mix of pharmacist functions, with an emphasis on population-focused
      functions, suggesting that a second model of ambulatory care pharmacist activity
      may be emerging. Ambulatory care functions of pharmacists in integrated health
      system settings have expanded broadly since 1997.

PMID- 10595804
TI  - Practical, reliable, comprehensive method for characterizing pharmacists'
      clinical activities.
AB  - A method for rating the value of pharmacists' clinical services was studied. An
      instrument was developed to measure the severity of medication errors and the
      value of pharmacists' clinical interventions. Pharmacists at a hospital pharmacy
      department used the instrument at the time they made an intervention. A single
      pharmacist reviewed and adjusted the scores assigned by the pharmacist who made
      the intervention. An expert panel consisting of two clinical pharmacists and two
      physicians also scored all the interventions using the same instrument. All
      rankings were compared using kappa (kappa) and weighted kappa statistics, and
      symmetry tests were applied to examine whether specific raters consistently rated
      higher or lower than other raters. Data were extracted from the pharmacy
      department's intervention database to rate 300 interventions. Agreement between
      the raters was substantial, both overall and for each dimension individually.
      However, the physicians rated severity of error and value of service lower than
      their pharmacist counterparts. The study indicated that severity of error and
      value of service are clearly related, but not linearly. Services can be
      identified as high value even when there are no prescribing errors. Pharmacists
      found the instrument usable and practical. A literature-based instrument for
      simultaneously assessing the severity of errors in medication orders and the
      value of pharmacists' interventions was constructed, tested in a hospital, and
      determined to be reliable.

PMID- 10595805
TI  - Permeability of nitrile rubber, latex, polyurethane, and neoprene gloves to 18
      antineoplastic drugs.
AB  - The permeability of four glove materials to various antineoplastic drugs was
      studied. Eighteen antineoplastic drugs posing potential health hazards to
      handlers were prepared at the highest concentrations normally encountered by
      hospital personnel. Four glove materials-nitrile rubber, latex, polyurethane, and
      neoprene-were exposed to the drugs for 30, 60, 90, and 120 minutes. Glove
      thickness was measured with an electronic digital caliper. Random samples of
      material were selected from the glove fingertips, and triplicate samples were
      tested for each drug at each interval. For a majority of the drugs, a bacterial
      mutagenicity assay was used to measure the amount of drug (if any) that permeated
      the material. High-performance liquid chromatography was used for drugs not
      tested with the bacterial assay. The nitrile gloves were the thinnest (0.12 mm),
      and the latex gloves were the thickest (0.18 mm). The four materials were
      generally impermeable to each drug. One sample of the nitrile gloves appeared to
      have a defect, allowing >5% of the drug solution to pass through at 30 minutes.
      One sample each of the latex, polyurethane, and neoprene gloves demonstrated
      minimal permeability (< or =1%): One latex glove sample was permeated by
      carmustine, and paclitaxel permeated one sample each of the polyurethane and
      neoprene materials. Nitrile rubber, latex, polyurethane, and neoprene gloves were
      impermeable to 18 antineoplastic drugs in most, but not all, cases.

PMID- 10595806
TI  - 1999 ASHP National Residency Preceptors Conference: mentoring for excellence.

PMID- 10595807
TI  - Transitions in pharmacy practice, part 4: can a leopard change its spots?
AB  - The personal and social characteristics of pharmacy practitioners that predispose
      them to reacting in a certain way to a change in practice are examined.
      Individuals tend to choose vocations they perceive to be a match with their
      personality. Studies suggest a dominant personality type among pharmacists
      characterized by a strong sense of responsibility, conscientiousness,
      practicality, logic, and, in about 20% of practitioners, fear of interpersonal
      communication. As the profession seeks to adapt to new practice models,
      individual practitioners may find a significant mismatch between their
      personality and aspects of the new models. Pharmacists' professional
      socialization-the process by which expected roles, behaviors, and attitudes are
      acquired-is another major contributor to their receptiveness to changes in
      practice. Managers wanting to promote practice changes face considerable variance
      in the professional socialization of their individual staff members. Few staff
      members have been socialized for pharmaceutical care. Some may not have any of
      the values or attitudes of the idealized professional, and may simply have "a
      job." Although personality is largely fixed, professional socialization is an
      ongoing process, so there is potential to resocialize practitioners for new
      practice models. Pharmacists are shaped by their personalities and professional
      socialization. Conflict may occur if a pharmacist's personality does not mesh
      with new professional roles. Most pharmacists will need resocialization to
      prepare them for changes in practice.

PMID- 10595809
TI  - Pharmacy-buzzword bingo.

PMID- 10595808
TI  - Acetohexamide-acetazolamide mix-up during emergency treatment.

PMID- 10595810
TI  - Current literature.

PMID- 10595811
TI  - Historical markers in the development of allogeneic hematopoietic cell
      transplantation.

PMID- 10595812
TI  - Pathophysiologic mechanisms of acute graft-vs.-host disease.
AB  - Graft-vs.-host disease (GVHD) remains the major toxicity of allogeneic bone
      marrow transplantation. Mechanistic studies in experimental animal models provide
      a better understanding of the complex relationships and cascade of events
      mediated by cellular and inflammatory factors. Also, advances in basic immunology
      have cleared the way for a more precise view of allogeneic reactions between
      donor and host. In addition, the use of mutant mice lacking critical cytolytic
      proteins has helped map out the molecular pathways by which GVHD targets organ
      damage. In this article, these mechanisms are reviewed and synthesized into a
      coherent conceptual framework, providing a state-of-the-art summary of the
      pathophysiology of acute GVHD.

PMID- 10595813
TI  - Graft-vs.-lymphoma effect in an allogeneic hematopoietic stem cell
      transplantation model.
AB  - It is known that an important curative benefit of allogeneic bone marrow
      transplantation (BAMT) in the treatment of hematolymphoid malignancies is a graft
      vs.-tumor (GVT) effect. GVT activity has been attributed to mature immune cells
      contained within the graft because T-cell depletion of bone marrow results in
      increased rates of disease relapse post-transplantation. We previously
      demonstrated successful engraftment of highly purified hematopoietic stem cells
      (HSCs) transplanted across major histocompatibility complex (MHC) barriers in
      mice. In the present study, we have developed a preclinical model of allogeneic
      HSC transplantation into lymphoma-inoculated mice, allowing us to directly test
      whether purified HSCs have measurable GVT activity. We then performed cotransfer
      studies of HSCs with purified immune cells to identify which population(s)
      confers tumor protection and the mechanism by which such cells suppress tumor
      growth. MHC-mismatched donor-recipient combinations were studied. All of the GVT
      activity was contained in the CD8+ cell fraction and, at the doses of CD8+ cells
      tested, tumor protection was separable from acute graft-vs.-host disease (aGVHD).
      Although there appears to be no functional difference between BM- and splenic
      derived CDS8+ cells with regard to GVT activity without aGVHD, this was not the
      case for purified CD3+ cells. CD3+ cells derived from BM were tumor protective,
      whereas transplantation of equivalent doses of CD3+ cells purified from spleen
      resulted in lethal GVHD. The mechanism by which the GVT-conferring cells protect
      recipient mice from tumors was studied using immune defective mice as donors. We
      found that an intact pathway of perforin-dependent cytolysis, as well as an
      intact Fas-ligand pathway, is required in order to exert maximal anti-tumor
      activity.

PMID- 10595815
TI  - Matched-pair analysis of hematopoietic progenitor cell mobilization using G-CSF
      vs. cyclophosphamide, etoposide, and G-CSF: enhanced CD34+ cell collections are
      not necessarily cost-effective.
AB  - Using matched-pair analysis, we compared two popular methods of stem cell
      mobilization in 24 advanced-stage breast cancer patients who underwent two
      consecutive mobilizing procedures as part of a tandem transplant protocol. For
      the first cycle, 10 microg/kg/day granulocyte colony-stimulating factor (G-CSF)
      was given and apheresis commenced on day 4 and continued for < or =5 days (median
      3 days). One week after the first cycle of apheresis, 4000 mg/m2
      cyclophosphamide, 400 mg/m2 etoposide, and 10 microg/kg G-CSF were administered
      for < or =16 days (cycle 2). Apheresis was initiated when the white blood cell
      (WBC) count exceeded 5000 cells/microL and continued for < or =5 days (median 3
      days). Mean values of peripheral blood WBC (31,700+/-3200 vs. 30,700+/
      3300/microL) were not significantly different between cycles 1 and 2. Mean number
      of mononuclear cells (MNC) collected per day was slightly greater with G-CSF
      mobilization than with the combination of chemotherapy and G-CSF (2.5+/
      0.21x10(8) vs. 1.8+/-0.19x10(8) cells/kg). Mean daily CD34+ cell yield, however,
      was nearly six times higher (12.9+/-4.4 vs. 2.2+/-0.5x10(6)/kg; p = 0.01) with
      chemotherapy plus G-CSF. With G-CSF alone, 13% of aphereses reached the target
      dose of 5x10(6) CD34+ cells/kg in one collection vs. 57% with chemotherapy plus G
      CSF. Transfusions of red blood cells or platelets were necessary in 18 of 24
      patients in cycle 2. Three patients were hospitalized with fever for a median of
      3 days after cycle 2. No patients received transfusions or required
      hospitalization during mobilization with G-CSF alone. Resource utilization (cost
      of drugs, aphereses, cryopreservation, transfusions, hospitalization) was
      calculated comparing the median number of collections to obtain a target CD34+
      cell dose of 5x10(6) cells/kg: four using G-CSF vs. one using the combination in
      this data set. Resources for G-CSF mobilization cost $7326 vs. $8693 for the
      combination, even though more apheresis procedures were performed using G-CSF
      mobilization. The cost of chemotherapy administration, more doses of G-CSF,
      transfusions, and hospitalizations caused cyclophosphamide, etoposide, and G-CSF
      to be more expensive than G-CSF alone. A less toxic and less expensive treatment
      than cyclophosphamide, etoposide, and G-CSF is needed to be more cost-effective
      than G-CSF alone for peripheral blood progenitor cell mobilization.

PMID- 10595814
TI  - Reduced dose intravenous immunoglobulin does not decrease transplant-related
      complications in adults given related donor marrow allografts.
AB  - Graft-vs.-host disease (GVHD) and infection are major complications of allogeneic
      bone marrow transplantation. Intravenous immunoglobulin (IVIg) given at a dose of
      500 mg/kg/wk has been shown to decrease the risk of acute GVHD, interstitial
      pneumonia, and infection in adults early after allogeneic transplantation. The
      current study is a controlled trial to determine whether a lower total dose of
      IVIg given with pretransplant loading reduces the incidence of transplant-related
      complications. In a randomized trial of 241 patients > or =20 years of age who
      were given related donor marrow allografts, 121 individuals receiving Ig
      prophylaxis (500 mg/kg/d loading from day -6 to -1 and then 100 mg/kg every 3
      days from day 3 to 90) were compared with 120 control patients who did not
      receive IVIg. Randomization was stratified by human leucocyte antigen-matching,
      remission status of malignancy, GVHD prophylaxis, and cytomegalovirus (CMV)
      serology. The study was powered to detect a reduction in acute GVHD by 18% and a
      decrease in transplant-related mortality by 17%. Pretransplant IVIg loading and
      posttransplant maintenance achieved median serum IgG levels >1350 mg/dL, which
      were approximately twofold greater than the untreated controls (p<0.01). White
      blood cell and platelet recoveries were similar for the two groups, although
      control patients required fewer units of platelets per day (2.5 vs. 3.3, p =
      0.008). No significant differences in the incidence of CMV infection,
      interstitial pneumonia, or bacteremia were observed. The incidence of acute GVHD
      did not differ between the two groups; however, acute GVHD was less frequent
      among IVIg recipients achieving maximum serum IgG levels >3000 mg/dL (60 vs.
      79%). Neither transplant-related mortality nor disease-free survival was
      significantly altered by Ig prophylaxis. However, the cumulative incidence of
      relapse of malignancy was higher in IVIg recipients than in controls (31 vs. 18%,
      p = 0.03). Multivariable regression analysis demonstrated a 1.89 increased
      relative risk of relapse for individuals given IVIg (p = 0.021). We conclude that
      pretransplant loading and a shorter course and lower total dose of IVIg
      prophylaxis did not appear to decrease the risk of acute GVHD or mortality among
      adults receiving related donor marrow transplants. Note, IVIg administration may
      be associated with an increased risk of recurrent malignancy, a finding that
      warrants further investigation.

PMID- 10595816
TI  - A prospective randomized trial of the anti-emetic efficacy of ondansetron and
      granisetron during bone marrow transplantation.
AB  - To determine the comparative anti-emetic efficacy of ondansetron and granisetron
      in patients undergoing bone marrow transplantation, we performed a double-blind,
      randomized trial in pediatric and adult patients receiving transplants at the
      University of Minnesota. The results in 187 patients stratified by age (<18
      years, n = 51; > or =18 years, n = 136) were analyzed. The average number of
      emetic episodes in the entire group from day -7 to 2 was 0.86/day for patients
      receiving ondansetron and 0.73/day for those receiving granisetron (p = 0.32). No
      differences were noted between the two drugs in total days of complete or major
      control of emesis or in the number of requests for additional drugs to alleviate
      symptoms of nausea. The use of total-body irradiation-containing conditioning
      regimens was associated with a decreased number of emetic episodes compared with
      regimens of chemotherapy alone. Perceived nausea was evaluated using a nausea
      scoring system, and no differences were apparent between the granisetron and
      ondansetron groups; however, reported nausea was significantly higher in females
      (p<0.01) and in the adult population (p = 0.05). We conclude that both
      ondansetron and granisetron provide good control of nausea and vomiting
      experienced with conditioning regimens for bone marrow transplantation. The
      relative cost of the drugs within an institution must be considered in developing
      standard anti-emetic regimens for bone marrow transplantation.

PMID- 10595817
TI  - Philadelphia chromosome-negative engraftment after autologous transplantation
      with granulocyte-macrophage colony-stimulating factor for chronic myeloid
      leukemia.
AB  - Autologous bone marrow transplantation (BMT) has not been curative in chronic
      myeloid leukemia (CML), because of the inability to purge CML from the autograft
      and the absence of the allogeneic T cell-mediated antileukemic activity. However,
      recent advances demonstrate that normal progenitors can be selected from CML
      marrows by a variety of techniques, including isolation by their small size.
      Furthermore, we found that myeloid growth factors have a potent antileukemic
      effect against CML progenitors in vitro by inducing their terminal
      differentiation. Based on these data, we initiated a trial of autologous BMT in
      patients with high-risk CML. Autografts were processed in an attempt to enrich
      for normal progenitors, first by isolating small cells by counterflow centrifugal
      elutriation and then incubating them in granulocyte-macrophage colony-stimulating
      factor (GM-CSF) for 72 hours. After a conditioning regimen of busulfan and
      cyclophosphamide, all patients received GM-CSF daily for 2 months. The median age
      of the 13 patients in the trial was 45 years (range 17-56 years). The median
      duration of disease before BMT was 24 months (range 13-72 months). Eight patients
      were in chronic phase (CP), and five were in accelerated phase (AP). All patients
      failed to achieve a cytogenetic response to interferon-alpha and were 100%
      Philadelphia chromosome (Ph)+ before BMT. There were three transplant-related
      deaths, all AP patients. All of the remaining 10 patients engrafted with some
      degree of Ph- hematopoiesis; despite high-risk features, nine patients engrafted
      100% Ph-. All patients relapsed cytogenetically at a median of 6 months (range 4
      22 months). These results demonstrate that autologous BMT can consistently induce
      complete Ph- engraftment in CP patients. GM-CSF appears to produce a clinical
      antileukemic effect against CML after autologous BMT.

PMID- 10595818
TI  - Remission of refractory Sezary syndrome after bone marrow transplantation from a
      matched unrelated donor.
AB  - Sezary syndrome is a leukemic variant of mycosis fungoides (MF)/cutaneous T-cell
      lymphoma (CTCL). Bone marrow transplantation (BMT) from a matched unrelated donor
      was performed in a 22-year-old woman with a 10-year history of Sezary syndrome
      who had failed treatment with corticosteroids, methotrexate, photochemotherapy,
      photopheresis, hydroxyurea, interferon-alpha, and cladarabine. At the time of
      BMT, she had persistent erythrodermic skin disease, adenopathy, circulating
      Sezary cells and bone marrow (BM) involvement. The patient underwent BMT from a
      6/6 HLA-matched unrelated male donor in August 1996. A BM biopsy obtained on day
      30 after BMT showed no evidence of lymphoma and complete male donor engraftment.
      Her skin lesions resolved within 100 days after transplant. Complete staging
      studies, including T-cell receptor gene rearrangement studies performed at 36
      months post-BMT, showed no evidence of recurrent Sezary syndrome. This represents
      her first durable remission since the initial diagnosis more than 12 years ago.
      To our knowledge, this is the first patient with refractory Sezary syndrome who
      has been successfully treated with allogeneic unrelated donor BMT. Our results
      indicate that this modality may be effective in inducing remission in refractory
      MF/CTCL, including Sezary syndrome.

PMID- 10595819
TI  - Prolonged activation of NF-kappaB following traumatic brain injury in rats.
AB  - Activation of transcription factor, nuclear factor kappa B (NF-kappaB), has been
      shown to play a key role in inflammatory response, neuronal survival and
      signaling. We investigated the regional and temporal distribution of activated NF
      kappaB in rats at 1 h, 2 h, 24 h, 48 h, 1 week, 2 weeks, 1 month, 2 months, 6
      months, and 1 year following brain injury in rats. Early after trauma (1-2 h),
      activated NF-kappaB was detected in axons, and subsequently found in the
      cytoplasm and nucleus of neurons by 24 h and lasting up to 1 week. In addition,
      by 24 h posttrauma, activated NF-kappaB was detected in microglia/macrophages and
      astrocytes in injured cortex. Surprisingly, this activation persisted for at
      least 1 year following injury in the cortex, primarily at the margins of
      progressively enlarging ventricle. Activated NF-kappaB was also detected in
      endothelial cells, as early as 1 h, and persisted for up to 1 year. These results
      suggest that a neuronal response to brain trauma includes the activation of NF
      kappaB first in the axon with subsequent translocation to the nucleus.
      Furthermore, these results demonstrate that remarkably prolonged activation of NF
      kappaB in glia is found in the same regions undergoing persistent atrophy,
      suggesting NF-kappaB activation may play a role in long-term inflammatory
      processes following brain trauma.

PMID- 10595820
TI  - Secondary hypoxia following moderate fluid percussion brain injury in rats
      exacerbates sensorimotor and cognitive deficits.
AB  - Human head trauma is frequently associated with respiratory problems resulting in
      secondary hypoxic insult. To document the behavioral consequences of secondary
      hypoxia in an established model of traumatic brain injury (TBI), intubated
      anesthetized animals were subjected to fluid percussion (FP) injury (1.87-2.17
      atm) followed by 30 min of either normoxic (TBI-NO, n = 10) or hypoxic (TBI-HY, n
      = 11; pO2 = 30-40 mm Hg) gas levels. Sham animals (n = 19) underwent all
      manipulations except for the actual trauma. Animals were tested on various
      sensorimotor tasks beginning 3 days after FP injury along with cognitive testing
      on days 22 through 29 posttrauma. The secondary hypoxic insult exacerbated the
      sensorimotor deficits on beam-walking compared to those animals only receiving
      trauma. Cognitive impairments were also observed in the TBI-HY group in the
      hidden platform task compared to FP injury alone. These data indicate that a
      secondary hypoxic insult exacerbates both sensorimotor and cognitive deficits
      after TBI. This study provides direct evidence that incidences of hypoxia after
      brain trauma may potentially result in an increase in neurological deficits for
      the subpopulation of head injured patients undergoing hypoxic conditions further
      warranting strict monitoring of these events.

PMID- 10595821
TI  - Effect of intracerebral and subdural hematomas on energy-dependent transport
      across the blood-brain barrier.
AB  - Although both intracerebral and subdural hematomas induce brain edema, previous
      studies have indicated that they may have different cerebrovascular effects. Our
      own investigations have demonstrated that while subdural hematomas (SDH) are
      associated with ischemia this is not the case following intracerebral hematomas
      (ICH). Previous studies have demonstrated a decrease in energy-dependent
      transport of glutamine across the blood-brain barrier (BBB) following focal
      cerebral ischemia. The present study investigates this further by examining the
      effects of SDH, ICH, and intracerebral thrombin injections, an agent involved in
      ICH-induced injury, on blood to brain glutamine transport. The injection of 200
      microL of blood into the subdural space induced a marked reduction in glutamine
      transport (Ki, influx rate constant) into the cerebral cortex at 4 and 24 h
      following SDH (sham, 105+/-4% of contralateral cortex; SDH 4 h, 63+/-5%, p<0.01;
      SDH 24 h, 47+/-12%, p<0.05). There were no significant changes in glutamine Ki in
      subcortical areas following SDH. Following ICH (200-microL clot); however, there
      were only modest decreases in glutamine Ki in subcortical areas (sham, 98+/-2% of
      right cortex; ICH 4 h, 91+/-5%, p<0.01; ICH 24 h, 91+/-2%, p<0.05). Intracerebral
      injection of thrombin (5U) had minimal effect on glutamine Ki, in subcortical
      areas, at 4 h and induced a modest decrease in transport at 24 h (sham, 98+/-2%
      of right cortex; thrombin 4 h, 98+/-2%; thrombin 24 h, 86+/-2%, p<0.05). The
      present studies demonstrate marked differences in the effects of ICH and SDH on
      BBB function.

PMID- 10595822
TI  - Effect of LF 16-0687MS, a new nonpeptide bradykinin B2 receptor antagonist, in a
      rat model of closed head trauma.
AB  - Bradykinin is an endogenous nonapeptide which potently dilates the cerebral
      vasculature and markedly increases vascular permeability. These effects are
      mediated by B2 receptors located on the vascular endothelium. Previous
      experimental studies have shown that blockade of the kallikreinkinin system,
      which mediates the formation of bradykinin, afforded a reduction of the brain
      edema that developed following a cryogenic cortical lesion. In the present study,
      we investigated the effect of LF 16-0687MS, a novel nonpeptide B2 receptor
      antagonist, on cerebral edema and neurological severity score (NSS) after closed
      head injury to rats. LF 16-0687MS or its vehicle (NaCl 0.9%) was continuously
      infused at 10, 30, and 100 microg/kg/min over 23 h starting 1 h after a focal
      trauma to the left hemisphere was induced using a weight-drop device. The extent
      of edema formation was evaluated 24 h after trauma from left and right
      hemispheres samples by measurement of specific gravity and water content. In a
      separate study, a neurological severity score based on scoring of behavioural and
      motor functions was evaluated 1 h and over 1 week after trauma. LF 16-0687MS at
      100 microg/kg/min markedly reduced the development of brain edema as indicated by
      a 68% increase in specific gravity (p<0.05) and a 64% decrease of water content
      (p<0.05) in the left hemisphere. In addition the recovery of neurological
      function was significantly improved by 100 microg/kg/min LF 16-0687MS from day 3
      to day 7 after CHT. In a separate experiment, we also showed that LF 16-0687MS at
      100 microg/kg/min given either 1 h before or 30 min after CHT did not affect mean
      arterial blood pressure. These results show that blockade of bradykinin B2
      receptors is an effective approach to reduce cerebral edema and to improve
      neurological outcome after a focal contusion to the cranium.

PMID- 10595823
TI  - Effect of N-acetylcysteine on mitochondrial function following traumatic brain
      injury in rats.
AB  - Efficacy of N-acetylcysteine (NAC) in traumatic brain injury (TBI)-induced
      mitochondrial dysfunction was evaluated following controlled cortical impact
      injury in rats. Respiratory function and calcium transport of rat forebrain
      mitochondria from injured and uninjured hemispheres were examined. NAC
      significantly restored mitochondrial electron transfer, energy coupling capacity,
      calcium uptake activity and reduced calcium content absorbed to brain
      mitochondrial membranes when examined 12 h post-TBI if NAC was administered i.p.
      5 min before injury or 30 min or 1 h postinjury. Glutathione (reduced form, GSH)
      levels in brain tissues were decreased at all time points examined over a 14-day
      observation period, while mitochondrial GSH levels significantly decreased only
      at 3 days and 14 days following TBI. NAC treatment given within 1 h greatly
      restored brain GSH levels from 1 h to 14 days and mitochondrial GSH levels from
      12 h to 14 days post-TBI. NAC did not show protective effects when given 2 h
      postinjury. Our data indicate that NAC administered postinjury at an early stage
      can effectively restore TBI-induced mitochondrial dysfunction and the protective
      effect of NAC may be related to its restoration of GSH levels in the brain.

PMID- 10595824
TI  - Effects of mild hypothermia on the cortical release of excitatory amino acids and
      nitric oxide synthesis following hypoxia.
AB  - Studies concerning neurotransmitter release following cerebral hypoxia are
      scarce, and the effects of mild hypothermia on hypoxia-induced neurotransmitter
      release are unknown. The purpose of this study was to investigate changes in
      excitatory amino acid (EAA) concentrations and nitric oxide (NO) synthesis
      following cerebral hypoxia in rats, and the effects of mild hypothermia on both.
      Cerebral hypoxia (PaO2, 30-40 mm Hg) was induced in each rat for 60 min. Cerebral
      blood flow (CBF) was measured by laser-Doppler flowmetry, and the extracellular
      concentrations of EAAs and NO end-products (nitrite and nitrate) were measured by
      in vivo microdialysis in normothermic (37 degrees C) and hypothermic (32 degrees
      C) rats. In both groups, CBF showed modest increases during hypoxia and returned
      to baseline during reoxygenation. The EAA levels of the normothermic rats
      increased markedly after hypoxia induction and returned to baseline levels during
      reoxygenation. Hypothermia abolished these increases completely. The NO end
      product levels under normothermic conditions declined slightly during hypoxia,
      and then increased transiently during reoxygenation. Hypothermia appeared to
      attenuate the NO end-product level and to delay the peak. When the relationship
      between glutamate and the NO end-products was examined on an individual-animal
      basis, glutamate release did not parallel NO synthesis. The results indicate that
      hypothermic neuroprotection during cerebral hypoxia may be attributable to the
      amelioration of damage by reduction of presynaptic EAA release. Although it is
      unclear from the present results alone whether endothelial NO synthase, neuronal
      NO synthase or both caused the elevation of the NO end-products during
      reoxygenation, it is possible that the attenuation and delay of the peak of the
      NO end-product level plays a role in protection from NO-induced neuronal damage.

PMID- 10595825
TI  - ICP monitoring in the rat: comparison of monitoring in the ventricle, brain
      parenchyma, and cisterna magna.
AB  - Various methods of continuous intracranial pressure (ICP) monitoring during
      experimental procedures in the rat have been described. However, no systematic
      comparison of ICP monitoring in the ventricle, brain parenchyma, and cisterna
      magna has been reported. Since accurate and reliable ICP measurements are
      important in experimental models of traumatic brain injury, the present study was
      conducted to compare simultaneous ICP measurements from ventricular, cisterna
      magna, and intraparenchymal monitors during ICP changes. Subdural hematoma was
      produced by infusion of 0.3 ml of autologous blood into the subdural space over 6
      min. The ventricular and the intraparenchymal fiberoptic catheter produced
      reliable and comparable pressure recordings, that did not statistically differ (p
      = 0.4), throughout the one hour monitoring time. In contrast, the cisterna magna
      catheter was less reliable and produced significantly lower readings throughout
      the monitoring time (p<0.001). The intraparenchymal device produced greater
      cortical damage than the ventricular catheter. In conclusion, ventricular ICP
      monitoring is the preferred method under these circumstances, since it is
      accurate and induces least brain damage.

PMID- 10595826
TI  - Validation of a controlled cortical impact model of head injury in mice.
AB  - A controlled cortical impact model of head injury was validated with mice. Mice
      were randomly assigned to moderate head injury, mild head injury, and sham injury
      groups. Beam balancing, open field activity, slant board inclination, grasp
      strength, and motor coordination were assessed prior to the injury and on days 1
      5 postinjury. Morris water maze performance was evaluated on days 11-15
      postinjury. Moderately head-injured mice took a significantly longer time to
      complete the motor coordination task and to find the hidden platform on the
      Morris water maze and had significantly fewer successful trials on both tasks
      than the mildly head-injured and sham-injured mice. Mildly head-injured and sham
      injured mice performed similarly on both tasks. Contusion volume at the site of
      impact varied with severity of injury. Moderately head-injured mice had
      significantly larger contusions than mice with a mild head injury, and these mice
      in turn had significantly larger contusions than the sham-injured mice. Both
      moderately and mildly head injured mice had significantly fewer surviving cells
      in CA1 than the sham-injured mice but did not differ from each other in this
      regard. Although there was a group effect, only the mildly head-injured mice had
      significantly fewer surviving cells in CA3.

PMID- 10595827
TI  - Metallothionein (MT)-III: generation of polyclonal antibodies, comparison with MT
      I+II in the freeze lesioned rat brain and in a bioassay with astrocytes, and
      analysis of Alzheimer's disease brains.
AB  - Metallothionein-III is a low molecular weight, heavy-metal binding protein
      expressed mainly in the central nervous system. First identified as a growth
      inhibitory factor (GIF) of rat cortical neurons in vitro, it has subsequently
      been shown to be a member of the metallothionein (MT) gene family and renamed as
      MT-III. In this study we have raised polyclonal antibodies in rabbits against
      recombinant rat MT-III (rMT-III). The sera obtained reacted specifically against
      recombinant zinc-and cadmium-saturated rMT-III, and did not cross-react with
      native rat MT-I and MT-II purified from the liver of zinc injected rats. The
      specificity of the antibody was also demonstrated in immunocytochemical studies
      by the elimination of the immunostaining by preincubation of the antibody with
      brain (but not liver) extracts, and by the results obtained in MT-III null mice.
      The antibody was used to characterize the putative differences between the rat
      brain MT isoforms, namely MT-I+II and MT-III, in the freeze lesion model of brain
      damage, and for developing an ELISA for MT-III suitable for brain samples. In the
      normal rat brain, MT-III was mostly present primarily in astrocytes. However,
      lectin staining indicated that MT-III immunoreactivity was also present in
      microglia, monocytes and/or macrophages in the leptomeninges and lying adjacent
      to major vessels. In freeze lesioned rats, both MT-I+II and MT-III
      immunoreactivities increased in the ipsilateral cortex. The pattern of MT-III
      immunoreactivity significantly differed from that of MT-I+II, since the latter
      was evident in both the vicinity of the lesioned tissue and deeper cortical
      layers, whereas that of the former was located only in the deeper cortical
      layers. This suggests different roles for these MT isoforms, and indeed in a new
      bioassay measuring astrocyte migration in vitro, rMT-III promoted migration to a
      higher extent than MT-I+II. Thus, MT-III could not only affect neuronal sprouting
      as previously suggested, but also astrocyte function. Finally, MT-III protein
      levels of patients with Alzheimer's disease (AD) were, if anything, increased
      when compared with similarly aged control brains, which was in agreement with the
      significantly increased MT-III mRNA levels of AD brains.

PMID- 10595828
TI  - Independent expression of serological markers of thyroid autoimmunity and
      hepatitis virus C infection in the general population: results of a community
      based study in north-western Sardinia.
AB  - To assess the relationship between serological markers of thyroid autoimmunity
      and chronic hepatitis C, we surveyed the general population of two villages in
      the region of Sardinia, Italy, where infection with hepatitis viruses is endemic
      and the prevalence of autoimmune diseases is elevated. A total of 1310 subjects
      aged 6-88 years (65% of the total resident population) participated in the
      survey, and 1233 (94%; 444 males and 789 females) agreed to provide a blood
      sample. Autoantibodies to thyroid peroxidase (anti-TPO) were measured by
      radioimmunoassay; antibodies to HCV (anti-HCV) by a third generation enzyme
      immunoassay and borderline positive results confirmed by recombinant immunoblot
      assay. For both anti-HCV and anti-TPO the age- and gender-standardized prevalence
      rates (SPR) were calculated and the significance of the association between the
      two antibodies tested by Yates corrected chi2 test. The overall SPR for anti-HCV
      was 50.7x10(-3) (86/1,233), similar between men [49.1x10(-3) (22/444)] and women
      [52.3x10(-3) (64/789)]. The overall SPR for anti-TPO was 136.9x10(-3)
      (204/1,233), and that among women [201x10(-3) (174/789)] was almost 3-fold that
      among men [71.6x10(-3) (30/444)]. A concurrent anti-HCV and anti-TPO positivity
      was found in a small minority of subjects [8/1,233 (0.65%)], all women aged 57-81
      years. The SPR for the two concurrent events was 3.3x10(-3), which was not
      significantly different (Yates corrected chi2 test = 0.65) from that expected
      under the assumption of unrelated events. To explore whether HCV infection is a
      risk factor for anti-TPO positivity, we designed a case-control study with anti
      TPO positive subjects as the cases, and anti-TPO negative subjects as the
      controls. The age- and gender-adjusted odd ratio (OR) was 0.4 (95% CI 0.2,0.7),
      indicating a negative association. In conclusion, no evidence for epidemiological
      association of circulating thyroid autoantibodies and antibodies to HCV was
      found. Our findings do not therefore support a pathogenetic link between HCV
      infection and thyroid autoimmunity.

PMID- 10595829
TI  - Glucocorticoids inhibit gonadotropin-releasing hormone by acting directly at the
      hypothalamic level.
AB  - Glucocorticoids, the end-product of the hypothalamic-pituitary-adrenal (HPA)
      axis, suppress gonadotropin release by acting at the level of the pituitary
      gland. However, experimental evidence suggests that they may also act at the
      hypothalamic level to suppress gonadotropin-releasing hormone (GnRH) release. The
      lack of a direct demonstration of this assumption, prompted us to evaluate the
      effects of glucocorticoids on hypothalamic GnRH release from individually
      incubated hemi-hypothalami explanted from male rats. Since testosterone (T),
      dihydrotestosterone (DHT), and progesterone suppress GnRH release and androgens
      potentiate the effects of glucocorticoids on GnRH release, we studied also the
      interaction of these steroids with glucocorticoids on GnRH release.
      Corticosterone (B), the main glucocorticoid of the rodents with greater affinity
      for the type I glucocorticoid receptor, and dexamethasone (DEX), a synthetic type
      II glucocorticoid receptor agonist, were able to suppress basal GnRH release in a
      concentration-dependent fashion. DEX induced a more profound suppression of GnRH
      release. Neither T (0.1 nM) nor DHT (0.01 nM) modulated the suppressive effects
      of low (10 nM) or high (100 nM) concentrations of B on GnRH release. On the other
      hand, progesterone counteracted the suppressive effect of low concentrations of B
      (10 nM) on GnRH release, but had no effect on the suppression caused by a higher
      concentration of B (100 nM). The ability of glucocorticoids to inhibit directly
      GnRH release suggests that these stress-responsive hormones act also at the
      hypothalamic level to suppress the reproductive function. The suppressive effect
      of B was not modulated by androgens, but it was neutralized by progesterone, at
      least when B was used at low concentrations. We speculate that this steroid
      "protects" the GnRH-secreting neuron only during basal, but not stress-induced,
      HPA axis activity when the concentrations of glucocorticoids are more elevated.

PMID- 10595830
TI  - Structure-function correlations of growth hormone or/and prolactin-producing
      pituitary adenomas: an in vitro study with the reverse hemolytic plaque assay.
AB  - The purpose of this study was to detect in vitro growth hormone (GH) and
      prolactin (PRL) secretion from adenomas clinically associated with GH or PRL
      hypersecretion. The reverse hemolytic plaque assay (RHPA) was applied in order to
      reveal possible differences among various morphologic adenoma types, and to
      examine the inhibitory effects of octreotide on GH release as well. The 20
      surgically resected pituitary adenomas studied included 15 from acromegalic
      patients and 5 from patients with hyperprolactinemia. All adenomas were diagnosed
      by histology, immunocytochemistry and electron microscopy. Among tumors
      associated with acromegaly, 5 were densely granulated (DG), 5 were sparsely
      granulated (SG) somatotroph (SM) adenomas, 2 were mammosomatotroph (MSM) and 3
      mixed somatotroph-lactotroph cell (mixed SM-LT) adenomas; tumors causing
      hyperprolactinemia included 4 lactotroph (LT) adenomas and 1 mixed SM-LT adenoma.
      GH release assessed by the RHPA corresponded to in vivo hormone secretion and to
      tissue immunoreactivity. Statistical analysis showed significant differences
      among all morphologic types of SM adenomas, exclusive of SG-SM adenomas compared
      to mixed SM-LT adenomas. The mean plaque size in DG-SM and MSM adenomas was
      significantly greater than that of SG-SM and mixed SM-LT adenomas, indicating
      higher GH secretion by the former two types during the same incubation time. PRL
      secretion was documented in 2 mixed SM-LT adenomas. Plaques for PRL, but not for
      GH were formed in all LT adenomas. In all SM and LT adenomas, cells producing
      large plaques represented a minority of the plaque-forming cell population,
      however, they accounted for the largest part of the total plaque area, thus the
      largest part of hormone secretion. Octreotide effects on GH release were studied
      in 6 adenomas by the RHPA. Octreotide treatment induced a rapid and significant
      reduction in GH secretion by SM cells in vitro, with a selective effect on high
      secreting cells.

PMID- 10595831
TI  - Dehydroepiandrosterone sulfate levels in women. Relationships with age, body mass
      index and insulin levels.
AB  - Sex and age are the major determinants of serum levels of dehydroepiandrosterone
      sulfate (DHEA-S): they are about twice in men than in women and show a
      progressive reduction from the end of the puberty to aging in both sexes. It has
      been reported that DHEA-S levels are also negatively influenced by insulin.
      Moreover, DHEA-S levels reduction has been associated to increased risk for
      cardiovascular disease, which connotes hyperinsulinemic states, such as obesity.
      We have evaluated serum levels of DHEA-S and insulin as function of age and body
      mass index (BMI) in 376 adult women (age 18.1-89.6 yrs, median 42.2; BMI 15.7
      57.8 kg/m2, median 32.7) by multiple regression and piecewise regression
      analysis. Insulin levels positively associated to BMI (p=0.000002) and DHEA-S
      levels negatively associated with age (p=0.000001). Considering the whole
      population, DHEA-S levels were related positively with BMI (p=0.0013)
      independently of age. DHEA-S were also directly related to insulin levels
      independently of age (p=0.042), but this association disappeared after correction
      for BMI. Piecewise regression analysis did not reveal a threshold level for the
      increase of BMI (p=0.0004). Interestingly, DHEA-S levels and BMI were positively
      associated before but not after menopause. Taking into account only obese
      population, (no.=143, age 18.7-67.3 yrs, mean 39.0, median 39.4) DHEA-S levels
      were again related negatively with age and positively with BMI, while were
      unrelated with waist to hip ratio (p=0.391). Our data show that increasing body
      mass and insulin secretion is not associated to DHEA-S reduction in women. This
      evidence suggests that DHEA-S is unlikely implicated in the pathogenesis of
      cardiovascular disease in obese women.

PMID- 10595832
TI  - Localization of parathyroid tumors using endoscopic ultrasonography in primary
      hyperparathyroidism.
AB  - Parathyroid adenomas responsible for primary hyperparathyroidism may be difficult
      to detect preoperatively. Furthermore parathyroid adenomas may arise behind the
      (nodular) thyroid gland, in a deep cervical location, and plans should be plane.
      The purpose of the present prospective study was to evaluate echoendoscopy, and
      to compare its accuracy to that of non invasive tests. Fourteen consecutive
      patients with primary hyperparathyroidism were prospectively studied. All
      patients underwent echoendoscopy, ultrasonography (US), CT scanning or magnetic
      resonance imaging (MRI) and Tc 99m sestamibi scanning before undergoing initial
      neck exploration. The parathyroid pathology was a solitary adenoma in 13 patients
      and a 4 glands hyperplasia in one. All tests were corroborating in 5 cases. Four
      adenomas were localized to the correc tside (33%), and no test accurately
      localized all hyperplastic glands. EUS, sestamibi and CT scanning or MRI
      correctly identified 10 parathyroid tumors in 14 cases (71%). US correctly
      localized only 5 adenomas (sensitivity 36%). The sensitivity of EUS to detect
      parathyroid adenomas is superior to US (p<0.05) and comparable to that of other
      non invasive tests. We conclude that EUS may be an useful tool to localize
      parathyroid lesions. This method may replace US prior to initial neck exploration
      with further miniaturization of probes, or find an intermediate place among
      invasive and noninvasive preoperative localization procedures in patients with
      persistent or recurrent PHPT.

PMID- 10595833
TI  - Prevalence of subclinical hypothyroidism in a population living in the Milan
      metropolitan area.
AB  - Subclinical hypothyroidism is a condition characterized by increased levels of
      thyroid-stimulating hormone (TSH) associated with normal levels of free
      triiodothyronine (FT3) and free thyroxine (FT4). The exact prevalence of this
      condition in Italy is not known. The aim of this study was to assess the presence
      of subclinical hypothyroidism in 1001 subjects living in the Milan area (age 17
      89) and apparently free from thyroid pathology. This sample which had applied to
      a large laboratory centre (Centro Diagnostico Italiano, Milano) for a routine
      check-up was seen from April to July 1996. A serum TSH assay was performed using
      a highly sensitive immunoenzymatic method, while an FT3 and FT4 assay was
      performed by means of a radioimmunologic method using commercial kits. The
      prevalence of subclinical hypothyroidism in the total population proved to be
      4.7% (95% CI-Confidence Interval: 3.4-6.0). Sex stratification showed a
      prevalence of 6.1% in females and 3.4% in males. Prevalence in patients up to 65
      was 4.2%. This value increased up to 8.0% in subjects over 65. By combining these
      variables, in females >65 prevalence increased to 11.3%. Overall, symptoms
      typical of overt hypothyroidism were found in 58.3% of patients suffering from
      subclinical hypothyroidism and in 39.9% of healthy subjects (p<0.02). The results
      of this study show that there is a significant presence (about 5%) of subclinical
      hypothyroidism in this population and that its frequency is more than doubled in
      women over 65. Early treatment might reduce the progression to overt
      hypothyroidism. The benefits of such a procedure were recently suggested by a
      decision making modelling approach applied to the Italian environment.

PMID- 10595834
TI  - Pituitary apoplexy probably due to TRH and GnRH stimulation tests in a patient
      with acromegaly.
AB  - Pituitary apoplexy is the most serious and life-threatening complication of
      pituitary adenomas. Most of the cases occur spontaneously but it may occur also
      after a number of events such as the pituitary stimulation tests. We report a
      case of acromegaly due to a giant pituitary adenoma in which pituitary apoplexy
      developed 88 hours after TRH/GnRH stimulation test. The patient had severe
      headaches, nausea, vomiting, visual disturbance and mental alteration and the
      computed tomography (CT) scans revealed intratumoral and intraventricular
      bleeding. The pituitary mass was removed by transsphenoidal approach. The patient
      developed pneumonia and died on the 9th postoperative day. Pituitary apoplexy was
      confirmed at surgery and on histological examination. Immunohistochemical
      staining was positive for GH and PRL. This case indicates that pituitary apoplexy
      may develop several days after TRH/GnRH stimulation test.

PMID- 10595835
TI  - Toxic adenoma and papillary thyroid carcinoma in a patient with Graves' disease.
AB  - A case of a very rare association of toxic adenoma and papillary carcinoma with
      Graves' disease is presented. A 34-year-old woman developed Graves' disease with
      mild ophthalmopathy. An ultrasound revealed diffuse thyroid enlargement with a
      hypoechoic pattern and a hypoechoic nodule with regular edges of 1.6 cm in
      diameter at the lower pole of the left lobe. A thyroid 131I scintiscan showed a
      diffuse and homogeneous 131I distribution. The 131I uptake (RAIU) was elevated.
      One year later, while still on a low dose of methimazole, the patient had a
      recurrence of hyperthyroidism following an iodine load from a contrast agent. A
      further thyroid ultrasound confirmed the previously described pattern but showed
      a new hypoechoic nodule of 1.1 cm with irregular edges in the left lobe. A
      thyroid 131I scintiscan this time demonstrated a hyperactive area localised in
      the larger nodule and a lower diffuse uptake of the remaining tissue. Because of
      the worsening of the symptoms of hyperthyroidism, the patient had a left
      lobectomy. On histological examination, the larger nodule was well encapsulated
      and showed the characteristics of a hyperfunctioning follicular adenoma. The
      smaller nodule was a typically unencapsulated papillary carcinoma. Several other
      microfoci of papillary carcinoma were also found in the adjacent tissue.
      Completion of thyroidectomy was therefore performed, followed by 131I ablative
      therapy and thyroxine suppressive treatment. This observation suggests that the
      chronic abnormal stimulation of the thyroid gland by the thyroid-stimulating
      antibody (TSAb) may facilitate the neoplastic transformation of the thyrocytes in
      individuals with a critical genetic background.

PMID- 10595836
TI  - Radioiodine and thyroid-associated ophthalmopathy: from the myth to the reality.

PMID- 10595838
TI  - Receptor imaging in the diagnosis and treatment of pituitary tumors.

PMID- 10595839
TI  - "Christ at the pool of Betheseda" (detail). William Hogarth. 1697-1764.

PMID- 10595840
TI  - Impact of water-induced diuresis on excretion profiles of ethanol, urinary
      creatinine, and urinary osmolality.
AB  - This article reports the impact of diuresis on urinary excretion of ethanol in
      seven healthy volunteers who drank 1000 mL of export beer (44 g ethanol) in 30
      min and, 120 min later, ingested 500 or 1000 mL of water within 5 min. Urine was
      voided before drinking started and every 30-60 min for 360 min after the start of
      drinking. The concentration of ethanol in urine (UAC) was determined by headspace
      gas chromatography, the creatinine content was determined by Jaffe's method, and
      osmolality was measured by freezing point depression. Maximum diuresis coincided
      with the peak UAC and was reached 60-90 min after the end of drinking. The
      urinary creatinine and osmolality dropped appreciably after drinking beer, and
      the lowest values coincided with peak diuresis. Creatinine was < 0.2 g/L in 22%
      of urine specimens, and osmolality was < 200 mOsm/kg in 31% of specimens.
      Production of urine decreased as UAC entered the postabsorptive phase but
      increased again after the subjects drank water 120 min after alcohol consumption.
      The amount of ethanol recovered in urine was 681 mg (standard deviation [SD] 203
      mg) corresponding to 1.5% (SD 0.46%) of the dose administered. The concentrations
      of ethanol in successive voids during the postabsorptive phase were not
      influenced after subjects drank 500 or 1000 mL of water although diuresis
      increased and urinary creatinine and osmolality decreased. Measuring UAC provides
      a reliable way to monitor recent drinking, and unlike the analysis of illicit
      drugs in urine, the concentrations of ethanol are not influenced by diuresis.

PMID- 10595841
TI  - The role of alcohol abuse in the etiology of heroin-related deaths. Evidence for
      pharmacokinetic interactions between heroin and alcohol.
AB  - In order to evaluate pharmacokinetic interactions between heroin and alcohol and
      their role in the etiology of heroin-related deaths (HRD), the alcohol
      concentration in blood (BAC), the free (FM) and total morphine (TM)
      concentrations in blood (determined by DPC Coat-A-Count radioimmunoassay before
      and after enzymatic hydrolysis), and the TM concentration in urine and bile (DPC
      Coat-A-Count after enzymatic hydrolysis) in a population of 39 lethal cases
      included in the records of the Department of Legal Medicine and Public Health at
      the University of Pavia from the period January 1997-April 1998 were examined.
      The cause of death in each case was attributed to either heroin or associated
      heroin-ethanol intoxication. Cases were arbitrarily divided into two groups
      according to BAC (low-ethanol group, LE, BAC < or = 1000 mg/L and high-ethanol
      group, HE, BAC > 1000 mg/L). The differences in the FM and TM concentrations in
      blood, bile, and urine and in the FM/TM ratios between the two . groups were
      statistically evaluated (Mann-Whitney U test). A similar statistical evaluation
      was carried out on data from a previously published study concerning the
      disposition of heroin and its metabolites (6-acetylmorphine and morphine) in
      blood and urine in 23 lethal cases attributed to either heroin or heroin and
      alcohol intoxication. The values of the following variables in the LE and HE
      groups were compared: FM, TM, and 6-acetylmorphine concentrations in blood (6
      AM); the FM/ (FM + 6-AM) ratio; the FM/TM ratio; and the urinary concentrations
      of heroin, 6-acetylmorphine, and free morphine. Statistical analyses of data
      indicated that high BACs are associated with reduced hydrolysis of 6-AM to
      morphine (FM/[FM + 6-AM], p = 0.0022) and that a good inverse correlation exists
      between BAC and hydrolysis of 6-AM to morphine (r2 = 0.67). High BACs were also
      found to be associated with an increased FM/TM ratio and with reduced excretion
      of free and total morphine. These results suggest the hypothesis that
      pharmacokinetic interactions between heroin and alcohol do occur in individuals
      exposed to high doses of these substances.

PMID- 10595842
TI  - Detection of stimulants in hair by laser microscopy.
AB  - In order to detect methamphetamine, a common stimulant, laser microscopy and
      immuno-histochemical staining, which uses anti-methamphetamine labeled with
      colloidal gold, were employed. The intensity of reflection of colloidal gold at a
      488- and 514-nm line of Ar laser was measured with a laser microscope equipped
      with a computerized image processing system. Microtomed hair samples from five
      drug users who died from methamphetamine intoxication were used. The drug
      distribution in the hair was quite different in these five cases, but the levels
      of drug concentration in two different hair samples from the same abuser were
      correlated. The results from two hair samples with roots showed a correlation
      between drug concentration in hair roots and plasma samples. The proposed method
      needs no melanin bleaching and is simple and sensitive enough to estimate the
      drug concentration using only a segment of hair.

PMID- 10595843
TI  - Sulfonium salts as derivatizing agents. 3. Quantitation of the cocaine metabolite
      benzoylecgonine in urine using gas chromatography with ion-pair extraction/on
      column alkylation.
AB  - Recent studies have demonstrated the utility of quantitative assays for
      benzoylecgonine in assessing the efficacy of cocaine-dependence-treatment
      programs to determine if the amount of cocaine consumed has been reduced. We
      describe a simple gas chromatographic method for determining benzoylecgonine
      concentrations in urine. BZE is extracted from urine as an ion pair with tri-n
      propylsulfonium ion. Injection into the heated injection port of the gas
      chromatograph results in thermal conversion of the ion pair to the n-propyl ester
      of BZE. Using the structural analogue of BZE, m-toluylecgonine, as the internal
      standard, the analysis is carried out on a (5% phenyl)methylpolysiloxane
      capillary column with nitrogen-phosphorus detection. There was a good correlation
      between BZE concentrations determined by gas chromatography-mass spectrometry and
      concentrations determined by the method described in this paper. Application to
      cocaine-dependence-treatment programs is discussed.

PMID- 10595837
TI  - Autocrine and paracrine mechanisms in the early stages of diabetic nephropathy.

PMID- 10595844
TI  - Determination by 1H NMR spectroscopy of paraquat in urine from acutely poisoned
      patients. Comparison with second-derivative spectroscopy method.
AB  - The application of 1H nuclear magnetic resonance (NMR) spectroscopy to
      characterize and quantitate paraquat in urine is described. Characterization was
      performed taking advantage of two NMR spectroscopy parameters: chemical shifts
      and coupling patterns. Without any pretreatment of the biological samples,
      herbicide was detected by its aromatic doublets at 8.49 and 9.02 ppm.
      Quantitation of the xenobiotic was realized by relative integration of the
      dipyridyl protons to an internal standard. After a validation step using control
      urine samples, quantitation was performed in urine obtained from two poisoned
      patients. On admission, mean paraquat concentrations were 985 (patient 1) and 500
      (patient 2) micromol/L. Results are compared and found to be in good agreement,
      using a second-derivative spectroscopy method.

PMID- 10595845
TI  - Simultaneous determination of ethylene glycol and glycolic acid in serum by gas
      chromatography-mass spectrometry.
AB  - We describe a gas chromatographic-mass spectrometric (GC-MS) procedure for the
      simultaneous determination of ethylene glycol (EG) and its major toxic
      metabolite, glycolic acid (GA), in serum. In this method, serum (50 microL) is
      treated with 150 microL of glacial acetic acid/acetonitrile (1:10, v/v; contains
      internal standard, 1,3-propanediol, 15 mg/dL) to precipitate protein. After
      centrifugation, 10 microL of supernate is treated with 500 microL of 2,2
      dimethoxypropane/dimethylformamide (80:20, v/v) to convert water to methanol, and
      the volume is then reduced to < 100 microL of dimethylformamide (but not to
      dryness). After formation of tertbutyldimethylsilyl derivatives, analysis is
      performed by capillary column GC-MS in selected ion mode. The method gives a
      linear response to 1000 mg/L each EG and GA (16.1 mmol/L and 13.2 mmol/L,
      respectively) and has a lower limit of detection and a lower limit of
      quantitation of 10 mg/L each EG and GA (0.16 mmol/L and 0.13 mmol/L,
      respectively). Total assay imprecision is CV < or = 6.4% (200 and 800 mg/L EG and
      GA [3.2 and 12.9 mmol/L EG; 2.6 and 10.5 mmol/L GA, respectively]). Absolute
      recovery from human serum was 91.1% for EG and 77.6% for GA. The procedure is
      free from any known interference. A complete analysis set (three calibrators,
      patient serum neat, patient serum diluted 1:5 (v/v), and two controls) may be
      completed in about 2 h. A preliminary result, based on a single calibrator and
      patient serum diluted 1:5 (v/v), is complete in about 1 h. The method has been
      used to aid the diagnosis and management in 34 cases of EG intoxication. Selected
      cases are briefly reviewed.

PMID- 10595846
TI  - On-line immunoaffinity extraction and HPLC analysis of flunitrazepam and its main
      metabolites in serum.
AB  - A sensitive, simple, and rapid method for the determination of flunitrazepam and
      its major metabolites (7-aminoflunitrazepam, 7-acetamidoflunitrazepam, and
      norflunitrazepam) in serum and plasma is presented. The on-line procedure uses an
      immobilized, highly reusable antibody against benzodiazepines for selective
      extraction from serum followed by analysis by high-performance liquid
      chromatography with ultraviolet detection. This reliable method provides a limit
      of detection of 1 ng/mL serum, and results are obtained in less than 40 min.

PMID- 10595847
TI  - A gas chromatography-mass spectrometry method for the quantitation of
      clobenzorex.
AB  - Drugs metabolized to amphetamine or methamphetamine are potentially significant
      concerns in the interpretation of amphetamine-positive urine drug-testing
      results. One of these compounds, clobenzorex, is an anorectic drug that is
      available in many countries. Clobenzorex (2-chlorobenzylamphetamine) is
      metabolized to amphetamine by the body and excreted in the urine. Following
      administration, the parent compound was detectable for a shorter time than the
      metabolite amphetamine, which could be detected for days. Because of the
      potential complication posed to the interpretation of amphetamin-positive drug
      tests following administration of this drug, the viability of a current
      amphetamine procedure using liquid-liquid extraction and conversion to the
      heptafluorobutyryl derivative followed by gas chromatography-mass spectrometry
      (GC-MS) analysis was evaluated for identification and quantitation of
      clobenzorex. Qualitative identification of the drug was relatively
      straightforward. Quantitative analysis proved to be a far more challenging
      process. Several compounds were evaluated for use as the internal standard in
      this method, including methamphetamine-d11, fenfluramine, benzphetamine, and
      diphenylamine. Results using these compounds proved to be less than satisfactory
      because of poor reproducibility of the quantitative values. Because of its
      similar chromatographic properties to the parent drug, the compound 3
      chlorobenzylamphetamine (3-Cl-clobenzorex) was evaluated in this study as the
      internal standard for the quantitation of clobenzorex. Precision studies showed 3
      Cl-clobenzorex to produce accurate and reliable quantitative results (within-run
      relative standard deviations [RSDs] < 6.1%, between-run RSDs < 6.0%). The limits
      of detection and quantitation for this assay were determined to be 1 ng/mL for
      clobenzorex.

PMID- 10595848
TI  - Methadone screening of racehorses.
AB  - The misuse of opiates in racehorses relates to their effect of increasing
      locomotor activity. Because methadone, a narcotic analgesic, has been suspected
      of use as a doping compound in the past, it was added to the list of banned drugs
      and should be considered in doping control. Because the literature fails to
      provide information on detection of methadone in blood or urine of horses, an
      enzyme-linked immunosorbent assay was developed to monitor this narcotic in
      equine body fluids. Combined with high-performance liquid chromatography, the
      immunoassay also served to confirm positives indicated by screening. Following
      intravenous administration of methadone (0.1 mg/kg), the drug was found for up to
      24 h in blood but was never identified in urine (10-pg/mL detection limit). Thus,
      urine is dismissed as a source of methadone control, and the use of blood to
      screen racehorses for this narcotic analgesic is suggested.

PMID- 10595849
TI  - Methadone conversion to EDDP during GC-MS analysis of urine samples.
AB  - During validation of a gas chromatography-mass spectrometry (GC-MS) method for
      the methadone metabolite 2-ethylidine-1,5dimethyl-3,3-diphenylpyrrolidine (EDDP),
      it was noted that detectable levels of EDDP were found during analysis of
      extracts from drug-free urine samples spiked with methadone. Different amounts of
      EDDP were detected by GC-MS during confirmation analysis; however, levels
      consistently exceeded 50 ng/mL at methadone concentrations > 10,000 ng/mL.
      Quantitation of EDDP was determined by the addition of EDDP-d3 to methadone
      spiked urine samples. Subsequent analysis of methadone-spiked urine extracts by
      high-performance liquid chromatography (HPLC) indicated no EDDP as a result of
      contaminated standard or conversion during solid-phase extraction. Reducing the
      GC injector-port temperature from 260 degrees C to 180 degrees C reduced the
      observed EDDP concentration in one sample from 201 ng/mL to 53 ng/mL at the
      initial methadone concentration of 10,000 ng/mL. These results indicate GC
      injector-port temperature induces thermal conversion of methadone to EDDP as an
      artifact. When confirmation of methadone and EDDP is critical to determining
      individual compliance with maintenance programs, alternative chromatographic
      methods (e.g., capillary electrophoresis, HPLC, or liquid chromatography-mass
      spectrometry) should be considered.

PMID- 10595850
TI  - Determination of opiates and cocaine and its metabolites in biological fluids by
      high-performance liquid chromatography with electrospray tandem mass
      spectrometry.
AB  - A rapid, sensitive, and specific method for the determination of opiates and
      cocaine and metabolites in urine, plasma, and blood was established. A one-step
      extraction followed by liquid chromatography-electrospray ionization tandem mass
      spectrometry operating in multiple reaction monitoring mode was used. Two
      chromatographic runs were performed, each in less than 6 min. The lower limit for
      accurate quantitative determination was 5 microg/L for cocaine and metabolites
      and 10 microg/L for opiates. Linearity was obtained from 10 to 1000 microg/L.
      Intraday (n = 6) and interday (n = 6) precisions and recoveries (n = 6) were
      determined at 10 or 25, 100, and 1000 microg/L concentrations. Precisions with a
      coefficient of variation less than 15% were obtained. Recoveries between 85 and
      115% were determined.

PMID- 10595851
TI  - Determination of germanium in human specimens: comparative study of atomic
      absorption spectrometry and microwave-induced plasma mass spectrometry.
AB  - The determination methods of germanium (Ge) in biological specimens such as blood
      plasma, erythrocytes, urine, hair, nail, and other organs were established using
      graphite furnace atomic absorption spectrometry (GFAAS) and microwave-induced
      plasma mass spectrometry (MIP-MS). The detection limits of Ge standard solution
      were 3 ng/mL with GFAAS and 0.05 ng/mL with MIP-MS. The detection limits in organ
      samples depended on the type of samples and sampling amounts: 3-30 ng/g by GFAAS
      and 0.05-0.5 ng/g by MIP-MS. The sensitivity of GFAAS was lower than that of MIP
      MS; however, it was adequate for determining Ge concentrations in specimens from
      patients who had ingested Ge. Samples were digested by a simple wet-ashing
      procedure using nitric acid and perchloric acid. To avoid the interfering effects
      of coexisting elements and perchloric acid residue, an extraction method using
      organic solvent was tried. When using MIP-MS, extraction was not necessary;
      however, both dilution and addition of an internal standard were needed. Special
      attention was required for iron-rich samples because a molecular ion of 56Fe16O
      was observed at nm/z72 where 2Ge was monitored. The results of Ge concentrations
      in human samples obtained by these methods agreed well. Interfering effects of
      perchloric acid, which was used for digestion and which remained in samples, were
      observed in both methods. Hair and nail samples from people who had ingested Ge
      were useful for monitoring Ge in the body. Hair samples were useful for
      determining past exposure to Ge when the distribution patterns from the scalp to
      the end of the strand were analyzed. In control subjects, Ge concentrations in
      the listed specimens and organs were lower than 0.1 microg/g or mL, and these low
      levels of Ge were able to be determined by MIP-MS in combination with the
      extraction method.

PMID- 10595852
TI  - Rapid extraction of clenbuterol from human and calf urine using empore C8
      extraction disks.
AB  - In the present paper, disk extraction was evaluated for the rapid isolation of
      clenbuterol from human and calf urine, followed by high-performance liquid
      chromatography analysis with UV detection. A method was developed for the
      extraction with standard density C8 disks. The disks could be washed with 25%
      methanol in 0.01M sodium hydroxide without significant losses of clenbuterol. The
      recovery of denbuterol was about 85%, and the extracts were clean. The detection
      limit was about 10 ng/mL. The main advantages of these disks were the saving of
      time and the reduced amounts of organic solvents needed.

PMID- 10595853
TI  - Forensic toxicology laboratory guidelines.

PMID- 10595854
TI  - Interference of diphenhydramine with the EMIT II immunoassay for propoxyphene.

PMID- 10595855
TI  - Serum thyroxine binding capacity-dependent bias in an automated free thyroxine
      assay.
AB  - The magnitude of serum thyroxine (T4) binding capacity (sBC) dependent bias in
      the AXSYM free thyroxine (FT4) assay was assessed using two recently described
      tests. One of the tests uses a direct equilibrium dialysis (ED) FT4 assay as the
      reference method. The results obtained with the AXSYM method were compared with
      those obtained by the ED FT4 method in patient sera having a wide range of sBC.
      The other test involves comparison of the FT4 results obtained following dilution
      of sera by an inert buffer, to theoretically derived FT4 results. As serum
      dilution causes a predictable decrease in sBC, the demonstration of a negative
      bias whose magnitude increases in parallel to the dilution, is indicative of an
      sBC-dependent bias. The AXSYM FT4 assay exhibited a significant sBC-dependent
      bias. This sBC-dependent bias is likely to have been caused by the presence of
      significant amounts of T4 binding proteins in the assay reagents.

PMID- 10595856
TI  - Monoclonal antibody-based sensitive enzyme-linked immunosorbent assay for murine
      serum amyloid A.
AB  - Enzyme-linked immunosorbent assay (ELISA) methods for measuring murine serum
      amyloid A (SAA), a representative acute phase reactant, were developed utilizing
      a newly produced monoclonal antibody. Two site-ELISA, in which the monoclonal
      antibody was used as the captured antibody, was sensitive enough to determine the
      SAA concentration in mice at the steady state. Direct binding ELISA, in which the
      sample SAA bound to the plastic wells was detected by the antibody, was simple
      and suitable for measuring the elevated SAA, but could not analyze the resting
      level of SAA because of the need for high dilution in plasma samples. Plasma SAA
      concentrations were measured in ten ICR mice on the day of purchase and at the
      end of seven days of ordinary rearing. The SAA concentration of one animal
      decreased from 1.6 to 0.5 mg/l during a week, while the others had no obvious
      changes. The plasma SAA of the ten animals after one week of rearing ranged from
      0.3 to 0.8 mg/l with a mean of 0.47. These mice, two days after 10 microg
      lipopolysaccharide were given, had increased SAA values up to a mean of 300 mg/l,
      though with variations between animals.

PMID- 10595857
TI  - Validation of an ELISA for the quantitation of lanoteplase, a novel plasminogen
      activator.
AB  - An ELISA was developed and validated for the quantitation of lanoteplase in human
      citrated plasma. The ELISA employed a monoclonal anti-lanoteplase antibody
      absorbed onto 96-well microtiter plates to capture lanoteplase in citrated human
      plasma samples containing PPACK, a protease inhibitor. The captured lanoteplase
      was detected using a biotinylated rabbit anti-lanoteplase polyclonal antibody.
      The standard curve range in human plasma for the ELISA was 7-100 ng/ml.
      Assessment of individual standard curve variability indicated reproducible
      responses with r2 values of > or = 0.985. The accuracy (% DEV) and precision
      (%RSD) estimates for the ELISA based on the predicted values from quality control
      (QC) samples were within 7.3% and 11%, respectively. Cross-reactivity with t-PA
      was determined to be less than 11% by ELISA. The stability of lanoteplase was
      established in human citrated PPACK plasma for 24 hours at 4 degrees C, for 2
      months at -20 degrees C, for 22 months at -70 degrees C, three weeks at room
      temperature, and through four freeze/thaw cycles. To quantify lanoteplase
      plasminogen activator (PA) activity, a commercially available chromogenic
      activity assay was also validated. This method and its application is described
      briefly here. The lanoteplase ELISA as well as the commercial activity method
      were successfully employed to evaluate the pharmacokinetic parameters of
      lanoteplase in support of clinical Phase II/III studies.

PMID- 10595858
TI  - Evaluation of a new troponin I method on the Bayer Immuno 1 immunoassay analyser.
AB  - We have evaluated the analytical and clinical performance of an automated
      immunoassay for serum cardiac troponin I (Bayer Immuno 1TM, Bayer Diagnostics,
      Tarrytown, NY). The between batch imprecision was found to be between 1.2 and
      3.2% over the concentration range 2.5 - 34.0 microg/L. The analytical range
      obtained from duplicate analysis of patient samples and defined as a coefficient
      of variation of 10% or less was 0.3 - 200 microg/L. The detection limit was found
      to be less than 0.1 microg/L. A method comparison with the Dade Stratus method
      (Dade Behring, Wilmington, DE) yielded regression statistics with a slope of
      0.705 and an intercept of -0.260. An analysis of samples from 40 patients with
      renal failure demonstrated six with detectable levels of troponin I (0.2 - 1.9
      microg/L). Samples from patients with paraproteinaemia did not demonstrate
      detectable troponin I (from n = 30); however, two patients with elevated
      rheumatoid factor titers (from n = 20) demonstrated a detectable amount of
      troponin I (0.1 and 0.2 microg/L). In a study of 100 patients admitted with acute
      chest pain and a diagnosis of unstable angina, 6 were subsequently diagnosed as
      having suffered a myocardial infarction. On admission the sensitivity and
      specificity of the troponin I results were 26.7% and 94.7%, respectively, moving
      to 100% and 83% 12 hours after admission.

PMID- 10595859
TI  - Helicobacter pylori eradication in patients with non-ulcer dyspepsia.
AB  - Epidemiological and pathophysiological studies, as well as clinical trials,
      attempting to identify a relationship between Helicobacter pylori infection and
      non-ulcer dyspepsia (NUD), or a subset of NUD, have produced inconsistent and
      confusing results. While it is possible that H. pylori eradication may be
      beneficial for symptom relief in a small proportion of patients, routine H.
      pylori testing and treatment in documented NUD is not currently widely accepted.
      Despite the lack of convincing evidence, the European Helicobacter pylori Study
      Group, an Asian Pacific Consensus Meeting, the American Digestive Health
      Foundation and the American Gastroenterology Association have all recommended
      considering H. pylori eradication in patients with NUD on a patient-by-patient
      basis. Recently, large prospective, randomised, double-blind, controlled clinical
      trials applying highly effective antimicrobial therapy have been conducted with
      12 months follow-up. Although these well-designed studies have reached differing
      conclusions, the results have been largely negative. H. pylori eradication
      therapy in NUD will fail to relieve symptoms in most patients in the long term.

PMID- 10595860
TI  - Balanced analgesia: what is it and what are its advantages in postoperative pain?
AB  - The concept of balanced analgesia was introduced to improve analgesic efficacy
      and reduce adverse effects. A large amount of clinical data has documented
      improved analgesia by combining different analgesics, but data on reducing
      adverse effects are inconclusive. Balanced analgesia should be used whenever
      possible, and future studies should be directed to define optimal combination
      regimens in individual surgical procedures.

PMID- 10595862
TI  - Overview of pharmacological treatment of Kawasaki disease.
AB  - Kawasaki disease has been researched for 32 years but its aetiology is still
      unknown. Conventional therapy for the disease includes corticosteroids and
      aspirin (acetylsalicylic acid) as anti-inflammatory and/or antithrombotic agents
      but they have not been proven to prevent coronary artery aneurysms. Although a
      high incidence of liver dysfunction in Japanese patients with Kawasaki disease
      receiving high dose aspirin (> or =80 mg/kg/day) suggests racial differences in
      salicylate sensitivity, the duration of fever in patients receiving high dose
      aspirin is shorter than that in patients receiving moderate dosages (30 to 50
      mg/kg/day). Furthermore, most corticosteroid-resistant patients were found to
      develop coronary artery aneurysms, many of which were large. With the
      clarification of the pathogenesis and clinical features of Kawasaki disease,
      advances in its treatment have been achieved. The introduction of high-dose
      intravenous gamma-globulin (IVGG) was an epoch in this field and IVGG is now a
      standard therapy with the incidence of persistent coronary aneurysms 1.9% in
      children with the disease receiving IVGG. Today, research is mainly directed
      toward the treatment of IVGG-resistant patients. One to 3 days of pulsed doses of
      methylprednisolone (30 mg/kg/day) or readministration of IVGG 1 g/kg (once to
      several times) has been recommended for patients with IVGG-resistant Kawasaki
      disease.

PMID- 10595861
TI  - Drugs acting on imidazoline receptors: a review of their pharmacology, their use
      in blood pressure control and their potential interest in cardioprotection.
AB  - Drugs acting within the autonomic nervous system are of particular interest when
      autonomic abnormalities are implicated in the development and maintenance of
      various cardiovascular pathologies. For example, it has been documented that in
      the early stages of hypertensive disease, i.e. hyperkinetic borderline
      hypertension, a sympathetic hyperactivity associated with a decreased
      parasympathetic activity results in increased cardiac output and heart rate.
      Several classes of drugs acting within the central, as well as the peripheral,
      autonomic nervous system are very efficient in treating hypertensive disease. One
      class - the second generation of a group of centrally acting drugs selective for
      imidazoline receptors - has proved beneficial in this respect, because drugs in
      this class are well tolerated and have interesting additional effects such as
      their antiarrhythmic action. Rilmenidine and moxonidine are the lead compounds of
      this class of drugs. Rilmenidine and moxonidine both proved more selective for
      cerebral imidazoline receptors than the reference drug, clonidine. It was
      suggested that this selectivity, attributable to their lower affinity for alpha2
      adrenoceptors, explains the low incidence of adverse effects (including sedation)
      associated with these drugs. In addition, potentially beneficial actions on
      cardiac dysrythmias and congestive heart failure enlarge the therapeutic
      potential of the second generation of imidazoline-related drugs. This review
      focuses on the main pharmacological and clinical properties of rilmenidine and
      moxonidine, paying particular attention not only to their efficacy in
      hypertension but also to other potential cardiovascular indications.

PMID- 10595863
TI  - Treatment of patients with Paget's disease of bone.
AB  - Paget's disease is a progressive bone disease, monostotic or polyostotic,
      characterised by hypertrophy of affected bones and accelerated disorganised bone
      remodelling. It results in bone deformities and pain, with a risk for articular
      and neurological complications, and fractures. The risk of complications, and
      thus the therapeutic decision, is a function of the age of the patient, and the
      severity and the activity of the disease. Bisphosphonates are first-line therapy
      for Paget's disease, and the advent of the new bisphosphonates permits a dramatic
      improvement in treatment. The optimal treatment regimen should obtain
      normalisation or quasi-normalisation of markers of bone remodelling. This result
      has the potential for a long-term control of the disease.

PMID- 10595864
TI  - Medical management of children with juvenile rheumatoid arthritis.
AB  - One of the most important and changing areas of research in paediatric
      rheumatology is the optimum approach to the treatment of children with chronic
      arthritis. Until recently all medications for children with arthritis were
      nonspecific in terms of our understanding, albeit poor, of the pathogenesis of
      these diseases. Of current therapies, low dose, once-a-week methotrexate has
      emerged as the therapeutic agent of choice for children who fail to respond
      adequately to administration of a nonsteroidal anti-inflammatory drug. Thereby,
      it has displaced the more traditional slower acting anti-rheumatic drugs,
      although one or more of them are often combined with methotrexate in the
      polypharmaceutical approach to childhood arthritis. Better and more specific
      agents are needed, especially for systemic onset disease, unremitting
      polyarticular involvement, and certain complications such as resistant chronic
      uveitis. At this time the introduction of the cyclo-oxygenase 2 inhibitors and
      etanercept (soluble tumour necrosis factoralpha.p75 fusion protein) may herald an
      era of more specific and effective therapy.

PMID- 10595865
TI  - Oseltamivir.
AB  - Oseltamivir is the oral prodrug of GS4071, a selective inhibitor of influenza A
      and B viral neuraminidase. After absorption from the gastrointestinal tract
      oseltamivir is efficiently converted to GS4071, which is maintained at high and
      sustained concentrations in plasma. Based on studies in rats and ferrets, GS4071
      appears to be effectively distributed to all tissues, including major sites of
      infection in the upper and lower respiratory tracts. Oral oseltamivir was an
      effective treatment in naturally occurring influenza when administered within 36
      hours of symptom onset, reducing both the duration and severity of symptoms and
      the incidence of secondary complications in influenza-infected patients enrolled
      in 2 large placebo-controlled, double-blind trials. Prophylactic oral
      administration of oseltamivir was effective in reducing the incidence of
      influenza illness according to pooled data from 2 large placebo-controlled,
      double-blind trials of healthy nonimmunised volunteers during periods of seasonal
      influenza activity. The reported incidence of viral resistance to GS4071 was low
      in clinical isolates from oseltamivir treatment studies. All known GS4071
      resistant genotypes are growth disadvantaged and display significantly reduced
      infectivity in animals. Oseltamivir was well tolerated in human volunteers and
      patients in clinical trials. Treatment-related adverse events (primarily
      gastrointestinal) were mild and transient in nature.

PMID- 10595866
TI  - Fibrin sealant: a review of its use in surgery and endoscopy.
AB  - Fibrin sealant (fibrin adhesive; fibrin glue; Beriplast P1) is a haemostatic and
      wound support product consisting of the blood coagulation factors fibrinogen,
      factor XIII and thrombin, the antifibrinolytic agent aprotinin and calcium
      chloride. Fibrin sealant has been used to good effect in a wide variety of
      surgical and endoscopic procedures. Suture support was provided in series of
      patients with oesophageal, gastric, colonic or rectal anastomoses, and fibrin
      sealant was as effective in haemostasis as microcrystalline collagen powder in
      hepatic surgery. It did not reduce postoperative peritoneal drainage after
      elective cholecystectomy, however. A 41% reduction (p<0.02) in incidence of air
      leakage was achieved when fibrin sealant was added to sutures in patients
      undergoing pulmonary resection in a randomised single-blind study. A high rate of
      complete remission of malignant pleural effusion has been reported after
      intrapleural instillation of fibrin sealant, and successful sealing of CSF leaks
      after trauma or surgery has also been achieved. Attenuation of prolonged or
      excessive haemorrhage after dental extraction has been achieved in patients on
      anticoagulant therapy or with haemorrhagic disorders who received fibrin sealant
      with packing and suturing. Repeated endoscopic injection of fibrin sealant was
      superior to single injection sclerotherapy with polidocanol 1% in a randomised
      study in 805 patients with bleeding peptic ulcers. Other data suggest that
      endoscopic injection of fibrin sealant is associated with lower recurrence of
      bleeding and need for emergency surgery than thrombin with adrenaline
      (epinephrine) or hypertonic saline with adrenaline. Similar haemostatic efficacy
      to laser photocoagulation or sclerotherapy was reported in a retrospective
      comparison. A statistically significant reduction relative to suturing in the
      incidence of wound dehiscence was reported after the use of fibrin sealant in
      cataract surgery, and benefit of the sealant has also been noted in patients
      receiving skin grafts and in those undergoing transurethral resection of the
      prostate gland. CONCLUSIONS: Although comparative studies would assist in the
      clarification of the place of the product discussed with respect to other
      haemostatic or wound support techniques and to other fibrin sealants, the
      formulation reviewed here has been shown overall to be effective and well
      tolerated in a variety of haemostatic and wound healing support roles in numerous
      types of surgery. Fibrin sealant has also been shown to be useful when
      administered endoscopically, with superiority over sclerotherapy being shown
      after repeated application in patients with peptic ulceration. Fibrin sealant can
      therefore be considered useful in a number of surgical and endoscopic settings.

PMID- 10595867
TI  - Rapacuronium bromide: a review of its use in anaesthetic practice.
AB  - Rapacuronium bromide (rapacuronium) is an aminosteroid, nondepolarising
      neuromuscular blocking agent (NMBA). At the recommended dose for endotracheal
      intubation (1.5 mg/kg), an intravenous bolus of rapacuronium has a rapid onset
      (approximately 1.2 to 1.8 minutes) and short duration of action (10.2 to 16.5
      minutes) in adults undergoing elective surgery. Rapacuronium 1.5 mg/kg produced
      clinically acceptable intubating conditions in 68 to 89% of these patients at
      about 1 minute after administration. The onset, extent and duration of action and
      clinical efficacy of an intubating dose of rapacuronium appeared to be similar in
      the general adult population, adult patients with renal or hepatic dysfunction,
      patients undergoing Caesarean section, and elderly, paediatric or obese adult
      patients. Onset time with rapacuronium 1.3 to 2.5 mg/kg (0.9 to 1.8 minutes) was
      similar to or slower than that with a 1 mg/kg dose of the depolarising NMBA
      suxamethonium chloride (0.8 to 1.2 minutes). Intubating conditions were
      clinically acceptable about I minute after administration in 86 to 100% of
      patients with rapacuronium 1.3 to 2.5 mg/kg compared with in 88 to 97% of
      patients with suxamethonium chloride 1 or 1.5 mg/kg. Spontaneous recovery was
      slower with rapacuronium than with suxamethonium chloride, but neostigmine 0.04
      or 0.05 mg/kg administered 2 or 5 minutes after rapacuronium 1.3 or 1.5 mg/kg
      accelerated recovery. In the few available comparative clinical trials,
      rapacuronium 1.5 mg/kg appeared to have a more rapid onset of action than the
      nondepolarising NMBAs mivacurium chloride 0.25 mg/kg, rocuronium bromide 0.45 or
      0.6 mg/kg or vecuronium bromide 0.07 mg/kg, and a shorter duration of action than
      rocuronium bromide 0.45 or 0.6 mg/kg or vecuronium bromide 0.07 mg/kg. Additional
      boluses (< or =3) of rapacuronium 0.5 or 0.55 mg/kg after an intubating bolus of
      1.5 mg/kg provided continued skeletal muscle relaxation during short surgical
      procedures in adult patients. However, these patients may recover more slowly
      than those who receive a single bolus of the drug. Bronchospasm was the most
      common treatment-related adverse event with rapacuronium 0.3 to 3 mg/kg (3.4% of
      adult patients). Tachycardia, injection site reaction and hypotension were also
      reported in small proportions of patients (1.6, 1.1 and 0.9%). The overall
      incidence of drug-related adverse events was similar with rapacuronium 1.5 or 2.5
      mg/kg or suxamethonium chloride 1 mg/kg (8 vs. 6%) but bronchospasm, tachycardia
      and injection site reaction tended to occur more often with rapacuronium.
      CONCLUSIONS: At the recommended dose of 1.5 mg/kg, the nondepolarising NMBA
      rapacuronium has a rapid onset and short duration of action. It may provide a
      nondepolarising alternative to suxamethonium chloride for endotracheal
      intubation. Rapacuronium may be preferred over rocuronium bromide, vecuronium
      bromide or mivacurium chloride in this indication.

PMID- 10595868
TI  - Stavudine: an update of its use in the treatment of HIV infection.
AB  - Stavudine is a thymidine nucleoside analogue which is phosphorylated
      intracellularly to an active metabolite, stavudine 5'-triphosphate. This
      metabolite inhibits HIV replication, either by competing with thymidine 5'
      triphosphate for incorporation into viral DNA by reverse transcriptase or by
      causing premature termination of the viral chain after incorporation. Resistance
      to stavudine, either alone or as part of resistance to multiple nucleoside
      reverse transcriptase inhibitors, has been reported; however, high-level
      resistance is uncommon even after long periods of treatment. Initial treatment
      with stavudine-containing triple therapies reduced HIV RNA levels to below the
      limit of detection (LOD; 500 copies/ml) in 68 to 100% of antiretroviral-naive
      patients after at least 20 weeks of treatment. Effects on clinical outcomes have
      not yet been established, although earlier trials showed significant improvements
      with stavudine (alone or with 1 other drug) in patients who had previously
      received zidovudine. Results from 2 randomised nonblind clinical trials indicated
      that the efficacy of stavudine-containing triple therapy was similar to that of
      zidovudine-containing triple therapy (when used in combination with the same
      drugs), although there were no statistical comparisons. Improvements in surrogate
      end-points have also been seen in trials in antiretroviral-experienced patients
      receiving stavudine and 2 or 3 other antiretroviral agents. Stavudine-containing
      combination therapies have also been effective in reducing viral load and
      increasing CD4+ lymphocyte count in children, although data are limited. Like
      other nucleoside analogues, stavudine treatment can cause mitochondrial toxicity.
      The major adverse effect from this observed with stavudine therapy is peripheral
      neuropathy, which is both dosage- and treatment duration-dependent. Most cases
      respond to short term cessation of treatment and reintroduction of stavudine at
      half the previous dosage. CONCLUSION: Stavudine-containing triple therapies are
      effective in the treatment of antiretroviral-naive adults with HIV infection as
      assessed by surrogate end-points; earlier trials involving 1 or 2-drug therapy
      showed that stavudine can significantly improve clinical end-points. Stavudine
      has also been beneficial as part of combination regimens in antiretroviral
      experienced patients and children with HIV infection, although data are limited
      and more studies are needed. High-level resistance to stavudine is uncommon. The
      major adverse event associated with treatment is peripheral neuropathy, which may
      limit its use in some patients. Currently, stavudine has a valuable role as part
      of initial triple therapy in antiretroviral-naive adults with HIV/AIDS.

PMID- 10595870
TI  - Local accumulations of B-50/GAP-43 evoke excessive bleb formation in PC12 cells.
AB  - B-50 (GAP-43) is an axonal, plasma membrane-associated protein involved in growth
      cone morphology and function. We have conducted immunocytochemical, electron
      microscopic, and time-lapse experiments to visualize morphological consequences
      of local accumulations of B-50 at the plasma membrane of B-50-transfected PC-B2
      cells, a clonal PC12 cell line with very low expression of endogenous B-50. The
      distribution of the transfected B-50 within these cells was inhomogeneous. At
      sites where the B-50 concentration was locally increased up to twofold, numerous
      filopodia were present in growth cone-like, substrate-attached regions. When
      local B-50 concentrations were even higher (up to 6.2-fold), blebs were formed,
      often containing vesicular structures, heavily decorated with B-50
      immunoreactivity. Double labeling with f-actin binding phalloidin revealed that
      local B-50 accumulations were accompanied by increased actin filament
      concentrations. Colocalization of B-50 with actin filaments was prominent in
      filopodia, but was virtually absent in blebs, suggesting a disconnection of the
      bleb plasma membrane from the actin cytoskeleton. We conclude that B-50 evokes
      distinct effects on cell-surface activity in PC12 cells depending on its local
      concentration.

PMID- 10595869
TI  - The alpha7 nicotinic acetylcholine receptor in neuronal plasticity.
AB  - A growing body of evidence indicates that neuronal nicotinic acetylcholine
      receptors (nAChRs), in addition to promoting fast cholinergic transmission, may
      modulate other neuronal activities within the central nervous system (CNS). In
      particular, the alpha7 nAChR is highly permeable to Ca2+ and may serve a distinct
      role in regulating neuronal plasticity. By elevating intracellular Ca2+ levels in
      discrete neuronal locations, these ligand-gated ion channels may influence
      numerous physiological processes in developing and adult CNS. In this article, we
      review evidence that both pre- and postsynaptic alpha7 nAChRs modulate
      transmitter release in the brain and periphery through Ca2+-dependent mechanisms.
      The possible role of alpha7 nAChRs in regulating neuronal growth and
      differentiation in developing CNS is also evaluated. We consider an interaction
      between cholinergic and glutamatergic transmission and propose a hypothesis on
      the possible coregulation of intracellular Ca2+ by N-methyl-D-aspartate (NMDA)
      receptors and alpha7 nAChRs. Finally, the clinical significance of alterations in
      the normal function of alpha7 nAChRs is discussed as it pertains to prenatal
      nicotine exposure, schizophrenia, and epilepsy.

PMID- 10595871
TI  - Signaling of neuronal cell death by the p75NTR neurotrophin receptor.
AB  - The neurotrophin receptor (p75NTR) is best known for mediating tropic support by
      participating in the formation of high-affinity nerve growth factor (NGF)
      receptor complexes with trkA, however, p75NTR more recently has been shown to act
      as a bona fide death-signaling receptor, which can signal independently of trkA.
      This article discusses the evidence for an active role of p75NTR in neuronal cell
      death and the mechanisms controlling this process, including roles for Bcl-2
      family members, the c-jun stress kinase JNK, the transcription factor nuclear
      factor kappa B (NFkappaB), and caspases.

PMID- 10595872
TI  - Molecular investigations on the nicotinic acetylcholine receptor: conformational
      mapping and dynamic exploration using photoaffinity labeling.
AB  - The nicotinic acetylcholine receptor (nAChR) is a well-understood member of the
      ligand-gated ion channels superfamily. The members of this signaling proteins
      group, including 5HT3, GABA(A), glycine, and ionotropic glutamate receptors, are
      thought to share common secondary, tertiary, and quaternary structures on the
      basis of a very high degree of sequence similarity. Despite the absence of X-ray
      crystallographic data, considerable progress on structural analysis of nAChR was
      achieved from biochemical, mutational, and electron microscopy data allowing the
      emergence of a three-dimensional image. Photoaffinity labeling and site-directed
      mutagenesis gave information on the tertiary structure with respect to the
      agonist/antagonist binding sites, the ion channel, and its selectivity filter.
      nAChR is an allosterical protein that undergoes interconversion among several
      conformational states. Time-resolved photolabeling was used in an attempt to
      elucidate the structural changes that occur in nAChR on neurotransmitter
      activation. Tertiary and quaternary rearrangements were found in the cholinergic
      binding pocket and in the channel lumen, but the structural determinant and the
      functional link between the binding of agonist and the channel gating remain
      unknown. Time-resolved photolabeling of the functional activated A state using
      photosensitive agonists might help in understanding the dynamic process leading
      to the interconversion of the different states.

PMID- 10595874
TI  - Gender differences in testing for syphilis in emergency department patients
      diagnosed with sexually transmitted diseases.
AB  - The purpose of this study was to investigate the effect of gender on the
      likelihood of syphilis screening in Emergency Department (ED) patients with
      suspected sexually transmitted diseases (STDs). We reviewed charts of patients
      diagnosed with STDs in an urban university hospital ED from January 1995 through
      June 1996. Exclusion criteria included documented history of syphilis, syphilitic
      lesions, return visit within 30 days of the original ED care, and hospital
      admission. Records for 208 eligible patients were included in the study. Twenty
      two of 45 male patients were screened for syphilis as opposed to 12 of 163 female
      patients (48.9% vs. 7.4%, respectively). This study demonstrates that male
      patients diagnosed and treated for STDs are more likely to be screened for
      syphilis than female patients.

PMID- 10595875
TI  - Large-diameter suction system reduces oropharyngeal evacuation time.
AB  - Aspiration of vomitus is associated with significant morbidity and mortality.
      Standard suction equipment may be incapable of rapidly evacuating vomitus from
      the oropharynx. In this prospective, randomized, controlled bench trial, we
      compared a large-diameter suction system (5/8-inch open-bore suction tip and 3/4
      inch tubing attached to a 1-inch pour spout) with two standard suction systems
      (small-diameter blunt-nosed and medium-diameter open-bore 1/4-inch suction tips
      connected to 1/4-inch tubing). Mean evacuation times from the mouth of a
      volunteer of 90 mL of water, activated charcoal, and Progresso vegetable soup
      were measured. All systems removed water within 3 s. With vegetable soup,
      however, both standard suction systems obstructed. Despite additional mechanical
      scooping with the standard suction wands, the large-diameter system significantly
      outperformed both standard systems, by 10 s with the soup and 40 s with the
      charcoal The reduction in oropharyngeal evacuation times of viscous and
      particulate material may have important clinical implications in the emergency
      management of the threatened airway.

PMID- 10595876
TI  - The Ottawa Ankle Rules in Asia: validating a clinical decision rule for
      requesting X-rays in twisting ankle and foot injuries.
AB  - This was a study to determine if the Ottawa Ankle Rules (OAR) for requesting x
      ray studies in twisting ankle and foot injuries are applicable in our Asian
      population. Four hundred ninety-four consecutive eligible patients presenting to
      the emergency department with twisting injuries about the ankle were examined by
      emergency physicians for clinical criteria requiring ankle and foot x-ray studies
      according to the OAR. Four hundred eighty-eight of these patients underwent x-ray
      studies that were interpreted by a radiologist. The sensitivity and specificity
      of the OAR for predicting the presence of fracture were calculated to be 0.9 and
      0.34, respectively. When the rules were modified to cast a wider screening net,
      sensitivity improved to 0.99. We conclude that the OAR are not applicable to our
      population because of inadequate sensitivity, but when modified become acceptable
      and can reduce the number of x-ray studies requested by 28%.

PMID- 10595873
TI  - The ordered visual transduction complex of the squid photoreceptor membrane.
AB  - The study of visual transduction has given invaluable insight into the mechanisms
      of signal transduction by heptahelical receptors that act via guanine nucleotide
      binding proteins (G-proteins). However, the cyclic-GMP second messenger system
      seen in vertebrate photoreceptor cells is not widely used in other cell types. In
      contrast, the retina of higher invertebrates, such as squid, offers an equally
      accessible transduction system, which uses the widespread second messenger
      chemistry of an increase in cytosolic calcium caused by the production of
      inositol-(1,4,5)-trisphosphate (InsP3) by the enzyme phospholipase C, and which
      may be a model for store-operated calcium influx. In this article, we highlight
      some key aspects of invertebrate visual transduction as elucidated from the
      combination of biochemical techniques applied to cephalopods, genetic techniques
      applied to flies, and electrophysiology applied to the horseshoe crab. We discuss
      the importance and applicability of ideas drawn from these model systems to the
      understanding of some general processes in signal transduction, such as the
      integration of the cytoskeleton into the signal transduction process and the
      possible modes of regulation of store-operated calcium influx.

PMID- 10595877
TI  - Practicing procedures on the recently dead.
AB  - We sought to measure the prevalence of practicing procedures on the recently dead
      in emergency departments. Surveys were mailed to all medical students, interns,
      residents in Emergency Medicine, emergency physicians, and trauma team leaders
      working in the teaching hospitals of a city with a population of 600,000. Of 447
      distributed surveys, 222 (49%) were returned. Participants were divided into
      learners and teachers. Of the learners (n = 162), 6 (4%) had practiced intubation
      and 4 (3%) had practiced pericardiocentesis on a recently dead patient. Of the
      teachers (n = 30), 8 (27%) had had learners practice intubation and 4 (13%) had
      had learners practice pericardiocentesis on a recently dead patient. Of the
      students and teachers who practiced procedures on recently dead patients, none
      had obtained consent. The prevalence of practicing procedures on recently dead
      patients appears to be less than has been reported previously. Intubation is the
      most commonly practiced procedure on recently dead patients. None of the
      participants obtained consent before practicing a procedure.

PMID- 10595878
TI  - The identification of high risk asthmatic children using the emergency department
      asthma visit count.
AB  - A subset of asthma patients accounts for a disproportionate amount of health care
      resources through repeat visits. A retrospective analysis of emergency department
      (ED) billing and admission databases was performed to assess the value of the
      asthma visit count as an indicator of future health care utilization. The asthma
      visit count was found to have a direct and linear relationship with both future
      ED visits and future inpatient admission for asthma. Children with 2 visits in
      1997 had a substantial (26.9%) risk of returning in the 1998 study period, and a
      6.6% risk of admission. Children who visited the ED 3 or more times in 1997 for
      asthma had a risk of repeat visit of more than 52%, and more than 12% of this
      highest risk group were admitted to the hospital at least once during the 1998
      study period. Once an annual asthma visit count of 3 or more is achieved, there
      can be little controversy with the "high utilizer" label. The substantial
      increase in the visit and admission risk warrants consideration of the asthma
      visit count as an easily obtainable, objective marker to identify high-risk
      children for both study and clinical purposes. Further research is needed.

PMID- 10595879
TI  - Comparison of wire-guided cricothyrotomy versus standard surgical cricothyrotomy
      technique.
AB  - We compared a wire-guided cricothyrotomy technique vs. standard surgical
      cricothyrotomy in terms of accuracy in placement, complications, performance
      time, incision length, and user preference. We conducted a randomized, crossover
      controlled trial in which Emergency Medicine (EM) attendings and residents
      performed cricothyrotomies by both standard and wire-guided techniques (using a
      commercially available kit) on human cadavers after a 15-min training session.
      Procedure time, incision length, and physician preference were recorded. Cadavers
      were inspected for accuracy of placement and complications. Airway placement was
      accurate in 13 of 15 cases for the standard technique (86.7%), and 14 of 15 cases
      for the wire-guided technique (93.3%). When comparing wire-guided vs. standard
      techniques, there were no differences in complication rates or performance times.
      The wire-guided technique resulted in a significantly smaller mean incision
      length than the standard technique (0.53 vs. 2.53 cm, respectively, p<0.0001).
      Overall, 14 of 15 physicians stated that they preferred the wire-guided to the
      standard technique. Our data suggest that this wire-guided cricothyrotomy
      technique is as accurate and timely to use as the standard technique and is
      preferred by our physician operators. In addition, the technique results in a
      smaller incision on human cadaver models.

PMID- 10595880
TI  - Pericardio-diaphragmatic rupture: five new cases and literature review.
AB  - This report adds five new cases to the world literature on pericardio
      diaphragmatic rupture (PDR). Five of 48 (10.4%) consecutive cases of traumatic
      diaphragmatic rupture (TDR) seen by a single surgeon over a 22-year period were
      PDR. These rare cases include a case associated with air bag deployment, a case
      of double rupture involving both the pericardium and left diaphragm, and a case
      resulting from penetrating trauma. This series suggests that PDR may be under
      reported as a percentage of TDR. Only 65 cases of PDR have been reported
      previously. Review of the world literature on PDR is included. Anatomic factors,
      mechanisms of injury, differential diagnosis, diagnostic techniques, and
      treatment considerations for PDR are discussed.

PMID- 10595881
TI  - Intersection syndrome: a case report and review of the literature.
AB  - Intersection syndrome is a condition that should be differentiated from
      DeQuervain's stenosing tenosynovitis, as there are many subtle differences in
      treatment and prognosis. We present a case of intersection syndrome, describing
      its characteristic clinical and anatomic features, and highlighting differences
      in the areas of diagnosis and treatment relative to the better known DeQuervain's
      tenosynovitis.

PMID- 10595882
TI  - Two cases of Munchausen's syndrome presenting as acute respiratory distress.
AB  - We present two cases of factitious disorder that presented as acute respiratory
      distress. The presentation was extreme to the point that the patients were
      intubated. Both patients were employed in an ancillary health care profession.

PMID- 10595883
TI  - Electric injury, part I: treatment priorities, subtle diagnostic factors, and
      burns.
AB  - Patients with electric injury present a significant challenge. Possible
      mechanisms of injury include electrical disruption of cardiac rhythm and
      breathing, burns of several types, and inhalation of gases from fires. Mechanical
      trauma may come from electric arc blast, explosion of gases, falls, and strong
      muscle contractions. Additionally, the patient may have multiple co-existent
      injuries, comorbidities, an abnormal mental status, and a severely disrupted acid
      base balance. These factors can make diagnosis and treatment difficult. In
      addition, electric injury can cause a number of slowly developing and subtle
      sequelae that may be difficult, if not impossible, to diagnose on initial
      examination.

PMID- 10595884
TI  - Overlooked sources of ethanol.
AB  - The case of a 55-year-old female who presented to the emergency department with
      acute ethanol intoxication and suicidal ideation is reported. After initiating
      routine management, we discovered that her serum ethanol levels remained
      persistently elevated as a result of the patient's secretly ingesting mouthwash.
      This occurred after she was searched and allowed to retain personal hygiene
      products. Alcohol-dependent patients may consume ethanol products that are not
      manufactured for ingestion. These products include cosmetics, cough and cold
      remedies, and personal hygiene products. The ethanol content of these nonbeverage
      ethanol (NBE) products exceeds that of many conventional alcoholic beverages.
      Financial constraints and ease of availability are factors leading to their
      consumption. This report serves as a reminder to be aware of the existence and
      popularity of NBE in order to avoid potential morbidity and even mortality
      associated with its use.

PMID- 10595885
TI  - Baclofen and ethanol ingestion: a case report.
AB  - The number of reported cases of skeletal muscle relaxant ingestion has been
      increasing in the United States, although fatalities are rare. A 30-year-old
      women ingested 300 mg of baclofen and ethanol. She was able to ambulate into the
      Emergency Department (ED) 50 min later, but within 30 min post-arrival had a
      Glasgow Coma Score of 3. She was treated with supportive care including
      mechanical ventilation for 36 h. Her neurologic status returned to her previous
      state. Coma may occur rapidly after baclofen overdose, and the respiratory
      depression may be exacerbated by the co-ingestion of ethanol. Primary importance
      in the treatment of such ingestions should be placed on maintenance of an airway
      and respiratory support.

PMID- 10595886
TI  - Acute quetiapine poisoning.
AB  - Quetiapine (Seroquel) is a member of a new class of antipsychotic agents used in
      the treatment of schizophrenia. Its pharmacologic effect is primarily mediated
      via antagonistic binding to serotonergic (5HT2) and dopaminergic (D2) receptors.
      Presented is a case of acute quetiapine overdose in a patient with associated
      tachycardia, hypotension, prolonged QTc, and rapid progression to coma.
      Management included activated charcoal, i.v. saline, and intubation for airway
      protection. The patient's mental status rapidly improved within several hours of
      the ingestion, and the prolonged QTc and tachycardia resolved by the second and
      third days of hospitalization, respectively, without further intervention. This
      case illustrates the potential for hemodynamic instability and sudden
      deterioration in level of consciousness, warranting close monitoring and early
      intubation for airway protection. All patients with acute quetiapine overdose
      requiring hospitalization should be admitted to an intensive care unit setting.

PMID- 10595887
TI  - Claims against a paramedic ambulance service: a ten-year experience.
AB  - Liability claims made against Emergency Medical Services (EMS) agencies are a
      source of significant anxiety, time expenditure, and often monetary loss. Past
      literature reviewing EMS liability has been limited in scope. In this study, all
      claims made against an urban 911 ambulance service, whether or not a lawsuit
      resulted, were analyzed for the 10-year period ending in 1993. Eighty-two claims
      resulting in 11 lawsuits were filed. Motor vehicle accidents involving an
      ambulance produced the overwhelming majority (72%) of claims and 53% of the
      dollars paid out. Medical negligence claims were few but were the next largest
      cause of dollars lost (35%). Review of all legal claims may be used to help guide
      risk management efforts.

PMID- 10595888
TI  - A survivor of near sudden death caused by giant left atrial myxoma.
AB  - Sudden hemodynamic collapse occurred in a 20-year-old man after an Emergency
      Department visit with a complaint of dizziness and chest discomfort. A left
      atrial myxoma was demonstrated by echocardiography. Resuscitation procedures
      followed by surgical repair resulted in an excellent outcome. Although sudden
      death is a serious manifestation of cardiac myxoma, reports of survivors of near
      sudden death caused by this tumor have been rare.

PMID- 10595889
TI  - Using ultrasound to determine external pacer capture.
AB  - Transcutaneous cardiac pacing is a temporary treatment of hemodynamically
      unstable bradycardias. However, the rhythmic skeletal muscle contractions that
      occur during external pacing can make it difficult to assess the hemodynamic
      status of the patient. We report a case of using bedside ultrasound to assess the
      effectiveness of transcutaneous pacer capture.

PMID- 10595890
TI  - Biomechanical performance of powder-free examination gloves.
AB  - Biomechanical performance studies were undertaken for powder-free, latex and
      nitrile examination gloves. Using standardized tests, examination glove
      performance was judged by measuring glove thickness, glove puncture force, glove
      tape adhesion force, glove donning force, glove stiffness, and immediate
      unrecovered stretch. Even though the nitrile examination gloves were thinner than
      the latex examination gloves, they exhibited a greater puncture resistance. In
      addition, tape adherence to the N-Dex nitrile glove was the lowest. Moreover,
      measurements of the handling characteristics of the nitrile examination gloves
      demonstrated that they are an acceptable alternative to latex examination gloves.
      While these biomechanical studies demonstrate the superiority of the nitrile
      examination gloves, clinical glove evaluation is still needed to determine their
      performance in the health care setting.

PMID- 10595891
TI  - The C-reactive protein.
AB  - C-reactive protein (CRP) was identified in 1930 and was subsequently considered
      to be an "acute phase protein," an early indicator of infectious or inflammatory
      conditions. Since its discovery, CRP has been studied as a screening device for
      inflammation, a marker for disease activity, and as a diagnostic adjunct.
      Improved methods of quantifying CRP have led to increased application to clinical
      medicine. In the emergency department (ED), CRP must be interpreted in the
      clinical context; no single value can be used to rule in or rule out a specific
      diagnosis. We conclude that CRP has limited utility in the ED. It may be a useful
      adjunct to serial examinations in equivocal presentations of appendicitis in
      those centers without ready access to computed tomography (CT) scan. It may be
      elevated with complications or treatment failures in patients with pneumonia,
      pancreatitis, pelvic inflammatory disease (PID), and urinary tract infections. In
      patients with meningitis, neonatal sepsis, and occult bacteremia, CRP is usually
      elevated. However, CRP has no role in diagnosing these clinical entities, and a
      normal CRP level should never delay antibiotic coverage.

PMID- 10595892
TI  - Amylase and lipase in the emergency department evaluation of acute pancreatitis.
AB  - Serum amylase and lipase levels are commonly obtained in the emergency department
      for the diagnosis of acute pancreatitis. The role of these enzymes has frequently
      been the subject of confusion and controversy. This article comprehensively
      reviews the history, biochemistry, clinical, and laboratory literature on both
      enzymes as used in the evaluation of pancreatitis. Specific guidelines are
      presented to assist the Emergency Physician in the appropriate use and
      interpretation of these clinical laboratory tests.

PMID- 10595893
TI  - Respiratory distress and hypertension in pregnancy.

PMID- 10595894
TI  - Silver nitrate as a radiopaque foreign body.

PMID- 10595895
TI  - A case of traumatic pneumocephalus.

PMID- 10595896
TI  - Challenging the dominant logic of Emergency Departments: guidelines from chaos
      theory.
AB  - Chaos is order without predictability (1 ). Any unfortunate patient who has
      recently made a trek to an Emergency Department (ED) or even better, has watched
      the immensely popular TV show, ER, knows that the visit can be a frustrating and
      a time consuming experience. The waits are so protracted that one can observe all
      cycles of birth, death, love, and romance in the waiting room. The process is
      tedious for the patient who must tell one's tale to a triage nurse, a
      registration clerk, the primary nurse, the nursing care partner, and finally the
      emergency physician. Then, the patient must face more delays while being pushed,
      ineffectively, in a horizontal fashion, through vertical functional silos of
      care, such as laboratory and radiology. The mind-set or dominant logic of this
      system of ED patient flow assumes that waits are acceptable and unavoidable, and
      that the function of the ED is to care for only the truly emergent patient. This
      dominant logic, coupled with the market constraints of population-based versus
      case-based payment mechanisms, has led to a declining trend in ED visits for the
      first time in 20 years (2). In order to improve the quality of ED care as well as
      to increase acceptability for patient and payer, the dominant logic must be
      challenged. An understanding of chaos theory and perception of the Emergency
      Department as a complex adaptive system foster methods for challenging the
      dominant logic.

PMID- 10595897
TI  - David R. Boyd lecture in trauma care and emergency medical systems: "The surgical
      complications of toxins.".
AB  - Toxins have had major roles in our societies for thousands of years. Interactions
      between surgeons, both generalists and subspecialists, and those caring for
      poisoned patients have been extensive throughout history. The advancement of the
      science of toxicology, the development of regional poison control centers, the
      development of emergency medicine, and the development of the subspecialty of
      medical toxicology have led to more appropriate and creative interactions between
      medical toxicologists, emergency physicians, and surgeons. This article will
      review the diverse interfaces between the medical toxicologist and the surgeon.

PMID- 10595898
TI  - Problem automated external defibrillator electrodes: are yours any better?

PMID- 10595899
TI  - Bushido in journal writing.

PMID- 10595900
TI  - Outcome measures of resident education.

PMID- 10595901
TI  - Acute glaucoma can present either silently or as a headache of variable severity.

PMID- 10595902
TI  - Weasel words and carbon monoxide poisoning.

PMID- 10595903
TI  - Cricothyrotomy technique: standard versus the rapid four step technique.

PMID- 10595904
TI  - Subcutaneous injection of hydrocarbons.

PMID- 10595905
TI  - Tau pathology generated by overexpression of tau.

PMID- 10595906
TI  - Genetic differences in endocrine pancreatic tumor subtypes detected by
      comparative genomic hybridization.
AB  - The molecular pathogenesis as well as histogenesis of endocrine pancreatic tumors
      (EPTs) is not well understood, and the clinical behavior of EPTs is difficult to
      predict using current morphological criteria. Thus, more accurate markers of risk
      and better understanding of tumor initiation and progression are needed to allow
      a precise classification of EPTs. We have studied 44 benign and malignant EPTs by
      comparative genomic hybridization to correlate the overall number of genetic
      alterations with clinical and histopathological parameters and to identify
      chromosomal regions which might harbor genes involved in EPT pathogenesis and
      progression. Aberrations were found in 36 EPTs, and chromosomal losses (mean,
      5.3) were slightly more frequent than gains (mean, 4. 6). The most frequent
      losses involved Y (45% of male EPTs), 6q (39%), 11q (36%), 3p, 3q, 11p (each
      30%), 6p (27%), and 10q and Xq (each 25%), whereas most common gains included 7q
      (43%), 17q (41%), 5q and 14q (each 32%), 7p, 9q, 17p, 20q (each 27%), and 12q and
      Xp (each 25%). A correlation was found between the total number of genetic
      changes per tumor and both tumor size and disease stage. In particular, losses of
      3p and 6 and gains of 14q and Xq were found to be associated with metastatic
      disease. Furthermore, characteristic patterns of genetic changes were found in
      the various EPT subtypes, eg, 6q loss in malignant insulinomas, indicating that
      these groups might evolve along genetically different pathways. The highlighted
      genetic aberrations, including the newly found involvement of 6q losses and sex
      chromosome alterations, should stimulate the further analysis of these
      chromosomal regions, which may lead to the discovery of novel genes important in
      the tumorigenesis and evolution of EPTs.

PMID- 10595907
TI  - Beta-catenin mutations are frequent in human hepatocellular carcinomas associated
      with hepatitis C virus infection.
AB  - Hepatocellular carcinoma (HCC) is one of the most common fatal cancers worldwide.
      Hepatitis B virus and hepatitis C virus infections, exposure to aflatoxin, and
      excessive intake of alcohol have been identified as major risk factors. However,
      the molecular mechanisms underlying their development are still poorly
      understood. Recently, beta-catenin, one of the key components of the Wnt
      signaling pathway, has been found to be mutated in about 20% of HCCs, suggesting
      a role of the Wnt pathway in their development. In this study, we examined beta
      catenin and APC mutations in 22 HCCs associated with HCV infection, using single
      strand conformation polymorphism (SSCP) followed by direct DNA sequencing. beta
      Catenin mutations were found in nine (41%) cases, but no APC mutations were
      found. beta-Catenin immunohistochemistry revealed nuclear accumulation of beta
      catenin protein in all nine tumors with a beta-catenin mutation and two
      additional tumors without a mutation. These results suggest that activation of
      the Wnt signaling pathway by beta-catenin mutation contributes significantly to
      the hepatocellular carcinogenesis associated with HCV infection.

PMID- 10595908
TI  - Analysis of E-cadherin in diffuse-type gastric cancer using a mutation-specific
      monoclonal antibody.
AB  - In-frame deletions from the E-cadherin mRNA, coding for a homophilic cell
      adhesion molecule, are characteristic for diffuse-type gastric carcinomas. Using
      immunohistochemical analysis the mutant form cannot be distinguished from normal
      E-cadherin, making results difficult to interpret. In this study, a rat
      monoclonal antibody, designated E-cad delta 9-1, was generated against a peptide
      spanning the fusion junction region between exons 8 and 10. This new epitope is
      present in an E-cadherin variant that lacks exon 9 from the mRNA due to different
      splice-site gene mutations. Using Western blotting and immunohistochemistry of E
      cadherin-transfected cells, we demonstrate that E-cad delta 9-1 specifically
      reacts with E-cadherin lacking exon 9 but not with the wild-type protein. No
      immunoreactivity was observed in 31 nontumorous and embryonal tissues analyzed.
      In gastric carcinoma specimens known to express mutant E-cadherin mRNA lacking
      exon 9, E-cad delta 9-1 targets exclusively tumor cells in routine formalin-fixed
      and paraffin-embedded material from biopsies, primary tumors, and lymph node
      metastases. In a retrospective series of 172 diffuse-type gastric carcinomas
      expressing E-cadherin, E-cad delta 9-1 reacted with 22 tumors (13%). This new
      tumor marker-monoclonal antibody system could open novel avenues for selective
      diagnosis and specific therapy of a subgroup of diffuse-type gastric cancer
      patients.

PMID- 10595909
TI  - Estrogen receptor-positive proliferating cells in the normal and precancerous
      breast.
AB  - Recently it has been shown that epithelial cell expression of the estrogen
      receptor (ER) and that of the proliferation-associated marker Ki-67 are almost
      mutually exclusive in the normal premenopausal human breast but that coexpression
      frequently occurs in estrogen receptor-positive (ER+) breast cancers. This
      coexpression may indicate disordered expression of ER in the cell cycle or
      failure to suppress division of ER+ cells and could be important in neoplastic
      transformation. The purpose of this study was to determine whether in situ
      proliferations known to be associated with different levels of risk for
      developing breast cancer contain these coexpressing cells and, if so, the stage
      at which they occur. We found that ER+ proliferating cells were rare in
      premenopausal lobules but increased with age in the normal breast. There was no
      difference in nonlesional tissue between cancerous and noncancerous breasts. The
      percentage of dual-expressing cells was significantly increased, however, in all
      of the in situ proliferations and correlated positively with the level of risk of
      developing breast cancer. We suggest that development of at least some human
      breast cancers is associated with increasing failure to down-regulate ER as cells
      enter the cycle or to suppress division of ER+ cells. The mechanism may involve
      the loss of a tumor suppressor gene.

PMID- 10595910
TI  - Exclusive detection of the t(11;18)(q21;q21) in extranodal marginal zone B cell
      lymphomas (MZBL) of MALT type in contrast to other MZBL and extranodal large B
      cell lymphomas.
AB  - Extranodal mucosa-associated lymphoid tissue (MALT)-type lymphomas and nodal and
      splenic marginal zone B cell lymphomas (MZBL) share morphological and
      immunophenotypic features with marginal zone B cells of reactive lymphoid
      tissues. Although displaying a similar immunophenotype, recent investigations
      suggest fundamental genetic differences among these subgroups. To determine the
      prevalence of the t(11;18) in a larger series of MALT-type lymphomas and to
      investigate a possible occurrence in other lymphomas, we screened 106 non
      Hodgkin's lymphomas (NHL) by interphase cytogenetics using yeast artificial
      chromosome (YAC) probes flanking the breakpoint at 11q21. A signal constellation
      indicating a disruption in 11q21 and thus pointing to the presence of the
      t(11;18) was observed in 9 of 33 (27%) low-grade lymphomas of MALT type. The
      complete absence of t(11;18)-positive cells in 32 primary and secondary
      extranodal high-grade lymphomas suggests that low-grade lymphomas of MALT type
      characterized by the t(11;18) are unlikely to transform into high-grade tumors.
      The absence of tumor cells carrying the t(11;18) in nodal MZBL challenges the
      assumption that most, if not all, of these tumors represent the nodal
      manifestation of a so far undetected low-grade lymphoma of MALT type. The
      t(11;18) was not detected in a single case of 29 splenic MZBL investigated. This
      observation strengthens the view that splenic MZBL are biologically different
      from extranodal MZBL of MALT type.

PMID- 10595911
TI  - Transcription factor GATA-4 is expressed in pediatric yolk sac tumors.
AB  - Yolk sac tumors (YSTs) are malignant tumors that occur in the gonads of children
      and young adults, and at extragonadal sites in young children. The histological
      features of YSTs are variable and can be superimposed on other germ cell tumor
      histologies. Malignant endodermal cells within YSTs express alpha-fetoprotein,
      which can be detected in tumor tissue or serum. However, additional markers of
      endoderm differentiation would be beneficial for the classification of these
      tumors. Transcription factor GATA-4 regulates the differentiation and function of
      murine yolk sac endoderm, and its expression correlates with proliferation and
      cell survival in certain tissues. To see whether GATA-4 plays a role in human
      YSTs, we surveyed its expression in human germ cell tumors and cell lines.
      Northern analysis demonstrated expression of GATA-4 mRNA in four human germ cell
      tumor lines exhibiting yolk sac endoderm differentiation. GATA-4 protein was
      detected in eight of nine pediatric YSTs by immunohistochemistry. Three of five
      immature teratomas exhibited GATA-4 in neural blastematous cells and in
      cylindrical epithelium, whereas all 16 mature teratomas were devoid of GATA-4. We
      conclude that GATA-4 is a clinically useful marker of human YSTs and speculate
      that it may play a role in the maintenance of the malignant phenotype.

PMID- 10595912
TI  - Synaptophysin: A novel marker for human and rat hepatic stellate cells.
AB  - Synaptophysin is a protein involved in neurotransmitter exocytosis and is a
      neuroendocrine marker. We studied synaptophysin immunohistochemical expression in
      35 human liver specimens (normal and different pathological conditions), in rat
      models of galactosamine hepatitis and carbon tetrachloride-induced cirrhosis, and
      in freshly isolated rat stellate cells. Synaptophysin reactivity was present in
      perisinusoidal stellate cells in both human and rat normal liver biopsies. The
      number of synaptophysin-reactive perisinusoidal cells increased in pathological
      conditions. Double staining for alpha-smooth muscle actin and synaptophysin,
      detected by confocal laser scanning microscopy, unequivocally demonstrated
      colocalization of both markers in lobular stellate cells. In addition, freshly
      isolated rat stellate cells expressed synaptophysin mRNA (detected by polymerase
      chain reaction) and protein. Finally, electron microscopy showed the presence of
      small electron translucent vesicles, comparable to the synaptophysin-reactive
      synaptic vesicles in neurons, in stellate cell projections. We conclude that
      synaptophysin is a novel marker for quiescent as well as activated hepatic
      stellate cells. Together with the stellate cell's expression of neural cell
      adhesion molecule, glial fibrillary acidic protein, and nestin, this finding
      raises questions about its embryonic origin and its differentiation. In addition,
      the presence of synaptic vesicles in stellate cell processes suggests a hitherto
      unknown mechanism of interaction with neighboring cells.

PMID- 10595913
TI  - Role of the Ets-1 transcription factor during activation of rat hepatic stellate
      cells in culture.
AB  - During liver tissue repair, hepatic stellate cells (HSCs), a pericyte-like
      nonparenchymal liver cell population, transform from a quiescent status (resting
      HSCs) into myofibroblast like cells (activated HSCs); the latter is the principal
      matrix-synthesizing cell of the liver. Although several factors have been shown
      to be involved in this important process, the molecular mechanisms regulating HSC
      activation are still under investigation. To identify key regulatory proteins
      involved in the HSC activation process, we used different mRNA display
      technologies, with cDNAs prepared from HSCs at different stages of in vitro
      activation. With the latter technique, the transcription factor Ets-1 was
      detected through its down-regulation during activation. As confirmed by Northern
      blot and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, mRNAs
      coding for Ets-1 were present in the highest amounts in freshly isolated HSCs and
      in HSCs 2 days after plating (classified as resting HSCs/early activated HSCs)
      and were diminished in HSCs 7 days after plating (activated cells). Ets-1 protein
      was present in HSC-lysates, as assessed by Western blot, and bound to an
      oligonucleotide containing the Ets-1 consensus cis-acting motif, as demonstrated
      by electrophoretic mobility shift assay. Ets-1 binding activity peaked in nuclear
      extracts prepared from resting/early activated cells and was diminished in
      extracts derived from fully activated cells. In contrast, binding activity of the
      transcription factors TFIID, AP-1, and SP-1 was highest in activated HSCs and
      only barely detectable in resting/early activated HSCs. By Northern blot and RT
      PCR analysis, Ets-1-specific transcripts were present in parenchymal and other
      nonparenchymal liver cells too, illustrating that hepatic Ets-1 expression is not
      specific or restricted to HSCs. However, the unique pattern of Ets-1 binding
      activity present in resting versus activated HSCs and its known implications for
      cellular differentiation and tissue remodeling suggest that Ets-1 could be of
      crucial importance for HSC activation and hepatic tissue repair.

PMID- 10595914
TI  - Microsatellite instability in adenomas as a marker for hereditary nonpolyposis
      colorectal cancer.
AB  - Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common of the well
      defined colorectal cancer syndromes, accounting for at least 2% of the total
      colorectal cancer burden and carrying a greater than 80% lifetime risk of cancer.
      Significant reduction in cancer morbidity and mortality can be accomplished by
      appropriate clinical cancer screening of HNPCC patients with mutations in
      mismatch repair (MMR) genes. Thus, it is desirable to identify individuals who
      are mutation-positive. In individuals with cancer, mutation detection can be
      accomplished relatively efficiently by germline mutation analysis of individuals
      whose cancers show microsatellite instability (MSI). This study was designed to
      assess the feasibility of screening colorectal adenoma patients for HNPCC in the
      same manner. Among 378 adenoma patients, six (1.6%) had at least one MSI adenoma.
      Five out of the six patients (83%) had a germline MMR gene mutation. We conclude
      that MSI analysis is a useful method of prescreening colorectal adenoma patients
      for HNPCC.

PMID- 10595915
TI  - Deletions of the INK4A gene occur in malignant peripheral nerve sheath tumors but
      not in neurofibromas.
AB  - The INK4A gene, a candidate tumor suppressor gene located on chromosome 9p21,
      encodes two protein products, p16 and p19(ARF). p16 is a negative cell cycle
      regulator capable of arresting cells in the G1 phase by inhibiting cyclin
      dependent kinases 4 (Cdk4) and 6 (Cdk6), thus preventing pRB phosphorylation.
      p19(ARF) prevents Mdm2-mediated neutralization of p53. Loss of INK4A is a
      frequent molecular alteration involved in the genesis of several neoplasms,
      including tumors of neuroectodermal origin. This study investigated the frequency
      of INK4A gene alterations in a series of malignant peripheral nerve sheath tumors
      (MPNSTs) and neurofibromas (NFs). INK4A gene and the p19(ARF)-specific exon 1beta
      were studied in 11 MPNST samples from 8 patients and 7 neurofibromas. Presence of
      INK4A deletions was assessed by Southern blotting hybridization and by a
      multiplex polymerase chain reaction (mPCR). INK4A point mutations were examined
      by single-strand conformation polymorphism (SSCP) and sequencing. The p16
      promoter methylation status was determined by PCR amplification of bisulfite
      treated DNA. Homozygous deletions of exon 2, thus affecting both p16 and
      p19(ARF), were identified in MPNSTs from 4 of 8 patients. Deletions, mutations,
      or silencing by methylation were not identified in the neurofibromas analyzed.
      Based on our results, we conclude that INK4A deletions are frequent events in
      MPNSTs and may participate in tumor progression. Silencing of p16 by methylation,
      which occurs often in several tumor types, is uncommon in MPNSTs.

PMID- 10595916
TI  - Overexpression of Bcl-x(L) promotes chemotherapy resistance of mammary tumors in
      a syngeneic mouse model.
AB  - Bcl-x(L), a prosurvival member of the Bcl-2 family that is expressed in many
      tumors, represses apoptosis induced by chemotherapeutic drugs in vitro. However,
      the contribution of apoptosis and prosurvival Bcl-2-related proteins to
      chemotherapy resistance in vivo is unknown and has been challenged by recent
      results with clonogenic survival assays. To test the ability of Bcl-x(L) to
      provide chemotherapy resistance to tumors, we transfected the mouse bcl-x(L) gene
      into the tumorigenic SCK mammary cell line and assessed the response of tumor
      cells to chemotherapeutic drugs in clonogenic assays and in a syngeneic mouse
      model. Bcl-x(L) conferred protection on SCK cells against methotrexate at certain
      drug concentrations, but not at all against 5-fluorouracil in clonogenic survival
      assays in vitro. Injection of SCK cells transfected with Bcl-x(L) or control
      plasmid in the mammary fat pads of syngeneic recipient mice resulted in tumors of
      similar size. However, although the volume of control tumors regressed up to 80%
      after 4 to 5 days of chemotherapy, SCK tumors expressing Bcl-x(L) did not regress
      and continued to grow in the presence of methotrexate or 5-fluorouracil. In
      addition, numbers of apoptotic cells were significantly higher in control tumors
      as compared to Bcl-x(L)-expressing tumors in animals treated with methotrexate or
      5-fluorouracil. These results provide evidence that inhibition of apoptosis
      through Bcl-x(L) overexpression can promote resistance to chemotherapy in tumors
      in vivo.

PMID- 10595917
TI  - The use of laser scanning cytometry to assess depth of penetration of adenovirus
      p53 gene therapy in human xenograft biopsies.
AB  - SCH58500 is an agent for gene therapy of cancer, consisting of a replication
      deficient type 5 adenovirus (Ad5) expressing the human p53 tumor suppressor gene
      (Ad5/p53). An important question about the use of Ad5/p53 gene therapy is how to
      achieve the therapeutically effective delivery of an Ad5/p53 vector to the tumor.
      We wanted to determine the effective depth of penetration of an Ad5/p53 vector by
      dosing the vector in an experimental human xenograft/SCID model. To assess depth
      of penetration, we developed a novel methodology for scanning tissue sections by
      laser scanning cytometry (LSC). SCID mice were given intraperitoneal injections
      of either p53(null) SK-OV-3 human ovarian tumor cells or p53(mut) DU-145 human
      prostate tumor cells to establish xenograft solid tumors. Mice were then dosed
      once or twice at 24-hour intervals by intraperitoneal injection with SCH58500
      (Ad5/p53), an adenovirus construct expressing beta-galactosidase (Ad5/beta-gal),
      or a buffer control. Additional groups of mice received a single intraperitoneal
      dose of 10 mg/kg paclitaxel either alone or coadministered with Ad5/p53. Twenty
      four hours after each last dose, the human solid tumor xenograft and relevant
      mouse tissue were removed from each mouse for the analysis of Ad5/p53
      penetration. Immunohistochemistry (IHC) for beta-galactosidase protein revealed a
      depth of penetration of between 1 and 10 cells from the tumor surface. In some
      mice, hepatocytes in the periportal regions of liver lobules were also positive,
      indicating systemic absorption of adenovirus from the peritoneal cavity. IHC
      staining for p53 and p21 proteins in SK-OV-3 solid tumor xenografts revealed
      similar Ad/p53 penetration. LSC was used to map and quantitate apoptosis in both
      tumor and liver tissue biopsies, with over 450,000 nuclei from liver tissue and
      150,000 nuclei from tumor tissue being evaluated. LSC analysis demonstrated a
      high level of apoptosis in the tumors that had been removed from Ad5/p53-dosed
      mice (12.7-19.7%). This level of apoptosis was significantly higher (P < 0.05)
      than was observed for liver tissues taken from Ad5/p53-dosed mice (2.7-8.0%) or
      tumor tissues taken from either Ad5/beta-gal-dosed mice (3.0-6.4%) or buffer
      control-dosed mice (3.0-5.3%). Scan bit maps from the extensive LSC analyses
      confirmed that apoptosis was present to about the same depth (1-10 cells) as had
      been identified by IHC for beta-galactosidase, p53, and p21 proteins. Paclitaxel
      coadministered with Ad5/p53 had no effect on Ad5 penetration into solid tumors in
      vivo as measured by IHC for p53 or p21 protein. However, the combination therapy
      did cause an elevation in the number of tumor cells undergoing apoptosis.

PMID- 10595918
TI  - Malignant transformation of neurofibromas in neurofibromatosis 1 is associated
      with CDKN2A/p16 inactivation.
AB  - Patients with neurofibromatosis 1 (NF1) are predisposed to develop multiple
      neurofibromas (NFs) and are at risk for transformation of NFs to malignant
      peripheral nerve sheath tumors (MPNSTs). Little is known, however, about the
      biological events involved in the malignant transformation of NFs. We examined
      the CDKN2A/p16 gene and p16 protein in NFs and MPNSTs from patients with NF1. On
      immunohistochemical analysis, all NFs expressed p16 protein. The MPNSTs, however,
      were essentially immunonegative for p16, with striking transitions in cases that
      contained both benign and malignant elements. None of the benign tumors had
      CDKN2A/p16 deletions, whereas three of six MPNSTs appeared to have homozygous
      CDKN2A/p16 deletions. Methylation analysis and mutation analysis of CDKN2A/p16 in
      MPNSTs did not reveal any abnormalities. These results show that malignant
      transformation of NF is associated with loss of p16 expression, which is often
      secondary to homozygous deletion of the CDKN2A/p16 gene. The findings suggest
      that CDKN2A/p16 inactivation occurs during the malignant transformation of NFs in
      NF1 patients and raises the possibility that p16 immunohistochemistry may provide
      ancillary information in the distinction of NF from MPNST.

PMID- 10595919
TI  - Expression of p27(kip) and other cell cycle regulators in malignant peripheral
      nerve sheath tumors and neurofibromas: the emerging role of p27(kip) in malignant
      transformation of neurofibromas.
AB  - There is little information regarding the status of cell cycle regulators in
      malignant peripheral nerve sheath tumors (MPNSTs) and neurofibromas (NFs). In
      this study, we investigated patterns of expression of p53 and pRB, cyclin
      dependent kinase inhibitors (CKIs) p21 and p27, as well as cyclins D1 and E, in a
      cohort of 35 well-characterized MPNSTs and 16 NFs. These phenotypes were
      correlated with proliferative index, as assessed by Ki-67, as well as
      clinicopathological parameters of poor outcome. p53 nuclear overexpression was
      found in 10 of 35 (29%) MPNSTs, and it was lacking in NFs (P = 0.02). There were
      no differences in the patterns of expression of pRB, cyclin D1, and p21 between
      MPNSTs and NFs. However, p27 nuclear expression was present in most NFs, but it
      was absent in the majority of MPNSTs, which displayed cytoplasmic staining (P <
      0.001). Nuclear cyclin E expression was more pronounced in MPNSTs than in NFs. We
      observed inverse patterns of expression for nuclear p27 and nuclear cyclin E
      expression. The staining profiles of cytoplasmic p27 and nuclear cyclin E
      expression were found to be statistically associated (P = 0.01). High Ki-67
      expression was found in 20 of 34 (59%) MPNSTs but was absent in NFs (P < 0.001).
      Furthermore, detection of cytoplasmic p27 expression was found to be a prognostic
      factor for poor survival in MPNSTs (P = 0.03, relative risk = 2.4).

PMID- 10595920
TI  - Pituitary adenylate cyclase-activating polypeptide inhibits transforming growth
      factor-beta1-induced apoptosis in a human pituitary adenoma cell line.
AB  - Pituitary adenylate cyclase-activating polypeptide (PACAP) was originally
      isolated from hypothalamic tissues based on its ability to stimulate cAMP
      production in cultured anterior pituitary cells. Recent studies have suggested a
      functional role for PACAP in the apoptosis of brain cells. However, the role of
      PACAP in regulating apoptosis in human pituitary adenomas has not previously been
      examined. Analysis of the cultured human pituitary adenoma cell line HP75, which
      expresses all three major PACAP receptors, showed that both PACAP-38 and PACAP-27
      inhibited TGF-beta1-induced apoptosis. Treatment with the PACAP receptor
      antagonists PACAP 6-38 (PACAP type I receptor antagonist) and (p-chloro-D-Phe(6),
      Leu(17))-VIP (PACAP type II receptor antagonist) blocked the effects of PACAP-38
      on the inhibition of transforming growth factor-beta1 (TGF-beta1)-induced
      apoptosis, confirming the specificity of the role of PACAP. Treatment with
      forskolin but not phorbol 12-myristate 13-acetate (PMA) also inhibited TGF-beta1
      induced apoptosis. TGF-beta1 treatment was associated with an increase in mitogen
      activated protein kinase (MAP kinase) when analyzed by Western blotting, but
      PACAP inhibition of TGF-beta1-induced apoptosis was not associated with
      activation of MAP kinase. Immunocytochemical analysis of the cell cycle cyclin
      dependent kinase inhibitor p27 showed that treatment with TGF-beta1, forskolin,
      PMA, and PACAP increased p27 expression in cultured HP75 cells. These results
      indicate that PACAP is a highly specific inhibitor of TGF-beta1-induced apoptosis
      in the HP75 human pituitary adenoma cell line and that PACAP, TGF-beta1,
      forskolin, and PMA all stimulate expression of the TGF-beta-regulated cell cycle
      protein p27 in the HP75 human pituitary adenoma cell line. The HP75 cell line can
      be used as a model to study the regulation of apoptosis in human pituitary cells.

PMID- 10595921
TI  - Familial encephalopathy with neuroserpin inclusion bodies.
AB  - We report on a new familial neurodegenerative disease with associated dementia
      that has presented clinically in the fifth decade, in both genders, and in each
      of several generations of a large family from New York State-a pattern of
      inheritance consistent with an autosomal dominant mode of transmission. A key
      pathological finding is the presence of neuronal inclusion bodies distributed
      throughout the gray matter of the cerebral cortex and in certain subcortical
      nuclei. These inclusions are distinct from any described previously and
      henceforth are identified as Collins bodies. The Collins bodies can be isolated
      by simple biochemical procedures and have a surprisingly simple composition;
      neuroserpin (a serine protease inhibitor) is their predominant component. An
      affinity-purified antibody against neuroserpin specifically labels the Collins
      bodies, confirming their chemical composition. Therefore, we propose a new
      disease entity-familial encephalopathy with neuroserpin inclusion bodies (FENIB).
      The conclusion that FENIB is a previously unrecognized neurodegenerative disease
      is supported by finding Collins bodies in a small kindred from Oregon with
      familial dementia who are unrelated to the New York family. The autosomal
      dominant inheritance strongly suggests that FENIB is caused by mutations in the
      neuroserpin gene, resulting in intracellular accumulation of the mutant protein.

PMID- 10595923
TI  - Interleukin-10 (IL-10) augments allograft arterial disease: paradoxical effects
      of IL-10 in vivo.
AB  - Interleukin-10 (IL-10) is an anti-inflammatory helper T cell type 2 (Th2)
      cytokine that modulates Th1-type cytokine production. Graft arterial disease
      (GAD) is a vascular obliterative process mediated via the Th1 cytokine interferon
      gamma (IFN-gamma); allografts in IFN-gamma-deficient animals do not develop GAD.
      We investigated the effect of IL-10 and anti-IL-10 on GAD in murine heart
      transplants and whether anti-IL-10 reestablishes GAD in IFN-gamma-deficient
      hosts. Major histocompatibility complex class II-mismatched hearts were
      transplanted for 8 weeks into wild-type or IFN-gamma-deficient mice. In one set
      of experiments, wild-type hosts received daily administration of phosphate
      buffered saline (PBS) or increasing IL-10; in a subsequent set of experiments,
      wild-type hosts received weekly PBS, rat IgG, or anti-IL-10 monoclonal antibody;
      IFN-gamma-deficient recipients received weekly PBS or anti-IL-10 monoclonal
      antibody. Explanted allografts were assessed for parenchymal rejection and GAD,
      cytokine profiles, and adhesion/costimulatory-molecule expression. Exogenous IL
      10 resulted in increased Th2-like cytokine production; nevertheless, it
      exacerbated parenchymal rejection and GAD and increased CD8(+) infiltration. Anti
      IL-10 did not significantly affect the extent of rejection or GAD, cytokine
      profiles, or immunohistology of the allografts in wild-type hosts. Adhesion
      molecule (CD54 and CD106) expression was not diminished by IL-10 treatment, and
      costimulatory-molecule (CD80 and CD86) expression was augmented by administration
      of exogenous IL-10. Allografts in IFN-gamma-deficient recipients showed mild
      rejection and no GAD, regardless of anti-IL-10 treatment. IL-10 in vivo thus has
      markedly different effects than predicted from in vitro experience. Although
      allografts develop Th2-like cytokine profiles treatment with IL-10 causes
      exacerbated rejection and GAD.

PMID- 10595922
TI  - Blood-brain barrier tight junction disruption in human immunodeficiency virus-1
      encephalitis.
AB  - The blood-brain barrier (BBB) plays a critical role in regulating cell
      trafficking through the central nervous system (CNS) due to several unique
      anatomical features, including the presence of interendothelial tight junctions
      that form impermeable seals between the cells. Previous studies have demonstrated
      BBB perturbations during human immunodeficiency virus encephalitis (HIVE);
      however, the basis of these permeability changes and its relationship to
      infiltration of human immunodeficiency virus type 1 (HIV-1)-infected monocytes, a
      critical event in the pathogenesis of the disease, remains unclear. In this
      study, we examined CNS tissue from HIV-1-seronegative patients and HIV-1-infected
      patients, both with and without encephalitis, for alterations in BBB integrity
      via immunohistochemical analysis of the tight junction membrane proteins,
      occludin and zonula occludens-1 (ZO-1). Significant tight junction disruption (P
      < 0.001), as demonstrated by fragmentation or absence of immunoreactivity for
      occludin and ZO-1, was observed within vessels from subcortical white matter,
      basal ganglia, and, to a lesser extent, cortical gray matter in patients who died
      with HIVE. These alterations were also associated with accumulation of activated,
      HIV-1-infected brain macrophages, fibrinogen leakage, and marked astrocytosis. In
      contrast, no significant changes (P > 0.05) were observed in cerebellar tissue
      from patients with HIVE compared to HIV-seronegative patients or HIV-1-infected
      patients without encephalitis. Our findings demonstrate that tight junction
      disruption is a key feature of HIVE that occurs in regions of histopathological
      alterations in association with perivascular accumulation of activated HIV-1
      infected macrophages, serum protein extravasation, and marked astrocytosis. We
      propose that disruption of this key BBB structure serves as the main route of HIV
      1-infected monocyte entry into the CNS.

PMID- 10595924
TI  - Altered centrosome structure is associated with abnormal mitoses in human breast
      tumors.
AB  - Centrosomes are the major microtubule organizing center in mammalian cells and
      establish the spindle poles during mitosis. Centrosome defects have been
      implicated in disease and tumor progression and have been associated with
      nullizygosity of the p53 tumor suppressor gene. In the present ultrastructural
      analysis of 31 human breast tumors, we found that centrosomes of most tumors had
      significant alterations compared to centrosomes of normal breast tissue. These
      alterations in included 1) supernumerary centrioles, 2) excess pericentriolar
      material, 3) disrupted centriole barrel structure, 4) unincorporated microtubule
      complexes, 5) centrioles of unusual length, 6) centrioles functioning as ciliary
      basal bodies, and 7) mispositioned centrosomes. These alterations are associated
      with changes in cell polarity, changes in cell and tissue differentiation, and
      chromosome missegregation through multipolar mitoses. Significantly, the presence
      of excess pericentriolar material was associated with the highest frequency of
      abnormal mitoses. Centrosome abnormalities may confer a mutator phenotype to
      tumors, occasionally yielding cells with a selective advantage that emerge and
      thrive, thus leading the tumor to a more aggressive state.

PMID- 10595925
TI  - Human vascular adhesion protein-1 in smooth muscle cells.
AB  - Human vascular adhesion protein-1 (VAP-1) is a dual-function molecule with
      adhesive and enzymatic properties. In addition to synthesis in endothelial cells,
      where it mediates lymphocyte binding, VAP-1 is expressed in smooth muscle cells.
      Here we studied the expression, biochemical structure, and function of VAP-1 in
      muscle cells and compared it to those in endothelial cells. VAP-1 is expressed on
      the plasma membrane of all types of smooth muscle cells, but it is completely
      absent from cardiac and skeletal muscle cells. In tumors, VAP-1 is retained on
      all leiomyoma cells, whereas it is lost in half of leiomyosarcoma samples. In
      smooth muscle VAP-1 predominantly exists as a approximately 165-kd homodimeric
      glycoprotein, but a trimeric (approximately 250 kd) form of VAP-1 is also found.
      It contains N-linked oligosaccharide side chains and abundant sialic acid
      decorations. In comparison, in endothelial cells dimeric VAP-1 is larger, no
      trimeric forms are found, and VAP-1 does not have N-glycanase-sensitive
      oligosaccharides. Unlike endothelial VAP-1, VAP-1 localized on smooth muscle
      cells does not support binding of lymphocytes. Instead, it deaminates exogenous
      and endogenous primary amines. In conclusion, VAP-1 in smooth muscle cells is
      structurally and functionally distinct from VAP-1 present on endothelial cells.

PMID- 10595926
TI  - Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and
      correlation with clinical pathological features.
AB  - Experimental evidence has shown, both in vitro and in animal models, that
      neoplastic growth and subsequent metastasis formation depend on the tumor's
      ability to induce an angiogenic switch. This requires a change in the balance of
      angiogenic stimulators and inhibitors. To assess the potential role of
      angiogenesis factors in human thyroid tumor growth and spread, we analyzed their
      expression by semiquantitative RT-PCR and immunohistochemistry in normal thyroid
      tissues, benign lesions, and different thyroid carcinomas. Compared to normal
      tissues, in thyroid neoplasias we observed a consistent increase in vascular
      endothelial growth factor (VEGF), VEGF-C, and angiopoietin-2 and in their
      tyrosine kinase receptors KDR, Flt-4, and Tek. In particular, we report the
      overexpression of angiopoietin-2 and VEGF in thyroid tumor progression from a
      prevascular to a vascular phase. In fact, we found a strong association between
      tumor size and high levels of VEGF and angiopoietin-2. Furthermore, our results
      show an increased expression of VEGF-C in lymph node invasive thyroid tumors and,
      on the other hand, a decrease of thrombospondin-1, an angioinhibitory factor, in
      thyroid malignancies capable of hematic spread. These results suggest that, in
      human thyroid tumors, angiogenesis factors seem involved in neoplastic growth and
      aggressiveness. Moreover, our findings are in keeping with a recent hypothesis
      that in the presence of VEGF, angiopoietin-2 may collaborate at the front of
      invading vascular sprouts, serving as an initial angiogenic signal that
      accompanies tumor growth.

PMID- 10595927
TI  - Basic fibroblast growth factor synthesis by human peritoneal mesothelial cells:
      induction by interleukin-1.
AB  - Peritoneal mesothelial cells are uniquely located to regulate cellular events in
      the peritoneal cavity and are an important source for various cytokines and
      growth factors. This study was conducted to analyze the capacity of human
      peritoneal mesothelial cells (HPMCs) to synthesize and release basic fibroblast
      growth factor (bFGF) and to characterize its regulation by inflammatory
      cytokines. HPMCs constitutively synthesized and released considerable amounts of
      bFGF as detected by a specific immunoassay. Almost 80% of bFGF (1547 +/- 173
      pg/10(5) cells) was localized intracellularly. Approximately 20% of the bFGF (357
      +/- 27 pg/10(5) cells) was associated with extracellular matrix components on the
      HPMC surface. Small amounts of bFGF (<1%) were detectable in tissue culture
      supernatants (8.4 +/- 1.4 pg/10(5) cells). Treatment of HPMCs with interleukin
      1beta (IL-1beta; 1 ng/ml) resulted in a significant increase in bFGF production.
      The intracellular bFGF content showed a rapid but only transient increase, which
      was significant above background levels after 24 hours (41% increase; P < 0.05).
      This increase in intracellular bFGF concentration was associated with an
      induction of the release of bFGF. Within 96 hours, the release of bFGF to the
      cell surface and into the supernatant increased by 58% (564 +/- 52.4 pg/10(5)
      cells; P < 0.01) and by 214% (26.4 +/- 3.2 pg/10(5) cells; P < 0.001),
      respectively. Neither tumor necrosis factor-alpha nor interferon-gamma affected
      bFGF synthesis by HPMCs. Stimulation of HPMCs with IL-1beta increased steady
      state levels of bFGF-specific mRNA. Immunohistochemical analyses of peritoneal
      tissue revealed constitutive expression of bFGF by HPMCs. This in situ expression
      proved to be most pronounced in areas of serosal inflammation in activated HPMCs.
      Our study demonstrates that HPMCs synthesize and release significant amounts of
      bFGF and that the expression of this growth factor is significantly up-regulated
      by the proinflammatory cytokine IL-1beta. The data support the view that HPMCs
      are key regulators of abdominal disease processes such as peritonitis, peritoneal
      fibrosis, or peritoneal tumor metastasis.

PMID- 10595928
TI  - Proliferative inflammatory atrophy of the prostate: implications for prostatic
      carcinogenesis.
AB  - Proliferation in the setting of longstanding chronic inflammation appears to
      predispose to carcinoma in the liver, large bowel, urinary bladder, and gastric
      mucosa. Focal prostatic atrophy, which is associated with chronic inflammation,
      is highly proliferative (Ruska et al, Am J Surg Pathol 1998, 22:1073-1077); thus
      the focus of this study was to more fully characterize the phenotype of the
      atrophic cells to assess the feasibility of the proposal that they may be targets
      of neoplastic transformation. The pi-class glutathione S-transferase (GSTP1), a
      carcinogen-detoxifying enzyme, is not expressed in >90% of prostate carcinomas
      (CaPs). GSTP1 promoter hypermethylation, which appears to permanently silence
      transcription, is the most frequently detected genomic alteration in CaP (Lee et
      al, Proc Natl Acad Sci USA 1994, 91:11733-11737; >90% of cases). In high-grade
      prostatic intraepithelial neoplasia (PIN), this alteration is present in at least
      70% of cases (Brooks et al, Cancer Epidemiol Biomarkers Prev, 1998, 7:531-536).
      Although normal-appearing prostate secretory cells rarely express GSTP1, they
      remain capable of expression, inasmuch as GSTP1 promoter hypermethylation is not
      detected in normal prostate. Fifty-five lesions from paraffin-embedded
      prostatectomy specimens (n = 42) were stained for GSTP1, using
      immunohistochemistry. Adjacent sections were stained for p27(Kip1), Ki-67,
      androgen receptor (AR), prostate-specific antigen (PSA), prostate-specific acid
      phosphatase (PSAP), Bcl-2, and basal cell-specific cytokeratins (34betaE12). With
      normal prostate epithelium as the internal standard, staining was scored for each
      marker in the atrophic epithelium. The lesions showed two cell types, basal cells
      staining positive for 34betaE12, and atrophic secretory-type cells staining
      weakly negative for 34betaE12. All lesions showed elevated levels of Bcl-2 in
      many of the secretory-type cells. All lesions had an elevated staining index for
      the proliferation marker Ki-67 in the secretory layer and decreased expression of
      p27(Kip1), a finding reminiscent of high-grade PIN (De Marzo et al, Am J Pathol
      1998, 153:911-919). Consistent with partial secretory cell differentiation, the
      luminal cells showed weak to moderate staining for androgen receptor and the
      secretory proteins PSA and PSAP. All atrophic lesions showed elevated GSTP1
      expression in many of the luminal secretory-type cells. Because all lesions are
      hyperproliferative, are associated with inflammation, and have the distinct
      morphological appearance recognized as prostatic atrophy, we suggest the term
      "proliferative inflammatory atrophy" (PIA). Elevated levels of GSTP1 may reflect
      its inducible nature in secretory cells, possibly in response to increased
      electrophile or oxidant stress. Elevated Bcl-2 expression may be responsible for
      the very low apoptotic rate in PIA and is consistent with the conclusion that PIA
      is a regenerative lesion. We discuss our proposal to integrate the atrophy and
      high-grade PIN hypotheses of prostate carcinogenesis by suggesting that atrophy
      may give rise to carcinoma either directly, as previously postulated, or
      indirectly by first developing into high-grade PIN.

PMID- 10595929
TI  - A short isoform of Col9a1 supports alveolar bone repair.
AB  - Bone wound created in intramembranous alveolar bone heals without the formation
      of cartilage precursor tissue. However, the expression of cartilage collagen
      mRNAs has been suggested. In this report, we examined the expression and the
      potential role of type IX collagen in bone restoration and remodeling. The
      sequence specific polymerase chain reaction demonstrated the exclusive expression
      of short transcriptional isoform of alpha1(IX) collagen (Col9a1) in alveolar bone
      wound healing, while the long isoform of Col9a1 transcript was absent. Type IX
      collagen was immunolocalized in the preliminary matrix organized in granulation
      tissue before trabecular bone formation in tooth extraction socket. In Col9a1
      null mutant mice, there were considerable variations in alveolar bone wound
      healing with the absence of or abnormally organized trabecular bone.
      Occasionally, unusual apposition of cortical-bone-like layers in bone marrow
      space was observed. The Col9a1-null mice indicated no growth retardation, and
      their facial and long bones maintained the normal size and shape. However, the
      primary spongiosa region of adult Col9a1 mutant mice showed an abnormal
      trabecular bone structure associated with abnormal immunostaining with the
      hypertrophic cartilage specific type X collagen antibody. These data suggest that
      type IX collagen short transcriptional variant is involved in the restoration and
      remodeling processes of trabecular bone.

PMID- 10595930
TI  - Eotaxin expression in Sephadex-induced lung injury in rats.
AB  - The CC chemokine eotaxin is a potent and specific eosinophil chemoattractant.
      Eosinophil-dependent tissue injury has been shown to contribute to airway
      inflammation such as that in asthma. In the present study, We investigated
      eotaxin expression in a rat model of pulmonary inflammation (featuring
      accumulation of eosinophils) induced by intratracheal instillation of cross
      linked dextran beads (Sephadex G200). Intratracheal instillation of 5 mg/kg
      Sephadex caused a time-dependent eosinophil infiltration into the lung, reaching
      a peak at 24 hours. Eotaxin mRNA in the lung paralleled the eosinophil influx.
      Eotaxin protein in bronchoalveolar (BAL) fluids and lung homogenates was shown by
      Western blot and immunostaining to be maximally expressed by 24 hours. Sephadex
      induced lung injury, as measured by (125)I-labeled albumin leakage from the
      pulmonary vasculature, developed in a time-dependent manner. Intravenous
      injection of blocking antibody to eotaxin significantly decreased eosinophil
      infiltration and lung permeability. These data suggest that, in the Sephadex
      model of lung inflammation, eotaxin up-regulation mediates intrapulmonary
      accumulation of eosinophils and the development of lung injury.

PMID- 10595931
TI  - Somatic mutations of the L12a gene in V-kappa(1) light chain deposition disease:
      potential effects on aberrant protein conformation and deposition.
AB  - Light chain deposition disease (LCDD) and light chain amyloidosis (AL) are
      disorders of monoclonal immunoglobulin deposition in which normally soluble serum
      precursors form insoluble deposits in tissues. A common feature in both is the
      clonal proliferation of B-cells that produce pathogenic light chains. However,
      the deposits in LCDD differ from those in AL in that they are ultrastructurally
      granular rather than fibrillar and do not bind Congo red or colocalize with
      amyloid P component or apolipoprotein E. The reason(s) for their differences are
      unknown but are likely multifactorial and related to their protein conformation
      and their interaction with other molecules and tissue factors in the
      microenvironment. Knowledge of the primary structure of the light chains in LCDD
      is very limited. In the present study two new kappa(1) light chains from patients
      with LCDD are described and compared to seven other reported kappa-LCDD proteins.
      The N-terminal amino acid sequences of light chain GLA extracted from the renal
      biopsy and light chain CHO from myocardial tissue were each identical to the
      respective light chains isolated from the urines and to the V-region amino acid
      sequences translated from the cloned cDNAs obtained from bone marrow cells. The
      germline V-region sequences, determined from the genomic DNA in both and in MCM,
      a previously reported kappa(1) LCDD light chain, were identical and related to
      the L12a germline gene. The expressed light chains in all three exhibit amino
      acid substitutions that arise from somatic mutation and result in increased
      hydrophobicity with the potential for protein destabilization and disordered
      conformation.

PMID- 10595932
TI  - Expression of costimulatory molecules in low-grade mucosa-associated lymphoid
      tissue-type lymphomas in vivo.
AB  - B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type develop against
      a background of chronic inflammation and have functional autoantigen receptors.
      Because they respond to environmental factors in vivo, the expression of
      costimulatory molecules, which play a key role in the differentiation of normal B
      lymphocytes and in T-/B-cell interaction, may be critical in early MALT-type
      lymphoma pathogenesis until further chromosomal aberration leads to progression.
      We found a high number of tumor-infiltrating T-lymphocytes (TITLs) in all low
      grade MALT-type lymphomas. The TITLs in low-grade lymphomas were activated and
      expressed a memory and immunocompetent phenotype. Reverse transcriptase
      polymerase chain reaction analyses and immunohistochemistry confirmed the
      presence of CD40-ligand and Fas-ligand in 80% of low-grade lymphomas. In contrast
      to the TITLs, the tumor B cells did not express CD40-ligand or Fas-ligand in vivo
      or in vitro. Moreover, the cytokine profile in vivo suggested a Th2/Th3-weighted
      profile (interleukin-10, interleukin-13, transforming growth factor beta(1))
      rather than Th1-weighted (interferon-gamma, interleukin-2). By interphase
      fluorescence in situ hybridization analysis the translocation t(11;18)(q21;q21)
      was found in four of nine (44%) cases studied. Interestingly, there was a four
      times higher proliferation and survival rate of purified t(11;18)-positive tumor
      B cells in vitro, although there were no significant profile differences from the
      TITLs in vivo. The finding of essential costimulating molecules in low-grade MALT
      type lymphomas in vivo indicates a locally directed cognate T-/B-cell
      interaction. Consequently, a potentially equipped inflammatory background may not
      only determine the fate of autoreactive B-cells, but is also crucial to lymphoma
      maintenance and progression.

PMID- 10595933
TI  - Frequent expression of the variant CD30 in human malignant myeloid and lymphoid
      neoplasms.
AB  - We earlier identified a variant of CD30 (CD30v) that retains only the cytoplasmic
      region of the authentic CD30. This variant is expressed in alveolar macrophages.
      CD30v can activate the nuclear factor-kappaB (NF-kappaB) as CD30, and its
      overexpression in HL-60 induced a differentiated phenotype. To better understand
      the physiological and pathological functions of CD30v, expression of this variant
      was examined using a multiple approach to examine 238 samples of human malignant
      myeloid and lymphoid neoplasms. Screening by reverse transcriptase-polymerase
      chain reaction (RT-PCR) revealed expression of CD30v transcripts in 52 of 72, 7
      of 11, 63 of 90, and 7 of 30 samples of acute myeloid leukemia (AML), myeloid
      blast crisis of myeloproliferative disorders (MBC), and lymphoproliferative
      disorders (LPDs) of B- and T-cell origin, respectively. CD30v expression was high
      in monocyte-oriented AMLs (FAB M4 and M5), B-cell chronic lymphocytic leukemia (B
      CLL), and multiple myeloma (MM). Using the specific antibody HCD30C2, prepared
      using a peptide corresponding to the nine amino acids of the amino-terminal
      CD30v, expression of CD30v protein was detected in 10 of 25 and 2 of 10 AML and
      ALL samples, respectively. In AMLs, immunocytochemical detection of CD30v
      revealed the presence of loose clusters of CD30v-expressing cells dispersed amid
      a population of CD30v-negative blasts. Finally, the parallel expression of CD30v
      mRNA and protein, as evidenced by Northern and Western blotting, was confirmed in
      selected cases of AMLs and LPDs. A significant correlation was found between
      expressions of CD30v and CD30 ligand transcripts in AML and LPD (P = 0.02, odds
      ratio = 3.2). The association of CD30v with signal-transducing proteins, tumor
      necrosis factor receptor-associated factor (TRAF) 2, and TRAF5 was demonstrated
      by coimmunoprecipitation analysis, as was demonstrated for authentic CD30
      protein. Expression of transcripts for TRAF1, TRAF2, TRAF3, and TRAF5, as
      demonstrated by RT-PCR, was noted in leukemic blasts that express CD30v.
      Collectively, frequent expression of CD30v along with TRAF proteins in human
      neoplastic cells of myeloid and lymphoid origin provide supportive evidence for
      biological and possible pathological functions of this protein in the growth and
      differentiation of a variety of myeloid and lymphoid cells.

PMID- 10595934
TI  - Heterogeneity of endothelial cells: the specialized phenotype of human high
      endothelial venules characterized by suppression subtractive hybridization.
AB  - High endothelial venules (HEVs) are specialized postcapillary venules, found in
      lymphoid organs and chronically inflamed tissues, that support high levels of
      lymphocyte extravasation from the blood. Molecular characterization of HEV
      endothelial cells (HEVECs) has been hampered by difficulties in their
      purification and in vitro maintenance. To overcome these limitations, we
      developed a strategy combining the use of freshly purified HEVECs ( approximately
      98% positive for the HEV-specific marker MECA-79) and the recently described
      polymerase chain reaction (PCR)-based cDNA subtraction cloning procedure called
      suppression subtractive hybridization (SSH). Subtracted probes prepared by SSH
      from small amounts of total RNA were used to screen a HEVEC cDNA library. This
      resulted in cloning of 22 cDNAs preferentially expressed in HEVECs, which encode
      the promiscuous chemokine receptor DARC, mitochondrial components, and
      matricellular proteins. The latter included hevin, thrombospondin-1, and
      mac25/IGFBP-rP1, which is a secreted growth factor-binding protein previously
      found to accumulate specifically in tumor blood vessels. Biochemical and
      histochemical analysis confirmed the identification of mac25 and DARC as novel
      markers of the HEVECs. Ultrastructural immunolocalization revealed a noticeable
      association of mac25 and MECA-79 antigens with microvillous processes near the
      endothelial cell junctions, suggesting a role for mac25 in the control of
      lymphocyte emigration. This study shows that PCR-based SSH is useful for cloning
      of differentially expressed genes in very small samples.

PMID- 10595935
TI  - Psoriasin (S100A7) expression and invasive breast cancer.
AB  - Alteration of psoriasin (S100A7) expression has previously been identified in
      association with the transition from preinvasive to invasive breast cancer. In
      this study we have examined persistence of psoriasin mRNA and protein expression
      in relation to prognostic factors in a cohort of 57 invasive breast tumors,
      comprising 34 invasive ductal carcinomas and 23 other invasive tumor types
      (lobular, mucinous, medullary, tubular). We first developed an IgY polyclonal
      chicken antibody and confirmed specificity for psoriasin by Western blot in
      transfected cells and tumors. The protein was localized by immunohistochemistry
      predominantly to epithelial cells, with both nuclear and cytoplasmic staining, as
      well as occasional stromal cells in psoriatic skin and breast tumors; however, in
      situ hybridization showed that psoriasin mRNA expression was restricted to
      epithelial cells. In breast tumors, higher levels of psoriasin measured by
      reverse transcriptase-polymerase chain reaction and Western blot (93%
      concordance) were significantly associated with estrogen and progesterone
      receptor-negative status (P < 0.0001, P = 0.0003), and with nodal metastasis in
      invasive ductal tumors (P = 0. 035), but not with tumor type or grade. Psoriasin
      expression also correlated with inflammatory infiltrates (all tumors excluding
      medullary, P = 0.0022). These results suggest that psoriasin may be a marker of
      aggressive behavior in invasive tumors and are consistent with a function as a
      chemotactic factor.

PMID- 10595936
TI  - Gastrin-releasing peptide receptors in non-neoplastic and neoplastic human
      breast.
AB  - The regulatory peptide gastrin-releasing peptide (GRP) may play a role in human
      cancer as a stimulatory growth factor. To understand the potential role of GRP in
      human breast cancer, we have evaluated GRP receptor expression in human non
      neoplastic and neoplastic breast tissues and in axillary lymph node metastases,
      using in vitro receptor autoradiography on tissue sections with [(125)I]Tyr(4)
      bombesin and with [(125)I]D-Tyr(6), beta Ala(11), Phe(13), Nle(14)-bombesin(6-14)
      as radioligands. GRP receptors were detected, often in high density, in
      neoplastic epithelial mammary cells in 29 of 46 invasive ductal carcinomas, in 11
      of 17 ductal carcinomas in situ, in 1 of 4 invasive lobular carcinomas, in 1 of 2
      lobular carcinomas in situ, and in 1 mucinous and 1 tubular carcinoma. A
      heterogeneous GRP receptor distribution was found in the neoplastic tissue
      samples in 32 of 52 cases with invasive carcinoma and 12 of 19 cases with
      carcinoma in situ. The lymph node metastases (n = 33) from those primary
      carcinomas expressing GRP receptors were all positive, whereas surrounding
      lymphoreticular tissue was negative. GRP receptors were also present in high
      density but with heterogeneous distribution in ducts and lobules from all
      available breast tissue samples (n = 23). All of the receptors corresponded to
      the GRP receptor subtype of bombesin receptors, having high affinity for GRP and
      bombesin and lower affinity for neuromedin B. All tissues expressing GRP
      receptors were identified similarly with both radioligands. These data describe
      not only a high percentage of GRP receptor-positive neoplastic breast tissues but
      also for the first time a ubiquitous GRP receptor expression in nonneoplastic
      human breast tissue. Apart from suggesting a role of GRP in breast physiology,
      these data represent the molecular basis for potential clinical applications of
      GRP analogs such as GRP receptor scintigraphy, radiotherapy, or chemotherapy.

PMID- 10595938
TI  - The deletion of transforming growth factor-beta-induced myofibroblasts depends on
      growth conditions and actin organization.
AB  - Myofibroblasts are important but transient mediators of normal wound contraction
      and are characterized phenotypically by their high levels of alpha-smooth-muscle
      actin (SMA). During wound maturation, these cells disappear. We have examined the
      mechanisms that lead to myofibroblast deletion in a fibroblast culture model.
      Transforming growth factor-beta (TGF-beta) was used to increase SMA content in
      gingival fibroblasts (three- to sixfold). After replating TGF-beta-induced cells
      at low density with serum, there was a fivefold decrease in SMA protein content,
      SMA protein synthesis, and SMA mRNA as cells proliferated. These reductions were
      due to reduced SMA mRNA stability. For TGF-beta-induced cells plated at high
      density without serum (ie, quiescent conditions), protein content was reduced by
      only 20% over 12 days. TGF-beta protected SMA-positive cells against apoptosis in
      serum-free cultures. Those cells that were protected against apoptosis exhibited
      well-developed stress fibers enriched in SMA. We conclude that, in quiescent
      myofibroblasts, SMA protein turnover is slow, and cells are long-lived. In
      proliferative conditions SMA protein and mRNA turn over quickly, and the
      myofibroblast phenotype dissipates. The reduced apoptosis of myofibroblasts in
      quiescent conditions is due in part to the organization of SMA into stress
      fibers.

PMID- 10595937
TI  - Primary central nervous system lymphomas are derived from germinal-center B cells
      and show a preferential usage of the V4-34 gene segment.
AB  - Primary central nervous system lymphomas (PCNSLs) have recently received
      considerable clinical attention due to their increasing incidence. To clarify the
      histogenetic origin of these intriguing neoplasms, PCNSLs from 10 HIV-negative
      patients were analyzed for immunoglobulin (Ig) gene rearrangements. All tumors
      exhibited clonal IgH gene rearrangements. Of the 10 cases, 5 used the V4-34 gene
      segment, and all of these lymphomas shared an amino acid exchange from glycine to
      aspartate due to a mutation in the first codon of the complementarity-determining
      region 1. No preferential usage of D(H), J(H), V(kappa), J(kappa), V(lambda), or
      J(lambda) gene segments was observed. All potentially functional rearrangements
      exhibited somatic mutations. The pattern of somatic mutations indicated selection
      of the tumor cells (or their precursors) for expression of a functional antibody.
      Mean mutation frequencies of 13. 2% and 8.3% were detected for the heavy and
      light chains, respectively, thereby exceeding other lymphoma entities. Cloning
      experiments of three tumors showed ongoing mutation in at least one case. These
      data suggest that PCNSLs are derived from highly mutated germinal-center B cells.
      The frequent usage of the V4-34 gene and the presence of a shared replacement
      mutation may indicate that the tumor precursors recognized a shared (super)
      antigen.

PMID- 10595939
TI  - Pathogenesis of dilated cardiomyopathy: molecular, structural, and population
      analyses in tropomodulin-overexpressing transgenic mice.
AB  - Dilated cardiomyopathy is characterized by decreased contractile function and
      loss of myofibril organization. Previously unexplored structural and molecular
      events that precede and initiate dilation can now be studied in tropomodulin
      overexpressing transgenic (TOT) mice exhibiting progressive dilated
      cardiomyopathy. Onset of dilation did not correspond to a change in transgene
      expression levels, which were more than threefold above normal at birth and
      remained elevated throughout postnatal life. Similarly, mitogen-activated protein
      kinase activation (p38, ERK1/ERK2, JNK1/JNK2) was not associated with dilation.
      In contrast, calcineurin was activated before dilation, presumably due to
      doubling of intracellular diastolic calcium levels in TOT cardiomyocytes.
      Amplitude of systolic calcium transients was greatly increased as well,
      demonstrating the novel and unique calcium handling profile of TOT
      cardiomyocytes. Loss of myofibril organization was not apparent by confocal
      microscopy until over 1 week after birth, although neonatal sarcomeric
      abnormalities were revealed by ultrastructural analysis. Rapid postnatal
      increases in heart:body weight ratio at 1.5 weeks were followed by two waves of
      mortality between 2 and 3 weeks after birth coincident with maturational stress.
      Ultimately, TOT pathogenesis is a compensatory response to altered sarcomeric
      structure driven by calcineurin activation within days after birth, making TOTs
      an excellent paradigm for studying the role of calcium overload in dilated
      cardiomyopathy.

PMID- 10595940
TI  - Agrin is a major heparan sulfate proteoglycan accumulating in Alzheimer's disease
      brain.
AB  - Heparan sulfate proteoglycans (HSPGs) have been suggested to play an important
      role in the formation and persistence of senile plaques and neurofibrillary
      tangles in dementia of the Alzheimer's type (DAT). We performed a comparative
      immunohistochemical analysis of the expression of the HSPGs agrin, perlecan,
      glypican-1, and syndecans 1-3 in the lesions of DAT brain neocortex and
      hippocampus. Using a panel of specific antibodies directed against the protein
      backbone of the various HSPG species and against the glycosaminoglycan (GAG) side
      chains, we demonstrated the following. The basement membrane-associated HSPG,
      agrin, is widely expressed in senile plaques, neurofibrillary tangles and
      cerebral blood vessels, whereas the expression of the other basement membrane
      associated HSPG, perlecan, is lacking in senile plaques and neurofibrillary
      tangles and is restricted to the cerebral vasculature. Glypican and three
      different syndecans, all cell membrane-associated HSPG species, are also
      expressed in senile plaques and neurofibrillary tangles, albeit at a lower
      frequency than agrin. Heparan sulfate GAG side chains are also associated with
      both senile plaques and neurofibrillary tangles. Our results suggest that
      glycosaminoglycan side chains of the HSPGs agrin, syndecan, and glypican, but not
      perlecan, may play an important role in the formation of both senile plaques and
      neurofibrillary tangles. In addition, we speculate that agrin, because it
      contains nine protease-inhibiting domains, may protect the protein aggregates in
      senile plaques and neurofibrillary tangles against extracellular proteolytic
      degradation, leading to the persistence of these deposits.

PMID- 10595941
TI  - Glycoprotein Ib is homogeneously distributed on external and internal membranes
      of resting platelets.
AB  - Recent ultrastructural studies have suggested that Glycoprotein Ib (GPIb) has a
      different distribution on external (surface) versus internal (open canalicular
      system) membranes in resting discoid platelets. The differential distribution
      proposed for GPIb differs from that reported for the fibrinogen receptor, GPIIb
      IIIa, and could have profound physiological significance when platelets are
      activated by surfaces. The present study explored the distribution of GPIb on
      external and internal membranes of resting platelets. Immunogold cytochemical
      techniques were applied to ultrathin cryosections of washed platelets. Polyclonal
      antibodies or mixtures of monoclonal antibodies (AP1 and 6D1) were used for
      labeling. To avoid the technical problem posed by limited accessibility of
      antigens located in very narrow portions of the open canalicular system (OCS) to
      antibodies, the same methods were applied to patients with giant platelets
      syndromes. The OCS of normal resting platelets was also dilated by exposure of
      platelets to hypertonic conditions or to cytochalasin-B, an agent that prevents
      assembly of actin, and, reportedly, movement of GPIb. Morphometric analysis
      revealed that rates of labeling on internal versus external membranes of giant
      platelets does not differ significantly (0.93 +/- 0.20), provided the OCS is
      sufficiently dilated. Platelets exposed to cytochalasin B (1.01 +/- 0.31) or to
      hypertonic conditions (0.96 +/- 0.20) revealed similar ratios for immunogold
      particles on external and internal membranes. Results of our study indicate that
      membranes of the exposed surface and lining OCS channels of resting platelets are
      continuous, identical structures and GPIb is homogeneously distributed on
      external and internal membranes.

PMID- 10595942
TI  - The repopulation potential of hepatocyte populations differing in size and prior
      mitotic expansion.
AB  - Recently the stem cell-like regenerative potential of adult liver cells was
      demonstrated by serial transplantation. This repopulation capacity could be
      useful for the treatment of genetic liver diseases by cell transplantation and/or
      expansion of genetically manipulated cells. However, previous experiments used
      unfractionated populations of liver cells, and therefore it remained undetermined
      whether all hepatocytes or only a subpopulation (stem cells) possessed this high
      regenerative ability. To address this question we used centrifugal elutriation to
      separate hepatocytes by cell density. Unexpectedly, small hepatocytes (16 microm)
      had lower repopulation capacity during the first round of transplantation when
      compared with both the medium-sized (21 microm) and large (27 microm) cells. We
      also compared the repopulation capacity of hepatocytes that had undergone
      different degrees of in vivo expansion. Previous cell division neither reduced
      nor increased the repopulation capacity of transplanted liver cells. Finally,
      retroviral tagging experiments demonstrated that liver-repopulating cells occur
      at a frequency of >1:10,000. We conclude that short-term therapeutic liver
      repopulation does not require progenitor or stem cells.

PMID- 10595943
TI  - Interleukin-1 and tumor necrosis factor receptor signaling is not required for
      bacteria-induced osteoclastogenesis and bone loss but is essential for protecting
      the host from a mixed anaerobic infection.
AB  - Bacterial infection causes significant morbidity, mediated in part by the up
      regulation of inflammatory cytokines. Cytokine induction is thought to stimulate
      osteolysis in conditions such as periodontal disease and otitis media. To
      establish the relative importance of interleukin-1 (IL-1) and tumor necrosis
      factor (TNF) in mediating the response to a mixed anaerobic infection, we used an
      in vivo model in which the dental pulp was inoculated with six anaerobic
      pathogens, in mice with functional deletions of receptors to IL-1 (IL-1RI(-/-)),
      TNF (TNFRp55(-/-)-p75(-/-)), or both (TNFRp55(-/-)-IL-1RI(-/-)).
      Polymorphonuclear and mononuclear phagocyte recruitment occurred to the greatest
      extent in TNFRp55(-/-)-IL-1RI(-/-) mice, and to a lesser extent in IL-1RI(-/-) or
      TNFRp55(-/-)-p75(-/-) mice, and the least in wild-type mice, demonstrating that
      recruitment of these phagocytes is not dependent on IL-1 or TNF receptor
      signaling. A similar pattern was observed for bacterial penetration into host
      tissue. Because it had recently been reported that TNF played a critical role in
      mediating lipopolysaccharide-induced bone loss, we anticipated that mice with
      targeted deletions of TNFRp55(-/-) would have reduced osteoclastogenesis.
      Surprisingly, osteolytic lesion formation was greatest in animals lacking TNF
      and/or IL-1 receptors. These results indicate that IL-1 or TNF receptor signaling
      is not required for bacteria-induced osteoclastogenesis and bone loss, but does
      play a critical role in protecting the host against mixed anaerobic infections.

PMID- 10595944
TI  - Prominent axonopathy in the brain and spinal cord of transgenic mice
      overexpressing four-repeat human tau protein.
AB  - Mutations in the human tau gene cause frontotemporal dementia and parkinsonism
      linked to chromosome 17. Some mutations, including mutations in intron 10, induce
      increased levels of the functionally normal four-repeat tau protein isoform,
      leading to neurodegeneration. We generated transgenic mice that overexpress the
      four-repeat human tau protein isoform specifically in neurons. The transgenic
      mice developed axonal degeneration in brain and spinal cord. In the model, axonal
      dilations with accumulation of neurofilaments, mitochondria, and vesicles were
      documented. The axonopathy and the accompanying dysfunctional sensorimotor
      capacities were transgene-dosage related. These findings proved that merely
      increasing the concentration of the four-repeat tau protein isoform is sufficient
      to injure neurons in the central nervous system, without formation of
      intraneuronal neurofibrillary tangles. Evidence for astrogliosis and
      ubiquitination of accumulated proteins in the dilated part of the axon supported
      this conclusion. This transgenic model, overexpressing the longest isoform of
      human tau protein, recapitulates features of known neurodegenerative diseases,
      including Alzheimer's disease and other tauopathies. The model makes it possible
      to study the interaction with additional factors, to be incorporated genetically,
      or with other biological triggers that are implicated in neurodegeneration.

PMID- 10595947
TI  - In support of findings on Pseudomyxoma peritonei.

PMID- 10595946
TI  - Diagnosis and classification of small round-cell tumors of childhood.

PMID- 10595948
TI  - Circulation online only : december 14, 1999

PMID- 10595945
TI  - Sympathoadrenal hyperplasia causes renal malformations in Ret(MEN2B)-transgenic
      mice.
AB  - The tyrosine kinase receptor Ret is expressed in the ureteric bud and is required
      for normal renal development. Constitutive loss of Ret, its co-receptor gfralpha
      1, or the ligand glial cell line-derived neurotrophic factor results in renal
      agenesis. Transgenic embryos that express a constitutively active form of Ret
      (Ret(MEN2B)) under the control of the dopamine-beta-hydroxylase (DbetaH) promoter
      develop profound neuroglial hyperplasia of their sympathetic ganglia and adrenal
      medullae. Embryos from two independent DbetaH-Ret(MEN2B)-transgenic lines exhibit
      renal malformations. In contrast with ret-/- embryos, renal maldevelopment in
      DbetaH-Ret(MEN2B)-transgenic embryos results from primary changes in
      sympathoadrenal organs extrinsic to the kidney. The ureteric bud invades the
      metanephric mesenchyme normally, but subsequent bud branching and nephrogenesis
      are retarded, resulting in severe renal hypoplasia. Ablation of sympathoadrenal
      precursors restores normal renal growth in vivo and in vitro. We postulate that
      disruption of renal development results because Ret(MEN2B) derived from the
      hyperplastic nervous tissue competes with endogenous renal Ret for gfralpha-1 or
      other signaling components. This hypothesis is supported by the observation that
      renal malformations, which do not normally occur in a transgenic line with low
      levels of DbetaH-Ret(MEN2B) expression, arise in a gdnf+/- background. However,
      renal maldevelopment was not recapitulated in kidneys that were co-cultured with
      explanted transgenic ganglia in vitro. Our observations illustrate a novel
      pathogenic mechanism for renal dysgenesis that may explain how putative
      activating mutations of the RET gene can produce a phenotype usually associated
      with RET deficiency.

PMID- 10595949
TI  - Threshold values for preserved viability with a noninvasive measurement of
      collateral blood flow during acute myocardial infarction treated by direct
      coronary angioplasty.
AB  - BACKGROUND: Quantitative measures of myocardial perfusion defect severity from
      acute (99m)Tc-sestamibi tomographic images (nadir) have correlated closely with
      collateral and residual antegrade blood flow during acute myocardial infarction.
      The purpose of this study was to determine whether a viability threshold could be
      identified from this measure in patients with acute myocardial infarction treated
      in a homogeneous manner with successful reperfusion therapy. METHOD AND RESULTS:
      The study group consisted of 61 patients with acute myocardial infarction with a
      risk area of >6% LV treated with primary angioplasty between 120 and 240 minutes
      after symptom onset. All patients were injected with 20 to 30 mCi of (99m)Tc
      sestamibi before primary angioplasty and imaged after the procedure. Acute
      myocardium at risk (MAR) and subsequent infarct size (IS) were quantified by a
      threshold program. Severity (nadir) from the acute image was the lowest ratio of
      minimal/maximum counts from 5 short-axis slices. Infarct location was anterior in
      22 and inferior in 39 patients. MAR was 33+/-15% LV and IS was 13+/-15% LV: 23
      patients had no infarction despite MAR similar to those with infarction. Receiver
      operator characteristic curve analysis identified a nadir value of 0.26 as
      providing the best separation of patients with and without infarction
      (sensitivity, 74%; specificity, 74%). This nadir threshold varied by infarct
      location: anterior defect, 0.21; inferior defect, 0.31. The sensitivity and
      specificity for absent infarction for these values were anterior, 69% and 67%,
      and inferior, 88% and 84%, respectively. CONCLUSIONS: In a time frame in which
      the presence of residual blood flow is important, the severity of the acute
      (99m)Tc-sestamibi defect can be used to predict whether infarction will develop
      despite successful reperfusion.

PMID- 10595950
TI  - Longitudinal analysis of fibroblast growth factor expression after
      transplantation and association with severity of cardiac allograft vasculopathy.
AB  - BACKGROUND: Vascular smooth muscle cell growth factors are postulated to
      contribute to cardiac allograft vasculopathy (CAV). Few data quantitatively
      address the timing, location, or stimuli for growth factor expression and
      relationship to CAV. METHODS AND RESULTS: Acidic fibroblast growth factor (aFGF)
      mRNA expression was determined in serial endomyocardial biopsies during the first
      year after transplantation. Patients with high levels of aFGF mRNA and elevations
      after the early posttransplant period had significantly more severe CAV than
      patients with low aFGF and no late elevations. CONCLUSIONS: Parenchymal aFGF
      expression varies between patients and in the same patient over time and
      correlates with development of CAV.

PMID- 10595951
TI  - Creatine kinase-MB enzyme elevation following successful saphenous vein graft
      intervention is associated with late mortality.
AB  - BACKGROUND: Although the risk for development of creatine kinase (CK-MB)
      elevation after saphenous vein graft (SVG) intervention is high, its prognostic
      significance remains unknown. This study evaluated the impact of periprocedural
      CK-MB elevation on late clinical events following successful SVG angioplasty.
      METHODS AND RESULTS: We studied 1056 consecutive patients with successful
      (defined by angiographic success and absence of major complications) intervention
      of 1693 SVG lesions. These patients were grouped as normal CK-MB (n=556), minor
      CK-MB rise (CK-MB 1 to 5 times normal, n=339), and major CK-MB rise (CK-MB >5
      times normal, n=161). There were no differences in major clinical events at 30
      day follow-up among the 3 groups. However, 1-year mortality was 4.8%, 6.5%, and
      11. 7%, respectively, P<0.05 (ANOVA). Even within a population without any
      intraprocedure or in-hospital complications (n=727, 69% of the overall cohort), 1
      year mortality remained significantly higher with CK-MB elevation: 2.4%, 5.5%,
      and 10.7%, respectively, P<0.05 (ANOVA). Multivariate analysis revealed major CK
      MB elevation as the strongest independent predictor of late mortality (odds ratio
      3.3, with 95% CI 1.7 to 6.2), followed by diabetes mellitus (odds ratio 2. 6,
      with 95% CI 1.5 to 4.5). CONCLUSIONS: Major CK-MB elevation occurs after 15% of
      otherwise successful SVG interventions and is associated with increased late
      mortality.

PMID- 10595952
TI  - Methylenetetrahydrofolate reductase genotypes and early-onset coronary artery
      disease.
AB  - BACKGROUND: Homozygosity for the common (677C-->T) mutation in the
      methylenetetrahydrofolate reductase (MTHFR) gene is associated with
      hyperhomocysteinemia, but there is uncertainty as to the association between this
      mutation and coronary artery disease (CAD). This study examined the association
      between MTHFR genotypes and age at onset of CAD. METHODS AND RESULTS: Patients
      (n=169) with documented myocardial infarction or angiographically documented CAD
      who were aged < or = 55 years at onset of CAD symptoms and DNA samples from
      control subjects (n=313) were studied. The prevalence of homozygosity among
      patients with early CAD onset (aged < or = 45 years) was 28%, which was
      significantly higher than that in patients with later onset (13%) and in control
      subjects (14%) (odds ratio 2.4, 95% CI 1.24 to 4.69, P=0.006, and odds ratio 2.7,
      95% CI 1.15 to 6.42, P=0.01, respectively). Plasma folate was lower in TT
      homozygotes who had early CAD onset than in those with later onset (P=0.005).
      Among patients with plasma folate in the lowest quintile (< or = 12.6 nmol/L),
      31% were homozygotes, as were 45% of those with low plasma folate and early CAD
      onset. There was no difference in the prevalence of traditional risk factors
      among genotypes. The frequency of homozygosity in patients with < or = 1 risk
      factor was higher than in those with > or = 2 risk factors (30% versus 12%,
      P<0.05). In multiple regression analysis, TT homozygosity and plasma folate were
      independently associated with CAD, but the impact of folate was small.
      CONCLUSIONS: Homozygosity for the 677C-->T mutation of MTHFR is common and is
      associated with an increased risk of premature CAD in this population.

PMID- 10595953
TI  - Ventilatory and heart rate responses to exercise : better predictors of heart
      failure mortality than peak oxygen consumption.
AB  - BACKGROUND: An abnormally low chronotropic response and an abnormally high
      ventilatory response (V(E)/V(CO2)) to exercise are common in patients with severe
      heart failure, but their relative prognostic impacts have not been well explored.
      METHODS AND RESULTS: Consecutive patients with heart failure referred for
      metabolic stress testing who were not taking beta-blockers or intravenous
      inotropes (n=470) were followed for 1.5 years. The chronotropic index was
      calculated while peak V(O2) and V(E)/V(CO2) were directly measured. Chronotropic
      index and peak V(O2) were considered abnormal if in the lowest 25th percentiles
      of the patient cohort, whereas V(E)/V(CO2) was considered abnormal if in the
      highest 25th percentile. For comparative purposes, a group of 17 healthy controls
      underwent metabolic testing as well. Compared with controls, heart failure
      patients had markedly abnormal ventilatory and chronotropic responses to
      exercise. In the heart failure cohort, there were 71 deaths. In univariate
      analyses, predictors of death included high V(E)/V(CO2) low chronotropic index,
      low V(O2), low resting systolic blood pressure, and older age. Nonparametric
      Kaplan-Meier plots demonstrated that by dividing the population according to peak
      V(E)/V(CO2) and peak V(O2), it is possible to identify low, intermediate, and
      very high risk groups. In multivariate analyses, the only independent predictors
      of death were high V(E)/V(CO2) (adjusted relative risk [RR] 3.20, 95% CI 1.95 to
      5.26, P<0.0001) and low chronotropic index (adjusted RR 1.94, 95% CI 1.18 to
      3.19, P=0.0009). CONCLUSIONS: The ventilatory and chronotropic responses to
      exercise are powerful and independent predictors of heart failure mortality.

PMID- 10595954
TI  - Oscillatory breathing patterns during wakefulness in patients with chronic heart
      failure: clinical implications and role of augmented peripheral chemosensitivity.
AB  - BACKGROUND: Oscillatory breathing patterns characterized by rises and falls in
      ventilation with apnea (Cheyne-Stokes respiration [CSR]) or without apnea
      (periodic breathing [PB]) commonly occur during the daytime in chronic heart
      failure (CHF). We have prospectively characterized patients with cyclical
      breathing in terms of clinical characteristics, indices of autonomic control,
      prognosis, and the role of peripheral chemosensitivity. METHODS AND RESULTS: To
      determine cyclical breathing pattern, power spectral analysis was applied to 30
      minute recordings of respiration in 74 stable CHF patients. Analyses of heart
      rate variability and baroreflex sensitivity were used to assess autonomic
      balance. Peripheral chemosensitivity was assessed with the transient hypoxia
      method. We also determined whether the suppression of peripheral chemoreceptor
      activity (hyperoxia or dihydrocodeine) would influence the respiratory pattern.
      Cyclical respiration was found in 49 (66%) patients (22 [30%] CSR, 27 [36%] PB)
      and was associated with more advanced CHF symptoms, impaired autonomic balance,
      and increased chemosensitivity (0.80 and 0.75 versus 0.34 L. min(-1). %SaO(2)(
      1), P<0.001, for CSR and PB versus normal breathing, respectively). Transient
      hyperoxia abolished oscillatory breathing in 7 of 8 patients. Dihydrocodeine
      administration decreased chemosensitivity by 42% (P=0.05), which correlated with
      improvement in respiratory pattern. Cyclical breathing predicted poor 2-year
      survival (relative risk 9.41, P<0.01, by Cox proportional hazards analysis),
      independent of peak oxygen consumption (P=0.04). CONCLUSIONS: An oscillatory
      breathing pattern during the daytime is a marker of impaired autonomic regulation
      and poor outcome. Augmented activity of peripheral chemoreceptors may be involved
      in the genesis of this respiratory pattern. Modulation of peripheral
      chemosensitivity can reduce or abolish abnormal respiratory patterns and may be
      an option in the management of CHF patients with oscillatory breathing.

PMID- 10595956
TI  - Long-term follow-up of patients with long-QT syndrome treated with beta-blockers
      and continuous pacing.
AB  - BACKGROUND: The long-QT syndrome is associated with sudden cardiac death.
      Combination of beta-blocker and pacing therapy has been proposed for treatment of
      drug-resistant patients. The purpose of this study was to summarize our long-term
      experience with combined therapy in patients with long-QT syndrome. METHODS AND
      RESULTS: A total of 37 patients with idiopathic long-QT syndrome were treated
      with combined therapy consisting of continuous cardiac pacing and maximally
      tolerated beta-blocker therapy and followed up for 6.3+/-4. 6 years (mean+/-SD).
      The group consisted of 32 female and 5 male patients with a mean age of 31.6
      years. The mean paced rate was 82+/-7 bpm (range, 60 to 100 bpm). On follow-up,
      recurrent symptoms caused by pacemaker malfunction were documented in 3 patients.
      Four patients died during the follow-up period: 2 adolescents stopped beta
      blocker therapy, 1 patient died suddenly while treated with combined therapy, and
      1 patient died of unrelated causes. In addition, 3 patients had resuscitated
      cardiac arrest while on combined therapy, and 1 patient had repeated, appropriate
      implantable cardioverter-defibrillator discharges on follow-up. CONCLUSIONS:
      Because 28 of 37 patients remain without symptoms with beta-blocker therapy and
      continuous pacing, combined therapy appears to provide reasonable, long-term
      control for this high-risk group. However, the incidence of sudden death and
      aborted sudden death (24% in all patients and 17% in compliant patients) strongly
      suggests the use of a "back-up" defibrillator, particularly in noncompliant
      adolescent patients. Implantable cardioverter-defibrillator therapy, however, may
      be associated with recurrent shocks in susceptible patients.

PMID- 10595955
TI  - Myocardial oxygen consumption is unchanged but efficiency is reduced in patients
      with essential hypertension and left ventricular hypertrophy.
AB  - BACKGROUND: Patients with hypertension and left ventricular hypertrophy (LVH) are
      prone to develop heart failure. We tested the hypothesis that compensatory LVH is
      associated with normalization of myocardial oxygen consumption and that this
      occurs at the expense of a decrease in the ratio between cardiac work and oxygen
      consumption (efficiency). METHODS AND RESULTS: Nine hypertensive men with LVH
      (LVH+) (age 42+/-2 years), left ventricular mass index (LVMI) 161+/-8 g/m(2),
      blood pressure (BP) 145+/-16/88+/-10 mm Hg (mean+/-SD); 8 hypertensive men
      without LVH (LVH-) (age 39+/-5 years, LVMI 107+/-15 g/m(2), BP 140+/-15/90+/-11
      mm Hg); and 10 normotensive men (CONT) were studied. Myocardial blood flow,
      oxygen consumption, and glucose uptake were measured during euglycemic
      hyperinsulinemia using PET techniques. LV dimensions, volumes, and workload were
      determined by echocardiography, and efficiency was calculated. Myocardial
      workload (2.5+/-0.8 versus 3.0+/-0.6 versus 2. 3+/-0.5 mm Hg. mL. min(-1). g(-1)
      for CONT versus LVH- versus LVH+; P<0.05, LVH- versus LVH+), myocardial blood
      flow (0.84+/-0.16 versus 1.06+/-0.22 versus 0.81+/-0.09 mL. g(-1). min,
      respectively; P<0.05, LVH- versus other groups) and oxygen consumption (0.09+/
      0.02 versus 0.14+/-0.03 versus 0.11+/-0.01 ml. g(-1). min(-1), respectively; P<0.
      05, LVH- versus other groups) were increased in the LVH- group. Myocardial
      efficiency was reduced in the LVH+ group (18.1+/-4.1% versus 15.1+/-2.3% versus
      13.5+/-1.9%, respectively; P<0.05, LVH+ versus CONT). CONCLUSIONS: Myocardial
      oxygen consumption per unit weight is increased in hypertensive patients without
      LVH but is normal in those with LVH. The normalization of oxygen consumption via
      hypertrophy occurs at the expense of efficiency, which may predispose
      hypertensive patients with LVH to heart failure.

PMID- 10595957
TI  - Systemic administration of calmodulin antagonist W-7 or protein kinase A
      inhibitor H-8 prevents torsade de pointes in rabbits.
AB  - BACKGROUND: The ventricular arrhythmia torsade de pointes (TdP) occurs after QT
      interval prolongation and is associated with sudden cardiac death. The
      afterdepolarizations that initiate TdP are facilitated by protein kinase A and
      the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase).
      METHODS AND RESULTS: In this study, we evaluated the feasibility of suppression
      of TdP through systemic therapy with kinase inhibitory agents in an established
      animal model. Under control conditions, TdP was inducible in 6 of 8 rabbits. CaM
      kinase blockade with the calmodulin antagonist W-7 reduced TdP in a dose
      dependent fashion (4 of 7 inducible at 25 micromol/kg and 1 of 7 inducible at 50
      micromol/kg). Increased intracellular Ca(2+) has been implicated in the genesis
      of afterdepolarizations, but pretreatment with high-dose W-7 did not prevent TdP
      in response to the L-type Ca(2+) channel agonist BAY K 8644 (300 nmol/kg),
      suggesting that CaM kinase-independent activation of L-type Ca(2+) current was
      not affected by W-7. Compared with control animals, W-7 reduced TdP inducibility
      without shortening the QT interval, increasing heart rate, or reducing the blood
      pressure. The protein kinase A antagonist H-8 also caused a dose-dependent
      reduction in TdP inducibility (5 of 6 at 1 micromol/kg, 4 of 6 at 5 micromol/kg,
      and 0 of 6 at 10 micromol/kg), but unlike W-7, H-8 did so by shortening the QT
      interval. CONCLUSIONS: These findings show that the acute systemic application of
      W-7 and H-8 is hemodynamically tolerated and indicate that kinase inhibition may
      be a viable antiarrhythmic strategy.

PMID- 10595958
TI  - Renal response to acute neutral endopeptidase inhibition in mild and severe
      experimental heart failure.
AB  - BACKGROUND: Neutral endopeptidase 24.11 (NEP) is a metalloprotease that is
      localized in the greatest abundance in the kidney and degrades natriuretic
      peptides, such as atrial natriuretic peptide (ANP). Mild congestive heart failure
      (CHF) is characterized by increases in circulating ANP without activation of the
      renin-angiotensin-aldosterone system (RAAS) or sodium retention. In contrast,
      severe CHF is characterized by sodium retention and coactivation of both ANP and
      the RAAS. METHODS AND RESULTS: We defined the acute cardiorenal actions of the
      NEP inhibitor candoxatrilat (8 microg. kg(-1). min(-1)) in 4 groups of
      anesthetized dogs (normal, n=8; mild CHF, n=6; severe CHF, n=5; and severe CHF
      with chronic AT(1) receptor antagonism, n=5). Mild CHF was produced by rapid
      ventricular pacing at 180 bpm for 10 days and severe CHF at 245 bpm for 10 days.
      In mild CHF, urinary sodium excretion and glomerular filtration rate were
      greatest in response to acute NEP inhibition compared with the response in either
      control animals or those with severe CHF. Furthermore, an increase in glomerular
      filtration rate was observed only in mild CHF in association with increases in
      renal blood flow and decreases in renal vascular resistance and distal tubular
      sodium reabsorption. Urinary ANP and cGMP excretion, markers for renal biological
      actions of ANP, were greatest in mild CHF. The renal actions observed in mild CHF
      were attenuated in severe CHF and not restored by chronic AT(1) receptor
      antagonism. CONCLUSIONS: The results of the present study demonstrate that acute
      NEP inhibition in mild CHF results in marked increases in renal hemodynamics and
      sodium excretion that exceed that observed in control animals and severe CHF.
      These studies underscore the potential therapeutic role for NEP inhibition to
      enhance renal function in mild CHF, an important phase of CHF that is marked by
      selective activation of endogenous ANP in the absence of an activated RAAS.

PMID- 10595959
TI  - Calcineurin plays a critical role in pressure overload-induced cardiac
      hypertrophy.
AB  - BACKGROUND: Cardiac hypertrophy is a fundamental adaptive response to hemodynamic
      overload; how mechanical load induces cardiac hypertrophy, however, remains
      elusive. It was recently reported that activation of a calcium-dependent
      phosphatase, calcineurin, induces cardiac hypertrophy. In the present study, we
      examined whether calcineurin plays a critical role in pressure overload-induced
      cardiac hypertrophy. METHODS AND RESULTS: Pressure overload produced by
      constriction of the abdominal aorta increased the activity of calcineurin in the
      rat heart and induced cardiac hypertrophy, including reprogramming of gene
      expression. Treatment of rats with a calcineurin inhibitor, FK506, inhibited the
      activation of calcineurin and prevented the pressure overload-induced cardiac
      hypertrophy and fibrosis without change of hemodynamic parameters. Load-induced
      expression of immediate-early-response genes and fetal genes was also suppressed
      by the FK506 treatment. CONCLUSIONS: The present results suggest that the
      calcineurin signaling pathway plays a pivotal role in load-induced cardiac
      hypertrophy and may pave the way for a novel pharmacological approach to prevent
      cardiac hypertrophy.

PMID- 10595960
TI  - Downregulation of delayed rectifier K(+) currents in dogs with chronic complete
      atrioventricular block and acquired torsades de pointes.
AB  - BACKGROUND: Acquired QT prolongation enhances the susceptibility to torsades de
      pointes (TdP). Clinical and experimental studies indicate ventricular action
      potential prolongation, increased regional dispersion of repolarization, and
      early afterdepolarizations as underlying factors. We examined whether K(+)
      current alterations contribute to these proarrhythmic responses in an animal
      model of TdP: the dog with chronic complete atrioventricular block (AVB) and
      biventricular hypertrophy. METHODS AND RESULTS: The whole-cell K(+) currents
      I(TO1), I(K1), I(Kr), and I(Ks) were recorded in left (LV) and right (RV)
      ventricular midmyocardial cells from dogs with 9+/-1 weeks of AVB and controls
      with sinus rhythm. I(TO1) density and kinetics and I(K1) outward current were not
      different between chronic AVB and control cells. I(Kr) had a similar voltage
      dependence of activation and time course of deactivation in chronic AVB and
      control. I(Kr) density was similar in LV myocytes but smaller in RV myocytes (
      45%) of chronic AVB versus control. For I(Ks), voltage-dependence of activation
      and time course of deactivation were similar in chronic AVB and control. However,
      I(Ks) densities of LV (-50%) and RV (-55%) cells were significantly lower in
      chronic AVB than control. CONCLUSIONS: Significant downregulation of delayed
      rectifier K(+) current occurs in both ventricles of the dog with chronic AVB.
      Acquired TdP in this animal model with biventricular hypertrophy is thus related
      to intrinsic repolarization defects.

PMID- 10595961
TI  - Images in Cardiovascular Medicine: Percutaneous myocardial gene transfer of
      phVEGF-2.

PMID- 10595962
TI  - Women and heart disease.

PMID- 10595963
TI  - Women's heart problems are poorly understood.

PMID- 10595964
TI  - Different ways of approaching the normal pericardial space.

PMID- 10595965
TI  - Myocardial perfusion after transmyocardial laser revascularization.

PMID- 10595966
TI  - Hyperinsulinemia predicts coronary heart disease risk in healthy middle-aged men.

PMID- 10595967
TI  - Exercise-induced ischemia and carotid atherosclerosis.

PMID- 10595968
TI  - 1999 aats scientific achievement award recipient-michael e. Debakey, md.

PMID- 10595969
TI  - Reoperative aortic valve replacement: partial upper hemisternotomy versus
      conventional full sternotomy.
AB  - OBJECTIVE: We developed techniques for partial upper hemisternotomy for
      reoperative aortic valve replacement and compared the results with those of
      reoperative aortic valve replacement by way of conventional full resternotomy.
      METHODS: We retrospectively analyzed data from 19 patients who underwent
      conventional full sternotomy and 20 patients who underwent partial hemisternotomy
      for isolated elective reoperative aortic valve replacements performed between
      November 1996 and September 1998. Univariable and multivariable analyses were
      used to document the differences between the groups. RESULTS: The 2 groups were
      similar with respect to age, sex, New York Heart Association functional class,
      valve pathologic characteristics, and numbers and types of previous operations.
      There were neither any operative deaths nor any postoperative valve-related
      morbidities in either group. There was 1 injury to a cardiac structure, which
      occurred in the conventional full sternotomy group. Univariable analysis
      documented that patients in the conventional full sternotomy group were
      significantly more likely to have at least 1000 mL blood loss during the first 24
      hours after the operation (odds ratio 8.1, P =.02), were more likely to require
      transfusion of more than 5 units of packed red blood cell (odds ratio 3.6, P
      =.08), and were more likely to have a total operative duration longer than 5
      hours (odds ratio 3.6, P =.08). In the multivariable analysis conventional full
      resternotomy remained a risk factor for greater blood loss (odds ratio 5.7, P
      =.06), greater transfusion requirement (odds ratio 2.4, P =.25), and longer total
      operative duration (odds ratio 7.7, P =.03). CONCLUSIONS: Partial upper
      hemisternotomy for reoperative aortic valve replacement avoids unnecessary lower
      mediastinal dissection, thereby reducing blood loss, transfusion needs, and total
      operative duration. These beneficial effects, which are accomplished without
      compromising the efficacy of the valve operation, make the partial upper
      hemisternotomy an excellent alternative to conventional full resternotomy for
      reoperative aortic valve replacement.

PMID- 10595970
TI  - Behavior of vital and killed autologous pericardium in the descending aorta of
      sheep.
AB  - OBJECTIVES: Cardiovascular implants of fresh autologous pericardium produced
      mixed results including fibrosis with retraction or thinning and dilatation. The
      reasons for these differences are unknown but may involve activation of cells
      intrinsic to the tissue implant. To better understand the behavior of autologous
      pericardial implants, we studied the outcomes of vital pericardium (fresh) versus
      ethanol-killed pericardium. METHODS: Fresh and ethanol-killed autologous
      pericardium was transplanted as a patch, a conduit, or a rectangular flap
      bisecting the lumen in the descending aorta of sheep. The implants, recovered at
      1, 5, 10, 15, and 30 days, were evaluated macroscopically and microscopically and
      by immunohistologic studies. RESULTS: Fresh implants showed good preservation
      with fibrin deposition on day 15. Microscopically, cells positive for alpha-actin
      and von Willebrand-related antigen appeared in the fibrin by day 10. By day 30
      the flap was fibrotic and retracted whereas the patch and conduit retained their
      original appearance on the luminal aspect. An endothelium-like layer expressing
      von Willebrand-related antigen was present in the patch and conduit but absent in
      the flap. In contrast, the ethanol-killed implants were free of fibrin by day 10.
      By day 30, there were no signs of fibrosis or retraction, and a surface layer of
      cells expressing von Willebrand-related antigen, characteristic of endothelial
      cells, was present on all implants. All ethanol-killed implants were repopulated
      by host cells. CONCLUSION: The transluminal flap is an interesting model for
      studying the behavior of intraluminal autologous pericardial cardiovascular
      implants. Killing of the pericardial implants alleviated the fibrosis and tissue
      retraction observed with fresh flap implants.

PMID- 10595971
TI  - Predictors of operative risk for coronary bypass operations in patients with left
      ventricular dysfunction.
AB  - OBJECTIVES: The prevalence of ventricular dysfunction in patients undergoing
      coronary operations, as well as the prevalence of other risk factors in these
      patients, has been increasing. We identified the predictors of mortality and
      morbidity in patients with ventricular dysfunction to permit more accurate
      evaluation of risk and to direct future strategies to improve outcomes. METHODS:
      Demographic, intraoperative, and outcome data were collected prospectively on
      20,614 patients undergoing isolated coronary operations at our institution from
      1982-1997. Multivariable regression analyses were used to identify the
      independent predictors of mortality and low-output syndrome. RESULTS: Moderate
      ventricular dysfunction (ejection fraction, 20%-40%) was noted in 4107 (19.9%)
      patients, and severe dysfunction (ejection fraction, <20%) was noted in 680
      (3.3%) patients. Patients with worse ventricular function had an increasing
      prevalence of other risk factors with time. Mortality decreased between the 1982
      1986 and 1987-1991 cohorts but did not decrease further. Low-output syndrome was
      less common in the 1992-1997 cohort than in previous years. The predictors of
      mortality were ventricular dysfunction, age, reoperation, year of operation,
      urgency, female sex, and left main stenosis. Low-output syndrome was predicted by
      ventricular dysfunction, reoperation, year of operation, female sex, urgency,
      extensive coronary disease, age, left main stenosis, and symptom class.
      CONCLUSIONS: Despite the increasing prevalence and risk profile of patients with
      ventricular dysfunction, mortality rates and incidence of low-output syndrome
      declined with time. Patients with severe dysfunction were at greatest risk when
      facing reoperation or urgent operation. Earlier intervention and more aggressive
      preoperative optimization may improve outcomes in these high-risk patients.

PMID- 10595972
TI  - Replacement of the proximal aorta and aortic valve using a composite bileaflet
      prosthesis and gelatin-impregnated polyester graft (Carbo-Seal): early results in
      143 patients.
AB  - OBJECTIVE: We report the combined early results from two centers in the United
      Kingdom using a composite conduit consisting of a bileaflet mechanical valve
      incorporated into a gelatin-impregnated, ultra-low porosity, woven polyester
      graft (Carbo-Seal; Sulzer Carbomedics, Inc, Austin, Tex). METHODS: Between August
      1992 and March 1997, 143 patients underwent aortic root replacement with the
      Carbo-Seal composite prosthesis. The indication for surgery was acute type A
      dissection in 31 (22%), chronic type A dissection in 9 (6%), ascending aortic
      aneurysm without dissection in 100 (70%), and false aneurysm of the ascending
      aorta in 3 (2%). Twenty-seven patients (19%) had undergone previous sternotomy,
      and 40 (28%) were seen as emergencies. Concomitant procedures were performed in
      38 (27%), including 18 aortic arch or hemiarch replacements. Total follow-up is
      270 patient-years. Follow-up is 100% complete. RESULTS: The early (30-day)
      mortality was 7% (10 patients). Permanent neurologic events occurred in 2%. At a
      mean follow-up of 23 months, 94% of survivors were in New York Heart Association
      functional class I. Freedom from reoperation was 97.2% +/- 1.6% (1 standard error
      [1 SE]) at 12 months and 95.7% +/- 2.2% at 48 months. Including early mortality,
      survival was 90.1% +/- 2.6% at 12 months and 83.1% +/- 3. 5% at 48 months.
      CONCLUSIONS: Aortic root replacement with use of the Carbo-Seal prosthesis can be
      undertaken with a relatively low early mortality and morbidity. A low reoperation
      rate and high intermediate-term survival can be expected, but continued follow-up
      is needed to determine the long-term efficacy of this prosthesis.

PMID- 10595973
TI  - Aortic stent grafting and side-branch embolization in an expanding chronic type B
      dissection.
AB  - OBJECTIVE: This is a report of endovascular treatment of a case of type B
      thoracoabdominal aortic dissection in a patient with progressive dyspnea,
      dorsolumbar pain, and expanding aortic diameter over a 1-year period. METHODS:
      Pretreatment imaging evaluation showed that the false lumen supplied only the
      celiac trunk. Endovascular treatment combined (1) embolization of the first
      segment of the celiac trunk to avoid distal back-flow into the false lumen and
      (2) stent grafting to occlude the initial entry tear. RESULTS: The treatment
      resulted in technical and clinical success. The patient remains asymptomatic 12
      months after treatment. CONCLUSION: Stent grafting offers an interesting
      therapeutic alternative to exclude the initial entry tear in aortic dissection
      and may be combined with other endovascular procedures.

PMID- 10595974
TI  - Impact of retrograde cerebral perfusion on aortic arch aneurysm repair.
AB  - OBJECTIVE: Protection of the brain is a primary concern in aortic arch surgery.
      Retrograde cerebral perfusion is a relatively new technique used for cerebral
      protection during profound hypothermic circulatory arrest. This study was
      designed to compare, retrospectively, the outcome of 109 patients undergoing
      aortic arch operation with and without the use of retrograde cerebral perfusion.
      METHODS: Fifty-five patients had profound hypothermic circulatory arrest alone,
      and 54 patients had supplemental cerebral protection with retrograde cerebral
      perfusion. Mean age was 61 +/- 13 years and 58 +/- 14 years, respectively (mean
      +/- standard deviation). Twenty-two preoperative and intraoperative
      characteristics, including age, sex, acuity, presence of aortic dissection, and
      aneurysm rupture, were similar in the 2 groups (P >.05). RESULTS: Mean
      circulatory arrest times (in minutes) were 30 +/- 19 in the group without
      retrograde cerebral perfusion and 33 +/- 19 in the group with retrograde cerebral
      perfusion, respectively. chi(2) Analysis revealed that patients operated on with
      the use of retrograde cerebral perfusion had significantly lower hospital
      mortality (15% vs 31%; P =.04) and in-hospital permanent neurologic complications
      (9% vs 27%; P =.01). Retrograde cerebral perfusion failed to reduce the
      prevalence of temporary neurologic dysfunction (17% vs 18%; P =.9). Stepwise
      multiple logistic regression revealed that extracorporeal circulation time, age,
      and lack of retrograde cerebral perfusion were statistically significant
      independent risk factors for hospital mortality. The same analysis revealed that
      lack of retrograde cerebral perfusion was the only significant independent risk
      factor for permanent neurologic dysfunction. CONCLUSION: Retrograde cerebral
      perfusion decreased the prevalence of permanent neurologic complications and the
      hospital mortality in patients undergoing aortic arch operations.

PMID- 10595975
TI  - Cardiac operations in patients with low-grade small lymphocytic malignancies.
AB  - BACKGROUND: Low-grade small lymphocytic (B cell) malignancies (encompassing
      chronic lymphocytic leukemia and some types of non-Hodgkin lymphoma) are diseases
      of the elderly. Open cardiac procedures are known to have increased risk of
      postoperative infection and other morbidities in these immunodeficient patients.
      Outcome of open cardiac procedures in these patients was reviewed
      retrospectively. PATIENTS: Thirteen patients (aged 58-82 years, 11 men, 2 women)
      with these lymphocytopathologic diseases (8 with chronic lymphocytic leukemia and
      5 with non-Hodgkin lymphoma) underwent cardiac operations between January 1977
      and June 1998. Mean age was 72 +/- 2.1 years. Isolated coronary artery bypass
      grafting was performed in 11 and combined procedures and double valve replacement
      were performed in 1 each. Preoperatively, 9 patients were in a low-risk clinical
      stage. Mean preoperative duration of lymphocytopathologic disease was 6.1 +/- 1.6
      years. Mean preoperative New York Heart Association functional class was 2.8.
      RESULTS: There was no operative death. Average stay in the intensive care unit
      was 41.4 +/- 8.6 hours. Postoperative leg and superficial sternal wound
      infections were encountered in 3 patients. Average postoperative hospital stay
      was 10.0 +/- 1.7 days. During the follow-up up to 72 months, 1 patient underwent
      a second cardiac operation. There was 1 late death 4 years later. Coronary
      stenting was done in 1 patient and a cardioverter-defibrillator was implanted in
      another patient for recurrent angina. Three patients underwent chemotherapy.
      Cardiac and lymphocytopathologic status remained stable in others. CONCLUSIONS:
      Acceptable outcome may be anticipated after cardiac operations in patients with
      low-grade chronic lymphocytic leukemia and non-Hodgkin lymphoma in early stages.
      However, the possibility of infection and progression of cardiac and
      lymphocytopathologic status in these patients should call for caution.

PMID- 10595976
TI  - The influence of regional spinal cord hypothermia on transcranial myogenic motor
      evoked potential monitoring and the efficacy of spinal cord ischemia detection.
AB  - OBJECTIVE: Myogenic motor-evoked responses to transcranial electrical stimulation
      (transcranial myogenic motor-evoked potentials) can rapidly detect spinal cord
      ischemia during thoracoabdominal aortic aneurysm repair. Recent evidence suggests
      that regional spinal cord hypothermia increases spinal cord ischemia tolerance.
      We investigated the influence of subdural infusion cooling on transcranial
      myogenic motor-evoked potential characteristics and the time to detect spinal
      cord ischemia in 6 pigs. METHODS: Regional hypothermia was produced by subdural
      perfusion cooling. A laminectomy and incision of the dura were performed at L2 to
      advance 2 inflow catheters at L4 and L6, to cool the lumbar subdural space with
      saline solution. Two temperature probes were advanced at L3 and L5, and 1
      cerebrospinal fluid pressure line was advanced at L4. Spontaneous cerebrospinal
      fluid outflow was allowed. Spinal cord ischemia was produced by clamping a set of
      critical lumbar arteries, previously identified by transcranial myogenic motor
      evoked potentials and lumbar artery clamping. The time between the onset of
      ischemia and detection with transcranial myogenic motor-evoked potentials
      (amplitude < 25%) was determined at cerebrospinal fluid temperatures of 37
      degrees C and 28 degrees C. Thereafter, the influence of progressive
      cerebrospinal fluid cooling on transcranial myogenic motor-evoked potential
      amplitude and latency was determined. RESULTS: The time necessary to produce
      ischemic transcranial myogenic motor-evoked potentials, after the clamping of
      critical lumbar arteries, was not affected at moderate subdural hypothermia (3.8
      +/- 0.9 min) compared with subdural normothermia (3.2 +/- 0.5 min; P =.6).
      Thereafter, progressive cooling resulted in a transcranial myogenic motor-evoked
      potential amplitude increase at 28 degrees C to 30 degrees C and was followed by
      a progressive decrease. Response amplitudes decreased below 25% at 14.0 degrees C
      +/- 1.1 degrees C. The influence of cerebrospinal fluid temperature on
      transcranial myogenic motor-evoked potential amplitude was best represented by a
      quadratic regression curve with a maximum at 29.6 degrees C. In contrast,
      transcranial myogenic motor-evoked potential latencies increased linearly with
      decreasing subdural temperatures. CONCLUSIONS: Detection of spinal cord ischemia
      with transcranial myogenic motor-evoked potentials is not delayed at moderate
      subdural hypothermia in pigs. At a cerebrospinal fluid temperature of 28 degrees
      C, transcranial myogenic motor-evoked potential amplitudes are increased. Further
      cerebrospinal fluid temperature decreases result in progressive amplitude
      decreases and latency increases.

PMID- 10595977
TI  - Improved results with selective management in pulmonary atresia with intact
      ventricular septum.
AB  - OBJECTIVE: Late outcome of neonatal pulmonary atresia with intact ventricular
      septum remains poor in most reported series. We have followed a selective
      approach toward either single ventricle repair versus complete or partial
      biventricular repair based on the presence of right ventricle-dependent coronary
      circulation and growth of the right ventricle. METHODS: A retrospective chart
      review was conducted of 47 patients who underwent surgery between January 1991
      and September 1998. RESULTS: Sixteen (34%) patients had a right ventricle
      dependent coronary circulation, with a tricuspid valve Z-score of -3.0 +/- 0.66
      versus -2.0 +/- 0.95 (P =.002) for those without a right ventricle-dependent
      coronary circulation. A systemic-pulmonary artery shunt only was performed in all
      patients with a right ventricle-dependent coronary circulation, with 1 death.
      Fourteen of 16 patients with a right ventricle-dependent coronary circulation
      underwent a bidirectional Glenn shunt at a median of 9 months after their first
      operation, 9 of whom have had a Fontan procedure (no deaths). In the 31 (66%)
      patients without a right ventricle-dependent coronary circulation, 6 patients
      underwent only a systemic-pulmonary artery shunt, 23 had a shunt and right
      ventricular decompression, and 2 had only a transannular patch. In this group, 10
      patients received a 2-ventricle repair, 6 a 1. 5-ventricle repair, and 8 patients
      had a Fontan procedure. There was 1 early death and the overall survival was 98%
      at 1 year, 5 years, and 7 years. CONCLUSIONS: If patients are stratified well,
      excellent survival can be achieved in the treatment of pulmonary atresia with
      intact ventricular septum. This result may be at the price of achieving a 1
      ventricle as opposed to a 2-ventricle repair.

PMID- 10595978
TI  - Commentary.

PMID- 10595979
TI  - Intraventricular repair of double-outlet right ventricle with noncommitted
      ventricular septal defect: advantages of multiple patches.
AB  - OBJECTIVE: The objective of this paper is to report our experience with
      biventricular repair of double-outlet right ventricle with noncommitted
      ventricular septal defect by means of multiple patches that simplify and render
      feasible the intraventricular correction of this complex anomaly. METHODS: From
      April 1987 to April 1999, in 18 patients with double-outlet right ventricle and
      noncommitted ventricular septal defect, a technical modification that used
      multiple patches of bovine pericardium was used to construct an intraventricular
      tunnel connecting the left ventricle to the aorta. Ages ranged from 2 months to
      13 years (mean age 4.73 +/- 3.41 years). RESULTS: The early mortality was of
      11.1% (2 patients). Surviving patients were followed up for a mean of 2.65 years.
      Three late deaths (16.6%) occurred: 5 months, 7 months, and 7 months after the
      operation. All but 1 patient are in New York Heart Association class I.
      CONCLUSION: The use of multiple patches for biventricular correction of this
      anomaly simplifies and renders feasible the intraventricular repair in cases in
      which the 1-patch technique was deemed impossible.

PMID- 10595980
TI  - Regional patterns of neuronal death after deep hypothermic circulatory arrest in
      newborn pigs.
AB  - OBJECTIVES: Deep hypothermic circulatory arrest (DHCA) widely used during
      neonatal heart surgery, carries a risk of brain damage. In adult normothermic
      ischemia, brain cells in certain regions die, some by necrosis and others by
      apoptosis (programmed cell death). This study characterized regional brain cell
      death after DHCA in newborn pigs. METHODS: Eighteen piglets underwent 90 minutes
      of DHCA and survived 6 hours, 2 days, or 1 week. Six piglets underwent surgery
      alone or deep hypothermic cardiopulmonary bypass and survived 2 days. Three
      piglets received no intervention (control). Brain injury was assessed by
      neurologic and histologic examination and correlated with perioperative factors.
      Apoptosis and necrosis were identified by light microscopic analysis of cell
      structure and in situ DNA fragmentation (TUNEL). RESULTS: All groups subjected to
      DHCA had brain injury by neurologic and histologic examination, whereas the other
      groups did not. DHCA damaged neurons in the neocortex and hippocampus and
      occasionally in the striatum and cerebellum. Damaged neurons in the neocortex
      were mainly apoptotic and in the hippocampus, a mixture of necrotic and apoptotic
      neurons. Apoptosis and necrosis were apparent in all DHCA groups even though
      neurologic deficits improved over the week's survival. Neocortical and
      hippocampal damage correlated with blood glucose, hematocrit, and arterial PO(2)
      during and after cardiopulmonary bypass. CONCLUSIONS: In neonates, neocortical
      and hippocampal neurons are selectively vulnerable to death after DHCA. Both
      apoptosis and necrosis contribute to neuronal death, beginning early in
      reperfusion and continuing for days. These data suggest the need for several
      neuroprotective strategies tailored to the region and death process, initiated
      during the operation and continued after the operation.

PMID- 10595981
TI  - Pharyngeal reflux after gastric pull-up esophagectomy with neck and chest
      anastomoses.
AB  - OBJECTIVE: Pharyngeal reflux after a gastric pull-up esophagectomy may cause
      aspiration. This study evaluates acid exposure to the esophageal remnant and to
      the pharynx after gastric pull-up esophagectomy and evaluates the impact of
      additional dissection of the esophagus that is necessary for neck anastomoses
      versus no neck exploration and proximal chest anastomoses. METHODS: Forty-seven
      patients had circular stapled anastomoses in the apex of the right chest (n = 27
      patients) or manually sutured neck anastomoses (n = 20 patients). A 24-hour
      double-pH study with the probes placed 3 cm cranial and 3 cm distal to the
      cricopharyngeal muscle was performed. The percent time pH less than 4 was
      registered 3, 6, and 12 months after the operation. RESULTS: Mean acid exposure
      to the proximal pH probe ranged between 0.2% and 0.96% and between 1.45% and 6.5%
      to the distal pH probe during the 3 measurements. Acid exposure was always lower
      to the proximal than to the distal probe (P =.001). Patients with neck
      anastomoses had increasing acid exposure to the distal (P =.023) and proximal (P
      =.002) pH probes during the study year, whereas patients with chest anastomoses
      had similar acid exposure. CONCLUSIONS: Acid exposure to the esophageal remnant
      and to the pharynx increased during the first postoperative year in patients with
      neck anastomoses but not in patients with proximal chest anastomoses. The results
      suggest a less favorable acid clearance in patients with the neck approach.

PMID- 10595982
TI  - The diaphragmatic flap: A multiuse material in thoracic surgery.
AB  - BACKGROUND: The use of diaphragmatic pedicle flaps for reconstructive procedures
      in thoracic surgery is not very popular. Nevertheless, it provides considerable
      advantages. METHODS: Our experience covers 10 years (1987-1997) with a total of
      25 patients in whom the diaphragmatic flap was used for different purposes. In 6
      patients we used the diaphragmatic flap to protect the bronchopleural fistula at
      its early onset, which was not beyond 12 hours from the clinical diagnosis. We
      performed prophylactic suture protection after neoadjuvant therapy in 9 high-risk
      patients who underwent pneumonectomy and in 2 who underwent sleeve lobectomy.
      Postpneumonectomy pericardial defect repair was performed in 4 patients. In
      another 4 patients the diaphragmatic flap was used after spontaneous (n = 2) and
      iatrogenic (n = 2) lesions of the esophagus after 24 to 72 hours. RESULTS: No
      perioperative mortality was recorded. Complications were mainly related to the
      severe preoperative conditions of the patients: arrhythmia, respiratory
      insufficiency, and empyema. We report only 2 cases of minimal persistent bleeding
      from the chest tube, which spontaneously ceased. For those patients who survived
      for more than 1 year (n = 11), no diaphragmatic hernias were recorded.
      Bronchopleural fistulas and pericardial defects healed in all instances. The
      diaphragmatic flap was also effective in bronchopleural fistula. A late fistula
      caused by cancer relapse at the bronchial stump developed in only one patient.
      Excellent repair was achieved in all patients with esophageal lesions.
      CONCLUSIONS: We conclude that the diaphragmatic flap can be considered a
      practical, safe, and redundant material particularly indicated for defect or
      fistula closure and for suture line protection in the thoracic cavity.

PMID- 10595983
TI  - Surgical treatment for both pulmonary and hepatic metastases from colorectal
      cancer.
AB  - OBJECTIVE: The role of surgery in the treatment of patients with pulmonary and
      hepatic metastases from colorectal cancer has not been delineated. METHODS: Of
      the 351 patients enrolled in the Metastatic Lung Tumor Study Group of Japan
      between June 1988 and June 1996 who underwent thoracotomy for pulmonary
      metastases from colorectal cancer, 47 also underwent hepatic resection for
      metastatic tumors. The records of these patients were studied. RESULTS: The 47
      patients who underwent pulmonary and hepatic resection had a 3-year survival of
      36% +/- 8%, a 5-year survival of 31% +/- 8%, and an 8-year survival of 23% +/-
      9%. The longest survival was 98 months. This patient was alive without
      recurrence. There was a significant difference in the cumulative survival of the
      patients with a solitary pulmonary metastasis and the patients with multiple
      pulmonary metastases (P =.04). Neither age, sex, location of the primary tumor,
      maximum diameter of the pulmonary metastases, method of pulmonary resection,
      number of hepatic metastases, nor method of hepatic resection was correlated with
      survival. However, 9 of 10 patients who survived 3 years or more after the
      initial thoracotomy had only one or two hepatic metastases. CONCLUSION: Surgical
      treatment of a solitary pulmonary metastasis concurrent with or after resection
      of hepatic metastases from colorectal cancer may be appropriate if the hepatic
      metastases are resectable for cure. Patients with a solitary pulmonary metastasis
      and a small number of hepatic metastases are good candidates for resection. Long
      term survival can be expected.

PMID- 10595984
TI  - Lung biopsy: is it necessary?
AB  - OBJECTIVE: Lung biopsy is associated with substantial mortality rates. We
      reviewed our experience with this operation, primarily in patients with
      immunocompetence, to determine whether the results justify the continued
      performance of this procedure. METHODS: We conducted a retrospective review of
      all diagnostic lung biopsies performed at 3 university-affiliated hospitals
      between July 1, 1992, and December 31, 1998. RESULTS: There were 75 patients: 25
      patients were treated electively, 17 were treated on an urgent basis, 27 patients
      on an emergency basis, and the urgency was unclear in 6 patients. Significant
      beneficial therapeutic changes were made in 15 of 25 elective procedures (60%),
      in 16 of 17 urgent procedures (94%), and in 11 of 27 emergency procedures (41%; P
      =.001). Significant beneficial therapeutic changes consisted of immunosuppression
      in 13 of 15 (87%) patients treated on an elective basis, in 9 of 16 (56%) treated
      on an urgent basis, and in 9 of 11 (82%) treated on an emergency basis in whom
      therapy was altered (P =.14). Operative death was 0 of 25 for elective operations
      (0%), 3 of 17 for urgent operations (18%), and 14 of 26 for emergency operations
      (54%). Multivariable analysis of operative death showed urgency to be the only
      significant predictor of death (P =.002). CONCLUSIONS: In patients with
      immunocompetence, elective and urgent lung biopsies have acceptable operative
      mortality rates and frequently result in important beneficial therapeutic
      changes. Consequently biopsies are appropriate in these patients. Emergency
      biopsies are associated with high operative mortality rates and rarely result in
      a therapeutic change other than immunosuppression. These patients should not
      undergo lung biopsy if they are in stable condition and should be treated
      empirically with immunosuppression without operation if their condition is
      deteriorating.

PMID- 10595985
TI  - Survival after unilateral versus bilateral lung volume reduction surgery for
      emphysema.
AB  - OBJECTIVE: Bilateral staple lung volume reduction surgery (LVRS) immediately
      improves pulmonary function and dyspnea symptoms in patients with advanced
      heterogeneous emphysema to a greater degree than do unilateral procedures.
      However, the long-term outcome after these surgical procedures needs to be
      critically evaluated. We compare 2-year survival of patients who underwent
      unilateral versus bilateral video-assisted LVRS in a large cohort treated by a
      single surgical group. METHODS: The cases of all 260 patients who underwent video
      assisted thoracoscopic stapled LVRS from April 1994 to March 1996 were analyzed
      to compare results after unilateral versus bilateral procedures. Overall survival
      was calculated by Kaplan-Meier methods; Cox proportional hazard methods were used
      to adjust for patient heterogeneity and baseline differences between groups.
      RESULTS: Overall survival at 2 years was 86.4% (95% CI 80. 9%-91.8%) after
      bilateral LVRS versus 72.6% (95% CI 64.2%-81.2%) after unilateral LVRS (P =.001
      for overall survival comparison). Improved survival after bilateral LVRS was seen
      among high- and low-risk subgroups as well. Average follow-up time was 28.5
      months (range, 6 days to 46.6 months) for the bilateral LVRS group and 29.3
      months (range, 6 days to 45.0 months) for the unilateral LVRS patients.
      CONCLUSIONS: Comparison of unilateral versus bilateral thoracoscopic LVRS
      procedures for the treatment of emphysema reveals that bilateral LVRS by video
      assisted thoracoscopy resulted in better overall survival at 2-year follow-up
      than did unilateral LVRS. This survival study, together with other studies
      demonstrating improved lung function after bilateral LVRS, suggests that
      bilateral surgery appears to be the procedure of choice for patients undergoing
      LVRS for most eligible patients with severe heterogeneous emphysema.

PMID- 10595986
TI  - Traumatic rupture of the aortic isthmus in a patient with an aberrant right
      subclavian artery: therapeutic implications.

PMID- 10595987
TI  - Partial aortectomy in hypothermic circulatory arrest: method of choice in
      patients with aortic arch atheroma.

PMID- 10595988
TI  - Is it only a mechanical matter? Histologic modifications of the aorta underlying
      external banding.

PMID- 10595989
TI  - Refractory ventricular tachycardia as an indication for ventricular assist device
      support.

PMID- 10595990
TI  - A free floating ball thrombus in the left atrial cavity.

PMID- 10595991
TI  - Surgical treatment of an asymptomatic large coronary saphenous vein graft
      aneurysm.

PMID- 10595992
TI  - Minimally invasive extracardiac conduit replacement via a left anterior small
      thoracotomy.

PMID- 10595993
TI  - Tetralogy of fallot with absent pulmonary valve: simplified technique for
      homograft repair.

PMID- 10595994
TI  - Concurrent vascular ring and occult left pulmonary artery associated with
      ventricular septal defect: A report of an uncommon constellation.

PMID- 10595995
TI  - The modified Norwood palliation on a beating heart.

PMID- 10595996
TI  - Congenital ostial membrane of left coronary artery in truncus arteriosus.

PMID- 10595997
TI  - Noninvasive large thymoma with a natural history of twenty-one years.

PMID- 10595998
TI  - Molecular pathogenesis of lung cancer.
AB  - Lung cancer is the largest cancer killer of men and women in the united states.
      In addition to the progress made from antismoking primary prevention measures,
      new tools to help treat patients with lung cancer are emerging from the rapid
      advances in knowledge of the molecular pathogenesis of lung cancer. These tools
      include molecular and cellular biology and are starting to provide an insight
      into how the tumor cell, by altering oncogenes and tumor suppressor genes,
      achieves growth advantage, uncontrolled proliferation and metastatic behavior via
      disruption of key cell-cycle regulators and signal transduction cascades.
      Moreover, new knowledge is being developed in terms of the molecular definition
      of individual susceptibility to tobacco smoke carcinogens. These tools are being
      translated into clinical strategies to complement surgery, radiotherapy, and
      chemotherapy and also to assist in primary and secondary prevention efforts. This
      review summarizes current knowledge of the molecular pathogenesis of lung cancer.
      From this we know that respiratory epithelial cells require many genetic
      alterations to become invasive and metastatic cancer. We can detect cells with a
      few such changes in current and former smokers, offering the opportunity to
      intercede with a biomarker-monitored prevention and early detection effort. This
      will be coupled with new advances in computed tomography-based screening.
      Finally, because the molecular alterations are known, new mechanism-based
      therapies are being developed and brought to the clinic, including new drugs,
      vaccines, and gene therapy, which also must be integrated with standard
      therapies.

PMID- 10595999
TI  - Axillary artery cannulation.

PMID- 10596000
TI  - Axillary cannulation: first choice for extra-aortic cannulation and brain
      protection.

PMID- 10596001
TI  - Cinefluoroscopic assessment of human mitral anulus after mitral valvuloplasty.

PMID- 10596002
TI  - Cinefluoroscopic assessment of human mitral anulus after mitral valvuloplasty.

PMID- 10596004
TI  - A word of caution in extrapolating the riluzole spinal cord injury protective
      effects obtained in a rabbit model under ketamine anesthesia.

PMID- 10596003
TI  - A word of caution in extrapolating the riluzole spinal cord injury protective
      effects obtained in a rabbit model under ketamine anesthesia.

PMID- 10596005
TI  - Measurement of chest wall forces on coughing with the use of human cadavers.

PMID- 10596006
TI  - Measurement of chest wall forces on coughing with the use of human cadavers.

PMID- 10596007
TI  - Genotypic differences in the hepatitis B virus core promoter and precore
      sequences during seroconversion from HBeAg to anti-HBe.
AB  - Hepatitis B virus (HBV) strains from anti-HBe positive patients often show
      specific mutations in the precore gene, the core promoter region, or both. The
      dynamics of seroconversion in relation to the appearance of these mutations has
      not been studied and compared between defined HBV genotypes. Samples from
      patients followed during seroconversion from HBeAg to anti-HBe were amplified by
      polymerase chain reaction (PCR), sequenced and genotyped. Among 16 sets of
      samples, 6 belonged to genotype A, 6 to genotype D, 2 to genotype B, 1 to
      genotype C, and 1 to genotype E. Whereas strains from genotypes B, C and E showed
      changes in the core promoter, precore codon 28 or both, genotype A and D strains
      displayed a different pattern. In 4 of 6 anti-HBe positive samples from genotype
      A, the precore had a wild-type sequence while the core promoter sequence showed a
      specific TGA mutation. In another genotype A strain a precore stop mutation was
      preceded by a mutation in codon 15, thus conserving base-pairing at the
      pregenomic RNA level in this region. In contrast, all genotype D strains showed
      wild-type sequences in both the core promoter and precore codon 28 in pre- and
      post-seroconversion samples. Thus, in 8 patients with a mean follow-up time of 17
      months, wild-type sequences in both the core promoter and precore codon 28 were
      found after seroconversion to anti-HBe. This study also confirmed, for genotype
      D, that HBeAg seroconversion often occurs earlier than genomic conversion.

PMID- 10596008
TI  - Effect of variation in the common "a" determinant on the antigenicity of
      hepatitis B surface antigen.
AB  - Antibody to the common "a" determinant of hepatitis B surface antigen (HBsAg)
      protects against infection with hepatitis B virus. A number of variant surface
      antigens with amino acid substitutions within the "a" determinant have been
      described in patients around the world. Both wild type and variant HBsAgs were
      expressed in the yeast Pichia pastoris and the antigens were semi-purified and
      quantitated. The effect on antigenicity of these changes was investigated in a
      quantitative fashion using four monoclonal antibodies known to bind to different
      epitopes within the common "a" determinant. The results suggest that amino acid
      substitution of T131I, K141E and G145R and insertion of 3 amino acids between
      residues 123 and 124 markedly affect the antigenic structure of HBsAg. These
      substitutions and insertions in the viral envelope may lead to evasion of the
      virus neutralizing antibody response and also to reduce efficiency of detection
      by immunoassays used for diagnosis and blood-bank screening.

PMID- 10596009
TI  - Changes in the epidemiology of hepatitis C infection in Germany: shift in the
      predominance of hepatitis C subtypes.
AB  - Hepatitis C virus (HCV) subtype distribution was studied in 395 chronically
      infected patients from Germany. HCV genotype 1 was most frequent (80.5%). One
      hundred forty-three individuals (36.2%) were infected with subtype 1a and 175
      (44.3%) were suffering from subtype 1b infection, respectively. HCV subtype 3a
      was found in 53 (13.42%) persons. Subtypes 2a, 2b, and 2c have been detected in 5
      (1.27%), 10 (2.53%), and 4 (1.01%) individuals. Genotypes 4 and 5a accounted for
      HCV infections in 4 (1.01%) and 1 (0.25%) subjects. There was a notable variation
      in the distribution of the prevalent subtypes 1a and 1b in different age groups.
      Subtype 1a was detected in 53.3% and 68.0% of patients aged 1-10 and 11-20 years,
      whereas subtype 1b in the same groups was present only in 33.3% and 28.0% of
      patients, respectively. In contrast, in individuals older than 50 years subtype
      1b was most frequent. Thus, subtype 1b has been gradually substituted for subtype
      1a during the last 20 years. Logistic regression analysis with adjustment for sex
      and different modes of HCV acquisition demonstrated that age of the infected
      subjects was a direct explanatory variable for subtype 1a and 1b distribution.
      Therefore, the observed shift in HCV subtype prevalence could not be attributed
      to changes in the epidemiological relevance of different known risk factors of
      HCV transmission, as had been assumed in previous studies. The altered subtype
      pattern reported here may have a profound influence on the future epidemiology of
      HCV infection.

PMID- 10596010
TI  - Long term response to interferon treatment in chronic hepatitis C patients is
      associated with a significant reduction in anti-E1 envelope antibody titers.
AB  - Interferon (IFN) alfa has been used widely for the treatment of chronic hepatitis
      C virus (HCV) infections but only a small number of patients treated have shown a
      sustained biochemical and virological response. Anti-envelope E1 and E2 antibody
      titers were assessed retrospectively before, during, and after treatment with IFN
      in order to evaluate their usefulness for the prediction and monitoring of
      therapy outcome in 115 patients infected chronically with HCV genotype 1b. At
      baseline, E2 induced more frequent and stronger immunogenic responses than E1,
      irrespective of patient response to therapy. E1 and E2 antibodies also tended to
      be higher in patients with a long-term or a transient response to IFN treatment
      than in patients who were absolute non-responders. In most patients, E1 and E2
      antibody levels tended to be lower after treatment. This reduction was most
      pronounced and occurred most frequently in long-term responders to therapy. In
      this patient group, the reduction of E1 antibodies was more pronounced than that
      of E2 antibodies. In contrast to E2 antibodies, the decrease of E1 antibodies
      could already be observed at the end of therapy (week 24) and was significantly
      larger (p<0.05) than that observed in relapsers and non-responders. Thus, a
      sustained elevation of E1 antibodies seems to be associated with ongoing
      infection even when HCV RNA levels were undetectable in serum. Monitoring of E1
      antibody titers may represent a useful additional marker to discriminate
      sustained responders from those who relapse in patients receiving interferon
      therapy.

PMID- 10596011
TI  - Effect of increasing dose of interferon on the evolution of hepatitis C virus 1b
      quasispecies.
AB  - The effects of interferon therapy on hepatitis C virus (HCV) genome are still
      controversial in terms of biological and clinical significance. Changes in the
      quasispecies of the hypervariable (HVR) and non-structural 5A (NS5A) regions of
      HCV 1b were evaluated in nine patients treated with increasing doses of
      interferon and five untreated controls. HCV quasispecies were analyzed in HVR and
      NS5A by single-strand conformation polymorphism assay. The HVR quasispecies
      varied over time both in treated and untreated patients. However, at least one
      persistent strain was present in all patients. With low doses of interferon,
      variations in HVR complexity were found in seven of nine patients and in four
      patients new variants became detectable. A reduction in the heterogeneity of the
      HVR quasispecies was observed after increase of the interferon dose. In contrast,
      NS5A profiles remained unmodified in all but three cases in which direct
      sequencing showed no changes in amino acid sequences of the predominant strain.
      The results suggest that interferon sensitivity of some HCV strains may be dose
      dependent. The homogeneity of NS5A pattern populations during treatment suggests
      that interferon exerts much less pressure on this region.

PMID- 10596012
TI  - Autoclaving eliminates hepatitis C virus from a hemodialysis monitor contaminated
      artificially.
AB  - Nosocomial transmission of the hepatitis C virus (HCV) has become the principal
      cause of HCV infection in hemodialysis units. Because HCV particles may pass
      through dialysis membranes and backfiltration occurs with high performance
      membranes, HCV transmission from contaminated dialysis monitors is likely. Thus
      it is important to have effective measures to disinfect hemodialysis monitors. In
      this study, autoclaving dialysate circuits were examined to establish an
      effective method to eliminate HCV particles from a monitor contaminated
      artificially. The dialysis monitor was contaminated in 2 different experiments
      with a 1/10 and 1/5 dilution of a serum pool containing 1.2 +/- 0.3 x 10(6) HCV
      genome copies/ml. During perfusion 2 samples were taken from the drainage tube at
      5 and 10 minutes. After perfusion, the dialysate circuit was autoclaved at 120
      degrees C for 20 minutes. Four samples were then taken from the autoclaved
      circuits and another from the drainage, which had not been autoclaved. The viral
      titer in the samples from the drainage before sterilization was similar to that
      of the serum dilution, showing the homogeneous distribution of the serum dilution
      in the dialysis circuits. After autoclaving, HCV RNA was not detectable in the
      samples obtained from the autoclaved circuits, whereas it was positive in the
      sample from the drainage. These results show that autoclaving is an effective
      method to eliminate HCV particles from contaminated hemodialysis monitors.

PMID- 10596014
TI  - Molecular epidemiology of an outbreak of HCV in a hemodialysis unit: direct
      sequencing of HCV-HVR1 as an appropriate tool for phylogenetic analysis.
AB  - Infection with hepatitis C virus (HCV) is still a serious problem in hemodialysis
      patients, despite screening of blood products for anti-HCV antibodies. The
      prevalence of HCV in HD patients is between 15% and 30% in Germany. We report the
      molecular epidemiology of an HCV outbreak in a hemodialysis unit in 1997 is
      determined. HCV hypervariable region 1 (HVR1) was amplified from serum samples of
      19 patients by polymerase chain reaction (PCR) and sequenced directly. In
      addition, HCV isolates from 3 of these 19 patients were cloned and sequenced. 14
      newly infected patients and two patients, who had been infected for several years
      had very closely related HCV isolates. Unrelated HCV isolates as well as
      sequences obtained from an HCV outbreak in a plasmapheresis center were found in
      different, distantly related branches. These findings provide strong evidence for
      nosocomial transmission of the virus, despite following strict general hygiene
      precautions. The production of anti-HCV antibody was delayed significantly or
      seroconversion did not occur at all during the period of observation in 8 out of
      14 newly infected HCV RNA positive patients. Close-meshed reverse transcription
      polymerase chain reaction (RT-PCR) analyses on apparently non infected patients
      within hemodialysis units and upon admission of new patients is strongly
      recommended for the early detection and prevention of outbreaks of HCV.

PMID- 10596013
TI  - Hepatitis C epitopes from phage-displayed cDNA libraries and improved diagnosis
      with a chimeric antigen.
AB  - A novel method for cloning DNase I fragments into bacteriophage display vector
      fUSE2 was used to create libraries expressing hepatitis C virus (HCV) protein
      fragments on the phage surface. Selection by panning with a mixture of sera from
      five HCV-seropositive individuals enabled identification of antigenic
      determinants in NS3 (amino acids 1,383-1,415), NS4 (amino acids 1, 930-1,938),
      and NS5 (amino acids 2,088-2,104). The NS3 result is the most accurate location
      to date of a major conformational determinant that cannot be mimicked by short
      peptides. Any expressed sequence from the phage library can be excised with Bgl
      II and cloned directly into the Bgl II site of an appropriate plasmid for
      bacterial expression. This enables production of chimeric proteins containing
      multiple antigenic determinants, illustrated by co-expression of the NS4P (amino
      acids 1,930-1,938) epitope with an NS4N fragment (amino acids 1,644-1,812)
      containing at least three linear HCV epitopes. When used to screen 35 individual
      HCV-positive sera by enzyme-linked immunosorbent assay (ELISA), the chimeric
      antigen detected eight more positives than NS4N alone and gave increased
      immunoreactivity with others. This approach of identifying antigenic regions by
      phage display and then co-expressing them as chimeric proteins may be generally
      applicable to the production of improved diagnostic antigens and recombinant
      vaccines.

PMID- 10596015
TI  - High prevalence of GB virus C/hepatitis G virus in Kinshasa, Democratic Republic
      of Congo: a phylogenetic analysis.
AB  - A prevalence of 10.3% of GB virus C (GBV-C)/hepatitis G virus (HGV) carriers was
      found in 97 pregnant women from Kinshasa, Congo (formerly Zaire), while
      prevalences of 1%, 4.1%, and 0% were found for hepatitis C virus, human
      immunodeficiency virus, and human T-lymphotropic virus respectively. Phylogenetic
      analysis of the ten GBV-C/HGV positives based on the 5' non-coding region using
      three different methods identified consistently three GBV-C/HGV genotypes. Four
      main clades were found within the type 1 sequences. All the Congolese isolates
      are GBV-C/HGV type 1 in two different clades. The clustering of seven Congolese
      isolates was inconsistent in different methods. Further likelihood-mapping
      analysis showed a well-resolved phylogeny, confirming the clustering of the seven
      Congolese isolates with a Belgian strain representing a new clade in the GBV
      C/HGV type 1 sequences.

PMID- 10596016
TI  - Clinical and epidemiological implications of swine hepatitis E virus infection.
AB  - In nonendemic areas, most patients with acute hepatitis E were infected through
      traveling to endemic areas. However, some patients did not have a history of
      foreign travel before infection. Furthermore, high seroprevalence rates of
      antibody to hepatitis E virus (anti-HEV) were found in the general adult
      population in some countries without any recorded outbreak of hepatitis E. The
      significance of anti-HEV assay in these subjects remains obscure. To study if
      swine might be a source of HEV infection, HEV was tested in sera of 235 pigs in
      Taiwan, and from 5 patients with acute HEV infection who either denied or did not
      provide any foreign travel history. Three (1.3%) pigs had detectable swine HEV
      RNA. The swine and human HEV strains from Taiwan formed a monophyletic group,
      distinct from three previously reported groups: the United States human and swine
      HEV strains, the Mexico strain, and the largest group composed of the Asian and
      the African strains. The identity of nucleotide sequences was 84-95% between
      swine and human HEV strains in Taiwan, and 72-79% between Taiwan strains and
      those from different areas. The predicted amino acid sequence of a Taiwan swine
      HEV strain within the peptide 3-2 used in commercial anti-HEV assay showed a high
      identity (91-94%) with those of other human and swine HEV strains. Swine may be a
      reservoir of HEV and subclinical swine HEV infection may occur. Cross-reactivity
      of current anti-HEV assay may account for the high prevalence rate of anti-HEV in
      the general population in nonendemic areas.

PMID- 10596017
TI  - Prevalence of TTV DNA among children with a history of transfusion or liver
      disease.
AB  - The prevalence rates of serum TT virus (TTV) DNA among children with or without a
      history of transfusion or liver disease were studied by polymerase chain reaction
      (PCR) using either the Okamoto primer set or the Takahashi primer set developed
      more recently. Using Okamoto and Takahashi primer sets, the prevalence rates were
      31.6% (12/38) and 78.9% (30/38), respectively, for children with a history of
      blood transfusion (including malignant and non-malignant groups) and 6.7% (2/30)
      and 60% (18/30), respectively, for children without a history of blood
      transfusion. Among pregnant women, these rates were 12.9% (4/31) and 61.3%
      (19/31), respectively. On the other hand, the prevalence rates were 0% (0/16) and
      50% (8/16), respectively, in hepatitis B patients, 21.4% (3/14) and 71.4%
      (10/14), respectively, for hepatitis C patients, and 20.0% (9/45) and 57.8%
      (26/45), respectively, for non-A to C hepatitis patients (including 27 acute
      hepatitis patients, 5 fulminant patients and 13 chronic hepatitis patients). In
      this study, the prevalence rates determined by the Takahashi primer set tended to
      be 2-9 times higher than those determined using the Okamoto primer set. These
      results suggest that TTV infection is widespread among Japanese children.
      Furthermore, blood transfusion does not appear to be the major route of
      infection. The similar prevalence rates between control children and children
      with various types of hepatitis using the Takahashi primer system suggest that
      TTV infection does not play a direct causative role in the development of liver
      disease in children.

PMID- 10596018
TI  - Clinical significance of TT virus infection in patients with chronic liver
      disease and volunteer blood donors in Egypt.
AB  - Clinical significance of TT virus (TTV) infection was investigated in Egyptian
      patients with chronic liver disease and volunteer blood donors by a cross
      sectional analysis. TTV DNA in serum was assessed by a semi-nested polymerase
      chain reaction. The prevalence of TTV DNA did not differ among patients with
      chronic hepatitis B (11/24, 46%), chronic hepatitis C (22/72, 31%), or
      schistosomal liver disease (14/39, 36%). No difference in prevalence was found
      between blood donors (32/109, 29%) and each of the patient groups. Clinical
      background including mean age, sex distribution, history of blood transfusion,
      and mean level of alanine aminotransferase did not differ between TTV DNA
      positive and -negative individuals in any of the study groups. Ultrasonographic
      evidence of liver cirrhosis was similar between TTV-positive and -negative
      patients in each of the chronic liver disease groups. TTV infection was not
      associated with hepatitis B or C virus infection in blood donors. The only
      significant difference observed was the lower concentration of serum HCV RNA in
      TTV DNA positive compared with negative patients with chronic hepatitis C (3.0 +/
      1.4 vs. 4.0 +/- 0.9 log copies/ml, P <. 001). In conclusion, TTV infection was
      not associated with either past history of blood exposure or infection with
      bloodborne hepatitis viruses in Egypt. No clinical significance of TTV was found
      in the present study. However, a reciprocal interaction was suggested between TTV
      and HCV replication.

PMID- 10596019
TI  - Efficacy and kinetics of glycerol inactivation of HIV-1 in split skin grafts.
AB  - Allogeneic split skin grafts are used widely in the treatment of burns. The
      relative simplicity of glycerol preservation of skin suggests it will be used
      increasingly in areas of high HIV-1 seroprevalence. The ability of glycerol
      preservation to inactivate HIV-1 present in skin graft infected in vitro was
      determined using a macrophage tropic strain HIV-1 as a cell-free virus
      suspension, within infected PBMCs, or within in vitro HIV-1 infected fresh
      cadaveric split skin. Different temperatures and concentrations of glycerol were
      used and infectivity determined by coculture with mitogen activated peripheral
      blood mononuclear cells (PBMCs) and measurement of reverse transcriptase activity
      after 7-10 days. Cell-free HIV-1 was inactivated within 30 min at 4 degrees C in
      glycerol concentrations of 70% or higher. During similar exposure cell- or skin
      associated HIV-1 titer was reduced but not eliminated with 70% and 85% glycerol
      at 4 degrees C. HIV-1 was recovered consistently from skin stored in 85% glycerol
      at 4 degrees C for up to 72 hr but virus isolation was infrequent after storage
      for more than 5 days. At 20 degrees C or 37 degrees C, 70% or 85% glycerol could
      inactivate cell- or skin-associated HIV-1 within 8 hr. The initial
      glycerolization procedures and the storage at 4 degrees C eliminated effectively
      HIV-1 from skin.

PMID- 10596020
TI  - Identification of H-2K(b)-restricted T-cell epitopes within the nucleocapsid
      protein of Hantaan virus and establishment of cytotoxic T-cell clones.
AB  - Although neutralizing antibodies against Hantaan virus (HTV) can protect hosts
      from viral infection, T-cell responses to HTV are also important in host defense
      against HTV. However, much less is known about cytotoxic T lymphocyte (CTL)
      responses to HTV. To identify CTL epitopes in the HTV nucleocapsid protein (NP),
      we selected 7 H-2K(b)-motif-fitting peptides. Of these peptides, 3 peptides (NP3,
      NP4, and NP7) were recognized by CTL responses derived from HTV-immunized mouse
      splenocytes. NP3 and NP4 peptides were also recognized by HTV-immunized
      splenocytes after secondary in vitro stimulation with the relevant peptide, but
      NP7 could not be recognized after in vitro stimulation. These results agree well
      with peptide immunization studies showing that peptide-specific CTL responses
      could be induced with NP3 and NP4 but not with NP7 peptide. Furthermore, CTL
      activity assay using targets, prepared to express the antigen (NP) endogenously,
      demonstrated that NP3 and NP4 peptides could be presented endogenously. CTL
      elicited with NP4 peptide retained some cross-reactivity and was difficult to
      long-term culture. However, NP3-elicited CTL was very specific for NP3 peptide
      and was stable enough to be cloned. Among many CTL lines elicited with HTV or HTV
      NP peptides, 6 NP3-specific CTL clones were established and have been maintained
      more than 2 years. All 6 CTL clones were characterized to be CD3+, CD4-, CD8+,
      CD25+, CD62L-, and NK1.1-, and to use TCR Vbeta6. This preferential usage of TCR
      Vbeta6 indicates that TCR Vbeta6 regions are important for recognition of the HTV
      NP3 epitope (NP221-228, SVIGFLAL) on H-2K(b) molecule. Our data demonstrate the
      definition of mouse CTL epitopes in HTV and the generation of HTV-specific mouse
      CTL clones.

PMID- 10596021
TI  - DNA vaccination of mice with plasmid expressing human papillomavirus 6 major
      capsid protein L1 elicits type-specific antibodies neutralizing pseudovirions
      constructed in vitro.
AB  - Human papillomavirus 6 (HPV 6) causes benign condylomata. As a model for HPV
      vaccine development, we tested a HPV 6 DNA vaccine candidate, constructed by
      subcloning the major capsid protein (L1) gene into an expression plasmid having
      the cytomegalovirus promoter, for its immunogenicity in BALB/c mice. Three
      intracutaneous inoculations of the plasmid with a gene gun at 2-week intervals
      elicited anti-L1 serum antibodies. The antibodies were found to recognize highly
      type-specific, conformation-dependent epitopes, including those to neutralize
      pseudovirions capable of inducing beta-galactosidase in infected monkey COS-1
      cells. The data support the idea that immunization with DNA capable of expressing
      HPV L1 can be used as an HPV vaccine strategy for humans.

PMID- 10596022
TI  - Cidofovir, a new approach for the treatment of cervix intraepithelial neoplasia
      grade III (CIN III).
AB  - Cervix intraepithelial neoplasia grade III (CIN III) is an intraepithelial
      proliferative process with different levels of severity depending on both the
      extension of the proliferation in the epithelium and the presence of cellular
      atypia. Human papillomavirus (HPV) has been clearly associated with such lesions.
      The results of a preliminary study are described on the local application of
      cidofovir, an acyclic nucleoside phosphonate derivative with broad-spectrum anti
      DNA virus activity for the treatment of CIN III. Cidofovir 1% in gel was applied
      three times, every other day, on the cervix of each of 15 women with biopsy
      proven CIN III. Within 1 month after the start of treatment, the cervix was
      removed surgically. Histology and human papillomavirus polymerase chain reaction
      (HPV-PCR) were carried out. In 7 of the 15 patients the histology showed a
      complete response, whereas 5 patients had a partial response characterized by the
      persistence of CIN II-III lesions, 1 patient had a dysplasia of lower grade (CIN
      I), and 2 patients did not show differences in the histology. Complete response
      was confirmed by PCR in 4 of the 7 patients, with complete response
      histologically. Cidofovir was not toxic to the normal epithelium. Cidofovir 1%
      gel was able to inhibit partially or completely cervical dysplasia lesions after
      only three applications (every other day). This effect was specific and tissue
      other than the dysplastic epithelium was not affected by the treatment.

PMID- 10596023
TI  - Antibody prevalence and specificity to group C rotavirus in Swedish sera.
AB  - Of 160 sera collected from different age groups throughout Sweden, 38% were found
      to be antibody positive for group C rotavirus. The highest antibody prevalence
      rate was found in individuals aged 11-30 years (45%). An immunoprecipitation
      assay revealed that the antibodies were directed against VP2, VP4, VP6, VP7, and
      NSP2, with VP6 being the most immunogenic protein. Neutralising antibodies
      against a cultivable porcine group C rotavirus (strain AmC-1/Cowden) were
      detected in 16/19 individuals at titres from 160 to 5,120. The results indicate
      that group C rotavirus infections are relatively common in older Swedish children
      and adults but appear to be less common in children younger than 5 years of age.
      It is concluded that porcine and human group C rotaviruses share epitopes
      critical for stimulation of neutralising antibodies.

PMID- 10596024
TI  - Characterization of tick-borne encephalitis virus from Latvia.
AB  - Viruses of the tick-borne encephalitis (TBE) antigenic complex, within the family
      Flaviviridae, cause a variety of diseases including uncomplicated febrile
      illness, encephalitis, meningo-encephalitis, hemorrhagic fever and chronic
      disease in humans, domesticated animals or wildlife species. TBE is a serious
      problem in Latvia with up to a 1,000 patients confirmed serologically annually
      1994-1995. No previous data had been reported on the causative agent of TBE in
      Latvia. In the present study, a virus was isolated from serum of a patient with
      clinical symptoms of an acute TBE infection. Nucleotide sequence information
      obtained by direct reverse transcription-polymerase chain reaction (RT-PCR) and
      the serological characteristics of the isolated virus strain, designated TBE
      Latvia-1-96, indicated a closer relationship to the Vasilchenko strain, isolated
      in Novosibirsk (Siberia, Russia), as compared to the western European or far
      eastern subtypes of TBE viruses. In a mouse neurovirulence assay, a significant
      difference in survival rates (days) was shown between Latvia-1-96 and the western
      European TBE virus subtype.

PMID- 10596025
TI  - Th1-type cytokines production is decreased in kidney transplant recipients with
      active cytomegalovirus infection.
AB  - Cytomegalovirus (CMV) infection is a major complication after kidney
      transplantation. Despite antiviral therapy the infection contributes
      significantly to high morbidity. The present study was aimed at determining: (a)
      the stimulation index (S.I.) of phytohemagglutinin (PHA)-stimulated peripheral
      blood mononuclear cells (PBMC) and (b) the levels of Th1- and Th2- related
      cytokines in kidney transplant recipients with and without active CMV infection.
      Thirty-five patients with, and 44 without active CMV infections, as diagnosed by
      a CMV antigenemia assay, were inducted into this study. After PHA stimulation of
      PBMC from patients, stimulation index (S.I.) was determined by radioactive
      thymidine uptake while the production of Th1-type cytokines (interleukin-2 [IL
      2], interferon-gamma [IFN-gamma], and tumor necrosis factor-alpha [TNF-alpha])
      and Th2-type cytokines (IL-4, IL-10) were measured by enzyme-linked immunosorbent
      assay. PBMC of patients with active CMV infection showed significantly lower S.I.
      values than patients without an ongoing CMV infection (P <.0001). Levels of Th2
      type cytokines in CMV-infected and uninfected kidney recipients were similar;
      however, the levels of the Th1-type cytokines were significantly lower in CMV
      infected patients. Low levels of Th1-type cytokines seem to correlate well with
      active CMV infection in kidney recipients.

PMID- 10596026
TI  - Correlation of maternal and pup NK-like activity and TNF responses against
      cytomegalovirus to pregnancy outcome in inbred guinea pigs.
AB  - Immunologic causes for poor outcome of pregnancy complicated by primary
      cytomegalovirus (CMV) infection are only partially understood. Maternal and pup
      tumor necrosis factor (TNF) and natural killer cell (NK)-like activity associated
      with primary gestational CMV infection initiated in either the first or third
      trimester equivalent in the inbred guinea pig model were investigated. Poor
      pregnancy outcome defined as fetal resorptions, premature delivery, stillbirths,
      and intrauterine growth retardation occurred with infection at either gestational
      time. Induction of TNF and NK activity by CMV infection during pregnancy
      correlated with resorptions in early pregnancy infection and with premature labor
      in late pregnancy infection. Stillbirths occurred with CMV infection at either
      time. Regardless of the gestational time of CMV acquisition, poor outcome
      correlated with higher maternal NK and TNF responses during the first weeks after
      maternal virus acquisition. Furthermore, CMV infected dams with loss of >/= 50%
      of conceptus had higher TNF responses than infected dams with < 50% conceptus
      loss. Likewise, pups born in litters from CMV-infected dams with resorptions
      and/or premature labor also had enhanced NK activity and TNF response to CMV
      compared with pups born to dams not having resorptions or premature labor. TNF
      responses in the delivered pups of infected dams were higher than from pups of
      uninfected dams regardless of litter outcome, whereas pup NK responses were
      enhanced only in pups from litters of dams with premature labor or resorptions.
      Enhanced NK and TNF activity appear to be associated with premature delivery and
      other poor outcomes of pregnancy.

PMID- 10596027
TI  - Hantavirus infection in Taiwan: the experience of a geographically unique area.
AB  - Hantaviruses are rodent-borne viruses, and they, mainly the Hantaan (HTN)
      serotype, are the causative agents of a group of febrile nephropathies known as
      "hemorrhagic fever with renal syndrome (HFRS). " Despite the fact that HFRS is
      frequently reported in China, with an annual incidence of 50,000-100,000 cases,
      one puzzling observation that no local case of HFRS has been confirmed in Taiwan
      has yet to be explained. We hypothesized that the hantavirus strain prevailing in
      Taiwan mainly belongs to the mild strain, the Seoul (SEO) strain, and the absence
      of severe disease was related to the absence of HTN. To test these hypotheses,
      this epidemiologic study was performed, including a seroprevalence survey and
      phylogenetic analysis on hantavirus isolated from the rodent population trapped
      in major seaports, rural, and mountainous areas of Taiwan. This study also
      included rodents and viruses from two isolated islands, Kinmen and Matzu, which
      are geographically adjacent to the east coast of mainland China. There were a
      total of 5,461 rodents of 16 species captured, and R. norvegicus was the most
      common species, with an antibody prevalence much higher in international seaports
      (20%) than in rural regions (approximately 5%) and intermediate in some domestic
      seaports. By reverse transcriptase polymerase chain reaction (RT-PCR), 33.9% of
      the seropositive R. norvegicus were found to have amplifiable hantavirus
      sequences in their lung tissues, and subsequent phylogenetic analyses indicated
      that almost all hantavirus in Taiwan was most closely related to the prototype
      SEO strain, and no HTN strain was recovered from any rodent species indigenous to
      Taiwan. The seroprevalence of SEO infection in R. norvegicus on Kinmen and Matzu
      was also different from that in southern provinces of China but closely resembled
      that in seaports in Taiwan, and the SEO identified was genetically linked to
      Taiwanese SEO strains. These results substantiate our hypotheses, and suggest
      that the epidemiology of hantavirus infection in Taiwan are different from that
      in China, where the HTN and SEO strains and HFRS concurrently prevail.

PMID- 10596028
TI  - Immune reconstitution: is there a potential role for Filgrastim (r-metHuG-CSF).

PMID- 10596029
TI  - Biopharmaceutical drug development: Filgrastim (r-metHuG-CSF) use in patients
      with HIV infection.
AB  - Hematopoietic growth factors are well known to increase neutrophil counts and
      support the administration of myelotoxic and myelosuppressive therapies,
      especially chemotherapies. Filgrastim (r-metHuG-CSF) has been used in the setting
      of HIV disease to treat neutropenia and HIV-associated neutrophil defects. This
      article reviews the biology, product characteristics, and preclinical and
      clinical development of Filgrastim. Emphasis is given on the use of Filgrastim in
      the setting of HIV infection and AIDS.

PMID- 10596030
TI  - The use of Filgrastim in AIDS-related neutropenia.
AB  - Neutropenic individuals are at high risk for bacterial and fungal infections.
      Filgrastim (r-metHuG-CSF, NEUPOGEN) has been shown to improve chemotherapy
      induced neutropenia significantly. Because a high incidence of HIV-infected
      patients have neutropenia, often associated with myelosuppressive antiretroviral
      medication, Filgrastim is frequently used as a treatment strategy for this HIV
      associated neutropenia. This review summarizes published work related to the use
      of Filgrastim in HIV-infected patients. Literature bases (EMBASE, MEDLINE, Int.
      Pharm. Abs., SciSearch, and Aidsline) from 1970 to 1998 were searched for
      articles describing the relationship of Filgrastim and ANC to bacterial infection
      rates, bacterial infection outcome, and overall survival. Thirty-five related
      articles were identified during this search. Filgrastim appears to have a
      significant role in increasing peripheral ANC and enhancing neutrophil function
      in patients with HIV infection and AIDS. This may translate into a clinical
      benefit of delivery of full-dose myelosuppressive antiretroviral therapy and
      decreased susceptibility to infections and increased survival in this patient
      population.

PMID- 10596031
TI  - Clinical experience with Filgrastim in AIDS.
AB  - Data have shown that neutropenia is a risk factor for severe bacterial
      infections. Two trials were done in HIV-infected patients to study the effect of
      Filgrastim on neutropenia and the incidence of severe bacterial infections. The
      incidence of Mycobacterium avium complex (MAC) infection in this setting was also
      evaluated. This paper reviews the results of these two studies, which suggest
      that Filgrastim is safe and effective in preventing severe neutropenia in
      patients with advanced HIV infection.

PMID- 10596032
TI  - Anti-inflammatory aspects of Filgrastim and impact on IL-2 release.
AB  - G-CSF has immunomodulatory effects of neutrophilic granulocytes and
      monocytes/macrophages. Two studies were done: one in normal volunteers and the
      other in HIV-infected patients plus their respective control donors to evaluate
      the effect of Filgrastim on cytokine responses. Filgrastim treatment of
      volunteers resulted in an anti-inflammatory cytokine response, when blood was
      stimulated ex vivo with the endotoxin lipopolysaccharide (LPS). Similarly, in the
      presence of Filgrastim in vitro, the LPS-inducible release of proinflammatory
      cytokines was attenuated. Blood from HIV-infected patients at advanced stages of
      disease showed reduced interleukin (IL)-2 formation in response to staphylococcal
      exotoxin B (SEB), which was restored in the presence of Filgrastim.

PMID- 10596033
TI  - Neutropenia in patients with HIV infection: a case control study in a cohort of
      1403 patients between 1982 and 1993.
AB  - The relationship between neutropenia and increased risks of severe infections in
      patients with HIV infection and the factors associated with neutropenia-induced
      infections was studied by a retrospective comparative study using matched case
      control analysis. A database (1982-1993) of 1870 patients with HIV infection was
      searched, and from 484 patients with neutropenia, 177 patients were paired with
      177 nonneutropenic control subjects. Descriptive analysis and development of
      logistic models were used to determine factors associated with the risk of
      developing bacterial infections and major fungal infections. The occurrence of
      severe bacterial and fungal infections was significantly higher in neutropenic
      patients (p < or = 0.001). Bacteremia was more common in neutropenic patients
      than in nonneutropenic patients (p < or = 0.02) in the matched case-control
      analysis. Risk of severe infections was strongly associated with the neutrophil
      count (p < or = 0.05), clinical stage, and hemoglobin level (p < 0.005) when
      paired patients were compared. More neutropenic episodes occurred between 1991 to
      1993, possibly due to prolonged survival and the increasing use of concomitant
      myelosuppressive therapies. Neutropenic HIV-infected patients are significantly
      at risk of developing severe infections at the end-stage of HIV disease, and this
      may have a major impact on hospitalization and death. Preventing neutropenia
      could dramatically improve the quality of life of these patients.

PMID- 10596034
TI  - [A model project on certification of continuous education by the Bavarian Chamber
      of Physicians].
AB  - Beginning with April 1st 1998 Bavarian physicians are invited to join a project
      on certification of continuing medical education on a voluntary basis. After a
      one year period, 1238 of practicing medical doctors (2.8%) received an official
      certificate on continuing medical education by the Bavarian Chamber of
      Physicians. In order to get the idea to certify postgraduate continuing medical
      education spread over the state of Bavaria, the Bavarian Chamber of Physicians
      takes every effort to support congress organizers to issue credit points.
      Customer oriented processes are applied as well as modern technologies such as
      bar-codes. The systematic approach to take part in continuing medical education
      as an important aspect of quality assurance in physician's profession reveals the
      chance to keep autonomy within the medical chambers.

PMID- 10596035
TI  - [Experiences with a "Diploma of Continuing Medical Education from the Chamber of
      Physicians of Thuringia"].
AB  - On March 18, 1995, the assembly of the delegates of the chamber of physicians of
      Thuringia passed a resolution to introduce a Diploma of continuing medical
      education (DCME), which is to be acquired on a voluntary basis. The objective
      hereby is to describe and document the physician's efforts towards continuing
      medical education and quality assurance. Since 1998 the first diplomas have been
      awarded. But the number of diplomas applied for has not yet met expectations,
      though questions about access conditions clearly show that there is real demand.
      It needs more convincing promotional ideas for the DCME and standardization of
      existing drafts/plan for certifying continuing medical education. Thus a higher
      degree of acceptance for a CME diploma/certificate could be reached.

PMID- 10596036
TI  - [Continuing medical education (CME) in neurology. Concept of the German Society
      of Neurology (DGN) and the Neurology Section of the Professional League of German
      Neurologic Medicine (BVDN)].
AB  - Continuous medical education in Neurology (CME-Neurology) has been promoted in a
      concept organized by both the German society of neurology, German association for
      occupational interests of neurologists and psychiatrists). CME-Neurology has been
      started in January 1999 and is closely adapted to the CME guidelines of neurology
      section of UEMS and EFNS. The program shall serve to the maintenance and
      upgrading of knowledge skills and competence of postgraduate training in
      neurology.

PMID- 10596037
TI  - [Concept for continuing medical education of the European Union of Medical
      Specialists--EUMS].
AB  - In Europe, emerging national structures of continuing medical education (CME)
      have to be connected in an umbrella structure of national authorities featuring
      the international exchange of accreditation and credits. In this umbrella
      structure, following topics need to be addressed: harmonization of the system of
      accreditation of providers of formally planned CME, the formulation of basic
      requirements for providers of formally planned CME, the system of quality
      assessment of the provided CME, and the system of awarding of CME credits to
      individual specialists.

PMID- 10596038
TI  - [Quality and structure of continuing medical education in internal medicine using
      the example of the Chamber of Physicians of the northern Rhine area].
AB  - A high quality of continuing medical education (CME) ensures an efficient and
      good medical care of the population. Despite the economical and medical
      significance, systematic studies of the available literature showed that there is
      no evaluation of CME in Germany regarding it's quality and structure. This pilot
      study by the chamber of physicians of the Northern Rhine area is supposed to be a
      first approach to demonstrate different characteristics of quality of CME. The
      results show that the guidelines by the chamber of physicians of Germany for the
      realization of CME can hardly be put in action: lessons with small groups is not
      realized, the student's experiences are not included in the CME and there is no
      feed-back between teachers and students. Additionally, the request by the chamber
      of physicians of Germany regarding CME events free of industrial interests is not
      met. Two thirds of so-called independent CME events by the academy for CME of the
      chamber of physicians of the Northern Rhine area has been realized with
      participation of the pharmaceutical industry. 57% of the participants stated that
      they saw no or hardly any value of the CME events. 16% gained some important
      knowledge, 22% gained knowledge of high professional relevance, 16% were
      motivated for intensified studies, and 27% were motivated for cooperation. Since
      only a CME of high quality can ensure an optimal care of the population, the
      development of an objective systematic evaluation followed by modification of the
      CME events is highly needed for the improvement of the German health care system.

PMID- 10596039
TI  - [Continuing medical education from the view of ambulatory care physicians-
      representative outcomes and needs in Bremen and Saxony-Anhalt].
AB  - RESEARCH QUESTION: To study the habits of ambulatory care physicians in CME, and
      to investigate the motivating and negative experiences with different types of
      CME in Germany. METHODS/SETTING: Survey with a five-page questionnaire posted to
      all ambulatory care physicians in the German states of Saxony-Anhalt (n = 3139)
      and Bremen (n = 1131). RESULTS: Response rates were 61.8% in Saxony-Anhalt and
      41.7% in Bremen. 2412 questionnaires were available in this largest survey on
      that topic in Germany. Mean time devoted to CME was 4.6 hours per week, the
      respondents participated on the average at 14 CME-events per year. A content
      analysis was made to investigate positive and negative experiences. Practice
      orientation and personal exchange in small groups was appraised; criticism was
      mostly directed towards the efficiency and effectiveness of CME at large events
      (e.g. congresses). CONCLUSIONS AND SUGGESTIONS: Regionally performed surveys are
      able to guide the planning of CME about habits, wants and needs of the target
      group and may increase the attendance as well as the involvement. Motivating as
      well as critical experiences of the participants should be regarded more
      rigorously in the planning. Consideration can increase the quality and the impact
      of CME. This applies the more, when certification of the quality of CME and of
      individual CME-efforts are planned. This article will be followed in one of the
      next issues by a second from the same survey focusing on the attitudes of
      ambulatory care physicians towards quality improvement and their intentions to
      join quality circles (peer review groups).

PMID- 10596040
TI  - [Quality assurance (general) at the medical school of Heidelberg as a model].
AB  - Because of new social and professional challenges, especially in the developed
      countries, there is a trend towards change and quality assurance is taking place
      in medical education over the past 20 years. In Heidelberg, the new way of
      teaching the students by general practitioners includes quality assurance by
      questionnaires, reports of practice visits, quality conferences of the teachers,
      and co-operation of the students. 90% of the students recommended the practice
      based structured program as very useful, especially the work with the patients in
      the general practices, 87% of the teaching general practitioners accepted special
      criteria for teaching; by this way an academic general practice can be
      established to meet the future expectations of primary medical care.

PMID- 10596041
TI  - [Patients' expectations of basic medical education].
AB  - Demonstrating to a patient that his worries are understood and his expectations
      are acknowledged leads to improved compliance, satisfaction with medical care and
      better quality of life. Consequently, patients' expectations of the "final
      product" of basic medical education refer not only to cure or relief of
      complaints but focus on communication, information and empathy. The best insight
      into patients' perspectives have physicians who have been patients themselves.
      Such experience is shown in six examples which do not criticize medical technique
      but deficits in communication, understanding and empathy. Because it is neither
      realistic nor desirable that doctors experience serious disease as part of their
      education we must emphasize sensible interaction and competent communication in
      our teaching efforts. This should enable students to learn the nature of illness
      during their clinical terms. Empiric studies show that these deficits can be
      improved or even abolished by modest means and small expenditure. The conversion
      into the medical curriculum should cover a mandatory communication course
      (including simulated and standardized patients), doctor-patient seminars, an
      ethics course and an enlarged course for physical examination (prepared in skills
      laboratories). Hopefully, the expected restructuring of the medical licensing
      code will consider these insights. Medical faculties could take their chances of
      an individual realisation.

PMID- 10596043
TI  - ["How do I get a good surgeon?" "How do I become a good surgeon?"].

PMID- 10596042
TI  - [Interdisciplinary quality circle for osteoporosis. First results from the
      Regional Advisory Board for Osteoporosis for Saxony-Thuringia].
AB  - The Regional Advisory Board Osteoporosis (REKO) for Saxony-Thuringia has
      established interdisciplinary quality circles in different districts with the
      goal to standardize the diagnosis of osteoporosis. Therefore, they developed a
      standardized program for general practitioners, gynecologists, internists and
      orthopedics. The documentation sheet covers 5 areas: Identification of the
      anamnestic osteoporosis risk with 7 standardized questions: If the patient
      reaches 3 or more out of 13 possible points, we assume he is at risk. 3 out of 5
      clinical symptoms, 3 out of 6 x-ray symptoms and osteoporosis typical results of
      the bone density measurement in combination with the anamnesis give us a scale
      which allows us to classify each symptom for diagnostic purpose. The differential
      diagnostic laboratory program includes: Blood sedimentation rate, calcium,
      alkaline phosphatase, creatine, TSH basal and 25 OH vitamin D3 in the serum. To
      check effectiveness of the antiresorptive therapy, bone specific resorption
      markers are sometimes usable. The program will be implemented this year in all
      quality circles, evaluated and then defined in its final form. Among the
      participants of the quality circles, the program is already usable and offers a
      reliable basis for the therapy.

PMID- 10596044
TI  - [How, when and what can we learn? Temporal and spatial characteristics of
      sensorimotor coordination].
AB  - On the basis of an account on elementary processes of spatio-temporal control of
      movements and on findings on motor learning, we propose in this article the
      employment of test and training procedures for motor skills in the training of
      surgeons. Elementary temporal and spatial factors of motor performance control
      underly the very precise complex motor behaviour of the activity of a surgeon. An
      established diagnosis of individual competence in this domain could help the
      doctors' decisions on whether to take up surgery. Training devices could improve
      the efficiency of the surgeons' motor functions. The inclusion of knowledge of
      motor abilities and learning processes could complement the present-day training
      of surgeons.

PMID- 10596045
TI  - [Clinical anatomy in the operating room. A model of integrated medical
      education].
AB  - Clinical relevance of theoretical knowledge is advantageous to be demonstrated
      early during preclinical education in medical schools. We describe a new way for
      anatomists and surgeons of teaching anatomy together during surgical procedures
      in the operating theatre, thus demonstrating successfully the need of keen
      insight in the field of gross anatomy. The students reported to be motivated to
      learn anatomy. A questionnaire was completely answered by 24 students after
      having finished the 96/97 course of anatomy in the operating theatre. The
      students reported that they have learned a lot as well as to be highly motivated
      to continue their efforts of gaining knowledge on the field of gross anatomy
      because of its clinical relevance.

PMID- 10596046
TI  - [How does aviation find the ideal pilot? Suitability testing: applicability to
      surgery? Methods for determining basic occupational suitability].
AB  - Pilot skills have a large influence on flight safety. A pilot needs certain basic
      abilities which cannot be trained. Specific tests are used to find out if someone
      has the required talents. A thorough selection process reduces the average pilot
      failure rate from about 30% to less than 3%. Studies proved that psychomotoric
      tests have a high prognostic validity. Modern surgery requires a high degree of
      spatial orientation and hand-eye-coordination. A specially developed test
      scenario could be used to predict career-success of a future surgeon.

PMID- 10596047
TI  - [Mental training--does it also help the modern surgeon?].
AB  - The demands on the modern surgeon are extremely complex. Especially in endoscopic
      surgery he must be able to carry out most complicated finemotoric motions which
      are not part of the natural action repertoire, sometimes under extreme conditions
      of stress. Such demands can be compared to those of top athletes. Within a
      cooperative project between the second chair of surgery of the University of
      Cologne and the sport psychologic working unit of the Heidelberg University
      department of sport and sports science the empirically sound Mental Practice (MP)
      which has been successfully applied in worldclass sports for a long time was
      modified so that an application of this training method is now possible for the
      training and continuing education of young surgeons. The following four types of
      surgery were emphasized: laparoscopic cholecystectomy, laparoscopic appendectomy,
      thyroidectomy and inguinal hernia. The article will focus on the detailed
      description of MP in surgery. At first, however, we are going to delineate MP in
      sports and will then turn to how it is modified and applied in the field of
      surgery. Besides the arrangement and exact description of surgeries, MP in this
      field requires the formulation of instructions which are summarized in
      instructional handbooks. These handbooks serve as target values for instrumental
      and cognitive simulation techniques which are applied in MP. The surgeon is thus
      provided with a foundation for the construction of functional mental
      representations of the surgery types which enables him to optimize the quality of
      his actions during the above mentioned surgeries.

PMID- 10596048
TI  - [Surgery school. Tradition-transition-change in paradigm?].
AB  - First Schools in Surgery already at the antiquity. During the medieval some slow
      developments in this regard throughout Europe, especially in France and Italy. In
      Germany because of the great changes and progresses in the medical sciences
      foundations of the first surgical schools in Vienna and Berlin. v. Langenbeck and
      Billroth have been the promoters. Tremendous changes in our time with a break of
      the generations, new structures at the universities, far reaching separation into
      subdisciplines of surgery and explosive technical developments question the
      meaning of surgical schools in the old sense. But there will apparently be a
      continuation, even in a changed matter and this on the background of a shift of
      the paradigm.

PMID- 10596049
TI  - [Postgraduate education of the surgeon from the viewpoint of medical boards.
      Reality and responsibility].
AB  - Postgraduate training in general surgery in Germany is regulated by state law and
      administrated by the Arztekammer. The formal conditions for the performance of
      the postgraduate training are published in the postgraduate regulations of the
      Arztekammer. The content of the postgraduate training is dictated by Guidelines
      that are based upon recommendations of scientific and professional organisations.
      The above mentioned regulations will be presented in this article as well as the
      procedure that is applied by the Arztekammer Nordrhein to evaluate the
      accreditation of those people and organisations who are eligible to administer
      the postgraduate training. Further perspectives on the professional future of
      surgeons in Germany are addressing the background of a growing number of doctors
      who are facing the changing conditions of the legal framework within which they
      will have to work.

PMID- 10596050
TI  - [Surgery education in the USA].
AB  - Surgical education in the United States historically was influenced by the German
      educational system. Currently residents spend five years to become general
      surgeons. Education focuses on the teaching of surgical basic sciences and
      practical instruction in the operating room and at the bedside. Students
      interested in General Surgery are selected largely based on their performance in
      medical school. Admission into first-rate programs is highly competitive. In many
      university-based programs residents are expected to spend an additional two years
      in research as part of their training. While on their clinical rotations
      residents usually spend 80 to 100 hours per week in the hospital. Resident
      salaries are moderate.

PMID- 10596051
TI  - [Surgery education in Europe].
AB  - Due to European law all examinations taken by officially recognized national
      boards have to be accepted in every member state. In 1958 the UEMS was founded on
      behalf of the European Council. Several Divisions in the "Section of Surgery" and
      the "European Board of Surgery" have to define the content and duration of their
      knowledge within the common trunk as well for the division's specialty itself.
      European Examinations today are offered in Surgery and Vascular Surgery.
      Continuing Medical Education is not yet organised officially in all member
      states. East European countries start to harmonize their structure due to the
      demands of the UEMS. The charter on continuing Medical Education was established
      by the UEMS in 1998. This concept was also accepted by the national authorities
      in Germany and will be officially structured in our country very soon.

PMID- 10596052
TI  - [Emergency and intensive care medicine as an interdisciplinary training
      requirement].
AB  - While substantial and practical qualification for medical practice within the
      framework of emergency medical services have to be proven by an advanced
      training, there are no special training programs for in-hospital emergency
      situations. As in the emergency room a transparent in-hospital emergency
      management has to be established including definite competencies to avoid time
      delays and inadequate treatment due to disputes about competence. Especially
      surgical intensive care medicine is an interdisciplinary task, requiring the
      participation of the surgeon as a responsible partner. Thus, the physician
      working in ICUs needs professional qualification and specialized knowledge as
      well as marked competence to co-operate. In any case the final clinical
      responsibility has to be taken over by physicians who not only have performed
      their internship on a ICU but are highly qualified in the whole range of
      intensive care medicine including all topics required in advanced intensive care
      medicine curricula.

PMID- 10596053
TI  - [Educational curriculum and organization in the general hospital].
AB  - With sufficient organization and personal activity comprehensive postgraduate
      medical education can successfully be carried out even at a small surgical
      department, especially--but not exclusively--in one's early years of postgraduate
      education and especially if external course offers are made use of. Postgraduate
      education is endangered not so much because of local circumstances, but because
      of external influences like official regulations on working-time, the lack of
      offers for rotations, and restrictions on our duty to take professional care of
      people.

PMID- 10596054
TI  - [Guidelines from the viewpoint of clinical economics].
AB  - In an experiment that compared the quality of medical guidelines in German cancer
      centers we were able to demonstrate that the selection of guidelines was not
      based on common criteria. These decisions were frequently based on personal
      preferences rather than on scientific evidence. We should consider that the
      scientific quality of clinical publications is easily assessed by simple methods
      in two dimensions, effectiveness and efficiency. This subsequently led to three
      conclusions: Clinical epidemiology/evidence-based medicine should be integrated
      into medical education. Interdisciplinary co-operation to create "common criteria
      for guidelines" should be supported. Politicians have the responsibility to
      provide the legal framework in order to ensure self administration in health
      care.

PMID- 10596055
TI  - [Implementing evidence-based medicine: what effects are measurable?].
AB  - Evidence-based medicine (EBM) was proposed as a possible method of solving two of
      health care's present problems: the increasing flood of information and rising
      expenditures. Although this concept appears to be plausible, the measurable
      improvements in health care brought about by possible implementation of EBM
      should be explicitly described. After having demonstrated the present problems as
      well as the necessity to solve them, we described the goals intended to be
      achieved by the implementation of EBM. Furthermore, the impact of EBM on medical
      education was described. The possible influence of EBM on the effectiveness and
      efficiency of health care was also considered. The conflicts caused by the
      introduction of EBM were demonstrated using the example of the "German Guideline
      Discussion". Finally, three proposals were made; the integration of EBM into
      education, the avoiding of conflicts similar to the German Guideline Discussion
      and the need to alter the political framework accompanying these processes.

PMID- 10596056
TI  - [Primary hypertrophic pyloric stenosis. A are form and stomach outlet stenosis in
      the adult].
AB  - A 38-year-old white female with primary hypertrophic pyloric stenosis is
      presented. The patient was admitted to our service with a history of upper
      digestive tract pain and postprandial vomiting since her 17th year of life.
      Diagnosis of benign pyloric stenosis was made preoperatively and the patient was
      successfully treated by Finney pyloroplasty. Primary hypertrophic pyloric
      stenosis in adults is a rare condition of unknown etiology. Only about 200 cases
      of primary hypertrophic pyloric stenosis in adults have been reported in the
      literature.

PMID- 10596057
TI  - [Endoscopic harvesting of the vena saphena magna for peripheral vascular
      reconstruction].
AB  - OBJECTIVE: By using an endoscopic, video-assisted instrumentarium we harvested
      the great saphenous vein for peripheral bypass surgery through minimal skin
      incisions with the purpose to reduce the wound complications. METHOD: Endoscopic
      subcutaneous saphenous vein harvesting was performed in 15 patients who underwent
      peripheral bypass surgery for intermittent claudication. In 6 patients the vein
      was taken from the affected leg and in 9 patients the vein was harvested from the
      opposite leg. RESULTS: In every case where the vein was taken from the affected
      leg we observed severe hematomas, which was in one case complicated by an
      abscess. Once we converted to the open procedure and in one patient endoscopic
      preparation led to a small vein injury. When the vein was harvested from the
      opposite leg no complications occurred. CONCLUSION: The endoscopic subcutaneous
      saphenous vein harvesting in peripheral bypass surgery with a special video
      assisted instrumentarium is feasible. The cosmetic advantages of this procedure
      are associated with high costs and a long operating time. Although we were not
      able to demonstrate a reduction of wound complications in our patients, the
      endoscopic vein harvesting in peripheral bypass surgery should be considered a
      very promising procedure. Nevertheless we cannot recommend the method for a wide
      clinical use at this time.

PMID- 10596059
TI  - [Hierarchy in surgery. Teupitzer Symposium. 18-19 September 1998].

PMID- 10596058
TI  - [Diseases of the small intestine, appendix, large intestine and rectum (2)].

PMID- 10596060
TI  - [Hierarchy in surgery. An antiquated system?].
AB  - Medical responsibility and hospital management, competency for resident's
      training and decision making in therapy are better performed in a system of
      hierarchy than other kinds of organisation of a surgical department. If all the
      duties and responsibilities are concentrated to a head of the department, it is
      also necessary to give him the adequate instruments for leadership, to stay
      alive.

PMID- 10596061
TI  - [Hierarchical structures in European countries].
AB  - The current form of organization and structure dates from the beginning of the
      20th century, but now developments show a trend toward teamwork, where work,
      power, and authority are evenly distributed among several persons and carried out
      correspondingly. According to a survey of 11 out of 16 countries in Europe, large
      surgical institutions are organized according to the hierarchic principle. In
      Austria, Belgium, and the Netherlands both types of organization exist, and only
      in Luxembourg, Ireland, and Great Britain does the cooperative system exist. The
      latter is also preferred in smaller and medium-sized hospitals, and in private
      institutions as well. This system appears to better correspond to the
      requirements of economics and specialization.

PMID- 10596062
TI  - [Hierarchy in surgery in the United States].
AB  - There are few if any hierarchical structures in American surgery. The surgical
      department consists of general surgery and a variable number of subspecialties.
      It usually has a small number of main teaching hospitals, frequently in addition
      to the University Hospital, a County Hospital and a Veterans Administration
      Hospital. The faculty consists of all physicians who have finished their
      specialty training and hold a teaching appointment at the university. The members
      of the faculty are free and independent in their clinical teaching and research
      activities. Each teaching hospital has chief of surgery and each academic
      division (i.e. general surgery, cardiovascular surgery, oncologic surgery) is
      also headed by a chief of this section. The chairman of the department represents
      the department externally and internally, is responsible for the organization and
      the finances of the department, the education and training of students and
      residents as well as quality control relating to clinical activities, research
      and teaching.

PMID- 10596063
TI  - [Hierarchy in the faculty of a university. Advantages and disadvantages for
      student education].
AB  - The faculty should determine its hierarchical structure by a democratic process.
      The common goal of excellence in undergraduate education should determine the
      sequence and the amount of teaching in the different fields of medicine. An
      analysis of practical needs should form the basis for the amount of instruction.

PMID- 10596064
TI  - [The so-called medical team system in surgery, an alternative to hierarchy?].
AB  - Since some years representatives of the "Bundesarztekammer" (German Board of
      physicians)--induced too by the German parliament of physicians--demanded the
      establishment of "team-work-models" as a new form of administration of our
      clinical departments. There are many reasons argueing against a reformation of
      the present structures like economical considerations, a well-organized education
      and especially patient-care-management. Only scientifically-based evidence could
      justify a change of the well-approved head-physician-system in Germany.

PMID- 10596065
TI  - [Introduction of flat hierarchy in surgery. Trial and error].
AB  - The introduction of flat structures indicated by e.g. fractal clinic and extended
      quality management is described by means of a fairy-tale and the longterm success
      of these measures is evaluated.

PMID- 10596066
TI  - [Division of responsibilities and team work in surgery].
AB  - Division of work and cooperation in surgery are defined in horizontal and
      vertical levels of decision and responsibility. The job situation in the
      hospitals becomes more and more difficult (increasing numbers of surgeons,
      reduction of jobs especially for surgical trainees due to the economic pressure).
      Job sharing and changes in organizing the surgical services are discussed as a
      possible situation.

PMID- 10596067
TI  - [Realization of ethics responsibilities in different surgical leadership
      structures].
AB  - The first century of modern surgery was dominated by strong personalities each of
      which have formed a leading surgical school and a great hospital. This was
      beneficial for the young science as long as all areas of the developing surgery
      could be mastered by one single man. A consequence of great and ever faster
      progress in all sciences and particularly in medicine is a more and more narrower
      specialization. This trend has made it impossible for an individual to be on the
      forefront of developments in the major surgical disciplines. Thus, to fulfill
      important tasks and especially for further progress it is mandatory to use the
      diverse skills of different individuals as a team.

PMID- 10596068
TI  - [The significance of hierarchy in postgraduate education].
AB  - There are structures of hierarchy in the postgraduate education. The postgraduate
      education is organized as a programme the young doctor has to absolve. The
      instruction and the control of the implementation of that programme must be
      carried out by a competent and experienced older physician, who is responsible
      for the correctness of that, the young doctor has to learn in his postgraduate
      education. The older physician unequivocally is integrated in the hierarchy above
      the young doctor legitimated by his knowledge, his experience and his
      personality. The hierarchy demonstrates itself as an indication of the moral
      integrity of the community and of each only individual.

PMID- 10596069
TI  - [Hierarchy and research].
AB  - Surgical research needs structural and organizational conditions. These have to
      ensure, that the young surgeon finds the opportunity for scientific activities
      and development in a highly professional environment.

PMID- 10596070
TI  - [Hierarchy and authority].
AB  - Although the term hierarchy isn't in keeping with the times for secular spheres,
      the identical term ranking omnipresent and indispensable in a political way.
      Without ranking there ist no final but only a general responsibility. Ranking is
      based on authority--to be distinguished between professional competence an
      official authority. The latter one should be gained with inner agreement--by
      sanctions only when needed.

PMID- 10596071
TI  - [Intuition in surgery].

PMID- 10596072
TI  - [Medical-surgical intuition and professional policy].
AB  - Many decisions in business and policy are made intuitively. According to
      scientific studies intuitive persons do not belong to a certain social group;
      they are unconventional, self-confident and self-reliant. In professional policy
      facts established by documentary evidence and legally guaranteed are the basis
      for decisions. Facts are dealing with the past. In order to consider the future
      and to react in situations of immediate interest intuitive abilities are just as
      important. (The appropriate argument at the right time at the right place).
      Beside the "Leitlinien" in surgical therapy the "Methodenfreiheit", which is
      connected to intuitive thinking, must be lasting.

PMID- 10596073
TI  - [Intuition in medicine and surgery. Prerequisites and limits].
AB  - Intuition as a philosophical category is commonly acknowledged, but certainly not
      undisputed. In medicine being a practical science and partly characterized by
      irrational decisions, intuitive thinking in diagnosis and therapy seems to be an
      essential part of successful medical activity. Preconditions for an intuitive
      comprehension of the patient in its whole as well as an unusual process in
      clinical life are know-how, experience and profound knowledge of the normal and
      pathological findings. Besides, the physician's and surgeon's moral integrity
      setting limits to the acceptance of intuition has to be rated as an aid to
      decision-making. Increase of technics, standards and rules narrow the intuitive
      scope in a high degree. Loss of intuition as a tool of medical thinking and
      acting may lead to a spiritual impoverishment of our profession and to a
      technocratic medicine.

PMID- 10596074
TI  - [Intuition and surgical responsibility].
AB  - The vast majority of surgical tasks can be managed by using basic, special and
      experts' knowledge gained during many years of clinical training and by applying
      solid surgical skills. This refers to elective cases as well as to emergency
      surgery and to general surgeons as well as to subspecialists. Consensus
      statements and standards of care derived from objective study results are aimed
      to be helpful as practice guidelines and in the decision making process. Only
      rare, non-foreseeable, unexpected and suddenly occurring exceptional situations
      require actions based on intuition, which results from a quick, sharp and
      brilliant decision founded on huge knowledge and experience. But in the scope of
      surgical work an overstatement or a mystic glorification of intuition should
      always be avoided.

PMID- 10596075
TI  - [The role of intuition in medical malpractice].
AB  - In a retrospective analysis of 502 surgical malpractice claims, the contribution
      of intuition was assessed. It was found that intuition, as a logical and directed
      intellectual approach, had an overall positive effect; this was not the case with
      an attitude of autistic intuition. However, judgement based on the physicians
      intuition alone did never result it negligence or misconduct.

PMID- 10596076
TI  - [Experience and intuition in surgery].
AB  - The article deals with the definition, the positive and negative assessment of
      intuition. Only in combination with experience and knowledge intuition many be as
      helpful as scores. Without these prerequisites intuition may tend to become a
      risk factor.

PMID- 10596077
TI  - [Can intuition in surgery by learned?].
AB  - Intuition, even at the end of the 20th century, has decisive significance in the
      field of medicine. Intuition within the medical field is understood to be a type
      of thinking based on experience, but without conscious recourse to its situations
      and thought processes; rather, it represents an act without reflection and one
      determining our medical actions to some extent. It is a cognitive process, an
      intuitive gain in recognition on the basis of experiential values called up from
      memory. Intuition is a combination of knowledge, ability, endurance, intellectual
      abilities, and discoursive methods of recognition, in short, the abilities of an
      expert. To become an expert, one must go through the stations of surgical
      training. In these the knowledge is imparted, which leads via decision-making to
      diagnosis and therapy. Intuition in the sense of the definition as experiential
      thinking cannot be learnt, but it can be schooled. The prerequisites for this are
      analytic thinking, expert knowledge, and metacognitive knowledge.

PMID- 10596078
TI  - [Intuition and research].
AB  - The manuscript defines the role of intuition in the surgical research
      (representability, accessability, "anchoreffect"). Sudden changes of direction in
      research can be caused by intuition (e.g. Polymerase chain reaction or
      Angiogenesis). Intuition leads to success when the basic idea is followed with
      externe diligence, consequence and perseverance. Evidence based medicine resulted
      from intuitive clinimetry. In the end research and intuition are tied together:
      continued work and commitment on one side and intuition as source of energy for
      perseverance and stamina.

PMID- 10596079
TI  - [New vaccines against Bordetella Pertussis].

PMID- 10596080
TI  - [The molecular etiology of neuronal ceroid lipofuscinosis].

PMID- 10596081
TI  - [Phytosterols].

PMID- 10596082
TI  - [Venous thrombosis in pediatric patients].

PMID- 10596083
TI  - [Immunoreactivity of the brain].

PMID- 10596084
TI  - [Risk of recurrence of non inherited chromosomal abnormalities].

PMID- 10596085
TI  - [Electrophysiological evaluation and head-up tilt test for the investigation of
      unexplained syncope].

PMID- 10596086
TI  - [Hepatic failure, indicating a prompt liver transplantation].

PMID- 10596087
TI  - [Osteomalacia due to celiac disease].

PMID- 10596088
TI  - [Insulin treatment in NIDDM].

PMID- 10596090
TI  - [Lower extremity pain and abnormal isotope scintigraphy].

PMID- 10596089
TI  - [Combination therapy of antihypertensive drugs].

PMID- 10596091
TI  - [Topical ophthalmic chloramphenicol].

PMID- 10596092
TI  - [Organ donation for transplantation in brain death].

PMID- 10596093
TI  - [Why screen for prostate cancer in Finland?].

PMID- 10596094
TI  - [Chronic otitis media with effusion].

PMID- 10596095
TI  - [Prenatal dexamethasone treatment of 21-hydroxylase deficiency].

PMID- 10596096
TI  - [Manual therapy, chiropractic, osteopathy. From alternative therapy to medicine].

PMID- 10596097
TI  - [The cardiac effects of Anthracycline].

PMID- 10596098
TI  - [Homicide behavior of females in Finland between years of 1980-1994].

PMID- 10596099
TI  - [Asthma mortality and utilization of antiasthmatic agents in Finland].

PMID- 10596100
TI  - [Folliculitis caused by Pityrosporum Ovale as a diagnostic problem].

PMID- 10596101
TI  - [Postoperative headache of a young female].

PMID- 10596102
TI  - [Meningitis caused by Francisella Tularensis].

PMID- 10596103
TI  - [Diaphragmatic paresis as a late radiation injury].

PMID- 10596104
TI  - [Psoriasis and epithelial changes of the tongue].

PMID- 10596105
TI  - [Bradycardia of an elderly patient caused by Timolol therapy in ocular
      hypertension].

PMID- 10596106
TI  - [Helicopter Science].

PMID- 10596107
TI  - [American Holocaust].

PMID- 10596109
TI  - [Risperidone and the "salami science"].

PMID- 10596108
TI  - [About Psa-screening].

PMID- 10596110
TI  - [Research in primary care].

PMID- 10596111
TI  - [The management of nausea].

PMID- 10596112
TI  - [New applications of magnetic nuclear imaging in the detection of acute cerebral
      ischemia].

PMID- 10596113
TI  - [Patient-physicians relationship and death].

PMID- 10596114
TI  - [Is immediate coronary angioplasty the best treatment in acute myocardial
      infarction?].

PMID- 10596115
TI  - [Pulmonary symptoms caused by gastroesophageal reflux in a child].

PMID- 10596116
TI  - [Ventricular tachycardia in conjunction with Valsalva maneuver].

PMID- 10596117
TI  - [Lumbar spinal stenosis].

PMID- 10596118
TI  - [Is it possible to eradicate inherited polyposis coli in colorectal cancer by
      using genetic diagnosis].

PMID- 10596119
TI  - [Unusual glaucoma of the right eye].

PMID- 10596120
TI  - [Indoor air quality].

PMID- 10596121
TI  - [Healthier buildings].

PMID- 10596122
TI  - [Airborne allergens].

PMID- 10596123
TI  - [The diagnosis of health risks due to humidity and mold in dwellings].

PMID- 10596124
TI  - [Chemical and physical risk factors of indoor climate].

PMID- 10596125
TI  - [The role of psychosocial factors in office building associated illness].

PMID- 10596126
TI  - [Positive future aspects in plastic surgery].

PMID- 10596127
TI  - [The development of plastic surgery in Finland].

PMID- 10596128
TI  - [Operative treatment of facial tumors].

PMID- 10596129
TI  - [Surgical treatment of malignant melanoma of the skin].

PMID- 10596130
TI  - [Microsurgical reconstruction in the salvage of lower extremities].

PMID- 10596131
TI  - [Immediate breast reconstruction].

PMID- 10596132
TI  - [Management of burn injuries].

PMID- 10596133
TI  - [Cleft lip and palate management of children before school age].

PMID- 10596134
TI  - [Correcting esthetic and dental problems of cleft lip caused by disturbed growth
      and development of maxillary, mandibular, dental and palatal structures in young
      adulthood].

PMID- 10596135
TI  - [Congenital ear malformation].

PMID- 10596136
TI  - [Operative management of transsexuals].

PMID- 10596137
TI  - [Conservative and surgical management of decubitus ulcer].

PMID- 10596138
TI  - [Esthetic surgeries].

PMID- 10596139
TI  - [Functional evaluation of free myocutaneous muscle flap and donor site].

PMID- 10596140
TI  - [Etiology of allergy and atopic diseases during early childhood].

PMID- 10596141
TI  - [Bright-light treatment in winter seasonal affective disorder].

PMID- 10596142
TI  - [MRI angiography].

PMID- 10596143
TI  - [Low molecular heparin in the prophylaxis of postoperative thrombosis].

PMID- 10596144
TI  - [Memory dysfunction of a patient, after temporal lobectomy].

PMID- 10596145
TI  - [The invasive treatment of ventricular arrhythmias].

PMID- 10596146
TI  - [Acute myocardial infarction and untreated sleep apnea].

PMID- 10596147
TI  - [Paraspinal muscle spasm].

PMID- 10596148
TI  - [Migraine as a first sign of antiphospholipid syndrome].

PMID- 10596149
TI  - [Vascular malformation of vertebral circulation as a reason for cerebral
      infarction of a young male].

PMID- 10596150
TI  - [Etiology, diagnosis and management of urinary lithiasis].

PMID- 10596151
TI  - [Recurrent cough].

PMID- 10596152
TI  - [The future role of the University of Helsinki].

PMID- 10596153
TI  - [The management of congenital heart diseases in childhood].

PMID- 10596154
TI  - [DNA vaccines].

PMID- 10596155
TI  - [Semen quality of Finnish men].

PMID- 10596157
TI  - [Intervention in the prevention psychiatric disorders in childhood].

PMID- 10596156
TI  - [The role of cerebellar function in cognitive process].

PMID- 10596158
TI  - [Dyspnoea as the first sign of latex allergy].

PMID- 10596159
TI  - [Diphyllobothriasis in a female patient].

PMID- 10596160
TI  - [Discitis in a pediatric patient].

PMID- 10596161
TI  - [Treatment of obsessive-compulsive disorder].

PMID- 10596162
TI  - [Luxation of mandibular-maxillary joint in a one year old patient].

PMID- 10596163
TI  - [The era of 100 years radiotherapy].

PMID- 10596164
TI  - [Does the recent advances in radiotherapy reflect positively in cancer cure and
      morbidity].

PMID- 10596165
TI  - [The principles of radiotherapy].

PMID- 10596166
TI  - [Organ preservation and radiation therapy].

PMID- 10596167
TI  - [Curative radiation therapy].

PMID- 10596168
TI  - [Palliative radiation therapy].

PMID- 10596169
TI  - [Intraluminal and interstitial radiation therapy].

PMID- 10596170
TI  - [Recent advances in radiation oncology].

PMID- 10596171
TI  - [Dietary fat as a cause for obesity].

PMID- 10596172
TI  - [The structure of the yeast genome].

PMID- 10596173
TI  - [Revolution in the liver transplantation surgery].

PMID- 10596174
TI  - [The role of fish oil in the prevention and treatment of diseases].

PMID- 10596175
TI  - [Coronary stents].

PMID- 10596176
TI  - [Diagnosis of occupational asbestosis].

PMID- 10596177
TI  - [Acute poisoning of children younger tahn 6 years].

PMID- 10596178
TI  - [Personal journal writing and self assessment among medical students].

PMID- 10596179
TI  - [Reccurent pseudomembranous colitis treated with the donor feces].

PMID- 10596180
TI  - [Esophagitis complicated with angina pectoris and mediastinitis].

PMID- 10596181
TI  - [Color Doppler imaging in ophthalmology].

PMID- 10596182
TI  - [Bilateral Achilles tendon rupture caused by oral fluoroquinolones].

PMID- 10596183
TI  - [Drug induced pulmonary symptoms in medicine].

PMID- 10596184
TI  - [Methotrexate in the treatment of rheumatoid arthritis].

PMID- 10596185
TI  - [Phytophototoxic dermatitis caused by Dictamnus alba].

PMID- 10596186
TI  - [Communication and patient-doctor relationship].

PMID- 10596187
TI  - [Dna transposition, HIV and Mendel].

PMID- 10596188
TI  - [The role of intestinal flora in rheumatoid arthritis].

PMID- 10596190
TI  - [Atlanto-axial rotatory subluxation].

PMID- 10596189
TI  - [Surgery of premature infants, weighing less than 1500 grams].

PMID- 10596191
TI  - [Kikuchi's lymphadenitis].

PMID- 10596192
TI  - [New indications for antidepressive medication].

PMID- 10596193
TI  - [Management of benign prostatic hyperplasia].

PMID- 10596195
TI  - [Alcohol consumption in Finland].

PMID- 10596196
TI  - [Trends in alcohol control policy in Finland].

PMID- 10596197
TI  - [Effects of alcohol intoxication].

PMID- 10596198
TI  - [Excessive alcohol consumption and alcohol addiction].

PMID- 10596199
TI  - [Somatic diseases due to alcohol consumption].

PMID- 10596200
TI  - [Mental disorders associated to alcohol abuse].

PMID- 10596201
TI  - [Primary, secondary and tertiary prevention to control alcohol abuse].

PMID- 10596202
TI  - [A method for continuous monitoring of total peripheral and pulmonary vascular
      resistance in high risk cardiac patients].
AB  - In this study we present a computer-assisted monitoring system ("Opserver") which
      allows a continuous registration of directly measured values: hear rate (HR),
      systolic, diastolic and mean arterial pressure (SAP, DAP, MAP): systolic,
      diastolic and mean pulmonary arterial pressure (PAPs, PAPd, PAPm), central venous
      pressure (CVP), mixed venous oxygen saturation (SvO2), pulse-oxymetrically
      measured oxygen saturation (SaO2), cardiac output (CO) and calculated
      haemodynamic parameters: cardiac index (CI), total peripheral vascular resistance
      (TPVR) and pulmonary vascular resistance (PVR). The basic principle of this on
      line monitoring system is the registration of calculated parameters combining
      data of various devices by specially-developed software. The procedure is shown
      in several clinical examples. The advantages of this system are:--monitoring of
      critical haemodynamic responses in cardiac high-risk patients relating to
      induction and finishing of anaesthesia including in- and extubation, recovery
      from anaesthesia, operation and transport and--exact documentation of the data
      for the purpose of clinical studies. Based on continuous measurement, this
      monitoring system allows an optimum evaluation of cardiorespiratory acute
      incidents, thereby permitting a problem-oriented therapy in high-risk patients
      with vasoactive medication in the perioperative period and in the intensive care
      unit.

PMID- 10596203
TI  - [Does method of anesthesia modify postoperative ischemia incidence? A study of
      patients after aortocoronary bypass operations].
AB  - In the postoperative period after coronary artery bypass graft surgery, the
      physician's enhanced attention should be focused on the incidence of myocardial
      ischaemia. The increased stress in the awakening patient as well as the return of
      autonomous reflexes can be the cause of imbalances in myocardial oxygen supply
      and uptake. Therefore, a probable influence of the pharmacologic profile of the
      intraoperatively applied anaesthetics on the incidence of postoperative
      myocardial ischaemia is of importance for adapting therapy on ICU to minimize any
      ischaemic risk. After approval by the ethics committee, a prospective randomized
      study was performed in 40 male patients who underwent coronary artery bypass
      graft surgery. The aim of the study was to compare balanced anaesthetic
      techniques performed with fentanyl and halothane, isoflurane and enflurane,
      respectively, with total intravenous anaesthesia performed with fentanyl and
      midazolam. An index to classify detection of ischaemia into three categories
      (ischaemia, probable ischaemia, no ischaemia) was established, based on
      measurements of myocardial lactate extraction and ST-segment analysis.
      Simultaneously, measurements of haemodynamic parameters and serum concentrations
      of catecholamines and intraoperatively applied anaesthetics were taken. In 8% of
      all measurements (30% of all patients) ischaemia was detected in the observation
      period and in 37% of all measurements (72.5% of all patients) probable ischaemia
      was detected. No significant difference was found concerning the incidence of
      myocardial ischaemia between all groups. The results of this investigation
      indicate that the application of inhalational anaesthetics for maintaining
      anaesthesia in coronary artery bypass graft surgery does not increase the risk of
      postoperative myocardial ischaemia.

PMID- 10596204
TI  - [Effects of priming technique on onset profile of cisatracurium].
AB  - Compared to atracurium, cisatracurium releases less laudanosine and histamine,
      but it has a longer onset time. The primary objective of this study was a
      blinded, randomized comparison of intubation scores and onset times of a
      threefold ED 95 of cisatracurium using the priming technique with two priming
      substances cisatracurium itself and pancuronium. To test the effect of priming
      with cisatracurium or pancuronium on the onset of cisatracurium, 45 patients were
      anaesthetised with 0.15-0.25 mg/kg alfentanil, 0.25-0.3 mg/kg edomidate i.v. and
      O2/N2O, and were randomisely divided into one of three groups. After induction,
      15 patients were primed with sodium chloride and thereafter received 0.15 mg/kg
      cisatracurium, 15 patients were primed with 0.01 mg/kg cisatracurium, another 15
      patients were primed with 0.015 mg/kg pancuronium and the last two groups
      received 0.14 mg/kg cisatracurium three minutes later. Neuromuscular response was
      monitored by adductor pollicis electromyogram (EMG) by stimulating in a TOF
      pattern. Times for T1 reduction to 75%, 50%, 25% and 0% and T1 recovery to 25%
      were taken. Intubation was performed 120 seconds after the main relaxant dose and
      scored in four grades. The two priming groups showed a significantly faster onset
      of neuromuscular blockade than the control group (cisatracurium priming group: T1
      = 0: 178.4 +/- 16.3 sec., pancuronium priming group 171.2 +/- 15.3 sec. vs.
      control group: T1 = 0: 205.5 +/- 18.9 sec.). Both primed groups showed no
      significantly better intubation scores, compared with the control group. Using
      the priming principle, cisatracurium will give good intubation scores 120 seconds
      after injection with a clinical duration profile comparable to an equipotent dose
      of atracurium.

PMID- 10596205
TI  - [Practical aspects of mechanical autotransfusion in tumor surgery in a
      decentralized clinic].
AB  - The surveys of Hansen et al. demonstrated the safe inactivation of tumor cells in
      salvaged blood by g-irradiation. This method opens up the possibility of
      extending the intraoperative autotransfusion to tumour surgery. A prospective
      survey at the University Hospital of Leipzig demonstrated the practicability of
      intraoperative autotransfusion with gamma-irradiation of salvaged blood at a
      hospital with a decentralized structure. A clinically-relevant reduction of
      quality of the blood product by gamma-irradiation with 50 Gray or by transport
      was not observed. Adherence to fixed working regulations ensures that gamma
      irradiation is conducted correctly and the salvaged erythrocyte concentrate is
      available in an acceptable period of time.

PMID- 10596206
TI  - Oxygen sensors based on luminescence quenching.

PMID- 10596207
TI  - Disinfection byproducts in drinking water: the analytical challenge.

PMID- 10596208
TI  - Direct profiling of proteins in biological tissue sections by MALDI mass
      spectrometry.
AB  - The direct profiling of proteins present in tissue sections for several organs of
      the mouse has been accomplished using matrix-assisted laser desorption ionization
      (MALDI) mass spectrometry (MS). Fresh tissue was sectioned and blotted on a
      conductive polyethylene membrane. The dried membrane blot was coated with matrix,
      typically sinapinic acid, and directly analyzed in the mass spectrometer.
      Generally, well over 100 peptide/protein signals in the 2000-30,000 Da range were
      observed, with 30-50 having relatively high signal intensities. Analysis of
      different areas of the same tissue gave remarkably similar mass spectra with
      greater than 90% homology. However, different parts of a segmented tissue, such
      as the proximal, intermediate, and distal colon, gave some unique protein
      signals. After treatment of the tissue blot with protease and subsequent MALDI MS
      analysis using postsource decay methods for peptide sequencing, some of the
      proteins were identified. The unique protein profiles measured from these tissue
      blots also showed differences from strain to strain of the mouse, with
      genetically similar strains having very similar patterns.

PMID- 10596209
TI  - A receptor-based bioassay for quantitative detection of gallium.
AB  - The detection of gallium in biological samples is required due to its role in the
      diagnosis of tumor and for possible treatment of malignancies. However, the use
      of purely instrumental techniques is unsuitable for detection of low levels of
      gallium in biological matrixes. We have synthesized new protein conjugates based
      on 4-(2-pyridylazo) ligands. The conjugates were successfully employed for the
      detection of gallium in biological matrixes using a nonantibody-based sandwich
      assay format. The recovery level obtained was between 97 and 101.3 with a
      relative standard deviation of less than 5%. The assay resulted in a detection
      limit of 5 x 10(-8) M and a remarkable selectivity for gallium(III) relative to
      other metals investigated. The new method provided adequate accuracy for gallium
      applicable for animal physiology and clinical toxicology.

PMID- 10596210
TI  - Determination of complex formation constants of lipophilic neutral ionophores in
      solvent polymeric membranes with segmented sandwich membranes.
AB  - A potentiometric method to determine ionophore complex formation constants in
      solvent polymeric membrane phases, proposed originally by Russian researchers, is
      critically evaluated and compared to other established methods. It requires
      membrane potential measurements on two-layer sandwich membranes, where only one
      side contains the ionophore. The resulting initial membrane potential reflects
      the ion activity ratio at both aqueous phase--membrane interfaces and can be
      conveniently used to calculate complex formation constants in situ. This method
      is potentially useful, since it does not require the use of a reference ion or
      second ionophore in the measurement. In this paper, the five ionophores
      valinomycin, BME-44, ETH 2120, tert-butylcalix[4]arene tetraethyl ester, and S,S'
      methylenebis(diisobutyldithiocarbamate) are characterized in poly(vinyl chloride)
      (PVC) plasticized with dioctyl sebacate (DOS) and compared with other established
      methods. The resulting formation constants correspond well to literature values.
      The influence of varying membrane concentrations and different anionic site
      additives is studied and found to be relatively small. Experiments are also
      performed with and without lipophilic inert electrolytes and with ionophore-free
      sandwich membranes to illustrate the effect of ion pairing and the membrane
      internal diffusion potential on the response of such sandwich membranes. These
      experiments suggest that ions are completely associated in PVC-DOS membranes, but
      that such ion pairs are rather nonspecific. Diffusion potentials seem to play a
      minor role with these systems. The results are explained with theory. This work
      indicates that the characterization of electrically charged ionophores, anion
      selective ionophores, and ionophores in membrane matrixes other than PVC
      plasticized with DOS may now be experimentally accessible.

PMID- 10596211
TI  - Acousto-optical deflection-based laser beam scanning for fluorescence detection
      on multichannel electrophoretic microchips.
AB  - Laser beam scanning driven by an acousto-optical deflector (AOD) is presented for
      multimicrochannel laser-induced fluorescence (LIF) detection during microchip
      based electrophoresis. While fast laser beam scanning for LIF detection on
      capillary or microchannel arrays can been achieved with galvanometric scanning or
      a translating stage, it can also be accomplished by using acoustic waves to
      deflect the laser beam in a manner that is dependent on the acoustic frequency.
      AOD scanning differs from other approaches in that no moving parts are required,
      and the scan frequency is faster than conventional approaches. Using a
      digital/analog (D/A) converter to provide addressing voltages to a
      voltage/frequency converter, rapidly changing the frequency input to the AOD
      allows the laser beam to be addressed accurately on a microchip. With the ability
      to change the frequency on the nanosecond time scale, scanning rates as high as
      30 Hz for Windows-based LabView programming are possible, with much faster scan
      rates achievable if a microprocessor-embedded system is utilized. In addition to
      spatial control, temporal control is easily attainable via raster scanning or
      random addressing, allowing for the scanning process to be self-aligning. Since
      the D/A output voltages drive the scanning of the laser beam over all channels,
      the software can define addressing voltages corresponding to the microchannel
      centers and, subsequently, fluorescence data can be collected from only those
      locations. This method allows for flexible, high-speed, self-align scanning for
      fluorescence detection in capillary or microchip electrophoresis and has the
      potential to be applied to a number of applications.

PMID- 10596212
TI  - A microcoil NMR probe for coupling microscale HPLC with on-line NMR spectroscopy.
AB  - An HPLC NMR system is presented that integrates a commercial microbore HPLC
      system using a 0.5-mm column with a 500-MHz proton NMR spectrometer using a
      custom NMR probe with an observe volume of 1.1 microL and a coil fill factor of
      68%. Careful attention to capillary connections and NMR flow cell design allows
      on-line NMR detection with no significant loss in separation efficiency when
      compared with a UV chromatogram. HPLC NMR is performed on mixtures of amino acids
      and small peptides with analyte injection amounts as small as 750 ng; the
      separations are accomplished in less than 10 min and individual NMR spectra are
      acquired with 12 s time resolution. Stopped-flow NMR is achieved by diversion of
      the chromatographic flow after observation of the beginning of the analyte band
      within the NMR flow cell. Isolation of the compound of interest within the NMR
      detection cell allows multidimensional experiments to be performed. A stopped
      flow COSY spectrum of the peptide Phe-Ala is acquired in 3.5 h with an injected
      amount of 5 micrograms.

PMID- 10596213
TI  - Quantitative analysis of molecular interaction in a microfluidic channel: the T
      sensor.
AB  - The T-sensor is a recently developed microfluidic chemical measurement device
      that exploits the low Reynolds number flow conditions in microfabricated
      channels. The interdiffusion and resulting chemical interaction of components
      from two or more input fluid streams can be monitored optically, allowing
      measurement of analyte concentrations on a continuous basis. In a simple form of
      T-sensor, the concentration of a target analyte is determined by measuring
      fluorescence intensity in a region where the analyte and a fluorescent indicator
      have interdiffused. An analytical model has been developed that predicts device
      behavior from the diffusion coefficients of the analyte, indicator, and analyte-
      indicator complex and from the kinetics of the complex formation. Diffusion
      coefficients depend on the local viscosity which, in turn, depends on local
      concentrations of all analytes. These relationships, as well as reaction
      equilibria, are often unknown. A rapid method for determining these unknown
      parameters by interpreting T-sensor experiments through the model is presented.

PMID- 10596214
TI  - High-resolution capillary isoelectric focusing of complex protein mixtures from
      lysates of microorganisms.
AB  - High-resolution capillary isoelectric focusing separations of complex protein
      mixtures have been obtained for cellular lysates of Saccharomyces cerevisiae,
      Eschericia coli, and Deinococcus radiodurans. High quality separations are shown
      to be achievable for total protein concentrations of < 0.1 mg/mL. The separation
      reproducibility was examined, and the influence of the capillary inner wall
      coating on resolution investigated using fusedsilica capillaries coated with
      various hydrophilic polymers including hydroxypropyl cellulose, poly(vinyl
      alcohol), and linear polyacrylamide. Proteins having an isoelectric point (pI)
      difference of 0.004 are shown to be separated using a linear carrier ampholyte
      (linear pH gradient between two electrodes) of 3-10. Approximately 45 discrete
      peaks in the pI range of 5-7 were obtained for S. cerevisiae, approximately 80
      peaks in the pI range of 4.5-8.5 for E. coli, and approximately 210 peaks in the
      pI range of 3-8.8 for D. radiodurans.

PMID- 10596215
TI  - Radial capillary array electrophoresis microplate and scanner for high
      performance nucleic acid analysis.
AB  - The design, fabrication, and operation of a radial capillary array
      electrophoresis microplate and scanner for high-throughput DNA analysis is
      presented. The microplate consists of a central common anode reservoir coupled to
      96 separate microfabricated separation channels connected to sample injectors on
      the perimeter of the 10-cm-diameter wafer. Detection is accomplished by a laser
      excited rotary confocal scanner with four color detection channels. Loading of 96
      samples in parallel is achieved using a pressurized capillary array system. High
      quality separations of 96 pBR322 restriction digest samples are achieved in < 120
      s with the microplate system. The practical utility and multicolor detection
      capability is demonstrated by analyzing 96 methylenetetrahydrofolate reductase
      (MTHFR) alleles in parallel using a noncovalent 2-color staining method. This
      work establishes the feasibility of performing high-throughput genotyping
      separations with capillary array electrophoresis microplates.

PMID- 10596216
TI  - Utility of postcolumn addition of 2-(2-methoxyethoxy)ethanol, a signal-enhancing
      modifier, for metabolite screening with liquid chromatography and negative ion
      electrospray ionization mass spectrometry.
AB  - A strategy for highly sensitive metabolite screening by liquid chromatography
      electrospray ionization (ESI) mass spectrometry with the negative-ion mode that
      involves the use of a reversed-phase column in gradient-elution mode and
      postcolumn addition of 2-(2-methoxyethoxy)ethanol (2-MEE), a novel signal
      enhancing modifier, has been described. When a mobile phase of 50 mM ammonium
      acetate/acetic acid buffer (pH 4.4) at a flow rate of 100 microL/min was
      employed, poor ESI response of ibuprofen as a model drug, probably due to both
      the high surface tension of the mobile phase and the ion-suppression effect of
      acetate anion in the mobile phase, was observed. On the other hand, the
      postcolumn addition of 2-MEE (50 microL/min) into the mobile phase counteracted
      the ion suppression as well as the surface tension problem, resulting in
      approximately 100-fold signal enhancement of the analyte. The metabolite
      screening of ibuprofen in human urine was subsequently carried out comparing the
      results with and without postcolumn addition of 2-MEE. The results indicated that
      the postcolumn addition of 2-MEE dramatically improved the ESI responses of all
      urinary metabolites detected without affecting the chromatographic separation.

PMID- 10596217
TI  - First attempt of odorant quantitation using gas chromatography-olfactometry.
AB  - An aroma compound was quantitated for the first time by GC-olfactometry (GC-O) on
      the basis of the detection frequency of odorants by a panel of 8-12 persons. The
      method was previously optimized regarding the coincidence of olfactometric peak
      apexes and the repeatability of peak height and area over 4 months. The number of
      required calibration points and the confidence interval of the curve were
      investigated. This technique was then tested by quantifying a model solution of 1
      octen-3-one. The standard addition method was found to be unsuitable in this
      context, but external calibration gave excellent results in the ppt range. GC-O
      was then challenged using one of the most sensitive and selective methods, GC/MS,
      to quantitate 1-octen-3-one in coffee, a complex aroma. Results showed
      performances comparable to GC/MS/MS for this odorant, or even better as the
      latter required 75-500 times more sample to perform the quantitation. However, at
      such a low concentration, overestimation cannot be excluded with either technique
      because of possible coelution of odorants or isobaric ions, respectively. These
      results show that GC-olfactometry can compete with the most sensitive and
      selective techniques, such as MS, for determination of extremely intense
      odorants, because little sample preparation is required and there is no need for
      the synthesis of labeled compounds.

PMID- 10596218
TI  - Disposable optical sensor chip for medical diagnostics: new ways in bioanalysis.
AB  - An optical sensor system is described which is particularly well suited for
      medical point-of-care diagnostics. The system allows for all kinds of
      immunochemical assay formats and consists of a disposable sensor chip and an
      optical readout device. The chip is built up from a ground and cover plate with
      in- and outlet and, between, of an adhesive film with a capillary aperture of 50
      microns. The ground plate serves as a solid phase for the immobilization of
      biocomponents. In the readout device, an evanescent field is generated at the
      surface of the ground plate by total internal reflection of a laser beam. This
      field is used for the excitation of fluorophor markers. The generated
      fluorescence light is detected by a simple optical setup using a photomultiplier
      tube. Because of the evanescent field excitation, washing or separation steps can
      be avoided. With this system the pregnancy hormone chorionic gonadotropin (hCG)
      could be determined in human serum with a detection limit of 1 ng/mL. Recovery
      values were 86, 106, and 102% for 5, 50, and 100 ng/mL hCG, respectively. The SD
      in repeated measurements (n = 10) was 5.6%. Furthermore, the feasibility of the
      system in competitive-type immunoassays was demonstrated for serum theophylline.
      A linear calibration curve of signal vs theophylline between 1 and 50 mg/L was
      obtained. Recovery values varied between 118% (10 mg/L) and 81.0% (20 mg/L).

PMID- 10596219
TI  - An Au nanoparticle/bisbipyridinium cyclophane-functionalized ion-sensitive field
      effect transistor for the sensing of adrenaline.
AB  - A film consisting of polyethyleneimine (PEI), Au nanoparticles (12 +/- 1 nm) and
      coadsorbed cyclobis(paraquat-p-phenylene) (1) was assembled as a sensing
      interface on the Al2O3 insulating layer of an ion-sensitive field-effect
      transistor (ISFET). Adrenaline (2) was sensed by the functionalized ISFET with a
      detection limit of 1 x 10(-6) M. The sensing ability of the nanostructured device
      for the analysis of adrenaline originates from the preconcentration of the
      analyte in the cyclophane by pi-pi donor-acceptor interactions. Analysis of
      adrenaline is accomplished by the measurement of the source-drain current, Isd,
      or by the gate-source voltage, Vgs. The sensing device is reusable (at least 100
      cycles) and exhibits high stability.

PMID- 10596220
TI  - [New vaccines against influenza via inhalation].

PMID- 10596221
TI  - [Blood glucose self-monitoring (BGSM): an evaluation of its prescription and
      results in type-2 diabetes. The Research Group in Primary Care of Tortosa].
AB  - OBJECTIVES: To investigate the results of metabolic control among type-2
      diabetics who practise self-monitoring of their blood glucose (MBG) and compare
      them with those who do not; the adequacy of MBG prescription according to
      clinical criteria and frequency of use; and to analyse the presence of factors
      predicting metabolic control. DESIGN: Descriptive and retrospective study
      covering 1995, 1996 and 1997. SETTING: The seven health districts in the
      territorial ambit of Tortosa Primary Care. PATIENTS: 597 type-2 diabetes patients
      were evaluated: 286 practising MBG, and 311 not doing so. All of them belonged to
      the health districts reference population. The sample was systematized and
      stratified by health districts in order to obtain data through a pre-designed
      data collection form. MEASUREMENTS AND MAIN RESULTS: 41.06% of diabetics
      practised MBG on a stable basis, without any significant differences showing in
      either HbA1c percentage, in any of the biological variables defining metabolic
      control in relation to the practice or otherwise of MBG, or in its frequency. An
      inverse relationship (p = 0.012) between the frequency of MBG and age was shown.
      Some clinical indication for prescribing MBG existed in 78.22% of the total
      diabetic population. In the diabetic population using MBG, inappropriate use of
      quantity was 54.89% (84.07% by too little, 15.92% in excess). Only 37.9%
      displayed quantitative and qualitative concordance simultaneously. The logistic
      model applied to the total diabetic population predicted 73.19% metabolic control
      with the variables of BMI (OR = 1.0542). Karnofsky index (OR = 0.9768) and
      presence of macroangiopathy (OR = 0.4249). CONCLUSIONS: 1. The practice of MBG is
      questionable, since the effectiveness found was not superior. 2. There is an
      imbalance between the real practice of MBG according to the clinical
      recommendations and consumption, which tends to be deficient. 3. The results do
      not seem to depend so much on MBG practice as on other linked circumstances which
      cannot be modified by MBG practice.

PMID- 10596223
TI  - [A quality study of self-medication in acute respiratory infection in a
      population utilizing an urban health center].
AB  - OBJECTIVE: To determine the quality of drugs use by patients when these were not
      prescribed by physicians. DESIGN: Cross-sectional survey, observational. SETTING:
      La Victoria Health Centre in the urban area of Valladolid. PARTICIPANTS: A survey
      was made of all patients who consulted their family practitioner about an acute
      respiratory infection during a three month period. The patients were classified
      according to the seriousness of their diagnosis, the time elapsed before
      consulting the doctor, the kind of medication and the source of it was evaluated
      and also the quality of the prescription with relation to the source.
      MEASUREMENTS AND MAIN RESULTS: 508 patients were studied, 61.4% women and 38.6%
      men, 57.9% of the total sample were on self-medication before they went to their
      physician (53.6% of men and 60.6% of women). The most common source of self
      medication was "self-pharmacy" in the case of 59.9% and the kind of medication
      most commonly taken was the antipyretic-analgesic group (in 42.9% cases). The
      quality evaluation of self-medication was considered correct in 63% of self
      medicated patients, no significant difference was found between the quality of
      self-medication and the source of it. CONCLUSIONS: The high prevalence of self
      medication in the general population, with the high rates of accurate use and the
      small percentages of adverse drug reactions, would lead us to think about of
      promoting self-medication and including it in specific educational health
      programs.

PMID- 10596222
TI  - [Cognitive deficit, its prevalence and associated factors in the population over
      74].
AB  - OBJECTIVE: To know the proportion of people older than 74, who are not
      institutionalized and not immobilized with cognitive alteration and to analyze if
      there is any association with social demographic characteristics and health
      factors. DESIGN: Cross-sectional descriptive study, made by interview. LOCATION:
      In an urban environment: Getafe, Parla, Pinto and rural environment: Grinon.
      PARTICIPANTS: The study population included all the people older than 74, that
      was registered in data base of individual health card, INSALUD. The sample,
      consisted by 704 elderly, who compliment including criterion, accuracy +/- 3.4%,
      p < 0.05 It's evaluated 615 persons. MEASUREMENTS AND MAIN RESULTS: It's made by
      questionnaire that included social demographic variables, information about the
      necessity of help for basic activities in daily life (ADLs), perceived health
      status, illness, sensorial alterations, falls, stay in hospital, social support,
      rotation, architectonics obstacles. For evaluating the likely cognitive
      deterioration, it was used the Short Potable Mental Questionnaire (SPSMQ) with 2
      cutting points: 2-4 errors and > 4 errors. The proportion of elderly people with
      cognitive deterioration (SPSMQ > 2) was 19% (95% CI, 16.2-22.4). This proportion
      grew with age, the same as men as in women (p < 0.0001), 11% (95% CI, 8-15) in <
      80 years, 29% (95% CI, 23.8-34.8) in > 79 years. It's proved a significant
      statistically association between cognitive deficit (SPSMQ > 4), in age > 84
      years OR = 4.1 (95% CI, 1.7-9.7), dependence degree for ADLs OR = 4.4 (95% CI,
      2.2-8.8), and low cultural level, OR = 6.2 (95% CI, 2-18). CONCLUSION: The
      prevalence of cognitive deficit in elderly population who lives in community
      environment, it's associated with the degree of functional damage, advanced age
      and the absence of studies, without any difference between urban and rural
      environment.

PMID- 10596224
TI  - [Breast feeding: knowledge, attitudes and sociocultural ambiguity].
AB  - OBJECTIVES: Found sociocultural attitude with regard to breast-feeding (BF)
      between the sanitary (SP) and no sanitary personnel (NSP) of health centers.
      DESIGN: Descriptive, cross-sectional study. SETTING: 4 health centres and 3
      hospitals of Valencia. PARTICIPANTS: 442 workers of these centres. INTERVENTION:
      Structured questionnaire. MAIN RESULTS: 88% of SP and 76% of NSP (p < 0.05)
      believed that BF has many advantages comparing with artificial-feeding in a
      developed country. SP said more advantages of BF than NSP (p < 0.0001). Most
      renowned advantages were immunological, affective relationship and comfort. Main
      inconveniences were dependence, work reasons, aesthetic nature and insecurity in
      the ingested amount. 56% of SP and 86% of NSP (p < 0.0001) believed milk's
      analysis necessary. 56% women and 38% men (p < 0.001) didn't see correct give BF
      in public. Men were more concerned than women (p < 0.05) for local problems of
      chest, aesthetic results, milk's quality and transmission of illnesses.
      CONCLUSIONS: It's necessary to support knowledge and re-evaluating the trust in
      the nutritious capacity of maternal milk between the personnel of health centers
      and hospitals. Generic ambiguity toward functions of feminine breast exists and
      public'BF isn't acceptable. It's necessary recover socioculturally the image of
      BF and keep in mind the existent ambiguity upon designing campaigns of promotion.

PMID- 10596225
TI  - [A cost-effectiveness analysis of strategies for the diagnosis-treatment of
      Helicobacter pylori-associated peptic ulcer in primary care].
AB  - OBJECTIVES: To undertake an economic evaluation of three strategies for
      diagnosing and treating Helicobacter pylori (HP)-related peptic ulcers (PU), and
      to find the most efficacious and efficient combination of medication for the most
      cost-effective strategy. DESIGN: Cost-effectiveness analysis based on
      retrospective information (systematic review of the literature) and Markov models
      for the simulation of a hypothetical cohort of patients with PU. PATIENTS:
      Patients seeking medical care at the primary level for an acute PU attack. The
      costs and health effects of the management of an attack were evaluated in a
      hypothetical cohort of adults (> 18 years old) with symptomatic peptic ulcer
      confirmed endoscopically and not associated with consumption of non-steroidal
      anti-inflammatory drugs (NSAIDs). INTERVENTIONS: Three strategies for handling PU
      patients were compared: pre- and post-treatment diagnosis of HP, pre-treatment
      diagnosis and empirical treatment. Then the most efficient strategy for comparing
      6 combinations of antibiotics was used. RESULTS: The empirical treatment strategy
      was markedly less costly (saving of between 15000 and 39000 pesetas per patient
      treated) than the diagnosis strategies, and obtained equivalent effectiveness
      under all analytical hypotheses. In comparing drug combinations, the classic
      triple therapies based on bismuth subcitrate were more effective and less costly
      than other therapies. CONCLUSIONS: Empirical treatment with combinations of
      irradicatory drugs was the most efficient strategy for tackling the
      diagnosis/therapy of patients with HP-related PU. In terms of efficiency, the
      choice between the various combinations of irradicatory drugs with over 80%
      success depends basically on the cost of the drugs.

PMID- 10596226
TI  - [The factors related to job satisfaction and professional burnout in the primary
      care physicians of Asturias].
AB  - OBJECTIVE: To determine the level of work satisfaction and professional wear and
      tear among primary care doctors, and related factors. DESIGN: Crossover
      descriptive study. SETTING: Asturias PC. SUBJECTS: General doctors (GD), family
      doctors (FD), residents, and PC paediatricians (n = 810). MEASUREMENTS: A survey
      for self-administration with social and demographic variables and suggestions.
      The Font Roja-PC questionnaire (FR). The Maslach Burnout Inventory (MBI).
      RESULTS: 497 (55.6% male) responded (61.35%). Mean age was 41 (SD = 7.18) 57.3%
      worked in an urban environment. 42% were FD, 35% GD, 15% paediatricians, 7%
      residents. The PC model was: 84% PC teams, 9% traditional model, 7% normal
      emergency service (NES). Mean seniority was 14 years (SD = 7.5). 89% worked
      solely in PC. 59% had a permanent contract, 31% provisional contracts, 7% were
      residents and 3% temporary. Overall mean satisfaction (OMS): 73.73 points. 43%
      had high professional wear and tear, 23% moderate and 32% low. Statistically
      significant associations: OMS/social and demographic variables: greater in men,
      the rural environment, paediatrics, NES, without stand-by, with less bureaucracy
      and less case pressure. Satisfaction/FR: greater NES, without stand-by, without
      sole dedication. Case pressure/FR: greater in men, rural environment,
      paediatrics, without sole dedication, NES, without stand-by and with less demand.
      Control/FR: greater in permanent and provisional posts. Relationship/FR: greater
      in men, FD, without stand-by. Suitability/FR: greater in men, paediatricians,
      permanent doctors, without stand-by. Relaxation/FR: greater in residents, young
      people, without sole dedication, NES. Variety/FR: greater in young people, those
      without children, residents, with sole dedication, those with stand-by.
      MBI/social and demographic variables: greater level of low emotional tiredness in
      workers in a rural environment and those with children. Greater low level of
      alienation in women. The older the doctor, the less the professional burnout.
      CONCLUSIONS: 1. High level of work satisfaction. 2. High-moderate professional
      wear and tear.

PMID- 10596227
TI  - [Gonarthrosis in primary care: can analytical and radiological tests de done away
      with?].
AB  - OBJECTIVES: To evaluate if the rheumatologic clinical criteria established for
      the diagnosis of knee osteoarthritis are valid in primary care and if it is
      possible to do without the laboratory and radiologic criteria. DESIGN:
      Descriptive study of the agreement between the diagnosis exclusively clinical and
      the clinical, laboratory and radiologic diagnosis according the American
      Rheumatism Association (ARA) criteria. SETTING: Population of the health area of
      Talavera de la Reina (Toledo). PATIENTS: People with one or both knees non
      referred pain during the previous month, in spite of their characteristics,
      length or periodicity. MEASUREMENTS AND RESULTS: The ARA and R.D. Altman clinical
      diagnosis criteria of knee osteoarthritis were applied to the sample and they
      were compared with the diagnosis obtained with the clinical, laboratory and
      radiological criteria (reference diagnosis). The clinical diagnosis of knee
      osteoarthritis was established according the ARA criteria in 93% cases, according
      Altman in 86% and according the reference diagnosis in 87%. The sensibility and
      positive predictive value obtained using both clinical criteria are high, but the
      specificity is very low. CONCLUSIONS: The clinical criteria can be used in
      primary care, although they have a low specificity. It could be necessary to
      establish new criteria to ameliorate the specificity and the handling of these
      patients in primary care, to avoid unnecessary explorations.

PMID- 10596228
TI  - [Compliance with antibiotic treatment in nonhospitalized children].
AB  - OBJECTIVE: To evaluate compliance with antibiotic treatment in children and to
      determine the factors that may be associated with compliance with antibiotic
      treatment in children not in hospital. DESIGN: Prevalence study. SETTING: La
      Rioja primary care centres. PATIENTS AND OTHER PARTICIPANTS: 384 children from 0
      to 10, not in hospital, who needed antibiotic treatment between October 1998 and
      January 1999. MEASUREMENTS AND MAIN RESULTS: Antibiotic compliance was measured
      with the Morisky-Green test through a phone survey of the parents ten days after
      the treatment was prescribed. The number of children who complied satisfactorily
      with the prescribed treatment was 214 (55.7%; 95% CI, 50.6-60.7). Correct
      compliance was more common in children with 12-hour rather than 8-hour intervals
      (OR: 1.87; CI OR, 1.23-2.85), and in children who went to nursery rather than
      children at school (OR: 1.77; CI OR, 1.08-2.91). CONCLUSIONS: Correct compliance
      in the study was low. Approximately half the children prescribed an antibiotic
      treatment at two or three doses a day took it as the paediatrician had indicated.

PMID- 10596229
TI  - [The prevalence of infection by the hepatitis B, C and human immunodeficiency
      viruses in drug users].
AB  - OBJECTIVE: Estimate the prevalence of the hepatitis B (HBV) infection, hepatitis
      C (HCV) and human immunodeficiency virus (HIV) and its coexistence in intravenous
      drug users, in order to start afterwards a vaccination and sanitary training
      programmes. PATIENTS AND METHODS: Intravenous drug users attended in a health
      centre and in the drugs addition deshabitation centre of reference located in a
      marginal urban quarter. Patients were detected from the health centre. During one
      year (June 1995-1996) facts were collected. The age, sex, consumption, type,
      administration mechanism and also the described serologies were analysed. It has
      been carried out descriptive statistics and applied the chi-square [correction of
      square-ji] test. RESULTS: A study of 355 patients, 295 (83.1%) males and 60
      (16.9%) females was carried out. The average age was 28.6 years (SD = 6.5). All
      serologies in 113 (31.8%) were available. The positive serologies for HIV, 64.6%
      for HBV and 64.4% had 71.1% for HCV. The three of them coexisted in a 35.4%
      between HIV, 39.1% of them were VHB and 88% VHC. 49.1% were VHB and VHC. The
      infection from any of the three virus was related with intravenous administration
      mechanism, but not with sex or drug type. CONCLUSION: The infection caused from
      the virus above mentioned is frequent in drug users. A not negligible percentage
      of patients could benefit from the hepatitis B vaccine administration (67.6%) or
      other preventive measures.

PMID- 10596230
TI  - [The EMBASE database. Excerpta Medica Database].

PMID- 10596231
TI  - [Does a relationship exist between the prescription of nonsteroid anti
      inflammatory (NSAIDs) and anti-ulcer agents?].

PMID- 10596232
TI  - [The influence of the new criteria for mild arterial hypertension on the concept
      of white-coat hypertension].

PMID- 10596233
TI  - [Letter to a tribunal].

PMID- 10596234
TI  - [Phamarcogenomics: personalized drugs and personalized medicine].

PMID- 10596235
TI  - [Diabetes mellitus: the epidemic of the 21th century].

PMID- 10596237
TI  - [Reactions and interactions of drugs].

PMID- 10596236
TI  - [European perspective on functional foods].

PMID- 10596238
TI  - [The effects of dioxins on human health].

PMID- 10596240
TI  - Generational transmission of child maltreatment.

PMID- 10596239
TI  - [Evaluation of film forming properties of a hydroxypropylmethylcellulose
      phthalate (HP 55) pseudolatex].
AB  - An hydroxypropylmethyl cellulose phthalate (HP55) pseudolatex was prepared by a
      nanoprecipitation method. This allows nanoparticles formation when a solution of
      the polymer in an organic solvent (phase S1 or organic phase) is introduced in a
      precipitant medium (phase S2 or aqueous phase) which consists of water containing
      surfactant. A modification of the solvent nature of phase S1 resulted in an
      improvement of the yield of the preparation. Then, the obtained pseudolatex was
      used to prepare films which were evaluated by mechanical tests and coating of
      tablets containing theophylline.

PMID- 10596241
TI  - Clonidine and methylphenidate.

PMID- 10596242
TI  - Mania and trichotillomania.

PMID- 10596243
TI  - Psychosis associated with pseudoephedrine and dextromethorphan.

PMID- 10596244
TI  - Fluoxetine in children with autism.

PMID- 10596245
TI  - Association of the dopamine transporter gene (DAT1) with poor methylphenidate
      response.
AB  - OBJECTIVE: This study attempted to relate the alleles of the D2 (DRD2), D4
      (DRD4), and dopamine transporter (DAT1) genes to the behavioral outcome of
      methylphenidate therapy. METHOD: African-American children with attention-deficit
      hyperactivity disorder were treated with methylphenidate in doses not in excess
      of 60 mg/day. The dosage was increased until behavioral change was achieved,
      using a decrement in scores of less than or equal to 1 on a commonly used rating
      scale or until the maximum tolerated dose was achieved. Blood samples were
      obtained at that point, and genotypes for polymorphism at the respective genes
      were identified. RESULTS: Genotypes were then tested by chi 2 to assess the
      significance of any association with drug response. Only the dopamine transporter
      gene was found to be significant. Homozygosity of the 10-repeat allele was found
      to characterize nonresponse to methylphenidate therapy (p = .008). CONCLUSIONS:
      While the results suggest that alleles of the dopamine transporter gene play a
      role in methylphenidate response, replication in additional studies is needed.

PMID- 10596246
TI  - The early development of child psychopharmacogenetics.

PMID- 10596247
TI  - A controlled comparison of family versus individual therapy for adolescents with
      anorexia nervosa.
AB  - OBJECTIVE: To compare the effectiveness of behavioral family systems therapy
      (BFST) with that of ego-oriented individual therapy (EOIT) as treatments for
      adolescents with anorexia nervosa. METHOD: Thirty-seven adolescents meeting DSM
      III-R criteria for anorexia nervosa were randomly assigned to receive BFST or
      EOIT, in addition to a common medical and dietary regimen. In BFST, the family
      was seen conjointly, the parents were placed in control of the adolescent's
      eating, distorted beliefs were targeted through cognitive restructuring, and
      strategic/behavioral interventions were used to change family interactions. In
      EOIT, the adolescent was seen individually, with an emphasis on building ego
      strength and uncovering the dynamics blocking eating; parents were seen
      collaterally. Measures administered before, after, and at 1-year follow-up tapped
      body mass index, menstruation, eating attitudes, ego functioning, depression, and
      family interactions. RESULTS: BFST produced greater weight gain and higher rates
      of resumption of menstruation than EOIT. Both treatments produced comparably
      large improvements in eating attitudes, depression, and eating-related family
      conflict, but very few changes occurred on ego functioning. CONCLUSIONS: BFST and
      EOIT proved to be effective treatments for adolescents with anorexia nervosa, but
      BFST produced a faster return to health.

PMID- 10596248
TI  - Childhood abuse and neglect: specificity of effects on adolescent and young adult
      depression and suicidality.
AB  - OBJECTIVE: To investigate the magnitude and independence of the effects of
      childhood neglect, physical abuse, and sexual abuse on adolescent and adult
      depression and suicidal behavior. METHOD: A cohort of 776 randomly selected
      children was studied from a mean age of 5 years to adulthood in 1975, 1983, 1986,
      and 1992 during a 17-year period. Assessments included a range of child, family,
      and environmental risks and psychiatric disorders. A history of abuse was
      determined by official abuse records and by retrospective self-report in early
      adulthood on 639 youths. Attrition rate since 1983 has been less than 5%.
      RESULTS: Adolescents and young adults with a history of childhood maltreatment
      were 3 times more likely to become depressed or suicidal compared with
      individuals without such a history (p < .01). Adverse contextual factors,
      including family environment, parent and child characteristics, accounted for
      much of the increased risk for depressive disorders and suicide attempts in
      adolescence but not in adulthood (p < .01). The effects of childhood sexual abuse
      were largest and most independent of associated factors. Risk of repeated suicide
      attempts was 8 times greater for youths with a sexual abuse history (odds ratio =
      8.40, p < .01). CONCLUSIONS: Individuals with a history of sexual abuse are at
      greater risk of becoming depressed or suicidal during adolescence and young
      adulthood. Adolescence is the most vulnerable period for those youths who may
      attempt suicide repeatedly. Many of the apparent effects of neglect, in contrast,
      may be attributable to a range of contextual factors, suggesting broader focus
      for intervention in these cases.

PMID- 10596249
TI  - Age- and sex-related risk factors for adolescent suicide.
AB  - OBJECTIVE: To examine the impact of age and sex on adolescent suicide risk.
      METHOD: A standard psychological autopsy protocol was used to compare 140 suicide
      victims with 131 community controls. The risk factors for older (> or = 16 years)
      and younger, and for male and female suicide were compared. RESULTS: Mood
      disorders, parental psychopathology, lifetime history of abuse, availability of a
      gun, and past suicide attempt conveyed significant risk for suicide across all 4
      demographic groups. Psychopathology, particularly substance abuse (alone and
      comorbid with mood disorder), was more common and conveyed a much higher risk for
      suicide in the older versus younger adolescents. Younger suicide victims showed
      lower suicidal intent. Males chose more irreversible methods, and conduct
      disorder was both more prevalent and a more significant risk factor in males.
      CONCLUSIONS: The increased rate of suicide in older versus younger adolescents is
      due in part to greater prevalence of psychopathology, namely substance abuse, and
      greater suicidal intent in the older population. The increased rate in males is
      less easily explained, but it may stem from method choice and the greater
      prevalence of and risk conveyed by conduct disorder in males.

PMID- 10596250
TI  - Using the suicide risk screen to identify suicidal adolescents among potential
      high school dropouts.
AB  - OBJECTIVE: To examine the validity of the Suicide Risk Screen (SRS) for
      identifying suicide-risk youths among potential high school dropouts. METHOD:
      Five hundred eighty-one potential dropouts, aged 14 to 20 years, participated in
      a 3-stage case identification protocol. A potential dropout pool was created in 7
      schools; students, randomly selected, completed a questionnaire containing the
      SRS and participated in an assessment interview. Validity measures included
      Reynolds' Suicide Ideation Questionnaire (SIQ-JR) and 2 clinician rating scales,
      the Direct Suicide Risk (DSR) and Clinical Risk Assessment (CRA). RESULTS:
      Suicide-risk severity was significantly associated with categorization defined by
      the SRS criteria. SRS sensitivity ranged from 87% to 100%, specificity from 54%
      to 60%. Of 7 SRS elements, depression, suicidal ideation, and suicide threats
      predicted all validity measures. Suicide attempts predicted the DSR and CRA, but
      not Reynolds' SIQ-JR. Drug involvement, though relatively weaker, consistently
      predicted all validity measures. No additional psychosocial indicators improved
      the prediction of SIQ-JR or the DSR. Family support, likelihood of dropout, and
      risky behaviors, however, were additional predictors of the CRA ratings.
      CONCLUSIONS: The SRS is an effective and pragmatic method for identifying suicide
      risk youths among potential dropouts in school settings.

PMID- 10596251
TI  - Psychiatric adjustment in adolescents with a history of chronic fatigue syndrome.
AB  - OBJECTIVE: To ascertain psychiatric adjustment in youngsters with a history of
      childhood chronic fatigue syndrome (CFS). METHOD: Subjects were 25 children and
      adolescents with CFS who were seen in tertiary pediatric/psychiatric clinics
      (mean age 15.6 years, seen a mean of 45.5 months after illness onset; 17 subjects
      had recovered and 8 were still ill) and 15 healthy matched controls. Youngsters
      and their parents (usually mothers) were interviewed and completed
      questionnaires. Instruments used included the Schedule for Affective Disorders
      and Schizophrenia for School-Age Children (K-SADS), the Child Behavior Checklist
      (CBCL), and the Harter Self-Esteem Questionnaire. RESULTS: At assessment,
      psychiatric disorders (mainly anxiety and depressive disorders) were present in
      half the subjects with a history of CFS, a rate significantly higher than in
      healthy controls. On the CBCL youngsters with a history of CFS had an excess of
      psychological symptoms and decreased social competence. On the Harter Self-Esteem
      Questionnaire they reported reduced self-esteem, especially in social competence.
      Anxiety disorders were significantly more common in recovered subjects than in
      those with active CFS illness status. CONCLUSIONS: Psychiatric disorders were
      found to be increased in adolescents with a history of severe CFS; CFS may
      enhance the risk for or share common predisposing factors with anxiety disorders.

PMID- 10596252
TI  - Case series: increased vulnerability to obsessive-compulsive symptoms with
      repeated episodes of Sydenham chorea.
AB  - The association between obsessive-compulsive symptoms (OCS) and Sydenham chorea
      (SC) supports the hypothesis of a common neuroimmunological dysfunction in basal
      ganglia associated with group A beta-hemolytic streptococcal infection underlying
      both conditions. Four children with 2 distinct SC episodes were evaluated to
      assess the course of OCS. All patients developed OCS during their second episodes
      (3 met criteria for obsessive-compulsive disorder [OCD]), but not in their first
      episodes (2 developed OCS and met criteria for OCD). These data suggest that the
      recurrence of SC episodes may result in a cumulative effect, thus increasing the
      risk of appearance and intensification of OCS.

PMID- 10596253
TI  - Risk factors for psychological maladjustment of parents of children with cancer.
AB  - OBJECTIVE: To examine risk variables for future, more immediate, and persistent
      psychological distress of parents of pediatric cancer patients. METHOD: Parents
      (n = 128) completed questionnaires at the time of diagnosis (T1) and 12 months
      later (T2). Multiple regression analyses were performed using the following as
      predictors: demographics, illness-related variables, other life events,
      personality, coping styles, and social support. RESULTS: Trait anxiety was the
      strongest predictor of both fathers' and mothers' future distress. Changes in
      trait anxiety during the year also accompanied changes in both parents' levels of
      distress. Additional prospective predictors for fathers were the coping style
      "social support-seeking" and dissatisfaction with support. Dissatisfaction with
      support also had short-term effects for fathers. An additional prospective
      predictor for mothers was the number of pleasant events they had experienced
      prior to diagnosis, while a short-term effect was found for performance in
      assertiveness. No predictors for the persistence of distress were found.
      CONCLUSIONS: These results underscore the importance of personality anxiety in
      predicting parents' risk for adjustment difficulties associated with the
      experience of cancer in one's child. An additional risk factor for fathers was
      social support. For mothers, previously experienced life events and the frequency
      of assertive behavior were additional risk factors.

PMID- 10596254
TI  - Velocardiofacial syndrome in childhood-onset schizophrenia.
AB  - OBJECTIVES: Deletion of chromosome 22q11 (velocardiofacial syndrome) is
      associated with early neurodevelopmental abnormalities and with schizophrenia in
      adults. The rate of 22q11 deletions was examined in a series of patients with
      childhood-onset schizophrenia (COS), in whom early premorbid developmental and
      cognitive impairments are more pronounced than in adult-onset cases. METHOD:
      Through extensive recruiting and screening, a cohort of 47 patients was enrolled
      in a comprehensive study of very-early-onset schizophrenia. All were tested with
      fluorescence in situ hybridization for deletions on chromosome 22q11. RESULTS:
      Three (6.4%) of 47 patients were found to have a 22q11 deletion. All 3 COS
      patients with 22q11 deletions had premorbid impairments of language, motor, and
      social development, although their physical characteristics varied. Brain
      magnetic resonance imaging revealed increased midbody corpus callosum area and
      ventricular volume in relation both to healthy controls and to other COS
      patients. CONCLUSIONS: The rate of 22q11 deletions in COS is higher than in the
      general population (0.025%, p < .001) and may be higher than reported for adult
      onset schizophrenia (2.0%, p = .09). These results suggest that 22q11 deletions
      may be associated with an earlier age of onset of schizophrenia, possibly
      mediated by a more salient neurodevelopmental disruption.

PMID- 10596255
TI  - "Only God decides": young children's perceptions of divorce and the legal system.
AB  - OBJECTIVE: To describe research on perceptions of children aged 6 and younger
      from 21 families of their parents' divorce, of its impact on their families, and
      of legal officials. METHOD: Semistructured play interviews were conducted during
      home visits as parents were conjointly interviewed as part of a larger study on
      divorce in legal context. RESULTS: Children had much mis-information about
      divorce as an event and process. What they did know was often inappropriate,
      frightening, and confusing. They resented how the process "ruined their parents'
      being friends any more" and proposed reforms based on their wishes and
      observations. CONCLUSIONS: Greater awareness is needed of the child's desire to
      be heard during the process, to feel safe and less lonely, and to stay in touch
      with both parents and extended families. Age-appropriate explanations of
      psychological and legal aspects of the divorce process are likely to support
      children's positive adjustment and mental health.

PMID- 10596256
TI  - A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity
      disorder.
AB  - OBJECTIVE: Meta-analysis was used to review the literature on the clinical use of
      clonidine to treat symptoms of attention-deficit hyperactivity disorder (ADHD).
      METHOD: A review of the literature from 1980 to 1999 revealed 39 studies that
      reported clonidine's efficacy and side effects for symptoms of ADHD and comorbid
      conditions. Of these, 11 reports provided sufficient information to be included
      in a meta-analysis. RESULTS: Meta-analysis using weighted variables revealed
      clonidine demonstrates a moderate effect size of 0.58 +/- 0.16 (95% confidence
      interval = 0.27-0.89) on symptoms of ADHD in children and adolescents with ADHD
      and ADHD comorbid with conduct disorder, developmental delay, and tic disorders.
      CONCLUSIONS: Clonidine may be an effective second-tier treatment for symptoms of
      ADHD, but it has an effect size less than that of stimulants. Clinical use of
      clonidine is associated with many side effects.

PMID- 10596257
TI  - Continuity of psychopathology in youths referred to mental health services.
AB  - OBJECTIVE: To investigate the stability and predictive strength of behavioral and
      emotional problems in childhood and adolescence. METHOD: A referred sample (N =
      1,652), aged 4 to 18 years at initial assessment, was followed up after a mean
      interval of 6.2 years. Problem scores derived from Child Behavior Checklist,
      Youth Self-Report, and Teacher's Report Form at initial assessment (T1) were
      related to scores on the same instruments at follow-up (T2). RESULTS:
      Correlations between T1 and corresponding T2 problem scores averaged 0.41
      intrainformant (range 0.22-0.61) and 0.22 interinformant (range -0.09-0.57).
      Stabilities were similar across gender, and larger for Externalizing versus
      Internalizing scores, except on youths' self-reports. Psychopathology scores at
      follow-up were predicted by corresponding T1 scores. Girls were predicted to have
      higher T2 Somatic Complaints, Anxious/Depressed, Thought Problems, and
      Internalizing scores than boys. Children younger at intake were predicted to have
      higher scores than older children on T2 Social and Attention Problems.
      CONCLUSIONS: Findings indicate continuity of specific behavioral and emotional
      problems in clinically referred children and adolescents.

PMID- 10596258
TI  - Parent and child contributions to diagnosis of mental disorder: are both
      informants always necessary?
AB  - OBJECTIVE: To examine the unique cases contributed by parent and child informants
      to diagnostic classification, with the goal of identifying those diagnoses for
      which either or both informants are needed. METHOD: The authors examined survey
      data from the Methods for the Epidemiology of Child and Adolescent Mental
      Disorders (MECA) Study, a 4-community epidemiology survey of 9- to 17-year-old
      children and their parents. Parent-child dyads (1,285 pairs) were independently
      interviewed by lay persons with the Diagnostic Interview Schedule for Children; a
      subset of these pairs (n = 247) were also interviewed by clinicians. Agreement
      between parents and children was examined with respect to levels of impairment,
      need for/use of services, and clinicians' diagnoses. RESULTS: Parents and
      children rarely agreed on the presence of diagnostic conditions, regardless of
      diagnostic type. Nonetheless, most child-only- and parent-only-identified
      diagnoses were similarly related to impairment and clinical validation, with 2
      exceptions: child-only-identified attention-deficit hyperactivity disorder (ADHD)
      and oppositional defiant disorder (ODD). CONCLUSIONS: Overall findings suggest
      that most "discrepant" diagnoses (those reported by one but not the other
      informant) reflect meaningful clinical conditions. In some instances, however,
      diagnoses reported by one but not the other informant should be treated with
      caution, as they may not reflect the full diagnostic condition (e.g., possibly
      child-only-identified ADHD or ODD). Further research is needed to determine the
      salience of child-only- or parent-only-reported cases.

PMID- 10596259
TI  - The MacArthur Three-City Outcome Study: evaluating multi-informant measures of
      young children's symptomatology.
AB  - OBJECTIVE: Three sites collaborated to evaluate the reliability and validity of 2
      measures, developed in tandem to assess symptomatology and impairment in 4- to 8
      year-old children: the Berkeley Puppet Interview Symptomatology Scales (BPI-S)
      and the Health and Behavior Questionnaire (HBQ). METHOD: In this case-control
      study, mothers, teachers, and children reported on multiple dimensions of
      children's mental health for 120 children (67 community and 53 clinic-referred
      children). RESULTS: The BPI-S and the parent and teacher versions of the HBQ
      demonstrated strong test-retest reliability and discriminant validity on a
      majority of symptom scales. Medium to strong effect sizes (Cohen d) indicated
      that children in the clinic-referred group were viewed by all 3 informants as
      experiencing significantly higher levels of symptomatology than nonreferred,
      community children. CONCLUSION: The availability of a set of multi-informant
      instruments that are psychometrically sound, developed in tandem, and
      developmentally appropriate for young children will enhance researchers' ability
      to investigate and understand symptomatology or the emergence of symptomatology
      in middle childhood.

PMID- 10596260
TI  - Cultural issues in diagnosis and treatment of ADHD.

PMID- 10596261
TI  - Quantitative research approaches.

PMID- 10596262
TI  - Genetics of childhood disorders: IX. Triplet repeat disorders.

PMID- 10596263
TI  - Summary of the Practice Parameters for the Assessment and Treatment of Children,
      Adolescents, and Adults with Mental Retardation and Comorbid Mental Disorders.
      American Academy of Child and Adolescent Psychiatry.
AB  - This summary provides an overview of the assessment and treatment recommendations
      contained in the Practice Parameters for the Assessment and Treatment of
      Children, Adolescents, and Adults With Mental Retardation and Comorbid Mental
      Disorders. The parameters were written to aid clinicians in the assessment and
      treatment of children, adolescents, and adults with symptoms of mental
      retardation (MR) and comorbid mental disorders. MR is a heterogeneous condition
      defined by significantly subaverage intellectual and adaptive functioning and
      onset before age 18 years. With an approach underscored by principles of
      normalization and the availability of appropriate education and habilitation,
      persons with MR generally live, are educated, and work in the community. Mental
      disorders occur more commonly in persons with MR than in the general population.
      However, the disorders themselves are essentially the same. Clinical
      presentations can be modified by poor language skills and by life circumstances,
      so a diagnosis might hinge more heavily on observable behavioral symptoms. The
      diagnostic assessment considers and synthesizes the biological, psychological,
      and psychosocial context of mental disorders. Comprehensive treatment integrating
      various approaches, including family counseling, pharmacological, educational,
      habilitative, and milieu interventions is the rule.

PMID- 10596264
TI  - Summary of the Practice Parameters for the Assessment and Treatment of Children,
      Adolescents, and Adults with Autism and other Pervasive Developmental Disorders.
      American Academy of Child and Adolescent Psychiatry.
AB  - This summary provides an overview of the assessment and treatment recommendations
      contained in the Practice Parameters for the Assessment and Treatment of
      Children, Adolescents, and Adults With Autism and Other Pervasive Developmental
      Disorders. The parameters were written to aid clinicians in the assessment and
      treatment of children and adolescents with autism and other pervasive
      developmental disorders. Autism and the related pervasive developmental disorders
      are characterized by patterns of delay and deviance in the development of social,
      communicative, and cognitive skills, which arise in the first years of life.
      Although frequently associated with mental retardation, these conditions are
      distinctive in terms of their course and treatment. These conditions have a wide
      range of syndrome expression, and their management presents particular challenges
      for clinicians. Individuals with these conditions can present for clinical care
      at any point in development. The multiple developmental and behavioral problems
      associated with these conditions often require the care of multiple providers;
      coordination of services and advocacy for individuals and their families is
      important. Early, sustained intervention is indicated, as is the use of various
      treatment modalities (e.g., pharmacotherapy, special education,
      speech/communication therapy, and behavior modification.

PMID- 10596265
TI  - [Is strong effectiveness dangerous?].

PMID- 10596267
TI  - [Natural and recombinant interferons].

PMID- 10596266
TI  - [TNF antagonists in therapy of rheumatoid arthritis].

PMID- 10596268
TI  - [Diseases of force. Current state of information about the "secret disease"].

PMID- 10596269
TI  - [Fats in nutrition. Fat and oil food groups].

PMID- 10596270
TI  - [An old disease with a new face: canine leptospirosis does not lose its
      relevance].
AB  - The clinical features of the disease are presented based on retrospective
      analysis of the records of eleven dogs diagnosed with leptospirosis using
      clinical signs and results of the microagglutination test (MAT) between 1991 and
      1996. Additionally, Leptospira titres were determined in 30 healthy dogs and 20
      hospitalised dogs without clinical or laboratory evidence of leptospirosis. A
      positive titre for L. grippotyphosa, L. pomona, L. bratislava, L. australis, L.
      icterohaemorrhagiae and/or L. canicola was found in 16 normal dogs and only one
      hospitalised patient. Eight of these dogs had titres of > or = 1:800. Only one of
      them had been vaccinated shortly before sampling. These results suggest that many
      dogs from the surroundings of Bern, Switzerland have contact with various
      Leptospira interrogans serovars. In ten healthy dogs, the Leptospira titre was
      determined before and four weeks after vaccination with leptospiral antigen. Only
      two of the dogs showed a serologically measurable response to the antigen
      contained in the vaccine. In dogs MAT titers presumably do not reliably reflect
      the immune status against leptospiral infections.

PMID- 10596271
TI  - [The prevalence of salmonella, yersinia and mycobacteria in slaughtered pigs in
      Switzerland].
AB  - Clinically healthy food animals can be reservoirs for various foodborne
      pathogens. In general, such animals do not have lesions that are visible during
      meat inspection. Pigs are considered to be carriers of salmonella, yersinia and
      mycobacteria, but the risk of transmission to humans is difficult to assess. The
      aim of this study was to estimate the actual prevalence of the three above
      mentioned pathogens in the Swiss pig population and to comment on their
      significance. A total of 570 samples each of tonsils and mesenteric lymphnodes,
      were collected at two slaughterhouses from carcasses of apparently healthy pigs
      and analyzed for the presence of salmonella, yersinia and mycobacteria. The
      prevalence of salmonella (0.9%) was found to be lower than--while that of
      yersinia (8.1%) and mycobacteria (12.8%) about equal to--results reported from
      other European countries. Yersinia typing showed that serotype O:9 of Yersinia
      enterocolitica (2.5%) was 6 to 7 times more frequent than serotype O:3 (0.4%)-
      formerly the most frequent serotype. Mycobacterium avium was the most frequent
      isolate (90.7%) among the mycobacteria isolated. Although all three pathogens are
      present in the Swiss pig population, we consider the risk of transmission to
      humans via consumption of pork as low. Appropriate preventive measures and
      quality management should contribute to keep the risk under control.

PMID- 10596272
TI  - [Species diagnosis of a tissue using the polymerase chain reaction].
AB  - The unambiguous identification of a biological specimen can deliver invaluable
      evidence to solve criminal cases. In this case the origin of a heart had to be
      clarified. Using the polymerase chain reaction technique and species-specific
      primer pairs for two genes it was clearly shown that this tissue was not from a
      human but from a pig.

PMID- 10596274
TI  - [Infections of the central nervous system--no problem for the doctor?].

PMID- 10596273
TI  - [Borna disease in Switzerland and in the principality of Liechtenstein].
AB  - Borna disease (BD) is a rare immunopathological disorder of the central nervous
      system (CNS) caused by infection with Borna disease virus (BDV) and
      histologically characterized by mononuclear encephalomyelitis. BD primarily
      affects equines and sheep in well defined endemic areas of central Europe, but
      BDV infections have also been reported in other host species including humans, as
      well as in non endemic regions. In this paper recent data on the pathogenesis of
      BD are reviewed and the current situation in Switzerland and the Principality of
      Liechtenstein is summarized.

PMID- 10596275
TI  - [Meningitis (I)--differential diagnosis; aseptic and chronic meningitis].
AB  - Meningitis is the most common serious manifestation of infection of the central
      nervous system. Inflammatory involvement of the subarachnoid space with meningeal
      irritation leads to the classical triad of headache, fever, and meningism, and to
      a pleocytosis of the cerebrospinal fluid (CSF). Meningitis is clinically
      categorized into an acute and chronic disease based on the acuity of symptoms.
      Acute meningitis develops over hours to days, while in chronic meningitis
      symptoms evolve over days or even weeks. Aseptic meningitis, in which no
      bacterial pathogen can be isolated by routine cultures, can mimic bacterial
      meningitis, but the disease has a much more favorable prognosis. Many cases of
      aseptic meningitis are caused by viruses, primarily enteroviruses, but bacteria
      and noninfectious etiologies also cause meningitis with negative cultures.
      Symptoms of meningeal inflammation with CSF pleocytosis that persist for more
      than 4 weeks define the chronic meningitis syndrome. The diagnosis is based on
      the patient history, clinical evidence of meningitis, CSF examination, and often
      imaging studies. The differential diagnosis is broad, and the predominant CSF
      cell type can provide clues as to the underlying disease. Empiric therapy is
      primarily based on the age of the patient, with modifications if there are
      positive findings on CSF gram stain or if the patient presents with special risk
      factors. In patients with chronic meningitis, a definite diagnosis is often not
      available or delayed for days, in which case empiric therapy may have to be
      initiated. It is important to cover the treatable causes of meningitis, for which
      the outcome is poor if treatment is delayed.

PMID- 10596276
TI  - [Meningitis (II)--acute bacterial meningitis].
AB  - Acute meningitis is a medical emergency, particularly in patients with rapidly
      progressing disease, mental status changes or neurological deficits. The majority
      of cases of bacterial meningitis are caused by a limited number of species, i.e.
      Streptococcus pneumoniae, Neisseria meningitis, Listeria monocytogenes, group B
      Streptococci (Streptococcus agalactiae), Haemophilus influenzae and
      Enterobacteriaceae. Many other pathogens can occasionally cause bacterial
      meningitis, often under special clinical circumstances. Treatment of meningitis
      includes two main goals: Eradication of the infecting organism, and management of
      CNS and systemic complications. Empiric therapy should be initiated without
      delay, as the prognosis of the disease depends on the time when therapy is
      started. One or two blood cultures should be obtained before administering the
      first antibiotic. Empiric therapy is primarily based on the age of the patient,
      with modifications if there are positive findings on CSF gram stain or if the
      patient presents with special risk factors. It is safer to choose regimens with
      broad coverage, as they can usually be modified within 24-48 hours, when
      antibiotic sensitivities of the infecting organism become available. Adjunctive
      therapy with dexamethasone is also administered in severely ill patients
      concomitantly with the first antibiotic dose. In patients who are clinically
      stable and are unlikely to be adversely affected if antibiotics are not
      administered immediately, including those with suspected viral or chronic
      meningitis, a lumbar puncture represents the first step, unless there is clinical
      suspicion of an intracerebral mass lesion. Findings in the CSF and on CT scan, if
      performed, will guide the further diagnostic work-up and therapy in all patients.

PMID- 10596277
TI  - [Viral encephalitis].
AB  - Viral encephalitis presents with fever, headache, focal and generalized
      neurologic symptoms and signs, seizures, and CSF pleocytosis. Herpes simplex
      Virus (HSV) 1 and arboviruses (flaviruses) are the most common causes of
      encephalitis in Switzerland. The initial work-up in a suspected encephalitis
      includes CSF analysis, EEG, and brain CT or MRI. The identification of the
      responsible agent usually occurs with polymerase chain reaction or serology. The
      differential diagnosis to other infectious and non-infectious acute CNS-disorders
      may initially be arduous. A specific treatment is possible only in encephalitis
      caused by viruses of the herpes group. Active immunization should be considered
      in subjects at high risk for tick-borne encephalitis. With early treatment the
      prognosis may be satisfactory also in HSV encephalitis.

PMID- 10596278
TI  - [Childhood meningitis].
AB  - Early and reliable diagnosis, prompt and adequate treatment, and intensive
      monitoring are the mainstays for normal outcome of patients with meningitis.
      Major progress has been achieved during the last 5-10 years. The successful
      implementation of the active immunization against Haemophilus influenzae type b
      has dramatically changed the epidemiology of bacterial meningitis: total
      incidence has been cut in half and approximately half of the cases now occur in
      adults. Important new insights into the pathogenesis and the pathophysiology have
      been gained resulting in specific supportive and antiinflammatory measures.
      Emergence of antibiotic-resistance in meningitis pathogens have lead to modified
      antimicrobial therapies. Knowledge about factors associated with a poor prognosis
      is important in selecting patients for more intensive surveillance and treatment,
      and in identifying candidates for new preventive or therapeutic strategies.

PMID- 10596279
TI  - [Diagnosis and treatment of brain abscesses].
AB  - The etiologic pathogens of brain abscesses vary depending on the underlying
      disease. Aerobic and anaerobic bacteria are frequently involved simultaneously.
      In most cases, the clinical course is subacute. C-reactive protein is the most
      sensitive inflammatory parameter in the blood. It is elevated in 80 to 90% of all
      cases. The diagnosis is made by cranial computer tomography without and with
      contrast enhancement. The rapid culture of pus from the abscess cavity is crucial
      for the identification of the pathogen. Antibiotic therapy alone is indicated 1.
      in the presence of multiple, small and/or deep-seated abscesses or 2. when the
      general condition of the patient does not allow surgery at an acceptable risk or
      3. in early cerebritis without capsule formation. Frequently used surgical
      procedures are abscess aspiration (usually by stereotaxic surgery), open
      craniotomy and excision of the abscess with the capsule, and open evacuation of
      the abscess cavity. For empirical treatment the combination of cefotaxime (3 x 2
      4 g/d i.v.) plus metronidazol (3-4 x 0.5 g/d i.v.) is preferred. Corticosteroids
      are indicated in the presence of a space-occupying effect and imminent brain
      herniation, or of multiple abscesses and abscesses in critical brain regions such
      as in the cerebellum.

PMID- 10596280
TI  - [Diagnosis and therapy of Lyme neuroborreliosis].
AB  - Lyme-Borreliosis which in Europe is transmitted by Ixodes ricinus presents in
      three stages with 1st a localised infection (erythema chronicum migrans), 2nd a
      disseminated infection (e.g., meningoradiculitis), and 3rd a persistent chronic
      infection (e.g., encephalomyelitis, cerebral vasculitis), whereby not all stages
      invariably become clinically apparent. The diagnosis is based on the typical
      clinical presentation, the lumbar puncture (lymphocytic pleocytosis), and
      serological test from the blood as well as from the CSF (intrathecal antibody
      production!). The frequency of positive serological results depends on the
      duration and the type of the disease. In stage 1 20-50% of the patients show
      increased IgM-antibodies, in stage 2 70-90% show increased IgM- and or IgG
      antibodies, and in stage 3 almost 100% of the patients have positive IgG
      antibodies. The Lyme-Neuroborreliosis usually is treated with Ceftriaxon 2 g/d
      intravenously over 14 (Stage 2) or 21 (Stage 3) days.

PMID- 10596281
TI  - [CNS-infections in HIV patients].
AB  - Neurological manifestations are frequent in patients with AIDS. Many neurological
      disorders have disappeared with the advent of highly active antiretroviral
      combination therapies. We can speculate that some of these disorders may reappear
      in patients under antiretroviral therapy, possibly with different clinical
      manifestations and at a different stage during HIV-infection. We discuss the
      appearance of the most common neurological complications in relation to the CD4
      cell count during HIV-infection. The most frequent causes of seizures and
      headache in HIV-infected patients are shown. We recommend a systematic diagnostic
      work-up in patients with headache, starting from 3 typical clinical situations:
      focal signs, convulsions or altered mental status; no focal signs, CD4-cells >
      200 microliters, meningism; fever and/or meningism, no focal signs. The analysis
      of the cerebrospinal fluid by polymerase chain reaction is now a well established
      diagnostic method for investigating the most common CNS-infections in AIDS
      patients. Neuroimaging (by MRI or CT-scan) is an additional, useful
      investigation. Cerebral toxoplasmosis, cryptococcosis, PML, encephalitis due to
      herpes-viruses and neurosyphilis are discussed.

PMID- 10596282
TI  - [Human prion diseases].
AB  - The interest in prion diseases, particularly the Creutzfeldt-Jakob type (CJD),
      rose dramatically in the last years for two reasons. 1) The general public wants
      to know whether eating beef may cause CJD. Discovering the new variant
      Creutzfeldt-Jakob disease (nvCJD) and experimental evidence that nvCJD and bovine
      spongiforme encephalopathy (BSE) are caused by the same prion strain make this
      idea probable. 2) Infectiologists and Neuroscientists recognise a model disease
      for a new infectious principle in that the same disease may occur as being
      inherited as well as transmitted. Additionally, it might allow new insights into
      the possible aetiologies of neurodegenerative disease.

PMID- 10596283
TI  - Absence of cerebrospinal fluid abnormalities and spinal cord lesions after
      iotrolan cervical myelography in normal cats: an open placebo-controlled study.
AB  - Iotrolan (Isovist 300, Schering AG) at a volume of 0.5 ml/kg B.W. was injected
      into the cerebellomedullary cistern of 12 cats (Isovist group); the same volume
      of normal saline was injected in four other cats (control group). Two ml of CSF
      was collected from each anaesthetized cat by cisternal tap immediately before,
      and 7 and 15 days after, injection. The physical characteristics, specific
      gravity, total cell count and total protein concentration of each CSF sample were
      recorded. The cats were euthanized on day 15 immediately after CSF samples and
      spinal cord specimens had been obtained. Spinal cord histopathology was examined
      with the aid of light and transmission electron microscopy. The physical
      characteristics of all the CSF samples were within the reference range. No
      significant differences were found for CSF specific gravity, total cell count and
      total protein concentration between the pre-injection samples and those collected
      7 and 15 days post-injection in both groups; no spinal cord lesions were detected
      in histopathology.

PMID- 10596284
TI  - Flow cytometry analysis of milk and peripheral blood cells from goats during
      lactation.
AB  - Cells from goat's milk and peripheral blood taken during the lactation period
      were analysed by flow cytometry. The investigated cells were populations of
      leucocytes, lymphocyte subpopulations (T, T-helper, T-cytotoxic, B, WC1-N2) and
      all MHC class II positive cells. Labelling of cells was performed on whole blood
      and milk cell suspensions. Statistically significant differences were found
      between percentages of B and WC1-N2 lymphocytes and MHC II positive cells from
      peripheral blood during the lactation period and all of examined milk cells
      during the same time.

PMID- 10596285
TI  - No expression of angiotensin II receptors and angiotensin-converting enzyme in
      myxomatous canine mitral valve leaflets. An autoradiographic study.
AB  - The renin-angiotensin system, including angiotensin (Ang) II and angiotensin
      converting enzyme (ACE), plays an important role in cardiac fibrous tissue
      formation. Since changes in valvular collagen are a central part of myxomatous
      mitral valve disease in the dog, we speculated that Ang II and ACE might play a
      role in the pathogenesis of this disease. In 10 mitral valves, five with and five
      without clear myxomatous changes, the presence and distribution of Ang II
      receptors and ACE was examined autoradiographically, using 125I-Ang II and 125I
      lisinopril, respectively. At postmortem examination, diseased valves were taken
      from old dogs, control valves from young adult dogs. No significant level of Ang
      II and lisinopril binding was found in normal as well as diseased valve leaflets.
      Equally low, insignificant levels of 125I-Ang II binding were found in the
      myocardium of dogs with and without valvular disease. No significant level of
      myocardial 125I-lisinopril binding was found. The lack of autoradiographic
      evidence of Ang II receptors and ACE in normal and diseased canine mitral valve
      leaflets suggests that the renin-angiotensin system does not play a major role in
      the pathogenesis of the valvular changes.

PMID- 10596286
TI  - Response of one-humped camel (Camelus dromedarius) to intravenous glucagon
      injection and to infusion of glucose and volatile fatty acids, and the kinetics
      of glucagon disappearance from the blood.
AB  - The effects of glucagon injection and infusion of glucose and volatile fatty
      acids were studied in one-humped camels. Twenty adult male camels were divided
      into four equal groups. The first group was infused with physiological saline and
      served as a control. The second group was injected with a single dose of
      glucagon, the third group was infused with glucose (50%) in sterile saline, and
      the fourth group was infused with a volatile fatty acid (VFA) mixture. In the
      first, third and fourth groups, sampling was performed before the beginning of
      infusions (control time), and at 15, 30, 60 and 120 min post-infusion. Plasma
      glucagon concentrations were monitored in the second group at 5, 10, 15, 20, 30,
      45, 90, 105 and 120 min after injection. For glucagon injection, glucose
      concentration peaked at 15 min post-injection, and tended to decrease thereafter.
      Plasma glucose concentrations showed significant rises above the basal value at
      all times after glucose infusion. VFA infusion had no apparent effect on plasma
      glucose concentration. After injection of glucagon, the plasma lactate
      concentration dropped significantly at 15 and 30 min, then increased gradually
      until it reached the original concentration of lactate at 120 min. However,
      glucose infusion elevated the plasma lactate concentration only at the end of the
      infusion period. A decrease in plasma lactate was observed at 60 min after VFA
      infusion. The present investigation provides evidence that the glucagon level in
      camels is higher than that in other ruminants and in man, and suggests that this
      is a probable species specificity, which would explain the higher level of
      glucose in the blood of camels than in that of other ruminants. The disappearance
      curve of injected glucagon had, as in other ruminants, an exponential two
      compartment function. The hormone was rapidly distributed and was eliminated with
      a high rate of clearance.

PMID- 10596287
TI  - Fractures secondary to nutritional bone disease in dogs: a review of 38 cases.
AB  - The pattern of bone fractures secondary to nutritional bone disease in 38 dogs
      was analysed using a radiographic survey. The majority of fractures were either
      caused by a fall (28.95%) or showed no history of direct trauma (31.58%).
      Mongrels were more commonly affected by pathological fractures, followed by
      Dobermanns and German Shepherds. Significantly more (P < 0.05) fractures were
      found in dogs aged less than 6 months (64.71%). The incidence of such fractures
      was significantly higher in males than in females (M:F = 2.70:1.00). General
      radiological signs included a generalized decrease in cortical density, thinning
      of cortices and widening of metaphyses/epiphyses in most of the animals.
      Fractures were found significantly more frequently (P < 0.01) in the femur
      (81.58%) than in any other bone. Of the different types of fracture, complete
      oblique and incomplete fractures were most common.

PMID- 10596288
TI  - Hind limb skeletal lesions in 12-month-old bulls of beef breeds.
AB  - In the present study, right hind limb bones from 46 12-month-old bulls with no
      clinical signs were examined to identify and describe lesions that could
      predispose the stifle and tarsal joints to osteoarthritis. The bulls came from a
      performance testing station and were slaughtered due to a low index at the end of
      the testing period 1996-97. Differences in frequency of lesions among breeds as
      well as the relationship between lesions and growth rate were evaluated. Forty
      five (97.8%) of the 46 bulls had lesions in the joints and/or growth plates.
      Prevalence of lesions was 100% in the Charolais (22/22), the Hereford (8/8), and
      the Limousin (4/4) breeds, and 85.7% (6/7) in the Simmental breed. The stifle was
      affected in 37, the tarsus in 33, and the growth plates in 34, of the 46 bulls.
      Lesions found in the stifle joint were: osteochondrosis of the articular
      epiphysical cartilage complex (AECC) (25), subchondral bone cyst of the distal
      femur (1), fragmentation of the medial intercondylar eminence of the tibia (20),
      cleft in the distal part of the patellar groove (28), and an avulsion fracture of
      the lateral condyle together with a partial tear of the cranial cruciate ligament
      (1). Lesions found in the tarsal joint were: osteochondrosis of the AECC (23),
      ulcerative lesions of the articular cartilage of the talus (25), and fracture of
      the medial malleolus (4). Twenty-eight bulls had lesions of osteochondrosis at
      the AECC and 37 at the growth plates. When osteochondrosis at the AECC and
      thickening of the growth plates were combined, 44 of the 46 bulls had at least
      one lesion at the AECC and/or the growth plate. Prevalence of bulls with at least
      one lesion was similar between breeds, but the number of lesions per bull was
      significantly higher in Charolais followed by Simmental, Hereford, and Limousin.
      Number of lesions per bull was significantly correlated with daily weight gain,
      carcase weight, and the width of the proximal tibial epiphysis. Lesions were
      statistically independent, indicating that local biomechanical factors within the
      joints are important in the pathogenesis. In conclusion, we suggest that the high
      incidence of hind limb osteoarthritis reported in the Swedish beef bull
      population can be explained by the high prevalence of skeletal lesions found in
      the present material. The lesions appeared to be related to high growth rate and
      to the breed.

PMID- 10596289
TI  - Acetylcholine-induced contractions in the porcine internal mammary artery:
      possible role of muscarinic receptors.
AB  - The effect of acetylcholine on the isolated, non-precontracted, porcine internal
      mammary artery (IMA) was investigated. Acetylcholine induced concentration
      dependent contractions of non-precontracted IMA rings with denuded endothelium
      (pEC50 = 5.80 +/- 0.04) and was without effect on arterial segments with intact
      endothelium. The muscarinic receptor antagonists atropine, pirenzepine,
      methoctramine and p-fluoro-hexahydro-sila-diphenidol (pFHHSiD) antagonized the
      response to acetylcholine. The constrained pA2 values were 10.14, 7.74, 7.34 and
      10.5, respectively. It is concluded that acetylcholine induces concentration
      dependent contractions of porcine internal mammary artery rings on basal tone and
      that this contractile effect is probably due to direct cholinergic stimulation of
      smooth muscle cells, maybe including activation of muscarinic M1 receptors.

PMID- 10596290
TI  - [View into the heart without catheter?].

PMID- 10596291
TI  - [Clinical value of magnetic resonance tomography in imaging coronary stenoses. A
      comparison with coronary angiography and myocardial scintigraphy].
AB  - BACKGROUND AND OBJECTIVE: The development of ultra-rapid gradient-echo sequence
      magnetic resonance imaging (MRI) makes it possible to visualize coronary
      arteries. But the clinical value of coronary artery MRI (MRCA) still needs to be
      established. It was the aim of this study to determine whether MRCA can
      demonstrate proximal parts of the coronary arteries and visualize
      haemodynamically relevant stenoses. PATIENTS AND METHODS: MRCA was performed,
      using segmented 2D sequences and a navigator pulse, in 29 patients (22 men, seven
      women, mean age 60 +/- 10 years) in whom coronary heart disease (CHD) was
      suspected or who, with proven CHD (> or = 50% stenosis) further treatment was to
      be established. Exercise myocardial scintigraphy with single proton emission
      tomography (SPECT) was additionally performed in 20 of the patients. RESULTS:
      Seven of 87 coronary arteries (8%) could not be demonstrated because the
      patients' claustrophobia necessitated premature termination of the investigation:
      these vessels were excluded from the final analysis. The mean length of the
      visualized coronary arteries was 12 +/- 4 mm for the main stem (LM), 36 +/- 14 mm
      for the left interventricular branch (LAD), 18 +/- 12 mm for the circumflex
      branch (CX) and 67 +/- 23 mm for the right coronary artery (RCA). Of 37 stenoses
      demonstrated by coronary angiography 29 were also visualized by MRCA: 13 of 18
      LAD stenoses, two of three CX stenoses and 14 of 16 RCA stenoses. Mean
      sensitivity of MRCA was 78%, mean specificity 86%. In patients who had undergone
      exercise SPECT, coronary angiography demonstrated 26 stenoses, of which 16 (six
      LAD, two CX and eight RCA stenoses) were haemodynamically significant. Of these
      16 stenoses MRCA demonstrated 13, but three stenoses (one RCA and two LAD
      stenoses) were not visualized, because the stenoses were distal to the
      demonstrated segments. CONCLUSION: MRCA can visualize moderately severe stenoses,
      especially of the proximal coronary arterial segments. This method represents an
      new approach to noninvasive diagnosis of CHD, but additional technical
      improvements will have to be made.

PMID- 10596292
TI  - [Initial manifestation of primary intestinal lymphangiectasis as acute abdomen].
AB  - HISTORY: A 32-year-old man had ten years previously undergone several
      laparotomies for recurrent ileus of the small intestine. They revealed severe
      intestinal oedema and histology showed hyperplasia of the lymphatic system but
      the aetiology was unclear. After a 10-year interval free of symptoms he presented
      with marked hypoproteinaemic oedema and exudative enteropathy the cause of which
      was to be clarified by exploratory laparotomy with excision of lymph nodes and a
      small section of small intestine. INVESTIGATIONS: Histology revealed intestinal
      lymphangiectasis with partly hyperplastic lymphoid tissue. Lymphangiography
      demonstrated several lymph nodes in the region of the aortic bifurcation and
      renal vessels with a central filling defect. It is thought likely that
      obstruction to lymphatic flow in this region resulted in oedema of the intestinal
      wall which caused the recurrent episodes of ileus. DIAGNOSIS: Retrospectively it
      is assumed that primary intestinal lymphangiectasis was responsible for the
      initial manifestation of an acute abdomen. For treatment of hypoproteiaemia with
      human albuminea prot system was implanted. The course was complicated by
      recurrent inflammation and thrombosis of the port catheter. Because of immune
      deficiency risk of carcinoma is high in primary intestinal lymphangiectasis.
      CONCLUSION: Primary intestinal lymphangiectasis, even though a rare condition,
      should be considered in the differential diagnosis of otherwise unclear acute
      abdomen.

PMID- 10596293
TI  - [Diagnosis and therapy of attention deficit-/hyperkinetic disorder in adulthood].

PMID- 10596294
TI  - [Antineutrophil cytoplasmatic antibodies and their diagnostic significance as
      serum markers].

PMID- 10596295
TI  - [Serum therapy--Emil von Behring and the beginnings of research in immunity].

PMID- 10596296
TI  - [Added 10% levy for inpatient care for university teachers. Decision of the
      Schleswig-Holstein Superior Court 27 July 1999].

PMID- 10596297
TI  - [Does budesonide affect growth?].

PMID- 10596298
TI  - [Recognizing, properly reading and understanding scientific data].

PMID- 10596299
TI  - Evaluation of the hazards of industrial exposure to tricresyl phosphate: a review
      and interpretation of the literature.
AB  - Commercial tricresyl phosphate (TCP) is a heterogeneous mixture of isomers and
      aryl phosphate congeners, known for many years to induce delayed neurotoxicity
      (OPIDN) in humans and experimental animals. In the past the isomer tri-o-cresyl
      phosphate (TOCP) was thought to be the component primarily responsible for OPIDN.
      It is now clear that other constituents, particularly the mono-o-esters, are not
      only neurotoxic but also may be more potent than pure TOCP. As a generality, the
      toxicity potential of a particular brand of TCP is related to its content of o
      phenolic residues, whereby the maximal potential is reached when o-phenolics are
      33% of the mix. Historically, human TCP toxicity has resulted from inadvertent or
      intentional contamination of foodstuffs or beverages. TCP products with high
      ortho-residues synthesized by older manufacturing methods were involved in most
      of these cases, and were likely much more neurotoxic milligram for milligram than
      TOCP. Because of the great variability of TCP products, there are no conventional
      workplace exposure standards. Based upon data from the hen and cat, estimated
      human safe exposure rates for pure TOCP are estimated to be 2.5 mg/kg for a
      single dose, and 0.13 mg/kg/d for repetitive exposures. These levels may also be
      applied to TCP when o-methyl-phenyl, o-ethyl-phenyl, and o-xylenyl components are
      appropriately limited during manufacture such that the TCP product is less
      neurotoxic than TOCP. There have been relatively few reports of toxicity
      associated with the manufacture or use of TCP in commerce and industry. Low vapor
      pressures of the constituents preclude the presence of significant quantities of
      TCP vapor in the atmosphere. A lubricant or other formulation containing TCP may
      appear in the air as a mist. By these criteria the U.S. Petroleum Oil Mist
      exposure standard is protective when the formulation contains 4% or less of low
      ortho-TCP. Exposure calculations indicate that estimated safe levels are not
      likely to be exceeded in the well-regulated workplace. If it is of short
      duration, even a heavy fog of oil particulate may not exceed the 8-h-average
      inhalation exposure standard. Modern manufacturing practices tend to minimize the
      ortho content and thus the toxicity of TCP. Because individual TCP brands and
      synthesis methods vary, manufacturers should be consulted concerning the
      properties of their individual products.

PMID- 10596300
TI  - Analysis of chlorpyrifos exposure and human health: expert panel report.
AB  - This report summarizes the deliberations of an eight-member panel of scientists
      convened by Dow AgroSciences in cooperation with the U.S. Environmental
      Protection Agency (EPA). The panel was charged with evaluating the scientific
      literature on the health effects potentially associated with exposure to the
      insecticide chlorpyrifos. Specifically, the panel was asked to (1) evaluate human
      experience data available and address the adequacy of the available current
      literature; (2) develop a list of recommendations for epidemiology studies,
      including appropriate endpoints and study populations, and strengths and
      weaknesses of each approach; and (3) draft a report to summarize its
      recommendations. The panel assessed the quality of the existing epidemiologic
      literature on chlorpyrifos and specific outcomes such as neuropathy (including
      organophosphate induced delayed neurotoxicity), behavior (cognition and affect),
      immunologic, and multiple complaints (also referred to as multiple chemical
      sensitivities). The majority of panel members (five members) agreed that the
      literature reviewed provided little or no scientific evidence that chlorpyrifos
      exposure causes harm to human health other than its known cholinergic effects
      associated with acute poisoning. Those panel members voting in the minority
      (three members) agreed that the studies reviewed provided inadequate evidence to
      preclude the possibility of adverse effects to human health from chlorpyrifos
      exposure at levels associated with its manufacture or professional application.
      Those voting in the minority suggested further investigation of cohort(s) of
      workers engaged in either the manufacture or the professional application of
      chlorpyrifos, or both. Compared to the general population, these groups have
      relatively high levels of exposure to chlorpyrifos. The primary health outcomes
      recommended for study were cognitive and affective disorders, with consideration
      of the assessment of peripheral neuropathy also suggested for at least a subset
      of the cohort.

PMID- 10596302
TI  - Pacing in cardiomyopathy.
AB  - Permanent cardiac pacing is an established treatment for the prevention of
      syncope or sudden death in patients with heart block or sinus node disease.
      Recent observations underscore the use of pacing in patients with various forms
      of cardiomyopathy, i.e. hypertrophic, dilated and tachycardia-induced
      cardiomyopathy. The evidence favouring the use of pacing in patients with
      cardiomyopathy is mainly derived from retrospective and uncontrolled
      investigations and the data from the scarce randomized investigations are rather
      disappointing. Therefore, the indications for pacing remain controversial.

PMID- 10596301
TI  - Derivation of wildlife values for mercury.
AB  - A procedure has been developed to estimate surface water concentrations of
      toxicants ("wildlife values") that will protect the viability of wildlife
      populations associated with aquatic resources. This procedure was designed
      primarily to protect piscivorous birds and mammals from compounds that
      bioaccumulate in fish and was used in the Great Lakes Water Quality Initiative
      (GLI) to calculate wildlife values (WV) for mercury, DDT/DDE, total
      polychlorinated biphenyls (PCBs), and 2,3,7,8-tetrachlorodibenzodioxin (TCDD).
      Published in 1995, and expressed as total mercury in unfiltered water, the final
      wildlife value (WVf) for mercury derived in the GLI was 1300 pg Hg/L. This value
      was selected as the wildlife criterion (WC) for mercury in the Great Lakes basin.
      A second WVf for mercury was derived in 1997 as part of a Congressionally
      mandated report on airborne mercury emissions. These calculations were based upon
      mercury speciation data that were largely unavailable when the GLI was developed.
      Important features of the WVf in the Report to Congress include its calculation
      on a dissolved methylmercury basis and a reliance on field data to estimate fish
      bioaccumulation factors. Calculated as methylmercury in filtered water, the WVf
      derived in the report is 50 pg Hg/L (equivalent to 54 pg MeHg/L). A comparison of
      WV in the GLI and the Report to Congress requires that average values be
      specified for mercury speciation in natural systems. Based on this information,
      the WVf given in the report corresponds to a value of 910 pg Hg/L, as total
      mercury in unfiltered water, or about 70% of the WVf derived in the GLI. In this
      article we describe the algorithm used to derive WV in the GLI and the Report to
      Congress and review its application to mercury. Scientific uncertainties in
      deriving WV, particularly as they apply to mercury, are critically examined.

PMID- 10596303
TI  - Internet in cardiology: a new toy or a new tool?

PMID- 10596304
TI  - The prevalence of coronary artery disease in an urban population in Isfahan,
      Iran.
AB  - OBJECTIVE: Cardiovascular diseases, especially coronary artery disease (CAD), are
      responsible for the highest mortality rate in Iran. This study was conducted to
      determine the prevalence of CAD in an urban sample in Isfahan by the Minnesota
      code of a 12-lead resting electrocardiogram (ECG), the Rose questionnaire on
      chest pain and a self-reported previous medical history. METHODS AND RESULTS:
      Among the target sample of 6,470 men and women aged 35-79 years who were randomly
      selected from 80 random clusters in Isfahan, 5,773 subjects (about 90%) have
      participated. The WHO (Rose) questionnaires (Q) on chest pain were completed for
      all participants and 12-lead ECGs were taken. The overall prevalence of CAD based
      on the Rose Q and/or ECG was 19.4% (95% CI 18.4% to 20.4%) which was
      significantly higher among women 21.9% (95% CI 20.5% to 23.3%) than men 16.0%
      (95% CI 14.5% to 17.5%) (p < 0.05). The prevalence of CAD increased with age in
      both sexes. The prevalence of definite and possible angina based on the
      questionnaire was higher among women compared to men (p < 0.05), also a greater
      prevalence of ECG-based possible ischaemia was observed among woman than men
      (12.3% vs. 7.5%) (p < 0.05). However, definite and possible MI and definite
      ischaemia based on ECG abnormalities were higher among men than women (p < 0.05).
      The total prevalence of symptomatic CAD was 9.3% and about 22% of those with
      symptoms of CAD on Q have some evidence on ECG. The findings also showed that CAD
      is more common among people with less education, lower income and the unemployed
      (p < 0.05). CONCLUSION: These findings indicate that there is a high prevalence
      of CAD among the Iranian population which need more programmes of health
      promotion and lifestyle changes and further studies to assess the used
      epidemiological methods for estimating CAD prevalence, especially among women.

PMID- 10596305
TI  - Combined protocols for myocardial perfusion imaging in patients with
      hypertension.
AB  - OBJECTIVE: Patients diagnosed previously with hypertension submitted to exercise
      testing for myocardial scintigraphy often respond with excessive elevation of the
      blood pressure, even when baseline blood pressure is normal, resulting in
      interruption of the test or false positive results for coronary artery disease.
      The aim of this study was to evaluate the haemodynamic changes and the safety of
      the combined examination protocols of dipyridamole plus handgrip exercise and of
      dipyridamole plus symptom-limited exercise testing on a treadmill in patients
      with hypertension. METHODS AND RESULTS: We performed scintigraphic myocardial
      single photon emission computed tomography in 240 patients with hypertension as
      follows: in 27 patients who were administered dipyridamole alone, in 126 patients
      who were administered dipyridamole and were also submitted to isometric handgrip
      exercise and in 87 patients who were administered dipyridamole and were also
      submitted to treadmill, symptom-limited exercise (modified Bruce protocol). Mean
      systolic blood pressure, mean diastolic blood pressure and heart rate did not
      rise excessively in patients submitted to exercise testing (192 +/- 18 mm Hg, 106
      +/- 14 mm Hg and 111 +/- 21 bpm for the dipyridamole plus handgrip group and 180
      +/- 28 mm Hg, 104 +/- 10 mm Hg and 149 +/- 19 bpm for the dipyridamole plus
      treadmill group, respectively), with two patients from each exercise group
      presenting a maximum systolic blood pressure higher than 220 mm Hg and no
      subsequent major cardiac complications (such as death, myocardial infarction,
      unstable angina or life-threatening arrhythmia). Moreover, patients in these
      exercise groups experienced fewer non-cardiac side effects than with dipyridamole
      alone, while attaining a good level of exercise stress. CONCLUSIONS: Both
      combined dipyridamole and exercise protocols for scintigraphic myocardial single
      photon emission computed tomography in patients with hypertension are safe and
      increase heart rate without an excessive elevation in blood pressure.
      Consequently, they can be recommended for clinical use. Dipyridamole combined
      with treadmill, symptom-limited exercise would be the first choice, with
      dipyridamole and isometric handgrip exercise reserved for patients with physical
      handicaps.

PMID- 10596306
TI  - Selenium levels and glutathione peroxidase activities in patients with acute
      myocardial infarction.
AB  - OBJECTIVE: Selenium (Se) is part of the enzyme glutathione peroxidase (GSH-Px)
      that plays an important role in the antioxidant defence of the body, including
      the myocardium, against the deleterious actions of free radicals and lipid
      peroxides. In order to evaluate the Se status and the GSH-Px activity in
      ischaemic heart disease, plasma, erythrocyte and urinary Se concentrations
      together with plasma and erythrocyte GSH-Px activities were determined in 27
      patients diagnosed as acute myocardial infarction (AMI). The control group
      consisted of 24 age-matched healthy individuals. METHODS AND RESULTS: Fasting
      blood and urine samples were collected within 24 hours after the onset of chest
      pain. Mean plasma, erythrocyte and urine Se concentrations were significantly
      lower in the patient groups (63.7 +/- 12 micrograms/l, 0.48 +/- 0.04 microgram/g
      Hb and 49.6 +/- 27.7 micrograms/g creatinine, respectively), compared to controls
      (82.2 +/- 14.6 micrograms/l, 0.51 +/- 0.03 microgram/g Hb and 93.4 +/- 62.6
      micrograms/g creatinine, p < 0.001, p < 0.02 and p < 0.003, respectively). No
      statistically significant difference was found between mean plasma GSH-Px
      activity in patients (0.36 +/- 0.1 U/ml) and controls (0.35 +/- 0.09 U/ml),
      whereas erythrocyte GSH-Px activity was higher in patients (48.1 +/- 10.2 U/g Hb)
      than in the controls (35.3 +/- 9.1 U/g Hb, p < 0.001). CONCLUSION: Our findings
      confirm the previous studies and demonstrate that patients suffering from AMI
      exhibit lower plasma, erythrocyte and urinary Se than the controls. Since the
      erythrocyte Se level represents a measure of the Se status over a period of
      several weeks due to its long biological half-life, low Se levels observed in the
      patient group might have been present before the acute event, thereby suggesting
      an aetiologic relevance. The presence of increased erythrocyte GSH-Px activity in
      these patients may be interpreted as an antioxidant defence against the chronic
      oxidant stress present before the AMI, presumably due to the process of coronary
      atherosclerosis.

PMID- 10596308
TI  - Ventricular fibrillation secondary to ergotamine in a healthy young woman.
AB  - A 34-year-old woman collapsed secondary to ventricular fibrillation 3 hours
      following the ingestion of ergotamine tartrate for migraine. She underwent
      defibrillation and recovered rapidly without any subsequent consequences. The
      mechanism of action and the side effects of ergotamine and other antimigraine
      drugs are discussed. We hypothesize that a coronary spasm induced by ergotamine
      could be the aetiologic factor leading to ischaemic ventricular fibrillation.

PMID- 10596307
TI  - Pulse wave velocity as an index of arterial stiffness: a comparison between newly
      diagnosed (untreated) hypertensive and normotensive middle-aged Malay men and its
      relationship with fasting insulin.
AB  - BACKGROUND: Arterial stiffness, an aging process which is accelerated by
      hypertension, is emerging as a useful index of vascular health. There are
      evidences to suggest that hyperinsulinaemia may be an independent risk factor for
      coronary artery disease, besides its possible pathogenic role in essential
      hypertension. The main objectives of this study were to compare arterial
      stiffness between untreated hypertensives and normotensives and to investigate
      the relationship between fasting serum insulin and arterial stiffness. METHODS: A
      cross-sectional observational study was designed. Forty normotensive (median age
      47 +/- 6 yrs.) and twenty untreated hypertensive Malay men (median age 50 +/- 7
      yrs.) without clinical evidence of cardiovascular complications were selected.
      Pulse wave velocity measured using the automated Complior machine was used as an
      index of arterial stiffness. Other measurements obtained were blood pressure,
      body mass index, fasting insulin, cholesterol, HDL-cholesterol, LDL-cholesterol,
      triglycerides, glucose and creatinine level. RESULTS: The blood pressure and
      pulse wave velocity (PWV) were significantly higher in the hypertensives compared
      to the normotensives (blood pressure 169/100 mm Hg +/- 14/7 vs. 120/80 mm Hg +/-
      10/4, p < 0.001; PWV 11.69 m/s +/- 1.12 vs. 8.83 m/s +/- 1.35, p < 0.001). Other
      variables such as body mass index, fasting insulin, cholesterol, HDL-cholesterol,
      LDL-cholesterol, triglycerides and haematocrit were comparable among the two
      groups. Within each group, there was a significant positive correlation between
      pulse wave velocity and systolic blood pressure (r = 0.76, p < 0.001 in
      normotensives; r = 0.73, p < 0.001 in hypertensives) and mean arterial pressure
      (r = 0.74, p < 0.001 in normotensives; r = 0.73, p < 0.001 in hypertensives). No
      correlation was noted between pulse wave velocity and diastolic blood pressure,
      age, body mass index, fasting insulin level, cholesterol, HDL-cholesterol, LDL
      cholesterol or triglyceride levels. CONCLUSION: Arterial stiffness as determined
      by PWV is increased in newly diagnosed untreated hypertensive subjects even
      before clinically evident cardiovascular disease. However, arterial stiffness is
      not correlated with the fasting insulin level in normotensives and newly
      diagnosed hypertensives.

PMID- 10596309
TI  - Pulmonary vein atresia with Shone's anomaly in an infant: a case report.
AB  - We report a case of individual pulmonary vein atresia associated with multiple
      levels of left heart obstruction, including aortic coarctation, valvular aortic
      stenosis, and parachute mitral valves with stenosis. The diagnosis of pulmonary
      vein obstruction is likely to be missed in patients who also have other left
      heart obstructive diseases, since the latter usually dominates the clinical
      presentation. We diagnosed the existence of individual pulmonary vein atresia
      preoperatively via cardiac catheterization. The pulmonary artery angiograms
      revealed back and forth motion of the dye with no visualization of either a
      capillary or venous phase on the lesion side. The pulmonary capillary wedge
      pressure was unevenly elevated and highest on the lesion side. The results were
      later confirmed by operation and autopsy. Thus, selective pulmonary artery
      catheterization and angiography remains a good diagnostic tool to rule out the
      existence of pulmonary vein obstruction in cases which have multiple levels of
      left heart obstruction.

PMID- 10596310
TI  - U wave alternans in severe ischaemia.
AB  - A patient with unstable angina and known heart failure, and marked U wave
      alternans on the electrocardiogram is reported. Alternans of the U wave with no
      change in the QRS complex is extremely rare. The relevant literature is reviewed.

PMID- 10596311
TI  - Surgical aspects of gastro-esophageal reflux disease--indication for surgery. An
      update.
AB  - Gastro-esophageal reflux disease is regarded as the single most common foregut
      disorder mainly in Western countries. The pathophysiological background of the
      disease is multifactorial. The primary aim of the management of gastro-esophageal
      reflux disease is relieving heartburn and healing esophagitis. The therapeutic
      objectives are alleviating symptoms, preventing complications and avoiding
      recurrence. Besides the effective medical treatment nowadays we possess the
      minimal invasive anti-reflux surgery which gives comparable, even better results
      than medical therapy does, in cases of patients who are suitable for anti-reflux
      surgery. The key question is the appropriate patient selection. In order to
      achieve the most adequate patient selection, diagnostic tools like endoscopy,
      radiotherapy, esophageal body and sphincter manometry, 24-hour esophageal pH
      monitoring and occasionally 24-hour bile exposure monitoring and gastric emptying
      studies are mandatory to carry out preoperatively. On the basis of the results of
      these tests the tailored concept of anti-reflux surgery can be applied. The
      importance of experienced surgeon should be pointed out, too.

PMID- 10596312
TI  - Treating morbid obesity with laparoscopically placed, adjustable gastric band.
AB  - The authors present their first experiences on the laparoscopically placed,
      adjustable gastric band treatment of morbid obesity. Treating of the morbid
      obesity in a surgical way, this particular method is widely accepted as the less
      invasive and most modern procedure, with the benefit of adjustability of the
      gastric band. During the spring of 1999, 4 patients were treated with the method
      described above, 3 male and 1 female, the average BMI was 47.5 kg/m2. The mean
      operating time was 150 minutes (90-270), the patients left hospital the third day
      after the operations. We noticed no early complications, except for 1 band being
      displaced, it was replaced immediately by laparoscopic technique. The method,
      widely used all over the world is opening new aspects on treating morbid obese
      patients in our country, if properly indicated and operated, giving long lasting
      effective results.

PMID- 10596313
TI  - Palliative treatment of malignant pleural effusions by video-assisted
      thoracoscopic surgery.
AB  - Malignant pleural effusion (MPE) are associated with significant morbidity.
      Prompt clinical evaluation followed by aggressive treatment often results in
      successful palliation. Video-assisted Thoracic Surgery (VATS) today can be
      employed in the diagnosis and treatment of idiopatic and known MPE. Between
      January 1994 and December 1998 233 MPE patients were treated with pleurodesis.
      206 of them underwent tube thoracostomy and drainage alone followed by chemical
      pleurodesis. In 27 out of the 233 cases VATS management was applied. These
      patients had undiagnosed pleural effusions or recurrent MPE following failed
      previous drainage and pleurodesis. The cause of the effusion was breast cancer in
      11 patients, lung cancer in 9, urogenital cancer in 3, mesothelioma in 2 and
      other in 2. VATS intervention was thoracoscopic exploration with biopsy and
      directed chemical sclerosis in undiagnosed MPE (19/27) and lysis of pleural
      adhesions with partial decortication and pleurodesis in recurrent effusions
      (8/27). VATS managements were successful 26/27 after mean follow up of 6 months.
      Had not mortality postoperatively and severe morbidity. Chest tubes were removed
      1.5 +/- 0.5 days postoperatively and hospital stay were averaged 4 +/- 1 days. We
      concluded that VATS is a safety and effective way of managing selected patients
      with pleural effusions.

PMID- 10596315
TI  - Video-choledochoscopy in bile duct surgery.
AB  - The authors report on common bile duct explorations performed in 92 patients and
      in one patient laparoscopically. In their practice usually ERCP and EST were
      attempted first when bile duct stones were suspected. Open choledochotomy was
      performed when the endoscopic approach was unsuccessful, or a stone was detected
      during selective intraoperative cholangiography. In 16 cases intraoperative video
      choledochoscopy was performed. The thing that increased the average operating
      time by 47 minutes. In 4 patients in this group residual stones were detected
      postoperatively, presumably because of the inexperience of the surgeons with the
      use of the choledochoscope. Postoperative cholangiography raised the suspicion of
      a residual stone altogether in 8 cases. Postoperative ERCP was negative in 2
      instances, EST and stone extraction were successful in 3 patients, but
      unsuccessful in 3 patients. In these last cases a successful reoperation was made
      in one, ESWL and dissolution therapy were performed in two patients. The authors
      advise to learn the technique of laparoscopic removal of the bile duct stones and
      the application of guide-wire, Dormia basket, Fogarty balloon catheter, and
      balloon dilatator. According to the data of the literature, the one stage
      laparoscopic procedure is successful in most of the patients, more comfortable,
      and cost saving.

PMID- 10596314
TI  - Laparoscopic cholecystectomy in acute cholecystitis.
AB  - The authors retrospective analyze the role of golden standard laparoscopic
      cholecystectomy for the treatment of acute cholecystitis. They make a comparison
      between the results of 50 early cholecystectomy and 44 "a froid" cholecystectomy
      (operation was postponed until 6 weeks after acute cholecystitis had healed).
      From January 1997 to December 1998 536 laparoscopic cholecystectomies were
      performed. In 491 cases (91.6%) laparoscopic, and in 45 cases (8.4%) traditional
      (opening) method was indicated. Converted cholecystectomies were in 36 cases
      (7.3%). Agreeing to the literature they can determine the optimal timing of the
      operation in 72 hours from the onset of acute cholecystitis [2, 4]. In this group
      (first group) there were 50 cases, with 14 conversions (28%). In the second group
      (postponed, so called "a froid" phase) there were 44 patients. From this group
      was the intraoperative diagnosis serious acute-subacute cholecystitis in 24 cases
      (54.54%) causing complicated laparoscopic cholecystectomy and resulting in 11
      conversions (11/44: 25%). The causes of the higher rate of conversion were the
      grave inflammation and slow dissection of central formation. There were no
      serious complication and mortality in both groups. It was diagnosed bile leak
      (two cases) which ceased spontaneously, one haematoma in abdominal layers, and
      one trocar's hernia. The authors have recommended the laparoscopic
      cholecystectomy for early diagnose acute cholecystitis in order to prevent the
      complications and reduce the sick-leave. Supporting their viewpoint the most
      important clinical end economical facts are: the recurrence of inflammation
      forced urgent surgery and caused more complication in the course of "a froid"
      phase there were scrutable anatomical situation the patients recovered in a
      shorter time.

PMID- 10596316
TI  - Sedation for ambulatory endoscopy.
AB  - Diagnostic and therapeutic fiberoscopy of gastrointestinal tract is often
      performed ambulatory and sedation is sometimes also required. Indication for
      sedation can be the intervention itself or the patient's psychological state. Aim
      of the study was to compare the effects of midazolam and combination of midazolam
      and fentanyl during endoscopy. Twenty eight cases were investigated:
      oesophagogastroduodenoscopy (n = 14) and colonoscopy (n = 14). Anaesthetics were
      midazolam (M) in 16 cases, midazolam-fentanyl (MF) in 12 cases. Non-invasive mean
      arterial pressure, pulse rate, acid-base balance and blood gases (by Astrup
      method) were recorded before endoscopy, at the 5th and 10th minutes of endoscopy,
      15 minutes after intervention and also before emission. Pulse rate changed
      between 78-92/min. Mean arterial pressure appeared between 84-90 mm Hg. In MF
      group both were lower but there was not significant difference between the
      groups. The values were in normal range, there were not metabolic acidosis which
      needed correction. Onset of sedative effect was 2.8 min. in M group, 2.3 min. in
      MF group. The ability for adequate reaction returned within 11 min. in M group,
      within 14 min. in MF group. Fentanyl prolongs sedative effect of midazolam and
      offers sufficient pain relief. After 3 hours, patients could be emitted from the
      hospital.

PMID- 10596317
TI  - Sequential treatment of the common bile duct stones and cholecystolithiasis.
AB  - The orthodox method of the treatment of gallstone disease is laparoscopic
      cholecystectomy (LC) days or weeks after endoscopic retrograde
      cholangiopancreatography + endoscopic spincterotomy (ERCP+ES). It can be
      advantageous from the point of financing, that is double reimbursement (2 x DRG).
      On the other hand there are some disadvantages of this procedure: longer hospital
      stay, further suffering of the patient, difficulties at operation because of
      inflammation provoked by ERCP (11% 14/120 in 3 month). We report on our
      experience with the treatment of common bile duct stones within 24 h by
      sequential endoscopic-laparoscopic management. The gallstone disease of a 32 year
      old woman was diagnosed by ultrasonography and laboratory tests. She had ERCP+ES
      in the morning and LC 7 hours later. There was no complication and the patient
      was discharged already on the 3rd day.

PMID- 10596318
TI  - Video-assisted thoracic surgery (VATS) for the treatment of primary pneumothorax
      (PTX): early indications and "blind resection".
AB  - AIM: To report our VATS procedure and results in the treatment of PTX. METHODS:
      Between 1992-1995, 156 patients with primary PTX were admitted and drained. On
      the basis of permanent air leak, lung reexpansion and type of PTX, 78 patients
      were operated on by VATS with early indications. In first episode PTX cases we
      performed "emergency VATS" in haemopneumothorax and "early or late acute VATS"
      between 8-48 hours after acute drainage in the others. In recurrent cases "late
      acute VATS" was done in 24 hours after acute drainage with permanent air leak. We
      performed "under water-test". In 57 Vanderschueren stage II-III-IV cases the lung
      disorders and the place of air leakage were resected. In 21 Vanderschueren stage
      I cases "blind apical resection" was performed. We carried out pleural abrasion,
      and two pleural drains were inserted. RESULTS: In every "blind resection" case
      the pathology revealed lung disorders: cystic deformation, fibrosis or
      inflammation. We had no operative deaths. In 1 case because of intercostal artery
      bleeding, thoracotomy had to be performed. We had 1 recurrent PTX. There was no
      late complications. CONCLUSION: The early indications reduced the
      hospitalization. The "blind apical resections" remove abnormal lung tissue,
      diagnose the underlying lung disease and the metal staples can cause adhesion
      reaction in the apex region.

PMID- 10596319
TI  - Video-assisted thoracoscopic pleurodesis for malignant pleural effusions.
AB  - AIM: The objective was to analyse the efficiency, and safety of thoracoscopic
      pleurodesis (TP). A retrospective study was made of an initial series of 75
      patients undergoing lifetime follow-up who received TP in our department for the
      treatment of malignant pleural effusions (MPE). MATERIAL AND METHODS: From May
      1994 to December 1998, 34 men and 41 women with a median age of 63.4 +/- 12.5
      years were treated by TP. We performed 36 partial diathermic abrasions on pleura
      combined with talc insufflation, and in 39 cases only talc poudrage. The mean
      duration of insention of the chest tube was 4.1 (range 2 to 17) days, with 8.4
      (range 5 to 20) days of postoperative hospitalization. There were no severe
      intraoperative or postoperative complications. The 30-day mortality rate was 1.3%
      (1 case). The period of follow-up ranged from 2.5 to 40 months (average 6.8). No
      case of late recurrence has been observed to date. CONCLUSION: Videothoracoscopic
      pleurodesis (talc poudrage) as a simple and efficient procedure seems to be the
      best alternative treatment regimen for the management of MPE in a group of
      selected patients.

PMID- 10596320
TI  - The history and the future of teaching and training of laparoscopic surgery in
      Hungary.
AB  - INTRODUCTION: Laparoscopic biliary surgery was introduced in Hungary at the end
      of the 1990. A variety of experimental training and teaching courses had been
      performed in basic techniques and the human field, which was followed by
      laparoscopic biliary surgery and various advanced fields. AIMS OF THE STUDY: To
      review the history of teaching and training of laparoscopic surgery in Hungary in
      both the experimental and the human field, and to draw the consequences of this
      experience. MATERIAL AND METHODS: In a period of 6 years 704 qualified surgeons
      received a full hands--on hands experimental training in laparoscopic biliary
      surgery, laparoscopic advanced surgery, laparoscopic gynaecologic and
      laparoscopic urology surgery. DISCUSSION: The courses performed in the first and
      the second phase were of theoretical and practical components. The theoretical
      knowledge was based with emphasise to the new instruments and equipment, the
      indications, the new surgical technique. The practical knowledge gave every
      participant the full time to acquire this new type of surgery. At the end of the
      courses the successful participants received certificates to shift for training
      to the human field. Each institution needs to wrestle with issues concerning
      credentialling in advanced laparoscopic surgery. Like many technical skills,
      proficiency is maintained through repetition. A philosophy must be developed to
      determine whether each surgeon will perform this highly specialised type of
      surgery or whether it will be considered a general skill.

PMID- 10596321
TI  - Laparoscopic gastric surgery. Early experiences.
AB  - In the Department of General Surgery the authors performed 12 elective
      laparoscopic gastric operations for gastric pathologies. The indications for the
      procedures were recurrent or therapy resistant and complicated peptic ulcer in 9
      cases, benign gastric tumors in 2 cases and early gastric cancer in 1 case.
      Operative procedures were the next: posterior truncal vagotomy with anterior
      lesser curve seromyotomy (5 patients), total truncal vagotomy with
      gastrojejunostomy (2 patients), total truncal vagotomy with pyloroplasty (1
      patient), total truncal vagotomy with antrectomy and Billroth-II reconstruction
      (1 patient), resection of benign gastric tumor by the transgastric approach (1
      patient), Billroth-II resection for benign gastric tumor (1 patient), wedge
      resection of gastric wall for early gastric cancer (1 patient). Intraoperative
      gastroscopy was used for location of the lesion in 4 of 12 cases. Apart from
      delayed gastric emptying (2 cases), patients recovered without any problem. The
      mean hospital stay was 5.7 days. Early experiences with laparoscopic gastric
      surgery has shown that there are certain important advantages to the approaches.
      They hold the promise of less pain, less immobility, quicker alimentation,
      shorter hospitalization, less wound and respiratory complications and an earlier
      return to normal activities.

PMID- 10596322
TI  - Laparoscopic wedge resection of the gastric wall for gastric benign tumour. The
      collaboration of the laparoscopic surgeon and the endoscopist.
AB  - INTRODUCTION: By the introduction of the laparoscopy for the management of
      gastric pathology many techniques are applied by now. In these techniques the
      collaboration of the endoscopist and the laparoscopic surgeon is mandatory. AIMS
      OF THE STUDY: To emphasise the necessity of the collaboration of the endoscopist
      and the laparoscopic surgeon for the management of the gastric pathology using
      the double lifting and wedge resection technique. METHOD: A case of a female with
      2 x 2.5 cm submucosal tumour is presented. The tumour was located in the antrum.
      After the onset of the general anaesthesia the gastroscope was introduced to
      locate the position of the tumour, the free edges of the tumour were elevated by
      a double lifting method and the tumour was resected by a laparoscopic linear
      stapler. The process of the proper resection was all through observed and
      directed by the view of the gastroscope. CONCLUSION: Correct wedge resection of
      the gastric wall can be safely performed, if the correct gastroscopic control is
      present. The collaboration of the endoscopist and the laparoscopic surgeon seems
      to be mandatory, thus avoiding the hazards arising from the use of tattooing.

PMID- 10596323
TI  - The judgement of adhesion formation following laparoscopic and conventional
      cholecystectomy in an animal model.
AB  - INTRODUCTION: The development of postoperative adhesions remains an almost
      inevitable consequence of visceral and gynaecologic surgery, appearing in 50-95%
      of all patients. Although decreased adhesion formation is one of the accepted
      advantages of laparoscopic surgery, only a small number of prospective studies
      have been done to support this claim. AIMS OF THE STUDY: To evaluate the extent
      of postoperative adhesion formation after laparoscopic and open cholecystectomy.
      MATERIAL AND METHOD: 60 experimental laparoscopic cholecystectomies (LC) were
      performed by qualified surgeons in dogs with the aim to acquire the laparoscopic
      technique. To assess the relation between the complications during the operation
      (bleeding, injury to the liver substance or gallbladder perforation) and the
      formation of adhesions, the surviving animals were divided into 4 groups
      according to the complications occurred. The assessment of the results was made
      by second--look laparoscopy 4 weeks following LC using the adhesion index. As a
      control group open cholecystectomy was then performed in 5 dogs without
      intraoperative complications. RESULTS: No adhesion formation was observed in the
      groups where no intraoperative complications occurred. In all the cases where
      bleeding or injury to the liver bed occurred adhesion formation occurred. No
      adhesion formation was observed in case of gallbladder perforation. In all the
      animals of the control group adhesion formation was observed. CONCLUSION: It
      seems that LC has a reduced rate of adhesion formation when compared with the
      open technique. Complications such as bleeding or injury to the liver substance
      during LC can enhance adhesion formation. No adhesion formation can be mentioned
      in relation with gallbladder perforation when the laparoscopic technique is
      applied.

PMID- 10596324
TI  - The importance of intraoperative endoscopy.
AB  - Nowadays it is an essential demand of the surgeon to make a correct preoperative
      diagnosis, that is a precondition of optimal operation. Unfortunately it cannot
      be clarified in each case, what is the location and extension of the alteration,
      or surgeon finds an unexpected disease during the operation. In similar cases the
      authors make an intraoperative upper gastrointestinal endoscopy and/or
      colonoscopy. During these procedures, the identification of the reason of
      bleeding and in some cases polypoid lesions were found. Over the past few years
      16 examinations have been carried out. The examination influenced the course of
      the operation in each case advantageously. Therefore, the diagnostic repertoire
      can also be extended by this method. This is, why preoperative endoscopy is of
      primary importance.

PMID- 10596325
TI  - Jejunal feeding in necrotising acute pancreatitis--a retrospective study.
AB  - The acute necrotising pancreatitis is the most serious form of pancreatic
      inflammatory disease leading to multiorgan failure and high (15-20%) mortality.
      The poor nutritional and metabolic condition and secondary bacterial
      translocation rise the mortality further on. A newly introduced clinical method
      of continuous nasojejunal feeding-based on experimental works--resulted in lower
      mortality rate (less than 4%) by perfusing adequate nutrients into the second
      loop of jejunum via a feeding tube. The better nutritional and immunological
      status of the patients, with restored absorption and intestinal motility promoted
      recovery, and prevented the septic complications. Although in some cases with
      serious progression operation became necessary; the timing of surgery was easier
      because of the less fragile state of the patient. The continuous nasojejunal
      feeding is a promising new method among the therapeutic modalities of the acute
      pancreatitis.

PMID- 10596326
TI  - Laparoscopic surgery of focal lesions of the liver.
AB  - In this work the laparoscopic surgical approach of two benignant hepatic lesions
      (focal nodular hyperplasia [1st case], and hepatic cyst with simultaneous
      cholecystolithiasis [2nd case]) will be discussed. The authors present the steps
      of the laparoscopic procedures: non-anatomical liver resection in the first,
      resection and cholecystectomy in the latter case. During the operations no
      surgical complications occurred, the postoperative course was also uneventful.
      The patients were discharged in the fifth day after the surgery, without any
      complains. During a short follow-up period, our patients were asymptomatic and
      free of recurrences. In our opinion, the laparoscopic hepatic surgery might be a
      feasible technique in the hands of surgeons with hepatic and laparoscopic
      experience, but careful selection criteria should be followed in the selection of
      such cases.

PMID- 10596327
TI  - Successful thoracoscopic surgical treatment of oesophageal cyst.
AB  - The authors report a video-thoracoscopically successfully treated case of
      oesophageal cyst. The symptomatic lesion was diagnosed by swallowing, X-ray,
      oesophagoscopy, chest CT scan and endoscopic ultrasonography. The benign tumour
      was removed by a videothoracoscopic method using selective intubation. There were
      no intraoperative and postoperative complications. The patient was discharged on
      the fifth postoperative day. The videothoracoscopic technique is safe, involves
      little pain and permits a rapid return to normal activity. It is a preferred
      method for removing benign lesions of the oesophagus.

PMID- 10596328
TI  - The role of diagnostic laparoscopy in staging of pancreatic cancers.
AB  - Authors report elective diagnostic laparoscopy, and the role of this method in
      evaluating operability of pancreatic cancer. At their department 11 diagnostic
      laparoscopic procedures of pancreatic cancer were performed during the last 5
      years. In 3 cases tumor proved to be resectable despite preoperative imaging
      results of unresectable condition. On the basis of international literature
      authors give brief summary of indications, cost and benefit of diagnostic
      laparoscopy, and its place in the diagnostic algorythm of pancreatic cancer.

PMID- 10596329
TI  - The laparoscopic technique for bilateral inguinal hernias.
AB  - From March 1994 to March 1999 359 laparoscopic hernioplasties have been performed
      on 295 patients. In 349 cases (97.2%) TAPP (transabdominal preperitoneal), in 10
      cases (2.8%) TEP (total extraperitoneal) method was used for the treatment. In 64
      cases (21.7%) bilateral hernias were operated using TAPP-method only. There were
      15 hidden hernias and 14 recurrences on the contralateral side in this group. The
      hernial ring was covered with two smaller meshes or one bigger. There were no
      intraoperative complications. In 21 cases (32.8%) subcutaneous emphysema and in 3
      cases (4.6%) sero-haematoma was developed. The emphysemas were solved
      spontaneously in 2-3 hours after the surgery. One haematoma was needed punction.
      The patients were discharged from the hospital on the second or third
      postoperative day. The authors found that the bilateral laparoscopic hernioplasty
      much more favourable for the patients.

PMID- 10596330
TI  - New surgical procedures in postgraduate medical education.
AB  - An outstanding role in developing the recent nation-wide postgraduate
      accreditation process in Hungary has been played by University Medical School of
      Pecs. GRADUATE TRAINING: By providing opportunities for students to practice
      basic surgical interventions on living tissues, the Department of Experimental
      Surgery has served as a bridge between theoretical and clinical phases of their
      education. Students benefit from the infrastructure of surgical training we
      provide, including even access to microsurgery and laparoscopic techniques.
      POSTGRADUATE TRAINING: One category of postgraduate training offered by our
      department is further training of young physicians in special branches of
      surgery, with emphasis on microsurgery and laparoscopy. The other category is in
      the form of special courses. A great number of applicants from across Hungary
      highlight the need for running such courses. Throughout Europe such training is
      available only at very high prices. With the invaluable assistance of Prof. Z.
      Szabo (San Francisco, USA), we have been able to create the right environment and
      offer expert technical training in laparoscopic procedures since 1995. We face
      new challenges in the year 1999. As part of the new resident training system,
      Department of Experimental Surgery will provide not only training in traditional
      surgical procedures, but also include training in the most up to date techniques.
      Organizing such sources, apart from financial backing, requires genuine
      professional commitment.

PMID- 10596331
TI  - Synchronically performed laparoscopic cholecystectomy and hernioplasty.
AB  - Cholecystectomies and hernioplasties are the two most frequently performed
      surgical interventions. The laparoscopic technique can be offered for the
      simultaneous treatment with both operating indications. The synchronical
      operation can give all the advantages of the minimally invasive technique.
      Authors had performed laparoscopic cholecystectomy with laparoscopic hernioplasty
      in five cases. Two inguinal and three postoperative hernias were reconstructed.
      The cholecystectomy was performed with a "three punction method", and the
      hernioplasty by using the same approach, completed by inserting a fourth
      assisting trocar as required. The hernial ring was covered with an
      intraperitoneally placed mesh, which was fixed by staplers (the so-called "IPOM
      method": intraperitoneal on-lay mesh). There was no intra-, nor postoperative
      complication. The hernioplasty combined with laparoscopic cholecystectomy did not
      have effect on postoperative pain and nursing time. The return to the normal
      physical activity was short, similar to laparoscopic hernioplasty (in 1-2 weeks).
      Authors conclude that the simultaneous, synchronous laparoscopic cholecystectomy
      and hernioplasty is recommended and should be the method of choice because it is
      more advantageous for patients.

PMID- 10596332
TI  - Laparoscopic adrenalectomy. New experiences.
AB  - Authors have performed 23 laparoscopic adrenalectomies between 03.04.1997 and
      02.04.1999. They have removed 16 cortical adenomas, 2 nodular hyperplasias, 2
      cysts, 1 carcinoma, 1 pheochromocytoma and 1 myolipoma. The operation time was 90
      260 minutes that gradually has been decreased by using "Ultracision" ultrasonic
      shear. They have made simultaneously two cholecystectomies and one liver wedge
      biopsy. During removing pheochromocytoma they have not detected extremely high
      blood pressure data. They had one intraoperative complication, the perforation of
      the diaphragm which required a temporary thoracic suction drainage. All
      operations were completed laparoscopically. Patients have been released on the
      2nd-3rd postoperative day. Their experiences confirm the literary data that the
      laparoscopic approach to adrenalectomy is the method of choice today.

PMID- 10596333
TI  - Effect of laparoscopic antireflux operation on esophageal manometry, 24 hours pH
      metry and quality of life in gastroesophageal reflux disease.
AB  - It has been suggested that laparoscopic Nissen fundoplication is an effective
      procedure for the treatment of gastroesophageal reflux disease (GERD). Twenty-six
      patients with chronic gastroesophageal reflux disease underwent laparoscopic
      floppy Nissen fundoplication. 24 hours pH-metry, manometry and Gastrointestinal
      Quality of Life Index (GIQLI) questionnaire were done preoperatively, six-month
      and one year after the operation. The six weeks control investigation was limited
      to 24 pH-metry and GIQLI interview. Adequate reflux control was obtained in all
      patients, with reduction in acid reflux variables at six weeks, six months as
      well as at one year after the operation. Preoperative reflux index and DeMeester
      score was significantly higher than those we found postoperatively at both time
      period. Preoperative lower esophageal sphincter tone and length was abnormal on
      average. Both parameters increased significantly at six-month and one year after
      the operation. GIQLI also showed characteristic changes. Compared to preoperative
      values we found significantly higher GIQLI at both six-month and one year
      following surgery. Laparoscopic Nissen fundoplication provides an excellent
      symptomatic and physiologic outcome in patients with esophageal reflux disease.

PMID- 10596334
TI  - First Hungarian, internet-based prospective, multicenter study: the hernia
      project.
AB  - In inguinal hernia repair, different laparoscopic and open techniques of tension
      free repair using synthetic meshes have been reported to result in better patient
      comfort and lower recurrence rates compared with conventional procedures like
      Shouldice's or Bassini's operation. In comparison with the laparoscopic
      procedure, open tension-free repair can be performed under local anaesthesia and
      is less expensive. For these reasons, the recent trend in inguinal hernia
      surgery, has been towards using an open, mesh-based tensionless repair
      (Lichtenstein technique). To evaluate and support the widespread use of this
      technique in Hungary a large, prospective multicentre trial was initiated at 15
      March 1999. Prospective registration of 1500 hernia operation using Lichtenstein
      technique is undertaken that is carried out in 15 hospitals. Postoperative
      outcome, complications and recurrence is recorded through a five years period.
      The case presentation and data collection is internet based. Each center
      participating in the study is connected by internet to the coordinating center
      and all information concerning this study is sent by this way. This system is
      able to generate actual statistical data in every moment of the study.

PMID- 10596335
TI  - The laparoscopic treatment of non-parasitic liver cysts. Five years experience.
AB  - The incidence of cystic liver lesions seems to be more frequent as previously
      suggested. The treatment of symptomatic non-parasitic cysts is controversial.
      Ultrasonography (US) or computer tomography (CT) guided drainage and/or
      sclerotization versus surgical fenestration or partial resection, even liver
      resection has been advocated. Recently with the development of laparoscopic
      surgery this minimal invasive approach was also applied in the surgical treatment
      of single or multiple cystic lesions. Between 1994 and April 1999 21 patients
      with non-parasitic cysts were treated by laparoscopic fenestration or partial
      resection at the 1st Department of Surgery, Semmelweis University of Medicine. In
      13 cases the symptomatic cyst presented the indication for surgery, while in the
      others cholelithiasis and GERD was the primary cause of intervention in 7 and 1
      patient respectively. There were 16 woman and 5 men with a mean age of 42.3 years
      (17-78). The cyst was solitary in 17 cases and multiple 3-6-number in four
      patients. The size varied between 1.5-25 cm (average 7.2 cm). Patients were
      selected for the laparoscopic approach according to the US and/or CT appearance
      and superficial localization of the cyst. Wide unroofing or partial resection of
      the cyst wall till the margin of normal liver tissue was performed in all cases.
      The cystic cavity was drained. All operations were completed laparoscopically.
      Intraoperative complication did not occur. Bleeding from the resected margin
      could be well controlled by electrocautery or clipping. Patients left the ward
      after the drains were removed on postoperative day 2-4 depending upon the amount
      of serious discharge. No complication was observed postoperatively. During the
      average of 12.5 months (1 to 54 months) follow-up of 19 patients no recurrence
      was observed. Two patients required reoperation. In one 17 year old male patient
      cystadenocarcinoma was verified by histology, upon reoperation the lesion was
      found unresectable. In another case left hemi-hepatectomy was performed because
      of cyst recurrence caused by cholangiocell adenoma. In selected cases of
      superficially located symptomatic, non-parasitic cysts the laparoscopic
      fenestration might be the first choice of treatment. The method is safe and
      effective in the hands of surgeons experienced in both laparoscopic and liver
      surgery. Careful exploration of the cystic cavity and histological examination of
      the resected cyst wall is mandatory to avoid diagnostic mishaps.

PMID- 10596336
TI  - [Therapeutic advances in breaking the tobacco habit].

PMID- 10596337
TI  - [The effect of peroperative transfusion on survival in resected lung carcinomas].
AB  - This paper analyzes the influence of perioperative transfusion on survival after
      lung cancer surgery. Between January 1991 and December 1995, we enrolled 405
      patients, 196 of whom received transfusions and 209 of whom did not. Follow-up
      extended to December 1997. Excluded were patients undergoing exploratory
      thoracotomy (n = 92), those who died during the postoperative period (n = 19) and
      those lost to follow-up (n = 13). The final number of patients in the study was
      281 (136 who received transfusions and 145 who did not). We analyzed age, sex,
      general clinical status measured on the Eastern Cooperative Oncology Group (ECOG)
      scale, histological type and TNM staging. Single and multiple variable analyses
      were performed. At the end of the study 158 patients were alive and 123 had died.
      Transfusions were used more often in pneumonectomies (p < 0.001) and in patients
      with an ECOG score of 2 (p < 0.01). Survival at 36 and 60 months, calculated
      using the Kaplan-Meier method was 52% and 30%, respectively, for those who had
      received transfusions, and 53% and 49%, respectively, for those who had not. The
      differences were not statistically significant (p > 0.1). Multivariant analysis
      failed to demonstrate an influence of transfusion on survival (relative risk of
      1.08; 95% confidence interval 0.72-1.61; p > 0.1). We conclude that there is no
      negative prognostic effect of perioperative transfusion.

PMID- 10596338
TI  - [Validation of the Spanish version of the Epworth Sleepiness Scale in patients
      with a sleep apnea syndrome].
AB  - A Spanish version of the Epworth Sleepiness Scale (ESS-Sp) was developed by
      translation, back-translation, formal discussion, and a meeting of researchers
      with a group of patients with sleep apnea syndrome (SAS). The translated
      questionnaire was then tested in 345 patients, 275 with SAS at various levels of
      severity and 70 without SAS. Significant differences existed between the two
      groups as to age (53 +/- 11 years versus 47 +/- 13, p < 0.001) and BMI (32 +/- 5
      versus 29.5 +/- 5, p < 0.001). Patients with SAS had significantly higher scores
      (14 +/- 5) than did those without SAS (10 +/- 5) (p < 0.001). Reproducibility was
      tested in 146 patients (113 SAS and 33 non-SAS), with no significant differences
      found among patients with SAS (14.9 +/- 5 versus 14.2 +/- 5, p = n.s.);
      significant differences in BMI were found, however, among the 33 non-SAS patients
      (12 +/- 5 versus 10 +/- 5, p < 0.01). Total scores and individual item scores
      were related in both groups. Likewise, each item was related to total score in
      patients with SAS. Sensitivity to post-treatment changes was assessed in 77 SAS
      patients, with initial scores of 16 +/- 4 seen to decrease to 4 +/- 3 after
      continuous positive airway pressure. ESS-Sp scores over 10 were recorded for 85%
      of patients with SAS: 78% of those with mild SAS, 85% of those with moderate
      disease and 92% of those whose SAS was severe. Significant inter-group
      differences were found upon applying a test of variance (p < 0.001). Differences
      continued to be detected when multiple correlations were looked for, with
      differences increasing with severity. SAS patients with ESS-Sp level one scores
      (< 10) had lower apnea-hypopnea indices (AHI) (35 +/- 18 versus 42 +/- 20, p <
      0.05), lower desaturation levels (21 +/- 21 versus 34 +/- 28, p < 0.01) and
      higher minimum saturation (80 +/- 10 versus 75 +/- 12, p < 0.05), with no
      differences in age or BMI. A significant correlation was found between ESS-Sp
      score and respiratory variables recorded during polysomnography: AHI, r = 0.23 (p
      < 0.001); percent time in apnea-hypopnea, r = 0.18 (p < 0.01); desaturation
      index, r = 0.27 (p < 0.01) and minimum saturation (r = -0.14, p < 0.05). We
      conclude that the Spanish version of the ESS is equivalent to the original, is
      reproducible in patients with SAS, sensitive to post-treatment changes and seems
      to discriminate level of severity, showing correlation with polysomnograph
      variables.

PMID- 10596339
TI  - [An assessment of the quality of life of patients with COPD and chronic hypoxemia
      by using the Spanish version of the Chronic Respiratory Disease Questionnaire].
AB  - INTRODUCTION: The Chronic Respiratory Disease Questionnaire (CRDQ) is a specific
      evaluation instrument that has been recently translated to Spanish and validated
      in patients with COPD without chronic respiratory insufficiency. OBJECTIVE: To
      study the relation of CRDQ scores to several lung function parameters in COPD
      patients with chronic hypoxemia (PaO2 < 65). MATERIAL AND METHODS: Forty-four
      middle aged [68 (7)] men with COPD (FEV1 post-PBD < 50%; PaO2 < 65 mmHg) were
      enrolled with established medical histories, including blood gas and spirometric
      data. We collected the patients' responses to the CRDQ and measured blood gas
      levels, spirometric and plethysmographic variables and DLCO. Performance on a six
      minute walking test was recorded, with dyspnea assessed on a visual analogue
      scale (VAS) initially and at the end of the walk. Nighttime pulse oximetry was
      also monitored. Pearson's and Spearman's correlation coefficients were used to
      study the relation between CRDQ scores and the aforementioned parameters. Gas and
      spirometric data were compared to CRDQ scores between groups of patients treated
      with continuous domiciliary oxygen therapy (CDOT) and the untreated group, using
      Student t-test and a Mann-Whitney U-test. RESULTS: Results are expressed as means
      and standard deviations within parentheses. FVC was 2,609 (618) ml, 72 (15)%;
      FEV1 867 (297) ml, 34 (11)%; FEV1/FVC 33 (8)%; PaO2 55(8) mmHg; and PaCO2 49(6)
      mmHg. The overall CRDQ score was related to FEV1 (0.38; p < 0.01); FEV1/FVC
      (0.43, p < 0.005); walking test distance (0.49, p < 0.01); final VAS (-0.64, p <
      0.0001) and DLCO (0.59, p < 0.01). No relation was observed between CRDQ score
      and blood gases, nighttime pulse oximetry or plethysmograph data. "Dyspnea",
      "fatigue", "emotional function" and "disease control" dimensions of the CRDQ were
      related to the same variables as was the overall score, with the exception of
      FEV1/FVC for the "fatigue" dimension and FEV1 and DLCO for the "disease control"
      dimension. The CRDQ scores were similar in the CDOT and non-CDOT groups in spite
      of differences in their spirometric and gasometric variables. CONCLUSIONS: 1)
      Score on the CRDQ is related to FEV1, the FEV1/FVC ratio, walking test distance,
      dyspnea and DLCO but not to blood gases, FVC, lung volume or nighttime pulse
      oximetry. 2) The VAS dyspnea score recorded at the end of the walking test is the
      variable that is most strongly related to CRDQ score. 3) We found that use of
      CDOT did not undermine the COPD patient's quality of life.

PMID- 10596340
TI  - [Information seeking and decision making in asthmatic patients].
AB  - Patient cooperation in controlling asthma is a key element for achieving the most
      efficient therapy possible according to current guidelines. Cooperation requires
      that the patient be adequately informed about his disease and able to make
      certain decisions. The aim of this study was to analyze whether patients really
      desire information about asthma and to what point they are disposed to cooperate
      actively in managing their disease. Ninety-five adult asthmatics with different
      levels of severity of disease were studied in stable condition. All responded to
      the Spanish version of the questionnaire on autonomy in asthma, an instrument
      with a scoring range of 0 to 100 and 26 items grouped in two subscales:
      preferences in the search for information (PSI) and preferences in decision
      making (PDM). The second subscale was based on three scenarios describing stable
      asthma, slight exacerbation and severe exacerbation. The results obtained
      indicate that although patients are greatly interested in receiving information
      (PSI scores of 86.4 +/- 8.7) they express substantially less desire to make
      decisions (PDM 45 +/- 10.2) (p < 0.01). Attitudes did not change in relation to
      education, number of exacerbations during the last year, duration of disease or
      severity as assessed by the patient. Only patient age (with older patients
      scoring higher on PSI) and presence of severe asthma (according to consensus
      guidelines) increased the desire for information (but not the preference for
      decision making). These data indicate the need to implement educational programs
      about asthma, components of which promote effective desire for self-management.

PMID- 10596341
TI  - [Respiratory muscle force and resistance in patients with SAHS. The effect of
      using nighttime CPAP].
AB  - During nighttime episodes of obstructive apnea in patients with sleep apnea
      hypopnea syndrome (SAHS), repeated and progressive inspiratory efforts are made.
      Such intense nighttime activity can have a deleterious effect on daytime function
      of respiratory muscles. OBJECTIVE: The objective of this study was to evaluate
      daytime respiratory muscle function in a group of SAHS patients before and after
      two months of treatment with nighttime continuous positive airway pressure
      (CPAP). METHODS: We enrolled 12 patients with SAHS and 10 normal subjects
      (control group). To evaluate respiratory muscle strength we measured maximum
      esophageal pressure (Pesmax), transdiaphragmatic pressure (Pdimax) and
      inspiratory pressure in the mouth (PM). Respiratory muscle resistance was
      assessed using peak pressure in the mouth (PMPeak), time of tolerance (Tlim) and
      maximum inspiratory pressure-time index (PTimax). We also analyzed the nighttime
      function of respiratory muscles during apneic episodes in 10 of the 12 SAHS
      patients. We propose and define an index of nighttime respiratory muscle activity
      (RMian) as the product of the tension-time index for the diaphragm observed at
      the end of nighttime apneic episodes (TTdiapnea) and the apnea-hypopnea index
      (AHI). RESULTS: Respiratory muscle strength was similar in the two groups and no
      changes were observed in SAHS patients after treatment with nighttime CPAP.
      However, tolerance was lower in SAHS patients (PMpeak--30%, Tlim--31% and PTimax-
      49%). Two months of nighttime CPAP normalized all three variables in these
      patients. MRian was related to percent improvement in PMpeak after treatment with
      nighttime CPAP in SAHS patients (r = 0.66, p < 0.04). CONCLUSION: SAHS has an
      adverse effect on the daytime endurance of respiratory muscles that is
      proportional to the increase of nighttime mechanical muscle activity. The
      application of nighttime CPAP is restorative, probably because it allows
      respiratory muscles to rest.

PMID- 10596342
TI  - [The current state of substitution treatment in congenital emphysema due to alpha
      1-antitrypsin deficiency. The report of the National Registry].

PMID- 10596343
TI  - [Pulmonary metastases of malignant melanoma. A rare endobronchial presentation].
AB  - Malignant melanoma has a tendency to metastasize to the lung in the course of
      tumor growth. Many such cases have been described in the literature, although
      cases of endobronchial metastasis of this type of tumor revealed during
      fiberoptic bronchoscopy are difficult to find. We report three cases of extension
      of the primary tumor to the lung, diagnosed by fiberoptic bronchoscopy during
      which biopsy specimens were obtained. After tissue inspection, the initial
      suspicion of metastasis of malignant melanoma was confirmed. We review the
      prevalence, radiologic presentation, prognosis and treatment options for this
      type of metastasis.

PMID- 10596344
TI  - [Costal osteolysis due to a giant arteriosclerotic aneurysm of the ascending
      thoracic aorta].
AB  - In this case report the patient had a giant saccular aneurysm caused by
      arteriosclerosis, located in the ascending aorta and protruding through the
      anterior thoracic wall, with osteolysis of the two adjacent ribs. Costal
      involvement in arteriosclerotic aneurysms has not been described in the
      literature. We review the incidence, types and clinical signs of aneurysms of the
      ascending aorta, emphasizing the complications caused by arteriosclerotic
      aneurysms.

PMID- 10596345
TI  - [A superior vena cava syndrome due to a surgical retractor].
AB  - A 56-year-old male diagnosed of epidermoid carcinoma of the right lung (T4 N0 M0,
      stage IIIb) is described. He had earlier received chemotherapy and radiotherapy
      and was scheduled for removal of the right lung. During surgery the need to
      resect tumor infiltration of the right atrium became evident. During weaning from
      by-pass sudden deterioration of hemodynamics occurred with poor response to
      volume and inotropic drugs. Superior vena cava syndrome due to traction of the
      innominate trunk from a surgical retractor was diagnosed; the crisis resolved
      when the retractor was withdrawn. We discuss the pathophysiology of this clinical
      picture and relevant intraoperative aspects.

PMID- 10596346
TI  - [Coital hemoptysis].

PMID- 10596347
TI  - [The importance of specialist consultations in oxygen therapy].

PMID- 10596348
TI  - [Recurrent pleural effusion as a manifestation of primary amyloidosis].

PMID- 10596349
TI  - [The suspicion of a pulmonary embolism in a hospital].

PMID- 10596350
TI  - [Variables that determine frequent hospital readmissions in patients with chronic
      obstructive pulmonary disease].

PMID- 10596351
TI  - [Varicella pneumonia: the complications of antiviral treatment].

PMID- 10596352
TI  - Effects of cellulose derivatives and additives in the spray-drying preparation of
      acetaminophen delivery systems.
AB  - Microcrystalline cellulose (MCC), sodium carboxymethylcellulose (NaCMC),
      hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC),
      hydroxypropylcellulose (HPC), and ethylcellulose (EC) were used for the
      production of time-controlled acetaminophen delivery systems using a spray-drying
      technique. The influence of factors such as polymer concentration, inlet
      temperature, and drug/polymer ratio were investigated. The product yields were a
      function of the type and concentration of the polymer, with the highest values
      being reached from feeds containing 1% MCC and EC. Parameters of 1% polymer
      concentration and an inlet temperature of 140 degrees C gave rise to optimal
      processing conditions. Using these parameters, the influence of some adjuncts,
      such as polyethylene glycol 6000 (PEG 6000), dibutyl sebacate (DBS),
      polyvinylpyrrolidone (PVP), and carboxylic acids such as citric acid (CA),
      phthalic acid (PA), succinic acid (SA), tartaric acid (TA), and oxalic acid (OA),
      on the spray-drying process was evaluated. Of the additives tested, PVP (with
      MCC), DBS (with EC), and PEG 6000 (with NaCMC) induced yield decreases from 70%
      to 49%, 66% to 39%, and 37% to 17%, respectively. As for carboxylic acids (with
      NaCMC), similar or better performances of 43%, 45%, 47%, and 49% were obtained
      with SA, OA, PA, and TA, respectively. Dissolution studies in pH 1 dilute HCl and
      pH 6.8 phosphate buffer dissolution media showed that formulations consisting of
      1% polymer with a drug/polymer ratio of 1/1 exhibited the slowest drug release,
      with the spheroids coated with NaCMC and HEC showing the longest T50% values
      (with 45 and 53 min at pH 1 and 49 and 55 min at pH 6.8, respectively). Slightly
      better sustained drug release in pH 6.8 dissolution medium was reached, showing
      the following trend: HEC > NaCMC > MCC > EC > HPMC. Concerning the additives, the
      trends in dissolution T50% of drug revealed TA > SA > CA > OA > PVP > PA > DBS in
      acidic pH 1 dissolution medium and PVP > OA > TA > SA > PA > CA > DBS in
      phosphate buffer at pH 6.8.

PMID- 10596353
TI  - A novel depot preparation of desferrioxamine-B: development of formulation
      principles.
AB  - This report describes the feasibility of simple oil-based depot formulations of a
      novel n-decanesulfonate salt of the iron chelator desferrioxamine-B. After
      subcutaneous administration in rodents, desferrioxamine-B n-decanesulfonate depot
      induces both (a) prolonged release of drug and (b) an increase of at least
      threefold to fourfold in iron excretion efficiency compared with the parent
      compound Desferal (desferrioxamine-B mesylate). Optimization experiments probing
      vehicle composition, surfactant loading, drug loading, and particle size
      distribution of the depot preparation are described, and the physiochemical
      stability of an identified pilot formulation is assessed.

PMID- 10596354
TI  - Optimization of a tablet containing chlorthalidone.
AB  - In pharmaceutical technological research, optimization studies generally deal
      with the search for the formulation that is as effective and as functional as
      possible. The effect of a formulation parameter (the amount of lactose in the
      composition of the tablets) and of a technological parameter (compression
      pressure) on four physical characteristics (tablet thickness, friability,
      hardness, and drug dissolution rate) of tablets containing the antihypertensive
      drug chlorthalidone were studied. The results obtained indicate that, in the
      development of a tablet formulation, it is possible to identify the most suitable
      formulation by applying a simple optimization method. The effect of the
      microclimatic stress (temperature and humidity) was also evaluated, and it was
      found that the optimized tablets were no longer within limits that had been
      established for them. This may indicate that it is opportune to keep the storage
      conditions of the excipients under control before their use.

PMID- 10596355
TI  - Influence of melting and rheological properties of fatty binders on the melt
      granulation process in a high-shear mixer.
AB  - The preparation of granules by melt granulation was investigated using a
      laboratory-scale high-shear mixer (Pellmix PL 1/8) and binary mixtures containing
      lactose and different lipidic binders, namely, Compritol 888, Cutina HR, or
      Precirol ATO5. During the process, the product temperature and the impeller motor
      power consumption were monitored. On the other hand, the melting behavior
      (thermal analysis) and the rheological properties (controlled stress capillary
      rheometer) of the different lipophilic binders were also determined. The granule
      formation was shown to be quite effective at product temperatures even below the
      melting point of the lipidic binder, that is, when the binder is sufficiently
      softened to be deformed by the very high shearing forces developed in the high
      shear mixer. On the other hand, the performance of lipidic binders during the
      melt granulation process was shown to be closely dependent on their melting and
      rheological properties. The granule growth rate was shown to be higher when the
      binder melting range is narrow and the influence of temperature on the viscosity
      of the unmelted product is high.

PMID- 10596356
TI  - Sugar-branched-cyclodextrins as injectable drug carriers in mice.
AB  - The purpose of this study was to investigate stable complexation of drug in blood
      by sugar-branched-beta-cyclodextrins (beta-CDs) such as glucose (glu)- or
      galactose (gal)-branched-beta-CDs and the pharmacokinetic disposition of drug in
      sugar-branched-beta-CD complex. Complexation of steroidal drugs in sugar-branched
      beta-CDs and their replacement by cholesterol were measured. The complexes of
      dexamethasone/glucosyl-beta-CDs (dexamethasone/glu-beta-CD or dexamethasone/glu
      glu-beta-CD) were not replaced by cholesterol, which is a representative
      endogenous compound, whereas the complex of dexamethasone/beta-CD was replaced by
      cholesterol. The same results were obtained in steroidal drugs such as
      hydrocortisone, triamcinolone, and prednisolone. Thus, the use of glu-beta-CD and
      glu-glu-beta-CD permitted the stable complexation of the drug in water. Stability
      constants of dexamethasone/glu-glu-beta-CD and dexamethasone/gal-glu-beta-CD
      complexes are the same, which means that the sugar moiety of the side chain in
      beta-CD has little effect on stability constants. After the dexamethasone/gal-glu
      beta-CD complex or the dexamethasone/glu-glu-beta-CD complex (dexamethasone: 1
      mg/body) was administered intravenously to mice, dexamethasone concentrations in
      liver tissue and blood were measured. The dexamethasone/gal-glu-beta-CD complex
      (66.1 +/- 1.7 micrograms as dexamethasone/gram of liver tissue) was distributed
      to liver tissue significantly more than the dexamethasone/glu-glu-beta-CD (beta
      CD) complex (59.9 +/- 1.0 micrograms as dexamethasone/gram of liver) at 30 min
      after administration (p < .05). Sugar-branched-beta-CD gave a water-soluble and
      stable complex for dexamethasone and changed the disposition of dexamethasone.
      Sugar-branched-beta-CDs are potentially excellent carriers for a steroidal
      injectable formulation.

PMID- 10596357
TI  - Solubilization of biphenyl dimethyl dicarboxylate by cosolvency.
AB  - Biphenyl dimethyl dicarboxylate (BDD) is a synthetic analogue of schizandrin C,
      one of the components isolated from Fructus schizandrae, and has been widely
      prescribed for improvement of liver functions and symptoms of patients with liver
      disease. However, its oral preparations have been known to have limited
      bioavailability due to its extremely low solubility in water, and its solubility
      problem also limits preparation of its parenteral dosage forms. In this research,
      we searched for solvent systems to solubilize BDD to overcome these problems. The
      ternary solvent systems of N,N'-dimethylacetamide (DMA)/alcohol/water and
      Cremophor EL/DMA/alcohol were studied intensively for this purpose. BDD was
      solubilized effectively in these cosolvents, and the results showed that the
      cosolvent systems were effective for solubilizing BDD up to the concentration
      that might be employed for preparation of parenteral dosage forms. Formulation of
      a BDD concentrate for intravenous infusion was proposed employing the cosolvent
      system of Cremophor EL/DMA/alcohol.

PMID- 10596358
TI  - In vitro conditions for the study of the in vivo performance of sustained-release
      theophylline matrix tablets administered in fasted conditions and with a high-fat
      diet.
AB  - Dissolution profiles of theophylline (TP) from three types of sustained-release
      (SR) matrix tablets (plastic [PL], lipid [LP], and hydrophilic [HP]) in different
      dissolution media, with and without enzymes, were established. Also investigated
      was the influence of a treatment of the tablets with peanut oil prior to the
      dissolution test. The in vivo behavior of the tablets under the fasted state and
      with the concomitant administration with a high-fat diet was previously
      evaluated; the diet produced changes in the absorption profiles for the three
      matrix tablets in comparison with fasted administration. Level A correlations
      were obtained between cumulative percentage dissolved (CPD) and cumulative
      percentage absorbed (CPA). For the fasted condition, better correlations were
      obtained with water as the dissolution medium for the HP and LP matrix; for PL
      matrix, the best correlation was obtained with a medium with gradual change of
      pH. The pretreatment with peanut oil showed better correlations for the fed
      state.

PMID- 10596359
TI  - Formulation development of allopurinol suppositories and injectables.
AB  - Allopurinol was formulated into injectable and suppository dosage forms. The
      injectable formulation was prepared by dissolving allopurinol in a cosolvent
      system consisting of dimethyl sulfoxide (DMSO) and propylene glycol (v/v =
      50/50). The stability of allopurinol in the cosolvent system was studied under
      accelerated storage conditions, and results indicate first-order degradation
      kinetics with an activation energy of 24.3 kcal/mol. The development of
      suppository dosage forms was performed by formulating allopurinol with
      polyethylene glycol (PEG) mixtures of different molecular weights. In vitro
      release profiles of suppositories formulated with different polyethylene bases
      were obtained in the pH 7.4 buffer solution using the USP 23 paddle method at 100
      rpm. Results indicate that the release rate of the suppository formulations
      containing PEG 1500/PEG 4000 at the ratio (w/w) of 2.5/10 to 10/2.5 appeared to
      be similar. However, the addition of sodium lauryl sulfate in the suppository
      decreased the release rate of allopurinol significantly. A future study to
      establish in vitro/in vivo correlation (iv/ivc) is suggested.

PMID- 10596360
TI  - Percutaneous transport of diclofenac sodium from mixtures of fatty alcohol (or
      fatty acid) and propylene glycol through the rabbit abdominal skin.
AB  - Diclofenac sodium is a nonsteroidal anti-inflammatory drug with analgesic,
      antipyretic, and anti-inflammatory activity. When used in a topical application,
      diclofenac can diffuse through the skin and into the subcutaneous tissue to
      effect the anti-inflammatory action. In this study, in vitro evaluations of the
      percutaneous transport of diclofenac sodium in various bases containing fatty
      alcohols/propylene glycol or fatty acid/propylene glycol mixtures through the
      abdominal skin of the rabbit were investigated. Results show that the transdermal
      flux of diclofenac sodium in the fatty alcohol/propylene glycol bases of the same
      ratio is affected by the chain length of the fatty alcohol, and its effect is in
      the order of C10 > C12 > C14 > C18. However, the transdermal flux of diclofenac
      sodium in the fatty acid/propylene glycol bases of the same ratio is also
      affected by the chain length of the fatty acid, but no absolute relationship was
      found. For the same chain length of fatty acid and fatty alcohol used in the
      formulation base that was otherwise the same, the transdermal flux of diclofenac
      sodium is higher in the formula containing fatty alcohol than that containing
      fatty acid.

PMID- 10596361
TI  - Effect of aging on the dissolution stability of glibenclamide/beta-cyclodextrin
      complex.
AB  - The effect of aging on the physicochemical stability of glibenclamide (GB)/beta
      cyclodextrin (CD) systems and tablets made with CD-complexed GB was studied.
      Infrared (IR) spectrometry and X-ray diffraction analyses showed that the
      properties of the products were unaffected even after a storage period of 4
      years, except that the crystallinity of GB/CD physical mixture was decreased with
      aging. The dissolution rate of the kneaded mixture, inclusion complex, and
      tablets made with the inclusion complex were unaffected on storage for 4 years.
      Thus, the age-related dissolution problems of GB can be overcome by utilizing the
      GB/CD complex in the tablet dosage form.

PMID- 10596362
TI  - Determination of micro-pH in solid drug delivery systems.

PMID- 10596363
TI  - IVIVC: indices for comparing release and response profiles.

PMID- 10596364
TI  - [Inclusion of psychopathologic methods for diagnosis of early neurotoxic effects
      from lead and organic solvent mixtures].
AB  - To verify occupational neurotoxic effects it will be necessary to enlist the help
      of clinical psychologists and psychiatrists. However, no unified professional
      test battery exists to date. 119 healthy workers (26 lead-exposed, 45 exposed to
      mixed organic solvents, and 48 controls) were tested using uniformly standardised
      psychological and psychiatric methods. Long-term lead-exposed employees showed an
      increased number of psychoneurovegetative symptoms and deficits in attention
      performance according to the results of the Seeber-PNF and the Brickenkamp-d2
      tests. There was no difference between the control group and persons exposed to
      the organic solvents test. Many parameters correlated to the dose of the toxic
      agent in the lead-exposed group. SCL-90-R, AMDP, and HAMD merely hinted at
      differences between the exposed subjects and the controls. Psychological and
      pathopsychological methods are necessary but will not suffice to detect early
      effects after long-term exposure to lead or organic solvents.

PMID- 10596365
TI  - [Dementia of the Alzheimer type in women].
AB  - Within the different kinds of dementia, Alzheimer's Disease (AD) obviously is the
      only one showing relevant gender differences, concerning epidemiology, risk
      factors and cognitive deficits. Women more often suffer from AD, achieve lower
      Mini Mental Status Test scores when demented and show lower verbal skills. The
      possibility of using estrogen as a therapeutic agent, either only or as an
      augmentation to acetylcholinesterase inhibitors, could become more important for
      clinical practice, as it is said to cause distinct improvements of cognitive
      skills. Epidemiological studies were able to show that estrogen replacement
      therapy in menopausal women lowers risk of AD.

PMID- 10596366
TI  - [The concept of negative and positive symptoms in a historical perspective].
AB  - Over the last years, the modern psychopathological classification of
      schizophrenic symptoms into the groups of negative and positive symptoms has
      gained more relevance to the diagnosis, therapy and prognosis of this disorder.
      We delineate the historical concept of negative and positive elements, which was
      developed by the British neurologist John Hughlings Jackson (1835-1911) to
      explain the pathophysiology of psychic disorders. These definitions are
      elucidated in view of the scientific context at the end of the 19th century, when
      evolutionism, positivism, psycho-physical parallelism, and the knowledge of
      neurosciences played an important part. In addition, the reception of Jackson's
      ideas by psychiatry is shown. Freud was essentially influenced by Jackson in
      developing his psychoanalytical theory of neurosis. Bleuler joined Freud and
      defined "primare" and "sekundare" symptoms of schizophrenia. In the
      phenomenological concept of schizophrenia of Huber, "Basissymptome" are
      distinguished from "End- und Uberbausymptome", which in part correspond to the
      negative and positive symptoms of today, respectively. The paper provides a
      historical survey of the Jacksonian influences on concepts of schizophrenia.

PMID- 10596367
TI  - [Patient satisfaction with psychiatric care. Historical perspective, methods and
      results from the international literature].
AB  - Whereas evaluations of patients' satisfaction have been made in the U.S.
      beginning in the early 50's, there has been an increasing interest in German
      language countries only in recent years. The present article summarizes the aims,
      methods and results of patient satisfaction surveys. A selection of
      questionnaires comprising the Client Satisfaction Questionnaire (CSQ, 43), the
      General Satisfaction Questionnaire (GSQ, 37) and the Verona Service Satisfaction
      Scale (VSSS, 72) is described in detail. The vast majority of the published
      studies suggest a high rate of general satisfaction with psychiatric inpatient
      services, whereas most of the more specific findings remain less well
      demonstrated. The main problem involved with this type of survey seems to be the
      term "patient satisfaction", which is defined as the relation between the
      patient's expectations in regard to psychiatric services and the perception of
      the service the patient has received. This means that the level of patient
      satisfaction itself does not allow a conclusion to be drawn on the objective
      quality of a psychiatric treatment. Nevertheless the authors are convinced of the
      importance of patient satisfaction questionnaires when these questionnaires are
      part of a quality assurance program.

PMID- 10596368
TI  - [Neuronal potassium channel opening with flupirtine].
AB  - The spectrum of action of flupirtine includes analgesic, muscle-relaxant and
      neuroprotective properties. The substance's mechanism of action has yet to be
      fully explained. Over the past few years, however, evidence has accumulated that
      flupirtine interacts with the glutamatergic N-Methyl-D-Aspartate (NMDA) receptor.
      Although it was not possible to demonstrate a direct effect on the NMDA receptor,
      all of the findings pointed to an indirect influence on the NMDA receptor in the
      sense of a functional NMDA antagonism. It was thus postulated that a site of
      action "up- or downstream" of the NMDA receptor is influenced. Such a site of
      action proved to be the G-protein-activated inwardly rectifying K+ channels
      (GIRK), the opening of which leads to a stabilization of the resting membrane
      potential of neuronal cells and thus causes an indirect inhibition of the NMDA
      receptor. At therapeutically relevant concentrations, flupirtine is a neuronal
      potassium channel opener. This mechanism may explain the spectrum of action of
      flupirtine. Selective neuronal potassium channel opening (SNEPCO) thus proves to
      be a new principle of action, making flupirtine the prototype of a new substance
      class with analgesic, muscle-relaxant and neuroprotective properties. The
      experimental basis for this working hypothesis and the resulting model concepts
      are presented from the perspective of a four-stage approach.

PMID- 10596369
TI  - [Virus encephalitis with symptomatic Parkinson syndrome, diabetes insipidus and
      panhypopituitarism].
AB  - Virusencephalitis is characterised by clinical symptoms of a parenchymatous
      inflammation. In addition, early mental status changes often occur as a result of
      virusencephalitis, beside focal neurological deficiencies, epileptic seizures,
      cerebral compression, even coma. Other pathological manifestations of
      virusencephalitis are disturbances of the neurohumoral and the endocrine system,
      which are often recognised and treated too late. This case report describes
      symptoms, treatment, and complications of a 76 year old female in-patient, who
      was diagnosed with virusencephalitis. The number of lymphocytes in the
      cerebrospinal fluid was increased to 30 cells per microliter, liquor albumin was
      1705 mg/l, liquor sugar was 53 mg/dl and liquor lactat was 1.9 mmol/l. IgM
      antibodies against herpes viruses were found in the cerebrospinal fluid and
      distinct contrasting foci were found near the mammillary bodies, hypothalamus,
      tractus opticus, hypophyseal stalk and right parahippocampal in the magnetic
      resonance imaging of the head, indicating a focal herpes simplex encephalitis.
      Within seven days, the following symptoms developed: akinetic parkinsonian
      syndrome, central diabetes insipidus with hypernatremia and polyuria (6 l/die),
      hypothyreosis, adrenal insufficiency with adynamia, sopor, hypotension and even
      hypophyseal coma. Panhypopituitarism was diagnosed after measuring the basal
      hormone levels (ACTH, TSH, FT3, FT4, Cortisol, Prolactin, LH, FSH, ADH) and
      conducting the pituitary stimulation test. The severeness of all symptoms was
      slightly improved after substitution with antidiuretic hormone at 0.4
      microgram/die and administration of hydrocortisone at 50 mg/die. Administration
      of amantadine sulphate at 0.6 g/die and L-dopa at 187.5 mg/die for 14 days
      resulted in a complete regression of the parkinsonism. After administration of
      aciclovir at 2.25 g/die for 21 days a complete regression of the clinical
      symptoms could be reached in connection with a decrease of 90% in number and size
      of cerebral contrasting foci in the magnetic resonance imaging of the head. Three
      month after therapy, clinical examination and blood serum analysis revealed
      persistent panhypopituitarism. The present case report is the first description
      of a viral infection on of the central nervous system (CNS) in combination with
      parkinsonism, diabetes insipidus, persistent panhypopituitarism and
      hyperprolactinemia. Early treatment of viral infections of the brain can improve
      a patient's prognosis dramatically. Early determination and early treatment of a
      patient's neurohumoral parameters is therefore critical to prevent or reverse
      early mental status changes like attention disturbances, alterations of
      personality and behavior, apathy, and slowed cognition.

PMID- 10596370
TI  - The coupling of differential display and AFLP approaches for nonradioactive mRNA
      fingerprinting.
AB  - We have modified the differential display of 3'-end restriction fragments of cDNA
      technique by combining it with the amplified fragment length polymorphism (AFLP)
      approach and silver staining. Modified oligo-dT primers were used for a reverse
      transcription step. ds cDNA was digested with the Mse I restriction enzyme and
      then ligated with an AFLP adapter. The modified template was amplified with oligo
      dT primers in a preamplification step (asymmetric PCR) that enriched the template
      for 3'-end sequences; subsequently, the enriched template was amplified with an
      AFLP primer having a selective extension and an anchored oligo-dT primer
      (conventional PCR step). We demonstrated that the asymmetric preamplification
      step facilitates the preferential amplification of 3'-end fragments and the
      resulting PCR products can be clear resolved on silver-stained gel. The presented
      procedure takes advantages of silver-stained gels, generates reproducible display
      patterns, and allows reliable reamplification of isolated fragments which contain
      both upstream and downstream primer sequences.

PMID- 10596371
TI  - The basic structure of filamentous phage and its use in the display of
      combinatorial peptide libraries.
AB  - Combinatorial peptide libraries have been playing a major role in the search for
      new drugs, ligands, enzyme substrates, and other specifically interacting
      molecules. The principal features of these libraries require a versatile
      repertoire, an easily identifiable tag for each of the library members, a simple
      method of synthesis, and a compatibility with the biochemical milieu. Two types
      of combinatorial libraries are in use: synthetic libraries and biological (mainly
      phage display) ones. An advantage of the biological libraries is due to the
      ability of each of the library members to replicate itself and to the fact that
      they carry their own coding sequences. The uniqueness of filamentous phage is
      that of its five virion proteins, three can tolerate the insertion of foreign
      peptides, each in a distinctive manner. The major coat protein, pVIII, is capable
      of displaying hundreds of peptide copies over the phage virion, pIII can display
      either one or five copies, and pVI, as opposed to the first two, displays its
      peptides such that the carboxy terminus is oriented outward. A major drawback of
      filamentous phage is its size. The length of an intact phage particle is 930 nm
      and it contains an ssDNA of 6400 bp. 2800 copies of the major coat protein form a
      "fish scale" cover over most of the virion DNA, whereas five copies of pIII,
      which has been the major protein used for library display, and five copies of pVI
      are located at one end of the filamentous virion. There is no doubt that in order
      to improve the quality of filamentous phage libraries, the size of phage should
      be drastically reduced. Comprehensive research on the phage life cycle and its
      structure will lead us to the construction of miniature phage and to other
      methods that will enable an in vivo expanding of the library repertoire as well
      as to binding-induced specific clone-proliferation.

PMID- 10596372
TI  - Heavy metals bioremediation of soil.
AB  - Historical emissions of old nonferrous factories lead to large geographical areas
      of metals-contaminated sites. At least 50 sites in Europe are contaminated with
      metals like Zn, Cd, Cu, and Pb. Several methods, based on granular
      differentiation, were developed to reduce the metals content. However, the
      obtained cleaned soil is just sand. Methods based on chemical leaching or
      extraction or on electrochemistry do release a soil without any salts and with an
      increased bioavailability of the remaining metals content. In this review a
      method is presented for the treatment of sandy soil contaminated with heavy
      metals. The system is based on the metal solubilization on biocyrstallization
      capacity of Alcaligenes eutrophus CH34. The bacterium can solubilize the metals
      (or increase their bioavailability) via the production of siderophores and adsorb
      the metals in their biomass on metal-induced outer membrane proteins and by
      bioprecipitation. After the addition of CH34 to a soil slurry, the metals move
      toward the biomass. As the bacterium tends to float quite easily, the biomass is
      separated from the water via a flocculation process. The Cd concentration in
      sandy soils could be reduced from 21 mg Cd/kg to 3.3 mg Cd/kg. At the same time,
      Zn was reduced from 1070 mg Zn/kg to 172 mg Zn/kg. The lead concentration went
      down from 459 mg Pb/kg to 74 mg Pb/kg. With the aid of biosensors, a complete
      decrease in bioavailability of the metals was measured.

PMID- 10596373
TI  - Flicker image comparison of 2-D gel images for putative protein identification
      using the 2DWG meta-database.
AB  - With the availability of two-dimensional (2-D) gel electrophoresis databases that
      have many characterized proteins, it may be possible to compare a researcher's
      gel images with those in relevant databases. This may lead to the putative
      identification of unknown protein spots in a researcher's gel with those
      characterized in a given database, saving the researcher time and money by
      suggesting monoclonal antibodies to try in confirming these identifications. We
      have developed two tools to help with this comparison: (1) Flicker,
      http:/(/)www.lecb.ncifcrf.gov/flicker/, a Java applet program running in the
      researcher's Web browser, to visually compare their gels against gels on the
      Internet; and (2) the 2DWG meta-database, http:/(/)www.lecb.ncifcrf.gov/2dwgDB /,
      a searchable database of locations of 2-D electrophoretic gel images found on the
      Internet. Recent additions to Flicker allow users to click on a protein spot in a
      gel that is linked to a federated 2D gel database, such as SWISS-2DPAGE, and have
      it retrieve a report from that Web database for that protein.

PMID- 10596375
TI  - An antibody-lectin sandwich assay for quantifying protein glycoforms.
AB  - We describe an antibody-lectin sandwich assay for quantitation of glycoforms of
      proteins. The assay uses deglycosylated IgG antibody immobilized on a microtiter
      plate to capture the protein of interest from the sample. The particular
      glycoform is then identified by reaction with biotin-labeled lectin, which is
      measured using streptavidin/alkaline phosphatase. The assay can be adapted to
      quantitate any protein's glycoforms by simply substituting the antibody and
      lectin with specific alternatives.

PMID- 10596377
TI  - Fast isolation of recombinant baculovirus by antibody screening.
AB  - We describe a rapid and efficient scheme for the isolation and purification of
      recombinant baculoviruses. The method is based on the detection of foreign
      proteins in cellular lysates of baculovirus-infected insect cells by antibody
      screening. The recombinant virus is purified by repeated serial dilutions. The
      method allows the identification and purification of recombinant viruses within 2
      to 3 wk. This procedure selects for recombinant baculoviruses that highly
      overproduce the desired protein product.

PMID- 10596376
TI  - Immunodiagnosis of childhood malignancies.
AB  - Immunodiagnosis utilizing immunohistochemical techniques is currently the most
      commonly utilized and readily available method of ancillary diagnosis in
      pediatric oncopathology. The methodology comprises relatively simple steps, based
      on straightforward biologic concepts, and the reagents used are generally well
      characterized and widely used. The principle of cancer immunodiagnosis is based
      on the determination of neoplastic lineage using detection of proteins typical of
      cell differentiation pathways. Methodology sensitivity varies and has become
      greater with each new generation of tests, but technical draw-backs should be
      considered to avoid excessive background or nonspecific results. Automated
      instrumentation offers a degree of accuracy and reproducibility not easily
      attainable by manual methods.

PMID- 10596378
TI  - Etomidate dose-response on somatosensory and transcranial magnetic induced spinal
      motor evoked potentials in primates.
AB  - There is growing interest and need to monitor reliably both motor (MEP) and
      somatosensory (SEP) evoked potentials under anesthesia. On a pre-established
      primate model, the present study examined the effect of incremental etomidate
      (ET) dosages on spinal neural MEPs to transcranial magnetic stimulation (TMS) and
      posterior tibial rate (PTN) SEPs. Through a small thoracic T11-T12 laminotomy, an
      insulated double bipolar electrode was inserted epidurally in seven cynomolgus
      monkeys. Spinal TMS-MEPs, PTN-SEPs, and frontal EEG were tested against graded
      increase of ET doses. Etomidate 0.5 mg kg-1 i.v. was initially given and followed
      by 30 min continuous infusion of 0.01 mg kg-1 min-1, 0.018, 0.032, 0.056, 0.1,
      and 0.18 mg kg-1 min-1 in that order. Measurable spinal MEPs and SEPs were
      recorded under deep ET anesthesia (total 12.38 mg kg-1 cumulative dose over 180
      min). The EEG showed marked slow wave and graded burst suppression at cumulative
      dose of > or = 3.14 mg kg-1. The direct (D) and subsequent initial indirect (I)
      waves (I1, I2, I3) were reproducible at doses < 0.18 mg kg-1 min-1 infusion. The
      latter I-waves (I4 and I5) showed graded loss at infusion dosage 0.056 mg kg-1
      min-1. Etomidate remains an anesthetic of attractive features in neuroanesthesia.
      In the primate model, neural MEPs-SEPs were reproducible despite the exceedingly
      high dose of ET and markedly depressed EEG. Moreover, MEP-SEP can be monitored
      during ET burst-suppressive neuroprotective state. The study may set a model in
      humans for intra-operative multi-modality neurophysiologic recording under ET
      based anesthesia.

PMID- 10596380
TI  - Tissue plasminogen activator and plasminogen activator inhibitor in patients with
      acute ischemic stroke: relation to stroke etiology.
AB  - Recent studies suggest that high plasma levels of tissue-type plasminogen
      activator (tPA) and its inhibitor (plasminogen activator inhibitor-1, PAI-1) are
      markers of an increased risk of atherothrombotic ischemic events such as stroke
      and myocardial infarction. In this prospective study, we measured tPA antigen,
      PAI-1 antigen and activity, as well as tPA/PAI-1 complex in patients with acute
      stroke. Stroke subtypes were classified according to the TOAST criteria. From 132
      consecutively screened patients, 89 (100%) were enrolled in this study, including
      42 patients (47%) with large artery atherosclerosis (LAA), 32 (36%) with small
      vessel occlusion (SVO), and 15 (17%) with cardioembolism (CE). Nineteen age
      matched neurologic patients without manifestations of cerebrovascular disease
      served as control subjects (CS). Patients with acute stroke had significantly
      higher plasma levels of tPA antigen (p < 0.001), PAI-1 antigen (p < 0.05) and PAI
      activity (p < 0.05) than patients in the control group. t-PA antigen, PAI
      activity and tPA/PAI-1 complex levels were similar regardless of stroke etiology.
      Only PAI-1 antigen was lower in patients with cardioembolic stroke than in stroke
      patients with LAA (p < 0.05). Plasma tPA antigen, PAI-1 antigen, and PAI activity
      are significantly increased in patients with acute ischemic stroke. Except for
      PAI-1 antigen, this increase appears not to be related to the underlying stroke
      etiology.

PMID- 10596379
TI  - Topographical analysis of proliferating cells in meningiomas. Regional
      heterogeneity of the ability of tumors to proliferate.
AB  - Regional heterogeneity of the ability of tumors to proliferate has been pointed
      out, but its topographical analysis has not been studied in detail. To evaluate
      the distribution of highly proliferating cells in totally resected meningiomas,
      seven cases (including one recurrent case) were investigated in this study.
      Immunostaining of PCNA was performed on the sections crossing the equator of the
      tumors. These sections were divided into multi-squares with sides of 500
      micrometers. The proliferating potential was determined as the PCNA positive cell
      count in each square. By painting those squares in eight kinds of color
      corresponding to the value of the PCNA positive cell count, maps of proliferative
      ability were made. To predict the localization of proliferating cells, we studied
      these maps in relation to the following: MR image, calcification, distance from
      the dural attachment and distance from the tumor capsule. Maps of the PCNA
      positive cell count showed the intra-tumoral heterogeneity of proliferative
      ability in all cases. Most of the cases showed homogeneous enhancement on MRIs
      and these images could not be a predicting factor of the highly proliferating
      area. There was no significant relationship between the calcification and the
      PCNA positive cell count. Although the proliferating ability was not correlated
      with the distance from the dural attachment, inner regions distant from the
      capsule showed higher proliferative ability in all cases. From these results, one
      should be aware that the information from the samples of meningiomas do not
      reflect the proliferating ability of the whole tumor.

PMID- 10596381
TI  - Paraclinoid aneurysms of the internal carotid artery: hydraulic simulation study
      on their locations and shape of the carotid siphon.
AB  - Hemodynamics of paraclinoid aneurysms were investigated focusing on the effects
      of their locations and shape of the carotid siphon. A transparent silicon model
      of the carotid siphon was constructed and a model aneurysm was attached to the
      outside of the curvature at three different sites. Glycerol solution was perfused
      into the model, and the half-life of the dye injected into the aneurysm was
      calculated as an index of the stagnant flow. Values of half-life changed
      significantly depending on the aneurysmal location and the siphon angle. When the
      siphon angle was 0 degree where C2 and C4 segments were parallel to each other,
      the half-life value was the lowest in the C2-C3 junction aneurysm, highest in the
      C3 segment aneurysm and intermediate in the C2 segment aneurysm. While the C2-C3
      junction aneurysm maintained low values regardless of the angle, the C3 segment
      aneurysm values decreased and C2 segment aneurysm values increased with increases
      in the angle. These changes of half-life occur because the point at which the
      faster moving fluid component strikes the curved wall changes according to the
      siphon angle. These results are considered useful to determine the surgical
      indications, treatment modalities and post-surgical management of the aneurysms.

PMID- 10596382
TI  - Middle cerebral artery blood flow velocity, end-tidal pCO2 and blood pressure in
      patients with obstructive sleep apnea and in healthy subjects during continuous
      positive airway pressure breathing.
AB  - There is conflicting evidence in the literature as to the potential effect of
      continuous positive airway pressure (CPAP) on cerebral perfusion. Compromising
      cerebral perfusion could possibly outweigh the benefit of improved oxygenation.
      Patients with the obstructive sleep apnea syndrome (OSAS) have been claimed to
      have a higher cerebrovascular reactivity to changes in end-tidal pCO2. In this
      study, we investigated 23 patients with OSAS and 16 healthy young adults in the
      waking state. Both groups performed a series of 10 min of normal breathing, 20
      min with 9 cmH2O nasal CPAP, and then 10 min of normal breathing while wearing a
      nasal CPAP mask. The following parameters were assessed: bilateral transcranial
      Doppler signal of the middle cerebral artery, systolic and diastolic blood
      pressure assessed manually, and cerebrovascular reactivity to changes in pCO2
      during hyperventilation and rebreathing into an airbag. Continuous end-tidal pCO2
      measurements were performed in 14 subjects. As compared with normal breathing
      middle cerebral artery blood flow velocity and pCO2 remained unchanged during
      CPAP. Systolic and diastolic blood pressure increased slightly by 1.2 mmHg (p =
      0.015) and 1.1 mmHg (p = 0.007), respectively. Cerebrovascular reactivity did not
      differ in the two groups. Nasal CPAP of 9 cmH2O is a safe treatment with respect
      to the maintenance of cerebral blood flow. Our study gives further evidence for
      the autoregulation's capacity to maintain cerebral blood flow velocity constant
      during different levels of intrathoracic pressure and different cerebral
      perfusion pressures. We could not demonstrate any difference in cerebrovascular
      reactivity between patients with OSAS and healthy persons.

PMID- 10596374
TI  - Generation of recombinant antibodies.
AB  - Recombinant antibody technology is opening new perspectives for the development
      of novel therapeutic and diagnostic agents. In this review we focus on advances
      in the generation of both genetically engineered humanized and fully human
      monoclonal antibodies. Methods for their production in different expression
      systems are also discussed.

PMID- 10596383
TI  - The impact-acceleration model of head injury: injury severity predicts motor and
      cognitive performance after trauma.
AB  - This study examines neuropsychological dysfunction after varying severities of
      the Impact Acceleration Model of diffuse traumatic brain injury. Adult rats (340
      g-400 g) were divided into five groups, and exposed to varying degrees of Impact
      Acceleration Injury (1 m, 2 m, 2.1 m/500 g and second insult). After injury,
      animals were allowed to recover; acute neurological reflexes, beam walk score,
      beam balance score, inclined plane score, and Morris Water Maze score were then
      assessed at multiple time points. Injury of all severities caused significant
      motor and cognitive deficits. With milder injuries these effects were transient;
      however, with more severe injuries no recovery in function was seen. The addition
      of hypoxia and hypotension made a moderate injury worse than a severe injury. The
      acute neurological reflexes, the beam balance test and the inclined plane test
      distinguished between the more severely injured groups, but were affected less by
      mild injury. The beam walk test was sensitive to mild injury, but appeared unable
      to distinguish between the severe groups. The Morris Water Maze was sensitive for
      all injury groups, but appeared to adopt a different response profile with
      secondary insult. This study has for the first time characterized the degree of
      motor and cognitive deficits in rodents exposed to differing severities of Impact
      Acceleration Injury. These data confirm that the tests considered, and the Injury
      Model used, provide a useful system for the consideration of potential therapies
      which might ameliorate neuropsychological deficits in diffuse brain injury.

PMID- 10596384
TI  - An MR image of spinal cord sarcoidosis.
AB  - We present a case of spinal cord sarcoidosis with a unique magnetic resonance
      imaging (MRI) finding. MRI of the cervical spine revealed an unusual lesion of
      low signal intensity on T2-weighted image at the core of the lesion surrounded by
      high signal intensity. T1-weighted gadolinium enhanced image showed a high signal
      at the core lesion. Low signal intensity on T2-weighted image in the case was
      suggested to be due to hemosiderin deposition. Steroid therapy dramatically
      improved clinical symptoms with a marked reduction of peripheral T2 high
      intensity area and the core lesion size detected by gadolinium enhancement.

PMID- 10596385
TI  - Hypertonic saline solution for control of elevated intracranial pressure in
      patients with exhausted response to mannitol and barbiturates.
AB  - Critically elevated intracranial pressure (ICP) represents the most important
      cause of morbidity and mortality in patients suffering from severe traumatic
      brain injury (TBI) and is a serious complication after subarachnoid hemorrhage
      (SAH). Thus new strategies for the control of ICP are required. Based on the
      evidence available hypertonic saline solution (HSS) may be a promising approach.
      It was therefore the aim of the present study to evaluate in a prospective manner
      the effects of HSS on ICP and cerebral perfusion pressure (CPP) in patients with
      therapy-resistant elevation of ICP. A total of 48 bolus infusions of HSS (7.5%, 2
      ml kg-1 b.w.; infusion rate 20 ml min-1) were given intravenously (range 1-15 per
      patient) to 10 patients (age 41 +/- 6 years) with TBI and SAH. Only patients with
      ICP > 25 mmHg not responding to standard ICP-management protocol and plasma
      sodium (Na+) concentration < 150 mmol l-1 were included in the study. Within the
      first hour after HSS application, ICP decreased from 33 +/- 9 mmHg to 19 +/- 6
      mmHg (p < 0.05) and further to 18 +/- 5 mmHg at the time of maximum effect (98 +/
      11 min post bolus). Decrease of ICP was accompanied by a rise of CPP from 68 +/-
      11 mmHg to 79 +/- 11 mmHg (p < 0.05) after 1 h and further to 81 +/- 11 mmHg at
      the time of maximum effect. Plasma Na+ concentration was 141 +/- 6 mmol l-1
      before and 143 +/- 5 mmol l-1 1 h after HSS bolus. Corresponding values for
      plasma osmolality were 302 +/- 11 and 308 +/- 12 mOsm l-1. When the ICP lowering
      effect was transient, subsequent HSS bolus was necessary 163 +/- 54 min after
      previous dosing. The present results indicate that repeated bolus application of
      HSS (7.5% NaCl, 2 ml kg-1 b.w.) is an effective measure to decrease ICP which is
      otherwise refractory to standard therapeutic approaches. Whether or not the
      therapy scheme is also suited as primary measure for the control of ICP remains
      to be established.

PMID- 10596386
TI  - Brain metabolic and ionic responses to systemic hypoxia in the newborn dog in
      vivo.
AB  - Newborns are less sensitive than adults to hypoxic/ischemic injury. However,
      research into the mechanism of the newborn's relative resistance to reduced brain
      oxygen levels is relatively scarce, and the time-scale for the disappearance of
      resistance is not known. The multiprobe assembly (MPA) has enabled us to examine
      the resistance of puppies at various ages to hypoxia via continuous,
      simultaneous, on-line measurement of various ionic, metabolic and electrical
      parameters from the cerebral cortex. The parameters measured included
      electrocorticogram (ECoG), direct current (DC) steady state potential,
      extracellular potassium (Ke+) and calcium ion concentrations and intra
      mitochondrial Nicotine amide adenine dinucleotide NADH redox levels. These
      parameters were measured under various degrees of hypoxia (fraction of
      inspiration oxygen was between 0-10%) in 6-h-old to 24-week-old puppies (n = 44).
      Sensitivity to hypoxia increased with age, being expressed in the leakage of
      potassium ions out of the cells (0.3 +/- 0.07 mM in the younger puppies and 3.0
      +/- 1.3 mM in the older puppies) following an increase in intra-mitochondrial
      NADH redox levels. Potassium ion (Ke+) leakage was apparently due to depleted
      energy stores resulting from an impairment in the balance between oxygen supply
      and demand. Although the overall effect was similar, the kinetics of these
      changes were much faster in the older puppies. The time to initial increase of
      extracellular K+ was 2.5 +/- 0.1 min in the younger puppies and 0.9 +/- 0.1 min
      in the older puppies. The time to maximum increase of NADH was 3.2 +/- 0.2 min in
      the younger puppies and 1.4 +/- 0.1 min in the older puppies. Our results
      indicate that the older puppies utilize the existing oxygen faster than the
      younger puppies. It is concluded that the increased resistance of newborn puppies
      to hypoxia is due to intrinsic properties of the brain itself, like the ability
      of the membrane to maintain ionic homeostasis.

PMID- 10596387
TI  - Decrease in N-acetylaspartate without commensurate accumulation of acetate in
      focal cerebral ischemia in rat.
AB  - N-acetylaspartate (NAA) is a plausible marker of neuronal viability which
      decreases in a variety of neurodestructive conditions. To elucidate the mechanism
      that leads to NAA decline in two different types of cerebral ischemia in rats, we
      simultaneously determined cortical concentrations of NAA and its hydrolytic
      metabolites, aspartate, and acetate by high-resolution 1H-NMR spectroscopy. NAA
      decreased almost linearly up to 24 h in both decapitation induced global cerebral
      ischemia, and in ischemic cortices of focal ischemia. Acetate was increased
      continuously for up to 24 h of global ischemia, while in focal cerebral ischemia
      it was increased transiently at 6 h. Aspartate did not show any change in global
      ischemia, while it was decreased in focal ischemia. Although NAA decreased
      similarly in the brain with global and focal ischemia, temporal changes of two
      NAA hydrolytic metabolites were different in each type of ischemia. The present
      results suggest hydrolytic degradation of NAA may be modified alternatively under
      each pathophysiologic condition.

PMID- 10596388
TI  - Corticotropin-releasing hormone synthesizing neurons in the hypothalamic
      paraventricular nucleus of rats neonatally treated with monosodium glutamate can
      respond to different stress paradigms.
AB  - Neonatal administration of monosodium glutamate (MSG) produces pathological
      lesions in many brain regions. There are indications that MSG treatment could
      also influence the neurons of the hypothalamic paraventricular nucleus (PVN). The
      goal of this study was to find out whether MSG treatment could alter the activity
      of the corticotropin-releasing hormone synthesizing neurons, i.e. the principal
      regulators of the corticotropin hormone secretion, located in the medial
      posterior subdivision of the PVN. The activity of CRH neurons was assessed by
      changes in CRH mRNA levels in response to both stimulatory and inhibitory
      conditions induced by immobilization and water deprivation, respectively. In
      addition, effect of the circulating glucocorticoid deficit induced by bilateral
      adrenalectomy was investigated. The obtained data show that in MSG-treated
      animals the rise in CRH mRNA in response to immobilization stress and
      adrenalectomy as well as the decrease after water deprivation were similar to the
      changes seen in controls. In addition POMC mRNA changes in MSG-treated animals
      indicate an uninterrupted capability of CRH neurons to transform different
      signals to corticotropin cells. It can be concluded that CRH neurons of the PVN
      are not functionally altered, in spite of the widespread neurotoxic effect of MSG
      treatment.

PMID- 10596389
TI  - D1/D2 receptor synergism on CREB DNA-binding activities in the caudate-putamen of
      rat.
AB  - Cyclic AMP-responsive element-binding protein (CREB) is a transcription factor
      that is activated by cyclic AMP-dependent protein kinase and regulates the
      induction of fos. In order to elucidate the cellular pathway of D1/D2 dopamine
      receptor synergism, the effect of D1 and D2 agonists on CREB DNA-binding
      activities was studied in the caudate-putamen of rats with an ipsilateral 6
      hydroxydopamine-lesion of the medial forebrain bundle. Combined administration of
      D1 (SKF38393) and D2 (bromocriptine or quinpirole) agonists resulted in enhanced
      CREB-binding activities at a dose that did not enhance it when given separately.
      These results suggest that D1/D2 dopamine receptors play synergistic role in
      inducing CREB DNA-binding activities in the dopamine-depleted caudate-putamen of
      rats.

PMID- 10596390
TI  - Glycerol attenuates the adherence of leukocytes in rat pial venules after
      transient middle cerebral artery occlusion.
AB  - Intravenous infusion of glycerol has been used in patients with a cerebral
      infarction, expecting improvement in brain edema and cerebral blood flow (CBF).
      However, the mechanism of the improvement of CBF has not been clearly
      demonstrated. The aim of this study in the rat pial microvasculature after
      transient middle cerebral artery occlusion (MCAO) is to examine the effects of
      glycerol on leukocyte-endothelium interaction, which plays a critical role in the
      pathogenesis of brain injury by ischemia/reperfusion and concerns induction of
      secondary brain damage. Rhodamine 6G-labeled leukocytes at the brain surface were
      visualized with intra-vital fluorescence videomicroscopy through a closed cranial
      window and an analysis was made of the number of adherent leukocytes and the
      centerline leukocyte velocity in the venule before MCAO, after reperfusion of
      MCAO and after infusion of glycerol (Group 1) or saline (Group 2). The number of
      adherent leukocytes decreased and the centerline leukocyte velocity increased
      statistically significantly immediately after the infusion of glycerol in Group
      1, but there was no significant change in Group 2. The infusion of glycerol
      washes away the adherent leukocytes and prevents them from interfering with the
      blood cell and plasma flow. Furthermore, secondary brain damage may be relieved
      by decreasing the adherence of leukocytes. In conclusion, modulating the
      adherence of leukocytes is one of the important factors in the neuroprotective
      effect of glycerol.

PMID- 10596391
TI  - Effect of intracarotid bradykinin infusion on cerebral blood flow in dogs.
AB  - We examined whether intracarotid infusion of bradykinin altered circulation in
      the normal canine brain. Twenty-four anesthetized dogs were divided into four
      groups receiving different doses of bradykinin (1, 2.5, 5, and 10 micrograms kg-1
      min-1). Regional cerebral blood flow (rCBF) was measured continuously using laser
      Doppler flowmetry through a burr hole in the frontal bone. Systemic blood
      pressure (SBP) and heart rate (HR) were monitored simultaneously. Higher doses of
      bradykinin significantly but temporarily decreased rCBF and SBP immediately after
      the start of infusion; these parameters rapidly recovered and then were stable
      through the rest of the infusion. During this period, percent change in rCBF and
      SBP was small, and differences between groups were not significant. On the other
      hand, HR increased during infusion and remained high. SBP, rCBF, and HR returned
      to pre-infusion levels after bradykinin was stopped. The results suggest that
      intracarotid infusion of bradykinin for treatment of brain tumors would be safe
      in terms of circulation to the uninvolved brain.

PMID- 10596392
TI  - Effect of craniopharyngioma fluid on femoral vessels of rat.
AB  - Craniopharyngioma fluid spillage during surgery is reported to cause aseptic
      meningitis, but effects of the spillage on vessels have not yet been studied.
      Therefore we experimentally studied the effect of external contact on femoral
      vessels of the rat to assess its possible role in the cerebral vascular
      complications. The major direct effect of the craniopharyngioma fluid on the
      femoral vessels was vasospasm, appearing on the fourth day after instillation.
      The vasospasm was observed in 83% of femoral vessels studied between 4-15 days
      and one of the vessels showed intra-luminal thrombus. The difference in the
      vessel diameter after instillation (4-15 days) was compared with the controls and
      was statistically significant (p < 0.01). These findings correspond well with the
      observed deterioration on post-operative days 5-7, due to vascular complications.
      No histopathologic (light-microscopic) changes of inflammation or necrosis were
      found in the femoral vessels. Our study shows that contact of craniopharyngioma
      fluid to arteries leads to vasospasm, and spillage during surgical excision may
      contribute to vascular complications encountered in the post-operative period.
      Prevention of spillage of this fluid and the routine use of cerebral vasodilators
      to prevent ischemic complications after craniopharyngioma surgery needs further
      evaluation.

PMID- 10596393
TI  - Zygomatic arch cracking for cosmetic improvement: technical note.
AB  - We describe a simple cracking method for removing the zygomatic arch. The
      drilling line of the zygomatic arch is partially drilled from the back, and the
      surface is left undrilled. The zygomatic arch is cracked during its removal in
      order to secure its position for later fixation. Dead bone spaces can be avoided
      by this method and the zygomatic arch can be replaced in its original position.
      By adding this procedure to the standard technique, this cracking method is a
      simple, safe and useful way to achieve better cosmetic results.

PMID- 10596394
TI  - Who will determine our practice standards in the new millennium.

PMID- 10596395
TI  - Transcatheter uterine artery embolization for the management of symptomatic
      uterine leiomyomas.
AB  - Transcatheter arterial embolization has been applied traditionally in obstetrics
      and gynecology for the emergency control of pelvic hemorrhage, usually after
      failure of conventional surgical measures. Pelvic trauma is the most common,
      nongynecologic etiology of uncontrollable pelvic hemorrhage requiring use of this
      hemostatic technique. Recently, elective transcatheter arterial embolization of
      uterine leiomyomas has been performed to decrease related symptomatology in an
      attempt to avoid surgical intervention. Our objective was to review current
      pertinent data regarding this new therapeutic modality. To this goal, all
      manuscripts published in the literature regarding this topic obtained from a
      MEDLINE search for 1966 through September 1998 were selected and reviewed.
      Additional sources were identified through cross-referencing. Currently,
      approximately 193 patients worldwide have been managed with this investigational
      procedure. Main indications include symptomatic uterine leiomyomata with
      menometrorrhagia, anemia, or pain. Success rates seem promising with a very low
      failure rate. This procedure results in significant (uterine and leiomyoma)
      volume reduction of between 20 and 80 percent. Postprocedural pain is common
      during the first day after the procedure, often requiring intravenous
      nonsteroidal antiinflammatory drugs and narcotic analgesia. Rare complications
      include endometritis, pyometra, and uterine necrosis, which may require
      hysterectomy. Reported follow-up time ranges between 6 and 60 months.
      Implications on subsequent fertility have not been established. Although
      successful pregnancies subsequent to this procedure have been reported, because
      of the unknown long-term effect of this procedure on fertility or perinatal
      outcome, this technique should not be performed when future fertility is desired.
      This review suggests that although not currently accepted as standard of care,
      transcatheter embolization of the uterine arteries can be considered as a
      nonsurgical technique for the management of appropriately selected patients.
      TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING
      OBJECTIVES: After completion of this article, the reader will be able to explain
      the current indications and contraindications of transcatheter uterine artery
      embolization of leiomyomas; to identify the various complications of the
      procedure and the type of embolic materials used; and to estimate the success
      rate of this procedure in the current literature.

PMID- 10596396
TI  - Heritable coagulopathies in pregnancy.
AB  - Heritable coagulopathies are leading causes of maternal thromboembolism and are
      associated with an increased risk of maternal and perinatal morbidity and
      mortality. The most common of these disorders are antithrombin III deficiency,
      protein C deficiency, protein S deficiency, activated protein C resistance
      resulting from the factor V Leiden mutation, elevated prothrombin activity
      associated with a mutation in the prothrombin gene, and hyperhomocystinemia. The
      maternal risk of a thromboembolic episode is increased by a factor of eight in
      the presence of any of these heritable states. In addition, the relative risk for
      a stillbirth in the presence of one of these disorders is 3.6. These conditions
      are also associated with intrauterine growth retardation and preeclampsia. Proper
      management of heritable coagulopathies during pregnancy is essential to reduce
      the risk of these serious sequelae. Patients with newly diagnosed deep-vein
      thromboses or pulmonary emboli should be treated with therapeutic levels of
      unfractionated or low molecular weight heparin, followed by subsequent
      prophylactic heparin therapy. All patients with a history of thromboembolism
      before pregnancy or evidence of any of these coagulopathies may be offered
      prophylactic therapy with low molecular weight heparin. Patients with
      antithrombin III deficiency should receive full therapeutic heparin therapy for
      the entire pregnancy, irrespective of their thromboembolic history. Postpartum
      therapy with either heparin or warfarin is required in all cases. TARGET
      AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES:
      After completion of this article, the reader will be able to describe the various
      heritable coagulopathies that can complicate pregnancy, to state the potential
      adverse effects of heritable coagulopathies in pregnancy, and to explain the
      management of heritable coagulopathies during pregnancy.

PMID- 10596398
TI  - [The ferret. Part 3: the diseases of the ferret classified by clinical symptoms].
AB  - The articles regarding the ferret supply a practical hand-out for the companion
      animal practitioner. Features regarding housing, nutrition, and reproduction are
      briefly described followed by, more in detail, diagnostic procedures such as
      blood collection, anesthesia, small surgical procedures, preventive veterinary
      care and hospitalization of the ferret. Frequently seen clinical problems with
      their differential diagnosis are discussed including cause, clinical disease,
      diagnosis, therapy and if applicable prevention and control.

PMID- 10596397
TI  - Sterilization and its consequences.
AB  - The purpose of this review is to analyze critically the two techniques of
      sterilization (bilateral tubal ligation [BTL] and vasectomy) so that a physician
      may provide informed consent about methods of sterilization. A MEDLINE search and
      extensive review of published literature dating back to 1966 was undertaken to
      compare preoperative counseling, operative procedures, postoperative
      complications, procedure-related costs, psychosocial consequences, and
      feasibility of reversal between BTL and a vasectomy. Compared with a vasectomy,
      BTL is 20 times more likely to have major complications, 10 to 37 times more
      likely to fail, and cost three times as much. Moreover, the procedure-related
      mortality, although rare, is 12 times higher with sterilization of the woman than
      of the man. Despite these advantages, 300,000 more BTLs were done in 1987 than
      vasectomies. In 1987, there were 976,000 sterilizations (65 percent BTLs and 35
      percent vasectomies) with an overall cost of $1.8 billion. Over $260 million
      could have been saved if equal numbers of vasectomies and BTLs had been
      performed, or more than $800 million if 80 percent had been vasectomies, as was
      the case in 1971. The safest, most efficacious, and least expensive method of
      sterilization is vasectomy. For these reasons, physicians should recommend
      vasectomy when providing counseling on sterilization, despite the popularity of
      BTL. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING
      OBJECTIVES: After completion of this article, the reader will be able to predict
      the failure rates and likelihood of successful reversal of tubal ligation and
      vasectomy; to recall the difference in cost between the two sterilization
      procedures, and to describe the short-term and long-term complications associated
      with each of the two methods of sterilization.

PMID- 10596399
TI  - [The occurrence of Shiga toxin-producing Escherichia coli in humans and animals].
AB  - Shiga toxin (Stx)-producing Escherichia coli (STEC) can cause haemorrhagic
      colitis and the diarrhoea-associated form of the haemolytic-uraemic syndrome in
      humans. The main cause of STEC infections in humans is the consumption of
      contaminated food. Both sporadic cases and outbreaks of STEC infections are
      mainly associated with the consumption of undercooked (minced) beef (mainly
      hamburgers) and unpasteurized milk. Therefore cattle are regarded as the primary
      reservoir of STEC. In this article the occurrence of STEC infections in humans
      and the occurrence of STEC in food and food-producing animals in the Netherlands
      are discussed, followed by a brief discussion of possible ways to prevent STEC
      infections in humans.

PMID- 10596401
TI  - [Alternative analysis].

PMID- 10596400
TI  - [Rhinopneumonia or mycotoxin intoxication? Neurologic phenomena in horses from a
      riding school].
AB  - In the course of several days most of the 40 riding-school horses turned out in
      paddocks developed ataxia of variable severity. Five of these horses showed
      severe ataxia and tremors, became paralyzed and were euthanized. Eleven privately
      owned horses which were stabled on the same premises showed no clinical signs.
      The most likely diagnosis seemed to be the 'neurological form of EHV1', although
      the signs were not entirely typical. A few weeks later a second outbreak occurred
      among the riding-school horses and one of the privately-owned horses also showed
      signs of ataxia. In the meantime it had been shown that EHV1 titers in paired
      serum samples had not increased and that the cerebrospinal fluid of one of the
      severely affected horses was normal. Toxicological examination of hay, delivered
      just before the first outbreak and stored for the winter, showed a significantly
      increased concentration of lolitrem B mycotoxin (5-6 mg/kg). The hay appeared to
      have been made of ryegrass used for lawns and playing fields. Retrospectively it
      became probable that this hay occasionally been fed to the horses just before the
      onset of clinical problems. It is concluded that the horses showed the 'ryegrass
      stagger syndrome'.

PMID- 10596402
TI  - [Reaction to purchase of infected koi carp].

PMID- 10596403
TI  - Borna disease: a possible emerging zoonosis.
AB  - The Borna disease virus (BDV) causes a disease of the central nervous system
      (CNS) in several vertebrate species. The progress made over the last 30 years in
      molecular biology has allowed us to identify the unique characteristics of the
      virus, such as its persistence in the CNS and the way it is expressed. This has
      allowed scientists to classify this pathogenic agent in a new family of RNA
      viruses. BDV affects a very large spectrum of hosts and is responsible for a
      disease characterised by behavioural anomalies. The large range of intra- or
      inter-specific symptoms of this disease (from persistence of the virus without
      clinical symptoms to CNS destruction) make epidemiological studies very
      difficult. Different diagnostic tools have allowed the detection of this
      infectious agent in different species around the world (central Europe, USA, UK,
      Japan, Iran, etc.). The disease can be fatal for sheep and horses (its primary
      natural hosts) and can infect other species such as rats, cattle, dogs, cats or
      pigeons. In human beings, BDV could be responsible for certain psychiatric
      disorders. In France, the limited number of epidemiological studies that have
      been conducted up until now (in veterinary and medical fields) does not allow
      scientists to ascertain whether the disease is present in France or not. Due to
      the suspected large geographical distribution of this infectious agent, however,
      we could expect the presence of BDV in France.

PMID- 10596404
TI  - Trichinella antigens: a review.
AB  - This paper presents a review of the Trichinella antigens within the context of
      species variation. As with other parasites, Trichinella antigens can be
      classified according to their localisation as surface, excretory/secretory (ES)
      and somatic components. Surface antigens are mainly constituents of the outer
      cuticle although secretions from inner parts of the body wall as well as from the
      oesophagus can temporarily accumulate in the surface. ES antigens come mainly
      from the excretory granules of the stichosome, whereas somatic constitutive
      antigens come from the internal parts of the worms. ES products are considered
      very important from an immunological point of view as they are easily targeted by
      the immune system, whereas parasite death is required for exposure of somatic
      products. Some of the antigenic components have been characterised chemically.
      Phosphorylcholine is an important hapten that modulates the immune responses in
      Trichinella infections. Glycoproteins are the major components of surface and
      excretory/secretory products. A 43-kDa glycoprotein has been regarded as a good
      candidate for diagnosis and vaccination purposes. Recently some glycans have
      received special attention either as relevant epitopes or as parasite evasion
      strategies.

PMID- 10596405
TI  - Changes in gastro-intestinal helminth species diversity in lambs under mixed
      grazing on irrigated pastures in the tropics (French West Indies).
AB  - The development of gastro-intestinal helminth diversity was monitored in lambs
      grazing alone or grazing with heifers in the ratio one heifer to four lambs. Five
      successive cohorts of lambs were studied from January 1994 to May 1996. Each
      cohort of lambs grazed irrigated pastures of Pangola grass for 4 months (from
      weaning to 6 months of age). A total of 50 lambs was necropsied and their worms
      counted and identified at the end of each grazing period. Four heifers were also
      necropsied on one occasion. Special attention was dedicated to the identification
      of the most pathogenic worm, i.e. Haemonchus spp. Malate dehydrogenase
      polymorphism in H. contortus was studied in order to evaluate changes between
      cohorts and between grazing managements. The species diversity was estimated by
      Shannon diversity indices (main species or all species). It was higher in the
      mixed grazing group than in the lambs that grazed alone. Diversity increased in
      successive cohorts. This was due in part to the acquisition of Cooperia spp. of
      cattle origin. The increase in diversity in the mixed grazing lambs corresponded
      to the lower faecal egg excretion and better weight gains recorded previously in
      that group. There seemed to be no cross-transmission of H. similis found in
      heifers and H. contortus harboured by lambs. The latter species was not
      morphologically or genetically different in the lambs grazed alone or with
      heifers, indicating that the presence of cattle did not modify qualitatively the
      transmission of H. contortus.

PMID- 10596406
TI  - Lectin histochemistry of dog major and minor salivary glands.
AB  - The distribution of different carbohydrates in dog major and minor salivary
      glands was investigated using a peroxidase-labelled avidin-biotin method to
      demonstrate binding of six lectins (Canavalia ensiformis agglutinin [Con A],
      Dolichos biflorus agglutinin [DBA], Arachis hypogaea (peanut) agglutinin [PNA],
      Glycine max agglutinin [SBA], Tetragonolobus purpurea agglutinin [TGP] and wheat
      germ agglutinin [WGA]). With PNA, there was only weak staining in serous acini of
      parotid glands. Other lectins bound, to different degrees, to different
      components of the salivary glands; differences could be detected between glands
      and between binding of different lectins to serous and mucous acinar cells and to
      the epithelial cell cytoplasm, luminal surface and contents of ducts. These
      results provide a basis for the comparison of possible changes in carbohydrates
      which may occur in salivary gland diseases.

PMID- 10596407
TI  - Rabies oral vaccination of foxes during the summer with the VRG vaccine bait.
AB  - The vaccination of foxes by distributing vaccine baits in the environment was
      initiated in France in 1986. Two campaigns per year were carried out: one in the
      spring and one in the autumn. After the spring campaigns, only 22-52% of fox cubs
      consumed vaccine baits compared to 75% of the adults and 70-80% of the adults or
      fox cubs after autumn campaigns. In order to reduce the period of time during
      which fox cubs do not have access to baits and are not immunised, a vaccination
      campaign was organised during the summer of 1992 over a contaminated area of
      25,748 km2 where vaccines had never previously been given. Vaccine bait stability
      was assessed during the same summer in the field and their appetence tested on
      captive foxes. The efficacy of the campaign was evaluated by the relative
      decrease in rabies incidence and the rate of bait uptake by foxes compared to
      those from neighbouring areas vaccinated for the first time with the same vaccine
      during the spring or autumn. Summer vaccination significantly increased (P <
      0.01) bait uptake by fox cubs (71%) compared with spring vaccination (39%), but
      no significant difference was observed for adult foxes. Moreover, the decrease in
      rabies incidence, measured during the 6-month period following the campaigns was
      less pronounced after summer vaccination (49% decrease) than when the first
      vaccination was carried out during the spring or autumn (79 and 72% decrease,
      respectively). Three campaigns led to an apparent elimination of rabies when the
      first campaign was performed in the spring or autumn, but only to a 76% decrease
      in rabies incidence density index when the first campaign was performed during
      the summer. The high thermostability of the Raboral VRG bait permits its use
      during the summer for an emergency campaign. For routine vaccination plans,
      however, the classical calendar of spring and autumn vaccination campaigns should
      continue to be preferred.

PMID- 10596408
TI  - Vaccination of Tunisian dogs with the lyophilised SAG2 oral rabies vaccine
      incorporated into the DBL2 dog bait.
AB  - The protective effect of the lyophilised SAG2 oral vaccine bait DBL2, already
      demonstrated on laboratory dogs, needed to be verified on common Tunisian dogs.
      Seven Tunisian dogs consumed totally or partially one DBL2 bait containing
      10(8.3) TCID50 of the highly attenuated rabies vaccine strain, SAG2. Five of the
      seven vaccinated animals survived a challenge administered 33 days later with a
      Tunisian canine street rabies virus to which five of the six controls that were
      not vaccinated and had no specific antibodies succumbed. The partial or total
      consumption of a single DBL2 bait thus conferred a protective immune response
      similar to that observed in laboratory dogs to dogs of poor health status. The
      sero-antibody response was, however, weak: only two vaccinated dogs exhibited a
      significant neutralising antibody response after vaccination and before the
      challenge, and four after the challenge.

PMID- 10596409
TI  - Serological and biochemical follow-up in cattle naturally infected with Fasciola
      hepatica, and comparison with a climate model for predicting risks of
      fasciolosis.
AB  - Several biological parameters were measured in 31 heifers naturally infected with
      Fasciola hepatica during one grazing season in the Belgian Ardennes. A forecast
      model based on daily temperature used to assess the risk of fasciolosis was
      fitted to this assay. Cattle were turned out to two pastures. Each pasture was
      divided into two plots: one was treated with calcium cyanamide and the other was
      left untreated. The Lymnaea truncatula snails were counted on three different
      occasions. The results indicated a poor molluscicide efficiency. Body weight
      gains, anti-Fasciola antibody levels, faecal egg counts, levels of sorbitol
      dehydrogenase (SDH) and gamma-glutamyl transferase (gamma GT), packed cell
      volumes, white blood cells and differential leucocyte counts were determined
      monthly. No statistically significant difference was observed between animals
      from the two plots regardless of the recorded data. No correlation was found
      between body weight gains and other biological data. The sampling date had a
      significant effect on the antibody responses within a same group, and on the
      enzymatic levels for all groups combined. The forecast results were consistent
      with the recorded data. Temperature was a major bioclimatic constraint on the
      transmission of life cycle, and risk of infection occurred mainly in late spring
      (May/June) and in early September. Current results might be used to issue advice
      on the need for flukicide treatment of cattle. The indicators of the infection
      considered alone were useless and it is concluded that herd diagnosis of
      fasciolosis may rely on the rise of specific antibody levels, possibly associated
      with an increase in hepatic enzyme activities.

PMID- 10596410
TI  - Effect of challenge dose and route on porcine reproductive and respiratory
      syndrome virus (PRRSV) infection in young swine.
AB  - Porcine reproductive and respiratory syndrome virus (PRRSV) is perceived to be
      highly infectious because of the rapid spread of the virus through populations of
      domestic swine throughout the world. However, no information has been published
      on the minimum infectious dose of PRRSV and the effect of challenge dose on
      clinical response. In this experiment, ten groups of pigs (n = 3 per group) were
      inoculated with one of five different quantities (10(1)-10(5) fluorescent foci
      units per millilitre) of PRRSV (isolate ISU-P) by either intramuscular or
      intranasal routes. Clinical signs and body temperature were monitored for 21
      days. Serum was collected periodically throughout the study period to monitor the
      presence of virus in serum and the early immune response of pigs. A 2-mL inoculum
      containing 10(1) fluorescent foci units of virus per millilitre was found
      sufficient to achieve infection by either route. Time to onset of clinical signs
      was highly associated with challenge dose (P < 0.01), regardless of route of
      exposure. However, no dose- or route-dependent differences in the severity of
      clinical manifestation were observed. No significant differences in the time of
      onset or degree of humoural immune response to PRRSV infection were observed
      between different treatment groups. However, intramuscular exposure appeared to
      induce a more uniform antibody response compared to intranasal exposure. These
      results confirmed that PRRSV is highly infectious; a fact that should be taken
      into consideration when designing strategies for the prevention and control of
      PRRSV.

PMID- 10596411
TI  - [Midwives and physicians--central figures of the obstetric team].

PMID- 10596412
TI  - [Pregnancy--time for a modified life style?].

PMID- 10596413
TI  - [Superoxide dismutase and catalase activity in tracheobronchial secretions after
      surfactant treatment of newborn infants with respiratory distress syndrome].
AB  - Oxygen toxicity and mechanical ventilation are main factors in the development of
      chronic lung disease in preterm infants. We examined two antioxidant enzymes,
      superoxide dismutase (SOD) and catalase, in tracheal fluid of preterm infants
      with severe respiratory distress syndrome (RDS) treated with surfactant. SOD and
      catalase catalyse the transformation of oxygen radicals and hydrogen peroxide to
      less toxic metabolites. 31 preterm infants were randomised to either single or
      multiple dose treatment with surfactant (Curosurf). Tracheal aspirates were
      obtained during routine tracheal suctioning and the two enzymes were measured
      during the first week of life. 11 of 31 preterm babies (35%) did not show any SOD
      activity in tracheal fluid. Four out of the eleven preterm infants developed
      bronchopulmonary dysplasia. Patients receiving multiple dose treatment had
      significantly higher SOD-activity (> 10 micrograms/mg albumin, p < 0.01) than
      patients with single dose treatment. Only 2 of 31 preterm babies (6%) lacked
      catalase activity in tracheal aspirate. 94% had catalase activity between 1 and
      12 micrograms/mg albumin. We conclude that, the majority of preterm infants with
      severe RDS do not have protective superoxide dismutase activity in tracheal
      fluid. Following multiple dose surfactant replacement significantly higher SOD
      activity was observed as compared to single dose therapy.

PMID- 10596414
TI  - [Rate of prenatal detection of congenital right heart defects].
AB  - Congenital right heart lesions (including tetralogy of Fallot, pulmonary valve
      stenosis, pulmonary atresia with intact ventricular septum, Ebstein's anomaly and
      dysplastic tricuspid valve) account for about 19% of congenital cardiac
      anomalies. We performed a retrospective study in order to assess the percentage
      of patients with significant right heart lesions (requiring therapy in the first
      year of life), which is detected prenatally and referred to a centre for
      perinatal treatment. From 1/1990 until 12/1997 congenital right heart lesions
      were diagnosed in 21 fetuses and 190 infants (211 patients. The majority of
      patients had tetralogy of Fallot (64%), less frequently we found critical
      pulmonary valve stenosis (9%), pulmonary atresia with intact ventricular septum
      (9%), tricuspid atresia (14%) and Ebstein's anomaly or dysplastic tricuspid valve
      (4%). Prenatally the cardiac anomaly was diagnosed in all 21 cases who were
      referred to our center (10%). The highest referral and detection rate was found
      among fetuses with Ebstein's anomaly or dysplastic tricuspid valve (5/8 patients
      = 63%) followed by fetuses with pulmonary atresia and intact ventricular septum
      (5/20 = 25%), critical pulmonary stenosis (4/18 = 22%) or tricuspid atresia (4/29
      = 14%). The prenatal referral rate was disappointing in children with tetralogy
      of Fallot (3/136 = 2.2%). A higher prenatal detection rate of congenital right
      heart lesions can be achieved only by an improvement of prenatal screening
      including the 4-chamber view and the origin of the great arteries. A first step
      would be the inclusion of the fetal 4-chamber view into the routine examination
      during the 18th-20th week of pregnancy (stage 1 of a multistage concept of
      prenatal screening) and by assessment of the outflow tracts and the great
      arteries in pregnancies associated with risk factors or anomalies of the fetus
      (stage 2 and 3 of a multistage concept).

PMID- 10596415
TI  - [Effects of oral administration of bifidobacteria on intestinal microflora in
      premature and newborn infants].
AB  - In a prospective, randomised study the effects of orally administered
      bifidobacteria on the intestinal microflora were investigated in 100 preterm and
      term neonates under intensive care conditions during the first 21 days of life.
      The 50 infants (group with bifidobacteria) received lyophilized bifidobacteria
      (Topfer Bifidus) via nasogastral tube with an initial dosage of 3 times daily
      1.25 x 10(8) bifidobacteria on day 2 of life and a daily dosage of 6 times 1.25 x
      10(8) bifidobacteria on day 3 until day 21 of life. The other 50 infants (control
      group) did not receive bifidobacteria. The preterm and term neonates were fed
      either with pasteurized mother's milk or milk from healthy female donors (n = 79)
      or with an infant formula (Alfare, n = 13) or initially with Alfare and
      thereafter with mother's milk (n = 8). The intestinal microflora of preterm and
      term neonates under intensive care conditions could be influenced by the oral
      administration of bifidobacteria. The administration of bifidobacteria resulted
      in the group of inoculated infants in a significantly earlier colonization of
      bifidobacteria (8.1 +/- 3.9 days of life) than in the control group (11.3 +/- 4.7
      days of life). On day 7 a bifidobacterial dominance (> 90% of the intestinal
      microflora) could be found in 26% of infants with inoculation of bifidobacteria
      and only in 2% of the control group (p < 0.001). These significant differences
      could be shown until day 21 of life. A difference in septicemia frequency between
      the two groups could not be demonstrated. At the beginning of the infection a
      bifidobacterial dominance was found in only one of 23 cases of septicemia.

PMID- 10596416
TI  - ["Maternal floor infarct", simultaneous manifestation of intrauterine fetal
      retardation and high maternal AFP level].
AB  - High AFP level (386.9 ng/ml) at the 16th gestational week in a 23-year old
      pregnant woman was observed. Fetal malformations or maternal causes could not be
      detected. Monitoring of fetal development and that of the fetal heart rate showed
      a worsening intrauterine growth retardation (IUGR). Due to the chronic hypoxia
      and IUGR cesarean section was performed in the 32nd gestational week and a 960 g
      female newborn was delivered. Histological examination of the placenta showed
      signs of maternal floor infarct (MFI): intervillous fibrin netlike deposition
      with the increase of extravillous trophoblast (X cells) and septal cystic
      formation. High unexplained AFP level and IUGR can draw attention to the
      possibility of intrauterine fetal demise, which indicates intensive intrauterine
      fetal monitoring.

PMID- 10596417
TI  - [Heart failure caused by myocardial hypertrophy in diabetic fetopathy].
AB  - Diabetic fetopathy is still a common clinical problem correlated with a high
      morbidity of the neonate. These children are often macrosome, suffer from
      respiratory distress syndrome due to delayed lung maturity, acidosis,
      hypoglycaemia, electrolyte-imbalances and polycythaemia. We describe a male
      neonate with diabetic fetopathy as a result of gestational diabetes of the
      mother. In addition to the symptoms described above, our patient clinically
      presented with severe hypertrophy of the right ventricle associated with
      intrauterine heart failure. The boy was born with serious prenatal asphyxia which
      made initial neonatal intensive care treatment necessary. The hypertrophic
      cardiomyopathy normalized within 6 weeks after birth without further treatment.
      Different causes of a hypertrophic cardiomyopathy (infections, metabolic
      disorders, neurologic affections, syndromes) could be ruled out, so that the
      diabetic fetopathy was the most probable cause for the condition. If we are
      looking at the heart only, this case-report suggests a good prognosis of
      septumhypertrophy as well as right ventricular hypertrophy in patients with
      diabetic fetopathy. The case also elucidates that not only the diabetes type I
      can entail serious fetal damage but also gestational diabetes can. Therefore, in
      suspect mothers screening for gestational diabetes should be expanded to oral
      glucose tolerance testing.

PMID- 10596418
TI  - Third Scientific Conference of the Charles University Faculty of Medicine and
      Teaching Hospital. 8-9 December 1998, Hradec Kralove. Abstracts.

PMID- 10596419
TI  - Influencing of spatial memory in rats by DSP-4 and mescaline.
AB  - Behavioural effects of two experimental neurotoxins, mescaline and DSP-4 (N-(2
      chloroethyl)-N-ethyl-2-bromobenzylamine), on retention of spatial orientation
      were studied in the T-maze. The stereotaxic administration of both neurotoxins
      into the selected brain structures was chosen to reveal this effect. The
      intensity and time course of the neurotoxic effect were dependent on the brain
      area administered. Nevertheless, the lengthening of the latencies in reaching the
      goal was generally more marked after mescaline in comparison with DSP-4.

PMID- 10596420
TI  - Study of the biotransformation of benfluron using the isolated perfused rat
      liver.
AB  - The isolated perfused rat liver method (IPRL) was used to find, isolate and
      identify further metabolites of Phase I and Phase II biotransformation of the
      potential cytostatic agent benfluron with special regard to the conjugation
      processes. Its pharmacokinetic profile during the perfusion was also estimated.
      The rat liver was isolated from the body and perfused in vitro using a
      recirculating perfusion system. Benfluron was added to the reservoir as a bolus
      in doses of 200, 100, 30 mg/kg of body weigh and 1 mg/perfusate volume and also
      as a continual infusion in a dose of 0.1 mg/min in separate series of
      experiments. The following metabolites formed during Phase I biotransformation
      were found in the perfusion liquid as well as in the bile: benfluron N-oxide, 9
      hydroxy benfluron, demethylated 9-hydroxy benfluron, demethylated benfluron, and
      reduced benfluron. The major Phase II metabolite found in the bile samples was
      the glucuronide of 9-hydroxy benfluron. The pharmacokinetic profile of benfluron
      in IPRL indicated its main disposition and metabolic pathway, i.e. its rapid
      extraction from perfusate by the liver (t1/2 alpha = 3.76 min), 9-hydroxylation
      followed up O-glucuronidation and excretion to the bile. It was revealed that 12%
      of the total dose of the parent compound was excreted to the bile in the form of
      conjugates during the first hour of perfusion, 32% during 1.5 hour, and 70%
      during 2 hours after the administration of benfluron. The conjugates with
      glucuronic acid represented 96-98% of all metabolites found in the bile.

PMID- 10596421
TI  - Looking back (to our hospital jubilee).

PMID- 10596422
TI  - Serological survey on immunity status against polioviruses in Italian young
      adults and in immigrants.

PMID- 10596423
TI  - [The in-vitro antigen-toxic activity of a Lactobacillus bulgaricus strain with
      regard to benzo(a)pyrene].

PMID- 10596424
TI  - [Vaccination against influenza in the elderly. Experience with adjuvant
      vaccines].

PMID- 10596425
TI  - [Physicians and vaccination against influenza: the experience of a Roman
      hospital].

PMID- 10596426
TI  - Epidemiology of Salmonella enterica serotype enteritidis in southern Italy in the
      period January 1995-June 1998.

PMID- 10596427
TI  - Seroprevalence of hepatitis A virus infection in general population of Latium.

PMID- 10596428
TI  - [The adoption of local hygiene and building regulations and their update in a
      sample of 338 Italian municipalities].

PMID- 10596429
TI  - [Quality control at the stage of meal distribution in a high-specialization
      hospital enterprise].

PMID- 10596430
TI  - [A remembrance of Prof. Mario Pitzurra].

PMID- 10596431
TI  - [Molecular methods in the epidemiology of gram-negative bacterial infections].

PMID- 10596432
TI  - [Helicobacter pylori infection in northern Sardinia: its diagnostic aspects and
      molecular characterization].

PMID- 10596433
TI  - [Molecular epidemiology in the identification of subjects susceptible to the
      effects of environmental carcinogens].

PMID- 10596434
TI  - [The role of HEV in acute non-A, non-C hepatitis and the identification of a new
      variant HEV in Italy].

PMID- 10596435
TI  - [The applicability of molecular biology in environmental virological research].

PMID- 10596436
TI  - [Multiplex RT-PCR in environmental samples].

PMID- 10596437
TI  - [A molecular epidemiology approach to assessing the genotoxic risk in the
      production of graphite electrodes: the cytogenetic markers and DNA damage].

PMID- 10596438
TI  - [Genetic screening: the contribution of 2-dimensional DNA electrophoresis].

PMID- 10596439
TI  - [The epidemiology of Salmonella enterica serotype enteritidis in southern Italy
      in 1980-98: the contribution of molecular typing].

PMID- 10596440
TI  - [The pheno- and genotyping of strains of S. enterica serotype enteritidis
      isolated on the occasion of epidemic foci in children's day care centers in
      Milan].

PMID- 10596441
TI  - [The phage typing and pulsed electrophoretic characterization of Salmonella
      enteritidis strains isolated in Tuscany].

PMID- 10596442
TI  - [Molecular typing technics in the epidemiological study of cryptococcosis].

PMID- 10596443
TI  - [The epidemiology of Burkholderia cepacia in cystic fibrosis patients: the
      initial results of a study including the genotypic typing of the strains
      isolated].

PMID- 10596444
TI  - [The genomic sequences of the human herpesvirus 8 in biological samples from HIV
      positive and -negative subjects in Sicily].

PMID- 10596445
TI  - [Molecular typing technics applied to the epidemiology of hepatitis C virus
      infection].

PMID- 10596446
TI  - [The distribution of hepatitis C virus (HCV) genotypes in the drug-dependent
      population in Palermo].

PMID- 10596447
TI  - [The molecular biology characterization of a poliomyelitis epidemic in Albania].

PMID- 10596448
TI  - [The typing of the HCMV strains responsible for congenital infection by molecular
      analysis of the UL55 gene].

PMID- 10596449
TI  - Why be a reviewer?

PMID- 10596450
TI  - Conspicuous similarities between the nervous and immune systems.

PMID- 10596451
TI  - Vascular alpha 1D-adrenoceptors: are they related to hypertension?
AB  - Heterogeneity of vascular alpha 1-adrenoceptor subtypes has been revealed by
      pharmacological and molecular biology studies (i.e., alpha 1A-, alpha 1B-, and
      alpha 1D-adrenoceptors). The alpha 1D-adrenoceptor subtype is predominantly
      involved in the contraction of a variety of vessels and its role in the control
      of blood pressure has been suggested, a phenomenon probably related to aging.
      Recent advances in the use of young pre-hypertensive rats and adult spontaneously
      hypertensive rats with one kidney and Grollman-type renal hypertension suggest
      vascular alpha 1D-adrenoceptor involvement in the increased blood pressure. The
      possible role of alpha 1D-adrenoceptors in the genesis/maintenance of
      hypertension is discussed in this review.

PMID- 10596452
TI  - Intracellular calcium and alpha 1b-adrenoceptor phosphorylation.
AB  - BACKGROUND: Desensitization of G protein-coupled receptors is associated with
      receptor phosphorylation. Two groups of kinases seem to participate in such
      receptor phosphorylation, i.e., second messenger-activated protein kinases and G
      protein-coupled receptor kinases. Calcium seems to play a role in the
      phosphorylation of some G protein-coupled receptors. The role of calcium in alpha
      1b-adrenoceptor phosphorylation has not been critically assessed. METHODS: Rat-1
      fibroblasts stably expressing the hamster alpha 1b-adrenergic receptor were used.
      To study receptor phosphorylation cells metabolically labeled with [32P]Pi were
      lysed and the receptor immunoprecipitated using a polyclonal antibody generated
      against the receptor carboxyl terminal decapeptide. Intracellular calcium was
      determined by using Fura-2 fluorescence. RESULTS: Norepinephrine, endothelin-1,
      and lysophosphatidic acid increased intracellular calcium concentration. All
      these agents and phorbol myristate acetate (PMA) induce alpha 1b-adrenoceptor
      phosphorylation. The intracellular chelator, BAPTA, abolished the increase in
      intracellular calcium induced by the previously mentioned agents but did not
      affect the receptor phosphorylation induced by norepinephrine, PMA, or
      lysophosphatidic acid. Under these conditions, receptor phosphorylation induced
      by endothelin was slightly but consistently decreased. Thapsigargin increased
      intracellular calcium concentration but was unable to induce alpha 1b
      adrenoceptor phosphorylation and decreased PMA-induced receptor phosphorylation.
      No increase in receptor phosphorylation was observed when calcium ionophores were
      used. CONCLUSIONS: Our data indicate that an increase in [Ca2+]i is not
      sufficient to induce alpha 1b-adrenoceptor phosphorylation and that buffering of
      [Ca2+]i does not alter the receptor phosphorylation induced by norepinephrine,
      lysophosphatidic acid, and PMA. A marginal role of calcium in the alpha 1b
      adrenoceptor phosphorylation induced by endothelin-1 cannot be discarded.

PMID- 10596453
TI  - Evaluation of adenosine deaminase activity in the Mycobacterium tuberculosis
      culture supernatants.
AB  - BACKGROUND: Adenosine deaminase (ADA) catalyzes hydrolytic and irreversible
      deamination of deoxyadenosine into deoxyinosine and of adenosine into inosine,
      and is related to lymphocytic proliferation and differentiation. The measurement
      of ADA activity in body fluids is a useful tool in the evaluation of
      mycobacterial infections. Elevated ADA activity has been found in pleural
      effusions of patients with pleural tuberculosis relative to those from patients
      with nontuberculous pleural diseases, and is mainly associated with cellular host
      factors such as monocyte-macrophages or lymphocytes. In contrast, there is little
      information about ADA activity measurement in mycobacteria culture supernatants.
      METHODS: We evaluated ADA activity as described by Giusti in the culture
      supernatants of eight Mycobacterium tuberculosis isolates. RESULTS: Mycobacteria
      culture supernatants did not display any ADA activity. CONCLUSIONS: This result
      supports the notion that Mycobacterium tuberculosis is not the source of ADA
      activity. However, increased ADA activity in biological fluids from tuberculosis
      patients might be due to the interaction of the mycobacterium with host factors.

PMID- 10596455
TI  - Evaluation of albendazole prodrugs in experimental trichinellosis.
AB  - BACKGROUND: Two albendazole (ABZ) prodrugs, N-methoxycarbonyl-N'-[(2-nitro-4
      propylthio) phenyl] thiourea (compound 2), and N-methoxycarbonyl-N'-[(2-nitro-5
      propylthio) phenyl] thiourea (compound 3) have recently been synthesized. These
      compounds showed greater solubility than ABZ itself. METHODS: In order to
      evaluate the biotransformation of compounds 2 and 3 to ABZ and/or ABZ-sulphoxide
      (ABZ-SO), plasma samples taken from mice treated with the prodrugs were analyzed
      by HPLC. Also, the anthelmintic activity of compounds 2 and 3 against Trichinella
      spiralis was evaluated in the mice experimentally infected with the parasite.
      RESULTS: The presence of ABZ and/or ABZ-SO was demonstrated in plasma samples
      taken at different time intervals after prodrug administration, although their
      levels were low compared to those reached in mice treated with ABZ. Additionally,
      prodrugs 2 and 3 were also detected in these samples. In regard to the
      anthelmintic activity of ABZ prodrugs, it was shown that compound 3 was more
      active than compound 2. Additionally, it was as effective as ABZ against T.
      spiralis pre-adult, adult, and female fecundity. However, compound 3 was not as
      active as ABZ against the muscle stage of the parasite. CONCLUSIONS: Compound 3
      had better anthelmintic activity against T. spiralis than compound 2. The
      bioconversion of compounds 2 and 3 to ABZ and/or ABZ-SO was demonstrated by HPLC,
      but they did not reach equivalent concentrations to that of ABZ. Prodrugs 2 and 3
      were also present in plasma samples, suggesting that prodrugs were not
      efficiently reduced in the intestine of mice.

PMID- 10596454
TI  - Mutation of highly conserved arginine residues disrupts the structure and
      function of annexin V.
AB  - BACKGROUND: Annexins are a family of structurally related proteins that bind to
      phospholipid membranes in a Ca(2+)-dependent manner. Annexins are characterized
      by highly conserved canonical domains of approximately 70 amino acids. Annexin V
      contains four such domains. Each of these domains has a highly conserved arginine
      (R). METHODS: To evaluate the role of the conserved arginines in the molecular
      structure of annexin V, negatively charged amino acids were substituted for
      arginines at positions R43, R115, R199, and R274 using site-directed mutagenesis.
      RESULTS: Mutants R199D and R274E were rapidly degraded when expressed in
      bacteria, and were not further characterized. R43E exhibited an electrophoretic
      mobility similar to the wild-type protein, while R115E migrated significantly in
      a slower fashion, suggesting a less compact conformation. R43E and R115E
      exhibited much greater susceptibility to proteolytic digestion than the wild
      type. While Ca(2+)-dependence for phospholipid binding was similar in both
      mutants (half-maximal 50-80 microM Ca2+), R43E and R115E exhibited a 6- and 2
      fold decrease in phospholipid affinity, respectively. Consistent with the
      different phospholipid affinities of the annexins, a phospholipid-dependent
      clotting reaction, the activated partial thromboplastin time (aPTT), was
      significantly prolonged by the wild-type protein and mutants R115E and R115A. The
      aPTT was unaffected by R43E. CONCLUSIONS: Our data suggest that mutation of these
      highly conserved arginine residues in each of the four canonical domains of
      annexin have differential effects on the phospholipid binding, tertiary
      structure, and proteolytic susceptibility of annexin V. The site I mutation,
      R43E, produced a large decrease in phospholipid affinity associated with an
      increase in proteolytic susceptibility. The site II mutation, R115E, produced a
      small change in phospholipid binding but a significant modification of
      electrophoretic mobility. Our data suggest that highly conserved arginine
      residues are required to stabilize the tertiary structure of annexin V by
      establishing hydrogen bonds and ionic bridges.

PMID- 10596456
TI  - Linkage disequilibrium between IDUA kpnI-VNTR haplotype in Mexican patients with
      MPS-I.
AB  - BACKGROUND: The MPS-I is an autosomal recessive disorder caused by mutations in
      the IDUA gene that induce to a deficiency of glycosidase alpha-L-iduronidase that
      is required for degradation of heparan and dermatan sulfate. This disorder
      expresses a wide range of clinical symptoms. METHODS: Kpnl (K) and VNTR (V)
      intragenic polymorphisms at the IDUA gene were studied in mestizo and Huichol
      Indian Mexican populations as well in 13 MPS-I patients. Data from Australian
      normal and MPS-I (2-4) individuals were also studied. RESULTS: Genotypes for IDUA
      K and V sites in Mexicans were in agreement with Hardy-Weinberg expectations,
      except for site K in Huichols. Individually, allele frequency distributions were
      different (p < 0.05) in the two normal groups for the V site. K-V haplotype
      frequency distributions (HFDs) in these two normal groups were also different as
      compared with normal Australians. In Mexican MPS-I patients, HFD was different (p
      < 0.05) with respect to both Mexican normal groups, and non-different when
      compared with normal or MPS-I Australians. This can be taken as evidence of
      linkage disequilibrium between K-V polymorphism and MPS-I gene mutation(s) at the
      IDUA region. A similar finding was reported. However, disequilibrium in Mexicans
      was determined by haplotypes different from those in Australia. In Mexican MPS-I
      patients, haplotype K2-V1 is increased and K1-V3 decreased with respect to the
      Mexican mestizo (p < 0.05), while in Australians, MPS-I patients had an increase
      of haplotypes K2-V2 and K1-V2 with respect to expected frequency. CONCLUSIONS:
      The similar HFD between Mexican and Australian MPS-I patients suggests a common
      genetic origin, that MPS-I mutations were introduced to Mexico by Spaniards, and
      that such mutations predate the dispersion between Mexican and Australian
      Caucasian ancestors. The differences in disequilibrium are explained rather by
      genetic drift.

PMID- 10596457
TI  - Non-cryopreserved unmanipulated hematopoietic peripheral blood stem cell
      autotransplant program: long-term results.
AB  - BACKGROUND: Methods to simplify bone marrow transplantation procedures are needed
      mainly in developing countries. METHODS: Between May 1993 and February 1999 in a
      private-practice setting, we performed 29 autotransplants in 28 patients using
      non-cryopreserved and unmanipulated peripheral blood stem cells mobilized from
      the bone marrow to the peripheral blood by means of hematopoietic growth factors.
      The autografting procedure was performed entirely on an outpatient basis in 19
      cases (65%). The median age of the patients was 30 years, with a range of 9-67.
      There were 15 patients with acute leukemia (9 with acute myelogenous leukemia), 3
      with chronic myelogenous leukemia, 2 with multiple myeloma, 3 with Hodgkin's
      disease, 2 with non-Hodgkin's lymphoma, and 4 with metastatic breast carcinoma.
      RESULTS: The median time to achieve > 0.5 x 10(9)/L granulocytes was 14 days
      (range 7-42), whereas the median time to achieve > 20 x 10(9)/L platelets was 20
      days (range 5-49). The 64-month post-transplant survival was 38%, whereas the
      median post-transplant survival was 18 months. The transplant-related mortality
      was 3.4%. The approximate cost of this simplified procedure was 10.8% for in
      hospital procedures and for outpatient autografts, substantially lower than
      figures reported from the U.S. for autotransplants. CONCLUSIONS: This simplified
      method for autografting patients, avoiding in-hospital stays, purging procedures
      and cryopreservation of the cells is feasible and results in a substantial
      decrease of the cost of autologous hematopoietic stem cell transplantation
      methods.

PMID- 10596458
TI  - Comparison between usual and low doses of insulin in the assessment of insulin
      sensitivity with a short insulin tolerance test in obese women.
AB  - BACKGROUND: The objective of this study is to compare, in obese women, the
      assessment of insulin sensitivity and the presence of hypoglycemia between the
      usual and low doses of insulin used in the short insulin tolerance test (ITT).
      METHODS: The patients were 12 obese women on whom a randomized, double-masked,
      auto-controlled clinical trial was carried out. An ITT was performed on each
      volunteer in duplicate with insulin at 0.1 (usual dose) or 0.05 U/kg (low dose).
      RESULTS: The constant for the rate serum glucose disappearance calculated for the
      ITT was not significantly different between both tests (4.3 +/- 0.5 vs. 4.4 +/-
      1.0%/min, usual dose and low dose of insulin, respectively; p = 0.49). There was
      a significant correlation between both tests (r = 0.59, r2 = 0.34, p < 0.05).
      Differences between both tests had estimated limits of agreement of -0.97 to
      0.65%/min. Between tests, the coefficient of variation was 16%. No subject
      developed hypoglycemia with any of the ITT measurements employing usual or low
      doses of insulin. CONCLUSIONS: We recommend a low dose of insulin in the
      assessment of insulin sensitivity with ITT in obese people. In our study usual
      and low doses of insulin used in the ITT were safe and had similar results
      between both doses for assessing insulin sensitivity.

PMID- 10596459
TI  - Prevalence of skin reactivity to coccidioidin and associated risks factors in
      subjects living in a northern city of Mexico.
AB  - BACKGROUND: Coccidioidomycosis is a reemerging fungal disease seen mainly in the
      states located at the Mexican-U.S. border. The finding of advanced cases of the
      disease are now more frequent. METHODS: A cross-sectional study was conducted to
      determine the prevalence of skin reactivity to coccidioidin in the city of
      Torreon, Coahuila, Mexico, located in the northern region of the country. A
      multifactorial association of environmental, social, and health conditions was
      analyzed. A total of 1,653 coccidioidin skin tests was applied in male and female
      subjects older than 8 years of age. RESULTS: The overall rate of positive
      reactivity in this city was 40.2%, with a 95% confidence interval of 37.8-42.5.
      This was related to time/life exposure risk and to the habitat of unpaved
      streets. No statistically significant difference regarding gender, socioeconomic
      level, and working activities was found. The highest reactivity was observed in
      subjects between 30 and 65 years of age. CONCLUSIONS: Positive results were
      related to exposure risk and habitat, principally in the southeast region of the
      city. These results were applied both to residents and outsiders with no
      differences between the groups. Of the total, 87.5% were considered high-risk
      subjects. It is recommended that future surveys be carried out in other northern
      cities of Mexico to obtain more useful data concerning the extent of the
      infection and mainly to establish preventive measures, such as appropriate
      reforestation and urbanization procedures.

PMID- 10596460
TI  - American trypanosomiasis (Chagas' disease) and blood banking in Mexico City:
      seroprevalence and its potential transfusional transmission risk.
AB  - BACKGROUND: American trypanosomiasis (Chagas' disease), an anthropozoonosis
      fairly common in rural Latin America, has become an urban disease due to
      continuous migration, intra- and internationally. Blood transfusion, the second
      important pathway for transmission, increases its impact. Recognition of
      seropositive subjects among blood donors is now recommended, and clinical and
      serological screening enforced. Maneuvers to inactivate or remove Trypanosoma
      cruzi present in collected blood are recommended. METHODS: We surveyed voluntary
      donors at the National Institute of Cardiology in Mexico City in search of anti
      T. cruzi by indirect immunofluorescence, ELISA, and Western blot analysis.
      Seropositive donors were identified and tested for immunoglobulin. We used types
      and fractions of donated blood to extract DNA and perform the PCR technique using
      kinetoplast primers seeking parasite DNA in blood. RESULTS: After 3,300 donors
      were screened, we identified 10 seropositive subjects (0.3%). These subjects were
      considered as indeterminate chagasic patients, came mainly from rural areas, and
      had IgG (100%) and IgA (30%) antibodies against a crude extract as well as a
      recombinant T. cruzi antigen. Identification of parasite DNA in red cell and
      platelet fraction was achieved from eight blood units. CONCLUSIONS: The present
      data provide evidence that blood donors at an urban hospital are seropositive for
      T. cruzi and at least 50% of donors carry the parasite potentially able to
      transmit T. cruzi in their cellular blood products. Serological screening should
      be included in routine blood-making. It is also necessary to adopt measures to
      inactivate or eliminate organisms in donated blood.

PMID- 10596461
TI  - Validation of the Cross-Cultural Alcoholism Screening Test (CCAST).
AB  - BACKGROUND: When screening instruments that are used in the assessment and
      diagnosis of alcoholism of individuals from different ethnicities, some cultural
      variables based on norms and societal acceptance of drinking behavior can play an
      important role in determining the outcome. The accepted diagnostic criteria of
      current market testing are based on Western standards. METHODS: In this study,
      the Munich Alcoholism Test (31 items) was the base instrument applied to subjects
      from several Hispanic-American countries (Bolivia, Chile, Ecuador, Mexico, and
      Peru). After the sample was submitted to several statistical procedures, these 31
      items were reduced to a culture-free, 31-item test named the Cross-Cultural
      Alcohol Screening Test (CCAST). RESULTS: The results of this Hispanic-American
      sample (n = 2,107) empirically demonstrated that CCAST measures alcoholism with
      an adequate degree of accuracy when compared to other available cross-cultural
      tests. CONCLUSIONS: CCAST is useful in the diagnosis of alcoholism in Spanish
      speaking immigrants living in countries where English is spoken. CCAST can be
      used in general hospitals, psychiatric wards, emergency services and police
      stations. The test can be useful for other professionals, such as psychological
      consultants, researchers, and those conducting expertise appraisal.

PMID- 10596462
TI  - Interoceptive accuracy and panic.
AB  - Psychophysiological models of panic hypothesize that panickers focus attention on
      and become anxious about the physical sensations associated with panic. Attention
      on internal somatic cues has been labeled interoception. The present study
      examined the role of physiological arousal and subjective anxiety on
      interoceptive accuracy. Infrequent panickers and nonanxious participants
      participated in an initial baseline to examine overall interoceptive accuracy.
      Next, participants ingested caffeine, about which they received either safety or
      no safety information. Using a mental heartbeat tracking paradigm, participants'
      count of their heartbeats during specific time intervals were coded based on
      polygraph measures. Infrequent panickers were more accurate in the perception of
      their heartbeats than nonanxious participants. Changes in physiological arousal
      were not associated with increased accuracy on the heartbeat perception task.
      However, higher levels of self-reported anxiety were associated with superior
      performance.

PMID- 10596463
TI  - Learning history in fear of blushing.
AB  - Two studies, investigating the learning history (i.e. traumatic conditioning
      experiences, vicarious learning, informational learning) of individuals with and
      without fear of blushing, are presented. In study 1, individuals high (n = 61)
      and low (n = 59) in fear of blushing completed the (revised) Phobic Origin
      Questionnaire [POQ; Ost, L. G., & Hugdahl, K. (1981). Acquisition of phobias and
      anxiety response patterns in clinical patients. Behavior Research and Therapy,
      19, 439-447]. In study 2, individuals who applied for treatment for fear of
      blushing (n = 31) and a nonfearful, matched control group (n = 31) were
      interviewed with the same instrument, taking into account only specific memories.
      High fearful individuals reported more negative learning experiences in
      connection with blushing than low fearful individuals, irrespective of the type
      of questioning. Meanwhile, study 1 (written POQ) produced higher percentages of
      negative learning experiences for both high and low fearful individuals than
      study 2 (interview). It is concluded that the POQ interview showed a more
      realistic picture than the written POQ. The possible role of learning history in
      the acquisition of fear of blushing is discussed.

PMID- 10596464
TI  - Establishing clinically significant change: increment of precision and the
      distinction between individual and group level of analysis.
AB  - Some essential adaptations to the method for determining clinically significant
      change originally introduced by Jacobson, Follette and Revenstorf [Jacobson, N.
      S., Follette, W. C. & Revenstorf, D. (1984a). Psychotherapy outcome research:
      methods for reporting variability and evaluating clinical significance. Behavior
      Therapy, 15, 336-352.] are presented. One adaptation deals with the failure in
      the original method to distinguish between analysis at the individual versus
      analysis at the group level. A second adaptation entails the provision of a
      closer approximation of the underlying true scores. This refinement represents an
      enhancement in precision. Specific aspects of this refinement may be understood
      in terms of a correction for error-based regression to the mean. Taking into
      account these adaptations, new procedures are described for determining
      (clinically significant) change. Some guidelines for the publication of outcome
      findings are also presented.

PMID- 10596465
TI  - A comparison of three methods of identifying reliable and clinically significant
      client changes: commentary on Hageman and Arrindell.
AB  - Objectives of this commentary are to (1) note major similarities and differences
      of three methods of identifying reliable and clinically significant client
      changes, (2) demonstrate how graphs can be used to identify reliable and
      clinically significant client changes with each method, (3) describe uses and
      interpretations of overlaid graphs, (4) draw attention to an alternative to the
      Hageman and Arrindell method of estimating true score changes, and (5) caution
      users of the three methods against interpreting reliable and/or clinically
      significant changes which occur in psychotherapy as evidence of therapy
      'efficacy' or 'effectiveness'.

PMID- 10596466
TI  - What is the role of two-wave designs in clinical research? Comment on Hageman and
      Arrindell.
AB  - Traditional beliefs about regression to the mean, difference scores (d-scores)
      and corrections for regression in determining the significance of individual
      person change have been challenged by proponents of growth curve modeling for the
      study of change. These challenges have generally not been adequately addressed by
      those proposing modifications to Jacobson's Reliable Change Index (RC). It is
      proposed that (1) two-wave designs and RC or variations of it are not very good
      methods for the scientific study of change, (2) multi-wave designs are better,
      (3) d-scores are unbiased data for analyzing two-wave studies, (4) RC is
      relatively more justifiable than most corrected or adjusted forms of RC, (5) the
      more appropriate place for two-wave designs and RC are in program or outcome
      evaluation and (6) the most appropriate function for RC is to facilitate
      communication among evaluators, public decision makers, providers and the public.
      In the absence of a 'gold standard' or consensus, it is recommended the only RC
      be used in outcome evaluation, in the near future, in order to enhance
      comparability of change rate data among different studies.

PMID- 10596467
TI  - Clinically significant but impractical? A response to Hageman and Arrindell.
AB  - Hageman, and Arrindell [Hageman, W.J., & Arrindell, W.A. (in press). Establishing
      clinically significant change: increment of precision and the distinction between
      individual and group level of analysis. Behavior Research and Therapy.] suggest
      adaptations to the traditional clinical significance model originally developed
      by Jacobson, Follette, and Revenstorf [Jacobson, N.S., Follette, W.C., &
      Revenstorf, D. (1984). Toward a standard definition of clinically significant
      change. Behavior Therapy, 17, 308-311.]. They observe that one must distinguish
      between analysis at the individual and group level and based upon an alternative
      decision-making strategy have formulated different procedures for assessing
      clinically significant change that incorporate the unreliability inherent in
      testing measures. A comparison of the traditional method with Hageman and
      Arrindell's suggested approach is conducted utilizing data originally presented
      by Jacobson and Truax [Jacobson, N.S., & Truax, P., CLINICAL SIGNIFICANCE: a
      statistical approach to defining meaningful change in psychotherapy research.
      Journal of Consulting and Clinical Psychology, 59, 12-19.] and implications of
      this comparison for the method developed by Hageman and Arrindell's method are
      discussed. Although this revised method has much to recommend it, it seems to
      yield results at the individual level that are quite similar to those derived
      from the traditional method. Given the complexity of the revised method, the
      traditional model developed by Jacobson, Follette, and Revenstorf (1984) still
      seems to be preferable.

PMID- 10596468
TI  - Clinically significant and practical! Enhancing precision does make a difference.
      Reply to McGlinchey and Jacobson, Hsu, and Speer.
AB  - Based on a secondary analysis of the Jacobson and Truax [Jacobson, N.S. & Truax,
      P. (1991). CLINICAL SIGNIFICANCE: a statistical approach to defining meaningful
      change in psychotherapy research. Journal of Consulting and Clinical Psychology,
      59, 12-19.] data using both their own traditional approach and the refined method
      advanced by Hageman and Arrindell [Hageman, W.J.J.M., & Arrindell, W.A. (1999).
      Establishing clinically significant change: increment of precision and the
      distinction between individual and group level of analysis. Behaviour Research
      and Therapy, 37, 1169-1193], McGlinchey and Jacobson [McGlinchey, J. B., &
      Jacobson, N. S. (1999). Clinically significant but impractical? A response to
      Hageman and Arrindell. Behaviour Research and Therapy, 37, 1211-1217.] reported
      practically identical findings on reliable and clinically significant change
      across the two approaches. This led McGlinchey and Jacobson to conclude that
      there is little practical gain in utilizing the refined method over the
      traditional approach. Close inspection of the data used by McGlinchey and
      Jacobson however revealed a serious mistake with respect to the value of the
      standard error of measurement that was employed in their calculations. When the
      proper index value was utilised, further re-analysis by the present authors
      disclosed clear differences (i.e. different classifications of S's) across the
      two approaches. Importantly, these differences followed exactly the same pattern
      as depicted in Table 2 in Hageman and Arrindell (1999). The theoretical
      advantages of the refined method, i.e. enhanced precision, appropriate
      distinction between analysis at the individual and group levels, and maximal
      comparability of findings across studies, exceed those of the traditional method.
      Application of the refined method may be carried out within approximately half an
      hour, which not only supports its practical manageability, but also challenges
      the suggestion of McGlinchey and Jacobson (1999) that the relevant method would
      be too complex (impractical) for the average scientist. The reader is offered the
      opportunity of obtaining an SPSS setup in the form of an ASCII text file by means
      of which the relevant calculations can be carried out. The ways in which the
      valuable commentaries by Hsu [Hsu, L. M. (1999). A comparison of three methods of
      identifying reliable and clinically significant client changes: commentary on
      Hageman and Arrindell. Behaviour Research and Therapy, 37, 1195-1202.] and Speer
      [Speer, D. C. (1999). What is the role of two-wave designs in clinical research?
      Comment on Hageman and Arrindell. Behaviour Research and Therapy, 37, 1203-1210.)
      contribute to a better understanding of the technical/statistical backgrounds of
      the traditional and refined methods were also discussed.

PMID- 10596469
TI  - [The status of soil contamination in areas of northern and northwestern Bohemia
      affected by pollution].
AB  - A regional study of soil contamination in North and Northwest immission-impacted
      Bohemian regions present the results of the assessment of soil loads of
      agricultural soils by hazardous trace elements and organic xenobiotic substances.
      The evaluation is based on the exceeding of background values of contaminants
      (upper limit of their variability). Two forms of soil loads by trace elements are
      differentiated, the anthropogenic and geogenic one. They occur simultaneously on
      the territory under study. Geogenic "loads" prevail (basalts, metallogenic
      zones). Anthropogenic contamination by both hazardous elements and organic
      xenobiotic substances occurs only in some parts of these severely immission
      impacted regions.

PMID- 10596470
TI  - [Treatment of Crohn's disease].
AB  - Dietetic treatment of Crohn's disease has the objective to calm down the gut
      either by a polymeric or elemental diet. In superacute conditions also total
      parenteral nutrition can be used. In the quiescent stage the patient must have an
      adequate energy intake and a low-residue (low-fibre) diet. As to medication,
      sulfasalazine which has some side-effects is abandoned and 5-ASA (5
      aminosalicylic acid) preparations are used, either by the oral route or in
      enemas, while 4-ASA is little used in this country and is known as PAS. The
      administration of corticoids which also have side-effects will be abandoned in
      favour of so-called rapidly metabolized corticoids (Tixocortol pivalate,
      beclomethasone, budenoside and fluticasone) by the oral route and in enemas and
      foams. As antimicrobial treatment ciprofloxacine is used combined with
      metronidazole. As to immunosuppressive drugs azathioprine, 6-mercaptopurine,
      cyclosporin A, cyclophosphamide and methotrexate are tested. A hope for the
      future is so-called biological treatment (anticytokines, monoclonal antibodies
      against cytokines, against CD4+ TNF, interleukines IL-10 and 11, immunoglobulin;
      plasmapheresis is also tested). Treatment must be individual and surgery as late
      as possible, only in case of complications, and should be very sparing, stenoses
      should be treated by plastic operations of strictures.

PMID- 10596471
TI  - [Direct DNA diagnosis of Friedreich's ataxia].
AB  - BACKGROUND: Friedreich's ataxia is an autosomal recessive, neurodegenerative
      disease with a prevalence of 1-2: 100,000. Ninety five % of cases are caused by
      Friedreich's ataxia expansion of GAA triplet repeat in the first intron of the
      X25 gene. The gene is mapped on chromosome 9q. The objective of the investigation
      was to introduce simple and reliable DNA diagnosis helping to specify of
      spinocerebellare ataxias. METHODS AND RESULTS: Our diagnosis is based on the
      differentiation of normal and mutant alleles of gene X25 with PCR and
      electrophoresis on agarose gel. Size of PCR product of normal allele is in our
      case 521-614 bp. It is responding to 7-38 GAA triplets. Size of mutant alleles
      with 200-1200 GAA triplets is as 4100 bp. After the method was introduced, we
      analysed 12 probands. Four of them suffered from Friedreich's ataxia.
      CONCLUSIONS: We introduced a fast, non-radioactive, reliable DNA diagnostic
      method. The contribution of this method is defection of carriers and we can
      screen of families with the risk of Friedreich's ataxia.

PMID- 10596472
TI  - [Effect of losartan and enalapril on urinary excretion of 8-isoprostane in
      experimental nephrotic syndrome].
AB  - BACKGROUND: Increased permeability of glomerular capillary wall in adriamycin
      nephropathy may be mediated by increased generation of free radicals and possibly
      also by the non-enzymatic production of isoprostanes induced by oxidative stress.
      ACE inhibitors may reduce proteinuria, possibly due to the decrease of
      intraglomerular pressure and increased permselectivity of the glomerular
      capillary wall. These effects may be partly mediated by the inhibition of the
      degradation of kinins. It is not clear if newly available angiotensin II
      antagonists have the same antiproteinuric and renoprotective effects. METHODS AND
      RESULTS: We compared the effect of an ACE inhibitor (enalapril, 0.4 mg/kg bw i.p.
      daily for 3 weeks) and angiotensin II antagonist (losartan, 2 mg/kg bw in the
      same way) on experimental nephrotic syndrome induced in rats by the
      administration of adriamycin (5 mg/kg bw i.v. in a single dose). To elucidate the
      potential differences between these two drugs we also measured total
      malondialdehyde in blood and urinary excretion some eicosanoids and their
      metabolites (TxB2, 6-keto-PGF1alfa, bicyclo-PGE2 and 8-isoprostane). Proteinuria
      increased in adriamycin treated rats after 3 weeks from 0.18 +/- 0.01 to 0.44 +/-
      0.14 g/mmol creat, p < 0.01. This increase was not prevented by losartan
      (increase from 0.18 +/- 0.12 to 0.50 +/- 0.11 g/mmol creat, p < 0.05), but tended
      to be partly blunted by enalapril (increase from 0.20 +/- 0.10 to only 0.32 +/-
      0.08 g/mmol creat, p < 0.05). Similarly there was no increase of serum
      cholesterol, only in enalapril treated rats. On the other hand, both losartan
      (1.27 +/- 0.13 vs. 1.91 +/- 0.30 mumol/l, p < 0.05) and enalapril (0.93 +/- 0.06
      mumol/l, p < 0.001) prevented adriamycin induced increase of total MDA in serum,
      but urinary excretion of 8-isoprostane was increased in nephrotic rats treated by
      losartan compared to controls. Enalapril induced increase of urinary excretion of
      bicyclo-PGE2 (4.32 +/- 0.62 vs. 1.66 +/- 0.81 ng/mmol creat, p < 0.001) was
      possibly mediated by kinins. There was no significant difference in the urinary
      excretion of other eicosanoids between different groups, but proteinuria
      correlated positively with urinary excretion of 8-isoprostane (p < 0.01).
      Proteinuric rats had also significantly higher urinary excretion of 8-isoprostane
      than non-proteinuric rats (44.8 +/- 7.1 vs. 26.7 +/- 3.4 ng/mmol. creat, p <
      0.05). CONCLUSIONS: Our data suggest that proteinuria in adriamycin nephropathy
      may mainly depend on free radical generation and the formation of 8-isoprostane.
      Haemodynamic parameters (glomerular pressure) do not seem to be so important. The
      mild antiproteinuric effect of enalapril may suggest a contributory role of the
      inhibition of kinin degradation in this model of nephrotic syndrome.

PMID- 10596473
TI  - [Leber's hereditary optic neuropathy].
AB  - BACKGROUND: Leber's hereditary neuropathy of the optic nerve (LHON) is manifested
      by bilateral affection of the eyes with acute or subacute loss of vision. The
      disease is caused by point mutations in the mitochondrial DNA (mtDNA) and is one
      of the most frequent mitochondrial diseases in the population. In patients with
      LHON 18 different point mutations in the mtDNA were described which correlate
      partly with the rate of progression of the disease and the severity and prognosis
      of the final affection of vision. METHODS AND RESULTS: The submitted paper deals
      with the results of molecular genetic examinations in three families with
      clinical manifestations of LHON. In three patients in the first family a
      homoplasmic mutation of mtDNA G3460A was found. In the second family in a young
      man with severely impaired vision a heteroplasmic mutation G3460A was found
      associated with a higher ratio of mutated mtDNA molecules than in his mother who
      is clinically healthy. In the third family the presence of homoplasmic mutation
      of mtDNA in position G11778A was detected. CONCLUSIONS: The diagnosis of LHON and
      genetic counselling in affected families should be based on close collaboration
      of ophthalmological and genetic departments with specialized laboratories engaged
      in molecular biological diagnosis of mitochondrial diseases.

PMID- 10596474
TI  - [Surgical treatment of macular hole and maculopathy associated with optic disk
      pits].
AB  - PURPOSE: To inform about the successful surgical treatment of the retinal
      detachment of the macula and macular hole, as a complication of the optic disc
      pit. PATIENT: The authors report about 32 years old patient with optic disc pit
      complicated with the retinal detachment and the macular hole. After pars plana
      vitrectomy with intraocular gas injection (20% C3F8) associated with the
      application of the autologous serum and follow up face down positioning, the
      retinal attachment of the macula and the closure of the macular hole were
      present. In the period 9 months after the operation the relapse of the retinal
      detachment was observed and the closure of the macular hole is still remained.
      Condition was treated by intraocular gas injection (1 ml C3F8) and
      argonlasercoagulation. During the period of more than a 13 months after the first
      operation and 5 months after the reoperation the retina is attached and the
      macular hole is closed. In campimetry, a detailed development of the central
      scotoma is documented. The final visual acuity with correction is 6/9, that is
      improvement in 3 lines in comparison to preoperative condition. CONCLUSION: The
      surgical treatment of macular hole by optic disc pit is currently the methods of
      choice. Using this methods successful anatomical as well as functional results
      could be obtained.

PMID- 10596475
TI  - [Retrolenticular lens fragments--a problem of phacoemulsification?].
AB  - In a group of 100 consecutive operations of cataract by the method of
      phacoemulsification in 1998 in 9% penetration of fragments of lenticular material
      into the retrolenticular space was observed. It is a less frequent associated
      phenomenon of phacoemulsification. It provides evidence of the possible
      penetration of larger particles through the relatively intact suspensory
      apparatus. The authors did not observe an association of the phenomenon with
      clinical complications.

PMID- 10596476
TI  - [Angiography of the iris in the diagnosis of pigmented tumors of the anterior
      uvea].
AB  - Authors present their observation of 28 pigmented tumors of the iris and
      iridociliary region during 8 years. While deciding whether to continue in
      observation or to indicate surgery, they were concentrated on observation of
      blood supply's abnormalities of pigmented mass and defect of blood-aqueous
      barrier during the iris angiography. Melanoma--mostly celullar type of high
      malignity--was confirmed in 11 cases, pigmented meduloepithelioma in 1 case,
      pigmented naevus in 2 cases out of 14 patients indicated for surgery. Authors
      correlated angiographical pictures with clinical observation and
      histopathological findings.

PMID- 10596477
TI  - [Surgical treatment of pigmented tumors of the iris and iridociliary region].
AB  - The authors present a group of six patients with pigmented tumours of the iris
      and the iridocorneal angle where they performed excision of the tumour by
      iridectomy (3 patients) or iridiocycletomyy (3 patients). In all six patients
      with a pigmented tumour of the iris an impaired blood-ocular fluid barrier was
      found and colouration of the tumour mass by fluorescein. In one patient a heavily
      pigmented tumour was detected which masked the vascular network. Impaired
      permeability was found more markedly at the margins. Histological examination
      confirmed in five instances melanoma of the iris, in one instance a pigmented
      naevus was involved. During the mean observation period of 32.5 months none of
      the patients developed a relapse or metastases. Consistent with the extent of the
      surgical intervention, within 6 months at the latest in all patients the disorder
      of the blood-ocular fluid barrier improved.

PMID- 10596478
TI  - [Diffuse retinal pigmented epitheliopathy--a variant of central serous
      chorioretinopathy of the aged].
AB  - The authors describe a group of eight patients (four women and four men) with
      diffuse retinal pigmented epiteliopathy (four times unilateral and four times
      bilateral) confirmed by fluoroangiography, in one instance with bullous elevation
      of the retina. The mean age of the patients was 57.3 years, the investigation
      period was 4 to 23 years, with a mean of 8.6 years. After laser coagulation which
      was implemented in four patients vision improved in one instance, in the
      remaining patients vision was stabilized. In the patient with the bullous
      elevation of the retina vision improved after spontaneous flattening of the
      ablation. The authors discuss the pathogenesis and clinical features typical for
      diffuse retinal pigmented epitheliopathy.

PMID- 10596480
TI  - [Aging and color discrimination after IOL implantation].
AB  - Colour discrimination was tested by FM 100-hue test in 106 patients (43 women and
      63 men) after implantation PMMA IOL to the posterior chamber. Examined group of
      patients aged from 41-70 years was represented by 132 eyes. As a control were
      groups of healthy people (without hypertension and diabetes) of the same age
      categories with physiological eye findings and still clear crystalline lens.
      After IOL implantation the resulting total score of the test in examined patients
      of all decades was similar to the control group of healthy people. Even in
      healthy patients with IOL the colour discrimination is better beginning with 61
      years (P < 0.05). Colour discrimination for red, green and blue colour has
      improved in comparison with the control groups and getting better with ageing.
      Clearly better sensitivity was in the area of green colour, it was observed in
      the age group starting with 61 years (P < 0.05) and for blue colour already since
      51 years (P < 0.05). The improvement of colour discrimination in pseudophakic
      eyes in comparison with healthy population is slightly improving with increasing
      age.

PMID- 10596479
TI  - [Electrophysiology in hypovitaminosis A].
AB  - Electroretinographic examinations performed according to the international
      standard were used in two patients with alimentary hypovitaminosis A. In one
      instance a mentally caused long-term deficiency of dietary vitamin A intake was
      involved, in the second instance a fistula from the proximal jejunum into the
      transverse colon. In both instances night blindness was reported. The initial
      vitamin A values were 1.0 and 0.6 micromol/l resp. and after substitution therapy
      they rose to 2 micromol/l. While the rod and maximal ERG responses improved
      gradually, the oscillation potentials remained pathological as regards amplitudes
      and latencies. We consider them therefore a sensitive indicator of the electric
      sensitivity of the retina also in other cases of confirmed or suspected vitamin A
      deficiency. The existence and orientation of our metabolic and gerontological
      clinic provides adequate opportunities for these investigations.

PMID- 10596481
TI  - [LASIK--comparison of oscillating and rotating microkeratotomy using scanning
      electron microscopy].
AB  - Scanning electron microscopy was used to evaluate the differences in the quality
      of the cut produced by oscilating microkeratome Flapmaker and Draeger rotating
      microkeratome. Higher quality of the edge of the cut was found with Flapmaker.
      Both microkeratomes produce uniform surface of the cut. Chatter is much less
      expressed with Flapmaker. No difference at the interface tissue was found with
      SEM three weeks postoperatively comparing the microkeratomes.

PMID- 10596482
TI  - [The optic nerve disk in myopic children with elevated intraocular pressure].
AB  - The optic nerve disc of short-sighted children with elevated intraocular pressure
      was investigated to achieve early assessment of glaucoma and to detect signs
      which differentiate changes in the disc caused by short-sightedness from changes
      caused by glaucoma. The authors examined 16 eyes of 8 short-sighted children with
      elevated intraocular pressure. In addition to the basic ophthalmological
      examination they made a digital analysis of the optic nerve disc incl.
      planimetric evaluation of the dimensions of the disc, excavation and the
      neuroretinal rim. In two patients despite the higher intraocular pressure the
      area of the rim was supraliminal. In three patients the narrower area of the
      neuroretinal rim increased the probability of glaucoma In two patients with
      anisometropia on the eye with greater myopia the intraocular pressure was higher
      and the neuroretinal rim narrower as compared with the other eye. In one patient
      the area of the rim was very narrow and the diagnosis of glaucoma was confirmed
      also by arcuate scotoma in the lower part of the visual field corresponding to
      the narrow rim on top.

PMID- 10596483
TI  - [Retinal cavernous hemangioma associated with intracerebral cavernous hemangioma
      in a 33-year follow-up study].
AB  - Cavernous hemangioma of the retina is congenital, mostly unilateral lesion, with
      autosomal dominant transmission. Usually can be easily recognized by its
      characteristic appearance of cluster of dark-red saccular aneurysms, partly
      covered by a fine glial membrane. It may be associated with similar lesions of
      the skin, brain and other organs. A 23-year-old patient with cavernous hemangioma
      of the retina, who preventively underwent argon laser therapy has been followed
      up in our department. During the observation no symptomatic ocular hemorrhage
      occurred. We presuppose that a preventive laser treatment forestalled a possible
      retinal and vitreous bleeding. However, in a long-term follow up we have detected
      slowly growing number of retinal hemangiomas. Patient's life is hardly damaged by
      complications of cavernous hemangioma of the brain. Because of autosomal dominant
      transmission all family members, with and without fundus findings, should undergo
      computed tomography or magnetic resonance imagining of the brain to preclude
      intracranial vascular anomaly.

PMID- 10596484
TI  - [Lens nucleus fragmentation in phacoemulsification: a technic of the 90s].

PMID- 10596486
TI  - [The correlation of arterial pressure with weight and body mass index].
AB  - OBJECTIVES: To analyze the influence of weight and different body mass indexes on
      blood pressure (BP) values. The study was carried out in 823 volunteers (345
      males, 478 females), aged 25/80 years. A standardized protocol, based on the
      recommendations provided by the V Joint National Committee was set up. The means
      of three consecutive readings taken at 2-min. intervals on three occasions were
      used. Weight and height were determined and the indexes were calculated.
      Correlations between weight and the selected indexes, with SBP and DBP,
      respectively, by sex and age interval were performed. The most representative
      indexes were body mass index (BMI) followed by lean BMI and weight. Analysis of
      BP values are BMI, for a period starting at 25 years and ending at 74 year, for
      both SPB and DBP, in comparison with the Humboldt Study data was performed,
      showing a strikingly similar pattern of behavior with our data. Additionally,
      weight and BMI are more closely associated with DBP in males than in females.
      Conversely, this association is closer in women with SBP. The importance of the
      ethnic factor is emphasized in order to establish body mass index cut-off values
      regarding the population under study, because the values proposed by the American
      Heart Association are probably rather high for our population.

PMID- 10596485
TI  - [The costs of hospital infections in a group of patients in a tertiary-care
      hospital].
AB  - OBJECTIVE: To know the cost generated by nosocomial infections, to establish the
      proportion of the total hospital budget used in extra-days of stay, drugs,
      laboratory and others items used for the treatment. METHODS: We studied 131
      nosocomial infections in 82 patients attended in hospital's departments from June
      to August 1995. We evaluated days of stay, type of infection, episodes per
      patient, drugs, laboratory, and others items used in the treatment of nosocomial
      infections. We took percentage of cost of every point and the mean of the total
      cost generated by year cause nosocomial infections and a cost per infection in
      every department. RESULTS: The total overtime of stay was 970 days, mean per
      infection was 7.4. Totals days of antimicrobials was 974, mean was 11.9 days per
      infection. The hospital processed 410 laboratory studies, 191 cabinet studies.
      The total cost generated by overtime stay was $3,415,860.00, and considering also
      drugs, laboratory and cabinet studies $3,516,421.00. CONCLUSIONS: The cost of the
      nosocomial infections depends on the overtime stay, drugs, laboratory and cabinet
      studies needed for their treatment. Neonatology generated presented more than one
      infection generating higher cost. Total cost in 3 months was $3'516,421.00,
      nosocomial infections would take $14'065,684.00 in a year, involving 12.1% of the
      hospital total budget. Preventive measures must be taken trying to diminish these
      costs.

PMID- 10596488
TI  - [The current status of the surgical treatment of severe obesity].

PMID- 10596487
TI  - [Gastroesophageal reflux in asthmatic patients: an incidence study and clinical
      correlation].
AB  - The prevalence of gastroesophageal reflux (GER) in asthmatic patients is
      elevated, but the exact frequency remains unknown. The relationship between GER
      and asthma has not been investigated in Mexico. The objective of this study is to
      know the frequency of GER in Mexican asthmatic patients and the possible
      relationship with the severity of asthma. Fifty patients with adult-onset asthma
      were studied. AII of them fulfill the diagnostic criteria of the National
      Institutes of Health, U.S. The evaluation included a symptoms questionnaire,
      spirometry, esophageal manometry, 24-h esophageal pH-recording, and an upper
      gastrointestinal endoscopy. Twenty-three patients had mild asthma (46%), 16
      moderate (32%) and 11 had severe asthma (22%). Twenty-seven (54%) reported
      heartburn and regurgitation at least twice a week. The esophageal pH-recording
      showed pathologic GER in 37 subjects (74%) and endoscopic esophagitis was found
      in 7 cases (14%). The pH-recording showed pathologic GER in 13 patients with mild
      asthma (57%), in 13 with moderate asthma (81%) and in all patients with severe
      asthma (100%). The frequency of GER in Mexican asthmatic patients is high and
      increases proportionately with the severity of asthma. This factor must be
      considered in the integral evaluation of these patients.

PMID- 10596489
TI  - [Current concepts of neuroimmunomodulation].
AB  - Over the last decade, a considerable wealth of information has expanded and
      strengthened our knowledge of the relations between the nervous, endocrine, and
      immune systems. The following areas of progress may be underlined 1) the cells of
      the three systems appear to secrete similar substances and are sensitive to them,
      thus suppressing traditional differences between neurotransmitters, hormones and
      immune mediators; 2) new knowledge is available on hormone actions on the immune
      system, and direct and mutual influences between the nervous and the immune
      system have been documented; 3) brain areas selectively involved in immune
      regulation have been identified; 4) various brain functions are now known to be
      influenced by immune mediators; 5) neurological and psychiatric components have
      been described in autoimmune diseases. An immune etiology has been unraveled in a
      wide range of neural disorders. A neuroimmunological component has been
      documented in a growing number of diseases. Altogether, a new chapter is emerging
      in our understanding of homeostatic functions and their medical implications.

PMID- 10596490
TI  - [The surgical risk in sleep apnea: the implications for tonsillectomies].
AB  - Hypertrophy of tonsils or adenoids is the commonest cause of obstructive sleep
      apnea (OSA) in children. Adenotonsillectomy (AT) is frequently curative in
      children with OSA but riskier than the same procedure without OSA. It is crucial
      to identify OSA among the patients programmed for AT because they require a
      detailed evaluation, frequently including total or limited polysomnogram.
      Patients with OSA need a continuous surveillance before, during, and after
      surgery, ideally in a referral hospital.

PMID- 10596491
TI  - [A 23-year-old man with a heart failure syndrome].

PMID- 10596492
TI  - [Acute methotrexate toxicity in psoriasis].
AB  - A 71-year-old man with psoriasis developed acute methotrexate toxicity after
      taking 10 mg daily on his own. A few days after, he showed painful erosions of
      psoriatic plaques and stomatitis. In addition to those mucocutaneous lesions, the
      clinical background includes bone marrow and intestinal involvement. The present
      clinical case underlies the relevance in selecting psoriasis patients regarding
      methotrexate treatment, following the particular guidelines.

PMID- 10596493
TI  - [Combined cefotaxime and amikacin for immunomodulation in the treatment of
      actinomycetoma resistant to conventional treatment].
AB  - Actinomycetoma is a chronic disease that affects subcutaneous tissue. We present
      a case of a patient with abdominal actinomycetoma caused by Nocardia brasiliensis
      resistant to different treatments over several years, who also presented
      phagocyte immunodeficiency. He received two cycles (23 day cycles) of cefotaxime,
      1 g every 8-h, and amikacin, 500 mg every 12 hours. Immunomodulation was carried
      out with levamisole 300 mg per week, during 4 weeks and bacterial antigen (at a
      concentration of 600,000,000 bacteria per mL), twice for a week during 20 months.
      The importance of susceptibility testing and immunological function investigation
      in this type of patients is discussed.

PMID- 10596494
TI  - [Humanism in medicine. A tribute to the memory of master Ignacio Chavez on the
      20th anniversary of his death].
AB  - The expression "humanism" reflects essentially a fundamental interest for all
      aspects pertaining to human nature. In fact, humanistic education is not the
      isolation in to a world of dark shades nor to take pleasure in sterile diatribes
      or rhetoric redundancies. The problem of today does not consist in fighting or
      excluding one or the other element from contemporary life, a vain and retrograde
      attempt, but in introducing all elements--or rather incorporate them--in the core
      of an integral concept of man. Mankind's works are valued only by their
      contributions as testimonies of the truth, for what they do in the progress of
      individual perfection and in the improvement of society. Perhaps, integral
      humanism will lead to a communitarian society on earth, animated by the ideal of
      universal brotherhood. These were the sublime ideals of doctor Ignacio Chavez and
      constitute an enduring legacy for his pupils in all countries and all times.

PMID- 10596495
TI  - [The extraction of an incrusted bullet in the ventricular wall of the heart].

PMID- 10596496
TI  - [The social service of physicians' assistants. 1936].

PMID- 10596497
TI  - [The acute respiratory insufficiency syndrome].

PMID- 10596498
TI  - [New functions of heparin within cells].

PMID- 10596499
TI  - [The basis for the management of osteoporosis in menopause for avoiding
      diagnostic and therapeutic consumerism].

PMID- 10596500
TI  - [Acute otitis media in Mexico: cases reported during the period from 1995 to
      1998].

PMID- 10596501
TI  - [The right to respect for patient dignity].

PMID- 10596502
TI  - [Erythema migrans as the clinical presentation of cutaneous larva migrans in
      Mexico City].

PMID- 10596503
TI  - [A 69-year-old man with pancytopenia and wasting syndrome].

PMID- 10596504
TI  - The effectiveness of a parenting skills program for parents of middle school
      students in small communities.
AB  - This study provides evidence of the effectiveness of behaviorally based parenting
      skills classes provided by carefully trained and supervised group leaders who
      were not mental health clinicians. A program for parents of at-risk middle school
      students was evaluated in a randomized controlled trial in 8 small Oregon
      communities. Parents (N = 303) were randomly assigned to immediate treatment or a
      wait-list condition. Data were analyzed using latent growth modeling.
      Participation in the program led to significant improvements in problem-solving
      interactions as indicated by parent reports and a Taped Situations Test. Parents'
      over-reactivity and laxness toward their children's behavior were reduced and
      their feelings toward their children improved significantly as a function of
      treatment. Parent-reported child antisocial behavior was also reduced.

PMID- 10596505
TI  - Characterizing interactions between anxious mothers and their children.
AB  - The present study assessed interactions between anxious mothers and their
      children, using observational techniques to elucidate potential mechanisms of
      anxiety transmission. Results revealed that anxious mothers were less warm and
      positive in their interactions with their children, less granting of autonomy,
      and more critical and catastrophizing in comparison with normal control mothers.
      Maternal anxiety status appeared to be the primary predictor of maternal warmth
      during interactions. Child anxiety status was most predictive of maternal
      granting of autonomy behavior. Maternal behaviors exhibited during interactions
      were the most salient predictors of child anxiety, contributing more than
      maternal psychopathology or ongoing strain to the development of child anxiety.
      Interventions focusing on family interactions that take into account the
      contributions of both members of the dyad may be more effective in curbing
      transmission than interventions that solely address maternal or child
      symptomatology.

PMID- 10596506
TI  - Therapist competence ratings in relation to clinical outcome in cognitive therapy
      of depression.
AB  - This study reports on the relationship of therapist competence to the outcome of
      cognitive-behavioral treatment in the National Institute of Mental Health
      Treatment of Depression Collaborative Research Program. Outpatients suffering
      from major depressive disorder were treated by cognitive-behavioral therapists at
      each of 3 U.S. sites using a format of 20 sessions in 16 weeks. Findings provide
      some support for the relationship of therapist competence (as measured by the
      Cognitive Therapy Scale) to reduction of depressive symptomatology when
      controlling for therapist adherence and facilitative conditions. The results are,
      however, not as strong or consistent as expected. The component of competence
      that was most highly related to outcome is a factor that reflects the therapist's
      ability to structure the treatment.

PMID- 10596507
TI  - Community services for rape survivors: enhancing psychological well-being or
      increasing trauma?
AB  - This research examined how contact with the legal, medical, and mental health
      systems affects rape survivors' psychological well-being. Although community
      services may be beneficial for some victims, there is increasing evidence that
      they can add trauma, rather than alleviate distress (termed secondary
      victimization). This study examined how secondary victimization affects rape
      survivors' posttraumatic stress (PTS) symptoms. Adaptive and snowball sampling
      were used to recruit a sample of 102 rape survivors. Victims of nonstranger rape
      who received minimal assistance from either the legal or medical system, and
      encountered victim-blaming behaviors from system personnel, had significantly
      elevated levels of PTS. This high-risk group of rape survivors had PTS levels
      significantly higher than all other victims in this study, including those who
      did not seek community assistance postrape. However, for these high-risk rape
      survivors, receiving sustained mental health services after these negative
      experiences was associated with a significant decrease in PTS.

PMID- 10596508
TI  - Depression, hopelessness, suicidality, and related factors in sexual minority and
      heterosexual adolescents.
AB  - In the present study, the researchers examined factors related to depression,
      hopelessness, and suicidality in gay, lesbian, and bisexual adolescents, compared
      with demographically similar heterosexual adolescents. Sexual minority
      adolescents reported greater depression, hopelessness, and past and present
      suicidality than did heterosexual adolescents. However, when controlling for
      other psychosocial predictors of present distress, significant differences
      between the 2 samples disappeared. For past suicidality scores, the effects of
      sexual orientation were reduced, but still significant, when accounting for the
      other predictor variables. These results suggest that environmental factors
      associated with sexual orientation, which can be targeted and changed through
      prevention and intervention efforts, play a major role in predicting distress in
      this population.

PMID- 10596509
TI  - Childhood victimization and drug abuse: a comparison of prospective and
      retrospective findings.
AB  - This study examined whether childhood victimization increases risk for drug abuse
      using prospective and retrospective victimization information. Substantiated
      cases of child abuse/neglect from 1967 to 1971 were matched on gender, age, race,
      and approximate social class with nonabused/nonneglected children and followed
      prospectively into young adulthood. Between 1989 and 1995, 1,196 participants
      (676 abused/neglected and 520 control) were administered a 2-hr interview,
      including measures of self-reported childhood victimization and drug use/abuse
      (the National Institute of Mental Health Diagnostic Interview Schedule--Version
      III--Revised). Prospectively, abused/neglected individuals were not at increased
      risk for drug abuse. In contrast, retrospective self-reports of childhood
      victimization were associated with robust and significant increases in risk for
      drug abuse. The relationship between childhood victimization and subsequent drug
      problems is more complex than originally anticipated.

PMID- 10596510
TI  - Association of parental psychopathology to the comorbid disorders of boys with
      attention deficit-hyperactivity disorder.
AB  - This study examined whether particular forms of parental psychopathology are
      related to similar forms of comorbid psychopathology in offspring with attention
      deficit-hyperactivity disorder (ADHD). Parental disorders were assessed using
      maternal interviews, and child disorders were assessed using multiple-informant
      interviews for 111 clinic-referred boys (aged 7-12) with Diagnostic and
      Statistical Manual of Mental Disorders (3rd ed., rev.; American Psychiatric
      Association, 1987) ADHD. Associations between parental and child internalizing
      disorders and between parental and child externalizing disorders were found, but
      associations across categories of disorder (i.e., internalizing and
      externalizing) were not. Similar relationships were observed in 66 clinic
      referred boys without ADHD. These findings support specific modes of familial
      transmission, in contrast to theories that comorbidity simply reflects more
      severe psychopathology in children with ADHD.

PMID- 10596511
TI  - Sudden gains and critical sessions in cognitive-behavioral therapy for
      depression.
AB  - In this study of cognitive-behavioral therapy for depression, many patients
      experienced large symptom improvements in a single between-sessions interval.
      These sudden gains' average magnitude was 11 Beck Depression Inventory points,
      accounting for 50% of these patients' total improvement. Patients who experienced
      sudden gains were less depressed than the other patients at posttreatment, and
      they remained so 18 months later. Substantial cognitive changes were observed in
      the therapy sessions preceding sudden gains, but few cognitive changes were
      observed in control sessions, suggesting that cognitive change in the pregain
      sessions triggered the sudden gains. Improved therapeutic alliances were also
      observed in the therapy sessions immediately after the sudden gains, as were
      additional cognitive changes, suggesting a three-stage model for these patients'
      recovery: preparation-->critical session/sudden gain-->upward spiral.

PMID- 10596512
TI  - Dysphoria-related bias in maternal ratings of children.
AB  - Circumstantial evidence suggests that dysphoria creates a negative bias in
      caregivers' descriptions of child functioning. Past research has confounded
      informant and setting, making it unclear whether caregivers are biased or
      veridically reporting worse behavior in the home. In the present study, 137 low
      income mothers watched videotapes of their own child and a control child
      performing a frustrating task. Mothers then completed 18 items assessing
      different positive and negative behaviors and emotions. The Beck Depression
      Inventory, The Differential Emotions Scale--Form IV, and The State-Trait Anxiety
      Inventory were used to assess maternal dysphoria. Correlations between mothers'
      dysphoria and descriptions of the control child showed small but significant
      dysphoria-related bias. Dysphoria provided approximately 10% predictive increment
      for mothers' ratings of their own children after partialing out independent
      judges' ratings. Results support an emotion-appraisal model predicting dysphoric
      bias.

PMID- 10596513
TI  - Assessing risk for violence among psychiatric patients: the HCR-20 violence risk
      assessment scheme and the Psychopathy Checklist: Screening Version.
AB  - This study evaluated the predictive validity of the HCR-20 (Historical, Clinical,
      and Risk Management) violence risk assessment scheme and the Psychopathy
      Checklist: Screening Version (PCL:SV). Files of 193 civilly committed patients
      were coded. Patients were followed up in the community for an average of 626
      days. Receiver operating characteristic analyses with the HCR-20 yielded strong
      associations with violence (areas under curve [AUCs] = .76-.80). Persons scoring
      above the HCR-20 median were 6 to 13 times more likely to be violent than those
      scoring below the median. PCL:SV AUCs were more variable (.68-.79). Regression
      analyses revealed that the HCR-20 added incremental validity to the PCL:SV and
      that only HCR-20 subscales predicted violence. Implications for risk assessment
      research, and the clinical assessment and management of violence, are discussed.

PMID- 10596514
TI  - Chronic low-back pain: what does cognitive coping skills training add to operant
      behavioral treatment? Results of a randomized clinical trial.
AB  - This study examined the supplemental value of a cognitive coping skills training
      when added to an operant-behavioral treatment for chronic low-back pain patients.
      The complete treatment package (OPCO) was compared with an operant program +
      group discussion (OPDI) and a waiting-list control (WLC). After the WL period,
      the WLC patients received a less protocolized operant program usually provided in
      Dutch rehabilitation centers (OPUS). Regression analyses showed that, compared
      with WLC, both OPCO and OPDI led to less negative affect, higher activity
      tolerance, less pain behavior, and higher pain coping and pain control. At
      posttreatment, OPCO led to better pain coping and pain control than OPDI.
      Calculation of improvement rates revealed that OPCO and OPDI had significantly
      more improved patients than OPUS on all the dependent variables. The discussion
      includes findings regarding treatment credibility, compliance, and contamination
      bias.

PMID- 10596515
TI  - Psychological sequelae of hate-crime victimization among lesbian, gay, and
      bisexual adults.
AB  - Questionnaire data about criminal victimization experiences were collected from
      2,259 Sacramento-area lesbians, gay men, and bisexuals (N = 1,170 women, 1,089
      men). Approximately 1/5 of the women and 1/4 of the men had experienced
      victimization because of their adult sexual orientation. Hate crimes were less
      likely than nonbias crimes to have been reported to police. Compared with other
      recent crime victims, lesbian and gay hate-crime survivors manifested
      significantly more symptoms of depression, anger, anxiety, and posttraumatic
      stress. They also displayed significantly more crime-related fears and beliefs,
      lower sense of mastery, and more attributions of their personal setbacks to
      sexual prejudice than did nonbias crime victims and nonvictims. Comparable
      differences were not observed among bisexuals. The findings highlight the
      importance of recognizing hate-crime survivors' special needs in clinical
      settings and in public policy.

PMID- 10596516
TI  - Efficacy of forced smoking cessation and an adjunctive behavioral treatment on
      long-term smoking rates.
AB  - This study evaluated the efficacy of a 6-week forced ban on smoking and brief
      behavioral counseling on long-term smoking rates. Participants were active-duty
      enrollees in U.S. Air Force basic military training over a 1-year period (N =
      25,996). All participants were under a 6-week ban from tobacco products, and 75%
      were randomized to a brief smoking cessation intervention, with the other 25%
      randomized to a control condition. At 1-year follow-up, 18% of smokers were
      abstinent; women, ethnic minorities, and those intending to stay quit at baseline
      were more likely to be abstinent. Among smokers not planning to remain abstinent
      at baseline, those receiving the intervention were 1.73 times more likely to be
      abstinent. Over time, substantial smoking initiation occurred among nonsmokers
      (8% of never smokers, 26% of experimental smokers, and 43% of ex-smokers). Forced
      cessation is associated with good levels of long-term cessation, and brief
      behavioral interventions enhance cessation in certain subgroups.

PMID- 10596517
TI  - Effectiveness of a video-based motivational skills-building HIV risk-reduction
      intervention for inner-city African American men.
AB  - Interventions to reduce HIV risk behavior have shown promise but have
      demonstrated inconsistent effects with heterosexual men. This article reports a
      cognitive-behavioral HIV risk reduction intervention designed for heterosexually
      active African American men. Men (N = 117) recruited from a public clinic were
      randomly assigned to either (a) a 6-hr video-based small group motivational
      skills intervention or (b) a 6-hr video-based contact-matched HIV education
      comparison group. Results showed men in the motivational-skills intervention
      reported lower rates of unprotected vaginal intercourse and higher rates of
      condom use at the 3-month follow-up. However, because of increased condom use in
      the comparison condition, differences between groups dissipated 6 months
      following the intervention. These findings are among the first to demonstrate
      effects from a motivational-skills intervention for reducing HIV risk in men who
      have sex with women using a model designed to facilitate transferring prevention
      technology to community settings.

PMID- 10596518
TI  - Naturalistic weight-reduction efforts prospectively predict growth in relative
      weight and onset of obesity among female adolescents.
AB  - This study examined the prospective relations of naturalistic weight-reduction
      efforts to growth in relative weight and onset of obesity with data from a
      community study of female adolescents (N = 692). Initial self-labeled dieting,
      appetite suppressant/laxative use, incidental exercise, vomiting for weight
      control purposes, and binge eating predicted elevated growth in relative weight
      over the 4-year period. Dietary restraint, self-labeled dieting, exercise for
      weight-control purposes, and appetite suppressant/laxative use predicted an
      increased risk for obesity onset. Data imply that the weight-reduction efforts
      reported by adolescents are more likely to result in weight gain than in weight
      loss and suggest the need to educate youth on more effective weight-control
      strategies.

PMID- 10596519
TI  - Modeling long-term parent outcomes of two universal family-focused preventive
      interventions: one-year follow-up results.
AB  - The present investigation extended prior work by R. Spoth, C. Redmond, and C.
      Shin (1998). These researchers reported findings that 2 universal family-focused
      preventive intervention programs each had direct effects on a proximal parenting
      outcome (intervention-targeted parenting behaviors) and indirect effects on 2
      global and distal outcomes (parent-child affective quality and general child
      management) at posttesting. A replication of the previously tested parenting
      outcome model was conducted with 1-year follow-up data and procedures identical
      to those used in the earlier study. Results of the present study (N = 404
      families) indicate that statistically significant effects on parenting outcomes
      were sustained through a 1-year period following the posttest.

PMID- 10596520
TI  - The relationship between acute stress disorder and posttraumatic stress disorder:
      a 2-year prospective evaluation.
AB  - Previous research established that 78% of a sample of motor vehicle accident
      survivors initially diagnosed with acute stress disorder (ASD) were subsequently
      diagnosed with posttraumatic stress disorder (PTSD) at 6 months posttrauma.
      Although the previous study provided initial evidence for the utility of the ASD
      diagnosis, the relationship between ASD and PTSD was assessed over a relatively
      short period. The present study reassessed that original sample 2 years following
      the trauma to establish the longer term relationship between ASD and PTSD. ASD
      was diagnosed in 13% of participants, and 21% were diagnosed with subsyndromal
      ASD. In terms of participants who participated in all 3 assessments, 63% who met
      the criteria for ASD, 70% who met the criteria for subsyndromal ASD, and 13% who
      did not meet the criteria for ASD were diagnosed with PTSD at 2 years posttrauma.
      These findings indicate the importance of considering multiple pathways to the
      development of PTSD.

PMID- 10596521
TI  - Brief intervention for harm reduction with alcohol-positive older adolescents in
      a hospital emergency department.
AB  - This study evaluated the use of a brief motivational interview (MI) to reduce
      alcohol-related consequences and use among adolescents treated in an emergency
      room (ER) following an alcohol-related event. Patients aged 18 to 19 years (N =
      94) were randomly assigned to receive either MI or standard care (SC). Assessment
      and intervention were conducted in the ER during or after the patient's
      treatment. Follow-up assessments showed that patients who received the MI had a
      significantly lower incidence of drinking and driving, traffic violations,
      alcohol-related injuries, and alcohol-related problems than patients who received
      SC. Both conditions showed reduced alcohol consumption. The harm-reduction focus
      of the MI was evident in that MI reduced negative outcomes related to drinking,
      beyond what was produced by the precipitating event plus SC alone.

PMID- 10596523
TI  - Suicidal ideation among college students in the United States.
AB  - This study analyzed data from the 1995 National College Health Risk Behavior
      Survey (NCHRBS) to assess the prevalence of suicidal ideation among college
      students in the United States and to examine the association between suicidal
      ideation and substance use in this population. The NCHRBS used a mail
      questionnaire to assess health-risk behaviors in a nationally representative
      sample of undergraduate students. During the 12 months preceding the survey, 10%
      of the students had seriously considered attempting suicide. When controlling for
      demographic characteristics, the analysis showed that students who had considered
      suicide were at increased odds of using tobacco, alcohol, and illegal drugs.
      These results suggest that colleges and universities should establish suicide
      prevention programs that also address the related problem of substance use.

PMID- 10596522
TI  - Treating anxiety disorders in children with group cognitive-behaviorial therapy:
      a randomized clinical trial.
AB  - A randomized clinical trial evaluated the therapeutic efficacy of group cognitive
      behavioral therapy (GCBT) versus a wait-list control (WLC) condition to treat
      anxiety disorders in children. Results indicated that GCBT, with concurrent
      parent sessions, was highly efficacious in producing and maintaining treatment
      gains. Children in GCBT showed substantial improvement on all the main outcome
      measures, and these gains were maintained at 3-, 6-, and 12-month follow-ups.
      Children in the WLC condition did not show improvements from the pre- to the
      postwait assessment point. These findings are discussed in terms of the need to
      continue to advance the development of practical, as well as conceptual,
      knowledge of efficacious treatment for anxiety disorders in children.

PMID- 10596524
TI  - Concern about weight gain associated with quitting smoking: prevalence and
      association with outcome in a sample of young female smokers.
AB  - This study investigated the relationship between weight gain concern and outcomes
      of a large-scale smoking cessation study among 506 young female smokers attending
      Planned Parenthood clinics. Results of this prospective study did not support the
      clinical importance of weight gain concerns. Using an index of weight concern
      that was predictive in previous research, baseline weight concern was unrelated
      to smoking cessation efforts, whether participants made a quit attempt, reduced
      the number of cigarettes they smoked, or reported a change in self-efficacy for
      stopping smoking. Both the overall level of concern expressed in this sample of
      predominantly White young women and the lack of relationship between weight gain
      concern and smoking cessation outcomes suggest that weight gain concern may not
      be a critical factor for cessation programs targeting similar female smokers.

PMID- 10596525
TI  - [New discoveries in the treatment of deep venous thrombosis: length of the
      treatment is the target of international studies].

PMID- 10596526
TI  - [Patients' caregivers or dogmatists?].

PMID- 10596527
TI  - [Are recommendations and guidelines by the Medical Product Agency evidence
      based?].

PMID- 10596528
TI  - [Methylcobalamin and chronic fatigue].

PMID- 10596529
TI  - [Gynecological ultrasound is of uncertain value in screening].
AB  - In the past ten years, gynecological ultrasonography has proliferated rapidly,
      and is by some gynecologists considered an integral part of the gynecological
      exam. Abnormalities are detected in a asymptomatic women at a high rate,
      resulting in a number of surgical interventions due to suspected malignancy.
      Present evidence is insufficient to determine the medical and economical value,
      if any, of surgical removal. Such intervention may in fact be as detrimental as
      leaving an abnormality in place. Gynecological ultrasonography should therefore
      be performed on strict medical indications. Proper training of operators is also
      vital.

PMID- 10596530
TI  - [Microscopic hematuria in adults--a diagnostic dilemma. Scientific guidelines for
      management are not available according to a review of the literature].
AB  - Red cell urinalysis is a very common laboratory procedure in health care, and
      microscopic haematuria a common finding in apparently healthy people. Response to
      a questionnaire sent to all departments of urology in Sweden and to general
      practitioners in the province of Ostergotland showed both groups to vary
      considerably in their approach to its management. Accordingly, to determine
      whether a reliable scientific basis exists for its management, a literature
      search for the period, 1975-97, was made in MEDLINE, under the headings
      haematuria, microscopic haematuria and microhaematuria, which yielded a total of
      845 items. After scrutiny of the abstracts, 203 reports were selected for closer
      study in the following respects: study design, series studied, selection
      criteria, age and gender distribution, test methods used, cut-off values for
      further investigation, and study results. In 17 series comprising a total of
      5,000 patients, urological cancer was diagnosed in less than three per cent of
      cases. Of almost 200,000 males and females patients tested for haematuria, less
      than one per cent were found to have disease requiring treatment. In general, the
      studies were characterised by an absence of control groups, and by differences in
      study design, selection criteria, test methods, definitions of microscopic
      haematuria, and investigatory procedures. There were no randomised prospective
      studies where patients undergoing investigation were compared with those
      undergoing follow-up only. Thus, as available documentation in professional
      journals and textbooks shows no consensus to exist as to management in cases of
      microscopic haematuria, further research is required in this field before
      scientifically sound guidelines can be issued.

PMID- 10596531
TI  - [Executive functions and serotonin activity in patients with depression. A
      connection mirrors the influence of serotonin on prefrontal cortex].

PMID- 10596532
TI  - [A study in the Northern Alvsborg. Almost half of the cases with fetal growth
      retardation were not diagnosed].

PMID- 10596533
TI  - [Report of a case. A common fungus caused a rare skin infection].

PMID- 10596534
TI  - [Use of percutaneous coronary vessel interventions should be increased. 400
      interventions per year is a minimum capacity of decentralized services].

PMID- 10596535
TI  - [Children with special support needs are helped by personnel with specialized
      competence. Educators, social workers and physicians cooperate in Orebro].

PMID- 10596536
TI  - [The sterilization issue of the 1930's and 1940's. The Medical Society played a
      passive role--neither warning nor pursuing].

PMID- 10596537
TI  - [Racial biology and the populatioN issue. A historical retrospect in the
      Lakartidningen].

PMID- 10596538
TI  - [The Medical Society and immigration of physicians, 1. Caring for the patients or
      protectionism?].

PMID- 10596539
TI  - [Openness, social security number and confidence. Ethical rules as a competitive
      agent for biobanks and genome firms].

PMID- 10596540
TI  - [The hand-arm vibration syndrome: (II). The diagnostic aspects and fitness
      criteria].
AB  - Part II of this paper reviews the clinical and laboratory methods to diagnose the
      neurological, vascular and osteoarticular components of the hand-arm vibration
      syndrome. The prognosis and reversibility of vibration-induced neurological and
      vascular disorders after cessation of vibration exposure or the introduction of
      powered tools equipped with vibration isolation systems are discussed on the
      basis of the results of follow-up clinical investigations and longitudinal
      epidemiologic studies. Finally, the review debates some of the methodological
      aspects connected with the health surveillance of vibration-exposed workers and
      considers the possible medical contra-indications for prolonged exposure to hand
      transmitted vibration.

PMID- 10596541
TI  - [Occupational agents and endocrine function: an update of the experimental and
      human evidence].
AB  - Many environmental and occupational agents have been shown to cause detrimental
      effects on endocrine function and growing scientific evidence supports the
      hypothesis that such alterations may produce serious consequences for health.
      Although those chemicals mimicking (or contrasting) estrogenic or androgenic
      actions have raised great concern, the relevance of disruption of other hormonal
      pathways is not negligible. This article reviews the effects of chemical and
      physical agents on the hypothalamus-pituitary unit, pineal gland, thyroid,
      parathyroid and calcium metabolism, adrenal glands, and glucose metabolism.
      Metals (Pb, Mn, Cd, organotin compounds), solvents (benzene, dioxane, styrene,
      tetrachloroethylene, toluene), organochlorines (PCBs, TCDD), and physical agents
      have been shown in human, animal or in vitro studies to cause alterations of the
      blood levels, and of the activity or circadian rhythm of pituitary hormones.
      Melatonin has been proposed as the link between environmental/occupational
      factors and the immunologic and neoplastic diseases, which in addition to
      disturbances of the circadian timing system, feature pineal hormone reduction.
      Thyroid gland diseases (goiter, autoimmune thyroiditis, carcinoma) are associated
      with exposure to many chemical or physical agents. Disruptions of calcium control
      secondary to metal exposures, as well as the effect of radiation on parathyroid,
      are addressed. Adrenal cortex and medulla function alterations by several
      chemical agents are considered. Finally, diabetes mellitus as an outcome of
      occupational or environmental exposures and as susceptibility to occupational and
      environmental factors is discussed.

PMID- 10596543
TI  - [Prevention, safety and prophylactic measures in occupational HIV infection in
      Italy, the European Union and the USA].
AB  - Numerous guidelines have been issued by Public Health institutions and related
      authorities in the last few years for the prevention of HIV infection among
      occupationally exposed workers. Our study was aimed at comparing the regulations
      and guidelines on this topic that have recently been adopted by Western
      countries, also taking into account the impact of the problem in current
      scientific literature. Health-care workers are the category with the highest risk
      for occupational exposure to HIV principally associated with accidental
      needlesticks, skin lesions and percutaneous injuries. In preventive and
      occupational medicine, Italy, the European Union and the USA have founded their
      recommendations on universal and specific precautions issued by the Center for
      Disease Control. Moreover, as long ago as 1990 the Italian Ministry of Health
      issued official guidelines for the prevention of occupational exposure to
      bloodborne pathogens. Post-exposure management is crucial for the protection of
      workers at risk. As a consequence of the failure of some monotherapeutic
      zidovudine treatments, different countries revised their guidelines and
      recommended the use of a combination of chemotherapeutic drugs for the post
      exposure regimen. However, most of the currently available data are derived from
      efficacy studies of combined therapy on HIV-infected patients. Therefore, further
      experimental investigations are needed aimed at evaluating the short- and long
      term effects of these treatments in the post-exposure protection of workers at
      risk for HIV infection.

PMID- 10596542
TI  - [A report of 3 cases of pleural mesothelioma with unusual asbestos exposure].
AB  - The occurrence of malignant pleural mesothelioma (MT) is a sentinel event in
      occupational and environmental medicine. The association of pleural MT and
      asbestos exposure is well documented and it is well known that no threshold can
      be demonstrated below which there is no risk of developing MT. During the period
      1994-1998, 3 patients were referred from the Pneumology Division to the
      Occupational Medicine Department of the Spedali Civili in Brescia. They had MT
      and they had a peculiar asbestos exposure. A thorough occupational and
      environmental history was taken by means of a standardized questionnaire. The
      first patient was environmentally exposed to crocidolite when she lived near an
      asbestos mine in Australia. The second was a teacher and the third was a
      goldsmith and both were occupationally exposed to asbestos. The case descriptions
      revealed the importance of a standardized evaluation of occupational and
      environmental exposure to asbestos. In this way otherwise ignored asbestos
      exposures can be identified therefore avoiding an underestimation of MT
      attributable to asbestos. The role of the occupational physician, both in
      hospital referrals and while taking standardized histories, is also stressed
      along with the importance of this contribution on the one hand to the
      epidemiological recording of sentinel events and on the other to the etiological
      definition of the cases, which was in fact our principal aim.

PMID- 10596544
TI  - Occupational health and safety in the mining industry in Morocco.
AB  - The mining sector is one of the pillars of our national economy. Our paper
      concerns safety and occupational health in the mining sector in Morocco. This
      sector employs 60,000 persons, more than half of them working in the phosphate
      sectors. There are 36 occupational medical services, with 83 practitioners 395
      nurses and 91 agents, protecting 43,926 workers (73% of all personnel). The task
      of labour inspection in this sector is entrusted to mining engineers. The
      statistics of the central department of industrial inspection in mines from 1975
      to 1995 show a fall in occupational injuries and a progressive increase reported
      in occupational diseases, 96% of which are silicosis. The improvement of
      prevention and health at work in the mining sector in Morocco has led to a
      reduction in occupational hazards and specially occupational injuries. However,
      an effort seems required so as to generalize occupational medical and safety
      services in all the mining enterprises and in the craft mining sector in
      particular.

PMID- 10596545
TI  - [The preparation and characterization of fine dusts carried out in the Clinica
      del Lavoro di Milano in support of experimental studies].
AB  - This paper aims to illustrate the conditions selected at the Clinica del Lavoro
      of the University of Milan to prepare and analyze a large number of fine dust
      samples produced over a period of about 50 years, that were initially used for
      studies within the Clinic performed in its own facilities, and since 1956 were
      sent to other Italian and overseas laboratories (Luxembourg, UK, Germany, Norway,
      Sweden, South Korea, USA). The total quantity of material distributed (with
      maximum size 7-10 microns) was about 2 kg and consisted of the following mineral
      and artificial compounds: quartz, HF-treated quartz, tridymite, HF-treated
      tridymite, cristobalite, chromite, anthracite, quartz sand for foundry moulds,
      sand from the Lybian desert, vitreous silica, pumice, cement, as well small
      quantities of metallic oxides, organic resins, chrysotile, crocidolite, fibres
      (vitreous, cotton and polyamidic). About half of the entire quantity of dusts
      produced consisted of partially HF-treated tridymite. Initially, research on the
      etiology of silicosis used quartz dust samples, simply sieved or ventilated
      (consisting of classes finer than 0.04 mm, containing a 15-20% respirable
      fraction). From 1956 to 1960 the dusts were produced by manual grinding in an
      agate mortar, below about 10 microns, starting from quartz from Quincinetto (near
      Ivrea, Province of Turin), containing about 99.5% quartz: particle size and
      composition were checked using an optical-petrographic technique, with
      identification of the free and total silica content. Subsequently, the dusts used
      for biological research were obtained by grinding coarse material with a cast
      iron pestle and planetary mills, agate and corundum jars. The grinding products
      were sized by means of centrifugal classification, using the selector developed
      by N. Zurlo, ensuring control of dust size both optically and by means of wet
      levigators and hydraulic classifiers (in cooperation with the Institute of Mines
      of Turin Polytechnic School). After 1990 pestles and rotating drum mills with
      autogenic grinding load were used for grinding: the size of the treated samples
      was reduced to 0.05 mm and an extremely fine fraction was extracted, smaller than
      7-10 microns, which was used for pneumoconioses research. The characterization of
      the dust produced was in any case achieved by means of preliminary examination
      under the optical microscope (polarized light, sometimes supplemented with phase
      contrast), followed by quantitative analysis using chemical/petrographic,
      chemical diffraction or, more commonly, petrographic/diffraction techniques.
      Microscopic examination, if necessary supplemented with photo-micrography, was
      also used for particle size control, for numerical counting and subsequent
      reference to weight proportion. For all operational procedures the essential data
      on instruments and methods are reported. During studies on production, separation
      of fine dusts and their characterization, partly performed with support from the
      European Community (EEC/European Coal and Steel Commission), the following topics
      in particular were addressed: connections between particle size and free silica
      content in the measurable dust size fraction of the grinding products and in
      airborne dusts; characteristics of the dusts and risk indices in Italian iron and
      pyrite mines; possibility of abatement of the ultrafine classes of airborne dusts
      in pneumatically filled stopes by the addition of salts; comparison of the latest
      dust selectors used within the European Community; influence of the grinding
      methods on the results of fibrous and soft mineral measurement using X-ray
      diffraction analysis.

PMID- 10596547
TI  - [Comments on the case: the course of applied prevention is sharable].

PMID- 10596546
TI  - [The problems inherent in judging work fitness for a nurse in immunosuppressive
      therapy].

PMID- 10596549
TI  - [High frequency diathermy--a new method in the treatment of malignant and benign
      stenosis of the airways].
AB  - High-frequency electrocautery is a relatively new method in the treatment of
      malignant or benign airway stenoses. We report on the results of 58 sessions in
      41 patients (malignant condition n = 30, benign n = 11) within a three-year
      period. Various instruments were available for coagulation (blunt probe, knives
      of 4, 5 and 7 mm length, forceps and wire snare). 53/58 sessions were performed
      under general anaesthesia, energy was limited to 40 W with unlimited duration of
      pulses. The knives were the most frequently used devices, preferably with a
      length of 5 mm, which enabled us to either cut the tumour or scar tissue
      precisely slice by slice or to resect by direct coagulation. The use of the blunt
      probes and forceps was frequently rendered more difficult by detritus covering
      the instrument during coagulation. Polypes were easily resected with the wire
      snare, but this kind of tumour was found in four patients only. Major (> 100 ml)
      bleeding occurred in two patients. Obstructing fibrinous membranes were never
      seen after electrocautery. In conclusion, high-frequency electrocautery is an
      effective and safe method for endobronchial resection and can be considered a
      good alternative to the laser as the classical method for endobronchial
      resection.

PMID- 10596548
TI  - [Diagnostic value of the tumor markers TPA-M, CYPFRA 21-1 and CEA in pleural
      effusion. Prospective comparison of thoracoscopic investigations in patients with
      pleural effusion].
AB  - The diagnostic value of tumour markers in pleural effusion is not yet clearly
      defined. CEA (Carcinoembryonic Antigen), CYFRA 21-1 (Cytokeratin 19-Fragment) and
      TPA-M, a new monoclonal-based radioimmunoassay for TPA (Tissue Polypeptide
      Antigen), were measured in pleural fluid and sera of 125 consecutive patients who
      underwent medical thoracoscopy. The group consisted of 79 patients with malignant
      and 45 with non-malignant pleural effusion and 1 patient without definitive
      diagnosis, and hence 124 patients were available for assessing the diagnostic
      value. In pleural fluid based on a specificity of 90% versus benign diseases the
      sensitivity for CEA was 52.5%; with the maximum achievable specificity of 80% for
      CYFRA 21-1 the sensitivity was 68% and for TPA-M with 67% the sensitivity was
      67%. Based on the cut-off values for these specificities the combined use of the
      three tumour markers resulted in a sensitivity of 85.7% but with a lower
      specificity of 59.1%. There is only a limited value for tumour markers in the
      diagnosis of pleural effusion.

PMID- 10596550
TI  - [Bronchial carcinoma in young adults].
AB  - Lung cancer in young adults has been differently described in publications from
      various regions of the world, in respect of relative incidence, distribution of
      morphology and stages, and prognosis of the disease. We analysed retrospectively
      the data from the cancer registry of the Lungenklinik Heckeshorn in Berlin
      between 1986 and 1995 with regard to this topic. 106/4939 patients were 40 years
      old or younger (2.1%). The proportion of female patients was higher in the
      younger group (42 vs. 29%). Adenocarcinoma was the leading subtype in young
      patients (33 vs. 24%). The younger group showed a higher proportion of inoperable
      stages IIIB and IV for non-small cell lung cancer (71 vs. 46%). Younger patients
      with operable stages I to IIIA non-small cell lung cancer underwent surgery much
      more often than patients older than 40 years (90 vs. 49%), but for all patients
      with this morphology there was no difference in survival between younger and
      older patients (302 vs. 314 patients). We conclude that lung cancer presents a
      clearly different clinical picture in younger patients but not a better
      prognosis.

PMID- 10596551
TI  - [Combined alternating radiochemotherapy in stage III (TNM) (limited disease)
      small cell bronchial carcinoma: a phase II study with
      carboplatin/etoposide/vincristine and alternating radiotherapy].
AB  - BACKGROUND: The combination of radio-chemotherapy is accepted standard in limited
      disease small cell lung cancer, but the best way of combining the two modalities
      is still unknown. To test an alternating regime of early radiotherapy with
      hypofractionated radiotherapy we performed a phase II study in stage III small
      cell lung cancer. METHOD: 32 SCLC patients (n = 7 IIIa, n = 25 IIIb) were treated
      with a weekly alternating regime with either chemotherapy or radiotherapy.
      Chemotherapy included carboplatin (AUC5), etoposide (3 x 120 mg/m2) and
      vincristine (2 mg), repeated on day 28 for six cycles. Radiotherapy started one
      week before chemotherapy and was applied weekly 1 x 4 Gy, using a split-course
      regimen. RESULTS: Combined radio-chemotherapy was well tolerated with dose
      limiting hemotoxicity and very few cases of oesophagitis. Overall response was
      75%, median survival 14.5 months and the 2-year survival was 34.4%. 5 patients
      are still living now for more than 29 months. Treatment failure was local and
      systemic in 34% of the patients. Systemic failure included 6 patients with brain
      metastases. CONCLUSION: Combined radio-therapy in small-cell lung cancer using an
      alternating hypofractionated regimen is well tolerated. Response rate and 2-year
      survival are promising. Local and systemic failure is an ongoing problem and
      requires better local and systemic control of the disease.

PMID- 10596552
TI  - Pathogenesis of malignant pleural effusions and talc pleurodesis.

PMID- 10596553
TI  - [German Society of Pneumology. Recommendations for the diagnosis of nosocomial
      infections].

PMID- 10596554
TI  - [Treatment of chondral and osteochondral defects of the knee].
AB  - Chondral and osteochondral defects play an important role in the knee surgery.
      The knee traumas are often followed by preterm development of osteoarthritis due
      to limited reparative processes in the cartilage. Today's diagnostic
      possibilities and progress in arthroscopic techniques promote the early
      diagnostic and exact classification of osteochondral defects. The prognosis of
      these injuries is improved by following early treatment. Authors present
      therapeutic ways of solving the defects of cartilage and adjacent part of the
      subchondral bone. The new possible method of solving the deep chondral defects on
      the weight-bearing site of the knee by combined mosaic plasty and autologous
      cultivated chondrocytes is described.

PMID- 10596555
TI  - [Appendicitis and ultrasound diagnosis in children].
AB  - The diagnosis of acute appendicitis remains despite all medical advances a
      difficult task even for an experienced surgeon. In the submitted paper the
      authors evaluated retrospectively a group of child patients operated with this
      diagnosis during the last two years in their department, in an attempt to assess
      the contribution of US diagnosis in acute appendicitis.

PMID- 10596556
TI  - [Our concept of defecography. Methods and reproducibility of results].
AB  - Defecography is used in the Czech Republic only exceptionally. Since 1988 the
      authors made 402 defecographic examinations. They submit a detailed description
      of hitherto assembled experience and their own modification of the examination.
      As contrast material they use at present Micropaque susp. thickened by means of
      wheat bran. They administer it by means of a modified press for dough
      preparation. The X-rays are taken on a modified ordinary stool made from soft
      timber. For screening of uncovered places in the visual field they use
      individually placed copper plates 2 mm thick. For better evaluation of the X-rays
      the authors place during examination an X-ray contrasting net behind the patient.
      Pictures are taken at rest, during contraction, during modified Valsalva's
      manoeuvre and during all stages of defecation. The authors mention the most
      interesting pathological pictures they encountered so far--internal prolapse,
      levator hernia, rectocele, sphincter defect, various forms of prolapses and
      dyskineses of the pelvic floor. In the authors opinion the basic quantifiable
      parameters are the magnitude of the anorectal angles. They used the assessment
      method described by Mahieu, as well as the mediorectal angle which in their
      opinion is a reflection of the patient's somatotype and levator function. More
      than the absolute values of the angles they emphasize the difference of the two
      angles and change of the latter during contraction and defecation. In their
      opinion enlargement of the difference during contraction and diminution to values
      close to zero is normal. Converse values are according to the authors evidence of
      dyssynergy of the pelvic floor. Independent assessment of the angles and
      magnitude of the lift of the pelvic floor by three subjects are subjected to
      statistical analysis. They provide evidence of complete reproducibility of
      results of anorectal angles according to the authors' definition. The results of
      assessment can be used to investigate relations with parameters of anorectal
      manometry (AM) or transrectal sonographyy (TRS) in subsequent investigations.

PMID- 10596557
TI  - [Systemic enzyme therapy in osteosynthesis of the long bones].
AB  - The authors focused their attention on the application of systemic enzyme therapy
      in traumatology, in particular on its anti-oedematous, fibrinolytic and analgetic
      effects during the postoperative period in osteosyntheses of the long bones. In a
      group of 40 patients they investigated postoperative changes of the volume of
      operated extremities. They found a very marked anti-oedematous effect of
      Phlogenzym. The authors draw attention to the great importance of anti-oedematous
      treatment and mention also possibilities of systemic enzyme therapy in this
      indication.

PMID- 10596558
TI  - [Pneumatosis cystoides intestinalis as a cause of obstructive ileus].
AB  - The authors present the case-history of a 83-year-old patient hospitalized and
      operated on account of ileus caused by pneumatosis cystoides intestinalis. In the
      discussion the authors pay attention to the etiology, pathogenesis, clinical
      picture and possible treatment of this disease.

PMID- 10596559
TI  - [Adverse hemodynamic changes during laparoscopic cholecystectomy and their
      possible suppression with clonidine premedication. Comparison with intravenous
      and intramuscular premedication].
AB  - Laparoscopic cholecystectomies have adverse haemodynamic effects which limit
      their use in risk patients with heart disease. This applies in particular to
      significant hypertension. The etiology is analysed in detail in a review of the
      literature. The authors confirmed in their work involving 21 patients the
      incidence of these effects and tried to suppress them by premedication with
      clonidine (CATAPRESAN, Boehringer). 21 patients were given 0.15 mg clonidine in
      an infusion 15 minutes before operation and 21 patients 0.15 mg clonidine by the
      i.m. route 60-90 min. before operation. Standard anaesthesia was administered. A
      highly significant drop in the incidence of hypertension was recorded during
      operation for systolic pressure (p < 0.001) after both ways of administration, as
      well as of diastolic pressure (p < 0.01 for intravenous and p < 0.05 for
      intramuscular premedication). Premedication with intravenous clonidine can be
      recommended as a routine procedure before laparoscopic cholecystectomies.

PMID- 10596561
TI  - [The diabetic foot syndrome--antibiotic therapy].
AB  - The authors present an account on cultivation findings assembled in defects of
      the lower extremities of diabetic patients hospitalized at the surgical
      department of the Pelhrimov hospital. In the polymicrobial flora a relatively
      high ratio of anaerobic microorganisms was found (58%). Based on the sensitivity,
      a combination of antibiotics was recommended which could be used in empirical
      treatment before cultivation results (clindamycin, ofloxacin, gentamycin and
      azlocillin). The authors prefer results of actual sensitivity tests. The authors
      discuss principles of collection and processing of microbiological material and
      treatment. Anaerobic cultivation is specially emphasized.

PMID- 10596560
TI  - [Use of procalcitonin in surgery].
AB  - Procalcitonin (PCT) is a new early indicator of developing systemic bacterial
      infection. As compared with other anti-inflammatory markers (cytokines, acute
      stage proteins), the attained plasma levels during extensive but uncomplicated
      surgery are by orders lower than maximal levels during sepsis. The authors assume
      that PCT will be used in surgical practice as an early indicator of developing
      systemic bacterial infection (in multiple injuries, after surgery) and for
      subsequent evaluation of the effectiveness of treatment of septic conditions.

PMID- 10596562
TI  - [Pitfalls of biofragmentable anastomotic ring construction].
AB  - The authors describe the main problems of the technical implementation and
      construction of biofragmentable anastomoses by means of the Valtrac ring, used
      for anastomosis after resections in the area of the gastrointestinal tract in a
      total of 72 patients. The authors evaluate postoperative technical difficulties
      and the main aspects of the implementation proper which may be the cause of
      serious complications during the immediate postoperative period.

PMID- 10596563
TI  - [True aneurysms of the popliteal artery--surgical treatment].
AB  - The authors discuss the history of treatment of popliteal aneurysm, causes of its
      development and its surgical treatment. They recommend surgery of an asymptomatic
      aneurysm with a diameter greater than 2 cm because of possible development of
      thrombosis with subsequent embolization into the periphery and development of
      gangrene of the extremity which may end by amputation. Early thrombolysis of a
      thrombotized aneurysm can be successful and combined with subsequent surgery can
      save the extremity. When a peripheral aneurysm is detected thorough surgical
      examination is necessary using ultrasonography, computed tomography and magnetic
      resonance resp. to detect aneurysms at other sites.

PMID- 10596564
TI  - [Continuous loop suture in a longitudinal arteriotomy].
AB  - The author describes a technical 8-shaped variation of continuous suture of
      longitudinal arteriotomy. He describes the technical details of implementation of
      the suture which by crossing of the thread between the margins of the arteriotomy
      prevents overlapping of the margins and thus narrowing the arterial lumen.
      Practical aspects of the use of the suture are described, incl. evaluation of
      conditions and local findings where this continuous suture can, due to its
      functional effect, replace autovenous or prosthetic plastic surgery of the
      artery.

PMID- 10596565
TI  - [Pathophysiologic aspects of chronic venous insufficiency].
AB  - Knowledge of the pathophysiology of the venous circulation and its evaluation
      before treatment determines not only the best therapeutic plan, but at the same
      time makes it possible to avoid operations which are not necessary and a priori
      doomed to lead to a relapse. The basic therapeutic principles in the treatment of
      chronic venous insufficiency after evaluation and localization of the functional
      disorder by an objective examination method (duplex sonography, phlebography ...)
      are: a) compression, b) severing of pathological points of insufficient
      perforators, orifices of both saphenous veins, c) antireflux operation of the
      deep veins with preference of the popliteal vein. Any therapeutic procedure which
      does not have the aim to reduce venous hypertension is a priori doomed to failure
      and very soon a relapse develops. From this aspect it is not important to remove
      chaotically and extensively superficial varicosities (surgically or by
      sclerotherapy) but to severe the insufficient perforators and the insufficient
      orifices of saphenous veins surgically or by sclerotherapy.

PMID- 10596566
TI  - [Laparoscopic hernioplasty--personal experience].
AB  - The place of minimally invasive surgery in the treatment of inguinal hernias is
      still unequivocal so far. The authors submit the results assembled in 400
      patients operated by the method of transabdominal preperitoneal implantation of a
      prolene net (TAPP) in the course of five years. They pay special attention to the
      incidence of relapses, peroperative and postoperative complications.

PMID- 10596567
TI  - [Changes in acid-base equilibrium, ventilation parameters and immunologic
      reactions in thoracoscopic operations].
AB  - In the thoracoscopic operations it is usually necessary to deflate completely the
      ipsilateral lung. The aim of this study was to determine changes of blood gases
      and alterations of immune response mediators during thoracoscopic surgery with
      one-lung ventilation OLV. In the study 38 patients were included undergoing
      thoracoscopic or video-assisted thoracic surgery. Arterial blood gases,
      respiratory parameters, heart rate, blood pressure were determined before one
      lung ventilation, at the peak of operation and after finishing OLV. The
      circulatory cytokines IL-1 beta, IL-2, IL-6, IL-8, TNF-alpha, and reactive oxygen
      species (ROS) were measured before and after operation, 3 h, 24 h and 48 h after
      operation. The obtained variables were statistically evaluated. One-lung
      ventilation caused a significant increase of PaCO2 (from 4.69 +/- 0.67 to 5.91 +/
      0.87 kPa) which was accompanied by an adequate decrease of pH (7.455 +/- 0.033
      7.368 +/- 0.037) and a number of patients developed respiratory acidosis (34%).
      There were no significant changes in levels of the investigated cytokines, only a
      mild increase of IL-6, IL-8 and TNF during first 24 h after operation was
      observed. The activity of ROS was highest at the end of the operation, but did
      not differ significantly from the start, but then decreased significantly for a
      period of 24 h. The authors conclude that the observed increase of carbon dioxide
      levels and decrease of pH had no impact on the fate of the patients.
      Thoracoscopic or VATS procedures were a minimal load for patients causing no
      significant changes of proinflammatory cytokines. The operations did not
      significantly elevate the activity of ROS.

PMID- 10596568
TI  - [Does insufflation of the abdomen in laparoscopic surgery affect acid-base and
      ventilatory parameters?].
AB  - The cardiopulmonary and metabolic changes experienced by patients undergoing
      laparoscopic cholecystectomy with CO2 pneumoperitoneum are not well understood.
      The purpose of this study is to determine changes of basal parameters during
      laparoscopy and evaluate their prognostic value. One hundred patients (26 obese,
      39 older than 60 years, 7 obese and older than 60) undergoing laparoscopic
      cholecystectomy for uncomplicated cholecystolithiasis were included in the study.
      Arterial blood gases, respiratory and ventilatory parameters, heart rate, blood
      pressure were determined before the induction of pneumoperitoneum, at the peak of
      operation and after exsufflation. The obtained variables were statistically
      evaluated. Pneumoperitoneum caused significant hypercapnia and a decrease of pH
      accompanied with increase of expiratory CO2 concentration, which continued after
      exsufflation (p < 0.001). The changes were more expressed in older and obese
      patients and were solely of a respiratory type. No significant changes were
      observed in the heart rate, blood pressure, minute ventilation, PaO2, SaO2, base
      excess. Although changes were highly significant, there was no impact on clinical
      status--all patients survived without problems. The authors conclude that
      observed increase of carbon dioxide levels and decrease of pH had no impact on
      survival of patients. Changes were caused mostly by CO2 absorption from the
      abdominal cavity. Laparoscopic cholecystectomy is a safe and effective procedure
      even in older and obese patients, especially when insufflation is as low as
      possible.

PMID- 10596569
TI  - [Preventive sclerotherapy of esophageal varices with a high risk of hemorrhage: a
      prospective randomized controlled study].
AB  - Endoscopic sclerotherapy (ES) is known to be effective in the treatment of
      bleeding esophageal varices, but the efficacy in the prophylaxis of first
      variceal bleeding has not been clear yet. The aim of this study was to
      investigate the frequency of first variceal bleeding, eradication and recurrence
      of varices, and survival after treatment with ES compared to non-treated control
      group. A total of 104 patients with liver cirrhosis and advanced esophageal
      varices with no previous history of upper gastrointestinal bleeding were randomly
      assigned to either endoscopic sclerotherapy group--SKL n = 56, or non-treated
      control group--KON n = 48. After eradication of esophageal varices in SKL group
      and in all control patients, the endoscopic examination was performed in 3 month
      intervals. The complete eradication of esophageal varices was achieved in 45
      (83%) patients of SKL group. The mean number of sessions required to obtain
      eradication was 7.8 +/- 2.5. The recurrence of esophageal varices occurred in 9
      (17%) patients. Total mortality was significantly lower in SKL patients as
      compared to controls (21.4% vs. 39.6%; p = 0.047, 95% CI 0.5-35.5). The
      significant decrease of variceal bleeding we observed in sclerotherapy (21%)
      versus controls (52%; p = 0.002, 95% CI 13-49%). Serious complications of ES were
      not observed. Endoscopic sclerotherapy is effective in the prevention of first
      variceal bleeding and in experienced hand, if the complication rate is low, is
      able to reduce total mortality of treated patients. The newer endoscopic method,
      variceal ligation, must be examined in this indication.

PMID- 10596570
TI  - [Benign tumors of the pancreas].
AB  - The contemporary incidence of the tumours of the pancreas is approximately 3.5%
      in the Czech Republic. Benign tumours represent only about 2% of them. We have
      found 7 such patients (2.3%) in our population of 303 patients operated for
      pancreatic tumours. This paper summarizes our experience with the diagnostics and
      surgical treatment of these patients.

PMID- 10596572
TI  - [Acute intestinal ischemia].
AB  - The objective of the paper is to review results of classical surgery of acute
      ischaemia of the gut in 32 patients in a retrospective study. The mortality of
      72% does not differ from data of other authors. The author emphasizes early
      diagnosis. The perspective is to make use of modern non-invasive diagnosis and
      and apply intervention radiology and mini-invasive surgery in treatment.

PMID- 10596571
TI  - [Peutz-Jeghers syndrome].
AB  - The authors describe Peutz-Jeghers syndrome in three members of one family. They
      discuss etiology, diagnosis, course and prognosis of this disease.

PMID- 10596573
TI  - [Complications of esophageal stents used in benign esophageal stenoses].
AB  - Oesophageal stents are used in the treatment of stenosis of the oesophagus in the
      last 10 years. The application of the stent in benign stenosis should be
      exceptional because it is associated with high morbidity and mortality. Two cases
      with severe complications treated by operation are demonstrated. Types of stents
      for the treatment of the oesophageal stenosis are presented.

PMID- 10596575
TI  - [Epistolae chirurgicae].

PMID- 10596574
TI  - [Carcinoid of the appendix in incarcerated femoral hernia].
AB  - Carcinoid tumor can be found in the appendix in approximately 20% cases of all
      carcinoids located in gastrointestinal tract, which represents the main site
      involved by 75% of all carcinoids. Primary carcinoid of appendix has been found
      in 0.5% of all appendectomies. Femoral hernia is also rather rare pathology
      occurring among all hernias in less than five percent cases. We describe clinical
      observation of an exceptional combination of these two pathological entities
      presented as unexpected appendiceal carcinoid found within the incarcerated
      femoral hernia.

PMID- 10596576
TI  - [Subacute appendicitis in children].
AB  - Over the period of 4 years from 1993 to 1996 the authors recorded a 6% incidence
      of patients with periappendicular mass (PM) in a group of 786 patients with acute
      appendicitis. The aim of the study is to compare the two methods in the
      management of patients (operation-A, conservative treatment-B) by applying the
      same criteria. In the subacute phase of the disease 22 patients (group A) were
      operated on, while 24 patients (group B) were successfully treated
      conservatively, with recommendation of elective appendectomy after 6 months. In
      group A indication for operation was PM in 7 patients, diagnostic problems
      (tumour, hydronephrosis) or complications (peritonitis, intestinal obstruction)
      in 15 patients. Antibiotic therapy was nearly the same in both group. Peritoneal
      drainage in postoperative care was performed in 10 patients of group A for 4.7
      days on the average. In this group, secondary wound healing was recorded in 3
      patients. In group B, elective appendectomy was performed only in 12 patients
      (50%). In 2 patients, however, a diagnostic error was revealed, i.e. Crohn's
      disease and an ovarian cyst had been suspected to be a periappendicular mass.
      Conservative treatment with subsequent elective appendectomy after 6 months seems
      to be an effective method in the treatment of patients with a typical clinical
      picture and well bordered periappendicular mass. Appendectomy in the subacute
      phase of the disease appears to be a safety technique of PM treatment in patients
      with complications or diagnostic problems.

PMID- 10596577
TI  - [Leiomyosarcoma of Meckel's diverticulum--a rare cause of acute hemorrhage in the
      lower part of the digestive system].
AB  - Meckel's diverticulum is a rare cause of haemorrhage into digestive tract in
      adults. A tumour arising in the diverticulum is also a rare cause of bleeding.
      Leiomyosarcomas represent 10-20% of malignant tumours in the small bowel and 1%
      of those located in the large bowel. These tumours have non-specific symptoms
      depending on their size, location and histology. Intestinal leiomyosarcomas may
      be the cause of surgical emergencies. We describe the case of an adult male with
      acute painless intestinal bleeding the cause of which was a leiomyosarcoma
      arising in Meckel's diverticulum. It was diagnosed during an acute operation. The
      main cause of the surgical emergency was an extremely rare complication of
      gastrointestinal leiomyosarcoma--intestinal bleeding.

PMID- 10596578
TI  - [An uncommon localized form of retroperitoneal fibrosis].
AB  - The authors describe an uncommon case of a localized form of idiopathic
      retroperitoneal fibrosis in a 70-year-old patient. They considered the tumour in
      the right hypogastrium (20 x 18 x 10 cm) malignant. The result of histological
      examination was surprising--Ormond's disease. The process could not be removed
      without damaging the common iliac artery. Simple suture of the artery proved
      unsuitable. During the postoperative period occlusion of the artery developed
      which was successfully resolved by an aorto-femoral bypass. Half a year after
      surgery the patient did not suffer a relapse.

PMID- 10596579
TI  - [Initial experience with reconstructive surgery of inguinal hernias using the
      Prolene Hernia System].
AB  - In the report a new method of tension-free repair of inguinal hernia using a
      prolene-mash PHS is described.

PMID- 10596580
TI  - [Incidental laparoscopic orchiectomy of intra-abdominal testis].
AB  - The authors present an incidental finding of intraabdominal testicle during
      laparoscopic operation for another diagnosis in an adult man. The surprising
      finding was managed by laparoscopy without conversion to an open procedure,
      adhering to rules of oncologic prevention because possible testicular cancer. Had
      an open approach been chosen in this patient, the intraabdominal testicle would
      have remained undetected.

PMID- 10596581
TI  - [Pancreatic head tumors--preoperative examination and reality].
AB  - The authors evaluated in a retrospective study the asset and accuracy of methods
      of preoperative diagnosis (ultrasonography, endoscopy, computed tomography and
      endoscopic sonography) in 47 patients with a preoperative finding of a tumour in
      the region of the head of the pancreas, where during the last three years a
      radical resection was performed. As compared with objective morphological
      findings of the resected tissues, endoscopic sonography proved the most sensitive
      and most reliable method for detection of focal changes in this area. The other
      compared methods also belong to the indispensible standard of preoperative
      diagnosis and in clear cases are sufficient for indication of surgery. Evaluation
      of nodal affection based on the finding of enlarged nodes during preoperative
      examination is very unreliable and should not influence decisions on indications
      for surgery.

PMID- 10596582
TI  - [Laparoscopic surgery of the colon].
AB  - The authors describe their experience with laparoscopic operations of the colon.
      The first operation was made on February 1, 1993 and by the end of 1998 the
      authors implemented 115 of these operations on account of benign and malignant
      diseases. On the results of their work they provide evidence that laparoscopic
      operations of the colon meet all demands of radicality of surgery, while they
      ensure a greater postoperative comfort and more rapid convalescence of the
      patient.

PMID- 10596583
TI  - [Ureteroureteral end-to-side anastomosis in kidney transplantation--personal
      experience].
AB  - The most widely used way of reconstruction of the urinary pathways in
      transplantations of the kidney is at present a ureteroneocysto anastomosis. In
      some patients this type of reconstruction is difficult, if not impossible
      (adhesions in the lesser pelvis of the recipient, atrophic urinary bladder, short
      ureter of the graft, transplantation of child kidneys). In these instances the
      authors indicated a uretero-uretero end-to-side anastomosis. The authors
      performed in 13 patients a total of 17 uretero-uretero end-to-side anastomoses.
      In six transplantation of child kidneys en bloc was involved. During the
      postoperative period one female patient developed a urinary fistula from the
      renal pelvis of the graft which healed after conservative treatment. End-to-side
      uretero-uretero anastomosis is a simple and safe way of reconstruction of the
      urinary pathways in renal transplantations.

PMID- 10596584
TI  - [Laparoscopic gastrostomy: report on 20 cases].
AB  - Establishment of a permanent gastrostomy for feeding the patient is even at the
      end of the 20th century a task for a surgeon, the operation being in the majority
      laparoscopic. This mutilating operation is however highly selective and unique
      and is used only after other possible ways to restore food intake by the natural
      route was exhausted. The most expedient way of recanalization of the oesophagus
      in inoperable tumours is nowadays insertion of an autoexpansive stent.

PMID- 10596585
TI  - [False aneurysms of the femoral artery].
AB  - The authors present an account on their experience with the treatment of false
      aneurysms of the femoral artery in their department. They mention the most
      frequent causes of development of false aneurysms in general and demonstrate on a
      group of patients the necessity of early surgical intervention in different
      patients. They emphasize the serious character of mycotic aneurysms associated
      with a high morbidity and mortality rate.

PMID- 10596586
TI  - [Endoscopic mobilization of the proximal portion of the great saphenous vein].
AB  - The authors describe a mini-invasive procedure in surgery of varicosities of the
      lower extremities. The objective is to reduce surgical trauma and improve the
      resulting cosmetic effect after extirpation of the great saphenous vein. The
      method was used in 9 patients of 35 operated between September and December 1998.
      The initial experience with endoscopic dissection of the proximal portion of the
      saphenous vein is favourable. The tissue traumatization is smaller, haematoma of
      the thigh is less common.

PMID- 10596588
TI  - [Standardized spiral CT examination in polytrauma patients].
AB  - The aim of this study was to develop a standardised spiral CT examination
      protocol including head, body and extremities to achieve good time efficiency and
      the diagnostic accuracy during initial radiological examination of
      polytraumatised patients. The precondition for this examination is circulatory
      stability of the patient. In instable patients the situation must be solved
      surgically without this examination. All 35 patients were examined according to a
      standardised CT protocol. After native examination of the head, the examination
      of the thorax, abdomen and pelvis was performed with administration of
      intravenous contrast medium (occasionally modified). All data in the medical
      report were completed and the outcome of the CT examination was compared with the
      final diagnosis. In total, 14 head injuries, 23 thoracic injuries, 17 abdominal
      and 20 pelvic injuries were examined, and 7 spinal fractures and 5 fractures of
      the extremities were found. The mean examination time was ca. 12 min. (range 8-15
      min.). The spiral CT examination in comparison with the sequential CT examination
      is markedly quicker and its diagnostic accuracy is higher. For these reasons we
      recommend this examination as the method of choice for initial radiological
      examination in polytraumatised patients.

PMID- 10596587
TI  - [Traumatic intracranial hemorrhage with a clinical temporal conus syndrome].
AB  - The authors investigated a consecutive group of 14 patients treated at the
      Neurosurgical Clinic on account of traumatic intracranial haemorrhage, admitted
      with the clinical temporal conus syndrome (GCS 3-5, ipsilateral or bilateral
      mydriasis, failure of vital functions). All had emergency operations and at the
      intensive care unit the cerebral perfusion pressure and the saturation in the
      jugular bulb was monitored continuously. On the first and fifth day after surgery
      a check-up CT and SPECT examination was made. Only two patients had ischaemia
      during the first CT check-up, while 11 patients had impaired perfusion on the
      first SPECT. Improving perfusion on the check-up SPECT was the sign of a
      favourable prognosis, while ischaemia on the first CT was in both instances
      fatal. The Glasgow Outcome Score (GOS) six months after the injury was as
      follows: 9 patients had a good result, 2 patients were moderately disabled 3
      patients died. The authors consider the following as basic prerequisites of a
      favourable outcome: not only early operation but also monitoring and treatment of
      impaired cerebral perfusion.

PMID- 10596589
TI  - [Transfer of injured patients. Analysis of injured patients transferred to the
      Casualty Hospital in Brno from other hospitals in 1997].
AB  - The author analyzes a group of casualties referred in 1997 to the Casualty
      Hospital Brno from other institutions where the patients were hospitalized after
      the injury, if the period did not exceed 30 days. Thus 361 casualties were
      referred. The reasons are summarized. Problematic is according to the author the
      admission of 37 patients with multiple injuries and 30 patients with a single
      injury. During the contemplated reduction of the number of health departments
      incl. surgical ones in the Czech Republic it will be difficult to justify the
      further existence of departments which are unable to cope permanently with
      uncomplicated bone fractures.

PMID- 10596590
TI  - [The Matti-Russe method of treatment of ununited fractures of the scaphoid bone].
AB  - The authors present their experience with treatment of scaphoid non-unions by the
      operation according to Matti-Russe. They compare their results with those of
      other authors and present a relatively high number of successfully treated
      patients with stable non-unions localized in the midline of the scaphoid bone as
      well as a high patient satisfaction rate with this method of treatment. The
      disadvantage of this treatment is long-term cast immobilization of the wrist and
      poor results in treatment of unstable non-unions and those localized in the
      proximal portion of the scaphoid bone. They conclude, that at present, it is more
      effective to support the surgery by osteosynthesis with an adequate implant and
      thus shorten the immobilization period in a cast.

PMID- 10596591
TI  - [The application of otoacoustic emission registration in the diagnosis of
      Meniere's disease].
AB  - 32 patients with Meniere's disease (MD) were examined audiologically in the trial
      of diagnostic potential of otoacoustic emission (OAE) method. Two classes of OAE
      were registered: delayed evoked otoacoustic emission (DEOAE) and otoacoustic
      emission at the frequency of the distortion product (DPOAE). DEOAE in MD patients
      is recordable in tonal hearing reduction to 50 dB, DPOAE--to 65 dB. Amplitude of
      both these otoacoustic emissions in normal ear (hearing tonal threshold under 20
      dB) of MD patients was significantly less than in control patients with normal
      hearing. OAE can be added to diagnostic tools for examining structures of the
      internal ear in MD.

PMID- 10596592
TI  - [Current knowledge on diagnosis and treatment of mastoiditis].
AB  - Causes and clinical course of atypical mastoiditis were studied by cases treated
      in the ENT clinic of the Moscow Medical Academy and relevant literature.
      Therapeutic policy in mastoiditis is described. Early surgical intervention is
      recommended in unfavorable mastoiditis course to prevent complications.

PMID- 10596593
TI  - [Surgical policy in chronic purulent otitis media in children].
AB  - Surgical outcomes in 603 children with otitis media purulenta chronica (OMPC)
      have shown that early microsurgery (endaural tympano-, attico-, aditotomy)
      improved or reestablished normal anatomy and physiology of the middle ear in 85%
      of the patients. One-stage cleansing or plastic surgery is preferable. In
      operations on mastoid process in the absence of complications, prevention of
      reoperation seems most effective by autotissue plastic reconstruction of the
      mastoid bone wound in the end of the operation.

PMID- 10596594
TI  - [Reconstruction of laryngopharynx and upper esophagus with mucosa of intact
      larynx in advanced laryngopharyngeal cancer].
AB  - An original surgical technique is proposed for management of primary
      laryngopharyngeal cancer. A special cut of the skin provides both effective
      operation on cervical fat, the tumor and reliable suturing of the operative
      wound. Plastic repair is performed by transplantation of mucosa and soft tissues
      from intact part of the larynx. This technique has been tested with satisfactory
      results in 21 patients with primary laryngopharyngeal cancer stage III-IV.
      Swallowing recovered in all the patients on postoperative day 10-16. As shown by
      a 13 month to 5.5 year follow-up 13 patients are alive without recurrence.

PMID- 10596595
TI  - [The study of parathyroid hormone in the serum of patient with hypopharyngeal
      cancer].
AB  - Measurements of parathyroid hormone concentrations were made in the serum of
      patients with vestibular larynx before treatment, after radiation treatment and
      after radiation treatment followed by surgery. Patients with laryngeal cancer
      were found to have impaired calcium metabolism, their serum parathyroid hormone
      concentrations were elevated. After radiotherapy, in a favorable clinical course,
      patients with cancer of the vestibular larynx stage II show normalization of the
      hormone levels, whereas the above combined treatment diminished the
      concentrations, but they still remain above normal.

PMID- 10596596
TI  - [On the modeling of acoustic perception in patients with implants].
AB  - Four laws of the spectrum division into frequency bands programmed into the
      implant Combi-40 were applied. After processing of the speech tables using
      specially developed program, frequency-restricted speech signal was obtained. It
      contained 8 bands covering 50 Hz each. These were central frequencies of band
      filters of the speech processor. Training was needed for all examinees with
      normal hearing to master a new speech picture after which words differentiation
      reached 100% in all the four variants of the spectrum division. Thus, excess of
      speech in terms of frequency representation is more than 92.3%. Parallels are
      given between speech perception of patients with implants and perception of
      speech changed according to the above program by subjects with normal hearing.

PMID- 10596597
TI  - [Clinical and therapeutic aspects of otogenic sepsis in the antibiotic era].
AB  - 152 cases of otogenic thrombophlebitis of the sigmoid sinus (TSS) are analysed.
      128 (84.2%) patients had thrombophlebitis and sepsis, 24 (15.8%) had
      thrombophlebitis without sepsis. TSS occurred more frequently in combination with
      other intracranial complications. In conditions of wide use of antibiotics and
      other drugs thromboembolic and toxicoinfectious otogenic complications may run
      with an atypical clinical picture: with reduced symptoms, without classic
      manifestations of sepsis. In diagnosis such investigations as computed
      tomography, MR-tomography, ultrasonography may be decisive. Major diagnostic
      criterium in diagnosis of otogenic sepsis is polyorganic insufficiency. Otogenic
      thrombophlebitis and sepsis is treated first of all surgically--the purulent
      focus in the ear should be cleansed. Postoperative treatment includes
      antimicrobial drugs, immunomodulators, anticoagulants, antihistaminic,
      detoxicating and antiedematic medicines, UV irradiation of autoblood and
      hyperbaric oxygenation.

PMID- 10596598
TI  - [The effectiveness of computer tomography in the assessment of laryngeal tumor
      staging].
AB  - The results of examination of 48 patients aged 14-62 years with pharyngeal tumors
      are reviewed. How to perform better CT and x-ray in laryngeal tumors is
      described. Opportunities of different diagnostic investigations in localization
      of pharyngeal tumors, staging, structure, invasion into the adjacent tissues,
      detection of bone destruction are shown.

PMID- 10596599
TI  - [Cortisol levels in the sera of children with chronic decompensated tonsillitis
      in different periods after tonsillectomy].
AB  - Radioimmunoassay measured serum levels of hydrocortisone in children with chronic
      decompensated tonsillitis (CDT) before and 7 days, 2-3 months, 3-5 years after
      tonsillectomy. Hydrocortisone in CDT patients tended to decrease irrespective of
      decompensation form. The hormone levels were higher in long-term, recurrent
      course and small mass of the removed tonsils. On posttonsillectomy day 7
      hydrocortisone lowered in patients with metotonsillar complications (MTC),
      remained unchanged in quinsy recurrence and rose in protracted CDT. 2-3 months
      after the operation adrenal cortex of the majority of patients enhanced its
      hydrocortisone-producing function. Hydrocortisonemia returned to normal 3-5 years
      after tonsillectomy, though in MTC its mean values stood higher than in quinsy
      recurrence.

PMID- 10596600
TI  - [Trephanopuncture of the frontal sinuses: the evolution of the method].
AB  - Historical evolution of frontal sinus trepanopuncture with description of its
      benefits and shortcomings is presented. The perfection of the method lies in
      introduction of technological innovations raising safety of the procedure and
      provision of the approach sufficient for modern therapeutic and diagnostic
      techniques.

PMID- 10596601
TI  - [Shunting and drainage of the frontal sinuses in the treatment of exudative
      frotitis].
AB  - A total of 63 cases of exudative frontitis were treated using probing and
      draining in an ENT department of a hospital from 1986 to 1998. 40 patients were
      males, 23 were females. The age ranged from 15 to 79 years. 43 patients had acute
      frontitis, 20 patients suffered of chronic frontitis. Probing and draining of the
      sinus was made with application of standard cannulas. Probing was unsuccessful in
      8 patients. Later, they have undergone radical surgery on the frontal sinuses or
      trephine puncture (2 and 6 patients, respectively). 23 patients who discharged
      pus and mucus after the initial probing of the frontal sinus were drained for
      some time with polyethelene catheter having the fixing device. Probing and
      draining of the frontal sinuses with subsequent introduction of medicines should
      be applied in all cases of purulent otitis. Only if no effect is reached,
      surgical intervention is justified.

PMID- 10596602
TI  - [On aspects of laryngeal tuberculosis].
AB  - In 1989-1998 the authors treated 50 patients (45 males and 5 females aged 21-68
      years, mean age 46.2 years) with tuberculosis of the lungs and larynx. Pulmonary
      lesions were for the most part disseminated (58%) or infiltrative (24%). One
      patient had laryngeal tuberculosis combination with cancer of the laryngeal
      pharynx. Progression of the disease occurs frequently because of
      otorhinolaryngologists who make diagnostic errors when consulting patients who
      seek primarily their advice (60% of those with laryngeal tuberculosis)
      complaining about throat pain and hoarseness. In obscure cases, an attempt of
      antituberculosis treatment should be made.

PMID- 10596603
TI  - [Combined treatment of esophageal stenosis following tonsillogenic phlegmon of
      the neck].

PMID- 10596604
TI  - [Observation of radiopaque foreign body of paravertebral soft tissue of the
      neck].

PMID- 10596605
TI  - [Effectiveness of maxaquin and tarivid in combined therapy of patients with
      chronic sinusitis].

PMID- 10596606
TI  - [Surgical rehabilitation of hearing in patients with chronic purulent otitis
      media].

PMID- 10596607
TI  - [Esthetic rhinoplasty. Current issues of cosmetic and functional correction of
      the external nose].

PMID- 10596609
TI  - Dentists behind bars.

PMID- 10596608
TI  - [Chronic suppurative otitis media and its complications].

PMID- 10596610
TI  - The bad apples: dentists who commit crimes.

PMID- 10596611
TI  - A genetic predisposition to periodontal disease.

PMID- 10596612
TI  - Exploring options. A career in research.

PMID- 10596613
TI  - Navigating the managed care maze.

PMID- 10596614
TI  - Factors associated with the presence of denture related stomatitis in complete
      denture wearers: a preliminary investigation.
AB  - Various factors have been associated with the presence of denture related
      stomatitis. These include local factors such as continuous denture wear, trauma
      from dentures and poor denture hygiene Systemic factors, use of various
      pharmacological agents and smoking have also been implicated. This investigation
      involved history taking and examination of 250 patients attending Guy's Hospital
      for the construction of complete dentures. No association was found between
      systemic factors, use of pharmacological agents or smoking and the presence of
      denture related stomatitis. Night wear of complete dentures was found to be
      significantly associated with the prevalence of denture related stomatitis.

PMID- 10596615
TI  - Effects of recasting on the amount of corrosion products released from two Ni-Cr
      base metal alloys.
AB  - The corrosion products released from two recast Ni-Cr base metal alloys Wirolloy
      and Wiron 99 were investigated. Cast samples were placed in Meyer's modified
      Fusayama solution for 2 months and in 0.1M Lactic acid 0.1M NaCl solution for 7
      days. The release of Ni, Cr and Mo ions from both alloys was measured by using a
      flame model Atomic Absorption Spectrophotometer. A Scanning Electron Microscope
      was used to evaluate the surface morphology of the samples before and after
      corrosion tests. Release of Ni and Cr from Wirolloy samples immersed in 0.1M
      Lactic acid 0.1M NaCl solution were much higher than those of Wiron 99. The
      number of recastings was found to have negligible effect on surface texture and
      on the amount of corrosion products released.

PMID- 10596616
TI  - Clinical and microbial findings on osseo-integrated implants; comparisons between
      partially dentate and edentulous subjects.
AB  - Clinical and microbiological parameters in partially dentate and edentulous
      patients treated with oral implants were compared in this study. Twenty-four
      subjects including 9 males and 15 females, aged 33 to 70 were treated with 98
      Branemark fixtures. Plaque index, gingival index, pocket depth, implant mobility
      and crevicular fluid flow rate were measured. Latex agglutination tests
      identified the presence of Actinobacillus Actinomycetem-comitans, Porphyromonas
      gingivalis and Prevotella intermedia. Partially dentate patients accumulated more
      plaque than edentulous patients (P = 0.05), whereas crevicular fluid flow rate
      was significantly higher (P < 0.001) in the partially dentate population.
      Porphyromonas gingivalis and Prevotella intermedia were more frequently detected
      (P < 0.01) in partially dentate patients. These results indicate that the
      presence of natural teeth alter clinical and microbiological parameters which
      could in turn affect the long term success rate of implants.

PMID- 10596617
TI  - The erosive potential of the alcoholic lemonade Hooch.
AB  - The aim of this in vitro study was to assess the erosive potential of four
      flavours of the alcoholic lemonade Hooch. This study measured the pH on opening,
      the volume of 0.1M sodium hydroxide required to raise the pH of 20 mls of the
      lemonade to neutrality and the fluoride content. The amount of surface enamel
      lost following immersion for one hour was also assessed compared to water as a
      control. The pH on opening ranged from 2.57-2.86 and the volume of 0.1M sodium
      hydroxide required to neutralise 50 mls of the lemonade ranged from 15.4-23.1
      mls. The fluoride content of the drinks ranged from 0.36-0.45 p.p.m. The amount
      of surface enamel lost over one hour ranged from 1.80-3.28 microns. This study
      suggests that the alcoholic lemonade Hooch has considerable erosive potential and
      seems likely to be as erosive as orange juice.

PMID- 10596618
TI  - A survey of the attitudes of members of the European Prosthodontic Association
      towards the shortened dental arch concept.
AB  - A survey of members of the European Prosthodontic Association was undertaken to
      assess their attitudes to the shortened dental arch concept, and to evaluate
      their experience with the approach. Data were collected using questionnaires.
      From an overall response of 42%, 96% of respondents agreed that the approach was
      acceptable in clinical practice. Almost all respondents had applied the shortened
      dental arch concept with 72% of respondents having treated less than 50 patients
      in this way over the previous 5 years. In terms of comfort and function,
      treatment outcome was satisfactory. However, 42% of respondents indicated that
      prosthetic extension of shortened dental arches was occasionally required.

PMID- 10596619
TI  - Case report: a tale of two dentures.
AB  - A case is presented where loss of an incisor tooth in a partial denture wearer
      created an aesthetic emergency. It was not possible to solve this simply by
      addition of a tooth to the existing denture. Reference to the previous dental
      history suggested that a further immediate solution might be unwise. The design
      of the existing denture lent itself to the novel solution of a second denture,
      retained by elements of the first.

PMID- 10596620
TI  - Case report: the high proximal survey line.
AB  - This case report demonstrates a method of adding composite to a tooth to move a
      high survey line closer to the gingival margin. The purpose of this modification
      is to facilitate clasping.

PMID- 10596621
TI  - Application of glass ionomer cements in restorative dentistry.
AB  - Dentistry was marked with radical changes in clinical restorative procedures. If
      the inherent characteristic of the ionomer cement was examined, it becomes very
      clear to the researcher as well as the dentist, that no other material has had an
      impact as comparable to glass ionomer cements on restorative dentistry. This
      scientific paper highlights the clinical applications of the cement in
      restorative dentistry. Glass ionomer cements are bioactive, by forming permanent
      adhesive bonds to dentin and enamel which enables them to prevent the development
      of secondary caries by providing an impermeable seal against the intrusion of
      oral fluids and other caries producing agents. The hydrophilic nature of the
      cement also makes them susceptible to the action of aqueous fluids before they
      are fully set, requiring that the freshly placed restoration be protected by
      varish, petroleum jelly or a low viscosity photo polymerizing bonding agent.

PMID- 10596622
TI  - Modification of glass ionomer cements.
AB  - Glass Ionomer cement (the term was coined by B.E. Kent) has been described as a
      hybrid of silicate cements and zinc polycarboxylates. Scientific efforts were
      devoted to improving properties to make it a fully practical material for
      anterior and posterior restorations and secondarily properties were modified to
      extend its range of application. First half of 90's witnessed modifications that
      replace part or most of the original formulation with alternative filler
      particles or matrix setting reactions to make these materials more composite
      like. This article focuses on the various modifications of the basic Glass
      ionomer cement.

PMID- 10596623
TI  - Marginal adaptation and sealability of orthograde and retrograde amalgam
      obturation. An in vitro study.
AB  - 60 recently extracted anterior teeth were subjected to an endodontic protocol and
      obturated with either orthograde or retrograde amalgam (n = 30). Specimens were
      evaluated for microleakage and marginal adaptation using 2% methylene blue dye
      and scanning electron microscopy respectively. Chi-square analysis of data showed
      significantly better (p < 0.001) marginal adaptation and sealability in
      orthograde amalgam apical fillings.

PMID- 10596624
TI  - A case of stapler pin in the root canal--extending beyond the apex.
AB  - There have been several reports describing the placement, by patients, of foreign
      objects into exposed pulp chambers and canals. In the present case, a 13-year-old
      patient reported with complaints of pain and a history of inserting a foreign
      object into the root canal of the left central incisor. On examination the
      foreign body was found to be a stapler pin which was projecting 5 millimeters
      from the apical foramen. Foreign bodies discovered from the root canal have
      varied from radiolucent objects like wooden tooth picks or tooth brush bristles
      to radioopaque materials like paper pins, needles, pencil leads etc. In the
      present case, despite our best efforts, the patient did not agree to undergo any
      treatment except for the extraction of the left central incisor.

PMID- 10596625
TI  - Oral pathology. Fall 1998 case of the month. Necrotizing sialometaplasia.

PMID- 10596626
TI  - The Oklahoma City bombing: the roles of the dental teams ... and the lessons
      learned.
AB  - The Oklahoma City bombing is considered by most historians the worst act of
      domestic terrorism ever to have occurred in the United States. The response to
      the disaster, however, is considered by most experts in the field as being the
      best; creating what is known as the "Oklahoma Standard". The roles of the dental
      teams in the resolution were pivotal and until now, the recognition of these
      roles have not been described, due to this being considered a case of mass
      murder. The purpose of this paper is to give an overview of the preparations, the
      initial responses, the roles of the dental teams in the resolution, the
      preparations for the criminal trials, and some of the lessons that were learned.

PMID- 10596627
TI  - A preliminary evaluation of the effect of ultrasonic root end cavity preparation
      and reverse filling on the ability of plastic core Thermafil obturations to
      maintain an air-tight seal.

PMID- 10596628
TI  - Oral pathology. May 1998 case of the month. Granular cell tumor.

PMID- 10596629
TI  - Malignant accessions 1974-1996.

PMID- 10596630
TI  - When the doctor becomes the patient: a personal case history of a low grade B
      cell lymphoma cancer patient.

PMID- 10596632
TI  - Contemporary care of cleft lip and palate patients.

PMID- 10596631
TI  - Microorganism presence in desquamative gingivitis.
AB  - Histologic tissue analysis was retrospectively performed on 19 cases which met
      the diagnostic criteria of desquamative gingivitis (DG) or benign mucous membrane
      pemphigoid (BMMP) to determine whether microorganisms were present. Original
      paraffin blocks were resectioned and tissue specimens were stained with
      hematoxylin and eosin and with Brown and Brenn solutions. The presence of
      microorganisms at specific sites was recorded and identification of gram type and
      histomorphology was made. Bacteria were seen in hematoxylin and eosin and Brown
      and Brenn stained specimens on the epithelial surface in 31.6% and 68.4% of
      cases, within the epithelium in 0% and 57.9% of cases, within the subbasilar
      cleft in 52.6% and 94.7% of cases, and within the submucosa in 5.3% and 57.9% of
      cases respectively. The epithelial surface was colonized primarily by gram
      positive cocci (47.4%) and gram negative bacilli (42.1%), which also were the
      most common types of bacteria seen within the epithelium (26.3% each). 94.7% of
      specimens examined demonstrated gram negative bacilli within the subepithelial
      cleft. The predominate form of bacteria found in the submucosa was gram negative
      cocci (42.1%). Results of this study show that colonization of desquamative
      gingivitis/benign mucous membrane pemphigoid tissue samples occurs.

PMID- 10596633
TI  - Dentoalveolar surgery.

PMID- 10596634
TI  - Anesthesia in the oral and maxillofacial surgery office: past, present and
      future.
AB  - In this day and age, the fear of not "waking up" from a general anesthetic has
      little basis in fact. Serious complications almost never occur in the absence of
      a preexisting medical problem. By virtue of extensive training, proper patient
      selection, vigilant monitoring, and judicious use anesthetic agents, the oral and
      maxillofacial surgeon continues to provide a very high level of anesthetic care.
      Besides being safe, it is also very cost effective. The surgical removal of four
      impacted third molars in the office costs four to five times less than a similar
      procedure in the typical ambulatory surgery unit. Thus, it would appear that the
      oral surgeon's expertise in delivering office anesthesia not only predates the
      current popularity of ambulatory surgery, but may well have been the pioneering
      model from which it arose.

PMID- 10596635
TI  - Surgical management of the temporomandibular joint.

PMID- 10596636
TI  - Orthognathic surgery.

PMID- 10596637
TI  - Cosmetic maxillofacial surgery.

PMID- 10596638
TI  - Trauma and reconstructive oral and maxillofacial surgery.

PMID- 10596640
TI  - Integrating cranial osteopathy with gnathologic orthopedics.

PMID- 10596639
TI  - Advances in site development for osseo-integrated implants.

PMID- 10596641
TI  - The orthodontic examination and diagnosis.

PMID- 10596642
TI  - The incidence of pain in the muscles of mastication in patients with
      fibromyalgia.
AB  - This study recognizes the high incidence of temporomandibular symptoms in a group
      of patients with documented fibromyalgia. Findings indicate that the diagnosis
      and treatment of temporomandibular disorders and fibromyalgia have many
      similarities.

PMID- 10596643
TI  - Tell that bridge to wait six weeks!
AB  - Improving productivity in the office is a challenge. Block booking is a method of
      handling appointment scheduling that can actually increase your productivity, not
      to mention improve your customer service.

PMID- 10596644
TI  - The complexities of restoring devitalized teeth: applying new principles to old
      ideas.
AB  - Because the physical and mechanical properties of vital and devitalized teeth
      differ, a variety of complexities can occur during the reconstruction of
      endodontically treated teeth. The three products described are recommended to
      help overcome some of the shortcomings encountered in present-day rehabilitation.

PMID- 10596646
TI  - A clinico-pathologic presentation. Verrucous carcinoma.

PMID- 10596645
TI  - Tuberculosis ... what dental health care workers need to know.
AB  - After a downward trend between 1960 and 1985, the number of Tuberculosis (TB)
      cases has increased since 1985. While the risk of TB transmission in dental
      settings is low, this risk could be reduced even further by surveillance,
      education, and attention to patient history.

PMID- 10596647
TI  - Oral pathology quiz #21. Presented by UMDNJ-New Jersey Dental School Biopsy
      Service.

PMID- 10596648
TI  - Metastatic cancer presenting as TMD. A case report.
AB  - The dentist's responsibility in managing patients should include the awareness
      that not every pain in the face is due to a toothache or a temporomandibular
      disorder (TMD). This paper reviews the case of a 66-year-old patient who
      presented to the dental office with a chief complaint of unilateral jaw pain. The
      symptoms seemed consistent with TMD. Two years prior, the patient had undergone
      successful removal of a cancerous prostate and had remained under urologist care
      with a favorable prognosis. Subsequent imaging studies confirmed that the facial
      pain was due to multiple metastatic lesions to areas including the zygoma,
      infratemporal fossa, maxilla and brain. However, these metastatic lesions were
      not of prostate origin, but rather were from a squamous cell carcinoma
      originating in a primary site other than the prostate.

PMID- 10596649
TI  - Realistic monetary evaluation of dental injuries (a current view).

PMID- 10596650
TI  - Radiographic bone fill following debridement of a periodontal abscess. A case
      report.
AB  - A periodontal abscess often develops in association with deepened periodontal
      pockets. Traditional management is by establishing drainage and prescribing
      antibiotics. This is usually followed by surgical pocket reduction. This case
      report discusses the remarkable healing of a periodontal abscess by establishing
      drainage alone without resorting to surgical pocket reduction. A 42-year-old
      white male presented with swollen gingivae associated with the mesiolingual of
      tooth #23. Increased probing depth and suppuration were evident. Radiographic
      bone loss on mesial #23 was present. A diagnosis of periodontal abscess was
      established. The abscess was drained through the orifice of the pocket. The
      patient failed to return for follow-up as instructed. A year later, the patient
      came back. Clinical evaluation showed healthy gingival tissues with probing depth
      of 3 mm on the mesiolingual of tooth #23. Radiographic evaluation showed bone
      fill of the osseous defect on the mesial of #23. The results of this case suggest
      that sufficient time should be allowed for healing prior to surgical pocket
      reduction.

PMID- 10596651
TI  - Reconstructive surgery for complex midface trauma using titanium miniplates: Le
      Fort I fracture of the maxilla, zygomatico-maxillary complex fracture and
      nasomaxillary complex fracture, resulting from a motor vehicle accident.
AB  - Maxillofacial injuries resulting from trauma can be a challenge to the Maxillo
      Facial Surgeon. Frequent causes of these injuries are attributed to automobile
      accidents, physical altercations, gunshot wounds, home accidents, athletic
      injuries, work injuries and other injuries. Motor vehicle accidents tend to be
      the primary cause of most midface fractures and lacerations due to the face
      hitting the dashboard, windshield and steering wheel or the back of the front
      seat for passengers in the rear. Seatbelts have been shown to drastically reduce
      the incidence and severity of these injuries. In the United States seatbelt laws
      have been enacted in several states thus markedly impacting on the reduction of
      such trauma. In the Philippines rare is the individual who wears seat belts.
      Metro city traffic, however, has played a major role in reducing daytime MVA
      related trauma, as usually there is insufficient speed in traffic areas to cause
      severe impact damage, the same however cannot be said for night driving, or for
      driving outside of the city proper where it is not uncommon for drivers to zip
      into the lane of on-coming traffic in order to overtake the car in front ...
      often at high speeds. Thus, the potential for severe maxillofacial injuries and
      other trauma related injuries increases in these circumstances. It is however
      unfortunate that outside of Metro Manila or other major cities there is no ready
      access to trauma or tertiary care centers, thus these injuries can be
      catastrophic if not addressed adequately. With the exception of Le Fort II and
      III craniofacial fractures, most maxillofacial injuries are not life threatening
      by themselves, and therefore treatment can be delayed until more serious cerebral
      or visceral, potentially life threatening injuries are addressed first. Our
      patient was involved in an MVA in Zambales, seen and stabilized in a provincial
      primary care center initially, then referred to a provincial secondary care
      center for further stabilization before his transfer to Manila and then
      ultimately to our Maxillo-Facial Unit. There was a two week-plus delay in the
      definitive management because of this. As a result of the delay, fibrous tissue
      and bone callus formation occurred between the various fracture lines, thus once
      definitive fracture management was attempted, it took on a more reconstructive
      nature. Hospital based Oral and Maxillo-Facial Surgeons are uniquely trained to
      manage all aspects of the maxillo-facial trauma, and their dental background
      uniquely qualifies them in functional restoration of lower and midface fractures
      where occlusion plays a most important role. Likewise, their training in clinical
      medicine which is usually integrated into their residency education (12 months or
      more) puts them in a unique position to comfortably manage the basic medical
      needs of these patients. In instances where trauma may affect other regions of
      the body, an inter-multi-disciplinary approach may be taken or consults called
      for. In this instance, an opthalmology consult was important. In fresh trauma,
      often seen in major trauma centers (i.e. overseas), a "Trauma Team" is on standby
      24 hours a day, and is prepared to assess and manage trauma patients almost
      immediately upon their arrival in the ER. The trauma team is usually composed of
      a Trauma Surgeon who is a general surgeon with subspecialty training in
      traumatology who assesses and manages the visceral injuries, an Orthopedic
      Surgeon who manages fractures of the extremities, a Neurosurgeon for cerebral
      injuries and an Oral and Maxillo-Facial Surgeon for facial injuries. In some
      institutions, facial trauma call is alternated between the "three major head and
      neck specialty services", namely Oral and Maxillo-facial Surgery, Otolaryngology
      Head & Neck Surgery and Plastic & Reconstructive Surgery. (ABSTRACT TRUNCATED)

PMID- 10596652
TI  - Natural fluoride content of drinking waters in the National Capital Region.

PMID- 10596653
TI  - Partial pulpotomy: a conservative approach to a complicated crown fractured
      permanent incisor.

PMID- 10596654
TI  - Unicystic amelobastoma of the mandible conservative surgical management: a
      preliminary report of two cases.

PMID- 10596655
TI  - Benign tumors of the parotid gland: surgical approach & management.

PMID- 10596656
TI  - Effectivity of the Electronic Dental Anesthesia in controlling pain caused by
      local anesthetic injections.
AB  - This study was designed to determine if an electrical signal can effectively
      control the pain caused by injection of local anesthesia for mildly and
      moderately apprehensive patients. Five techniques were used in this study: the
      Mandibular Block injection, Long Buccal nerve injection, Maxillary Infiltration
      injection, Incisive Papilla injection, and the Great Palatine nerve injection.
      Two injections, using the Electronic Dental Anesthesia (EDA/EA) as the adjunct,
      and the other using a topical anesthetic ointment of Xylocaine 5%, were performed
      on 30 patients who passed the criteria we have set including the indications for
      use of the EDA. The volunteers were asked on the spot to report the level of pain
      they felt during the penetration of the needle in the mucosa, and during the
      deposition of the local anesthetic solution. A pool of 47 patients were gathered
      for this experiment. Of this number, 11 failed to pass for reasons of high
      anxiety level and 2 were contraindicated for use of the EDA. Of the 34 who
      successfully passed the screening, only 30 patients were chosen. A total of 6
      patients each, 3 males and 3 females, were used for the five techniques. The
      results of this study show that in all five injection techniques, the EDA is
      effective in blocking pain transmission. The EDA is proven to be an effective
      adjunct to local anesthetic injections.

PMID- 10596657
TI  - Is honesty still the best policy?

PMID- 10596658
TI  - Endoscopic technique for the diagnosis and treatment of obstructive salivary
      gland diseases.
AB  - PURPOSE: This article describes the use of endoscopy for diagnostic and surgical
      intervention in the major salivary glands of patients who have obstructive
      pathology, reviews past experience with this technique, and describes the
      microanatomy and pathophysiologic findings encountered during endoscopy of these
      glands. PATIENTS AND METHODS: A total of 154 salivary glands (96 submandibular
      glands, 57 parotid glands, 1 sublingual gland) suspected of having obstructive
      pathology (89 males, 65 females; aged 5 to 72 years) were treated using a mini
      endoscope. Most procedures were performed under local anesthesia in an outpatient
      clinic. All patients underwent preoperative and postoperative screening by
      routine radiography, sialography, and ultrasound. The indications for endoscopy
      were: 1) calculus removal that could not be performed by conventional methods, 2)
      screening of the salivary ductal system for residual calculi after
      sialolithotomy, 3) positive evidence of ductal dilatation or stenosis on the
      sialogram or ultrasound examination, and 4) recurrent episodes of major salivary
      gland swellings without known cause. RESULTS: Of the 154 endoscopies performed, 9
      were immediate failures as a result of technical problems. Of the remaining 145
      glands, 112 had obstructions and 33 had sialadenitis alone. The success rate was
      82% for calculus removal. Thirty-two percent of the submandibular and 63% of the
      parotid sialoliths, and the 1 stone in the Bartholin's duct, were undetected
      before sialoendoscopy. Multiple endoscopic findings were encountered. No major
      complications were noted. CONCLUSIONS: Sialoendoscopy is a minimal invasive
      technique for the diagnosis and removal of obstructive pathologic tissue in the
      major salivary glands.

PMID- 10596659
TI  - Preoperative antibiotic prophylaxis in orthognathic surgery: a randomized, double
      blind, and placebo-controlled clinical study.
AB  - PURPOSE: This study evaluated the need for antibiotic prophylaxis in orthognathic
      surgery. PATIENTS AND METHODS: Fifty-four patients (age range, 18 to 40 years)
      underwent bimaxillary orthognatic surgery. After randomization, a placebo (n =
      19), 2,200 mg amoxicillin-clavulanic acid (n = 18), or 1,500 mg cefuroxime (n =
      17) was administered in a double-blind fashion. During the first month, the
      postoperative course was observed according to the clinical parameters of
      infection, total leukocyte count and erythrocyte sedimentation rate (ESR).
      RESULTS: Fifteen of 54 patients developed a wound infection. Of these, 10 had
      received a placebo; 3, cefuroxime; and 2, amoxicillin-clavulanic acid.
      CONCLUSIONS: There was a statistically significant (P<.004) increased risk of
      having an infectious complication after bimaxillary orthognathic surgery without
      antibiotic prophylaxis. No significant difference in the incidence of infectious
      complications was found between the 2 medications.

PMID- 10596660
TI  - The incidence of altered sensation of the mental nerve after mandibular implant
      placement.
AB  - PURPOSE: This study was designed to determine the incidence of altered sensation
      in patients undergoing mandibular endosseous implant placement. PATIENTS AND
      METHODS: Ninety-four consecutive patients who underwent the placement of
      mandibular implants constituted the study group. The only patients that were
      excluded from this study were those who had preexisting injury to the trigeminal
      nerve. Patients were followed using standard neurologic testing during the period
      immediately following implant placement through 6 months. Four hundred five
      implants were placed in 43 female and 51 male patients. Implant length selection
      was based on panoramic radiographs using known markers to correct for distortion.
      In 13 of the patients, the mandibular canal was not adequately visualized, and a
      computed tomography (CT) scan was used to plan the implant locations. Implants
      were selected to be located 2 mm above the inferior alveolar canal based on the
      panoramic images and 1 mm above the canal based on CT images. RESULTS: Eight
      patients reported altered nerve sensation at their first postimplant visit
      (8.5%). None of the patients experienced hyperesthesia or dysesthesia. Four of
      the eight patients with altered sensation had no objective findings or decreased
      nerve function. One of the patients remained totally anesthetic for 2 months, but
      reported return to normal function at 4 months. CONCLUSIONS: These findings
      indicate that a small percentage of patients experience altered sensation after
      the placement of mandibular endosseous implants. Unlike previous studies, no
      permanent altered sensation was found. By using proper treatment planning, one
      can offer endosseous implants with minimal risk of injury to the trigeminal
      nerve.

PMID- 10596661
TI  - Clinical experience with interactive teleconsultation and teleassistance in
      craniomaxillofacial surgical procedures.
AB  - PURPOSE: The objective of this study was to evaluate the clinical value and
      feasibility of surgical telenavigation and teleassistance technology in the field
      of craniomaxillofacial surgery. MATERIALS AND METHODS: The technology is based on
      the principles of augmented reality environment technology and remote
      stereotactic visualization. A consultant surgeon in a remote location receives
      video, audio, and stereotactic navigation data from the operation site almost in
      real-time and, using a head-mounted display, is emerged in the surgical augmented
      reality environment. By telepresence or teleconsultation, the composite images
      and superimposed graphics (instruments, target structures, landmarks, contours)
      can be seen and discussed in connected clinics with the possibility of
      interactive manipulation and assistance. RESULTS: Interactive teleassistance was
      used in 27 cases of various types craniomaxillofacial surgery. The principles of
      computer-aided telenavigation were applied successfully. Technical problems in 6
      cases did not cause a breakdown of overall system performance. CONCLUSION:
      Teleconsultation with remote experts is a useful tool, although some shortcomings
      exist. The financial and personal effort involved is considerable.

PMID- 10596662
TI  - Long-term effect of mandibular midline distraction osteogenesis on the status of
      the temporomandibular joint, teeth, periodontal structures, and neurosensory
      function.
AB  - PURPOSE: This study retrospectively evaluated the long-term effects of transverse
      symphyseal distraction osteogenesis (DO) on the temporomandibular joint (TMJ)
      symptoms, periodontal health, tooth vitality, and nerve injury after surgery.
      PATIENTS AND METHODS: Twenty-three patients were treated with symphyseal DO
      during a 4-year period. Fifteen patients were available for follow-up from 7 to
      45 months postoperatively (ave, 24.5 months). The patients were clinically
      evaluated for TMJ symptoms, periodontal pocket formation, tooth vitality and
      mobility, crestal bone loss, and attached gingival tissue changes. Radiographs of
      the mandibular anterior teeth were used to evaluate for periodontal bone loss,
      periapical lesions, or widening of the periodontal ligament (PDL). RESULTS:
      Preoperatively, 47% of the patients had TMJ symptoms. No patient had symptom
      worsening or developed new symptoms postoperatively. Five patients' TMJ symptoms
      improved, and 3 experienced complete resolution of symptoms. No periodontal bone
      loss or soft tissue recession were evident. Tooth vitality was maintained in 13
      patients. Two patients developed Class II mobility of 1 mandibular central
      incisor, 1 patient had tooth pain and a widened PDL adjacent to the
      osteotomy/corticotomy site, and 1 patient experienced mental nerve paresthesia.
      CONCLUSIONS: DO can be used to treat transverse discrepancies of the mandible
      with limited morbidity.

PMID- 10596663
TI  - Subjective and objective outcomes in patients reconstructed with a custom-fitted
      alloplastic temporomandibular joint prosthesis.
AB  - PURPOSE: This study looked at prospective subjective and objective preoperative
      and postoperative outcome data from a set of multiply operated, anatomically
      mutilated, functionless, chronic temporomandibular joint (TMJ) pain patients who
      have undergone TMJ reconstruction with a custom-fitted prosthetic system.
      PATIENTS AND METHODS: Two hundred fifteen patients (363 joints: 296 bilateral, 67
      unilateral) who had undergone total TMJ reconstruction with a custom-fitted TMJ
      prosthesis (Techmedica; now TMJ Concepts, Camarillo, CA) made up the subjects
      reviewed in this study. The mean follow-up period was 30.7 months. The patients
      were divided into 3 groups based on the number of prior unsuccessful TMJ
      arthrotomies they had undergone (group 1 = 0 to 2; group 2 = 3 to 8; and group 3
      = 9 or more) RESULTS: Subjective improvement ratio data indicated that
      postoperatively group 1 had a 61.3% improvement in subjective parameters, group 2
      had a 51.0% improvement, and group 3 had only a 27.5% improvement. Objective
      improvement ratio data showed that postoperatively group 3 had the largest
      increase in maximum interincisal opening, whereas the other groups had less
      improvement. CONCLUSION: The data from this study confirm, as previously reported
      in the literature, that the greater the number of surgical procedures performed
      on the TMJ, the less the chance of significant subjective improvement.

PMID- 10596664
TI  - Biomechanical testing of resorbable screws used for mandibular sagittal split
      osteotomies.
AB  - PURPOSE: The object of the study was to determine the suitability of specific
      resorbable screws for fixation of mandibular sagittal split osteotomies by in
      vitro biomechanical strength testing. MATERIALS AND METHODS: Resorbable screws
      (2.5 mm diameter) composed of a polylactic acidpolyglycolic acid copolymer were
      placed in an inverted L-pattern in overlapping urethane blocks representative of
      sagittal split mandibular surgery. In an in vitro model at room temperature, the
      test specimens were statically loaded until tensile failure occurred. On a
      different set of test specimens, dynamic testing was done in an in vitro water
      bath at body temperature through cyclic loads representative of mastication until
      failure. RESULTS: In static testing, three 2.5-mm resorbable screws sustained an
      average peak load of 131 Kiloponds (Kp) (standard deviation, 5.2 Kp) with 5.5%
      strain at yield. In dynamic testing, the resorbable screws tolerated a 45.3-Kp
      load for an average of 340,675 cycles (22,783 standard deviation). Several of
      these test specimens did not ultimately fail and were further evaluated by static
      testing with an average load of 77.4 Kp until fixation failure occurred.
      CONCLUSIONS: These laboratory results indicate a relatively high resistance to
      biomechanical loads representative of mastication and suggest that 2.5-mm
      resorbable screws of this particular polylactic acid-polyglycolic acid copolymer
      may be effective in fixation of the postoperative unrestrained sagittal split
      mandibular osteotomy.

PMID- 10596665
TI  - Experimental computer-assisted alloplastic sandwich augmentation of the atrophic
      mandible.
AB  - PURPOSE: This study evaluated the effectiveness of a technique that combined
      computer-aided surgery with alloplastic augmentation and implant-borne
      prosthodontic rehabilitation of the atrophic mandible. MATERIALS AND METHODS:
      Computed tomographic (CT) data from an atrophic cadaver mandible were transferred
      to a computer-aided design (CAD) system that prepared an anterior sandwich
      osteotomy. The cranial segment was moved upward and backward to provide an ideal
      alveolar relationship, and the geometry of the intermediate space was used to
      design a titanium implant. Furthermore, a surgical template was derived for the
      osteotomies, and insertion of dental implants was planned to stabilize both the
      transposed bone and the intermediate implant on the bony base. An identical
      implant for augmentation was also fabricated from poly-D,L-lactide in a mold as a
      possible resorbable carrier for osteoinductive proteins. RESULTS: The
      experimental surgery was successfully performed with maximum precision on the
      dried mandible. The fabrication of an implant made out of poly-D,L-lactide for
      the same purpose was also possible. CONCLUSIONS: This preliminary experiment
      showed that it is possible to use CAD/computer-aided manufacturing (CAM)
      technology to prepare a prefabricated template and a corresponding titanium
      implant for mandibular augmentation with a high degree of exactness. Dental
      implants could be planned and integrated in this procedure as well. The
      fabrication of a mold using this method also provided the opportunity to give a
      complex shape to possible carriers of osteoinductive substances.

PMID- 10596666
TI  - Evaluation of a semiburied, fixed-trajectory, curvilinear, distraction device in
      an animal model.
AB  - PURPOSE: This study evaluated a new small, buried distractor, capable of
      curvilinear movement while following a fixed trajectory. The geometrical basis
      for such devices and the 3-dimensional treatment planning system required to make
      buried distractors practical are discussed. MATERIALS AND METHODS: A curved rack
      and worm-gear device, based on the design of a hose clamp, was constructed to
      produce a curved distraction path, and this distractor was tested in 2 minipigs
      using a protocol with zero latency and 1 mm/d x 7 days of distraction. Serial
      standardized lateral cephalograms were used to verify distractor function and
      path. RESULTS: Curvilinear distraction was documented by clinical examination and
      serial cephalometric analysis in the 2 minipigs. Observed angulation of the
      margins of the wedge-shaped distraction gap conformed to the calculated
      angulation based on the fixed radius of curvature of the distractor. CONCLUSION:
      Distraction along a curved trajectory using a small, semiburied, curvilinear
      device of novel design is feasible in the minipig mandible.

PMID- 10596667
TI  - Fungating mass of the anterior maxilla.

PMID- 10596668
TI  - Active condylar hyperplasia treated by high condylectomy: report of case.

PMID- 10596669
TI  - A technique for recovery of a third molar from the infratemporal fossa: case
      report.

PMID- 10596670
TI  - Sebaceous lymphadenoma in the midline of the maxilla: report of case.

PMID- 10596671
TI  - Vertebrobasilar ischemia after a dental procedure.

PMID- 10596672
TI  - Feeding complications in a six-week-old infant secondary to distraction
      osteogenesis for airway obstruction: a case report.

PMID- 10596673
TI  - Pneumoparotid in childhood: report of two cases.

PMID- 10596674
TI  - Finding a solution for the post-traumatic parotid sialocele.

PMID- 10596675
TI  - Granulocyte colony-stimulating factor: its potential role in infectious disease.
AB  - Studies on the role of endogenous granulocyte colony-stimulating factor (G-CSF)
      in host defense indicate that, in addition to its anti-infectious role, this
      cytokine has an immunomodulatory function and also augments antibiotic efficacy.
      Pre-clinical and clinical trials with Filgrastim, recombinant-methionyl human G
      CSF, in neutropenic and non-neutropenic infections demonstrate a reduction in
      morbidity and mortality. This is attributed to Filgrastim's ability to control
      infectious complications and permit continuation of immunosuppressive therapies.

PMID- 10596676
TI  - HIV disease-related neutropenia: an independent risk factor for severe
      infections.
AB  - An increasing number of clinical studies have been reported in which neutropenia
      has been identified as an important independent risk factor in the development of
      infectious complications in patients with HIV and AIDS. Information on the
      clinical significance of infecting pathogens and the causes of neutropenia within
      different patient groups will be discussed, and may have clinical implications in
      subsequent disease management in these groups. Although the use of highly active
      antiretroviral therapy has shown some promise in the treatment of HIV-associated
      hematologic disturbances and immune dysfunction, the rate of virological failure
      with this treatment over time suggests that these disturbances could reappear in
      the near future, as well as their associated infectious complications.

PMID- 10596677
TI  - Prevention of bacterial infections in patients with advanced HIV infection.
AB  - In a study of 258 moderately neutropenic HIV-infected patients, Filgrastim
      (recombinant methionyl human granulocyte colony-stimulating factor) treatment
      significantly reduced the incidence of severe neutropenia and bacterial
      infections. Filgrastim-treated patients also had 54% fewer severe bacterial
      infections and 45% fewer days in hospital for any bacterial infections. No
      unexpected or new adverse events were observed and there were no differences in
      plasma HIV-1 RNA levels between the groups.

PMID- 10596678
TI  - Filgrastim treatment of HIV-infected patients improves neutrophil function.
AB  - The effect of Filgrastim (recombinant methionyl human granulocyte colony
      stimulating factor) treatment on neutrophil function was studied in HIV-infected
      patients. Filgrastim therapy significantly increased oxidative capacity of
      neutrophils, increased bacterial killing, and reduced accelerated apoptosis of
      neutrophils observed in this patient population.

PMID- 10596679
TI  - Supplemental oxygen for COPD patients with nocturnal desaturations?

PMID- 10596680
TI  - New treatment for sarcoidosis: where's the proof?

PMID- 10596681
TI  - A randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary
      disease patients.
AB  - The beneficial effects of nocturnal oxygen therapy (NOT) in chronic obstructive
      pulmonary disease (COPD) patients with mild-to-moderate daytime hypoxaemia
      (arterial oxygen tension (Pa,O2) in the range 7.4-9.2 kPa (56-69 mmHg)) and
      exhibiting sleep-related oxygen desaturation remains controversial. The
      effectiveness of NOT in that category of COPD patients was studied. The end
      points included pulmonary haemodynamic effects after 2 yrs of follow-up, survival
      and requirement for long-term oxygen therapy (LTOT). Seventy-six patients could
      be randomized, 41 were allocated to NOT and 35 to no NOT (control). The goal of
      NOT was to achieve an arterial oxygen saturation of >90% throughout the night.
      All these patients underwent polysomnography to exclude an associated obstructive
      sleep apnoea syndrome. The two groups exhibited an identical meansD daytime Pa,O2
      of 8.4+/-0.4 kPa (63+/-3 mmHg) at baseline. Twenty-two patients (12 in the NOT
      group and 10 in the control group, p=0.98) required LTOT during the whole follow
      up (35+/-14 months). Sixteen patients died, nine in the NOT group and seven in
      the control group (p=0.84). Forty-six patients were able to undergo pulmonary
      haemodynamic re-evaluation after 2 yrs, 24 in the NOT and 22 in the control
      group. In the control group, mean resting pulmonary artery pressure increased
      from 19.8+/-5.6 to 20.5+6.5 mmHg, which was not different from the change in mean
      pulmonary artery pressure in the NOT group, from 18.3+/-4.7 to 19.5+/-5.3 mmHg
      (p= 0.79). Nocturnal oxygen therapy did not modify the evolution of pulmonary
      haemodynamics and did not allow delay in the prescription of long-term oxygen
      therapy. No effect of NOT on survival was observed, but the small number of
      deaths precluded any firm conclusion. These results suggest that the prescription
      of nocturnal oxygen therapy in isolation is probably not justified in chronic
      obstructive pulmonary disease patients.

PMID- 10596682
TI  - Bronchodilator responsiveness and serum total IgE levels in families of probands
      with severe early-onset COPD.
AB  - Bronchodilator responsiveness has been associated with a subsequent accelerated
      decline in forced expiratory volume in one second (FEV1). Therefore,
      bronchodilator responsiveness and total serum immunoglobulin E(IgE) levels were
      assessed in 184 adult first-degree relatives of probands with severe early-onset
      chronic obstructive pulmonary disease (COPD) and a control group. Greater
      bronchodilator responsiveness was found among current smokers or exsmokers who
      were first-degree relatives of early-onset COPD probands than in currently or
      exsmoking controls, expressed as increase in FEV1 as a percentage of baseline
      (5.8+/-8.1 versus 2.9+/-5.1%, p<0.01), absolute increase in FEV1 from baseline
      (120+/-130 versus 60+/-110 mL, p<0.05), and increase in FEV1 as a percentage of
      the predicted value (3.6:4.1 versus 2.2+/-3.9%, p<0.05). However, elevated total
      serum IgE levels were not found in first-degree relatives of early-onset COPD
      probands compared with control subjects. The increased bronchodilator
      responsiveness among currently smoking/exsmoking first-degree relatives of early
      onset COPD probands suggests that these individuals may have enhanced
      susceptibility to the detrimental effects of cigarette smoking.

PMID- 10596683
TI  - Airway inflammation and bronchial microbial patterns in patients with stable
      chronic obstructive pulmonary disease.
AB  - The effect of bacterial colonization of the bronchi on the progress of airflow
      limitation is not well known. Therefore, the pattern of airway inflammation in
      smokers and patients with stable chronic obstructive pulmonary disease (COPD) and
      its relation to bronchial microbial colonization was assessed. Eight nonsmoking
      and 18 smoking controls as well as 52 patients with COPD (28 mild, 11 moderate
      and 13 severe) were studied. All subjects were investigated by means of flexible
      bronchoscopy including protected specimen brush and bronchoalveolar lavage (BAL)
      sampling. Differential cell counts, cytokine (interleukin (IL)-1beta, IL-6, IL-8,
      IL-10 and tumour necrosis factor-alpha(TNF-alpha) concentrations and microbial
      patterns were determined in BAL fluid. Forced expiratory volume in one second
      (FEV1) % of the predicted value was inversely correlated with pack-yrs of
      cigarette smoking (r=-0.47, p<0.0001), the percentage of neutrophil (p=-0.56,
      p<0.0001) and IL-6 (p=-0.37, p=0.01) and IL-8 concentration (p=-0.43, p=0.004) in
      BAL fluid. Accordingly, pk-yrs of cigarette smoking (p=0.39, p=0.01) and IL-8
      (p=0.69, p<0.0001) and TNFalpha (p=0.4, p<0.005) were positively correlated with
      the percentage of neutrophils in BAL fluid. Smoking controls and COPD patients
      were mainly colonized in the bronchial tree (33%) by community endogenous
      potentially pathogenic micro-organisms (PPMs). Colonization rates and patterns of
      PPMs were not affected by severity of airflow obstruction. The presence of PPMs
      was significantly associated with higher percentages of neutrophils (33.2+/-10.4%
      versus 10.1+/-3.5%, p=0.02) and TNF-alpha concentration (29.9+/-10.8 versus 6.3+/
      2.1 pg x mL(-1), p=0.01) in BAL fluid. In conclusion, bronchial neutrophilia is a
      key inflammatory pattern in chronic obstructive pulmonary disease patients.
      Bronchial colonization with potentially pathogenic micro-organisms may represent
      an independent stimulus for additional airway inflammation.

PMID- 10596684
TI  - Prostaglandins mediate bradykinin-induced reduction of exhaled nitric oxide in
      asthma.
AB  - Bradykinin (BK) is a mediator of inflammation in asthma with potent
      bronchoconstrictor actions. Endogenous release of nitric oxide may inhibit BK
      induced bronchoconstriction. This study investigated whether bradykinin
      inhalation could modulate exhaled NO levels in normal and asthmatic subjects, and
      whether the bradykinin-induced effects were mediated through the production of
      cyclo-oxygenase products in patients with asthma, by studying the effect of the
      cyclo-oxygenase inhibitor, L-acetylsalicylic acid (L-ASA). Exhaled NO
      concentration and forced expiratory volume in one second (FEV1) were measured by
      chemiluminescence following inhalation of increasing concentrations of BK. In
      asthmatics (n=11), BK induced a dose-dependent decrease in exhaled NO
      concentration from 21.3+/-1.6 to 6.+/-0.5 parts per billion (ppb) (p<0.01) at the
      highest concentration, associated with a significant fall in FEV1. In normal
      subjects (n=10), the exhaled NO concentration fell from 7.2+/-0.13 to 4.3+/-0.51
      ppb (p<0.001) 15 min, after a single inhalation of BK, but without a significant
      change in FEV1. In asthmatic subjects, pretreatment with inhaled L-ASA (90 x mg x
      mL(-1), 4 mL) did not alter exhaled NO levels, but prevented a BK-induced fall in
      exhaled NO concentration, as indicated by a significant increase in exhaled NO
      levels at the provocative concentration of BK causing a 20% fall in FEV1, (5.7 +/
      0.94 ppb after placebo and 12.0 +/- 1.8 ppb after L-ASA; p<0.05). L-ASA
      significantly reduced bronchial responsiveness to BK 3.9-fold (p<0.01). Inhaled
      bradykinin induced bronchoconstriction and a reduction in exhaled nitric oxide
      levels in asthmatic subjects, an effect that is partly mediated by cyclo
      oxygenase products.

PMID- 10596685
TI  - Do hormonal contraceptives influence asthma severity?
AB  - There is some evidence that endogenous progesterone and oestrogen levels
      influence asthma severity in females, but little is known about the effects of
      hormonal contraceptives. This study aimed to describe how females with asthma
      perceived the effects of hormonal contraceptives on symptom severity, and to
      describe the association between asthma severity and current use of hormonal
      contraceptives. A questionnaire was sent to 891 females with asthma aged 20-30
      yrs recruited from general practice registers in South London, UK. It asked about
      perceptions of the effects of hormonal contraceptives on asthma severity, about
      current use of hormonal contraceptives, and included an asthma quality of life
      questionnaire as a measure of asthma severity. About 6% of respondents who had
      ever used hormonal contraceptives reported that these had influenced asthma
      severity, -4% reporting worsening and 2% an improvement. There were no
      significant differences in asthma quality of life score between females currently
      taking hormonal contraceptives and those not, between those taking combined and
      progesterone-only preparations, or between users of different progestagen types.
      This study found no evidence of any important effect of hormonal contraceptives
      or their components on asthma severity in a group of females with relatively mild
      asthma.

PMID- 10596686
TI  - Multiple inhalers confuse asthma patients.
AB  - This study investigated the influence of the use of different types of inhalers
      on the adequacy of inhalation technique among adult asthmatics. Three hypotheses
      were tested: first, patients using only one type of inhaler will demonstrate
      adequate inhalation technique more often than those with two or more types.
      Secondly, patients using a combination of dry powder inhalers (DPIs) will
      demonstrate correct inhalation technique more often than those using the
      combination of a metered dose inhaler (MDI) and a DPI. Thirdly, some inhalers or
      combinations of inhalers are more prone to erroneous inhalation technique than
      others. Adult outpatients with asthma who regularly used inhaled steroid therapy
      (n=321) participated in the study. The inhalers investigated were MDIs on the one
      hand, and the DPIs Turbuhaler, Diskhaler, Cyclohaler, Inhaler Ingelheim and
      Rotahaler on the other. Of 208 adult asthmatics with only one inhaler, 71% made
      no inhalation errors versus 61% of 113 patients with two or more different
      inhalers. Of patients with a combination of DPIs 68% performed all essential
      checklist items correctly, versus 54% of patients with the combination of
      "regular" MDI and DPI. Patients using only the Diskhaler made fewest errors.
      Whenever possible, only one type of inhaler should be prescribed. If a
      combination is unavoidable, combinations of DPIs are preferable to MDI and DPI.
      The Diskhaler seems to be the most foolproof device.

PMID- 10596687
TI  - Asthma quality of life during 1 year of treatment with budesonide with or without
      formoterol.
AB  - The Formoterol and Corticosteroids Establishing Therapy (FACET) study has
      provided the first opportunity to examine the long-term effects of inhaled
      steroids and long-acting beta2-agonists on asthma-specific quality of life. The
      objectives of the present study were to: evaluate the effects of long-term (1 yr)
      formoterol and increasing doses of budesonide on asthma quality of life; 2) to
      determine whether initial improvements in quality of life are sustained when
      improvements in clinical indices persist; and 3) to evaluate the long-term
      relationship between changes in clinical indices and changes in quality of life.
      Of the 852 asthmatic adults enrolled, 470 from five countries participated in
      this quality of life evaluation. After a 4-week run-in on 1,600 microg
      budesonide, patients were randomized to either 200 microg (Bud200) or 800 microg
      budesonide (Bud800) in combination with either 24 microg formoterol (F) or
      placebo daily for 1 yr. The Asthma Quality of Life Questionnaire (AQLQ) was
      completed and conventional clinical indices measured at enrolment and
      randomization and on seven occasions during the following 12 months. During the
      run-in, there was an improvement in AQLQ score (changes (delta) in overall score
      approximately 0.50; p<0.0001). After randomization, there was a further
      improvement in the Bud800+F group (delta=0.21; p=0.028). One month post
      randomization, improvements in all groups stabilized and were sustained
      throughout the 12 months in a pattern very similar to that observed for the
      conventional clinical indices. The correlation of individual patient changes in
      clinical indices and changes in AQLQ score during the 12-month randomized period
      were weak to moderate (maximum r=0.51). Improvements in quality of life, which
      were greatest in the 800 microg budesonide plus 24 microg formoterol group, were
      sustained throughout the 12 months in a similar manner to the clinical indices.
      Long-term changes in conventional clinical indices cannot be used to predict the
      effect of treatment on individual patient experience.

PMID- 10596688
TI  - A new questionnaire for the repeat of the first stage of the European Community
      Respiratory Health Survey: a pilot study.
AB  - In the early 1990s a multicentre survey on asthma was performed on the young
      adult population (European Community Respiratory Health Survey - ECRHS). This
      study is to be repeated in order to estimate changes in the prevalence of asthma
      like symptoms during the last decade and to assess the social and economic costs
      of the disease and their variations among countries. The self-administered
      questionnaire devised for this purpose is a two-page questionnaire. The first
      page contains the same items as those used in the first survey with four
      additional questions related to: 1) the frequency and severity of asthma attacks;
      2) the presence of chronic bronchitis; 3) smoking habits; and 4) a visual
      analogue scale assessing perception of outdoor pollution. The second page aims to
      collect information regarding the direct and indirect costs of asthma. The
      influence of the length of the questionnaire on the response rate was assessed in
      a pilot study in Italy. Two random samples of 150 subjects received either the
      one-page questionnaire (first page) or the two-page questionnaire. The response
      rate was compared with that obtained from the first postal wave in the 1991-1992
      survey. Although the response rate was unchanged when using the one-page
      questionnaire (45% versus 45%), it decreased by 7% when the two-page
      questionnaire was used (38% versus 45%). On the basis of these results, no
      problem should arise if four more questions are added to the one-page
      questionnaire. The slight reduction in the response rate of the two-page
      questionnaire is worrying but could be corrected by the use of telephone
      interviews.

PMID- 10596689
TI  - Perception of bronchoconstriction in asthma patients measured during histamine
      challenge test.
AB  - This study investigated two aspects of the perception of bronchoconstriction
      ("sensitivity" and "absolute perceptual magnitude") in asthmatic patients and
      identified which clinical characteristics are related to these two aspects of
      perception of bronchoconstriction. The perception of histamine induced
      bronchoconstriction was measured in 128 asthmatic patients. Subjects quantified
      their breathlessness on a Visual Analogue Scale (VAS) before forced expiratory
      volume in one second (FEV1 was measured after each inhalation of histamine. The
      perceptive "sensitivity" for changes in FEV1 was analysed by the "VAS percentage
      fall in FEV1" slope. The "absolute perceptual magnitude" was determined by the
      VAS value at a 20% fall in FEV1. Spearman correlations were used for analysis
      between the two aspects of perception and asthma symptoms, peak flow variability,
      bronchial responsiveness and FEV1 % predicted. Patients with a low "sensitivity"
      for changes in FEV1 were more likely to show a frequent peak flow variability
      (Rs=-0.21; p<0.05), a high bronchial responsiveness (Rs= 0.37; p<0.001) and a low
      baseline FEV1 % pred (Rs=0.22; p<0.05). Patient's "absolute perceptual magnitude"
      correlated positively with symptoms during daily life (significant correlations
      varied 0.21-0.32) but not with the lung function parameters. The severity of
      asthma reflected by a low lung function and a high bronchial responsiveness, is
      associated with a low "sensitivity" for changes in forced expiratory volume in
      one second. A patient's "absolute perceptual magnitude" is positively related
      with asthma symptoms during daily life.

PMID- 10596690
TI  - Reduction in bronchodilation following a deep inhalation is poorly related to
      airway inflammation in asthma.
AB  - In patients with bronchial asthma, forced expiratory flows are differently
      sensitive to a previous volume history. A reduced ability of a deep inhalation
      (DI) to dilate obstructed airways has been hypothesized to be a physiological
      marker for the degree of airway responsiveness and to relate to the presence and
      magnitude of inflammation in the lung, even in mild stable asthma. However, there
      are at present doubts as to whether functional changes could be used as a
      substitute for airway inflammation studies. In order to investigate the
      interrelations among airway inflammation, bronchial hyperresponsiveness and
      effects of volume history, 58 consecutive asthmatics with mild to moderate asthma
      were studied. The effects of DI were assessed as the isovolumic ratio of flows
      from forced expiratory manoeuvres started from maximal (M) or partial (P) lung
      inflation. Airway inflammation was assessed by using induced sputum. Sputum was
      analysed for total and differential cell counts, and levels of eosinophil
      cationic protein (ECP) which reflects eosinophil activation. Airway
      responsiveness was assessed as the provocative concentration of histamine which
      caused a 20% fall in forced expiratory volume in one second (FEV1) from control
      (PC20). The M/P ratio was significantly related to ECP (r=-0.31, p<0.03) and
      eosinophils (r=-0.29, p<0.03), FEV1/vital capacity (VC) (r=0.32; p<0.01),
      clinical score (r=-0.33; p<0.03) and age (r=-0.41; p<0.0001). In a stepwise
      multiple regression analysis including age, score, baseline lung function, ECP,
      number of eosinophils and the response to beta2-agonist, age (p<0.037) predicted
      a small amount of the variance in M/P ratio (r2=0.12). It is concluded that
      volume history response is substantially independent of both sputum outcomes
      (inflammatory cell number and eosinophil cationic protein) and bronchial
      hyperresponsiveness; rather it seems to be associated with anthropometric
      characteristics. Functional aspects do not provide information on eosinophilic,
      probably central, airway inflammation.

PMID- 10596691
TI  - Effects of respiratory syncytial virus persistence on airway responsiveness and
      inflammation in guinea-pigs.
AB  - Recurrent wheezing and asthma often develop after acute respiratory syncytial
      virus (RSV) bronchiolitis, but the mechanisms of these sequelae are poorly
      understood. Using a guinea-pig model of human RSV lung infection, the effects of
      long-term viral persistence on three hallmarks of asthma: nonspecific airway
      responsiveness, airway inflammation and airway remodelling were examined. Guinea
      pigs were studied 100 days after intranasal instillation of either human RSV or
      uninfected vehicle, using: 1) acetylcholine challenge to test for airway
      hyperresponsiveness (AHR); 2) lung histology to quantify the numbers of airway
      eosinophils and metachromatic cells (mast cells/basophils); 3) airway morphometry
      of the areas of the airway subepithelial connective tissue, smooth muscle and
      adventitia, to test for airway remodelling; and 4) immunohistochemistry to
      identify lung cells containing RSV antigens. The RSV-inoculated group had
      significantly elevated AHR and airway eosinophils compared to uninfected control
      animals (p<0.05). There were no significant differences between the two groups in
      terms of numbers of airway metachromatic cells, or the areas of subepithelial
      connective tissue, smooth muscle or adventitia. Viral proteins were identified by
      immunohistochemistry within several types of lung cells. In conclusion, long-term
      persistence of respiratory syncytial virus in the guinea-pig lung is associated
      with airway hyperresponsiveness and airway eosinophilia, and these changes may be
      pertinent to the pathogenesis of postbronchiolitis wheezing and asthma in
      children.

PMID- 10596692
TI  - Epinastine (WAL 801CL) inhibits the electrical field stimulation-induced
      cholinergic contraction in guinea pig and human airways in vitro.
AB  - Epinastine is an antihistamine drug with binding affinities at 5
      hydroxytryptamine (5-HT) receptors. The current study was performed to
      investigate whether epinastine could modulate the cholinergic contraction in
      guinea pig and human airways in vitro. Isolated guinea pig and human airway
      preparations were suspended in organ baths containing modified Krebs-Henseleit
      solution. Electrical field stimulation was applied to elicit cholinergic
      contractions. Epinastine produced a concentration-dependent inhibition of the
      cholinergic contraction in guinea pig airways and pretreatment with methysergide
      (5-HT1/2/7 antagonist) significantly attenuated these inhibitory effects of
      epinastine. Pretreatment with tropisetron (5-HT3/4 antagonist), ketanserin (5-HT2
      antagonist), SDZ216-525 (5-HT1A antagonist) or phentolamine (alpha-adrenergic
      antagonist) had no effect. Epinastine did not displace the concentration-response
      curve to acetylcholine. These results suggest that epinastine inhibits the
      cholinergic contraction in guinea pig airways through stimulation of
      prejunctional 5-hydroxytryptamine receptors, located to postganglionic
      cholinergic nerves. Inhibitory effects of epinastine on the cholinergic
      contraction in human airways in vitro were also demonstrated, which suggests that
      a similar mechanism might be present in human airways. The pharmacological
      profile of epinastine, which shows binding affinity at the 5-hydroxytryptamine7
      receptor but not at the 5-hydroxytryptamine1 receptor subtypes corroborates the
      hypothesis that the inhibitory prejunctional 5-hydroxytryptamine receptor on
      cholinergic nerves is of the 5-hydroxytryptamine7 subtype.

PMID- 10596693
TI  - Adrenomedullin inhibits ovalbumin-induced bronchoconstriction and airway
      microvascular leakage in guinea-pigs.
AB  - Human adrenomedullin is a potent vasodilator with bronchodilation properties. The
      effects of adrenomedullin on antigen-induced bronchoconstriction and airway
      microvascular leakage in guinea-pigs was investigated. The portion of the
      adrenomedullin molecule possessing these pulmonary active profiles was also
      examined, using two truncated adrenomedullin molecules: adrenomedullin (1-25) and
      adrenomedullin (22-52). Four weeks after sensitization with ovalbumin (0.1 mg x
      k(-1)), the guinea-pigs were anaesthetized and mechanically ventilated.
      Respiratory resistance, dynamic compliance and arterial blood pressure were
      monitored. Airway microvascular leakage was evaluated by extravasation of 20 mg x
      kg(-1) Evans blue into airway interstitial tissue. In order to enhance the
      pulmonary effects of adrenomedullin, the active production of endogenous nitric
      oxide was inhibited by coadministration of a nitric oxide synthase inhibitor, L
      N(G)-nitroarginine methethyl ester (10 mg x kg(-1)). Intravenous pretreatment
      with adrenomedullin (10, 30 and 100 microg x mL(-1)) dose-dependently inhibited
      ovalbumin-induced bronchoconstriction and airway microvascular leakage in all
      airway segments. Inhaled adrenomedullin (100 microg.mL(-1), 1 min) also
      significantly inhibited pulmonary changes induced by ovalbumin inhalation (3 mg x
      mL (-1) , 3 min). These pulmonary profiles of adrenomedullin were enhanced by
      inhibiting the active production of endogenous nitric oxide. In conclusion,
      adrenomedullin has inhibitory effects on antigen-induced microvascular leakage
      and bronchoconstriction in guinea-pigs. These beneficial effects strongly related
      to its unique ring structure and N-terminal segment, making it a potential anti
      asthma.

PMID- 10596694
TI  - Effect of cromolyn on adenosine-induced airway microvascular leakage in
      sensitized rats.
AB  - Inhalation of adenosine causes bronchoconstriction in asthmatic subjects, but the
      effect of this purine nucleotide on airway vascular permeability is unknown. In
      order to determine whether adenosine produces airway microvascular leakage and,
      if so, to examine the effect of cromolyn (sodium cromoglycate (SCG)) on this
      extravasation of Evans blue was measured in the airways of ovalbumin-sensitized
      Brown Norway rats. Inhaled adenosine caused microvascular leakage in sensitized
      but not in non-sensitized rats, and the response was abolished by capsaicin
      pretreatment or the tachykinin neurokinin-1 receptor antagonist FK888. Adenosine
      induced vascular leakage became apparent in nonsensitized rats when treated with
      phosphoramidon, and airway neutral endopeptidase activity was lower in sensitized
      than in non-sensitized animals. The extravasation induced by adenosine in
      sensitized rats was dose dependently inhibited by SCG aerosols, SCG likewise
      inhibited microvascular responses to substance P, but had no effect on those to
      platelet-activating factor. These results suggest that: 1) adenosine induces
      airway microvascular leakage in sensitized rats through stimulation of neurokinin
      1 receptors; 2) this effect is associated with a sensitization-induced decrease
      in neutral endopeptidase activity; and 3) sodium cromoglycate inhibits adenosine
      induced extravasation, presumably via functional antagonism of tachykinins.

PMID- 10596695
TI  - Role of neutrophil elastase in ozone-induced airway responses in guinea-pigs.
AB  - Ozone-induced airway hyperresponsiveness occurs concurrently with neutrophilic
      inflammation and epithelial injury in various species including humans. The
      mechanism of neutrophil-induced airway hyperresponsiveness, however, has not yet
      been fully clarified. Neutrophil elastase (NE) is a multipotent protease released
      from activated neutrophils, which may play a role in ozone-induced airway
      hyperresponsiveness. In order to address this issue, the effects of ONO-5046, a
      specific NE inhibitor, were investigated in ozone-exposed guinea-pigs. Awake
      animals were exposed to ozone at 3 parts per million for 2 h, airway
      responsiveness to acetylcholine (ACh) measured and examination of bronchoalveolar
      lavage fluid (BALF) performed. Ozone exposure increased airway responsiveness to
      both inhaled and intravenous ACh, the concentration of NE in BALF and the number
      of neutrophils and airway epithelial cells in BALF. Although pretreatment with
      ONO-5046 (200 mg x kg(-1), i.p.) had no effect on these changes immediately after
      the exposure, it significantly inhibited airway hyperresponsiveness to inhaled
      ACh, whilst decreasing the number of neutrophils and epithelial cells in BALF 3-5
      h after the exposure. In contrast, ONO-5046 showed no significant effect on
      airway hyperresponsiveness to intravenous ACh at any time. These results suggest
      that neutrophil elastase contributes to ozone-induced airway hyperresponsiveness
      developing during the hours after exposure, presumably by means of inducing
      epithelial injury.

PMID- 10596696
TI  - Cigarette smoke exposure causes constriction of rat lung.
AB  - Cigarette smoke is known to cause acute increases in airway resistance, but the
      mechanisms behind this effect are unknown. Lung explants were utilized to examine
      the constrictive effects of acute cigarette smoke exposure on bronchioles from
      rats in vitro that had or had not been previously exposed to cigarette smoke in
      vivo. It was found that smoke induced a small but consistent degree of
      contraction of the airways in vitro, which could be reduced by an endothelin
      receptor antagonist in the animals which had had no previous smoke exposure in
      vivo, and reduced by the oxidant scavengers superoxide dismutase or catalase in
      the animals with previous smoke exposure. In conclusion, cigarette smoke induces
      acute small airways constriction through both endothelin release and direct
      oxidant effects; which mechanisms are operative depends on the prior smoking
      status.

PMID- 10596697
TI  - Production of oxidants in alveolar macrophages and blood leukocytes.
AB  - Increased production of oxidants subsequent to phagocyte stimulation has been
      associated with tissue damage in lung inflammatory disorders. The overall
      oxidative burden of the lung may vary with inflammatory cell composition. Flow
      cytometry using three different dyes, dihydroethidium (DHE), dichlorofluorescein
      diacetate (DCFH-DA) and dihydrorhodamine 123 (DHR), all compounds that by
      interaction with oxidants are transformed to fluorescent products, was used to
      examine the production of intracellular oxidants in alveolar macrophages (AMs),
      including size-defined subpopulations, monocytes (Ms) and polymorphonuclear
      neutrophils (PMNs) during in vitro incubation in the presence or absence of
      phorbol myristate acetate (PMA). PMA stimulation led to slightly increased (two
      fold) (p<0.05) DHE-induced fluorescence in AMs, whereas it was greatly increased
      in Ms and PMNs (13-fold and 113-fold, respectively). The levels of DCFH-DA- and
      DHR-induced fluorescence were significantly (p<0.05) increased (four-fold and 110
      fold, respectively) by PMA stimulation of PMNs, but not of AMs and Ms.
      Significant differences (p<0.05) in the levels of DHE- and DCFH-DA-induced
      fluorescence in small and large AMs were also demonstrated. The results show that
      the potential to increase the generation of various oxidants upon stimulation
      was: PMNs> Ms>AMs, suggesting that the total oxidative burden of the lungs is
      dependent on the type of inflammatory cells present, as well as on their state of
      activation.

PMID- 10596698
TI  - Effects of theophylline, dexamethasone and salbutamol on cytokine gene expression
      in human peripheral blood CD4+ T-cells.
AB  - CD4+ T-cells are considered as pivotal in orchestrating the airway inflammation
      in asthma through the actions of their cytokines. Current hypothesis suggests
      that the anti-asthma effect of theophylline may be due to its anti-inflammatory
      actions, although the exact mechanisms remain unclear. The in vitro effect of
      theophylline on cytokine gene expression in peripheral blood CD4+ T-cells in
      normal subjects was compared with that of dexamethasone and salbutamol. CD4+ T
      cells were cultured with phytohaemagglutin and phorbol myristate acetate in the
      presence of different concentrations of theophylline (10(-8)-10(-3) M or 0.0018
      180 microg x mL(-1)) in one group of subjects (n=8), dexamethasone (10(-9)-10(-6)
      M or 0.39-390 ng x mL(-1)) in a second group (n=8) and salbutamol (10(-9)-10(-4)
      M or 0.00058-58 microg x mL(-1)) in a third group (n=8). Gene expression of
      interleukin (IL)-3, IL-4, IL-5, granulocyte-macrophage colony-stimulating factor
      (GM-CSF) and interferon (IFN)-gamma was semiquantified by reverse transcription
      polymerase chain reaction. Suppressed expression of IL-3 (36.9%), IL4 (38.8%), GM
      CSF (24.6%) and IFN-gamma (37.7%), but not of IL-5, was only seen with
      theophylline at a concentration of 10(-3) M (180 microg x mL(-1)) (p<0.05) and
      not at lower concentrations. In contrast, dexamethasone caused a dose-dependent
      suppression of transcription of all cytokines, with 39.5% for IL-3, 84.4% for IL
      4, 40.6% for IL-5, 50.9% for GM-CSF and 31.8% for IFN-gamma at 10(-6) M (390 ng x
      mL(-1)) (p<0.05-0.001). Salbutamol did not suppress gene expression of any of the
      cytokines at the concentrations examined. These data suggest that cytokine gene
      expression of CD4+ T-cells is not affected at therapeutic concentrations of
      theophylline and salbutamol, but its suppression is likely to be an important
      mechanism underlying the therapeutic effect of corticosteroids in asthma.

PMID- 10596699
TI  - Effects of long-term administration of erythromycin on cytokine production in rat
      alveolar macrophages.
AB  - Low-dose long-term erythromycin treatment has recently been reported to be very
      effective in patients with chronic respiratory infection and inflammation. This
      effect of erythromycin was thought to be not antibacterial but anti-inflammatory.
      However, the exact mechanism of the effect of erythromycin has not yet been
      clarified. The aims of this study were to investigate the effects of erythromycin
      on cytokine production and its mechanisms of actions in rat alveolar macrophages.
      Using rats with or without administration of erythromycin for 3 months, the
      production of the cytokines tumour necrosis factor-or (TNF-alpha), cytokine
      induced neutrophil chemoattractant (CINC)-1 and CINC-2alpha by enzyme-linked
      immunosorbent assay and the expression of TNF-alpha and CINC-1 messenger
      ribonucleic acid (mRNA) by Northern blotting in rat alveolar macrophages were
      analysed. CINC-1 is the rat counterpart of human interleukin-8, and CINC-2alpha
      of human macrophage inflammatory peptide-2. Erythromycin reduced cytokine
      production and secretion when cytokines was induced by lipopolysaccharide
      treatment. Conversely, erythromycin slightly upregulated the expression of
      cytokine mRNA. These results suggest that erythromycin inhibits cytokine
      production and exhibits anti-inflammatory effects by means of a translational
      and/or posttranslational mechanism.

PMID- 10596700
TI  - Treatment of chronic sarcoidosis with an azathioprine/prednisolone regimen.
AB  - In a few patients with chronic sarcoidosis, prolonged, unacceptably high doses of
      corticosteroids are required to achieve symptomatic relief. In these cases, a
      corticosteroid-sparing drug might be administered to allow long-term treatment
      without the adverse effects of corticosteroids. This study examines azathioprine
      as a prednisolone-sparing treatment. In an open study, the course of 11 patients
      with chronic sarcoidosis was analysed. In an induction phase, 2 mg azathioprine x
      kg body weight (BW)(-1) x day(-1) in combination with 0.6-0.8 mg prednisolone x
      kg BW(-1) x day(-1) were administered with prednisolone being reduced to 0.1 mg x
      kg BW(-1) x day(-1) within 2-3 months. This was followed by a 21-22-month
      maintenance phase with 2 mg azathioprine x kg BW(-1) x day(-1) and 0.1 mg
      prednisolone x kg BW(-1) day(-1). Clinical parameters and immunological findings
      of bronchoalveolar lavage (BAL) were analysed. All patients had significant
      symptomatic relief and improvements or resolutions of physiological, serological
      and radiographic findings without suffering from serious adverse effects. Nine of
      11 patients completed therapy after 19-26 months, and 2/11 patients terminated
      therapy after 8 and 12 months, respectively. Eight patients had remissions
      lasting 4-73 months. Three relapses occurred after 8, 18, and 22 months. During
      the induction phase, BAL cell composition changed and their activity in terms of
      cytokine release was suppressed. This preliminary study suggests that
      azathioprine may be effective as a corticosteroid-sparing agent in long-term
      therapy of sarcoidosis, but a much larger study is necessary to give the
      definitive answer.

PMID- 10596702
TI  - Haemodynamic response to dynamic exercise after heart-lung transplantation.
AB  - The purpose of this study was to investigate the haemodynamic response to dynamic
      exercise after heart-lung transplantation (HLT). Nine stable HLT recipients (6
      males) were studied 12-55 months after transplantation. While sitting on a cycle
      ergometer, they first underwent a maximal symptom-limited exercise test (power
      increment was 10 W x min(-1)) to determine the maximal tolerable workload. On the
      next day, they performed a second exercise test at 0, 40, 60 and 80% of their
      predetermined maximal workload (mean+/-sD: 108+/-20 W). Stage duration was 6 min.
      Respiratory, gas exchange, and haemodynamic measurements were performed at rest,
      during the last minute of each stage, and after recovery. Haemodynamic variables
      at rest were within normal limits except heart rate (HR) which was greater and
      stroke volume index (SVI) which was lower than normal. Peak oxygen consumption
      was 61+/-8% of predicted. HR showed an initial slow increase followed by a
      steeper rise, and a delayed return to baseline during the recovery period. SVI
      and cardiac index (CI) increased at the onset of exercise but did not change
      significantly at 40-80% of the maximal workload. Pulmonary capillary wedge
      pressure increased from 4+/-2 mmHg at rest to 14+/-3 mmHg at maximal exercise. It
      is concluded that during dynamic exercise, heart-lung transplantation recipients
      demonstrate a chronotropic incompetence, a reduced increase in cardiac index and
      stroke volume index, and an excessive rise in left ventricular filling pressures.
      These alterations may contribute to the persistent exercise limitation.

PMID- 10596701
TI  - Persistent high BAL fluid granulocyte activation marker levels as early
      indicators of bronchiolitis obliterans after lung transplant.
AB  - The major cause of mortality in the long-term in lung transplant recipients is
      chronic rejection. This is a fibroproliferative process in the small airways
      leading to obliterative bronchiolitis and progressive loss of lung function, both
      constituting the clinical entity bronchiolitis obliterans syndrome (BOS).
      Granulocyte activation has been implicated as one factor behind BOS. Granulocyte
      markers in bronchoalveolar lavage (BAL) fluid were prospectively and
      longitudinally studied in order to identify possible association with BOS. BAL
      fluid from 266 bronchoscopy procedures performed in twelve single lung, eight
      bilateral lung and five heart/lung transplant recipients were analysed. The
      majority (19 of 25) were studied for a period of 2 yrs after surgery.
      Myeloperoxidase (MPO), eosinophil cationic protein (ECP) and interleukin-8 (IL-8)
      levels were used as indirect markers of activation and attraction of
      granulocytes. Five patients developed BOS. Ninety-eight episodes of acute
      rejection, nine of bacterial infection, 19 of cytomegalovirus pneumonitis, nine
      of Pneumocystis carinii infection, two of aspergillus infection and two of
      respiratory syncytial virus infection were diagnosed. BOS patients had
      significantly higher mean levels of MPO, ECP and IL-8 compared to patients
      without BOS, irrespective of acute rejection status. Over time, the five patients
      with BOS had significantly elevated BAL fluid levels of MPO and ECP as well as
      neutrophil percentages, and in four patients this increase preceded the clinical
      diagnosis of BOS by several months. Elevated bronchoalveolar lavage fluid
      neutrophil percentage as well as levels of the granulocyte activation markers
      myeloperoxidase and eosinophil cationic protein appear to be early signs of
      development of BOS in lung transplant recipients.

PMID- 10596703
TI  - Cytokine expression in bronchial biopsies of cystic fibrosis patients with and
      without acute exacerbation.
AB  - In patients with cystic fibrosis (CF), the progression of pulmonary disease
      differs considerably, even in identical cystic fibrosis transmembrane conductance
      regulator-genotypes which could reflect an additional influence of the host's
      immune response. This study therefore measured cytokine expression patterns in CF
      patients with different clinical presentation. Expression of interleukin (IL)-8,
      interferon gamma (IFN-gamma), IL-4, IL-10, and transforming growth factor
      (TGF)beta(I) was assessed in bronchial mucosal biopsies of eight CF patients with
      acute exacerbation (age 6.0-14.2 yrs), eight CF patients with chronic stable
      disease (age 7.3-17.4 yrs), and in five normal control subjects by
      semiquantitative and quantitative reverse transcriptase polymerase chain reaction
      combined with histopathological assessment and immunohistochemical staining. All
      CF patients expressed IL-8. In acute exacerbation, expression of TGF-beta1 and
      IFN-gamma was either absent or extremely low. In contrast, all patients with
      stable disease strongly expressed TGF-beta1. The highest expression of TGF-beta1
      and IFN-gamma was found in CF patients with mild disease and a history of
      infrequent exacerbations. No correlation was found between the expression of IL-4
      and IL-10 and patient history. In normal control subjects, only a weak expression
      of TGF-beta1 was observed. These results show a remarkable correlation between
      cytokine pattern and the clinical course of cystic fibrosis. High expression of
      transforming growth factor-beta1 and interferon gamma was associated with mild
      disease, whereas no or very weak expression of these cytokines was typical for
      patients with acute disease and frequent exacerbations suggesting a contribution
      of the immune response to the progression of pulmonary disease in cystic
      fibrosis.

PMID- 10596705
TI  - Effects of short-term inhaled fluticasone on oxidative burst of sputum cells in
      cystic fibrosis patients.
AB  - Inhaled corticosteroids have been proposed to decrease pulmonary inflammation in
      cystic fibrosis (CF). In this study the effects of therapy with inhaled
      fluticasone on clinical and sputum outcomes (leukocyte count, activity of
      myeloperoxidase, superoxide anion release) in adult CF patients were investigated
      in an open label design. Twenty-six stable patients (median+/-SD forced
      expiratory volume in one second (FEV1) 58.1+/-19.9% pred.) were randomly assigned
      to the study group (500 microg b.i.d., for three weeks) or the control group
      (n=14; nonsteroid medication). Sputum samples were obtained during inhalation of
      hypertonic saline (3%, 20 min), which was found not to alter the investigated
      sputum parameters. No significant changes in clinical parameters, sputum
      leukocyte count, activity of myeloperoxidase, and baseline superoxide anion
      release where observed following therapy. Surprisingly, stimulated superoxide
      anion release increased significantly after therapy (34.1+/-17.7 versus 25.2+/
      17.4 nmol x hr(-1) x 10(6) cells, p<0.03) and exceeded spontaneous variability of
      this parameter (p=0.02 versus control group). In conclusion, in adult cystic
      fibrosis patients short-term fluticasone therapy had no evident effect on
      clinical and sputum parameters. Further investigations are necessary to evaluate
      whether the observed up-regulation of oxidative capacity of inflammatory cells is
      of concern or benefit in these patients.

PMID- 10596704
TI  - Human neutrophil lipocalin, a highly specific marker for acute exacerbation in
      cystic fibrosis.
AB  - Cystic fibrosis (CF) is characterized by the production of abnormally thick
      secretions in the airways, chronic bacterial endobronchial infections and a
      chronic, predominantly neutrophilic inflammatory response. Therefore,
      myeloperoxidase (MPO) and lactoferrin are frequently used as inflammatory
      markers. Recently, a new protein in the neutrophil granules, human neutrophil
      lipocalin (HNL) has been discovered. The aim of the present study was to
      investigate HNL in sera of patients with CF and its relation to MPO and
      lactoferrin as well as to acute pulmonary exacerbation. Serum concentrations of
      HNL, MPO and lactoferrin were determined in 42 patients with CF and in 25 healthy
      subjects. Patients with CF were divided into groups with and without acute
      pulmonary exacerbation (APE) and also with and without colonization with
      Pseudomonas aeruginosa (Pa). Median serum levels of HNL (200.5 microg x L(-1)),
      MPO (595 microg x L(-1)) and lactoferrin (1,356.5 microg x L(-1)) were
      significantly increased in patients with CF compared to control subjects (57.7,
      178 and 478 microg x L(-1), respectively; p<0.0001). CF patients with APE had
      significantly increased serum concentrations of HNL (321 versus 97.7 microg x L(
      1); p<0.0001), MPO (1,125 versus 300 microg x L(-1); p<0.005) and lactoferrin
      (4,936 versus 980 microg x L(-1); p<0.001) compared with patients in stable
      clinical condition. Similarly, patients colonized with Pa had significantly
      higher concentrations of HNL, MPO and lactoferrin than Pa negative patients.
      These results indicate that in patients with cystic fibrosis, serum
      concentrations of human neutrophil lipocalin are markedly increased with a strong
      relationship to myeloperoxidase and lactoferrin. Thus, determination of serum
      human neutrophil lipocalin concentrations may be another useful diagnostic tool
      to monitor neutrophil inflammation in cystic fibrosis. The more marked difference
      in human neutrophil lipocalin compared with myeloperoxidase concentrations with
      no overlap between patients with acute pulmonary exacerbation and those in stable
      condition even suggests that human neutrophil lipocalin may be a more sensitive
      and specific discriminator.

PMID- 10596706
TI  - In vitro investigations of jet-pulses for the measurement of respiratory
      impedance in newborns.
AB  - The aim of this in vitro study was to investigate the measuring range and
      accuracy of a miniaturized equipment for respiratory impedance (Zrs) measurements
      in newborns using jet-pulses. Brief flow pulses (peak flow=16 L x min(-1),
      width=10 ms) were generated by a jet-generator consisting of a solenoid valve and
      an injector, situated between pneumotachograph and outflow resistance. Serially
      arranged resistance-inertance-compliance (R-I-C) lung models (RM=1.3-6.4 kPa x L(
      1) x s, CM=7.4-36.9 mL x kPa(-1), IM=1.5 Pa x L(-1) x s2) were used to measure
      the real and imaginary part of Zrs between 4 and 50 Hz and to determine R, C and
      I by means of the method of least squares. The median errors for R, C and I were 
      0.1 kPa x L(-1) x s (-2%), 2.4 mL x kPa(-1)(13%) and -0.2 Pa x L(-1) x s2 (-13%)
      for measurements without breathing signals and 0.11 kPa x L(-1) -s (3%), 3 mL x
      kPa(-1) (16%) and 0.28 Pa x L (-1) x s2 (19%) in mechanically ventilated models.
      During spontaneous breathing the influence of the breathing flow on Zrs was
      negligible. The equipment did not show any nonlinearity when different pulse
      amplitudes were used (Vmax=13-22 L x min(-1)). The investigations have shown that
      jet-pulses allow reliable measurements of respiratory impedance and have the
      potential to provide valuable information about lung mechanics in spontaneously
      breathing and mechanically ventilated newborns. The developed measuring head has
      a low apparatus dead space, is easy to disinfect, has standard connections and
      can be used as the T-piece in a ventilator circuit.

PMID- 10596707
TI  - A simple new technique to measure the effective dead space of the face mask with
      a water volumeter in infants.
AB  - Measuring the effective dead space (EDS) of a face mask has been difficult in
      infants and the appropriate volume being deducted from lung volume measurements
      has varied between laboratories. This study measured EDS in 16 infants (age
      range, 5-36 months) who have cystic fibrosis, undergoing lung volume measurement
      by N2 washout. A thin plastic bladder, whose neck resided in the mask port, was
      shaped to fill a size 1 clear face mask. A water volumeter was made by inserting
      the body of a 20 mL plastic syringe into the neck of the bladder forming a tight
      seal with a snug fit against the inner surface of the mask port. The mask was
      placed on a horizontal surface and water was added until a level appeared in the
      syringe body (V1). At end-inspiration, the mask was briefly placed on the mouth
      and nose of the sleeping infant, causing the water level to rise in the syringe
      body (V2). The actual total dead space (V) of the mask when connected to the
      mouth port of the slide valve was 23 mL. EDS = V- (V2 - V1). Mean (95% confidence
      interval (95%CI)) EDS was 12.4 (95% CI 11.2, 13.6) mL. The smallest EDS was 8 mL
      since the connected ports (dead space, 8 mL) were unlikely to be penetrated by
      the infant's nose or lips. EDS decreased with increasing body weight and height,
      but seemed to be influenced by individual facial features too. In conclusion, a
      reliable noninvasive volumetric technique for the routine measurement of the
      effective dead space in infants has been developed.

PMID- 10596708
TI  - Methacholine-induced volume dependence of respiratory resistance in preschool
      children.
AB  - Enhanced negative volume dependence of airway resistance is associated with
      bronchoconstriction in tracheostomized paralysed open-chest animals. Significant
      upper airways responses may be associated with bronchoconstriction and could
      thereby alter the pattern of volume dependence in spontaneously breathing
      subjects. The aim of the study was to test whether volume dependence of
      respiratory resistance (Rrs) could be demonstrated in preschool children
      undergoing routine methacholine challenge. The volume dependence of respiratory
      oscillation resistance at 12 and 20 Hz (Rrs,12 and Rrs,20) was examined in eight
      4-5.5-yr-old children showing a positive response to methacholine. Multiple
      linear regression analysis was also used to account for flow dependence during
      tidal breathing (Rrs,12 or Rrs,20=K1+K2?V'?+K3V). Rrs,12 and Rrs,20 yielded
      similar results. Negative volume dependence was present at baseline and
      significantly enhanced by methacholine (p<0.01). For instance, the mean+/-SD
      inspiratory K3 at 20 Hz was 4.1+/-1.3 hPa x s x L(-2) at baseline and -15.0+/-4.3
      hPa x s x L(-2) after methacholine, in which case it was also larger on
      expiration than on inspiration (p<0.05), possibly as a result of upper airway
      responses. A significant increase in the negative volume dependence of
      respiratory resistance may thus be shown in preschool children in response to
      methacholine. The volume dependence (K3) during inspiration may be particularly
      useful in detecting bronchoconstriction, because it is less likely to be affected
      by upper airway mechanisms than during expiration.

PMID- 10596710
TI  - Lack of a late asthmatic response after hypertonic saline challenge in children.
AB  - Hypertonic saline challenge has become a standardized method for measuring airway
      responsiveness. However, there is still uncertainty about the occurrence of a
      late asthmatic response. Therefore, the present study was designed to assess a
      possible late asthmatic response after hypertonic saline challenge in children.
      Twenty-one children with mild to moderate bronchial hyperresponsiveness were
      studied. On days 1 and 2, forced expiratory volume in one second (FEV1) was
      measured hourly from 10:00 h to 22:00 h to assess diurnal variation of lung
      function. On the third study day, a hypertonic saline challenge was performed and
      FEV1 was measured as on control days. The possibility of a late asthmatic
      response was tested by comparing FEV1 levels up to 12 h after the challenge on
      the intervention day to FEV1 levels on control days. In no subjects were the FEV1
      values following the challenge found to be considerably below the individual mean
      of the control days. Furthermore, a nonparametric approach was applied for each
      child and the population looked into as a whole. Again, no late asthmatic
      response was detectable. The results of this study suggest that in children with
      mild to moderate bronchial hyperresponsiveness a late asthmatic response does not
      occur 4-12 h after a 4.5% saline challenge.

PMID- 10596709
TI  - Methacholine challenge in preschool children: methacholine-induced wheeze versus
      transcutaneous oximetry.
AB  - Tracheal/chest auscultation for wheeze and transcutaneous oximetry have both been
      suggested as measures of outcome in bronchial provocation tests in young
      children. This study aimed to compare the sensitivity and safety of these two
      techniques as end-points for methacholine challenge in children aged <4 yrs.
      Seventy-two methacholine challenges were performed in 39 children aged <4 yrs
      with recurrent wheeze. Arterial oxygen saturation (Sa,O2) and transcutaneous
      oxygen pressure tcPO2 continuously, and the test was terminated when wheeze was
      heard or at Sa,O2 <91%. tcPO2 was not used as an end-point. Wheeze or
      desaturation occurred at < or =8 mg x mL(-1) methacholine in every test. One
      child had transient clinical cyanosis, but no other ill-effects were seen. Fifty
      six tests (78%) were terminated for wheeze, seven (10%) for fall in Sa,O2 and
      nine (12%) showed simultaneous responses in both parameters. Twenty-eight tests
      (39%) contained a fall in tcPO2 >3 kPa but six of these also showed a significant
      rise. Fifty-three tests (75%) contained a fall in tcPO2 >15%, but 20 of these
      also showed a significant rise. Tracheal/chest auscultation with Sa,O2 monitoring
      is a sensitive and relatively safe end-point for bronchial challenges in
      preschool children. The erratic pattern of transcutaneous oxygen pressure
      response in some children casts doubt on its reliability as a proxy measure of
      bronchial obstruction.

PMID- 10596711
TI  - Lung function and short-term outcome in young asthmatic children.
AB  - The aims of this study were to investigate lung function in 2-5-yr-old stable
      asthmatic children consecutively referred from general practitioners and to
      analyse the outcome on the basis of their requirement for antiasthmatic treatment
      and symptoms after 1.6-4.5 yrs. Lung function was measured in 110 children with a
      mean+/-SD age of 3.8+/-1.0 yrs using the interruptor technique (resistance
      assessed using the interruptor technique (Rint)), whole body plethysmography
      (specific airway resistance (sRaw) and respiratory resistance (Rrs,5)and
      reactance at 5 Hz (Xrs,5) using the impulse oscillation technique. Rint, sRaw,
      Xrs,5 and Rrs,5 were suggestive of impaired lung function in 44%, 14%, 11% and
      7.5% of the children, respectively, with a predominance of children aged 2-3 yrs.
      Sixty-five per cent were treated with inhaled steroids, and 35% were treated only
      with beta2-agonists as needed; lung function was not significantly different
      between these two groups. Outcome after 2.9+/-0.7 yrs was not significantly
      different between children with Rint measurements above and those children with
      Rint measurements within the reference range at enrolment. Of these children, 58
      and 59% were currently on antiasthmatic treatment, and 40% and 49% had current
      symptoms, respectively. Impairment of lung function may be a common finding in
      stable young asthmatic children, but apparently this is not a risk factor for
      persistence of asthmatic symptoms.

PMID- 10596712
TI  - Assessment of a simple scoring system applied to a screening questionnaire of
      asthma in children aged 5-15 yrs.
AB  - The aim of the present study was to validate a simple scoring system using a
      parent-completed screening questionnaire to identify children aged 5-15 yrs who
      may have asthma. A stratified random sample of 157 children of 1,808 whose
      parents had answered a postal respiratory questionnaire underwent detailed
      clinical evaluation. The results were reviewed by three independent
      paediatricians whose opinions were combined to reach, for each child, decisions
      regarding three standards: 1) "possible asthma" defined as >50% likelihood of
      having asthma; 2) "possible asthma" defined as meriting a clinical trial of
      asthma medication; and 3) "probable asthma" defined as >90% likelihood of having
      asthma. The combined decisions were compared to three sets of questionnaire
      scores, in order to determine the positive predictive value, sensitivity and
      specificity of each set in identifying children with probable/possible asthma.
      The three sets of chosen questionnaire scores all had positive predictive values
      of 79-96% for predicting possible asthma, using either the combined expert
      opinion ">50% likelihood of asthma" or that of "warrants a trial of treatment" as
      the definition. This suggests that a low proportion of false positives would be
      obtained were this scoring system to be used for a screening programme. The
      combined decision >90% chance of asthma could be used as a means of estimating
      prevalence of asthma in the survey. When used for this, the prevalence of asthma
      in the surveyed population was 18.8% (95% confidence interval 13.1-26.3). In
      conclusion, the present scoring system, based on a simple respiratory
      questionnaire, provides a valid method of identifying children likely to have
      asthma, and who, if unknown to the medical services, would benefit from clinical
      review.

PMID- 10596713
TI  - Alveolar macrophage immaturity in infants and young children.
AB  - Very little is known about alveolar macrophage (AM) immunological function in
      early childhood. Using nonbronchoscopic bronchoalveolar lavage (BAL), this study
      sought to compare the proportion, number, and function of AM between very young
      and older children. BAL fluid (BALF) leukocyte parameters were determined in 63
      children, and data divided into 3 age groups: group 1 (<2 yrs), group 2 (> or =2
      < or =5 yrs) and group 3 (> or =6-< or =17 years). In a further subgroup of
      children, AM function and immune receptor expression were assessed, and data
      categorized into two age groups: <2 yrs and > or =2 yrs of age. Compared to
      groups 2 and 3, the AM percentage in the BAL in group 1 was significantly
      increased (median: 98% versus 92% and 91%), as was the albumin-adjusted AM
      concentration. AM from children <2 yrs expressed less human leukocyte antigen
      (HLA)-DR (versus > or =2 yrs of age), were less effective in reducing nitro blue
      tetrazolium, and released less interleukin (IL)-1 and tumour necrosis factor on
      lipopolysaccharide stimulation. There was no difference in release of IL-6,
      expression of intercellular adhesion molecule-1 (CD54), and AM stimulation of
      allogeneic T-cells, between children <2 yrs and > or =2 yrs of age. It was
      concluded that the capacity of alveolar macrophage to stimulate T-cells is not
      enhanced in early childhood, and that immaturity of alveolar macrophage function
      may contribute to an increased susceptibility to respiratory infections in this
      age group.

PMID- 10596714
TI  - A comparative study on the efficacy of levofloxacin and ceftazidime in acute
      exacerbation of bronchiectasis.
AB  - A prospective randomized study was performed in order to compare the efficacy of
      oral levofloxacin, a new S- isomer of ofloxacin, with intravenous ceftazidime in
      the empirical treatment of acute exacerbations of bronchiectasis. Consecutive
      patients with acute exacerbation of bronchiectasis were recruited at a tertiary
      referral centre and were randomized to receive 10 days' treatment with either
      oral levofloxacin (300 mg b..d.) or ceftazidime (1 g i.v.t.d.). Body temperature,
      cough score, dyspnoea score, sputum purulence and volume and white blood cell and
      neutrophil count were assessed on day 1 and day 10. Thirty-five patients (mean
      age 61 yrs, 15 males) completed the study; 17 of these were in the levofloxacin
      group. There was no significant difference in the distribution of sputum
      pathogens or clinical parameters between the two groups at entry to and
      completion of the study. Both groups of patients showed significant improvement
      in 24-h sputum volume, sputum purulence score, cough score and dyspnoea score
      (p<0.001) but there was no significant difference between these two groups at
      entry to or on completion of the study (p>0.05). The results of this study
      suggest that oral administration of levofloxacin is as effective as parenteral
      ceftazidime in the empirical treatment of exacerbations in bronchiectasis.

PMID- 10596715
TI  - The importance of genetic influences in asthma.
AB  - Asthma is a complex genetic disorder in which the mode of inheritance is not
      known. Many segregation studies suggest that a major gene could be involved in
      asthma, but until now different genetic models have been obtained. Twin studies,
      too, have shown evidence for genetic influences in asthma, but have also revealed
      substantial evidence for environmental influences, in which nonshared
      environmental influences appeared to be important. Linkage, association studies
      and genome-wide screening suggest that multiple genes are involved in the
      pathogenesis of asthma. At least four regions of the human genome, chromosomes
      5q31-33, 6p21.3, 11q13 and 12q14.3-24.1, contain genes consistently found to be
      associated with asthma and associated phenotypes. Not only genes associated with
      asthma but also genes which are involved in the development and outcome of asthma
      will be found in the future. This will probably provide greater insight into the
      identification of individuals at risk of asthma and early prevention and greater
      understanding for guiding therapeutic intervention in asthma. Exchange of
      information between researchers involved in the genetics of asthma is important
      because of mandatory agreement on phenotypes and analytical approaches. Genetics
      will contribute to the a better understanding and management of asthma in the
      future.

PMID- 10596716
TI  - Development of irreversible airflow obstruction in a patient with eosinophilic
      bronchitis without asthma.
AB  - Eosinophilic bronchitis is a recently described condition presenting with chronic
      cough and sputum eosinophilia without the abnormalities of airway function seen
      in asthma. The patient, a 48-yr-old male who had never smoked, presented with an
      isolated chronic cough. He had normal spirometric values, peak flow variability
      and airway responsiveness, but an induced sputum eosinophil count of 33% (normal
      <1%). Although his cough improved with inhaled corticosteroids the sputum
      eosinophilia persisted. Over 2 yrs he developed airflow obstruction, which did
      not improve following nebulized bronchodilators and a 2-week course of
      prednisolone 30 mg once daily sufficient to return the sputum eosinophilia to
      normal (0.5%). It is suggested that the progressive irreversible airflow
      obstruction was due to persistent structural change to the airway secondary to
      eosinophilic airway inflammation, and it is further speculated that eosinophilic
      bronchitis may be a prelude to chronic obstructive pulmonary disease in some
      patients.

PMID- 10596717
TI  - Human herpes virus-8 associated primary effusion lymphoma of the pleural cavity
      in HIV-negative elderly men.
AB  - Human herpes virus-8 (HHV-8)-associated primary effusion lymphoma (PEL) is an
      unusual lymphoma confined to the body cavities, which primarily affects human
      immunodeficiency virus (HIV)-positive men at high risk for Kaposi's sarcoma (KS).
      We describe two HIV-negative elderly Italian men, who developed pleural HHV-8
      positive PEL in association with other diseases (systemic hypertension, colonic
      carcinoma, chronic obstructive airways disease, dilated cardiomyopathy), but
      without KS. Thoracic computed tomography revealed unilateral pleural effusion and
      pleural thickening. Thoracentesis disclosed large lymphoma cells, with no T- or B
      cell associated antigens, clonal rearrangement of the immunoglobulin heavy chain
      gene and the presence of HHV-8 but not Epstein-Barr virus deoxyribonucleic acid
      sequences. Our cases differ from most pleural effusion lymphomas, in that they
      are non-acquired immunodeficiency syndrome-related. This highlights the possible
      human herpes virus-8-associated primary effusion lymphoma risk among elderly
      human immunodeficiency virus-negative patients, particularly Italians, in whom
      human herpes virus-8 seroprevalence rates and incidence of classic Kaposi's
      sarcoma are high.

PMID- 10596718
TI  - Alexander Pope (1688-1744): his spinal deformity and his doctors.
AB  - Alexander Pope was the towering figure of 18th century England. A poet and a wit
      he commanded unswerving loyalty from his friends and penetrating hatred from his
      enemies. His spinal deformity, either due to tuberculosis, trauma or congenital
      weakness, shaped his career. This brief report highlights the illness and the
      medical men who were involved in treating Alexander Pope.

PMID- 10596719
TI  - Acute stridor due to an upper tracheal membrane following endotracheal
      intubation.

PMID- 10596720
TI  - Effects of maternal infections on fetal adrenal steroid production.
AB  - We sought to determine the effect of maternal infections on the fetal
      hypothalamic-pituitary-adrenal axis. Umbilical cord blood was collected at
      vaginal delivery after labor (24-44 wk. gestation) from 361 infants of women
      having normal pregnancy ( apart from preterm delivery in some) and 110 infants of
      women diagnosed with infections: 86% of these women had amnionitis. Infants
      exposed to antenatal corticosteroids, being growth retarded, or having
      developmental abnormalities that would be expected to alter function of the
      hypothalamic-pituitary unit were excluded. Umbilical cord serum was assayed for
      dehydroepiandrosterone sulfate (DS) and for cortisol. The data were analyzed by
      use of SAS. The gestational age of the infants of normal women (35.8+/-0.2 wk.,
      Mean +/- SE) was greater than that of the infants of women having infections
      (34.3+/-0.4 wk., P = 0.003). Umbilical cord serum levels of DS and cortisol rose
      as a function of gestational age in both groups of infants (P<0.01). Despite
      being, on average, 1 wk. younger than the normal infants are, the infants of
      women having infections during pregnancy had higher serum levels of cortisol and
      DS than did those infants of the normal women. These data are consistent with
      activation of the fetal hypothalamic-pituitary-adrenal axis in pregnancies
      complicated by maternal infections. Such a fetal response could be the
      consequence of transplacental passage of products of the activated maternal
      immune system.

PMID- 10596721
TI  - Effect of an aproteic diet on gonadotropin release response to GnRH and estrogen
      progesterone in rats.
AB  - The fasting-induced gonadotropin function decrease is unspecific, because in this
      situation there is a lack of all nutrients. We report here the effect of specific
      protein lack in the diet during 21 days, on pituitary gonadotropin synthesis and
      response to exogenous GnRH in adult male rats. We also studied the effect of the
      aproteic diet (AP) on the positive feedback mechanism in adult female castrated
      rats. The AP diet decreased significantly, both LH and FSH pituitary
      concentration and also basal gonadotropin plasma levels in male rats. GnRH
      produced a significantly increment in LH secretion in both treated and control
      groups, reaching similar levels after stimulation. Nevertheless, the percentile
      increment from basal levels in the aproteic group was almost four times the
      controls, suggesting an increased sensitivity in pituitary response to GnRH in
      rats fed with AP diet. In female castrated rats, the aproteic diet imposed 3
      weeks after the surgery was unable to reduce basal gonadotropin secretion, and so
      also prolactin secretion. Estradiol/progesterone (EP) administration produced the
      activation of positive feedback mechanism, increasing significantly LH and FSH
      secretion in both controls and AP groups. Nevertheless, both gonadotropin
      responses to EP were significantly greater in rats fed with AP diet. Basal
      prolactin levels and response to EP were not different between both groups. This
      results suggest that selective protein lack in a diet, reduced pituitary LH and
      FSH synthesis and secretion. This type of diet also increments pituitary
      sensitivity to GnRH administration in male rats, and gonadotropin response to
      positive feedback mechanism in female rats.

PMID- 10596722
TI  - Pro-oxidating properties of melatonin in the in vitro interaction with the
      singlet oxygen.
AB  - In an aqueous system, the oxidation of the erythrocyte membrane by the singlet
      oxygen formed during the photoactivation of the rose bengal coloring was
      examined. The effects of the singlet oxygen on lipids and proteins were studied
      through the simultaneous quantification of peroxidation products, lipoperoxides
      and carbonyl groups, the oxidation of protein SH groups and the activity of the
      glyceraldehyde 3-phosphate dehydrogenase (G3PD) associated with the erythrocyte
      membrane. The antioxidant activity of melatonin was tested and compared to that
      of two antioxidants in extreme cases of hydrosolubility, ascorbate and beta
      carotene, with the purpose of comparing the protective ability of melatonin
      against singlet oxygen. The results show the expected effect even at low (0.125
      0.75 mM; 0.015-0.90 mM, respectively) for ascorbate and beta-carotene,
      antioxidants known to possess important antioxidant qualities against singlet
      oxygen. It is shown that melatonin, under the conditions described, and at the
      concentrations at which the other two compounds are efficacious, not only confers
      little antioxidant protection, but that a pro-oxidant tendency was proven both on
      lipids and proteins, as well as on G3PD enzymatic activity. The results show that
      the antioxidant protective effect that melatonin can exert on biological systems
      is probably not by a direct interaction with oxidant species, but probably, as
      has been previously proposed, through the regulation of antioxidant defense
      systems. The formation of secondary oxidation products, such as melatonin-derived
      endoperoxides, may explain the evidence found on pro-oxidant qualities of this
      molecule.

PMID- 10596723
TI  - Growth hormone has no direct effect on human adrenal steroid and insulin-like
      growth factor-binding protein secretion.
AB  - Although it is known that growth hormone (GH) exerts its growth-promoting effects
      mainly via Insulin-like growth factor-I (IGF-I), an increasing number of direct
      effects of GH has been described in many tissues. In vivo, mice transgenic for
      human growth hormone (hGH) show significantly elevated levels of corticosterone,
      enlarged adrenal glands, and altered levels of insulin-like growth factor binding
      proteins (IGF-BPs). Recently, we have shown that IGF's induce the secretion of
      cortisol and IGF-BP's in adult human adrenocortical cells. However, since human
      adrenal glands express the intact GH-receptor, the objective of this study was to
      investigate whether GH exerts a direct effect on the steroidogenesis and IGF-BP
      synthesis in adult human adrenocortical cells. Primary cell cultures in monolayer
      were incubated under serum-free conditions with human growth hormone and/or ACTH
      for up to 72 hours. Cortisol was measured by specific RIA and the secretion of
      insulin-like growth factor binding proteins was analyzed by Western ligand
      blotting. hGH alone was unable to stimulate basal or ACTH-induced cortisol
      secretion. Additionally, neither hGH alone or in combination with ACTH did
      significantly alter the secretion of IGF-BP's. Therefore we conclude that hGH is
      unable to directly stimulate cortisol secretion and IGF-BP secretion in cultured
      human adrenocortical cells.

PMID- 10596724
TI  - NT-3: an additional neurotrophin expressed in the adult rat pituitary.
AB  - Neurotrophins mediate a variety of essential biological functions in the nervous
      system. Evidence has emerged that this class of proteins is also implicated
      outside the nervous system, in the pituitary. The study described here aims to
      understand the expression of neurotrophins in the pituitary. We previously
      reported the presence of nerve growth factor (NGF) and brain derived neurotrophic
      factor (BDNF) proteins in association with the thyroid stimulating hormone (TSH)
      and the corresponding mRNAs in the anterior lobe (AL) of the pituitary of adult
      rats (1). The present study reveals the expression of NGF and BDNF mRNAs in the
      intermediate plus posterior lobe (IL+PL) as well, and the previously unidentified
      NT-3 mRNA in the AL and IL+PL. In addition, NGF, BDNF and NT-3 mRNAs are
      expressed by dissociated AL cells and IL+PL cells, demonstrating their in situ
      synthesis in endocrine cells of the gland. These findings are new inference for
      the investigation of the regulation of the synthesis and the secretion of
      neurotrophins by pituitary cells, with the goal to gain more insight into their
      function in the hypophysis.

PMID- 10596725
TI  - Impact of neonatal onset hypothyroidism on Sertoli cell number, plasma and
      testicular interstitial fluid androgen binding protein concentration.
AB  - The impact of neonatal onset hypothyroidism from day 1 postpartum through
      different postnatal developmental events on rat testis was studied in vivo.
      Hypothyroidism was induced in neonates by feeding the lactating mother or
      directly with 0.05% methimazole (MMI) through drinking water from the day of
      birth and were killed at day 10, 15, 30, 40 and 60 postpartum. Hypothyroidism was
      confirmed by radioimmunoassay of thyroid hormones and TSH. Sertoli cell number,
      plasma and testicular interstitial fluid (TIF) androgen binding protein (ABP)
      concentration was quantified. Sertoli cell number was consistently decreased in
      all hypothyroid rats. Plasma ABP was also decreased irrespective of the duration
      of hypothyroidism. Unlike plasma ABP, TIF ABP concentration in hypothyroid rats
      increased at day 10, and 15 postpartum and decreased in other age groups. Plasma
      FSH level was increased significantly in all hypothyroid groups. The present
      investigation points out that suppression of T3 during the critical period of
      Sertoli cell proliferation affects their number and functional activity.

PMID- 10596726
TI  - Duration-dependent effect of transient neonatal hypothyroidism on sertoli and
      germ cell number, and plasma and testicular interstitial fluid androgen binding
      protein concentration.
AB  - The impact of transient neonatal hypothyroidism on growth and function of puberal
      testis during different milestones of postnatal testicular development was
      studied in Wistar rats. Rat pups were made hypothyroid for 10, 15, 30, 40 and 60
      days of postnatal age from birth by providing 0.05% (W/V) methimazole (MMI) in
      the drinking water of the mother, from day 1 postpartum till weaning (25 days
      postpartum) and thereafter in the drinking water. Control rats were raised
      without MMI treatment. Sertoli cell number and its function was assessed on day
      60 postpartum. Sertoli cell number increased consistently in 10, 15, 30 and 40
      days transient hypothyroid rats but decreased in rats subjected to continuous
      hypothyroidism from birth to 60 days postpartum. Rats subjected to continuous
      hypothyroidism from birth showed spermatogenic arrest at puberty and had only a
      single layer of spermatogonia. Transient neonatal hypothyroidism for 10 (or) 15
      days from birth increased spermatocytes (pachytene and zygotene), spermatids
      (elongated and round) whereas, that of 30 and 40 days decreases the number of
      germ cells. Plasma androgen binding protein (ABP) concentration decreased in
      puberal rats belonging to all groups, whereas the testicular interstitial fluid
      (TIF) concentration of ABP increased significantly in 10 and 15 days hypothyroid
      rats while it decreased in all other groups. These findings indicate that the
      mitogenic activity of Sertoli cell is increased irrespective of the duration of
      transient neonatal hypothyroidism. However, the functional activity of Sertoli
      cells (ABP production) in these puberal rats varies depending upon the postnatal
      period at which the animals were in hypothyroid state.

PMID- 10596727
TI  - Studies on the effect of growth hormone in vivo and in vitro on lipogenic enzymes
      and transaminases in a teleost Anabas testudineus (BLOCH).
AB  - The specific activities of three lipogenic enzymes, malic enzyme (ME), glucose-6
      phosphate dehydrogenase (G6PDH) and isocitrate dehydrogenase (ICDH), in liver and
      heart and two transaminases (AST & ALT) in liver and muscle, were studied in
      response to the in vivo and in vitro administration of growth hormone (GH) in a
      teleost Anabas testudineus. Ovine growth hormone (oGH) in vivo significantly
      reduced the activities of lipogenic enzymes, except for heart G6PDH, which showed
      an increase at the highest dose of hormone. Transaminase activity either
      increased or decreased depending on the dose of GH. The lowest dose of hormone
      employed (0.1 microg/gm b/w) exhibited a stimulatory effect and the highest dose
      (0.5 microg/gm. b/w) an inhibitory effect on transaminase activity. Both ovine GH
      and carp GH (oGH and cGH) in vitro significantly reduced the activities of ME,
      G6PDH and ICDH. Activities of AST and ALT were increased by oGH and cGH in vitro.
      The present study reveals that irrespective of origin, GH in vitro has a direct
      inhibitory effect on lipogenic enzymes ME, G6PDH, ICDH and a stimulatory effect
      on transaminases AST and ALT in A. testudineus, thus favoring gluconeogenesis.

PMID- 10596728
TI  - The relationship of serum leptin levels and parameters of endurance training
      status in top sportsmen.
AB  - Leptin is a hormone that reflects the body fat content. It was reported that
      serum leptin levels were decreased in highly endurance-trained sportsmen in
      comparison with control non-sporting subjects. The aim of our work was to study
      the relation of serum leptin to blood viscosity and selected spiroergometric
      parameters of endurance capacity in a group of top rugby players and top race
      walkers. We have found that both body fat content and serum leptin levels were
      significantly lower in race walkers than in rugby players (9.68+/-3.65 vs 15.95+/
      3.15% and 2.84+/-1.1 vs 3.89+/-1.09 ng x ml(-1) respectively, p<0.05). The
      positive correlation of serum leptin levels with body fat in both groups. The
      level of endurance training status was significantly higher in the race walkers
      group. Serum leptin levels significantly negatively correlated oxygen uptake per
      body and pulse oxygen per body weight only in rugby players but not in race
      walkers. Partial correlation test after adjusting for the effect of body fat
      content showed that leptin itself is not an independent predictor of endurance
      trainability in this group. Serum leptin levels correlated positively with blood
      viscosity only in race walkers, but not in the rugby players group. We conclude
      that serum leptin levels in top sportsmen parallel the changes in body fat
      content and are not an independent predictor of endurance training of these
      subjects.

PMID- 10596729
TI  - Accelerated conversion of dehydroepiandrosterone sulfate to estrogen in a patient
      with Crow-Fukase syndrome and diabetes mellitus.
AB  - About 28% of patients with the Crow-Fukase syndrome exhibit glucose intolerance
      which may be induced by low serum levels of dehydroepiandrosterone (DHEA). We
      report a patient with the Crow-Fukase syndrome who exhibited non-insulin
      dependent diabetes mellitus (NIDDM) worsened prior to admission. He received the
      DHEA sulfate (DHEA-S) infusion test to evaluate aromatase activity. This patient
      exhibited an increase in aromatase activity measured by the conversion of the
      intravenously loaded DHEA-S to estrogen, and low serum levels of DHEA and DHEA-S.
      These abnormalities returned to nearly normal during the administration of
      prednisolone, 60 mg per day. No adverse effect on his diabetes was observed
      during the corticosteroid treatment. Five control patients with diabetes but
      without the Crow-Fukase syndrome showed no increase in the conversion of DHEA-S
      to estrogen, which suggests that aromatase activity is normal in diabetes. The
      increase in aromatase activity in our patient may have led to a low serum
      concentration of DHEA that in turn caused glucose intolerance and a deterioration
      of the diabetes prior to admission. Glucocorticoid therapy may be beneficial in
      Crow-Fukase syndrome to improve the distorted metabolism of DHEA with no adverse
      effect on the diabetes.

PMID- 10596730
TI  - Effects of rhG-CSF on neutrophil functions and bone marrow parameters in diabetic
      rats.
AB  - Neutrophils have an important role in the host defense. The elevated serum
      glucose levels of diabetics affect traditional host defenses such as neutrophil
      counts and functions. The causes of these impairments are not clear. We aimed to
      investigate changes of peripheral neutrophil counts and functions and their
      relation with bone marrow cells in diabetic rats. Thirty-two rats were divided
      into four equal groups. Group 1 were controls and Groups 2 and 4 were made
      diabetic by a single intraperitoneal injection of streptozotocin. Granulocyte
      colony stimulating factor (G-CSF) was injected subcutaneously into Groups 3 and
      4. White blood cell count, neutrophil counts and function and bone marrow cell
      count were determined. Peripheral blood cell counts, neutrophil phagocytosis
      index were decreased but neutrophil adhesivity index was not different in the
      diabetes-induced group. There was a difference in circulating white blood cell
      counts and neutrophil counts between the rhG-CSF treated and non-treated groups.
      The phagocytosis index of neutrophil in diabetic rats was significantly
      diminished by rhG-CSF treatment. A hyperplasia of early cells of the myeloid
      series in G-CSF treated groups was observed when compared with those of
      nontreated groups (p<0.001). A significant decrease was noted in the number of
      mature marrow segmented cells diabetic groups (p<0.001). Finally, G-CSF has been
      shown to cause neutrophilia by acting as a releasing factor for mature marrow
      neutrophils in diabetic rats. These results suggest that G-CSF may be used to
      improve nonspecific immunity in diabetic patients.

PMID- 10596731
TI  - Developmental changes in molecular forms of immunoreactive adrenocorticotropin in
      the anterior pituitary gland of humans.
AB  - In extracts of anterior pituitary tissue obtained at autopsy of fetal, infant,
      and adult humans, five molecular forms of immunoreactive ACTH (ACTHi) were
      detected that had apparent molecular weights of approximately 4044, 30-34, 24-28,
      16-18, and 4.5 kilodaltons (K). The relative proportion of each molecular form of
      ACTHi was similar in tissues that were extracted at the time of autopsy and in
      tissues that were stored frozen (-20 degrees C) for up to 2 years prior to
      extraction. We found that 40-44K ACTHi comprised a significantly greater
      proportion of total ACTHi in fetuses (12.3+/-3.5%) than in adults (3.8+/-0.8%);
      intermediate amounts of this form of ACTHi (8.0+/-4.1%) were found in tissues
      obtained from infants. On the other hand, the proportion of 4.5 K ACTHi in fetal
      pituitaries (67 %) was less than that in those of adults (84 %). The ratio of 40
      44/30-34K ACTHi was significantly greater (P<0.001) in fetuses (1.46+/-0.12) and
      infants (1.31+/-0.07) than in adults (0.52+/-0.07). The ontogenetic differences
      in molecular forms of pituitary ACTHi are thought to reflect alterations in the
      processing of proopiomelanocortin as a function of human development.

PMID- 10596732
TI  - A brief history of psychiatry: millennia past and present. Part IV.
AB  - Biological scientists have been trying to look inside the black box of the brain
      since the middle of the nineteenth century. Techniques in many disciplines were
      being developed in the last century that would lead beyond philosophical
      speculation about the mind/body relation and the meaning of insanity. Only in the
      last several years have molecular biology and the beginnings of understanding of
      its relation to mind, body, behavior, and the human environment made it possible
      to start to find solutions to some of the problems. Neurobiology, psychology, and
      sociology now seem much more closely related, albeit in enormously complex ways.

PMID- 10596733
TI  - Prevalence of axis II comorbidity in bipolar patients with and without alcohol
      use disorders.
AB  - OBJECTIVE: This study sought to determine the prevalence of comorbid personality
      disorder in euthymic bipolar I patients. METHOD: Sixty-one outpatients were
      assessed using the Structured Clinical Interview for DSM-III-R Personality
      Disorders (SCID II) and/or the Personality Diagnostic Questionnaire-Revised (PDQ
      R). RESULTS: Thirty-eight percent of bipolar patients met criteria for an Axis II
      diagnosis based on the SCID II. Bipolar subjects with a history of comorbid
      alcohol use disorder were significantly more likely to have a SCID II diagnosis
      (52%) compared to those bipolar subjects without an alcohol use disorder history
      (24%). Cluster A diagnoses were significantly more common in the bipolar/alcohol
      use disorder group. The PDQ-R consistently overdiagnosed Axis II disorders,
      finding 62% of the overall bipolar group to have an Axis II diagnosis.
      CONCLUSIONS: Euthymic bipolar patients may have an increased rate of personality
      disorders, but much less so than previously reported in studies that did not take
      into account (1) current mood state, (2) comorbidity for an alcohol use disorder,
      and (3) instrument used for assessment of Axis II psychopathology.

PMID- 10596734
TI  - Six-month clinical status as a predictor of 24-month clinical outcome in first
      admission patients with schizophrenia.
AB  - The aim of this study was to determine whether clinical status at 6-month follow
      up is a predictor of 2-year clinical status in first-admission schizophrenic
      patients. If short-term status is indeed a strong predictor of subsequent
      functioning, the relationship would support earlier initiation of aggressive
      interventions. An epidemiologically based sample of 162 first-admission
      schizophrenic patients was examined at index hospitalization and at 6- and 24
      month follow-up, using a variety of diagnostic and clinical assessment
      instruments. Respondents were divided into three groups based on their 6-month
      clinical status: delusions or hallucinations present at 6-month follow-up with or
      without negative symptoms (n = 63); moderate to high levels of negative symptoms
      (but not positive symptoms) present (n = 42); neither positive nor negative
      symptoms present (n = 57). Differences in 24-month clinical functioning were
      evaluated (GAF scores, BPRS factors, role functioning, number of
      rehospitalizations, and illness course). No significant differences were found
      among the three groups on demographic characteristics, substance abuse history,
      or extent of treatment during the follow-up. At 24-month follow-up, respondents
      with positive psychotic symptoms at 6-month follow-up had the worst, and those
      with no positive or negative symptoms the best functioning, with the negative
      symptom group intermediate on most indices. Thus, among schizophrenic patients,
      poor 6-month clinical status identified a patient subgroup at high risk for
      continued poor clinical status at 24 months, suggesting the need for earlier
      intensive intervention in an attempt to prevent this progression.

PMID- 10596735
TI  - Sexual dysfunction associated with the treatment of depression: a placebo
      controlled comparison of bupropion sustained release and sertraline treatment.
AB  - This study compared the sexual functioning effects as well as the safety and
      efficacy of bupropion sustained release (bupropion SR) and sertraline. Three
      hundred sixty-four patients with normal sexual functioning and recurrent major
      depression were treated with bupropion SR (150-400 mg/day), sertraline (50-200
      mg/day), or placebo for 8 weeks in this randomized, double-blind, multicenter
      study. Patients' depression, sexual functioning, and overall safety were assessed
      at regular clinic visits. Significantly (P < 0.05) more patients treated with
      sertraline experienced orgasm dysfunction compared with patients treated with
      bupropion SR or placebo. Bupropion SR, but not sertraline, was statistically
      significantly superior to placebo in improving scores on all depression scales by
      the end of the study. Headache occurred with similar frequency in all groups.
      Gastrointestinal disturbances occurred more frequently with sertraline; insomnia
      and agitation occurred more frequently with bupropion SR. Small decreases in mean
      weight were seen with both active treatments; the placebo group experienced a
      minor increase in mean weight. Both bupropion SR and sertraline were generally
      well tolerated, although sertraline was more often associated with sexual
      dysfunction. Bupropion SR, but not sertraline, was statistically superior to
      placebo in relieving depression by the end of the study. Bupropion SR may offer
      advantages over sertraline in treating depressed patients concerned with sexual
      functioning.

PMID- 10596736
TI  - Gabapentin as an adjunct to standard mood stabilizers in outpatients with mixed
      bipolar symptomatology.
AB  - Gabapentin is a new adjunctive medication to antiseizure therapies. Anecdotal
      evidence suggests that it may also help to alleviate mood symptoms in patients
      with bipolar illness. An open-label study examined the effects of adjunctive
      gabapentin in bipolar patients with mixed symptoms who had previously
      demonstrated only partial treatment responses. Mood ratings and side-effect
      profiles were followed weekly in 10 patients for 1 month. Decreases in Hamilton
      depression (P < 0.05) and Bech mania ratings (P < 0.01) were evident in the first
      week of treatment and were sustained. Potent early improvements were noted in
      early, middle, and late insomnia. The results suggest that gabapentin may be of
      benefit to bipolar patients who only partially respond to other mood stabilizers.
      A favorable side-effect profile and rapid action make this drug an attractive
      choice as an adjunctive therapy.

PMID- 10596737
TI  - Anabolic androgenic steroids and suicide.
AB  - Eight medicolegally examined cases of suicide, in 21- to 33-year-old males, with
      a history of current or discontinued use of anabolic androgenic steroids (AAS)
      are described, five of which were approached by means of systematic interviews
      with survivors. Five suicides were committed during current use of AAS, and two
      following 2 and 6 months of AAS withdrawal. In one case it was unclear whether
      the suicide was committed during current use or after recent discontinuation. In
      five cases family members had noted depressive symptoms associated with AAS
      withdrawal. After prolonged use, four persons had developed depressive syndromes.
      Two subjects exhibited hypomania-like symptoms during the time immediately
      preceding the suicide. Four subjects had recently committed acts of violence
      while using AAS. In some cases these acts exacerbated the subjects' problems in
      personal relationships or at work, which in turn seem to have precipitated the
      suicides. Only one of them had experienced suicidal ideation before starting to
      use AAS. In all cases examined by psychological autopsy, risk factors of
      suicidality likely to be independent of the use of AAS were present. In
      conclusion, this study presents data suggesting that psychiatric symptoms and
      conflicts resulting from long-term use of AAS may contribute to completed suicide
      in certain predisposed individuals.

PMID- 10596738
TI  - Management of child and adolescent stuttering with olanzapine: three case
      reports.
AB  - Vast arrays of medications have been used, with limited success, to manage
      stuttering. Haloperidol and risperidone are the only two medications that have
      shown efficacy via double-blind studies in controlling stuttering symptoms. We
      present the first case reports of olanzapine in the management of stuttering.
      Three case histories are presented: a 10-year-old boy, a 16-year-old male
      adolescent with developmental stuttering, and a 9-year-old boy with medication
      induced stuttering whose symptoms are successfully controlled with olanzapine.
      These case studies suggest that olanzapine may be a pharmacologic option in the
      management of stuttering.

PMID- 10596739
TI  - Effects of antidepressants during pregnancy and lactation.
AB  - Depression is one of the most common psychiatric disorders. A variety of
      different chemical structures have been found to have antidepressant activity.
      The number is constantly growing; however, as yet, no one group has been found to
      have a clear therapeutic advantage over the others. The major indication for
      antidepressant drugs is depression, but a number of side effects have been
      established by clinical experience and controlled trials. It is clear that, to
      some extent, any drug or chemical substance administered to the mother is able to
      cross the placenta unless it is destroyed or altered during metabolism. Placental
      transport of maternal substrates to the fetus and of substances from the fetus to
      the mother is established at about the fifth week of fetal life. Traditionally,
      teratogenic effects of antidepressants or other drugs have been noted as anatomic
      malformation. It is clear that these are dose- and time-related and that the
      fetus is at great risk during the first 3 months of gestation. However, it is
      possible for antidepressants to exert their effects on the fetus at other times
      during pregnancy as well as to infants during lactation. Administration of
      antidepressants to pregnant women presents a unique problem for the physician.
      Not only must maternal pharmacologic mechanisms be taken into consideration when
      prescribing an antidepressant drug, but the fetus must also be regarded as a
      potential recipient of the drug. Certain results are evident with regard to drugs
      administered during lactation. It is essential that physicians need to be aware
      of the results of animal studies in this area and of the potential risk of
      maternal drug ingestion to the suckling infant.

PMID- 10596740
TI  - Tardive dyskinesia: review of treatments past, present, and future.
AB  - The aim of this article is to review the theories purported to explain the
      pathophysiology of tardive dyskinesia (TD) and the various agents investigated
      for its treatment. The methods used included a review of studies in English, a
      Medline search, as well as a check of references listed at the end of the
      articles was conducted to obtain the relevant studies for review. The results
      show that vitamin E appears to be a promising agent both for the treatment and
      prophylaxis of TD. Complete remission has been reported with clozapine, but there
      is a need for further studies. There are cases reported of benefits with numerous
      miscellaneous agents, including electroconvulsive therapy, but there are no well
      designed, substantiating studies. We conclude that there is no universally
      effective treatment for TD. Vitamin E is promising both for the treatment and
      possibly prophylaxis of TD. Clozapine therapy should be considered in patients
      refractory to traditional antipsychotics who develop TD. Judicious use of
      antipsychotics and periodic monitoring remain the cornerstone of therapy. None of
      the atypical antipsychotics (risperidone, olanzapine, clozapine, quetiapine) have
      been used long enough or adequately studied for their effects on TD.

PMID- 10596741
TI  - Pathophysiology and management of insomnia during depression.
AB  - Depressed patients often report problems sleeping, and epidemiologic evidence
      suggests that insomnia may precede the onset of depression. Insomnia is
      associated with marked impairment in quality of life and ability to function
      effectively. Many studies have indicated that patients with chronic sleep
      problems have impaired mood and that effective management of insomnia in
      depressed patients can markedly improve their depression. Diagnosis of insomnia
      is challenging because there can be many different causes and the clinical
      picture can be blurred by the presence of other psychiatric illnesses.
      Pharmacotherapy provides reliable and rapid relief from insomnia, whereas
      behavioral therapies help produce long-term improvement. For many years,
      benzodiazepines have been the mainstay of drug treatment for insomnia. However,
      these drugs have significant side effects, and tolerance and dependence have
      discouraged use. Many doctors use sedating antidepressants in low doses to treat
      chronic insomnia. However, there is little evidence supporting the efficacy of
      these agents, and many have adverse side effects, including impairment of sleep.
      The newer selective hypnotic drugs, including the imidazopyridines, may offer
      patients a better short-term alternative to benzodiazepines or sedating
      antidepressants.

PMID- 10596742
TI  - An embargoed Cuban science.

PMID- 10596743
TI  - Biotecnologia Habana '98: Latin America in the Collimator.

PMID- 10596744
TI  - Increasing public involvement in enriching our fish stocks through genetic
      enhancement.
AB  - A total of 70%, of the world's conventional commercial fish species are now fully
      exploited, overexploited, depleted or recovering from depletion. This dramatic
      crash in the capture world fisheries production has led to problems in foods
      distribution, balance of payments, employment, and ecological depletion. Public
      support for breeding programs with terrestrial farm animals and plants in
      agriculture have revolutionized this industry over the past few hundred years.
      However, new genetic rearing technologies to improve marine animal production
      through aquaculture that utilize modern biology to obtain sustainable aquaculture
      and preserve biodiversity provide a promise to address these problems. However
      aquaculture has not been subject to public discussion and approval. Public
      involvement, not necessarily acquiescence, provide value added in the decision
      making process. Public understanding and involvement involves three stages. (i)
      Public concern over the pool of genetic information; (ii) if aquaculture is to
      respond to the fisheries crises with innovation, the knowledge gap between public
      understanding and scientific information must be bridged; and (iii) strategies
      must be developed for achieving this. Release of recombinant DNA to the
      environment, and handling exotic species, are useful case studies. Illustrations
      will be given of communication bridges to the public and ways to involve the
      public in making policy decisions.

PMID- 10596745
TI  - Growth regulation and enhancement in tilapia: basic research findings and their
      applications.
AB  - Growth manipulation in fish is one of the targets of gene transfer experiments.
      The aim is to produce strains with improved growth performance. The transfer of
      growth hormone transgenes has been successful in many fish species. Now detailed
      knowledge of the molecular events that control growth in fish is necessary in
      order to efficiently manipulate this process. We have selected tilapia for our
      studies because these species are suitable for basic research as well as for the
      development of improved strains for aquaculture. Here we review the results of
      basic and applied research in the field of growth control and manipulation in
      tilapia. Our experiments produced new scientific results on growth control in
      tilapia. These results were used to develop a new aquacultured line with improved
      growth performance. Many of these results are probably applicable to other
      teleosts.

PMID- 10596746
TI  - Transfer of growth hormone (GH) transgenes into Arctic charr. (Salvelinus alpinus
      L.) I. Growth response to various GH constructs.
AB  - Four constructs containing salmonid growth hormone (GH) genes were transferred to
      Arctic charr (Salvelinus alpinus L.). Cytomegalovirus (CMV) and piscine
      metallothionein B (OnMT) and histone 3 (OnH3) promoters connected to sockeye
      salmon growth hormone 1 gene (OnGH1) were used for ectopic expression, and
      Atlantic salmon growth hormone 2 gene with 5'flanking region (SsGH2) was tested
      for pituitary-specific expression. Charr carrying the OnGH1 constructs showed a
      dramatic increase in growth rate. The 10-month old transformed fish were 14-fold
      heavier than control siblings. The ability of the CMVGH1 construct to promote
      growth was greater than that obtained in fish with piscine promoters. Analysis of
      individual growth curves of charr carrying the OnH3GH1 transgene indicated a
      stable ratio of specific growth rates in transformed and control fish regardless
      of fish size. No alteration in growth performance was found in fish carrying the
      SsGH2 transgene. There was evidence that the transformed rainbow trout
      (Oncorhynchus mykiss) were unable to produce SsGH2 mRNA in their pituitary
      glands. The presence of the transgene in various tissues was examined in trout to
      evaluate the reliability of one-tissue sampling.

PMID- 10596747
TI  - Transfer of growth hormone (GH) transgenes into Arctic charr. (Salvelinus alpinus
      L.) II. Nutrient partitioning in rapidly growing fish.
AB  - To examine whether the utilization of protein and lipids is altered in the
      genetically modified, rapidly growing charr, we compared CMVOnGH1 transgenic and
      sibling fish. Muscle composition and rates of gas exchange were analyzed. Plasma
      metabolites were determined in the recently fed and post-absorptive state. No
      difference was found in muscle composition. At equal rates of protein accretion,
      the rate of NH4 excretion was 43% greater in sibling charr. The lower molar ratio
      of NH4 to O2 exchange implied the reduced expenditure of metabolized protein in
      transgenic charr. Plasma NH4 concentration in transgenic fish did not differ from
      that in sibling charr whereas the greater level of total CO2 indicated enhanced
      oxidation of non-protein nutrients. Decreased plasma triglycerides concentration
      and lower triglyceride to cholesterol ratio showed faster utilization of ingested
      lipids in transgenic charr, especially of energy-containing fraction. However,
      this was not accompanied with a reduced lipid content or altered fatty acid
      composition of muscle triglycerides or phospholipids. Comparative studies
      suggested that the transgenic charr had acquired features of domesticated
      salmonid fish. Their increased metabolic rate and enhanced utilization of dietary
      lipids, especially triglycerides, resembled the characteristics of domestic
      rainbow trout rather than wild counterparts.

PMID- 10596748
TI  - Growth hormone effects on essential amino acid absorption, muscle amino acid
      profile, N-retention and nutritional requirements of striped bass hybrids.
AB  - Improvements in modern commercial aquaculture are linked to the utilization of
      biotechnological methods and processes. The most visible approach has been the
      use of growth hormone (GH) and/or insulin-like growth factor I and II (IGF-I and
      II), to accelerate the growth of fish. Previously we have reported that the
      injection of bovine GH, (bGH) in striped bass hybrids increased the specific
      growth rate and food conversion efficiency without significant alteration of food
      consumption rate. In this paper we present the results of experiments in which
      growth, food consumption, conversion efficiency, ammonia excretion, and amino
      acid absorption were monitored for individual fish after bGH injection. The
      specific growth rate was stimulated by 50% without significant change in relative
      food consumption rate. Food conversion efficiency increased by 51%. Intestinal L
      leucine absorption was increased by 25-40% at various concentrations tested. The
      relative N-retention was stimulated by 20% when computed raw. When a correction
      factor derived from the elevated amino acid absorption was introduced into the
      computations. the calculated relative N-retention was increased by 56%. Muscle
      amino acid profile was appreciably altered. We conclude GH supplementation or
      over-expression in aquaculture profoundly alters the physiological and
      nutritional conditions of fish. Nutritional profiles of fish food must be altered
      relative to these physiological changes in order to maximize growth.

PMID- 10596749
TI  - Gene transfer for targeted modification of salmonid fish metabolism.
AB  - The reviewed studies addressed the possibility of using gene transfer for
      correction of L-ascorbic acid biosynthesis and carbohydrate utilization in
      rainbow trout. Analyses of enzymatic activities in the L-AAB pathway indicated
      that reasons for the lack of L-AA production can be common in fish and scurvy
      prone animals. Rat gulonolactone oxidase cDNA was transferred into trout.
      Regardless of the fact that rGLO transcription occurred in embryos, neither GLO
      protein, nor enzyme activity were detected. There was no production of L-AA in
      transgenic fish raised on vitamin C-free diets or injected with L-gulonolactone.
      These results indicated that the conditions required for translation or stability
      of rGLO were not present in trout tissues. To augment carbohydrates utilization,
      human glucose transporter 1 and rat hexokinase II cDNAs were tested. In the
      transfected embryos. HK activity, rates of hexose uptake and glucose oxidation
      were increased. The effect of hGLUT1 on glucose metabolism was greater than that
      of rHKII. Trout carrying hGLUT1 and rHKII with viral or piscine promoters were
      created. Though interpretation of the metabolic effects of the transgenes was
      complicated with mosaicism, a tendency to improved carbohydrate utilization was
      revealed in some of the transgenic individuals.

PMID- 10596750
TI  - Evaluation of eukaryotic promoters for the construction of DNA vaccines for
      aquaculture.
AB  - We evaluated fish promoters as an alternative to viral promoters in the
      construction of DNA vaccines for aquaculture. A carp beta-actin promoter drove
      expression of the luciferase gene in live fish tissue to levels comparable to the
      CMVtk promoter.

PMID- 10596751
TI  - Towards obtaining ES cells in the marine fish species Sparus aurata; multipassage
      maintenance, characterization and transfection.
AB  - Animal Embryonic-Stem (ES) cells represents a unique tool in animal genetic
      manipulation. Though putative ES cells from several species have been reported,
      only those from mice proved successful. In this work, a long-term embryonic cell
      culture, derived from the commercial fish (Sparus aurata), is reported. These
      cells have been in vitro characterized for totipotency and transfected with a GFP
      plasmid.

PMID- 10596752
TI  - Immunological control of ectoparasites: past achievements and future research
      priorities.
AB  - Recombinant vaccines are available for the control of the tick Boophilus
      microplus, while progress has been made in the development of vaccines against
      Lucilia cuprina and Chrysomya bezziana. Literature suggests that the control of
      other ectoparasites is feasible, either through the duplication in a vaccine of
      naturally acquired immunity or through 'concealed' antigen vaccines. Major
      deficiencies in our current knowledge however point to possible research
      opportunities for the future. The identification of protective antigens from all
      species is proceeding slowly, particularly for the antigens of naturally acquired
      immunity. Our capacity to produce effective recombinant antigens has progressed
      greatly, though there remains a major difficulty where some or all of the
      protective effect is due to immunogenic oligosaccharide. Our understanding of
      protective mechanisms is limited. The delivery of the appropriate immunological
      response remains difficult. Nevertheless, some of the most critical areas of
      ignorance are in basic biological issues: factors which affect the susceptibility
      of particular pest species to immunological attack and the implications of
      vaccine-induced effects for pest and disease control under field conditions.
      Increasingly too, effective pest control is likely to demand the integration of a
      variety of control technologies. The study of this integration is in its infancy.

PMID- 10596753
TI  - Evidence and mechanisms of immunosuppression in tick infestations.
AB  - The abundance and ubiquity of ticks from ancient times long ago suggested that
      they have eluded host immunity. In the last 15 years, several authors have
      demonstrated suppression of the Th1 responses (cell-mediated immunity), and
      sometimes the Th2 responses (humoral immunity), subsequent to tick infestations
      in laboratory and natural models. Although the mechanisms to produce suppression
      are not well-defined yet, evidences for antigenic competition, lymphocyte
      cytotoxicity, presence of immuno-inhibiting substances in the saliva, and
      existence of modulators of cytokines in salivary extracts have been reported.
      Management of tick-induced immunosuppression is essential to replace tick control
      by acaricide application with more environmentally sound vaccination.

PMID- 10596754
TI  - Vaccination against ticks (Boophilus spp.): the experience with the Bm86-based
      vaccine Gavac.
AB  - The control of tick infestations and the transmission of tick-borne diseases
      remain a challenge for the cattle industry in tropical and subtropical areas of
      the world. Traditional control methods have been only partially successful and
      the parasites continue to result in significant losses for the cattle industry.
      Recently, vaccines containing the recombinant B. microplus gut antigen Bm86 have
      been developed. Our vaccine formulation (Gavac, Heber Biotec S.A., Havana, Cuba)
      has been registered and is commercially available in Cuba, Colombia, Dominican
      Republic, Brazil and Mexico. In controlled pen trials, Gavac has been effective
      for the control of artificial infestations of B. annulatus, B. decoloratus and
      chemical-sensitive and resistant B. microplus strains from Australia, Africa,
      America and Iran. In controlled field trials in Cuba, Brazil, Argentina and
      Mexico, Gavac has shown a 55-100% efficacy in the control of B. microplus
      infestations in grazing cattle 12-36 weeks after the first vaccination. Field
      trials under production conditions have been conducted in Cuba, Colombia, Brazil
      and Mexico in pure and cross-bred cattle herds. The application of Gavac has
      increased the time between acaricide treatments by an average of 32 /-21 days (P
      = 0.0005) resulting in important savings for the cattle industry. In Cuba, a cost
      effectiveness analysis was conducted in more than 260000 animals. The cost
      effectiveness analysis showed a 60% reduction in the number of acaricide
      treatments, together with the control of tick infestations and transmission of
      babesiosis, which resulted in savings of 23.4 dollars animal(-1) year (-1). These
      results clearly demonstrate the advantage of vaccination and support the
      application of Gavac for the control of Boophilus spp. infestations.

PMID- 10596755
TI  - The multi-epitope polypeptide approach in HIV-1 vaccine development.
AB  - The application of a preventive HIV vaccine is the only hope for most developing
      countries to halt the AIDS pandemic. A project aimed to develop a preventive AIDS
      vaccine is being carried out since 1992 by three Cuban research institutions:
      Centro de Ingenieria Genetica y Biotecnologia de La Habana, Instituto de Medicina
      Tropical 'Pedro Kouri' and Laboratorio de Investigaciones de SIDA de La Habana.
      The project includes two main strategies: (a) generation of recombinant multi
      epitope polypeptides (MEPs) bearing several copies of the V3 loop from different
      HIV-1 isolates; and (b) development of immunogens capable of inducing a cytotoxic
      T cell response (CTL) specific for human immunodeficiency virus type 1 (HIV-1)
      antigens. This article summarizes the work in the first of these strategies.
      Based on the sequence of the V3 loop of HIV-1 we constructed a series of MEPs and
      evaluated their immunogenicity in mice, rabbits and macaques. The MEP TAB9,
      containing six V3 epitopes from isolates LR10, JY1, RF, MN, BRVA and IIIB, was
      selected together with the oil adjuvant Montanide ISA720 (SEPPIC, France) to
      perform a Phase I clinical trial in HIV seronegative Cuban volunteers. The trial
      was double blinded, randomized, and fulfilled all ethical and regulatory
      requirements. All TAB9 vaccinated volunteers developed a strong immune response
      and neutralizing antibodies were observed in the 50% of the subjects. However the
      second and third inoculations of the vaccine were not well tolerated because
      transient severe local reactions appeared in some individuals. A new formulation
      of TAB9 is currently in pre-clinical studies and is expected to enter clinical
      trials in 1999.

PMID- 10596756
TI  - Transgenic pigs as bioreactors: a comparison of gamma-carboxylation of glutamic
      acid in recombinant human protein C and factor IX by the mammary gland.
AB  - The mammary gland of transgenic livestock can be used as a bioreactor for
      producing complex therapeutic proteins. However, the capacity for making a given
      post-translational modification upon any given polypeptide is uncertain. For
      example, the efficiency of gamma-carboxylation of glutamic acid in the amino
      terminal regions of recombinant human protein C (rhPC) and recombinant human
      Factor IX (rhFIX) is different at similar expression levels. At an expression
      level of about 200 microg/ml in the milk of transgenic pigs, rhFIX is highly
      gamma-carboxylated as indicated by pro-coagulant activity and amino acid
      sequencing. However, only about 20-35% of rhPC has a native, gamma
      carboxyglutamic acid-dependent conformation and anti-coagulant activity. Thus,
      this work provides an example of apparent differences in substrate specificity
      between two homologous proteins to the endogenous carboxylase of porcine mammary
      epithelium which leads to varying degrees of post-translational modification.

PMID- 10596757
TI  - The optimal use of IRES (internal ribosome entry site) in expression vectors.
AB  - In higher eucaryotes, natural bicistronic mRNA have been rarely found so far. The
      second cistron of constructed bicistronic mRNAs is generally considered as not
      translated unless special sequences named internal ribosome entry site (IRES) are
      added between the two cistrons. These sequences are believed to recruit ribosomes
      independently of a cap structure. In the present report, a new IRES found in the
      HTLV-1 genome is described. A systematic study revealed that this IRES, but also
      the poliovirus (polio) and the encephalomyocarditis virus (EMCV) IRES work
      optimally when they are added about 100 nucleotides after the termination codon
      of the first cistron. Unexpectedly, these IRES became totally inefficient when
      added after 300-500 nucleotide spacers. This result and others are not compatible
      with the admitted mechanism of IRES action. The IRES appear to be rather potent
      translation stimulators. Their effects are particularly emphasized in cells in
      which the normal mechanism of translation initiation is inhibited. For these
      reasons, we suggest to call IRES rescue translation stimulators (RTS).

PMID- 10596758
TI  - Dolly, Polly and other 'ollys': likely impact of cloning technology on biomedical
      uses of livestock.
AB  - The idea of generating transgenic livestock which secrete into their milk large
      quantities of proteins for therapeutic use, was pioneered in the late 1980s with
      the disclosure of the production of a number of transgenic sheep. One particular
      animal, a sheep called Tracy, produced milk where over 50% of the protein
      consisted of human alpha 1 anti-trypsin. Sheep-derived protein has now entered
      clinical trials for cystic fibrosis (UK, USA) and congenital emphysema (UK).
      There are many other examples where this technology is making inroads into more
      traditional ways of making biopharmaceuticals. However, although robust, this
      technology has several limitations, including an inability to allow targeted
      insertion/modification of the animal genome, long timelines to production
      flocks/herds, and the rather unpredictable expression levels seen when different
      transgenic founders are compared. We believe that there is now a technical
      solution to all of these problems. Dolly is a high profile example of a new
      technology comprising the generation of identical animals from cultured somatic
      cells. This work has many implications. In the commercial context, the real
      benefits of this advance will be seen when genetically engineered somatic cells
      are shown to be suitable nuclear donors, and particularly when the manipulations
      are targeted to pre-determined sites in the host cell genome. The first objective
      has now been achieved with the birth of Polly, a cloned sheep which contains the
      human gene encoding Factor IX, a protein involved in preventing haemophilia.

PMID- 10596759
TI  - The use of yeast artificial chromosomes in transgenic animals: expression studies
      of the tyrosinase gene in transgenic mice.
AB  - Variegation and inherited somatic mosaicism has been observed in transgenic mice
      carrying yeast artificial chromosomes (YACs) in which a DNAse I hypersensitive
      site (HS) located -12 kb upstream of the mouse tyrosinase gene had been deleted.
      At present, we are generating new transgenic animals with minor deletions of the
      HS.

PMID- 10596760
TI  - Transgenic rabbits for the production of biologically-active recombinant proteins
      in the milk.
AB  - The use of live bioreactors for the expression of human genes in the mammary
      gland of transgenic animals is one of the most cost-effective ways for the
      production of valuable recombinant therapeutic proteins. Among the transgenic
      species used so far, rabbits are good candidates for the expression of tens to
      hundreds of grams of complex proteins in the milk during lactation. The lactating
      mammary gland of rabbits has proven to be effective in the processing of complex
      proteins. In this work. the potential use of rabbits as bioreactors is discussed
      based on our results and the published data.

PMID- 10596762
TI  - Optimal blood pressure: how low should we go?
AB  - The Joint National Committee on Prevention, Detection, Evaluation, and Treatment
      of High Blood Pressure defines hypertension as systolic blood pressure > or =140
      mm Hg or diastolic blood pressure (DBP) > or =90 mm Hg. Evidence shows that even
      slightly elevated blood pressure significantly increases the risk of morbidity
      and mortality and only aggressive efforts to reduce blood pressure can
      significantly reduce this risk. In the recently completed Hypertension Optimal
      Treatment trial, patients were assigned to one of three target blood pressure
      groups, reflecting DBP goals of < or =90, < or =85, and < or =80 mm Hg.
      Aggressive antihypertensive treatment allowed more than 90% of patients to
      achieve goal DBP of < or =90 mm Hg. This study clearly showed that these defined
      goals could be safely met and even exceeded. Too few patients with hypertension
      receive the level of effective treatment achieved in clinical trials. Individuals
      with poorly controlled blood pressure are at significant risk for cardiovascular
      and cerebrovascular morbidity and mortality and represent a potentially
      substantial burden to the healthcare system. Setting appropriate blood pressure
      goals and working to meet them through aggressive antihypertensive treatment,
      with multiple agents if necessary, can reduce those risks.

PMID- 10596761
TI  - From the molecular biology of prolactin and its receptor to the lessons learned
      from knockout mice models.
AB  - Prolactin (PRL), a polypeptide hormone secreted mainly by the pituitary and, to a
      lesser extent, by peripheral tissues, affects more physiological processes than
      all other pituitary hormones combined since it is involved in > 300 separate
      functions in vertebrates. Its main actions are related to lactation and
      reproduction. The initial step of PRL action is the binding to a specific
      membrane receptor, the PRLR, which belongs to the class 1 cytokine receptor
      superfamily. PRL-binding sites have been identified in a number of tissues and
      cell types in adult animals. Signal transduction by this receptor is mediated, at
      least in part, by two families of signaling molecules: Janus tyrosine kinases and
      signal transducers and activators of transcription (STATs). Disruption of the
      PRLR gene has provided a new mouse model with which to identify actions directly
      associated with PRL or any other PRLR ligands, such as placental lactogens. To
      date, several different phenotypes have been analyzed and are briefly described
      in this review. Coupled with the SAGE technique, this PRLR knockout model is
      being used to qualitatively and quantitatively evaluate the expression pattern of
      hepatic genes in two physiological situations: transcriptomes corresponding to
      livers from both wild type and PRLR KO mice are being compared, and following
      statistical analyses, candidate genes presenting a differential profile will be
      further characterized. Such a new approach will undoubtedly open future avenues
      of research for PRL targets. To date, no pathology linked to any mutation in the
      genes encoding PRL or its receptor have been identified. The development of
      genetic models provides new opportunities to understand how PRL can participate
      to the development of pathologies throughout life, as for example the initiation
      and progression of breast cancer.

PMID- 10596763
TI  - Treating multiple-risk hypertensive populations.
AB  - The majority of patients with hypertension have one or more additional risk
      factors for cardiovascular disease. In planning an appropriate treatment program,
      it is useful to identify and stratify hypertensive patients according to their
      risk of developing cardiovascular, cerebrovascular, or renal disease. At
      particular risk are the elderly, patients with diabetes, and those with target
      organ damage manifested by impaired renal function. Evidence supports increased
      risk in these patients, and clinical trial results demonstrate the considerable
      benefits realized through aggressive blood pressure (BP) control. The number of
      elderly individuals continues to increase in the United States and other
      industrialized countries. The prevalence of isolated systolic hypertension (ISH)
      is higher in the elderly than in younger individuals. ISH is associated with
      significant morbidity and mortality and should not be considered a physiologic
      manifestation of the normal aging process. Type 2 diabetes is also increasing in
      prevalence. Patients with diabetes are at increased risk for coronary heart
      disease, stroke, renal failure, and other cardiovascular complications.
      Aggressive treatment of elevated BP can produce dramatic decreases in the
      cardiovascular complications of diabetes. The incidence of end-stage renal
      disease has increased 2.5-fold in the past two decades, and poorly controlled BP
      is a major contributor to the increase. Lowering BP to levels well below the
      traditional goal of 140/90 mm Hg is needed to slow the progression of renal
      dysfunction and prevent renal failure in hypertensive patients with renal
      disease, whether related to diabetes or to another etiology. Aggressive treatment
      of hypertension in multiple-risk populations (to the goals of JNC VI and the
      recent WHO-ISH Guidelines for the Management of Hypertension) can be expected to
      produce significant reductions in the incidence and prevalence of stroke, heart
      failure, coronary heart disease, chronic renal failure, and total cardiovascular
      mortality.

PMID- 10596764
TI  - Current antihypertensive treatment: can we do better?
AB  - Results of various randomized, controlled clinical trials have shown that
      antihypertensive treatment is accompanied by reductions in morbidity and
      mortality caused by cardiovascular, cerebrovascular, and renal disease. Treatment
      confers a protective benefit against stroke, coronary artery disease, and heart
      failure, as well as against conditions previously considered unrelated to
      elevated blood pressure (eg, loss of cognitive function and dementia). Overall
      benefits of antihypertensive treatment are probably even greater than those shown
      in clinical trials. More rigorous blood pressure control in high-risk and
      multiple-risk patients provides even greater benefits. Because epidemiologic
      findings indicate that elevated systolic blood pressure (SBP) may be a greater
      risk factor for cardiovascular disease than elevated diastolic blood pressure
      (DBP), more attention should be paid to the control of SBP. Pulse pressure may be
      a better indicator of target-organ damage than either SBP or DBP, but further
      evaluation of its prognostic value is required. New monotherapies that can
      significantly reduce blood pressure, especially SBP, and confer protection on the
      target organs most affected by chronic hypertension may substantially add to
      current treatment.

PMID- 10596765
TI  - Emerging treatments for hypertension: potential role for vasopeptidase
      inhibition.
AB  - Hypertension remains uncontrolled worldwide despite the availability of several
      classes of antihypertensive agents. There is an increased risk of serious
      cardiovascular, cerebrovascular, and renal events if the disease goes untreated
      or is poorly treated. Thus, the high incidence of hypertension coupled with its
      poor control make it imperative that more effective and well-tolerated treatments
      that exhibit target-organ protection be developed. Vasopeptidase inhibitors are a
      new class of cardiovascular agents that simultaneously inhibit neutral
      endopeptidase and angiotensin converting enzyme. They enhance peptides with
      vasodilatory and possibly organ-protective properties and also inhibit the
      production of the vasoconstrictor angiotensin II. In preclinical studies,
      omapatrilat has shown blood pressure-lowering effects independent of renin status
      and has increased survival in an animal model of congestive heart failure. Human
      studies with omapatrilat, the most clinically advanced vasopeptidase inhibitor,
      administered orally once daily have demonstrated powerful dose-dependent
      reduction of systolic and diastolic blood pressures, regardless of age, race, or
      gender. Omapatrilat is particularly effective in lowering systolic blood
      pressure; this article summarizes data from recent clinical trials. This drug is
      well tolerated, with adverse effects comparable to those of currently available
      antihypertensive agents. Omapatrilat and other vasopeptidase inhibitors have
      potential applications in the treatment of hypertension, heart failure, and other
      cardiac and vascular disorders.

PMID- 10596766
TI  - Human error and crew resource management failures in Naval aviation mishaps: a
      review of U.S. Naval Safety Center data, 1990-96.
AB  - The present study examined the role of human error and crew-resource management
      (CRM) failures in U.S. Naval aviation mishaps. All tactical jet (TACAIR) and
      rotary wing Class A flight mishaps between fiscal years 1990-1996 were reviewed.
      Results indicated that over 75% of both TACAIR and rotary wing mishaps were
      attributable, at least in part, to some form of human error of which 70% were
      associated with aircrew human factors. Of these aircrew-related mishaps,
      approximately 56% involved at least one CRM failure. These percentages are very
      similar to those observed prior to the implementation of aircrew coordination
      training (ACT) in the fleet, suggesting that the initial benefits of the program
      have not persisted and that CRM failures continue to plague Naval aviation.
      Closer examination of these CRM-related mishaps suggest that the type of flight
      operations (preflight, routine, emergency) do play a role in the etiology of CRM
      failures. A larger percentage of CRM failures occurred during non-routine or
      extremis flight situations when TACAIR mishaps were considered. In contrast, a
      larger percentage of rotary wing CRM mishaps involved failures that occurred
      during routine flight operations. These findings illustrate the complex etiology
      of CRM failures within Naval aviation and support the need for ACT programs
      tailored to the unique problems faced by specific communities in the fleet.

PMID- 10596767
TI  - Effects of FOV and aircraft bank on pilot head movement and reversal errors
      during simulated flight.
AB  - BACKGROUND: Recent studies have shown that while flying under visual
      meteorological conditions (VMC) pilots tilt their head to keep the horizon
      stabilized on their fovea. This reflex, referred to as Opto-Kinetic Cervical
      Reflex (OKCR), may improve spatial awareness by establishing the horizon retinal
      image as a stabilized primary visual-spatial cue. Since the limited field of view
      (FOV) provided by helmet-mounted displays (HMDs) significantly decreases visual
      stimuli, the purpose of this research was to determine how reduced FOV affects
      head movements. HYPOTHESES: As FOV is decreased, there will be a significant
      reduction in OKCR-induced head movement. Reduced FOV will also increase control
      reversal errors. METHODS: Twelve pilots completed simulated flight tasks in a
      stationary dome. Head tilt, pitch, and yaw were examined as a function of
      aircraft bank and FOV (40 degrees, 60 degrees and 100 degrees circular). The
      number of control reversal errors was analyzed to investigate signs of spatial
      disorientation. RESULTS: During VMC manuevers pilots exhibited significant OKCR;
      however there were no significant differences among the three levels of FOV. FOV
      significantly affected head pitch movements under both VMC and instrument
      meteorological conditions (IMC). Pilots yawed their heads in the direction of
      aircraft bank under VMC. Pilots committed 22 reversal errors out of 72 trials
      (30.55%). The magnitude of the error was largest for the 40 degrees FOV
      condition. CONCLUSIONS: Pilots exhibit the OKCR under all tested levels of FOV
      and also make head yaw movements in order to keep the way point in sight during
      banking maneuvers. Pilots demonstrated stick reversal errors when transitioning
      from following a lead aircraft under both VMC and IMC conditions.

PMID- 10596768
TI  - Effect of time exposure to high altitude on zinc and copper concentrations in
      human plasma.
AB  - BACKGROUND: Research has focused mainly on the relationship of zinc and copper
      contents and physical stresses like running, cycling, etc. It has also been
      reported that other forms of stresses change the concentration of these trace
      elements in humans. However,there are no reports on the effects of high altitude
      induced hypoxic stress on the plasma levels of these metals. Since hypoxia is one
      of the important stresses, we considered it appropriate to observe the changes in
      the levels of zinc and copper concentrations and in certain related zinc and
      copper enzymes and hormones in the plasma of human volunteers on acute induction
      to high altitude. From these findings, we intended to ascertain whether
      supplementation of these trace elements would be required for optimal health
      under such conditions. HYPOTHESIS: On acute induction to hypoxia, contents of
      these trace elements may change as the requirements of stressed organs and tissue
      may increase. Hence, further supplementation may be beneficial under hypoxic
      stress for better adaptability. METHOD: Volunteers were divided into two groups:
      with and without zinc and copper salt supplementation. Blood samples were
      collected at sea level and on induction to acute hypoxia on days 3 and 10. Trace
      mineral contents and their related enzyme (alkaline phosphatase) and hormone
      (ceruloplasmin) levels were determined in plasma samples. RESULTS: Plasma zinc
      contents were significantly reduced upon induction to high altitude in the non
      supplemented group, but not in the zinc-supplemented group. Alkaline phosphatase
      activity increased significantly upon induction to the high altitude stress. The
      enzyme activity remained elevated up to day 10 of the stress. Plasma copper
      contents and ceruloplasmin activity did not change upon induction to high
      altitude. CONCLUSION: Under hypoxic stress, circulating levels of zinc and
      alkaline phosphatase in plasma changed appreciably as plasma zinc was transported
      into the organs and tissues. However, circulating levels of copper and
      ceruloplasmin in plasma did not change, indicating no extra supplementation of
      copper is required under hypoxic stress.

PMID- 10596769
TI  - Models of the apparent mass of the seated human body exposed to horizontal whole
      body vibration.
AB  - BACKGROUND: Many environments contain vibration with simultaneous vertical and
      horizontal components. Mathematical lumped parameter models of the mechanical
      impedance of the seated human body have previously been defined for exposure to
      vertical vibration. This paper proposes models for the response of the seated
      body when exposed to horizontal vibration. METHODS: Four target functions were
      derived from previously reported measurements of the apparent masses of seated
      subjects exposed to fore-and-aft and lateral vibration at both 0.5 and 1.0 ms(-2)
      r.m.s. Parameters were optimized for six different three degree-of-freedom models
      to fit the modulus of the model responses to the four target functions. RESULTS:
      The modulus and phase of the apparent masses optimized for all combinations of
      vibration magnitude and direction were close to the responses previously measured
      and reported in the literature. Fitted parameters for all models with elements in
      series showed at least one element with a parameter that tended to zero.
      CONCLUSIONS: Models with three parallel single degree-of-freedom systems with a
      rigid support generally gave the closest representation of the apparent mass of
      the seated body exposed to horizontal vibration. More experimental data on the
      effect of gender, posture and magnitude of vibration on the apparent masses of
      seated subjects would be useful to enable these models to be improved.

PMID- 10596770
TI  - Short-arm (1.9 m) +2.2 Gz acceleration: isotonic exercise load-O2 uptake
      relationship.
AB  - BACKGROUND: The deconditioning syndrome from prolonged bed rest (BR) or
      spaceflight includes decreases in maximal oxygen uptake (VO2max), muscular
      strength and endurance, and orthostatic tolerance. In addition to exercise
      training as a countermeasure, +Gz (head-to-foot) acceleration training on 1.8-2.0
      m centrifuges can ameliorate the orthostatic and acceleration intolerances
      induced by BR and immersion deconditioning. PURPOSE: Study A was designed to
      determine the magnitude and linearity of the heart rate (HR) response to human
      powered centrifuge (HPC) acceleration with supine exercise vs. passive (no
      exercise) acceleration. Study B was designed to test the hypothesis that moderate
      +Gz acceleration during exercise will not affect the respective normal linear
      relationships between exercise load and VO2max, HR, and pulmonary ventilation
      (VEBTPS). Study C: To determine if these physiological responses from the HPC
      runs (exercise + on-platform acceleration) will be similar to those from the
      exercise + off-platform acceleration responses. METHODS: In Study A, four men and
      two women (31-62 yr) were tested supine during exercise + acceleration and only
      passive acceleration at 100% [maximal acceleration (rpm) = Amax] and at 25%, 50%,
      and 75% of Amax. In Studies B and C, seven men (33+/-SD 7 yr) exercised supine on
      the HPC that has two opposing on-platform exercise stations. A VO2max test and
      submaximal exercise runs occurred under three conditions: (EX) exercise (on
      platform cycle at 42%, 61%, 89% and 100% VO2max) with no acceleration; (HPC)
      exercise + acceleration via the chain drive at 25%,50%, and 100% Gzmax (35%, 72%
      and 100% VO2max); and (EXA) exercise (on-platform cycle at 42%, 61%, 89%, and
      100% VO2max) with acceleration performed via the off-platform cycle operator at
      +2.2+/-0.2 Gz [50% of max (rpm) G]. RESULTS: Study A: Mean (+/-SE) Amax was
      43.7+/-1.3 rpm (mean = +3.9+/-0.2, range = 3.3 to 4.9 Gz). Amax run time for
      exercise +acceleration was 50-70 s, and 40-70 s for passive acceleration.
      Regression of X HR on Gz levels indicated explained variances (r2) of 0.88
      (exercise) and 0.96 (passive). The mean exercise HR of 107+/-4 (25%), to 189+/-13
      (100%) bpm were 43-50 bpm higher (p < 0.05) than comparable passive HR of 64+/-2
      to 142+/-22 bpm, respectively. Study B: There were no significant differences in
      VO2, HR or VEBTPS at the submaximal or maximal levels between the EX and EXA
      runs. Mean (+/-SE) VO2max for EX was 2.86+/-0.12 L x min(-1)(35+/-2 ml x min(-1)
      x kg(-1)) and for EXA was 3.09+/-0.14 L x min(-1) (37+/-2 ml-min(-1) x kg(-1)).
      Study C: There were no significant differences in the essentially linear
      relationships between the HPC and EXA data for VO2 (p = 0.45), HR (p < 0.08),
      VEBTPS (p = 0.28), or the RE (p = 0.15) when the exercise load was % VO2max.
      CONCLUSION: Addition of + 2.2 Gz acceleration does not significantly influence
      levels of oxygen uptake, heart rate, or pulmonary ventilation during submaximal
      or maximal cycle ergometer leg exercise on a short-arm centrifuge.

PMID- 10596771
TI  - MRI cervical spine findings in asymptomatic fighter pilots.
AB  - MRI of the cervical spine for evaluation concerning degenerative lesions was
      performed on asymptomatic experienced military high performance aircraft pilots
      (mean age 42 yr with mean accumulated flying time of 2600 h), and for comparison
      on age-matched controls without military flying experience. Young military high
      performance aircraft pilots (mean age 23 yr with 220 h of flying per person) were
      also examined. There were significantly more osteophytes, disk protrusions,
      compressions of the spinal cord and foraminal stenoses in the experienced pilots
      than in the age-matched controls. Low frequency of low grade degenerative lesions
      was found in the young and inexperienced pilots.

PMID- 10596772
TI  - Slow deep breathing prevents the development of tachygastria and symptoms of
      motion sickness.
AB  - BACKGROUND: The purpose of this study was to see if slow deep breathing, a non
      pharmacological procedure known to increase parasympathetic nervous system (PNS)
      activity, would prevent the development of gastric dysrhythmias and symptoms of
      motion sickness when subjects were exposed to a rotating optokinetic drum.
      METHODS: Participating in this study were 46 healthy males and females aged 17-26
      who were pre-tested in the rotating drum and found to be susceptible to motion
      sickness. They were randomly placed into one of the following three conditions:
      Slow Deep Breathing (n = 18), Counting Breaths (subjects were asked to count
      their breaths and asked for the count every 3 min, n = 16), and Control (subjects
      breathed normally, n = 12). Electrogastrograms were recorded from all subjects
      during a 6-min baseline and a 16-min rotation period. Subjects were asked about
      their symptoms every 3 min. RESULTS: A significant difference in percent
      tachygastria from baseline to rotation was found between the three conditions.
      Percent tachygastria increased during rotation for the Counting Breaths group and
      the Control group, but remained the same as baseline for the Slow Deep Breathing
      group. The Slow Deep Breathing group (5.3) reported significantly fewer symptoms
      than the Counting Breaths group (9.0), but not the Control group (7.8).
      CONCLUSION: In conclusion, slow deep breathing in a situation previously
      demonstrated to provoke tachygastria prevented the development of gastric
      dysrhythmias and decreased symptoms of motion sickness.

PMID- 10596773
TI  - Do standard monitoring sites affect true brain temperature when hyperthermia is
      rapidly induced and reversed.
AB  - BACKGROUND: Accurate measurements of brain and core temperatures during warming
      and cooling of the whole organism, accidentally or therapeutically, are important
      for studies of thermoregulation and cerebral insults and resuscitation.
      HYPOTHESIS: During steady states and normal circulation, temperatures in the
      brain, nasopharynx, esophagus and rectum (the latter are core temperatures)
      equilibrate quickly; and that during rapid cooling or warming, slight temperature
      gradients occur, with esophageal core temperature reflecting brain temperature
      better than rectal temperature. METHODS: We evaluated 5 mongrel dogs and 12
      pigtail monkeys. The animals were exposed to total body hyperthermia by immersion
      into water at 45 degrees C to achieve cerebral temperature 42 degrees C which was
      maintained until cardiac arrest. In monkeys, at cardiac arrest, surface cooling
      and cardiopulmonary resuscitation were attempted for up to 30 min to determine
      resuscitability at 38.5 degrees C. Continuously monitored were brain (epidural)
      (Tep), esophageal (Tes), rectal (Tre) and nasopharyngeal temperatures (Tnp). Also
      monitored were mean arterial pressure and intracranial pressure. RESULTS: At
      normothermia, in dogs and monkeys, Tep, Tre, Tes and Tnp correlated well. In the
      dogs, during heating, Tes, Tnp and Tre at first correlated well. Vigorous panting
      started as Tep reached 41 degrees C, which immediately lowered Tnp and Tep to
      increase less steeply than Tes and Tre. After about 40 min of panting, with
      cerebral perfusion pressure still normal, Tep decreased sharply and reached the
      levels of Tnp, while Tre remained high. In the monkeys during heating, Tep, Tes
      and Tre correlated well. When cerebral perfusion pressure decreased below 50
      mmHg, Tep declined significantly as compared with Tre, which continued to be high
      in severe arterial hypotension. Tes at that time achieved levels between Tep and
      Tre. During cooling in monkeys, the decline in Tre was slower as compared with
      the decline in Tes and Tep. CONCLUSIONS: In normal dogs and monkeys, rectal,
      esophageal and nasopharyngeal temperatures are almost identical with brain
      temperatures; but during rapid external warming or cooling, brain temperature is
      reflected in nasopharyngeal temperature, somewhat in higher esophageal
      temperature, but not in even higher rectal temperature. For clinical monitoring
      during temperature changes, one should use primarily esophageal temperature and,
      if feasible, brain (epidural) temperature as well.

PMID- 10596774
TI  - Repetitive high G exposure is associated with increased occurrence of cardiac
      valvular regurgitation.
AB  - BACKGROUND: Exposure to repeated high +Gz loads and the methods to prevent loss
      of consciousness cause unique stresses on the cardiovascular system. The purpose
      of this study was to determine if the +Gz environment is associated with an
      increased occurrence of valvular regurgitation in pilots of high performance
      aircraft. METHODS: There were 247 subjects who were divided into pilot (n = 46)
      and non-pilot (n = 201) groups. Pilots were defined as those individuals who had
      flown at least 1000 h in high performance aircraft. The echocardiographic data of
      these subjects were examined retrospectively. RESULTS: We found a statistically
      significant association between pulmonic insufficiency and exposure to high +Gz
      stress in pilots vs. non-pilots (chi2 = 13.09, p = 0.0002). In addition, there
      was a greater incidence of tricuspid regurgitation (chi2 = 4.97, p = 0.025) and
      concurrent pulmonic insufficiency and tricuspid regurgitation (chi2 = 14.1, p =
      0.0002) in the pilot group. CONCLUSIONS: There is a direct relationship between
      repetitive exposure to a +Gz environment and pulmonic insufficiency, tricuspid
      regurgitation, or concurrent pulmonic insufficiency and tricuspid regurgitation.
      This may be secondary to the transient increase in right ventricular pressure due
      to acceleration forces or straining maneuvers utilized to prevent or postpone +Gz
      induced loss of consciousness (G-LOC).

PMID- 10596775
TI  - Is the Gauer-Henry reflex important for immersion diuresis in men?
AB  - BACKGROUND: This study examines the relationship between the threshold for plasma
      vasopressin concentration [PVP] responses and diuresis (Gauer-Henry reflex), and
      tests the hypothesis that water intake would not influence diuresis. METHODS:
      Eight men (19-25 yr) underwent four treatments: euhydration in air (Eu-air),
      euhydration in water immersion (Eu-H2O), and with prior 3.6% hypohydration in air
      (Hypo-air), and hypohydration in immersion (Hypo-H2O). Ad libitum drinking was
      allowed during the 3-h experimental and 1-h recovery periods. RESULTS: Drinking
      was greatest during the first 10 min: 3.5 ml x kg(-1) with Hypo-air (450 ml x 3
      h(-1)) and only 1.7 ml x kg(-1) (p < 0.05) with Hypo-H2O (235 ml x 3 h(-1)). At 1
      h, concomitant [PVP] decreased from a control level of 6.6+/-1.5 to 4.0+/-1 .0 pg
      x ml(-1) (delta = 2.6 pg x ml(-1), p < 0.05) with Hypo-air, and from 5.9+/-0.6 to
      2.3+/-0.2 pg x ml(-1) (delta = 3.6 pg x ml(-1), p < 0.05) with Hypo-H2O. Urine
      flow was unchanged from control level (<1.0 ml x min(-1)) with Hypo-air, Hypo
      H2O, and Eu-air, but increased to 4-5 ml x min(-1) with Eu-H2O. Neither water
      intake volume nor urine flow was related to the magnitude of [PVP] depression.
      Regression of Uosm/Posm ratio on [PVP] and urine flow indicated that [PVP] above
      2 pg x ml(-1) did not affect urine flow. Thus, ad libitum water intake in
      previously hypohydrated subjects did not affect urine flow or the decrease in
      [PVP]. The threshold [PVP] to initiate significant diuresis was about 2 pg x ml(
      1), and significant diuresis can occur with no change in [PVP] maintained at
      about 1 pg x ml(-1) during immersion in euhydrated subjects. CONCLUSIONS: Thus,
      it appears that the Gauer-Henry reflex is not the major mechanism for immersion
      induced diuresis. Clearly, other diuretic factors are also involved.

PMID- 10596776
TI  - Finger cold-induced vasodilation during mild hypothermia, hyperthermia and at
      thermoneutrality.
AB  - BACKGROUND: Exposure of the fingers to severe cold leads to cold-induced
      vasodilation (CIVD). The influence of ambient temperature on the CIVD-response is
      well understood and documented, but the response of CIVD to hyperthermia and mild
      hypothermia has rarely been investigated. METHODS: To investigate the influence
      of body thermal status on the CIVD response, eight subjects immersed their right
      hand in 5 degrees C water for 40 min during mild hypothermia (C),
      thermoneutrality (N) and hyperthermia (W). The mean skin temperature of the body
      (Tsk), the esophageal temperature (Tes), the temperature of the volar side of the
      distal phalanx of each immersed finger (Tfi) and the skin perfusion of the
      immersed middle finger (Qsk) were continuously measured. RESULTS: During the W
      condition the body temperatures were higher (Tes: 38.0+/-0.1 degrees C; Tsk:
      37.9+/-0.7 degrees C) than during N (Tes: 36.8+/-0.2 degrees C; Tsk: 31.8+/-0.7
      degrees C) and during C (Tes: 36.1+/-0.8 degrees C; Tsk: 21.2+/-1.9 degrees C).
      Tfi and Qsk were higher during the W condition (Tfi: 16.5+/-2.3 degrees C; Qsk:
      133+/-53 perfusion units (PU)) than during N (Tfi: 8.1+/-1.7 degrees C; Qsk: 57+/
      39 PU) and during C (Tfi: 6.8+/-1.2 degrees C; Qsk: 22+/-14 PU). The onset time
      of CIVD was significantly prolonged in condition C (13.0+/-3.8 min) as compared
      with N (7.2+/-2.2 min). CONCLUSION: It was concluded that the CIVD response is
      significantly affected by body core and skin temperatures.

PMID- 10596777
TI  - Incidence of Epstein-Barr virus in astronaut saliva during spaceflight.
AB  - BACKGROUND: Astronauts experience psychological and physical stresses that may
      result in reactivation of latent viruses during space-flight, potentially
      increasing the risk of disease among crewmembers. HYPOTHESIS: The shedding of
      Epstein-Barr virus (EBV) in the saliva of astronauts will increase during
      spaceflight. METHODS: A total of 534 saliva specimens were collected from 11 EBV
      seropositive astronauts before, during, and after four space shuttle missions.
      The presence of EBV DNA in saliva, assessed by polymerase chain reaction (PCR),
      was used to determine shedding patterns before, during, and after space-flight.
      RESULTS: EBV DNA was detected more frequently before flight than during (p <
      0.001) or after (p < 0.01) flight. No significant difference between the inflight
      and postflight periods was detected in the frequency of occurrence of EBV DNA.
      CONCLUSIONS: The increased frequency of shedding of EBV before flight suggests
      that stress levels may be greater before launch than during or after spaceflight.

PMID- 10596778
TI  - A descriptive analysis of asthma in the U.S. Navy Submarine Force.
AB  - BACKGROUND: The U.S. Navy Submarine Force offers a unique opportunity to study
      asthma because of the relative socioeconomic and physical homogeneity of the
      population and the closed environment occupational exposure. Currently, asthma is
      disqualifying from submarine service, which results in a significant loss of
      experienced personnel. METHODS: We performed a retrospective analysis of 119 U.S.
      Navy submariner disqualification packages for asthma between 1989-1993. RESULTS:
      We found a 0.16% annual period prevalence of asthma in the active duty enlisted
      Atlantic Fleet Submarine Force. Two groups of asthma disqualifications were
      identified with a significant increase above their proportional representation in
      the fleet: enlisted personnel (p < 0.01) and submarine recruits (p < 0.0001). The
      proportion of African-American personnel also had a tendency toward increased
      asthma disqualification (p < 0.08). There were no differences in prevalence of
      asthma between crews of ballistic missile submarines or fast attack submarines.
      Asthma risk factors reported in the civilian literature (childhood history of
      asthma, family history of asthma and non-drug allergies) were highly represented
      in our study (41%, 46% and 68% of submariners, respectively). Most disqualified
      submariners had "mild" asthma based on the diagnostic work-up. The methacholine
      challenge test appeared to carry a disproportionate diagnostic weight despite its
      low specificity. CONCLUSION: Although the period prevalence of asthma is low in
      the U.S. Navy Submarine Force, submariners disqualified for asthma have similar
      historical and ethnic risk factors as the civilian population.

PMID- 10596779
TI  - Acquired left bundle branch block in an asymptomatic fighter pilot: a case
      report.
AB  - This report describes a case of acquired left bundle branch block (LBBB) in an
      asymptomatic F/A-18 fighter pilot of the Royal Australian Air Force. The
      previously fit and healthy pilot was found to have LBBB on routine
      electrocardiographic screening prior to his annual aircrew medical. He was
      completely asymptomatic, and the only potential etiological factor was a short
      lived acute gastrointestinal infectious illness some 4 mo previously. The pilot
      was extensively investigated with the full range of available diagnostic
      procedures, including coronary angiography and cardiac biopsy. No cause was
      determined for his LBBB pattern, and he was assessed as having normal
      cardiovascular function. The aeromedical disposition of this aviator and the
      issues involved in determining fitness to fly in such a case are discussed. The
      importance of thorough clinical investigation and appropriate follow-up are
      highlighted.

PMID- 10596780
TI  - Prevalence of the metabolic syndrome in military and civilian flying personnel.
AB  - BACKGROUND: The metabolic syndrome (MS) affects 20-30% of the middle-aged
      population in highly industrialized countries, consisting of a cluster of
      diseases including obesity, hypertension, dyslipoproteinemia and glucose
      intolerance. HYPOTHESIS: If the population of flying personnel (FP) faces a high
      risk to develop MS, due to the specific workload of specialized aircrew, the
      consequences for aeromedical screening are to be reconsidered. METHODS: Data of
      the complete military flying personnel (MFP) of Germany were screened to develop
      MS-related risk factors, regular physical activity and determination of nicotin
      and alcohol consumption. A comparable screening of a population of German
      civilian flying personnel (CFP) was undertaken by questionnaire. Statistics were
      completed by comparison of averages by t-test for independent random-samples of
      different variances and testing of independence of single characteristics by chi2
      test. RESULTS: Data of approximately 10,000 aircrew members were obtained. It was
      possible to determine a group of MFP with higher risk to develop MS later in
      life, called "possible future metabolics" (PFM). Comparison of PFM with the MFP
      control group (MCG) and CFP clearly showed that obesity, dyslipoproteinemia and
      hypertension are the main single and/or combined risk factors. As a new aspect,
      data of MFP showed possible connections between thyroideal dysfunction and the
      prevalence of relevant MS-risk factors. CONCLUSIONS: The purpose of this
      investigation was to determine the actual risk of MS in German FP and to confirm
      the current MS-related regular screening measures. This study revealed that
      German MFP and CFP show a high quality health status without significant
      differences between both groups. Continuing the current regular flight medical
      screening will prevent FP from losing its high quality health status.

PMID- 10596781
TI  - Intracranial pressure in microgravity conditions: non-invasive assessment by
      ophthalmodynamometry.
AB  - BACKGROUND: As well known from former manned spaceflight experiments (German D2
      Mission/German D1-Mission 1985/German-Russian MIR-Mission 1 992/German-D2-Mission
      1993), fluid shift after entry into microgravity leads to a rapid increase in
      pressure and volume within the upper compartments of the human body. This has
      been proven by precise measurements with automatic selftonometers for intraocular
      pressure. HYPOTHESIS: There is little doubt, that a very similar--even more,
      marked--increase of intracranial pressure happens soon after entry into
      microgravity. This may be the cause for some of the reported hormonal and even
      neurological changes in metabolism. There is no non-invasive method to assess
      these important increases in pressure. METHODS: Ophthalmodynamometry in general
      allows for rather precise estimation of intracranial BP, but so far the method
      was too complicated for routine application, specifically in spaceflight
      conditions. Therefore, using the microprocessor controlled technology of our
      automatic selftonometer we have designed a very precise automatic instrument
      which can be applied by the astronaut/kosmonaut. The measurement takes only a few
      seconds. CONCLUSIONS: This easily applied, non-invasive method would allow for
      completely new insights into these important changes and explain some of the
      clinical consequences noted so far.

PMID- 10596782
TI  - Ejection associated injuries within the German Air Force from 1981-1997.
AB  - From 1981-1997 there were 86 ejections from 56 aircraft within the German Air
      Force. Of these, 24 accidents were associated with the F-104 Starfighter, 14 with
      the PA 200 Tornado, 12 from the F-4 Phantom, 5 from the Alpha Jet and 1 from a
      MiG 29 Fulcrum. One case involved a front seat pilot, who had already sustained
      fatal injuries from midair collision, being command ejected by the rear seat
      pilot. The remaining 85 ejections are the basis of this study. One weapons system
      officer died from hypothermia after landing in the sea and another from bleeding
      into the medulla oblongata after flailing; all other participants survived. This
      is an overall success rate of 97.6%. Of all 85 participants, 12 (14%) were
      uninjured, 41 (48.2%) were slightly injured, and 30 (35.3%) were severely
      injured. Typical injuries were those of the spine and lower limbs. The most
      common severe injury was a vertebral fracture caused by ejection acceleration.
      This is followed by lower limb injuries received during the parachute landing
      fall. At the time of ejection, all uninjured crews were flying below 3500 ft
      altitude and below 260 kn airspeed. Of all ejections from each aircraft type, the
      percentage of vertebral fractures is highest with the F-4 Phantom (31.8%),
      followed by the F-104 (16.6%) and the PA 200 Tornado with only 14.8%. The PA 200
      is equipped with the most modern type of ejection seat of these aircraft. A
      conclusion of the gained data is that more modern ejection seat types provide
      lower injury severity but not fewer total injury numbers, and that the medical
      data taken during accident investigation should be taken more accurately and in a
      more standarized fashion to be comparable.

PMID- 10596783
TI  - Dystonia, botulinum neurotoxin, and the aviator.
AB  - Dystonia is both a symptom and the name for group of illnesses called the
      dystonias. The physical manifestation consists of sustained, involuntary
      contractions of the muscles in one or more parts of the body, resulting in
      twisting or distortion of that part of the body. For focal dystonias including
      torticollis, blepharospasm and spasmodic dysphonia, botulinum toxin injections
      have become the treatment of choice because of the ability of this toxin to
      sufficiently weaken the muscle to reduce the spasm but not so much as to cause
      paralysis. This paper involves the fate of four airmen all afflicted with a form
      of dystonia who had been reviewed in the Aeromedical Certification Division of
      the FAA Civil Aeromedical Institute.

PMID- 10596784
TI  - You're the flight surgeon. Paronychia.

PMID- 10596785
TI  - Activation of the cholinergic system of the striatum improves attention to
      conditioned reflex stimuli.
AB  - Chronic experiments were performed on 16 dogs using a model of an operant
      defensive reflex associated with maintenance of a flexion pose to study the
      effects of uni- and bilateral microinjections of the acetylcholine agonist
      carbacholine (0.05-0.4 microg) and the choline receptor blocker scopolamine (0.5
      microg) into the dorsolateral part of the head of the caudate nucleus and CM-Pf
      intralaminar thalamic nuclei. These experiments produced data showing that the
      cholinergic system of the striatum has an important role in realizing the sensory
      and motor components of the learned movement. Activation of the cholinergic
      system of the dorsal striatum led to general calming of behavior and inhibition
      of intersignal limb elevation and the phasic components of the movement, along
      with ordering and stabilizing of the pose and an increase in the tonic component
      of the operant response. This suggests that the cholinergic system of the
      striatum receives an indirect efferent output via motor structures and takes part
      in preparing the motor apparatus needed for transferring attention to significant
      stimuli. Microinjections of scopolamine had the opposite effects. Use of
      differential signals in the same behavioral model, along with special tests for
      attention, showed that the cholinergic system of the striatum plays an important
      role in the sensory control of attention. Activation of the striatal cholinergic
      system led to a significant improvement in responses to differential signals and
      defensive signals of intensity 2-3 times slower than normal signals, and these
      changes were accompanied by clearer responses in special tests for attention.
      Scopolamine microinjections had the opposite effects. Carbacholine
      microinjections into the intralaminar thalamic nuclei potentiated the effects of
      cholinergic activation of the striatum. These data indicate that the dorsal
      striatum can be regarded not only as a parallel level of information processing,
      but also as a control system for passing this information to various levels of
      both sensory and motor structures. One important result of this type of control
      may be that of improving attention to significant stimuli.

PMID- 10596786
TI  - Changes in the spike activity of neurons in the ventrolateral nucleus of the
      thalamus in humans during performance of a voluntary movement.
AB  - The responses of neurons in the ventrolateral nucleus (VL) of the thalamus were
      studied in humans during performance of voluntary motor tests; recordings were
      made with microelectrodes during stereotaxic operations in patients with
      Parkinson's disease. Two previously classified types of polyvalent neurons (A, B)
      were found to show different patterns of responses during the functional stages
      of carrying out a voluntary movement (preparation, initiation, performance). A
      and B neurons showed concordant changes in the dynamics of ongoing network
      activity in the form of linked (activation-inhibition) and synergic (activation)
      response patterns, correlating with the preparation-trigger and performance
      phases of movements. It is suggested that the simultaneous activity of both types
      of neuron, with their common functional nature, reflects integrative processes
      occurring in the ventrolateral nucleus and associated with programming and
      processing of general signal parameters but not with the performance of any
      particular movement. The anterior (Voa nucleus) and posterior (Vop) parts of the
      ventrolateral nucleus were found to have different roles in organizing voluntary
      movements, associated with differences in their cellular organization and
      mechanisms of transmitting motor signals. It is suggested that the concordant
      changes in the activities of the two types of neurons in these areas seen during
      the performance of voluntary movements gives the ventrolateral nucleus a key role
      in the motor control system in humans.

PMID- 10596787
TI  - The effects of high-frequency microstimulation of the cortex on interhemisphere
      synchronization in the rat motor cortex.
AB  - Studies were carried out on long-term changes in the synchronization of neuronal
      activity in networks including callosal cells of the opposite hemispheres evoked
      by high-frequency microstimulation in the motor cortex of anesthetized rats. The
      level of synchronization was assessed in terms of the amplitude and width of
      peaks located symmetrically on cross-correlograms relative to the coordinate
      origin. Tetanization predominantly decreased synchronization in a group of
      initially background-active neurons, while there was a significant number of
      synchronously firing neurons in a group of cells which became activated. "Super
      narrow" peaks appeared in interhemisphere interactions. There was a correlation
      between the type of modification of "narrow" (<20 msec) and "intermediate" (30-80
      msec) peaks and changes in the efficiencies of mono- and polysynaptic
      connections.

PMID- 10596788
TI  - The properties and possible mechanisms of interhemisphere synchronization in the
      motor cortex of the rat.
AB  - Cross-correlation analysis was used to observe interhemisphere synchronization of
      motor cortex neuron activity in anesthetized rats, which was seen on cross
      correlograms as peaks located symmetrically relative to the coordinate origin.
      Peaks included "narrow" peaks (less than 20 msec) and "intermediate" peaks (30-80
      msec). The results showed that the "common" source synchronizing the discharges
      of pairs of neurons located in different hemispheres of the brain might be a
      neuron (or group of neurons) located in one of the hemispheres and playing this
      role when there were reciprocal excitatory connections between it and each neuron
      in a pair. Comparison of the widths of symmetrical peaks with latent periods
      corresponding to transcallosal connections suggested that mono- and polysynaptic
      connections underlie the formation of "narrow" and "intermediate" peaks
      respectively.

PMID- 10596789
TI  - The motivational dominant in goal-directed behavior.
AB  - Results of experimental studies on discontinuation of the motivational dominants
      thirst and hunger and the "polarization" motor dominant, taken together with a
      theoretical analysis of the development of types I and II conditioned reflexes,
      lead to the conclusion that discontinuation of the motivational dominant plays a
      key role in organization goal-directed behavior. The activation of reciprocal
      connections between the appropriate centers provides a basis for the performance
      of goal-directed behavior.

PMID- 10596790
TI  - The structure of cortical-subcortical relationships between electrical processes
      of the brain during a motor polarization dominant.
AB  - Coherence analysis of electrical activity was applied to chronic experiments on
      rabbits and showed that the formation of a motor polarization dominant, created
      by the action of an anodic direct current applied to the sensorimotor cortex,
      evoked a general rearrangement of the structure of cortical-subcortical
      relationships between electrical processes not only in the "dominant," but also
      in the opposite half of the brain. Zones of primary excitation foci became
      isolated in the cortex of the "dominant" hemisphere, with a reduction in their
      coherent electrically active connections, in the delta range, with other areas of
      the cortex. In conditions of an optimal dominant, interstimulus intervals showed
      asymmetry in delta-range coherence in the electrical activity of the sensorimotor
      cortex and the ventrolateral nucleus of the thalamus and field CA3 of the
      hippocampus of the "dominant" and "non-dominant" halves of the brain, which was
      increased in response to sound stimuli. Asymmetry in the alpha and beta ranges of
      coherence spectra for the electrical activity of the areas studied, coinciding
      with the performance of a motor "dominant" response, was associated with the
      processes involved in organizing the movement.

PMID- 10596791
TI  - Interaction of two "polarization" dominant foci in the mortor cortex.
AB  - The effects of sequential treatments (with intervals of 30-60 min) to weak anodic
      direct currents (0.5-3 microA) to the representation area of the fore- and
      hindlimbs of the motor cortex were studied in conscious, non-immobilized rabbits.
      This procedure created foci of excitation with the properties of dominants, i.e.,
      distant stimuli (sound, light) produced responses corresponding to behavioral
      reactions (limb movement). During formation of the second dominant focus, linked
      inhibition of excitation foci was seen at different time points: there was long
      term inhibition of the first dominant focus by the second, which was followed by
      reciprocal inhibition between the excitation foci, which resembled a mutual
      relationship. The interaction of the two "polarization" dominant foci, consisting
      of the transient dominance of one and then the other focus, persisted over a long
      time scale (more than 1 h) after the current inducing the foci was switched off.
      These results provide evidence of the redistribution of excitation within the
      motor apparatus during formation of dominant foci in the motor cortex.

PMID- 10596792
TI  - Coherence analysis of electrical activity in the rabbit brain during the process
      of substitution of dominants.
AB  - Coherence analysis was used to study intercenter relationships between
      biopotentials in the sensorimotor cortex (forelimb and blink representation
      areas) and the visual cortex in both hemispheres and the ventrolateral nucleus of
      the thalamus (VPL) of the left and right thalami during the formation of a motor
      defensive dominant (electrical stimulation of the limb skin) on a background of
      an induced (by stimulation of the cornea with an air jet) blink dominant.
      Characteristic electrophysiological measures of the dominant state (increases in
      the mean coherence level of potentials in the delta frequency range in structures
      involved in the functional defensive limb reflex system), along with the absence
      of behavioral manifestations of the motor dominant in the blink dominant,
      indicated that a cryptic potential dominant focus was created in the CNS in these
      conditions, and that this affected ongoing animal activity.

PMID- 10596793
TI  - The time distribution of linked spike activity of rabbit sensorimotor cortex
      neurons in the presence of a rhythmic motor dominant.
AB  - The existence of a cryptic stationary focus of excitation induced in the cortex
      by rhythmic electrical stimulation of the paw was detected using sound test
      stimuli which were previously indifferent to the experimental animals. Neuron
      activity was recorded in the sensorimotor cortex of rabbits. Neuron pairs were
      identified which operated in a correlated fashion in the dominant focus. Analysis
      of linked spike activity in such neuron pairs demonstrated the predominant
      appearance of linked spikes with intervals of about 2 sec when the focus was
      created by stimulation with a 2-sec rhythm; intervals were at or about 3 sec when
      the focus was created by stimulation with a 3-sec rhythm. The studies
      demonstrated that long-term persistence of the rhythmic nature of the dominant
      focus occurred at the level of interneuron interactions, i.e., it was a system
      process. The assimilated rhythm in linked cell activity was observed not only at
      the point of summation, when output was sent to an effector-i.e., when the
      dominant was realized as a movement response-but also in the intervals between
      test stimuli.

PMID- 10596794
TI  - Changes in the constant potential in brain structures in rats during focal
      ischemia and systemic hypoxia.
AB  - The functional consequences of spreading depression (SD) during the evolution of
      ischemic damage was studied in two models: focal cortical ischemia induced by
      photothrombosis of the middle cerebral artery (MCA) and systemic hypoxia induced
      by 0.8% carbon monoxide (CO). These studies showed that cortical waves of SD,
      arising spontaneously during MCA thrombosis and after arterial occlusion delayed
      thrombus formation and promoted the establishment of a collateral blood supply in
      the perifocal zone of ischemic lesions. The underlying mechanism consisted of
      episodes of intense vasodilation at the decay phase of every wave of SD.
      Respiration of 0.8% CO increased the blood carboxyhemoglobin level to 50-60%. In
      lightly anesthetized rats (pentobarbital 20 mg/kg), cortical and subcortical
      spontaneous waves of SD were transformed into stable hypoxic depolarization,
      leading to death of 60% of the animals or severe lesions of the central nervous
      system, in 20% of animals. Increases in the level of anesthesia (50 mg/kg
      anesthetic) prevented the spontaneous appearance of SD during long-lasting
      exposure to CO. In these conditions, experimentally induced waves of SD
      demonstrated that the hippocampus has a high sensitivity to moderate levels of
      hypoxia. The duration of hypoxic depolarization of the hippocampus, provoking a
      single SD wave, reached 30-60 min. Selective neuron damage in field CA1 was seen
      30 days after hypoxia. Additionally, the left hippocampus of rats frequently
      showed profound morphological lesions in the form of "granules." Cerebrolysine
      (2.5 ml/kg daily for 10 days) completely prevented the formation of these
      lesions.

PMID- 10596795
TI  - Principles of the structural organization of the chemosensory systems of
      freshwater gastropod mollusks.

PMID- 10596796
TI  - Long-term morphofunctional survival of guinea pig hippocampal slices after brief
      treatment with cyclooxygenase inhibitors.

PMID- 10596797
TI  - Clinical-neurophysiological features of motor lesions in patients with post
      stroke epilepsy.
AB  - Twenty-two patients with post-stroke epilepsy (group 1) were studied, along with
      30 stroke patients without epilepsy (group 2). Bilateral (on both the paralyzed
      and intact sides) decreases in the central conduction time (CCT) along the
      pyramidal tract were found in group 1, which were not seen in group 2, who had
      similarly severe motor lesions (p < 0.01). The tendency to decreased CCT was also
      seen 5-6 days after ischemic stroke in patients without epileptic manifestations,
      though CCT in this group increased by day 10-14; low values persisted in group 1
      for prolonged periods. The facilitation differentiation (deltaF, the difference
      in CCT between resting and effort conditions) was also found to increase. In
      patients with post-stroke epilepsy, motor lesions were characterized by higher
      levels of muscle tone than in other stroke patients, though the levels of
      paralysis were similar.

PMID- 10596798
TI  - Comparative characteristics of learning and behavior processes in conditions of
      elevated sex hormone levels.
AB  - The effects of elevated levels of sex hormones resulting from systemic
      administration of hormone preparations on the abilities to learn and retain
      memory traces and on behavior were studied in rats of both sexes. Experiments
      were performed using models of conditioned active and passive avoidance reflexes
      and in the "open" field test. Increases in testosterone and estradiol levels had
      no effect on passive learning. Increases in testosterone levels in male rats led
      to derangement of active learning but had no effect on animal behavior. Elevated
      estradiol levels in female rats accelerated active learning and increased the
      animals' behavioral activity.

PMID- 10596799
TI  - Isolation of parapoxvirus from a cow treated with interferon-gamma.
AB  - A virus was isolated from peripheral blood leukocytes of a cow which was kept in
      an isolated pen after it was injected with recombinant bovine interferon-gamma.
      The virus was identified as a member of genus Parapoxvirus in the family
      Poxviridae on the basis of electron microscopic observations and serological
      tests. Parapoxvirus has seldom been isolated other than from papular lesions, the
      characteristic sign of parapoxvirus infection. This is the first report of
      parapoxvirus isolation from the peripheral blood of a cow without any clinical
      signs. These results show that parapoxviruses are capable of causing persistent
      infection in cattle without clinical signs and can be activated by stress factors
      that induce modification of immune reactions. Relationships between the isolated
      virus and other parapoxviruses isolated previously from cattle in Japan were
      investigated and discussed.

PMID- 10596800
TI  - High prevalence of Borna disease virus in domestic cats with neurological
      disorders in Japan.
AB  - A total of 15 (T-1-T-15) domestic cats with neurological disorders in Tokyo area
      were examined for association with Borna disease virus (BDV). None had detectable
      antibodies to feline immunodeficiency virus (FIV), feline leukemia virus, feline
      infectious peritonitis virus and Toxoplasma gondii, and only cat T-8 had
      detectable antibody to FIV. Serological and molecular epidemiological studies
      revealed a significantly high prevalence of BDV infection in these cats:
      antibodies against BDV p24 and/or p40 proteins in 10/15 (66.7%) and p24 and/or
      p40 RNA in peripheral blood mononuclear cells in 8/15 (53.3%). Further, in situ
      hybridization and immunohistochemistry analyses of the autopsied brain samples
      derived from one of the cats (T-15) revealed BDV RNA predominantly in neuronal
      cells in restricted regions, such as olfactory bulb and medulla of cerebrum.
      Thus, BDV is present in Japanese domestic cats with neurological disorders at a
      high prevalence.

PMID- 10596801
TI  - Persistence of encephalomyocarditis virus (EMCV) infection in piglets.
AB  - Six piglets that had survived experimental infection with encephalomyocarditis
      virus (EMCV) were treated with dexamethasone for a period of 5 days. The virus
      had not been detected in excretions of putative carriers for a period of 13-20
      days before the treatment. All piglets showed a rise in cardiac isoenzyme (CK-MB)
      activity, from the first day of treatment, suggesting myocardial damage. Antibody
      titres against EMCV remained stable or slightly decreased during treatment. EMCV
      was isolated from blood, nasal and faecal samples from all piglets on days 2 and
      3 after initiation of treatment and from various tissues of three piglets. Four
      contact piglets, that were housed together with the dexamethasone-treated
      piglets, became infected, indicating that EMCV was shed by treated piglets. It is
      suggested that recovered pigs may play an important role in the dissemination of
      EMCV.

PMID- 10596802
TI  - A comparative study of the pathogenic properties and transmissibility of a Greek
      and a Belgian encephalomyocarditis virus (EMCV) for piglets.
AB  - Thirteen susceptible piglets, aged 40 days, were divided into two groups and were
      experimentally infected either with a Greek (myocardial) or a Belgian
      (reproductive) encephalomyocarditis virus (EMCV) strain (total dose 5 x 10(6)
      TCID50, intramuscularly and intranasally). Six piglets were placed in the same
      rooms, 24 h later, as contact controls. The following criteria were studied: ante
      mortem: clinical signs, serum cardiac isoenzyme activities (CK-MB and LD-1),
      viraemia, nasal and faecal virus excretion and serological response. Post mortem
      (after death or euthanasia): gross lesions, virus isolation from tissues, RT-PCR,
      as well as histopathological and immunohistochemical findings. The Greek strain
      was more pathogenic, producing mortality, with high cardiac isoenzyme activities
      and pronounced macroscopic myocardium lesions. The Belgian strain was able to
      induce mild heart lesions, as detected only by cardiac isoenzyme activity and
      histopathologically. All contact pigs were infected, within the first 1-2 days of
      their introduction, that coincided with the period of viral excretion by the
      experimentally infected pigs (up to the 3rd day post infection). Disease was
      mild, with no mortality.

PMID- 10596803
TI  - Validation of enzyme-linked immunosorbent assays for the diagnosis of bovine
      brucellosis.
AB  - The purpose of this study was to evaluate the performance of the indirect enzyme
      immunoassay (IELISA) and the competitive enzyme immunoassay (CELISA) for the
      diagnosis of bovine brucellosis in comparison to conventional serological tests
      routinely used in Argentina. Serum samples (n = 3500), from Brucella-free herds,
      from vaccinated cattle and from naturally infected cattle, were tested by the
      following tests: buffered antigen agglutination test (BPAT), rose bengal test
      (RBT), 2-mercaptoethanol test (2-ME), complement fixation test (CFT), IELISA and
      CELISA. Sensitivity and specificity of the BPAT, RBT, IELISA and CELISA were
      determined relative to the 2-ME and the CFT. The CELISA was considered suitable
      for eliminating most serological reactions of vaccinated animals and was more
      specific than the other tests. The results indicate the potential use of the
      CELISA as a complementary assay in the brucellosis control and eradication
      program in Argentina and other countries, where Brucella abortusstrain 19
      vaccination is mandatory.

PMID- 10596804
TI  - Presence of the Streptococcus suis suilysin gene and expression of MRP and EF
      correlates with high virulence in Streptococcus suis type 2 isolates.
AB  - Nineteen Streptococccus suis type 2 isolates that had been analyzed previously
      for hemolysin production, ribotype, and virulence in pigs were examined for
      presence of the gene coding for suilysin by PCR amplification, and southern blot
      and hybridization techniques. Based on southern blot and hybridization analysis,
      all isolates tested contained at least a portion of the suilysin gene. PCR
      amplification of the entire gene resulted in gene fragments from five of the
      seven highly virulent isolates and none of the moderately virulent or avirulent
      isolates. Additional PCR analysis showed that mutation or deletions at the 5' end
      of the suilysin gene in the less virulent isolates prevented amplification of the
      sly gene fragment from those isolates. The MRP+ (muramidase-released protein) EF+
      (extracellular protein) phenotype was also expressed by the same five highly
      virulent/sly+ isolates.

PMID- 10596805
TI  - Analyses of lipopolysaccharides, outer membrane proteins and DNA fingerprints
      reveal intraspecies diversity in Moraxella bovis isolated in Argentina.
AB  - Intra-specific diversity within Moraxella bovis was investigated analysing DNA
      fingerprints, outer membrane proteins (OMP) and lipopolysaccharides (LPS)
      profiles. Three collection strains and 57 isolates of M. bovis, collected during
      3 years from cattle with infectious bovine keratoconjunctivitis (IBK) symptoms,
      from diverse geographical locations of Argentina, were examined. The LPS and OMP
      profiles were studied through SDS-PAGE analysis and genotype was determined by
      PCR-DNA fingerprinting. Genotyping identified five DNA types while analysis of
      LPS and OMP profiles identified three rough LPS types and three OMP types among
      the 60 isolates of M. bovis including the three collection strains. None of the
      three methods employed to assess diversity was discriminating when used alone
      because the degree of heterogeneity in each group of surface structures was
      limited, but when data of each typing method were combined, 15 distinct subgroups
      were determined. This subgrouping was clearly able to differentiate isolates of
      the same genotype. These typing methods appear to be useful to assess different
      aspects of the disease such as the diversity within a population of M. bovis
      associated to epidemic conditions, track the causal agent in an outbreak of the
      disease, monitoring vaccination programs and studies on virulence.

PMID- 10596806
TI  - Emended descriptions of indole negative and indole positive isolates of
      Brachyspira (Serpulina) hyodysenteriae.
AB  - Two type/reference strains of Brachyspira (B.) hyodysenteriae, 14 Belgian and
      German indole negative, and 14 Belgian, German and Swedish indole positive field
      isolates of strongly beta-haemolytic intestinal spirochaetes were compared by
      pulsed-field gel electrophoresis (PFGE) patterns, biochemical reaction patterns,
      16S rDNA sequences and MIC determinations of six antibacterial substances. Three
      tests for indole production, including a spot indole test, were compared with
      congruent results. All field isolates were classified as B. hyodysenteriae due to
      a high genetic and phenotypic similarity with the type strains. The Belgian and
      German indole negative isolates had identical and unique PFGE patterns for the
      tested restriction enzymes MluI and SalI, as well as identical 16S rDNA
      sequences, and they could not be differentiated by any of the methods used. Seven
      unique PFGE patterns were achieved from the 14 indole positive field isolates.
      The patterns were identical and unique for epidemiologically related isolates.
      Type/reference strains and isolates without known relation to other tested
      isolates showed unique banding patterns. The MICs of tylosin, tiamulin,
      erythromycin, clindamycin, carbadox and virginiamycin were determined in broth
      for all isolates. In contrast to Belgian and German isolates, the majority of the
      Swedish field isolates were susceptible to tylosin, erythromycin and clindamycin.
      Probable pathways of infection for some of the Swedish isolates were determined.
      The PFGE patterns of epidemic clones of B. hyodysenteriae remained stable for a
      period of up to 8 years. In vivo development of resistance to macrolide and
      lincosamide antibiotics due to use of tylosin was clearly indicated for two
      epidemic clones.

PMID- 10596807
TI  - Occurrence and characterization of gastric Helicobacter spp. in naturally
      infected dogs.
AB  - Helicobacter-like organisms are frequently observed in the stomach of dogs but
      the relationship between these microorganisms and gastric pathology has not been
      clearly established. Different species of helicobacters are known to be present
      in the canine stomach but their specific prevalence in naturally infected dogs is
      unknown. The aims of this study were to isolate and characterize helicobacters in
      canine gastric biopsies, to compare the commonly used tests for the
      identification of Helicobacter spp. and to determine the occurrence of these
      species in dogs. Twenty-three out of 25 dogs (92%) were positive for Helicobacter
      like organisms in cytological screening. Culture was successful from biopsies of
      5/25 dogs. The isolates were analyzed by electron microscopy, biochemical and
      physiological tests, whole protein analysis and 16S rDNA sequencing. Helicobacter
      felis was identified in four samples and Helicobacter bizzozeronii in one sample.
      Only the whole protein analysis in combination with electron microscopy was able
      to clearly discriminate the two species. Compared to the high prevalence of
      Helicobacter-like organisms, the occurrence of H. felis and H. bizzozeronii, was
      low (17 and 4%, respectively). No Flexispira rappini-like organisms or H.
      salomonis were detected. Electron microscopy revealed that H. bizzozeronii-like
      microorganisms were present in three additional biopsies where we were unable to
      culture any Helicobacter-like organisms. These observations indicate that in the
      stomach of dogs not all helicobacters are culturable. The unculturable bacteria
      appeared to be the prevalent ones and may represent different spiral organisms.
      The presence of distinct helicobacters with different characteristics can reflect
      different roles in the pathogenesis of canine gastric disease.

PMID- 10596808
TI  - Distribution of IS900 restriction fragment length polymorphism types among animal
      Mycobacterium avium subsp. paratuberculosis isolates from Argentina and Europe.
AB  - Sixty-one Mycobacterium avium subsp. paratuberculosis isolates from cattle and
      deer from the Buenos Aires province, an important livestock region in Argentina,
      were typed by restriction fragment length polymorphisms (RFLP) analysis based on
      IS900. Four different RFLP patterns (designated 'A', 'B', 'C' and 'E') were
      identified in BstEII digests of genomic DNA. The most frequently observed type,
      pattern 'A', was found in 46 isolates (75%). The second, pattern 'E', included 8
      isolates (13%), while the third, pattern 'B', included 6 isolates (10%). Pattern
      'C' was found for only one isolate. All of the deer isolates were classified as
      pattern 'A', while cattle isolates represented all four RFLP patterns. Twenty-one
      isolates representing the four different BstEII-RFLP patterns were digested with
      PstI. Twenty isolates showed identical PstI-RFLP pattern. BstEII-RFLP patterns
      from Argentine cattle and deer were compared with patterns found in cattle, goat,
      deer, rabbit, and human isolates from Europe. The most common pattern in
      Argentina, pattern 'A', was identical to a less frequently occurring pattern R9
      (C17) from Europe. The other Argentine patterns 'B', 'C' and 'E', were not found
      in the Europe. These results indicate that the distribution of M. avium subsp.
      paratuberculosis genotypes in the Buenos Aires province of Argentina is different
      from that found in Europe.

PMID- 10596809
TI  - Characterization of Escherichia coli isolated from healthy dogs.
AB  - Five month old dogs from a Midwestern research kennel occasionally developed
      bloody diarrhea after shipment to other facilities. As previous diagnostic
      efforts failed to reveal any potential pathogens in feces from normal and
      diarrheic dogs, Escherichia coli was investigated for select virulence properties
      that may contribute to the occurrence of bloody diarrhea. Fecal swabs from 52
      healthy dogs were examined for E. coli. Two hundred and sixty E. coli-like
      colonies were screened by PCR for the attaching and effacing (eae) gene, Shiga
      toxin (stx) genes, and the heat-stable enterotoxin type A (sta) gene. One hundred
      forty two of the 260 E. coli-like colonies (54.6%) from 43 dogs were eae or sta
      positive; and 60 of the eae and/or sta positive isolates were examined further.
      Among the 60 isolates, 23 (38.3%) possessed the eae gene, 32 (53.3%) possessed
      the sta gene, and five (8.3%) possessed both eae and sta genes (eae+/sta+). Of
      the 60 isolates, six sta+ and one eae+/sta+ isolates were hemolytic. When
      examined in the suckling mouse assay, five of six sta+ isolates and three of four
      eae+/sta+ isolates gave gut-to-remaining carcass ratios > or =0.083, indicating
      expression of heat-stable enterotoxin. These enterotoxin-producing isolates
      belonged to serogroups O42, O170, and O-negative.

PMID- 10596810
TI  - Molecular fingerprinting confirms extensive cow-to-cow intra-herd transmission of
      a single Mycobacterium bovis strain.
AB  - In this study we have characterized M. bovis isolates from a herd of cattle in
      Uvalde, Texas in which 52 of the 193 animals selected at random in 1994 from a
      herd of 331 were caudal fold skin-test positive. Thirty-two of 52 skin-test
      positive cattle had gross lesions at slaughter, and isolations of M. bovis were
      made from 29 animals. The herd was comprised of Red Devon cattle purchased
      between 1978 and 1980 (n = 26) and breeding bulls (n = 3) introduced at later
      times, and all were tuberculosis test negative at the time of purchase. Other
      animals were natural additions (offspring) of these cattle. One additional
      animal, a Holstein present on the ranch at the time of purchase in 1976, was
      retained to nurse orphaned and weak calves. Using several molecular
      fingerprinting techniques we have verified a clonal relationship among the M.
      bovis isolates consistent with infection originating with a single strain. The
      molecular fingerprint patterns demonstrate the stability of the profiles despite
      persistence and spread of the organism within the herd for two decades and
      confirms their use in epidemiological tracing.

PMID- 10596811
TI  - Is Escherichia coli STb enterotoxin sufficient to cause pig diarrhea?

PMID- 10596812
TI  - Selectivity in capillary electrokinetic separations.
AB  - This review gives a survey of selectivity modes in capillary electrophoresis
      separations in pharmaceutical analysis and bioanalysis. Despite the high
      efficiencies of these separation techniques, good selectivity is required to
      allow quantitation or identification of a particular analyte. Selectivity in
      capillary electrophoresis is defined and described for different separation
      mechanisms, which are divided into two major areas: (i) capillary zone
      electrophoresis and (ii) electrokinetic chromatography. The first area describes
      aqueous (with or without organic modifiers) and nonaqueous modes. The second area
      discusses all capillary electrophoretic separation modes in which interaction
      with a (pseudo)stationary phase results in a change in migration rate of the
      analytes. These can be divided in micellar electrokinetic chromatography and
      capillary electrochromatography. The latter category can range from fully packed
      capillaries, via open-tubular coated capillaries to the addition of
      microparticles with multiple or single binding sites. Furthermore, an attempt is
      made to differentiate between methods in which molecular recognition plays a
      predominant role and methods in which the selectivity depends on overall
      differences in physicochemical properties between the analytes. The calculation
      of the resolution for the different separation modes and the requirements for
      qualitative and quantitative analysis are discussed. It is anticipated that
      selectivity tuning is easier in separation modes in which molecular recognition
      plays a role. However, sufficient attention needs to be paid to the efficiency of
      the system in that it not only affects resolution but also detectability of the
      analyte of interest.

PMID- 10596813
TI  - Chiral electrokinetic chromatography using dipeptide polymeric surfactants:
      present state of the art.
AB  - Polymeric amino acid based surfactants have been recently employed as
      pseudostationary phases in capillary electrophoresis. These phases are effective
      for chiral separation of analytes in different charge states and
      hydrophobicities. This review paper focuses on polymeric dipeptide surfactants.
      The benefits of dipeptide over single amino acid micelle polymers are shown. Some
      aspects of dipeptide surfactants that are presented here includes the amino acid
      order, effect of number and position of chiral centers, and steric factors on
      enantiomeric separation of chiral compounds in different charge states. In
      addition, the preferential site of interaction of the chiral analyte using
      diastereomers of polymeric dipeptide surfactants is discussed.

PMID- 10596814
TI  - Applications of capillary electrochromatography.
AB  - Applications performed by capillary electrochromatography (CEC) in all its modes,
      namely packed column CEC (packed-CEC), open tubular CEC (OT-CEC) and pressure
      assisted CEC (pseudo-CEC), and published by June 1999 are reviewed. The review is
      divided into (i) separation of neutral, acidic and basic analytes with the main
      goal of evaluating column and system performance, (ii) separation according to
      field of application and/or chemical class, and (iii) separation of chiral
      analytes.

PMID- 10596815
TI  - Recent developments in DNA sequencing by capillary and microdevice
      electrophoresis.
AB  - The present review covers papers published in the years 1997 and 1998 on DNA
      sequencing by capillary and microdevice electrophoresis. The article does not
      include other electrophoretic DNA applications such as analysis of
      oligonucleotides, genotyping, and mutational analysis. Capillary gel
      electrophoresis (CGE) is starting to become a viable competitor to slab gel
      electrophoresis for DNA sequencing. Commercially available multicapillary array
      sequencers are now entering sequencing facilities which to date have totally
      relied on traditional slab gel technology. CGE research on DNA sequencing
      therefore becomes increasingly concerned with the critical task of fine-tuning
      the operational parameters to create robust sequencing systems. Electrophoretic
      microdevices are being considered the next technological step in DNA sequencing
      by electrophoresis.

PMID- 10596816
TI  - Recent advancements in amino acid analysis using capillary electrophoresis.
AB  - Recent advances in the analysis of amino acids using capillary electrophoresis
      are addressed. This area of research continues to receive increased attention as
      is evident from the 62 references reviewed. This review discusses current
      detection strategies including UV absorbance, laser-induced fluorescence,
      electrochemical, and others. Separation methodologies for both derivatized and
      underivatized amino acids are reviewed. Both direct and indirect enantiomeric
      resolution of amino acids are addressed. Applications utilizing capillary
      electrophoresis for the analysis of amino acids are discussed. This review covers
      literature published in 1997 and 1998.

PMID- 10596817
TI  - Capillary electrophoresis of peptides.
AB  - This article gives a review of the recent developments in capillary
      electrophoresis (CE) of peptides. New approaches to the theoretical description
      of electromigration behavior of peptides are described, and methodological
      aspects of CE separations of peptides such as selection of separation conditions,
      sample treatment, suppression of peptide adsorption to the capillary wall and
      specificities of CE separation modes are discussed. Progress in application of
      high performance detection schemes, namely laser-induced fluorescence and mass
      spectrometry, in peptide separations by CE is presented. Applications of
      different CE techniques, zone electrophoresis, isotachophoresis, isoelectric
      focusing, affinity electrophoresis, electrokinetic chromatography and
      electrochromatography to peptide analysis, preparation and physicochemical
      characterization are demonstrated.

PMID- 10596818
TI  - Recent developments in capillary zone electrophoresis of proteins.
AB  - This review article with 125 references describes recent developments in
      capillary zone electrophoresis of proteins. It encompasses approximately the last
      two years, from the previous review (V. Dolnik, Electrophoresis 1997, 18, 2353
      2361) through Spring 1999. Topics covered include modeling of the electrophoretic
      properties of proteins, sample preconcentration and derivatization, wall
      coatings, improving selectivity, special detection techniques, and applications.

PMID- 10596819
TI  - Capillary electrophoresis of proteins for proteomic studies.
AB  - Analyses of proteins in complex mixtures such as cell lyzates are presently
      performed mainly by sodium dodecyl sulfate (SDS)-polyacrylamide gel
      electrophoresis. For structural analysis, each protein in a spot is digested with
      proteases and the fragment peptides are subjected to Edman sequencing and/or mass
      spectrometry. These works aim at the total analysis of proteins in a complex
      mixture and reconstruction of their cooperative functions. Genomic studies are
      now being combined with these proteomic studies. This review article focuses on
      the application of capillary electrophoresis aiming at the total analysis of
      complex protein systems or structural analysis of each separated protein. From
      this viewpoint, articles on capillary zone electrophoresis, capillary isoelectric
      focusing, and sieving SDS capillary electrophoresis are reviewed. Since these
      techniques of capillary electrophoresis have been thoroughly reviewed previously,
      papers published in 1997 and 1998 are mainly covered.

PMID- 10596820
TI  - Identification, quantitation, and characterization of biomolecules by capillary
      electrophoretic analysis of binding interactions.
AB  - The high resolving power of capillary electrophoresis combined with the
      specificity of binding interactions may be used with advantage to characterize
      the structure-function relationship of biomolecules, to quantitate specific
      analytes in complex sample matrices, and to determine the purity of
      pharmaceutical and other molecules. We here review recent and innovative
      methodologies and applications of high resolution affinity electrophoresis within
      the fields of binding constant determination, structure-activity studies,
      quantitative microassays, analysis of drug purity and protein conformation, and
      immobilized affinity ligands. Despite the virtues of these approaches with
      respect to applicability, resolving power, speed, and low sample consumption,
      problems remain with respect to analyte identification and low concentration
      limits of detection. The ongoing development of new detector technologies for
      capillary electrophoresis such as mass spectrometry, and possibly nuclear
      magnetic resonance and other spectroscopic methods, is therefore very promising
      for the continued increased use of affinity capillary electrophoresis.

PMID- 10596821
TI  - Recent developments in capillary electrophoresis and capillary
      electrochromatography of carbohydrate species.
AB  - This review article is concerned with the recent developments in capillary
      electrophoresis (CE) and capillary electrochromatography (CEC) of carbohydrates.
      The literature shows that CE possesses impressive potential in the analysis of
      carbohydrates. On the other hand, CEC has just started to show promise in the
      analysis of carbohydrates. Advances in separation and detection approaches of
      derivatized and underivatized carbohydrates are discussed based on the available
      literature. In addition, important applications are illustrated.

PMID- 10596822
TI  - Applications of capillary electrophoresis in biotechnology.
AB  - Capillary electrophoresis (CE)-related techniques are increasingly being used as
      a matter of routine practice in the biotechnology discipline. Since recombinant
      DNA-derived proteins and the antisense oligonucleotides constitute a large
      portion of the applications of these techniques, they have been emphasized in
      this review. Analyses by CE of Escherichia coli-derived proteins and glycosylated
      proteins derived from mammalian cell cultures are summarized, as well as those of
      the carbohydrate chains that have been enzymatically removed from the protein.
      Applications of CE in the analysis of the antisense oligonucleotides for the
      determination of purity and the analytical studies on the metabolism of these
      modified oligonucleotides, by CE are reviewed. The literature mainly covers the
      period from 1996.

PMID- 10596823
TI  - The development and application of capillary electrophoresis methods for food
      analysis.
AB  - Capillary electrophoresis (CE) offers the analyst a number of key advantages for
      the analysis of the components of foods. CE offers better resolution than, say,
      high-performance liquid chromatography (HPLC), and is more adept at the
      simultaneous separation of a number of components of different chemistries within
      a single matrix. In addition, CE requires less rigorous sample cleanup procedures
      than HPLC, while offering the same degree of automation. However, despite these
      advantages, CE remains under-utilized by food analysts. Therefore, this review
      consolidates and discusses the currently reported applications of CE that are
      relevant to the analysis of foods. Some discussion is also devoted to the
      development of these reported methods and to the advantages/disadvantages
      compared with the more usual methods for each particular analysis. It is the aim
      of this review to give practicing food analysts an overview of the current scope
      of CE.

PMID- 10596824
TI  - Capillary electrophoresis of glucosinolates and their degradation products.
AB  - Glucosinolates are important natural products occurring mainly in plants of the
      Cruciferae family. This review article is aimed at describing the recent progress
      made in capillary electrophoresis of glucosinolates and their degradation
      products. It describes the various electrophoretic systems and detection schemes
      introduced to date for the capillary electrophoresis (CE) of glucosinolates and
      their degradation products. Also included in this review are the applications of
      CE to the qualitative and quantitative determination of glucosinolates and their
      degradation products in plant extracts.

PMID- 10596825
TI  - Capillary electrophoresis of natural products-II.
AB  - Capillary zone electrophoresis (CZE) and micellar electrokinetic capillary
      chromatography (MEKC) were used for the separation of widely different compounds
      from natural materials including compounds from tea, acids from different
      matrices, flavonoids and alkaloids, toxins and toxicological compounds, proteins
      and polypeptides, biogenic amines, phenolic compounds in alcoholic beverages,
      Chinese medicinal drugs, compounds in cells and cell extracts, and miscellaneous
      other applications. A section dealing with recent reviews related to natural
      products is also included.

PMID- 10596826
TI  - Capillary electrophoresis in clinical and forensic analysis: recent advances and
      breakthrough to routine applications.
AB  - This paper is a comprehensive review article on capillary electrophoresis (CE) in
      clinical and forensic analysis. It is based upon the literature of 1997 and 1998,
      presents CE examples in major fields of application, and provides an overview of
      the key achievements encountered, including those associated with the analysis of
      drugs, serum proteins, hemoglobin variants, and nucleic acids. For CE in clinical
      and forensic analysis, the past two years witnessed a breakthrough to routine
      applications. As most coauthors of this review are associated with diagnostic or
      forensic laboratories now using CE on a routine basis, this review also contains
      data from routine applications in drug, protein, and DNA analysis. With the first
      hand experience of providing analytical service under stringent quality control
      conditions, aspects of quality assurance, assay specifications for clinical and
      forensic CE and the pros and cons of this maturing, cost-and pollution-controlled
      age technology are also discussed.

PMID- 10596827
TI  - Capillary electrophoresis of drugs: current status in the analysis of
      pharmaceuticals.
AB  - The current status of capillary electrophoresis (CE) in pharmaceutical analyses
      is reviewed with about 300 references, mainly from 1996 until 1999. This article
      covers the use of CE for assay and purity determination of the main component,
      analysis of natural medicines, antisense DNA, peptides, and proteins. Analysis of
      hydrophobic and/or electrically neutral drugs by electrokinetic chromatography,
      capillary electrochromatography and nonaqueous CE is critically evaluated.
      Detailed techniques for the separation of enantiomers are given in the text with
      some actual applications. Furthermore, this review includes sensitivity and
      regulatory aspects for the actual use of CE in new drug applications (NDA). The
      analytical validation required for CE in NDA is also treated.

PMID- 10596828
TI  - Pharmacokinetic applications of capillary electrophoresis.
AB  - This review briefly discusses the use of capillary electrophoretic (CE) methods
      for the investigations of different aspects of pharmacokinetics. In most
      investigations, CE was the method of choice because of its unique features,
      including high resolving power for chiral or metabolite separation, small sample
      volume for pediatric pharmacokinetics or for cell-based investigations, in situ
      microdialysis sampling for rapid eliminations, low UV wavelength detection for
      nonderivatized analytes, fast and simplified sample processing for existing
      methods that require tedious sample preparation, or as a second method for
      verifications. Moreover, instrumental aspects of CE-based assays for
      pharmacokinetic studies, such as different modes of CE methods for analyzing
      biological samples, sample stacking for increasing detection sensitivity, and
      coupling techniques with microdialysis and mass spectrometry, are also discussed
      in this review. Furthermore, the advantages and limitations of CE methods as well
      as the future outlook for pharmacokinetic studies are summarized.

PMID- 10596829
TI  - Analysis of antibiotics by capillary electrophoresis.
AB  - The broad category of antibiotics encompasses some of the most widely prescribed
      pharmaceuticals in the world. As is the case with any pharmaceutical, an
      antibiotic must be characterized in terms of its potency and the presence and
      quantity of impurities. Additionally, any residue or metabolite that may be
      present as a result of its use must be monitored. Many capillary electrophoretic
      techniques have been utilized in the analysis of antibiotics, addressing the
      various aspects of quantifying, profiling, and monitoring. Some of the more
      recent applications are summarized in this review article.

PMID- 10596830
TI  - Capillary electrophoresis and electrochromatography of pesticides and
      metabolites.
AB  - Synthetic pesticides are important chemicals since they are widely used to
      control many types of weeds, insects and other pests in a wide variety of
      agricultural and nonagricultural settings. This review article is aimed at
      describing the recent progress made in capillary electrophoresis (CE) and
      capillary electrochromatography (CEC) of pesticides and their metabolites. The
      various electrophoretic systems and detection schemes that have been introduced
      so far for the CE and CEC of pesticides are discussed. Also included in this
      review article are the various approaches for trace enrichment that are involved
      in the analysis of dilute pesticide samples.

PMID- 10596831
TI  - Capillary electrophoresis and capillary electrochromatography of organic
      pollutants.
AB  - Capillary electrophoresis (CE) has a unique capability for separation of analytes
      of environmental concern, particularly those that are more polar and ionic, based
      on the complementary separation principle of electrophoresis. In the past few
      years, CE has been selectively used to analyze various classes of compounds
      having current or potential environmental relevance. This review outlines the
      current status of CE for the determination of environmental pollutants, based
      predominantly on research results published from the beginning of 1997 to early
      1999. Covered are environmental pollutants of all types except pesticides and
      inorganics. Certain naturally produced toxins are also covered because of their
      significant impacts upon human health and the environment. CE methods, as with
      all methods, must be judged on their ability to provide approaches that are
      reliable, sensitive, selective, and rapid, while meeting "green chemistry"
      initiatives for pollution prevention. We also compare CE methods to benchmark
      environmental techniques involving gas chromatography-mass spectrometry (GC-MS),
      liquid chromatography-mass spectrometry (LC-MS), and high performance liquid
      chromatography (HPLC).

PMID- 10596832
TI  - Determination of surfactants by capillary electrophoresis.
AB  - Capillary electrophoresis has been increasingly used during the past few years
      for the separation and determination of surfactants. These substances are applied
      in many household and industrial products such as laundry detergents, cosmetics
      and pharmaceuticals, often as homologous and isomeric mixtures. Product
      development and control as well as toxicological and environmental analyses
      require selective and sensitive analytical methods. This review presents
      capillary electrophoretic techniques to determine important representatives of
      cationic, anionic, and neutral surfactants. The application of different buffer
      additives such as organic solvents, cyclodextrins or micelles to enhance the
      resolution of complex mixtures is discussed. Besides direct and indirect UV and
      fluorescence detection, examples for conductivity and mass spectrometric
      detection are also given. Derivatization procedures to improve the detectability
      and implement charge in neutral analytes are described. The successful use of
      capillary electrophoresis for surfactant determinations has proven that it can
      serve as a routine technique in many real-world applications. Robust, validated
      methods for the quantitation of single compounds, such as alkylbenzene
      sulfonates, sodium dodecyl sulfate and benzalkonium salts, are now available.
      Characteristic peak patterns (fingerprint analysis) can be used for the
      identification of surfactants in multicomponent formulations (e.g. ethoxylates
      and phosphonates).

PMID- 10596834
TI  - The intrinsic electrophysiological characteristics of fly lobula plate tangential
      cells: III. Visual response properties.
AB  - In this last paper in a series (Borst and Haag, 1996; Haag et al., 1997) about
      the lobula plate tangential cells of the fly visual system (CH, HS, and VS
      cells), the visual response properties were examined using intracellular
      recordings and computer simulations. In response to visual motion stimuli, all
      cells responded mainly by a graded shift of their axonal membrane potential.
      While ipsilateral motion resulted in a graded membrane potential shift,
      contralateral motion led to distinct EPSPs. For HS cells, simultaneous
      extracellular recorded action potentials of a spiking interneuron, presumably the
      H2 cell, corresponded to the EPSPs in the HS cell in a one-to-one fashion. When
      HS cells were hyperpolarized during ipsilateral motion, they mainly produced
      action potentials, but when they were hyperpolarized during contralateral motion
      only a slight increase of EPSP amplitude, could be observed. Intracellular
      application of the sodium channel blocker QX 314 abolished action potentials of
      HS cells while having little effect on the graded membrane response to
      ipsilateral motion. HS and CH cells were also studied with respect to their
      spatial integration properties. For both cell types, their graded membrane
      response was found to increase less than linearly with the size of the
      ipsilateral motion pattern. However, while for HS cells various amounts of
      hyperpolarizing current injected during motion stimulation led to different
      saturation levels, this was not the case for CH cells. In response to a
      sinusoidal velocity modulation, CH cells followed pattern motion only up to 10 Hz
      modulation frequency, but HS cells still revealed significant membrane
      depolarizations up to about 40 Hz. In the computer simulations, the compartmental
      models of tangential cells, as derived in the previous papers, were linked to an
      array of local motion detectors. The model cells revealed the same basic response
      features as their natural counterparts. They showed a response saturation as a
      function of stimulus size. In CH-models, however, the saturation was less
      pronounced than in real CH-cells, indicating spatially nonuniform membrane
      resistances with higher values in the dendrite. As in the experiments, HS models
      responded to high-frequency velocity modulation with a higher amplitude than did
      CH models.

PMID- 10596833
TI  - Implications of G-protein-mediated Ca2+ channel inhibition for neurotransmitter
      release and facilitation.
AB  - G-protein-mediated inhibition of Ca2+ current is ubiquitous in neurons, and in
      synaptic terminals it can lead to a reduction in transmitter release (presynaptic
      inhibition). This type of Ca2+ current inhibition can often be relieved by
      prepulse depolarization, so the disinhibition of Ca2+ current can combine with
      Ca2+ -dependent mechanisms for activity-induced synaptic facilitation to amplify
      this form of short-term plasticity. We combine a mathematical model of a G
      protein-regulated Ca2+ channel with a model of transmitter secretion to study the
      potential effects of G-protein-mediated Ca2+ channel inhibition and disinhibition
      on transmitter release and facilitation. We investigate several scenarios, with
      the goal of observing a range of behaviors that may occur in different synapses.
      We find that the effects of Ca2+ channel disinhibition depend greatly on the
      location and distribution of inhibited channels. Facilitation can be greatly
      enhanced if all channels are subject to inhibition or if the subpopulation of
      channels subject to inhibition are located closer to release sites than those
      insensitive to inhibition, an arrangement that has been suggested by recent
      experiments (Stanley and Mirotznik, 1997). We also find that the effect of
      disinhibition on facilitation is greater for longer action potentials. Finally,
      in the case of homosynaptic inhibition, where Ca2+ channel inhibition occurs
      through the binding of transmitter molecules to presynaptic autoreceptors, there
      will be little reduction in transmitter release during the first of two
      successive bursts of impulses. The reduction of release during the second burst
      will be significantly greater, and if the unbinding rate of autoreceptors is
      relatively low, then the effects of G-protein-mediated channel inhibition become
      more pronounced as the duration of the interburst interval is increased up to a
      critical point, beyond which the inhibitory effects become less pronounced. This
      is in contrast to presynaptic depression due to the depletion of the releasable
      vesicle pool, where longer interburst intervals allow for a more complete
      replenishment of the pool. Thus, G-protein-mediated Ca2+ current inhibition leads
      to a reduction in transmitter release, while having a highly variable amplifying
      effect on synaptic facilitation. The dynamic properties of this form of
      presynaptic inhibition are very different from those of vesicle depletion.

PMID- 10596835
TI  - Computational consequences of temporally asymmetric learning rules: I.
      Differential hebbian learning.
AB  - Temporally asymetric learning rules governing plastic changes in synaptic
      efficacy have recently been identified in physiological studies. In these rules,
      the exact timing of pre- and postsynaptic spikes is critical to the induced
      change of synaptic efficacy. The temporal learning rules treated in this article
      are approximately antisymmetric; the synaptic efficacy is enhanced if the
      postsynaptic spike follows the presynaptic spike by a few milliseconds, but the
      efficacy is depressed if the postsynaptic spike precedes the presynaptic spike.
      The learning dynamics of this rule are studied using a stochastic model neuron
      receiving a set of serially delayed inputs. The average change of synaptic
      efficacy due to the temporally antisymmetric learning rule is shown to yield
      differential Hebbian learning. These results are demonstrated with both
      mathematical analyses and computer simulations, and connections with theories of
      classical conditioning are discussed.

PMID- 10596836
TI  - Activity-driven computational strategies of a dynamically regulated integrate-and
      fire model neuron.
AB  - Activity-dependent slow biochemical regulation processes, affecting intrinsic
      properties of a neuron, might play an important role in determining information
      processing strategies in the nervous system. We introduce second-order
      biochemical phenomena into a linear leaky integrate-and-fire model neuron
      together with a detailed kinetic description for synaptic signal transduction. In
      this framework, we investigate the membrane intrinsic electrical properties
      differentiation, showing the appearance of activity-dependent shifts between
      integration and temporal coincidence detection operating mode, for the single
      unit of a network.

PMID- 10596837
TI  - A feedback model of attention and context dependence in visual cortical networks.
AB  - We have modeled biologically realistic neural networks that may be involved in
      contextual modulation of stimulus responses, as reported in the
      neurophysiological experiments of Motter (1994a, 1994b) (Journal of Neuroscience,
      14:2179-2189 and 2190-2199). The networks of our model are structured
      hierarchically with feedforward, feedback, and lateral connections, totaling
      several thousand cells and about 300,000 synapses. The contextual modulation,
      arising from attention cues, is explicitly modeled as a feedback signal coming
      from the highest-order cortical network. The feedback signal arises from mutually
      inhibitory neurons with different stimulus preferences. Although our model is
      probably the simplest one consistent with available anatomical and physiological
      evidence and ignores the complexities that may exist in high-level cortical
      networks such as the prefrontal cortex, it reproduces the experimental results
      quite well and offers some guidance for future experiments. We also report the
      unexpected observation of 40 Hz oscillations in the model.

PMID- 10596838
TI  - The Frey-Werle Foundation award ceremony, Friday, October 23, 1998, Noh Hall,
      Nara New Public Hall.

PMID- 10596839
TI  - The purification and structural elucidation of bradykinin--a reminiscence of
      1960.

PMID- 10596840
TI  - Plasma and tissue kallikrein in arthritis and inflammatory bowel disease.
AB  - To ascertain the participation of the plasma kallikrein-kinin system (KKS) in
      arthritis and inflammatory bowel disease, we used two rat models resembling
      rheumatoid arthritis and Crohn's disease. Proteoglycan-polysaccharide from group
      A streptococcus (PG-APS) produced chronic destructive inflammation and systemic
      response in the genetically susceptible Lewis rat, in the joints when injected
      intraperitoneally and in the bowel when injected into the gut wall. In both
      models, the KKS is activated, as evidenced by decreased prekallikrein, factor XI
      and high molecular weight kininogen. A specific plasma kallikrein inhibitor, Bz
      Pro-Phe-boroarginine, reverses the plasma changes as well as the clinical gross
      and microscopic pathology of both the experimental arthritis and the inflammatory
      bowel disease in the genetically susceptible rats. We have also shown that the
      tissue kallikrein system is involved in the intestinal inflammatory changes.
      Intestinal tissue kalikrein (ITK) is localized in goblet cells in both normal and
      inflamed tissue. In chronic granulomatous inflammation, ITK is localized in
      macrophages. ITK decreases in chronic inflammation, probably due to secretion,
      since the mRNA is unchanged. Kallikrein binding protein, the ITK inhibitor,
      decreases due to enzyme-inhibitor complexes. Both plasma and tissue kallikrein
      are appealing targets for drug therapy of rheumatoid arthritis and Crohn's
      disease.

PMID- 10596841
TI  - Activation of the plasma kallikrein/kinin system on endothelial cell membranes.
AB  - For more than three decades, it has been known that the plasma kallikrein/kinin
      system becomes activated when exposed to artificial, negatively charged surfaces.
      The existence of an encompassing in vivo, negatively charged surface capable of
      activation of the plasma kallikrein/kinin system has, however, never been
      convincingly demonstrated. In this report, we describe current knowledge on how
      the proteins of the plasma kallikrein/kinin system assemble to become activated
      on cell membranes. On endothelial cells, the activation of the plasma
      kallikrein/kinin system is not initiated by factor XII autoactivation as seen on
      artificial surfaces. On endothelial cells, prekallikrein is activated by an
      antipain sensitive protease. Prekallikrein activation is dependent on the
      presence of high molecular weight kininogen and an optimal free Zn2+
      concentration. Kallikrein generated on the surface of endothelial cell is capable
      of activating factor XII. Further, kallikrein formed on endothelial cell
      membranes is capable of cleaving its receptor and native substrate, high
      molecular weight kininogen, liberating bradykinin and the HK PK complex from the
      endothelial cell surface. Endothelial cell-associated kallikrein also is capable
      of kinetically favorable pro-urokinase and, subsequent, plasminogen activation.

PMID- 10596842
TI  - Kallikrein-kinin in infection and cancer.
AB  - This review article describes the mechanism of enhancement of vascular
      permeability in infectious disease and cancer. This phenomenon is primarily
      mediated by bradykinin, nitric oxide and other unique vascular mediators. They
      are highly intermingled with each other in these disease states. Furthermore,
      these mediators are elicited in various in vivo settings most frequently induced
      by bacterial proteases, and indirect or direct activation of kallikrein-kinin
      cascade at one or more steps. The key steps involve bacterial proteases or
      cellular components including lipopolysaccharides. Thus, the use of appropriate
      protease inhibitors or antagonists, or scavengers in the case of nitric oxide,
      superoxide or peroxynitrite, are anticipated to attenuate the clinical
      manifestation induced by such mediators. It also explained that fluid
      accumulation in ascitic or pleural compartments in the case of carcinomatosis in
      terminal cancer patients can be largely attributed to bradykinin or related
      mechanism. Systemic bacterial dissemination is also facilitated by bradykinin, or
      suppressed by kinin antagonists as well as by the inhibition of kinin production,
      respectively. Thus, control of the level of such vascular mediators appears
      important both in infectious disease and in cancer. alpha1-Protease inhibitor,
      which inhibits neutrophil elastase, is inactivated by oxidative metabolites such
      as superoxide and peroxynitrite, and this effect activates matrix
      metalloproteinases. This indicates that oxidative stress activates proteolytic
      potential, and thus accelerates the degenerative process upon infection.

PMID- 10596843
TI  - Altered cardiac tissue and plasma kininogen levels in hypertensive and diabetic
      rats.
AB  - The present investigation was aimed at evaluating the cardiac and total plasma
      kininogen levels, as well as LVWT in hypertensive and diabetic rats. STZ-induced
      diabetes produced a significant (P < 0.001) rise in mean arterial blood pressure
      (BP). The LVWT increased (P < 0.001) in SHR with and without diabetes) and
      diabetic WKYR. The cardiac tissue, as well as total plasma kininogen levels fell
      significantly (P < 0.001) in diabetic WKYR and SHR with and without diabetes
      compared to the control WKYR. These findings suggest that reduced kininogen
      levels may indicate a deficiency in kinin generation in the heart and in the
      peripheral circulation in diabetic and hypertensive rats. This effect may
      contribute to the development of LVH.

PMID- 10596844
TI  - The relationship between the onset of labor mechanisms and the hemostatic system.
AB  - The relationship between onset of labor and the hemostatic system was evaluated
      in 38 pregnant women. The hemostatic system consists of blood coagulation, kinin
      kallikrein system, the fibrinolytic system, and platelet function. The most
      prominent changes take place in the kinin-kallikrein system. After the onset of
      labor, prekallikrein decreases rapidly which may trigger changes in blood
      coagulation and the fibrinolytic system. Platelet hemostatic capacity (PHC) was
      also measured using the PFA-100 (platelet function analyzer) system. Closure
      times (CT) were shorter during pregnancy, compared to non-pregnant controls,
      suggesting an increase in PHC. Platelet aggregation by ADP at the end of
      pregnancy was decreased at the onset of labor. At the same time a slight increase
      in FDP (fibrin degeneration product) was also seen. While FDP increased, platelet
      aggregation decreased, which seems to suggest FDP inhibits platelet aggregation.
      In this manner, these three systems(kinin-kallikrein system, blood coagulation,
      and fibrinolytic system) and platelet aggregation are closely interrelated,
      possibly affecting uterine contractility during pregnancy and the onset of labor.

PMID- 10596845
TI  - Effects of the propofol combination anesthesia on the intrinsic blood-clotting
      system.
AB  - Fat emulsions can cause changes in blood-clotting and fibrinolysis. The aim of
      this study was to examine the relation between the use of the short-acting
      hypnotic propofol and alteration of the blood clotting system. In a double-blind
      randomized study, 36 patients with an aortocoronary bypass operation were given
      either midazolam/fentanyl or propofol/alfentanil. Eleven blood samples were taken
      at fixed times pre-, intra- and postoperatively to determine changes caused by
      the anesthetic agents on the hemostaseologic parameters during the whole
      operation. Perioperative blood pressures of both groups were measured at seven
      fixed points. From the beginning of the extracorporeal circulation (ECC) to the
      end of the operation, the measured values of the factor XIIa- and kallikrein-like
      activity in the propofol group were significantly higher than those of the
      midazolam group. Also the values of the kallikrein inhibition capacity and the
      indicators of fibrinolysis (t-PA and D-dimers) suggest a stronger activation of
      the contact phase at the start of the recirculation and as a result of it a
      stronger fibrinolysis within the propofol group. Besides, the hypotensive side
      effect in the propofol group was evident in contrast to the midazolam group. With
      this investigation, a correlation between the application of propofol/alfentanil,
      contact phase activation with activation of the kallikrein-kinin-bradykinin
      system and the observed hypotension can be set up.

PMID- 10596846
TI  - Cardiopulmonary bypass increases plasma bradykinin concentrations.
AB  - An increase of bradykinin (BK) plasma levels together with the activation
      coagulation cascade, fibrinolysis, complement and cytokines was observed during
      cardiopulmonary bypass (CPB). Since the procedure of extracorporeal circulation
      completely excludes the lung, the major site of BK catabolism, our data suggest
      that a reduced catabolism could contribute to the increase of BK during CPB.

PMID- 10596847
TI  - Increased adsorption of high molecular weight kininogen to heparin-coated
      artificial surfaces and correlation to hemocompatibility.
AB  - During the past 10 years investigations have demonstrated that heparin-coated
      devices used for extracorporeal circuits show an improved hemocompatibility. We
      investigated the pathway of adsorption of plasma proteins at heparin-coated
      artificial surfaces and the further activation of the humoral and cellular
      defense mechanisms of the blood. Twenty milliliters of fresh human blood (1 IU
      heparin/ml) filled a 50 cm long tubes (with and without covalent heparin
      coating), prepared as an in vitro "Closed-Loop" model and recirculated at a
      temperature of 37 degrees C. After 5, 15, 30, 60 and 120 min fibrinogen and high
      molecular weight kininogen (HMWK) adsorption was measured by a newly developed
      modified ELISA technique. In addition, changes in coagulation and platelet
      activation were measured by well established assays. High concentrations of
      fibrinogen were detected after very short blood material contact, both on
      uncoated as well as heparin-coated tubes. However, high amounts of HMWK were only
      found on the heparin-bonded surfaces. In addition, the concentrations of the
      soluble coagulation marker prothrombin fragment F1+2 and the marker for platelet
      activation beta-thromboglobulin were significantly higher in the non-coated
      tubes. We presume that adsorption of HMWK to heparin-coated surfaces contributes
      to the improved hemocompatibility of these bondings.

PMID- 10596848
TI  - Bradykinin antagonists: present progress and future prospects.
AB  - Bradykinin (BK) antagonist peptides have been powerful tools for delineating
      roles of kinins in both normal and pathological physiology and offer promise of
      drug development for a variety of inflammatory conditions and cancers. At the
      present time, potent peptide antagonists are available that are either specific
      for BK B1 or B2 receptors, or are effective on both receptor classes. Non-peptide
      BK B2 antagonists are now being announced and are under investigation in several
      companies. The best peptide B1-B2 peptide antagonist is stable against all
      kininases, is orally available, and has a very long lifetime in vivo. Certain
      dimers of this antagonist, as well as several smaller molecules, are active
      against several cancers, both in vitro and in vivo.

PMID- 10596849
TI  - Discovery of orally active nonpeptide bradykinin B2 receptor antagonists.
AB  - Orally active nonpeptide bradykinin (BK) B2 receptor antagonists have been
      discovered by using directed random screening and chemical modification. These
      compounds displaced [3H]BK binding to B2 receptors in guinea-pig ileum membranes,
      rat uterus membranes and human lung fibroblasts with nanomolar IC50s. They did
      not inhibit different specific radio-ligand bindings to other receptor sites
      including B2 receptors. In isolated guinea-pig ileum preparations, these
      compounds had no agonistic effect on smooth muscle contraction at 10(-6) M, and
      caused parallel rightward shifts of the concentration-response curves to BK on
      contraction with higher p A2 values. They also blocked human B2 receptor-mediated
      phosphatidylinositol hydrolysis without agonistic effect. In vivo, the oral
      administrations of these antagonists potently inhibited BK-induced
      bronchoconstriction in guinea-pigs. They also reduced carrageenin-induced paw
      edema and caerulein-induced pancreatitis in rats. Moreover, these compounds
      alleviated kaolin-induced pain in mice by oral administration. These results show
      that our compounds are potent, selective, and orally active BK B2 receptor
      antagonists and that they may have therapeutic potential against inflammatory
      diseases and pain.

PMID- 10596850
TI  - Small molecule antagonists of the bradykinin B1 receptor.
AB  - Screening Pharmacopeia's encoded combinatorial libraries has led to the
      identification of potent, selective, competitive antagonists at the bradykinin B1
      receptor. Libraries were screened using a displacement assay of [3H]-des-Arglo
      kallidin ([3H]-dAK) at IMR-90 cells expressing an endogenous human B1 receptor
      (Bmax = 20,000 receptors/cell, K(D) = 0.5+/-0.1 nM) or against membranes from
      293E cells expressing a recombinant human B1 receptor (Bmax = 8,000
      receptors/cell, K(D) = 0.5 +/- 0.3 nM). Compound PS020990, an optimized,
      representative member from the class of compounds, inhibits specific binding of
      3H-dAK at IMR-90 cells with a KI of 6 +/- 1 nM. The compound inhibits dAK-induced
      phosphatidyl inositol turnover (K(Bapp) = 0.4 +/- 0.2 nM) and calcium
      mobilization (K(Bapp) = 17 +/- 2 nM) in IMR-90 cells. Compounds from the lead
      series are inactive at the B2 receptor and are > 1000-fold specific for B1 vs. a
      variety of other receptors, ion channels and enzymes. PS020990 and other related
      chemotypes therefore offer an excellent opportunity to explore further the role
      of B1 receptors in disease models and represent a potential therapeutic avenue.

PMID- 10596851
TI  - Characterization of non-peptide bradykinin B2 receptor agonist (FR 190997) and
      antagonist (FR 173657).
AB  - Pharmacologic parameters for a novel non-peptide bradykinin (BK)-B2 receptor
      agonist, 8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoylcinnamidoacetyl]-N-+
      ++methylano] benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (FR 190997)
      (pEC50, ED50 values) and for the antagonist (E)-3-(6-acetamido-3-pyridyl)-[N-[2,4
      dichloro-3-[(2-methyl-8-quinolinyl ) oxymethyl] phenyl]-N
      methylaminocarbonylmethyl] acrylamide (FR 173657) (pIC50, ID50 values) were
      measured using conventional contractile B2 receptor bioassays from rabbit, guinea
      pig and rat tissues and by mean of animal blood pressure models performed on
      anesthetized animals in the same species. In vitro assays (on the rabbit jugular
      vein and the guinea pig ileum) demonstrated that both the onset and duration of
      action of FR 190997 are prolonged compared to BK. These in vitro effects of FR
      190997 strongly desensitized upon repeated tissue applications. Similar pEC50
      values (7.7) were measured on the rabbit and the guinea pig tissues. In vivo,
      when injected intraarterially, FR 190997 produced hypotensive responses in
      rabbits and guinea pigs with ED50 values of 3.7 +/- 0.5 and 8.9 +/- 3.6 nmol/kg,
      respectively. Both the contractile and the hypotensive effects of FR 190997 were
      abolished by pretreating tissues (1 microM) or animals (0.1-0.5 micromol/kg) with
      D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]BK (HOE 140) or FR 173657. FR 173657 (pIC550
      approximately 8.40), as well as other known antagonists (e.g., HOE 140, D-Arg
      [Hyp3,D-Phe7,Leu8]BK), inhibited the in vitro myotropic effects of BK on the
      rabbit, guinea pig and rat tissues. FR 173657 also abrogated the in vivo
      hypotensive responses elicited by BK in the rabbit (ID50 57 +/- 9 nmol/kg), the
      guinea pig (ID50 215 +/- 56 nmol/kg) and the rat (ID50 187 +/- 50 nmol/kg). The
      in vivo duration of action of FR 173657 was significantly lower in the rabbit (=
      20 min) than in the guinea pig and the rat (> 90 min). It is concluded that the
      non-peptides FR 190997 and FR 173657 enable efficient activation and antagonism
      of rabbit and guinea pig B2 receptors. These non-peptide molecules represent a
      marked progress in medicinal chemistry and may be useful to define the role
      played by the kallikrein/kinin system in vivo.

PMID- 10596852
TI  - Pharmacological profile of LF 16-0687, a new potent non-peptide bradykinin B2
      receptor antagonist.
AB  - LF 16-0687 (1-[[2,4-dichloro-3-[[(2,4-dimethylquinolin-8-yl)oxy]
      methyl]phenyl]sulfonyl]-N-[3-[[4-(aminoimethyl) phenyl] carbonylamino]propyl]
      2(S)-pyrrolidinecarboxamide) has been selected from a large-scale medicinal
      chemistry program for further development. In competition binding studies using
      [3H]bradykinin (BK), LF 16-0687 bound to the human, rat and guinea-pig
      recombinant B2 receptor expressed in CHO cells giving K(i) values of 0.67 nM,
      1.74 nM and 1.37 nM, respectively. It also bound to the native BK B2 receptor
      from human umbilical vein (HUV), rat uterus (RU) and guinea-pig ileum (GPI)
      giving K(i) values of 0.89 nM, 0.28 nM and 0.98 nM, respectively. It inhibited BK
      induced IP1, IP2 and IP3 formation in INT407 cells yielding pK(B) values of 8.5,
      8.6 and 8.7, respectively. In isolated organs experiments, LF 16-0687 behaved as
      a competitive antagonist of BK-mediated contractions giving pA2 values of 9.1 in
      HUV, 7.7 in RU and 9.1 in GPI. Binding and functional studies performed over 40
      different receptors revealed that LF 16-0687 was selective for the BK B2
      receptor. A continuous intravenous infusion of LF 16-0687 antagonized in a dose
      dependent manner and with a rapid onset of action BK-induced hypotensive
      response. Subcutaneous administration of LF 16-0687 at 1.1 micromol/kg to rats
      markedly reduced BK-induced edema of the stomach (- 69%), duodenum (-65%) and
      pancreas (-56%).

PMID- 10596853
TI  - 5-hydroxytryptamine release from skin mast cells in vivo induced by peptide but
      not by nonpeptide ligands for bradykinin receptors.
AB  - A number of biologically active peptides including bradykinin (BK) are known to
      elicit an unspecific, non-receptor-mediated release of mediators from mast cells.
      We have investigated whether novel, nonpeptide BK B2 receptor ligands, i.e., the
      antagonists N-[N-[3-[(3-bromo-2-methylimidazo(1,2-a]pyridin-8-yl)oxymethyl]-2, 4
      dichlorophenyl]-N-methylaminocarbonylmethyl]-4-(dimethylamino
      carbonyl)cinnamylamide hydrochloride (FR167344) and (E)-3-(6-acetamido-3-pyridyl)
      N-[N-(2,4-dichloro-3-?(2-methyl-8-quinolin yl)oxymethyl? phenyl]-N
      methylaminocarbonylmethyl]acryamide (FR173657), and the agonist 8-[2,6-dichloro-3
      [N-[(E)-4-(N-methylcarbamoyl)cinnamidoacetyl+ ++]-N-methylamino] benzyloxy]-2
      methyl-4-(2-pyridylmethoxy)quinoline (FR190997), would be devoid of this
      unspecific action. Paw oedema in anaesthetized rats was observed following
      subplantar injection of BK, FR190997, the B2 antagonist D-Arg-[Hyp3, Thi5, D
      Tic7, Oic8]-BK (icatibant, previously Hoe-140), the B1 agonist des-Arg9-BK (DABK)
      and the B1 antagonist des-Arg9 [Leu8]-BK (DALBK). The effect of BK was inhibited
      by systemic pretreatments with icatibant and methysergide in an additive manner,
      whereas the local effect of icatibant was only sensitive to methysergide. Oedema
      induced by DABK and DALBK was also attenuated by methysergide. Mepyramine
      pretreatment was ineffective for all oedema-producing agents. Effects of FR190997
      were abolished by pretreatment with icatibant. FR167344 and FR173657 did not
      induce oedema formation. Depletion of mast cells by compound 48/80 mimicked the
      effects of methysergide on BK and icatibant and had no effect on FR190997. It is
      concluded that the novel nonpeptide receptor ligands are devoid of the unspecific
      mast cell-degranulating action observed with the peptide ligands.

PMID- 10596854
TI  - Interaction of factor XII and high molecular weight kininogen with cytokeratin 1
      and gC1qR of vascular endothelial cells and with aggregated Abeta protein of
      Alzheimer's disease.
AB  - High molecular weight kininogen (HK) attaches to endothelial cells at separate
      sites on the heavy and light chains by a process which requires 15-50 microM
      zinc. Previously identified binding proteins include gClqR, cytokeratin 1, and
      the urokinase plasminogen activator receptor (U-par), however, their relative
      contribution to binding are not yet clarified. We have purified the binding
      proteins by affinity chromatography, in the presence of zinc ion, and identified
      cytokeratin 1 and gC1qR by amino acid sequencing of an internal peptide and by
      immunoblot as heavy chain and light chain binding proteins, respectively.
      Antibody to cytokeratin 1 inhibited HK binding to endothelial cells by 30%,
      antibody to gClqR inhibited HK binding to endothelial cells by 72%, and a mixture
      of both inhibited binding by 86%. The binding and activation of the proteins of
      the kinin-forming cascade along the cell surface is zinc-dependent. Similarly,
      proteins of the plasma kinin-forming cascade can be activated by binding to
      aggregated A(beta) protein of Alzheimer's disease. Activation of the cascade
      using purified proteins or upon addition of Abeta to plasma requires aggregation
      of A(beta) and the reactions are zinc-dependent. In plasma, HK is cleaved and
      bradykinin is liberated. The data demonstrate that aggregated A(beta) can bind
      and activate proenzymes of the plasma kinin-forming cascade to release bradykinin
      and these reactions are dependent on zinc ion.

PMID- 10596855
TI  - Hydrolysis of kininogens by degranulated human neutrophils and analysis of
      bradykinin as chemotactic factor for cells isolated from peripheral blood.
AB  - Human neutrophils play a pivotal role in acute inflammation including the
      regulation of vascular permeability. We have examined the capacity of neutrophil
      enzymes to hydrolyse human kininogens in vitro and have also explored the
      potentiality of bradykinin to induce chemotactic migration on neutrophils
      isolated from peripheral blood. Isolated neutrophils were stimulated with either
      f-Met-Leu-Phe, thrombin or silica particles coated with human IgG. Neutrophil
      enzymes obtained by degranulation produced, after 45 min of incubation with high
      and low molecular weight kininogens, the complete transformation of both proteins
      in polypeptides ranging from 20 to less than 10 kDa in molecular mass.
      Supernatants obtained from nonstimulated neutrophils did not modify the molecular
      size of kininogens. The assay used to test the chemoattractant capacity of
      synthetic bradykinin on human neutrophils showed that this peptide has no
      chemotactic activity on cells isolated from healthy subjects. Our results show
      that stimulation of human neutrophils with opsonized silica, thrombin and the
      chemotactic peptide f-Met-Leu-Phe induces release of kininogen-hydrolyzing
      enzymes from these cells.

PMID- 10596856
TI  - Inhibition of kinin action and kinin generation compared to dexamethasone
      pretreatment with respect to vascular effects and pancreatic enzymes in
      experimental acute pancreatitis.
AB  - It was determined earlier that inhibition of the action of endogenous kinins by
      the bradykinin B2 antagonist, icatibant (Hoe-140; D-Arg-[Hyp3, Thi5, D-Tic7,
      Oic8]-bradykinin), prevents pancreatic oedema formation during caerulein-induced
      acute pancreatitis, and simultaneously improves the egress of activated
      pancreatic enzymes from the pancreas. We have now investigated whether inhibition
      of increases in vascular permeability by another approach, i.e., pretreatment
      with dexamethasone, would have comparable effects. In addition, preliminary data
      are presented on the effects of the selective low molecular weight inhibitor of
      tissue kallikrein, H-(4-Cl)-D-Phe-1Nal-(3-aminopropyl)-guanidine (CH-2856).
      Icatibant abolished plasma extravasation into the pancreatic tissue and prevented
      the development of hypovolaemia. Caerulein-induced increases of amylase activity
      in the pancreas were significantly reduced by icatibant, while amylase activity
      in blood was augmented. Inhibition of kinin generation by CH-2856 had similar
      effects, as oedema formation was inhibited and enzyme activities were reduced in
      the pancreas and augmented in the blood serum. Dexamethasone completely abolished
      oedema formation, but only partially inhibited the development of hypovolaemia
      and haemoconcentration. Amylase activities in the pancreas and in blood remained
      completely unaffected by dexamethasone. The results suggest that retention of
      activated enzymes in the pancreatic tissue during acute pancreatitis involves a
      B2 receptor-mediated, but glucocorticoid-insensitive mechanism.

PMID- 10596857
TI  - Correlation of kinin generating activity with Helicobacter pylori-associated
      gastric infection.
AB  - The kallikrein-kinin system involves a biologically complex set of interactive
      proteases that signal the first-line onset of inflammation and associated
      cellular processes. The basic enzymatic cleavage of kininogen substrate by the
      serine protease tissue kallikrein to liberate kinins is regulated by a number of
      factors. These may include the recently discovered bacterial involvement in the
      causation of gastritis. The gram-negative Helicobacter pylori organism, colonises
      the human gastric epithelium and initiates ulcerogenesis and may induce, in the
      longer term, tumour formation. The aim of this study was to investigate the role
      of kinins in H. pylori-induced gastric dyspepsia. During endoscopic examination,
      lavage aspirates of 23 patients were collected, and the tissue kallikrein content
      measured by a kinin-generating assay and an enzyme-linked immunosorbent assay.
      Gastric antral and pyloric biopsy tissue was histologically examined for degrees
      of inflammation and H. pylori infection, and then immunolabelled for tissue
      kallikrein and kinin receptors. Results show that labelled tissue kallikrein in
      the fundic glands and parietal cells of the diseased antrum was elevated with
      increasing severity of gastritis. Further, kinin-generating potential of the
      lavage fluid appeared to be greater with increasing evidence of infection. Tissue
      kallikrein immunosorbent assay levels were significantly raised in patients
      showing mild to moderate H. pylori infection. One outcome of this study may be
      the inclusion of kinin antagonists in management of gastric dyspepsia.

PMID- 10596858
TI  - Induction of the bradykinin B2-receptor, but not of the bradykinin B1-receptor,
      by interleukin-1beta in cultivated human decidua-derived cells.
AB  - Aspects of the pathophysiological steps leading to preterm labor after
      intrauterine infection can be studied in a cell culture model of decidua-derived
      cells. In this model, bradykinin (BK) increases the release of arachidonic acid
      (AA), the precursor of labor-promoting prostaglandins. The release is more than
      additively increased when cells are pretreated with interleukin-1beta (IL-1beta).
      Binding studies indicate that the expression of the bradykinin B2-receptor (B2R)
      protein rises to up to 300% of control after incubation with IL-1beta for 24 h.
      Thus, there is an increased capacity of mediating the response to BK. These
      findings suggest a pivotal role for the kallikrein-kinin system (KKS) during
      labor caused by intrauterine infection. However, there was no binding to the
      bradykinin B1-receptor (B1R), and it could not be induced by IL-1R, which is a
      unique finding compared with other cell systems.

PMID- 10596859
TI  - Renal ischemia-induced increase in vascular permeability is limited by
      hypothermia.
AB  - The purpose of the present work was to evaluate the kallikrein-kinin system and
      effects of hypothermia during renal ischemia and reperfusion. Male C57BL/KSJmdb
      mice were subjected to 20 or 60 min ischemia for different periods of
      reperfusion. Our results demonstrate that short periods of ischemia followed by
      reperfusion did not cause significant alterations in kallikrein activity, Evans
      Blue (EB) extravasation, prokallikreins, myeloperoxidase activity or plasma
      creatinine concentration. Edema was evident at 1 h reperfusion in the treated
      mice, but returned to basal values after 24 h reperfusion. Kallikrein activities
      and EB extravasation showed a significant increase in 60 min ischemic mice.
      Myeloperoxidase activity in the kidney of the mice confirmed net infiltration in
      the group with 60 min ischemia and 24 h reperfusion. The generation of kinins and
      activation of matrix degrading enzymes by tissue kallikrein, liberated from both
      renal and infiltrated leukocytes, could be responsible at least in part for the
      damage observed in the kidney of mice subject to 60 min ischemia and reperfusion.
      The hypothermia significantly reduced the inflammatory process in the 60 min
      ischemic mice, and did prevent an increase in vascular permeability.
      Nevertheless, the tissue edema was not shown to change between normothermic and
      hypothermic ischemic mice.

PMID- 10596860
TI  - Bradykinin B2 antagonist HOE 140 inhibits late allergic microvascular leakage in
      guinea pig airways.
AB  - Because bradykinin has potent inflammatory actions, this molecule may be involved
      in the late allergic response (LAR). We investigated the role of the molecule in
      airway microvascular hyperpermeability during the LAR. Three weeks after
      ovalbumin (OVA) sensitization, animals were pretreated with bradykinin B2
      receptor antagonist HOE 140 or vehicle for 30 min before the OVA inhalation
      challenge. The occurrence of LAR was judged by a two-fold increase in
      transpulmonary pressure (Ptp) from the baseline values. The microvascular
      permeability in the trachea was assessed by an index defined as the ratio of the
      area of vasculature labeled by the Monastral blue dye (area density percent).
      Significant microvascular hyperpermeability were observed during the LAR. The
      bradykinin concentrations in the bronchoalveolar lavage-fluid (BAL-f) were
      increased during the LAR. HOE 140 (0.1-10 mg/kg, s.c.) inhibited the airway
      microvascular hyperpermeability during the LAR dose-dependently. These findings
      suggest that bradykinin may play an important role in microvascular
      hyperpermeability during the LAR.

PMID- 10596861
TI  - Kinin receptors are expressed in human astrocytic tumour cells.
AB  - Tissue kallikrein (TK) is known to be present in several tumours in which
      increased KLK1 (TK) gene expression has been demonstrated. By degrading
      components of the extracellular matrix, TK may facilitate tumour proliferation
      and invasion. The vasodilatory effect of the bioactive kinin peptides causes an
      increase in vascular permeability, thereby enhancing metastasis. Since kinins act
      by receptor-linked signal transduction mechanisms, the aim of this study was to
      elucidate the localization and expression of kinin B1 and B2 receptors in
      surgical samples of human astrocytic tumours. Tumour tissue collected was
      processed for light, confocal and electron microscopy (EM) and RNA extraction.
      The mean high intensity of immunolabeling in tumour cells was quantified in
      pixels per square micrometer using the Analysis 2.1 Prosystem (Soft-Imaging
      Software, Germany, 1996). The ultrastructural localization of B1 and B2 kinin
      receptors was performed on ultrathin sections of the resin-embedded tissue, using
      immunogold-labeled probes. In the human brain, immunoreactive B2 occurs in
      cortical neurones but not in glial cells, and immunolabeling for B1 receptors is
      absent in cortical areas. In the present study, in all of the tumours studied so
      far, immunolabeling for B2 (28.42 pixels/microm2, n = 12) and B1 (14.07 pixels/
      microm2, n = 10) was observed on the astrocytic cells. Immunoreactive kinin
      receptors were also present in endothelial cells of the stromal blood vessels. At
      EM, the average number of immunogold particles was 14 for B2 receptors and eight
      for B1 receptors. The immunoreactive B2 receptors were located closer to the
      periphery of the tumour cells while B1 immunolabeling was observed throughout the
      cell.

PMID- 10596862
TI  - Rhesus differential susceptibility to endotoxin is not associated with activation
      of plasma prekallikrein.
AB  - This study is part of a project aimed at understanding individual responses to
      acute endotoxemia in a catheter-free rhesus (Macaca mulatta) model of
      inflammation. In the previous study [J. Endotoxin Res. 2 (1995) 411-420.], we
      showed that of 14 endotoxin 0111:B4 (ETX)-infused monkeys, only three died at <
      13.5 h and one at 6 days postinfusion. Doses of ETX correlated neither with the
      magnitude of hypotension nor with rhesus outcome. Survival (and death at 6 days)
      or death at < 13.5 h was rather associated with controllable or uncontrollable
      rise of plasma levels of proinflammatory cytokines and reversible or irreversible
      shock. In the current study, we used plasmas of 5 survivors and of one of the
      monkeys that died at < 13.5 h (each infused with 3 X 10(6) EU ETX/kg), and of two
      saline control monkeys of the previous study. We analyzed changes in parameters
      of coagulation and contact systems. After ETX infusion, activated partial
      thromboplastin time (APTT) and prothrombin time (PT) values increased modestly in
      survivors but markedly in the nonsurvivor; responses of platelet counts and
      levels of fibrinogen, antithrombin, alpha2-macroglobulin (alpha2M), Cl-inhibitor
      (C1INH) and alpha1 -antitrypsin were similar in survivors and the nonsurvivor;
      the rate of plasma prekallikrein (PK) activation measured by hydrolysis of the
      kallikrein (KAL) substrate D-Pro-Phe-Arg-p-nitroanilide was not altered by ETX
      infusion; and the distribution of PK activation products, analyzed by MAb
      13G11/immunoblotting in plasmas with or without artificial activation, was
      similar in survivors and the nonsurvivor. Responses in controls were relatively
      stable. Since we used defined experimental conditions, this primate model has the
      potential to be useful to study further correlation of inflammatory parameters
      with differential outcome.

PMID- 10596863
TI  - The possible role of plasma kallikrein-kinin system and leukocyte elastase in
      pathogenesis of schizophrenia.
AB  - The main purpose of this paper is to study the possible causes of blood-brain
      barrier (BBB) damage during the acute condition of schizophrenia (Sch), which
      makes brain antigens accessible to the immunocompetent cells. The development of
      autoimmune reactions in this disease has to be preceded by the damage of BBB. We
      have studied the level of activity of plasma kallikrein-kinin (KKS) and
      complement systems, C-reactive protein (CRP) concentration, proteinase inhibitory
      potential as well as the oxidized and degranulating activity of neutrophils as
      the main factors affected the permeability of tissue-blood barrier. Our results
      suggested that the acute stage of Sch was accompanied by the activation of KKS on
      the background of enhance in the functional activity of the alpha-1-proteinase
      inhibitor. The increased level of CRP, the high haemolytic activity of complement
      and significant degranulating activity of polymorphonuclear leukocytes testified
      to inflammatory character of Sch. The treatment with psychotropic drugs have led
      to decrease of polymorphonuclear elastase (PMN-E) activity in patient's plasma.
      Our in vitro study indicates that Haloperidol causes the lowering of PMN-E
      activity in the dose-dependent fashion.

PMID- 10596864
TI  - The effect of high molecular weight kininogen on neutrophil adhesion to polymer
      surfaces.
AB  - The adhesion of neutrophils on a biomaterial surface depends on the surface
      chemistry of the material and the cell, as well as the composition and
      conformation of adsorbed protein and the adherence of other cells when the
      biomaterial is exposed to circulating blood. In this study, HK and HKa were
      allowed to adsorb on three different polyurethanes: underivatized (PU-base),
      quaternized (PU-NR4), sulfonated (PU-SO3). The effect of kininogen adsorption on
      the degree of neutrophil adhesion was examined. The surface density of the
      adsorbed protein was also investigated. The PU-NR4 surface adsorbed the most HK
      and HKa and had the high degree of neutrophil adhesion. Although the surface
      density of adsorbed HK and HKa on the PU-SO3 surface, the degree of neutrophil on
      adhesion was significantly lower when compared to the PU-NR4 and PU-base
      surfaces. HK and HKa contain binding sites for both anionic surfaces and
      neutrophils in the same domain (D5H). When adsorbed to the anionic PU-SO3
      surfaces, HK and HKa did not have the neutrophil binding sites available and
      therefore, exhibited an anti-adhesive effect. In contrast, the neutrophil binding
      domains D3 and DsH of adsorbed kininogens were available on the PU-NR4 and PU
      base surfaces. Thus, adsorbed kininogens on these two surfaces lost their anti
      adhesive property and this led to a high degree of neutrophil adhesion.

PMID- 10596865
TI  - Identification and occurrence of mRNAs for components of the kallikrein-kinin
      system in human skin and in skin diseases.
AB  - Bradykinin and kallidin are released during dermal injury and inflammation as a
      result of activation of kallikreins which cleave high- and low-molecular weight
      kininogen (HMW and LMW kininogen, respectively). In the skin, kinins are
      involved, e.g., as co-mitogens in cellular proliferation or in processes
      propagating pain and inflammation. The aim of our study was to investigate the
      specific occurrence of mRNAs for components of the kallikrein-kinin system in
      normal human skin and in skin biopsies of patients with selected skin diseases
      (psoriasis, lichenificated atopic eczema, basalioma). In normal skin, reverse
      transcription polymerase chain reaction (RT-PCR) with specific primer pairs
      followed by separation of products by polyacrylamide gel electrophoresis (PAGE)
      revealed the presence of mRNAs for tissue kallikrein, for the B2 and the B1
      bradykinin receptors, but not for kininogen. In biopsies of lichenificated atopic
      eczema and basalioma, additionally, the mRNAs for HMW and LMW kininogen were
      detected, whereas in psoriatic skin mRNA for HMW kininogen was not expressed.
      These differences in mRNA expression may reflect the different contribution of
      kallikrein-kinin system components to the maintenance of chronic skin diseases
      like psoriasis. In acute dermal reactions occurring in lichenificated atopic
      eczema or in basalioma, tissue mRNA for HMW kininogen appears to be arisen from
      sources not pre-existing in normal skin.

PMID- 10596866
TI  - Serum metabolism of bradykinin and des-Arg9-bradykinin in patients with
      angiotensin-converting enzyme inhibitor-associated angioedema.
AB  - Angioedema (AE) associated with angiotensin-converting enzyme inhibitors (ACEi)
      is a rare, but potentially life-threatening adverse reaction. Several studies
      have suggested that bradykinin (BK) is responsible for ACEi-induced AE, but the
      mechanism remains unclear. We investigated the metabolism of BK and des-Arg9-BK
      in the serum of 20 patients with a history of ACEi-associated AE and 21 control
      (C) subjects. Synthetic BK was incubated with the sera for various periods of
      time and residual BK and generated des-Arg9-BK were quantified by specific and
      sensitive enzyme immunoassays. No significant difference of half-life (t1/2) of
      both BK and des-Arg9-BK could be measured between C subjects and patients with AE
      (AE) in absence of ACEi. However, an analysis according to the prolonged (+) or
      not (-) t1/2 of des-Arg9-BK allowed a new stratification of C subjects and AE
      patients in four subgroups. The preincubation of sera with enalaprilat at a
      concentration inhibiting ACE significantly prevented the rapid degradation of BK
      and des-Arg9-BK in these four subgroups. In presence of ACEi, a subgroup (50%) of
      AE patients (AE + ) had a particularly significant rise of the t1/2 of des-Arg9
      BK. Once ACE was inhibited, the concentration or the nature of the ACEi had no
      significant effect on the t1/2 of des-Arg9-BK. However, a test dilution of AE +
      sera with a control (C) serum showed that an enzyme defect rather than a
      circulating inhibitor could be responsible for the abnormal metabolism of des
      Arg9-BK when ACE is inhibited. In conclusion, half of the patients with ACEi
      associated AE present in serum had an enzyme defect involved in the des-Arg9-BK
      metabolism leading to its accumulation. The B1 agonist could be responsible, at
      least in part, for the local inflammatory reaction associated with the AE.

PMID- 10596867
TI  - Visualisation of tissue kallikrein and kinin receptors in oesophageal carcinoma.
AB  - Gene expression of tissue kallikrein (TK) and the subsequent formation of kinins
      may stimulate proliferation of tumour cells by increasing vascular permeability,
      and enhancing metastasis. Our study was undertaken to immunolocalise TK and B2
      receptor in specimens of oesophageal carcinoma immediately following
      oesophagectomy. The diagnosis and grading of oesophageal carcinoma was performed
      histologically. For localisation of TK, tissue prokallikrein (T proK) and the
      kinin receptors, slide-mounted tissue sections were subjected to peroxidase
      antiperoxidase method and immunofluorescent staining using primary antibodies
      raised against each antigen. TK was immunolocalised in giant cells of both well
      and poorly differentiated squamous cell carcinomas (SCCs). The precursor of the
      enzyme, T proK, was also immunolocalised. The most intense tissue-prokallikrein
      labelling was observed in giant tumour cells. Kinin receptors were
      immunolocalised in giant tumour cells, and the mature squamous cells. These
      findings suggests that TK, tissue-prokallikrein and kinin receptors are present
      in oesophageal carcinoma, and may be important in the process of tumourogenesis
      in this disease.

PMID- 10596868
TI  - Anti-inflammatory activity of Crinum asiaticum plant and its effect on bradykinin
      induced contractions on isolated uterus.
AB  - Crinum asiaticum Linn plant is used in Malaysia as a rheumatic remedy and to
      relieve local pain. In the present study, we examined the anti-inflammatory
      effects of this plant extract on carrageenan-induced hind paw oedema in mice. C.
      asiaticum was serially extracted with petroleum ether, followed by chloroform and
      lastly, methanol. The chloroform and methanol extracts of the plant given orally
      (50 mg kg-1) caused significant (p < 0.05; n = 7) reduction in paw oedema but the
      petroleum ether extract did not induce significant effect (p > 0.05) on paw
      oedema. The methanol extract was then dissolved in water and extracted
      consecutively with chloroform, ethyl acetate and butanol. The chloroform fraction
      of methanol extract (CFME) treatment (50 mg kg(-1)) significantly reduced (p <
      0.05; n = 7) the acute paw oedema. This may indicate that active anti
      inflammatory compounds are present in the CFME. In an attempt to study the
      mechanism of action of its anti-inflammatory activity, the effects of CFME on BK-
      and histamine-induced contractions were investigated in isolated rat uterus and
      guinea-pig ileum preparations, respectively. It was found that CFME caused dose
      dependent reduction (p < 0.05; n = 6) of the contractile response induced by BK
      and shifted the log dose-response curve of histamine to the right. The present
      findings suggest that C. asiaticum possessed an anti-inflammatory activity as
      suggested by its use in traditional medicine. The anti-inflammatory activity of
      this plant could not have been due to its anti-bradykinin activities as CFME non
      specifically inhibited BK-induced contraction. It also suggest that CFME may
      contain compound(s) with anti-histaminic properties. The significance of these
      findings is discussed.

PMID- 10596869
TI  - Companion animal welfare--is there a role for the 'Five Freedoms'?

PMID- 10596870
TI  - Epidemiological, clinical, haematological and biochemical characteristics of
      canine hypothyroidism.
AB  - Hypothyroidism was diagnosed in 50 dogs and excluded in 86 dogs suspected of
      hypothyroidism, on the basis of the results of bovine thyrotropin response tests.
      Breed, pedigree, sex or neutering status did not significantly influence the
      likelihood of the dogs being hypothyroid. The hypothyroid dogs were significantly
      older than the non-hypothyroid dogs referred to the University of Glasgow during
      the same period. However, when dogs under two years of age were excluded from the
      statistical analyses there was no significant difference in age between the two
      groups. The most common clinical characteristics associated with hypothyroidism
      were metabolic signs (84 per cent of cases), particularly lethargy (76 per cent),
      obesity or weight gain (44 per cent), and exercise intolerance (24 per cent); and
      dermatological abnormalities (80 per cent), including alopecia (56 per cent),
      poor coat quality (30 per cent) and hyperpigmentation (20 per cent). When
      compared with the laboratory reference limits the most common biochemical and
      haematological abnormalities were increased concentrations of triglycerides (88
      per cent), cholesterol (78 per cent), glucose (49 per cent), and fructosamine (43
      per cent), and increased activities of creatine kinase (35 per cent), and
      decreased concentrations of inorganic phosphate (63 per cent), and a low red
      blood cell count (40 per cent). When compared with reference limits derived from
      the euthyroid dogs the most common abnormalities were increased concentrations of
      gamma-glutamyltransferase (21 per cent), cholesterol (18 per cent), and aspartate
      aminotransferase (15 per cent) and a decreased red blood cell count (29 per
      cent), and decreased neutrophils (18 per cent) and decreased activity of creatine
      kinase (15 per cent). Assessment of cholesterol, creatine kinase, aspartate
      aminotransferase, gamma-glutamyltransferase, and red blood cell and neutrophil
      counts may be particularly useful in distinguishing hypothyroid dogs from
      euthyroid animals with similar clinical signs.

PMID- 10596871
TI  - Impact of injuries and disease on a cohort of two- and three-year-old
      thoroughbreds in training.
AB  - A prospective study of injuries and disease in a cohort of Australian
      thoroughbreds in training was conducted with the participation of 24 trainers.
      From the horses catalogued at a major yearling sale in 1995, 169 were enrolled in
      the study and followed through their two- and three-year-old racing seasons. The
      principal aim was to quantify the time lost in training as a result of the
      various categories of injuries and disease, recorded as either days of modified
      training, or weeks rested at pasture. Shin soreness was the most common condition
      in two-year-olds (affecting 42 per cent of the horses that had entered training),
      followed by fetlock problems (25 per cent), and coughs and nasal discharge (16
      per cent). Lameness, excluding lacerations and traumatic injuries, was the most
      common reason for lost training days (56.2 per cent of total days modified) and
      for resting horses at pasture (81.2 per cent of total weeks rested for injury or
      disease). Of the individual categories of injury or disease, lacerations and
      traumatic injuries, coughs and nasal discharge, shin soreness, carpal problems
      and fetlock problems were the most important causes of modified training days. In
      terms of weeks rested at pasture, fetlock problems, shin soreness, carpal
      problems, and coughs and nasal discharge had the greatest impact. Major injury
      was uncommon in young horses in training, but there was a high incidence of
      relatively low-grade injuries and disease during the training of two-year-olds.

PMID- 10596872
TI  - Unilateral eye abnormalities in reared Mediterranean gilthead sea bream.
AB  - Eye abnormalities in reared gilthead sea bream (Sparus aurata) were investigated
      clinically and by histological techniques. A significant number of fish had a
      cataract in one eye and ocular inflammation including gross exophthalmos. In a
      small number of fish gas bubbles were observed in the anterior chamber of the
      eye. Histological examination provided no evidence of an infectious process and a
      possible behavioural aetiology is discussed.

PMID- 10596873
TI  - Isolation and cultivation of a spirochaete from bovine digital dermatitis.

PMID- 10596874
TI  - Cardiac output measurement in an anaesthetised giraffe.

PMID- 10596875
TI  - Survival of verocytotoxin-producing Escherichia coli O157 under simulated farm
      conditions.

PMID- 10596876
TI  - Isolation of Clostridium difficile from the ruminal reservoir of newborn lambs.

PMID- 10596877
TI  - Agriculture at sea.

PMID- 10596878
TI  - Cost of endemic diseases.

PMID- 10596879
TI  - Electrical stunning of poultry.

PMID- 10596880
TI  - Microchipping tortoises.

PMID- 10596881
TI  - Congenital non-syndromal sensorineural hearing impairment due to connexin 26 gene
      mutations--molecular and audiological findings.
AB  - We screened DNA from 72 sibships and 138 sporadically affected individuals with
      congenital non-syndromal sensorineural hearing impairment (NSSNHI) for mutations
      in the 26 (CX26) gene. A total of 20 (27.8%) of the sibships and 11 (7.9%) of the
      sporadically affected individuals were homozygous or compound heterozygotes for
      CX26 mutations. A total of 11 (17.2%) of 64 individuals with severe and 30 (30%)
      of 100 with profound NSSNHI compared to eight (8.7%) of 92 persons with moderate
      and none (0%) of 19 individuals with mild hearing impairment were homozygous or
      compound heterozygotes for CX26 mutations (chi2 test, 3 df, P = 0.000). CX26
      mutation status bad no effect on the symmetry of the hearing impairment or
      configuration of the audiogram. In addition, serial audiograms showed no evidence
      of progression of the hearing impairment or differences in the severity of the
      hearing impairment in affected siblings in persons whether or not due to CX26
      mutations. Sporadically affected individuals with congenital NSSNHI should be
      routinely tested for mutations in CX26, especially if the hearing impairment is
      severe or profound in severity, since identification of a mutation in CX26 allows
      use of Mendelian recurrence risks.

PMID- 10596882
TI  - Antibiotic prophylaxis post-tonsillectomy: is it of benefit?
AB  - The decision to prescribe antibiotics post-tonsillectomy still remains
      controversial. However, recent changing trends in the tonsillar tissue microflora
      have been widely reported, with Haemophilus influenzae, Staphylococcus aureus and
      anaerobic organisms all being implicated. All of the above are beta-lactamase
      producers and thus render lactamase prone antibiotics inactive. We compared two
      groups of children, one on Amoxycillin and clavulanic acid (a lactamase stable
      antibiotic with anaerobic cover) for 1 week post tonsillectomy--Group A (N = 44),
      and another group on no treatment--Group B (N = 34). We compared tonsillar core,
      surface and postoperative tonsillar fossae bacteriological profiles in the two
      groups. The tonsil core pathogens included H. influenzae (64%) of which 9.5% were
      beta-lactamase producers, Streptococcus viridans (55.9%), S. aureus (37%) of
      which 86% were beta-lactamase producers, and anaerobes which were found in 25% of
      samples. We found that there was considerably less morbidity in those children
      receiving postoperative antibiotics compared to those who did not, as judged by
      the amount of analgesia consumed (p = 0.379), time to resumption of normal diet
      (p = 0.0072) and pain analogue scores (p = 0.0006). We feel that treating
      children who have undergone tonsillectomy with amoxycillin and clavulanic acid
      significantly reduces postoperative morbidity.

PMID- 10596883
TI  - Nasal brushing: a clinically useful procedure in pediatric patients with
      rhinosinusitis?
AB  - Sinusitis is a common complication of non-allergic and allergic rhinitis, and can
      trigger lower respiratory diseases, such as bronchitis and asthma. Standard
      radiography is unable to give any data about the underlying pathological
      mechanisms (infectious or allergic) involved and infectious rhinosinusitis is
      very common in pediatric age, even in allergic patients. We investigated the
      possibility of obtaining more useful diagnostic information, performing nasal
      brushing (NB) on 117 children with recurrent respiratory symptoms. The following
      hypothesis were evaluated: (1) whether NB neutrophil/eosinophil percentages
      and/or NB culture could predict the radiological evidence of maxillary sinusitis;
      and (2) whether differences between nonallergic and allergic patients could be
      detected. In the total patient group and in the nonallergic group, the comparison
      of NB neutrophil percentages in patients with and without maxillary sinusitis
      showed a statistically significant difference (median 2 and 18%, respectively; P
      < 0.001). In the nonallergic group, a NB neutrophil rate > or = 5% was chosen as
      a cut-off between positive and negative NB diagnosis of rhinosinusitis and NB
      data were compared with radiological investigations. The results obtained showed
      that NB was fairly sensitive (91%) and predictive (84%). In allergic patients,
      neither neutrophil nor eosinophil percentages significantly correlated with the
      presence of sinusitis. Microbiological studies showed that, even if the presence
      of bacteria in NB resulted associated with sinusitis, a negative culture was not
      predictive of the absence of the disease. We therefore suggest that NB describes
      the present inflammatory status of the upper airways, hence, it is more suitable
      to describe the inflammation related to ongoing upper respiratory tract
      infections rather than chronic inflammation due to allergic rhinitis,
      characterized by relapsing episodes of acute inflammation. In conclusion, we
      propose to consider NB a reliable tool in the diagnosis of rhinosinusitis,
      particularly in nonallergic pediatric patients. Compared to standard radiological
      techniques, NB makes it possible to avoid radiation exposure and gives
      information about the pathological mechanisms involved in the single patient.

PMID- 10596884
TI  - Using the carbon dioxide laser for tonsillotomy in children.
AB  - Carbon dioxide laser tonsillotomies were performed on 33 children aged 1-12 years
      for the relief of obstructive symptoms due to tonsillar hyperplasia. As opposed
      to conventional tonsillectomy, only the protruding part of each tonsil was
      removed. A carbon dioxide laser delivering 20 W was used for the excision. Twenty
      one children were seen in active short-term follow-up and the records of all the
      children were checked for possible surgery related events up to 20-33 months
      after surgery. Laser tonsillotomy was uniformly effective in relieving the
      obstruction, with good hemostasis. The tonsillar remnants healed completely
      within 2 weeks. No major adverse events occurred. Post-operative pain appeared
      slight and easily controlled. There was no gain in operating time compared with
      conventional tonsillectomy. The laser tonsillotomies were in most cases done in
      day surgery. No recurrence of obstructive problems was reported up to 20-33
      months after surgery. It was concluded that tonsillotomy, using a carbon dixoide
      laser, is a valid treatment for obstructive symptoms caused by enlarged tonsils,
      which can be performed with little bleeding and post-operative pain. The improved
      hemostasis may enable a shift from in-patient to day surgery.

PMID- 10596885
TI  - Where are the receptors for Streptococcus pyogenes located on the tonsillar
      surface epithelium?
AB  - Streptococcus pyogenes is the most frequent causative agent of acute
      pharyngotonsillitis (AT). The first events in the etiopathogenesis of an AT
      infection caused by these bacterial pathogens are their penetration through the
      mucus film covering the oropharyngeal mucosa, and their attachment to the surface
      epithelium. Adherence of S. pyogenes to tonsillar epithelial cells is a
      precondition for bacterial colonisation, for triggering off cell activation,
      internalising of bacteria into the epithelial cells and cytokine release from the
      epithelial cells with subsequent induction of an inflammatory reaction in
      underlying tissues. Scanning and transmission electron microscopic studies
      revealed that the surface epithelium of the human palatine tonsils consisted of a
      weakly keratinized, stratified squamous epithelium built up of pentangular cells
      where the apical cell surface formed an irregular pattern of microridges. The
      distance between two adjacent microridges was roughly one-third of the diameter
      of a S. pyogenes bacterium. By using gold-labelled antiserum to S. pyogenes, we
      showed that the target region for these pathogens on the epithelial cells during
      an on-going AT infection was located on the crests of the microridges where
      bacterial pili made adhesin-receptor contact with the tonsillar surface
      epithelium.

PMID- 10596886
TI  - How easily do topical antibiotics pass through tympanostomy tubes?--an in vitro
      study.
AB  - BACKGROUND: Despite potential ototoxicity, eardrops containing aminoglycosides
      remain in widespread use in the presence of indwelling tympanostomy tubes
      (grommets). It is unclear how readily they pass into the middle ear during
      administration, nor whether this is affected by middle ear secretions. MATERIALS
      AND METHODS: The trans-tympanic pressure required to force antibiotic solutions
      through a tympanostomy tube in an artificial middle ear model was investigated
      with six ototopical preparations and two sizes of tube. To assess the effect of
      middle ear secretions, tympanostomy tubes removed from patients ears were
      investigated in addition to new tubes. The intra-canal pressure generated during
      tragal massage was also measured. RESULTS: Pressures required for leakage of
      solutions differed significantly between solutions (P=0.001) and tube sizes,
      smaller lumen tubes requiring higher trans-tympanic pressure for leakage to
      occur. The presence of middle ear secretions reduced the pressure required for
      leakage of solution. Tragal massage generated pressures of over 20 cm of H20
      which would be enough to force solution into the middle ear in all tube/solution
      combinations. DISCUSSION: Some antibiotic solution is likely to leak into the
      middle ear during most applications of antibiotic solution. Although the risk is
      small, this suggests the possibility of ototoxicity, previously demonstrated in
      animal experiments. The relatively low incidence of this occurrence in clinical
      practice is thought to be related to inter-species anatomical variations.

PMID- 10596887
TI  - Single-or-two-stage laryngotracheal reconstruction; comparison of outcomes.
AB  - To compare single-stage laryngotracheal reconstruction (SSLTR) and reconstruction
      with tracheostomy and indwelling stent (two-stage LTR), a retrospective review
      was made of 69 patients undergoing laryngotracheal reconstruction for subglottic
      stenosis at Great Ormond Street Hospital for Sick Children. Pre-operative details
      recorded included grade and aetiology of subglottic stenosis, history of previous
      laryngeal surgery, sex of patient and age at reconstruction. As a measure of
      outcome, the total number of procedures including all endoscopy and further
      reconstruction was recorded as well as de-cannulation rate, and the need for more
      than one reconstruction. The patients undergoing two-stage reconstruction tended
      to have more severe stenosis (mean grade = 2.56) compared to the SSLTR group
      (mean grade = 2.14) and were more likely to have had previous laryngeal surgery.
      Inevitably, the outcome after reconstruction in the two-stage patients is
      therefore less favourable, and direct comparison of the two groups is not
      statistically valid. However, multiple regression analysis reveals that single
      stage reconstruction does confer a significant independent advantage over the two
      stage procedure in terms of average number of post reconstruction procedures (p =
      0.006), and a significant advantage in de-cannulation rate (p = 0.03). No
      difference was noted in the requirement for further reconstruction between the
      two groups. Although a two-stage procedure is still required in certain cases
      such as those with very severe stenosis or respiratory insufficiency, the single
      stage reconstruction is the procedure of choice for uncomplicated paediatric
      subglottic stenosis.

PMID- 10596888
TI  - Does adenotonsillectomy cure hypoxaemia in children with sleep apnoea and
      congenital cardiac pathology?
AB  - INTRODUCTION: Adenotonsillectomy usually cures obstructive sleep apnoea in
      otherwise healthy children. When children, with congenital cardiac pathology,
      suffer sleep hypoxaemia following their corrective cardiac surgery, they are
      referred to an otolaryngologist for adenotonsillectomy. Hardly any studies have
      been published to show how effective this operation is for these children.
      OBJECTIVE: To determine whether adenotonsillectomy significantly improves
      hypoxaemia in children with congenital cardiac pathology following corrective
      cardiac surgery. METHODS: Thirty children with sleep apnoea (aged 2-8 years) were
      recruited. Fifteen children with congenital cardiac pathology (Gp I) and 15
      children who were otherwise healthy (Gp II). All children were assessed pre
      operatively and at 1 and 3 months post-operatively with transcutaneous oxygen
      saturation monitoring. Tonsillar size, base oxygen saturation level, apnoeic
      episodes and snoring were recorded. Sleep apnoea and snoring was graded on a 5
      point scale from I (no apnoea/snoring) to V (severe apnoea and snoring). RESULTS:
      All children had an initial sleep grade of IV or V. Tonsillar size did not appear
      to be a significant factor on sleep grade in Gp I and Gp II. The median base line
      oxygen saturation was 88 and 93%, respectively in Gp I and II pre-operatively and
      improved to 90.1 and 99.2%, post-operatively. Following surgery, snoring and
      sleep apnoea disappeared in group II. In group I, there was significant reduction
      in the number of apnoeic episodes at 3 months, but the majority of children were
      still snoring with hypoxaemic episodes. CONCLUSION: This study shows that
      adenotonsillectomy significantly reduces the apnoeic episodes in children with
      cardiac pathology but does not abolish it. At 3 months after surgery there was
      significant overall improvement in the baseline oxygen saturation.

PMID- 10596889
TI  - The role of computed tomography scans in evaluating sinus disease in pediatric
      patients.
AB  - OBJECTIVES: To determine the incidence and severity of sinus abnormalities in
      children undergoing computed tomography (CT) of the sinuses for suspected chronic
      sinusitis. To compare these findings with abnormalities noted on random CT scans.
      METHODS: Sixty CT scans, performed for evaluation of sinus disease in symptomatic
      children aged 2-12, were compared with 50 CT scans of children aged 2-12 of the
      orbits or sinuses obtained for indications other than sinusitis. A staging system
      was applied to assess the severity of abnormalities. RESULTS: Mucoperiosteal
      thickening was present in 60% of symptomatic and 46%, of random CT scans
      (logistic regression, P = 0.144). Children aged 2-4 and 9-12 had an increased
      prevalence of abnormalities in both groups, although these findings were not
      statistically significant (logistic regression, P = 0.817). Early stage sinus
      disease was present in the majority of random (96%) and symptomatic (85%)
      children. CONCLUSIONS: There is a high incidence of mucoperiosteal thickening in
      the paranasal sinuses of children. CT scans of the sinuses should be obtained
      from children who are being considered for sinus surgery after failing the
      appropriate medical therapy. Decisions regarding the need for sinus surgery
      should not be solely based on imaging abnormalities.

PMID- 10596890
TI  - Parapharyngeal space mesenchymal chondrosarcoma in childhood.
AB  - A case of extra osseous mesenchymal chondrosarcoma occuring in the parapharyngeal
      space in a 7-year-old girl, is being presented for its rarity. It is a slow
      growing, locally aggressive tumour with a high incidence of local recurrence as
      well as distant metastasis. It is rare in the pediatric age group and rarer in
      the parapharyngeal space. It has a poor prognosis, the 5-year survival rate
      varies between 30 and 50%. Radical surgery is the treatment of choice.
      Radiotherapy and chemotherapy have an adjuvant role. More experience with this
      tumour is required to evaluate the most effective treatment. Current literature
      on this subject has been reviewed.

PMID- 10596891
TI  - Pediatric hemorrhagic thyroid nodule: a case report.
AB  - Hemorrhagic thyroid nodules are rare in the pediatric age group. They present as
      rapidly enlarging neck masses. Diagnostic modalities available are laboratory
      evaluation, ultrasound, radionuclide imaging, and fine needle aspiration.
      Depending on the pattern of growth of the lesion, one may observe or proceed with
      surgery. A rapidly enlarging thyroid mass raises the suspicion of malignancy, and
      hemorrhagic nodules, though rare, must be considered in the differential
      diagnosis.

PMID- 10596892
TI  - Megalin in normal tissues and carcinoma cells carries oligo/poly alpha2,8
      deaminoneuraminic acid as a unique posttranslational modification.
AB  - In rat kidney, megalin, a member of the low density lipoprotein receptor gene
      family, is the sole glycoprotein which carries oligo/poly alpha2,8
      deaminoneuraminic acid (KDN) as a posttranslational modification. We have
      investigated immunoprecipitated megalin from rat brain, lung and placenta, mouse
      yolk sac carcinoma and megalin synthesizing carcinoma cell lines, for presence of
      this unique glycan structure. Our immunoblot analysis revealed the presence of
      oligo/poly alpha2,8 KDN on megalin in all the studied normal tissues and
      carcinoma cells. Furthermore, it is demonstrated to be part of oligosaccharides O
      glycosidically linked to megalin.

PMID- 10596893
TI  - Facile enzymatic conversion of lactose into lacto-N-tetraose and lacto-N
      neotetraose.
AB  - Lacto-N-tetraose (Galbeta1 -3GlcNAcbeta1-3Galbeta1-4Glc, LNT) and lacto-N
      neotetraose (Galbeta1-4GlcNAcbeta1-3Galbeta1-4Glc, LNnT) were enzymatically
      synthesized by consecutive additions of GlcNAc and Gal residues to lactose. Lacto
      N-triose II (GlcNAcbeta1-3Galbeta1-4Glc) was prepared first by the transfer of
      GlcNAc from UDP-GlcNAc to lactose by beta-1,3-N-acetylglucosaminyltransferase
      from bovine serum. The resulting lacto-N-triose II was converted into LNT and
      LNnT utilizing two kinds of beta-D-galactosidase-mediated transglycosylations.
      Thus, beta-D-galactosidase from Bacillus circulans ATCC31382 induced
      regioselective galactosyl transfer from o-nitrophenyl beta-D-galactoside to the
      OH-3" position of lacto-N-triose II, and commercially available beta-D
      galactosidase from B. circulans to the OH-4" position of lacto-N-triose II. These
      convenient processes are suitable for large-scale preparations of LNT and LNnT.
      As another method, LNT was directly synthesized from lactose as an initial
      substance, utilizing lacto-N-biosidase (Aureobacterium sp. L-101)-mediated
      transglycosylation with Galbeta1-3GlcNAcbeta-pNP donor.

PMID- 10596894
TI  - A procedure for the preparation of GM3 ganglioside from GM1-lactone.
AB  - A simple procedure is described for preparing GM3 ganglioside, from a few
      milligrams to grams, from GM1-lactone (Sonnino et al., (1985) Glycoconjugate J 2:
      343-54) [1]. The synthesis was carried out under the following optimal
      conditions: 30 mM GM1-lactone in 0.25 M H2SO4 in DMSO, 30 min, 70 degrees C,
      nitrogen atmosphere, strong stirring. The yield of GM3 was 55%. The procedure
      applied to milligram amounts of GD1b-dilactone gave GD3 ganglioside.

PMID- 10596895
TI  - The living factory: in vivo production of N-acetyllactosamine containing
      carbohydrates in E. coli.
AB  - Scientific and commercial interest in oligosaccharides is increasing, but their
      availability is limited as production relies on chemical or chemo-enzymatic
      synthesis. In search for a more economical, alternative procedure, we have
      investigated the possibility of producing specific oligosaccharides in E. coli
      that express the appropriate glycosyltransferases. The Azorhizobium chitin
      pentaose synthase NodC (a beta(1,4)GlcNAc-oligosaccharide synthase), and the
      Neisseria beta(1,4)galactosyltransferase LgtB, were co-expressed in E. coli. The
      major oligosaccharide isolated from the recombinant strain, was subjected to LC
      MS, FAB-MS and NMR analysis, and identified as
      betaGal(1,4)[betaGlcNAc(1,4)]4GlcNAc. High cell density culture yielded more than
      1.0 gr of the hexasaccharide per liter of culture. The compound was found to be
      an acceptor in vitro for betaGal(1,4)GlcNAc alpha(1,3)galactosyltransferase,
      which suggests that the expression of additional glycosyltransferases in E. coli
      will allow the production of more complex oligosaccharides.

PMID- 10596896
TI  - A novel cytokine-inducing glycolipid isolated from the lipoteichoic acid fraction
      of Enterococcus hirae ATCC 9790: a fundamental structure of the hydrophilic part.
AB  - Previously, we showed that quantitatively minor several glycolipids totaling only
      less than 5% of the lipoteichoic acid (LTA) fraction from Enterococcus hirae ATCC
      9790 possessed cytokine-inducing activity, whereas the major component (over 90%)
      did not [Suda et al. (1995) FEMS Immun Med Microbiol 12:97-112]. The major
      inactive component was shown to have the chemical structure as was proposed for
      the LTA by Fischer [Hashimoto et al. (1997) J Biochem 121:779-86], suggesting
      that so-called LTA is not a cytokine-inducing component in the Gram-positive
      bacteria. In the present paper, the structure of the hydrophilic part of one of
      the cytokine-inducing glycolipid tentatively named GL4 is elucidated. GL4 was
      first subjected to hydrolysis with aqueous HF to give a polysaccharide and a
      mixture of low molecular weight products. The polysaccharide was composed mainly
      of highly branching mannan as concluded from NMR and MS analyses of its
      acetolysis products. The low molecular weight products consisted of phosphate and
      glycerol, suggesting the presence of a poly(glycerophosphate) structure in the
      original GL4. From these observations, the hydrophilic part of GL4 was shown to
      consist of mannose-rich polysaccharide and poly(glycerophosphate), the latter
      being bound to the former by a phosphodiester linkage.

PMID- 10596897
TI  - Binding affinity of GM3 lactone for influenza virus.
AB  - We investigated the interaction of GM3 lactone with influenza virus. The specific
      bindings of influenza virus and its hemagglutinin to GM3 lactone-containing mixed
      monolayers were studied by using a quartz-crystal microbalance. It has been known
      that gangliosides as receptors for influenza virus are also substrates for virus
      neuraminidase. GM3 lactone, however, was found to bind to influenza virus
      hemagglutinin, but not to be substrate for virus neuraminidase.

PMID- 10596898
TI  - Specificity studies of an antibody developed against a mucin-type glycoprotein.
AB  - The specificity of a new anti-epiglycanin antibody (AE-3) which recognizes a
      mucin-type glycoprotein, the Human Carcinoma Antigen, found in the blood of
      patients with carcinomas, was studied. Information regarding the chemical nature
      of the antibody binding site was obtained by altering the structure of
      epiglycanin by chemical or enzymic means and testing the product in a competitive
      binding assay for inhibition of the binding of AE-3 to epiglycanin. The need for
      a high molecular weight antigen containing clustered T disaccharide, Gal,1
      3GalNAc, was demonstrated. The specificity was further explored by inhibition
      studies with glycopeptides having one to three mono- to disaccharides. The
      results were interpreted using computer graphics molecular modeling which
      predicted the specific recognition of hydroxyl groups on oligosaccharides on
      adjacent amino acids. Thus T antigen O-linked glycopeptide tumour markers can be
      designed to be distinguished by antibodies by the amount of clustering of their
      oligosaccharides.

PMID- 10596899
TI  - 3'-Azidothymidine significantly alters glycosphingolipid synthesis in melanoma
      cells and decreases the shedding of gangliosides.
AB  - In this report, we establish that 3'-azido-3'-deoxythymidine (AZT) treatment of
      melanoma cells greatly alters the pattern of glycosphingolipid biosynthesis. In
      SK-MEL-30 cells, synthesis of the gangliosides GM3 and GD3 was significantly
      inhibited (60% and 50% of control, respectively) and the production of their
      precursor, lactosylceramide, was stimulated by 2.5-fold. Control experiments
      established that phospholipid synthesis was not affected by AZT treatment,
      consistent with AZT treatment only affecting lipid biosynthetic reactions that
      involve glycosylation. Likely as a consequence of decreased rates of ganglioside
      synthesis, AZT treatment of SK-MEL-30 cells also significantly suppressed the
      amount of gangliosides shed from the membranes of these cells. Since shedding of
      gangliosides has been proposed to allow melanoma cells to avoid destruction by
      the immune system and alterations of glycosphingolipid levels are likely
      important for the malignant cell phenotype, these results may have important
      implications regarding the potential use of AZT or related glycosylation
      inhibitors as cancer chemotherapeutics.

PMID- 10596900
TI  - Immune-stimulating properties of polysaccharides from Phellodendri cortex
      (Hwangbek).
AB  - Heteropolysaccarides were isolated from the Korean medicinal plant, Phellodendri
      cortex (Hwangbek), by hot water and alkali extractions. The extracted
      polysaccharides were fractionated into eight fractions and they are mainly
      composed of D-N-acetylglucosamine, D-galactose, D-mannose, and D-glucose. Among
      the polysaccharide fractions, Fr.-2 showed a potent B-lymphocyte-stimulating
      activity in a system using polyclonal antibody forming cells in C57BL/6XC3H mice
      at dosages of 2-10 mg. On the basis of their solubility in aqueous ethanol, four
      fractions of Fr.-2-1 to Fr.-2-4 were further obtained from the Fr.-2, and Fr.-2-3
      was divided into Fr.-2-3-1, 2, 3, and 4 by DEAE cellulose chromatography. The
      main activity was found in Fr.-2-3-2, which contained 100% (w/w) of carbohydrates
      and further purified to Fr.-2-3-2-2 by gel filtration chromatography using TSK
      Gel HW50S. Fr.-2-3-2-2, having a molecular weight of about 230 kDa, showed the
      highest B-cell-stimulating activity and the half-maximal concentration for B
      lymphocyte-stimulating activity was ca. 2.2 microg/ml.

PMID- 10596901
TI  - Mechanisms and therapeutic applications of immune stimulatory cpG DNA.
AB  - Aside from its function as the "blueprint of life" that encodes genetic
      information, DNA can have direct immune activities. The immune system has evolved
      a defense mechanism that is able to distinguish microbial DNA from our own
      because of differences in the frequency and methylation of CpG dinucleotides in
      particular base contexts. Within minutes of detecting such "CpG-S DNA," cells of
      the innate immune system become activated and produce cytokines that promote the
      generation of antigen specific T-helper-1-like immune responses. Animal studies
      indicate therapeutic utility for CpG-S DNA as a vaccine adjuvant and for the
      immunotherapy of cancer and infectious and allergic diseases.

PMID- 10596902
TI  - The use of heterologously expressed drug metabolizing enzymes--state of the art
      and prospects for the future.
AB  - The first report of the functional, heterologous expression of a mammalian
      cytochrome P450 (CYP) enzyme occurred more than a decade ago. In the intervening
      years, these expression systems have been optimized with regard to the specific
      requirements for production of catalytically active enzymes. In this review, we
      discuss the strengths and limitations of heterologously expressed enzymes as they
      affect in vitro drug metabolism studies. Emphasis is given to new applications
      (screens for CYP inhibition and novel enzyme mixtures) that have been enabled by
      high level, functional expression of CYP enzymes.

PMID- 10596903
TI  - Dopamine receptors--physiological understanding to therapeutic intervention
      potential.
AB  - There are two families of dopamine (DA) receptors, called D1 and D2,
      respectively. The D1 family consists of D1- and D5-receptor subtypes and the D2
      family consists of D2-, D3-, and D4-receptor subtypes. The amino acid sequences
      of these receptors show that they all belong to a large superfamily of receptors
      with seven transmembrane domains, which are coupled to their intracellular signal
      transduction systems by G-proteins. The implications of DA receptors in
      neuropsychiatry and cardiovascular and renal diseases are discussed.
      Neuropsychiatry indications include Parkinson's disease, schizophrenia, migraine,
      drug dependence, mania and depression, and Gilles de la Tourette syndrome. The
      underlying dysfunction of dopaminergic systems and the potential benefits of
      dopaminergic therapy in these different indications are critically examined. With
      respect to the pharmacological treatment of Parkinson's disease, a range of DA
      agonists are in various stages of preclinical and clinical development. D2
      receptor agonist activity is predominant in most effective antiparkinsonian DA
      agonists. However, in practice, it is difficult to treat patients for several
      years with DA agonists alone; therapeutic benefit is not sustained. Rather, the
      use of a combination of DA agonists and levodopa is considered preferable.
      Reports of the efficacy of DA partial agonists await confirmation, and recent
      clinical investigations also suggest the potential of D1 receptor agonists as
      antiparkinson drugs. Regarding migraine pathogenesis, clinical and
      pharmacological evidence suggests that DA is involved in this disorder. Most
      prodromal and accompanying symptoms may be related to dopaminergic activation.
      Several drugs acting on DA receptors are effective in migraine treatment.
      Furthermore, migraine patients show a higher incidence of dopaminergic symptoms
      following acute DA agonist administration, when compared with normal controls. In
      cardiology, the therapeutic benefits of DA agonists are noted in the treatment of
      heart failure. Low doses of DA are widely used for its specific dopaminergic
      effects on renal function, which are suggested to be beneficial, and for its
      alpha- and beta-adrenergic-mediated responses that occur with higher doses.
      However, studies have been unable to demonstrate that DA can prevent acute renal
      failure or reduce mortality. It appears that the significant progress that is
      being made in the molecular understanding of DA receptors will continue to have a
      tremendous impact in the pharmacological treatment of neuropsychiatric,
      cardiovascular, and renal diseases.

PMID- 10596904
TI  - Pharmacological modulation of nitric oxide synthesis by mechanism-based
      inactivators and related inhibitors.
AB  - Nitric oxide synthase (NOS) (EC 1.14.13.39) is a homodimeric cytochrome P450
      monooxygenase analog that generates nitric oxide (NO) from the amino acid L
      arginine. Enzymatically produced NO acts as an intracellular messenger in
      neuronal networks, blood pressure regulatory mechanisms, and immune responses.
      Isoform-selective pharmacological modulation of NO synthesis has emerged as a new
      therapeutic strategy for the treatment of diverse clinical conditions associated
      with NO overproduction. Mechanism-based inactivators (MBIs) represent a class of
      NOS mechanistic inhibitors that require catalytic turnover to produce
      irreversible inactivation of the ability of NOS to generate NO. Diverse isoform
      selective NOS MBIs have been characterized with respect to their kinetic
      parameters and chemical mechanisms of inactivation. In studies with isolated and
      purified NOS isoforms, MBIs produce irreversible inactivation of NOS enzymatic
      activities. The inactivation process is associated with covalent modification of
      the NOS active site and proceeds either through heme destruction, its structural
      alteration, or covalent modification of the NOS protein chain. The behavior of
      NOS MBIs in intact cells is different from their behavior observed with the
      isolated NOS isoforms. In cytokine-induced RAW 264.7 macrophages, treatment with
      MBIs produces a complete loss of cellular NOS synthetic competence and inducible
      NOS activity. However, following drug removal, cells can recover at least
      partially in the absence of protein synthesis. In GH3 cells containing the
      neuronal NOS isoform, calcium transients are too low and abbreviated to allow
      significant NOS inactivation; hence, the cellular effects of MBIs on the neuronal
      isoform are almost completely and immediately reversible.

PMID- 10596905
TI  - Computational approaches to structure-based ligand design.
AB  - The first computational structure-based drug design methods came into existence
      in the early 1980s and are, to an extent, still in their infancy. There have been
      a few successes to date. With dramatic increases in computer speed, improved
      accuracy in ligand scoring functions, and the advent of combinatorial chemistry,
      there promises to be many more. In addition, the virtual explosion in the amount
      of available sequence and structural information has increased the need to
      develop these computational techniques to exploit this vast body of information.
      In this review, recent advances in computational methods for database searching
      and docking, de novo drug design, and estimation of ligand binding affinities are
      discussed.

PMID- 10596906
TI  - Localization and trafficking of alpha2-adrenergic receptor subtypes in cells and
      tissues.
AB  - The three alpha2-adrenergic receptor (alpha2AR) subtypes, all of which couple to
      multiple effectors via Gi/Go proteins, perform various functions, including the
      mediation of decreases in adenylyl cyclase activity, activation of receptor
      mediated K+ channels, and inhibition of voltage-gated Ca2+ channels. The
      alpha2ARs are polarized in many target cells, such as neurons in the peripheral
      and central nervous system and in intestinal and renal epithelia. Precise
      targeting and polarization of molecules are crucial for many physiological
      processes, and may confer a degree of specificity that, in the case of the
      adrenergic receptors, could represent a reasonable strategy by which
      catecholamines coordinate cellular function in a highly specific way. Receptors
      also redistribute in response to agonist occupancy by means of sequestration,
      endocytosis, recycling, or, alternatively, down-regulation (degradation). The
      focus of this review is to compare the similarities and differences among the
      three alpha2AR subtypes in terms of specificity, signaling, and trafficking. It
      is anticipated that a molecular understanding of receptor trafficking will lead
      to novel therapeutic strategies for diseases linked to aberrant adrenergic
      receptor function or localization.

PMID- 10596907
TI  - Functional, structural, and dynamic basis of electrical heterogeneity in healthy
      and diseased cardiac muscle: implications for arrhythmogenesis and anti
      arrhythmic drug therapy.
AB  - The electrophysiological properties of the ventricular myocardium are extremely
      heterogeneous. There are intrinsic electrical differences between the myocytes
      from different regions of the heart (most notably between the epicardium,
      midmyocardium, and endocardium), which are the result of different contributions
      of ionic currents to the transmembrane action potential. Sources of local
      anisotropy include directional differences in the distribution of gap junctions
      between adjacent myocytes and the presence of intercalated non-myocytes (e.g.,
      fibroblasts), propagation boundaries, and wavefront collisions, which can lead to
      local variability of electrical load and, therefore, to nonuniform depolarisation
      and repolarisation. In addition, the complex anatomical arrangement of the
      myocardial fibres and nonuniform distribution of transmural mechanical stresses
      also contribute to electrical heterogeneity. Finally, dispersion of
      repolarisation is dynamically modified by the restitution properties of
      individual myocytes, stimulation rate, and the direction of conduction. All
      aspects of this electrical heterogeneity can be affected by different
      pathological conditions, such as myocardial ischaemia and cardiac hypertrophy. In
      particular, differential responses of various myocyte populations to these
      pathological stimuli and a marked increase in nonuniform anisotropy may be
      responsible for increased pro-arrhythmic potential in these conditions. In
      addition, the clinical effectiveness of anti-arrhythmic drugs may be related to
      their effects on electrical heterogeneity.

PMID- 10596908
TI  - Genes involved in melanoma: an overview of INK4a and other loci.
AB  - Melanoma is the most aggressive of the skin cancers and its prognosis is often
      poor. The only known environmental risk factor for this tumour is ultraviolet
      light exposure. This fact together with the existence of melanoma-prone families
      has prompted investigation of genetic risk factors that may be involved in
      melanoma development. Inactivation of the INK4a/p16 gene is known to play a role
      in familial cases. Data on genes or loci involved in sporadic melanoma are less
      definitive and require more detailed research. In addition to the INK4a locus,
      other genes involved in melanoma development are discussed here, in particular
      those genes that participate in the same functional pathway, such as CDK4 and Rb,
      and p53, which is regulated by the alternative product of INK4a. Evidence showing
      the possible location of melanoma susceptibility genes on chromosomes 1p, 6, 10q
      and 11q is analysed along with data showing N-ras, betacatenin, c-myc and MC1R
      involvement. Melanoma is a well-characterized disease in terms of its progression
      stages; therefore obtaining precise genetic information is crucial in the
      development of a stepwise model of melanoma pathogenesis.

PMID- 10596909
TI  - Expression of tyrosinase, TRP-1 and TRP-2 in ultraviolet-irradiated human
      melanomas and melanocytes: TRP-2 protects melanoma cells from ultraviolet B
      induced apoptosis.
AB  - Tyrosinase related protein (TRP)-1 and TRP-2 are known to regulate the quality of
      melanin, and recently their potential role in inhibiting apoptosis have also been
      reported. To study the role of tyrosinase, TRP-1 and TRP-2 in the growth,
      differentiation and cell death of ultraviolet B (UVB) irradiated melanocytes, the
      expression of these proteins in amelanotic and melanotic cells was examined.
      Expression of tyrosinase and TRP-1 correlated with melanin content, which was
      upregulated after repeated irradiation of melanotic cells by low doses of UVB. In
      contrast, the expression and activity of TRP-2 correlated with cell
      proliferation, but not with pigmentation. In one melanotic melanoma cell line,
      significant suppression of cell proliferation was observed after low or high
      doses of UVB irradiation, possibly due to apoptotic changes. TRP-2 expression was
      remarkably reduced in UVB-irradiated cells, and transfection with TRP-2
      expression vector rescued these cells from UVB-induced apoptosis. These results
      indicate that TRP-2 expression is closely associated with the regulation of cell
      growth/survival of melanocytes exposed to UVB and that TRP-2 plays a role in
      protecting melanoma cells from UVB-induced apoptosis.

PMID- 10596910
TI  - Expression of angiogenic and immunosuppressive factors by uveal melanoma cell
      lines.
AB  - Dissemination of uveal melanomas is almost exclusively haematogenous, making
      angiogenesis of the tumour a prerequisite for the formation of metastases. Uveal
      melanomas must employ strategies to evade the immune system in order to escape
      immune surveillance. We therefore determined the expression of the following
      angiogenic and immunosuppressive factors in seven human uveal melanoma cell lines
      using reverse transcriptase-polymerase chain reaction (RT-PCR): secreted
      interleukin-1 receptor antagonist (sIL-1ra), interleukin (IL)-6, IL-8, IL-10,
      transforming growth factor (TGF)-alpha, TGFbeta, vascular endothelial growth
      factor (VEGF), platelet derived growth factor (PDGF), basic fibroblast growth
      factor (bFGF), angiopoietin-1 and angiopoietin-2. In addition, the secretion of
      sIL-1ra, IL-6, IL-8, IL-10, TGFbeta and VEGF was assayed by enzyme linked
      immunosorbent assay (ELISA). The potential of uveal melanoma cell lines to
      convert plasminogen to angiostatin was tested in an in vitro assay. All the
      factors except angiopoietin-1 were determined in one or more cell lines using RT
      PCR, although these results were not necessarily confirmed by ELISA. Expression
      of VEGF and angiopoietin-2 was found in all seven cell lines. Production of
      angiostatin was observed in one cell line. All seven cell lines examined
      expressed angiogenic factors and most cell lines expressed immunosuppressive
      factors. The expression of VEGF and angiopoietin-2 in combination with a lack of
      angiopoietin-1 expression suggest high vascular remodelling capacity and could be
      of great relevance for the metastatic potential of uveal melanoma.

PMID- 10596911
TI  - Sensitivity to extrinsically supplied interferon and the endogenous expression of
      interferon in melanoma cell lines.
AB  - Interferons (IFNs) have been shown to Induce loss of growth potential in melanoma
      cell lines. However, human melanomas have shown limited responsiveness to
      clinical therapy with IFN. In a previous study on melanoma cell lines we found
      that greatest sensitivity to IFN was found in cell lines with the greatest number
      of copies of chromosome 9p, where the IFN gene family is located. In the present
      study the expression In melanoma cell lines of IFN genes, IFN receptor genes and
      standard control genes (beta-actin, glyceraldehyde-3-phosphate dehydrogenase, 18S
      rRNA and cyclophilin) was investigated using the reverse transcription-polymerase
      chain reaction, together with an exogenous standard (cyclophllin armoured RNA).
      We found that the sensitivity to extrinsically supplied IFN seems to correlate
      with the expression of endogenous IFN genes. The two melanoma cell lines
      producing the highest relative amount of IFN mRNA transcripts also demonstrated
      the most marked response to extrinsically supplied IFN. We hypothesize that
      tumours with enhanced endogenous IFN production may respond more positively to
      IFN treatment.

PMID- 10596912
TI  - Lack of p21waf1 and p27kip1 protein induction by interferon-alpha2a in human
      melanoma cell lines.
AB  - The ability of human recombinant interferon-alpha2a (IFNalpha2a) to induce the
      expression of cyclin-dependent kinase inhibitors p21waf1 and p27kip1 consequent
      to signal transducers and activators of transcription (STAT) protein activation
      was investigated in six human melanoma cell lines with different susceptibilities
      to the antiproliferative effect of the cytokine. All the cell lines expressed
      IFNalpha and IFNalpha/beta receptors. Exposure for 24 h to IFNalpha2a markedly
      enhanced the nuclear expression of STAT1 and STAT2 proteins in all the cell
      lines. However, no induction of p21waf1 or p27kip1 was consistently observed.
      Overall, results from the study suggest that the induction of such cyclin
      dependent kinase inhibitors is not a major mechanism for the antiproliferative
      effect of IFNalpha2a, at least in human melanoma cell lines.

PMID- 10596913
TI  - The detection of circulating melanoma cells correlates with tumour thickness and
      ulceration but is not predictive of metastasis for patients with primary
      melanoma.
AB  - We analysed peripheral blood samples from 143 patients with primary melanoma (PM)
      for the presence of tyrosinase mRNA by reverse transcription-polymerase chain
      reaction (PCR) to determine whether the early detection of circulating melanoma
      cells (CMCs) is of clinical value in monitoring melanoma progression. Ten of the
      patients (7%) with PM had detectable CMCs. The percentage of PCR-positive
      patients was higher for stage II patients (9.0%) than for stage I (5.3%), but the
      difference was not significant. A significantly higher percentage (P<0.05) of PCR
      positive patients were found to have tumours greater than 1.5 mm in thickness or
      had ulcerated tumours. This suggests that tumour thickness and ulceration are the
      two most significant prognostic factors. The detection rate of 9% for patients
      with stage II disease is much lower than would be expected, since 23.9% (16 out
      of 67) of the stage II patients subsequently developed metastases. Of these 16
      patients, only one was PCR-positive, 1 week before the metastases became
      clinically evident. Thus, the current technique fails to predict the likelihood
      of developing metastatic disease (P=0.3485). The other nine PCR-positive patients
      had not developed metastases after a median follow-up period of 4 years. It is
      concluded that this technique for the detection of CMCs is of limited clinical
      value in predicting the likelihood of metastasis in patients with PM. It is
      suggested that the detection of micrometastases in other anatomical compartments,
      such as sentinel lymph nodes, should be explored for the identification of
      patients at risk for developing metastases.

PMID- 10596914
TI  - Immature human monocyte-derived dendritic cells migrate rapidly to draining lymph
      nodes after intradermal injection for melanoma immunotherapy.
AB  - Injected antigen-loaded immature monocyte-derived dendritic cells (DCs) may be
      incapable of migrating from skin to draining lymph nodes for antigen
      presentation. The in vivo migratory capacity of intradermally administered
      immature monocyte-derived DCs was therefore investigated during a phase I/II
      clinical trial for metastatic melanoma. DCs cultured from adherent monocytes in
      the presence of autologous serum, granulocyte-macrophage colony stimulating
      factor and interleukin-4 were pulsed with antigen and labelled with technetium
      99m hexamethylpropylene-amineoxime (99mTc-HMPAO) ex vivo, then injected
      intradermally. A 99mTc-HMPAO control containing an equivalent amount of
      radioactivity was injected into the opposite thigh. The pelvis was then imaged
      with a gamma camera. The DCs were characterized as immature by functional and
      phenotypic analysis. Labelled DCs travelled to the draining inguinal lymph nodes
      within 10 min, and the draining lymph nodes were clearly outlined up to 4 h after
      injection. Free NmTc outlined draining lymph nodes after 10 min but was cleared
      from the nodes within 1 h. Thus, immature human monocyte-derived DCs migrate
      rapidly to and remain in draining lymph nodes after intradermal injection for
      immunotherapy.

PMID- 10596915
TI  - Pilot study of intra-arterial cisplatin and intravenous vinblastine and
      dacarbazine in patients with melanoma in-transit metastases.
AB  - For melanoma, in-transit metastases (ITMs) are a harbinger of systemic disease in
      over 70% of patients and thus warrant a systemic approach to management. In this
      study, previously untreated patients with ITMs (n=15) received a systemic regimen
      of 'CVD' in 21 day cycles (median, three cycles) as follows: dacarbazine 800
      mg/m2 intravenously (i.v.) on day 1, vinblastine 1.6 mg/m2 i.v. on days 1-5, and
      cisplatin (CDDP) 100 mg/m2 by 24 h intra-arterial (i.a.) infusion in 1l of
      heparinized saline via the iliac or subclavian artery on day 3. There were three
      clinical complete responses (CRs) in patients with a modest burden of ITMs (< 3
      cm in size) and seven partial responses (PRs), yielding a 67% response rate (95%
      confidence interval, 38-88%). One of the clinical CRs had microscopic residual
      disease at surgery (a pathological PR). The times to progression (TTP) for the
      CRs were 5, 21 and 38+ months; the median TTP for the PRs was 4.5 months (range,
      2-10 months). Overall median survival was 31 months. Systemic toxicities were
      similar to those induced by i.v. CVD. However, patients noted more pronounced
      paraesthesia in the infused extremity. Also, two patients experienced severe CDDP
      induced burns, one patient developed brachial plexopathy, and one patient had a
      haemorrhage in an occult brain metastasis. The high clinical activity of this
      regimen will have to be confirmed in more patients before a first-pass i.a.
      advantage can be claimed. Furthermore, the dose, schedule and technique of i.a.
      CDDP delivery must be further refined before it can be routinely incorporated in
      regimens as an alternative to isolated regional hyperthermic perfusion, which is
      technically more difficult and is not readily available in community-based
      hospitals.

PMID- 10596916
TI  - Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or
      without interferon-gamma for the treatment of in-transit melanoma metastases: a
      multicentre randomized phase II study.
AB  - This open, multicentre, randomized phase II trial was conducted to determine the
      effect of isolated limb perfusion (ILP) with tumour necrosis factor-alpha
      (TNFalpha) in combination with melphalan with or without interferon-gamma
      (IFNgamma) in patients with in-transit metastases of melanoma of the limbs (MD
      Anderson stage IIIA or IIIAB, AJCC stage III). The 64 patients included were
      randomized to receive either a two- drug regimen consisting of TNFalpha and
      melphalan (TM-ILP) or a three-drug regimen consisting of TNFalpha, melphalan and
      INFgamma (TIM-ILP). Patients randomized to receive IFNgamma were pretreated for 2
      days before the ILP with once daily 0.2 mg IFNgamma subcutaneously and also
      received the same amount of IFNgamma during ILP. A total of 47 complete responses
      (73%) were reported, 22 (69%) of which occurred in the TM-ILP group and 25 (78%)
      in the TIM-ILP group; the difference was not significant. The 14 partial
      responses (22%) were split evenly between the treatment groups. In the TM-ILP
      group, two cases of stable disease and one case of progressive disease were
      reported. The overall response rate (complete plus partial responses) was 100% in
      the TIM-ILP group and 91% in the TM-ILP group, yielding an overall response of
      95% for this study. In the historical control data, where 103 patients had
      received melphalan alone (M-ILP), there were 54 records of complete responses
      (52%) and 80 of complete or partial responses (78%). The median survival time
      estimated by the Kaplan-Meier method was 819 days for the TM-ILP group, > 705
      days for the TIM-ILP group and 873 days for the combined study population;
      estimates for time to local progression or recurrence were 327 days, in excess of
      498 days and 405 days, respectively. The corresponding figure for the historical
      controls was 338 days. These data suggest that TNFalpha associated with melphalan
      may be superior to melphalan alone for ILP.

PMID- 10596917
TI  - Multi-institutional phase II randomized trial of integrated therapy with
      cisplatin, dacarbazine, vindesine, subcutaneous interleukin-2, interferon alpha2a
      and tamoxifen in metastatic melanoma. BREMIM (Biological Response Modifiers in
      Melanoma).
AB  - The aim of this study was to evaluate the toxicity and efficacy of a
      monochemotherapy regimen of dacarbazine (DTIC), tamoxifen , interferon-alpha2a
      and interleukin-2 (IL-2) and two polychemotherapy regimens of cisplatin, DTIC,
      vindesine, tamoxifen, interferon-alpha2a with or without IL-2 in patients with
      metastatic melanoma. Consecutive patients with metastatic melanoma were enrolled
      in this trial and were randomized to arm A, consisting of DTIC 800 mg/m2 every 21
      days, IL-2 9 MIU subcutaneously days 1-5 and 8-12, arm B, consisting of cisplatin
      30 mg/m2 days 1-3, DTIC 250 mg/m2 days 1-3 and vindesine 2.5 mg/m2 day 1 every 28
      days (CVD), or arm C, consisting of CVD plus IL-2 6 MIU days 1-5 and 8-12 every
      28 days. In all three arms Interferon 3 MU subcutaneously three times a week and
      tamoxifen 20 mg orally were given throughout. Ninety-two patients were included
      in this study. Patient characteristics in the three groups were well balanced.
      The three regimens were delivered on an outpatient basis without major toxicity.
      The toxicities that did occur consisted primarily of flu-like symptoms in the IL
      2 arms (A and C) and haematological toxicities in the CVD arms (B and C). No
      grade IV toxicities were encountered and no treatment-related deaths occurred.
      The total response rate was 13% in arm A, 35% in arm B and 37% in arm C. The
      median duration of response was 6 months and the median survival was 11 months.
      According to this phase II randomized trial polychemoimmunotherapy with CVD has
      an objective response rate of 35-36%, while monochemoimmunotherapy with DTIC has
      a response rate of 13%.

PMID- 10596918
TI  - Infections and melanoma risk: results of a multicentre EORTC case-control study.
      European Organization for Research and Treatment of Cancer.
AB  - Immune function plays a prominent role in the defence against cutaneous malignant
      melanoma and the increased risk of melanoma development during immunosuppression.
      Since the immune system is challenged beyond its routine activity by an
      infection, the effect of previous infectious diseases on the risk of melanoma may
      also be crucial. In a European Organization for Research and Treatment of Cancer
      (EORTC) case-control study performed in six European countries and Israel, we
      compared the history of severe infections in 603 melanoma patients with that in
      627 population controls. We calculated adjusted odds ratios (ORs) to estimate the
      effect of infectious diseases on melanoma risk. The ORs for melanoma risk were
      below 1 for nearly all types of infections (except two) if body temperature was
      not taken into consideration, and for all infections with a body temperature
      above 38.5 degrees C. In the latter category significantly lowered ORs were found
      for pulmonary tuberculosis (0.16; 95% confidence interval [CI] 0.01-0.98),
      Staphylococcus aureus infections (0.54; 95% CI 0.31-0.94), sepsis (0.23; 95% CI
      0.06-0.70), influenza and related infections (0.65; 95% CI 0.48-0.86) and
      pneumonia (0.45; 95% CI 0.27-0.73). Analysis of the cumulative influence revealed
      a consistent pattern of results pointing to a reduction in melanoma risk with
      increasing numbers of recorded infections and fever height. This apparent dose
      response relationship suggests a causal association. Speculations on the
      underlying mechanism include a Shwartzman-like phenomenon when melanoma formation
      precedes the infection and/or an infection-related Th1-cell activation preventing
      the establishment of the tumour.

PMID- 10596919
TI  - Decreased density of epidermal dendritic cells in melanocytic naevi: the possible
      role of in vivo sun exposure.
AB  - Melanocytic naevi are benign skin tumours that originate in the epidermis. The
      pathogenesis of naevi and cutaneous malignant melanoma has been linked to sun
      exposure. This study evaluates alterations in the density of immunologically
      active epidermal dendritic cells (EDCs) in naevi in response to sun exposure.
      Immunohistologically stained sections of 266 naevi from patients from Israel
      (n=135) and Germany (n=131) were evaluated. The proportion of naevi with
      decreased density of HLA-DR+ (dDR+) and CD1a+ (dCD1a+) EDCs was analysed
      according to country, last exposure to sunlight, anatomical location and
      histological subtype. The risk of dDR+ was found to be linked to residence in
      Israel compared with Germany (odds ratio [OR] = 4.2; 95% confidence interval [CI]
      = 2.0-8.9), suggesting a latitude-dependent effect. Naevi removed in summer had a
      higher risk of dCD1a+ (OR = 4.7; 95% CI = 2.3-9.8) compared with those removed in
      winter. The most conspicuous dDR+ among the German cases, and dCD1a+ among the
      Israelis, occurred in naevi located on commonly exposed skin. The similar
      densities of EDCs in the lesional and perilesional skin of the majority of the
      naevi indicates that the underlying naevus cells have no effect on EDC density.
      It is not unlikely that an altered immune response due to dDR+ and dCD1a+ in sun
      exposed skin in the vicinity of naevi contributes to the subsequent melanoma risk
      in highly susceptible individuals.

PMID- 10596920
TI  - Nodular histogenetic type.

PMID- 10596921
TI  - Adjuvant treatment of melanoma using placebo or no therapies as control-arm: is
      it ethically correct?

PMID- 10596922
TI  - Biological control of parasitic nematodes of the horse; the need, practicalities
      and prospects.

PMID- 10596923
TI  - Equine dysautonomia: has grass been blamed unfairly all this time?

PMID- 10596924
TI  - Anatomy rises from the ashes.

PMID- 10596925
TI  - Review of equine laparoscopy and an analysis of 158 laparoscopies in the horse.

PMID- 10596926
TI  - Characterisation of lymphocyte subpopulations in the skin and circulation of
      horses with sweet itch (Culicoides hypersensitivity).
AB  - Circulating lymphocyte numbers are elevated in horses with the allergic skin
      disease sweet itch and skin lesions are typified by an infiltrate of eosinophils
      and mononuclear cells, the latter of which have not been fully characterised. The
      aim of the present study was to characterise the lymphocyte subpopulations in the
      circulation and skin of ponies with sweet itch by flow cytometry and a newly
      developed modified alkaline phosphatase immunohistochemical technique. Sweet itch
      ponies were found to have significantly greater numbers of circulating CD5+ and
      CD4+ T-lymphocytes than normal animals. Increased numbers of CD3+ T-lymphocytes,
      most of which were CD4+, and eosinophils were present in the skin of these
      animals following intradermal injection of a Culicoides antigen extract (97 +/-
      21 vs. 449 +/- 49 CD3+ T-lymphocytes/mm2 in deep dermis of vehicle vs. antigen
      injected sites; 83 +/- 8% CD4+ T-lymphocytes at antigen injected site). T
      lymphocytes, which are thought to be important in the pathogenesis of human
      allergic skin disease, may therefore contribute to the development of sweet itch
      lesions via the release of cytokines which can cause eosinophil accumulation and
      activation. An understanding of the pathology of this disease may lead to a more
      rational approach to therapy.

PMID- 10596927
TI  - A serological and clinical follow-up in horses with confirmed equine granulocytic
      ehrlichiosis.
AB  - For diagnosis of equine granulocytic ehrlichiosis (EGE) serological testing of
      antibodies to Ehrlichia equi is frequently used. An elevated antibody level is
      often misinterpreted as confirmative of active infection and results in treatment
      with antibiotics. If only seropositivity is considered as the diagnostic
      criterium, many horses showing convalescence titres will be treated. This study
      was undertaken to obtain information about the kinetics of antibodies during the
      course of infection and, for this purpose, 45 horses with clinical signs of EGE
      and confirmed ehrlichiaemia were monitored serologically and clinically over
      time. For a correct handling of cases with suspected EGE, the following results
      should be helpful: (i) 44% of the horses in the acute ehrlichiaemic stage were
      found to be serologically positive to E. equi; (ii) all horses showed a rapid
      increase in antibody titre, reaching maximum value within a month after the
      ehrlichiaemic stage; (iii) when 8 months had passed, titres had decreased, but 18
      of 24 examined horses were still serologically positive; (iv) after 12-15 months
      most of the horses (n = 10) were serologically negative; and (v) the period
      required for complete clinical recovery varied from one day up to 6 months after
      antibiotic treatment.

PMID- 10596928
TI  - Encephalopathy with idiopathic hyperammonaemia and Alzheimer type II astrocytes
      in equidae.
AB  - In 3 mature female horses of varying breeds, episodes of colic and depression for
      14 days preceded an encephalopathic disorder with maniacal behaviour, anxiety,
      profuse sweating and, in one case, terminal opisthotonus. Blood ammonia levels
      were elevated approximately 10-fold. At necropsy, there were gastrointestinal
      serosal and mesenteric haemorrhages. Histologically, all 3 cases revealed diffuse
      Alzheimer type II astrocytes in the cerebral grey matter. Alzheimer type II
      astrocytes were glial fibrillary acidic protein (GFAP) negative or only weakly
      positive, weakly S-100 positive, and vimentin negative. In the absence of primary
      hepatic and/or renal lesions, an increase in intestinal ammonia absorption due to
      ileus or increased ammonia production by colonic bacteria is hypothesised.

PMID- 10596929
TI  - Transabdominal ultrasonographic determination of fetal gender in the horse during
      mid-gestation.
AB  - Gender determination of the equine fetus using transabdominal ultrasonography was
      studied in 20 mares. One group of 10 research mares was scanned repeatedly every
      2 weeks from 100 days gestation to parturition, while the second group of 10
      client mares was subjected to echography once during mid-gestation. In males, the
      penis and/or prepuce was observed on 71 occasions from 102 days to 258 days
      gestation. On cross-sectional views, the male external genitalia had a round
      shape with parallel linear echogenic foci up to approximately 140 days gestation
      and then appeared triangular. Fetal testes were oval in shape in frontal view and
      had an homogeneous ultrasonographic appearance. Females were diagnosed on 23
      occasions from 118 days to 227 days gestation based on the presence of the
      mammary glands and teats. Fetal ovaries appeared homogeneous with a
      characteristic circular echo from 100 days to 134 days gestation. Gender
      identifications (n = 98) based on the presence of the penis and/or prepuce in
      males and mammary glands and teats or fetal gonads in females were all correct,
      in agreement with the sex of the foals at birth. The optimal window of time was
      defined in both sexes as 100 to 220 days gestation. Thereafter, it was
      increasingly difficult to identify the anatomical structures cited above. Fetal
      sex was mainly determined using the transabdominal approach (87/98). However, the
      transrectal approach was useful in cases in which fetuses were either in
      posterior presentation or located very high in the mares abdomen. Good quality
      diagnostic scanners used typically in equine reproduction and equipped with a 5.0
      MHz probe can be used for this procedure up to 160 days gestation, after which a
      3.5 MHz transducer is often necessary due to increasing fetal size.

PMID- 10596930
TI  - A new isolate of the nematophagous fungus Duddingtonia flagrans a biological
      control agent against free-living larvae of horse strongyles.
AB  - An experiment was carried out in 1997 to test the efficacy of an isolate of the
      microfungus Duddingtonia flagrans against free-living stages of horse strongyles
      under conditions in the field and to assess the eventual effect of the fungus on
      the normal degradation of faeces. Faecal pats were made from faeces of a
      naturally strongyle infected horse, which had been fed fungal material at a dose
      level of 106 fungal unit/kg bwt. Control pats without fungi were made from faeces
      collected from the same animal just before being fed fungi. Faecal cultures set
      up for both groups of faeces to monitor the activity of the fungus under
      laboratory conditions showed that the fungus significantly reduced the number of
      infective third-stage larvae (L3) by an average of 98.4%. Five faecal pats from
      each batch of faeces were deposited on pasture plots at 3 times during spring
      summer. The herbage around each pat was sampled fortnightly to recover L3
      transmitted from faeces. The results showed that the herbage infectivity around
      fungus-treated pats was reduced by 85.8-99.4%. The remaining faecal material at
      the end of each sampling period was collected, and the surviving L3 were
      extracted. Significantly fewer larvae were recovered from the fungus-treated
      pats. Analysis of wet and dry weight of the collected pats, as well as their
      organic matter content, were performed to compare the degradation of faeces of
      both groups. The results indicated that the presence of the fungus did not alter
      the degradation of the faeces.

PMID- 10596931
TI  - The association of Clostridium botulinum type C with equine grass sickness: a
      toxicoinfection?
AB  - The cause of grass sickness, an equine dysautonomia, is unknown. The disease
      usually results in death. Gastrointestinal (GI) dysfunction is a common clinical
      manifestation in all forms of the disease. It is generally thought that equine
      grass sickness (EGS) is caused by an ingested or enterically produced neurotoxin
      which is absorbed through the GI tract. Clostridium botulinum was first
      implicated as a causative agent when it was isolated from the GI tract of a horse
      with EGS in 1919. The aim of the present study was to investigate the hypothesis
      that EGS results from toxicoinfection with C. botulinum type C: growth of the
      bacterium in the GI tract with production of toxin (BoNT/C). Ileum contents and
      faeces from horses with EGS were investigated for BoNT/C, and indirectly for the
      presence of C. botulinum type C, and compared with control samples from horses
      without EGS. BoNT/C was detected directly by ELISA in the ileum of 45% (13/29) of
      horses with EGS compared to 4% (1/28) of controls, and in the faeces of 44%
      (20/45) of horses with EGS compared to 4% (3/77) of controls. Levels of up to 10
      Mlg toxin/g wet weight of gut contents were observed. The one control horse with
      detectable toxin in the ileum had been clinically diagnosed as having acute EGS,
      but this was not confirmed by histopathology. The organism was detected
      indirectly by assaying for BoNT/C by ELISA after enrichment in culture medium. C.
      botulinum type C was shown to be present in 48% (14/29) of ileum samples and 44%
      (20/45) of faecal samples from horses with EGS, compared with 7% (2/27) of ileum
      samples and 8% (6/72) of faecal samples from controls. These results support the
      hypothesis that EGS results from a C. botulinum type C toxicoinfection.

PMID- 10596932
TI  - Retrospective study of subchondral sclerosis and lucency in the third carpal bone
      of Standardbred trotters.
AB  - The aim was to investigate radiographic findings of subchondral sclerosis and
      subchondral lucency in the dorsoproximal-dorsodistal (DPr-DDi) projection of the
      third carpal bone (C3) in relation to clinical appearance and to prognosis for
      racing. In a retrospective study, case records of 89 Standardbred trotters
      diagnosed with traumatic carpitis confirmed with intra-articular anaesthesia were
      examined. Records included data on degree of lameness at presentation and after
      flexion tests and a radiographic examination of the carpus, including a DPr-DDi
      projection of the C3. Subchondral lucency was found significantly to influence
      the degree of lameness at presentation and the time to start but did not
      significantly affect the chance of racing within 30 months post examination. In
      the present material no significant relationship between degree of sclerosis and
      lameness or prognosis for racing within 30 months was found, but the low number
      of C3 with severe sclerosis limited conclusions about that group.

PMID- 10596933
TI  - In vitro mechanical properties of different equine hoof wall crack fixation
      techniques.
AB  - Hoof wall cracks need mechanical stabilisation to allow healing. Common
      techniques are fixation with screws, wires and plates or bonding of a patch
      across the crack. An in vitro system to determine the shear properties of equine
      hoof crack repairs is described. The force and displacement at yield, stiffness
      and ultimate force were determined for 4 repair techniques based on an acrylic
      material, polyurethane patch attached with cyanoacrylate adhesive, steel plate
      attached with screws and a transverse metal bar cut into the hoof wall. The
      cyanoacrylate bonded patch repair had lower values for all parameters measured (n
      = 8, P<0.05) and the other 3 repairs had similar mechanical properties. This
      study demonstrates that acrylic adhesive repairs can resist similar shear forces
      to traditional screw plate repairs without risk of penetrating into the sensitive
      structures of the foot. The transverse bar mounted across the crack had similar
      resistance to shear as the much larger screw plate and plain bonding repair
      techniques. This novel technique may be a useful adjunct to other repair methods.

PMID- 10596934
TI  - Radiological study to evaluate suspected scapulohumeral joint dysplasia in
      Shetland ponies.
AB  - A radiological study was performed to test the hypothesis that osteoarthritis of
      the scapulohumeral joint in Shetland ponies is secondary to shoulder dysplasia.
      Animals were selected into 3 groups: Group 1: Shetland ponies with a radiological
      and clinical diagnosis of scapulohumeral osteoarthritis (n = 8); Group 2:
      Shetland ponies without forelimb lameness (n = 12); Group 3: Horses/ponies
      without a history or clinical signs of forelimb lameness (n = 22). Anatomical
      indices were measured from mediolateral radiographs of a scapulohumeral joint
      from each animal. There was a significant difference in the mean radius of
      curvature of the glenoid cavity of the scapula (RCG) between the 3 groups (MANOVA
      test, P = 0.003). The mean RCG of both Group 1 (P = 0.001) and Group 2 (P =
      0.022) was significantly greater than that of Group 3. There was no significant
      effect of group on the radius of curvature of the humeral head or on the
      Conformity Index. There was a significant effect of group on the Glenoid Ratio
      (MANOVA test, P = 3 x 10(-6)). The mean Glenoid Ratio was significantly lower in
      both Group 1 (P = 2 x 10(-6)) and in Group 2 (P = 0.006) than in Group 3. These
      results indicate that the glenoid cavity of the scapula is 'flatter' and
      'shallower' in Shetland ponies which we postulate to be a primary dysplasia in
      this breed.

PMID- 10596935
TI  - A survey of white line disease in Japanese racehorses.
AB  - A survey was carried out into white line disease in 1781 Thoroughbred racehorses
      kept in stables at the Japan Racing Association (JRA) Miho Training Center (MTC)
      September-October 1996. The survey was conducted while horses were being shod by
      farriers. The horses that still exhibited damaged white lines after regular
      trimming were diagnosed as having white line disease. The factors recorded were
      age, sex, number of diseased horses, number of diseased hooves, number of lesions
      by region over the bearing border of the hoof and the classified length of such
      lesions. The percentage of total diseased horses was 11.5% (204 animals), with
      incidence increasing significantly with age (P< or =0.01). Occurrence was
      independent of sex (P>0.05) was more frequent in the fore- than in the hindhoof
      and developed more frequently at the toe than at any other region of the forehoof
      bearing border. Most lesions ranged from 20 to 30 mm in length.

PMID- 10596936
TI  - Equine dental disease part 2: a long-term study of 400 cases: disorders of
      development and eruption and variations in position of the cheek teeth.
AB  - Of 400 referred horses with dental disorders, 349 cases suffered from primary
      disorders of their cheek teeth, ninety of these from disorders of development or
      eruption, or displacements. These included 20 cases with rostral maxillary and
      caudal mandibular cheek teeth overgrowths, 16 with diastemata, 15 with grossly
      enlarged mandibular 'eruption cysts', 4 with grossly enlarged maxillary cheek
      teeth 'eruption cysts', 10 cases with supernumerary cheek teeth and 23 cases with
      displaced cheek teeth. These displacements were believed to be developmental in
      16 cases and acquired in the remaining 7 cases. Long-term response to treatments,
      that included removal of overgrowths and extraction of teeth with deep secondary
      periodontal disease was excellent for most disorders except diastemata.

PMID- 10596937
TI  - Ultrasonographic anatomy of the equine temporomandibular joint.

PMID- 10596938
TI  - General anaesthesia decreases osteocalcin plasma concentrations in horses.

PMID- 10596939
TI  - The use of scintigraphy in the diagnosis of aortic-iliac thrombosis in a horse.

PMID- 10596940
TI  - Persistent vitelline arteries in a foal.

PMID- 10596941
TI  - Ultrastructural characterization of the interstitial cells of Cajal.
AB  - Recent studies on the interstitial cells of Cajal (ICC) have determined
      ultrastructural criteria for the identification of these previously enigmatic
      cells. This review deals with the electron microscopic findings obtained by the
      author's research group in different tissue regions of the gut in mice, rats and
      guinea-pigs, comparing these with reports from other groups in different species
      and in humans. ICC are characterized by the following morphological criteria:
      numerous mitochondria, abundant intermediate filaments and large gap junctions
      which connect the cells with each other and with smooth muscle cells. Due to
      their location in the gut and the specific species, the ICC are markedly
      heterogeneous in appearance, ranging from cells closely resembling smooth muscle
      cells to those similar to fibroblasts (Table 1). Nevertheless, the above
      mentioned morphological features are shared by all types of ICC and serve in
      identifying them. Recent discoveries on a significant role of c- kit in the
      maturation of the ICC and their specific immunoreactivity to anti-c-Kit antibody
      have confirmed the view that the ICC comprise an independent and specific entity
      of cells. This view is reinforced by the findings of the author's group that the
      ICC characteristically possess vimentin filaments and are stained with the zinc
      iodide-osmium tetroxide method which provides a staining affinity similar to
      methylene blue, the dye used in the original work by Cajal, (1911). Developmental
      studies indicate that the ICC are derived from a non-neuronal, mesenchymal
      origin. This paper further reviews advances in the physiological studies on the
      ICC, in support of the hypothesis by THUNEBERG (1982) that they function as a
      pacemaker in the digestive tract and a mediator transmitting impulses from the
      nerve terminals to the smooth muscle cells.

PMID- 10596942
TI  - Scanning electron microscopic detection of nuclear structures involved in DNA
      replication.
AB  - In order to evaluate at the ultrastructural level the three dimensional chromatin
      arrangement during interphase and particularly during the S phase, the immunogold
      detection of Bromodeoxyuridine (BrdU), as a marker of DNA synthesis, was
      performed in human HeLa, HL60, and in murine Friend leukemia cells (FLC). Field
      emission in lens scanning electron microscopy analysis of ultrathin cryosections
      revealed the presence of a regular three-dimensional network of fibers in
      dispersed chromatin. This spatial architecture was apparently constituted mainly
      of 10 nm filaments organized in loops of about 80-100 nm. Nodal points and the
      overlapping of such coils appeared as thicker structures of about 30 nm in
      diameter. Thin filaments of about 5 nm did not show a regular distribution. This
      three-dimensional fiber organization seemed quite constant in the dispersed
      chromatin of all the cell lines analyzed. The DNase treatment of the samples
      selectively removed the 10 nm class fibers, whereas the BrdU labeling confirmed
      the presence of newly synthesized DNA organized into chromatin units with a
      regular arrangement. These data suggest that the 10 nm chromatin fiber likely
      represents the DNA condensation order at which DNA duplication starts and the
      main weft of a three dimensional network within the interphase nucleus.

PMID- 10596943
TI  - Growth of collagen fibrils produced by human osteosarcoma cells: high-resolution
      scanning electron microscopy.
AB  - To demonstrate three-dimensionally the process of the collagen fibril growth, the
      bottom of culture dishes with human osteosarcoma cells (NOS-1) and their extracts
      were examined by conventional scanning electron microscopy (SEM). Backscattered
      electron (BSE) imaging of SEM was also applied to the specimens, which were
      stained with phosphotungustic acid and uranyl acetate. Conventional SEM images
      showed several stages of collagen fibril assembly. Short collagen fibrils with
      tapered ends were distributed at the bottom of the dish just beneath and/or
      around the cultured cells; they were 1 microm long and 20-30 nm in diameter at
      the thickest middle portion. These fibrils were often twisted and united in a
      right helical direction, and consequently increased in length (5-10 microm) and
      diameter (more than 100 nm). In BSE images, the periodical bands stained with
      phosphotungstic acid and uranyl acetate were visualized throughout the individual
      fibrils. The banding pattern indicated that the polarity of the collagen
      molecules was unidirectional; namely, that all molecules were pointed in the same
      direction throughout the length of the fibrils.

PMID- 10596944
TI  - Regional differences in the cellular proliferation activity of the regenerating
      rat pancreas after partial pancreatectomy.
AB  - The proliferation activity of component cells and its regional differences in the
      regenerating rat pancreas after 90% pancreatectomy were examined by
      bromodeoxyuridine (BrdU) immunohistochemistry. Cells of the ductal system and the
      centroacinar cells showed a rapid increase in labeling indices at day 2 after
      pancreatectomy, followed by a second peak of a mild increase at days 5 to 7. No
      regional difference in the labeling index was recognized in the ductal elements.
      In contrast, the labeling index of acinar cells started to increase at day 3,
      reaching a definite peak at day 5. Furthermore, acinar cells in the region close
      to the duodenum had labeling indices more than 2 times higher than those in the
      portions further away from the duodenum. Acinar cells increased in number as
      early as from day 3 after surgery. These result suggested that the parental cells
      of regeneration were located in the ductal epithelium. It is highly probable that
      the proliferation of acinar cells is controlled by some unknown trophic factor(s)
      which is released locally from the duodenum, but does not involve a neural or a
      circulatory route. The phenomenon may be closely linked to the known fact that
      the incidence of pancreatic cancer is highest in the head region.

PMID- 10596945
TI  - The serous demilune of rat sublingual gland is an artificial structure produced
      by conventional fixation.
AB  - The ultrastructure of the secretory end-piece of the rat sublingual gland was
      examined in samples prepared by rapid freezing and freeze-substitution method,
      and results were analyzed in combination with 3-D images reconstructed by
      computer graphics from light micrographs of serial sections. Fixation by rapid
      freezing followed by freeze-substitution preserved cellular ultrastructures,
      especially the membrane structure, in perfect condition, and demonstrated the
      terminal portion of the sublingual gland to be a compound branched tubulo
      alveolar gland with serous cells distributed throughout the end-pieces. All the
      serous cells aligned with mucous cells to surround a common lumen, leaving no
      demilune structure. In contrast, samples fixed by the conventional immersion
      method showed distended mucous cells displacing the serous cells toward the basal
      portion of the acinus to form the demilune structure. The luminal space was also
      compressed and appeared disconnected from the serous cells. From these
      observations, the serous demilune that for more than 130 years has been believed
      to be an actual histological entity was proved to be an artificial structure
      produced through compression by the hydrated and expanded mucous cells during
      immersion fixation.

PMID- 10596946
TI  - Dynamics of astrocyte adhesion as analyzed by a combination of atomic force
      microscopy and immuno-cytochemistry: the involvement of actin filaments and
      connexin 43 in the early stage of adhesion.
AB  - We observed the time-dependent morphological alteration of astrocytes during
      their adhesion by atomic force microscopy (AFM) and investigated the
      relationships between this morphological alteration and the localization of actin
      filaments and connexin 43 by immunocytochemistry. The fine processes observed as
      fine ridge-like structures by AFM were closely concerned with actin filaments by
      immunocytochemistry. During the adhesion of astrocytes, actin filaments appeared
      to be aligned regularly beyond the borders among different cells. Detectable
      connexin immunoreactivity was changed in the following regions: 1) the tips of
      fine cell processes and the cell margin when astrocytes started to adhere; 2) the
      border of cells when astrocytes tightly adhered; and 3) non-specific sites when
      astrocytes became a cluster. In the former two cases, the immunopositive spots
      for connexin were observed to colocalize with the tips of cell processes with
      actin filaments. These results strongly suggest that connexin associated with
      actin filaments at the tip of cell processes plays an important role in the early
      stage of the adhesion of astrocytes. These observations afford valuable clues for
      understanding the glial communication.

PMID- 10596947
TI  - Heterogeneous reactivity of murine epidermal Langerhans cells after application
      of FITC: a histochemical evaluation.
AB  - To elucidate the detailed kinetics of epidermal Langerhans cells after topical
      contact sensitizer stimulation, we examined ATPase or Ia positive epidermal cells
      of BALB/c mice in a time-spaced manner after the topical application of
      fluorescein isothiocyanate (FITC). We also performed double labeling of
      Langerhans cells in epidermal sheets with ATPase activity and Ia antigen or
      costimulatory molecules (B7-1 and B7-2) after the same stimulation. Observations
      showed that the density of ATPase positive cells and Ia positive cells decreased
      following a different time course; the former reached a nadir (77.4% of control)
      at 4 h but the latter reached a minimum (82.8% of control) at 16 h after the
      application of FITC. A double labeling technique revealed an increase in Ia
      single positive cells at 4 h as opposed to that of ATPase single positive cells
      at 16 h after application. Both costimulatory molecules were expressed on the
      dendritic processes of many Langerhans cells as a dotty pattern at 4 h after
      application; B7 positive and ATPase negative areas were observed at this time. On
      electron microscopic observation, a few activated Langerhans cells found in the
      dermis at 4 h after application had distinctive profiles compared with residual
      Langerhans cells in the epidermis. These findings suggest that there is a
      heterogeneity of reactivity to FITC in epidermal Langerhans cells, and that only
      a small portion of them migrates from the epidermis during sensitization. The
      findings also indicate the importance of the interaction between the Langerhans
      cell and its surrounding microenvironment in the epidermis for its activation. In
      addition, the results indicate that the enzymatic and the phenotypic markers do
      not definitively reflect the presence (or absence) of Langerhans cells.

PMID- 10596948
TI  - Three-dimensional architecture of the keratin filaments in epithelial cells
      surrounding taste buds in the rat circumvallate papilla.
AB  - The three-dimensional architectures of the perigemmal cells and their keratin
      bundles in the rat circumvallate papillae were studied by transmission and
      scanning electron microscopy. The perigemmal cells were classified into three
      layers: basal, middle and upper. The basal layer consisted of polygonal cells
      located close to the basal lamina, the middle layer comprised longitudinally
      elongated cells fitting the lateral convexity of the taste bud, and the upper
      layer was imbricating flat cells along the upper portion of the taste bud. When
      fresh specimens were jointly treated with Triton X-100 and sonication, the taste
      buds were often detached and the cytoplasmic matrices of the perigemmal cells
      were effectively removed. Consequently, we were able to demonstrate an extensive
      network of the subplasmalemmal keratin bundles of the perigemmal cells. The
      framework appeared either as a thin lacework, a thick fence-like structure, or a
      lattice work in the basal, middle, and upper layers, respectively. The thin
      lacework in the basal layer was considered to be a developing process of the
      framework. The thick fence-like structure in the middle layer probably plays a
      primary role in supporting the taste bud. The latticework in the upper layer is
      believed to reflect a remodeling in reducing the keratin framework.

PMID- 10596949
TI  - Cytoplasmic delayed neuronal death in the myenteric plexus of the rat small
      intestine after ischemia.
AB  - The present study demonstrates light and electron microscopic changes in neurons
      in the myenteric plexus of the rat ileum following four-hour ischemia.
      Macroscopically, an intestinal constriction occurred at the damaged portion at
      three weeks after ischemia; the segment oral to the constriction markedly swelled
      at four weeks. In light microscopy, at three weeks after ischemia, the myenteric
      neurons appeared spongy or foamy, containing many vacuoles in their somatic
      cytoplasm. At four weeks, the neuronal cytoplasm and nerve fiber bundles had
      disintegrated to form vacant spaces in the myenteric plexus. The neuronal nucleus
      of the damaged plexus did not show positive nick-end labeling. In electron
      microscopy, neuronal cytoplasm revealed degenerative signs already at one week
      after ischemia: a distended endoplasmic reticulum and swollen mitochondria with
      fragmentary cristae. The nerve fibers also showed destruction of the
      mitochondria, and degenerative changes in the postsynaptic sites appeared earlier
      than the presynaptic terminals. The results suggest that intestinal ischemia
      causes delayed neuronal death, which differs from the apoptotic process
      previously demonstrated in the ischemia-damaged brain.

PMID- 10596950
TI  - Succinate dehydrogenase activities of fibers in the rat extensor digitorum
      longus, soleus, and cardiac muscles.
AB  - Succinate dehydrogenase (SDH) activities and cross-sectional areas (CSAs) of
      different types of fibers in the superficial (EDLs) and deep (EDLd) regions of
      the extensor digitorum longus and soleus (SOL) muscles and the left ventricular
      muscle of the heart (HEART) of 10-week-old male rats were determined using
      quantitative histochemistry and a computer-assisted image processing system. The
      fibers were classified as type I, type IIA, type IIB, or type IIC according to
      their histochemically assessed adenosine triphosphatase activities. The mean SDH
      activity was higher and the mean CSA was smaller in type IIA fibers than in type
      IIB fibers in both the EDLs and EDLd. The mean SDH activity of type IIA fibers in
      the SOL was higher than that of type I fibers. Fibers in the HEART showed the
      highest mean SDH activity and the smallest mean CSA among all fiber types in the
      muscles examined. There was an inverse correlation between CSA and SDH activity
      for the different fiber types in different muscles. These data suggest that the
      SDH activity of fibers in muscle is fiber type- and size-specific, and that the
      highest SDH activity of fibers in the left ventricular muscle of the heart
      contributes to their functional properties, i.e., high fatigue resistance.

PMID- 10596951
TI  - Artificial neural networks in laboratory medicine and medical outcome prediction.
AB  - Since the early nineties the number of scientific papers reporting on artificial
      neural network (ANN) applications in medicine has been quickly increasing. In the
      present paper, we describe in some detail the architecture of network types used
      most frequently in ANN applications in the broad field of laboratory medicine and
      clinical chemistry, present a technique-structured review about the recent ANN
      applications in the field, and give information about the improvements of
      available ANN software packages. ANN applications are divided into two main
      classes: supervised and unsupervised methods. Most of the described supervised
      applications belong to the fields of medical diagnosis (n = 7) and outcome
      prediction (n = 9). Laboratory and clinical data are presented to multilayer feed
      forward ANNs which are trained by the back propagation algorithm. Results are
      often better than those of traditional techniques such as linear discriminant
      analysis, classification and regression trees (CART), Cox regression analysis,
      logistic regression, clinical judgement or expert systems. Unsupervised ANN
      applications provide the ability of reducing the dimensionality of a dataset. Low
      dimensional plots can be generated and visually understood and compared. Results
      are very similar to that of cluster analysis and factor analysis. The ability of
      Kohonen's self-organizing maps to generate 2D maps of molecule surface properties
      was successfully applied in drug design.

PMID- 10596952
TI  - Mitochondrial disorders. A diagnostic challenge in clinical chemistry.
AB  - Mitochondria play a pivotal role in cellular metabolism and in energy production
      in particular. Defects in structure or function of mitochondria, mainly involving
      the oxidative phosphorylation (OXPHOS), mitochondrial biogenesis and other
      metabolic pathways, have been shown to be associated with a wide spectrum of
      clinical phenotypes. The ubiquitous nature of mitochondria and their unique
      genetic features contribute to the clinical, biochemical and genetic
      heterogeneity of mitochondrial diseases. We will focus on the recent advances in
      the field of mitochondrial disorders and their consequences for an advanced
      clinical and genetic diagnostics. In addition, an overview on recently identified
      genetic defects and their pathogenic molecular mechanisms will be given.

PMID- 10596953
TI  - Enrichment of mutant alleles by chromatographic removal of wild type alleles: a
      new principle for the detection of alleles with unknown point mutations at excess
      of wild type alleles.
AB  - In human carcinomas, mutations that alter tumour genes such as the KRAS, P53, or
      APC genes, are mostly point mutations. The detection of mutant alleles of tumour
      genes in specimens such as urine, pancreatic juice, sputum, and stool holds great
      promise for an early diagnosis of cancer. In addition, the detection of mutant
      tumour genes in tissue samples, such as lymph nodes or resection margins, may
      allow a sensitive diagnosis of residual malignant disease. However, the reliable
      detection of mutant alleles in excess of wild type alleles remains an unresolved
      analytical problem when the mutations are not known a priori. In the present
      communication, a new approach is described which makes possible the detection of
      unknown point mutations in tumour genes at excess of wild type alleles. The
      method is based on the removal of wild type alleles by hybridisation to
      immobilised complementary oligonucleotides. Using this approach, an enrichment of
      mutant KRAS, P53 and APC alleles of one mutant in up to 10(3) normal alleles has
      been achieved. Parallel miniaturised separation units with oligonucleotides
      complementary to defined sequences of a wild type allele should allow the
      detection of unknown point mutations as well as small insertions or deletions
      which occur in the sequence range covered by the oligonucleotides.

PMID- 10596954
TI  - Quantitative differences between aberrant transcripts which occur as common
      isoforms and due to mutation-based exon skipping of the mismatch repair gene
      hMLH1.
AB  - About one-third of hereditary non-polyposis colorectal cancer-related mutations
      in the mismatch repair gene hMLH1 result in the loss of entire exons from the
      wild type transcripts. Here we describe quantitative differences of hMLH1
      transcripts without exon 15, exon 16 or exon 17 in several members of a family
      with hereditary non-polyposis colorectal cancer. The transcript lacking exon 15
      is caused by a G to A transition affecting the last nucleotide of the respective
      exon and results in a truncated protein. The transcripts lacking exon 16 or exon
      17, which are in-frame deletions, were also found in all tested samples of a
      normal population and represent common isoforms. Reverse transcription-polymerase
      chain reaction-based relative quantification revealed about 50 % signal intensity
      for the mutation-based transcript, but less than 10% for the common isoforms, if
      compared to the wild type. All aberrant transcripts were detected from blood
      derived cDNAs but not from samples of normal colon epithelium. Although the
      biological significance of the common isoforms is unknown, they might lead to
      false risk assessment in hereditary non-polyposis colorectal cancer cases.

PMID- 10596955
TI  - Analytical and clinical performance of two cardiac troponin I immunoassays.
AB  - Cardiac troponin I assays for Axsym (Abbott Diagnostics, Abbott Park, IL, USA)
      and Immuno 1 (Bayer Corporation, Tarrytown, NY, USA) analysers were evaluated.
      Heparin plasma or serum could be used for both assays. Samples were stable for 24
      h at ambient temperature, 3 days at 4-8 degrees C and 3 months at -20 degrees C.
      After 10 months' storage at -80 degrees C, the recoveries were well above 100% by
      both assays. Total coefficients of variation for Axsym assay were 9.0%, 5.8% and
      5.3% at concentrations of 2.6 microg/l, 9.83 microg/l and 34.3 microg/l
      respectively; for Immuno 1 these were 4.4 %, 1.6% and 1.8% at 2.3 microg/l, 6.27
      microg/l and 44.35 microg/l respectively. It was > or =20% at concentration of <
      or =0.5 microg/l for Axysm assay and < or =0.15 microg/l for Immuno 1 assay.
      Recoveries were < or =90% at < or =0.22 microg/l on Axsym and at < or =1.47
      microg/l on Immuno 1. Neither method showed significant interference with
      haemoglobin, bilirubin, triglycerides or rheumatoid factor. Correlation between
      the two methods was excellent (r = 0.997, Y (Axsym) = 4.2X (Immuno 1) +3.2). The
      highest concentrations detected in 50 healthy subjects were 0.3 microg/l and 0.1
      microg/l by Axsym and Immuno 1 methods, respectively. Twelve out of 43 renal
      failure patients had troponin I 0.13-0.9 microg/l using Axsym method and 4 had
      levels of 0.07-0.13 microg/l using Immuno 1. In muscle trauma patients, troponin
      I was undetectable.

PMID- 10596956
TI  - Development of an automated immunoturbidimetric ferritin assay.
AB  - We have developed a new procedure for turbidimetric measurement of ferritin
      concentration in human serum, based on latex microparticle agglutination
      technology. The procedure has been automated using the Falcor 300 analyzer.
      Carboxilated latex particles (336 nm in diameter) were covalently coupled with
      immunopurified F(ab')2 fragments of anti-ferritin IgG antibodies. Coated
      microparticles were automatically mixed with undiluted sample and the resulting
      absorbance due to agglutination was measured at 550 nm. The procedure generated a
      calibration curve with a measuring range of 0 to 558 microg/l, showing a day-to
      day imprecision lower than 5.7%. The detection limit was 4 microg/l. There were
      no interferences from bilirubin, hemoglobin or rheumatoid factors. Turbid and
      lipemic samples caused an important interference which could be avoided by
      pretreating those samples prior to measurement. A prozone effect was
      provisionally obtained with ferritin concentrations over 1800 microg/l. The
      results suggested a hook-like effect due to a rapid microparticle precipitation
      in the reaction media, that could be avoided by increasing the reaction medium
      density by adding sucrose to the buffer, up to 150 g/l concentration. This
      sucrose addition resulted in a displacement of the Heidelberger curve with a
      prozone phenomenon occuring at concentration higher than 3000 microg/l of
      ferritin. Results obtained with the present procedure correlated well with those
      obtained by a nephelometric procedure and with those obtained by an RIA. We
      conclude that this latex turbidimetric immunochemical procedure is simple, rapid,
      has a good analytical and operational performance on the Falcor 300 analyzer and
      is well suited for the measurement of ferritin concentration in human serum.

PMID- 10596957
TI  - Does the uncertainty of commonly performed glucose measurements allow
      identification of individuals at high risk for diabetes?
AB  - Revised recommendations for diagnosis of diabetes introduce the intermediary risk
      group of impaired fasting glucose (IFG), defined as individuals with a fasting
      blood-glucose concentration between 5.6 and 6.0 mmol/l. We apply the concept of
      uncertainty to identifiable steps of sampling and measuring blood-glucose. Since
      many instruments in primary health care measure plasma-glucose and report results
      as blood-glucose and vice versa, factors affecting the transformation are also
      considered. The study identifies the measurement procedure as the major source of
      uncertainty, closely followed by preanalytical sources. The estimated
      uncertainties indicate that the presently available procedures do not allow
      identification of IFG by a single investigation. The approach to establish an
      uncertainty budget can be used to evaluate the clinical usefulness of
      measurements.

PMID- 10596958
TI  - Autoantibodies against oxidized LDL in the first phase of life. Low density
      lipoproteins.
AB  - The study presents a comparison of data concerning lipid metabolism and lipid
      oxidation (oxidative stress) in children at the time of their birth and 3 months
      later, as well as of their mothers at the time of delivery, compared to a control
      group of non-pregnant women of the same age. The data confirm that labour
      represents an oxidative stress for both mother and child; it is expressed as a
      significant increase of malondialdehyde concentration in mothers immediately
      after delivery in comparison with non-pregnant women (p<0.001). Its concentration
      in newborns was even higher than in their mothers (p<0.005). Concentration of
      antibodies against oxidized LDL (oxLDLAb) was comparable in mothers and newborns
      due to their transplacental transport. During the first three months of life
      these autoantibodies increased almost two-fold. The importance of this unique
      observation is discussed with respect to possible early atherogenesis.

PMID- 10596959
TI  - Recommendations of the German Working Group on medical laboratory testing (AML)
      on the introduction and quality assurance of procedures for Point-of-Care Testing
      (POCT) in hospitals.
AB  - The following recommendations were drawn up by the Working Group "Point-of-Care
      Testing" of the DGKC and DGLM which was set up in 1997. This first document from
      the Working Group sets out the principles which should be observed when
      introducing point-of-care testing. These general recommendations are to be
      followed by further specific recommendations on individual procedures or groups
      of procedures, e.g. blood glucose, electrolytes in whole blood, blood gases,
      coagulation, toxicology, quality control and others, which will be drawn up by
      experts at the suggestion of the Working Group.

PMID- 10596960
TI  - Assays for serum amyloid A (SAA)

PMID- 10596961
TI  - Effect of clofibrate on malic enzyme and leptin mRNAs level in rat brown and
      white adipose tissue.
AB  - Two previous studies have reported contradictory results regarding the effect of
      fibrates treatment on obese (ob) gene expression in rodents. The purpose of the
      present study was to reinvestigate this issue. We examined the effect of
      clofibrate (fibrate derivative) administration for 14 days to rats on malic
      enzyme (as an adequate control of fibrates action) and leptin mRNAs level in the
      white and brown adipose tissues (WAT and BAT, respectively). The malic enzyme
      activity and malic enzyme mRNA level in white adipose tissue increased
      significantly after clofibrate feeding. In brown adipose tissue, the drug
      treatment resulted in depression of malic enzyme activity and malic enzyme mRNA
      level. Under the same conditions, leptin mRNA level did not change in these
      tissues. The results presented in this paper provide further evidence that the
      clofibrate (activator of peroxisome proliferator activated receptor alpha),
      feeding is without effect on ob gene expression in rat white and brown adipose
      tissue. Furthermore, the present study demonstrates that clofibrate causes
      opposite effects on malic enzyme gene expression in WAT (up-regulation) and BAT
      (down-regulation).

PMID- 10596962
TI  - Impaired parathyroid hormone action on urinary phosphorus excretion in isolated
      perfused kidney of streptozotocin-induced diabetic rats.
AB  - To study the effects of diabetes on the renal actions of parathyroid hormone
      (PTH), we observed urinary excretion of cyclic adenosine monophosphate (cAMP) and
      phosphorus in isolated perfused rat kidney. Diabetic rats were kept for 7 days
      after an intraperitoneal injection of 70 mg/kg streptozotocin (STZ). STZ-induced
      diabetic rats were treated with a daily injection of 20 U/kg lente-type insulin
      for 7 days. Plasma albumin, calcium, phosphorus, and PTH levels were not
      different among normal control, diabetic and insulin-treated diabetic groups. In
      the control rat kidney, the addition of PTH increased urinary cAMP excretion from
      8 +/- 3 to 190 +/- 49 pmol/5 min and urinary phosphorus excretion from 11.3 +/-
      4.4 to 33.6 +/- 10.8 microg/5 min. In the STZ-diabetic rat kidney, basal urinary
      cAMP was impaired, and PTH altered neither urinary cAMP nor phosphorus excretion
      (from below 0.7 to below 0.7 pmol/5 min, and from 15.5 +/-4.5 to 13.6 +/- 8.1
      microg/5 min, respectively). Insulin treatment completely recovered the PTH
      actions. These results show that insulinopenic diabetes induces PTH resistance in
      the kidney.

PMID- 10596963
TI  - Differential effects of palmitate on glucose uptake in rat-1 fibroblasts and 3T3
      L1 adipocytes.
AB  - Non-esterified fatty acids are thought to be one of the causes for insulin
      resistance. However, the molecular mechanism of fatty acid-induced insulin
      resistance is not clearly known. In this study, we first examined the effect of
      palmitate on insulin signaling in 3T3-L1 adipocytes. We found that 1h treatment
      with 1 mmol/l palmitate had no effect on insulin binding, tyrosine
      phosphorylation of insulin receptors, 185 kDa proteins and Shc, and PI3 kinase
      activity in 3T3-L1 adipocytes. Then, the effects of palmitate on MAP kinase
      activity and glucose uptake in fully differentiated 3T3-L1 adipocytes were
      compared with those in poorly differentiated 3T3-L1 cells and in HIRc-B cells.
      Palmitate treatment had no effect on MAP kinase activity in fully differentiated
      3T3-L1 adipocytes, while it inhibited MAP kinase in poorly differentiated 3T3-L1
      cells and HIRc-B cells. Glucose transport in 3T3-L1 adipocytes treated with
      palmitate for 1 h, 4 h and 16 h was higher than that in control cells, but
      palmitate treatment caused a rightward shift of the insulin-dose responsive curve
      for glucose uptake in HIRc-B cells. Palmitate treatment did not significantly
      affect basal and insulin-stimulated GLUT4 translocation. When the cells were
      treated with PD98059, a specific MEK inhibitor, insulin-stimulated glucose uptake
      was not affected in 3T3-L1 adipocytes, while it was almost completely inhibited
      in HIRc-B cells. These results suggest the primary effect of palmitate on
      adipocytes may not involve insulin resistance of adipocytes themselves.

PMID- 10596964
TI  - Glutamate decarboxylase (GAD) autoantibody epitope shift during the first year of
      type 1 diabetes.
AB  - Autoantibodies in Type 1 diabetes patients may differentiate between glutamate
      decarboxylase (GAD65) cloned from human, mouse and rat with a significant better
      binding to the human antigen. A subgroup of 15% (27/183) patients showed
      significantly better binding to rodent than to human GAD65. The aim of this study
      was to determine whether the autoantibody specificity would remain anti-rodent
      during longitudinal follow-up for one year. We observed 1) that the average slope
      of the difference between human and mouse GAD65 autoantibodies binding increased
      between onset and after one year, which demonstrates reduced binding to rodent
      GAD65 and 2) that, in a group followed every third month, 9/11 (80%) children
      with rodent specific GAD65 autoantibodies at onset converted within one year to
      preference against human GAD65. This shift in preference was confirmed by
      significantly lower EC50 values in the initially anti-rodent GAD65 autoantibodies
      compared to samples taken one year after clinical diagnosis as determined in
      displacement studies with unlabeled human GAD65. We speculate that the evolution
      of GAD65 autoantibodies in Type 1 diabetes includes reactivity to a non-human
      GAD65 N-terminal end conformation. Progression towards Type 1 diabetes is,
      however, associated with a maturation of the immune response towards human GAD65
      autoreactivity.

PMID- 10596965
TI  - Scores of coronary calcification determined by electron beam computed tomography
      are closely related to the extent of diabetes-specific complications.
AB  - This study was aimed at investigating the degree of calcification of coronary
      arteries in type II diabetes mellitus for the purpose of examining as risk
      factors for coronary disease as well as parameters of diabetic complications. One
      hundred and three patients with type II diabetes were studied by the newly
      developed noninvasive technology of electron beam computed tomography, in which
      the degree of calcification was expressed as coronary calcification scores. The
      mean +/- SE value of coronary calcification scores were 247.5 +/- 48.1, which
      were significantly greater than the control patients without diabetes (148.9 +/-
      48.3, p<0.05). In the diabetics, the coronary calcification scores had a
      significant (p < 0.01) correlation with patient age and duration of diabetes. The
      scores also had a significant (p<0.05) difference between patients who did and
      did not smoke cigarettes, and between patients with and without hypertension. The
      scores were significantly (p < 0.01) different between patients with and without
      hypertension. The scores were significantly (p < 0.01) different between presence
      and absence of diabetes-specific complications including retinopathy, neuropathy,
      and nephropathy. In a subgroup of patients without any signs of coronary disease,
      the scores showed a significant (p<0.01) difference between presence and absence
      of diabetes-specific complications, but no significant difference with smoking or
      hypertension. These data suggest that the extent of coronary calcifications and
      the development of ischemic heart disease seem to be closely related to the
      association of diabetic complications. Use of electron beam computed tomography
      seems to be useful in obtaining the information to predict future development of
      diabetic-specific complications.

PMID- 10596966
TI  - The combination of antibodies to GAD-65 and IA-2ic can replace the islet-cell
      antibody assay to identify subjects at risk of type 1 diabetes mellitus.
AB  - First-degree relatives of type 1 diabetic patients are at increased risk of
      developing diabetes and, until recently, islet cell antibodies (ICA) have
      represented the major risk marker used for identification of individuals at
      increased risk for subsequent progression to diabetes. In order to determine the
      value of antibodies to GAD-65 and IA-2ic to identify individuals at high risk for
      type 1 diabetes mellitus, we measured both autoantibodies and ICA in 1436 first
      degree relatives of patients with type 1 diabetes. In addition, the sera were
      analyzed for thyroid, adrenal and gastric-parietal cell autoantibodies as markers
      for possible polyendocrine involvement. GAD-65 Abs were found in 135 out of 1436
      (9.4%) first-degree relatives and in 57 of 98 (58.2%) ICA-positive subjects. IA
      2ic were detected in 52 of 1436 (3.6%) first-degree relatives and in 44 of 98
      (44.8%) ICA-positive relatives. IA-2ic and/or GAD-65 were detected in 73 of 98
      (74.5%) ICA-positive relatives. Interestingly, antibodies to GAD-65 and/or IA-2ic
      were present in 91.2% of individuals with more than 20JDF-units. Anti-IA-2ic and
      GAD-65 were positively correlated with high levels of ICA. Anti-IA-2ic and GAD-65
      were found in 19% and 48.5% of subjects with ICA levels of 5-20JDF-u but in 68.8%
      and 76.5% of individuals with ICA of 40JDF-u or more, respectively (p < 0.001),
      compared to subjects with ICA levels less than 5 JDF-u. When autoantibody
      frequencies among the relatives were analyzed according to relationship to the
      proband, the offspring and siblings had a higher frequency of ICA and IA-2ic
      (p<0.05) than the subgroup of parents. A significant association was observed
      between IA-2ic and thyroid antibodies. In addition, higher levels of IA-2ic were
      found in relatives with positive TPO antibodies (p < 0.001); this correlation was
      particularly strong in offspring and siblings (p < 0.01). Determination of GAD-65
      and IA-2ic antibodies may be considered as an alternative to primary ICA
      screening, enabling the screening of large populations.

PMID- 10596967
TI  - Initiation of hyperinsulinemia and hyperleptinemia is diet dependent in C57BL/6
      mice.
AB  - C57BL/6 female mice were fed high fat diets containing different types of
      carbohydrate (sucrose or corn starch) and contents of cholesterol (0.03 % or 1 %)
      to identify early metabolic changes leading to increases in leptin levels and
      eventual insulin resistance. Under identical dietary fat conditions, type of
      carbohydrate and cholesterol content contributed to the timing of leptin
      increases. Mice fed a high-fat, high-sucrose diet showed early (4 weeks) and
      robust increases in circulating insulin and leptin levels (2-fold and 5-fold,
      respectively). In contrast, mice fed this diet with added cholesterol or with
      sucrose substituted by corn starch led to marked delays (8-10 weeks) in the
      elevations of insulin and leptin, although body weight gains were nearly
      identical among test diet groups. Thus, sucrose in combination with saturated fat
      played a specific role in initiating early metabolic changes associated with
      elevated leptin and insulin levels. Because leptin levels were most reflective of
      changes in insulin, our data support a role for insulin in determining plasma
      leptin levels in mice.

PMID- 10596968
TI  - Thyroid hormone modulates insulin-like growth factor-I(IGF-I) and IGF-binding
      protein-3, without mediation by growth hormone, in patients with autoimmune
      thyroid diseases.
AB  - The expression and synthesis of insulin-like growth factor-1 (IGF-I) and IGF
      binding protein-3 (IGFBP-3) are regulated by various hormones and nutritional
      conditions. We evaluated the effects of thyroid hormones on serum levels of IGF-I
      and IGFBP-3 levels in patients with autoimmune thyroid diseases including 54
      patients with Graves' disease and 17 patients with Hashimoto's thyroiditis, and
      in 32 healthy age-matched control subjects. Patients were subdivided into
      hyperthyroid, euthyroid and hypothyroid groups that were untreated, or were
      treated with methylmercaptoimidazole (MMI) or L-thyroxine (L-T4). Serum levels of
      growth hormone (GH), IGF-I and IGFBP-3 were determined by radioimmunoassay. Serum
      GH levels did not differ significantly between the hyperthyroid and the age
      matched euthyroid patients with Graves' disease. The serum levels of IGF-I and
      IGFBP-3 showed a significant positive correlation in the patients (R=0.616,
      P<0.001). The levels of both IGF-I and IFGBP-3 were significantly higher in the
      hyperthyroid patients with Graves' disease or in those with Hashimoto's
      thyroiditis induced by excess L-T4 administration than in control subjects.
      Patients with hypothyroid Graves' disease induced by the excess administration of
      MMI showed significantly lower IGFBP-3 levels as compared to those in healthy
      controls (P<0.05). Levels of IGFBP-3, but not IGF-I levels, showed a significant
      positive correlation with the levels of free T4 and free T3. In Graves' disease,
      levels of TPOAb, but not of TRAb, showed a significant positive correlation with
      IGFBP-3. We conclude that in patients with autoimmune thyroid diseases, thyroid
      hormone modulates the synthesis and/or the secretion of IGF-I and IGFBP-3, and
      this function is not mediated by GH.

PMID- 10596969
TI  - A simple acute in vivo comparative test for sensitivity to insulin in the mouse.
AB  - A method is described for measuring the acute blood glucose response to an
      insulin challenge which requires only 6 samples of 20 microl of blood collected
      over a 4 hour period. This evaluation of sensitivity to insulin was validated by
      comparing the effects of gliclazide, metformin and a novel antidiabetic
      imidazoline compound (S22068) on the blood glucose response. The test
      distinguished between the insulin-secreting and hypoglycaemic action of
      gliclazide and the insulin-sensitizing actions of metformin and S22068. The test
      has the advantage that it can be repeated in the same animal after a period of
      recovery and thus enables the overall sensitivity to insulin to be compared
      before and after acute or chronic dose regimes.

PMID- 10596970
TI  - Chromatographic properties of reversed-phase stationary phases under pressure-
      and electro-driven conditions.
AB  - Seven different reversed-phase (RP) stationary phases were examined under high
      performance liquid chromatographic (pressure-driven, HPLC), and capillary
      electrochromatographic (electro-driven, CEC) conditions. Characterization of the
      stationary phases was performed following well-established test procedures
      providing a number of distinct column descriptors: hydrophobicity, hydrophobic
      selectivity and silanol activity. These parameters were used to describe the
      behavior of the RP-columns under both HPLC and CEC conditions. It is shown that
      chromatographic characteristics of porous RP-phases greatly depend on the mode of
      operation. By contrast, column descriptors of a non-porous viz. solid RP-phase
      material hardly differed for HPLC and CEC conditions.

PMID- 10596971
TI  - Sample cleanup and reversed-phase high-performance liquid chromatographic
      analysis of polar aromatic compounds in groundwater samples from a former gas
      plant.
AB  - A method for the analysis of the polar aromatic compounds 1H-quinolin-4-one (Q),
      10H-acridin-9-one (A), 5H-phenanthridin-6-one (P) and 9H-fluoren-9-one (F) in
      aqueous solutions has been developed. The method comprises steps for sample
      preparation (solid-phase extraction, cleanup) and analytical determination by
      means of reversed-phase high-performance liquid chromatography (RP-HPLC). For the
      cleanup step the suitability of two different sorbents (alternative A: silica
      gel, alternative B: LiChrolut EN) was investigated. Alternative B depicted
      several advantages, in particular higher sorbent capacity, faster and less
      complicated handling, higher recovery and better reproducibility. For Q, A and P,
      reproducibility of all method steps is better than 13%, with recovery rates
      ranging from 76% to 105% (n=3). Alternative B was applied to groundwater samples
      from a former gas plant. The analytes A and P could be detected at concentrations
      in the micro/l range.

PMID- 10596972
TI  - Reversed-phase liquid chromatographic behavior of the mycotoxins citrinin and
      ochratoxin A.
AB  - The reversed-phase (RP) chromatographic behavior of citrinin (CT) and ochratoxin
      A (OA), the latter introduced as reference substance, were studied as a function
      of hydrophobicity and silanophilic activities of the stationary phase, pH, type
      of acid in the eluent, its composition as well as of the column temperature.
      While OA's affinity to RP materials was not influenced by phase material
      properties, CT showed a high affinity to hydrophobic phase materials, and its
      elution order, compared to OA, depended strongly on the phase material chosen. In
      practice, all octadecyl stationary phases under investigation allowed proper
      conditions for CT and OA chromatography if judicious selection of influencing
      parameters, especially a low pH and applying an acid with a pKa<2.3, were chosen.

PMID- 10596973
TI  - Glutathione oxidation in real time by thermospray liquid chromatography-mass
      spectrometry.
AB  - The oxidation and reduction of glutathione and oxidized glutathione were studied
      in real time by liquid chromatography-mass spectrometry during exposure to
      hydrogen peroxide and mercaptoethanol. By mass spectrometry mixed disulfides and
      both reversible and irreversible oxidations of sulfur to higher states (sulfinic
      and sulfonic acids) were directly observed during exposure to hydrogen peroxide.
      The irreversible oxidation of glutathione to glutathione sulfonic acid could be
      detected after 30 min exposure of glutathione to 40 mM H2O2 at 20 degrees C. A
      peak consistent with glutathione-sulfinic acid was transiently present,
      suggesting this compound behaved as an oxygen consuming antioxidant. Liquid
      chromatography-mass spectrometry appears to be an excellent method to study
      oxidation and reductions of sulfur containing peptides and amino acids.

PMID- 10596974
TI  - Rapid screening procedures for the hydrolysis products of chemical warfare agents
      using positive and negative ion liquid chromatography-mass spectrometry with
      atmospheric pressure chemical ionisation.
AB  - Qualitative screening procedures have been developed for the rapid detection and
      identification of the hydrolysis products of chemical warfare agents in aqueous
      samples and extracts, using liquid chromatography-mass spectrometry with positive
      and negative atmospheric pressure chemical ionisation (APCI). Previously reported
      screening procedures, which used positive APCI or electrospray ionisation (ESI),
      were modified by using LC conditions that allowed acquisition of positive and
      negative ion mass spectra. APCI was generally found to be more robust than ESI,
      probably due to variable adduct ion formation with ESI, depending on the
      condition of the sample and the system. Negative APCI provided selective
      detection of acidic analytes and allowed facile differentiation of alkyl
      alkylphosphonic acids from isomeric dialkyl alkylphosphonates. The combination of
      positive and negative APCI, using a C18 column and water-methanol mobile phase
      modified with ammonium formate, provides a rapid screening procedure for chemical
      warfare agent degradation products, with limits of detectability in the range 10
      100 ng/ml. In the case of proficiency test samples, where analyte concentrations
      are in the range 1-10 ppm, introduction of the sample by infusion may provide an
      even faster preliminary screening procedure.

PMID- 10596975
TI  - Detection of new sequences of peptaibol antibiotics trichotoxins A-40 by on-line
      liquid chromatography-electrospray ionization mass spectrometry.
AB  - Using high-performance liquid chromatography (HPLC) coupled to electrospray
      ionization mass spectrometry (ESI-MS) the sequences of the microheterogeneous
      peptide mixture of the 18-residue "peptaibol" antibiotics trichotoxins A-40,
      isolated from the mold Trichoderma viride strain NRRL 5242, were reinvestigated.
      The structures of two major and one minor component [J. Chromatogr., 296 (1984)
      236] could be confirmed and hitherto not known sequences of a further major and
      two minor peptides could be determined. It is demonstrated that ESI-MS in the
      positive ionization mode is advantageously completed by applying negative
      ionization. The methods used make possible the sequence determination of
      components of peptaibols without previous isolation and allow, in certain cases,
      sequencing of peptides which are incompletely or not resolved by HPLC.

PMID- 10596976
TI  - Analysis of anatoxin-a in freshwaters by automated on-line derivatization-liquid
      chromatography-electrospray mass spectrometry.
AB  - Anatoxin-a is a toxin produced from cyanobacterial blooms in freshwaters. In
      order to determine trace anatoxin-a in freshwaters, an automated on-line
      derivatization procedure with fluorenyl methylchloroformate using liquid
      chromatography-electrospray ionization mass spectrometry was developed. Anatoxin
      a was extracted using solid-phase extraction with adequate recovery (75.7+/-7.2%,
      n=6) at 20 ng/l. The limits of quantification and detection were calculated to be
      15.2 ng/l and 2.1 ng/l, respectively, using selected ion monitoring.

PMID- 10596977
TI  - New hydrolysis method for extremely small amount of lipids and capillary gas
      chromatographic analysis as n(O)-tert.-butyldimethylsilyl fatty acid derivatives
      compared with methyl ester derivatives.
AB  - The organic basic solution, 1 M tetramethylammonium hydroxide (TMAH) in methanol,
      was employed for the hydrolysis of extremely small amounts of lipids compared to
      the classical inorganic basic solution, 1 M KOH in ethanol. The hydrolysed fatty
      acids were derivatized as N(O)-tert.-butyldimethylsilyl (tBDMSi) esters with N
      methyl-N-(tert.-butyldimethylsilyl) trifluoroacetamide (MTBSTFA) and compared
      with the classical derivatives, the methyl esters, made by the BF3-methanol
      method. Recoveries of fatty acids determined on the standard fatty acids and
      soybean oil hydrolysed with TMAH were high: about 1.1-2.1- and 2.0-5.4-times,
      respectively, in all fatty acids compared with the hydrolysis by KOH regardless
      of derivatization method. The relative standard deviations (RSDs) on the
      recoveries of standard fatty acids were less than 5% when hydrolysed with TMAH,
      regardless of derivatives, but when hydrolysed with KOH, RSDs were more than 5%
      for most fatty acids, especially for long-chain fatty acids. The RSDs on the
      recoveries of fatty acids on the soybean oil were also very high in the KOH
      hydrolysis. Fatty acid compositions of soybean oil were similar in the main fatty
      acids regardless of hydrolysis methods, but showed slightly different values,
      depending on the methods of derivatization. RSDs were also very high in the KOH
      hydrolysis. In view of these results, precision of analysis by KOH hydrolysis was
      very poor, so we could not rely on the data. On the other hand, the reliability
      of data by TMAH hydrolysis method was very high, so it is a useful new hydrolysis
      method for extremely small amounts of lipid samples. Both derivatives of 35
      standard fatty acids were successfully separated on a HP-1 nonpolar capillary
      column. tBDMSi derivatives were completely resolved in 70 min by 295 degrees C.
      In the methyl ester derivatives it took about 80 min to get satisfying
      resolution, but these derivatives were completely resolved by 250 degrees C. The
      sensitivity of tBDMSi derivatives was about 1.5-6.3-times higher than that with
      methyl ester derivatives. The stability of tBDMSi derivatives was constant for
      about 144 h except arachidic, docosahexanoic, behenic and heneicosanoic acids,
      which were stable for only 86 h.

PMID- 10596978
TI  - High-performance thin-layer chromatography method for monitoring norfloxacin
      residues on pharmaceutical equipment surfaces.
AB  - This paper presents a high-performance thin-layer chromatography (HPTLC) method
      with direct fluorescence measurement for the determination of norfloxacin. The
      method was validated for the monitoring of norfloxacin residues on stainless
      steel surfaces at the allowed limit of 10 mg of norfloxacin per square meter.
      However, it can be adapted for lower amounts of residues owing to the low
      detection limit of norfloxacin (about 5 ng) and can also be used for other
      surface materials. Test solutions were analyzed by the new HPTLC method and the
      known HPLC method for comparison. Accuracy and precision of the new HPTLC method,
      with a subsequent quantification by densitometer or video system, are comparable
      with those of the HPLC method.

PMID- 10596979
TI  - Improved liquid chromatographic separation of different proteins by designing
      functional surfaces of cattle bone-originated apatite.
AB  - Spherical particles of cattle bone-originated hydroxyapatite (r-HAp) were
      prepared by dissolution-precipitation, spray-drying using a two fluid-nozzle
      apparatus, and subsequent heat treatment. The product had effective pore
      structures for liquid chromatographic separation of albumin, myoglobin,
      ribonuclease, lysozyme and cytochrome c. The activated surfaces of the r-HAp
      particles were easily prepared with desired proportions of P- and C-sites and
      appropriate acid-basic strength for selective protein adsorption by optimizing
      the synthesis conditions. Liquid chromatography columns packed with the particles
      exhibited high resolution and durability in protein separation, reflecting stable
      distribution of pore size.

PMID- 10596980
TI  - Separation and identification of hydrocarbons and other volatile compounds from
      cultured blue-green alga Nostoc sp. by gas chromatography-mass spectrometry using
      serially coupled capillary columns with consecutive nonpolar and semipolar
      stationary phases.
AB  - The complex hydrocarbons and volatile compounds produced by cultured blue-green
      alga Nostoc sp. were separated by serially coupled capillary columns with
      consecutive nonpolar and semipolar stationary phases. More than 130 metabolites
      including, cyclohexane, cyclopentane, normal saturated hydrocarbons (C7-C30),
      fatty acids and benzene derivatives were identified by GC-MS. The most abundant
      family of hydrocarbons identified were derivatives of cyclohexane (41) and
      cyclopentane (11). Most of these compounds have not been reported previously in
      blue-green algae studies.

PMID- 10596981
TI  - DNA-binding affinities of MyoD and E47 homo- and hetero-dimers by capillary
      electrophoresis mobility shift assay.
AB  - A simple capillary electrophoresis mobility shift assay (CEMSA), with no gel and
      uncoated capillaries, for the accurate determination of protein-DNA affinities
      free in solution was applied to constructs of the MyoD/E47 DNA-binding proteins.
      The determined affinities are compared to those obtained by EMSA. MyoD-E47
      covalent heterodimer binds DNA more tightly (Kd=1.8 nM) than MyoD (Kd=14.2 nM) or
      E47 (Kd= 11.5 nM) covalent homodimers. The effect of non-specific DNA on binding
      affinities was more important than salt concentration in the MyoD/E47 series.
      Application of this method to the MyoD/E47 system demonstrates the generality of
      our CEMSA.

PMID- 10596982
TI  - Determination of methacrylic acid in the drain of a biotrickling filter using
      isotachophoresis and capillary zone electrophoresis.
AB  - The performance of a biotrickling filter for treatment of concentrated waste
      gases was investigated. The macrokinetics of methylmethacrylate degradation in
      the biotrickling filter is studied by measuring the degradation product
      methacrylic acid in the drain of the filter. The drain was analysed using
      isotachophoresis (ITP) and capillary zone electrophoresis (CZE). The CZE analyses
      were carried out in an I.D. 75 microm capillary at 20 kV (negative inlet
      polarity) using a 0.01 M Tris-acetate buffer of pH 4.45. The electroosmotic flow
      (EOF) was suppressed by addition of CTA and PVA to the buffer. Detection was at
      214 nm. After filtration through a 0.45-microm filter, samples were directly
      injected. The calibration graph was linear between 10 and 800 mg/l methacrylic
      acid, with an analysis time under 2 min.

PMID- 10596983
TI  - Current outlook of infectious diseases in Taiwan.
AB  - The "emerging" infectious diseases have received global attention. Taiwan is a
      country which is going through the process of becoming "developed" from being
      "developing". If we compare five leading causes of death in 1952 and in 1993,
      three were infectious diseases in 1952 and there was none in 1993. And yet today,
      infectious diseases remain a major problem in this country as well in every
      country in the world, whether developing or developed. Some of the problems
      Taiwan faces are old problems with old faces. They have never been adequately
      solved because the societal and environmental sanitary infrastructure does not
      ensure proper sewage disposal, safe potable water and freedom from dangerous
      vectors. Examples are the diarrheal diseases, parasitic diseases, scrub typhus
      and Japanese encephalitis. Some of the Taiwan's problems are caused by old agents
      which present a new face. Mortality from tuberculosis took a dramatic and
      gratifying plunge in the last fifty years. Yet tuberculosis is ever present and a
      constant public health threat. Dengue has become a problem again because of a
      world breakdown in the control of the mosquito, Aedes egypti, and it is partly
      contributed to by increased urbanization and world travel. The problem of
      antibiotic resistant bacteria causing hospital acquired and community acquired
      infections is probably the most serious "new" problem. The most important cause
      is excessive and indiscriminate use of antibiotics in the community and in
      hospitals. We propose the establishment of "Bacterial Infections Reference
      Laboratory" at the National Health Research Institutes to be a national facility
      to study the epidemiology and control of antibiotic resistance. All infectious
      diseases require a rigorous system of surveillance, and precise etiological
      diagnosis before they can be treated or prevented. This should be kept clearly in
      mind when one considers the changing role of the infectious disease physician in
      Taiwan in the face of unsolved disease problems and a new health care system.
      There is inadequate attention to precise microbiological definition of most
      infectious diseases in Taiwan. The community of infectious disease specialists
      may well redirect its attention to improving the competence and utilization of
      microbiological laboratory diagnosis.

PMID- 10596984
TI  - Taenia saginata asiatica: epidemiology, infection, immunological and molecular
      studies.
AB  - The taeniasis in East Asia has a special epidemiological pattern: people eat meat
      and/or viscera of pigs and acquire infection of Taenia saginata-like tapeworms.
      However, cysticercosis is more often found in pigs than cattles. In order to
      elucidate the taxonomic status of this parasite, we have conducted extensive
      field surveys, experimental infections, and morphological as well as
      immunological studies since 1981. After obtaining sufficient information from our
      studies, we finally came to the conclusion that the T. saginata-like tapeworm in
      Asia is a new subspecies of T. saginata and was named as T. saginata asiatica.
      The classical T. saginata was renamed as T. saginata saginata. In this paper, we
      provide the history of T. s. asiatica in Asia.

PMID- 10596985
TI  - Comparison of detection of extended-spectrum beta-lactamases by agar dilution
      method, E-test ESBL screen and double disk test.
AB  - The extended-spectrum beta-lactamases (ESBL) are derived from TEM-or SHV-enzymes.
      They mediate resistance to broad-spectrum beta-lactams and can cause infectious
      outbreaks in hospitals. Rapid recognition and diagnosis are important for the
      clinician to prescribe more effective treatment. In the present study, a group of
      52 probable ESBL-producing Klebsiella pneumoniae and Escherichia coli having a
      suspected resistant antibiogram phenotype were included. The E-test ESBL screen
      and the double disk test were performed for these isolates for detection of ESBL
      producing strains, as compared with the conventional agar dilution method. The
      agreement between the E-test ESBL screen or the double disk test and the
      conventional agar dilution method was good and the degree of agreement were 86.5%
      and 92.3% respectively. The results showed that both the E-test ESBL screen and
      the double disk test were useful and convenient for detection of ESBLs.

PMID- 10596986
TI  - Differential expression of cytokine genes and apoptosis in glioma cell lines upon
      exposure to bacteria and lipopolysaccharides.
AB  - The influences of Escherichia coli, Streptococcus pyogenes and
      lipopolysaccharides (LPSs) on the expression of cytokines and apoptosis were
      investigated in two glioma cell lines. IL-1beta and TNF-alpha genes were
      modulated by bacteria in a time dependent fashion and their expression levels
      varied from sources of bacteria and cell lines used. E. coli and LPSs induced
      apoptosis in a very limited cell population as judged by cell counts, membrane
      alternation and DNA break in situ. The expression of fas and IL-6 genes was not
      affected by bacterial components. In conclusion, aberrant expression of cytokines
      but not apoptosis may be the major responses of the cells of glial origin upon
      exposure to bacteria and their components.

PMID- 10596987
TI  - Bacteremia and fungemia in hematological and oncological children with
      neutropenic fever: two-year study in a medical center.
AB  - A retrospective study of bacteremia in children with neutropenic fever admitted
      to a medical center in Taiwan from Jan. 1994 to Dec. 1995 was performed. There
      were in total 273 episodes of neutropenic fever during this period, but only 79
      pathogens were isolated from blood specimens in 70 episodes. Klebsiella
      pneumoniae (27.8%), E. coli (10.1%), Staphylococcus aureus (10.1%) and
      Pseudomonas aeruginosa (7.6%) were the most common pathogens. All the isolates of
      S. aureus were methicillin sensitive. About half of K. pneumoniae (10/22) was
      multiple-drug resistant. There were seven infection-related mortality cases,
      three due to multiple-drug resistant K. pneumoniae, one due to S. aureus, one
      alpha-hemolytic streptococcus and two fungemia (Cryptococcus neoformans and
      Fusarium sp.). Vancomycin is not necessary in initial empiric therapy of
      neutropenic fever, while cefazolin or oxacillin may be included in cases with
      central venous access device. Antibiotics to cover intestinal flora, especially
      K. pneumoniae, are paramount in our hospital.

PMID- 10596988
TI  - Group B streptococcal infections in children: the changing spectrum of infections
      in infants.
AB  - During a 9-year period from January 1988 to December 1996, 36 patients less than
      18 years of age with Lancefield group B streptococcal infections were seen in the
      National Cheng Kung University Hospital. Among 33 infants with invasive group B
      streptococcal infections, 3 (9%) were early onset disease (EOD), 27 (82%) late
      onset disease (LOD) and 3 (9%) onset beyond the third month of life. All cases of
      EOD were detected during the first day of life and 2 of them were premature
      births. In the infants with LOD, a high incidence of meningitis occurred (78%).
      The most common clinical presentation in group B streptococcal infections was
      fever (81%), followed by irritable crying (42%) and poor feeding (39%). Seizure
      was noted in 57% of meningitis cases. Obstetric and neonatal risk factors were
      compared between EOD and LOD, with prematurity and low birth weight significantly
      (P=0.01) more common among infants with EOD compared with LOD. Of the strains
      tested, the sensitivity to penicillin, ampicillin and erythromycin were 83%, 74%,
      and 75%, respectively. All strains were resistant to tetracycline and gentamicin.
      There were 2 case fatalities (6%) and 6 (17%) had major neurologic sequelae.
      These data provide that the vast majority of EOD are recognized on the first day
      of life and prematurity is an important risk factor. In comparison to the
      previous report in Taiwan, a changing spectrum of GBS infections in infants
      occurs during the study period. The observed incidence of EOD is decreased and
      meningitis is still predominantly in LOD. It is suggested early recognition and
      aggressive therapy have resulted in a much lower mortality rate than previously
      reported.

PMID- 10596989
TI  - Tuberculous peritonitis: analysis of 35 cases.
AB  - Thirty five patients with tuberculous peritonitis were studied retrospectively.
      Tuberculous peritonitis was defined as the isolation of Mycobacterium
      tuberculosis from ascites or dialysate, and/or caseating granuloma/acid-fast
      bacilli from peritoneal biopsy specimens from patients with pulmonary
      tuberculosis or a response to treatment for tuberculosis. Among the patients
      studied, nine with cirrhosis of the liver; seven with diabetes mellitus and six
      with end-stage renal disease, of whom four had undergone continuous ambulatory
      peritoneal dialysis. The most frequent signs of tuberculous peritonitis included
      ascites, fever and anemia. Ascites was found in 31 patients (89%). Abnormal
      findings on chest radiographs were found in 26 patients (74%), of whom 22
      patients (63%) had pleural effusion and five had miliary lung lesions. Seven out
      of 35 patients were found to have positive culture of sputum or pleural effusion
      for M. tuberculosis. Two patients were found to have concomitant tuberculous
      peritonitis and enteritis. Multiple organ involvement was found in eight
      patients. Eleven patients (31%) died: eight were older than 60 years; six had
      cirrhosis of the liver and nine were diagnosed post-mortemly. In Taiwan,
      tuberculous peritonitis should be considered in patients with abnormality of
      chest radiography and nonresolving peritonitis.

PMID- 10596990
TI  - Acinetobacter calcoaceticus-baumannii complex bacteremia: analysis of 82 cases.
AB  - Eighty-two cases of Acinetobacter calcoaceticus-baumannii complex bacteremia were
      identified during a 33-month period, from November 1993 to July 1996, at the
      Veterans General Hospital, Taipei. All cases were due to hospital-acquired
      infections, with 28 cases of polymicrobial bacteremia. Most patients had severe
      debilitating conditions: 26 had malignancies, 40 required stay in Intensive Care
      Unit and 17 had undergone major operations. The main predisposing factors
      included central venous catheterization, endotracheal intubation or tracheostomy,
      prior antibiotic therapy and prolonged hospitalization. Amikacin, tobramycin, and
      ceftazidime were the most effective agents in vitro against A. calcoaceticus
      baumannii complex. 32 patients (39 %) died during hospitalization, 19 of the
      cases (23 %) directly attributed to septicemia. Factors that adversely influenced
      mortality included polymicrobial bacteremia, inappropriate antimicrobial therapy
      and prior antibiotic treatment. Of particular interest is the fact that none of
      the patients who did not receive appropriate antimicrobial therapy survived.
      Early diagnosis and appropriate antibiotic therapy are critical for improving the
      prognosis of A. calcoaceticus-baumannii complex bacteremia.

PMID- 10596991
TI  - Acute pulmonary hemorrhage following a honeybee sting: a case report.
AB  - A generalized allergic reaction to or anaphylaxis from honeybee sting may involve
      the skin with erythema, puritus, urticaria, or angioedema; the respiratory tract
      with laryngeal edema, and brochospasm; the cardiovascular system with myocardial
      depression, hypotension, and shock; and the gastrointestinal system with nausea,
      vomiting, and incontinence. Acute pulmonary hemorrhage following a honeybee sting
      has never been reported. We describe a previously healthy 14-year-old girl who
      developed acute pulmonary hemorrhage, hypotension, and generalized skin rash
      after a single honeybee sting on her right fourth finger. Her serum
      immunoglobulin E (IgE) was high (360 IU/mL). Chest X-ray revealed perihilar
      alveolar infiltrative lesions. Metabolic acidosis and hypoxemia were also found.
      After treatment with antihistamines, dopamine, corticosteroids, bronchodilaters,
      fluid replacement, and mechanical ventilation, her condition improved
      dramatically. A hypersensitivity reaction to honeybee venom is the most likely
      explanation for this unusual case of acute pulmonary hemorrhage.

PMID- 10596992
TI  - The use of micro-dose aprotinin with continuous infusion in coronary artery
      bypass surgery.
AB  - BACKGROUND: To evaluate the efficacy of aprotinin at a dose far less than
      standard. METHODS:  EXPERIMENTAL DESIGN: Retrospective, case-control study.
      SETTING: community-based, teaching hospital PATIENTS: one hundred one patients
      undergoing primary, non-emergent, coronary artery bypass during two, six-month
      periods were studied. INTERVENTIONS: during the first period aprotinin was not
      administered, and these patients served as controls (n = 52). During the second
      period all patients received aprotinin via a micro-dose regimen (n = 49).
      MEASURES: postoperative bleeding and blood product usage served as determinants
      of efficacy. RESULTS: A significant difference existed in postoperative bleeding
      with the mean thoracic drain outputs being reduced in the aprotinin group both at
      6 hours (p = 0.0003) and in total (p = 0.0004). This was further supported by
      significantly higher hematocrits (p = 0.03) on the first postoperative day in
      patients receiving aprotinin. Likewise, there was a significant reduction in
      total blood product exposures (p = 0.04) and platelet usage (p = 0.02) in the
      aprotinin group with a tendency towards decreased red cell usage. Further, when
      all patients with a hematocrit < or =30% prior to bypass were excluded, the
      significant reduction in total blood product exposures persisted (p = 0.04), and
      there was a significant reduction in red cell usage (p = 0.04) with a trend
      towards decreased platelet usage (p = 0.06) in the aprotinin group. CONCLUSIONS:
      Micro-dose aprotinin significantly reduces postoperative bleeding and blood
      product usage in primary, non-emergent, CABG patients.

PMID- 10596993
TI  - Methods of acute postcardiotomy left ventricular assistance.
AB  - OBJECTIVE: Despite many technological advances in cardiovascular surgery, some
      patients still experience postcardiotomy left ventricular (LV) failure that is
      refractory to both inotropic support and intra-aortic balloon pump (IABP)
      placement. The primary author (MJR) recently changed from inflow cannulation at
      the right superior pulmonary vein/left atrial junction to inflow cannulation at
      the dome of the left atrium. The purpose of this study was to compare data
      collected during placement of a left ventricular assist device (LVAD) at the
      junction of the right superior pulmonary vein with positioning the device in the
      dome of the left atrium. Experimental design, setting, and participants: the
      medical records of all patients undergoing cardiac surgery by one author (MJR)
      between 1994 and 1997 were retrospectively reviewed, and 4 patients requiring
      LVAD placement for short term postcardiotomy support were identified. Each
      patient's chart was reviewed for duration of LVAD support, average LVAD blood
      flows, pulmonary capillary wedge pressures (PCWP), preoperative characteristics,
      postoperative complications, and final outcome for the patients. RESULTS:
      Accessing the left atrium through the dome resulted in excellent blood flow
      through the LVAD and allowed for good LV decompression. Hemostasis remained the
      most common complication regardless of the technique employed; however, the
      enhanced visibility provided by accessing the left atrium via the dome made
      repairs less technically difficult. Three patients (75%) were able to be weaned
      from the LVAD and were discharged from the hospital to home. Two of these
      patients were cannulated via the left atrial dome making removal of the LVAD
      easier, thus exposing the patients to less additional operative time. One patient
      could not be weaned from LVAD support secondary to development of right
      ventricular failure requiring RVAD insertion and subsequent development of
      multiple organ failure syndrome. CONCLUSIONS: Patients requiring LV assistance
      following cardiopulmonary bypass surgery traditionally have high levels of
      morbidity and mortality. In spite of the complications associated with the
      placement of an assist device, we remain encouraged by the excellent LV
      decompression and systemic flows we achieved following implantation of the LVAD
      through the dome of the left atrium. The superior ease of implantation and
      decannulation provided better operative care and postoperative management for our
      patients.

PMID- 10596994
TI  - Cardiac interleukin-6 release and myocardial recovery after aortic crossclamping.
      Crystalloid versus blood cardioplegia.
AB  - BACKGROUND: Pro-inflammatory cytokines may play an important role in patient
      response to cardiopulmonary bypass (CPB). Since the myocardium is proposed to be
      a major source of cytokines, we studied the influence of the cardiolpegia type on
      interleukin-6 release and early myocardial recovery. METHODS:  EXPERIMENTAL
      DESIGN: prospective, randomized study. SETTING: university hospital, operative
      and intensive care. PATIENTS: 20 consecutive patients (3 females) scheduled for
      elective coronary artery bypass grafting (CABG), mean age 62.8+/-5 years, history
      of myocardial infarction 11/20, left ventricular ejection fraction 62.9+/-15%.
      INTERVENTIONS: patients were operated on using randomly either cold blood
      cardioplegia (B, n = 10) or cold crystalloid cardioplegia (C, n = 10). MEASURES:
      plasma levels of interleukin-6 (IL-6) were measured prior to CPB, after aortic
      declamping, after CPB, 1 hour, 6 hours and 12 hours postoperatively. RESULTS:
      Groups were comparable with respect to demographic data, left ventricular
      function, number of grafts, CPB and aortic crossclamp time. Group B patients
      demonstrated significant lower IL-6 levels after 1 hour (210+/-108 vs. 578+/-443
      pg/ml), 6 hours (204+/-91 vs. 1210+/-671 pg/ml) and 12 hours (174+/-97 vs. 971+/
      623 pg/ml). Post-CPB cardiac index was superior in group B (3.9+/-0.3 vs. 3.2+/
      0.3 l/min/m2, p<0.05) with similar doses of inotropes. Group B patients could
      earlier be weaned off respirator (10+/-4 vs. 13+/-4 hours, p<0.05) and showed
      minor blood loss (635+/-211 vs. 918+/-347 ml, p<0.05). CONCLUSIONS: Inflammatory
      response to CPB is associated with delayed myocardial recovery. The use of blood
      cardioplegia may attenuate inflammatory reactions.

PMID- 10596995
TI  - The significance of creatine kinase in cardiac patients with acute limb
      ischaemia.
AB  - OBJECTIVE: The value of creatine kinase (CK) and aspartate transaminase (AST) has
      not been previously evaluated following cardiac surgery in the diagnosis of acute
      limb ischaemia. Our objective was to assess the value of CK and AST with
      reference to the diagnosis of limb ischaemia, effect on renal function and
      prognosis following cardiac surgery. DESIGN: all patients entering ICU had daily
      CK and AST measurements over a two -year period. A retrospective study of
      patients with CK values >5,000 U/L was performed. SETTING: adult intensive care
      unit of a secondary and tertiary referral centre for cardiothoracic surgery with
      on site facilities for vascular surgery. PATIENT: twenty-seven patients had CK
      values greater than 5,000 U/L. A further random sample of 35 patients, with no
      limb ischaemia were used to give medians for CK and AST following cardiac
      surgery. INTERVENTIONS: twelve of twenty-seven (44%) patients were noted to have
      acutely ischaemic limbs; 6 of these (CK>16,000 U/L) underwent surgical
      intervention. MEASURES: serum levels of CK, Peak CK, AST, Peak AST and CK/AST
      ratios. Related to procedure and outcome in terms of mortality and morbidity
      including, acute limb ischaemia defined on clinical grounds and renal failure
      defined as creatinine >200 pmoles/L. RESULTS: The median values for CK and AST
      immediately following uncomplicated cardiac surgery were 135 (IQR 36-383) and 43
      (IQR 26-58) respectively. Median CK for the patients (CK>5,000) without clinical
      ischaemia was 7,440 U/L compared to the group with ischaemia 17,472 U/L (p<0.05).
      Renal failure developed in 48% of all patients. Eight of the 9 patients with
      CK>15,000 developed renal failure compared to 5 of the 13 with CK 5,000-15,000
      U/L (p<0.01). 30% of patients underwent haemofiltration; of these, 87% died. For
      patients with ischaemia peak CK and creatinine correlated. (r = 0.83, p<0.05) Day
      of peak CK and peak AST correlated (r = 0.92, p<0.01). Logged values of CK with
      log values of AST showed a highly significant relationship (beta = 1.16,
      p<0.001). The overall mortality was 33%. CONCLUSIONS: PATIENTs who develop limb
      ischaemia following cardiac surgery have a high morbidity and mortality. A CK of
      17,000 U/L (5667-46539) is indicative of serious limb ischaemia. Renal failure is
      likely to develop in patients with CK>15,000 U/L. AST may become a useful
      additional marker of limb ischaemia.

PMID- 10596996
TI  - Real time measurement of heparin concentration during cardiopulmonary bypass.
AB  - BACKGROUND: A heparin/protamine titration system for measurement of heparin
      levels (Hepcon) is promising for efficient anticoagulation during cardiopulmonary
      bypass (CPB). METHODS: Fifty-seven patients subjected to CPB were divided into
      two groups, control (n = 24) and Hepcon groups (n = 33). The Hepcon group was
      further divided into three subgroups according to perfusion temperature. For the
      control group, conventional administration of an anticoagulant (300 IU/kg of
      heparin) and reversal protocol (heparin 1: protamine 1) was performed. For the
      Hepcon group, a heparin dose-response assay directed the initial dose of heparin.
      Hepcon also determined the dose of protamine by the titration. The initial dose
      of heparin in the control group (300 IU/kg) was statistically less than that of
      Hepcon group (360+/-80 IU/kg). RESULTS: In the Hepcon group, the sensitivity to
      heparin was correlated with coagulation time (r = -0.78) and antithrombin III
      levels (r = 0.70), and individual difference of sensitivity resulted in a wide
      range of dosage (160 to 490 IU/kg). A strong correlation was observed between
      plasma and whole blood concentration of heparin (r = 0.86). However, they did not
      correlate with ACT values. Perfusion temperature didn't affect the heparin level,
      but did the ACT value. In the Hepcon group, the dose of protamine was
      significantly less and adverse events were rare. CONCLUSIONS: In conclusion,
      whole blood heparin measurements correlated well with plasma heparin
      concentration. Protamine titration of heparin reduced the dose of protamine and
      decreased the chance of adverse reactions.

PMID- 10596997
TI  - Red blood cell energy metabolism during cardiopulmonary bypass.
AB  - BACKGROUND: During cardiopulmonary bypass (CPB) an intracellular ATP deficit
      could theoretically play a role in changes of erythrocyte shape and deformability
      caused by mechanical trauma. We therefore studied erythrocyte energy metabolism
      in 12 patients undergoing normothermic CPB for myocardial revascularization.
      METHODS: Blood samples were collected prior to and 45 minutes after CPB beginning
      and analyzed for erythrocyte ATP, ADP, and AMP and their metabolites, erythrocyte
      NAD and NADP, plasma and whole blood lactate (Lact(p) and Lact(b) respectively),
      and whole blood pyruvate (Pyr(b)). RESULTS: Values were expressed as mean +/-
      standard deviation or median (lower and higher quartiles) on the ground of a test
      for normality. During CPB erythrocyte nucleotides and their metabolites did not
      change significantly (ATP: 60.2+/-12.1 vs. 68.3+/-13.0; ADP: 12.2+/-3.6 vs.
      12.0+/-3.1; AMP: 0.43+/-24 vs. 0.44+/-0.26; adenosine: 0.063 (0.034-0.203) vs.
      0.77 (0.032-0.221); inosine: 0.064 (0.023-0.072) vs. 0.075 (0.025-0.111);
      hypoxanthine: 0.330+/-0.272 vs. 0.367+/-0.223; xanthine: 0.193+/-0.090 vs.
      0.220+/-0.095; NAD: 3.149+/-0.743 vs. 3.358+/-0.851; values in microM/mM packed
      red blood cell hemoglobin) while NADP increased (2.110+/-0.390 vs. 2.433+/-0.288
      microM/mM packed red blood cell hemoglobin; p<0.05). Ringer lactate, with which
      the extracorporeal circuit was primed, caused Lact(p) to increase (1.87+/-0.81
      vs. 3.27+/-1.15 mM/l; p<0.01). Some lactate entered erythrocytes since
      Lact(p)/Lact(b) ratio did not change (1.09+/-0.25 vs. 1.07+/-0.23) and some was
      transformed into pyruvate since Pyr(b) increased [62.9 (30.3-73.3) vs. 100.5
      (61.0-146.9) microM/l; p<0.01]. Lact(b)/Pyr(b) ratio did not change significantly
      [22.6 (16.1-40.5) vs. 27.9 (17.5-35.2)] so that NAD/NADH ratio and, consequently,
      the rate of glycolysis were unlikely to change too. CONCLUSIONS: Erythrocyte
      energy metabolism is not affected by CPB, at least during the period of time
      taken into account in this study.

PMID- 10596998
TI  - The heparin-protamine interaction. A review.
AB  - The heparin-protamine interaction is a topic of intense scrutiny due to its
      mandatory use during cardiopulmonary bypass. It can be estimated that over
      2,000,000 patients are exposed to the heparin-protamine interaction each year.
      From clinical and experimental observation it is known that protamine
      neutralization of heparin causes increased pulmonary artery pressures and
      decreased systolic and diastolic blood pressure, myocardial oxygen consumption,
      cardiac output, heart rate, and systemic vascular resistance. These multiple
      cardiovascular effects are mediated via complement activation, histamine release,
      thromboxane and nitric oxide production, and antibody formation. This article
      reviews the current understanding of the heparin-protamine interaction from the
      world's literature.

PMID- 10596999
TI  - Right ventricular infarction complicating coronary artery bypass grafting.
AB  - Intraoperative right ventricular infarction immediately after coronary artery
      bypass grafting is a rare and potentially serious complication. We report a case
      in which an additional coronary artery bypass graft to a right ventricular branch
      with 99% stenosis brought about recovery from profound acute right ventricular
      failure. This case shows that complete revascularization to all graftable
      vessels, including even the right ventricular branch, is mandatory for successful
      coronary artery bypass grafting.

PMID- 10597000
TI  - Traumatic rupture of the aortic valve and ascending aorta diagnosed by
      transesophageal echocardiography.
AB  - The most common site for rupture of the aorta as a consequence of blunt chest
      trauma is at the level of the isthmus. Rupture of the aortic valve with
      concomitant rupture of the ascending aorta is an uncommon entity and only
      relatively few patients sustaining such an injury survive to surgery. Early
      diagnosis of such injuries are critical to facilitate timely intervention. We
      report a case of a 17-year old male who sustained a rupture left coronary cusp
      and ascending aorta in a road traffic accident. The diagnosis was preoperatively
      made by transesophageal echocardiography and he underwent successful surgical
      repair with primary apposition of the torn cusp and closure of the aorta with a
      pericardial patch. Preoperative diagnosis of this rare combination of injury has
      hitherto not been made by transesophageal echocardiography.

PMID- 10597001
TI  - Mediastinitis due to Gordona sputi after CABG.
AB  - Genus Gordona is included in mycolic acid containing bacteria. This genus
      infection is very rare and occurs classically in immuno-compromised patients. We
      report a patient who developed mediastinitis due to Gordona sputi after coronary
      artery bypass grafting (CABG) using left internal mammary artery.
      Immunocompromised factors were not noticed in this case but postoperative
      bleeding, the most important risk factor of mediastinitis, was found in his
      course. The treatment was antibiotic therapy, surgical soft tissue debridement
      and open irrigation with dilute povidone-iodine solution. However, infectious
      reaction continued and Gordona sputi repeated cultured from wound. Next
      procedure, debridement of sternal bone and omental transfer, was performed and
      skin was closed primarily. Inflammatory reaction was attenuated and the wound was
      healed Broad debridement and omental transfer were very effective for
      mediastinitis due to Gordona sputi after CABG.

PMID- 10597002
TI  - Left ventricular pseudoaneurysm and mitral valve regurgitation. Conservative
      surgical therapy.
AB  - A patient with posterolateral left ventricular pseudoaneurysm, severe mitral
      regurgitation and coronary artery disease is reported. Mitral valve insufficiency
      was almost completely cured by simple closure of the left ventricular defect by
      edge to edge apposition along the long axis of the heart.

PMID- 10597003
TI  - Pressure traps in femoro-popliteal reversed vein grafts. Are valves culprits?
AB  - BACKGROUND: Stenosis is a major cause of vein graft failure in peripheral
      arterial surgery. Our goal is to determine whether vein valves play a role in
      this process by creating a "pressure trap". METHODS: Seventeen patients with
      femoro-popliteal reversed saphenous vein grafts were studied intraoperatively.
      Flow and pressure in the grafts were measured, while the graft outflow was
      gradually occluded and released for 2-4 seconds. In 3 patients the graft flow was
      reduced by compressing calf muscles. RESULTS: Patients heart rates were 54-84
      BPM, blood pressures 170/80-110/55 mm Hg, and normal graft flow was 40-180
      ml/min. In 12 patients with competent vein valves, at reduced flow (<30 m/min)
      the valves opened and closed in each cardiac cycle. At each closure the pressure
      was "trapped" distal to the valve producing diastolic hypertension. Also the flow
      was stagnant for a considerable portion of the cardiac cycle. Maximum diastolic
      pressure gradient across the valve ranged from 35 to 60 mm Hg and the level of
      pressure trapped was inversely proportional to the graft flow. CONCLUSIONS: In
      patients in whom reversed vein grafts with competent valves are placed in the
      femoro-popliteal positions a "pressure-trap" develops in the distal segment. This
      segmental hypertension combined with the flow stagnation could play an important
      role in the graft thickening and stenosis.

PMID- 10597004
TI  - Surgical treatment of paragangliomas of the carotid body and other rare
      localisations.
AB  - BACKGROUND: Cervical paragangliomas are uncommon benign or malignant neoplasms,
      deriving from stem cells of the neural crest. Compared to all the tumors of the
      head and neck, they occur less frequently. They can be found in any part of the
      body where there are sympathetic ganglia including chemoreceptors, suprarenal
      medulla, retroperitoneal ganglia and the extreme branches of the vagus nerves. It
      is not easy nowadays to define properly their biological behaviour, the possible
      multicentric location and the association with Multiple Endocrine Neoplasms; this
      is considered particularly important and occurs in 42 per cent of the cases of
      familial neoplasms of the paraganglion system. METHODS: After a review of recent
      diagnostic, pathological and clinical findings, the authors report their
      experience, between 1970-1995, of 10 patients affected by sporadic paraganglioma
      and 1 by familial multicentric neoplasm localised in the carotid bodies of both
      sides, left vagus nerve and left hypoglossus nerve. All patients but one were
      treated by a curative resection of the neoplasm. In one case only an explorative
      laparatomy was possible because of visceral and vascular involvement. RESULTS:
      There is no mortality. There are no modifications in arterial blood pressure and
      catecholamine values in all patients. The complications were a recurrential palsy
      in a patient operated on for vagal paraganglioma; a recurrential palsy and
      temporary dysarthria in the patient affected by multiple familial paraganglioma;
      another patient operated on for carotid body paraganglioma showed a cerebral
      ischemic lesion which caused a slightly transitory facial-brachial motor deficit
      on the right side and speech impairment. CONCLUSIONS: We can venture to say that
      any type of cervical, mediastinal or retroperitoneal swelling in persons
      belonging to a genetically prone family must be first of all considered a
      possible paraganglioma. For this reason the patient with more than one growth of
      this type, whether synchronous or not, must undergo genetic investigation, along
      with the rest of his family.

PMID- 10597005
TI  - Popliteal venous aneurysms. Report of a case and review of the literature.
AB  - Venous aneurysms are uncommon in the vascular pathology of the lower limb. They
      are more commonly encountered in the neck, thoracic veins and visceral veins.
      Involvement of the popliteal veins is not often encountered. These aneurysms
      often cause thrombosis and subsequently pulmonary embolism. Phlebography and
      duplex scanning give the most accurate diagnosis. As the risk of associated
      pulmonary embolism is high, elective surgery is recommended since it has been
      proven that proper anticoagulation treatment does not prevent the risk of
      pulmonary embolism.

PMID- 10597006
TI  - Acute dissection of the abdominal aorta.
AB  - A 64-year-old man presented with sudden lower abdominal pain and diffuse lumbago.
      He was diagnosed as having primary dissection of the abdominal aorta. Entry
      closure and aneurysmal wall plication was performed, and the subsequent course
      was satisfactory. Surgical intervention is recommended for patients with
      abdominal aortic dissection in the infrarenal segment, where the extent of
      dissection is limited and access is comparatively easy. Enhanced computed
      tomography is useful both in diagnosis and follow-up of this aortic disease.

PMID- 10597007
TI  - Dissecting aneurysm of the infrarenal abdominal aorta.
AB  - The aim of this study was to report the case of a patient with chronic dissecting
      infrarenal abdominal aortic aneurysm (AAA) and to review the literature for this
      rare vascular disorder. The preoperative assessment, surgical treatment, and
      postoperative course of a patient with a dissecting AAA and associated left iliac
      artery dissection were analyzed. The literature is reviewed with respect to
      etiology and pathogenesis as well as diagnostic and therapeutic management of
      infrarenal dissecting AAA. The preoperative diagnosis of dissecting infrarenal
      AAA was made by computed tomography and aortography and confirmed during surgery.
      Successful repair was accomplished by use of a bifurcated aortobiiliacal Dacron
      graft. A review of the literature demonstrates the rarity of dissecting aneurysm
      exclusively involving the infrarenal aortic segment. Primary dissecting aneurysm
      of the infrarenal abdominal aorta is a rare morphologic finding. Principles of
      diagnostic and therapeutic management of common atherosclerotic AAA also apply to
      dissecting AAA.

PMID- 10597008
TI  - Transient paraplegia following elective infrarenal aortic aneurysm repair. Case
      report.
AB  - Paraplegia is a well known complication after surgery for thoracic and thoraco
      abdominal aneurysm but is very rare when the level involved is lower than the
      renal arteries. It is seen most often after treatment of ruptured aneurysm and
      very few cases are found in the literature reporting spinal cord ischemia after
      elective repair of an infrarenal abdominal aortic aneurysm. A new case of
      transient paraplegia following elective repair of an infrarenal abdominal aortic
      aneurysm is reported and different aspects of this complication are discussed. In
      our case, probably the interruption of blood flow in lumbar arteries and the
      duration of crossclamping were likely contributive factors and it suggest that a
      failure to appreciate the significance of collateral sources of spinal cord blood
      flow may be responsible for at least some cases of postoperative paraplegia.

PMID- 10597009
TI  - Injuries of large vessels in high stage neuroblastoma surgery. A case report.
AB  - Complete resection of the primary lesion in stage III neuroblastoma improves
      survival Neuroblastoma has a tendency towards surrounding and infiltrating the
      large vessels, leading to injuries during tumor resection. We operated on a stage
      III neuroblastoma, which resulted in the right and left common iliac artery and
      vein damage. The right common iliac artery and, veins were repaired by end to end
      anastomosis. There was a long gap between the two ends of the left common iliac
      artery and it was repaired using a mesenteric vein (marginal vein of the colon)
      graft. Digital subtraction angiography performed 6 months after the operation did
      not reveal any stenosis or aneurysmatic changes in the anastomoses. We conclude
      that short segments of large vessels may be sacrificed during the resection of
      neuroblastomas invading the vessel wall, and the resulting defects may be
      repaired by end to end anastomosis, or even by substituting mesenteric vein
      grafts, for the purpose of total or near total removal

PMID- 10597010
TI  - Resection for bronchogenic carcinoma in the elderly.
AB  - BACKGROUND: The aim of this report was to assess postoperative complications,
      mortality and long term survival of surgical therapy for non small cell lung
      cancer in patients aged 70 years or more. Results and the significance of various
      prognostic factors were analysed. METHODS: At Thoracic Surgery Department of
      Torino, from January 1980 to December 1997, 258 patients aged 70 years or more
      were operated on for lung cancer. For the first 11 years of the series, more
      restrictive selection criteria were adopted (clinical stage I or II lung cancer,
      absence of major concomitant disease or previous malignancy in the last 5 years);
      60 patients were operated in this period. After 1990, such criteria were no
      longer considered mandatory; since then 198 patients have been operated. Clinical
      data are reviewed in the search for predictors of mortality and morbidity and
      survival data are analysed. RESULTS: Overall postoperative mortality was 3.1% and
      morbidity was 39.1%. Pneumonectomy resulted in higher rate of mortality (9.1%, p
      0.03). Complications proved to be more frequent in patients with concomitant
      disease (55.5%). Multivariate analysis on survival showed the importance of stage
      (5 years survival was 73.6% in stage I, 23% in stage II, 8.9% in stage IIIa) and
      type of selection (57% for the highly selected, 40% for the others). CONCLUSIONS:
      Selection criteria have the same impact on survival as stage in surgical
      treatment of lung cancer in the elderly. This factor should be analysed in series
      covering a long period of time. Low mortality and acceptable long term survival
      from this study confirmed that surgery is worthwhile in elderly patients.

PMID- 10597011
TI  - Usefulness of video-assisted thoracic surgery (Two Windows Method) in the
      treatment of lung cancer for elderly patients.
AB  - BACKGROUND: We have been performing it less invasively by making just two, small
      skin incisions (Two Windows Method) for lung cancer surgery. We assess the
      usefulness of VATS by the Two Windows Method in elderly patients. METHODS: The
      subjects were 32 of the 75-year-old or older patients with primary lung cancer in
      our department. We assessed cases in which thoracotomy was performed and the
      cases in which VATS by Two Windows Method was performed, and compared
      postoperative complications, hospital deaths, and postoperative length of stay.
      RESULTS: Operations by video-assisted thoracic surgery (VATS) by the Two Windows
      Method were completed in 20 of the 32 patients, and a conversion to thoracotomy
      was done in two patients (rate 9%). Ultimately, thoracotomy was performed in a
      total of 12 cases, including these two. In the thoracotomy patients, the most
      common postoperative complication was pneumonia/atelectasis (4 cases) secondary
      to poor sputum expectoration. There were 2 hospital deaths due to septicemia, and
      there was 1 due to pulmonary artery embolism. In the VATS patients, the rate of
      occurrence of postoperative complications was 30%, and clearly lower than the 67%
      among the thoracotomy patients (p<0.05). No hospital death occurred among the
      VATS patients. The postoperative hospital stay of the VATS patients (21 days) was
      shorter than that of the thoracotomy patients (31 days), (p<0.05). CONCLUSIONS:
      VATS by the Two Windows Method is safer than thoracotomy, and it should be
      considered first for lung cancer surgery in the aged.

PMID- 10597012
TI  - Surgical correction of pectus excavatum and carinatum.
AB  - The author presents three decades of experience in the management of anterior
      chest wall deformities. During this period more than 800 operations were
      performed on patients with pectus excavatum and carinatum. In this series, there
      was no death and serious complications were rare. The author believes that the
      principles on which surgical treatment of pectus excavatum should be based are as
      follows: (1) bilateral removal of the "culprit" costal cartilages, (2) adequate
      mobilization of the sternum and correction of the sternal positional deformity by
      transverse osteotomy, (3) stabilizing the corrected position of the sternum with
      a substernal "hammock" support. Using this technique the author developed new
      surgical techniques for the correction of different varieties of chest wall
      deformities: Pectus excavatum, asymmetric pectus excavatum, pectus carinatum with
      xiphoid angulation, horizontal pectus excavatum, asymmetric pectus carinatum,
      chondrosternal prominence with chondrogladiolar depression, and recurrent pectus
      excavatum. The present method applied for correction of pectus excavatum utilizes
      the above principles and a substernal Marlex mesh support with bilateral muscle
      coverage. For carinatum repair, the author routinely uses positional correction
      of the sternum and sternal shortening. Patients who have significant pectus
      deformities should undergo surgical repair, preferably between one and eight
      years of age.

PMID- 10597013
TI  - Funnel chest. Psychological and psychosomatic aspects in children, youngsters,
      and young adults.
AB  - BACKGROUND: When considering the indications for operative correction of funnel
      chest, the first question is what is medically actually necessary, and what is
      founded simply on 'doctors opinion'. Furthermore symptoms are often only
      indirectly correlated with the basic illness. This paper suggests a possible way
      of objectivating the symptoms in 56 patients with funnel chest. METHODS:
      According to the results of our retrospective examinations the differentiation
      between 'physical' and (merely) 'cosmetic' findings in the definition of
      indications for operation of funnel chests in children, youngsters and young
      adults, should be dispensed with. The symptoms of "funnel chest" can be of varied
      significance, according to the degree of deformity, ranging from cosmetic fault
      to a severe handicap. Definition of indication thus depends in each case on all
      inclusive plus differential plus interlocking-systemic diagnosis. In the course
      of this, not only somatic data, but also psychosocial characteristics can be
      objectivated and quantified. RESULTS: The results of our examinations show that
      the handicaps of a funnel chest influence all areas of life. Older children (over
      11 years) display as a whole more psychological disorders. Along with specific
      embarassment reactions, social anxiety, feelings of stigma, limited capacity for
      work, orientation towards failure, reduced tolerance of frustration and
      temptation, limited capacity for communication and even markedly depressive
      reactions are observed. CONCLUSIONS: The underlying deformity and the
      psychological reactions to it make a long-term psychotherapy necessary. This may
      be laid out methodically more simply and takes less time, when a permanent
      correction is brought about at operation.

PMID- 10597014
TI  - Significance of three-field lymphadenectomy for carcinoma of the thoracic
      esophagus based on depth of tumor infiltration, lymph nodal involvement and
      survival rate.
AB  - BACKGROUND: Significance of three-field lymhpadenectomy for carcinoma of the
      thoracic esophagus was examined retrospectively based on depth of tumor
      infiltration, lymph nodal involvements and long-term survival. METHODS: One
      hundred and fifty-two consecutive patients who underwent curative esophagectomy
      for thoracic carcinoma invading to submucosa (pT1) or deeper layers of the
      esophageal wall from 1983 to 1996 were examined. Sixty-six patients underwent
      three-field lymphadenectomy (3F) and 86 underwent two-field lymphadenectomy (2F).
      Survival curves were compared between 3F and 2F after stratifications according
      to depth of tumor infiltration, the number of positive nodes (0, 1 to 4, 5 or
      more), and positive intrathoracic recurrent nerve-chain nodes. RESULTS: Overall 5
      year survival rate for 3F was 43.8%, while it was 30.2% for 2F (p = 0.07). In 41
      patients with pT1 cancers, the 5-year survival rate for 3F was 55.7%, while it
      was 41.4% for 2F (p = NS). In patients with cancers invading to muscularis
      propria (pT2), the 5-year survival rate for 3F was 49.4%, while it was 30.7% for
      2F (p = 0.06). In patients with tumors invading to adventitia, there was no
      significant difference. In patients with one to four positive nodes, the 5-year
      survival rates for 3F was 50.1%, while it was 24.1% for 2F (p = 0.01). There was
      no significant difference in the subgroups with no positive nodes and five or
      more. In subgroups with positive recurrent nerve-chain nodes, the 5-year survival
      rate for 3F was 27.9%, while it was 0% for 2F (p = 0.01). CONCLUSIONS:
      Significance of three-field lymphadenectomy was found in patients with one to
      four positive nodes or positive intrathoracic recurrent nerve-chain nodes.

PMID- 10597015
TI  - FDG/PET and spiral CT image fusion for medistinal lymph node assessment of non
      small cell lung cancer patients.
AB  - BACKGROUND: To assess the potential usefulness of 18F-FDG/PET and spiral-CT
      images concurrent assessment and coregistration in staging mediastinal lymph node
      involvement in patients with non small cell lung cancer. METHODS: 28 patients
      waiting to undergo surgical treatment underwent spiral-CT and PET examinations on
      the same day. The results of the two studies were interpreted separately,
      together (CT&PET) and following their fusion in a single image (CT+PET). Results
      of spiral-CT, PET, CT&PET and CT+PET were assessed with respect to the
      histological diagnosis. RESULTS: A correct assessment of mediastinal lymph nodes
      was achieved by spiral-CT in 21 of the 28 patients, in 22 of the 28 patients by
      PET, in 24 patients by CT&PET and in 25 patients by CT+PET. CONCLUSIONS: CT+PET
      is more accurate than spiral-CT and PET alone in staging mediastinal lymph node
      involvement in lung cancer patients, with possible implications for their
      prognosis and therapy.

PMID- 10597016
TI  - Extended resection of the pulmonary artery and the aorta for primary lung cancer.
      Report of a case.
AB  - We report a case of squamous cell carcinoma of the lung in which a left
      pneumonectomy combined resection of the pulmonary artery and aorta was performed
      using a cardiopulmonary bypass. The bifurcation of the pulmonary artery was
      repaired with a pericardial patch and the descending aorta was replaced with an
      artificial vessel Eleven months later, the patient underwent dissection of the
      contralateral mediastinal lymph nodes because of a recurrence of the disease.
      Even though pulmonary metastases have again recently appeared, he is alive and
      doing well two years after operation. To obtain a better prognosis in cases
      demonstrating an involvement of the bifurcation of pulmonary artery, more
      effective combined treatment still needs to be developed.

PMID- 10597017
TI  - Pulmonary abnormalities in Cowden's disease.
AB  - Cowden's disease is an inheritable multiple neoplastic syndrome represented by
      benign and malignant lesions of skin, digestive tract, mucosae, breast and
      thyroid. The syndrome, first described by Lloyd and Dennis in 1963, includes
      benign lung lesions, described in the literature only as hamartomas. The unusual
      condition of our case consists of multiple and bilateral lipomatous lesions of
      the lung and of adipose colonic polyps, diagnosed respectively by video assisted
      mini-thoracotomy and by endoscopic biopsies.

PMID- 10597018
TI  - Paraesophageal omental hernia mimics pleural lipomatous tumor.
AB  - Paraesophageal omental herniation (POH) is uncommon. CT scan and MRI are
      complementary in diagnosis. We present a posterior mediastinal mass in a 43 year
      old male with a history of myxoid liposarcoma raising the suspicion of latent
      secondary tumor. Subsequently, at thoracotomy he was found to have a POH.
      Differential diagnosis, work-up and surgical approach are discussed.

PMID- 10597019
TI  - Esophagopleural fistula originating from diverticulum after pneumonectomy. A case
      report and review of the literature.
AB  - Esophagopleural fistula (EPF) is a very rare and fatal disease. A 56 year-old man
      developed a pyothorax resulting from an EPF with esophageal diverticulum after a
      right pneumonectomy. The patient was successfully treated with a three-stage
      operation and control of infection and nutritional status. First, fenestration
      was performed, then an ante-thoracic gastroplasty, and a radical thoracoplasty
      was performed. Surgical management, nutritional support, and control of infection
      were the cornerstones of the treatment of EPF.

PMID- 10597020
TI  - Technique for preventing air embolism during cardiac surgery.

PMID- 10597021
TI  - Saphenous vein sparing surgery. Principles, techniques and results.

PMID- 10597022
TI  - Pulmonary embolism, patent foramen ovale and paradoxical embolism.

PMID- 10597023
TI  - Stannous chloride mediates single strand breaks in plasmid DNA through reactive
      oxygen species formation.
AB  - Stannous ion (Sn) has been employed in nuclear medicine and in food industry. We
      described that Stannous Chloride (SnCl2) inactivation effect in Escherichia coli
      is mediated by a Fenton-like reaction. The effect of SnCl2 was studied through:
      (i) the alteration of plasmid topology in neutral and acidic pH by gel
      electrophoresis; and (ii) the transformation efficiency of an wild type E. coli
      strain. Treatment of plasmid DNA pUC 9.1 with SnCl2, at pH 7.4, results in DNA
      single-strand breaks (SSB), in a dose-dependent manner. Addition of sodium
      benzoate partly inhibited the DNA damage, while EDTA completely abolishes DNA
      SSB. Furthermore, the ability of the plasmid to transform E. coli was reduced. At
      pH 1.3, SnCl2 exerts a protective effect on plasmid against HCI depurination. Our
      results suggest the generation of ROS, such as *OH by a Fenton-like reaction,
      close to the site of the lesions due to a possible complexation of stannous ion
      to DNA.

PMID- 10597025
TI  - Methylglyoxal in living organisms: chemistry, biochemistry, toxicology and
      biological implications.
AB  - Despite the growing interest towards methylglyoxal and glyoxalases their real
      role in metabolic network is still obscure. In the light of developments several
      reviews have been published in this field mainly dealing with only a narrow
      segment of this research area. In this article a trial is made to present a
      comprehensive overview of methylglyoxal research, extending discussion from
      chemistry to biological implications by reviewing some important characteristics
      of methylglyoxal metabolism and toxicity in a wide variety of species, and
      emphasizing the action of methylglyoxal on energy production, free radical
      generation and cell killing. Special attention is paid to the discussion of alpha
      oxoaldehyde production in the environment as a potential risk factor and to the
      possible role of this a-dicarbonyl in diseases. Concerning the interaction of
      methylglyoxal with biological macromolecules (DNA, RNA, proteins) an earlier
      review (Kalapos, Toxicology Letters, 73, 1994, 3-24) means a supplementation to
      this paper, thus hoping the avoidance of unnecessary bombast. The paper arrives
      at the conclusion that since the early stage of evolution the function of
      methylglyoxalase pathway has been related to carbohydrate metabolism, but its
      significance has been changed over the thousands of years. Namely, at the
      beginning of evolution methylglyoxalase path was essential for the reductive
      citric acid cycle as an anaplerotic route, while in the extant metabolism it
      concerns with the detoxification of methylglyoxal and plays some regulatory role
      in triose-phosphate household. As there is a tight junction between methylglyoxal
      and carbohydrate metabolism its pathological role in the events of the
      development of diabetic complications emerges in a natural manner and further
      progress is hoped in this field. In contrast, significant advancement cannot be
      expected in relation to cancer research.

PMID- 10597024
TI  - The effect of repeat administration of GTS-21 on mixed-function oxidase
      activities in rat.
AB  - The effect of repeat administration of GTS-21 on hepatic microsomal enzymes was
      determined in rats administered the drug at levels of 3, 60 and 300 mg/kg/day for
      7 days. Liver weight and cytochrome P450 (CYP) contents were not changed.
      Cytochrome b5 contents were increased at the mid and high doses of GTS-21, as the
      contents increased with increasing dose, but were unchanged at the low dose. Five
      selective activities of CYP isoforms, acetanilide hydroxylase (CYP1A2),
      tolbutamide hydroxylase (CYP2C6), dextromethorphan O-demethylase (CYP2D1), p
      nitrophenol hydroxylase (CYP2E1) and erythromycin N-demethylase (CYP3A) were
      examined. Enzyme activities were changed only at the highest dose; the activity
      of CYP1A2 was increased by 71% and the activities of CYP2C6 and CYP2D1 were
      decreased by 37 and 19%, respectively. At low and mid doses of GTS-21, all
      activities were unchanged. These data indicate that GTS-21 is not a strong
      modulator of the mixed-function oxidase system.

PMID- 10597026
TI  - Quantitative relationship between steady-state blood concentrations and
      structural features of aliphatic hydrocarbons.
AB  - The objective of this study was to investigate the quantitative relationship
      between steady-state blood concentrations and structural features of aliphatic
      hydrocarbons. The literature data on steady-state blood concentrations (Cb(ss))
      of 11 C6 to C10-aliphatic hydrocarbons (five n-alkanes, three alkenes, and three
      iso-alkanes) obtained in rats after exposure to 100 ppm of these chemicals were
      analyzed using a commercially available software (QSAR-PC). Based on a multiple
      linear regression analysis, the contribution values of (i) the basic structure
      [=C1H2-CH2-CH2-CH2C5H2-, + 6.8009], (ii) the substituents at carbon position 1 [(
      H)2,=CH2, and (-CH3)2, associated with values of - 3.25, + 7.44 and - 2.02,
      respectively) and (iii) the substituents at carbon position 5 (CH3, C2H5, C3H7,
      C4H9 and C5H11 associated with values of - 1.20, - 1.69, +0.71, + 1.26 and +
      2.82, respectively) were quantified. This analysis explained 98.8% of the
      variability in rat Cb(ss) among the hydrocarbons investigated. The present work
      represents the first attempt to characterize the quantitative contributions of
      specific molecular fragments to the toxicokinetic behavior of aliphatic
      hydrocarbons.

PMID- 10597027
TI  - Induction of lipid peroxidation in human fibroblasts by the antioxidant propyl
      gallate in combination with copper(II).
AB  - The antioxidant propyl gallate (PG) induced lipid peroxidation in combination
      with non-toxic Cu(II) concentrations in human fibroblasts. This was measured by
      the thiobarbituric acid assay (TBA assay) and by detection of accumulating
      fluorescent products after a 1-h treatment of cells with CuCl2/PG at
      concentrations higher than 0.125 mM. PG alone led to a significant reduction of
      thiobarbituric acid-reactive substances (TBARS) demonstrating its antioxidative
      properties. Time course studies of lipid peroxidation by PG/Cu(II) showed that
      formation of TBARS was preceded by a lag phase of 60 min. Thereafter, the TBARS
      value increased rapidly for 1 h and then reached a constant maximum or slightly
      decreased. The induction of lipid peroxidation by PG/Cu(II) is probably due to
      the formation of reactive species like reactive oxygen species (ROS), Cu(I) and
      semiquinone radicals which are able to participate in initiation and propagation
      of lipid peroxidation. Combination effects of PG/Cu(II) were demonstrated also on
      inhibition of membrane-bound succinate dehydrogenase. Cytosolic esterases were
      affected only slightly. The greater susceptibility of membrane-bound enzymes is
      in accordance with the lipid peroxidation-inducing effects of PG/Cu(II).

PMID- 10597028
TI  - Suppression of N-methyl-N'-nitro-N-nitrosoguanidine- and S-nitrosoglutathione
      induced apoptosis by Bcl-2 through inhibiting glutathione-S-transferase pi in
      NIH3T3 cells.
AB  - In this study, both NIH3T3 and Bcl-2 transfected NIH3T3 cells were examined for
      their propensity to undergo nitroso compound-induced apoptosis. Bcl-2-expressing
      NIH3T3 prevented N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)- and S
      nitrosoglutathione (GSNO)-induced apoptosis as compared with the control NIH3T3
      cells. Flow cytometry revealed that NIH3T3 cells treated with MNNG undergo
      apoptotic death, which occurred after G2-M arrest in the second cycle of cell
      proliferation. The mechanism of MNNG-induced NIH3T3 cells apoptosis was observed
      throughout the activation of caspase-3 protease, PARP degradation and cytochrome
      c release; it was independent of p53 activation. Glutathione-S-transferanse pi
      (GST pi) is activated through the transcription activation of antioxidant
      response element (ARE) during MNNG- and GSNO-induced cell apoptosis. Moreover,
      overexpression of Bcl-2 in NIH3T3 cells can prevent these features of cell death.
      Furthermore, both MNNG- and GSNO-induced apoptosis of NIH3T3 cells were
      accompanied with a decrease in the level of glutathione (GSH); whereas Bcl-2
      overexpression led to an increase in total cellular glutathione. MNNG was
      metabolized rapidly to nitric oxide that reacted with glutathione under the
      catalysis of GSH transferase in NIH3T3 cell to form GSNO. In short, the
      production of GSNO in cells was found capable of apoptosis initiation while the
      overexpression of Bcl-2 can prevent MNNG-mediated cell apoptosis through the
      elevation of glutathione levels.

PMID- 10597029
TI  - Studies on the mutagenic activity of hydralazine and dihydralazine in Salmonella
      typhimurium strains differing in expression of antioxidant genes.
AB  - The mutagenic activity of two antihypertensive drugs, hydralazine and
      dihydralazine was investigated in oxyR- proficient (TA104) and -deficient
      (TA4125) Salmonella typhimurium strains showing different ability to induce
      proteins involved in protection of the cells against oxidative damage. The
      results of the Ames test demonstrated that dihydralazine, in contrast to
      hydralazine, was mutagenic for oxyR- strain at concentrations that were
      nonmutagenic for oxyR+ strain. The scavenger of superoxide anion, superoxide
      dismutase decreased in both strains the number of revertants induced by
      dihydralazine but not by hydralazine. The results may suggest that active oxygen
      species generated by dihydralazine contribute to its mutagenicity.

PMID- 10597030
TI  - Cadmium effects on hypothalamic activity and pituitary hormone secretion in the
      male.
AB  - Cadmium specifically modify amine metabolism at the central nervous system and
      pituitary hormone secretions. Thus, the physiological functions controlled by
      these hormones can be modulated by cadmium. This xenobiotic is associated with
      deleterious effects on the gonadal function and with changes in the secretory
      pattern of other pituitary hormones like prolactin, ACTH, GH or TSH. The observed
      changes in pituitary hormone secretion do not correlate with the modifications of
      central nervous system metabolism of the neurotransmitters involved in their
      regulation. The accumulative data indicates the existence of a disruption in the
      regulatory mechanisms of the hypothalamic-pituitary axis. The physiological
      significance of these effects remains to be elucidated.

PMID- 10597031
TI  - Oxidative damage on lymphocyte membranes is increased in patients suffering from
      acute carbon monoxide poisoning.
AB  - Increased oxidative damage seems to be a relevant mechanism in the
      pathophysiology of patients with an acute carbon monoxide (CO) poisoning. We have
      investigated the degree of membrane oxidative damage through the assessment of
      lipid peroxidation in circulating lymphocytes from five patients acutely
      intoxicated by CO. Since mitochondria are a major source of reactive oxygen
      species and mitochondrial cytochrome c oxidase (COX) has been reported to be
      inhibited after acute CO poisoning, we have also assessed the lymphocyte COX
      activity and its relationship with the degree of lipid peroxidation. Data were
      compared with those from 32 non-smoker healthy controls comparable in terms of
      age, gender and physical activity. In intoxicated patients, we have found a
      significant increase of lipid peroxidation compared to control individuals (P <
      0.05), as well as a marked COX inhibition (P < 0.001). Both parameters showed a
      positive, nearly significant correlation (r = 0.81, P = 0.09). We conclude that
      oxidative damage of lymphocyte membranes is increased after acute CO poisoning,
      and suggest that such increase could be partially mediated by mitochondrial COX
      inhibition caused by CO.

PMID- 10597032
TI  - Ribozymes--why so many, why so few?
AB  - The RNA world scenario posits the existence of catalytic and genetic networks
      whose reactions are catalyzed by RNAs. Substantial progress has been made in
      recent years in the selection of RNA catalysts by SELEX, thus verifying one
      prediction of the model. However, many selected catalysts are long molecules,
      leading to a question of whether they could have been synthesized by a primitive
      replicator. It is proposed that the efficiency of some small ribozymes may have
      been augmented by other RNAs acting as transactivators.

PMID- 10597033
TI  - DNA computing the Hamiltonian path problem.
AB  - The directed Hamiltonian path (DHP) problem is one of the hard computational
      problems for which there is no practical algorithm on a conventional computer
      available. Many problems, including the traveling sales person problem and the
      longest path problem, can be translated into the DHP problem, which implies that
      an algorithm for DHP can also solve all the translated problems. To study the
      robustness of the laboratory protocol of the pioneering DNA computing for the DHP
      problem performed by Leonard Adleman (1994), we investigated how the graph size,
      multiplicity of the Hamiltonian paths, and the size of oligonucleotides that
      encode the vertices would affect the laboratory procedures. We applied Adleman's
      protocol with 18-mer oligonucleotide per node to a graph with 8 vertices and 14
      edges containing two Hamiltonian paths (Adleman used 20-mer oligonucleotides for
      a graph with 7 nodes, 14 edges and one Hamiltonian path). We found that depending
      on the graph characteristics such as the number of short cycles, the
      oligonucleotide size, and the hybridization conditions that used to encode the
      graph, the protocol should be executed with different parameters from Adleman's.

PMID- 10597034
TI  - Purification and partial characterization of NADPH-cytochrome P450 reductase from
      Gentiana triflora flowers.
AB  - Reduced form of nicotineamide adenine dinucleotide phosphate (NADPH)-cytochrome
      P450 reductase was solubilized from a microsomal fraction of Gentiana triflora
      flowers by 3-[(3 Cholamidopropyl)-dimethylammonio]-1-propane sulfonate detergent
      and purified to electrophoretic homogeneity. The purification was achieved by
      adenosine 2', 5'-bisphosphate-Sepharose chromatography, followed by high
      performance anion-exchange chromatography. A Mr value of 82,000 was obtained by
      SDS/polyacrylamide-gel electrophoresis. Western blot analysis showed that the
      purified protein cross-reacted with polyclonal antibody raised against rabbit
      anti-Gentiana triflora NADPH-cytochrome P450 reductase antibodies. The
      temperature and pH optimum for reduction of cytochrome c was 25 degrees C and 7.4
      respectively. The Km values for the binding of NADPH and cytochrome c were 9.4
      and 3.2 microM, respectively. In this paper, we present some results of the
      purification and partial characterization of microsomal NADPH-cytochrome P450
      reductase from Gentiana triflora flowers.

PMID- 10597035
TI  - Glucocorticoid receptor-induced down-regulation of MMP-9 by ginseng components,
      PD and PT contributes to inhibition of the invasive capacity of HT1080 human
      fibrosarcoma cells.
AB  - We examined the effects of the purified ginseng components, panaxadiol (PD) and
      panaxatriol (PT), on the expression of matrix metalloproteinase-9 (MMP-9) in
      highly metastatic HT1080 human fibrosarcoma cell line. A significant down
      regulation of MMP-9 by PD and PT was detected by Northern blot analysis. However,
      the expression of MMP-2 was not changed by treatment with PD and PT. Quantitative
      gelatin based zymography confirmed a markedly reduced expression of MMP-9, but
      not MMP-2 in the treatment of PD and PT. To investigate whether the reduced level
      of MMP-9 by PD and PT affects the invasive capacity of HT1080 cells, we conducted
      an in vitro invasion assay with PD and PT treated cells. The results of the in
      vitro invasion assay revealed that PD and PT reduced tumor cell invasion through
      a reconstituted basement membrane in the transwell chamber. Because of the
      similarity of chemical structure between PD, PT and dexamethasone (Dexa), a
      synthetic glucocorticoid, we investigated whether the down-regulation of MMP-9 by
      PD and PT were mediated by the nuclear translocation of glucocorticoid receptor
      (GR). Increased GR in the nucleus of HT1080 human fibrosarcoma cells treated by
      PD and PT was detected by immunocytochemistry. Western blot and gel retardation
      assays confirmed the increase of GR in the nucleus after treatment with PD and
      PT. These results suggest that GR-induced down-regulation of MMP-9 by PD and PT
      contributes to reduce the invasive capacity of HT1080 cells.

PMID- 10597036
TI  - Cloning and characterization of the chloroplast elongation factor EF-Tu cDNA of
      Oryza sativa L.
AB  - From the rice leaf cDNA library, we have cloned a cDNA encoding rice chloroplast
      translational elongation factor EF-Tu (tufA). The rice tufA cDNA clone contains
      1678 nucleotides and codes for a 467 amino acid protein including a putative
      chloroplast transit peptide of 59 amino acid residues. The predicted molecular
      mass of the mature protein is approximately 45 kDa. This cDNA clone contains the
      61 nucleotides of the 5' untranslated region (UTR) and the 213 nucleotides of 3'
      UTR. Amino acid sequence identity of the rice tufA with the mature chloroplast EF
      Tu proteins of tobacco, pea, arabidopsis, and soybean ranges from 83% to 86%. The
      deduced polypeptide of the rice tufA cDNA contains GTP binding domains in its N
      terminal region and chloroplast EF-Tu signature regions in the C-terminal region.
      The rice tufA appears to exist as a single copy gene, although its homologues of
      maize and oat exist as multiple copy genes. The rice tufA gene is located in
      chromosome 1 and is more highly expressed in the leaf than in root tissue.

PMID- 10597037
TI  - Cloning of a cysteine proteinase gene from Acanthamoeba culbertsoni.
AB  - Free living amoeba, including pathogenic Acanthamoeba culbertsoni, are widely
      distributed in soil and fresh water. It has been found that cysteine proteinases
      are more active in pathogenic strains of amoeba whereas serine proteinases are
      found in both pathogenic and nonpathogenic strains. Cysteine proteinases thus
      play important roles in the pathogenesis of several parasitic infections and have
      been proposed as targets for the structure-based strategy of drug design. As the
      first step toward applying this strategy to design inhibitors as antiparasitic
      agents for A. culbertsoni, we isolated and sequenced the full length clone of a
      cysteine proteinase gene from A. culbertsoni by performing reverse transcription
      polymerase chain reaction (RT-PCR) with degenerate oligonucleotide primers
      derived from conserved cysteine proteinase sequences. The 5' and the 3' regions
      of the cysteine proteinase gene were amplified using the PCR protocol for the
      rapid amplification of cDNA ends (RACE). It has an open reading frame of 1359 bp.
      The deduced amino acid sequence has the sequence homology with the cysteine
      proteinase genes of Paragonimus westermani metacercaria, Schistosoma mansoni,
      human cathepsin L and Fasciola hepatica, each by 45.3%, 45.9%, 57.9% and 50.8%
      respectively. Sequence analysis and alignment showed significant similarity to
      other eukaryotic cysteine proteinases, including the conservation of the
      cysteine, histidine, and asparagine residues that form the catalytic triad. A 1.5
      kbp mRNA was detected on Northern blot analysis using full-length cysteine
      proteinase cDNA as a probe. The A. culbertsoni cysteine proteinase gene (AcCP2)
      was found to contain Ex3Rx3Wx2N at the proregion and also a proline/threonine
      rich C-terminal extension. Therefore, it has cathepsin L-like characteristics.
      Phylogenetic analysis based on the amino acid sequences of cysteine proteinase
      indicated that AcCP2 was closely related with papaya, while it was remotely
      related with those of Schistosoma.

PMID- 10597038
TI  - Neuregulin induces the expression of mesodermal genes in the ectoderm of Xenopus
      laevis.
AB  - The primary patterning event in early vertebrate development is the formation of
      mesoderm and subsequent induction of the neural tube by the mesoderm. Some of the
      transforming growth factor (TGF)-beta family (Activin, Vg1) and the fibroblast
      growth factor (FGF) family molecules have been implicated for their roles in
      mesoderm induction. Here we show first the evidence that neuregulin, an epidermal
      growth factor (EGF)-like growth factor known for its role in neural and muscle
      differentiation, participates in mesoderm induction. Neuregulin could induce the
      ectopic expression of mesoderm specific gene Xbra in animal cap explants reared
      to the midgastrula stage, when animal caps dissected from late blastula were
      cultured with Neuregulin at a low concentration (10 ng/ml). In situ hybridization
      study showed that alpha-cardiac actin was expressed in animal caps that were
      treated with Neuregulin overnight. Skeletal and cardiac muscle specific genes
      such as MyoD family genes (myoD, MRF4, myf5) and SL1 as well as NCAM, a pan
      neural marker, were also ectopically expressed by treatment with Neuregulin.
      However, the expression of NCAM is presumed to be a secondary result of the
      initial mesoderm induction by Neuregulin. The temporal expression pattern of
      neuregulin during the early developmental stages was analyzed by RT-PCR in order
      to determine if neuregulin is expressed at the time of mesoderm induction. It has
      been found that the neuregulin transcript was already detected from the 16-cell
      stage (stage 5) and continued to be expressed till the tailbud stage (stage 25),
      the latest embryonic stage analyzed in this study. Considering that the mesoderm
      is induced at early blastula before the start of zygotic transcription, maternal
      neuregulin is expressed at the right time to participate in mesoderm induction.
      These data strongly suggest that neuregulin plays an important role in mesoderm
      induction.

PMID- 10597039
TI  - Development of a novel expression vector system using Spodoptera exigua
      nucleopolyhedrovirus.
AB  - To develop a novel Spodoptera exigua nucleopolyhedrovirus (SeNPV) expression
      vector system, we examined characteristics of the SeNPV polyhedrin expression in
      S. exigua cells (Se301). While the extracellular virus titer of SeNPV was 100
      fold lower than that of Autographa californica nucleopolyhedrovirus (AcNPV), the
      levels of polyhedral inclusion body (PIB) formation and polyhedrin expression
      were higher in SeNPV. To investigate foreign gene expression under the control of
      the polyhedrin promoter, polyhedrin-based transfer vector pSeKSK2 was
      constructed, and then recombinant virus SeK1-LacZ was constructed by inserting E.
      coli lacZ gene as a reporter gene into a genomic DNA of SeNPV using this transfer
      vector. The beta-Galactosidase activity of SeK1-LacZ in Se301 was about 1.3 times
      higher than that of BacPAK6. Thus, the SeNPV expression vector system constructed
      in this study would be very useful in the expression of foreign proteins,
      specifically for the enhancement of the pesticidal properties of SeNPV by
      inserting pesticidal genes.

PMID- 10597040
TI  - Role of -35 sequence and its cooperativity with vir-box for the expression of
      virE gene.
AB  - To elucidate the role of the -35 sequence and its cooperativity with vir box in
      the expression of the virE gene, various mutants were constructed by either site
      directed mutation or deletional mutation of the virE promoter. The expression
      level of pHBAV, a mutant where its putative -35 sequences (CCGAGT) have been
      substituted with the consensus -35 sequences of the Escherichia coli promoter
      (TTGACA), was increased by 386%. pECHV, containing the conserved -35 sequence but
      lacking the vir box and the 5'-half of the imperfect dyad symmetry region (DSR)
      showed an increase of 286% in its promoter activity. pESHV, containing the
      conserved -35 sequence but lacking the complete 5'-upstream region from the mid
      region of imperfect DSR, exhibited 244% of the native virE promoter activity.
      pHBCA, containing the conserved -35 sequence but destroying the vir box, was
      constructed by substitution of A, C, T at the positions -62, -63, and -65 on the
      vir-box to T, A, C, respectively. These mutations increased promoter activities
      by 319%. On the other hand, when the vir box was mutated from imperfect DSR to
      almost perfect DSR with T to A and G to T substitutions at -60 and -61 positions
      of the virE promoter containing the conserved -35 sequence (pHBNA), a higher
      activity of 671% was observed. These results demonstrate that when the putative 
      35 sequence of virE promoter is replaced with the consensus -35 sequence, the
      virE gene can be expressed independently without the binding of VirG protein to
      the vir-box and/or the induction of acetosyringone. Moreover, the presence of an
      almost perfect dyad symmetry of the vir-box can increase the expression of virE
      synergistically with the consensus -35 sequence.

PMID- 10597041
TI  - Isolation and identification of Fur binding genes in Escherichia coli.
AB  - Fur (ferric uptake regulation) binding fragments were isolated by in vitro
      binding of purified Fur protein with Sau3AI-digested genomic DNA fragments. The
      Fur-bound DNA fragments were filtered on nitrocellulose paper, isolated, cloned,
      and sequenced. The protein binding was confirmed by gel retardation assay for
      five DNA fragments. The sequence data were used to identify the genes by
      comparison with the GenBank data. The proposed Fur binding regions lie on or near
      the putative promoter regions of marAB (multiple antibiotic resistance), pyrC
      (dihydroorotase), mreB (mecillinam resistance) and an unidentified gene (ecouw93)
      near argI and in the middle of the treBC (trehalose permease enzyme II) coding
      region. The proposed Fur binding sites of the known iron regulating operators
      including the genes of this work are AAT(pyrimidine) and A(purine)TT. The two
      conserved sequences are 10 bases apart and palindromic to each other, which might
      suggest the classical pattern of protein binding toward one side of the DNA in
      contrast to the concept of the Fur protein wrapping around the DNA.

PMID- 10597042
TI  - Survey of the Korean population for 9 short tandem repeat loci.
AB  - The short tandem repeats with repeat units ranging from two to several
      nucleotides became a powerful tool in the field of forensic identification and
      paternity determination as well as for research in human gene mapping. Allele and
      genotype frequencies for 9 short tandem repeats including HUMCSF1PO, HUMTH01,
      HUMPLA2A1, HUMF13A01, HUMCYAR04, HUMLIPOL, HUMHPRTB, HUMCD4, and HUMFABP were
      determined using PCR and subsequent analysis of the PCR products by denaturing
      polyacrylamide gel electrophoresis followed by silver-staining. DNA samples were
      obtained from about 100 Korean people and amplified in a thermocycler adopting
      glass capillaries rather than traditional tubes. We found that the bovine serum
      albumin was an essential additive for the capillary PCR, presumably to coat the
      inner surface of the capillary which may adsorb Taq DNA polymerase. The capillary
      thermocycler was very effective in reducing the cycling time such that most of
      the amplification reactions could be finished within 30 min albeit the PCR
      product was less than that for the tube systems. All loci except HUMHPRTB met the
      Hardy-Weinberg expectations according to the exact test. The cumulative power of
      discrimination (PD) was 0.9999998 and the power of exclusion (POE) for the
      paternity test was a little low, being 0.9873989.

PMID- 10597043
TI  - elt-1, a gene encoding a Caenorhabditis elegans GATA transcription factor, is
      highly expressed in the germ lines with msp genes as the potential targets.
AB  - The Caenorhabditis elegans ELT-1 protein, a homolog of the vertebrate GATA
      transcription factor family, is a transcription activator that can recognize the
      GATA motif. We previously showed that the elt-1 mRNA was primarily expressed in
      C. elegans embryos. To examine whether the elt-1 mRNA in embryos is maternal,
      paternal or zygotic, Northern blot analysis was performed with RNA isolated from
      the C. elegans germ-line mutant strains, fem-2 (b245)lf, fem-3 (q20)gf, him-8
      (e1489), and glp-4 (bn2). This analysis revealed that the high level of elt-1
      mRNA in the C. elegans embryos resulted from either the maternal or the paternal
      transcription, rather than from the zygotic expression. These results further
      demonstrated that elt-1 was highly expressed in the germ-line of both sexes. To
      investigate the possible target genes for the ELT-1 protein in the germ line, the
      ELT-1 protein was expressed and tested for its binding specificity to the GATA
      motif that is present in the promoter region of the C. elegans major sperm
      protein genes. It was found that two conserved cis-elements, AGATCT and AGATAA,
      in the proximal promoter region of the msp-113 gene provided the best recognition
      site for ELT-1. Mutational analysis showed that the GATC core sequence was
      necessary for strong transactivation of the reporter gene, and that the
      combination of GATC and GATA motif resulted in a stronger transactivation by ELT
      1 than either the duplicated GATC or GATA motif. These results suggest that the
      potential target for the ELT-1 protein in the germ-line may be one of the major
      sperm protein gene family.

PMID- 10597044
TI  - Localization of calcium-binding protein parvalbumin-immunoreactive neurons in
      mouse and hamster visual cortex.
AB  - Calcium-binding proteins are thought to play important roles in regulating
      intracellular calcium in the central nervous system. In the present study, we
      investigated the distribution and morphology of neurons containing parvalbumin in
      the visual cortex of mouse and hamster. The calcium-binding proteins were
      localized using immunocytochemistry. Parvalbumin-immunoreactive neurons were
      located in all layers except layer I. The highest density of parvalbumin
      immunoreactivity was found in layer V of both mouse and hamster. The labeled
      neurons varied in morphology. The majority of the parvalbumin-immunoreactive
      neurons both in mouse and hamster visual cortex was stellate and round, or oval
      with multipolar dendrites. These results indicate that the calcium-binding
      protein parvalbumin is contained in specific layers and in selective cell types
      of the mouse and hamster visual cortex. The distribution of parvalbumin in the
      mouse visual cortex is very similar to that of hamster.

PMID- 10597045
TI  - Isolation of a putative tobacco host factor interacting with cucumber mosaic
      virus-encoded 2b protein by yeast two-hybrid screening.
AB  - The cucumber mosaic virus (CMV)-encoded 2b protein has been implicated to play a
      role in long distance movement of the virus through the plant's transport system.
      It is unknown, however, how it mediates virus movement and whether any intrinsic
      components of plant cells also participate in this process. To isolate a host
      factor that interacts with 2b, the yeast two-hybrid system was used. First, it
      was found that the 2b protein per se could function as a transcriptional
      activator in yeast. However, its two carboxyl terminal deletion mutants,
      2bdelta98 and 2bdelta95, which lacked 12 and 15 amino acids from the carboxyl
      terminus respectively, showed complete absence of transcriptional activation in
      yeast. A tobacco cDNA library expressing the GAL4 activation domain fusion
      proteins was screened using 2bdelta98 as a bait. A clone named 2bip (2b
      interacting protein) was isolated whose translation product apparently interacted
      with 2b. Consistent with this observation, bacterially expressed GST-2bip fusion
      protein bound tightly to 2bdelta95 and 2bdelta98 polypeptides in vitro, as well
      as to the unmodified 2b protein. Nucleotide sequencing and database searches
      revealed that the amino acid sequence deduced from it was similar to a
      prokaryotic LytB protein and an unknown protein of Arabidopsis. DNA and RNA gel
      blot analyses showed that 2bip-related sequences were present in the tobacco
      genome and that transcripts corresponding to 2bip were expressed constitutively
      in various plant organs and in response to CMV infection. These results suggest
      2bip as a novel host factor that is capable of interacting with CMV2b.

PMID- 10597046
TI  - Aspects of mammalian spermatogenesis: electrophoretical analysis of protamines in
      mammalian species.
AB  - Protamines are small, highly basic proteins that replace histones and testicular
      basic proteins during the development of mature spermatozoa, spermatogenesis. In
      mammals, extensive disulfide crosslinking of protamines result in the formation
      of a compact chromatin structure devoid of transcriptional activity. As
      determined by isolation and electrophoresis of protamines, only one protamine has
      been detected in the mature spermatozoa of most mammalian species. However, in
      the spermatozoa of the mouse and human, two different protamines called P1 and
      P2, have been found. In this report we demonstrated by electrophoretic analysis
      that these two protamines are also present in the spermatozoa of Microtus
      arvalis, Microtus agretis, Apodemus flavicollis, Apodemus sylvaticus,
      Clethrionomys glareolus, the Chinese and the golden hamster. However, only one
      protamine is found in the spermatozoa of the guinea pig, dog, bull, black monkey,
      and the rhesus monkey. The mammalian protamines are highly conserved during
      mammalian evolution. In general, the homologies on the amino acid sequence of the
      various mammalian protamines range from 52% to 96%. Furthermore, in the case of
      mouse and human protamines, the genes of the protamines are closely linked and
      located on chromosome 7 and 16, respectively. Accordingly, it can be assumed that
      both types of protamine genes have arisen by gene duplication during mammalian
      evolution. According to the results of an electrophoretical analysis of the
      mammalian protamines, the predicted point of gene duplication during evolution is
      deduced carefully.

PMID- 10597047
TI  - Functional characterization of TEL/AML1 fusion protein in the regulation of human
      CR1 gene promoter.
AB  - The TEL/AML1 fusion gene occurs in childhood B-cell acute lymphoblastic leukemia
      (ALL) as a result of the translocation of human chromosome 12;21. Using reporter
      gene assays, we have functionally characterized TEL, AML1 and TEL/AML1 fusion
      proteins in the regulation of the human CR1 gene. Analysis of transcription
      activities showed that AML1 increased the CR1 promoter activity and that TEL
      repressed the basal activity of the promoter. Increased activities of the CR1
      promoter by AML1 protein were reduced by the TEL protein in a concentration
      dependent manner. When TEL/AML1 and AML1 proteins are present in cells at the
      same time, the TEL/AML1 protein inhibits the transactivation activities of AML1
      protein on the human CR1 promoter even though TEL/AML1 retains the
      transactivation domain of AML1. A mutation analysis of the human CR1 promoter
      revealed that the binding sites for TEL and AML1 are necessary for the action of
      TEL and TEL/AML1, respectively. Thus, production of the TEL/AML1 protein by
      translocation of human chromosome 12;21 may contribute to leukemogenesis by the
      specific inhibition of AML1-dependent activation of myeloid promoters.

PMID- 10597048
TI  - Selection of Drosophila genes encoding secreted and membrane proteins.
AB  - With the use of a yeast-based signal sequence trap (YSST) method, we screened a
      Drosophila cDNA library to isolate genes encoding secreted and membrane proteins.
      Of the 136 unique cDNA clones sequenced, 11 clones (8.1%) are identical to
      previously known Drosophila genes, 18 clones (13.2%) are homologous to other
      genes identified in various organisms, and 91 clones (66.9%) are novel. Most of
      these genes are secreted or membrane proteins, or appear to contain putative
      signal sequences at their amino termini. This indicates that YSST is an effective
      tool for the isolation and analysis of Drosophila genes that play roles in
      intercellular communication.

PMID- 10597049
TI  - Fibre type characteristics and function of the human paraspinal muscles: normal
      values and changes in association with low back pain.
AB  - This review focuses on the role of the paraspinal muscles in relation to the
      development and existence of low back pain. It begins with a discussion of the
      deficits in paraspinal muscle strength and fatigue-resistance observed in low
      back pain patients and addresses the issue of 'cause or effect' with respect to
      muscle dysfunction and back pain. Our current knowledge regarding the 'normal'
      fibre type characteristics of the human erector spinae is then presented and the
      influence of these fibre type characteristics on the muscle's performance
      capacity is discussed. Alterations in the 'microanatomy' of the musculature in
      connection with low back pain, and the associated implications for the
      performance capacity of the patient, are then considered. Finally, a number of
      outstanding issues in relation to the clinical significance of back muscle
      dysfunction are identified, leading to the proposal of areas for future research.

PMID- 10597050
TI  - Progressive resistance training in neuromuscular patients. Effects on force and
      surface EMG.
AB  - In a randomized clinical trial the efficacy of strength training was studied in
      patients with myotonic dystrophy (n = 33) and in patients with Charcot-Marie
      Tooth disease (n = 29). Measurements were performed at the start and after 8, 16
      and 24 weeks of progressive resistance training. Surface electromyography (SEMG)
      of proximal leg muscles was recorded during isometric knee extension at maximum
      voluntary contraction (MVC) and at 20, 40, 60 and 80% of MVC. Changes in MVC,
      maximum electrical activity and torque-EMG ratios (TER) were calculated. Fatigue
      was studied by determining the changes in endurance and in the decline of the
      median frequency (Fmed) of the SEMG during a sustained contraction at 80% MVC.
      These parameters showed no significant changes after the training in either of
      the diagnostic groups. Only the Charcot-Marie-Tooth training group showed a
      gradual significant increase in mean MVC over the whole training period (21%).
      After 24 weeks, the increase in mean RMS was similar (25%), but this was mainly
      due to a sharp rise during the first 8 weeks of training (20%). The findings
      indicate that the initial strength increase was due to a neural factor, while the
      subsequent increase was mainly due to muscle hypertrophy.

PMID- 10597051
TI  - Coefficient of cross correlation and the time domain correspondence.
AB  - Time histories of neuromuscular and mechanical variables of human motion are
      often compared by using discrete timing events (onset, offset, time to peak, zero
      crossing, etc). The determination of these discrete timing points is often
      subjective and their interpretation can cause confusion when attempting to
      compare patterns. In this technical note, cross correlation and the 95%
      confidence interval of its maximum value are proposed as an objective means of
      pattern recognition and comparison. EMG patterns of cycling at different cadences
      were used as an example to demonstrate the effectiveness of this cross
      correlation method in identification of changes between conditions. Using a
      standard method of threshold identification, different onset and offset values
      can be found by using different thresholds, and the sequence of the offset
      timings between conditions can change. This is a clear indication of the inherent
      subjectivity with these discrete timing methods. In contrast, calculation of
      cross correlation for incremental phase shifts permits the identification of a
      maximal value that is an objective measure of the actual phase shifting between
      the two time series. Further, calculation of the 95% confidence interval allows
      one to determine whether the phase shifting is statistically significant. The
      application of this method is not limited to EMG pattern comparison, and can also
      be applied to other time histories such as kinematic and kinetic parameters of
      human motion.

PMID- 10597052
TI  - Dynamic muscle force predictions from EMG: an artificial neural network approach.
AB  - EMG signals of dynamically contracting muscle have never been used to predict
      experimentally known muscle forces across subjects. Here, we use an artificial
      neural network (ANN) approach to first derive an EMG-force relationship from a
      subset of experimentally determined EMGs and muscle forces; second, we use this
      relationship to predict individual muscle forces for different contractile
      conditions and in subjects whose EMG and force data were not used in the
      derivation of the EMG-force relationship; and third, we validate the predicted
      muscle forces against the known forces recorded in vivo. EMG and muscle forces
      were recorded from the cat soleus for a variety of locomotor conditions giving a
      data base from three subjects, four locomotor conditions, and 8-16 steps per
      subject and condition. Considering the conceptual differences in the tasks
      investigated (e.g. slow walking vs. trotting), the intra-subject results obtained
      here are superior to those published previously, even though the approach did not
      require a muscle model or the instantaneous contractile conditions as input for
      the force predictions. The inter-subject results are the first of this kind to be
      presented in the literature and they typically gave cross-correlation
      coefficients between actual and predicted forces of >0.90 and root mean square
      errors of <15%, thus they were considered excellent. From the results of this
      study, it was concluded that ANNs represent a powerful tool to capture the
      essential features of EMG-force relationships of dynamically contracting muscle,
      and that ANNs might be used widely to predict muscle forces based on EMG signals.

PMID- 10597053
TI  - Subclinical skeletal muscle involvement in long-QT syndrome.
AB  - Deafness is said to be the only extracardiac manifestation of long-QT syndrome.
      Whether long-QT syndrome manifests in the skeletal muscle as well, has not been
      investigated so far. Six affected members of two families with long-QT syndrome
      without deafness (Romano-Ward syndrome) underwent a clinical neurological
      examination, nerve conduction studies and needle electromyography. The clinical
      neurological examination and nerve conduction studies were normal but abundant
      spontaneous activity (fibrillations and bursts of fibrillations) could be
      recorded from the right biceps brachii muscle (one patient) and the right
      abductor pollicis brevis muscle (all patients). Since all other causes were
      excluded, spontaneous discharges were interpreted to be related to the long-QT
      syndrome. In conclusion, long-QT syndrome does not seem to be confined to the
      heart but may involve the skeletal muscle subclinically as well.

PMID- 10597054
TI  - The role of general surgery in the age of surgical specialization.

PMID- 10597055
TI  - The role of pancreaticoduodenectomy in the treatment of severe chronic
      pancreatitis.
AB  - Chronic pancreatitis remains a debilitating disease with few definitive options
      for treatment. The purpose of this study was to evaluate the benefit of
      pancreaticoduodenectomy in the treatment of chronic pancreatitis. The results
      were evaluated by standard descriptive statistics. In a retrospective study, we
      reviewed the patients at a single institution undergoing pancreaticoduodenectomy
      between 1994 and 1997 for complications of chronic pancreatitis. Patients were
      evaluated for preoperative indication for surgery and perioperative morbidity and
      mortality, as well as long-term results. Thirty-two patients underwent
      pancreaticoduodenectomy for chronic pancreatitis; 56 per cent (18) underwent
      pylorus-preserving and 44 per cent (14) underwent classic
      pancreaticoduodenectomy. The mean age of these patients was 56+/-14.7 years
      (range, 23-79). All patients underwent preoperative CT scan and endoscopic
      retrograde cholangiopancreatography. The preoperative indication for surgery in
      81 per cent (26) of these patients was intractable pain in the setting of a
      nondilated pancreatic duct. The other 19 per cent were treated for
      biliary/pancreatic duct stricture and pancreatic head fibrosis (mass suspicious
      of malignancy). Fifty-three per cent of the patients had a history of previous
      abdominal surgery. There were no perioperative deaths. The mean postoperative
      stay was 12.2+/-7.4 days. The postoperative morbidity rate was 31 per cent (10),
      consisting of 25 per cent with delayed gastric emptying, 3 per cent with
      pneumonia, and 3 per cent with wound infections. There was no occurrence of
      pancreatic fistulas. With a mean follow-up of 40 months (range, 10-52 months), 85
      per cent reported a significant improvement in pain with 71 per cent being pain
      free and not requiring narcotics. Twenty per cent developed new-onset diabetes.
      The overall event survival rate at 5 years was 97 per cent. Thus, in a selected
      group of patients with severe chronic pancreatitis, resection of the head of the
      pancreas achieved relief of symptoms and was a safe and effective treatment for
      chronic pancreatitis.

PMID- 10597056
TI  - Life-threatening nail gun injuries.
AB  - The use of pneumatic and explosive cartridge-activated nail guns is common in the
      construction industry. The ease and speed of nailing these tools afford enhance
      productivity at the cost of increased potential for traumatic injury. Although
      extremity injuries are most common, life-threatening injuries to the head, neck,
      chest, or abdomen and pelvis may occur. During a 20-month period, eight
      potentially life-threatening nail gun injuries were admitted to a Level I trauma
      center, including injuries to the brain, eye, neck, heart, lung, and femoral
      artery. Mechanism of injury included nail ricochet, nail gun misuse due to
      inadequate training, and successful suicide. Nail guns have significant potential
      for causing severe debilitating injury and death. These findings indicate a need
      for improved safety features and user education. The various types of nail guns,
      their ballistic potential, and techniques for operative management are discussed.

PMID- 10597057
TI  - Operative management of severe constipation.
AB  - This report investigates the concept that severe constipation requiring major
      abdominal surgery may result from one of three common causes: 1) colonic inertia,
      2) pelvic hiatal hernia, or 3) both colonic inertia and pelvic hernia. This study
      evaluates the symptoms, anatomy and outcome in 201 patients with severe surgical
      constipation treated by a single surgeon. In 2042 patients with constipation
      referred to one colon and rectal surgeon, 211 major abdominal surgical procedures
      were performed on 201 patients for severe constipation between 1989 and 1999.
      There were 187 women and 14 men. Mean age was 49 years (range, 9-84). Five high
      risk patients had ileostomy; 196 had major colonic surgery for anatomic or
      physiologic causes of constipation, excluding malignancy, diverticular disease,
      and inflammatory bowel disease. Pelvic hiatal hernia was defined as the
      herniation of bowel through the hiatus of the pelvic diaphragm seen on pelvic
      videofluoroscopy or physical examination. Of these 196 patients, 44 per cent had
      pelvic hiatal hernia repair (PHHR), 27 per cent had total abdominal colectomy and
      ileorectal anastomosis for colonic inertia, and 29 per cent had surgery for both
      colonic inertia and pelvic hiatal hernia. Of the 144 patients undergoing PHHR, 95
      had Gore-Tex patch (W. L. Gore and Associates, Inc., Phoenix, AZ) sacral
      colpopexy. PHHR for pelvic hiatal hernia without colonic inertia included sigmoid
      resection, rectopexy, and Gore-Tex patch sacral colpopexy. Mean duration of
      follow-up was 20 months. Symptoms noted preoperatively included abdominal pain
      (84%), straining at stool (90%), incomplete rectal emptying (85%), painful bowel
      movements (74%), pelvic pain (69%), vaginal bulge (55%), digital assistance with
      evacuation (35%), and incontinence of stool (38%). Outcome assessed by symptom
      relief was successful in 89.1 per cent of patients. 8.6 per cent of patient
      conditions were unchanged, and 2.3 per cent were unsatisfied with the outcome.
      There were no postoperative deaths. The complication rate was 6.1 per cent (small
      bowel obstruction, 7; anastomotic leak, 2; ureteral stenosis, 2; and patch
      erosion, 1). In our experience, severe surgical constipation can be due to
      colonic inertia, pelvic hiatal hernia, or both. Careful preoperative evaluation
      identifies these disorders, and surgical therapy aimed at correction of anatomic
      and physiologic defects results in high patient satisfaction and improvement in
      bowel function.

PMID- 10597058
TI  - Acute calf vein thrombosis: outcomes and implications.
AB  - The purpose of this study was to define the incidence of and outcomes associated
      with isolated acute calf vein thrombosis (CVT). From 11/95 through 6/97, 3096
      patients underwent lower extremity venous duplex testing in a hospital-based
      vascular laboratory in which bilateral tibial and peroneal vein imaging were
      standard components of the venous duplex examination. CVT was present in 118
      patients (3.8%), and 339 patients (10.9%) had acute proximal deep venous
      thrombosis (PDVT). Patients with CVT were 56.4+/-17.2 years of age (range, 18
      92). Approximately 25 per cent with CVT had cancer (n = 30). Of the 18 patients
      with CVT who underwent ventilation-perfusion (V/Q) lung scanning, 56 per cent (n
      = 10) had high-probability scans. Venous duplex reports for those with CVT
      recommended follow-up venous duplex examination, which was done in 60 per cent (n
      = 71) of patients. Of the 71 patients with CVT who underwent follow-up testing,
      15.5 per cent (n = 11) progressed to PDVT. The incidence of progression to deep
      venous thrombosis was 25 per cent (9 of 36) in those receiving anticoagulants at
      the time of initial venous duplex examination versus 5.7 per cent (2 of 35) in
      those not receiving anticoagulants (P = 0.046). With progression to PDVT,
      patients were more likely to have cancer (35% versus 7.8%; P = 0.009), more
      likely to have high-probability V/Q scans (36% versus 6.7%; P = 0.017), and more
      likely to die (27% versus 1.7%; P = 0.011) during follow-up. CVT was less common
      than proximal deep vein thrombosis and was also associated with pulmonary
      embolism. Progression of CVT was an adverse clinical event associated with
      greater chance of pulmonary embolism and death.

PMID- 10597059
TI  - Thoracoscopic resection of posterior neurogenic tumors.
AB  - Video-assisted thoracic surgery (VATS) may be used for resection of posterior
      mediastinal tumors to avoid thoracotomy and shorten hospital stay. Between
      October 1990 and June 1998, 23 patients had VATS resection of posterior
      neurogenic tumors. The 14 females and 9 males ranged in age from 14 months to 70
      years, with a median of 35 years. Operation time ranged from 30 to 120 minutes
      (median, 83), and intraoperative complications were limited to minor problems as
      well as conversion to thoracotomy to enhance complete tumor resection in four
      cases. Tumor pathology included nerve sheath origin (20) and autonomic ganglia
      (3). There was only one malignant schwannoma. Tumor size ranged from 0.7 to 13 cm
      in diameter. Median chest tube days was 1 day (range, 1-4), and hospital stay was
      2 days (range, 1-9). Postoperative complications included transient paresthesia
      (three cases), ileus (two cases), pleural effusion (one case), and transient
      intercostal pain (one case). Posterior neurogenic tumors may be resected safely
      using video-assisted techniques. Conversion to thoracotomy to enhance complete
      resection is both possible and encouraged. The use of VATS seems to decrease
      hospital stay and minimize postoperative complications. In posterior neurogenic
      tumors without tumor extension to the spinal canal, VATS has become our preferred
      method for resection.

PMID- 10597060
TI  - Ingested endotracheal tube in an adult following intubation attempt for head
      injury.
AB  - General surgeons are often consulted for assistance in the management of ingested
      foreign bodies. Deglutition of an endotracheal tube is an unusual complication of
      airway management. In these cases, the artificial airway is "lost" when it
      becomes lodged deep into the esophagus. Endoscopic extraction has been described
      as therapeutic. We report a case in which prehospital endotracheal intubation
      attempt for the management of closed head injury resulted in a swallowed
      endotracheal tube. The tube remained undetected until radiographs were performed
      for a second unrelated traumatic event 2 years later. Endoscopic extraction was
      unsuccessful, due to rigidity of the tube. Surgical extraction via gastrotomy was
      uneventful. Surgeons involved in trauma and other emergency settings should be
      aware of this complication and options in management.

PMID- 10597061
TI  - Transhiatal versus transthoracic esophagectomy: complication and survival rates.
AB  - The classic approach for esophagectomy is via a combined thoracic and abdominal
      approach. Concerns persist regarding the adequacy of this approach as a cancer
      operation. A study was carried out to compare these approaches, with particular
      reference to complication rates and long-term survival. The charts of all adult
      patients undergoing esophagectomy for carcinoma at the University of
      Miami/Jackson Memorial Hospital between July 1991 and June 1996 were reviewed.
      Patients who had transabdominal resections alone or colon interpositions were
      excluded. Of 65 esophageal resections, 38 (58%) were performed transhiatally
      (THE) and 27 (42%) were performed via the transthoracic (TTE) route. Treatment
      groups were matched for age and site, stage, and histology of tumor. Similarly,
      the treatment groups were homogeneous with respect to distribution of neoadjuvant
      chemotherapy/radiation. The number of patients experiencing any postoperative
      complication was similar in both treatment groups, occurring in 22 THE (58%) and
      17 TTE (63%) patients (P>0.05). Anastomotic leak occurred in five THE patients
      (13%) and one TTE patient (4%) (P>0.05). The single TTE patient with a leak died
      within 3 months without leaving the hospital. All five THE patients who developed
      a leak left the hospital. Although there was a tendency toward a higher
      percentage of patients in the TTE group to suffer respiratory failure and sepsis
      and a higher percentage of THE patients to experience anastomotic leak, these did
      not reach statistical significance. Again, although perioperative mortality
      tended to be higher in the TTE group, this did not reach statistical
      significance. Four and 5-year survival rates were similar in both groups. Whereas
      a 4-year cumulative survival difference of 42% for THE patients and 31% in TTE
      patients extended at 58 months to 28% and 8%, respectively, these did not reach
      statistical significance. Similarly, analysis by stage and preoperative treatment
      type (+/- neoadjuvant chemotherapy/radiation) failed to demonstrate any survival
      difference between the two groups. These findings demonstrate that there is
      little difference in operative morbidity and mortality between THE and TTE
      routes. Anastomotic leaks that occur after cervical anastomosis tend to run a
      more benign course. Survival data do not support routine TTE as a superior
      oncological operation, despite the theoretical benefit of better lymphatic
      clearance. We continue to advocate THE because it allows a cervical anastomosis
      without thoracotomy and we feel it is better tolerated by patients.

PMID- 10597062
TI  - Adenocarcinoma of the head of the pancreas: effects of surgical and nonsurgical
      therapy on survival--a ten-year experience.
AB  - A retrospective analysis of all patients treated for adenocarcinoma of the head
      of the pancreas from 1989 to 1998 was performed. Excluded were cancers in the
      body and tail, cystic neoplasms, ampullary tumors, and cancers of the duodenum
      and bile ducts. One hundred forty-five patients were reviewed, and 43 patients
      underwent pancreaticoduodenectomy. Data collected included the stage, lymph node
      status, surgical margins, adjuvant therapies, and survival. Statistical analysis
      was performed with Cox's Proportional Hazards Analysis and Log-Rank Life Table
      Analysis. The surgical population had a 21 per cent 3-year survival rate and a 7
      per cent operative mortality rate. Median survival was: 1) the resection group
      versus no resection was 13.5 versus 3.1 months; 2) adjuvant therapy versus no
      therapy after resection was 16.1 versus 5.1 months; and 3) chemoradiation therapy
      versus no therapy for unresectable disease was 5.3 versus 1.8 months. The
      presence of positive surgical margins was found in 33 per cent of the surgical
      specimens and carried an increased mortality hazard ratio of 3.1. Patients with
      negative lymph nodes had a 15 per cent 5-year survival, versus 0 per cent with
      positive nodes. Seventy-three per cent of those resected had a T2 lesion, and 46
      per cent of patients presented with metastatic disease. Surgical resection and
      adjuvant therapy significantly improves survival in patients with adenocarcinoma
      of the head of the pancreas. All patients who underwent resection as part of
      their therapy showed extended survival compared with chemoradiation therapy
      alone. Adjuvant chemoradiation improved survival when compared with surgery
      alone. Multimodality treatment in carcinoma of the head of the pancreas provides
      the best treatment option. However, better adjuvant therapies are needed.

PMID- 10597063
TI  - Malar metastasis from rectal carcinoma: a case report.
AB  - Facial metastasis from colorectal carcinoma is extremely rare. Only two cases
      have been reported in the literature. This is the first reported case of malar
      metastasis from colon carcinoma. The patient was a 64-year-old, white woman who
      underwent a low anterior resection for a nearly obstructive carcinoma at 20 cm.
      Her chest X-ray revealed lung metastases. Postoperatively she was treated with
      fluorouracil and leucovorin. Twenty months later, she presented with left facial
      edema, which progressively increased in size. CT scan and magnetic resonance
      imaging with gadolinium showed a large soft tissue mass centered about the left
      anterior zygomatic arch. The platysma muscle was displaced laterally, and the
      masseter muscle was involved. There was extension into the masticator space and
      bony involvement of the zygomatic arch. True-cut biopsy of the left cheek
      revealed metastatic adenocarcinoma. Histology was similar to that of the primary
      rectal adenocarcinoma. Metastasis to the malar region is extremely rare. It is a
      grave prognostic sign, as it is associated with advanced terminal disease.
      Because of the widespread metastases, only palliative treatment can be provided.

PMID- 10597064
TI  - Primary squamous cell carcinoma of the breast presenting as a breast abscess.
AB  - Primary squamous cell carcinoma (SCC) of the breast is a very rare neoplasm, with
      only 75 cases reported in the English literature. Herein, we report four new
      cases and discuss the diagnostic and therapeutic challenges of this unusual tumor
      in a retrospective review of all cases of SCC of the breast at our institution
      from 1990 to 1998. Four patients with breast SCC were identified, with a mean age
      of 70 years. Two patients with "pure" SCC (no features of ductal carcinoma) were
      initially treated for breast abscess. Two other patients with features of both
      SCC and ductal carcinoma had skin erythema associated with an underlying mass,
      and infectious etiology was considered in each case. Mean tumor size was 4.9 cm.
      Both patients with pure SCC underwent extensive evaluation for primary tumors at
      other sites. Two patients developed early systemic metastasis. SCC of the breast
      is often diagnosed at an advanced stage and may be confused with breast abscess.
      For this reason, breast biopsy should be considered in cases of breast abscess.
      Treatment of primary SCC of the breast is similar to that of more common types of
      breast cancer (i.e., breast conservation is possible and lymph node dissection is
      recommended). Because metastasis to the breast from other primary tumor sites has
      been reported (lung, cervix, skin, and esophagus), patients with pure SCC should
      undergo evaluation to exclude this possibility.

PMID- 10597065
TI  - The continuing challenge of Fournier's gangrene in the 1990s.
AB  - Fournier's disease is a potentially fatal acute, gangrenous infection of the
      scrotum, penis, or perineum associated with a synergistic bacterial infection of
      the subcutaneous fat and superficial fascia. Thrombosis of small subcutaneous
      arterioles with resultant ischemia contributes to the rapid extension of the
      infection. During a 12-year period, the clinical and operative records of 14
      patients with Fournier's gangrene were analyzed. All patients were treated with
      broad spectrum antibiotics and serial surgical debridements. Nine patients had
      polymicrobial isolates from the initial wound culture; two patients had Group A
      Streptococcus species as the sole isolate. The etiology of the infection was
      identified in 12 patients. Five patients died for an overall mortality of 38 per
      cent. The mean age of survivors was 51 years compared with 75 years for
      nonsurvivors (P<0.05). The last six patients in this series survived. The mean
      hospital stay was 29 days. Four patients (31%) had a prior history of diabetes;
      however, 11 patients (85%) had elevated serum glucose levels (>120 mg/dL) on
      admission. All patients were hypoalbuminemic on admission. Survivors had an
      average serum creatinine on admission of 1.28 mg/dL compared with 3.1 mg/dL for
      nonsurvivors. Although supportive care is required in these patients, the
      mainstay for treatment of Fournier's gangrene entails an aggressive approach with
      frequent and extensive soft tissue debridements to control the invasive nature of
      the infection with delayed wound coverage once the infection has been controlled.
      Elderly patients with evidence of renal dysfunction on admission have a poor
      prognosis despite aggressive therapy.

PMID- 10597066
TI  - Air travel following traumatic pneumothorax: when is it safe?
AB  - The safety of air travel for patients sustaining a recent traumatic pneumothorax
      has long been a subject of debate. The Aerospace Medicine Association has
      suggested that patients should be able to fly 2 to 3 weeks after radiographic
      resolution of their pneumothorax. To validate these recommendations, a
      prospective study was performed. Twelve consecutive patients with recent
      traumatic pneumothorax expressing a desire to travel by commercial airline were
      evaluated. Ten patients waited at least 14 days after radiographic resolution of
      their pneumothorax before air travel (mean, 17.5+/-4.9 days), and all were
      asymptomatic in-flight. One of two patients who flew earlier than 14 days
      developed respiratory distress in-flight, with symptoms suggestive of a recurrent
      pneumothorax. We conclude that commercial air travel appears to be safe 14 days
      following radiographic resolution of a traumatic pneumothorax.

PMID- 10597067
TI  - Large bowel obstruction due to intrauterine device: associated pelvic
      inflammatory disease.
AB  - Pelvic actinomycosis associated with the use of intrauterine contraceptive
      devices (IUDs) can mimic pelvic malignancy. Recognizing this rare, but not
      uncommon complication of IUD use can spare a patient from an extensive surgical
      procedure. If recognized preoperatively, a simple regimen of antibiotics can be
      curative; however, if symptomatic, a limited surgical procedure is warranted. We
      present the case of a 55-year-old woman with a slow, indolent course of partial
      large bowel obstruction and a history of IUD use for over 20 years. A
      preoperative CT scan revealed a frozen pelvis mimicking a pelvic malignancy.
      Exploratory laparotomy revealed a firm, indurated, fibrotic reaction in the
      pelvis involving the uterus, adnexa, and sigmoid colon. A diverting loop
      colostomy was performed, and pathology revealed sulfur granules from the
      extracted IUD that grew Actinomyces. The patient was treated with the appropriate
      antibiotics, and during the takedown of the colostomy 6 months later the pelvic
      inflammation was completely resolved. An extensive review of the literature
      involving actinomycotic abscesses associated with IUD use reveals a limited
      number of studies reported in the general surgical literature. It behooves the
      general surgeon to be aware of this unusual case so that the appropriate
      consultation and treatment can be performed with limited morbidity to the
      patient.

PMID- 10597068
TI  - Current role of scapulectomy.
AB  - Tumors of the scapula are an unusual clinical challenge. Partial or complete
      resection of the scapula, with its attached musculoaponeurotic tissue, is a
      seldom used technique for the treatment of primary bone and soft tissue tumors,
      as well as selected metastatic involvement of the scapula. Scapulectomy may allow
      wide margins of resection without amputation. The purpose of this study is to
      review our recent experience with scapulectomy. This study describes the recent
      experience with scapulectomy by the Section of Surgical Oncology and the
      Department of Orthopedics at Louisiana State Medical Center (New Orleans, LA).
      Between 1994 and 1998, 12 patients (between 16 and 79 years of age) underwent a
      resection of the scapula. Eleven of these patients had soft tissue tumors; one
      had a metastasis from a thyroid carcinoma. Six of these patients underwent a
      scapulectomy as a primary treatment, five for recurrence. Six patients also
      received postoperative radiation and/or chemotherapy. The follow-up ranged from 6
      months to 4 years. There was no mortality or wound infection associated with
      scapulectomy. All patients had normal hand and wrist function after surgery.
      Three distant recurrences occurred, with no local or regional failures
      encountered during the follow-up period. Scapulectomy can result in excellent
      local tumor control. Whereas some loss of active shoulder motion may occur, hand,
      wrist and elbow function is preserved. Although maintenance of shoulder function
      should not take precedence over adequacy of resection, scapulectomy remains an
      excellent procedure for malignant disease that preserves hand, wrist, and elbow
      function.

PMID- 10597069
TI  - Pulmonary embolism in Veterans Affairs Medical Centers: is vena cava interruption
      underutilized?
AB  - Veterans with venous thrombosis or pulmonary embolism (PE) were evaluated using
      Veterans Affairs patient treatment file (PTF) data from fiscal years 1990-1995,
      inclusive, to define outcomes for those with PE. The specific aims of the study
      were to define how often those with PE underwent vena cava interruption (VCI) and
      whether VCI affected in-hospital mortality rates. Outcomes were defined using PTF
      data and Patient Management Category (PMC) software for 26,132 veterans
      discharged from all Veterans Affairs Medical Centers (VAMCs) with venous
      thromboembolism, which included a subset of 4,882 patients identified by both PTF
      data and PMC software to have PE. PMC software also generated measures of illness
      severity, patient complexity (PMC count), and resource utilization (called
      resource intensity scale) for each hospital admission. The in-hospital mortality
      rate for those with PE was 15.9 per cent (775 of 4882). Only 157 VCIs were
      performed in those with PE which constituted 3.2 per cent of the latter group.
      Those with PE who had VCI experienced a 13.4 per cent unadjusted in-hospital
      mortality rate (21 of 157) versus a 16 per cent unadjusted mortality rate without
      VCI (754/4725; not significant). In a logistic regression model of in-hospital
      mortality in those with PE, increasing age and illness severity were directly
      related to mortality, whereas VCI was independently associated with reduced
      mortality. The odds of death were reduced by 0.482 (0.287-0.807, 95% limits) for
      patients with PE who underwent VCI (P<0.005). Utilization of VCI varied among
      VAMCs: the hospital rates that VCI were performed in those with PE ranged from 0
      to 16.7 per cent. Mortality associated with PE was substantial in VAMCs, and VCI
      was independently associated with reduced in-hospital mortality. The low
      percentage of veterans with pulmonary embolism who underwent VCI was surprising.
      VCI may be underutilized in veterans with PE.

PMID- 10597070
TI  - Radiation-related arterial disease.
AB  - Arterial occlusive disease has been recognized in association with radiation
      arteriopathy and, rarely, with spontaneous arterial disruption. This association
      results from the greater role of radiation therapy in the current management of
      malignant diseases coupled with longer patient survival and the lengthy latency
      period between radiation and clinical manifestations of radiation arteriopathy.
      Experience with six patients having radiation-associated arterial disease was
      retrospectively reviewed. There were four men and two women, with a mean age of
      51 years (range, 36-74). Arteries exposed to radiation include two carotids,
      three subclavians, one coronary, and one femoral. The time from radiation therapy
      until clinical arterial disease was a mean of 14.3 years (range, 4-30). Operative
      repairs with polytetrafluoroethylene and saphenous vein bypass grafts were
      performed in four patients, stent placement in one patient, and one patient had
      spontaneous carotid disruption that ultimately was treated with ligation. In
      conclusion, elective bypass can be performed safely and successfully for arterial
      occlusive disease in a previously irradiated artery. In contrast, life
      threatening arterial disruption secondary to radiation arteriopathy usually
      requires concomitant exposure to a source of bacterial contamination, and
      ligation may be the best choice to prevent recurrent hemorrhage.

PMID- 10597071
TI  - Hemoperitoneum from spontaneous bleeding of a uterine leiomyoma: a case report.
AB  - Bleeding from uterine leiomyoma is a rare cause of hemoperitoneum. In most cases
      bleeding is a result of trauma or torsion. Spontaneous rupture of a superficial
      vein is extremely rare. Fewer than 100 cases have been reported. Our patient is a
      44-year-old black woman who presented in the emergency room with acute onset of
      epigastric pain. Past medical and surgical history was not contributory except
      for a uterine "fibroid." In the emergency room, the patient's abdomen became
      diffusely tender. Her pregnancy test was negative, and the abdominal ultrasound
      showed fluid in the peritoneal cavity. The patient became hemodynamically
      unstable, and there was a significant drop of the hemoglobin/hematocrit. A
      surgical consultation was requested, and the patient underwent exploratory
      laparotomy. A subserosal uterine leiomyoma was found, with an actively bleeding
      vein on its dome. The leiomyoma was excised and 3 liters of blood and blood clots
      were evacuated from the peritoneal cavity. The patient was premenopausal and had
      a known leiomyoma. The clinical course was similar to that of previously reported
      cases. Although extremely rare, when there is no history of trauma, pregnancy, or
      other findings, spontaneous bleeding from uterine leiomyoma should be in the
      differential diagnosis. Emergent surgical intervention is recommended to
      establish the diagnosis and stop the hemorrhage.

PMID- 10597072
TI  - The use of FDG-positron emission tomography for the evaluation of colorectal
      metastases of the liver.
AB  - Each year at least 130,000 people in the United States are diagnosed with
      colorectal carcinoma. Approximately 14,000 of these patients will have liver
      metastases, and 20 per cent of these patients will die from these metastases.
      Surgical resection is the only possible chance for cure in patients with only
      intrahepatic metastases, and extrahepatic disease is a contraindication to
      glucose metabolism. Positron emission tomography (PET) allows the in vivo study
      of the uptake and use of glucose in human cells. Here, we review our experience
      with the use of PET imaging for the diagnosis and management of colorectal
      metastases of the liver. We conducted a retrospective chart review of 14 patients
      undergoing PET imaging for known or suspected hepatic metastases from colorectal
      carcinoma. Results of CT, magnetic resonance imaging, and PET images were
      compared with pathological specimens. CT scan identified 7 lesions, and PET
      identified 31 intrahepatic lesions. Of the 6 patients who underwent surgery, CT
      identified 4 (20%) and PET identified 17 (85%) of the 20 intrahepatic metastases
      histologically confirmed. The accuracy (number of lesions) of CT and PET was 20
      per cent and 85 per cent, respectively. CT scans had a sensitivity (number of
      patients) of 50 per cent, and PET had a sensitivity of 100 per cent in patients
      undergoing surgical resection. PET imaging altered the management in 49 per cent
      of patients. Twenty-one per cent of patients had their surgery cancelled due to
      previously undiagnosed extrahepatic metastases. Twenty-one per cent of patients
      had negative CT scans and underwent surgery on the basis of their PET images, and
      all had histologically proven disease. One patient avoided a second-look
      laparotomy when PET revealed a lesion seen on CT to be false positive. PET is an
      ideal imaging modality to detect intra- and extrahepatic metastases from
      colorectal carcinomas and would aid in the surgical management of these patients.

PMID- 10597073
TI  - Parathyroidectomy: new criteria for evaluating outcome.
AB  - Following successful parathyroidectomy, subjective improvement in recognized
      symptoms and in the overall "well being" of asymptomatic primary hyperparathyroid
      patients has been well documented. Because quantitative methods for measuring
      parathyroid hormone (PTH) and normal reference ranges of serum calcium have
      changed in recent years, a revised biochemical criteria for evaluating
      postoperative outcome has become necessary. Two hundred seventy-one selected
      patients were followed for an average of 6.3 years after parathyroidectomy.
      Although 257 patients had serum calcium levels <10.6 mg/dL during the entire
      follow-up period, 15 per cent of them had elevated intact PTH (iPTH) levels.
      Fourteen patients had calcium levels > or =10.6 mg/dL at some point during follow
      up, with nine patients (64%) showing high iPTH levels and eight (57%) of them
      developing recurrent hyperparathyroidism (calcium > or =11 mg/dL and iPTH > or
      =68 pg/mL). Of the 14 remaining patients, 5 had hypercalcemia with normal iPTH
      levels. In patients with successfully treated primary hyperparathyroidism, the
      recommended annual follow-up is: 1) monitor total serum calcium only if serum
      calcium level is <10.6 mg/dL, or if serum calcium level is > or =10.6 mg/dL; and
      2) monitor serum calcium and PTH levels, because these patients have an increased
      incidence of hyperfunctioning parathyroid glands, which may point to late
      recurrence.

PMID- 10597074
TI  - Edwin Smith Surgical Papyrus: the oldest known surgical treatise.

PMID- 10597075
TI  - Re: Hypothermia reduces resistance to surgical wound infections.

PMID- 10597076
TI  - Geriatric trauma: outcomes of elderly patients discharged from the ED.
AB  - This study was undertaken to investigate which patients 65 years of age or older
      have adverse outcomes after discharge from the emergency department (ED) after an
      injury. Patients were enrolled prospectively at an urban university center from
      September 15, 1996, until August 31, 1997. Patients sustaining any potentially
      serious form of injury were included. Data about comorbid conditions, preinjury
      medications, and types of injuries sustained were recorded. Patients were
      contacted at home at least 30 days after discharge and were questioned about
      their overall health, need for admission since ED discharge, and whether any
      complications developed. One hundred five consecutive patients were enrolled, but
      5 patients were lost to follow-up. There were 74 low-mechanism falls (LMFs), 11
      low-mechanism motor vehicle crashes (LMMVCs), 8 high-mechanism motor vehicle
      crashes (HMMVCs), 3 high-mechanism falls (HMFs), and 4 other types of injuries.
      Follow-up ranged from 30 to 147 days, with a mean of 49 days. On follow-up, 88
      patients were doing well, 9 were fair, and 3 were doing poorly; of the latter,
      their poor health was unrelated to their injuries. Complications included 2
      extremity infections and 1 poorly healing wound. Eleven patients were seen in an
      ED within the first 30 days after injury, 6 of whom for problems related to their
      initial injury or its management. These results show that there is a subset of
      elderly victims of trauma who may be safely discharged home after appropriate
      evaluation. Return visits to the ED were just as often related to comorbid
      conditions as to initial injury.

PMID- 10597077
TI  - Cost-effective adenosine dosing for the treatment of PSVT.
AB  - We reviewed our experience with adenosine for the conversion of paroxysmal
      supraventricular tachycardia (PSVT) to determine whether the recommended dosing
      strategy of 6 mg, followed by 12 mg, is cost-effective in actual practice. We
      observed a 65% conversion rate to sinus rhythm with the initial dosage of 6 mg
      adenosine (95% CI, 54% to 75%), and, based on subsequent cost analysis, conclude
      that the current strategy should not be replaced by a 12-mg-first strategy. If
      the packaging of adenosine was changed so that 12 mg cost less than twice 6 mg,
      this analysis should be revisited.

PMID- 10597078
TI  - The effect of physician gender on women's perceived pain and embarrassment during
      pelvic examination.
AB  - In this article we try to determine if the examiner's gender affects women's
      perceived pain and embarrassment during emergency department pelvic examination,
      using a prospective comparative study in a university teaching hospital. Test
      subjects were taken from a convenience sample of female emergency department (ED)
      patients undergoing pelvic examination as part of their evaluation. 100 mm visual
      analog scales were used to gauge each subject's perceived pain and embarrassment.
      Subject age and complaint, and the examiner's gender and level of training were
      collected. Two-tailed Mann-Whitney or Kruskal-Wallis tests were used to test for
      significant differences among group median pain and embarrassment scores. One
      hundred and sixty-seven subjects completed the study (median age = 25 y,
      interquartile range 20-33 y). Seventy-seven subjects had abdominal or pelvic
      pain, 49 complained of vaginal bleeding, and the rest had dysuria, pregnancy,
      genital lesions, or other conditions. Ninety-four examiners were female and 73
      were male. The mean pain scores were similar for female (33.6 mm) and male (38.8
      mm) examiners. The medians were 19.5 mm and 41.0 mm respectively (difference,
      21.5 mm; 95% Cl, -3.5 to 34 mm; P = 0.385). The mean embarrassment score was
      lower for female (19.6 mm) than for male (37.4 mm) examiners. The medians were
      5.0 mm and 28.0 mm respectively (difference, 23 mm; 95% Cl, 11.5 to 40 mm; P =
      0.00012). The level of examiner training did not appear to affect either score (P
      > 0.6). Emergency department patients perceive pelvic examination by a male
      examiner as more embarrassing but not more painful than examination by a woman.

PMID- 10597079
TI  - Evolution of abstracts presented at the annual scientific meetings of academic
      emergency medicine.
AB  - There has been a general trend in medicine towards greater sophistication in
      research design. In order to assess this trend in emergency medicine we compared
      the characteristics of abstracts presented at the 1974, 1983, 1989, and 1997
      annual scientific meetings of academic emergency medicine. All 870 abstracts were
      reviewed by 1 of 3 investigators who determined research design attributes using
      a standardized classification scheme that has good interrater reliability. Over
      the last 25 years the following trends were noted: more surveys (0% v1% v3% v8%,
      P = 0.002), more randomized studies (0% v10% v12% v15%, P = 0.05), and more
      blinded studies (0% v7% v5% v11%, P = 0.01). Tests of statistical significance
      were reported with increasing frequency (8% v26% v59% v69%, P < 0.001) as were
      power calculations (0% v0% v1% v3%, P = 0.02). During the study period there were
      also increases in the median number of authors, proportion of foreign lead
      authors, and the proportion of studies involving human subjects. These results
      reflect considerable improvement in the degree of research design sophistication
      reported in selected abstracts of academic emergency medicine over the study
      period. Further strategies to assure continued enhancement of emergency medicine
      research should be explored.

PMID- 10597080
TI  - Patient satisfaction and diagnostic accuracy with ultrasound by emergency
      physicians.
AB  - In recent years, there has been considerable interest and controversy concerning
      the performance of ultrasound by emergency physicians (ED Sono), but patient
      satisfaction with ED Sono has not been well studied. The primary purpose of this
      investigation was to assess the level of patient satisfaction with ED Sono and to
      compare satisfaction with ED Sono with ultrasound by the Medical Imaging
      Department (MI Sono). A secondary objective was to assess the accuracy of ED Sono
      at our facility. During a 5-month period, which included the startup phase of a
      program for ED Sono, emergency physicians prospectively identified patients who
      were candidates for ultrasound as a part of their workup. Patients were contacted
      by telephone after their ED visit and asked to rate satisfaction on a 0 to 10
      scale for various aspects of their care, including the ultrasound if one was
      done. The accuracy of ED Sono was determined by comparing ED ultrasound
      interpretations with surgical pathology, repeat imaging studies, or clinical
      follow-up. Two hundred forty patients were entered into the study, and 186 (78%)
      responded to the satisfaction survey. Satisfaction ratings were similarly high
      for ED Sono (mean, 8.9; 95% Cl, 8.6 to 9.2) and for MI Sono (mean, 8.8; 95% Cl,
      8.2 to 9.4). Eighteen percent of ultrasounds performed by emergency physicians
      were indeterminate. Excluding indeterminate scans and scans for which
      confirmation was not possible, the accuracy of ED Sono was 99.1% (95% Cl, 95.1%
      to >99.9%). We conclude that during the startup phase of our ED Sono program,
      patient satisfaction was high, and the error rate was very low.

PMID- 10597081
TI  - Acute myocardial infarction complicated by hemodynamically unstable
      bradyarrhythmia: prehospital and ED treatment with atropine.
AB  - The purpose of this study was to investigate the therapeutic response to atropine
      of patients experiencing hemodynamically compromising bradyarrhythmia related to
      acute myocardial infarction (AMI) in the prehospital (PH) setting and the
      therapeutic impact of the PH response to atropine on further Emergency Department
      (ED) care. In addition, the prevalence of AMI in patients presenting with
      atrioventricular block (AVB) is noted. Retrospective review of PH, emergency
      department (ED), and hospital records. PH patients, with hemodynamically
      compromising bradycardia or AVB with evidence of spontaneous circulation, who
      received atropine as delivered by emergency medical services (EMS) personnel,
      were used. Urban/suburban fire department-based emergency medical services (EMS)
      system with on-line medical control serving a population of approximately 1.6
      million persons. Hemodynamic instability was defined as the presence of any of
      the following: ischemic chest pain, dyspnea, syncope, altered mental status, and
      systolic blood pressure less than 90 mm Hg. Bradycardia was defined as sinus
      bradycardia, junctional bradycardia, or idioventricular bradycardia (grouped as
      bradycardia), whereas AVB included first-, second- (types I and II), or third
      degree (grouped as AVB). The response that occurred within 1 minute of atropine
      dosing was recorded as none, partial, complete, or adverse. Comparisons were made
      between patients with AMI and non-AMI hospital discharge diagnoses. The diagnosis
      of AMI was confirmed by abnormal elevations in creatinine phosphokinase MB
      fraction. One hundred seventy-two patients meeting entry criteria were
      identified. Of these, 131 (76.1%) had complete PH, ED, and hospital records and
      were used for data analysis. Forty-five patients (34.3%) had a primary hospital
      discharge diagnosis of AMI; the remaining patients had a non-AMI discharge
      diagnosis. AMI patients were significantly younger (67 +/- 12 v 73 +/- 13 years,
      P = .025), were less likely to have a history of heart disease (35.5% v54.7%, P =
      .038), and were more likely to present with chest pain (68.9% v24.4%, P < .001)
      or hypotension (60% v37.2%, P = .013) compared with non-AMI patients. Forty-five
      of 131 patients presented with AVB, of which 25 had a hospital discharge
      diagnosis of AMI (55.6%). The mean time from first dose of atropine to ED arrival
      and the total dose of atropine received in the PH setting did not differ between
      AMI and non-AMI groups (15.2 +/- 7.7 v 16.2 +/- 8.7 minutes, P= .5; and 0.9 +/-
      0.49 v 1.0 +/- 0.58 mg, P = .25). The likelihood of achieving normal sinus rhythm
      in the PH setting did not differ between AMI and non-AMI groups (40% v 18.6%, P =
      .07). No differences were found between AMI and non-AMI groups in the amount of
      additional atropine given (1.2 +/- 0.58 v 1.3 +/- 1.1 mg, P = .58) or the use of
      other resuscitative therapies after ED arrival (isoproterenol, 13.3% v12.8%, P =
      .93; dopamine, 28.9% v26.7% P = .79; transcutaneous pacing, 26.7% v26.7%, P =
      .99; transvenous pacing, 8.9% v5.8%, P = .51), with the exception of thrombolytic
      therapy (24.4% v 0%, P< .001) and cardiac catheterization (22.2% v3.4%, P =
      .001). Despite a lack of significant difference in achieving a normal sinus
      rhythm in the prehospital or ED setting, AMI patients were more likely to achieve
      a normal sinus rhythm over the total course of PH and ED care than non-AMI
      patients (44.4% v24.4%, P = .019). Hemodynamically unstable (by ACLS criterion)
      AVB presenting in the PH setting is associated with a hospital diagnosis of AMI
      in most (55.6%) patients in this study. AMI patients with hemodynamically
      unstable AVB or bradycardia are no more likely to respond to atropine therapy in
      the PH setting than patients with non-AMI hospital diagnoses. Finally, although
      there is no difference in the treatment of compromising AVB or bradycardia
      received by AMI versus non-AMI patients in the PH or ED setting, AMI patients are
      more likely to achieve a normal sinus rhythm over the t

PMID- 10597082
TI  - Prereduction radiographs in clinically evident anterior shoulder dislocation.
AB  - The main study objective was to determine if experienced emergency physicians can
      accurately identify a subgroup of patients with anterior shoulder dislocation for
      whom prereduction radiographs do not alter patient management. Our prospective
      study evaluated 97 patients who presented to 2 ski-hill clinics and to our rural
      emergency department with possible shoulder dislocation between November 1996 and
      May 1997. Emergency physicians were certain of shoulder dislocation by clinical
      examination alone in 40 of 59 cases (67.8%) of possible dislocation. All 40 cases
      were found to have a dislocation (100%; 95% Cl, 91.19% to 100%), and the
      prereduction radiograph did not affect management of the injury. Prereduction
      radiographs added 29.6 +/- 12.68 minutes to treatment. We conclude that shoulder
      dislocation is often readily apparent from history and physical examination. When
      the experienced emergency physician is certain of the diagnosis of anterior
      shoulder dislocation, prereduction radiography delays treatment and does not
      alter management.

PMID- 10597083
TI  - Must antidysrhythmic agents be given to all patients with new-onset atrial
      fibrillation?
AB  - We investigated the spontaneous conversion rate of new-onset atrial fibrillation
      (AF) in emergency department patients and the recurrence rate of AF during a 1
      month follow-up period. Sixty-six consecutive hemodynamically stable patients
      presenting to a university hospital emergency department with new-onset atrial
      fibrillation (less than 72 hours duration) comprised the study population.
      Patients were initially monitored for 8 hours and observed for spontaneous
      conversion of AF to sinus rhythm. If conversion did not occur in the first 8
      hours, an oral loading dose (600 mg) of propafenone was given, and patients were
      observed for an additional 8 hours. All patients were reevaluated at 24 hours and
      at 1 month. The spontaneous conversion rate in patients presenting within 6 hours
      of AF onset during the initial 8-hour observation period was 71%. The spontaneous
      conversion rate for all patients during the initial observation period was 53%.
      The conversion rates between patients presenting "early" (less than 6 hours) and
      "late" (7-72 hours) were significantly different (P < 0.001). Many patients with
      new-onset AF, especially those with atrial fibrillation duration less than 6
      hours, may need observation only, rather than immediate intervention, to treat
      their dysrhythmia.

PMID- 10597084
TI  - Academic emergency physicians' perception of patient charges resulting from
      routine ED care.
AB  - This project was undertaken to assess academic emergency physicians' awareness of
      emergency department charges for routine care. A 60-item worksheet requiring
      estimates of patient charges for selected emergency department services,
      supplies, medications, and composite scenarios was used. The study was conducted
      at a university-affiliated academic emergency department and included 20
      emergency medicine attendings and 20 emergency medicine residents. The
      questionnaires were distributed to the participants, independently completed, and
      immediately returned without discussion or consultation. All 40 surveys were
      analyzed. Answers were scored correct if the estimate was no more than 20% above
      or below the actual charge. The attending physicians scored an average of 19% of
      the items correctly, and the residents scored an average of 18% correctly. The
      average absolute error for attendings and residents were 89% and 105%,
      respectively. The proportion of those overestimating and underestimating each
      category were virtually identical in the 2 groups. We conclude from this study
      that emergency medicine attending physicians and residents do not have a good
      appreciation of patient charges for routine emergency care.

PMID- 10597085
TI  - Plain abdominal radiographs and abdominal CT scans for nontraumatic abdominal
      pain--added value?
AB  - We conducted a retrospective descriptive study to determine the value of plain
      abdominal radiographs in emergency department (ED) patients also receiving
      abdominal computed tomography scans (CT) for the evaluation of nontraumatic
      abdominal, back and flank pain (NTAP). Cases were identified through radiology
      log books. Medical records and radiology reports were reviewed to determine
      whether the CT confirmed the findings of the plain abdominal radiographs, and
      whether the clinical course confirmed the results of either. Test characteristics
      for the plain abdominal radiograph and for the CT, using the clinical course
      including subsequent invasive procedures as the gold standard, were calculated.
      Of 177 patients who received CTs, 97 (55%) also received plain abdominal
      radiographs. Among the 74 patients who were admitted to the hospital and had
      complete data, the sensitivity and specificity for the plain abdominal
      radiographs were .43 and .75 respectively, compared to .91 and .94 for the CT
      scan (P(sens.) < .05, P(spec.) < .05). In 4 patients (5%), both studies failed to
      identify pathology shown in a subsequent procedure. In ED patients with NTAP, the
      plain abdominal radiograph may have some value as a screening tool; however, in
      patients in whom a CT is likely to be ordered anyway, a plain abdominal
      radiograph is unhelpful and often misleading.

PMID- 10597086
TI  - Seasonal variation in the occurrence of nontraumatic rupture of thoracic aorta.
AB  - Research has identified circadian and seasonal patterns for several acute
      cardiovascular diseases. In order to investigate the possible existence of a
      seasonal variation in the onset of acute nontraumatic ruptures of thoracic aorta,
      this study considered all patients referred to the emergency department of St
      Anna Hospital of Ferrara, Italy, from January 1985 to December 1996. In the
      considered period, 85 patients (52 males, 33 females) of nontraumatic ruptures of
      thoracic aorta were observed. Cosinor analysis and partial Fourier series with up
      to 4 harmonics were applied to monthly data, and the best-fitting curves for
      circannual rhythmicity were calculated. A higher winter occurrence with a
      significant peak in January was found for the total population and the male
      subgroup. Although the underlying factors are not fully known, such patterns
      strictly resemble that of arterial blood pressure. Emergency doctors can put to
      practical use the recognition of a clearly identified chronorisk for aortic
      rupture, increasing alertness, and providing the most effective antihypertensive
      protection at the specific vulnerable periods.

PMID- 10597087
TI  - Rectus abdominis endometrioma.
AB  - A 31-year-old woman presented with complaints of increasingly severe right lower
      quadrant discomfort that had occurred for several days each month over the course
      of the previous 6 months. A tender mass of the abdominal wall was palpated on
      physical examination, and subsequent ultrasonography and magnetic resonance
      imaging disclosed a discrete mass of the body of the right rectus abdominis
      muscle which was confirmed as endometrial tissue on biopsy. Rectus abdominis
      endometrioma is a relatively rare cause of abdominal pain which may mimic an
      acute abdomen. Clinical clues to the diagnosis include previous uterine or
      gynecological surgery/invasive procedure (with preservation of ovarian function),
      cyclical nature of the discomfort, and the presence of a palpable mass with or
      without associated skin color changes.

PMID- 10597088
TI  - Subcutaneous emphysema and pneumomediastinum after dental extraction.
AB  - Pneumomediastinum, pneumothorax, and subcutaneous emphysema can occur
      occasionally after a surgical procedure. Facial swelling is a common complication
      of dental management. The occurrence of subcutaneous emphysema, pneumothorax, and
      pneumomediastinum after dental procedures is rare. We present a case with
      subcutaneous emphysema of the upper chest, neck, chin, and pneumomediastinum
      after a tooth extraction and discuss the possible mechanism of subcutaneous
      emphysema. To prevent these complications during dental procedures, dental hand
      pieces that have air coolant and turbines that exhaust air in the surgical field
      should not be used.

PMID- 10597089
TI  - Methamphetamine abuse and rhabdomyolysis in the ED: a 5-year study.
AB  - Patients with methamphetamine toxicity are presenting in greater numbers each
      year to emergency departments (ED) in the US. These patients are frequently
      agitated, violent, and often require physical and chemical restraint. The
      incidence and risk of rhabdomyolysis in this subpopulation is unknown. We
      conducted a 5-year retrospective review of all ED patients who received the final
      diagnosis of rhabdomyolysis. Patients with toxicology screens positive for
      methamphetamine were identified, and demographics, laboratory results, resource
      utilization, disposition, and outcome were compared to the remaining patients. Of
      the total 367 patients identified, 166 (43%) were toxicology positive for
      methamphetamine. Methamphetamine patients differed significantly from
      nonmethamphetamine patients with regard to demographics and hospital utilization.
      Methamphetamine patients had significantly higher mean initial creatine
      phosphokinase (CK), 12,439 U/L versus 5,678 U/L (P = 0.02), and lower mean peak
      CK, 16,827 U/L versus 19,426 U/L (P = 0.03). The development of acute renal
      failure was not significantly different between the 2 groups. There were 16 total
      deaths in the study population, 11 from concomitant infection/sepsis. An
      association between methamphetamine abuse and rhabdomyolysis may exist, and CK
      should be measured in the ED as a screen for potential muscle injury in this
      subpopulation. Patients with rhabdomyolysis with an unclear cause should be
      screened for methamphetamine or other illicit drugs.

PMID- 10597090
TI  - Intranasal salbutamol instillation in asthma attack.
AB  - Beta-two sympathomimetic drugs are the treatment of choice for asthmatic attack.
      Their main effect is to dilate the bronchi by a direct action on beta-two
      adrenoreceptors on the smooth muscle, and also by mediator release inhibition
      from mast cells. Salbutamol is widely used in the treatment of bronchial asthma,
      and is usually administered either by inhalation, orally, or parenterally. The
      nasal route seems to afford an effective way to administer medications, since the
      nasal mucosa has a relatively large surface area, and there is no
      gastrointestinal-hepatic first pass-effect, thus avoiding extensive loss of the
      administered drug. We describe herein the use of nasal salbutamol in 3 patients
      with severe asthma attacks who were refractory to conventional therapy, with
      favorable responses and without significant undesirable effects.

PMID- 10597091
TI  - Domestic violence homicides: ED use before victimization.
AB  - The purpose of this study was to document prior emergency department (ED) use and
      injuries presented by victims of domestic violence (DV) homicides. We identified
      all female DV homicide cases investigated by Kansas City, Missouri, Police
      Department (KCPD) officials over 5 years. Medical Records from 12 hospitals were
      searched to determine how many homicide victims were in the ED within the 2 years
      preceding their homicide. The records were reviewed and classified according to
      the Flitcraft Criteria. KCPD documented 139 female homicides victims, with 34
      (24.5%) of these ruled DV-related. Of these 34 victims, 15 (44%) presented to an
      ED within 2 years of homicide. The 15 subjects made 48 total visits, which
      included 20 (42%) injury-related visits. Fourteen (93%) of the victims seen in
      the ED presented with injuries on at least 1 encounter. Eight patients had head
      injuries (53.3%), 2 had perineal lacerations (13.3%), 2 had rapes (13.3%), and 1
      had a suicide attempt (6.7%). The medical records of 8 (53.3%) of the 15 victims
      yielded at least suggestive evidence of battering. There was documented domestic
      violence in 2 cases and intervention in none. Because nearly half of all women
      who were victims of a DV-related homicide had been in the ED within 2 years
      before their deaths, the ED could play an important role in prevention.
      Approximately one half had documentation at least suggestive of battering. These
      results suggest the potential for universal screening, and documented safety
      assessments.

PMID- 10597092
TI  - Collaboration among emergency medicine physician researchers and statisticians:
      resources and attitudes.
AB  - We examined the statistical resources within emergency medicine residency
      programs, and the attitudes of emergency medicine physician researchers toward
      activities wherein collaboration with a statistician is useful. Anonymous surveys
      were mailed to 104 emergency medicine physician researchers (1/program). Sixty
      four (62%) responses were analyzed. Sixty-seven percent of respondents were their
      program's research director. Their highest level of statistical training was self
      taught/nondegree course work for 88% of respondents. Forty-two percent said they
      were the person used most often by their program for statistical expertise. One
      quarter of programs employed a full-time statistician. Collaboration among
      researchers and statisticians was considered sometimes or always useful for
      protocol development (aims 84%, design 99%, outcomes 99%, procedures 73%,
      sampling 97%, inclusion criteria 93%, number of subjects 100%); data entry 73%;
      statistical analysis 100%; and manuscript preparation 86%. Although most
      emergency medicine residencies lacked statistical resources within their program,
      physician researchers expressed positive attitudes toward collaboration with a
      statistician for all aspects of research.

PMID- 10597093
TI  - Occurrence of multiphasic anaphylaxis during a transcontinental air flight.
AB  - Anaphylaxis, a multisystem allergic reaction, represents a true medical
      emergency. Anaphylaxis is characterized by a combination of the following:
      urticaria, angioedema, distributive shock, and respiratory failure. Most often,
      the patient is rapidly treated with prompt resolution of the anaphylaxis in
      either the out-of-hospital or emergency department (ED) setting. Infrequently,
      recurrent, or multiphasic, anaphylaxis is encountered, involving a reappearance
      of allergic phenomena after complete resolution of the original reaction.
      Recurrence may involve nuisance-level issues such as urticaria; alternatively,
      multiphasic reactions may be characterized by cardiovascular collapse and/or
      respiratory compromise. Initially aggressive pharmacological therapy followed by
      prolonged observation in either the ED or the in-hospital setting is strongly
      recommended to monitor for potential recurrence.

PMID- 10597094
TI  - Subarachnoid hemorrhage following permissive hypercapnia in a patient with severe
      acute asthma.
AB  - In this article, we describe a case of a subarachnoid hemorrhage (SAH) in an
      acute severe asthma patient following mechanical hypoventilation. A 49-year-old
      man was admitted to an Intensive Care Unit with an acute exacerbation of asthma.
      After 3 days of mechanical ventilation (hypercapnia and normoxaemia), it was
      noted that his right pupil was fixed, dilated, and unreactive to light. Computed
      tomography (CT) scan showed localized SAH within the basilar cisterns and diffuse
      cerebral swelling. On the fourth day, a new CT scan showed hemorrhage resorption
      and a cerebral swelling decrease. In the following days, the patient's condition
      continued improving with no detectable neurological deficits. A review of similar
      published reports showed that all patients performed respiratory acidosis,
      normoxaemia, and hypercapnia. The most frequent neurological sign was mydriasis,
      and all subjects showed cerebral edema. Since normoxaemic hypercapnia has been
      associated with absence, or less cerebral edema, we considered additional factors
      to explain cerebral edema and intracranial hypertension causes. Thus,
      intrathoracic pressures due to patient's efforts by forcibly exhaling, or during
      mechanical ventilation, would further increase intracranial pressure by limiting
      cerebral venous drainage. This case emphasizes the fact that patients with acute
      severe asthma who have developed profoundly hypercarbic without hypoxia before or
      during mechanical ventilation, may have raised critical intracranial pressure.

PMID- 10597095
TI  - Painless limited dissection of the ascending aorta presenting with aortic valve
      regurgitation.
AB  - Aortic dissection is a medical emergency carrying high morbidity and mortality.
      Prompt diagnosis is sometimes difficult because of its varying presentations, but
      it is critical to the achievement of good clinical outcomes. This report
      describes 2 cases of painless aortic dissection that presented with aortic valve
      regurgitation. In both, the dissection was limited to the ascending aorta just
      distal to the aortic valve. These dissections were diagnosed by transthoracic and
      transesophageal echocardiography.

PMID- 10597096
TI  - False-negative abdominal CT scan in a cocaine body stuffer.
AB  - Computed tomography (CT) imaging has been touted as one of the best techniques to
      detect body packets in body packers and stuffers. The majority of experience has
      been with body packers. We describe a case of a body stuffer who presented with
      abdominal pain after ingesting a large packet containing multiple small packets,
      with a falsely negative abdominal CT scan without contrast. This case raises
      questions regarding the best method of detection of body packets in body
      stuffers.

PMID- 10597097
TI  - Electrocardiography in the patient with the Wolff-Parkinson-White syndrome:
      diagnostic and initial therapeutic issues.
AB  - The Wolff-Parkinson-White syndrome (WPW), estimated to occur in approximately
      0.1% to 3% of the general population, is a form of ventricular preexcitation
      involving an accessory conduction pathway. The definition of WPW relies on the
      following electrocardiographic features: (1) a PR interval less than 0.12 seconds
      (2) with a slurring of the initial segment of the QRS complex, known as a delta
      wave, (3) a QRS complex widening with a total duration greater than 0.12 seconds,
      and (4) secondary repolarization changes reflected in ST segment-T wave changes
      that are generally directed opposite (discordant) to the major delta wave and QRS
      complex changes. The accessory pathway bypasses the atrioventricular (AV) node,
      creating a direct electrical connection between the atria and ventricles. The
      majority of patients with preexcitation syndromes remain asymptomatic throughout
      their lives. When symptoms do occur they are usually secondary to
      tachyarrhythmias; the importance of recognizing this syndrome is that these
      patients may be at risk to develop a variety of supraventricular tachyarrhythmias
      which cause disabling symptoms and, in the extreme, sudden cardiac death. The
      tachyarrhythmias encountered in the WPW patient include paroxysmal
      supraventricular tachycardia (both the narrow QRS and wide QRS complex
      varieties), atrial fibrillation, atrial flutter, and ventricular fibrillation.
      Diagnostic and urgent, initial therapeutic issues based on initial
      electrocardiographic information are presented via 5 illustrative cases.

PMID- 10597098
TI  - Succinylcholine: adverse effects and alternatives in emergency medicine.
AB  - Succinylcholine has long been the favored neuromuscular blocking agent for
      emergent airway management because of its rapid onset, dependable effect, and
      short duration. However, it has a plethora of undesirable side effects, ranging
      from the inconsequential to the catastrophic. When patients requiring tracheal
      intubation present with potential contraindications to succinylcholine use, the
      emergency physician will need to substitute a rapid-onset nondepolarizing
      neuromuscular blocking agent, such as rocuronium or mivacurium. An understanding
      of the pharmacology of these agents is essential.

PMID- 10597099
TI  - Ketamine in the ED: medical politics versus patient care.
AB  - The safe and effective use of ketamine for sedation/analgesia by emergency
      physicians has been validated in the medical literature. Nonetheless, arbitrary
      restrictions of this medication to anesthesia practitioners have prohibited
      emergency physician use in some locations. We explore the scientific evidence
      related to the use of ketamine by emergency physicians for sedation/analgesia,
      the history of sedation, the operational definitions of conscious sedation and
      dissociative anesthesia, and the Joint Commission on Accreditation of Healthcare
      Organizations (JCAHO) related standards. We conclude that ketamine sedation/
      analgesia offers many specific advantages for emergency patients and that it is
      safely administered by emergency physicians in the appropriately monitored
      setting.

PMID- 10597100
TI  - Sexual assault: an annotated bibliography.

PMID- 10597101
TI  - Steroid-induced psychosis treated with haloperidol in a patient with active
      chronic obstructive pulmonary disease.

PMID- 10597102
TI  - Conflict resolution in emergency medicine.

PMID- 10597103
TI  - Neuroleptic malignant syndrome associated with nortriptyline.

PMID- 10597104
TI  - Peripheral facial paralysis revealing HIV infection.

PMID- 10597105
TI  - Adnexal torsion during late pregnancy.

PMID- 10597106
TI  - Methylene blue dye-induced knee effusion.

PMID- 10597107
TI  - Is a rapid bedside troponin T assay predictive of outcomes in unstable angina?

PMID- 10597108
TI  - Fatal atlanto-occipital dislocation secondary to airbag deployment.

PMID- 10597109
TI  - Systemic capillary leak syndrome associated with rhabdomyolysis and compartment
      syndrome.

PMID- 10597110
TI  - The effects of a weapon surveillance system.

PMID- 10597111
TI  - Fourth-year elective recommendations for medical students interested in emergency
      medicine.

PMID- 10597112
TI  - Right hemisphere dysfunction: therapeutic intervention from acute care to home
      health.
AB  - This article discusses clinical practice variances in speech-language treatment
      of patients with right hemisphere dysfunction by therapeutic milieu. With an eye
      toward enhanced cost effectiveness, a model of intervention is presented that
      takes a patient from acute care management through rehabilitation. Issues
      discussed include assessment, family training, goal setting, and documentation. A
      right hemisphere screening tool is included in an appendix for use in acute and
      transitional care settings where in-depth testing might be inappropriate because
      of time constraints or the acute or transitory nature of the patient's symptoms.

PMID- 10597113
TI  - Evanston Northwestern Healthcare--right hemisphere screen.
AB  - This article consists of a screening test that has been developed and used by the
      speech-language pathologists at Evanston Northwestern Healthcare. It is an
      informal tool designed to quickly determine the cognitive and communication
      status of right hemisphere-injured patients and is most appropriate for use in
      acute care and transitional care settings, where speech-language pathologists are
      asked to determine whether or not a full evaluation is warranted.

PMID- 10597114
TI  - Process-oriented treatment of right hemisphere communication disorders.
AB  - Lacking knowledge about the cognitive processes that underlie communication
      impairments in patients with right hemisphere damage (RHD) and driven by
      increasingly limited treatment duration, speech-language pathologists often give
      little thought to process-oriented treatment. However, operating from a
      theoretical perspective in which treatment targets the processes that underlie
      symptoms can result in more effective treatment of a range of symptoms due to a
      common processing impairment. This article provides research-driven therapeutic
      approaches based on sound theoretical perspectives that can be combined with task
      specific therapy to maximize therapeutic outcomes with this clinical population.

PMID- 10597115
TI  - Cognitive-communicative disorders of right cerebrovascular accident patients and
      reimbursement for treatment.
AB  - Speech-language pathologists frequently diagnose and treat individuals with
      cognitive-communicative disorders, but they sometimes encounter difficulty
      receiving reimbursement for those services from third-party payers. Often,
      reimbursement becomes an issue because the documentation provided fails to
      emphasize the linguistic and communication aspects of treatment that are
      precisely the components that make the speech-language pathologist's role with
      this population unique. By analyzing how the elements of language, cognition, and
      communication are interactively affected for each patient and by emphasizing
      those relationships in treatment, speech-language pathologists can communicate
      the importance of their role in the treatment process and increase the likelihood
      of reimbursement for services.

PMID- 10597116
TI  - An inclusive management approach for individuals with right hemisphere deficits.
AB  - Diversity, multiculturalism, and individual differences are concepts that are
      becoming of greater interest to speech-language pathologists as they strive to
      make clinical management more functional and meaningful for all clients. This
      article discusses a new way of viewing these concepts and suggests how to weave
      them into the framework of clinical management. Specific attention to those
      aspects of performance likely to be influenced by culture, communication style,
      and individual differences among people with right hemisphere impairments are
      discussed. In addition, ways in which this information can be used to enhance the
      assessment and treatment of these individuals are suggested.

PMID- 10597118
TI  - Use of proton-pump inhibitors in complicated ulcer disease and upper
      gastrointestinal tract bleeding.
AB  - The use of proton-pump inhibitors in the management of complicated peptic ulcer
      disease and upper gastrointestinal bleeding is described. Treatment of peptic
      ulcers in patients who are Helicobacter pylori positive should include
      antimicrobial therapy to eradicate the infection; based on considerations of
      primary antimicrobial resistance and safety, one recommended regimen is the
      combination of a proton-pump inhibitor (lansoprazole 30 mg or omeprazole 20 mg),
      clarithromycin 500 mg, and amoxicillin 1 g, each twice daily for 14 days. The
      proportion of H. pylori-negative ulcers has increased in the United States, now
      accounting for 39% of patients with ulcers who report no intake of nonsteroidal
      anti-inflammatory drugs (NSAIDs). Compared with H. pylori-positive ulcers, H.
      pylori-negative ulcers are more aggressive, characterized by high recurrence
      rates and increased risk of bleeding and perforation. Long-term therapy with a
      proton-pump inhibitor may be useful in these patients. Acid suppressants may also
      have a role in the initial treatment of patients who have a bleeding ulcer,
      including those associated with NSAID use. For patients who require continuous
      NSAID therapy, proton-pump inhibitors have been shown to heal a significantly
      higher percentage of peptic ulcers in eight weeks than histamine H2-receptor
      antagonists, and maintenance therapy with either lansoprazole or omeprazole
      reduces ulcer recurrence. Preliminary data suggest a role for proton-pump
      inhibitors in the prevention of stress ulcers among critically ill patients.
      Proton-pump inhibitors play an important role in the treatment of both H. pylori
      negative and H. pylori-positive peptic ulcers, as well as in upper
      gastrointestinal tract bleeding. Further study is needed regarding their role in
      preventing stress ulcers in critically ill patients.

PMID- 10597119
TI  - Safety profile of the proton-pump inhibitors.
AB  - The adverse effect profile of proton-pump inhibitors is presented. The proton
      pump inhibitors are a well-tolerated class of drugs. The most common adverse
      events of headache, diarrhea, and nausea have been reported in fewer than 5% of
      patients treated with lansoprazole or omeprazole. The frequency of these adverse
      events with the two proton-pump inhibitors is comparable to that of placebo and
      histamine H2-receptor antagonists. Few clinically important interactions have
      been observed between proton-pump inhibitors and other drugs metabolized by the
      cytochrome P-450 system. The interaction potential should be considered when
      drugs with a narrow therapeutic window, such as phenytoin, warfarin, and
      theophylline, are used concomitantly with proton-pump inhibitors. Theoretical
      concerns about the consequences of chronic administration of proton-pump
      inhibitors, such as the impact of sustained hypergastrinemia on gastric
      morphology and the development of atrophic gastritis, have been dismissed. While
      increased gastrin levels are observed among patients taking proton-pump
      inhibitors, for the majority they remain within the normal range. After long-term
      use of the drugs, patients do not appear to be at increased risk of atrophic
      gastritis or gastric cancer. Helicobacter pylori infection, rather than acid
      suppression, may be the more important factor for the development of atrophic
      gastritis. Bacterial overgrowth and altered nutrient absorption resulting from
      sustained hypochlorhydria induced by chronic administration of proton-pump
      inhibitors have not been realized as clinical concerns. Not only are proton-pump
      inhibitors well tolerated during short-term administration, but there also do not
      appear to be clinically important adverse sequelae associated with their long
      term use.

PMID- 10597120
TI  - Comparison of 24-hour intragastric pH using four liquid formulations of
      lansoprazole and omeprazole.
AB  - The results of previous studies evaluating the effect of four liquid formulations
      of proton-pump inhibitors on 24-hour intragastric pH are described. Patients with
      a gastrostomy who were resident in a Veterans Affairs medical center or its
      affiliated nursing home were eligible for enrollment in one of four open-label
      studies in which each patient served as his own control. Patients underwent 24
      hour intragastric pH studies before and after receiving seven consecutive days of
      one of the following liquid formulations of a proton-pump inhibitor administered
      once daily: omeprazole granules 20 mg in orange juice, lansoprazole granules 30
      mg in orange juice, simplified omeprazole suspension 20 mg, and simplified
      lansoprazole suspension 30 mg. The suspensions were prepared with 10 mL of 8.4%
      sodium bicarbonate solution. Mean intragastric pH was measured, as was the time
      pH stayed above 3.0 and 4.0 during the 24-hour period. Six to 14 patients
      participated in each study. The mean posttreatment pH was 4.9+/-0.8, 4.7+/-0.6,
      4.1+/-1.5, and 5.1+/-1.1 for omeprazole granules in orange juice, lansoprazole
      granules in orange juice, simplified omeprazole suspension, and simplified
      lansoprazole suspension, respectively. Both drugs in orange juice maintained pH
      above 4.0 longer than 14 hours and above 3.0 for close to 20 hours, which are the
      levels deemed optimal for healing erosive esophagitis and duodenal ulcers,
      respectively. Simplified lansoprazole suspension maintained pH above those
      thresholds for the optimal times, but simplified omeprazole suspension did not
      (20 and 15 hr above 3.0, 17 and 12 hr above 4.0 for lansoprazole and omeprazole,
      respectively). Further development of liquid formulations of proton-pump
      inhibitors may have important implications for the treatment of acid-related
      diseases in patients, including children, who are unable to swallow capsules.

PMID- 10597121
TI  - Comparison of mobile lithotripters at one institution: healthtronics lithotron,
      Dornier MFL-5000, and Dornier Doli.
AB  - BACKGROUND AND PURPOSE: Extracorporeal shockwave lithotripsy (SWL) has replaced
      most surgical and endourologic procedures for upper urinary tract stone disease.
      Our institution contracted with mobile lithotripter companies to provide SWL. We
      reviewed the outcomes of 50 patients treated on each machine with regard to
      efficacy, complications, and retreatment rates. PATIENTS AND METHODS: One hundred
      fifty patients over 21 years of age were treated at Ochsner Foundation Hospital
      from April 1995 through June 1998. All stones were in either the kidney or the
      upper ureter, and all were <20 mm. Three mobile lithotripters-the Dornier MFL
      5000 (4/95-9/96), the Dornier Doli (9/96-11/97), and the HealthTronics Lithotron
      (12/97-4/98)-were each used to treat 50 patients. Conscious monitored intravenous
      sedation was used in all patients. Post-treatment evaluations were made at 2
      weeks, 1 month, and 3 months. RESULTS: A successful outcome (stone free or
      fragments <4 mm) was achieved in 72% (MLF-5000), 68% (Doli), and 80% (Lithotron)
      of patients (P = 0.39). Treatments that were followed by retreatments or other
      further procedures (ureteroscopy or percutaneous nephrolithotomy) were counted as
      failures. The retreatment rate was 10%, 22%, and 10%, respectively. There were
      three significant complications with the Doli unit: two large perirenal hematomas
      (4%) and one delayed splenic rupture in a patient with a history of pelvic
      surgery that necessitated transfusions and urgent splenectomy. The minor
      complication rates with all three lithotripters were similar to those reported in
      the literature. The three-month efficiency quotients were 0.55 for the Lithotron
      and MFL-5000 and 0.41 for the Doli. CONCLUSIONS: Statistically equivalent success
      rates were achieved with all three machines. The electromagnetic unit (Doli) had
      higher rates of retreatment and significant complications than the
      electrohydraulic lithotripters (MFL-5000, Lithotron).

PMID- 10597122
TI  - Extracorporeal piezoelectric shockwave lithotripsy of ureteral stones: are second
      generation lithotripters obsolete?
AB  - BACKGROUND: The role of extracorporeal shockwave lithotripsy (SWL) for ureteral
      calculi is still being debated. We evaluated our results in a large series to
      clarify the role of this modality. PATIENTS AND METHODS: A total of 478 patients
      with solitary ureteral stones were treated by in situ piezoelectric
      extracorporeal shockwave lithotripsy (SWL) using a Wolf Piezolith 2300 ultrasound
      guided lithotripter. Two hundred fifty stones (52.3%) were located in the upper
      ureter and 228 (47.7%) in the distal ureter. Seventy of the upper ureteral stones
      were located in the ureteropelvic junction and 180 in the lumbar ureter. The
      diameter of the stones ranged from 5 to 30 mm. Four hundred sixty-seven patients
      were followed up for a mean of 4 months. RESULTS: Four hundred forty patients
      (94.2%) were stone free after in situ SWL alone. Complete removal of all stone
      fragments was achieved in 95.4% of the 216 patients with calculi of 5 to 10 mm in
      diameter, in 94.3% of the 229 with stones of 11 to 20 mm, and in 81.8% of the 22
      with calculi of 21 to 30 mm. In situ treatment completely removed 61 of 69
      ureteropelvic junction stones (88.4%), 166 of 175 lumbar stones (94.8%), and 213
      of 223 distal ureteral stones (95.5%). In situ treatment failed in 27 stones
      (5.8%). After 4 months, 12 stone fragments and 15 unfragmented stones persisted
      despite retreatments and required endoscopic procedures. The mean number of
      sessions and shockwaves per patient was 1.8 and 4884, respectively. Morbidity was
      low. Renal colic in 57 patients (11.9%) was managed successfully by analgesics.
      In 36 patients, stone fragments obstructed the ureter; in 28 of these 36 (78%),
      the obstruction was resolved and the patients were stone free after in situ
      retreatments alone. All these results were achieved on an outpatient basis
      without sedation or local or general anesthesia. CONCLUSION: Piezoelectric SWL is
      an effective and noninvasive method for eliminating ureteral stones. Second
      generation ultrasound-guided lithotripters are not yet obsolete.

PMID- 10597123
TI  - Treatment of Peyronie's disease by extracorporeal shockwave therapy: evaluation
      of our preliminary results.
AB  - BACKGROUND: Peyronie's disease is an idiopathic disorder of the penis that
      produces erectile dysfunction. It affects mainly the tunica albuginea. We
      describe our preliminary results with extracorporal shockwave therapy (ESWT) as a
      new noninvasive modality for the treatment of Peyronie's disease. PATIENTS AND
      METHODS: In this study, 24 patients aged 36 to 67 years were treated with ESWT on
      the Lithostar overhead-module (Siemens). All our patients had unsuccessful
      medical treatment before ESWT. The average plaque was 7x15 mm. The number of
      shockwaves ranged from 15,000 to 25,000 (18-21 kV) delivered in four to ten
      sessions. Most patients needed local anesthesia before therapy. RESULTS: Four
      patients (17%) showed marked improvement and complete remission of the penile
      deviation. Six patients (25%) showed partial remission with painless erections
      after treatment. Four patients had painless erections after treatment but still
      had some penile deviation. In 10 patients (41%), ESWT failed, necessitating
      subsequent penile surgery. CONCLUSIONS: Our preliminary results with a response
      rate of 59% with ESWT for Peyronie's disease, including a 17% complete remission
      rate, is encouraging. However, further multicenter studies will have to prove if
      ESWT is a real therapeutic option for this disease.

PMID- 10597124
TI  - Effect of urinary stone disease and extracorporeal shockwave lithotripsy on
      excretion of glycosaminoglycans.
AB  - BACKGROUND AND PURPOSE: The effect of glycosaminoglycans (GAGs) in urinary
      crystal inhibition has been shown in vitro, but their inhibitor role in vivo has
      not been precisely determined in stone-forming patients. The aim of this study
      was to compare the levels of total GAGs and their components in primary stone
      forming patients and a healthy control group and to investigate the impact of
      shockwave lithotripsy (SWL). PATIENTS AND METHODS: Thirty-eight patients with
      primary kidney stones and 31 healthy controls were included in this prospective
      study. Total urinary GAG concentrations were determined by the dimethylene blue
      assay (DMB), and GAG fractions (chondroitin sulfate, heparan sulfate, and
      dermatan sulfate) were studied by cellulose acetate electrophoresis. Analysis was
      repeated after SWL in the stone patients. RESULTS: Chondroitin sulfate was the
      major component secreted in the urine of the control subjects. Heparan sulfate
      was the major component in the urine of the stone patients with less chondroitin
      sulfate and dermatan sulfate (48%, 35%, 16.5%, respectively). Our study showed a
      significant increase in total urinary GAGs (4.75 v. 7.43 microg/mg of creatinine;
      P<0.0001) after SWL. Dermatan sulfate was the main component in this group
      (P<0.0001). The total urinary GAG concentrations remained high for at least 2
      days after SWL. CONCLUSION: The elevation in total GAGs after SWL indicates the
      presence of tissue injury, which also renders dermatan sulfate the principal
      excreted component. Studies with longer follow-up periods are needed to determine
      whether these changes in the excretion of GAG components persist.

PMID- 10597125
TI  - Holmium: YAG lithotripsy: optimal power settings.
AB  - PURPOSE: We tested the hypothesis that holmium:YAG laser lithotripsy speed is
      best maximized by using low pulse energy at high pulse frequency. MATERIALS AND
      METHODS: To demonstrate that optical fiber damage increases with pulse energy and
      irradiation, the 365-microm optical fiber irradiated calcium hydrogen phosphate
      dihydrate (CHPD), calcium oxalate monohydrate (COM), cystine, magnesium ammonium
      phosphate hexahydrate (MAPH), and uric acid calculi at pulse energies of 0.5 to
      2.0 J. Optical energy output was measured with an energy detector after 10 J to
      200 J of total energy. To demonstrate that lithotripsy efficiency varies with
      power, fragmentation was measured at constant power settings at total energies of
      200 J and 1 kJ with the 365-microm optical fiber. Fragmentation was measured for
      the 272-microm optical fiber at pulse energies of 0.5 J to 1.5 J at 10 Hz. To
      demonstrate that low pulse energy produces smaller fragments than high pulse
      energy, fragment size was characterized for COM and uric acid calculi after 0.25
      kJ of irradiation using the 272-microm to 940-microm optical fibers at 0.5 J to
      1.5 J. RESULTS: Damage to the 365-microm optical fiber was greatest for
      irradiation of CHPD, followed by MAPH, and COM (P<0.001). There was no
      significant optical fiber damage after cystine and uric acid lithotripsy. For the
      365-microm optical fiber and CHPD, fragmentation after 200 J was greatest for
      pulse energies < or =1.0 J (P< 0.001). For other compositions, fragmentation was
      not statistically different among the power settings for constant irradiation. No
      significant difference was noted in fragmentation for any composition at
      different pulse energies (1.0 v. 2.0 J) for 1-kJ irradiation. However, for all
      compositions, the calculated lithotripsy speed was greatest at high power
      settings (P<0.001). For the 272-microm optical fiber, CHPD fragmentation was
      greatest for the 1.0-J pulse energy. The mean fragment size and relative quantity
      of fragments > or =2 mm both increased as pulse energy increased. CONCLUSIONS:
      Optical fiber degradation varies with stone composition, irradiation, and pulse
      energy. Holmium:YAG lithotripsy speed is maximized with higher power (either
      increased pulse energy or higher pulse frequency). Because low pulse energy may
      be safer and yields smaller fragments than high pulse energy, holmium:YAG
      lithotripsy speed is best increased by using pulse energies < or =1.0 J at a high
      repetition rate.

PMID- 10597126
TI  - Retroperitoneal access for transperitoneal laparoscopy in patients at high risk
      for intra-abdominal scarring.
AB  - BACKGROUND AND PURPOSE: Adhesions from prior extensive open abdominal surgery can
      make initial transperitoneal access for laparoscopy hazardous. An alternative to
      open port placement is a retroperitoneal approach to the peritoneal cavity. We
      describe our retroperitoneal access for transperitoneal laparoscopy and evaluate
      the success of the subsequent laparoscopic procedure. PATIENTS AND METHODS: Eight
      patients with a history of abdominal surgery have undergone retroperitoneal
      access to the peritoneum prior to a laparoscopic urologic procedure. With the
      patient in a lateral decubitus position, the retroperitoneum is entered with a 10
      mm Visiport device (US Surgical Corp., Norwalk, CT) along the posterior axillary
      line. A working space is bluntly created, the peritoneum identified anterior to
      the colon, and the endoscope passed through a peritoneotomy. The abdomen is then
      inspected, transperitoneal ports are strategically placed under direct vision,
      and the intended procedure is commenced. RESULTS: In all cases, retroperitoneal
      access to the peritoneum and subsequent trocar placement was successful. In five
      cases, the intended procedure was completed laparoscopically. In a case of
      bilateral ureterolysis, one side was completed laparoscopically; however, the
      other required open conversion. In two nephrectomies for xanthogranulomatous
      pyelonephritis (XGP), open conversion was necessary because of fibrosis.
      CONCLUSION: Retroperitoneal access to the peritoneal cavity permits safe and
      effective port placement when previous abdominal surgery makes initial
      transabdominal access difficult. However, despite successful access, in patients
      at risk for extensive perinephric fibrosis (e.g., XGP), a high incidence of open
      conversion may be expected.

PMID- 10597127
TI  - Laparoscopic-assisted continent urinary diversion in obese patients.
AB  - BACKGROUND AND PURPOSE: The Pfannenstiel incision provides good access to the
      bladder and bladder neck for major reconstructive surgery in the thin patient,
      whereas a midline incision is often necessary to get adequate exposure in the
      obese patient. We describe our experience using laparoscopic-assisted continent
      urinary diversion in conjunction with other bladder and bladder neck surgery in
      obese patients. PATIENTS AND METHODS: Three female patients (mean age 18; mean
      weight 175 pounds) with neurogenic bladder underwent Mitrofanoff
      appendicovesicostomy continent urinary diversion to the umbilicus and pubovaginal
      sling. An umbilical port for the telescope and two lateral ports were used. Once
      the appendix and right hemicolon had been completely mobilized up to the hepatic
      flexure, reconstruction was completed through a low Pfannenstiel incision.
      RESULTS: There were no laparoscopic complications. None of the laparoscopic port
      sites was visible postoperatively, as one was in the base of the umbilicus, and
      the other two had been incorporated into the Pfannenstiel incision. With a mean
      follow-up of 1 year, all patients were continent and catheterizing their
      umbilicus easily. Pfannenstiel incisions were well healed, and the patients were
      quite satisfied with their cosmesis. CONCLUSION: Laparoscopic-assisted
      Mitrofanoff appendicovesicostomy continent urinary diversion to the umbilicus can
      be performed in conjunction with a Pfannenstiel incision to complete major
      bladder and bladder neck surgery in the obese patient with good postoperative
      cosmesis. This procedure represents a nice compromise between a very lengthy
      bladder reconstructive procedure done purely laparoscopically and a midline
      incision with good exposure but suboptimal cosmesis.

PMID- 10597128
TI  - Retrograde Acucise endopyelotomy: long-term results.
AB  - PURPOSE: We evaluated the long-term outcome of retrograde endopyelotomy with the
      Acucise cutting balloon as a first-line treatment of ureteropelvic junction
      obstruction (UPJO) in 36 patients (median age 44 years). PATIENTS: Twenty-three
      patients had a primary UPJO. The median follow-up in the series was 24 (6-42)
      months. RESULTS: Success, defined as a subjective and objective improvement, was
      obtained in 27 (75%). In multivariate analysis, only the presence of a crossing
      vessel (45% v. 81%) was a significant covariate for success. The success rates
      for primary and secondary UPJO were 74% and 77% respectively. The grade of
      obstruction had no impact on results. The median time to the nine failures was 3
      months, and no failure occurred more than 6 months after the endopyelotomy. In
      75% of the failures with no crossing vessel, redo retrograde Acucise
      endopyelotomy was successful. CONCLUSION: Retrograde Acucise endopyelotomy is an
      efficient long-term treatment of UPJO with low morbidity. This technique is a
      reasonable choice for first-line treatment of UPJO.

PMID- 10597129
TI  - Percutaneous endoscopic trigonoplasty in children: long-term outcomes and
      modifications in technique.
AB  - PURPOSE: Long-term outcomes of a minimally invasive method of correcting
      vesicoureteral reflux are presented with a discussion of the modification in our
      original technique. PATIENTS AND METHODS: A total of 29 children (46 refluxing
      ureters), 14 months to 18 years old, underwent percutaneous endoscopic
      trigonoplasty (PET) between December 1994 and June 1996. Follow-up ranged from 19
      to 37 months. Reflux was grade 1 in 2, grade 2 in 16, grade 3 in 19, grade 4 in
      8, and grade 5 in 1. The technique was a Gil-Vernet method in the first 23
      patients and Cohen reimplantation in the last 6 patients. RESULTS: Resolution of
      reflux was observed to decrease from 63% to 47% with long-term (30-37 months')
      follow-up using the Gil-Vernet technique. Resolution was greater with unilateral
      reflux than bilateral reflux (83% v. 27%, respectively). The Cohen technique
      resulted in resolution of reflux in 83%; however, the operating time nearly
      doubled when compared with the Gil-Vernet group. In both groups, failure was
      unrelated to grade of reflux, age, operative sequence, or bladder instability.
      CONCLUSIONS: Although showing an improvement in resolution of reflux over the Gil
      Vernet PET procedure, the Cohen PET reimplant has a lower success rate than
      traditional open operative reimplants. The PET also requires more operating time
      and two operating surgeons. Despite some advantages in the promptness of
      recovery, we do not recommend PET by either technique at this time. Future
      modifications may make this approach more tenable.

PMID- 10597130
TI  - Balloon dilation of posterior urethral stricture secondary to radiation and
      cryotherapy in a patient with a functional artificial urethral sphincter.
AB  - Severe urethral stricture disease as an isolated entity can be a management
      dilemma. In the patient described here, this problem was associated with prior
      external-beam radiation and cryosurgical ablation of the prostate, and a
      functional artificial urethral sphincter (AUS) had been placed. An attempt to
      relieve partial urinary obstruction while preserving AUS function led to
      successful balloon dilation proximal to the sphincter cuff.

PMID- 10597131
TI  - Endoprosthesis implantation in the treatment of recurrent urethral stricture: a
      multicenter study. Sicilian-Calabrian Urology Society.
AB  - PURPOSE: This study was conducted by nine urology departments in southern Italy
      to assess the efficacy of and tolerance to treatment of recurrent urethral
      stricture using a permanent prosthesis. PATIENTS AND METHODS: Since 1992, 99
      prostheses have been implanted to treat inflammatory and iatrogenic (seven
      departments) or all types (two departments) of urethral strictures. The Urolume
      Wallstent was used in 94 cases. Three centers implanted more than one prosthesis
      when this was indicated. Local anesthesia was used by six centers, spinal
      anesthesia by two, and local or general by one. At three centers, urethrotomy was
      performed immediately prior to implantation; two centers used dilation to 30F,
      and two centers performed urethrotomy 24 or 36 hours before implantation. The
      median follow-up is 29.1 months (range 3-53 months). RESULTS: The results were
      good in 52%, fair in 34%, and poor in 14% of patients. The maximum flow rate
      increased >75% in 82% of patients. All departments reported complete
      reepithelialization of the urethra by 6 months. The short-term complications (7
      28 days) were perineal discomfort (86%) and dribbling (14%). The long-term
      complications were painful erection (44%), mucous hyperplasia (44%), recurring
      stricture (29%), and incontinence (14%). All departments performed resection for
      hyperplasia in many cases. CONCLUSION: Permanent urethral endoprostheses can
      produce excellent results in patients with recurrent urethral strictures.

PMID- 10597132
TI  - Is transurethral vaporization a remake of transurethral resection of the
      prostate?
AB  - PURPOSE: Transurethral resection of the prostate (TURP) is still the gold
      standard method to treat benign prostatic hyperplasia (BPH). Transurethral
      vaporization of the prostate (TUVP) is compared with the transurethral resection
      of benign prostatic hyperplasia. PATIENTS AND METHODS: Over a 10-month period, 78
      patients presenting with moderate and severe symptomatic BPH were randomized into
      two groups. A total of 38 patients underwent TURP, and 40 men underwent TUVP. The
      protocol included urinary flow rate (Qmax), symptomatology evaluated by the
      International Prostatic Symptom Score (I-PSS), and an ultrasonographic estimate
      of the postvoiding residual volume (PVR). The TUVP was carried out using a
      regular loop with the electrical source set at 250 to 300 W in the pure cutting
      mode. The same technique was used in the TURP, but the electrosurgical unit was
      set at 50 to 80 W for cutting and 50 W for hemostasis. The mean follow-up was 17
      months (range 11-23 months). RESULTS: The data showed significant improvement in
      the symptom score, maximum flow rate, and postvoiding residual urine volume after
      treatment (P<0.01) in both groups. Comparing the symptom score, there was no
      difference between the two techniques (P = 0.88), the same occurring with the PVR
      (P = 0.78). However, the Qmax was higher after TURP (P = 0.02). The amount of
      tissue resected showed no statistical difference between the two techniques
      (P>0.05). Operative time, postoperative irrigation, catheter removal, and
      hospital stay were better with TUVP (P = 0.001). There was a statistically
      significant difference (P = 0.003) when we compared the occurrence of retrograde
      ejaculation with TURP (32%) and TUVP (65%) The TUVP using a regular loop, in
      addition to the advantage of the equipment and technique already being familiar
      to urologists, is efficient and reduces capital expenditure. CONCLUSION: The TUVP
      is a remake of TURP, with higher energy offering better results.

PMID- 10597133
TI  - Mapping complex traits in diseases of the hair and skin.
AB  - The past decade has witnessed the ascendance of human genetics in modern
      medicine, and at the forefront of this movement is the identification of genetic
      factors underlying inherited diseases. The methods of genetic mapping and
      positional cloning have made the discovery of genes with alleles that cause
      simple Mendelian diseases commonplace. The elucidation of the genetic basis of
      such disorders has vitalized both human genetics and the entire medical community
      as the field has gained prominence. The fact remains, however, that diseases
      resulting from the action of alleles of a single gene comprise only a minor
      percentage of traits that are medically relevant to humanity. The majority of
      these are multifactorial "complex traits", which result from the aggregate
      contribution of an unknown number of genes interacting with each other and with
      the environment. The current challenge has become one of parlaying successes in
      the mapping of Mendelian diseases into the discovery of genes whose alleles
      predispose the development of a complex disease. In light of this challenge, this
      review summarizes the methods and addresses some of the central issues of complex
      trait mapping, while using examples from dermatologically-relevant complex traits
      such as psoriasis and alopecia. Additionally, current technical and theoretical
      advances as well as the potential impact of the Human Genome Project will be
      discussed.

PMID- 10597134
TI  - Detection of melanocortin-1 receptor antigenicity on human skin cells in culture
      and in situ.
AB  - The proopiomelanocortin (POMC) products alpha-melanocyte stimulating hormone
      (alpha-MSH) and adrenocorticotropin (ACTH) bind to specific receptors known as
      the melanocortin (MC) receptors. There is increasing evidence that the MC
      receptor subtype 1 (MC-1R) is expressed in vitro by several other cutaneous cell
      types besides melanocytes and keratinocytes. Our knowledge on the MC-1R
      expression in skin, however, remains fragmentary. In order to examine the
      expression of MC-1R in human skin cells in vitro and In situ, we made use of a
      recently described antibody directed against the amino acids 2-18 of the human MC
      1R. Flow cytometry analysis revealed the highest MC-1R antigenicity in normal
      melanocytes and keratinocytes, followed by dermal fibroblasts, microvascular
      endothelial cells and WM35 melanoma cells. Little or no expression was detected
      in KB carcinoma cells and Fs4 fibroblasts. In normal human skin, immunoreactivity
      for the anti-MC-1R antibody was detected in hair follicle epithelia, sebocytes,
      secretory and ductal epithelia of sweat glands, and periadnexal mesenchymal
      cells. Interfollicular epidermis was largely unreactive in adult skin as opposed
      to undifferentiated keratinocytes of fetal skin. Our findings form a framework
      within which MC-1 receptor expression can be studied in various skin diseases.

PMID- 10597135
TI  - Analysis of the desmoplakin gene reveals striking conservation with other members
      of the plakin family of cytolinkers.
AB  - Members of the plakin family of cytolinker proteins integrate filaments into
      cellular networks and anchor these networks to the plasma membrane. Their
      importance is supported by the existence of cell and tissue fragility disorders
      caused by mutations in certain family members. In this study, the human gene
      encoding desmoplakin (DSP) was characterized and its structure compared with the
      related family members: plectin, bullous pemphigoid antigen 1 (BPAG1), envoplakin
      (EVPL) and periplakin (PPL). Sequence analysis of genomic clones was carried out
      in combination with a PCR-based strategy to define intron-exon borders. DSP was
      mapped using the GB4 radiation hybrid mapping panel to the interval between
      markers D6S296 and AFM043 x f2, corresponding to cytogenetic band 6p24. In
      addition, the murine gene (Dsp) was mapped to mouse chromosome 13 by
      interspecific backcross mapping. DSP encompasses approximately 45 kb organized
      into 24 exons and 23 introns, and the pattern of intron-exon borders bears a
      striking resemblance to other members of the plakin family. Notable features
      include the fact that a single large exon encodes the entire C-terminus of each
      gene. In contrast, the N-termini comprise numerous smaller exons with
      conservation of many intron-exon borders. Detailed characterization and mapping
      of these genes will facilitate their further evaluation as targets of genetic
      disorders and provide insights into the evolutionary relationships among
      molecules in this emerging gene family.

PMID- 10597136
TI  - Skin roughness and wrinkle formation induced by repeated application of squalene
      monohydroperoxide to the hairless mouse.
AB  - The present study examines the cumulative effects of sub-erythema application of
      squalene-monohydroperoxide (Sq-OOH), the initial products of UV-peroxidated
      squalene, to the skin of hairless mice. Sq-OOH was isolated by the methanol
      extraction and preparative HPLC method. Repeated topical application of 10 mM Sq
      OOH to hairless mice for 3 weeks induced definite skin roughness and crinkle
      formation. 3-D surface parameter analysis revealed changes in all roughness
      parameters (number of furrows and crests, distance between a furrow and next
      crest, and irregularity) of the group treated with more than 3 mM Sq-OOH compared
      to the control group. These skin surface changes were not induced by squalene,
      squalene-monohydroxide (Sq-OH) or organic hydroperoxides such as tert-butyl
      hydroperoxide and cumene-hydroperoxide at 10 mM. Similarly, such changes were not
      induced by primary irritants, such as sodium lauryl sulfate and n-tetradecane
      under the same experimental conditions. Skin conductance decreased, following
      application of 10 mM Sq-OOH. Histological observation revealed that application
      of 10 mM Sq-OOH induced slight hyperkeratosis, moderate epidermal thickening and
      slight hyperplasia of sebaceous glands.

PMID- 10597137
TI  - Hepatitis C virus (HCV) in cryoglobulinaemic leukocytoclastic vasculitis (LCV):
      could the presence of HCV in skin lesions be related to T CD8+ lymphocytes, HLA
      DR and ICAM-1 expression?
AB  - An association between mixed cryoglobulinaemia (MC) and hepatotropic viruses,
      chiefly hepatitis C virus (HCV), has been widely reported. The presence of HCV
      genomic sequences or HCV-related viral proteins in the serum, purified
      cryoglobulins, peripheral blood mononuclear cells and into several tissues has
      suggested an important triggering role for HCV in MC patients. However, only few
      reports investigated the presence of HCV in cutaneous vasculitis and its
      potential pathogenetic role. Biopsies of cutaneous purpuric lesions from 5 MC
      female patients (aged from 40 to 80 years) were carried out for virological and
      histopathological evaluation. A leukocytoclastic vasculitis pattern was found in
      4/5 subjects, while the presence of HCV RNA was detected in 3/5. In only 3 cases
      biopsy specimens were sufficient for immunohistochemical and direct
      immunofluorescence (DIF) studies. Immunohistochemical evaluation was performed by
      means of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP)
      immune-complexes. In the same skin specimen APAAP and DIF findings were compared
      with the presence/absence of HCV genomic sequences (PCR technique). In 1 MC
      patient, the detection of HCV-RNA was associated to a prevalent CD8+ T suppressor
      pattern with a perivascular and subjunctional distribution as well as an intense
      expression of second class (HLA-DR) and intercellular adhesion (ICAM-1) molecules
      on basal keratinocytes, endothelial cells and perivascular infiltrate. These
      findings suggest a marked inflammatory activation that spreads from endothelial
      cells to keratinocytes and Langerhans cells. In the 2 HCV-RNA negative specimens
      the scanty immunopathological staining could indicate a residual activity due to
      the previous inflammatory event triggered by cryoglobulins. The deposition of
      circulating HCV-containing immune complexes (CIC) in the skin could be the
      initial pathogenic event for cryoglobulinemic vasculitis; subsequently CIC could
      spread from the vascular bed to the perivascular tissue and then could be very
      rapidly eliminated. If confirmed in larger patients' series these findings could
      definitely demonstrate a direct role of HCV in the pathogenesis of
      cryoglobulinemic vasculitis.

PMID- 10597138
TI  - Maturation of epidermal Langerhans cells: increased expression of beta- and gamma
      actin isoforms as a basis of specialized cell functions.
AB  - Epidermal Langerhans cells (LC) represent immature dendritic cells. During in
      vitro culture in the presence of keratinocytes they mature into potent
      immunostimulatory cells for naive T cells. This process is thought to simulate in
      vivo maturation of LC following activation by antigen contact. Maturation of LC
      is accompanied by morphological alterations. Applying a differential screening
      procedure we isolated differentially expressed cDNAs involved in the maturation
      events including cDNAs of the cytoskeletal actin isoforms beta- and gamma-actin.
      Stronger signals with hybridization probes derived from cultured LC compared with
      probes derived from freshly isolated LC indicate upregulation of actin
      expression. Upregulated expression of actin was confirmed by RT-PCR, Western blot
      and immunofluorescence analysis. Staining with fluorescence-labelled phalloidin
      that selectively binds to polymerized F-actin, indicates an increase in F-actin
      levels in cultured LC. Thus our data show that maturation of LC, which involves
      formation of dendritic structures and movement of formerly immobile cells, is
      accompanied by augmented expression of actin and formation of additional actin
      filaments. Furthermore, actin mRNA, often used as reference to assess mRNA
      amounts for Northern blotting or competitive RT-PCR because of its high and
      ubiquitous expression, is an inappropriate standard for the analysis of LC and
      DC.

PMID- 10597139
TI  - Tumor necrosis factor-alpha impairs contact hypersensitivity induction after
      ultraviolet B radiation via TNF-receptor 2 (p75).
AB  - Acute, low dose ultraviolet B radiation (UVR) impairs induction of contact
      hypersensitivity (CH) in genetically susceptible mice. Polymorphic alleles at the
      TNF-alpha locus dictate the susceptibility phenotype, and neutralizing anti-TNF
      alpha antibodies restore CH induction in mice exposed to UVR. This circumstantial
      evidence strongly implicates TNF-alpha in the pathogenesis of failed CH induction
      after UVR. Using mice genetically deficient in TNF-receptor 1 (p55) or TNF
      receptor 2 (p75), we now report that the capacity of TNF-alpha to impair CH
      induction after UVR required signaling via TNF-receptor 2, rather than TNF
      receptor 1. Moreover, acting via the same receptor, TNF-alpha altered the density
      and morphology of class II MHC-bearing epidermal Langerhans cells. However, UVR
      retained its capacity to induce tolerance in both TNF-receptor 1 and TNF-receptor
      2 deficient mice, indicating that TNF-alpha plays no role in the systemic immune
      deficit created by UVR.

PMID- 10597140
TI  - Epidermolytic hyperkeratosis with polycyclic psoriasiform plaques resulting from
      a mutation in the keratin 1 gene.
AB  - Epidermolytic hyperkeratosis (EHK) is a genodermatosis caused by mutations in
      either the keratin 1 (K1) or keratin 10 (K10) genes, and characterized by
      erythroderma and blistering at birth, with development of a ribbed, ichthyotic
      hyperkeratosis and palmoplantar keratoderma. A wide variety of mutations within
      the highly conserved helix termination motifs of the central rod domains of the
      K1 or K10 genes correlate with the highly variable phenotypic severity observed
      in EHK. We report a unique EHK-like phenotype exhibiting autosomal dominant
      inheritance with variable expressivity in four affected individuals in a single
      family. Clinically, affected individuals manifest transient blistering at birth
      followed by chronic diffuse palmoplantar keratoderma without transgradiens.
      Intermittent flares of non-migratory polycylic erythematous psoriasiform plaques
      which worsen and abate in severity were present in all affected individuals, but
      showed immense individual variation in both severity and duration, ranging from
      weeks to months. Histopathologic examination of the psoriasiform plaques
      demonstrated the characteristic features of EHK. Sequencing of the K1 gene in
      affected family members revealed a heterozygous A-to-T transversion at nucleotide
      1435 within exon 7, converting isoleucine (ATT) to phenylalanine (TTT), (I479F).
      The mutation resides within the highly conserved helix termination motif of the
      helix 2B segment of the K1 gene. This unique clinical phenotype and the
      associated K1 mutation have not been previously described, and it is referred to
      here as EHK with polycyclic, psoriasiform plaques (EHK/PPP).

PMID- 10597141
TI  - Integrating cranial osteopathy with gnathologic orthopedics.

PMID- 10597142
TI  - Osseous reconstruction using iliac crest graft for a mandibular defect secondary
      to gunshot injury.

PMID- 10597143
TI  - Oligodontia in the permanent dentition.

PMID- 10597144
TI  - Hereditary enamel hypoplasia.

PMID- 10597145
TI  - Surgical management of a displaced mandibular symphyseal fracture in a partially
      dentulous patient.

PMID- 10597146
TI  - Management of a gunshot wound to the face resulting in a mandibular body fracture
      with burying of a bicuspid crown into the tongue.
AB  - Gunshot wounds to the maxillofacial region are unpredictable and run the gamut
      from minor injuries to severe mutilating and life threatening injuries. This
      patient although unfortunate to have been the victim of mistaken identify
      resulting in the gunshot wound, was fortunate that the bullet hit his bicuspid,
      which probably served to deflect its path away from vital structures, thus saving
      his life. This accounts for the buried bicuspid crown found in the midline of the
      body of the tongue. Rigid internal fixation of maxillofacial fractures minimizes
      risks to the airway that may occur if patients are in post-operative maxillo
      mandibular fixation during the post-anesthetic recovery phase. In addition, the
      use of rigid internal fixation speeds up the recovery and the patient's ability
      to return to function after surgery. Above, we presented an interesting case of a
      mandibular anterior body fracture resulting from a gunshot wound in the face and
      resulting in the burying of a bicuspid crown in the substance of the tongue,
      treated under general nasoendotracheal anesthesia and the use of rigid internal
      fixation (EDCP).

PMID- 10597147
TI  - Fan blade injury of the face.

PMID- 10597148
TI  - A preliminary clinical study on the oral lesions among the Dumagats.
AB  - The objectives of the preliminary study is to gather baseline data on oral
      lesions among Dumagat samples living in the vicinity of Angat Dam, San Jose Del
      Monte, Bulacan. Scores for CPITN (Community Periodontal Index for Treatment
      Needs), Loss of Attachment, DMFT (Decayed, Missing and Filled Teeth) and clinical
      oral lesions were determined from 41 Dumagat samples. Results of the study showed
      61% had oral lesions of some type (37.8% females and 62.5% males). Lesions
      clinically detected were; betal nut chewer's mucosa (44%), leukoedema (6%),
      melanin pigmentation (8%), geographic tongue (16%), Fordyce's spots (8%),
      leukoplakia (6%) and Fibroepithelial papilloma (8%).

PMID- 10597149
TI  - A study on how military dependents at Philippine Navy Officers Wives Association
      (PNOWA) Child Learning Center brush their teeth.

PMID- 10597151
TI  - Ten steps to excellent scheduling.

PMID- 10597150
TI  - Postoperative dental bleaching: effect of microleakage on Class V tooth colored
      restorative materials.
AB  - The effect of 3 percent, 11 percent, and 16 percent carbamide peroxide bleaching
      solutions and 35 percent hydrogen peroxide bleaching gel on microleakage of Class
      V composite resins, resin modified glass ionomer cements, and compomer
      restorative materials together with corresponding (if indicated) fourth/fifth
      generation bonding agents was evaluated using previously extracted human teeth.
      Five groups of Class V cavity preparations were placed in enamel of the facial
      surfaces of 200 teeth. Groups A through D included 40 restorations each (4
      different restorative materials and their accompanying bonding agent multiplied
      by 10 teeth) treated with 3 percent, 11 percent, and 16 percent carbamide
      peroxide bleach and 35 percent hydrogen peroxide bleach. Group E included 40
      restorations without treatment of bleach and stood as the control. The
      restorative materials included were: Fuji II LC resin modified glass ionomer
      cement, Helioprogress composite resin/-Heliobond adhesive system, Aelitefil
      composite resin/Allbond 2 adhesive and Dyract compomer material/Prime & Bond
      adhesive system. Bleaching agents included were Rembrandt 3 percent peroxide gel,
      Perfecta 16 percent carbamide peroxide gel, White & Brite 11 percent carbamide
      peroxide solution and Superoxyl 35 percent hydrogen peroxide gel. All teeth were
      thermally stressed for 100 cycles and microleakage were assessed by dye
      penetration. The results were tabulated using Analysis of Variance (ANOVA)
      testing procedures. The Aelitefil composite resin material behaved the least
      favorably (relative to microleakage) compared to the other materials when exposed
      to various concentrations of dental bleaching agents.

PMID- 10597152
TI  - Implant surface alterations from a nonmetallic ultrasonic tip.
AB  - This study evaluates surface alterations produced on various implant surfaces by
      an ultrasonic scaler fitted with a nonmetallic tip. Commercially pure titanium
      and titanium alloy abutments, plasma-coated implants, and hydroxyapatite-coated
      implants were contacted with the nonmetallic tip for 10 seconds and then
      evaluated for surface changes by SEM examination. The commercially pure titanium
      and titanium alloy surfaces showed negligible alterations from the control, thus
      indicating possible clinical use as a maintenance device. More severe changes
      were evidenced with the plasma- and hydroxyapatite-coated surfaces.

PMID- 10597153
TI  - Treatment of traumatic dental displacement in dogs: six cases of lateral
      luxation.
AB  - In dogs and cats, the most common causes of dental injury are fights with other
      animals, car accidents, falls from a height, and chewing on hard materials such
      as bones or rocks. The trauma more often causes fracture of the teeth, but
      sometimes avulsion or luxation can occur. Avulsion is the complete displacement
      of the tooth out of the alveolar socket and luxation is the partial displacement
      of the tooth. Tooth luxation and avulsion represent dental emergencies. Time is
      an important factor for successful treatment; the prognosis becomes poorer the
      longer the tooth is out of the socket. This paper describes the guidelines for
      treatment of dental displacement in cats and dogs and presents six cases of
      dental lateral luxation in dogs seen at the Veterinary Hospital of the University
      of Pennsylvania (VHUP) in the period from May 1996 to September 1997.

PMID- 10597154
TI  - Radiographic study of the maxillary canine tooth in mesaticephalic dogs.
AB  - Radiology is the most important diagnostic technique for evaluation of the
      radicular structure of the tooth and adjacent areas. However, superimposition of
      other oral or nasal structures often creates difficulties when interpreting
      radiographic images. The purpose of this study was to identify and locate any
      anatomical structures that may be superimposed over the root of the maxillary
      canine tooth in radiographs of dogs. Results showed that the nasal conchae
      minimally interfere with the visualization of the tooth. The vomer bone and
      maxillary structures (the conchal crest, the line of conjunction between the
      maxillary body and the palatine process, and the palatine sulcus) are visible as
      linear radiopacities, and were found to be responsible for most of the
      radiographic features in this area. The incisivomaxillary canal and the palatine
      fissure caused radiolucent images. The incisivomaxillary suture and the
      nasoincisive suture may appear as radiolucent images in young skulls and linear
      radiopacities in older skulls. It appears from this study that a compromise
      between minimal superimposition of dental and non-dental structures and small
      image distortion is needed to obtain diagnostic radiographic views of the
      maxillary canine tooth in mesaticephalic dogs. The relative positions of the
      conchal crest, the line of conjunction between the vertical body of the maxilla
      and its palatine process, the incisivomaxillary canal, and the tooth, cannot be
      changed radiographically because of the close anatomic position of these
      structures.

PMID- 10597155
TI  - Dental caries in the dog.
AB  - The dental records of 435 dogs seen in a dental referral practice were reviewed.
      Twenty-three dogs (5.3%) had one or more caries lesions. Of the 47 caries
      lesions, 19 (40%) were pit and fissure caries, 17 (36%) were smooth surface
      caries, and 11 (23%) were root caries. Twelve dogs had symmetrical lesions. The
      teeth most commonly involved were the fourth premolar and first and second molar
      teeth. Twenty affected teeth were extracted and 17 were treated by cavity
      preparation and restoration with composite or glass ionomer materials. Ten
      restorations in four dogs were examined one year or more following treatment; all
      of the restorations were intact and there was no progression of the caries.

PMID- 10597156
TI  - Alveolar osteitis (dry socket) in a dog: a case report.
AB  - Following extraction of a maxillary left first molar tooth in an eight year-old
      retriever, the dog re-presented five days later because of oral pain, which did
      not respond to analgesic therapy. The extraction site contained a foul-smelling
      fluid, but did not contain a clot or granulation tissue. Alveolar osteitis (dry
      socket) was diagnosed. The alveolus was curetted and flushed, and the dog was
      given cefalexine and prednisolone. The alveolus was filling with healthy
      granulation tissue one week later and the dog was no longer in pain.

PMID- 10597157
TI  - A review of the expanding field of exotic animal oral health care--veterinary
      dentistry.
AB  - This article reviews the clinical literature of the field of Veterinary Dentistry
      from its conception in the late 1960's to its rapidly expanding role today as an
      emerging clinical specialty practice in veterinary medicine. It defines eight
      dental sub-disciplines in contemporary veterinary oral health care from a
      practical point of view and provides information concerning standardization of
      key words searches, definition of terms, and use of the expanded Medical Subject
      Headings (MeSH) necessary for a comprehensive review of the rapidly expanding
      literature stored in electronic databases.

PMID- 10597158
TI  - Effect on canine oral health of adding chlorhexidine to a dental hygiene chew.
AB  - A study to compare the effect of a dental hygiene chew with or without 0.2%
      chlorhexidine on the development of gingivitis and the accumulation of dental
      deposits was performed using 11 small dogs. Confirming previous data, the daily
      addition of a standard chew to a dry diet resulted in significantly less
      gingivitis and calculus after 3 weeks compared with feeding the dry diet alone.
      Addition of chlorhexidine to the chew made no difference to the degree of
      gingivitis or the amount of calculus that accumulated, but did result in
      significantly less plaque accumulation after 3 weeks. The abrasiveness of the
      chew, rather than the antibacterial activity of chlorhexidine, is likely to have
      contributed the most to the maintenance of oral health in dogs with mild
      gingivitis.

PMID- 10597159
TI  - Benefits of a 'dental hygiene chew' on the periodontal health of cats.
AB  - A study was undertaken to determine the clinical efficacy of a chew designed to
      improve dental hygiene in the cat. The accumulation of dental deposits (plaque
      and calculus) and the effect on gingival inflammation were assessed in 15 client
      owned cats while on two different regimens. In the first leg of the study, the
      cats were fed a nutritionally complete dry diet supplemented with one dental
      hygiene chew. In the second leg of the study, the same cats were fed only the
      nutritionally complete diet. This study demonstrated that the daily addition of
      the chew to the dry diet resulted in significantly less plaque and calculus
      accumulation on tooth surfaces. It was our experience that daily feeding of the
      chew helped maintain dental hygiene in cats; however, regular professional
      therapy is still indicated.

PMID- 10597160
TI  - Root abscess in an aardvark (Orycteropus afer).

PMID- 10597161
TI  - Clinical pathology case conference. Granular cell tumor.

PMID- 10597162
TI  - A case of supernumerary teeth in the premaxilla, maxillary cuspid, and mandibular
      premolar regions.
AB  - A case of several developing supernumerary teeth is reported. A seven-year-old
      African-American boy presented with retained primary maxillary central incisors,
      two impacted mesiodens, and unerupted permanent maxillary central incisors. A
      dentigerous cyst was removed at the time of surgical removal of the mesiodens.
      Approximately fourteen months post-extraction, a new panoramic radiograph showed
      the presence of six previously unidentified developing and unerupted
      supernumerary teeth, one on each of the maxillary cuspid areas and two on the
      mandibular premolar regions bilaterally. Practitioners should be aware that
      supernumerary teeth may develop late. Thus, periodic reevaluation with
      appropriate radiographs is indicated, especially in patients who have presented
      with supernumerary teeth.

PMID- 10597163
TI  - Endodontic emergency procedures for injured permanent teeth.

PMID- 10597164
TI  - The changing periodontal paradigm.

PMID- 10597165
TI  - Sub-epithelial connective tissue grafts for esthetic ridge augmentation: a case
      report.

PMID- 10597166
TI  - Why do I need a root canal?
AB  - Bacteria invading the pulp cause pulpal necrosis and the need for endodontic
      treatment. If bacteria are present after treatment, the root canal may fail. For
      the root canal to be successful in necrotic cases or retreating failing cases,
      the bacteria in the root canal walls must be removed and the canal sterilized
      with calcium hydroxide.

PMID- 10597167
TI  - Comparing the outcome of necrotic cases using two different treatment methods.
AB  - This study compared the six to nine month follow-up results of endodontic
      treatment completed on necrotic cases in either two appointments using calcium
      hydroxide as an intercanal medicament or one appointment using no intercanal
      medicaments. The root canals of 43 necrotic single-rooted teeth with the presence
      of periapical bone loss were thoroughly instrumented and irrigated with sodium
      hypochloride solution. Twenty-three teeth were treated with calcium hydroxide for
      10-21 days, then obturated. Twenty teeth were treated in one appointment. Then
      each case was seen one year later for a recall appointment. The post-op x-ray was
      compared to the recall x-ray. A case was considered a success if either no apical
      lesion was present or the lesion had reduced in size and no symptoms were
      present. A case was considered a failure if the size of the apical lesion had
      remained the same or increased or if symptoms were present. All 23 of the
      necrotic teeth treated with calcium hydroxide were successful. Twelve of the 20
      necrotic teeth treated in one appointment were successful. This study shows a
      connection with using calcium hydroxide in necrotic cases and a more reliably
      achievement for success.

PMID- 10597168
TI  - Goals and strategies for improving dental care in the nursing home: Part One.

PMID- 10597169
TI  - The integration of TQM at Park Dental

PMID- 10597170
TI  - Chemoprevention of oral cancer: the need for effective biological monitoring.
AB  - A major limiting factor in the successful implementation of chemoprevention for
      oral cancer has been the lack of suitable endpoints to measure efficacy and
      success of clinical trials. To depend on the measure of the ultimate goal of such
      trials, namely cancer incidence as an endpoint has serious feasibility problems
      including a need for large numbers of participants, long periods of follow up and
      high costs. The application of selected biological markers as intermediate
      endpoints to reveal responses to chemopreventive regimens within a limited time
      frame is therefore an attractive concept. By serving as surrogates for cancer
      they could become valuable tools for monitoring patient compliance, defining the
      process of carcinogenesis and evaluating effects of the chemopreventive agents on
      tumour progression. This paper examines various biological markers of oral
      carcinogenesis and their relevance to chemoprevention trials. If validated, these
      biological markers could take oral cancer chemoprevention to new frontiers and
      help fulfil the ultimate goal of disease prevention through intervention.

PMID- 10597171
TI  - Head positioning and projection errors in submentovertex radiographic analysis.
AB  - This study examined the changes seen on the submentovertex radiograph when the
      head is not extended sufficiently. A human dry skull supported on a cephalostat
      was used to simulate head extension. The range of rotation tested was an under
      rotation of the skull of 30 degrees to an over-rotation of 10 degrees in
      intervals of 5 degrees. The measured variables were the intercondylar axis
      angles, corpus lengths and condylar widths. The relationships between skull
      rotation and changes in these variables were determined. Three selected
      landmarks, the spinosa points (right and left) and the pogonion point of each
      radiograph were located and compared spatially with the same points on the ideal
      radiograph. The results showed that variation in skull rotation affects both
      linear and angular measurements significantly (P < 0.01). Landmarks further away
      from the axis of rotation are affected by distortion more than those nearer to
      it.

PMID- 10597172
TI  - Hazard: denture clasps embedded in oral tissues--case reports.
AB  - Three patients presented with their dentures stuck in their mouths due to a
      retainer clasp becoming embedded in either the anterior fauces or the soft
      palate. All three dentures were extricated successfully and the resulting
      puncture wounds were left to heal spontaneously with only antibiotics and
      analgesics. In all three cases, a sharp pointed molar clasp tip was found to be a
      common factor. The management and prevention of such cases are presented.

PMID- 10597173
TI  - Endodontic interappointment emergencies in a Singapore private practice setting:
      a retrospective study of incidence and cause-related factors.
AB  - One thousand and sixteen consecutive records of patients treated by the author
      for endodontic treatment was surveyed for the incidence of endodontic
      interappointment emergencies (EIE) and the major factors contributing to it. The
      overall incidence of EIE was 3.15% and unrelated to the patients' sex or tooth
      location. Caucasians were more likely to experience flare-ups than Chinese (p <
      0.01). Patients < 20 years and > 60 years were less likely to experience EIE (p <
      0.05). EIE was significantly higher in necrotic teeth than in vital teeth (p <
      0.01). A clinical diagnosis of necrotic pulp with acute apical abcess (NP/AAA)
      increased the incidence of flare-ups significantly (p < 0.05). Retreatment cases
      also had a higher incidence of EIE and this was statistically significant (p <
      0.01). The possibility of EIE was the highest after the first visit (p < 0.01)
      and this was reduced significantly with subsequent visits.

PMID- 10597174
TI  - Die relief, seating methods and fit of full crowns.
AB  - This study investigated the influence of different frequencies of vibration
      supplied by an electropneumatic condenser on the seating rate and vertical
      discrepancy of full crowns with four different internal configurations: A)
      unrelieved; B) four layers of die spacer; C) eight layers of die spacer and D)
      unrelieved but vented occlusally. Crowns were luted with zinc phosphate cement
      under a static 5 Kg load alone and with three frequencies of vibration. The
      seating process was monitored electronically to determine seating rate and final
      fit. Venting and die relief enhanced seating under static load. Vibration
      increased the seating rate and reduced vertical discrepancy of groups B to D
      crowns compared to group A crowns. Medium frequency vibration with group C and D
      crowns gave the smallest vertical discrepancies. Vibration did not improve the
      final seating of group A crowns. This suggests that vibration is only effective
      when an escapeway of some kind is provided.

PMID- 10597175
TI  - Oral health of Singapore adults.
AB  - In a study conducted by the Dental Division of the Ministry of Health in 1992,
      3157 Singapore adults aged 20 to 65 years and over were interviewed on their
      knowledge, attitude and practice of dental care and given an examination. About
      66% indicated they required dental treatment. Utilisation of dental services was
      low with 39% visiting the dentist at least once in 2 years. About 72% brushed
      their teeth morning and night. The dental examination showed that 79.2% had
      calculus, 92% needed prophylaxis and oral hygiene instruction and only 0.2%
      needed complex periodontal treatment. A large proportion (96.6%) of the sample
      was dentate. The mean DMFT was 10.7 and the mean number of decayed root for the
      dentate population was 0.2. The age-group 65 years and over had the highest
      percentage (63.6%) of persons wearing dentures and the age group 50-54 years had
      the highest percentage (54.2%) requiring dentures. This study has shown that oral
      health promotion for home and professional care should be stressed to the adult
      population, particularly the older age groups.

PMID- 10597176
TI  - The prevalence of caries and enamel defects in 229 Malaysian children 16 years
      after water fluoridation (a pilot study).
AB  - Two hundred and twenty-nine children aged 12-15 years who were continuous
      residents of Penang island, in the north of Peninsular Malaysia were examined for
      caries and enamel defects. Caries prevalence was 82.2% with a DMFT score of 3.4
      and DMFS score of 4.9; there were very few missing teeth and very little
      untreated caries in the population examined. Majority of DF (decayed/filled)
      lesions were pits and fissures with approximal and smooth surfaces relatively
      caries free. The prevalence of enamel defects was 76.4% with 19.1% of all teeth
      examined being affected. More posterior than anterior teeth were affected by
      enamel defects just as there were more maxillary than mandibular teeth affected
      by enamel defects. Diffuse patchy opacities were the most common defect diagnosed
      and this was found in 60.2% of the population examined. A bilateral distribution
      of diffuse patchy opacities was seen in 41.5% of the population examined. Tooth
      surfaces with enamel defects were no more susceptible to caries than defect-free
      surfaces.

PMID- 10597177
TI  - Unilateral comminuted and complicated fracture of the mandible due to dog attack.
AB  - Fractures of the mandible and their management are discussed in detail in
      textbooks and articles dealing with facial trauma. This paper presents the
      management and treatment of a case of a unilateral comminuted and complicated
      fracture of the mandible due to dog attack on a geriatric patient. The attack
      also severed the patient's right arm. Due to the severity of the trauma, an
      emergency surgery was performed on the mandible and arm.

PMID- 10597178
TI  - Adenomatoid odontogenic tumour: a case study with radiographic differential
      diagnostic considerations.
AB  - Adenomatoid odontogenic tumours (AOT) are benign, hamartomatous odontogenic
      lesions that not uncommonly mimic a dentigerous cyst radiographically. Such a
      case as found involving an unerupted left maxillary canine in a 19-year-old
      Chinese female is described. The differential diagnosis of some common
      odontogenic cysts and neoplasms occurring in Malaysians, that may present in a
      dentigerous relationship to an unerupted tooth is discussed. A brief review of
      the radiographic literature on AOT is also included.

PMID- 10597179
TI  - The glass ionomer-dentine bond. A comparison of destructive and non-destructive
      assessment.
AB  - The traditional laboratory testing (mechanical testing and microleakage testing)
      of the adhesion of restorative materials to dentine is of a destructive nature. A
      non-destructive laboratory method of testing the material-dentine bond using
      ultrasonics has been devised and compared to mechanical shear testing. Similar
      results were obtained with both testing methods. It this study thermocycling was
      shown to have no statistically significant effect on the glass-ionomer dentine
      bond.

PMID- 10597180
TI  - The use of removable partial dentures amongst private dental practitioners in
      Singapore.
AB  - A questionnaire survey was carried out in 1995 amongst university trained general
      dental practitioners in the city state of Singapore to assess the use of
      removable partial dentures (RPD). 37% of the original sample of 469 completed and
      returned the questionnaire. The results of this survey indicate that RPDs are a
      common treatment modality in Singapore. Acrylic partial dentures appear to be the
      preferred choice for RPD treatment. The work profile of those who had a
      postgraduate qualification in removable prosthodontics did not differ from that
      of the general dental practitioner.

PMID- 10597181
TI  - Incidence of pain after biomechanical preparation: a review of 302 cases treated
      by dental students.
AB  - Records of 302 root-filled teeth treated by dental undergraduates were reviewed
      by four lecturers in the Department of Conservative Dentistry, University of
      Malaya. Preoperative and operative factors were evaluated for their association
      with postoperative pain experience of patients during the visit immediately after
      completion of biomechanical preparation. Eighty four percent of patients did not
      experience any pain after biomechanical preparation whilst the remaining 16
      percent only complained of slight or moderate pain. The incidence of pain after
      biomechanical preparation is not high even when performed by inexperienced
      undergraduates. Teeth with a pre-existing painful condition had a higher chances
      of postoperative of pain. The incidence of postoperative pain was halved when
      teeth were associated with a sinus tract.

PMID- 10597182
TI  - Immunology of oral cancer--a review.
AB  - Cancer of the oral cavity forms the major cancer in India constituting about 20%
      of all cancers. In spite of the advances made in diagnostic and therapeutic
      modalities, the morbidity and mortality due to this disease remains high. The
      overall five year survival rate is only 34%. The reason for this is mainly lack
      of markers for early detection, prognosis and identification of the high risk
      group. Immune depression is recognised as a consistent metabolic defect in oral
      cancer patients and our study shows that this precedes the development of the
      malignancy. The cancer probably enhances the depression. Monitoring of the
      immunoregulatory status has shown to correlate well with the prognosis of the
      patient in our study. Hence the monitoring of the various immune parameters would
      probably be a reliable marker to identify a high risk group in precancerous
      lesions, a prognostic indicator in oral cancer patients and an intermediate
      marker in intervention studies.

PMID- 10597183
TI  - Parental occupation and other factors and cancer risk in children: I. Study
      methodology and non-occupational factors.
AB  - A population-based case-control study of risk factors for childhood cancer was
      conducted for 593 cases diagnosed over the period 1986-1988 in Moscow children 0
      to 14 years of age. Two healthy controls to every case were selected from
      registers of local pediatric polyclinics by age, gender and residence. The
      parents of 593 cases and 1181 controls were interviewed face-to-face.
      Significantly higher odds ratios (OR) were associated with cancer in close
      relatives [OR 1.6; 95% confidence interval (CI) 1.3-1.9], any pathology
      associated with pregnancy (OR 2.9; 95% CI 2.4-3.6), including threatened
      miscarriage (OR 2.1; 95% CI 1.5-3.0), toxemia (OR 2.2; 95% CI 1.8-2.8) and
      hormone treatment during pregnancy (OR 2.2; 95% CI 1.0-4.5). Pre-term births were
      significantly associated with brain-cancer risk (6/1; OR 13.3; 95% CI 1.5-301.2).
      For low birth weight (< or = 2500 g) children born from full-term pregnancy, the
      OR for all cancers combined was 2.5 (23/22; 95% CI 1.4-4.7) and for leukemias 4.7
      (9/4; 95% CI 1.4-16.5). In all, 100 cases and 151 controls had birth weight > or
      = 4000 g (OR 1.4; 95% CI 1.1-1.9). Risk of nephroblastoma was also significantly
      related to this factor (11/5; OR 5.1; 95% CI 1.6-16.4). A positive trend of OR
      with decreasing duration of breastfeeding was significant for all cancer combined
      (p < 0.05). Significantly higher OR were observed for dermatitis (12/6; OR 4.0;
      95% CI 1.4-12.1) and viral hepatitis (40/22; OR 3.8; 95% CI 2.3-6.3) in child
      medical history.

PMID- 10597184
TI  - Parental occupation and other factors and cancer risk in children: II.
      Occupational factors.
AB  - A population-based case-control study was conducted on 593 cancer cases in
      children from 0 to 14 years of age diagnosed in Moscow from 1986 to 1988. The
      study included 1181 healthy controls matched by age, gender and residence.
      Parental exposures prior to conception, including exposures to petroleum
      products, organic solvents, unspecified chemicals, soldering aerosols, ionizing
      radiation, electromagnetic fields (EMF), visual display units (VDU) and high
      temperature in the work environment, were significantly more frequent among the
      cases than among the controls (p < 0.05). Leukemia risk was associated with
      paternal exposure to ionizing radiation [odds ratio (OR) 6.7; 95% confidence
      interval (CI) 2.8-15.8], EMF (OR 4.6; 95% CI 1.8-11.9), VDU (OR 2.4; 95% CI 1.0
      5.8) and unspecified chemicals (OR 2.0; 95% CI 1.02-4.1). Leukemia risk was also
      higher when mothers were exposed to solvents (OR 3.1; 95% CI 1.5-6.3),
      unspecified chemicals (OR 2.0; 95% CI 1.0-4.3), ionizing radiation (OR 10.3; 95%
      CI 1.3-83.4) and EMF (OR 5.2; 95% CI 1.6-16.8). Increased risk of non-Hodgkin's
      lymphoma was shown to be related to maternal exposure to oil products (OR 3.3;
      95% CI 1.01-10.7) and unspecified chemicals (OR 3.3; 95% CI 1.01-10.7). Exposure
      to VDU was found to be associated with increased risk of neuroblastoma (6/1; OR
      13.8; 95% CI 1.9-100.0).

PMID- 10597185
TI  - Association of A vitamin D receptor polymorphism with sporadic breast cancer
      development.
AB  - Breast cancer is the leading cause of cancer death among Australian women and its
      incidence is annually increasing. Genetic factors are involved in the complex
      etiology of breast cancer. The seco-steroid hormone, 1.25 dihydroxy vitamin D3
      can influence breast cancer cell growth in vitro. A number of studies have
      reported correlations between vitamin D receptor (VDR) gene polymorphisms and
      several diseases including prostate cancer and osteoporosis. In breast cancer,
      low vitamin D levels in serum are correlated with disease progression and bone
      metastases, a situation also noted in prostate cancer and suggesting the
      involvement of the VDR. In our study, 2 restriction fragment length polymorphisms
      (RFLP) in the 3' region (detected by Apa1 and Taq1) and an initiation codon
      variant in the 5' end of the VDR gene (detected by Fok1) were tested for
      association with breast cancer risk in 135 females with sporadic breast cancer
      and 110 cancer-free female controls. Allele frequencies of the 3' Apa1
      polymorphism showed a significant association (p = 0.016; OR = 1.56, 95% CI =
      1.09-2.24) while the Taq1 RFLP showed a similar trend (p = 0.053; OR = 1.45, 95%
      CI = 1.00-2.00). Allele frequencies of the Fok1 polymorphism were not
      significantly different (p = 0.97; OR = 0.99, 95% CI = 0.69-1.43) in the study
      population. Our results suggest that specific alleles of the VDR gene located
      near the 3' region may identify an increased risk for breast cancer and justify
      further investigation of the role of VDR in breast cancer.

PMID- 10597186
TI  - Assessment of glutathione-S-transferase and glutathione reductase in patients
      with squamous-cell carcinoma of buccal mucosa.
AB  - Serum and tumor cytosolic levels of glutathione-S-transferase (GST) and
      glutathione-reductase (GR) activity were determined spectrophotometrically. The
      levels were correlated with clinicopathological criteria and a tobacco-associated
      protein band (T band) found in serum. The results showed significantly decreased
      mean serum GST levels (p < 0.02) in cancer patients as compared with controls.
      However, mean serum GR levels were significantly higher in patients than in
      controls (p < 0.01). T-band-positive patients showed low GST and low GR activity
      as compared with T-band-negative patients. Tumor cytosolic-enzyme levels of GST
      and GR activity were significantly higher (p < 0.0003 and p < 0.0001,
      respectively) than in corresponding adjacent noncancerous mucosa. Tumour
      cytosolic GST and GR activity showed significant association with
      clinicopathologic criteria, e.g., stage, histologic grade and nodal involvement.
      T-band-negative patients showed significantly higher levels of GST (p < 0.0001)
      than did T-band-positive patients. Low levels of cytosolic GST may be associated
      with increased susceptibility towards carcinogen-induced damage. The results
      suggest that the presence of T band in the sera may be associated with a high
      risk phenotype due to decreased detoxification ability.

PMID- 10597187
TI  - Enhanced coexpression of YB-1 and DNA topoisomerase II alpha genes in human
      colorectal carcinomas.
AB  - The transcription factor YB-1 is expressed in a wide range of cell types and has
      been implicated in the regulation of various genes involved in cell
      proliferation. Nuclear expression of YB-1 is correlated with MDR-1 gene
      expression in breast cancer and osteosarcoma. In this study, we asked whether YB
      1 expression is enhanced in human colorectral carcinoma and if it is associated
      with the expression of target genes such as MDR-1, DNA topoisomerase II alpha and
      PCNA. YB-1, DNA topoisomerase II alpha, PCNA and MDR-1 expression were assessed
      by Western blotting, Northern blotting and immunohistochemistry in 26 human
      colorectal carcinomas. The involvement of YB-1 in DNA topoisomerase II alpha gene
      expression was examined by transient DNA transfection assays. YB-1 was
      overexpressed in almost all cancerous lesions in comparison with normal mucosa in
      surgically resected colorectal carcinomas of 26 patients. YB-1 expression
      correlated well with both DNA topoisomerase II alpha and PCNA expression. In
      contrast, no correlation was observed between YB-1 and MDR-1 expression. We also
      found that a transient co-transfection with a DNA topoisomerase II alpha promoter
      luciferase plasmid and an antisense YB-1 expression construct resulted in a
      significant reduction of the promoter activity in KM12C human colon cancer cells.
      YB-1 may be an excellent proliferation-associated marker and may be a
      transcription factor regulating DNA topoisomerase II alpha gene expression in
      human colorectal carcinoma.

PMID- 10597188
TI  - Expression of glycodelin in human breast and breast cancer.
AB  - Glycodelin is a 28 kDa glycoprotein with structural homology to beta
      lactoglobulins, particularly expressed in steroid-responsive tissues of the
      female reproductive tract. We previously found that transfection of glycodelin
      cDNA into MCF-7 breast cancer cells induces differentiation into organized acinar
      epithelium and up-regulation of epithelial markers. In this study, we used
      immunohistochemistry, Northern blotting and reverse transcription-polymerase
      chain reaction (RT-PCR) analyses to study glycodelin expression in normal and in
      malignant breast tissues. The results were compared with the expression of
      estrogen (ER) and progesterone receptors (PR) and p53 tumor suppressor protein.
      Glycodelin was found in ductal and lobular epithelium of 6/6 normal breast
      tissues, 27/29 morphologically normal breast tissues from breast cancer patients,
      6/6 benign lactating adenomas, 21/35 ductal carcinomas, 9/9 tubular carcinomas,
      9/9 mucinous carcinomas, 3/3 mixed ductal/tubular carcinomas and 7/11 lobular
      carcinomas. In the latter, of particular interest was the presence of glycodelin
      in paranucleolar vacuoles of carcinoma cells. Northern blot analysis of fresh
      frozen tissues revealed the normal full length 0.9 kb mRNA of glycodelin in
      ductal breast carcinoma. Using RT-PCR analysis, glycodelin messenger ribonucleic
      acid was found in 13/13 ductal and in 3/3 tubular tumor tissues. We also detected
      a splicing variant lacking exon 4, which includes the nucleotide sequence
      encoding the potential N-glycosylation site at Asn-85. Our results demonstrate
      the synthesis of glycodelin in normal breast and breast cancer. In addition, we
      show that the paranuclear vacuole, characteristically present in lobular breast
      cancer cells, contains abundant amounts of glycodelin.

PMID- 10597189
TI  - Genetic predisposition, environment and cancer incidence: a nationwide twin study
      in Finland, 1976-1995.
AB  - Twin studies integrate genetic and environmental (including physical environment
      and life-style) information by comparing monozygotic and dizygotic twins for the
      occurrence of disease. Our objectives were to compare cancer incidence in twins
      with national rates and to estimate both the probability that co-twins of
      affected twins may develop cancer and the importance of genetic predisposition
      and environment in cancer development. The nationwide record linkage of the
      Finnish Twin Cohort Study, the Finnish Cancer Registry and the Central Population
      Register allowed the follow-up of 12,941 same-sexed twin pairs for incident
      primary cancers from 1976 to 1995. Zygosity was determined by use of a validated
      questionnaire in 1975. Methods included calculation of standardized incidence
      ratios and concordances and fitting of structural equation models. A total of
      1,613 malignant neoplasms occurred in the cohort. The overall cancer incidence
      among twins resembled that among the general population. Monozygotic co-twins of
      affected twins were at 50% higher risk than were dizygotic co-twins. Based on
      genetic modeling, inherited genetic factors accounted for 18% (95% confidence
      interval 4-32%) of the liability in inter-individual variation in the risk of
      overall cancer, while non-genetic factors shared by twins accounted for 7% (0
      16%) and unique environmental factors for 75% (65-85%). Our results appear to
      exclude a contribution greater than one-third for genetic predisposition in the
      development of cancer in the general population, thus pointing to the earlier
      confirmed substantial role of environment.

PMID- 10597190
TI  - Transcriptional repression of the human galactocerebrosidase gene in squamous
      cell carcinomas of the larynx.
AB  - Alterations of gene expression in squamous cell carcinoma (SCC) cell lines
      derived from the larynx and keratinocytes derived from adjacent normal mucosa of
      the larynx have been studied using the mRNA differential display technique. Lane
      to-lane comparison of reverse transcribed mRNA showed a strong repression of a
      148 bp fragment in SCC cells. The fragment was reamplified and cloned. Sequencing
      revealed a 99.3% homology with a region in exon 17 of the human
      galactocerebrosidase (GALC) gene. Northern blot analysis confirmed the
      differential expression of this gene in both carcinoma cell lines and laryngeal
      SCC biopsies in contrast with corresponding normal mucosa. To provide further
      evidence for the differential expression rate, both types of cells were
      transiently transfected with a 152 bp (-176 to -24) high regulatory promoter
      element of the 5' flanking region of the GALC gene. Results of 3 independent
      transfection experiments indicated a 16-fold repression of the GALC gene
      expression in SCC cells compared with benign keratinocytes. However, neither
      mutation nor other alterations of the promoter sequence were detected. Expression
      of the GALC gene is thus greatly affected in SCCs of the larynx.

PMID- 10597191
TI  - A tyrosinase peptide presented by HLA-B35 is recognized on a human melanoma by
      autologous cytotoxic T lymphocytes.
AB  - We previously described different cytotoxic T lymphocyte (CTL) clones isolated
      from the blood lymphocytes of a melanoma patient after in vitro stimulation with
      autologous tumor cells. These CTL clones recognized at least 2 distinct antigens
      on the melanoma cells. Here, we show that one of them consists of a peptide
      derived from tyrosinase and presented by HLA-B35. The peptide is 9 amino acids
      long and has the sequence LPSSADVEF. It can be presented by the 2 major B35
      allelic subtypes, B*3501 and B*3503. As HLA-B35 is one of the most frequent HLA-B
      specificities, being present in about 20% of Caucasian individuals, it may be a
      useful target for peptide-based immunotherapy of melanoma.

PMID- 10597192
TI  - Expression of the tumor-rejection antigen SART1 in brain tumors.
AB  - We have reported a tumor-rejection antigen, SART1(259), possessing tumor epitopes
      capable of inducing cytotoxic T lymphocytes (CTLs) in epithelial-cancer patients.
      This study investigated the expression of SART1(259) antigen in brain tumors, to
      explore for a potential molecule for use in specific immunotherapy of patients
      with brain tumors. The SART1(259) antigen was detected in the cytosol fraction of
      13 of 18 (72%) glioma cell lines and in 12 of 34 (35%) brain-tumor tissues, with
      a higher rate of expression among malignant gliomas (5/10, 50%) and schwannomas
      (3/4). HLA-A24-restricted and SART1-specific CTLs recognized the HLA-A24+ and
      SART1(259)+ glioma cells, and the levels of recognition correlated both with HLA
      A24-antigen expression level and with the concentration of the SART1 peptide
      antigen. Therefore, the SART1(259) antigen could be a target molecule for
      specific immunotherapy of patients with brain tumors expressing HLA-class-1
      antigens.

PMID- 10597193
TI  - Nucleophosmin/B23 regulates the susceptibility of human leukemia HL-60 cells to
      sodium butyrate-induced apoptosis and inhibition of telomerase activity.
AB  - Stable clones of HL-60 cells in which nucleophosmin/B23 was over-expressed or
      down-regulated were established. The nucleophosmin/B23 protein levels in
      nucleophosmin/B23 over-expressed (pCR3-B23) or down-regulated (pCR3-32B) cells
      during BuONa/vanadate-induced apoptosis were characterized as compared with
      control vector-transfected (pCR3) cells. Over-expression of nucleophosmin/B23
      resulted in decreased susceptibility of the cells to BuONa/vanadate-induced
      apoptosis. The response to inhibition of telomerase activity under BuONa/vanadate
      treatment also decreased in nucleophosmin/B23 over-expressed (pCR3-B23) cells. On
      the other hand, down-regulation of nucleophosmin/B23 made the cells more
      susceptible to BuONa-induced apoptosis or inhibition of telomerase activity. More
      precisely, by serial dilutions of each extract, the telomerase activity of the
      cells without drug treatment was determined and was found to be higher in
      nucleophosmin/B23 over-expressed (pCR3-B23) cells and lower in nucleophosmin/B23
      down-regulated (pCR3-32B) cells as compared with the control vector-transfected
      (pCR3) cells. Our results indicate that nucleophosmin/B23 plays a functional role
      in the control of cellular apoptosis and immortalization.

PMID- 10597194
TI  - CD40 cross-linking enhances the immunogenicity of Burkitt's-lymphoma cell lines.
AB  - Epstein-Barr-virus (EBV)-positive Burkitt's-lymphoma (BL) cell lines are not
      recognized by EBV-specific T cells, due to their non-immunogenic phenotype and
      restricted expression of latent EBV genes. We tested whether triggering of CD40
      can alter the phenotype of the tumor cells with regard to: (i) expression of
      surface markers, (ii) expression of viral antigens, (iii) presentation of
      endogenous antigens to MHC-class-1 restricted cytotoxic T lymphocytes (CTLs),
      (iv) stimulatory capacity in allogeneic mixed-lymphocyte cultures (MLCs), (v)
      sensitivity to natural-killer (NK)-cell-mediated lysis. Co-culture of EBV
      positive BL cells with CD40-ligand-transfected L cells induced up-regulation of
      CD54 and CD80 but did not affect the expression of viral genes. In spite of
      significant up-regulation of TAP1 and TAP2, and increased expression of MHC class
      1, the BL cells remained unable to present endogenously expressed viral antigens
      to EBV-specific CTL. However, the up-regulation of adhesion and co-stimulatory
      molecules was associated with increased stimulatory capacity in MLC and enhanced
      sensitivity to NK cells. These findings indicate that, while inducing only a
      modest phenotype shift, cross-linking of CD40 under physiologic conditions may
      selectively enhance the sensitivity of BL cells to anti-tumor immune responses.

PMID- 10597195
TI  - Constitutive expression of G-CSF and GM-CSF in human skin carcinoma cells with
      functional consequence for tumor progression.
AB  - Tumor progression is characterized by an increasing escape of tumor cells from
      the growth control of their microenvironment, often caused by aberrant expression
      of growth factors. In the human skin carcinoma model system, based on the HaCaT
      keratinocyte line, tumor progression to high-grade malignant cells is associated
      with constitutive expression and secretion of the hematopoietic growth factors G
      CSF and GM-CSF in vitro and in vivo. All HaCaT keratinocyte variants express the
      G-CSF and the GM-CSF receptors at levels comparable to normal keratinocytes.
      Consequently, they exhibit a stimulation of cell proliferation and migration in
      culture when treated with these factors. Moreover, both proliferation and
      migration of the high-grade malignant cells were strongly inhibited by
      neutralizing antibodies to G-CSF and GM-CSF, respectively. This demonstrates the
      functional role of these factors in high-grade malignant HaCaT cells through an
      autocrine mechanism in vitro and implies their significance in tumor progression
      in vivo. In light of the increasing use of G-CSF and GM-CSF in adjuvant tumor
      therapy, our data, as well as those discussed for head-and-neck tumors and
      gliomas, warrant a careful re-evaluation of the clinical application of both
      factors.

PMID- 10597196
TI  - p21Waf1/Cip1 acts in synergy with bcl-2 to confer multidrug resistance in a
      camptothecin-selected human lung-cancer cell line.
AB  - The realization that chemotherapeutic agents induce apoptosis raises the concern
      that tumors resistant to chemotherapy are unable to initiate the apoptotic
      program. In the present study, we examined the apoptosis-resistance mechanism of
      a multidrug-resistant cell line, A549/CPT, which was established from the human
      lung-cancer cell line A549 by in vitro selection with gradually increased
      camptothecin (CPT) concentrations. We found that A549/CPT cells were resistant to
      anti-cancer drug-induced apoptosis in which caspase-3-like protease activity was
      attenuated remarkably, compared with parental A549 cells. We observed 2
      mechanisms associated with apoptosis resistance in A549/CPT cells: over
      expression of anti-apoptotic bcl-2 and elevated expression of p21Waf1/Cip1.
      Transfection of either bcl-2 or p21Waf1/Cip1 cDNA into parental A549 cells
      resulted in resistance to apoptosis. Furthermore, the co-treatment of
      p21Waf1/Cip1 and bcl-2 anti-sense oligodeoxy-nucleotides restored drug
      susceptibility in A549/CPT cells more effectively than either one of them alone.
      These results indicate that co-induction of bcl-2 and p21Waf1/Cip1 in A549/CPT
      cells may be involved in acquired drug resistance by inhibiting caspase-mediated
      apoptosis. Agents aimed at preventing both bcl-2 and p21Waf1/Cip1 expression may
      increase the efficiency of chemotherapy.

PMID- 10597197
TI  - In vivo assessment of vascular endothelial growth factor-induced angiogenesis.
AB  - To determine whether vascular endothelial growth factor (VEGF)-induced tumor
      microvascularity is detectable by in vivo NMR imaging, an experimental study was
      conducted in nude mice. Human breast cancer cells (MCF-7) and MCF-7 cells stably
      transfected with the cDNA for the VEGF165 isoform (MV165) were grown in nude mice
      and models were characterized by RT-PCR, Western blotting, ELISA,
      immunohistochemistry and NMR imaging using a novel synthetic protected graft
      copolymer (PGC) as a vascular probe. MV165 tumors showed a 1.6-fold higher
      microvascular density by histology. Both tumors showed identical MR signal
      intensities on non-contrast and Gd-DTPA enhanced images. PGC enhanced MR imaging
      of tumoral vascular volume fraction (VVF), however, revealed significant
      differences between the 2 tumor types (MV165: 8.9 +/- 2.1; MCF-7: 1.7 +/- 0.5; p
      < 0.003), as expected from histology. VVF changes were more heterogeneous in the
      MV165 model both among tumors as well as within tumors as determined 3
      dimensionally at submillimeter resolutions. Our results have potential
      applications for non-invasive assessment of angiogenesis by in vivo imaging and
      for clinical monitoring during angiogenic therapies.

PMID- 10597198
TI  - An absence of founder BRCA2 mutations in individuals with squamous cell carcinoma
      of the head and neck.

PMID- 10597199
TI  - Risk of lung cancer from exposure to environmental tobacco smoke from cigars,
      cigarillos and pipes.

PMID- 10597200
TI  - A molecular model for the development of germ cell cancer.
AB  - Human germ cell tumors comprise a heterogeneous group of neoplasms. Those of the
      adult testis, known as TGCTs, originate from carcinoma in situ (CIS), which are
      initiated during intra-uterine development. We present here a molecular model for
      the development of TGCTs, including various parameters, such as apoptosis,
      chromosomal constitution, as well as genomic imprinting. We assume that TGCTs
      originate from a pluripotent, erased embryonic germ cell, of which
      aneuploidization is one of the early events. Subsequently, net loss and gain of
      specific chromosomal regions result in the consistent pattern of chromosomal
      aberrations that are observed in these tumors, including gain of 12p-sequences.
      By means of analysis of a relatively small region of the short arm of chromosome
      12, we are in the process of identifying the relevant genes. Possibly, this
      gene(s) suppresses apoptosis outside the specific micro-environment of the
      seminiferous tubule.

PMID- 10597201
TI  - Carcinoma in situ of the testis: review of biological and clinical features.
AB  - Carcinoma in situ of the testis (CIS) is the uniform precursor of testicular germ
      cell tumours. Morphologically, CIS consists of large, intratubular, gonocyte-like
      cells with large nuclei and abundant glycogen. CIS cells are probably derived
      from primordial germ cells and are supposed to be present in the testis of a
      future testis cancer patient at the time of birth. CIS cells appear to spread
      inside the seminiferous tubules until CIS progresses to invasive cancer.
      Diagnosis is best achieved by surgical biopsy of the testis and subsequent
      immunohistological staining of placental alkaline phosphatase (PlAP). This enzyme
      is present in embryonal germ cells, CIS and seminoma as well as several other
      types of germ-cell tumour but usually not in normal germ cells. CIS is found in
      testicular tissue adjacent to testicular germ-cell tumours in about 90% of cases,
      and it is observed in all clinical groups known to be at risk for testicular
      cancer: cryptorchidism (2% to 4%), infertility (0% to 1%), ambiguous genitalia
      (25%) and contralateral testis of patients with testicular cancer (5%).
      Conversely, CIS is found in less than 1% of the normal male population, and this
      prevalence corresponds well to the life-time risk of testicular cancer in males.
      If CIS is left untreated, there is a 50% probability of progressing to frank germ
      cell neoplasm within 5 years. Localised low-dose radiotherapy to the testis
      eradicates CIS and germ cells, while Leydig cells are preserved. The patient can
      thus be spared orchiectomy and hormone supplementation. Currently, dose-reduction
      studies are looking for the optimal radiation dose, which is expected to be
      around 14 to 16 Gy. After chemotherapy, there is a cumulative risk of 42% for
      recurrence of CIS within 10 years. The concept of CIS offers the chance of very
      early detection of testicular cancer and organ-preserving early treatment.

PMID- 10597202
TI  - Radiotherapy for stages I and IIA/B testicular seminoma.
AB  - Radiotherapy is generally accepted as a standard treatment for early-stage
      testicular seminoma. Relapse rates of 2% to 5% in clinical stage I and 10% to 20%
      in stage IIA/B (according to the Royal Marsden classification) can be achieved.
      Disease-specific survival reaches 100%. With such excellent cure rates, treatment
      related side effects gain particular importance. Therefore, a prospective
      multicenter trial was initiated for radiotherapy of testicular seminoma with
      limited treatment portals and low total doses of irradiation. In clinical stage
      I, 483 patients were treated with 26 Gy to the para-aortic region only. In stage
      IIA, 42 patients and, in stage IIB, 18 patients received irradiation to the para
      aortic and high iliac lymph nodes with 30 and 36 Gy, respectively. With a median
      time to follow-up of 55 months for stage I and 55.5 months for stage IIA/B, there
      were 18 (3.7%) and 4 (6.7%) cases of relapse in both treatment groups. Disease
      specific survival was 99.6% in stage I and 100% in stage IIA/B. Acute toxicity
      was dominated by moderate gastro-intestinal side effects. No major late toxicity
      has been observed to date. Limited volume pure para-aortic treatment for stage I
      and para-aortic/high iliac irradiation for stage IIA/B with 26, 30 and 36 Gy,
      respectively, yields excellent cure rates with only moderate acute toxicity and
      is therefore recommended as standard treatment.

PMID- 10597203
TI  - Risk factors for relapse in stage I non-seminomatous germ-cell tumors:
      preliminary results of the German Multicenter Trial. German Testicular Cancer
      Study Group.
AB  - Risk factor analysis to identify low-risk patients for occult metastatic disease
      (vascular invasion, percentage embryonal carcinoma, MIB-I proliferation rate)
      yields reliable results if performed by experts. A correct prediction is possible
      at the 90% level. Similar accuracy, however, may be achieved if the computed
      tomography (CT) staging is optimized and the evaluation performed by an
      experienced investigator. The combination of both methods (biological risk factor
      analysis and CT staging) may virtually exclude the risk of relapse in a limited
      number of patients. However, so far, no risk factor that is able to reliably
      predict occult metastatic disease or relapse in clinical state I patients has
      been identified in prospective trials. The preliminary results of the current
      German Multicenter Trial suggest an inferior value of prediction for low-risk
      patients if risk factor analysis and/or CT staging is performed in non
      specialized centers.

PMID- 10597204
TI  - Management of intermediate-prognosis germ-cell cancer: results of a phase I/II
      study of Taxol-BEP.
AB  - The standard chemotherapy regimen in metastatic germ-cell cancer is bleomycin,
      etoposide and cisplatin (BEP). Chemotherapy studies testing cisplatin dosage and
      the substitution of ifosfamide for bleomycin have not shown this to be superior
      to BEP. Paclitaxel (Taxol) has demonstrated promising activity as a second-line
      treatment in patients with relapsing or cisplatin-refractory germ-cell cancer.
      Hence, the potential of incorporating paclitaxel in first-line chemotherapy
      should be investigated. We assessed the feasibility of the addition of paclitaxel
      to BEP (T-BEP) in a phase I/II study in patients with intermediate- or poor
      prognosis germ-cell cancer or with carcinoma of unknown primary (CUP). Paclitaxel
      was investigated at dose levels of 75, 125, 175 and 200 mg/m2 given as a 3 hr
      infusion on day 1, before the start of BEP. BEP comprised etoposide at a dose of
      either 120 mg/m2 on days 1, 3 and 5 or 100 mg/m2 on days 1-5. To deliver the
      highest possible dose of paclitaxel into BEP, all patients received filgrastim (G
      CSF). Thirty patients were entered, 14 of whom had intermediate- (n = 7) or poor-
      (n = 7) prognosis germ-cell cancer. Paclitaxel up to 200 mg/m2 and BEP at 360
      mg/m2 was well tolerated. There was minimal neurosensory and no neuromotor
      toxicity with the use of 4 T-BEP cycles. More pronounced myelotoxicity and
      diarrhea at the higher dose level of etoposide resulted in a recommended dose
      level for multicenter phase II/III testing of paclitaxel 175 mg/m2 and BEP 500
      mg/m2. Of the 13 evaluable patients with intermediate- or poor-prognosis germ
      cell cancer, all achieved complete response. With a median follow-up of 18
      months, none of these patients has relapsed. We conclude that T-BEP is a well
      tolerated induction regimen that should be further tested for its therapeutic
      potential. A randomized phase II/III study of T-BEP vs. BEP has been started as
      an EORTC trial in patients with intermediate-prognosis disease.

PMID- 10597205
TI  - High-dose chemotherapy as primary treatment for poor-risk germ-cell tumors: the
      Memorial Sloan-Kettering experience (1988-1999).
AB  - Although the majority of patients with poor-risk germ-cell tumors (GCTs) will
      achieve a durable complete remission (CR) with standard first-line therapy, 20%
      to 30% of them will either relapse or fail to achieve an initial CR and
      eventually die. For this reason, the strategy of using high-dose (HD)
      chemotherapy with autologous stem-cell support has been investigated to improve
      the chances of cure attainable in the salvage setting, but at a cost of
      significant morbidity and mortality. Treatment using HD therapy in the first-line
      setting offers the promise of reducing morbidity and mortality while increasing
      efficacy. At Memorial Sloan-Kettering Cancer Center (MSKCC), trials were
      conducted to test this hypothesis. Patients at high risk of relapse following
      conventional therapy were identified, based on post-treatment serum marker
      concentrations that failed to appropriately decline by predicted half-life after
      several cycles of standard treatment. These patients received first-line HD
      treatment. Patients received a 2-drug HD regimen in one trial and an intensified
      3-drug regimen in another, each with autologous bone marrow transplantation.
      These patients had improved overall and event-free survival rates (p = 0.001 and
      0.003, respectively) compared with historical controls who underwent standard
      first-line treatment, with a lower incidence of treatment-related mortality than
      patients who received HD therapy in the salvage setting. Randomized trials are
      under way to prospectively verify these results.

PMID- 10597206
TI  - High-dose salvage chemotherapy. Germ-cell tumor treatment results in Germany.
AB  - During the past 10 years, high-dose chemotherapy (HDCT) has emerged as a feasible
      and curative treatment option for patients with multiply relapsed and/or
      refractory germ-cell tumors. Increasing experience and the results from clinical
      trials have helped to optimize the application of HDCT and to define its role in
      the salvage concepts for germ-cell tumors.

PMID- 10597207
TI  - High dose chemotherapy--results of American studies.
AB  - The role of high dose chemotherapy in the treatment of solid tumors is a subject
      of robust debate. Opinions range from the adoption of high dose chemotherapy with
      hematopoietic progenitor support as standard therapy for a number of solid tumors
      to the view that the application of such expensive and potentially toxic therapy
      is always experimental and should be the subject of clinical trials to define the
      role, if any. In germ cell tumors, the role of high dose chemotherapy is somewhat
      less contentious. In the US, high dose carboplatin and etoposide-based
      chemotherapy is routinely accepted as standard therapy for those patients failing
      prior standard dose regimens. There is increasing acceptance of the role of
      similar high dose therapy as a component of aggressive second line therapy and
      some initial acceptance of a potential role in primary treatment of poor risk
      disease. Formal study of these questions has been hampered by the rarity of the
      illness, the success of standard therapy and the smaller number of patients
      presenting with far advanced disease. This review will highlight the scientific
      underpinning of the role of high dose chemotherapy in multiply relapsed patients,
      as a component of initial salvage therapy and, finally as an attempt to improve
      outcome in patients with poor risk presenting features. As well, an attempt will
      be made to highlight where new prognostic information has influenced the design
      of current studies.

PMID- 10597208
TI  - High-dose chemotherapy with hematopoietic stem-cell support in germ-cell tumor
      patient treatment: the French experience.
AB  - Germ-cell tumors (GCTs) are very chemosensitive and highly curable cancers. For
      the small proportion of patients who fail conventional chemotherapy (CT), high
      dose CT (HDCT) was introduced in France and elsewhere in 1982-1984. We report
      here on the French experience with HDCT in GCTs. At the Centre Leon Berard, 75
      patients were treated with HDCT between 1982 and 1996. Patients received HDCT in
      2 different settings: 46 in consolidation of first-line treatment or in
      incomplete response, 29 in salvage of relapse or refractory disease. The most
      common regimens of HDCT were the combination of etoposide, double-dose cisplatin
      and either ifosfamide (VIC regimen, n = 46) or cyclophosphamide (PEC regimen, n =
      9) and the combination of carboplatin, etoposide and cyclophosphamide (Carbo-PEC
      regimen, n = 17). Seven patients died of toxicity. The median follow-up was 42
      months. Forty-five of 75 patients are alive and free of disease at long term, 2
      of whom had refractory disease. The median time to recovery of a granulocyte
      count > or = 0.5 x 10(9)/l and a platelet count > or = 25 x 10(9)/l was 14 and 11
      days, respectively. The French development was based on double-dose cisplatin
      until the results of the French randomized trial, which showed no advantage of
      HDCT in the first-line treatment of poor-risk group patients. Then carboplatin
      was associated with etoposide and cyclophosphamide in a phase I trial. A European
      randomized trial, which studies the role of HDCT in the first-line salvage
      treatment of non-refractory disease, is ongoing. So far, HDCT is not a standard
      treatment of GCT.

PMID- 10597209
TI  - Treatment of patients with cisplatin-refractory testicular germ-cell cancer.
      German Testicular Cancer Study Group (GTCSG).
AB  - With the use of cisplatin-based combination chemotherapy, metastatic testicular
      germ-cell tumors can be cured in 70% to 80% of patients. The combination of
      cisplatin, etoposide and bleomycine (PEB) is considered standard therapy.
      Patients refractory to cisplatin-based chemotherapy have a markedly poor
      prognosis. Several chemotherapeutic agents have been evaluated in intensively pre
      treated or cisplatin-refractory patients. Neither the anthracyclines nor
      vinorelbine, topotecan or biological agents such as suramin and retinoic acid
      have demonstrated clinical activity. Paclitaxel has been evaluated at different
      doses and schedules and yielded a response rate of 21% (range 11-30%), with
      single patients achieving complete remissions. This has led to the inclusion of
      paclitaxel in salvage regimens in combination with cisplatin and/or ifosfamide.
      Two studies have evaluated gemcitabine in refractory germ-cell tumors and
      demonstrated a response rate of 17% (95% CI 7-28%) in 52 intensively pre-treated
      patients, two-thirds of whom had relapsed after previous high-dose chemotherapy
      plus autologous stem-cell transplantation. The non-hematological toxicity of
      weekly gemcitabine at doses of 1,000 to 1,250 mg/m2 was tolerable, and
      hematological side effects included thrombocytopenia in approximately 20% of
      patients. Ongoing studies in refractory germ-cell tumors performed by the German
      Testicular Cancer Study Group are evaluating bendamustine, an alkylating agent
      with activity in breast and small-cell lung cancer, and oxaliplatin, a platinum
      derivative with incomplete cross-resistance to cisplatin. Future trials combining
      new active agents may examine alternating treatment strategies in patients with
      poor-prognostic disease or as salvage treatment.

PMID- 10597210
TI  - Management of the post-chemotherapy residual mass in patients with advanced stage
      non-seminomatous germ cell tumors (NSGCT).
AB  - Since it is difficult to predict the probability of persistent teratoma or of a
      viable tumor in patients with normalized tumor markers and a normal CT scan
      following chemotherapy for advanced stage testis cancer, recommendations
      regarding adjunctive surgery have ranged from observation to surgical exploration
      for all patients. Suggested variables for patients in whom surgery can be omitted
      safely, include normal post-chemotherapy CT scans, residual abdominal masses of
      less than 1.5 cm, a 90% or greater decrease in the volume of the retroperitoneal
      mass with chemotherapy and no teratomatous elements in the orchiectomy specimen.
      In contrast, during several investigations, the application of the above
      mentioned criteria resulted in a false-negative prediction of approximately 20%.
      However, recognizing the morbidity of the operative procedure itself in addition
      to the fact that only 2-4% of patients will develop recurrent tumor confined to
      the retroperitoneal space that can then be managed surgically or by
      administration of further chemotherapy, secondary surgery should be avoided if a
      sufficient follow-up after chemotherapy is guaranteed. The extent of adjunctive
      surgery in patients revealing a residual tumor mass after first-line chemotherapy
      remains a subject of ongoing discussions. It has been indicated that extensive
      retroperitoneal surgery after chemotherapy is associated with significant
      clinical morbidity. A limitation of post-chemotherapy surgery to a resection of
      the residual mass with or without an additional modified template dissection
      appears to result in an acceptable frequency of retroperitoneal recurrences and a
      decreased complication rate.

PMID- 10597211
TI  - Prediction models for the histology of residual masses after chemotherapy for
      metastatic testicular cancer. ReHiT Study Group.
AB  - Patients with metastatic non-seminomatous testicular cancer can be cured by
      cisplatin-based chemotherapy. After chemotherapy, surgical resection is a
      generally accepted treatment to remove remnants of the initial metastases since
      residual tumor may still be present (mature teratoma or viable cancer cells). We
      review here several policies for the selection of patients for retroperitoneal
      lymph node dissection. We consider one simple policy as a reference, which bases
      the selection solely on the diameter of the residual mass (> or = 10 mm).
      Further, we distinguish 4 rule-based policies, which combine several clinical
      characteristics (e.g., primary tumor teratoma-positive or insufficient reduction
      in size), and 2 probability-based policies, where a regression or tree model is
      used that statistically combines well-known, important clinical predictors for
      the absence of residual tumor. The policies were evaluated in an international
      data set containing 716 patients. The reference policy would leave 204 masses <
      10 mm unresected, where mature teratoma was present in 50 (25%) and cancer in 11
      (5%). Compared with this policy, most of the rule-based policies left fewer
      patients with residual tumor unresected, at the expense of more resections. The
      probability-based policies could refine the selection without such an increase in
      the number of resections. Prediction models for the residual histology therefore
      merit wider application in clinical practice.

PMID- 10597212
TI  - Therapy-related malignancies following treatment of germ cell cancer.
AB  - Given the young age at which testicular cancer is treated and the excellent
      prognosis for patients suffering from this disease, therapy-related malignancies
      represent a significant problem. Therapy-related solid tumors are associated
      mainly with the use of radiation therapy. The risk for developing a therapy
      related solid tumor is approximately 2- to 3-fold increased compared with the
      general population. Therapy-related leukemias are associated predominantly with
      chemotherapy, particularly with the use of topoisomerase-II inhibitors and
      alkylating agents. In general, the cumulative incidence of therapy-related
      leukemia is low. It is approximately 0.5% and 2% at 5 years of median follow-up
      for patients receiving etoposide at cumulative doses < or = 2 g/m2 and > 2 g/m2,
      respectively. High cumulative doses of etoposide given over a short period of
      time appear to be less leukemogenic than a similar dose of etoposide given over a
      longer period of time. There might, additionally, be a synergistic effect of
      cisplatin and etoposide on the induction of therapy-related leukemia. For
      patients who receive high-dose chemotherapy with autologous stem-cell support,
      the risk of therapy-related myelodysplastic syndrome and leukemia appears to be
      substantially lower compared with that reported in non-Hodgkin's lymphoma
      patients undergoing high-dose chemotherapy. The transplantation procedure itself
      does not appear to add to the therapy-related leukemia risk. The risk-benefit
      analysis in patients with testicular cancer clearly favors the use of current
      treatment regimens including high-dose chemotherapy. However, even the acceptably
      low number of therapy-related leukemias should encourage the search for equally
      effective but less toxic therapies.

PMID- 10597213
TI  - Impact of cytotoxic treatment on long-term fertility in patients with germ-cell
      cancer.
AB  - More than half of the patients with testicular germ-cell cancer show impaired
      spermatogenesis before undergoing cytotoxic treatment. The known pre-treatment
      infertility and the reversibility of the fertility problems observed in some
      after successful anti-cancer treatment have so far prevented an assessment of the
      true role of cytotoxic therapy in long-term fertility. The introduction of wait
      and-see strategies (surveillance) for testicular cancer patients and recent
      prospective trials comparing patients with and without cytotoxic treatment have
      provided the means for estimating the extent to which treatment itself affects
      long-term fertility. Whether or not spermatogenesis is irreversibly impaired by
      chemotherapy is determined by the cumulative dose of cisplatin: at doses below
      400 mg/m2, long-term effects on sperm production as well as on endocrine function
      are unlikely to occur. Higher doses should be expected to cause long-term losses
      of exocrine and endocrine gonadal function. In contrast, for adjuvant
      retroperitoneal radiotherapy in stage I seminoma patients, no data are available
      comparing long-term gonadal function with patients on surveillance. However,
      using modern radiation techniques, radiation doses to the para-aortic field (< 30
      Gy) and testis shielding providing testis scatter radiation (< 30 cG), radiation
      induced impairment of fertility is very unlikely.

PMID- 10597214
TI  - Platinum organ toxicity and possible prevention in patients with testicular
      cancer.
AB  - Advances in the management of metastatic testicular cancer are attributed mainly
      to the introduction of cisplatin into combination chemotherapy. In parallel with
      the development of effective chemotherapy resulting in long-term survival for the
      majority of patients, possible adverse effects of treatment have been
      systematically investigated. Besides acute side effects of cisplatin, such as
      gastro-intestinal toxic effects and moderate myelosuppression, reduction in
      glomerular filtration rate occurs in 20% to 30% of patients despite prophylactic
      intensive hydration and forced diuresis. Such changes in glomerular function are
      essentially irreversible. Persistent effects on tubular renal function occur less
      commonly, but hypomagnesemia due to hypermagnesiuria is often seen.
      Neurotoxicity, mainly sensory peripheral neuropathy, is common during treatment
      but disappears in the majority of patients after its completion. However,
      persistent paresthesias are found in 20% to 60% of patients. A typical
      audiometric abnormality affecting up to 50% of patients is bilateral loss of
      hearing at 4 to 8 kHz. A correlation between the cumulative cisplatin dose
      applied and the frequency of neuro- and nephrotoxicity has been demonstrated in
      some studies. The administration schedule additionally appears to influence the
      extent of toxicity, whereby single-day infusion schedules are associated with
      pronounced neural and renal toxicity, possibly due to higher peak plasma levels
      of cisplatin. Other long-term abnormalities after treatment with cisplatin-based
      combination regimens are a weak predisposition to secondary malignancies,
      infertility and chronic vascular toxicity. Several strategies have been developed
      to reduce such side effects. Ongoing trials are investigating the role of the
      aminothiol amifostine as a nephro- and neuroprotectant.

PMID- 10597215
TI  - 190th Meeting of the Society for Endocrinology. London, United Kingdom, 8-9
      November 1999. Abstracts.

PMID- 10597216
TI  - Bis, a Bcl-2-binding protein that synergizes with Bcl-2 in preventing cell death.
AB  - Bcl-2 is the best characterized inhibitor of apoptosis, although the molecular
      basis of this action is not fully understood. Using a protein interaction cloning
      procedure, we identified a human gene designated as bis (mapped to chromosome
      10q25) that encoded a novel Bcl-2-interacting protein. Bis protein showed no
      significant homology with Bcl-2 family proteins and had no prominent functional
      motif. Co-immunoprecipitation analysis confirmed that Bis interacted with Bcl-2
      in vivo. DNA transfection experiments indicated that Bis itself exerted only weak
      anti-apoptotic activity, but was synergistic with Bcl-2 in preventing Bax-induced
      and Fas-mediated apoptosis. These results suggest that Bis is a novel modulator
      of cellular anti-apoptotic activity that functions through its interaction with
      Bcl-2.

PMID- 10597217
TI  - Telomerase inhibition by peptide nucleic acids reverses 'immortality' of
      transformed human cells.
AB  - Telomerase activity, the ability to add telomeric repeats to the ends of
      chromosomes, has been detected in most immortal cell lines including tumor cells,
      but is low or absent in most diploid, mortal cells such as those of somatic
      tissues. Peptide nucleic acids (PNAs), analogs of DNA or RNA which bind to
      complementary nucleic acids with very high affinity, were co-electroporated into
      immortal human cells along with a selectable plasmid. Introduction of PNAs
      inverse-complementary to telomerase RNA effectively inhibited telomerase activity
      in intact cells, shortened telomeres, reduced colony size, and arrested cell
      proliferation after a lag period of 5-30 cell generations, consistent with
      suppression of their 'immortality'. Electroporation of selection plasmid alone
      had no effect, while PNAs of altered sequence were markedly less effective in
      each assay. This constitutes the first demonstration of cell growth arrest
      through telomerase inhibition, upon treatment of intact cells with an exogenous
      compound which can be efficiently delivered in vivo. The phenotype of telomerase
      inhibited transformed cells differs from senescence of normal diploid
      fibroblasts, but rather resembles the crisis state of incompletely transformed
      cells.

PMID- 10597218
TI  - The generation of nfkb2 p52: mechanism and efficiency.
AB  - nfkb2 encodes two members of the NF-kappa B/Rel family of proteins: p52 and p100.
      The p100 polypeptide has been proposed to serve as a precursor of p52, which
      corresponds to the N-terminal half of p100. While p52 functions as a Rel
      transcription factor, the larger p100 protein acts as a cytoplasmic inhibitor of
      select NF-kappa B/Rel transcription factor complexes. Because of their distinct
      functions, we have studied the biochemical basis for the production of these two
      nfkb2-derived gene products. Like the p50 product of the nfkb1 gene, p52 is
      principally generated in a cotranslational manner involving proteolytic
      processing by the proteasome. The generation of p52 is dependent on a glycine
      rich region (GRR) located upstream of the p52 C-terminus, and repositioning of
      this GRR alters the location of proteasome processing. In most cells, small
      amounts of p52 are produced relative to the levels of p100, unlike the usually
      balanced production of nfkb1-derived p50 and p105. Using p100/p105 chimeras
      containing different segments of the nfkb1 and nfkb2 genes, we have found that
      diminished p52 processing is a property conferred by peptide sequences located
      downstream of the GRR, flanking the site of p52 processing.

PMID- 10597219
TI  - Granulocytic differentiation of myeloid progenitor cells by p130, the
      retinoblastoma tumor suppressor homologue.
AB  - The retinoblastoma protein (pRB) and the related pocket proteins, p107 and p130,
      play crucial roles in mammalian cell cycle control. Recent studies indicate that
      these pocket proteins are also involved in cellular differentiation processes. We
      demonstrate in this work that the pRB-related p130 selectively accumulates during
      the in vitro differentiation of the myeloid progenitor cell, 32Dcl3, into
      granulocyte in response to granulocyte-colony stimulating factor (G-CSF). This G
      CSF-dependent granulocytic differentiation is blocked by the adenovirus E1A
      oncoprotein, which binds to and inactivates the pRB family of pocket proteins
      including p130. Furthermore, enforced overexpression of p130 but not pRB inhibits
      the myeloid cell proliferation that is concomitantly associated with granulocytic
      differentiation morphologically characterized by nuclear segmentation. However,
      simple G1-cell cycle arrest induced by cytokine deprivation or ectopic
      overexpression of the p27 cyclin-dependent kinase inhibitor, or inhibition of E2F
      activities by dominant negative DP-1 is not sufficient to trigger granulocytic
      differentiation. The differentiation-promoting activity of p130 in myeloid cells
      requires both the pocket domain and the spacer domain. Our results indicate that
      the pRB-related p130 plays a critical role in myeloid cell differentiation and
      suggest that coupling of cell cycle exit with the cellular differentiation
      program may be specifically achieved by p130.

PMID- 10597220
TI  - CHF: a novel factor binding to cyclin A CHR corepressor element.
AB  - Cell cycle modulation of cyclin A expression is due to the periodic relief of a
      transcriptional repression mediated by a bipartite negative DNA regulatory
      region. The 5' element (Cell Cycle Responsive Element: CCRE; cell Cycle Dependent
      Element: CDE) is clearly occupied in a cyclic manner in vivo, whereas the 3'
      element, whose sequence is shared by B-myb, cdc25C and cdc2 genes (cell Cycle
      gene Homology Region: CHR), is involved in more subtle interactions. Mutation of
      either element results in complete deregulation of cyclin A promoter activity.
      Whereas some reports claim that E2F/DP can bind to the CCRE/CDE, the nature of
      the protein(s) interacting with the CHR is unknown. In the present work we have
      characterized an activity present in quiescent cells and absent in cells blocked
      in S phase, which binds specifically to cyclin A CHR, but not to B-myb, or to
      cdc25C, or to cdc2 CHRs. A 90 kD protein, named CHF (cyclin A CHR binding
      factor), has been identified through preparative electrophoresis and UV
      crosslinking experiments. In order to address in more functional terms the
      binding of CHF to cyclin A CHR, we developed in vitro and in vivo oligonucleotide
      competition assays. Both in vitro transcription and in vivo microinjection
      experiments demonstrate that a functional difference exists between the composite
      CCRE/CDE-CHR repressor regions of cell cycle regulated genes such as cyclin A and
      cdc25C.

PMID- 10597221
TI  - The genomic structure of the DMBT1 gene: evidence for a region with
      susceptibility to genomic instability.
AB  - Increasing evidence has accumulated for an involvement of the inactivation of
      tumour suppressor genes at chromosome 10q in the carcinogenesis of brain tumours,
      melanomas, and carcinomas of the lung, the prostate, the pancreas, and the
      endometrium. The gene DMBT1 (Deleted in Malignant Brain Tumours 1) is located at
      chromosome 10q25.3-q26.1, within one of the putative intervals for tumour
      suppressor genes. DMBT1 is a member of the scavenger-receptor cysteine-rich
      (SRCR) superfamily and displays homozygous deletions or lack of expression in
      glioblastoma multiforme, medulloblastoma, and in gastrointestinal and lung
      cancers. Based on these properties, DMBT1 has been proposed to be a candidate
      tumour suppressor gene. We have determined the genomic sequence of DMBT1 to allow
      analyses of mutations. The gene has at least 54 exons that span a genomic region
      of about 80 kb. We have identified a putative exon with coding potential for a
      transmembrane domain. Our data further suggest that alternative splicing gives
      rise to isoforms of DMBT1 with a differential utilization of SRCR domains and
      SRCR interspersed domains. The major part of the gene harbours locus specific
      repeats. These repeats may point to the DMBT1 locus as a region susceptible to
      chromosomal instability.

PMID- 10597222
TI  - Key role of the cyclin-dependent kinase inhibitor p27kip1 for embryonal carcinoma
      cell survival and differentiation.
AB  - Hexamethylen-bisacetamide (HMBA) represents the prototype of a group of hybrid
      polar compounds, which induce differentiation in a variety of transformed cells
      including human embryonal carcinoma cells. Therefore, HMBA has been used in the
      differentiation therapy of cancer for patients with both hematological and solid
      malignancies. Upon HMBA treatment, the embryonal carcinoma cell line NTERA-2
      clone D1 (NT2/D1) accumulates in G1 and undergoes terminal differentiation. Here
      we demonstrate that growth arrest and differentiation of NT2/D1 cells induced by
      HMBA involve increased expression of the cyclin-dependent kinase inhibitor p27,
      enhanced association of p27 with cyclin E/CDK2 complexes and suppression of
      kinase activity associated to cyclin E/CDK2 (but not to cyclin D3/CDK4). When
      HMBA differentiation was induced in the presence of p27 antisense
      oligonucleotides, NT2/D1 cells failed to arrest growth properly and, in parallel
      with the reduction of the anti-apoptotic Bcl-2 gene expression, cells underwent
      massive programmed cell death. Conversely, constitutive expression of p27 into
      NT2/D1 cells induced a marked reduction in the growth potential of these cells
      and partially reproduced HMBA-induced modification of surface antigen expression
      (down-regulation of SSEA-3 expression and up-regulation of VINIS-53 expression).
      Expression of p21 induced growth arrest but not differentiation. Likewise,
      inhibition of CDK2 by transfection of a dominant negative CDK2 in NT2/D1 cells or
      treatment with the kinase inhibitor olomucine induced growth arrest but not
      differentiation. Therefore, we propose that p27 represents a crucial molecule in
      HMBA signaling that cannot be replaced by p21. Furthermore, the results obtained
      with CDK2 inhibitors demonstrate that the block of CDK2 activity is sufficient
      for growth arrest but not for cell differentiation and suggest that, at least in
      these cells, growth arrest and differentiation are regulated by two overlapping
      but different pathways.

PMID- 10597223
TI  - Ras induces p21Cip1/Waf1 cyclin kinase inhibitor transcriptionally through Sp1
      binding sites.
AB  - p21Cip1/Waf1 cyclin-dependent kinase inhibitor (p21) is inducible by Raf and
      mitogen-activated protein kinase kinase (MAPKK), but the level of regulation is
      unknown. We show here by conditional and transient Ras-expression models that Ras
      induces p21. Induction of p21 in conditionally Ras-expressing cells is
      posttranscriptional utilizing mitogen-activated protein kinase (MAPK) pathway.
      Transient, high-level Ras-expression induces transcriptional activation of p21
      mediated by a GC-rich region in p21 promoter -83-54 bp relative to the
      transcription initiation site containing binding sites for Sp1-family
      transcription factors. Mutation of either Sp1-binding site 2 or 4 in this region
      decreases the magnitude of induction of promoter activity by Ras, but only the
      simultaneous mutation of both sites abolishes fully the induction.
      Electrophoretic mobility shift assays using an oligonucleotide corresponding to
      Sp1-binding site 2 indicate that both Sp1 and Sp3 transcription factors bind to
      this region. The results demonstrate that the central cytosolic growth regulator
      Ras is a potent transcriptional and posttranscriptional inducer of the nuclear
      growth inhibitor p21.

PMID- 10597224
TI  - 17q21-q25 aberrations in breast cancer: combined allelotyping and CGH analysis
      reveals 5 regions of allelic imbalance among which two correspond to DNA
      amplification.
AB  - Chromosome 17q is frequently rearranged in breast cancer. Allelotyping studies
      have proposed the existence of at least four regions of allelic imbalance (AI).
      Here we present a study combining allelotyping using 19 CA repeat markers mapping
      in the 17q21-25 region and molecular cytogenetics (CGH and FISH). Allelotyping
      was undertaken on 178 pairs of cognate tumor and normal DNA in order to determine
      the number of regions of AI and define the shortest overlaps. AI ranged from 34
      54% of the informative cases according to the marker and, overall, 66% of the
      tumors presented AI at one of the markers tested. Analysis of the patterns of
      imbalances revealed at least five common regions of imbalance respectively
      defined by markers: D17S855, which is intragenic of BRCA1 (SRO 1), D17S1607 (SRO
      2), D17S1855 (SRO 3), between D17S789 and D17S785 (SRO 4) and D17S784 (SRO 5). In
      order to characterize the nature of the genetic events revealed by allelotyping
      we performed CGH analysis on a subset of 43 tumors presenting variable patterns
      of imbalance. CGH showed that AI at 17q could represent four different types of
      genetic events: loss of chromosome 17, gain of 17q, gain of 17q22-q24, loss of
      17q11-q21 and/or 17q25-qter. Some of these anomalies could occur concomitantly
      within the same tumor. Since 35% of the tumors analysed by CGH presented gains,
      these data indicated that AI at 17q were not solely indicative of losses of
      genetic material and could also represent DNA amplification. Gains were most
      commonly observed in the 17q23-q24 regions. This suggested that AI in SRO 2 and
      SRO 3 corresponded to DNA amplification. To assess this, we isolated BAC clones
      by PCR screening for markers D17S1607 and D17S1855 and used these in FISH
      experiments on six breast tumor cell lines and 14 breast cancer specimens. FISH
      results showed that both D17S1607 and D17S1855 were frequently involved in DNA
      amplification (8-30 copies). Altogether, our data show that allelotyping can be
      efficiently used in amplicon mapping. Clinico-pathological correlations indicated
      that imbalance at 17q preferentially occurred in high grade, PR- and ERBB2
      amplified tumors.

PMID- 10597225
TI  - Dysregulation of cyclin dependent kinase 6 expression in splenic marginal zone
      lymphoma through chromosome 7q translocations.
AB  - The increased or inappropriate expression of genes with oncogenic properties
      through specific chromosome translocations is an important event in the
      pathogenesis of B-cell lymphoproliferative diseases. Recent studies have found
      deletions or translocations of chromosome 7q to be the most common cytogenetic
      abnormality observed in SLVL, a leukemic variant of SMZL, with the q21-q22 region
      being most frequently affected. In three patients with translocations between
      chromosomes 2 and 7, the cloning of the breakpoints at 7q21 revealed that each
      was located within a small region of DNA 3.6 kb upstream of the transcription
      start site of cyclin dependent kinase 6 (CDK6). In each case the translocation
      event was consistent with aberrant VJ recombination between the immunoglobulin
      light chain region (Ig kappa) on chromosome 2p12 and DNA sequences at 7q21,
      resembling the heptamer recombination site. The t(7;21) breakpoint in an
      additional patient with splenic marginal zone lymphoma (SMZL), resided 66 kb
      telomeric to the t(2;7) breakpoints juxtaposing CDK6 to an uncharacterized
      transcript. In two of the SLVL patient samples, the CDK6 protein was found to be
      markedly over expressed. These results suggest that dysregulation of CDK6 gene
      expression contributes to the pathogenesis of SLVL and SMZL.

PMID- 10597226
TI  - Characterization of the human and mouse ETV1/ER81 transcription factor genes:
      role of the two alternatively spliced isoforms in the human.
AB  - The Ets transcription factors of the PEA3 group--E1AF/PEA3, ETV1/ER81 and ERM-
      are almost identical in the ETS DNA-binding and the transcriptional acidic
      domains. To accelerate our understanding of the molecular basis of putative
      diseases linked to ETV1 such as Ewing's sarcoma we characterized the human ETV1
      and the mouse ER81 genes. We showed that these genes are both encoded by 13 exons
      in more than 90 kbp genomic DNA, and that the classical acceptor and donor
      splicing sites are present in each junction except for the 5' donor site of
      intron 9 where GT is replaced by TT. The genomic organization of the ETS and
      acidic domains in the human ETV1 and mouse ER81 (localized to chromosome 12)
      genes is similar to that observed in human ERM and human E1AF/PEA3 genes.
      Moreover, as in human ERM and human E1AF/PEA3 genes, a first untranslated exon is
      upstream from the first methionine, and the mouse ER81 gene transcription is
      regulated by a 1.8 kbp of genomic DNA upstream from this exon. In human, the
      alternative splicing of the ETV1 gene leads to the presence (ETV1 alpha) or the
      absence (ETV1 beta) of exon 5 encoding the C-terminal part of the transcriptional
      acidic domain, but without affecting the alpha helix previously described as
      crucial for transactivation. We demonstrated here that the truncated isoform
      (human ETV1 beta) and the full-length isoform (human ETV1 alpha) bind similarly
      specific DNA Ets binding sites. Moreover, they both activate transcription
      similarly through the PKA-transduction pathway, so suggesting that this
      alternative splicing is not crucial for the function of this protein as a
      transcription factor. The comparison of human ETV1 alpha and human ETV1 beta
      expression in the same tissues, such as the adrenal gland or the bladder, showed
      no clear-cut differences. Altogether, these data open a new avenue of
      investigation leading to a better understanding of the functional role of this
      transcription factor.

PMID- 10597227
TI  - Silencing of metallothionein-I gene in mouse lymphosarcoma cells by methylation.
AB  - Metallothionein-I (MT-I) gene is silenced by methylation of CpG islands in mouse
      lymphosarcoma P1798 cells but not in the thymus, the cell type from which the
      tumor was derived. Bisulfite genomic sequencing revealed that all 21 CpG
      dinucleotides present within -216 bp to +1 bp with respect to transcription start
      site are methylated in the tumor cell line, but none is methylated in the thymus.
      The lymphosarcoma cells induced MT-I in response to heavy metals only after
      demethylation with 5-azacytidine (5-AsaC). The electrophoretic mobility shift
      assay using specific oligonucleotide probes showed that the key transcription
      factors regulating MT-I gene (e.g., MTF-1, Sp 1 and MLTF/USF) are active in P1798
      cells. In vivo footprinting of the proximal promoter region showed that none of
      the metal regulatory elements (MREs) or MLTF/USF are occupied in response to
      heavy metals. Demethylation of the lymphosarcoma cells with 5-AzaC resulted in
      constitutive footprinting at MLTF/ARE, and zinc-inducible footprinting at MRE-c,
      MRE-d and MRE-e sites. Demethylation of just 10-20% of the CpG islands was
      sufficient to render the gene inducible by cadmium or zinc. The MT-I induction
      persisted in the cancer cells for several generations even after withdrawal of 5
      AzaC from the culture medium.

PMID- 10597228
TI  - The bacterial cytolethal distending toxin (CDT) triggers a G2 cell cycle
      checkpoint in mammalian cells without preliminary induction of DNA strand breaks.
AB  - The bacterial cytolethal distending toxin (CDT) was previously shown to arrest
      the tumor-derived HeLa cell line in the G2-phase of the cell cycle through
      inactivation of CDK1, a cyclin-dependent kinase whose state of activation
      determines entry into mitosis. We have analysed the effects induced in HeLa cells
      by CDT, in comparison to those induced by etoposide, a prototype anti-tumoral
      agent that triggers a G2 cell cycle checkpoint by inducing DNA damage. Both CDT
      and etoposide inhibit cell proliferation and induces the formation of enlarged
      mononucleated cells blocked in G2. In both cases, CDK1 from arrested cells could
      be reactivated both in vitro by dephosphorylation by recombinant Cdc25B
      phosphatase and in vivo by caffeine. However, the cell cycle arrest triggered by
      CDT, unlike etoposide, did not originate from DNA strand breaks as demonstrated
      in the single cell gel electrophoresis assay and by the absence of slowing down
      of S phase in synchronized cells. Together with additional observations on
      synchronized HeLa cells, our results suggest that CDT triggers a G2 cell cycle
      checkpoint that is initiated during DNA replication and that is independent of
      DNA damage.

PMID- 10597229
TI  - Dephosphorylation of p53 at Ser20 after cellular exposure to low levels of non
      ionizing radiation.
AB  - Induction of the transactivation function of p53 after cellular irradiation was
      studied under conditions in which upstream signaling events modulating p53
      activation were uncoupled from those regulating stabilization. This investigation
      prompted the discovery of a novel radiation-responsive kinase pathway targeting
      Ser20 that results in the masking of the DO-1 epitope in undamaged cells.
      Unmasking of the DO-1 epitope via dephosphorylation occurs in response to low
      doses of non-ionizing radiation. Our data show that phosphorylation at Ser20
      reduces binding of the mdm2 protein, suggesting that a function of the Ser20
      kinase pathway may be to produce a stable pool of inactive p53 in undamaged cells
      which can be readily activated after cellular injury. Phospho-specific monoclonal
      antibodies were used to determine whether the Ser20 signaling pathway is coupled
      to the Ser15 and Ser392 radiation-responsive kinase pathways. These results
      demonstrated that: (1) dephosphorylation at Ser20 is co-ordinated with an
      increased steady-state phosphorylation at Ser392 after irradiation, without p53
      protein stabilization, and (2) stabilization of p53 protein can occur without
      Ser15 phosphorylation at higher doses of radiation. These data show that the
      Ser20 and Ser392 phosphorylation sites are both targeted by an integrated network
      of signaling pathways which is acutely sensitive to radiation injury.

PMID- 10597230
TI  - Formation of PML/RAR alpha high molecular weight nuclear complexes through the
      PML coiled-coil region is essential for the PML/RAR alpha-mediated retinoic acid
      response.
AB  - Retinoic Acid (RA) treatment induces disease remission of Acute Promyelocytic
      Leukaemia (APL) patients by triggering terminal differentiation of neoplastic
      cells. RA-sensitivity in APL is mediated by its oncogenic protein, which results
      from the recombination of the PML and the RA receptor alpha (RAR alpha) genes
      (PML/RAR alpha fusion protein). Ectopic expression of PML/RAR alpha into
      haemopoietic cell lines results in increased response to RA-induced
      differentiation. By structure-function analysis of PML/RAR alpha-mediated RA
      differentiation, we demonstrated that fusion of PML and RAR alpha sequences and
      integrity of the PML dimerization domain and of the RAR alpha DNA binding region
      are required for the effect of PML/RAR alpha on RA-differentiation. Indeed,
      direct fusion of the PML dimerization domain to the N- or C-terminal extremities
      of RAR alpha retained full biological activity. All the biologically active
      PML/RAR alpha mutants formed high molecular weight complexes in vivo. Functional
      analysis of mutations within the PML dimerization domain revealed that the
      capacity to form PML/RAR alpha homodimers, but not PML/RAR alpha-PML
      heterodimers, correlated with the RA-response. These results suggest that
      targeting of RAR alpha sequences by the PML dimerization domain and formation of
      nuclear PML/RAR alpha homodimeric complexes are crucial for the ability of
      PML/RAR alpha to mediate RA-response.

PMID- 10597231
TI  - Rapid signalling by androgen receptor in prostate cancer cells.
AB  - Androgens are important growth regulators in prostate cancer. Their known mode of
      action in target cells requires binding to a cytoplasmic androgen receptor
      followed by a nuclear translocation event and modulation of the expression of
      specific genes. Here, we report another mode of action of this receptor.
      Treatment of androgen responsive prostate cancer cells with dihydrotestosterone
      leads to a rapid and reversible activation of mitogen-activated protein kinases
      MAPKs (also called extracellular signal-regulated kinases or Erks). Transient
      transfection assays demonstrated that the androgen receptor-mediated activation
      of MAP kinase results in enhanced activity of the transcription factor Elk-1.
      This action of the androgen receptor differs from its known transcriptional
      activity since it is rapid and insensitive to androgen antagonists such as
      hydroxyflutamide or casodex. Biochemical studies as well as analyses with
      dominant negative mutants showed the involvement of kinases such as MAPK/Erk
      kinase, phosphatidyl-inositol 3-kinase and protein kinase C in the androgen
      receptor-mediated activation of MAP kinase. These results demonstrate a novel
      regulatory action of the androgen receptor and prove that in addition to its
      known transcriptional effects, it also uses non-conventional means to modulate
      several cellular signalling processes.

PMID- 10597232
TI  - Chromosomal breakpoint positions suggest a direct role for radiation in inducing
      illegitimate recombination between the ELE1 and RET genes in radiation-induced
      thyroid carcinomas.
AB  - The RET/PTC3 rearrangement is formed by fusion of the ELE1 and RET genes, and is
      highly prevalent in radiation-induced post-Chernobyl papillary thyroid
      carcinomas. We characterized the breakpoints in the ELE1 and RET genes in 12 post
      Chernobyl pediatric papillary carcinomas with known RET/PTC3 rearrangement. We
      found that the breakpoints within each intron were distributed in a relatively
      random fashion, except for clustering in the Alu regions of ELE1. None of the
      breakpoints occurred at the same base or within a similar sequence. There was
      also no evidence of preferential cleavage in AT-rich regions or other target DNA
      sites implicated in illegitimate recombination in mammalian cells. Modification
      of sequences at the cleavage sites was minimal, typically involving a 1-3
      nucleotide deletion and/or duplication. Surprisingly, the alignment of ELE1 and
      RET introns in opposite orientation revealed that in each tumor the position of
      the break in one gene corresponded to the position of the break in the other
      gene. This tendency suggests that the two genes may lie next to each other but
      point in opposite directions in the nucleus. Such a structure would facilitate
      formation of RET/PTC3 rearrangements because a single radiation track could
      produce concerted breaks in both genes, leading to inversion due to reciprocal
      exchange via end-joining.

PMID- 10597233
TI  - Regulation by Gi2 proteins of v-fms-induced proliferation and transformation via
      Src-kinase and STAT3.
AB  - We previously showed that Gi2 proteins interfere with the transduction of CSF-1
      receptor (CSF-1R) proliferation signals (Corre and Hermouet, 1995). To identify
      CSF-1R pathways controlled by Gi2, we transfected v-fms, the oncogenic equivalent
      of CSF-1R, in NIH3T3 cells in which Gi2 proteins were inactivated by stably
      expressing a dominant negative mutant form of the alpha subunit of Gi2 (alpha i2
      G204A). Expression of alpha i2-G204A resulted in decreased Src-kinase activity,
      delayed activation of p42 ERK-MAPK, decreased cyclin D1 expression and reduced
      proliferation in response to serum. In alpha i2-G204A cells transfected with v
      fms, Src-kinase activity remained deficient but p42 MAPK activity and cyclin D1
      expression were similar to those of vector/v-fms cells, suggesting that v-fms
      bypasses Src to activate the ERK-MAPK cascade. However, DNA synthesis and focus
      formation were inhibited by up to 80% in alpha i2-G204A/v-fms cells compared to
      vector/v-fms cells. We found that tyrosine phosphorylation of STAT3, also
      activated by CSF-1R/v-fms, was inhibited in alpha i2-G204A/v-fms cells; in
      addition, expression of an 85 kDa, C-terminal truncated form of STAT3 (STAT3
      delta) was constitutively increased. Both the inhibition of v-fms-induced STAT3
      tyrosine phosphorylation and the increased expression of STAT3 delta were
      reproduced by transfecting a dominant negative mutant of Src. Last, we show that
      expression of STAT3 delta 55C, a mutant form of STAT3 lacking the last 55 C
      terminal amino acids, is sufficient to inhibit DNA synthesis and v-fms-induced
      transformation in NIH3T3 cells. In summary, adequate regulation by Gi2 proteins
      of the activity of both Src-kinase and STAT3 is required for optimal cell
      proliferation in response to CSF-1R/v-fms.

PMID- 10597234
TI  - Conditional transformation of rat embryo fibroblast cells by a cyclin D1-cdk4
      fusion gene.
AB  - Cyclin D1 gene overexpression is a frequent event in a number of human cancers.
      These observations have led to the suggestion that cyclin D1 alterations might
      play a role in the etiology of cancer. This possibility is supported by the
      finding that transfection of mammalian cells with cyclin D1 can accelerate
      progression through the G1 phase of the cell cycle. Moreover, cyclin D1 can
      function as an oncogene by cooperating with activated Ha-ras to transform primary
      rat embryo fibroblasts (REFs). In addition, cyclin D1 transgenics develop
      hyperplasia and neoplasia of the thymus and mammary gland. We have constructed a
      novel fusion gene consisting of full-length human cyclin D1 and cdk4 genes. This
      fusion gene was expressed in insect cells and the fusion protein was shown to be
      enzymatically active. The fusion gene was expressed in mammalian cells under the
      control of tet-repressor. This fusion gene immortalized primary REFs, and
      cooperated with activated Ha-ras to transform primary REFs, in terms of anchorage
      independent growth in vitro and formation of tumors in vivo. Utilizing a tet
      regulated gene expression system, we have shown that proliferation of stably
      transfected primary REFs in vitro and in vivo is dependent on the continued
      expression of the cyclin D1-cdk4 fusion gene. These cell lines could be useful in
      the discovery of novel cancer therapeutics to modulate cyclin D1.cdk4 activity.

PMID- 10597235
TI  - Absence of APOBEC-1 mediated mRNA editing in human carcinomas.
AB  - The transgene expression of the catalytic subunit APOBEC-1 of the apo B mRNA
      editing enzyme-complex can cause hepatocellular carcinoma in mice and rabbits. It
      has been proposed that aberrant editing of mRNA may represent a novel oncogenic
      principle. This investigation aimed to define whether such aberrant hyperediting
      mediated by APOBEC-1 occurs in human carcinomas. Editing and hyperediting of apo
      B, NAT1 or NF1 mRNA was not identified in any of 28 resected tumor specimens,
      including hepatocellular, bile duct, gastric, colorectal, pancreatic adeno- and
      neuroendocrine, lung adeno-, medullary thyroid and breast carcinoma, soft tissue
      sarcoma and neuroblastoma. In most types of carcinoma, significant levels for
      full-length APOBEC-1 mRNA could not be detected. Low level expression of APOBEC-1
      was found in colorectal and gastric carcinoma where most of the APOBEC-1 mRNA is
      inactivated by alternate splicing. The 'auxiliary' components of the apo B mRNA
      editing enzyme-complex are missing in many tumors including colorectal and
      gastric carcinoma, but are highly expressed in hepatocellular, lung adeno- and
      breast carcinoma all of which lack APOBEC-1. Taken together, either APOBEC-1 or
      the 'auxiliary' components of the apo B mRNA editing enzyme-complex or both are
      missing in human carcinomas resulting in the absence of mRNA editing. Currently,
      there is no evidence that aberrant editing mediated by APOBEC-1 contributes to
      the tumorigenesis of natural human carcinomas.

PMID- 10597236
TI  - Absence of PPP2R1B gene alterations in primary ovarian cancers.
AB  - The PPP2R1B gene has recently been implicated as a tumor suppressor based on the
      finding of somatic alterations in lung and colon cancers. PPP2R1B is located on
      chromosome 11q22-24 which coincides with the site of frequent loss of
      heterozygosity (LOH) in ovarian cancer. We investigated if the PPP2R1B gene was
      inactivated in ovarian cancer by single strand conformational polymorphism (SSCP)
      and heteroduplex (HD) analysis of 99% of the coding region. LOH at the PPP2R1B
      locus was detected in 32% of the malignant tumors but no somatic alterations were
      detected in any of 65 malignant, five borderline or six benign tumors. A germline
      G > A transition (GGC > GAC) in codon 90 was detected in 4/76 tumors. This
      alteration has previously been described as a mutation but on further
      investigation we found that the frequency of this variant among 167 ovarian
      cancers (4.2%) was not statistically significantly different from that observed
      in 247 non-cancer random controls (2.4%). We conclude that the PPP2R1B gene is
      not involved in the pathogenesis of ovarian cancer. The codon 90 Gly > Asp
      alteration may represent a non-pathological polymorphism and consequently the
      mutation frequency reported in lung cancers may have been overstated and the
      designation of PPP2R1B as a tumor suppressor gene should be regarded with
      caution.

PMID- 10597237
TI  - Interactions between progestins and heregulin (HRG) signaling pathways: HRG acts
      as mediator of progestins proliferative effects in mouse mammary adenocarcinomas.
AB  - The present study addressed links between progestin and heregulin (HRG) signaling
      pathways in mammary tumors. An experimental model of hormonal carcinogenesis, in
      which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary
      adenocarcinomas in female Balb/c mice, was used. MPA induced an in vivo up
      regulation of HRG mRNA expression in progestin-dependent (HD) tumor lines.
      Mammary tumor progression to a progestin-independent (HI) phenotype was
      accompanied by a high constitutive expression of HRG. The HRG message arose from
      the tumor epithelial cells. Primary cultures of malignant epithelial cells from a
      HD tumor line were used to investigate HRG involvement on cell proliferation. HRG
      induced a potent proliferative effect on these cells and potentiated MPA
      mitogenic effects. Blocking endogenous HRG synthesis by antisense
      oligodeoxynucleotides (ASODNs) to HRG mRNA inhibited MPA-induced cell growth,
      indicating that HRG acts as a mediator of MPA-induced growth. High levels of ErbB
      2 and ErbB-3 expression and low ErbB-4 levels were found in HD cells. Treatment
      of these cells with either MPA or HRG resulted in tyrosine phosphorylation of
      both ErbB-2 and ErbB-3. Furthermore, both HRG and MPA proliferative effects were
      abolished when cells were treated with ASODNs to ErbB-2 mRNA, providing evidence
      for a critical role of ErbB-2 in HRG-induced growth. Finally, blocking type I
      insulin-like growth factor receptor (IGF-IR) expression with ASODN resulted in
      the complete inhibition of HRG proliferative effect, demonstrating that a
      functional IGF-IR is required for HRG mitogenic activity. These results provide
      the first evidence of interactions between progestins and HRB/ErbB signal
      transduction pathways in mammary cancer and the first demonstration that IGF-IR
      is required for HRG proliferative effects.

PMID- 10597238
TI  - Implication of mitochondria-derived reactive oxygen species, cytochrome C and
      caspase-3 in N-(4-hydroxyphenyl)retinamide-induced apoptosis in cervical
      carcinoma cells.
AB  - N-(4-Hydroxyphenyl)retinamide (4HPR) is currently used in cancer prevention and
      therapy trials. It is thought that its effects result from induction of
      apoptosis. 4HPR-induced apoptosis in human cervical carcinoma C33A cells involves
      enhanced generation of reactive oxygen species (ROS). In this study we explored
      the mechanism by which 4HPR increases ROS and induces apoptosis in these cells.
      4HPR induced cytochrome c release from mitochondria to cytoplasm, activated
      caspase-3, and caused a membrane permeability transition (MPT). All these 4HPR's
      effects, as well as the induction of apoptosis, were inhibited by antioxidants,
      which decrease ROS. Thenoyltrifluoroacetone, a mitochondrial respiratory chain
      (MRC) complex II inhibitor, and carbonylcyanide m-chlorophenyl hydrazone, which
      uncouples electron transfer and ATP synthesis and inhibits ROS generation by MRC,
      inhibited 4HPR-induced ROS generation very effectively. Rotenone, an MRC complex
      I inhibitor was less effective and azide, an MRC complex IV inhibitor, exhibited
      a marginal effect. In contrast, antimycin A, an MRC complex III inhibitor,
      enhanced 4HPR-induced ROS generation. These findings suggest that 4HPR enhances
      ROS generation by affecting a target between complex II and complex III,
      presumably coenzyme Q. This effect is followed by release of cytochrome c,
      increased caspase-3 activity, induction of MPT and eventual DNA fragmentation and
      cell death.

PMID- 10597239
TI  - Antiproliferative function of p27kip1 is frequently inhibited in highly malignant
      Burkitt's lymphoma cells.
AB  - Lack of detectable expression of p27kip1 cyclin dependent kinase inhibitor has
      previously been correlated with high degree of malignancy in human breast,
      colorectal, gastric and small cell lung carcinomas. Here we demonstrate that an
      inverse correlation between p27kip1 expression and tumour malignancy also exists
      in most types of human B cell lymphomas examined. A clear exception was Burkitt's
      lymphoma (BL), a highly malignant tumour which often expresses high levels of
      p27kip1. Analysis of p27kip1 derived from Burkitt's lymphoma cell lines
      expressing high levels of p27kip1, BL40 and BL41, in a cyclin E/cdk2 kinase
      inhibition assay demonstrated that p27kip1 is not permanently inactivated since
      heat treatment can restore the inhibitory activity of p27kip1. However, p27kip1
      expressed in these two cell lines is largely sequestered in inactive complexes
      and we have no evidence that c-myc or Epstein-Barr virus are responsible for the
      sequestration of p27kip1 in these two cell lines although c-myc and EBV are two
      oncogenic agents often associated with Burkitt's lymphomas. Interestingly, we
      observed that high level p27kip1 expression often correlated with cyclin D3
      overexpression both in vivo and in BL cell lines. The majority of p27kip1 in BL40
      cells was complexed with cyclin D3 indicating that overexpressed cyclin D3 may at
      least be part of the sequestering activity for the inhibitory function of
      p27kip1. Furthermore, cyclinD3/cdk4 complex could sequester p27kip1 in a cyclin
      E/cdk2 kinase assay in vitro. Finally, we show that cyclin D3 transfected into an
      inducible p27kip1 cell line could overcome the G1 arrest mediated by p27kip1.
      These results argue that in addition to down-regulation of p27kip1 expression,
      some tumour cells can sequester and tolerate the antiproliferative function of
      p27kip1. They also suggest a novel role for the overexpression of D-type cyclins
      as one pathway allowing tumour cells to overcome the antiproliferative function
      of p27kip1.

PMID- 10597240
TI  - Association of Pur alpha and E2F-1 suppresses transcriptional activity of E2F-1.
AB  - Protein-protein interaction can play an important role in the control of several
      biological events including gene transcription, replication and cell
      proliferation. E2F-1 is a DNA-binding transcription factor which, upon
      interaction with its target DNA sequence, induces expression of several S phase
      specific genes allowing progression of the cell cycle. Evidently, the activity of
      this protein is modulated by its cellular partner, pRb, which in the
      hypophosphorylated form, binds to E2F-1 and inactivates its transcriptional
      ability. In this study, we have demonstrated that expression of a sequence
      specific single-stranded DNA binding protein, Pur alpha, in cells decreases the
      ability of E2F-1 to exert its transcriptional activity upon the responsive
      promoter derived from DHFR. Results from band shift experiments revealed that
      while Pur alpha does not recognize the double-stranded DNA fragment containing
      the E2F-1 binding site, it has the ability to inhibit E2F-1 interaction with its
      target DNA sequence. Results from GST pull-down assays and the combined
      immunoprecipitation/Western blot analysis of nuclear extracts revealed a direct
      association of E2F-1 with Pur alpha in the absence of the DNA molecule containing
      the E2F-1 binding site. The association of Pur alpha with E2F-1 may increase the
      stability of E2F-1, as a higher level of E2F-1 was detected in cells coexpressing
      Pur alpha and E2F-1. The importance of these observations with respect to the
      role of Pur alpha in the control of cell cycle progression is discussed.

PMID- 10597241
TI  - p53 accumulation in apoptotic macrophages is an energy demanding process that
      precedes cytochrome c release in response to nitric oxide.
AB  - Apoptosis in response to stress signals activates effector caspases known to be
      regulated by the release of cytochrome c (Cyt c) from mitochondria and the
      subsequent ATP-dependent activation of the death regulator apoptotic protease
      activating factor 1 (Apaf-1). Experiments were carried out to determine whether
      the release of Cyt c is evoked by NO. in RAW 264.7 macrophages and to position
      signaling components relative to mitochondria. S-nitrosoglutathione and spermine
      NO caused a fast p53 accumulation, followed by Bcl-xL downregulation, Cyt c
      release, and caspase activation. These alterations were absent in p53 antisense
      expressing macrophages (R delta p53asn-11). In Bcl-2 overexpressing cells (Rbcl2
      14) Cyt c relocation and caspase activation were abrogated although p53
      accumulation remained intact. The use of caspase inhibitors revealed Cyt c
      release and decreased Bcl-xL expression to be caspase independent. ATP-depleted
      cells showed a shift from apoptosis towards necrosis and no p53 accumulation or
      caspase activation upon NO. addition. Conclusively, NO.-mediated apoptosis in
      macrophages is entirely controlled by the mitochondrial pathway with the
      implication that Cyt c relocation demands p53 accumulation. Moreover, pulse-chase
      experiments in combination with the ATP-depletion protocol identified p53
      accumulation and stabilization as an energy requiring process. This allowed to
      dissect two ATP-dependent steps, one is in association with Apaf-1 formation,
      while the other resides in p53 accumulation.

PMID- 10597242
TI  - Induction of the TRAIL receptor KILLER/DR5 in p53-dependent apoptosis but not
      growth arrest.
AB  - The TRAIL death receptor KILLER/DR5 is induced by DNA damaging agents in wild
      type p53-expressing cells. Here we show that, unlike the p53-target CDK-inhibitor
      p21WAF1/CIP1, the TRAIL death receptor KILLER/DR5 is only induced in cells
      undergoing p53-dependent apoptosis and not cell cycle arrest. Thus GM
      glioblastoma cells carrying an inducible MMTV-driven p53 gene undergo cell cycle
      arrest and upregulate p21 but not KILLER/DR5 expression upon dexamethasone
      exposure. WI38 normal lung fibroblasts undergoing cell cycle arrest in response
      to ionizing irradiation also induce p21 but not KILLER/DR5 gene expression.
      KILLER/DR5 upregulation is also deficient in irradiated lymphoblastoid cells
      derived from patients with Ataxia Teleangiectasia suggesting a role for the ATM
      p53 pathway in regulating KILLER/DR5 expression after DNA damage. Inhibition of
      transcription by Actinomycin D blocks both KILLER/DR5 and p21 induction in cells
      undergoing p53-dependent apoptosis. Our results suggest that the p53-dependent
      transcriptional induction of KILLER/DR5 death receptor is restricted to cells
      undergoing apoptosis and not cells undergoing exclusively p53-dependent G1
      arrest.

PMID- 10597243
TI  - A translation repressor element resides in the 3' untranslated region of human
      p53 mRNA.
AB  - The 3' untranslated region of human p53 mRNA represses translation both in vitro
      and in vivo. Here, we identify a cis-acting 66-nucleotide U-rich sequence in the
      human p53 mRNA 3' untranslated region that mediates translational repression.
      Using UV cross-linking, we detect a 40 kDa protein that interacts specifically
      with the p53 3'UTR containing the repressor element. Enhanced translation of p53
      mRNA contributes to the accumulation of p53 protein in cells exposed to gamma
      radiation and could be a consequence of relieving the inhibition mediated by the
      repressor element.

PMID- 10597244
TI  - Functional Rac-1 and Nck signaling networks are required for FGF-2-induced DNA
      synthesis in MCF-7 cells.
AB  - The effects of Fibroblast Growth Factor-2 (FGF-2) on breast cancer cell DNA
      synthesis are controversial. To elucidate the mechanisms by which FGF-2
      stimulates or inhibits DNA synthesis, we analysed FGF-2 signaling pathways in
      breast cancer MCF-7 and MCF-7 cells overexpressing Ha-Ras (MCF-7ras). We found
      that FGF-2-induction of DNA synthesis correlates with Ras transient activation,
      FRS-2 tyrosine phosphorylation and low level of expression of p66Shc. In
      addition, Nck-associated proteins are highly tyrosine phosphorylated and JNK
      reaches a higher level of activation when FGF-2 triggers DNA synthesis.
      Interestingly upon FGF-2 treatment, JNK activation and DNA synthesis are
      dependent on Rac-1 activity. These results confirm that in MCF-7 cells, induction
      of DNA synthesis by FGF-2 requires a transient activation of the Ras/MAPK cascade
      and demonstrates for the first time that intact Rac-1 and Nck signaling networks
      are required.

PMID- 10597245
TI  - Rac regulates the stability of the adherens junction and its components, thus
      affecting epithelial cell differentiation and transformation.
AB  - We have previously reported that activated rac (V12rac) can bring about
      hypertransformation of ras-transformed epithelial cells, which can be suppressed
      by the dominant negative form of rac (N17rac). Starting with primary epithelial
      cells, a series of cell lines expressing wild type (WT) or mutated forms of ras
      or rac were generated and analysed for their adhesive function and expression and
      association of adherens junction (AJ) proteins. Normal, primary epithelial cells
      were self-adhesive and expressed AJs that were very stable. The expression of
      constitutively active ras resulted in a decrease in, but not loss of, cell-cell
      adhesion, with concomitantly decreased stability of AJ components. This was
      extremely exacerbated by the co-expression of constitutively activate rac, but
      was suppressed by dominant negative rac, which resulted in increased cell-cell
      adhesion and extremely stable AJs. alpha-catenin also failed to associate with E
      cadherin-beta-catenin complexes in cells expressing V12rac. Expression of V12rac
      resulted in the loss of epithelial morphology. The extent of transformation of
      each cell type corresponded to the stability of the respective AJ complexes.
      Thus, rac seems to be involved in regulating the stability of AJs, which promote
      epithelial cell differentiation, and consequently, modulating tumor progression.

PMID- 10597246
TI  - 2-acetaminofluorene blocks cell cycle progression after hepatectomy by p21
      induction and lack of cyclin E expression.
AB  - In the Solt-Faber model DENA and 2-Acetaminofluorene (AAF) treatment combined
      with hepatectomy induces hepatocellular carcinoma in rats. In this model AAF
      blocks proliferation of hepatocytes, while oval cells restore liver mass. Here we
      studied the molecular mechanism involved in blocking AAF-dependent cell cycle
      progression of hepatocytes. AAF inhibits cell proliferation of hepatocytes shown
      by the lack of Cyclin E expression before the G1/S phase restriction point.
      Immunfluorescence studies revealed that Cyclin E positive signals were restricted
      to oval cells, while hepatocytes remained negative. Additionally, AAF treatment
      induces strong nuclear p53 expression which is associated with increased p21 mRNA
      levels. Inhibition of active Cyclin/CdK (cyclin dependent kinase) complexes is
      reflected in AAF-treated animals by decreased RB expression and phosphorylation.
      The decrease in RB expression and phosphorylation, which is essential in
      triggering DNA synthesis and Cyclin A expression, leads to a deficiency in
      transcriptionally active E2F complex formation after hepatectomy. Thus, two
      molecular explanations are evident to account for AAF-dependent cell cycle
      progression of hepatocytes in vivo: first, induction of p53 expression which
      leads to higher p21 mRNA levels, and second, a lack of Cyclin E expression at the
      G1/S phase restriction point after hepatectomy.

PMID- 10597247
TI  - Inhibitory effect of p21 in MCF-7 cells is overcome by its coordinated
      stabilization with D-type cyclins.
AB  - Coordinated accumulation of cyclin D1 and D3 is observed in 15% of primary breast
      cancers and in the breast cancer cell line MCF-7 this simultaneous overexpression
      is due to a defect in their ubiquitin-mediated proteolysis. The F-box protein
      Skp2 is a component of an SCF ubiquitin ligase complex and can associate with
      cyclin D1 and the cdk inhibitor p21 (Zhong-Kang et al., 1998). We extend this
      observation and show that cyclin D3 can also associate with Skp2 suggesting that
      cyclins D1, D3 and p21 may share the same SCF complex. In agreement with this
      hypothesis we report here that in primary breast cancers and in MCF-7 cells where
      cyclins D1 and D3 are elevated the level of p21 is also elevated. Further, we
      demonstrate that the turnover of p21 protein is reduced in MCF-7 cells. We show
      that p21 is active as a cdk inhibitor in this cell line but that the presence of
      elevated levels of cyclin D3 titrates p21 away from cyclin D1-cdk4/6 complexes
      and cdk2 complexes resulting in increased kinase activities. Our results suggest
      that a defect in the SCF complex may occur in 15-20% of breast cancers and that
      the resulting coordinated elevation of cyclins D1 and D3 overcomes the inhibition
      of cell cycle progression by p21. We propose that in the context of cyclins D1
      and D3 overexpression, p21 may promote cell cycle progression.

PMID- 10597248
TI  - Regulation of BRCA1 by protein degradation.
AB  - BRCA1, a tumor suppressor protein implicated in hereditary forms of breast and
      ovarian cancer, is transcriptionally regulated in a proliferation-dependent
      manner. In this study, we demonstrate a substantial role for proteolysis in
      regulating the BRCA1 steady-state protein level in several cell lines. N-acetyl
      leu-leu-norleucinal (ALLN), an inhibitor of the proteasome, calpain, and
      cathepsins, caused BRCA1 protein to accumulate in the nucleus of several human
      breast, prostate, and melanoma cell lines which express low or undetectable basal
      levels of BRCA1 protein, but not in cells with high basal expression of BRCA1.
      Protease inhibition did not increase BRCA1 synthesis, nor change its mRNA level,
      but it dramatically prolonged the protein's half-life. In contrast to ALLN,
      lactacystin and PS341, two specific proteasome inhibitors, as well as calpastatin
      peptide and PD150606, two selective calpain inhibitors, had no effect on BRCA1
      stability, whereas ALLM, an effective calpain and cathepsin inhibitor but weak
      proteasome inhibitor, did stimulate accumulation of BRCA1. Moreover, three
      inhibitors of acidic cysteine proteases, chloroquine, ammonium chloride and
      bafilomycin, were as effective as ALLN. These results demonstrate that
      degradation by a cathepsin-like protease in fine balance with BRCA1 transcription
      is responsible for maintaining the low steady-state level of BRCA1 protein seen
      in many cancer cells.

PMID- 10597249
TI  - Basic fibroblast growth factor induces a transformed phenotype in normal human
      melanocytes.
AB  - Basic fibroblast growth factor (bFGF or FGF-2) is produced by nearly all
      melanomas in vitro and in vivo but not by normal melanocytes, which require
      exogenous bFGF for growth. In this study, we transduced normal human melanocytes
      to overexpress two forms of bFGF: (bFGF-Long and bFGF-Short) using replication
      deficient adenovirus 5 vectors. bFGF-Long induced the 17.8, 22.5, 23.1 and 24.2
      kDa forms of bFGF, whereas bFGF-Short induced only the 17.8 kDa mature form.
      Growth of cultured melanocytes transduced with either vector was similar to that
      of nevus and melanoma cells and was independent of exogenous bFGF and of
      insulin/insulin-like growth factor 1, and cyclic AMP enhancers, requiring only
      phorbol ester as an exogenous mitogen. Like primary melanoma cells, transduced
      normal melanocytes grew anchorage independently in soft agar. When injected into
      the dermis of human skin grafted to mice, bFGF-transduced melanocytes
      proliferated for at least 20 days, whereas cells from control cultures showed
      poor survival and no proliferation. These results demonstrate that bFGF
      upregulation is a critical component in melanoma progression.

PMID- 10597250
TI  - LOT1 is a growth suppressor gene down-regulated by the epidermal growth factor
      receptor ligands and encodes a nuclear zinc-finger protein.
AB  - We previously reported cloning the rLot1 gene, and its human homolog (hLOT1),
      through analysis of differential gene expression in normal and malignant rat
      ovarian surface epithelial cells. Both human and rat ovarian carcinoma cell lines
      exhibited lost or decreased expression of this gene. Interestingly, the LOT1 gene
      localized at band q25 of human chromosome 6 which is a frequent site for LOH in
      many solid tumors including ovarian cancer. In this report we have further
      characterized the potential role of LOT1 in malignant transformation and
      developed evidence that the gene is a novel target of growth factor signaling
      pathway. Assays using transient transfections showed that LOT1 is a nuclear
      protein and may act as a transcription factor. In vitro and in vivo studies
      involving ovarian cancer cell lines revealed that expression of LOT1 is directly
      associated with inhibition of cellular proliferation and induction of
      morphological transformations. Additionally, we show that in normal rat ovarian
      surface epithelial cells Lot1 gene expression is responsive to growth factor
      stimulation. Its mRNA is strongly down-regulated by epidermal growth factor
      receptor (EGFR) ligands, namely EGF and TGF-alpha. Blocking the ligand-activated
      EGFR signal transduction pathway by the specific EGF receptor inhibitor,
      tyrphostin AG1478, and the MEK inhibitor, PD098059, restores the normal level of
      Lot1 gene expression. It appears that the regulation of Lot1 gene is unique to
      these ligands, as well as the growth promoting agent TPA, since other factors
      either did not affect Lot1 expression, or the effect was modest and transient.
      Altogether, the results suggest that Lot1 expression is primarily mediated via
      EGF receptor or a related pathway and it may regulate the growth promoting
      signals as a zinc-finger motif containing nuclear transcription factor.

PMID- 10597251
TI  - FMIP, a novel Fms-interacting protein, affects granulocyte/macrophage
      differentiation.
AB  - Hematopoietic cell growth, differentiation, and commitment to a restricted
      lineage are guided by a set of cytokines acting exclusively on cells expressing
      the corresponding cytokine receptor. The macrophage colony stimulating factor (M
      CSF, also termed CSF-1) and its cognate receptor, the tyrosine kinase c-Fms, are
      essential for monocyte and macrophage development. The underlying molecular
      mechanism, however, is poorly understood. Here we identified a novel Fms
      interacting protein (FMIP, MW 78 kDa) which binds transiently via its N-terminal
      144 residues to the cytoplasmic domain of activated Fms-molecules. Binding of
      FMIP was paralleled by rapid tyrosine phosphorylation within the binding domain
      which drastically reduced its ability to associate with Fms. Binding was specific
      as evidenced by co-immunoprecipitation and association with recombinant GST-Fms
      fusion proteins. No binding was observed with the tyrosine phosphorylated
      cytoplasmic domains of c-Kit, TrkA, c-Met, and the insulin receptor. The role of
      FMIP in hematopoietic differentiation was studied in the bipotential myeloid
      progenitor cell line, FDC-P1Mac11. Overexpression of FMIP prevented M-CSF induced
      macrophage differentiation. Instead, cells differentiated into granulocytes. Our
      data suggest that the level of FMIP expression could form a threshold that
      decides about differentiation either into macrophages or into granulocytes.

PMID- 10597252
TI  - VEGI, a new member of the TNF family activates nuclear factor-kappa B and c-Jun N
      terminal kinase and modulates cell growth.
AB  - Recently a new member of the human tumor necrosis factor (TNF) family named as
      VEGI was reported. However, very little is known about the biological activities
      displayed by this cytokine. In this report, we show that in myeloid cells VEGI
      activated the transcription factor kappa B (NF-kappa B) as determined by the
      electrophoretic mobility shift assay, induced degradation of I kappa B alpha, and
      nuclear translocation of p65 subunit of NF-kappa B. VEGI also activated NF-kappa
      B-dependent reporter gene expression. In addition, VEGI activated c-Jun N
      terminal kinase. When examined for growth modulatory effects, VEGI inhibited the
      proliferation of breast carcinoma (MCF-7), epithelial (HeLa), and myeloid (U-937
      and ML-1a) tumor cells; and activated caspase-3 leading to PARP cleavage. VEGI
      induced cytotoxicity was potentiated by inhibitors of protein synthesis. VEGI
      also induced proliferation of normal human foreskin fibroblast cells. The
      activity of VEGI could neither be neutralized by antibodies against TNF, nor
      could it compete with TNF binding, indicating that the activity of VEGI is not
      due to TNF and it binds to a distinct receptor. These results suggest that VEGI,
      a new member of the TNF family, has a signaling pathway similar to TNF and is
      most likely a multifunctional cytokine.

PMID- 10597253
TI  - The roles of caspase-3 and bcl-2 in chemically-induced apoptosis but not necrosis
      of renal epithelial cells.
AB  - The kidney is a target for toxicants including cisplatin and S-(1,2
      dichlorovinyl)-L-cysteine (DCVC), a metabolite of the environmental contaminant,
      trichloroethylene. Necrosis is well characterized in kidney cells, but pathways
      leading to apoptosis are less clear. Cysteine conjugates are useful toxicants
      because they induce either necrosis or apoptosis depending on chemical structure
      or antioxidant status. Herein, we show that in the renal epithelial cell line LLC
      PK1, activation of caspase-3 (CPP32/Yama/apopain) is crucial for apoptosis, but
      not necrosis. Apoptosis was blocked by zVAD.fmk, and partially by a cathepsin
      inhibitor. Caspase-3 activity and cleavage of poly(ADP-ribose) polymerase (PARP)
      was detected only during apoptosis. S-(1,1,2,2-Tetrafluoroethyl)-L-cysteine
      (TFEC), a metabolite of tetrafluoroethylene, kills cells only by necrosis, and
      did not activate caspases under any conditions. Apoptosis and activation of
      caspase-3 by cisplatin, but not DCVC, was prevented by bcl-2. Thus, caspase-3
      activation by bcl-2-dependent and -independent mechanisms is a terminal event in
      chemical-apoptosis of renal epithelial cells.

PMID- 10597254
TI  - Antisense expression for amphiregulin suppresses tumorigenicity of a transformed
      human breast epithelial cell line.
AB  - The epidermal growth factor (EFG) family of receptors and their respective
      ligands play a major role in breast cancer progression and are the targets of new
      therapeutic approaches. Following immortalization with SV40 T antigen of normal
      human breast epithelial cells, a transformed variant cell line (NS2T2A1) was
      selected for its increased tumorigenicity in nude mice. This cell line was shown
      to have a higher expression of EGF receptors (EGFR) and amphiregulin (AR) when
      compared to their normal counterparts or less aggressive transformed cells. Dual
      staining of EGFR and AR was observed in 50-60% of NS2T2A1 cells, while 30-40%
      cells expressed AR only. To explore the potential tumorigenic role of AR, a 1.1
      kb AR cDNA in an antisense orientation was transfected in NS2T2A1 cells. Three
      clones, selected by hygromycin B, expressed AR antisense RNA (AR AS1, AR AS2 and
      AR AS3 cell lines) in which AR protein expression was reduced (ranging from about
      50 to < 5%). The anchorage-independent growth of AR AS cell lines was reduced to
      levels ranging from 32.4-6.8% relative to the control cell line transfected with
      the vector alone. The clones expressing AR antisense RNA showed a reversion of
      the malignant phenotype when injected in nude mice, since a significant reduction
      of tumor intake was observed coincident with a significant tumor mass reduction
      (> 96%). Moreover, intra-tumoral vascularization decreased significantly in
      tumors derived from AR AS cells (26.7, 70.7 and 50.4% of control). These in vitro
      and in vivo data reveal the oncogenic nature of AR in transformed breast
      epithelial cells and imply a role for AR in tumor angiogenesis.

PMID- 10597255
TI  - Testicular wild-type p53 expression in transgenic mice induces spermiogenesis
      alterations ranging from differentiation defects to apoptosis.
AB  - While p53 is dispensable for development, an excess of p53 has dramatic
      consequences on the embryogenesis and on the cell differentiation. In an attempt
      to analyse in vivo the effects of p53 activity, we have generated transgenic mice
      expressing the wild-type p53 under the control of the metallothionein I promoter.
      In the three transgenic lines established, exogenous p53 is expressed
      constitutively in the postmeiotic cells of transgenic males and two lines are
      subfertile. Transgenic males expressing the upper level of p53 produce few
      spermatozoa since the majority of developing spermatids undergo apoptosis. In the
      subfertile males exhibiting an intermediate amount of p53, teratozoospermia is
      obvious suggesting an altered terminal differentiation of postmeiotic cells. In
      contrast lower level of p53 does not lead the third line to sterility. These
      results suggest that the activity of p53 is dependent in vivo on the amount of
      p53 present within cells, as it has been already demonstrated in vitro.

PMID- 10597256
TI  - Activation of Hex and mEg5 by retroviral insertion may contribute to mouse B-cell
      leukemia.
AB  - AKXD recombinant inbred mice develop a variety of leukemias and lymphomas due to
      retrovirally mediated insertional activation of cellular proto-oncogenes. We
      describe a new retroviral insertion site that is the most frequent genetic
      alteration in AKXD B-cell leukemias. Multiple genes flank the site of viral
      insertion, but the expression of just two, Hex and mEg5, is significantly
      upregulated. Hex is a divergent homeobox gene that is transiently expressed in
      many hematopoietic lineages, suggesting an involvement in cellular
      differentiation. mEg5 is a member of the bim-C subfamily of kinesin related
      proteins that are necessary for spindle formation and stabilization during
      mitosis. Our data provide the first genetic evidence for the activation of these
      genes in leukemia, and suggest that unscheduled expression of Hex and mEg5
      contributes to the development of B-cell leukemia. In addition, this work
      highlights the use of genomic approaches for the study of position effect
      mutations.

PMID- 10597257
TI  - A p53 and apoptotic independent role for p21waf1 in tumour response to radiation
      therapy.
AB  - Loss of p21 in human cancer cells results in checkpoint failure, induction of
      polyploidy and subsequent apoptosis following DNA damage. Tumours in
      immunodeficient mice derived from cells lacking p21 are also more sensitive to
      ionizing radiation than their wild-type counterparts. Abrogation of p53 in the
      p21+/+ parental cells results in an in vitro phenotype that is indistinguishable
      from that of the p21 knockout cells. Thus, the in vitro phenotype resulting from
      loss of p21 is consistent with its well-established role in the p53/p21 damage
      response pathway. However, despite the similar in vitro phenotype, p21+/+ cells
      with abrogated p53 show no evidence of the sensitivity observed in the p21-/-
      cells when grown as tumours in immunodeficient mice. The increased radio
      sensitization stabilization of p21-/- tumours is also unrelated to the increase
      in apoptosis observed in these tumours following radiation treatment. Apoptosis
      in the p21-/- tumours was significantly reduced by expression of bcl-2 without
      any corresponding change in the overall response of the tumour. Similarly,
      abrogation of p53 in the p21+/+ tumours substantially increased radiation-induced
      apoptosis within the tumours without increasing their radiation sensitivity.
      Dissociation of these in vivo and in vitro phenotypes indicates that p21
      participates in a novel in vivo specific damage response pathway that is distinct
      from its role in the p53 pathway, and therefore that it may be an effective
      therapeutic target for cancer therapy.

PMID- 10597258
TI  - Regulation of the Wilms' tumour suppressor protein transcriptional activation
      domain.
AB  - The Wilms' tumour suppressor protein WT1 contains a transcriptional regulatory
      domain that can either activate or repress transcription depending upon its
      cellular environment. The mechanistic basis for this dichotomy is unclear
      however. Here, we dissect the transcriptional regulatory domains of WT1. We find
      that a region within the domain of WT1 attributed to transcriptional repression
      is a potent suppressor of the activation domain at several promoters and in
      different cell types. In vitro transcription analysis suggests that the mechanism
      of suppression of the activation domain occurs at the level of transcription
      initiation. Furthermore we find that the WT1 suppression domain is able to
      inhibit a heterologous activation domain when fused in cis. Dissection of this
      domain resulted in the delineation of a 30 amino acid region that was sufficient
      to confer suppression of a transcriptional activation domain both in vivo and in
      vitro. Additionally, we find that the WT1 transcriptional activation domain
      interacts with the general transcription factor TFIIB and that this interaction
      is not affected by the suppression domain. Taken together, these studies suggest
      that the suppression domain of WT1 interacts with a cosuppressor protein to
      mediate inhibition of the WT1 transcriptional activation domain.

PMID- 10597259
TI  - Ras pathway is required for the activation of MMP-2 secretion and for the
      invasion of src-transformed 3Y1.
AB  - To search for the signaling pathway critical for tumor invasion, we examined the
      effects of dominant negative ras (S17N ras) expression on the activation of
      matrix metalloproteinase-2 (MMP-2) in src-transformed 3Y1, SR3Y1, under the
      control of conditionally inducible promoter. In SR3Y1 clones transfected with
      S17N ras, augmented secretion and proteolytic activation of MMP-2 were
      dramatically suppressed by S17N Ras expression, while tyrosine phosphorylation of
      cellular proteins was not suppressed. We found that invasiveness of SR3Y1 cells
      assayed by the modified Boyden Chamber method was strongly suppressed by S17N Ras
      expression. In contrast, cell morphology reverted partially and glucose uptake
      remained unchanged by S17N Ras expression. In addition, treatment of SR3Y1 with
      manumycin A, a potent inhibitor of Ras farnesyltransferase, strongly suppressed
      both augmented secretion and proteolytic activation of MMP-2. Contrary, treatment
      of SR3Y1 with wortmannin or TPA showed no clear effect on MMP-2 activation. Thus,
      these results strongly suggest that Ras-signaling, but neither P13 kinase- nor
      protein kinase C-signalings, plays a critical role in activation of MMP-2 and,
      subsequently, in the invasiveness of src-transformed cells.

PMID- 10597260
TI  - Protein kinase C-alpha overexpression stimulates Akt activity and suppresses
      apoptosis induced by interleukin 3 withdrawal.
AB  - To investigate the role of protein kinase C (PKC) in apoptotic signaling induced
      by cytokine withdrawal, we expressed PKC-alpha, -delta and -epsilon individually
      in the 32D myeloid progenitor cells. The parental and PKC-delta- and PKC-epsilon
      transfected 32D cells underwent apoptosis within 24 h in the absence of
      interleukin 3. In contrast, expression of PKC-alpha inhibited the onset of
      apoptosis as determined by genomic DNA fragmentation and flow cytometric
      analysis. Correlating with the inhibition of apoptosis, PKC-alpha transfectants
      exhibited increased activity of the endogenous Akt serine/threonine kinase.
      Furthermore, PKC-alpha, but not PKC-delta or -epsilon, specifically activated
      overexpressed Akt. PKC-alpha-induced Akt activity was partially dependent on
      phosphoinositol 3' kinase (PI 3'K) since a PI 3'K inhibitor was able to suppress
      PKC-alpha-induced Akt activation. Both basal and interleukin 3-stimulated
      phosphorylation of Akt on serine 473 was enhanced in the PKC-alpha and Akt
      contransfectants. Coexpression of wild type Akt and PKC-alpha resulted in greater
      suppression of apoptosis than PKC-alpha expression alone. Together, our results
      demonstrate that suppression of apoptosis by PKC-alpha correlates with its
      ability of activating endogenous Akt. Furthermore, activation of overexpressed
      Akt by PKC-alpha is consistent with their synergistic effect on suppressing
      apoptosis, providing the strong evidence of cross talk between Akt and PKC-alpha.

PMID- 10597261
TI  - Cytokine response gene 6 induces p21 and regulates both cell growth and arrest.
AB  - Cytokine response gene #6 (CR6), cloned from interleukin 2-stimulated T
      lymphocytes, is homologous to GADD45 and MyD118, genes which promote cell cycle
      arrest and apoptosis. To determine how this gene family could possibly mediate
      both cell survival/proliferation and cell cycle arrest/death, transfectants were
      generated so that the genes could be expressed ectopically, independently from
      their normal inducing agents. In cycling retinoblastoma protein-negative (pRb-)
      cells, ectopic CR6 expression blocked G2/M transition, but did not prevent G1/S
      transition so that endoreduplication resulted. By comparison, when CR6, GADD45,
      and MyD118 genes were expressed ectopically in proliferating pRb+ cells, either
      G1/S or G2/M transition was effectively blocked, so that there was no
      endoreduplication. Consistent with these findings, in proliferating pRb-cells,
      ectopic expression of CR6 promoted the expression of both G1 and G2/M cyclins. By
      comparison, in pRb+ cells, the expression of G1 cyclins was increased, while
      expression of the mitotic cyclins was decreased. However, in pRb+ cells, cyclin
      dependent kinase activities associated with both G1 and G2/M cyclins were
      decreased. Moreover, ectopic expression of all three genes resulted in the
      expression of the CKI, p21, both in pRb- and pRb+ cells. The physiologic
      induction of CR6 expression by IL2 in quiescent normal human T cells occurs
      transiently in the first half of G1, coordinately with the expression of p21.
      Therefore, this gene family regulates G1 and G2, and promotes either cell growth
      or arrest by a common mechanism.

PMID- 10597262
TI  - Close correlation between beta-catenin gene alterations and nuclear accumulation
      of the protein in human hepatocellular carcinomas.
AB  - Several lines of evidence indicate that beta-catenin acquires oncogenic activity
      when its intracellular concentration increases as a result of either mutation in
      the beta-catenin gene itself or inactivation of the adenomatous polyposis coli
      (APC) gene. In an attempt to elucidate the molecular mechanisms underlying
      hepatocellular carcinogenesis, we have studied the frequency of beta-catenin gene
      alterations in exon 3, a region known to represent a mutation hot spot, and its
      inappropriate protein expression by immunohistochemistry in 73 hepatocellular
      carcinomas (HCCs). The results were correlated with different clinical and
      pathological data, particularly with the presence or not of an associated
      cirrhosis. Fourteen (19%) HCCs showed beta-catenin gene alterations with missense
      mutations in nine cases and interstitial deletions in five cases. These genetic
      alterations were present in both cirrhotic and non-cirrhotic groups. By contrast,
      we did not find any beta-catenin gene alterations in the nine fibromellar
      carcinomas we examined. Nuclear accumulation of the protein was observed in 18 of
      them (25%). Remarkably, these included ten of the 14 tumors harboring somatic
      mutations in the beta-catenin gene (P < 0.001). Our results indicate that
      accumulation of beta-catenin resulting from genetic mutations is a frequent event
      in non-fibrolamellar type hepatocellular carcinoma. The close association between
      increased beta-catenin protein stability and mutation indicates that
      immunohistochemistry may be a powerful method for the detection of the mutated
      protein in future clinical practice.

PMID- 10597263
TI  - Loss of anti-mitotic effects of Bcl-2 with retention of anti-apoptotic activity
      during tumor progression in a mouse model.
AB  - Bcl-2 is an anti-apoptotic and anti-proliferative protein over-expressed in
      several different human cancers including breast. Gain of Bcl-2 function in
      mammary epithelial cells was superimposed on the WAP-TAg transgenic mouse model
      of breast cancer progression to determine its effect on epithelial cell survival
      and proliferation at three key stages in oncogenesis: the initial proliferative
      process, hyperplasia, and cancer. During the initial proliferative process, Bcl-2
      strongly inhibited both apoptosis and mitotic activity. However as tumorigenesis
      progressed to hyperplasia and adenocarcinoma, the inhibitory effects on mitotic
      activity were lost. In contrast, anti-apoptotic activity persisted in both
      hyperplasias and adenocarcinomas. These results demonstrate that the inhibitory
      effect of Bcl-2 on epithelial cell proliferation and apoptosis can separate
      during cancer progression. In this model, retention of anti-apoptotic activity
      with loss of anti-proliferative action resulted in earlier tumor presentation.

PMID- 10597264
TI  - Bcl-2 expression delays mammary tumor development in dimethylbenz(a)anthracene
      treated transgenic mice.
AB  - Bcl-2 is known to have dual antiproliferative and antiapoptotic roles.
      Overexpression of Bcl-2 in the mammary gland using a whey acidic protein (WAP)
      promoter-driven Bcl-2 transgene inhibits apoptosis in the mammary gland during
      pregnancy, lactation, and involution, and also counteracts apoptosis induced by
      overexpression of a mutant p53 transgene (WAP-p53 172 R-L). WAP-Bcl-2 mice and
      nontransgenic controls were treated with the carcinogen dimethylbenz(a)anthracene
      (DMBA). Surprisingly, the nontransgenic mice developed mammary tumors with
      decreased latency. Tumors arising in WAP-Bcl-2 mice displayed substantially
      reduced levels of proliferation relative to those seen in nontransgenic mice (P <
      0.015), perhaps resulting in the observed increase in tumor latency following
      carcinogen treatment. This WAP-Bcl-2 mouse tumor model reflects the situation
      seen in some human breast cancers overexpressing Bcl-2, where expression of Bcl-2
      has been shown to correlate with a lower proliferative index in tumors.

PMID- 10597266
TI  - Predominance of beta-catenin mutations and beta-catenin dysregulation in sporadic
      aggressive fibromatosis (desmoid tumor).
AB  - Aggressive fibromatosis (also called desmoid tumor) occurs as a sporadic lesion
      or as part of Familial Adenomatous Polyposis, which is caused by germ line
      mutations in the Adenomatous polyposis Coli (APC) gene. APC is involved in the
      regulation of the cellular level of beta-catenin, which is a mediator in Wnt
      signaling. Mutational analysis of the beta-catenin and APC genes was performed in
      42 sporadic aggressive fibromatoses. Nine tumors had mutations in APC, and 22 had
      a point mutation in beta-catenin at either codon 45 or codon 41 (producing a
      stabilized beta-catenin protein product). Immunohistochemistry showed an elevated
      beta-catenin protein level in all tumors, regardless of mutational status. Beta
      catenin localized to the nucleus, and was not tyrosine phosphorylated in the six
      tumors in which this was tested. The demonstration of mutations in two mediators
      in the Wnt-APC-beta-catenin pathway implicates beta-catenin stabilization as the
      key factor in the pathogenesis of aggressive fibromatosis. This is the first
      demonstration of somatic beta-catenin mutations in a locally invasive, but non
      metastatic lesion composed of spindle cells, illustrating the importance of beta
      catenin stabilization in a variety of cell types and neoplastic processes.
      Moreover, this tumor has one of the highest reported frequencies of beta-catenin
      mutations of any tumor type.

PMID- 10597265
TI  - BRCA1 signals ARF-dependent stabilization and coactivation of p53.
AB  - The hereditary breast and ovarian tumor suppressor BRCA1 can activate p53
      dependent gene expression. We show here that BRCA1 increases p53 protein levels
      through a post-transcriptional mechanism. BRCA1-stabilized p53 has increased
      sequence-specific DNA-binding and transcriptional activity. BRCA1 does not
      stabilize p53 in p14ARF-deficient cells. A deletion mutant of BRCA1 which
      inhibits p53-dependent transcription confers resistance to topoisomerase II
      targeted chemotherapy. Our results suggest that BRCA1 may trigger the p53 pathway
      through two potentially separate mechanisms: accumulation of p53 through a direct
      or indirect induction of p14ARF as well as direct transcriptional coactivation of
      p53. BRCA1 may also enhance chemosensitivity and repair of DNA damage through
      binding to and coactivation of p53.

PMID- 10597267
TI  - Mmip-2, a novel RING finger protein that interacts with mad members of the Myc
      oncoprotein network.
AB  - Mad proteins are basic-helix-loop-helix-leucine zipper (bHLH-ZIP)-containing
      members of the myc oncoprotein network. They interact with the bHLH-ZIP protein
      max, compete for the same DNA binding sites as myc-max heterodimers and down
      regulate myc-responsive genes. Using the bHLH-ZIP domain of mad1 as a yeast two
      hybrid 'bait', we identified Mmip-2, a novel RING finger protein that interacts
      with all mad members, but weakly or not at all with c-myc, max or unrelated bHLH
      or bZIP proteins. The mad1-Mmip-2 interaction is mediated by the ZIP domain in
      the former protein and by at least two regions in the latter which do not include
      the RING finger. Mmip-2 can disrupt max-mad DNA binding and can reverse the
      suppressive effects of mad proteins on c-myc-responsive target genes and on c-myc
      + ras-mediated focus formation in fibroblasts. Tagging with spectral variants of
      green fluorescent protein showed that Mmip-2 and mad proteins reside in separate
      cytoplasmic and nuclear compartments, respectively. When co-expressed, however,
      the proteins interact and translocate to the cellular compartment occupied by the
      more abundant protein. These observations suggest a novel way by which Mmip-2 can
      modulate the transcriptional activity of myc oncoproteins.

PMID- 10597268
TI  - Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated
      protein kinase pathway.
AB  - The function of the pro-apoptotic molecule BAD is regulated by phosphorylation of
      two sites, serine-112 (Ser-112) and serine-136 (Ser-136). Phosphorylation at
      either site results in loss of the ability of BAD to heterodimerize with the
      survival proteins BCL-XL or BCL-2. Phosphorylated BAD binds to 14-3-3 and is
      sequestered in the cytoplasm. It has been shown that phosphorylation of BAD at
      Ser-136 is mediated by the serine/threonine protein kinase Akt-1/PKB which is
      downstream of phosphatidylinositol 3-kinase (PI3K). The signaling process leading
      to phophorylation of BAD at Ser-112 has not been identified. In this study, we
      show that phosphorylation of the two serine residues of BAD is differentially
      regulated. While Ser-136 phosphorylation is concordant with activation of Akt,
      Ser-112 phosphorylation does not correlate with Akt activation. Instead, we
      demonstrate that activated Ras and Raf, which are upstream of mitogen-activated
      protein kinases (MAPK), stimulate selective phosphorylation of BAD at Ser-112.
      Furthermore, phosphorylation of Ser-112, but not Ser-136 requires activation of
      the MAPK pathway as the MEK inhibitor, PD 98059, blocks EGF-, as well as
      activated Ras- or Raf-mediated phosphorylation of BAD at Ser-112. Therefore, the
      PI3K-Akt and Ras-MAPK pathways converge at BAD by mediating phosphorylation of
      distinct serine residues.

PMID- 10597269
TI  - Mitochondrial DNA determines the cellular response to cancer therapeutic agents.
AB  - Mutations in the mitochondrial genome leading to mitochondrial dysfunction have
      been reported in a variety of cancers. However, the potential implication of
      these findings in the cellular response to cancer therapeutic agents is unclear.
      To examine the importance of mitochondrial DNA (mitDNA) encoded functions in
      cancer therapeutic response, we determined the clonogenic survival of HSL2 (Rho+,
      HeLa subline), and its derivative cell line lacking mitDNA (Rho0) after exposure
      to different anticancer agents. We found that isogenic Rho0 cells lacking mitDNA
      were extremely resistant to adriamycin and photodynamic therapy (PDT) induced
      cell death, whereas the Rho+ cell line was sensitive. However, there was no
      measurable difference in the responses of these cell lines to either alkylating
      agent or gamma-radiation. We show that the development of resistance to
      adriamycin was not due to changes in apoptotic cell death, cell cycle response or
      to the uptake of adriamycin in isogenic Rho0 cells. We also demonstrate that
      exposure of HeLa cells to adriamycin leads to mutations in mitDNA. These studies
      provide direct evidence that mitDNA plays an important role in cellular
      sensitivity to cancer therapeutic agents.

PMID- 10597270
TI  - Concentration-dependent positive and negative regulation of a MAP kinase by a MAP
      kinase kinase.
AB  - There are at least three distinct MAP kinase signaling modules in mammalian
      cells, distinguished by the family of kinases (Erk, SAPK/JNK, or p38) that is
      ultimately activated. Many input signals activate multiple MAP kinase cascades,
      and the mechanisms that control the specificity of signal output are not well
      understood. We show that SEK1/MKK4, a MAP kinase kinase proposed to activate
      SAPK/JNK, is a very potent inhibitor of p54 SAPK beta/JNK3 both in vitro and in
      vivo if present at equimolar or higher ratios. In contrast SEK can activate SAPK
      when present in substoichiometric amounts, but this activation is slow,
      consistent with the rate-limiting step in activation being the dissociation of an
      inactive SEK:SAPK complex. The N-terminal unique region of SEK is both necessary
      and partially sufficient for inhibition of SAPK, and is also necessary for
      activation of SAPK by SEK in vitro. We have also used the p38 MAP kinase and its
      activator MKK6 to examine the regulatory relationships among different kinases
      involved in stress responses. We show using purified kinases that inhibitory
      activity is specific for the combination of SEK and SAPK: SEK can activate but
      not inhibit p38, and MKK6 can activate but not inhibit SAPK beta and p38. These
      results reveal a potential mechanism for regulating stress-activated kinases,
      adding to a growing body of evidence suggesting that MAP kinases are controlled
      by relatively stable interactions with their activators.

PMID- 10597271
TI  - The alpha isoform of protein kinase C mediates phorbol ester-induced growth
      inhibition and p21cip1 induction in HC11 mammary epithelial cells.
AB  - To clarify the roles of specific isoforms of PKC in regulating growth and cell
      cycle progression of the HC11 mammary epithelial cell line, we investigated the
      effects of activating endogenous PKC isoforms with the phorbol ester tumor
      promoter TPA, and also the effects of TPA on genetically engineered cells
      containing increased levels of individual PKC isoforms. We found that TPA
      treatment of HC11 cells induced a transient cell cycle arrest in G0/G1. Western
      blot analyses of the TPA treated cells provided evidence that the endogenous PKC
      alpha present in these cells mediated these effects. Indeed, derivatives of the
      HC11 cell line that inducibly overexpress an exogenous PKC alpha or ectopic PKC
      beta 1 exhibited more marked growth inhibition by TPA than control cells.
      Immunohistochemical staining of cells following treatment with TPA revealed
      selective translocation of PKC alpha into the nucleus, whereas PKC beta 1
      remained in the cytoplasm. The transient arrest of HC11 cells following treatment
      with TPA was associated with marked induction of both p21cip1 mRNA and protein.
      This induction was exaggerated in the derivatives that overexpressed either PKC
      alpha or PKC beta 1. Therefore, in mouse mammary epithelial cells activation of
      the endogenous PKC alpha can transiently arrest cells in G0/G1 which may be due,
      at least in part, to induction of the transcription of p21cip1.

PMID- 10597272
TI  - Growth factor-regulated expression of enzymes involved in nucleotide
      biosynthesis: a novel mechanism of growth factor action.
AB  - Keratinocyte growth factor (KGF) is a potent and specific mitogen for epithelial
      cells, including the keratinocytes of the skin. We investigated the mechanisms of
      action of KGF by searching for genes which are regulated by this growth factor in
      cultured human keratinocytes. Using the differential display RT-PCR technology we
      identified the gene encoding adenylosuccinate lyase [EC 4.3.2.2] as a novel KGF
      regulated gene. Adenylosuccinate lyase plays an important role in purine de novo
      synthesis. To gain further insight into the potential role of nucleotide
      biosynthesis in the mitogenic effect of KGF, we cloned cDNA fragments of the key
      regulatory enzymes involved in purine and pyrimidine metabolism (adenylosuccinate
      synthetase [EC 6.3.4.4], phosphoribosyl pyrophosphate synthetase [EC 2.7.6.1],
      amidophosphoribosyl transferase [EC 2.4.2.14], hypoxanthine guanine
      phosphoribosyl transferase [EC 2.4.2.8] and the multifunctional protein CAD which
      includes the enzymatic activities of carbamoyl-phosphate synthetase II [EC
      6.3.5.59], aspartate transcarbamylase [EC 2.1.3.2] and dihydroorotase [EC
      3.5.2.3]). Expression of all of these enzymes was upregulated after treatment
      with KGF and also with epidermal growth factor (EGF), indicating that these
      mitogens stimulate nucleotide production by induction of these enzymes. To
      determine a possible in vivo correlation between the expression of KGF, EGF and
      the enzymes mentioned above, we analysed the expression of the enzymes during
      cutaneous wound repair, where high levels of these mitogens are present. Indeed,
      we found a strong mRNA expression of all of these enzymes in the EGF- and KGF
      responsive keratinocytes of the hyperproliferative epithelium at the wound edge,
      indicating that their expression might also be regulated by growth factors during
      wound healing.

PMID- 10597273
TI  - Homozygous deletions and point mutations of the Ikaros gene in gamma-ray-induced
      mouse thymic lymphomas.
AB  - Our previous genome-wide analysis of allelic loss for thymic lymphomas that were
      induced by gamma-irradiation in F1 hybrid mice between BALB/c and MSM strains
      suggested the centromeric region on chromosome 11 as a site harboring a tumor
      suppressor gene. Interestingly, to this region the mouse Ikaros gene was mapped
      which was postulated to participate in oncogenic process from the study of Ikaros
      knockout mice. Here we show fine allelic loss mapping in the vicinity of Ikaros
      in 191 lymphomas, indicating that the critical region of allelic loss was
      centered at the Ikaros locus. PCR analysis revealed that nine lymphomas failed to
      give PCR-amplification for either of two exon primer pairs, indicative of
      homozygous deletion. Six and five mutations were detected in the N-terminal zinc
      finger domain and the activation domain of Ikaros, respectively, and six of the
      eleven were frameshift or nonsense mutations that resulted in truncation of
      Ikaros protein. The results strongly suggest a direct role for Ikaros in
      development of mouse thymic lymphomas. This provides the experimental basis for
      further analysis of Ikaros mutations in human cancer.

PMID- 10597274
TI  - The Brn-3b POU family transcription factor represses expression of the BRCA-1
      anti-oncogene in breast cancer cells.
AB  - The BRCA-1 tumour supressor gene was identified on the basis of mutations which
      occur in familial breast cancer indicating that its inactivation can cause this
      disease. Although BRCA-1 does not appear to be mutated in sporadic breast cancer,
      its expression has been shown to be reduced in tumour material from such cases.
      We show here that mammary tumours which have reduced levels of BRCA-1 expression
      show enhanced expression of the Brn-3b POU family transcription factor at both
      the mRNA and protein levels. This elevated expression of Brn-3b is not found in
      normal mammary cells, benign tumours or in malignant tumour samples which do not
      exhibit reduced levels of BRCA-1. In contrast, no correlation was noted between
      BRCA-1 and expression of the related factor Brn-3a. Moreover, Brn-3b but not Brn
      3a can strongly repress the BRCA-1 promoter approximately 20-fold in mammary
      tumour cells. To our knowledge, this is the first report of a transcription
      factor which regulates BRCA-1 expression. Thus, Brn-3b may play an important role
      in regulating expression of BRCA-1 in mammary tumours with enhanced expression of
      Brn-3b resulting in reduced BRCA-1 expression and thereby being potentially
      important in tumour development.

PMID- 10597275
TI  - Overexpression of activated neu/erbB2 initiates immortalization and malignant
      transformation of immature Schwann cells in vitro.
AB  - The neu/erbB2 protooncogene is overexpressed in numerous human cancers and is
      mutationally activated in N-ethyl-N-nitrosourea (ENU)-induced rodent tumors of
      the Schwann cell lineage. We investigated whether expression of activated neu in
      Schwann cells is sufficient to initiate their immortalization and transformation.
      Clones of embryonic dorsal root ganglia cells infected with a retrovirus bearing
      activated neu (NID cells) were selected based on their expression of Schwann cell
      specific markers. Compared to embryonic Schwann cells infected with a virus
      encoding empty vector, we found that NID cells have altered shapes and
      disorganized cytoskeletons, grow in the absence of growth factors required for
      normal Schwann cell survival and proliferation, and can be repeatedly passaged.
      Furthermore, NID cells are invasive in an in vitro matrix invasion assay and form
      metastatic tumors when injected into syngeneic animals. The neu-induced growth
      and invasive phenotypes could be reversed by drugs that inhibit Ras and Src
      activity. Interestingly, later stage Schwann cells infected with activated neu
      failed to become immortalized. These findings indicate that constitutive
      activation of erbB2 is sufficient to initiate the immortalization and
      transformation of immature Schwann cells, and support the notion that Schwann
      cells have particular developmental stages during which they are susceptible to
      immortalizing and transforming events.

PMID- 10597276
TI  - Src is required for cell migration and shape changes induced by fibroblast growth
      factor 1.
AB  - Fibroblast growth factor 1 (FGF-1) is a potent chemotactic factor and induces
      tyrosine phosphorylation of a cortical actin-associated protein (cortactin). The
      tyrosine phosphorylation of cortactin induced by FGF-1 requires the tyrosine
      residues 421, 482 and 466, which are targeted by the protein tyrosine kinase Src
      in vitro. Furthermore, FGF-1 is unable to induce tyrosine phosphorylation of
      cortactin within the cells derived from Src knockout mice (Src-/-), indicating
      that Src is required for the tyrosine phosphorylation of cortactin induced by FGF
      1. Although Src-/- cells are able to undergo rapid proliferation, they are
      impaired to respond to FGF-1 for the shape change and cell migration.
      Morphological analysis further reveals that FGF-1 fails to induce the formation
      of polarized lamellipodia and the translocation of cortactin into the leading
      edge of Src-/- cells. Consistent with the mitogenic response to FGF-1, the lack
      of Src does not affect the tyrosine phosphorylation of Snt (or Frs2), a FGF-1
      early signaling protein that links to Ras. Therefore, our data support the notion
      that Src and cortactin participate in a FGF signal pathway for cell migration and
      shape change rather than mitogenesis.

PMID- 10597277
TI  - ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate
      specificity distinct from DNA-PK.
AB  - ATR is a large, > 300 kDa protein containing a carboxy-terminus kinase domain
      related to PI-3 kinase, and is homologous to the ATM gene product in human cells
      and the rad3/MEC1 proteins in yeast. These proteins, together with the DNA-PK,
      are part of a new family of PI-3 kinase related proteins. All members of this
      family play important roles in checkpoints which operate to permit cell survival
      following many forms of DNA damage. We have expressed ATR protein in HEK293 cells
      and purified the protein to near-homogeneity. We show that pure ATR is a protein
      kinase which is activated by circular single-stranded, double-stranded or linear
      DNA. Thus ATR is a new member of a sub-family of PIK related kinases, founded by
      the DNA-PK, which are activated in the presence of DNA. Unlike DNA-PK, ATR does
      not appear to require Ku proteins for its activation by DNA. We show directly
      that, like ATM and DNA-PK, ATR phosphorylates the genome surveillance protein p53
      on serine 15, a site which is up-regulated in response to DNA damage. In
      addition, we find that ATR has a substrate specificity similar to, but unique
      from, the DNA-PK in vitro, suggesting that these proteins have overlapping but
      distinct functions in vivo. Finally, we find that the kinase activity of ATR in
      the presence and absence of DNA is suppressed by caffeine, a compound which is
      known to induce loss of checkpoint control. Our results are consistent with the
      notion that ATR plays a role in monitoring DNA structure and phosphorylation of
      proteins involved in the DNA damage response pathways.

PMID- 10597278
TI  - The human papillomavirus type 16 E5 protein modulates phospholipase C-gamma-1
      activity and phosphatidyl inositol turnover in mouse fibroblasts.
AB  - The human papillomavirus type 16 E5 (HPV16-E5) protein is a membrane protein that
      has been associated with malignant growth. The protein affects growth factor
      mediated signal transduction in a ligand-dependent manner. We show now that E5
      expression in A31 fibroblasts results in an increased level of diacylglycerol
      (DAG) and inositol phosphates. Immunoprecipitation of phospholipase C-gamma-1
      (PLC-gamma-1) with specific antibodies and immunoblotting with anti
      phosphotyrosine antibodies reveal a large increase in tyrosine phosphorylation of
      the enzyme in E5-expressing cells compared to control vector-transfected cells.
      This activation of tyrosine phosphorylation is growth factor independent. In
      addition, an enhanced formation of phosphatidic acid (PA) was observed in E5
      cells. This increase did not result from activation of phospholipase D (PLD),
      although the enzyme was activatable by treatment with phorbol ester Thus, a
      phosphohydrolase-mediated DAG synthesis from PLD-produced PA can be excluded. The
      observed effects were not further enhanced by EGF showing that the presence of
      the growth factor is not necessary for maintaining permanent activation of PLC
      gamma-1 in E5-expressing cells. The DAG- and inositol phosphate-mediated signal
      cascade within the cells is thus effectively uncoupled from external control via
      EGF and its receptor in the presence of E5 protein.

PMID- 10597279
TI  - Nuclear 24 kD fibroblast growth factor (FGF)-2 confers metastatic properties on
      rat bladder carcinoma cells.
AB  - The tumorigenic and metastatic properties of rat bladder carcinoma NBT-II cells
      transfected with a cDNA encoding the 24 kD nuclear isoform of human fibroblast
      growth factor-2 (FGF-2) were analysed and compared with those cells producing the
      18 kD cytoplasmic isoform FGF-2. In transfected clones, 24 kD FGF-2 was found in
      the nucleus, and no FGF-2 was secreted. RT-PCR analysis showed no upregulation of
      FGF-2-specific receptor FGFR2c expression in these proliferating transfected
      cells. A shorter latency period for in vivo tumor formation and abundant
      spontaneous lung metastases were only seen if nuclear FGF-2-producing cells were
      injected subcutaneously into nude mice. Intravenous injection of 24 kD FGF-2
      producing cells led to extensive experimental lung metastases whereas injection
      of control NBT-II cells or 18 kD FGF-2-producing cells did not. As FGF-2
      producing cells have no specific FGF-2 receptors, our results suggest that the 24
      kD FGF-2 has nuclear targets, and activates metastatic property of carcinoma
      cells via a mechanism other than the conventional FGF receptor-mediated signaling
      pathway.

PMID- 10597280
TI  - The induction and activation of STAT1 by all-trans-retinoic acid are mediated by
      RAR beta signaling pathways in breast cancer cells.
AB  - Retinoic acid receptor-beta (RAR beta) and signal transducer and activator of
      transcription 1 (STAT1) are important mediators of the antiproliferative and
      apoptotic actions of retinoids and cytokines/growth factors, respectively.
      Expression of both RAR beta and STAT1 is lost in most breast cancer cell lines
      but it can be induced by retinoids in estrogen receptor-positive cells. We
      investigated a possible functional connection between these two mediators and
      present evidence supporting RAR beta as a tumor suppressor. First, by using
      different receptor-selective retinoids, we demonstrated that RAR beta induction
      in MCF-7 cells by all-trans-retinoic acid (atRA) was associated with the
      activation of STAT1 gene transcription. The direct involvement of RAR beta in
      atRA-induced STAT1 gene activation was further demonstrated by showing that
      transfection with an anti-sense RAR beta construct blocked atRA-induced STAT1
      expression in MCF-7 cells whereas introduction of a sense-RAR beta construct
      resulted in STAT1 induction by atRA in MDA-MB 231 cells. In addition, we showed
      that STAT1 was phosphorylated/activated under atRA treatment of MCF-7 cells; this
      process required the involvement of RAR beta and protein synthesis. STAT1
      phosphorylation/activation was accompanied by increased tyrosine kinase activity
      that was not due to the activation of JAK1, JAK2 or Tyk 2, suggesting the
      possible involvement of an unidentified tyrosine kinase.

PMID- 10597281
TI  - RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cells.
AB  - Related Adhesion Focal Tyrosine Kinase (RAFTK; also known as Pyk2), is a member
      of the Focal Adhesion Kinase (FAK) subfamily and is activated by TNF alpha, UV
      light and increases in intracellular calcium levels. However, the function of
      RAFTK remains largely unknown. Our previous studies demonstrated that treatment
      with dexamethasone (Dex), ionizing radiation (IR), and anti-Fas mAb induces
      apoptosis in multiple myeloma (MM) cells. In the present study, we examined the
      potential role of RAFTK during induction of apoptosis in human MM cells triggered
      by these three stimuli. Dex-induced apoptosis, in contrast to apoptosis triggered
      by anti-Fas mAb or IR, is associated with activation of RAFTK. Transient
      overexpression of RAFTK wild type (RAFTK WT) induces apoptosis, whereas transient
      overexpression of Kinase inactive RAFTK (RAFTK K-M) blocks Dex-induced apoptosis.
      In contrast, transient overexpression of RAFTK K-M has no effect on apoptosis
      triggered by IR or Fas. In Dex-resistant cells, Dex does not trigger either RAFTK
      activation or apoptosis. Finally, interleukin-6 (IL-6), a known survival factor
      for MM cells, inhibits both activation of RAFTK and apoptosis of MM.1S cells
      triggered by Dex. Our studies therefore demonstrate Dex-induced RAFTK-dependent,
      and IR or Fas induced RAFTK-independent apoptotic signaling cascades in MM cells.

PMID- 10597282
TI  - let-756, a C. elegans fgf essential for worm development.
AB  - In vertebrates, Fibroblast Growth Factors (FGFs) and their receptors are involved
      in various developmental and pathological processes, including neoplasia. The
      number of FGFs and their large range of activities have made the understanding of
      their precise functions difficult. Investigating their biology in other species
      might be enlightening. A sequence encoding a putative protein presenting 30-40%
      identity with the conserved core of vertebrate FGFs has been identified by the C.
      elegans sequencing consortium. We show here that this gene is transcribed and
      encodes a putative protein of 425 amino acids (aa). The gene is expressed at all
      stages of development beyond late embryogenesis, peaking at the larval stages.
      Loss-of-function mutants of the let-756 gene are rescued by the wild type fgf
      gene in germline transformation experiments. Two partial loss-of-function
      alleles, s2613 and s2809, have a mutation that replaces aa 317 by a stop. The
      truncated protein retains the FGF core but lacks a C-termins portion. These worms
      are small and develop slowly into clear and scrawny, yet viable and fertile
      adults. A third allele, s2887, is inactivated by an inversion that disrupts the
      first exon. It causes a developmental arrest early in the larval stages. Thus, in
      contrast to the other nematode fgf gene egl-17, let-756/fgf is essential for worm
      development.

PMID- 10597283
TI  - Increased protein kinase C delta in mammary tumor cells: relationship to
      transformtion and metastatic progression.
AB  - Relatively little is known about the molecular mechanisms of tumor
      promotion/progression in mammary carcinogenesis. Increased protein kinase C (PKC)
      activity is known to promote tumor formation in several tissues; however, its
      role in mammary carcinogenesis is not yet known. To determine if individual PKCs
      may selectively regulate properties of mammary tumor cells, we compared PKC
      isozyme levels in mammary tumor cell lines with low, moderate and high metastatic
      potential. All three cell lines expressed alpha, delta, epsilon and zeta PKCs;
      however, PKC delta levels were relatively increased in the highly metastatic
      cells. To determine if increased PKC delta could contribute to
      promotion/progression, we overexpressed PKC delta in the low and moderately
      metastatic cell lines. PKC delta overexpression had no significant effect on
      growth of adherent cells, but significantly increased anchorage-independent
      growth. Conversely, expressing the regulatory domain of PKC delta (RD delta), a
      putative PKC delta inhibitory fragment, inhibited anchorage-independent growth.
      The efficacy of RD delta as a PKC delta inhibitor was demonstrated by showing
      that RD delta selectively interfered with PKC delta subcellular location and
      significantly interfered with phosphorylation of the PKC cytoskeletal substrate,
      adducin. PKC-dependent phosphorylation of cytoskeletal substrate proteins, such
      as adducin, provides a mechanistic link between increased PKC delta activity and
      phenotypic changes in cytoskeletal-dependent processes such as migration and
      attachment, two processes that are relevant to metastatic potential. The
      reciprocal growth effects of expressing PKC delta and RD delta as gain and loss
      of function constructs, respectively, provide strong evidence that PKC delta
      regulates processes important for anchorage-independent growth in these mammary
      tumor cells.

PMID- 10597284
TI  - Association with cullin partners protects ROC proteins from proteasome-dependent
      degradation.
AB  - Cullin 1/CDC53 represents a multigene family and has been linked to the ubiquitin
      mediated proteolysis of several different proteins. We recently identified two
      closely related RING finger proteins, ROC1 and ROC2, that share considerable
      sequence similarity to an APC subunit, APC11, and demonstrated ROC1 as an
      essential subunit of CUL1 and CDC53 ubiquitin ligases. We report here that the
      expression of ROC1, ROC2 and APC11 genes are induced by mitogens and remain
      constant during the cell cycle. Unlike other subunits of SCF and APC E3 ligases,
      ectopically expressed ROC family proteins are degraded by a proteasome-inhibitor
      sensitive pathway and are stabilized by associating with cullins. Mutations at
      the conserved Phe79 and His80 residues in the RING finger of ROC1 diminish its
      binding with cullins, resulting in a loss of cullin protection and ubiquitin
      ligase activity. These results suggest a potential mechanism for regulating the
      activity of ROC-cullin ligases through complex assembly and ROC/APC11 subunit
      ubiquitination.

PMID- 10597285
TI  - Ectopic expression of human p53 inhibits entry into S phase and induces apoptosis
      in the Drosophila eye imaginal disc.
AB  - Transgenic flies in which ectopic expression of human p53 was targeted to the
      Drosophila eye imaginal disc were established. On sectioning of adult fly eyes
      which displayed a severe rough eye phenotype, most ommatidia were found to be
      fused and irregular shapes of rabdomeres were observed. In addition, many pigment
      cells were lost. In the developing eye imaginal disc, photoreceptor cell
      differentiation was initiated normally despite the ectopic expression of p53.
      However, expression of p53 inhibited cell cycle progression in eye imaginal disc
      cells and the S phase zone (the second mitotic wave) behind the morphogenetic
      furrow was almost completely abolished. Furthermore, expression of p53 induced
      extensive apoptosis of eye imaginal disc cells, and co-expression of baculovirus
      P35 in the eye imaginal disc suppressed the p53-induced rough eye phenotype.
      These results are consistent with the known functions of human p53 and indicate
      the existence of signaling systems with elements corresponding to human p53 in
      Drosophila eye imaginal disc cells. Genetic crosses of transgenic flies
      expressing p53 to a collection of Drosophila deficiency stocks allowed us to
      identify several genomic regions, deletions of which caused enhancement or
      suppression of the p53-induced rough eye phenotype. The transgenic flies
      established in this study should be useful to identify novel targets of p53 and
      its positive or negative regulators in Drosophila.

PMID- 10597286
TI  - Coendocytosis of cadherin and c-Met coupled to disruption of cell-cell adhesion
      in MDCK cells--regulation by Rho, Rac and Rab small G proteins.
AB  - Both E-cadherin, a cell-cell adhesion molecule, and c-Met, the hepatocyte growth
      factor (HGF)/scatter factor (SF) receptor, were colocalized at cell-cell adhesion
      sites of MDCK cells. HGF/SF or a phorbol ester, 12-O-tetradecanoylphorbol-13
      acetate (TPA), induced disruption of cell-cell adhesion, which was accompanied by
      endocytosis of both E-cadherin and c-Met. Reduction of medium Ca2+ to a
      micromolar range showed the same effects. Re-increase in medium Ca2+ to a
      millimolar range formed cell-cell adhesion, which was accompanied by exocytosis
      of E-cadherin and c-Met, followed by their re-colocalization at the cell-cell
      adhesion sites. These results suggest that E-cadherin and c-Met are colocalized
      at cell-cell adhesion sites and undergo co-endo-exocytosis. We have previously
      shown that TPA does not induce disruption of cell-cell adhesion and subsequent
      scattering of MDCK cells stably expressing a dominant active mutant of RhoA or
      Rac1 small G protein or a dominant negative mutant of Rab5 small G protein. In
      these cell lines, the HGF- or TPA-induced coendocytosis of E-cadherin and c-Met
      was inhibited, but the coendocytosis of E-cadherin and c-Met in response to
      reduction of medium Ca2+ was not affected. Wortmannin, an inhibitor of
      phosphoinositide (PI) 3-kinase, inhibited the HGF-induced disruption of cell-cell
      junction and endocytosis of E-cadherin and c-Met, but not the TPA-induced ones.
      These results suggest that disruption of cell-cell adhesion is involved in the
      HGF- or TPA-induced coendocytosis of E-cadherin and c-Met in MDCK cells, and that
      the Rho and Rab family members indirectly regulate this coendocytosis. In
      addition, coendocytosis of E-cadherin and c-Met in response to HGF is partly
      mediated by PI 3-kinase. The cross-talk between cell-cell and cell-matrix
      adherens junctions is discussed.

PMID- 10597287
TI  - Molecular interactions between telomerase and the tumor suppressor protein p53 in
      vitro.
AB  - The telomere DNA polymerase (telomerase) and the tumor suppressor protein p53 are
      frequently associated with human cancers, and activation of telomerase and
      inactivation of p53 involved in cancer cell immortalization. In this report, we
      demonstrate a direct interaction of telomerase with p53 in the nuclear lysates of
      human breast cancer cells, and with recombinant human p53, by affinity
      chromatography and immunoprecipitation. On activity criteria, the interaction is
      between the carboxyl-terminal region of p53 and a region close to the amino
      terminus of human telomerase-associated protein 1 (hTEP1). Incubation of
      recombinant p53 with nuclear telomerase extracts results in inhibition of
      telomerase activity, with the C-terminal region of p53 being essential for
      inhibition. This effect is not mediated by binding to telomerase substrate DNA,
      but requires the region near the N-terminus of hTEP1, in that a synthetic peptide
      derived from this region of hTEP1 similarly inhibits telomerase activity.
      Together, these in vitro interactions between telomerase and p53 suggest that the
      activity of telomerase may be regulated by p53, down-regulation of which in turn
      would favor up-regulation of telomerase activity in cancer cell development.

PMID- 10597289
TI  - Variable mutation frequencies in coding repeats of TCF-4 and other target genes
      in colon, gastric and endometrial carcinoma showing microsatellite instability.
AB  - Frameshift mutations in genes containing mononucleotide repeats are often
      observed in cancers exhibiting a high frequency of microsatellite instability
      (MSI-H). Several tumor types, including colorectal, gastric, and endometrial
      carcinomas, display this phenotype in a significant proportion of cases. We
      recently showed in a large series of MSI-H colorectal tumors that approximately
      40% of them exhibited frameshift mutations in an (A)9 tract within the coding
      region of the TCF-4 gene, a crucial member of the APC/beta-catenin/TCF pathway.
      In the present study, we have examined MSI-H cancers from other primary tumor
      sites for mutations in this new target gene. Two of 22 (9%) MSI-H primary gastric
      cancers and none of 23 MSI-H endometrial primary tumors and cell lines were found
      to have a 1 bp deletion in the TCF-4 repeat. In the same series of tumors we also
      looked for frameshift mutations in other coding repeats localized within the TGF
      beta-RII, BAX, IGFIIR, hMSH3 and hMSH6 genes. Our results suggest that the TCF-4
      gene, in a similar manner to some of these latter genes, is differentially
      altered in MSI-H tumors from different primary sites.

PMID- 10597288
TI  - GOOSECOID inhibits erythrocyte differentiation by competing with Rb for PU.1
      binding in murine cells.
AB  - Misexpression of the dorsal mesodermal patterning factor goosecoid on the ventral
      side of amphibian embryos results in inhibition of blood formation in early
      embryogenesis. To investigate the mechanism of this inhibition, we ectopically
      expressed goosecoid in erythroleukemia cells. While erythroid differentiation of
      these cells can be induced by activin, goosecoid expressing cells were
      unresponsive to activin. We demonstrate an in vitro interaction between the
      oncogene PU.1, an ets family transcription factor thought to play a role in
      erythropoiesis, and the goosecoid protein (GSC). Interaction with PU.1 was
      specific as GSC did not bind to the ets family members, Fli-1 or Ets-2. The
      ability of goosecoid expressing erythroleukemia cells to differentiate in
      response to activin was rescued by coexpression of the GSC-binding N-terminal
      portion of PU.1. The N-terminal portion of PU.1 was co-immunoprecipitated with
      anti-GSC antibodies as well. The N-terminal domain of PU.1 is the region
      recognized by the retinoblastoma protein (Rb), a tumor suppressor gene presumably
      involved in erythroid differentiation. We show that GSC competitively inhibits
      binding of Rb to PU.1. Our data suggest that the suppression of blood formation
      by GSC could, at least in part, be mediated by binding to PU.1.

PMID- 10597290
TI  - Nmi protein interacts with regions that differ between MycN and Myc and is
      localized in the cytoplasm of neuroblastoma cells in contrast to nuclear MycN.
AB  - Myc family proteins play an important role in cellular processes such as
      proliferation, differentiation, apoptosis and transformation. A number of
      interaction partners of Myc have been identified, such as Max, p107, TBP, YY1,
      Miz-1, AP-2 and Nmi. Both Max and Nmi also bind to MycN. In contrast to the well
      defined binding of Max to Myc family proteins the interaction of Nmi with Myc or
      MycN is only poorly characterized. By employing the yeast two-hybrid system we
      have mapped the regions of MycN and Myc responsible for binding to Nmi. For MycN
      exclusively a central region mediates binding to Nmi. In contrast, for Myc a C
      terminal portion of the protein, and possibly also a central part, is involved in
      Nmi interaction. Nmi does not interact with Max and has no transactivation
      capabilities in yeast, suggesting that Nmi alone is not a transcriptional
      activator in mammalian cells. Immunofluorescence demonstrates that both in 293
      embryonic kidney cells and in Kelly neuroblastoma cells all detectable
      ectopically expressed Nmi is localized in the cytoplasm, in part in a punctate,
      granular pattern. MycN, which is highly expressed in Kelly cells consequent to
      amplification, appears to be localized exclusively in the nuclei. This directly
      demonstrates that in the same cell at least the major proportion of MycN and Nmi
      is localized in different cellular compartments. This result is confirmed by the
      finding that endogenous Nmi, which is expressed in Kelly cells only after
      stimulation with interferon gamma, is detected exclusively in the cytoplasm of
      these cells. Therefore only a very small amount of MycN and Nmi is likely to be
      involved in MycN/Nmi interaction in vivo.

PMID- 10597292
TI  - Requirement for focal adhesion kinase in tumor cell adhesion.
AB  - Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase and a major
      phosphotyrosine-containing protein. FAK is found in cell-matrix attachment sites
      (focal adhesions), and is activated on integrin-ligand binding and by other
      signaling pathways. Several roles have been proposed for FAK; here we report a
      novel function. We observed abundant FAK protein in all human melanoma cell lines
      tested except COLO839, a line that grows predominantly in suspension and was
      derived from peripheral blood. Five adherent lines, isolated from solid
      metastases in the same patient as COLO839, did express FAK. We derived four
      adherent sublines from COLO839. These did express FAK, even when plated on
      bacteriological plastic, to which they did not adhere. Thus, substrate attachment
      was not required for FAK expression. Three of the adherent sublines were then
      grown in the presence of antisense oligonucleotides to the initial FAK coding
      sequence. All showed substantially reduced FAK expression and, interestingly, the
      cells largely detached from the substrate while continuing to grow. Similar
      results were obtained with an independent melanoma line, DX3. Thus, FAK
      expression appears to be required by melanoma cells for substrate adhesion.

PMID- 10597291
TI  - Ventral neuroblasts and the heartless FGF receptor are required for muscle
      founder cell specification in Drosophila.
AB  - Muscle founder cells are uniquely specified cells that fuse with neighboring
      myoblasts to generate the complex pattern of body wall muscles in the Drosophila
      embryo. We have investigated the positional specification of founder cells for
      ventral oblique muscles, marked by the restricted expression of tinman RNA and
      the activity of a D-mef2 enhancer. The formation of these ventral myoblasts
      requires the function of the Heartless FGF receptor in the mesoderm and the
      presence of ventral neuroblasts in the central nervous system. Overproduction of
      ventral neuroblasts due to the forced expression of the homeodomain protein Vnd
      leads to increased numbers of founder cells. These results suggest the use of a
      neuroectoderm-to-mesoderm signaling pathway in the specification of ventral
      muscle precursors.

PMID- 10597293
TI  - Covalent modification of all members of human cullin family proteins by NEDD8.
AB  - Recently we found that NEDD8, a ubiquitin-like protein, was linked covalently to
      human cullin-4A (abbreviated Cul-4A) by a new ubiquitin-related pathway that is
      analogous to but distinct from the ligating system for SUMO1, another ubiquitin
      like protein. However, it remained unknown whether the other five members of the
      family of human cullin/Cdc53 proteins are modified by NEDD8. Here we report that
      all Hs-Cul family proteins, such as Cul-1, Cul-2, Cul-3, Cul-4B, and Cul-5, in
      addition to Cul-4A, were modified by covalent attachment of NEDD8 in rabbit
      reticulocyte lysates. Moreover, by comprehensive Northern-blot analyses, we
      examined multiple tissue distributions of the messages for all Cul-family
      proteins, NEDD8, and the NEDD8-ligating system consisting of APP-BP1/hUba3, and
      hUbc12, which function as E1- and E2-like enzymes, respectively. The expressions
      of Cul-1, Cul-2, and Cul-3 resembled each other and were apparently correlated to
      those of NEDD8 and the NEDD8-ligating system in various human cells and tissues.
      However, the mRNA levels of Cul-4A, Cul-4B, and Cul-5 differed considerably from
      each other as well as from other Cul-family proteins. The enhanced expression of
      all Cul-family proteins except Cul-5 was observed in a variety of tumor cell
      lines.

PMID- 10597294
TI  - Cloning of a novel human Rac1b splice variant with increased expression in
      colorectal tumors.
AB  - Rac1 is a member of the Ras superfamily of small GTPases involved in signal
      transduction pathways that induce the formation of lamellipodia, stimulate cell
      proliferation and activate the JNK/SAPK protein kinase cascade. Here we describe
      that amplification by RT-PCR of the entire Rac1 coding sequence from a series of
      human adult and fetal tissues revealed beside the expected Rac1 cDNA, a variant
      product which contained additional 57 nucleotides between codons 75 and 76. This
      variant resulted in an in-frame insertion of 19 new amino acids immediately
      behind the switch II region, including two potential threonine phosphorylation
      sites for casein kinase II and protein kinase C. Primers designed within and
      downstream of the inserted nucleotide sequence allowed isolation of a genomic
      clone with intronic consensus sequences demonstrating that the insertion
      corresponds to a novel, yet undescribed exon 3b. This Rac1 splice variant,
      designated Rac1b, was predominantly identified in skin and epithelial tissues
      from the intestinal tract. Most notably, the expression of rac1b versus rac1 was
      found to be elevated in colorectal tumors at various stages of neoplastic
      progression, as compared to their respective adjacent tissues. We suggest that
      the 19 amino acid-insertion following the switch II region may create a novel
      effector binding site in rac1b, and thus participate in signaling pathways
      related to the normal or neoplastic growth of the intestinal mucosa.

PMID- 10597295
TI  - Association of hepatitis B virus X protein with mitochondria causes mitochondrial
      aggregation at the nuclear periphery, leading to cell death.
AB  - Hepatitis B virus (HBV) X protein activates many viral and cellular genes in
      trans and functional disruption of the p53 tumor suppressor gene product occurs
      when X protein is transiently expressed in the cytoplasm of cultured cells. We
      have carried out investigations to determine the exact location of X protein in X
      gene transfected cells by using a fluorescent staining technique as well as by
      biochemical analyses. Aggregation of mitochondrial structures became evident at
      the periphery of nucleus in the cytoplasm of X transfected cells. X protein was
      found associated with the aggregated mitochondrial structures. Furthermore,
      transiently expressed p53 protein co-localized with X protein in X transfected
      cells. However, the appearance of aggregated mitochondrial structures at the
      nuclear periphery was independent of the presence of p53 protein in X transfected
      cells. X protein expression also caused an appearance of TUNEL positive nucleus,
      cytochrome c release from mitochondrial, the decrease of mitochondrial membrane
      potential and the membrane blebbing of X transfected cells, which are
      characteristic of cell death. Our data suggest that X protein causes an abnormal
      aggregation of mitochondrial structures in the cell, which may be eventually
      connected with cell death.

PMID- 10597296
TI  - Role of c-Jun N-terminal kinase 1 (JNK1) in cell cycle checkpoint activated by
      the protease inhibitor N-acetyl-leucinyl-leucinyl-norleucinal.
AB  - The cysteine protease inhibitor N-acetyl-leucinyl-leucinyl-norleucinal (LLnL)
      inhibited the growth of the Calu-1 lung carcinoma cells and induced a prolonged
      cell cycle arrest in the S phase. c-Jun N-terminal kinases (JNKs) participate in
      cellular responses to mitogenic stimuli, environmental stresses, and apoptotic
      signals but its role in cell cycle checkpoint control has not been elucidated. In
      this report, we examined the role of JNK in LLnL-induced S phase checkpoint by
      overexpression of a dominant-negative mutant of JNK1 (JNK1-APF) in Calu-1 cells.
      Expression of high levels of JNK1-APF blocked the growth-inhibitory effects of
      LLnL and abrogated S phase arrest induced by LLnL. These results support the role
      of JNK in the activation of cell cycle checkpoint induced by LLnL.

PMID- 10597297
TI  - MKP5, a new member of the MAP kinase phosphatase family, which selectively
      dephosphorylates stress-activated kinases.
AB  - Dual-specificity protein tyrosine phosphatases are a burgeoning family of
      enzymes, some of which, the MKPs, are implicated in the regulation of mitogen
      activated protein (MAP) kinases. MKPs have been shown to reverse the activation
      of the MAP kinases by hydrolyzing phosphothreonine and phosphotyrosine residues
      present in the substrates. Here we describe the characterization of a novel
      member of the MKP family, MKP5. The MKP5 gene, which maps to human chromosome
      1q32, is expressed tissue-specifically as two transcripts of approximately 3.4
      and 2.4 kb in human liver and skeletal muscle. When expressed in mammalian cells,
      MKP5 blocks the enzymatic activation of MAP kinases with the selectivity p38
      approximately JNK/SAPK >> ERK. Immunoprecipitation of endogenous MAP kinases by
      the catalytically inactive transfected MKP5 demonstrates that it preferentially
      binds to the p38 and JNK/SAPK kinases. These findings suggest that the
      selectivity of this phosphatase may be determined at least in part at the level
      of substrate binding.

PMID- 10597298
TI  - Dual G1 and G2/M phase inhibition by SC-alpha alpha delta 9, a combinatorially
      derived Cdc25 phosphatase inhibitor.
AB  - The Cdc25 dual specificity phosphatase family has a central role in controlling
      cell cycle progression and has been implicated in the etiology of cancer. One
      compound, 4-(benzyl-(2-[(2, 5-diphenyl-oxazole-4-carbonyl)-amino]-ethyl)
      carbamoyl)-2-decanoylami no butyric acid (SC-alpha alpha delta 9), was previously
      identified as the most potent reported synthetic inhibitor of Cdc25 phosphatases
      in vitro. In the present study, we demonstrate that SC-alpha alpha delta 9
      inhibited Cdc25-dependent cell cycle progression at both G1 and G2/M phase using
      tsFT210 cells, which express a temperature-sensitive Cdc2 mutant. SC-alpha alpha
      delta 9 blocked both G2/M transition and dephosphorylation of Cdc2 in a
      concentration-dependent manner. SC-alpha alpha delta 9 also enhanced tyrosine
      phosphorylation of both Cdk2 and Cdk4, and decreased Cdk4 kinase activity. Both
      of the kinases are potent regulators of G1 transition. Furthermore, closely
      related chemical analogs that lacked Cdc25 inhibitory activity failed to block
      cell cycle progression at both G1 and G2/M, and did not affect Cdc2
      phosphorylation or Cdk4 kinase activity. SC-alpha alpha delta 9 did not alter
      p53, p21 or p16 levels. Our results support the hypothesis that the disruption in
      cell cycle transition caused by SC-alpha alpha delta 9 was due to intracellular
      Cdc25 inhibition. We propose that the SC-alpha alpha delta 9 pharmacophore could
      be useful in further clarifying the role of Cdc25 phosphatase-dependent pathways
      in checkpoint control, oncogenesis, and apoptosis.

PMID- 10597299
TI  - Impaired nucleotide excision repair in UV-irradiated human oral keratinocytes
      immortalized with type 16 human papillomavirus genome.
AB  - We previously reported that 'high risk' human papillomaviruses (HPV) induce
      genetic instability in human oral keratinocytes. To understand the mechanisms of
      HPV-induced genetic instability, we determined the nucleotide excision repair
      (NER) capacity of normal (NHOK) and human papillomavirus type-16 immortalized
      oral keratinocytes (HOK-16B) by strand-specific removal of UV-induced cyclobutane
      pyrimidine dimers (CPDs) from a 16 Kb fragment of the p53 gene. In NHOK the NER
      activity was initiated in both DNA strands immediately, although the process in
      the non-transcribed strand was notably slower than that of the transcribed
      strand. In HOK-16B cells the initiation of CPDs removal was delayed for at least
      8 h in both DNA strands, and the process was significantly slower than that in
      NHOK. UV-irradiation enhanced the p53 protein level more than 30-fold in NHOK,
      but it did not significantly alter the protein level in the HOK-16B cells. UV
      irradiation also increased the p21WAF1/CIP1 protein level only in NHOK. These
      data indicate that 'high risk' HPV induces genetic instability by impairing NER
      capacity of cells. Impaired NER activity of HOK-16B cells may be implicated with
      their inability to enhance active p53 when challenged by genotoxic stress.

PMID- 10597300
TI  - Disruption of ATM in p53-null cells causes multiple functional abnormalities in
      cellular response to ionizing radiation.
AB  - ATM is a member of the large phosphatidylinositol-3 kinase family and plays an
      important role in cellular response to DNA damage. To further define the
      physiological roles of ATM at the cellular level, we created an isogenic set of
      stable cell lines differing only in their ATM status from the chicken B cell line
      DT40 by targeted integration. These stable DT40 cell lines, as most of
      transformed chicken cell lines, do not express p53. However, ATM-/- DT40 cells
      displayed retarded cellular proliferation, defective G2/M checkpoint control and
      radio-resistant DNA synthesis. Furthermore, ATM-/- DT40 cells were sensitive to
      ionizing radiation and showed highly elevated frequencies of both spontaneous and
      radiation-induced chromosomal aberrations. In addition, a slight but significant
      reduction in targeted integration frequency was observed in ATM-/- DT40 cells.
      These results suggest that ATM has multiple p53-independent functions in cell
      cycle checkpoint control and in maintenance of chromosomal DNA. These ATM
      deficient DT40 clones therefore provide a useful model system for analysing p53
      independent ATM functions.

PMID- 10597301
TI  - Overexpression of dominant negative PARP interferes with tumor formation of HeLa
      cells in nude mice: evidence for increased tumor cell apoptosis in vivo.
AB  - Poly(ADP-ribose) polymerase (PARP4) catalyzes the formation of ADP-ribose
      polymers covalently attached to proteins by using NAD+ as substrate. PARP is
      strongly activated by DNA single- or double-strand breaks and is thought to be
      involved in cellular responses to DNA damage. We characterized a dominant
      negative PARP mutant, i.e. the DNA-binding domain of this enzyme, whose
      overexpression in cells leads to increased genetic instability following DNA
      damage. In order to study whether PARP activity is also implicated in the process
      of tumorigenesis, we generated stably transfected HeLa cell clones with
      constitutive overexpression of dominant negative PARP and investigated tumor
      formation of these clones in nude mice. We found that inhibition of PARP activity
      dramatically reduces tumor forming ability of HeLa cells. Moreover, we provide
      strong evidence that the observed reduction in tumor forming ability is due to
      increased tumor cell apoptosis in vivo. Viewed together, our data and those from
      other groups show that inhibition of PARP enzyme activity interferes with DNA
      base excision repair and leads to increased genetic instability and recombination
      but, on the other hand, can sensitize cells to apoptotic stimuli and by this
      mechanism may prevent tumor formation.

PMID- 10597302
TI  - Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic
      acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun,
      and p21CIP1, but independent of p53.
AB  - Determinants of differentiation and apoptosis in myelomonocytic leukemia cells
      (U937) exposed to the novel hybrid polar compound SAHA (suberoylanilide
      hydroxamic acid) have been examined. In contrast to hexamethylenbisacetamide
      (HMBA), SAHA-related maturation was limited and accompanied by marked cytoxicity.
      SAHA-mediated apoptosis occurred within the G0G1 and S phase populations, and was
      associated with decreased mitochondrial membrane potential, caspase-3 activation,
      PARP degradation, hypophosphorylation/cleavage of pRB, and down-regulation of c
      Myc, c-Myb, and B-Myb. Enforced expression of Bcl-2 or Bcl-XL inhibited SAHA
      induced apoptosis, but only modestly potentiated differentiation. While SAHA
      induced the cyclin-dependent kinase inhibitor p21CIP1, antisense ablation of this
      CDKI increased, rather than decreased, SAHA-related lethality. In contrast,
      conditional expression of wild-type p53 failed to modify SAHA actions, but
      markedly potentiated HMBA-induced apoptosis. Finally, SAHA modestly increased
      expression/activation of the stress-activated protein kinase (SAPK/JNK);
      moreover, SAHA-related lethality was partially attenuated by a dominant-negative
      c-Jun mutant protein (TAM67). SAHA did not stimulate mitogen-activated protein
      kinase (MAPK), nor was lethality diminished by the specific MEK/MAPK inhibitor
      PD98059. These findings indicate that SAHA potently induces apoptosis in human
      leukemia cells via a pathway that is p53-independent but at least partially
      regulated by Bcl-2/Bcl-XL, p21CIP1, and the c-Jun/AP-1 signaling cascade.

PMID- 10597303
TI  - A novel exon within the mdm2 gene modulates translation initiation in vitro and
      disrupts the p53-binding domain of mdm2 protein.
AB  - The mdm2 protein interacts with a number of proteins involved in cell growth
      control. Such interactions favour cell proliferation and may explain the
      oncogenic potential of mdm2 when over-expressed in cells. Interaction with the
      tumour suppressor p53 involves the N-terminus of mdm2 and targets p53 for rapid
      degradation by the ubiquitin pathway. We now describe a novel, highly conserved
      exon of mdm2 (exon alpha) which includes an in-frame UGA stop codon. Expression
      of exon alpha disrupts in vitro translation of the p53 binding domain of mdm2. We
      propose that exon alpha induces translation re-initiation at an internal AUG
      codon within the mdm2 alpha mRNA isoform. The putative mdm2 alpha protein lacks
      the N-terminus of mdm2 and shows little, if any, binding capacity for p53. Mdm2
      alpha mRNA is expressed in a tissue-specific manner and is observed predominantly
      in testis and peripheral blood lymphocytes. We propose that mdm2 alpha expression
      may provide a mechanism for uncoupling mdm2-p53 interaction in certain cell types
      and/or under specific conditions of cell growth.

PMID- 10597304
TI  - The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces
      apoptosis and anoikis in breast cancer cells.
AB  - The PTEN/MMAC1/TEP (PTEN) tumor suppressor gene at 10q23.3 is mutated in multiple
      types of sporadic tumors including breast cancers and also in the germline of
      patients with the Cowden's breast cancer predisposition syndrome. The PTEN gene
      encodes a multifunctional phosphatase capable of dephosphorylating the same sites
      in membrane phosphatidylinositols phosphorylated by phosphatidylinositol 3'
      kinase (PI3K). We demonstrate herein that loss of PTEN function in breast cancer
      cells results in an increase in basal levels of phosphorylation of multiple
      components of the P13K signaling cascade as well as an increase in duration of
      ligand-induced signaling through the P13K cascade. These alterations are reversed
      by wild-type but not phosphatase inactive PTEN. In the presence of high
      concentrations of serum, enforced expression of PTEN induces a predominant G1
      arrest consistent with the capacity of PTEN to evoke increases in the expression
      of the p27Kip1 cyclin dependent kinase inhibitor. In the presence of low
      concentrations of serum, enforced PTEN expression results in a marked increase in
      cellular apoptosis, a finding which is consistent with the capacity of PTEN to
      alter the phosphorylation, and presumably function, of the AKT, BAD, p70S6 kinase
      and GSK3 alpha apoptosis regulators. Under anchorage-independent conditions, PTEN
      also induces anoikis, a form of apoptosis that occurs when cells are dissociated
      from the extracellular matrix, which is enhanced in conjunction with low serum
      culture conditions. Together, these data suggest that PTEN effects on the PI3K
      signaling cascade are influenced by the cell stimulatory context, and that
      depending on the exposure to growth factors and other exogenous stimuli such as
      integrin ligation, PTEN can induce cell cycle arrest, apoptosis or anoikis in
      breast cancer cells.

PMID- 10597305
TI  - An FH domain-containing Bnr1p is a multifunctional protein interacting with a
      variety of cytoskeletal proteins in Saccharomyces cerevisiae.
AB  - Proteins containing formin homology domains, FH1 and FH2, are involved in
      cytokinesis or establishment of cell polarity in a variety of organisms. Bni1p
      and Bnr1p are FH proteins and potential targets of the Rho family small GTP
      binding proteins in S. cerevisiae. We have shown that Bnr1p is localized at the
      bud neck to interact with Hof1p, involved in cytokinesis. We report here that the
      overexpression of BNR1 causes a cytokinesis deficiency which is similar to the
      phenotypes of the septin mutants, including cdc3, cdc10, cdc11, and cdc12. The
      region required for the septin mutant phenotypes was mapped to Bnr1p (35-500),
      which coincided with the region required for the bud-neck localization. To
      further isolate a gene interacting with BNI1 or BNR1, a multicopy suppressor of
      the bni1 bnr1 mutant was isolated. This gene encoded Smy1p, a kinesin-related
      protein. Bnr1p, but not Bni1p, directly interacted with the C-terminal region of
      Smy1p. The Smy1p-interacting region of Bnr1p was mapped to a region containing
      the FH2 domain. Bnr1p also directly interacted with Bud6p, a novel actin-binding
      protein. Bnr1p is thus a multifunctional protein which interacts with the septin
      system, a microtubule-dependent motor protein, and the actin system, to regulate
      cytoskeletal functions in S. cerevisiae.

PMID- 10597306
TI  - Characterization of the chronic myelomonocytic leukemia associated TEL-PDGF beta
      R fusion protein.
AB  - The t(5;12) translocation, associated with chronic myelomonocytic leukemia,
      generates a novel gene encoding a protein, TEL-PDGF beta R, composed of the 154
      amino-terminal amino acids of the transcription factor TEL and the transmembrane
      and intracellular part of the PDGF beta-receptor (PDGF beta R). TEL also occurs
      as a tumor-associated fusion partner for the tyrosine kinases c-ABL, JAK2 and TRK
      C. Previous studies have demonstrated growth promoting activity of TEL-PDGF beta
      R and also indicated that the TEL moiety activates the tyrosine kinase of the
      PDGF beta R through the formation of TEL-PDGF beta R oligomers. We demonstrate
      that tyrosine phosphorylation of the fusion protein can be attenuated through
      overexpression of the TEL part of TEL-PDGF beta R, suggesting a strategy for
      antagonizing the signaling of TEL-PDGF beta R, and other TEL-fusion proteins
      containing tyrosine kinase domains. Comparison of BaF/3 cell lines expressing TEL
      PDGF beta R and ligand-stimulated PDGF beta R revealed that only TEL-PDGF beta R
      expression conferred IL-3-independent growth, suggesting differences in signaling
      capacity of the two proteins. Finally, tyrosine residues 17 and 27 in TEL-PDGF
      beta R was identified as autophosphorylation sites in TEL-PDGF beta R.

PMID- 10597307
TI  - Frequent loss of imprinting at the IGF2 and H19 genes in head and neck squamous
      carcinoma.
AB  - Genomic imprinting is an inherited epigenetic phenomenon that results in parental
      origin-specific gene expression in somatic cells. Relaxation or loss of this
      feature in certain genes has been demonstrated in several pediatric and adult
      neoplasms, suggesting an association with tumorigenesis. We analysed 64 primary
      untreated head and neck squamous carcinoma for the loss of imprinting in the IGF2
      and H19 genes to determine the implications of this alteration in the development
      and progression of these tumors. Forty-nine (77%) of the 64 tumors were
      informative for imprinting analyses of these genes. IGF2 and H19 were imprinted
      in all normal squamous epithelium examined. Twelve (37.5%) of 32 tumors
      informative for H19 and 11 (40.7%) of 27 tumors informative for IGF2 manifested
      loss of imprinting. Ten tumors were informative for both genes, of which four
      maintained the constitutional imprinting and six showed loss of imprinting at
      either H19 or IGF2. These data suggest that loss of imprinting at the IGF2 and
      H19 loci play a role in the oncogenesis of head and neck carcinoma.

PMID- 10597308
TI  - Isolation and characterization of Xenopus ATM (X-ATM): expression, localization,
      and complex formation during oogenesis and early development.
AB  - ATM, the gene product mutated in Ataxia Telangiectasia (A-T) encodes a 350-kDa
      protein involved in the regulation of several cellular responses to DNA breaks.
      We used a degenerate PCR-based strategy to isolate a partial clone of X-ATM, the
      Xenopus homologue of human ATM. Sequence analysis and confirmed that the clone
      was most closely related to human ATM. Xenopus ATM protein (X-ATM) is 85%
      identical to human ATM within the kinase domain and 71% identical over the
      carboxyl-terminal half of the protein. Polyclonal antibodies raised against
      recombinant X-ATM are highly specific for the ATM protein and recognize a single
      polypeptide of 370-kDa in oocytes, embryos, egg extracts and a Xenopus cell line.
      We found that X-ATM was expressed maternally in eggs and as early as stage II pre
      vitellogenic oocytes, and the protein and mRNA were present at relatively
      constant levels throughout development. Subcellular fractionation showed that the
      protein was nuclear in both the female and male germlines. The level of X-ATM
      protein did not change throughout the meiotic divisions or the synchronous
      mitotic cycles of cleavage stage embryos. In addition, we did not observe any
      change in the level or mobility of X-ATM protein following gamma-irradiation of
      embryos. Finally, we also demonstrated that X-ATM was present in a high molecular
      weight complex of approximately 500 kDa containing the X-ATM protein and other,
      as yet unidentified component(s).

PMID- 10597309
TI  - Calcium influx triggers the sequential proteolysis of extracellular and
      cytoplasmic domains of E-cadherin, leading to loss of beta-catenin from cell-cell
      contacts.
AB  - Cadherins are major cell-cell adhesion molecules in both tumor and normal
      tissues. Although serum levels of soluble E-cadherin have been shown to be higher
      in the cancer patients than in healthy volunteers, the detail mechanism
      regulating release of soluble E-cadherin remains to be elucidated. Here we show
      that the ectodomain of E-cadherin is proteolytically cleaved from some cancer
      cells by a membrane-bound metalloprotease to yield soluble form, and the residual
      membrane-tethered cleavage product is subsequently degraded by intracellular
      proteolytic pathway. Futhermore, we show that extracellular calcium influx, that
      is induced by mechanical scraping of cells or ionomycin treatment, enhances the
      metalloprotease-mediated E-cadherin cleavage and the subsequent degradation of
      the cytoplasmic domain. Immunocytochemical analysis demonstrates that the
      sequential proteolysis of E-cadherin triggered by the calcium influx results in
      translocation of beta-catenin from the cell-cell contacts to cytoplasm. Our data
      suggest that calcium influx-induced proteolysis of E-cadherin not only disrupts
      the cell-cell adhesion but also activates beta-catenin-mediated intracellular
      signaling pathway, potentially leading to alterations in motility and
      proliferation activity of cells.

PMID- 10597310
TI  - The promyelocytic leukemia protein PML interacts with the proline-rich
      homeodomain protein PRH: a RING may link hematopoiesis and growth control.
AB  - Acute promyelocytic leukemia (APL) is characterized by a block in myeloid cell
      differentiation. As a result of a chromosomal translocation in these patients,
      the promyelocytic leukemia protein PML is disrupted as are the nuclear bodies it
      forms. Disruption of PML and PML nuclear bodies in APL is linked to a loss of
      growth control and subsequent leukemogenesis. PML contains a zinc-binding domain
      known as the RING which is required for formation of these bodies. Using yeast 2
      hybrid techniques, we found that PML and a related RING protein, Z, bind the
      proline rich homeodomain protein (PRH) through their RING domains. Previous
      reports indicate that PRH functions in hematopoiesis and may act as a
      transcriptional repressor. Our data indicate that PML and Z both bind the
      repressor domain of PRH and are the first protein partners reported for PRH. We
      observe that PRH has a punctate pattern in both the nucleus and cytoplasm of
      chronic myelogenous leukemia K562 cells and in the APL cell line, NB4.
      Immunoprecipitation and co-localization studies indicate that PML and PRH
      interact in both cell lines. The effect on cell growth by PML and the
      hematopoietic actions of PRH raises the possibility that the interaction between
      PML and PRH represents a link between growth control and hematopoiesis.

PMID- 10597311
TI  - SIAH-1 inhibits cell growth by altering the mitotic process.
AB  - SIAH-1, the human homologue of the drosophila seven in absentia gene, is a p53
      p21Waf-1 inducible gene. We report that stable transfection with SIAH-1 of the
      epithelial breast cancer cell line MCF-7 blocks its growth process. The
      transfectants show a redistribution of SIAH-1 protein within the nucleus, more
      specifically to the nuclear matrix, associated to dramatic changes in cell
      morphology and defective mitosis. Multinucleated giant cells (2-12 nuclei in more
      than 50% cells) were a most striking observation associated with tubulin spindle
      disorganization and defective cytokinesis. There were also present at high
      frequency abortive mitotic figures, DNA bridges and persistance of intercellular
      bridges and midbodies, along with an increased expression of p21Waf-1. These
      results indicate that the mechanism of growth arrest induced by SIAH-1 in MCF-7
      cells involves disorganization of the mitotic program, mainly during nuclei
      separation and cytokinesis.

PMID- 10597312
TI  - Gamma-heregulin: a fusion gene of DOC-4 and neuregulin-1 derived from a
      chromosome translocation.
AB  - gamma-Heregulin was identified as an isoform resulting from alternate splicing of
      the neuregulin-1 gene, after cloning of its cDNA from the MDA-MB-175 breast
      cancer cell line. gamma-Heregulin was shown to promote growth of cultured MDA-MB
      175 cells resulting from activation of its cognate ErbB tyrosine kinase
      reporters. We show here that gamma-heregulin is transcribed from a fusion gene
      resulting from a chromosome translocation in MDA-MB-175 cells. The fusion
      chromosome is described as dic(8:11)(8qter-->8p12::11q13-->11pter). As a result,
      the 5' end of the gamma-heregulin gene is derived from the stress-induced gene,
      DOC-4 (11q13), while the 3' end is from the neuregulin-1 gene (8p12). Thus,
      expression of gamma-heregulin is under the control of the DOC-4 promoter. By
      contrast with MDA-MB-175 cells, RT-PCR failed to detect a gamma-heregulin
      transcript in either E9.5 to E13.5 embryonic mouse tissues, adult mouse tissues
      or other human tumour cell lines. We conclude, therefore, that gamma-heregulin is
      not a native isoform of the neuregulin-1 gene, but a novel growth factor that may
      contribute to tumour cell proliferation.

PMID- 10597313
TI  - Negative regulation of Par-4 by oncogenic Ras is essential for cellular
      transformation.
AB  - Oncogenic variants of the cellular Ras protein are often associated with
      different types of human cancers. However, the mechanisms by which oncogenic Ras
      induces transformation are not fully established. Expression of the
      transcriptional repressor Par-4 was down-regulated by oncogenic Ras via the Raf
      MEK-ERK pathway. Restoration of Par-4 levels by abrogation of the Raf-MEK-ERK
      pathway with the MEK-inhibitor PD98059 or by ectopic Par-4, that acted to inhibit
      ERK expression and activation, was sufficient to suppress oncogenic Ras-induced
      transformation. These findings identify Par-4 as a novel target that has to be
      down-modulated by oncogenic Ras for successful transformation.

PMID- 10597314
TI  - A full-length Cbfa1 gene product perturbs T-cell development and promotes
      lymphomagenesis in synergy with myc.
AB  - The Cbfa1/PEBP2 alpha A/AML3 gene plays an essential role in osteogenesis but is
      also expressed in the T-cell lineage where it has been implicated in lymphoma
      development as a target for retroviral insertional mutagenesis. As lymphoma cells
      with til-1 insertion express at least five distinct Cbfa1 isoforms, it is
      important to establish which, if any, have intrinsic oncogenic potential. We have
      generated transgenic mice in which the most abundant lymphoma isoform (G1/p57) is
      expressed under the control of the CD2 locus control region. Co-precipitation
      analysis of transgenic thymus revealed high levels of Cbfa1 protein in an
      abundant complex containing the binding cofactor Cbfb. CD2-Cbfa1-G1 mice
      displayed abnormal T-cell development, with a pronounced skew towards CD8 SP
      cells in the thymus and developed a low incidence of spontaneous lymphomas (6% at
      12 months) with cells of similar phenotype. Strongly synergistic tumour
      development was seen when CD2-Cbfa1-G1 mice were crossed with lines carrying myc
      transgenes (CD2-myc or tamoxifen-regulatable CD2-mycER) and Cbfa1 was found to
      rescue expression of the CD2-myc transgene in pre-leukaemic mice. However,
      synergy did not appear to be due to a dominant block of myc-induced apoptosis by
      Cbfa1 as explanted primary tumours and cell lines from CD2-Cbfa1-G1/CD2-mycER
      mice showed accelerated death on induction with tamoxifen at similar rates to CD2
      mycER controls. Moreover, thymocytes from preleukaemic CD2-Cbfa1-G1 mice showed
      reduced survival in vitro and increased sensitivity to the inhibitory effects of
      TGF-beta. This study demonstrates that a full-length Cbf alpha-chain gene can act
      as an oncogene without fusion to a heterologous protein.

PMID- 10597315
TI  - SHIP-mediated inhibition of K562 erythroid differentiation requires an intact
      catalytic domain and Shc binding site.
AB  - Growing evidence supports a role for the SHIP inositol 5'-phosphatase in the
      negative regulation of a variety of receptor-mediated signaling pathways in
      hematopoietic cells. SHIP expression among cultured cell lines was examined and
      found to be restricted to cells of hematopoietic origin, with the exception of
      the K562 erythroleukemia cell line, in which SHIP protein and mRNA were
      undetectable. The absence of endogenous SHIP in K562 cells provided a useful
      system to study the role of SHIP in growth and differentiation. When stably
      expressed in K562 cells, SHIP was found to be constitutively tyrosine
      phosphorylated and associated with endogenous Shc and Grb-2. Stable expression of
      SHIP did not affect growth of the cells but resulted in decreased synthesis of
      hemoglobin protein and epsilon-globin mRNA in response to hemin, an inducer of
      erythroid differentiation. This effect was not due to increased cell death in the
      SHIP-expressing lines following hemin stimulation, but was likely the result of
      an impaired differentiation program in these cells. Mutational analysis indicated
      that SHIP must retain both an intact catalytic domain and Shc binding site to
      efficiently inhibit K562 erythroid differentiation.

PMID- 10597316
TI  - Ras stimulates DNA topoisomerase II alpha through MEK: a link between oncogenic
      signaling and a therapeutic target.
AB  - Topoisomerase II alpha (topo II alpha) is a major target of antitumor treatments.
      In an effort to determine why this protein might be a better target in tumor
      cells than in normal cells, we attempted to determine if the altered
      proliferative signaling in a tumor cell might effect the levels of expression of
      the topo II alpha gene. In support of this idea, it was found that topo II alpha
      was elevated following microinjection of oncogenic Ras protein. Oncogenic ras was
      further shown to stimulate the topo II alpha promoter. Stimulation by ras was
      independent of the normal cell cycle regulation of this promoter. Transactivation
      of topo II alpha by ras required both the MEK/ERK pathway, and the stress
      associated protein kinase (SAPK) signaling pathway. As a direct confirmation that
      both ERK and SAPK were involved in topo II alpha regulation, a constitutively
      active MEKK that stimulates these two kinases simultaneously was shown to
      strongly induce topo II alpha promoter activity. Activation of either pathway
      alone, on the other hand, only slightly stimulated the topo II alpha promoter.
      Deletion analyses showed that elements near both the 5' and 3' ends of the
      promoter were responsible for the ras stimulation. Site-directed mutagenesis
      further demonstrated that an Ets-like binding site near the 5' end (-480 to -475)
      was one of the responsive elements. Taken together, these studies demonstrate the
      direct role of Ras signaling in stimulation of topo II alpha expression, and
      thereby establish a link between the action of a common tumor mutation and the
      target of multiple anti-tumor reagents.

PMID- 10597317
TI  - Latent membrane protein 1 associated signaling pathways are important in tumor
      cells of Epstein-Barr virus negative Hodgkin's disease.
AB  - The latent membrane protein 1 (LMP1) oncogene of Epstein-Barr virus (EBV) is
      selectively expressed in the Reed-Sternberg (RS) cells of EBV-associated
      Hodgkin's disease (HD). However, no differences in clinical presentation and
      course are found between EBV positive and EBV negative forms of HD suggesting a
      common pathogenetic mechanism. We have studied the LMP1 associated signaling
      pathways and their dominant negative inhibition in the myelomonocytic HD-MyZ and
      the B-lymphoid L-428 HD cell lines. In both EBV negative cell lines expression of
      LMP1 is associated with the formation of multinuclear RS cells. Dominant negative
      inhibition of NF-kappa B mediated signaling at the step of I kappa B-alpha
      phosphorylation results in increased cell death with only a few typical RS cells
      resistant to overexpression of the dominant negative inhibitor I kappa B-alpha-N
      delta 54. However, dominant negative inhibition of NF-kappa B mediated signaling
      at the early step of TRAF2 interaction results in the formation of multinuclear
      cells in both cell lines and, in addition, in clusters of small mononuclear cells
      in the HD-MyZ cell line. In HD-MyZ cells overexpression of the powerful JBD
      inhibitor of the JNK signal transduction pathway is restricted to small cells and
      never observed in RS cells. These small cells undergo apoptosis as shown by the
      TUNEL technique. Apoptosis of small cells is still observed after co-transfection
      of JBD and LMP1 but in addition a few apoptotic HD-MyZ cells with large fused
      nuclear masses are identified suggesting that specific inhibition of JNK leads
      also to apoptosis of LMP1 induced RS cells. Thus, activation of the JNK signaling
      pathway is also important in the formation of Reed-Sternberg cells. Our findings
      are consistent with a model where all three LMP1 associated functions, i.e. NF
      kappa B mediated transcription, TRAF2 dependent signaling, and c-Jun activation
      act as a common pathogenetic denominator of both EBV negative and EBV positive
      HD.

PMID- 10597318
TI  - Inhibition of growth of human malignant glioblastoma in nude mice by antagonists
      of bombesin/gastrin-releasing peptide.
AB  - The effects of antagonists of bombesin/gastrin-releasing peptide (GRP) on the
      growth of human malignant glioblastoma cell line U-87MG xenografted into nude
      mice were evaluated. Nude mice bearing s.c. implanted U-87MG tumors were treated
      with bombesin/GRP antagonists RC-3095 and RC-3940-II. RC-3095 and RC-3940-II
      administered s.c. at a dose of 20 micrograms/day for 4 weeks decreased the volume
      of U-87MG xenografts by 60 and 74%, respectively, compared with controls. RT-PCR
      analysis showed that U-87MG xenografts expressed mRNA for bombesin receptor
      subtype (BRS)-1 (GRP receptor) and BRS-2 (neuromedin-B receptor), but the mRNA
      for GRP ligand was not detected in U-87MG cells suggesting that GRP may stimulate
      the growth of U-87MG glioblastomas by a paracrine mechanism. The levels of mRNA
      for c-fos oncogene were decreased by 30-40% in U-87MG tumors treated with RC-3095
      or RC-3940-II. In U-373MG glioblastoma cells, which also express BRS-1, and U
      87MG cells, cultured in vitro, GRP(14-27) induced the expression of c-fos mRNA,
      and some c-jun mRNA, in a time-dependent manner with the maximal effect occurring
      2 h after the stimulation and a return to basal levels after 8 h. Antagonist RC
      3940-II inhibited the stimulation of c-fos by GRP(14-27). Our results indicate
      that antagonists of bombesin/GRP inhibit the growth of U-87MG glioblastomas by a
      mechanism that may involve the downregulation of c-fos oncogene.

PMID- 10597319
TI  - Murine Siva-1 and Siva-2, alternate splice forms of the mouse Siva gene, both
      bind to CD27 but differentially transduce apoptosis.
AB  - CD27, a member of the TNFR family known to provide essential co-stimulatory
      signals for T cell growth and B cell Ig synthesis, can also mediate cell death.
      Using the CD27 cytoplasmic tail as the bait in yeast two hybrid assay, we
      previously cloned human Siva, a pro-apoptotic molecule. Here we report the
      characterization of the mouse Siva gene as a 4 kb sequence containing 4 exons and
      3 introns. RT-PCR has revealed the presence of two forms of mouse Siva mRNA, the
      longer full length form Siva-1 and the shorter Siva-2 lacking the sequence coded
      by exon 2. Immunoblotting with anti-Siva (human) antibodies clearly demonstrate
      the presence of both Siva-1 and Siva-2. Cotransfection experiments in 293T cells
      reveal that mouse CD27 receptor can interact with both forms of Siva. Although
      mouse Siva-1 can trigger apoptosis in Rat-1 cells and in some of the mouse cell
      lines in transient transfection experiments, similar to the observation made with
      human Siva, intriguingly its alternate splice form, Siva-2 appears to be much
      less toxic. It is therefore likely that Siva-2 could regulate the function of
      Siva-1.

PMID- 10597321
TI  - 22nd Annual San Antonio Breast Cancer Symposium. December 8-11, 1999. San
      Antonio, Texas, USA. Abstracts.

PMID- 10597320
TI  - Search for in vivo somatic mutations in the mitotic checkpoint gene, hMAD1, in
      human lung cancers.
AB  - We previously reported the presence of mitotic check-point impairment in about
      40% of lung cancer cell lines. To gain an insight into the molecular basis of
      this impairment, we examined 49 lung cancer specimens for alterations in the
      hMAD1 mitotic checkpoint gene and identified a somatic, non-conservative missense
      mutation, which substitutes alanine (GCG) for threonine (ACG) at codon 299,
      together with a number of amino acid substituting, single nucleotide
      polymorphisms. This is the first demonstration of hMAD1 mutation in any type of
      human cancers. The present finding marks hMAD1 as a potential target, although
      with low frequency, for genetic alterations in lung cancer. Thus, further studies
      of hMAD1 dysfunction caused by other mechanisms appear to be warranted, as well
      as potential involvement of other components of the mitotic checkpoint.

PMID- 10597322
TI  - British Society for Clinical Cytology, 38th annual meeting. Manchester, United
      Kingdom, 12-15 September 1999. Abstracts.

PMID- 10597323
TI  - [Therapy of arrhythmia. Amiodarone retains its high value].

PMID- 10597324
TI  - [Conference on Secretolysis in the town of Husum 1999. Inflammatory diseases of
      the upper and lower respiratory tracts].

PMID- 10597325
TI  - 15th Congress of the European Committee for Treatment and Research in Multiple
      Sclerosis, 4th annual meeting of America's Committee for Treatment and Research
      in Multiple Sclerosis (ECTRIMS/ACTRIMS). Basel, Switzerland, September 15-18,
      1999. Joint RIMS-CMSC Symposium, Basel, Switzerland, September 14-16, 1999.
      Abstracts.

PMID- 10597326
TI  - [93rd French Congress of Urology, Paris, France, 17-21, November 1999.
      Abstracts].

PMID- 10597327
TI  - [74th Annual meeting of the French Society of Trauma and Orthopedic Surgery.
      Abstracts].

PMID- 10597328
TI  - [Epiphyseal Cartilage Trauma. Proceeding from the 73rd annual meeting of the
      French Society of Trauma and Orthopedic Surgery].

PMID- 10597329
TI  - [Ruptures of the rotator cuff and subscapularis muscle. Proceedings of the 73rd
      annual meeting of the French Society of Trauma and Orthopedic Surgery].

PMID- 10597330
TI  - [The value of surfactant therapy in secondary surfactant-deficiency syndromes.
      Current status and prospects for the future].

PMID- 10597331
TI  - [25th Annual Meeting of the Society for Neonatology and Pediatric Intensive
      Medicine. Munchen, 26-29 May 1999].

PMID- 10597332
TI  - Introduction: anti-TNF strategies in the treatment of Crohn's disease.

PMID- 10597333
TI  - Review article: targeting TNF alpha as a key cytokine in the inflammatory
      processes of Crohn's disease--the mechanisms of action of infliximab.
AB  - Crohn's disease is a chronic, debilitating gastrointestinal disorder in which a
      variety of cellular processes and pro-inflammatory mediators influence the
      pathogenesis of the disease. Although the potential roles and functions of the
      pro-inflammatory mediators continue to be debated, several mediators,
      specifically tumour necrosis factor-alpha, have been clearly identified as having
      a pivotal role in the inflammation of the bowel mucosa of these patients.
      Therapies specifically focusing on the inflammatory process underlying Crohn's
      disease have the potential for providing disease modification and prolonged
      remission. Infliximab, an antitumour necrosis factor-alpha monoclonal antibody,
      has been demonstrated to neutralize tumour necrosis factor-alpha and restore and
      reset the immunological dysbalance of the inflamed mucosa. Preliminary studies
      with infliximab suggested that treatment resulted in a rapid and almost complete
      inhibition of multiple inflammatory pathways. In clinical studies of infliximab,
      patients with Crohn's disease achieved rapid reduction in clinical signs and
      symptoms, substantiated by both endoscopic and microscopic evaluation.

PMID- 10597334
TI  - Review article: efficacy of infliximab in Crohn's disease--induction and
      maintenance of remission.
AB  - The primary goals of treating patients with Crohn's disease are to induce a
      clinical remission, maintain the remission, and prevent associated complications.
      Various treatment regimens for patients with Crohn's disease induce a response
      and remission; however, most prove ineffective for maintenance of the clinical
      effect. A therapeutic agent that can induce and maintain remission, while
      promoting the restoration of intestinal mucosa, would prove to be most beneficial
      in such a patient population. Several studies with infliximab have clinically
      demonstrated that the antitumour necrosis factor-alpha therapy rapidly reduced
      the signs and symptoms in patients with moderate-to-severe Crohn's disease. In
      acute studies with the chimeric monoclonal antibody, clinical benefit was
      associated with healing and reduction of inflammation in the bowel mucosal
      tissue. In a maintenance study, retreatment with infliximab maintained remission
      of the active disease. Additionally, treatment with the lowest infusion dose of
      infliximab (5 mg/kg) provided a high degree of clinical benefit with a long-term
      outcome.

PMID- 10597335
TI  - Review article: safety of infliximab in clinical trials.
AB  - Infliximab, a chimeric monoclonal antibody to tumour necrosis factor-alpha,
      contains murine protein elements and targets the immune system, raising concerns
      about the potential for immune sensitization and immunosuppressive sequelae.
      However, long-standing inflammatory disease with high activity and chronic
      immunosuppressant therapy can also predispose patients to immunosuppressive
      sequelae. Patients with Crohn's disease, rheumatoid arthritis and other
      indications received single or multiple doses of infliximab and their condition
      was followed for up to 3 years. Adverse events, most frequently headache, nausea,
      and upper respiratory tract infection, were generally mild and occurred in 76% of
      infliximab-treated patients vs. 57% of placebo-treated recipients. Human
      antichimeric antibodies developed in 13% of patients, increasing the potential
      for subsequent infusion reactions. Antibodies to double-stranded DNA developed in
      a small percentage of patients. Other antinuclear antibodies characteristic of
      serum lupus erythematosus were not found; no patient developed a true lupus
      syndrome and no other autoimmune disorders were reported. Infliximab is not
      associated with typical immunosuppressive sequelae, such as infections and
      malignancy, or with autoimmune disorders. Infliximab therapy was well tolerated,
      serious adverse events were infrequent, successfully managed with medication and
      without sequelae, and overall mortality was within the expected incidence for
      this patient population.

PMID- 10597336
TI  - Review article: the efficacy of infliximab in Crohn's disease--healing of
      fistulae.
AB  - In the management of fistulae, the current therapeutic approach is the use of a
      combination of antibiotics and/or a combination of immunomodulatory agents.
      However, clinicians treating patients with fistulae, particularly those with
      fistulizing Crohn's disease, have little data from controlled clinical trials of
      these pharmacologic agents or regimens to substantiate their use in treating this
      complication. Therapy with the anti-tumour necrosis factor-alpha antibody,
      infliximab, has shown promise in treating patients with Crohn's disease and those
      with the disease complicated by fistulae. A recent clinical trial was designed
      specifically to evaluate infliximab in the treatment of fistulizing Crohn's
      disease. Study results demonstrated infliximab to be the first therapeutic agent
      to show statistical efficacy in fistulae closure in a placebo-controlled trial.
      Therapy with the chimeric monoclonal antibody was characterized by a rapid onset
      of closure and a lasting benefit of action. Two patient cases from the clinical
      trial are presented to exemplify the dramatic effectiveness of this novel
      therapeutic approach in modulating the immune response of patients with this
      debilitating complication of Crohn's disease.

PMID- 10597337
TI  - Review article: economic issues in Crohn's disease--assessing the effects of new
      treatments on health-related quality of life.
AB  - The advent of highly effective yet costly new treatments for Crohn's disease will
      force clinicians, patients, and society to make important choices regarding the
      allocation of resources. Pharmacoeconomic analyses can be useful in deciding
      whether new technologies are of good value in comparison to established treatment
      regimens. In Crohn's disease conventional cost-effectiveness analyses are of
      limited use because surgery, death, and disease-related complications occur
      relatively infrequently. Alternatively, cost-utility models relate the
      incremental cost of new treatments to improvements in health-related quality of
      life. These analyses require the collection of valid cost and utility inputs that
      have only recently become available. Ultimately, cost-utility models should allow
      decision makers to make sensible choices for patients and society. This article
      describes the techniques of pharmacoeconomic analysis and reviews existing data
      on the measurement of costs and quality-of-life outcomes in Crohn's disease.

PMID- 10597338
TI  - Peaceful coexistence: of church, state, and the state of evolutionary theory
      education.

PMID- 10597339
TI  - The American Association of Clinical Anatomists (AACA): the other American
      anatomy association.

PMID- 10597340
TI  - A national survey of graduate students in Canadian Departments of Anatomy and
      Cell Biology.

PMID- 10597341
TI  - Allosaurus, crocodiles, and birds: evolutionary clues from spiral computed
      tomography of an endocast.
AB  - Because the brain does not usually leave direct evidence of its existence in the
      fossil record, our view of this structure in extinct species has relied upon
      inferences drawn from comparisons between parts of the skeleton that do fossilize
      or with modern-day relatives that survived extinction. However, soft-tissue
      structure preservation may indeed occasionally occur, particularly in the
      endocranial space. By applying modern imaging and analysis methods to such
      natural cranial "endocasts," we can now learn more than ever thought possible
      about the brains of extinct species. I will discuss one such example in which
      spiral computed tomography (CT) scanning analysis has been successfully applied
      to reveal preserved internal structures of a naturally occurring endocranial cast
      of Allosaurus fragilis, the dominant carnivorous dinosaur of the late Jurassic
      period. The ability to directly examine the neuroanatomy of an extinct dinosaur,
      whose modern-day relatives are birds and crocodiles, has exciting implications
      about Allosaurus' behavior, its adaptive responses to its environment, and its
      eventual extinction.

PMID- 10597343
TI  - A duty of quality.

PMID- 10597342
TI  - Coincident development of sesamoid bones and clues to their evolution.
AB  - Sesamoid bones form within tendons in regions that wrap around bony prominences.
      They are common in humans but variable in number. Sesamoid development is
      mediated epigenetically by local mechanical forces associated with skeletal
      geometry, posture, and muscular activity. In this article we review the
      literature on sesamoids and explore the question of genetic control of sesamoid
      development. Examination of radiographs of 112 people demonstrated that the
      relatively infrequent appearances of the fabella (in the lateral gastrocnemius
      tendon of the knee) and os peroneum (in the peroneus longus tendon of the foot)
      are related within individuals (P < 0.01). This finding suggests that the
      tendency to form sesamoids may be linked to intrinsic genetic factors.
      Evolutionary character analyses suggest that the formation of these sesamoids in
      humans may be a consequence of phylogeny. These observations indicate that
      variations of intrinsic factors may interact with extrinsic mechanobiological
      factors to influence sesamoid development and evolution.

PMID- 10597344
TI  - Aetiology and distribution of mandibular fractures in the National University
      Hospital, Singapore.
AB  - Sixty-seven consecutive mandibular fractures treated mainly in 1998 were surveyed
      retrospectively. Treatment was performed at the National University Hospital,
      Singapore. Males outnumbered females by 5:1, with Chinese the commonest racial
      group involved (56.7%). Most patients were between 20 and 29 years of age. Road
      traffic accidents formed the largest proportion (61.2%) followed by industrial
      accidents and assaults. The symphyseal and parasymphyseal regions were most
      commonly fractured (46.5%). Almost a third of the patients sustained other facial
      fractures. Treatment was commonly administered within one to two days of
      discovery of the fracture and open reduction was the treatment plan of choice in
      79.1% of the time. Discussion on how aetiology affects the fracture pattern in
      Singapore is carried out.

PMID- 10597345
TI  - A review of mandibular fractures in a craniomaxillofacial trauma centre.
AB  - This report is a retrospective review of 74 cases of mandibular fractures managed
      in a craniomaxillofacial trauma centre between January 1994 and May 1998.
      Demographic data revealed that 85% of the patient population were male, with a
      mean age of 27.5 years. The commonest causes of injury were motor vehicle
      accidents (48.6%), followed by assault (16.2%) and accidental falls (17.6%). In
      25 patients (33.8%) the fractures were single. Of these, fractures of the
      condylar region were the most common (8 patients). The remaining patients
      sustained fractures in two or more anatomic sites. There were other associated
      facial fractures in 45.9% of patients. Trauma to other systems was present in
      37.8%, with orthopaedic and neurosurgical injuries being the most common.
      Surgical management in the form of open reduction and internal fixation was
      carried out in 61 patients (82.4%). Maxillo-mandibular fixation was used as an
      adjunct to maintain occlusion and bony reduction in unstable and comminuted
      fractures (15 patients, 20.3%), and as the primary mode of treatment in patients
      with stable, undisplaced fractures, particularly condylar fractures, in which the
      pretraumatic occlusal relationship was not disrupted (9 patients, 12.2%). A
      successful outcome was defined as a stable and healed fracture, with restoration
      of functional occlusion, facial symmetry and facial aesthetics. Complications
      observed included temporomandibular joint dysfunction (10.8%), malocclusion
      (9.5%), infection (8.1%), implant exposure (5.4%), and non-union or delayed union
      (4.1%).

PMID- 10597346
TI  - Intraoral mandibular distraction: indications, technique and long-term results.
AB  - This report describes the experience of the Trousseau Hospital, Paris, France,
      with distraction osteogenesis of the mandible using an intraoral distraction
      device. From 1993 to 1998, 26 paediatric patients with mandibular hypoplasia
      underwent distraction of the mandible using the Leibinger Intraoral Distractor.
      The majority of the patients had hemifacial microsomia. Distraction was performed
      at a rate of 1 mm a day following complete osteotomy of the mandible. A mean of
      15 mm of distraction was obtained. In conjunction with combined orthodontic
      management, satisfactory morphologic results were achieved in the majority of
      patients with good facial symmetry, adequate occlusal relationships and balanced
      maxillary mandibular relationships. Radiographic evaluation revealed that
      substantial new bone formation and remodelling was induced by the intraoral
      distraction along the entire hemimandible on the distracted side and that this
      contributed significantly to the aesthetically pleasing clinical results.

PMID- 10597347
TI  - Surface laser scanning of the cleft palate deformity--validation of the method.
AB  - Innovations in laser technology have led to the development of three-dimensional
      surface laser digitisation techniques capable of registering surface topology
      accurately. The clinical application of this technology in cleft palate
      documentation requires validation of the technique. This study determined the
      reliability of the surface laser scanning technique and assessed the reliability
      of interactive three-dimensional landmark localization. Original and duplicate
      plaster models of an infant with a complete unilateral cleft lip and palate were
      digitised with the Cyberware 3030R-HIREZ surface laser scanner. Seven anatomic
      landmarks were marked permanently on the palatal surface of the duplicate model
      only, which acted as visual cues for landmark localisation. Each model was
      scanned ten times serially, and ten composite three-dimensional images were
      obtained for each. On-line interactive computer landmark localisation permitted
      the assessment of variance for the x, y and z coordinates of each landmark. The
      precision of the laser scanning technique was found to be less than 0.06 mm in
      all three axes. Anatomic landmarks with the clearest visual cue were the least
      variable after ten rounds of scanning. Significant differences existed between
      visually aided and non-aided landmark localisation (P < 0.05). While landmarks
      could be localised repeatedly without the aid of a visual marker, landmarks well
      defined by a clearly visible visual cue on the three-dimensional image were more
      reliable.

PMID- 10597348
TI  - Sutures, growth plates and the craniofacial base--experimental studies in the
      toothless (tl-osteopetrotic) rat.
AB  - The craniofacial skeleton develops from a base in which coordinated growth at
      sutures and growth centres assures the development of normal form. In this report
      we describe features of retarded postnatal craniofacial development in the
      osteopetrotic mutation, toothless (tl), in the rat in which bone growth in both
      the nasal area and the cranial base is reduced, suggesting that the mutation
      affects bone formation in sutures and growth plates. We began a systematic search
      for potential mechanisms by analysing the expression in time and intensity of RNA
      coding for collagens type I (Col I) and type III (Col III) analysed by in situ
      hybridisation of cells in the premaxillary-maxillary suture (PMMS). In the centre
      of the PMMS of tl rats, cells expressing Col I and Col III appeared later than in
      normal littermates and exhibited lower signal. During osteoblast recruitment from
      the suture centre into the bone domains, Col III RNA expression is switched off.
      Osteoblasts expressing Col I in abundance, but no Col III, appeared in the
      flanking bone regions of tl rats later than in normal littermates. It is proposed
      that the tl mutation restricts the number of available osteoblast progenitor
      cells, and that the shortage of these cells affects bone growth in the PMMS and
      in the cranial base. Additional analyses are needed to test this hypothesis and
      to understand the developmental dynamics in the cranial base.

PMID- 10597349
TI  - Epidemiology of cleft lip and palate in Singapore--a 10-year hospital-based
      study.
AB  - During the study period from January 1985 to December 1994, there were 1105 new
      cleft cases seen in the Department of Plastic Surgery, Singapore General
      Hospital. These included newborn as well as unoperated children and adult cases.
      During the same period, the total number of recorded births in Singapore was
      474,542. Out of the 1105 new cleft cases seen, 984 were Singaporeans. The
      incidence of this hospital-based study of cleft population in Singapore was 2.07
      per 1000 livebirths. Chinese had the highest incidence of 1.64 per 1000 as
      compared to Malay, Indian and other races. The most common type of cleft
      deformity was complete cleft lip and palate. The left side was found to be more
      affected than the right side in all types of cleft deformity. There was no
      significant difference in sex distribution; the male to female ratio was 1.1:1.
      However, females had a higher incidence of cleft palate than males. Associated
      congenital deformities occurred in 1.5% of the total cleft population.

PMID- 10597350
TI  - The role of multiple segment osteotomies in orthognathic surgery.
AB  - Multiple segment orthognathic (MSO) surgery is an effective approach to deal with
      a wide range of dento-facial deformities that have occlusal problems. The
      indications for MSO surgery were patients with dentofacial deformities and
      malocclusion requiring stable correction within a short overall treatment period.
      From 1991 to 1998, 107 patients had MSO orthognathic procedures done at Chang
      Gung Memorial Hospital for maxillary protrusion/deformity (34 cases), maxillary
      protrusion and mandibular prognathism (69 cases), and non-cleft maxillary
      retrusion (4 cases). Follow up period ranged from 6 months to 7 years and results
      showed stability in movements with only 3 complications. The average overall
      treatment time was approximately 15 months. Our experience with 107 consecutive
      patients have shown the results of MSO surgery to be good and the procedure safe
      with no tooth or segment loss.

PMID- 10597351
TI  - A 5-year survey of oral biopsies in an oral surgical unit in Singapore: 1993
      1997.
AB  - A survey of oral biopsies performed in an oral surgical centre in Singapore from
      1993 to 1997 was carried out to determine the relative frequency of oral
      pathologies encountered. A total of 2057 reports were reviewed, of which 1986
      separate diagnoses were counted. The great majority of patients were Asian. The
      20 most common diagnoses were: fibrous epulis (10.3%), periapical granuloma
      (8.8%), mucocele (8.6%), radicular cyst (7.6%), lichen planus (5.7%), mucosal
      inflammation (3.6%), squamous cell carcinoma (3.5%), granulation tissue (3.3%),
      fibrous hyperplasia (3.1%), keratosis (3.1%), pyogenic granuloma (2.6%),
      keratocyst (2.4%), osteomyelitis (2.3%), dentigerous cyst (2.3%), dental follicle
      (1.9%), non-specific ulcer (1.8%), ameloblastoma (1.8%), papilloma (1.5%),
      odontoma (1.5%) and residual cyst (1.3%). Oral malignancies accounted for 5.2% of
      all diagnoses, with squamous cell carcinoma (67.0% of malignancies) as the most
      common malignancy. Odontogenic cysts made up 14.9% of all specimens, with
      radicular cysts (50.7% of odontogenic cysts) being most common. Non-odontogenic
      cysts comprised 0.5% of all biopsies. Odontogenic tumours accounted for 5.0% of
      all diagnoses, with ameloblastoma as the most common tumour (35.0%). Similar
      surveys in the literature were reviewed. The relative frequency of some
      conditions appear to be higher than in other studies, including squamous cell
      carcinoma, odontogenic keratocysts and ameloblastomas.

PMID- 10597352
TI  - An anatomic evaluation of the furlow double opposing Z-plasty technique of cleft
      palate repair.
AB  - The aim of this investigation was to examine velar anatomy following the Furlow
      double opposing Z-plasty in order to analyse the theoretical effects of this
      technique. Thirty patients with cleft lip and/or cleft palate who underwent
      primary Furlow palatoplasties between 1989 and 1994 were reviewed. The mean age
      at the time of surgery was 6.4 months. Evaluation was performed at a mean time of
      2.9 years postoperatively, and consisted of oral examination of the position of
      the velar dimple and measurements of velar dimensions from standard lateral
      cephalograms. A comparative statistical analysis of velar length (n = 17) and
      thickness (n = 14) was performed using 2 historical control groups (non-cleft
      norms and non-Furlow cleft palate repairs). The Furlow procedure produced
      posterior dimples in 19 of 26 patients adequately rated on oral examination,
      suggesting successful repositioning of the velar musculature in transverse
      orientation. The mean velar length was not significantly different from that of
      norms (being 0.72 mm less), suggesting that the Furlow Z-plasty results in the
      attainment of near normal velar length. In contrast, the mean velar length was
      0.46 mm greater compared to non-Furlow repairs. Although this difference was not
      statistically significant, it suggests that the Furlow Z-plasty may be more
      effective in increasing velar length compared to non-Furlow palatoplasty
      techniques. Velar thickness was significantly greater compared to both norms (P =
      0.002) and non-Furlow repairs (P = 0.001). These data suggest that the Furlow
      double opposing Z-plasty repositions the velar muscles in transverse orientation,
      and increases both velar length and thickness, lending weight to the theoretical
      effects of this procedure. The anatomic basis of these changes and their
      functional implications are discussed.

PMID- 10597353
TI  - Lessons learnt from the management of 1500 complex facial fractures.
AB  - The lessons learnt from the management of 1500 consecutive patients with complex
      facial fractures have been analysed. This analysis and the major changes in
      treatment principles have resulted in dramatic improvement in results. The
      application of craniofacial surgical principles, extended exposure of the
      craniofacial skeleton, accurate fracture reduction with rigid internal bony
      fixation and primary bone graft reconstruction has revolutionised the care of
      these patients. The reattachment of the soft tissue to the reconstructed skeleton
      provides the final link in this comprehensive one stage reconstruction. Analysis
      of results has demonstrated the majority of complications and failures to be due
      to inadequate exposure and reduction of fractures with bone segments rigidly
      plated in their unreduced position. Inadequate bone grafting and failure to re
      suspend the soft tissue and canthi results in post treatment deformity even if
      the bony reconstruction is adequate. Adherence to the principles of
      reconstruction will almost always result in a one-stage correction no matter how
      severe the initial injury.

PMID- 10597354
TI  - Repair of complex orbital fractures: technical problems, state-of-the-art
      solutions and future perspectives.
AB  - Within the wide range of severity of orbital fractures, the small group of
      complex fractures causes most of the sequelae. Therefore identification of severe
      injuries and adequate treatment is of major importance. The introduction of
      craniofacial techniques made possible a wide exposure of even large orbital wall
      defects and their reconstruction by grafts. In spite of significant progresses,
      repair of complex orbital wall defects remains a difficult surgical problem even
      for the experienced. This paper outlines the specific technical problems
      concerning surgical anatomy, exposure and defect reconstruction of this type of
      injuries. A number of new developments providing interesting future perspectives
      for orbital wall reconstruction such as intraoperative navigation, endoscopic
      techniques and new materials are discussed.

PMID- 10597355
TI  - Reconstruction of cranial bone defects using alloplastic implants produced from a
      stereolithographically-generated cranial model.
AB  - Larger cranial bone defects can cause cranial disfigurement as well as potential
      mechanical brain trauma. Conventionally pre-fabricated acrylic cranioplasty
      implants require complicated procedures and result in potential dimensional and
      contour inaccuracies. The development of stereolithographic techniques for
      generating acrylic resin skull models allows the pre-fabrication of custom
      acrylic resin cranial implants with greater clinical predictability.

PMID- 10597356
TI  - Oral rehabilitation using dental implants and guided bone regeneration.
AB  - The advent of osseointegrated dental implants focused initially on functional
      rehabilitation. Interest today centres on aesthetics and the philosophical ideal
      of replicating nature. Implants can be placed beyond resorbed anatomic
      limitations where the final prosthesis should be, rather than within the pre
      existing resorbed bone. In order to achieve this, the following must be
      considered: implant positioning, adequate bone support and the overlying soft
      tissue envelope. Common techniques to modify the surgical environment include
      different methods of bone grafting and regeneration, ridge expansion and sinus
      augmentation. With the advent of growth factors like bone-morphogenetic proteins,
      restoration of bony contours will become more predictable. Soft tissue management
      techniques include tissue expansion and contouring, gingiva grafts and
      advancement or rotational flaps. Though some of these procedures can be done
      concurrently with implant placement, a secondary surgical procedure is often
      required. Ideal implant positioning involve establishing correct orientation in
      all dimensions. Due consideration should also be given to occlusion and harmony
      of the final restoration with the adjacent dentition.

PMID- 10597357
TI  - A review of common mucocutaneous disorders affecting the mouth and lips.
AB  - Most oral involvement in the mucocutaneous diseases is related mainly to
      disorders with a prominent immunological component, especially lichen planus and
      pemphigoid. However, less common conditions such as pemphigus, dermatitis
      herpetiformis, linear IgA disease, erythema multiforme, chronic ulcerative
      stomatitis and other conditions may need to be excluded. Diagnosis is initially
      clinical, based on a full history, general, and oral examination but precise
      diagnosis can be difficult without further data and therefore biopsy and
      immunological studies are invariably required to confirm the specific diagnosis.
      Apart from improving oral hygiene, immunosuppressive therapy is typically
      required to control many of these conditions.

PMID- 10597358
TI  - Pathogenesis and morphogenesis of craniofacial developmental anomalies.
AB  - A condensed review of the morphogenetic mechanisms of facial fabrication,
      providing insights into developmental anomalies of clinical concern. Genetics,
      epigenetics and regulation of molecular, cellular, tissue and organ formation are
      being elucidated in normal and dysmorphological patterns. The pathogenesis of
      craniosynostosis is related to fibroblast growth factor expression. Analysis of a
      28-month-old-child's dysmorphic synostotic skull explores possible mechanisms of
      malformation and deformation.

PMID- 10597359
TI  - The role of laser surface imaging in the evaluation of craniomaxillofacial
      disorders: the Singapore General Hospital experience.
AB  - The medical profession today, has the choice of many imaging techniques for
      documenting, investigating, assessing or planning treatment. Amongst them, the
      laser surface imaging system is emerging as a useful tool to capture and store
      digital data for reformatting into a three-dimensional computer model. The laser
      scanning system captures only the surface morphology of a subject, and is highly
      appropriate for the evaluation of surface morphological changes of craniofacial
      disorders. Although originally acquired for the study of facial anthropometry,
      many other clinical uses have been found for the scanner and this paper describes
      our experience with the laser scanner in our department. These include archival,
      preoperative assessments, projective linear and surface measurements, area
      measurements, comparative analysis, planning and prediction of surgical outcomes,
      and in the fabrication of physical models and external prostheses.

PMID- 10597360
TI  - Alveolar bone grafts: the surgical/orthodontic management of the cleft maxilla.
AB  - The purpose of this paper is to discuss the management of the cleft maxilla with
      emphasis on the controversies concerning the decisions which a cleft palate team
      makes with limited evidence but strong beliefs in the anticipated outcomes. The
      orthodontist and the surgeon need to collaborate in determining the timing and
      sequencing of alveolar bone grafting. Currently the emphasis on secondary bone
      grafting has superseded primary bone grafting in its effectiveness and
      efficiency. Contemporary management of infants born with clefts of the lip and
      palate is to delay bone grafting until the early mixed dentition stage of dental
      development with the optimal timing being related to the development of the
      unerupted permanent canine. In the management of patients with cleft palate, the
      surgeon and the orthodontist need to evaluate the mixed dentition stage of dental
      development to determine the optimum timing of treatment to coincide with the
      most favourable eruption of the maxillary canine or the lateral incisor when this
      tooth is on the distal side of the cleft. The issues which have led to
      controversy relate to (i) the age at which alveolar bone grafting should be
      performed, (ii) the type of bone graft and the site from which the donor bone
      will be harvested and (iii) the timing of the maxillary expansion and whether
      this should be performed before or after the alveolar bone graft is placed. A
      review of contemporary management of the palatal and alveolar cleft is discussed
      and illustrated in unilateral and bilateral clefts of the maxilla.

PMID- 10597361
TI  - The role of distraction osteogenesis in the management of craniofacial disorders.
AB  - Since its introduction in the medical literature in 1992 by McCarthy, distraction
      osteogenesis of the craniofacial skeleton has become a standard surgical therapy.
      The present report attempts to trace the development of craniofacial distraction
      from the perspective of one of the early proponents of the technique. Although
      the earliest application of distraction was in children with severe unilateral or
      bilateral mandibular deficiency, its use for functional abnormalities such as
      apnoea were especially appealing. Distraction osteogenesis for the midface began
      with external appliances that were attached to the teeth. Newer, buried devices
      have eliminated the need for external devices in all LeFort III and monobloc
      cases. For LeFort I and mandibular cases, the ideal internal device has not been
      manufactured.

PMID- 10597362
TI  - Selective laser sintering: application of a rapid prototyping method in
      craniomaxillofacial reconstructive surgery.
AB  - Advances in technology have benefited the medical world in many ways and a new
      generation of computed tomography (CT) scanners and three-dimensional (3-D) model
      making rapid prototyping systems (RPS) have taken craniofacial surgical planning
      and management to new heights. With the development of new rapid prototyping
      systems and the improvements in CT scan technology, such as the helical scanner,
      biomedical modelling has improved considerably and accurate 3-D models can now be
      fabricated to allow surgeons to visualise and physically handle a 3-D model on
      which simulation surgery can be performed. The principle behind this technology
      is to first acquire digital data (CT scan data) which is then imported to the RPS
      to fabricate fine layers or cuts of the model which are gradually built up to
      form the 3-D models. Either liquid resin or nylon powder or special paper may be
      used to make these models using the various RPS available today. Selective laser
      sintering (SLS), which employs a CO2 laser beam to solidify special nylon powder
      and build up the model in layers is described in this case report, where a 23
      year old Chinese female with panfacial fracture and a skull defect benefited from
      SLS biomodelling in the preoperative workup.

PMID- 10597363
TI  - Oral manifestations of Schimmelpenning syndrome: case report and review of
      literature.
AB  - Schimmelpenning syndrome (SS) is characterised by specific skin manifestations,
      skeletal defects, and central nervous system abnormalities. Here, the SS is
      briefly reviewed, and the oral and dental manifestations are described in a
      patient whose medical findings were previously published and included severe
      hypophosphatemic rickets. Significant oral and dental features included
      papillomatous lesions of the gingiva, hemihyperplasia (hemihypertrophy) of the
      tongue, bone cysts, aplasia of teeth, enlarged pulp chambers, hypoplastic or
      absent enamel, and an odontodysplasia-like permanent tooth.

PMID- 10597364
TI  - Odontoameloblastoma: report of a case.
AB  - Odontoameloblastoma is a very rare odontogenic tumour that is similar to
      ameloblastoma in its locally aggressive behaviour. Its clinical presentation,
      however, often mimics the more innocuous odontoma, and hence the recognition of
      its aggressive nature is commonly only ascertained after its histopathologic
      diagnosis following enucleation. This paper presents a case of
      odontoameloblastoma. Some of the difficulties that may be encountered in the
      diagnosis and treatment planning of odontoameloblastomas are discussed.

PMID- 10597365
TI  - A case report of a vital replanted tooth with unfavourable extra-alveolar
      condition: a 10-year follow-up.
AB  - This case report describes the survival of a maxillary left central incisor after
      an avulsion injury under unfavourable extra-alveolar condition, when the patient
      was 9 years old. At subsequent clinical follow-ups, the tooth maintained vitality
      10 years after the injury. There was sign of gradual obliteration of the root
      canal space. Concomitantly, the replanted tooth manifested typical
      characteristics of ankylosis with minimally detectable resorption complication.

PMID- 10597366
TI  - Midface distraction osteogenesis in cleft patients: a case report.
AB  - We present a case of midface distraction in a bilateral cleft lip and palate
      patient. The patient was a 10-year-old who underwent a high LeFort I osteotomy
      followed by placement of the Rigid External Distraction halo. Distraction was
      commenced on the fifth postoperative day at a rate of 1 to 1.5 mm per day until a
      total of 17 mm of maxillary advancement had been achieved. There were no
      complications and follow up was at 9 months post distraction. Results show that
      the patient had improved facial aesthetics and dental occlusion which was
      overcorrected to a Class III relationship. Velopharyngeal function was
      unaffected. Distraction osteogenesis of the midfacial skeleton in cleft patients
      offers the possibility to remodel not only the underlying bony skeleton but also
      all the soft tissues of the face and palate.

PMID- 10597367
TI  - New treatment and research strategies for the improvement of care of cleft lip
      and palate patients in the new millennium.
AB  - Surveillance studies have shown that cleft lip and palate (CLP) is one of the
      commonest craniofacial anomalies (CFA), occurring in approximately 1 in 500
      livebirths. Taking into consideration the world population and annual birth
      rates, it is estimated that there are well over a quarter million babies born
      each year with CLP. The cost of managing this huge number of clefts is enormous
      and exceeds the available resources of most developing countries in Asia, Africa
      and Latin America. Thus, CLP constitutes a major health problem which requires
      globally-based strategies to deal with the issues of epidemiology, primary
      prevention and treatment strategies which are evidence-based and cost-effective.
      Basic research to unravel the aetiological factors responsible for clefting
      disorders is occurring on a worldwide scale, especially in the areas of molecular
      genetics and gene-environment interactions. There are also in place international
      organisations such as the WHO Task Force on CFA, the International Consortium on
      Oral Cleft Genetics (ICOCG), Interplast and other international volunteer cleft
      missions to help in the treatment of patients with cleft disorders in developing
      countries, in data collection, in pooling of genetic material and sharing of
      information. However, there is an urgent need for more randomised clinical trials
      (RCTs) to evaluate the outcomes of treatment so that clinical guidelines and
      treatment protocols are based on strong evidence. Currently, there is a dearth of
      RCT-based information and multicentre trials on treatment outcomes should
      therefore be actively pursued and encouraged.

PMID- 10597368
TI  - Biochemistry of food allergens.

PMID- 10597369
TI  - The role of food allergy and other allergic disease in atopic dermatitis.

PMID- 10597370
TI  - Skin testing and food challenges in allergy and immunology practice.
AB  - Skin tests by prick technique offer considerable guidance in the diagnosis of
      food allergy. Negative prick skin tests are powerful evidence against food
      allergy. Positive food skin tests are slightly to moderately predictive of
      reaction to a food on DBPCFC. Oral food challenge is necessary for confirmation
      of food allergy, except where the history is overwhelmingly convincing. Open,
      incremental food challenge as described is diagnostic if negative, but only 50%
      of all positive open challenges are confirmed on blinded challenge. DBPCFC can be
      designed for any food with simple blinding techniques. The technique of DBPCFC
      can be modified for investigation of atypical symptoms.

PMID- 10597371
TI  - Anaphylaxis and food allergy.

PMID- 10597373
TI  - Germline and somatic mutations in von Hippel-Lindau disease gene and its
      significance in the development of kidney cancer.

PMID- 10597372
TI  - Immunotherapy for food allergies. Past, present, future.

PMID- 10597374
TI  - Hereditary papillary renal carcinoma: pathology and pathogenesis.

PMID- 10597375
TI  - Renal cell carcinomas in patients on long-term hemodialysis.

PMID- 10597376
TI  - TSC1 and TSC2 gene mutations in human kidney tumors.

PMID- 10597377
TI  - Classification of renal cell cancer based on (cyto)genetic analysis.

PMID- 10597378
TI  - Wilms' tumor and the WT1 gene.

PMID- 10597379
TI  - Gene-modified immunotherapy for renal cell carcinoma.

PMID- 10597380
TI  - Wilms' tumor (nephroblastoma).

PMID- 10597381
TI  - Pathogenesis of renal cell adenomas and carcinomas in animal models.

PMID- 10597382
TI  - Management of haemophilia in patients with high-titre inhibitors: focus on the
      evolution of activated prothrombin complex concentrate AUTOPLEX T.
AB  - Numerous therapeutic strategies have been applied to the management of patients
      with inhibitors to factors VIII or IX. Different treatment approaches are
      analysed including prothrombin complex concentrates (PCCs), activated prothrombin
      complex concentrates (aPCCs), porcine factor VIII concentrate, inhibitor
      neutralization, immune tolerance therapy, immunosuppressive regimens and
      recombinant factor VIIa. Clinical data are reported in the analysis of several
      treatments. PCCs and aPCCs have gained widespread acceptance as the standard
      first-line approach for patients with inhibitors. The aPCC AUTOPLEX T has
      achieved a high response rate with a low level of thrombotic events. Four case
      studies are presented in which AUTOPLEX T has been used successfully.
      Administration of platelet concentrate or, in elective surgery, waiting for
      inhibitor levels to decline are useful adjuncts to some treatments. The optimal
      treatment depends on the patient's inhibitor status--low responder (minimal or no
      increase in inhibitor levels upon administration of replacement clotting factor)
      or high responder (replacement clotting factor generates inhibitor production). A
      suggested algorithm for treating high-responder inhibitor patients is presented.

PMID- 10597383
TI  - Complications associated with the treatment of haemophiliacs with inhibitors.
AB  - To examine the safety profile of products used to treat inhibitor patients
      unresponsive to factor VIII, a review of published clinical experience was
      performed. The products evaluated were activated prothrombin complex concentrates
      (aPCCs), such as AUTOPLEX T, porcine factor VIII and recombinant activated factor
      VII (rVIIa). Safety characteristics included potential for transmission of
      infectious agents, anamnesis, thrombogenicity, thrombocytopenia and allergic
      reactions. While viral transmission has been virtually eliminated, the risk is
      theoretically higher with plasma-derived products such as aPCC and porcine factor
      VIII than with rVIIa, although contamination of cultured cells is a concern.
      Anamnesis occurs with aPCCs and porcine factor VIII, and may induce resistance to
      further therapy with porcine factor VIII. Thrombosis and disseminated
      intravascular coagulation are very infrequently reported in patients exposed to
      aPCCs and rVIIa, and never with porcine factor VIII. The latter is occasionally
      associated with thrombocytopenia, but this uncommonly limits treatment with this
      agent. Lastly, allergic reactions occur with about equal frequency with all
      products, but anaphylaxis is mainly a concern after administration of porcine
      factor VIII. In conclusion, products currently available are reasonably safe.
      Considerations such as efficacy, availability, ease of administration and cost
      must also be considered in making treatment choices.

PMID- 10597384
TI  - Efficacy of viral clearance methods used in the manufacture of activated
      prothrombin complex concentrates: focus on AUTOPLEX T.
AB  - Various methods are described for the elimination of infectious viruses from
      activated prothrombin complex concentrates (aPCCs) and for the analysis of the
      final products (AUTOPLEX T and FEIBA VH). Viruses of concern in human plasma
      derived products are enveloped (hepatitis B and C, cytomegalovirus, Epstein-Barr
      virus, and human immunodeficiency virus [HIV]) and nonenveloped (hepatitis A and
      parvovirus B19). Donated blood used for AUTOPLEX T is screened for antihepatitis
      C, HBsAg, anti-HIV types 1 and 2, and p24 antigen. Plasma pools utilized for raw
      materials are also tested by PCR for HIV and hepatitis C virus. Partial virus
      inactivation and partitioning are achieved by purification of the aPCC. Further
      reduction of virus infectivity is accomplished by lyophilization and dry-heat
      treatment. Each step undergoes virus elimination validation studies in which a
      relevant sample is 'spiked' with the appropriate virus or model virus. The total
      reduction in virus from raw material to final product can then be calculated. For
      AUTOPLEX T the cumulative log10 reduction factors for several viruses vary from
      4.2 to 14.3. This ensures an exceptionally high margin of safety. Definitive
      evidence for product safety was obtained by clinical observation of treated
      patients. The viral inactivation process of AUTOPLEX T involves a four-tier viral
      safety program, including Cohn alcohol fractionation and dry-heat treatment, in
      place of the two-stage vapour-heating process for FEIBA.

PMID- 10597385
TI  - Use of prothrombin complex concentrates and activated prothrombin complex
      concentrates as prophylactic therapy in haemophilia patients with inhibitors.
AB  - Haemophilia patients with inhibitors are treated for acute bleeding with
      prothrombin complex concentrates (PCCs) or activated prothrombin complex
      concentrates (aPCCs). Despite this therapy, patients with high-level inhibitors
      are at increased risk of developing devastating joint disease. This paper
      examines available information that supports the study of PCCs and/or aPCCs as
      prophylactic therapy for haemophilia patients with inhibitors. This strategy
      would require that PCCs or aPCCs be administered repetitively in a dose that is
      sufficient to prevent haemarthrosis without causing thrombogenic events, or
      causing anamnestic response in inhibitor titre. PCC doses ranging from 30 to 50 U
      kg-1 every other day for up to 8 months have resulted in subjective improvement
      both in bleeding associated with target joints and in the management of chronic
      joint inflammation. aPCC doses as low as 50-100 U kg-1 every other day have been
      useful in postsurgical prophylaxis. The risk of developing a myocardial
      infarction or clinically relevant disseminated intravascular coagulation is
      linked to total dosages of either PCCs or aPCCs greater than 200 U kg-1 day-1. It
      is uncertain what anamnestic response would result from prophylaxis, but with
      typical therapy the aPCCs cause such a response in only a small percentage of
      patients. Based on these findings, a clinical trial of these products used in
      doses of 50-100 U kg-1 every other day would appear to be warranted in patients
      who have permanent inhibitors and frequent joint bleeding.

PMID- 10597386
TI  - Treatment options for bleeding episodes in patients undergoing immune tolerance
      therapy.
AB  - Inhibitors to factor VIII develop in 4-20% of haemophilia A patients, with the
      percentage rising to 52% in certain subpopulations. The management of inhibitor
      patients is directed toward stopping acute haemorrhages, providing short-term
      haemostasis before and after surgery, and inducing immune tolerance to factor
      VIII (immune tolerance therapy or ITT). Several different protocols have been
      used for ITT, but they are all centred around ongoing exposure to high doses of
      factor VIII. High responders (those patients with a large increase in inhibitor
      level after exposure to factor VIII) are the prime candidates for ITT, but low
      responders may also benefit from this treatment. It is often necessary to treat
      bleeding episodes during ITT, because elimination of inhibitors may require many
      years of therapy. Treatment of haemorrhages in inhibitor patients is reviewed for
      both low and high responders during ITT and in the absence of ITT. The choice of
      clotting agent for inhibitor patients who have not yet responded to ITT depends
      on current and past inhibitor levels, the severity of the haemorrhage, the site
      of the haemorrhage or the setting in which it occurs (e.g. surgical), and the
      extent of inhibitor cross-reactivity with porcine factor VIII. Patients with high
      titre inhibitors experiencing a critical haemorrhage are generally best managed
      with bypassing agents (AUTOPLEX T or FEIBA VH), porcine factor VIII or rFVIIa.

PMID- 10597387
TI  - Recombinant factor VIIa versus aPCCs in haemophiliacs with inhibitors: treatment
      and cost considerations.

PMID- 10597388
TI  - Duodenal ulcer relapse is not always associated with recurrence of H. pylori
      infection: a prospective three-year follow-up study.
AB  - BACKGROUND: Long-term data concerning the reappearance of Helicobacter pylori
      infection and duodenal ulcer (DU) recurrence after successful eradication are
      still few and conflicting. Inadequate histological assessment or use of indirect
      tests for the determination of H. pylori and bias in the selection of patients to
      be controlled can influence reported results. The aim of this study was to
      determine the rate of recurrence of H. pylori infection and ulcer relapse in a
      population of cured DU patients followed up for 3 years irrespective of their
      symptomatology. METHODS: Between 1992 and 1994, 126 patients with DU disease were
      treated with double or triple therapy. Patients using nonsteroidal
      antiinflammatory drugs or aspirin or receiving maintenance antisecretory therapy
      were excluded. H. pylori infection was assessed by three bioptic tests from both
      the antrum and the body (culture, urease, histopathological examination). After 2
      months from cessation of treatment, DU had healed and H. pylori infection was
      cured in 102 of 126 patients (81%). These patients were endoscopically followed
      up after 1 and 3 years, respectively, and were advised to contact us at symptom
      recurrence. At 1 and 3 years, we studied 95 (93.2%) and 79 (77.4%) patients,
      respectively, of the 102 who were cured. The other patients were untraceable or
      refused endoscopy because they were asymptomatic. RESULTS: After 1 year, no
      patient had H. pylori recurrence, whereas three patients had a relapse of DU
      without evidence of infection. After 3 years, recurrence of H. pylori occurred in
      six patients (annual rate, 2.5%), DU relapsed in five H. pylori-positive patients
      (6.3%) and in two H. pylori-negative patients (annual rate, 1.9%). Fasting
      gastrin and acid secretion values studied in all relapsed patients were within
      the normal range except for one H. pylori-positive patient. CONCLUSIONS:
      Recurrence of H. pylori infection is very low where treatment is effective, but a
      DU relapse, not related to acid hypersecretion, can occur in a small percentage
      of cured patients.

PMID- 10597389
TI  - Pretreatment antimicrobial susceptibilities of paired gastric Helicobacter pylori
      isolates: antrum versus corpus.
AB  - BACKGROUND: Antimicrobial susceptibility testing of Helicobacter pylori isolates
      is the most useful tool for guiding specific therapy, especially when primary
      resistance is suspected. However, the most informative gastric biopsy site for
      detection of resistant H. pylori isolates is uncertain. We sought to determine
      whether susceptibilities to commonly used antimicrobials (amoxicillin,
      clarithromycin, minocycline, and metronidazole) were related to biopsy site.
      METHODS: H. pylori isolates were obtained from patients who had duodenal ulcer
      and had not received any therapy directed against H. pylori. Agar-dilution
      minimum inhibitory concentrations of each antimicrobial were compared between
      paired H. pylori isolates from the antrum and the proximal corpus. RESULTS:
      Differences in minimum inhibitory concentrations exceeding twofold were observed
      within the pairs of H. pylori isolates in 5 of the 40 patients tested. In three
      patients with clarithromycin-resistant isolates and two with metronidazole
      resistant isolates, both antral and corporeal specimens revealed resistance.
      However, no patient had pairs of isolates categorized as resistant at one site
      and sensitive at the other. CONCLUSIONS: While we found that an individual may
      have a mixed H. pylori infection with respect to differing antimicrobial
      susceptibility in different parts of the stomach, a single biopsy specimen from
      either the antrum or the corpus should provide reliable detection of H. pylori
      isolates with primary resistance.

PMID- 10597390
TI  - Quadruple therapy is effective for eradicating Helicobacter pylori after failure
      of triple proton-pump inhibitor-based therapy: a detailed, prospective analysis
      of 21 consecutive cases.
AB  - BACKGROUND: Data regarding the effectiveness of second-line treatment of
      Helicobacter pylori infection are limited, especially if microbiological studies
      are considered. METHODS AND PATIENTS: We conducted a prospective, uncontrolled
      study of a consecutive series of 21 peptic ulcer patients with failure of 1-week
      lansoprazole, amoxicillin, and clarithromycin. H. pylori status was evaluated by
      urease test, histology, culture, and urea breath test. Susceptibility to
      amoxicillin, clarithromycin, and metronidazole was studied by E-test. Cure of
      infection was defined as negative results from endoscopy-based tests 1 month
      after treatment and negative results from a urea breath test at 2 months.
      Treatment consisted of a 1-week combination of lansoprazole (30 mg bid),
      tetracycline (500 mg qid), metronidazole (500 mg tid), and bismuth subcitrate
      (120 mg qid). RESULTS: H. pylori was resistant to metronidazole in three cases,
      to clarithromycin in three cases, and to both clarithromycin and metroinidazole
      in an additional three patients. No resistance to amoxicillin was found.
      Eradication was obtained in 20 cases (95.2% confidence interval [CI], 76.2-99.9).
      The only patient in whom infection was not eradicated harbored a metronidazole
      resistant (minimum inhibitory concentration > 32 micrograms/ml) strain. No
      significant side effects were reported. CONCLUSION: Quadruple therapy obtains a
      high eradication rate even in patients with clarithromycin- and metronidazole
      resistant strains. Further randomized and controlled studies are warranted and
      are urgently needed.

PMID- 10597392
TI  - 13C-urea breath test and gastric mucosal colonization by Helicobacter pylori in
      children: quantitative relation and usefulness for diagnosis of infection.
AB  - OBJECTIVE: Because in children Helicobacter pylori colonization could differ as
      compared to that in adults, gastric metabolism of urea and the reliability of the
      breath test must be evaluated. The aim of this study was to quantify the
      relationship between breath test and colonization. METHODOLOGY: We studied data
      from 50 endoscopies performed in 39 children and adolescents (20 girls, 19 boys,
      aged 3-18 years); 28 were infected with H. pylori. Biopsies were analyzed for
      histological and microbiological diagnosis of infection and for quantitative
      antral culture of H. pylori. A 13C urea breath test was performed on the same day
      as that of endoscopy (n = 33) or delayed between 2 and 90 days (n = 17). RESULTS:
      Using a cut-off value of 3 delta/1000, sensitivity was 96.5%, and specificity was
      91.5%. The three children showing discrepancies between breath test and biopsy
      results had a delta/1000 value close to the cut-off. For the 26 cases with a
      positive culture, we noted a significant correlation (r = 0.63; p < .001) that
      was not affected by the delay between breath test and gastroscopy. CONCLUSION:
      This quantitative relation between bacterial density and delta/1000 permits
      increasing the reliability of the test by interpreting carefully those results
      that approach the cut-off value.

PMID- 10597391
TI  - Effect of cagA status on the sensitivity of enzyme immunoassay in diagnosing
      Helicobacter pylori-infected children.
AB  - BACKGROUND: The aims of our study were twofold. First, we sought to evaluate in
      symptomatic children the influence of the Helicobacter pylori genotype on
      gastritis, abdominal pain, and circulating anti-H. pylori IgG antibodies (anti-H.
      pylori IgG) or pepsinogen A (PGA) and C (PGC). Additionally, we sought to assess
      anti-H. pylori IgG, PGA, and PGC patterns in a large cohort (N = 921) of
      asymptomatic children. MATERIALS AND METHODS: In 183 symptomatic children, H.
      pylori infection and the presence of gastritis were evaluated by histology. In a
      subgroup of 20 H. pylori-positive children, the H. pylori genotype was evaluated
      also by polymerase chain reaction. Nine hundred and twenty-one asymptomatic
      children, aged 11 to 14 years, were studied by anti-H. pylori IgG, PGA, and PGC
      serum determination. RESULTS: The infection was found in 33 of 183 symptomatic
      children; among the 20 H. pylori-positive children for which the H. pylori
      genotype was available, cagA was present or absent in equal percentages. H.
      pylori infection was associated with more severe gastritis and higher serum
      levels of anti-H. pylori IgG and PGC but not with abdominal pain. In infected
      children, higher levels of anti-H. pylori IgG and the presence of abdominal pain
      were associated with infections caused by cagA-positive strains. In the cohort of
      921 asymptomatic children, raised levels of anti-H. pylori IgG, PGA, and PGC were
      found in approximately 5% of the cases. CONCLUSIONS: Infection with cagA-positive
      H. pylori strains can be associated with increased frequency of reported
      abdominal pain and higher circulating levels of anti-H. pylori IgG. The
      serological assessment of H. pylori IgG using H. pylori antigens containing
      significant amounts of cagA protein may, therefore, underestimate the true
      prevalence of infection.

PMID- 10597393
TI  - Clinical and pathological importance of cagA-positive Helicobacter pylori strains
      in children with abdominal complaints.
AB  - BACKGROUND: The aim of this study was to assess the correlation between the
      prevalence of Helicobacter pylori strains possessing cytotoxin-associated gene A
      (cagA) in children and the intensity of clinical complaints and morphological
      changes of the gastric mucosa. MATERIALS AND METHODS: A group of 80 children with
      gastrointestinal complaints was included in this study. Pathologists examined
      mucosal biopsy specimens from these patients. The urease test and multiplex
      polymerase chain reaction (MPCR) were used to identify H. pylori strains.
      RESULTS: In the group of children infected with cagA-positive H. pylori strains,
      fourth-degree gastritis was more frequent than in the group with cagA-negative H.
      pylori colonization. In histopathological assessment, infection with cagA
      positive H. pylori was associated also with higher grades of inflammatory
      intensity and activity. CONCLUSIONS: Marked inflammation of the antral mucosa was
      significantly more frequent in children infected with cagA-positive H. pylori
      than in those infected with cagA-negative H. pylori, as assessed endoscopically
      and histopathologically. No specific symptoms for cagA-positive and cagA-negative
      H. pylori infection were observed.

PMID- 10597394
TI  - Practice patterns for peptic ulcer disease: are family physicians testing for H.
      pylori?
AB  - BACKGROUND: Peptic ulcer disease (PUD) is a problem common in family medicine.
      Recent evidence of Helicobacter pylori as an etiological agent of PUD has led to
      National Institutes of Health recommendations for treatment to eradicate H.
      pylori through antibiotic therapy. The purpose of this study is to examine
      practice patterns of family physicians in treating PUD, their use of H. pylori
      testing, and knowledge of current recommendations for PUD. MATERIALS AND METHODS:
      A mail survey was sent to a random sample of 1,500 members of the American
      Academy of Family Physicians. Six hundred thirty useable surveys (49.1%) were
      available for analysis. Descriptive statistics were obtained, as were inferential
      statistics focusing on the relationship of physician background characteristics
      to practices. RESULTS: Thirty-eight percent of the respondents order diagnostic
      procedures for the majority (50% or more) of their suspected PUD cases. Of the
      physicians who reported ordering any diagnostic tests, 52% ordered the
      combination of upper gastrointestinal series and endoscopic gastroduodenoscopy.
      For patients with clinical diagnoses of PUD, 77% of doctors reported ordering a
      diagnostic test for H. pylori. Approximately 68% were aware that some kind of
      guidelines existed; only 11% reported that they were familiar with the National
      Institutes of Health recommendations for PUD. CONCLUSIONS: Although some of the
      practices of family physicians for treatment of PUD deviate from current
      recommendations, the majority of practices are consistent with current evidence.

PMID- 10597395
TI  - Colonization and tissue tropism of Helicobacter pylori and a novel urease
      negative Helicobacter species in ICR mice are independent of route of exposure.
AB  - BACKGROUND: In humans, Helicobacter pylori is known to colonize the stomach and
      to induce persistent gastritis; selected reports also suggest it causes
      extragastric disease, including hepatitis. H. pylori and a novel urease-negative
      Helicobacter sp. induce gastritis and typhlocolitis, respectively, when
      inoculated orally into mice. Experimental typhlocolitis and hepatitis have been
      caused by intraperitoneal (i.p.) injection of H. hepaticus, H. bilis, and the
      novel Helicobacter spp. However, the route by which i.p.-inoculated organisms
      localize to specific areas of the gastrointestinal system is unknown. MATERIALS
      AND METHODS: To determine whether Helicobacter spp. can be isolated from blood,
      can preferentially colonize specific tissues, and can cause pathological changes,
      we inoculated 6-week-old outbred mice orally or intraperitoneally with H. pylori
      or a novel Helicobacter sp. RESULTS: When these mice were inoculated by the i.p.
      route, H. pylori was cultured from lungs, spleen, liver, cecum, and stomach on
      day 1 after inoculation, from liver and stomach mucosa on day 3 after
      inoculation, and from the stomach on day 30 after inoculation, suggesting
      preferential colonization of the stomach. After inoculation by the i.p. route,
      the novel intestinal Helicobacter sp. was cultured from the blood, lungs, spleen,
      liver, kidneys, cecum, and feces but not from stomach mucosa on day 1 after
      inoculation. By day 30 after inoculation, the novel Helicobacter sp. was cultured
      from cecum and feces only, suggesting that it had preferentially colonized the
      lower bowel. By the i.p. route, the novel Helicobacter sp. induced hepatitis that
      persisted for 30 days after inoculation. Though mice inoculated intraperitoneally
      with H. pylori developed an acute hepatitis, the liver lesion began to resolve 30
      days after inoculation. Mice inoculated orally with either H. pylori or the novel
      Helicobacter sp. did not have hepatitis on day 30 after inoculation but developed
      100% colonization of stomach and cecum, respectively. CONCLUSION: The isolation
      of H. pylori and the novel Helicobacter sp. from multiple tissues infers that a
      transient helicobacter bacteremia occurs when Helicobacter spp. are injected
      intraperitoneally, but organisms are cleared rapidly from nontarget tissues and
      preferentially colonize specific regions of the gastrointestinal tract.

PMID- 10597396
TI  - Factors affecting the validity of the 13C-urea breath test for in vivo
      determination of Helicobacter pylori infection status in a mouse model.
AB  - BACKGROUND: The mouse model using a human isolate of Helicobacter pylori is being
      widely accepted as an economical means of studying gastric infection. A
      noninvasive monitoring method would be useful for repeated testing to establish
      the time course of infection and the efficacy of treatments. In this study, we
      describe factors that affected interpretation of 13C urea breath test results for
      the assessment of H. pylori infection status in this model. MATERIALS AND
      METHODS: Female C57B1/6 mice that underwent gavage with H. pylori or saline were
      breath-tested using 50 micrograms of 13C urea at intervals up to 2 months after
      inoculation. The generation of 13CO2 (excess delta 13CO2) by infected mice was
      compared to that of uninfected controls. The effects of diet, fasting, and
      coprophagy on the reliability of the 13C urea breath test were quantitated.
      RESULTS: Both commercial and synthetic mouse diets exhibited marked in vitro
      urease activity. A minimum fasting time of 13 hours prior to breath testing
      significantly reduced this dietary contribution to excess delta 13CO2 values. The
      coprophagic tendency of the mice caused spuriously high excess delta 13CO2 counts
      in the breath of both control and H. pylori-infected mice. CONCLUSIONS: Although
      the dietary contribution to spuriously high values of excess delta 13CO2 in mice
      breath-tested for H. pylori infection was reduced by fasting, the high
      nonspecific urease activity generated by coprophagy severely limited the
      reliability of the urea breath test in the assessment of H. pylori infection
      status.

PMID- 10597397
TI  - Pantoprazole suppresses Helicobacter pylori without affecting cure.
AB  - BACKGROUND: Short-term, low-dose triple regimens composed of proton-pump
      inhibitors (PPI) and two antibiotics are the current gold standard therapy for
      cure of Helicobacter pylori infection. To date, the effect of PPI pretreatment on
      eradication outcome is not known. The aim of this study was to evaluate the
      influence of pretreatment with pantoprazole on the efficacy of an ensuing triple
      therapy. METHODS: In this open, randomized, monocenter, parallel group
      comparison, 107 patients with duodenal ulcer or functional dyspepsia were
      assigned to receive one of the following treatment regimens: a 7-day triple
      therapy with pantoprazole, 40 mg bid; clarithromycin, 250 mg bid; and
      metronidazole, 400 mg bid, which was either preceded or followed by a 7-day
      therapy with pantoprazole, 40 mg (P-PCM or PCM-P). Assessment of H. pylori status
      was performed by a biopsy urease test and 13C urea breath test at the initial
      visit and 13C urea breath test at all follow-up visits. RESULTS: The 7-day
      pantoprazole pretreatment resulted in a significant decline of the delta values
      of the 13C urea breath test. H. pylori infection was cured in 47 of 52 intention
      to-treat patients of the P-PCM group (90%; 95% confidence interval, 79-97%) and
      in 46 of 53 of the PCM-P group (87%; 95% confidence interval, 75-95%).
      CONCLUSIONS: Pretreatment with pantoprazole suppresses H. pylori but does not
      impair the efficacy of a consecutive short-term, low-dose triple therapy.

PMID- 10597398
TI  - Helicobacter pylori vaccine development and use: a cost-effectiveness analysis
      using the Institute of Medicine Methodology.
AB  - BACKGROUND: Prophylactic vaccination has been suggested as a better strategy than
      antibiotics to control Helicobacter pylori infection. We evaluated the cost
      effectiveness (CE) of H. pylori vaccine development and use in the United States
      and developing countries, using a method developed by the Institute of Medicine
      (IOM). METHODS: The IOM model includes costs of vaccine development, vaccination
      program, and averted medical treatments; morbidity and mortality prevented;
      expected efficacy and use; and proportion of disease that is vaccine-preventable.
      The model employs infant mortality equivalence (IME) to estimate disease burden;
      with IME, the societal cost of infection-related morbidity is expressed as
      equivalent to a specific rate of infant deaths. We tested model assumptions by
      univariate sensitivity analyses. RESULTS: In the United States, H. pylori vaccine
      would save 1,176 IME and would cost $58.71 million (1997 dollars) annually,
      yielding a CE ratio of $49,932 per IME; the health benefits would exceed all IOM
      studied vaccines, even when efficacy dropped to 55%. H. pylori vaccine could be
      cost-saving if priced at less than $60 per course. In developing countries, H.
      pylori vaccine would rank unfavorably both in terms of health benefits (33,518
      IME) and costs ($5,254 million). None of the changes in assumptions improved
      significantly the H. pylori vaccine's ranking relative to other IOM-studied
      vaccines. CONCLUSIONS: Compared to other vaccines evaluated in the IOM study, H.
      pylori vaccine warrants public resource allocation for accelerated development
      and use in the United States but not for use in developing countries.

PMID- 10597399
TI  - An inverse relation between cagA-positive strains of Helicobacter pylori
      infection and risk of esophageal and gastric cardia adenocarcinoma.

PMID- 10597400
TI  - Which etiology causes the most severe acute pancreatitis?
AB  - BACKGROUND: The aim of the study was to define the prognostic role of etiology in
      the course of acute pancreatitis. METHODS: The study involved 208 consecutive
      patients with a first attack of acute pancreatitis. Etiology was biliary in 81
      (39%) patients and alcohol abuse in 69 (33%); other etiologies were present in 16
      (8%), and etiology remained unknown in 42 (20%). Etiology was correlated with the
      following parameters of severity of the disease: days in an intensive care unit
      (ICU); total hospital stay (THS); Ranson, Imrie, and Balthazar scores (contrast
      enhanced computed tomography [CT] within 72 h of admission); indication of
      artificial ventilation, dialysis, or surgery; development of pancreatic
      pseudocysts; mortality. RESULTS: Alcoholic etiology correlated significantly more
      frequently than other subgroups with necrotizing pancreatitis, need for
      artificial ventilation, and development of pancreatic pseudocysts. For the other
      parameters, there were no significant differences between the etiologies.
      CONCLUSION: Patients with alcohol-induced acute pancreatitis should be given
      special attention because of the higher incidence of necrotizing pancreatitis and
      necessity for artificial ventilation. Whether the pronounced frequency of
      pseudocysts in alcoholics suggests progression to chronic pancreatitis has to be
      clarified in follow-up studies.

PMID- 10597401
TI  - Impaired pancreatic exocrine function in rats with carbon tetrachloride-induced
      liver cirrhosis.
AB  - BACKGROUND: Substantial numbers of studies have revealed the close correlation
      between chronic pancreatitis and cirrhosis in human. However, the situation with
      regard to pancreatic enzyme secretion is less clear. AIM: The aim of the study
      was to investigate pancreatic exocrine function in rats with carbon tetrachloride
      induced liver cirrhosis in rats. METHODS: Pancreatic exocrine function and
      morphology in Sprague-Dawley rats with carbon tetrachloride-induced liver
      cirrhosis were investigated. Pancreatic exocrine functions stimulated by
      cholecystokinin-8 and other secretagogs were assessed in isolated pancreatic
      acini, and in vivo and morphological changes were studied by routine histological
      examination and electron microscopy. RESULTS: The basal and cholecystokinin-8
      stimulated amylase releases from acini and acinar amylase content were
      significantly lower in the cirrhotic rats than the control. None of the
      secretagogs induced the some amount of amylase release in cirrhotic as in control
      rats. Volume of the pancreatic juice and outputs of amylase and protein were
      significantly decreased under basal and cholecystokinin-8-stimulated conditions
      in vivo. Electron microscopy revealed most of the rough-surfaced endoplasmic
      reticulum accompanying less numbers of ribosomes to be dilated and some
      mitochondria to be swollen in cirrhotic rats. CONCLUSION: Pancreatic exocrine
      functions are decreased in cirrhotic rats owing to alterations at the electron
      microscopic levels, reflecting an impaired acinar intracellular messenger system.

PMID- 10597402
TI  - Immunohistochemical analysis of cyclooxygenase-2 expression in pancreatic tumors.
AB  - BACKGROUND: A considerable amount of evidence collected from several experimental
      systems and clinical studies with nonsteroidal Anti-inflammatory drugs (NSAIDs)
      indicates that Cox-2 may play a major role in colorectal tumorigenesis, but
      little information about Cox-2 expression in pancreatic tumors is available. In
      this study, we investigated Cox-2 expression by means of both immunohistochemical
      analysis and immunoblot analysis in pancreatic tumors. METHODS: Fifty invasive
      ductal adenocarcinomas and 26 intraductal papillary-mucinous tumors (IPMTs) were
      used for immunohistochemical analysis, and five pancreatic cancer tissues and
      five pancreatic cancer cell lines for immunoblot analysis. RESULTS: Cox-2 was
      expressed in 72% of the invasive ductal adenocarcinomas, 31% of intraductal
      papillary-mucinous adenocarcinomas, and none of intraductal papillary-mucinous
      adenomas. The expression rate of Cox-2 in intraductal papillary-mucinous
      adenocarcinomas was significantly higher than that in intraductal papillary
      mucinous adenomas, and that in invasive ductal adenocarcinomas was significantly
      higher than that in intraductal papillary-mucinous carcinomas. However, there was
      no significant correlation between Cox-2 expression and the prognosis and
      clinicopathological factors. Immunoblot analysis identified Cox-2 in all of
      pancreatic cancer tissues and 60% of cell lines. CONCLUSION: The biological role
      of cyclooxygenase-2 (Cox-2) in carcinoma cells should be investigated with
      reference to the cancer progression of the pancreas.

PMID- 10597403
TI  - Significance of proliferative activity and DNA ploidy in pancreatic cancer and
      chronic pancreatitis.
AB  - BACKGROUND: Precise preoperative assessment of diagnosis and prognosis in
      patients with pancreatic tumors would facilitate improvement of treatment
      strategies. In this context, we evaluated the significance of the proliferative
      index and of static DNA cytophotometry in the diagnosis and prognosis of
      pancreatic tumors. METHODS: Consecutive surgical specimens from 26 patients with
      ductal pancreatic cancers and eight patients with chronic pancreatitis were
      investigated by: 1. Staging; 2. Conventional histological and cytological
      grading; 3. MIB-1 (Ki-67 labeling) proliferating index; and 4. Static DNA
      cytophotometry. RESULTS: All patients with chronic pancreatitis had a normal MIB
      1 labeling index and a euploid DNA content. In contrast, patients with pancreatic
      cancers rarely had a normal labeling index (1 of 26 patients) or a euploid DNA
      content (6 of 26 patients). Staging significantly correlated with survival time.
      However, it did not correlate with cytological criteria. Cytological criteria,
      such as conventional grading, MIB-1 proliferating index, and DNA ploidy, were not
      significantly correlated with survival time. Conventional grading was
      significantly correlated (p < 0.02) with proliferating index, but not with DNA
      ploidy. CONCLUSION: Proliferating index and DNA ploidy are relevant cytological
      markers that can help to discriminate between chronic pancreatitis and pancreatic
      cancer. The prognostic significance of these markers in pancreatic cancer
      patients, however, seems to be less relevant than tumor stage and of limited
      relevance for the individual cancer patient.

PMID- 10597404
TI  - Adenosquamous carcinoma of the pancreas.
AB  - BACKGROUND: Adenosquamous carcinoma of the pancreas most probably represents
      squamous metaplasia of an adenocarcinoma. Metastases are typically an admixture
      of both elements, but more frequently, adenocarcinoma. METHODS: A review of 102
      pancreaticoduodenectomies for masses of the head of the pancreas done between
      1994 and 1998 revealed two patients with adenosquamous carcinoma of the pancreas.
      RESULTS: Both patients underwent successful pancreaticoduodenctomy, but were
      found to have nodal metastasis. One patient lived 13 mo and the other lived 14 mo
      with both dying from metastatic disease. CONCLUSION: Adenosquamous carcinoma of
      the pancreas is a rare tumor, and because its presentation, clinical features,
      and course are identical to adenocarcinoma of the pancreas, it should be
      considered in the differential diagnosis for any mass of the head of the
      pancreas. Survival is poor for these patients. In this series, it was 13 and 14
      mo, respectively.

PMID- 10597405
TI  - Case of intraductal papillary mucinous tumor (noninvasive adenocarcinoma) of the
      pancreas resected 27 years after onset.
AB  - A case of intraductal papillary mucinous tumor (IPMT) of the pancreas resected 27
      yr after onset is presented. In March of 1997, a 71-yr-old man was admitted to
      our hospital with a complaint of severe epigastric pain. He had initially
      undergone endoscopic retrograde pancreatography (ERP) in April 1971 in our
      hospital and the patient had been followed up for pancreatografic changes for 26
      yr. Dilatation of the main pancreatic duct gradually progressed during follow-up,
      and the filling defect owing to the tumor became demonstrable. On admission, ERP
      revealed diffuse dilatation of the main pancreatic duct, which was 20 mm in
      diameter, and the filling defect of 35 mm in diameter. We diagnosed this patient
      as having an IPMT of the pancreas. Considering his general condition, pancreatic
      segmentectomy was carried out, and the postoperative course was favorable.
      Histological findings were compatible with those of noninvasive papillary
      adenocarcinoma. This is a precious case for studying the natural history of
      intraductal papillary tumor of the pancreas and to evaluate the application of
      surgery, because the biologic behavior of this tumor is much less aggressive than
      that of pancreatic ductal cell carcinoma.

PMID- 10597406
TI  - Exploring genetic analysis of complex traits through the paradigm of alcohol
      dependence: summary of GAW11 contributions.
AB  - We discuss the Genetic Analysis Workshop 11 analyses of data from the
      Collaborative Study on the Genetics of Alcoholism from a methodological
      perspective, concentrating on approaches and issues relevant to linkage and
      association studies of complex human phenotypes. Genome screening by parametric
      linkage, nonparametric linkage, association, and combined linkage/association
      methods are discussed. Issues particular to complex disease include etiologic
      heterogeneity, multivariate phenotype modeling, and parent-of-origin effects.
      Other methodological topics discussed are new and enhanced methods,
      ascertainment, weighting of nonindependent sib pairs, and data cleaning and
      validation.

PMID- 10597407
TI  - Description of the Genetic Analysis Workshop 11 Collaborative Study on the
      Genetics of Alcoholism.
AB  - Problem 1 of Genetic Analysis Workshop 11 consists of data from a family study of
      the genetics of alcoholism and related traits contributed by the six centers
      making up the National Institute for Alcohol Abuse and Alcoholism sponsored by
      the Collaborative Study on the Genetics of Alcoholism (COGA). The family data
      included 1,214 members of 105 pedigrees ascertained for having three or more
      individuals affected with alcoholism. Data available to workshop participants
      included clinical phenotypes, personality measures, smoking behavior, event
      related potentials, platelet monamine oxidase B activity, and a genome scan of
      296 markers.

PMID- 10597408
TI  - Quantitative trait locus detection using combined linkage/disequilibrium
      analysis.
AB  - We describe an extension of the variance component linkage method that augments
      identity-by-descent information from relatives with identity-by-state information
      from unrelated individuals, exploiting disequilibrium to facilitate fine mapping
      of quantitative trait loci. An advantage of the combined linkage/disequilibrium
      test is that it detects association only in the presence of linkage and is not
      biased by population stratification.

PMID- 10597409
TI  - Brain event-related potentials, dopamine D2 receptor gene polymorphism, and
      smoking.
AB  - This paper explores the relationship between the DRD2 gene polymorphism, P300,
      and smoking. Both smoking and DRD2 have significant reducing effects on P300
      amplitude. The effect of smoking is apparent only in the presence of the A1
      allele of the DRD2 locus. Transmission/disequilibrium analyses show a negative
      association between the A2 allele and smoking initiation, suggesting a protective
      effect of this allele. When the sample is stratified into lower- and higher-P300
      categories, we find a significant association between A1 and current smoking only
      in individuals with lower P300. Both concordance for smoking and DRD2 genotype
      are significant predictors of sib-pair similarity in P300 amplitude. These
      results suggest a synergistic effect of different neurogenetic risk factors
      contributing to nicotine dependence. Neurocognitive variation (P300) may moderate
      the association between DRD2 and smoking. Alternatively, DRD2 genotype may
      modulate the long-term impact of nicotine on neurocognitive functioning.

PMID- 10597410
TI  - Mapping alcoholism genes using linkage/linkage disequilibrium analysis.
AB  - Using a recently developed semiparametric method for combined linkage/linkage
      disequilibrium analysis, we analyzed the Collaborative Study on the Genetics of
      Alcoholism data subset developed for Genetic Analysis Workshop 11 (GAW11). This
      semiparametric approach estimates recombination fractions for linkage, marker log
      odds ratios for linkage-disequilibrium, their product for combined
      linkage/linkage-disequilibrium, and corresponding z-scores. We used two outcomes:
      alcohol dependence and "alcoholism-free" and a genome-wide significance level of
      4.1 (which corresponds to a genome-wide lod score of 3.6). For the alcohol
      dependence outcome, we observed significant linkage signals at D1S1588-D1S1631,
      D1S547, D2S399, D2S425, D4S2361, D7S1796, and D7S1824. We also found significant
      linkage-disequilibrium signals at D1S547 and D7S1795. For the "alcoholism-free"
      outcome, we found significant linkage signals at D4S2457, D41651 (both flank
      ADH3), D11S2359, and D16S47 and significant linkage-disequilibrium signals at
      D4S2361, FABP2, D11S2359, D19S431 and D19S47-D19S198-D19S601.

PMID- 10597411
TI  - Assessing linkage of monoamine oxidase B in a genome-wide scan using a univariate
      variance components approach.
AB  - We report results when one alcoholism related quantitative trait, monoamine
      oxidase B (MAOB), is analyzed by the variance components approach for linkage
      [Amos, 1994; Amos et al., 1996] using the Collaborative Study on the Genetics of
      Alcoholism data set provided for the Genetic Analysis Workshop 11. We used two
      different covariate models, one with age at interview, sex, ethnicity, and
      smoking status and the other with age at interview, sex, and ethnicity. The
      univariate analysis showed 24 markers on four different chromosomes (1, 4, 9, and
      12) to have evidence for linkage with the quantitative trait (single-point and
      multipoint linkage). However, when outliers for MAOB were removed, the
      significant evidence for linkage disappeared.

PMID- 10597412
TI  - A genome-wide search for loci contributing to smoking and alcoholism.
AB  - Using the Collaborative Study on the Genetics of Alcoholism (COGA) data, we
      performed a sib-pair linkage analysis of two smoking-related traits and one
      alcoholism phenotype. The first trait, EVRNVR, was a dichotomous one we
      constructed based on epidemiological definitions of smoking. The second trait,
      PKYRS, used the quantitative pack-year history provided, and the third trait was
      the COGA alcoholism classification, ALDX1. There was some evidence for linkage of
      the EVRNVR trait to regions-on chromosomes 6, 9, and 14. Smaller numbers of loci
      provided nominal evidence for linkage to PKYRS, although some candidate gene
      regions were identified. The number of loci identified using EVRNVR suggests that
      a threshold-based phenotype may better identify loci affecting smoking history.
      Approximately one-third of the loci that showed evidence for linkage to EVRNVR at
      a nominal significance level (p < 0.01) also showed evidence for linkage to
      ALDX1. Some of these regions may represent loci increasing vulnerability to both
      smoking and alcoholism.

PMID- 10597413
TI  - The effect of phenotype variation on detection of linkage in the COGA data.
AB  - Error in phenotypic measurement can significantly compromise ability to detect
      linkage. We assessed the impact of introducing phenotypic measurement error on
      our ability to detect a quantitative trait locus in the Collaborative Study on
      the Genetics of Alcoholism (COGA) data. The impact of introducing three different
      types of errors was evaluated: 1) errors generated by sampling from a normal
      distribution; 2) errors generated by permuting phenotype values between subjects;
      and 3) errors generated by sampling from a uniform error distribution.

PMID- 10597414
TI  - Oligogenic model selection using the Bayesian Information Criterion: linkage
      analysis of the P300 Cz event-related brain potential.
AB  - The traditional likelihood-based approach to hypothesis testing may not be an
      optimal strategy for evaluating oligogenic models of inheritance. Under
      oligogenic inheritance the number of possible multilocus models can become very
      large; there may be several competing linkage models having similar likelihoods;
      and comparisons among non-nested models can be required to determine if a given
      multilocus model provides a significantly better fit to observed phenotypic
      variation than an alternative model. We propose an efficient Bayesian approach to
      oligogenic model selection that makes use of existing model likelihoods, and show
      how model uncertainty can be incorporated into parameter estimation.

PMID- 10597415
TI  - The impact of marker allele frequency misspecification in variance components
      quantitative trait locus analysis using sibship data.
AB  - In cases where sibship data are collected for a quantitative trait locus (QTL)
      linkage study without access to parental genotypes, the proportion of genes
      shared identical by descent must be estimated using the marker allele
      frequencies. No systematic study has been conducted to date to evaluate the
      effect of misspecification of these frequencies on a test of quantitative trait
      linkage. Analysis of both simulated and actual data on quantitative traits was
      carried out under various sets of allele frequency estimates. While correctly
      specifying the allele frequency distribution led to a slightly more powerful test
      and higher lod scores, the differences were small and would not likely alter the
      conclusion of a study. These results suggest that, at least for QTL analysis,
      there is a great deal of tolerance for misspecifying marker allele frequencies
      with little, if any, appreciable effect on the linkage test. However, the
      observed variations may be sufficiently large to alter the priority on might give
      to a positive finding for follow up.

PMID- 10597416
TI  - Cleaning genotype data.
AB  - The identification of genes contributing to variation in complex phenotypes
      requires genetic data of high fidelity. Thus, the identification of pedigree and
      genotyping errors is a crucial prerequisite to the analysis of data from a genome
      scan for disease genes. The problem has been given little attention in most gene
      hunting papers; the focus has often been on eliminating mendelian inconsistencies
      in order that the analysis may proceed, rather than on achieving the best
      possible data. Though a number of computer programs are available to assist in
      the identification of genotyping and pedigree errors, the process is still not
      completely automated. While the Collaborative Study on the Genetics of Alcoholism
      (COGA) data set for GAW11 is completely compatible with Mendel's rules, there are
      still some errors present. We inspected the COGA data for the presence of
      additional errors, and identified five possible pedigree errors.

PMID- 10597417
TI  - A low density genome-wide search for loci involved in alcohol dependence using
      the transmission/disequilibrium test, sib-TDT, and two combined tests.
AB  - The transmission/disequilibrium test (TDT), sib-TDT and two combined tests have
      been implemented in an attempt to identify loci across the genome that may be
      involved in alcohol dependence. Since these tests are based on the existence of
      association between marker and disease loci, the low-density map used (13 cM)
      will have missed any disease loci situated between markers. Nevertheless, genome
      wide suggestive linkage results were found at three markers--D6S474, D8S1715, and
      D12S372--two of which also gave nominally significant evidence by two-point
      linkage analysis. These are regions that deserve further investigation with
      respect to their involvement in alcohol dependence, and in order to evaluate the
      relative efficacy of the different methods used.

PMID- 10597418
TI  - Comparison of evidence supporting a chromosome 6 alcoholism gene.
AB  - A whole genome scan has been conducted on 105 families ascertained for probands
      with a diagnosis of alcoholism by the Collaborative Study on the Genetics of
      Alcoholism (COGA). To identify chromosomal regions likely to contain genes
      contributing to the development of this disorder, data from 296 highly
      polymorphic markers have been analyzed using the MAPMAKER/SIBS [Kruglyak and
      Lander, 1995] and GENEHUNTER-PLUS [Kruglyak et al., 1996; Kong and Cox, 1997]
      multipoint linkage programs. Chromosome 6 exhibited lod scores greater than 3.0
      and was further tested by two-point linkage analyses at each marker along the
      chromosome to assess the consistency of results from these allele sharing linkage
      programs. Two-point linkage was assessed with MAPMAKER/SIBS, GENEHUNTER-PLUS and
      the SIBPAL subprogram of the SAGE package of genetic epidemiology programs
      [Elston, 1997].

PMID- 10597419
TI  - Assessment of estimation procedures for risk and onset hazard with dependent
      data.
AB  - Analysis of the role of candidate genes as risk factors for age-dependent
      hereditary conditions often ignores the importance of dependence among sibships
      or other family clusters for age of onset. We examined the performance of several
      methods of survival analysis with dependent data using Collaborative Study on the
      Genetics of Alcoholism families as submitted for GAW11. Additionally, an
      arbitrary truncation of cluster size was performed to explore the potential
      impact of heterogeneity of family size on the resulting inferences concerning the
      role of candidate genes. Our results showed substantial differences in
      attribution of risk to candidate genes according to whether the method utilized
      allowed for dependence in onset age and according to whether the sample was
      truncated or arbitrarily stratified. Further work needs to be done to clarify the
      importance of properly accounting for dependent data in age-dependent phenotypes
      and in integrating these methods into widely used genetic analysis computer
      programs.

PMID- 10597420
TI  - Comparison of empirical strategies to maximize GENEHUNTER lod scores.
AB  - We compare four strategies for finding the settings of genetic parameters that
      maximize the lod scores reported in GENEHUNTER 1.2. The four strategies are
      iterated complete factorial designs, iterated orthogonal Latin hypercubes,
      evolutionary operation, and numerical optimization. The genetic parameters that
      are set are the phenocopy rate, penetrance, and disease allele frequency; both
      recessive and dominant models are considered. We selected the optimization of a
      recessive model on the Collaborative Study on the Genetics of Alcoholism (COGA)
      data of chromosome 1 for complete analysis. Convergence to a setting producing a
      local maximum required the evaluation of over 100 settings (for a time budget of
      800 minutes on a Pentium II 300 MHz PC). Two notable local maxima were detected,
      suggesting the need for a more extensive search before claiming that a global
      maximum had been found. The orthogonal Latin hypercube design was the best
      strategy for finding areas that produced high lod scores with small numbers of
      evaluations. Numerical optimization starting from a region producing high lod
      scores was the strategy that found the highest maximum observed.

PMID- 10597421
TI  - Correcting for ascertainment bias in the COGA data set.
AB  - The effects of several corrections for ascertainment bias on a linkage result in
      the COGA data are examined. A correction that models the complete ascertainment
      protocol markedly reduces the evidence for linkage. Different partial corrections
      increase the linkage signal and recover good estimates of the population trait
      prevalence, but do not represent adequately the complexity of the COGA
      ascertainment scheme. Evidently the present size of the COGA data set cannot
      support a complete correction for ascertainment bias, but an effective partial
      correction can and should be implemented.

PMID- 10597422
TI  - Comparison of GENEHUNTER and MFLINK for analysis of COGA linkage data.
AB  - We compared the NPLALL statistic from GENEHUNTER with two-point and three-point
      MALODs and MFLODs from MFLINK for all autosomal markers in the Collaborative
      Study on the Genetics of Alcoholism (COGA) data set. In general MFLINK produced
      more significant results than GENEHUNTER and implicated two regions containing
      candidate genes (ADH3 and DRD2). Many regions of interest identified in other
      studies reported at this workshop produced MALODs significant at p < or = 0.05,
      but these would not have been picked up by GENEHUNTER unless a less significant
      threshold were used.

PMID- 10597423
TI  - Genetic analysis of personality traits and alcoholism using a mixed discrete
      continuous trait variance component model.
AB  - Bivariate analyses can improve power to detect linkage. This paper describes one
      application of a bivariate variance component method for estimating joint
      likelihoods of a continuous and a discrete trait. This method is applied to the
      Collaborative Study on the Genetics of Alcoholism data set to investigate the
      relationship between personality traits derived from the tridimensional
      personality questionnaire (TPQ) and alcoholism. The results indicate that the
      novelty-seeking subscale of the TPQ and alcoholism share a strong and significant
      genetic correlation (rho G = 0.83) and modest environmental correlation (rho E =
      0.31). When both traits are considered jointly in a multipoint linkage model
      compared with the alcoholism trait alone, there is an improvement in the ability
      to detect and localize a quantitative trait locus on chromosome 4.

PMID- 10597424
TI  - Nonparametric linkage analysis of alcohol dependence with chromosome 1 and 7
      markers.
AB  - We analyzed 105 multiplex families from the Collaborative Study on the Genetics
      of Alcoholism (COGA) for markers on chromosome 1 (n = 20) and chromosome 7 (n =
      19) with the GENEHUNTER program. On chromosome 1, three markers (D1S532, D1S1588,
      and D1S534) in single-point analysis and five markers in multipoint analysis
      (D1S532, D1S1588, D1S1675, D1S534, and D1S1595) showed a nonparametric linkage
      (NPL) p-value < 0.05. They mapped in two different but nearby regions, spanning,
      respectively, 18 cM (D1S532, D1S1588) and 19 cM (D1S1675, D1S534, and D1S1595)
      and separated by a 20-cM interval. The highest NPL score was obtained for D1S534
      (NPL = 2.26, p = 0.013 for single-point analysis and NPL = 2.81, p = 0.0029, for
      multipoint analysis). The maximum NPL score on chromosome 7 was observed for
      D7S1793 (NPL = 1.72, p = 0.044 for single-point analysis and NPL = 2.02, p =
      0.023 for multipoint analysis). The markers which showed NPL p-values < 0.05 on
      chromosome 1 (D1S532, D1S1588, D1S1675, D1S534, and D1S1595) and on chromosome 7
      (D7S1793) were analyzed for association using the transmission/disequilibrium
      test. None of the alleles at these six loci showed a distorted transmission
      pattern. These data indicate that the two loci "suggestively" linked to alcohol
      dependence are either in linkage equilibrium with a susceptibility locus or are
      too far from the susceptibility locus to show disequilibrium, if present.

PMID- 10597425
TI  - Monte Carlo Markov chain methods for genome screening.
AB  - We used Monte Carlo Markov chain (MCMC) methods to analyze a quantitative trait,
      MAO level, and a discrete trait, Collaborative Study on the Genetics of
      Alcoholism (COGA) alcoholism. Segregation, linkage, and haplotype sharing were
      analyzed and effects of marker map features were examined. For MAO, modest
      signals were found on chromosomes 1 and 17 for raw data, and 15 for covariate
      adjusted data. For alcoholism, a strong signal was found on chromosome 1 with
      modest signals on chromosomes 4 and 10.

PMID- 10597426
TI  - Smoking behavior is under the influence of a major quantitative trait locus on
      human chromosome 5q.
AB  - Despite some evidence that smoking behavior is influenced by both genetic and
      environmental factors, efforts at identifying specific genes that influence
      smoking are extremely limited. Using information on smoking behavior history for
      973 individuals distributed across 105 COGA families and a multipoint variance
      components method, we tested for linkage between smoking behavior (as defined by
      number of cigarette packs per day for 1 year) and chromosomal locations across
      the genome using information from 296 markers. We found strong evidence (lod =
      3.2) for linkage of smoking behavior to a genetic location on chromosome 5q
      (D5S1354). Weaker evidence was found for linkage of smoking behavior to genetic
      locations on chromosomes 4 (between markers D4S244 and D4S2393), 15 (D15S642),
      and 17 (GATA193). Oligogenic linkage analyses suggest the putative locus on
      chromosome 5q is the primary determinant of genetic variation in smoking.
      Although the magnitude of the lod score is compelling, the large gap between the
      markers D5S1456 and D5S1354 (which is also at the end of chromosome 5q) in the
      COGA data set reduces the enthusiasm for this putative quantitative trait locus.
      However, typing of additional markers in this region may provide greater support
      for the localization of a susceptibility locus at this chromosomal location,
      which is not far from the DRD1 (D1 dopamine receptor gene) locus.

PMID- 10597427
TI  - Detection of quantitative trait loci associated with alcohol-dependence: use of
      model-free sib-pair method and combined segregation-linkage analysis based on
      regressive models.
AB  - Two linkage methods were used to detect loci underlying neurophysiological
      measures associated with alcohol dependence 1) the Haseman-Elston (H-E) sib pair
      method for genome-wide search, and 2) the combined segregation-linkage (CSL),
      based on regressive models, to confirm positive linkages found by the genome
      screening. Among 14 linkage results that were significant at the 0.5% level using
      H-E, the CSL method leads to similar p-values in only three cases but to higher p
      values in all others. Investigation of these discrepancies shows that assumptions
      (normality and homoscedasticity of the error term) of H-E least-squares
      regression method are not verified. A robust estimator of slope parameters
      without assuming any distribution function for the linear model error terms
      increases the p-values and reduces the difference between H-E and CSL results.
      Alternatively, the CSL approach may lack power when multiple genes with small
      effects are involved.

PMID- 10597428
TI  - The impact of redefining affection status for alcoholism on affected-sib-pair
      analysis.
AB  - The analysis of a complex disease such as alcohol dependence requires a more
      precise definition of affection status. Collaborative Study on the Genetics of
      Alcoholism (COGA) provided a variety of qualitative and quantitative measures as
      well as genotype information, in addition to two criteria of affection status. To
      identify two groups of phenotypically "more homogeneous" individuals among
      alcoholics (COGA criterion), we redefined affection status by using cluster
      analysis and classification and regression tree, incorporating some important
      covariates such as event related potentials, monoamine oxidase B activity, status
      of smoking, age of onset, three variables of personality assessed with the
      Tridimensional Personality Questionnaire and three latent class variables. With
      redefined affection status, we repeated nonparametric analysis by three sib pair
      analysis programs (SIBPAL, SIBPAIR, and BETA) using nine candidate DNA markers
      identified by Reich et al. [1998] and Long et al. [1998]. The goals of our
      analysis are 1) to confirm previous results for these nine markers with redefined
      affection status and 2) to compare the performance from these three programs.

PMID- 10597429
TI  - Linkage and association analyses of alcoholism using a regression-based
      transmission/disequilibrium test.
AB  - Recently, George et al. proposed a regression-based transmission/disequilibrium
      test for linkage using information on the parent-to-offspring transmission status
      of an allele at a marker locus. We extended this test by simultaneously testing
      for any population association by incorporating the presence/absence status of
      the associated allele as a covariate in the model. We used this method to analyze
      markers on chromosomes 1 through 21 of the Collaborative Study on the Genetics of
      Alcoholism data on alcoholism for possible association and linkage. We found
      nominal significance (at the 0.02 level) at eight different regions for linkage,
      though statistical significance may not be concluded due to multiple testing. The
      strongest evidence of linkage was observed for markers D4S2639 and D12S397 with p
      values less than 0.005. We also found strong association between the trait and
      alleles 149 of D7S691 and 131 of D21S1437.

PMID- 10597430
TI  - Comparison of two linkage inference procedures for genes related to the P300
      component of the event related potential.
AB  - Our goal was to detect genes contributing to the P300 component of the event
      related potential (ERP). We found that all of the ERP traits were highly
      correlated. Most of them distinguished alcoholics from nonalcoholics. To have one
      summary variable for the ERP traits, we calculated the first principal component
      (PRIN1). After adjusting for age and sex, we screened for linkage of PRIN1 to all
      of the markers using the two-point Haseman-Elston sib-pair test. We compared
      results obtained from computing a moving average of two-point p-values
      ("regional" inference) in an approximately 10 cM region with those obtained from
      single, two-point tests. Different "suggestive" and "significant" linkage regions
      were found using the two methods. Based on the regional method, areas on
      chromosomes 2 and 5 should be followed up in future studies.

PMID- 10597431
TI  - An empirical test of the significance of an observed quantitative trait locus
      effect that preserves additive genetic variation.
AB  - We propose a constrained permutation test that assesses the significance of an
      observed quantitative trait locus effect against a background of genetic and
      environmental variation. Permutations of phenotypes are not selected at random,
      but rather are chosen in a manner that attempts to maintain the additive genetic
      variability in phenotypes. Such a constraint maintains the nonindependence among
      observations under the null hypothesis of no linkage. The empirical distribution
      of the lod scores calculated using permuted phenotypes is compared to that
      obtained using phenotypes simulated from the assumed underlying multivariate
      normal model. We make comparisons of univariate analyses for both a quantitative
      phenotype that appears consistent with a multivariate normal model and a
      quantitative phenotype containing pronounced outliers. An example of a bivariate
      analysis is also presented.

PMID- 10597432
TI  - Model-based and model-free multipoint genome-wide linkage analysis of alcoholism.
AB  - We analyzed a subset of the Collaborative Study on the Genetics of Alcoholism
      (COGA) data set as provided by the 11th Genetic Analysis Workshop (GAW11).
      Linkage analyses were performed using each of the diagnostic criteria for
      alcoholism included in the data: the COGA criteria (DSM-III-R plus the Feighner
      criteria) and the narrower World Health Organization diagnosis ICD-10 criteria.
      Formal segregation analysis using these data was not attempted because only a
      subset of all the originally ascertained families was made available.
      Nevertheless, an attempt was made to estimate the best one-locus two-allele
      genetic model for these data. Model-based multipoint linkage analysis was
      performed using the results of our trait model fitting, and model-free multipoint
      linkage analysis was performed with an improved version of the Haseman and Elston
      linkage method for sib pairs.

PMID- 10597433
TI  - A semiquantitative whole genome screen analysis of alcohol dependence.
AB  - Two whole genome screens were applied to sibling pairs from the Collaborative
      Study on the Genetics of Alcoholism (COGA) family data to compare a
      semiquantitative method with a standard qualitative approach. The
      semiquantitative method used a score derived from 11 symptoms, and the
      qualitative approach used the COGA criteria for alcohol dependence. There was no
      concordance in the regions identified by the two models. Three regions of nominal
      significance were identified using the symptom score. In these three regions,
      correlated traits were also analyzed to determine whether linkage could be
      attributed to their intermediate effect. The evidence for linkage to one locus on
      chromosome 6 could be explained by linkage to the personality trait harm
      avoidance.

PMID- 10597434
TI  - Sib-pair analysis of the collaborative study on the genetics of alcoholism data
      set.
AB  - Nonparametric sib-pair analysis was performed on the Collaborative Study on the
      Genetics of Alcoholism data set. Concordant and discordant pair groups were
      examined using the ASPEX package of programs. Allele sharing and multipoint lod
      scores for six comparison groups were obtained. Sharing and lod score patterns
      were not consistent with a simple genetic interpretation.

PMID- 10597435
TI  - Possible linkage of alcoholism, monoamine oxidase activity and P300 amplitude to
      markers on chromosome 12q24.
AB  - Multipoint linkage analysis was used to screen for evidence of linkage between
      alcoholism and five alcoholism-related quantitative traits. The results suggest
      that a susceptibility locus that influences monoamine oxidase activity and P300
      amplitude at the Pz lead, and increases the risk of alcohol dependence may be
      linked to markers in the 12q24 region. Furthermore, the susceptibility for
      alcoholism may be associated with allele 3 (allele size 144) of D12S392.

PMID- 10597436
TI  - Familial analysis of event related potentials.
AB  - This report summarizes our analysis of the auditory and visual event related
      evoked potentials. These data were collected as a component of the Collaborative
      Study on the Genetics of Alcoholism and distributed as a part of the data
      available for the Genetic Analysis Workshop 11. For this analysis, we collapsed
      the data collected from eight leads using principal components methods. Using
      four collapsed variables derived from the principal components, we used
      regression analysis to adjust for environmental and demographic variables. We
      then fit the best fitting regression model and calculated the residuals. Using
      the residuals, we performed segregation analysis using S.A.G.E. Finally, we
      applied Markov chain Monte Carlo reverse jump methods to identify areas with
      potential quantitative trait loci. Our findings indicate that there may be an
      underlying genetic component to the potentials.

PMID- 10597437
TI  - Sib-pair linkage analyses of alcoholism: dichotomous and quantitative measures.
AB  - We hypothesized that a quantitative alcoholism trait would have greater power
      than the Collaborative Study on the Genetics of Alcoholism (COGA) dichotomous
      alcoholism traits, ALDX1 and ALDX2, to detect putative alcoholism loci. To test
      this, we performed nonparametric sib-pair linkage analysis to screen 285
      polymorphic autosomal markers for evidence of linkage to ALDX1, ALDX2, and a
      quantitative trait, QUANT, defined from the 11 COGA latent class variables. We
      also examined the effects on the analyses of including covariates (sex, age, and
      pack-years of smoking) and of transforming QUANT (log and square root). ALDX1 and
      ALDX2 showed the greatest evidence for linkage to markers on chromosome 1, by
      both the affected sib-pair and the Haseman-Elston tests. Regions of interest were
      also identified on chromosomes 4, 8, 16, and 17. QUANT showed little evidence for
      linkage to any chromosomal region, having no more significant results than were
      expected by chance. Including covariates or transforming QUANT had little effect
      on the analyses. A quantitative trait based on all 37 latent class variables,
      with each variable appropriately weighted, may have had more power than QUANT to
      detect genomic regions of relevance to alcoholism.

PMID- 10597438
TI  - Exploring the impact of extended phenotype in stratified samples.
AB  - We have performed initial nonparametric sib-pair genome scans in the early (N =
      52) and late (N = 53) onset subgroups of the COGA pedigrees, stratified near the
      median value of pedigree mean age of onset for ALDX1 diagnosis of alcoholism.
      Because the early group contained a higher proportion of smokers, traits of
      alcoholism, smoking, and addiction (defined as either alcoholism or smoking) were
      examined. Subgroups and phenotypic definitions influenced initial linkage
      results, corrected for the number of analyzed traits. Evidence for linkage to the
      ALDX1 alcoholism phenotype at the ADH3 functional candidate gene was increased in
      the late onset subgroup (Bonferroni corrected significance level < 0.002), as
      compared with the unstratified sample that replicated COGA linkage obtained in
      the same analysis; there was no evidence for linkage at this locus in the early
      onset subgroup. The theoretical implication of this result is that the loss of
      power due to contracting sample size through stratification may in some cases be
      more than offset by extraction of a more homogeneous subgroup from the
      etiologically complex trait.

PMID- 10597439
TI  - Searching for alcoholism susceptibility genes using Markov chain Monte Carlo
      methods.
AB  - Markov chain Monte Carlo (MCMC) methods offer a rapid parametric approach that
      can test for linkage throughout the entire genome. It has an advantage similar to
      nonparametric methods in that the model does not have to be completely specified
      a priori. However, unlike nonparametric methods, there are no limitations on
      pedigree size and MCMC methods can also handle relatively complex pedigree
      structures. In addition MCMC methods can be used to carry segregation analysis in
      order to answer questions on the genetic components of a disease phenotype.
      Segregation analysis gave evidence for between two and eight alcoholism
      susceptibility loci, each having a modest effect on the phenotype. MCMC methods
      were used to map alcoholism loci using the phenotypes ALDX1 (DSM-III-R and
      Feighner criteria) and ALDX2 (World Health Organization diagnosis ICD-10
      criteria). There was mild evidence for quantitative trait loci on chromosomes 2,
      10, and 11.

PMID- 10597440
TI  - Design of artificial neural network and its applications to the analysis of
      alcoholism data.
AB  - Artificial neural networks were applied to the alcoholism data to reveal
      nonlinear relationships between intermediate phenotypes, marker identity-by
      descent sharing, and the affection status. A variable number of hidden units were
      considered to achieve a balance between the minimal mean-squared error and over
      fitting of the data. The predictability of the affection status based on
      intermediate phenotype information (event-related potential 300, monoamine
      oxidase, and gender) was 65% to 75%, and sensitivity/specificity ranged around
      50% to 80%. The IBD approach succeeded in identifying the same marker as previous
      studies, but also found additional peaks.

PMID- 10597441
TI  - A multiple locus analysis of the collaborative study on the genetics of
      alcoholism data set.
AB  - Parametric and nonparametric statistical methods have been applied to the alcohol
      dependence data set collected in the Collaborative Study on the Genetics of
      Alcoholism (COGA). Our nonparametric linkage analyses (NPL) were based on the
      S(all) statistic of GENEHUNTER [Kruglyak et al., 1996] and the improved NPL
      statistic of GENEHUNTER-PLUS [Kong and Cox, 1997]. Based on likely regions for
      alcohol susceptibility genes identified from our nonparametric analyses, we
      reanalyzed the data using several two-locus models. We used the TMLINK program
      [Lathrop and Ott, 1990] in the LINKAGE package for these parametric analyses.

PMID- 10597442
TI  - Incorporating larger families in identity-by-descent based linkage analysis.
AB  - Genome scans for alcoholism susceptibility genes were carried out using identity
      by-descent-based statistics for qualitative traits. We compared the results when
      1) multipoint information was used for all families, where some had to be
      truncated, 2) multipoint information was used only for small families while large
      (untruncated) pedigrees were analyzed with a single-point approach, and 3) single
      point analysis was used for all pedigrees. Differences between the methods were
      observed, but neither method could identify regions related to the susceptibility
      for alcoholism.

PMID- 10597443
TI  - Exploring linkage for alcoholism using affection status and quantitative event
      related potential phenotypes.
AB  - Using genome-scan data from the Collaborative Study on the Genetics of Alcoholism
      (COGA), we compared results of linkage analyses using a qualitative alcoholism
      phenotype to results of linkage analyses using event related potential (ERP)
      quantitative phenotypes, and compared our results to the results of Reich et al.
      [1998] and Begleiter et al. [1998]. We describe a general and simple strategy for
      identifying regions of the genome which may harbor genes involved in alcohol
      dependence which takes into consideration the results of both the affection
      status and ERP linkage analyses.

PMID- 10597444
TI  - Alcoholism as a complex trait: comparison of genetic models and role of
      epidemiological risk factors.
AB  - A genetic component for alcoholism appears likely, but the genes involved have
      yet to be identified. The mode of inheritance is probably more complex than for
      traditional mendelian disorders. In particular, there are marked differences in
      alcoholism by gender, parent-of-origin effects, ethnicity, and other
      epidemiological factors. We investigated the evidence for the presence of
      susceptibility genes for alcohol dependence in the Collaborative Study on the
      Genetics of Alcoholism data set.

PMID- 10597445
TI  - Evidence of linkage in subtypes of alcoholism.
AB  - We believed that subtyping alcoholism might be an efficient strategy for mapping
      susceptibility genes. Cluster analysis is one of the possible statistical
      techniques for such a purpose. We required that, ideally, the variables to be
      used in cluster analysis should be: 1) related to alcoholism, 2) related to the
      severity of alcoholism, and 3) familial, i.e., correlated within families. Only
      three variables met all three conditions. Those included age of onset of ALDX1,
      smoking, and TPQ-HA. A global score of symptoms of alcoholism was systematically
      introduced as one of the variables composing a subset for cluster analysis,
      although this score did not show any familial aggregation. Our strategy led to a
      strong evidence of linkage at D15S230 in only 20 families whose members are
      mainly characterized by heavy smoking.

PMID- 10597446
TI  - Identifying influential individuals in linkage analysis: application to a
      quantitative trait locus detected in the COGA data.
AB  - Once linkage is detected to a quantitative trait locus (QTL), the next step
      towards localizing the gene involved may be to identify those families, or
      individuals, in whom the putative mutations are segregating. In this paper, we
      describe a jackknife procedure for identifying individuals (and families) who
      contribute disproportionately to the linkage. Following initial detection of
      linkage to a QTL, the strategy involves sequentially removing each individual (or
      each family) from the analysis and recomputing the lod score associated with the
      linked region using data from all remaining subjects (or families). This
      procedure can be used to determine if particular observations have substantial
      impact on evidence for linkage. Identification of such observations may provide
      insights for further efforts to localize the QTL.

PMID- 10597447
TI  - Novel tests for marker-disease association using the Collaborative Study on the
      Genetics of Alcoholism data.
AB  - We applied several novel tests for association and linkage in the presence of
      association to the Genetic Analysis Workshop 11 Problem 1 data set. Our analyses
      included a Hardy-Weinberg test for association between a marker and a disease
      susceptibility locus, a Bayesian transmission/disequilibrium test, and a Bayesian
      case-control test. Positive results for each of these methods require the
      presence of population association between the marker and a disease
      susceptibility locus.

PMID- 10597448
TI  - Linkage of chromosome 1 markers to alcoholism-related phenotypes by sib pair
      linkage analysis of principal components.
AB  - Using the Collaborative Study on the Genetics of Alcoholism data and affected-sib
      pair linkage methods, Reich et al. [1998] reported linkage of alcohol dependence
      to a region near D1S1588 on chromosome 1. In this paper, we assessed the ability
      of multivariate sib-pair linkage analysis of the neurophysiologic measurements
      (including age and sex) to evaluate evidence for linkage to chromosome 1.
      Principal components of 16 neurophysiologic measurements, plus age and sex, were
      analyzed separately using sib-pair linkage analysis, and a cumulative sum of the
      resulting t2-statistics computed at each point on the chromosome. The first four
      principal components, which accounted for 74% of the total variation, showed
      little or no evidence for linkage in the D1S1588 region, while the remaining
      components showed substantial evidence for linkage. We conclude that potentially
      important linkage results can be missed if investigators limit attention only to
      major sources of variability.

PMID- 10597449
TI  - Genome scans for genetic predisposition to alcoholism by use of transmission
      disequilibrium test analyses.
AB  - We report the results of the analysis of three measures of alcoholism and six
      associated symptoms using transmission disequilibrium (TDT) analysis on data from
      the Collaborative Study on the Genetics of Alcoholism data set. Implementation of
      identity-by-state (IBS) routines for error checking revealed 10 reported full
      siblings that were rejected as a full sibling to all of their purported full
      siblings with p < 0.05. TDT analysis revealed two loci with significant
      transmission disequilibrium (p < 0.001) on chromosomes 1 and 7. Analysis by
      parental origin found alleles at three loci displaying significant disequilibrium
      in the transmission of the paternal alleles for at least three of the nine tested
      traits. These loci are on chromosomes 6, 9, and 13. Analyses of Caucasian
      families alone and the use of a single affected individual from each family also
      yielded significant results for the loci on chromosomes 6, 9, and 13.

PMID- 10597450
TI  - Genome-wide linkage analysis using genetic variance components of alcohol
      dependency-associated censored and continuous traits.
AB  - We used variance-components analysis to investigate the additive genetic effects
      regulating some of the phenotypes included in the GAW11 data set. Variance
      components models were fitted using Gibbs sampling methods in BUGS v 0.6. Linkage
      analyses for both multivariate normal (MvN) traits and right censored survival
      times (age-of-onset) were based upon standard Haseman-Elston identity-by-descent
      sib-pair methods applied directly to traits showing evidence of substantial
      additive genetic determination (residualized for any important covariates) and to
      the estimated sigma A2 residuals for those traits. Harm avoidance behavior (TPQ
      subscale) showed evidence of linkage to markers on chromosomes 1, 13, and 18.
      P300 levels at the Fp1 site showed evidence of linkage to markers on chromosomes
      2, 3, 9, 12, 17, 19, and 20. Platelet monoamine oxidase B (MAOB) levels showed
      evidence of linkage to D4S1651. The age-of-onset for ALDX1 in those over 30 years
      old showed evidence of linkage to markers on chromosomes 1, 6, 14, and 15. The
      age-of-onset for the more strictly defined ALDX2 in those over 30 years old
      showed evidence of linkage to markers on chromosomes 7 and 14. These results are
      consistent with a complex, multifactorial susceptibility to alcohol dependency.

PMID- 10597451
TI  - Sex-based linkage analysis of alcoholism.
AB  - A high degree of locus heterogeneity is likely in alcoholism, and linkage
      heterogeneity analysis may be helpful in mapping susceptibility loci. The genetic
      contribution to alcoholism in females may be higher than in males, and therefore
      sex of affected individuals was used in linkage analysis. Families with female
      alcoholics demonstrated evidence for linkage to chromosomes 10p11-p15 and 21q22.1
      q22.2 while those with male alcoholics did not provide evidence for linkage to
      these regions. Sharing of maternal and paternal alleles was also investigated
      separately, and evidence for linkage of maternal alleles on chromosomes 1 and 8,
      and paternal alleles on chromosome 2 was observed, suggesting parental origin
      effects. Mapping of complex traits may benefit from tests of linkage
      heterogeneity based on sex, and parental origin.

PMID- 10597452
TI  - A genome-wide search for susceptibility genes linked to alcohol dependence.
AB  - We performed two-point linkage analysis during a genome-wide search for
      susceptibility genes that predispose to alcohol dependence with the Collaborative
      Study on the Genetics on Alcoholism (COGA) data made available for the Genetic
      Analysis Workshop 11 (GAW11). For chromosomes 1 and 4 our findings supported
      results reported by Reich et al. [1998] based on the same data. We found
      similarity between our findings in regions on chromosomes 8 and 10 and reported
      results for schizophrenia linkage studies. Differences between our results with
      COGA data and those obtained by Reich et al. [1998] are due to our use of a lod
      score method versus their use of the affected relative pair (sib pair) method.

PMID- 10597453
TI  - Haplotype analysis in the Collaborative Study on the Genetics of Alcoholism data:
      double recombinants.
AB  - The presence of close double recombinants in genotyping data may help identify
      genotyping errors. Alternatively, putative double recombinants may be associated
      with genetic mechanisms that may be related to disease. Phase-known apparent
      double recombination events were identified in the Collaborative Study on the
      Genetics of Alcoholism data, and compared to the sex-specific genetic map at each
      region. A number of double recombinants occurred within a short genetic distance.
      Also, in some families multiple double recombinants were observed flanking the
      same genetic marker, both suggesting possible genotyping error. An excess of
      paternal double recombinants was identified, which is consistent with reports of
      sex-specific differential meiotic interference.

PMID- 10597454
TI  - Quantitative trait transmission disequilibrium test: allowance for missing
      parents.
AB  - The association of a quantitative trait with transmission disequilibrium of
      parental marker alleles can be a powerful method to discover the genetic basis of
      the trait. However, current methods require marker genotypes on all parents. We
      present a new method that allows the assessment of the association of a
      quantitative trait with transmission disequilibrium of marker alleles when
      parental marker genotypes are missing, but marker genotypes for sibships are
      available. Because our approach is based on regression methods, additional
      covariates, including multiple marker loci, can be included in our proposed
      method of analysis. Application of this methodology to the COGA data to assess
      the association of quantitative traits (ERPs) with marker loci on chromosome 7
      failed to identify statistically significant transmission disequilibrium.

PMID- 10597455
TI  - Analysis of principal component based quantitative phenotypes for alcoholism.
AB  - Principal component analysis was used to construct quantitative phenotypes for
      alcoholism. These were analyzed for linkage to genomic regions with a variance
      components approach. The four phenotypes considered were a factor describing
      medical symptoms of alcohol dependency, a factor describing a psychological
      profile correlated with susceptibility to alcoholism, monoamine oxidase B (MAOB)
      activity and an average measurement of the P3 component of event-related
      potentials (ERP) at the Fp electrode placements. One region (around marker
      GATA123C09 on chromosome 3) with suggestive evidence for linkage was detected for
      the P3 (Fp) measurement. For three of the four distinct phenotypes, modest
      evidence for linkage to a similar region (around marker ADH3 on chromosome 4) was
      found.

PMID- 10597457
TI  - Structural decomposition of genetic diversity in families with alcoholism.
AB  - Using genotypes of 280 marker loci on the 22 autosomes of 105 alcohol-dependent
      probands, their affected and unaffected sibs, as well as their parents, we
      iteratively constructed a genetic similarity function that enabled us to quantify
      the interindividual genetic distances d(x(i), xj) between feature vectors x(i),
      xj made up by the allelic patterns of individuals i, j with respect to loci l1,
      l2,...,ln. Based on this similarity function, we investigated the sib-sib
      similarities that are expected to deviate from "0.5" in affected sib pairs if the
      region of interest contains markers close to disease-causing genes. The reference
      value "0.5" was derived from the parents-offspring similarities, because these
      are independent of the affection status. The question of population admixture was
      addressed by means of multivariate structural analyses. These analyses led to
      four "natural" groups whose validity was tested through the father-mother
      similarities. Additionally, we determined the eigenvectors that optimally
      represented the genetic variation and found several marker configurations on
      chromosomes 1, 3, 7, 15, and 17 that reproducibly discriminated (p < or = 0.01)
      affected probands/sibs from unaffected sibs, while no such differences were found
      between affected probands and affected sibs.

PMID- 10597456
TI  - Analyses of the COGA data set in one ethnic group with examinations of
      alternative definitions of alcoholism.
AB  - We used GENEHUNTER and GENEHUNTER-PLUS to search for linkage with the markers in
      the Collaborative Study on the Genetics of Alcoholism (COGA) data set in a single
      ethnic group. Analyses of a complex disorder such as alcoholism depend on the
      definition of affection status. The COGA study provides two definitions of
      alcoholism (variables ALDX1 and ALDX2). To identify more severely affected
      alcoholics that might be more homogeneous genetically, we developed two other
      ways of characterizing subjects as alcohol dependent: (1) by combining the
      symptom variable values equally into a 24-point scale and (2) by weighting
      optimally the symptoms and other descriptive variables into a single score using
      logistic regression. We applied these definitions within a single ethnic group to
      map alcoholism-related loci. We found two regions on chromosome 1 that have
      adjacent markers significant at p-values < or = 0.05. ALDX1 provided the highest
      Z-scores compared to the alternatives.

PMID- 10597458
TI  - Linkage analysis with adequate modeling of a parent-of-origin effect.
AB  - We present an extension to parametric linkage analysis that allows modeling
      diseases with a parent-of-origin effect (i.e., imprinting). Different penetrances
      are assumed for individuals being heterozygous at the disease locus, depending on
      their having inherited the disease allele from the father or mother. Motivated by
      the finding of a maternally expressed locus influencing alcohol consumption in
      mice (Alcp2), the analysis method has been included into the program GENEHUNTER
      for application to Problem 1, Collaborative Study on the Genetics of Alcoholism
      of Genetic Analysis Workshop 11. By this extension, a powerful tool is provided
      for adequately modeling an inherited disease in linkage analysis that supposedly
      has imprinting effects. The program has been used to analyze the data set on
      alcohol dependence in humans and can be applied to other genetically determined
      traits as well.

PMID- 10597459
TI  - Whole genome association studies for genes affecting alcohol dependence.
AB  - We applied the transmission/disequilibrium test (TDT) for sibs (S-TDT) and for
      families with one parent (1-TDT), to the Collaborative Study on the Genetics of
      Alcoholism data set. The combined test is used to screen the whole genome to
      locate genes responsible for alcohol dependence. This analysis supports the
      previous finding that the region close to GABRB1 on chromosome 4 might be
      associated with alcohol dependence. The regions close to D6S474 and D11S1998 are
      also of particular interest. We found segregation distortion at the GR1K1 locus.
      The segregation distortion might be due to the binning method used in genotyping
      at this locus.

PMID- 10597460
TI  - Association and linkage analysis of ICD-10 diagnosis for alcoholism.
AB  - We analyzed the GAW11 data on alcoholism provided by the Collaborative Study on
      the Genetics of Alcoholism (COGA) using an extension of a new test of linkage and
      association for quantitative traits developed by George et al. [1999]. This
      method determines linkage between marker loci and quantitative traits, when
      allelic association is present between the trait and marker loci, by regressing
      the disease trait on the parental transmission of the allele of interest. We
      found no strong evidence of linkage to any markers. However, we found several
      markers suggestive of possible linkage that may deserve further investigation.

PMID- 10597461
TI  - Sib-pair linkage analysis of alcohol dependence taking into account covariates
      and age-of-onset variability: evaluation of the residual approach.
AB  - The construction of residuals allowed us to consider a phenotype related to
      alcohol dependence (ALDX1) adjusted for age, gender and current smoking status.
      Using the Haseman and Elston regression test, we compared genome scan results for
      detection of loci for the unadjusted and adjusted ALDX1 phenotypes in the
      Collaborative Study on the Genetics of Alcoholism (COGA) data. More markers were
      significant at the 1% level for the binary than for the residual analyses.
      Overall, our residual analyses do not show substantial improvement in their
      ability to detect linkage for alcohol dependence in the COGA data. This may be
      due to the relatively small sample size of discordant sib pairs.

PMID- 10597462
TI  - Effects of genotype x sex interaction on linkage analysis of visual event-related
      evoked potentials.
AB  - Autosomal genes contributing to variation in many complex traits are influenced
      by male or female physiological "environments." Accounting for such genotype-by
      sex (G x S) interactions has been shown to be important in quantitative genetic,
      segregation, and linkage analyses of a number of sexually dimorphic traits. In
      analyses of data simulated for GAW10, we showed that incorporating sex-specific
      variance components into a variance components-based linkage method increased the
      power to detect linkage in a trait that exhibited G x S interaction. The goals of
      this study of data from the Collaborative Study on the Genetics of Alcoholism
      (COGA) were to screen the event-related brain potential (ERP) data from COGA
      participants for G x S interaction, and then to conduct variance components
      linkage analysis of ERP phenotypes showing evidence of G x S interaction using
      models incorporating sex-specific variance components. Significant G x S
      interaction was found in four ERP phenotypes: N100 measured at occipital leads 1
      and 2, and P300 measured at occipital leads 1 and 2. In linkage analyses of these
      traits, the most significant lod score found was that between N100 occipital lead
      1 amplitude and marker D7S490. The peak lod score at the D7S490 locus was 2.45
      without sex-specific variance components, and 3.25 with sex-specific marker and
      residual polygenic components.

PMID- 10597463
TI  - Family density of alcoholism and linkage information in the analysis of the COGA
      data.
AB  - In this study of GAW11 Problem 1, we analyzed the genome scan data in families
      weighted according to the density of alcoholism among the probands' siblings. We
      hypothesized that certain disease-predisposing alleles may be common in the
      general population, rendering high-density sibships less informative for linkage.
      Three types of families were found in the data, with the prevalence of alcoholism
      of 1.0, 0.78, and 0.24 in the probands' sibships. The linkage results showed
      several peak lod scores on chromosomes 1, 2, 4, 8, 11, 19, and 21, the majority
      of which originated in only one or two types of families. However, for almost all
      markers, the maximum lod scores observed without the weights were equal to or
      exceeded the values obtained for any single type of family. These results
      indicate that although the stratification of families may be theoretically
      justified, in practice the best strategy is to use all available information.

PMID- 10597464
TI  - Evidence for linkage and association to alcohol dependence on chromosome 19.
AB  - An association study on markers showing suggestive evidence for linkage to severe
      alcoholism was performed on the Collaborative Study on the Genetics of Alcoholism
      (COGA) data set. Our linkage study was restricted to the autosomal markers on
      chromosomes 2, 3, 4, 13, and 19, with low homozygosity (below 30%) and high
      identity-by-state sharing in affected sib pairs (ASPs). We used a strict
      phenotype definition, only individuals diagnosed as affected both on the ALDX1
      (COGA criterion) and ALDX2 (ICD-10) scales were used in the analyses. Linkage was
      assessed by excess identity-by-descent allele sharing in ASPs. The strongest
      evidence of linkage was detected on chromosome 19, in particular at markers
      D19S49 (p < 0.0001) and D19S431 (p < 0.002). An association study of allele and
      haplotype data was then carried out on chromosome 19 markers using affected
      family-based controls. A haplotype defined by alleles at markers D19S49, D19S43,
      and D19S200 in chromosome 19 shows significant association (p < 0.003, odds ratio
      2.82). Further, significant differences were observed in the distribution of the
      harm avoidance subscale among genotypes defined by D19S49 (p < 0.0001). These
      results provide evidence for the existence of a locus in chromosome 19
      potentially involved in alcohol dependence susceptibility.

PMID- 10597465
TI  - The importance of watching our weights: how the choice of weights for non
      independent sib pairs can dramatically alter results.
AB  - Handling non-independent sib pairs in families with multiple affected sibs
      presents a problem in likelihood-based nonparametric linkage analyses. We
      contrast the more stable partial-likelihood solution in MAPMAKER/SIBS with the
      extremely variable partial-likelihood approach used in ASPEX, and the potential
      inflation of lods when the problem is ignored as in BETA.

PMID- 10597466
TI  - A logistic regression extension of the transmission disequilibrium test for
      continuous traits: application to linkage disequilibrium between alcoholism and
      the candidate genes DRD2 and ADH3.
AB  - The transmission disequilibrium test (TDT) recently has become a popular method
      of testing for linkage in the presence of association due to its simplicity and
      advantages over other within-family analytic methods. In this paper, we describe
      a logistic regression extension to the TDT that can be used to test for
      differences in linkage disequilibrium as a function of one or more continuous
      and/or categorical explanatory variables. We highlight important features of this
      method and demonstrate some of its possible uses. We applied these analyses to
      test for linkage disequilibrium between the dopamine receptor D2 (DRD2) and
      alcohol dehydrogenase 3 (ADH3) genes and both diagnostic and quantitative indices
      of alcoholism. Using data from the Collaborative Study on the Genetics of
      Alcoholism data set, we found evidence suggesting linkage disequilibrium between
      DRD2 and ADH3 and quantitative indices of alcoholism and correlated phenotypes
      corresponding to smoking and personality. None of the evidence for linkage
      disequilibrium varied by sex or age.

PMID- 10597467
TI  - Application of an ordered subset analysis approach to the genetics of alcoholism.
AB  - For complex diseases, underlying etiologic heterogeneity may reduce power to
      detect linkage. Thus, methods to identify more homogeneous subgroups within a
      given sample in a linkage study may improve detection of putative susceptibility
      loci. In this study we describe an ordered subsetting approach that utilizes
      disease-related quantitative trait data to complement traditional linkage
      analysis. This approach uses family-based lod scores derived from the initial
      genome screen and a family-based descriptor of the trait of interest. The goal of
      the approach is to identify more homogeneous subgroups of the data by ranking
      families based on their quantitative trait data. Permutation testing is used to
      assess statistical significance. This approach can be adapted to a variety of
      linkage methods and may provide a means to dissect some of the underlying
      heterogeneity in complex disease genetics.

PMID- 10597468
TI  - Using recursive partitioning for exploration and follow-up of linkage and
      association analyses.
AB  - We first conducted a genome-wide screen for association with discordant sibships
      using the multi allelic and diallelic SDT. Markers at D4S1628, D8S1109, D9S66 and
      D7S1797 showed multi-allelic association. Deleterious diallelic association was
      found for markers at D1S1613, D1S534, D3S2459, D7S1817, and D9S131. Protective
      association was found at markers D8S1109, D8S1136, and D9S66. We then
      incorporated these findings with previous linkage findings in the exploration of
      oligogenes and epistasis using recursive partitioning. We conclude that recursive
      partitioning can be a useful adjunct to traditional linkage and association
      analyses in the exploration of these effects.

PMID- 10597469
TI  - Asymptotic power of likelihood-ratio tests for detecting quantitative trait loci
      using the COGA data.
AB  - We investigated the asymptotic power of the likelihood-ratio test for detecting
      linkage to a quantitative trait locus (QTL) using the data set from the
      Collaborative Study on the Genetics of Alcoholism (COGA). Assuming a total trait
      heritability of 50% as determined for the COGA Cz P300 phenotype, we determined
      the minimum QTL heritability required at each point in the genome to achieve 80%
      power to detect linkage with a lod of 3.0. We find that there are regions of the
      genome where it is not possible to detect a QTL of any effect with 80% power, and
      that the overall minimum detectable QTL heritability for the COGA data is 0.35
      0.40.

PMID- 10597470
TI  - Linkage analysis in alcohol dependence.
AB  - Alcohol dependence often is a familial disorder and has a genetic component.
      Research in causative factors of alcoholism is coordinated by a multi-center
      program, COGA [The Collaborative Study on the Genetics of Alcoholism, Begleiter
      et al., 1995]. We analyzed a subset of the COGA family sample, 84 pedigrees of
      Caucasian ancestry comprising 745 persons, 339 of whom are affected according to
      DSM-III-R and Feighner criteria. Using parametric and nonparametric methods,
      evidence for linkage was found on chromosome 1 (near markers D1S532, D1S1588, and
      D1S534), as well as on chromosome 15 (near marker D15S642). Other regions of the
      genome showed suggestive evidence for contributing loci. Related findings are
      discussed in recent publications investigating linkage in humans [Reich et al.,
      1998] and mice [Melo et al., 1996].

PMID- 10597471
TI  - Parental sex effect in families with alcoholism.
AB  - Parental sex effects have been shown to influence the inheritance of a number of
      complex disorders. In this paper we performed affected sib-pair analyses on 105
      families with recurrent alcoholism to evaluate the effects that the parent of
      origin might have on this disorder. Three alternative classification schemes were
      used and the families were grouped as maternal, paternal, mixed, or unknown.
      Paternal effects were observed at D9S64, D16S475, and D16S2622, while maternal
      effects were expressed at FABP2, D8S280, D8S1715, and D8S1988. Except for
      D16S2622, none of these markers resulted in a significant p-value when all
      families were analyzed together. These results suggest that the parental sex
      should not be ignored and that a discriminatory analysis should always be
      performed.

PMID- 10597472
TI  - A more powerful method to evaluate p-values in GENEHUNTER.
AB  - The determination of statistical significance in genetic linkage studies is
      complicated by many factors, such as missing individuals or uninformative
      markers, and the validity of theoretical results is often questionable. Although
      many simulation-based methods have been proposed to determine empirically the
      statistical significance, they are either not generally applicable to complex
      pedigree structures, or not able to preserve the observed genetic information
      content at each locus in the pedigrees. We have developed and implemented a
      general and computationally efficient randomization procedure in GENEHUNTER that
      applies to arbitrary pedigree structure and preserves the observed information
      content at each locus. We applied this method to the Problem 1 data set of the
      Genetic Analysis Workshop 11. The performance of this new method was similar to
      the method implemented in GENEHUNTER-PLUS, and both outperformed the conservative
      approach in GENEHUNTER.

PMID- 10597473
TI  - Genome search for alcohol dependence using the weighted pairwise correlation
      linkage method: interesting findings on chromosome 4.
AB  - The nonparametric (model-free) method of linkage analysis Weighted Pairwise
      Correlation (WPC) has been proposed by Commenges [1994], and extended to
      incorporate identity-by-descent (IBD) information [Zinn-Justin and Abel, 1999].
      We performed an autosome-wide scan in the Collaborative Study on the Genetics of
      Alcoholism data using the WPC-IBD method, considering two phenotypes related to
      alcohol dependence defined as residuals of binary traits adjusted for age and
      sex. Three chromosome 4 markers located in a region of 50 cM spanning from GABRB1
      to D4S1651 provided Monte Carlo (MC) p-values lower than 0.005, confirming the
      possible influence of beta 1 GABA receptor and ADH genes in alcoholism.
      Furthermore, marker D15S642, not far from the ALDH6 gene, provided an MC p-value
      of 0.0005 in ethnic groups "White, Hispanic" and "White, non-Hispanic."

PMID- 10597474
TI  - Summary of analyses of problem 2 simulated data for GAW11.
AB  - The simulated data for Problem 2 of the 11th Genetic Analysis Workshop (GAW11)
      consisted of family linkage data and disease data from three populations, each
      population with different genetic parameters. The disease was simulated such that
      there were two genetically distinct diseases, one caused by a single locus with
      three alleles and the other by two epistatically interacting loci. The two
      diseases were clinically identical. Each of the diseases had a severe and mild
      form. One of the diseases was influenced by an environmental factor and one by an
      allele at one of the marker loci (association). Linkage data consisted of 300
      polymorphic markers. Investigators analyzed these data in a myriad of ways, using
      most currently available linkage techniques and association analysis methods. In
      addition, investigators also tested newly developed methods, some of which took
      advantage of the existence of the environmental component. Other types of
      analyses included meta-analyses, methods of combining data from different
      studies, questions of replication, how much information is available in a single
      data set, and analyses for gene x gene and gene x environment interaction.

PMID- 10597475
TI  - Simulated data for a complex genetic trait (problem 2 for GAW11): how the model
      was developed, and why.
AB  - This paper describes a simulated data set created as Problem 2 for GAW11. The
      generating model for Problem 2 involved two different genetic diseases, or
      "types," in three separate populations. The two-locus (2L) type results from the
      epistatic interaction of two genetic loci, and the three-allele type, from a
      single locus with two disease-causing alleles and one normal allele. Each type
      has two phenotypic forms: Mild and Severe. Both forms are subject to both genetic
      and environmental influences. The disease occurs in three different hypothetical
      populations, each with different disease allele frequencies and penetrances. In
      two populations there is also a fourth locus with an allele that is associated
      with the 2L type. Misdiagnosis can occur, but only after a family has already
      been ascertained through > or = 2 "genetically" affected offspring. Finally, the
      three different populations are studied by four different hypothetical research
      groups. These groups each have their own ideas about how the disease is inherited
      and have therefore devised different ascertainment schemes based on those
      beliefs. Each research group collected 100-family data sets, including data on
      300 markers on six chromosomes and measurements on disease status and on the
      proposed two environmental factors. GAW participants were supplied with 25 random
      replicates of each data set.

PMID- 10597476
TI  - Genetic linkage analysis of simulated complex disease data.
AB  - The purpose of this analysis was to apply current analytic methods to a simulated
      data set with a recognized genetic model in order to identify the loci that
      affect a complex disease, detect evidence for the interaction among two of the
      loci, and detect the gene-environment interaction. The following analytic tools
      were used: two multipoint linkage analysis programs, a stratification strategy
      based on the results of the multipoint analysis, and a case-control analysis
      using discordant sib pair data. The results were consistent with the underlying
      genetic model: a disease due to a major gene on chromosome 3 associated with an
      environmental risk factor, and two minor interacting loci on chromosomes 1 and 5.

PMID- 10597477
TI  - Genetic model-free linkage analysis using the maximum-likelihood-binomial method
      for categorical traits.
AB  - Within the simulated data of the 11th Genetic Analysis Workshop, we searched for
      the genes controlling the disease. We analyzed 200 families from Studies 2 and 3
      presenting both mild and severe forms of disease. Linkage analysis was performed
      using the recently developed genetic model-free maximum-likelihood-binomial (MLB)
      method which overcomes the problem of multiple sibs by considering the sibship as
      a whole. The MLB allowed us to consider the disease as either a binary
      (affected/unaffected) or an ordered categorical (differentiating the two forms of
      disease and including effects of environmental factors) phenotype. In both
      studies, two regions provided evidence for linkage at a significance level below
      10(-4). One is located on chromosome 3 (from D3G041 to D3G047), and the other on
      chromosome 5 (from D5G034 to D5G041). In Study 2, the most significant results
      were obtained by combining both forms of disease, suggesting that they are under
      the same genetic control, while in Study 3, the stronger results were obtained
      when considering severe subjects alone, suggesting that only the severe form is
      under the control of both locus B and C. The subsequent knowledge of the true
      model allowed a posterior interpretation of our results, in particular the
      difference in optimal coding schemes observed between Studies 2 and 3, and the
      failure to locate locus A.

PMID- 10597478
TI  - Complete genomic screen for disease susceptibility loci in nuclear families.
AB  - We performed genome-wide model dependent and independent analyses on a simulated
      data set of 400 families segregating for a rare disorder. Regions on chromosomes
      1, 3, and 5 were consistently indicated across the various analyses performed.
      Follow-up analyses included stratification for locus heterogeneity and clinical
      phenotype and studies of gene x gene and gene x environment interaction. The
      region around D1G024 was most notable, showing strong association and linkage
      with the trait. We also identified regions D3G043-46 and D5G037-39 by strong
      linkage and association findings and region D1G001-09 by linkage analysis. A
      complex statistical interaction was suggested between D1G024, D3G046 and
      environmental factor 1. This report suggests that traditional methods of analysis
      can be implemented to analyze and describe the mechanisms that may underlie the
      more complex genetic disorders.

PMID- 10597479
TI  - Strategies for detecting susceptibility genes in a complex disease.
AB  - One of the current issues in genetic epidemiology is detecting susceptibility
      genes on the genome. It is common now to undertake systematic screening of the
      genome using approaches based on a measure of the haplotype sharing in sib pairs.
      Here, we compare the efficiency of two statistics, the maximum likelihood score
      (MLS) and the nonparametric linkage score (NPLa) on the simulated data provided
      for GAW11. A question often raised is whether it is better to perform a single
      step or a two-step strategy. For the simulated model, and whatever the strategy
      used, we show here that the answer is not unequivocal. In both cases, the power
      to detect susceptibility genes in a single replicate with MLS or NPL is extremely
      low. With two replicates, only one of the four simulated loci could be detected
      with reasonable power. When gametic disequilibrium is suspected, methods testing
      for both linkage and association might be more powerful.

PMID- 10597480
TI  - Meta-analysis of linkage studies.
AB  - Lander and Kruglyak [1995] gave guidelines for interpreting linkage results based
      on estimating how often a particular threshold for significance would be exceeded
      by chance in a single genome scan. What is unknown is how often two or more
      genome scans would exceed a particular threshold within the same region. We
      develop theoretical estimates of these values and compare these with the
      empirical estimates derived from the GAW11 data. For single-point analysis, the
      theoretical estimates predict the empirical estimates. For multipoint analysis,
      the theoretical values overestimate what is observed. For both single point and
      multipoint, modest p-values within a single genome scan may give highly
      significant results when replicated in the same region in other scans.

PMID- 10597481
TI  - Search for a gene x environment interaction: G x E hunt.
AB  - We developed a method to identify gene x environment interactions (G x Es). To
      test this method in the simulated data (Problem 2, GAW11), we first identified an
      environmental factor (E1) that was associated with the simulated disorder. We
      stratified affected sibling pairs (ASPs) into two groups, those concordant for
      the presence of E1 and those concordant for the absence of E1. We then localized
      genes on chromosomes 3 and 5 using identity-by-descent (IBD) sharing rates among
      ASPs. Because the stratified IBD sharing rates are independent of the
      environmental factor if there is no G x E, we inferred the existence of a G x E
      near loci 3G44 and 3G45 by testing whether the proportion of ASPs sharing no
      alleles IBD differed among the two groups.

PMID- 10597482
TI  - A simple allele sharing statistic for multiple locus systems.
AB  - For complex disorders where the actions of several interacting loci must be taken
      into account, current methods of joint linkage analysis are problematic. We have
      undertaken an exploration of simultaneous search statistics originally proposed
      by Dupuis et al. [1995]. Additionally, we have extended these methods slightly
      and propose here a simple simultaneous search statistic based upon the single
      point allele sharing statistic calculated from GENEHUNTER (GH). The use of
      conditional search techniques is also explored.

PMID- 10597483
TI  - Analysis of complex traits using neural networks.
AB  - A recently developed approach that employs artificial neural networks (ANNs) was
      applied to the simulated data set to identify sets of marker loci involved in
      disease etiology. In this implementation, ANNs are trained to predict the disease
      state (output) from the given genetic marker data (input). A contribution value
      (CV) for each locus is calculated from the weights that represent the strength of
      the connections for the trained ANN; a higher CV indicates a higher probability
      of linkage. The highest CV values were chosen as the most likely candidate
      regions involved in the disease.

PMID- 10597484
TI  - Disease-marker associations: power and heterogeneity in independent population
      samples.
AB  - We applied generalized transmission disequilibrium testing (TDT) models in
      combined replicates 1 through 5 from each of four simulated population samples.
      All analyses were conducted without knowledge of the generating models. To assess
      power and consistency of results within and between samples, analyses were
      repeated in all 25 replicates combined and in each replicate. With the exception
      of sample-specific findings for locus D, power was generally low to detect
      linkage in a genome scan or to confirm linkages detected by allele sharing in
      affected relatives, due to lack of linkage disequilibrium. We proposed likelihood
      ratio and Wald tests to detect heterogeneity among samples in disease-marker
      associations. Pooling data across heterogeneous populations may not improve power
      of the TDT method.

PMID- 10597485
TI  - Multipoint linkage analysis using the weighted-pairwise correlation statistic.
AB  - The weighted pairwise correlation (WPC) approach provides simple and flexible non
      parametric tests for genetic linkage which may be adapted to qualitative,
      quantitative or age-dependent traits. Although this statistic has often been used
      with identity-by-state (IBS) information, there is much to gain by using
      multipoint identity-by-descent (IBD) information. The purpose of this paper is to
      use the unified multipoint approach of Kruglyak et al. [1996] with the WPC
      statistic. We used the simulated data of a complex disease proposed in GAW11
      (problem 2) to validate this approach and to compare the multipoint WPC to the
      IBS-WPC and to the multilocus approach using the conventional non-parametric
      statistics S(pairs) and S(all). The results suggest that the multipoint WPC may
      be the most powerful approach.

PMID- 10597486
TI  - Improving the power for disease locus detection in affected-sib-pair studies by
      using two-locus analysis and multiple regression methods.
AB  - In this paper we present a summary of an analysis of the simulated data (Problem
      2) for GAW11. We used sib-pair and affected-sib-pair (ASP) methods to evaluate
      linkage to the mild form of disease at markers across the genome, in data sets of
      realistic moderate size (containing between 100 and 300 families selected from
      the simulated replicates). The true 'answers' were known in advance. Although in
      most cases we were successful in detecting linkage to disease in the correct
      regions, it was often difficult to distinguish these results from false positives
      elsewhere in the genome. We used two-locus methods to see whether the
      significance was improved by simultaneously modeling linkage to two disease loci,
      and found a modest increase in significance using two-locus methods in several
      cases.

PMID- 10597487
TI  - Analysis of simulated data: evidence for genetic and environmental effects.
AB  - We approached the simulation as though it were an international study with
      similar but not identical information being collected from different populations.
      In keeping with this we analyzed one replicate from each population. Initially we
      examined the risk of disease in relatives of cases to determine whether the
      disease appeared to be "more genetic" in one population than in the others and we
      examined the evidence for environmental risk factors in each population.
      Nonparametric linkage analysis and transmission/disequilibrium testing (TDT) were
      used to search for loci linked to the disease in each population. Using these
      methods we identified several candidate regions for a susceptibility gene which
      on examination of the answers are explicable in terms of the underlying model.

PMID- 10597488
TI  - Evaluation of the contribution of environmental factors.
AB  - For the simulated data of GAW11, the roles of two environmental factors, E1 and
      E2, were investigated. Logistic regression analyses measuring the association
      between outcome (either mild or severe disease versus no disease) and E1 and E2
      exposure indicated that E1 was a risk factor for disease (either mild or severe)
      but that E2 was not associated with outcome. Linkage analyses were performed for
      strata defined by E1 and E2 exposure. A specific disease locus was identified in
      these stratified analyses where this locus would not have been identified with an
      unstratified linkage analysis. Finally, stratified generalized transmission
      disequilibrium test analyses yielded several false positive results.

PMID- 10597489
TI  - Search for susceptibility genes, gene x gene interactions, and gene x environment
      interactions utilizing nonparametric linkage analysis.
AB  - There may be a different genetic basis for the two forms of the disease simulated
      in Problem 2 and the complex disease may be affected by environmental factors.
      Hence, we investigate the effects of two environmental factors. We selected 400
      nuclear families from the data generated for Problem 2. Affection status was
      investigated in several ways. Individuals with severe and mild forms of the
      disease were both considered affected, individuals with only the severe form were
      considered affected while those with the mild form were considered unknown, and
      individuals with only the mild form were considered affected while those with the
      severe form were considered unknown. We found evidence of linkage between
      putative disease loci and markers in the D3G042-D3G049 and D5G031-D5G042 regions
      when we considered severely and mildly affected individuals as affected and also
      in the region D1G004-D1G013 when mildly affected individuals were considered
      unknown. We observed interactions between the first environmental factor and
      D1G043 among healthy sib pairs.

PMID- 10597490
TI  - Genetic analysis of a complex disease in the presence of an environmental risk
      factor.
AB  - The role of a gene in a disease may be hidden by the presence of another risk
      factor such as an environmental factor. In that case, stratifying the data
      according to this factor strengthens power to detect linkage or association. We
      followed this strategy on the simulated data provided by GAW11. The
      transmission/disequilibrium test (TDT) and the maximum likelihood score (MLS)
      were performed on the first replicate of 100 sib pairs from the population in
      which the disease risk was significantly influenced by an environmental factor
      (E1). However, only the TDT was powerful enough to detect one of the four loci
      involved in the genetic determination of the disease. The MLS showed no evidence
      for linkage after taking into account the fact that multiple tests were
      performed. Even when stratifying the sample according to the presence of E1, no
      additional loci could be detected. Given the simulated models, 100 sib pairs are
      too low a sample size for a systematic screening of the genome, which in this
      case was an analysis of 300 markers.

PMID- 10597491
TI  - Systematic search for disease loci for complex genetic traits: a study based on
      simulated population data.
AB  - Simulated family data were analyzed using one- and two-locus disease models to
      detect linkage. Regions of interest, found on chromosomes 3 and 5, were then
      further analyzed to look for evidence of locus interaction and/or genetic
      heterogeneity. Methods described by Falk [1993] were used to separate families
      into subsets likely to be genetically homogeneous. Based on the results, it was
      concluded that there were at least two distinct disease loci, one on chromosome 3
      and one on chromosome 5, and that these loci were probably not interacting but
      were expressing two distinct forms of the disease. The identification of these
      loci was in agreement with the generating model. However, the analysis did not
      show any indication of a two-locus form of the disease or detect a disease locus
      on chromosome 1. This could be due to lack of power and/or too small a sample
      size for the method of analysis.

PMID- 10597492
TI  - Hunting genetic diseases: exploring a multistage approach to identifying disease
      loci.
AB  - Genomic screen data for a hypothetical disease was used in a two-stage analysis
      to search for disease loci. We performed both trait-model-dependent and trait
      model-free analyses to test their relative power. Results of our first-stage
      screen in 200 families suggested 13 regions for further analysis. Second-stage
      follow-up in another 200 families confirmed a single region on chromosome 3 near
      marker D3G045 with a combined lod score across all 400 families of 6.24 and a sib
      pair maximum lod score (MLS) of 4.79. The MLS were highly correlated with both
      the autosomal dominant and autosomal recessive lod scores in all data sets,
      suggesting that both trait-model-dependent and trait-model-free methods can be
      useful for identifying candidate regions for complex disease loci. Reanalysis of
      the data using alternative sampling schemes suggested that sampling variation has
      a significant effect on locus detection.

PMID- 10597493
TI  - A joint test of linkage and gene x environment interaction, with affected sib
      pairs.
AB  - In the presence of gene x environment (G x E) interaction, the expected
      proportion of alleles shared identical by descent at a linked marker locus by a
      pair of affected sibs depends on the exposure profile of the two sibs, i.e.,
      whether both are exposed to E, only one is exposed, or neither are exposed. In
      this paper, we propose an extension of the commonly used mean test of linkage to
      test for differential identical-by-descent (IBD) sharing across sib-exposure
      profiles. The method can be viewed as a test for linkage in the presence of G x E
      interaction, or as a test for G x E interaction in the presence of linkage.
      Applied to the simulated GAW11 data, our method successfully localized disease
      locus C and its interactive relationship with environmental factor E1. At the 5%
      significance level, use of our method led to increased power to detect linkage
      (56%) to this disease locus compared to use of the standard mean test (32%); at
      the 0.001 significance level, the corresponding power estimates were 20% and 4%,
      respectively. For a gene that interacts with an environmental factor, we conclude
      that use of the environmental factor in linkage analysis can improve detection
      rates while also providing information about underlying mechanisms.

PMID- 10597494
TI  - Detection and modeling of disease susceptibility locus effects: how much can be
      learned from contrast of populations?
AB  - We report the results of our analyses of the GAW11 Problem 2 data set, using
      information from three different populations. In the first part of the paper, we
      used classical population genetic tests to compare affected individuals from the
      different populations, stratifying on the environmental factors. Thanks to
      existing linkage disequilibrium in one population, we found one of the disease
      susceptibility loci. In the second part of the paper, we used the marker
      association segregation chi 2 method to model the role of this disease
      susceptibility locus in the different populations and draw some inferences
      regarding the model used at that locus to generate the data.

PMID- 10597495
TI  - Impact of family structure on the power of linkage tests using sib-pair methods.
AB  - This analysis sought to determine the impact of specific ascertainment criteria
      based upon nuclear family affectation structures. Specifically, we evaluated the
      predicted and observed proportion of alleles shared identical by descent
      conditional on the number of affected and unaffected siblings in a pedigree, and
      compared sib-pair method linkage results under two ascertainment schemes, random
      vs. selected ascertainment, for this simulated complex genetic disease. These
      results suggest that samples differing in the composition of affected and
      unaffected siblings in the family will differ in their power to detect linkage.
      An effect of sampling scheme on power to map using affected-sib-pair methods
      should be considered when a reported linkage is not found in another study
      population.

PMID- 10597496
TI  - Meta-analysis by combining parameter estimates: simulated linkage studies.
AB  - Several meta-analytic techniques have been developed for combining information
      from multiple studies in contexts other than linkage detection. We apply the
      technique of combining parameter estimates to the problem of finding disease loci
      in the simulated data and compare results with those obtained by reanalyzing
      pooled raw data. To facilitate the combination of study results, we highly
      recommend that parameter estimates and their standard errors be reported in
      published studies. If different research groups were to make original data
      available, progress toward disease gene location and characterization may be more
      quickly made.

PMID- 10597497
TI  - Power loss for multiallelic transmission/disequilibrium test when errors
      introduced: GAW11 simulated data.
AB  - Many researchers are considering the use of transmission/disequilibrium tests
      (TDT) for trios of genotypes (father, mother, child) as a method for localizing
      genes associated with complex diseases. We evaluate the effect of random errors
      (allele changes) in trios on the power to detect linkage. For a marker in the
      simulated data set, one allele is associated with the fictitious disease in a
      certain subpopulation. For the data as given (no errors), our power to detect
      linkage using the multiallelic TDT (TDTmhet) is 68% (critical p-value set at
      0.0001). We introduce errors into trios at various rates (1%, 5%, or 10%), remove
      only trios displaying mendelian inconsistencies, and recalculate power to detect
      linkage. Our principal finding is that there is power loss to detect linkage with
      the TDTmhet when errors are introduced. We observe power losses of 8%, 16%, and
      48% for error rates of 1%, 5%, and 10%, respectively. To determine the source of
      the power loss, we perform Monte Carlo simulations. At the 1% and 5% rates, we
      conclude that power loss is due primarily to loss in sample size. At the 10%
      rate, we observe substantial power loss due to error introduction in addition to
      sample size reduction. We also determine, given a particular error rate, the
      probability that we detect errors if we use only mendelian consistency as a
      check. We find that the mean detection rates for the data sets with 1%, 5%, or
      10% error rates are 58%, 60%, and 62%, respectively. As a result, the apparent
      error rate appears to be almost half the true error rate. Based on these results,
      we recommend that researchers maintain error rates below 5% when using the
      TDTmhet for linkage, use additional methods beyond mendelian consistency checks
      when searching for errors in their data, and modify sample size calculations when
      accounting for errors in their genotype data.

PMID- 10597498
TI  - Validation of linkage by sampling based on environmental exposures.
AB  - After detecting linkage in one sample, most researchers will attempt to validate
      this finding in another sample. Three strategies for validating a primary linkage
      were compared, with a focus on methods that might be appropriate in the presence
      of gene x environment interaction. First, a validation sample was collected and
      analyzed using the same ascertainment procedure and methods as the primary
      sample. Second, a sample of families with particular exposure patterns were
      ascertained subsequent to a significant test for heterogeneity due to the
      exposure in the primary sample. A third strategy ascertained by exposure status
      when exposure-defined subgroup tests were significant in the primary sample. The
      second strategy reduced the number of false positive linkage signals identified
      through exposure subgroup identification (i.e., the third strategy), but in this
      GAW11 data that contained no qualitative gene x environment interactions, it had
      poor sensitivity. Power to detect heterogeneity depends on the differences in
      risk between exposed and unexposed.

PMID- 10597499
TI  - Meta-analysis of genetic linkage to quantitative trait loci with study-specific
      covariates: a mixed-effects model.
AB  - A method of meta-analysis was used to combine summary linkage information from
      four hypothetical study groups simulated in GAW11 Problem 2 with no knowledge of
      the answer. Five replication studies were selected from each group, and a pool of
      20 primary studies was used for combining. Using a mixed-effects model with the
      among-study variation as random effects, we pooled results from all the 20
      studies and detected strong linkage signals on chromosome 5 at D5G38 and on
      chromosome 3 near D3G45. We also found suggestive signals on chromosome 1 near
      D1G9, and possible interaction of D1G24 with the selection for the severe form of
      the disease.

PMID- 10597500
TI  - Meta-analysis by combining p-values: simulated linkage studies.
AB  - Meta-analysis has been little explored to make an overall assessment of linkage
      from different studies. In practice, it is likely that published linkage studies
      will only report p-values. We compared the performance of the widely used Fisher
      method for combining p-values with that of pooling raw data. More loci were
      consistently found by pooling raw data. In the absence of further information,
      combining p-values can provide an overall, but limited, assessment of different
      linkage studies. However, meta-analysis would be better viewed as a preliminary
      step toward the goal of analyzing the pooled raw data.

PMID- 10597501
TI  - Performance of the nonparametric linkage analysis using GENEHUNTER for a
      complicated genetic disease.
AB  - The nonparametric linkage (NPL) analysis of the GENEHUNTER program was applied to
      one set of the simulated data of Problem 2, GAW11. We conducted a straightforward
      screening of the genome to evaluate the performance of the NPL test, with respect
      to its ability to detect linkage on specific disease loci. Our findings indicate
      that disease genes were detected with relatively good power, despite the presence
      of a complex inheritance pattern. We found that the NPL test varies depending on
      penetrance rates and gene frequencies, however, we conclude that it is a useful
      tool for linkage analysis.

PMID- 10597502
TI  - Markov chain Monte Carlo linkage analysis of a complex qualitative phenotype.
AB  - We tested a new computer program, LOKI, that implements a reversible jump Markov
      chain Monte Carlo (MCMC) technique for segregation and linkage analysis. Our
      objective was to determine whether this software, designed for use with
      continuously distributed phenotypes, has any efficacy when applied to the
      discrete disease states of the simulated data from the Mordor data from GAW
      Problem 1. Although we were able to identify the genomic location for two of the
      three quantitative trait loci by repeated application of the software, the MCMC
      sampler experienced significant mixing problems indicating that the method, as
      currently formulated in LOKI, was not suitable for the discrete phenotypes in
      this data set.

PMID- 10597503
TI  - A genome-wide scan for a simulated data set using two newly developed methods.
AB  - A genome-wide scan of a simulated data set for fictitious disease genes was
      conducted using both semiparametric and nonparametric methods. The semiparametric
      model-based method, which tests for linkage/linkage disequilibrium separately and
      together, correctly identified all three underlying disease loci along with two
      false positives through the linkage analysis. However, the nonparametric model
      free method which tests combined linkage/linkage disequilibrium, failed to yield
      any results due to the lack of linkage disequilibrium information in the data.

PMID- 10597504
TI  - Nonparametric linkage and family-based association studies of a simulated complex
      disorder.
AB  - Affected sibling pairs are widely used to identify chromosomal regions harboring
      genetic loci underlying common disease. We explore the utility of nonparametric
      sibling pair and family-based association methods to search for disease
      susceptibility loci in simulated pedigree data for a qualitative disease trait.
      Logistic regression was used to model gene x gene and gene x environment
      interactions when significant linkage and association were detected. Using these
      methods, we were able to detect three of the four susceptibility loci underlying
      the disease trait with multipoint lod scores of 1.0 or greater.

PMID- 10597505
TI  - Genetic dissection of a complex trait.
AB  - A number of genetic and statistical tools were applied to various partitions of
      the simulated data to identify susceptibility loci, relevant environmental
      factors, and their interaction(s). The distribution of genotypes at D1G24 among
      affected children in the first population was found to differ significantly from
      Hardy-Weinberg expectation. Two transmission/disequilibrium tests identified the
      preferential transmission of allele 1 as the source of the disequilibrium. Simple
      contingency table analysis revealed a positive association between exposure to
      environmental factor E1 and disease phenotype. Multipoint linkage analyses on
      various subsets of the data identified three "signal" regions (in addition to the
      aforementioned D1G24) localized at D1G9-10, D3G45, and D5G38. The even numbered
      chromosomes appeared to be devoid of susceptibility loci. Further analyses of
      subsamples of affected sib pairs, selected according to their disease phenotype
      and their exposure to E1, clarified some linkage relationships, particularly for
      D3G45, thereby suggesting the presence of a specific gene x environment
      interaction. Logistic analysis designed to clarify the relationship between
      disease phenotype and two risk factors (E1 exposure and the presence of allele 1
      at D1G24) in the first population, revealed a significantly negative interaction
      which, upon learning the details of the generating model, we now attribute to the
      presence of heterogeneity.

PMID- 10597506
TI  - A comparison of some allele-sharing based linkage analysis methods for detecting
      complex trait loci.
AB  - Using randomly selected sib pairs from a subset of the GAW11 simulated data in
      Problem 2, we compared the results of some linkage analysis methods based on
      allele sharing. One method was the Haseman-Elston test for a binary disease
      outcome (unaffected vs. mild or severe). The other methods, which analyzed the
      trinary ordered outcome unaffected/mild/severe were the Haseman-Elston test, an
      extended Haseman-Elston incorporating sib-pair sums, variance components
      analysis, and regression analysis. Our analysis was done without knowledge of the
      generating model.

PMID- 10597507
TI  - Environmental covariates: effects on the power of sib-pair linkage methods.
AB  - The effect of inclusion of environmental risk factors on the power of sib-pair
      linkage methods was tested for a qualitative trait. It was found that inclusion
      of an environmental variable did not increase the power of the Haseman-Elston (H
      E) sib-pair nonparametric linkage analysis test. However, a significant increase
      in power was observed for both the H-E and affected-sib-pair tests, even in small
      samples, when persons unexposed to the environmental risk factor were coded as
      unknown.

PMID- 10597508
TI  - A comparison of two algorithms, MultiMap and gene mapping system, for automated
      construction of genetic linkage maps.
AB  - Using the GAW11 Problem 2 data set, we compared the performance of two automated
      map construction algorithms, MultiMap and GMS (Gene Mapping System). The MultiMap
      algorithm iteratively adds markers in a stepwise manner to the map, while the GMS
      algorithm seeks to find the best order of the whole set of markers by selective
      permutations of logically formed subgroups of the markers. While it is difficult
      to compare these two rather different algorithms, we found that, on these data,
      GMS performed better than MultiMap, placing more markers in their true order on
      average, with little order ambiguity. In addition, as the number of markers
      increased, GMS was less computationally demanding than MultiMap. However, it
      MultiMap placed a marker, it was almost always in the correct order. In contrast,
      GMS often placed a group of markers on the wrong end of the map; such incorrect
      placements occur when the evidence for placement on one end or the other is not
      strong. Thus, there is room for further algorithmic developments that combine the
      strengths of both the MultiMap and GMS approaches.

PMID- 10597509
TI  - Two tests of association for a susceptibility locus for families of variable
      size: an example using two sampling strategies.
AB  - A two-stage approach was used to analyze Problem 2 simulated data from Genetic
      Analysis Workshop 11. In the first stage, we tested for linkage with the Haseman
      Elston test in SIBPAL. Markers that were significant in the first stage were
      followed up with two types of association tests. These association tests differ
      in the type of family information used: 1) parental transmissions to affected
      children or 2) differences in marker allele frequencies between affected and
      unaffected siblings. We also explored how the conclusions changed when different
      sampling strategies were used. Of particular interest was whether the entire data
      set should be used to test for both linkage and association or whether the data
      set should be halved to allow for replication of the initial association results.

PMID- 10597510
TI  - Generalization of the extended transmission disequilibrium test to two unlinked
      disease loci.
AB  - The extended transmission disequilibrium test (ETDT) of Sham and Curtis [1995] is
      a powerful test of the null hypothesis of no linkage between a multi-allelic
      marker locus and a disease susceptibility locus of unknown location in the
      presence of association between alleles at the two loci. We propose a
      generalization of the ETDT to test simultaneously for linkage of markers to two
      unlinked disease loci. Analysis of the simulated data for Problem 2 would suggest
      improvements in power to detect linkage to pairs of disease loci over single
      locus tests. This is as a result of the two locus model taking account of
      epistasis between the disease loci.

PMID- 10597511
TI  - Application of probabilistic neural network analysis to a disease with complex
      inheritance: the GAW11 simulated data.
AB  - A probabilistic neural network analysis was applied to the simulated GAW11 data.
      Six replicates drawn at random from one of the simulated populations were used to
      generate training and test vectors for pairs of siblings. The vectors
      incorporated two environmental indicators as well as identical-by-descent allele
      sharing scores from each of 300 genetic markers. The performance of a 'naive'
      probabilistic neural network (PNN) was fair. However, by combining a traditional
      linkage analysis with a PNN which incorporated gene x environment interaction,
      the performance was considerably enhanced.

PMID- 10597512
TI  - A normalized identity-by-state statistic for linkage analysis of sib pairs.
AB  - A sib-pair analysis was performed on a simulated data set for a fictitious
      disease, with a prevalence of approximately 3% to 6%. The disease could manifest
      itself in a severe or mild form and the analyses focused primarily on families
      with the mild form, barring any misdiagnoses. The numbers of shared genes
      identical by descent (IBD) and identical by state (IBS) were used to detect
      linkage between the marker loci and the disease. The results of the two methods
      were compared. We considered the distribution of the number of shared alleles IBS
      (for different parental allele combinations) and suggest a normalized IBS method.
      A large proportion of pedigrees in this data set had at least one homozygous
      parent or both parents sharing a common gene, thus generating the need for an
      adjustment of the IBS method. Our results indicate that the normalized IBS method
      gives results similar to those obtained by the traditional IBD approach. The
      adjusted score requires no assumptions be made with regard to the allele
      frequencies.

PMID- 10597513
TI  - Power of concordant versus discordant sib pairs at different penetrance levels.
AB  - Knowing the answers, we used the GAW11 data set to compare the power and
      efficiency of discordant versus concordant affected sib pairs for qualitative
      traits at different levels of penetrance. Samples of 200 concordant sib pairs
      outperformed discordant sib pairs for low penetrance (40%) and 70% penetrance
      models while at 90% penetrance they performed equally well. Increasing the sample
      size of discordant sib pairs to twice that of concordant pairs was not enough to
      reach the power of concordant sib pairs at the 40% and 70% penetrance models. For
      low penetrance using a combination of concordant and discordant sib pairs
      resulted in higher power than using discordant sib pairs alone. At 90%
      penetrance, the power of concordant and discordant sib pairs was similar in the
      region close to the gene while concordant sib pairs performed better at locations
      further from the gene.

PMID- 10597514
TI  - Departure from the triangle constraints in discordant sib pairs: a test for
      genetic heterogeneity.
AB  - For any genetic model, Holmans showed that the proportions of affected sibs
      sharing 2, 1, or 0 identical-by-descent parental marker alleles are constrained
      to belong to a specific triangle. The triangle constraints do not hold when the
      sib phenotypes are determined by different models. We test the rejection of
      triangle constraints on affected sib pairs discordant for severity, to determine
      whether different models control the severe and mild forms of the disease in the
      simulated data. With this method we show that a locus on chromosome 5 plays a
      different role in the two forms of the disease.

PMID- 10597515
TI  - Covariates in linkage analysis.
AB  - We apply a novel technique to detect significant covariates in linkage analysis
      using a logistic regression approach. An overall test of linkage is first
      performed to determine whether there is significant perturbation from the
      expected 50% sharing under the hypothesis of no linkage; if the overall test is
      significant, the importance of the individual covariate is assessed. In addition,
      association analyses were performed. These methods were applied to simulated data
      from multiple populations, and detected correct marker linkages and associations.
      No population heterogeneity was detected. These methods have the advantages of
      using all sib pairs and of providing a formal test for heterogeneity across
      populations.

PMID- 10597516
TI  - Issues in genomic screening: critical values, sample sizes, and the ability to
      detect linkage.
AB  - The aims of this study were to empirically investigate the ability of affected
      sib pairs (ASPs) to localize a gene through screening and to explore estimation
      of lod score critical values through resampling. To do so, we repartitioned 25
      replicates of 100 simulated nuclear families into six data sets of sizes 100,
      200, 300, 400, 500, and 1,000 and chose at most one mildly ASP per family. Using
      all marker data, we calculated maximum lod scores across the six-chromosome
      genome for each set. Then, we determined the cutoff value corresponding to a 5%
      genome-wide false positive rate using both the method of Lander and Kruglyak
      [1995] and a simple resampling algorithm that allows greater scan-specific
      flexibility. For chromosome 1, the ability of the ASPs to detect the region
      between markers 9 and 10 clearly increases with the sample size, and genome-wide
      significance is achieved for samples of size 400 or greater. Also, as expected,
      the critical values based on the less conservative resampling approach are
      generally slightly smaller than those from theoretical calculations based on the
      Ornstein-Uhlenbeck diffusion process of Lander and Kruglyak.

PMID- 10597517
TI  - Mapping genotype to phenotype for linkage analysis.
AB  - We model functions that use genetic information as input and trait information as
      output to understand genetic linkage in complex diseases. Using simulated data
      from GAW11, we have applied categorical classification methods and neural network
      analysis. We use sharing at selected markers as input, and the classification of
      the sib pair (for example, affected-affected or affected-unaffected) as output.
      In addition, our methods include environmental risk factors as predictors of
      phenotype. Categorical and neural network methods each led to results consistent
      with findings from other methods such as the logistic regression method of Rice
      et al. [this issue]. Post-analysis comparison with the GAW11 answers showed that
      these methods are capable of detecting correct signals in a single replicate. One
      advantage of our methods is that they allow analysis of the entire genome at
      once, so that interactions among multiple trait-influencing loci may be detected.
      Furthermore, these methods can use a variety of sib pairs rather than affected
      pairs only.

PMID- 10597518
TI  - Systematic search for susceptibility genes in different populations.
AB  - We analyzed the first replicate of each of the four simulated population samples
      from three distinct populations by linkage and association genome scans and could
      identify three regions with susceptibility loci for the disease: on chromosome 1,
      marker D1G024, with strong evidence for gene x environment interaction; or
      chromosome 3, around marker D3G045; and on chromosome 5, markers D5G035-D5G042.
      Our results were obtained without knowing the true disease model and are compared
      with this model in the discussion.

PMID- 10597519
TI  - Exploring the role of environmental factors in association and linkage studies.
AB  - We analyzed some simulated data to assess the success of statistical
      methodologies to establish the role of the environmental factors (EF) and to
      identify associated and linked markers. We considered five replicates for each of
      the four studies, and, with the knowledge of the generating model, concentrated
      our analyses on chromosomes (CH) 1, 3, and 5. To determine the influence of EF
      and associated markers on the affection status (AS), we utilized chi-square tests
      for independence and recursive partitioning (via the CART software). To identify
      linked markers, we scanned the relevant chromosomes with nonparametric multipoint
      linkage (NPL) and transmission/disequilibrium tests. These analyses were
      performed on the whole data set as well as on subsets of individuals and families
      defined by exposure to EF. CART correctly selected the associated marker (D1G024)
      and EF1 for Study (ST) 1 and did not generate trees for the other studies. NPL
      identified the relevant regions on CH3 and CH5 but failed to do so for CH1,
      except in ST4. Stratifying families by exposure to EF1 did not consistently
      increase sensitivity of NPL to the relevant CH3 markers, but did help
      characterize the genetic heterogeneity and identify linked families.

PMID- 10597520
TI  - Detecting interactions between gene, site, and environmental variables using GAP.
AB  - Regressive models that incorporate measured variables and assumed genetic
      parameters were used to detect interactions between gene, research site, and
      environmental variables in GAW11 Problem 2. Replicates 1 to 5 were used in the
      analyses. Significant three-way gene x environment x site interactions were seen
      for all models, regardless of what assumptions were made about genetic
      transmission. Therefore, regressive models within each of the four sites were
      examined for significant gene x environment interactions. At one site, there was
      a pattern of gene x environment interaction that was consistent in most of the
      genetic models assumed. Joint and separate segregation and linkage analyses were
      compared in this site. No patterns of gene x environment interaction were seen in
      the other sites. Results from this analysis show that regressive modeling can
      identify complex interactions in data from heterogeneous populations even when
      ascertainment assumptions are violated.

PMID- 10597521
TI  - An evaluation of affected-sib-pair methods and transmission/disequilibrium tests
      for detecting genes underlying a complex trait.
AB  - For the analysis of complex traits, it is of interest to compare a few
      nonparametric methods such as affected-sib-pair (ASP) analyses and
      transmission/disequilibrium tests (TDT). The affected-sib-pair approaches we have
      examined here are ASP and ALL-SP which are implemented in SIBPAIR program. We
      also applied the BETA program which has not so far been extensively compared with
      other methods. The study indicates that the ASP program and the BETA program give
      concordant results although BETA tends to give higher lod scores. However, when
      all sibs were included in the analysis (ALL-SP), linkage signals became weaker,
      compared with ASP and BETA. The TDT detected 66 positive signals at a
      significance level of 0.05 and identified a true locus. Overall, our results
      suggest that affected-sib-pair analysis has reasonable power (p < 0.0001) to
      detect linkage given the disease model and the family structure specified in the
      GAW11 Problem 2 data set.

PMID- 10597522
TI  - Association tests using unaffected-sibling versus pseudo-sibling controls.
AB  - We used family-matched case-control data to screen the genome for markers
      associated with disease in the simulated data set. Two different types of
      controls were considered: (1) unaffected siblings and (2) 'pseudo siblings,' a
      comparison sample created using the parental alleles. The scans were conducted on
      the first replicate of each study population. Overall, the two methods identified
      14 marker loci associated with disease at the 0.001 significance level. Marker
      D1G24 (locus D) was the only true disease locus found by both approaches. No
      associations were found at any of the markers flanking the unobserved disease
      susceptibility loci (A, B, or C). We subsequently pooled the 25 replicates from a
      single population. This large sample still did not yield any associations at the
      flanking markers. We tested for association at locus D using a pseudo-sib
      approach restricted to alleles shared identical by descent between affected sib
      pairs. The power was 44% (11/25 replicates) at a significance level of 0.001.

PMID- 10597523
TI  - A generalized estimating equations approach to linkage analysis in sibships in
      relation to multiple markers and exposure factors.
AB  - We describe a multiple regression approach to nonparametric linkage analysis in
      sibships incorporating multiple genetic loci, environmental covariates, and
      interactions. The covariance in trait residuals between sib pairs is treated as
      the dependent variable, regressed upon identical-by-descent sharing probabilities
      and interaction effects, using generalized estimating equations to allow for the
      correlations among multiple sib pairs within a sibship. Individual covariates can
      also be introduced in the model for the trait means. An application to the GAW11
      simulated data revealed linkage with each of the four simulated loci, as well as
      gene x environment interactions of E1 with loci C and D and gene x gene
      interactions among the cluster of loci A, B, and D.

PMID- 10597524
TI  - A Bayesian Markov chain Monte Carlo approach to map disease genes in simulated
      GAW11 data.
AB  - A Bayesian method for multipoint mapping of disease genes based on Markov chain
      Monte Carlo algorithms was applied to the simulated GAW11 data (Study 2). The
      method is based on repeated Gibbs and more general Metropolis-Hastings steps. For
      simplicity we assumed a single disease locus model with two alleles. A normal
      distribution for the underlying latent variable of the qualitative phenotype was
      assumed. Based on a single replicate of the data no clear evidence of any of the
      genes underlying the simulated disease was found. However, when three replicates
      were combined the method was able to locate the locus C correctly on chromosome
      3.

PMID- 10597525
TI  - A Bayesian approach to replication of linkage findings.
AB  - A novel Bayesian approach to replication studies, allowing for locus
      heterogeneity, is introduced. Compared with currently used approaches to
      replication, it offers a natural way to accumulate evidence across independently
      collected data sets and yields more interpretable results. Using for replicates
      (one as initial study and the other three as replication studies) from Problem 2
      of the Genetic Analysis Workshop 11 data, we show the performance of this method.
      All four disease susceptibility loci (D1G009, D1G024, D3G045, D5G035) are
      identified and accurately mapped, with no false positive signals.

PMID- 10597526
TI  - Modeling linkage and association with evaluation of common sampling schemes.
AB  - The probability model of parental transmission (of a multiallelic marker) to
      affected offspring has been reparameterized in such a way as to distinguish the
      recombination fraction parameter from the association parameters. The advantage
      of this reparameterization is that statistical tests can be developed which
      disentangle linkage and association. It is shown that these tests perform well
      compared with a standard approach that is commonly used. Further, the simulated
      data (Problem 2) enable a comparison to be made of the performance of these tests
      under different family sampling schemes.

PMID- 10597527
TI  - Stratification techniques to explore genotype environment interactions.
AB  - Linkage analysis was performed on the GAW11 Problem 2 data set using
      stratification to explore the effects of the environmental risk factors and the
      differences between mild and severe phenotypes. Analysis of the four study
      populations stratified by the two risk factors identified regions on chromosomes
      3 and 5 with significant evidence for linkage. Other loci were sought by removing
      families consistent with linkage to the chromosome 3 locus. Our studies
      identified a locus on chromosome 3 (markers 43-46) associated with the mild
      phenotype in the presence of risk factor 1 and with the severe phenotype
      independent of risk factor 1. This suggests that distinct allelic variants at the
      chromosome 3 locus may cause different forms of disease. The locus identified on
      chromosome 5 (markers 36-39) was linked to the severe phenotype, but exposure to
      factor 1 or 2 may have a protective effect. The regions on chromosomes 3 and 5
      appeared to have independent roles in disease etiology. Evidence for two loci on
      chromosome 1 linked to the mild form was found. The methods successfully
      identified linkages and interaction consistent with the generating model.

PMID- 10597528
TI  - A method for meta-analysis of genome searches: application to simulated data.
AB  - Genome searches have been performed for many complex traits, and in some cases
      several searches have been performed in a single disease. Replication of
      significant results is rare, and a systematic method of reviewing results from a
      number of searches is needed. A method for meta-analysis is presented which
      provides a systematic descriptive overview of the separate analyses while dealing
      with some of the problems specific to meta-analysis of genome searches. The
      results of two separate meta-analyses correctly indicate the presence of
      susceptibility loci on chromosomes 1, 3, and 5 in the GAW11 Problem 2 data.

PMID- 10597529
TI  - Evaluation of replication studies, combined data analysis, and analytical methods
      in complex diseases.
AB  - Due to genetic heterogeneity, phenocopies, incomplete penetrance, misdiagnosis,
      and unknown mode of inheritance, linkage studies of most complex diseases are
      unlikely to provide conclusive findings with unambiguously high lod scores.
      Typically, several marginally significant lod scores or elevated lod scores are
      observed in a genome-wide screen. However, it is usually difficult to
      differentiate these findings from false positives (type I errors). Two approaches
      are commonly used to guard against false positives: replication studies in
      independent samples and combined data analysis. In the current paper, we
      evaluated these two common approaches using simulated data where data from
      multiple groups were available and locations of disease genes were known. We
      found replication studies and combined data analysis performed similarly in terms
      of their ability to identify true and false positive linkages. Both approaches
      confirmed two true linkages and did not confirm any false positive linkages. The
      results also indicated that it is not appropriate to apply the criteria proposed
      for confirming significant evidence for linkage to confirm regions with only
      suggestive evidence for linkage. The current results support previous findings
      that parametric analysis using an incorrect genetic model can still identify a
      true linkage.

PMID- 10597530
TI  - Using case-control designs for genome-wide screening for associations between
      genetic markers and disease susceptibility loci.
AB  - We used a case-control design to scan the genome for any associations between
      genetic markers and disease susceptibility loci using the first two replicates of
      the Mycenaean population from the GAW11 (Problem 2) data. Using a case-control
      approach, we constructed a series of 2-by-3 tables for each allele of every
      marker on all six chromosomes. Odds ratios (ORs) and 95% confidence intervals
      (95% CI) were estimated for all alleles of every marker. We selected the one
      allele for which the estimated OR had the minimum p-value to plot in the graph.
      Among these selected ORs, we calculated 95% CI for those that had a p-value < or
      = adjusted alpha level. Significantly high ORs were taken to indicate an
      association between a marker locus and a suspected disease-susceptibility gene.
      For the Mycenaean population, the case-control design identified allele number 1
      of marker 24 on chromosome 1 to be associated with a disease susceptibility gene,
      OR = 2.10 (95% CI 1.66-2.62). Our approach failed to show any other significant
      association between case-control status and genetic markers. Stratified analysis
      on the environmental risk factor (E1) provided no further evidence of significant
      association other than allele 1 of marker 24 on chromosome 1. These data indicate
      the absence of linkage disequilibrium for markers flanking loci A, B, and C.
      Finally, we examined the effect of gene x environment (G x E) interaction for the
      identified allele. Our results provided no evidence of G x E interaction, but
      suggested that the environmental exposure alone was a risk factor for the
      disease.

PMID- 10597531
TI  - Significant evidence for linkage of a simulated trait to D1G024--a conclusion
      reached using multiallelic transmission/disequilibrium tests.
AB  - We applied three versions of the transmission/disequilibrium test (TDT) for
      detecting linkage in nuclear families using the a priori information of possibly
      present association. For our analyses we employed all marker data for a simulated
      trait. Results for replicate 11 showed significant linkage to D1G024 using the
      multiallelic Tmhet statistic and the extended TDT. The TDT for the most frequent
      parental allele which had been applied successfully in previous studies failed to
      detect linkage. This result may have happened because the data did not arise from
      a realistic simulation of the evolution of a real population, where mutations
      might be expected to occur against a specific haplotype. Simulation studies are
      required to elucidate the applicability of the TDT for the most frequent parental
      allele in realistic situations. Furthermore, guidelines have to be developed for
      how to pool categories in large, sparse contingency tables to obtain larger cell
      frequencies and lower degrees of freedom.

PMID- 10597532
TI  - Some pharmacokinetic parameters of the trypanocidal drug homidium bromide in
      Friesian and Boran steers using an enzyme-linked immunosorbent assay (ELISA).
AB  - Pharmacokinetic studies on the trypanocidal drug homidium bromide using a
      competitive enzyme immunoassay (detection limit 0.1 ng/mL) are reported for non
      infected Friesian and Boran steers following treatment with homidium bromide at a
      dose of 1.0 mg/kg b.w. Following intravenous (i.v.) treatment of Friesian steers
      (n = 5), the mean serum drug concentrations were 31.9 +/- 2.1 and 3.9 +/- 0.4
      ng/mL at 1 and 24 h, respectively. The decline in serum drug concentration was
      tri-exponential with half-lives of 0.064 +/- 0.037 h for t1/2 alpha, 7.17 +/-
      1.87 h for t1/2 beta and 106.3 +/- 6.6 h for t1/2 gamma for distribution and
      elimination phases 1 and 2, respectively. Drug was detectable in serum for 17
      days following treatment. The mean residence time (MRT) was 63.4 +/- 7.5 h.
      Following intramuscular (i.m.) treatment of Friesian steers (n = 5), the drug
      concentration at 1 h after treatment was 72.5 +/- 2.2 ng/mL. This declined to 9.8
      +/- 1.8 ng/mL at 24 h. Low concentrations of between 0.1 and 0.3 ng/mL remained
      in circulation for up to 90 days post-treatment. Following intramuscular
      treatment of Boran steers (n = 5), the mean serum drug concentration at 1 h after
      treatment was 112.1 +/- 40.3 ng/mL. By 24 h after treatment, the concentration
      had fallen to 13.0 +/- 3.3 ng/mL. Thereafter, the serum drug concentration-versus
      time profile and the pharmacokinetic parameters obtained following non
      compartmental analysis were similar to those obtained following intramuscular
      treatment of Friesian steers.

PMID- 10597533
TI  - Development and evaluation of an enzyme-linked immunosorbent assay (ELISA) for
      the determination of the trypanocidal drug homidium in serum of treated cattle.
AB  - Two enzyme-linked immunosorbent assays (ELISA) for the determination of homidium
      in serum of treated cattle have been developed and evaluated. One is a direct
      competition (Assay 1) and the other an indirect competition assay (Assay 2). Both
      assays are highly sensitive with a limit of detection of 0.1 ng homidium per mL
      serum. Homidium levels were measurable in serum of cattle for over 2 months
      following administration of a single intramuscular (i.m.) dose at 1 mg/kg
      bodyweight. The level of sensitivity afforded by these assays makes them
      potentially useful tools in the pharmacokinetic evaluation of homidium and for
      investigating drug resistance or causes of drug failure. Assay 2 was chosen as
      being most suitable for further studies.

PMID- 10597534
TI  - Absorption kinetics and bioavailability of cephalexin in the dog after oral and
      intramuscular administration.
AB  - The pharmacokinetics of cephalexin, a first generation cephalosporin, were
      investigated in dogs using two formulations marketed for humans, but also often
      employed by practitioners for pet therapy. Cephalexin was administered to five
      dogs intravenously and intramuscularly as a sodium salt and by the oral route as
      a monohydrate. The dosage was always 20 mg/kg of active ingredient. A
      microbiological assay with Sarcina lutea as the test organism was adopted to
      measure cephalexin concentrations in serum. The mean residence time (MRT) median
      values after intravenous (i.v.), intramuscular (i.m.) and oral administration
      (p.o.) were 86 min, 200 min, and 279 min, respectively. After i.m. and oral
      dosing the peak serum concentrations (24.2 +/- 1.8 micrograms/mL and 20.3 +/- 1.7
      micrograms/mL, respectively) were attained at 90 min in all dogs and
      bioavailabilities were 63 +/- 10% and 57 +/- 5%, respectively. The time course of
      the cephalexin serum concentrations after oral administration was best described
      by a model incorporating saturable absorption kinetics of the Michaelis-Menten
      type: thus in the gastrointestinal tract of dogs a carrier mediated transport for
      cephalexin similar to that reported in humans, may exist. The predicted average
      serum concentrations of cephalexin after repeated i.m. and oral administration
      indicated that, in order to maintain the therapeutic concentrations, the 20 mg/kg
      b.w. dosage should be administered every 6-8 h.

PMID- 10597535
TI  - Pharmacokinetics of ketorolac after intravenous and oral single dose
      administration in dogs.
AB  - The pharmacokinetics of ketorolac (Toradol), a human non-narcotic, nonsteroidal
      anti-inflammatory drug (NSAID) of the pyrrolo-pyrrole group, was studied in six
      mixed breed dogs of varying ages (1-5 years). The study was performed using a
      randomized crossover design, with each dog initially assigned to one of two
      groups (intravenous (i.v.) or oral (p.o.)). Each group of three dogs received
      either the injectable or oral formulation of ketorolac tromethamine at 0.5 mg/kg.
      Serial blood samples were collected before and over 96 h following treatment.
      Samples were analysed by reverse phase HPLC. Individual ketorolac plasma
      concentration-time curves were initially evaluated by computerized curve
      stripping techniques followed by nonlinear least squares regression. Following
      i.v. administration mean (+/- SD) pharmacokinetic parameters were: elimination
      half-life (t1/2 beta) = 4.55 h, plasma clearance (Clp) = 1.25 (1.13) mL/kg/min,
      and volume of distribution at steady state (Vss) = 0.33 (0.10) L/kg. Mean (+/-
      SD) p.o. pharmacokinetic values were: t1/2 beta = 4.07 h, time to reach maximum
      concentration (tmax) = 51.2 (40.6) min, and p.o. bioavailability (F) = 100.9
      (46.7)%. These results suggest that the pharmacodisposition characteristics of a
      clinically effective 0.5 mg/kg i.v. or p.o. single dose of ketorolac tromethamine
      administered to dogs is fairly similar to that observed in humans.

PMID- 10597536
TI  - Influence of experimentally induced theileriosis (Theileria annulata) on the
      pharmacokinetics of a long-acting formulation of oxytetracycline (OTC-LA) in
      calves.
AB  - The effects of experimental Theileria annulata infection on the i.m. (20 mg/kg)
      pharmacokinetics of oxytetracycline were investigated in crossbred calves. The
      serum concentration-time curves of oxytetracycline (OTC-LA), before and after
      experimental infection, were best described by a one-compartment open model. The
      experimental infection by subcutaneous administration of ground-up tick supernate
      (GUTS), equivalent to 30 Hyalomma anatolicum anatolicum ticks infected with
      Theileria annulata, produced a clear temperature rise and signs of clinical
      disease in calves. Subsequently, haemoglobin, packed cell volume, total leucocyte
      count and serum Cu, Fe and Zn concentrations decreased after infection. The
      absorption and elimination half-lives (t1/2 Ka and t1/2 Ke), mean absorbance time
      (MAT), time to peak concentration (Tmax), mean residence time (MRT), area under
      the serum concentration time curve (AUC infinity) and the bioavailability (F)
      were significantly (P < 0.05) decreased. The peak serum concentration (Cmax),
      however, remained unchanged after infection. These changes may necessitate
      alterations in the dosage regimen of oxytetracycline used to treat Theileria
      annulata infections in cattle under field conditions.

PMID- 10597537
TI  - Influence of platelet activating factor on gastrointestinal electrical activity
      and some haematological and clinical parameters in the conscious miniature pig.
AB  - The effects of intravenous (i.v.) infusion of platelet-activating factor (PAF),
      100 ng/kg/min for 10 min, with and without pretreatment with a selective PAF
      antagonist on gastrointestinal electrical activity, arterial pressure and
      clinical and haematological parameters were studied. Conscious miniature pigs
      with electrodes implanted in the wall of the antrum pylori and small and large
      intestine were used. Platelet-activating factor induced restlessness or
      depression, shivering, tachypnoea and coughing, retching and vomiting,
      hypotension and a delayed and sustained increase in leucocyte count with an
      increase in percentage of segmented neutrophils. The PAF-antagonist, SAH 63-675,
      administered at 10 mg/kg intravenously, inhibited these effects. Platelet
      activating factor resulted in a decrease in electrical activity in the antrum and
      large intestine, whereas small intestinal activity was not significantly
      influenced. Pretreatment with the antagonist suppressed these inhibitory effects.

PMID- 10597538
TI  - The confirmation and control of metabolic caffeine in standardbred horses after
      administration of theophylline.
AB  - The origin of caffeine detections in equine serum and urine after theophylline
      administrations was examined. Three different preparations containing
      theophylline were administered to standardbred mares. Both blood and urine
      samples were collected. Caffeine was detected and quantified in theophylline
      administration samples by high performance liquid chromatography (HPLC) and
      liquid chromatography-tandem mass spectrometry (LC-MS-MS). Further in vitro
      analysis showed that caffeine metabolites were not detected when caffeine, or
      caffeine-containing products, were added to urine. Data derived from HPLC-UV and
      LC-MS-MS analysis of dosages of theophylline and caffeine are used to propose the
      establishment of a threshold limit to control and discern between metabolic and
      administered caffeine concentrations. A serum caffeine concentration of 250 ng/mL
      and a urine caffeine concentration of 1000 ng/mL are suggested. Based on the data
      supplied, these threshold concentrations could effectively control orally
      administered caffeine in racehorses, up to the dosage used in this work, up to 72
      h before sampling time.

PMID- 10597539
TI  - Tolerability of orally administered enrofloxacin in adult horses: a pilot study.

PMID- 10597540
TI  - Atypical attachment in infancy and early childhood among children at
      developmental risk. I. Atypical patterns of early attachment: theory, research,
      and current directions.

PMID- 10597541
TI  - Atypical attachment in infancy and early childhood among children at
      developmental risk. II. Neurological aspects of the disorganized/disoriented
      attachment classification system: differentiating quality of the attachment
      relationship from neurological impairment.

PMID- 10597542
TI  - Atypical attachment in infancy and early childhood among children at
      developmental risk. III. Maternal sensitivity, child functional level, and
      attachment in Down syndrome.

PMID- 10597543
TI  - Atypical attachment in infancy and early childhood among children at
      developmental risk. IV. Maternal frightened, frightening, or atypical behavior
      and disorganized infant attachment patterns.

PMID- 10597544
TI  - Atypical attachment in infancy and early childhood among children at
      developmental risk. V. Maltreatment, negative expressivity, and the development
      of type D attachments from 12 to 24 months of age.

PMID- 10597545
TI  - Atypical attachment in infancy and early childhood among children at
      developmental risk. VI. Stability and change in infant attachment in a low-income
      sample.

PMID- 10597546
TI  - Atypical attachment in infancy and early childhood among children at
      developmental risk. VII. Danger and development: the organization of self
      protective strategies.

PMID- 10597547
TI  - Atypical attachment in infancy and early childhood among children at development
      risk. VIII. Atypical patterns of early attachment: discussion and future
      directions.

PMID- 10597548
TI  - Is paediatric research an ethical dilemma?

PMID- 10597549
TI  - Venous thromboembolism in paediatric practice.

PMID- 10597550
TI  - Sevoflurane versus propofol for induction and maintenance of anaesthesia with the
      laryngeal mask airway in children.
AB  - We compared patient outcomes for propofol vs sevoflurane with the laryngeal mask
      airway (LMA) using either spontaneous breathing (SB) or pressure controlled
      ventilation (PCV). One hundred and twenty children undergoing minor surgery below
      the umbilicus were randomly assigned to receive either (1) propofol 3 mg.kg-1
      followed by a maintenance infusion of 5 mg.kg-1.h-1, or (2) induction with
      sevoflurane 7% followed by maintenance with 1.7%. Following LMA insertion,
      patients were given atracurium and underwent PCV if surgery was expected to last
      > or = 30 min. The following assessments were made: time to LMA
      insertion/removal, airway problems, cardiorespiratory effects and recovery
      characteristics. The first time insertion success rates were similar, but
      insertion time was shorter with sevoflurane (115 +/- 67 s vs 252 +/- 107 s, P <
      0.0001). One patient coughed during placement, but there were no other problems
      during any phase of anaesthesia in any group. Heart rate was higher in the
      sevoflurane group following insertion, during maintenance and emergence (all P <
      0.03). There were no differences in blood pressure and oxygen saturation among
      groups PECO2 in the SB group was unaffected by the agent used. Emergence was more
      rapid (232 +/- 104 s vs 348 +/- 127 s, P < 0.0001) and postoperative agitation
      more common (15% vs 0%, P = 0.02) with sevoflurane. There were no differences in
      the Aldrete scores among groups. Patient outcome was similar for the SB and PCV
      groups. We concluded that the techniques described here using propofol and
      sevoflurane are equally suitable for induction and maintenance of anaesthesia
      with the LMA in children undergoing minor surgery below the umbilicus. Emergence
      is more rapid, but postoperative agitation more common with sevoflurane.

PMID- 10597551
TI  - Alfentanil for intubation under halothane anaesthesia in children.
AB  - Intubating conditions under halothane anaesthesia aided with alfentanil 20
      micrograms.kg-1 were compared with suxamethonium 2 mg.kg-1 in 40 children
      presenting for day dental procedures. The condition of vocal cords, jaw
      relaxation and presence of movement and coughing were scored to give the overall
      intubating conditions. Successful intubation was achieved in 100% of the
      suxamethonium group and 94.7% of the alfentanil group. The cardiovascular
      response to intubation was attenuated in the alfentanil group. Some 43.7% of
      those receiving suxamethonium developed myalgia the day after surgery compared
      with 0% in the alfentanil group (P < 0.01).

PMID- 10597552
TI  - Propofol-nitrous oxide versus sevoflurane-nitrous oxide for strabismus surgery in
      children.
AB  - Vomiting is a common problem following strabismus surgery. We compared the
      effects of propofol-N2O and sevoflurane-N2O on the incidence of oculocardiac
      reflex and postoperative nausea and vomiting. Forty unpremedicated children, aged
      3-15 years were randomly assigned to two groups of 20 patients. In group 1,
      anaesthesia was induced and maintained with propofol infusion (173 +/- 41
      micrograms.kg-1.min-1). In group 2, anaesthesia was induced with N2O (66%) in O2
      and incremental sevoflurane via face mask and maintained with sevoflurane. Both
      groups received 66% N2O in O2 throughout surgery. The overall incidence of
      vomiting and antiemetic requirement in the first 24 h was significantly higher in
      sevoflurane-N2O group than propofol-N2O group (P < 0.05). The propofol-N2O group
      had significantly more episodes of oculocardiac reflex than sevoflurane-N2O group
      (P < 0.05). Propofol-N2O anaesthesia results in a significantly lower incidence
      of postoperative vomiting, yet a significantly higher incidence of oculocardiac
      reflex.

PMID- 10597553
TI  - Central venous catheter placement in children: evaluation of electrocardiography
      using J-wire.
AB  - Misplacement of a central venous catheter may lead to myocardial perforation and
      dysrhythmia. Atrial electrocardiography (ECG) through a saline column is an
      effective but complex method to determine the accurate location of catheters. We
      evaluated a simplified variant of this technique using the guidewire as an
      internal electrode in 23 children (5-16 years old) undergoing spinal surgery.
      Catheters were placed using a Seldinger technique after jugular or subclavian
      venous puncture. Each time the operator recognized the atrial signal, the
      catheter was found to be correctly placed on the chest radiograph (20/23). In
      three patients, the atrial signal was not obtained. A technical error was
      responsible in one case whereas the two others were related to aberrant
      migrations of the catheter either into a subclavian vein or into the pleura. In
      this latter case, the complication was unrecognized on the first radiograph
      despite malposition having been predicted by atrial ECG. We conclude that a
      method using atrial ECG guidance is sensitive and specific, and may be an
      alternative to the classical chest radiograph to detect accurate placement of
      central venous catheters in children.

PMID- 10597555
TI  - Laryngeal mask airway use in children with acute burns: intraoperative airway
      management.
AB  - Paediatric patients with acute burns often require many operative procedures in
      short succession; yet due to inhalation injury or recent extubation their airways
      may be susceptible to tracheal tube induced damage. We proposed the laryngeal
      mask airway (LMA) as a useful airway management tool in this setting. In this
      prospective study, 80 eight (88) patients with mean age (+/- SD) of 7.8 +/- 4.7
      years and average percentage total body surface area burned (%TBSA) of 21 +/- 18%
      had their airways managed with an LMA while in the operating room for 141
      procedures. Twenty-five patients (28.4%) had been previously intubated for burn
      management and 19 (21.6%) had evidence of inhalation injury. During each
      procedure, the patient was evaluated for airway obstruction, laryngospasm,
      inability to ventilate, hypoxaemia, evidence of aspiration/regurgitation or any
      situation which required intraoperative manipulation/removal of the LMA. Of the
      141 procedures, 122 were without airway problems. Of the remaining 19, nine
      required only a simple reseating of the LMA for correction. The other 10 events
      include arterial desaturation (n = 3), partial laryngospasm (5), airway
      obstruction (1) and regurgitation without aspiration (1). In each case,
      corrective action led to resolution of the problem with no patient morbidity.
      This series demonstrates the LMA is a safe and efficacious airway management
      device in the paediatric burn population.

PMID- 10597554
TI  - Oliguria during corrective spinal surgery for idiopathic scoliosis: the role of
      antidiuretic hormone.
AB  - Patients undergoing surgery for idiopathic scoliosis were studied to determine
      the incidence and aetiology of oliguria during the perioperative period and to
      evaluate the efficacy of low dose dopamine in preventing its occurrence. Thirty
      patients, aged 6-18 years undergoing elective surgery were studied. Anaesthesia
      was standardized. Patients were randomized to receive either dopamine infusion (3
      micrograms.kg-1.min-1) (Group A) (n = 15) or dextrose infusion (control) (Group
      B) (n = 15). Serum and urinary electrolytes and osmolalities and serum
      antidiuretic hormone (ADH) concentrations were measured. Urine output and
      haemodynamic parameters were recorded. Intraoperative oliguria occurred in 7% of
      patients in Group A and 47% in Group B (P < 0.05). Postoperative oliguria
      occurred in 20% of patients in Group A and 47% in Group B (P > 0.05). Urine and
      serum biochemical analysis revealed a statistically significant decrease in serum
      sodium and osmolality (P < 0.005) and an increase in urinary sodium and
      osmolality in both groups. Serum ADH concentrations were increased in both groups
      (P < 0.05), returning to baseline 18 h postoperatively. We conclude that oliguria
      during corrective spinal surgery occurs in association with excess ADH secretion
      as opposed to perioperative hypovolaemia. Dopamine increases urine output in the
      perioperative period but does not prevent the release of ADH and its subsequent
      biochemical effects.

PMID- 10597556
TI  - Incidence of nausea and vomiting in children after strabismus surgery following
      desflurane anaesthesia.
AB  - In a prospective, randomized parallel study, 60 ASA I-III children aged 1-17
      years, scheduled for elective strabismus surgery, were anaesthetized with
      desflurane without prophylactic antiemetic medication. The objective of the study
      was to determine the incidence of postoperative nausea and vomiting after general
      anaesthesia with desflurane. To decide whether nitrous oxide further influences
      these symptoms, the patients were randomly assigned to two groups of 30 patients
      each. One group received desflurane in oxygen/air and a second group received
      desflurane in oxygen/nitrous oxide. In all children, after intravenous induction
      and tracheal intubation, anaesthesia was administered as minimal flow anaesthesia
      with oxygen and nitrous oxide or air according to the random plan. The patients
      were observed for 48 postoperative hours until their discharge from the ward. The
      overall incidence of nausea was found to be 37%, and vomiting was seen in 32% of
      all patients. No statistical correlation was found between the incidence of
      postoperative emesis and the administration of nitrous oxide or the duration of
      general anaesthesia. Instead, the incidence of vomiting was 2.5-fold higher when
      surgery was performed on both eyes compared with one eye. The relatively low
      incidence of postoperative nausea and vomiting, as well as the quick recovery
      from anaesthesia, permitting an early discharge from the postoperative care unit
      to the ward, show desflurane to be a suitable volatile anaesthetic in strabismus
      surgery in children.

PMID- 10597557
TI  - Prevention of postoperative vomiting with granisetron in paediatric patients with
      and without a history of motion sickness.
AB  - A history of motion sickness is one of the patient-related factors associated
      with postoperative emesis. This prospective, randomized, double-blind, placebo
      controlled study was undertaken to assess the efficacy of granisetron, a
      selective 5-hydroxytryptamine type 3 receptor antagonist, for preventing
      postoperative vomiting after tonsillectomy in 120 children with (n = 60) and
      without (n = 60) a history of motion sickness. Patients received a single dose of
      granisetron (40 micrograms.kg-1) or placebo (saline) (n = 30 of each)
      intravenously after an inhalation induction of anaesthesia. A complete response,
      defined as no vomiting, no retching and no need for another rescue medication,
      during the first 24 h after anaesthesia was 77% and 13% in patients with a
      history of motion sickness who had received granisetron or placebo, respectively;
      the corresponding incidence was 83% and 40% in those without it (P < 0.05; chi 2
      test with Yates' continuity correction). No clinically serious adverse effects
      due to the study drug were observed in any of the groups. In conclusion,
      prophylactic antiemetic therapy with granisetron is effective for preventing
      postoperative emesis in children with a history of motion sickness as well as in
      those without it.

PMID- 10597558
TI  - Localized tracheomalacia as a complication of the Cole tracheal tube.
AB  - The Cole tracheal tube is designed for use in neonates. Subglottic stenosis is a
      recognized complication of prolonged use of the tube. We report a case of
      tracheomalacia as a further complication of prolonged use of the tube. A 4-month
      old infant with a history of repeated failed extubation and multiple medical
      problems was found to have an unusual region of severe inspiratory collapse
      localized to the upper 1 cm of the trachea. This was felt to be the result of
      pressure from the shoulder of the Cole tube which had been used for prolonged
      intubation. A tracheostomy was performed to bypass the collapse, but the infant
      subsequently died due to other medical problems.

PMID- 10597560
TI  - Guillain-Barre syndrome: delayed diagnosis following anaesthesia.
AB  - Guillain-Barre syndrome following anaesthesia or surgery is rare. Diagnosis is
      often delayed, which may lead to an increase in morbidity. There is now good
      evidence that early diagnosis and treatment reduces this morbidity. The two cases
      highlight the difficulties with diagnosis in the perioperative period and further
      discuss the aetiology, diagnostic features and complications of childhood
      Guillain-Barre syndrome.

PMID- 10597559
TI  - Anaesthetic management of a patient with adrenocortical tumour.
AB  - Adrenocortical tumours in children are rare. They produce many changes in
      haemodynamics and blood chemistry due to hormones of the adrenal cortex. The
      details of perioperative management and the need for perioperative steroid
      supplementation are discussed.

PMID- 10597561
TI  - Unintentional paediatric subdural catheter with oculomotor and abducens nerve
      palsies.
AB  - A 13-year-old female with a past history of lumbar laminectomy developed a
      subdural block 18 h after the commencement of an epidural infusion of bupivacaine
      0.125% and fentanyl 2 micrograms.ml-1. Signs at presentation included bilateral
      abducens nerve palsies in the absence of headache and a previously unreported
      unilateral third cranial nerve palsy. An epidurogram displayed subdural
      placement.

PMID- 10597562
TI  - Acute epiglottitis despite vaccination with haemophilus influenzae type B
      vaccine.
AB  - We present the case of a 20-month-old child who required admission to the
      intensive care with a presumptive diagnosis of acute laryngo-tracheo-bronchitis,
      for the management of acute upper airway obstruction. This child had received a
      complete course of Haemophilus influenzae type B (Hib) vaccine. Subsequent events
      showed that the diagnosis was not laryngo-tracheo-bronchitis but acute
      epiglottitis. We propose that a full course of vaccination is no guarantee
      against a subsequent illness with Hib and may actually lead to the wrong
      diagnosis and possibly life-threatening consequences.

PMID- 10597563
TI  - Postoperative hyponatraemic encephalopathy following elective surgery in
      children.

PMID- 10597564
TI  - Intraoperative QRS-interval changes.

PMID- 10597565
TI  - Use of the laryngeal mask airway during repair of atrial septal defect in
      children.

PMID- 10597566
TI  - Use of the laryngeal mask airway during repair of atrial septal defect in
      children.

PMID- 10597567
TI  - Localized adverse skin reactions to topical anaesthetics.

PMID- 10597568
TI  - Bronchoscopy technique.

PMID- 10597569
TI  - Source memory in Parkinson's disease.
AB  - Three experiments (ns = 14 per group) are reported which investigated the ability
      of Parkinson patients to remember the characteristics of conditions under which a
      memory was acquired. In Exp. 1, subjects were required to indicate for each item
      in a recognition memory test whether it was spoken by Experimenter 1 or by
      Experimenter 2 (external-external source memory). In Exp. 2, subjects had to
      indicate for each item whether it was generated by themselves or by the
      experimenter (internal-external source memory). In Exp. 3, subjects had to judge
      whether an item was generated by themselves in saying or in thinking (internal
      internal source memory). We found that patients with Parkinson's disease were not
      impaired in the previous two kinds of source memory (Exp. 1 and 2) but were
      impaired in internal-internal source memory (Exp. 3) relative to the age-matched
      control groups. In addition, both groups' performance could be improved when
      given distinctive cues, i.e., perceptual cues in Exp. 1 and different-domain cues
      in Exp. 2. These results suggest that the availability of cues was critical for
      Parkinson's disease in source memory. Finally, the result of Exp. 2 also showed
      generation effects for patients with Parkinson's disease. The generation effect
      refers to better memory of information by people when they had to produce it,
      e.g., producing associates to a word, compared with memory of information given
      to them.

PMID- 10597570
TI  - A linear relationship between postnatal geomagnetic activity and self-reports of
      epileptic seizures in young adults.
AB  - To test the hypothesis of a linear relationship between the intensity of
      geomagnetic activity during the first two days after birth and the development of
      epilepsy, the responses of the item "I have had an epileptic seizure" was
      obtained from the Personal Philosophy Inventories of 1,453 students who had been
      enrolled in first-year psychology courses over a 13-yr. period. The only
      statistically significant effect was linear and was between the successive 10 nT
      (nanoTesla) increments of the intensity of geomagnetic activity during the two
      days after birth and the percentage of students who reported epileptic seizures.
      The percentage of subjects reporting a history of seizures ranged from 1% for
      those born when the activity was less than 10 nT to 4% for those born when this
      activity exceeded 40 nT.

PMID- 10597571
TI  - Hand preference as related to development and behavior in infancy.
AB  - 55 healthy infants were assessed for their developmental and behavioral patterns
      at the age of 9 mo. Hand preference was assessed at 20 mo. of age. The
      distribution of hand preference showed 12 were right-handed, 11 left-handed and
      23 ambidextrous. This distribution appears shifted more to the left than that
      reported for older children. Although their data were based on different tests
      not appropriate for 9-mo.-old infants, ambidexterity appeared to reflect part of
      the hand-preference continuum. No significant relationship between hand
      preference and developmental attainments was noted. Perhaps a larger sample would
      provide a clear developmental behavioral pattern and hand preference in infancy.

PMID- 10597572
TI  - Association of birthdate with success of nationally ranked junior tennis players
      in the United States.
AB  - The objective was to assess the effect of birthdate on successful performance in
      tennis by junior tennis players in the United States and to address the question
      of whether "birthdate effect" persisted with ongoing age toward adulthood. The
      national rankings and birthdates of junior tennis players in each age division
      were obtained from the United States Tennis Association. The number of male and
      female junior tennis players ranked within the top 100 in their respective age
      divisions with birthdates in the first half of the year were counted and compared
      with the number of junior athletes born in the second half of the year. A
      significant chi squared for birthdate by success in tennis was present in the 14
      years and under and 16 years and under age divisions for boys. This effect was
      less for older ages. Among girls, the effect of birthdate on tennis ranking was
      not significant in any age group. Among male junior tennis players in the 14
      years and under and 16 years and under age divisions, athletes born in the first
      half of the year had an advantage over those born in the second half, but not for
      girls.

PMID- 10597573
TI  - Sustained attention and related perceptuomotor functions.
AB  - The present study examined the relationship between two measures of sustained
      attention on the Continuous Performance Test (reaction time and omission errors)
      and several performance measures on neuropsychological tests. Analysis suggests
      that sustained attention as measured by processing speed predicts performance on
      neuropsychological measures of relatively greater complexity and that the Stroop
      test, which requires maintaining steady focus on a changing stimulus field, may
      be more sensitive to lapses in attention than other neuropsychological tests.

PMID- 10597574
TI  - Neuropsychological correlates of violence and aggression: an extension to
      suicidal behavior.
AB  - This paper presents evidence that neuropsychological syndromes which characterize
      some externally violent people may also explain some suicidal behavior,
      particularly in adolescents and those who repeat their suicidal behavior.

PMID- 10597575
TI  - Relation between self-paced and synchronized movement in persons with mental
      retardation.
AB  - The relation between self-paced and synchronized tapping in 64 persons with
      mental retardation whose mental ages ranged from 2 to 11 years and chronological
      ages from 13 to 23 years was investigated. In a self-paced tapping task no
      stimulus was presented, and subjects' easy and spontaneous tapping was measured.
      In a synchronized tapping task their synchronous tapping with an auditory
      stimulus present at a quick or slow tempo was measured. Under both tempo
      conditions, the lower the subjects' mental age, the larger the errors in the
      intertap interval they made. The subjects of low mental age showed significantly
      larger errors in the intertap interval in the Slow than in the Quick Tempo
      condition and tended to tap at a rate near the self-paced tapping. These results
      may suggest that ability to adjust one's self pace is one of the key factors in
      the development of motor synchronization in persons with mental retardation.

PMID- 10597576
TI  - EEG correlates of behavioural laterality: right-handedness.
AB  - Among right-handers, the magnitude of differences in proficiency between the left
      and right hands varies considerably. Yet significance of the extent of right
      handedness is still a controversial issue. To examine whether individual
      differences in asymmetry of hand skill can partly be attributed to individual
      differences in asymmetrical hemispheric activation, handedness and
      electroencephalographic (EEG) laterality were correlated in two large samples (ns
      = 60 and 128). Analysis indicated that part of the variability in right
      handedness may arise from activation asymmetries in the cortex, but whether this
      relation becomes apparent depends on the cortical area examined and on the
      experimental condition under which the EEG measures are taken.

PMID- 10597577
TI  - Are European and American golf players different? Reply to Engelhardt (1997).
AB  - Analysis of 1998 statistics for individual performance in the PGA European Tour
      yielded significant differences between some shot-making skills (drive distance,
      total driving, greens in regulation, and sand saves) between the top 10 and
      bottom 10 money winners, replicating (with partially different results) a result
      found for the 1995 American PGA Tour by Engelhardt.

PMID- 10597578
TI  - The type A behavior pattern and immune reactivity to brief stress: change of
      volume of secretory immunoglobulin A in saliva.
AB  - This article presents findings of a laboratory experiment on the association of
      the Type A behavior pattern with reactivity of secretory immune functioning to
      brief stress. 38 female undergraduate students classified as Type A (n = 19) or
      as Type B (n = 19) on the basis of their scores on the Kwansei Gakuin Type A
      scale performed a continuous arithmetic task in a situation in which they were
      exposed to aversive loud noise. Secretory immunoglobulin A (s-IgA) in saliva and
      autonomic measures (heart rate and frequency of eyeblink) were evaluated before
      and after the manipulation of stress. The volume of s-IgA at baseline was
      significantly higher for the Type A group than for the Type B group, suggesting
      that the former relative to the latter might be chronically higher in mucosal
      immune functioning. Also, the volume of s-IgA significantly increased after
      exposure to a brief stress for the Type B group but did not change for the Type A
      group, a finding which might indicate that the Type A group may have less immune
      reactivity to a brief stress.

PMID- 10597579
TI  - The relationship between collective efficacy and precompetitive affect in rugby
      players: testing Bandura's model of collective efficacy.
AB  - This study extended research examining Bandura's (1997) proposed model of
      collective efficacy. Specifically, it examined the relationships between groups'
      collective efficacy and the precompetitive anxiety and affect they experienced.
      Prior to a competitive match 66 male Rugby Union footballers from 6 teams (2
      university teams and 4 county league teams) completed a single-item measure of
      confidence in their team winning the forthcoming match, a 10-item measure of
      confidence in their team performing well in the forthcoming match, the modified
      Competitive State Anxiety Inventory-2, and the Positive and Negative Affect
      Schedule. Stepwise (forward) multiple regression analyses indicated that scores
      for collective efficacy accounted for only 6.3% of the variance in the
      intensities of cognitive state anxiety and only 22% of the variance in the
      positive affect experienced prior to the rugby match. The results indicate that
      concerns with the team's ability to win a match were associated with high
      cognitive state anxiety and that doubts regarding the team's ability to perform
      well were related to low positive affect. Given the magnitude of predicted
      variances, the findings seem to give some support to Bandura's proposal that the
      beliefs in collective efficacy of individuals engaged in a team task are related
      to precompetitive affective reactions and the experience of state anxiety.

PMID- 10597580
TI  - Cognitive influence on motor control in reaching.
AB  - The purpose of this study was to assess the effects of objects with different
      attributes on motor control in the act of reaching for them. Much about reaching
      has been studied from the point of view of spatial relations between objects and
      subjects, and kinematic approaches have played an important role in this field.
      Recently, some researchers have proposed that factors other than spatial
      relations characterize reaching. Therefore, we focused on reaching for an empty
      glass (empty condition) and a water-filled glass (filled condition) where the
      positions of the glasses were the same to examine the importance of the objects
      when reaching for them. Eight young adults participated. We translated the
      position of the index finger into X-Y-Z coordinate values and examined movement
      time, length of trajectory, and velocity between the empty and filled conditions.
      It took longer to reach for an empty than a filled glass, and the filled
      condition showed a longer trajectory and slower velocity than the empty
      condition. This indicated that objects with different attributes influenced the
      reaching and that the role of cognition of attributes is important in the act of
      reaching.

PMID- 10597581
TI  - Selective attention in perceptual adjustments to voice.
AB  - The effects of perceptual adjustments to voice information on the perception of
      isolated spoken words were examined. In two experiments, spoken target words were
      preceded or followed within a trial by a neutral word spoken in the same voice or
      in a different voice as the target. Over-all, words were reproduced more
      accurately on trials on which the voice of the neutral word matched the voice of
      the spoken target word, suggesting that perceptual adjustments to voice interfere
      with word processing. This result, however, was mediated by selective attention
      to voice. The results provide further evidence of a close processing relationship
      between perceptual adjustments to voice and spoken word recognition.

PMID- 10597582
TI  - Physique and personality in kindergarten children.
AB  - Ectomorphy scores were not associated with cerebrotonia scores in a sample of 105
      kindergarten children.

PMID- 10597583
TI  - Preferences for body type and body characteristics associated with attractive and
      unattractive bodies: Jackson and McGill revisited.
AB  - The present investigation replicates Jackson and McGill's study (1996) and
      extends it by considering the effects of respondents' own height, weight, and
      body mass on perceptions of attractiveness. Results, although generally
      supportive of those found by Jackson and McGill, point to the influence of
      respondents' own physical characteristics in the process of perceptions of
      attractiveness: only 1 of Jackson and McGill's 3 (of a possible 19) differences
      between responses of African- and Euro-American women was corroborated (the
      importance of silky hair for Euro-American women), whereas a second difference
      (the importance of round buttocks for African-American women) disappeared when
      controlling for respondents' weight, height, and body mass. Although differences
      between the two investigations may be attributed to regional differences in the
      surveyed students (Michigan and North Carolina), the small effect of one's own
      weight, height, and body mass in assessing an other-sex person's attractiveness
      may reflect adherence to norms learned very early in life that are subject to
      regional variations.

PMID- 10597584
TI  - Image control from childhood to adolescence.
AB  - Despite the recognized importance of imagery use by children as well as the
      developmental relevance for maturity and health of imagery properties such as
      vividness and control, only a few studies have investigated imagery of children.
      The aim of the present study was to examine the development of control of mental
      images in a sample of boys and girls aged 7 to 17 years. Children were assessed
      on two aspects of mental imagery, vividness and control, and teachers were asked
      to rate the children's intellectual and socioemotional performance. Analysis
      showed that the capacity for image control increased in adolescence and that
      children characterized by vivid and uncontrolled imagery received the lowest
      ratings from teachers, whereas those with nonvivid and controlled imagery
      received the highest ratings. The implications of these results were discussed in
      relation to normal and abnormal development as well as suggestions for research.

PMID- 10597585
TI  - Facilitation of seizures in limbic epileptic rats by complex 1 microTesla
      magnetic fields.
AB  - On three separate sessions 24 male rats with histories of limbic epilepsy were
      exposed to 10 temporal configurations for 5 min. each of one of two patterns of
      magnetic fields. Their intensities averaged about 1 microTesla (microT). The
      numbers of Level 5 (Racine) seizures, inferred by the rat's rearing, rapid
      forelimb clonus, and falling, were statistically more frequent for the frequency
      modulated (Thomas) pattern when its pixel duration and interstimulus presentation
      were 3 msec. The effectiveness of this temporal configuration was replicated in a
      second within-subjects experiment (n = 9) that directly compared the numbers of
      seizures during exposures to each of the two patterns and to a sham-field. These
      results suggest that brains with sensitive limbic systems might respond to weak
      magnetic fields, generated from multiple overlapping fields from communication
      and computer systems whose temporal derivatives emerge as complex sequences with
      pixel durations within the millisecond range.

PMID- 10597586
TI  - Effect of "group spell" upon Shotokan black-belt performance of Heian kata.
AB  - 11 experienced black-belt subjects were individually timed on each of the five
      Heian kata and then timed again when performing as part of a group. The pull of
      the group had a significant effect upon timing on two of the kata.

PMID- 10597587
TI  - Ecological relevance of stereopsis in one-handed ball-catching.
AB  - The aim of this study was to compare one-handed catching performance between
      catchers with high (n = 10) and low (n = 10) binocular depth vision or
      stereopsis. In two sessions of 90 trials, tennis balls were projected at three
      different velocities towards the subject's shoulder region. Participants with
      good stereopsis were more successful, although the difference in number of
      correct catches fell short of significance. More specifically, catchers with low
      stereopsis made more temporal errors, but no differences in spatial errors. As
      the velocity of the ball increased, the initiation of the catch was delayed and
      catching performance decreased. The finding that stereopsis affected timing of
      the catch challenges the 'monocular tau hypothesis' in the control of
      interceptive timing, while the velocity effect shows that the act of catching a
      ball is not initiated at a constant time-to-contact.

PMID- 10597588
TI  - Perception of the form of stimulus increment as a method in assessment of the
      psychophysical relationship.
AB  - Among numerous procedures for determination of the psychophysical relation, one
      approach has seldom been applied. Essential in this method is to present a set of
      stimuli whose intensity increases in fixed time following different forms. The
      objective stimulus increment, which the subjects perceive as linear growth
      directly, represents the inverse psychophysical relation. In this paper the
      method was tested in the fields of click frequency and sound pressure. This
      procedure was named "Perception of the Form of Stimulus Increment in Time". In
      comparison to other psychophysical approaches, this one has several advantages.
      The principal ones are the following: (1) In assessing the psychophysical
      relation it is not necessary to try to measure the perceptual magnitude; and (2)
      the psychophysical relation is directly determined by its dynamic pattern. In
      this paper modifications to the method are reported which facilitate the
      subject's task and avoid some differences in subjects' individual approaches to
      the task. The modified procedure leads to results satisfactory independent of the
      influence of the factors irrelevant to the psychophysical relationship.

PMID- 10597589
TI  - "Blue and seven phenomena" among Japanese students.
AB  - To investigate color and number preferences in Japan, 586 university
      undergraduates (239 men and 347 women; M age = 20.9 yr.) were asked to name a
      color (Question 1), to name their preferred color (Question 2), and to name their
      preferred number between zero and nine (Question 3). The results showed that
      Japanese students chose blue (33.5%) or red (26.0%) when asked to name a color
      but that red was not chosen as frequently as blue as a preferred color (red:
      11.1%, blue: 37.1%). Sex differences were found on both Questions 1 and 2 by chi
      squared test. Black was chosen more by men, while pink was selected more by
      women. 22.5% subjects also selected the number seven, supporting Simon's
      observation of the "blue-seven phenomenon." The reasons given for the choice
      showed that seven was "a lucky number" and "represented happiness" among Japanese
      students. Four colors (blue, red, white, and black) accounted for 76.8% and 65.1%
      of responses to Questions 1 and 2, respectively, and odd numbers 68.4% for
      Question 3.

PMID- 10597590
TI  - Men and women holding hands: II. Whose hand is uppermost?
AB  - Sex differences in the way men and women hold hands were investigated in a series
      of six studies. Specifically, it was hypothesized that men would have the
      uppermost hand in male-female couples holding hands in public significantly more
      often than women. Also, the American couples observed in Study 1 were classified
      by height, those in Study 2 by age, those in Study 3 by hand preference, those in
      Study 4 by ethnic group, and those in Study 6 by sex of initiator of the
      handholding; the handholding couples in Study 5 were Japanese adults. A combined
      total of 15,008 handholding couples were observed in these six studies, and
      across differences in height, age, hand preference, ethnicity, culture, and sex
      of the initiator of handholding in public, men were significantly more likely
      than women to have the uppermost hand.

PMID- 10597591
TI  - Measurement of range of motion in individuals with mental retardation and with or
      without Down syndrome.
AB  - The purpose of this study was to assess differences in variability of three
      joints' range of motion in the lower extremity among individuals with Down
      syndrome, mentally retarded individuals without Down syndrome, and sedentary
      subjects without mental retardation (ns = 13, 25, and 30, respectively). Range of
      motion for hip and knee flexion was obtained using a Myrin goniometer. For hip
      abduction the range of motion was obtained using a double protractor goniometer
      (Brodin type). Three test repetitions were carried out, and the greatest value
      was recorded. As no significant differences were found between left and right
      sides for each motion, the average was used to represent the range of motion. The
      Down syndrome group had significantly higher mean range of motion in hip flexion
      than the mentally retarded group. No significant differences in mean range of
      motion were found between Down syndrome and sedentary groups, but a significant
      difference was observed between the control and mentally retarded groups. In hip
      abduction, the Down syndrome group showed significantly higher mean range of
      motion than the control and mentally retarded groups. The control group had
      significantly a higher mean range of motion than the mentally retarded group. No
      significant differences were found in knee flexion between the two mentally
      disabled groups, but significant differences in mean range of motion were found
      between each of the two groups of mentally retarded individuals and the control
      group. Because differences exist in mean range of motion between the two mentally
      disabled groups, individualized and differentiated training programs to improve
      flexibility must be designed based on the type of handicap.

PMID- 10597592
TI  - Response differentiation to facial expression of emotion as increasing exposure
      duration.
AB  - This study investigated whether the underlying structure of responses to facial
      expressions of emotion would emerge when the exposure time was increased. 25
      participants judged facial photographs presented for varying durations of
      exposure, ranging from 4 msec. to 64 msec. in 4-msec. steps. A dual scaling
      method was carried out to analyze possible response differentiation as a function
      of exposure time. Two major components were extracted. Based on the configuration
      of variables they were interpreted as valence (hedonic tone) and activation.
      Results indicated that a positive emotion and a highly activated emotion such as
      surprise and fear were easily recognized under a relatively brief exposure to the
      stimuli.

PMID- 10597593
TI  - Motion direction distribution as a determinant of circular vection.
AB  - Visually induced self-translation is called linear vection, while visually
      induced self-rotation is called circular vection. Impressions of circular vection
      and linear vection were measured using flow patterns presented on a flat screen.
      Subjects reported strong circular vection when the flow simulated a projected
      pattern of a rotating cylinder, which had gradients in speed and direction of
      moving elements on the screen. When speed gradients in a horizontal dimension
      were removed while not changing the direction distribution on the screen, strong
      circular vection was still reported. On the other hand, when the motion direction
      of all elements was the same (horizontal), having speed gradients, the circular
      vection was weak. The impression of linear vection showed the opposite trend.
      This result indicates not a speed distribution pattern but one of a two
      dimensional direction on the retina determines the type of vection.

PMID- 10597594
TI  - Shadows as sources of cues for distance of shadow-casting objects.
AB  - Shadows are neglected sources of information about shadow-casting objects'
      distance (location). In an experiment using real shadows, participants judged the
      distance of two rods, either with shadows (illumination from the left) or without
      shadows. Without shadows, a thin rod raised slightly above the surface was
      incorrectly judged to be more distant than a thick rod, but with shadows the thin
      rod was accurately judged to be closer. For judgments to be correct, shadows had
      to overwhelm competing height and stimulus-size cues. Exp. II involved
      nonoverlapping shadows produced by a light placed in front of the rods. Again,
      without shadows the thin-elevated rod was incorrectly judged to be more distant,
      but with shadows it was correctly judged to be closer. Exp. III involved two sets
      of thick and thin elevated rods and frontal lighting. Judgments were accurate
      when shadows were present but inaccurate when shadows were absent. Experiments
      conducted through the American Psychological Society Web-research site replicated
      results of Exp. I, II, and III. A final Web experiment replicated results of the
      others, but with shadows produced by illumination from the right. Three
      properties of shadows--angles, interposition, and positioning--are possible
      sources of distance information associated with cast shadows.

PMID- 10597595
TI  - Achromatic visual backward masking of colored stimuli as a function of age
      differences.
AB  - To test the hypothesis that accelerated aging factors may be responsible for
      previous findings of reduced performance by diabetics in a visual backward
      masking task with colored stimuli, we compared masking performances of observers
      from three age cohorts (20-, 40-, and 60-yr.-olds). Since masking performance
      declined in a very similar fashion for all colors with age, it was concluded that
      the differential color-performance decrements associated with diabetes cannot be
      attributed to visual processes associated with normal aging. The application of
      the Lagged Accrual Model showed that sensory transmission time increases and
      asymptotic performance decreases as a function of age. Suggestions for the
      normative use of the present data and for further research are discussed.

PMID- 10597596
TI  - Relationship between exercise professionals' behavioral styles and clients'
      adherence to exercise.
AB  - Exercise professionals (n = 15) were tested to assess whether specific personal
      traits or behavioral styles were associated with their clients' adherence to
      exercise. Assessments with the Personal Profile and the Personal Strengths
      Profile yielded one trait, "Controlling," that showed a mean difference (z =
      2.99, p < .01) between the high and low adherence groups of professionals.
      Controlling was also significantly correlated (rs = .66, p < .01) with clients'
      adherence. This trait may be consistent with the interpersonal delivery
      requirements of interventions known to support adherence to exercise. Limitations
      and practical implications across exercise venues and types of participants were
      discussed.

PMID- 10597597
TI  - Conceptualizing a better understanding of diagnosing and treating posttraumatic
      stress disorder: a review of two case studies.
AB  - Clinical and epidemiological studies have supported the belief that human beings
      exposed to stressful life events are vulnerable to the symptomatology consistent
      with posttraumatic stress disorder (PTSD). However, early detection of symptoms
      consistent with PTSD oftentimes does not occur within the medicolegal arena. The
      importance of an early and accurate diagnosis is emphasized. Fortunately, the
      diagnosis of PTSD has become more clearly conceptualized in the DSM-IV criteria.
      Many of the characteristics consistent with this diagnosis are measured through
      the use of relatively recently developed and refined psychometric measures
      including the Posttraumatic Stress Diagnostic Scale, the Trauma Symptom
      Inventory, and the Personality Assessment Inventory-2. Additional measures
      including the Computerized Response Bias Test, the Word Memory Test, and the
      Validity Indicator Profile can detect exaggeration of symptoms without using
      specific tests for symptom validity. These measures, as well as biochemical
      determinations, are reviewed and presented along with the over-all structured
      clinical interviews and mental status examinations of two patients for a better
      understanding of the multimethod approach which establishes the reliability of
      the PTSD diagnosis.

PMID- 10597598
TI  - Diurnal pattern of luminance discrimination in humans.
AB  - The visual discrimination threshold can be considered as an image of the
      resolution power of the visual system. Measured with a psychophysical method, it
      shows a diurnal pattern with a low threshold in the morning, i.e., high
      sensitivity and an increase in the afternoon that persists until the early
      evening.

PMID- 10597599
TI  - Discrepancies between standardized measures of cognitive level and Halstead
      Reitan impairment indices as inferences of brain damage following head injuries.
AB  - z scores for measures of intelligence, memory, educational achievement, and
      neuropsychological impairment were obtained for 193 patients who had sustained
      impacts of mechanical energy to their skulls. Two sets of normative data,
      adjusted for age and sex and not adjusted for these variables, were employed to
      compute indices of neurocognitive proficiency (the inverse of impairment). 80% or
      76 of the 96 patients whose Halstead-Reitan Indices were greater than 0.4
      displayed scores for neurocognitive proficiency that were two or more standard
      deviations below the averages of their scores for intelligence, memory, and
      educational achievement. None of the patents whose Impairment Indices were 0.4 or
      less displayed this discrepancy. There were no statistically significant
      differences between these two groups of patients with respect to the presence of
      unconsciousness following the injury or the duration of posttraumatic memory
      disruptions. The results indicate that quantitative scores for neuropsychological
      impairments are still the most accurate criteria to discern brain dysfunction
      within the mild to moderate range.

PMID- 10597600
TI  - Validity and reliability of visual ratings of the vertical jump.
AB  - The validity and reliability of visual estimates of the kinematics of the
      vertical jump as would be common in qualitative analysis of human movement was
      studied. Sagittal plane videotapes of 12 females performing vertical jumps were
      rated on two occasions by three samples of subjects: 6 basketball coaches, 10
      kinesiology students, and 5 kinesiology professors. Visual ratings were compared
      to values quantified by biomechanical analysis using the Peak Performance
      Technologies system. Assistant collegiate basketball coaches were unable to rate
      discrete body angles in the vertical jump accurately or consistently. Six of 10
      college student raters could accurately and consistently rate over-all range of
      motion. Since only one of the kinesiology professors could accurately and
      consistently rate range of motion compared to the majority of the students,
      professional experience did not affect the ability to rate range of motion in the
      vertical jump in these subjects.

PMID- 10597601
TI  - Analysis of factor structure in a dream inventory.
AB  - Intercorrelations of responses to the KJP dream inventory, initially a checklist
      of dream elements, were factor analyzed from a database from 65 graduate majors
      in psychology. Six factors were identified within the checklist: repetitive
      traumatic dreaming, reoccurring pleasantness, openness or depth,
      discontentedness, dissociative avoidance, and uninhibitedness. Scoring criteria
      were developed for each subscale.

PMID- 10597602
TI  - Spacing effects on the memory for faces.
AB  - 25 undergraduate women studied 12 stimulus pictures of female faces successively
      presented in spaced or massed conditions and made affective judgments for the
      pictures along a dimension of like to dislike. One week after the exposure
      (study) period, subjects were given an identification test comprised of
      photographs of the same female faces with different expressions. Analysis showed
      that the pictures presented in the spaced condition were more frequently and
      accurately identified than those presented under the massed condition and that
      affective judgment was unrelated to conditions of presentation.

PMID- 10597603
TI  - Performance of elderly and young normals on the Gollin Incomplete Pictures Test.
AB  - Our study compared 26 young and 28 elderly subjects on the Gollin Incomplete
      Pictures Test. Young and elderly subjects differed, the older group requiring
      less fragmentation and more time for identification; response accuracy and
      latency were not correlated with one another.

PMID- 10597604
TI  - Pattern of cortical activity, degree of synchronization, binocular fusion, and
      binocular rivalry.
AB  - The synchronization hypothesis is the likely idea for the binding problem in the
      brain. Here we tested whether the theory is applicable for the occurrence of
      either binocular fusion or binocular rivalry. We first showed patterns of
      activated patches in V1 with proceeding from fusion to rivalry on the basis of
      Hubel and Wiesel's 1979 illustration. We then assumed that the strength of
      synchrony between the patches in the left-eye and right-eye ocular dominance
      columns is a crucial determinant for the divergence between fusion and rivalry.
      By using the strength of fusion between the paired images as a measure of degree
      of synchrony, we confirm the assumption about interocular vision and the
      synchronization hypothesis as well.

PMID- 10597605
TI  - Regulation of exercise intensity using ratings of perceived exertion during
      passive visual distraction.
AB  - The purpose of this investigation was to determine if passive visual distraction
      altered ability to regulate exercise intensity as, assessed by ratings of
      perceived exertion during a 30-min. treadmill run. 10 trained females (VO2max,
      52.7 ml.kg-1.min.-1) performed a graded exercise test on a treadmill to assess
      maximal aerobic power and rating of perceived exertion, oxygen uptake (VO2),
      heart rate, and running velocity at the 2.5 mmol.L-1 blood lactate concentration.
      Subjects then used the target rating of perceived exertion to regulate exercise
      intensity during a control condition, and two treatment runs with passive visual
      distractions. During the treatment sessions, the subjects ran on a treadmill
      while viewing a high-action or a low-action video with no audio. The subjects
      were allowed to adjust the treadmill speed throughout the run to maintain the
      target rating of perceived exertion; however, subjects were not allowed to view
      the speed setting. There were no significant differences in blood lactate
      concentration among the conditions for the control, low action, high action, or
      graded exercise test (p < or = .05). No significant differences in VO2 or running
      velocity were found within or among the 30-min. treatment runs and the graded
      exercise test. Heart rate at 5 min. of exercise during control (158 +/- 3 b.min.
      1), low action (158 +/- 3 b.min.-1), and high action (159 +/- 2 b.min.-1) was
      significantly lower than the graded exercise test (169 +/- 3 b.min.-1). Based on
      the data collected, visual passive distraction did not alter regulation of
      intensity using ratings of perceived exertion during a 30-min. treadmill run.

PMID- 10597606
TI  - An exploratory study of undergraduates' attributions of success or failure on
      spatial tests.
AB  - Seven spatial tests from the CTY Spatial Test Battery and four subscales of an
      attribution scale were administered to 23 female and 28 male undergraduates.
      Three hypotheses were tested. The seven spatial tests and three of the
      attribution subscales were found reliable; sex differences were found for the
      spatial tests but not the attribution scales; and subjects' attributions did not
      predict spatial performance.

PMID- 10597607
TI  - Report of workshop on the significance of excursions of intake above the ADI.
AB  - The acceptable daily intake (ADI) for humans was originally developed by the
      Joint FAO/WHO Expert Committee on Food Additives (JECFA) and defined as "an
      estimate of the amount of a food additive, expressed on a body weight basis, that
      can be ingested daily over a lifetime without appreciable health risk." JECFA has
      not provided any firm guidance on how to evaluate excursions of intake above the
      ADI, but WHO in 1987 stated that "because in most cases, data are extrapolated
      from life-time animal studies, the ADI relates to life-time use and provides a
      margin of safety large enough for toxicologists not to be particularly concerned
      about short-term use at exposure levels exceeding the ADI, providing the average
      intake over longer periods of time does not exceed it." In discussing short-term
      intakes in excess of recommended limits, JECFA in 1989 concluded that short-term
      exposures to levels exceeding the provisional tolerable weekly intake (PTWI) for
      a contaminant is not a cause of concern, provided the individual's intake
      averaged over longer periods of time does not exceed the level set. JECFA also
      stated that it was impossible to make a generalization concerning the length of
      time during which intakes in excess of the PTWI would be toxicologically
      detrimental. Any detrimental effect would depend upon the nature of the toxicity
      and the biological half-life of the chemical concerned. JECFA considered intakes
      of food additives in excess of the ADI less likely to occur and easier to control
      than in the case of contaminants which are allocated either a PTWI or a tolerable
      daily intake (TDI). The ILSI Europe Acceptable Daily Intake Task Force together
      with the Food Chemical Intake Task Force initiated a workshop which took place
      April 21-23, 1998, in Milan, Italy, in order to help identify what information
      would be needed, with what precision, and what is already available to evaluate
      the significance of excursions of intake above the ADI. The specific aims of the
      workshop were to address the following questions: By how much can the ADI be
      exceeded? For how long can excursions above the ADI be tolerated with respect to
      chronic toxicity, accumulation, and mechanisms of toxicity? What methods should
      be used to estimate intakes so that the estimates are relevant to the ADI? Do the
      same principles apply to contaminants that have TDI or PTWI values?

PMID- 10597608
TI  - Assessment of extreme levels of chronic food intakes.
AB  - Acceptable daily intake (ADI) of food constituents refers to "daily ingestion
      over a lifetime." There is a need to determine mean and extreme daily intakes of
      defined constituents, in order to compare them with their ADI. The significance
      of overstepping the ADI during long periods must be discussed in relation with
      the definition of chronic toxicity. It is seldom possible to obtain original data
      on the intakes of food constituents, which must be evaluated from data on food
      intakes. Such data issued mainly from the French Observatoire des Consommations
      Alimentaires are used to present and discuss the choice of cut-off points
      (percentiles) to determine unacceptable high-level intakes. When distributions of
      individual intakes of food are available, the estimation of extreme levels of
      food intakes from mean intakes is possible with precautions. The characterization
      of extreme consumers is helpful to define target groups for informative or
      preventive actions. Foresight of extreme consumptions is made difficult due to
      time-related and generation effects.

PMID- 10597609
TI  - Health risk above the reference dose for multiple chemicals.
AB  - Recent work indicates that the regression of toxicity data viewed as categories
      of pathological staging is useful for exploring the likely health risk at doses
      above a Reference Dose (RfD), which is an estimate (with uncertainty spanning
      perhaps an order of magnitude) of a daily exposure to the human population
      (including sensitive subgroups) that is likely to be without an appreciable risk
      of deleterious effects during a lifetime. Toxic effects, which may include both
      quantal and continuous data, are classified into ordered categories of total
      toxic severity (e.g., none, mild, adverse, severe). These severity categories are
      regressed on explanatory variables, such as dose or exposure duration, to
      estimate the probability of observing an adverse or severe effect. In this paper,
      categorical regression has been expanded to compare the likely risks across
      multiple chemicals when exposures are above their RfDs. Existing health risk data
      for diazinon, disulfoton, S-ethyl dipropylthiocarbamate, fenamiphos, and lindane
      were analyzed. As expected, the estimated risks of adverse effects above the RfD
      varied among the chemicals. For example, at 10-fold above the RfD these risks
      were modeled to be 0.002, 0.0001, 0.0007, 0.002, and 0.02, respectively. The
      results and impacts of this analysis indicate that categorical regression is a
      useful screening tool to analyze risks above the RfD for specific chemicals and
      suggest its application in evaluating comparative risks where multiple chemical
      exposures exist.

PMID- 10597610
TI  - Situations with enhanced chemical risks due to toxicokinetic and toxicodynamic
      factors.
AB  - Recognizing toxicokinetic and toxicodynamic variability is important in risk
      assessment of chemicals and may help to explain interindividual differences in
      susceptibility in exposed populations. Both toxicokinetic and toxicodynamic
      factors may be influenced by age and disease processes and show genetic
      polymorphic variation. Decreased metabolic activity in the very young or very old
      may enhance chemical toxicity caused by the parent chemical. Similarly, disease
      processes affecting hepatic metabolism and renal excretion may delay inactivation
      of many xenobiotics. Genetic polymorphisms may enhance toxicity in rapid
      metabolizers when the toxicity is caused by a reactive intermediate and increase
      toxicity in slow metabolizers when the toxicity is caused by a parent chemical.
      Some cells of the developing conceptus are exquisitely sensitive to chemical
      exposure. Also, organs and tissues of newborns and elderly individuals may show
      increased responses toward xenobiotics. In addition, disease-induced altered
      receptor sensitivity and tissue repair may result in enhanced chemical toxicity.
      Further, tissue antioxidant defense against radical damage may be compromised
      under nutritional deficiencies and starvation. Hereditary peculiarities in
      individual responses to environmental chemicals may be due to polymorphic
      variation of receptor proteins and tissue repair enzymes, although the database
      for such variation is quite limited.

PMID- 10597611
TI  - Dietary intake methods for estimating food additive intake.
AB  - Given the wide array of demands on food intake databases for estimating food
      chemical intake, there is no possibility of an all-embracing methodology. Whereas
      initial estimates should always begin at a crude level, when more refined
      estimates are needed methodologies range from indirect (household, national
      level) to direct (retrospective or prospective, individual level). The indirect
      methods cannot provide data on consumer-only intakes but percentage households
      purchasing can be used as a surrogate for percentage individuals consuming. For
      the direct methods, the greater the duration, the higher the estimate of
      percentage consumers and the lower the estimate of intakes among consumers only.
      In considering excursions above the acceptable daily intake (ADI), databases need
      to be constructed which allow estimates of intake per eating occasion, where
      intakes at each eating occasion through the day or days are collapsed into intake
      per day or week, and the possibility of measuring excursions above the ADI is
      lost.

PMID- 10597612
TI  - The variation of pesticide residues in fruits and vegetables and the associated
      assessment of risk.
AB  - High levels of triazophos residues detected in carrots during routine monitoring
      led to the discovery of a wide variability between levels in individual roots.
      Conventional point estimates of consumer exposure were carried out. Due to the
      assumptions used, these calculations were likely to give rise to gross
      overestimates. In 1997, data were obtained for individual apples, pears, peaches,
      nectarines, oranges, bananas, and tomatoes that showed similar levels of
      variability in a range of organophosphate and carbamate residues. Point estimate
      models that had previously been used for intake estimates for carrots were not
      appropriate since it was necessary to take account of not only the variation of
      residue levels from crop item to crop item but also the variation in eating
      patterns in individual consumers. Probabilistic modeling was identified as a
      suitable way to produce multifactorial submodels and address some of the problems
      of combining distributions of consumption and residues. Consumption data from
      1675 toddlers were linked with residue distributions from individual crop items
      not only to allow combinations of fruit consumed but also to allow for the
      variability in residue levels that occur between individual crop items. The model
      was also capable of taking account of the percentages of crops that did not
      contain any detectable residues; this information was available from initial
      screens of bulked samples and percentage of crop not treated in the case of
      carrots. The outputs from the models were given as percentages of consumers that
      could exceed a toxicological end point; this could be the acute reference dose or
      a factor of the no-observable-adverse-effect level. Modeling in this way was
      considered to give a realistic view of the likely short-term exposure and the
      output was used as an aid to decision making in terms of necessary regulatory
      action. BACKGROUND: As a result of high levels of triazophos detected in carrots
      during routine monitoring, studies were carried out to determine the variability
      of organophosphate residue levels in individual roots. Results obtained indicated
      that the highest residue levels could be 25 times the mean level in bulked
      samples (which were used in routine monitoring). Since sufficient levels of
      organophosphate compounds can give rise to toxicological effects after a single
      exposure, it was considered necessary to carry out assessments of short-term or
      acute consumer risk. At that time, models available worldwide were designed only
      to carry out point estimates of long-term exposure. From consumption data, it was
      possible to derive the levels of carrot consumption during a single day and
      calculations were carried out assuming all carrots contained the highest levels
      of residues found in trials. This led to a gross overestimate of likely exposure
      but was considered to give to intakes that eroded margins of safety; these were
      not a cause for extreme regulatory action. Further studies were carried out on
      other crops that may be eaten whole, at one sitting, and without processing to
      consider whether the large variability of organophosphate residues was a
      phenomenon that was common to other fruits and vegetables.

PMID- 10597613
TI  - Temporal equivalence between test species and humans: general toxicity issues.
AB  - The question of whether temporal equivalence can be established between test
      species and humans and be useful in the safety assessment of food additives has
      puzzled risk assessors throughout decades. The basic biological elements in any
      mammalian species, including humans, such as homeostasis, basal metabolism and
      body size/surface area, reproduction features, the timing of cellular
      proliferation, and aging and health as well as the relation between aging and the
      diet are essential in this discussion. It is concluded that exposure studies
      covering selected segments of the total lifetime of any animal species cannot
      replace lifetime studies in the same animal species in the routine safety testing
      of food additives, but they may in many cases turn out to become the pivotal
      study for the entire safety assessment.

PMID- 10597614
TI  - Dependence of dietary intake estimates on the time frame of assessment.
AB  - Food chemical risk management needs, among other things, assessment of exposure.
      For dietary intake food consumption surveys are the data source to be used. One
      complicating factor in the usage of these data is the dependence of dietary
      intake estimates on the time frame of assessment. Central to this time dependence
      is the within-subject variation regarding the usage of food products and, as a
      consequence, the intake of chemicals. Within-subject variation is mostly as large
      as or larger than between-subject variation. Expressed per kilogram body weight,
      average (total) variation in intake variables depends on the age group, with
      variation usually being greater at younger age, most likely as a result of the
      higher intake levels at that age. Combination of age groups results in an
      increase in between-subject variation, and correction based on the figures for
      the total population will be too small. Ideally, exposure data for all days of
      one's life should be available to assess lifetime exposure. Since information on
      all these days is not an attainable and practical option, and not an option to
      strive for either, the most recent available data should be used that can be
      extended with simulation studies to anticipate future developments. The present
      food consumption surveys available in European countries are based on data that
      vary from 1 day (24-h recall and dietary record) to habitual intake (dietary
      history and food frequency). The data of a survey based on 1 day refer to 0.004%
      of an average lifetime of 70 years. Based on the demographic picture of the
      population, a reasonable approximation of lifetime intake can be obtained. The
      proportion of users and the consumption level among users depend on the time
      frame of assessment, especially for irregularly consumed products. Usage of the
      concept of "users only" overestimates lifetime exposure of the population, the
      extent of overestimation depending on the duration of the survey. The likelihood
      that all consumers have been exposed to a chemical once during a lifetime period
      is realistic in the sense of the best approximation of reality. As a result of
      this assumption all exposure assessments will have a similar point of departure
      and the dependence of the results on the food consumption method will be reduced.

PMID- 10597615
TI  - Excursions of intake above ADI: case study on cadmium.
AB  - High oral intake of cadmium via food or drink in a single dose by humans gives
      rise to vomiting, abdominal pain, and diarrhea. Concentrations of cadmium in
      drinks giving rise to such symptoms have been 16 mg/liter and higher
      corresponding to doses of 3 mg and higher. Longer term intakes of food (rice)
      with concentrations around 1 mg/kg corresponding to daily intakes of 600
      micrograms have given rise to some less pronounced symptoms including signs of
      malabsorption. Reproductive and developmental effects have been observed in
      animal experiments at oral and other exposures. The present provisional tolerable
      weekly intake (PTWI) for Cd is 500 micrograms (a weekly intake of 7 micrograms/kg
      body wt), corresponding to a daily intake of 70 micrograms or 1 microgram per kg
      body wt. Recent data demonstrating renal dysfunction in humans at even lower
      lifelong oral exposures indicate that the PTWI needs to be lowered in the future.
      An estimated lowest-observed-adverse-effect level (LOAEL) for symptoms from the
      gastrointestinal tract in humans after intake of a single oral dose is 43
      micrograms/kg body wt. If a safety factor of 3-10 is used based on LOAEL, a
      tolerable single dose would be 0.3-1 mg (4 to 14 micrograms/kg body wt). For
      longer time exposures (months-a few years) daily intakes of 200 micrograms (3
      micrograms/kg body wt) may be tolerated without obvious gastrointestinal symptoms
      or signs. At present, there is no convincing human evidence that such doses can
      cause reproductive or developmental effects, but since such effects have been
      reported in animals, it may be advisable not to exceed a daily intake of 1
      microgram/kg body wt for such potentially sensitive subsections of the population
      as children and women who are pregnant or lactating. Any excursions above the
      PTWI need to be compensated for by a corresponding period with intake below the
      PTWI in order for the cumulative dose to be low enough to avoid the long-term
      effects of cadmium on the kidney.

PMID- 10597616
TI  - Polychlorinated dibenzodioxins and polychlorinated dibenzofurans.
AB  - Polychlorinated dibenzodioxins and polychlorinated dibenzofurans (dioxins) are
      contaminants with long biological half-lives. The most toxic dioxin, 2,3,7,8
      tetrachlorodibenzodioxin (TCDD), has a half-life in humans of 9 years. A
      tolerable daily intake (TDI) of 10 pg/kg body wt/day has been recommended, which
      was derived from steady-state concentrations of TCDD at the no-observed-adverse
      effect level in animal studies. Intakes of dioxins by breast-fed babies can
      exceed the TDI by almost 20-fold. However, assuming a half-life of 9 years for
      all dioxins, it can be shown that the steady-state body burden is not increased
      by the short period of high intake during breast feeding, compared to that
      resulting from ingestion of the TDI daily from birth. Therefore, the TDI appears
      to accommodate the high intakes of dioxins by breast-fed babies. For dioxins with
      a significantly shorter half-life than TCDD, it can be shown that breast feeding
      will lead to higher body burdens in early life than would have been reached by
      ingestion of the TDI daily from birth. However, these peak body burdens will
      still be below the steady-state body burden achieved by ingestion of 10 pg
      TCDD/kg body wt/day from birth.

PMID- 10597617
TI  - Duration of intake above the ADI/TDI in relation to toxicodynamics and
      toxicokinetics.
AB  - The duration of intake necessary for the production of a toxic response depends
      on the mechanism of toxicity and the accumulation of the chemical to reach a
      toxic body load. There is a paucity of data on the cellular processes and changes
      associated with non-cancer effects detected in subchronic and chronic studies,
      and which are usually the basis for calculation of health-based exposure limits,
      such as the ADI. Data on the time course for the critical mechanistic process are
      normally unknown at the cellular level. Consequently, the duration of an excess
      intake in humans must be compared with the time course for the generation of the
      overall toxic effects in animals, which will include both toxicodynamic and
      toxicokinetic components. The extent of accumulation of a chemical during chronic
      intake is directly proportional to the half-life. The duration of intake at
      dosages above the ADI, necessary to produce body loads greater than those
      resulting from intake at the ADI, depends on the magnitude of the excess intake,
      the elimination half-life of the chemical, and the initial intake and body load.
      The effect on the body load of a short period of intake above the ADI is
      inversely proportional to the half-life of the chemical.

PMID- 10597618
TI  - Incidence and severity in relation to magnitude of intake above the ADI or TDI:
      use of critical effect data.
AB  - Noncancer effects are considered to show thresholds, such that no effect would be
      produced when the intake is below the threshold. Application of a 100-fold
      uncertainty factor to the no-observed-adverse-effect level (NOAEL) for the
      critical effect in animal studies provides an estimate of an intake for sensitive
      humans (the acceptable daily intake or ADI) without significant adverse health
      effects. The risks of intakes by humans above the ADI theoretically move the most
      sensitive subjects from negligible risk to possible risk. An increase in intake
      above the ADI would move the population distribution of internal dose toward the
      dose-response curve for sensitive subjects. The proportion of a population
      affected depends on the magnitude of the excess intake, the relationship of the
      NOAEL and the biological threshold in animals, and the coefficient of variation
      for the kinetic parameters (e.g., clearance and bioavailability) which determine
      the internal dose in humans. The severity of any effect in sensitive and high
      intake individuals depends on the magnitude of the excess intake, the nature of
      the critical effect, and the slope of the dose-response relationship.

PMID- 10597619
TI  - Precision of estimates of an ADI (or TDI or PTWI).
AB  - Factors influencing the precision of an acceptable daily intake (ADI) are
      discussed in this paper. As the same principles apply to tolerable daily intake
      (TDI) or provisional tolerable weekly intake (PTWI), although not specifically
      mentioned, this paper also refers to TDI and PTWI. The allocation of an ADI is in
      principle based on the most critical (many times the lowest) no-observed
      (adverse)-effect level [NO(A)EL] established in toxicological studies in
      experimental animals or in humans by applying a uncertainty factor for
      extrapolation from animals or humans to the general human population (and for the
      extrapolation from high to low intake levels). As the ADI predicts a virtual safe
      intake level for a life span exposure, to establish a NO(A)EL in general the
      toxicological database should include long-term studies, otherwise only a
      provisional ADI will be allocated for which a higher uncertainty factor is
      applied. The validity of an ADI greatly depends on the precision of the
      toxicological studies considered for the safety of a food additive or
      contaminant. The precision of the ADI is also inversely related to the
      uncertainty factors applied, although these uncertainty factors are not totally
      independent of the completeness and precision of the toxicological data from
      which a NO(A)EL is derived. This paper focuses on the precision of the
      toxicological data and the established NO(A)EL. Human data on the toxicity of a
      chemical which are preferred for the safety evaluation or hazard assessment are
      frequently not available or incomplete with respect to a quantitative dose
      response assessment. Epidemiological studies will have inherent difficulties for
      hazard assessment such as possible confounders, restricted number of
      toxicological end points which can be studied, and limited quantitative data on
      oral exposure levels. Case report studies include the same limitations but in
      addition the exposure data are usually very imprecise due to reconstruction of
      the possible dose level(s). Case reports of intoxication are mainly restricted to
      acute and at best subacute effects. Controlled human exposure studies (human
      volunteer studies) are restricted in their experimental design such as the level
      of the dose and the toxicological end points due to medical ethical reasons.
      Therefore, quite rarely a safety evaluation of a food chemical will be solely
      based on human data. In the practice of hazard assessment of chemicals in foods
      the experimental animal studies will be totally or partly the basis for
      establishing an ADI. In these toxicological studies in animals there are many
      experimental variables which can affect the precision of an ADI, such as (1)
      duration of the experiment, dose ranges, identity, and purity of the substance;
      (2) the parameters and toxicological end points studied; (3) the species and
      strain used; (4) the gut microflora of the test animals; (5) dietary composition;
      (6) statistics performed; and (7) knowledge about the kinetic behavior and
      metabolism (e.g., elimination half-life and bioavailability of the chemical and
      its main metabolites) of the chemical considered. How these factors can influence
      the precision of a NO(A)EL, respectively the ADI, is illustrated by several
      examples. In relation to the question of incidental excursions of an ADI, it can
      be concluded that due to the variation in precision of experiments slight
      incidental excursions would not lead to an increased risk. However, to answer in
      general the question of how often and/or how much the total intake of a chemical
      in food may exceed the ADI is not possible. This should be considered case by
      case. To answer such a question, the precision for those studies representative
      for incidental excursions should be considered. Other factors which should be
      considered are (1) type of effect on which the ADI was based, (2) mechanism of
      toxicity, (3) toxicokinetics and metabolism, and (4) difference in NO(A)ELs from
      short-term toxicity studies with the NO(A)EL on

PMID- 10597620
TI  - Significance of excursions of intake above the acceptable daily intake: effect of
      time and dose in developmental toxicology.
AB  - Three major factors to be considered in assessing the possible effects on
      developmental toxicology of excursions above the acceptable daily intake (ADI)
      are discussed. If maternal toxicity occurs at lower doses than developmental
      toxicity, then there may be adequate protection for the fetus if the mother is
      protected. In other cases, the first adverse developmental effects are usually
      small and reversible changes in fetal weight and it is unlikely that brief
      excursions, for a few days, above the ADI, would induce changes in final birth
      weight. The importance of excursions above the ADI on teratogenic responses would
      likely depend on the mechanism of teratogenesis and whether the agent acted
      primarily as a result of a high peak plasma level, a Cmax effect, or depended
      more on the total body exposure, an area under the curve (AUC) effect. This type
      of information is usually not available from current safety study designs.
      Finally, the temporal equivalence factors must be taken into account. There are
      10- to 100-fold differences in time span for pre- and postnatal development up to
      sexual maturity, in rodents compared with humans. This can be contrasted with the
      relatively small pharmacokinetic differences, perhaps of up to 2- or 3-fold in
      plasma levels of chemicals with the same administered dose in the two species.
      Thus, single episodes of high chemical exposure have greater opportunity to
      produce permanent effects on development in rodents compared with humans. The
      limited evidence from acute poisonings in pregnant women tends to support this
      hypothesis and it seems unlikely that occasional excursions by women above the
      ADI would result in developmental toxic effects.

PMID- 10597621
TI  - Estimating acute dietary intakes of chemicals.
AB  - In some cases a single dose above an acceptable daily intake could elicit an
      adverse effect. In other cases a cumulative dose over several days may be
      necessary before an effect is expressed. Estimates of acute intake must relate to
      what is known about the toxicokinetics of the substance, in relation to the
      toxicological studies associated with the relevant end point. This is because
      estimates of intake can vary considerably over even a few days in some
      circumstances. Acute reference doses should therefore be qualified by an exposure
      interval. Default values can introduce considerable conservatism into intake
      estimates. Techniques for estimating acute intakes are very varied. They can
      range in complexity from conservative screening methods to sophisticated
      techniques designed to simulate real situations. Monte Carlo models allow for the
      distributions of chemical concentrations and food consumption patterns to be
      taken into account. For acute dietary risk assessments very high upper percentile
      cutoffs are sometimes applied, even as high as 99.9%. However, assumptions
      applied in such methods can lead to misleading results. Great care must also be
      used when interpreting such statistics because uncertainty and inaccuracy in the
      data increase considerably in the upper "tail" of the distribution.

PMID- 10597622
TI  - Identification of risk groups for intake of food chemicals.
AB  - This paper summarizes by four recent examples the procedure of the
      characterization of groups at risk for ingestion of food chemicals and its
      limitations. The examples concern two food additives (sulfites and aspartame),
      one nutrient (calcium), and one food contaminant (patuline). On the one hand,
      results show that the empirical description of a group at risk is nowadays the
      best way to provide to risk managers information useful for consumer protection.
      On the other hand, these examples show that in any case if risk 0 does not exist,
      it is impossible to completely avoid any group at risk. The responsibility of
      risk managers is to decide what is the minimum size of the population to protect
      as a function of the risk and of the cost of the protection.

PMID- 10597623
TI  - Background to the ADI/TDI/PTWI.
AB  - International scientific committees such as the Joint FAO/WHO Expert Committee on
      Food Additives (JECFA) and the Joint FAO/WHO Meeting on Pesticide Residues
      (JMPR), regional scientific committees such as those of the European Union, and
      national regulatory agencies generally use the safety factor approach for
      establishing acceptable or tolerable intakes of substances that exhibit
      thresholds of toxicity. The acceptable daily intake (ADI) is used widely to
      describe "safe" levels of intake; other terms that are used are the reference
      dose (RfD) and tolerable intakes that are expressed on either a daily (TDI or
      tolerable daily intake) or weekly basis. JECFA uses the term PTWI, or provisional
      tolerable daily intake, for contaminants that may accumulate in the body. The
      weekly designation is used to stress the importance of limiting intake over a
      period of time for such substances. When using this approach no-observed-effect
      levels (NOELs) or no-observed-adverse-effect levels (NOAELs) are identified in
      the critical studies, to which appropriate safety or uncertainty factors are
      applied. Although the value of safety factors varies depending upon a number of
      factors, 100 is most often used, which is designed to account for interspecies
      and intraspecies variations. Within the framework of the IPCS project on
      harmonization of approaches to the assessment of risk from exposure to chemicals,
      issues relating to uncertainty and variability are being addressed with the aim
      of relying, whenever appropriate, on data-derived safety/uncertainty factors. The
      ILSI Europe ADI Task Force has, for the past few years, been considering the
      scientific basis for the safety factor, which will be discussed by other speakers
      in the workshop. The value of the NOAEL is dependent on the design of the study.
      Because of the expense and time required conduct many studies, doses are usually
      spread over wide intervals. Thus, the no-observed-adverse-effect level may be
      considerably less than a marginally effective dose. In addition, use
      traditionally has not been made of the dose-response relationship when
      establishing ADIs. Newer approaches such as the benchmark dose may provide ways
      of making use of dose-response information. It is unlikely that consumption at
      the level of the ADI will result in significant risk to the consumer because of
      the conservatisms that are built into it. It usually is based on long-term
      studies that are intended to mimic consumption over the lifetime of humans. The
      ADI is applied to "discretionary" chemicals (food additives, veterinary drugs,
      and pesticides) by JECFA and JMPR, which are relatively easy to control if safety
      problems are identified. On the other hand, when tolerable intakes are derived
      for contaminants that are present in the environment at high levels, the use of
      standard safety factors could result in discarding large portions of the food
      supply. Thus, it is very important that the basis for the tolerable intake is
      fully described so that informed judgments can be made about the health
      consequences of exceeding it.

PMID- 10597624
TI  - The significance of excursions above the ADI: duration in relation to pivotal
      studies.
AB  - The significance of excursions of intake above the ADI, TDI, or PTWI can only be
      assessed by reference to the database which led to the derivation of these, most
      particularly the duration of the pivotal study (chronic, subchronic, acute), the
      pharmacokinetic parameters, and the nature of toxicity and mechanism of action.
      Although this implies a case by case assessment, a number of typical situations
      may be recognized: (1) The substance (usually a contaminant, not an additive) has
      a very long half-life leading to accumulation in target organs/tissues, e.g., Cd
      or dioxin. The chronic toxicity is manifested when critical concentrations are
      achieved in these tissues and there is a large difference between the acutely
      toxic dose and the chronic NOAEL. In such a case, the effect of excursions above
      the PTWI on tissue levels is readily calculated; peak excursions of several times
      the PTWI for short periods (days, weeks, or even months) or lower peak intakes
      for even longer periods (months to years) may be inconsequential provided that
      the integrated exposure over longer periods does not lead to critical steady
      state tissue concentrations being achieved. (In such cases, it is clearly
      inappropriate to divide the PTWI by 7 and treat this as an ADI.) (2) A more
      common situation for food additives is where the ADI is based on a chronic study,
      but the t1/2 is short, i.e., the situation is one of chronic stress rather than
      cumulative toxicity. In such cases, e.g., BHA or BHT, the effects on the target
      organ (hyperplasia, foci of altered cells, etc.) can usually be identified in
      subchronic studies, although progressive changes may occur in chronic studies.
      Two subsituations then arise. First, when the effects seen at the LOAEL in
      subacute/subchronic studies are truly reversible (e.g., methemoglobinemia), short
      term studies with a reversibility component may become pivotal in assessing the
      consequences of short-term excursions above the ADI. Second, when the short-term
      effects are not fully reversible, or are even progressive, the consequences of
      short-term peaks of intake above the ADI would require careful evaluation against
      the NOAEL or LOAEL in subacute or subchronic studies. (3) A rare situation might
      arise where the ADI is based on a chronic toxicity study but the margins between
      the chronic NOAEL and some aspects of acute toxicity may be small. For example,
      for a compound which behaved like retinol, the ADI might be based on chronic
      effects on the liver but at maternally nontoxic doses the substance may be
      teratogenic following acute exposure during early pregnancy. Clearly in such a
      situation, the acute NOAEL for teratogenicity would be used appropriately to
      evaluate the risks associated with short-term peaks of exposure, i.e., a
      different study may be pivotal in determining the effects of large excursions
      above the ADI than that which was used to calculate it. Clearly, these cases are
      not comprehensive but do provide a framework against which to discuss the
      potential effects of excursions above the ADI and to reach rational conclusions
      which are not based on the misapprehension that the ADI (or worse, the PTWI x 7)
      is a lower bound of toxicity.

PMID- 10597625
TI  - The significance of excursions above the ADI. Case study: monosodium glutamate.
AB  - Monosodium glutamate (MSG) has been allocated an "ADI not specified" by the
      JECFA, which indicates that no toxicological concerns arise associated with its
      use as a food additive in accordance with good manufacturing practice (GMP) and
      for that reason it is not necessary to allocate a numerical ADI. The question in
      this case, then, is not whether excursions above a numerical ADI might occur but
      whether high peak intakes might arise which could invalidate the assumption of
      absence of hazard. Two major issues have arisen in relation to high intakes of
      MSG: (1) What is the significance of neural damage (focal necrosis in the
      hypothalamus) seen following high parenteral or intragastric doses of MSG to
      neonatal animals and is this a particular risk for children? (2) What is the role
      of MSG in "Chinese Restaurant Syndrome" (flushing, tightness of the chest,
      difficulty in breathing, etc.) following consumption of Chinese foods? In
      relation to the first issue, human studies have been crucial in resolving the
      question. The threshold blood levels associated with neuronal damage in the mouse
      (most sensitive species) are 100-130 mumol/dl in neonates rising to > 630
      mumol/dl in adult animals. In humans, plasma levels of this magnitude have not
      been recorded even after bolus doses of 150 mg/kg body wt (ca. 10 g for an
      adult). Additionally, studies in infants have confirmed that the human baby can
      metabolize glutamate as effectively as adults. It is concluded that blood levels
      of glutamate + aspartate do not rise significantly even after abuse doses and
      babies are no more at risk than adults. Intake levels associated with the use of
      MSG as a food additive and natural levels of glutamic acid in foods therefore do
      not raise toxicological concerns even at high peak levels of intake. It is not
      envisaged that use of MSG according to GMP requires the allocation of a numerical
      ADI. With regard to the second issue, controlled double-blind crossover studies
      have failed to establish a relationship between Chinese Restaurant Syndrome and
      ingestion of MSG, even in individuals reportedly sensitive to Chinese meals, and
      MSG did not provoke bronchoconstriction in asthmatics. Thus, high usage of MSG in
      ethnic cuisines does not represent a situation in which intakes might achieve
      unsafe levels, even among individuals claiming idiosyncratic intolerance of such
      foods. In the light of the toxicological studies, the human metabolic studies in
      neonates and adults, and the physiological and nutritional role of glutamic acid
      and the fact that food additive use does not markedly increase the total dietary
      burden, no foreseeable circumstances arise in which intakes would be such as to
      invalidate the appropriateness of allocating an ADI not specified to MSG.

PMID- 10597626
TI  - Introduction: molecular chaperones of the ER: their role in protein folding and
      genetic disease.

PMID- 10597627
TI  - Protein folding in the ER.
AB  - The endoplasmic reticulum (ER) is a major protein folding compartment for
      secreted, plasma membrane and organelle proteins. Each of these newly-synthesized
      polypeptides folds in a deterministic process, affected by the unique conditions
      that exist in the ER. An understanding of protein folding in the ER is a
      fundamental biomolecular challenge at two levels. The first level addresses how
      the amino acid sequence programs that polypeptide to efficiently arrive at a
      particular fold out of a multitude of alternatives, and how different sequences
      obtain similar folds. At the second level are the issues introduced by folding
      not in the cytosol, but in the ER, including the risk of aggregation in a
      molecularly crowded environment, accommodation of post-translational
      modifications and the compatibility with subsequent intracellular trafficking.
      This review discusses both the physicochemical and cell biological constraints of
      folding, which are the challenges that the ER molecular chaperones help overcome.

PMID- 10597628
TI  - Procollagen folding and assembly: the role of endoplasmic reticulum enzymes and
      molecular chaperones.
AB  - Procollagen assembly occurs within the endoplasmic reticulum, where the C
      propeptide domains of three polypeptide alpha-chains fold individually, and then
      interact and trimerise to initiate folding of the triple helical region. This
      highly complex folding and assembly pathway requires the co-ordinated action of a
      large number of endoplasmic reticulum-resident enzymes and molecular chaperones.
      Disease-causing mutations in the procollagens disturb folding and assembly and
      lead to prolonged interactions with molecular chaperones, retention in the
      endoplasmic reticulum, and intracellular degradation. This review focuses
      predominantly on prolyl 1-hydroxylase, an essential collagen modifying enzyme,
      and HSP47, a collagen-specific binding protein, and their proposed roles as
      molecular chaperones involved in fibrillar procollagen folding and assembly,
      quality control, and secretion.

PMID- 10597629
TI  - Role and regulation of the ER chaperone BiP.
AB  - BiP, an HSP70 molecular chaperone located in the lumen of the endoplasmic
      reticulum (ER), binds newly-synthesized proteins as they are translocated into
      the ER and maintains them in a state competent for subsequent folding and
      oligomerization. BiP is also an essential component of the translocation
      machinery, as well as playing a role in retrograde transport across the ER
      membrane of aberrant proteins destined for degradation by the proteasome. BiP is
      an abundant protein under all growth conditions, but its synthesis is markedly
      induced under conditions that lead to the accumulation of unfolded polypeptides
      in the ER. This attribute provides a marker for disease states that result from
      misfolding of secretory and transmembrane proteins.

PMID- 10597630
TI  - Calnexin family members as modulators of genetic diseases.
AB  - The endoplasmic reticulum (ER) is an intracellular compartment devoted to the
      synthesis, segregation and folding of soluble and membrane secretory proteins.
      Some mutations in these proteins lead to their incorrect or incomplete folding in
      the ER. The ER has a quality control system which detects misfolded proteins and
      then specifies their fate. Some mutated proteins are retained in the ER wherein
      they accumulate (Russell bodies for misfolded immunoglobulin heavy chains, the
      PiZZ for alpha 1-antitrypsin), others are retrotranslocated from the ER and
      degraded by the cytosolic proteasomal system, and yet other proteins are
      eventually secreted (in AZC-treated cells). In this review we summarize the role
      of ER resident proteins in quality control of mutated secretory proteins.

PMID- 10597631
TI  - Protein disulfide isomerase: the multifunctional redox chaperone of the
      endoplasmic reticulum.
AB  - Protein disulfide isomerase (PDI) is a protein-thiol oxidoreductase that
      catalyzes the oxidation, reduction and isomerization of protein disulfides. In
      the endoplasmic reticulum PDI catalyzes both the oxidation and isomerization of
      disulfides on nascent polypeptides. Under the reducing condition of the
      cytoplasm, endosomes and cell surface. PDI catalyzes the reduction of protein
      disulfides. At those locations, PDI has been demonstrated to participate in the
      regulation of reception function, cell-cell interaction, gene expression, and
      actin filament polymerization. These activities of PDI will be discussed, as well
      as its activity as a chaperone and subunit of prolyl 4-hydroxylase and microsomal
      triglyceride transfer protein.

PMID- 10597632
TI  - GRP94, an ER chaperone with protein and peptide binding properties.
AB  - GRP94 is the ER representative of the HSP90 family of stress-induced proteins. It
      binds to a limited number of proteins in the secretory pathway, apparently by
      recognizing advanced folding intermediates or incompletely assembled proteins,
      GRP94 also binds peptides and can act as a tumor vaccine, delivering the peptides
      for presentation to T lymphocytes. Here, we review the current data about GRP94
      and propose a structural model that integrates the biochemical data and known
      functions of the protein.

PMID- 10597633
TI  - ER protein quality control and proteasome-mediated protein degradation.
AB  - A variety of mutant polypeptides that are associated with human disease are
      targeted for degradation by an endoplasmic reticulum (ER) quality control system.
      In addition, physiological signals and viral gene products can target the
      degradation of several ER resident proteins and secreted proteins passing through
      the ER. Although the mechanism of protein quality control and the site of
      degradation were obscure, recent data indicate that degradation requires the
      cytosolic proteasome. Biochemical and genetic analyses have indicated that both
      lumenal and integral membrane proteins are selected for proteolysis and exported
      to the cytosol by a process that in several cases requires ER associated
      molecular chaperones.

PMID- 10597634
TI  - Introduction: gene duplication in development and evolution.

PMID- 10597635
TI  - Gene duplication and the uniqueness of vertebrate genomes circa 1970-1999.
AB  - In this article I review research undertaken over the past 30 years into the role
      that gene duplication played in shaping vertebrate genomes. I discuss early
      karyotype studies that pointed to a relative stability of mammalian and avian
      genomes, the discovery and possible evolutionary significance of enormous genomes
      in urodele amphibians and lungfish, genome compaction in certain specialised bony
      fish, evidence for two rounds of total genome doubling in early vertebrate
      evolution and the fate of duplicated genes in polyploid fish.

PMID- 10597636
TI  - Gene duplications in early metazoan evolution.
AB  - Major increases in complexity during animal evolution occurred at the transition
      from a unicellular protozoan to a multicellular metazoan, the evolution of
      Bilateria from diploblasts (possibly the Cambrian explosion) and during early
      vertebrate evolution. A role for gene duplication in the third event has been
      widely discussed. Here I examine the possible role of gene duplications and
      domain shuffling in the first two events. There is evidence for a wave of gene
      duplications and shuffling which may have paved the way for multicellularity;
      there are also examples of gene duplications that may have facilitated the
      transition from diploblasts to Bilateria.

PMID- 10597637
TI  - Hox gene duplication in fish.
AB  - The study of Hox gene clusters continues to serve as a paradigm for those
      interested in vertebrate genome evolution. Recent exciting discoveries about Hox
      gene composition in fishes challenges conventional views about vertebrate Hox
      gene evolution, and has initiated lively debates concerning the evolutionary
      events making the divergence of the major vertebrate lineages. Comparative
      analyses indicate that Hox cluster duplications occurred in early vertebrate
      evolution, and again within the order Cypriniformes of teleost fish. Loss of Hox
      genes was more widespread than duplication during fish evolution.

PMID- 10597638
TI  - Gene duplication: past, present and future.
AB  - Gene duplication is of central interest to evolutionary developmental biology,
      having been implicated in evolutionary increases in complexity. These ideas stem
      principally from the Lewis model for the evolution of the BX-C and Ohno's
      proposal for genome duplications during chordate evolution. Here I revisit these
      models and show how recent data have confirmed their essential features, but
      forced some important revisions. These include revised dates for homeotic gene
      duplications and for widespread gene duplication in vertebrate evolution. I also
      outline the major unresolved questions in the study of gene duplication, and its
      relevance to evolution and development.

PMID- 10597639
TI  - Gene function, gene networks and the fate of duplicated genes.
AB  - For both copies of a duplicated gene to become fixed in a population and
      subsequently maintained, selection must favour individuals with both genes over
      individuals with one. Here I review and assess some of the proposed ways that
      gene structure and function might affect the likelihood of both copies acquiring
      distinct functions and therefore positive selection. In particular I focus on the
      interacting pathways of genes that make up gene networks, and how these may
      affect genes duplicated both singly and en masse. Using the Wnt and hedgehog
      pathways as examples and data from developmental and genome analyses, I show
      that, while some of these theories may genuinely reflect what has occurred in
      animal evolution, there are still insufficient data to rigorously assess their
      relative importance. This, however, is likely to change in the near future.

PMID- 10597640
TI  - Evolutionary preservation of redundant duplicated genes.
AB  - Gene duplication events produce both perfect and imperfect copies of genes.
      Perfect copies are said to be functionally redundant when knockout of one gene
      produces no 'scoreable', phenotypic effects. Preserving identical, duplicate
      copies of genes is problematic as all copies are prone to accumulate neutral
      mutations as pseudogenes, or more rarely, evolve into new genes with novel
      functions. We summarise theoretical treatments for the invasion and subsequent
      evolutionary modification of functionally redundant genes. We then consider the
      preservation of functionally identical copies of a gene over evolutionary time.
      We present several models for conserving redundancy: asymmetric mutation,
      asymmetric efficacy, pleiotropy, developmental buffering, allelic competition and
      regulatory asymmetries. In all cases, some form of symmetry breaking is required
      to maintain functional redundancy indefinitely.

PMID- 10597641
TI  - Some new terms for duplicated genes.
AB  - If we are to investigate the relationships between genes, which can involve
      complex combinations of duplication, deletion and speciation, we need precise
      terminology. The terms 'paralogy' and 'orthology' have proved very useful in
      distinguishing two different relationships between homologous genes. Some
      relationships, however, are not included in either of these terms. I propose
      three new terms, for use in situations in which one or both lineages that lead to
      two present-day genes involve gene duplications.

PMID- 10597642
TI  - Child sexual abuse as a public health issue: recommendations of an expert panel.
AB  - Child sexual abuse (CSA) is a widespread problem that has been associated with a
      variety of negative health outcomes. There has been a call for prevention of
      first occurrences of CSA. Public health provides a unique framework for
      conceptualizing and implementing these prevention efforts. This article explains
      a model of the public health approach to prevention and illustrates the
      applicability of this model to CSA. The Centers for Disease Control and
      Prevention convened a panel of experts to advise the agency about raising
      awareness of CSA as a public health problem. A summary of the recommendations
      developed by this expert panel is presented.

PMID- 10597643
TI  - Preventing sexual abuse and assault.
AB  - This article reviews prevention of sexual abuse and assault from a public health
      approach. The public health approach identifies three levels of prevention:
      primary, secondary, and tertiary. Several programs are reviewed in the area of
      primary prevention. The article discusses the efficacy of different approaches.
      Information from offenders and victims is reviewed to gain insight into primary
      prevention approaches. Review of innovative approaches to secondary prevention
      are introduced. This section focuses on changing the behavior of potential
      offenders rather than changing the behavior of potential victims. Special
      consideration is given to the role of alcohol in abuse and possible prevention
      strategies to reduce abuse risk by reducing high-risk alcohol use. Discussion of
      intervention strategies and offender characteristics are reviewed to address
      tertiary prevention.

PMID- 10597644
TI  - Evaluation of a child sexual abuse prevention program.
AB  - A half-million children are believed to be sexually abused each year in the
      United States. In 1995, the American Medical Association declared sexual assault
      "a silent violent epidemic." The majority of efforts to stop child sexual abuse
      have focused on punishing abusers and treating victims and their families;
      prevention programs are uncommon and rely on educating children to report sexual
      abuse. This case study describes the evaluation of the first public health
      campaign designed to target adults for prevention. A baseline assessment of
      attitudes, awareness, knowledge, and policies was conducted in Vermont to
      identify facilitators and barriers to adult prevention of child sexual abuse.
      These included predisposing factors (50% of Vermont residents did not know the
      characteristics of an abuser), enabling factors (60% of Vermont residents did not
      know where to refer someone who may have sexual behavior problems), and
      reinforcing factors (when focus group participants knew an abuser, they were less
      likely to take action). This process guided the intervention, which included a
      broad-based media campaign targeting adults; a one-to-one communications strategy
      that provided information to agencies working with families at risk and a toll
      free helpline for adults in an abuse situation; and a systems change strategy
      designed to educate decision-makers and leaders. Program evaluation measures
      included a random-digit dial survey, focus groups, a survey of Vermont decision
      makers, and other data sets. The successes and limitations of these
      interventions, both as strategies in themselves and as data sources for
      evaluation, are discussed.

PMID- 10597645
TI  - Partnering in response to sexual violence: how offender treatment and victim
      advocacy can work together in response to sexual violence.
AB  - The role of interagency collaboration is extremely important in response to
      sexual violence. This article examines the conceptual underpinnings of
      collaborative responses in this arena, including the guiding principle of victim
      and community safety, as well as the need for coherent system responses. The
      Connecticut Collaborative model is discussed, along with the necessary components
      to develop a successful collaborative response, the typical problems likely to be
      encountered, and strategies to overcome these problems. The central thesis of the
      article is that a collaborative response is critical to combating sexual violence
      effectively.

PMID- 10597646
TI  - Judges' knowledge about sexual offenders, difficulties presiding over sexual
      offense cases, and opinions on sentencing, treatment, and legislation.
AB  - Forty-two Midwestern trial judges responded to a survey designed to assess
      knowledge about sexual offenders; attitudes toward adjudication, sentencing,
      treatment, and release; and opinions regarding sexual offender-related
      legislation. Results indicated that the judges held a variety of beliefs
      regarding the etiology and dynamics involved in sexual offending which differ
      from those of most professionals in the field of sexual offender management.
      However, the judges accurately identified important issues related to victims and
      some myths about offenders. The importance of retribution and rehabilitation for
      sexual offenders was emphasized, and considerable support was revealed for
      controversial legislative issues such as community notification, mandatory
      registration, and civil commitment of sexual predators. Of particular interest is
      the finding that, compared to other cases, sexual offense cases were rated by
      judges as more difficult over which to preside from a legal and technical
      standpoint, a personal and emotional viewpoint, and a public scrutiny and public
      pressure perspective. These issues, as well as judges' comments on current
      systemic and decision-making difficulties, are discussed in terms of the
      importance of judicial education programs and future research.

PMID- 10597647
TI  - Having new eyes: viewing child sexual abuse as a public health problem.

PMID- 10597648
TI  - Comprehensiveness and collaboration: key ingredients of an effective public
      health approach to preventing child sexual abuse.

PMID- 10597649
TI  - The Massachusetts Behavioral Health Program year 5: transition to a new managed
      care organization.
AB  - Year 5 of the Massachusetts Behavioral Health Program was a transition to
      management by a new private managed care organization. Fifty-eight providers
      interviewed for an ongoing panel survey reported slightly lower levels of
      quality, access, utilization, and length of stay than a year earlier.
      Relationships with providers and advocates improved after an initial difficult
      period, while consumer and family involvement at all levels remained low. The
      greatest changes in managed care appeared to take place during the initial
      transition from fee-for-service care, but intractable problems continue, and full
      participation of stake-holders seems difficult to achieve.

PMID- 10597650
TI  - The impact of knowledge and opinions on the implementation of public policies for
      mentally ill offenders.
AB  - New legislation may not always have its intended effect. Agencies targeted by the
      legislation must be aware of it, understand its demands, develop procedures to
      insure implementation, and monitor compliance. This paper reports a study of the
      extent to which several new state statutes impacted policy, procedures, and
      services for mentally ill offenders in a large urban Texas county. Key informant
      interviews, document reviews and surveys of knowledge and opinions were used to
      assess implementation, understanding, and acceptance of these new statutes.
      Results were reported to local constituencies, and used to shape recommendations
      for local action. Following the study, the community formed a council that has
      made specific improvements in the system.

PMID- 10597651
TI  - The value of program certification for performance contracting.
AB  - A survey of clubhouses listed in the 1996 ICCD Clubhouse Directory provided a
      research sample of 80 ICCD-certified clubhouses and 88 non-certified clubhouses
      with which to test the discriminant validity of ICCD certification. A
      statistically significant logistic regression model revealed that ICCD
      certification status could be clearly predicted for 78% of the clubhouses in the
      survey sample on the basis of director-reported compliance with representative
      measures of the Standards for Clubhouse Programs. The predictive power of
      compliance with the Standards was obtained even while controlling for other
      organizational variables, including clubhouse age, total staff salaries, and
      receipt of Medicaid funding. These findings provide support for the practical
      utility of adopting program certification as a performance indicator in an era of
      managed care, as well as the specific value of relying on ICCD certification as a
      quality assurance indicator.

PMID- 10597652
TI  - Families of persons with mental illness and substance use related disorders:
      considerations for service delivery.

PMID- 10597653
TI  - Substitution of psychiatric care by primary care physicians: impact of the Iowa
      Medicaid managed mental health care plan.

PMID- 10597654
TI  - Communication and social skills training for peer helpers: an East European
      program.

PMID- 10597655
TI  - The impact of capillary electrophoresis in drug analysis and bioanalysis.
AB  - Capillary electrophoresis (CE) has penetrated a wide variety of areas of
      separation science during the last ten years. The relative strengths and
      weaknesses of this technique are here overviewed, by citing the most recent
      literature and updated Medline search, keeping an eye on technology news, as
      technology and the development of CE and its applicability progress in parallel.
      The issues discussed include micellar electrokinetic chromatography (MEKC), which
      permits non-ionic solutes to be solubilized and separated. Enantioselective
      applications in CE exploit addition to the run buffer of cyclodextrins,
      macrocyclic antibiotics and proteins for analysis of chiral drugs and the state
      of the art of this field will be emphasized. CE has significant potential for
      drug metabolism studies, especially coupled with MS for high sensitivity
      detection and structural characterisation. Strategies for the analysis of drugs
      and metabolites in body fluids include on-capillary methods of sample
      concentration and single-step analyses with direct injection of body fluids on
      column, where detection techniques other than conventional UV are essential to
      achieve adequate sensitivity. The potential contribution of the hybrid technique
      of capillary electrochromatography (CEC), which couples the separating power of
      reversed-phase HPLC and the high efficiency of CE, has recently attracted growing
      interest and is therefore discussed. Finally, validation issues which are
      peculiar to CE are illustrated.

PMID- 10597656
TI  - Bioadhesive delivery of hydrochlorothiazide using tacca starch/SCMC and tacca
      starch/Carbopols 940 and 941 admixtures.
AB  - Tacca starch and its admixtures with Carbopols 940 and 941; and sodium
      carboxymethylcellulose (SCMC) were evaluated for bioadhesive delivery of
      hydrochlorothiazide into the gastrointestinal tract (GIT). The bioadhesive
      properties were evaluated using the adhesion of polymer-coated glass beads on the
      antrum region of the porcine gastrointestinal tract and Lecomte Du Nouy
      tensiometer. The swellings and release characteristics of the films/hydrogels of
      tacca starch and its admixtures were also studied. Results of the bioadhesive
      properties indicated that although tacca starch is a poor bioadhesive biopolymer
      at low concentration, the admixtures showed improved bioadhesive properties. The
      swelling and the release characteristics also confirmed that the admixtures could
      be used for bioadhesive drug delivery into the GIT.

PMID- 10597657
TI  - Cardiovascular changes after treatment with dexfenfluramine and yohimbine in
      obese women measured by thoracic electrical bioimpedance.
AB  - An anorectic drug, dexfenfluramine (dF) is commonly used in obesity treatment.
      The aim of our study was to investigate if dexfenfluramine used alone or together
      with alpha 2-adrenolitic yohimbine (Y), can change cardiovascular state in obese
      women.

PMID- 10597658
TI  - Development and validation study for the chromatographic purification process for
      tetanus anatoxin on Sephacryl S-200 High Resolution.
AB  - The tetanus purified anatoxin is used in the preparation of multiple
      immunoprophylactics. WHO (World Health Organization) specifies that the tetanus
      anatoxin must exhibit a degree of purity greater than or equal to 1,000 Lf/mg
      protein nitrogen (PN). Today liquid chromatography is a well established
      technique for the purification of tetanus anatoxin and several different methods
      are used in production scale. On a small scale, we purified tetanus anatoxin on
      Sephacryl S-200 High Resolution (gel filtration) and we obtained a successful
      high-yield purification. On the basis of these results, by combining conventional
      tangential flow filtration (TFF) at 50,000 N.M.W.L. (Nominal Molecular Weight
      Limit) ultrafiltration membrane with gel filtration on Sephacryl S-200 High
      Resolution, we have been able to purify 14 lots of tetanus anatoxin using the
      Bioprocess System (Amersham Pharmacia Biotech) to a large scale operation. Using
      this method, 77,401,332 doses of tetanus toxoid were prepared in 14 consecutive
      lots, supporting the reproducibility and reliability of the method presented
      here.

PMID- 10597659
TI  - Preliminary report on antimicrobial activity of Helichrysum litoreum Guss.
AB  - The authors present the preliminary results regarding the antibacterial action of
      extracts of Helichrysum litoreum Guss. The leaves and the young stems of this
      species, gathered on the slopes of Mt Vesuvius, in the Campania region, were
      ground and four extracts were made as follows: with dichloromethane, ethanol and
      water (70:30 v/v), water and methanol. The antibacterial activity of each of the
      samples was tested in order to determine which of the extracts was more
      antibacterial. The results of the test showed that the extract with the
      ethanol/water (70/30 v/v) was the most active one. This will allow us to advance
      in the research, purifying the extract and hopefully identifying the active
      principles.

PMID- 10597660
TI  - The healing profession needs healers: the crisis in medical education.
AB  - In this article, Dean and professor Albert E. Gunn explains that there is
      something wrong with the medical profession today. The lack of opposition by
      physicians to current practices that contravene basic human nature is disturbing.
      Gunn believes an origin of the problem lies in the process of the selection of
      medical students. Selection has been biased against the very traits that should
      make a person a good, caring physician. Gunn recommends looking favorably upon,
      even recruiting, applicants with a broad education in such subjects as history,
      philosophy, and literature, rather than just basic, technical science knowledge
      that they are currently being encouraged to study. Applicants should be recruited
      who are highly educated and able to think for themselves on important issues.
      Another bias the author has observed is that against applicants who possess a
      religiously justified morality. Such applicants are asked to justify and defend
      such a stance. Gunn believes that the fact that applicants who possess these
      traits are not considered highly desirable, much less preferred, is the basis of
      the deterioration of the medical profession, and recruiting such independent
      minded, ethical, religiously motivated candidates could be the answer to reviving
      it.

PMID- 10597661
TI  - Narrating genetic disabilities: social constructs, medical treatment, and public
      policy.
AB  - The article compares three memoirs of genetically based disability: Lisa Roney's
      sweet, invisible body, Georgina Kleege's Sight Unseen, and Alice Wexler's Mapping
      Fate. The essay explores the tension between the narrow and the broad
      construction of disability, as demonstrated by the 1999 Supreme Court rulings on
      the ADA and as experienced by these three memoirists. It concludes that the
      approach of narrative bioethics, as exemplified by such a study of disability and
      illness narratives, can offer the medical and public policy community a valuable
      alternative perspective on genetic disability not as an incapacity, but as a set
      of social relations and practices.

PMID- 10597662
TI  - Physician-assisted suicide and public virtue: a reply to the liberty thesis of
      "the Philosophers' Brief".
AB  - The "Philosophers' Brief," penned by six of today's most influential
      philosophers, was submitted as an amicus curiae brief to the Supreme Court as it
      prepared to consider the cases of Washington v. Glucksberg and Vacco v. Quill. It
      set precedent as the first such brief submitted by a group representing itself
      solely as moral philosophers. The brief became an overnight gold standard
      statement of the liberal philosophical understanding of the relationship of the
      State to so-called 'private morality.' The main thesis of the brief is that
      physician-assisted suicide regards the deeply personal event of death, and that
      individuals have a constitutionally guaranteed right to make decisions for
      themselves about the intimate details of their lives. In this article, James
      DuBois calls this the 'liberty thesis,' and he argues that the brief's
      application of this principle is both contradictory and impracticable. The
      contradiction arises as the brief proposes restrictions on the right to physician
      assisted suicide--restrictions that require the State to abandon neutrality on
      intimate value judgments about life's worth. The impracticability arises insofar
      as the brief fails to leave room for a compelling State interest in promoting a
      minimal level of public virtue. Ironically, one of the strongest arguments that
      can be proffered on behalf of a State interest in preserving a minimal level of
      public virtue stems from its role in safeguarding human liberty.

PMID- 10597663
TI  - Brief of Ronald Dworkin, Thomas Nagel, Robert Nozick, John Rawls, Thomas Scanlon,
      and Judith Jarvis Thomson as Amici Curiae in support of respondents.

PMID- 10597664
TI  - Kevin Sampson v. State of Alaska.

PMID- 10597665
TI  - [Thromboembolic complications in surgery: prophylaxis, diagnosis, treatment].

PMID- 10597666
TI  - National Ambulatory Medical Care Survey: 1995-96 summary.
AB  - OBJECTIVE: This report describes ambulatory medical care visits to nonfederally
      employed, office-based physicians in the United States during 1995 and 1996.
      Statistics are presented on selected physician, patient, and visit
      characteristics. METHODS: The data in this report were collected in the 1995 and
      1996 National Ambulatory Medical Care Surveys (NAMCS). The NAMCS is part of the
      ambulatory care component of the National Health Care Survey (NHCS), which
      measures health care utilization across a variety of providers. The NAMCS is a
      national probability sample survey of visits to nonfederally employed, office
      based physicians in the United States. Sample data were weighted to produce
      annual estimates. Estimates are presented in this report as annual averages
      unless otherwise noted. RESULTS: During 1995-96, an estimated 1.4 billion visits
      were made to physician offices in the United States, an annual average of 715.8
      million visits. The visit rate was 2.7 visits per person per year. This rate did
      not differ significantly from visit rates observed in any previous survey year.
      Females made 59.4 percent of the visits, or 3.2 visits per person annually. This
      was higher than the visit rate for males. White persons had a higher visit rate
      than black persons. Six of every 10 visits were to primary care providers. Injury
      related visits accounted for 11.8 percent of all office visits, or 84.6 million
      per year. The annual rate of injury-related office visits was 32.2 visits per 100
      persons. The most frequent reason for visiting the physician was for a general
      medical examination (6.8 percent). Cough was the most frequent symptomatic
      reason. Acute respiratory infections and essential hypertension were the
      diagnoses reported most frequently.

PMID- 10597667
TI  - Global AIDS surveillance--Part I.

PMID- 10597668
TI  - Progress towards poliomyelitis eradication, WHO eastern Mediterranean region.
      January 1998-October 1999.

PMID- 10597669
TI  - Sclerotherapy of craniofacial venous malformations: complications and results.
AB  - Of all vascular anomalies, venous malformations are the most common, and they
      have a propensity for the head and neck. The authors retrospectively analyzed 40
      patients with craniofacial venous malformations who underwent sclerotherapy
      between October of 1994 and June of 1996 to determine (1) the results of
      sclerotherapy with ethanol and/or sodium tetradecyl sulfate, (2) the types and
      rate of complications, and (3) whether outcome correlated with age, sex,
      location, size, tissues involved, morphology (lobular or varicose), venous
      outflow, or number of sclerotherapy sessions. The authors also reviewed the
      results after sclerotherapy and contour resection (n = 18). Comparisons between
      the results with ethanol and sodium tetradecyl sulfate and between sclerotherapy
      alone and sclerotherapy and resection combined were not done. The study was
      composed of three parts. They were (1) a review of records and imaging studies,
      (2) a panel evaluation of pretreatment and posttreatment photographs, and (3) a
      questionnaire that determined the patient's (or parent of the patient's)
      impression of therapy. Interrater and intrarater agreement were analyzed.
      Sclerotherapy was performed in an angiographic suite, under general anesthesia,
      using absolute ethanol and/or sodium tetradecyl sulfate. Complications of the
      treatment included acute blistering (50 percent), hemoglobinuria (28 percent),
      deep ulceration (13 percent), and nerve injury (7.5 percent). Two patients
      suffered transient facial paresis, and one had permanent unilateral vocal cord
      paralysis. Thirty patients (75 percent) were rated as having marked improvement
      or as being cured by all three members of the panel; 10 patients (25 percent)
      were rated as having no change or only slight improvement by one or more members
      of the panel. Interrater reliability was moderately positive, and intrarater
      reliability was highly positive. Thirty-seven patients or parents of patients (93
      percent) responded to the questionnaire. The outcome was considered to be marked
      improvement or cured in 28 patients (76 percent), and nine respondents (24
      percent) described only minor improvement or no change. Logistic regression
      analysis revealed that only male sex and number of sclerotherapeutic procedures
      were significant multivariate predictors of outcome. Size, location, tissues
      involved, morphology, or venous outflow were not determinant. In conclusion,
      sclerotherapy with ethanol or sodium tetradecyl sulfate is an effective and safe
      treatment for craniofacial venous malformations. Often, sclerotherapy has to be
      repeated. For extensive perioral malformations, combined sclerotherapy and
      resection give the best result.

PMID- 10597670
TI  - Quantitative assessment of osseous, ocular, and periocular changes after
      hypertelorism surgery.
AB  - The purpose of this study was to develop a methodology to quantify osseous,
      ocular, and periocular fat changes caused by correction of orbital hypertelorism
      to test the hypothesis that there is a quantitatively predictable relationship
      between the movement of the osseous orbit and that of the ocular globe. A
      retrospective review was performed of 10 patients who were status post unilateral
      or bilateral transcranial medial orbital translocation, for whom there were
      archival digital data for preoperative and postoperative (mean interval = 30
      months) three-dimensional computed tomographic (CT) scans. In addition to
      standard demographic and surgical data, the clinical preoperative and
      postoperative interpupillary and intermedial canthal distances were recorded. By
      using a computer graphics workstation, the CT digital data were registered to
      four surgically unaltered anatomic fiducial points to allow longitudinal
      quantitative comparisons. The following three-dimensional measurements were made
      for each patient preoperatively and postoperatively: interdacryon and interocular
      centroid distances, and on a standard series of three horizontal and two vertical
      planes, the position of the medial and lateral orbital walls, and the thickness
      of the medial and lateral periorbital fat (20 orbits). CT digital distances were
      compared with similar clinical distances when possible. The age at operation
      ranged from 4.0 to 12.5 years (mean, 6.6 years). The reduction in interdacryon
      distance exceeded the reduction in intercentroid distance (mean interdacryon
      change = -5.3 mm versus mean intercentroid change = -2.7 mm). Although there was
      a strong correlation between the amount of reduction of the lateral orbital wall
      and intercentroid distances, there was only a moderate correlation between the
      reduction in the intercentroid distance and that of the medial orbital wall.
      Similarly, there was a moderate correlation between the decrease in thickness of
      the lateral periorbital fat and the reduction of intercentroid distance but not
      of the medial orbital fat. In conclusion, medial translocation of the orbit does
      not produce equivalent movement of the ocular globe; neither the intermedial
      canthal nor the interdacryon distance is a useful predictor of ocular centroid
      position; and if the goal of hypertelorism operation is reduction of interocular
      distance, then CT measurement of globe intercentroid distance is essential for
      outcome assessment.

PMID- 10597671
TI  - Lower auricular malformations: their representation, correction, and embryologic
      correlation.
AB  - Seventy-seven lower auricular malformations in 74 patients treated during the
      last 6 years were analyzed. Sixty cases (77.9 percent) were of malformations
      involving the earlobe; 54 cases involved the earlobe alone, and 6 cases were of
      complex deformities involving the earlobe and adjacent helix and/or tragus. Cleft
      earlobe was the most common lower auricular malformation (49 cases, 63.6
      percent); four subtypes and their corrective methods are described. Cases of
      complex earlobe malformations, corrected by fabricated costal cartilage and
      expanded skin flap, are presented. A question mark ear (5 cases, 6.5 percent), a
      malformation with an ectopic anthelical fold (5 cases, 6.5 percent), and a
      malformation with a lower conchal stria (5 cases, 6.5 percent) are considered to
      be major lower auricular malformations. An attempt has been made to correlate the
      presented malformations with the embryologic-fetal development of the auricle. It
      is suggested that "clefting" ear malformations such as the cleft earlobe, the
      question mark ear, and the ectopic anthelical fold deformity may provide clues to
      understanding the embryologic-fetal development of the human auricle. It appears
      that hillocks 1 and 6 produce the earlobe and that hillock 4 or 5 produces the
      anthelix or helix.

PMID- 10597672
TI  - Management of the hairline using a local flap in total reconstruction for
      microtia.
AB  - In cases of microtia with a low hairline, the manner in which hair is removed
      from the reconstructed auricle must be taken into consideration. This is one of
      the most common but difficult problems with reconstruction for microtia. The
      authors describe a new technique that uses a simple regional flap to resolve this
      problem. The hair-bearing skin in the estimated auricular region and its covering
      are removed using a local flap from the hairless mastoid region. This is done in
      the first stage of auricular reconstruction, the costal cartilage grafting is
      done in the second stage, and elevation of the auricle is done in the last stage.
      In 38 auricles of 36 patients who were treated from 1993 to 1995, eight auricles
      of eight patients were treated with this technique. In all cases, the hairless
      flap healed well, without vascular stasis or skin necrosis. In addition, no
      complications from using this technique occurred in the later stages of auricular
      reconstruction. With this technique, the skin of the flap provides a good texture
      and color match to the auricle. In addition, the skin of the flap has good
      elasticity for the cutaneous pocket for cartilage grafting. The harvested area of
      the flap can be hidden behind the reconstructed auricle. The authors initially
      wondered whether the marginal scar of the transposed flap's position in the
      auricle would be conspicuous. However, all of the scar became inconspicuous
      because it was positioned in the scaphoid fossa.

PMID- 10597673
TI  - Intraocular and intraorbital compartment pressure changes following orbital bone
      grafting: a clinical and laboratory study.
AB  - Visual loss is an uncommon but catastrophic complication after intraorbital bone
      grafting for the reconstruction of acute traumatic defects or long-standing
      enophthalmos. Increased intraocular or intraorbital compartment pressure may be
      pathogenic in this setting. A two-part study was designed to test the null
      hypothesis that intraocular and intraorbital compartment pressure values remain
      constant despite orbital volume reduction with graft material. Laboratory study:
      Intraocular and intraorbital compartment pressures were measured during
      sequential orbital volume reduction in New Zealand White rabbits that had been
      randomized to one of three groups: intact orbits (n = 10), acute orbital wall
      defects (n = 8), and chronic (3 months) orbital wall defects (n = 11).
      Intraocular pressure was significantly (p<0.05) elevated in all three groups of
      orbits undergoing orbital volume reduction compared with control, nonoperated
      orbits. Intraorbital compartment pressure values did not change significantly
      from control levels throughout the grafting sequence. Although no significant
      differences existed between groups in the maximum levels of intraocular pressure
      attained, the chronic group demonstrated a greater rate of rise and slower rate
      of decline. Clinical study: Using applanation tonometry, intraocular pressure was
      measured before and serially after orbital floor exploration and intraorbital
      placement of split calvarial bone grafts in 19 patients who presented with
      orbital-zygomatic complex fractures that required surgery. A separate group of 16
      patients with orbital-zygomatic complex fractures that required exploration of
      the orbital floor but not bone grafting was used for comparison. A significant
      (p<0.05) elevation of intraocular pressure was observed immediately after bone
      grafting compared with nongrafted orbits, but values returned to normal within 30
      minutes and remained stable through the third postoperative day. There were no
      cases of visual impairment in any patients in either group as the result of
      surgical treatment. These data indicate that orbital volume reduction with graft
      material results in significant, temporary elevation of intraocular pressure. No
      significant elevations of intraorbital compartment pressure were detected in the
      rabbit orbits. Data from this study may have direct relevance in defining
      guidelines for "tolerable" changes in orbital tissue and globe pressures after
      surgery.

PMID- 10597674
TI  - New buccinator myomucosal island flap: anatomic study and clinical application.
AB  - The authors studied the vascular anatomy of the buccinator muscle by dissecting
      fresh cadavers. The anatomy of the buccal branches of the facial artery
      consistently confirmed the existence of a posterior buccal branch, a few inferior
      buccal branches, and anterior buccal branches to the posterior, inferior, and
      anterior portions of the buccinator. The buccal artery and posterior buccal
      branch anastomose to each other and ramify over the muscle. Several veins
      originate from the lateral aspect of the muscle, converge into the buccal venous
      plexus, and drain into the facial vein (from two to four tributaries) or into the
      pterygoid plexus and the internal maxillary vein (from the buccal vein). These
      vessels and nerves enter the posterior half of the buccinator posterolaterally.
      The facial artery and vein are located at variable distances from each other
      around the oral commissure and the nasal base. Two patterns of buccinator
      musculomucosal island flaps supplied by these buccal arterial branches are
      proposed in this article. The buccal musculomucosal neurovascular island flap
      (posteriorly based), supplied by the buccal artery, its posterior buccal branch,
      and the long buccal nerve, can be passed through a tunnel under the
      pterygomandibular ligament for closure of mucosal defects in the palate,
      pharyngeal sites, the alveolus, and the floor of the mouth. The buccal
      musculomucosal reversed-flow arterial island flap (superiorly based), supplied by
      the distal portion of the facial artery through the anterior buccal branches, can
      be used to close mucosal defects in the anterior hard palate, alveolus, maxillary
      antrum, nasal floor and septum, lip, and orbit. The authors have used the flaps
      in 12 patients. There has been no flap necrosis, and results have been
      satisfactory, both aesthetically and functionally.

PMID- 10597675
TI  - Stigmata: part I. Shame, guilt, and anger.
AB  - The aesthetic surgeon may occasionally be consulted by a patient who wishes to
      discuss what can be done for the scars of self-inflicted wounds on the forearms.
      These scars are popularly referred to as "hesitation marks" or "suicide
      gestures." Unlike patients suffering from factitial ulcers or Munchhausen
      syndrome, these patients will admit to the physician that the scars are the
      result of self-inflicted wounds. These scars often consist of multiple, parallel,
      white lines extending up and down the forearms (usually volar surface), with more
      on the nondominant side. Although the pattern of these scars is apparently what
      drives these patients to the aesthetic surgeon for relief (because even lay
      people identify these scars as self-inflicted suicide marks), the authors propose
      a new and deeper motivation for surgery. Recent experiences with three of these
      patients resulted in an epiphany that prompted this report. Once the symbolic
      meaning of these scars was broached, a torrent of thoughts and theories followed.
      This article will recount these three cases and present a central thesis for this
      type of self-inflicted injury. A proposal for the proper surgical treatment of
      this condition will be offered. Uniquely, two of the patients will relate their
      own stories and propose guidelines and warnings for the aesthetic surgeon.

PMID- 10597676
TI  - Reduction mammaplasty improves breast sensibility.
AB  - The belief that breast hypesthesia is an expected consequence of reduction
      mammaplasty is based on past reports that failed to objectively quantify breast
      sensibility. Forty-five women undergoing reduction mammaplasty by one plastic
      surgeon using a single operative technique were followed prospectively for change
      in breast sensation. Pressure threshold measurements were taken preoperatively
      and at 2 and 6 weeks postoperatively, by using Semmes-Weinstein monofilaments.
      Areas tested included the nipple, four points on the areola, and four points 1 cm
      from the areola on the breast skin. The data were nonparametric and were analyzed
      by using the Wilcoxon signed rank test. For all areas tested, sensation
      significantly improved from preoperatively to 2 weeks (i.e., nipple: 33.1 versus
      29.3, p<0.0004) and again from 2 to 6 weeks (i.e., nipple: 29.3 versus 19.3,
      p<0.002). Relief of chronic nerve traction injury is conjectured as the reason
      for sensibility improvement. Numb nipples persisted in 2 percent of breasts at 6
      weeks.

PMID- 10597677
TI  - Retrospective study of the skin-sparing mastectomy in breast reconstruction.
AB  - The final appearance of the reconstructed breast is greatly dependent on the
      relative amounts of skin and breast tissue excised at the time of the mastectomy
      and on the exact location of the skin incision. A complete mastectomy may be
      performed using modified skin incisions to avoid the sacrifice of unnecessary
      breast skin. The type of skin-sparing incision used varies based on the exact
      location of the tumor and the size of the breast, but it always includes the
      nipple-areola complex and the biopsy site. The presence of local recurrence,
      distant disease, or death was determined in 50 consecutive patients who had skin
      sparing mastectomies and immediate breast reconstruction between 1985 and 1991 to
      ascertain the safety of the procedure. The period of follow-up ranged from 23 to
      121 months, with a mean of 57 months and a median of 51.5 months. There was no
      local recurrence, active distant disease was present in five patients, two
      patients died of distant disease, and there were two unrelated deaths.

PMID- 10597678
TI  - The angular branch of the thoracodorsal artery and its blood supply to the
      inferior angle of the scapula: an anatomical study.
AB  - An anatomical study of the thoracodorsal arterial system was performed; it
      focused on the angular branch. The aim of the study was to document the
      anatomical variations of this pedicle and to delineate the area of supply to the
      inferior angle of the scapula with a view to free bone transfer. A total of 81
      cadaver dissections were performed; they revealed the constant presence of the
      thoracodorsal artery and four vascular patterns of origin of the angular branch.
      Selective India ink perfusion studies performed on 11 sides in six fresh cadavers
      demonstrated a reliable supply to the inferior angle of the scapula to the extent
      of 6 cm of the vertebral margin and 3 cm of the lateral margin of the scapula.
      Histologic analysis of sections of this region of the scapula confirmed the
      presence of ink within the periosteal, cortical, and medullary vascular channels,
      implying the viability of this area of bone if transferred based on the angular
      branch.

PMID- 10597679
TI  - Microsurgery costs and outcome.
AB  - Reliable information on cost and value in microsurgery is not readily available
      in the literature. Driving factors for cost, determinants of complications, and
      cost-reduction strategies have not been elucidated in this population, despite
      such progress in other areas of medicine. Clearly, the time-consuming and costly
      nature of this endeavor demands that appropriate indications and patient
      management be delineated; to operate proactively in this cost-conscious time,
      financial and outcome determinations are critical. One hundred seven consecutive
      free-tissue transfers performed from 1991 to 1994 by a single microsurgeon were
      studied. Retrospective chart review for clinical parameters was combined with
      analysis of hospital costs and professional charges. Operating room and
      anesthesia costs were based on a microcost analysis of actual operating room
      time, materials, labor, and overhead. Other patient level costs were generated by
      Transition 1, a hospital cost-accounting system. The following issues were
      addressed: (1) flap survival; (2) total costs and length of stay for all free
      flaps; (3) payments received from various insurers; (4) breakdown of operating
      room costs by labor, supplies, and overhead; (5) breakdown of inpatient costs by
      category; (6) additional costs of complications and takebacks; (7) factors
      associated with complications and flap takebacks; and (8) cost-reduction
      strategies. Mean free flap operating room costs (exclusive of professional fees)
      ranged among case types from $4439 to $6856 and were primarily a function of
      operating room times. Elective patient cases lasted a mean 440 minutes. There was
      a large disparity in reimbursement: private insurers covered hospital costs (not
      charges) completely, whereas Medicare paid 79 percent and Medicaid only 64
      percent. Length of stay, operative procedures, and complications had the greatest
      influence on inpatient costs in this group of free flap patients. Potential cost
      savings as a result of possible practice changes (e.g., shortening intensive care
      unit stays and avoiding staged operations) can be predicted. This analysis has
      caused a revision in these institutions' practice patterns and lays the
      foundation for planned outcome studies in this population.

PMID- 10597680
TI  - Efficacy of conventional monitoring techniques in free tissue transfer: an 11
      year experience in 750 consecutive cases.
AB  - Conventional free flap monitoring techniques (clinical observation, hand-held
      Doppler ultrasonography, surface temperature probes, and pinprick testing) are
      proven methods for monitoring free flaps with an external component. Buried free
      flaps lack an external component; thus, conventional monitoring is limited to
      hand-held Doppler ultrasonography. Free flap success is enhanced by the rapid
      identification and salvage of failing flaps. The purpose of this study was to
      compare the salvage rate and final outcomes of buried versus nonburied flaps
      monitored by conventional techniques. This study is a retrospective review of 750
      free flaps performed between 1986 and 1997 for reconstruction of oncologic
      surgical defects. There were 673 nonburied flaps and 77 buried flaps. All flaps
      were monitored by using conventional techniques. Both buried and nonburied flaps
      were used for head and neck and extremity reconstruction. Only nonburied flaps
      were used for trunk and breast reconstruction. Buried flap donor sites included
      jejunum (n = 50), fibula (n = 16), forearm (n = 8), rectus abdominis (n = 2), and
      temporalis fascia (n = 1). Overall flap loss for 750 free flaps was 2.3 percent.
      Of the 77 buried flaps, 5 flaps were lost, yielding a loss rate of 6.5 percent.
      The loss rate for nonburied flaps (1.8 percent) was significantly lower than for
      buried flaps (p = 0.02, Fisher's exact test). Fifty-seven (8.5 percent) of the
      nonburied flaps were reexplored for either change in monitoring status or a wound
      complication. Reexploration occurred between 2 and 400 hours postoperatively
      (mean, 95 hours). All 44 of the salvaged flaps were nonburied; these were usually
      reexplored early (<48 hours) for a change in the monitoring status. Flap
      compromise in buried flaps usually presented late (>7 days) as a wound
      complication (infection, fistula). None of five buried flaps were salvageable at
      the time of reexploration. The overall salvage rate of nonburied flaps (77
      percent) was significantly higher than that of buried flaps (0 percent, p<0.001,
      chi-square test). Conventional monitoring of nonburied free flaps has been highly
      effective in this series. These techniques have contributed to rapid
      identification of failing flaps and subsequent salvage in most cases. As such,
      conventional monitoring has led to an overall free flap success rate commensurate
      with current standards. In contrast, conventional monitoring of buried free flaps
      has not been reliable. Failing buried flaps were identified late and found to be
      unsalvageable at reexploration. Thus, the overall free flap success rate was
      significantly lower for buried free flaps. To enhance earlier identification of
      flap compromise in buried free flaps, alternative monitoring techniques such as
      implantable Doppler probes or exteriorization of flap segments are recommended.

PMID- 10597681
TI  - Neurovascular anatomy of the rectus femoris muscle related to functioning muscle
      transfer.
AB  - To describe the intramuscular neurovascular anatomy of the rectus femoris muscle
      and to evaluate whether the muscle can be split into two functional units, 40
      rectus femoris muscle specimens were studied. Ten fresh human cadavers were
      injected with a mixture of lead oxide, gelatin, and water through the femoral
      arteries. The rectus femoris muscle with its neurovascular pedicles was dissected
      out and then radiographed. Computer wire was sutured to each nerve branch in the
      muscle, and the muscle was radiographed again. Radiographs with and without
      radiopaque wire were then analyzed. In 10 preserved cadavers, the rectus femoris
      muscle was dissected out. Note was made of the vessel and nerve to the muscle.
      All muscles were cut serially into 2-cm cross-sections, and the position and
      course of the intramuscular tendon were then grossly examined. Three different
      vascular patterns in 40 rectus femoris muscles were found, based on the number of
      vascular pedicles and their relative dominance within the muscle. The rectus
      femoris muscle received either a single vascular pedicle (12.5 percent), a
      dominant vascular pedicle and one or two minor pedicles (80 percent), or two
      dominant vascular pedicles (7.5 percent). The rectus femoris was innervated by a
      large nerve branch from the posterior division of the femoral nerve, and the
      branch generally divided into two sub-branches before it reached the muscle. Both
      branches were respectively accompanied by arterial branches to form neurovascular
      hila. Furthermore, this present study has provided a detailed description of the
      intramuscular neurovascular territories. Also, the pattern of neurovascular
      supply of the muscle makes it possible to subdivide the muscle into two
      functional units for segmental muscle transfer.

PMID- 10597682
TI  - Muscle flaps in osteomyelitis of the lower extremity: a 20-year account.
AB  - Between 1977 and 1993, 64 patients had local muscle flap transposition as an
      integral portion of treatment for lower-extremity osteomyelitis. All muscle flaps
      were performed by a single surgeon. There were 54 men and 10 women with an
      average age of 45 years (range, 16 to 87 years). Median follow-up period was 9.3
      years (range, 5 to 21 years). The muscles used included medial gastrocnemius (n =
      28), soleus (n = 19), lateral gastrocnemius (n = 13), and peroneus tertius (n =
      1). At final follow-up, the recurrence free rates at 5, 10, and 15 years were 94,
      92.5, and 86 percent, respectively. These long-term results support the use of
      local muscle flap transposition as an important management method in the
      treatment of lower extremity osteomyelitis; however, the risk of treatment
      failure may arise after extended periods of time.

PMID- 10597683
TI  - Simultaneous reconstruction of the Achilles tendon and soft-tissue defect using
      only a latissimus dorsi muscle free flap.
AB  - The combined loss of the Achilles tendon and the overlying soft tissue in the
      young ambulant patient with expectations of a normal life is a challenging
      problem. These patients need not only soft tissue but also dynamic and functional
      reconstruction. Four cases of major defects of the Achilles tendon and overlying
      soft tissue after trauma are presented. In each case, the tendon and the
      overlying soft tissues were reconstructed using only a latissimus dorsi muscle
      free flap and overlying split-thickness skin graft. In conventional methods,
      evolved in the reconstruction of the Achilles tendon and soft tissue, the size of
      the defect was a limit. However, this technique can be used to reconstruct an
      extensive defect, including distal calf muscle to the plantar metatarsal area. In
      one case, the flap was harvested in a myocutaneous unit, and the skin portion was
      deepithelialized for the coverage and enough padding on the bony exposure area in
      reverse position. The purpose of the present study was to reevaluate the
      potential of denervated muscle flap for a force-bearing conduit as an alternative
      reconstructive method of the Achilles tendon. The denervated latissimus dorsi
      muscle in this study eventually experienced the process of atrophy and fibrosis
      but maintained its original length. Although there remained some atrophic muscle
      fibers, a fibrosis of the muscle fibers formed a tendon-like fibrous band, and so
      the action of the posterior calf muscle could be transmitted through the tendon
      like fibrotic change of the denervated latissimus dorsi muscle. The advantages of
      this technique are that (1) it is a single procedure, (2) it is adaptable to a
      wide range of defect sizes, (3) it allows faster wound healing supported by well
      vascularized tissues, (4) it produces satisfactory function of the ankle joint
      and a padding effect, and (5) it produces good contour of the posterior calf to
      the sole and an acceptable donor-site morbidity.

PMID- 10597684
TI  - First webspace deepening: comparing the four-flap and five-flap Z-plasty. Which
      gives the most gain?
AB  - A two-part investigation was undertaken to determine whether a four- or a five
      flap Z-plasty gives the greatest increase in length (deepening) over the same
      radius of a web. In part A, flaps were designed on a model of a webspace made
      from a plastic frame and Speedo fabric; four types of flaps, three different
      central limb lengths, and three trials for each length gave a total of 36
      observations. In part B, flaps were designed on the natural axillary webs of the
      pig; three Yorkshire pigs with one type of flap per axillary web gave a total of
      12 observations. In part A, the stereometric elongation (percent deepening)
      produced by the five-flap Z-plasty was similar to that of a single 60-degree Z
      plasty (4-cm central limb; five-flap versus a single Z procedure, 72.5+/-4.3
      versus 75.0+/-2.5 percent). The 90-degree four-flap procedure gave a 1.59 times
      greater deepening than the five-flap procedure (4-cm central limb; 90-degree four
      flap technique, 114.2+/-1.4 percent). The 120-degree four-flap technique gave 2.0
      and 1.26 times greater deepening than the five-flap and 90-degree four-flap
      procedures, respectively (4-cm central limb; 120-degree four-flap technique,
      144.2+/-1.4 percent). In part B, the 90-degree four-flap Z-plasty again produced
      a significantly greater lengthening (1.57 times) than the five-flap procedure
      (132.7+/-6.4 versus 84.0+/-4.0 percent; p<0.05), and the percentage of elongation
      of the 120-degree four-flap procedure was 1.27 times greater than that of the 90
      degree four-flap technique (167.3+/-7.0 versus 131.3+/-2.3 percent; p < 0.05). In
      conclusion, the four-flap Z-plasty produced greater webspace deepening than that
      of the five-flap Z-plasty. The 120-degree four-flap procedure gave the greatest
      percentage of elongation, but it was more difficult to design and close than the
      90-degree four-flap Z-plasty.

PMID- 10597685
TI  - Increased IGF-I and IGF-II mRNA and IGF-I peptide in fusing rat cranial sutures
      suggest evidence for a paracrine role of insulin-like growth factors in suture
      fusion.
AB  - Premature cranial suture fusion, or craniosynostosis, can result in gross
      aberrations of craniofacial growth. The biology underlying cranial suture fusion
      remains poorly understood. Previous studies of the Sprague-Dawley rat posterior
      frontal suture, which fuses at between 12 and 20 days, have suggested that the
      regional dura mater beneath the cranial suture directs the overlying suture's
      fusion. To address the dura-suture paracrine signaling that results in osteogenic
      differentiation and suture fusion, the authors investigated the possible role of
      insulin-like growth factors (IGF) I and II. The authors studied the temporal and
      spatial patterns of the expression of IGF-I and IGF-II mRNA and IGF-I peptide and
      osteocalcin (bone morphogenetic protein-4) protein in fusing posterior frontal
      rat sutures, and they compared them with patent coronal (control) sutures. Ten
      Sprague-Dawley rats were studied at the following time points: 16, 18, and 20
      days of gestation and 2, 5, 10, 15, 20, 30, 50, and 80 days after birth (n =
      110). Posterior frontal and coronal (patent, control) sutures were analyzed for
      IGF-I and IGF-II mRNA expression by in situ hybridization by using 35S-labeled
      IGF-I and IGF-II antisense riboprobes. Levels of IGF-I and IGF-II mRNA were
      quantified by counting the number of autoradiograph signals per cell. IGF-I and
      osteocalcin immunoreactivity were identified by avidin-biotin peroxidase
      immunohistochemistry. IGF-I and IGF-II mRNA were expressed in dural cells beneath
      fusing sutures, and the relative mRNA abundance increased between 2 and 10 days
      before initiation of fusion. Subsequently, IGF-I and IGF-II mRNA were detected in
      the suture connective tissue cells at 15 and 20 days during the time of active
      fusion. In contrast, within large osteoblasts of the osteogenic front, the
      expression of IGF-I and IGF-II mRNA was minimal. However, IGF-I peptide and
      osteocalcin protein were intensely immunoreactive within these osteoblasts at 15
      days (during the period of suture fusion). These data suggest that the dura
      suture interaction may be signaled in a paracrine fashion by dura-derived growth
      factors, such as IGF-I and IGF-II. These peptides, in turn, stimulate nearby
      osteoblasts to produce bone-promoting growth factors, such as osteocalcin.

PMID- 10597686
TI  - A comparative analysis of the microarchitecture of cortical membranous and
      cortical endochondral onlay bone grafts in the craniofacial skeleton.
AB  - Previous work in this laboratory established that an onlay bone graft's survival
      is determined primarily by its relative cortical and cancellous composition
      rather than its embryologic origin. A volumetric analysis of external bone graft
      resorption, however, does not explain the internal microarchitectural changes
      that may be occurring as these grafts become incorporated. To expand the
      knowledge of bone graft dynamics beyond volumetric parameters, a better
      understanding of the internal processes of bone graft remodeling is needed. In
      this comparative study of cortical onlay bone graft microarchitecture, the
      authors propose to show that cortical onlay bone grafts undergo measurable
      internal microarchitectural changes as they become incorporated into the
      surrounding craniofacial skeleton. In addition, the authors propose to further
      demonstrate similarities between the internal microarchitecture of cortical onlay
      bone grafts of different embryologic origin over time. Twenty-five adult New
      Zealand White rabbits were used for this study. They were divided into two groups
      of eight animals and one group of nine. The groups were killed at 3, 8, and 16
      weeks. Cortical membranous and endochondral bone grafts were placed
      subperiosteally onto each rabbit's cranium. In addition, five ungrafted cortical
      endochondral and membranous bone specimens were used as controls. Microcomputed
      tomography (MCT) scanning and histomorphometric analysis were performed on all of
      the specimens to obtain detailed information regarding the microarchitecture of
      the cortical bone grafts. The parameters of bone volume fraction, bone surface
      area to volume, mean trabecular number, and anisotropy were used to give
      quantitative information about a bone's micro-organization. The results showed
      that there is no statistically significant difference between the cortical
      endochondral and the cortical membranous bone grafts for bone volume fraction,
      bone surface to volume, mean trabecular number, and anisotropy measurements for
      all time points. There were, however, statistically significant differences when
      comparing the control and 3-week groups to the 16-week group for all parameters.
      The advanced MCT technology and histomorphometric techniques proved to be
      effective in providing a qualitative and quantitative ultrastructural comparison
      of cortical endochondral and membranous onlay bone grafts over time. In this
      study, a statistically significant change in the internal microarchitecture of
      cortical onlay bone grafts of different embryologic origins was seen as they were
      remodeled and resorbed at all time points. Specifically, the onlay cortical bone
      grafts developed a less dense, more trabecular, and less organized internal
      ultrastructure. In addition, no difference in the three-dimensional
      ultrastructure of cortical endochondral and membranous bone was found. These
      results challenge some of the currently accepted theories of bone-graft dynamics
      and may eventually lead to a change in the way clinicians approach bone-graft
      selection for craniofacial surgery.

PMID- 10597687
TI  - Improved vitality of experimental random dorsal skin flaps in rats treated with
      enriched cell culture medium.
AB  - A defined, serum-free cell culture medium supplemented with nonsteroidal anabolic
      hormones, insulin, thyroxin, and growth hormone was found to accelerate wound
      healing by stimulating vascularized granulation tissue formation,
      epithelialization, and angiogenesis. The aim of this work was to study the effect
      of cell culture medium on the survival rate of cephalically based random dorsal
      skin flaps in an animal model. A total of 77 Sprague-Dawley rats were randomized
      into five treatment groups: pharmacologic delay with cell culture medium, flap
      enhancement with cell culture medium, surgical delay, biological delay with
      saline, and control. Statistically significant differences in distal flap
      necrosis were found among all groups (p<0.003). The rats treated with cell
      culture medium before flap elevation showed a significant increase in flap
      viability: a survival rate of 83 percent, compared with the control group, which
      demonstrated a survival rate of only 58 percent (p<0.0001). The surgical delay
      and the groups treated with cell culture medium yielded similar results with no
      significant difference between them. This study indicates that preoperative
      injection of cell culture medium may play a role in decreasing skin flap
      necrosis.

PMID- 10597688
TI  - Revascularization of peripheral nerve autografts and allografts.
AB  - The timing and mechanisms of peripheral nerve revascularization were investigated
      using a 2-cm sciatic nerve graft model in 58 rats. Epineurial perfusion was
      consistently established by 48 hours and endoneurial perfusion by 72 hours. The
      pattern of endoneurial perfusion was "all-or-none"--either all or none of the
      vessels in a fascicle exhibited blood flow. Conventional allografts exhibited
      similar revascularization dynamics and patterns. Capping the ends of the
      autograft with Silastic significantly delayed revascularization; no flow was
      observed at 4 days, and only a peripheral rim of perfused fascicular vessels was
      observed at 7 days. These patterns suggested that the primary method of
      revascularization in the conventional graft was longitudinal inosculation; no
      evidence of peripheral neovascularization or dependence on the graft bed as a
      source of revascularization was observed. The introduction of a major
      histocompatibility complex barrier between the grafted tissue and the recipient
      animal did not alter the timing or the mechanics of blood flow reestablishment.

PMID- 10597689
TI  - Effect of anti-ICAM-1 antibodies on macromolecular leakage and leukocyte
      activation: a study of hindlimb allografts in the rat.
AB  - We investigated the ability of anti-ICAM-1 monoclonal antibodies to reduce
      endothelial cell damage by assessing microvascular permeability and
      microcirculatory function during the acute phase of allograft rejection. The
      composite rat hindlimb-cremaster muscle transplantation model was employed in
      three experimental groups of 18 animals each. Isograft control transplantations
      were performed between genetically identical Lewis (LEW, RT11) rats. Allograft
      transplantations were performed across a major histocompatibility barrier between
      Lewis-Brown-Norway (LBN, RT-11+n), and Lewis (LEW, RT11) rats. In addition, a
      third group of animals receiving allografts was treated with 1 mg/kg/day of anti
      ICAM-1 monoclonal antibody. After 24 hours, 72 hours, and 7 days, we measured
      microvascular permeability, leukocyte activation, functional capillary perfusion,
      red blood cell velocity, vessel diameters, and endothelial edema index in six
      animals per each follow-up period. Endothelial cell damage was assessed by
      measuring graft permeability to fluorescein isothiocyanate-labeled albumin (0.2
      ml/100 g body weight) with computer-aided image analysis. Mean microvascular
      permeability was lower in the treated allograft group than in untreated controls
      at all follow-up times (p<0.001). In addition, anti-ICAM-1 treatment
      significantly reduced the activation of sticking leukocytes at 24 and 72 hours
      (p<0.001) and the activation of transmigrating leukocytes at 72 hours and 7 days
      (p<0.05). The allografts presented a characteristic microcirculatory pattern of
      acute rejection as early as 24 hours after transplantation. The dysfunction of
      the endothelial cell barrier at all time points was indicated by significant
      increases in the degree of allograft macromolecular permeability and in the
      number of activated sticking and transmigrating leukocytes. Treatment with anti
      ICAM-1 antibodies significantly reduced the surge of leukocytes in the allograft
      transplants and protected the endothelial barrier from the acute effects of
      transplantation trauma.

PMID- 10597690
TI  - An unusual presentation of constriction band syndrome.
AB  - Congenital constriction band syndrome is a rare entity with a wide spectrum of
      associated congenital anomalies. Review of the pathogenesis and an unusual case
      of constriction band syndrome in a newborn are presented. Surgical excision of
      the deformity and the band was performed within the first week of life. There
      were no vascular or neural structures within the excised tissue, and there were
      no other associated anomalies other than dextrocardia and an equinovarus
      deformity of the foot. The wound was closed primarily without the need for Z
      plasties. This alternative method of treatment can be considered in such unusual
      locations of constriction band syndromes.

PMID- 10597691
TI  - Cultured palmar keratinocytes after auto-engraftment to plantar surface maintain
      site and function specificity.

PMID- 10597692
TI  - Breast cancer in Poland syndrome.
AB  - A 33-year-old African-American woman with a severe manifestation of Poland
      syndrome developed breast cancer in the ipsilateral breast. She had a severely
      hypoplastic upper extremity, including symbrachydactyly, and a hypoplastic
      forearm and upper arm. In addition, she lacked the sternal origin of the
      pectoralis muscle. She had a very small nipple-areola complex and no axillary
      hair. This is the first case report of breast cancer developing in the
      ipsilateral breast of a patient with Poland syndrome.

PMID- 10597693
TI  - Abdominal wall reconstruction with an expanded rectus femoris flap.
AB  - The expanded rectus femoris flap has several advantages for massive abdominal
      wall reconstruction. The expanded flap can easily reach the xyphoid, and it has
      impressive width. The donor site can be closed primarily with an acceptable scar.
      The muscle remains innervated and functional, which may help prevent bulging.
      When performing the surgery in conjunction with intra-abdominal procedures, such
      as fistula repair, a simultaneous two-team approach can be used without awkward
      positioning. The expansion provides some thinning of the muscle, providing a
      contour more like that of the native abdomen. Its use should be considered in
      cases of abdominal wall defects extending above the umbilicus.

PMID- 10597694
TI  - An experience of pubic hair reconstruction using free temporoparietal
      fasciocutaneous flap with needle epilation.
AB  - Lack of pubic hair may cause suffering for pubescent and adult patients; thus,
      rapid and precise reconstruction is required for their mental health. We reported
      pubic hair reconstruction for burn alopecia using a free temporoparietal
      fasciocutaneous flap transfer with needle epilation. Fourteen months after the
      reconstruction, an acceptable aesthetic result was obtained, and our patient is
      satisfied with her reconstructed pubic hair. We conclude that reconstruction
      using a free temporoparietal fasciocutaneous flap with needle epilation is a
      useful method for selected patients.

PMID- 10597695
TI  - One size fits all: a surgical technique for the correction of all types of
      prominent ears.
AB  - Patient satisfaction after surgery to correct the prominent ear relates to the
      degree of retroposition of the ear. Angular breaks in the cartilage seen with
      other cartilage-transecting procedures (and even after conchal resections), which
      are noticed by patients, led to the development of this technique. It is an easy
      operative technique that may be modified to suit all prominent ears, including
      the constricted cup ear, and it does not leave any sharp, visible ridges in the
      region of the anti-helix or concha. The procedure combines and modifies a number
      of techniques that have been described previously, which allows more flexibility
      in the treatment of this deformity.

PMID- 10597696
TI  - Reconstruction of an extreme frontal and frontobasal defect by microvascular
      tissue transfer and a prefabricated titanium implant.
AB  - A 30-year-old man was referred to us with an extreme frontal and frontobasal
      defect from a motorbike accident 12 years before. Multiple attempts at frontal
      and frontobasal revision and reconstruction had been performed over the years,
      with several episodes of meningitis. Reconstruction was planned in two steps.
      First, a revision of the anterior skull base with mobilization of meningeal
      adhesions and duraplasty, removal of infected masses of polymethylmethacrylate
      out of the upper ethmoid sinuses, and coverage with a deepithelialized latissimus
      dorsi free flap were performed. In the second step 3 months later, aesthetic
      forehead reconstruction was achieved with a pre-fabricated individual titanium
      implant. The predictable result of this two-step reconstruction was very
      pleasing. Safe separation of the cranial cavity from the upper airways was
      essential, requiring free tissue transfer in this case, and is a prerequisite for
      any alloplastic forehead reconstruction. Timing of the two-step procedure,
      including the CT data acquisition; handling of soft tissues, bone, and foreign
      material; and construction details of the implant demonstrate the necessary
      complex management of this, the most difficult case of the 88 applications of the
      new computer aided design and manufacturing technique thus far. Even the most
      elaborate computer aided preparation cannot be successful without consideration
      of established surgical principles.

PMID- 10597697
TI  - Umbilical reconstruction after repair of omphalocele and gastroschisis.
AB  - This article presents our technique of umbilical reconstruction after the repair
      of omphalocele and gastroschisis. We have treated 8 patients with an average
      follow-up period of 13 months (range, 6 approximately 24 months). No major
      complications have occurred; minor complications have included delayed wound
      healing, decreased umbilical depth, and hematoma. Our procedure is especially
      useful for patients who have a midline abdominal scar and relatively intact
      bilateral rectus abdominis muscles. Most of the patients and their parents have
      been satisfied with the results of umbilical reconstruction.

PMID- 10597698
TI  - Langer's lines: to use or not to use.
AB  - Thirty-six differently named guidelines have developed as surgeons have searched
      for an ideal guide for elective incisions. Many surgeons prefer Langer's lines.
      These lines were developed by Karl Langer, an anatomy professor, from cadavers in
      rigor mortis. However, Kraissl preferred lines oriented perpendicular to the
      action of the underlying muscles. Later, Borges described relaxed skin tension
      lines, which follow furrows formed when the skin is relaxed and are produced by
      pinching the skin. However, these are only guidelines; there are many
      contributors to the camouflaging of scars, including wrinkle and contour lines.
      Borges's and Kraissl's lines (not Langer's) may be the best guides for elective
      incisions of the face and body, respectively.

PMID- 10597699
TI  - Effective surgical treatment of cubital tunnel syndrome based on provocative
      clinical testing without electrodiagnostics.
AB  - This study evaluated the effectiveness of identifying surgically correctable
      ulnar nerve compression at the elbow based on provocative clinical testing alone
      in patients with cubital tunnel syndrome after failure of conservative treatment.
      Twenty-four patients were included in the study (mean age, 60 years). Three
      patients underwent bilateral procedures. Patients complaining of symptoms in the
      distribution of the ulnar nerve were tested by elicitation of Tinel's sign and
      combined flexion and pressure testing at the elbow and wrist. Two-point
      discrimination was determined. After a failed 6-week trial of conservative
      therapy patients underwent anterior submuscular transposition of the ulnar nerve
      with carpal tunnel release. Postoperatively, the change in two-point
      discrimination as measured at 6 months was significantly improved, with a mean
      improvement per digital nerve of 2.52 mm (p<0.001). Mean time to relief was 7.2
      weeks. Complications included one hematoma and one seroma. A total of 26 of the
      27 limbs chosen for surgical treatment by provocative clinical testing alone
      experienced relief of symptoms with anterior submuscular transposition of the
      ulnar nerve and carpal tunnel release. This study demonstrates the effectiveness
      of surgical therapy in patients with lesions identified by clinical examination
      without electrodiagnostic testing.

PMID- 10597700
TI  - Streamlining cosmetic surgery patient selection--just say no!

PMID- 10597701
TI  - Revision surgical hair restoration: repair of undesirable results.
AB  - Surgical hair restoration has been performed as a treatment for male pattern hair
      loss for more than 40 years. Although techniques have changed dramatically over
      the past several years, making it possible to achieve natural-appearing results,
      there are still many patients with unacceptable outcomes. These patients may have
      had procedures performed in the past with antiquated techniques or performed
      recently with substandard techniques. The causes of unfavorable results can be
      classified into one of three categories: technical errors, poor planning, or
      complications. The results in these patients can be dramatically improved through
      a number of different reparative surgical techniques. The majority of these
      techniques can be performed in an office outpatient setting. More than 40
      patients unsatisfied with previous surgical hair restoration have been treated
      with the different techniques reviewed in this article. All patients had
      successful outcomes with significant improvement in appearance. Despite the
      increased challenges when performing reparative surgery, outcomes were favorable
      in all patients, with small to significant improvements in appearance achieved.
      Some of these challenges include the limited supply of donor hairs, reduced scalp
      laxity, and theoretically reduced vascularity due to scarring and transected
      blood vessels, and patient skepticism. Furthermore, the few complications that
      occurred were minor and correctable, including one case each of poor hair growth
      associated with extensive small graft (consisting of one to four hairs)
      transplanting, and of scalp scarring associated with the removal and primary
      closure of a large number of "plug" grafts (typically grafts 3 to 4 mm in size
      consisting of seven or more hairs) in a single procedure.

PMID- 10597702
TI  - Multiplane face lift with the subperiosteal dissection for orientals.
AB  - A subperiosteal face lift rejuvenates the midface and periorbital region by
      restoring facial muscle tone. Since 1993, the authors have performed this
      procedure on Oriental patients who have their own distinct facial contours: the
      brachycephalic cranium and a prominent zygoma and mandibular angle. Although it
      was thought that these protuberances might disturb the subperiosteal procedure,
      especially in the anterior midface, the procedure could be performed easily by
      adopting the ancillary upper buccovestibular and subciliary incisions; the
      authors found that the protuberances actually act as fulcrums to keep up the
      lifting vectors reliably. For older patients, the procedure was combined with a
      deep subcutaneous dissection. A simple lift of the periosteum would not improve a
      severe nasolabial fold deformity and prominent wrinkles adequately because of
      "lag-lifting" of the superficial layer. It was concluded that the multiplane face
      lift, consisting of the subperiosteal and the deep subcutaneous approaches,
      achieves a natural-appearing rejuvenation of the Oriental aging face.

PMID- 10597703
TI  - Laser hair removal: where are we now?
AB  - The hair removal market is evolving rapidly. The goal has always been long-term
      epilation. Success is dependent on understanding hair biology and physiology and
      on knowledge of laser physics, skin optics, and tissue preservation with respect
      to these emerging laser technologies. These topics will be reviewed, as will
      specific categories of laser systems in the hair removal arena and the clinical
      aspects of laser hair removal today.

PMID- 10597704
TI  - Hiding the posterior scar in rhytidectomy: the omega incision.
AB  - A periauricular pattern of incision is presented for rhytidectomy that resembles
      an inverted omega. Although the anterior component remains similar to existing
      recommended patterns, the posterior component allows confinement of the scar to
      the postauricular sulcus and superior scalp. Although hidden, the scar placement
      permits full correction of redundant neck skin. The technique entails significant
      posterior dissection of the scalp, adding operative time and costs, along with
      increased potential for hematoma and sensory alteration of the scalp. On the
      other hand, the pattern of scar appears to reduce significantly the incidence of
      scar hypertrophy, whereas it conceals the scar from view, allowing an
      unrestricted range of postoperative hair styles.

PMID- 10597705
TI  - Revising the unsatisfactory breast augmentation.
AB  - Revising an unsatisfactory result after breast augmentation requires a thorough
      understanding of the cause of the abnormality to develop a rational and effective
      treatment plan to achieve the best possible result. Often, more than one
      manipulation is required to correct the deformity. Using the techniques presented
      here, successful revision can be performed in the vast majority of cases.

PMID- 10597706
TI  - The tarsal tuck procedure: avoiding eyelid retraction after lower blepharoplasty.

PMID- 10597708
TI  - Auto erotic, M.D.

PMID- 10597707
TI  - Who needs, who kills, who saves plastic surgery?

PMID- 10597709
TI  - Extrusion of an expanded polytetrafluoroethylene implant after rhinoplasty.

PMID- 10597710
TI  - A new technique in closure of wide clefts of ear lobule.

PMID- 10597711
TI  - Treatment of partial loss of the helix.

PMID- 10597712
TI  - Endoscopic brow lifts with injury to the supraorbital nerve and neuroma
      formation.

PMID- 10597713
TI  - Deep plane rhytidectomy.

PMID- 10597714
TI  - A case of free flap failure and internal jugular vein occlusion.

PMID- 10597715
TI  - Bra cup size depends on band size.

PMID- 10597716
TI  - Muscle and myocutaneous flap denervation: functional and aesthetic improvement.

PMID- 10597717
TI  - Internal mammary vein.

PMID- 10597718
TI  - Chicken bones: an unusual foreign body.

PMID- 10597721
TI  - Surgeon and healer

PMID- 10597719
TI  - Small bowel strangulation as yet another complication of the rectus abdominis
      donor site.

PMID- 10597720
TI  - "Grateful" musings on managed care

PMID- 10597722
TI  - History of burns.

PMID- 10597724
TI  - Repetitive valsalva maneuver as an uncommon cause of late massive arterial
      bleeding after free flap transfer.

PMID- 10597723
TI  - Deep vein thrombosis prophylaxis in the moderate- to high-risk patient undergoing
      lower extremity liposuction.

PMID- 10597725
TI  - Advances in the application of prostate-specific antigen in the detection of
      early-stage prostate cancer.
AB  - Prostate-specific antigen (PSA) has revolutionized the detection of prostate
      cancer. PSA-based screening has been shown to be effective in detecting prostate
      cancer at an early, potentially curable stage; however, this tumor marker is
      limited by appreciable false-positive and false-negative results. This is
      especially problematic when the PSA level is in the upper limit of normal (2.5 to
      4.0 ng/mL) or the intermediately increased range (4.1 to 10.0 ng/mL). Several PSA
      related indexes and assays have been proposed in an attempt to improve the power
      of PSA in the early detection of prostate cancer: PSA density (PSAD), age
      referenced PSA, volume-referenced PSA, PSAD of the transition zone (PSA-TZ),
      ProstAsure Index, (Global Health Net, Savannah, GA) and percent free PSA. These
      indexes may improve the sensitivity and specificity of PSA-based screening,
      facilitating the early detection of prostate cancer and reducing the number of
      unnecessary biopsies.

PMID- 10597726
TI  - Prostate cancer treatment with radiotherapy: maturing methods that minimize
      morbidity.
AB  - Technological advances in treatment delivery and planning have provided the
      backdrop for an unprecedented number of options in the treatment of prostate
      cancer with radiotherapy. The more common choices include classical external-beam
      radiotherapy, external-beam radiotherapy using three-dimensional treatment
      planning and conformal radiotherapy (3DCRT), ultrasound-guided transperineal
      implant monotherapy alone or in combination with external-beam radiotherapy, and
      intensity-modulated radiotherapy (IMRT) techniques. This chapter reviews the data
      from these methods with an emphasis on dose escalation, provides comparisons with
      prostate-specific antigen (PSA)-era radical prostatectomy series where
      appropriate, and highlights future initiatives designed to further improve
      outcome.

PMID- 10597727
TI  - Optimal hormonal therapy for advanced prostatic carcinoma.
AB  - Although the clinical presentation of stage D2 (M+) prostate cancer is decreasing
      because of screening, we are witnessing a new spectrum of advanced disease.
      According to our concept of incurable or advanced prostate cancer, more than half
      of currently diagnosed prostate cancer patients are potential candidates for
      hormonal therapy. Hormonal therapy has been the mainstay of treatment for
      advanced phases of prostate cancer for more than 50 years. However, the optimal
      form of this therapy is still an enigma. The choice of hormonal therapy for
      carcinoma of the prostate depends not only on the desired progression-free and
      overall survival, but also on the patient's quality of life, treatment costs, and
      treatment toxicities. At present, several important questions have been raised
      over the optimal treatment modalities for advanced prostate cancer. This review
      discusses some of the current challenges in the hormonal management of advanced
      prostate cancer.

PMID- 10597728
TI  - Response criteria in prostatic carcinoma.
AB  - Assessment of response in advanced prostate cancer is hampered by the
      preponderance of nonmeasurable, "bone-only" disease. Although bone scans are
      accurate in assessing new lesions, they are frequently unreliable in evaluating
      tumor regression. Alternatively, evaluation of response based on changes in
      prostate-specific antigen (PSA), a biochemical marker, is now routinely
      incorporated into clinical trials as a surrogate end point for response. However,
      despite general acceptance of its use as an end point in clinical trials, there
      is no standardized definition of PSA response. Furthermore, changes in PSA do not
      always correlate with regression of measurable tumor, especially in response to
      noncytotoxic agents. PSA changes are most defensibly used to define initial hints
      of a drug's potential usefulness, rather than as a validation of benefit.
      Improvement in quality of life has emerged as a clinically relevant endpoint,
      especially in the setting of hormone-refractory disease, in which therapy has yet
      to have an impact on survival. There is a current trend toward reporting response
      to therapy as reflecting changes in biochemical markers, measurable disease, bone
      only disease, and quality of life separately, rather than trying to pigeon-hole
      "response" into traditional categories of "complete" and "partial." This
      independent reporting of outcome parameters provides a more accurate picture of
      the potential therapeutic benefit of the assessed new treatments, and allows more
      informed decision-making by physicians and their patients.

PMID- 10597729
TI  - Chemotherapy of advanced prostatic carcinoma.
AB  - Metastatic prostate cancer remains incurable. Historically, therapy options for
      patients with nonlocalized disease have been limited to hormonal therapy and
      palliative radiation therapy. The use of cytotoxic chemotherapy has not been
      routine, and is still not rigorously demonstrated to alter the natural history of
      androgen-independent prostate cancer. Nonetheless, there is an established, if
      not universally accepted, role for chemotherapy in symptom palliation, and
      several combinations have been described that produce response rates in the range
      that are associated with alteration of disease progression and improved survival
      in other cancers. The further refinement of such combination regimens, and their
      application to patients much earlier in the course of the disease, are the most
      important immediate challenges for medical oncologists who treat prostate cancer.
      At present, the curative potential of all local therapies remains disappointing;
      it is expected that the advent of truly effective systemic therapy will bring
      much improved prospects for cure by the application of combined modality
      treatment.

PMID- 10597730
TI  - Prostate cancer vaccines: current status.
AB  - Recent insights into cell-mediated immunotherapy have led to a wave of new trials
      involving immunotherapy for prostate cancer. Vaccines have evolved from
      nonspecific immune stimulants like Bacillus Calmette-Guerin (BCG) to much more
      specific and potent strategies. Techniques currently being investigated include
      passive immunotherapy with monoclonal antibodies, adoptive transfer of activated
      effector T cells, and active immunotherapy involving immunization with whole-cell
      or antigen-specific vaccines. These therapies are being modified with cytokines
      and other immune modulating agents. Understanding the mechanisms of antitumor
      immunity and identifying relevant tumor-specific antigens will likely improve
      these vaccine strategies and provide them with a niche in the future of prostate
      cancer therapy.

PMID- 10597731
TI  - The challenge of locally advanced prostate cancer.
AB  - Locally advanced prostate cancer can be reliably identified and has a disease
      specific death rate of approximately 75%. Monotherapy treatment options have
      limited efficacy for locally advanced disease. Multimodality therapy may improve
      survival. This article reviews the current results of multimodality therapy,
      including hormonal therapy plus radiation therapy, hormonal therapy plus radical
      prostatectomy, and brachytherapy plus external-beam radiation therapy (EBRT), and
      presents current ideas for novel multimodality approaches.

PMID- 10597732
TI  - Drug development in prostate cancer.
AB  - Despite strategies aimed at early detection and treatment, prostate cancer
      remains a leading cause of morbidity and mortality among males. Current therapies
      have limited impact on the natural history of metastatic hormone-refractory
      prostate cancer (HRPC). With an improved understanding of tumor biology,
      including apoptosis, differentiation, cell cycling and signaling, and
      angiogenesis, many potential new targets for therapy have been unveiled.
      Modulation of these processes may result in cytotoxic or cytostatic effects. The
      evaluation of therapies based on manipulation of these targets may not be
      adequately addressed by current study designs and traditional parameters of
      efficacy. Examples of agents currently in clinical trials that illustrate some of
      the challenges presented to clinical investigators include monoterpenes such as
      perillyl alcohol (POH), vitamin D analogs, flavones such as flavopiridol, and
      angiogenesis inhibitors. Agents such as these are aimed at unique cellular
      targets and will require novel approaches to determine their clinical utility.
      Unfortunately, in the United States, only a small proportion of cancer patients,
      including prostate cancer patients, are enrolled in clinical trials. We must do
      better to efficiently assess promising new treatment approaches and improve
      outcome for our patients.

PMID- 10597733
TI  - Function and therapeutic implication of C-CAM cell-adhesion molecule in prostate
      cancer.
AB  - Human neoplasms are often caused by cumulative alterations in oncogenes and tumor
      suppressor genes. By identifying the early genetic changes involved in
      tumorigenesis, one can develop strategies to prevent and detect cancers at early
      stages, when treatment is most effective. C-CAM1, a cell-adhesion molecule (CAM)
      isoform (I), was recently shown to play a critical role in prostate cancer
      initiation and progression. Loss of C-CAM1 expression occurs early in the
      development of prostate cancer, suggesting that C-CAM1 may help maintain the
      differentiated state of the prostate epithelium. Reintroduction of C-CAM1 into
      cancer cells can reverse their cancerous growth. Thus, the C-CAM1 molecule itself
      or drugs that increase C-CAM1 expression are promising agents for prostate cancer
      treatment. The mechanisms by which C-CAM1 suppresses tumorigenesis are different
      from those of p53 and Rb. Therefore, C-CAM1 therapy is a new form of prostate
      cancer treatment. To exploit C-CAM1's therapeutic potential, a human C-CAM1
      adenovirus expression vector (Ad-hu-C-CAM1) has been used to treat prostate tumor
      xenografts in nude mice. The preliminary results have shown great promise. In
      addition, while C-CAM gene therapy may have immediate application in prostate
      cancer treatment, the knowledge to be learned from mechanistic studies of C-CAM1
      mediated tumor suppression may also help us design better strategies for
      prevention and treatment for prostate cancer.

PMID- 10597734
TI  - Novel molecular targets for prostate cancer therapy.
AB  - The treatment options available for advanced prostate cancer are increasing.
      These improved therapies are the result of research involving cellular targets
      other than DNA proliferation. For example, therapy directed against the
      intracellular matrix has yielded clinical responses in patients. Other novel
      targets are being investigated. This review examines both laboratory and clinical
      advances using cell structure, growth factors, differentiating agents,
      angiogenesis, metastasis, and the cell cycle in the treatment of prostate cancer.

PMID- 10597735
TI  - Racial differences in prostate-specific antigen levels and prostate-specific
      antigen densities in patients with prostate cancer.
AB  - To compare serum prostate-specific antigen (PSA) levels and PSA density (PSAD)
      among African American (AA), white, and Hispanic men with prostate cancer (PC)
      seen in an urban, equal-access urology clinic. Between January 1988 and January
      1993, 1,105 men were screened for PC at Cook County Hospital in Chicago,
      Illinois. A total of 529 men underwent transrectal ultrasound-guided prostate
      gland biopsies for abnormal digital rectal examination, suspect transrectal
      ultrasound, elevated PSA, or any combination of these abnormalities. PC was found
      in 246 patients (204 AAs, 22 whites, and 20 Hispanics). We analyzed the
      differences in PSA and PSAD among the three racial groups using univariate and
      multivariate analyses adjusting for race, age, clinical stage, and grade. AAs
      have a higher mean serum PSA levels (21.56 ng/ml) than whites (mean PSA of 10.96
      ng/ml) and Hispanics (mean PSA of 8.25 ng/ml) (p = 0.04). The mean PSAD also was
      higher in AAs than in the other two groups (0.68 versus 0.34 for whites and 0.31
      for Hispanics, p = 0.05). On a multivariate analysis, the PC stage and grade were
      overwhelmingly significant, whereas the race and age lost their statistical
      significance. AAs have higher serum PSA and PSAD than whites or Hispanics in an
      equal-access healthcare environment. Race is a significant factor in determining
      PSA and PSAD on univariate but not on multivariate analysis. Preliminary studies
      suggest that these differences are due to sociological, not biologic causes.
      These findings warrant a large, prospective study to investigate the extent and
      the causes of the racial differences in PSA and PSAD.

PMID- 10597736
TI  - Squamous cell carcinoma antigen, circulating immune complexes, and
      immunoglobulins in monitoring squamous cell carcinoma of head and neck: a study
      of the hellenic co-operative oncology group (HeCOG).
AB  - This study investigates the clinical utility of squamous cell carcinoma antigen
      (SCC-Ag), circulating immune complexes (CIC), and immunoglobulins (IgA, IgG, IgM)
      in the diagnosis, monitoring, and prognosis of 117 squamous cell carcinoma of the
      head and neck (SCC-HN) patients having local and/or systemic treatment. Serum
      marker levels were measured in a prospective study. SCC-Ag was positive in 28.2%
      of patients, the CIC in 63.2%, the IgA in 11.1%, the IgG in 15.4%, and the IgM in
      9.44%. Statistically significant correlation was found between the initial SCC-Ag
      levels and tumor localization, whereas the CIC levels were increasing
      significantly with progressing disease stages. It was also found that the
      significant decrease of SCC-Ag, IgA, and CIC levels at the end of treatment was
      correlated with an increased incidence of disease-free status. The initial values
      of IgG and the disease stage were significantly correlated with a favorable
      treatment outcome. The pretreatment elevated SCC-Ag and IgM serum values showed a
      significant trend to predict a disease progression. Using a Cox proportional
      hazards model the IgG serum values, the primary site, and the disease stage were
      significant predictors for time to progression. The significant decrease of SCC
      Ag, IgA, and CIC values at the completion of treatment was correlated with an
      increased incidence of disease-free status. This study indicates that only the
      estimation of SCC-Ag and in some degree the IgM and/or IgG is a potential tool
      for monitoring the efficacy of treatment or disease recurrence in SCC-HN.

PMID- 10597737
TI  - A phase II study of carboplatin plus gemcitabine in advanced non-small-cell lung
      cancer (NSCLC): a hoosier oncology group study.
AB  - The purpose of this study was to evaluate the toxicity and determine the response
      rate, duration of remission, and survival using gemcitabine plus carboplatin in
      non-small cell lung cancer (NSCLC). This was a phase II study of gemcitabine and
      carboplatin in chemotherapy-naive patients with advanced NSCLC and Karnofsky
      Performance Status of at least 80. Gemcitabine was administered intravenously at
      1,000 mg/m2 weekly for 3 weeks followed by 1 week rest. Carboplatin was
      administered immediately after gemcitabine at an area under the curve (AUC) of 5
      given intravenously on day 1 of an every-4-week cycle. Seven patients were
      entered in the study and five were evaluable for toxicity. The median age of
      patients was 68 years (range, 52-72). The protocol was prematurely terminated
      because of severe and unexpected hematologic toxicity. Grade 3-4 thrombocytopenia
      was observed in four of the first five patients. These toxicities were all
      observed with the first course of chemotherapy. There were no objective responses
      seen. Median survival time was 130 days. Carboplatin plus gemcitabine was a
      logical combination. However, because of the severe thrombocytopenia associated
      with this regimen, we do not recommend this two-drug combination in the dose and
      schedule used in this study.

PMID- 10597738
TI  - Experience-based demand scheduling: a more efficient model for radiation
      oncology.
AB  - The supply of radiation therapists has increased, whereas reimbursements have
      decreased. One hypothesis is that if we choose to employ as permanent staff
      sufficient therapists to handle the low-volume periods and scheduled temporary
      staff as the demand for radiation therapy services warrants, we would increase
      efficiency. Using current economic assumptions and the treatments delivered
      during the past 12 months, we analyzed the labor expense and revenue consequences
      of both full staffing and a lower level of staffing with per diem supplementation
      based on the scheduled patient load. We then correlated the scheduled treatments
      with the actual treatments delivered and finally, reexamined both the full
      staffing model and the per diem supplementation model based on the predictions of
      our scheduling model. The reduction in full-time therapists and per diem
      supplementation did not produce substantial incremental revenue. However,
      examining the relationship between patients scheduled for treatment on the next
      day and patients actually treated, revealed an 11% "no show" rate with a 95%
      confidence interval of 1%. Our new, experienced-based model demonstrated
      considerable revenues to be realized by using the no-show factor to better use
      therapists by more aggressive scheduling of outpatients, therapists, and more
      flexible transportation of inpatients. We conclude that the experience-based
      model predicts the marginal revenue, but is silent on the quality of the medical
      care provided.

PMID- 10597739
TI  - Mature results of a prospective randomized trial comparing a three-weekly with an
      accelerated weekly schedule of cisplatin in advanced ovarian carcinoma.
AB  - In a retrospective analysis of a series of clinical trials by Levin and Hryniuk
      in 1987, the average relative dose intensity of first-line chemotherapy for
      advanced ovarian cancer correlated significantly with clinical response and
      survival, and cisplatin was the only drug for which the outcome correlated with
      the individual drug relative dose intensity. There was a need to test whether and
      to what extent this evidence would be confirmed in a prospective evaluation. In
      this study 101 patients with advanced ovarian carcinoma were randomized to
      receive the same total dose of cisplatin but at the conventional 3-weekly
      schedule (CTWS) (100 mg/m2 every 3 weeks for six cycles) (51 patients) or at an
      experimental accelerated weekly schedule (AWS) (100 mg/m2 every week for two
      triplets of three cycles separated by a 5-week interval) (50 patients). To
      benefit from a multidrug regimen at the same extent, patients in both arms
      sequentially received four cycles of doxorubicin and cyclophosphamide. The median
      follow-up period of this study is 9.7 years. In 42 and 40 patients of the two
      arms having evaluable response, the clinical complete response rates to cisplatin
      were 14% and 22% and the complete plus partial response rates were 48% and 55% in
      the CTWS and in the AWS arm, respectively. These differences were not
      statistically significant. However, the survival curves were similar during the
      first 2 years but clearly diverged thereafter in favor of the AWS arm (p = 0.07).
      At 5 years, 12% and 30% of the patients were still alive in the CTWS and in the
      AWS arm, respectively. Hematologic toxicity was not relevant in either arm of the
      study. Nonhematologic toxicity, especially ototoxicity, was substantial and
      significantly higher in the AWS arm. Although statistically nonsignificant, this
      AWS regimen of cisplatin is associated with long-term better survival compared to
      the CTWS regimen in advanced ovarian carcinoma. This accelerated approach
      administering cisplatin should be further investigated, especially in patients
      with low residual disease after primary surgery.

PMID- 10597740
TI  - First-line treatment of metastatic breast cancer with mitoxantrone, vinorelbine,
      and carboplatin.
AB  - A phase II trial was conducted with mitoxantrone (12 mg/m2, day 1), vinorelbine
      (30 mg/m2, day 1), and carboplatin (250 mg/m2, day 2) every 21 days. Fifty
      eligible women who had not received prior chemotherapy for metastatic breast
      cancer (MBC) entered the study. Objective responses were observed in 28 patients
      (56%; 95% confidence interval: 42.4-69.74%), with 4 complete (8%) and 24 partial
      responses (48%). Stable disease was observed in 12 patients (24%) and disease
      progression in 10 (20%). Responses were documented in all involved sites. The
      median duration of response was 6 months and the median time to tumor progression
      8 months. The median survival was 26 months and the estimated 2-year survival was
      52%. Grade 3/4 neutropenia was observed in 29 patients (58%) with four
      neutropenic episodes. Grade 3/4 anemia and thrombocytopenia was observed in 7
      (14%) and 11 (22%) patients, respectively. Other toxicities included grade 2/3
      nausea and vomiting in 26 patients (52%) and grade 1/2 alopecia in 38 (76%).
      Grade 1/2 neurosensory toxicity occurred in four patients (8%). In conclusion,
      this three-drug regimen is effective and well tolerated for the treatment of MBC.

PMID- 10597741
TI  - Late radiation toxicity after whole brain radiotherapy: the influence of
      antiepileptic drugs.
AB  - This retrospective study had the following aims: (a) calculation of actuarial
      rate of late radiation toxicity after whole-brain radiotherapy (WBRT), (b)
      correlation of clinical symptoms with changes of computed tomography (CT) scans,
      and (c) analysis of potentially predictive factors with special regard to
      concomitant treatment with antiepileptic drugs. We analyzed 49 adult patients,
      selected from a preexisting data base. Inclusion criteria were as follows: no
      previous brain irradiation; WBRT without boost; CT, clinical, and neurologic
      examination before and more than 3 months after completion of WBRT. Uni- and
      multivariate tests of various patient- and treatment-related parameters as
      possible predictive factors for clinical symptoms of late radiation toxicity
      (scored according to the RTOG/EORTC system) as well as cerebral atrophy and white
      matter abnormalities were performed. Median age was 54 years. Patients were
      treated for brain metastases (n = 37), primary cerebral lymphoma (n = 2), primary
      brain tumors (n = 7), or with prophylactic intention (n = 3). Carbamazepine was
      given to 15 patients, phenytoin to 12, and barbiturate to 7, respectively; 42
      patients also received corticosteroids. The median dose of WBRT was 30 Gy (range
      27-66 Gy). Median fraction size was 3 Gy (1-3 Gy). Nine patients received two
      fractions per day. The biologically effective dose (BED) according to the linear
      quadratic model ranged between 90 and 141 Gy (median, 120 Gy; alpha/beta value, 1
      Gy). Median follow-up was 10 months (range, 4-130 months). In 16 cases, symptoms
      of late radiation toxicity grade I-III appeared. Actuarial rates were 32% after 1
      year, 49% after 2 years, and 83% after 5 years. Actuarial rates of cerebral
      atrophy were 50% after 1 year and 84% after 2 years (white matter abnormalities:
      25% and 85%, respectively). There was a significant correlation between atrophy
      and white matter abnormalities, but not between CT changes and clinical symptoms.
      CT changes were dependent on BED, absence of barbiturate use, and preexisting
      cerebral atrophy. Clinical symptoms usually were dependent on BED too, but
      treatment with carbamazepine was more important in the multivariate model.
      Neither other drugs nor other factors influenced late radiation toxicity. A
      detailed analysis showed that most carbamazepine-treated symptomatic patients
      took the drug during WBRT as well as during follow-up. Actuarial rates of grade I
      III symptoms were 18% versus 50% after 1 year with or without carbamazepine. Even
      after exclusion of carbamazepine-treated patients, CT changes and clinical
      symptoms did not correlate. In conclusion, a BED <120 Gy was associated with a
      lower rate of late radiation toxicity after WBRT. The anticonvulsant drug
      carbamazepine showed a surprisingly clear influence on clinical symptoms of late
      radiation toxicity; that might be explained by the fact that the side effects of
      long-term drug treatment are indistinguishable from mild or moderate true
      radiation sequelae, rather than that it has a role in the pathogenesis of
      radiation-induced changes.

PMID- 10597742
TI  - Phase II trial of the combination of paclitaxel and 5-fluorouracil in the
      treatment of advanced gastric cancer: a novel, safe, and effective regimen.
AB  - This prospective phase II clinical trial was performed to explore the activity
      and efficacy of the combination of paclitaxel and 5-fluorouracil in the treatment
      of advanced gastric adenocarcinoma. Thirty-one patients ages 18 to 70 years, with
      Karnofsky performance status (KPS) >50, adequate cardiac, renal, and hepatic
      functions, measurable metastatic or locally unresectable disease, life expectancy
      > or =3 months, signed written informed consent, and without any previous
      chemotherapy were assigned to receive on an outpatient basis: paclitaxel--175
      mg/m2, in a 3-hour infusion on day 1 and 5-fluorouracil--1.5 g/m2, also in a 3
      hour infusion on day 2 every 21 days, for a maximum of seven cycles. A system to
      assess clinical benefit based on KPS, analgesic consumption, and weight gain was
      also used in this trial. Median age was 61 years (range, 31-70 years). The 29
      patients eligible for response and toxicity evaluation underwent 147 cycles of
      chemotherapy. There were 19 (65.5%) objective responses (95% confidence interval:
      48%-83%), including 7 (24.1%) complete responses and 12 (41.4%) partial
      responses. Three patients had the complete response pathologically confirmed. In
      three of six patients who went to second-look laparotomy, a potentially curative
      esophagogastrectomy was possible. The toxicity of this combination was considered
      low, predictable, and manageable and was characterized mainly by reversible
      alopecia, peripheral neuropathy, myalgia, and mild neutropenia. Fifteen (51.7%)
      patients attained a clinical benefit response. The median overall survival was 12
      months (range, 2-30+ months) and the 30-month overall survival was 20%. This
      novel regimen appears to be very effective in advanced gastric cancer. The
      projected 2-year survival of 20% is higher than that achieved with other first
      line regimens. These encouraging results indicate the need for further studies to
      confirm the merit of this regimen.

PMID- 10597743
TI  - Clinicopathologic features and prognostic factors of primary extranodal non
      Hodgkin's lymphomas in Turkey.
AB  - Clinical, histopathologic, and prognostic features of 114 patients with primary
      extranodal non-Hodgkin's lymphoma were evaluated. Median age of the patients was
      48 (range, 15-76) and the ratio of male/female was 55/59. Thirty-seven patients
      had stage 1, 55 patients stage II, 6 patients stage III, and 16 patients stage
      IV. The most common sites of primary extranodal non-Hodgkin's lymphoma were the
      gastrointestinal (GI) tract and head-neck region. Stomach (66%) and tonsils (33%)
      were the most frequently involved organ in GI tract and head-neck region,
      respectively. Eighty percent of patients had intermediate or high-grade
      lymphomas, 20% had low-grade subtypes. Complete remission was achieved in 83% of
      all patients with chemotherapy +/- radiotherapy +/- surgery. Overall and disease
      free survival at 5 years were 63% and 59%, respectively. In conclusion, clinical
      and histopathologic characteristics and prognosis of our cases with primary
      extranodal non-Hodgkin's lymphoma were usually similar to those of the cases in
      Western countries with some differences in the incidence of some specific primary
      extranodal non-Hodgkin's lymphomas and in the histopathologic subtypes.

PMID- 10597744
TI  - Comparison of CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) with a
      rotational crossing and a sequential intensification regimen in advanced breast
      cancer: a prospective randomized study.
AB  - The Italian Oncology Group for Clinical Research tested two experimental
      chemotherapy strategies in an attempt to improve the results achievable with
      conventional chemotherapy in metastatic breast cancer. One hundred sixty-two
      patients were randomly allocated as follows: (a) to the conventional
      cyclophosphamide, methotrexate, 5-fluorouracil chemotherapy regimen (CMF); (b) to
      a rotational crossing program (ROT-CROSS); or (c) to a sequential intensification
      program (SEQ-INT). The same single agents (C, M, F, cisplatin, etoposide, and
      doxorubicin) were administered in both experimental arms, but following a
      different policy. The SEQ-INT program induced a significantly higher complete
      response (32% vs. 6%, p = 0.0006) and objective response rate (72% vs. 42%, p =
      0.0047) than CMF did. There were no differences in survival between CMF and
      either experimental arm. A number of side effects were significantly more with
      both experimental chemotherapies than with CMF, but the treatments were generally
      tolerable. Although some caution is required when interpreting a significant
      advantage found between an entire chemotherapeutic strategy and a single
      conventional combination, this study documents the potential therapeutic
      advantage of administering different sequential chemotherapies, and changing each
      at the time of maximum result without waiting for a progression. The impressive
      cytoreductive effects achievable with this policy (SEQ-INT) in metastatic disease
      merit further investigation in the adjuvant setting.

PMID- 10597746
TI  - Radiotherapy review on national surgical adjuvant breast and bowel project
      (NSABP) phase III breast cancer clinical trials: is there a need for submission
      of portal/simulation films?
AB  - In all National Surgical Adjuvant Breast and Bowel Project (NSABP) breast cancer
      trials in which patients are treated with lumpectomy and postoperative breast
      irradiation, the quality assurance requirements dictate submission of a completed
      radiotherapy data form with the stated administered doses, the volumes treated,
      treatment prescription and daily treatment record sheets, dosimetry and
      calculation sheets, isodose distributions on the breast contour, photos of the
      patient in the treatment position, and portal or simulation films. A review of
      radiotherapy data on 1,982 patients who had lumpectomies accrued to seven recent
      NSABP breast cancer studies revealed only 2 patients who were judged to have
      inadequate fields. In both cases, a very small portion of the breast tissue was
      not included in the irradiated volume as demonstrated by the submitted films. On
      this basis, it was argued that submission of portal or simulation films for
      patients receiving postlumpectomy breast irradiation is not necessary. However,
      there was concern as to the incidence of patients with a possible excess amount
      of lung tissue included in the irradiated volume. To address this concern, the
      amount of irradiated lung was determined for the first 208 patients who had
      lumpectomies, with submitted data entered into the recent NSABP pathologic node
      positive protocol B-28. Current NSABP radiation therapy guidelines suggest
      limiting the thickness of the irradiated lung in the portal beams to < or =3 cm.
      Only two patients (<1%) were found to have >3 cm of irradiated lung tissue in the
      treatment volume. Portal film submission is a considerable inconvenience to the
      individual institutions and is costly in terms of shipping, handling, and
      storage. These results indicate that submission of portal films is not a
      necessary part of quality assurance in NSABP breast cancer protocols. The NSABP
      has therefore eliminated the requirement for routine submission of portal films
      in protocols for which radiotherapy is not part of the test question.

PMID- 10597745
TI  - A phase I/II dose escalation study of carboplatin in the treatment of newly
      diagnosed patients with advanced ovarian cancer receiving paclitaxel.
AB  - The objective of this study was to determine the maximum tolerated dose of
      carboplatin when administered with paclitaxel in previously untreated patients
      with ovarian cancer. Patients were treated with paclitaxel at 225 mg/m2 for 3
      hours followed by carboplatin at an area under the curve (AUC) of 6, 7, 8, or 9
      every 3 weeks. Granulocyte colony-stimulating factor was added if needed to
      maintain dose intensity before dose reductions were used for grade 4 hematologic
      toxicity or febrile neutropenia. Twenty-two patients were enrolled in the study.
      At the AUC 6 level, five of six patients finished all six cycles. At the AUC 7
      level, four of five patients completed six cycles, although three required dose
      reductions for toxicity. At the AUC 8 level, all four patients completed six
      cycles and two required dose reductions. The AUC 9 level was not well tolerated.
      Only four of seven patients completed six cycles. Neutropenia was common, and
      transient thrombocytopenia was more severe and required dose reduction,
      especially in later cycles. An AUC of 8 is the maximum tolerated dose of
      carboplatin in combination with paclitaxel at 225 mg/m2 for 3 hours.

PMID- 10597747
TI  - Extraskeletal osteosarcoma of the mediastinum after treatment of a mediastinal
      germ-cell tumor.
AB  - Three years after four cycles of bleomycin, etoposide, and cisplatin (BEP)
      chemotherapy for a nonseminomatous germ-cell tumor of the mediastinum followed by
      complete resection of residual teratoma in a 21-year-old man, a mediastinal
      recurrence was diagnosed as an extraskeletal osteosarcoma. After unsuccessful
      chemotherapy and removal of the tumor, the patient died of cerebral metastases.
      Histologic transformation of the teratomatous components of nonseminomatous germ
      cell tumors is an uncommon phenomenon showing a particular aspect of germ-cell
      tumor biology. We review the literature and discuss the pathogenesis concerning
      this subject.

PMID- 10597748
TI  - Usefulness of the epithelial tumor marker CA-125 in non-Hodgkin's lymphoma.
AB  - CA-125, a commonly used tumor marker for epithelial ovarian cancer, is a
      glycoprotein found in normal tissues derived from coelomic epithelia. Increased
      serum levels of CA-125 have also been found in nongynecologic tumors and
      nonmalignant diseases involving the peritoneum. A few recent studies and sporadic
      case reports have reported increased CA-125 levels in patients with non-Hodgkin's
      lymphoma (NHL). In our study, we aimed to evaluate the serum levels of CA-125 in
      patients with NHL and determine its potential role to show disease activity in
      NHL. Serum levels of CA-125 were measured in 61 patients with NHL and were found
      to be correlated with clinical stage, site of involvement, and disease activity.

PMID- 10597749
TI  - Metastatic adenocarcinoma of the pancreas to the testicle: a case report.
AB  - We report a 58-year-old man who presented with a 1-month history of left
      testicular pain and swelling that was eventually diagnosed as metastatic
      adenocarcinoma from the pancreas. Currently, there are only three accounts in the
      English literature of metastatic pancreatic carcinoma to the testis.

PMID- 10597750
TI  - Subclinical disease revisited.
AB  - It has become commonplace to treat postoperative patients with adjuvant
      radiotherapy to increase local control. The reduction in local recurrences seen
      in patients with head and neck cancer following radiotherapy led to coining of
      the term "subclinical disease" to describe the presumed presence of small,
      clinically undetectable, nests of tumor cells which remain even after the most
      aggressive of surgeries. The basic assumption fundamental to the concept of
      subclinical disease is that any patient with residual disease will suffer a local
      failure if left untreated. For example, lymph node involvement, either clinically
      evident or pathologically proven, is considered an absolute indication for
      adjuvant therapy. A positive or "close" or "microscopically positive" margin is
      also considered grounds for further treatment. The purpose of this communication
      is to critically discuss recent reports that challenge this assumption.

PMID- 10597751
TI  - The benefits of lowering cholesterol in subjects with mild hyperglycemia.

PMID- 10597752
TI  - Data vs opinion, phenytoin vs fosphenytoin: the saga continues.

PMID- 10597753
TI  - The economics of therapeutic advances: the paradigm of sympathetic suppression in
      chronic heart failure.

PMID- 10597754
TI  - Guidelines for nonemergency use of parenteral phenytoin products: proceedings of
      an expert panel consensus process. Panel on Nonemergency Use of Parenteral
      Phenytoin Products.
AB  - This document summarizes the proceedings of an expert panel consensus process
      addressing the nonemergency use of parenteral phenytoin products for management
      of seizures in pediatric and adult patients. The algorithm and consensus
      statements developed by the expert panel emphasize strategies for lowering the
      probability of adverse events associated with the use of parenteral phenytoin
      products. Specific patient characteristics are defined to guide administration
      and monitoring of parenteral phenytoin therapy. The algorithm provides a decision
      pathway for the selection of the product and the route of administration of
      phenytoin sodium or fosphenytoin sodium after it has been determined that a
      parenteral phenytoin product is appropriate. Key factors covered in the algorithm
      include a list of patient characteristics and considerations necessary to prevent
      parenteral phenytoin adverse effects during selection of administration route and
      recommendations for monitoring of parenteral phenytoin therapy once it has been
      initiated. Situations requiring rapid attainment of high phenytoin
      concentrations, such as in the management of acute seizures, are not addressed in
      these guidelines.

PMID- 10597755
TI  - The continuing importance of bile acids in liver and intestinal disease.
AB  - Bile acids, the water-soluble, amphipathic end products of cholesterol
      metabolism, are involved in liver, biliary, and intestinal disease. Formed in the
      liver, bile acids are absorbed actively from the small intestine, with each
      molecule undergoing multiple enterohepatic circulations before being excreted.
      After their synthesis from cholesterol, bile acids are conjugated with glycine or
      taurine, a process that makes them impermeable to cell membranes and permits high
      concentrations to persist in bile and intestinal content. The relation between
      the chemical structure and the multiple physiological functions of bile acids is
      reviewed. Bile acids induce biliary lipid secretion and solubilize cholesterol in
      bile, promoting its elimination. In the small intestine, bile acids solubilize
      dietary lipids promoting their absorption. Bile acids are cytotoxic when present
      in abnormally high concentrations. This may occur intracellularly, as occurs in
      the hepatocyte in cholestasis, or extracellularly, as occurs in the colon in
      patients with bile acid malabsorption. Disturbances in bile acid metabolism can
      be caused by (1) defective biosynthesis from cholesterol or defective
      conjugation, (2) defective membrane transport in the hepatocyte or ileal
      enterocyte, (3) defective transport between organs or biliary diversion, and (4)
      increased bacterial degradation during enterohepatic cycling. Bile acid therapy
      involves bile acid replacement in deficiency states or bile acid displacement by
      ursodeoxycholic acid, a noncytotoxic bile acid. In cholestatic liver disease,
      administration of ursodeoxycholic acid decreases hepatocyte injury by retained
      bile acids, improving liver tests, and slowing disease progression. Bile acid
      malabsorption may lead to high concentrations of bile acids in the colon and
      impaired colonic mucosal function; bile acid sequestrants provide symptomatic
      benefit for diarrhea. A knowledge of bile acid physiology and the perturbations
      of bile acid metabolism in liver and digestive disease should be useful for the
      internist.

PMID- 10597756
TI  - Reduced coronary events in simvastatin-treated patients with coronary heart
      disease and diabetes or impaired fasting glucose levels: subgroup analyses in the
      Scandinavian Simvastatin Survival Study.
AB  - BACKGROUND: Patients with diabetes mellitus (DM) have a marked increase in
      coronary heart disease (CHD) events relative to those without DM. In a previous
      report from the Scandinavian Simvastatin Survival Study using a clinical case
      definition of DM (n = 202), simvastatin-treated patients had significantly fewer
      CHD events compared with placebo-treated control subjects. OBJECTIVE: To examine
      the effect of simvastatin therapy on CHD in patients with DM and impaired fasting
      glucose levels. METHODS: Using the 1997 American Diabetes Association diagnostic
      criteria, we assessed the effect of simvastatin therapy post hoc for an average
      of 5.4 years in Scandinavian Simvastatin Survival Study patients with normal
      fasting glucose (n = 3237), impaired fasting glucose (n = 678), and DM (n = 483).
      RESULTS: Simvastatin-treated patients with DM had significantly reduced numbers
      of major coronary events (relative risk [RR] = 0.58; P = .001) and
      revascularizations (RR = 0.52; P = .005). Total (RR = 0.79; P = .34) and coronary
      (RR = 0.72; P = .26) mortality were also reduced in DM, but not significantly,
      due to small sample size. In impaired fasting glucose (IFG) subjects, simvastatin
      use significantly reduced the number of major coronary events (RR = 0.62; P =
      .003), revascularizations (RR = 0.57; P = .009), and total (RR = 0.57; P = .02)
      and coronary (RR = 0.45; P = .007) mortality. CONCLUSION: Our results extend
      previous findings in patients with DM to a larger cohort, confirming the benefit
      of cholesterol lowering with simvastatin treatment on CHD events. In addition,
      significant decreases in total mortality, major coronary events, and
      revascularizations were observed in simvastatin-treated patients with impaired
      fasting glucose levels. These results strongly support the concept that
      cholesterol lowering with simvastatin therapy improves the prognosis of patients
      with elevated fasting glucose levels (> or =6.0 mmol/L [> or =110 mg/ dL]) or DM
      and known CHD.

PMID- 10597757
TI  - Evaluating hypertension control in a managed care setting.
AB  - BACKGROUND: We conducted a retrospective cohort study on a random sample of adult
      patients with hypertension in a large health maintenance organization to assess
      the feasibility of documenting blood pressure (BP) control and to compare
      different measures for defining BP control. METHODS: Three criteria for BP
      control were assessed: systolic BP less than 140 mm Hg; diastolic BP less than 90
      mm Hg; and combined BP control, with systolic BP less than 140 mm Hg and
      diastolic BP less than 90 mm Hg. Four methods of assessing hypertension control
      by the above criteria were examined: proportion of patients with BP under control
      at 75% and 50% or more of their office visits; the mean of all pressures during
      the study period; and the BP from the last visit during the study period.
      RESULTS: The proportion of patients meeting each criterion for control was
      similar whether we used the mean BP for all visits, the last recorded BP, or
      control at 50% or more of visits. Control rates were substantially lower when the
      more stringent assessment, 75% of visits, was used. The proportion of patients
      with combined BP control at 75% or more of their visits was half that of the
      other methods. CONCLUSIONS: In this health maintenance organization population,
      results with the use of the simplest approach, the last BP measurement recorded,
      were similar to results with the mean BP. Our findings indicate that evaluation
      of BP control in a large health maintenance organization will find substantial
      room for improvement, and clinicians should be encouraged to be more aggressive
      in their management of hypertension, especially with regard to the systolic BP,
      which until recent years has been underemphasized.

PMID- 10597758
TI  - Cranial computed tomography before lumbar puncture: a prospective clinical
      evaluation.
AB  - OBJECTIVE: To prospectively identify which patients can safely undergo lumbar
      puncture (LP) without screening cranial computed tomography (CT). METHODS:
      Emergency department physicians examined patients before CT. Examiners recorded
      the presence or absence of 10 clinical findings and answered 8 additional
      questions. The criterion standard was noncontrast cranial CT interpreted by staff
      radiologists. Clinical findings were prospectively compared with those of CT.
      RESULTS: One hundred thirteen consecutive adults with the urgent need for LP
      (median age, 42 years) were studied. Fifteen percent of patients meeting entrance
      criteria had new CT-documented lesions, with 2.7% having lesions that
      contraindicated LP. Sensitivity, specificity, and likelihood ratios (LRs) were
      measured for the clinical findings. Three statistically significant predictors of
      new intracranial lesions were identified: altered mentation (positive LR, 2.2;
      95% confidence interval [CI], 1.5-3.2), focal neurologic examination (positive
      LR, 4.3; 95% CI, 1.9-10), and papilledema (positive LR, 11.1; 95% CI, 1.1-115).
      No single item adequately predicted the absence of CT abnormalities, but the
      clinical screening items in aggregate significantly predicted the results
      (negative LR, 0; upper 95% confidence limit, 0.6). The overall clinical
      impression had the highest predictive value in identifying patients with CT
      defined contraindications to LP (positive LR, 18.8; 95% CI, 4.8-43). CONCLUSIONS:
      Because of the low prevalence of lesions that contraindicate LP, screening
      cranial CT solely to establish the safety of performing an LP typically provides
      limited additional information. Physicians can use their overall clinical
      impression and 3 clinical predictors to identify patients with the greatest risk
      of having intracranial lesions that may contraindicate LP.

PMID- 10597759
TI  - Reliability of self-reported blood pressure measurements.
AB  - BACKGROUND: Home blood pressure (BP) monitoring improves BP control, but it is
      unknown whether patients accurately report home BP readings to their physician.
      This study compared self-reported with electronically stored home BP and heart
      rate (HR) readings and evaluated this agreement in patients with controlled vs.
      uncontrolled hypertension. METHODS: A single-blind, randomized clinical trial was
      conducted in an ambulatory managed care population. Subjects were identified by
      hypertension-related codes from the International Classification of Diseases,
      Ninth Revision (401.0, 401.1, and 401.9). Subjects recorded systolic BP (SBP),
      diastolic BP (DBP), and HR 3 times daily for 1 week by means of a digital BP
      monitor. Subjects were unaware that the monitor electronically stored results.
      RESULTS: Thirty subjects were enrolled (29 complete data sets); their mean age
      (+/-SD) was 56+/-9 years, and 15 (52%) were women. Sixty-eight percent of subject
      recorded SBP, DBP, and HR measurements were identical to electronically stored
      results. Twenty percent of recorded SBPs and 17% of recorded DBPs differed from
      stored SBP and DBP by more than 10 mm Hg. Erroneous reporting was evident in 9%
      of uncontrolled vs 4% of controlled SBPs (P<.001). Similarly, 21% of uncontrolled
      and 4% of controlled DBPs were erroneously reported (P<.001). In cases where the
      stored HR exceeded 100 beats/min, 43% of HR readings were recorded as 100
      beats/min or less (P<.001). CONCLUSIONS: Most self-reported BP and HR readings
      were identical to electronically stored measurements. However, erroneous
      reporting occurred significantly more often in cases of uncontrolled BP and HR,
      which may misguide physicians in the optimal treatment of their patients with
      hypertension.

PMID- 10597760
TI  - Treatment patterns among adult patients with asthma: factors associated with
      overuse of inhaled beta-agonists and underuse of inhaled corticosteroids.
AB  - BACKGROUND: Overuse of inhaled beta-agonists and underuse of inhaled
      corticosteroids by patients with asthma may have adverse consequences. This study
      was performed to identify factors associated with misuse of these types of asthma
      medication. METHODS: We examined baseline data from a longitudinal survey of
      adult patients with asthma. The setting was a consortium of 15 national managed
      care organizations serving 11 large employers. Baseline surveys were completed by
      6612 health plan enrollees at least 18 years old who had had at least 2 visits
      with a diagnostic code for asthma in the preceding 2 years. The main outcome
      measures were the overuse of inhaled beta-agonists and the underuse of inhaled
      corticosteroids. Independent variables were patient and process of care factors.
      RESULTS: Among patients with moderate or severe asthma, 16% of users of inhaled
      beta-agonists reported overuse (>8 puffs per day on days of use), and 64% of
      users of inhaled corticosteroids reported underuse (use on < or =4 days/wk or <
      or =4 puffs per day). Overuse of inhaled beta-agonists was most strongly
      associated with concomitant treatment with inhaled corticosteroids or
      anticholinergic agents, increased asthma symptom severity, problems in obtaining
      asthma medication, and male sex. Underuse of inhaled corticosteroids was
      associated with nonwhite race, younger age (18 to 34 years), lower use of inhaled
      beta-agonist, lower symptom severity, and not possessing a peak flow meter. Rates
      of misuse of medication also varied by speciality of the patient's provider
      (generalist, allergist, or pulmonologist). CONCLUSIONS: Overuse of inhaled beta
      agonists may be caused by symptom severity, while underusers of corticosteroids
      may interrupt use as symptoms abate. This study demonstrated an important
      opportunity to improve medication use among patients with asthma.

PMID- 10597761
TI  - Partial thromboplastin time: prediction of adverse events and poor prognosis by
      low abnormal values.
AB  - BACKGROUND: Clinical observations suggest an increased incidence of bleeding and
      thrombosis in association with a shortened partial thromboplastin time (PTT).
      OBJECTIVE: To determine whether abnormally fast PTTs are associated with an
      increased risk of death, thromboses, bleeding, and the overall occurrence of
      morbid events. METHODS: The medical records of 199 patients admitted in a 1-year
      period to a Veterans Affairs medical center were reviewed for PTTs and the events
      of death, thromboses, and severe bleeding. Group 0 (n = 49) consisted of patients
      with abnormally fast PTTs (<23 seconds). Group 1 (n = 50) consisted of patients
      with fast normal PTTs (23-25 seconds), and the control group, group 2 (n = 100),
      contained patients with PTTs from 28 to 31 seconds. The Cox proportional hazards
      regression was used to analyze the time-independent covariates of PTT groups,
      surgery, cancer, and other clinical variables as predictors of 3 outcome
      variables: bleeding, thrombosis, and death. RESULTS: Of the covariates examined,
      the PTT was found to be the most significant predictor of poor outcome. A
      statistically significant association was found between the PTT and time to death
      (P<.001), thrombotic events (P<.001), and bleeding (P<.006), and between the PTT
      and overall occurrence of morbid events (P<.001). Furthermore, survival curves
      showed that the greatest hazards of death, thrombosis, bleeding, and overall
      morbidity consistently occurred in group 0 compared with groups 1 and 2.
      CONCLUSIONS: Abnormally fast PTTs, particularly if confirmed on repeated testing,
      indicate a significant risk of subsequent death, thrombosis, bleeding, and
      overall morbidity. Careful examination of patients with low PTTs may reduce such
      associated morbidity and mortality.

PMID- 10597762
TI  - Thyroid carcinomas after irradiation for a first cancer during childhood.
AB  - BACKGROUND: The thyroid gland is among the most radiosensitive organs. However,
      little is known about the long-term risk of developing a thyroid tumor after
      fractionated external radiotherapy for cancer during childhood. OBJECTIVE: To
      study the long-term risk of developing a thyroid tumor in 4096 three-year
      survivors of childhood cancer treated between May 1942 and December 1985 in 8
      centers in France and the United Kingdom, 2827 of whom had received external
      radiotherapy. METHODS: A wide range of radiation doses were given to the thyroid:
      1164 children received less than 0.5 Gy and 812 received more than 5.0 Gy, the
      average dose being 7.0 Gy. RESULTS: After mean follow-up of 15 years (range, 3-45
      years), 14 patients-all of whom had received radiotherapy-developed a clinical
      thyroid carcinoma. Within the cohort, the relation between radiation dose to the
      thyroid and risk of thyroid carcinoma and adenoma was similar to that observed in
      patients who received radiotherapy during childhood for other reasons, such as an
      excess relative risk per gray of 4 to 8, up to a few gray. In contrast, compared
      with thyroid cancer incidence in the general population, the standardized
      incidence of thyroid carcinoma was much higher than expected from the dose
      response relationship estimated within the cohort and from patients who received
      radiotherapy during childhood for other reasons: a dose of 0.5 Gy was associated
      with a standardized incidence ratio of 35 (90% confidence interval, 10-87) and a
      dose of 3.6 Gy with a standardized incidence ratio of 73 (90% confidence
      interval, 28-153). We did not show a reduction in excess relative risk per gray
      with use of an increasing number of fractions. CONCLUSION: Although we cannot
      estimate the exact proportion, it is probable that some or all children who are
      treated for cancer are predisposed to developing a thyroid carcinoma.

PMID- 10597763
TI  - Time course of reversal of anticoagulant effect of warfarin by intravenous and
      subcutaneous phytonadione.
AB  - BACKGROUND: Excessive anticoagulation increases the risk of hemorrhagic
      complications associated with oral anticoagulant therapy. Oral or parenteral
      phytonadione is used to reverse excessive anticoagulation. Intravenous (IV)
      phytonadione, while effective, is associated with a small risk of serious
      anaphylactic reactions. Subcutaneous (SC) administration is safer, but there is
      little information on its relative efficacy in small doses. METHODS: Twenty-two
      patients with asymptomatic prolongation of prothrombin time were prospectively
      randomized and treated with 1 mg of phytonadione IV or 1 mg SC. Prothrombin time
      was measured at baseline and at 8 and 24 hours after phytonadione administration
      and expressed as international normalized ratio (INR). RESULTS: Mean INR at
      baseline was 8.0 and 8.5 in the IV and SC groups, respectively (P = .70). At 8
      hours, mean INR was 4.6 in the IV group and 8.0 in the SC group (P = .006), and
      at 24 hours, mean INR was 3.1 in the IV group and 5.0 in the SC group (P = .009).
      Mean decrease in INR 8 hours after administration of phytonadione was 3.4 in the
      IV group and 0.4 in the SC group (P = .02), and mean decrease in INR after 24
      hours was 4.9 in the IV group and 3.4 in the SC group (P = .18). CONCLUSIONS: For
      patients who are excessively anticoagulated with warfarin, small doses of SC
      phytonadione may not correct the INR as rapidly or as effectively as when
      administered IV. Higher doses must be considered for more rapid and complete
      reversal of anticoagulation by the SC route.

PMID- 10597764
TI  - Lesbians' sexual history with men: implications for taking a sexual history.
AB  - BACKGROUND: Health care providers may not solicit a comprehensive sexual history
      from lesbian patients because of provider assumptions that lesbians have not been
      sexually active with men. We performed this study to assess whether women who
      identify themselves as lesbians have a history of sexual activities with men that
      have implications for receipt of preventive health screening. OBJECTIVE: To
      convey the importance for health care providers to know their patients' sexual
      history when making appropriate recommendations for preventive health care.
      METHODS: A survey was printed in a national news magazine aimed at homosexual
      men, lesbians, and bisexual men and women. The sample included 6935 self
      identified lesbians from all 50 US states. The outcomes we measured were
      respondents' number of lifetime male sexual partners and partners during the past
      year, their lifetime history of specific sexual activities (e.g., vaginal
      intercourse, anal intercourse), their lifetime condom use, and their lifetime
      history of sexually transmitted diseases. RESULTS: Of respondents, 77.3% had 1 or
      more lifetime male sexual partners, 70.5% had a lifetime history of vaginal
      intercourse, 17.2% had a lifetime history of anal intercourse, and 17.2% had a
      lifetime history of a sexually transmitted disease. Exactly 5.7% reported having
      had a male sexual partner during the past year. CONCLUSION: These findings
      reinforce the need for providers to know their patients' sexual history
      regardless of their reported sexual orientation, especially with regard to
      recommendations for Papanicolaou smears and screening for sexually transmitted
      diseases.

PMID- 10597765
TI  - Chronic disease management: treating the patient with disease(s) vs treating
      disease(s) in the patient.
AB  - The treatment of chronic disease is often complicated by the coexistence of
      multiple medical conditions and by the presence of social and psychological
      impediments. The needs posed by patients with chronic disease are overwhelming
      the capacity of the American health care system. Alternative disease management
      systems that rely on specially trained nurse case managers to implement detailed
      clinical protocols, including drug algorithms, have shown efficacy in managing
      chronic medical conditions, singly and in combination. By fostering integration
      of care across subspecialty and medical-social boundaries, such systems enable
      treatment of the patient with disease(s), not simply treatment of disease(s) in
      the patient. Working closely with primary care physicians, often by telephone
      mediated interaction with patients, nurse case managers may take an expanded role
      in meeting the challenges posed by chronic disease.

PMID- 10597766
TI  - Drug-induced neutropenias: now and then.

PMID- 10597767
TI  - Hyperglycemia-induced hyponatremia: is it time to correct the correction factor?

PMID- 10597768
TI  - Amoxicillin can induce aseptic meningitis.

PMID- 10597769
TI  - Laboratory diagnosis of vitamin B12 and folate deficiency.

PMID- 10597770
TI  - Folate is not what it is cracked up to be.

PMID- 10597771
TI  - Additive effects of IL-2 and protein kinase A type I antagonist on function of T
      cells from HIV-infected patients on HAART.
AB  - OBJECTIVE: To explore the basis for a possible immunomodulatory combination
      therapy with IL-2 and agents inhibiting protein kinase A (PKA) type I. DESIGN:
      Highly active antiretroviral therapy (HAART) has dramatically improved HIV
      therapy, but fails to eradicate the virus, and the persistence of HIV-associated
      immunodeficiency demonstrates the need for additional immunomodulating therapies.
      We have previously shown that hyperactivation of PKA type I inhibits the function
      of HIV-infected patient T cells. The separate and combined effect of a PKA type I
      selective antagonist (Rp-8-Br-cAMPS) and Interleukin (IL)-2 on the function of T
      cells from HIV-infected patients on HAART was examined. METHODS: The effect of Rp
      8-Br-cAMPS on anti-CD3 stimulated proliferation and IL-2 production and the
      combined effect with exogenous IL-2 was studied in vitro with cells from 13 HIV
      infected patients on HAART and six uninfected controls. RESULTS: The PKA type I
      selective antagonist improved cell proliferation (median 1.5-fold, maximal 2.8
      fold) and IL-2 production (median 1.5-fold, maximal 2.4-fold) in T cells from HIV
      infected patients on HAART, but not in controls. The addition of IL-2 enhanced
      proliferation of T cells from HIV-infected patients (approximately 1.9-fold) and
      that of controls (approximately 1.4-fold), but IL-2 had no effect at the
      concentrations produced by treatment with PKA type I antagonist. However, the
      combined effect of IL-2 and PKA type I antagonist was additive and resulted in a
      further increase in T-cell proliferation (median 2.5-fold, maximal 5.8-fold),
      reaching levels comparable with those of uninfected controls in most of the
      patients. CONCLUSION: Our findings suggest a basis for a novel strategy in
      treatment of HIV infection by combining IL-2 therapy and treatment modalities
      counteracting PKA type I activity with HAART.

PMID- 10597772
TI  - Severe hepatic cytolysis: incidence and risk factors in patients treated by
      antiretroviral combinations. Aquitaine Cohort, France, 1996-1998. Groupe
      dEpidemiologie Clinique de Sida en Aquitaine (GECSA).
AB  - OBJECTIVE: To study hepatic cytolysis in patients treated by highly active
      antiretroviral therapy (HAART) with protease inhibitor or with two nucleoside
      reverse transcriptase inhibitors (NRTIs). METHODS: We selected patients of the
      Aquitaine Cohort who initiated HAART or two NRTIs before 1 January 1998, had
      alanine amino-transferase (ALT) < or = 200 IU/I at baseline and at least one
      follow-up measure. Cox model was used to study the association between occurrence
      of severe hepatic cytolysis (ALT>200 IU/l) and age, gender, HIV transmission
      group, baseline CD4 and CD8 cell count, history of hepatic cytolysis,
      antiretroviral drug, baseline liver enzymes (WHO classification level 0: < or =
      50 IU/l, level 1: 51 to 100, level 2: 101 to 200), hepatitis B and C co
      infection. RESULTS: Sixty-four of 748 (8.5%) patients treated with HAART and 71
      of 1249 (5.7%) treated with two NRTIs developed cytolysis. The probability of
      occurrence was 7.9% after 1 year [95% confidence interval (CI), 5.9-10.4] for
      patients treated with HAART and 4.8% (95% CI, 3.6-6.4) for patients treated with
      two NRTIs (log-rank test, P = 0.01). The median time to occurrence was 164 days
      for HAART-treated patients and 252 days for those treated with two NRTIs. In
      multivariate analysis, the history of cytolysis [hazard ratio (HR) = 2.3; 95% CI,
      1.2-4.4], baseline value of ALT (HR = 2.4; 95% CI, 1.2-4.8 and HR = 3.3; 95% CI,
      1.4-7.4 for levels 1 and 2, respectively), hepatitis B (HR = 3.0; 95% CI, 1.4
      6.2) and C co-infections (HR = 3.2; 95% CI, 1.7-6.2) remained significantly
      associated with the occurrence of severe hepatic cytolysis among HAART-treated
      patients. History of cytolysis, hepatitis B and C were associated with cytolysis
      in patients treated with two NRTIs (HR = 14.8, 2.6 and 2.7, respectively).
      CONCLUSION: Hepatic cytolysis is more frequent among patients treated with HAART
      than with two NRTIs. Hepatitis B and C are the major risk factors after
      initiation of HAART or treatment with NRTIs. Co-infections with hepatitis B virus
      or hepatitis C virus may modify the management of HIV-infected patients treated
      by HAART.

PMID- 10597773
TI  - Promoting early HIV diagnosis and entry into care.

PMID- 10597774
TI  - Stable expression of HIV-1 Nef induces changes in growth properties and
      activation state of human astrocytes.
AB  - OBJECTIVE: Nef was shown to be the predominant viral protein expressed in HIV-1
      infected astrocytes in vivo and in vitro suggesting a distinct role of Nef in
      this cell type. Nef-induced activation of T cells is well described, whereas the
      functional activities of Nef in astrocytes are unknown. Our aim was to examine
      the effect of Nef on growth properties and activation of astrocytes. DESIGN:
      Human Nef-expressing astrocytic cell lines were established by stable
      transfection with different wild-type and mutant nef genes derived from
      laboratory isolates and brain tissue. METHODS: Nef-expressing astrocytes were
      characterized in terms of growth properties (proliferation, growth in soft agar,
      focus formation) and morphology. Apoptotic cell death and expression of
      activation markers were determined by fluorescent antibody cell sorting. RESULTS:
      Astrocytic cell lines revealed persistent Nef expression--detectable at the
      levels of mRNA and protein--and showed altered growth properties and morphology.
      Elevated expression of activation markers such as glial fibrillary acidic protein
      and CD88 (complement receptor C5a) was observed; these are regarded as markers
      for inflammatory processes in the brain. This effect was independent of the nef
      type or the expression level of the Nef protein. In contrast with previous
      reports no evidence for increased apoptotic cell death was found in astrocytes
      expressing Nef stably. CONCLUSIONS: Our findings suggest that Nef changes the
      cellular properties of astrocytes, thus contributing to astrocyte activation and
      induction of astrogliosis in the central nervous system of individuals with AIDS.

PMID- 10597775
TI  - Evidence of blood-brain barrier alteration and activation in HIV-1 gp120
      transgenic mice.
AB  - OBJECTIVE: To verify whether HIV envelope protein gp120 changes the blood-brain
      barrier in vivo, as a fundamental mechanism of early central nervous system
      damage by HIV-1. DESIGN: Analysis of the functional integrity and immune
      activation of the blood-brain barrier in brains of HIV-1 gp120 transgenic mice
      secreting circulating gp120 at levels similar to those detected in AIDS patients.
      METHODS: Number of vessels/mm2 section area with perivascular albumin and
      percentage of vessels expressing adhesion molecules (ICAM-1 and VCAM-1) were
      determined by immunohistochemistry in frozen brains from autopsied transgenic and
      non-transgenic mice. The percentage of vessels showing substance P
      immunoreactivity was also calculated, as this neuropeptide is known to mediate
      the increase in permeability of the rat brain endothelium in vitro caused by HIV
      1 gp120. RESULTS: The number of vessels with albumin extravasation was
      significantly higher in transgenic than non-transgenic mice brains (P = 0.0003).
      A greater percentage of ICAM-1- and VCAM-1-positive brain vessels in transgenic
      than non-transgenic mice was shown (P = 0.0017 and P = 0.0008 respectively).
      Significant immunoreactivity for substance P was detected in brain vessels in
      transgenic mice and a significant correlation was found between the percentage of
      substance P-positive and ICAM-1-positive brain vessels (P < 0.0001) in transgenic
      mice. CONCLUSIONS: These findings demonstrate that HIV-1 gp120 is capable of
      changing and activating in vivo the vascular component of the blood-brain
      barrier.

PMID- 10597776
TI  - Increased fitness of drug resistant HIV-1 protease as a result of acquisition of
      compensatory mutations during suboptimal therapy.
AB  - OBJECTIVE: It is thought as a consequence of continuous replication, HIV-1 has
      acquired an optimal fitness state and that suboptimal antiretroviral therapy
      selects for drug resistant variants which show impaired fitness in the absence of
      the drug. In this paper we studied the evolution and fitness of viral populations
      appearing in a patient who received protease monotherapy. METHODS: Two factors
      contributing to fitness, drug resistance and protease catalytic activity, were
      studied at the enzymatic and virological level. RESULTS: The first drug resistant
      viral variants that were selected in vivo harboured one to three protease
      substitutions. These mutants showed reduced protease activity and consequently a
      reduction in viral replication capacity. During continued in vivo replication of
      these viruses in the presence of the drug, novel variants harbouring additional
      substitutions in the viral protease appeared. These variants did not display any
      further increase in drug resistance but demonstrated clearly increased protease
      activity. Consequently the replication capacity of these viruses was raised to a
      level at which they replicated better than the original wild-type virus.
      CONCLUSION: This study indicates that the viral population in the patient does
      not have to represent the fittest possible variants, and thus antiretroviral
      therapy may drive the viral population first through a lower fitness level and
      then to a higher fitness level.

PMID- 10597777
TI  - Do gender differences in CD4 cell counts matter?
AB  - OBJECTIVE: To examine the effect of gender on disease progression and whether
      gender differences in CD4 lymphocyte counts persisted for the entire course from
      HIV seroconversion until (death from) AIDS. METHODS: CD4 lymphocyte counts were
      modelled in 221 female and 443 male seroconverters following seroconversion,
      backwards from AIDS and backwards from death using regression analysis for
      repeated measurements. RESULTS: In the period before use of highly active
      antiretroviral therapy (HAART), progression to AIDS and to death were marginally
      slower in women than in men as assessed by proportional hazards analysis. Women
      seroconverted for HIV, developed AIDS and died at higher CD4 cell counts than men
      (women: 815, 146 and 44 x 10(6) cells/l, respectively; men: 727, 49 and 22 x
      10(6) cells/l, respectively), although differences were only statistically
      significant at AIDS onset. Declines in CD4 lymphocyte counts were not
      significantly affected by gender and absolute differences between men and women
      were stable, with exception for the trajectory close to AIDS when the decline
      became steeper for men than women. CONCLUSION: These gender differences in CD4
      lymphocyte counts suggest a delay of initiation of therapy in women compared with
      men (our model predicted that women reach the threshold of starting HAART at
      about 12 months later than men). If this delay unfavourably influences
      progression, treatment guidelines should be revised so that women can benefit
      equally from HAART.

PMID- 10597778
TI  - Activation of CD8 T cells normalizes and correlates with the level of infectious
      provirus in tonsils during highly active antiretroviral therapy in early HIV-1
      infection.
AB  - OBJECTIVES: To study the effects of antiretroviral therapy on T cell activation
      in blood and tonsils from HIV-1 infected individuals in relation to CD4 cell
      count, plasma viremia, and infectious HIV-1 provirus. DESIGN: A 48-week study of
      viral load and T cell subsets in blood and tonsils from 12 HIV-1-positive
      individuals with a mean CD4 cell number of 400 x 10(6) cells/l treated with a
      combination of zidovudine, lamivudine, and indinavir. METHODS: Tonsil biopsies
      and blood samples were collected at regular intervals. Lymphocytes were
      phenotyped and quantified by three-color flow cytometry; infectious provirus was
      quantified by a limiting dilution assay. HIV-1-negative individuals were included
      as controls. RESULTS: The fraction of tonsillar CD8 T cells expressing CD69,
      CD38, or HLA-DR in the patients with suppressed virus replication declined to
      levels comparable with that in controls by 48 weeks and showed a strong positive
      correlation with tonsillar infectious provirus and plasma viremia. The level of
      CD4 T cell activation was within normal range in tonsils throughout the study.
      The fraction of HLA-DR+ cells within CD4 and CD8 T cells in blood declined
      rapidly in parallel with plasma viremia but remained slightly higher compared
      with that in uninfected individuals. CONCLUSION: Antiretroviral therapy
      normalizes tonsillar CD8 T cell activation in HIV-1-positive individuals in
      parallel with suppression of viral replication, indicating reduced CD8 cell
      turnover. Normal tonsillar CD4 T cell activation suggests limited CD4 cell
      turnover in early HIV infection. Activated CD8 T cells in lymphoid tissue is
      superior to that in blood as an immunological marker for the virological response
      to antiretroviral therapy.

PMID- 10597779
TI  - A randomized study comparing triple versus double antiretroviral therapy or no
      treatment in HIV-1-infected patients in very early stage disease: the Spanish
      Earth-1 study.
AB  - BACKGROUND: Most current guidelines state that antiretroviral therapy should be
      considered for HIV-infected patients with plasma HIV RNA > 5000-10000 copies/ml
      and CD4 cells > 500 x 10(6) cells/l. However, there is increasing concern about
      whether this is the optimal point to begin treatment or whether it is better to
      delay the initiation to more advanced stages. OBJECTIVE: To study the
      immunological and virological benefits of starting antiretroviral therapy at
      these early stages. METHODS: A total of 161 HIV-infected asymptomatic patients
      with CD4 cell count > 500 x 10(6) cells/l and viral load > 10000 copies/ml were
      randomly assigned to one of five treatment groups: no treatment, twice daily
      zidovudine and thrice daily zalcitabine (ZDV-ddC), twice daily zidovudine and
      didanosine (ZDV-ddI), twice daily stavudine and didanosine (D4T-ddI), or a twice
      daily three-drug regimen with stavudine and lamivudine and ritonavir. The
      endpoints were progression to < 350 x 10(6) cells/l CD4 cells, to < 500 x 10(6)
      cells/l with either two Centers for Disease Control class B symptoms or an
      increase of viral load > 0.5 log10 copies/ml above baseline, or to AIDS or death.
      In various substudies, the lymphoid tissue and cerebrospinal fluid viral load,
      development of genotypic resistance, proliferative responses to mitogens and
      cytomegalovirus, and HIV-1 specific antigens and other immunophenotypic markers
      were also analysed. RESULTS: Progression rates to study endpoints within 1 year
      were greater in the control group (31%) than in all groups receiving
      antiretroviral therapy pooled together (5%; estimated hazard ratio 7.41; 95%
      confidence interval 5.72-74.55; P < 0.001). The peak mean viral load decrease was
      greater in the three-drug group when compared with any of the three groups with a
      two-drug regimen (2.32, 1.65, 1.72 and 1.84, respectively; P < or = 0.001). At 1
      year, viral load remained below 20 copies/ml in 30 out of 33 patients in the
      three-drug group (91%) and in only eight out of 94 patients (9%) in two-drug
      groups (P = 0.001). The peak mean increase in CD4 cells was also greater in the
      three-drug group than in the double treatment arms (259 versus 85, 144 and 145 x
      10(6) cells/l, respectively; P = 0.001). By comparison, 36% of patients in the
      three-drug group regimen had to change the therapy as a result of adverse events.
      Substudies were performed in 60 patients recruited at two sites. Tonsillar tissue
      HIV RNA was measured in seven patients (two in the two-drug groups and five in
      the three-drug group) in whom plasma HIV RNA was < 20 copies/ml at 1 year. It was
      15151 and 133333 copies/mg tissue in the two patients from the two-drug group, <
      40 copies/mg tissue in four patients in the three-drug group, and 485 copies/mg
      in one patient in the three-drug group. At 1 year there was a mean increase of
      4.21+/-2.94% in CD8+CD38+ cells in the control group and a decrease of 9.48+/
      3.36% in the two-drug groups (P = 0.01), and 19.87+/-3.64 in the three-drug group
      (P = 0.001 and P = 0.05, for comparisons with control group and two-drug groups,
      respectively). Although proliferative responses to cytomegalovirus antigens were
      significantly greater in those receiving antiretroviral therapy, response to HIV
      1 p24 antigen was not detected in any patient in either treatment group.
      CONCLUSIONS: This study supports the recommendation to start antiretroviral
      therapy with a three-drug combination during very early stages of HIV-1 disease,
      at least if viral load is above a cut-off point (10000 copies/ml in our study).
      The risk of progression was sevenfold higher in non-treated patients at 8 months
      of follow-up. Some immune system parameters improved toward normal values after 1
      year of antiretroviral therapy, but the proliferative response of CD4 T
      lymphocytes against the p24 HIV-1 antigen was not recovered. Therapeutic
      approaches with more potent, better-tolerated and more convenient regimens will
      increasingly favour early intervention with antiretroviral t

PMID- 10597780
TI  - Beneficial effects of protease inhibitors on body composition and energy
      expenditure: a comparison between HIV-infected and AIDS patients.
AB  - OBJECTIVES: (i) To investigate whether protease inhibitor (PI) (nelfinavir)
      containing highly active antiretroviral therapy (HAART) affects body composition
      differently in HIV-infected and AIDS patients without wasting syndrome. (ii) To
      delineate the changes in resting energy expenditure (REE) under PI therapy, and
      to determine whether sustained reductions in HIV RNA would decrease REE. DESIGN:
      Prospective longitudinal cohort study with individually matched healthy controls.
      SETTING: Tertiary care centre at a University Hospital. METHODS: HIV-seropositive
      (n = 20) and AIDS patients (n = 17) with a plasma viral load of at least 10000
      copies/ml and 37 healthy volunteers were enrolled. All participants were weight
      stable, free of acute opportunistic infections, and naive to PI therapy. Patients
      underwent testing of bioelectrical impedance analysis (BIA), indirect calorimetry
      and food intake, shortly before the initiation of HAART and 24 weeks thereafter.
      RESULTS: Both patient groups gained weight, body mass index (BMI), and fat-free
      mass (FFM) (P < 0.05 versus baseline), whereas only AIDS patients gained fat
      mass. Increases were more pronounced in the AIDS group. REE was elevated compared
      with corresponding controls at baseline, and decreased similarly in HIV and in
      AIDS patients during PI therapy (P < 0.05). The reduction in the viral burden
      preceded the decrease in REE by several weeks. CONCLUSION: Body composition and
      metabolic parameters improved during PI therapy in HIV-infected and AIDS patients
      without wasting. Although an early reduction in viral load as a result of HAART
      does not seem to influence REE directly, sustained viral load suppression may
      promote a decrease in energy expenditure.

PMID- 10597781
TI  - A randomized, controlled, safety study using imiquimod for the topical treatment
      of anogenital warts in HIV-infected patients. Imiquimod Study Group.
AB  - OBJECTIVE: To assess the safety of imiquimod, an immune response modifier, in the
      topical treatment of external anogenital warts in HIV-infected patients. SETTING:
      Clinical sites in the United Kingdom (eight) and the United States (five).
      DESIGN: A prospective, randomized, double-blind, vehicle-controlled study of
      imiquimod 5% cream or vehicle applied for 8+/-2 h three times per week for a
      maximum of 16 weeks in HIV-seropositive males (n = 97) and females (n = 3) aged
      18 years or more with clinically diagnosed external anogenital warts, CD4 T
      lymphocyte count of > or = 100 x 10(6) cells/l and Karnofsky score > or = 70.
      MAIN OUTCOME MEASURES: Safety was assessed through the incidence and severity of
      local skin reactions and other adverse events, and through clinical laboratory
      tests. Wart clearance was documented by two-dimensional measurements of warts and
      by photography. RESULTS: Among the patients treated with imiquimod (n = 65) and
      vehicle (n = 35), the most common local skin reaction was erythema, (41.9 and
      26.7%, respectively) and the incidence of patients reporting at least one adverse
      event was 69.2 and 65.7%, respectively. No clinically meaningful differences or
      changes in laboratory values were observed between treatment groups, nor were
      drug-related adverse effects observed in regard to HIV disease. While there was
      no significant difference between treatment groups in the number of patients who
      totally cleared their baseline warts (imiquimod 11% versus vehicle 6%, P =
      0.488), more imiquimod-treated patients experienced a > or = 50% reduction in
      baseline wart area (38% versus 14%, P = 0.013). CONCLUSION: Most local skin
      reactions were mild and no adverse effects on HIV disease were observed.
      Topically applied imiquimod 5% cream reduced wart area and may have clinical
      utility in treating external anogenital warts in some HIV-infected patients.

PMID- 10597782
TI  - Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected
      patients on potent antiretroviral therapy.
AB  - BACKGROUND: A stable reservoir of latently infected, resting CD4 T cells has been
      demonstrated in HIV-1-infected patients despite prolonged antiretroviral
      treatment. This is a major barrier for the eradication of HIV by antiretroviral
      agents alone. Activation of these cells in the presence of antiretroviral therapy
      might be a strategy to increase the turnover rate of this reservoir. METHODS:
      Three HIV-1-positive patients on potent antiretroviral therapy, in whom plasma
      viremia had been suppressed to below 5 copies/ml for at least 26 weeks, were
      treated with a combination of OKT3 (days 1-5) and recombinant human IL-2 (days 2
      6). RESULTS: The side-effects were fever, headache, nausea, diarrhea, and in one
      of the patients transient renal failure and seizures. The regimen resulted in
      profound T cell activation. In one patient plasma HIV-1 RNA transiently increased
      with a peak at 1500 copies/ml. In the other two patients plasma HIV-1 RNA levels
      remained below the detection limit, but HIV-1 RNA levels in the lymph nodes
      increased two- to threefold. All patients developed antibodies against OKT3.
      CONCLUSION: OKT3/IL-2 resulted in T cell activation and proliferation, and could
      stimulate HIV replication in patients having achieved prolonged suppression of
      plasma viremia. OKT3/IL-2 therapy was toxic and rapidly induced antibodies
      against OKT3.

PMID- 10597783
TI  - A phase II safety and efficacy study of amprenavir in combination with zidovudine
      and lamivudine in HIV-infected patients with limited antiretroviral experience.
      Amprenavir PROAB2002 Study Team.
AB  - OBJECTIVE: To determine the safety and efficacy of amprenavir (APV) in
      combination with lamivudine (3TC) and zidovudine (ZDV). DESIGN: Multicenter,
      randomized, partially blinded trial. SETTING: Nine study sites in the United
      States and Europe. PATIENTS: A group of 84 HIV-infected subjects with no prior
      3TC or protease inhibitor therapy experience, CD4 cell count > or = 150 x 10(6)
      cells/l, and plasma HIV RNA > 10000 copies/ml. INTERVENTIONS: 3TC/ZDV with one of
      three doses of APV (900, 1050, or 1200 mg) versus 3TC/ZDV with 1050 mg placebo.
      All medications were dosed twice daily. The 1050 mg placebo and the APV 1050 mg
      dose were administered blinded. After 12 weeks, APV 1050 mg was substituted for
      1050 mg placebo in the control group and the blind was maintained. MAIN OUTCOME
      MEASURES: Reduction in plasma HIV RNA from baseline; proportion of subjects with
      plasma HIV RNA < 400 copies/ml; and an increase in CD4 cell count from baseline.
      RESULTS: During the initial 12-week study period, APV/3TC/ZDV-treated subjects
      had greater viral suppression than the group receiving two nucleosides. By 48
      weeks, 89% of subjects in the group taking the highest APV dose (1200 mg) had
      plasma HIV RNA < 400 copies/ml while 42% of the 900 mg group and 60% of the
      3TC/ZDV group (1050 mg APV added at week 12) had plasma HIV RNA < 400 copies/ml
      using an as-treated analysis. By 60 weeks, 86% of subjects in the APV 1200 mg
      group had plasma HIV RNA < 400 copies/ml in the as-treated analysis, while 25%
      (900 mg), 43% (1050 mg), and 20% (1200 mg) of subjects had viral load <400
      copies/ml in a strict intent-to-treat analysis owing to treatment
      discontinuations. Median CD4 cell count increases at week 60 were highest for the
      three treatment groups who received APV throughout the study, by intent-to-treat
      and as-treated analyses. The most common adverse events considered to be possibly
      drug related were nausea, rash, oral paresthesia, diarrhea, and fatigue.
      CONCLUSIONS: Treatment with APV, dosed at 1200 mg twice daily in combination with
      3TC/ZDV, resulted in sustained viral suppression. This combination represents a
      potent alternative initial antiretroviral regimen for protease inhibitor-naive
      individuals.

PMID- 10597784
TI  - Invasive amoebiasis: an emerging parasitic disease in patients infected with HIV
      in an area endemic for amoebic infection.
AB  - OBJECTIVES: To describe the incidence and presentations of invasive amoebiasis
      (IA) in patients with HIV infection in an area endemic for amoebic infection and
      to assess the role of the indirect haemagglutination (IHA) assay in the diagnosis
      of IA in HIV-infected patients. DESIGN: Retrospective study of 18 cases of IA and
      HIV infection. SETTING: A university hospital, the largest centre for management
      of HIV-associated complications in Taiwan. METHODS: Medical, microbiological and
      histopathological records of 296 HIV-infected patients and serological data of
      IHA assay of 126 HIV-infected patients were reviewed to identify cases of IA from
      23 June 1994 to 31 March 1999. An IHA titre > or = 1 : 128 was considered
      positive. Clinical characteristics of HIV-infected patients with IA and without
      IA were compared. RESULTS: Eighteen of the 296 patients (6.1%) with HIV infection
      were diagnosed with IA: 12 patients were diagnosed with definite IA and six with
      probable IA. The clinical manifestations included amoebic colitis (13 patients),
      amoebic liver abscess (nine), both colitis and abscess (four), and pleural
      effusion (two). IA was the initial presentation of HIV infection in nine
      patients. Co-infection with other enteric pathogens was diagnosed in six patients
      with IA. Compared with the 161 patients without IA who were newly diagnosed with
      HIV infection, the nine patients with IA had a higher median CD4+ lymphocyte
      count (202 x 10(6)/l versus 33 x 10(6)/l; P = 0.0017), were less likely to be
      diagnosed with AIDS (55.6% versus 85.4%; P = 0.039), and had fewer concurrent
      AIDS-defining illnesses (median number 0 versus 2; P = 0.003). Estimated mean
      survival duration was not significantly different between the two groups (597
      days versus 611 days). Fourteen out of 126 patients (11.1%) had an IHA titre > or
      = 1 : 128. Of the 18 patients diagnosed with IA, 13 had a titre > or = 1 : 128.
      The sensitivity of IHA assay in the diagnosis of IA was 72.2% (13 out of 18) and
      the specificity was 99.1% (107 out of 108). The positive predictive value of IHA
      test for IA of this patient population was 92.9% (13 out of 14) whereas the
      negative predictive value was 95.5% (107 out of 112). CONCLUSION: IA is an
      increasingly important parasitic disease among patients with HIV infection in
      Taiwan. IHA assay has a good specificity and high negative predictive value in
      diagnosis of IA.

PMID- 10597785
TI  - Epidemiology of AIDS in incarcerated persons in the United States, 1994-1996.
AB  - OBJECTIVE: To compare demographic, behavioral, and geographic characteristics of
      incarcerated persons with AIDS and those of all persons with AIDS reported from
      January 1994 through December 1996. DESIGN: Population-based surveillance.
      SETTING: Medical records of persons for whom AIDS diagnosis was made in
      hospitals, clinics, and other settings (e.g., prisons) in the United States.
      PATIENTS: Adults (13 years or older) with AIDS reported from January 1994 through
      December 1996. RESULTS: Of the 220000 AIDS cases in adults, 4% were reported in
      incarcerated persons. Compared with all persons with AIDS, a higher proportion
      were male (89% versus 82%), black (58% versus 39%), younger at time of diagnosis
      (35 versus 37 years), had injected drugs (61% versus 27%), and were reported on
      the basis of the 1993 immunologic criteria (71% versus 50%). Fewer cases in
      incarcerated persons were diagnosed at death (3% versus 10%). The South (38%) and
      the Northeast (37%) United States accounted for the largest proportion of
      incarcerated persons. The 1996 AIDS rate for incarcerated persons (199 per
      100000) was six times the national rate of 31 per 100000. Among persons
      incarcerated at time of diagnosis, rates for women were higher than for men (287
      versus 185 per 100000) and higher for blacks and Hispanics than for whites (253,
      313, and 100 per 100000, respectively). By state of report, Connecticut had the
      highest rate among incarcerated persons (1348 per 100000). CONCLUSION: These data
      illustrate differences in demographic, behavioral, and geographic characteristics
      of incarcerated persons compared with all persons with AIDS. However, they
      reflect only the minimum numbers of incarcerated persons with AIDS in the United
      States. Our results highlight the need for state health departments to work with
      correctional systems to ensure accurate and timely reporting of AIDS cases and to
      develop HIV prevention, education, and treatment both in prison and on release
      into the community.

PMID- 10597786
TI  - Effect of the worldwide epidemic on HIV prevalence in the United Kingdom: record
      linkage in anonymous neonatal seroprevalence surveys.
AB  - OBJECTIVE: To assess the impact of the worldwide HIV/AIDS epidemic on the
      prevalence of HIV in women in the United Kingdom (UK), particularly in the large
      immigrant and ethnic minority communities. METHOD: Unlinked anonymous neonatal
      seroprevalence survey with electronic record linkage of data from child health
      computers (maternal age and ethnic status) and birth registration (parent's
      country of birth). RESULTS: Of a total 137456 samples collected in 1997-1998, 188
      (0.14%) were anti-HIV-1 seropositive. Seroprevalence was highest in women born in
      East Africa (2.3%) and Central Africa (1.9%). 76.4% of seropositive newborns were
      delivered to mothers born in sub-Saharan Africa; a further 6.0% had fathers from
      sub-Saharan Africa. However, there was little evidence of HIV in women born in
      Southern Asia [prevalence 0.0081%; 95% confidence interval (CI) 0-0.04], and none
      within UK-born Asian communities. Prevalence among the UK-born Black African
      community was low (0.14%; 95% CI 0-0.6). Among infants with both parents known to
      be born in the UK, seroprevalence was 0.023% (95% CI 0.01-0.04) in London, and
      zero (95% CI 0-0.007) in non-Metropolitan areas. Irrespective of mother's region
      of birth, seroprevalence was 4.2 times higher (95% CI 3.0-5.8) in newborns whose
      father's details were not recorded at birth registration, a marker for single
      unsupported mothers. CONCLUSION: The risk of HIV among pregnant women from sub
      Saharan Africa has been recognized. However, in southern England, HIV is very
      rare in women from Southern Asia and in UK-born women in ethnic minority
      communities, in spite of cultural and travel ties to high-prevalence countries.
      Data linkage in anonymous surveys assists in monitoring the impact of the
      worldwide epidemic on prevalence and incidence locally.

PMID- 10597787
TI  - Country-specific estimates and models of HIV and AIDS: methods and limitations.
AB  - OBJECTIVE: This paper presents the methods used to calculate the end of 1997
      country-specific estimates of HIV and AIDS produced by the UNAIDS/WHO Working
      Group on Global HIV/AIDS and STD Surveillance. The objective of this exercise was
      to improve estimates on HIV/AIDS by using country-specific models of HIV/AIDS
      epidemics. The paper describes and discusses the processes and obstacles that
      were encountered in this multi-partner collaboration including national and
      international experts. METHODS: The 1997 estimates required two basic steps.
      First, point prevalence estimates for 1994 and 1997 were carried out and the
      starting year of the epidemic was determined for each country. The procedures
      used to calculate the estimates of prevalence differed according to the assumed
      type of the epidemic and the available data. The second step involved using these
      estimates of prevalence over time and the starting date of the epidemic to
      determine the epidemic curve that best described the spread of HIV in each
      particular country. A simple epidemiological program (EPIMODEL) was used for the
      calculation of estimates on incidence and mortality from this epidemic curve.
      RESULTS: Regional models that were used in previous estimation exercises were not
      able to capture the diversity of HIV epidemics between countries and regions. The
      result of this first country-specific estimation process yielded higher estimates
      of HIV infection than previously thought likely, with over 30 million people
      estimated to be living with HIV/AIDS. The application of survival times that are
      specific to countries and regions also resulted in higher estimates of mortality,
      which more accurately describe the impact of the epidemics. At the end of 1997,
      it was estimated that 11.7 million people worldwide had died as a result of
      HIV/AIDS since the beginning of the epidemic. CONCLUSION: This exercise is an
      important step in improving understanding of the spread of HIV in different parts
      of the world. There are, however, shortcomings in the current systems of
      monitoring the epidemic. Improvements in HIV surveillance systems are needed in
      many parts of the world. In addition, further research is needed to understand
      fully the effects of the fertility reduction as a result of HIV, differing sex
      ratios in HIV infection and other factors influencing the course and measurement
      of the epidemic.

PMID- 10597788
TI  - Severe adverse life events and depressive symptoms among women with, or at risk
      for, HIV infection in four cities in the United States of America.
AB  - OBJECTIVE: To examine frequency and predictors of severe adverse life events and
      depressive symptoms among HIV-infected women and a comparison group of uninfected
      women. DESIGN: Analysis of baseline data collected from HIV-infected and
      uninfected women in a prospective cohort study of HIV infection and women, the
      HIV Epidemiologic Research Study. METHOD: The sample of 871 HIV-infected and 439
      demographically and behaviorally similar uninfected women were recruited from
      four metropolitan areas in the USA. Women provided interview information that
      included sociodemographic characteristics, sexual and drug-using behaviors, and
      social and psychological functioning. The outcome measures were number of severe
      adverse life events (e.g., insufficient money for necessities, physical attack or
      rape, death of a person close to them) and levels of depressive symptoms.
      RESULTS: HIV-infected and uninfected women reported numerous adverse life events
      and high levels of depressive symptoms. The two groups, however, did not differ
      on either outcome measure. Low socio-economic status, injecting drug and crack
      cocaine use, and high risk sexual activity were related to reports of more
      adverse events and depressive symptoms for both groups. CONCLUSIONS: HIV-infected
      and uninfected women in socially and economically disadvantaged environments
      experience many adverse events and high levels of depressive symptoms. HIV
      infection, at least during the early phase, may be less important than socio
      environmental factors in predicting negative psychosocial outcomes for women.

PMID- 10597789
TI  - HIV counselling and testing: overemphasizing high acceptance rates a threat to
      confidentiality and the right not to know.
AB  - OBJECTIVE: To examine factors affecting the readiness for HIV-related voluntary
      confidential counselling and testing (VCT). METHODS: In a population-based HIV
      survey in selected urban and rural areas in Zambia, adults aged > or = 15 years
      were selected by stratified random cluster sampling. The participants were asked
      to provide a saliva sample for anonymous HIV testing (n=4812, consent rate 93.5%)
      and, as a part of an interview, were asked about previous HIV testing experience
      and if they wished to be counselled and tested for HIV. Those indicating interest
      (initially willing) were provided with an invitation letter to see a counsellor.
      In rural areas, VCT was provided by personnel brought in from outside the local
      community, whereas in urban areas it was provided by locally recruited staff.
      RESULTS: The overall HIV test rate was 6.5%, but rates appeared to be
      considerably biased towards higher educational groups. The proportion initially
      willing was 37% while 3.6% actually came for counselling and were tested (9.3% of
      those initially willing), of which 47% returned for the result. Actual use was
      four to five times higher in rural compared with urban areas. Self-perceived risk
      and high-risk behaviour were positively associated with initial willingness but
      not with actual use. CONCLUSIONS: The readiness for VCT in the general population
      was found to be very low. Provision factors such as concerns about
      confidentiality and length of time waiting for the test result contributed to the
      low utilization rate. Results of this study contrast sharply with reported VCT
      acceptance rates of 70-90% among women attending antenatal care in Zambian and in
      other African populations, suggesting an urgent need to evaluate testing policy
      and practice of antenatal VCT in particular.

PMID- 10597790
TI  - HIV care among incarcerated persons: a missed opportunity.

PMID- 10597791
TI  - Severe adverse life events and depressive symptoms among women with or at risk of
      HIV infection.

PMID- 10597792
TI  - Leptin levels in HIV-positive patients treated with HAART.

PMID- 10597793
TI  - Recombinant human growth hormone improves truncal adiposity and 'buffalo humps'
      in HIV-positive patients on HAART.

PMID- 10597794
TI  - Bitter pill: the current state of antiretroviral care in selected nations around
      the globe.

PMID- 10597795
TI  - Selective vertical transmission of HIV: lamivudine-resistant maternal clone
      undetectable by conventional resistance testing.

PMID- 10597796
TI  - Antiretroviral treatment among HIV-1 seroconverters from Lyon, France (1985
      1998). Lyon CISIH Collaborators.

PMID- 10597797
TI  - Recovery of haematopoietic abnormalities in HIV-1 infected patients treated with
      HAART.

PMID- 10597798
TI  - Occurrence of Pneumocystis carinii pneumonia in HIV-1-infected patients
      responding to HAART: is prophylaxis discontinuation a safe tool?

PMID- 10597800
TI  - AIDS dementia complex: response to highly active antiretroviral therapy.

PMID- 10597799
TI  - Effect of tuberculosis therapy on nevirapine trough plasma concentrations.

PMID- 10597801
TI  - Measuring medication adherence: is assessment of missed doses sufficient?

PMID- 10597802
TI  - Increasing muscle mass in spinal cord injured persons with a functional
      electrical stimulation exercise program.
AB  - OBJECTIVE: To determine the magnitude of changes in muscle mass and lower
      extremity body composition that could be induced with a regular regimen of
      functional electrical stimulation (FES)-induced lower-extremity cycling, as well
      as the distribution of changes in muscle mass among the thigh muscles in persons
      with spinal cord injury (SCI). STUDY DESIGN: Thirteen men with neurologically
      complete motor sensory SCI underwent a 3-phase, FES-induced, ergometry exercise
      program: phase 1, quadriceps strengthening: phase 2, progressive sequential
      stimulation to achieve a rhythmic pedaling motion (surface electrodes placed over
      the quadriceps, hamstrings, and gluteal muscles); phase 3, FES-induced cycling
      for 30 minutes. Participants moved from one phase to the next when they met the
      objectives for the current phase. MEASURES: Computed tomography of legs to assess
      muscle cross-sectional area and proportion of muscle and adipose tissue. Scans
      were done at baseline (before subjects started the program), at first follow-up,
      typically after 65.4+/-5.6 (SD) weekly sessions, and at second follow-up,
      typically after 98.1+/-9.1 sessions. RESULTS: Increases in cross-sectional areas
      were found in the following muscles: rectus femoris (31%, p<.001). sartorius
      (22%, p<.025), adductor magnus-hamstrings (26%, p<.001), vastus lateralis (39%, p
      = .001), vastus medialis-intermedius (31%, p = .025). Cross-sectional area of
      adductor longus and gracilis muscles did not change. The ratio of muscle to
      adipose tissue increased significantly in thighs and calves. There was no
      correlation among the total number of exercise sessions and the magnitude of
      muscle hypertrophy. CONCLUSIONS: Muscle cross-sectional area and the muscle to
      adipose tissue ratio of the lower extremities increased during a regular regimen
      of 2.3 FES-induced lower extremity cycling sessions weekly. The distribution of
      changes was related to the proximity of muscles to the stimulating electrodes.

PMID- 10597803
TI  - Age differences in postural sway during volitional head movement.
AB  - OBJECTIVE: To examine the role of a volitional self-paced head-turn movement on
      the postural sway characteristics of healthy young and elderly subjects. DESIGN:
      Cross-sectional design. SETTING: Motor control research laboratory. SUBJECTS: Ten
      young adults and 10 elderly subjects. MAIN OUTCOME MEASURES: Postural sway
      characteristics of each subject were examined using a Kistler force platform.
      Each subject was tested under four experimental conditions: (1) static postural
      sway with vision; (2) static postural sway without vision; (3) postural sway with
      vision and self-paced head-turn movement; and (4) postural sway with no vision
      and a self-paced head-turn movement. Subjects performed six 15-second trials in
      each experimental condition. Dependent variables analyzed on each trial were mean
      sway amplitude (in millimeters), sagittal sway standard deviation, lateral sway
      standard deviation, and frequency of sway (in hertz). RESULTS: During the static
      conditions (e.g., no voluntary movement), the young subjects produced
      significantly less postural sway than the elderly in both the vision condition
      (sway amplitude in the young, 3.80 mm; in the elderly, 4.89 mm) and the no-vision
      condition (young, 5.44 mm; elderly, 5.95 mm). This increased sway was the result
      of greater lateral sway in the elderly for the vision condition (3.73 vs. 2.68
      mm), and greater sagittal sway for the elderly in the no-vision condition (5.55
      vs. 4.70 mm). There were no significant differences between the groups in the
      frequency of sway. When asked to initiate and complete the head-turn, elderly
      subjects significantly increased their mean sway amplitude and decreased their
      frequency of sway, whereas the young subjects did not significantly alter their
      postural sway profiles. CONCLUSIONS: These results demonstrate different postural
      sway control strategies for young and elderly subjects when asked to perform
      volitional movements.

PMID- 10597804
TI  - Extent and direction of joint motion limitation after prolonged immobility: an
      experimental study in the rat.
AB  - OBJECTIVES: To test the hypotheses that contractures progress at different rates
      in relation to the time after immobilization, that immobilization in flexion
      leads to loss of extension range of motion, and that joints of sham-operated
      animals are better controls than the contralateral joint of experimental animals.
      STUDY DESIGN: Experimental, controlled study in which 40 adult rats had one knee
      joint immobilized at 135 degrees of flexion for up to 32 weeks and 20 animals
      underwent a sham procedure. At intervals of 2, 4, 8, 16, and 32 weeks, 8
      experimental and 4 sham-operated animals were killed and their knee motion
      measured in flexion and extension. RESULTS: In the experimental group, the range
      of motion decreased in the first 16 weeks of immobility at an average rate of 3.8
      degrees per week (p<.0001) to reach 61.1 degrees of restriction. A plateau was
      then observed from which the contracture did not progress further. The loss in
      range of motion occurred in extension, not in flexion. CONCLUSION: This study
      defined an acute stage of contractures starting at the onset of immobility and
      lasting 16 weeks, during which the range of motion was progressively restricted,
      and a chronic stage during which no additional limitation was detected. The loss
      in motion was attributed to posterior knee structures not under tension during
      immobilization in flexion. Contrary to the hypothesis, the contralateral joint
      was validated as a control choice for range-of-motion experiments.

PMID- 10597805
TI  - Spasticity after traumatic spinal cord injury: nature, severity, and location.
AB  - OBJECTIVE: To assess spasticity in a prevalence population of persons with
      traumatic spinal cord injury (SCI), and determine the degree of correspondence
      between self-reported spasticity and investigator-elicited spasticity using the
      modified Ashworth scale. DESIGN: Survey of a near total (88%) prevalence
      population. SETTING: Outpatient clinic of a university hospital. PATIENTS: A
      total of 354 individuals with SCI. MAIN OUTCOME MEASURES: The survey includes
      self-reported symptoms, neurologic examination (American Spinal Injury
      Association [ASIA] classification), physical therapy examination, range of motion
      (ROM), and complications. RESULTS: Presence of problematic spasticity was
      significantly correlated with cervical incomplete (ASIA B-D) injury. Reports of
      beneficial effects of spasticity were significantly less common in women. Self
      reported problematic spasticity was significantly correlated with extensor
      spasticity. Spasticity was elicitable by movement provocation in 60% of the
      patients reporting spasticity. Significant correlations were found between
      elicitable spasticity and limited ROM. CONCLUSION: Flexion, extension, and
      abduction movements performed with the patient placed in a standardized supine
      test position are suitable both for test of ROM and degree of spasticity.
      Spasticity was not elicitable by movement provocation on physical examination in
      40% of the patients who reported spasticity, thus indicating that the patient's
      self-report is an important complement to the clinical assessment. A significant
      association between spasticity and contractures (reduced ROM) was seen.

PMID- 10597807
TI  - Determining the relation between quality of life, handicap, fitness, and physical
      activity for persons with spinal cord injury.
AB  - OBJECTIVE: Determining relationships among fitness, physical activity, subjective
      quality of life, and handicap in persons with spinal cord injury (SCI). DESIGN:
      Cross-sectional exploratory study. SETTING: University research laboratory
      setting. PARTICIPANTS: Twenty-eight men and 10 women (age 35.9+/-9.3 yrs) with
      SCI (17 quadriplegic, 21 paraplegic). MAIN OUTCOME MEASURES: Fitness (maximal
      incremental exercise test on arm ergometer), physical activity (leisure time
      exercise questionnaire), subjective quality of life (Quality of Life Profile:
      Physical and Sensory Disabilities Version), and level of handicap (Craig Handicap
      Assessment Reporting Technique). Correlational analyses examined relationships
      between the measures. RESULTS: Physical activity was correlated with composite
      handicap score in quadriplegic and paraplegic persons. Handicap domain scores for
      physical independence, mobility, and occupation were correlated with physical
      activity in quadriplegic persons. There was no relation between the subjective
      quality of life scores and fitness and physical activity in either group.
      CONCLUSIONS: Physical activity may play an important role in handicap for persons
      with SCI, particularly persons with quadriplegic injuries. The lack of a relation
      between activity variables and subjective quality of life may be related to the
      global nature of the measure used.

PMID- 10597806
TI  - Postural control during stance in paraplegia: effects of medially linked versus
      unlinked knee-ankle-foot orthoses.
AB  - OBJECTIVE: To investigate the effect of medially linking knee-ankle-foot orthoses
      (KAFOs) on postural stability and sway during (1) quiet standing and (2)
      functional activities for persons with spinal cord injury (SCI). DESIGN: A
      randomized, mixed design, with the factors being activity (quiet standing and two
      function-mimicking tasks), SCI (present or not), and type of orthosis used in SCI
      group (linked or unlinked KAFO). PARTICIPANTS: Nine men with T5 to T12
      paraplegia, 8 of whom had complete lesions and 1 with some sacral sparing
      (American Spinal Injury Association grade B) without proprioception, matched to 9
      able-bodied men. MAIN OUTCOME MEASURES: Mean amplitude of sway and sway path in
      anteroposterior and mediolateral directions, derived from center of pressure
      measurements on a force platform. RESULTS: All men with SCI were able to stand
      unsupported and perform function-mimicking activities in medially linked KAFOs;
      however, when wearing unlinked KAFOs only 5 could maintain balance during quiet
      stance and 3 could maintain balance during activity. Significant differences were
      found between linked and unlinked KAFOs; side-to-side mean amplitude of sway was
      less and sway path was greater for SCI subjects when they wore the linked KAFOs.
      CONCLUSION: Medial linkage of bilateral KAFOs provides an effective strategy to
      improve stability and increase postural control for persons with SCI,
      facilitating performance of functional activities during standing without upper
      limb support.

PMID- 10597808
TI  - The Frail Elderly Functional Assessment questionnaire: its responsiveness and
      validity in alternative settings.
AB  - OBJECTIVE: To test the Frail Elderly Functional Assessment (FEFA) questionnaire
      for responsiveness (sensitivity to change) to low-level functional tasks in a
      frail elderly cohort and to evaluate its validity over the telephone or when
      administered to a caregiver proxy. SUBJECTS: Fifty-eight elderly patients from
      three urban inpatient rehabilitation settings and an outpatient geriatrics
      center. METHODS: A prospective, clinical, comparative trial. The FEFA
      questionnaire was administered serially. For validity, subjects were observed
      performing the tasks on the questionnaire within 24 hours of each interview. For
      responsiveness, repeat measures were performed within a 1- to 2-week period.
      Validity and sensitivity to change (responsiveness) of the questionnaire were
      determined by correlating patient responses to direct observations by
      rehabilitation staff. Responsiveness was also determined based on the Guyatt
      technique that divides clinically significant change by the normal variance,
      sigma/(2x [mean squared error])1/2, as well as by measures of effect size,
      standardized response means, and relative efficiency tests for responsiveness. To
      evaluate FEFA validity in alternative settings, kappa statistic and regression
      analyses were used based on the previously validated interviewer-administered
      format. RESULTS: Responsiveness was excellent with effect size (.35),
      standardized response means (.48), and relative efficiency (2.67) tests as well
      as Guyatt (1.26). There was 83% agreement when compared with FEFA task
      performance. Regression between change in FEFA score versus performance testing
      was significant (r2 = .33; p = .01). ANOVA was significant at a p = .03 for FEFA
      scores at first measure in rehabilitation compared to second. Correlation for
      caregiver proxy administration was .92 (p< or =.0001) and for telephone
      administration was .99 (p<.0001). CONCLUSIONS: The FEFA questionnaire, previously
      demonstrated to be reliable and valid, is sensitive to functional change
      (responsive) in frail elderly people. It is also valid when administered by phone
      or to a caregiver proxy.

PMID- 10597809
TI  - Clinical use of the Odstock dropped foot stimulator: its effect on the speed and
      effort of walking.
AB  - OBJECTIVE: To assess the clinical effectiveness of the Odstock dropped foot
      stimulator by analysis of its effect on physiological cost index (PCI) and speed
      of walking. This functional electrical stimulation (FES) device stimulates the
      common peroneal nerve during the swing phase of gait. DESIGN: A retrospective
      study of patients who had used the device for 4 1/2 months. SUBJECTS: One hundred
      fifty-one patients with a dropped foot resulting from an upper motor neuron
      lesion. SETTING: A medical physics and biomedical engineering department of a
      district general hospital specializing in the clinical application of FES and a
      neurophysiotherapy department at a separate hospital. MAIN OUTCOME MEASURES:
      Changes in walking speed and effort of walking, as measured by PCI over a 10
      meter course. RESULTS: There was a 92.7% compliance with treatment. Stroke
      patients showed a mean increase in walking speed of 27% (p<.01) and reduction in
      PCI of 31% (p<.01) with stimulation, and changes of 14% (p<.01) and 19% (p<.01),
      respectively, while not using the stimulator. Multiple sclerosis patients gained
      similar orthotic benefit but no "carry-over." CONCLUSIONS: The measured
      differences in walking with and without stimulation were statistically
      significant in the stroke and multiple sclerosis groups. In this study use of the
      stimulator improved walking. Those with stroke demonstrated a short-term "carry
      over" effect.

PMID- 10597810
TI  - Anesthesia for the superior laryngeal nerves and tartaric acid-induced cough.
AB  - OBJECTIVE: The internal branch of the superior laryngeal nerve (ibSLN) conveys
      impulses for the laryngeal cough reflex, which protects the laryngeal aditus and
      prevents the development of aspiration pneumonia. The purpose of this study was
      to determine the effect of bilateral anesthesia of the ibSLN on the cough reflex
      after inhalation of a nebulized chemoirritant solution of tartaric acid. DESIGN:
      Prospective, clinical investigation. SETTING: Outpatient. PARTICIPANTS: Nine
      healthy volunteers. INTERVENTIONS: Bilateral injections of 2% lidocaine solution
      without epinephrine into the paraglottic space containing the ibSLN. MAIN OUTCOME
      MEASURES: The tidal volume after inhalation of a nebulized 20% tartaric acid
      solution and forced vital capacity (FVC) were measured before and after
      injection. Data were analyzed using the Wilcoxon signed ranks, Mann-Whitney, and
      sign tests. RESULTS: Complete anesthesia of the ibSLN abolished the laryngeal
      cough reflex. Postinjection tidal volumes were significantly lower than
      preinjection volumes (p<.01). The decrease in tidal volumes for six subjects with
      complete bilateral anesthesia was significantly larger than the decrease in tidal
      volumes for three subjects with partial anesthesia (p<.05). FVC in both the six
      subjects with complete bilateral anesthesia and the three subjects with partial
      anesthesia did not significantly change from preinjection to postinjection. None
      of the subjects in this study had complications or adverse respiratory sequelae.
      CONCLUSION: Tartaric acid-induced cough may be useful in assessing the integrity
      of the laryngeal cough reflex after anesthesia or in patients with neurologic
      injury who are at risk of developing aspiration pneumonia. It may also be useful
      in making the decision whether to resume oral feeding.

PMID- 10597811
TI  - Anterior ankle-foot orthosis effects on postural stability in hemiplegic
      patients.
AB  - OBJECTIVES: To evaluate the effects of an anterior ankle-foot orthosis (AFO) on
      static and dynamic postural stability in hemiplegic patients. DESIGN: A cross
      sectional assessment of hemiplegic subjects with and without an AFO. SETTING:
      Outpatient department of a rehabilitation hospital. PATIENTS: A convenience
      sample of 24 subjects who had been prescribed an anterior AFO. OUTCOME MEASURES:
      Postural sway index and postural symmetry (body weight distribution through the
      affected leg) when standing were measured as static postural stability. Maximal
      balance range in anterior-posterior and lateral directions and the affected leg's
      weight bearing after weight shift to affected side were measured as dynamic
      postural stability. RESULTS: When wearing the anterior AFO, there was no
      significant difference and small effect size (r<0.3) in postural sway index (p =
      .35), postural symmetry (p = .21), and maximal balance range in anterior
      posterior direction (p = .46). There was a significant improvement and large
      effect size (r>0.5) in lateral weight shifting (p<.01) and weight bearing through
      the affected leg after weight shifted to the affected side (p<.01). CONCLUSIONS:
      The significant effects of the anterior AFO in long-term hemiplegic patients were
      on lateral weight shifting and weight bearing through affected leg after weight
      shifted to the affected side. Postural sway, postural symmetry, and anterior
      posterior weight shifting were not significantly affected.

PMID- 10597812
TI  - Effects of prosthetic mass and mass distribution on kinematics and energetics of
      prosthetic gait: a systematic review.
AB  - OBJECTIVE: To introduce the theoretical models used in literature that describe
      the relation between prosthetic inertial loading and amputee gait and to derive
      specific predictions from these models: to systematically review experimental
      studies on the relation between prosthetic inertial loading and energetics and
      kinematics of lower-limb prosthetic gait; and to compare the review outcomes with
      predictions derived from theoretical models. DATA SOURCES: Studies selected from
      Medline and from examining references in the selected Medline publications. STUDY
      SELECTION: Theoretical models were selected that are used in the present
      literature to predict the effects of prosthetic mass and mass distribution on
      kinematics and energetics of prosthetic gait. Experimental studies were selected
      that investigated the effects of prosthetic mass or center of mass location on
      the economy, self-selected walking speed, stride length, or stride frequency of
      lower limb amputee patients. DATA EXTRACTION: The design and methodologic quality
      was assessed using a checklist of nine criteria. Data on economy, self-selected
      walking speed, stride frequency, and stride length were extracted from the
      studies selected. DATA SYNTHESIS: The predictions of the theoretical models
      suggest that inertial loading of the present lightweight prostheses need not be
      decreased and sometimes may need to be increased to improve the gait of amputee
      patients. The methodologic quality of most of the experimental studies was
      limited. Review of the experimental studies suggests that the inertial loading of
      the present lightweight prostheses need not be further reduced. The discrepancy
      between theoretical models and experimental findings may be related to both the
      poor methodologic quality of the experiments as well as to the limited predictive
      value of the existing models.

PMID- 10597813
TI  - Death after acute withdrawal of intrathecal baclofen: case report and literature
      review.

PMID- 10597814
TI  - Constraint-induced movement therapy.

PMID- 10597815
TI  - Functional correlates with visual evoked potentials?

PMID- 10597816
TI  - How environment and lifestyle choices influence the aging process.
AB  - Differences in the physical appearance of identical twins attributable to aging
      were studied. Because these individuals are identical genetically, any
      differences found were believed to result from external factors. Twins showing
      the greatest discrepancies in visible aging signs also had the greatest degree of
      discordance between personal lifestyle choices and habits. The most notable
      exogenous factors influencing degree of aging were sun exposure and smoking.
      Other possibly contributory lifestyle factors include alcohol consumption,
      stress, diet, exercise, disease, and medication. In summary, the genetic
      influences on aging may be highly overrated, with lifestyle choices exerting far
      more important effects on physical aging.

PMID- 10597817
TI  - Bourdonnement and other benign temporary breast implant sounds.
AB  - During the early postoperative period, a variety of sounds may be detected
      emanating from the augmented breast. These sounds are nearly always benign and
      are temporary. The sounds can be described as crepitation, popping, sloshing,
      squeaking, buzzing, and humming, and a new term, bourdonnement, is applied to one
      of these phenomena. Patients are understandably alarmed by sounds emanating from
      their breasts, and it is helpful for the surgeon to be able to discuss them, and
      to reassure the patient of the lack of any long-term significance of the
      phenomena. This report includes intraoperative techniques by which some of the
      sounds can be avoided or minimized.

PMID- 10597818
TI  - Reconstruction of the posttraumatic short upper lip.
AB  - Treatment of the posttraumatic, vertically shortened upper lip is a difficult
      surgical problem. It requires careful evaluation of the underlying injury
      followed by staged therapeutic interventions. Both surgical and nonsurgical
      treatments need to be employed to optimize results. The authors present three
      distinct cases of posttraumatic upper lip reconstruction that utilize a variety
      of treatment modalities. All patients were treated by the senior author.

PMID- 10597819
TI  - Modified temporalis muscle transfer for paralytic eyelids.
AB  - The major problems in paralytic eyelids are the inability to close the eye, lower
      lid sagging, and epiphora. The upper eyelid is responsible for most of the
      opening and closing of the eye, whereas a lower eyelid positioned properly
      against the globe is necessary for collection and flow of the tear fluid.
      Modification of temporalis muscle transfer, a classic technique, was planned to
      restore these functions selectively in paralytic eyelids. Twelve unilateral and
      one bilateral irreversible facial paralysis patients with different degrees of
      lagophthalmos and ectropion were included. Twice as much muscle mass (in
      thickness) to the upper eyelid than the lower was taken and passed submuscularly
      5 to 6 mm away from the limbus for stronger motion of the upper eyelid, and a
      thinner muscle mass was passed subcutaneously beneath the lower cilia for
      longevity of the correction of ectropion and epiphora. Fixation of these strips
      was performed to the medial canthal ligament and 3 to 4 mm above it. The average
      duration of follow-up was 35.5 months. Excellent eyelid closure and correction of
      ectropion and epiphora were achieved with one procedure in all patients without
      creating a cosmetic deformity.

PMID- 10597820
TI  - Subjective recovery of nerve graft donor site.
AB  - Nerve graft procedures require the use of a donor nerve to supply the graft
      material. This results in an area of numbness in a less critical region. The
      purpose of this study was to assess donor site recovery using patient subjective
      evaluation. Thirty-one patients (mean age, 38 years) who were at least 2 years
      past a nerve graft procedure participated in the telephone survey. The mean time
      since surgery was 65 months. Donor nerves from the lower extremity were utilized
      in 16 patients and from the upper extremity in 15 patients. The subjective
      patient evaluations indicated low levels of pain, numbness, and cold sensitivity
      in the donor nerve sensory distribution. Patient factors, including workers'
      compensation and legal involvement, did not have a significant effect on recovery
      at the donor site. Function and daily activity were not affected significantly by
      donor site factors. Satisfaction with nerve graft recovery was related
      significantly to reported patient satisfaction of the donor site (p = 0.002).

PMID- 10597821
TI  - Anatomic variations of the infraorbital foramen.
AB  - The aims of this study were to locate the infraorbital foramen and to determine
      the frequency and location of any accessory foramen, which may be troublesome
      during anesthetization of this region. In 45 cadavers, the infraorbital foramen
      was dissected according to classic principles for location. The line between the
      angulus oculi medialis and the angulus oculi lateralis was divided into three
      equal pieces, and a second line was drawn downward, perpendicular to the point
      uniting the internal and medial thirds. The position of the infraorbital foramen
      was determined in relation to that line and the infraorbital margin. For the
      right and left sides, the infraorbital foramen was found to be on that line in
      75.6% and 68.9% of the specimens, respectively. The infraorbital foramen was 10.9
      mm and 8.3 mm under the infraorbital margin in men and women, respectively.
      Regarding accessory foramen, 119 crania and 229 maxilla were observed (a total of
      467 infraorbital foramen), and it was found that single accessory foramen were
      present in 11.5% of specimens and double accessory foramen were present in 1.28%
      of specimens. In 79.6% of specimens with single accessory foramen, the accessory
      foramen was superior and medial to the main opening. These results are helpful in
      decreasing anesthetic complications.

PMID- 10597822
TI  - Dancing girl flap: a new flap suitable for web release.
AB  - To create a deep web, a flap must be designed to have a high elongation effect in
      one direction along the mid-lateral line of the finger and also to have a
      shortening effect in the other direction, crossing at a right angle to the mid
      lateral line. The dancing girl flap is a modification of a four-flap Z-plasty
      with two additional Z-plasties. It has a high elongation effect in one direction
      (>550%) and a shortening effect in the other direction at a right angle (<33%),
      creating a deep, U-shaped surface. This new flap can be used to release severe
      scar contracture with a web, and is most suitable for incomplete syndactyly with
      webs as high as the proximal interphalangeal joint.

PMID- 10597823
TI  - Experimental study of a sleeve microanastomotic technique.
AB  - Sleeve anastomosis is an end-to-end variant (i.e., end in end) that makes it
      possible to suture two vessels quickly and with few stitches. Various methods
      have been described in the literature concerning experimental surgery
      (microsurgery and transplantation) and clinical microsurgery. The authors tested
      for a method that would eliminate narrowing of the inserted vessel segment and
      that would improve efficiency and feasibility of the technique. The experimental
      study was performed in 60 rats weighing 200 to 400 g. Telescoping
      microanastomosis consists of hemi-invagination of a 2-mm-caliber artery at high
      pressure (subrenal aorta), sidecut of the distal wall of the external arterial
      segment, and suture with three endoluminal stitches. A total of 61 anastomoses
      were subdivided in three groups: (1) one-sleeve anastomosis, (2) double-sleeve
      anastomosis with interposition of an arterial graft, and (3) a control series of
      conventional end-to-end anastomoses. Patency rates of 95% to 100% at 1 week and 1
      month demonstrated no differences among groups.

PMID- 10597824
TI  - Gene-enhanced tissue engineering: applications for wound healing using cultured
      dermal fibroblasts transduced retrovirally with the PDGF-B gene.
AB  - The treatment of difficult wounds remains a considerable clinical challenge. The
      goal of this study was to determine whether genetic augmentation of dermal cells
      on resorbable matrices can stimulate the healing process, leading to increased
      tissue repair in a rat full-thickness excisional wound repair model. The human
      platelet-derived growth factor B (PDGF-B) gene was the initial gene chosen to
      test this hypothesis. The human PDGF-B gene was obtained from human umbilical
      vein endothelial cells (HUVEC) by reverse transcriptase-polymerase chain
      reaction, cloned into retroviral vectors under control of either the
      cytomegalovirus promoter or the rat beta-actin promoter, and introduced into
      primary rat dermal cells. In vitro results demonstrate that rat dermal cells are
      transduced and selected readily using retroviral vectors, and engineered to
      secrete PDGF-B at a steady-state level of approximately 2 ng per milliliter
      culture per 1 million cells per 24 hours. Seeding of the gene-modified cells onto
      polyglycolic acid (PGA) scaffold matrices and introduction into the rat model
      resulted in substantially increased fibroblast hypercellularity over control
      wounds at both 7 and 14 days posttreatment. Our results demonstrate that gene
      augmentation of rat dermal fibroblasts with the PDGF-B gene introduced into this
      animal model via PGA matrices modulates wound healing and suggests that
      experimentation with additional genes for use separately or in combination with
      PDGF-B for additional, improved wound healing is warranted.

PMID- 10597825
TI  - Necrotizing infection of the face secondary to intranasal impaction of "crack"
      cocaine.
AB  - "Crack" is a crystalline form of cocaine that is readily available and sold in
      the form of small granules. The authors report a unique case of forced intranasal
      impaction of crack cocaine with subsequent extensive necrosis of the nose and
      upper lip accompanied by a necrotizing infection of the subcutaneous soft tissue
      of the cheeks, forehead, and temporal regions. The treatment of extensive facial
      necrosis resulting from infection and ischemia centers around the early diagnosis
      of the infectious process, prompt and aggressive surgical debridement, and the
      administration of broad-spectrum antibiotics.

PMID- 10597826
TI  - Ulnar nerve lesion due to cutaneous anthrax.
AB  - Anthrax is an acute infectious disease caused by the spore-forming bacterium
      Bacillus anthracis. Anthrax is most common in agricultural regions, where it
      occurs in animals. It can also infect humans. Cutaneous anthrax infections occur
      when the bacterium enters a cut or abrasion on the skin. A case of cutaneous
      anthrax infection of the arm is presented. The patient needed to undergo a skin
      graft. He subsequently developed an ulnar nerve lesion after severe edema in his
      arm and hand.

PMID- 10597827
TI  - Revascularization of the upper extremity in a preterm infant: a case report and
      review of the literature.
AB  - Upper extremity arterial injuries in preterm infants are usually of iatrogenic
      origin. Current microsurgical techniques permit extremity revascularization in
      these patients. The authors report the microsurgical repair of a 0.7-mm brachial
      artery in a 940-g preterm infant. The preterm infant warrants special
      consideration due to physiological immaturity. Rapid fluid shifts, a relative
      polycythemia, and the potential for low cardiac output states increase the risk
      for vascular thrombosis. Systemic heparinization is contraindicated in this
      population due to the risk of intraventricular hemorrhage. Optimization of
      various physiological variables should reduce the risk of thrombosis.

PMID- 10597828
TI  - Hair transplantation using a freely transferred nonhair-bearing skin flap.
AB  - Cicatricial alopecia is a common sequela of burns involving the head region. The
      authors present a case of an extensive form of cicatricial alopecia in an 18-year
      old female patient who sustained a burn to the head at 2 years of age. The
      patient was treated with combined scalp reduction with the aid of tissue
      expanders and micrografting of the freely transferred, preexpanded deep inferior
      epigastric artery nonhair-bearing skin flap. The aim of this article is to show
      that hair transplantation on the freely transferred nonhair-bearing skin flap may
      be associated with infection and fat necrosis, and the end result is not
      satisfactory, as in the cases of hair transplantation on a normal bald scalp.

PMID- 10597829
TI  - A rare case of pneumosinus dilatans of the frontal sinus and review of the
      literature.
AB  - Pneumosinus dilatans is a rare condition of unknown etiology in which there is
      enlargement of the paranasal sinuses by air, with extension beyond the normal
      boundaries of bone. The authors present a case of pneumosinus dilatans of the
      frontal sinus and review the literature.

PMID- 10597830
TI  - New tumor formation on split-thickness skin grafted areas in xeroderma
      pigmentosum.
AB  - Xeroderma pigmentosum is a relatively rare systemic disease transmitted through
      an incomplete sex-linked recessive gene. It is characterized by malignant skin
      degeneration. One of the most effective treatment choices for the malignant
      changes is full-face resurfacing with skin grafts. Grafts harvested from areas
      that have some freckles may show malignant degeneration by ultraviolet exposure.
      The authors present a patient whose face was resurfaced with a split-thickness
      skin graft and was admitted due to new tumor formation on her resurfaced face.

PMID- 10597831
TI  - Painful neuromas: a review of treatment modalities.
AB  - There are numerous methods cited in the literature on the treatment of painful
      neuroma. Nonsurgical methods range from injections with various materials into
      the nerve end to desensitization of nerve pain conduction pathways. Some surgical
      treatments aim to alter the environment of the amputated nerve end by transposing
      it into muscle or bone, others have designed various flaps to protect truncated
      nerve ends from scar tissue, and still others try to "cap" the nerve with
      silicon, a nerve graft, or epineurium to prevent nerve regeneration. All of these
      methods have proved efficient. However, none of these methods work universally.
      The authors review the common treatments for painful neuromas. In addition, they
      review the preliminary results of the extended autologous venous nerve conduit as
      a novel technique of treating painful neuromas. They also report recent
      investigations into the pathophysiology of injured nerves.

PMID- 10597832
TI  - An endoscopic technique for decompressive fasciotomy.
AB  - A guiding principle of minimally invasive techniques in plastic surgery is
      improvement of the aesthetic outcome, usually by reducing morbidity from
      postsurgical scarring. The elimination or reduction of scars has already been so
      achieved during elevation of fascial flaps and for the harvest of fascial grafts.
      A natural extension of this endoscopic experience is decompressive fasciotomy,
      which has now been performed successfully in the upper extremity. Using
      endoscopic guidance, this is actually a simple, rapid, and safe procedure with
      minimal morbidity, and should also be apropos for the lower extremity, where
      compartment syndromes are a more common malady.

PMID- 10597833
TI  - The Gen-X-files.

PMID- 10597834
TI  - Treatment of recurrent mandibular dislocation: arthroplasty with cryopreserved
      bone allograft.

PMID- 10597835
TI  - Giant cutaneous horns.

PMID- 10597836
TI  - Never throw away a living thing: a principle revisited.

PMID- 10597837
TI  - An unusual presentation of squamous cell carcinoma of the skin.

PMID- 10597838
TI  - Warm up.

PMID- 10597839
TI  - Make lemons into lemonade.

PMID- 10597840
TI  - Girls and fitness: fact and fiction.

PMID- 10597841
TI  - Role of sport and exercise medicine in the NHS.

PMID- 10597842
TI  - The genetics of physical fitness.

PMID- 10597843
TI  - Acute mountain sickness--the "poison of the pass".

PMID- 10597844
TI  - Can exercise induced muscle damage be avoided?

PMID- 10597845
TI  - Is there a role for exercise in the prevention of osteoporotic fractures?
AB  - OBJECTIVES: To examine whether there is a role for exercise in improving bone
      mineral density (BMD), particularly in postmenopausal women. The effects of
      different types of exercise are examined together with their effects at selected
      skeletal sites. The role of activity in reducing falls and hip fractures will
      also be considered as well as the potentially negative effects of excessive
      exercise. METHODS: A literature search over the past 20 years was conducted and
      landmark papers selected. RESULTS: Certain types of exercise have been found to
      exert moderate benefits on BMD of the wrist, spine, and hip. Most studies do not
      detect a difference between the effects of endurance activities and strength
      training for BMD of the spine. It has been more difficult to isolate the optimal
      type of activity for effecting an osteogenic response at the hip, but recent
      evidence suggests that high impact work such as stepping and jumping may be
      effective at this site. The combination of hormone replacement therapy and
      exercise would appear to be more effective than either intervention on its own.
      Certain types of exercises have additional benefits, such as muscle
      strengthening, which could reduce the incidence of falls. Excessive exercise can
      lead to menstrual disturbances in female athletes and this in turn can cause bone
      loss, particularly from the spine. CONCLUSIONS: Exercise across the life span
      should be encouraged in order to maximise peak bone mass, reduce age related bone
      loss, and maintain muscle strength and balance. Although the effects of exercise
      on BMD later in life are small, epidemiological evidence suggests that being
      active can nearly halve the incidence of hip fractures in the older population.
      This effect is most probably multifactorial through the positive effects on bone,
      muscle strength, balance, and joint flexibility. Younger women should be aware of
      the dangers to the skeleton of menstrual disorders.

PMID- 10597846
TI  - Heart dimensions may influence the occurrence of the heart rate deflection point
      in highly trained cyclists.
AB  - OBJECTIVES: To determine whether the heart rate (HR) response to exercise in 21
      highly trained cyclists (mean (SD) age 25 (3) years) was related to their heart
      dimensions. METHODS: Before performing an incremental exercise test involving a
      ramp protocol with workload increases of 25 W/min, each subject underwent
      echocardiographic evaluation of the following variables: left ventricular end
      diastolic internal diameter (LVIDd), left ventricular posterior wall thickness at
      end diastole (LVPWTd), interventricular septal wall thickness at end diastole
      (IVSTd), left ventricular mass index (LVMI), left atrial dimension (LAD),
      longitudinal left atrial (LLAD) and right atrial (LRAD) dimensions, and the ratio
      of early to late (E/A) diastolic flow velocity. RESULTS: The HR response showed a
      deflection point (HRd) at about 85% VO2MAX in 66.7% of subjects (D group; n = 14)
      and was linear in 33.3% (NoD group; n = 7). Several echocardiographic variables
      (LVMI, LAD, LLAD, LRAD) indicative of heart dimensions were similar in each
      group. However, mean LPWTd (p<0.01) and IVSTd (p<0.05) values were significantly
      higher in the D group. Finally, no significant difference between groups was
      found with respect to the E/A. CONCLUSIONS: The HR response is curvilinear during
      incremental exercise in a considerable number of highly trained endurance
      athletes-that is, top level cyclists. The departure of HR increase from linearity
      may predominantly occur in athletes with thicker heart walls.

PMID- 10597847
TI  - Effect of precooling on high intensity cycling performance.
AB  - OBJECTIVE: To examine the effects of precooling skin and core temperature on a 70
      second cycling power test performed in a warm and humid environment (29 degrees
      C, 80% relative humidity). METHODS: Thirteen male national and international
      level representative cyclists (mean (SD) age 24.1 (4.1) years; height 181.5 (6.2)
      cm; weight 75.5 (6.4) kg; maximal oxygen uptake (VO2peak) 66.1 (7.0) ml/kg/min)
      were tested in random order after either 30 minutes of precooling using cold
      water immersion or under control conditions (no precooling). Tests were separated
      by a minimum of two days. The protocol consisted of a 10 minute warm up at 60% of
      VO2peak followed by three minutes of stretching. This was immediately followed by
      the 70 second power test which was performed on a standard road bicycle equipped
      with 172.5 mm powermeter cranks and mounted on a stationary ergometer. RESULTS:
      Mean power output for the 70 second performance test after precooling was
      significantly (p<0.005) increased by 3.3 (2.7)% from 581 (57) W to 603 (60) W.
      Precooling also significantly (p<0.05) decreased core, mean body, and upper and
      lower body skin temperature; however, by the start of the performance test, lower
      body skin temperature was no different from control. After precooling, heart rate
      was also significantly lower than control throughout the warm up (p<0.05).
      Ratings of perceived exertion were significantly higher than the control
      condition at the start of the warm up after precooling, but lower than the
      control condition by the end of the warm up (p<0.05). No differences in blood
      lactate concentration were detected between conditions. CONCLUSIONS: Precooling
      improves short term cycling performance, possibly by initiating skin
      vasoconstriction which may increase blood availability to the working muscles.
      Future research is required to determine the physiological basis for the
      ergogenic effects of precooling on high intensity exercise.

PMID- 10597848
TI  - Effect of changing the saddle angle on the incidence of low back pain in
      recreational bicyclists.
AB  - OBJECTIVE: According to the literature, 30-70% of cyclists suffer from cervical,
      dorsal, or lumbar back pain. This study was conducted to evaluate one of the
      possible causes of low back pain and to suggest a solution by appropriate
      adjustments to the bicycle. METHODS: Serial fluoroscopic studies were performed
      while cyclists sat on different types of bicycle (sports, mountain, and city).
      Pelvic/spine angles were measured at different seat angles, and the related force
      vectors analysed. RESULTS: There was a tendency towards hyperextension of the
      pelvic/spine angle which resulted in an increase in tensile forces at the
      promontorium. These forces can easily be reduced by appropriate adjustment of the
      seat angle--that is, by creating an anterior inclining angle. The findings of the
      biomechanical analysis were then applied to a group of cyclists who were members
      of a cycling club and who complained of low back pain. After appropriate
      adjustment of the saddle angle, most of the cyclists (>70%) reported major
      improvement in the incidence and magnitude of their back pain. CONCLUSIONS: The
      incidence and magnitude of back pain in cyclists can be reduced by appropriate
      adjustment of the angle of the saddle. It is important that these findings be
      conveyed to cyclists, bicycle salesmen, trainers, and members of the general
      public who engage in cycling, in order to decrease the prevalence of back pain.

PMID- 10597849
TI  - Upright posture and maximal exercise increase platelet aggregability and
      prostacyclin production in healthy male subjects.
AB  - BACKGROUND: It is well accepted that heavy physical exertion can trigger the
      onset of myocardial infarction, but the mechanism is uncertain. As platelet and
      endothelial function play an important role in thrombotic events, platelet and
      prostacyclin responses to maximal treadmill exercise were studied.
      METHODS/RESULTS: The study subjects were 40 healthy men, mean (SEM) age 29 (5)
      years. Platelet aggregation was measured on a four channel aggregometer. Plasma 6
      keto-prostaglandin F1alpha was analysed using an enzyme immunoassay technique.
      Upright posture and exercise produced an increase in platelet aggregability, as
      indicated by a fall in the threshold concentration of adrenaline (epinephrine)
      from 7.6 (1.5) microM at rest to 4.3 (1.0) microM after exercise (p = 0.002). The
      collagen lag time became significantly shorter with exercise (from 79.1 (3.1)
      seconds at rest to 71.9 (2.6) seconds after exercise, p = 0.003). Exercise was
      also associated with a 55% increase in plasma 6-keto-prostaglandin F1alpha (from
      38.1 (75%CI 29.0 to 46.5) pg/ml at rest to 59.2 (47.3 to 66.8) pg/ml after
      exercise, p<0.001). CONCLUSIONS: In healthy male subjects, upright posture and
      maximal exercise increased platelet aggregability but this increase was
      counteracted by an increase in prostacyclin production. In patients with
      endothelial dysfunction, a reduced prostacyclin response to exercise may promote
      a transient prothrombotic imbalance that may trigger cardiovascular disease
      onset.

PMID- 10597850
TI  - Eccentric and concentric isokinetic moment characteristics in the quadriceps and
      hamstrings of the chronic isolated posterior cruciate ligament injured knee.
AB  - OBJECTIVE: Functional strength deficits associated with chronic isolated
      posterior cruciate ligament (PCL) insufficiency have received limited attention
      in the literature. The purpose of this study was to determine the eccentric and
      concentric isokinetic moment characteristics of the quadriceps and hamstrings in
      a sample of patients with isolated PCL injury. METHODS: Eccentric and concentric
      mean average and average peak moments were measured for 17 patients with a
      history of conservatively treated isolated PCL injury using an isokinetic
      dynamometer. Quadriceps and hamstring isokinetic moments were recorded from 10
      degree to 90 degree of knee flexion. Strength ratios were calculated and compared
      with those reported in the literature for healthy subjects. RESULTS: The
      hamstrings of the involved side (eccentric/concentric (E/C) ratio = 1.06) were
      significantly weaker (p<0.05) eccentrically than those of the contralateral side
      (E/C ratio = 1.29). All hamstrings/quadriceps (H/Q) ratios were less than the
      universally accepted value of 0.60 and the eccentric H/Q ratio for the injured
      extremity was significantly lower than the non-injured (p<0.05). In a bilateral
      comparison, the injured/non-injured (I/N) ratio was less than 1.00 for concentric
      quadriceps, eccentric quadriceps, and hamstring isokinetic moments. Calculation
      of the E/C ratio showed that, for the quadriceps, it was 1.08 on the injured side
      and 1.07 on the non-injured extremity. CONCLUSIONS: Eccentric strengthening
      should be an integral part of functionally rehabilitating the quadriceps and
      hamstrings of athletes who suffer from the complications associated with chronic
      isolated PCL insufficiency.

PMID- 10597851
TI  - Landing in netball: effects of taping and bracing the ankle.
AB  - OBJECTIVES: To investigate the effect of bracing and taping on selected
      electromyographic, kinematic, and kinetic variables when landing from a jump.
      METHODS: Fifteen netball players performed a jump, so as to land on their
      dominant limb on a force plate. Electromyographic activity was recorded from the
      gastrocnemius, tibialis anterior, and peroneus longus muscles. Subjects were also
      filmed and measures of rearfoot motion were derived. RESULTS: Significantly less
      electromyographic activity (p<0.007) was observed from the gastrocnemius and
      peroneus longus muscle groups when subjects were braced. No other significant
      electromyographical findings were observed. Peak vertical ground reaction force
      and time to peak for vertical ground reaction force were not affected by bracing
      and taping, nor were the rearfoot and Achilles tendon angles at foot strike.
      CONCLUSIONS: The effect of bracing and taping on the selected biomechanics
      variables associated with landing was specifically limited to a reduction in
      muscle action, particularly for the braced condition. Netball players can be
      confident that the biomechanics of their landing patterns will not be altered
      whether they choose to wear a brace or tape their ankle joints.

PMID- 10597852
TI  - Silent meniscal abnormalities in athletes: magnetic resonance imaging of
      asymptomatic competitive gymnasts.
AB  - BACKGROUND: Magnetic resonance imaging (MRI) produces exceptionally detailed
      images of the intra-articular structures of the knee. Recognising the range of
      MRI appearances within a normal population is therefore necessary in order to
      avoid attributing a greater significance to these than is clinically justified.
      OBJECTIVE: To compare MRI appearances in asymptomatic gymnasts with those in a
      less active population in order to identify findings that may be seen in the
      absence of significant pathology and thereby aid the clinical management of this
      athletic group. METHODS: MR images were obtained from 24 knees of asymptomatic
      competitive American collegiate gymnasts aged 18-22. The menisci were evaluated
      according to established grading criteria, and compared with a group of controls
      matched for age and sex. RESULTS: Grade 3 intrameniscal signal abnormalities are
      considered to be highly correlated with meniscal tears. When compared with
      control group, the experimental group of gymnasts had a significantly different
      distribution (p<0.001) of grade 3 intrameniscal signal changes, preferentially
      involving the lateral meniscus. The overall incidence of grade 3 changes (13%) in
      gymnasts was not, however, significantly different from the incidence in the
      controls. CONCLUSIONS: A knowledge of these MRI appearances is important when
      evaluating the lateral menisci within this group of athletes to prevent
      unnecessary treatment or intervention. This is particularly pertinent when the
      imaging findings do not closely correlate with the site of symptoms.

PMID- 10597853
TI  - Prospective decrease in progesterone concentrations in female lightweight rowers
      during the competition season compared with the off season: a controlled study
      examining weight loss and intensive exercise.
AB  - The purpose of this study was to monitor ovarian hormone function response to
      intense exercise and body weight changes in female athletes. Ovarian hormone
      function was evaluated in 12 female lightweight rowers and 10 age-height-weight
      matched sedentary controls. Ovarian hormone function was assessed during
      consecutive competition season and off season, by measurement of peak and average
      alternative day overnight urinary oestrone glucuronide (E1G) and pregnanediol
      glucuronide (PdG) excretion. Competition season was associated with a 5.8 kg
      (9.3%) body weight loss in the lightweight rowers. Significantly lower
      competition season peak and average urinary excretion of PdG were found in the
      lightweight rowers compared with the controls. Lower competition season peak and
      average urinary excretion of E1G were also found in the lightweight rowers
      compared with the controls, but the difference did not reach significance. The
      number of rowing training hours was a significant determinant of peak PdG
      excretion in the rowers (R2 = 0.40; p<0.02). The seasonal suppression of PdG
      excretion was associated with degree of weight loss (R2 = 0.46; p<0.01). The
      competition related decrease in E1G and PdG excretion for the lightweight rowers
      was predominantly restored during the off season when exercise intensity and
      duration were decreased and body weight increased. These results showed a
      significant (p<0.05) reduction in progesterone metabolite excretion and a non
      significant decrease in oestrone metabolite excretion associated with intensive
      competition season training loads and body weight reduction in female lightweight
      rowers.

PMID- 10597854
TI  - Common extensor tendon rupture following corticosteroid injection for lateral
      tendinosis of the elbow.
AB  - Corticosteroid injections are commonly administered to athletes to relieve
      symptoms of lateral elbow tendinosis. This report presents a case of almost total
      rupture of the common extensor origin in a 45 year old female squash player
      secondary to such a procedure.

PMID- 10597855
TI  - Sport medicine and the ethics of boxing.
AB  - In the light of medical evidence of the health risks associated with boxing, a
      watchful agnostic position among sport physicians is no longer justifiable. The
      normal activity in a boxing match places the athletes at risk of head injury,
      some of which may be difficult to detect and impossible to repair. This suggests
      that sport physicians and others expert in the prevention and diagnosis of such
      injuries should take a public stand against boxing, as other medical associations
      have. Although there is a need for continuing research into the health risks,
      doctors can in the interim take steps to increase public awareness of these
      risks. Sport physicians in particular can make a strong public statement by also
      ending their professional involvement with boxing. This need not be interpreted
      as paternalism; doctors are qualified neither to make laws nor to restrict
      private behaviour. Sport physicians are, however, well equipped to advise those
      who do make laws and those who choose to engage in boxing. In the end, because
      this stance against boxing will probably reduce the number of brain injuries in
      certain athletes, autonomy will be preserved, rather than restricted.

PMID- 10597856
TI  - Five year results of rotator cuff repair.
AB  - In thirty nine patients with either an acute rotator cuff rupture or a chronic
      impingement syndrome plus a cuff tear, a standard acromioplasty was performed
      along with a cuff repair using a bone detaching approach. Postoperative active
      motion was allowed in all but three. Follow up examination was performed two and
      five years after the operation. Continuous improvement in function, range of
      movement, and strength was observed, while pain increased slightly. The size of
      the tear and delay in treatment were determining factors in the outcome.

PMID- 10597857
TI  - Eating disorders among male and female elite athletes.

PMID- 10597858
TI  - Groin pain in professional soccer players: a comparison of England and the rest
      of Western Europe.

PMID- 10597859
TI  - Drug testing.

PMID- 10597860
TI  - Frostbite at the gym: it's not the ice but the temperature that matters!

PMID- 10597861
TI  - Frostbite at the gym.

PMID- 10597862
TI  - Assessing the cardiac safety of ebastine. Prologue.

PMID- 10597863
TI  - The QT interval and torsade de pointes.
AB  - The QT interval on the electrocardiogram is the time from the onset of
      ventricular depolarisation (the Q wave) to completion of repolarisation (the end
      of the T wave). It is influenced by heart rate, autonomic factors, electrolyte
      levels, gender and age. Aprolonged QT interval indicates an increased risk of
      developing malignant ventricular tachyarrhythmias, particularly torsade de
      pointes. QT prolongation may be primary (inherited, familial, congenital,
      idiopathic) or caused by disease, drugs or toxins. Drugs that have been
      associated with the development of torsade de pointes include antiarrhythmic,
      antibacterial and psychotropic agents and antihistamines. Several of these drugs
      depress myocardial ion channels, particularly the rapidly activating delayed
      rectifier (repolarising) potassium current (I(Kr)). Overdosage of drugs that
      affect the delayed rectifier (repolarising) potassium currents (I(K)), or
      coadministration of these drugs with another medication that inhibits their
      metabolism (e.g. an antihistamine such as terfenadine with an antifungal agent
      such as ketoconazole, which inhibits the cytochrome P450 3A4 hepatic enzyme), can
      induce torsade de pointes. Torsade de pointes is a potentially life-threatening
      ventricular tachyarrhythmia and the risks of administering drugs that can induce
      this condition must be carefully considered.

PMID- 10597864
TI  - Blockade of cardiac potassium and other channels by antihistamines.
AB  - The use of terfenadine and astemizole, two long-acting nonsedating histamine H1
      receptor antagonists, has been associated with prolongation of the QT interval,
      development of ventricular arrhythmias, particularly torsade de pointes, and
      sudden cardiac death. Both drugs block the rapidly activating component of the
      delayed rectifier channel, I(Kr). At much higher concentrations, they also block
      several other cardiac channels (Na+, Ca2+, K+). Since many other antihistamines
      can also block one or other of the cardiac ion currents (e.g. loratadine blocks
      the human cardiac K+ channel, hKv1.5, with the same potency as terfenadine),
      these results are also reviewed and their clinical relevance discussed. Because
      of the proarrhythmic risk, some antihistamines should be taken only at the
      recommended doses and avoided in patients with liver disease or in those taking
      medications that inhibit oxidative cytochrome P-450 enzymes. These drugs should
      also be avoided in those with the congenital long QT syndrome or with secondary
      forms of delayed repolarisation (hypokalaemia, bradycardia, drug-induced QT
      prolongation). Identification of predisposing factors could enable physicians to
      anticipate, and thereby avoid, this potentially lethal complication of
      antihistamine therapy.

PMID- 10597865
TI  - Preclinical in vitro cardiac electrophysiology: a method of predicting
      arrhythmogenic potential of antihistamines in humans?
AB  - The cardiac action potential results from a dynamic balance between inward
      depolarising Na+ and Ca2+ currents and outward K+ repolarising currents. During a
      cardiac cycle, the resultant of repolarisation phase from all ventricular cells
      is represented by the QT interval of the surface ECG. Congenital long QT syndrome
      (LQTS) is characterised by polymorphic ventricular tachycardia sometimes with
      twisting QRS morphology (torsade de pointes) which, although usually self
      limiting, can result in sudden cardiac death. Acquired LQTS can be induced by a
      variety of drugs, including some nonsedative histamine H1 receptor antagonists
      (astemizole, terfenadine). The Committee for Proprietary Medicinal Products of
      the European Union has recently proposed studying the action potential in in
      vitro heart preparations as a preclinical test for predicting the propensity of
      noncardiovascular drugs to induce malignant QT prolongation in humans. The
      effects of several histamine H1 receptor antagonists on the electrically evoked
      action potential have been evaluated in rabbit Purkinje fibres. In this
      preparation, astemizole (0.3 to 10 micromol/L) prolongs the duration of the
      action potential measured at the level where repolarisation is 90% complete
      (APD90). This effect is dependent on drug concentration, incubation time, pacing
      frequency and K+ or Mg2+ concentration. Astemizole also markedly depresses the
      rate of rise of the action potential (Vmax). Terfenadine showed qualitatively
      similar, but quantitatively smaller, effects in this model. The histamine H1
      receptor antagonists cetirizine, ebastine, carebastine, loratadine and
      fexofenadine do not significantly affect APD90 at 1 micromol/L, but cetirizine
      and carebastine prolong it slightly at 10 micromol/L. In conclusion, in rabbit
      Purkinje fibres, astemizole and terfenadine produce adverse electrophysiological
      effects at concentrations which may be achieved in the human myocardium in
      certain clinical situations. APD90 lengthening induced by carebastine and
      cetirizine is minor and occurs at concentrations that are very unlikely to be
      encountered clinically, since these drugs, in contrast to astemizole and
      terfenadine, do not accumulate in the myocardium. Direct extrapolation of
      preclinical results to humans requires great caution, since malignant QT
      prolongations by terfenadine and astemizole are extremely rare clinical events.
      However, since prolongation of the QT interval often precedes the development of
      torsade de pointes, any significant delay in cardiac repolarisation produced by
      noncardiovascular drugs in preclinical, and particularly in clinical, studies
      should, in general, be considered to indicate a potential cardiac risk in humans.
      Its significance should subsequently be evaluated in appropriate studies in
      patients with conditions known to predispose to arrhythmias.

PMID- 10597866
TI  - Cardiotoxicity of histamine and the possible role of histamine in the
      arrhythmogenesis produced by certain antihistamines.
AB  - Since 1990 it has repeatedly been reported that some histamine H1 receptor
      antagonists (e.g. terfenadine and astemizole) are able to produce ventricular
      arrhythmias (e.g. torsade de pointes) when they are given at dosages above the
      therapeutic range and/or administered together with cytochrome P-450 3A4
      inhibitors, such as ketoconazole or erythromycin. Although the mechanism by which
      these arrhythmias are produced remains unclear, the recently reported ability of
      these drugs to block outward K+ currents has been suggested as the cause of their
      arrhythmogenic effects. Alternatively, we have observed that some H1
      antihistamines, including terfenadine and astemizole, are able to release
      histamine from guinea-pig cardiac mast cells. Thus, we have proposed that the
      liberated histamine, acting through an H2 receptor-stimulating mechanism, can
      prolong the action potential duration and hence induce arrhythmogenic effects.
      This paper describes experimental observations supporting the hypothesis that
      some H1 antihistamines can induce severe cardiac arrhythmias via the local
      release of histamine.

PMID- 10597867
TI  - Effects of H1 antihistamines on animal models of QTc prolongation.
AB  - OBJECTIVE: The clinical use of some nonsedating H1 antihistamines (histamine H1
      receptor antagonists) has been associated with a rare but life-threatening type
      of arrhythmia, torsade de pointes, especially when these drugs are coadministered
      with cytochrome P450 (CYP) 3A4 enzyme inhibitors. On the basis of the latter
      observation and the fact that most of these H1 antihistamines undergo extensive
      first-pass metabolism to active metabolites apparently devoid of cardiovascular
      adverse effects, this arrhythmogenicity has been attributed to the parent drug.
      The objective of this study was to find an animal model with the ability to
      predict the proclivity of drugs to produce torsade de pointes. DESIGN: Two
      experimental approaches were used: (i) blockade of CYP3A4 metabolism by
      coadministration of ketoconazole to increase the plasma concentrations of the
      parent compound in the conscious guinea-pig, and (ii) administration of the
      compound directly into the coronary circulation of the anaesthetised dog in order
      to circumvent first-pass metabolism. RESULTS: The first approach demonstrated
      that terfenadine administered in the presence of ketoconazole prolongs the
      corrected QT (QTc) interval of the electrocardiogram, whereas ebastine does not.
      Similarly, when terfenadine was administered through the coronary circulation, a
      statistically significant increase in the QTc interval was also seen, whereas
      ebastine and carebastine were without effect. Thus, it is clear that ebastine was
      much better tolerated than terfenadine from a cardiovascular standpoint, since
      ebastine and its metabolite are devoid of effects on cardiac repolarisation, as
      measured by the QTc interval in these animal models.

PMID- 10597868
TI  - Computer-assisted comparison of the structural and electronic dispositions of
      ebastine and terfenadine.
AB  - OBJECTIVE: Ebastine and terfenadine are both marketed nonsedating H1 histamine
      receptor antagonists. Although apparently similar in chemical structure, the
      compounds have different pharmacological profiles, particularly with respect to
      cardiac effects. These effects are consistently observed in a wide range of
      experimental models with terfenadine, but not with ebastine, despite the fact
      that the latter is more potent as an antihistamine. The objective of this study
      was to provide a structural basis to explain such differences. DESIGN: A complete
      computer-assisted conformational and electronic characterisation was made for
      both drugs. RESULTS: The preferred 3-dimensional spatial orientations were found
      to be different, as were the molecular locations of the highest occupied and
      lowest unoccupied molecular orbitals. Furthermore, for terfenadine, additional
      points of interaction as a hydrogen bond donor were found, which were not evident
      in ebastine or other noncardiotoxic antihistamines. These extra points of
      interaction were also found in other compounds that have shown cardiac effects
      similar to those of terfenadine.

PMID- 10597869
TI  - Comparative clinical studies with ebastine: efficacy and tolerability.
AB  - Ebastine is a nonsedating and selective histamine H1 receptor antagonist without
      anticholinergic or sedative effects at therapeutic doses. It has shown a rapid
      onset and long duration of action, and doses of 10 and 20mg once daily are
      effective in relieving the nasal and non-nasal symptoms of seasonal and perennial
      allergic rhinitis (SAR and PAR, respectively). In 3 randomised double-blind,
      multicentre clinical trials in patients with SAR, ebastine 10 and 20mg once daily
      for 2 to 3 weeks significantly reduced symptoms (nasal discharge, stuffiness,
      sneezing, itchy nose, itchy/watery eyes) when compared with placebo. Similarly,
      in patients with PAR, two 3-week studies demonstrated that ebastine 10mg twice
      daily and 20mg once daily significantly relieved the symptoms of PAR, as measured
      by the Perennial Index. Ebastine was well tolerated in these studies and had no
      effect on the QTc interval.

PMID- 10597870
TI  - Cardiac effects of ebastine and other antihistamines in humans.
AB  - The electrocardiographic effects of ebastine and its active metabolite,
      carebastine, have been studied alone and in relevant drug-interaction studies in
      various patient populations. The overall cardiac tolerability of ebastine is
      excellent. In ebastine dose-ranging studies in adults and children, there were no
      meaningful dose-related changes in the QTc interval. At high doses of ebastine (5
      to 10 times the recommended dose), a modest 10.3 msec increase in QTc was
      observed. Recommended doses of ebastine had no meaningful effect on QTc in the
      elderly or in patients with renal or hepatic insufficiency. Interaction studies
      involving ebastine with ketoconazole revealed a significant increase in the serum
      ebastine concentration and in the elimination half-life of ebastine, with a
      modest 18.1 msec increase in QTc (approximately 10 msec above ketoconazole alone)
      and a plateau QTc-ebastine relationship at higher ebastine levels. Similar,
      though more minor, QTc findings were observed during coadministration of ebastine
      with erythromycin. No QTc effects were noted when ebastine was administered with
      theophylline, and the QTc was similar when ebastine was administered with or
      without food. These findings indicate that ebastine is well tolerated and, in
      contrast to terfenadine and astemizole, has no clinically meaningful effect on
      the QTc interval even at high serum concentrations. As with other 'safe'
      antihistamines, which have shown similar modest increases in QTc when
      coadministered with ketoconazole, caution should be exercised when administering
      ebastine to patients having the long QT syndrome or hypokalaemia, and in patients
      receiving azole antifungals or macrolide antibacterials.

PMID- 10597871
TI  - Assessing the cardiac safety of ebastine. Epilogue.

PMID- 10597872
TI  - The Middle Years Group: a holistic approach to the management of the menopause in
      primary care.
AB  - OBJECTIVES: The menopause is attaining greater significance as symptoms and long
      term sequelae are amenable to hormone replacement treatment. However, hormone
      replacement treatment is no panacea and all women undergoing the menopause need
      to make informed decisions about its use. The aim of this study was to assess the
      effects of a series of group sessions for women aged 45-55 years, dealing with
      physical, social, emotional and medical aspects of the climacteric. METHODS: All
      women registered at the Roborough surgery were invited to join a group for four
      sessions, led by the health visitor and counsellor, with a doctor leading one
      session on hormone replacement treatment. Women's views on the group were
      obtained by questionnaire. Prescribing data on hormone replacement treatment and
      antidepressants were analysed for attenders and a matched group of those invited
      who did not attend. RESULTS: Twelve percent of invited women attended. All stated
      that sessions helped an understanding of the physical and emotional changes at
      this time. No significant differences were found in the use of hormone
      replacement treatment, antidepressants or in subsequent use of the counsellor's
      services between the attenders and a matched group of non-attenders. CONCLUSIONS:
      This group offered all women at risk the opportunity to discuss, share and learn
      about all aspects of the menopause. It was well received and made no major
      differences to the uptake of hormone replacement treatment.

PMID- 10597873
TI  - Why do postmenopausal women discontinue hormone replacement therapy?
AB  - OBJECTIVES: To study the prevalence and acceptance of hormone replacement therapy
      (HRT) in the Finnish population and to ascertain the factors leading to premature
      discontinuation of HRT. METHODS: A questionnaire survey was conducted among all
      women aged 50-60 selected from the age-sex register, 1065 women were identified
      and 884 (response rate 84%) agreed to participate. RESULTS: 111 women were
      premenopausal and 773 postmenopausal; 302 (39%) were current HRT users, 126 (16%)
      previous users and 345 (45%) non-users. Of the previous users 27% had used
      oestrogen for less than 6 months and 46% had ceased treatment within 1 year. The
      main reason for discontinuation was side-effects; 41% of the women had suffered
      from them. Fear of cancer (16%), recommendation of a physician (12%),
      inefficiency (4%), and advice of a friend (3%) were other causes of
      discontinuation. Of the current users, 20% had continuous side-effects from the
      treatment and 15% had been advised to discontinue the treatment. Eleven percent
      of current users and 11% of previous users reported not having received any
      information about HRT. CONCLUSIONS: in this survey, more than half of
      postmenopausal women had used HRT at menopause. Every third of the women had
      discontinued the treatment, mainly because of side-effects but also because of
      fear of cancer and advice of physicians.

PMID- 10597874
TI  - Correlates of hormone replacement therapy use in Italian women, 1992-1996.
AB  - OBJECTIVES: we analyzed the determinants of hormonal replacement therapy (HRT)
      use in Italy for the period 1992-1996, using data from a framework of case
      control studies of colon and rectal neoplasm. METHODS: a total of 1574 women aged
      45-74 years were considered. This group comprised women with acute, non
      neoplastic, non-hormone-related diseases admitted to a network of hospitals in
      six areas of Italy. RESULTS: a total of 146 women (8.5%) reported ever HRT use.
      The multivariate odds ratio (OR) of ever use was 1.6 (95% CI 1.0-2.6) for women
      with 12 years of education or more, compared with those with < 7 years. The
      frequency of use of HRT tended to decrease with increasing parity: the OR was 0.6
      for women with four or more children as compared to nulliparae (chi2 trend 3.5, P
      = 0.06). Ever HRT users were more frequently smokers. HRT use was more frequent
      in women reporting surgical menopause (OR = 2.7) than those with natural
      menopause. Among post menopausal women, HRT use was related with early age at
      menopause (chi2 trend 4.6, P = 0.03). HRT use was more common among women
      reporting lower body mass index (BMI) both at interview and at age 30 years and
      the difference between current BMI and BMI at age 30 years, was not related with
      HRT use. CONCLUSIONS: women of higher socioeconomic status or education reported
      more frequent HRT use and nulliparae and smokers were also more likely to use
      HRT. Further HRT use was directly associated with early age at menopause and
      surgical menopause and inversely related with measures of body weight.

PMID- 10597875
TI  - Postmenopausal weight status, body composition and body fat distribution in
      relation to parameters of menstrual and reproductive history.
AB  - OBJECTIVES: In the present study the association between menstrual and
      reproductive history patterns and weight status, fat distribution and body
      composition during postmenopause was tested. METHODS: In 106 healthy
      postmenopausal women ranging in age from 48 to 58 years (x = 53.7 year) the
      weight status was classified according to the recommendations of the WHO.
      Additionally body composition was estimated by dual energy X-ray absorptiometry
      and fat distribution was calculated using the fat distribution index. Weight
      status, body composition and fat distribution were correlated with self-reported
      parameters of menstrual and reproductive history (age at menarche, average cycle
      length, number of births, age at first and last birth, average pregnancy weight
      gain, age at menopause). RESULTS: It was shown that number of births, age at
      first birth and pregnancy weight gain were related significantly to the
      postmenopausal weight status, body composition and fat distribution. CONCLUSION:
      An early first birth a low number of births and a high weight gain during
      pregnancies can be assumed as risk factors for overweight, a higher amount of
      adipose tissue, android fat patterning and therefore for the development of the
      metabolic syndrome during postmenopause. In contrast no adverse effect of
      menstrual and reproductive parameters on postmenopausal bone mass was found.

PMID- 10597876
TI  - Prevalence, incidence, and awareness in the treatment of menopausal urinary
      incontinence.
AB  - OBJECTIVES: To investigate the prevalence of urinary incontinence and to evaluate
      the awareness of treatment in postmenopausal women. METHODS: The study group was
      comprised of 3026 postmenopausal women consulting the outpatient clinic. One
      component of the urological questions was formulated to determine the voiding
      habits and presence or absence of urinary incontinence. The incontinent
      responders were questioned further regarding the nature of the urine loss to
      determine the severity of incontinence. RESULTS: It was reported by 26.3%
      (795/3026) of the respondents that they currently had urinary incontinence. They
      were classified by types as follows: stress 64.9%, urge 18.6%, and mixed
      incontinence 7.3%. The incidence of women who desired medical treatment for
      incontinence was only 2.9% (87/3026), while the incidence of women who actually
      received medical treatment for urinary incontinence was 1.9% (56/3026).
      CONCLUSIONS: We conclude that urinary incontinence was prevalent to a significant
      extent among postmenopausal women, but that few affected individuals in this
      group consulted the medical center desiring clinical treatment. The present study
      demonstrated that it is necessary to improve the awareness of postmenopausal
      women concerning the benefits of seeking treatment for urinary incontinence, in
      order to improve their quality of life.

PMID- 10597877
TI  - Depressive vulnerability is not an independent risk factor for osteoporosis in
      postmenopausal women.
AB  - Major depression has been repeatedly but not consistently reported to be
      associated with low bone mineral density (BMD) and to an increased risk for
      fracture in women. We have investigated, in healthy postmenopausal women, whether
      depressive symptomatology, assessed by the General Health Questionnaire (GHQ),
      was associated to a significant decrease in BMD, hence supporting the hypothesis
      of an independent pathogenetic link between the two disorders. We investigated
      121 postmenopausal women, aged 48-77 years, spontaneously attending a screening
      visit for osteoporosis in an outpatient facility. BMD of the spine and the non
      dominant hip (total and neck areas) were measured by Dual Energy X-Ray
      absorptiometry. All subjects completed to the 'General Health Questionnaire'
      translated and validated in French. No significant correlations were observed
      between the GHQ score and BMD of the spine (P = 0.54), the total hip area (P =
      0.65), or the femoral neck area (P = 0.65). No differences in terms of spinal or
      femoral BMD were observed between women with GHQ score < 5 or > or = 5. When
      comparing values of BMD between women within the upper and the lower quartiles
      for GHQ score, no difference was observed for spine (P = 0.69), total hip (P =
      0.80), or femoral neck (P = 0.93). Similarly, GHQ scores were not significantly
      different when comparing women in the upper and lower quartiles of BMD
      distribution at the spine or the hip. In conclusion, notwithstanding the clinical
      pattern of postmenopausal osteoporosis can lead to depression and, on the other
      hand, hormonal and behavioral disturbances reported in depression might be
      enhancing factors for accelerated bone loss, our present results do not support
      the hypothesis that otherwise healthy postmenopausal women with increased
      depressive complaints are also more prone to exhibit osteoporotic fractures.

PMID- 10597878
TI  - Transvaginal sonography and hysteroscopy in postmenopausal uterine bleeding.
AB  - OBJECTIVE: To compare the diagnostic accuracy of transvaginal ultrasound and
      hysteroscopy in the detection of endometrial pathologies in women with
      postmenopausal bleeding not using hormonal replacement therapy (HRT). METHODS:
      Between January 1997 and April 1998, 106 postmenopausal women with uterine
      bleeding not using HRT underwent a diagnostic work-up including pelvic
      examination, transvaginal ultrasound, hysteroscopy and endometrial biopsy.
      Sonographic measurement of endometrial thickness and hysteroscopic findings were
      compared with histological results. The 'classification tree' method was used to
      identify cut-off values of sonographic endometrial thickness that could be
      indicative of a class of uterine pathology. Statistical analysis was performed
      with the McNemar test. RESULTS: No case of endometrial cancer was found with a
      cut-off point of 5 mm of endometrial thickness evaluated by ultrasound, whereas
      all patients with endometrial thickness > or = 15 mm at sonography had an
      endometrial carcinoma. In the group of patients with endometrial thickness
      between 6 and 14 mm, we found normal atrophic endometria, benign and malignant
      pathology. On the other hand, the McNemar test showed a very good correspondence
      between hysteroscopy and histology (sensitivity 97.5% and specificity 100%),
      confirming its usefulness in diagnosis of postmenopausal uterine bleeding.
      CONCLUSIONS: Transvaginal ultrasound has revealed some limitations, mainly in the
      group of patients with endometrial thickness between 6 and 14 mm. The absence of
      endometrial malignancy in women with endometrial thickness < or = 5 mm and the
      high possibility of cancer in those with endometrial thickness > or = 15 mm
      should be confirmed in larger series. Hysteroscopy proved to be a simple and safe
      outpatient procedure with a high diagnostic accuracy, and in our opinion it
      should be considered in all women with postmenopausal uterine bleeding.

PMID- 10597879
TI  - The acute effects of sublingual estradiol on left ventricular diastolic function
      in normotensive and hypertensive postmenopausal women.
AB  - AIM: limited information is available on estrogen influences on diastole. We
      aimed to investigate the acute effects of a single dose of sublingual 17beta
      estradiol on left ventricular diastolic function in postmenopausal women.
      METHODS: the study included 28 women aged 55.6 +/- 6 (15 normotensive and 13
      hypertensive), who underwent Doppler echocardiography and estradiol plasma levels
      determination before and 60 min after sublingual administration of 4 mg of 17beta
      estradiol. RESULTS: there were no modifications in heart rate. Both systolic and
      diastolic blood pressure dropped significantly in the hypertensives and remained
      unchanged in normotensives. Estradiol levels were 1790 +/- 869 pg/ml in the
      normotensives and 2664 +/- 1490 in the hypertensives (P < 0.05). Peak early
      velocity, in the population as a whole, increased from 84 +/- 18 to 91 +/- 18
      cm/s and the early-to-atrial velocity ratio from 1.1 +/- 0.4 to 1.4 +/- 0.6 (P <
      0.0001 for both). Both acceleration and deceleration rates increased
      significantly (P < 0.0001). These changes were shared by all the patients. In
      addition, the hypertensive patients, who presented a baseline pattern
      characterized mainly by a grossly increased peak atrial velocity with reduction
      in the early-to-atrial velocity ratio, demonstrated a decrease in peak atrial
      velocity from 92 +/- 12 to 78 +/- 10 cm/s (P < 0.0001), associated with
      significant reductions in deceleration time (P < 0.0001) and pressure half time
      (P < 0.005). Therefore, the typical picture of impaired ventricular relaxation
      was favorably changed after estradiol administration. CONCLUSIONS: the sublingual
      administration of estradiol induces acute modifications in left ventricular
      diastolic function in postmenopausal women, with improvement in the age-related
      left ventricular relaxation pattern, and that these beneficial changes are more
      pronounced in hypertensive that in normotensive women.

PMID- 10597880
TI  - Impact on postmenopausal symptoms of adding continuous C-21 versus C-19 progestin
      to estrogen.
AB  - OBJECTIVE: To compare the effects of (i) continuous low dosage C-19 progestin (dl
      norgestrel, NG) plus cyclical conjugated estrogen (CEE) versus (ii) continuous
      low dosage C-21 progestin [medroxyprogesterone acetate (MPA)] plus CEE on
      postmenopausal vaginal bleeding, mood and somatic, psychosomatic and
      psychological symptoms. METHODS: Nine hypercholesterolemic postmenopausal women
      with intact uteri were randomly assigned in a prospective, double-blind, two
      period cross-over study of CEE (25/28 days) plus either (i) NG, (0.05 mg/day) or
      (ii) MPA (2.5 mg/day) for 1 year and after an appropriate wash-out period were
      switched to the alternative regimen for another year. Four hysterectomized
      control subjects received the CEE only. RESULTS: Administration of CEE + MPA
      versus CEE + NG resulted in a significantly higher percent of cycles which were
      free of vaginal bleeding (97 vs 85%), spotting (92 vs 79%) and either spotting or
      bleeding (92 vs 76%, P < 0.01). All three regimens significantly reduced the
      overall combined scores for postmenopausal somatic, psychosomatic and
      psychological symptoms (P < 0.05). CONCLUSIONS: Vaginal bleeding and/or spotting
      were significantly less frequent with CEE + MPA versus CEE + NG. However, each of
      the three hormonal regimens improved mood and significantly reduced
      postmenopausal symptoms in comparison to untreated control values.

PMID- 10597881
TI  - GH, IGFBP-1, and IGFBP-3 response to oral glucose tolerance test in
      perimenopausal women: no influence of body mass index.
AB  - OBJECTIVES: an increasing interest is being focused on the role of the
      somatotropic axis in the modulation of body weight and fat distribution,
      particularly in climacteric women. The influence of the glycometabolic state on
      the somatotropic axis in postmenopausal and in obese subjects has not been
      investigated. The aim of the present study is to evaluate whether menopause and
      body mass index (BMI) affect the response of growth hormone (GH), insulin-like
      growth factor-binding protein-1 (IGFBP-1) and -3 (IGFBP-3) to the oral glucose
      tolerance test (OGTT). METHODS: the study included 24 women, aged 45-55 years,
      categorized into 4 groups, premenopausal pre-obese (BMI = 28.5 +/- 0.8 Kg/m2) and
      normal body weight (BMI = 22.2 +/-1.1 Kg/m2), and postmenopausal pre-obese and
      normal body weight. All women underwent: (1) a biophysical evaluation with
      determination of waist/hip ratio; (2) an assessment of fat and lean tissue mass
      and body fat distribution by total body DEXA; and to (3) an OGTT. RESULTS: in
      response to OGTT plasma GH levels significantly decreased in all groups, but the
      relative decrease was more prominent in the lean subjects. A significant decrease
      of IGFBP-1 levels in response to OGTT was observed in all women, regardless of
      menopausal age and BMI, while IGFBP-3 levels did not significantly change in
      either group. CONCLUSIONS: in conclusion, the impact of both BMI and menopausal
      condition on GH, IGFBP-1, and -3 response to OGTT is limited to a blunted GH
      response in overweight women compared with normally-weighing ones. These findings
      appear to rule out the hypothesis that a common glycometabolic derangement may
      affect both the modifications of body weight and of the somatotropic axis
      observed in perimenopausal women.

PMID- 10597882
TI  - The effects of 17beta-estradiol on ectopic rhythm in human atrial strips.

PMID- 10597883
TI  - The role of dopamine in the nucleus accumbens in analgesia.
AB  - Opioid and psychostimulant drugs have long been used for the relief of chronic
      pain in the clinical situation. Animal studies confirm that these drugs alleviate
      persistent or tonic pain. Little is known, however, about the neural systems
      underlying the suppression of tonic pain except that they are different from
      those mediating the suppression of phasic (i.e., sharp and short-lasting) pain.
      Although spinal and brainstem-descending pain suppression mechanisms play a role
      in mediating the inhibition of tonic pain, it appears that this response is
      additionally mediated by the activation of mechanisms lying rostral to the
      brainstem. Recent studies suggest that the activation of mesolimbic dopamine (DA)
      neurons, arising from the cell bodies of the ventral tegmental area (VTA) and
      projecting to the nucleus accumbens (NAcc), plays an important role in mediating
      the suppression of tonic pain. Other studies suggest that this pain-suppression
      system involving the activation of mesolimbic DA neurons is naturally triggered
      by exposure to stress, through the endogenous release of opioids and substance P
      (SP) in the midbrain.

PMID- 10597884
TI  - Ibuprofen protects low density lipoproteins against oxidative modification.
AB  - Oxidative modification of LDL by vascular cells has been proposed as the
      mechanism by which LDL become atherogenic. The effect of ibuprofen on LDL
      modification by copper ions, monocytes and endothelial cells was studied by
      measuring lipid peroxidation products. Ibuprofen inhibited LDL oxidation in a
      dose-dependent manner over a concentration range of 0.1 to 2.0 mM. Ibuprofen (2
      mM, 100 microg/ml LDL) reduced the amount of lipid peroxides formed during 2 and
      6 h incubation in the presence of copper ions by 52 and 28%, respectively. Weak
      free radical scavenging activity of ibuprofen was observed in the DPPH test. The
      protective effect of ibuprofen was more marked when oxidation was induced by
      monocytes or endothelial cells. Ibuprofen (1 mM, 100 microg/ml LDL) reduced the
      amount of lipid peroxides generated in LDL during monocyte-mediated oxidation by
      40%. HUVEC-mediated oxidation of LDL in the absence and presence of Cu2+ was
      reduced by 32 and 39%, respectively. More lipid peroxides appeared when
      endothelial cells were stimulated by IL-1beta or TNFalpha and the inhibitory
      effect of ibuprofen in this case was more pronounced. Ibuprofen (1 mM, 100
      microg/ml LDL) reduced the amount of lipid peroxides formed during incubation of
      LDL with IL-1beta-stimulated HUVEC by 43%. The figures in the absence and
      presence of Cu2+ for HUVEC stimulated with TNFalpha were 56 and 59%,
      respectively. To assess the possibility that ibuprofen acts by lowering the
      production rate of reactive oxygen species, the intracellular concentration of
      H2O2 was measured. Ibuprofen (1 mM) reduced intracellular production of hydrogen
      peroxide in PMA-stimulated mononuclear cells by 69%. When HUVEC were stimulated
      by IL-1beta or TNFalpha the reduction was 62% and 66%, respectively.

PMID- 10597885
TI  - Comparison of nerve growth factor mRNA expression in cardiac and skeletal muscle
      in streptozotocin-induced diabetic mice.
AB  - To address the role of nerve growth factor (NGF) in diabetes mellitus (DM)
      induced cardiac autonomic neuropathy, we quantitated and compared the expression
      of NGF mRNA in the cardiac and the skeletal muscle in experimental DM mice with
      the RT-PCR-HPLC method, which we have developed previously, using a NGF deletion
      mutant RNA as an internal standard. DM was induced in ICR mice via
      intraperitoneal injection of streptozotocin. RT-PCR was performed using total RNA
      extracted from left ventricle and soleus muscle, and the levels of NGF mRNA were
      quantitated by HPLC analysis. NGF mRNA content of the cardiac muscle was 17-fold
      higher than the skeletal muscles in control mice. NGF mRNA content of the cardiac
      muscle in diabetic mice at 6 weeks was 4.0-fold higher than that in the control
      mice, while that of the skeletal muscle in diabetic mice was not different from
      the controls. These results indicated that the DM-induced increase in NGF mRNA
      content was higher in cardiac muscle than skeletal muscle, and that NGF might
      play an important role in cardiac autonomic neuropathy.

PMID- 10597886
TI  - Postnatal ontogeny of GTP binding protein in the human frontal cortex.
AB  - The postnatal development of G protein in membrane preparations from frontal
      cortex regions in postmortem brains of various ages was investigated by
      immunoblotting with polyclonal antibodies against several specific G protein
      subtypes (the short and long form of Galphas(:Gs), Galphai1.2(:Gi), Galphao(:Go)
      and Galphaq/11(:Gq)) and tubulinbeta, and functional photoaffinity GTP binding.
      The amounts of Go showed steep increases at about 2 years, and there were similar
      tendency about Gs, Gi1.2 and Gq/11. Moreover, tubulinbeta was constant with
      development. The guanine nucleotide binding of Gs, Gi and Go also transiently
      increased at about the age of 2 years but the ratio of Gs to Gi.o was unchanged.
      Our results might have relevance for developmental neuroplasticity in signal
      transduction.

PMID- 10597887
TI  - Increased myofibroblast contractile sensitivity in paraquat pretreated rat lung
      tissue.
AB  - In numerous tissues, contractility to certain characteristic agents is associated
      with cells other than muscle, e.g. actin-containing so-called myofibroblasts.
      Such cells are present in pulmonary interstitium of several mammalian species but
      their contractility has only been demonstrated from the proliferation of
      myofibroblasts in fibrotic lung tissues. This study has been done to evaluate
      such responses in normal tissues in contrast with fibrotic lungs and it was
      necessary to take account also of smooth muscle reactivity. Distinctive agonists:
      mepyramine and sodium tungstate characterised myofibroblast mediated
      contractility, in contrast with acetylcholine and barium chloride as specific
      smooth muscle stimulants. Histology and immunohistochemistry were used to
      evaluate the pharmacological results more precisely.

PMID- 10597888
TI  - Effects of hirsutine and dihydrocorynantheine on the action potentials of sino
      atrial node, atrium and ventricle.
AB  - The effects of hirsutine, an indole alkaloid from Uncaria rhynchophylla MIQ.
      JACKSON with antihypertensive, negative chronotropic and antiarrhythmic activity,
      and its C3 structural epimer, dihydrocorynantheine, on membrane potentials of
      rabbit sino-atrial node and guinea-pig right ventricle and left atrium were
      studied with microelectrode techniques. In sino-atrial node preparations,
      hirsutine and dihydrocorynantheine (0.1 microM to 10 microM) concentration
      dependently increased cycle length, decreased slope of the pacemaker
      depolarization (phase 4 depolarization), decreased maximum rate of rise and
      prolonged action potential duration. In atrial and ventricular preparations, both
      compounds (0.1 microM to 30 microM) concentration-dependently decreased maximum
      rate of rise and prolonged action potential duration. These results indicate that
      hirsutine and dihydrocorynantheine have direct effects on the action potential of
      cardiac muscle through inhibition of multiple ion channels, which may explain
      their negative chronotropic and antiarrhythmic activity.

PMID- 10597889
TI  - Nuclear transport as an ultimate step of multidrug resistance.
AB  - Adriamycin (ADM) incorporation into nuclei of whole multidrug resistant (MDR) CEM
      cells is lower than into sensitive ones (S), that is mostly thought to be the
      consequence of a decrease of drug related to the activity of the multidrug
      resistance plasma membrane protein P 170. Isolated nuclei of the lymphoblastic
      tumor cell line CEM, which structures were controlled by scanning electron
      microscopy (SEM), transmission electron microscopy (TEM), and confocal
      microscopy, where incubated with 10(-6) mole/l of ADM. Incorporation into DNA was
      quantified by spectrofluorimetry. It was lower and slower into MDR nuclei than
      into S ones. Different modulators of active transport influence drug transfer
      into S nuclei and had no effect in MDR nuclei. The nuclear transfer into S nuclei
      appeared divided into two components: one was decreased by WGA, increased by
      cytosolic factors and an other part was purely passive in an identical intensity
      to MDR nuclei. Resistance of MDR nuclei seemed indebt to a defect, in these
      cells, of factors that mediate and/or activate nuclear transport of drug.

PMID- 10597890
TI  - Exposure with the environmental estrogen bisphenol A disrupts the male
      reproductive tract in young mice.
AB  - Environmental estrogens (endocrine disruptive chemicals) have been shown to
      affect reproduction in wild life and it has been reported that maternal exposure
      with those chemicals have adverse effects on the male reproductive tract.
      However, little is known about the potential effects of prepubertal or pubertal
      exposure with environmental estrogens on the male reproductive tract. Here we
      examine plasma hormone levels and histology in the testis of mice following
      either 4- or 8-week oral administration of bisphenol A. Plasma free testosterone
      levels were dramatically decreased following 8 weeks of bisphenol A treatment
      compared with control group and morphologically multinucleated giant cells having
      greater than three nuclei were found in seminiferous tubules in the testis
      following the 8-week bisphenol A treatment. No differences in plasma
      corticosterone and luteinizing hormone levels were seen between bisphenol A and
      control groups. Thus, exposure with bisphenol A around pubertal period may
      directly disrupt the male reproductive tract. These facts suggest that more
      detailed studies will warrant the assessment of the risk to the developing human
      testis from exposure to bisphenol A and other environmental estrogens in
      prepubertal and pubertal period.

PMID- 10597891
TI  - Transfer of morphine across the human placenta and its interaction with naloxone.
AB  - The purpose of this investigation was to measure the transfer rate and clearance
      of morphine across the placenta with and without naloxone. Term human placental
      cotyledons were perfused in vitro. The placenta was perfused with 50 ng/mL of
      morphine in the absence (n=4) and presence (n=5) of 100 ng/mL of naloxone.
      Maternal and fetal samples were collected. Student's t-test or one-way repeated
      measures ANOVA were used for all comparisons. The maternal-to-fetal morphine
      transfer rate was 0.73+/-0.44 ng/mL/min in the morphine and 0.69+/-0.26 ng/mL/min
      in the morphine-naloxone experiments (p=0.89). The clearance of morphine was
      0.89+/-0.39 mL/min without naloxone and 0.87+/-0.27 mL/min with naloxone
      (p=0.92). Final morphine concentrations in the morphine experiments were 9.78+/
      6.17 ng/mL (maternal) and 3.43+/-2.14 ng/mL (fetal) and 10.04+/-3.89 ng/mL
      (maternal) and 4.16+/-1.64 ng/mL (fetal) in the morphine-naloxone experiments.
      Morphine readily crosses the term human placenta. Naloxone does not alter
      placental transfer or clearance of morphine, suggesting that transfer across the
      placental barrier is not altered by changes in vascular resistance. Placental
      retention of morphine prolongs fetal exposure to morphine.

PMID- 10597892
TI  - Modulation of lipid peroxidation and antioxidant enzymes in murine salivary gland
      by dietary fatty acid ethyl esters.
AB  - The present study was undertaken to investigate the effect of n-9, n-6, and n-3
      dietary fatty acid ethyl esters on basal (uninduced) and Fe2+/ascorbate (induced)
      lipid peroxidation (LPO) in salivary gland (SG) of mice. Feeding n-3 ethyl ester
      polyunsaturated fatty acids (PUFA) increased the uninduced and induced LPO in SG
      homogenates. In contrast, feeding olive oil ethyl esters (n-9) significantly
      lowered the induced and uninduced LPO in SG tissue. Salivary gland susceptibility
      to LPO increased in the order of: olive oil < corn oil < safflower oil < n-3
      ethyl esters. Olive oil esters in the diet increased primarily the 18:1 levels in
      SG tissue. Whereas feeding n-3 PUFA notably increased the superoxide dismutase
      (SOD) and catalase activities in SG homogenates, no significant changes were seen
      between n-9 and n-6 PUFA-fed mice. Lower levels of Vitamin E (Vit E) in the
      tissues of n-3 PUFA-fed mice indicate that the higher the dietary lipid
      unsaturation, the higher the requirement for Vit E in the diet. Our results
      indicate that, similar to other organs, salivary gland susceptibility to
      uninduced or induced oxidation depends on the source of dietary PUFA. In
      conclusion, feeding olive oil increases the resistance of SGs to induced and
      uninduced LPO.

PMID- 10597893
TI  - Angiotensin II stimulates the Na+/H+ exchanger in human umbilical vein
      endothelial cells via AT1 receptor.
AB  - Angiotensin II (Ang II) has an important role in cardiovascular regulation and in
      the control of electrolyte balance, and its role in the regulation of Na+
      transcellular movements through its actions on the activity of Na+/K+ ATPase is
      well documented. We showed previously that human umbilical vein endothelial cells
      (HUVEC) express the Ang II type 1 (AT1) receptor, which mediates Ang II
      modulation of Na+/K+ ATPase activity (1). We here investigate the effects of Ang
      II on the activity of the Na+/H+ exchanger in HUVEC. When compared with controls,
      incubation of HUVEC for 20 min with different concentrations of Ang II provoked
      significant increases in Na+/H+ activity. The stimulation was dose dependent
      between 1 and 10 nM Ang II and varied with time of incubation up to 20 min. The
      maximal response, obtained with 10 nM Ang II after 20 min treatment, resulted in
      a 65% increment in Na+/H+ activity. Preincubation of HUVEC with 10 microM DuP753
      blocked Na+/H+ activation by Ang II. These results suggest that the effects of
      Ang II on both the Na+/K+ ATPase and the Na+/H+ exchanger may increase the
      transendothelial flux of Na+ and are mediated by the AT1 receptor.

PMID- 10597894
TI  - Hyperforin attenuates various ionic conductance mechanisms in the isolated
      hippocampal neurons of rat.
AB  - Effects of hyperforin, an acylphloroglucinol derivative isolated from
      antidepressive medicinal herb Hypericum perforatum (St. John's Wort), on voltage-
      and ligand-gated ionic conductances were investigated. Whole-cell patch clamp and
      concentration clamp techniques on acutely isolated hippocampal pyramidal neurons
      and on cerebellar Purkinje neurons of rat were used. At concentrations between 3
      to 100 microM hyperforin induced a dose and time dependent inward current which
      completely stabilized within a few seconds. Although 1 microM hyperforin
      inhibited virtually all investigated conductances (GABA > or = I(Ca(N)) > I(Na) >
      I(Ca(P) > or = AMPA > or = I(K(A)) > NMDA > I(K(DR))), its effects on several of
      them could not be reversed by repeated washings. Dose response studies revealed
      that although AMPA induced current is inhibited by hyperforin in a competitive
      manner, these responses are not completely blocked by very high concentration of
      the agent. On the contrary, however, NMDA receptor-activated ionic conductance
      could be completely and uncompetitively inhibited by the agent. Taken together
      these observation not only reconfirm that hyperforin is a major neuroactive
      component of hypericum extracts but also demonstrate that this structurally
      unique and naturally abundant molecule is a potent modulation of mechanism
      involved in the control of neuronal ionic conductances. Various observed effects
      of hyperforin do not, however, seem to be mediated by one single molecular
      mechanism of action of the agent.

PMID- 10597895
TI  - Brain receptor binding characteristics and pharmacokinetics of JTP-2942, a novel
      thyrotropin-releasing hormone (TRH) analogue.
AB  - JTP-2942 competed with [3H]-Me-TRH for the binding sites in rat brain in vitro,
      and its inhibitory effect was approximately 17 times less potent than TRH, as
      shown by Ki values of 673 and 39.7 nM, respectively. Both JTP-2942 and TRH
      significantly increased apparent dissociation constant (Kd values) for brain [3H]
      Me-TRH binding. Intravenous injection of JTP-2942 (0.3-3 mg/kg) and TRH (3 and 10
      mg/kg) produced a significant reduction of [3H]-Me-TRH binding sites (Bmax
      values) in rat brain. Although the decrease by TRH was maximal 10 min after the
      injection and declined rapidly with time, the decrease by JTP-2942 (1 and 3
      mg/kg) tended to be maximal at 30 min later and it lasted until 120 min. The
      intravenous injection of JTP-2942 was at least 3 times more potent than that of
      TRH in decreasing Bmax values for brain [3H]-Me-TRH binding. Plasma concentration
      of JTP-2942 (0.3-3 mg/kg) after intravenous injection in rats rose with the
      increase of dose, and it peaked immediately after the injection, thereafter
      decreasing with t1/2 of 19.3-29.9 min. It is concluded that JTP-2942, compared to
      TRH, may exert fairly potent and sustained occupation of brain TRH receptors
      under in vivo condition. Thus, JTP-2942 could be clinically useful for the
      treatment of CNS disorders.

PMID- 10597896
TI  - Interactions of Hsp90 with histones and related peptides.
AB  - The 90 kDa heat shock protein (Hsp90) induces the condensation of the chromatin
      structure [Csermely, P., Kajtar, J., Hollosi, M., Oikarinen, J., and Somogyi, J.
      (1994) Biochem. Biophys. Res. Commun. 202, 1657-1663]. In our present studies we
      used surface plasmon resonance measurements to demonstrate that Hsp90 binds
      histones H1, H2A, H2B, H3 and H4 with high affinity having dissociation constants
      in the submicromolar range. Strong binding of the C-terminal peptide of histone
      H1 containing the SPKK-motif and a pentaeicosa-peptide including the Hsp90
      bipartite nuclear localization signal sequence was also observed. However, a
      lysine/arginine-rich peptide of casein, and the lysine-rich platelet factor 4 did
      not display a significant interaction with Hsp90. Histones and positively charged
      peptides modulated the Hsp90-associated kinase activity. Interactions between
      Hsp90, histones, and high mobility group (HMG) protein-derived peptides raise the
      possibility of the involvement of Hsp90 in chromatin reorganization during
      steroid action, mitosis, or after cellular stress.

PMID- 10597897
TI  - Effect of endothelin-1(1-31) on intracellular free calcium in cultured human
      mesangial cells.
AB  - We found that human chymase selectively produces 31-amino-acid length endothelins
      (1-31) (ETs(1-31)). We investigated the effect of synthetic ET-1(1-31) on
      intracellular free Ca2+ concentration ([Ca2+]i) in cultured human mesangial
      cells. ET-1(1-31) increased [Ca2+]i in a concentration-dependent manner to a
      similar extent as ET-1. The ET-1 (1-31)-induced [Ca2+]i increase was not
      influenced by removal of extracellular Ca2+ but was inhibited by thapsigargin. ET
      1(1-31)-induced [Ca2+]i increase was not affected by phosphoramidon. It was
      inhibited by BQ123, but not by BQ788. These results suggest that ET-1(1-31) by
      itself exhibits bioactive properties probably through endothelin ET(A) or ET(A)
      like receptors. Since human chymase has been reported to exist in the kidney, ET
      1(1-31) may be a candidate substance for mesangium-relevant diseases.

PMID- 10597898
TI  - Effects of AQ4N and its reduction product on radiation-mediated DNA strand
      breakage.
AB  - Supercoiled plasmid pBR322 DNA was irradiated in phosphate buffer by 60Co gamma
      rays at a dose rate 19.26 Gy/min and total dose of 10 Gy in the presence of a
      bioreductive antitumour prodrug namely 1,4-bis [?2-(dimethylamino-N-oxide)ethyl?
      amino] 5, 8-dihydroxyanthracene-9,10-dione (AQ4N) and its DNA affinic reduction
      product 1,4-bis[?2(dimethylamino)ethyl? amino] 5,8-dihydroxyanthracene-9,10-dione
      (AQ4) under air and nitrogen. AQ4N and AQ4 were found to protect against
      radiation-induced plasmid single and double strand breakage as assessed by
      agarose gel electrophoresis. The differences between the two agents, and between
      atmospheres of air or nitrogen were negligible. It was also found that the
      protection efficiencies of the compounds were pH dependent and showed maximum
      protection at pH 6. These results indicate that protection of DNA by AQ4 and AQ4N
      against radiation damage is an indirect effect since both agents are equally
      effective despite major differences in their DNA affinity. It is likely that
      radiation-induced phosphate buffer radicals are intercepted by AQ4 and AQ4N in a
      pH-dependent process.

PMID- 10597899
TI  - Cellular pharmacology of cis and trans pairs of platinum complexes in cisplatin
      sensitive and -resistant human ovarian carcinoma cells.
AB  - The cellular pharmacology of two pairs of cis and trans platinum complexes has
      been studied in three human ovarian carcinoma cell lines, a parental relatively
      cisplatin-sensitive line (CH1), a subline possessing acquired cisplatin
      resistance (3-fold; CH1cisR) and an intrinsically cisplatin resistant line (13
      fold; SKOV-3). Growth inhibition studies showed that both JM335 [trans ammine
      (cyclohexylaminedichloro dihydroxo) platinum(IV)] and its platinum(II) dichloro
      homolog JM334 were relatively less cross-resistant against both acquired and
      intrinsic cisplatin resistant cells. In contrast, resistance circumvention was
      not apparent in these cell lines with their cis isomeric counterparts (JM149 for
      JM335 and JM118 for JM334). The trans compound JM335 was more potent than its cis
      isomer against all three cell lines. There was no clear correlation between
      intracellular accumulation following 2 h exposure to each compound and resulting
      DNA platination or growth inhibition. The selective activity of the trans
      platinum complexes against the SKOV-3 cell line correlated with a deficiency in
      the repair of adducts within a fragment of the N-ras gene induced by trans
      compounds whereas adducts induced by the cis counterparts, and cisplatin, were
      repaired. The CH 1 parental line appeared repair deficient at the gene-specific
      level to adducts induced by both cis (including cisplatin) and trans compounds.
      Resistance in CH1cisR was associated with a lack of gene-specific repair of
      lesions formed by JM118 and JM149. All four compounds induced apoptosis in all
      three cell lines, as measured by fluorescent microscopy and field inverted gel
      electrophoresis, although the kinetics of apoptosis was markedly faster for the
      trans versus cis compounds. In summary, the trans platinum complexes JM335 and
      JM334 possess unique cellular properties compared to their cis counterparts
      particularly with respect to gene specific repair of DNA adducts and the rate of
      induction of apoptosis.

PMID- 10597900
TI  - Inhibition of CYP1A1 enzyme activity in mouse hepatoma cell culture by soybean
      isoflavones.
AB  - The mechanisms by which soybean- and soybean isoflavone-enriched diets inhibit
      carcinogenesis are not known. We found that the isoflavones genistin and daidzin,
      and their respective aglucone forms daidzein and genistein, block 2,3,7,8
      tetrachlorodibenzo-p-dioxin (TCDD; dioxin)-induced CYP1A1 enzyme activity. This
      inhibition is correlated with the capacity of the isoflavones to prevent CYP1A1
      mediated covalent binding of benzo[a]pyrene (BaP) metabolites to DNA. We further
      evaluated daidzein and genistein, believed to be the active forms of the
      isoflavones, for the mechanism of the inhibitory process. Although daidzein and
      genistein appear structurally similar to known aromatic hydrocarbon receptor
      (AHR) agonists and antagonists, gel mobility shift assays indicated that the
      isoflavones do not inhibit dioxin-induced activation of the AHR or the
      accumulation of CYP1A1 mRNA, suggesting that the isoflavones do not act at the
      transcriptional level. We therefore evaluated the isoflavones for direct effects
      on the CYP1A1 enzyme. Daidzein and genistein non-competitive with the CYP1A1
      substrate BaP for microsomal BaP hydroxylation, with apparent Ki values of 325
      microM and 140 microM, respectively. The extent of CYP1A1 inhibition increases
      with time of preincubation at 37 degrees C, but not at 4 degrees C, in the
      presence of isoflavone plus NADPH; after 60 min preincubation the inhibition
      remains non-competitive, with apparent Ki values of 55 microM and 50 microM,
      respectively. Inhibition is neither prevented nor reversed by the thiol
      antioxidant dithiothreitol, nor by the iron chelator deferoxamine. Repeated
      washing of the microsomes does not reverse the inhibition. The dependency on
      NADPH, temperature and time for inhibition of CYP1A1 suggests that metabolism of
      either isoflavone or molecular oxygen to reactive species is required. Isoflavone
      mediated inhibition of CYP1A1 activity may contribute to the mechanism by which
      these soybean isoflavones protect against carcinogenesis.

PMID- 10597901
TI  - Inactivation of creatine kinase induced by dopa and dopamine in the presence of
      ferrylmyoglobin.
AB  - We investigated the effect of dopa and dopamine on creatine kinase (CK) activity
      in the presence of ferrylmyoglobin (ferrylMb). CK was sharply inhibited by dopa
      and dopamine in the presence of ferrylMb. Dopa and dopamine markedly promoted the
      reduction of ferrylMb to metmyoglobin (metMb). The semiquinone from dopa and
      dopamine may be involved in CK inactivation. During inactivation of the enzyme,
      both kinetic parameters Vmax and Km changed. In addition, reduced glutathione
      restored the activity of CK at an early stage. These results suggest that
      inactivation of CK is dominantly due to oxidation of sulfhydryl (SH) groups of
      the enzyme. Other catechols, such as adrenaline and noradrenaline, little
      inactivated CK activity, whereas they promoted the reduction of ferrylMb to
      metMb. Other SH enzymes, including alcohol dehydrogenase (ADH) and glyceraldehyde
      3-phosphate dehydrogenase (GAPDH), were inactivated to a lesser extent by dopa
      and dopamine in the presence of ferrylMb. Adrenaline and noradrenaline did not
      significantly prevent the inactivation of ADH and very slightly inhibited GAPDH.
      These results suggest that dopa and dopamine act as prooxidants to inactivate SH
      enzymes in the presence of ferrylMb.

PMID- 10597902
TI  - In vitro inhibition of human liver drug metabolizing enzymes by second generation
      antihistamines.
AB  - Cetirizine, terfenadine, loratadine, astemizole and mizolastine were compared for
      their ability to inhibit marker activities for CYP1A2, CYP2C9, CYP2C19, CYP2D6,
      CYP3A4 and for some glucuronidation isoenzymes in human liver microsomes. The
      most pronounced effects were observed with terfenadine, astemizole and loratadine
      which inhibited CYP3A4-mediated testosterone 6beta-hydroxylation (IC50 of 23, 21
      and 32 microM, respectively) and CYP2D6-mediated dextromethorphan O-demethylation
      (IC50 of 18, 36 and 15 microM, respectively). In addition, loratadine markedly
      inhibited the CYP2C19 marker activity, (S)-mephenytoin 4-hydroxylation (Ki of
      0.17 microM). Furthermore, loratadine activated the CYP2C9-catalyzed tolbutamide
      hydroxylation (ca. 3-fold increase at 30 microM) and inhibited some
      glucuronidation enzymes. Mizolastine appeared to be a relatively weak and
      unspecific inhibitor of CYP2E1, CYP2C9, CYP2D6 and CYP3A4 (IC50Ss in the 100
      micromolar range). Cetirizine demonstrated no effect on the investigated
      activities. A comparison of the inhibitory potencies of cetirizine, terfenadine,
      loratidine, astemizole and mizolastine with their corresponding plasma
      concentrations in humans suggests that these antihistamines are not likely to
      interfere with the metabolic clearance of coadministered drugs, with the
      exception of loratidine, which appears to inhibit CYP2C19 with sufficient potency
      to warrant additional investigation.

PMID- 10597903
TI  - The mycotoxin patulin induces intra- and intermolecular protein crosslinks in
      vitro involving cysteine, lysine, and histidine side chains, and alpha-amino
      groups.
AB  - As previous studies have indicated a multiple electrophilic reactivity of patulin
      (PAT) towards simple thiol nucleophiles, we have methodically investigated the
      ability of PAT to covalently crosslink proteins in vitro. By means of sodium
      dodecylsulphate polyacrylamide gel electrophoresis, the formation of PAT-induced
      intermolecular protein-protein crosslinks was clearly demonstrated for bovine
      serum albumin containing one thiol group per molecule, but also for the thiol
      free hen egg lysozyme. Characterization of the crosslink sites was carried out by
      (1) modulation of the thiol groups with N-ethylimaleimide and 2-iminothiolane;
      (2) comparison with various known crosslinking agents, i.e. phenylenedimaleimide,
      glutardialdehyde, and dimethylsuberimidate, and (3) fluorescence incorporation
      studies using dansyl-labeled amino acids and a fluorescent glutathione
      derivative. The thiol group of cysteine was preferred for PAT-mediated crosslink
      reactions, but the side chains of lysine and histidine, and alpha-amino groups
      also exhibited reactivity. PAT can act both as a homobifunctional as well as a
      heterobifunctional crosslinking agent. The initial formation of a monoadduct with
      a thiol group appears to activate PAT for the subsequent reaction with an amino
      group, but also leads to rapid loss of further electrophilic properties when no
      second nucleophile for crosslink completion is available. Studies using
      microtubule proteins as a protein with experimentally controllable quarternary
      structure and a proposed cellular target for PAT toxicity emphasized the
      influence of specific sterical conditions on crosslink formation at low protein
      concentrations. Non-polymerized microtubule proteins, i.e. tubulin alpha,beta
      dimers, formed a defined product with PAT consisting of an intramolecularly
      crosslinked beta-tubulin, whereas guanosine triphosphate- or paclitaxel-induced
      polymerization to microtubule-like quarternary structures prior to treatment with
      PAT gave rise to intermolecular crosslink formation between alpha- and beta
      tubulin. In contrast, denaturated tubulin yielded none of those two new protein
      species, but only unspecific intramolecular crosslinks and highly crosslinked
      aggregates. Thus, in addition to the amino acid composition, the tertiary and
      quarternary superstructures of proteins appear to markedly influence their
      reactivity towards PAT. Under appropriate conditions, the generation of protein
      crosslinks could easily be observed at concentrations of PAT equal to or even
      below the concentration of the protein. The relevance of these novel reaction
      pathways of PAT demonstrated in vitro for its in vivo mechanisms of toxicity
      remains to be investigated.

PMID- 10597904
TI  - The effect of inducing agents on the metabolism of ethidium bromide by isolated
      rat hepatocytes.
AB  - The metabolism of ethidium bromide by isolated rat hepatocytes is significantly
      enhanced by pre-treatment of animals with phenobarbitone (PB) and 3
      methylcholanthrene (3-MC). Pre-treatment with PB and 3-MC results in a 2.5- and
      1.5-fold increase, respectively in the amount of the principal metabolite,
      ethidium 8-N-glucuronide, compared with that formed by hepatocytes from untreated
      rats. The formation of ethidium 3-N-glucuronide is not enhanced by pre-treatment
      with either PB or 3-MC. Two new metabolites, hydroxyethidium glucuronide and a
      transient unidentified species, have been detected by HPLC and are formed only by
      hepatocytes from animals pre-treated with 3-MC.

PMID- 10597905
TI  - Chromium(VI)-mediated DNA damage: oxidative pathways resulting in the formation
      of DNA breaks and abasic sites.
AB  - Inside cells chromium(VI) is activated to its ultimate carcinogenic form by
      reducing agents including glutathione (GSH) and ascorbate (AsA). The precise
      mechanism by which DNA damaging species are formed is unclear. In earlier in
      vitro work with isolated DNA we have shown that chromium(VI) in combination with
      GSH or AsA is able to induce similar numbers of single strand breaks and
      apurinic/apyrimidinic sites (AP-sites). Moreover, the formation of both lesions
      followed a similar temporal pattern. It is conceivable that the two forms of DNA
      damage arise from a common precursor lesion (e.g. hydrogen abstraction at C4' of
      the DNA sugar moiety) with a partitioning along two pathways, one yielding an AP
      site, the other a single strand break (SSB) and a base propenal. The present
      study is intended to test this hypothesis by analysing whether oxidation products
      of deoxyribose can be formed in the presence of chromium(VI) and GSH or AsA. It
      was found that mixtures of chromium(VI) and GSH or AsA were able to oxidise 2
      deoxyribose to yield malondialdehyde, which was detected by reaction with
      thiobarbituric acid. The characteristic pink chromogen, which forms upon reaction
      with thiobarbituric acid, was also observed with calf thymus DNA as the
      substrate. In both experimental systems the addition of catalase prevented the
      formation of deoxyribose breakdown products. Hydroxyl radicals did not seem to be
      important for the generation of DNA damage as the characteristic modified DNA
      bases could not be detected by using gas chromatography-mass spectrometry. These
      results lead us to conclude that the formation of SSB during the reductive
      conversion of chromium(VI) proceeds primarily via hydrogen abstraction from C4'.
      The observation that Fenton chemistry is not involved in these processes is
      intriguing and necessitates further research into the ways in which chromium can
      activate molecular oxygen to form DNA damaging species.

PMID- 10597906
TI  - HPLC analysis of benzo[a]pyrene-albumin adducts in benzo[a]pyrene exposed rats.
      Detection of cis-tetrols arising from hydrolysis of adducts of anti- and syn-BPDE
      III with proteins.
AB  - Quantitation of protein-benzo[a]pyrene adducts represent a more sensitive
      analysis method than quantitation of benzo[a]pyrene-DNA adducts. By accurate
      analysis of benzo[a]pyrene-protein adducts several different molecular adduct
      forms can be studied. Male Wistar rats were injected i.p. with benzo[a]pyrene,
      and serum albumin was isolated and subjected to acid hydrolysis at 90 degrees C
      for 3 h. The hydrolysate was analyzed by HPLC with fluorescence detection. The
      HPLC profiles obtained after albumin hydrolysis from benzo[a]pyrene exposed
      animals were compared to similar HPLC profiles from in vitro adducted bovine
      serum albumin (BSA) and direct hydrolysis of both r-10,t-9-dihydrodiol-c-7,8-oxy
      7,8,9,10-tetrahydrobenzo[a]pyrene (syn-BPDE-III) and r-10,t-9-t-dihydrodiol-t-7,8
      oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE-III). After acid hydrolysis of
      albumin from benzo[a]pyrene exposed rats, 6 fluorescent peaks were separated.
      Four of the peaks were isomers of benzo[a]pyrene-tetrahydrotetrols, (+/-)
      benzo[a]pyrene-r-7,t-8,9,10-tetrahydrotetrol, (+/-)-benzo[a]pyrene-r-7,t-8,9,c-10
      tetrahydrotetrol, (+/-)-benzo[a]pyrene-r-7,t-8,c-9,t-10-tetrahydrotetrol and (+/
      )-benzo[a]pyrene-r-7,t-8,c-9,10-tetrahydrotetrol. In addition we found two
      fluorescent peaks, named X1 and X2 with retention times similar to the
      benzo[a]pyrene-tetrols. The unknown fluorescent peaks reacted similar to the four
      known tetrols in both dose response experiments and time course experiments.
      Fluorescent material with retention times equal to X1 and X2 were found after
      acid hydrolysis of syn-BPDE-III and anti-BPDE-III in acid and in hydrolysates
      from BSA treated in vitro with syn-BPDE-III and anti-BPDE-III. The ratio X1/X2
      was relatively constant indicating epimerization equilibrium between these to
      species. Synchronous fluorescence analysis of fractions containing X1 or X2 from
      both in vivo and in vitro experiments showed fluorescence spectra characteristic
      of benzo[a]pyrene tetrols using a wavelength difference of 34 nm.

PMID- 10597907
TI  - Captan impairs CYP-catalyzed drug metabolism in the mouse.
AB  - To investigate whether the fungicide captan impairs CYP-catalyzed drug metabolism
      in murine liver, kidney and lung, the modulation of the regio- and stereo
      selective hydroxylation of testosterone, including 6beta-(CYP3A), 6alpha-(CYP2A1
      and CYP2B1) and 16alpha-(CYP2B9) oxidations was studied. Specific substrates as
      probes for different CYP isoforms such as p-nitrophenol (CYP2E1),
      pentoxyresorufin (CYP2B1), ethoxyresorufin (CYP1A1), aminopyrine (CYP3A),
      phenacetin and methoxyresorufin (CYP1A2), and ethoxycoumarin (mixed) were also
      considered. Daily doses of captan (7.5 or 15 mg/kg b.w., i.p.) were administered
      to different groups of Swiss Albino CD1 mice of both sexes for 1 or 3 consecutive
      days. While a single dose of this fungicide did not affect CYP-machinery,
      repeated treatment significantly impaired the microsomal metabolism; in the
      liver, for example, a general inactivating effect was observed, with the sole
      exception of testosterone 2alpha-hydroxylase activity which was induced up to 8.6
      fold in males. In vitro studies showed that the mechanism-based inhibition was
      related to captan metabolites rather than the parental compound. In the kidney,
      both CYP3A- and CYP1A2-linked monooxygenases were significantly induced (2-fold)
      by this pesticide. Accelerated phenacetin and methoxyresorufin metabolism
      (CYP1A2) was also observed in the lung. Data on CYP3A (kidney) and CYP1A2 (kidney
      and lung) induction were corroborated by Western immunoblotting using rabbit
      polyclonal anti-CYP3A1/2 and CYP1A1/2 antibodies. By means of electron spin
      resonance (EPR) spectrometry coupled to a spin-trapping technique, it was found
      that the recorded induction generates a large amounts of the anion radical
      superoxide (O*2-) either in kidney or lung microsomes. These findings suggest
      that alterations in CYP-associated activities by captan exposure may result in
      impaired (endogenous) metabolism as well as of coadministered drugs with
      significant implications for their disposition. The adverse outcomes associated
      to CYP changes (e.g. cotoxicity, comutagenicity and promotion) may also have
      harmful consequences.

PMID- 10597908
TI  - The response of human glioma cell lines to low-dose radiation exposure.
AB  - PURPOSE: To examine the low-dose radiation response of a series of radioresistant
      human glioma cell lines and determine if low-dose hypersensitivity is a
      characteristic of these cells. MATERIALS AND METHODS: The clonogenic survival of
      six radioresistant human glioma cell lines was measured following exposure to
      graded, single, very low doses of X-rays in vitro. High resolution was achieved
      using either a Dynamic Microscopic Image Processing Scanner (DMIPS) or a cell
      sorter (CS). RESULTS: In five of the six cell lines tested, low-dose
      hypersensitivity (HRS) was demonstrated although in the sixth, a grade III
      astrocytoma line, it was not. These results are consistent with previous data
      indicating that low-dose hypersensitivity is more marked in more radioresistant
      cell lines although the difference between the glioblastoma cell lines with
      differing SF2 is not marked. CONCLUSION: Low-dose hypersensitivity is common in
      radioresistant glioma cell lines. This may have implications for the treatment of
      these tumours if further studies confirm that HRS translates to increased
      effectiveness per gray in vivo when very low doses per fraction are used.

PMID- 10597909
TI  - Lack of effect of caffeine post-treatment on X-ray-induced chromosomal
      aberrations in Werner's syndrome lymphoblastoid cell lines: a preliminary report.
AB  - PURPOSE: To investigate whether in Werner's syndrome cells the G2 phase of the
      cell cycle has some abnormal response to post-treatment with agents such as
      caffeine and hydroxyurea known to interfere with cellular response to DNA damage.
      MATERIALS AND METHODS: Two Werner's syndrome lymphoblastoid cell lines (KO375 and
      DJG) and the normal cell line SNW646 were exposed to 50 cGy of X-rays or
      mitomycin-C and posttreated with caffeine or hydroxyurea in the G2 phase of the
      cell cycle. RESULTS: Hydroxyurea post-treatment potentiated the X-ray-induced
      aberration levels both in the normal and Werner's syndrome (KO375 and DJG) cell
      lines; in contrast caffeine was only effective in the normal cell line. Similar
      results were observed when Werner's syndrome cells were treated in the G1 phase
      with the S-dependent agent mitomycin-C and post-treated with caffeine in G2,
      extending the observation that Werner's syndrome cells are unaffected by caffeine
      G2 post-treatment. CONCLUSIONS: These results show a lack of caffeine effect in
      Werner's syndrome cells, suggesting an involvement of the Werner's syndrome
      protein in the signal transduction pathway by which caffeine could override the
      DNA damage induced G2 checkpoint.

PMID- 10597910
TI  - RBE for carbon track-segment irradiation in cell lines of differing repair
      capacity.
AB  - PURPOSE: The LET position of the RBE maximum and its dependence on the cellular
      repair capacity was determined for carbon ions. Hamster cell lines of differing
      repair capacity were irradiated with monoenergetic carbon ions. RBE values for
      cell inactivation at different survival levels were determined and the
      differences in the RBE-LET patterns were compared with the individual sensitivity
      to photon irradiation of the different cell lines. MATERIAL AND METHODS: Three
      hamster cell lines, the wild-type cell lines V79 and CHO-K1 and the
      radiosensitive CHO mutant xrs5, were irradiated with carbon ions of different
      energies (2.4-266.4 MeV/u) and LET values (13.7-482.7 keV/microm) and
      inactivation data were measured in comparison to 250 kV x-rays. RESULTS: For the
      repair-proficient cell lines a RBE maximum was found at LET values between 150
      and 200 keV/microm. For the repair-deficient cell line the RBE failed to show a
      maximum and decreased continuously for LET values above 100 keV/microm.
      CONCLUSIONS: The carbon RBE LET relationship for inactivation is shifted to
      higher LET values compared with protons and alpha-particles. RBE correlated with
      the repair capacity of the cells.

PMID- 10597911
TI  - p53 status, cellular recovery and cell cycle arrest as prognosticators of in
      vitro radiosensitivity in human pancreatic adenocarcinoma cell lines.
AB  - PURPOSE: To investigate the factors contributing to the in vitro radiosensitivity
      of four human pancreatic adenocarcinoma cell lines differing in p53 status, and
      the basis for the lack of post-irradiation G1 arrest in the two cell lines that
      have retained a wild-type p53 allele. MATERIALS AND METHODS: Cells were X
      irradiated and the parameters related to radiosensitivity, as well as the
      modulation of gene products linked to regulation of cell cycle transit (p53,
      p21/WAF1/CIP1, pRb) or DNA replication and repair (DNA topoisomerase I and II),
      were determined. RESULTS: Both cell lines expressing either mutant (mt) R248W or
      R273H p53 proteins were more radioresistant. All the cell lines arrested in G2.
      None of the cell lines arrested in G1 and this was linked to the inability to
      upregulate p21/WAF1/CIP1. There were no correlations between p53 status and the
      magnitude or time of maximum G2 arrest. However, there was a negative correlation
      between a protracted arrest in G2 and the ability to recover from potentially
      lethal damage (PLD). CONCLUSIONS: Variation in radiosensitivity is related to p53
      status, but the survival advantage conferred by having mutant p53 status is not
      readily explained neither by recovery from PLD nor by cell cycle arrest kinetics.
      There is no p53-independent pathway for the recruitment of p21 in these cell
      lines following irradiation.

PMID- 10597912
TI  - Radiobiological and immunohistochemical assessment of hypoxia in human melanoma
      xenografts: acute and chronic hypoxia in individual tumours.
AB  - PURPOSE: Tumour hypoxia causes resistance to treatment and may promote the
      development of metastatic disease. The mean fraction of radiobiologically hypoxic
      cells has been determined for a large number of tumour cell lines, but
      quantitative information on intertumour heterogeneity in radiobiological hypoxia
      is sparse, and it is not known whether radiobiological hypoxia is mainly either
      chronic or acute in nature. The purpose of the work reported here was (1) to
      determine the fraction of radiobiologically hypoxic cells in individual tumours
      and (2) to differentiate quantitatively between chronic and acute hypoxia.
      MATERIALS AND METHODS: Four human melanoma xenograft lines (A-07, D-12, R-18, U
      25) were included. A radiobiological assay based on the paired survival curve
      method was established to measure the fraction of radiobiologically hypoxic
      cells. An immunohistochemical assay using the hypoxia marker pimonidazole was
      developed to determine the fraction of chronically hypoxic cells. The fraction of
      acutely hypoxic cells was estimated from the fraction of radiobiologically
      hypoxic cells and the fraction of chronically hypoxic cells. RESULTS: The
      fractions of radiobiologically hypoxic cells were in the ranges of 1-49% (A-07),
      10-69% (D-12), 22-87% (R-18) and 23 85% (U-25); the fractions of chronically
      hypoxic cells were in the ranges of 0-15% (A-07), 5-25% (D-12), 4-17% (R-18) and
      9-25% (U-25); the fractions of acutely hypoxic cells were in the ranges of 1-47%
      (A-07), 1-57% (D-12), 9-80% (R-18) and 5-69% (U-25). The fraction of acutely
      hypoxic cells was higher than the fraction of chronically hypoxic cells in most A
      07, R-18 and U-25 tumours. The fraction of chronically hypoxic cells was higher
      than the fraction of acutely hypoxic cells in 16 of 25 D-12 tumours. CONCLUSION:
      This study indicates that acute hypoxia in tumours is a far more serious problem
      than chronic hypoxia and, consequently, it may be beneficial to focus on acute
      hypoxia rather than chronic hypoxia when searching for clinically useful
      predictive assays of hypoxia-induced radiation resistance and malignant
      progression and for methods to overcome treatment resistance caused by hypoxia.

PMID- 10597913
TI  - Lack of correlation between G1 arrest and radiation age-response in three
      synchronized human tumour cell lines.
AB  - PURPOSE: To determine radiosensitivity as a function of cell age (the age
      response) in three human tumour cell lines, and investigate the dependence of the
      age-response on G1 arrest and on cell-age heterogeneity in synchronized cell
      populations. MATERIALS AND METHODS: Variation in radiosensitivity throughout the
      cell cycle and G1 arrest was measured in mitotically selected populations of
      synchronized human tumour cells. In order to examine the effects of
      desynchronization and cell age heterogeneity on the measured age-response, a
      mathematical model was developed based on an existing kinetic model of the cell
      cycle. The model was used to describe the age-response for mitotically selected
      populations of cells, which was then compared with experimentally measured age
      responses. RESULTS: Three different human tumour cell lines had qualitatively
      similar age-responses, with periods of radiosensitivity in mitosis and in late G1
      phase/early S phase, and periods of radioresistance in early/mid G1 phase and
      late S/G2 phase. Radiosensitivity appeared to increase in G1 phase before the
      onset of DNA synthesis. One of the cell lines displayed a prolonged G1 arrest
      after irradiation in G1 phase. Model results demonstrated that the measured age
      responses were consistent with a simple model in which the cell cycle was divided
      into four regions. Radiosensitivity was assumed to be constant within each
      region, and changed abruptly at the borders between regions. CONCLUSIONS: Human
      tumour cell lines can exhibit qualitatively similar age-responses despite having
      markedly different G1 checkpoint responses. This suggests that modulation of the
      G1 arrest response may not prove to be a useful clinical strategy because it may
      not lead to significant cell age specific changes in radiosensitivity. The
      mathematical model of the radiation response of mitotically selected synchronized
      cells was a useful way to quantitatively describe cell age heterogeneity in these
      populations, and demonstrated the important impact of this heterogeneity on
      measured age-responses.

PMID- 10597914
TI  - Cell-age heterogeneity and deviations from the LQ model in the radiation survival
      responses of human tumour cells.
AB  - PURPOSE: To determine whether some of the deviations from the simple linear
      quadratic (LQ) theory in the radiation dose survival responses of asynchronous
      cultures of human tumour cell lines are caused by the presence of cell-age
      specific subpopulations which all individually follow LQ theory, but have
      different radiosensitivities. MATERIALS AND METHODS: Human tumour cells were
      synchronized by mitotic selection and their survival dose responses were measured
      at doses from 0.05 Gy to 12 Gy, using a high-precision survival assay. These
      responses were compared with a kinetic model of radiation survival in
      synchronized cells, which assumed that age-specific populations individually
      obeyed the LQ theory. The cell lines used included HT-29 and A549, which have
      typical dose responses, and U1, which is somewhat atypical. RESULTS: In two of
      the three cell lines, A549 and HT-29, observed deviations from the LQ model were
      consistent with those expected from cell-age heterogeneity. In the third cell
      line, U1, survival responses could not be described by the LQ theory, even when
      cell-age heterogeneity was considered. CONCLUSIONS: The LQ model provided an
      adequate description of cell survival for two of three tumour cell lines in this
      study when cell-age related heterogeneity in survival responses was accounted
      for. However, some alternative survival models (such as the repair saturation
      model) provided better characterizations of the survival response of the third
      cell line and, in fact, gave good descriptions of survival for all three cell
      lines.

PMID- 10597915
TI  - Rapid induction of cytokine gene expression in the lung after single and
      fractionated doses of radiation.
AB  - PURPOSE: To investigate cytokine gene expression in the lung after single and
      fractionated doses of radiation, and to investigate the effect of steroids and
      the genetic background. MATERIALS AND METHODS: Expression of cytokine genes (mTNF
      alpha, mIL-1alpha, mIL-1beta, mIL-2, mIL-3, mIL-4, mIL-5, mIL-6, mIFN-gamma) in
      the lungs of C3H/HeJ and C57BL/6J mice was measured by RNase protection assay at
      different times after various doses of radiation. The effects of dexamethasone
      and fractionated radiation treatment on gene expression were also studied.
      RESULTS: IL-1beta was the major cytokine induced in the lungs of C3H/HeJ mice
      within the first day after thoracic irradiation. Radiation doses as low as 1 Gy
      were effective. Responses to 20 Gy irradiation peaked within 4-8h and subsided by
      24 h. With the exception of IL-1alpha and TNF-alpha, the other cytokines that
      were investigated had undetectable pre-treatment mRNA levels and were not
      radiation inducible. Similar responses were seen in C57BL/6J mice, although TNF
      alpha was induced and there were some quantitative differences. Pre-treatment of
      C3H/HeJ mice with dexamethasone reduced basal and induced IL-1 levels, but
      complete inhibition was not achieved. Dexamethasone was also effective if given
      immediately after irradiation. Fractionated daily doses of radiation (4 Gy/day)
      helped to maintain cytokine gene expression for a longer period. CONCLUSIONS:
      Inflammatory genes are rapidly induced in the lung by irradiation. This response
      cannot be readily abolished by steroid pre-treatment. Fractionated treatment
      schedules help to perpetuate the response.

PMID- 10597916
TI  - Changes in transforming growth factor-beta (TGF-beta 1), procollagen types I and
      II mRNA in the rat heart after irradiation.
AB  - PURPOSE: To study alteration in gene transcription (transforming growth factor
      beta 1 and procollagen types I and III) involved in radiation-induced cardiac
      damage. MATERIALS AND METHODS: Female Sprague-Dawley rats were irradiated with a
      single dose of 0, 15, 20 or 25 Gy locally on the heart. At intervals up to 16
      months after irradiation, absolute amounts of mRNA were quantified using a (semi
      nested) competitive PCR assay. All values were normalized to equal input cDNA
      with respect to their GAPDH content. RESULTS: After irradiation, left ventricular
      TGF-beta 1 mRNA levels increased sharply. This response was bi-phasic with peaks
      at days 1 and 12 (maximum 6-fold baseline), then returning to control levels by 1
      month. After 20 Gy, a persistent elevation was observed from 6 months, but this
      elevation was less profound (approximately 1.5-fold baseline) when compared with
      the early response (1-12 days). Absolute mRNA levels of procollagen type I hardly
      changed during the first 6 months, but thereafter these levels increased
      progressively until the end of observation. An age-related increase in
      procollagen I was also observed. Procollagen type III mRNA levels were increased
      between days 1 and 12, returned to control values and remained low up to 6
      months, then mRNA levels rose again with increasing time post-treatment.
      CONCLUSION: The difference in time-course between TGF-beta 1 and procollagen mRNA
      expression after local heart irradiation and ageing strongly suggest that the
      late up-regulation of both procollagen types in the left ventricle occurs without
      TGF-beta 1 over-expression.

PMID- 10597917
TI  - Short- and long-term histopathological changes in the canine liver following
      single high-dose intraoperative radiation therapy (IORT).
AB  - PURPOSE: The histopathological changes in the canine liver following single high
      dose intraoperative radiation therapy (IORT) were investigated in order to
      establish the tolerance of liver tissue to IORT, thus providing a framework for
      clinical IORT treatment of patients with metastatic disease to the liver.
      MATERIALS AND METHODS: Following partial resection of the liver, IORT in doses of
      10, 20, 25, or 30 Gy was applied to the resection plane and a non-surgically
      manipulated part of the liver of 25 beagles. RESULTS: There were no postoperative
      complications, and no morbidity or mortality during a maximal follow-up of 5
      years. Dogs were killed at 3 months, and 1, 2, 3 and 5 years following IORT.
      Light microscopic examination revealed capsular thickening, severe parenchymal
      fibrosis, liver cell atrophy, and bile duct proliferation at the irradiated area
      1 2 years following IORT. At 3-5 years, however, only mild parenchymal changes
      were found that consisted of slight periportal fibrosis, an incidental portal
      central fibrous septum and vascular changes with endothelial proliferation and
      focal arteriolar hyalinosis. CONCLUSIONS: This study demonstrated that following
      partial hepatic resection, IORT to the liver in the canine model can be applied
      safely, without short- or long-term treatment morbidity. Although doses up to
      30Gy resulted in severe local tissue damage 1-2 years following IORT, these
      changes were largely reversible due to hepatic regeneration.

PMID- 10597918
TI  - Changes in the pattern of growth in stature related to prenatal exposure to
      ionizing radiation.
AB  - PURPOSE: To examine the pattern and spurt in growth and development of prenatally
      exposed atomic-bomb survivors and to determine whether a statistically
      significant radiation-related growth retardation exists. MATERIALS AND METHODS:
      The stature of 1566 individuals exposed prenatally to the atomic bombings has
      been employed to study the effect of such exposure on growth. Among these
      survivors, 30 were severely mentally retarded, and 66 individuals on whom no
      physical measurements between ages 9 and 19 exist were excluded from this study.
      Thus this analysis rests on the measurements obtained on 1470 survivors 9 to 19
      years of age at the time of examination. RESULTS: When the > or =0.50 Sv group
      was compared to the other two prenatally exposed groups, a significant
      retardation of growth was observed only among those survivors exposed in the
      first trimester of gestation. The onset of the growth spurt among males in the
      three exposure groups was at approximately the same age, 11.34 years, but this
      was not true in females. The maximum velocity in growth for males was at 14.38
      years of age, but for females no clear peak velocity was demonstrable.
      CONCLUSION: A radiation-related growth retardation was demonstrable in this
      longitudinal study of the stature of individuals prenatally exposed. It is
      further demonstrated that among these survivors the growth velocity was faster in
      the high-dose group than in the low-dose group for both males and females.

PMID- 10597919
TI  - Chemical toxicity of some actinides and lanthanides towards alveolar macrophages:
      an in vitro study.
AB  - PURPOSE: To compare the toxicity of lanthanides (cerium, gadolinium) with
      actinides (thorium, neptunium, uranium) added in soluble form to rat alveolar
      macrophage cultures. MATERIALS AND METHODS: The metals were added 1 day after
      seeding alveolar macrophages extracted by pulmonary lavage, and the metal
      toxicity was scored 3 days later. Cell death was measured after vital staining to
      distinguish between apoptosis and necrosis; relative cell density was also
      quantified. The physico-chemical form of the metals in the culture medium was
      characterized using filtration and radioactive measurements. RESULTS: Except for
      thorium, induction of cell death was observed for all the elements studied and
      the death mechanism involved was apoptosis. Graduated toxicity was observed from
      uranium to neptunium, cerium and gadolinium, in the range of concentration from
      10(-3)-10(-6) M. From pilot experiments, it was hypothesized that soluble
      compounds were mainly involved in lanthanide toxicity, whereas insoluble forms
      were mainly involved in actinide toxicity. CONCLUSION: This study demonstrates
      that the toxicity of neptunium and uranium was concomitant with the presence of
      insoluble forms in the culture medium. Further studies are needed to characterize
      the cell death mechanisms involved and the potential synergistic effects of
      chemical toxicity and irradiation.

PMID- 10597920
TI  - Efficacy of ethane-1-hydroxy-1,1-bisphosphonate (EHBP) for the decorporation of
      uranium after intramuscular contamination in rats.
AB  - PURPOSE: To obtain compounds that will effectively reduce the fixation of uranium
      in its main target organs: bone and kidney. There is an urgent need for a
      chelating agent that is suitable and available for human use. MATERIALS AND
      METHODS: The efficacy of ethane-1-hydroxy-1,1-bisphosphonate (EHBP), already in
      use as a therapeutic agent, was investigated in animal experiments. The effect of
      different treatment regimens was investigated on rats (EHBP: 50-100 micromol kg(
      1); ligand/uranium ratio 2500 to 5000). RESULTS: The present study shows that one
      prompt injection of EHBP reduced uranium deposition in kidneys by a factor of
      five after acute intramuscular contamination in rats. At the same time, the total
      body uranium in the treated animals was 70% of controls. When the treatment was
      delayed 30 min after contamination, the kidney content was still reduced by a
      factor of two. CONCLUSIONS: EHBP has the advantage of clinical acceptance as a
      therapeutic agent for other purposes and its toxicity has been well studied. It
      therefore has a role in the treatment of human contamination with uranium.

PMID- 10597921
TI  - Is Dupuytren's disease caused by an imbalance between proliferation and cell
      death?
AB  - Dupuytren's contracture shares certain properties with malignant tumours,
      characterized by proliferation and lack of apoptosis, which may be induced by the
      c-myc oncogene. Because of these similarities, the relationship between the c-myc
      oncogene expression, bcl-2 oncogene (anti-apoptotic gene) and proliferation was
      investigated in Dupuytren's disease. Proliferation was assessed by
      immunohistochemical staining of the mib-1 antibody. Results were compared with
      those from fibrosarcoma specimens, representing a related malignant tumour. Non
      diseased fascia from Dupuytren patients and flexor retinaculum from patients
      undergoing carpal tunnel release without Dupuytren's disease were used as
      controls. Expression of c-myc was elevated in primary Dupuytren's disease and
      fibrosarcoma specimens, whilst recurrent Dupuytren's disease, non-diseased
      Dupuytren fascia and flexor retinaculum exhibited significantly lower levels.
      Neither bcl-2 nor mib-1 were detected in Dupuytren's disease, non-diseased fascia
      or flexor retinaculum, in contrast to fibrosarcoma. The imbalance between
      proliferation and apoptosis, producing malignant growth was thus confirmed for
      fibrosarcoma, but not for Dupuytren's disease.

PMID- 10597922
TI  - Increased mortality in Dupuytren's disease.
AB  - A previous study showed a dip in the prevalence curve of Dupuytren's disease in
      men over 79 years of age. This may indicate increased mortality. The aim of the
      present investigation was to study this hypothesis. Four hundred and twenty-six
      men with Dupuytren's disease, born between 1900 and 1924 were followed for 26
      years (1969-1996). Their mortality was compared with that of an age-matched
      control group of 426 men. In 1996, 361 with Dupuytren's disease and 336 in the
      control group had died. Overall, patients with Dupuytren's disease had a
      significantly increased mortality of 22%. The mortality was highest among those
      with onset of disease before the age of 60. In this age group men with
      Dupuytren's disease had 70% higher mortality than that of the control group.
      Disease duration did not seem to influence the mortality.

PMID- 10597923
TI  - Arterialized venous toenail flaps for treating nail loss in the fingers.
AB  - Ten arterialized venous toenail flaps with two venous pedicles, one of which was
      anastomosed to a digital artery and the other to a dorsal vein of the finger,
      were used in nine patients to reconstruct nail loss due to trauma. Four flaps
      were taken from the lateral part of the big toe and six flaps from the second
      toe. Four toenail flaps with pulp and three flaps with the distal half of distal
      phalanx were used. Nine flaps survived completely and one had partial necrosis.
      All showed excellent aesthetic and functional results except for one case with
      minimal deformity in growth of the nail. The mean operating time was 2 hours.

PMID- 10597924
TI  - Dorsal adipofascial turn-over flap for fingertip amputations.
AB  - We designed a dorsal adipofascial pedicled flap to cover amputations of the tip
      of the same digit. This flap includes all the adipofascial tissues from the
      dermis to the paratenon of the extensor tendons. After elevation of the skin, the
      adipofascial tissues are raised as a flap and turned over to resurface the
      exposed bone or joint and then covered with a split thickness skin graft. Ten
      digital amputations between the distal phalanx proximal to the nail matrix and
      the mid portion of the middle phalanx were successfully resurfaced with dorsal
      adipofascial turn-over flaps. All flaps survived completely and the mean follow
      up was 11 months. This one-step procedure would seem to be a relatively simple
      way of achieving early recovery because it does not require the use of distant
      flaps immobilization of adjacent digits, or homodigital flaps that might
      jeopardize an already injured finger.

PMID- 10597925
TI  - The surface anatomy of the germinal matrix of the nail bed in the finger.
AB  - Nail spicules result from incomplete excision of the nail matrix of the finger.
      We report a histological study to delineate the surface anatomy of the nail
      matrix. Sections were cut longitudinally and transversely in 19 fingertips. The
      proximal midline extent of the nail matrix was measured and expressed as a ratio
      of the distance from the nail fold to the distal interphalangeal joint. In the
      lateral sections, the angle subtended between the midline vertical and the
      lateral extent of the nail matrix was measured. The mean ratio of the proximal
      extent was 0.55 in the midline and the lateral angular extent was 66 degrees. The
      authors recommend that excision of the nail matrix should be rectangular,
      extending to the midlateral lines and proximally to a point three-quarters of the
      distance from the nail fold to the distal interphalangeal joint crease.

PMID- 10597926
TI  - Free toe pulp transfer for digital reconstruction after high-pressure injection
      injury.
AB  - We report two cases of high-pressure injection injuries to the fingertip in which
      free toe pulp flaps were used to resurface the palmar surface of the finger
      following extensive wound debridement. There was good return of sensibility and,
      because of the high durability of the donor skin, both patients regained good
      functional use of the injured digits and returned to heavy manual work. There was
      minimal associated morbidity of the donor sites. The free toe pulp flap
      represents an excellent alternative for resurfacing the digit with a large
      residual skin defect after high-pressure injection injury.

PMID- 10597927
TI  - Digital prostheses for single finger amputations.
AB  - After amputation digital prostheses are infrequently used. With modern methods of
      fabrication both cosmetic and functional use are now possible. We have assessed
      the use of single digit prostheses in a district general hospital setting.

PMID- 10597928
TI  - The lateral pectoral flap.
AB  - The lateral pectoral flap is a new pedicled flap based on the superficial
      thoracic artery which arises from the subscapular artery and courses along the
      lateral border of pectoralis major. The flap consists of skin, subcutaneous
      tissue and the underlying pectoral epimysium. It has been used successfully to
      resurface contralateral soft tissue defects over the fingers, thumb and dorsum of
      the hand in eight cases. The advantages of this flap are that it provides
      reliable soft tissue cover to the hand, which can be kept in an elevated position
      resting comfortably on the contralateral pectoral region with the forearm and arm
      aligned conveniently in the cross-chest position. It does not interfere with
      clothing and dressing the lower part of the body in contrast to the groin,
      hypogastric or lower abdominal flaps, and it allows early ambulation. Primary
      closure of the donor site in the majority of cases is an added benefit.

PMID- 10597929
TI  - Self-mutilation in children with obstetric brachial plexus palsy.
AB  - In a prospective study, the incidence and clinical presentation of self
      mutilation was documented in 127 consecutive cases of obstetric brachial plexus
      injury. Six out of the 127 cases (4.7%) had clinical evidence of self-mutilation.
      The incidence of self-mutilation was much higher among children with total palsy
      (4/37) than Erb's palsy (2/90). All affected children were able to bring the
      mutilated hand or forearm to the mouth without assistance from the contralateral
      normal limb. Mutilation in patients with total palsy was generally severe and
      usually involved biting the tips of the digits. However, mutilation in patients
      with upper (Erb's) palsy was mild in degree and tended to involve the dorsum of
      the hand. Similarity between human self-mutilation and animal autotomy following
      denervation are discussed along with the different theories explaining the
      mechanism of this abnormal behaviour.

PMID- 10597930
TI  - The role of magnetic resonance imaging in the management of traction injuries to
      the adult brachial plexus.
AB  - Magnetic resonance imaging (MRI) of the cervical spine and brachial plexus was
      performed on 26 consecutive patients presenting with traction injuries of the
      brachial plexus during 1996 and 1997. These included T1 and T2 weighted coronal,
      sagittal and axial images of the cervical spine and coronal images of the
      brachial plexus. The results were compared with surgical findings, intraoperative
      neurophysiology, and subsequent clinical progress. Operations for exploration and
      repair have been performed in 23 and 26 patients scanned. Evidence of root
      avulsion was seen in 11 patients in the form of displacement or oedema of the
      spinal cord, haemorrhage or scarring within the spinal canal, absence of roots in
      the intervertebral foramena, and meningoceles. Characteristic abnormalities were
      evident in the MR scans of all cases where exploration confirmed some root
      avulsions. There were no false positives. MRI underestimated the number of
      individual roots avulsed; sensitivity was 81%. Post-ganglionic lesions were seen
      as swelling on T1 images associated with increasing signal on T2 images. It was
      usually possible to define the level of the injury within the plexus. This study
      suggests that MR imaging, performed early after traction injury to the brachial
      plexus, provides useful additional information towards establishing the level of
      the lesion. It also provides information about injury to the plexus outside the
      spinal canal.

PMID- 10597931
TI  - Clinical results of contralateral C7 root neurotization to the median nerve in
      brachial plexus injuries with total root avulsions.
AB  - This prospective study was carried out to assess motor and sensory recovery after
      contralateral C7 root to median nerve neurotization in brachial plexus injuries
      with total root avulsions. The survey was carried out from 1993 to 1995 and the
      patients were followed up for at least 3 years. There were 96 male patients with
      ages ranging from 13 to 48 years. All had a unilateral brachial plexus injury
      with avulsion of all roots. This was confirmed by clinical assessment and
      exploration. The anterior part of the contralateral C7 root was used for
      neurotization via a reversed pedicular ulnar nerve graft and the proximal end of
      the graft was connected to the median nerve. Furthermore, phrenic nerve to
      suprascapular nerve and spinal accessory nerve (via a sural nerve graft) to
      musculocutaneous nerve neurotizations were also carried out to obtain shoulder
      abduction and elbow flexion. At the 3 year follow-up, most patients had
      encouraging recovery of sensory function in the hand but motor function of the
      forearm and hand muscles was rather poor. Acceptable motor function was found in
      only 50 to 60% of the patients who were younger than 18 years.

PMID- 10597932
TI  - The effect of the additional use of grommets in silicone implant arthroplasty of
      the metacarpophalangeal joints.
AB  - After silicone arthroplasty of the metacarpophalangeal (MP) joint there is
      increasing osteolysis, subsidence and fracture of the implants in the longer
      postoperative term. In 44 patients with rheumatoid arthritis (54 hands) 151
      arthroplasties of the metacarpophalangeal joint were assessed at a mean of 3.9
      years postoperatively. In 57 arthroplasties titanium protectors (grommets) were
      used. There were no significant differences in the clinical outcomes with respect
      to swelling, correction of ulnar deviation, range of active movement and grip
      strength. The additional use of grommets in MP joint arthroplasty slightly
      reduced reactive osteolysis, protected the spacers from breakage and slightly
      reduced the amount of pain with only a few additional complications in the
      midterm follow-up.

PMID- 10597933
TI  - Arthroplasty of the proximal interphalangeal joint using the Sutter implant for
      traumatic joint destruction.
AB  - We report the functional results in a series of 21 Sutter arthroplasties for post
      traumatic arthritis with an average follow-up of more than 2 years. The dorsal
      approach was used in every case. Pain was always present preoperatively and
      mobility was reduced to an average range of motion of 15 degrees.
      Postoperatively, pain was absent in 18 cases. The average active range of motion
      was 55 degrees. There were two fractures of implants. Although the follow-up is
      limited, the Sutter arthroplasty has given results that are similar to, or better
      than, those reported for other techniques.

PMID- 10597934
TI  - Anomalies of the flexor digitorum superficialis muscle.
AB  - Three anomalies of the human flexor digitorum superficialis are presented. The
      normal development of this muscle from the amphibian to the human is discussed
      and the described anomalies of the muscle in humans classified.

PMID- 10597935
TI  - Variations of the extensor indicis muscle and tendon.
AB  - Variations of the extensor indicis muscle were examined in 164 hands from 86
      Japanese cadavers. Anomalous cases exhibiting supernumerary muscles or tendons
      were found in 22 hands. These variations were classified into four types: type 1,
      an additional tendon slip from the extensor indicis tendon; type 2, an extensor
      indicis radialis or extensor pollicis et indicis accessorius; type 3, an extensor
      medii proprius with or without extensor medii brevis; and type 4, an extensor
      indicis radialis and extensor medii proprius. The extensor medii proprius was the
      most common variation, followed by extensor indicis radialis. There were no clear
      differences in incidence of variations between men and women or between right and
      left hands. When variations were bilateral, both sides were identical or similar
      in type.

PMID- 10597936
TI  - Italian multicentre study of carpal tunnel syndrome. Differences in the clinical
      and neurophysiological features between male and female patients.
AB  - The Italian Carpal Tunnel Syndrome Study Group has carried out a multicentre
      study on 1123 hands with idiopathic carpal tunnel syndrome. We have compared the
      findings on clinical examination, the neurophysiological data and a patient
      oriented assessment in men and women. The patient-oriented assessment showed that
      men complain of less discomfort than women; clinical examination was similar in
      the two populations and neurophysiological investigations showed greater changes
      in men.

PMID- 10597937
TI  - Carpal tunnel release by the Agee endoscopic technique. Results at 4 year follow
      up.
AB  - Ninety-five hands (86 patients) were treated by endoscopic carpal tunnel release
      using the technique of Agee. They were the first ones operated on by the senior
      author (GF) using this technique. The patients were interviewed at a mean follow
      up of 4.5 years: 72% of hands were free of symptoms and 94% were described by the
      patients as functionally normal. Seventeen hands (out of 27) with residual or
      recurrent symptoms were examined. Nine hands (nine patients) were only partially
      improved (mean 6.7 on a 10 point scale) and in eight hands (seven patients), some
      symptoms had recurred after a mean delay of 3.8 years. It was possible to find a
      second pathology in most of these cases. It is necessary to inform the patient
      before operation that incomplete relief or recurrence of symptoms can occur after
      endoscopic carpal tunnel release, as with conventional release.

PMID- 10597938
TI  - The prognostic value and reproducibility of the radiological features of the
      fractured scaphoid.
AB  - We investigated whether the radiological features of the fractured scaphoid could
      be reproducibly measured and used to predict the likelihood of union with
      conservative plaster cast immobilization. We found that the inter- and intra
      observer reproducibility of the Compson, Herbert and Russe classification systems
      were only fair and that none predicted fracture union. Assessments of fracture
      level, comminution and displacement showed moderate inter- and intra-observer
      reproducibility but did not predict the likelihood of fracture union. We conclude
      that the radiological features of acute scaphoid fractures cannot be used to
      predict the likelihood of fracture union.

PMID- 10597939
TI  - The symptomatic carpal boss. Is simple excision enough?
AB  - We reviewed 48 patients with symptomatic carpal boss seen during the 10 year
      period 1985-1994. Thirty-one patients had undergone either local excision of the
      boss or arthrodesis of the affected carpometacarpal joint. The mean follow-up was
      3 years and nine cases have been revised. Twenty-four patients remained
      symptomatic and considered that surgery had failed to relieve their symptoms.
      These findings are in sharp contrast to previous reports that suggest simple
      excision of the carpal boss gives uniformly good results.

PMID- 10597940
TI  - Kienbock's disease in women.
AB  - We examined 133 patients with Kienbock's disease, five of whom had bilateral
      disease. There were 47 women and 86 men. The mean age of patients was 42.7 years
      (range, 14-80 years). The frequencies of involvement of the right and left sides
      were approximately equal for women, but male patients tended to have right wrist
      joint involvement. The side of the affected wrist in the female group differed
      significantly from that in the male group. The age at onset for women was
      significantly higher than that for men. The percentage of manual workers was
      significantly lower among women than among men. The characteristics of Kienbock's
      disease in women differed from those in men and those previously reported for
      this disease. These findings suggest that the pathogenesis of Kienbock's disease
      in women differs from that in men.

PMID- 10597941
TI  - Clinical diagnosis of triquetrolunate ligament injuries.
AB  - The clinical diagnosis of peritriquetral injuries is difficult. We describe our
      diagnostic technique based on specific questions and three clinical tests. The
      accuracy of our diagnostic technique was compared prospectively with the
      definitive diagnosis made at arthroscopy. Preoperatively, 19 patients were
      diagnosed as having triquetrolunate dissociation. This was confirmed at
      arthroscopy in 17. Another five patients not diagnosed preoperatively were also
      diagnosed at arthroscopy as having mainly triquetrolunate dissociation. The
      sensitivity of our diagnostic protocol was 0.77 and the positive predictive value
      was 0.89.

PMID- 10597942
TI  - Nonunion of the distal radius.
AB  - We report five cases of nonunion of the distal radius. There were three women and
      two men. The mean age was 44 years (range, 34-56). All five patients were heavy
      tobacco smokers and three had a history of alcohol abuse. In three patients,
      union of the distal radius was obtained. Two had a persistent nonunion which was
      salvaged with a total wrist fusion.

PMID- 10597943
TI  - The radio-radial external fixator in the treatment of fractures of the distal
      radius.
AB  - The technique of radio-radial monobloc-fixation with the small AO external
      fixator device has been applied to 17 consecutive Colles' fractures. The fracture
      types were mainly A3 and C2, according to the AO classification. We found this
      technique to be easy and quick in application and stable in fixation. Direct,
      precise and atraumatic reduction can be achieved by using the distal pins as joy
      sticks. Furthermore, disimpaction of the fracture to regain length is possible
      without bone grafting. Normal carpal mobility and load transfer is preserved
      during fracture healing and the injured hand can be used in daily life with
      certain restrictions. To prevent pin-track infections, early mobilization of the
      wrist should be avoided. We recommend this technique in the treatment of
      comminuted AO-type A3 fractures of the distal radius and in certain type C2
      cases.

PMID- 10597944
TI  - A simple technique for applying local splintage to the fingers.
AB  - We report a simple method of splinting the interphalangeal joints that we have
      employed as our standard technique without complication.

PMID- 10597945
TI  - A simple splinting method for correction of supple congenital clasped thumbs in
      infants.
AB  - A splint has been designed to correct the congenital clasped thumb. It is like a
      short opponens splint that can keep the thumb in a position of abduction and
      extension without limiting wrist movement. The application of the splint was easy
      and adjustment for fit could be made at each visit if necessary. The device has
      been used in 11 infant patients (17 thumbs) with congenital clasped thumb of the
      supple type. The functional results were excellent in 15 of 17 thumbs, and the
      other two were good according to the grading system of Weckesser et al. (1968).

PMID- 10597946
TI  - Paediatric hand injuries caused by spiked railings.
AB  - We report five cases of hand injuries caused by spiked palisade railings. One
      patient sustained an open fracture of the distal phalanx with a disruption of the
      nail bed, and two patients had digital nerve injuries. Two patients presented
      with the railing still impaled in the fingers, one of whom had an ischaemic digit
      at presentation. All patients were male, between 9 and 12 years of age, and
      presented in the course of 1 month. Railings of this type would appear to be a
      significant cause of hand injuries, which may be prevented by legislation or a
      change in railing design.

PMID- 10597947
TI  - Pinch reconstruction by hand to hand finger transfer associated with hallux
      transfer after a severe frostbite injury.
AB  - We report a case of severe frostbite in which a pincer hand was created by
      microsurgical transfer of a partially amputated small finger from the opposite
      hand combined with microsurgical transfer of a partially amputated great toe
      which was subsequently lengthened.

PMID- 10597948
TI  - Osseodistraction after traumatic amputation of the little finger in a young
      musician.
AB  - We lengthened the stump of a traumatically amputated little finger by
      osseodistraction in a young musician, who required a widened span to enable him
      to reach the octave on the piano. A mini external distraction device was used. No
      major complications occurred. The bone lengthening gave a good functional and
      cosmetic result.

PMID- 10597949
TI  - Histoplasmosis of the wrist.
AB  - We present a case of synovitis of the wrist due to histoplasmosis, diagnosed only
      after extensive surgery and culturing. Treatment with amphotericin B in
      combination with radical surgery was effective in curing the disease. This
      manifestation was probably an exacerbation of a latent chronic infection with
      Histoplasma capsulatum, although it was unclear why the exacerbation occurred.
      Synovitis resistant to treatment should be assessed with great care, especially
      in view of the growing number of immunocompromised patients. Close collaboration
      between surgeon, rheumatologist, pathologist and microbiologist is paramount in
      such cases.

PMID- 10597950
TI  - Desmoid tumours of the hand.
AB  - We report a case of a 3-year-old child with a desmoid tumour of the hand, which
      is an exceedingly rare location. Desmoid tumours of the hand are difficult to
      treat because of the many important structures concentrated in the area as well
      as the infiltrative and recurrent character of these tumours.

PMID- 10597951
TI  - Neurothekeoma of the hand.
AB  - Neurothekeomas are rare, benign connective tissue tumours probably of Schwann
      cell origin. We report an unusual case of a neurothekeoma involving the hand.
      Histological examination revealed characteristic myxoid nodules with spindle
      shaped cells. The immunocytochemical reaction for S-100 protein and neuron
      specific enolase was positive. Complete excision proved curative as the tumour
      was well encapsulated.

PMID- 10597952
TI  - The technique of finger lengthening by gradual phalangeal distraction and bone
      grafting.

PMID- 10597953
TI  - Recent literature on total wrist replacement not carefully reviewed.

PMID- 10597954
TI  - "Rupture of the tendon of flexor digitorum profundus in association with an
      enchondroma of the terminal phalanx".

PMID- 10597955
TI  - The influence of folic acid supplement on the outcome of pregnancies in the
      county of Funen in Denmark. Part I.
AB  - OBJECTIVE: To determine whether a supplement of folic acid given
      preconceptionally or early in pregnancy had any influence on, birth weight,
      incidence of preterm labour, low birth weight and small for gestational age.
      Furthermore, the aim was to elucidate, whether the outcome differed following the
      administration of two different dosages of folic acid, namely 2.5 and 1.0 mg.
      MATERIAL: All women in the childbearing age living on the island of Funen,
      Denmark (population 500,000) were offered a supplement of folic acid over a
      period of 3 years and 3 months. 14,021 women, who gave birth to 13,860 single
      born and 325 multiborn children, were registered. A total of 8184 women took part
      in the double-blind randomized trial: 2310 had a supplement of folic acid without
      being randomized and 2721 women received no folic acid supplement. No information
      regarding the use of folic acid was available in 806 pregnancies. Abortions (512)
      were excluded. RESULTS AND CONCLUSIONS: A supplement 1.0 mg folic acid had the
      same effect as 2.5 mg. The effects of supplementing the diet with folic acid
      given preconceptionally or in the first half of pregnancy in an affluent Northern
      country were a slight increase of birth weight and a decrease in the incidence of
      preterm labour, infants with low birth weight and small for gestational age. The
      greatest effect was seen in the groups receiving folic acid preconceptionally.

PMID- 10597956
TI  - The influence of folic acid supplement on the outcome of pregnancies in the
      county of Funen in Denmark. Part II. Congenital anomalies. A randomised study.
AB  - OBJECTIVE: The effect of folic acid supplement on the prevalence of congenital
      anomalies was studied in a Danish population. MATERIAL AND METHODS: From 1983 to
      1986 all Danish women resident in the county of Funen were offered free folic
      acid when pregnant or planning a pregnancy. Folic acid dose was randomised to 2.5
      or 1.0 mg. A randomised control group was not feasible for ethical reasons.
      Hospitals, midwives and most general practitioners cooperated to procure
      information on close to all pregnancies and congenital anomalies were recorded.
      RESULTS AND CONCLUSIONS: In a total of 14,021 pregnancies resulting in child
      birth 8184 women (58.4%) had folic acid with randomisation. Supplement was
      started in the randomised group before the last menstrual period in 1359/8184
      (16.6%) and in the first 19 weeks of pregnancy in 6825/8184 (83.4%). The
      prevalence of congenital anomalies was 224 in 8293 children (27.0/1000). No dose
      dependent differences were found in either total anomalies or in those specific
      malformations which have been reported to occur with reduced prevalence with
      periconceptional folic acid. The result was probably influenced by a start of
      supplement too late to affect malformation development in many cases and by the
      high level of both folic acid doses given compared to usual recommendations.
      Pregnancies without folic acid supplement showed prevalences similar to the
      supplemented groups.

PMID- 10597957
TI  - The influence of folic acid supplement on the outcome of pregnancies in the
      county of Funen in Denmark. Part III. Congenital anomalies. An observational
      study.
AB  - OBJECTIVE: The effect of folic acid supplement on the prevalence of congenital
      anomalies was studied in a Danish population. MATERIAL AND METHODS: From 1983 to
      1986 all Danish women resident in the county of Funen were offered free folic
      acid when pregnant or planning a pregnancy. Data concerning the starting time of
      folic acid supplement and congenital anomalies were recorded on close to all
      pregnancies. Children of folic acid supplemented mothers were subdivided as to
      start of supplement with dividing lines at week 7 and week 11 calculated from the
      last menstrual period. Structural malformations were subdivided into an early
      group with malformation development in the first 7 weeks from the last menstrual
      period and a late group where malformations develop in weeks 8 to 11. RESULTS: In
      a total of 14,021 pregnancies 10,494 pregnant women (74.8%) had folic acid
      supplement. No folic acid was taken by 2721 women (19.4%) and in 806 cases (5.8%)
      information was lacking. The prevalence of congenital anomalies was 380 in 14,185
      children (26.7/1000). Children whose mothers started folic acid supplement before
      the 7th week of pregnancy showed a significantly lower prevalence of the
      malformations which develop in the first 7 weeks, when compared to pregnancies
      with a later start of supplement. The result was interpreted as a clearcut trend.

PMID- 10597958
TI  - With a positive feeling: the grief process after stillbirth in relation to the
      role of the professional caregivers.

PMID- 10597959
TI  - Integrin-mediated adhesion of uterine endometrial cells from endometriosis
      patients to extracellular matrix proteins is enhanced by tumor necrosis factor
      alpha (TNF alpha) and interleukin-1 (IL-1).
AB  - OBJECTIVES: (1) to demonstrate specificity of integrin function in endometrial
      cell adhesion; (2) to investigate their regulation by tumor necrosis factor alpha
      (TNF alpha) and interleukin-1 (IL-1); and (3) to detect differences between cells
      from patients with and without endometriosis. STUDY DESIGN: Endometrial cell
      cultures from ten patients with and 13 without endometriosis were tested for
      their expression of integrins alpha2beta1, alpha5beta1, alpha(v)beta3, and
      alpha4beta1 by immunocytochemistry and for their adhesion to collagen type IV,
      laminin, and fibronectin. RESULTS: Integrin expression was independent of
      cytokine treatment. Addition of antiintegrin antibodies inhibited adhesion. A
      significant increase in adhesion to laminin and fibronectin was seen in
      endometriosis after IL-1 treatment and additionally to collagen after TNF alpha.
      Cells from women without endometriosis showed a significant increase only to
      fibronectin. CONCLUSIONS: Human endometrial cells express functional integrins in
      vitro. TNF alpha and IL-1 had more pronounced effects on adhesion in
      endometriosis. Inflammatory cytokines in the peritoneal cavity may facilitate
      adhesion of retrogradely menstruated endometrial fragments in endometriosis.

PMID- 10597960
TI  - Risk factors for rupture of the anal sphincter.
AB  - OBJECTIVE: To evaluate risk factors for rupture of the anal sphincter during
      vaginal delivery. MATERIAL AND METHODS: All 292 parturients with rupture of the
      anal sphincter in four neighbouring central hospitals in southern Sweden between
      1988 and 1990 were identified retrospectively. For each case a control was
      selected, the sole matching criterion being that the control woman was the next
      to give birth vaginally in the same unit as the case. Only singleton deliveries
      were included. For comparison of risk factors among cases and controls, McNemar's
      test was used for bivariate testing; multiple regression analysis was restricted
      to those variables found to be significant in the bivariate analysis. Odds ratios
      (OR) were calculated with 95% confidence limits (CL). RESULTS: In all, 292 of
      22,653 deliveries (1.3%) had a rupture of the anal sphincter. Of a total of 14
      independent variables explored, 8 were found to be significantly associated with
      rupture of the anal sphincter in the bivariate testing. In the following
      multivariate analysis, three variables remained significantly associated with
      rupture of the anal sphincter: birthweight > or = 4000 g (OR 2.6; CL 1.7, 3.9),
      primiparity (OR 2.2; CL 1.5, 3.3) and episiotomy (OR 1.7; CL 1.1, 2.6).
      CONCLUSION: Episiotomy appears to be significantly associated with rupture of the
      anal sphincter. In contrast to primiparity and birthweight, the incidence of
      episiotomy during vaginal delivery may easily be reduced. However, only a
      prospective, controlled study will disclose the true negative or positive effects
      of episiotomy.

PMID- 10597961
TI  - Maternal serum concentrations of CA-125 in second trimester pregnancy complicated
      by congenital fetal anomalies.
AB  - OBJECTIVE: The purpose of the study was to determine the value of maternal serum
      CA-125 concentrations in pregnancies complicated by fetal anomalies with or
      without hydramnios. STUDY DESIGN: The study population (n=40) consisted of the
      following four groups of patients: (1) 10 women with abnormal maternal serum
      alpha fetal protein (MSAFP) in whom no fetal anomalies were observed; (2) 10
      women in whom fetal anomalies were diagnosed in addition to abnormal MSAFP; (3)
      10 women with fetal anomalies accompanied by hydramnios and abnormal MSAF, and
      (4) 10 women had normal MSAFP and were diagnosed with hydramnios without fetal
      anomaly. The control group consisted of 10 patients who were matched for
      gestational age with normal MSAFP and normal ultrasonographic examination. In all
      50 cases MSAFP and maternal serum CA-125 levels were assessed. CA-125 was
      measured using OC 125 monoclonal antibody (IMX CA-125, Abott Lab. IL) and a value
      of >20 U/ml was defined as abnormal. RESULTS: Maternal serum CA-125 levels were
      significantly higher in the study group than in the control group, 19.8+/-15.9
      U/ml and 9.9+/-4.0 U/ml (P=0.015). The difference was even greater when patients
      with malformed fetuses and hydramnios were compared to those with fetal anomalies
      and normal amount of amniotic fluid, 32.4+/-12.7 U/ml and 7.2+/-2.1 U/ml,
      respectively (P=0.0005). The maternal serum CA-125 levels in patients with
      hydramnios but without fetal anomalies were significantly lower when compared
      with those of the malformed fetuses and hydramnios, 9.8+/-2.3 U/ml and 32.4+/
      12.7 U/ml, respectively (P=0.002). CONCLUSION: Maternal serum CA-125 is lacking
      in value for screening fetal structural anomalies as a significant increase in
      maternal serum CA-125 levels was found only in patients with fetal anomalies
      accompanied by hydramnios.

PMID- 10597962
TI  - Determinants of response to intracervical prostaglandin E2 for cervical ripening.
      Gruppo di Studio sull'Induzione del Travaglio di Parto.
AB  - OBJECTIVE: To analyze the determinants of response to intracervical prostaglandin
      E2 (PGE2) in cervical ripening. STUDY DESIGN: A total of 250 women with normal
      pregnancy, parae three or less, with intact membranes between 40 and 42 weeks of
      gestation and Bishop's score < or = 4 were treated with 0.5 mg PGE2 intracervical
      repeated after 12 hours if cervical Bishop's score was still < or = 4. RESULTS:
      After the first administration of PGE2, labor was induced in 106 (42.4%) women.
      Nulliparae had a significant longer interval from the first PGE2 dose to delivery
      and more failures of treatment and caesarean sections than parae. There was a
      tendency towards a shorter interval between the first administration and delivery
      and a decrease in the frequency of treatment failures with increasing Bishop's
      score, but the finding was not statistically significant. No fetal or neonatal
      death occurred. There were eight neonates at one min and three neonates at five
      min with an Apgar score less than seven. There were 22 neonates admitted to
      Neonatal Intensive Care Unit. There were 20 cases of jaundice. CONCLUSIONS: The
      study confirms that the main determinant of treatment failure with PGE2 gel in
      cervical ripening is nulliparity.

PMID- 10597963
TI  - Analysis of the pregnancy-related deaths within the last two decades: a
      university hospital-based study from Turkey.
AB  - OBJECTIVE: To analyse the causes of pregnancy-related deaths at Ondokuz Mayis
      University Hospital. STUDY DESIGN: The death of a woman while pregnant or within
      42 days of termination of pregnancy regardless of the cause of death, including
      accidental or incidental causes, was accepted as a 'pregnancy-related death'.
      Such deaths were evaluated in Ondokuz Mayls University Hospital in the years 1978
      1997 inclusive. They were classified as direct obstetric, indirect obstetric, and
      accidental or incidental deaths. RESULTS: Eighty-seven pregnancy-related deaths
      were identified via hospital death records. Maternal mortality ratio was
      calculated to be 822.2 per 100,000 live births. Seventy seven percent of the
      deaths were due to direct obstetric causes; most commonly due to toxemia,
      infection and hemorrhage. CONCLUSION: Direct obstetric deaths, which are largely
      preventable with proper antenatal care and health services, are still problems in
      our country.

PMID- 10597964
TI  - Vasoconstrictive activity of meconium stained amniotic fluid in the human
      placental vasculature.
AB  - OBJECTIVE: The purpose of this study was to study was to determine the effect of
      meconium stained amniotic fluid on the vasculature of isolated perfused human
      placental cotyledon. STUDY DESIGN: Isolated placental cotyledons were dually
      perfused. Fetal perfusion pressure was used as an index of vascular resistance.
      Meconium stained amniotic fluid (MSAF) was collected from patients after
      artificial rupture of membranes in term gestation. A dilution of meconium (1:2;
      1:4; 1:8; 1:16) was performed. Optical density (OD) of MSAF varied between 0 and
      35.0 units/g as determined by spectrophotometry. Bolus injections of 1.0 ml of
      MSAF at different concentrations were injected into the fetal circulation. Heated
      and dialyzed MSAF after adequate dilution and evaluation of optical density were
      injected into fetal circulation in separate experiments. RESULTS: Analysis of
      variance (ANOVA) and paired t-test were used for statistical analysis. Bolus
      injections of MSAF into the fetal circulation resulted in a concentration
      dependent increase in perfusion pressure. MSAF with the highest OD resulted in a
      greater change in perfusion pressure as compared to more dilute MSAF (P=0.0001).
      After high OD amniotic fluid injections the provoked contractions lasted longer
      compared to dilute MSAF (P=0.006). MSAF after dialyzation did not exhibit any
      vasoconstrictive effect. CONCLUSION: Meconium is a vasoconstrictive agent in the
      fetal-placental vasculature and has a concentration dependent effect.

PMID- 10597965
TI  - Fetal arterial pressure and heart rate changes in surviving and non-surviving
      immature fetal sheep following brief repeated total umbilical cord occlusions.
AB  - OBJECTIVES: To describe the changes in fetal heart rate and mean arterial
      pressure during repetitive total umbilical cord occlusions in immature sheep
      fetuses, resulting in severe asphyxia or fetal death. To describe the
      relationship between these changes and concurrent changes in acid-base status.
      STUDY DESIGN: We performed brief repeated total umbilical cord occlusions, two
      out of every five min, in 14 immature sheep fetuses (at 90 days of gestation),
      until fetal mean arterial pressure dropped below 50% of baseline value during two
      successive occlusions. Fetal blood gas analyses were performed at regular
      intervals just before cord occlusions. RESULTS: Progressive acidemia and
      hypotension developed with ongoing occlusions. The degree of hypotension during
      occlusions increased with ongoing occlusions. The minimum fetal arterial blood
      pressure during occlusions correlated well with the progressive acidemia. Six
      fetuses died at the end of the repetitive occlusion period. In the non-survivors,
      acidemia was more severe and paCO2 gradually increased during the entire
      repetitive occlusion period. In the survivors group, a period of transient
      hypoxia and hypotension was observed with a nadir at +60 min following the final
      occlusion. CONCLUSION: Repetitive umbilical cord occlusions in immature sheep
      fetuses resulted in repetitive periods of hypotension, bradycardia, progressive
      fetal acidemia and ultimately fetal demise. Minimum fetal arterial blood pressure
      during occlusions correlated well with the progressive fetal acidemia.

PMID- 10597967
TI  - Epidermal cyst of the clitoris: a rare cause of clitorimegaly.
AB  - Epidermal cysts are slowly growing, intradermal or subcutaneous tumors with a
      wall composed of true epidermis. They occur most commonly on the face, scalp,
      neck, and trunk. We report the unusual case of a 16-year-old girl with an
      epidermal cyst of the clitoris. The tumor was removed by local excision.

PMID- 10597966
TI  - Scant XYqh- testicular cells with normal SRY was enough to differentiate
      bilateral testes in a 45,X/46,XYqh- patient.
AB  - OBJECTIVE: It has been established that in 45,X/46,XY individuals predominance of
      XY or XO gonadal cells determines gonadal differentiation. However, in some cases
      there is no concordance between the predominance of XY cells and testis
      differentiation. Here we describe the SRY findings in a patient bearing a
      45,X/46,XYqh- karyotype. STUDY DESIGN: The patient presented two small testes
      (one with spermatogenesis), a male phenotype, and a predominant 45,X karyotype in
      leukocytes and gonadal cells. PCRs of SRY, ZFY and Yqh were performed on DNA from
      leukocytes and from left gonadal tissue. SRY-PCR products were purified and
      sequenced. RESULTS: A normal SRY sequence was found in both tissues. CONCLUSIONS:
      Despite the predominance of 45,X cells in gonads, some patients in whom SRY is
      normal can develop testes, probably due to the presence of alternative mechanisms
      involved in testicular differentiation; however, further gonadal development
      could be impaired.

PMID- 10597968
TI  - Advanced extra-uterine pregnancy--a case of fimbrial expulsion of the fetus with
      complete placental development in the fallopian tube.
AB  - A case report is presented of a 30-year-old woman, gravida 3 para 2, presented
      with an advanced extra-uterine pregnancy with complete development of the
      placenta in the fallopian tube.

PMID- 10597969
TI  - Reduction of aseptic measures in gynecologic endoscopy: a comparative clinical
      trial.
AB  - OBJECTIVE: A prospective comparative clinical study was conducted on 200 patients
      to evaluate the consequences of minimizing the following standard hygienic
      measures in gynecologic laparoscopy: surgical scrub, patient draping, surgical
      gowns. STUDY DESIGN: A group of 100 patients treated according to maximum
      hygienic protocol was compared to a group of 100 patients undergoing laparoscopic
      procedures with only limited aseptic precautions. Clinical control parameters
      were perioperative temperature and white blood cell count up to the 4th
      postoperative day. Furthermore, patients and their gynecologists were interviewed
      2-4 weeks after surgery to rule out any delayed manifestation of an infection.
      RESULTS: Perioperative infection was low in both groups. CONCLUSION: As we found
      no significant difference between the two collectives' control parameters, we
      conclude that a reduction in perioperative hygiene seems feasible for certain
      laparoscopic procedures. However, a larger collective should be studied in order
      to confirm this action.

PMID- 10597970
TI  - Combined maternal and congenital myotonic dystrophy managed by a
      multidisciplinary team.
AB  - Myotonic dystrophy is a rare autosomal dominant degenerative neuromuscular and
      neuroendocrine disease. Pregnancy can aggravate the maternal disease. Obstetrical
      complications include stillbirth, premature labor, polyhydramnion, abnormal
      presentation, prolonged labor, increased operative delivery, postpartum
      hemorrhages and anesthetic accidents. If the fetus is affected severe neonatal
      morbidity and mortality with arthrogryposis and mental retardation is common. We
      present a case where the family chose continuation of pregnancy with a known
      diagnosis of maternal and severe fetal myotonic dystrophy. A multidisciplinary
      team was used in the management of pregnancy and counseling the patient.

PMID- 10597971
TI  - Female adnexal tumour of probable Wolffian origin in a 23-year-old woman.
AB  - This report describes a case of female adnexal tumour of probable Wolffian origin
      in a 23-year-old woman. This is the youngest patient so far described in
      association with this tumour. Following surgical management 11 years ago, there
      was neither recurrence nor metastasis and the patient gave birth to three
      children.

PMID- 10597972
TI  - Villoglandular papillary adenocarcinoma of the cervix. Beware of a wolf in
      sheep's clothing.
AB  - Villoglandular papillary adenocarcinoma of the cervix is a well differentiated
      form of cervical adenocarcinoma with a favourable prognosis and a conservative
      procedure is suggested. We present three cases of villoglandular papillary
      adenocarcinoma of the cervix. Histological examination of a biopsy of each cervix
      showed well differentiated villoglandular papillary adenocarcinoma, stage Ib
      according to FIGO classification. In all cases the disease was limited to the
      cervix. Nevertheless, histopathological examination of the surgical specimen
      revealed an infiltrating component with squamous differentiation in one case,
      while in a second case histopathological examination revealed a moderately
      differentiated papillary adenocarcinoma with a superficially infiltrating growth
      pattern besides the villoglandular papillary adenocarcinoma. Before conservative
      therapy is considered, careful evaluation of the presence of poor prognostic
      features must be made. One should consider whether conservative therapy is
      sufficient because of the predominance of concomitance of other carcinoma besides
      the villoglandular papillary adenocarcinoma.

PMID- 10597973
TI  - An audit of European training in obstetrics and gynaecology.
AB  - During 1997, The European Network of Trainees in Obstetrics and Gynaecology
      (ENTOG) circulated a questionnaire to audit training in Europe. Results describe
      number and gender in each country, access to training, duration of training,
      tutor/tutee scheme, logbooks, minimum curriculum, assessment, criteria for
      accreditation, training abroad, final examination, hospital inspection,
      subspecialty, academic training, and career progression. Quality of life is tried
      to address with questions relating to salary, working hours, maternity leave,
      annual leave and study leave. EBCOG has drawn up recommendations to try and
      achieve a standardisation of quality of training whilst fully understanding that
      complete standardisation of training is not a realistic possibility due to
      social, cultural and ethical differences. A repeat audit is planned after 3 years
      to close the feedback loop.

PMID- 10597974
TI  - The implementation of a European Network of Trainees in Obstetrics and
      Gynaecology (ENTOG).

PMID- 10597975
TI  - What lessons can be learned for cancer registration quality assurance from data
      users? Skin cancer as an example.
AB  - BACKGROUND: In cancer registration, data cleaning (i.e. amendments made by data
      users to datasets released by registries) is potentially informative for quality
      assurance, but generally underreported. AIM: To assess the scope for learning
      lessons about cancer registration quality assurance from a data user (using skin
      cancer as the example). METHODS: The main design features were: (i) A descriptive
      study identifying, qualitatively and quantitatively, the breadth, depth, and
      impact of quality assurance issues raised by a user cleaning Merseyside and
      Cheshire Cancer Registry skin cancer data. Errors were rectified and pitfalls for
      interpretation were identified. (ii) A nested validation of morphology and site
      coding on random samples of cutaneous malignant melanomas, basal cell carcinomas
      (BCC), and squamous cell carcinomas. The 33132-record dataset comprised: all
      registered skin lesions, except metastases; most recorded variables (about
      patient, lesion, treatment, outcome); for Merseyside and Cheshire residents
      diagnosed 1970-1991. RESULTS: (i) Ineligible cases represented 0.3% (97/33132),
      and were detected best by morphology checks. Most quality assurance issues
      identified related to local custom and practice, staff training, and
      computerization, being particularly illustrated by problematic BCC registration
      practice (e.g. records written over unchallenged by range checks; and
      idiosyncratic use of variables). (ii) Post-cleaning, morphology coding errors
      were minimal in the random samples. CONCLUSION: There is great scope for data
      users to contribute to cancer registration quality assurance. Ultimately, the
      study dataset appeared fit for epidemiological analysis and important quality
      assurance messages emerged. Shared explicit standard guidelines for data
      preparation and validation are needed by users, whose insights could and should
      be better recognized by cancer registries.

PMID- 10597976
TI  - Breast cancer risk in young women and history of selected medical conditions.
AB  - BACKGROUND: Several common medical conditions are associated with altered hormone
      levels, and may thus plausibly influence breast cancer risk. Few studies have
      examined such relationships, and we utilized a population-based case-control
      study of young women in the US to examine breast cancer risk following a history
      of various medical conditions. Relationships between breast cancer and each
      medical condition examined are biologically plausible, and relevant in terms of
      public health. METHODS: The study included 2173 breast cancer cases and 1990
      population-based controls from three areas of the US, under 55 years, who were
      administered a questionnaire including details of physician-diagnosed medical
      conditions. RESULTS: No significantly increased or decreased breast cancer risk
      was associated with a history of thyroid disease, gallbladder disease, colorectal
      polyps, diabetes, high blood pressure, high cholesterol or surgery for
      endometriosis. There was some evidence of an increased breast cancer risk
      associated with ovarian cysts among women who did not receive an oophorectomy
      (relative risk [RR] = 1.94, 95% CI: 1.0-3.9). Non-significant increases in breast
      cancer risk were observed following diagnoses of several other cancers, including
      thyroid cancer, basal cell carcinoma, Hodgkin's disease and malignant melanoma.
      CONCLUSIONS: To conclude, our generally null results from this large, population
      based study support results from previous studies in providing reassurance that
      women with a history of several common medical conditions do not appear to be at
      an increased risk of breast cancer at a young age.

PMID- 10597977
TI  - Effects of husbands' smoking on the incidence of lung cancer in Korean women.
AB  - BACKGROUND: Although smoking remains uncommon among Korean women, lung cancer
      mortality is rapidly escalating. METHODS: We investigated the effects of spousal
      smoking in 160130 Korean women, aged 40-88, who received health insurance from
      the Korea Medical Insurance Corporation (KMIC). Exposure data were collected
      during medical examinations conducted between April 1992 and June 1994. The
      primary outcome variable was the incidence of lung cancer defined by hospital
      admissions between July 1994 and December 1997. Standardized rates for the
      incidence of lung cancer were assessed according to the smoking habits of their
      husbands. RESULTS: At baseline (n = 160 130), 53.9% of husbands were smokers and
      23.3% were ex-smokers, while 1.1% of wives (n = 1756) were current smokers and
      0.6% (n = 938) were ex-smokers. During follow-up, 79 cases of lung cancer
      occurred among non-smoking wives (n = 157436). Wives of heavy smokers were found
      to have a higher risk of developing lung cancer. The husbands' smoking habits did
      not affect their wives' risk of developing other cancers such as those of the
      stomach, liver and cervix, but they did affect breast cancer, which has a
      significantly higher risk in relation to the longer duration of husbands'
      smoking. In Poission regression models, adjusting for the age of both husband and
      wife, socioeconomic status, occupation, residency and vegetable intake, the rate
      ratio (RR) of lung cancer in non-smoking wives was 1.9 (95% CI: 1.0-3.5) in
      current smokers and 1.3 (95% CI: 0.6-2.7) in ex-smokers. The RR of lung cancer
      was 3.1 (95% CI: 1.4-6.6) in wives of husbands who had smoked for 30 years or
      more compared with wives of non-smoking husbands. CONCLUSION: In Korea, the
      incidence of lung cancer is higher among non-smoking women whose husbands smoke,
      and a dose-response relationship seems to exist.

PMID- 10597978
TI  - GSTM1, smoking and lung cancer: a case-control study.
AB  - BACKGROUND: We conducted a case-control study to examine the risk of lung cancer
      in relation to GSTM1 polymorphism and cigarette smoking (primarily of black
      tobacco) in a French population. METHODS: The 611 subjects were 301 incident lung
      cancer cases and 310 hospital controls. We were able to constitute a DNA bank for
      547 subjects (89.5%) and gather detailed information on smoking history for all
      of them. Results presented here concern 247 cases and 254 controls. RESULTS:
      Taking non- or light smokers as the reference category, we estimated odds ratios
      (OR) of 4.2 (95% CI: 2.6-6.7) and 5.2 (95% CI: 3.3-8.3) for the medium and heavy
      smokers respectively. On the other hand we estimated that the crude OR
      associating GSTM1 with lung cancer was 1.3 (95% CI: 0.9-1.8). Furthermore our
      data do not depart significantly from a multiplicative model of the combined
      effects of smoking and GSTM1 deficiency. CONCLUSIONS: We conclude that smoking
      and the GSTM1 gene are each a risk factor for lung cancer, and that their
      combined effect does not differ significantly from that of a multiplicative
      model.

PMID- 10597979
TI  - Associations between stomach cancer incidence and drinking water contamination
      with atrazine and nitrate in Ontario (Canada) agroecosystems, 1987-1991.
AB  - BACKGROUND: Nitrate and atrazine are two chemicals that are heavily used in
      certain sectors of agriculture. They are suspected to be associated with the
      development of certain types of tumours. METHODS: Existing data were obtained on
      the incidence of specific types of cancers, contamination of drinking water with
      atrazine and nitrate, and related agricultural practices for the 40 ecodistricts
      in the province of Ontario. The data were merged into a georelational database
      for geographical and statistical analyses. Weighted (by population size) least
      squares regression analyses were conducted while controlling for confounding
      socioeconomic and lifestyle factors. Maximum likelihood spatial error models were
      estimated when least square regression error terms were found to be spatially
      autocorrelated using the Moran's I statistic. RESULTS: Atrazine contamination
      levels (range 50-649 ng/l, maximum acceptable concentration [MAC] = 60000 ng/l)
      were positively associated (P < 0.05) with stomach cancer incidence and
      negatively associated with colon cancer incidence. Nitrate levels, (range 0-91
      mg/l, MAC = 10 mg/l) were negatively associated with stomach cancer incidence.
      CONCLUSION: The associations found at the ecodistrict level, both positive and
      negative, if confirmed by other studies, raise serious questions about maximum
      allowable limits for atrazine, as well as possibilities of complex trade-offs
      among disease outcomes, and interactions of biophysical and social mechanisms
      which might explain them. Although the negative associations appear to have no
      direct biological explanations, such counter-intuitive outcomes may occur in
      complex systems where social and biological variables interact.

PMID- 10597980
TI  - Cardiovascular risk factors and the neighbourhood environment: a multilevel
      analysis.
AB  - BACKGROUND: This article examines whether the neighbourhood environment
      influences intermediate cardiovascular disease (CVD) risk factors, such as
      obesity (body mass index [BMI]), and lifestyle factors, such as no physical
      activity and smoking, when adjusted for the individual socioeconomic status
      (SES). METHODS: The study consists of face-to-face interviews from the Swedish
      Annual Level of Living Survey (SALLS) matched with the social status of the
      respondents' residential areas measured by two composite indices, the Care Need
      Index (CNI) and the Townsend score. The response rate was about 80%. This study
      was limited to the residents aged 25-74 years and consists of 9240 interviews
      from the years 1988-1989, when there were extended items in the SALLS about
      health and lifestyle. The data were analysed using a hierarchical logistic
      regression model. RESULTS: There was a gradient within every SES group so that
      respondents with a low (or intermediate or high) educational level exhibited an
      increasing proportion of daily smokers, physically inactive people and obese
      individuals with increasing neighbourhood deprivation. The multilevel model
      showed that respondents living in the most deprived neighbourhoods had an
      increased risk for being a daily smoker, engaging in no physical activity and
      being obese when adjusted for the individual SES. CONCLUSIONS: We showed that the
      area level has an important influence on risk factors for CVD which goes beyond
      the individual educational attainment. An increased level of living standard,
      more resources for primary health care and health promotion targeting the
      community level should be beneficial.

PMID- 10597981
TI  - Do simple prudent health behaviours protect men from myocardial infarction?
AB  - BACKGROUND: We tested whether behaviours such as discarding obvious fat on meat,
      cessation of smoking, avoidance of passive smoking, habitual use of reduced fat
      milk, prudent consumption of alcohol and regular but moderate physical exercise
      are associated with a reduction of cardiovascular risk. METHODS: This was a
      population-based case-control study done in Perth, Western Australia. The cases
      (n = 336) were men aged 27-64 years with a first-ever acute myocardial infarction
      (AMI) during the period 1992-1993, and who survived at least 28 days. The
      controls (n = 735) were participants in a population-based survey of
      cardiovascular risk factors conducted during May-November 1994. Both groups
      completed the same questionnaire and the data were analysed with multiple
      logistic regression using backward elimination technique. RESULTS: Among men aged
      27-64 years simple measures such as participation in nonvigorous exercise (odds
      ratio [OR] = 0.5, 95% CI: 0.4-0.7), and avoidance of added salt (OR = 0.6, 95%
      CI: 0.4-0.9) are associated with significant and important protection from AMI.
      CONCLUSION: After 25 years of falling mortality in Australia, lifestyles can
      still be significantly improved to reduce heart disease even further.

PMID- 10597982
TI  - The 1996 Leicestershire Community Stroke & Ethnicity Study: differences and
      similarities between South Asian and white strokes.
AB  - OBJECTIVE: To estimate the number of strokes in Leicestershire and investigate
      possible differences between South Asian and white patients. DESIGN: Prospective
      incidence sample survey. SETTING: Leicestershire. PARTICIPANTS: Acute stroke
      cases occurring in registered populations of 12 'high Asian' and 11 'low Asian'
      general practices. RESULTS: The age-specific incidence rates of stroke in
      Leicestershire were similar to those of the Oxford Community Stroke Project.
      South Asian patients were less likely to be living alone at home before their
      stroke and they tended to be younger than whites. However, only 12% of South
      Asian patients with a stroke were not admitted to hospital within 7 days of their
      stroke compared to 23% of white patients (chi2 = 3.24, d.f. = 1, P = 0.07). Only
      21% of South Asian patients died within 28 days of their stroke compared to 33%
      of white patients (age-adjusted odds ratio = 0.37; 95% CI: 0.14-0.97).
      CONCLUSIONS: Overlapping case-finding was crucial to finding all 'possible'
      strokes and this required close collaborative working between general practices,
      community health services, hospitals and the health authority. Relatively fewer
      South Asian patients were managed in the community in the first 7 days.
      Interestingly, South Asian patients were less likely than white patients to die
      within 28 days. This is an area worthy of further research.

PMID- 10597983
TI  - Effects of ambient air pollution and environmental tobacco smoke on respiratory
      health of non-smoking women in Hong Kong.
AB  - BACKGROUND: Two-thirds of complaints received by the Hong Kong Environmental
      Protection Department in 1988 were related to poor air quality. In July 1990
      legislation was implemented to reduce fuel sulphur levels. The intervention led
      to a reduction in respiratory symptoms and bronchial hyperresponsiveness of
      primary school children. The objectives of this study were to investigate the
      differences in respiratory health between non-smoking women living in the more
      polluted district (Kwai Tsing) and those living in the less polluted district
      (Southern); to assess the impact of the government air quality intervention; and
      to study the effect of environmental tobacco smoke on respiratory health in non
      smoking women in both districts. METHOD: A total of 3405 non-smoking women, aged
      36.5 years (standard deviation = 3.0), from two districts with good and poor air
      quality respectively before the intervention were followed yearly from 1989 to
      1991. Binary latent variable modelling was used to summarize the six respiratory
      symptoms and to estimate the effects of risk factors. RESULTS: In 1989, living in
      the polluted district was associated with poor respiratory health (odds ratio
      [OR] = 1.55, 95% confidence interval [CI]: 1.11-2.17, P < 0.01). After the
      intervention, in the polluted district only, sulphur dioxide levels fell by up to
      80% and sulphate concentrations in respirable particulates by 38%. Between 1989
      and 1990-1991, there was no significantly greater decline (P > 0.241) in the more
      polluted compared with the less polluted district for poor respiratory health. In
      1989, the effects on poor respiratory health for exposure to two or more
      categories of smokers relative to none in the home (OR = 1.80, 95% CI: 1.15-2.83,
      P < 0.01) were higher but not significantly than those for living in polluted
      relative to less polluted district (95% CI of the two effects overlapping each
      other). CONCLUSIONS: Environmental tobacco smoke (ETS) and outdoor air pollution
      had independent adverse effects on respiratory health of non-smoking women and
      improvement in air quality had produced some but non-significant benefits.

PMID- 10597984
TI  - Airway diseases and allergies in East and West German children during the first 5
      years after reunification: time trends and the impact of sulphur dioxide and
      total suspended particles.
AB  - BACKGROUND: East-West comparison studies in Europe find higher prevalences of
      infectious airway diseases and lower prevalences of allergies in eastern areas.
      Pollution from sulphur dioxide (SO2) or total suspended particles (TSP) are
      discussed as causes of this difference. METHODS: In four differently polluted
      areas of East Germany where pollution decreased dramatically between 1989 and
      1995 cross-sectional studies in about 7-year-old children were repeated every
      year between 1991 and 1995. In two differently polluted areas of West Germany
      studies with the same design were done in 1991 and 1994. In all, 19090 children
      participated in the study. Thirteen different questions about airway diseases and
      allergies were evaluated. Logistic regression was used to adjust for confounding.
      RESULTS: With the exception of pneumonia, all infectious airway diseases and
      irritations of the airways show a steeper temporal decrease in East than in West
      Germany or are positively associated with either SO2 or TSP in East Germany. For
      allergies and related symptoms no differences in time trends could be detected or
      no association with SO2 or TSP could be seen in East Germany. CONCLUSION: Most
      airway diseases were more frequent in East than in West Germany in 1991 and were
      associated with SO2 or TSP. The decrease in these pollutants between 1991 and
      1995 has already had a favourable effect. An effect of SO2 or TSP pollution on
      allergies and related symptoms could not be detected. This pollution does not
      protect against the development of allergies.

PMID- 10597985
TI  - Respiratory infections reduce the growth response to vitamin A supplementation in
      a randomized controlled trial.
AB  - BACKGROUND: Studies on the effect of vitamin A supplementation on growth have
      yielded various results. It is possible that such growth is dependent on the
      burden of infectious diseases in the population. METHODS: We analysed data from a
      randomized, double-masked, placebo-controled trial to examine the role of
      respiratory infections and diarrhoea in modifying the growth response to vitamin
      A supplementation. A single high dose of vitamin A or placebo was given every 4
      months to 1405 children aged 6-48 months, and 4430 child treatment cycles were
      used in this analysis. RESULTS: Vitamin A supplementation modestly improved
      linear but not ponderal growth of children who experienced little respiratory
      infection and especially of those who had vitamin A intake below the normative
      requirement (<400 RE/day). Children who received vitamin A and were free of
      respiratory infection grew 0.22 cm/4 months (95% CI: 0.08, 0.37) more in height
      than the placebo group, but those with > or =21.5% of days of respiratory
      infection did not show a significant growth response to vitamin A
      supplementation. Children who experienced no respiratory infection and had
      vitamin A intake <400 RE/day benefited most, gaining 0.31 cm/4 months (95% CI:
      0.10, 0.52) more in height compared to the placebo group. Diarrhoea was
      associated with poorer growth, but did not significantly modify the effect of
      vitamin A supplementation on growth. CONCLUSIONS: Vitamin A supplementation
      improves the linear growth of children who have a low intake of vitamin A but
      this impact is muted with increasing levels of respiratory infections.

PMID- 10597986
TI  - Day care attendance, recurrent respiratory tract infections and asthma.
AB  - OBJECTIVE: Our objective was to use a causal model for childhood asthma to
      determine whether the effect of day care attendance on asthma was mediated by
      recurrent respiratory tract infections. DESIGN: A cross-sectional survey among
      1447 children aged 6-16 years in Oslo. Their parents completed written
      questionnaires. A recursive logit model was used to estimate direct effects in
      terms of adjusted odds ratios (aOR). RESULTS: Year of birth, number of siblings
      and length of maternal education were significantly associated with day care
      attendance. Attendance at day care increased the risk of early infections, aOR =
      1.8 (1.3-2.5), and infections were associated with asthma, aOR = 4.9 (3.4-7.3).
      The crude association between day care and asthma was cOR = 1.5 (1.0-2.2),
      whereas the estimated direct effect was small and nonsignificant, aOR = 1.2 (0.8
      1.9). The results may be influenced by overreporting of infections among parents
      of children with asthma. CONCLUSIONS: Our results suggest that children who
      attend day care have an increased risk of asthma with early infections as a
      mediator of risk.

PMID- 10597987
TI  - Risk factors for the incidence of hyperuricaemia: a 6-year longitudinal study of
      middle-aged Japanese men.
AB  - BACKGROUND: Few longitudinal studies on the determinants of increase in serum
      uric acid (SUA) have been completed. METHODS: In all, 1445 hyperuricaemia-free
      (<7.5 mg/dl SUA, no medication for and no past history of hyperuricaemia) male
      office workers aged 30-54 years of T Corporation in Osaka, Japan were re-examined
      for six successive years. Subjects who were found to be hyperuricaemic or had
      started medication for hyperuricaemia during repeat surveys were defined as
      incident cases. RESULTS: Among the subjects (n = 1365) not receiving medication
      for hypertension, diabetes mellitus or renal disease, multivariate analysis using
      the Cox proportional hazards model indicated that the incidence of hyperuricaemia
      had significant relationships with body mass index (adjusted hazard ratio [HR] =
      1.13 for a 2 kg/m2 increase; 95% CI: 1.02-1.26), mean blood pressure (HR = 1.07
      for a 5 mmHg increase; 95% CI: 1.00-1.13), log triglyceride level (HR = 2.21 for
      a 10 mg/dl increase; 95% CI: 1.12-4.37), alcohol intake (HR = 2.33 for drinking
      46.0 g of ethanol per day or more relative to non-drinking; 95% CI: 1.55-3.50)
      and smoking (HR = 0.65 for current-smoking relative to non-smoking; 95% CI: 0.46
      0.92). Age (HR = 0.89 for a 5-year increase; 95% CI: 0.78-1.00) and haemoglobin
      A1c (HbA1c) (HR = 0.89 for a 0.5% increase; 95% CI: 0.78-1.00) achieved marginal
      significance. CONCLUSIONS: Obesity, high blood pressure, high triglyceride level,
      and alcohol intake are contributory factors for the development of hyperuricaemia
      among middle-aged Japanese men. High HbA1c level and smoking may be negative
      factors for the incidence of hyperuricaemia.

PMID- 10597988
TI  - Potential gains in life expectancy or years of potential life lost: impact of
      competing risks of death.
AB  - BACKGROUND: Measuring the impact of competing risks of death on society is
      important for setting public health policy and allocating resources. However,
      various indicators may result in inconsistent conclusions. The potential gains in
      life expectancy (PGLE) by elimination of deaths from HIV/AIDS, diseases of the
      heart and malignant neoplasms were compared to the years of potential life lost
      (YPLL) due to these causes in measuring the impact of premature death for the US
      population of working age (15-64 years). METHODS: The PGLE and the YPLL were
      computed from mortality reports (1987-1992) by race and gender group for deaths
      from HIV/AIDS, diseases of the heart and malignant neoplasms for the US
      population of working age. RESULTS: The YPLL overestimated the importance of
      premature deaths from HIV/AIDS compared to the PGLE. For the total US population
      and total US white population of working age, the YPLL were about 20-30% higher
      than the PGLE. However, the YPLL were about 20-30% lower than the PGLE for the US
      black population of working age. Furthermore the relative importance of the
      impact of death from various diseases may be interchanged by these two
      indicators. For example, for US black males of working age, the impact of deaths
      from HIV/AIDS by PGLE in 1992 was higher than that from malignant neoplasms and
      lower than that from diseases of the heart, but by using YPLL, the impact of
      premature deaths from HIV/AIDS was higher than that from both diseases of the
      heart and malignant neoplasms. CONCLUSIONS: The PGLE by elimination of deaths
      from diseases takes into account the competing risks on the population and it can
      be compared easily across populations. The YPLL is an index that does not take
      into account competing risks and it is also heavily influenced by the age
      structure and total population size. Although there are several standardization
      techniques proposed to improve the comparability of the YPLL across different
      populations, the YPLL fails to address the central issue of competing risks
      operating on the population. For this reason, we prefer the PGLE to the YPLL in
      measuring the impact of premature deaths on a population.

PMID- 10597989
TI  - Bias related to the exclusion of the economically inactive in studies on social
      class differences in mortality.
AB  - BACKGROUND: To assess how the exclusion of the economically inactive affects
      levels and trends in social class differences in mortality among men and women at
      different durations of follow-up. METHODS: Records of the 1970, 1975, 1980 and
      1985 censuses on Finnish men and women aged 35-64 linked with records of all
      deaths during 1971-1990. RESULTS: Exclusion of the economically inactive
      population underestimates the class differences in the total population by about
      25% among men and 60% among women. The bias does not disappear if the first 5
      years of follow-up are excluded and the bias can lead to erroneous conclusions
      about the trends in social class differences in mortality. CONCLUSIONS: Analyses
      based on the economically active population may lead to significant
      underestimation of social class differences in mortality, introduce biases in
      international comparison and may only partially capture the causal mechanisms
      underlying these mortality differences. Our results further show that although
      the bias diminishes during the follow-up, it is by no means eliminated after the
      first 5 years. The underestimation of social class differences in mortality
      created by the exclusion of the inactive should be more widely recognized and
      more accurate data on previous occupations should be collected.

PMID- 10597990
TI  - The impact of the major causes of death on life expectancy in Italy.
AB  - BACKGROUND: This study aims to evaluate the contribution of the reduction in
      major cardiovascular diseases (CVD), malignant neoplasms (MN), accidents and AIDS
      mortality to the gains in life expectancy observed during the decade 1985-1994,
      as well as to calculate and compare the potential gains due to the partial or
      total elimination of these causes. METHODS: Mortality data from the Italian
      Mortality Data Base were analysed by the method of decomposition of changes in
      life expectancy and the partial multiple decrement life table technique. RESULTS:
      In Italy, considering the decade 1985-1994, the gain in life expectancy at birth
      was 2.27 years for men and 2.16 for women. The major contribution to this
      increase was the reduction in CVD mortality followed by fewer deaths from
      accidents and MN. Conversely, AIDS caused a loss in the length of life of adults.
      Major potential gains in life expectancy at birth could be obtained by the
      elimination or even partial reduction of CVD and MN mortality. When working life
      (15-64 years) is considered, the relative importance of the causes changes. The
      elimination of accidents and AIDS would result in increased life expectancy
      longer than that associated with a 50% reduction in CVD. CONCLUSIONS: The
      findings of this study provide useful information which could contribute to a
      more effective allocation of resources for research activity and public health
      programmes.

PMID- 10597991
TI  - Social background, adult body-height and health.
AB  - STUDY OBJECTIVE: To study the socio-demographic determinants of body-height and
      the bearing of these determinants on the association between body-height and
      health among Finnish adults. DATA AND METHOD: Cross-sectional population survey
      including questions on social background, body-height and health, and
      retrospective questions on childhood living conditions. The data derive from a
      representative Survey on Living Conditions collected by Statistics Finland in
      1994. The response rate was 73%. Male and female respondents > or =20 years were
      included in the analysis (N = 8212). Statistical methods include regression
      analysis and logistic regression analysis. RESULTS: Body-height was strongly
      associated with year of birth, region, childhood living conditions and education
      among adult men and women. Body-height was also associated with limiting long
      standing illness and perceived health as below good. Tall men had the best health
      and short men the poorest health. Among women the association of body-height with
      health differed from men, as tall women showed high levels of limiting long
      standing illness, notably musculo-skeletal diseases. Adjusting for the background
      variables weakened but did not abolish the association between poor health and
      short stature among men and women. CONCLUSIONS: Short stature is associated with
      poor health among Finnish men and women. A non-linear association among women was
      found for musculo-skeletal diseases. The studied social background factors
      explained only little of the association between body-height and health.

PMID- 10597992
TI  - Trends in maternal mortality ratio among women of German and non-German
      nationality in West Germany, 1980-1996.
AB  - BACKGROUND: Maternal mortality is a sensitive indicator for inequity in health.
      We describe recent trends in overall and cause-specific maternal mortality ratio
      among women of German and non-German nationality residing in West Germany.
      METHODS: Using birth and death register data for 1980-1996 we related 1067 cases
      of maternal death (ICD 9: 630-676) to 11.2 million live births. We assessed the
      effects of nationality and of marital status, a proxy for socioeconomic status,
      controlling for year of death and age of the mother in a Poisson regression
      model. RESULTS: Maternal mortality ratio in West Germany decreased from 13 per
      100000 live births in 1980-1988 to 6.1 in 1989-1996. The crude relative risk for
      non-German nationality decreased from 1.9 (95% CI: 1.6-2.3) to 1.3 (1.0-1.7);
      after adjusting for age, year of death and marital status it was 1.7 (95% CI: 1.4
      2.1) and 1.6 (95% CI: 1.2-2.1). Unmarried women incurred an adjusted relative
      risk of 1.8 (95% CI: 1.5-2.3). Non-German women experienced an excess mortality
      from abortions which largely disappeared in 1989-1996; concurrently, being
      unmarried no longer conveyed an additional risk to them. The risk status of
      German mothers developed unfavourably: increasing proportions are unmarried,
      which continues to be a marker of elevated relative risk in this group.
      CONCLUSIONS: Our findings suggest continuously improving accessibility and
      quality of obstetric services, in particular for women of non-German nationality.
      Still, inequity in maternal risk continues to exist. Maternal risk, however, is
      not determined by the simple distinction 'German' versus 'non-German'; its
      association with socioeconomic status extends beyond nationality.

PMID- 10597993
TI  - Can accurate data on birthweight be obtained from health interview surveys?
AB  - BACKGROUND: Because hospital records rarely exist for a representative sample of
      the population in developing countries, researchers frequently rely on
      birthweight data from surveys. Yet, the quality of these data has rarely been
      evaluated. This study explores the accuracy of birthweight information in six
      demographic and health surveys in Latin America conducted in the early 1990s: two
      in Guatemala, and one each in Bolivia, Costa Rica, El Salvador and Peru. METHODS:
      The quality of the birthweight reports is assessed by examining the plausibility
      of estimates of the proportion of newborns reported to have been weighed and
      estimates derived from the numerical weights, by characteristics of the delivery
      and maternal education. RESULTS: The estimates suggest that a substantial
      proportion of women whose newborns were probably never weighed report a
      birthweight. For all of the surveys, with the possible exception of Costa Rica,
      the average birthweights appear to be too high, and the estimates of the
      prevalence of low birthweight too low. In addition, the data reveal anomalous
      patterns, such as higher birthweights for home as compared with hospital
      deliveries. CONCLUSIONS: These findings suggest that estimates of low birthweight
      derived from surveys in developing countries are likely to portray an overly
      optimistic picture of children's and women's health status. More information
      about the underlying source of these data are needed not only to provide
      additional insight into the degree of error characterizing existing estimates,
      but also to improve data collection strategies in future health interview
      surveys.

PMID- 10597994
TI  - European stillbirth proportions before and after the Chernobyl accident.
AB  - BACKGROUND: Numerous investigations have been carried out concerning the possible
      impact of the Chernobyl accident, in April 1986, on the prevalence of anomalies
      at birth and on perinatal mortality. The accident has contaminated Eastern Europe
      more heavily than Western Europe. If there was an effect of the radioactive
      contamination on perinatal mortality or stillbirth proportions one would expect
      to find it more pronounced in Eastern Europe as compared to Western Europe. We
      therefore studied long-term time trends in European stillbirth proportions.
      METHODS: Linear logistic regression was applied to model the time trends in
      stillbirth proportions. Dummy variables were used to account for effects that can
      be associated with certain years or locations. A synoptic logistic regression
      model is suggested for the western, central, and eastern parts of Europe.
      RESULTS: There is a marked differential effect in the long-term stillbirth time
      trends between Western Europe (Belgium, France, Great Britain, Iceland, Ireland,
      Luxembourg, Portugal, Spain), Central Europe (Austria, Denmark, Germany, Italy,
      Norway, Switzerland), and Eastern Europe represented by four countries (Greece,
      Hungary, Poland, Sweden). In contrast to the western and central European trends,
      the eastern European trend exhibits an absolute increase of the stillbirth
      proportion in 1986 as compared with 1985 and an apparent upward shift of the
      whole trend line from 1986 on. CONCLUSION: Our results are in contrast to those
      of many analyses of the health consequences of the Chernobyl accident and
      contradict the present radiobiological knowledge. As we are dealing with highly
      aggregated data, other causes or artefacts may explain the observed effects.
      Hence, the findings should be interpreted with caution and further independent
      evidence should be sought.

PMID- 10597995
TI  - Evaluation of the impact of Chernobyl on the prevalence of congenital anomalies
      in 16 regions of Europe. EUROCAT Working Group.
AB  - BACKGROUND: Surveillance data from population-based congenital anomaly registers
      in 16 regions of Europe (mainly Western Europe) were analysed to assess the
      impact of the Chernobyl accident on the prevalence of selected congenital
      anomalies. METHODS: Three cohorts of pregnancies were defined: those exposed
      during the first month following Chernobyl (External Exposure Cohort), the first
      year (Total Exposure Cohort) and the two subsequent years (Control Cohort).
      Expected numbers of congenital anomalies in these cohorts were calculated from
      1980-1985 baseline rates. Registries were grouped into three exposure categories
      according to first-year exposure estimates. RESULTS: There was no overall or dose
      related increase in prevalence in the two exposed cohorts for Down's Syndrome,
      neural tube defects, other central nervous system defects or eye defects. There
      was a statistically significant overall 22% (95% CI: 13-31%) excess of Down's
      Syndrome in the Control Cohort, with no dose-response relationship. CONCLUSIONS:
      Chernobyl had no detectable impact on the prevalence of congenital anomalies in
      Western Europe, suggesting that in retrospect the widespread fear in the
      population about the possible effects of exposure on the unborn fetus was not
      justified. An increasing prevalence of Down's Syndrome in the 1980s, probably
      unrelated to Chernobyl, merits further investigation.

PMID- 10597996
TI  - Prevalence of cerebral palsy in China.
AB  - BACKGROUND: A population-based study on the prevalence of cerebral palsy has not
      been previously carried out in China. The purpose of the present paper was to
      determine the overall and birthweight-specific prevalence of cerebral palsy.
      METHODS: A cross-sectional study of cerebral palsy was carried out among 388192
      children aged <7 years in seven cities of Jiangsu province in China from May to
      July 1997. Information about birthweight was obtained from routine health care
      records. Doctors from township and city hospitals examined all eligible children
      and doctors at city level finally diagnosed all cases. All the doctors involved
      had taken part in a training programme held by Beijing Medical University in
      April 1997. RESULTS: The total prevalence of cerebral palsy was 1.6 per 1000
      children and the birthweight-adjusted prevalence 2.8 per 1000 children (using
      Australia's neonatal survivors 1994 as a standard population). The overall
      neonatal mortality rate was 6.8 per 1000 live births, being highest (581.1 per
      1000) in the 1000-1499 g birthweight group. The birthweight-specific cerebral
      palsy prevalence ranged from 0.8 per 1000 children in children weighing 3750-3999
      g to 67.3 in children weighing 1500-1749 g. Children weighing 3500-3999 g at
      birth were at the lowest risk of cerebral palsy. In a given low birthweight group
      the prevalence of cerebral palsy in China was higher than that in developed
      countries even though this study was unable to include those who died at risk of,
      or with cerebral palsy. However, the prevalence of cerebral palsy at normal
      birthweight was almost the same as that in developed countries. In all, about 2%
      of all children were of low birthweight (<2500 g), with those weighing <1500 g
      accounting for about 0.02%. Children weighing <2500 g at birth contributed 24% of
      all cerebral palsy cases with 99% in the group 1500-2499 g. CONCLUSIONS: The
      prevalence of cerebral palsy for children aged <7 years is 1.6 per 1000 children.
      It is estimated that there are 310000 children with cerebral palsy in China and
      as the survival of low birthweight infants improves the prevalence of cerebral
      palsy will rise. Survival of low birthweight infants is lower in China than in
      developed countries and our findings suggest the survival quality of these
      Chinese children needs to be improved and that intrapartum and neonatal
      antecedents might play an important role in the aetiology of cerebral palsy
      compared to developed countries.

PMID- 10597997
TI  - Simultaneous modelling of time trends and regional variation in mortality rates.
AB  - BACKGROUND: We seek to model the regional component of the variance in the
      mortality rates in the UK and to ascertain if there is evidence that this
      regional variance is increasing in recent periods. METHODS: Age Period Cohort
      (APC) models, based on the local 'curvatures', are used in each region to
      describe the changes in the trends in the mortality rates. This is extended to a
      multilevel model to estimate the regional component of the variance in the rates
      and to estimate the effect of regional differences in the trends in the rates. We
      show how the use of a multilevel APC model can help to distinguish the cohort and
      period trends in the mortality rates from the cohort and period effects on the
      regional variance in these rates. RESULTS: For both sexes, but particularly for
      females, a reduction in the rate of decrease in mortality was found around 1960.
      In addition, particularly for females, cohorts born after 1930 appear to show
      reductions in mortality at an increased rate. It is demonstrated that there is
      evidence that the between-region variation in the rates has not remained constant
      and that it is much less now than it was at the beginning of the data series.
      Further, there is evidence that the trends in the rates are not the same in all
      regions and that while there is a convergence of the rates in many regions,
      Scotland, in particular, stands out as a region which contributes most to the
      regional variation in mortality rates. CONCLUSION: Evidence of regional variation
      in mortality rates has been found with a suggestion of a decrease over the period
      of the study though with some stability since 1951.

PMID- 10597998
TI  - The use of fractional polynomials to model continuous risk variables in
      epidemiology.
AB  - BACKGROUND: The traditional method of analysing continuous or ordinal risk
      factors by categorization or linear models may be improved. METHODS: We propose
      an approach based on transformation and fractional polynomials which yields
      simple regression models with interpretable curves. We suggest a way of
      presenting the results from such models which involves tabulating the risks
      estimated from the model at convenient values of the risk factor. We discuss how
      to incorporate several continuous risk and confounding variables within a single
      model. The approach is exemplified with data from the Whitehall I study of
      British Civil Servants. We discuss the approach in relation to categorization and
      non-parametric regression models. RESULTS: We show that non-linear risk models
      fit the data better than linear models. We discuss the difficulties introduced by
      categorization and the advantages of the new approach. CONCLUSIONS: Our approach
      based on fractional polynomials should be considered as an important alternative
      to the traditional approaches for the analysis of continuous variables in
      epidemiological studies.

PMID- 10597999
TI  - The spectrum of AIDS-defining diseases: temporal trends in Italy prior to the use
      of highly active anti-retroviral therapies, 1982-1996.
AB  - OBJECTIVE: To evaluate time trends of the spectrum of AIDS-defining diseases in
      Italy, 1982-1996. METHODS: Surveillance data from the Italian National AIDS
      Registry were used to assess temporal patterns of all AIDS-defining diseases
      diagnosed among adults as of December 1996. Twenty-six initial clinical
      manifestations of AIDS were grouped into 12 categories. Relative frequencies were
      calculated by year of diagnosis and stratified by age, gender, HIV-exposure
      category, and CD4+ cell count. A multivariate polychotomous logistic model was
      used to estimate the proportions of each diagnostic category over time, adjusting
      simultaneously for the remaining diagnostic categories and for variables of
      interest. RESULTS: This analysis was based on 41772 diagnoses of AIDS-defining
      diseases among 36 638 reported cases. Mycoses represented the most frequent
      condition (27.3%), followed by Pneumocystis carinii pneumonia (PCP) (21.4%) and
      viral infections (8.9%). Cancers accounted for less than 10% of diseases.
      Downward trends were observed for mycoses, PCP (in the last part of the study
      period), Kaposi's sarcoma (KS), and non-Hodgkin's lymphomas (NHL). Upward trends
      were observed for mycobacterioses, and bacterial and protozoal infections. Brain
      toxoplasmosis increased up to 1994, and, thereafter, it appeared to decrease.
      These trends were less marked when the analysis was restricted to the diseases
      included in the pre- 1987 AIDS definition. Trends stratified by CD4+ cell count
      for the period 1990-1996 were substantially consistent with the above-reported
      results. CONCLUSIONS: The downward temporal trends in the most recent years of
      the study period for PCP and for brain toxoplasmosis are likely to be related to
      the use of prophylactic treatment. This analysis confirms a decline in KS but
      suggests that this was largely over by 1990.

PMID- 10598000
TI  - American cutaneous leishmaniasis in Southeast Brazil: space-time clustering.
AB  - BACKGROUND: American cutaneous leishmaniasis (ACL) is endemic in many rural areas
      of Brazil where different transmission patterns of the disease have been
      described. This ecological study was carried out in a municipality located in
      Southeast Brazil and aimed to investigate the space-temporal patterns of the
      disease and environmental risk factors from 1966 to 1996. METHODS: Incident ACL
      cases were defined by clinical diagnosis, confirmed by a positive skin test
      and/or parasitological examination. Age-adjusted morbidity rate of ACL was
      calculated by year for this municipality and their different census enumeration
      districts. The homogeneity chi2 test, Moran and empirical Bayes index and Knox
      procedure were employed for testing the significance of clusters in time, space
      and in time-space, respectively. A Poisson regression model was used to identify
      environmental factors related to rate variability. RESULTS: A total of 1712 new
      ACL cases were reported with a yearly incidence rate of 48/100000 inhabitants.
      Higher incidence rates were detected in 1968, 1974, and 1988 (100, 160, and 190
      cases/100000, respectively) with evidence of spatial clustering from 1986 to
      1993. Significant space-time clustering with epidemic peaks followed by low
      incidence in subsequent periods was observed. The incidence rates of ACL were
      independently associated with rural areas; areas lacking sanitary installations
      and with higher proportion of exposed garbage (P < 0.01). CONCLUSIONS: This study
      suggests that ACL rates vary across space and time. Rural areas and some
      environmental factors could explain part of this variation. Environmental
      modifications in the vicinity of households over time and accumulation of
      susceptible individuals are discussed as possible factors responsible for
      variability.

PMID- 10598001
TI  - Inappropriate use of daily mortality analyses: a response.

PMID- 10598002
TI  - The contribution of incidence variations to 'available mortality'.

PMID- 10598003
TI  - Epidemiology in progress: thoughts, tensions and targets.

PMID- 10598004
TI  - Epidemiology in transition.

PMID- 10598005
TI  - Epidemiology, medicine and public health.

PMID- 10598006
TI  - What should be the concerns of epidemiology?

PMID- 10598007
TI  - The future of molecular epidemiology.

PMID- 10598008
TI  - Epidemiology as a population science.

PMID- 10598009
TI  - Should the epidemiologist be a social scientist or a molecular biologist?

PMID- 10598010
TI  - Glucocorticoid regulation of inflammation: the plot thickens.
AB  - While glucocorticoids are widely used in the suppression of immune-inflammatory
      diseases, much remains unknown about the contribution of endogenous adrenal
      glucocorticoids to inflammatory regulation. It is now well understood that
      glucocorticoids are increased by inflammatory stress and provide for responsive
      limitation of inflammation. It is self-evident that the immune response in
      healthy animals takes place in a milieu characterised by background levels of
      glucocorticoids. It is less well appreciated, however, that basal levels of
      glucocorticoids may in fact be a requirement for a normal immune response. In
      fact, extensive data exist supporting the hypothesis that glucocorticoids
      interact with the immune-inflammatory system in a biphasic, concentration
      dependent fashion. No mechanistic explanation for this apparent paradox has
      previously existed. Recently, the cytokine macrophage migration inhibitory factor
      (MIF), while possessing pleiotropic pro-inflammatory properties, has been
      demonstrated to be glucocorticoid-inducible. This observation has the potential
      to explain key aspects of the biphasic regulation of inflammatory response by
      endogenous glucocorticoids.

PMID- 10598011
TI  - Cardioprotective activity of endogenous and exogenous nitric oxide on ischaemia
      reperfusion injury in isolated guinea pig hearts.
AB  - BACKGROUND: We evaluated the contribution of endogenous and exogenous nitric
      oxide (NO) in ischaemia reperfusion (IR) injury and histamine release in the
      isolated guinea pig heart. METHODS: Ischaemia reperfusion was performed in
      isolated Langendorff perfused guinea pig heart throughout the ligature of the
      left anterior descending coronary (LAD) artery for 20 min, and following the
      release of the ligature for a further 20 min. RESULTS: IR promoted a linear
      release of lactate dehydrogenase (LDH) and a preferential release of histamine in
      the reperfusion phase. The amount of nitrite (NO2-, one of the breakdown products
      of NO) released during IR was significantly lower than in the control hearts.
      These effects were accompanied by an increase in calcium levels and malonyl
      dialdehyde (MDA) production in the left ventricle and by a decrease in cardiac
      mast cell metachromasia. Perfusion of the hearts with two inhibitors of the
      nitric oxide synthase pathway, namely N(G)-monomethyl-L-arginine (L-NMMA, 10(-4)
      M) or nitroarginine methylester (L-NAME, 10(-5) M) significantly enhanced
      histamine and LDH release; these effects were attenuated by co-infusion with L
      arginine (10(-4) M) but not D-arginine (10(-4) M), while L-arginine (10(-4) M)
      alone had no effect. Perfusion of the heart with sodium nitroprusside (SNP), 3
      morpholinosydnonimine (SIN-1), glyceryl trinitrate (GTN), all at 10(-5) M,
      reduced histamine release, LDH release, calcium overload and MDA production
      induced by IR. These effects were amplified by concomitant perfusion with
      superoxide dismutase (SOD, 50 IU/ml). CONCLUSION: The endogenous production of NO
      provides significant myocardial protection from IR injury and histamine release.
      These effects were mimicked by various NO donors.

PMID- 10598012
TI  - Mechanism of action of the nonlipophilic antiallergic drug eclazolast (REV 2871)
      in the inhibition of mediator release in a mast cell model.
AB  - OBJECTIVE AND DESIGN: In this study, we compared eclazolast with other lipophilic
      antiallergic drugs, relating to effects on signal transduction pathways, leading
      to inhibition of exocytosis in a rat basophilic leukemia cell (RBL-2H3).
      MATERIALS AND METHODS: Effects of the drugs on mediator release (beta
      hexosaminidase, arachidonic acid metabolites) after Fc(epsilon)RI activation in
      RBL-2H3 cell were quantified. Furthermore, effects of the drugs on cellular
      signalling (Ca2+ influx, intracellular Ca2+ concentration, inositol 1,4,5
      trisphosphate (IP3) concentration) were assayed. Effects of the drugs on bilayer
      and cell membranes have been recorded. RESULTS: It is shown that eclazolast down
      regulates IP3 levels. In contrast to lipophilic drugs, eclazolast does not affect
      artificial bilayers and erythrocyte membranes, and there is no effect on
      thapsigargin induced Ca2+ influx. The effect of eclazolast was highly dependent
      on the antigen concentration with which the cells were triggered. CONCLUSIONS:
      The mechanism of action of eclazolast is deviant from lipophilic antiallergic
      agents. It inhibits exocytosis by intracellularly affecting only direct
      Fc(epsilon)RI linked processes and not through inhibition of Ca2+ influx
      channels, as found for membrane disturbing lipophilic drugs.

PMID- 10598013
TI  - The molecular mechanism of inhibition of interleukin-1beta-induced cyclooxygenase
      2 expression in human synovial cells by Tripterygium wilfordii Hook F extract.
AB  - OBJECTIVE: Several extracts of Tripterygium wilfordii Hook F (TWHF) have been
      reported to be effective in patients with rheumatoid arthritis. We investigated
      the effect of multi-glycosides ofTWHF (GTW), a TWHF extract, on interleukin (IL)
      1beta stimulated human rheumatoid synovial cells. MATERIALS AND METHODS: IL-1beta
      stimulated synovial cells were used to detect the effects of GTW on
      cyclooxygenase (COX)-1 and COX-2 activities, expression of COX protein and mRNA,
      and nuclear transcription factors in experiments using respective reporter
      plasmids. RESULTS: GTW inhibited prostaglandin E2 production by IL-1beta
      stimulated synovial cells in a concentration-dependent manner, and also inhibited
      COX-2 protein and mRNA expression in a similar fashion to dexamethasone. However,
      GTW did not act as a glucocorticoid agonist. GTW repressed IL-1beta-induced
      nuclear factor-kappaB activity, but did not have a significant influence on
      activating protein-1 activity. CONCLUSION: The anti-rheumatic effect of GTW or
      TWHF may be partly mediated through the inhibition of prostaglandin E2 production
      in human synovial cells due to suppression of COX-2 mRNA, possibly via inhibition
      of nuclear factor-kappaB activity.

PMID- 10598014
TI  - Histamine release during the induction of anesthesia with propofol in allergic
      patients: a comparison with the induction of anesthesia using midazolam-ketamine.
AB  - OBJECTIVE: A prospective randomized controlled study was performed for patients
      with a history of allergy to evaluate the effect of the induction of anesthesia
      with propofol against histamine release, skin reactions, hemodynamic changes and
      other clinical symptoms, while also comparing these parameters during the
      induction of anesthesia with midazolam-ketamine for patients with a history of
      allergy. SUBJECTS: We examined 40 patients undergoing oral surgery, who had a
      history of allergy and/or the percentage of eosinophils in the leukocytes was
      more than 3%. METHODS: Forty patients were randomly allocated into two groups and
      thus received either midazolam-ketamine (M-K group, n = 20) or fentanyl-propofol
      (propofol group, n = 20) for the induction of anesthesia. Venous blood samples (4
      ml each) were obtained before induction as a control and at 0.5, 1, 3, 5 minutes
      after the administration of each induction agent, and then furthermore at 0.5, 1,
      3, 5 minutes after tracheal intubation in order to measure the plasma histamine
      level by using the HPLC post-label system. In addition, the blood pressure and
      heart rate were also simultaneously recorded. Skin reactions were also evaluated
      by two anesthesiologists. RESULTS: The incidence of 50% histamine release during
      the induction of anesthesia with propofol occurred in 15% of the patients with a
      history of allergy. Sixteen patients out of 20 (80%) showed a decrease in the
      systolic blood pressure after the administration of propofol without any evidence
      of histamine release. The incidence of 50% histamine release, skin reactions and
      an increase in the heart rate between the two groups were not statistically
      significant after the administration of each anesthetic agent. Moreover, some
      patients also demonstrated histamine release after tracheal intubation.
      Hemodynamic changes after tracheal intubation showed a similar tendency in both
      groups. No significant difference was observed regarding the incidence of
      histamine release, skin reactions and hemodynamic changes between both groups
      after tracheal intubation. CONCLUSIONS: Propofol was found to show a similar
      incidence of histamine release during the induction of anesthesia using midazolam
      ketamine, and thus was also found to be a useful induction agent against
      histamine release for patients with a history of allergy when hydroxizine was
      used as a premedication.

PMID- 10598015
TI  - Appearance of cytokine-induced neutrophil chemoattractant isoforms and
      immunolocalization of them in lipopolysaccharide-induced acute lung inflammation
      in rats.
AB  - OBJECTIVE AND DESIGN: Recently, rat cytokine-induced neutrophil chemoattractant
      (CINC), which belongs to the interleukin-8 family, was grouped into four
      isoforms, CINC-1, CINC-2a, CINC-2beta, and CINC-3. To determine the major
      component and the source of CINC in airways, we investigated the change in
      appearance of CINC isoforms after exposure of rats to lipopolysaccharide.
      METHODS: Male Sprague-Dawley rats, 8-10 weeks old, were used in the present
      study. Bronchoalveolar lavage (BAL) was performed at 1, 2, 4, 6, 12, and 24 h
      after lipopolysaccharide inhalation (4 mg/ml for 30 min). The concentrations of
      each specific rat CINC in the BAL supernatant were measured by use of
      commercially available kits. Furthermore, lung tissue was employed for
      immunohistochemical staining of CINCs (CINC-1, -2alpha,-2beta, and -3) using the
      streptavidin-biotin technique. RESULTS: Inhalation of lipopolysaccharide caused
      increases in CINC-1, CINC-2aalpha, and CINC-3 in BAL fluids, whereas CINC-2beta
      was not detected. The increases in CINC-2a and CINC-3 were less than the increase
      in CINC-1. Positive immunohistochemical staining for CINC-1 was detected in
      bronchial noncilliated cells and in certain neutrophils that had infiltrated into
      the submucosa. CONCLUSIONS: These findings suggest that CINC-1 is the major
      isoform among the four CINCs in lipopolysaccharide-induced acute lung
      inflammation in rats. Its sources are likely to be bronchial noncilliated cells
      and certain infiltrating neutrophils.

PMID- 10598016
TI  - High concentrations of histamine stimulate equine polymorphonuclear neutrophils
      to produce reactive oxygen species.
AB  - OBJECTIVE AND DESIGN: Because high concentrations of histamine are locally
      released in inflammation, we investigated the effects of supraphysiological doses
      of histamine on the production of reactive oxygen species (ROS) by neutrophils.
      MATERIALS AND METHODS: Isolated equine neutrophils were activated by 10(-4) to 5
      x 10(-3) M histamine. The production of ROS and free radicals was estimated by
      luminol-enhanced chemiluminescence (CL) and electron spin resonance (ESR) with
      spin trapping technique. In this model of histamine-stimulated neutrophils, we
      tested the antagonists of H1 and H2 histamine receptors, the role of Ca2+ and
      Mg2+, the role of staurosporine and pertussis toxin (inhibitors of protein kinase
      C and proteins G) and the effects of superoxide dismutase, catalase, hydroxyl
      radical scavengers (phenylalanine and mannitol) and N(G)-monomethyl-L-arginine (L
      NMMA), inhibitor of NO-synthase. RESULTS: Histamine (from 10(-5) to 10(-3) M)
      stimulated neutrophils to produce CL and ESR signals characterized by spin
      adducts of superoxide anion and/or hydroxyl radicals. The CL response was
      inhibited by 10(-4) and 10(-3) M H1 receptor antagonists (promethazine,
      pyrilamine, and diphenhydramine), by Ca2+ and Mg2+ depletion and by 10 nmoles
      staurosporine. CL was partially inhibited by pertussis toxin (4 microg/ mL). The
      ESR signals were practically suppressed by pyrilamine (an H1 receptor antagonist)
      and superoxide dismutase, and partially inhibited by catalase, hydroxyl radical
      scavengers and L-NMMA (respectively 59, +/- 30% and 68% inhibition). CONCLUSIONS:
      High concentrations of histamine stimulated the neutrophils to product ROS and
      free radicals via H1 receptors and the NADPH-oxidase pathway.

PMID- 10598017
TI  - Antigen-stimulated lung CD4+ cells produce IL-5, while lymph node CD4+ cells
      produce Th2 cytokines concomitant with airway eosinophilia and
      hyperresponsiveness.
AB  - OBJECTIVE AND DESIGN: We investigated whether airway inflammation in a mouse
      model of allergic asthma is related to antigen-specific T cell responses in the
      effector organ, the lung, and in the lung draining lymph nodes (LN). MATERIALS
      AND SUBJECTS: In BALB/c mice pathophysiological parameters were measured in vivo,
      and lung draining LN and lung cells were restimulated in vitro. TREATMENT: Mice
      were sensitized with ovalbumin and repeatedly challenged with ovalbumin or saline
      inhalation. METHODS: Airway reactivity, inflammation in the airways, serum levels
      of IgE were measured, and cytokine levels and proliferative responses were
      determined in antigen-stimulated lymphocyte cultures. RESULTS AND CONCLUSIONS:
      Sensitization results in antigen-specific Th0-like LN cells, despite the presence
      of antigen-specific IgE. Repeated antigen inhalation induced airway
      hyperresponsiveness and eosinophil infiltration concomitant with a shift towards
      Th2 cytokine production exclusively by lung draining LN T cells. Furthermore,
      these airway symptoms are associated with antigen-specific CD4+ effector T cells
      in the airway tissue producing only IL-5, but not IL-4, which are unable to
      proliferate.

PMID- 10598018
TI  - Inhibitory effect of murine kidney extracts on the proliferation of murine mast
      cells.
AB  - We examined the effect of murine kidney extract (MKE) on the clonal growth of
      mast cells from murine peritoneal cells. Adding MKE resulted in a 40% inhibition
      of colony formation of mast cells in a methylcellulose culture, and a 90%
      decrease in mast cell numbers and histamine content in mast cells in a liquid
      culture containing stem cell factor and interleukin-3. The mast cell inhibitory
      factors in MKE were heat sensitive proteins of approximately 560 and 24 kDa.
      These results suggest that MKE contains regulators that suppress the growth of
      murine mast cells and histamine synthesis.

PMID- 10598019
TI  - Regulation of gelatin-binding protein 28 (GBP28) gene expression by C/EBP.
AB  - We have previously reported the isolation of human gelatin-binding protein 28
      (GBP28) gene which is specifically expressed in adipose tissue. The
      transcriptional activity of the flanking region of the GBP28 gene was examined by
      the transient transfection of promoter-luciferase reporter constructs into 3T3
      adipocytes and electrophoretic mobility shift assay. This revealed the existence
      of a protein which binds to the 5'-flanking region of the GBP28 gene in nuclear
      extracts from human adipose tissue, but not in nuclear extracts from mouse liver.
      The C/EBP sites contained in this region are thought to take part in the
      regulation of GBP28 gene expression.

PMID- 10598020
TI  - Fas-mediated apoptosis is enhanced by glycyrrhizin without alteration of caspase
      3-like activity.
AB  - We demonstrate that glycyrrhizin (GL) enhanced Fas-mediated apoptotic body
      formation and DNA fragmentation in T cell lines although GL alone did not induce
      apoptosis. The enhancement effect of Fas-mediated apoptosis by GL was dose
      dependent above 0.3 microM. Time course study revealed that simultaneous co
      treatment of GL and anti-Fas antibody was crucial for the enhancement of
      apoptosis and pretreatment with GL was not effective. Anti-Fas antibody elicited
      caspase-3-like activity. However caspase-3-like activity with co-treatment of GL
      and anti-Fas antibody was the same level as the antibody alone. Glycyrrhetic
      acid, the aglycon of GL, did not enhance Fas-mediated apoptosis. The amphipathic
      property of GL might enable it to interact with the plasma membrane and lead to
      the enhancement of apoptosis.

PMID- 10598021
TI  - Inhibition of listeriolysin O-induced hemolysis by bovine lactoferrin.
AB  - Lactoferrin (LFR) plays an important role in the anti-microbial defense through
      iron binding, lipopolysaccharide binding and immunomodulation. In this study, we
      demonstrate that bovine LFR specifically inhibits the hemolytic activity of
      listeriolysin O (LLO) produced by Listeria monocytogenes. The hemolytic activity
      of LLO was completely inhibited in the presence of bovine LFR that was highly
      purified on two cation-exchange columns, whereas that of streptolysin O or
      perfringolysin O was not inhibited at all. A rabbit anti-LFR antibody canceled
      this inhibitory activity of bovine LFR. Although human transferrin exhibits 62%
      amino acid identity with bovine LFR, human apo-transferrin could not inhibit LLO
      induced hemolysis. An increase in the concentration of FeCl3 or the Fe3+
      saturation of bovine LFR, however, slightly reduced its inhibition of the
      hemolysis. The inhibitory activity of bovine LFR was dependent on pH, since it
      was observed under neutral and alkali conditions, but not under acidic
      conditions. These results suggest that the inhibition of LLO-induced hemolysis by
      bovine LFR is influenced by pH and iron ions, both of which may lead to
      conformational changes of LFR.

PMID- 10598022
TI  - Effect of dextran derivatives on arginine amidase activities released from
      isolated rabbit arteries.
AB  - In the present research we examined the levels and types of arginine amidase
      activities that were released from isolated rabbit arteries treated with heparin
      or chondroitin sulfate. Heparin accelerated the release of arginine amidase
      activity from the isolated rabbit ear artery, the induction was not significant;
      a slight increase in activity was observed in the level of arginine amidase
      released from isolated rabbit aorta, but no significant difference was observed.
      On the other hand, it was revealed that the addition of chondroitin sulfate,
      accelerated this release from isolated rabbit ear artery with 5% significant
      differences. After the addition of chondroitin sulfate, the arginine amidase
      activity released from isolated rabbit arteries was analyzed using various
      affinity adsorption methods. This analysis confirmed the presence of two types of
      fibrinolytic enzymes: plasminogen/plasmin activity and plasminogen activators,
      but no thrombin was detected.

PMID- 10598023
TI  - The anticonvulsive effect of glutathione in mice.
AB  - To explore the role of glutathione as a neuromodulator, we investigated effects
      of reduced (GSH) and oxidized glutathione (GSSG) on drug-induced convulsions in
      mice. Intracerebroventricular administration of GSH or GSSG (10-300 nmol) did not
      produce convulsions. When GSH was administered prior to subcutaneous
      administration of pentylenetetrazol (80 mg/kg), it significantly inhibited
      pentylenetetrazol-induced convulsions. The inhibitory effect of GSH was dose
      dependent, and mimicked by GSSG. In addition, neither GSH nor GSSG affected
      convulsions induced by subcutaneous administration of N-methyl-DL-aspartate (400
      mg/kg). These findings suggest that glutathione has a specific anticonvulsive
      effect.

PMID- 10598024
TI  - Suppressive effects of Hochu-ekki-to, a traditional Chinese medicine, on IgE
      production and histamine release in mice immunized with ovalbumin.
AB  - We examined the effects of Bu-Zhong-Yi-Qi-Tang (Japanese name: Hochu-ekki-to,
      HET), a traditional Chinese medicine, on IgE production and histamine release in
      mice immunized intraperitoneally with a mixture of ovalbumin (OA) and aluminum
      hydroxide (alum adjuvant). Three groups of mice were orally administered 0, 1.7
      or 17 mg of HET on day 13 after the first immunization with a mixture of 1 microg
      OA and 1 mg alum adjuvant. They were again immunized with the same dose of OA
      plus alum adjuvant on day 14. The immunological changes in mice treated with OA
      alone or OA plus HET were examined, and the following findings were obtained. In
      the HET-treated mice, the elevation of anti-OA IgE in serum, and histamine
      release from basophils in blood, were significantly suppressed. A significant
      suppression of interleukin-4 (IL-4) secretion and proliferation of splenic
      lymphocytes in primary culture was also observed. A tendency to suppress the
      elevation of anti-OA IgG1 in serum and interleukin-2 (IL-2) secretion from
      splenic lymphocytes was observed in the HET-treated mice. These findings suggest
      that oral administration of HET suppresses IgE antibody production and histamine
      release in type I allergic reaction in mice immunized with OA plus alum adjuvant;
      this shows the efficacy of HET in treating type I allergic diseases, such as
      asthma.

PMID- 10598025
TI  - Dimethylarsinic acid exposure causes accumulation of Hsp72 in cell nuclei and
      suppresses apoptosis in human alveolar cultured (L-132) cells.
AB  - We previously found that 72-kDa heat shock protein (Hsp72) was induced and
      accumulated in the nuclei, together with DNA damage, in human alveolar epithelial
      (L-132) cells by exposure to dimethylarsinic acid (DMAA), which is a main
      metabolite of inorganic arsenics in mammals. In the present study, the
      intracellular behavior of Hsp72 was investigated during the recovery from the DNA
      damage induced by exposure to DMAA. L-132 cells were exposed to 10 mM DMAA for 3
      h, and then incubated in DMAA-free medium. The induction of Hsp72 by exposure to
      DMAA reached a peak at 6-9 h after removal of DMAA. However, the cell-nuclear
      distribution of Hsp72 was observed until 3 h after the start of DMAA-free
      incubation. We further investigated the appearance of apoptosis of L-132 cells
      after exposure to 10 mM DMAA for 3 h. Internucleosomal DNA fragmentation and
      morphological changes, as criteria for the evidence of apoptosis, were observed 6
      22 h after the start of DMAA-free incubation. The appearance of apoptosis was
      followed by the release of Hsp72 from the cell nuclei. These results suggest a
      possibility that the cell-nuclear Hsp72 may suppress the appearance of apoptosis
      in DNA-damaged cells.

PMID- 10598026
TI  - Studies of the active substances in herbs used for hair treatment. II. Isolation
      of hair regrowth substances, acetosyringone and polyporusterone A and B, from
      Polyporus umbellatus Fries.
AB  - Fractionation of the 50% ethanol extract of Polyporus umbellatus Fries by column
      chromatography on Amberlite XAD-2, silica gel, Sephadex LH-20 and octadecyl
      silica gel (ODS) (C18)) monitored by a hair-regrowth activity assay, afforded
      three active principles, 1, 2 and 3. The structures of 1, 2 and 3 were determined
      as acetosyringone, polyporusterone A, and polyporusterone B by comparison of
      their spectral data with that of authentic samples, respectively. The effects of
      several compounds related to acetosyringone, 3,4-dihydroxybenzaldehyde or
      polyporusterone A on hair regrowth were also investigated.

PMID- 10598027
TI  - New 6-O-acyl isoflavone glycosides from soybeans fermented with Bacillus subtilis
      (natto). I. 6-O-succinylated isoflavone glycosides and their preventive effects
      on bone loss in ovariectomized rats fed a calcium-deficient diet.
AB  - Three new 6-O-acylated isoflavone glycosides were isolated from soybeans
      fermented with Bacillus subtilis (natto) and identified as daidzein 7-O-beta-(6''
      O-succinyl)-D-glucoside (1), genistein 7-O-beta-(6''-O-succinyl)-D-glucoside (2),
      and glycitein 7-O-beta-(6''-O-succinyl)-D-glucoside (3) on the basis of spectral
      data and chemical transformations. During fermentation, the content of the
      isoflavone glycosides first decreased and then increased, whereas the
      corresponding 6''-O-succinyl derivatives first accumulated and then decreased, in
      either soybeans or soybean cooking solution. These changes suggest that enzymatic
      interconversion of isoflavone glycosides and the corresponding 6''-O-succinylated
      derivatives occurs in these media during fermentation. The 6-O-succinylated
      isoflavone glycosides 1, 2 and 3 accounted for 4.8, 7.2 and 0.6%, respectively,
      of the total isoflavones in commercial fermented soybeans (Japanese natto). Oral
      administration of 1 or 2 alone for 4 weeks at a dose of 50 mg/kg/d prevented bone
      loss in ovariectomized (ovx) rats fed a calcium-deficient diet, being as
      effective as the positive controls, daidzin and genistin, respectively. Compound
      1 seems to be proestrogenic, like daidzin, which suppresses bone resorption to
      prevent bone loss after ovariectomy by directly acting on bone sites, while 2
      appears to have a different mechanism of action, like that of genistin.

PMID- 10598028
TI  - Inflammatory action of 8-methoxypsoralen-spermine photoproduct (8-MOP-Spm-P(GFC))
      and effects of various drugs on rat paw edema induced by 8-MOP-Spm-P(GFC).
AB  - The photoproducts produced by irradiating 8-methoxypsoralen (8-MOP) in the
      presence of spermine (Spm) were fractionated using gel filtration chromatography
      (GFC) on a Sephadex G-25 column. As a result, two bands which were characterized
      by the effects on hyaluronidase activity were obtained. The first band strongly
      activated the hyaluronidase, but a second band did not exhibit any effect on the
      enzyme activity. The first and second bands contained photoproducts with
      molecular weights (MW)>2700 and MW<728, respectively, determined by the GFC
      method. The photoproducts, 8-MOP-Spm-P(GFC) obtained from the first band, but not
      the photoproducts with lower MW from the second band, showed enzyme activating
      action. 8-MOP-Spm-P(GFC) induced paw edema, which was stronger in the first phase
      than the second one in rats, differing from that induced by carrageenin. This
      photoproduct was a substance with lower cell toxicity because it did not cause
      hemolysis on red blood cells or the release of lactic dehydrogenase from mast
      cells in rats. The effects of various drugs on 8-MOP-Spm-P(GFC)-induced edema
      were investigated. As a result, edema formation was inhibited by drugs with an
      anti-histaminic action, such as alimemazine, dl-chlorpheniramine, promethazine,
      ketotifen and azelastine, and with anti-serotonin action such as cyproheptadine.
      On the other hand, tranilast did not show significant inhibition and indomethacin
      showed a tendency to increase its formation. These results suggested that 8-MOP
      Spm-P(GFC) is a new inflammatory substance and is very useful as an agent to
      develop new anti-inflammatory drugs without cyclooxygenase inhibitory action.

PMID- 10598029
TI  - Studies of the time-dependent inactivation of aromatase by 4beta,5beta-epoxy-6
      one and 5beta,6beta-epoxy-4-one steroids under various conditions.
AB  - The time-dependent inactivation of aromatase by epoxy analogs of the good
      aromatase inhibitors, androst-4-ene-6,17-dione (3) and androst-5-ene-4,17-dione
      (7), 4beta,5beta-epoxy and 5beta,6beta-epoxy compounds 10 and 13 and their 19-oxo
      derivatives 11 and 14, was examined in either the presence or absence of NADPH.
      The 4beta,5beta-epoxy-19-oxo steroid 11 along with the 19-methyl-5beta,6beta
      epoxide 13 inactivated human placental aromatase in a mechanism-based manner, in
      the presence of NADPH, with rate constants for inactivation (k(inact)) of 0.133
      min(-1) for steroid 11 and 0.100 min(-1) for steroid 13, whereas the two other
      steroids, 10 and 14, did not. On the other hand, none of four epoxides studied
      caused time-dependent inactivation of aromatase in an affinity-labeling manner in
      the absence of NADPH. These results are the first report showing that inhibitors
      11 and 13 are suicide substrates having an epoxyketone structural feature.

PMID- 10598030
TI  - Deconvolution analysis for absorption and metabolism of aspirin in microcapsules.
AB  - We have previously proposed a novel deconvolution method, which can estimate
      first-pass metabolism of orally administered drugs. In the present study, we
      examined whether this deconvolution method is useful for evaluating oral dosage
      forms. The absorption and first-pass metabolism of orally administered aspirin
      formulated in several forms were analyzed. Two types of microcapsules consisting
      of Eudragit L100 alone and Eudragit L100/ethylcellulose (4:6) were prepared as
      sustained release formulations, for comparison with aspirin in powder form. The
      deconvolution analysis revealed that absorption of aspirin was sustained by
      encapsulating it in microcapsules. Interestingly, it also revealed that the
      percentage metabolized during absorption was different among the three types of
      formulations. Thus, the deconvolution method has enabled a comprehensive analysis
      of orally administered drugs. This method is believed to contribute to the
      evaluation of oral drug formulations.

PMID- 10598031
TI  - Effect of the opioid antagonist naloxone on the regional metabolic rate for
      glucose in the conscious rat brain.
AB  - The effect of naloxone, a potent and specific opioid antagonist, on cerebral
      glucose utilization was investigated in conscious rat. For quantitative
      evaluation of the functional activity in brain, the regional cerebral metabolic
      rate for glucose (rCMRglc) was measured by the double tracer technique, using
      [14C]2-deoxyglucose and [3H]3-o-methylglucose. Intravenous administration of
      naloxone significantly increased rCMRglc in the medulla and thalamus at a dose of
      1 or 10 mg/kg, and in the cerebral cortex, midbrain and cerebellum at a dose of
      10 mg/kg. Our findings strongly suggest that naloxone by itself affects the
      cerebral functional activity within 10 min of administration.

PMID- 10598032
TI  - Comparative study of autologous fibrin glues prepared by cryo-centrifugation,
      cryo-filtration, and ethanol precipitation methods.
AB  - To establish a speedy preparation method for the fibrinogen-rich fraction (FRF)
      from autologous plasma using fibrin glue, we compared the concentrations and
      yields of coagulation factors in FRF prepared by 3 methods. Human plasma from
      healthy volunteers was divided into 3 samples. Two samples were frozen at -20
      degrees C in a freezer and defrosted in a 4 degrees C water bath. One sample of
      defrosted plasma was centrifuged and FRF was obtained (C method). Another sample
      of defrosted plasma was filtered and FRF was obtained (F method). The last sample
      was treated with cold ethanol(1/10) in a 4 degrees C water bath and FRF was
      obtained after centrifugation (E method). The concentrations of fibrinogen,
      fibronectin, factor XIII, and plasminogen in each obtained FRF were measured and
      yields were calculated. (1) The volume of FRF obtained by the E method was
      greater than that by the C method, but less than that by the F method. While the
      variation in volume obtained by the E method was the lowest among the 3 methods;
      (2) the concentrations of fibrinogen obtained by the E and C method were similar,
      but the yield from the E method was the highest; (3) the concentration and yield
      of fibronectin from the E and C method were similar and were greater than those
      by the F method; (4) the concentration and yield of factor XIII from the E method
      were significantly higher than those from the other methods; (5) the E method
      preparation time was about 1 h, the shortest among the 3 methods. These results
      indicate that high quality FRF from autologous plasma can be prepared easily and
      within 1 h by the E method.

PMID- 10598033
TI  - Antioxidant roles of cellular ubiquinone and related redox cycles: potentiated
      resistance of rat hepatocytes having stimulated NADPH-dependent ubiquinone
      reductase against hydrogen peroxide toxicity.
AB  - Protective effect of the cellular ubiquinone (UQ) reducing system linked to
      cytosolic NADPH-dependent ubiquinone reductase (NADPH-UQ reductase) against
      hydrogen peroxide (H2O2)-induced lipid peroxidation was investigated using UQ and
      control hepatocytes freshly isolated from rats injected with UQ-10 and the
      vehicles 14 d in advance, respectively. The UQ hepatocytes had higher levels of
      ubiquinol (UQH2)-10 content and NADPH-UQ reductase activity than the control
      hepatocytes but did not differ in other antioxidant factors from the latter
      cells. The UQ hepatocytes exhibited higher cell viability and lower release of
      lactate dehydrogenase than the control hepatocytes when they were exposed to H2O2
      of up to 100 mM for 1 h at 37 degrees C. Furthermore, the formation of
      thiobarbituric acid reactive substances (TBARS) by H2O2 was almost completely
      inhibited in the UQ hepatocytes. Decreases in UQH2 and alpha-tocopherol contents
      and NADPH-UQ reductase activity by H2O2 exposure were observed in both types of
      the hepatocytes, but those levels in the UQ hepatocytes after the exposure were
      still higher than in the control hepatocytes. The decreases in ascorbic acid,
      reduced glutathione and protein thiol contents and DT-diaphorase activity by H2O2
      were not different between in the two types of hepatocytes. Antioxidant enzyme
      activities of catalase, superoxide dismutase, glutathione peroxidase, glutathione
      S-transferase and glutathione reductase in the hepatocytes were not inhibited by
      H2O2. From these results, it was concluded that the cellular UQ reducing system
      linked to cytosolic NADPH-UQ reductase functions mainly as an antioxidant defense
      for cellular membranes.

PMID- 10598034
TI  - Inhibitory activities of 2-pyridinecarboxylic acid analogs on phytogrowth and
      enzymes.
AB  - Five 2-pyridinecarboxylic acid-related compounds (1, 2 and 5-7) showed
      germination inhibition against the seed of Brassica campestris L. subsp. rapa
      HOOK fil et ANDERS at a concentration of 5.0 x 10(-4) M. These compounds also
      demonstrated inhibitory activity on the growth of the root of this plant at a
      concentration of 3.0 x 10(-4) M; among these compounds, 2-pyridylacetic acid (5)
      showed the strongest inhibitory activity, and the effect was slightly stronger
      than that of sodium 2,4-dichlorophenoxyacetate (2,4-D) used as a positive
      control. The amounts of chlorophyll in the cotyledons of this plant treated with
      these active compounds was lower than that of the control group. Four compounds
      (1 and 5-7) with germination inhibition also showed inhibitory activities against
      alpha-amylase and carboxypeptidase A, and 5 was the strongest inhibitor toward
      both enzymes.

PMID- 10598035
TI  - Effect of propolis extract on D-galactosamine-induced hepatic injury in rats.
AB  - The preventive effect of propolis extract on D-galactosamine-induced hepatic
      injury was examined in rats. Serum aspartate aminotransferase (AST) and alanine
      aminotransferase (ALT) activities were significantly increased at 24 h after
      intraperitoneal injection of D-galactosamine (400 mg/kg) in the animals. Propolis
      extract was administered orally three times in doses of 3 or 30 mg/kg at 18 h and
      1 h before and 8 h after D-galactosamine injection. The extract itself and the
      vehicle alone (dextran) caused no significant changes in serum AST or ALT
      activities. Treatment with the extract dose-dependently prevented the increases
      in serum AST and ALT activities induced by D-galactosamine, and significant
      inhibition was observed at a dose of 30 mg/kg. These results suggested that
      propolis extract may have an ameliorating effect on hepatic dysfunction.

PMID- 10598036
TI  - Involvement of serotonin in zimelidine-induced hyperglycemia in mice.
AB  - Effects of a selective serotonin reuptake inhibitor, zimelidine, on plasma
      glucose was studied in mice. Zimelidine dose-dependently induced hyperglycemia,
      although it did not change insulin levels. To determine the involvement of the
      serotonergic system in zimelidine-induced hyperglycemia, effects of the 5-HT
      depleter p-chlorophenylalanine(pCPA) were examined. pCPA significantly reduced
      zimelidine-induced hyperglycemia. This suggests that zimelidine-induced
      hyperglycemia is mediated by the serotonergic system through its 5-HT reuptake
      inhibition.

PMID- 10598037
TI  - Substance P causes adhesion of neutrophils to endothelial cells via protein
      kinase C.
AB  - The sensory neuropeptide substance P is known to be involved in neurogenic
      inflammation. We examined the effect of substance P on neutrophil adhesion to
      human umbilical vein endothelial cells (HUVEC). Stimulation of HUVEC with
      substance P increased their adhesion to neutrophils in a time- and concentration
      (10(-10)-10(-7) M)-dependent manner. The adhesion was inhibited by the tachykinin
      NK1 receptor antagonist (+)-(2S,3S)-3-(2-Methoxybenzylamino)-2-phenylpiperidine
      (CP-99,994) and also by the protein kinase C inhibitors 1-(5
      Isoquinolinesulfonyl)-2-methyl piperazine (H-7) and bisindolylmaleimide (BIM),
      but not by the protein kinase A inhibitor N-12-(p-Bromocinnamylamino) ethyl]-S
      isoquinoline sulfonamide (H-89). These results indicate that substance P induces
      adhesion of neutrophils to HUVEC by activation of protein kinase C via the NK1
      receptor on the HUVEC.

PMID- 10598038
TI  - Purification and some properties of hamster liver aldehyde oxidase.
AB  - Aldehyde oxidase was purified from hamster liver cytosol by ammonium sulfate
      fractionation, chromatography on DEAE-cellulose and Phenyl-Toyopearl, and HPLC
      gel filtration on TSK-gel G3000SW(XL) column. The purified enzyme was homogeneous
      by the criterion of sodium dodecyl sulfate-polyacrylamide gel electrophoresis
      (SDS-PAGE). Its molecular weight was determined to be 144800 by SDS-PAGE and
      288000 by HPLC gel filtration. The isoelectric point was pH 5.1. The apparent Km
      and Vmax for benzaldehyde and 2-hydroxypyrimidine were 19.0 and 4.4 microM, and
      165 and 211 nmol/min/mg protein, respectively. The benzaldehyde oxidase activity
      was markedly inhibited by menadione and chlorpromazine. The substrate specificity
      was different from those of the enzymes from other animals.

PMID- 10598039
TI  - Studies of the active substances in herbs used for hair treatment. III. Isolation
      of hair-regrowth substances from Polygara senega var. latifolia TORR. et GRAY.
AB  - Four active principles, 1, 2, 3 and 4, were isolated from Polygara senega var.
      latifolia TORR. et GRAY by a combination of partition and column chromatography
      on silica gel and octadecyl silica gel (ODS), monitored by a hair-regrowth
      activity assay. Compounds 1, 2, 3 and 4 were identified as senegose A, senegin
      II, senegin III, and senegasaponin b by comparison of their spectral data with
      those of authentic samples.

PMID- 10598040
TI  - Effect of the methanolic extract of Glinus lotoides on Dalton's ascitic lymphoma.
AB  - The antitumour activity of the methanolic extract of Glinus lotoides (MGL) has
      been evaluated against Dalton's ascitic lymphoma (DAL) in Swiss albino mice. A
      significant enhancement of mean survival time of tumour bearing mice and
      peritoneal cell count in normal mice was observed with respect to the control
      group. When these MGL treated animals underwent i.p. inoculation with DAL cells,
      tumour cell growth was found to be inhibited. After 14 d of inoculation, MGL is
      able to reverse the changes in the haemotological parameters, protein and packed
      cellular volume consequent to tumour inoculation.

PMID- 10598041
TI  - Characterization of ocular pharmacokinetics of tilisolol after instillation into
      anesthetized rabbits.
AB  - The purpose of this study was to characterize the ocular pharmacokinetics of a
      beta-blocker, tilisolol, after instillation into anesthetized rabbits using a
      mathematical model including a diffusion process. The samples were analyzed by
      HPLC. Anesthetized rabbit was used as a model of tear secretion deficiency.
      Anesthetized rabbits showed higher drug concentration in the tear fluid and
      aqueous humor after instillation than unanesthetized rabbits. A mathematical
      model including a diffusion process and in vivo penetration parameters well
      described the concentrations of tilisolol in the aqueous humor after instillation
      in anesthetized rabbits.

PMID- 10598042
TI  - Prostate-specific antigen found in type I breast cyst fluids is a secretory
      product of the apocrine cells lining breast gross cysts.
AB  - Prostate-specific antigen (PSA), a serine protease thought to be exclusively
      produced by the prostate epithelial cells, has been recently found in human
      breast tissues and fluids. PSA in breast cancer is associated with the presence
      of steroid-hormones and receptors, and its presence seems to be a favourable
      prognostic indicator. In order to clarify whether the cells lining breast cysts
      may represent the source of PSA found in human breast cyst fluid, we performed an
      ultrastructural immunolocalization of PSA in the cells surrounding Type I breast
      cysts, obtained from breast cyst fluids of women affected by breast gross cystic
      disease, the most commonly occurring benign breast lesions associated with
      increased cancer risk. These apocrine cells show morphological features typical
      of actively synthesizing and secreting cells, and a PSA labelling distributed on
      free ribosomes, RER cisternae, and secretory granules, indicating that the
      metabolically active apocrine cells lining the Type I cysts are responsible for
      the production and secretion of PSA in Type I breast cyst fluids. The synthesis
      and intracystic accumulation of this serine protease in biosynthetically active
      apocrine Type I cysts can play an important role in the natural history of breast
      gross cystic disease as well as in the mechanism of cyst evolution.

PMID- 10598043
TI  - Unfavourable change in mammographic patterns and the breast cancer risk factors.
AB  - The purpose of the study was to estimate the incidence of unfavourable
      mammographic pattern by risk factors of breast cancers. Data consisted of 1890
      Finnish women with mammographic pattern of either N1 or P1 (Wolfe's
      classification) at the initial screening. The screening was repeated every second
      year from 1982 to 1990 and at each screening round the mammographic pattern was
      assessed. The incidence rate of P2,DY pattern was 1.9/100 woman years. The
      incidence of P2,DY pattern was significantly related to age. The age-adjusted
      odds ratio (OR) (based on logistic regression) was 2.0 (95% CI 1.0-3.9) among
      women with hormonal replacement therapy (HRT), 0.6 (95% CI 0.4-0.9) among
      postmenopausal women, 0.2 (95% CI 0.1-0.4) among women with large breasts and 0.2
      (95% CI 0.1-0.3) among women with large body mass index (BMI). After multivariate
      adjustment by logistic regression only the effect of BMI remained statistically
      significant, odds ratio of P2,DY pattern for women with BMI 25 or more was 0.2
      (95% CI 0.1-0.6) compared to women with BMI less than 20.

PMID- 10598044
TI  - 17Beta-hydroxysteroid dehydrogenases in normal human mammary epithelial cells and
      breast tissue.
AB  - 17Beta-hydroxysteroid dehydrogenase activity represents a group of several
      isoenzymes (17HSDs) that catalyze the interconversion between highly active
      17beta-hydroxy- and low activity 17-ketosteroids and thereby regulate the
      biological activity of sex steroids. The present study was carried out to
      characterize the expression of 17HSD isoenzymes in human mammary epithelial cells
      and breast tissue. In normal breast tissues 17HSD types 1 and 2 mRNAs were both
      evenly expressed in glandular epithelium. In two human mammary epithelial cell
      lines, mRNAs for 17HSD types 1, 2 and 4 were detected. In enzyme activity
      measurements only oxidative 17HSD activity, corresponding to either type 2 or
      type 4 enzyme, was present. The role of 17HSD type 4 in estrogen metabolism was
      further investigated, using several cell lines originating from various tissues.
      No correlation between the presence of 17HSD type 4 mRNA and 17HSD activity in
      different cultured cell lines was detected. Instead, oxidative 17HSD activity
      appeared in cell lines where 17HSD type 2 was expressed and reductive 17HSD
      activity was present in cells expressing 17HSD type 1. These data strongly
      suggest that in mammary epithelial cell lines the oxidative activity is due to
      type 2 17HSD and that oxidation of 17beta-hydroxysteroids is not the primary
      activity of the 17HSD type 4 enzyme.

PMID- 10598045
TI  - The effect of combining aromatase inhibitors with antiestrogens on tumor growth
      in a nude mouse model for breast cancer.
AB  - We have previously established a model for postmenopausal, hormone-dependent
      breast cancer in nude mice which is responsive to both antiestrogens and
      aromatase inhibitors. In this model, MCF-7 human breast carcinoma cells
      transfected with the aromatase gene (MCF-7CA) synthesize sufficient estrogen to
      form tumors in ovariectomized nude mice. In the present study we used this
      intratumoral aromatase model to investigate the effects on tumor growth of the
      new nonsteroidal aromatase inhibitors letrozole (CGS 20,267) and anastrozole (ZD
      1033) and the antiestrogens tamoxifen (ICI 47,474) and faslodex (ICI 182,780).
      Furthermore, we determined whether the inhibition of estrogen synthesis together
      with inhibition of estrogen action would be more effective in controlling breast
      tumor growth. The results of our studies indicate that the aromatase inhibitors
      anastrozole and letrozole, as well as the new pure antiestrogen faslodex, have
      potent antitumor effects in the mouse model. In the treatment of mice with
      mammary tumors, letrozole was more effective in suppressing tumor growth than
      anastrozole. This was consistent with the Ki values of these inhibitors against
      placental aromatase and the IC50 values in cell culture (MCF-7CA), which
      indicated the greater potency of letrozole as an aromatase inhibitor. Letrozole
      also had greater antitumor effects than tamoxifen and faslodex. The antitumor
      effect of letrozole was substantial, making it difficult to detect any additional
      effect on the tumors when letrozole was combined with the antiestrogens. However,
      the combined treatment of anastrozole + tamoxifen and anastrozole + faslodex also
      did not increase efficacy compared to the aromatase inhibitor alone. In addition,
      combining the two antiestrogens did not suppress tumor growth more effectively
      than faslodex alone. Our results show that treatment with the combinations of
      aromatase inhibitors with either tamoxifen or faslodex are not more effective in
      blocking estrogen stimulation of tumor growth than the aromatase inhibitors
      alone.

PMID- 10598046
TI  - Color Doppler ultrasound in benign and malignant breast tumors.
AB  - To study the flow indices of color Doppler ultrasound in the differentiation of
      malignant and benign breast tumors, data of 1124 female patients with breast
      lesions were analyzed. Of 1124 breast lesions, 590 (525%) were benign and 534
      (47.5%) were malignant. Color Doppler scanning detected vascularity in 505
      (85.6%) of benign lesions and 509 (95.3%) of malignant tumors. The tumors without
      detectable vascularization (1.9 +/- 0.1 cm) were significantly (p < 0.0001)
      smaller than the tumors with vascularization (2.7 +/- 0.1 cm). The age of the
      patients with malignant tumors was older than that of the patients with benign
      lesions. The size of malignant tumors was significantly larger than that of
      benign lesions. Significantly higher values of vessel number, resistance index
      (RI), pulsatility index (PI), and systolic peak flow velocity (Vmax) were found
      in carcinomas but the striking overlap of the values did not allow defining
      cutoff values which allow an accurate differentiation. Vmax did not correlate
      with the size of tumors. When tumors were grouped as T1 (2 cm or less), T2 (>2
      cm, but not >5 cm), and T3 (>5 cm), the results were similar to those of all
      breast tumors. In conclusion, number of vessels, RI, PI, and Vmax do not provide
      accurate differentiation of benign and malignant tumors. However, average values
      of these flow indices of malignant tumors were significantly larger than those of
      benign lesions. Tumors with larger values of vessel number, RI, PI or Vmax
      require further studies to disclose the possibility of malignant tumors.

PMID- 10598047
TI  - Phase II study of cisplatin and 5-fluorouracil in previously treated metastatic
      breast cancer: an Eastern Cooperative Oncology Group study (PA 185).
AB  - PURPOSE: The present study was conducted to investigate the efficacy and toxicity
      of a cisplatin and 5-fluorouracil (5-FU) combination in previously treated
      advanced breast cancer. METHODS: Thirty-six women with recurrent metastatic
      breast cancer were entered on a phase II study of 5-FU 1000 mg/m2/day given
      intravenously as a continuous infusion on days 1-3 and cisplatin 30 mg/m2/day
      given intravenously over 1 h on days 2-4, repeated every 21 days. All subjects
      had received one previous chemotherapy regimen for metastatic disease and either
      progressed during treatment or relapsed after responding to previous
      chemotherapy. Fourteen patients had also received previous adjuvant chemotherapy,
      17 patients had previous radiation therapy, and 29 patients had previous hormonal
      therapy. RESULTS: Among 32 response-evaluable patients, there were 10 partial
      remissions (31%) and 1 complete remission (3%), with an overall objective
      response rate of 34%. Median duration of response was 4 months. Median survival
      was 10.5 months for responders and 9.5 months for the entire group. Toxicity was
      mild to moderate in most patients. Overall twelve patients experienced grade 3
      toxicity (10 hematologic, 1 mucositis, and 2 nausea). There were no grade 4 or 5
      toxicities. CONCLUSION: Infusional cisplatin and 5-FU is a well tolerated and
      active regimen in women with previously treated advanced breast cancer.

PMID- 10598048
TI  - 5-HT3 antiemetic therapy for patients with breast cancer.
AB  - Antiemetic treatment should be considered for breast cancer patients receiving
      moderately emetogenic chemotherapy. Although the extent of chemotherapy-induced
      emesis is largely dependent on the emetogenic potential of the specific agents
      employed, patient characteristics such as age and sex also contribute. Recent
      clinical studies show that treatment with the currently available 5-HT3
      antagonists effectively reduces the incidence of chemotherapy-induced nausea and
      vomiting and improves quality of life in a substantial number of these patients.
      A Medline search from 1994 through February 1998 identified clinical trials that
      included previously untreated breast cancer patients using antiemetic therapy
      such as granisetron, ondansetron, dolasetron, and metoclopramide. The studies
      reviewed here indicate that the antiemetic efficacy of 5-HT3 antagonists is
      equivalent in previously untreated patients receiving moderately emetogenic
      chemotherapy for breast cancer, depending on the doses and schedules utilized. In
      particular, two comparative studies of granisetron and ondansetron with specific
      data for breast cancer patients showed that both agents eliminate nausea in
      approximately 50%, and vomiting in 60-70% of these patients, with the higher
      values observed when steroids were added to the 5-HT3 receptor antagonist
      regimen. Although the chemotherapy regimens employed for breast cancer are
      considered only moderately emetogenic, these regimens account for 60-90% of
      patients experiencing nausea and vomiting. The most recent clinical studies
      demonstrate that 5-HT3 antagonists can significantly reduce the incidence of
      nausea in breast cancer patients receiving moderately emetogenic chemotherapy and
      should be employed in this setting.

PMID- 10598049
TI  - Glycogen-rich carcinomas of the breast display unique characteristics with
      respect to proliferation and the frequency of oligonucleosomal fragments.
AB  - We determined the proliferation rate and apoptotic activity of glycogen-rich
      carcinomas of the breast as opposed to non-clear cell tumors by means of MIB-1
      immunohistochemistry and in situ detection of oligonucleosomal fragments (TUNEL
      reaction). The retrospective biopsy series included six invasive clear cell
      carcinomas of the glycogen-rich type as well as 15 randomly selected cases of
      invasive ductal carcinoma without evidence of glycogen storage. Three patients in
      the clear cell group and seven patients in the control cohort developed lymph
      node metastasis. The MIB-1 labeling index of glycogen-rich carcinomas averaged
      9.05%, while that of the controls was 30.03%. Apoptotic nuclei were present in a
      mean of 1.26% of glycogen-rich carcinoma cells. The control tumors exhibited an
      average apoptotic frequency of 5.85%. Tumor size, hormone receptor status, and
      presence or absence of lymph node involvement were found not to correlate with
      either proliferation or apoptosis. We conclude that glycogen-rich breast
      carcinomas are characterized by a peculiar 'low proliferation-low apoptosis' cell
      kinetic profile. The aggressive clinical behavior of these neoplasms may possibly
      be accounted for by an ineffective apoptotic elimination of otherwise slowly
      proliferating tumor cells.

PMID- 10598050
TI  - Staging efficacy of breast cancer with sentinel lymphadenectomy.
AB  - Seventy-two patients underwent dye-guided or dye- and gamma probe-guided sentinel
      lymphadenectomy (SLND) followed by complete axillary lymph node dissection
      (ALND). The results of imprint cytology, frozen sections, and permanent sections
      of the sentinel lymph node (SLN) were compared to each other and to the
      histologic findings in the nonsentinel nodes. The SLN was identified in 62 (88%)
      of 72 patients. Evaluation of the SLN on the permanent sections yielded a
      diagnostic accuracy of 95%, a sensitivity of 89%, and a specificity of 100%,
      although the reliability of SLN diagnosis using frozen sections or imprint
      cytology is limited. Therefore, it may be concluded that SLND with multiple
      sectioning and histopathologic examination of the SLNs can predict the presence
      or absence of axillary-node metastases in patients with breast cancer. However,
      further studies will be needed to investigate the value of SLND in respect to the
      long-term regional control and any possible detriment or benefit to survival,
      before it can replace routine ALND as the preferred staging operation for
      operable breast cancer.

PMID- 10598051
TI  - Towards a greater understanding of the pathogenesis of holoprosencephaly.
AB  - Holoprosencephaly is a malformation of the cerebral hemispheres resulting in the
      absence of the inter-hemispheric fissure along with other defects of brain
      development. Frequently midline defects of the craniofacial structures are also
      present. This malformation sequence has been of interest for many years because
      of the well recognized genetic and environmental pathogeneses, although the
      molecular pathogenesis remained elusive. Recent studies have begun clarifying the
      molecular pathogenesis of holoprosencephaly. Herein is reviewed the syndromes
      associated with holoprosencephaly, the pathology of this disorder, genetic and
      environment factors, and a current understanding of the molecular pathogenesis of
      this disorder.

PMID- 10598052
TI  - Stereotyped behaviours in blind children.
AB  - Stereotyped behaviours occur frequently in blind children. Most authors attribute
      stereotyped mannerisms to factors such as hospitalisation, motor limitations, and
      reduced capacity for exploration. There seems to be a specific association
      between blindness and behavioural mannerisms, such as eye pressing and eye
      poking, which have been observed in children with peripheral blindness. We
      studied the prevalence of stereotyped motor behaviours in a sample of
      congenitally blind children with and without other neurodevelopmental
      disabilities in order to assess the types and features of such stereotyped
      behavioural traits. Twenty-six congenitally blind children (11 male and 15
      female) were assessed through videotape recording and through a questionnaire
      focusing on the type, frequency, form of manifestation and duration of the
      children's stereotyped behaviours. Stereotyped behavioural traits were observed
      in 19 (73%) of the patients. Stereotyped behaviours most frequently observed were
      body rocking (8; 30.7%), repetitive handling of objects (8; 30.7%), hand and
      finger movements (7; 26.9%), eye pressing and eye poking (8; 30.7%), and lying
      face downwards (6; 22.8%) and jumping (3; 11.4%). We found that a reduction in
      stereotyped behavioural traits could be obtained by stimulating appropriate
      adaptive behaviour in children, while these behaviours were increased by
      restricted environmental conditions, reduced sensory stimulation and reduced
      motility.

PMID- 10598053
TI  - Cyclical fluctuations in blood pressure, heart rate and cerebral blood volume in
      preterm infants.
AB  - Many recently published papers describe cyclical changes of cerebral circulatory
      variables, mainly in cerebral blood flow velocity (CBFV) performed with Doppler
      sonography. In this paper we focus on another important variable of cerebral
      circulation: on cerebral blood volume (CBV) measured by near infrared
      spectrophotometry (NIRS). In a retrospective analysis of NIRS measurements in 20
      preterm infants (median 27 3/7 weeks of gestation), the dominating frequencies
      and prevalence of cyclical changes of CBV and its possible correlation with
      peripheral circulatory variables (mean arterial pressure and heart rate) was
      examined. In 19 out of the 20 infants cyclical changes of CBV were found within a
      frequency range of 2-4.7 cycles/min which is comparable to the results of the
      Doppler studies describing fluctuations in CBFV. A dominating frequency of heart
      rate (HR), was found only in 12 out of 20 infants, and it was with 2.1-3.8
      cycles/min in a similar range compared to CBV. In mean arterial blood pressure
      (MABP), however we detected cycles with longer periods every 1-2.5 min in 14 out
      of 20 infants. There was a significant coherence between MABP/CBV and HR/CBV. The
      area under the coherence curve, however, was significantly larger between MABP
      and CBV as compared to HR and CBV (P = 0.0007, Wilcoxon signed-rank test).

PMID- 10598054
TI  - Stages of increased cerebral blood flow accompany stages of rapid brain growth.
AB  - Stages of increased cerebral blood flow accompany stages of rapid brain growth
      The existence of stages of rapid brain growth implies the existence of associated
      stages of increased cerebral blood flow (CBF) to supply the substances and energy
      needed for the added brain weight. Studies in the literature give developmental
      data for CBF in humans which show stages of increased cerebral blood flow at ages
      starting just preceding and/or coincident with the ages of the rapid brain growth
      stages. Confirmation of the implication for one of the earliest stages is also
      found in PET data. Additionally, data for rodents show a similar association of
      stages of increasing CBF and their brain growth stages. Thus, to the accuracy of
      the data, the implication is confirmed. Finding stages in cerebral blood flow
      predicts the existence of stages of brain growth. In addition; finding correlated
      blood flow stages also supports the age spans of the stages of rapid brain growth
      in both species. Such correlations also suggest that measurements of blood flow
      anywhere in the body might serve to reveal rapid growth stages in particular
      localities or organs if the blood flow shows significant stages. The ratio of
      energy consumed in brain to that in total body decreases from close to 100% at
      birth to the adult value of about 20% by age 18 years.

PMID- 10598055
TI  - Epilepsy in patients with spastic cerebral palsy: correlation with MRI findings
      at 5 years of age.
AB  - The aim of this study was to determine the relationship between epilepsy and the
      magnetic resonance imaging (MRI) findings in patients with spastic cerebral palsy
      at five years of age. We studied 14 patients with congenital anomaly and 116 with
      perinatal injury. The patients with perinatal injury were subdivided into two
      groups; those with preterm type injury alone (group P), and those with term type
      injury with or without preterm type injury (group T). Epilepsy was found in 37 of
      the 130 patients. The initial type of seizures was partial in 12 patients.
      infantile spasms in 20 and generalized in five. Kaplan-Meier analysis
      demonstrated that patients with congenital anomaly had a higher incidence and an
      earlier onset of epilepsy than those with perinatal injury. Of the patients with
      perinatal injury, group T patients showed a higher incidence and a later onset of
      epilepsy than group P patients.

PMID- 10598056
TI  - Neurological prognosis correlated with variations over time in the number of
      subependymal nodules in tuberous sclerosis.
AB  - In tuberous sclerosis (TS), brain CT reveals subependymal nodules, cortical
      tubers and white matter lesions. This study is a retrospective analysis of the
      relationship between the variations over time in the number of subependymal
      nodules and the clinical course in cases of tuberous sclerosis. Twenty-four
      children with tuberous sclerosis, who attended the National Children's Hospital
      as outpatients, were followed by means of brain CT examinations for 7 years and 1
      month on average. Cranial MRI was also performed in 22 cases. Brain CT disclosed
      subependymal nodules already in early infancy. In almost all cases, the number of
      subependymal nodules gradually increased with age, especially around the frontal
      horn of the lateral ventricle. The increase stopped at around age 10. The cases
      with five or more subependymal nodules at the initial or subsequent CT
      examination ( 17 patients; Group A) exhibited a significantly greater number of
      cortical tubers than those with less than five (five patients; Group B) and had
      white matter lesions unlike Group B. In addition, the number of cases with either
      infantile spasms or mental retardation was significantly higher in Group A than
      Group B (P < 0.005). In conclusion, the number of ventricular subependymal
      nodules may allow prediction of the severity of the cerebral dysfunction in TS.
      Our results suggest that its variation may reflect the degree of the embryologic
      disorder when neuronal cells grow in the early gestational period.

PMID- 10598057
TI  - Sleep abnormalities in mentally retarded autistic subjects: Down's syndrome with
      mental retardation and normal subjects.
AB  - We compared sleep parameters in mentally retarded infantile autism (MRIA) and
      mentally retarded Down's syndrome (MRDS) by means of polysomnography, evaluating
      traditional analysis with particular attention to the phasic components in each
      disorder. Data were compared with those obtained in normal subjects matched for
      age and sex. Mental age, Intellectual Quotient and the Childhood Autism Rating
      Scale were performed to obtain an estimation of the neuropsychological deficit.
      Abnormalities of phasic components of sleep and the presence of REM sleep
      components into non-REM sleep were observed in both MRIA and MRDS even if in
      different ways. In fact, MRDS subjects presented a reduction of REM sleep
      percentage and R index (number of high frequency REMs against number of low
      frequency REMs) and this was positively correlated to a low IQ. Unlike MRDS
      subjects, MRIA subjects did not show any parallelism between intellectual
      abilities and REM sleep deficit. In addition, the presence of undifferentiated
      sleep in autistic subjects implies a maturational deficit that is still present
      in adulthood. Finally, a high R index in MRIA was observed. This finding, which
      is not present in MRDS, could represent an estimation of the disorganized arrival
      of information caused by a dyscontrol or a reduction of inhibitor pathway. With
      reference to sleep mechanisms, our results suggest that the cognitive deficit in
      MRIA may differ from that of MRDS subjects. A maturational deficit of CNS with a
      dysfunction of brainstem monoaminergic neurons could represent the underlying
      mechanism.

PMID- 10598058
TI  - Acute relapsing encephalopathy mimicking acute necrotizing encephalopathy in a 4
      year-old boy.
AB  - A 4-year-old boy showed two episodes of encephalitis/encephalopathy involving
      disturbed consciousness, convulsion, and paresis associated with the elevated
      levels of protein and myelin basic protein of the cerebrospinal fluid. MRI
      studies of the brain revealed symmetrical lesions in the brain stem and thalami
      at the first episode, and additional lesions were found in the cerebellum
      involving both the gray and white matter in the second episode. The intensities
      of MRI lesions were low in T I and high in T2. These episodes were followed by an
      elevation of the anti-viral antibody titers, for influenza A virus during the
      first episode and for adenovirus during the second. In the second episode,
      intravenous methylprednisolone therapy resulted in rapid improvement of his
      neurological signs.

PMID- 10598059
TI  - Cerebral fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography
      (FDG PET), MRI, and clinical observations in a patient with infantile G(M1)
      gangliosidosis.
AB  - The clinical, biochemical, pathological and neuroradiological findings of a 2
      year-old Saudi boy with infantile G(M1) gangliosidosis are reported. The patient
      had a progressive neurologic deterioration, manifesting with developmental
      regression, sensorimotor and psychointellectual dysfunction and generalized
      spasticity that started at 4 months of age. Cherry-red macula, facial dysmorphia,
      hepatomegaly, exaggerated startle response to sounds, skeletal dysplasia, and
      vacuolated foamy lymphocytes that contain finely fibrillar material in addition
      to lamellar membranes and electron-dense rounded bodies were seen. MRI of the
      brain demonstrated mild diffuse brain atrophy and features of delayed
      dysmyelination and demyelination. Brain FDG PET scan revealed a mild decrease in
      the basal ganglia uptake, and moderate to severe decrease in thalamic and visual
      cortex uptake, and an area of increased glucose uptake in the left frontal lobe,
      probably representing an active seizure focus. The functional changes indicated
      by FDG PET scan and the structural abnormalities shown on MRI were found to be
      complementary in the imaging evaluation of infantile G(M1) gangliosidosis.

PMID- 10598060
TI  - Lennox-Gastaut syndrome after a further attenuated live measles vaccination.
AB  - We reported a 2-year-old boy with Lennox-Gastaut syndrome, of which the cause
      could be an adverse effect of further attenuated live (FL) measles vaccine. The
      pre- and peri-natal histories of the patient were uneventful, except that he was
      one of monozygotic twins. He had developed normally until 24 months of life, when
      tonic seizures began on postvaccination day 14 without a preceding episode of
      continuous fever or any neurologic symptoms. The tonic seizures and atypical
      absence have been intractable as to various antiepileptic drugs, while his twin
      brother has experienced no epileptic seizures.

PMID- 10598061
TI  - How should patients with porencephaly and generalized seizures such as West
      syndrome be treated?

PMID- 10598062
TI  - Antiviral therapeutic intervention in poliomyelitis-like syndrome.

PMID- 10598063
TI  - Comment on Rett syndrome and genetic drift, Buhler et al., Brain Dev 1999;21: 175
      178.

PMID- 10598064
TI  - Sleep disorder in Rett syndrome and melatonin treatment.

PMID- 10598065
TI  - Chronic pulmonary paracoccidioidomycosis in the state of Rio Grande do Sul,
      Brazil.
AB  - Since 1942, when paracoccidioidomycosis was first identified in the state of Rio
      Grande do Sul, paracoccidioidal pulmonary lesions became a great concern to
      physicians. The present study focuses on 53 patients diagnosed over a seven-year
      period who presented paracoccidioidal lesions circumscribed to the lungs. These
      patients presented clinical and radiological features that simulated several
      pulmonary infectious and non-infectious conditions. Four unusual cases are
      briefly discussed. A sequence of laboratorial tests should be established for the
      diagnosis of pulmonary paracoccidioidomycosis.

PMID- 10598066
TI  - Differentiation of three biotypes of Malassezia species on human normal skin.
      correspondence with M. globosa, M. sympodialis and M. restricta.
AB  - One hundred and twenty lipid dependent Malassezia spp. isolates were obtained
      from the clinically normal skin of 38 healthy adult volunteers by swabbing three
      different body sites (back, chest and scalp). Ninety-six percent of these strains
      could be grouped into three biotypes on the basis of microscopic, cultural,
      metabolic and biochemical (catalase, esculin and lipase (C-14)) characteristics.
      The differential features were simple to determine and easily reproduced.
      Moreover, the three biotypes were referable to the species M. globosa (biotype
      1), M. sympodialis (biotype 2) and M. restricta (biotype 3). Based on their
      microscopic features, cultural properties and body site locations, we suggest
      that biotype 1 /M. globosa corresponds to the description of Pityrosporum
      orbiculare (round yeast cells with a narrow base, very frequently found on the
      upper trunk), and biotype 3/M. restricta corresponds to the concept of P. ovale
      (oval yeast cells with a broad budding base, located mainly on the scalp).
      Pleomorphic biotype 2/M. sympodialis, most frequently found in the back, does not
      clearly fit into any of the Pityrosporum species.

PMID- 10598067
TI  - Chronic pulmonary histoplasmosis in the State of Rio de Janeiro, Brazil.
AB  - Three cases of chronic pulmonary histoplasmosis affecting aged patients with
      chronic obstructive pulmonary disease are reported. They had a history of
      recurrent episodes of respiratory infection and presented radiological lung
      lesions inducing a misdiagnosis of chronic pulmonary tuberculosis of the adults.
      The diagnosis of histoplasmosis, suggested by the immunodiffusion test and the
      detection of yeastlike cells in smeared and stained sputum, was confirmed by the
      isolation and identification of Histoplasma capsulatum var. capsulatum in
      selective media. The treatment was carried out with amphothericin B and
      ketoconazole or itraconazole. Clinical, radiologic, mycologic and serologic
      improvement was obtained in all the patients. However, relapses occurred within a
      period of 1 to 18 months after the interruption of the treatment. Mycological
      diagnosis and the difficulties observed in the treatment were discussed. In
      addition data on the epidemiology of histoplasmosis in the state of Rio de
      Janeiro, Brazil, were presented.

PMID- 10598068
TI  - Experimental paracoccidioidomycosis in hamsters (Mesocricetus auratus):
      gestational interactions.
AB  - Paracoccidioides brasiliensis is a dimorphic fungus presenting specific steroid
      hormone receptors, both in the yeast and mycelial forms and estrogen inhibits the
      transition from mycelium to yeast. In the acute phase, the disease occurs with
      equal frequency in both sexes but in adults, females are spared. Placental fungal
      infection has been reported, but references to fetal infection have not been
      confirmed. We used 78 Syrian female hamsters divided into 3 groups: GI consisted
      of 30 infected mated females, GII of 20 infected unmated females and GIII of 28
      uninfected mated females. Animals of group I were mated 4 weeks after infection
      and half of them were submitted to cesarean section on day 15 after successful
      mating; the other half was maintained and submitted to cesarean section and
      sacrificed 14 weeks after infection. Half of the animals of group II were
      sacrificed seven weeks and the other half 14 weeks after infection. Uninfected
      animals of group III were treated the same as the animals of group I. The animals
      were infected with strain 18 of P. brasiliensis by the intracardiac route. We
      evaluated the disease by the volume of granulomas in different organs, number of
      fungi in liver and spleen and the immunologic responses [ELISA, Double
      Immunodifusion (DID), Delayed Hypersensitivity Skin Test (DHT) and Macrophage
      Migration Inhibition (MMI)]. We studied the infection through the gestation by
      evaluation of the abortions, morphologic and clinic examinations of the fetuses.
      Our results showed that the infection did not transfer to the fetus through the
      placenta, but the number of abortions was larger among infected females. The
      newborns of GI females were smaller, weighed less and showed little vitality. The
      disease was more severe and disseminated in infected mated females, especially in
      the second sacrifice 14 weeks after inoculation, when the total volume of
      granulomas in them (56.3 mm) was much greater than in the infected unmated
      females (12 mm).

PMID- 10598069
TI  - Fungi associated with black tea and tea quality in the Sultanate of Oman.
AB  - Forty-eight samples of four popular commercial brands of black tea (Camellia
      sinensis L.) were purchased from the local markets in Muscat area, Sultanate of
      Oman. Tea leaves were surveyed for mycoflora. Five fungal species were isolated
      with A. niger as the most dominant in all the brands having percentage
      contamination ranging between 0.66% and 30.34%. Other fungi isolated were
      Aspergillusflavus, Penicillium spp. and Pacelomyces spp. but having average
      percentages of 0.6%, 0.84% and 0.21% respectively. Significant differences were
      found among the batches contaminated by A. niger. None of the 25 A. flavus
      strains screened for aflatoxins were found aflatoxigenic. The total ash, water
      soluble ash, and mineral concentration of the samples were within the British
      standards and were not affected by fungal contamination. The results showed that
      black tea is contaminated by fungi that might constitute health hazards for
      humans. The post harvest contamination of tea could be eliminated or reduced if
      processing is conducted under more hygienic conditions.

PMID- 10598070
TI  - Mycoflora and mycotoxins of Brazilian cashew kernels.
AB  - Kernel samples of common and dwarf Brazilian cashew nuts were highly contaminated
      with field and storage fungi in comparison to healthy ones. In general, dwarf
      cashews were more contaminated than common. A total of 37 fungal species were
      identified. Aspergillus niger was the dominant species with more colonies being
      isolated from dwarf kernels. A. flavus was the next most frequently isolated
      species. Penicillium brevicompactum, and P. glabrum were the most frequently
      isolated penicillia, with higher contamination recorded from dwarf kernels.
      Chaetomium globosum was recorded at a high level. Nine species were recorded from
      cashew kernels for the first time. Multimycotoxin analysis by tlc and hplc were
      positive for mycotoxins and other secondary metabolites particularly from the
      infected samples. Hplc was only carried out on dwarf cashews. Aflatoxins were not
      detected by quantitative high performance thin layer chromatography.

PMID- 10598071
TI  - Lactoferrin concentration in milk of bovine clinical mastitis.
AB  - The lactoferrin (LF) concentration in the milk from dairy cows with clinical
      mastitis was determined to evaluate the relationship between the LF concentration
      (LFC) in milk and the non-specific defensive capability of the udder. The mean
      LFC in 368 milk samples from 319 cows with clinical mastitis was significantly
      higher (p < 0.01) than that of normal cows. The mean LFC in milk from quarters
      infected with Mycoplasma bovis or Staphylococcus aureus was significantly higher
      (p < 0.05) than that of quarters infected with coagulase-negative staphylococci
      (CNS). In Escherichia coli mastitis, the level of LFC in milk from cows with
      peracute mastitis was significantly lower (p < 0.01) than that from cows with
      acute mastitis. In cases of mastitis due to E. coli, the mean LFC in milk from
      cows that needed more than 10 days to recover from the mastitis or were not cured
      was significantly lower (p < 0.05) than that for cows which took less than 10
      days to be cured. The mean LFC in milk from cows with peracute E. coli mastitis
      was significantly lower (p < 0.05) than that for cows with mastitis associated
      with environmental streptococci or CNS, although these low LF levels were
      somewhat increased after 46 h from the occurrence of mastitis. These results
      suggest that the decreased levels of LF in peracute E. coli mastitis may be
      associated with the progress of inflammation in the early phase of mastitis.

PMID- 10598072
TI  - The effect of dexamethasone on some immunological parameters in cattle.
AB  - Immunosuppression as a consequence of acute and chronic stress can increase the
      susceptibility of cattle to a range of infectious diseases. In order to develop a
      panel of immune function assays for investigating the effects of potential
      stressors on immune competence in cattle, the effect of treatment with short- and
      long-acting preparations of the synthetic glucocorticoid dexamethasone was
      examined. Short-acting dexamethasone (dexamethasone sodium phosphate 0.08 mg/kg)
      followed 37 h later by long-acting dexamethasone (dexamethasone-21 isonicotinate
      0.25 mg/kg) was injected intramuscularly and blood was collected to assess immune
      functions at intervals over the subsequent 11 days from 6 treated and 6 control
      Hereford steers. Dexamethasone induced leukocytosis (neutrophilia, eosinopenia,
      lymphopenia, monocytosis), an increased neutrophil:lymphocyte ratio, an elevated
      percentage of CD4+ lymphocytes, a decreased total CD8+ lymphocyte count,
      decreased total and percentage WC1+ lymphocytes, an elevated percentage of IL-2
      receptor alpha (IL-2Ralpha)+ lymphocytes, and an elevated percentage of B
      lymphocytes. In vitro chemotaxis of peripheral blood neutrophils to human C5a and
      ovine IL-8 was increased by dexamethasone treatment. Lymphocyte proliferation in
      the presence of phytohaemagglutinin, and serum concentrations of IgM, but not IgA
      or IgG1, were suppressed by dexamethasone treatment, whereas mitogen-induced
      production of interferon-gamma (IFN-gamma), neutrophil expression of CD18,
      neutrophil myeloperoxidase activity and natural killer (NK) cell activity were
      not influenced by dexamethasone treatment. The results indicate the potential for
      haematology and immune function assays to reflect elevated activity of the
      hypothalamic-pituitary-adrenocortical axis in cattle. Immunological parameters
      may thus provide a useful adjunct to cortisol and behavioural observations for
      assessing the impact of stress on the welfare of cattle.

PMID- 10598073
TI  - Experimental salmonellosis in guinea-pigs: haematological and biochemical
      studies.
AB  - Some haematological and biochemical parameters were studied in guinea-pigs
      infected intraperitoneally with Salmonella dublin 493 at 1 x 10(6) viable cells
      per animal. The infected animals showed a rise in temperature within 24 h,
      followed by depression and loss of body weight. On the 15th day post infection,
      haematological studies revealed a significant increase in the total leukocyte
      count due to both lymphocytosis and neutrophilia, and a decrease in the total
      erythrocyte count and haemoglobin concentration. There was also a significantly
      higher mean corpuscular volume and lower mean corpuscular haemoglobin
      concentration, indicating a macrocytic hypochromic anaemia. The infection caused
      a significant increase in alanine aminotransferase activity and creatinine, blood
      urea nitrogen and globulin concentrations, and a decrease in albumin and
      triiodothyronine. There was no significant effect on serum total protein or on
      thyroxine, or in the activity of aspartate aminotransferase in the serum.

PMID- 10598074
TI  - Factors influencing the bioavailability of peroral formulations of drugs for
      dogs.
AB  - The oral route is presently the preferred route of drug delivery. Poor oral
      bioavailability results in variable concentrations of drugs in the plasma and
      variable pharmacological responses, in addition to higher product costs. The
      unique canine physiology, anatomy and biochemistry makes designing canine dosage
      forms a challenging exercise. This article reviews the physicochemical,
      physiological, pharmacokinetic, pharmacological and formulation factors that can
      influence the drug availability of the oral formulations in dogs in an effort to
      provide a source of data to aid development of canine drug products with superior
      bioavailability.

PMID- 10598075
TI  - Some pharmacokinetic parameters of eprinomectin in goats following pour-on
      administration.
AB  - Some pharmacokinetic parameters of eprinomectin were determined in goats
      following topical application at a dose rate of 0.5 mg/kg. The plasma
      concentration versus time data for the drug were analysed using a one-compartment
      model. The maximum plasma concentration of 5.60+/-1.01 ng/ml occurred 2.55 days
      after administration. The area under the concentration-time curve (AUC) was
      72.31+/-1.15 ng day/ml and the mean residence time (MRT) was 9.42+/-0.43 days.
      Thus, the systemic availability of eprinomectin to goats was significantly lower
      than that for cows. The low concentration of eprinomectin in the plasma of goats
      suggests that the pour-on dose of 0.5 mg/kg would be less effective in this
      species than in cows. Further relevant information about the optimal dosage and
      residues in the milk of dairy goats is needed before eprinomectin should be used
      in this species.

PMID- 10598076
TI  - Some observations on endemic fluorosis in domestic animals in Southern Rajasthan
      (India).
AB  - Chronic fluoride toxicity in the form of osteo-dental fluorosis was observed in
      cattle, buffaloes, sheep and goats from 21 villages of Banswara, Dungarpur and
      Udaipur districts of Southern Rajasthan where the mean fluoride concentration in
      drinking water varied from 1.5 to 4.0 ppm. The prevalence of dental fluorosis in
      calves (< 1 year age) was greater than that in adult cattle and buffaloes. At a
      fluoride concentration in the water of 4.0 ppm, 100% of calves, 65.6% of
      buffaloes and 61.0% of cattle were found to be affected with dental fluorosis to
      varying degrees. In the older group of buffaloes, their teeth were brownish black
      instead of creamy yellow as found in calves and cattle. Out of 780 goats and 564
      sheep, none revealed evidence of osteo-dental fluorosis. The overall prevalence
      of skeletal fluorosis was 8.5%, with the highest prevalence of 29.0% in cattle
      and 37.5% in buffaloes at a fluoride concentration of 3.2 ppm. None of the calves
      were affected with skeletal fluorosis. Intermittent lameness was observed in the
      older group of animals (> 7 years age) at 2.8 ppm fluoride or more in the water.
      None of the fluorotic animals exhibited any apparent evidence of hypothyroidism,
      stunted growth or low milk production. There was no correlation between gender
      and the prevalence of fluorosis, but the prevalence and severity of skeletal
      fluorosis increased with increasing fluoride concentration and age. Possible
      factors causing variation in fluorosis in the cattle and buffaloes in villages
      with identical fluoride concentrations are discussed.

PMID- 10598077
TI  - A simple and reliable protocol for the detection of apple stem grooving virus by
      RT-PCR and in a multiplex PCR assay.
AB  - Primers were identified which amplify specifically a 499 bp fragment in the coat
      protein coding region of apple stem grooving virus (ASGV) genome. These primers
      were used in various RT-polymerase chain reaction (PCR) analyses for the
      detection of ASGV in Chenopodium quinoa, Nicotiana occidentalis, and in species
      of Malus and Pyrus. Isolates of ASGV in Malus and Pyrus from locations in Canada,
      China, Israel, Japan, Nepal, Pakistan, South Africa, and the U.S.A. were reliably
      detected in leaf and bark (budwood) tissue. Storage of the tissues at -80 degrees
      C for more than 4 months did not affect the reliability of detection by
      immunocapture (IC) RT-PCR. Triton-X was not necessary for the detection of ASGV
      by IC/RT-PCR, and it was also possible to combine the antibody incubation and
      virus sap incubation into a single step without any obvious loss in sensitivity.
      A Tube Capture (TC) RT-PCR procedure was developed that eliminated the need for
      antibody binding of the virus. Phosphate buffered saline with 2% PVP was
      identified as the most effective sample-grinding buffer for the detection of ASGV
      by IC/RT-PCR and TC/RT-PCR. TC/RT-PCR facilitated the simultaneous detection
      (multiplex PCR) of ASGV and cherry mottle leaf virus.

PMID- 10598078
TI  - A quantitative PCR method for the assay of HIV-1 provirus load in peripheral
      blood mononuclear cells.
AB  - The use of high activity antiretroviral therapies (HAART) to treat HIV-infected
      patients frequently results in the long-term suppression of plasma virus RNA
      loads below levels detectable by current assays. The measurement of provirus DNA
      load in peripheral blood mononuclear cells provides a means of continuing to
      monitor the efficacy of treatment and the decline in reservoirs of latent virus.
      A quantitative PCR assay was developed for HIV-1 provirus using a three-point
      internal calibrator system to give high reproducibility and accuracy at the low
      copy numbers of provirus seen in clinical samples. Provirus DNA copies are
      related to cell number in the samples using a fluorescent dye-binding assay for
      measurement of input DNA. The assay agreed closely with an end-point dilution PCR
      and gave accurate quantification of extracts from an HIV-1 infected continuous
      cell line containing known provirus copy numbers. The inclusion of a second
      primer set in the LTR region of the HIV-1 genome, optimised to non-clade-B virus
      strains improved the detection and quantification of samples from patients
      infected with genetically divergent virus strains. Application of the assay to
      clinical trial patients showed no relationship between changes in provirus DNA
      loads and plasma virus RNA and changes in provirus load over 24 weeks were small.

PMID- 10598079
TI  - Storage of viruses on filter paper for genetic analysis.
AB  - The purpose of this study was to develop a method to store viruses on filter
      paper without the need for special conditions for future use of the genetic
      material. Two non-enveloped viruses were used as models. Infectious bursal
      disease virus (IBDV), a double-stranded RNA virus that infects chickens, belongs
      to the Birnaviridae family. Hemorrhagic enteritis virus (HEV), with double
      stranded DNA, belongs to the Adenoviridae family. Three different solutions were
      found suitable for loading the virus. The viruses were stored at room temperature
      or at 37 degrees C for periods of 5-30 days. Direct reverse transcription
      polymerase chain reaction (RT-PCR) (without previous extraction of the RNA) was
      carried out on filter paper loaded with IBDV, and fragments of the expected size
      were detected. HEV DNA was extracted from filter paper loaded with purified virus
      or crude tissue. PCR fragments were found to be of similar intensity to those of
      control virus that was kept in a tube at -20 degrees C. This method permits the
      storage and transport of viruses from the field or from clinics to a regional
      laboratory or any laboratory elsewhere, without the need for prior treatment or
      special environmental conditions.

PMID- 10598080
TI  - A solvent-free, rapid and simple virus RNA-release method for potato leafroll
      virus detection in aphids and plants by reverse transcription polymerase chain
      reaction.
AB  - A one-step, rapid and economical method for potato leafroll virus (PLRV) RNA
      release that is applicable to the use on a microcentrifuge scale is described.
      Discs (3-6 mm diameter) from leaves, petioles, stems, and tubers of potato plants
      were incubated in microcentrifuge tubes with detergent solution. The supernatants
      were used directly for reverse transcription (RT) and polymerase chain reaction
      (PCR). Of the seven nonionic detergents of the TritonX series evaluated, Triton
      X405R was the most effective, although X-405 and X-1OOR were also effective in
      releasing PLRV RNA. Application of the detergent method for detecting PLRV in
      greenhouse-grown potato organs (leaves, petioles, stems, tubers) and in field
      grown tubers was demonstrated and compared to the multi-step phenol method. When
      individual aphids, Myzus persicae, were ground in 20 microl of detergent solution
      and supernatants were used for RT-PCR, virus was detected in single aphids in
      undiluted solutions and up to a dilution of 1:4. The concentration of PLRV RNA
      released by the detergent method was substantially lower than that released by
      the phenol method. However, the detergent method was sensitive enough to detect
      PLRV from potato leaves, petioles, and stems 2 weeks after graft inoculation. The
      detergent method was rapid and economical, and has potential for large-scale
      application. The extracts survived over 37 days at room temperature, thus making
      it possible to mail extracts from remote areas lacking specialised RT-PCR
      facilities to a central laboratory for PLRV testing.

PMID- 10598081
TI  - Detection of field isolates of human and animal group C rotavirus by reverse
      transcription-polymerase chain reaction and digoxigenin-labeled oligonucleotide
      probes.
AB  - Rotaviruses (RV) are important etiological agents of acute gastroenteritis in
      infants and young children, as well as the young of a variety of animals
      worldwide. These viruses belong to Reoviridae family and contain a genome of 11
      segments of double-stranded RNA (dsRNA). Two major proteins, VP4 and VP7, encoded
      by genome segments 4 and 7, 8 or 9, respectively, evoke a neutralizing antibody
      response and form the basis for the current classification of group (gp) A
      rotavirus into P (VP4) and G (VP7) serotypes. Although much recent progress has
      been made on the molecular biology of gp C RV, routine methods to detect and
      discriminate human, porcine, and bovine strains are not available widely. In this
      study, a multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) and
      digoxigenin-labeled (dig) oligonucleotide probes using chemiluminescence has been
      developed to detect and discriminate VP7 genes from culture-adapted and field
      isolates of human, porcine and bovine gp C RV. The multiplex RT-PCR and dig
      probes were specific for the VP7 genes of human, porcine and bovine gp C RV and
      allowed detection and characterization of single and mixed infections of porcine
      gp C RV with porcine gp A or gp B rotaviruses. Detection rates for gp C RV were
      more than 50% when compared with polyacrylamide gel electrophoresis. These new
      diagnostic assays may help determine the epidemiological importance of these
      viruses in human and animal infections.

PMID- 10598082
TI  - Infection of the erythroid cell line, KU812Ep6 with human parvovirus B19 and its
      application to titration of B19 infectivity.
AB  - A human parvovirus B19 (B19) infectivity assay was developed using the erythroid
      cell line, KU812Ep6. KU812Ep6 was cloned for high efficiency infection with B19
      in vitro, in the presence of erythropoietin by a limiting dilution method from
      the parent cell line, KU812. B19 was effectively propagated in KU812Ep6 and was
      detected for B19 antigens, VP1 and VP2. The titers of B19 positive sera measured
      with KU812Ep6 cells were in the range of 10(6) to 10(8) TCID50 ml. This KU812Ep6
      infectivity assay had a 10(3)-10(4.5) higher sensitivity than the colony forming
      unit-erythroid (CFU-e) injury assay. It was calculated that one TCID50 needed
      10(3) B19 genome copies, judging from the infectivity assay and semi-quantitative
      PCR. The KU812Ep6 infectivity assay was also used to determine infectivity of B19
      in vitro, and to evaluate inactivation, as well as clearance of the virus. The
      inactivation of B19 by heating was carried out and infectivity declined from
      10(4) TCID50 ml to < 10 TCID50 ml (lower limit of detection) at 60 degrees C for
      3 h or at 70 degrees C for 30 min, but only decreased to 10(2.5) TCID50 ml at 50
      degrees C for 8 h.

PMID- 10598083
TI  - Improved detection of five closely related ruminant alphaherpesviruses by
      specific amplification of viral genomic sequences.
AB  - The detection and discrimination of five closely related ruminant
      alphaherpesviruses, bovine herpesvirus 1 (BHV-1), bovine herpesvirus 5 (BHV-5),
      caprine herpesvirus 1 (CapHV-1), cervine herpesvirus 1 (CerHV-1), and rangiferine
      herpesvirus 1 (RanHV-1), were achieved by the development of specific PCR
      systems. The highly variable N-terminal of the glycoprotein C was chosen to
      select the diagnostic primers, except for the CerHV-1 primers, which targeted the
      glycoprotein D region. All the assays proved specific since no heterologous virus
      was amplified. BHV-1 and BHV-5 were detected by using the same PCR assay and the
      different sizes of the amplification products allowed their identification on
      agarose gels. The practical diagnostic applicability of the novel PCR assays,
      with special regard to the BHV-1 system, has been evaluated on clinical samples
      from experimentally infected animals.

PMID- 10598084
TI  - RT-PCR detection and identification of three species of cucumoviruses with a
      genus-specific single pair of primers.
AB  - Reverse transcription and polymerase chain reaction (RT-PCR) was used for
      detection and identification of three cucumoviruses (cucumber mosaic virus, CMV;
      peanut stunt virus, PSV; tomato aspermy virus, TAV) in various plants sources
      with a single pair of primers, designed as CPTALL-3 and CPTALL-5. The pair of
      cucumovirus genus-specific primers that flank the coat protein gene were designed
      and used to amplify a DNA fragment of approximately ranging from 938 to 966 bp.
      The RT-PCR with the set of primers specifically amplified the target size of DNA
      fragment in all the tested cucumoviruses (CMV S-IA, S-IB and S-II, PSV and TAV).
      No DNA product of any length was produced when brome mosaic virus or tobacco
      mosaic virus RNA was used as templates. The cucumoviruses examined were
      differentiated by PCR-restriction fragment length polymorphism with different
      enzymes. This indicates that the designed primers are only specific for the
      cucumoviruses and useful for reliable information of identification of members of
      the Cucumovirus genus.

PMID- 10598085
TI  - A comparison of virus isolation, indirect immunofluorescence and nested multiplex
      polymerase chain reaction for the diagnosis of primary and recurrent herpes
      simplex type 1 and type 2 infections.
AB  - 134 swabs in viral transport medium were received from 126 patients with
      suspected clinical HSV-1 and HSV-2 infections. They were tested by (i) nested
      multiplex polymerase chain reaction NMPCR (strongly positive specimens had
      visible bands on both rounds of PCR) without prior extraction, (ii) culture in
      primary rhesus monkey kidney, E6-Vero, RD and HEp-2 cells and (iii) antigen
      detection by immunofluorescence (IF). Antigen detection employed four novel pools
      (A-D) of monoclonal antibodies (Mab): A was HSV-1 specific, B was HSV-2 specific
      while C and D were generic. In comparison to NMPCR the sensitivity and
      specificity of (i) culture was 59% (22/37) and 100% (134/134), (ii) IF by Pool A
      was 59% (16/27) and 100% (117/117), (iii) IF by Pool B was 40% (4/10) and 100%
      (130/130) and (iv) IF by Pools C and D were 60% (18/30) and 100% (96/96).
      Specimens positive by culture were more likely to be strongly positive by NMPCR
      (chi2 P = 0.004). Typing by each method concurred on all occasions. NMPCR was
      cost effective, easier to perform and was the most sensitive method for HSV
      detection. It should become the method of choice for HSV diagnosis.

PMID- 10598086
TI  - Characterization of monoclonal antibodies against bovine herpesvirus 1 gD fusion
      protein expressed in E. coli.
AB  - A total of 20 hybridoma cell lines secreting monoclonal antibodies (MAbs) against
      E. coli expressed bovine herpesvirus-1 (BHV-1) gD fusion protein were produced
      following the fusion of Sp2/0 myeloma cells with splenocytes from BALB/c mice
      immunized previously with immunoaffinity purified BHV-1 gD fusion protein. An
      indirect fluorescent antibody test (IFAT) using BHV-1 infected MDBK cells was
      used for the selection of positive hybridomas secreting specific antibody. The
      monoclonal antibody isotypes were 11 IgM, six IgG2b, one IgG1 and two IgG3. All
      MAbs reacted positively with the E. coli expressed BHV-1 gD fusion protein, BHV-1
      infected MDBK cell lysates and PCR BHV-1 gD transcription-translation polypeptide
      antigens by an ELISA.

PMID- 10598087
TI  - Sequence diversity in the 5'-UTR region of GB virus C/hepatitis G virus assessed
      using sequencing, heteroduplex mobility analysis and single-strand conformation
      polymorphism.
AB  - GB virus C/hepatitis G virus (GBV-C/HGV) is a positive-sense RNA virus belonging
      to the Flaviviridae family identified recently. Reverse transcription polymerase
      chain reaction (RT-PCR) was used to detect GBV-C/HGV RNA using nested primers
      designed to amplify 245 bp of the 5'-untranslated region (UTR). GBV-C/HGV RNA was
      detected in 20.7% of 101 HCV-RNA positive and 6.8% of 44 HCV-RNA negative
      specimens. Sequencing of the PCR products demonstrated they had between 84.3 and
      100% nucleotide identity. Most of the diversity corresponded to two variable
      regions identified within the 5'-UTR. Phylogenetic analysis indicated that GBV
      C/HGV subtypes present in Australia belonged to group 2 and were closest in
      evolutionary terms to isolates from the USA and Europe. All isolates were
      analysed using single-strand conformation polymorphism (SSCP) and heteroduplex
      mobility analysis (HMA) on 8% non-denaturing polyacrylamide gels. SSCP of the
      isolates identified a number of distinct conformation polymorphisms that
      corresponded with sequence-determined genetic diversity. HMA was developed to
      assess the amount of genetic diversity between isolates without the need for
      sequencing. The average difference between the predicted divergence of two
      isolates calculated from the mobility of the heteroduplex and the actual value
      (based on nucleotide sequence) was 2.3% in this sample of isolates, where the
      mean sequence divergence was 8.52%.

PMID- 10598088
TI  - Single primer pair designs that facilitate simultaneous detection and
      differentiation of peach mosaic virus and cherry mottle leaf virus.
AB  - Peach mosaic virus (PMV) and cherry mottle leaf virus (CMLV) are viruses which
      are related serologically and share common Prunus hosts, but cause distinct
      diseases. An RT-PCR procedure using a single oligonucleotide primer pair that
      allows simultaneous detection and differentiation of the two viruses was
      developed. A sense primer with 100% complementarity to PMV and 83%
      complementarity to the corresponding site of the CMLV genome was combined with
      either of two antisense primers (one of PMV origin and the other of CMLV origin)
      with 3' end complementarity at variable sites. This allowed the differential
      amplification of PMV and CMLV specific fragments, 419 and 705 bp, respectively.
      When oligo (dT) was used to generate the cDNA template, differential
      amplification was not observed, only amplification of the homologous virus
      associated with the antisense primer. This indicates polyadenylation of both
      viruses. Incorporation of the antisense primer into cDNA at the reverse
      transcription step was shown to be essential for this approach. The PMV primer
      pair reliably detected all isolates of PMV tested by RT-PCR analysis, both in
      peach leaf and budwood tissue.

PMID- 10598089
TI  - Diagnosis of foot-and-mouth disease by RT-PCR: evaluation of primers for
      serotypic characterisation of viral RNA in clinical samples.
AB  - Multiple primers designed from the 1D and 2AB regions of the foot-and-mouth
      disease (FMD) viral genome were evaluated extensively for the detection of all
      seven serotypes of the virus by reverse transcription polymerase chain reaction
      (RT-PCR) at the OIE/FAO World Reference Laboratory for FMD (WRL), Pirbright. The
      primers had been characterised previously elsewhere on a relatively small number
      of cell culture grown isolates and epithelial suspensions and had been shown to
      identify and differentiate all seven serotypes of FMD virus. The extended study
      evaluated several RT-PCR protocols on epithelial suspensions and supernatant
      fluids, resulting from their passage in cell culture, derived from clinical
      samples of diverse molecular characteristics. Each of the serotype-specific
      primers in selected RT-PCR protocols demonstrated suitable specificity and
      detected cell culture passaged isolates with some success but were not adequate
      for the serotyping of suspensions prepared from clinical samples of epithelium.
      The results showed that the primers can be used in RT-PCR procedures in
      conjunction with the routine detection methods of virus isolation and ELISA for
      the diagnosis and serotyping of FMD virus.

PMID- 10598090
TI  - Confirmation of Norwalk-like virus amplicons after RT-PCR by microplate
      hybridization and direct sequencing.
AB  - A large number of Norwalk-like viruses (NLVs) have been identified from stool
      samples by RT-PCR by amplifying part of the polymerase-coding gene. A set of
      probes were selected based on sequence analysis of the viruses circulating in
      Finland during the years 1996-97 for confirmation of the findings by
      hybridization. A microplate hybridization test, which provides a rapid semi
      automatic detection for PCR products, was designed and compared with agarose gel
      electrophoresis. From the material of 210 stool samples, mainly from diarrheal
      outbreaks during years 1997-1998, three probes, one for NLV genogroup GGI and one
      for each of the two GGII subgroups (Toronto-like and Lordsdale-like), were
      sufficient to detect 87.8% (36/41) of GGI and 89.0% (49/55) of GGII samples
      positive by gel electrophoresis. Amplicon sequencing of the strains not detected
      by the above probes revealed genetic variability in the sequences. Biotin
      streptavidin binding was used both for microplate hybridization assays and for
      direct sequencing to identify the amplicons. Based on the sequences three more
      probes for the hybridization panel were added so that all the different NLVs of
      this study could be recognized.

PMID- 10598091
TI  - Detection of measles specific IgG in oral fluid using an FITC/anti-FITC IgG
      capture enzyme linked immunosorbent assay (GACELISA).
AB  - An IgG antibody capture enzyme linked immunosorbent assay (GACELISA) for the
      detection of measles specific IgG in oral fluid was developed using an FITC/anti
      FITC amplification system. The GACELISA was evaluated by testing paired oral
      fluid and serum samples from 787 subjects in an epidemiological study of measles
      in rural Ethiopia. Oral fluids were tested by GACELISA and corresponding serum
      samples by a sensitive indirect ELISA for measles IgG (Behring Enzygnost). By
      comparison with the serum measles IgG assay, the oral fluid GACELISA had a
      sensitivity of 97.4% (95% confidence intervals: 95.9, 98.2) and a specificity of
      90.0% (81.9, 94.3), with no significant differences observed by age group. Total
      IgG concentrations were measured on a subset of 160 oral fluids by an in-house
      ELISA. This showed that false negative GACELISA results tended to occur in
      samples with low concentrations of total IgG, although the trend was not
      statistically significant. It is concluded that the overall performance of the
      GACELISA was satisfactory, showing close agreement to the serum ELISA, and has
      potential to serve as an easily transferable tool for large scale epidemiological
      studies as required for the World Health Organisation's programme for the global
      control of measles.

PMID- 10598092
TI  - Design and evaluation of a primer pair that detects both Norwalk- and Sapporo
      like caliciviruses by RT-PCR.
AB  - A primer pair (p289/290) based on the RNA polymerase sequence of 25 prototype and
      currently circulating strains of human caliciviruses (HuCVs) was designed for the
      detection of both Norwalk-like caliciviruses (NLVs) and Sapporo-like
      caliciviruses (SLVs) by reverse transcription-polymerase chain reaction (RT-PCR).
      This primer pair produces RT-PCR products of 319 bp for NLVs and 331 bp for SLVs.
      The usefulness of this primer pair was shown by its detection of prototype NLVs
      (Norwalk, Snow Mountain, Hawaii and Mexico viruses) and SLVs (Sapporo/82, Hou/86,
      Hou/90 and Lon/92) and currently circulating strains of NLVs and SLVs in children
      and adults. This primer pair also detected more viruses in either NLV or SLV
      genera than previously designed primers. This primer pair is useful for broad
      detection of HuCVs for clinical and epidemiologic studies as well as for
      environmental monitoring.

PMID- 10598093
TI  - Detection of varicella-zoster virus and herpes simplex virus by the polymerase
      chain reaction with degenerate primers.
AB  - Varicella-zoster virus (VZV) and herpes simplex virus (HSV) are human pathogens
      of significance involved in multiple diseases with either typical or atypical
      clinical features. In neonates and immunocompromised patients these
      alphaherpesviruses may cause life-threatening diseases such as encephalitis.
      Detection of VZV by virus culture is difficult. Polymerase chain reaction (PCR)
      is quicker and more sensitive and applicable in most clinical microbiological
      laboratories. Using degenerate primers, glycoprotein B (gB) DNA was amplified
      from all alphaherpesvirus field strains present in clinical samples. The
      amplification of gB allowed virus typing of VZV, HSV-1 and HSV-2 using
      restriction enzyme digestion of the PCR products. Degenerate primers can replace
      conventional primers in diagnostic PCR without loss of sensitivity and
      specificity.

PMID- 10598094
TI  - A sensitive and specific PCR/Southern blot assay for detection of bovine
      herpesvirus 4 in calves infected experimentally.
AB  - A PCR/Southern blot assay for detection of bovine herpesvirus 4 (BHV-4) in the
      background of bovine cellular DNA was developed. A BHV-4 specific sequence within
      the gene coding for the glycoprotein B (gB) was selected for primer sequences to
      guarantee the specificity of the assay. With a detection limit of six molecules
      BHV-4 DNA in the background of 1 microg of cellular DNA (equals about 150,000
      bovine cells) this PCR/Southern blot assay represents a highly sensitive method
      for detection of BHV-4 DNA. At low concentrations of BHV-4 genomes, this assay
      also allows to estimate the copy number of BHV-4: a distinction between fewer
      than 6, 6-59 and more than 60 BHV-4 genomes/100 microl DNA suspension was
      possible. Tissue and blood samples of two calves, infected experimentally with
      BHV-4 were examined for the prevalence of BHV-4 DNA 130 days post infection. Ten
      days before taking samples, one of the calves was immuno-suppressed with
      dexamethasone. In both calves, BHV-4 DNA was detected in the leucocyte fraction
      of the blood, and beyond that in lower quantities in the spleen and the kidney of
      the immuno-suppressed calf. It is assumed that a latent BHV-4 infection was
      activated after application of dexamethasone and that the leucocyte fraction of
      the blood represents one site of latency of BHV-4 in cattle.

PMID- 10598095
TI  - Rapid detection of lamivudine-resistant hepatitis B virus polymerase gene
      variants.
AB  - The amino acid substitution from methionine to valine or isoleucine at the YMDD
      (tyrosine, methionine, aspartate, aspartate) motif of the HBV polymerase gene is
      the main mutation responsible for resistance to lamivudine treatment. Detection
      of emerging HBV variants by direct sequencing of the HBV genome is excessively
      time-consuming for studying large numbers of clinical samples. The aim of the
      study was to analyse the emergence of lamivudine-resistant HBV genotypes by means
      of restriction fragment length polymorphism (RFLP) of the PCR product generated
      from a fragment of domain C of the polymerase gene, in clinical samples from
      patients receiving treatment. The results with this method were compared with
      those obtained with a direct sequencing technique. In total, 139 serum samples
      were studied from 37 patients with chronic hepatitis B, obtained at pre-treatment
      and at 9, 12, 18 and 24 months of treatment. Variants were detected by cleavage
      of the products of the three PCRs with the following enzymes: FokI (identifies
      the normal variant, YMDD, and the mutant variant YVDD), SspI (identifies the
      mutant variant, YIDD) and Alw44I (identifies the variant, YVDD). The digested
      fragments were separated by electrophoresis in 3% agarose gel. Of the 139 serum
      samples analysed, the wild-type YMDD sequence was detected in 106 (76%), the YVDD
      variant in 20 (15%) and the YIDD variant in 13 (9%) cases. The non-mutated
      variant, YMDD, was detected in all the pre-treatment samples. After 9 months of
      treatment the mutant variant was detected in four of 37 serum samples analysed
      (11%) (two YVDD and two YIDD). At 12 months, 12 of the 37 serum samples (32%)
      showed mutations in the YMDD sequence (seven YVDD and five YIDD). Among the 16
      serum samples obtained at 18 months, nine had the YMDD variant (56%) (seven YVDD
      and two YIDD). At 24 months, variants in the YMDD sequence were detected in eight
      of the 12 patients treated (66%) (four YVDD and four YIDD). HBV genotypes were
      confirmed by direct sequencing, with consistent results. In 45% of cases, the
      emergence of HBV variants was not associated with ALT breakthrough. The PCR-RFLP
      assay used in this study, in perfect concordance with direct sequencing, is an
      accurate method for genotyping lamivudine-resistant HBV variants. Since it is a
      rapid low-cost technique, PCR- RFLP is suitable for large-scale screening of
      these polymorphisms in clinical samples.

PMID- 10598096
TI  - Isolation of homologous arbovirus cultures from heterologous mixtures using limit
      dilution and virus-specific enzyme immunoassays.
AB  - Viral cultures were identified recently that contained both Kunjin virus and the
      closely related flavivirus West Nile. The observation that the KUN virus
      population grew more efficiently in a mosquito cell line (C6/36) while the WN
      population replicated more effectively in mammalian cells (Vero) allowed
      enrichment for either virus by culturing the mixture in the appropriate cell
      line. Limit dilution of the enriched virus preparations was then performed by
      infecting microtitre cultures with serial ten fold dilutions. Culture wells that
      contained a pure population of virus were then identified by immunostaining fixed
      cell monolayers with virus-specific monoclonal antibodies. Subsequent passage of
      the 'cloned' viruses in either C6/36 or Vero cells and analysis of the infected
      cultures by specific monoclonal antibody staining, PCR and nucleotide sequencing
      confirmed the identity of the virus and that in each case an homogeneous virus
      population had been obtained. This procedure is particularly useful for isolating
      virus populations from heterogeneous mixtures that fail to develop discrete
      plaques in infected cell monolayers.

PMID- 10598097
TI  - Retinoblastoma proteins in plants.
AB  - The retinoblastoma protein Rb is part of a conserved pathway that controls the
      activation of cell division in animals. Rb represses cell cycle transcription
      factors of the E2F family, and thereby prevents uncontrolled cell proliferation.
      Rb itself is inactivated when phosphorylated by cyclin-dependent kinases, and the
      D-type cyclin kinases are particularly important in this process during the
      reactivation of cell division in quiescent cells. In addition, Rb has important
      developmental roles in controlling the onset of cellular differentiation in a
      number of cell types. The recent discovery in plants of both Rb proteins and
      other components of the Rb pathway suggests that, far from being restricted to
      the animal kingdom, Rb may have a conserved role in allowing multicellular
      organisms to develop complex body plans consisting of many different cell types.
      This review assesses the potential roles of Rb proteins in plant cell cycle
      control and development.

PMID- 10598098
TI  - cDNA cloning and characterization of maize phosphoenolpyruvate carboxykinase, a
      bundle sheath cell-specific enzyme.
AB  - We isolated a full-length cDNA that encodes ATP-dependent phosphoenolpyruvate
      carboxykinase (EC 4.1.1.49, PCK) from leaves of maize, an NADP-malic enzyme type
      C4 plant. The mRNA was specifically and rather abundantly expressed in bundle
      sheath cells in accordance with the recent finding of cell-type-specific
      localization of PCK protein in maize, which has been detected with antibodies
      against cucumber PCK protein. The predicted protein had an N-terminal extension,
      which is characteristic of plant PCKs. The transcript level was much higher in
      the daytime than at night in 14-day old seedlings. However, in 42-day old plants
      the extent of diurnal change decreased. The maize PCK was expressed in
      Escherichia coli with the pET32 plasmid and purified to homogeneity. Through
      digestion with enterokinase, two types of enzyme were prepared; one with an
      intact N-terminus and the other lacking its N-terminal 77 amino acid residues due
      to over-digestion. The truncated protein had about 2-fold higher specific
      activity than the intact one, and was inhibited by 3-phosphoglycerate (3-PGA)
      with an I0.5 of 17.5 mM. In contrast, the intact protein was almost insensitive
      to 3-PGA. These results strongly suggest that the intact N-terminal extension may
      be involved in the regulation of PCK activity in vivo through some modification
      such as reversible phosphorylation.

PMID- 10598099
TI  - Coexpression of a defensin gene and a thionin-like via different signal
      transduction pathways in pepper and Colletotrichum gloeosporioides interactions.
AB  - The anthracnose fungus, Colletotrichum gloeosporioides, interacts incompatibly
      with the ripe fruit of pepper (Capsicum annuum). It interacts compatibly with the
      unripe-mature fruit. We isolated a defensin gene, jl-l, and a thionin-like gene,
      PepThi, expressed in the incompatible interaction by using an mRNA differential
      display method. Both genes were developmentally regulated during fruit ripening,
      organ-specifically regulated, and differentially induced during the compatible
      and incompatible interactions. Expression of the PepThi gene was rapidly induced
      in the incompatible-ripe fruit upon fungal infection. The fungus-inducible PepThi
      gene is highly inducible only in the unripe fruit by salicylic acid. In both ripe
      and unripe fruit, it was induced by wounding, but not by jasmonic acid.
      Expression of the jl-l gene is enhanced by jasmonic acid in the unripe fruit but
      suppressed in the ripe fruit. These results suggest that both small and cysteine
      rich protein genes are induced via different signal transduction pathways during
      fruit ripening to protect the reproductive organs against biotic and abiotic
      stresses.

PMID- 10598100
TI  - Two ftsH-family genes encoded in the nuclear and chloroplast genomes of the
      primitive red alga Cyanidioschyzon merolae.
AB  - The red algal chloroplast genome encodes an essential prokaryotic cell division
      gene, ftsH, which has never been found in the mitochondrial genome of any
      organism. To compare the conserved prokaryote-derived mechanism for mitochondrial
      division with that of chloroplasts, we cloned chloroplast- and nuclear-encoded
      ftsH genes from the primitive red alga Cyanidioschyzon merolae. The deduced amino
      acid sequence of chloroplast ftsH (ftsHcp) consists of 603 amino acids and shows
      the highest similarity with algal-chloroplast and cyanobacterial FtsH. On the
      other hand, the nuclear-encoded ftsH (ftsH2) encodes a protein of 920 amino acids
      and has the highest similarity with two yeast mitochondrial FtsHs, Rca1p and
      Afg3p. Furthermore, the amino-terminal extension of FtsH2 appears to be an
      amphipathic alpha-helix, a characteristic mitochondrial targeting signal,
      suggesting that FtsH2 is a mitochondrial protein. Southern hybridization revealed
      that ftsH2 is a single gene located on chromosome III of the 17 C. merolae
      chromosomes. The level of expression of the 3.0 and 4.0 kb transcripts of this
      gene decreased in concert during the organelle division phase of a synchronized
      culture, indicating a cell-cycle-dependent manner of ftsH2 transcription, while
      northern hybridization did not detect ftsHcp transcripts. Nevertheless, reverse
      transcription-PCR and immunoblotting demonstrated for the first time that
      chloroplast-encoded ftsH is transcriptionally and translationally active.
      Overproduction of FtsHcp and FtsH2 in Escherichia coli disrupted cytokinesis and
      produced filamentous cells, but had no effect on the replication, segregation, or
      distribution of their nucleoids, as also occurs in ftsH-deficient E. coli. These
      observations suggest the possible involvement of both C. merolae FtsHs in
      organelle division.

PMID- 10598102
TI  - Occurrence of five different chromosomal HMG1 proteins in various maize tissues.
AB  - The nuclear HMG1 proteins of higher plants are small non-histone proteins that
      have DNA-bending activity and are considered architectural factors in chromatin.
      The occurrence of the chromosomal HMG1 proteins, HMGa, HMGc1/2 and HMGd, in
      various maize tissues was analyzed, and in the course of these studies a novel
      HMG1 protein, now termed HMGe, was identified. Purification and characterization
      of HMGe (M(r) 13,655) and cloning of the corresponding cDNA revealed that it
      displays only moderate similarity to other members of the plant HMG1 protein
      family. The five maize HMG1 proteins could be detected in kernels, leaves, roots
      and suspension culture cells, indicating that these proteins can be expressed
      simultaneously and occur relatively ubiquitously. However, the various HMG1
      proteins are present in significantly different quantities with HMGa and HMGc1/2
      being the most abundant HMG1 proteins in all tissues tested. Furthermore, the
      relative amounts of the various HMG1 proteins differ among the tissues examined.
      The HMG1 proteins were found to be relatively stable proteins in vivo, with
      HMGc1/2, HMGd and HMGe having a half-life of ca. 50 h in cultured cells, while
      the half-life of the HMGa protein is ca. 65 h. Collectively, these findings are
      compatible with the concept that the different plant HMG1 proteins might act as
      general architectural proteins in concert with site-specific factors in the
      assembly of certain nucleoprotein structures involved in various biological
      processes.

PMID- 10598101
TI  - The maize EmBP-1 orthologue differentially regulates opaque2-dependent gene
      expression in yeast and cultured maize endosperm cells.
AB  - In addition to the bZIP protein Opaque2 (O2), there are other maize endosperm
      nuclear proteins that recognize the O2 box in 22 kDa zein gene promoters. In an
      effort to understand the effect of these factors on 22 kDa zein expression, we
      have cloned one of these and identified it as the putative maize (Zea mays L.)
      orthologue of the wheat bZIP protein EmBP-1 (mEmBP-1). The mEmBP-1 protein
      exhibits 52% sequence identity and 68% similarity with the wheat protein and
      recognizes a similar spectrum of DNA sequences, albeit with slightly altered
      specificity. The mEmBP-1 gene exists as duplicate loci in maize on chromosomes 7S
      (mEmBP-1a) and 2L (mEmBP-1b). The mEmBP-1 genes are expressed in endosperm,
      embryo, immature ears, tassel, roots, and seedling shoots at low levels. Although
      mEmBP-1 binds to the O2 box from the 22 kDa zein gene promoter as a homodimer, it
      is unable to heterodimerize with O2. The mEmBP-1 protein can activate
      transcription from a truncated promoter containing a pentamer of the O2 site in
      yeast cells; however, it inhibited regulated transcription of a 22 kDa zein
      promoter in a transient expression assay using cultured maize endosperm cells.

PMID- 10598103
TI  - Specific in vitro phosphorylation of plant eIF2alpha by eukaryotic eIF2alpha
      kinases.
AB  - Phosphorylation of the alpha subunit of eukaryotic initiation factor 2
      (eIF2alpha) is known to be an important translational control mechanism in all
      eukaryotes with the major exception of plants. Regulation of mammalian and yeast
      eIF2alpha activity is directly governed by specific phosphorylation on Ser-51. We
      now demonstrate that recombinant wheat wild-type (51S) but not mutant 51-Ala
      (51A) protein is phosphorylated by human PKR and yeast GCN2, which are defined
      eIF2alpha kinases. Further, only wheat wild-type eIF2alpha is a substrate for
      plant-encoded, double-stranded RNA-dependent kinase (pPKR) activity. Plant PKR
      and GCN2 phosphorylate recombinant yeast eIF2alpha 51S but not the 51A mutant
      demonstrating that pPKR has recognition site capability similar to established
      eIF2alpha kinases. A truncated version of wild-type wheat eIF2alpha containing
      51S but not the KGYID motif is not phosphorylated by either hPKR or pPKR
      suggesting that this putative eIF2alpha kinase docking domain is essential for
      phosphorylation. Taken together, these results demonstrate the homology among
      eukaryotic eIF2alpha species and eIF2alpha kinases and support the presence of a
      plant eIF2alpha phosphorylation pathway.

PMID- 10598104
TI  - Pollination, wounding and jasmonate treatments induce the expression of a
      developmentally regulated pistil dioxygenase at a distance, in the ovary, in the
      wild potato Solanum chacoense Bitt.
AB  - Pollination and fertilization trigger unique developmental programs leading to
      embryogenesis, ovary maturation and seed set. Pistil tissues are actively
      involved in pollen tube growth and respond to the presence of the growing pollen
      tubes by modulating the expression of specific genes. Using subtractive
      hybridization to isolate genes involved in pollen-pistil interactions and
      fertilization, we have isolated a pollination- and fertilization-induced
      dioxygenase which is predominantly expressed in the pistil. In situ hybridization
      analyses revealed that the SPP2 dioxygenase (Solanum pollinated pistil) from the
      self-incompatible wild potato Solanum chacoense Bitt. is also developmentally
      regulated, with mRNA levels gradually regressing from the tip of the style
      towards the ovary during pistil development. At maturity, the upper limit of SPP2
      transcript distribution coincided with the abscission zone of the style and SPP2
      dioxygenase expression in ovaries coincided with the fertilization receptivity
      period of the flower. Pollination, as well as wounding of the style, induced an
      increase in SPP2 mRNA steady-state levels at a distance, in the ovary. Treatments
      with stress hormones including methyl jasmonate, jasmonic acid and salicylic acid
      mimicked the wound response and also induced SPP2 transcripts in the ovary. The
      SPP2 dioxygenase could be involved in the biosynthesis of deterrent alkaloids in
      reproductive tissues or in generating chemical signals involved in pollen tube
      guidance.

PMID- 10598105
TI  - Structure and expression of the gene family encoding putrescine N
      methyltransferase in Nicotiana tabacum: new clues to the evolutionary origin of
      cultivated tobacco.
AB  - The structure and nuclear genomic organization of the gene family encoding
      putrescine N-methyltransferase (PMT), the key enzyme in diverting polyamine
      metabolism towards the biosynthesis of nicotine and related alkaloids, was
      examined in Nicotiana tabacum. Five genes encoding PMT are present in the N.
      tabacum genome and all are expressed. The complete coding region and immediate 5'
      and 3'- flanking regions were characterized for four members of the gene family
      and the Exon 1 region of the fifth member of the family was determined.
      Comparison of the nucleotide and deduced amino acid sequences of the N. tabacum
      PMT genes with those of presumed progenitor species, N. sylvestris, N.
      tomentosiformis and N. otophora, revealed that three members of the N. tabacum
      PMT gene family were most similar to the three genes present in N. sylvestris,
      whereas the two remaining PMT genes were similar to PMT genes present in N.
      tomentosiformis and N. otophora genomes, respectively. These data are consistent
      with an evolutionary origin of N. tabacum resulting from a cross involving N.
      sylvestris and an introgressed hybrid between N. tomentosiformis and N. otophora.
      The five PMT genes present in N. tabacum are expressed in the roots of wild-type
      plants, but not in other organs. The steady-state level of all five PMT
      transcripts is transiently increased in roots following topping (removal of the
      floral meristem), although the maximum level of induction for the individual
      transcripts varies considerably. In contrast to wild-type plants, no increase in
      PMT transcript levels was observed in a low-alkaloid (nic1nic2) mutant of Burley
      21. These data support a role for nic1 and nic2 in the global regulation of
      alkaloid formation in tobacco and provide for the first time molecular
      confirmation of the presumed origin of cultivated tobacco.

PMID- 10598106
TI  - Evidence for factors regulating transfer cell-specific expression in maize
      endosperm.
AB  - In maize, a layer of basal endosperm cells adjacent to the pedicel is modified
      for a function in solute transfer. Three genes specifically expressed in this
      region, termed the basal endosperm transfer layer (BETL-2 to -4), were isolated
      by differential hybridization. BETL-2 to -4 are coordinately expressed in early
      and mid-term endosperm development, but are absent at later stages. BETL-2 to -4
      coding sequences all predict small (< 100 amino acids), secreted, cysteine-rich
      polypeptides which lack close relatives in current database accessions. BETL-3
      and BETL-1 display some sequence similarities with each other and to plant
      defensins. BETL-2 to -4 promoter regions were isolated and compared, revealing
      the presence of a promoter-proximal microsatellite repeat as the most highly
      conserved sequence element in each sequence. Electrophoretic mobility shift
      assays (EMSA) showed that specific BETL-2 to -4 promoter fragments competed for
      binding to the same DNA-binding activity in nuclear extracts prepared from maize
      endosperm. Although BETL-2 to -4 are only expressed in basal endosperm cells, the
      DNA-binding activities detected were of two types: distal endosperm-specific, or
      present in both basal and distal endosperm extracts. On the basis of these
      findings, a model to account for the coordinate regulation of BETL genes in
      endosperm cells is proposed.

PMID- 10598107
TI  - Selection of Arabidopsis genes encoding secreted and plasma membrane proteins.
AB  - Secreted and plasma membrane proteins play crucial roles in a variety of
      physiological and developmental processes of multicellular organisms. Systematic
      cloning of the genes encoding these proteins is therefore of general interest. An
      effective method of trapping signal sequences was first described by Tashiro et
      al. (1993), and a similar yet more efficient method was reported by Klein et al.
      (1996) and Jacobs et al. (1997). In this study, we carried out the latter yeast
      based signal sequence trap to clone genes from Arabidopsis thaliana encoding
      secreted and plasma membrane proteins. Of 144 sequenced cDNA clones, 18% are
      identical to previously cloned Arabidopsis thaliana genes, 12% are homologous to
      genes identified from various organisms, and 46% are novel. All of the isolated
      genes identical or homologous to previously reported genes are either secreted or
      plasma membrane proteins, and the remaining novel genes appear to contain
      functional signal sequences based on computer-aided sequence analysis. The full
      length cDNA clones of one homologous gene and another novel gene were isolated
      and sequenced. The deduced amino acid sequences suggest that the former encodes a
      secreted protein, and the latter encodes a type 1 membrane protein. These results
      indicate that the signal sequence trap method is effective and useful for the
      isolation of plant genes encoding secreted and plasma membrane proteins.

PMID- 10598108
TI  - Thiol redox state regulates expression of psbA genes in Synechococcus sp. PCC
      7942.
AB  - Three psbA genes encode two different forms of the photosystem II reaction centre
      protein D1 in Synechococcus sp. PCC 7942. The psbAI gene encoding D1 protein form
      I (D1:1) is mainly expressed under low growth light conditions while the psbAII
      and psbAIII genes, encoding D1 protein form II (D1:2), are induced under stress
      conditions (e.g. high light or low temperature). In this paper we show that
      psbAII/III genes can be rapidly induced even under low growth light conditions by
      adding the thiol reductant (DTTred) to Synechococcus cell culture, at a
      concentration that does not affect cell growth or photosynthetic activity.
      Similar induction of psbAII/III genes was obtained by illuminating the cells with
      photosystem I light. In both instances psbAI gene down-regulation coincided with
      the up-regulation of psbAII/III genes. DTTred-induced exchange in transcript
      pools was subsequently followed by an exchange of D1:1 for D1:2 at the protein
      level. Thiol oxidants, iodosobenzoic acid or diamide, reverted the effects of
      DTTred on psbA gene expression. Thiol oxidants and the thiol-modifying agent N
      ethylmaleimide also totally prevented high-light induction of psbAII/III genes.
      These data strongly suggest that the up-regulation of psbAII/III genes that
      occurs under stress conditions is mediated by production of thiol reductants,
      whereas the expression of the psbAI gene is sustained by the more oxidizing
      conditions that prevail during the steady-state growth of cells.

PMID- 10598109
TI  - A review of traditional fermented foods and beverages of Zimbabwe.
AB  - Several traditional fermented foods and beverages are produced at household level
      in Zimbabwe. These include fermented maize porridges (mutwiwa and ilambazi
      lokubilisa) fermented milk products (mukaka wakakoralamasi and hodzeko) non
      alcoholic cereal-based beverages (mahewu, tobwa and mangisi) alcoholic beverages
      from sorghum or millet malt (doroluthwala and chikokivana) distilled spirits
      (kachasu) and fermented fruit mashes (makumbi). There are many regional
      variations to the preparation of each fermented product. Research into the
      processing technologies of these foods is still in its infancy. It is, therefore,
      important that the microbiology and biochemistry of these products, as well as
      their technologies be studied and documented in order to preserve them for future
      generations. This article reviews the available information regarding traditional
      fermented foods in Zimbabwe and makes recommendations for potential research
      areas.

PMID- 10598110
TI  - Influence of sodium chloride concentration on the controlled lactic acid
      fermentation of "Almagro" eggplants.
AB  - The effect of a commercial Lactobacillus starter and sodium chloride
      concentration on the fermentation of "Almagro" eggplants (Solanum melongena L.
      var. esculentum depressum) was studied. The results of fermentation using added
      starter and varying salt concentrations (4, 6, and 10% w/v) in brine were
      compared with the results of spontaneous fermentation taking place in brine with
      a salt concentration of 4%. Fresh fruits, medium in size (34-44 g), were used in
      all cases; all fruits were blanched under identical conditions. Temperature in
      the fermenters was 32+/-2 degrees C. The results obtained indicate that addition
      of a suitable starter shortened the fermentation process, provided the salt
      concentration in the brine did not exceed 6%. In the conditions tested, the
      eggplants obtained after fermentation were found to be of good quality though
      somewhat bitter which may explained by the starter employed.

PMID- 10598111
TI  - Use of time-temperature integrators and predictive modelling for shelf life
      control of chilled fish under dynamic storage conditions.
AB  - A systematic approach for fish shelf life modelling and Time Temperature
      Integrator (TTI) selection in order to plan and apply an effective quality
      monitoring scheme for the fish chill chain was developed. The temperature
      behaviour of the natural microflora of the Mediterranean fish boque (Boops boops)
      was studied and growth of the specific spoilage bacteria Pseudomonas spp. and
      Shewanella putrefaciens was modelled and correlated to organoleptic shelf life.
      Arrhenius and square root functions were used to model temperature dependence of
      maximum growth rates. Bacterial growth and shelf life models were validated under
      dynamic storage conditions with independent variable temperature experiments. The
      response of several TTIs from similar storage experiments was also modelled. The
      reliability of the TTI monitoring was cumulatively expressed by the error in the
      TTI derived effective temperature (Teff) for different variable temperature
      distributions. Teff was directly translated to shelf life of the fish.

PMID- 10598112
TI  - Improved screening procedure for biogenic amine production by lactic acid
      bacteria.
AB  - An improved screening plate method for the detection of amino acid decarboxylase
      positive microorganisms (especially lactic acid bacteria) was developed. The
      suitability and detection level of the designed medium were quantitatively
      evaluated by confirmation of amine-forming capacity using an HPLC procedure. The
      potential to produce the biogenic amines (BA) tyramine, histamine, putrescine,
      and cadaverine, was investigated in a wide number of lactic acid bacteria (LAB)
      of different origin, including starter cultures, protective cultures, type
      strains and strains isolated from different food products. Also, several strains
      of Enterobacteriaceae were examined. Modifications to previously described
      methods included lowering glucose and sodium chloride concentrations, and
      increasing the buffer effect with calcium carbonate and potassium phosphate. In
      addition, pyridoxal-5-phosphate was included as a codecarboxylase factor for its
      enhancing effect on the amino acid decarboxylase activity. The screening plate
      method showed a good correlation with the chemical analysis and due to its
      simplicity it is presented as a suitable and sensitive method to investigate the
      capacity of biogenic amine production by LAB. Tyramine was the main amine formed
      by the LAB strains investigated. Enterococci, carnobacteria and some strains of
      lactobacilli, particularly of Lb. curvatus. Lb. brevis and Lb. buchneri, were the
      most intensive tyramine formers. Several strains of lactobacilli, Leuconostoc
      spp., Weissella spp. and pediococci did not show any potential to produce amines.
      Enterobacteriaceae were associated with cadaverine and putrescine formation. No
      significant histamine production could be detected for any of the strains tested.

PMID- 10598113
TI  - Protective cultures inhibit growth of Listeria monocytogenes and Escherichia coli
      O157:H7 in cooked, sliced, vacuum- and gas-packaged meat.
AB  - Contamination of cooked meat products with Listeria monocytogenes poses a
      constant threat to the meat industry. The aim of this study was therefore to
      investigate the use of indigenous lactic acid bacteria (LAB) as protective
      cultures in cooked meat products. Cooked, sliced, vacuum- or gas-packaged ham and
      servelat sausage from nine meat factories in Norway were inoculated with 10(3)
      cfu/g of a mixture of three rifampicin resistant (rif-mutant) strains of L.
      monocytogenes and stored at 8 degrees C for four weeks. Growth of L.
      monocytogenes and indigenous lactic acid flora was followed throughout the
      storage period. LAB were isolated from samples where L. monocytogenes failed to
      grow. Five different strains growing well at 3 degrees C. pH 6.2, with 3% NaCl,
      and producing moderate amounts of acid were selected for challenge experiments
      with the rif-resistant strains of L. monocytogenes. a nalidixic acid/streptomycin
      sulphate-resistant strain of Escherichia coli O157:H7 and a mixture of three rif
      resistant strains of Yersinia enterocolitica O:3. All five LAB strains inhibited
      growth of both L. monocytogenes and E. coli O157:H7. No inhibition of Y.
      enterocolitica O:3 was observed. A professional taste panel evaluated cooked,
      sliced, vacuum-packaged ham inoculated with each of the five test strains after
      storage for 21 days at 8 degrees C. All samples had acceptable sensory
      properties. The five LAB strains hybridised to a 23S rRNA oligonucleotide probe
      specific for Lactobacillus sakei. These indigenous LAB may be used as protective
      cultures to inhibit growth of L. monocytogenes and E. coli O157:H7 in cooked meat
      products.

PMID- 10598114
TI  - A rapid strip immunoblot assay for the specific detection of Salmonella
      enteritidis infection in chickens.
AB  - A rapid strip immunoblot assay (RSIA) was developed using recombinant SEF14
      antigen. The rSEF14-RSIA was very specific in detecting antibodies to Salmonella
      enteritidis in chickens. When serum samples obtained from groups of chickens (N =
      5) inoculated with six different Salmonella serovars were tested in rSEF14-RSIA,
      only serum samples obtained from S. enteritidis inoculated birds reacted with
      rSEF14 antigen except for a group of chickens that had been inoculated with S.
      dublin. To assess the sensitivity of the rSEF14-RSIA, groups of chickens were
      inoculated with either 10(4) cfu or 10(10) cfu of S. enteritidis and the serum
      and egg yolk were analyzed for SEF14 antibodies. By 1 week after infection 66-78%
      of chickens were found positive for SEF14 antibodies in the serum and the number
      of positive birds increased subsequently to 89-100%. The S. enteritidis specific
      antibodies appeared as early as 6 days after infection in the egg yolk of
      infected chickens. The antibodies to SEF14 in both the serum and egg yolk
      persisted for at least 7 weeks after infection in a significant proportion of
      chickens. Our results suggest that rSEF14-RSIA can be a practical and efficient
      screening test for identifying S. enteritidis infected chickens.

PMID- 10598115
TI  - Thermal inactivation of Bacillus cereus spores affected by the solutes used to
      control water activity of the heating medium.
AB  - The heat resistance of B. cereus spores (ATCC 7004, 4342 and 9818) over a wide
      temperature range (92-125 degrees C) in aqueous solutions of NaCl, LiCl, sucrose
      and glycerol at different water activities (1.00-0.71) was investigated. Sodium
      chloride in the heating medium tended to protect the spores of B. cereus against
      heat. The z-values increased significantly (P < 0.05) at and above a
      concentration of 4.0 M. The effects of LiCl were lower than those caused by the
      NaCl at the same a(w) values. An increase in z-values was observed. but the
      differences were only statistically significant (P<0.05) at the highest
      concentration tested (5.0 M). A concentration of sucrose 0.87 M caused in all
      cases a reduction in D-values, which was most pronounced for strains 4342 and
      9818. With increasing concentration of sucrose ( > 0.87 M), the D-values showed
      an increase, although only those obtained for strain 4342 in sucrose solutions
      2.22 M were higher than those found in pure water. The z-values were
      significantly higher (P < 0.05) when sucrose was added at concentrations above
      1.42 M, except for strain 4342. When a(w) was lowered from 0.96 to 0.71 with
      glycerol, D-values obtained gradually increased, about 30, 50 and 60 fold for
      4342, 7004 and 9818 strains, respectively. No significant effect on z-values were
      detected.

PMID- 10598116
TI  - A comparison of bacterial adherence to bare hands and gloves following simulated
      contamination from a beef carcass.
AB  - One of the risks for contamination of edible product in the pre-inspection area
      of processing lines in meat plants is cross contamination. This can occur
      directly as a result of carcass-to-carcass contact or indirectly via knives or
      the hands of butchers. Standard procedures require that operators rinse their
      hands and knives to remove any visible contamination. In New Zealand, protective
      gloves are not allowed in the pre-inspection area because they are considered a
      potential risk for cross contamination until the carcasses have passed the final
      meat inspection. However, the risk of injury to the bare hands is as high in this
      area as in other parts of the plant, where such gloves are permitted. There is
      therefore a need to evaluate the risk of bacterial cross contamination via bare
      hands and via protective gloves. The present study compared bacterial adherence
      to bare hands and to gloves after rinsing for 5 s in a shower of water at 40
      degrees C and after rinsing gloves in hotter water (60 degrees C) following
      simulated contact with the hide of a recently slaughtered animal. Under
      laboratory conditions there were no statistically significant differences between
      bacterial adherence to bare hands or to gloves rinsed in water at 40 degrees C or
      60 degrees C.

PMID- 10598117
TI  - Incidence of Listeria monocytogenes in different types of meat products on the
      Belgian retail market.
AB  - A survey was undertaken to determine the incidence and numbers of L.
      monocytogenes in a variety of meat products (cooked meat products, raw cured meat
      products (dried or not), mayonnaise based salads and prepared meals). As
      expected, raw cured meat products were significantly higher contaminated with L.
      monocytogenes than cooked meat products, 13.71% (113/824) and 4.90% (167/3405),
      respectively. Also a larger proportion of raw cured meat product samples
      contained a high initial level of the pathogen ( > 10 cfu/g). Higher incidence
      rates were obtained for whole cooked meat products (e.g. cooked ham, bacon) after
      slicing than before slicing, 6.65 and 1.56%, respectively, indicating cross
      contamination. Due to multiple handling and processing steps, the incidence rate
      of the pathogen was higher for cooked minced meat products than for whole cooked
      meat products, 6.14 and 3.96%, respectively. No significant differences were
      obtained in the incidence of L. monocytogenes in whole cured meat products (e.g.,
      raw ham) and minced cured meat products (e.g., dry fermented sausage), 14.92 and
      11.69%, respectively. Lower incidence rates of L. monocytogenes were obtained for
      raw, cured meat products using beef or horse meat, 4.65 and 5.88%, respectively,
      A high incidence rate of L. monocytogenes was noted for the mayonnaise based
      salads (21.28% (186/874)) as well as for prepared meals (11.70% (92/786)), the
      latter especially due to contamination of vegetarian meals.

PMID- 10598118
TI  - Damaging effects of the calcium paradox are reduced in isolated hearts from
      ethanol-dependent rats: paradoxic effects of dihydropyridine drugs.
AB  - Previous experiments showed that isolated hearts from ethanol-exposed rats show a
      marked increase in sensitivity to anoxic myocardial damage, and we suggested that
      this may be due to excess calcium entry through L-type voltage-operated calcium
      channels (L-VOCCs). To challenge this hypothesis, we investigated the effect of
      ethanol treatment ex vivo on a damaging stimulus, the "calcium paradox," which is
      associated with removal of calcium from the perfusate. Adult male Sprague-Dawley
      rats were exposed to intoxicating concentrations of ethanol for 6-10 days by
      inhalation. Isolated hearts from these animals were perfused with Krebs-Henseleit
      buffer by using a modified Langendorff technique, and the calcium paradox induced
      by a 10-min period of perfusion with calcium-free buffer, followed by reperfusion
      with calcium-containing buffer. Compared with controls, hearts from ethanol
      exposed rats were significantly protected against myocardial damage, as shown by
      a marked reduction in release of intracellular proteins (lactate dehydrogenase,
      creatine phosphokinase, and myoglobin) during the reperfusion phase. These
      indices of myocardial damage were modified by the presence of the dihydropyridine
      (DHP) calcium channel antagonist nitrendipine (10(-6) M) and the DHP L-VOCC
      activator Bay K 8644 (10(-7) M) in the perfusate during the calcium paradox.
      Paradoxically, both drugs appeared to increase the damaging effects of calcium
      free perfusion, with this effect being generally greater in the preparations from
      ethanol-exposed rats. As a result, the difference between these hearts and those
      from control rats was reduced, although a significant degree of protection
      against the calcium paradox remained. The results support the hypothesis that
      long-term exposure to ethanol in vivo produces marked alterations in the toxic
      effects of changes in myocardial calcium concentration. The increased sensitivity
      to DHP drugs of isolated hearts from ethanol-treated rats is consistent with
      previous experiments showing increased DHP radioligand-binding sites in these
      tissues.

PMID- 10598119
TI  - Combined selective angiotensin II AT1-receptor blockade and angiotensin I
      converting enzyme inhibition on coronary flow reserve in postischemic heart
      failure in rats.
AB  - We investigated whether angiotensin I-converting enzyme inhibition (ACEI) and
      angiotensin II AT1-receptor blockade (AT1-) would exert beneficial additive
      effects on coronary hemodynamics and on cardiac remodeling in post-myocardial
      infarction (MI) heart failure in rats. Wistar rats with MI were treated daily for
      6 weeks with either trandolapril (0.1 mg/kg), losartan (3 mg/kg), or their
      combination, after which coronary hemodynamics (basal and at maximal
      vasodilation, fluospheres), systemic hemodynamics, and cardiac remodeling were
      investigated. Neither trandolapril nor losartan (both in nonantihypertensive
      doses) nor their combination (which significantly decreased blood pressure)
      proved to be effective at improving MI-induced impairments of basal coronary
      hemodynamics and of coronary flow reserve, and at preventing cardiac fibrosis
      development. In contrast, both trandolapril and losartan significantly improved
      the hemodynamic status [e.g., left ventricular end diastolic pressure: -27% and 
      39%, urinary cyclic guanosine monophosphate (GMP): -37%, and -26%, respectively]
      and slightly limited cardiac hypertrophy (-5% and -3%, respectively), and, in
      their combination, tended to exert additive effects on these three parameters (
      49, -42, and -10%, respectively). Thus whereas the ACEI/AT1- combination tended
      to exert additive effects on systemic hemodynamics and cardiac hypertrophy in
      post-MI heart failure rats, no such effect was found for coronary hemodynamics,
      probably in relation to the lack of prevention of cardiac fibrosis. We conclude
      that an early (6 weeks) drug-induced improvement in coronary hemodynamics does
      not contribute to the long-term survival prolongation observed in this
      experimental model after either ACEI or AT1-.

PMID- 10598120
TI  - Vasopeptidase inhibition with omapatrilat improves cardiac geometry and survival
      in cardiomyopathic hamsters more than does ACE inhibition with captopril.
AB  - Vasopeptidase inhibitors are single molecules that inhibit neutral endopeptidase
      (NEP) and angiotensin-converting enzyme (ACE) simultaneously. Omapatrilat, the
      first in this new class of cardiovascular agents, potentiates vasodilatory and
      cardioprotective peptides and represses angiotensin II. This study compared the
      effects of omapatrilat with those of a pure ACE inhibitor on cardiac geometry and
      survival in animals with heart failure. BIO TO-2 cardiomyopathic hamsters (CMHs)
      in the early stages of dilated heart failure were treated with vehicle or maximal
      ACE inhibitory doses of captopril (750 micromol/kg/day) or omapatrilat (200
      micromol/kg/day). Prolonged vasopeptidase inhibition increased median survival
      time after the start of treatment by 99 and 31% compared with vehicle and
      captopril, respectively (median survival times: 146, 221, and 290 days with
      vehicle, captopril, and omapatrilat, respectively; p < 0.001 for all
      comparisons). In similar CMHs, captopril or omapatrilat administered for 2 months
      significantly (p < 0.05) decreased heart weight, pulmonary congestion (lung
      weight), and left ventricular (LV) chamber volume compared with vehicle.
      Omapatrilat significantly increased LV mass-to-volume ratio compared with vehicle
      and captopril. Omapatrilat, but not captopril, significantly increased urinary
      atrial natriuretic peptide excretion, indicating NEP inhibition. Thus
      vasopeptidase inhibition with omapatrilat was more effective than ACE inhibition
      with captopril in preventing changes in LV geometry and premature mortality in
      hamsters with dilated heart failure.

PMID- 10598121
TI  - Pharmacodynamic activity and antithrombotic efficacy of RPR120844, a novel
      inhibitor of coagulation factor Xa.
AB  - These studies were designed to examine the pharmacodynamic profile and
      antithrombotic efficacy of RPR120844, a competitive inhibitor of coagulation
      factor Xa, with a K(i) of 7 nM against human factor Xa. In vitro, RPR120844
      doubled activated partial thromboplastin time (APTT) at concentrations of 1.54,
      1.48, and 0.74 microM in plasma obtained from humans, dogs, and rats,
      respectively. Intravenous bolus administration of RPR 120844 at 0.3, 1, and 3
      mg/kg to rats resulted in maximal increases in APTT of 1.8-, 2.6-, and 8.4-fold
      over baseline, respectively. The effect on prothrombin time (PT) was less
      pronounced, resulting in a 4.4-fold increase at 3 mg/kg. These effects were
      rapidly reversible; APTT and PT returned to control values by 30 min after
      dosing. Intragastric administration to rats at 50, 100, and 200 mg/kg resulted in
      modest increases in APTT and PT of 1.5- and 1.3-fold over baseline at the highest
      dose. Plasma levels were estimated by anti-Xa activity by using an amidolytic,
      chromogenic assay. Plasma levels were 0.65, 1.29, and 2.45 microM at 30 min after
      dosing at 50, 100, and 200 mg/kg, respectively. Intravenous administration to
      dogs at 0.1 and 0.3 mg/kg produced maximal increases in APTT of 1.7- and 2.4-fold
      over baseline, respectively. Intragastric administration to dogs at 50 mg/kg
      resulted in maximal increases in APTT and PT of 1.7- and 1.1-fold over baseline,
      with peak plasma levels of 3.9 microM observed at 15 min after dosing. In a rat
      model of FeCl2-induced carotid artery thrombosis, RPR120844 (3 mg/kg, i.v. bolus
      + 300 microg/kg/min constant infusion; n = 4) significantly increased time-to
      occlusion from 18+/-1 min (vehicle, n = 4) to 60 min (maximal observation time)
      and reduced thrombus mass from 5.5 +/- 0.2 mg (vehicle) to 1.4 +/- 0.2 mg. These
      results indicate that RPR120844 is a potent, selective inhibitor of Xa that
      exhibits oral activity and is efficacious in a standard model of arterial
      thrombosis.

PMID- 10598122
TI  - Tolerance to nitrates with enhanced radical formation suppressed by carvedilol.
AB  - Enhanced oxidant stress occurs under many pathophysiologic conditions (e.g.,
      inflammation) and can be induced and mimicked by continuous nitrate therapy,
      eliciting increases in platelet activity, enhanced formation of reactive oxygen
      species (ROS), and impaired nitrate-induced vasorelaxation. Analysis was
      performed of effects of coinfusion of glycerol trinitrate (GTN) either with a
      carvedilol metabolite with antioxidant properties or with antioxidant vitamin C
      (Vit-C) on various hemodynamic parameters during enhanced oxidant stress
      associated with nitrate tolerance. Carvedilol metabolite (BM910228: 4.5
      microg/kg/min) or Vit-C (55 microg/kg/min) was coadministered with GTN (1.5
      microg/kg/min) for 5 days in chronically instrumented dogs. Changes in coronary
      diameters (CD) and other hemodynamic parameters were continuously monitored, as
      well as changes in platelet function. At the beginning of GTN treatment, CD
      increased by 9.8 +/- 0.4% and progressively declined to basal control values
      within 3 days. However, with additional antioxidant protection either with
      BM910228 or with Vit-C, the GTN-induced increase in CD was maintained (8.6 +/-
      0.4% or 10.5 +/- 0.6%) and remained elevated for the entire infusion period. The
      thrombin-stimulated intracellular Ca2+ concentrations of platelets remained
      nearly unchanged during Vit-C or BM910228 in contrast to the increase with GTN.
      The basal cyclic guanosine monophosphate (cGMP) contents of platelets after GTN
      coadministered with BM910228 or with Vit-C increased on day 1 to 233 or to 250%
      versus control and remained at that level. Additional in vitro tests with
      xanthine oxidase-induced oxidant stress resulted in a more or less pronounced
      scavenging of O2- radicals by BM920228, Vit-C, or superoxide dismutase (SOD).
      Coadministration of carvedilol metabolite BM910228 or of Vit-C along with GTN
      suppressed noxious effects of GTN-induced oxidant stress such as increased
      platelet activity and impaired nitrate-induced vasorelaxation.

PMID- 10598123
TI  - Milrinone improves arterial oxygenation in dogs with acute lung injury induced by
      oleic acid.
AB  - The aim of the study was to investigate effects of milrinone on pulmonary
      permeability in dogs with acute lung injury induced by oleic acid. To induce
      acute lung injury, we administered 0.08 mg/kg of oleic acid to 19 adult mongrel
      dogs and then measured hemodynamic parameters and performed blood gas analysis.
      An injection of oleic acid depressed the mean arterial pressure, cardiac index,
      and arterial oxygenation. Dogs were divided into three groups: six received a
      bolus of milrinone (50 microg/kg) followed by a continuous (0.5 microg/kg/min,
      low-dose), seven received a bolus (100 microg/kg) followed by a continuous (1.0
      microg/kg/min; i.e., a low-dose twice; high-dose), and six no milrinone
      (control). Milrinone administration improved the cardiac index and arterial
      oxygenation and simultaneously depressed the intrapulmonary shunt fraction and
      the extravascular thermal lung water as extravascular water content of the lung.
      These changes produced by milrinone are different according to the doses. In
      conclusion, milrinone acts on the capillary endothelium and inhibits an
      accumulation in the extravascular water content of the lung, which may induce an
      improvement in arterial oxygenation. Milrinone may also improve arterial
      oxygenation through an inhibition of platelet aggregation and chemical mediators
      that are released from platelets. The latter mechanism also may improve arterial
      oxygenation, and the exact property responsible for causing the effect of
      milrinone has not yet been identified.

PMID- 10598124
TI  - Effect of sodium orthovanadate treatment on cardiovascular function in the
      hyperinsulinemic, insulin-resistant obese Zucker rat.
AB  - We recently demonstrated that oral vanadate treatment ameliorates exaggerated
      vasoconstriction in aortic tissue from the hyperinsulinemic/insulin resistant
      obese Zucker rat. It has been suggested that changes in large artery
      contractility might contribute to the development of hypertension in this strain.
      Thus we examined the effect of vanadate treatment (0.5 mg/ml, p.o.) on
      conductance and resistance vessel function as well as blood pressure (BP) in
      Zucker rats. Vasoconstrictor responses to endothelin-1 (ET-1) and methoxamine and
      vasodilator responses to acetylcholine in the aorta and perfused mesenteric
      vascular bed served as indices of conductance and resistance function,
      respectively. Separate groups were treated with insulin (12 mU/kg/min, s.c.) to
      determine its role in the actions of vanadate. Vanadate treatment reduced (2.5
      fold; p < 0.05) elevated plasma insulin levels and abolished exaggerated aortic
      vasoconstriction in obese rats. Vasoconstrictor responses in the mesenteric bed,
      however, were similar between obese and lean rats, and were unaffected by
      vanadate. Vanadate did not affect elevated BP in obese rats and actually
      increased BP in the lean group. Insulin treatment per se failed to affect
      vasomotor function or BP in either strain, and acetylcholine-evoked relaxation
      was similar in all groups. We conclude that whereas vanadate overcomes
      exaggerated central artery contractility in obese Zucker rats, it fails to affect
      resistance vessel function or BP in this strain, and might conversely elevate BP
      in normotensive lean control rats. The vascular actions of vanadate in obese rats
      appear to occur independent of changes in plasma insulin or endothelial function.

PMID- 10598125
TI  - Effects of ACTH-induced hypertension in the pregnant ewe.
AB  - Adrenocorticotropic hormone (ACTH; 5 microg/kg/ day) infused into 10 pregnant
      ewes (gestation age, 127-139 days) for 72 h caused an increase in arterial
      pressure within 1-2 h (p < 0.05), which was sustained for the rest of the
      experiment. Cardiac output was increased at 24 h (p < 0.05). Total peripheral
      resistance did not change. There were no changes in four pregnant ewes infused
      with 0.15 M saline at the same rate for 72 h. In ACTH-treated pregnant ewes, a
      relation between arterial pressure and plasma renin activity observed in
      nontreated pregnant ewes (r = 0.71; p = 0.0005) was no longer evident. Compared
      with nonsurgical pregnant ewes, total angiotensin II (Ang II)-receptor density in
      the uterine artery was decreased in ewes that had previously had surgery (p =
      0.015) and further reduced in ACTH-treated ewes (p < 0.0005). This was due to a
      reduction in the AT2-receptor density, which was inversely related to plasma
      cortisol levels (r = 0.73; p < 0.03). AT1-receptor density and the affinities of
      the AT1 and AT2 receptors were unchanged. The correlation between plasma cortisol
      and AT2-receptor density in uterine blood vessels may partly explain why these
      receptors are downregulated after surgery.

PMID- 10598126
TI  - The effects of long-term infusions of angiotensin II into the pregnant ewe on
      uterine blood flow and on the fetus.
AB  - The effects of intravenous (i.v.) infusions of 62.5 microg/h of angiotensin II
      (Ang II) on maternal arterial pressure (MMAP), cardiac output (CO), and
      uteroplacental blood flow (UPF) were studied in 11 chronically catheterized
      pregnant ewes and their fetuses. Over the first 4 h of infusion, MMAP (p < 0.01)
      increased and CO decreased (p < 0.05). UPF and fetal PO2, PCO2, and pH were
      unchanged. After 16-24 h, MMAP increased further (p < 0.05-p < 0.005); UPF
      decreased (p < 0.05), and vascular resistance increased (p < 0.05). Fetal
      arterial PO2 decreased and PCO2 increased (p < 0.001; p < 0.05). There were
      correlations between fetal arterial PO2 and UPF (r = 0.6; p < 0.00005; n = 81),
      pH and UPF (r = 0.39; p < 0.0003; n = 81) and a negative correlation between PCO2
      and UPF (r = -0.5; p < 0.00005; n = 81). Infusions of 33 microg/h of
      noradrenaline initially caused a decrease in UPF. In the longer term, UPF was
      unchanged, as was UVR. There were no changes in fetal blood gases or pH, but
      there was a correlation between fetal arterial PO2 and UPF (r = 0.48; p < 0.01; n
      = 27). The short-term effects of Ang II and noradrenaline on UPF and UVR are
      similar to effects reported previously. The finding that long-term infusions of
      Ang II caused a reduction in UPF and compromised fetal gas exchange was
      unexpected. Thus the protective effect of reduced vascular reactivity of the
      uteroplacental circulation to Ang II is only a transient phenomenon.

PMID- 10598127
TI  - Potential downregulation of HMG-CoA reductase after prolonged administration of P
      407 in C57BL/6 mice.
AB  - This study investigated the potential alteration in the amount of 3-hydroxy-3
      methylglutaryl coenzyme A (HMG-CoA) reductase messenger RNA (mRNA) and
      lipoprotein lipase (LPL) mRNA in the livers of C57BL/6 mice after long-term (200
      days) treatment with the nonionic surfactant called poloxamer 407 (P-407).
      Previously, P-407 has been used to produce a dose-controlled hyperlipidemic state
      in C57BL/6 mice with subsequent formation of atherosclerotic lesions. Five groups
      of mice were studied; controls (C); mice fed a standard chow diet enriched with
      only cholic acid (CH); mice fed the high-cholesterol, high-fat Paigen diet (HF);
      mice treated with 0.5 g/kg P-407 every third day (P); and mice administered 0.5
      g/kg P-407 every third day while consuming a diet identical to that of mice in
      group CH (PC). Neither a significant (p < 0.05) weight loss nor alteration in
      liver enzymes (AST and ALT) were observed for any group throughout the study when
      compared with the control mice. Total plasma cholesterol (CHOL) was significantly
      elevated compared with controls for mice in groups HF, P, and PC, whereas total
      plasma triglycerides (TG) were significantly increased for mice in only groups P
      and PC. Long-term ingestion of a high-fat diet or a diet enriched in cholic acid
      resulted in a significant (p < 0.05) reduction in HDL-CHOL when compared with
      controls. Plasma samples assayed at 200 days for mice in groups HF and P showed a
      shift in the lipoprotein fraction distribution primarily to VLDL-CHOL as compared
      with mice in group C in which, as expected, most of the CHOL was contained in the
      HDL fraction. The biologic activity of HMG-CoA reductase assayed in hepatic
      microsomal homogenates was significantly reduced for mice in groups CH (p <
      0.01), HF (p < 0.01), and PC (p < 0.05), but not for mice in group P, when
      compared with control. A statistical analysis of the data demonstrated
      significant (p < 0.05) reductions in the HMG-CoA reductase mRNA levels in hepatic
      tissue for all treatment groups relative to mRNA levels determined for mice in
      group C. In contrast, no treatment group demonstrated a significant difference in
      hepatic LPL mRNA levels when compared with mRNA levels determined for control
      animals. These data demonstrate that P-407 administration to C57BL/6 mice
      significantly decreased the amount of HMG-CoA reductase mRNA detected in liver.

PMID- 10598128
TI  - Direct cardiac effects of a novel vesamicol receptor ligand, m-iodobenzyl
      trozamicol, assessed in the canine isolated, blood-perfused heart preparations.
AB  - MIBT, m-(iodobenzyl)trozamicol, is a recently discovered vesamicol analogue that
      can be used as a functional marker of cholinergic activity in the heart as well
      as the brain. The purpose of this study was to assess the effects of MIBT on
      sinus node automaticity, ventricular contraction, and coronary blood flow in
      addition to the action-potential duration of the ventricle by using canine
      isolated, blood-perfused sinoatrial node and papillary muscle preparations.
      Intracoronary administration of MIBT (1-300 microg) exerted negative
      chronotropic, inotropic, and coronary vasodilator effects in a dose-related
      manner. Pretreatment of the preparations with the muscarinic receptor antagonist
      atropine did not change these effects of MIBT. Moreover, MIBT had little effect
      on the repolarization phase of the ventricular action potential. Because the
      doses of MIBT needed for imaging cardiac cholinergic function were much lower
      than those affecting the cardiovascular system, MIBT may be used safely in future
      clinical applications.

PMID- 10598129
TI  - Preischemic and postischemic treatment with a new Na+/H+-exchange inhibitor,
      FR183998, shows cardioprotective effects in rats with cardiac ischemia and
      reperfusion.
AB  - This study describes the pharmacologic profile of a new Na+/H(+)-exchange
      inhibitor, FR183998, in anesthetized rats. FR183998 had a potent inhibitory
      effect on Na+/H+ exchange of rat lymphocytes with median inhibitory (IC50) value
      of 0.3 nM. Treatment with FR183998 (0.01-0.32 mg/kg, i.v.) reduced or completely
      abolished ventricular fibrillation and mortality induced by 5-min ischemia
      followed by reperfusion, when it was administered not only 5 min before ischemia
      but also 1 min before reperfusion. Myocardial infarct size induced by 30-min
      ischemia and 60-min reperfusion was reduced significantly in a dose-dependent
      manner by FR183998 (0.1-1.0 mg/kg, i.v.) when the drug was administered
      preischemically or at an early phase of ischemia. The ventricular tachycardia and
      the ventricular fibrillation observed during the ischemic period also were
      suppressed significantly. These results indicate that FR183998 has a strong
      inhibitory effect on Na+/H+ exchange and suggest that treatment with FR183998
      either before or immediately after the onset of ischemia can prevent the
      occurrence of arrhythmias and myocardial cell necrosis in situations of ischemia
      and reperfusion.

PMID- 10598130
TI  - Effects of the 21-aminosteroid U74389G in a model of chronic myocardial
      infarction in the rat.
AB  - 21-Aminosteroids are a group of new synthetic compounds developed as
      antiperoxidants. Although several studies have demonstrated their
      cardioprotective properties in acute ischemic models, none has assessed their
      long-term benefits after chronic myocardial infarction. In this investigation, we
      examined the cardioprotective effects of U74389G, a novel 21-aminosteroid, in a
      model of chronic myocardial infarction in the rat. After permanent ligation of
      the proximal branch of the left coronary artery, the experimental animals were
      treated daily by gavage with U74389G (10 mg/kg) for 21 days. After the study
      period, harvested hearts were perfused ex vivo and submitted to cold cardioplegia
      with 90-min global ischemia and 30-min reperfusion (surgical stress). Myocardial
      function and coronary endothelial (bradykinin, 1 microM) and smooth muscle
      (sodium nitroprusside, 1 microM) reactivity were assessed before and after
      exposure to the surgical stress. Percentage infarct size of the left ventricle
      was computed as the ratio of infarct area (mg)/total left ventricle (mg) x 100.
      During or immediately after surgery, there were eight deaths, which were
      considered technical failures. No further deaths occurred during the follow-up
      period (21 days). Compared with vehicle-treated rats, long-term administration of
      U74389G elicited a significant reduction of infarct size (percentage of left
      ventricle, 9 +/- 5% in the U74389G-treated group vs. 32 +/- 5% in the vehicle
      treated group; p < 0.01). Ex vivo heart-perfusion studies showed no significant
      difference in baseline coronary flow, left ventricular developed pressure, and
      heart rate between normal and chronic infarcted hearts treated with the vehicle
      or with U74389G. However, a reduced endothelium-dependent coronary dilator
      response was observed in infarcted hearts from vehicle-treated controls but not
      in those from U74389G-treated rats. When cardioplegia and global myocardial
      ischemia/reperfusion were added, most of the benefits from U74389G were lost.
      These results indicate that 21-aminosteroids can reverse oxygen-derived free
      radicals and lipid peroxidation-induced myocardial and coronary dysfunction
      associated with chronic myocardial infarction. However, additive protective
      measures are required when an acute ischemic stress is superimposed.

PMID- 10598131
TI  - Comparative effects of sodium bicarbonate and sodium chloride on reversing
      cocaine-induced changes in the electrocardiogram.
AB  - Cocaine abuse is associated with a number of cardiovascular complications that
      include arrhythmias and sudden cardiac death. Although the mechanism(s) remain
      unclear, cocaine-induced block of sodium channels resulting in slowed cardiac
      conduction is thought to play an important role. Several reports suggest that the
      effects of cocaine effects on cardiac sodium channels can be reversed by
      administration of sodium bicarbonate. Whether the beneficial effects of sodium
      bicarbonate are due to sodium ions or an increase in blood pH is unknown.
      Therefore the purpose of this study was to compare the effects of sodium loading
      alone (by using sodium chloride) versus sodium loading with an associated
      increase in arterial pH (by using sodium bicarbonate) on reversing cocaine
      induced effects on the electrocardiogram (ECG) in a canine model. Seventeen
      anesthetized dogs received three i.v. injections of cocaine, 5 mg/kg, with each
      dose separated by 15 min. Two minutes after the third cocaine dose, each dog was
      randomly assigned to receive 2 mEq/kg i.v. sodium bicarbonate (1 mEq/ml) or 2
      mEq/kg i.v. sodium chloride (1 mEq/ml). ECG, electrophysiologic, and hemodynamic
      data were recorded at baseline, after each cocaine injection, and after
      administration of sodium bicarbonate or sodium chloride. In both groups of
      animals, the first cocaine injection significantly (p < 0.05) prolonged the PR,
      QTc, AH, and HV intervals, and QRS duration compared with baseline. All intervals
      continued to lengthen in a dose-dependent manner after the second and third
      cocaine doses. Sodium bicarbonate significantly (p < 0.05) reduced cocaine
      induced prolongation of PR [(147 +/- 5-130 +/- 5 ms), AH (81 +/- 6 - 72 +/- 6
      ms), and HV intervals (55 +/- 2 - 39 +/- 1 ms). and QRS duration (96 +/- 6 - 66
      +/- 4 ms), peak effect after third cocaine dose versus after sodium bicarbonate,
      respectively]. Sodium chloride had no effect on reversing cocaine-induced effects
      on the ECG. Cocaine produces dose-dependent slowing of cardiac conduction that is
      effectively reversed by sodium bicarbonate. The lack of efficacy of sodium
      chloride suggests that the increase in arterial pH associated with sodium
      bicarbonate is responsible for reversal of the effects of cocaine on the ECG.
      Therefore sodium bicarbonate may be clinically useful in the treatment of cocaine
      induced cardiac arrhythmias, primarily as a result of its effects on arterial pH.

PMID- 10598132
TI  - Effects of atrial and brain natriuretic peptides on lysophosphatidylcholine
      mediated endothelial dysfunction.
AB  - Lysophosphatidylcholine (LPC), a major atherogenic lysophospholipid contained in
      oxidized low-density lipoprotein (ox-LDL), induces endothelial dysfunction.
      Recent studies showed that natriuretic peptides (NPs) have antiatherogenic
      properties by inhibiting vascular smooth-muscle cell proliferation, but their
      effects on endothelial cells are little known. We examined whether atrial and
      brain NPs (ANP and BNP) have a protecting action against LPC-induced endothelial
      dysfunction. LPC (10 microM) significantly inhibited thrombin (0.001-1 U/ml)
      induced endothelium-dependent relaxation without affecting endothelium
      independent relaxation to sodium nitroprusside in isolated porcine coronary
      arteries. The impaired endothelium-dependent relaxation induced by LPC was
      prevented by treatment with ANP or BNP (i microM). In cultured bovine aortic
      endothelial cells (BAECs), LPC (10 microM) significantly attenuated bradykinin (1
      microM)-stimulated nitric oxide (NO) release; however, this was prevented by ANP
      and BNP. Because LPC-induced endothelial dysfunction has been shown to be
      mediated at least in part by activation of the protein kinase C (PKC)-dependent
      signaling pathway, we also examined the effects of ANP and BNP on LPC-induced
      modulation of PKC activities in BAECs. LPC (10 microM) significantly stimulated
      PKC activity in BAECs. However, ANP or BNP significantly inhibited LPC (10
      microM)-induced PKC activation. In conclusion, ANP and BNP protected endothelial
      cells from LPC-induced dysfunction in both isolated coronary arteries and
      cultured ECs. The mechanism appears to be at least in part related to the
      inhibition of LPC-induced PKC activation by NPs. These new actions of ANP and BNP
      against lysolipid-induced endothelial cytotoxicity may partly account for
      antiatherogenic properties of NPs.

PMID- 10598133
TI  - Nitric oxide as a signaling molecule in the vascular system: an overview.
AB  - In retrospect, basic research in the fields of nitric oxide (NO) and cyclic
      guanosine monophosphate (cGMP) during the past two decades appears to have
      followed a logical course, beginning with the findings that NO and cGMP are
      vascular smooth muscle relaxants, that nitroglycerin relaxes smooth muscle by
      metabolism to NO, progressing to the discovery that mammalian cells synthesize
      NO, and finally the revelation that NO is a neurotransmitter mediating
      vasodilation in specialized vascular beds. A great deal of basic and clinical
      research on the physiologic and pathophysiologic roles of NO in cardiovascular
      function has been conducted since the discovery that endothelium-derived relaxing
      factor (EDRF) is NO. The new knowledge on NO should enable investigators in this
      field to develop novel and more effective therapeutic strategies for the
      prevention, diagnosis, and treatment of numerous cardiovascular disorders. The
      goal of this review was to highlight the early research that led to our current
      understanding of the pathophysiologic role of NO in cardiovascular medicine.
      Furthermore, we discussed the possible mechanism of some drugs interfering with
      NO signaling cascade.

PMID- 10598134
TI  - The influence of nanomolar ouabain on vascular pressor responses is modulated by
      the endothelium.
AB  - Ouabain has been shown to be an endogenous hormone that is synthesized and
      released from the adrenal cortex and is present in nanomolar to subnanomolar
      concentrations in plasma. It has been proposed that endogenous ouabain can
      increase vascular resistance and induce hypertension. This substance inhibits the
      Na(+)-pump activity, which leads to intracellular Na+ accumulation and ultimately
      to increased vascular tone. It is also suggested that circulating ouabain
      influences the vascular smooth muscle response to vasopressor substances.
      However, the mechanisms by which low concentrations of ouabain influence the
      smooth muscle, directly or acting through the endothelium, have not been
      completely elucidated. We tested the hypothesis that the endothelium exerts a
      modulatory effect on the actions of ouabain. In these studies, isolated rat-tail
      vascular bed preparations obtained from normotensive animals were used. The
      effects of 10 nM ouabain on the reactivity of the vascular smooth muscle to
      phenylephrine were determined under conditions in which endothelial function was
      preserved or reduced by endothelial removal and treatment with N(omega)-nitroL
      arginine methyl ester (L-NAME) or potassium channel blocker (tetraethylammonium;
      TEA). Results showed that ouabain enhanced the reactivity to phenylephrine. The
      enhancement of the reactivity to phenylephrine produced by ouabain was
      potentiated by deendothelialization and by using TEA, but it was reduced by
      treatment with L-NAME. The effect of 10 nM ouabain on the functional activity of
      the Na+,K(+)-adenosine triphosphatase (ATPase) also was evaluated. Na+,K(+)
      ATPase activity was reduced after 1-h treatment with ouabain. These results
      suggested that low concentrations of ouabain reduced the functional activity of
      the Na+,K(+)-ATPase and stimulated the release of a potassium channel opener,
      suggesting that the effects of ouabain are partially modulated by the
      endothelium.

PMID- 10598135
TI  - Cloning and characterization of marmoset renin: comparison with human renin.
AB  - The poor interspecies conservation of the renin-angiotensin system prevents the
      use of nonprimate in vivo models to test renin inhibitors. Thus the small New
      World monkey marmoset is used in many instances as a model. However, large
      differences between the potencies of renin inhibitors as measured in human and
      marmoset plasma were observed. To understand this phenomenon, we cloned marmoset
      renin and angiotensinogen. They were highly homologous to their human
      counterparts, except for a six-residue deletion in the marmoset renin propeptide.
      Human and marmoset recombinant renins were found in vitro to display comparable
      activities, suggesting that the observed differences in plasma apparent affinity
      of inhibitors could be due to different plasma protein binding of the inhibitors.

PMID- 10598136
TI  - The class III effect of azimilide is not associated with reverse use-dependence
      in open-chest dogs.
AB  - Certain class III antiarrhythmic agents manifest loss of effect at short cycle
      lengths (CLs). This effect may limit their efficacy in the presence of
      tachycardia. We studied the frequency-dependent effect of azimilide (NE-10064), a
      new class III agent, on the right ventricular monophasic action potential (APD90)
      in 12 open-chest dogs. The monophasic action-potential duration at different
      pacing CLs (140-400 ms), during sinus rhythm, and ventricular fibrillation CL
      (VFCL) from left epicardial electrograms were recorded before and after
      increasing doses of intravenous azimilide. At pacing CL of 400 ms, APD90 was
      significantly prolonged after 7, 17, and 30 mg/kg of azimilide by 5.4, 7.7, and
      10.7%, respectively. The extent of APD90 prolongation was independent of rate.
      Azimilide increased the APD90 by similar amounts at CL of 400 ms and at the
      fastest possible stimulation rate maintaining 1:1 capture (mean, 171 +/- 23 ms):
      by 2.6 +/- 8.6% and 5.6 +/- 5.9% at 2 mg/kg, 5.4 +/- 4.8% and 4.8 +/- 4.7% at 7
      mg/kg, 7.7 +/- 5.6% and 9.9 +/-4.5% at 17 mg/kg, and 10.7 +/- 2.6% and 19.3 +/-
      11.9% at 30 mg/kg, respectively. Azimilide caused no changes in arterial blood
      pressure or heart rate. Azimilide prolongs APD90 even at very short CLs. The
      absence of reverse use-dependence of effect on APD90 may have clinical
      importance.

PMID- 10598137
TI  - Effect of aging on the negative chronotropic and anti-beta-adrenergic actions of
      adenosine in the rat heart.
AB  - The effect of aging on the antiadrenergic actions of adenosine was studied in
      vitro and in vivo by using adult (6-month-old) and old (24-month-old) male
      Fischer 344 rats. In anesthetized animals, adenosine (0.01-0.1 micromol/kg),
      given as a rapid bolus into the right atrium, exerted a negative chronotropic
      effect manifested by a dose-dependent transient prolongation of sinus cycle
      length (SCL). This effect was similar in both age groups (n = 6, each; i.e., the
      percentage maximal prolongation of SCL (%deltaSCL) ranged from 12 +/- 2% to 63 +/
      14% in the adult and from 20 +/- 7% to 57 +/- 15% in the old rats. In the
      presence of isoproterenol (0.2 microg/kg/min), the negative chronotropic action
      of adenosine was potentiated in the adult rats much more than in the old rats
      [i.e., %deltaSCL ranged from 60 +/- 28% to 183 +/- 48% vs. 40 +/- 12% to 70 +/-
      13%, respectively (p < 0.05, adult vs. old)]. In the isolated perfused hearts,
      isoproterenol (1 microM for 1 min) exerted similar chronotropic and inotropic
      effects in adult (n = 9) and old hearts [n = 6; i.e., heart rate, left
      ventricular pressure (LVP), and LVdp/dt increased by 56 +/- 3%, 17 +/- 1%, and 37
      +/- 2%, and 57 +/- 2%, 17 +/- 1%, and 35 +/- 3%, respectively, in the absence of,
      and by 27 +/- 2%, 7 +/- 1%, and 19 +/- 2% and 41 +/- 3%, 12 +/- 1%, and 25 +/-2%
      in the presence of adenosine (5 microM for 1 min)]. Adenosine administration
      after isoproterenol caused only an insignificant increase in coronary blood flow.
      Finally, the adenosine attenuation of either isoproterenol- or forskolin-induced
      production of 3',5'-cyclic adenosine monophosphate (cAMP) was significantly less
      in atrial membranes isolated from old versus adult rats (n = 6, each). It was
      concluded that in the old Fischer 344 rat hearts, the antiadrenergic action of
      adenosine is attenuated as compared with its action in adult rat hearts.

PMID- 10598138
TI  - Norepinephrine release and ventricular fibrillation in myocardial
      ischemia/reperfusion: roles of angiotensin and bradykinin.
AB  - Exogenous bradykinin (BK), acting at B2-receptors, enhances norepinephrine (NE)
      release and exacerbates arrhythmias (VF) in myocardial ischemia/reperfusion.
      Inhibition of BK formation (with serine proteinase inhibitors) alleviates NE
      release and VF, whereas prevention of BK degradation (with kininase inhibitors)
      potentiates them. Yet serine proteinase and kininase inhibitors also prevent the
      formation of angiotensin (AII), a potent NE-release enhancer. Thus we assessed
      the respective contribution of AII and BK to NE release and VF by using selective
      B2- and AT1-receptor antagonists. Isolated guinea pig hearts were subjected to 10
      and 20-min global ischemia and 45-min reperfusion. NE overflow (pmol/g) was
      approximately 8 (exocytotic) and approximately 750 (carrier mediated). VF,
      associated with carrier-mediated NE release, lasted approximately 2 min. The B2
      receptor antagonist Hoe 140 (30 nM) affected neither NE overflow nor VF. In
      contrast, the AT1-receptor antagonist EXP3174 (100 nM) markedly reduced
      exocytotic and carrier-mediated NE release and shortened VF. When EXP3174 was
      combined with Hoe 140, NE overflow and VF were decreased even further. Thus in
      myocardial ischemia, local AII production contributes to NE release and VF via
      AT1-receptors. Although BK production increases in myocardial ischemia, the
      effects of BK on adrenergic nerve terminals are uncovered only when BK half-life
      is prolonged and/or when AII effects are suppressed.

PMID- 10598139
TI  - Comparative genomic hybridization reveals novel chromosome deletions in 90
      primary soft tissue tumors.
AB  - Comparative genomic hybridization (CGH) was used to detect chromosomal gains and
      losses in a series of 90 frozen soft tissue primary tumors (STTs), all untreated.
      The material consisted of 69 malignant sarcomas, including 20 malignant fibrous
      histiocytomas (MFH), 23 liposarcomas (LPS), 6 leiomyosarcomas (LMS), 4 synovial
      sarcomas, 4 primitive neuroectodermal tumors (PNETs), and various others
      subtypes, in addition to 21 benign tumors. Within the benign tumors, only 2 of
      the 3 schwannomas showed genetic changes. In malignant sarcomas, genetic changes
      were detected in 64 of the 69 samples analyzed (92%), with a mean of 4.5 per
      sample (range 0-10). Gains and losses on chromosome 13 were observed in 32% of
      the sarcomas with genomic imbalance. Recurring low-level copy number increases
      were found at new sites on chromosomes 7 (6 MFH samples, 30%) and 8 (10 LPS
      samples, 43%), the minimal common regions being 7p15-pter and 8q24. No new
      recurring high-level amplifications were found. Surprisingly, losses of DNA
      sequences were more frequent than gains; particularly, losses were the main
      feature in LMS, with highly recurrent common minimal losses at 11q14-qter and
      13q21-q22 (4 samples, 66%, and 5 samples, 83%, respectively). Losses of
      chromosome 2 sequences (minimal common regions at 2p24-pter and 2q32-qter) were
      observed in 50% of the MFH analyzed. New recurrent losses of whole or part of
      chromosome 14 were found in 57% of the pleomorphic LPS (PLPS) analyzed. This
      study uncovers new clues for the diagnosis of malignant STTs and shows the
      importance of deletions as events in the early steps involved in the
      tumorigenesis of STTs.

PMID- 10598140
TI  - Cytogenetic study of 33 ependymomas.
AB  - Ependymomas are glial tumors. They constitute approximately 5-10% of intracranial
      tumors. Ependymomas are tumors which can recur. Predictive factors of outcome in
      ependymomas are not well-established. Karyotypic studies on ependymomas are
      relatively scarce, and no specific chromosomal change has been described in these
      neoplasms. We performed a cytogenetic study of 33 ependymomas, of which eight
      were recurrent tumors, to determine the type and incidence of cytogenetic
      changes.

PMID- 10598141
TI  - Hemizygous deletions of chromosome band 16q24 in Wilms tumor: detection by
      fluorescence in situ hybridization.
AB  - Loss of heterozygosity (LOH) for markers on chromosome arm 16q in Wilms tumor has
      been linked to an increased risk of treatment failure. We therefore postulated
      that fluorescence in situ hybridization (FISH) with probes from this region might
      enhance current strategies for identifying high-risk patients at diagnosis. In a
      blinded comparative pilot study of 19 Wilms tumor samples from 18 patients with
      favorable histology, FISH and DNA polymorphism analysis yielded concordant
      results in 14 cases, either retention (n = 6) or loss (n = 8) of chromosome arm
      16q markers. Discordant findings in 4 of the 5 remaining cases resulted from
      detection of LOH, but no loss by FISH. Two of these cases, directly comparable at
      marker D16S422, appeared to have tumor-specific uniparental disomy, in that 2
      copies of D16S422 and the 16 centromere were evident, despite LOH. In 2 other
      cases, the discrepancies could be explained by LOH confined to loci distal to the
      D16S422 locus. In the fifth case, FISH detected 2 distinct populations of tumor
      cells, one characterized by normal diploidy and the other by monosomy 16, whereas
      DNA polymorphism analysis failed to indicate LOH altogether. Thus, FISH confirmed
      the presence of allelic loss (hence, the possible location of biologically
      important tumor suppressor genes) on the distal long arm of chromosome 16 in
      cases of favorable-histology Wilms tumor, with the advantages of technical
      simplicity, successful analysis of samples that were otherwise uninformative by
      analysis of DNA polymorphisms, and the addition of internal controls for
      chromosomal aneusomy. We suggest that combined analysis of the chromosome 16q
      region in Wilms tumor by FISH and DNA polymorphism analysis would improve
      evaluations to identify high-risk patients who might benefit from alternative
      therapy.

PMID- 10598142
TI  - Discordant detection of monosomy 7 by GTG-banding and FISH in a patient with
      Shwachman-Diamond syndrome without evidence of myelodysplastic syndrome or acute
      myelogenous leukemia.
AB  - The myelodysplastic syndromes (MDS) are a group of hematologic disorders commonly
      affecting elderly persons and often leading to acute myelogenous leukemia (AML).
      Although rare in children, when MDS does occur, it is frequently part of a
      congenital disorder such as Shwachman-Diamond syndrome (SDS). Monosomy 7 and/or
      deletion of part or all of 7q are poor prognostic signs in MDS and AML, although
      the pathophysiologic relationship between this finding and MDS or AML is unclear.
      Shwachman-Diamond syndrome is an inherited illness characterized by exocrine
      pancreatic insufficiency and by congenital neutropenia. Patients with SDS are at
      increased risk of developing myelodysplastic syndrome (MDS) and acute myelogenous
      leukemia (AML). Because monosomy 7 is a poor prognostic sign in MDS and AML,
      establishing its presence is important. However, different methods of detection
      of monosomy 7 may lead to different results in some patients. We present the case
      of a 10-year-old girl known to have SDS, who had a bone marrow aspiration and
      biopsy done to rule out MDS and AML. By light microscopy, the patient's bone
      marrow was unremarkable. GTG-banding showed the following karyotype: 45,XX,
      C[3]/47,XX,+C[1]/46,XX[45]. Fluorescence in situ hybridization (FISH) was
      performed with a chromosome 7-specific alpha-satellite probe (D7Z1). Almost all
      (373 of 376) cells exhibited only one chromosome 7 signal. A second marrow
      aspiration done 6 months later showed an essentially normal karyotype by GTG
      banding. Fluorescence in situ hybridization with the same chromosome 7 probe
      showed 230 of 250 cells to be monosomic for chromosome 7. A whole chromosome 7
      painting probe demonstrated disomy for chromosome 7 in 90 of 90 cells; however,
      subtle heteromorphism in the centromeric regions of the 2 copies of chromosome 7
      was noted in some cells. This case demonstrates that FISH and GTG-banding can
      give discordant results, that the two should be viewed as complementary
      technologies, and that both have a place in a full karyotypic analysis.
      Furthermore, this case demonstrates for the first time that heteromorphism and/or
      subtle structural abnormalities of chromosome 7, previously associated with MDS
      and AML, can exist without clinical or morphologic signs of these illnesses. It
      will be of interest to further study the relationship, if any, between SDS and
      various structural abnormalities of chromosome 7 in MDS and AML, and to elucidate
      the molecular mechanisms of pathogenesis, physiology, and treatment of these
      disorders.

PMID- 10598143
TI  - Chromosomal aberrations in young cancer patients.
AB  - Spontaneous level of chromosomal aberrations (CA) is considered to be indicative
      of inherent cancer predisposition, which plays a major role in total cancer
      incidence. We have studied spontaneous CA levels in in vitro cultured peripheral
      blood lymphocytes of pediatric cancer patients (n = 77). Results were compared
      with those of control subjects (n = 72), including: age-matched controls; elder
      controls (minimum age 60 years); and healthy first-degree relatives (FDR) of
      pediatric cancer patients. Pediatric cancer patients showed the highest mean
      CA/cell value, which was statistically significant as compared to their age
      matched counterparts, elder controls, and the FDRs. As compared to 7% of all the
      three control groups collectively, 32.4% of pediatric cancer patients showed >
      0.1 mean CA/cell value. One of the FDRs with a very high frequency of CA
      developed cancer within three years. The results suggest that spontaneous levels
      of chromosomal aberrations may be used as one of the biomarkers for cancer
      predisposition study.

PMID- 10598144
TI  - TP53 status and gene amplification in human colorectal carcinomas.
AB  - Gene amplification is one of the characteristics of cancer cells. In vitro
      studies suggested that alterations of the TP53 gene might be responsible for gene
      amplification. We have examined the presence of TP53 mutations and looked for
      cytogenetic evidence of gene amplification in a series of 79 primary colorectal
      carcinomas. Other parameters such as the pattern of cytogenetic alterations,
      microsatellite instability, tumor site, and histological staging were also
      considered. A multiparametric study supported by statistical analyses suggests
      the existence of two major pathways of colorectal carcinogenesis. No
      relationships could be established between the presence of TP53 alterations and
      gene amplification.

PMID- 10598145
TI  - Cytogenetic analysis of upper urinary tract transitional cell carcinomas.
AB  - Ten primary (nine regular and one post-radiation) upper urinary tract
      transitional cell carcinomas (TCC), i.e., tumors of the renal pelvis and ureter,
      were obtained from 10 patients following nephroureterectomy and processed for
      cytogenetic analysis after short-term culturing. Clonal chromosomal aberrations
      were found in eight tumors. While 10 karyotypically related and/or unrelated
      clones were detected in the post-radiation tumor, cytogenetic monoclonality was
      seen in all other tumors. With the exception of two tumors with loss of the Y
      chromosome as the only change, chromosome 9 was invariably involved, either with
      loss of the entire chromosome or with partial loss from the short arm. Our
      findings indicate that the karyotypic profile of upper urinary tract TCC is
      identical to that of bladder TCC, an indication that the same pathogenetic
      mechanisms are at work in both regions.

PMID- 10598146
TI  - Clonal karyotypic abnormalities in gynecomastia.
AB  - Gynecomastia is a benign condition that frequently occurs in the male breast
      gland; however, the cytogenetic data on this entity are very limited. To our
      knowledge, three cases have been reported in the literature, and the only one
      with an abnormal karyotype had a concomitant breast carcinoma. In this study we
      report clonal chromosomal alterations in a gynecomastia sample without any signs
      of adjacent malignant tissue. The nonrandom abnormalities observed were a
      deletion of 12p, monosomies of chromosomes 9, 17, 19, and 20, and the presence of
      a marker chromosome. Most of these alterations have been previously described in
      the literature in other breast lesions, including benign and malignant (male and
      female) tumors, indicating their recurrence and nonrandomness in abnormal
      processes of the mammary gland.

PMID- 10598147
TI  - der(11)t(1;11)(q11;p15) as an additional cytogenetic abnormality in Ph+ adult
      acute lymphoblastic leukemia.

PMID- 10598148
TI  - [Pain in the elderly. A study of 183 consecutive subjects hospitalized in a
      geriatric medical ward].
AB  - OBJECTIVES: Determine the prevalence of pain and related demographic, somatic,
      emotional, and therapeutic variables in hospitalized elderly subjects. PATIENTS
      AND METHODS: One hundred eighty-three elderly patients consecutively hospitalized
      in the geriatric medical unit were included in a cross-sectional study. RESULTS:
      Pain was observed in 48.3% of patients with sustained cognitive function and
      67.7% of patients with impaired cognitive function. In the first group (sustained
      cognitive function) no variable was significantly associated with pain except the
      diagnosis of general geriatric problems (falls, dehydration, drug intoxication).
      Conversely, in the second group (patients with impaired cognition) the presence
      of pain was significantly associated with a serious alteration of the somatic
      status (malnutrition, inflammation, bedridden status), poor prognosis (long
      lasting hospitalization, death), and the presence of anxiety. Finally, patients
      suffering from pain did not receive pore pain killers than patients without pain.
      CONCLUSION: This study clearly demonstrates that pain has a high prevalence in
      aged hospitalized patients, especially those who have impaired cognitive
      function. It reveals a relationship between pain, somatic and psychic
      deterioration, and deficiency in pain-killer prescriptions.

PMID- 10598149
TI  - [Evaluation of intravenous immunotherapy with purified F(ab')2 fragments
      (Viperfav)].
AB  - OBJECTIVES: To assess early clinical and biological prognosis factors in viper
      envenomings, and assess efficacy of Viperfav immunotherapy. Viperfav contains
      purified F(ab')2 fragments of equine antibodies. PATIENTS AND METHODS: A
      retrospective case review study of viper envenomings collected by two poison
      centers in France, treated or not treated by Viperfav, was conducted. Two hundred
      seven cases of viper bites including 119 moderate or severe envenomings (Grade II
      and III, recorded in adults and children and collected from 1992 to 1997 were
      included. Before treatment, clinical gradation and early biological severity
      criteria were collected. After treatment, or grade II and III envenomings, the
      two treatment groups were compared concerning severity and frequency of
      complications and sequelae, duration of hospitalization in intensive care unit
      (ICU) and duration of total hospital stay. RESULTS: Before treatment, both groups
      were not significantly different. In the Viperfav treatment group, there was a
      significantly lower incidence of complications (4% vs. 21%, p = 0.02) and
      sequelae (0% vs 14%, p = 0.006). ICU stay greater than 3 days occurred in 28% of
      patients in the symptomatic treatment group and no case was recorded in the
      Viperfav group (p = 0.0002). Total hospital stay was reduced significantly in the
      Viperfav group versus symptomatic treatment group (3.3 vs. 8.7 days, p =
      0.000002). CONCLUSIONS: Viperfav immunotherapy was safe and effective for rapidly
      counteracting venom toxicity and improved markedly the prognosis of viper
      envenomations. The studied clinical and biological prognosis factors are valuable
      tools for predicting moderate or severe envenomings and are helpful for early
      prescription of Viperfav antivenom.

PMID- 10598150
TI  - [Hypokalemic quadriplegia with distal tubular acidosis revealing a a case of
      primary Gougerot-Sjogren syndrome].
AB  - BACKGROUND: Primary Sjogren's syndrome is associated in 6 to 25% of cases with
      kidney involvement Most often it is a chronic interstitial nephritis, generally
      asymptomatic but sometimes responsible for distal tubular acidosis which can be
      complicated by severe hypokalemia. CASE REPORT: A 48-year-old woman had
      hypokalemic quadriplegia, distal renal tubular acidosis and chronic interstitial
      nephritis at kidney biopsy. Primary Sjogren's syndrome was diagnosed. DISCUSSION:
      We discuss briefly the clinical, biological and immunological features of 18
      similar cases reported in the literature.

PMID- 10598151
TI  - [Aseptic meningitis after ranitidine treatment for systemic lupus erythematosus].

PMID- 10598152
TI  - [Corynebacterium glucuronolyticum lower urinary tract infection].

PMID- 10598153
TI  - [Nosocomial pneumococcal meningitis complicating herpes meningoencephalitis].

PMID- 10598154
TI  - [Breast cancer screening: 14 years of surveillance].

PMID- 10598155
TI  - [Desirudine (Revasc): preventive therapy for deep venous thrombosis].

PMID- 10598156
TI  - [Vaccinations. Recent changes].

PMID- 10598157
TI  - [Anorectal echo-endoscopy: applications in pediatrics].
AB  - PEDIATRIC INDICATIONS: Anorectal echoendoscopy is widely used in adults for the
      pretreatment work-up of rectal cancer and for the exploration of fecal
      incontinence. It can also be useful in the pediatric setting as recently
      described with rotative or linear heads. The exploration can be performed after
      an evacuating enema or if needed after giving a neuroleptanalgesic. The anorecal
      walls and neighboring areas-bladder, genital organs, perirectal spaces, vessels
      can be explored. The ultrasonographic aspect of the walls is similar to that
      described in adults although less thick, particularly at the level of the anus
      sphincters. Signs of defects, abscesses and fistulizations are the same as in
      adults. BOWEL DISORDERS AND INCONTINENCE: Echoendoscopy can characterize rare
      subepithelial tumors of the rectum and vascular anomalies, but its main interest
      is for the exploration of bowel disorders and incontinence, particularly after
      surgical treatment for anorectal malformations. The quality of the muscular
      tissue and the quality of the surgical repair can be assessed before deciding on
      the need for a second operation. In this context, anorectal echoendoscopy can
      also disclose Hirschsprung's disease and other forms of idiopathic megarectum,
      including certain types with major thickening of the internal sphincter. It can
      also detect defects induced by prior disimpaction maneuvers. A NONINVASIVE EXAM:
      Anorectal echoendoscopy is a promising exploration technique in pediatric
      gastroenterology. Descriptions of the sphincters and anorectal anatomy are very
      precise and descriptions of functional disorders, whether primary or secondary to
      surgery, can be quite helpful for guiding subsequent management.

PMID- 10598158
TI  - [Smoke poisoning].
AB  - SYSTEMIC AND LOCAL EFFECT: Smoke inhalation causes systemic and local, mainly
      respiratory, toxicity due to the asphyxiant and irritant properties of toxic
      gases. OXYGEN DEPRIVATION AND INTOXICATION: The syndrome of oxygen deprivation
      and intoxication by asphyxiant gases is caused by combustion-induced oxygen
      deprivation and exposure to carbon monoxide (CO) and cyanide (CN), but also to
      other toxic gases. A loss of consciousness is a good sign of systemic toxicity;
      however, the respective role of CO, CN and other toxic gases cannot be
      determined. The presence of apnea, lactic acidosis, and severe cardiovascular
      disturbances is consistent with CN poisoning. A correlation exists between blood
      CO concentration determined on a sample obtained at the site of the fire, and the
      occurrence and severity of the clinical disorders. IRRITANT GASES INTOXICATION:
      This syndrome explains the mucosal injury affecting the eyes and the lungs. These
      complications are better diagnosed by clinical examination rather than by various
      investigations such as chest X-ray or fiberoptic bronchoscopy. Dysphonia is
      always a sign of severe poisoning. CLINICAL COURSE: In non-burned victims,
      delayed neurological and respiratory complications can be observed. Oxygen
      administration is the cornerstone supportive therapy. Hyperbaric oxygen should be
      discussed according to the severity of the syndrome of oxygen deprivation and
      intoxication by asphyxiant gases. In case of cyanide poisoning, a safe and
      effective antidote should be given; hydroxocobalamine seems to be the drug of
      choice. Supportive treatment is efficient to treat respiratory failure.
      Endotracheal intubation should be considered in patients exhibiting early
      dysphonia associated with dyspnea.

PMID- 10598159
TI  - [Systemic mastocytosis].
AB  - HEMATOPOIESIS DISORDER: Systemic mastocytosis is a primary proliferation of mast
      cells in several noncutaneous tissues. It remains an uncommon disease, difficult
      to diagnosis and often missed. The spectrum of clinical signs is wide and the
      course and prognosis are quite variable. CLINICAL ASPECTS: Sudden release of
      mediators by mast cell degranulation lead manifestations of paroxysmal
      congestion. Pigmentary urticaria is the most frequent cutaneous form. Among
      visceral localizations, bone involvement is encountered in 90% of the cases,
      digestive tract and hematological involvement are less frequent. Respiratory and
      cardiovascular involvement is exceptional. DIAGNOSIS: Osteomedullary biopsy is
      required for diagnosis. Urinary histamine metabolites may be suggestive.
      PROGNOSIS: Prognosis depends on the presence of an associated hematological
      disorder, found in 30% of the cases. TREATMENT: Symptomatic treatment is the
      rule, aimed at blocking histamine release by mast cell degranulation and avoid
      the subsequent paroxysmal manifestations.

PMID- 10598160
TI  - [Erysipelas, cellulitis and other severe Streptococcus pyogenes skin infections].
AB  - INCIDENCE AND GRAVITY: Invasive Streptococcus pyogenes infections are a common
      reason for hospitalization. Serious forms may occur in patients with no known
      risk factor, including young patients. Inversely, erysipela is observed more
      readily in the elderly population with a more vulnerable venous system. Disease
      gravity is related to the high risk of recurrence. For cellulitis, predominantly
      a disease of young subjects with no past history, severity is related to local
      extension and development of shock syndrome. Besides the immediate life
      threatening situation, functional prognosis may be compromised, depending on the
      localization of the infection. PATHOGENESIS OF GROUP A STREPTOCOCCAL INFECTIONS:
      Adherence and invasion properties of group A streptococci, particularly the
      capsule and protein M, as well as streptococcal toxins cause severe septic and
      toxinic syndromes. Strains most frequently associated with invasive infections
      are: biotype 1, serotype M1 and biotype 3, serotype M3. TREATMENT: An antibiotic
      regimen by intravenous infusion of penicillin G is the gold standard treatment.
      Clindamycin should be added in case of septic shock. Extensive cellulitis or
      necrotizing fasciitis requires surgical debridement of the necrotic tissue and
      intensive care for the shock syndrome.

PMID- 10598161
TI  - [Differential diagnosis of space-occupying adrenal masses].
AB  - Computed tomography (CT) and magnetic resonance (MR) imaging are first line
      modalities in the evaluation of patients with adrenal gland masses, and have the
      potential to be very accurate for the localization of adrenal gland masses in
      patients with diseases associated with hyperfunctioning conditions of the adrenal
      gland. Both CT and MR imaging allow a specific diagnosis of acute adrenal
      hemorrhage, adrenal myelolipoma, and adrenal cysts. CT is also helpful in the
      assessment of patients with Addison's disease, particularly the subacute form
      secondary to granulomatous diseases. Quantitative evaluation of adrenal masses on
      unenhanced CT scans and/or qualitative analysis on chemical-shift MR imaging have
      been shown to be accurate in distinguishing adrenal adenomas from non-adenomas.
      Attenuation of 11 HE or less on unenhanced CT scans and/or signal loss on opposed
      phase MR images indicate adenoma with a high specificity and acceptable
      sensitivity. More recently, delayed-enhanced CT has yielded higher sensitivity
      and specificity values in distinguishing between adrenal adenomas and non
      adenomas than both unenhanced CT and chemical-shift MR imaging do. On delayed
      enhanced CT scans, adrenal adenomas exhibit a greater washout of contrast
      material than do adrenal non-adenomas. Therefore, adrenal non-adenomas have
      significantly higher attenuation than adenomas on delayed-enhanced CT scans
      obtained at several arbitrarily chosen time points (3-60 min) after the
      initiation of contrast material administration.

PMID- 10598162
TI  - [Simple volumetry of ischemic cerebral infarction using computerized tomography.
      Interobserver and method comparison].
AB  - PURPOSE: To study the reliability of brain infarct volume assessment with ruler
      and calculator. METHODS: The brain infarctions of 45 patients were measured using
      3 different methods on CT scans: In each section showing the lesion, the largest
      diameters were measured and multiplied by the slice thickness using the formula
      for A) an ellipsoid and B) a cylinder. The sectional volumes were summed up to
      calculate the entire lesion volume. C) Using the ellipsoid formula, the thickness
      of all sections showing the lesion were added and used as the third diameter
      which was multiplied with the two largest diameters of the lesion. The lesion
      volume was also assessed by planimetry on a workstation and served as reference.
      Using method A, two independent investigators measured 93 brain infarcts of 49
      patients to assess the 95% confidence interval (CI) of agreement. RESULTS:
      Compared to the reference, method A underestimated the volumes by -25%, method B
      overestimated the volumes by +12.5%, and method C by +18.6%. The mean difference
      between the two investigators was 2 ml. The 95% CI for small infarcts < or = 50
      ml was 60%-150%, for larger infarcts +/- 26 ml. CONCLUSION: This simple method is
      only reliable when changes in infarct volume exceeding 26 ml are to be detected.

PMID- 10598163
TI  - [Rotational digital subtraction angiography of carotid bifurcation stenosis].
AB  - PURPOSE: A prospective study was designed to evaluate, whether multiplanar
      imaging with rotational digital subtraction angiography (R-DSA) could improve
      assessment of carotid artery bifurcation stenosis. PATIENTS AND METHODS: 45
      patients with suspected stenosis of the ICA were examined with DSA in standard
      projections (0 degree-(45 degrees)-90 degrees) and additional R-DSA of each ICA
      from 0-90 degrees in 10 degrees steps. We compared imaging quality and degree of
      stenosis as well as exposure of the patients to radiation and contrast media.
      RESULTS: 79/82 R-DSA (96%) were suitable for evaluation of stenosis, 58/82 (70%)
      matched the quality standard of single projection DSA. Specificity and
      sensitivity of the R-DSA to diagnose high grade ACI stenosis were 100% and 94%,
      respectively. 7/79 R-DSA revealed a higher and 3/79 a lower degree of stenosis
      than the corresponding DSA. Regarding the degree of stenosis there was no
      significant difference between the two modalities (p > 0.05), but R-DSA detected
      4 stenoses greater than 60% that were estimated to be lower than 60% by DSA.
      Radiation dose for R-DSA was equivalent to one DSA run (170 cGycm2). The average
      amount of contrast media (25 ml) was slightly higher than for 2-3 single
      projection DSA (19.8 ml). CONCLUSIONS: R-DSA provides high quality imaging of the
      carotid bifurcation with multiplanar projections facilitating exact grading of
      vessel stenosis. The number of cases (n = 2) is to small to judge the value of R
      DSA as to (tandem-) stenosis of the distal ICA. Still, diagnostic value and low
      radiation exposure justify the use of R-DSA as additional series to standard
      protocols.

PMID- 10598164
TI  - [MRI with fat suppression in the visualization of wall hematoma in spontaneous
      dissection of the internal carotid artery].
AB  - PURPOSE: Comparison of different MR-examination techniques for the diagnosis of
      acute spontaneous internal carotid artery dissection. PATIENTS AND METHODS: 13
      patients (age range 23-59 years) with symptomatic spontaneous dissection of the
      internal carotid artery were examined. The MRI protocol contained a transverse
      spin echo sequence, a time-of-flight MR-angiography and a coronal fat suppressed
      T1-weighted sequence. The earliest examination was performed three days after
      symptom onset. Follow-up extended up to 30 months. We compared the three
      different sequences to find out the one that demonstrated the hematoma best.
      RESULTS: MR-angiography shows a narrowing of the vessel diameter in early
      examinations. During the subacute stage methemoglobin can obscure this finding.
      From the third day on fat suppressed T1-weighted images showed a hyperintense
      hematoma that strongly contrasted to the surrounding fatty tissue. Fat suppressed
      images showed a hyperintense hematoma up to 10 months after symptom onset while
      MRA and spin echo sequences did not. CONCLUSIONS: Fat suppressed T1-weighted
      images are superior in showing vessel wall hematoma and should thus be used in
      the standard MR-protocol for spontaneous internal carotid artery dissection.

PMID- 10598165
TI  - [Importance of digital thoracic radiography in the diagnosis of pulmonary
      infiltrates in patients with bone marrow transplantation during aplasia].
AB  - PURPOSE: Evaluation of digitized chest x-ray for the detection of pulmonary
      infiltrations in bone marrow transplant patients during aplasia. METHODS:
      Digitized chest x-rays of 40 patients (21 female, 19 male) with "Fever of unknown
      origin" (FUO) were evaluated concerning radiological signs of pulmonary
      infiltrations and correlated to clinical findings, blood chemistry, microbiology
      and bronchoscopy. Additionally, an individual risk profile was established.
      RESULTS: In 11/40 patients pulmonary infiltrations were detected in digitized
      chest x-rays (group 1). 10/11 developed an infectious pulmonary infiltration.
      29/40 patients developed no pulmonary infiltration (group 2). When fever
      increased for the first time (initial chest x-ray) a sensitivity, specificity,
      positive and negative predictive value of 46%, 86%, 56%, 81% and for the chest x
      rays in progress of 61%, 79% 68% and 73% was found. C-reactive protein and
      temperature increase occurred statistically significantly earlier (p < 0.05) in
      group 1 compared to group 2. The average latency of digital chest x-rays in
      comparison to c-reactive protein and temperature increase was 6 days. The
      incidence of risk factors was significantly higher in group 1 in comparison to
      group 2 (p < 0.05). CONCLUSION: Digitized chest x-rays are not a reliable method
      for primary detection of pulmonary infiltrations after bone marrow
      transplantation. Individual risk factors have to be taken into consideration to
      indicate further diagnostic methods such as computed tomography at an earlier
      time.

PMID- 10598166
TI  - [Detection of microcalcifications in breast specimens by 4-fold DIMA direct
      magnification radiography compared to 1.5-fold conventional magnification
      radiography].
AB  - AIMS OF STUDY: The purpose of this study was to investigate the efficacy of 4
      fold magnification breast specimen radiography (direct magnification, DIMA)
      compared to conventional 1.5-fold magnification radiography in evaluating the
      presence or absence of carcinoma at the surgical margins by detection of
      microcalcification. METHODS: Fifty breast specimens with non-palpable
      microcalcifications were examined during surgical biopsy using both DIMA (4-fold)
      and conventional (1.5-fold) magnification specimen radiography. The number of
      detected microcalcifications of the whole specimen, of an area of 5 mm distance
      to the margins and of the area of the suspicious cluster of microcalcifications
      was counted and the results compared with the histological examination as a gold
      standard. RESULTS: In 50 specimen 2821 (1305 within 3 mm distance to the margins)
      microcalcifications were detected with the DIMA mammography technique compared to
      1608 (446) microcalcifications with the conventional technique. This increased
      detection rate by DIMA-magnification radiography was accompanied by a decreased
      specificity in comparison to the conventional magnification radiography (33.3%
      DIMA versus 83.3% conventional) regarding the evaluation of presence or absence
      of carcinoma at the surgical margins. Differentiating the microcalcifications
      into calcifications belonging to the suspicious cluster and those that are
      located outside the cluster led to an increase in specificity (83.3% DIMA versus
      100% conventional). CONCLUSIONS: The efficacy of breast specimen radiography in
      evaluating the presence or absence of carcinoma at the surgical margins by
      detection of microcalcification is not improved by 4-fold magnification
      radiography (direct magnification, DIMA) compared to conventional 1.5-fold
      magnification radiography due to an increase in false-positive results. Analysis
      of the attachment of the microcalcifications to the cluster can improve the
      specificity.

PMID- 10598167
TI  - [A prospective study on the detection of lesions of the labrum glenoidale by
      indirect MR arthrography of the shoulder].
AB  - PURPOSE: Aim of this prospective study was the evaluation of signal-alterations
      of anatomic shoulder structures before and after intravenous application of Gd
      DTPA. Furthermore the tested clinical value of indirect MR-arthrography in
      detecting labrum lesions was tested. MATERIAL AND METHODS: 52 patients with
      suspected shoulder injury were examined on a 1.5 T system: Sequences were T1
      weighted axial and oblique-coronary, additionally oblique-coronary T2-weighted,
      PD-weighted- and axial FLASH-2D-Sequences. After intravenous injection of
      contrast medium T1-weighted sequences were repeated. Signal-intensities (SI) of
      anatomic structures were measured by ROI-technique, the percentual contrast
      enhancement (CE) and alterations in SNR (signal-noise-ratio) and CNR (contrast
      noise-ratio) were calculated. Labrum tears were graded by three observers, their
      results could be confirmed by arthroscopy or open surgery in 24 patients.
      RESULTS: Contrast-enhancement was shown in all structures, most remarkable in the
      joint cavity. In pathologic findings of the labrum the SI and CE were
      significantly higher compared to intact strictures (p < 0.05). Sensitivity and
      specificity in the detection of labrum tears were 70% and 71.4% without contrast
      media, respectively 100% and 71.4% with indirect arthrography. CONCLUSIONS: The
      indirect arthrography improves the signal parameters of the structures. The
      detection of labrum lesions is improved, but still remains difficult.

PMID- 10598168
TI  - [Contrast enhanced MR angiography in the preoperative evaluation of living kidney
      donors].
AB  - PURPOSE: To compare Gadolinium-enhanced MR angiography with conventional DSA in
      the preoperative evaluation of living kidney donors. MATERIAL AND METHODS: 27
      potential living kidney donors were examined with contrast-enhanced MR
      angiography after conventional angiography. The MR angiograms were evaluated for
      the number of renal arteries, the presence of early arterial branching and
      vascular pathologies by two independent readers. The results were compared with
      those of selective conventional angiography and intraoperative findings. RESULTS:
      Conventional angiography detected 14 accessory renal arteries. Reader A detected
      13 of 14 accessory arteries with no false positive result (sensitivity 93%,
      specificity 100%). Reader B detected 11 of 14 accessory vessels with one false
      positive finding (sensitivity 79%, specificity 98%). Early arterial branching was
      detected by both readers in 9 of 12 vessels with no false positive result
      (sensitivity 75%, specificity 100%). None of the patients had additional vascular
      pathology. DISCUSSION: Gadolinium-enhanced MR angiography is a non-invasive
      alternative to conventional angiography in the preoperative evaluation of living
      kidney donors. In order to achieve high accuracy in detecting accessory renal
      arteries and early arterial branching extensive experience with the method and
      the specific preoperative needs is required. Selective conventional angiography
      is still superior in detecting very small accessory vessels and early arterial
      branching.

PMID- 10598169
TI  - [Diagnosis and visualization of renal artery stenosis by color-coded Doppler
      ultrasonography. Comparison of central and peripheral flow patterns].
AB  - PURPOSE: Comparison between central and peripheral flow patterns with color-coded
      duplex sonography in the diagnosis of renal artery stenosis. MATERIALS AND
      METHODS: In a prospective study with sixty-six patients systolic velocity
      (central examination) and acceleration index (peripheral examination) were
      determined using color-coded duplex sonography examination in order to detect and
      visualize renal artery stenosis. If the central and peripheral measurements were
      negative, no angiography was performed. In contrast, if one of the methods
      yielded a pathological finding, catheter angiography was performed to verify the
      results (21 patients), as well as in two other unclear cases. RESULTS: An
      agreement between central and peripheral measuring was seen in 49 of 66 patients.
      In ten patients central and peripheral measurements showed different results. In
      seven cases the peripheral measurements were not clear. Compared to angiography,
      peripheral measurement showed a sensitivity of 60%, a specificity of 75% and a
      positive predictive value of 81.8%. In contrast, central examination had a
      sensitivity of 100%, a specificity of 75% and a positive predictive value of
      88.2%. CONCLUSIONS: Based on our preliminary results, the measurement of the
      systolic velocity peak seems to be an effective method to detect renal artery
      stenosis.

PMID- 10598170
TI  - [Radiological evaluation of complications of implantable venous access port
      systems].
AB  - OBJECTIVE: Clinical signs and symptoms sometimes throw suspicion on functional
      complications and venous thrombosis due to implantable venous access ports.
      Objective was to determine frequency of these problems using radiologic imaging.
      METHODS: 61 patients were examined by means of fluoroscopy. If indication was
      given we injected radiopaque (contrast) medium. In the case of suspected vascular
      thrombosis the radiological finding was verified by sonography, phlebography or
      by venous magnetic resonance imaging angiography. RESULTS: Altogether 46
      complications were documented in 37 out of 61 examined patients (61%). Occlusions
      of port-catheter were proved in 24 cases. It was the radiologically most
      frequently recorded complication (52%;) and found coincident with other problems
      in 9 patients (37%;). Pain frequently indicates break of catheters. Implantation
      of catheters into jugular and axillary veins predisposes to break of catheters
      just as port-catheters lateral implanted into subclavian veins ("pinch-off
      sign"). CONCLUSIONS: Functional tests of venous access systems using fluoroscopy
      and phlebography give information that helps to decide if clinically problematic
      port-systems should be used furthermore. Directions of catheter which are
      predestined to complications should be avoided.

PMID- 10598171
TI  - [Frequency of repeated examinations in the ultrasonographic section of a
      radiological university department].
AB  - PURPOSE: What is the percentage of repeat examinations in the ultrasonographic
      section of a radiological university department? METHODS: All 4116 patients, who
      were first examined in the sonographic section of the Radiologic Department of
      the University of Cologne from 5/97 to 5/98, were asked by the medical staff,
      whether, how often and by whom ultrasonographic, CT or MR examinations of the
      same organ system had been carried out during the last 4 weeks without evidence
      of clinical changes. The data were documented using a structured questionnaire.
      RESULTS: Sonographic repeated examinations documented in 443 (10.8%) of the 4116
      consultations. The proportion of in- to outpatients with repeat examinations was
      26.0% to 74.0%. Contrarily, the repeated ultrasonographies were done by
      practitioners in 62.3% and by the university staff in 33.2% (radiology 48.2%).
      With regard to the 4116 consultations, the abdomen (81.1%) was the organ system
      most often examined repeatedly. Computed tomographies were already done or
      planned in 305 of 4116 patients (7.4%) and MR-tomographies were already done or
      planned in 57 patients (1.4%). CONCLUSION: The rate of repeated ultrasonographic
      examinations in a radiological university hospital was 19.6%.

PMID- 10598172
TI  - [Pulse synchronous tinnitus as the only symptom of fibromuscular dysplasia of
      cervical arteries].

PMID- 10598173
TI  - [Intermittent invagination in Peutz-Jeghers syndrome: CT and MR findings].

PMID- 10598174
TI  - [MR visualization in rhabdomyolysis with compartment syndrome of the pelvis and
      thigh].

PMID- 10598175
TI  - [Computerized tomography diagnosis of nephro-intestinal fistula].

PMID- 10598176
TI  - [Unusual manifestation of chronic recurrent multifocal osteomyelitis of the
      spine].

PMID- 10598177
TI  - [Re: Prostaglandin E1 for prevention of contrast medium-induced kidney
      dysfunction. Fortsch Rontgenstr 170 (1999) 557-563].

PMID- 10598178
TI  - American Association of Endocrine Surgeons. Presidential address: chasin'
      hormones.

PMID- 10598179
TI  - The evolution of parathyroidectomy failures.
AB  - BACKGROUND: Reported operative failure rates for primary hyperparathyroidism
      range from 5% to 10%. Failure has been due to multiglandular disease, ectopic
      parathyroid glands, errors in frozen section, and missed diagnoses. Recently, our
      operative approach has changed from bilateral cervical exploration to direction
      by preoperative localization and intraoperative quick parathyroid hormone assay.
      The purpose of this study is to examine the causes and rates of failure in this
      evolving approach to parathyroidectomy. METHODS: Among 447 consecutive cases of
      primary hyperparathyroidectomy, 20 operative failures were examined. Three
      different operative approaches were compared with respect to causes and rates of
      failure. RESULTS: From 1969 to 1989, with bilateral neck exploration, failure was
      due to missed diagnoses, ectopic glands, multiglandular disease, and unknown
      causes, with a failure rate of 5%. From 1990 to 1993, with bilateral neck
      exploration and quick parathyroid hormone assay, failure was due to ectopic
      mediastinal glands, misinterpretation of frozen section, and operative judgment,
      with a failure rate of 10%. From 1993 to 1998, with preoperative localization and
      quick parathyroid hormone assay, the two operative failures (1.5%) were due to
      operative judgment and misinterpretation of the quick parathyroid hormone assay.
      CONCLUSIONS: The new surgical approach combining preoperative localization
      studies and intraoperative parathyroid hormone monitoring has eliminated the most
      common causes of parathyroidectomy failure and has significantly decreased the
      operative failure rate.

PMID- 10598180
TI  - Unilateral neck exploration under local anesthesia: the approach of choice for
      asymptomatic primary hyperparathyroidism.
AB  - BACKGROUND: Conventional parathyroidectomy involves a bilateral neck exploration
      with the patient under general anesthesia with a thorough search for all
      parathyroid tissue. The purpose of this study was to assess the efficacy and
      safety of unilateral neck exploration under local anesthesia in patients with
      asymptomatic primary hyperparathyroidism (first-degree hyperparathyroidism).
      METHODS: Of 679 patients who underwent parathyroidectomy for first-degree
      hyperparathyroidism from July 1989 to June 1997, 230 asymptomatic patients
      underwent unilateral neck exploration under local anesthesia. Selection criteria
      for this approach included the successful identification of a solitary
      parathyroid adenoma on preoperative imaging, no thyroid disease, and no family
      history of multiple endocrine neoplasia. Intact parathyroid hormone levels were
      monitored during the operation. RESULTS: Total serum calcium levels were normal
      in 220 patients (96%) 3 to 6 months after surgery. Ten patients (4%) experienced
      persistent hypercalcemia, 8 of whom had multiple gland disease and 2 of whom had
      false-positive imaging. Two of these patients underwent bilateral neck
      exploration under general anesthesia and were cured, although 8 patients remained
      asymptomatic and were followed up non-operatively. The mean operating time was 30
      minutes (range, 12-65 minutes). There were two complications (0.87%) including
      one wound hematoma and one transient recurrent laryngeal nerve palsy.
      CONCLUSIONS: Unilateral neck exploration under local anesthesia is an efficacious
      and safe approach to the treatment of first-degree hyperparathyroidism and should
      be considered in all patients with asymptomatic disease.

PMID- 10598181
TI  - Bilateral neck exploration for parathyroidectomy under local anesthesia: a viable
      technique for patients with coexisting thyroid disease with or without sestamibi
      scanning.
AB  - BACKGROUND: Bilateral neck exploration (BNE) with the patient under general
      anesthesia has been the standard for parathyroidectomy. In efforts to minimize
      invasiveness and recovery from the procedure, unilateral neck exploration with
      the patient under local anesthesia in combination with sestamibi scanning is
      being done. Patients with a nonlocalized adenoma, concurrent thyroid disease,
      and/or multiple parathyroid adenomas have been excluded from this minimally
      invasive procedure. METHODS: Two hundred thirty-six patients underwent BNE under
      local anesthesia for primary hyperparathyroidism that was performed by a single
      surgeon between 1988 and April 1999. RESULTS: The percentage of patients who
      underwent parathyroidectomy under local anesthesia increased from 3% in 1988 to
      97% in 1999. Twenty-three percent of patients underwent a concurrent thyroid
      procedure, and 84% of patients had a single adenoma removed. Sixty-two percent of
      patients had a negative preoperative sestamibi scan or did not have a scan at
      all. The incidence of frozen section decreased in the initial 50 cases from 100%
      to 39% during the last 100 cases. Average operative time was 43 minutes without a
      thyroid procedure and 66 minutes with a thyroid procedure. Overall, 70% of
      patients were discharged within 6 hours of the surgical procedure; this
      percentage increased to 91% during the last 5 months. CONCLUSIONS: BNE with the
      patient under local anesthesia can be performed safely and effectively in
      patients with coexisting thyroid disease and a nonlocalized adenoma.

PMID- 10598182
TI  - Outpatient minimally invasive parathyroidectomy: a combination of sestamibi-SPECT
      localization, cervical block anesthesia, and intraoperative parathyroid hormone
      assay.
AB  - BACKGROUND: Despite the high cure rate and low morbidity of bilateral neck
      exploration for primary hyperparathyroidism, there is a movement toward
      minimizing the process in terms of incision, cost, extent of exploration, and
      length of hospital stay, while maintaining excellent outcomes. METHODS: Between
      March and November 1998, 33 patients with primary hyperparathyroidism underwent
      minimally invasive parathyroidectomy. All had preoperative sestamibi-SPECT scans
      suggesting a single adenoma, underwent anterior cervical block anesthesia by the
      surgeon, and were explored through a 1- to 4-cm incision. Intraoperative
      parathyroid hormone assays were performed before and 5 to 10 minutes after
      parathyroid resection. Outcomes were compared with those of 184 consecutive
      patients who underwent bilateral parathyroid exploration under general anesthesia
      by the same surgeon between August 1990 and May 1996. RESULTS: The mean age of
      the patients undergoing minimally invasive parathyroidectomy was 61 +/- 2 years,
      and 24 of the 33 patients were women. Thirty (91%) had resection of a single
      adenoma under regional anesthesia; 26 of these were done as outpatient
      procedures. Three patients underwent conversion to general anesthesia for
      bilateral exploration and were found to have multigland disease (two double
      adenomas, one hyperplasia). All 33 patients were normocalcemic postoperatively.
      There was no morbidity. When the minimally invasive parathyroidectomy and
      bilateral parathyroid exploration groups were compared, they were found to be
      similar with respect to age, preoperative calcium and parathyroid hormone levels,
      cause of primary hyperparathyroidism, weight of resected glands, cure rates, and
      morbidity. However, the minimally invasive parathyroidectomy group had a
      significantly shorter length of hospital stay (0.3 +/- 0.2 vs 1.8 +/- 0.1 days, P
      < .001) and lower costs ($3174 +/- $386 vs $6328 +/- $292, P < .001).
      CONCLUSIONS: Minimally invasive parathyroidectomy is a safe, cost-effective
      alternative to bilateral exploration and may be the procedure of choice for
      select patients with primary hyperparathyroidism.

PMID- 10598183
TI  - The 20% rule: a simple, instantaneous radioactivity measurement defines cure and
      allows elimination of frozen sections and hormone assays during
      parathyroidectomy.
AB  - BACKGROUND: Although primary hyperparathyroidism is a physiologic disease,
      surgeons rely on anatomical characteristics (gross and histologic) to determine
      appropriate operative decisions. After the development of radioguided
      parathyroidectomy, we hypothesized that the amount of radioactivity contained
      within resected tissue would be the only information needed to establish the
      nature of the tissue and to determine a cure for the disease. METHODS: A total of
      1290 tissue specimens were obtained from 345 patients who had sporadic primary
      hyperparathyroidism. Ex-vivo radioactivity, in counts per second, was measured in
      parathyroid and other tissues within 3.5 hours of sestamibi injection. Background
      radioactivity was measured after tissue excision, and ratios were calculated.
      RESULTS: Lymph nodes, normal parathyroids, and fat never contained more than 2.2%
      of background radioactivity, whereas thyroid and hyperplastic parathyroids
      contained 5.5% and 7.5%, respectively, and never more than 16%. In contrast,
      adenomas contained 59% +/- 9% of background radioactivity (P < .000001 vs all
      other tissues), with a range of 18% to 136%. CONCLUSIONS: Radioactive ratios are
      an instantaneous measure of metabolic activity, thereby determining parathyroid
      function. Any excised tissue containing more than 20% of background radioactivity
      in a patient with a positive sestamibi scan result is a solitary parathyroid
      adenoma. This alleviates the need to identify other glands, obtain frozen
      sections, or measure serum parathyroid hormone levels intraoperatively.

PMID- 10598184
TI  - The validity of quick intraoperative parathyroid hormone assay: an evaluation in
      seventy-two patients based on gross morphologic criteria.
AB  - BACKGROUND: Parathyroidectomy for primary hyperparathyroidism has conventionally
      required identification of all parathyroid glands with excision of grossly
      abnormal glands. Using this approach, cure rates exceed 95%. Directed cervical
      exploration has been advocated using quick intraoperative parathyroid hormone
      (QPTH) assay with preoperative localization. Adoption of this approach requires
      validation of the accuracy of QPTH assay. METHODS: Patients with primary
      hyperparathyroidism undergoing bilateral neck exploration during a 31-month
      period were reviewed. Uniglandular (UGD) or multiglandular (MGD) disease was
      determined by gross morphologic criteria. QPTH assays were performed before skin
      incision and at 5, 10, and 20 minutes after excision of each abnormal gland. A 10
      minute QPTH decrease of 50% from baseline levels indicated curative excision.
      These data were not used to guide extent of exploration or tissue resection.
      RESULTS: Of 72 patients, 55 (76%) had UGD and 17 (24%) had MGD. QPTH assay
      accurately predicted the disease state in 89%. Four (7%) UGD patients did not
      have an appropriate QPTH decline at 10 minutes. Four (24%) MGD patients had an
      inappropriate QPTH decline at 10 minutes. CONCLUSIONS: Using QPTH guided
      exploration, 6% (4 of 72) of patients would undergo unnecessary extended
      exploration and 6% (4 of 72) (95% CI, 1% to 13%) may require reoperation for
      unidentified MGD. These results validate the accuracy of QPTH assay.

PMID- 10598185
TI  - Is sestamibi-guided parathyroidectomy really cost-effective?
AB  - BACKGROUND: Sestamibi-guided limited neck explorations are an alternative to the
      standard bilateral neck exploration for patients with primary
      hyperparathyroidism. A recently published meta-analysis by Denham and Norman
      (JACS vol.186, 1998) suggested that a sestamibi-directed approach offers a cost
      benefit because it decreases operative and recovery room times, hospital stay,
      and the number of frozen sections needed. METHODS: We reviewed 41 bilateral neck
      explorations for primary hyperparathyroidism and compared our results with those
      reported by the meta-analysis to determine whether a sestamibi-directed approach
      is cost effective. RESULTS: Operative and recovery room times averaged 60.3 +/-
      19.3 and 45 minutes, respectively. Forty six percent of the patients were treated
      as outpatients, and 1.21 +/- 0.57 frozen sections were obtained per case. Our
      standard bilateral exploration cost 47% less than the bilateral approach and 17%
      less than the sestamibi-directed operation calculated in the meta-analysis. There
      were no cases of nerve injury or permanent hypocalcemia, 98% of patients were
      cured, and 61% of patients did not require narcotics postoperatively.
      CONCLUSIONS: Sestamibi-guided parathyroidectomy may not offer any advantage over
      the standard bilateral exploration. In our experience, a bilateral neck
      exploration can be performed on an outpatient basis and at low cost, with a high
      success rate and minimal morbidity. Most patients do not require narcotics, and
      the cosmetic results are excellent.

PMID- 10598186
TI  - Results of heterotopic parathyroid autotransplantation: a 13-year experience.
AB  - BACKGROUND: The reported success of heterotopic parathyroid autotransplantation
      (HPA) in patients with primary hyperparathyroidism varies from 20% to 60%. The
      purpose of this study was to evaluate our results with HPA to help define its
      role in this patient group. METHODS: Between July 1985 and June 1998, 44 patients
      underwent 51 HPA procedures at our institution. Twenty to 25 fragments of
      parathyroid tissue measuring 1 to 3 mm3 each were placed into the forearm
      musculature. HPA results were scored as nonfunctional (requiring calcium and
      vitamin D), partially functional (normocalcemia on calcium alone), fully
      functional (normocalcemia without supplementation), or hyperfunctional
      (hypercalcemia without supplementation). RESULTS: Follow-up data were available
      for 39 patients who underwent 46 autografts (20 immediate and 26 cryopreserved).
      With a median follow-up of 35 months, 19 autografts (41%) were nonfunctional; 9
      autografts (20%) were partially functional; 15 autografts (33%) were fully
      functional, and 3 autografts (7%) were hyperfunctional. Full function was
      observed in 35% of immediate and 31% of delayed autografts. CONCLUSIONS: One
      third of parathyroid autografts develop full function, and an additional one
      fifth develop partial function. Recurrent hyperparathyroidism is uncommon. No
      benefit was observed from immediate versus delayed HPA, and the modest success
      rate of HPA suggests that improvements in technique are warranted.

PMID- 10598187
TI  - Endothelial vasodilatory dysfunction in primary hyperparathyroidism is reversed
      after parathyroidectomy.
AB  - BACKGROUND: Primary hyperparathyroidism (HPT) is accompanied by hypertension and
      a cardiovascular mortality. Impaired endothelium-dependent vasodilatation (EDV)
      occurs in hypertension but has not been fully investigated in HPT despite the
      vasoactive influences of parathyroid hormone. METHODS: Twenty-five HPT patients
      and 25 normocalcemic control subjects, matched for age and gender, underwent
      forearm venous occlusion plethysmography. EDV and endothelium-independent
      vasodilatation (EIDV) were evaluated during local infusion of metacholine (2 and
      4 micrograms/min) and nitroprusside (5 and 10 micrograms/min), respectively. The
      endothelial function index was calculated as the ratio of forearm blood flows
      during the high doses of metacholine and nitroprusside. Ambulatory 24-hour blood
      pressures and thickness of the intima-media complex of the carotid arteries were
      also measured; the latter is considered an early marker of atherosclerosis.
      RESULTS: Endothelial function index was lower in the HPT patients compared with
      control subjects (1.01 +/- 0.26 vs 1.27 +/- 0.31, P = .003). Reinvestigation 10
      months after parathyroidectomy showed normalization of the index (1.31 +/- 0.39,
      P = .01) due to a numeric increase in EDV and decrease in EIDV. The carotid
      intima-media thickness and blood pressure were similar in the groups and
      unaltered postoperatively. CONCLUSIONS: Endothelial vasodilatory dysfunction is
      another indicator of the vascular disturbance of HPT and can be normalized by
      parathyroidectomy.

PMID- 10598188
TI  - Vascular endothelial growth factor-C gene expression in papillary and follicular
      thyroid carcinomas.
AB  - BACKGROUND: Vascular endothelial growth factor-C (VEGF-C) is known to be related
      to development of lymphatic vessels. Papillary thyroid carcinoma
      characteristically metastasizes to regional lymph nodes, whereas follicular
      thyroid carcinoma commonly spreads hematogenously. The present study was designed
      to determine whether expression of the VEGF-C gene is related to the different
      metastatic features of these 2 types of thyroid carcinoma. METHODS: Thyroid
      carcinoma specimens were obtained from 15 patients with papillary carcinoma and 4
      patients with follicular carcinoma of the thyroid. VEGF-C gene expression was
      examined by Northern blotting and in situ hybridization. Immunohistochemistry was
      performed to localize the deposition of VEGF-C protein. RESULTS: The ratios of
      VEGF-C gene expression determined by Northern blot analysis were significantly
      higher in papillary than in follicular carcinoma. Nonmalignant thyroid tissue
      from patients with papillary carcinoma also expressed higher levels of VEGF-C
      than tissue from patients with follicular carcinoma. Expression of the VEGF-C
      gene was observed by in situ hybridization in cells of papillary thyroid
      carcinoma but not in those of follicular carcinoma. Positive staining with
      antibody against VEGF-C was detected in papillary cancer cells. CONCLUSIONS:
      Concurrent overexpression of the VEGF-C gene by both tumor cells and the
      surrounding tissue may be related to the prevalence of intrathyroidal spread
      through lymphatics and regional lymph node metastasis in patients with papillary
      thyroid carcinoma.

PMID- 10598189
TI  - Classification and treatment of follicular thyroid neoplasms are discordant
      between and within medical specialties.
AB  - BACKGROUND: The histologic criteria to classify follicular thyroid neoplasms are
      controversial. Criteria used for diagnosis and treatment varies both within and
      between specialty groups. This discordance makes it difficult to compare disease
      and management practice. This is especially problematic in issues concerning
      reoperations and survival. To determine the degree of disparity, we surveyed 3
      groups of specialists. METHODS: A questionnaire describing 10 histologic
      scenarios was sent to an equal number of thyroidologists, endocrine surgeons, and
      endocrine pathologists. Individuals were randomly selected from rosters of 3
      corresponding societies. Each item asked for a rating of a diagnosis and
      treatment. Questionnaires were distributed and received by facsimile, and
      responses were kept confidential. The response rate was 60%. RESULTS: Responses
      were analyzed by nonparametric statistical tests. Two scenarios had significant
      disagreement among specialties in both diagnosis and treatment: one scenario
      involved the assessment of neoplasms with minimal capsular invasion; the other
      scenario involved Hurthle cell features. In both scenarios pathologists tended to
      be more conservative in assigning the term carcinoma and recommending total
      thyroidectomy. Significant disagreement within specialty groups was also noted.
      Two other scenarios dealt with the distinction between minimally and widely
      invasive carcinoma; significantly, pathologists viewed tumors as less invasive.
      CONCLUSIONS: This study indicates that much disparity exists among specialists in
      pathology, endocrinology, and surgery and among experts in each of these
      disciplines. It highlights that there is no uniform classification. If
      multicenter trials to evaluate treatment options are to occur, a universal
      classification must be accepted.

PMID- 10598190
TI  - Coexistent Hashimoto's thyroiditis with papillary thyroid carcinoma: impact on
      presentation, management, and outcome.
AB  - BACKGROUND: This study was performed to assess the relationship between
      Hashimoto's thyroiditis and the development, presentation, management, and
      outcome of papillary thyroid carcinoma. METHODS: Two complementary analytic
      methods were used. The clinical study was a retrospective case-control study,
      including patients seen with papillary thyroid carcinoma presenting during a 12
      year period. We also used a systematic literature review to identify suitable
      reports and meta-analysis to statistically combine published results. RESULTS:
      The prevalence of Hashimoto's thyroiditis is significantly higher in patients
      with papillary thyroid cancer (odds ratio, 1.89; 95% CI, 1.02-3.50). These
      patients typically have a dominant nodule, 44% of which are discovered
      incidentally on routine examinations. Fine-needle aspiration has a sensitivity of
      91% for the identification of papillary cancer. The prognostic variables at the
      time of a diagnosis of papillary cancer and the approach to management are not
      altered by the presence of coexistent Hashimoto's thyroiditis. In addition, the
      rate of surgical complications was not higher in patients with coexistent
      Hashimoto's disease. Meta-analysis suggested a positive correlation between
      Hashimoto's disease and disease-free survival (r = 0.09; 95% CI, 0.05-0.12) and
      overall survival (r = 0.11; 95% CI, 0.07-0.15). CONCLUSIONS: There is an
      increased prevalence of Hashimoto's thyroiditis in patients with papillary
      thyroid carcinoma. The presence of coexistent Hashimoto's thyroiditis does not
      affect the diagnostic evaluation or management of papillary thyroid cancers. The
      survival of patients who have papillary thyroid cancers may be superior in
      coexistent Hashimoto's thyroiditis.

PMID- 10598191
TI  - Invasive differentiated thyroid carcinoma: tracheal resection and reconstruction
      procedures in the hands of the endocrine surgeon.
AB  - BACKGROUND: Although differentiated carcinoma of the thyroid gland is a
      relatively benign tumor, up to 20% of patients are endangered by potentially
      fatal complications resulting from infiltrating tumor growth into the upper
      aerodigestive tract. METHODS: This study included 33 patients who underwent 34
      tracheal or laryngotracheal procedures for invasive differentiated thyroid
      carcinoma under the direction of a single surgeon (G.F.W.S.). From 1990 to 1994,
      radical tumor extirpation was performed by "window" resection, and from 1995 to
      1998, radical surgery consisted of either circumferential sleeve resection or
      laryngotracheal "step" resection--a novel method of reconstruction in cases of
      unilateral tumor infiltration into the larynx and trachea. Resection was limited
      to laminar ablation in 17 cases. The mean follow-up of 16 patients who survived
      was 42.5 months (range, 2 months to 8.9 years). RESULTS: Procedures resulting in
      primary end-to-end anastomosis of the upper airways were associated with lower
      perioperative morbidity and improved recurrence-free survival when compared with
      "window" resections with muscle flap reconstruction. In cases of superficial
      tracheal tumor infiltration, laminar ablations were sufficient for local tumor
      control. CONCLUSIONS: Radical eradication of differentiated thyroid carcinoma
      infiltrating the upper airways followed by radioiodine application should be
      considered the treatment of choice. Laryngotracheal "step" resection allows tumor
      extirpation with preservation of neural and muscular structures of the larynx.

PMID- 10598192
TI  - Is medullary thyroid cancer predictable? A prospective study of 86 patients with
      abnormal pentagastrin tests.
AB  - BACKGROUND: The aim of this prospective study was to distinguish biochemically
      between C-cell hyperplasia (CCH) and medullary thyroid cancer (MTC) before
      surgery. METHODS: Eighty-six consecutive patients with an abnormal stimulated
      calcitonin level (> 100 pg/mL) underwent thyroidectomy and lymph node dissection.
      In sporadic MTC, histopathologic findings and postoperative biochemical outcomes
      were documented prospectively and correlated with preoperative basal and
      stimulated calcitonin levels. RESULTS: Analysis of variance revealed a highly
      significant difference in basal/stimulated calcitonin levels (P < .0001), with a
      comparison of CCH (n = 39 patients) and sporadic MTC (n = 38 patients). With a
      comparison of sporadic MTC N0 M0 (n = 25 patients) and N1 M0/1 (n = 12 patients),
      the basal calcitonin level was significantly different (P < .05). There was a
      close correlation between the n-log of basal/stimulated calcitonin level and the
      n-log of the tumor volume; there were also different distributions of the n-log
      of basal/stimulated calcitonin level among CCH, MTC N0, and MTC N1. Assuming that
      a basal calcitonin level of more than 64 pg/mL and/or a stimulated calcitonin
      level of more than 560 pg/mL implies MTC, 31 of 38 patients with sporadic MTC
      were detected before surgery. Three patients were predicted false positive
      (neoplastic CCH). Patients with stimulated calcitonin levels of less than 129
      pg/mL had CCH only. Patients with basal calcitonin levels of less than 22 pg/mL
      and sporadic MTC (7/38 patients) were node negative. CONCLUSIONS: All patients
      with abnormal pentagastrin tests showed C-cell pathologic evidence. Sporadic MTC
      was predicted in 81% of the patients; CCH or N0 was predicted in 36% of the
      patients. Central neck dissection is recommended to avoid difficult reoperations.
      Lateral neck dissection is possible "on demand."

PMID- 10598193
TI  - Screening for MEN1 mutations in patients with atypical endocrine neoplasia.
AB  - BACKGROUND: Most patients from typical multiple endocrine neoplasia type 1 (MEN1)
      kindreds harbor mutations in the MEN-1 gene, MEN1. We hypothesized that some
      patients with atypical endocrine neoplasia would also have mutations in MEN1.
      METHODS: DNA sequencing analysis of mutations in the coding region of MEN1 was
      performed with genomic DNA obtained from peripheral blood lymphocytes in a total
      of 21 patients who had: typical MEN1 (n = 8), clinical features suggestive of
      MEN1 but without a family history of endocrinopathy (n = 7), and atypical
      endocrine neoplasia and a family history of endocrinopathy suggestive of MEN1 (n
      = 6). RESULTS: All 8 patients with typical MEN1 had mutations in MEN1. None of
      the 7 patients with features of MEN1, but without a family history of
      endocrinopathy, had a MEN1 mutation. In contrast, 4 of 6 patients with atypical
      endocrine neoplasia that included components of MEN1 and a family history of
      endocrinopathy had mutations in MEN1, including 2 patients with pheochromocytoma.
      CONCLUSIONS: Genomic mutations in MEN1 may frequently be identified in patients
      with atypical endocrine neoplasia, especially in the setting of a family history
      of endocrinopathy. Atypical presentations of MEN1 may include pheochromocytoma.

PMID- 10598194
TI  - Foregut carcinoids: a clinical and biochemical analysis.
AB  - BACKGROUND: Gastrointestinal foregut carcinoids make up a small percentage (3% to
      6%) of all reported carcinoids. Because these tumors are so uncommon, comparisons
      between the subtypes have been difficult. The goal of this study was to compare
      the hormonal and clinical characteristics of gastric, duodenal, and pancreatic
      carcinoids. METHODS: A prospective database of approximately 750 carcinoid
      patients seen by one author over 25 years was reviewed, and the 104 patients with
      gastric (33), duodenal (17), or pancreatic (54) carcinoids were selected as the
      subgroup for analysis. These patients were compared with regard to hormone
      levels, clinical course, treatment, and survival. RESULTS: Duodenal carcinoids
      exhibited significantly lower serotoninergic hormone levels than did the gastric
      and pancreatic carcinoids (urine 5-hydroxyindoleacetic acid [mg/24 h], 5 +/- 1 vs
      16 +/- 5 and 47 +/- 12, respectively, P = .03). Pancreatic carcinoids presented
      with more advanced stage (distant metastases 87% vs 42% and 20% for gastric and
      duodenal, respectively) and had worse outcomes than patients with gastric and
      duodenal tumors with 10-year survivals of 10%, 59%, and 58%, respectively (P =
      .003). CONCLUSIONS: Pancreatic carcinoids produce higher levels of serotoninergic
      hormones and have a significantly higher stage and worse outcome than other
      foregut carcinoids. This study demonstrates that the organ of origin is an
      important determinant of hormonal activity and clinical course for patients with
      foregut carcinoids.

PMID- 10598195
TI  - Laparoscopic versus open adrenalectomy in Cushing's syndrome and disease.
AB  - BACKGROUND: Adrenalectomy in Cushing's syndrome and disease involves particular
      risks and complications. The aim of the study was to compare the open posterior
      and the flank laparoscopic approaches in this group of patients. METHODS: Forty
      patients who underwent unilateral or bilateral adrenalectomy for hypercortisolism
      between 1991 and 1999 were studied. Patients were divided as follows: adenoma--5
      laparoscopic and 6 open; hyperplasia--17 laparoscopic and 12 open. Demographics,
      surgical details, outcome, and complications were comparatively analyzed.
      RESULTS: Patients undergoing laparoscopic or open adrenalectomy were comparable
      in terms of age, sex distribution, body mass index, respiratory status, and
      anesthetic risk. Operative time was longer in the laparoscopic group. One patient
      in the laparoscopic group died of upper gastrointestinal tract bleeding on
      postoperative day 17. Two patients in the open group and one in the laparoscopic
      group experienced postoperative complications. Cure of the disease occurred in
      all patients. Mild abdominal wall pain developed in one patient in each group. No
      abdominal wall weakness was identified in either group. CONCLUSIONS: Cure rate
      and operative and long-term morbidity were similar for laparoscopic and open
      adrenalectomies in this series. However, it is important to emphasize that late
      complications in our patients who underwent the posterior open procedure were
      rather infrequent.

PMID- 10598196
TI  - Video-assisted versus conventional parathyroidectomy in primary
      hyperparathyroidism: a prospective randomized study.
AB  - BACKGROUND: Several studies demonstrated the feasibility of minimally invasive
      parathyroidectomy as a treatment for primary hyperparathyroidism. We compared its
      results with those of traditional surgery in a prospective randomized study.
      METHODS: From March to November 1998, 38 patients eligible for video-assisted
      parathyroidectomy (VAP) were referred to us. They were randomly divided into 2
      groups: patients of group A underwent a conventional cervicotomy with bilateral
      exploration and frozen section of the removed adenoma; patients of group B
      underwent VAP with intraoperative measurement of parathyroid hormone. Operative
      time, postoperative pain, fever and hypocalcemia, cosmetic result, and costs were
      compared. Two cases of VAP were performed with locoregional anesthesia. RESULTS:
      Groups A (18 patients) and B (20 patients) were statistically balanced. Operative
      time was significantly shorter in group B (57 vs 70 minutes). Cosmetic result was
      significantly better in group B, which also experienced less postoperative pain
      (P < .05). No cases of persistent primary hyperparathyroidism were present in
      either group, but recurrent laryngeal nerve palsy occurred in 1 patient in group
      B. CONCLUSIONS: Compared with conventional surgery, VAP is associated with a
      shorter operative time, a better cosmetic result, and a less painful
      postoperative course.

PMID- 10598197
TI  - Correlation of parathyroid scanning and anatomy in 261 unselected patients with
      sporadic primary hyperparathyroidism.
AB  - BACKGROUND: Despite abundant literature on parathyroid scanning with technetium
      99m-labeled cationic complexes, comprehensive clinical reports that unequivocally
      correlate scanning findings with the anatomy of parathyroid glands in extensive
      and homogeneous cohorts of patients are lacking. METHODS: We analyzed the records
      of patients with sporadic primary hyperparathyroidism who had had a preoperative
      scan with either 99mTc-labeled sestamibi or 99mTc-labeled tetrofosmin at our
      institution and who were cured after a bilateral surgical neck exploration
      procedure. RESULTS: In 261 patients, 710 normal and 347 abnormal glands (1494 +/-
      2626 mg), including 15 glands within the mediastinum, were identified.
      Sensitivity, specificity, positive predictive value, negative predictive value,
      and accuracy of scanning were 82%, 98%, 91%, 94%, and 94%, respectively, in 197
      patients with uniglandular disease and 53%, 98%, 98%, 60%, and 72%, respectively,
      in 64 patients with multiglandular disease. False-positive uptakes were
      encountered in 17 patients (7%), 3 false-positive uptakes being within the
      mediastinum. If the unilateral approach had been followed, guidance with
      preoperative scanning would have significantly increased the number of effective
      unilateral neck exploration procedures (164 patients (63%) vs 78 patients (30%);
      P < .001). One abnormal gland would also have been neglected in 28 patients
      (11%). CONCLUSIONS: Preoperative scanning would limit neck exploration procedures
      in two thirds of patients with sporadic primary hyperparathyroidism but may also
      increase the risk of failure in the most challenging cases.

PMID- 10598198
TI  - Initial experience with intraoperative PTH determinations in the surgical
      management of 130 consecutive cases of primary hyperparathyroidism.
AB  - BACKGROUND: Successful surgical management of primary hyperparathyroidism (1
      degree HPT) historically has required bilateral neck exploration. The
      intraoperative parathyroid hormone (IO-PTH) assay allows a more limited procedure
      by confirming complete removal of hypersecreting tissue. METHODS: Plasma samples
      were obtained from 130 consecutive patients both before (preincision and
      preexcision baselines) and at approximately 5 and 10 minutes (and additional
      times) after removal of abnormal parathyroid tissue. Samples were assayed for IO
      PTH by a rapid, two-site immunochemiluminescent assay (ICMA) with a 7-minute
      incubation at 45 degrees C. RESULTS: Plasma IO-PTH decreased by at least 50% in
      126 of 130 cases; however, three of these cases were false positives. The four
      cases in which IO-PTH fell < 50% were classified as two true negatives and two
      false negatives. A single adenoma was removed in 125 cases, and two or three
      hyperplastic glands were removed in five cases. CONCLUSIONS: IO-PTH predicted the
      postoperative outcome in 125 of 130 cases (96.2%), including two of five cases in
      which multiple hyperplastic glands were removed, and 1 degree HPT was
      successfully treated in 97.7% (127/130) of the cases. The IO-PTH procedure can
      provide valuable confirmation to the endocrine surgeon; however, other sources of
      information must also be used to ensure that all hyperplastic glands are
      identified.

PMID- 10598199
TI  - Retrospective analysis of sequential changes in serum intact parathyroid hormone
      levels during conventional parathyroid exploration.
AB  - BACKGROUND: The purpose of this study was to assess sequential changes in serum
      parathyroid hormone (PTH) levels during conventional parathyroidectomy. METHODS:
      Sera were collected before and 10 minutes after resection of each parathyroid
      tumor from 112 consecutive patients and assayed postoperatively within 48 hours
      for PTH. RESULTS: PTH reductions corroborated cures for 94 of 112 cases (84%),
      including 70 of 71 patients with solitary adenomas (SAs). However, there were 15
      false positives (13%), in which PTH decreased more than 50% within 10 minutes of
      resection of 1 parathyroid tumor while additional parathyroid tumors remained in
      situ (1 of 71 SAs, 4 of 6 double adenomas, 7 of 15 primary hyperplasias, and 3 of
      17 tertiary hyperplasias). There were 3 false negatives (3%), with PTH unchanged,
      even though postoperative PTH and calcium values confirmed cure (1 SA, 1 primary
      hyperplasia, and 1 tertiary hyperplasia). There were only 2 of 112 failed
      explorations (1.8%), which would not have been avoided by PTH monitoring because
      both subsequently were found to have mediastinal parathyroid adenomas.
      CONCLUSIONS: We conclude that intraoperative PTH changes corroborated outcome in
      SA but may under-estimate the extent of resection required in parathyroid
      hyperplasia.

PMID- 10598200
TI  - Kinetic analysis of the rapid intraoperative parathyroid hormone assay in
      patients during operation for hyperparathyroidism.
AB  - BACKGROUND: Rapid intraoperative parathyroid hormone (RI-PTH) assay is used to
      guide adequacy of resection during operation for hyperparathyroidism. We compared
      the RI-PTH assay (15 minutes) with a standard PTH assay, determined whether the
      PTH half-life varied between patients, and constructed a kinetic analysis of the
      RI-PTH data. METHODS: Forty-five patients with hyperparathyroidism had blood
      sampled at baseline and at times after parathyroid resection. Intact PTH was
      determined using RI-PTH and a standard assay. Values were fitted to an
      exponential decay curve using the baseline and the follow-up time points. PTH
      half-life and the new postexcision baseline value were calculated from the decay
      curve. RESULTS: The RI-PTH assay and the standard PTH assay correlated well.
      Average PTH half-life was 1.68 +/- 0.94 minutes (0.42 to 3.81 minutes). A kinetic
      analysis yielded a formula for the generation of a PTH decay curve. Using a 50%
      reduction in RI-PTH at 5 minutes as the criterion for adequate resection, 2
      patients were incorrectly classified as not being cured. These patients were
      correctly classified using the kinetic analysis. CONCLUSIONS: PTH half-life can
      vary substantially. A kinetic analysis may be more accurate in assessing adequacy
      of resection. This method allows the surgeon to interpret RI-PTH data independent
      of the timing of samples.

PMID- 10598201
TI  - Subcutaneous forearm transplantation of autologous parathyroid tissue in patients
      with renal hyperparathyroidism.
AB  - BACKGROUND: Parathyroidectomy is required in up to 5% of patients with chronic
      renal failure. Intramuscular transplantation of autologous parathyroid tissue in
      the forearm has been the traditional method of transplantation at the time of
      total parathyroidectomy. The removal of an intramuscular transplantation can be
      technically difficult should graft-dependent hyperparathyroidism (GRH) occur.
      This problem resulted in our initiating a study of subcutaneous transplantation
      with total parathyroidectomy in patients with renal failure. METHODS: Twenty-six
      patients who were receiving dialysis therapy underwent total parathyroidectomy
      and subcutaneous transplantation. Parathyroid tissue was diced into 1- to 2-mm
      pieces, and 6 pieces were grafted into 6 subcutaneous pockets of the forearm.
      Intact parathyroid hormone was measured within 48 hours of operation and in the
      bilateral antecubital veins 1 to 24 months after the operation to assess
      completeness of resection and graft function, respectively. RESULTS: No major
      surgical complications occurred. Symptoms improved in 24 patients (85%). Graft
      failure rate was 4.3%. No GRH was observed. Follow-up was 4 to 55 months (mean,
      27 months). CONCLUSIONS: This study indicates that the subcutaneous
      transplantation function is comparable to intramuscular transplantation and
      suggests a decreased incidence of GRH. Subcutaneous transplantation is
      technically easier than intramuscular transplantation and has the additional
      advantage of easy removal should GRH occur.

PMID- 10598202
TI  - Diabetes mellitus with hyperparathyroidism: another indication for
      parathyroidectomy?
AB  - BACKGROUND: Patients with hyperparathyroidism have alterations in carbohydrate
      metabolism characterized by insulin resistance, hyperinsulinemia, and glucose
      intolerance. The clinical significance of these findings in the management of
      patients with diabetes mellitus (DM) after parathyroidectomy for
      hyperparathyroidism has been controversial. METHODS: A retrospective review
      identified 87 patients with DM and hyperparathyroidism who underwent
      parathyroidectomy. The follow-up documentation of 70 patients who underwent
      diabetic management was then evaluated to assess the benefit of parathyroidectomy
      on glucose management. RESULTS: Thirteen patients had type 1 DM, and 74 patients
      had type 2 DM. Primary hyperparathyroidism was present in 93% of patients with
      type 2 DM; 64% of patients with type 1 DM had secondary hyperparathyroidism. At
      follow-up, glucose control was stable in 40% of patients, had improved in 37% of
      patients, and had deteriorated in 23% of patients (P = .003). Improved glucose
      control was not dependent on age, duration of DM, duration of
      hyperparathyroidism, length of follow-up, or calcium levels. The patients with
      decreased requirements had a significantly lower parathyroid hormone level (P =
      .05). Improved glucose control was most significant in patients whose condition
      was managed with oral hypoglycemics (P = .05) or insulin (P = .03). CONCLUSIONS:
      The clinical and laboratory investigations on the influence of
      hyperparathyroidism on DM support the benefit of parathyroidectomy in patients
      with DM. Patients with type 1 and type 2 DM show improvement in glucose control
      after parathyroidectomy. The presence of DM and hyperparathyroidism is an
      indication for parathyroidectomy because it results in either stabilization or
      improved glucose control in 77% of patients.

PMID- 10598203
TI  - Recommendations for management of cystic thyroid disease.
AB  - BACKGROUND: Thyroidectomy has been advocated for cystic nodules that recur after
      2 fine-needle aspiration biopsies (FNABs) because of concern for malignancy.
      METHODS: A review of patients with nodular thyroid disease was completed to
      determine the frequency of cystic nodules, significance of the color and volume
      of aspirated fluid, frequency and factors predictive of cyst resolution, and
      incidence of carcinoma in cystic nodules. RESULTS: Thyroid nodules were cystic in
      70 (18%) of 389 patients. FNAB was diagnostic in 50 (71%) patients with no false
      negative results. Cyst resolution occurred in 10 (14%) patients. The mean volume
      of fluid aspirated from cysts that resolved was 14 +/- 12 mL compared with 8 +/-
      18 mL from recurrent cysts (P > .05). Thyroidectomy was performed in 28 (40%)
      patients because of an abnormal or persistently nondiagnostic FNAB or compressive
      symptoms. Six patients (8.6%) had cancer, with a mean nodule size of 3.8 +/- 2.3
      cm compared with 3.7 +/- 2.6 cm in patients with benign cysts (P > .05).
      Hemorrhagic fluid was aspirated in 4 patients with and 36 without cancer (P >
      .05). CONCLUSIONS: FNAB of cystic thyroid nodules is rarely therapeutic and is a
      common cause of nondiagnostic rather than false-negative results. Recommendations
      for thyroidectomy should be based on FNAB rather than on size, fluid color, or
      failure of cyst resolution alone.

PMID- 10598204
TI  - Impact of primary surgery on outcome in 300 patients with pathologic tumor-node
      metastasis stage III papillary thyroid carcinoma treated at one institution from
      1940 through 1989.
AB  - BACKGROUND: The pathologic tumor-node-metastasis (pTNM) system is universally
      used to define the extent of disease in human malignancies. This study evaluated
      the impact of initial therapy on cause-specific mortality (CSM) rates and
      recurrence rates in pTNM stage III papillary thyroid carcinoma. METHODS: Three
      hundred patients (median age, 58 years) were followed on average for 14
      postoperative years. Of these, 246 patients (82%) had complete primary tumor
      resection; 208 patients (69%) had nodal metastases; 161 (54%) had locally
      invasive primary tumors; 45 patients (15%) underwent initial unilateral lobectomy
      (UL). Bilateral lobar resection (BLR) accounted for 242 patients (near-total,
      54%; total thyroidectomy, 23%). RESULTS: The 30-year rates for CSM, distant
      metastases, nodal metastases, and local recurrence (LR) were 29%, 22%, 19%, and
      16%, respectively. The 20-year rates for CSM were significantly higher (50% vs
      14%) when primary tumor was incompletely resected (P = .0001). After complete
      resection, 20-year rates for CSM and LR after BLR were 12% and 10%, respectively,
      which were significantly lower (P < .05) than the 23% and 26% rates seen after
      UL. There were no significant differences in nodal metastases or distant
      metastases rates between UL and BLR (P > .4). The 20-year LR rate after total
      thyroidectomy (13%) was not different (P = .5) from the 11% seen after near-total
      thyroidectomy. CONCLUSIONS: In this nonrandomized evaluation of patients with
      pTNM stage III papillary thyroid carcinoma, the extent of primary thyroid
      resection appeared to significantly impact CSM and LR but did not apparently
      influence regional or distant metastasis.

PMID- 10598205
TI  - Expression of matrix metalloproteinase gelatinase A messenger ribonucleic acid in
      parathyroid carcinomas.
AB  - BACKGROUND: The incidence of parathyroid cancer in patients with
      hyperparathyroidism is less than 1%. However, these few cases cause diagnostic
      problems in the absence of clear-cut invasion of adjacent organs or metastasis.
      New markers are needed to increase diagnostic accuracy. METHODS: Thirty-one
      parathyroid tumors from patients with primary hyperparathyroidism were collected
      worldwide. Eighteen tumors were classified as unequivocal cancers, whereas 13
      tumors were considered equivocal because of a lack of infiltrative growth or
      evidence of recurrence. Paraffin sections were hybridized with a 35S-labeled
      riboprobe complementary to gelatinase A mRNA, dipped in photographic emulsion,
      developed, counterstained, and then evaluated by light- and dark-field
      microscopy. RESULTS: Fourteen of the 18 unequivocal parathyroid cancers expressed
      gelatinase A, as compared with the equivocal tumors, of which only 4 of 13 showed
      expression. The strongest hybridization signal was seen in stromal cells at the
      tumor border, most likely fibroblasts and macrophages. No expression was detected
      in tumor cells. CONCLUSIONS: Invasive growth of many tumors is facilitated by
      proteolytic enzymes, such as gelatinase A. The presence of gelatinase A mRNA in
      parathyroid tumors strengthens the suspicion of malignancy but cannot be used as
      a definitive marker of malignancy.

PMID- 10598206
TI  - Mapping of a gene predisposing to familial thyroid tumors with cell oxyphilia to
      chromosome 19 and exclusion of JUN B as a candidate gene.
AB  - BACKGROUND: Familial nonmedullary thyroid carcinoma (FNMTC) is a clinical entity
      characterized by a more aggressive phenotype than the sporadic counterpart. The
      transmission of susceptibility of FNMTC is compatible with autosomal dominant
      inheritance. We report the identification of a new entity of FNMTC and the
      mapping of the responsible gene named TCO (for thyroid tumor with cell
      oxyphilia). METHODS: In one family, multinodular goiters were diagnosed in six
      individuals and papillary thyroid carcinoma was diagnosed in three. Eight
      patients were operated on. Blood samples were collected from the nine affected
      patients and from eight unaffected relatives. The gene was mapped by linkage
      analysis with a whole-genome panel of microsatellite markers. RESULTS: The
      neoplastic cells from all lesions showed characteristic faint to marked
      cytoplasmic oxyphilia. We found a logarithm of odd ratio (LOD) score of 2.41 at
      theta = 0 for marker D19S586. Additional markers were typed in the region and
      were found to be in linkage, with LOD scores peaking at markers D19S916 (Zmax =
      3.01 at theta = 0) and D19S413 (Zmax = 2.95 at theta = 0). All these markers have
      been physically mapped to 19p13.2. CONCLUSIONS: TCO was mapped to chromosome
      19p13.2. Interestingly, both the benign and malignant thyroid tumors in this
      family exhibit some degree of oxyphilia, which has not been described until now
      in the familial forms of NMTC.

PMID- 10598207
TI  - Human telomerase reverse transcriptase (hTERT) gene expression in FNA samples
      from thyroid neoplasms.
AB  - BACKGROUND: Although fine-needle aspiration (FNA) is the most sensitive method
      for the detection of thyroid carcinoma, it cannot provide a definitive diagnosis
      of malignancy in 60% of the patients operated on for suspicious lesions.
      Recently, human telomerase reverse transcriptase (hTERT) has been found to be a
      diagnostic marker of malignancy. We therefore sought to determine whether hTERT
      gene expression could serve as an adjunct to FNA in the differential diagnosis of
      thyroid nodules. METHODS: Twenty-four FNA samples from thyroid nodules that were
      suspected of malignancy were collected. RNA was extracted, and hTERT gene
      expression was examined by RT-PCR. Cytologic and histologic examinations were
      also performed. RESULTS: Two of three follicular, three of three Hurthle cell,
      and eight of eight papillary thyroid carcinomas had corresponding FNA samples
      that were positive for hTERT. One of two Hurthle cell adenomas was hTERT
      positive. FNA samples from three follicular adenomas and five hyperplastic
      nodules were negative for hTERT. Positive and negative predictive values were 93%
      and 90%, respectively. CONCLUSIONS: The detection of hTERT gene expression in
      thyroid FNA samples holds promise as a diagnostic marker in the distinction of
      benign from malignant thyroid lesions. Its application could alter the surgical
      management of these patients.

PMID- 10598208
TI  - The value of thyroid peroxidase immunohistochemistry for preoperative fine-needle
      aspiration diagnosis of the follicular variant of papillary thyroid cancer.
AB  - BACKGROUND: With the use of May-Grunwald-Giemsa staining, cytologic features of
      the follicular variant of papillary thyroid cancers (FVPTCs) on thyroid fine
      needle aspiration (FNA) often resemble those of hyperplastic and adenomatous
      nodules. Detection of reduced staining after thyroid peroxidase (TPO)
      immunohistochemistry with monoclonal antibody MoAb47 has been shown to be a
      helpful diagnostic marker. The purpose of this study was to assess the value of
      TPO immunohistochemistry for the diagnosis of FVPTC. METHODS: Of 3505 patients
      with adequate FNA samples, 1576 patients underwent surgical procedures.
      Histologic examination of the surgical specimen demonstrated papillary thyroid
      cancer in 227 cases, including 42 FVPTCs (18%). The diagnostic accuracy of
      standard thyroid FNA and TPO immunohistochemistry, which we use routinely, was
      compared in these 42 FVPTCs. RESULTS: Standard FNA allowed accurate diagnosis of
      malignancy in 32 of the 42 FVPTCs and in 170 of the 185 typical papillary thyroid
      cancers. TPO-immunohistochemistry staining was accurate in all 42 FVPTCs and in
      182 of 185 typical PTCs. CONCLUSIONS: FVPTC is a frequent source of false
      negative results on standard thyroid FNA. This study shows that TPO
      immunostaining accurately demonstrates malignancy in these tumors.

PMID- 10598209
TI  - Allergenic oxidation products in ethoxylated non-ionic surfactants. Chemical
      characterization and studies on allergenic activity and physicochemical behavior.

PMID- 10598210
TI  - Genetics of alcoholism: a review of recent studies in human and animal models.
AB  - There is substantial evidence for a significant genetic component to the risk of
      alcoholism. In searching for genes that contribute to this risk, several
      approaches may be utilized in order to identify the genetic loci underlying
      alcoholism susceptibility. Several candidate genes have been evaluated for their
      role in alcoholism; however, with the exception of the enzymes of alcohol
      metabolism, results from these studies have been inconsistent. Recently, two
      large studies have employed a genome screen methodology to identify novel genes
      contributing to the risk of alcoholism. As an alternative strategy, researchers
      have utilized mouse and rat models to identify quantitative trait loci
      influencing alcohol preference. Through the development of congenic lines and
      transgenic and knock-out animals, candidate genes can be identified and evaluated
      for their role in alcohol preference.

PMID- 10598211
TI  - Dialectical behavior therapy for patients with borderline personality disorder
      and drug-dependence.
AB  - A randomized clinical trial was conducted to evaluate whether Dialectical
      Behavior Therapy (DBT), an effective cognitive-behavioral treatment for suicidal
      individuals with borderline personality disorder (BPD), would also be effective
      for drug-dependent women with BPD when compared with treatment-as-usual (TAU) in
      the community. Subjects were randomly assigned to either DBT or TAU for a year of
      treatment. Subjects were assessed at 4, 8, and 12 months, and at a 16-month
      follow-up. Subjects assigned to DBT had significantly greater reductions in drug
      abuse measured both by structured interviews and urinalyses throughout the
      treatment year and at follow-up than did subjects assigned to TAU. DBT also
      maintained subjects in treatment better than did TAU, and subjects assigned to
      DBT had significantly greater gains in global and social adjustment at follow-up
      than did those assigned to TAU. DBT has been shown to be more effective than
      treatment-as-usual in treating drug abuse in this study, providing more support
      for DBT as an effective treatment for severely dysfunctional BPD patients across
      a range of presenting problems.

PMID- 10598212
TI  - A 12-year follow-up of a methadone medical maintenance program.
AB  - Methadone Medical Maintenance (MDM) is an alternative for treatment of stable
      methadone maintained individuals. It involves a monthly physician's visit, at
      which methadone take-home doses are dispensed to last until the next appointment.
      The safety and efficacy of this treatment modality is currently under
      investigation. The purpose of this study was to evaluate the long-term safety and
      efficacy of MDM in a methadone program in Baltimore. A sample of 21 patients was
      enrolled in the study and followed for 12 years. They were evaluated once a month
      by a primary care physician affiliated with a methadone clinic who collected
      urine toxicology samples and dispensed the monthly methadone dose. The results
      showed that only 6 (28.6%) patients dropped out during the 12 years of the study.
      Twelve (0.5%) of 2,290 urine samples collected were positive for drugs. No
      methadone overdose or diversion was observed. Participants reported significant
      improvement in their quality of life. The results of this study support the
      safety and efficacy of medical maintenance of stable methadone maintained
      individuals.

PMID- 10598213
TI  - Gender differences in treatment-seeking cocaine abusers--implications for
      treatment and prognosis.
AB  - This study examined gender differences in demographics, psychosocial functioning,
      substance abuse severity, psychopathology, and 1-year outcome in cocaine
      dependent patients with the goal of identifying factors important to improving
      treatment and identifying prognostic indicators. The sample included 298 cocaine
      dependent adults (92 women). Ninety-four patients (29 women) provided 1-year
      follow-up assessments. Compared to men, women consumed similar quantities of
      cocaine by more addictive routes and experienced more rapid progression of drug
      dependence, thus highlighting the need to facilitate treatment entry. The
      substantial rates of positive treatment outcomes emphasizes the effectiveness of
      treatment for cocaine-dependent individuals.

PMID- 10598214
TI  - Age-related patterns of factors associated with completed suicide in men with
      alcohol dependence.
AB  - Seven factors associated with completed suicide among male alcoholics were
      investigated to determine if victims of differing ages would show different
      patterns of factors. Data on 56 male alcoholic suicide victims were collected
      post-mortem. Subjects were divided into three age groups: 21-34, 35-49, and > or
      = 50 years. Consistent with the hypotheses, unemployment and recent loss due to
      separation from a domestic partner were more likely with younger age, and serious
      medical problems and mood disorders were associated with increased age. There
      were no differences on other presumed risk factors among the age groups. Results
      suggest that factors associated with suicide may cluster in male alcoholics of
      differing ages, with implications for risk recognition and intervention.

PMID- 10598215
TI  - A two-rate hypothesis for patterns of retention in psychosocial treatments of
      cocaine dependence: findings from a study of African-American men and a review of
      the published data.
AB  - In this article, we examine patterns of retention in psychosocial treatment
      programs for cocaine dependence. We present new data from a comparison trial of
      Drug Counseling and Supportive-Expressive Psychotherapy and review published data
      from all studies utilizing psychosocial interventions alone. We compared Drug
      Counseling and Psychotherapy on rates of pretreatment and during-treatment
      attrition in a sample of 294 African-American men seeking treatment for cocaine
      dependence (mean age, 37.6). Survival analyses were utilized to identify
      significant differences in during-treatment attrition between the two treatments
      and to identify significant changes in the rate of attrition during the course of
      each treatment. We then compared the patterns of retention in this study with
      those from other available published reports of psychosocial treatments for
      cocaine abuse. The weekly during-treatment attrition rate was not constant in
      either treatment condition, and the change in rate of attrition occurred at week
      six for both Drug Counseling and Psychotherapy. Comparison with other studies
      suggested that the during-treatment pattern of attrition among most psychosocial
      treatments for cocaine abuse is typified by two rates, with the rate of subject
      attrition early in treatment being greater than the rate of later attrition and
      also exhibiting greater variance. Future studies of treatment retention should
      identify significant shifts in the rate of during-treatment attrition, examine if
      the pattern of attrition is typified by two rates, and, if so, determine where
      the shift occurs. Future studies should also assess if changes in the rate of
      during-treatment attrition signal the timeframes within which strategies that
      enhance retention can be implemented in the treatment program.

PMID- 10598216
TI  - Social resources and social function in comorbid eating and substance disorder: a
      matched-pairs study.
AB  - OBJECTIVE: To assess social resources and function among patients with comorbid
      Eating Disorder (ED) and substance abuse/dependence, referred to here as
      Substance Related Disorder (SRD). DESIGN: Descriptive, cross-sectional,
      comparative. SETTINGS: A university medical center with an Alcohol-Drug Program
      located within a Department of Psychiatry. SUBJECTS: 70 patients with Substance
      Related Disorder and Eating Disorder (SRD-ED), matched for gender, age, and race
      ethnicity with 70 SRD-only patients. METHODS: A research associate assessed
      current social resources and social function based on data obtained from patients
      and collateral sources while blind to the ED status of the patient. Addiction
      psychiatrists made the diagnoses of SRD and ED and conducted assessments for axis
      4 psychosocial stressors and axis 5 psychosocial function. RESULTS: SRD-ED
      patients had more advantageous social resources than SRD-only patients, including
      residence with family or friends, more education, higher socioeconomic status,
      and larger social networks. However, SRD-ED patients manifested martial status,
      employment, stressors, and coping levels similar to SRD-only patients.
      CONCLUSIONS: Several alternative explanations exist for these expected though
      unusual findings. Further analyses will be required to understand this lack of
      articulation between social resources and social function across two diagnostic
      groups.

PMID- 10598217
TI  - Lofexidine for opiate detoxification: review of recent randomised and open
      controlled trials.
AB  - The objective of this article was to review the data from recently published
      trials of lofexidine in the treatment of opiate withdrawal, with particular
      attention to evidence on efficacy, side-effects (particularly hypotension), and
      the acceptability of this new treatment to the patient population. The authors
      reviewed data contained within peer-reviewed published reports of clinical trials
      of lofexidine compared with detoxification using reducing doses of the opiate
      agonist methadone or the alpha-adrenergic agonist clonidine. Five published
      reports of clinical trials of lofexidine have been identified from peer-reviewed
      journals in the eight years between 1990 and 1998--all published within the last
      three years. Three of the reports compare lofexidine with clonidine, while the
      remaining two compare it with methadone detoxification. The three comparisons
      with clonidine find lofexidine to be similar in its moderating effect on the
      withdrawal syndrome, but without the same extent of problems with hypotension.
      Comparisons with methadone show a more rapid resolution of withdrawal symptoms
      with lofexidine--particularly with the accelerated 5-day lofexidine protocol.
      Such problems of hypotension as were encountered with lofexidine were adequately
      managed with dose reduction. Acceptability of the treatment to the patient (as
      measured by retention in treatment) appears to be greater with lofexidine than
      clonidine, although possibly less than with methadone. Lofexidine is an alpha-2
      adrenergic agonist that is increasingly used in the management of opiate
      withdrawal--notably in the UK. The available data indicate that it is a useful
      new addition to the armamentarium of the clinician. Future studies should explore
      its application with improved protocols and in new treatment settings. This
      article reviews the recent advances in the study of lofexidine as a new treatment
      for opiate detoxification. It examines the background of the development and
      introduction of lofexidine into the U.K., with data on the extent to which it is
      now used in the U.K. in the treatment of opiate addiction. A review is then
      provided of the published evidence on the use of lofexidine in the management of
      opiate detoxification, mainly concentrating on the data from recent double-blind
      randomised trials. Finally, the possible future role of lofexidine in this field
      is considered.

PMID- 10598218
TI  - Response to "Use of anticonvulsants in benzodiazepine withdrawal".

PMID- 10598219
TI  - [Smoking cessation assistance: a medical act].

PMID- 10598220
TI  - [Evaluation of prognosis after Q wave myocardial infarction. Comparison of
      invasive and noninvasive diagnostic strategies].
AB  - The predictive value of several diagnostic strategies after myocardial infarction
      was assessed in 178 patients (mean age 55 +/- 9 years) treated medically after a
      primary Q wave myocardial infarction. Within 6 weeks of onset of symptoms the
      authors performed exercise stress test coupled with Thallium 201 scintigraphy,
      isotopic left ventriculography and conventional coronary angiography with
      ventriculography. The average left ventricular ejection fraction was 45 +/- 12%.
      Two non-invasive diagnostic strategies with and without results of scintigraphy
      and two invasive strategies with and without ventricular volumes were studied.
      The average follow-up period was 58 +/- 22 months. Sixteen cardiac deaths
      occurred. Multivariate Cox analysis showed that, in contrast to left ventricular
      volumes, coronary angiography did not provide additional prognostic value
      compared with the non-invasive model with Thallium scintigraphy and did not
      appear to be essential in terms of predictive value in this population. Moreover,
      the size of reversible defect on Thallium scintigraphy was an independent
      predictive factor of cardiac death and provided additional and independent
      prognostic information in the non-invasive and invasive strategies. Therefore,
      the reduction of residual ischaemia by coronary revascularisation could improve
      the long-term prognosis after myocardial infarction.

PMID- 10598221
TI  - [Failure of internal thoracic-coronary artery bypass graft. What are the
      reasons?].
AB  - The aim of this study was to identify the causes of failure of coronary bypass
      grafting with the internal thoracic artery. A total of 512 internal thoracic
      artery grafts in 302 patients were reviewed. Control coronary angiography was
      performed after an average of 17.3 months (sigma = 4.1 months). Were considered
      as failures: 11 (2%) occluded grafts and 19 (4%) non-functional (narrowed
      internal thoracic artery) grafts. The appearances of the anastomosis, presence or
      absence of stenosis, origin of flow at the anastomosis and distal run-off of the
      grafted coronary artery, were analysed. Of the 19 non-functional grafts, there
      were no stenosis of the anastomosis of the narrowed internal thoracic arteries;
      in 14 cases, competitive flow was observed (2 internal thoracic artery steal
      syndromes by non-obstructed proximal collateral branches, 8 initially
      overestimated coronary stenoses, 4 secondary regressions of coronary stenosis);
      there was poor distal run-off of the grafted artery in 4 cases and significant
      coronary stenosis distal to the graft in one case. This study shows that, of the
      30 failures of internal thoracic artery grafting, at least 2/3 were "avoidable"
      by a more accurate evaluation of the coronary stenosis on the preoperative
      coronary angiography and by better surgical technique.

PMID- 10598222
TI  - [Aortic valve replacement in patients over 80 years of age. Short- and medium
      term results in 140 patients].
AB  - One hundred and forty aortic valve replacements (AVR) performed between 1986 and
      1995 at Rouen University Hospital in octogenarians (52 men and 88 women),
      including 9 emergency procedures, were analysed. One hundred and fifteen patients
      had pure aortic stenosis, 25 had mixed aortic valve disease with mainly aortic
      incompetence. The surgical decision was taken by the patient with the surgeon
      after an interview, in order to exclude too handicapped or undecided patients.
      Significant coronary artery disease was observed in 42% of cases. Isolated AVR
      was undertaken in 74% of cases and associated coronary bypass surgery in 23% of
      cases. Bioprostheses were used in 90% of cases. The valvular lesions were
      predominantly those of Monckeberg disease. The operative mortality was of 13
      patients (9.3%). Functional recovery was satisfactory in 78% of cases; the
      average duration of the hospital stay was 12 days. All known risk factors for
      AVR: age, coronary lesions, cardiac failure, low ejection fraction, aortic
      regurgitation, were associated with insignificant increases in mortality. The
      secondary mortality was of 28 patients; 99 patients are still alive 4 to 91
      months after surgery. The actuarial survival graph showed a 56.5% probability of
      5 year survival. Eighty per cent of survivors live at home without loss of
      autonomy.

PMID- 10598223
TI  - [Percutaneous suture of femoral artery after diagnostic coronary angiography].
AB  - Complete local haemostasis after femoral artery catheterization can be performed
      using percutaneous suture devices. To evaluate efficacy and safety of these
      systems after diagnostic coronary angiography, we performed a randomized study
      where patients were treated either with a manual compression (group C) or a
      percutaneous suture (group T). Fifty patients were included in each group.
      Patients in group C had to rest at bed during 24 hours while patients in group T
      had to stand up and walk immediately after complete haemostasis was obtained. All
      angiographies were performed using a 6 F sheath. All patients had a clinical
      evaluation and an echography 24 hours after the procedure and all were reached by
      phone call at 15 days. Both groups were similar in term of age, sex ratio,
      diabetes, height and weight. Complete haemostasis was obtained in 20 +/- 6 mn in
      group C and in 6 +/- 10 mn in group T (p < 0.001). Device technical success rate
      in group T was 90%; 70% of patients walked immediately down the X ray table and
      90% before the 4 hours. Ambulation delay was 24 +/- 5 hours in group C and 5 +/-
      9 hours in group T (p < 0.0001). Clinical and echographic complications rate were
      similar in both groups (8%). There was no post procedure complication in group T
      (especially after ambulation) nor at the phone call. CONCLUSION: Femoral artery
      percutaneous suture after diagnostic coronary angiography is as safe and working
      than manual compression. It allows an immediate mobilization and ambulation, far
      earlier than compression.

PMID- 10598224
TI  - [Plasma homocysteine is not a predictive factor of restenosis after coronary
      angioplasty].
AB  - Hyper-homocysteinaemia is a cardiovascular risk factor. In parallel,
      anatomopathological studies of post-angioplasty coronary restenosis show
      histological appearances similar to those observed in patients with severe hyper
      homocysteinaemia. Based on these histological observations, the authors tried to
      assess the predictive value of raised plasma homocysteine levels for coronary
      restenosis after angioplasty. Two hundred and twenty-two patients treated by
      coronary angioplasty were followed up clinically for 6 months. Thallium 201
      myocardial scintigraphy was performed in 179 patients and coronary angiography in
      74 patients. Seventy-nine patients had coronary restenosis diagnosed by coronary
      angiography in 55 cases, by myocardial scintigraphy in 23 cases and strongly
      suspected clinically in only one patient. No significant differences in
      homocysteine levels were observed between patients with multiple restenosis or
      requiring revascularisation, and those without restenosis and not requiring
      revascularisation. Plasma homocysteine does not therefore seem to be a predictive
      factor of post-angioplasty coronary restenosis.

PMID- 10598225
TI  - [Psychosocial effects of angina. Results of a cross-sectional survey of 3,654
      patients].
AB  - The consequences of angina were assessed by a questionnaire completed by 1,528
      out-hospital doctors (79% of general practitioners, 21% of cardiologists) on
      3,654 patients. This population comprised 2,304 men (64%) and 1,282 women (36%)
      with a mean age of 69.5 years (men: 67.1, women: 73.8 years). Previous myocardial
      infarction was present in 36.6% of cases and the average number of angina attacks
      was 3.1 per month. Angina seemed to affect the social behaviour of 25 to 30% of
      patients, the affective behaviour of 40% of patients and everyday life style in
      60% of cases. Sixty per cent of patients had difficulties in their work and 60%
      also had psychological consequences of the angina. The social consequences of
      angina were different according to the patient's gender. Women were more affected
      in family life and men in their affective behaviour. The psychological
      consequences were also different: women were more likely to be anxious or
      depressed whereas men were usually more irritable. The incidence of anxio
      depressive reactions with age was not studied (the female population was older).
      The higher incidence of anxio-depressive symptoms in women may be partially
      explained by their age at the time of diagnosis and the difference in prognosis
      between men and women when coronary artery disease is established.

PMID- 10598226
TI  - [Ischemic neuropathy in occlusive lower limb arterial disease at the state of
      ischemia on effort].
AB  - Acute or chronic prolonged ischaemia of the limbs may cause lasting neurological
      damage. This has been shown in clinical, electrophysiological and
      anatomopathological studies. The aim of this study was to search for signs of
      neurological suffering during ischaemia of effort. Twenty patients with occlusive
      lower limb arterial disease with ischaemia of effort were studied. None of the
      patients had other causes of neuropathy: none of the patients had potentially
      neurotoxic therapy. All underwent haemodynamic assessment (Doppler
      ultrasonography treadmill test, transcutaneous oxygen diffusion) and
      electrophysiological study (nerve conduction studies and an electromyogramme).
      Ten patients had abnormalities during stimulation-detection and on
      electromyography. These abnormalities were always observed in the limbs with the
      poorest blood flow. The pressure index and transcutaneous oxygen diffusion in
      lying position were significantly lower (pressure index: 0.43 vs 0.72, p < 0.03;
      TcPO2: 20.3 vs 27.2, p < 0.04). The authors consider that effort ischaemia is
      associated with neurological damage. Repeated transient episodes of ischaemia
      could cause neuropathy.

PMID- 10598227
TI  - [Cardiac pacing. Percutaneous extraction of infected pacing catheter].
AB  - Infection of a cardiac pacemaker is a rare but serious complication. Percutaneous
      ablation of the pacemaker and pacing catheter is the only effective treatment.
      Techniques of extraction of pacing systems have been evaluated but the long term
      results require analysis. Eighteen patients with infection of cardiac pacemakers
      underwent extraction of one or more pacing catheters (14 atrial and 20
      ventricular) in one same centre. The indication was infection of the pacemaker
      unit (12 cases) or septicaemia (6 cases) The causal organism was a staphylococcus
      (aureus: 7 cases, epidermidis: 10 cases, capitis: 1 case). Three techniques were
      used: 1) direct external manual traction, 2) internal traction with several
      devices, 3) endovascular counter-traction (Byrd-Cook system). The time from
      primary implantation of the pacing catheter to its extraction was 42 months and
      from last pacemaker manipulation to infection, 23 months. The average duration of
      the extraction procedure was 120 +/- 45 minutes; that of fluoroscopy was 10 +/- 6
      minutes. The first technique was used 12 times, the second 8 times and the third
      14 times, with complete extraction of the catheter in 88.2% of cases. The
      metallic tip of the distal electrode embolised in 2 cases and remained stuck in
      the right ventricle in 1 case. Only one pacing catheter was abandoned. After an
      average follow-up of 45 months, none of the patients had recurrent infection or
      any other complication. The authors conclude that extraction of infected pacing
      catheters is safe and effective. It is the treatment of choice of this
      complication.

PMID- 10598228
TI  - [Dobutamine doppler echocardiography in severe aortic stenosis with left
      ventricular dysfunction. Comparison with postoperative examination].
AB  - The association of left ventricular dysfunction with aortic stenosis worsens the
      spontaneous prognosis and increases operative mortality. The aim of this
      prospective study was to assess the predictive value of dobutamine Doppler
      echocardiography on the indices of left ventricular contractile function in
      patients with aortic stenosis and left ventricular dysfunction (LVEF < 0.45)
      undergoing aortic valve replacement. Eighteen patients, including 9 with coronary
      artery disease, were included in a protocol consisting of analysis of left
      ventricular function and of the severity of aortic stenosis before, during
      dobutamine infusion, and after valvular replacement. The dobutamine was given in
      progressive increments of 5 micrograms/Kg up to a maximum of 20 micrograms/Kg.
      During pharmacological stress, the functional aortic valve area increased from
      0.46 +/- 0.15 to 0.56 +/- 0.23 cm2. Tolerance of the procedure was good. All but
      2 patients improved their postoperative ejection fraction with values equivalent
      to those observed during the last increment of dobutamine (r = 0.73; p < 0.003).
      The patients with initial mean pressure gradients > 50 mmHg normalised their LVEF
      after valve replacement. The authors conclude that dobutamine echocardiography is
      useful for predicting the values of postoperative left ventricular contractile
      indices when severe aortic stenosis is associated with systolic dysfunction. It
      allows evaluation of the expected short term benefits to these indices after
      aortic valve replacement.

PMID- 10598229
TI  - [Stop tobacco consumption].

PMID- 10598230
TI  - [Metabolic and genetic investigations in childhood cardiomyopathies].
AB  - Metabolic cardiomyopathy of babies and children accounts for approximately 15% of
      all cardiomyopathies presenting at these ages. The confirmation of the aetiology
      is essential for treatment, which is rarely curative. For establishing a
      prognosis which is often poor, and, above all, for family counselling in cases of
      mendelian transmission or mitochondrial disease. Cardiomyopathy due to glycogen
      (Pompe's disease) or mucopolysaccharide (Hurler's disease) disorders are easy to
      diagnose because of obvious extracardiac manifestations. The diagnosis of the
      enzyme deficiency only requires a blood and/or urine test. Cardiomyopathies due
      to a deficit of oxidative metabolism are usually associated with multi-system
      abnormalities but may be isolated or the presenting sign of the deficit. The
      diagnosis should be suspected in cases of a positive family history of
      cardiomyopathy or sudden death, of co-sanguinity, of unusual or unexplained
      extracardiac disease, of atypical ECG changes or of hypoglycaemia. Chromatography
      of organic acids, analysis of acylcarnitines and -oxidation of the fatty acid
      oxidation. Of these conditions, only primary carnitine deficits are curable. The
      diagnosis of mitochondrial cardiomyopathy is based on the ratios of
      oxidoreduction and, above all, on spectrophotometric analysis of the respiratory
      chain complexes in skeletal or cardiac muscle (when the heart is the only organ
      involved). Genetic counselling is difficult and punctual mutations or deletions
      of mitochondrial DNA are rarely observed, and also few nuclear genes coding for
      the proteins of the respiratory chain have been identified to this day.

PMID- 10598231
TI  - [Aortic valve myxoma. Conservative valvular surgery].
AB  - The authors report a case of aortic valve myxoma discovered in a 35 years-old
      patient who suffered a transient ischemic attack. At operation a helicoidal
      gelatinous mass was found attached to the ventricular side of the right coronary
      cusp of the aortic valve by a pedicle. Through a mini-sternotomy approach the
      mass was excised and the cusp was repaired. Recovery was uneventful.

PMID- 10598232
TI  - [Traumatic left ventricle-right atrial communication. A case report].
AB  - The authors report the case of an acquired left ventricle-right atrial
      communication after open chest trauma. The initial clinical presentation was a
      haemothorax and haemopericardium responding well to emergency surgical drainage.
      Secondarily, a systolic murmur suggesting a ventricular septal defect and signs
      of right heart failure were observed. Colour Doppler echocardiography led to the
      diagnosis of a left ventricle-right atrial communication associated with
      tricuspid regurgitation with dilatation of the right heart chambers and pulmonary
      hypertension. At surgery, a defect in the membranous interventricular septum was
      confirmed with rupture of the septal tricuspid leaflet causing tricuspid
      regurgitation. The surgeon closed the defect with a patch and performed a De Vega
      tricuspid valvuloplasty. The postoperative outcome was uneventful.

PMID- 10598233
TI  - [Paradoxical pulmonary embolism. A rare complication of arteriovenous
      fistulization of an aorto-iliac aneurysm].
AB  - Aneurysms of the infra-renal abdominal aorta or iliac arteries result in ilio
      caval compression in about 10% of cases which may cause venous thrombosis by
      stasis and pulmonary embolism. Fistulisation of these aneurysms into the inferior
      vena cava or an iliac vein is rare and paradoxical pulmonary embolism from
      arterial thrombus of the aneurysmal pouch is exceptionally rare. The authors
      report a new case in which the ilio-iliac arteriovenous fistula caused high
      output cardiac failure, ischaemia of the homolateral leg and pulmonary embolism.
      Doppler ultrasonography diagnosed the fistula and excluded a deep vein
      thrombosis. This case illustrated the essential value of clinical examination and
      of Doppler ultrasonography, especially of the abdomen, in the investigation of
      the causes of pulmonary embolism.

PMID- 10598234
TI  - [Balloon angioplasty].
AB  - Balloon angioplasty of the coronary arteries is about 20 years old and has become
      the main technique of myocardial revascularisation. It is performed under local
      anaesthetic by arterial puncture and some centres are already performing the
      procedures on an ambulatory basis. Optimally, the procedure should be performed
      in a well-equipped catheter laboratory with trained operators and experienced
      personnel. The most impressive results are obtained in single vessel disease.
      However, double and triple vessel disease may also be treated, especially in
      elderly, frail patients, in cases of high surgical risk or with a previous
      history of coronary bypass surgery. Balloon angioplasty has an important role in
      the treatment of acute myocardial infarction, either as an alternative or as a
      complement to thrombolytic therapy. The major limitations of this technique, in
      the absence of stenting, are the failure to pass chronic lesions, the occurrence
      of major complications in about 1% of cases, of acute occlusion in about 5% of
      cases, and, finally, of restenosis estimated between 30 and 50%, depending on the
      publication. In the general population, the success rate is over 95% with an
      immediate return to normal life and the possibility of repeating an angioplasty
      in cases of restenosis. Coronary stents are a major technical adjuvant to balloon
      angioplasty and the indications of their implantation have exceeded 50% of
      procedures in recent years.

PMID- 10598235
TI  - [Coronary stents].
AB  - Coronary stents are widely used in percutaneous revascularisation and are
      associated with excellent primary results in the majority of cases. The anti
      GPIIb/IIIa molecules and the association of ticlopidine and aspirin are part of
      the pharmacological environment which contributes to the short-term success of
      these procedures. The essential problem remains restenosis which, in its diffuse
      form, is difficult to treat. Physicians should be vigilant with respect to the
      quality of the stents which they use and should enforce the conditions which the
      working group of the European Society of Cardiology recently proposed. Finally,
      in indications not yet validated or in the process of validation, they should be
      very careful and good results of balloon angioplasty should be respected.

PMID- 10598236
TI  - [Coronary atherectomy. An essential tool for specific indications].
AB  - Technological advances in the manufacturing of stents have extended the
      indications of angioplasty and considerably reduced the immediate complications,
      death and myocardial infarction. Nevertheless, intra-stent restenosis remains a
      problem and some complex lesions are still inaccessible. Atherectomy has not been
      shown to be effective in limiting restenosis but it has a primordial role in the
      treatment of lesions of bifurcation and could improve long-term results as a
      complement of angioplasty and stenting. Rotational atherectomy is still useful,
      even essential, for lesions which cannot be passed with the balloon and for
      calcified plaques of atheroma. A possible new indication may be the treatment of
      intra-stent stenosis. The indications of directional atherectomy are more
      limited, mainly non-calcified ostial stenosis and of bifurcations of large
      arteries. The association with stenting has given encouraging results which
      require confirmation. These techniques have a place in the in the angioplasty
      physician's arsenal even though they are reserved for specific anatomical
      situations.

PMID- 10598237
TI  - [Acute complications of coronary angioplasty: prevention and management].
AB  - The immediate results of transluminal coronary angioplasty (TCA) have improved
      considerably during recent years. Balloon dilatation of the arterial stenosis is
      the basis of this technique of revascularisation but new tools may be used to
      treat specific lesions. Coronary occlusion is the most feared complication of
      TCA. It may cause myocardial infarction or death of the patient. It is usually
      secondary to dissection and/or thrombus of the artery. The implantation of a
      stent successfully treats most cases of dissection. New anti-platelet (GP
      IIb/IIIa) drugs seem to be very effective in the prevention and treatment of the
      thrombosis. The systematic use of ticlopidine limits the risk of stent occlusion.
      Improved features enable satisfactory implantation of stents in the majority of
      cases. In some patients, the clinical consequences of occlusion may be limited by
      vascular bypass techniques, especially intra-aortic balloon pumping. In other
      cases, emergency coronary bypass surgery may be necessary. When TCA is considered
      to be a very high risk procedure, effective surgical cover is essential.

PMID- 10598238
TI  - [Restenosis after angioplasty].
AB  - Restenosis remains the main limitation of endocoronary methods of
      revascularisation. It is observed in 20 to over 50% of cases, depending on the
      prevailing risk factors and techniques used. The mechanism of post balloon
      angioplasty restenosis consists of neointimal hyperplasia, vascular remodelling
      and thrombosis. Intra-stent thrombosis is mainly caused by the neointimal
      hyperplasia. The strategies developed to prevent restenosis may be grouped in two
      categories: mechanical and pharmacological strategies. Stenting is the only
      mechanical method to have been shown to be effective. With respect to
      pharmacological methods, the general impression is rather negative even if some
      positive results have been reported recently. Of the new strategies which may
      provide a solution in the coming years, gene therapy and endocoronary irradiation
      justify a special mention.

PMID- 10598239
TI  - [Diagnosis of restenosis].
AB  - Transluminal coronary angioplasty (TCA) has become a well established technique
      of coronary revascularisation. The medium-term results are however limited by the
      risk of restenosis. This restenosis occurs in the 6 months following angioplasty,
      above all between the 1st and 3rd month. The restenosis rate after balloon
      angioplasty is about 40% and about 20% after implantation of a stent, at least in
      short lesions. Some factors related to the underlying disease (diabetes), the
      clinical status and the date of TCA (unstable angina) or the type of lesion
      (chronic occlusion, stenosis of venous grafts) are associated with a high risk of
      restenosis. The occurrence of angina in the 6 months after TCA may be due to
      restenosis but also to incomplete revascularisation or the progression of non
      significant lesions. This explains the low predictive value of angina for the
      diagnosis of restenosis. In asymptomatic patients, the diagnosis depends on non
      invasive tests. The positive and negative predictive values of exercise stress
      testing are low (about 50% and 75%, respectively). Nevertheless, stress testing
      remains useful for assessing the functional capacity of patients, to confirm the
      absence of symptoms and to document silent ischaemia. The sensitivity of stress
      Thallium scintigraphy, associated or not with dipyridamole, is higher. Stress
      echocardiography, currently under evaluation, would seem to be as useful as
      Thallium scintigraphy for the diagnosis of restenosis.

PMID- 10598240
TI  - [Curative treatment of restenosis].
AB  - It has been clearly demonstrated that post-angioplasty restenosis is the result
      of the combination of three distinct mechanisms associated to different degrees:
      constrictive remodelling, neo-intimal hyperplasia and elastic recoil. In
      contrast, after stent implantation, constrictive remodelling is nil, elastic
      recoil is very mild and restenosis, when observed, is essentially due to a
      reaction of intimal hyperplasia. These physiopathological features are important
      as they affect the therapeutic opportunities. With rates of stent implantation
      attaining 100% in some centres, intra-stent restenosis is a new pathology which
      poses serious problems in everyday practice as the best management of this
      situation has not yet been determined. For a long time, redilatation with a
      balloon catheter was the only possible solution. Secondarily, ablative techniques
      were evaluated, such as rotational and laser atherectomy, techniques with the
      theoretic advantage of eliminating part of the intimal proliferation. Directional
      atherectomy has also been used by some groups. More recently, other approaches,
      such as implantation of a second stent inside the first, the cutting balloon and
      radiotherapy, have been suggested. A surgical option is always possible in cases
      of repeat and/or diffuse restenosis. Finally, abstention from any local treatment
      may be justified in asymptomatic patients. These different approaches are
      discussed in this paper.

PMID- 10598241
TI  - [Long-term outcome of dilated or stented segments].
AB  - Coronary angioplasty with a balloon catheter or stent should be shown to prolong
      life and improve its quality. Many clinical and angiographic studies have
      provided information on the long-term outcome of dilated or stented segments. In
      general, a lesion treated by balloon or stent which has not restenosed within 6
      months has a good long-term prognosis. The compensatory widening and arterial
      remodelling of the dilated segments seem to be the determining factors whereas
      intimal hyperplasia may be reduced by a decrease in the cellular components of
      stented segments. The recurrence of coronary events is more usually related to
      progression of the coronary artery disease than to deterioration of the dilated
      or stented segments. However, these general concepts should be modulated with
      respect to local (lesion-dependant) or general (patient-dependant) factors. The
      properties of the lesion (type, site), the diffusion of the atherosclerosis,
      partial primary result of angioplasty and associated diabetes, coronary bypass
      grafting, unstable angina and left ventricular dysfunction are the prognostic
      factors of long-term coronary outcome.

PMID- 10598242
TI  - [Treatment of stable angina. Coronary angioplasty versus medical treatment].
AB  - Stable angina is a common clinical condition in everyday practice. Several
      studies (ACME, MASS, RITA 2) compared the efficacy of angioplasty with medical
      management in this context with concordant results: significant reduction in the
      frequency of angina and improved exercise capacity, without reduction in the
      number of serious events (death, infarction). Even though developments in the
      field of angioplasty have provided better clinical results, especially with the
      use of stents, the indication of dilatation should be clearly defined by a series
      of clinical and angiographic parameters. Although resistance to well conducted
      medical treatment is an indication for revascularisation when possible, the
      indications should be reconsidered if persistent ischaemia with medical therapy
      has not been proved.

PMID- 10598243
TI  - [Angioplasty in unstable chest angina. Angioplasty in unstable angina].
AB  - Angioplasty in acute coronary syndromes without ST elevation (angina + non Q wave
      infarction) is traditionally associated with an increased risk of major cardiac
      complications compared with angioplasty in stable angina. The recent development
      of instrumental techniques, in particular the introduction of stenting and
      pharmacological support for angioplasty have transformed the immediate prognosis
      in unstable angina. Consequently, angioplasty has become better tolerated and
      more easily recommended. Angioplasty cannot be considered without active medical
      therapy, including aspirin, betablockers, and non-fractionated or low molecular
      weight heparin, the use of the only inhibitor of GP IIb/IIIa receptors available
      in France, abciximab, remaining limited to the pharmacological environment of
      angioplasty in the absence of governmental authorization for its use in other
      indications. In high risk clinical situations, refractory angina, angina
      complicated by ventricular arrhythmias, left ventricular failure, mitral
      regurgitation, patients with a history of infarction or coronary bypass surgery,
      the indications of angioplasty and revascularization should be liberal as the
      prognosis of this patient group is improved. In situations of intermediate or low
      risk, there is no consensus about the best strategy, systematic or elective
      invasive procedures, that is to say guided by residual or recurrent myocardial
      ischaemia after initial stabilisation. However, the most recent trials, in
      particular FRISC II, seem to prove that systematic invasive procedures after
      stabilization by medical treatment, have a favourable influence on the prognosis
      compared with a conservative strategy. Other on-going trials may provide a
      definitive answer to this very controversial question.

PMID- 10598244
TI  - [Angioplasty or surgery in the patient with multivessel disease].
AB  - The aims of myocardial revascularisation are to treat angina, reduce ischaemia
      and improve life expectancy. Patients with multivessel disease have a poor
      prognosis, especially when the lesions are proximal, when the preseptal left
      anterior descending artery is involved and when left ventricular dysfunction is
      present. In this particular group of patients, coronary bypass surgery has been
      shown to improve 10 year survival. Coronary angioplasty has been compared with
      surgical treatment in many clinical trials. The medium-term survival is the same
      in both groups, but with a higher number of repeat procedures except in diabetic
      patients in whom mortality is higher after angioplasty. The use of coronary
      stents should reduce the number of post-angioplasty procedures. Constant
      technical improvements, the introduction of surgery without cardiopulmonary
      bypass, combined revascularisation procedures, new antiplatelet drugs, the
      absence of long-term comparative results, all this results in a personalized
      choice of revascularisation procedure based on the overall clinical and
      angiography features of each particular case.

PMID- 10598245
TI  - [Angioplasty in acute myocardial infarction].
AB  - Primary PTCA has become a common method for achieving recanalization of the
      infarct vessel in acute myocardial infarction. The excellent results of large
      randomised trials comparing it to intravenous thrombolysis however have not been
      consistently duplicated in large registries reflecting clinical practice in the
      real world. Therefore, there is a need for critical and careful assessment of
      angioplasty performance, specifically criteria related to operator and center
      volume as well as the ability to implement angioplasty rapidly after diagnosis.
      It has been specifically established that intra-hospital delays in the time to
      balloon angioplasty are associated with clear increases in mortality rates. It is
      therefore necessary to implement quality insurance programs to continuously
      monitor centers using primary PTCA as their reperfusion method of choice. Recent
      studies have demonstrated that stents and adjuvant pharmacological therapies,
      specially GpIIb/IIIa antagonists are associated with improved results. Despite
      the high patency rates achieved with angioplasty, a consistent series of
      experimental and clinical observations indicate that the quality of myocardial
      reperfusion downstream of the epicardial coronary vessel is a critical
      determinant of prognosis. Specifically, no-reflow, which can be ascertained using
      perfusion imaging techniques, but also indirectly, using the electrocardiogram,
      is an ominous element. The challenge of the coming years will be to test
      effective preventive or curative treatments for no-reflow.

PMID- 10598246
TI  - [Coronary angioplasty in diabetic patients. Analysis of the problems to improve
      results].
AB  - The object of this review is to update our knowledge of the results of
      revascularisation by angioplasty in diabetics. The authors discuss: 1. the
      clinical results in diabetic patients compared with non-diabetics and the results
      of coronary bypass surgery; 2. the factors influencing the prognosis of these
      patients after balloon angioplasty, especially with respect to restenosis; 3. the
      possibilities of improving the results by the use of modern techniques of
      revascularisation and prevention and 4. the strategies of revascularisation which
      may be proposed, based on available data.

PMID- 10598247
TI  - [Angioplasty of venous grafts].
AB  - Degeneration of venous aorto-coronary bypass grafts results in a reduction in
      their patency: 60% are patent at 10 years and only 50% are disease-free. Balloon
      angioplasty has been proposed as a therapeutic alternative to surgical
      reoperation. This delicate technique is associated with immediate, medium and
      long-term results which are less satisfactory than those obtained on the native
      coronary vessels. The risk of distal embolisation influences the immediate
      operative results. Restenosis, more common than after angioplasty of native
      vessels, and the progression of atherosclerosis, explain the mediocre long-term
      results. Of all the techniques of interventional cardiology, coronary stenting
      seems to provide the best results, especially on short, focal lesions. The
      immediate and long-term results are more disappointing in cases of diffuse
      degeneration of the graft. The pre-, peri- and postoperative medical environment,
      especially treatment with platelet inhibitors and statins, seems to play a
      decisive part in the improvement of long-term clinical results.

PMID- 10598248
TI  - [Angioplasty in chronic coronary occlusion].
AB  - In the last few years, coronary angioplasty has been the object of real progress
      in the treatment of total chronic coronary occlusion; The primary success rate of
      the procedure regularly exceeds 70% with the use of improved equipment; however,
      these procedures are not without risk with a reported complication rate close to
      that of angioplasty of non-occlusive stenosis. The use of stents has
      significantly reduced the restenosis rate, mainly by decreasing the risk of
      reocclusion. The indications of angioplasty for chronic occlusion remain
      controversial: the procedure is justified in patients with angina; in
      asymptomatic patients, angioplasty may improve global and regional left
      ventricular function in those with documented myocardial viability and limit
      ventricular remodelling but the results of a randomised trial of systematic
      angioplasty versus medical treatment in this type of indication are not yet
      available.

PMID- 10598249
TI  - [Coronary surgery in the stenting era].
AB  - In recent years, the intensive use of coronary stents has had more of a
      qualitative than a quantitative impact on the practice of coronary bypass
      surgery. Whereas the general tendency, which started with balloon angioplasty
      alone, to select the most severe cases for surgery has without doubt increased,
      some surgical indications (emergency bypass for acute post-angioplasty occlusion)
      have disappeared, others have changed (reoperations where stenting has become an
      alternative to surgery for venous graft stenosis), and still others have appeared
      (single bypass for intra-stent stenosis). The first randomised trials to compare
      balloon angioplasty and surgery, clearly showed the benefits of the latter
      technique with respect to the reduction of recurrent coronary events requiring
      repeat revascularisation procedures. The problem now is to determine whether
      these conclusions have to be revised in view of the reduction in risk of post
      angioplasty stenosis with the use of stents. To date, this has not been proved.
      On the one hand, the superiority of stenting over balloon angioplasty alone has
      only been established in very selected groups of patients not representative of
      everyday practice, and, on the other hand, the increasing use of arterial grafts
      should improve the long-term results of surgery. These questions should be
      answered by on-going trials comparing coronary bypass surgery and stenting.
      Hopefully, they should also clarify the respective indications of these two
      effective methods which are without doubt more complementary than competitive.

PMID- 10598250
TI  - [Antithrombotics and interventional cardiology].
AB  - Angioplasty is a technique associated until recently with aspirin and heparin
      therapy, two classical molecules, for the prevention of thrombotic complications.
      The first therapeutic innovation has been the introduction of Reopro (abciximab,
      c7E3). The abciximab has been shown to be useful in the short term, sometimes in
      the medium (EPIC, EPILOG) and long term (EPIC) in all acute or stable coronary
      coronary syndromes requiring angioplasty with or without stenting. Other changes
      are awaited shortly with the arrival of low molecular weight heparin which some
      have shown to be effective in unstable angina. The association of antithrombotics
      will become the rule but the number of molecules should decrease to consist only
      of the most effective drugs and exclude the redundant ones. The risk of
      haemorrhage increases with the increased efficacy of the antithrombotic agent.
      Global evaluation of the clinical benefits should be advocated with a register of
      ischaemic and serious haemorrhagic events amongst the criteria of evaluation of
      the trials.

PMID- 10598251
TI  - [Endocoronary ultrasonography and angioplasty].
AB  - At the end of the 20th century, endocoronary ultrasonography has become
      established in many catheter laboratories. The information provided by this
      technique of invasive imaging has many qualitative and quantitative features. Is
      endocoronary ultrasonography a research or an everyday clinical tool to be used
      systematically or occasionally in routine procedures? Endocoronary
      ultrasonography is really a research tool because it is not redundant with
      conventional coronary angiography. Ultrasonography investigates the whole
      arterial wall. Its spatial resolution is twice that of angiography. Its
      contribution in this field in rich with many reports on arterial modelling, post
      angioplasty remodelling, plaque rupture and atherothrombosis, the accurate
      description of the mechanical effects of angioplasty tools, two and three
      dimensional quantification of atherosclerotic plaques and, finally, providing a
      very accurate biomechanical approach. Its use in routine procedures is only
      occasionally justified as there is no scientific proof in favour of a more
      widespread use with respect to changing the procedure or to evaluating patient
      prognosis. Endocoronary ultrasonography, a very rich technique, should be
      available in all catheter laboratories for occasional use. This technique is
      useful for all cardiologists performing coronary angioplasty by improving the
      evaluation of atheromatous plaques and countering the intrinsic ambiguities of
      coronary angioplasty.

PMID- 10598252
TI  - [Physiology of coronary circulation and angioplasty: utopia or clinical
      reality?].
AB  - Small pressure transducer and Doppler quartz placed at the tip of angioplasty
      guide wire give the opportunity to measure coronary flow physiology parameters,
      the physiopathologic impact of an epicardic coronary stenosis and the efficacy of
      its treatment. This gives the opportunity to over ride the coronary imaging
      limitations. Doppler and pressure investigate a different and complementary
      aspect of the pressure-flow relation and may be used together in some special
      cases. Myocardial fractional flow reserve (FFRmyo) and relative coronary reserve
      concepts allow to evaluate patients with heterogeneous coronary reserve. Clinical
      application field is very broad and can be applied to each step of coronary
      angioplasty from the evaluation of intermediate lesions and the indication of
      angioplasty to the guidance of the procedure to the evaluation of the result,
      through the stenting indication and the stent placement optimization. Numerous
      studies has emphasized the role of physiologic coronary assessment in the
      cathlab. The time and economic gain of such an attitude has to be confirmed by
      future trials but it is clear now that it is not possible to continue to take
      decision on the sol visual aspect of a lesion.

PMID- 10598253
TI  - [Local treatment during angioplasty].
AB  - Intracoronary thrombosis and post-angioplasty complications (acute occlusion) are
      now controlled. Restenosis is the principal obstacle to transluminal coronary
      revascularisation. The conviction of the multifactorial and focal nature of the
      process leading to this excessive scarring is acquired. Constrictive remodelling
      is now established as the main mechanism of restenosis. Failure to prevent
      restenosis by systemic therapy has led several groups to experiment local
      treatment for this problem. The object of this article is to review the different
      systems of local treatment at the site of angioplasty. Even if some results are
      encouraging, there is no solution as yet to the problem of restenosis. Although
      local therapy is possible, the agent(s) of choice remain(s) to be defined.

PMID- 10598254
TI  - [150th anniversary of the Pathology Department of the I.M. Sechenov Moscow
      Medical Academy].
AB  - Chair of pathology of I. M. Sechenov Moscow Medical Academy, which, in the past,
      was medical faculty of Moscow University, maintains the traditions of its
      founders and during the 150 years of its activity was in line with the progress
      of science. Such advanced methods of investigation as light microscopy, histo-
      and cytochemistry, immunoluminescence, electron microscopy, autoradiography,
      molecular biology contributed much to solution of urgent problems of fundamental
      and practical medicine. The chair was in the past and is now an important center
      for training pathologists in Russia. Among the teachers are outstanding
      scientists known in the world. Continuity of the tradition is supported by
      succession of the chair chiefs--the teacher passes his responsibilities to the
      other scientist who has been his talented student.

PMID- 10598255
TI  - [History of creation of the Pathology Department of the I.M.Sechenov Moscow
      Medical Academy].
AB  - M. Ya. Mudrov was initiator of teaching pathology at the medical faculty of
      Moscow University. He proposed this in 1805, but regular lectures in this
      discipline started in 1825 by M. Ya Mudrov and Yu. Kh. Loder. Ten years later,
      due to Yu. Kh. Loder's activity, pathology became an independent course at the
      chair of normal anatomy. In 1849, an independent chair of pathology was set up.

PMID- 10598256
TI  - [History of development of teaching materials at the Pathology Department of the
      I.M. Sechenov Moscow Medical Academy].
AB  - The teachers of the chair of pathology have been preparing textbooks and guides
      for students and physicians for all 150 years of its activity. Educational
      supplies on pathological anatomy in current use have also been created for the
      most part by them.

PMID- 10598257
TI  - [Research at the Pathology Department of the I.M. Sechenov Moscow Medical
      Academy].
AB  - The clinico-anatomical principle and principle of the structural-functional unity
      have been underlying in the research activities of the pathology chair as long as
      150 years of its existence. The chair staff have always held front line positions
      in science, being devoted to the service of urgent needs of medicine and public
      health.

PMID- 10598258
TI  - [The role of Pathology Department of the I.M. Sechenov Moscow Medical Academy in
      the development of forensic medicine].
AB  - The chair of pathology has greatly contributed to establishment and development
      of prosector's speciality: training of pathologists, initiation of first clinico
      anatomical conferences and their upgrading, introduction of novel morphological
      techniques and other advanced methods, publication of books, guidelines, manuals.
      The chair, A. I. Abrikosov and I. V. Davydovsky especially, contributed much to
      transformation of the pathology service in Russia after 1917.

PMID- 10598259
TI  - [Methodological improvement of laboratories of the Pathology Department of the
      I.M. Sechenov Moscow Medical Academy].
AB  - The history of the equipment of the laboratories of the chair of pathology began
      with 2 monoocular microscopes mounted in 1849. Nowadays it is equipped with
      modern facilities including a confocal laser scanning microscope. Leading
      position of the chair in research, practice and education is largely due to
      renewal of technical facilities of its laboratories.

PMID- 10598260
TI  - [Current approaches to classification of glomerulonephritis].
AB  - Using methods of molecular pathology, the authors showed that characteristics of
      inflammatory-reparative processes in the kidney glomeruli depends on both nature
      of etiologic agents and specific features of the affected zone
      histoarchitectonics. They believe that subdivision of glomerulopathies into
      inflammatory (glomerulonephritis) and non-inflammatory is justified even though
      it is somewhat arbitrary.

PMID- 10598261
TI  - [Subdivision of certain morphological variants of chronic glomerulonephritis].
AB  - Modern methods allow to detail morphological classification of chronic
      glomerulonephritis, to adapt it to the clinical classification and to recommend
      it for practical use. This specification concerns minimal changes and a group of
      mesangial chronic glomerulonephritis. The term "minimal changes" is a light
      microscopic definition and covers rather a heterogeneous group of diseases or
      their initial manifestations. Differential diagnosis of these diseases is
      feasible only at the electron microscopic level. A group of chronic
      glomerulonephritis (mesangioproliferative and mesangiocapillary) includes
      variants distinguished on the basis of immunohistochemical, light microscopic and
      electron microscopic methods. Of them, the immunohistochemical method is most
      valuable for differentiation of mesangioproliferative glomerulonephritis.

PMID- 10598262
TI  - [Comparative study of Hashimoto thyroiditis and "focal thyroiditis"].
AB  - As shown by a semiquantitative analysis of histological changes in the thyroid
      tissue, there is a correlation between some characteristic features of autoimmune
      thyroiditis (Hashimoto's thyroiditis). Formation of lymphoid nodules in the
      thyroid in autoimmune thyroiditis was followed up and its three stages were
      distinguished. Autoimmune thyroiditis has three degrees of activity by diffuse
      lymphoid-plasmocytic infiltration, thyroid tissue destruction and lymphoid
      nodules formation. Differences between autoimmune thyroiditis and focal
      thyroiditis are revealed. The above differences include spread and cellular
      composition, content of the lymphoid-plasmocytic infiltrate, the degree of the
      destructive changes, B-cell hyperplasia, expression of CD-4 on T-helpers and CD
      19 on B-lymphocytes, cytological picture. These differences allow differential
      diagnosis between these diseases.

PMID- 10598263
TI  - [Extrahepatic manifestations of chronic viral liver diseases].
AB  - The study of large groups of patients with chronic liver diseases of viral
      etiology (including those induced by HBV and HCV) has revealed extrahepatic
      manifestations which by their mechanisms formed 2 groups. The first group
      represents disorders related to delayed hypersensitivity in combination with
      immunocomplex reactions (lesions of the joints, skeletal muscles, lungs,
      myocardium, etc). The second group includes disorders of primarily immunocomplex
      genesis (vasculitis): skin vasculitis, Raynaud's syndrome, nodular
      periiarteritis, mixed cryoglobulinemia, etc.). Special group represents diseases
      of blood: immune cytopenias, monoclonal immunoglobulinopathy, malignant
      lymphoproliferative diseases. These findings and literature data on extrahepatic
      replication of HBV and HCV validate the diagnosis of "chronic generalized HBV or
      HCV infection" with listing of all manifestations of these infections.

PMID- 10598264
TI  - [Molecular pathology of lung cancer and insulin-like growth factors].
AB  - Molecular pathology of lung cancer (LC) investigates molecular-genetic
      rearrangements initiating development and growth of the tumor. The system of
      insulin-like growth factors (IGF) and binding proteins (IGFBP) regulates cell
      proliferation in the majority of embryonal and tumor tissues of man and animals
      in the course of reparation processes and productive inflammatory reaction. A
      general property of all LC histological types is presence in their cells of
      various members of IGF-system. Content of IGFII in tumor cells correlated with
      IGFBP-1, IGFBP-2, IGFBP-5. Location of IGFII and IGFBP in LC was different. IGFBP
      1, -2, and -5, blocking IGFII, are detected in large amounts in areas of cell
      death inducing apoptosis while IGFII accumulates in dividing cells and foci of
      keratinization. Nuclear deposits of IGFBP-3 in bronchioloalveolar LC create
      phenomenon of intranuclear inclusion of "owl's eye" type. Synthesis of the
      majority of IGF occurs in tumor cells. Stromal cells also produce and transport
      into the tumor some quantity of IGFII and IGFBP.

PMID- 10598266
TI  - [Chordoma].
AB  - Chordoma is characterized clinicomorphologically and epidemiologically using own
      observations for 1955-1995 and literature data. Chordoma is a rare tumor. Its
      histogenetic association with the notochorda remnants and location in the region
      of axial skeleton results in a grave clinical course due to alteration of nervous
      structures of the brain and spinal cord. The diagnosis is based on
      roentgenological data showing the connection of the tumor with axial skeleton (in
      sacral-coccygeus and occipital-basilar regions in 90% of cases) and on typical
      histologic structure.

PMID- 10598265
TI  - [Adenocarcinoma of the cervix uteri].
AB  - 105 cases of uterine cervix adenocarcinoma (11 histological types) have been
      studied clinicomorphologically and immunohistochemically. Molecular-biological
      examination (in situ hybridization) for human papilloma viruses (HPV) detected
      HPV of 16/18 types not only in the coilocytes of the uterine cervix surface
      epithelium but in adenocarcinoma cells as well. Uterine cervix adenocarcinoma
      metastasize differently from uterine cervix squamous cell carcinoma.

PMID- 10598267
TI  - [Electron microscope study of lung carcinoid].
AB  - 123 lung carcinoids were studied, 32 of them electron-microscopically.
      Ultrastructural features were evaluated with the use of multivariate analysis.
      The most informative ultrastructural features were the following: correlation
      between differentiated and undifferentiated cells, the number of cytoplasm
      organoids including endocrine granules, degree of nuclei polymorphism and their
      size, specialized contacts, mitoses. Up to 18% of carcinoids, on the average,
      need ultrastructural verification of the anaplasia degree, this percentage
      increasing to 27.2% in atypical carcinoids. The above ultrastructural criteria
      allow to specify malignant potential of carcinoids, facilitate differential
      diagnosis and make their prognosis.

PMID- 10598268
TI  - [Tuberculosis mortality in the megapolis].
AB  - 1097 lethal cases of tuberculosis were analysed by 3 groups: Moscow citizens
      registered or not registered in the tuberculosis dispensaries (83%) and Moscow
      migrants (37%). Tuberculosis was diagnosed post mortem in 18%. Clinicoanatomical
      forms of tuberculosis were gravest in patients not observed in the dispensaries
      (disseminated tuberculosis, tuberculous pneumonia, generalized hematogenic
      tuberculosis--80.3%, fibrocavernous tuberculosis--18.9%). The main cause of this
      situation is poor economical situation and non-controlled migration.

PMID- 10598269
TI  - [Tuberculosis: socio-medical aspects].
AB  - Tuberculosis is an ubiquitous infection. The epidemiological situation is now
      critical. 2.5 million people die every year in the world due to different types
      of tuberculosis. In Russia, tuberculosis morbidity and mortality are also on the
      increase. Clinical manifestations of the disease became grave while the treatment
      less efficient. The key element in tuberculosis pathogenesis is interaction
      between bacteria, T-lymphocytes and macrophages with cytokines participation this
      resulting in elimination of the bacteria and formation of hypersensitivity. One
      of the main control mechanisms may be macrophage apoptosis in the center of the
      granulomas following with caseous necrosis. Methods of molecular biology open new
      perspectives in diagnosis, understanding of pathogenesis and tuberculosis
      treatment.

PMID- 10598270
TI  - Cell surface, Ca2+(cation)-sensing receptor(s): one or many?
AB  - In mammals Ca2+ concentration in the extracellular fluids ([Ca2+]o) is essential
      for a number of vital processes varying from bone mineralization to blood
      coagulation, regulation of enzymatic processes, modulation of permeability and
      excitability of plasma membranes. For this reason [Ca2+]o is under strict control
      of a complex homeostatic system that includes parathyroid glands, kidneys, bones
      and intestine. The extracellular Ca(2+)-sensing receptor (CaR) is an essential
      component of this system, regulating parathyroid hormone secretion, calcium (and
      magnesium) excretion by the kidney, bone remodeling and Ca2+ reabsorption by the
      gastrointestinal tract. Structurally, the CaR is a novel member of a growing G
      protein-coupled receptor superfamily, which includes metabotropic glutamate
      receptors (mGluRs) [1], [gamma]-aminoisobutyric acid (GABA-B) receptors [2] and
      vomeronasal organ receptors [3]. Initially identified from bovine parathyroid
      glands [4], within the 5 years following its identification CaR presence has
      rapidly been identified as extending to organs where the link with mineral ion
      metabolism has not been elucidated (i.e. brain, stomach, eye, skin and many other
      epithelial cells) (see [5] for review). The role of the receptor in these regions
      is largely unknown, but it appears to be somewhat related to phenomena such as
      chemotaxis, cell proliferation and programmed cell death. This review will
      describe the discovery of a novel class of ion-sensing receptor(s), receptor
      effector coupling and the roles of the CaR inside and outside the Ca2+o
      homeostatic system.

PMID- 10598271
TI  - The annexins: structure and functions.

PMID- 10598272
TI  - Ins and outs of calcium: a workshop on chromaffin cells.

PMID- 10598273
TI  - Thimerosal increases the responsiveness of the calcium receptor in human
      parathyroid and rMTC6-23 cells.
AB  - Parathyroid cells express a plasma membrane calcium receptor (CaR), which is
      stimulated by a rise in extracellular calcium concentration ([Ca2+]ext). A
      decreased sensitivity to [Ca2+]ext occurs in adenomatous parathyroid cells in
      patients with primary hyperparathyroidism, but the underlying functional
      mechanism is not yet fully understood. This study explored whether CaR
      responsiveness is influenced by increasing the affinity of IP3 receptors--a major
      signalling component of other G-protein-coupled receptors. The sulphydryl reagent
      thimerosal was used to increase the responsiveness of IP3-receptors. Quantitative
      fluorescence microscopy in Fura-2-loaded cells was used to investigate the
      effects of thimerosal on the cytoplasmic calcium concentrations ([Ca2+]i) in
      human parathyroid cells and to compare its effects in a rat medullary thyroid
      carcinoma cell line (rMTC6-23) also expressing CaR. During incubation in Ca(2+)
      free medium, thimerosal 5 microM induced a rapid sustained rise in [Ca2+]i in
      human parathyroid cells and no further [Ca2+]i increase appeared in response to
      the CaR agonist Gd3+ (100 microM). Thimerosal 1 microM induced only slow and
      minimal changes of basal [Ca2+]i and allowed a rapid response to Gd3+ 20 nM (a
      concentration without effect in control cells). The slope of the thimerosal
      induced [Ca2+]i responses was steeper following exposure to CaR agonists. In the
      presence of 1 mM [Ca2+]ext, thimerosal (0.5 microM) induced a sharp increase in
      [Ca2+]i to a peak (within 60 s), followed either by return to basal [Ca2+]i or by
      a plateau of slightly higher amplitude. Similar results were obtained using rMTC6
      23 cells. Thimerosal increases the responsiveness to CaR agonists through
      modulation of the sensitivity of the IP3 receptor in both parathyroid and rMTC6
      23 cells.

PMID- 10598274
TI  - Intracellular calcium oscillations regulate ciliary beat frequency of airway
      epithelial cells.
AB  - The effect of ATP-induced Ca2+ oscillations on ciliary activity was examined in
      airway epithelial cells by simultaneously measuring the ciliary beat frequency
      (CBF) and the intracellular Ca2+ concentration ([Ca2+]i) near the base of the
      cilia. Exposure to extracellular ATP (ATPo) induces a rapid and large increase in
      both [Ca2+]i and CBF, followed by oscillations in [Ca2+]i and a sustained
      elevation in CBF. After each Ca2+ oscillation, the [Ca2+]i returned to near basal
      values. By contrast, the CBF remained elevated during these Ca2+ oscillations,
      although each Ca2+ oscillation induced small variations in CBF. During Ca2+
      oscillations, increases in CBF closely followed the rising phase of increases in
      [Ca2+]i, but declines in CBF lagged behind declines in [Ca2+]i. Higher frequency
      Ca2+ oscillations reduced variations in CBF, producing a stable and sustained
      elevation in CBF. The maximal CBF was induced by Ca2+ oscillations and was 15%
      greater than the CBF induced by the substantially larger initial [Ca2+]i
      increase. These data demonstrate that the rate of CBF is not directly dependent
      on the absolute [Ca2+]i, but is dependent on the differential changes in [Ca2+]i
      and suggest that CBF in airway epithelial cells is regulated by frequency
      modulated Ca2+ signaling.

PMID- 10598275
TI  - Ca increase in secretory granules of stimulated mast cells.
AB  - The elemental content of rat peritoneal mast-cell secretory granules has been
      measured by X-ray micro-analysis. Two distinct categories of granules were
      analyzed: intact granules, seen in control samples, and spumous granules,
      corresponding to exocytosed granule matrices. The average Ca content of intact
      granules was found to be approximately equal to cytosolic concentration, and to
      increase up to 40-fold in spumous granules. A significant increase was also
      observed for Na and Cl. These changes were not observed (for Ca) or weaker (for
      Na and Cl) if the cells had been challenged in the absence of nominal
      extracellular Ca; in this case, there was also a significant decrease in the
      sulphur content, suggesting a partial dispersion of the organic matrix
      components. In exocytosed granule matrices, in the presence but not in the
      absence of extracellular Ca, a slow and long-lasting increase of intragranular
      free Ca was monitored by changes in the fluorescence of the Ca-sensitive probes
      Fluo-3 and Calcium Green-5N, accumulated within rat mast-cell secretory granules.
      These findings are discussed along two lines: It is proposed that the calcium
      uptake by the exocytosed mast-cell granule matrices can have a physiological
      relevance for the surrounding tissue. Mast-cell granules do not disperse after
      exocytosis. The major uptake of Ca which is seen after opening of the exocytotic
      pore could be responsible for the exceptional stability of the externalized
      matrices.

PMID- 10598276
TI  - Permeability transition pore regulates both mitochondrial membrane potential and
      agonist-evoked Ca2+ signals in oligodendrocyte progenitors.
AB  - In this study, we investigated the importance of mitochondrial permeability
      transition pore (PTP) in agonist-evoked cytosolic Ca2+ ([Ca2+]c) signals in
      oligodendrocyte progenitor cells (OP cells). We measured transmembrane potential
      across the mitochondrial inner membrane (delta psi m) and [Ca2+]c in the
      immediate vicinity simultaneously using tetramethylrhodamine ethyl ester (TMRE)
      and calcium green respectively. Stimulation of OP cells with methacholine evoked
      robust [Ca2+]c signals in approximately 80% of cells which were either
      oscillatory or showed a peak followed by a plateau. Elevations in [Ca2+]c induced
      by supramaximal concentrations of the agonist (> 200 microM) were accompanied by
      changes in delta psi m in 33-42% of the total mitochondria investigated. The
      mitochondria that responded either depolarized (26-29%), hyperpolarized (7-13%)
      or showed no change (58-67%). Thus, of the responsive mitochondria, most (70%)
      depolarized during agonist-evoked [Ca2+]c signals. Blockade of PTP with
      cyclosporin A (CSA) reduced the number of mitochondria that depolarized with a
      corresponding increase in the number that hyperpolarized. In addition, CSA or its
      analogue methyl valine-4- CSA (MeVal-CSA), reduced the frequency of agonist
      evoked global [Ca2+]c oscillations. In resting cells, CSA (63%) and MeVal-CSA
      (77%) hyperpolarized a majority of the mitochondria suggesting that PTP is
      constitutively active and may show flickering openings. Such hyperpolarizations
      were not mimicked by either cyclosporine H or verapamil and were inhibited by
      Ru360, which blocks the mitochondrial uniporter. This observation suggested that
      in resting cells, Ca2+ ions might redistribute between cytosol and mitochondrial
      matrix through the uniporter and the PTP. Taken together, these data suggest that
      PTP may play an important role in regulating delta psi m and local [Ca2+]c
      signals during agonist stimulation in OP cells.

PMID- 10598277
TI  - Effect of cell ageing on Ca2+ influx into human red cells.
AB  - The effect of cell ageing on Ca2+ entry was studied in this work, using sub
      populations of young and old human red cells, separated by stringent percoll
      density gradients. Additionally, the influence of an osmotic gradient was
      investigated as a model for shear stress. Ca2+ entry was assessed at 37 degrees
      C, under conditions where the Ca2+ pump was either inhibited by NaVO3 (0.5-10 mM)
      or inactivated by ATP depletion. The entry was linear with time up to 1 h. No
      differences in Ca2+ influx between the two sub-populations were detected in
      isotonic Na(+)-medium. In contrast, after incubation in anisosmotic media, Ca2+
      entry into old cells was significantly higher than into younger cells. In
      hypotonic Na(+)-medium, the entry into old cells was not affected by La3+ (10
      microM) whilst it was partially blocked by Gd3+ at a similar level (half-maximal
      effect attained with about 1 microM Gd3+). The entry into young cells was only
      slightly stimulated by these lanthanides at low concentrations (10 microM),
      regardless of the tonicity of incubation medium. Further increasing Gd3+ levels
      above 10 microM markedly enhanced Ca2+ entry into both cell types. The selective
      blockade of Ca2+ influx by low Gd3+ concentrations suggests presence of mechano
      sensitive channels, that become preferentially activated in old cells. Activation
      of these channels during in-vivo microcirculation may help to explain the
      increased Ca2+ content of senescent cells.

PMID- 10598278
TI  - Metabotropic glutamate receptor activation and intracellular cyclic ADP-ribose
      release Ca2+ from the same store in cultured DRG neurones.
AB  - The whole cell patch clamp technique has been used to record Ca(2+)-activated
      cation and chloride conductances evoked by release of Ca2+ from intracellular
      stores of cultured neonatal dorsal root ganglion neurones. The aim of this study
      was to investigate metabotropic glutamate receptor (mGluR) mechanisms and
      evaluate a possible role for cyclic ADP-ribose as an intracellular signalling
      molecule. Glutamate and the metabotropic glutamate receptor agonist (1S, 3R)-ACPD
      evoked transient depolarizations, Ca(2+)-activated inward currents and rises in
      intracellular Ca2+. The (1S, 3R)-ACPD-activated currents were insensitive to
      InsP3 signalling inhibitors, heparin and pentosan polysulphate. Intracellular
      application of ryanodine alone activated currents in this study and proved a
      difficult tool to use as a potential inhibitor of cyclic ADP-ribose-mediated
      responses. However, intracellular dantrolene did attenuate both (1S, 3R)-ACPD and
      cyclic ADP-ribose responses. Intracellular photo-release of cGMP and cyclic ADP
      ribose mimicked the responses to mGluR receptor activation. Intracellular
      application of nicotinamide and W7 inhibited the responses to photo-released cGMP
      but did not prevent responses to mGluR activation. The cyclic ADP-ribose receptor
      antagonist 8-amino cyclic ADP-ribose attenuated responses to (1S, 3R)-ACPD, cGMP
      and cyclic ADP-ribose, but some Ca(2+)-activated inward currents were still
      observed in the presence of this antagonist. In conclusion, mGluR receptor
      activation, cGMP and cyclic ADP-ribose release Ca2+ from intracellular stores.
      Some evidence suggests that pharmacologically related pathways are involved.

PMID- 10598280
TI  - Isolation of the North American strain of viral hemorrhagic septicemia virus
      (VHSV) associated with epizootic mortality in two new host species of Alaskan
      marine fish.
AB  - Thousands of dead Pacific herring Clupea pallasi, Pacific hake Merluccius
      productus and walleye pollock Theragra chalcogramma were reported in Lisianski
      Inlet near Pelican, Alaska, USA, on August 1, 1998. The Pacific hake and pollock
      continued to die through the end of September. Virological examinations of dead
      fish identified the North American strain of viral hemorrhagic septicemia virus
      (VHSV) from all 3 species of fish as well as associated high virus titers and
      possible histopathological lesions. No other primary fish pathogens were detected
      and there were no apparent environmental causes for fish mortality. This is the
      first report of VHSV in 2 new Alaskan fish host species and of a natural
      epizootic associated with VHSV in which progressive mass mortality was observed
      simultaneously in herring and 2 other species of free-ranging marine fish.

PMID- 10598279
TI  - Ca2+ signaling down-regulation in ageing and Alzheimer's disease: why is Ca2+ so
      difficult to measure?
AB  - Ca2+ signaling is a central process in brain function, but the direction of its
      change in ageing and in the presymptomatic stages of Alzheimer's disease has been
      controversial. A great deal of studies have been interpreted as supportive to the
      current hypothesis that intracellular Ca2+ levels are steadily increased in
      ageing. We, however, believe that, although current studies have provided
      valuable knowledge for the mechanisms of the signal transduction process, they
      have not furnished relevant information regarding the global Ca2+ changes in the
      ageing brain, because the cognition-related Ca2+ pulses exist only in the intact
      brain.

PMID- 10598281
TI  - Isolation of different types of birnavirus from ayu Plecoglossus altivelis and
      amago salmon Oncorhynchus rhodurus cultured in the same geographic area.
AB  - A birnavirus was recently isolated from cultured ayu Plecoglossus altivelis on
      Shikoku island, Japan. The diseased fish displayed vertebral or vertical
      curvature and mild haemorrhage around the brain. Cytopathic effects (CPE) of the
      virus, including cell roundness, filamentous change and cell lysis, were observed
      in CHSE-214, RTG-2 and RSBK-2 cells. The virus isolated from ayu, designated the
      AY-98 strain, was found to be antigenically related to the marine birnavirus
      (MABV) Y-6 strain that originated from yellowtail Seriola quinqueradiata. AY-98
      had a bi-segmented RNA genome and the same nucleotide sequence in the 310 bp
      VP2/NS junction as MABV Y-6. At the same time that the ayu epizootics occurred,
      another birnavirus (AM-98) was isolated from amago salmon Oncorhynchus rhodurus
      which were cultured 66 km away from the ayu farm. AM-98 showed a similar CPE and
      had the same host cell ranges as AY-98. However, AM-98 was serologically similar
      to the VR-299 strain of infectious pancreatic necrosis virus (IPNV) and their
      nucleotide sequences in the VP2/NS junction region showed 98% homology without
      changes at the amino acid level. In this study, the ayu strain AY-98 was grouped
      into MABV, whereas the amago salmon strain AM-98 was grouped into IPNV. This
      indicates that the 2 birnaviruses originated from different sources in spite of
      the fact that the places where they were isolated are close to one another. The
      results in this paper show a new aspect of the traditional consensus that the
      same serogroup of birnavirus distribute in close geographic areas.

PMID- 10598282
TI  - Differential expression of the virulence-associated protein p57 and
      characterization of its duplicated gene msa in virulent and attenuated strains of
      Renibacterium salmoninarum.
AB  - Virulence mechanisms utilized by the salmonid fish pathogen Renibacterium
      salmoninarum are poorly understood. One potential virulence factor is p57 (also
      designated MSA for major soluble antigen), an abundant 57 kDa soluble protein
      that is predominately localized on the bacterial cell surface with significant
      levels released into the extracellular milieu. Previous studies of an attenuated
      strain, MT 239, indicated that it differs from virulent strains in the amount of
      surface-associated p57. In this report, we show overall expression of p57 in R.
      salmoninarum MT 239 is considerably reduced as compared to a virulent strain,
      ATCC 33209. The amount of cell-associated p57 is decreased while the level of p57
      in the culture supernatant is nearly equivalent between the strains. To determine
      if the lowered amount of cell-associated p57 was due to a sequence defect in p57,
      a genetic comparison was performed. Two copies of the gene encoding p57 (msa1 and
      msa2) were found in 33209 and MT 239, as well as in several other virulent
      isolates. Both copies from 33209 and MT 239 were cloned and sequenced and found
      to be identical to each other, and identical between the 2 strains. A comparison
      of msa1 and msa2 within each strain showed that their sequences diverge 40 base
      pairs 5' to the open reading frame, while sequences 3' to the open reading frame
      are essentially identical for at least 225 base pairs. Northern blot analysis
      showed no difference in steady state levels of msa mRNA between the 2 strains.
      These data suggest that while cell-surface localization of p57 may be important
      for R. salmoninarum virulence, the differences in localization and total p57
      expression between 33209 and MT 239 are not due to differences in msa sequence or
      differences in steady state transcript levels.

PMID- 10598283
TI  - Association of plasma IgM with body size, histopathologic changes, and plasma
      chemistries in adult Pacific herring Clupea pallasi.
AB  - Pacific herring Clupea pallasi immunoglobulin is an IgM-like molecule comprised
      of heavy and light chains with molecular weights of 79 and 25 to 27 kD,
      respectively. Purified immunoglobulin was used to generate highly specific
      polyclonal antibodies for development of a sandwich ELISA. The ELISA was used to
      quantify total plasma IgM in 602 Pacific herring captured in Prince William Sound
      and Sitka Sound, Alaska, USA. Plasma IgM concentrations ranged from 0.13 to 5.32
      mg ml-1. Using multiple stepwise regression analysis, plasma IgM was highly
      correlated (p < or = 0.01) with body length, Ichthyophonus hoferi infection,
      plasma albumin, plasma cholesterol, liver macrophage aggregates, and focal skin
      reddening. I. hoferi was the only organism significantly associated with plasma
      IgM. Gender, site, and season (spring vs fall) did not contribute to significant
      differences in plasma IgM. This study contributes to the understanding of the
      interaction of body size, plasma chemistries, and pathological changes upon
      circulating immunoglobulins in fish.

PMID- 10598284
TI  - Proliferative lesions in swimbladder of Japanese medaka Oryzias latipes and guppy
      Poecilia reticulata.
AB  - Thirteen cases of proliferative lesions of the swimbladder were encountered in
      Japanese medaka Oryzias latipes and guppy Poecilia reticulata from about 10,000
      medaka and 5000 guppies used in carcinogenicity tests and histologically
      examined. Two of the 4 cases from medaka and 8 of the 9 from guppies occurred in
      untreated control specimens. The lesions affected the gas gland epithelium and
      included hyperplasia, adenoma, and adenocarcinoma. One medaka had hyperplasia of
      the gas gland epithelium and in 1 guppy the gland was enlarged with an increase
      in the number of epithelial layers. Gas gland adenomas, 3 cases in medaka and 1
      in the guppy, were typically larger than the hyperplastic lesions, formed
      expansive masses up to 1 mm in greatest dimension, and exhibited a solid or
      glandular growth pattern and mild cellular pleomorphism. Adenocarcinoma was the
      most advanced lesion and all 7 cases occurred in guppies. Adenocarcinomas
      sometimes filled the entire swimbladder and measured up to 2.5 mm in diameter.
      Cells of adenocarcinomas were highly pleomorphic, with atypical nuclei, and an
      elevated mitotic activity. Because most of these tumors occurred in fish from
      control groups or in tests with noncarcinogenic compounds, the lesions observed
      here are probably spontaneous rather than chemically induced. Their rare
      occurrence, however, makes swimbladder proliferative lesions in small-fish
      carcinogenesis models sensitive indicators of compounds that might target cells
      of the gas gland.

PMID- 10598285
TI  - [The place of acute psychotic disorders in current classification systems].
AB  - The current upheavals in psychiatric nosology preoccupy most psychiatric teams
      while many practitioners continue to be unaware of the proposed changes in the
      ICD10-DSM IV international classifications. Certain entities, considered firmly
      established, have been excluded from those classifications. This applies to
      hysteria and acute paranoid reactions, for example. Acute psychosis, consisting
      in two clinical entities specific to the French school, paranoid reactions and
      states of mental confusion, are frequently encountered by North-African
      psychiatrists. Those acute states, sufficiently differentiated and with a good
      prognosis, have been scattered in a multitude of disorders making any attempt at
      understanding and summarizing impossible. Should the current classifications be
      considered a regression or an opportunity of beginning the third millennium with
      components enabling enhanced prospects for psychiatric progress and research?

PMID- 10598286
TI  - [Acute exacerbations in schizophrenia].
AB  - In a context of acute psychotic episodes, the occurrence of acute exacerbations
      offers an interesting perspective on the long-term progression of schizophrenia,
      which has for too long been considered as a chronic illness. The most recent
      clinical and epidemiological data confirm the episodic progression of this
      illness. These data concerning progression have given rise to a proposed model of
      vulnerability to psychosis. The appearance of the first signs of such an
      exacerbation in a hitherto stabilised patient requires the immediate institution
      of medico-psycho-social management strategies for the treatment of this new
      episode. It has been amply demonstrated that long-term maintenance therapy
      considerably reduces the risk of relapse. Using this model, a number of authors
      have proposed that schizophrenia be considered as the outcome of an interaction
      between permanent vulnerability of multifactorial origin and stress factors. In
      this theory, only episodic decompensation, and thus acute exacerbation, is
      modeled rather than the entire schizophrenic pathology. Patients living in
      families with low emotional expression exhibit a lower range (13%) of relapse
      than those living in families that are highly emotionally expressive.

PMID- 10598287
TI  - [Depression, suicidal ideation and schizophrenia].
AB  - The aim of this study was to find out the prevalence of depressive symptoms in
      patients with schizophrenia, with a special emphasis on suicidal thoughts and
      behaviors. 183 schizophrenic patients, according to ICD-10 criteria, were
      included. The interview was done by a psychiatrist using a questionnaire (socio
      demographic data, premorbid functioning, schizophrenic and depressive antecedents
      and current depressive and suicidal thoughts and behaviors). The mean age was
      34.3 +/- 8 years; 90% of the sample were males; 12.6% were married and 17% had
      children. RESULTS: The mean age at onset of the illness was 24 +/- 5.9 years and
      its mean duration was 4.8 +/- 1.3 years. The paranoid type was found in 78% of
      cases, and the schizo-affective one in 7.8%. During the assessment, 44.3% of the
      patients had depressive symptoms, 2.7% of them had suicidal ideas and 5% had a
      specific plan to implement them; 40% of the patients with suicidal ideas had a
      depression or had a painful consciousness of their illness. These results confirm
      the ones of other studies in the field: depression is frequent among patients
      with schizophrenia. An emphasis should be put on the necessity of treating both
      conditions when they co-exist in the same patient.

PMID- 10598288
TI  - [Acute postpartum psychoses].
AB  - The post-partum is a high risk period for the development of acute psychotic
      disorders. The frequence of post-partum psychoses is evaluated at 1 to 2 per
      1,000 births. Post-partum psychosis include major affective disorders which is
      the most frequent diagnosis. The clinical pictures have specific characteristics:
      rapid change of symptomatology, liability of mood, and frequent confusional
      signs. The short-term prognosis is generally good but the risk of recurrence of
      the mental disorder, in or outside puerperal context, is high. At clinical,
      evolutive and genetic levels, the studies do not provide arguments for
      nosological autonomy of post-partum psychosis. At therapeutic level, the ECT is
      particularly efficient in this indication.

PMID- 10598289
TI  - [Acute peri-traumatic dissociative experiences: assessment and course].
AB  - Previous research has identified acute stress symptoms, particularly peri
      traumatic dissociative symptoms (the distortion of consciousness,
      depersonalization, derealization, automatic movements, flashbacks with illusions
      or hallucinations), as risk factors for the development of later posttraumatic
      stress disorder. Numerous retrospective assessments and current prospective
      studies confirm these findings. It is suggested that peri-traumatic dissociation
      be assessed immediately after traumatic exposure and during the weeks following.
      But traumatized victims may present other categories of acute reactions; panic
      attacks, acute depression, conversion reaction, excessive emotional expression,
      and psychotic reactions. Brief reactive psychosis is a major differential
      diagnosis with peri-traumatic dissociative experiences. During emergency
      interventions it may be difficult to distinguish between dissociative and
      psychotic symptoms. It is cautioned that these disorders be evaluated with a
      follow-up of several months.

PMID- 10598290
TI  - [Delirium and hallucinations in depression: cultural aspects].
AB  - Study of depression in North-Africa and Sub-Saharan Africa has shown that, since
      the seventies, the clinical expression of depression is markedly different from
      that of depression in the West. Several authors have noted the rareness of guilt
      themes and the frequency of persecution themes and somatic complaints in
      depressed Africans, even those living in the West. More recent studies have shown
      an evolution in depressive symptoms in North-Africa with an increase in guilt and
      a decrease in persecution and somatic complaints. This shift in symptoms brings
      the expression of depression closer to that observed in the West. Our study
      addresses delusional depression: in 73 cases of delusional depression, delusions
      of guilt were present in 31% of cases, persecution in 48% and hallucinations in
      31.5%. A comparison of the sub-groups consulting in 1991 and a second sub-group
      consulting in 1998 shows a marked increase in guilt (23.5 versus 39%).

PMID- 10598291
TI  - [The development and prognosis of acute psychotic disorders (polymorphic delirium
      flushes)].
AB  - The DSM IV classification of brief psychotic disorders and schizophreniform
      disorders is unsatisfactory because of its purely temporal criteria for
      diagnosing acute psychotic disorders, which are seen as a preliminary diagnosis
      to schizophrenia. We thus decided to use a more inclusive concept, with greater
      diagnostic possibilities, that of the bouffee delirante polymorphe (BDP) or non
      specific delusional episode of Magnan, and then analyze its clinical use. This
      study examines the use of this diagnosis in a walk-in clinic for patients
      referred to the ER of a general hospital for acute psychiatric pathology. Over an
      18-month period, out of 331 hospitalizations, 91 admissions corresponded to the
      diagnosis of BDP, with median age of 29 years and a median length of stay of 10
      days. The initial diagnosis was of needs only approximate and became more
      specific with longer length of stay, results of response to therapeutic
      management, more exact phenomenology of the BDP, more information about the days
      preceding the episode, and a better knowledge of previous psychiatric episodes.
      Also useful were the immediate triggering circumstances: intellectual deficit,
      possible absorption of toxic substances, psychologically traumatic events. The
      subsequent time course showed the following pathologies in order of decreasing
      frequency: acute psychotic episodes of schizophrenia, delusional manic episodes,
      acute paranoid episodes, delusional depressive episodes. Finally, there were bona
      fide acute psychotic episodes meeting the criteria of BDP, which remained
      isolated or possibly repetitive and of short duration, partly because of
      pharmacotherapeutic treatment, but also because of an intrinsically favorable
      prognosis. Such cases are habitually labeled in the literature reactional
      psychosis, and should be in our opinion considered separate from schizophrenia.

PMID- 10598292
TI  - [Biological approaches to acute psychoses].
AB  - According to the ICD 10 only acute psychotic disorders and transitory acute
      disorders are specified, whereas DSM IV index, in the same class,
      schizophreniform disorder, schizoaffectif disorder and atypical psychosis. State
      biological markers of these disorders are present during the acute episode and
      disappear with it. A few studies concerns trait predispositional markers of these
      acute psychotic disorders. In addition, several studies of acute psychotic states
      are indexed as a partition of usual schizophrenic disorder, as a simple
      occurrence of that chronic disease. From the biological point of view,
      dysfunctions of norepinephrine and dopaminergic metabolisms are reported within
      these acute schizophrenic disorganisation, especially hyperdopaminergia,
      causality, consequence or evidence of the state syndrome. Those kinds of data are
      also reported in mood disorder with delusional symptoms. A hypothetic
      dysregulation of the balance between oxydation and antioxydation system has been
      searched in these acute states of schizophrenia. From the electrophysiologic
      perspective, no abnormalities are found for ocular movement functions during
      these acute psychotic disorders. Besides the clouding of consciousness of
      confusional states, neuropsychological abnormalities are reported: attention
      disorders, lack of inhibition of non relevant informations, abnormalities of
      working memory. Brain imaging can substantiate a diminution of the caudate
      nucleus size and a possible increase of D2 receptors number. Also, in these acute
      psychotic states abnormalities of humoral and cellular immunologic system have
      been found. Lastly, street drugs can originate confusional states and
      depersonalization, through their serotoninergic, dopaminergic and anticholinergic
      properties. Ethical drugs can also create an acute psychosis disorder: individual
      vulnerability and somatic disease cooccurrence act as risk-factors.

PMID- 10598293
TI  - [Treatment of depression secondary to psychotic disorders].
AB  - More than 25% patients suffering from psychotic disorders would show during their
      evolution some depressive disorders. More than 10% would die from suicide.
      Secondary depressions following psychotic disorders are heterogeneous. They have
      to be specified in order to assess therapeutics including biological
      psychological and socio-environmental approaches. Treatment of depressive
      disorders correlated to psychotic symptomatology, being mood congruent or not, is
      the same as characterized depression. However it is preferred to associate
      antidepressant and neuroleptic or electroconvulsivotherapy. Depressive
      symptomatology in psychotic disorders is mostly secondary due to delusion,
      negative or even deficit symptomatology. It often requires to adapt individual
      choice and posology of antipsychotic treatment. Depressive states in "post
      psychotic" phase, secondary to acute phase or in the evolution of chronic
      psychosis, may be for some of them linked to neuroleptic treatment side effects:
      in this case, posology and indication have to be discussed. In other cases, it
      may be indicated to prescribe antidepressant or even electroconvulsivotherapy
      after having considered the existence of psycho-dynamic reorganization and the
      need of psychotherapic, social or institutional support. The existence of
      depressive disorders in the evolution of psychosis leads to ask about their
      significance: psychological reaction, comorbidity of two distinct pathologies,
      evidence of continuum between affective disorders and schizophrenia.

PMID- 10598294
TI  - [Therapeutic strategies in the first psychotic episode].
AB  - A first psychotic episode includes a wide range of disorders with different
      outcomes: schizophrenia, bipolar disorder, schizophreniform disorder,
      schizoaffective disorder, drug-induced psychosis, brief reactive psychosis,
      organic psychoses and delusional disorder. The course and outcome of a first
      psychotic episode is greatly dependent on its initial management. Major clinical,
      etiopathogenic and therapeutic advances have been achieved in this field and have
      allowed specific management strategies to be adopted. The primary task of
      therapists involved in the management of patients who have experienced a first
      episode of psychosis is promotion of recovery and prevention of secondary
      morbidity, relapse and persistent disability. The main guidelines of an early
      psychosis management are:--to keep in mind that early psychosis is not early
      schizophrenia. Thus, clinicians and therapists should avoid an early diagnosis of
      schizophrenia. Diagnosis in early psychosis can be highly unstable. A diagnosis
      of schizophrenia, with its implications of pessimism, relapse and disability,
      does not contribute anything positive in terms of guiding treatment. On the
      contrary, such a diagnosis may damage the patient and family by stigmatizing them
      and affecting the way they are viewed and managed by healthcare professionals.-
      To integrate biological, psychological and social interventions: effective
      medications is useful in reducing the risk of relapse, but is not a guarantee
      against it. Psychological and social interventions can greatly help promote
      recovery.--To tailor the various strategies to met the needs of an individual: as
      an example, it is important to formulate appropriate strategies for the different
      stages of the illness (prodromal phase, acute phase, early recovery phase and
      late recovery phase) because patients have different therapeutic needs at each
      stage.--In the acute treatment, not to concentrate on short-term goals in
      indicating antipsychotic treatment: prescribing principles for first-episode
      psychosis are to maximise benefit and minimise side effects because the first
      experience of medication may influence a patient's future attitudes of therapy of
      all types. Effective strategies which may reduce long-term morbidity and improve
      recovery are currently available but their implementation is too often delayed.
      The time lag between the onset of symptoms and the start of treatment can be many
      months or years and this delay can have serious consequences. The critical period
      of the first 2-5 years after the first psychotic episode is a time of maximum
      vulnerability and of maximum opportunity. Consequently, actions should be
      undertaken to promote early recognition and assistance in psychotic disorders:
      understanding of the factors that may cause delay in treatment can help minimise
      this problem and lead to the initiation of appropriate treatment at the earliest
      opportunity. Training the general practitioners who have an important part to
      play in the early recognition is also of crucial importance.

PMID- 10598295
TI  - [New antipsychotic agents].
AB  - Since the discovery of the neuroleptics in 1952, french psychiatrists have
      proposed a classification of neuroleptics taking into account the pharmalogical
      and therapeutic differences between these drugs. They distinguished three
      different clinical effects of neuroleptics: sedative effects, effects on the
      positive symptoms of schizophrenia and effects on the negative symptoms. However
      these agents have many side effects including the extrapyramidal syndrome (EPS),
      akathisia, dystonia and parkinsonism. These side effects occur in up to 75% of
      patients receiving typical neuroleptics and are the main cause of non-compliance.
      Since the eighties, clozapine was introduced for use in refractory patients
      because it has a better efficacy (than haloperidol) specifically on negative
      symptoms, a better tolerance and fewer effects. After clozapine, several new
      antipsychotic agents are now available, such as risperidone, olanzapine,
      sertindole, quietapine, ziprasidone ... Their therapeutical effects are probably
      linked with a dual antagonist effect on 5HT2 and D2 receptors. The present
      article reviews the evolution of the use of these new agents, their real
      efficacy, their adverse effects and their expanding indications. Future research
      will more clearly establish appropriate treatment guidelines for their use. These
      new antipsychotics should add a positive modification in schizophrenia care and
      in some mood disorders. The approach consisting on individualizing dimensions and
      clusters analysis might be useful to test the efficiency of each antipsychotic on
      a syndromic dimension.

PMID- 10598296
TI  - [Acute psychosis in Reunion Island. Retrospective study performed on the 4th
      sector of psychiatry (west region) on the year 1997].
AB  - A retrospective study in the West psychiatry service in Reunion island (an area
      with 85,000 inhabitants) includes 19 files for patients hospitalized for the
      first time during the year 1997 with a diagnosis of acute psychosis. It excludes
      the troubles linked to the acute or chronic use of alcohol and the mental
      aberrations. This study regroups a young population, basically male and more
      often disadvantaged. The deliriums are stereotyped, essentially borrowed from the
      local culture. Two important points become visible: in more then half of the
      cases, drug taking (polyintoxication systematically associating cannabis) is
      evoked as the main etiologic factor. The prognosis in the short term of those
      acute psychosis is good, with a rapid regression of symptomatology under
      neuroleptic treatment. The evolution in the long term must be more moderated:
      four patients will develop a chronic psychosis; whatever the situation (taking
      drug or not), this acute psychotic episodes are revealing of an underlying
      chronic psychosis in nine cases out of nineteen. This fact underlines the
      interest of following those patients regularly to obtain a withdrawal with the
      addicted persons (risk of acute psychotic relapse) and of anticipating a chronic
      psychotic evolution.

PMID- 10598297
TI  - [Psychopathological and psychotherapeutic approach to the first psychotic
      episode].
AB  - The studies and research on the psychopathology of delusions are extremely
      numerous and varied and have resulted in the construction of psychoanalytic,
      systemic, cognitive and other explanatory models. All the theories stress the
      interaction between the subject and his/her environment, in particular when an
      initial psychotic episode emerges. In addition to their etiopathogenic interest,
      these models have the advantage of constituting specific therapeutic approaches,
      which indubitably increase the impact of treatment when associated with
      chemotherapy.

PMID- 10598298
TI  - [The contribution of brain imaging in acute psychotic disorders].
AB  - In recent years research on the neuronal substrate for mental disorders has
      considerably developed thanks to new brain imaging methods. Functional brain
      imaging has attracted several workers in their investigations of psychiatric
      diseases. Some authors have addressed the position of imaging in the diagnosis
      and, above all, prognosis of acute psychotic disorders. In the following paper,
      the authors review the published results. Both structural and functional imaging
      confirm the hypothesis of a neurophysiological contribution to acute psychotic
      disorders, as shown by ventricular dilatation and functional abnormalities.
      Nonetheless, imaging does not seem to have a precise and absolute diagnostic and
      prognostic value, although of undeniable heuristic interest.

PMID- 10598299
TI  - [Antidepressant pharmacotherapy: a review of pharmaco-economic research].
AB  - Recent pharmacotherapeutic advances in the treatment of depression have included
      the development of selective serotonin reuptake inhibitors (SSRIs), thereby
      providing an alternative to tricyclic antidepressants (TCAs). SSRIs have achieved
      a rapid acceptance by prescribers worldwide due to a superior safety profile to
      that observed with the TCAs, and the potential for once daily administration.
      However, to date there exists limited data regarding the effect of antidepressant
      pharmacotherapy on health service expenditures. Herein, we review the inherent
      strengths and weaknesses of the five study designs which have been employed in
      the economic appraisal of antidepressant pharmacotherapy: randomized controlled
      trials; meta-analyses stemming from the results of controlled clinical trials;
      decision-analytical models predicated on results stemming from randomized
      clinical trials and/or meta-analyses; retrospective data archive investigations;
      and prospective randomized naturalistic inquiry. What emerges is the necessity of
      establishing a portfolio of evidence as to the safety, efficacy, and
      effectiveness of a given pharmacotherapeutic category (e.g. SSRIs) and/or a
      specific medication. Thus, the economic appraisal of antidepressant
      pharmacotherapy will require an iterative process extending from the
      developmental through post-marketing phase.

PMID- 10598300
TI  - [Sleep electroencephalography in depression and mental disorders with depressive
      comorbidity].
AB  - Traditional scoring of sleep EEG in depressed patients shows abnormalities in
      sleep maintenance, sleep architecture, REM sleep, the distribution of slow wave
      and REM sleep during the night. Computerized analysis that comprises the period
      amplitude analysis procedure and spectral analysis discloses changes in delta
      activity and distribution of delta activity. However, these methods of analysing
      EEG sleep are not able to distinguish the various concepts of depression:
      endogenous and non-endogenous depression, unipolar and bipolar depression,
      psychotic and non-psychotic depression. Polysomnographical data in patients with
      recurrent depression show alteration during remission suggesting trait-like
      abnormalities of sleep in depression illness. Shortened REM latency is not
      specific in depression. This sleep parameter is defined in many different ways
      explaining the heterogeneousness of study results and the failure of constituting
      a biological marker. Many sleep parameters are affected by several factors such
      as age, gender and severity. Several physiopathological hypotheses have been
      proposed to explain EEG sleep alterations. They refer either to circadian rhythms
      such as the two process model of Borbely, the phase advance hypothesis and the
      circadian amplitude hypothesis, or to neurotransmitter abnormalities such as the
      cholinergic hypothesis. None of them takes sufficient account of all the sleep
      abnormalities. Sleep abnormalities have also been described in other psychiatric
      disorders such as mania, panic and obsessional-compulsive disorders, generalized
      anxiety, phobias, post-traumatic stress disorder, eating disorders, borderline
      personality, schizophrenia and dementia. None of them have a particular sleep EEG
      profile which allows to differentiate between them. A concomitant episode of
      major depression cannot be uncovered by sleep recordings.

PMID- 10598301
TI  - [Prophylactic treatment of mood disorders: cost effectiveness analysis comparing
      lithium and carbamazepine].
AB  - Economic impact of lithium therapy has seldom been assessed, economic comparisons
      with alternative mood stabilizers are almost non existent. This economic
      evaluation of preventive treatment of mood disorders recurrences (whether
      unipolar or bipolar) compared lithium with carbamazepine, through data from a
      randomized controlled clinical trial. A retrospective analysis of medical files
      of index patients is included in this trial, with experts' global ratings. A
      brief survey checked for representativity of in-patients length of stay. The
      model compared two cohorts of patients followed-up for two years after
      prophylactic treatment had begun. Rates of recurrence and direct medical costs
      related to mood disorders (prophylactic treatment, treatment of recurrences and
      serious adverse effects) were assessed. Data extrapolation was necessary because
      of variable lengths of follow-up during the trial and was based on medical review
      of index patients. Assessment of consumed health care resources were derived from
      the available database of the clinical trial, when necessary practice guidelines
      and experts' opinions were added to the model. Costs were valued according to
      available french unit costs (Vidal, NGAP, and Comptes de la sante). Analysis only
      included direct costs. An estimate of mean cost of care of 15,404 French francs
      per year per patient was calculated. The components of health costs show that in
      patient costs are the most important part of annual medical costs for mood
      disorders (70% of the total costs). Prophylactic medication costs accounted for
      only 6.9% of total costs. Comparison of prophylactic alternatives gave lithium a
      clinical benefit with 27% fewer recurrences than carbamazepine. Lithium led to an
      economic benefit of 4,280 French francs per year of treatment for a single
      patient. Robustness of this finding was assessed through a sensitivity analysis
      on estimate of length of stay. Total costs of treatment would be equal between
      lithium and carbamazepine if length of stay in hospital for lithium patients was
      increased by 51%. According to the cost-effectiveness analysis developed in this
      study, lithium should stay the "gold standard" of prophylactic treatment of
      recurrent mood disorders, and has both clinical and economic advantages compared
      to carbamazepine.

PMID- 10598303
TI  - [The evaluation of perceived responsibility among obsessive-compulsive patients].
AB  - Although many authors agree that excessive responsibility is associated with
      Obsessive-Compulsive Disorder (OCD), some believe that the manifestations of
      responsibility are more easily observed among patients suffering from checking
      compulsions (36, 42). This study compares a group of obsessive-compulsive
      patients that have been sub-divided into three groups (washers, checkers,
      ruminators) with a group of normal volunteers that are healthy with regards to
      responsibility. The sample consisted of 58 adults who meet diagnostic criteria
      for OCD and 20 normal individuals. During an individual interview, a clinician
      administered the ADIS III-R (section on OCD) as well as other instruments in
      order to precise the diagnosis. The participants then filled out questionnaires
      that assess symptoms, responsibility, perfectionism and general functioning. The
      results confirm that OC patients obtain higher scores than the normal group with
      regards to responsibility. However, no significant difference was found between
      the three sub-groups of OC patients. Thus, it seems to be pertinent of consider
      excessive responsibility as a characteristic of OC clients, for checkers and
      washers, as well as ruminators.

PMID- 10598302
TI  - [Clinico-economic assessment of milnacipran in the prevention of depressive
      episodes].
AB  - The objective of this study was to evaluate, for patients at risk of a new
      depressive episode, the net cost of maintenance therapy with milnacipran compared
      with a symptomatic treatment of further episodes. Using clinical decision
      analysis techniques, a Markov-state transition was constructed to estimate the 12
      months direct costs of the two therapeutic strategies. Model construction and
      probabilities for performing the analysis were primarily based on a controlled
      phase III clinical trial demonstrating the prophylactic efficacy of milnacipran
      compared to placebo. Others parameters and unit costs were obtained from
      published sources. For each group (maintenance and episodic treatment groups),
      the model simulated the clinical evolution of patients on 6 successive 2-months
      cycles. Costs were affected for each health state period (remission, depression,
      abandonment of health care, suicide). The baseline analysis showed the mean costs
      per patient and year were 627 FF (105 US$) higher for maintenance treatment.
      Sensitivity analysis suggested that costs were equal under a 25% rate of
      hospitalization hypothesis for a depressive episode. Maintenance costs were 1,587
      FF (265 US$) lower than episodic treatment costs for depressed subjects with a
      good initial response to milnacipran (HDRS-21 score at remission < 5); this
      economic benefit remained under a lower rate of hospitalization hypothesis (12%).
      Based on the study assumptions, maintenance treatment with milnacipran appears to
      be clinically and economically justified for patients at high risk of
      hospitalization when having a recurrence, and even more for patients with an
      excellent initial acute response.

PMID- 10598304
TI  - [Preliminary studies of the structured diagnostic interview for personality
      disorders: SCID II].
AB  - The aim of the study was to compare control subjects and consultant patients with
      the SCID II (interview and questionnaire), then to compare clinical diagnosis
      with the SCID II (interview and questionnaire). The preliminary study was carried
      out to assess the feasibility of the procedure. This appraisal was conducted with
      a group of patients (n = 26) and a control group (n = 16). Only the patients were
      diagnosed according to DSM IV criteria. The patients and the control group
      completed the Mini-Mult and the SCID II (questionnaire and interview). The two
      groups were matched on sex, age and educational level. The two groups were
      discriminated on all Mini-Mult scales but one: the internalization index. The
      results showed that the SCID questionnaire and the SCID interview differentiate
      the two groups. The SCID questionnaire showed high sensitivity in the group of
      patients. It is a more efficient instrument to screen control subjects except one
      personality disorder (obsessive-compulsive). The diagnostic agreement between the
      clinical diagnosis and the structured interview was poor. However our results are
      comparable to the other studies.

PMID- 10598305
TI  - [French translations and adaptations of questionnaires of magical thinking (MIS,
      Eckblad and Chapman, 1983) and perception disorders (PAS, Chapman et al., 1978)].
AB  - Meehl used the term "schizotype" to refer to individuals who possess an
      underlying vulnerability for schizophrenia. Because of the extremely varying
      degrees of the schizotype's clinical expression, he recommended assessing
      schizotypic signs through objective measures rather than clinical judgement. In
      this way, Chapman et al. have developed symptom-oriented scales based on Meehl's
      manual, such as the Social Anhedonia (SA) and Physical Anhedonia (PhA) Scales,
      the Magical Ideation Scale (MIS), the Perceptual Aberration Scale (PAS) and the
      Impulsive Nonconformity Scale (IN). Whereas Chapman's scales of psychosis
      proneness are the most internationally used instruments for the assessment of
      schizotypy, some of them, such as MIS and PAS, were still not available in
      French. Therefore, the first aim of this report was to offer French translations
      of the Magical Ideation and the Perceptual Aberration Scales; the agreement of
      the original authors were obtained for both translated versions and their back
      translations. The second aim of our study was to establish French norms for each
      of these scales. The preliminary norms presented here [MIS: 19/30 (for females)
      and 20/30 (for males); PAS: 18/35 (for both genders)] were obtained by
      administering both scales to a sample of 134 French students. They are very close
      to those found by Chapman et al. for University of Wisconsin undergraduate
      students. We will confirm them with a larger sample of French students.

PMID- 10598306
TI  - [Social anxiety in patients with social phobia: validation of the Liebowitz
      social anxiety scale: the French version].
AB  - The Liebowitz's Social Anxiety Scale (LSAS) (Liebowitz, 1987) is a rating scale
      of fear and avoidance in social interaction (12 items) and performance-oriented
      situations (12 items). This paper present the study of empirical and concurrent
      validation of the LSAS. Ninety-six patients suffering from social phobia
      according to DSM IV were included and compared with 64 non-clinical control
      subjects. Both patients and controls were divided into two sub-groups: the LSAS
      passation by hetero-evaluation or auto-evaluation. Social phobics had much higher
      scores on anxiety and avoidance of the LSAS than control subjects, whatever the
      method. There were no differencies between hetero and auto-evaluation in both
      groups of patients and non-clinical subjects, either on anxiety or on avoidance.
      The LSAS correlated better with social anxiety and negative cognition in social
      situations than with anxiety-depression in social phobics. The French version of
      the LSAS showed a good empirical and concurrent validity and the scale presents a
      good sensitivity to change after cognitive behavioral therapy in social phobics.

PMID- 10598307
TI  - [Mental disorders and migraine: epidemiologic studies].
AB  - Epidemiologic studies in the general population, taking into account certain bias
      inherent to the clinical observation have confirmed the clinical impression
      reporting a higher psychiatric comorbidity with persons suffering from migraine
      than in persons without migraine. Persons with migraine are at increased risk for
      affective and anxiety disorders, personality traits disorders (neuroticism),
      suicide attempts, but not for alcohol or illicit drug abuse. The comorbidity is
      more important in migraine with aura than in migraine without aura. Concerning
      affective disorders, the lifetime prevalence of major depression is 34.4% in
      persons with migraine and 10.4% in persons without migraine. For bipolar I
      disorder, prevalence is 6.8% in migraine with aura versus 0.9% when no migraine.
      Compared to no migraine, the lifetime prevalence of anxiety disorders in migraine
      is significantly increased in: panic disorder (10.9% vs 1.8%); generalized
      anxiety disorder (10.2% vs 1.9%); obsessive-compulsive disorder (8.6% vs 1.8%);
      phobic disorder (39.8% vs 20.6%). In addition, no psychopathological, biological
      or genetic explanation seems to be meaningful for the comprehension of this
      comorbidity pattern. These results remain primarily descriptive but they justify
      a clinical investigation of affective and anxiety disorders, and suicide
      attempts, in all person with migraine, and it also justifies the treatment of
      pain associated with the treatment of eventual affective or anxiety disorders.

PMID- 10598308
TI  - [Defense mechanisms and the prediction of PTSD].
AB  - The purpose of this study was to assess mental defense mechanisms,
      characteristics of trauma and life events predicting the development of
      posttraumatic stress disorder. Victims of traumatic events were recruited from a
      general university hospital. 23 participants were examined with a semi structured
      clinical interview, according to DSM IV criteria. All of them were assessed with
      the Social Readjustment Scale (Holmes et al., 1967), with the Traumatic Disorder
      Inventory Scale (Steinitz et al., 1992) and completed the Impact of Event Scale
      of Horowitz. All the subjects completed the Defense Style Questionnaire-40 (DSQ
      40). The different mechanisms were ranked in three categories: mature, neurotic,
      and immature. Finally, we compared defense scores, trauma scores and life events
      scores between PTSD subjects and non PTSD subjects. 8 subjects were diagnosed as
      having PTSD compared to 15 not considered to have PTSD. Being alone during
      exposure significantly enhances the risk for the development of PTSD. Among PTSD
      subjects only reaction formation, a neurotic defense, was employed significantly
      more often than in those without PTSD. These findings suggest that mental defense
      mechanisms may be indicative of a risk for the development of PTSD after event
      exposure. Using DSQ-40, mature and immature defenses didn't differ, although
      reaction formation played a role, particularly in regard to traumatic memories
      and perseverative thoughts.

PMID- 10598309
TI  - [The relationship between the burnout and self esteem among prison wardens].
AB  - Our aim in this research has been to show the link existing between "burn-out"
      and self-esteem. Several studies have outlined that link without actually
      bringing is to light. The present study has been carried out among prison
      officers. The concept had actually never been applied to such a population and
      has rather been used for social assistance jobs, such as social workers, tutors
      or teachers. A "burn-out" questionnaire has been made so as to estimate how tired
      the staff were. Maslach's test (1982) has revealed difficult to use here.
      Coopersmith's SEI has been used to estimate people's self-image. The results have
      revealed positive, as the elder staff have shown a higher burn-out rate than the
      younger ones. The younger staff also have a better self-image than the elder
      ones. Eventually, the global level of self-esteem and total level of exhaustion
      are inversely correlated. From these results, it can be said that prison warders
      tend to endure an occupational exhaustion syndrome and that the lower their self
      esteem the higher their "burn-out" rate.

PMID- 10598310
TI  - [A controlled study of irrational interpretations of intrusive thoughts in
      obsessive-compulsive disorder].
AB  - Recent research suggested that the irrational interpretations of intrusive
      thoughts might be cognitive structures underlying obsessive compulsive disorder
      (OCD). We present a study on intrusive thoughts and their interpretations in 36
      patients suffering from OCD (DSM IV criteria), compared with 36 sex and age
      matched non clinical subjects, with the Intrusive Thoughts and their
      Interpretations Questionnaire-revised version (ITIQ-r). This questionnaire
      measures intrusive thoughts intensity and three types of interpretation:
      responsibility, guilt and inferiority. The measures of OCD, of depression, of
      social phobia and of anxiety have been used. RESULT: OCD patients reported more
      frequent intrusive thoughts and higher irrational interpretations than controls.
      The higher the intrusive thoughts, the higher the irrational interpretations. The
      multiple regression showed that both intrusive thoughts and irrational
      interpretations were respectively predicted by obsessional compulsive pathology
      (the Obsessive Thoughts Checklist or the Y-BOCS). The Y-BOCS was the only
      predictor for inferiority interpretation, but there was no significant predictor
      for responsibility or for guilt interpretations. Responsibility correlated only
      with aggressive intrusive thoughts. Guilt was related to intrusions about fear of
      loss. Inferiority was highly correlated with intrusive thoughts about
      perfectionism and sexuality.

PMID- 10598311
TI  - [Pharmacokinetics of SSRI antidepressants: half-life and clinical applicability].
AB  - The selective serotonin reuptake inhibitors (SSRIs) antidepressants are at
      present time the most useful for the treatment of depression. SSRIs exhibit
      differences in potency of inhibiting serotonin reuptake, although the differences
      do not correlate with clinical efficacy. There are substantial pharmacokinetic
      differences among the five SSRIs, fluvoxamine, fluoxetine, paroxetine, sertraline
      and citalopram. Optimum use of these drugs requires a working knowledge of these
      differences. Among these pharmacokinetic parameters, half-life and metabolism
      pathways are the most relevant. There are substantial differences in term of
      their half-life between fluoxetine and others SSRIs. The half-life of fluoxetine
      and its active metabolite norfluoxetine is respectively 2 to 4 days and 7 to 15
      days, more extended than other SSRIs (approximately 1 day). The extended half
      life of fluoxetine and its active metabolite may be an advantage in the poorly
      compliant patient and may offer a potential safety advantage over shorter-acting
      SSRIs, with respect to abrupt discontinuation of therapy. Conversely, this long
      half-life needs a long period of wash-out (5 weeks) before introducing other
      drugs (MAOIs, sumatriptan) which can interact with serotonin function and can
      lead to the serotoninergic syndrome. SSRIs are potent inhibitors of the hepatic
      isoenzyme P450-2D6 and would be expected to have effects on the clearance of
      drugs metabolized by this enzyme. Paroxetine is the most potent inhibitor,
      followed by fluoxetine, sertraline, citalopram and fluvoxamine. The metabolite
      elimination of citalopram, paroxetine and fluvoxamine is delayed by renal disease
      and dosages should be lowered in elderly patients. Conversely the pharmacokinetic
      of fluoxetine and sertraline are not affected by either age or renal impairment
      and, for fluoxetine, by obesity.

PMID- 10598312
TI  - [The use of therapeutic isolation and confinement in psychiatry. A prospective
      study].
AB  - Despite recent developments in psychopharmacology and a better understanding of
      agitation patterns in psychiatric patients, the use of seclusion and restraint
      procedures remains a matter of daily practice. Little or no time is spent on its
      teaching in a formal way. There is almost no literature on these issues, and it
      has grown only since legal procedures initiated by patients, which forced
      practitioners to spend some time analysing these methods. Facing this problem, we
      realized a prospective study at the CHS de la Savoie, in Chambery, so as to
      clarify the current modes of these procedures. This study was led among 460
      secluded patients, during one year. 11 data were studied, such as the duration of
      the seclusion, the reason and the medical history, the desire of the patient to
      be liberated ... The review or awareness of certain variables may give clinicians
      a better perspective on the use of procedures which, unfortunately, continue to
      be the cause of deaths in psychiatric practice.

PMID- 10598313
TI  - [Between efficiency and toxicity: the case of a patient improved by lithium who
      developed iatrogenic nephropathy].
AB  - Although almost fifteen cases have been reported since 1970, renal failure during
      a long term lithium therapy remains in the epidemiologic studies a rare
      pathology. Lithium treatment side effects can be considered in term of
      morphologic damages or in terms of kidney physiology impairments in filtration or
      concentration. For example it has long been known that lithium generates polyuria
      which results from an induced nephrotic diabetes insipidus (NDI). Fortunately
      most of these common impairments are reversible without any alarming or starting
      consequences. Moreover histological injures may also occur such as interstitial
      fibrosis, sclerotic glomeruli, tubular atrophy or dilatation ... whose evidence
      still raises some controversy concerning their incidence and specificity. We
      report here the case of a Bipolar I patient stabilized for at least fifteen years
      with lithium at a high level of social and professional life, in whom renal
      failure was found with tubular damage. This injury correlated to the lithium
      therapy even if always controlled at a normal rate during fifteen years, forced
      us to withdraw this treatment and switch to valproate. Is our goal to protect the
      renal function against the patient wishes totally justified since he relapsed in
      hypomania 63 days after the drop out? We had to choose between renal preservation
      and mental health.

PMID- 10598315
TI  - [Pharmacotherapy in personality disorders: methodological issues and results].
AB  - The pharmacotherapy of personality disorders is less developed than are
      psychological treatments in this area, but they are a logical prolongation of
      psychobiological models of personality and temperament, and respond to the need
      of many clinicians in front of difficult patients. The assessment of drugs
      effects in personality disorders includes some important conceptual and
      methodological issues. Categorical or dimensional instruments evaluating baseline
      personality and under-treatment changes are now available. Such studies are
      necessary of long duration, with difficult patients, and use specific outcome
      criteria. The results obtained in the field of pharmacotherapy of personality
      disorders can be classified according to DSM IV axis-II categorization. In
      anxious personalities (cluster C), some isolated studies suggest a favourable
      effect of antidepressants on obsessive-compulsive dimension, on avoidant
      personality disorder, and on inhibition and trait-anxiety, especially when
      serotoninergic agents are used. Few studies have been conducted in cluster A
      personality disorders, and some are in favour of the interest of low doses of
      antipsychotic drugs in this group. Most studies have been conducted in cluster B,
      and especially in antisocial and borderline personality disorders. Partial
      positive results have been obtained using various classes of drugs for dealing
      with aggression and impulsive behaviors, including lithium, beta-blockers,
      carbamazepine, valproate, antipsychotic drugs, and also SSRIs. Self-harm and
      suicidal behaviors seem to be partially but significantly improved by
      antidepressants and low doses of antipsychotics. Opioid antagonisms may be
      helpful for these indications in the future. Other symptom-oriented strategies
      for psychopharmacology have been conceptualized, focused on depressive
      personality, emotional lability, cognitive and perceptual disturbances, or
      interpersonal sensitivity. Overall, the pharmacotherapy of personality disorder
      remains to date one of the less explored in psychiatry research. Nevertheless, it
      may lead in the future to the development of effective treatments, in complement
      to psychotherapy, for actually severe, chronic, and disabling disorder.

PMID- 10598314
TI  - [What's bugging him?].
AB  - The purpose of this study is to report the case of a 34 year old patient, from
      Zaire for whom a wrong diagnosis could have been fatal. Recent events in his
      affective and professional life, associated with typical symptoms, suggested a
      major depression. However after two months of being admitted a psychiatric ward,
      the resistance to treatment together with some biological data suggested further
      investigations. They revealed a subacuse meningo-encephalitis of parasitological
      etiology. The psychiatric aspects of trypanosomiasis commonly known by clinicians
      in Africa justifies, in patients from that continent, a systematic test for
      trypanosomiasis.

PMID- 10598316
TI  - [New synthesis empathogenic agents].
AB  - The use of synthesis drugs is the object of numerous written articles and TV
      programs in the last, decade. These synthesis drugs or "designer drugs", are well
      known for their ability to enhance, reinforce or appease social difficulties and
      relationships. In the research for empathetic and entactogenic relations one
      discover an obvious lack of communication and "warmth" in personal or
      professional relationship. An image of chemical "well being" has become a
      frequent stereotype of a society with an atrophying of performance and values
      while supposedly dedicating itself to individual performance. The youths are the
      first victims of these new drugs, the economical and social environment are the
      main reinforcing factors of this behaviour. The main characteristic of these
      drugs, is the non-recognition of their danger, some users go so far as to
      describe this category of substances as "drugs which are not drugs". As a
      characteristic, the use of a these synthesis drugs is almost recreative, during
      the week-end and holiday. The drug addiction is different than that of opiates or
      cocaine. One can observe some cases of real dependence--corresponding to the DSW
      IV criterion--when the personality of the users is the main characteristic
      (narcissic failure, immature personality, family and school problems). Many
      adverse effects--hypertension, kidney failure, psychoses--were declared. The mass
      media has presented many articles concerning Ecstasy (MDMA). This is the most
      used drug during the rave parties. Its adverse effects are well known and proven.
      The authors would like to present other more recent synthesis drugs, also known
      as "analogs". These drugs, a kind of mixture between amphetamine-like (MDMA,
      MBDB, MDA) and misused medicines (ketamine, gamma OH, atropine) represent a real
      danger. GHB, 2 CB, HMB, are some of these recent substances. The possibility to
      procure them on the Web, or to produce them by oneself, add to their danger
      because of the lack of controls on toxicity and quality. The original danger
      signs were revealed by the FDA and currently a major preoccupation within french
      specialised services. The major problem for the practitionner is to inform the
      users, in order to prevent addiction and analyse the solutions.

PMID- 10598317
TI  - [Depression and sexual disorders].
AB  - Nowadays, we talk more and more often about sexual disorders, and depression in
      one of the possible etiologies of them. Depression could lead to sexual disorders
      or induce them indirectly. Paradoxically, depression treatments, such as
      tricyclic antidepressant or SSRI could induce this kind of disorder. Tianeptine,
      the only molecule representative of this pharmacological class, has proved its
      good acceptability on the libido, as shown by the results of a meta-analysis. The
      respect of the sexual function is essential to obtain a good observance of the
      antidepressant treatment.

PMID- 10598318
TI  - Developmental changes in phosphatidylinositol transfer protein concentration and
      phospholipid transfer activities in rat type II cells.
AB  - The phospholipid transfer proteins (PLTPs) are cytosolic proteins that have been
      characterized by their ability to facilitate the transfer of phospholipids
      between membranes in vitro. The goals of this study were to determine whether
      PITP alpha concentration and phospholipid transfer activities are enriched in
      type II cells compared with whole lung and to determine the developmental changes
      in PITP alpha concentration and phospholipid transfer activities during late
      gestation and newborn period. The concentration of PITP alpha in type II cell
      cytosol measured by enzyme-linked immunosorbent assay (ELISA) increased during
      late fetal gestation to 2.2-fold adult levels and declined 41% during the first
      postnatal day. However, compared to whole adult lung cytosol, type II cell
      cytosol was not significantly enriched with PITP alpha. Phospholipid transfer
      activities were determined by a vesicle-rat lung membrane transfer assay. In
      adult lung, transfer activities for all the phospholipids were enriched in adult
      type II cell cytosol compared to whole lung cytosol (phosphatidylglycerol [PG],
      12.5-fold; phosphatidylinositol [PI], 9.2-fold; phosphatidylcholine [PC], 6.5
      fold; and phosphatidylethanolamine [PE], 6.6-fold; P < .05 in each case). The
      rate of phospholipid transfer in type II cell cytosol increased during late fetal
      gestation to levels 4.9 (PG), 3.7 (PI), and 2.8 (PC) times greater than adult
      levels. In cytosol from cells from different stages, the order of transfer rate
      was PG > PI > PC > PE. PITP alpha immunodepletion of adult type II cytosol did
      not significantly affect phospholipid transfer activities, suggesting that other
      PLTPs are responsible for the majority of the observed transfer activities in
      these cells. Developmental increases in PITP alpha concentration and other PLTPs
      parallel developmental changes in type II cell surfactant phospholipid
      metabolism, suggesting a possible role of these transfer proteins in the unique
      function of the type II cell.

PMID- 10598319
TI  - The interaction of phosphatidylcholine with alveolar type II pneumocytes is
      dependent on its physical state.
AB  - Dipalmitoylphosphatidylcholine, the principal phospholipid component of
      surfactant, inhibits agonist stimulated surfactant secretion whereas
      dioleoylphosphatidylcholine does not. As knowledge of the type of interaction of
      phosphatidylcholines is important for the detailed analysis of surfactant
      homeostasis, this was examined in isolated rat type II pneumocytes in primary
      culture. Solid state [3H]-dipalmitoylphosphatidylcholine liposomes associated
      with the cells rapidly. No effect of blockade of endocytosis on the cellular
      association was observed, whereas that of the fluid phase marker [14C]-sucrose
      was reduced. No evidence for the fusion of the dipalmitoylphosphatidylcholine
      liposomes or for phospholipid exchange with the cells was detected, suggesting
      that the cells primarily bound the dipalmitoylphosphatidylcholine liposomes.
      Although a "specific" site with a saturable binding capacity (20 nmol
      dipalmitoylphosphatidylcholine/mg protein, KD 25 microM) was demonstrated, the
      interaction did not exhibit all the characteristics of a typical pharmacological
      receptor. The preincubation with nonlabeled dipalmitoylphosphatidylcholine almost
      completely inhibited binding to the cells. In accordance with their effects on
      stimulated surfactant secretion, various other phosphatidylcholine liposomes
      inhibited binding that was very much dependent on their physical state, as only
      those in a solid state were inhibitory by more than 50%. These results support
      the view that the binding of dipalmitoylphosphatidylcholine may be involved in
      the feedback regulation of surfactant secretion in type II pneumocytes and that
      these processes are dependent on the physical state of the interacting liposomes.

PMID- 10598320
TI  - Calcium-dependent degradation of surfactant protein A by activated neutrophils
      due to serine proteases.
AB  - The effects of activated leukocytes on surfactant function and composition were
      examined to better define the mechanisms by which acute inflammation contributes
      to respiratory distress syndrome (ARDS). Peripheral blood leukocytes from healthy
      volunteers were incubated in vitro with surfactant for 4 hours: (1) in the
      absence of activation; (2) following activation by addition of phorbol myristate
      acetate (PMA); (3) following addition of PMA + FeCl2/EDTA; (4) PMA + FeCl2; (5)
      PMA + EDTA; (6) PMA + FeCl2 + superoxide dismutase (SOD) + catalase; (7) PMA +
      EDTA + serine or cysteine protease inhibitors. Surfactant was then repurified by
      sucrose gradient centrifugation, and function, phospholipid and protein
      composition, and extent of lipid peroxidation were assessed. PMA caused
      activation of leukocytes as detected by dichlorofluorescene assay. Lipid
      peroxidation (assessed by conjugated diene assay) was detected in all samples
      containing PMA. Abnormal function was noted in surfactant exposed to activated
      cells with 1 mM EDTA, whereas activation alone, or with FeCl2, had no effect. SOD
      + catalase prevented lipid peroxidation, but did not prevent leukocyte-mediated
      dysfunction, which was associated with a marked reduction in surfactant protein A
      (SP-A), but no detectable change in surfactant protein B (SP-B) or phospholipid
      composition. Serine protease inhibitors prevented SP-A degradation and
      dysfunction, whereas cysteine protease inhibitors had no protective effect.
      Addition of purified SP-A (5% w/w) to dysfunctional surfactant restored normal
      function, while SP-B/C mixture (3%) did not. Activated leukocytes cause
      surfactant dysfunction in vitro by serine protease-mediated degradation of SP-A,
      which occurs only in the presence of EDTA, and is prevented by addition of
      calcium. Although lipid peroxidation mediated by leukocyte release of free
      radical products was also detected, surfactant dysfunction appears to be
      unrelated to this process.

PMID- 10598321
TI  - Regulation of 5-lipoxygenase metabolism in mononuclear phagocytes by CD4 T
      lymphocytes.
AB  - Alveolar macrophages (AM) are the primary resident effector cells in the
      alveolus. Leukotrienes (LT) are secreted by AM in their role as defender of the
      lung. 5-Lipoxygenase (5-LO) catalyzes the synthesis of LT in association with 5
      LO-activating protein, termed "FLAP." AM demonstrate increased 5-LO metabolism
      compared to peripheral blood monocytes (PBM). Activated lymphocytes release
      mediators which upregulate 5-LO metabolism in PBM. The lymphocyte population of
      the lung consists predominantly of CD4+ helper constitutively "activated" T
      cells. We hypothesized that mediators released by pulmonary CD4+ T cells may
      upregulate and maintain of 5-LO metabolism in PBM as they enter the alveolar
      space and differentiate into AM. 5-LO metabolism in AM from CD4-depleted mice
      demonstrated reduced LT synthesis (LTC4: 66.9 +/- 8%; LTB4 61.4 +/- 6.2%
      control). The decrease in 5-LO metabolism was associated with reduced FLAP (30.1
      +/- 14.5% of control) and 5-LO expression (49 +/- 13.7% of control). This defect
      in AM 5-LO metabolism in CD4-depleted mice was further associated with reduced
      LTC4 levels in bronchoalveolar lavage (BAL) fluid. In summary, factors secreted
      constitutively by lung lymphocytes, in particular CD4 cells, contribute to the
      increased 5-LO metabolism in AM.

PMID- 10598323
TI  - Muscle-mediated gene therapy.
AB  - Transfer of therapeutic genes into muscle tissue holds promise for the treatment
      of a variety of muscular dystrophies, serum protein deficiencies and vascular
      proliferative disorders. Recent progress achieved in development of improved
      vectors allowed prolonged and efficient expression of genes encoding therapeutic
      proteins in muscle cells. The most important advances include: novel plasmid DNA
      vectors and methods for their efficient transfection in vivo, helper-dependent
      adenoviral vectors, allowing long-term gene expression and effective
      readministration in immunocompetent hosts and adeno-associated vectors. On the
      other hand, recent progress in this field has been facilitated by development of
      systems that enable regulated therapeutic gene expression in muscle tissue.

PMID- 10598322
TI  - Survival, lung injury, and lung protein nitration in heterozygous MnSOD knockout
      mice in hyperoxia.
AB  - This study tested whether a strain of heterozygous Mn superoxide dismutase (SOD)
      knockout mice differed from wild types in response to lethal (100 or 85%) or
      sublethal (50 or 75%) oxygen exposures. Lung MnSOD activity was significantly (
      40%) less in the heterozygous mice, and lung catalase activity was also
      significantly decreased. Total SOD activity, glutathione peroxidase, and
      glutathione reductase did not differ between heterozygous (+/-) and wild-type
      (+/+) mice. We exposed both heterozygous and wild-type mice to hyperoxia (50, 75,
      85, or 100% oxygen) until death or for 48 hours to assess sublethal lung injury.
      Survival of the heterozygous and wild-type mice did not differ significantly in
      100 or 85% oxygen. No mice of either genotype died in 50 or 75% oxygen (14-day
      exposures). Hyperoxia exposures significantly increased (by two-way ANOVA) the
      alveolar lavage protein concentration, percent neutrophils, and lung wet-dry/dry
      weight ratios. No significant differences occurred between the heterozygous and
      wild-type mice for any marker of injury at any oxygen level. Lavage fluid total
      nitrite concentrations did not differ at any oxygen level. Hyperoxia caused a
      similar degree of nitration of lung structural proteins detected by
      immunohistochemistry in both groups.

PMID- 10598324
TI  - Intralesional injection of interferon gamma affects reactive proliferation of
      astrocytes in the neonatal rat brain. A preliminary study of the age-dependent
      effect.
AB  - Following a mechanical lesion of the left cerebral hemisphere, newborn male rats
      received a single injection of recombinant rat interferon gamma (IFN gamma) into
      the lesion cavity at doses of 5, 50 and 500 U. One or two days after the injury
      the rats were injected with 3H-thymidine. Brain sections were immunostained for
      glial fibrillary acidic protein (GFAP), subjected to autoradiography and examined
      microscopically to record proliferating GFAP-immunopositive (GFAP+) astrocytes
      labeled with 3H-thymidine. Following the intermediate 50 U dose of IFN gamma,
      numbers of GFAP+ astrocytes and of their mitoses on day 1 after injury were
      significantly higher than in controls. Nevertheless, the astrocyte labeling index
      remained at the control level. Injections of the minimal 5 U or the maximal 500 U
      doses of IFN gamma had no effect on that day. On day 2, however, each of the
      three doses evoked a statistically significant but dose-independent reduction of
      the labeling index without similar changes in total number of GFAP+ astrocytes or
      in numbers of their divisions. The changes appear to indicate a non-linear
      relation between the intensity of reactive behaviour of astrocytes and the amount
      of IFN gamma injected into the lesion area. On the basis of previous
      publications, IFN gamma effects on the astrocyte reactivity are discussed as
      being age-dependent.

PMID- 10598325
TI  - Ultrastructural evidence for dendritic release of acetylcholinesterase in the rat
      substantia nigra.
AB  - Morphological evidence for dendritic secretion of acetylcholinesterase (AChE) in
      rat substantia nigra--a physiologically known phenomenon--was searched by means
      of a modified cytochemical method devised for fine localization of AChE activity
      at the electron microscopic level. DAB precipitate was observed in cluster of
      small vesicles in contact with the plasma membrane and in the extracellular space
      in the vicinity of the vesicles. Single coated or uncoated large vesicles filled
      with stained material were found in the cytoplasm of the dendrites at distance
      from or in contact with the plasma membrane. Immunoperoxidase staining with
      specific anti-serum against rat AChE gave similar localization of AChE. These
      results suggest that AChE is released from the dendrites of the nigral neurons by
      a process of vesicular exocytosis and captured by endocytosis. The relation of
      this process to a putative release from the smooth endoplasmic reticulum remains
      to be elucidated.

PMID- 10598326
TI  - BN52021 stabilizes the oxidant-antioxidant equilibrium in peritoneal lavage fluid
      in experimental hemorrhagic shock.
AB  - The overproduction of highly reactive oxygen metabolites initiates and
      contributes to the damage to abdominal organs in hemorrhagic shock (HS).
      Peritoneal environment including free cells located in peritoneal cavity may
      interact with the inflammatory processes occurring in abdominal organs during HS.
      Peritoneal lavage was carried out in 48 rats divided into following groups: (1)
      control, (2) untreated HS for 75 minutes, (3) HS + restoration of blood volume
      with polyelectrolyte solution (PES) 60 minutes after blood withdrawal, and (4) HS
      + platelet activating factor (PAF) receptor antagonist BN52021 directly after
      bleeding + PES after 60 minutes of HS. Peritoneal lavage fluid (PLF) was examined
      for Cu-, Zn-superoxide dismutase (SOD) activity, sulfhydryl compound (-SH)
      concentration, and malondialdehyde (MDA) level measured as thiobarbituric acid
      reactive substances (TBARS). The untreated shock (group 2) as well as HS + PES
      (group 3), resulted in significant increase in cell numbers in PLF. In groups 2
      and 3, the SOD activities were not detected while -SH group levels were
      significantly higher, than those in the control. The group of shocked rats after
      blood volume restoration with PES was the only group where the MDA in PLF was
      found. The highest -SH group concentrations and detectable SOD activities were
      recorded in shocked rats treated with BN52021 and PES. Systemic hemorrhage may
      cause significant alterations in the oxidant-antioxidant (O-A) balance in
      peritoneal cavity, accompanied by significant elevation of number of cells
      lavaged from peritoneal cavity. There is an escalation of disturbances in O-A
      balance in peritoneal lavage fluid due to restoration of blood volume. BN52021
      may exert beneficial effects stabilizing peritoneal antioxidant system in the
      hemorrhagic shock.

PMID- 10598327
TI  - Different methods of tissue preparation for X-ray microanalysis combined with
      scanning electron microscopy based on zebra fish, Brachydanio rerio muscle
      fibres.
AB  - Four preparation methods for electron probe X-ray microanalysis (EPXMA) of muscle
      fibres were compared: (1) dissection, freezing in LN2 (liquid nitrogen), cutting
      in cryostat, freeze-drying and analysis; (2) dissection, immersing in Tissue-Tek,
      freezing in LN2, cutting in cryostat, the following steps as in method 1; (3)
      dissection, freezing in LN2, freeze-drying, separation of fibres into groups; (4)
      dissection, cutting into 2 mm thick slices by razor blade, freezing in LN2,
      following steps as in method 1. The contents of Na, Cl, and K as well as K/Na,
      Cl/K, ratios were taken as criteria of good preservation of muscle fibres. The
      best results were obtained by method 1. Good morphological preservation can be
      routinely observed in sections prepared by methods 3 and 4. However, the
      diffusible elements and K/Na, Cl/K ratios were not retained at relatively
      constant level among the individual samples. Fibres prepared by methods 1 and 3
      showed, despite of freezing artefacts, high K/Na, and low Cl/K ratio. After
      method 1, high level of the elemental contents was retained, and it did not
      differ significantly among the samples, showing relatively low standard deviation
      values.

PMID- 10598328
TI  - The formation of primary and secondary lysosomes in Balantidium coli, Ciliata.
AB  - Trophozoites, vegetative forms of Balantidum coli isolated from pigs affected by
      acute and asymptomatic balantidiasis were studied. Lysosomes and food vacuoles
      were revealed by cytochemical detection of lysosomal marker, acid phosphatase.
      The cytoplasm of all the B. coli trophozoites examined was found to contain
      numerous structures which differed widely in shape, size and location in the
      cells. One of them was located among the rough endoplasmic reticulum membranes
      and another one in the vicinity of endosomes. Those structures were regarded as
      the primary lysosomes. The two types of vesicular structures most probably
      represent two stages of the primary lysosome formation. Trophozoites were also
      found to contain secondary lysosomes which are formed by fusion of several
      primary lysosomes with phagosomes. The ultrathin sections of B. coli trohozoites
      showed the presence of two types of phagosomes. They were divided, based on their
      contents, into auto- and heterophagosomes.

PMID- 10598329
TI  - Methylation-sensitive restriction endonuclease digestion patterns revealed in
      Vicia faba L. chromosomes by in situ nick-translation.
AB  - Restriction endonucleases sensitive to cytosine methylation (HpaII, MspI and
      HhaI) and 5-azacitidine were used to study the localization of target sequences
      in Vicia faba metaphase chromosomes by in situ digestion and radioactive or non
      radioactive nick-translation. In control experiments, neither isolated DNA nor
      chromosomes in situ were digested by HpaII and MspI. Pretreatment with
      demethylating agent, 5-azacitidine resulted both in increased effectiveness of in
      situ digestion and nick-translation. In 5-azacitidine-treated material, negative
      bands in M chromosomes appeared. HhaI cleaved isolated DNA, digested it in situ
      and gave positive signals as a result of nick-translation procedure in metaphase
      chromosomes. In S chromosomes containing heterochromatin without target sequences
      for HpaII and MspI, negative bands were shown after nick-translation. Such
      heterochromatin contains FokI sequences and in situ nick-translation driven by
      that restriction enzyme resulted in positive bands.

PMID- 10598330
TI  - [In Process Citation]
AB  - BACKGROUND: We investigated the association of cigarette smoking with high-grade
      carotid artery stenosis in patients with ischemic stroke and transient ischemic
      attacks. METHODS: Prospectively collected data from 404 patients with focal brain
      ischemia were used for a cross-sectional study estimating the association between
      cigarette smoking and high-grade carotid artery stenosis (diagnosed by Doppler
      ultrasound and defined as a luminal narrowing of > or = 70%). Cerebral ischemia
      patients with normal sonographic findings served as a comparison group.
      Multivariate logistic regression models were used for statistical tests to
      determine the association between smoking and high-grade carotid stenosis. Age,
      gender, hypertension, diabetes mellitus, hypercholesterolemia and co-existing
      heart disease (myocardial infarction, angina, heart failure) were considered
      potential confounders. RESULTS: High-grade carotid stenoses were found in 25% (n
      = 101) of the patients; 39% (n = 156) were classified as smokers. Smoking (odds
      ratio 3.6, 95% confidence interval [CI] 2.2 to 5.8), hypercholesterolemia (odds
      ratio 1.8; CI 1.1 to 2.8) and preexisting heart disease (odds ratio 1.7; CI 1.1
      to 2.7) were significantly associated with carotid stenosis > or = 70%. The
      impact of smoking augmented with increasing degree of stenosis (odds ratio for
      stenoses > or = 80%: 4.3, CI 2.3 to 7.7), whereas the association with
      hypercholesterolemia, and co-existing heart disease decreased in strength for
      stenoses greater than 80%. Hypertension and diabetes mellitus were not found to
      be significantly with high-grade carotid artery stenoses. CONCLUSION: Smoking is
      an independent determinant of severe carotid artery stenosis in patients with
      focal cerebral ischemia.

PMID- 10598331
TI  - [In Process Citation]
AB  - On the basis of a representative paper and pencil survey with office based
      psychiatrists, neurologists, psychiatric out-patient clinics and psychiatric
      wards/hospitals it is shown that in Germany in 1997 about 136,000 adult patients
      with diagnosed schizophrenia (F20 according to ICD 10) are attended by
      specialists. 75.4% of these patients are in attention of office based
      specialists, and 21.3% are attended by out-patient clinics. According to the
      details of psychiatric wards and hospitals, 3.3% of the patients are under long
      term (> 1 year) medical attention at hospitals. The amount of schizophrenia
      patients being under attention of specialists corresponds to 0.21% of the German
      population > 18 years. For patients who receive out-patient treatment it is shown
      that they are under medical attention at hospitals for average 22 days per year,
      and for 3.4 days they are under medical attention at rehabilitation centers.

PMID- 10598332
TI  - [In Process Citation]
AB  - In this survey 16 cases were analysed where members of the Health Service
      repeatedly committed homicides of patients in hospitals and nursing-homes. The
      data were selected from legal documents and publications. The object was to
      receive detailed information about the victims, the offenders and the places
      where the crimes were committed. The working environment was examined with regard
      to the work-place atmosphere, the position of the offender in the social order,
      persistent conflicts at work and how the first internal warnings concerning
      suspicious behaviour were dealt with. Each invidivual case was analysed in order
      to find out whether there are any indicators that could serve as a warning with
      regard to homicides of patients. The data were also analysed as to specific
      similarities concerning the victims, the offenders and the respective working
      environment. The main conclusion of this study is that homicides of patients in
      hospitals and nursing-homes become more unlikely if the fact that these things do
      happen is known and no longer tabooed.

PMID- 10598333
TI  - [In Process Citation]
AB  - Empirical studies showed that alcohol and drug addicted delinquents are
      problematic patients whose treatment is under strain due to difficulties
      resulting from hospitalisation by court. In the course of treatment it turned out
      that there is usually a high rate of relapses to addictive drugs and alcohol as
      well as break-outs. Between 11 and 47% of the patients have to be returned to the
      penal system. This study investigates which patient groups can very probably be
      treated successfully and which patient groups have to be classified as risk
      groups. An analysis of files of 103 concluded treatments at a psychiatric centre
      in South Germany, ZfP Weinsberg (Massregelvollzug according to section 64 German
      Penal Code), showed that the factors low age at the time of hospitalisation,
      lacking education and vocational qualification, drug addiction, early first-time
      sentencing, and a broken home in the family of origin are accompanied by
      unsuccessful treatment attempts. A cluster analysis on the basis of these factors
      identified several patient groups: a completely successful group (delinquents
      with several previous convictions and a high tendency to offences), a very
      probable unsuccessful group (delinquents with several previous convictions and a
      high tendency to offences), and a poorly predictable group (young patients with
      an early onset of delinquency). The results suggest to thoroughly consider the
      "prospect of successful treatment" according to section 64 German Penal Code
      regarding identified risk groups when deciding on hospitalisation by court.
      Considering the profile of unsuccessful patients, it is advisable to supplement a
      therapy programme focussing on the treatment of drug addiction with elements that
      focus on delinquency.

PMID- 10598334
TI  - [In Process Citation]
AB  - Pure word deafness (auditory verbal agnosia) is characterized by an impairment of
      auditory comprehension, repetition of verbal material and writing to dictation
      whereas spontaneous speech production and reading largely remain unaffected.
      Sometimes, this syndrome is preceded by complete deafness (cortical deafness) of
      varying duration. Perception of vowels and suprasegmental features of verbal
      utterances (e.g., intonation contours) seems to be less disrupted than the
      processing of consonants and, therefore, might mediate residual auditory
      functions. Often, lip reading and/or slowing of speaking rate allow within some
      limits to compensate for speech comprehension deficits. Apart from a few
      exceptions, the available reports of pure word deafness documented a bilateral
      temporal lesion. In these instances, as a rule, identification of nonverbal
      (environmental) sounds, perception of music, temporal resolution of sequential
      auditory cues and/or spatial localization of acoustic events were compromised as
      well. The observed variable constellation of auditory signs and symptoms in
      central hearing disorders following bilateral temporal disorders, most probably,
      reflects the multitude of functional maps at the level of the auditory cortices
      subserving, as documented in a variety of non-human species, the encoding of
      specific stimulus parameters each. Thus, verbal/nonverbal auditory agnosia may be
      considered a paradigm of distorted "auditory scene analysis" (Bregman 1990)
      affecting both primitive and schema-based perceptual processes. It cannot be
      excluded, however, that disconnection of the Wernicke-area from auditory input
      (Geschwind 1965) and/or an impairment of suggested "phonetic module" (Liberman
      1996) contribute to the observed deficits as well. Conceivably, these latter
      mechanisms underly the rare cases of pure word deafness following a lesion
      restricted to the dominant hemisphere. Only few instances of a rather isolated
      disruption of the discrimination/identification of nonverbal sound sources, in
      the presence of uncompromised speech comprehension, have been reported so far
      (nonverbal auditory agnosia). As a rule, unilateral right-sided damage has been
      found to be the relevant lesion.

PMID- 10598335
TI  - [Cognition in psychopathology].

PMID- 10598336
TI  - [Cognition and psychopathology in schizophrenia].

PMID- 10598337
TI  - [The significance of cortical neural plasticity mapping for treatment of
      schizophrenic diseases].

PMID- 10598338
TI  - [The use of functional imaging methods for the study of cognition disorders].

PMID- 10598339
TI  - [The measurement of cognitive ability with the use of cognitive function--studies
      of labyrinth function].

PMID- 10598340
TI  - [Cognition and driving in schizophrenic patients under treatment with risperidone
      vs. haloperidol].

PMID- 10598341
TI  - [Psychological methods of cognitive deficit reduction. Experiences with a
      computer training program].

PMID- 10598342
TI  - [Cognitive performance loss: what are the consequences for patients? Results of a
      survey of psychiatrists].

PMID- 10598343
TI  - [Diagnosis and treatment of polycystic ovary syndrome].
AB  - Obesity, ultrasonic ovarian morphology, serum LH levels and LH/FSH ratio are
      inconstant symptoms of the polycystic ovary syndrome (PCOS) and are thus no
      longer essential for diagnosis. PCOS is diagnosed today by the finding of chronic
      anovulation and hyperandrogenism characterized by a high serum level of "free"
      testoterone. The other causes of hyperandrogenism, as well as anovulations due to
      hyperprolactinemia, high levels of FSH and abnormal thyroid function have to be
      ruled out. PCOS is very often associated with insulin resistance (IR) and
      hyperinsulinemia (hyper I). From in vitro and vivo studies and treatment of hyper
      I, it has been shown that the hyper I of PCOS stimulates androgen production.
      Hyper I of PCOS increases the activity of androgens: by first provoking an
      important decrease of the sex hormone binding globulin (SHBG) thus increasing the
      "free", bioactive testosterone level. and then by activating the cytochrome P 450
      c 17 alpha enzymatic system that controls androgen production. Subsequent to
      metformin administration, the reduction of hyper I and androgen serum levels
      creates a favorable condition for the resumption of ovarian function and
      clomiphene citrate action. This explains the high percentage of ovulations and
      pregnancies.

PMID- 10598344
TI  - [Current aspects of symphysiotomy. Apropos of 1 case and review of the
      literature].
AB  - Symphysiotomy is regularly performed in developing countries where cesarean
      section can be a source of significant short-term and long-term morbidity.
      However, this method can be useful in some rare occasions and should be taught in
      our countries, at least theoretically. Such a case is presented with a review
      describing the present surgical technique, its indications and limits with
      special reference to its possible complications.

PMID- 10598345
TI  - [Feasibility of the laparoscopic sub-urethral sling procedure].
AB  - OBJECTIVE: To evaluate the feasibility of the laparoscopic sling procedure, 44
      patients 26 to 66 years old (average 45) with sphincter incompetence were
      included in this prospective series between 1993 and 1999. PATIENTS AND METHODS:
      Patient selection for a sling procedure was based on urodynamic findings (average
      closure pressure was 34 cm of water). The operative procedure is described.
      RESULTS: The follow up ranged from two to 66 months (average 27.6). Seven
      conversions into laparotomy had to be performed. 35 slings could be set
      successfully. Four of these slings had to be removed during the year following
      the procedure; two because of bladder neck erosion and two because of chronic
      bladder distension. The success rate of the 35 slings is 88.6%. The overall
      complication rate is 27% including five bladder injuries, 2 urether injuries and
      one hemorrhage. Ten of the twelve complications occurred in the 12 first patients
      and the complication rate decreased to 9% in the 32 last patients. Average
      hospital stay was 4 days. CONCLUSION: The laparoscopic sling procedure seems to
      be promising in the management of refractory urinary incontinence due to
      sphincter incompetence. But it is an advanced laparoscopic procedure for
      experienced laparoscopic surgeons, needing a long learning curve.

PMID- 10598346
TI  - [Microdeletion of 22q11 and conotruncal cardiopathies: contribution of prenatal
      diagnosis].
AB  - OBJECTIVE: We report our experience on prenatal diagnosis of 22q11 deletion by
      fluorescent in situ hybridation (FISH). PATIENTS AND METHODS: From February 1997
      to April 1998, prenatal diagnosis of 22q11 deletion was performed in 13 cases of
      congenital conotruncal heart defects. FISH was carried out using D22S75
      DiGeorge's chromosome region probe. RESULTS: Microdeletions of 22q11 were
      detected in 4 fetuses with tetralogy of Fallot (3 cases) and pulmonary atresia
      with ventricular septal defect (1 case). Termination of pregnancy was performed
      in two cases for severe congenital heart defect. A third malformed fetus died
      immediately after a blood sampling procedure. The last fetus, with a tetralogy of
      Fallot malformation, was born and underwent corrective cardiac surgery. The
      dysmorphic features of this fetus was suggestive of DiGeorge's syndrome, and the
      development status was normal. CONCLUSION: Prenatal detection of 22q11 only
      played a minor role in the decision to terminate the pregnancy in our study.

PMID- 10598347
TI  - [Nuchal translucency: screening for chromosomal abnormalities and congenital
      malformations. Multicenter study].
AB  - OBJECTIVE: To value the rate of chromosomal abnormalities and evolution of
      children who had a prenatal diagnosis of fetal nuchal translucency in the first
      trimester. MATERIAL AND METHODS: Multicenter prospective study conducted in 4,582
      patients who had a first ultrasonography between 10 and 14 weeks' gestation
      (abdominal and/or transvaginal sonography). The measurement of fetal nuchal
      translucency was performed by mid-sagittal section and when it was higher than
      2.5 mm a fetal karyotype was made. RESULTS: Three hundred and fifty eight nuchal
      translucencies (> 2.5 mm) were diagnosed and 334 karyotypes were done. We found
      25 chromosomal anomalies (7.4%): 14 trisomies 21; 7 trisomies 18; 2 trisomies 13;
      one triploidy and one trisomy X. The postnatal examination of children detected
      three congenital malformations (0.9%): one facial dysmorphia, one complex
      abnormal heart anatomy and one renal agenesia. CONCLUSION: Nuchal translucency (>
      2.5 mm) is therefore a sonography sign associated with 7.4% of chromosomal
      anomalies. The distribution by size and mother ages is low. It should need
      superior larger-scale studies are needed for representative data. But this study
      shows that if fetal karyotype is normal, the incidence of congenital
      malformations seems to be the same by comparison with the general population.

PMID- 10598348
TI  - [Resistance to activated protein C and pregnancy: thromboprophylaxis with low
      molecular weight heparin].
AB  - OBJECTIVE: The utilization, during pregnancy, of low molecular weight heparin
      (enoxaparine) for obstetric thromboprophylaxis for patients with activated
      protein C resistance, following Factor V Leiden mutation. STUDY DESIGN:
      Prospective study enrolling 10 pregnant patients heterozygote or homozygote for
      Factor V Leiden mutation. They all had familial or personal history of severe
      thrombotic disease and received 40 mg per day of enoxaparine. RESULTS: No
      thrombosis or hemorrhage were recorded during pregnancies or deliveries. All the
      infants were doing well. After birth, low molecular, weight heparin were
      continued between 6 to 12 weeks accordingly allelic status and history. We
      reviewed the literature on this subject. CONCLUSION: This series confirmed the
      efficacy, safety and tolerance of low molecular weight heparins which will
      probably become the next gold standard for obstetric thromboprophylaxis.

PMID- 10598349
TI  - [Pregnancy after renal transplantation. Obstetrical follow up and long term
      outcome of the renal graft].
AB  - OBJECTIVES: To study the course of pregnancy after renal transplantation and to
      assess the impact of the pregnancy on the renal graft. MATERIAL AND METHODS:
      [corrected] Retrospective study of 20 pregnancies from 16 renal transplant
      recipients between January 1987 and December 1998. Mean patient age was 30.3 +/-
      4 years. Mean time between transplantation and the onset of pregnancy was 56.4 +/
      34.8 months. RESULTS: The main maternal complications were hypertensive
      disorders (7 cases) of which 3 preeclampsia. The mean gestational age at delivery
      was 36 +/- 3.1 weeks. Ten patients delivered prematurely of which 9 were induced
      prematurity. Nine cesarean sections were carried out either for obstetrical
      reasons or for causes not directly related to the transplantation. The mean
      neonatal weight was 2386 +/- 644 g with five small for gestational age. We did
      not observe any acute rejection. The follow up revealed six cases of chronic
      rejection. None of them seemed directly related to the pregnancy. CONCLUSIONS:
      The course of pregnancy after renal transplantation is generally uncomplicated
      without increased risk of graft lose. However, a stable renal function and an
      interval of two years or more after the transplantation are requested before
      allowing a pregnancy. Hypertension, diabetes mellitus or impaired renal function
      (creatininemia > 150 mumol/l) are contraindications for pregnancy.

PMID- 10598350
TI  - [Delivery after scarred uterus at the University Hospital Center of Dakar].
AB  - The objective of this retrospective study was to analyze the prognosis of
      delivery after previous cesarean section in Dakar University Hospital from
      January 1, 1996 to December 31, 1997. For 9,068 registered deliveries, 134 were
      on scarred uterus (1.5% of all deliveries). Average age of these women was 29
      years. Prophylactic cesarean was performed in 61 cases (45.5%). The main
      indications were multi-scarred uterus, breach presentation and macrosomy. A trial
      of labor was undertaken in the 73 other patients (54.5%), 85% were successful.
      Vaginal delivery rate was 46.3% on scarred uterus. There were no maternal deaths.
      Only one case of uterin rupture occurred in the prophylactic cesarean group.
      There were no perinatal deaths caused by trial of labor. These results confirm
      that trial of labor on scarred uterus should be the rule whenever possible, even
      when electronic cardiotocographic monitoring is not available.

PMID- 10598351
TI  - [Persistent right umbilical vein discovered by ultrasonography: prognostic value.
      Apropos of 2 cases].
AB  - Two cases of ultrasound prenatal diagnosis of persistent right umbilical vein are
      reported. Provided that no other malformations are present, this anatomy
      variation has a good prognostic.

PMID- 10598352
TI  - [Significance of post-partum diagnosis of congenital toxoplasmosis primary
      maternal infection at the end of the pregnancy].
AB  - We report two cases of congenital toxoplasmosis following maternal primary
      infection occurring late during pregnancy. These congenital infections are often
      asymptomatic at birth and can be recognized only by an appropriate serological
      screening program performed in mothers after delivery.

PMID- 10598354
TI  - [Antibiotic growth promoters for the view of animal nutrition].
AB  - From 01. 07./09. 1999 on six further antibiotic growth promoters have been banned
      -with only four substances remaining in this group of feed additives. Therefore,
      the discussion on a possible induction of bacterial resistance by antibiotic
      growth promoters, especially in potentially pathogenic bacteria, will sooner or
      later come to an end which is not least in the interest of the reputation of
      animal husbandry and food of animal origin. Unfortunately, no short-term solution
      for health problems by legislation--especially in the gastrointestinal tract-
      during rearing and the beginning of the fattening period is possible as
      experiences in Sweden have distinctively shown. Anyway, growth promoting feed
      additives were not a cure-all of rearing problems, in spite of their use
      considerable amounts of antibiotics were prescribed during this period. But
      growth promoters (especially chinoxalines) were most suitable for the prophylaxis
      of a microbial imbalance in the gastrointestinal tract. Therefore, after the ban
      of these effective representatives of feed additives the amount of prescribed
      antimicrobial drugs for metaphylaxis and therapy should be critically observed.
      The questions of practicable alternatives will be primarily addressed to the
      fields of animal nutrition, veterinary medicine and feed industry. To answer
      these questions and to evolve new solutions (as well as to check their
      suitability in practice) is considerably more intricate than simply to ban these
      substances which is more attractive for the media, however. It is no progressive
      solution to give up antimicrobial growth promoters as feed additives and to use
      the same substances (for example olaquindox) as therapeutics now (prescribed by
      veterinarians) or to switch to zincoxide or copper (in a dosage high above all
      nutrient requirements) in order to prevent postweaning problems due to E. coli.
      But one has to take into consideration the reasons for the use of antibiotics
      (growth promoters and therapeutics) or other "aids" (e.g. ZnO, Cu) in food
      producing animals (especially in beef-cattle, pigs and poultry) in "modern"
      production systems. The matter for conflict is the contrast between a minimised
      use of antimicrobial substances, as science as well as general public demand, and
      the requirements of "modern" livestock industry (rationalisation, increase in
      performance, specialisation, concentration) and general economy (save of
      resources, lowering of production costs). These well-known and expected problems
      arise in an almost exemplary manner in the case of antibiotic growth promoting
      feed additives. Therefore it is most difficult to impart suggestions to the
      persons involved as well as to the public.

PMID- 10598353
TI  - [Food as a potential vector for antibiotic resistance. 1. Relevance of residues
      and selected foodborne infections and intoxicants].
AB  - Food of animal origin has been considered as an important vector for the transfer
      of antibiotic resistances from animal to man. Such a transfer is possible by
      three ways: through antibiotic residues in food, through the transfer of
      resistant foodborne pathogens or through the ingestion of resistant parts of the
      original food microflora and resistance transfer to pathogenic microorganisms. A
      literature review and own investigations were performed in order to asses the
      potential impact of antibiotic resistance in food on the consumer health. In the
      first report Salmonella and Staph, aureus isolates were screened for their
      antibiotic resistance profiles. As a result it could be shown that residues in
      fresh meat or milk are quantitatively of minor interest. The resistance profile
      of Salmonella depended on the origin (pig or poultry), but only serovars could be
      identified which are generally not responsible for systemic infections. Staph.
      aureus isolates did not show any resistances relevant for human medicine. In
      these cases food can be considered as safe concerning its role as a vector for
      antibiotic resistances. However, a resistance monitoring seems to be necessary.

PMID- 10598355
TI  - [Increase of bacterial resistance in human medicine by resistance genes of
      bacteria from meat supplying animals].
AB  - Two different groups of bacteria carrying genes encoding for resistance to
      antibiotics may be transmitted from animals to humans via food products: a.)
      obligate infectious agents (enteric pathogens, e.g. Salmonella enterica spp.,
      Campylobacter spp., EHEC) and b) facultative pathogenic species (e.g. E. coli,
      enterococci). Thus far, it is unknown whether genes encoding for resistance to
      antibiotics from these bacteria may be transferred to bacteria in normal flora of
      the host. The transfers of genes encoding for resistance to vancomycin from
      animal sources to the mucosa of humans has been suggested. Thus, there is a
      threat that these plasmid-encoded resistance genes may also be transferred to
      other gram-positive organisms present in the human flora. Vancomycin is the
      antibiotic in reserve for treatment of infections caused by oxacillin
      (methicillin) resistant strains of S. aureus and by strains of pneumococcus
      resistant to penicillin.

PMID- 10598356
TI  - [Detection and prevalence of verotoxin-producing Escherichia coli (VTEC) in raw
      sausage].
AB  - We investigated 158 samples of shortly ripened raw sausages bought in
      supermarkets of Dessau within 4 month. In 14 (8.8%) samples Verotoxin-producing
      E. coli were detected. 13 VT-positive samples were found in the group of easily
      spread raw sausages. The 14 isolates belonged to 6 different O-serotypes. 4 VT1-,
      8 VT2- and 2 VT1/VT2-producers were found. 4 isolates belonged to serogroups
      which were already described in WHO tables and associated with EHEC infections in
      human beings. One strain of serogroup O22: H8, isolated from a "Teewurst",
      possessed the complete virulence gene combination of EHEC (eae, hlyA, stx). The
      detection procedure, already successfully used for detection and isolation of
      VTEC from raw milk, soft cheese and raw minced beef showed a sensitivity of
      approximately 10 CfU/25 g of raw sausages. It has to be considered that VTEC are
      frequently (8.8%) present in shortly ripened raw sausages. The group of easily
      spread raw sausages has a higher VTEC-contamination rate than firm raw sausages.
      Raw sausages, especially easy to spread types, belong to the risk foods for EHEC
      infections in human beings.

PMID- 10598357
TI  - [35 leptospira isolated from the vitreous body of 32 horses with recurrent
      uveitis (ERU)].
AB  - 130 vitreous samples, systematically collected in 1998 from 117 horses during
      vitrectomy, were cultured for the presence of leptospires. All horses suffered
      from equine recurrent uveitis (ERU), also known as periodic ophthalmia or moon
      blindness, and were treated surgically to combat painful attacks, and to preserve
      vision. In 35 out of 130 vitreous samples (35/130 = 26.9%), leptospires could be
      isolated. These isolates belong to the grippotyphosa serogroup (n = 31) and to
      the australis serogroup (n = 4). So, for the first time, leptospires were
      recovered from eyes in vivo in a large number of horses with ERU. Vitreous
      samples and one serum sample from each horse were also tested for leptospiral
      antibodies using the microscopic agglutination test (MAT). In 92 vitreous samples
      (92/130 = 70.7%) and 96 serum samples (96/117 = 82.0%) leptospiral antibodies
      were detected at a dilution of > 1:100. The presence of intact leptospires and
      specific antibodies in eyes affected with ERU demonstrates a local antibody
      production to leptospiral antigen. These results indicate an important
      etiological role of leptospires in equine recurrent uveitis.

PMID- 10598358
TI  - [Comparison of factor VIII:C and factor IX sensitivity of different commercial
      APTT reagents for canine plasma].
AB  - In the present study, six commercial reagents for the determination of the
      activated partial thromboplastin time (APTT) were compared with respect to their
      factor VIII:C and factor IX sensitivity for measurements of canine plasma. For
      this purpose, plasma with different levels of factor VIII:C or factor XI activity
      (100, 80, 70, 60, 50, 40, 30, 20, 15, and 10% [factor VIII:C: additionally 5%])
      was prepared by mixing pool plasma with plasma of dogs with haemophilia A or B.
      Double measurements of three different sample mixtures were carried out for each
      activity level. The sensitivity of the reagents was measured first based on the
      ratios of the coagulation time to the 100% values. In addition, the single factor
      activity (F VIII:C/IX(X0.975)), whose accompanying APTT corresponded to the upper
      limit of the reference range (97.5%-quantile, n = 50) of the respective reagent,
      was determined graphically. The APTT reflected a decrease of factor IX activity
      generally more sensitive than a reduction of factor IX activity of an identical
      degree. Based on ratios distant differences respecting factor VIII:C and factor
      IX sensitivity were found between different reagents using two way analysis of
      variance (p < 0.05). Significant differences between various reagents were also
      found with respect to the F VIII:C(X0.975) and the F IX(X0.975). These
      corresponded to values between 27 and 50% or 32 and 64%, respectively, dependent
      on the reagent. As a result, the more sensitive reagents fulfilled the demands on
      the sensitivity of APTT in humans. Based on the latter criterion the highest
      sensitivity for both factors was found for the same reagent (Pathromtin)
      consisting of kaolin as a contact activator and human placental phospholipid.
      Respecting all proofed reagents, however, no relation was found between contact
      activator and single factor sensitivity.

PMID- 10598359
TI  - [Efficacy and tolerance of a calcium-magnesium-aspartate solution in the
      treatment of hypocalcemic parturient paresis in cows].
AB  - The systemic tolerance of a solution of calcium aspartate and magnesium aspartate
      was studied in 7 cows. Intravenously administered dosages of 500 ml per cow were
      well tolerated. A twofold increase of the serum calcium concentration was
      measured. In 2 cows which were treated with 1000 ml of the solution a threefold
      increased calcium concentration and heart arrhythmia were found. The clinical
      efficacy of the solution was demonstrated in a study with 44 hypocalcemic cows. A
      long lasting increase of the serum calcium as well as an enhanced phosphorus
      concentration were measurable. In conclusion, the calcium-magnesium-aspartate
      solution seems to be an efficacious and well tolerated alternative for the
      treatment of hypocalcemia in cows.

PMID- 10598360
TI  - Issues and controversies in venous thromboembolism.

PMID- 10598361
TI  - Should a hospital without a neurologist use t-PA to treat stroke?

PMID- 10598362
TI  - A 43-year-old woman with shortness of breath.

PMID- 10598364
TI  - How physicians can help create useful clinical practice guidelines.

PMID- 10598363
TI  - The threat of bioterrorism: a reason to learn more about anthrax and smallpox.
AB  - Threats of domestic terrorism and international news about germ warfare research
      have forced us to recognize the potential menace of biological weapons. Both
      smallpox and anthrax could be used as biological weapons. It is important for
      physicians to reacquaint themselves with these diseases, because if a domestic
      attack were to occur, it might first be recognized when patients with unusual
      symptoms began presenting to hospitals and primary care physicians. In this
      article, we discuss symptoms and treatments for smallpox and anthrax, and suggest
      resources for physicians who wish to learn more about the subject.

PMID- 10598365
TI  - Hormone replacement and breast cancer: implications of the Iowa Women's Health
      Study.
AB  - Amid conflicting reports about the link between hormone replacement therapy and
      breast cancer, the Iowa Women's Health Study gives grounds for cautious optimism.
      According to the study, women on hormone replacement therapy had a higher
      incidence of breast cancer, but the excess cancers were of a "favorable"
      histologic type. This paper discusses clinical decision-making in light of the
      study results.

PMID- 10598366
TI  - Aspirin, ticlopidine, and clopidogrel in acute coronary syndromes: underused
      treatments could save thousands of lives.
AB  - Aspirin is the cornerstone of therapy for unstable angina and acute myocardial
      infarction and the foundation on which other therapies are added, both in the
      short term and the long term. Yet, despite clear data, aspirin is woefully
      underused or is often used late. Prompt administration of aspirin could save
      thousands of lives each year. Ticlopidine and clopidogrel have a synergistic
      effect when used with aspirin, and can also have a role in treating patients who
      are aspirin-resistant or have diffuse atherosclerosis.

PMID- 10598367
TI  - Early recognition of spinal cord compression in cancer patients.
AB  - Spinal cord compression is a relatively common complication of a number of
      malignant diseases. Back pain is the presenting symptom in more than 90% of
      cases. Early recognition and prompt treatment, while the patient can still walk,
      are the most important factors in preventing permanent and debilitating
      neurologic dysfunction.

PMID- 10598368
TI  - [The hypothesis of infectious etiology for idiopathic nervous system diseases:
      from the postulates of Koch to the criteria of Hill].
AB  - The evaluation of the hypothesis of an infectious etiology to some neurological
      diseases comprises four different situations. First, numerous neurological
      diseases have an obvious infectious etiology (encephilitis, meningoencephilitis).
      Second, some neurological disorders were primarily suspected to be have an
      infectious etiology, but the causative microorganism was discovered either
      longtime after the princeps description of the disease (neurologic Whipple
      disease, due to Tropheryma whippelii), or at the same time (tropical spastic para
      paresis secondary to HTLV-I infection). Third, for other neurological diseases,
      an infectious etiology that was not suspected at time of their anatomoclinic
      descriptions, was further demonstrated in the context of a generally complex
      physiopathology (Guillain-Barre syndrome and infection by Campylobacter jejuni).
      Finally, some idiopathic neurological diseases could be related to well known or
      yet unknown microorganisms, in association with some environmental factors, and
      with a particular genetic or acquired susceptibility of the host. The evaluation
      of an infectious etiology to these idiopathic neurological disorders must be
      envisioned according to 3 possibilities: 1) generally, the neurological disease
      is well defined, but its etiology remains unknown and an infectious hypothesis
      could be relevant (multiple sclerosis, post-polio syndrome, amyotrophic lateral
      sclerosis); 2) sometimes, a microorganism that is not associated with a known
      disease, and then qualified as "orphelin", could be associated with neurological
      disorders (spumaretrovirus); 3) finally, a new neurological disease could be
      associated with a known or yet unknown microorganism, directly or indirectly. In
      conclusion, some idiopathic neurological diseases could have an infectious
      etiology, with physiopathologic, diagnostic, prophylactic (vaccination) and
      therapeutic (use of anti-infectious drugs) consequences.

PMID- 10598369
TI  - [Histological changes related to scleral buckling for treatment of retinal
      detachment].
AB  - Treatment of retinal detachment frequently uses biocompatible materials to obtain
      scleral buckling. These materials are not devoid of consequences on surrounding
      tissues. In 3 eyes enucleated for failure of surgical treatment using scleral
      buckling materials, the changes prompted by episcleral implants could be
      observed. The sclera underwent both an inversion of its curvature and a reduction
      of its thickness under the material, as well as an encapsulation of the material
      was observed. While a silicone sponge was used in part to encircle one of these
      eyes, its capsular inner surface was regular and smooth. In contrast, hydrogel
      implants used in the three eyes showed a peripheral fragmentation prompting in
      two of them a typical foreign body giant cell granulomatous reaction. Changes in
      scleral curvature and scleral thinning were observed reflecting the consequences
      of the buckling procedure. The capsule formation occurred as it does for any
      nonabsorbable material implanted in tissues. Degradation and fragmentation of the
      hydrogel material suscitated a granuloma in response to fragments. These hydrogel
      specific changes should be recognized on microscopic examination of slides of
      either capsule or eyes previously in contact with this implanted material. They
      attested of the instability of hydrogel after implantation.

PMID- 10598371
TI  - Whipple's disease: benefit of the fine-needle aspiration cytology from lymph
      nodes.
AB  - We report a case of Whipple's disease with predominant neurological symptoms and
      without any clinical digestive sign. The diagnosis was suspected by fine-needle
      aspiration from an axillary lymph node and confirmed by the duodenal biopsy and
      ultrastructural results. Whipple's disease is a rare, chronic, systemic
      infectious disease. Electron microscopy and PCR on paraffin blocks are very
      helpful when histologic findings are not discriminant. On cytologic examination,
      the major differential diagnosis is mycobacterial adenitis. Here we highlight the
      possibility of diagnosis Whipple's disease on mere cytological material.

PMID- 10598370
TI  - Frozen section of lymph nodes in uterine cervical carcinoma.
AB  - The aim of this study was to evaluate the accuracy of frozen section examination
      of lymph nodes in cervical cancer. METHODS: This retrospective study was based on
      55 patients with stage Ib or IIa invasive cervical carcinoma treated by surgery
      followed by irradiation. All patients underwent a pelvic lymphadenectomy with
      frozen section analysis of lymph nodes. RESULTS: A total of 1249 nodes were
      removed (23 per patient) and 501 nodes (40%) were examined during the frozen
      section analysis. The sensitivity of frozen sections analysis in detecting
      metastatic nodes was 89%, its specificity and positive predictive value was 100%
      and its negative predictive value was 97%. CONCLUSIONS: The frozen section
      diagnosis of pelvic nodes should be performed in patients with a small cervical
      carcinoma to avoid systematic para-aortic lymphadenectomy. This is an accurate
      procedure and should be carried out on obturator, external iliac and common iliac
      nodes.

PMID- 10598372
TI  - Immunohistochemical detection of p53, mdm2, waf1/p21, and Ki67 proteins in bone
      marrow biopsies in myelodysplastic syndroms, acute myelogenous leukaemias and
      chronic myeloproliferative disorders.
AB  - The aim oof this study was to investigate the immunohistochemical expression of
      p53, mdm2, and waf1/p21 proteins in myelodysplastic syndromes (MDS), acute
      myelogenous leukaemias (AML), and chronic myeloproliferative disorders (CMPD).
      Paraffin-sections of bone marrow biopsies from 30 cases of MDS (6 cases of RAEB
      and RAEB-T) 22 AML (4 cases occurring in the setting of MDS), 16 chronic
      myeloproliferative disorders (CMPD), and 10 cases without alterations were
      investigated by immunohistochemistry for p53, waf1/p21, mdm2 and Ki67 proteins.
      P53 was detected in immature myeloid cells in 6/30 MDS (20%) and in 6/22 AML
      (27%) while it was not expressed in CMPD. Of the 6 p53 positive AML, 3 occurred
      as evolution of MDS and 3 were de novo acute leukaemias. Waf1/p21 was detected in
      5/22 (23%) AML in immature myeloid cells. Waf1/p21 was also expressed in 18/30
      (60%) MDS and 10/16 (63%) CMPD in variable proportion (5-25%) of the mature
      myeloid cells and megakaryocytes. Waf1/p21 was not detected in immature myeloid
      cells in MDS and CMPD. Mdm2 protein was expressed in 3/30 (10%) MDS in the
      immature myeloid cells and in 1/22 AML in blastic cells. The combined
      immunophenotypes of immature myeloid cells of MDS were: p53+/mdm2+/waf1-: 3,
      p53+/mdm2-/waf1-: 3, while the immunohistochemical patterns of AML were:
      p53+/mdm2-/waf1-: 4, p53+/mdm2+/waf1+: 1, p53+/mdm2-/waf1+: 1, p53-/mdm2-/waf1+:
      3. Ki67/MIB1 staining was found in at least 30% of immature myeloid cells in MDS
      and AML and in at least 20% of these cells in CMPD. In conclusion, our results
      indicate that p53 protein is overexpressed in the myeloid lineage in a proportion
      of AML and MDS, while is not detected in CMPD and normal bone marrow, p53
      expression was much more frequent in AML occurring as an evolution of MDS than in
      de novo AML. The combined immunophenotypes of p53 positive AML and MDS suggest
      that p53 overexpression may be due to mutation, in some AML and MDS cases with
      the p53+/mdm2-/waf1- phenotype. However, it would be also possible that p53
      protein accumulation is not related to p53 mutation but to inhibition of p53/mdm2
      binding due to mdm2 defects and/or other events related to cell stress signals.
      On the other hand, waf1/p21 protein overexpression without p53 expression in some
      AML could be p53-independent and may represent an attempt to control the high
      proliferation rate which was evidenced by Ki67/MIB1 immunostaining. However, the
      possibility of p21 to arrest cell-cycle, in these cases of AML, seems to be
      overridden, suggesting that cell-cycle deregulation may be involved in a
      proportion of AML.

PMID- 10598373
TI  - [Lymphoid nodules of the breast. Report of 10 cases observed in Cameroon].
AB  - The aim of this study was to present clinico-pathological aspects of breast
      lymphoid nodules in Cameroon. From the collection of the pathology laboratory of
      the Yaounde Central Hospital, all the cases of breast lymphoid nodules diagnosed
      between 1st January 1993 and 30th June 1998 were recorded. For each case, the
      following data were noted: age of the patient, clinical informations (signs and
      symptoms), microscopical aspects and histological description. 10 cases of breast
      lymphoid nodules were recorded. These were observed in women aged 19 to 50 and
      most of them were painless. All were mobile and felt by the patients before
      excision-biopsy. They were mostly found on the right and were less than 1 cm in
      diameter. Histologically, they presented as diffuse lymph node hyperplasia.

PMID- 10598374
TI  - [Bronchiolitis obliterans organizing pneumonia or BOOP. Report of a new case,
      reflections on the concept of BOOP].
AB  - A new case of bronchiolitis obliterans with organizing pneumonia (BOOP) is
      reported. The clinical, radiographical and histological characteristics of the
      BOOP are reviewed. It is a rare affection which has been described for a long
      time but the nosological situation of which among diseases of bronchioles has
      been only recently established. It corresponds to an unspecific inflammatory
      answer to a pulmonary aggression and can therefore be observed in numerous
      circumstances. It may represent a model for the understanding of the mechanisms
      of pulmonary fibrosis.

PMID- 10598375
TI  - [Fibrocartilaginous mesenchymoma of bone. A case report].
AB  - Fibrocartilaginous mesenchymoma of bone is a tumoral entity which is somewhat
      controversial. It has been delineated in 1984 by Dahlin and al. Fifteen cases
      have been reported in the literature. We report a new case which involves
      proximal humerus. X-ray data, microscopic findings and local recurrence indicate
      a low grade malignancy. Metastasis have never been reported. The main
      differential diagnosis are desmoplastic fibroma, fibrous dysplasia and
      fibrosarcoma with low grade malignancy. Treatment is surgical.

PMID- 10598376
TI  - Chondrolipomatous tumor of the breast with myoid differentiation.
AB  - Benign human breast lesions containing chondroid tissue are uncommon. Their
      classification and nomenclature are confusing. We report a case of a voluminous,
      well circumscribed painless breast mass in a 47-year-old woman. The mass had been
      present for nine years and measured 17 x 8 x 6 cm. Histologically it was composed
      of breast parenchymal elements, fat mature cartilage and fibrous tissue with
      small fascicles of eosinophilic spindle-shaped cells intensely stained with actin
      and desmin antibodies. A careful review of the literature showed only one similar
      case reported by Metcalf and Ellis in 1985 and called "choristoma". We discuss
      this terminology and the other breast lesions containing cartilage.

PMID- 10598377
TI  - [Teratoma and medulloblastoma of the cerebellum: a case].
AB  - The majority of intracranial teratoma are localized in pineal and sellar regions.
      In cerebellum, the teratoma is quite rare, the association with medulloblastoma
      is exceptional and was differentiated from medullomyoblastoma. We report one case
      of 5 years old boy with intracranial hypertension for 3 months. The cerebral
      computed tomography showed a tumor in the fourth ventricle. The histologic study
      of surgical specimens found a proliferation of component of medulloblastoma
      adjacent to mature teratoma with smooth and striated muscles, chondroid
      component, adipose tissue and epithelial elements. Our objective is to discuss
      the diagnosis, the hitogenesis and the prognosis of this tumor.

PMID- 10598378
TI  - 'All the history that you can remember'.

PMID- 10598379
TI  - Respiratory syncytial virus: an underestimated cause of respiratory infection,
      with prospects for a vaccine.
AB  - Respiratory syncytial virus (RSV) infects most people by the time they are 2
      years old and reinfects throughout life. RSV is best recognised for causing
      bronchiolitis in infants--it is one of the most important respiratory pathogens
      in childhood in industrialised countries. The clinical manifestations of RSV
      infection in adults and elderly people, from upper respiratory tract infection to
      pneumonia, are less well known. Part of the burden of winter mortality in elderly
      people is attributable to RSV infection and it may be as important a cause of
      death as influenza. Recent advances in RSV vaccines have made RSV a more
      important topic for epidemiological research and surveillance. Basic research
      required before vaccine programmes can be developed includes describing the
      natural history of RSV infection in adults, quantifying the burden of disease
      attributable to RSV, and defining the best surveillance methods with which to
      evaluate different vaccination strategies.

PMID- 10598380
TI  - Control of diphtheria: guidance for consultants in communicable disease control.
      World Health Organization.
AB  - These guidelines for the control and management of diphtheria are intended for
      consultants in communicable disease control and regional epidemiologists in
      England and Wales. They are intended to complement existing guidance from the
      World Health Organization. The guidelines cover the immediate steps to be taken
      following identification of a case, what is required to confirm the diagnosis,
      steps to be taken to minimise the likelihood of further linked cases, and what
      should be done to disseminate information after a case.

PMID- 10598381
TI  - Laboratory guidelines for the diagnosis of infections caused by Corynebacterium
      diphtheriae and C. ulcerans. World Health Organization.
AB  - These guidelines represent an application of the World Health Organization
      European Region's manual for the laboratory diagnosis of diphtheria for
      laboratories in the United Kingdom (UK), but they could be applied to
      laboratories overseas. The manual was rewritten in response to the re-emergence
      of diphtheria in eastern Europe and the emergence of other infections caused by
      Corynebacterium diphtheriae and C. ulcerans in the UK and overseas. The
      guidelines summarise our current recommendations and procedures for the
      microbiological diagnosis of infections caused by toxigenic and non-toxigenic
      isolates of corynebacteria, with particular reference to C. diphtheriae and C.
      ulcerans.

PMID- 10598382
TI  - Guidance on the investigation and management of occupational exposure to
      hepatitis C. PHLS Advisory Committee on Blood Borne Viruses.
AB  - This document updates previous PHLS guidance on the risks and management of
      occupational exposure to hepatitis C. In line with recent guidance from the UK
      Health Departments, the PHLS now recommends that all source patients, subject to
      appropriate consent, should be tested for evidence of hepatitis C infection. A
      baseline serum should be obtained from the exposed health care worker and stored
      for at least two years. Health care workers exposed to known infected sources
      should be followed up at six, 12, and 24 weeks after exposure. Serum taken at six
      and 12 weeks should be tested for hepatitis C virus (HCV) RNA and serum taken at
      12 and 24 weeks for anti-HCV. Health care workers exposed to a source believed
      not to be infected do not require active follow up for hepatitis C unless
      requested or if they develop symptoms or signs of liver disease. Management of
      personnel exposed to a source whose hepatitis C status is unknown or a source
      unavailable for testing will depend upon a risk assessment by a designated
      doctor. Health care workers who are found to be positive for HCV RNA or antibody
      to hepatitis C should be referred to an appropriate consultant for consideration
      of early treatment.

PMID- 10598383
TI  - Transmission of Vero cytotoxin producing Escherichia coli O157 infection from
      farm animals to humans in Cornwall and west Devon.
AB  - A study of Vero cytotoxin producing Escherichia coli (VTEC) O157 infections in
      Cornwall and West Devon was conducted to identify associations between human
      infection and contact with farm animals. In three years from November 1994 to
      October 1997, 63,000 stool specimens were submitted to four participating
      microbiology laboratories and screened for E. coli O157. Sixty-nine confirmed
      cases were interviewed to assess the extent of any direct or indirect contact
      with farm animals. Nine out of 22 investigations conducted on farms--in which
      animal rectal swabs, faecal specimens, fore-stream milk samples (first draw-off
      from teats), and various environmental samples were tested--yielded VTEC O157. In
      seven incidents one or more isolates from animals were indistinguishable from the
      isolate(s) from the human case(s) using phenotypic and genotypic subtyping. Cases
      associated with animal contact included farm visitors, holidaymakers, and members
      of farming families and farm workers.

PMID- 10598384
TI  - Enhanced surveillance of meningococcal disease in the West Midlands: 1996 to
      1998.
AB  - Surveillance of meningococcal disease is vital if we are to respond to a changing
      burden of disease, but current sources of routine data suggest different trends.
      A scheme for enhanced surveillance of meningococcal disease began in the West
      Midlands in January 1996 using several data sources, including case reporting
      from consultants in communicable disease control, data from the PHLS
      Meningococcal Reference Unit, and monitoring of statutory notifications and
      laboratory reports. One thousand two hundred and twenty-eight cases of probable
      meningococcal infection were identified in three years (1996-1998), 594 of which
      were laboratory confirmed. Routine data for the same period yielded smaller
      totals--920 notifications and 412 laboratory reports--suggesting that these
      sources underestimate incidence by 25% to 30%. Diagnosis by polymerase chain
      reaction became increasingly important, and accounted for 38% of confirmed cases
      in 1998. A significant excess of male cases was observed (p < 0.01), most obvious
      in children under 5 years of age. There was no increase in N. meningitidis C2a
      strains, which had been identified as a threat nationally. A national system of
      enhanced surveillance has now been set up to inform programmes that aim to reduce
      the burden of meningococcal infection.

PMID- 10598385
TI  - Influenza activity in England and Wales: October 1998 to June 1999.
AB  - Influenza activity in England and Wales in the winter of 1998/1999 reached the
      highest weekly levels seen since the epidemic of 1989/1990. Activity peaked at
      Christmas and the New Year, adding to the winter pressures on general
      practitioner and hospital services. Adults aged 65 years and over consulted with
      general practitioners at the highest rates. Outbreaks of influenza or flu-like
      illness occurred in several schools and nursing homes and, in June 1999, on a
      British cruise ship in the Mediterranean. Deaths from all causes reached a higher
      peak in week 1 of 1999 than occurred in the peak week of the influenza epidemic
      of 1989/90.

PMID- 10598386
TI  - Legionnaires' disease in residents of England and Wales: 1998.
AB  - Two hundred and twenty-six cases of legionnaires' disease who acquired infection
      in 1998 have been reported to the PHLS Communicable Disease Surveillance Centre.
      Twenty-five cases (11%) were reported to have died. One hundred and fifteen cases
      were associated with travel, either abroad or in the United Kingdom, three cases
      acquired infection in hospital, and the remaining 108 were presumed to have
      acquired infection in the community. Thirty-five cases were linked to industrial
      or community associated outbreaks in England and Wales, 22 cases to outbreaks or
      clusters abroad, and the remaining 169 cases (75%) were reported as single cases.
      The proportion of cases diagnosed by detection of urinary antigen has continued
      to increase; in 1998 it contributed to the diagnosis of 117 cases.

PMID- 10598387
TI  - Legionella infections in Scotland: 1998.

PMID- 10598388
TI  - Management of occupational exposure to HIV--what actually happens.
AB  - A year after the Department of Health issued guidelines on post exposure
      prophylaxis (PEP) for health care workers exposed to HIV, we conducted a
      telephone survey of occupational health nurses and junior doctors in London
      teaching hospitals, to assess implementation of the guidelines and awareness
      among junior doctors of local policies. The management and administration of PEP
      for HIV differed considerably between hospitals. Many junior doctors did not know
      what to do in the event of a needlestick injury. Both the implementation of and
      the briefing of staff about current management policies need to improve.

PMID- 10598389
TI  - Pneumococcal vaccine uptake in medical patients discharged from a district
      hospital.
AB  - A survey of 400 patients discharged from medical wards found that 161 (40%) had
      risk factors for severe pneumococcal infection, but that only half of these had
      received pneumococcal vaccine. Improved vaccine uptake in high risk patients
      could be achieved by universal vaccination of people aged over 65 years.

PMID- 10598390
TI  - Cases of meningococcal infection and bacterial meningitis occur every day and
      require an 'out of hours' public health response.
AB  - Analysis of hospital admissions data over three years in Ireland showed that the
      1478 cases of meningococcal disease and meningitis were admitted at the same
      frequency every day of the week. The need for and the cost effectiveness of an
      'out of hours' service in order to manage the community aspects of meningococcal
      disease/meningitis requires further attention.

PMID- 10598391
TI  - Legionella pneumonia from a novel industrial aerosol.
AB  - After a worker from a plastics factory was diagnosed with legionella pneumonia it
      was learnt that a retired employee at the factory had been in hospital with a
      serious chest infection six months before and legionella pneumonia was diagnosed
      in retrospect from stored serum. The likeliest common source was a machine
      cooling system that took water from an uncovered water tank outdoors (from which
      Legionella pneumophila was isolated) and which generated an aerosol through a
      crack in the flow meter sight glass.

PMID- 10598392
TI  - Innovation in vaccine provision for drug users.

PMID- 10598393
TI  - In saliva veritas.

PMID- 10598394
TI  - Automation of the polymerase chain reaction. Part 4. Detecting and characterising
      the product.

PMID- 10598395
TI  - Document control and document management.
AB  - Most schemes for the accreditation (e.g. United Kingdom Accreditation Service)
      and certification (e.g. BS EN ISO 9002) of laboratories include a requirement to
      establish and maintain procedures for the management and control of documents
      generated internally. Such documents include policy statements, procedures,
      specifications, and some notices and memoranda. Organisations benefit from using
      agreed and approved information and from knowing that staff are using agreed and
      approved methods in their operating procedures. Document control systems are
      likely to become compulsory as accreditation schemes, such as Clinical Pathology
      Accreditation (CPA) for clinical microbiology laboratories, align with
      international standards. The Technical Services Division (TSD) in PHLS
      Headquarters has been developing a control system for various documents that it
      issues to the PHLS and control of documentation that forms the TSD quality
      system. The document control system has recently developed into a document
      management system that provides a mechanism for managing all documents generated
      or received by the division. TSD's approach is described here to provide
      laboratories and other organisations with ideas for how they could set up or
      develop their own document management system to improve accessibility to
      information.

PMID- 10598396
TI  - The sick building syndrome.
AB  - The phenomenon of 'sick building syndrome' is associated with several factors
      rather than a single readily and directly observable cause and various symptoms
      and behaviours rather than one clinical syndrome. Like another modern
      occupational ill health problem--repetitive strain injury--its existence may be
      questioned or doubted by the employers of staff who work in modern buildings.
      This article looks at what makes a building sick and how a sick building can
      affect its occupants. It guides staff in the recognition of the syndrome and
      suggests ways to reduce the risks of working in a building whose poor design or
      maintenance constitutes a hazard for occupants.

PMID- 10598397
TI  - Monitoring the impact of the serogroup C meningococcal conjugate vaccination
      programme.

PMID- 10598398
TI  - Monitoring the transmission of antiviral resistance in HIV in the United Kingdom.

PMID- 10598399
TI  - The shape of the inferior horn of the lateral ventricle in relation to collateral
      and occipitotemporal sulci.
AB  - The shape of the inferior horn of the lateral ventricle has been investigated in
      100 (50 right and 50 left) human brain hemispheres which were fixed in 40%
      formaldehyde solution and cut frontally. It has been found that the shape of the
      inferior horn depends on the course and depth of the collateral and
      occipitotemporal sulci. In most cases a part from two main ventricular surfaces:
      the hippocampal and superolateral, there is one surface more, either the inferior
      collateral eminence (Type I--97% of cases in the posterior part of the inferior
      horn, 49%--in the middle and 42%--in the anterior part) or the inferolateral,
      adjecent to the occipitotemporal sulcus (Type II--0%, 26% and 35%, respectively).
      In a few cases both collateral eminence and inferolateral surface were present
      (Type III--3%, 2% and 6% respectively). In type IV neither collateral eminence
      nor the inferolateral surface appeared (0%, 23%, 17% respectively). The authors
      suggest to designate the inferolateral surface, not mentioned in the literature,
      as the occpitotemporal eminence (of the inferior horn).

PMID- 10598400
TI  - The oculomotor nuclear complex at the end of the embryonic period (stage 23).
AB  - Investigations were made on serial sections of human embryos at developmental
      stage 23 (56 days). The oculomotor complex in embryos at this stage consists of
      lateral, median, and accessory nuclei. The lateral (chief) nucleus forms the
      greatest part of the oculomotor complex and it is subdivided into ventromedial
      and dorsolateral groups. Between the posterior portions of lateral nuclear groups
      is the median nucleus. Dorsally and medially to the lateral nucleus is the
      accessory (parasympathetic) nucleus.

PMID- 10598401
TI  - Length of the femur and tibia in human embryos aged 7 and 8 weeks.
AB  - In 34 human embryos of 7th and 8th week the length of femur and tibia was
      measured. It was shown that the length of femur increased from 2.65 mm to 5.10 mm
      during investigated period. These values for tibia were 2.09 mm and 3.21 mm.

PMID- 10598402
TI  - Ultrastructural observations of the neurocytes in pterygopalatine ganglion of
      Japanese quail (Coturnix coturnix v. Japonica).
AB  - Cells of the pterygopalatine ganglion in quail are elliptical, oval and often
      spindle shape. They have single nuclei, which are spindle or lentiform in shape.
      The rough endoplasmic reticulum was observed in a great amount, especially in the
      vicinity of nucleus. It was organised in structure corresponding to Nissl's body.
      The mitochondria are present mainly at the periphery of the cells. Several flat,
      elongated cisterns form the Golgi apparatus. There are a few lysosomes, mostly
      primary ones. Profiles of the end section of axons and button synapses were
      observed. They contain mainly agranular vesicles.

PMID- 10598403
TI  - Long-term effect of neonatal monosodium glutamate (MSG) treatment on reproductive
      system of the female rat.
AB  - The study aimed at determining effects of monosodium glutamate (MSG), introduced
      in the perinatal period, on the reproductive system of sexually mature female
      rats. In days 2, 4, 6, 8, 10 the newborns received s.c. injections of MSG (4 mg/g
      body weight) or 2% NaCl solution. When the animals reached the age of 6, 12 or 18
      months, their ovaries and uteri were isolated for histological and morphometric
      studies while in their sera estradiol level was estimated by the RIA technique.
      The perinatal injection of MSG was found to decrease relative weights of ovaries
      and uteri. In the ovaries increased numbers of primordial follicles and decreased
      numbers of graafian follicles were detected. Also the thickness of endometrium
      and of the epithelium, which lined the endometrium, were lowered in females,
      which received perinatal injections of MSG, as compared to the controls. Serum
      estradiol level in MSG injected females was lowered at the age of 12 and 18
      months. In 12 and 18 month old females the alterations were accompanied by
      obesity and a decreased body length.

PMID- 10598404
TI  - Variations in ovarian arteries in fetuses and adults.
AB  - The present studies were carried out on 80 female fetuses and adults, aged 20 to
      28 weeks and 18 to 90 years, respectively. Attention was paid to the place of
      origin of ovarian arteries from the aorta or renal artery, the location of these
      vessels in relation to the trunk of inferior vena cava, and to their courses
      relative to the renal veins. Four most frequently encountered types of ovarian
      artery courses were identified, and subsequently the discovered variations of
      basic types were described.

PMID- 10598405
TI  - Skeletopy of the brachiocephalic trunk and the common carotid arteries in human
      fetuses.
AB  - By means of anatomical and radiological methods and with help of the Computer
      Digital Image Analysis System the brachiocephalic trunk and the common carotid
      arteries in relation to the vertebral column were studied in 60 human fetuses.
      The vessels were found to be between the upper borders: of the third thoracic
      vertebra and the first cervical vertebra (Th3s-C1s). In the 6th month of the
      ontogenetic development the vessels descended by one vertebra and established
      their location in the next prenatal compartment (8-9) between the lower borders:
      of these same vertebra (Th3i-C1i). We have counted the skeletopie age correlation
      coefficients of these vessels and found the diminuation of their values. Sexual
      skeletopic dimorphism have not been observed. These investigations have clinical
      implications.

PMID- 10598406
TI  - A spatial configuration of the lumbo-sacral part of the vertebral column--an
      importance in the etiology of low back pain.
AB  - Chronic low back pain is a very important problem in our civilization. Does a
      spatial configuration of the vertebral column have an influence on the occurrence
      of chronic low back pain? Author has compared values of Whitman-Fergusson's angle
      and Cobb's angle for standing position in patients and controls. No significant
      differences between both groups have been founded. Beside of this, inclination od
      sacrum to a horizontal line has had an influence on a value lumbar lordosis in
      both groups.

PMID- 10598407
TI  - The significance of radiometry in examination of flexibility referring to part
      lumbo-sacralis of the vertebral column in cases of chronic low back pain.
AB  - A drop in flexibility of the vertebral column is connected with chronic low back
      pain. Qualification of vertebral column flexibility is not so simple. Beside of
      clinical methods (for example Schober test), we can use a radiological method.
      Comparing values of Whitman-Fergusson's angle and Cobb's angle for standing and
      supine-lying position, author has stated a significant drop in elastic properties
      of the vertebral column in patients with chronic low back pain.

PMID- 10598408
TI  - Formation of multinucleated variant endothelial cells in vitro and investigation
      of MVECs' features.
AB  - Multinucleated variant endothelial cells (MVECs) have frequently been observed in
      the human aorta, and the ratio of MVECs to typical endothelial cells correlates
      well with the severity of atherosclerosis. MVECs showed no capacity of
      proliferation in vitro, making their study extremely difficult. We attempted to
      obtain reproducible MVECs in vitro in order to understand their functional
      characteristics and their roles in atherosclerosis. This study was designed to
      derive MVECs from human umbilical cord vein endothelial cells (HUVECs) with
      different reagents such as Meso-4,4'-(2,3-butanediyl) bis (2,6-piperazinedione)
      (ICRF-193), low density lipoprotein (LDL), interleukin-4 (IL-4), polyethylene
      glycol (PG), H2O2, and linoleic acid hydroperoxide (LAHO). We found that 10
      microM ICRF-193 was most effective in inducing MVECs. We then investigated the
      features of aortic endothelial cells (AECs) and ICRF-193 treated HUVECs (I
      HUVECs) in the following four aspects: morphology, by light microscopy; cell
      cycle phase, by uptake of BrdU; expression of endothelial cell (EC) related
      markers such as von Willebrand Factor (vWF), endothelin-1 (ET-1), prostacyclin
      (PGI2) and intercellular adhesion molecule CD34 by immunocytochemistry; and
      biological activity by analyzing their uptake of low density lipoprotein (LDL).
      Furthermore, we compared aortic MVECs (AMVECs) and other aortic endothelial cells
      (A-others), as well as A-MVECs and ICRF-193 induced MVECs (I-MVECs) in every
      parameter examined. We found: 1. Compared with A-others, A-MVECs expressed more
      vWF (p < 0.01), more ET-1 (p < 0.05) and less CD34 (p < 0.01). In the uptake of
      LDL, A-MVECs took up more nLDL than A-others; 2. Both A-MVECs and I-MVECs
      contained multiple nuclei, but the nuclei differed in shape. A-MVECs and I-MVECs
      were similar in the nuclear incorporation of BrdU, in the uptake of nLDL and
      oxLDL, and in the expression of vWF, ET-1 and PGI2, but different in the
      expression of CD34 (p < 0.01). Our findings suggested that A-MVECs may transfer
      more plasma LDL to the subendothelial space because they took up more LDLs. I
      MVECs were similar to A-MVECs morphologically and functionally. Thus, I-MVECs
      could be considered as substitutes in the study of A-MVECs.

PMID- 10598409
TI  - [A case of successful thromobolytic therapy in a patient with cerebral embolism
      during angiography].
AB  - We report a case of successful thromobolytic therapy in a patient with cerebral
      embolism during angiography. A 57 year-old male lost his consciousness during
      angiography. His neurologic symptoms were semi-comatose and right oculomotor
      palsy. According to these symptoms, we estimated the lesion in the right
      midbrain. Immediately after we denied a cerebral hemorrhage by computed
      tomography, we infused 60,000 u of urokinase intravenously within an hour from
      the onset followed by diffusion weighted magnetic resonance imaging (DW-MRI). DW
      MRI showed hyper-intense lesion in the midbrain. We sequentially performed
      thrombolytic therapy with urokinase by selective cerebral angiography within
      three hours from the onset. His symptoms gradually resolved, but his
      consciousness was still confused state. His all neurologic symptom completely
      resolved in the next day after hyperbaric oxygenation therapy.

PMID- 10598410
TI  - Transcriptionally targeted in vivo gene therapy for carcinoembrionic antigen
      producing adenocarcinoma.
AB  - Inoperable adenocarcinoma in colon or lung shows resistance to conventional anti
      cancer therapy. For these cancers, the feasibility of transcriptionally targeted
      killing of carcinoembryonic antigen (CEA)-producing adenocarcinoma cells was
      investigated. Adenovirus vectors carrying a CEA promoter to express E. coli lacZ
      (AdCEALacZ) or herpes simplex thymidine kinase (AdCEATK) were made and their in
      vitro and in vivo tumoricidal effects on CEA-producing or non-producing colon and
      lung cancer cells were evaluated. In vitro infection with AdCEALacZ showed
      significantly higher CEA promoter-driven lacZ expression in CEA-producing
      adenocarcinoma cells including VMRC-LCD and LoVo than in CEA-non-producing cells.
      AdCEATK-infected LoVo showed higher sensitivity to ganciclovir than control
      vector-infected LoVo or AdCEATK-infected HeLa both in vitro and in subcutaneously
      implanted tumors of nude mice. Moreover, total tumor elimination in vivo was
      achieved by either pre-infection of as few as 30% of cells comprising tumors or
      by direct in vivo injection of AdCEATK to pre-established LoVo tumors. In
      addition, CEA promoter-driven lacZ expression in LoVo cells was enhanced by the
      addition of interleukin-6 (IL-6) in vitro. These results provide a rationale for
      CEA-promoter-driven, adenovirus-mediated gene therapy for CEA-producing
      adenocarcinomas in colon and lung with reduced toxicity to normal cells.

PMID- 10598411
TI  - Brain metastasis from hepatocellular carcinoma after radical hepatectomy.
AB  - Brain metastasis from hepatocellular carcinoma (HCC) is a rare, yet perplexing
      problem in patients with cancer. We report on 5 patients with metastasis of HCC
      to the brain after radical hepatectomy. Intrahepatic recurrence occurred in 3
      patients, and distant metastasis to sites other than the brain was observed in 3
      patients (lung, 2; bone, 1). The symptoms for brain metastasis included headache,
      hemiparesis, and vomiting. Hemorrhage was found in 4 of 5 patients. All patients
      had a single nodular lesion in the brain. The alpha-fetoprotein levels were more
      than 10,000 ng/ml in 4 patients. Two patients underwent surgical resection, 1
      received cranial irradiation, and 2 were administered corticosteroids. The
      interval between diagnosis of the primary cancer and detection of brain
      metastasis ranged from 2 to 54 months. The mean survival period was only 3 months
      after diagnosis of brain metastasis. All 5 patients died of neurologic causes.
      Because no effective treatment for brain metastasis from HCC is available,
      further study is needed.

PMID- 10598412
TI  - Infrequent microsatellite instability in papillary carcinomas of the thyroid.
AB  - The aim of the present study was to confirm the frequency of microsatellite
      instability in thyroid cancers. We investigated 26 patients suffering from
      thyroid cancer (25 papillary carcinomas, 1 follicular carcinoma) using 8
      microsatellite markers. Microsatellite instability (MSI) was found in two (7.7%)
      papillary carcinomas. Our data indicate that MSI is a relatively rare event and
      may seldom contribute to the carcinogenesis of papillary carcinomas of the
      thyroid.

PMID- 10598413
TI  - Irreducible juxta-epiphyseal fracture due to entrapment of extensor hood: a case
      report.
AB  - A case of irreducible juxta-epiphyseal fracture of the proximal phalanx of the
      little finger is presented. The extensor hood was trapped under the proximal end
      of the distal fracture fragment and open reduction was necessary. An open
      reduction was performed using the dorsal approach, with good results.

PMID- 10598414
TI  - Two asymptomatic cases with sarcoidosis demonstrated sequential evolution from
      radiographic stage I to III within five years.
AB  - There are no guidelines regarding the treatment of pulmonary sarcoidosis.
      Generally, oral corticosteroids are considered the first-line treatment for
      symptomatic patients with pulmonary sarcoidosis. We report here two Japanese
      cases with pulmonary sarcoidosis who demonstrated sequential evolution from
      radiographic stage I to III within five years. Although these two cases had no
      symptoms, persistent, progressive pulmonary involvements were observed on chest X
      ray. Considering the effectiveness of corticosteroids on patients with
      radiographic type II or III sarcoidosis reported by the British Thoracic Society,
      corticosteroid therapy might be a choice even in asymptomatic cases, if they
      demonstrate developing pulmonary involvement.

PMID- 10598415
TI  - Prevention of transmission of blood-borne diseases--a welcome beginning but a
      lost opportunity.

PMID- 10598416
TI  - Optimal management of extradural haematoma.

PMID- 10598417
TI  - The Barker hypothesis.

PMID- 10598418
TI  - Treatment and management of psoriasis.

PMID- 10598419
TI  - Treatment compliance in the mental health service.

PMID- 10598420
TI  - Hepatitis A outbreak in an institution.
AB  - In February 1996, four serologically confirmed cases of hepatitis A virus (HAV)
      occurred in one household. Investigation showed that the source was a family
      member with sub-clinical HAV who attended a Unit for Learning Disabilities.
      Reports of two further cases in the institution followed and control measures
      were instigated. Contacts were unwilling to accept human normal immunoglobulin
      (HNIG). Following salivary antibody and serological testing, hepatitis A vaccine
      was offered to the non-immune. An investigation found that sub-clinical infection
      was significantly associated with being less than 5 years old (RR = 6.07, p <
      0.005) and being in one particular classroom (RR = 6.21, p < 0.0005). None of the
      staff in the institution became infected. In all, 31 cases of hepatitis A (18
      clinical and 13 subclinical cases) occurred. This paper (a) describes an outbreak
      of hepatitis A (b) refers to the use of a salivary antibody test (assay
      performance to be published elsewhere) (c) identifies factors associated with the
      acquisition of HAV and (d) endeavours to assess the effectiveness of the vaccine
      to contain the outbreak.

PMID- 10598421
TI  - The use of basic life support kits in general practice.
AB  - Donegal is a predominantly rural area with many general practices situated
      considerable distances from a district hospital. Fifty Life Support Kits were
      supplied to General Practitioners by the Donegal Pre-Hospital Emergency Care
      Project in 1995 following appropriate training. This is a survey of the use of
      items in these kits. To determine the frequency of use of the equipment, the type
      and location of the incidents, the kit items utilised and patient outcome.
      Retrospective questionnaire survey of 49 participating GPs. 208 patient incidents
      were described by 46 doctors (average 4.5 per doctor) Most incidents were outside
      the surgery (88.24%). Road Traffic Accidents (36%) were the commonest reason for
      use, followed by cardiac emergencies (28%), other medical emergencies (14%) and
      other trauma (11%). All items except the burns sheet had been used. The most used
      items were cannulae, (64.7% of incidents) and fluids (50.9% incidents). Other
      useful items were emergency drugs, dressings, collars, airways, suction and
      torch. Regarding outcome, 162 patients required hospital transfer and 25 died.
      Eleven did not require hospital treatment. The participating doctors judged that
      the basic life support kits positively contributed to outcome in 79.4% of cases
      described. Basic Life Support kits contribute to the pre-hospital care of
      patients when used by GPs with immediate care training.

PMID- 10598422
TI  - Nocturnal nasal intermittent positive pressure ventilation (NIPPV) therapy for
      chronic respiratory failure: long-term effects.
AB  - The development of positive pressure ventilation delivered through a nasal or
      face mask has greatly expanded the use of non-invasive ventilation in patients
      with chronic respiratory insufficiency, particularly during sleep. Disorders
      ranging from neurologic and neuromuscular, such as polio and muscular dystrophy,
      central alveolar hypoventilation, thoracic cage disorders such as kyphoscoliosis,
      and pulmonary disorders such as COPD, particularly of the blue-bloater type. The
      relative hypoventilation that is common to each condition is due to varying
      combinations of an inadequate respiratory drive and an increase in the work of
      breathing. Previous studies have shown sustained reversal of awake hypercapnia in
      patients with alveolar hypoventilation syndrome using nocturnal NIPPV. We
      analysed 10 consecutive patients with chronic respiratory insufficiency due to
      diverse aetiologies over a period of time using long-term domiciliary nocturnal
      NIPPV. Awake hypercapnia and hypoxaemia improved in nine patients over time and
      deteriorated in one patient. There was no significant change in pulmonary
      function apart from one patient with progressive muscular dystrophy who
      deteriorated. A considerable reduction in the need for subsequent hospital
      admission was noted in the group as a whole following institution of NIPPV. We
      conclude that nocturnal NIPPV improves awake gas exchange in patients with
      chronic respiratory failure.

PMID- 10598423
TI  - Reporting delay in the AIDS Surveillance System of the Eastern Health Board.

PMID- 10598424
TI  - An acute presentation of unilateral diaphragmatic agenesis in adulthood.

PMID- 10598425
TI  - [Development of Italian research in anesthesiology and intensive care].
AB  - The development of the Italian research in Anaesthesia and Intensive Care
      medicine has been evaluated by comparing the total number of papers in this field
      and the number of the Italian papers in this field published in the years 1977,
      1987, 1997. The results showed: a) an increase of the total number of papers
      published in the indexed journals dedicated to Anesthesia and Intensive Care with
      an increase higher than 50% per decade. In the same period the number of Italian
      papers increased from virtual representation (1 paper/year) to 19 papers per year
      in 1997. b) The papers dedicated to intensive care medicine showed a similar
      increase. In spite of this, the indexed scientific production of the Italian
      scientific community remains underexpressed.

PMID- 10598426
TI  - Hyperventilation in head injuries: who, when, which ... how long.

PMID- 10598427
TI  - [Comparison of manual infusion of propofol and target-controlled infusion:
      effectiveness, safety and acceptability].
AB  - BACKGROUND: Diprifusor TCI is a newly developed target-controlled system for the
      infusion of propofol. Purpose of this study is to evaluate the acceptability,
      efficacy and safety of Diprifusor TCI in comparison with the manually controlled
      technique. METHODS: This multicentre, randomised, parallel group study was
      carried out in 160 patients undergoing surgical procedures of 10 min to 4 h
      duration in 8 centres. In each centre 20 male or female patients, aged > or = 18
      years, ASA I-III were randomised to treatment with either Diprifusor TCI (TCI
      group--80 patients) or manually controlled infusion (MI group--80 patients).
      Assessments included hemodynamics; adverse events, including accidents, actual or
      possible; recovery times; anesthetist ratings of quality of induction and
      maintenance, and of ease of control and use of technique. Ratings were summed up
      in a global quality score (study end-point). RESULTS: Induction doses were
      significantly lower (median values 1.4 vs 1.9 mg/kg) and maintenance infusion
      rate significantly higher (median values 10.2 vs 8.8 mg/kg/h) in the TCI group;
      anesthetists ratings obtained maximum scores in most patients of either group,
      but more frequently in the TCI group, with significant differences for ease of
      control (good 91.2% TCI vs 74.7% IM; adequate 8.8 vs 21.5%; poor 0 vs 3.8%), and
      of use of technique (good 91.2% TCI vs 60.8% IM; adequate 8.8 vs 39.2%); the
      global quality score showed a significant advantage for the TCI system (median
      value 12 vs 11). CONCLUSIONS: The TCI technique is effective and safe, and has a
      better acceptability than the manually controlled infusion technique.

PMID- 10598428
TI  - [Epidural analgesia for painless delivery. Our experience].
AB  - BACKGROUND: We know that a stress condition causes hormonal responses (cortisol,
      prolactin, TSH, ACTH, catecholamines, beta-endorphines). This hormonal "storm"
      causes metabolic and haemodynamic changes that can get worse postoperative
      outcome as well as birth. Analgesia for labour is an anesthesiological procedure
      which spreading in Italy resulted very difficult, for instance, especially in
      southern Italy, "old popular believes" (such as paralysis risk after lumbar
      puncture, Post-Dural Puncture Headache (PDPH) and the confusion between epidural
      and subdural anesthesia). METHODS: In front of these problems we report our
      experience in this field. Experimental plan: in our retrospective study we
      examined painless labour cases and we compared them with natural labour cases
      without analgesia. ENVIRONMENT: women of this study were pregnant admitted in
      obstetrics department of our hospital at the end of pregnancy. PATIENTS: pregnant
      women who wanted epidural analgesia were 50 (group A); data group A were compared
      with data of 50 pregnant women who refused analgesia (group B). TECHNIQUE:
      beginning labour, when cervical dilatation was 3 cm and foetal head was going
      down we performed epidural puncture and positioned, catheter in epidural space
      giving opiate and local anesthetic drugs using "top-up" method. DATA: we compared
      APGAR-score after birth and the judgement expressed by women of the two groups.
      RESULTS AND CONCLUSIONS: APGAR-score in new-borns with epidural analgesia in
      higher than new-born without epidural analgesia; furthermore, patients who choose
      painless labour expressed a better judgement than women who refused epidural
      analgesia.

PMID- 10598429
TI  - [Comparison of SAPS II, MPM II24 and SAPS in intensive care].
AB  - OBJECTIVE: To compare the performance of the new SAPS II, new MPM2 and SAPS in a
      cohort of patients admitted to our polyvalent ICU. METHODS:  DESIGN: the ability
      of the SAPS II scoring system to predict the probability of hospital mortality
      was assessing calibration and discrimination (ROC curve) measures obtained using
      published coefficients and within relevant subgroups using formal statistic
      assessment (goodness of fit). PATIENTS: from May 1997 to May 1998, 420
      consecutive patients over 18 years old. RESULTS: When the parameters based on the
      standard model were applied, the SAPS II discrimination (area under ROC curve)
      was = 0.889 and calibration (chi square test) of SAPS II was = 4.448 with p =
      0.879; MPM2 chi 2 = 0.9385, p = 0.402 and SAPS chi 2 = 27.089, p = 0.0001. The
      performance of SAPS II model was very good. Worst predictive accuracy was
      achieved in trauma and elective surgery patients. CONCLUSIONS: SAPS II model gave
      good results in terms of calibration and discrimination. SAPS II has better
      accuracy then SAPS and MPM2. Concerning the performance of models, large
      differences were apparent in relevant subgroups: trauma and sepsis patients.
      Moreover the choice of adequate statistic method to compare intensive care
      populations appeared to need more research.

PMID- 10598430
TI  - [Hormone evaluation in brain death].
AB  - BACKGROUND: In this study, the level and the variation of a number of hormone and
      metabolic parameters during brain death treatment in potential organ donors have
      been monitored. METHODS: Thirty-nine consecutive brain-dead patients were
      enrolled in 3 Intensive Care Units of Regional Hospitals of the North of Italy.
      All patients were potential organ donors and free from diseases before the
      accident leading to death. The levels of ADH, ACTH, TSH, prolactin, cortisol,
      aldosterone, FT3, FT4, renin, serum lactate and plasma osmolality were measured
      immediately after the diagnosis of brain death (T0), certified following the
      Italian law of December 29, 1993, n. 578, and after 6 hours (T6). RESULTS:
      Hormone levels were normal in the majority of subjects, and there was no
      significant variation during the 6 hours of the observation period. No
      correlation was found between the hormone levels considered and the metabolic
      parameters; ADH levels were not correlated with plasma osmolality. FT3 levels
      were below the normal range in the majority of subjects, but were not associated
      with a higher lactate level, which is used as a marker of a shift toward tissue
      anaerobic metabolism. CONCLUSIONS: In conclusion, triiodothyronine administration
      to improve metabolic order and thus the function of organs for transplantation is
      not justified in brain-dead patients.

PMID- 10598431
TI  - [Sciatic, femoral and cutaneous nerve block for arthroscopic meniscectomy in a
      patient with Eisenmerger's syndrome. Case report].
AB  - The principal complication to prevent in Eisenmerger disease with left-right
      shunt during surgery decreasing of systemic pressure with reduction of pulmonary
      perfusion and break-down of central oxigenation. A 32 ys old male patient (ASA
      risk 3) to undergo an extirpation of meniscus by arthroscopic surgery, suffering
      from Eisenmerger's syndrome with left-type only ventricle, diagnosed when he was
      3 ys old and but no repaired by any operation. We performed a sciatic, femoral
      and lateral cutaneous of thigh nerves block with ropivacaine, that consents a
      prolonged antalgic effect in postoperative period with minimizing of systemic and
      pulmonary hypotension risk compared to general, epidural or spinal anaesthesia.
      Basing on our experience and literature references we think that the
      anaesthesiological technique with the lowest risk for lower limb surgery in
      Eisenmerger's syndrome is truncular block.

PMID- 10598432
TI  - Prolonged mivacurium-induced neuromuscular block. Case report.
AB  - A 38-year-old white male patient was admitted to the hospital for elective
      surgery. General anesthesia was performed with propofol, alfentanil, nitrous
      oxide and mivacurium as neuromuscular blocker. Seven months before he had the
      same surgery without anesthetic problems (he received: propofol, vecuronium
      bromide, fentanil, nitrous oxide). Neuromuscular monitoring was carried out
      because the patient was included in a study assessing the clinical effect of
      mivacurium in microlaryngoscopy surgery. After mivacurium administration the
      first signs of recovery from neuromuscular block were observed after 255 min. The
      tracheal tube was withdrawn after 410 min from mivacurium administration, at this
      time the T1 was 80% of the control values and 7 min later the T1 reached 98%.

PMID- 10598433
TI  - Effects of diclofenac and intra-articular morphine/bupivacaine on
      postarthroscopic pain control.
AB  - BACKGROUND: This study was undertaken to compare analgesic effects and
      requirements for supplemental analgesic therapy after knee arthroscopy in
      patients given intraarticular morphine/bupivacaine, diclofenac i.m., or both
      compared with placebo. METHOD: In a randomised, double-blind controlled trial 40
      patients were divided into four groups. Patients received 25 ml of 0.25%
      bupivacaine and 2 mg of morphine intraarticularly in group I, 75 mg of diclofenac
      i.m. in group III, the combination of 75 mg of diclofenac i.m. and 25 ml of 0.25%
      bupivacaine and 2 mg of morphine intraarticularly in group II, and placebo in
      group IV. Postoperative analgesia was provided with fentanyl in the recovery room
      and acetaminophen was given for subsequent pain relief. RESULTS: In the
      postoperative period, VAS scores for pain were highest in the placebo group,
      whereas they were lowest in the combination group. VAS scores were significantly
      lower in group I and II than group IV at the postoperative 2nd hour (p < 0.05).
      VAS score was significantly lower in group II than groups III and IV at the
      postoperative 3rd hour (p < 0.01). VAS scores were significantly lower in group
      I, II and III than group IV at the postoperative 6th hour (p < 0.05). Fentanyl
      consumption was significantly lower in group II than group IV (p < 0.05).
      Acetaminophen consumption in groups II and III were significantly lower than
      group IV (p < 0.05). CONCLUSION: The combination of diclofenac i.m. and
      intraarticular morphine/bupivacaine appears to be the most beneficial analgesic
      combination due to its lower VAS scores and supplemental analgesic requirements
      in the postoperative period.

PMID- 10598434
TI  - [The measurement of osmolality in neurologic intensive care].
AB  - Serum osmolality is one of the end-points in the management of neurologic
      intensive care patient. Its leading role in the concept of cerebrovascular
      homeostasis is underlined. Normal plasma osmolality is generally 285 mOsm kg-1, a
      value determined almost entirely by small molecules and ions (Na+, K+, urea and
      lactate). The plasma osmolality value is determined by measuring the changes in
      freezing point related to the zero value of a sample of distilled water. The
      measurement of plasma osmolality is very easy and inexpensive; its widely use
      could be very useful in the neurologic intensive care units to improve the
      treatment of neurological critical patient. According to the authors the
      monitoring of plasma osmolality should be mandatory to evaluate the effectiveness
      of treatment of brain edema.

PMID- 10598435
TI  - [Succinylcholine and Mendelson's syndrome].

PMID- 10598436
TI  - [The coordinator for transplantations].

PMID- 10598437
TI  - Trends in the attendant, place, and timing of births, and in the use of obstetric
      interventions: United States, 1989-97.
AB  - OBJECTIVES: This report presents recent trends in the circumstances surrounding
      live births in the United States. Specifically, this report will examine the
      changes in the attendant and place of birth as well as changes in the day and
      month of birth. Trends in the use of four obstetric procedures (electronic fetal
      monitoring, ultrasound, induction of labor, and stimulation of labor) are
      examined as well as trends in cesarean births, vaginal births after a previous
      cesarean, and births delivered by forceps and vacuum extraction. METHODS:
      Descriptive tabulations were calculated for each year between 1989 and 1997 using
      data reported on birth certificates. RESULTS: While the vast majority of births
      in 1997 were attended by physicians, 92 percent, this has declined steadily as
      the percent of births attended by midwives has slowly increased to account for 7
      percent of all births. About 99 percent of births were in hospitals, basically
      unchanged from 1989, but the percent of out-of-hospital births that were in
      residences increased whereas those in freestanding birthing centers declined.
      While births were more common on weekdays than on weekends in 1989, they have
      become even more concentrated on weekdays since 1989. The most popular months to
      give birth continue to be July, August, and September. The percent of mothers
      receiving electronic fetal monitoring, ultrasound, induction, and stimulation all
      increased over the period with the most dramatic increase being the doubling of
      the use of induction. Between 1989 and 1996, the rate of cesarean births dropped
      by 9 percent whereas the rate of vaginal birth after a previous cesarean (VBAC)
      increased by 50 percent. However, the trends appear to have changed between 1996
      and 1997--the cesarean rate increased slightly while the VBAC rate declined by 3
      percent. There is wide variation by State in both of these rates. The percent of
      births that were delivered by forceps consistently declined during the period
      whereas the use of vacuum extraction consistently increased.

PMID- 10598438
TI  - Treatment of intradural paraclinoidal aneurysms.
AB  - Intradural paraclinoidal aneurysm still presents conceptual confusion and
      technical surgical problems. The clinical features of 68 consecutive patients
      with paraclinoidal aneurysms were analyzed. The pterional approach was used in
      all patients. Subarachnoid hemorrhage (SAH) occurred in 37 patients from the
      paraclinoidal aneurysm and in 10 patients from another associated aneurysm.
      Thirty-four of the 37 ruptured paraclinoidal aneurysms were clipped, two blister
      like aneurysms required trapping, and one blister-like aneurysm was coated.
      Thirteen of the 31 unruptured paraclinoidal aneurysms, consisting of 10 with
      ruptured associated aneurysm, four symptomatic, and 17 incidental, were clipped
      and 18 were coated. Favorable outcomes were obtained in 38 of 47 patients with
      SAH and 17 of 21 patients without SAH. Nine unfavorable outcomes in SAH patients
      were caused by primary brain damage (5), vasospasm (2), cerebral infarction after
      trapping (1), and pneumonia (1). All four unfavorable outcomes in non-SAH
      patients were due to surgical procedures for giant aneurysms or associated
      basilar artery aneurysm. Removal of the anterior clinoid process was performed to
      secure the proximal neck in 15 patients with large or giant aneurysms. Multiple
      clips with or without fenestrated clips were required in all giant aneurysms, and
      exposure of the cervical internal carotid artery (ICA) in 17 giant or large
      aneurysms. Fenestrated clips were also useful for one small aneurysm projecting
      posteriorly. A favorable outcome was achieved in 17 of 19 patients undergoing
      coating. Coating without clipping might be better for some blister-like ICA
      aneurysms, even if ruptured. Paraclinoidal aneurysms can be clipped with
      favorable results using these techniques except for giant aneurysms and
      associated basilar artery aneurysm.

PMID- 10598439
TI  - Sudden death in a rat subarachnoid hemorrhage model.
AB  - The pathogenesis of sudden death during subarachnoid hemorrhage (SAH) still
      remains to be elucidated. A new rat common carotid artery-prechiasmal
      extracorporeal shunt model was designed to study the effect of different
      severities of SAH on intracranial pressure (ICP), regional cerebral blood flow
      (rCBF), and mortality. Different severities of SAH were induced by controlling
      the bleeding period (from 30 to 90 sec) and number of bleedings (one or three
      times). SAH caused a dramatic increase in ICP and immediate depression of rCBF,
      which recovered slowly to a certain extent. ICP increased sharply within the
      first 30 seconds and reached a plateau concomitant with nearly zero rCBF, which
      suggested the occurrence of cerebral circulation arrest. Bleeding of more than 60
      seconds and increased ICP over 80 mmHg were directly correlated with the
      mortality. Respiratory arrest was the first sign of death, immediately followed
      by cardiac depression resulting in sudden death. This model combines arterial
      bleeding with systemic blood pressure and controlled bleeding time to simulate
      the acute period of SAH.

PMID- 10598440
TI  - Neuroimaging of a wooden foreign body retained for 5 months in the temporalis
      muscle following penetrating trauma with a chopstick--case report.
AB  - A 48-year-old female was stabbed by her husband with a chopstick made of wood in
      the left temporal region during a quarrel. She suffered laceration of the left
      temporal scalp. At initial examination, she concealed the assault with a
      chopstick. Radiography showed no abnormality, so the wound was sutured. One month
      after the injury, a painless subcutaneous mass appeared in the left temporal
      region which grew rapidly for 3 months. She was then admitted to our department.
      Computed tomography (CT) on admission showed a hyperdense area at the center of
      the mass. This area was hypointense on both T1- and T2-weighted magnetic
      resonance (MR) images. Temporalis muscle tumor with accompanying central
      necrosis, old hematoma, and inflammatory granuloma was considered. The mass was
      totally resected for cosmetic purposes and was found to be wooden foreign body
      granuloma. High density on CT and hypointensity on both T1- and T2-weighted MR
      images are characteristic of a chronically retained wooden foreign body in the
      living body and are useful for detecting wooden foreign bodies in the chronic
      granulomatous phase.

PMID- 10598441
TI  - Persistent primitive trigeminal artery imaged by three-dimensional computed
      tomography angiography--two case reports.
AB  - Three-dimensional computed tomography (3D CT) angiography was used to investigate
      two cases of persistent primitive arteries. 3D CT angiography and 3D CT
      demonstrated a persistent primitive trigeminal artery variant penetrating the
      lateral edge of the posterior clinoid process and running to the posterior medial
      side, and a persistent primitive trigeminal artery perforating the canal of the
      posterior clinoid process and the petrosal bone junction. 3D CT angiography can
      delineate these persistent primitive arteries and the anatomy relative to the
      bone structure simultaneously, so is very useful to identify the arterial line
      where the canal is penetrated.

PMID- 10598442
TI  - Acute subdural hematoma due to near-drowning--case report.
AB  - A 46-year-old male was transferred to our hospital after near-drowning when
      swimming. Examination found no subcutaneous hematoma or abrasion on his head.
      Cardiopulmonary resuscitation was started immediately. Emergent computed
      tomography (CT) revealed no abnormalities. The next day, his consciousness level
      improved and repeat CT suggested an acute spontaneous subdural hematoma in the
      parieto-occipital region. The acute subdural hematoma was evacuated. The source
      of bleeding was probably an abnormally large vein located in the center of the
      hematoma. The patient was discharged without neurological deficit. Repeat CT is
      needed even if there were no abnormality on initial CT after drowning.

PMID- 10598443
TI  - Isolated metastases of adenocarcinoma in the bilateral internal auditory meatuses
      mimicking neurofibromatosis type 2--case report.
AB  - A 56-year-old male with a history of lung cancer presented with isolated
      metastases of adenocarcinoma in the bilateral internal auditory meatuses (IAMs),
      mimicking the bilateral acoustic schwannomas of neurofibromatosis type 2, and
      manifesting as rapidly worsening tinnitus and bilateral hearing loss. Magnetic
      resonance imaging showed small tumors in both IAMs with no sign of leptomeningeal
      metastasis. The preoperative diagnosis was neurofibromatosis type 2. Both tumors
      were removed and the histological diagnoses were adenocarcinoma. Neuroimaging
      differentiation of a solitary metastatic IAM tumor from a benign tumor is
      difficult, although rapidly progressive eighth cranial nerve dysfunction suggests
      a malignant process. Metastases should be considered as a rare diagnostic
      possibility in a patient with small tumors in both IAMs.

PMID- 10598444
TI  - Calcifying pseudotumor of the neural axis--case report.
AB  - A 22-year-old female presented with a calcifying pseudotumor of the neural axis
      manifesting as generalized convulsive seizure twice within 1 year. Computed
      tomography revealed a small, calcified mass lesion located in the right parietal
      lobe adjacent to the skull. The tumor was composed of an extensively calcified
      mass with accompanying peripheral epithelioid cells and focal mature bone
      structure, consistent with the diagnosis of a calcifying pseudotumor of the
      neural axis. Following complete excision of the tumor, the patient has been free
      from seizures for 8 years.

PMID- 10598445
TI  - Dandy-Walker syndrome successfully treated with cystoperitoneal shunting--case
      report.
AB  - A neonate presented with Dandy-Walker syndrome manifesting as a large posterior
      cranial fossa cyst, aplasia of the lower cerebellar vermis, and elevation of the
      confluence of the sinuses but without hydrocephalus. A cystoperitoneal shunt was
      placed at one month after birth. The cyst diminished in size, and marked
      development of the cerebellar hemispheres and descent of the confluence of
      sinuses were observed, but not vermis development. The primary pathology of Dandy
      Walker syndrome is posterior cranial fossa cyst formation due to passage
      obstruction in the fourth ventricle exit area and aplasia of the lower cerebellar
      vermis. The first choice of treatment in patients with Dandy-Walker syndrome in
      whom the cerebral aqueduct is open is cystoperitoneal shunt surgery, regardless
      of the presence or absence of hydrocephalus.

PMID- 10598446
TI  - Dorsally sequestrated thoracic disc herniation--case report.
AB  - A 53-year-old male presented with a rare dorsally sequestrated thoracic disc
      herniation manifesting as acute low back pain and weakness. He had no history of
      trauma. Magnetic resonance (MR) imaging demonstrated a mass at T10-11
      intervertebral level connected with the T-10 disc. Axial MR imaging showed the
      mass had surrounded and compressed the dural sac from the lateral and dorsal
      sites. MR imaging with gadolinium-diethylenetriaminepenta-acetic acid showed
      slight rim enhancement of the lesion. Computed tomography detected no abnormal
      calcification. The diagnosis was thoracic disc herniation. Laminectomy resulted
      in rapid and satisfactory recovery. The histological diagnosis was thoracic disc
      herniation. MR imaging was very effective for the diagnosis based on the
      connection between the mass and the disc space. The differential diagnosis
      includes metastatic epidural tumor, epidural hematoma, and epidural abscess.

PMID- 10598447
TI  - Telemedicine in neurosurgery using international digital telephone services
      between Japan and Malaysia--technical note.
AB  - A new image transmission and teleconference system using international digital
      telephone services was established between Japan and Malaysia. This new system
      consists of an ordinary personal computer, image scanner, and terminal adapter
      for digital telephone lines. The quality of images transferred using this system
      was high enough for diagnosis and discussion except for images such as
      radiographs requiring huge data transfer. Transmission of one image took
      approximately 20 seconds. The cost performance was almost equal to the
      conventional mailing system. The most remarkable advantage of this new system is
      the high quality of transferred images, the cost and time performance, and
      security of the medical information. New communication systems using
      international digital networks including the internet may allow re-distribution
      of medical resources between advanced countries and developing countries in
      neurosurgery.

PMID- 10598448
TI  - Go for wool and come home shorn.

PMID- 10598449
TI  - [The investigation of age-specific PSA reference range as the cut-off values in
      the mass screening for prostatic cancer].
AB  - BACKGROUND: The objective of this study is to determine age-specific PSA
      reference ranges in Japanese healthy men and investigate the effectiveness of
      these ranges as the cut-off values in the mas screening for prostatic cancer.
      METHODS: The study included a total of 5,206 male aged from 55 to 89 years old
      who wished to submit the mass screening for prostatic cancer in an urban area of
      Kyoto in 1995-1997, but had no evident prostatic cancer. We measured serum PSA
      levels by the filter paper method (Delfia PSA kit). RESULTS: We found the
      increase in serum PSA levels with the advancing age. With the 95th percentile for
      serum PSA as the upper limit, the age-specific PSA reference ranges were
      determined to be 2.1 ng/ml for patients aged 55 to 59 years old, 3.2 ng/ml for 60
      to 69 years old, 4.4 ng/ml for 70 to 79 years old, 6.5 ng/ml for 80 to 89 years
      old. If we used these ranges as the cut-off values in the mass screening this
      time, five cases from 76 to 89 years old of prostatic cancer were overlooked.
      CONCLUSIONS: We found the increase in serum PSA levels with advancing age. But
      the positive proof of using this range to a mass screening for prostatic cancer
      was not certified, because time incidence of prostatic cancer in the examinees
      was uncertain and there is a possibility of overlooking some cases.

PMID- 10598450
TI  - [Implication of two additional lateral peripheral zone biopsy in the detection of
      prostate cancer].
AB  - BACKGROUND: Despite the strenuous efforts in improving detection of prostate
      cancer, no standard technique for prostatic biopsy has been established to date.
      Extended tissue sampling in peripheral zone may possibly lead to enhanced
      prostate cancer detection. METHODS: Four hundred thirty-three candidates for
      ultrasound-guided prostatic biopsy were alternately assigned to two groups
      regarding biopsy techniques between January 1997 and June 1998, Group A, sextant
      biopsy group and Group B, two additional lateral peripheral zone sampling after
      standard sextant biopsy. The outcomes of prostatic biopsy were compared. RESULTS:
      Cancer detection rates were 19.2% (43/217) in Group A and 18.5% (40/216) in Group
      B. No statistically significant difference was noted (p > 0.05). Clinical stage,
      Gleason score and the presence of metastasis did not differ significantly between
      groups (p > 0.05). The incidence and duration of hematuria, hematospermia were
      essentially the same between groups (p > 0.05). High fever due to possible
      bacteremia developed only in Group B patients (p = 0.04). CONCLUSIONS: Routine
      use of additional peripheral zone biopsy is not recommended owing to the
      equivalent cancer detection rates between groups. The application of additional
      biopsy should be determined carefully since this may lead to increased incidence
      of serious complications.

PMID- 10598451
TI  - [Long-term results of venous surgery for cavernous erectile dysfunction].
AB  - BACKGROUND: It is well known that the effectiveness of venous surgery declines
      during the follow-up period. The onset of recurrence after surgery varies greatly
      among patients. There are only a few studies which have evaluated the
      effectiveness of venous surgery with objective tests. METHODS: We treated 123
      cases of cavernous erectile dysfunction with venous surgery, and evaluated the
      results objectively. We performed intracavernous injection tests using 20
      micrograms of prostaglandin E1 every 3 months until the recurrence of cavernous
      erectile dysfunction. RESULTS: Mean follow up period was 32 months (0.2-134.0
      months). According to the Kaplan-Meier analysis, the effectiveness of surgery at
      1 year, 3 years, 5 years, and 10 years was 85%, 61%, 30%, and 26%, respectively.
      CONCLUSION: There was no statistically significant difference between the
      outcomes following deep dorsal vein surgery and crural ligation surgery.
      Operative complications were more frequent, however in deep dorsal vein surgery.

PMID- 10598452
TI  - [Validity analysis of Sapporo Medical University-sexual function questionnaire].
AB  - BACKGROUND: We evaluated the validity of the Sapporo Medical University-sexual
      function questionnaire, comparing the response to each question of patients
      having sexual dysfunction with those of normal volunteers as controls. PATIENTS
      AND METHODS: Responses from 335 patients with sexual dysfunction and 490 normal
      volunteers aged from 20 to 39 years old were evaluated. We compared mean scores
      of each question for patients having sexual dysfunction with those for controls.
      Discriminant analysis was used for evaluating which questions contributed more
      strongly to discriminating patients having the disease from controls. The
      analysis was also used for validating the questionnaire. RESULTS: Mean scores for
      patients with sexual dysfunction were significantly lower than those for controls
      in all questions. Nine of the 11 questions were statistically useful to
      discriminate these two groups with discriminant analysis. The analysis also
      revealed that questions about frequency of erection, rigidity of the erectile
      penis and duration of erection highly contributed to discriminate these two
      groups. The discriminant analysis achieved high sensitivity and specificity for
      classifying the groups. CONCLUSION: These results suggest that the use of the
      Sapporo Medical University-sexual function questionnaire is valid for
      discriminating patients with sexual dysfunction from subjects with normal sexual
      function.

PMID- 10598453
TI  - [Xanthogranulomatous epididymitis. A case report].
AB  - A 45-year-old man with spinal injury and diabetes mellitus who complained high
      fever and progressive enlargement of left intrascrotal mass visited to our
      hospital. Preoperative ultrasonography demonstrated epididymitis and abscess
      formation. Left high orchiectomy was performed because testicular tumor could not
      be denied. Epididymis was replaces by bright yellow mass associated with abscess
      and adhered to testis strongly. Histopathologically, the mass diagnosed
      xanthogranulomatous epididymitis consisted of foamy macrophages and chronic
      inflammatory cells. This is the first case in Japanese medical literature.

PMID- 10598454
TI  - [A case of pelvic aggressive angiomyxoma involving urinary bladder].
AB  - A 23-year-old man visited hospital with the complaints of hematuria and miction
      pain. Computed tomography and magnetic resonance imaging of the pelvis showed a
      large pelvic tumor contiguous to the urinary bladder. Resection of the tumor with
      partial cystectomy was performed on February, 1998. Histopathological examination
      showed that the tumor composed of angiomyxoma infiltrating into the urinary
      bladder. The patient is alive without recurrence of aggressive angiomyxoma 12
      months after surgery. To our knowledge, this is the first report in the Japanese
      literature of aggressive angiomyxoma involving the urinary bladder. Awareness of
      this uncommon neoplasma is important in the diagnosis of pelvic tumor to prevent
      an extensive surgery.

PMID- 10598455
TI  - [In Process Citation]
AB  - To prevent disturbances of blood gas-transport function in hemorrhagic shock, we
      used cross-over protective effect of adaptation to short-term immobilisation
      stress. Adaptation of rats to stress was associated with a rise in baseline
      arterial pressure, hematocrit, oxygen capacity and concentration of buffer bases
      in arterial blood, pH in venous blood; fall in PO2, PCO2, P50. Stress-adapted
      rats appeared more resistant to blood loss. Gas transport 1 hour after hemorrhage
      was better than in non-adapted animals. In hemorrhagic shock, the adapted animals
      demonstrated more active compensatory reactions in low hypoxic damage to the
      tissues. 2.5-h survival after start of bleeding in control animals made up 35%,
      in the group of adapted animals--67%. Thus, adaptation to short-term
      immobilization stress is a non-pharmacological method to prevent hemorrhagic
      shock.

PMID- 10598456
TI  - [In Process Citation]
AB  - Heart overloading due to pressure as a result of 8 periodic full aortic
      constriction in heart failure (HF) caused by 10-day toxic-allergic myocarditis
      (TAM) leads to deterioration of heart contractility (pupm function). This is
      explained by additional decline in functional activity of all three systems of
      cardiomyocyte responsible for contraction-relaxation. In particular, by a sharp
      fall of ATP and CP content in the myocardium, a 400% decrease in myofibril power,
      200% reduction in efficiency of contraction and marked deterioration of calcium
      transport. The resultant exhaustion of myocardial reserve brought 70% lethality
      among the animals. Under the above conditions coordination between the systolic
      and diastolic cardiac functions, correlation between myocardial functional
      activity and subcellular systems of cardiomyocyte are impaired. In pressure heart
      overloading refracterin initiates profound metabolic rearrangements improving
      metabolism, remodelling of the system of energy supply, reestablishment of
      systemic homeostasis, normalization of cardiomyocyte and cardiac reserves.

PMID- 10598457
TI  - [The antioxidant protection of the heart by coenzyme Q10 in stable stenocardia of
      effort].
AB  - It was found that patients with angina of effort (functional class II and III)
      exhibit enhanced generation of active oxygen forms by leukocytes, higher
      concentration of malonic dialdehyde in plasma and lower antiperoxide resistance
      of plasma. These changes increase with increasing severity of the disease.
      Adjuvant use of coenzyme Q10 in combined antianginal therapy suppresses
      generation of active oxygen forms by leukocytes, lipid peroxidation. Antiperoxide
      plasma resistance rises. In this way clinical improvement of effort angina is
      achieved.

PMID- 10598458
TI  - [The effect of a new phenylalkyl taurine derivative on the size of the necrotic
      area in experimental myocardial infarct in rats].
AB  - The study of an anti-ischemic action of a new phenilalkyl taurin derivative TAU
      60 has discovered that this drug attenuates ECG signs of myocardial infarction
      and reduces the size of necrosis zone on the anterior wall of the left
      ventricular myocardium in rats with experimental myocardial infarction.

PMID- 10598459
TI  - [The effect of cytochrome c on the myocardium during reperfusion].
AB  - Experimental and clinical trials have shown high effectiveness of cytochrome c
      (0.5 mg/kg) in prevention of reperfusion myocardial disorders in cardiosurgical
      patients. Cytochrome c inhibits development of myocardial ischemic contracture,
      depression of coronary circulation, activation of lipid peroxidation. It reduces
      myocardial consumption of oxygen and promotes earlier restoration of fatty acids
      metabolism under lower glucose consumption by the heart muscle. By correction of
      myocardial metabolism, the drug suppresses fermentemia in early reperfusion.

PMID- 10598461
TI  - [Aerobic-hemodynamic support of physical exertion in virtually healthy persons
      with different levels of cholesterol in the blood and in patients with
      stenocardia of effort].
AB  - Oxygen transport and central hemodynamics were studied in 66 healthy males with
      different blood cholesterol levels and 24 patients with angina of effort under
      standard exercise test. Increased blood cholesterol was found to influence
      exercise energy maintenance in healthy people. Subnormal efficacy of oxygen
      transport system provokes intensification of cardiac activity. Oxygen-hemodynamic
      maintenance of exercise in healthy subjects with hypercholesterolemia is similar
      to that in patients with ischemic heart disease. This indicates the same
      pathophysiological processes in the above individuals.

PMID- 10598460
TI  - [The types of the structural-functional connections of the coronary circulation
      and the state of the myocardium in patients with isolated and combined forms of
      ischemic heart disease and arterial hypertension].
AB  - The analysis of evidence obtained at coronaroangiography, myocardial
      scintigraphy, echocardiography, severity of coronary and heart insufficiency in
      patients with isolated and combined forms of ischemic heart disease and arterial
      hypertension has identified three types of structural-functional relations
      between characteristics of coronary circulation and myocardial status: myocardio
      perfusional (concentric myocardial hypertrophy with diastolic dysfunction leading
      to perfusional defects), coronaro-myocardial (affection of coronary arteries
      resulting in myocardial lesion with primarily systolic dysfunction), coronaro
      perfusional (disturbed coronary circulation in involvement of coronary and
      myocardial factors).

PMID- 10598462
TI  - [The beginnings and development of pathophysiology at the Imperial Moscow
      University--the 1st Moscow Medical Institute--the I. M. Sechenov Moscow Medical
      Academy (on the 150th anniversary of the Department of Pathophysiology of the I.
      M. Sechenov Moscow Medical Academy)].

PMID- 10598463
TI  - Infants' sensitivity to allophonic cues for word segmentation.
AB  - A series of four experiments was conducted to determine whether English-learning
      infants can use allophonic cues to word boundaries to segment words from fluent
      speech. Infants were familiarized with a pair of two-syllable items, such as
      nitrates and night rates and then were tested on their ability to detect these
      same words in fluent speech passages. The presence of allophonic cues to word
      boundaries did not help 9-month-olds to distinguish one of the familiarized words
      from an acoustically similar foil. Infants familiarized with nitrates were just
      as likely to listen to a passage about night rates as they were to listen to one
      about nitrates. Nevertheless, when the passages contained distributional cues
      that favored the extraction of the familiarized targets, 9-month-olds were able
      to segment these items from fluent speech. By the age of 10.5 months, infants
      were able to rely solely on allophonic cues to locate the familiarized target
      words in passages. We consider what implications these findings have for
      understanding how word segmentation skills develop.

PMID- 10598464
TI  - Neural dynamics of perceptual order and context effects for variable-rate speech
      syllables.
AB  - How does the brain extract invariant properties of variable-rate speech? A neural
      model, called PHONET, is developed to explain aspects of this process and, along
      the way, data about perceptual context effects. For example, in consonant-vowel
      (CV) syllables, such as /ba/ and /wa/, an increase in the duration of the vowel
      can cause a switch in the percept of the preceding consonant from /w/ to /b/
      (J.L. Miller & Liberman, 1979). The frequency extent of the initial formant
      transitions of fixed duration also influences the percept (Schwab, Sawusch, &
      Nusbaum, 1981). PHONET quantitatively simulates over 98% of the variance in these
      data, using a single set of parameters. The model also qualitatively explains
      many data about other perceptual context effects. In the model, C and V inputs
      are filtered by parallel auditory streams that respond preferentially to the
      transient and sustained properties of the acoustic signal before being stored in
      parallel working memories. A lateral inhibitory network of onset- and rate
      sensitive cells in the transient channel extracts measures of frequency
      transition rate and extent. Greater activation of the transient stream can
      increase the processing rate in the sustained stream via a cross-stream automatic
      gain control interaction. The stored activities across these gain-controlled
      working memories provide a basis for rate-invariant perception, since the
      transient-to-sustained gain control tends to preserve the relative activities
      across the transient and sustained working memories as speech rate changes.
      Comparisons with alternative models tested suggest that the fit cannot be
      attributed to the simplicity of the data. Brain analogues of model cell types are
      described.

PMID- 10598465
TI  - Predictability of the cue-target relation and the time-course of auditory
      inhibition of return.
AB  - The possibility that the time-course of auditory inhibition of return (IOR) might
      depend on the temporal or spatial predictability of the cue-target relation was
      investigated. In all the experiments, a location cue was followed by a target
      that was to be localized. An inhibitory effect became apparent at a longer
      stimulus onset asynchrony (SOA) when either the temporal or the spatial relation
      was predictable, rather than when either was unpredictable. A facilitative effect
      was apparent at a 100-msec SOA, irrespective of the predictability of the cue
      target relation. These results establish that the time-course of the inhibitory
      component of location-based auditory IOR depends on the predictability of the
      temporal and spatial relations of cue and target. The theoretical implications of
      these results are considered, and a dual-process model of auditory selective
      attention is offered.

PMID- 10598466
TI  - A confusion matrix for the study of taste perception.
AB  - Taste stimulus identification was studied in order to more thoroughly examine
      human taste perception. Ten replicates of an array of 10 taste stimuli--NaCl,
      KCl, Na glutamate, quinine. HCl, citric acid, sucrose, aspartame, and NaCl
      sucrose, acid-sucrose, and quinine-sucrose mixtures--were presented to normal
      subjects for identification from a list of corresponding stimulus names. Because
      perceptually similar substances are confused in identification tasks, the result
      was a taste confusion matrix. Consistency of identification for the 10 stimuli
      (T10) and for each stimulus pair (T2) was quantified with measures derived from
      information theory. Forty-two untrained subjects made an average of 57.4% correct
      identifications. An average T10 of 2.25 of the maximum 3.32 bits and an average
      T2 of 0.84 of a maximum 1.0 bit of information were transmitted. In a second
      experiment, 40 trained subjects performed better than 20 untrained subjects. The
      results suggested that the identification procedure may best be used to assess
      taste function following 1-2 training replicates. The patterns of taste confusion
      indicate that the 10 stimuli resemble one another to varying extents, yet each
      can be considered perceptually unique.

PMID- 10598467
TI  - Anisotropy in the extended haptic perception of longitudinal distances.
AB  - Using horizontal rotational motions of a hand-held rod, participants in four
      experiments probed the aperture between two blocks separated in depth. The
      farther block could be either on the outer or on the inner side of the hand-rod
      system, defining apertures of opposite sense. The participants reported the
      perceived size of the in-depth intervals by adjusting, with the nonprobing hand,
      the lateral separation between two blocks or the egocentric distances of two
      blocks. Over variations in hand and geometric arrangement of stimulus and report
      blocks, perceived aperture size depended on the aperture's sense: Apertures with
      the farther edge on the outer side of the hand-rod were reported as being larger
      than their mirror image counterparts. The effect was not observed in judgments of
      a single edge distance (Experiment 5); it was configuration dependent. The sense
      effect would not be expected from the physical quantity accommodating perceived
      frontal apertures. Possible expansions of the physical model are discussed.

PMID- 10598468
TI  - Orthographic neighborhood effects in perceptual identification and semantic
      categorization tasks: a test of the multiple read-out model.
AB  - How should a word's orthographic neighborhood affect perceptual identification
      and semantic categorization, both of which require a word to be uniquely
      identified? According to the multiple read-out model (Grainger & Jacobs, 1996),
      inhibitory neighborhood frequency effects should be observed in these types of
      tasks, and facilitatory neighborhood size effects should not be. In Experiments 1
      and 2 (perceptual identification), these effects were examined as a function of
      stimulus visibility (i.e., high vs. low visibility) to provide as full a test as
      possible of the model's predictions. In the high-visibility conditions, words
      with large neighborhoods were reported less accurately than words with small
      neighborhoods, but there was no effect of neighborhood frequency (i.e., whether
      the word had a higher frequency neighbor). In the low-visibility conditions, low
      frequency words with large neighborhoods and low-frequency words with higher
      frequency neighbors showed superior identification performance. In the semantic
      categorization task (Experiment 3), words with large neighborhoods were responded
      to more rapidly than words with small neighborhoods, but there was no effect of
      neighborhood frequency. These results are inconsistent with two of the basic
      premises of the multiple read-out model--namely, that facilitatory neighborhood
      size effects are due to a variable response criterion (the sigma criterion),
      rather than to lexical selection processes, and that the lexical selection
      processes themselves produce an inhibitory neighborhood frequency effect (via the
      M criterion). Instead, the present results, in conjunction with previous
      findings, suggest that large neighborhoods (and perhaps higher frequency
      neighbors) do aid lexical selection.

PMID- 10598469
TI  - Perception of artificial stereoscopic stimuli from an incorrect viewing point.
AB  - The present study investigates the distortions in the perception of artificial
      stereoscopic displays seen from an inappropriate distance and/or orientation.
      Stereoscopic displays represent 3-D information correctly, provided they are seen
      from the correct station point. The viewing point may differ from the correct
      station point in its distance or in its orientation to the screen. These
      differences lead to distortions that can be predicted mathematically. However,
      the perceptual function may be different from the predictions, since people may
      possibly compensate for the distortions. To test the degree of this compensation,
      participants saw anaglyphic stereoscopic stimuli that showed angles in the
      horizontal plane, and their perception of the configuration was tested for
      various orientations and distances. The estimates were compared with the values
      predicted from the mathematical functions, and participants' virtual positions
      were reconstructed via nonlinear regressions. The analyses revealed a moderate
      compensation for viewing orientations and a systematically overestimation of the
      viewing distances. These results indicate that people compensate partially for
      distortions in stereopsis, given that the relevant information is available.

PMID- 10598470
TI  - The material-weight illusion revisited.
AB  - Experiment 1 documents modality effects on the material-weight illusion for a low
      mass object set (58.5 g). These modality effects indicate that the material
      weight illusion is principally a haptically derived phenomenon: Haptically
      accessed material cues were both sufficient and necessary for full-strength
      illusions, whereas visually accessed material cues were only sufficient to
      generate moderate-strength illusions. In contrast, when a high-mass object set
      (357 g) was presented under the same modality conditions, no illusions were
      generated. The mass-dependent characteristic of this illusion is considered to be
      a consequence of differing grip forces. Experiment 2 demonstrates that the
      enforcement of a firm grip abolishes the low-mass material-weight illusion.
      Experiment 3 documents that a firm grip also diminishes perceptual
      differentiation of actual mass differences. Several possible explanations of the
      consequences of increasing grip force are considered.

PMID- 10598471
TI  - The visual perception of surface orientation from optical motion.
AB  - Observers viewed monocular animations of rotating dihedral angles and were
      required to indicate their perceived structures by adjusting the magnitude and
      orientation of a stereoscopic dihedral angle. The motion displays were created by
      directly manipulating various aspects of the image velocity field, including the
      mean translation, the horizontal and vertical velocity gradients, and the manner
      in which these gradients changed over time. The adjusted orientation of each
      planar facet was decomposed into components of slant and tilt. Although the tilt
      component was estimated with a high degree of accuracy, the judgments of slant
      exhibited large systematic errors. The magnitude of perceived slant was
      determined primarily by the magnitude of the velocity gradient scaled by its
      direction. The results also indicate that higher order temporal derivatives of
      the moving elements had little effect on observers' judgments.

PMID- 10598472
TI  - Orientation invariance in naming rotated objects: individual differences and
      repetition priming.
AB  - In naming drawings of complex common objects, unpracticed naming times increase
      with rotation away from the upright, but this orientation effect is attenuated
      with practice. In principle, attenuation could result from learning to extract
      orientation-invariant information or from learning view-specific representations
      at the trained orientations. We contrasted these approaches by examining
      repetition priming for prime-target pairs presented on successive trials in
      either the same orientation (horse at 51 degrees primes horse at 51 degrees) or a
      different orientation (horse at 154 degrees primes horse at 51 degrees), for two
      subgroups of subjects. One subgroup showed no orientation effect, even when
      unpracticed, and a correspondingly high generalization of priming across
      different views. The other subgroup initially showed high sensitivity to
      misorientation and little priming across orientations but, with sufficient
      practice, came to show no orientation effect and complete generalization of
      priming. Thus, some subjects always used orientation-invariant procedures,
      whereas others learned to do so.

PMID- 10598473
TI  - Objects of attention, objects of perception.
AB  - Four experiments were conducted, to explore the notion of objects in perception.
      Taking as a starting point the effects of display content on rapid attention
      transfer and manipulating curvature, closure, and processing time, a link between
      objects of attention and objects of perception is proposed. In Experiment 1, a
      number of parallel, equally spaced, straight lines facilitated attention transfer
      along the lines, relative to transfer across the lines. In Experiment 2, with
      curved, closed-contour shapes, no "same-object" facilitation was observed.
      However, when a longer time interval was provided, in Experiment 3, a same-object
      advantage started to emerge. In Experiment 4, using the same curved shapes but in
      a non-speeded distance estimation task, a strong effect of objects was observed.
      It is argued that attention transfer is facilitated by line tracing but that line
      tracing is encouraged by objects.

PMID- 10598474
TI  - Stimulus-response compatibility effects in go-no-go tasks: a dimensional overlap
      account.
AB  - According to the automatic response activation hypothesis of the dimensional
      overlap (DO) model (Kornblum, Stevens, Whipple, & Requin, 1999), stimulus
      response compatibility effects are expected to occur in go-no-go tasks. This
      prediction is confirmed in two experiments in which subjects moved a hand to one
      side of the field on presentation of a go stimulus. Although the direction of
      movement was known in advance and the spatial attribute of the go stimuli was
      irrelevant to the go-no-go decision, the subjects' response time was shorter when
      the spatial attribute to the go stimulus corresponded to that of the response
      than when it did not. These effects are shown to depend on the similarity of the
      go and the no-go stimuli, as well as on whether the spatial attribute of the go
      stimuli was its actual location or its meaning. We discuss these results in terms
      of the temporal dynamics of automatic and controlled response processes, as
      hypothesized in the DO model.

PMID- 10598475
TI  - Range effects of an irrelevant dimension on classification.
AB  - In univariate classification tasks, subjects sort stimuli on the basis of the
      only attribute that varies. In orthogonal classification tasks, often called
      filtering tasks, there additionally are trial-to-trial variations in irrelevant
      attributes that the subjects are instructed to ignore. Performance is generally
      slower in filtering tasks than in univariate control tasks. We investigated this
      slowing in experiments of how the range of irrelevant trial-to-trial variation
      affects responses in pitch/loudness classification tasks. Using two levels of
      pitch and of loudness as stimuli, Experiment 1 replicated prior work showing that
      responses are slowed more when the range of the irrelevant dimension is made
      larger. Also in Experiment 1, sequential analyses showed that response time
      depends both on sequence and on the stimulus set independent of sequence.
      Experiments 2 and 3 used several levels on the irrelevant dimension and showed
      that responses to categorize loudness are slowed more by larger trial-to-trial
      pitch differences, but only on trials when the response repeats. When the
      response changes, performance is essentially unaffected by trial-to-trial
      irrelevant variation. This interaction supports the conclusion that slowed
      average performance in orthogonal classification tasks, which is known as Garner
      interference, is not due to difficulties that subjects have in filtering stimulus
      attributes. It is due to how subjects process successive stimulus differences. We
      call for more frequent reports of sequential analyses, because these can reveal
      information that is not available from data averages.

PMID- 10598476
TI  - Relative mislocalization of briefly presented stimuli in the retinal periphery.
AB  - We studied the ability to localize flashed stimuli, using a relative judgment
      task. When observers are asked to localize the peripheral position of a probe
      with respect to the midposition of a spatially extended comparison stimulus, they
      tend to judge the probe as being more toward the periphery than is the
      midposition of the comparison stimulus. We report seven experiments in which this
      novel phenomenon was explored. They reveal that the mislocalization occurs only
      when the probe and the comparison stimulus are presented in succession,
      independent of whether the probe or the comparison stimulus comes first
      (Experiment 1). The size of the mislocalization is dependent on the stimulus
      onset asynchrony (Experiment 2) and on the eccentricity of presentation
      (Experiment 3). In addition, the illusion also occurs in an absolute judgment
      task, which links mislocalization with the general tendency to judge peripherally
      presented stimuli as being more foveal than they actually are (Experiment 4). The
      last three experiments reveal that relative mislocalization is affected by the
      amount of spatial extension of the comparison stimulus (Experiment 5) and by its
      structure (Experiments 6 and 7). This pattern of results allows us to evaluate
      possible explanations of the illusion and to relate it to comparable tendencies
      observed in eye movement behavior. It is concluded that the system in charge of
      the guidance of saccadic eye movements is also the system that provides the
      metric in perceived visual space.

PMID- 10598477
TI  - Color spaces of color-normal and color-abnormal observers reconstructed from
      response times and dissimilarity ratings.
AB  - With multidimensional scaling analysis, color spaces were reconstructed from
      reaction times (RTs) required to make same-different judgements of pairs of 15
      equiluminant colors and from dissimilarity ratings between them. In addition to
      normal trichromats, observers with red-green color deficiency were tested. Two
      main purposes were served by this study: (1) to compare spatial representations
      of colors derived from discriminative RTs with those derived from dissimilarity
      measures and (2) to examine whether the task may selectively affect the dimension
      reflecting, in color-abnormal spaces, the deficient red-green mechanism.
      Contradicting our hypothesis of lower dimensionality of RT spaces, as compared
      with rating spaces, no consistent differences in solution dimensionality were
      found. However, configurations derived from the two measures diverged. The rating
      procedure yielded the most logical results for recovering color space. The RT
      configuration revealed contraction in the tritanopic direction, indicating longer
      color processing when the short-wavelength mechanism is involved, and in
      addition, for color-abnormal observers, clustering in the protanopic and
      deuteranopic directions, indicating even longer processing by the deficient red
      green mechanism. This finding implies that RTs are suitable for detecting
      temporal differences in color processing but, for that very same reason, rather
      ill-suited for reconstructing color spaces.

PMID- 10598478
TI  - Research note: a multidimensional scaling comparison of color metrics for
      response times and rated dissimilarities.
AB  - Individual-differences multidimensional scaling was applied to a set of proximity
      data for equiluminant lights (Paramei & Cavonius, 1999) to explore any
      differences between two data collection procedures (rated dissimilarities, and
      same/different response times [RTs]), as well as between color-normal and
      abnormal observers. Two conclusions emerged: (1) The pattern of similarities from
      observers with anomalous color vision can be understood in terms of a compressed
      color plane (the weighted Euclidean model of individual differences); and (2)
      there is evidence that the color "plane" is either curved or governed by a non
      Euclidean distance function. When color-normal observers are examined in the
      weighted-Euclidean framework, minor differences emerge between RT and rating
      data. But the main distinguishing feature of RT data is a pattern of decreasing
      accuracy for larger color distances. This must be taken into account, since it
      can itself induce curvature.

PMID- 10598479
TI  - Charpentier (1891) on the size-weight illusion.
AB  - This paper offers background for an English translation of an article originally
      published in 1891 by Augustin Charpentier (1852-1916), as well as a summary of
      it. The article is frequently described as providing the first experimental
      evidence for the size-weight illusion. A comparison of experiments on the judged
      heaviness of lifted weights carried out by Weber (1834) and by Charpentier (1891)
      supports the view that Charpentier's work deserves priority; review of other
      experimental studies on the size-weight illusion in the 1890s suggests that the
      idea that the illusion depended on "disappointed expectations," especially with
      respect to speed of lift, became dominant almost immediately following the
      publication of Charpentier's paper. The fate of this and other ideas, including
      "motor energy," in 20th-century research on the illusion is briefly described.

PMID- 10598480
TI  - [The role of leukotrienes in inflammation and leukotriene inhibitors].
AB  - Over recent years it has become widely accepted that asthma is a chronic
      persistent inflammatory condition regulated by a variety of inflammatory cells
      and mediators such as leukotrienes. It has been shown that there are increased
      levels of cysteinyl leukotrienes in biological fluids from patient with chronic
      asthma and in acute bronchospasm experimentally induced by allergen or other
      stimuli. The evidence suggests that blocking the formation or action of cysteinyl
      leukotrienes may be benefit in the treatment of chronic inflammatory diseases. In
      this article the leukotriene pathway, the biological role of these lipid
      mediators and their antagonists are widely characterised. There are three groups
      of leukotriene inhibitors: 5-lipooxygenase inhibitors, FLAP (activating protein)
      inhibitors and Cys-Lt1 receptor antagonists. On Polish market two representative
      drugs are currently: montelukast and zafirlukast, both leukotriene receptor
      antagonists. They bind competitively and selectively to Cys-Lt1 receptors
      blocking the pro-inflammatory effects of the cysteinyl leukotrienes. They offer
      protection against cold, dry air or exercise-induced bronchoconstriction
      significantly greater than placebo. These agents produce a modest improvement in
      lung function, symptom control and reduce the need for short acting inhaled beta2
      agonist therapy. Some guidelines suggest that they may be considered as an
      alternative treatment to low dose inhaled corticosteroid therapy and cromones
      therapy of mild persistent asthma. It seems likely that aspirin-sensitive
      asthmatic patients may be benefited by LTD4-antagonists. These drugs have the
      great advantage of efficacy by oral administration and they do not appear any
      class-specific side effects. Also some basic information about zileuton--5
      lipooxygenase inhibitor are given. Due to its induction of hepatic enzyme
      activity zileuton is not available in Poland, but it is important agent in
      evaluation of the leukotriene inhibitors in some models of inflammation. The
      introduction of leukotriene antagonists is undoubtedly an important breakthrough
      in asthma therapy.

PMID- 10598481
TI  - [Allergic laryngitis].
AB  - Reports of allergic laryngitis are sparse. This paper reports on 34 patients in
      order to show that laryngitis can be caused by pollens or mites with mechanisms
      of immediate allergy. All the cases were confirmed with skin prick tests and
      natural provocation in which the patients displayed a change in vocal cord
      status.

PMID- 10598482
TI  - [Cefotaxime in sequential therapy of community acquired pneumonia].
AB  - Recent studies indicate clinical value of intra-venous to oral switch therapy.
      The aim of this study was to analyze our results i.v. Cefotaxime to oral
      Cefetamet Piroxil switch therapy in lower respiratory tract infections. Group
      consists 35 patients in whom 27 has bacterial pathogen definitely established.
      Cefotaxim (Tarcefoksym-Polfa) i.v. has been used for 3-4 days followed with oral
      Cefetamet Pivoxil (Tarcevis-Polfa). Patients has been treated for 7 days in
      hospital and then as an out-patients afterwards. Excelent result has been
      observed in 27 cases (77% of the study group). Mild symptoms of medication
      intolerance has been observed in 8 patients (23% of all patients). Results of our
      experience with third generation cefalosporin i.v. to oral switch therapy are
      satisfactory. This method reduced total cost of treatment, reduced in-hospital
      days and was very well accepted by patients.

PMID- 10598483
TI  - [Mycoplasma pneumonia in own clinical material].
AB  - The majority of community acquired pneumonia patients are treated by family
      doctors, most frequently in empiric way, what delays the treatment when a choice
      of antibiotic is not proper. In this case the resistance to the antibiotics of
      the bacteria can occurred and there is more often the necessity of patient
      admission to the hospital. The aim of the study was to analyse retrospectively
      the treatment of mycoplasmal pneumonia patients. The material consisted of
      consecutive 27 patients (17 females and 10 males; average age 31.9 yrs.) treated
      in the Pneumonology Department of Medical University of Gdansk in the period from
      1995 to 1997 year because of mycoplasmal pneumonia. The etiologic diagnosis was
      defined first of all on the base of serologic test, measuring the complement
      fixing antibodies, beside clinical data. The retrospective analysis revealed that
      all patients had been admitted to the hospital after previous not effective anti
      bacterial or anti-viral treatment as out-patient. At the admission no patients
      had the temperature exceeding 38 degrees C, myalgia and headache occurred in 44%
      and 40.7% of patients respectively, splenomegaly was reported in 4 patients. In
      chest roentgenograms pulmonary infiltrations were observed in all patients, most
      frequently unilaterally (68% of pts.), in 29% of patients complicated by pleural
      effusion. The titers of complement-fixing antibodies against Mycoplasma
      pneumoniae antigen ranged from 1:245 to 1:2000. In the treatment most frequently
      (70.3% of cases) doxycycline in monotherapy was used. Eight patients were treated
      with doxycycline together with erythromycine. In 33.3% patients the
      antimycoplasmal treatment was ordered only on the base of clinical data. The
      period of hospitalisation ranged from 18 to 34 days, on an average 24 days.
      CONCLUSION: In case of mild community acquired pneumonias with not defined
      ethiology, if the initial antibacterial or antiviral treatment is not effective,
      tetracyclines or/and erythromycine should be ordered without the necessity to
      confirm the diagnosis of mycoplasamal pneumoniae with the serological test.

PMID- 10598484
TI  - [Fine needle biopsy in diagnosis of lung tumors].
AB  - Fine-needle biopsy is one of the method used in diagnosis of lung tumors. In this
      study the results of 192 biopsies performed by x-ray apparatus inspection were
      analysed. There was shown that lung cancer was recognized in over 50% of patients
      studied. In another cases non-specific inflammation (31%), lung fibrosis (1%),
      tuberculosis (1%), purulent inflammation (1%), blood (7%) were recognized. These
      results indicate for usefulness of this method in diagnosis of not only
      peripheral, but also central localized lung tumors.

PMID- 10598485
TI  - [Alveolar-arterial oxygen gradient in patients with clinical symptoms of
      pulmonary embolism].
AB  - The accurate detection of pulmonary embolism is possible by means of non-invasive
      but very expensive ventilation-perfusion lung scanning or invasive and with high
      rate of complications pulmonary angiography. Thus monitoring of many clinical and
      biochemical parameters has been recently attempted to increase the probability of
      correct diagnosis of pulmonary embolism. The alveolar-arterial oxygen gradient is
      a more sensitive indicator of disturbance in oxygenation than occurrence of
      hypoxia in gasometry. The aim of our study was to examined the changes of the
      alveolar-arterial oxygen gradient in patients with pulmonary embolism. The survey
      was made in 35 patients aged from 41 to 75 with acute pulmonary embolism, of
      these 17 were men and 18 were women. We excluded patients with coexisting serious
      heart or lung disease. Pulmonary embolism was diagnosed on the grounds of
      presence of commonly known risk factors, sudden onset, findings on the chest
      radiography, hypoxia resistant to oxygen therapy, electrocardiography,
      echocardiography and catheterization of pulmonary artery using a Swan-Ganz
      catheter. The alveolar-arterial oxygen gradient was measured in arterial blood
      samples obtained 15 minutes after 100% oxygen ventilation, using standard
      formulae. All patients were administered heparin, oxygen and warfarine therapy.
      The control group consisted of 20 patients, 11 women and 9 men aged from 37 to
      74, with deep venous thrombosis without coexisting heart or lung disease. In our
      study we showed that the alveolar-arterial oxygen gradient is a very useful
      parameter helping with diagnosis and monitoring efficacy of treatment in patients
      with pulmonary embolism without coexisting heart or lung diseases.

PMID- 10598486
TI  - [Plasma concentrations of endothelin-1 and endothelin-2 in patients with
      pulmonary hypertension].
AB  - Increased pressure in pulmonary artery is connected among other things with
      increased endothelin plasma concentration. The aim of the study was to assess
      plasma endothelin concentration in patients with pulmonary hypertension. The
      analysis comprised 22 patients with increased pressure in pulmonary artery in the
      course of pulmonary thromboembolism or chronic exacerbated left ventricular
      failure and 10 patients with chronic exacerbated left ventricular failure without
      pulmonary hypertension. Plasma endothelin concentration was measured in pulmonary
      artery and capillary wedge pressure were evaluated with Swan-Ganz catheter and
      also peripheral and pulmonary vascular resistance were calculated. Endothelin
      plasma concentration in peripheral vein was compared between patients and healthy
      volunteers. Plasma endothelin concentration in pulmonary artery, peripheral
      artery and vein was higher in patients with pulmonary hypertension than in
      patients with chronic exacerbated left ventricular failure without pulmonary
      hypertension. Plasma endothelin concentration in patients with chronic
      exacerbated left ventricular failure without pulmonary hypertension was higher in
      pulmonary artery than in peripheral artery and vein. At these patients plasma
      endothelin concentration in the peripheral vein didn't differ significantly from
      the healthy volunteers.

PMID- 10598487
TI  - [The use of LGM-type filters inserted into the vena cava in patients with
      neoplasms. Preliminary report].
AB  - The aim of the study was to assess effectiveness and safety of inferior vena cava
      filters in patients with cancer and concurrent thromboembolic disease. The LGM
      filters were inserted in 10 cancer patients. Diagnosis of malignancy was
      established prior filter placement in 8 patients and after the procedure in 2
      patients. Follow-up physical examination and ultrasound procedures (Echo, Duplex
      Doppler) were performed after 1, 3, 6, 12, 24 months. Mean period of observation
      lasted 12 month. All patients received prolonged anticoagulation either oral
      anticoagulants or low molecular weight heparins after filter placement. Our
      results confirm that the LGM filters are effective and well tolerated in patients
      with malignancies. There were no important complications both early and late
      related to filter placement and no evidence of recurrent pulmonary emboli.

PMID- 10598488
TI  - [The extrapulmonary tuberculosis in a 58-year-old man].
AB  - A case of rare form of colliquative tuberculosis in a 58-year old man is
      presented. The preliminary diagnosis was made on the basis of clinical
      observation. Confirmation was achieved after obtaining a significant improvement
      of the general and local condition as a positive results after antituberculous
      therapy.

PMID- 10598489
TI  - [A incidence of cancer in the lateral side of the neck in a 65-year-old woman].
AB  - Branchiogenic carcinoma is a rare condition and should not be diagnosed in the
      absence of the criteria laid down by Dr Hayes Martin. The authors describe a 65
      year-old woman with a cystic mass on the side of the neck. The woman was admitted
      to the hospital for possible branchial cyst. The histopathological analysis
      showed a carcinoma developed on a branchial cyst. The authors stress the
      importance of careful and repeated clinical examinations, which exclude the
      possibility of a primary tumor of other localization.

PMID- 10598490
TI  - [Granular cell tumor of the larynx].
AB  - Granular cell tumor is an unusual growth of probably neuroectodermal
      histogenesis, first reported by Abrikossoff in 1926 with the name of
      myoblastenmyoma. Authors described a case of a 54 year man with laryngeal seat of
      granular-cell myoblastoma. In this case Abrikossoff tumor was located in the
      right vocal chord. The tumor was treated successfully surgically by
      microlaryngoscopy. The etiology, clinical features and diagnostic difficulties
      are discussed.

PMID- 10598491
TI  - [Hypersensitivity to penicillin therapy in the course of treatment: a case
      report].
AB  - Adverse reactions to benzylpenicillin are well known. Full allergy testing is
      time-consuming, expensive and doesn't exclude anaphylaxis to penicillin. It is
      accepted that penicillin allergy is overdiagnosed. Therefore clinical
      observations are not useful for pathogenesis research without follow up
      examination. 100 patients with negative skin test before and with symptoms of
      penicillin hypersensitivity during treatment was diagnosed. We report only 4
      cases of patients, whose allergy to penicillin was confirmed by the same skin
      test. They had received penicillin during serious bacterial infections and had
      experienced allergic symptoms. Skin rush, asthma or hypotension have been
      observed during treatment with penicillin. Immediate hypersensitivity was
      confirmed by positive skin test after treatment. This study reinforce findings of
      our experimental study, when intraperitoneal injections of penicillin and Freunds
      adjuvant or bacterial lysate lead to anaphylactic shock and death of guinea pigs.
      Eastaway et all published similar case report of gas gangrene complicated by
      penicillin allergy. These observations indicate that pathogenesis of penicillin
      allergy may be associated with bacterial infection and nonspecific inflammation.

PMID- 10598492
TI  - [Viral infections, allergy and bronchial asthma].
AB  - In the paper the current views on interrelationship between viral infections and
      bronchial asthma and allergy are reviewed. Data of incidence of viruses in
      bronchial tissue and development of cellular and molecular mechanisms in mucosa
      are presented.

PMID- 10598493
TI  - [Bacteriologically unconfirmed pulmonary tuberculosis: minimal changes problem].
AB  - The correct diagnosis in patients with small radiographic changes sputum smear
      negative is usually time consuming and highly problematic. In this report the
      sensitivity of the new direct amplification tests was evaluated in these clinical
      situations and the immunological criteria of active disease were discussed.
      Patients with small radiographic changes were evaluated in epidemic terms and
      different kinds of therapeutic regimens were assessed.

PMID- 10598494
TI  - [Advances in botulinum toxin applications].
AB  - Botulinum toxin type A is one of the seven serotype /A-G/ produced by the
      anerobic bacterium Clostridium botulinum. It is one of the most potent toxins
      available. Botulinum toxin binds to the motor nerve end-plate and prevents
      acetylcholin release, causing presynaptic neuromuscular blockade. The toxin is
      being increasingly used in the treatment of several form of disorders
      characterized by excessive or inappropriate muscle contraction, including stroke,
      cerebral palsy, multiple sclerosis. Botulinum toxin type A has brought a new
      approach to the effective treatment of dystonias. It has demonstrated additional
      analgesic effect. Among recently describes applications are the treatment of
      tics, tremors, hyperhydrosis, myoclonus, etc.

PMID- 10598495
TI  - [Pet allergens in a house-dust and elimination procedures against them].
AB  - The paper presents a group of allergens carried by the most popular home-kept
      animals (furred animals). Ubiquitous presence of these allergens (at schools and
      in public places) is caused by their specific characteristics different from
      those of house-dust-mites. It is stressed that the serum albumines coming from
      such animals can be the cause of allergic symptoms in the respiratory tract of
      patients suffering from bronchial asthma. The trials carried out so far have
      confirmed the reduction of the animal allergens' amount in different indoor
      environments when several ways of their elimination were applied. However only
      few clinical trials have been made to estimate the improvement of ventilation
      parameters, bronchodilatators requirement and the symptom intensification in
      bronchial asthma cases, after employing some of the recommended methods often in
      the continuing presence of the animal at home. Education and encouraging
      bronchial asthma patients and their families to get rid of animals from their
      homes and acquiting them with various reservoirs of animal allergens as well as
      the allergens' distribution and translocation should become the basis of
      therapeutic management in that group of patients.

PMID- 10598496
TI  - [Anti-flu prophylaxis in the opinion of primary care physicians and specialists].
AB  - Epidemics of influenza occurring each year in Poland in winter are a serious
      health problem and bring underestimated financial losses. Complications from
      influenza are the main threat to health and life of very young and very old
      people or those who are chronically ill. Economic consequences, especially those
      of health care and absenteeism at work and school, are underestimated. All of
      them may be made less intense by the influenza vaccinations. Unfortunately, this
      is the influenza vaccine that is the less often used for prophylactic purposes.
      It seems that the main cause is that most physicians and patients have little
      knowledge about the seriousness of the complications and the possibility of
      avoiding them by applying the vaccination. However, according to the unanimous
      opinion of experts, artificial immunisation is the most sufficient way of
      individual and mass protection against the catastrophic results connected with
      the disease and its complications. It should become a rule that each patient who
      is a member of high-risk group for complications of influenza, should be advised
      by his or her physician to take the vaccination every year to avoid the
      consequences of possible influenza. In order to obtain the maximum protection
      level, the members of high-risk group and the people who are in close contact
      with them should be the subjects of a vaccination schedule. The Advisory
      Committee on Immunisation Practices (ACIP) has appointed the groups of particular
      indications for influenza vaccination. The frequent reason of giving up the
      vaccination is a wrong conviction that the influenza vaccination may often cause
      complications or even influenza itself. In fact, serious complications after the
      vaccination, in modern terminology called Adverse Event Following Immunisation
      (AEFI), are extremely rare, and after the vaccination they are almost always
      connected with previously undistinguished allergy to the components of the
      vaccination, what makes a contraindication. Vaccination of members of the high
      risk group each year before the influenza season in now the most sufficient way
      of the reduction of financial and health losses made by an epidemic of influenza.
      Primary-care physicians and specialists are to play a special role in prevention
      by advising their patients to be vaccinated and by organising mass vaccinations.
      The influenza vaccination should be one of the basic medical procedures in health
      care in case of the members of high-risk group. It should also become one of the
      services financed by social health insurance.

PMID- 10598497
TI  - [New data on paroxysmal atrial fibrillation].

PMID- 10598498
TI  - [Malassezia infections in animals].

PMID- 10598499
TI  - [Multiple sclerosis: one or several diseases?].
AB  - The various clinical courses of multiple sclerosis (relapsing-remitting, primary
      progressive, secondary progressive, progressive-relapsing) are likely related to
      different severity or distribution of the main lesions that constitute the
      plaques (inflammation, demyelination, axonal injury and loss, necrosis). They
      might lead to different therapeutic approaches. Some cases of the other clinico
      radiological or clinico-pathological variants (pseudo-tumoral, concentric
      sclerosis of Balo, acute disseminate encephalomyelitis, Devic's neuromyelitis
      optica) obviously share similar mechanisms with multiple sclerosis. Other cases
      are, on the contrary, linked to different diseases. Do the variants of multiple
      sclerosis could be the consequence of different diseases? This is, today, a
      highly speculative conjecture. The prevalent hypothesis suggests that the clinico
      pathological heterogeneity of multiple sclerosis is linked to the variability of
      the reaction of the nervous tissue to an initial injury. This different
      vulnerability, that depends on unknown factors, would explain the variants of the
      disease.

PMID- 10598500
TI  - [Environment, genetics and immunology in multiple sclerosis].
AB  - The cause of multiple sclerosis remains unknown. Epidemiological studies indicate
      that it is a multi-factorial disease. The environmental factors are still
      unknown. No virus has been yet demonstrated to play a role in multiple sclerosis.
      The role of HLA in the genetic susceptibility has been known since the seventies;
      the detailed analysis is underway. Immunological factors playing a role in the
      course of multiple sclerosis are better known and may serve as basis to new
      therapeutical approaches.

PMID- 10598501
TI  - [Diagnosis of multiple sclerosis].
AB  - Diagnosis of multiple sclerosis is based on detection of a disseminated
      demyelinating inflammatory disorder of the central nervous system with a
      progressive course and(or) exacerbations. Essential data is obtained by study of
      the cerebrospinal fluid and magnetic resonance imaging. Other causes of white
      matter disorders (vascular, compressive or tumoral) are less important in
      differential diagnosis than are other monophasic demyelinating inflammatory
      disorders, such as acute disseminated encephalomyelitis, idiopathic optic
      neuritis and idiopathic myelitis.

PMID- 10598502
TI  - [Evolution and surveillance of multiple sclerosis].
AB  - Multiple sclerosis is a highly complex disease due to the great diversity of
      symptoms and signs from disseminated demyelinating CNS lesions which lead to
      different levels of handicap, and to the different types of evolution
      (exacerbations or slow progression). Most of the patients with multiple sclerosis
      have a normal longevity. The main concern is the accumulation of disabilities. In
      order to follow accurately the progression of these disabilities, specific
      scales, especially EDSS, have been validated allowing more uniformity in method
      of collecting data from multiple sclerosis.

PMID- 10598503
TI  - [Towards a reliable prognosis for multiple sclerosis].
AB  - Although the general course of multiple sclerosis is well known from natural
      history studies, the determination of a detailed prognosis in a given individual
      is almost an insurmountable task. Cerebral magnetic resonance imaging is the best
      predictor of conversion to definite multiple sclerosis after a first
      demyelinating event. The main factors indicative of long-term bad prognosis are:
      onset after the age of 40, initial pyramidal or cerebellar signs, high relapse
      rate during the first two years, and onset of the progressive phase. Altogether,
      up to 20% of patients have a benign course.

PMID- 10598504
TI  - [Treatment of symptoms and relapses of multiple sclerosis].
AB  - Multiple sclerosis is a demyelinating disease of the central nervous system, with
      relapses. For more than 30 years steroids have been used in order to treat
      relapses. Available trials performed to determine which posology or
      administration route, and their efficacy, provided poor certitudes. Multiple
      sclerosis leads to symptoms that alter the quality of life. For fatigue, pain,
      spasticity and micturition disorder a treatment will be proposed.

PMID- 10598505
TI  - [Disease-modifying treatments in multiple sclerosis].
AB  - The number of available disease-modifying agents in multiple sclerosis has been
      increasing dramatically since 1993. First, interferon beta-1b has been licensed
      for exacerbating-remitting forms. Then, efficacy has been demonstrated for
      intramuscular or subcutaneously administered interferon beta-1a in the same
      indication. More recently, utility of interferon beta-1b in secondary progressive
      forms has also been proved. Concomitantly, with glatiramer acetate, the concept
      of a specific intervention on myelin auto-reactive T-cells been validated.
      Lastly, the classical approach of a global immunosuppression is still of
      interest. A better utilization of the currently available medications, an
      improvement of their efficacy/tolerance ratio, the exploration of new concepts
      such as neuro-protection and remyelination may soon lead to more significant
      advances.

PMID- 10598506
TI  - [Social and economic impact of multiple sclerosis].
AB  - The evolution of multiple sclerosis is unforeseeable; it can induce disability
      and fatigue; thus, it has a socio-economical impact. Married and family life,
      relationships and work are the most affected areas. Financial problems can also
      occur. Counselling and aid services must be provided. All these social impacts
      induce an indirect cost which is the major component of the total cost of
      multiple sclerosis. Data show that there are great differences between countries
      and that the cost increases when there is a disability. The economic impact of
      the "new" drugs is unknown and must be assessed.

PMID- 10598507
TI  - [Continuing medical education (19990-2000): the stages (I)].

PMID- 10598508
TI  - [Erythema nodosum. Diagnostic orientation].

PMID- 10598509
TI  - [Shoulder pain. Diagnostic orientation].

PMID- 10598510
TI  - [Acute dehydration in the infant. Physiopathology, diagnosis, urgent treatment].

PMID- 10598511
TI  - [Parkinson's disease. Physiopathology, diagnosis, evolution, treatment].

PMID- 10598512
TI  - [Cancer of the uterine cervix. Epidemiology, pathologic anatomy, diagnostic
      evolution, principles of treatment, staging].

PMID- 10598513
TI  - [Manic-depressive disease. Diagnosis, evolution, treatment].

PMID- 10598514
TI  - [Rabies. Epidemiology, prevention].

PMID- 10598515
TI  - [Erosions and wedge-shaped defects in Swiss Army recruits].

PMID- 10598516
TI  - [The type testing of light-polymerization equipment, I: the testing protocol].
AB  - With the spread of light polymerisation in dentistry for curing light-activated
      filling and luting materials the visible-light curing unit has become a standard
      device in the dental office. The light intensity is the main factor for the
      degree of polymerisation. However, there are other factors like comfort, handling
      and intensity control influencing daily use. The light curing unit industry is
      large and always changing. Consumer information is rare and often out of date.
      Considering these facts the present study presents a concept of investigating
      light curing units. In a further study all light curing units available on the
      Swiss market will be investigated using this protocol. Newly released light
      curing units should be investigated in this manner to actualize the existing
      results. Initially specifications and features are summarised using a
      questionnaire. Several tests are performed to investigate the parameters of the
      units. The light intensity emitted from the curing tip is analysed by the radiant
      power, the radiance and the light distribution across the face of the light
      curing tip as a function of time. Precise radiometers and a camera for picture
      processing are used for these measurements. Density filters are used to reduce
      the radiant power. The measurements of the precise radiometer are compared with
      those of the integrated radiometer of the light-curing unit. In this way the
      precision of integrated radiometers is controlled at maximum and reduced output.
      For evaluating the presence and the quality of integrated voltage stabilizer, the
      line voltage is varied from 230 V down to 207 V and up to 244 V and the radiant
      power is measured. The integrated timer is measured for its accuracy in each
      unit. The time intervals are controlled using a stopwatch. Finally the cooling
      device is tested. Using a phonometer the noise of the cooling fan is measured.
      Furthermore, the overheating protector is controlled by recording the activating
      and resetting time.

PMID- 10598517
TI  - [The mechanisms of the development of secondary exacerbation during laser therapy
      in patients with ischemic heart disease and the possible ways to prevent it].
AB  - In view of possible exacerbation of ischemic heart disease in laser therapy as a
      result of structural modification of biomembranes it is suggested to prevent
      secondary exacerbation by combination of laser therapy with membranoprotectors
      including antioxidants, lipase inhibitors, phospholipases and essential
      phospholipids.

PMID- 10598518
TI  - [Magneto-optic therapy in patients with complicated forms of postthrombotic
      disease].

PMID- 10598519
TI  - [The characteristics of the geroprotective action of magnetotherapy in elderly
      patients with combined cardiovascular pathology].
AB  - Central hemodynamics, diastolic and pumping functions of the heart, myocardial
      reactivity, microcirculation and biological age of cardiovascular system were
      studied in 66 elderly patients suffering from hypertension and ischemic heart
      disease. The patients received systemic magnetotherapy which produced a
      geroprotective effect as shown by improved microcirculation, myocardial
      reactivity, central hemodynamics reducing biological age of cardiovascular system
      and inhibiting its ageing.

PMID- 10598520
TI  - [A comparative evaluation of the efficacy of the monotherapy of peptic ulcer
      using EHF-puncture and basic drug therapy].
AB  - 20 patients with gastric ulcer and 82 ones with duodenal ulcer received basic
      chemotherapy. 23 patients with gastric ulcer and 97 patients with duodenal ulcer
      were treated with EHF-puncture. Pain and dyspeptic syndromes in EHF-puncture
      patients were relieved 2.5-3 times quicker than in chemotherapy. Time of scarring
      of ulcer defect reduced, on the average, 1.5-fold. Fibrogastroduodenoscopy
      detected mucosal erosions in 55% of patients with gastric and 26% of duodenal
      ulcer patients given ampicillin. In patients treated with EHF-puncture erosions
      were found in 2.2% of patients.

PMID- 10598521
TI  - [The effect of acupuncture on the gastric acid-forming function in patients with
      duodenal peptic ulcer].
AB  - Acupuncture of points E36 Zusanli and auricular points is shown to influence acid
      production in the body of the stomach and alkalinization in the stomach antrum in
      patients with duodenal ulcer and hyperacidity. 20-min acupuncture on points E36
      intensifies acid production while 40-min procedure inhibits acid production.
      Combination of auricular and corporal acupuncture enhances acid production
      suppression in gastric body and improves alkalinizing function of the antrum.

PMID- 10598522
TI  - [The effect of pharmacopuncture on the blood biochemical indices of patients with
      tunnel syndromes of the hands].
AB  - Concentrations of serotonin, beta-endorphine, myoglobin, basic myelin protein
      were measured in blood of patients with tunnel hand syndromes treated by
      actovegin or physiological solution pharmacopuncture and acupuncture to the same
      acupuncture points (AP). The above biochemical indices showed similar changes in
      pharmacopuncture with actovegin and the solution. These changes were different in
      acupuncture. This indicates specificity of AP stimulation by introduction of
      fluid, but not specificity of drug effects.

PMID- 10598523
TI  - [The efficacy of the additional (at night) taking of potable mineral water in
      chronic secondary pyelonephritis in children].

PMID- 10598524
TI  - [Heparin electrophoresis by sinusoidal modulated currents in the combined
      treatment of chronic fetoplacental insufficiency].
AB  - Physicochemical grounds are presented for application of heparin electrophoresis
      with sinusoidal modulated currents (SMC) for correction of impaired
      fetouteroplacental circulation and blood rheocoagulation basing on the evidence
      obtained in 95 gravidae on gestation trimester II. 25% of them were in the group
      of risk by chronic fetoplacental insufficiency (CFPI), 63% had compensated CFPI
      and 12% of patients--subcompensated CFPI. 50 patients were treated with drugs SMC
      heparin electrophoresis, 25 patients received SMC and basic medication, 20
      patients were given drugs only. Compared to drugs or SMC treatment only, SMC
      heparin electrophoresis produced more beneficial effects on hemostasis, barrier
      placental function, reduced frequency of premature and operative labour.

PMID- 10598525
TI  - [Sodium humate in the treatment of osteoarthrosis patients].
AB  - The authors' study of sodium humate balneotherapy in rehabilitation of
      osteoarthrosis patients has shown that such balneotherapy produces analgetic,
      antiinflammatory and lipid modulating effects, improves metabolic processes. Low
      concentration of the preparation and lack of effects of other mud factors make
      sodium humate procedures rather tolerable. Osteoarthrosis patients can apply the
      procedure in home setting.

PMID- 10598526
TI  - [Electrophysiological studies by the method of measuring the transcutaneous
      electrical current with Nakatani tables in healthy men exposed in a thermal
      chamber].
AB  - Impedance measurement is a simple and adequate method which can provide rapid
      diagnosis and therefore control of human health. In compensated diseases table
      method of Y. Nakatani is perspective in diagnosis.

PMID- 10598527
TI  - [The characteristics of the action of low-frequency magnetic fields with
      different parameters in experimental endotoxemia].
AB  - Rat experiments were made to study effects of magnetic fields varying in
      parameters on the course of endotoxemia and relevant changes. Dynamics of
      temperature and pain reactions, some biochemical indices depends much on
      frequency and impulse characteristics of low-frequency magnetic field.

PMID- 10598528
TI  - [Spermatogenesis in rats given potable sulfated mineral water in the early
      postradiation period].
AB  - Rat experiments have shown that course intake (21 days) of sulphate sodium
      magnesium-calcium water with sulphate concentration 2.6 mg/l and mineralization
      3.1 g/l in early postradiation period (1-2 Gy) inhibits development of dystrophic
      and destructive processes in spermatogenic epithelium of the testes and maintains
      spermatogenesis at higher level than control.

PMID- 10598529
TI  - [The combined action of different forms of iodine and organic iodine compounds
      and of superhigh-frequency electromagnetic fields on the excitability and
      accommodative capacity of nervous and muscular tissues in frogs].
AB  - Experiments on 130 male lake frogs were made to study a combined action of SHF
      electromagnetic fields (microwaves) and baths KI + I2, DMSO, KI + I2 + DMSO,
      iodinol, iodinol + DMSO, humic acids, humic acids + KI + I2, humic acids + DMSO,
      sapropel + DMSO on excitability and accommodation ability of nervous and muscular
      tissues. The most perspective combinations (by the number of statistically
      significant shifts of 6 electrophysiological parameters) were selected for
      screening on warm-blooded animals. These were SHF microwaves + KI + I2, SHF
      microwaves + iodinol.

PMID- 10598530
TI  - [The effect of a simulated speleologic aerosol from a karst cave on patients with
      chronic bronchitis].

PMID- 10598531
TI  - [The effect of laser therapy on the quality of life of rheumatoid arthritis
      patients].

PMID- 10598532
TI  - [The use of the methods of traditional and nontraditional medicine in the
      combined treatment of headaches].

PMID- 10598533
TI  - [The combined treatment of acute serous mastitis with cold, an alternating
      magnetic field and ultrasound].

PMID- 10598534
TI  - [Sodium-calcium sulfate mineral water in the rehabilitation of convalescent
      patients after hemorrhagic fever with renal syndrome].

PMID- 10598535
TI  - [V. I. Sukharev, Moscow health resort specialist and physiotherapist].

PMID- 10598536
TI  - [A. S. Presman--one of the founders of the biophysical trend in physiotherapy].

PMID- 10598537
TI  - [Physical methods in the rehabilitative treatment of patients with chronic
      nonspecific epididymitis].

PMID- 10598538
TI  - [The review of standards documents in the field of physiotherapeutic care for the
      population].

PMID- 10598539
TI  - Molecular mechanisms.
AB  - The clinically useful and potent distal acting diuretics enhance urinary NaCl
      excretion by specific inhibition of distinct sodium transport processes in the
      loop of Henle and distal nephron. When these compounds were first used as
      diuretics little was known about their cellular mechanisms of action.
      Physiological investigations over the past 25 years, however, have shown that
      each class of diuretics inhibits a specific ion transport system in the kidney.
      Over the past few years, the molecular cloning of the distal diuretic-sensitive
      Na+ transporters has significantly enhanced our understanding of the mechanism of
      action of each class of diuretics and has clearly defined the specific protein
      (and its gene) that is the target for each of these diuretics. The identification
      of mutations in the genes encoding these transporters in inherited disorders
      characterized by alterations in salt balance has provided unequivocal evidence
      for roles of the cloned diuretic-sensitive transporters in sodium homeostasis.
      Many laboratories are actively engaged in defining the structural sites for ion
      transport and diuretic binding, and the molecular mechanisms of transport
      regulation. This information may enable the design of new diuretics and provide
      the basis for improved use of diuretics. This review will focus on this recent
      molecular information.

PMID- 10598540
TI  - Mechanism of action of amiloride: a molecular prospective.
AB  - Amiloride is a prototypic inhibitor of epithelial sodium channels. Rapid progress
      has been made in our understanding of the structure of the sodium channel and
      related cation-selective channels. This work, coupled with experiments examining
      how selected sodium channel mutations affect amiloride binding, provides critical
      clues towards defining sites within the channel that bind amiloride. Residues
      within the channel pore and within its extracellular domain participate in
      amiloride binding. These results suggest that sites that interact with amiloride
      within the channel's extracellular domain may be in close proximity to residues
      within the channel's pore.

PMID- 10598541
TI  - Aquaporin mediated water flux as a target for diuretic development.
AB  - Within the past decade an entire family of membrane proteins--aquaporins--which
      function as transmembrane water channels has been identified; they occur
      throughout the plant, animal, and bacterial kingdoms. Several family members
      permit glycerol and urea permeability. Most aquaporins are inhibited by mercury.
      Constitutively expressed aquaporin 1 is the major permeability channel of the
      proximal tubule, descending thin limb of the loop of Henle, and it is also found
      in vasa recta. Aquaporin 2 is expressed in the principal cells of the collecting
      duct where it shuttles between intracellular vesicles and the apical membrane in
      response to vasopressin. Aquaporin 2 mutations cause nephrogenic diabetes
      insipidus; increased aquaporin 2 activity is implicated in the pathophysiology of
      heart failure, cirrhosis, and nephrotic syndrome. Aquaporins 3 and 4 provide
      basolateral membrane water channels in the collecting duct. These 4 channels and
      6 others are also found elsewhere throughout the body. The physiological
      importance of several of the channels remains unknown. Aquaporin 1 inhibitors
      might induce useful diuresis, but humans who lack aquaporin 1 have no significant
      clinical disease. Inhibition of aquaporin 2 activity by vasopressin receptor
      antagonists may be useful in heart failure, cirrhosis, nephrotic syndrome, and
      the syndrome of inappropriate antidiuretic hormone (ADH) release.

PMID- 10598542
TI  - Diuretic effects on calcium metabolism.
AB  - Diuretics have numerous effects on calcium metabolism. The loop diuretics
      promote, and the thiazide diuretics inhibit, renal calcium excretion. In this
      review we detail the basic mechanisms of renal calcium excretion and then explain
      how diuretics influence this excretion. Finally we review how these agents can be
      used to alter calcium homeostasis in a clinically efficacious manner.

PMID- 10598543
TI  - Metabolic and adverse effects of diuretics.
AB  - Diuretics are among the most frequently prescribed drugs. They enjoy a very high
      clinical reputation for safety and efficacy. However, more than 3 decades of
      clinical investigation have disclosed a number of abnormalities in fluid
      electrolyte handling, metabolism, and other adverse effects that can complicate
      therapy with diuretic drugs. Some of these complications are a direct extension
      of the wanted action of the drug. These include extracellular fluid volume
      depletion, associated orthostatic hypotension, and prerenal azotemia. Others are
      not a direct action of the diuretic, but can be explained as an intranephronal
      compensation to the diuretic action. These include hypokalemia, in part to
      increased potassium secretion secondary to the enhanced tubular fluid flow and
      aldosterone secretion induced by diuretic administration. Metabolic abnormalities
      are usually mild. Hyperglycemia and carbohydrate intolerance have been related to
      diuretic-induced hypokalemia, which inhibits insulin secretion by the beta cells,
      and reductions in extracellular fluid volume and cardiac output. This is
      compounded by increases in catecholamines from sympathetic nerve activity which
      decrease peripheral glucose utilization. A mild increase in serum cholesterol
      concentration is seen frequently during initiation of diuretic therapy, but
      during steady state therapy after 6 to 12 months, values usually return to
      baseline. Knowledge of the more common adverse effects induced by diuretics helps
      the physician in predicting patients at risk and taking effective steps to
      anticipate or treat adverse responses.

PMID- 10598544
TI  - Diuretics: correct use in hypertension.
AB  - The use of diuretics for the treatment of hypertension had fallen significantly
      from 1990 until 1997, when their use again began to increase. Their recent return
      to popularity reflects 3 major factors: (1) the recognition of the effectiveness
      of much lower doses than used previously, thereby providing good antihypertensive
      action with fewer side effects; (2) the excellent reductions in morbidity and
      mortality achieved by low-dose diuretic-based therapy in multiple, randomized
      controlled trials in elderly hypertensives; and (3) the increasing recognition
      that some diuretic-induced shrinkage of effective blood volume is essential for
      adequate treatment of many, if not most, hypertensives.

PMID- 10598545
TI  - Use of diuretics in cirrhosis and nephrotic syndrome.
AB  - Patients with cirrhosis and with nephrotic syndrome have subnormal responses to
      diuretics. The mechanism of this effect in cirrhosis is decreased
      pharmacodynamics of response. Large doses of diuretic are not useful in this
      setting. Instead, more frequent administration of modest doses is required. In
      nephrotic syndrome, substantial amounts of diuretic are rendered inactive by
      binding to urinary albumin, thereby mandating larger doses. In addition, the
      pharmacodynamics of response are altered so that doses must be administered more
      frequently. Rarely, patients may benefit from combinations of albumin and a loop
      diuretic.

PMID- 10598546
TI  - Diuretic resistance: physiology and therapeutics.
AB  - Diuretic drugs are usually effective treatment for edema when used judiciously.
      However, some patients become resistant to their effects. Adaptation to diuretic
      drugs and diuretic resistance may be caused by similar mechanisms. Diuretic
      adaptations can be classified as those that occur during diuretic action, those
      that cause sodium retention in the short term (causing 'post-diuretic NaCl
      retention'), and those that increase sodium retention chronically (the 'braking
      phenomenon'). Recent experimental work has indicated ways in which kidneys adapt
      to chronic diuretic treatment. First, nephron segments downstream from the site
      of diuretic action increase NaCl reabsorption during diuretic administration
      because delivered NaCl load is increased. Second, when diuretic concentrations in
      the tubule decline, the kidney tubules act to retain Na until the next dose of
      diuretic is administered. Third, the ability of the diuretic to increase renal
      NaCl excretion declines over time, an effect that results both from depletion of
      the extracellular fluid volume and from structural and functional changes of
      kidney tubules themselves. These adaptations all increase the rate of NaCl
      reabsorption and blunt the effectiveness of diuretic therapy. Many times, a
      second diuretic drug is effective treatment for diuretic resistance. Recent
      experimental results suggest that a second drug may act synergistically because
      it blocks the adaptive processes limiting the effectiveness of the first
      diuretic. Based on an understanding of the mechanisms of diuretic adaptation and
      resistance, treatment regimens can be designed to block specific adaptive
      mechanisms and improve diuretic effectiveness.

PMID- 10598547
TI  - Thoughts about medicine in the new millennium.

PMID- 10598548
TI  - Antifolates: the next millennium.

PMID- 10598549
TI  - An overview of folate metabolism: features relevant to the action and toxicities
      of antifolate anticancer agents.

PMID- 10598550
TI  - Recent advances in the understanding of the mechanism of membrane transport of
      folates and antifolates.
AB  - Transport of folates and antifolates in most cells is mediated by the reduced
      folate carrier (RFCI), an anion exchanging concentrative process, which is
      opposed by independent exit pump(s) that are directly coupled to energy
      metabolism. The balance of these processes governs the free intracellular folate
      level that is the substrate for folylpolyglutamate synthetase and determines the
      rate of metabolism of many folates and antifolates to polyglutamate derivatives.
      The RFCI has a high affinity for new-generation antifolates, but the relationship
      between transport and polyglutamylation for all these compounds has not, as yet,
      been defined. Analysis of mutations in RFCI indicate highly selective functional
      changes in binding affinity and/or carrier mobility, raising the possibilities
      that (1) enhanced transport and accumulation of natural folates can result in
      resistance to antifolate inhibitors of purine and pyrimidine synthesis by
      blocking their polyglutamylation to active derivatives, or by competition at the
      target enzyme site without substantial changes in antifolate transport, and (2)
      transport-related resistance to one antifolate might not produce comparable cross
      resistance to another. Impaired export pump function, which results in enhanced
      accumulation of folates in cells and inhibition of antifolate polyglutamylation,
      represents another potential mechanism of resistance to new-generation
      antifolates. Folate receptor-mediated transport is another route of entry of
      folates and antifolates into cells, but its importance has not been well-defined.
      Finally, a low pH transport mechanism is present in a variety of mammalian cell
      lines. However, its relationship to RFCI and other low pH epithelial transporters
      and its ability to transport new-generation antifolates remain to be established.

PMID- 10598551
TI  - Roles of folylpoly-gamma-glutamate synthetase in therapeutics with
      tetrahydrofolate antimetabolites: an overview.
AB  - Folylpoly-gamma-glutamate synthetase (FPGS) catalyzes the addition of several
      equivalents of glutamic acid to the gamma-carboxyl group in the side chain of
      folate cofactors and analogs. Folylpoly-gamma-glutamate synthetase has three
      functions in folate homeostasis in mammals: polyglutamation prevents efflux of
      folate cofactors from the cell, it increases the binding of folate cofactors to
      some of the enzymes of folate interconversion and biosynthesis, and it appears to
      allow the accumulation of folates in the mitochondria that are required for
      glycine synthesis. The efficient substrate activity of the newer generations of
      tetrahydrofolate analogs results in levels of intracellular accumulation of
      cytotoxic drug in any cell expressing FPGS in which the enzyme activity is not
      suppressed by feedback, and the binding of folate inhibitors of thymidylate
      synthase and glycinamide ribonucleotide formyltransferase is substantially
      increased by polyglutamation. Resistance to these drugs appears to be most
      frequently due to mutations that change the level of polyglutamation of parent
      compound, a clear indication of the centrality of the process to the cytotoxicity
      of these drugs. Folylpoly-gamma-glutamate synthetase is widely expressed in human
      tumors and is tightly linked either to proliferation or to a lack of
      differentiation. The cytotoxicity of both thymidylate synthase and purine
      inhibitors requires continued inhibition of target for greater than one
      generation time, so that the integrative function of FPGS adds considerably to
      the efficiency of folate antimetabolites.

PMID- 10598552
TI  - Glutamyl hydrolase: properties and pharmacologic impact.
AB  - Glutamyl hydrolase cleaves the poly-gamma-glutamate chain folate and antifolate
      poly-gamma-glutamates. Its cellular location is lysosomal with large amounts of
      the enzyme constitutively secreted. The highest levels of glutamyl hydrolase mRNA
      in humans is found in the liver and kidney. Baculovirus-expressed human enzyme
      has been used to evaluate the method of hydrolysis of methotrexate-gamma-glu4 and
      MTA-gamma-glu4. In both cases, the substrates are hydrolyzed by removal of the
      outer two gamma-glutamate linkages, yielding glu and gamma-glu2 as the glutamate
      products. Cell lines resistant to 5,10-dideazatetrahydrofolate (lometrexol) have
      sevenfold higher activities of glutamyl hydrolase. These cultures have a 60% to
      90% reduced amount of antifolate polygamma-glutamates and 30% reduced folyl poly
      gamma-glutamates. These results suggest the possibility of using glutamyl
      hydrolase to favorably modulate the activity of antifolate therapy.

PMID- 10598553
TI  - Accumulation of plasma reduced folates after folic acid administration.
AB  - The pharmacokinetics of folic acid, and resultant metabolites thereof, have been
      determined after administration orally and intravenously at 25 mg/m2 and 125
      mg/m2. Saturation behavior was observed for uptake of folic acid into plasma and
      with regard to metabolism to methylenetetrahydrofolate and tetrahydrofolate as
      well as methyltetrahydrofolate. Repetitive oral administration every 6 hours
      resulted in consistently elevated levels of each metabolite pool with the same
      general saturation behavior as observed with single dose administration. This
      repetitive oral administration is concluded to be a suitable means to provide
      uniform elevation of metabolites that could offer protection from undesirable
      toxic effects of drugs such as MTA.

PMID- 10598554
TI  - Enzyme inhibition, polyglutamation, and the effect of LY231514 (MTA) on purine
      biosynthesis.
AB  - The pyrrolopyrimidine-based antifolate, N-?4-[2-(2-amino-3,4-dihydro-4-oxo-7H
      pyrrolo[2,3-d]pyrimidin-5-yl)ethyl ]benzoyl?glutamic acid, LY231514 (MTA) has
      demonstrated antitumor activity in a broad array of human tumors, including
      breast cancer, colon cancer, non-small cell lung cancer, head and neck cancer,
      pancreatic cancer, and other solid tumors. The biochemical basis of this activity
      was explored by measuring activation of MTA by polyglutamation and the activity
      of MTA to inhibit several folate-dependent enzymes: thymidylate synthase,
      dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase
      (GARFT). The enzyme folylpolyglutamate synthase (FPGS) activated MTA very
      efficiently. Using FPGS from two different species, Km values below 2 micromol/L
      and high relative first order rate constants, k' (Vmax/Km) of 6.4 and 13.7
      compared with another substrate, lometrexol, were obtained. The formation of
      polyglutamates of several antifolates were compared in vitro at high and low
      substrate concentrations. At low MTA concentrations, tetraglutamated and
      pentaglutamated MTA were the predominant forms identified after a 24-hour
      incubation period. In contrast, only diglutamyl methotrexate and a mixture
      triglutamylated, tetraglutamylated, and pentaglutamylated forms of the GARFT
      inhibitor lometrexol were formed under the same conditions. At higher substrate
      concentrations (20 micromol/L, 24 hours), greater amounts of each product were
      formed. The major metabolites, however, were triglutamated MTA or triglutamated
      lometrexol, while only diglutamyl methotrexate was recovered. Thus, MTA was an
      excellent substrate for FPGS and it was efficiently metabolized to highly
      polyglutamated species by this enzyme. The activity of MTA and its polyglutamated
      metabolites to inhibit several folate-dependent enzymes was measured. In vitro,
      MTA and its polyglutamates were potent, tight-binding inhibitors of several
      folate-dependent enzymes, including thymidylate synthase, dihydrofolate
      reductase, and GARFT. Preliminary cell-based assays (CCRF-CEM) demonstrated
      inhibition of the purine de novo pathway by MTA, consistent with its
      multitargeted mechanism of action against tumor cells. The combined effects of
      activation of MTA to highly polyglutamated metabolites and the potency of these
      polyglutamates to inhibit multiple folate-dependent enzymes provide a mechanistic
      basis for understanding the broad antitumor activity of this compound against
      many human tumor types.

PMID- 10598555
TI  - Cellular pharmacology of MTA: a correlation of MTA-induced cellular toxicity and
      in vitro enzyme inhibition with its effect on intracellular folate and nucleoside
      triphosphate pools in CCRF-CEM cells.
AB  - The mechanism of action of an antifolate may be investigated using a variety of
      experimental methods. These include experiments in a cell culture setting to
      observe possible protection against drug effects afforded by the end products of
      metabolic pathways, assessing the activity of purified target enzymes in the
      presence of the antifolate, and, finally, the measurement of drug effects on
      intracellular folate and nucleoside triphosphate pools. The current discussion is
      focused on studies using CCRF-CEM leukemia cells that were designed to compare
      and contrast mechanisms of action of the antifolates methotrexate, which is
      primarily a dihydrofolate reductase inhibitor, raltitrexed, a thymidylate
      synthase inhibitor, LY309887, a glycinamide ribonucleotide formyltransferase
      inhibitor, and MTA (multitargeted antifolate), which is a novel antifolate
      antimetabolite. The results of these studies support the hypothesis that MTA
      affects multiple enzymatic targets and has a distinct mechanism of action from
      methotrexate, raltitrexed, and LY309887.

PMID- 10598556
TI  - MTA (LY231514) in combination treatment regimens using human tumor xenografts and
      the EMT-6 murine mammary carcinoma.
AB  - An important component in the development of a new anticancer drug is an
      understanding of its potential for inclusion in combination treatment regimens.
      LY231514, a multitargeted antifolate (MTA), was tested in combination with
      cisplatin, methotrexate, 5-fluorouracil, paclitaxel, docetaxel, doxorubicin,
      LY329201 (a glycinamide ribonucleotide formyltransferase [GARFT] inhibitor), and
      fractionated radiation therapy in vivo using EMT-6 mammary carcinoma, human HCT
      116 colon carcinoma, and human H460 nonsmall cell lung carcinoma grown as
      xenografts in nude mice. Isobologram methodology was used to determine the
      additivity or synergy of the combination regimens. MTA administered with
      cisplatin, paclitaxel, docetaxel, or fractionated radiation therapy produced
      additive to greater than additive tumor response by tumor cell survival assay and
      tumor growth delay. While an additive tumor response was observed when MTA was
      administered with methotrexate, synergistic tumor responses were seen when MTA
      was administered with the GARFT inhibitor, LY329201, or with the topoisomerase I
      inhibitor, irinotecan. MTA was administered in combination with full doses of
      each anticancer agent studied, with no evidence of increased toxicity resulting
      from the combination.

PMID- 10598557
TI  - Prevention of thymidine and hypoxanthine rescue from MTA (LY231514) growth
      inhibition by dipyridamole in human lung cancer cell lines.
AB  - The novel multitargeted antifolate, MTA (N-[4[2-(2-amino-3,4-dihydro-4-oxo-7H
      pyrrolo[2,3-d]pyrimidin-5-yl)-ethy l]-benzoyl]-L-glutamic acid; LY23 1514)
      inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide
      ribonucleotide formyltransferase. The resultant inhibition of the de novo
      thymidylate and purine biosynthesis can be circumvented by salvage of
      extracellular thymidine and hypoxanthine. The first step in the salvage pathway
      is the transport of nucleosides and bases across the cell membrane. Dipyridamole
      inhibits nucleoside transport and in vitro studies have demonstrated that
      dipyridamole can prevent thymidine salvage rescue from antifolate thymidylate
      synthase inhibitors. More recently, dipyridamole also has been shown to prevent
      hypoxanthine rescue from antipurine antifolates in some cell lines but not
      others. The effects of dipyridamole on MTA growth inhibition and end product
      reversal by thymidine and hypoxanthine was investigated in two lung cancer cell
      lines with (A549) and without (COR L23) dipyridamole-sensitive hypoxanthine
      rescue. The IC50 values for MTA-induced growth inhibition were 28 and 640 nmol/L
      for COR L23 and A549 cells, respectively. End product reversal studies show that
      thymidine can completely reverse growth inhibition by IC50 concentration of MTA
      but only partially rescue cells from 10 times the IC50 concentration of MTA. The
      combination of thymidine and hypoxanthine was required for complete reversal from
      MTA at 10 times the IC50 concentration. Dipyridamole blocked the partial rescue
      from MTA-induced growth inhibition by thymidine alone as well as the complete
      rescue by thymidine plus hypoxanthine not only in A549 cells, which have
      dipyridamole-sensitive hypoxanthine transport, but also in COR L23 cells, in
      which hypoxanthine uptake is insensitive to dipyridamole. These studies
      demonstrate that nucleoside and base salvage can compromise the activity of MTA
      in human tumor cell lines, but that dipyridamole can readily prevent salvage and
      restore growth inhibition.

PMID- 10598558
TI  - Biological activity of the multitargeted antifolate, MTA (LY231514), in human
      cell lines with different resistance mechanisms to antifolate drugs.
AB  - Prior studies have indicated that MTA requires intracellular polyglutamation for
      optimal cytotoxic effect and that these polyglutamates potently inhibit several
      key enzymes of folate metabolism, including thymidylate synthase (TS),
      dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase
      (GARFT). In the present studies, we have investigated the mechanistic basis for
      resistance to MTA in several human tumor cell lines. The cell lines were
      developed for resistance by the gradual exposure to stepwise (fivefold) increases
      in the concentration of MTA over a 5-month period. The degree of resistance was
      140-fold for GC3 colon carcinoma, 117-fold for HCT-8 ileocecal carcinoma, and 729
      fold for CCRF-CEM leukemia cells adapted to 2 micromol/L MTA. The lines had
      strong cross-resistance (>3,200-fold) to raltitrexed. Only modest resistance was
      noted for methotrexate and the GARFT inhibitor, LY309887. The cytotoxicity of MTA
      in wild-type cells was only partially alleviated by thymidine addition (5
      micromol/L) and complete protection required the addition of both hypoxanthine
      (100 micromol/L) and thymidine. In contrast, thymidine alone totally lacked
      protective activity in the MTA-resistant lines. The cells either demonstrated a
      GARFT-like reversal pattern (complete protection by hypoxanthine) for GC3MTA or a
      dihydrofolate reductase-like reversal pattern (complete protection by the
      combination of hypoxanthine and thymidine) for HCT-8MTA and CCRF-CEM(MTA) cells.
      Cellular resistance was multifactorial and stable on removal of selective
      pressure. Only GC3MTA cells showed increased TS activity (approximately 40-fold).
      Accumulations of 3H-MTA at 24 hours in CCRF-CEM(MTA), HCT-8MTA, and GC3MTA cells
      were 2%, 6%, and 46% of wild-type values, respectively. We also evaluated the
      cytotoxic activity of MTA in MCF-7 breast carcinoma and H630 colon carcinoma
      cells selected for resistance to raltitrexed and 5-fluorouracil, respectively,
      via TS amplification (provided by Dr P.G. Johnston, Belfast, Ireland). These
      cells demonstrated more than 200-fold less resistance to MTA compared with
      raltitrexed and MTA-induced cytotoxicity was prevented by hypoxanthine. These
      studies suggest that in addition to TS modulation, secondary targets emerge
      during the development of MTA resistance.

PMID- 10598559
TI  - Clinical pharmacokinetics of antitumor antifolates.
AB  - Antifolate drugs, as a class, have broad-spectrum activity against both
      hematologic and solid human malignancies. The pharmacokinetics of the classical
      antifolate methotrexate have been well-defined and pharmacokinetic data can be
      exploited to reduce the toxicity and enhance the activity of the drug.
      Methotrexate remains the only anticancer drug for which plasma drug level
      monitoring is used in routine clinical practice. Recently, novel classical and
      nonclassical antifolates have been developed that target either specific folate
      dependent enzymes (e.g., thymidylate synthase [CB3717, raltitrexed, ZD9331,
      1843U89, nolatrexed, AG331], glycinamide ribonucleotide transformylase
      [lometrexol, LY309887, AG2034] or multiple folate-dependent enzymes (e.g.,
      MTA/LY231514). In the early clinical trials of these agents, a number of
      pharmacokinetic-pharmacodynamic relationships were identified and it is highly
      likely that the full therapeutic potential of these new drugs will also require
      the exploitation of pharmacokinetic data.

PMID- 10598560
TI  - Overview of phase I trials of multitargeted antifolate (MTA, LY231514).
AB  - Multitargeted antifolate (MTA, LY231514) is a novel antifolate antimetabolite,
      with antitumor activity via inhibition of thymidylate synthase, glycinamide
      formyl transferase, and dihydrofolate reductase. Three dosing schedules have been
      investigated in the phase I setting: daily x5 every 21 days, weekly x4 every 42
      days, and once every 21 days. The maximum tolerated doses on these schedules were
      4.0 mg/m2, 30 mg/m2, and 600 mg/m2, respectively. The major dose-limiting
      toxicity seen on all schedules was neutropenia, with a greater degree of
      reversible liver biochemistry disturbances observed on the daily x5 schedule.
      Given that toxicities were manageable and reversible, the antitumor activity
      exhibited, and the convenience of an every-21-day dosing schedule, this schedule
      was selected for phase II evaluation.

PMID- 10598561
TI  - Preliminary results of a phase I study with MTA (LY231514) in combination with
      cisplatin in patients with solid tumors.
AB  - MTA (multitargeted antifolate, LY231514) is a novel antimetabolite resulting from
      structure/activity studies of the lometrexol-type antifolates. It has been shown
      to inhibit various enzymes of folate pathways and has broad antitumor activity in
      a variety of in vitro and in vivo tumor models. Clinical phase 1 studies have
      been performed using different administration schedules, and subsequently the
      every-21-days schedule has been selected for further development. We report the
      preliminary findings from a combination phase I study of MTA and cisplatin
      administered every 21 days. In the first cohort (34 patients), both agents were
      administered on day 1 with a starting dose of 300 mg/m2 MTA and 60 mg/m2
      cisplatin. In a second cohort (10 patients), MTA (500 or 600 mg/m2) was
      administered on day 1 followed by cisplatin (75 mg/m2) on day 2. The maximum
      tolerated doses were reached at 600 mg/m2 MTA/100 mg/m2 cisplatin (cohort 1) and
      600 mg/m2 MTA/75 mg/m2 cisplatin (cohort 2). In cohort 1, dose-limiting
      toxicities consisted of reversible myelosuppression with leukopenia and
      neutropenia. In addition, delayed fatigue also was of clinical significance.
      Pharmacokinetic analyses indicated that hydration administered before the
      administration of cisplatin did not influence the major pharmacokinetic
      parameters of MTA. Eleven objective remissions were observed, including one
      complete response in a patient with relapsed squamous cell carcinoma of the head
      and neck and partial responses in four of seven patients with mesothelioma In
      contrast, the dose-limiting toxicities in patient cohort 2 consisted of
      neutropenic sepsis, diarrhea, and skin toxicity with two possibly treatment
      related deaths on study. No objective remissions are presently observed in cohort
      2. We conclude that the combination of MTA and cisplatin is feasible and
      clinically active when both agents are administered on day 1 and that it should
      be pursued for further clinical development.

PMID- 10598562
TI  - A phase I trial of MTA and gemcitabine in patients with locally advanced or
      metastatic cancer.
AB  - MTA has demonstrated activity in breast, lung, bladder, and gastrointestinal
      malignancies in early clinical trials. Gemcitabine is a cytotoxic pyrimidine
      antimetabolite with broad activity against solid tumors. We have demonstrated
      sequence-dependent in vitro cytotoxic synergy when gemcitabine exposure preceded
      MTA exposure in cultured human HCT-8 colon carcinoma cells. A phase I study
      testing this synergy in patients is in progress. To date, 14 patients with solid
      tumors have received 42 courses of treatment at a fixed gemcitabine dose of 1,000
      mg/m2 on days 1 and 8 and escalating doses of MTA (200, 300, and 400 mg/m2) given
      90 minutes after gemcitabine on day 1. Courses are repeated every 3 weeks. The
      median number of courses received is three (range, one to seven). National Cancer
      Institute Common Toxicity Criteria grade 4 hematologic toxicity lasting less than
      5 days has been leukopenia and neutropenia. Mild to moderate nonhematologic
      toxicities include arthralgia, nausea, fatigue, fever, rash, and liver function
      test abnormalities. One partial response occurred in a patient with previously
      treated metastatic gallbladder cancer. Dose escalation continues.

PMID- 10598563
TI  - Overview of phase II trials of MTA in solid tumors.
AB  - MTA (LY231514, multitargeted antifolate) represents a new class of folate
      antimetabolites and inhibits multiple enzymes in the purine and thymidine
      biosynthetic pathways, including thymidylate synthase, dihydrofolate reductase,
      and glycinamide ribonucleotide formyl transferase. Based on the results of phase
      I investigation, the dose and schedule of 600 mg/m2 administered intravenously
      every 21 days was selected to carry into the phase II setting. A number of phase
      II studies are completed or ongoing in a wide range of tumor types, and
      encouraging results have been observed in colorectal, breast, non-small cell
      lung, head and neck, bladder, and cervical cancers.

PMID- 10598564
TI  - MTA, a novel multitargeted antifolate, from preclinical to phase I and beyond:
      summary and conclusions.

PMID- 10598565
TI  - Meiotic studies in Dysdercus Guerin Meneville 1831 (Heteroptera: Pyrrhocoridae).
      I. Neo-XY in Dysdercus albofasciatus Berg 1878, a new sex chromosome determining
      system in Heteroptera.
AB  - The genus Dysdercus Guerin Meneville 1831 represents the only taxon within the
      family Pyrrhocoridae in the New World. Based on morphological features, it has
      been suggested that American species derived from immigrants from the Old World,
      most probably from the Ethiopian Region. So far, 10 species from Dysdercus,
      including six species from the Old World and four species from the Neotropical
      Region have been cytogenetically analyzed. As is characteristic of Heteroptera,
      they possess holokinetic chromosomes and a prereductional type of meiosis. While
      the X1X20 sex chromosome system has been reported in all cytologically analyzed
      species of Dysdercus from the Old World, the system X0 has been found in all but
      one species from the New World, regardless of the number of autosomes in the
      complement. In the present study the male meiosis of D. albofasciatus Berg 1878
      was studied in specimens from four different populations from Argentina. The
      diploid chromosome number was found to be 2n = 10 + neo-XY. The neo-X shows at
      each subterminal region a positively heteropycnotic and DAPI-bright segment which
      corresponds to the ancestral X-chromosome. The origin of this neo-XY system
      involved, most probably, a subterminal insertion of the ancestral X chromosome in
      an autosome, followed by a large inversion, which included part of the original X
      chromosome.

PMID- 10598566
TI  - Comparative chromosome painting between marsupial orders: relationships with a 2n
      = 14 ancestral marsupial karyotype.
AB  - A 2n = 14 karyotype is shared by some species in each of the marsupial orders in
      Australian and American superfamilies, suggesting that the ancestral marsupial
      chromosome complement was 2n = 14. We have used chromosome painting between
      distantly related marsupial species to discover whether genome arrangements in 2n
      = 14 species in two Australian orders support this hypothesis. Cross-species
      chromosome painting was used to investigate chromosome rearrangements between a
      macropodid species Macropus eugenii (2n = 16) and a wombat species in a different
      suborder (Lasiorhinus latifrons, 2n = 14), and a dasyurid species in a different
      order (Sminthopsis macroura, 2n = 14). We demonstrate that many chromosome
      regions are conserved between all three species, and deduce how the similar 2n =
      14 karyotypes of species in the two orders are related to a common ancestral 2n =
      14 karyotype.

PMID- 10598567
TI  - Exclusive localization of tandem repetitive sequences in subtelomeric
      heterochromatin regions of Leymus racemosus (Poaceae, Triticeae).
AB  - Two kinds of tandem repetitive sequences were isolated from Leymus racemosus
      (Lam.) Tzvelev. One of them was classified in the 350-bp family originally
      isolated from Secale. The other was a novel repetitive sequence family, named
      'TaiI family', which consisted of a repeat unit of 570 bp. Fluorescence in-situ
      hybridization of the chromosomes of L. racemosus indicated that both families
      were located in subtelomeric heterochromatin and that the 350-bp family and TaiI
      family occupied different heterochromatin regions. In addition, even homologous
      chromosomes did not show the same patterns of TaiI and 350-bp families. The
      combination of these two families of repetitive sequences, together with Afa
      family sequences and rDNAs, helps to identify the ten homologous chromosome pairs
      of L. racemosus. From these data, we proposed a karyotype of L. racemosus and
      compared it with other karyotypes already reported.

PMID- 10598568
TI  - Genomic differentiation of 18S ribosomal DNA and beta-satellite DNA in the
      hominoid and its evolutionary aspects.
AB  - The chromosome localization of two human multisequence families, rDNA and beta
      satellite (beta-sat) DNA, was determined in humans and apes using double color
      fluorescence in-situ hybridization. Both DNA probes showed a distinct
      hybridization pattern with species-specific variations in hominoids. The stepwise
      differentiation of the integration, amplification, multilocalization, and
      reduction of the DNAs were observed interspecifically through the seven species
      examined. The stepwise events allowed us to trace back a phylogenetic divergence
      of the hominoid at the cytogenetic level. The manifestation of the events
      revealed that variations of the Y chromosome and acrocentric autosomes were
      synapomorphic characters in the divergence and those of metacentric autosomes
      were autapomorphic characters. Multilocalization of rDNA in the hominoid could
      also be interpreted as a result of translocations in terms of hetero-site
      crossover followed by a centric fission and formation of an acrocentric
      chromosome. Based on the observed rearrangements of rDNA and beta-sat DNA, we
      propose the following chromosomal phylogenetic divergence order in hominoids:
      gibbon-siamang-orangutan-gorilla-human-chimpanzee-bonobo. Our data provide
      additional evidence that evolution of the hominoid can be effectively studied
      using cytogenetic approaches.

PMID- 10598569
TI  - The ZW pairs of two paleognath birds from two orders show transitional stages of
      sex chromosome differentiation.
AB  - Pachytene oocytes from the two presumably most primitive orders (Paleognathae)
      among living birds were used to study the pairing behaviour and location of
      recombination nodules (RNs) in the sex pair. In the ratite Pterocnemia pennata
      (Rheiformes), the 42 analyzed ZW pairs show an average of 2.2 RNs distributed
      along 80% of the synaptonemal complex (SC) that covers the long arm of the
      acrocentric Z and W chromosomes in this homomorphic sex pair. In the tinamid
      Rynchotus rufescens (Tinamiformes), the 60 analyzed ZW pairs show an average of
      1.35 RNs distributed along 66% of the SC covering most of the long arms of this
      visibly heteromorphic ZW pair. RNs are non-randomly distributed and show
      interference in both species, but in the tinamou they are restricted to a
      significantly smaller stretch. The discovery of an intermediate degree in the
      restriction of RN location, between the extremes of free recombination along most
      of the W in ratites and strict localization of a single RN in Neognath birds,
      suggests its relationship with the mechanism of sex chromosome differentiation
      among Aves.

PMID- 10598570
TI  - Homozygotes for FRA16B are normal.
AB  - Homozygotes for the rare folate-sensitive autosomal fragile sites have never been
      recorded. Two non-folate-sensitive rare fragile sites (FRA10B and FRA17A) have
      been previously recorded in normal individuals. We document two unrelated normal
      individuals who are homozygotes for the rare fragile site FRA16B and record the
      patterns of induction of this fragile site with berenil. The existence of normal
      homozygotes for FRA16B suggests that this fragile site is not within a gene
      essential for normal development.

PMID- 10598571
TI  - Comparative chromosome banding of two South-American species of rice rats of the
      genus Oligoryzomys (Rodentia, Sigmodontinae).
AB  - Comparative analysis of G- and C-banding patterns in two species of pygmy rice
      rats, namely Oligoryzomys microtis from Peru (Ucayali and Loreto departments) and
      O. flavescens from Bolivia (Tarija department) established that the diploid
      number of the former species is 64 (NFa = 66), whereas, in the latter, it varies
      between 64 and 66 (NFa = 66-68) due to the presence of 0-2 heterochromatic
      supernumerary or B chromosomes. The G-banding pattern of the euchromatic part of
      their karyotypes is similar in spite of differences in morphology of the largest
      and smallest autosomal pairs caused by a centromeric shift and the presence of
      heterochromatic arms, respectively. In addition, the total quantity of C
      heterochromatin is smaller in the karyotype of O. microtis than in that of O.
      flavescens, resulting in differences in the number and size of chromosome pairs
      (including sex chromosomes) bearing C-blocks. It follows from present and
      previous data that these karyotypic features are stable in each of these species
      and thus may be used as species-specific markers.

PMID- 10598573
TI  - A molecular cytogenetic clone resource for chromosome 22.

PMID- 10598572
TI  - The relative rDNA content of a NOR determines its level of expression and its
      probability of becoming active. A sequential silver staining and in-situ
      hybridization study.
AB  - Silver staining was used to estimate the expression of nucleolar organizing
      regions (NORs), and in-situ hybridization (ISH) with rDNA probes was used to
      estimate the relative content of rDNA in each NOR in chromosome preparations of
      the dormouse, Eliomys quercinus, a species with two NOR-bearing chromosome pairs.
      Both types of signals were sequentially investigated on every NOR by using an Ag
      ISH sequential staining method, which made it possible to demonstrate that the
      relative amount of rDNA in a NOR in comparison with the other chromosomes of the
      complement determines its level of expression and its likelihood of becoming
      active, regardless of whether the NORs are homologous or not. We suggest that the
      NORs in each cell are activated in accordance with an established hierarchy. We
      propose a two-stage model to relate NOR structure and function, which is
      consistent with these results and with current knowledge on the molecular
      regulation of NOR transcription.

PMID- 10598574
TI  - Human FUSE binding protein 3 gene (FBP3). Map position 9q33-34.1.

PMID- 10598575
TI  - A role for AKAP (A kinase anchoring protein) scaffolding in the loss of a cyclic
      adenosine 3',5'-monophosphate inhibitory response in late pregnant rat
      myometrium.
AB  - During pregnancy in the rat, there is a change in the ability of chlorophenylthio
      (CPT)-cAMP to inhibit myometrial phosphatidylinositide turnover. This is
      accompanied by a change in the association of proteins with a plasma membrane A
      kinase anchoring protein (AKAP). Both CPT-cAMP and isoproterenol inhibited
      oxytocin-stimulated phosphatidylinositide turnover on days 12 through 20 of
      gestation, whereas neither agent had an effect on day 21. Accompanying this
      change was a dramatic decrease in the concentration and activity of cAMP
      dependent protein kinase [protein kinase A (PKA)] and an increase in the
      concentration of protein phosphatase 2B (PP2B) in plasma membranes from day 21
      compared with day 19 pregnant rats. In contrast, both PKA and PP2B concentrations
      and activities increased in total myometrial homogenates. Both PKA and PP2B
      coimmunoprecipitated with an antibody against the 150-kDa AKAP found in rat
      myometrial plasma membranes. More PKA was associated with AKAP150 on day 19 than
      on day 21, while the reverse was true for PP2B. Disruption of PKA/AKAP
      association in day 19 pregnant rat myometrial cells with the specific interaction
      inhibitor peptide S-Ht31 resulted in the loss of the cAMP-inhibitory effect on
      phosphatidylinositide turnover. PP2B activity in myometrial homogenates
      dephosphorylated PLCbeta3, a PKA substrate targeted in the inhibition of Galphaq
      stimulated phosphatidylinositide turnover. The dramatic loss of the cAMP
      inhibitory effect on day 21 of pregnancy may alter the balance between uterine
      contraction and relaxation near parturition. The changes in the relative
      concentrations of PKA and PP2B associated with AKAP150 are consistent with a
      functional role for AKAP150 scaffolding in the alteration of cellular signaling.

PMID- 10598576
TI  - Pertussis toxin-sensitive and -insensitive thrombin stimulation of Shc
      phosphorylation and mitogenesis are mediated through distinct pathways.
AB  - Activation of both receptor tyrosine kinases (RTKs) and G protein-coupled
      receptors (GPCRs) result in phosphorylation of the adaptor protein Shc, providing
      sites of interaction for proteins in downstream signal transduction cascades. The
      mechanism of Shc phosphorylation and its function in G protein signaling pathways
      is still unclear. By examining Shc phosphorylation in response to thrombin in two
      cell lines, we have defined distinct pertussis toxin (PTX)-sensitive and 
      insensitive mechanisms by which GPCRs can stimulate tyrosine phosphorylation of
      Shc. By mutating the tyrosines in Shc, we show that the three sites of tyrosine
      phosphorylation, Y239, Y240, and Y317, are necessary for thrombin signaling in
      both systems. The SH2 (src homology 2) domain of Shc is also critical for
      signaling, but not required for phosphorylation of Shc. In both cell types,
      inhibition of src family member kinases by chemical inhibitors or microinjection
      block Shc phosphorylation and bromodeoxyuridine (BrdU) incorporation in response
      to thrombin. However, in the PTX-sensitive thrombin pathway, both betagamma
      function and the epidermal growth factor receptor (EGFR) are necessary for Shc
      phosphorylation and BrdU incorporation. In contrast, signaling in the PTX
      insensitive pathway is not mediated through betagamma or the EGFR. Thus, while
      phosphorylation and function of Shc appear to be the same in both thrombin
      pathways, the mechanism of tyrosine kinase activation proximal to Shc is
      different. The differences in signaling between the two thrombin pathways may be
      representative of mechanisms used by other PTX-sensitive and -insensitive GPCRs
      to mediate specific responses. In addition, transactivation of RTKs may be a
      manner by which GPCRs can amplify their signal.

PMID- 10598577
TI  - Protein kinase Cdelta mediates insulin-induced glucose transport in primary
      cultures of rat skeletal muscle.
AB  - Insulin activates certain protein kinase C (PKC) isoforms that are involved in
      insulin-induced glucose transport. In this study, we investigated the possibility
      that activation of PKCdelta by insulin participates in the mediation of insulin
      effects on glucose transport in skeletal muscle. Studies were performed on
      primary cultures of rat skeletal myotubes. The role of PKCdelta in insulin
      induced glucose uptake was evaluated both by selective pharmacological blockade
      and by over-expression of wild-type and point-mutated inactive PKCdelta isoforms
      in skeletal myotubes. We found that insulin induces tyrosine phosphorylation and
      translocation of PKCdelta to the plasma membrane and increases the activity of
      this isoform. Insulin-induced effects on translocation and phosphorylation of
      PKCdelta were blocked by a low concentration of rottlerin, whereas the effects of
      insulin on other PKC isoforms were not. This selective blockade of PKCdelta by
      rottlerin also inhibited insulin-induced translocation of glucose transporter 4
      (GLUT4), but not glucose transporter 3 (GLUT3), and significantly reduced the
      stimulation of glucose uptake by insulin. When overexpressed in skeletal muscle,
      PKCdelta and PKCdelta were both active. Overexpression of PKCdelta induced the
      translocation of GLUT4 to the plasma membrane and increased basal glucose uptake
      to levels attained by insulin. Moreover, insulin did not increase glucose uptake
      further in cells overexpressing PKCdelta. Overexpression of PKCdelta did not
      affect basal glucose uptake or GLUT4 location. Stimulation of glucose uptake by
      insulin in cells overexpressing PKCdelta was similar to that in untransfected
      cells. Transfection of skeletal myotubes with dominant negative mutant PKCdelta
      did not alter basal glucose uptake but blocked insulin-induced GLUT4
      translocation and glucose transport. These results demonstrate that insulin
      activates PKCdelta and that activated PKCdelta is a major signaling molecule in
      insulin-induced glucose transport.

PMID- 10598578
TI  - Caveolin-1 interacts with the insulin receptor and can differentially modulate
      insulin signaling in transfected Cos-7 cells and rat adipose cells.
AB  - Caveolae may function as microdomains for signaling that help to determine
      specific biological actions mediated by the insulin receptor (IR). Caveolin-1, a
      major component of caveolae, contains a scaffolding domain (SD) that binds to a
      caveolin-1 binding motif in the kinase domain of the IR in vitro. To investigate
      the potential role of caveolin-1 in insulin signaling we overexpressed wild-type
      (Cav-WT) or mutant (Cav-Mut; F92A/V94A in SD) caveolin-1 in either Cos-7 cells
      cotransfected with IR or rat adipose cells (low and high levels of endogenous
      caveolin-1, respectively). Cav-WT coimmunoprecipitated with the IR to a much
      greater extent than Cav-Mut, suggesting that the SD is important for interactions
      between caveolin-1 and the IR in intact cells. We also constructed several IR
      mutants with a disrupted caveolin-1 binding motif and found that these mutants
      were poorly expressed and did not undergo autophosphorylation. Interestingly,
      overexpression of Cav-WT in Cos-7 cells significantly enhanced insulin-stimulated
      phosphorylation of Elk-1 (a mitogen-activated protein kinase-dependent pathway)
      while overexpression of Cav-Mut was without effect. In contrast, in adipose
      cells, overexpression of either Cav-WT or Cav-Mut did not affect insulin
      stimulated phosphorylation of a cotransfected ERK2 (but did significantly inhibit
      basal phosphorylation of ERK2). Furthermore, we also observed a small inhibition
      of insulin-stimulated translocation of GLUT4 when either Cav-WT or Cav-Mut was
      overexpressed in adipose cells. Thus, interaction of caveolin-1 with IRs may
      differentially modulate insulin signaling to enhance insulin action in Cos-7
      cells but inhibit insulin's effects in adipose cells.

PMID- 10598579
TI  - Dual signaling of human Mel1a melatonin receptors via G(i2), G(i3), and G(q/11)
      proteins.
AB  - Mel 1a melatonin receptors belong to the super-family of guanine nucleotide
      binding regulatory protein (G protein)-coupled receptors. So far, interest in Mel
      1a receptor signaling has focused mainly on the modulation of the adenylyl
      cyclase pathway via pertussis toxin (PTX)-sensitive G proteins. To further
      investigate signaling of the human Mel 1a receptor, we have developed an antibody
      directed against the C terminus of this receptor. This antibody detected the Mel
      1a receptor as a protein with an apparent molecular mass of approximately 60 kDa
      in immunoblots after separation by SDS-PAGE. It also specifically precipitated
      the 2-[125I]iodomelatonin (125I-Mel)-labeled receptor from Mel 1a-transfected HEK
      293 cells. Coprecipitation experiments showed that G(i2), G(i3), and G(q/11)
      proteins couple to the Mel 1a receptor in an agonist-dependent and guanine
      nucleotide-sensitive manner. Coupling was selective since other G proteins
      present in HEK 293 cells, (G(i1), G(o), G(s), G(z), and G12) were not detected in
      receptor complexes. Coupling of the Mel 1a receptor to G(i) and G(q) was
      confirmed by inhibition of high-affinity 125I-Mel binding to receptors with
      subtype-selective G protein alpha-subunit antibodies. G(i2) and/or G(i3) mediated
      adenylyl cyclase inhibition while G(q/11) induced a transient elevation in
      cytosolic calcium concentrations in HEK 293 cells stably expressing Mel 1a
      receptors. Melatonin-induced cytosolic calcium mobilization via PTX-insensitive G
      proteins was confirmed in primary cultures of ovine pars tuberalis cells
      endogenously expressing Mel 1a receptors. In conclusion, we report the
      development of the first antibody recognizing the cloned human Mel 1a melatonin
      receptor protein. We show that Mel 1a receptors functionally couple to both PTX
      sensitive and PTX-insensitive G proteins. The previously unknown signaling of Mel
      1a receptors through G(q/11) widens the spectrum of potential targets for
      melatonin.

PMID- 10598580
TI  - c-Jun enhancement of cyclic adenosine 3',5'-monophosphate response element
      dependent transcription induced by transforming growth factor-beta is independent
      of c-Jun binding to DNA.
AB  - Transforming growth factor-beta (TGFbeta) enhances transcription from reporter
      genes regulated by a single consensus cAMP-response element (CRE) upon
      transfection into the immortalized human keratinocyte cell line, HaCaT. Whereas
      both CRE-binding protein (CREB) and c-Jun present in extracts of unstimulated
      cells can complex with a CRE in gel-shift experiments, TGFbeta treatment
      increases the amount of c-Jun found in the complex. Overexpression of c-Jun is
      sufficient to increase CRE and GAL4-CREB-dependent transcription and mimics the
      stimulatory effects of TGFbeta on transcription from either reporter gene.
      Surprisingly, although a portion of CREB in unstimulated cells is phosphorylated
      on the activating serine residue, Ser-133, this level of phospho-CREB is not
      altered by TGFbeta treatment. In fact, the CREB-dependent transcriptional effects
      of TGFbeta or c-Jun do not require phosphorylation of Ser-133, although CREB
      binding protein (CBP) is required as evidenced by the observation that the
      adenoviral oncoprotein E1A can block the effects of both agents. c-Jun
      enhancement of CRE or GAL4-CREB-dependent transcription neither requires the DNA
      binding nor N-terminal domains of c-Jun. Collectively, these results are
      consistent with a model in which signaling pathways initiated by TGFbeta can
      stimulate CREB-dependent transcription by increasing the cellular concentration
      of c-Jun, which participates in activation of the CBP-containing transcription
      complex.

PMID- 10598581
TI  - Differentiation-dependent prolactin responsiveness and stat (signal transducers
      and activators of transcription) signaling in rat ovarian cells.
AB  - PRL activates an important cytokine signaling cascade that is obligatory for
      maintaining luteal cell function in the rat ovary. To determine when specific
      components of this cascade are expressed and can be activated by PRL, we analyzed
      the expression of receptor subtypes (short, PRL-R(s), and long, PRL-R(L)), the
      presence and kinetics of Stat (signal transducer and activator of transcription)
      activation using the PRL-response element (PRL-RE) of the alpha2M (alpha2
      macroglobulin) gene, and the content and hormonal regulation of three specific
      modulators of cytokine signaling; the tyrosine phosphatases (SHP-1 and SHP-2),
      and the protein inhibitor of activated Stat3 (PIAS-3). These components were
      analyzed in differentiating granulosa/ luteal cells of hypophysectomized (H) rats
      and in corpora lutea of pregnant rats. Levels of PRL-R mRNAs increased as
      granulosa cells differentiated and reached maximal levels in luteal cells of
      pregnant rats where levels of PRL-R(s) approached those of PRL-R(L). The relative
      concentrations shifted from a 27-fold excess of PRL-R(L) in preovulatory
      granulosa cells to a 3.7-fold difference in luteal cells during midgestation.
      Despite the increased PRL-R(L) expression in differentiated granulosa cells, PRL
      did not stimulate detectable activation of Stats. Rather PRL activation of Stat5,
      principally Stat5b, occurred in association with luteinization. In contrast,
      granulosa cells of untreated immature and H rats contained a high level of DNA
      binding activity, which was shown to be comprised entirely of activated,
      phosphorylated Stat3. Treatment with estrogen and FSH reduced the amount of
      phosphorylated Stat3 and abolished its ability to bind DNA, an effect temporally
      related to increased PIAS-3. Expression of SHP-1 (but not SHP-2) was also
      hormonally regulated; SHP-1 mRNA and protein were high in granulosa cells of H
      rats, decreased by estrogen and FSH, and subsequently increased dramatically with
      luteinization. Of particular note, SHP-1 was localized in cytoplasm of granulosa
      cells in atretic follicles but was distinctly nuclear in luteal cells, indicative
      of different functional roles. Collectively, these results indicate that Stat3
      and Stat5 are activated by distinct cytokine-signaling pathways modulated through
      differentiation-dependent transcriptional regulation of signaling pathway
      components and mediate distinct functional processes in the rat ovary: early
      follicle growth and atresia vs. luteinization.

PMID- 10598582
TI  - A C619Y mutation in the human androgen receptor causes inactivation and
      mislocalization of the receptor with concomitant sequestration of SRC-1 (steroid
      receptor coactivator 1)
AB  - Androgen ablation therapy is a primary treatment for advanced prostate cancer,
      but tumors become refractive to therapy. Consequently, the role of the androgen
      receptors (ARs) and of mutations in the AR in prostate cancer has been a subject
      of much concern. In the course of analyzing tumors for mutations, we identified a
      somatic mutation that substitutes tyrosine for a cysteine at amino acid 619
      (C619Y), which is near the cysteines that coordinate zinc in the DNA binding
      domain in the AR. The mutation was re-created in a wild-type expression vector
      and functional analyses carried out using transfection assays with androgen
      responsive reporters. The mutant is transcriptionally inactive and unable to bind
      DNA. In response to ligand treatment, AR619Y localizes abnormally in numerous,
      well circumscribed predominantly nuclear aggregates in the nucleus and cytoplasm.
      Interestingly, these aggregates also contain the bulk of the coexpressed steroid
      receptor coactivator SRC-1, suggesting, in analogy to AR in spinal bulbar
      muscular atrophy, that this mutant may alter cellular physiology through
      sequestration of critical proteins. Although many inactivating mutations have
      been identified in androgen insensitivity syndrome patients, to our knowledge,
      this is the first characterization of an inactivating mutation identified in
      human prostate cancer.

PMID- 10598583
TI  - In vitro and in vivo analysis of the regulation of a transcription factor gene by
      thyroid hormone during Xenopus laevis metamorphosis.
AB  - A novel, basic region leucine zipper transcription factor (TH/bZIP) is
      dramatically up-regulated at the climax of metamorphosis in Xenopus laevis. It
      can be induced in tadpoles prematurely by thyroid hormone (TH) with kinetics that
      are intermediate between early and late Xenopus TH response genes. A small amount
      of early, cycloheximide-resistant up-regulation is observed, but the majority of
      TH/ bZIP mRNA accumulation occurs after 12 h of treatment in parallel with late
      response gene induction. There are two genomic TH/bZIP genes in the
      pseudotetraploid X. laevis genome that are coordinately regulated. They have
      highly conserved regulatory regions that contain two conserved, adjoining DR+4
      thyroid response elements (TRE) in opposite orientation. The early/late TH
      induction kinetics has been reproduced in transient transfection assays. The
      secondary rise of transcriptional activity requires DNA regions other than the
      TREs and, therefore, the interaction of transcription factors other than the TH
      receptors. Finally, the regulatory region of the TH/bZIP gene has been used to
      drive green fluorescent protein in transgenic X. laevis tadpoles. Regulation of
      the transgene during spontaneous and induced metamorphosis mimics that of the
      endogenous TH/bZIP gene. The newly developed X. laevis transgenesis method has
      distinct advantages for the analysis of transcriptional regulatory elements over
      transient transfection assays and will be useful for further in vivo studies of
      TH-response gene regulation during development.

PMID- 10598584
TI  - Determinants of DNA sequence specificity of the androgen, progesterone, and
      glucocorticoid receptors: evidence for differential steroid receptor response
      elements.
AB  - While androgen, progesterone, and glucocorticoid receptors perform distinct
      physiological functions by regulating unique sets of genes, in vitro they can
      transactivate a common high-affinity DNA-binding target. Naturally occurring
      steroid response elements display nucleotide divergence that lowers binding
      affinity in comparison to the optimal binding element, but enhances receptor-type
      specificity. We investigated the role of nucleotide deviations within the DNA
      binding site for contribution to steroid receptor specificity. We hypothesized
      that receptor specificity drives the evolution of binding site sequence, rather
      than strictly receptor-binding affinity. Receptor-selective targets can evolve by
      some nucleotides selected on the basis of additional bond energy, and others may
      be selected by differential tolerance to discourage binding from inappropriate
      receptors. To identify receptor-specific binding sites, we mimicked these dual
      selection pressures in a receptor-competitive environment in which DNA binding
      sites for the androgen or progesterone receptors were selected in the presence of
      the glucocorticoid receptor. These analyses also demonstrated that steroid
      receptors strongly select nucleotides in the spacer and flanking regions of the
      half-site and do so in an asymmetric fashion, indicating that steroid receptors
      interact with DNA in an allosteric manner that affects the transcriptional
      activation potential.

PMID- 10598585
TI  - Opposing effects of corepressor and coactivators in determining the dose-response
      curve of agonists, and residual agonist activity of antagonists, for
      glucocorticoid receptor-regulated gene expression.
AB  - A distinguishing, but unexplained, characteristic of steroid hormone action is
      the dose-response curve for the regulation of gene expression. We have previously
      reported that the dose-response curve for glucocorticoid induction of a
      transfected reporter gene in CV-1 and HeLa cells is repositioned in the presence
      of increasing concentrations of glucocorticoid receptors (GRs). This behavior is
      now shown to be independent of the reporter, promoter, or enhancer, consistent
      with our proposal that a transacting factor(s) was being titrated by added
      receptors. Candidate factors have been identified by the observation that changes
      in glucocorticoid induction parameters in CV-1 cells could be reproduced by
      varying the cellular levels of coactivators [transcriptional intermediary factor
      2 (TIF2), steroid receptor coactivator 1 (SRC-1), and amplified in breast cancer
      1 (AIB1)], comodulator [CREB-binding protein (CBP)], or corepressor [silencing
      mediator for retinoid and thyroid-hormone receptors (SMRT)] without concomitant
      increases in GR. Significantly, the effects of TIF2 and SMRT were mutually
      antagonistic. Similarly, additional SMRT could reverse the action of increased
      levels of GRs in HeLa cells, thus indicating that the effects of cofactors on
      transcription may be general for GR in a variety of cells. These data further
      indicate that GRs are yet an additional target of the corepressor SMRT. At the
      same time, these cofactors were found to be capable of regulating the level of
      residual agonist activity displayed by antiglucocorticoids. Finally, these
      observations suggest that a novel role for cofactors is to participate in
      processes that determine the dose-response curve, and partial agonist activity,
      of GR-steroid complexes. This new activity of cofactors is disconnected from
      their ability to increase or decrease GR transactivation. An equilibrium model is
      proposed in which the ratio of coactivator-corepressor bound to either receptor
      agonist or -antagonist complexes regulates the final transcriptional properties.

PMID- 10598586
TI  - A fusion protein of the estrogen receptor (ER) and nuclear receptor corepressor
      (NCoR) strongly inhibits estrogen-dependent responses in breast cancer cells.
AB  - Nuclear receptor corepressor (NCoR) mediates repression (silencing) of basal gene
      transcription by nuclear receptors for thyroid hormone and retinoic acid. The
      goal of this study was to create novel estrogen receptor (ER) mutants by fusing
      transferable repressor domains from the N-terminal region of NCoR to a functional
      ER fragment. Three chimeric NCoR-ER proteins were created and shown to lack
      transcriptional activity. These fusion proteins silenced basal transcription of
      the ERE2-tk-Luc reporter gene and inhibited the activity of co-transfected wild
      type ER (wtER), indicating that they possess dominant negative activity. One of
      the fusion proteins (CDE-RD1), containing the ER DNA-binding and ligand-binding
      domains linked to the NCoR repressor domain (RD1), was selected for detailed
      examination. Its hormone affinity, intracellular localization, and level of
      expression in transfected cells were similar to wtER, and it bound to the
      estrogen response element (ERE) DNA in gel shift assays. Glutathione-S
      transferase pull-down assays showed that CDE-RD1 retains the ability to bind to
      steroid receptor coactivator-1. Introduction of a DNA-binding domain mutation
      into the CDE-RD1 fusion protein eliminated silencing and dominant negative
      activity. Thus, the RD1 repressor domain prevents transcriptional activation
      despite the apparent ability of CDE-RD1 to bind DNA, ligand, and coactivators.
      Transcriptional silencing was incompletely reversed by trichostatin A, suggesting
      a histone deacetylase-independent mechanism for repression. CDE-RD1 inhibited ER
      mediated transcription in T47D and MDA-MB-231 breast cancer cells and repressed
      the growth of T47D cells when delivered to the cells by a retroviral vector.
      These ER-NCoR fusion proteins provide a novel means for inhibiting ER-mediated
      cellular responses, and analogous strategies could be used to create dominant
      negative mutants of other transcription factors.

PMID- 10598587
TI  - Effect of ligand and DNA binding on the interaction between human transcription
      intermediary factor 1alpha and estrogen receptors.
AB  - Hormonal regulation of gene activity is mediated by nuclear receptors acting as
      ligand-activated transcription factors. To achieve efficient regulation of gene
      expression, these receptors must interact with different type of molecules: 1)
      the steroid hormone, 2) the DNA response element, and 3) various proteins acting
      as transcriptional cofactors. In the present study, we have investigated how
      ligand and DNA binding influence the in vitro interaction between estrogen
      receptors (ERs) and the transcription intermediary factor hTIF1alpha (human
      transcriptional intermediary factor 1alpha). We first optimized conditions for
      the coactivator-dependent receptor ligand assay to lower ED50, and we then
      analyzed the ability of various natural and synthetic estrogens to allow the
      binding of the two types of proteins. Results were compared with the respective
      affinities of these ligands for the receptor. We then developed a protein-protein
      DNA assay allowing the quantification of cofactor-ER-estrogen response element
      (ERE) complex formation in the presence of ligand and used measurements of
      fluorescence anisotropy to define the equilibrium binding parameters of the
      interaction. We demonstrated that the leucine-charged domain of hTIF1alpha is
      sufficient to interact with ERE-bound ERalpha in a ligand-dependent manner and
      showed that binding of ERalpha onto DNA does not significantly affect its hormone
      dependent association with TIF1alpha. Finally, we show that, mainly in the
      absence of hormone, hTIF1alpha interacts better with ERbeta than with ERalpha
      independently of the presence of ERE.

PMID- 10598588
TI  - Constitutive activation of transcription and binding of coactivator by estrogen
      related receptors 1 and 2.
AB  - In this report, we demonstrate that, in contrast to most previously characterized
      nuclear receptors, hERR1 and hERR2 (human estrogen receptor-related protein 1 and
      -2) are constitutive activators of the classic estrogen response element (ERE) as
      well as the palindromic thyroid hormone response element (TRE(pal)) but not the
      glucocorticoid response element (GRE). This intrinsically activated state of
      hERR1 and hERR2 resides in the ligand-binding domains of the two genes and is
      transferable to a heterologous receptor. In addition, we show that members of the
      p160 family of nuclear receptor coactivators, ACTR (activator of thyroid and
      retinoic acid receptors), GRIP1 (glucocorticoid receptor interacting protein 1),
      and SRC-1 (steroid receptor coactivator 1), potentiate the transcriptional
      activity by hERR1 and hERR2 in mammalian cells, and that both orphan receptors
      bind the coactivators in a ligand-independent manner. Together, these results
      suggest that hERR1 and hERR2 activate gene transcription through a mechanism
      different from most of the previously characterized steroid hormone receptors.

PMID- 10598589
TI  - Cloning of two novel mammalian paralogs of relaxin/insulin family proteins and
      their expression in testis and kidney.
AB  - Based on sequence homology to insulin and relaxin, we have isolated two novel
      genes of the insulin superfamily from mouse tissues. Because these proteins show
      a high similarity to relaxin and relaxin-like factor (RLF or Ley I-L), they were
      named as RIF1 (relaxin/insulin-like factor 1) and RIF2 (relaxin/insulin-like
      factor 2). After RT-PCR, full-length cDNAs of RIF1 and RIF2 were obtained from
      mouse testis and ovary, respectively. In addition, a putative human ortholog of
      RIF1 was isolated from human testis. The deduced coding regions of mRIF1, mRIF2,
      and hRIF1 were 191, 145, and 213 amino acids, respectively, and all three
      proteins contain a typical signal sequence for secretion at their amino terminus.
      Sequence comparison indicated that RIFs encode proteins consisting of B and A
      subunits connected by a long C domain peptide, and the deduced mature proteins of
      these putative ligands are most closely related to relaxin, RLF, and insulin from
      different species. Northern blot analysis showed that RIF1 transcripts are
      approximately 1.2 kb in size and are expressed mainly in testis of mouse and
      human. In contrast, RIF2 message of 2.0 and 1.2 kb are preferentially expressed
      in mouse kidney and are lower in testis, heart, and brain. In addition,
      immunohistochemical analysis showed that testis expression of RIF1 is restricted
      to interstitial cells surrounding seminiferous tubules. In kidney, the RIF2
      message is localized to selected epithelial cells of loop of Henle. The exclusive
      expression pattern of RIF1 and related RLF in testis interstitial cells suggested
      potential physiological roles of these two distinct insulin/relaxin family
      ligands in testis function. Additionally, the spatial expression pattern of RIF2
      suggests a novel role of RIF2 in nephrophysiology. Identification of RIF
      polypeptides expands the family of relaxin- and insulin-like hormones and allows
      future elucidation of the physiological role and hormonal mechanisms for these
      tissue-specific factors.

PMID- 10598590
TI  - The biological action of choriogonadotropin is not dependent on the complete
      native quaternary interactions between the subunits.
AB  - Human CG (hCG) is a member of the glycoprotein hormone family characterized by a
      heterodimeric structure consisting of a common alpha-subunit noncovalently bound
      to a hormone-specific beta-subunit. The two subunits are highly intertwined and
      only the heterodimer is functional, implying that the quaternary structure is
      critical for biological activity. To assess the dependence of the bioactivity of
      hCG on the heterodimeric interactions, alpha- and beta-subunits bearing mutations
      that prevent assembly were covalently linked to form a single chain hCG. Receptor
      binding and signal transduction of these analogs were tested and their structural
      integrity analyzed using a panel of monoclonal antibodies (mAbs). These included
      dimer-specific mAbs, which react with at least four different epitope sites on
      the hormone, and some that react only with the free beta-subunit. We showed that
      there was significant loss of quaternary and tertiary structure in several
      regions of the molecule. This was most pronounced in single chains that had one
      of the disulfide bonds of the cystine knot disrupted in either the alpha- or beta
      subunit. Despite these structural changes, the in vitro receptor binding and
      signal transduction of the single chain analogs were comparable to those of the
      nonmutated single chain, demonstrating that not all of the quaternary
      configuration of the hormone is necessary for biological activity.

PMID- 10598591
TI  - A novel spliced variant of the type 1 corticotropin-releasing hormone receptor
      with a deletion in the seventh transmembrane domain present in the human pregnant
      term myometrium and fetal membranes.
AB  - CRH exerts its actions via activation of specific G protein-coupled receptors,
      which exist in two types, CRH-R1 and CRH-R2, and arise from different genes with
      multiple spliced variants. RT-PCR amplification of CRH receptor sequences from
      human myometrium and fetal membranes yielded cDNAs that encode a novel CRH-R type
      1 spliced variant. This variant (CRH-R1d) is present in the human pregnant
      myometrium at term only, which suggests a physiologically important role at the
      end of human pregnancy and labor. The amino acid sequence of CRH-R1d is identical
      to the CRH-R1alpha receptor except that it contains an exon deletion resulting in
      the absence of 14 amino acids in the predicted seventh transmembrane domain.
      Binding studies in HEK-293 cells stably expressing the CRH-R1d or CRH-R1alpha
      receptors revealed that the deletion does not change the binding characteristics
      of the variant receptor. In contrast, studies on the G protein activation
      demonstrated that CRH-R1d is not well coupled to the four subtypes of G proteins
      (G(s), G(i), G(o), G(q)) that CRH-R1alpha can activate. These data suggest that
      although the deleted segment is not important for CRH binding, it plays a crucial
      role in CRH receptor signal transduction. Second messenger studies of the variant
      receptor showed that CRH and CRH-like peptides can stimulate the adenylate
      cyclase system, with reduced sensitivity and potency by 10-fold compared with the
      CRH-R1alpha. Furthermore, CRH failed to stimulate inositol trisphosphate
      production. Coexpression studies between the CRH-R1d or CRH-R1alpha showed that
      this receptor does not play a role as a dominant negative receptor for CRH.

PMID- 10598592
TI  - Transgenics identify distal 5'- and 3'-sequences specifying gonadotropin
      releasing hormone expression in adult mice.
AB  - GnRH neurons play a critical role in regulating gonadotropin secretion, but their
      scattered distribution has prevented detailed understanding of their molecular
      and cellular properties in vivo. Using GnRH promoter-driven transgenics we have
      examined here the role of 5'- and 3'-murine GnRH sequences in specifying GnRH
      expression in the adult mouse. Transgenic mice bearing a lacZ construct
      incorporating 5.5 kb of 5'-, all the introns and exons, and 3.5 kb of 3'-murine
      GnRH sequence were found to express beta-galactosidase (betagal) immunoreactivity
      in approximately 85% of all GnRH neurons. Deletion of GnRH sequence 3' to exon II
      had no effect upon transgene expression in the GnRH population (89%) but resulted
      in the appearance of ectopic betagal immunoreactivity in several regions of the
      brain. The production of additional mice in which 5'-elements were deleted to
      leave only -2.1 kb of sequence resulted in an approximately 40% reduction in the
      number of GnRH neurons expressing betagal. Mice in which further deletion of 400
      bp allowed only -1.7 kb of 5'-sequence to remain exhibited a complete absence of
      betagal immunoreactivity within GnRH and other neurons. These results suggest
      that elements 3' to exon II of the GnRH gene have little role in enabling GnRH
      expression within the GnRH phenotype but, instead, are particularly important in
      repressing the GnRH gene in non-GnRH neurons. In contrast, elements located
      between -2.1 and -1.7 kb of distal 5'-sequence appear to be critical for the in
      vivo activation of GnRH expression within GnRH neurons in the adult brain.

PMID- 10598593
TI  - Differential activation of pituitary hormone genes by human Lhx3 isoforms with
      distinct DNA binding properties.
AB  - Lhx3 is a LIM homeodomain transcription factor essential for pituitary
      development and motor neuron specification in mice. We identified two isoforms of
      human Lhx3, hLhx3a and hLhx3b, which differ in their ability to trans-activate
      pituitary gene targets. These factors are identical within the LIM domains and
      the homeodomain, but differ in their amino-terminal sequences preceding the LIM
      motifs. Both isoforms are localized to the nucleus and are expressed in the adult
      human pituitary, but gene activation studies demonstrate characteristic
      functional differences. Human Lhx3a trans-activated the alpha-glycoprotein
      subunit promoter and a reporter construct containing a high-affinity Lhx3 binding
      site more effectively than the hLhx3b isoform. In addition, hLhx3a synergized
      with the pituitary POU domain factor, Pit-1, to strongly induce transcription of
      the TSHbeta-subunit gene, while hLhx3b did not. We demonstrate that the
      differences in gene activation properties between hLhx3a and hLhx3b correlate
      with their DNA binding to sites within these genes. The short hLhx3b-specific
      amino-terminal domain inhibits DNA binding and gene activation functions of the
      molecule. These data suggest that isoforms of Lhx3 may play distinct roles during
      development of the mammalian pituitary gland and other neuroendocrine systems.

PMID- 10598594
TI  - Spinal hypotension associated with Cesarean section: will preload ever work?

PMID- 10598595
TI  - Ventilatory management of severe acute respiratory failure for Y2K.

PMID- 10598596
TI  - Effects of crystalloid and colloid preload on blood volume in the parturient
      undergoing spinal anesthesia for elective Cesarean section.
AB  - BACKGROUND: The role of crystalloid preloading to prevent hypotension associated
      with spinal anesthesia in parturients during cesarean section has been
      challenged. Direct measurement of blood volume should provide insight regarding
      the volume-expanding effects. The aim of the current study was to clarify the
      effects of volume preload with either crystalloid or colloid solution on the
      changes in blood volume of parturients undergoing spinal anesthesia for cesarean
      section. METHODS: Thirty-six healthy parturients scheduled for elective cesarean
      section during spinal anesthesia were allocated randomly to one of three groups
      receiving 1.5 l lactated Ringer's solution (LR; n = 12), 0.5 l hydroxyethylstarch
      solution, 6% (0.5 l HES; n = 12), and 1.0 l hydroxyethylstarch solution, 6% (1.0
      l HES; n = 12), respectively. Blood volume and cardiac output were measured
      before and after volume preloading with indocyanine green (ICG), and the
      indocyanine green blood concentrations were monitored by noninvasive pulse
      spectrophotometry. RESULTS: After volume preload, the blood volume significantly
      increased in all three groups (P < 0.01). The volume of infused solution
      remaining in the vascular space in the LR, 0.5-l HES, and 1.0-l HES groups were
      0.43+/-0.20 l, 0.54+/-0.14 l, and 1.03+/-0.21 l, respectively, corresponding to
      28% of lactated Ringer's solution and 100% of hydroxyethylstarch solution
      infused. Significant increases in cardiac output were observed in the 0.5-l and
      1.0-l HES groups (P < 0.01). A significant correlation between the percentage
      increase in blood volume and that of cardiac output was observed by volume
      preloading (r2 = 0.838; P < 0.001). The incidence of hypotension was 75% for the
      LR group, 58% for the 0.5-l HES group, and 17% for the 1.0-l HES group,
      respectively. CONCLUSIONS: The incidence of hypotension developed in the 1.0-l
      HES group was significantly lower than that in the LR and 0.5-l HES groups,
      showing that greater volume expansion results in less hypotension. This result
      indicates that the augmentation of blood volume with preloading, regardless of
      the fluid used, must be large enough to result in a significant increase in
      cardiac output for effective prevention of hypotension.

PMID- 10598597
TI  - Controlled airway pressure therapy, nitric oxide inhalation, prone position, and
      extracorporeal membrane oxygenation (ECMO) as components of an integrated
      approach to ARDS.
AB  - BACKGROUND: Recent years have seen the introduction of innovative additive
      therapies for acute respiratory distress syndrome. However, because there are no
      reliable predictors of response to a particular therapy, potential responders to
      a specific therapeutic intervention may be lost. Therefore, the authors evaluated
      the effect of a combined therapeutic approach on the survival of patients with
      acute respiratory distress syndrome, when treated according to a strict
      algorithm. METHODS: During a 2.5-yr period, 84 patients with acute respiratory
      distress syndrome were assigned to a standardized treatment protocol. Data
      analysis was performed by retrospective review of patient charts. Patients were
      treated using a stepwise treatment algorithm of pressure-controlled ventilation
      (peak airway pressure < 35 cm H2O), positive end-expiratory pressure (PEEP; 12-15
      cm H2O), permissive hypercapnia, inhaled nitric oxide (5-20 ppm), and prone
      positioning. These interventions were termed "conventional therapy." Response to
      treatment was defined as a more than 20% increase in arterial oxygen tension
      (PaO2). Nonresponders were triaged to extracorporeal membrane oxygenation.
      RESULTS: The overall survival rate was 80%. All patients received conventional
      therapy up to 96 h; 71 responded to conventional therapy and 59 survived (83%).
      Thirteen patients (15%) did not respond to conventional therapy and underwent
      extracorporeal membrane oxygenation; 8 of these patients (62%) survived. For the
      group, the mean admission lung injury score was 3.3+/-0.5, the PaO2/fractional
      inspired oxygen tension (F(I)O2) ratio was 96+/-45, and the Acute Physiology and
      Chronic Health Evaluation (APACHE) II score was 18+/-6. CONCLUSIONS: The 80%
      overall survival rate achieved in this group of patients with severe acute
      respiratory distress syndrome may in part reflect the additive beneficial effects
      of combined treatment methods, such as airway pressure control, nitric oxide
      inhalation, prone position, and early triage of nonresponders to extracorporeal
      membrane oxygenation.

PMID- 10598598
TI  - Effect of dobutamine on splanchnic carbohydrate metabolism and amino acid balance
      after cardiac surgery.
AB  - BACKGROUND: As a predominant beta-adrenergic agonist, dobutamine may modify blood
      flow distribution and increase metabolic demands. The authors investigated the
      effect of a dobutamine-induced increase in cardiac output on splanchnic and
      femoral blood flow and metabolism in patients after cardiac surgery. METHODS:
      Seventeen stable patients were randomized to receive dobutamine or placebo (n = 8
      per group, one dropout). After baseline measurement for systemic, splanchnic, and
      femoral blood flow (by dye dilution); oxygen consumption; gastric mucosal
      pressure of carbon dioxide (Pco2); total and splanchnic glucose production (by
      stable isotope tracer dilution); and regional lactate and amino acid balance,
      patients received either dobutamine, at a dosage (6 microg x kg(-1)min(-1))
      sufficient to increase cardiac index by at least 25%, or placebo. A second set of
      measurements was performed 60 min after the start of dobutamine or placebo
      infusion. RESULTS: Dobutamine increased cardiac index (3.0+/-0.6 to 4.4+/-1.0 l x
      min(-1)m(-2), mean +/- SD; P < 0.05), splanchnic blood flow (from 0.8+/-0.2 to
      1.0 + 0.2 l x min(-1)m(-2); P < 0.05), femoral blood flow (from 0.2+/-0.1 to
      0.3+/-0.1 l x min(-1)m(-2); P < 0.05), and the arterial-gastric mucosal Pco2 gap
      (from 11.4+/-9.5 to 11.9+/-8.0 mmHg; P < 0.05). Dobutamine increased systemic
      oxygen consumption (from 132+/-14 to 146+/-13 ml x min(-1) x m(-2); P < 0.05) but
      not splanchnic or femoral oxygen consumption. Splanchnic glucose production and
      lactate and amino acid balance did not change. CONCLUSION: After coronary artery
      bypass surgery, dobutamine increased systemic and regional blood flow and
      decreased systemic and regional oxygen extraction. Dobutamine did not affect
      splanchnic glucose production or lactate or amino acid balance. This suggests
      that dobutamine increases splanchnic blood flow without a concomitant increase in
      hepatosplanchnic metabolism.

PMID- 10598599
TI  - Epileptiform electroencephalogram during mask induction of anesthesia with
      sevoflurane.
AB  - BACKGROUND: Sevoflurane is suggested as a suitable anesthetic agent for mask
      induction in adults. The authors recently found that hyperventilation during
      sevoflurane-nitrous oxide-oxygen mask induction is associated with cardiovascular
      hyperdynamic response. We tested the hypothesis that the hyperdynamic response
      can be explained by electroencephalography (EEG) findings. METHODS: Thirty women
      were randomly allocated to receive sevoflurane-nitrous oxygen-oxygen mask
      induction using a single-breath method, followed by either spontaneous breathing
      (n = 15) or controlled hyperventilation (n = 15) for 6 min. EEG was recorded.
      Blood pressure and heart rate were recorded at 1-min intervals. RESULTS:
      Epileptiform EEG activity (spikes or polyspikes) was seen in all patients with
      controlled hyperventilation, and in seven patients with spontaneous breathing (P
      < 0.01). Jerking movements were seen in three patients with controlled
      hyperventilation. In the controlled hyperventilation group, heart rate increased
      54% from baseline at 4 min after induction (P < 0.001). Mean arterial pressure
      increased 17% (P < 0.05), peaking at 3 min. In the spontaneous breathing group,
      heart rate showed no change, and mean arterial pressure decreased by 14% (P <
      0.01) at 6 min. Heart rate and mean arterial pressure differed significantly
      between the groups from 2 min after beginning of the induction to the end of the
      trial. An increase in heart rate of more than 30% from baseline always was
      associated with epileptiform EEG activity. CONCLUSIONS: Sevoflurane mask
      induction elicits epileptiform EEG patterns. These are associated with an
      increase in heart rate in patients with controlled hyperventilation and also
      during spontaneous breathing of sevoflurane.

PMID- 10598600
TI  - Changes in electroencephalogram and autonomic cardiovascular activity during
      induction of anesthesia with sevoflurane compared with halothane in children.
AB  - BACKGROUND: This study was design to assess clinical agitation,
      electroencephalogram (EEG) and autonomic cardiovascular activity changes in
      children during induction of anesthesia with sevoflurane compared with halothane
      using noninvasive recording of EEG, heart rate, and finger blood pressure.
      METHODS: Children aged 2-12 yr premedicated with midazolam were randomly assigned
      to one of three induction techniques: 7% sevoflurane in 100% O2 (group
      SevoRAPID); 2%, 4%, 6%, and 7% sevoflurane in 100% O2 (group SevoINCR); or 1%,
      2%, 3%, and 3.5% halothane in 50% N2O-50% O2 (group HaloN2O). An additional group
      of children who received 7% sevoflurane in 50% N2O-50% O2 (group SevoN2O) was
      enrolled after completion of the study. Induction was videotaped. EEG, heart
      rate, and finger blood pressure were continuously recorded during induction until
      5 min after tracheal intubation and analyzed in frequency domain using spectral
      analysis. RESULTS: Agitation was more frequent when anesthesia was induced with
      100% O2 compared to the mixture of oxygen and nitrous oxide. No seizures were
      recorded in any group. In the four groups, induction of anesthesia was associated
      with an increase in EEG total spectral power and a shift toward the low-frequency
      bands. Sharp slow waves were present on EEG tracings of the three sevoflurane
      groups, whereas slow waves and fast rhythms (spindles) were observed in the
      halothane group. Sevoflurane induced a greater withdrawal of parasympathetic
      activity than halothane and a transient relative increase in sympathetic vascular
      tone at loss of eyelash reflex. CONCLUSIONS: Agitation observed during
      sevoflurane induction was not associated with seizures. Sevoflurane induction
      induced a marked inhibition of parasympathetic control of heart rate.

PMID- 10598601
TI  - Do pipecuronium and rocuronium affect human bronchial smooth muscle?
AB  - BACKGROUND: Muscle relaxants affect nicotinic and muscarinic receptors.
      Interaction of muscle relaxants with muscarinic receptors of human airways has
      been studied incompletely. METHODS: The effects of pipecuronium bromide (long
      acting, nondepolarizing) and rocuronium bromide (intermediate-acting,
      nondepolarizing) on prejunctional and postjunctional muscarinic receptors were
      studied in 96 isolated human bronchial rings from 12 patients. Contractile
      isometric responses to electric field stimulation of pilocarpine-stimulated and
      nonstimulated M2 muscarinic receptors were compared before and after incubation
      with the two muscle relaxants. The effect on postjunctional muscarinic receptors
      was studied by comparing acetylcholine concentration-response curves before and
      after incubation with the two muscle relaxants. RESULTS: Pipecuronium bromide,
      but not rocuronium bromide, inhibited pilocarpine-stimulated prejunctional M2
      muscarinic receptors. Neither pipecuronium bromide nor rocuronium bromide had
      significant inhibitory effects on nonstimulated M2 muscarinic receptors and on
      postjunctional M3 muscarinic receptors. CONCLUSIONS: The inhibitory effect of
      pipecuronium bromide on pilocarpine-stimulated prejunctional M2 muscarinic
      receptors occurred at clinical concentrations.

PMID- 10598602
TI  - Effect of the duration of electrical stimulation on the analgesic response in
      patients with low back pain.
AB  - BACKGROUND: Electrical stimulation of peripheral nerves produces acute analgesic
      effects. This randomized, sham-controlled, crossover study was designed to
      evaluate the effect of differing durations of electrical stimulation on the
      analgesic response to percutaneous electrical nerve stimulation in 75 consenting
      patients with low back pain. METHODS: All patients received electrical
      stimulation for four different time intervals (0, 15, 30, and 45 min) in a random
      sequence over the course of an 11-week study period. All active percutaneous
      electrical nerve stimulation treatments were administered using alternating
      frequencies of 15 and 30 Hz three times per week for 2 consecutive weeks. The
      prestudy assessments included the health status survey short form questionnaire
      and 10-cm visual analog scale scores for pain, physical activity, and quality of
      sleep, with 0 being the best and 10 being the worst. The pain scoring was
      repeated 5-10 min after each 60-min study session and 24 h after the last
      treatment session with each of the four methods. The daily oral analgesic
      requirements were assessed during each of the four treatment blocks. At the end
      of each 2-week treatment block, the questionnaire was repeated. RESULTS:
      Electrical stimulation using percutaneously placed needles produced short-term
      improvements in the visual analog scale pain, physical activity, and quality of
      sleep scores, and a reduction in the oral analgesic requirements. The 30-min and
      45-min durations of electrical stimulation produced similar hypoalgesic effects
      (48+/-21% and 46+/-19%, respectively) and were significantly more effective than
      either 15 min (21+/-17%) or 0 min (10+/-11%). The 30- and 45-min treatments were
      also more effective in improving physical activity and sleep scores over the
      course of the 2-week treatment period. In contrast to the sham treatment (0 min),
      the health status survey short form revealed that electrical stimulation for 15
      to 45 min three times per week for 2 weeks improved patient function. CONCLUSION:
      The recommended duration of electrical stimulation with percutaneous electrical
      nerve stimulation therapy is 30 min.

PMID- 10598603
TI  - Efficiency of a new fiberoptic stylet scope in tracheal intubation.
AB  - BACKGROUND: Failed or difficult tracheal intubation is an important cause of
      morbidity and mortality during anesthesia. Although a number of fiberoptic
      devices are available to circumvent this problem, many do not allow manual
      control of the flexion of the tip and necessitate time-consuming preparation,
      special training, or the use of an external light source. To improve these
      limitations, the authors designed a new fiberoptic stylet scope (FSS) that has a
      simple form of a standard stylet with the fiberoptic view and maneuverability of
      its tip. This study was undertaken to prospectively evaluate the effectiveness of
      the FSS in tracheal intubation. METHODS: Thirty-two patients undergoing general
      surgery participated in this study. The authors used a standard laryngoscope only
      to elevate the tongue, then tracheal intubation was attempted with the glottic
      opening being viewed only through the FSS. The success rate, time necessary for
      intubation, hemodynamics, and adverse effects were recorded. RESULTS: The success
      rate of tracheal intubation on the first attempt using the FSS was 94% (30 of 32
      patients), and the remaining two patients were intubated successfully on the
      second attempt. The mean time necessary for the intubation procedure was 29+/-14
      s in all patients (mean +/- SD). Changes in hemodynamics during intubation were
      well within acceptable ranges. There were no major adverse effects, but minor
      sore throat (28%) and minor hoarseness (25%) on the first postoperative day.
      CONCLUSIONS: Tracheal intubation using the FSS proved to be a simple and
      effective technique for airway management.

PMID- 10598604
TI  - Experimental pain augments experimental dyspnea, but not vice versa in human
      volunteers.
AB  - BACKGROUND: Pain and dyspnea frequently coexist in many clinical situations.
      However, whether the two different symptoms interact with each other has not been
      elucidated. To elucidate the interaction between pain and dyspneic sensations,
      the authors investigated separately the effects of pain on dyspnea and the
      effects of dyspnea on pain in 15 healthy subjects. METHODS: Subjects were asked
      to rate their sensation of pain or dyspnea using a visual analog scale (VAS)
      during pain stimulation produced by tourniquet inflation (inflation cuff
      pressure: 350 mmHg) around the calf, and/or the respiratory loading consisted of
      a combination of resistive load (77 cm H2O x l(-1) x s(-1)) and hypercapnia
      induced by extra mechanical dead space (255 ml). In addition to changes in VAS
      scores, changes in ventilatory airflow and airway pressure were continuously
      measured. RESULTS: Pain stimulation and loaded breathing increased VAS scores,
      ventilation, and occlusion pressure (P0.1). The addition of a pain stimulus
      during loaded breathing increased the dyspneic VAS score (median 56
      [interquartile range 50-62] vs. 64 [55-77]: before vs. after addition of pain
      stimulus, P < 0.05) with concomitant increases in minute ventilation (10.8 [10.1
      13.3] vs. 12.4 [11.0-14.8] l/min, P < 0.05) and P0.1 (5.5 [4.9-7.2] vs. 6.8 [5.8
      9.0] cm H2O, P < 0.05). The addition of respiratory loading during pain
      stimulation did not cause a significant change in pain VAS score (40 [33-55] vs.
      31 [30-44]: before vs. after addition of respiratory loading), although both
      additional burdens increased further minute ventilation (10.0 [8.8-10.9] vs. 12.0
      [10.6-13.2] l/min, P < 0.05) and P0.1 (2.5 [2.0-3.0] vs. 6.2 [4.9-7.0] cm H2O, P
      < 0.05). CONCLUSION: The authors' findings suggest that pain intensifies the
      dyspneic sensation, presumably by increasing the respiratory drive, whereas
      dyspnea may not intensify the pain sensation.

PMID- 10598605
TI  - Rapid opioid detoxification during general anesthesia: a review of 20 patients.
AB  - BACKGROUND: Opioid addiction therapy includes successful detoxification,
      rehabilitation, and sometimes methadone maintenance. However, the patient may
      have physical, mental, and emotional pain while trying to achieve abstinence. A
      new detoxification technique that incorporates general anesthesia uses a high
      dose opioid antagonist to compress detoxification to within 6 h while avoiding
      the withdrawal. METHODS: After Institutional Review Board approval and detailed
      informed consent, 20 patients, American Society of Anesthesiologists status I-II,
      addicted to various opioids underwent anesthesia-assisted rapid opioid
      detoxification. After baseline hemodynamics and withdrawal scores were obtained,
      anesthesia was induced. After testing with 0.4 mg intravenous naloxone, 4 mg
      nalmefene, was infused over 2 to 3 h. After emergence, severity of withdrawal was
      scored before and after administration of 0.4 mg intravenous naloxone. After 24
      h, patients began outpatient follow-up treatment while taking oral naltrexone.
      RESULTS: All 20 patients were successfully detoxified with no adverse anesthetic
      events. After the first post-treatment test dose of 0.4 mg naloxone, 13 of 20
      patients had no signs of withdrawal and hemodynamic changes were minimal.
      Withdrawal scores were always very low and similar before and after
      detoxification. Three of 17 patients (18%) available for follow-up have remained
      abstinent from opioids since treatment (< or = 18 months). Four other patients
      are clean after brief relapses. CONCLUSIONS: Anesthesia-assisted opioid
      detoxification is an alternative to conventional detoxification.

PMID- 10598606
TI  - Evaluation of neuromuscular and cardiovascular effects of two doses of
      rapacuronium (ORG 9487) versus mivacurium and succinylcholine.
AB  - BACKGROUND: This study compares the neuromuscular blocking and cardiovascular
      effects of rapacuronium (ORG 9487), a new aminosteroid nondepolarizing muscle
      relaxant, to recommended intubating doses of succinylcholine and mivacurium.
      METHODS: Adult patients were randomized in an open-label fashion to receive 1-5
      microg/kg fentanyl before 1.5 mg/kg propofol induction followed by 1.5 or 2.5
      mg/kg rapacuronium, 1.0 mg/kg succinylcholine, or 0.25 mg/kg mivacurium (i.e.,
      0.15 mg/kg followed by 0.1 mg/kg 30 s later). RESULTS: Patient neuromuscular
      blockade status was monitored by measuring the train-of-four response to a
      supramaximal stimulus at the ulnar nerve every 12 s. Percentage of the first
      twitch of the train-of-four (T1) at 60 s was similar in patients receiving 1.5
      mg/kg rapacuronium, 2.5 mg/kg rapacuronium, and succinylcholine and was
      significantly less than in patients in the mivacurium group (26, 16, and 18%,
      respectively, vs. 48%; P < 0.01). Times to 80% T1 depression were also similar
      among patients in the 1.5 mg/kg rapacuronium, 2.5 mg/kg rapacuronium, and
      succinylcholine groups and significantly longer in the mivacurium group (62, 54,
      and 54 s, respectively, vs. 112 s; P < 0.01). Clinical duration was longer in all
      groups compared with the succinylcholine group; however, clinical duration in the
      1.5 mg/kg rapacuronium group was shorter compared with the mivacurium group (15
      vs. 21 min, respectively; P < 0.01). Heart rate changes were mild in the 1.5
      mg/kg rapacuronium, succinylcholine, and mivacurium groups. The patients in the
      2.5 mg/kg rapacuronium group had significantly higher heart rates compared with
      patients in the mivacurium group. No differences were found in blood pressure
      changes among patients in the four groups. CONCLUSIONS: Rapacuronium, 1.5 and 2.5
      mg/kg, produced neuromuscular blockade as rapidly as succinylcholine and
      significantly faster than mivacurium. Although succinylcholine continued to show
      the shortest duration, 1.5 mg/kg rapacuronium used a rapid onset and a relatively
      short duration and may be considered an alternative to succinylcholine.

PMID- 10598607
TI  - A new anterior approach to the sciatic nerve block.
AB  - BACKGROUND: Although several anterior approaches to sciatic nerve block have been
      described, they are used infrequently. The authors describe a new anterior
      approach that allows access to the sciatic nerve with the patient in the supine
      position. METHOD: Sciatic nerve blocks were performed in 22 patients. A line was
      drawn between the inferior border of the anterosuperior iliac spine and the
      superior angle of the pubic symphysis tubercle. Next, a perpendicular line
      bisecting the initial line was drawn and extended 8 cm caudad. The needle was
      inserted perpendicularly to the skin, and the sciatic nerve was identified at a
      depth of 10.5 cm (9.5-13.5 cm; median and range) using a nerve stimulator and a
      15-cm b-beveled insulated needle. After appropriate localization, either 30 ml
      mepivacaine, 1.5% (group 1 = knee arthroscopy; n = 16), or 15 ml mepivacaine,
      1.5%, plus 15 ml ropivacaine, 0.75%, (group 2 = other procedures; n = 6) was
      injected. RESULTS: Appropriate landmarks were determined within 1.3 min (0.5-2.0
      min). The sciatic nerve was identified in all patients within 2.5 min (1.2-5
      min), starting from the beginning of the appropriate landmark determination to
      the stimulation of its common peroneal nerve component in 13 cases and its tibial
      nerve component in 9 cases. A complete sensory block in the distribution of both
      the common peroneal nerve component and the tibial nerve component was obtained
      within 15 min (5-30 min). A shorter onset was observed in patients who received
      mepivacaine alone compared with those who received a mixture of mepivacaine plus
      ropivacaine (10 min [5-25 min] vs. 20 min [10-30 min]; P < 0.05). Recovery time
      was 4.6 h (2.5-5.5 h) after mepivacaine administration. The addition of
      ropivacaine produced a block of a much longer duration 13.8 h (5.2-23.6 h); P <
      0.05. No complications were observed. CONCLUSIONS: This approach represents an
      easy and reliable anterior technique for performing sciatic nerve blocks.

PMID- 10598608
TI  - Pharyngeal mucosal pressure and perfusion: a fiberoptic evaluation of the
      posterior pharynx in anesthetized adult patients with a modified cuffed
      oropharyngeal airway.
AB  - BACKGROUND: Pharyngeal airway devices can exert substantial pressures against the
      pharyngeal mucosa. The authors assess the relation between pharyngeal mucosal
      perfusion and directly measured mucosal pressure (MP) in the posterior pharynx
      using a fiberoptic technique with a modified cuffed oropharyngeal airway (COPA).
      The authors also measure in vivo intracuff pressure (CP), airway sealing pressure
      and MP at four locations using an unmodified COPA. METHODS: Twenty adult
      patients, American Society of Anesthesiologists status I or II, undergoing
      general anesthesia were allocated randomly to receive either (1) a COPA with a
      millimeter microchip sensor fixed on the external cuff surface to record distal
      posterior pharyngeal MP or (2) a COPA with a fiberoptic scope inserted inside the
      cuff to record digitized images of the distal posterior pharyngeal mucosa. MP and
      digitized images were obtained at the same location over an in vivo CP range of
      10-160 cm H2O in 10- to 20-cm H2O increments. The digitized images were scored
      according to blood vessel caliber and mucosal color by two investigators blinded
      to MP and CP. In an additional 20 matched patients, in vivo CP, airway sealing
      pressure, and MP was measured at four different cuff locations (corresponding to
      the anterior, lateral, and posterior pharynx and the distal oropharynx) with
      increasing cuff volume. RESULTS: Blood vessel caliber and mucosal color was
      normal in all patients when the mean mucosal pressure was 17 cm H2O. Blood vessel
      caliber was first reduced when the mean mucosal pressure was 34 cm H2O. There was
      a progressive incremental reduction in blood vessel caliber and mucosal color
      when the mean mucosal pressure increased from 34 to 80 cm H2O (P < or = 0.05).
      Complete blood vessel collapse and mucosal paling first occurred with the mean
      mucosal pressure was 73 cm H2O and was present in 90% of patients when the mean
      mucosal pressure was 80 cm H2O. Mean MP was always higher in the posterior
      pharynx compared with the other locations when the cuff volume was 20 ml or
      greater (P < 0.001). In vivo CP is an excellent predictor of mucosal pressure.
      Mean (95% confidence interval [CI]) MP in the posterior pharynx was 35 (5-67) and
      78 (50-109) cm H2O when the airway sealing pressure was 10 (6-16) and 17 (13-21)
      cm H2O respectively. CONCLUSION: Pharyngeal mucosal perfusion is reduced
      progressively in the posterior pharynx when MP is increased from 34 to 80 cm H2O
      with the COPA. CP provides reliable information about MP and should be less than
      120 cm H2O to prevent mucosal ischemia.

PMID- 10598609
TI  - Alfentanil causes less postoperative nausea and vomiting than equipotent doses of
      fentanyl or sufentanil in outpatients.
AB  - BACKGROUND: The relative potencies of alfentanil, fentanyl, and sufentanil as a
      risk factor for postoperative nausea and vomiting have not been determined. They
      were compared in a randomized study designed to obtain equipotent plasma
      concentrations of these three opioids at the beginning of the recovery period.
      METHODS: The study included 274 patients treated on an outpatient basis. The
      steady state opioid plasma concentration providing a predicted 50% reduction of
      the minimum alveolar concentration of isoflurane was used to determine the
      relative potency of the opioids. The opioids were prepared in equal volumes at
      concentrations of alfentanil 150 microg/ml, fentanyl 50 microg/ml, and sufentanil
      5 microg/ml and were administered in vol/kg. Anesthesia was induced in a blinded
      fashion with a bolus of the study opioid (0.05 ml/kg) and 4-6 mg/kg thiopental
      and was maintained with isoflurane (0.6-1%) in a nitrous oxide-oxygen mixture
      with a continuous infusion of the study opioid (0.06 ml x kg(-1) x h(-1)). If
      necessary, up to five additional boluses of opioid (0.02 ml/kg) could be given.
      This opioid administration protocol was tested by pharmacokinetic simulations.
      RESULTS: The incidence of postoperative nausea and vomiting was not different in
      the postanesthesia care unit, but in the ambulatory surgery unit it was
      significantly lower for alfentanil compared with fentanyl and sufentanil (12, 34,
      and 35%, respectively P < 0.005). Pharmacokinetic modeling showed that the end
      anesthesia opioid plasma concentrations were approximately equipotent in the
      three groups. However, modeling does not support that the difference between
      groups in the postoperative period can be explained by a more rapid disappearance
      of alfentanil from the plasma. CONCLUSIONS: Alfentanil, compared with
      approximately equipotent doses of fentanyl and sufentanil, is associated with a
      lower incidence of postoperative nausea and vomiting in outpatients.

PMID- 10598610
TI  - Beneficial effects from beta-adrenergic blockade in elderly patients undergoing
      noncardiac surgery.
AB  - BACKGROUND: Perioperative beta-blockade has been shown to improve long-term
      cardiac outcome in noncardiac surgical patients. A possible mechanism for the
      reduced risk of perioperative myocardial infarction is the attenuation of the
      excitotoxic effects of catecholamine surges by beta-blockade. It was hypothesized
      that beta-blocker-induced alteration of the stress response was responsible for
      the reported improvements in cardiovascular outcome. Several variables associated
      with the perioperative use of beta-blockade were also evaluated. METHODS: Sixty
      three patients were randomly assigned to one of three groups: group I, no
      atenolol; group II, pre- and postoperative atenolol; group III, intraoperative
      atenolol. Hormonal markers of the stress response (neuropeptide Y, epinephrine,
      norepinephrine, cortisol, and adrenocorticotropic hormone) were evaluated
      preoperatively and for 72 h after surgery. RESULTS: Perioperative beta-blockade
      did not significantly alter the hormonal stress response. However, the beta
      blocked patients showed improved hemodynamic stability during emergence and
      postoperatively. They also received less fentanyl intraoperatively (27.7%, P <
      0.0001), experienced faster early recovery, had lower pain scores, and required
      less analgesia in the postanesthesia care unit. Cardiac troponin I release was
      detected in 8 of 19, 4 of 20, and 5 of 20 patients in groups I, II, and III,
      respectively (not significant). Three patients in group I had cardiac troponin I
      levels consistent with myocardial infarction. CONCLUSION: Beta-blockade does not
      reduce the neuroendocrine stress response, suggesting that this mechanism is not
      responsible for the previously reported improved cardiovascular outcome. However,
      it confers several advantages, including decreased analgesic requirements, faster
      recovery from anesthesia, and improved hemodynamic stability. The release of
      cardiac troponin I suggests the occurrence of perioperative myocardial damage in
      this elderly population, which appears to be independent of the neuroendocrine
      stress response.

PMID- 10598612
TI  - Pharmacokinetics of thiopental enantiomers during and following prolonged high
      dose therapy.
AB  - BACKGROUND: Thiopental is used as a racemate; however, this is not generally
      recognized. During conditions of prolonged high-dose therapy, the
      pharmacokinetics of thiopental may become nonlinear, but whether this derives
      from one or both enantiomers has not been evaluated. The authors determined the
      pharmacokinetics of R- and S-thiopental and serum concentrations of R- and S
      pentobarbital from prolonged high-dose infusion of thiopental for
      neuroprotection. METHODS: Twenty patients received a mean thiopental dose of 41.2
      g over a mean duration of 95 h. R- and S-thiopental enantiomer serum
      concentration-time data from 18 patients were fitted with two models: a linear
      one-compartment model with first-order output, and a nonlinear one-compartment
      model with Michaelis-Menten output. RESULTS: Nonlinear models were preferred in
      16 of 18 patients. Paired analysis indicated that steady state clearance (Clss)
      and volume of distribution (Vd) were higher for R-thiopental (0.108 vs. 0.096
      l/min, P < 0.0001; and 313 vs. 273 l, P < 0.0005, respectively); maximal rate of
      metabolism (Vm) was higher for S- than for R-thiopental (1.01 vs. 0.86 mg x l(-1)
      x h(-1), P = 0.02); elimination half-lives did not differ (14.6 vs. 14.7 h, P =
      0.8); unbound fractions (f(u)) of R- and S-thiopental were 0.20 and 0.18,
      respectively, P < 0.0001). The differences in mean Clss, Vd and Vm were not
      significant when adjusted by f(u). Plasma concentrations of R- and S
      pentobarbital were relatively small and unlikely to be of clinical significance.
      CONCLUSION: The pharmacokinetics of R- and S-thiopental became nonlinear at these
      doses. The pharmacokinetic differences between R- and S-thiopental, although
      small, were statistically significant and were influenced by the higher f(u) of R
      thiopental.

PMID- 10598611
TI  - Does epidural anesthesia have general anesthetic effects? A prospective,
      randomized, double-blind, placebo-controlled trial.
AB  - BACKGROUND: Clinically, patients require surprisingly low end-tidal
      concentrations of volatile agents during combined epidural-general anesthesia.
      Neuraxial anesthesia exhibits sedative properties that may reduce requirements
      for general anesthesia. The authors tested whether epidural lidocaine reduces
      volatile anesthetic requirements as measured by the minimum alveolar
      concentration (MAC) of sevoflurane for noxious testing cephalad to the sensory
      block. METHODS: In a prospective, randomized, double-blind, placebo-controlled
      trial, 44 patients received 300 mg epidural lidocaine (group E), epidural saline
      control (group C), or epidural saline-intravenous lidocaine infusion (group I)
      after premedication with 0.02 mg/kg midazolam and 1 microg/kg fentanyl. Tracheal
      intubation followed standard induction with 4 mg/kg thiopental and
      succinylcholine 1 mg/kg. After 10 min or more of stable end-tidal sevoflurane, 10
      s of 50 Hz, 60 mA tetanic electrical stimulation were applied to the fifth
      cervical dermatome. Predetermined end-tidal sevoflurane concentrations and the
      MAC for each group were determined by the up-and-down method and probit analysis
      based on patient movement. RESULTS: MAC of sevoflurane for group E, 0.52+/-0.18%
      (+/- 95% confidence interval [CI]), differed significantly from group C, 1.18+/
      0.18% (P < 0.0005), and from group I, 1.04+/-0.18% (P < 0.001). The plasma
      lidocaine levels in groups E and I were comparable (2.3+/-1.0 vs. 3.0+/-1.2
      microg/ml +/- SD). CONCLUSIONS: Lidocaine epidural anesthesia reduced the MAC of
      sevoflurane by approximately 50%. This MAC sparing is most likely caused by
      indirect central effects of spinal deafferentation and not to systemic effects of
      lidocaine or direct neural blockade. Thus, lower concentrations of volatile
      agents than those based on standard MAC values may be adequate during combined
      epidural-general anesthesia.

PMID- 10598613
TI  - Airway injury during anesthesia: a closed claims analysis.
AB  - BACKGROUND: Airway injury during general anesthesia is a significant source of
      morbidity for patients and a source of liability for anesthesiologists. To
      identify recurrent patterns of injury, the authors analyzed claims for airway
      injury in the American Society of Anesthesiologists (ASA) Closed Claims Project
      database. METHODS: The ASA Closed Claims database is a standardized collection of
      case summaries derived from professional liability insurance companies closed
      claims files. All claims for airway injury were reviewed in depth and were
      compared to other claims during general anesthesia. RESULTS: Approximately 6%
      (266) of 4,460 claims in the database were for airway injury. The most frequent
      sites of injury were the larynx (33%), pharynx (19%), and esophagus (18%).
      Injuries to the esophagus and trachea were more frequently associated with
      difficult intubation. Injuries to temporomandibular joint and the larynx were
      more frequently associated with nondifficult intubation. Injuries to the
      esophagus were more severe and resulted in a higher payment to the plaintiff than
      claims for other sites of airway injury. Difficult intubation (odds ratio = 4.53,
      95% confidence interval [CI] = 2.36, 8.71), age older than 60 yr (odds ratio =
      2.97, 95% CI = 1.51, 5.87), and female gender (odds ratio = 2.43, 95% CI = 1.09,
      5.42) were associated with claims for pharyngoesophageal perforation. Early signs
      of perforation, e.g., pneumothorax and subcutaneous emphysema, were present in
      only 51% of perforation claims, whereas late sequelae, e.g., retropharyngeal
      abscess and mediastinitis, occurred in 65%. CONCLUSION: Patients in whom tracheal
      intubation has been difficult should be observed for and told to watch for the
      development of symptoms and signs of retropharyngeal abscess, mediastinitis, or
      both.

PMID- 10598614
TI  - Propofol-induced depression of cultured rat ventricular myocytes is related to
      the M2-acetylcholine receptor-NO-cGMP signaling pathway.
AB  - BACKGROUND: It is well-known that propofol sometimes causes bradycardia or
      asystole during anesthesia; however, the direct effect of propofol on the
      myocardium remains unclear. Previous reports showed the contribution of
      muscarinic acetylcholine receptors to propofol-induced bradycardia. Conversely,
      it was suggested recently that nitric oxide (NO) plays an important role in
      mediating the effect of vagal stimulation in the autonomic regulation of the
      heart. Therefore, the authors investigated the effects of propofol on spontaneous
      contraction and NO production in cultured rat ventricular myocytes. METHODS: The
      authors measured chronotropic responses of cultured rat ventricular myocytes
      induced by propofol stimulation with a sensor, a fiber-optic displacement
      measurement instrument. The authors also quantitatively analyzed NO metabolite
      production in cultured myocytes by measuring the levels of nitrite and nitrate in
      a high-performance liquid chromatography reaction system. The influence of
      propofol on muscarinic acetylcholine receptors of myocyte membranes was also
      measured with a competitive binding assay using [3H]quinuclidinyl benzilate
      ([3H]QNB). RESULTS: Propofol caused negative chronotropy in a dose-dependent
      manner. Propofol (IC50) also caused the enhancement of nitrite production in
      cultured myocytes. Eighty percent of the enhancement of nitrite production
      induced by propofol (IC50) stimulation was abolished by pretreatment with
      atropine, methoctramine, or N(G)-monomethyl-L-arginine acetate (L-NMMA). The
      negative chronotropy induced by propofol (IC50) stimulation was reduced to 40-50%
      by pretreatment with atropine, methoctramine, L-NMMA, or 1H[1,2,4]oxadiazolo[4,3
      alpha]quanoxalin-1-one, a selective inhibitor of guanylyl cyclase. Propofol
      displaced [3H]QNB binding to the cell membrane of myocytes in a concentration
      dependent manner. CONCLUSION: These results suggest that the negative chronotropy
      induced by propofol is mediated in part by M2-acetylcholine receptor activation,
      which involves the enhancement of NO production in cultured rat ventricular
      myocytes.

PMID- 10598615
TI  - Local coupling of cerebral blood flow to cerebral glucose metabolism during
      inhalational anesthesia in rats: desflurane versus isoflurane.
AB  - BACKGROUND: It is not known whether the effects of desflurane on local cerebral
      glucose utilization (LCGU) and local cerebral blood flow (LCBF) are different
      from those of other volatile anesthetics. METHODS: Using the autoradiographic
      iodoantipyrine and deoxyglucose methods, LCGU, LCBF, and their overall means were
      measured in 60 Sprague-Dawley rats (10 groups, n = 6 each) during desflurane and
      isoflurane anesthesia and in conscious controls. RESULTS: During anesthesia, mean
      cerebral glucose utilization was decreased compared with conscious controls: 1
      minimum alveolar concentration (MAC) desflurane: -52%; 1 MAC isoflurane: -44%; 2
      MAC desflurane: -62%; and 2 MAC isoflurane: -60%. Local analysis showed a
      reduction of LCGU in the majority of the 40 brain regions analyzed. Mean cerebral
      blood flow was increased: 1 MAC desflurane: +40%; 1 MAC isoflurane: +43%; 2 MAC
      desflurane and 2 MAC isoflurane: +70%. LCBF was increased in all brain structures
      investigated except in the auditory cortex. No significant differences (P < 0.05)
      could be observed between both anesthetics for mean values of cerebral glucose
      use and blood flow. Correlation coefficients obtained for the relation between
      LCGU and LCBF were as follows: controls: 0.95; 1 MAC desflurane: 0.89; 2 MAC
      desflurane: 0.60; 1 MAC isoflurane: 0.87; and 2 MAC isoflurane: 0.68. CONCLUSION:
      Differences in the physicochemical properties of desflurane compared with
      isoflurane are not associated with major differences in the effects of both
      volatile anesthetics on cerebral glucose utilization, blood flow, and the
      coupling between LCBF and LCGU.

PMID- 10598616
TI  - Selective iNOS inhibition attenuates acetylcholine- and bradykinin-induced
      vasoconstriction in lipopolysaccharide-exposed rat lungs.
AB  - BACKGROUND: Nonselective nitric oxide synthase (NOS) inhibition has detrimental
      effects in sepsis because of inhibition of the physiologically important
      endothelial NOS (eNOS). The authors hypothesized that selective inducible NOS
      (iNOS) inhibition would maintain eNOS vasodilation but prevent acetylcholine- and
      bradykinin-mediated vasoconstriction caused by lipopolysaccharide-induced
      endothelial dysfunction. METHODS: Rats were administered intraperitoneal
      lipopolysaccharide (15 mg/kg) with and without the selective iNOS inhibitors L-N6
      (1-iminoethyl)-lysine (L-NIL, 3 mg/kg), dexamethasone (1 mg/kg), or the
      nonselective NOS inhibitor Nomega-nitro-L-arginine methylester (L-NAME, 5 mg/kg).
      Six hours later, the lungs were isolated and pulmonary vasoreactivity was
      assessed with hypoxic vasoconstrictions (3% O2), acetylcholine (1 microg),
      Biochemical Engineering, and bradykinin (3 microg). In additional
      lipopolysaccharide experiments, L-NIL (10 microM) or 4-Diphenylacetoxy-N
      methylpiperidine methiodide (4-DAMP, 100 microM), a selective muscarinic M3
      antagonist, was added into the perfusate. RESULTS: Exhaled nitric oxide was
      higher in the lipopolysaccharide group (37.7+/-17.8 ppb) compared with the
      control group (0.4+/-0.7 ppb). L-NIL and dexamethasone decreased exhaled nitric
      oxide in lipopolysaccharide rats by 83 and 79%, respectively, whereas L-NAME had
      no effect. In control lungs, L-NAME significantly decreased acetylcholine- and
      bradykinin-induced vasodilation by 75% and increased hypoxic vasoconstrictions,
      whereas L-NIL and dexamethasone had no effect. In lipopolysaccharide lungs,
      acetylcholine and bradykinin both transiently increased the pulmonary artery
      pressure by 8.4+/-2.0 mmHg and 35.3+/-11.7 mmHg, respectively, immediately after
      vasodilation. L-NIL and dexamethasone both attenuated this vasoconstriction by
      70%, whereas L-NAME did not. The acetylcholine vasoconstriction was dose
      dependent (0.01-1.0 microg), unaffected by L-NIL added to the perfusate, and
      abolished by 4-DAMP. CONCLUSIONS: In isolated perfused lungs, acetylcholine and
      bradykinin caused vasoconstriction in lipopolysaccharide-treated rats. This
      vasoconstriction was attenuated by administration of the iNOS inhibitor L-NIL but
      not with L-NAME. Furthermore, L-NIL administered with lipopolysaccharide
      preserved endothelium nitric oxide-dependent vasodilation, whereas L-NAME did
      not.

PMID- 10598617
TI  - Ketamine distribution described by a recirculatory pharmacokinetic model is not
      stereoselective.
AB  - BACKGROUND: Differences in the pharmacokinetics of the enantiomers of ketamine
      have been reported. The authors sought to determine whether these differences
      extend to pulmonary uptake and peripheral tissue distribution and to test the
      hypothesis that tissue distribution of the stereoisomers differs because of
      carrier-mediated drug transport. METHODS: The dispositions of markers of
      intravascular space and blood flow (indocyanine green, ICG) and total body water
      and tissue perfusion (antipyrine) were determined along with S-(+)- and R-(-)
      ketamine in five mongrel dogs. The dogs were studied while anesthetized with 2.0%
      halothane. Marker and drug dispositions were described by recirculatory
      pharmacokinetic models based on frequent early and less-frequent later arterial
      blood samples. These models characterize pulmonary uptake and the distribution of
      cardiac output into parallel peripheral circuits. RESULTS: Plasma elimination
      clearance of the S-(+)-ketamine enantiomer, 29.9 ml x min(-1) x kg(-1), was
      higher than that of the R-(-)-enantiomer, 22.2 ml x min(-1) x kg(-1). The
      apparent pulmonary tissue volumes of the ketamine S-(+) and R-(-)-enantiomers
      (0.31 l) did not differ and was approximately twice that of antipyrine (0.16 l).
      The peripheral tissue distribution volumes and clearances and the total volume of
      distribution (2.1 l/kg) were the same for both stereoisomers when elimination
      clearances were modeled from the rapidly equilibrating peripheral compartment.
      CONCLUSIONS: Although the elimination clearance of S-(+)-ketamine is 35% greater
      than that of the R-(-)-enantiomer, there is no difference in the apparent
      pulmonary tissue volume or peripheral tissue distribution between the
      stereoisomers, suggesting that physicochemical properties of ketamine other than
      stereoisomerism determine its perfusion-limited tissue distribution.

PMID- 10598618
TI  - Congenital NOS2 deficiency protects mice from LPS-induced hyporesponsiveness to
      inhaled nitric oxide.
AB  - BACKGROUND: In animal models, endotoxin (lipopolysaccharide) challenge impairs
      the pulmonary vasodilator response to inhaled nitric oxide (NO). This impairment
      is prevented by treatment with inhibitors of NO synthase 2 (NOS2), including
      glucocorticoids and L-arginine analogs. However, because these inhibitors are not
      specific for NOS2, the role of this enzyme in the impairment of NO responsiveness
      by lipopolysaccharide remains incompletely defined. METHODS: To investigate the
      role of NOS2 in the development of lipopolysaccharide-induced impairment of NO
      responsiveness, the authors measured the vasodilator response to inhalation of
      0.4, 4, and 40 ppm NO in isolated, perfused, and ventilated lungs obtained from
      lipopolysaccharide-pretreated (50 mg/kg intraperitoneally 16 h before lung
      perfusion) and untreated wild-type and NOS2-deficient mice. The authors also
      evaluated the effects of breathing NO for 16 h on pulmonary vascular
      responsiveness during subsequent ventilation with NO. RESULTS: In wild-type mice,
      lipopolysaccharide challenge impaired the pulmonary vasodilator response to 0.4
      and 4 ppm NO (reduced 79% and 45%, respectively, P < 0.001), but not to 40 ppm.
      In contrast, lipopolysaccharide administration did not impair the vasodilator
      response to inhaled NO in NOS2-deficient mice. Breathing 20 ppm NO for 16 h
      decreased the vasodilator response to subsequent ventilation with NO in
      lipopolysaccharide-pretreated NOS2-deficient mice, but not in lipopolysaccharide
      pretreated wild-type, untreated NOS2-deficient or untreated wild-type mice.
      CONCLUSIONS: In response to endotoxin challenge, NO, either endogenously produced
      by NOS2 in wild-type mice or added to the air inhaled by NOS2-deficient mice, is
      necessary to impair vascular responsiveness to inhaled NO. Prolonged NO
      breathing, without endotoxin, does not impair vasodilation in response to
      subsequent NO inhalation. These results suggest that NO, plus other
      lipopolysaccharide-induced products, are necessary to impair responsiveness to
      inhaled NO in a murine sepsis model.

PMID- 10598619
TI  - Diaspirin cross-linked hemoglobin effectively restores pancreatic
      microcirculatory failure in hemorrhagic shock.
AB  - BACKGROUND: Microvascular reperfusion failure of splanchnic organs is a crucial
      hallmark in organ damage induced by hemorrhagic shock, which should be prevented
      by a resuscitation solution. Because the vasoactive properties of the hemoglobin
      based oxygen carrier diaspirin cross-linked hemoglobin (DCLHb) could adversely
      influence restoration of pancreatic capillary perfusion during resuscitation, the
      authors investigated its effects on the microcirculation of the rat pancreas in
      comparison with whole blood and 6% hydroxyethylstarch resuscitation from severe
      hemorrhagic shock. METHODS: Twenty-eight pentobarbital-anaesthetized rats were
      bled to a mean arterial pressure (MAP) of 40 mmHg and maintained at this level
      for 1 h. Using an intravital microscope, mean arterial pressure, the length of
      erythrocyte-perfused pancreatic capillaries per observation area (functional
      capillary density), the adherence of leukocytes in postcapillary venules, and
      pancreatic lipid peroxidation, measured as thiobarbituric acid-reactive material
      in pancreatic tissue, were determined in animals resuscitated by volumes of
      hydroxyethylstarch, DCLHb, and whole blood (WB) equivalent to the shed blood
      volume or in control animals without shock induction for a period of 2 h after
      resuscitation. RESULTS: Compared with control animals (366+/-28 cm(-1)), animals
      resuscitated with DCLHb (294+/-45 cm(-1)), WB (306+/-11 cm(-1)), and
      hydroxyethylstarch (241+/-34 cm(-1)) showed a significant reduction of functional
      capillary density after 2 h of resuscitation. DCLHb was as effective as WB and
      superior to hydroxyethylstarch in restoring functional capillary density and mean
      arterial pressure. Leukocyte adherence in postcapillary venules was not enhanced
      by DCLHb (369+/-148/mm2) infusion when compared with hydroxyethylstarch- (615+/
      283/mm2) and WB-treated (510+/-415/mm2) animals. Lipid peroxidation of pancreatic
      tissue was significantly elevated after treatment with both oxygen-carrying
      solutions compared with hydroxyethylstarch. CONCLUSION: DCLHb is as effective as
      WB for preservation of the pancreatic microcirculation.

PMID- 10598620
TI  - Deep hypothermia and rewarming alters glutamate levels and glycogen content in
      cultured astrocytes.
AB  - BACKGROUND: Deep hypothermia has been associated with an increased incidence of
      postoperative neurologic dysfunction after cardiac surgery in children. Recent
      studies suggest an excitotoxic mechanism involving overstimulation of glutamate
      receptors. Extracellular glutamate uptake occurs primarily by astrocytes.
      Astrocytes also store glycogen, which may be used to sustain the energy-consuming
      glutamate uptake. Extracellular glutamate and glycogen content were studied
      during temperature changes mimicking cardiopulmonary bypass in vivo. METHODS:
      Primary cultures of cerebral cortical astrocytes were used in a specially
      designed incubator allowing continuous changes of temperature and ambient gas
      concentrations. The sequence of events was as follows: normothermia, rapid
      cooling (2.8 degrees C/min) followed by 60 min of deep hypothermia (15 degrees
      C), followed by rewarming (3.0 degrees C/min) and subsequent 5 h of mild
      hyperthermia (38.5 degrees C). Two different conditions of oxygenation were
      studied: (1) normoxia (25% O2, 70% N2, 5% CO2); or (2) hyperoxia (95% O2, 5%
      CO2). The extracellular glutamate concentrations and intracellular glycogen
      levels were measured at nine time points. RESULTS: One hundred sixty-two cultures
      were studied in four independent experiments. The extracellular concentration of
      glutamate in the normoxic group increased significantly from 35+/-10 nM/mg
      protein at baseline up to 100+/-15 nM/mg protein at the end of 5 h of mild
      hyperthermia (P < 0.05). In contrast, extracellular glutamate levels did not vary
      from control in the hyperoxic group. Glycogen levels decreased significantly from
      260+/-85 nM/mg protein at baseline to < 25+/-5 nM/mg protein at the end of 5 h in
      the normoxic group (P < 0.05) but returned to control levels after rewarming in
      the hyperoxic group. No morphologic changes were observed in either group.
      CONCLUSION: The extracellular concentration of glutamate increases, whereas the
      intracellular glycogen content decreases when astrocytes are exposed to a
      sequence of deep hypothermia and rewarming. This effect of hypothermia is
      prevented when astrocytes are exposed to hyperoxic conditions.

PMID- 10598621
TI  - Isoflurane blunts electroencephalographic and thalamic-reticular formation
      responses to noxious stimulation in goats.
AB  - BACKGROUND: Anesthetics, including isoflurane, depress the electroencephalogram
      (EEG). Little is known about the quantitative effects of isoflurane on EEG and
      subcortical electrical activity responses to noxious stimulation. The authors
      hypothesized that isoflurane would depress the results of EEG and subcortical
      response to noxious stimulation at concentrations less than those needed to
      suppress movement. Furthermore, determination of regional differences might aid
      in elucidation of sites of anesthetic action. METHODS: Ten goats were
      anesthetized with isoflurane, and minimum alveolar concentration (MAC) was
      determined using a noxious mechanical stimulus. Depth electrodes were inserted
      into the midbrain reticular formation and thalamus. Needle electrodes placed in
      the skull periosteum measured bifrontal and bihemispheric EEG. The noxious
      stimulus was applied at each of four anesthetic concentrations: 0.6, 0.9, 1.1,
      and 1.4 MAC. RESULTS: At an isoflurane concentration of 0.6 MAC, the noxious
      stimulus activated the midbrain reticular formation, thalamic, and bifrontal
      hemispheric regions, as shown by decreased high-amplitude, low-frequency power.
      For all channels combined (mean +/- SD), total (-33+/-7%), delta (-47+/-12%),
      theta (-23+/-12%), and alpha (-21+/-6%) power decreased after the noxious
      stimulus (P < 0.001); beta power was unchanged. At 0.9 MAC, total (-35+/-5%),
      delta (-42+/-7%), theta (-35+/-8%), and alpha (-23+/-11%) power decreased after
      the noxious stimulus (P < 0.001); beta power was unchanged. At 1.1 MAC only one
      site, and at 1.4 MAC, no site, had decreased power after the noxious stimulus.
      CONCLUSIONS: Isoflurane blunted EEG and midbrain reticular formation-thalamus
      activation response to noxious stimulation at concentrations (1.1 MAC or greater)
      necessary to prevent movement that occurred after noxious stimulation. It is
      unknown whether this is a direct effect or an indirect effect via action in the
      spinal cord.

PMID- 10598622
TI  - First-pass lung uptake and pulmonary clearance of propofol: assessment with a
      recirculatory indocyanine green pharmacokinetic model.
AB  - BACKGROUND: The principal site for elimination of propofol is the liver. The
      clearance of propofol exceeds hepatic blood flow; therefore, extrahepatic
      clearance is thought to contribute to its elimination. This study examined the
      pulmonary kinetics of propofol using part of an indocyanine green (ICG)
      recirculatory model. METHODS: Ten sheep, immobilized in a hammock, received
      injections of propofol (4 mg/kg) and ICG (25 mg) via two semipermanent catheters
      in the right internal jugular vein. Arterial blood samples were obtained from the
      carotid artery. The ICG injection was given for measurement of intravascular
      recirculatory parameters and determination of differences in propofol and ICG
      concentration-time profiles. No other medication was given during the experiment,
      and the sheep were not intubated. The arterial concentration-time curves of ICG
      were analyzed with a recirculatory model. The pulmonary uptake and elimination of
      propofol was analyzed with the central part of that model extended with a
      pulmonary tissue compartment allowing elimination from that compartment. RESULTS:
      During the experiment, cardiac output was 3.90+/-0.72 l/min (mean +/- SD). The
      blood volume in heart and lungs, measured with ICG, was 0.66+/-0.07 l. A
      pulmonary tissue compartment of 0.47+/-0.16 l was found for propofol. The
      pulmonary first-pass elimination of propofol was 1.14+/-0.23 l/min. Thirty
      percent of the dose was eliminated during the first pass through the lungs.
      CONCLUSIONS: Recirculatory modeling of ICG allows modeling of the first-pass
      pulmonary kinetics of propofol concurrently. Propofol undergoes extensive uptake
      and first-pass elimination in the lungs.

PMID- 10598623
TI  - Halothane and isoflurane increase spontaneous but reduce the N-methyl-D-aspartate
      evoked dopamine release in rat striatal slices: evidence for direct presynaptic
      effects.
AB  - BACKGROUND: Experimental data suggest that volatile anesthetics induce
      significant changes in extracellular dopamine concentrations in the striatum, a
      restricted but functionally important brain area. In the present study, the
      authors used a superfused slice preparation to examine the effects of halothane
      and isoflurane on both spontaneous and N-methyl-D-aspartate (NMDA)-evoked
      dopamine release in the striatum, and whether these effects involved actions of
      these anesthetics mediated by gamma-aminobutyric acid receptors in this
      structure. METHODS: Radioactivity collected from 5-min fractions was compared in
      the absence (basal release) or presence (evoked release) of NMDA alone and
      combined with various pharmacologic or anesthetic agents in slices of the
      dorsolateral striatum and synaptosomes of the whole striatum preloaded with 3H
      dopamine and superfused with artificial cerebrospinal fluid. RESULTS: In
      tetrodotoxin-treated striatal slices, halothane and isoflurane significantly
      increased dopamine basal release (EC50 = 0.33 mM and 0.41 mM for halothane and
      isoflurane, respectively). Both agents decreased the NMDA-evoked dopamine release
      in both the absence (IC50 = 0.15 mM and 0.14 mM for halothane and isoflurane,
      respectively) and presence (IC50 = 0.15 mM for both halothane and isoflurane) of
      tetrodotoxin in slices, and in synaptosomes (IC50 = 0.19 mM for both halothane
      and isoflurane). NMDA-induced dopamine release was significantly enhanced by
      bicuculline, a gamma-aminobutyric acid receptor antagonist. Halothane and
      isoflurane inhibitory effects on NMDA-evoked dopamine release were significantly
      reduced in the presence of bicuculline. CONCLUSION: These results indicate that
      halothane and isoflurane decrease the NMDA-evoked dopamine release by acting
      directly at dopamine terminals in striatal slices. They support the involvement
      of both depression of presynaptic NMDA receptor-mediated responses and
      enhancement of gamma-aminobutyric acid receptor-mediated responses in these
      effects.

PMID- 10598624
TI  - Dibucaine and tetracaine inhibit the activation of mitogen-activated protein
      kinase mediated by L-type calcium channels in PC12 cells.
AB  - BACKGROUND: An elevation of the intracellular calcium level, which is mediated by
      N-methyl-D-aspartate receptors and L-type Ca2+ channels both, activates the
      mitogen-activated protein (MAP) kinase signaling pathway involved in synaptic
      modification. It has recently been suggested that MAP kinase plays a role in
      coupling the synaptic excitation to gene expression in the nucleus of
      postsynaptic neurons. Because the effects of local anesthetics on cellular signal
      transduction in neuronal cells are not well-known, the authors investigated
      whether they affect the MAP kinase signaling pathway using PC12 cells. METHODS:
      The cells were stimulated with either 50 mM KCl or 1 microM ionomycin, and
      activated MAP kinase was thus immunoprecipitated. The immunocomplexes were then
      subjected to an Elk1 phosphorylation assay. Both the phosphorylation of MAP
      kinase and the induction of c-Fos were detected by immunoblotting. RESULTS:
      Pretreatment of the cells with 1 mM (ethylenedioxy)-diethyl
      enedinitrilotetraacetic acid or 5 micron nifedipine blocked the MAP kinase
      activation induced by 50 mM KCl, whereas pretreatment with 2 microM omega
      conotoxin GIVA did not. The expression of c-Fos induced by potassium chloride was
      also suppressed by dibucaine, tetracaine (concentrations that inhibited 50% of
      the activity of positive control [IC50s] were 16.2+/-0.2 and 73.2+/-0.7 microM,
      respectively), and PD 98059, a mitogen-activated/extracellular receptor-regulated
      kinase inhibitor. Higher concentrations of dibucaine and tetracaine were needed
      to suppress the activation of MAP kinase induced by ionomycin (the IC50 values of
      dibucaine and tetracaine were 62.5+/-2.2 and 330.5+/-32.8 microM, respectively)
      compared with potassium chloride (the IC50 values of dibucaine and tetracaine
      were 17.7+/-1.0 and 70.2+/-1.2 microM, respectively). Although probable targets
      of these local anesthetics might be L-type Ca2+ channels or components between
      Ca2+ and Ras in MAP kinase pathway, the possibility that they directly affect MAP
      kinase still remains. CONCLUSIONS: Dibucaine and tetracaine at clinical
      concentrations were found to inhibit the activation of MAP kinase and the
      expression of c-Fos mediated by L-type Ca2+ channels in PC12 cells. The
      suppression of MAP kinase pathway may thus be a potential target site for the
      actions of dibucaine and tetracaine, including the modification of the synaptic
      functions.

PMID- 10598625
TI  - Intestinal luminal microdialysis: a new approach to assess gut mucosal ischemia.
AB  - BACKGROUND: The authors developed a microdialysis method for sampling lactate
      from the gut lumen to evaluate the metabolic state of the intestinal mucosa. The
      aim of the study was to evaluate the method in vivo during nonischemic systemic
      hyperlactatemia and gut ischemia. METHODS: Microdialysis capillaries were
      inserted in the lumen of jejunum, in the jejunal wall, and in the mesenteric
      artery and vein in anesthetized, normoventilated pigs. In the first experiment,
      infusion of lactate was used to clamp the arterial blood lactate at 5 mM and 10
      mM (n = 6). In the second experiment, 90 min of intestinal ischemia was induced
      by total (n = 6) or partial (n = 6) occlusion of the superior mesenteric artery
      followed by 60 min of reperfusion. Sham-operated animals were used as controls (n
      = 6). RESULTS: Gut luminal lactate increased only slightly during the nonischemic
      hyperlactatemia: from a median baseline value of 0.10 (range, 0.06-0.28) to 0.50
      (range, 0.15-1.18) and 0.86 (range, 0.35-2.05) mM. Total occlusion of superior
      mesenteric artery increased luminal lactate from a median of 0.09 (range, 0.06
      0.17) to 2.37 (range, 1.29-2.98) and further up to 3.80 (range, 2.55-6.75) mM
      during reperfusion. Partial occlusion of superior mesenteric artery induced an
      increase from a median of 0.09 (range, 0.06-0.51) to 1.66 (range, 0.07-3.97) mM.
      Gut wall microdialysate lactate in deep and superficial layers followed the
      arterial and mesenteric vein microdialysate lactate. CONCLUSIONS: Luminal lactate
      concentration, as measured by microdialysis, increases substantially during gut
      ischemia but does not respond to systemic hyperlactatemia per se. In contrast,
      gut wall microdialysis cannot distinguish between gut ischemia and systemic
      hyperlactatemia. Gut luminal microdialysis provides a method for the assessment
      of intestinal ischemia with a potential for clinical application.

PMID- 10598626
TI  - Colchicine inhibits isoflurane-induced preconditioning.
AB  - BACKGROUND: When administered before prolonged myocardial ischemia and
      reperfusion, isoflurane exerts potent cardioprotective effects similar to those
      inferred by ischemic preconditioning. To determine whether an intact cytoskeleton
      is critically important in isoflurane-induced preconditioning, the authors used a
      rabbit model in which isoflurane-induced myocardial preconditioning decreases
      myocardial infarct size (IS) substantially. In this model, the authors tested
      whether the microtubule depolymerizing agent, colchicine, would inhibit
      isoflurane-induced myocardial preconditioning. METHODS: Myocardial IS was
      measured in four groups of propofol-anesthetized rabbits, each subjected to 30
      min of anterolateral coronary occlusion followed by 3 h of reperfusion. Groups
      differed only in the pretreatments given, and only the control group received no
      pretreatment. An isoflurane-preconditioned group was pretreated with 15 min of
      end-tidal isoflurane, 1.1%, and then 15 min of washout. An isoflurane-plus
      colchicine group was administered 2 mg/kg colchicine intravenously before
      isoflurane pretreatment. A colchicine-control group was administered 2 mg/kg
      colchicine but no isoflurane pretreatment. Myocardial IS and area at risk (AR)
      were defined by staining. Data were analyzed by analysis of variance or
      covariance. RESULTS: Infarct size, expressed as a percentage of AR (IS:AR) was
      33.6%+/-8.8% (SD) in the control group. Isoflurane preexposure reduced myocardial
      IS:AR significantly, to 11.8%+/-9.1%. Colchicine pretreatment eliminated the
      preconditioning-like effect of isoflurane (IS:AR = 32.6%+/-8.7%). Colchicine
      alone did not alter IS (IS:AR = 27.6%+/-7.1%; P = not significant). CONCLUSIONS:
      Colchicine abolished the preconditioning effect of isoflurane but did not
      increase IS when administered alone. An intact microtubular cytoskeleton is
      critically important in the process of volatile anesthetic-induced
      preconditioning.

PMID- 10598628
TI  - Different ventilation strategies affect lung function but do not increase tumor
      necrosis factor-alpha and prostacyclin production in lavaged rat lungs in vivo.
AB  - BACKGROUND: Using an in vivo animal model of surfactant deficiency, the authors
      compared the effect of different ventilation strategies on oxygenation and
      inflammatory mediator release from the lung parenchyma. METHODS: In adult rats
      that were mechanically ventilated with 100% oxygen, acute lung injury was induced
      by repeated lung lavage to obtain an arterial oxygen partial pressure < 85 mmHg
      (peak pressure/positive end-expiratory pressure [PEEP] = 26/6 cm H2O). Animals
      were then randomly assigned to receive either exogenous surfactant therapy,
      partial liquid ventilation, ventilation with high PEEP (16 cm H2O), ventilation
      with low PEEP (8 cm H2O), or ventilation with an increase in peak inspiratory
      pressure (to 32 cm H2O; PEEP = 6 cm H2O). Two groups of healthy nonlavaged rats
      were ventilated at a peak pressure/PEEP of 32/6 and 32/0 cm H2O, respectively.
      Blood gases were measured. Prostacyclin (PGI2) and tumor necrosis factor-alpha
      (TNF-alpha) concentrations in serum and bronchoalveolar lavage fluid (BALF) as
      well as protein concentration in BALF were determined after 90 and 240 min and
      compared with mechanically ventilated and spontaneously breathing controls.
      RESULTS: Surfactant, partial liquid ventilation, and high PEEP improved
      oxygenation and reduced BALF protein levels. Ventilation with high PEEP at high
      mean airway pressure levels increased BALF PGI2 levels, whereas there was no
      difference in BALF TNF-alpha levels between groups. Serum PGI2 and TNF-alpha
      levels did not increase as a result of mechanical ventilation when compared with
      those of spontaneously breathing controls. CONCLUSIONS: Although alveolar protein
      concentration and oxygenation markedly differed with different ventilation
      strategies in this model of acute lung injury, there were no indications of
      ventilation-induced systemic PGI2 and TNF-alpha release, nor of pulmonary TNF
      alpha release. Mechanical ventilation at high mean airway pressure levels
      increased PGI2 levels in the bronchoalveolar lavage-accessible space.

PMID- 10598627
TI  - Exposure to cigarette smoke impairs alveolar macrophage functions during
      halothane and isoflurane anesthesia in rats.
AB  - BACKGROUND: Smoking alters numerous alveolar macrophage functions and is an
      important risk factor for postoperative pulmonary complications. The authors
      therefore tested the hypothesis that smoke exposure impairs antimicrobial and
      proinflammatory responses in alveolar macrophages during halothane and isoflurane
      anesthesia with mechanical ventilation. METHODS: Thirty control rats and 30 rats
      exposed to cigarette smoke were mechanically ventilated with 1.5 minimum alveolar
      concentration halothane and isoflurane. Ten smoke-exposed and control animals
      were assigned to one of three different anesthetic durations (0, 2, and 6 h). The
      fraction of aggregated cells and cell distribution were determined. Opsonized and
      unopsonized phagocytosis was measured. Microbicidal activity was determined as
      the ability to kill Listeria monocytogenes. The expression of interleukin (IL)
      1alpha, IL-1beta, IL-6, macrophage inflammatory protein-2, interferon-gamma, and
      tumor necrosis factor-alpha was measured by semiquantitative reverse
      transcription polymerase chain reaction. Pulmonary lavage concentrations of these
      cytokines were measured by enzyme-linked immunosorbent assay. RESULTS: During
      both halothane and isoflurane anesthesia, the fraction of aggregated macrophages
      increased, whereas unopsonized and opsonized phagocytosis and microbicidal
      activity decreased significantly over time in both groups. Responses observed in
      smoke-exposed rats were almost twice as great as those observed in the control
      rats. Gene expression and production of all proinflammatory cytokines except IL-6
      increased 2-20-fold during anesthesia. The increases in IL-1beta, interferon
      gamma, and tumor necrosis factor-alpha in the control rats were 1.5-8 times
      greater than those in the smoke-exposed rats. CONCLUSION: Antimicrobial and
      proinflammatory responses of alveolar macrophages during anesthesia were markedly
      suppressed by smoke exposure. Our data suggest that smoke exposure reduces the
      efficacy of immune defenses during anesthesia.

PMID- 10598630
TI  - Interaction of intravenous anesthetics with human neuronal potassium currents in
      relation to clinical concentrations.
AB  - BACKGROUND: Neuronal voltage-dependent potassium (K) currents are crucial for
      various cellular functions, such as the integration of temporal information in
      the central nervous system. Data for the effects of intravenous anesthetics on
      human neuronal K currents are limited. It was the authors' aim to evaluate the
      concentration-related effects of three opioids (fentanyl, alfentanil, sufentanil)
      and seven nonopioids (thiopental, pentobarbital, methohexital, propofol,
      ketamine, midazolam, droperidol) used in clinical anesthesia on neuronal voltage
      dependent K currents of human origin. METHOD: K currents were measured in SH-SY5Y
      cells using the whole cell patch-clamp technique. Currents were elicited by step
      depolarization from a holding potential of -80 to -50 mV through +90 mV, and
      their steady state amplitudes were determined. RESULTS: All drugs inhibited the K
      currents in a concentration-dependent and reversible manner. Because time
      dependence of inhibition differed among the drugs, effects were measured after 54
      64 ms of the test pulse. The IC50 values (concentration of half-maximal
      inhibition) for current suppression ranged from 7 microM for sufentanil to 2 mM
      for pentobarbital. Suppression of the K currents by the opioids occurred at 10
      fold lower IC50 values (concentration of half-maximal inhibition) than that by
      the barbiturates. As estimated from the concentration-response curves, K-current
      suppression at clinical concentrations would be less than 0.1% for the opioids
      and approximately 3% for the other drugs. CONCLUSIONS: Effects of intravenous
      anesthetics on voltage-dependent K currents occur at clinical concentrations. The
      IC50 values for current inhibition of the nonopioid anesthetics correlated with
      these concentrations (r = 0.95). The results suggest that anesthetic drug action
      on voltage-dependent K currents may contribute to clinical effects or side
      effects of intravenous anesthetics.

PMID- 10598629
TI  - Tissue factor expression in vital organs during murine traumatic shock: role of
      transcription factors AP-1 and NF-kappaB.
AB  - BACKGROUND: Tissue factor (TF) is a cell-surface glycoprotein responsible for
      initiating the extrinsic pathway of coagulation that has been shown to have a
      role in the pathophysiology of sepsis and reperfusion injury. The purpose of this
      study was to investigate TF expression in vital organs and to determine possible
      regulatory mechanisms of TF expression in the lung during traumatic shock in
      rats. METHODS: Noble-Collip drum trauma was induced in anesthetized Sprague
      Dawley rats. Anesthetized rats without trauma served as controls. TF activity was
      measured in plasma and lung tissue. TF messenger RNA (mRNA) was measured in the
      lung, liver, and small intestine using ribonuclease protection assays.
      Electromobility shift assays were used to quantify binding of nuclear extracts
      from lung to TF-specific consensus domains for transcription factors NF-kappaB
      and AP-1. RESULTS: TF activity in plasma increased up to 14-fold and +232% in the
      lung (P < 0.001 for plasma and lung) 2 h after trauma. TF mRNA level was
      significantly increased in the lungs (P < 0.01), small intestine (P < 0.01), and
      liver (P < 0.05) 1 h after trauma compared to sham-operated control rats. TF mRNA
      expression continued to increase in the lungs and the liver (both, P < 0.001) 2 h
      after trauma TF sequence-specific complex binding to AP-1 and NF-kappaB domains
      was enhanced in the lungs of trauma rats (+395%, P < 0.001 and +168%, P < 0.001,
      respectively). CONCLUSIONS: These results suggest that TF may play an important
      role in the pathophysiology of severe trauma and that regulatory elements AP-1
      and NF-kappaB may be involved in the regulation of TF mRNA expression in
      traumatic shock.

PMID- 10598631
TI  - Hemodilution during venous gas embolization improves gas exchange, without
      altering V(A)/Q or pulmonary blood flow distributions.
AB  - BACKGROUND: Isovolemic anemia results in improved gas exchange in rabbits with
      normal lungs but in relatively poorer gas exchange in rabbits with whole-lung
      atelectasis. In the current study, the authors characterized the effects of
      hemodilution on gas exchange in a distinct model of diffuse lung injury: venous
      gas embolization. METHODS: Twelve anesthetized rabbits were mechanically
      ventilated at a fixed rate and volume. Gas embolization was induced by continuous
      infusion of nitrogen via an internal jugular venous catheter. Serial hemodilution
      was performed in six rabbits by simultaneous withdrawal of blood and infusion of
      an equal volume of 6% hetastarch; six rabbits were followed as controls over
      time. Measurements included hemodynamic parameters and blood gases, ventilation
      perfusion (V(A)/Q) distribution (multiple inert gas elimination technique),
      pulmonary blood flow distribution (fluorescent microspheres), and expired nitric
      oxide (NO; chemoluminescence). RESULTS: Venous gas embolization resulted in a
      decrease in partial pressure of arterial oxygen (PaO2) and an increase in partial
      pressure of arterial carbon dioxide (PaCO2), with markedly abnormal overall
      V(A)/Q distribution and a predominance of high V(A)/Q areas. Pulmonary blood flow
      distribution was markedly left-skewed, with low-flow areas predominating.
      Hematocrit decreased from 30+/-1% to 11+/-1% (mean +/- SE) with hemodilution. The
      alveolar-arterial PO2 (A-aPO2) difference decreased from 375+/-61 mmHg at 30%
      hematocrit to 218+/-12.8 mmHg at 15% hematocrit, but increased again (301+/-33
      mmHg) at 11% hematocrit. In contrast, the A-aPO2 difference increased over time
      in the control group (P < 0.05 between groups over time). Changes in PaO2 in both
      groups could be explained in large part by variations in intrapulmonary shunt and
      mixed venous oxygen saturation (SvO2); however, the improvement in gas exchange
      with hemodilution was not fully explained by significant changes in V(A)/Q or
      pulmonary blood flow distributions, as quantitated by the coefficient of
      variation (CV), fractal dimension, and spatial correlation of blood flow. Expired
      NO increased with with gas embolization but did not change significantly with
      time or hemodilution. CONCLUSIONS: Isovolemic hemodilution results in improved
      oxygen exchange in rabbits with lung injury induced by gas embolization. The
      mechanism for this improvement is not clear.

PMID- 10598632
TI  - Effects of halothane and enflurane on ventricular conduction, refractoriness, and
      wavelength: a concentration-response study in isolated hearts.
AB  - BACKGROUND: Effects of halothane and enflurane on ventricular conduction,
      anisotropy, duration and dispersion of refractory periods, and wavelengths were
      studied, and putative antiarrhythmic or arrhythmogenic properties on ventricles
      were discussed. METHODS: High-resolution epicardial mapping system was used to
      study the effects of 1, 3, and 5 vol% halothane and enflurane in 30 isolated
      rabbit hearts. Ten hearts were kept intact to study the effects on spontaneous
      sinus cycle length (RR interval), perfusion pressure, and the occurrence of
      spontaneous dysrhythmias. In 20 other hearts, a thin epicardial layer was
      obtained (frozen hearts) to study ventricular conduction velocity, ventricular
      effective refractory period (VERP in four sites) and wavelengths. RESULTS:
      Halothane induced a concentration-dependent lengthening of RR interval, whereas
      enflurane did not. Both agents slowed longitudinal and transverse ventricular
      conduction velocity with no anisotropic change. Ventricular effective refractory
      period was prolonged at 1 vol% and was shortened at higher concentrations, with
      no significant increase in dispersion. Ventricular longitudinal and transverse
      wavelengths decreased in a concentration-dependent manner. Although changes in
      wavelengths could express proarrhythmic effects of volatile anesthetics, no
      arrhythmia occurred in spontaneously beating hearts or in frozen hearts.
      CONCLUSIONS: The ventricular electrophysiologic effects of halothane and
      enflurane were slight, suggesting that both agents are unable per se to induce
      functional conduction block and therefore reentrant ventricular arrhythmias.

PMID- 10598633
TI  - Nursing workload associated with adverse events in the postanesthesia care unit.
AB  - BACKGROUND: The authors used a nursing task inventory system to assess nursing
      resources for patients with and without adverse postoperative events in the
      postanesthesia care unit (PACU). METHODS: Over 3 months, 2,031 patients were
      observed, and each task/activity related to direct patient care was recorded and
      assigned points according to the Project Research in Nursing (PRN) workload
      system. PRN values for each patient were merged with data from an anesthesia
      database containing demographics, anesthesia technique, and postoperative adverse
      events. Mean and median PRN points were determined by age, sex, duration of
      procedure, and mode of anesthesia for patients with and without adverse events in
      the PACU. Three theoretical models were developed to determine the effect of
      differing rates of adverse events on the requirements for nurses in the PACU.
      RESULTS: The median workload (PRN points) per patient was 31.0 (25th-75th
      percentile, 25-46). Median workload was 26 points for patients with no
      postoperative events and 155 for > or = six adverse events. Workload varied by
      type of postoperative event (e.g., unanticipated admission to the intensive care
      unit, median workload = 95; critical respiratory event = 54; and nausea/vomiting
      = 33). Monitored anesthesia care or general anesthesia with spontaneous
      ventilation used less resources compared with general anesthesia with mechanical
      ventilation. Modeling various scenarios (controlling for types of patients)
      showed that adverse events increased the number of nursing personnel required in
      the PACU. CONCLUSIONS: Nursing care documentation based on requirements for
      individual patients demonstrates that the rate of postoperative adverse events
      affects the amount of nursing resources needed in the PACU.

PMID- 10598634
TI  - Intrathecal drug therapy for chronic pain: from basic science to clinical
      practice.

PMID- 10598636
TI  - Incidence of spinal epidural abscess after epidural analgesia: a national 1-year
      survey.

PMID- 10598635
TI  - Intraoperative and postoperative analgesic efficacy and adverse effects of
      intrathecal opioids in patients undergoing cesarean section with spinal
      anesthesia: a qualitative and quantitative systematic review of randomized
      controlled trials.

PMID- 10598637
TI  - Treatment of lumbosacral radiculopathy with epidural steroids.

PMID- 10598638
TI  - Circulatory failure after anesthesia induction in a patient with severe primary
      pulmonary hypertension.

PMID- 10598639
TI  - The intraoperative diagnosis of a tracheoesophageal fistula in an adult.

PMID- 10598640
TI  - The changes in bispectral index during a hypovolemic cardiac arrest.

PMID- 10598641
TI  - Extreme intraoperative blood loss and hemodilution in a Jehovah's Witness: new
      aspects in postoperative management.

PMID- 10598642
TI  - Epileptiform discharges during 2 MAC sevoflurane anesthesia in two healthy
      volunteers.

PMID- 10598643
TI  - Catastrophic caudad spread of a peritonsillar abscess: a case report.

PMID- 10598644
TI  - Behavioral outcomes methodology.

PMID- 10598645
TI  - Causes of nitrous oxide contamination in operating rooms.

PMID- 10598646
TI  - Minimizing venous air embolism from reinfusion bags.

PMID- 10598647
TI  - Liquid ventilation: a theoretically beneficial approach in treating systemic air
      embolism in lung trauma.

PMID- 10598648
TI  - The three axis alignment theory and the "sniffing position": perpetuation of an
      anatomic myth?

PMID- 10598649
TI  - Attempted placement of a thoracic epidural catheter via the caudal route in a
      newborn.

PMID- 10598650
TI  - Mathematical equivalent of metabolic alkalosis part of the Goldberg acid-base
      map.

PMID- 10598651
TI  - Idiopathic trigeminal neuralgia associated with a severe atypical facial pain
      exacerbated by hydrocephalus.

PMID- 10598652
TI  - An adverse effect of carboxymethylcellulose in lidocaine jelly.

PMID- 10598653
TI  - Juvenile myelomonocytic leukemia: what we don't know.

PMID- 10598655
TI  - Idiopathic thrombocytopenic purpura: reasons to resolve the chaos.

PMID- 10598654
TI  - Long-term follow-up of cancer survivors.

PMID- 10598656
TI  - Bone marrow transplantation for sickle cell disease: where do we go from here?
AB  - Bone marrow transplantation has curative potential for patients who have sickle
      cell disease. However, concerns about short-term and long-term toxicity, lack of
      suitable stem cell donors, and limited access to this treatment currently make it
      an infrequently utilized treatment for sickle cell disease. The current results
      of bone marrow transplantation for sickle cell disease and barriers to wider
      application are reviewed. Strategies that might lead to broader availability and
      reduced toxicity of bone marrow transplantation are discussed.

PMID- 10598657
TI  - Rebirth of granulocyte transfusions: should it involve pediatric oncology and
      transplant patients?
AB  - Several methodologic advances, particularly use of recombinant granulocyte colony
      stimulating factor to stimulate donors, have made it possible to collect
      extraordinarily large numbers of normal neutrophils for transfusion into
      neutropenic patients with life-threatening infections. Because larger doses of
      neutrophils can be transfused, renewed interest has arisen in the use of
      neutrophil (granulocyte) transfusions to treat adult oncology patients and
      progenitor cell transplant recipients, in whom neutropenia complicated by severe
      infections persists as a significant problem, despite combination antibiotic
      therapy, recombinant cytokines, myeloid growth factors, and use of mobilized
      peripheral blood progenitor cells. In this commentary, consideration is given as
      to whether pediatric oncology and transplant patients might benefit from modern
      granulocyte transfusion therapy. If children are found to experience significant
      morbidity or mortality from neutropenic infections despite modern supportive
      care, it is logical to explore the efficacy, potential toxicity, and cost
      effectiveness of granulocyte transfusion therapy by properly designed, randomized
      clinical trials.

PMID- 10598658
TI  - Alternative donor bone marrow transplantation for children with juvenile
      myelomonocytic leukemia.
AB  - The purpose of this study was to evaluate the outcome of children with juvenile
      myelomonocytic leukemia (JMML) treated with alternative donor bone marrow
      transplantation (BMT). Twelve consecutive patients with JMML confirmed by in
      vitro clonogenic assays underwent alternative donor BMT. Ten patients received
      pretransplant chemotherapy for one to seven cycles (cytosine arabinoside
      regimens). Eight underwent splenectomy before the transplant. Donors were
      unrelated for nine patients and partially matched related for three. Conditioning
      included total body irradiation for all but one patient. Graft-versus-host
      disease (GVHD) prophylaxis included in vitro partial T-lymphocyte depletion for
      five patients with cyclosporine arabinoside, and cyclosporine arabinoside and
      methotrexate for seven. Acute GVHD developed in all patients, and chronic GVHD
      developed in 7 of 11 evaluable patients. Relapses occurred in two patients, and
      two died of transplant-related causes. Eight patients remain in remission with a
      median follow-up of 31 months after the BMT. The event-free survival rate for
      this series is 64% (95% confidence interval, 27%-85%). The roles of pretransplant
      chemotherapy and splenectomy for leukemic reduction to prevent relapse, and the
      use of conditioning regimens with total body irradiation require study in a
      larger series of patients. GVHD may be beneficial in preventing relapses, which
      has been the major cause of treatment failure for these patients.

PMID- 10598659
TI  - Late events in pediatric patients with Ewing sarcoma/primitive neuroectodermal
      tumor of bone: the Dana-Farber Cancer Institute/Children's Hospital experience.
AB  - The outcome for 82 pediatric patients with Ewing sarcoma (ES) and primitive
      neuroectodermal tumor (PNET) of bone is reported; the patients were treated at
      the Dana-Farber Cancer Institute (DFCI) and Children's Hospital (CH) in Boston,
      MA (USA) from 1971-1988. The charts of all patients with ES/PNET of bone treated
      during this period were reviewed for disease status, therapy, sites of relapse,
      information on second malignancies, and survival status. Eighty-two patients with
      ES/PNET of bone treated at DFCI/CH were identified. The 10-year event-free
      survival (EFS) rates were 12% (95% confidence interval [CI] 0, 27%) and 38% (95%
      CI 26, 51%) for patients with and without metastases, respectively (P = 0.002);
      the overall survival (OS) rates were 17% (95% CI 1, 33%) and 48% (95% CI 35, 61%)
      for patients with and without metastases (P = 0.001). Median follow-up for
      surviving patients is 10.2 years. Primary site in the pelvis also was associated
      with a poor outcome for patients with no metastatic disease (P = 0.006 OS, P =
      0.03 EFS). Thirty-one patients survived in first remission at least 5 years from
      diagnosis, and of these, five experienced relapse of original disease, and five
      experienced secondary malignancies. Pediatric patients treated for ES/PNET of
      bone remain at risk for life-threatening events into the second decade of follow
      up. After 5 years, the risk of second malignant neoplasm is at least as high as
      the risk of late relapse. Prolonged follow-up of patients with ES and PNET of
      bone is indicated.

PMID- 10598661
TI  - Infections in children with cancer: a continued need for the comprehensive
      physical examination.
AB  - Few studies have addressed the influence of profound myelosuppressive therapy in
      contemporary protocols on infectious morbidity in pediatric oncology patients.
      This study evaluates the types of infections and the methods used to diagnose
      infection in patients enrolled in current Children's Cancer Group (CCG)
      protocols. Data were collected on patients enrolled in CCG protocols from January
      1, 1992, through December 31, 1995. Of the 155 protocol patients, 102 were
      completely evaluated and had data collected through August 1, 1996. Patients were
      divided into two diagnosis groups: leukemia/lymphoma (N = 51) and solid tumor (N
      = 51). Eighty-five (83%) patients had documented infections and 17 (17%) did not.
      Overall, 96 (94%) patients had in-dwelling central venous catheters. Twelve
      categories of infection were identified. Data were analyzed for age, gender,
      diagnosis, neutropenia, organism, and disease state (primary active, recurrent
      active, primary remission, and secondary remission). Statistical comparisons were
      made only on rates, whereas descriptive comparisons were given for numbers of
      infections and organisms. The infection rates for patients with active disease
      were 1.01 and 1.15 per 100 patient days (primary versus recurrent) and 0.59 and
      0.38 per 100 patient days for patients with disease in remission (primary versus
      secondary). Diagnosis-group infection rates were 0.66 and 0.68 per 100 patient
      days for patients with solid tumors and leukemia/lymphoma, respectively. Three
      hundred thirty infections, including 19 polymicrobial infections, were recorded.
      The three most common types of infection were otitis media, septicemia, and
      urinary tract infection. More infections were associated with an age at diagnosis
      of less than 3 years, a leukemia/lymphoma diagnosis in remission, and an absolute
      neutrophil count >500 cells/microL. One hundred ninety-four organisms were
      isolated from 330 infections. Gram-positive organisms (n = 74) such as coagulase
      negative Staphylococci (n = 38) predominated over gram-negative organisms (n =
      63) for all infectious categories. Specifically, gram-positive organisms (n = 39)
      were isolated more often from blood cultures than were gram-negative organisms (n
      = 27). The overall mortality for patients was 36%. Seven of the 37 (19%) patient
      deaths were attributed to infection. These patients predominantly were girls with
      neutropenia and leukemia/ lymphoma in active disease who died of gram-negative
      sepsis. Infections with gram-positive organisms continue to be major causes of
      morbidity in pediatric oncology patients receiving contemporary CCG protocols.
      However, infection-related mortality, especially with gram-negative organisms,
      occurs less frequently than does malignancy-related mortality. Common childhood
      infections (such as otitis media) seem equally as prevalent as bacteremia in
      pediatric oncology patients. Thus, a comprehensive physical examination is as
      imperative as the microbiologic evaluation in diagnosing infection in this
      patient population.

PMID- 10598660
TI  - Phase I and pharmacokinetic study of CI-980 in recurrent pediatric solid tumor
      cases: a Pediatric Oncology Group study.
AB  - To establish the maximum tolerated dosage (MTD), the dose-limiting toxicities
      (DLTs), and pharmacokinetic parameters of CI-980, a novel tubulin binder, in
      children with solid tumors refractory to standard therapy. Patients 21 years of
      age or younger with adequate nutritional, hematopoietic, renal, and hepatic
      function were eligible. The patient must not have been pregnant. Patients with
      brain tumors were not eligible for any dosage level until it was demonstrated the
      level did not produce DLT in patients with extracranial solid tumors. The
      starting dosage level was 3.5 mg/m2/day, for 3 days, administered as a continuous
      intravenous infusion (80% of the adult MTD). If a dosage level was associated
      with dose-limiting myelotoxicity, growth factors were to be added. Thirty-three
      patients received CI-980. Twenty-four had solid tumor; 9 had brain tumor. The MTD
      achieved without granulocyte colony stimulating factor (G-CSF) was 3.5 mg/m2/day
      (DLT: neutropenia) and with G-CSF, it was as follows: patients with brain tumor,
      4.2 mg/m2/day (DLT: myelosupression); and patients with solid tumor, 5 mg/m2/day
      (DLT: cortical toxicity). Several responses were seen, most notably prolonged
      stable disease in two of five patients with medulloblastoma. Pharmacokinetic data
      showed a mean steady state level of 1.74 ng/mL for two patients treated with the
      5 mg/m2/day regimen, with rapid decay after the termination of the infusion. CI
      980 showed preliminary evidence of activity in recurrent pediatric malignancies,
      with tolerable, reversible toxicities.

PMID- 10598662
TI  - Malignant peripheral nerve sheath tumors in children: a single-institution twenty
      year experience.
AB  - A retrospective series of pediatric patients with localized malignant peripheral
      nerve sheath tumors (MPNST) treated during a 20-year period at one institution is
      reported. Between 1976 and 1996, 24 consecutive children were treated by a
      multimodality approach. Conservative surgery was the treatment of choice: primary
      radical surgery was performed in 10. Postoperative radiotherapy was administered
      in 12 and adjuvant chemotherapy in 19. Eight patients were alive without evidence
      of disease, six in first complete remission and two in second complete remission,
      after a median follow-up of 230 months. The 10-year event-free survival (EFS) and
      survival were 29% and 41%, respectively. Survival was 80% for the patients who
      underwent radical surgery, and 14% for the others; 71% for patients with tumors
      smaller than 5 cm, and 29% for those with tumors 5 cm or larger. Local recurrence
      was the major cause for treatment failure (13 of 17; 76%); the rate of local
      relapse was 33% v 75% in patients who either received or did not receive
      radiotherapy. Complete surgical excision remains the most effective treatment for
      MPNST and represents the main prognostic factor along with tumor size.
      Radiotherapy seems to play a role in achieving local control, whereas the role of
      chemotherapy is uncertain.

PMID- 10598663
TI  - Corticosteroid prophylaxis for neurologic complications of intravenous
      immunoglobulin G therapy in childhood immune thrombocytopenic purpura.
AB  - To assess in a retrospective analysis if there is evidence suggesting
      corticosteroids can prevent the neurologic complications of intravenous
      immunoglobulin (IVIG) therapy in children with immune thrombocytopenic purpura
      (ITP). From March 1985 to September 1997, 112 children received IVIG (1 g/kg/day
      for one or two dosages) for the treatment of ITP. During the years 1990 to 1997,
      23 children nonrandomly received a short course of prednisone (2 mg/kg/day during
      and for 3 days after the completion of IVIG therapy) as a prophylaxis against the
      neurologic complications of IVIG therapy. The authors analyzed the data of all
      112 children and compared the incidence of neurologic complications in those who
      received prednisone prophylaxis with those who did not. The severity of the
      complications was assessed as follows: grade 1, headache only; grade 2, headache
      plus vomiting; grade 3, headache, vomiting, and fever; grade 4, headache,
      vomiting, fever, and meningeal signs (aseptic meningitis). Of the 23 children who
      received prednisone prophylaxis, 2 (8.7%) experienced headache and vomiting after
      the completion of prednisone prophylaxis. Of the 89 children without prednisone
      prophylaxis, 27 (30.3%) experienced neurologic symptoms of varying severity,
      including one patient with aseptic meningitis proven by examination of the spinal
      fluid. Twelve of these patients needed additional hospital care for the
      complications. Children receiving prednisone had a 78% lower risk of neurologic
      complications (OR = 0.22; CI = 0.05-0.90; P = 0.036). This retrospective study
      shows a short course of prednisone therapy, given during and until 3 days after
      the completion of IVIG infusion, is likely to decrease the incidence and severity
      of neurologic complications of IVIG in children with ITP.

PMID- 10598664
TI  - Prevalence of priapism in children and adolescents with sickle cell anemia.
AB  - A questionnaire survey was conducted of patients with homozygous sickle cell
      anemia (Hb SS) and sickle cell beta(0)-thalassemia (Hb S-beta(0)) between 5 and
      20 years of age to determine the prevalence and characteristics (number of
      episodes, timing, duration, cause, or precipitating event) of priapism. Ninety
      eight male patients or their parents were surveyed by the same male investigator
      using a structured verbal interview, which was modified according to the age of
      the patient. Ninety-four patients had Hb SS and four Hb S-beta(0) thalassemia.
      Eleven (11%) patients were known to have experienced priapism previously. In
      response to the questionnaire, 16 of the remaining 87 (18%) patients reported
      having had priapism on one or more occasions. The actuarial probability of
      experiencing priapism by 20 years of age was 89% (+/- 9%). The mean age at the
      initial episode was 12 years, the mean number of episodes per patient was 15.7
      (median, 1; range, 1-100), and the mean duration of an episode was 125 minutes.
      Episodes typically occurred around 4:00 am, and 75% of the patients surveyed had
      at least one episode starting during sleep or upon awakening from sleep. The
      prevalence of priapism in children and adolescents with SCA is much higher than
      previously described. Since early intervention and treatment may prevent
      irreversible penile fibrosis and impotence, patients and parents should be
      educated about this complication in advance of its occurrence.

PMID- 10598665
TI  - Juvenile myelomonocytic leukemia and Noonan syndrome.
AB  - A case of juvenile myelomonocytic leukemia (JMML, previously referred to as JCML)
      in a neonate with Noonan syndrome (NS) is described. The boy presented with
      bilateral congenital hydrothoraces, nonimmune hydrops, dysmorphic facies,
      persistent thrombocytopenia, and leukocytosis. The diagnosis of JMML was made on
      bone marrow cell culture studies. Review of the literature reveals an unusual
      preponderance of hematologic malignancies, in particular JMML, among patients
      with NS. Of 40 NS patients admitted to the authors' institution during a 10-year
      period, there were 4 (10%) with evidence of a monocytic proliferation, which
      resolved spontaneously. The authors postulate that patients with NS may have an
      increased incidence of myeloproliferative disorders, which in most cases appears
      to be benign but may be preleukemic or even lethal.

PMID- 10598666
TI  - Duchenne muscular dystrophy and concomitant metastatic alveolar rhabdomyosarcoma.
AB  - The authors report the concomitant occurrence of Duchenne muscular dystrophy
      (DMD) and alveolar rhabdomyosarcoma (RMS). A 4-year-old boy presented with
      symptoms involving his neuromuscular system that affected primarily his left hip
      and leg. Duchenne muscular dystrophy was diagnosed. Seven months later,
      metastatic alveolar RMS in the ipsilateral pelvis was documented. The diagnosis
      of one major disorder affecting striated muscle (DMD) may have prevented the
      early detection of another (RMS).

PMID- 10598667
TI  - Improved hematopoiesis using amifostine in secondary myelodysplasia.
AB  - An 11-year-old boy with multiply relapsed lymphoblastic disease became
      transfusion dependent with myelodysplasia and chromosomal abnormalities after 5
      years of aggressive therapy. At 5 years of age, he presented with transient
      idiopathic hypoplastic anemia and neutropenia that spontaneously resolved within
      a month. Three months later, he experienced lymphoblastic lymphoma in the left
      parotid region and subsequently experienced disease relapse in his testicles,
      bone marrow, and central nervous system during a 3-year period. He has received
      multiagent chemotherapy, autologous peripheral blood stem-cell transplantation,
      and testicular and whole neuraxis irradiation therapy. After craniospinal
      irradiation, he did not recover normal bone marrow function. His bone marrow was
      hypocellular, and he required platelet and erythrocyte transfusions and
      granulocyte colony-stimulating factor. Marrow cytogenetic studies revealed new
      multiple translocations. Within a month of the initiation of intravenous
      amifostine at 200 mg/m2/dose three times a week, his leukocyte count, neutrophil
      count, and hemoglobin level normalized. His platelet count also improved
      sufficiently to achieve transfusion independence. He has returned to school and
      engages in other normal activities for his age. Amifostine may improve
      hematopoiesis in secondary myelodysplastic syndromes in children.

PMID- 10598668
TI  - Parotid carcinoma as a second malignancy after treatment of childhood acute
      lymphoblastic leukemia.
AB  - The occurrence of second malignant neoplasms (SMN) in children who survive their
      primary malignancy is a major cause for concern. Two children with diagnoses of
      intermediate-risk acute lymphoblastic leukemia (ALL) at 22 months and 2 years of
      age were treated with multiagent chemotherapy and prophylactic cranial
      irradiation. They experienced painless parotid swelling 6 and 7 years after
      successful treatment of the ALL. The patients underwent total parotidectomy, and
      a diagnosis of mucoepidermoid carcinoma was made. Both patients experienced
      transient facial nerve paresis. The incidence of SMN in children successfully
      treated for primary malignancies is 3% to 12%. Salivary gland tumors are being
      increasingly described in this setting. Long-term follow-up for survivors of
      childhood ALL is recommended with prompt assessment and resection of parotid
      swellings, particularly in children who have received cranial irradiation.

PMID- 10598669
TI  - Clinical presentation of fibrodysplasia ossificans progressiva: pitfalls in
      diagnosis.
AB  - A patient presented with a rapidly growing mass in the cervicothoracic
      paraspinous region. Associated clinical and radiographic skeletal abnormalities
      and histopathologic findings showing mild to moderate proliferation of spindle
      cells in a myxoid stroma led to the diagnosis of fibrodysplasia ossificans
      progressiva. Recognizing the clinical features of this disease is important and
      should avoid the need for obtaining tissue to make the diagnosis, because
      performing a biopsy may be particularly morbid in these patients.

PMID- 10598671
TI  - Uterine cervical extrarenal Wilms tumor managed without hysterectomy.
AB  - This report describes an unusual case of uterine cervical Wilms tumor treated
      successfully without hysterectomy or radiation therapy. The 12-year-old white
      girl developed a persistent vaginal discharge. Her pelvic examination revealed a
      large mass involving the entire upper vagina, obscuring the cervix. Biopsy of the
      mass was consistent with Wilms tumor with favorable histology. The tumor was not
      initially resected because the resection would involve hysterectomy and partial
      resection of the bladder wall. The patient was treated with preexcisional
      chemotherapy consisted of alternating vincristine, doxorubicin, cyclophosphamide
      and carboplatin/etoposide. Repeat magnetic resonance imaging after 5 weeks of
      chemotherapy demonstrated marked reduction of the tumor size. The tumor was
      easily removed by transsection of the stalk followed by cold-knife conization of
      the cervix. The patient received four more cycles of chemotherapy and remained in
      complete remission 12 months after completion of chemotherapy. This report
      suggests that in selected cases, chemotherapy can reduce tumor size sufficiently
      in patients with bulky cervical Wilms tumor to allow local resection and avoid
      hysterectomy.

PMID- 10598670
TI  - Metastatic paraganglioma and paraneoplastic-induced anemia in an adolescent:
      treatment with hepatic arterial chemoembolization.
AB  - Mediastinal paragangliomas are rare neoplasms in children. Anemia, as a
      paraneoplastic syndrome, has been described in adults with metastatic
      paraganglioma. The management of paraneoplastic anemia from metastatic
      paraganglioma has been problematic, with no reports in the literature describing
      successful treatment. This article describes a 17-year-old Jehovah's Witness with
      a mediastinal paraganglioma, hepatic metastases, and severe anemia. The patient
      and his family refused blood products and the anemia was refractory to
      erythropoietin and elemental iron therapy. Serial chemoembolization of the
      hepatic lesions resulted in resolution of the anemia, allowing subsequent
      debulking of the mediastinal paraganglioma.

PMID- 10598672
TI  - Aeromonas abscess in an immunocompromised child.
AB  - An 11-year-old immunocompromised child developed cellulitis and abscess due to
      Aeromonas hydrophila at the site of bone marrow aspiration after swimming in a
      freshwater lake. The patient required treatment with intravenous antibiotics and
      surgical debridement to eradicate the infection. Both common and unusual
      organisms may complicate infections at the sites of percutaneous procedures.

PMID- 10598673
TI  - Recurrent viral associated hemophagocytic syndrome in a child with Langerhans
      cell histiocytosis.
AB  - Langerhans cell histiocytosis (LCH) with subsequent viral-associated
      hemophagocytic syndrome (VAHS) or secondary hemophagocytic lymphohistiocytosis
      (HLH) is extremely rare. A 15-month-old girl with disseminated LCH experienced
      three episodes of VAHS during maintenance therapy. Viral infection, with
      influenza A, herpes simplex, and adenovirus, respectively, was documented at each
      episode. She recovered each time after interruption of maintenance therapy. The
      occurrence of fever and pancytopenia in patients with chemotherapy-treated LCH
      can be associated with VAHS and not with relapsing LCH.

PMID- 10598674
TI  - Association between autosomal dominant optic atrophy and Ewing sarcoma.

PMID- 10598675
TI  - A simple and accurate mathematical method for calculation of the EC50.
AB  - A simple, accurate, and speedy noncomputational technique for the calculation of
      the EC50 or any other concentration-related parameter of concentration-effect
      curves is presented. It avoids the necessity for graph construction or
      computational curve-fitting programs and allows accurate calculation of the EC50,
      where the value falls between two known concentrations The technique has been
      applied to a concentration-response curve constructed to hepatic arterial (HA)
      vasoconstrictor responses to HA injections of noradrenaline in an isolated dual
      perfused rat liver preparation. EC50 values calculated by the new technique were
      compared to those calculated by conventional, established, noncomputational
      techniques. The new technique is faster, more accurate, and simpler to perform
      than other established noncomputational techniques used for the calculation of
      the EC50 and can be widely applied to many other pharmacological investigations.

PMID- 10598677
TI  - Dose of doxorubicin determines severity of renal damage and responsiveness to ACE
      inhibition in experimental nephrosis.
AB  - Nephrosis induced by doxorubicin (adriamycin) is an experimental model of
      glomerulosclerosis with relative stable proteinuria which is commonly used for
      pharmacological intervention studies. It is induced by a single or a double dose
      of doxorubicin, with doses that vary considerably among investigators from 2 to
      7.5 mg/kg. Intervention studies with ACE-inhibitors in this model have provided
      conflicting results. We hypothesized that these discrepancies might be due to
      different properties of the doxorubicin model, related to the dose of doxorubicin
      used to induce proteinuria. We tested this hypothesis by inducing doxorubicin
      nephrosis with 1, 2 and 3 mg/kg, and evaluating the response to intervention with
      lisinopril. The 1-mg/kg doxorubicin dose did not induce significant proteinuria.
      The 2- and the 3-mg/ kg dose resulted in a proteinuria of 684+/-215 mg/24 h and
      736+/-277 mg/24 h 6 weeks after induction, respectively (Mean+/-SD). Treatment
      with lisinopril 2 mg/kg/day reduced proteinuria to 160+/-170 mg/24 h(p<0.01) in
      the 2-mg/kg doxorubicin group, whereas in the 3-mg/kg doxorubicin group,
      proteinuria did not respond to lisinopril (529+/-264 mg/24 h). In time control
      rats, proteinuria remained stable. Renal damage developed in both time control
      groups, with a glomerulosclerosis score of 29+/-22 in the 2-mg/kg group and 84+/
      41 in the 3-mg/kg doxorubicin group. Lisinopril resulted in a significantly lower
      glomerulosclerosis score in the 2-mg/kg doxorubicin group only (16+/-15, p<0.05),
      whereas the 3-mg/kg group showed no significant reduction (56+/-29, NS). In
      conclusion, the dose of doxorubicin used to induce nephrosis is an important
      determinant not only of the severity of the ensuring renal damage, but also of
      the response to intervention by ACE-inhibition. These findings have an impact on
      the interpretation of intervention studies in this model.

PMID- 10598676
TI  - Interactive computerized microscopy as a tool for quantifying vascular
      remodelling effects of diabetes and V1a receptor antagonist SR 49059 on rat
      mesenteric arterial bed.
AB  - A methodology using interactive computerized microscopy (ICM) was developed to
      quantify in the mesenteric arterial bed the morphometric changes associated with
      diabetes and the influence of treatment with SR 49059, an antagonist of
      vasopressin V1a receptors. Four groups of rats were studied: untreated normal (N)
      or streptozotocin- (60 mg/kg i.v.) induced diabetic (D), and treated (0.4 mg/g SR
      49059 included in food) normal (NT) or diabetic (DT) animals. Treatment was
      initiated 4 days after diabetes induction and continued for 3 weeks. Nested
      (hierarchical) analysis of variance of ICM data was performed on raw diameter or
      after logarithmic normalization of area and nuclei values. Diabetes was
      associated with an increase in arterial diameters, and in total vessel, wall,
      media, adventitia, and lumen areas. The same parameters, with the exception of
      the lumen, were also increased in DT as compared to D. The number of nuclei in
      the media or adventitia was increased in D as compared to N, and in DT as
      compared to D. In summary, ICM is allowed to further characterize the vascular
      mesenteric changes and describe for the first time the enlargement of adventitia
      associated with diabetes. Our study also suggested that the blockade of Via
      receptors is unable to prevent diabetes-related vascular changes, although the
      slight increase in food intake associated with SR 49059 treatment may have had an
      indirect influence on angiopathy development.

PMID- 10598678
TI  - A method for normalizing drug responses to enhance reliability of parametric
      statistical tests.
AB  - Experimental constraints often require that pharmacologists study the effects of
      treatments upon responses elicited with a single concentration of agonist. The
      choice of statistical analysis, nonparametric or parametric, will depend upon
      whether or not the responses are normally distributed. This study uses both Monte
      Carlo and theoretical approaches to examine the normality assumption as it
      applies to drug responses. Responses measured in systems where drug sensitivities
      follow a lognormal distribution are generally not normally distributed. A simple
      transformation of responses, however, can restore normality. Researchers may find
      it beneficial to transform response data prior to performing t tests, analysis of
      variance or other parametric statistics in order to preserve the power and
      confidence level of the test.

PMID- 10598679
TI  - Quantitative cell membrane-based radioligand binding assays for parathyroid
      hormone receptors.
AB  - Most current assays of PTH receptor ligand binding employ whole cells as the
      vehicle for receptor. Whole cell binding does not easily permit the estimation of
      physically meaningful binding parameters, the detection of multiple receptor
      states, or the evaluation of the effects of receptor modulators such as guanine
      nucleotides. We have developed quantitative methods for the measurement of
      equilibrium ligand binding parameters at cloned parathyroid hormone (PTH)
      receptors in cell membrane preparations. Centrifugation is used to separate bound
      and free [125I]-labeled peptide radioligands, and nonfat dried milk is used as a
      blocking agent to reduce nonspecific binding. This method is useful for
      measurement of agonist and antagonist radioligand binding at the PTH-1 receptor
      and binding of [125I]PTH(1-34) at the PTH-2 receptor. Less than 25% of
      [125I]PTH(1-34) or [125I]PTHrP(1-36) is degraded during the assay incubation. We
      demonstrated the utility of the assay using measurements of ligand binding
      properties at the PTH-1 receptor. (1) Homologous displacement experiments
      provided estimates of Kd and Bmax for the radioligands. (2) Displacement of
      radiolabeled antagonist binding ([125I]PTH(3-34)) by an unlabeled agonist (RS
      66271) revealed multiple affinity states of agonist-receptor interaction. (3)
      Comparison of RS-66271 displacement in the presence and absence of GTP-gammaS
      demonstrated that the highest affinity state is guanine nucleotide-sensitive,
      suggesting that this state requires stabilization by G-protein. This assay thus
      allows more mechanistic interpretation of binding data than PTH binding assays in
      current use. A more convenient rapid-filtration method was also developed for
      measurement of radioligand binding at PTH-1 and PTH-2 receptors.

PMID- 10598680
TI  - Gas chromatography-mass spectrometry assay for determination of ketamine in
      brain.
AB  - A sensitive and precise gas chromatography-mass spectrometry method with selected
      ion monitoring has been developed for determination of ketamine in the brain
      using chlorpheniramine as an internal standard. The assay is based on the acid
      extraction of brain homogenate with hexane and ethyl ether with subsequent
      alkaline ethyl ether extraction. The analytical procedure has a coefficient of
      variation of 3.0-5.3% and from 3.8 to 6.1% for extraction from water or spiked
      brain samples, respectively. The lowest detectable level of ketamine was 1 ng in
      any brain region. This level of detection was used to measure the ketamine
      concentrations in cerebellum, brain stem, midbrain, hypothalamus, and cortex of
      C57B1/6 mice at awakening following intraperitoneal injection of a hypnotic dose.
      The ketamine concentrations in mouse brain were in the range from 41.6 to 48.6
      ng/mg of tissue.

PMID- 10598681
TI  - A rat model of acute respiratory distress syndrome (ARDS) Part 2, influence of
      lavage volume, lavage repetition, and therapeutic treatment with rSP-C
      surfactant.
AB  - The influence of lavage volume, and lavage repetition with physiological saline
      solution (groups 1-3: 3x4, 4x4, 5x4, groups 7-9: 3x8, 5x8, 7x8, mL per animal)
      was studied in a rat lung lavage model of the acute respiratory distress syndrome
      (ARDS). Anesthetized and tracheotomized rats (12 rats/group) were pressure
      controlled ventilated with 100% oxygen at a respiratory rate of 30 breaths/min,
      inspiration: expiration ratio of 1:2, peak inspiratory pressure of 28 cm H2O at
      positive end-expiratory pressure of 8 cm H2O during the whole experimental
      period. To investigate the influence of therapeutic treatment, a recombinant
      surfactant protein C (rSP-C) containing surfactant was used. Therefore, rats
      which received a lavage of 4x4 mL per animal (groups 4 to 6) or 7x8 mL per animal
      (groups 10-12) were treated intratracheally with surfactant doses of 12.5, 25, or
      100 mg phospholipids (PL) per kg body weight (bw). In all groups, partial
      arterial oxygen pressures (PaO2, mm Hg) and partial arterial carbon dioxide
      pressures (PaCO2, mm Hg) were determined 30 min before, directly after, and 5,
      30, 60, 90, 120, 150, 180, and 210 min after the last lavage. Additionally,
      animals were euthanized 210 min after the last lavage for semiquantitative
      histopathological grading of coded lung slides. Grading was performed with
      respect to the severity of hyaline membrane formation (HM), margination and
      infiltration of polymorphonuclear neutrophil leukocytes (PMNL) into the lung
      alveoli and interstitial and intraalveolar edema (E). The intrapulmonary
      distribution of intratracheally applied rSP-C was estimated in selected lung
      slides stained with polyclonal anti-rSP-C antibody and was compared to unlavaged
      control rats and unlavaged rats which received 100 mg/kg bw rSP-C. The repetitive
      lavage depleted the lung from its natural surfactant resources leading to a
      pathophysiological cascade similar to that of the acute respiratory distress
      syndrome. PaO2 levels and HM formation showed a lavage-induced decrease. Both
      changes were significantly dependent on the repetition and volume of the lavage;
      however, the parameters PMNL and E did not show such a dependence. Treatment with
      rSP-C surfactant significantly improved oxygenation and reduced HM-formation in a
      dose-dependent manner independent from the lavage volume. All doses of rSP-C
      surfactant showed no clear influence on the parameters PMNL and E independently
      from the lavage volume. In lavaged rat lungs (ARDS-model), the exogenously
      applied rSP-C was distributed homogeneously along the alveolar lining. Unlavaged
      rats that received a similar dose of rSP-C showed a marked inhomogeneous
      extracellular distribution, mainly associated with larger bronchi, while the type
      II pneumocytes were stained positively in unlavaged control and unlavaged rSP-C
      treated rats. CONCLUSION: This model mimics very closely the wide spectrum of the
      clinical situation of human acute lung injury (ALI) because the variation of
      lavage volume and repetition lead to reproducible different severity grades and
      states of ALI. The significant reduction of pathognomic changes due to treatment
      with rSP-C surfactant showed that this is a useful model to estimate the
      influence of therapeutic concepts in ALI and ARDS.

PMID- 10598682
TI  - Analysis of asymmetry of agonist concentration-effect curves.
AB  - We have developed a fitting procedure, based on nonlinear mixed effect modelling
      and original work by Richards (1959, J Exp Botany 10, 290-300), to describe the
      degree of asymmetry of concentration-effect E/[A] curves and analysed the shape
      of E/[A] curves obtained with alpha1-adrenoceptor agonists in rat aorta. The four
      parameter Richards model provided a significantly better fit of the data than the
      standard logistic/Hill model for all ligands investigated, which implies that
      E/[A] curves were asymmetrical. With the exception of ST 587, the asymmetry
      parameter (delta) tended toward zero and the Richards model could be replaced
      without significant loss of goodness-of-fit by the three-parameter, asymmetrical
      Gompertz model. The alpha1-adrenoceptor antagonist, prazosin (10 nM), had no
      effect on the asymmetry of the noradrenaline E/[A] curve but significantly
      increased the slope at the point of inflection. In contrast, pretreatment with
      the irreversible antagonist, phenoxybenzamine (60 nM), produced a shift of the
      delta estimate for noradrenaline from zero to unity, indicating a change from an
      asymmetrical to a symmetrical curve. Therefore, detailed statistical analysis of
      E/[A] curve asymmetry demonstrates that alpha1-adrenoceptors in rat aorta do not
      operate as a homogenous one-receptor-one-transducer system. This conclusion could
      not have been reached by either an analysis with the standard logistic/Hill model
      or visual inspection of experimental data. Overall, the curve-fitting analysis
      developed in this study provides a quantitative and sensitive measure of
      asymmetry and a novel method for the objective discrimination of agonist action
      on the basis of curve shape. The method is generally applicable to other
      pharmacological assays and provides a new tool in receptor classification
      studies.

PMID- 10598683
TI  - Analysis of receptor inactivation experiments with the operational model of
      agonism yields correlated estimates of agonist affinity and efficacy.
AB  - The aim of this study was to evaluate whether the operational model of agonism
      can yield independent estimates of agonist affinity (pK(A)) and efficacy (log
      tau) when Furchgott's method of irreversible receptor inactivation is employed.
      For this purpose, the interaction between noradrenaline and phenoxybenzamine was
      studied in rat small mesenteric artery using a paired-curve design.
      Phenoxybenzamine pretreatment produced a significant rightward shift and
      depression of the upper asymptote of the noradrenaline concentration-effect
      (E/[A]) curve. Although the operational model of agonism appeared to provide an
      adequate fit of the individual E/[A] curves, a highly significant correlation was
      found between the estimates of pK(A )and log tau (r = -0.80, p < 0.0001),
      inconsistent with the assumption that affinity and efficacy are independent
      parameters (best line fit: pK(A) = -0.96 x log tau + 6.75). The pK(A) and log tau
      estimates were not correlated with either the pEC50s of the control curves or
      upper asymptotes of the phenoxybenzamine-treated curves. Simulations showed that
      the correlation between affinity and efficacy can be explained by the effect on
      the outcome of the analysis of random errors in the response measurements.
      Therefore, although in theory the operational model of agonism should provide
      independent estimates of agonist affinity and efficacy, this is unlikely to be
      the case with experimental data.

PMID- 10598685
TI  - Specific targeting immunotherapy of cancer with bispecific antibodies.
AB  - In order to enhance cell mediated cytotoxicity, bispecific antibodies (BsAbs),
      molecules combining two or more antibodies with different antigenic
      specificities, have been developed as new agents for immunotherapy. Our recent
      studies revealed that simultaneous administration of two kinds of BsAbs (anti
      tumor x anti-CD3 plus anti-tumor x anti-CD28) together with lymphokine activated
      killer cells with a T cell phenotype (T-LAK cells) inhibited growth of human
      xenotransplanted tumors in severe combined immunodeficient (SCID) mice, while
      single BsAb was without effect. Three kinds of BsAbs (anti-tumor x anti-CD3, anti
      tumor x anti-CD28, anti-tumor x anti-CD2) showed the highest cytotoxicity against
      tumor cells when given simultaneously with T-LAK cells or peripheral blood
      mononuclear cells in vitro and in vivo. BsAbs can be preserved for immediate
      application, while cytotoxic T lymphocytes (CTLs) must be made-to-order, and are
      time-consuming to prepare. Tumor associated antigens, such as MAGE antigens, SART
      antigens, MUC1 antigen, c-erbB 2 antigen or cancer/testis antigens can be served
      to target antigens for BsAb production. By conjugation with antibodies to
      effector cells (anti-CD3, anti-CD28, anti-CD16, anti-CD64, anti-CD89 or anti
      CD2), many kinds of BsAbs can be produced to cover most types of cancers from
      different organs. Therefore this strategy might be ubiquitously applicable to
      most malignancies.

PMID- 10598684
TI  - A coculture model of synoviocytes and bone for the evaluation of potential
      arthritis therapies.
AB  - OBJECTIVE: To evaluate the symbiotic relationship between musculoskeletal cells
      in the intact joint utilizing a coculture system and to determine if the model
      can be utilized to evaluate potential treatments for articular diseases. METHODS:
      Two neonatal mouse calvariae were placed on steel supports on a monolayer of
      rabbit synovial fibroblasts, and net calcium flux, bone cell activity, and
      undecalcified histology were determined at 6, 24, and 48 h. To determine if the
      model was predictive of response to known therapies for articular disease, the
      coculture was incubated in the presence and absence of indomethacin or
      doxycycline, and the net calcium flux was measured. RESULTS: The coincubation of
      calvariae with synoviocytes led to a fivefold increase in net calcium efflux
      compared to calvariae alone. The concentration in the media of the osteoblastic
      enzyme alkaline phosphatase increased at 6 h but decreased thereafter, whereas
      the concentration of osteoclastic enzyme beta-glucuronidase increased with time.
      Undecalcified bone histology revealed progressive demineralization and an
      increase in the number of osteoclasts in calvariae incubated with synoviocytes
      compared to calvariae alone. Both indomethacin and doxycycline inhibited calcium
      flux from cocultures but the predominant effect of doxycycline was on the
      synoviocyte whereas the predominant effect of indomethacin was on bone.
      CONCLUSION: The coincubation of synoviocytes with calvariae led to an increase in
      bone mineral dissolution with time. This effect could be partially inhibited by
      known treatments for rheumatoid arthritis. Thus, the coculture model may simulate
      certain aspects of the in vivo processes relevant to rheumatoid arthritis. This
      model should prove useful for the study of potential therapies for inflammatory
      arthritis and distinguish between effects of these therapies on different
      cellular components of the joint.

PMID- 10598686
TI  - Two outbreaks of influenza A (H3N2) in a Japanese nursing home in the winter of
      1996-1997, with differing vaccine efficacy.
AB  - Sixty of 128 (46.9%) residents of a nursing home were immunized with two doses of
      the trivalent split influenza vaccine. They developed 7.4-11.5-fold antibody
      increases, with a 69-82% protection rate, presenting good immune response rates
      to the influenza vaccine. Two outbreaks of influenza A (H3N2) occurred. There
      were no significant antigenic differences among the vaccine strain and the
      strains isolated from both outbreaks in haemagglutination-inhibition tests,
      suggesting that the second might have been a reoccurrence. There were no
      residents who were infected in both outbreaks. The vaccine efficacy against
      clinical illness in the first outbreak of typical influenza-like-illness (ILI)
      was 51% (relative risk: 0.49), and the febrile period was reduced significantly
      by vaccination. In the second outbreak, however, in which all patients had
      atypical ILI with a high fever but not respiratory symptoms, vaccine efficacy was
      not apparent for unknown reason.

PMID- 10598687
TI  - Morphological adaptation of the cardiovascular system in fetal rats during late
      gestation.
AB  - The aim of this study was to evaluate morphological changes of the cardiovascular
      system in fetal rats during late gestation. We used the rapid whole-body freezing
      technique for rats of day 17 through 21 of gestation. The right and left
      ventricular volumes increased markedly and significantly during this period by
      about 11- and 24-fold, respectively. Although the right ventricular volume was
      108% larger with statistical significance than the left ventricular volume on day
      17, they were almost equal after day 19. The length of the primum septum of the
      atrium significantly increased by 92% within 4 days, but the opening distance of
      foramen ovale significantly decreased by 14%. The ratio of the inner diameter
      (the sum of right and left pulmonary arteries to ductus arteriosus) significantly
      increased from 0.72+/-0.03 on day 17 to 1.17+/-0.07 on day 21. There was also a
      significant increase in the ratio of the inner diameters of the ascending to
      descending aorta. These observations suggest that the reduction of the opening
      distance of foramen ovale reflect the growth of pulmonary arteries.

PMID- 10598688
TI  - Molecular epidemiology of hepatitis C virus infection in an area endemic for
      community-acquired acute hepatitis C.
AB  - The southern district of N city (U area), Yamagata Prefecture, is highly endemic
      for hepatitic C virus (HCV) infection. Around 20% of the general population are
      positive for antibodies to HCV (anti-HCV). Community-acquired, acute non-A, non-B
      hepatitis was epidemic from 1967 to 1972 in this area. Our previous study
      revealed that these people are actually infected with HCV, but a relationship
      between this outbreak and the high positivity rate of anti-HCV in the U area has
      not been shown. We followed up 15 anti-HCV-positive individuals who developed
      hepatitis during the epidemic and used the serum collected to conduct molecular
      evolutional analysis to reveal the characteristics of the HCV epidemic in the U
      area. HCV genotypes in the U area were also analyzed. Phylogenetic analysis of
      the HCV core gene sequences showed that the subjects' HCV sequences were closely
      related and derived from the same cluster. All subjects were infected with HCV
      genotype 1b, which was frequently detected with a high positivity of over 80% of
      HCV-infected individuals in the U area. These results confirm that the community
      acquired hepatitis C epidemic occurred around three decades ago through an
      unidentified route, and suggest that this episode may result in a continuing
      increase in the number of HCV-1b positive patients in this small area.

PMID- 10598689
TI  - Automated metabolic profiling and interpretation of GC/MS data for organic
      acidemia screening: a personal computer-based system.
AB  - We have developed a personal computer-based system designed for automated
      metabolic profiling of urinary organic acids by gas chromatography-mass
      spectrometry (GC/MS) and data interpretation for organic acidemia screening. For
      the automated profiling, we compiled retention indices, two target ions and their
      intensity ratio for 126 urinary metabolites. Metabolites above the cut-off values
      were flagged as abnormal compounds. The data interpretation was based on
      combination of the flagged metabolites. Diagnostic or index metabolites were
      categorized into three groups, "AND," "OR" and "NO," and compiled for each
      disorder to improve the specificity of the diagnosis. Groups "AND" and "OR"
      comprised essential and optional compounds, respectively, which and both to reach
      a specific diagnosis. Group "NO" comprised metabolites that must be absent to
      make a definite diagnosis. We tested this system by analyzing urine specimens
      from 48 patients previously diagnosed as having organic acidemias. In all cases,
      the diagnostic metabolites were identified and each correct diagnosis could be
      found among the possible diseases suggested by the system. Hence, with this
      simplified automated system, more people will be able to participate extensively
      in any screening programs using GC/MS.

PMID- 10598690
TI  - Renal nerve stimulation induces alpha2-adrenoceptor-mediated antinatriuresis
      under inhibition of prostaglandin synthesis in anesthetized dogs.
AB  - The interaction between prostaglandins and alpha-adrenoceptors in neural control
      of tubular sodium reabsorption was examined in anesthetized dogs. Renal nerve
      stimulation (RNS; 0.5-1.0 Hz, 10 V, 1.0-milliseconds duration) reduced fractional
      excretion of Na+ (FENa) with minimal changes in hemodynamics and glomerular
      filtration. Intrarenal arterial infusion of prazosin (0.7 microg x kg(-1) x min(
      1)), an alpha1-adrenoceptor antagonist, inhibited the RNS-induced reduction in
      FENa. However, the RNS-induced reduction in FENa was resistant to prazosin under
      pretreatment with indomethacin (5 mg/kg, i.v.), a cyclooxygenase inhibitor.
      Intrarenal arterial infusion of yohimbine (1 microg x kg(-1) x min(-1)), an
      alpha2-adrenoceptor antagonist, failed to inhibit the RNS-induced reduction in
      FENa in the absence or presence of indomethacin, but combined infusion of
      prazosin and yohimbine abolished the RNS-induced reduction in FENa in the
      presence of indomethacin. These results suggest that both alpha1- and alpha2
      adrenoceptors mediate the RNS-induced antinatriuresis, but the alpha2
      adrenoceptor-mediated portion is impaired by prostaglandins.

PMID- 10598691
TI  - The efficacy and safety of the dorzolamide-timolol combination versus the
      concomitant administration of its components.
AB  - OBJECTIVE: To evaluate whether a fixed combination of 2% dorzolamide and 0.5%
      timolol given twice daily showed equivalent efficacy to the concomitant
      administration of 2% dorzolamide given three times daily and 0.5% timolol given
      twice daily in patients whose intraocular pressure (IOP) remained elevated during
      monotherapy with 0.5% timolol twice daily. DESIGN: Multicenter, parallel,
      randomized, double-masked clinical trial with an open-label extension.
      PARTICIPANTS AND INTERVENTION: In the masked phase, 242 patients received either
      the dorzolamide-timolol combination twice daily and placebo three times daily or
      dorzolamide three times daily and timolol twice daily for up to 3 months. In the
      open-label extension, 220 patients received the dorzolamide-timolol combination
      twice daily for up to 9 months. MAIN OUTCOME MEASURES: The criterion for
      establishing treatment equivalency was a 95% or greater confidence that the
      absolute difference in the mean change in IOP from baseline was less than 1.5
      mmHg between treatments. RESULTS: During 3 months of treatment, the dorzolamide
      timolol combination reduced IOP relative to the 0.5% timolol baseline by
      approximately 14% at hour 0 (just before the morning dose), 20% at hour 2, and
      15% at hour 8. The IOP-lowering effect of concomitant therapy with dorzolamide
      and timolol was approximately 16% at hour 0, 20% at hour 2, and 17% at hour 8. At
      hours 0, 2, and 8, there was greater than 97% confidence that the treatments were
      equivalent. During the open-label extension, the mean IOP reduction ranged from
      14% to 15% at hour 0 and from 20% to 21% at hour 2. The treatment groups were
      generally comparable in terms of adverse events, symptoms, ocular signs, visual
      acuity, visual fields, physical examination, and laboratory measures.
      CONCLUSIONS: The IOP-lowering effect of the dorzolamide-timolol combination is
      comparable to that of dorzolamide three times daily plus timolol twice daily and
      is maintained for up to 1 year. The dorzolamide-timolol combination provides
      clinically important reduction in IOP relative to baseline treatment with timolol
      alone and is generally well-tolerated for up to 1 year.

PMID- 10598692
TI  - A randomized trial comparing the dorzolamide-timolol combination given twice
      daily to monotherapy with timolol and dorzolamide.
AB  - OBJECTIVE: To compare the efficacy and safety of a fixed combination of 2.0%
      dorzolamide and 0.5% timolol administered twice daily with each of the individual
      components administered in their usual monotherapy dose regimens in patients who
      had washed out all ocular hypotensive medications. DESIGN: A 3-month, parallel,
      randomized, double-masked, active-controlled, multicenter clinical trial.
      PARTICIPANTS: A total of 335 patients with bilateral ocular hypertension or open
      angle glaucoma participated. INTERVENTION: After completing a washout of ocular
      hypotensive medications, patients were randomized to receive either the
      dorzolamide-timolol combination twice daily plus placebo once daily, 0.5% timolol
      twice daily plus placebo once daily, or 2.0% dorzolamide three times daily. MAIN
      OUTCOME MEASURES: Intraocular pressure (IOP) was measured at morning trough (hour
      0) and peak (2 hours postdose) on day 1, week 2, and months 1, 2, and 3. Ocular
      and systemic safety were evaluated at each study visit. RESULTS: Intraocular
      pressure reduction was greater on average in the combination group than in the
      dorzolamide and timolol groups. At morning trough (month 3, hour 0), the mean
      reduction in IOP from baseline was 27.4% (-7.7 mmHg) for the combination, 15.5% (
      4.6 mmHg) for dorzolamide, and 22.2% (-6.4 mmHg) for timolol. At morning peak
      (month 3, hour 2), the mean IOP reduction from baseline was 32.7% (-9.0 mmHg),
      19.8% (-5.4 mmHg), and 22.6% (-6.3 mmHg) for the combination, dorzolamide, and
      timolol, respectively. Overall, the incidence of clinical adverse experiences was
      comparable between the combination and each of its components. The proportion of
      patients who discontinued from the study because of clinical adverse experiences
      was also comparable between the combination and dorzolamide, although it was
      significantly greater in the combination group than in the timolol group (7% vs.
      1%, P = 0.035). Similarly, comparable numbers of patients in the combination and
      dorzolamide groups reported ocular symptoms; however, when compared to the
      timolol group, more patients receiving the combination reported blurred vision,
      burning eye, stinging eye, and tearing eye. CONCLUSIONS: After a washout of
      ocular hypotensive therapy, the IOP-lowering effect of the dorzolamide-timolol
      combination was greater than that of either of its components administered as
      monotherapy. The combination is generally well-tolerated and provides a
      convenient alternative to concomitant therapy with its individual components.

PMID- 10598693
TI  - A randomized trial in patients inadequately controlled with timolol alone
      comparing the dorzolamide-timolol combination to monotherapy with timolol or
      dorzolamide.
AB  - OBJECTIVE: To compare the dorzolamide-timolol fixed combination twice daily to
      its components, timolol maleate and dorzolamide hydrochloride, given in their
      usual monotherapy regimens in patients whose intraocular pressure (IOP) was not
      controlled on timolol twice daily alone. DESIGN: Parallel, randomized, double
      masked, and active-controlled study. PARTICIPANTS: Enrolled were 253 patients
      from 22 sites throughout the United States. INTERVENTION: After a 3-week run-in
      of timolol (TIMOPTIC; Merck & Co., Inc., Whitehouse Station, NJ) twice daily,
      eligible patients received either the combination (COSOPT; Merck & Co., Inc.,
      Whitehouse Station, NJ) twice daily (plus placebo to ensure masking), timolol
      twice daily (plus placebo to ensure masking), or dorzolamide (TRUSOPT; Merck &
      Co. Inc., Whitehouse Station, NJ) three times daily for 3 months. MAIN OUTCOME
      MEASURES: Intraocular pressure taken at hours 0 (trough) and 2 (peak) after week
      2 and months 1, 2, and 3 was compared to baseline within each treatment group and
      between the combination and each component group. The safety profile of the
      combination was compared to each component. RESULTS: The combination was
      numerically superior at all study timepoints and was statistically superior at
      all timepoints except for month 2, hour 0 for timolol, and month 2, hour 2 for
      dorzolamide. The safety profile of the combination reflected those of its two
      components. The number of patients reporting ocular or local adverse experiences
      was greater for the combination (45%) and dorzolamide (45%) than for timolol
      (27%), with burning and/or stinging eye being the most frequently reported.
      CONCLUSION: The dorzolamide-timolol combination provides additional IOP lowering
      compared to either of its individual components and generally is well-tolerated.

PMID- 10598694
TI  - Oligodendroglioma: an appraisal of recent data pertaining to diagnosis and
      treatment.
AB  - OBJECTIVE: This article reviews and summarizes recent data on the diagnosis,
      prognosis, and treatment of oligodendroglial tumors. METHODS: Histological
      criteria for optimized diagnosis and grading of oligodendroglial tumors are
      described and discussed. The therapeutic approaches are analyzed in light of the
      results of recent series. RESULTS: Oligodendroglial tumors may be more common
      than is generally thought. Perinuclear halo and "chicken-wire" pattern, although
      considered classic histological features of oligodendrogliomas, are unreliable as
      sole criteria for diagnosis. Nuclear regularity and roundness and an eccentric
      rim of eosinophilic cytoplasm lacking obvious cell processes are more constant
      features. Grading should be accomplished using a composite of radiological and
      histopathological relevant features. The allelic loss of chromosome arms 1p and
      19q might be a marker for both chemosensitivity and longer survival after
      chemotherapy. Oligodendrogliomas are notably chemosensitive when compared with
      other gliomas. For aggressive lesions, chemotherapy should be used upfront, after
      surgery. CONCLUSION: Oligodendrogliomas are underdiagnosed. One unfortunate
      implication is that a large number of patients may be receiving suboptimal care.
      A simplification in grading of oligodendroglioma to two grades would reduce the
      confusion surrounding the classification and better define prognosis and response
      to treatment modalities. A better definition of the so-called mixed tumor should
      also allow a better classification of these lesions in an intermediate prognostic
      class between astrocytic and oligodendroglial lesions. Loss of 1p and 19q could
      be used as a cytogenetic marker in assisting grading. New concepts emerging in
      the recent literature should help optimize the diagnosis of these lesions and
      reduce interobserver variability.

PMID- 10598695
TI  - Quality of life of adult survivors of germinomas treated with craniospinal
      irradiation.
AB  - OBJECTIVE: To assess the quality of life (QOL) of a group of patients treated for
      intracranial germinoma with biopsy followed by prophylactic whole-neuraxis
      radiation therapy. METHODS: The Short-form-36 and Functional Assessment of Cancer
      Therapy QOL questionnaires were completed by 22 of 27 eligible adults treated
      with whole-neuraxis irradiation for biopsy-proven, marker-negative intracranial
      germinomas between 1976 and 1996. In addition, data were obtained regarding
      height and weight, medications, ability to work, and educational achievement.
      RESULTS: The patients' QOL was generally good. All of the patients are in or have
      completed high school; nine are in or have completed college, and five have
      advanced degrees. Patients rated themselves lower on the physical composite scale
      of the Short-form-36 (average, 46 versus 54 in a normal population). On the
      mental composite scale, patients rated themselves more favorably than the normal
      population (average, 54 versus 49 in a normal population). Patients were normally
      proportioned for height and weight, but female patients tended to be short. Age
      at radiation did not correlate with QOL. CONCLUSION: The QOL of adults treated
      for marker-negative germinoma with prophylactic whole-neuraxis irradiation is
      generally good. These data should serve as a benchmark for newer treatment
      protocols eliminating or reducing radiation.

PMID- 10598697
TI  - Cavernous hemangiomas in the cavernous sinus.
AB  - OBJECTIVE: Cavernous hemangiomas located within the cavernous sinus are rare
      vascular tumors that are very difficult to remove because of severe
      intraoperative bleeding. The purpose of this study was to analyze the clinical,
      neuroimaging, and pathological features and the surgical treatment of these
      tumors. METHODS: Ten patients with cavernous hemangiomas in the cavernous sinus
      who were surgically treated from August 1985 to October 1997, in our hospital,
      were retrospectively studied. RESULTS: Among the 10 patients, total tumor removal
      was performed in four cases, partial removal in two cases, and tumor biopsies in
      four cases. The four patients who underwent total tumor removal experienced
      uneventful postoperative courses, with no postoperative neurological deficits for
      one patient, no new neurological deficits for two patients, and complete
      ophthalmoplegia and diminished sensation in the distribution of Cranial Nerve V1
      for one patient. The two patients who underwent partial removal developed
      complete ophthalmoplegia and diminished sensation in the distribution of Cranial
      Nerve V1 after surgery, and one of them experienced contralateral paralysis. All
      four patients who underwent tumor biopsies experienced severe intraoperative
      tumor bleeding; one exhibited Cranial Nerve III, IV, and VI injuries after
      surgery. CONCLUSION: The features of prominent hyperintensity in T2-weighted
      scans, with well-defined borders in enhancing magnetic resonance imaging scans,
      or marked enhancement in computed tomographic and magnetic resonance imaging
      scans, with no tumor blush in angiographic analyses, facilitate the diagnosis of
      these tumors. These tumors can be divided into two subgroups on the basis of
      intraoperative findings and pathological features. We do not recommend division
      and piecemeal removal of the tumor during surgery if the main supplies of the
      tumor have not been interrupted.

PMID- 10598696
TI  - Fractionated stereotactic radiosurgery and preservation of hearing in patients
      with vestibular schwannoma: a preliminary report.
AB  - OBJECTIVE: Microsurgery and stereotactic radiosurgery (SRS) for vestibular
      schwannomas are associated with a relatively high incidence of sensorineural
      hearing loss. A prospective trial of fractionated SRS was undertaken in an
      attempt to preserve hearing and minimize incidental cranial nerve injury.
      METHODS: Thirty-three patients with vestibular schwannomas were treated with 2100
      cGy in three fractions during a 24-hour period using conventional frame-based
      linear accelerator radiosurgery. The median tumor diameter was 20 mm (range, 7-42
      mm). Baseline and follow-up evaluations included audiometry and contrast-enhanced
      magnetic resonance imaging. End points were tumor progression, preservation of
      serviceable hearing, and treatment-related complications. RESULTS: Thirty-one
      patients (32 tumors) were assessable for tumor progression and treatment-related
      complications and 21 patients for preservation of serviceable hearing, with a
      median follow-up interval of 2 years (range, 0.5-4.0 yr). Tumor regression or
      stabilization was documented in 30 patients (97%) and tumor progression in 1
      (3%). The patient with tumor progression remains asymptomatic and has not
      required surgical intervention. Five patients (16%) developed trigeminal nerve
      injury at a median of 6 months (range, 4-12 mo) after SRS; two of these patients
      had preexisting trigeminal neuropathy. One patient (3%) developed facial nerve
      injury (House-Brackmann Class 3) 7 months after SRS. Preservation of useful
      hearing (Gardner-Robertson Class 1-2) was 77% at 2 years. All patients with
      pretreatment Gardner-Robertson Class 1 to 2 hearing maintained serviceable (Class
      1-3) hearing as of their last follow-up examination. CONCLUSION: Three-fraction
      SRS with a conventional stereotactic frame is feasible and well tolerated in the
      treatment of acoustic neuroma. This study demonstrates a high rate of hearing
      preservation and few treatment-related complications among a relatively high-risk
      patient cohort (tumors >15 mm or neurofibromatosis Type 2). Longer follow-up will
      be required to assess the durability of tumor control.

PMID- 10598698
TI  - Computed tomographic angiography versus digital subtraction angiography for the
      diagnosis and early treatment of ruptured intracranial aneurysms.
AB  - OBJECTIVE: Computed tomographic angiography (CTA) is a rapid and minimally
      invasive method of detecting intracranial aneurysms. We wished to determine
      whether CTA could replace digital subtraction angiography (DSA) in the diagnosis
      and operative planning of ruptured cerebral aneurysms. METHODS: In a prospective
      study, patients with subarachnoid hemorrhage diagnosed by plain computed
      tomography underwent CTA, DSA, or both. Computed tomographic scans and CTA
      studies were first reviewed by the treating surgeon, along with a
      neuroradiologist, and a decision to proceed to DSA or directly to surgery was
      made on the basis of the type and quality of information provided by CTA. All
      patients underwent postoperative DSA. RESULTS: A total of 173 patients were
      studied. In 24 patients, both CTA and DSA were negative for a source of
      subarachnoid hemorrhage. Twelve patients underwent DSA without prior CTA because
      a technologist capable of performing CTA was not available when the patient was
      evaluated. Nine patients in poor neurological condition underwent CTA, and all
      tested positive for aneurysms but died without surgical intervention. Of the 126
      patients who underwent CTA and surgery, 65 (52%) also required preoperative DSA.
      The decision to proceed to DSA after CTA was influenced by aneurysm location;
      posterior communicating artery (62%) and posterior circulation locations (67-75%)
      more commonly proceeded to DSA than middle cerebral artery aneurysms (34%; 0.025
      > P > 0.01). The sensitivity and specificity of CTA for the detection of all
      aneurysms, ruptured and unruptured, in the group of patients who underwent both
      types of angiograms preoperatively were 84 and 100%, respectively. In the group
      of 61 patients in whom aneurysm surgery was performed on the basis of CTA results
      alone, the sensitivity and specificity for the detection of all aneurysms, as
      compared with postoperative DSA, were 90 and 100%, respectively. Missed aneurysms
      (n = 24) were always small (<4 mm) and were usually found in patients with
      multiple aneurysms in whom the larger, ruptured aneurysm was identified by CTA.
      In one patient, the aneurysm missed by preoperative CTA would have resulted in a
      different operation if detected preoperatively. CONCLUSION: It is possible to
      proceed to ruptured aneurysm repair entirely on the basis of good-quality CTA
      studies that demonstrate an aneurysm consistent with the pattern of bleeding
      observed on plain computed tomography (48% of the patients in this series and
      most common middle cerebral artery aneurysms). However, detection of small
      unruptured aneurysms in patients with multiple lesions remains a problem.

PMID- 10598699
TI  - Postoperative brainstem high intensity is correlated with poor outcomes for
      patients with spontaneous cerebellar hemorrhage.
AB  - OBJECTIVE: The outcomes for patients with cerebellar hemorrhage are thought to be
      influenced by anatomic damage to the brainstem. In this study, we investigated
      the magnetic resonance imaging findings in the brainstem, to examine the
      relationship between the degree of brainstem damage and the outcomes for patients
      with spontaneous cerebellar hemorrhage who are in poor-grade condition. METHODS:
      The results for 31 patients with spontaneous cerebellar hemorrhage, with Glasgow
      Coma Scale scores of 8 or less at admission, who underwent magnetic resonance
      imaging examinations were reviewed. All patients underwent surgical intervention.
      The patients were divided into two groups according to their Glasgow Outcome
      Scale scores at the time of discharge, i.e., patients who experienced good
      recoveries or exhibited moderate disabilities (Group I, n = 8) and patients who
      exhibited severe disabilities, were in a persistent vegetative state, or had died
      (Group II, n = 23). We investigated obliteration of the fourth ventricle and the
      perimesencephalic cistern and the presence of hydrocephalus in initial computed
      tomographic scans and the presence of areas of high signal intensity in the
      brainstem in T2-weighted images. RESULTS: Eight patients experienced good
      outcomes, and 23 patients experienced poor outcomes. The overall mortality rate
      was 32.3%. There were no significant differences between groups with respect to
      computed tomographic findings such as hematoma size, but the incidence of high
      signal intensities in the pons and midbrain in T2-weighted images for Group II
      was significantly higher than that for Group I (P < 0.01). CONCLUSION: Magnetic
      resonance imaging clearly demonstrated brainstem damage, and high signal
      intensity in the brainstem was a significant prognostic factor for determining
      outcomes for patients with spontaneous cerebellar hemorrhage who were in poor
      grade condition.

PMID- 10598700
TI  - Change in ventricular size and effect of ventricular catheter placement in
      pediatric patients with shunted hydrocephalus.
AB  - OBJECTIVE: The multicenter, randomized pediatric cerebrospinal fluid shunt valve
      design trial found no difference in the rate of shunt failure between a standard
      valve, a siphon-reducing valve (Delta; Medtronic PS Medical, Goleta, CA), and a
      flow-limiting valve (Orbis Sigma; Cordis, Miami, FL); however, the valves were
      expected to have different effects on ultimate ventricular size. Also, the
      catheter position or local environment of the ventricular catheter tip might have
      affected shunt failure. Therefore, we performed a post hoc analysis to understand
      what factors, other than valve design, affected shunt failure and to identify
      strategies that might be developed to reduce shunt failure. METHODS: Ventricular
      size was measured at as many as six different intervals, using a modified Evans'
      ratio (with incorporation of the frontal and occipital dimensions), in 344
      patients. Ventricular catheter location was defined as being in the frontal horn,
      occipital horn, body of the lateral ventricle, third ventricle, embedded in
      brain, or unknown. The ventricular catheter tip was described as surrounded by
      cerebrospinal fluid, touching brain, or surrounded by brain parenchyma within the
      ventricle (slit ventricle). Repeated measures analysis of variance for unbalanced
      data was used to analyze ventricular size. A Cox model (with incorporation of
      time-dependent covariates) was used to evaluate the contribution of age,
      etiology, shunt design, ventricular size, ventricular catheter location, and
      environment among the cases. RESULTS: Ventricular volume decreased in an
      exponential fashion, forming a plateau at 14 months, and was similar for the
      three valves (P = 0.4). Frontal and occipital ventricular catheter tip locations
      were associated with a reduced risk of shunt failure (hazard ratios, 0.60 [P =
      0.02] and 0.45 [P = 0.001], respectively). Ventricular catheter tips surrounded
      by cerebrospinal fluid or touching the brain were associated with a reduced risk
      of failure (hazard ratios, 0.21 and 0.33, respectively; P = 0.0001). Patients
      with myelomeningocele or large ventricles had increased risk of malfunction
      (hazard ratios, 1.78 [P = 0.006] and 2.33 [P = 0.03], respectively). CONCLUSION:
      Decline of ventricular size over time is not affected by these different shunt
      valve designs. This suggests that the mechanical models of hydrocephalus on which
      the designs were based are inadequate. Ventricular catheter tip location and
      ventricular catheter environment are important. Techniques to accurately place
      ventricular catheters and new valve designs that effectively control ventricular
      size might reduce shunt malfunction.

PMID- 10598701
TI  - Idiopathic hypertrophic cranial pachymeningitis: clinicoradiological spectrum and
      therapeutic options.
AB  - OBJECTIVE: Idiopathic hypertrophic cranial pachymeningitis is a rare disease, of
      undetermined pathogenesis, that is characterized by inflammation and fibrosis of
      the dura mater. METHODS: We encountered six patients with idiopathic hypertrophic
      cranial pachymeningitis and analyzed their clinical presentations, radiological
      findings, and treatment. RESULTS: In the six patients, the main manifestations
      were cranial nerve palsies and headache. Three associations were present, namely
      optic neuropathy, Tolosa-Hunt syndrome, and diabetes insipidus. Gadolinium
      enhanced magnetic resonance imaging was diagnostic, showing intense dural
      enhancement in a linear or nodular pattern. The responses to corticosteroid
      therapy were better for patients who exhibited linear, rather than nodular, dural
      enhancement. For one patient, surgical decompression of the superior orbital
      fissure provided lasting relief. The course of the disease followed one of three
      patterns, i.e., sustained remission, relapse with corticosteroid independence, or
      relapse with corticosteroid dependence. Pulse corticosteroid therapy provided
      significant relief, while reducing the daily corticosteroid requirement and
      avoiding side effects, for a corticosteroid-dependent relapsing patient.
      CONCLUSION: Idiopathic hypertrophic cranial pachymeningitis exhibits varied
      clinical courses. It is important to prevent irreversible cranial neuropathy
      during the active phase of the disease, using daily administration of
      corticosteroids, pulse corticosteroid therapy, or surgical decompression.

PMID- 10598702
TI  - Calvarial tuberculosis.
AB  - OBJECTIVE: Tuberculosis is endemic in developing countries. However, calvarial
      tuberculosis is rare and only a few cases have been reported. In a review of the
      literature, we found only six cases of calvarial tuberculosis reported with
      computed tomographic findings. We report a series of seven patients with
      calvarial tuberculosis, and we discuss their presentations and treatments.
      METHODS: The patients were studied with respect to age and sex prevalences,
      previous histories of trauma and tuberculosis, and presenting complaints. Plain
      cranial x-ray films and computed tomographic scans were used for diagnoses. All
      patients underwent surgery and antituberculous chemotherapy. RESULTS: Of the
      presenting patients, 71.42% were less than 20 years of age. There was a female
      predominance, with a male/female ratio of 1:6. Painless swelling and discharging
      sinuses over the scalp were the most common presenting features. One patient
      presented with osteomyelitis and sinus formation, with associated meningitis. All
      patients recovered well after surgery and antituberculous chemotherapy, except
      for one patient who discontinued drug treatment. CONCLUSION: Although calvarial
      tuberculosis is rare, the possibility of this disease should be considered when
      patients report previous histories of tuberculosis or are from areas in which the
      disease is endemic. Surgery is indicated in cases with associated neurological
      deficits or sinus formation. Antituberculous therapy should be continued for 18
      months.

PMID- 10598703
TI  - Terminal syringomyelia in association with the tethered cord syndrome.
AB  - OBJECTIVE: With the increasing use of magnetic resonance imaging, terminal
      syringomyelia (segmental cystic dilation of the caudal one-third of the spinal
      cord) in association with the tethered cord syndrome has become an appreciable
      finding. This study attempted to define the clinical significance of this
      associated pathological condition by describing its clinical and radiological
      characteristics and its contribution to the clinical status of patients with
      tethered spinal cords. METHODS: Of 132 consecutive patients with tethered cord
      syndrome who presented to our department between 1990 and 1997, 32 patients with
      terminal syringomyelia were enrolled in this study. Clinical findings were
      correlated with syrinx morphological features, as defined using magnetic
      resonance imaging. Surgical treatment used two basic approaches, i.e., simple
      untethering or untethering with concurrent syrinx drainage. RESULTS: Analysis of
      the neurological deficits established a contribution of segmental symptoms, which
      were correlated with the extension and dilation of the syrinx cavity. Magnetic
      resonance imaging scans revealed the frequency of sacral tethering (40.6%), the
      intramedullary paracentral position of the syrinx (75%), and disturbances in
      regional cerebrospinal fluid flow (42%). The clinical outcomes seemed to be
      correlated with syrinx shrinkage; all patients who experienced collapse of the
      cavity achieved better symptom resolution. CONCLUSION: Radiologically significant
      terminal syringomyelia affects the clinical presentation of tethered cord
      syndrome, by increasing or inducing neurological deficits. Better clinical
      outcomes after syrinx decompression emphasize the importance of the recognition
      and treatment of this pathological condition.

PMID- 10598704
TI  - Percutaneous endoscopic recanalization of the catheter: a new technique of
      proximal shunt revision.
AB  - OBJECTIVE: Proximal ventricular catheter obstruction by the choroid plexus is a
      frequent occurrence in children with shunted hydrocephalus. In some cases, the
      flow is obstructed owing to membranous occlusion by a small amount of tissue. It
      has been shown that only a few of the multiple catheter openings need be patent
      to maintain adequate shunt function. Recent advances in technology have improved
      our ability to perform intraluminal endoscopic catheter dissection and minimize
      the morbidity associated with shunt maintenance. METHODS: Percutaneous endoscopic
      shunt recanalization was performed in 20 cases (18 children) under institutional
      review board study protocol. The mean age was 32 months, and all children had
      signs and symptoms of shunt malfunction, confirmed by computed tomography and
      magnetic resonance imaging and verified by shunt taps. Under aseptic conditions
      in the operating room, the Rickham reservoir was entered with a 16-gauge
      intravenous catheter, and the obstruction was visualized with a fiber endoscope
      (0.5-0.8 mm). Intraluminal dissection using electrocautery was performed with
      endoscopic guidance to visualize the catheter and flushing of the valve. RESULTS:
      At a mean follow-up time of 20 months (range, 15-29 mo), the children are doing
      well, with computed tomographic and magnetic resonance imaging confirmation of
      adequate ventricular decompression in the 17 successful cases (85%). There were
      three failures in the study, necessitating a standard open shunt revision.
      CONCLUSION: The percutaneous endoscopic shunt recanalization procedure can be
      used successfully to treat proximal shunt malfunction.

PMID- 10598705
TI  - Long-term outcomes after carotid stent placement treatment of carotid artery
      dissection.
AB  - OBJECTIVE: To assess the long-term outcomes after stent placement for the
      treatment of carotid artery dissections. METHODS: Between 1992 and 1998, seven
      patients underwent stenting procedures for treatment of extracranial carotid
      artery dissections resulting from various causes, including trauma (n = 2),
      iatrogenesis (n = 2), spontaneous development (n = 2), and fibromuscular
      dysplasia (n = 1). Stenting procedures were performed for large, nonhealing,
      dissection-induced pseudoaneurysms (four cases) or severe preocclusive stenosis
      (three cases). A total of 11 stents were placed (Palmaz stents, n = 8;
      Wallstents, n = 3). Radiological follow-up examinations were performed after a
      mean period of 17.7 months (range, 1-67 mo), using conventional or computed
      tomographic angiography. Clinical follow-up data were obtained after a mean
      period of 42.9 months (range, 13-72 mo). RESULTS: All stent placements resulted
      in complete resolution of dissection-induced stenosis. For two of the four
      patients with aneurysms, the lesions occluded spontaneously at the time of the
      procedure. The third patient required coil embolization of the pseudoaneurysm.
      One patient exhibited progressive shrinkage of the aneurysm in serial follow-up
      examinations, with healing after 18 months. No clinical complications were
      associated with the procedures. One patient exhibited progression to asymptomatic
      occlusion 3 months after stenting. The remaining six patients exhibited no
      significant changes in luminal diameters. All patients remained in clinically
      stable condition, with no ischemic symptoms, during more than 3.5 years (mean
      period) of follow-up monitoring. CONCLUSION: This experience suggests that stents
      placed for treatment of extracranial carotid artery dissections remain patent and
      patients remain free of symptoms on a long-term basis. Additional studies will be
      required to determine the optimal types of stents and intervals for follow-up
      monitoring using imaging.

PMID- 10598706
TI  - Comparison of pallidal and subthalamic nucleus deep brain stimulation for
      advanced Parkinson's disease: results of a randomized, blinded pilot study.
AB  - OBJECTIVE: Deep brain stimulation (DBS) of the globus pallidus internus (GPi) and
      subthalamic nucleus (STN) has been reported to be effective in alleviating the
      symptoms of advanced Parkinson's disease (PD). Although recent studies suggest
      that STN stimulation may be superior to GPi stimulation, a randomized, blinded
      comparison has not been reported. The present study was designed to provide a
      preliminary comparison of the safety and efficacy of DBS at either site. METHODS:
      Ten patients with idiopathic PD, L-dopa-induced dyskinesia, and response
      fluctuations were randomized to implantation of bilateral GPi or STN stimulators.
      Neurological condition was assessed preoperatively with patients on and off L
      dopa and on DBS at 10 days and 3, 6, and 12 months after implantation. Patients
      and evaluating clinicians were blinded to stimulation site throughout the study
      period. Complete follow-up data were analyzed for four GPi patients and five STN
      patients. RESULTS: When off-L-dopa, both GPi and STN groups demonstrated a
      similar response, with approximately 40% improvement in Unified PD Rating Scale
      motor scores after 12 months of DBS. Rigidity, tremor, and bradykinesia improved
      in both groups. In combination with L-dopa, Unified PD Rating Scale motor scores
      were more improved by GPi stimulation than by STN stimulation. On-L-dopa axial
      symptoms were clinically improved in the GPi but not the STN group. L-Dopa
      induced dyskinesia was reduced by DBS at either site, although medication
      requirement was reduced only in the STN group. There were no serious
      intraoperative complications among patients in either group. CONCLUSION: Pallidal
      and STN stimulation appears to be safe and efficacious for the management of
      advanced PD. A larger study is needed to investigate further the differences in
      symptom response and the interaction of L-dopa with stimulation at either site.

PMID- 10598707
TI  - Zygomatic-transmandibular approach for giant tumors of the infratemporal fossa
      and parapharyngeal space.
AB  - OBJECTIVE: The surgical anatomy of the infratemporal fossa and parapharyngeal
      space is often not properly understood by neurosurgeons, because these areas are
      more related to other medical disciplines. This article provides a detailed
      description of the infratemporal fossa and parapharyngeal space anatomy in
      cadaveric specimens and offers a neurosurgical perspective on a surgical approach
      that allows wide exposure and complete resection of giant tumors in this
      location. METHODS: Ten cadaveric specimens were prepared for anatomic study.
      Dissections were performed to emphasize the relationship between bone, muscles,
      and neurovascular structures and to simultaneously expose the middle cranial
      fossa, the infratemporal fossa, and the parapharyngeal space. Ten patients with
      giant lesions in these areas (with maximum tumor diameter >8 cm) were treated via
      this approach. RESULTS: The main obstacles to approaching the infratemporal fossa
      and the parapharyngeal space are the zygomatic arch, the parotid gland, the
      facial nerve, and the ascending ramus of the mandible. Thus, by combining a
      pterional-zygomatic craniotomy with transmandibular access, working up and down
      the parotid gland, the exposure is wider and safer. Among the 10 patients
      treated, tumors were totally resected in 7, subtotally resected in 2, and
      partially resected in 1. Morbidity was unremarkable, and, in 8 patients, clinical
      status improved dramatically. CONCLUSION: The zygomatic-transmandibular approach
      allows resection of giant lesions in the middle cranial base, when they are
      invading the infratemporal fossa and parapharyngeal space, with a low morbidity
      rate.

PMID- 10598708
TI  - A randomized, controlled study of a programmable shunt valve versus a
      conventional valve for patients with hydrocephalus. Hakim-Medos Investigator
      Group.
AB  - OBJECTIVE: A multicenter prospective randomized controlled study was performed to
      assess the safety and efficacy of a Codman Hakim programmable shunt valve
      (Codman/Johnson & Johnson, Raynham, MA) versus a conventional valve system of the
      surgeon's choice for the treatment of patients with hydrocephalus. METHODS:
      Enrollment was stratified on the basis of whether the patient was undergoing
      initial shunt insertion or revision of an existing valve system at study entry.
      Study end points were: 1) valve explantation, and 2) shunt failure (surgical
      intervention for any component of the shunt). A total of 377 patients were
      enrolled onto the study, with 235 undergoing first shunt insertion (119
      experimental, 116 control) and 142 undergoing revisions (75 experimental, 67
      control). RESULTS: During a follow-up interval of 104 weeks after the first
      implantation on-study, explantation of the valve was required in 62 (32%) of 194
      experimental valves, compared with 71 (39%) of 183 control valves. Two-year
      survival rates of the original shunt without revision of any component were 52%
      (62 of 119) and 50% (58 of 116) in experimental and control patients,
      respectively, who underwent initial shunt insertion, and 43% (32 of 75) and 43%
      (29 of 67) in experimental and control patients, respectively, who underwent
      replacement of an existing valve. No statistically significant difference was
      observed between experimental and control patients in the survival of either the
      valve or the overall shunt system. Control of hydrocephalus as assessed
      symptomatically and by imaging was comparable in the two treatment groups.
      Although problems related to inability to achieve the desired pressure setting
      were reported in 22 experimental valves, in all but four instances no additional
      programming was attempted because the patients were functioning well clinically.
      The most common reasons cited for valve explantation and shunt revision were
      infection (9.8% frequency in the overall cohort) and proximal shunt malfunction,
      which occurred with comparable frequency in the experimental and control groups.
      CONCLUSION: Safety and efficacy of the Codman Hakim programmable shunt valve is
      comparable to conventional valves in the overall population of patients with
      hydrocephalus. However, the current study was not designed to assess the efficacy
      of programmable versus conventional valves in the management of individual
      hydrocephalus problems, and it had insufficient statistical power to support such
      comparisons. This study provides a rationale for examining whether the
      theoretical advantages of a programmable valve for managing challenging
      hydrocephalus problems can translate into meaningful improvements in shunt and
      valve survival.

PMID- 10598709
TI  - Cerebral cortical neuron apoptosis after mild excitotoxic injury in vitro:
      different roles of mesencephalic and cortical astrocytes.
AB  - OBJECTIVE: Increasing evidence supports the presence of neuronal apoptosis after
      ischemic or excitotoxic brain injury. Astrocytes, which exhibit significant
      regional differences in function, may exert a protective effect on neurons
      exposed to ischemic injury. We examined the effects of astrocytes derived from
      different regions of the central nervous system on neuronal apoptosis after mild
      excitotoxic injury in tissue culture. METHODS: Purified astrocyte cultures
      derived from P4 rat cerebral cortex or mesencephalon showed transient cell
      swelling but no cell death when exposed to 50 micromol/L glutamate for 5 minutes.
      When mixed neuronal/glial cocultures were exposed to the same glutamate dose,
      neuron death was observed. Necrotic and apoptotic cell death during 24 hours was
      examined using morphological criteria, nuclear staining, triphosphate nick end
      labeling, and trypan blue exclusion. RESULTS: We found that cortical neurons that
      elaborate a more extensive dendritic arbor when grown on homotypic astrocytes are
      more likely to undergo apoptosis than neurons with a limited dendritic arbor
      grown on heterotypic astrocytes. By contrast, a similar number of neurons undergo
      necrotic cell death. CONCLUSION: This finding may be associated with 1) increased
      vulnerability of neurons with a more elaborate dendrite structure to mild
      excitotoxic injury, or 2) regional differences in the ability of astrocytes to
      attenuate apoptosis.

PMID- 10598710
TI  - Development of a unique phantom to assess the geometric accuracy of magnetic
      resonance imaging for stereotactic localization.
AB  - OBJECTIVE: To test the spatial accuracy of coordinates generated from magnetic
      resonance imaging (MRI) scans, using the Brown-Roberts-Wells head frame and
      localizer system (Radionics, Inc., Burlington, MA). METHODS: An anthropomorphic
      head phantom, consisting of a two-dimensional lattice of acrylic spheres (4-mm
      diameter) spaced 10 mm apart and embedded in a brain tissue-mimicking gelatin
      agar gel, was constructed. The intersphere distances for the target lattice
      positions in MRI and computed tomographic scan sets were compared. The data sets
      were fused, and differences in fiducial marker and intraphantom target positions
      were measured. RESULTS: Intersphere distances were identical for the MRI and
      computed tomographic scan sets (10 +/- 0.1 mm). Differences in fiducial marker
      positions [maximal lateral difference, 0.97 mm; mean absolute lateral difference,
      0.69 +/- 0.22 mm; maximal anteroposterior (AP) difference, 1.99 mm; mean absolute
      AP difference, 1.29 +/- 0.67 mm] were correlated with differences in intraphantom
      target positions (maximal lateral difference, 0.83 mm; mean absolute lateral
      difference, 0.28 +/- 0.24 mm; maximal AP difference, -1.97 mm; mean absolute AP
      difference, 1.63 +/- 25 mm; maximal vertical difference, -0.73 mm; mean absolute
      vertical difference, 0.34 +/- 0.21 mm). This suggested that improper fiducial rod
      identification and the subsequent transformation to stereotactic coordinate space
      were the greatest sources of spatial uncertainty. CONCLUSION: With computed
      tomographic data as the standard, these differences resulted in maximal and
      minimal composite uncertainties of 2.06 and 1.17 mm, respectively. The measured
      uncertainties exceed recommended standards for radiosurgery but allow the
      possible use of MRI-based stereotactic treatment planning for certain
      intracranial lesions, if the errors are corrected using appropriate software.
      Clinicians must recognize that error magnitudes vary for different systems, and
      they should perform systematic, scheduled, institutional error analyses as part
      of their ongoing quality assurance processes. This phantom provides one tool for
      measuring such variances.

PMID- 10598711
TI  - Matrix metalloproteinases and their inhibitors in human pituitary tumors.
AB  - OBJECTIVE: To determine the expression of matrix metalloproteinases (MMP)-1, -2,
      and -3 and the tissue inhibitors of metalloproteinases (TIMP)-1, -2, and -3 in 12
      tissue samples from normal pituitary glands and in 28 human pituitary tumors
      ranging from Grade 0 to Grade IV, and to establish a correlation between the
      level of expression of MMPs and TIMPs and the tumor grade. METHODS: The
      expression of MMPs and TIMPs was determined by Western blotting. MMP activity was
      detected by gelatin zymography. RESULTS: MMPs were expressed in the majority of
      tumors, and their levels of expression were unrelated to tumor grade or to their
      invasive phenotype. Some correlation was observed between MMP activity detected
      by zymography and tumor grade. TIMP-2 and TIMP-3 were poorly expressed in high
      grade tumors and strongly expressed in normal pituitary glands and in the
      majority of low-grade tumors. CONCLUSION: No correlation could be established
      between the invasive potential of tumors and MMP-1, -2, and -3 expression levels.
      Some correlation was observed between MMP activity detected by zymography and
      tumor grade. A good inverse correlation was observed between TIMP-2 and TIMP-3
      expression levels and tumor grade. These data suggest that monitoring the
      expression of TIMP-2 and TIMP-3 or gelatinolytic activity could be of prognostic
      value.

PMID- 10598712
TI  - Expression of activated epidermal growth factor receptors, Ras-guanosine
      triphosphate, and mitogen-activated protein kinase in human glioblastoma
      multiforme specimens.
AB  - OBJECTIVE: Amplification of the epidermal growth factor receptor (EGFR) is a
      common event in the molecular pathogenesis of high-grade astrocytic tumors,
      occurring in 50% of glioblastoma multiforme (GBM) cases. A subset of GBMs also
      express a constitutively phosphorylated truncated receptor (EGFRvIII). Expression
      of transfected EGFRvIII in cells has been reported to activate the Ras-mitogen
      activated protein kinase pathway and to provide a growth advantage. Novel
      therapeutic agents targeting signal transduction pathways are entering early
      clinical trials; determination of which GBMs express EGFRvIII might help identify
      patients who might benefit from these biological agents. METHODS: A cohort of 15
      flash-frozen surgical specimens (12 GBMs, 2 gliosarcomas, and 1 adult low-grade
      glioma) were evaluated for EGFR and EGFRvIII expression and for EGFR activation
      status using immunohistochemical (IHC) analysis, Western blotting, and reverse
      transcription-polymerase chain reaction assays. Levels of activated Ras-guanosine
      triphosphate were measured using a nonradioactive luciferase-based technique.
      Mitogen-activated protein kinase activation was determined using a myelin basic
      protein assay. IHC analysis was performed on paraffin-embedded, formalin-fixed,
      pathological specimens. Normal control samples included white matter specimens
      distal to tumors (n = 5), a sample obtained during a lobectomy for treatment of
      epilepsy (n = 1), and cultured fetal human astrocytes (n = 1). RESULTS: We
      demonstrated higher levels of activated Ras and mitogen-activated protein kinase
      in GBM specimens, compared with normal brain tissue or the low-grade glioma.
      There was a very good correlation between results obtained using specialized
      molecular techniques and those obtained using routine IHC techniques. Screening
      for EGFRvIII expression may be of prognostic importance, because patients with
      EGFRvIII-positive tumors exhibited shorter life expectancies (mean survival time
      for patients with EGFRvIII-positive tumors, 4.5 +/- 0.6 mo; mean survival time
      for patients with EGFRvIII-negative tumors, 11.2 +/- 0.9 mo). CONCLUSION: We
      demonstrated that routine IHC techniques using commercially available antibodies
      are capable of identifying which GBM specimens express EGFRvIII and whether the
      EGFRs are activated. Such a molecular classification of GBMs might allow us to
      determine which patients might benefit from biologically targeted therapies. In
      addition, characterization of specimens with respect to their EGFRvIII status
      seems to be of prognostic value.

PMID- 10598713
TI  - World War II: a neurosurgeon in New Guinea.
AB  - During World War II, many doctors joined the military after completing their
      medical training. Civilian careers were put on hold until after the war was over.
      In 1942, Eben Alexander, Jr., joined the Air Force, then the United States Army,
      and served 4 years, much of it overseas, as a "3131C" neurosurgeon.

PMID- 10598714
TI  - Long-term survival of a patient with invasive cranial base rhinocerebral
      mucormycosis treated with combined endovascular, surgical, and medical therapies:
      case report.
AB  - OBJECTIVE: Rhinocerebral mucormycosis is a clinical syndrome resulting from an
      opportunistic infection caused by a fungus of the order Mucorales. The prognosis
      of rhinocerebral mucormycosis, once considered uniformly fatal, remains poor.
      Even with early diagnosis and aggressive surgical and medical therapy, the
      mortality rate is high. We present a patient with rhinocerebral mucormycosis
      involving the paranasal sinuses and cranial base who experienced long-term
      survival after multimodality treatment. Clinical characteristics of the disease
      are discussed, and the literature is reviewed. CLINICAL PRESENTATION: A 24-year
      old diabetic man presented with invasive rhinocerebral mucormycosis involving the
      paranasal sinuses, right middle fossa, and right cavernous sinus. INTERVENTION:
      The patient underwent endovascular sacrifice of the involved carotid artery and
      radical resection of the cranial base, including exenteration of the cavernous
      sinus. Reconstruction with a local muscle flap was performed. He continued to
      receive intravenous and intrathecal administration of antibiotics. CONCLUSION:
      Long-term survival with invasive rhinocerebral mucormycosis is rare, but
      possible, with aggressive multimodality treatment, including carotid sacrifice
      for en bloc resection of the pathology, when indicated.

PMID- 10598715
TI  - Acute traumatic posteroinferior cerebellar artery aneurysms: report of three
      cases.
AB  - OBJECTIVE AND IMPORTANCE: Posterior fossa subarachnoid hemorrhage secondary to
      blunt head trauma is rarely associated with traumatic aneurysms of the posterior
      circulation. CLINICAL PRESENTATION: We present three cases of posterior fossa
      subarachnoid hemorrhage from ruptured posteroinferior cerebellar artery (PICA)
      aneurysms after blunt head trauma. In each case, there was no associated
      penetrating injury or cranial fracture. All three patients presented with acute
      hydrocephalus requiring ventriculostomy. Two of the three patients had a proximal
      PICA aneurysm visible on emergent angiography. The remaining patient's aneurysm,
      although not visible on his initial angiogram, was detected on a subsequent
      angiogram 72 hours later. INTERVENTION: All patients underwent successful
      surgical clipping of their aneurysms. Two cases required sacrificing of the
      parent vessels because of the friable nature of the false aneurysms. In each
      case, severe symptomatic vasospasm occurred, requiring angioplasty. All three
      patients also required a ventriculoperitoneal shunt for persistent hydrocephalus.
      CONCLUSION: Features of these three cases and similar cases reported in the
      literature support the theory that vascular ruptures and traumatic aneurysms of
      the proximal PICA may be related to anatomic variability of the PICA as it
      transverses the brainstem. This variability predisposes individuals to vascular
      lesions, which occur in a continuum based on the severity of the injury.
      Posterior fossa subarachnoid hemorrhage after head injury requires a high index
      of suspicion and warrants aggressive diagnostic and therapeutic interventions.

PMID- 10598716
TI  - Marked regional heterogeneity in venous oxygen saturation in severe head injury
      studied by superselective intracranial venous sampling: case report.
AB  - OBJECTIVE: Continuous monitoring of jugular venous oxygen saturation (SjvO2) is
      useful in the management of severe head injury. Abnormally high SjvO2 values can
      be caused by increased cerebral blood flow, decreased cerebral metabolism, brain
      death, contamination from extracerebral venous blood, or traumatic arteriovenous
      fistula. CLINICAL PRESENTATION: A 20-year-old man with severe head injury was
      diagnosed to have a traumatic dural carotid-cavernous sinus fistula on the day of
      trauma. Continuous left SjvO2 monitoring from Days 4 to 12 revealed oxygen
      saturation ranging between 85 and 98%. INTERVENTION: Superselective intracranial
      and extracranial venous sampling on Day 5 demonstrated marked regional
      heterogeneity in venous oxygen saturation as follows: superior sagittal sinus, 95
      to 97%; straight sinus, 88%; right transverse sinus, 94%; left transverse sinus,
      74%; right SjvO2, 95%; left SjvO2, 89%; the basilar plexus, 99%; right internal
      jugular vein, 98%; the left internal jugular vein, 94%. Extremely high oxygen
      saturation in the superior sagittal sinus and basilar plexus was attributed to
      severe brain damage and carotid-cavernous sinus fistula, respectively.
      CONCLUSION: Although jugular bulb oximetry is useful in the management of severe
      head injury, high oxygen saturation values should be interpreted with caution
      because they cannot show the intracranial heterogeneity of venous oxygen
      saturation.

PMID- 10598717
TI  - Meningioma of the pituitary stalk without dural attachment: case report and
      review of the literature.
AB  - OBJECTIVE AND IMPORTANCE: Tumors in the suprasellar region such as adenomas of
      the pituitary gland, craniopharyngiomas, nonneoplastic cystic lesions (especially
      Rathke's cleft cysts), and meningiomas are frequently encountered in
      neurosurgical practice. Meningiomas originate from the arachnoid layer connected
      to the dura of the anterior or posterior clinoidal process, or the tuberculum,
      dorsum, or diaphragma sellae. Tumors originating from the pituitary stalk are
      rare. Such lesions may include germinomas, astrocytomas, histiocytosis X,
      hamartomas, and sarcoidosis. We report a patient with a suprasellar meningioma
      originating from the pituitary stalk with no connection to the adjacent dura.
      CLINICAL PRESENTATION: A 50-year-old man was assessed for impotence and loss of
      libido. Physical examination revealed no abnormalities. Endocrinological
      investigations disclosed nearly complete hypopituitarism, and magnetic resonance
      imaging revealed a suprasellar homogeneously enhancing tumor. INTERVENTION:
      Complete surgical resection was performed in an endoscope-assisted right-sided
      supraorbital craniotomy. The tumor originated from the pituitary stalk with no
      connection to the surrounding dura. The histopathological diagnosis was
      meningioma. CONCLUSION: Although meningiomas frequently occur in the suprasellar
      region, this patient with a suprasellar meningioma is unique because the tumor
      originated from the pituitary stalk with no connection to the surrounding dura.
      The absence of dural attachment has been described in 43 extracerebral
      meningiomas, but a suprasellar location has been reported only once previously.
      Recognition of this phenomenon is important, because meningiomas require a
      different therapeutic strategy than most other tumors of the pituitary stalk.

PMID- 10598718
TI  - Intravascular papillary endothelial hyperplasia causing cauda equina compression:
      case report.
AB  - OBJECTIVE AND IMPORTANCE: Intravascular papillary endothelial hyperplasia
      (Masson's vegetant hemangioendothelioma) is a rare condition affecting the
      neuraxis. In the literature, only one case of this lesion involving the vertebral
      canal with spinal cord compression has been reported. We present a case of cauda
      equina compression due to this abnormality. CLINICAL PRESENTATION: A 17-year-old
      boy was admitted at our hospital with pain, numbness, paresis of the left lower
      extremity, and bladder dysfunction of approximately 1 month's duration. Computed
      tomography and magnetic resonance imaging of the spine revealed a tumor within
      the spinal canal at the T12-L1 level. INTERVENTION: The patient underwent a T12
      L1 laminectomy. An epidural red nodular tumor was visualized and totally
      resected. The findings of the pathological examination were compatible with
      intravascular papillary endothelial hyperplasia. At follow-up examination 1 month
      after the operation, the patient had complete resolution of the pain, and the
      motor deficit and bladder dysfunction had improved significantly. CONCLUSION:
      This rare benign vascular lesion may be clinically and histopathologically
      mistaken for an angiosarcoma. Because the intravascular papillary endothelial
      hyperplasia can be cured by complete surgical resection, it is important to
      distinguish between these two lesions to avoid inappropriate aggressive
      treatment.

PMID- 10598720
TI  - Anchoring method for hemifacial spasm associated with vertebral artery: technical
      note.
AB  - OBJECTIVE: We describe an easy and useful method for treating hemifacial spasm
      related to the vertebral artery. METHODS: The technique entails the manufacture
      of a dural belt harvested from the cerebellar convexity dura and a dural bridge
      made at the petrous dura combined with the use of an aneurysm clip. The dural
      belt holds the vertebral artery and is anchored to the dural bridge by fixation
      with an aneurysm clip after the vertebral artery is transposed to an appropriate
      position. RESULTS: The technique proved to be safe and effective in a series of
      six patients with hemifacial spasm who were followed up for a period of 2 months
      to more than 10 years after surgery. All patients were affected on the left side.
      Multiple offending arteries were present in three cases. Hemifacial spasm
      completely disappeared in all patients. CONCLUSION: This method represents a
      feasible option for the treatment of hemifacial spasm caused by a tortuous,
      elongated, or enlarged vertebral artery.

PMID- 10598719
TI  - A new surgical technique: open-window corpectomy in the treatment of ossification
      of the posterior longitudinal ligament and advanced cervical spondylosis:
      technical note.
AB  - OBJECTIVE: To achieve satisfactory cervical spinal cord decompression with
      minimal removal of bone. METHODS: The open-window corpectomy technique is
      designed to remove a minimal amount of bone and achieve satisfactory
      decompression. With the use of a high-speed drill under a surgical microscope,
      only the dorsal surface of the corpus is removed after appropriate
      microdiscectomies. This leaves the anterior and the lateral portions of the
      vertebral corpus intact. RESULTS: In a 15-month period, a total of 11 patients
      were treated with this technique. Five patients improved, and the remaining six
      patients remained the same neurologically during a mean follow-up period of 8.3
      months. No complications were observed in any patients. CONCLUSION: The open
      window corpectomy provides satisfactory spinal cord decompression in a
      biomechanically sound manner.

PMID- 10598721
TI  - A set of coaxial microneurosurgical instruments.
AB  - OBJECTIVE: In an effort to lessen surgical trauma, neurosurgeons are developing
      more contained approaches requiring minimal or no brain retraction. The mobility
      of traditional microsurgical tools within such narrow corridors is severely
      restricted. A substantial portion of the surgical field may be obscured by the
      relatively large size of these instruments. To overcome some of these problems,
      the author has designed a set of new, low-profile, coaxial microinstruments.
      DESCRIPTION OF INSTRUMENTATION: The coaxial shaft of these instruments is
      obtained by coupling a tube and a rod, rotating in opposite directions along
      their major axis. The rotational movement is delivered by compressing and
      releasing a spring-loaded, bayonet-shaped handle. The tips are obtained by
      flanging the two elements of the shaft. The initial set includes microscissors
      and microforceps, as well as tumor-grasping forceps. The two elements of the
      shaft can be disengaged easily by releasing a catch at the end of the shaft and
      disassembled for cleaning and basic maintenance purposes. DISCUSSION: The design
      of the present set of instruments combines a low-profile coaxial shaft with well
      established ergonomic features, such as a pencil grip handle and an angled
      bayonet. CONCLUSION: The use of the least possible number of moving components
      enhances the reliability of these tools. The different profiles and angles of the
      tips partially compensate for the absence of a rotatable shaft, a potential
      shortcoming of these instruments.

PMID- 10598722
TI  - I and the Village, by Marc Chagall (1887-1985).

PMID- 10598723
TI  - Elastin degradation in the superficial temporal arteries of patients with
      intracranial aneurysms reflects changes in plasma elastase.

PMID- 10598724
TI  - Chiari I malformation redefined: clinical and radiographic findings for 364
      symptomatic patients.

PMID- 10598725
TI  - Long-term follow-up of patients treated with cervical radiofrequency neurotomy
      for chronic neck pain.

PMID- 10598726
TI  - Comparison of functional capacity in patients with end-stage heart failure
      following implantation of a left ventricular assist device versus heart
      transplantation: results of the experience with left ventricular assist device
      with exercise trial.
AB  - BACKGROUND: Use of a permanent left ventricular assist device (LVAD) has been
      proposed as an alternate treatment of patients with end-stage heart failure. The
      purpose of this study was to compare the functional capacity of patients
      following implantation of a LVAD vs heart transplant (HTx). METHODS: Eighteen
      patients from 6 centers who received an intracorporeal LVAD as a bridge to HTx
      underwent treadmill testing 1 to 3 months post-LVAD and again post-HTx. Baseline
      and peak measurements, including oxygen consumption, blood pressures, and
      respiratory rate were made during each treadmill test. RESULTS: Peak oxygen
      consumption was 14.5+/-3.9 ml/kg/minute post-LVAD and 17.5+/-5.0 ml/kg/minute
      post-HTx (p < .005). The percentage of the predicted peak oxygen consumption
      based on gender, weight, and age was 39.5%+/-5.5% post-LVAD and 47.7%+/-10.9%
      post-HTx (p < .005). Exercise duration was lower post-LVAD than post-HTx (10.3+/
      4.2 minute vs 12.5+/-5.4 minute, p < .05). After LVAD implantation, peak total
      oxygen consumption correlated with peak LVAD rate and output. Eight patients
      reached an LVAD rate of 120 beats per minute (bpm) before the conclusion of
      exercise, the maximum rate for the outpatient electric device. The peak
      respiratory exchange ratio post-LVAD was 1.15+/-0.22 and post-HTx was 1.15+/
      0.18, consistent with a good effort in both groups. CONCLUSIONS: Patients
      demonstrated a lower functional capacity post-LVAD than post-HTx. For some
      patients functional capacity post-LVAD may be improved by a higher maximum LVAD
      rate and output.

PMID- 10598727
TI  - Pulmonary hypertension: pathophysiology as a basis for clinical decision making.

PMID- 10598728
TI  - Cardiac function of transplanted rat hearts using a working heart model assessed
      by magnetic resonance imaging.
AB  - BACKGROUND: A direct correlation between graft rejection and cardiac contractile
      function in small-animal models has been difficult to establish because (i) the
      conventional non-working heart model is greatly different from the orthotopic
      heart in terms of left ventricular work and (ii) it is difficult to obtain
      hemodynamic data in situ. We have used magnetic resonance imaging (MRI)
      techniques to obtain noninvasive, in-situ quantitation of ventricular volume
      after heterotopic cardiac transplantation. METHODS: Infra-renal heterotopic
      cardiac transplantation was performed on rats using syngeneic and allogeneic
      untreated donors in both working and non-working left heart models. An occluding
      balloon catheter in the inferior vena cava was used to vary the pre-load to the
      graft. An arteriovenous fistula was created to raise inferior caval oxygen
      saturation. Magnetic resonance imaging measurements were carried out at day 3, 4,
      and 5 post-transplantation. Left ventricle end-diastolic and end-systolic volumes
      were calculated using a biplanar ellipsoid model. RESULTS: Stroke volume was
      significantly increased in the working heart model as compared to the non-working
      model. At day 4 post-transplant, the diastolic pressure-volume relationship in
      the allograft group was significantly shifted, indicative of decreased myocardial
      distensibility, whereas the indices of systolic function were preserved.
      CONCLUSIONS: We have developed a heterotopic transplant working rat heart model
      and have used it to assess in-situ cardiac function by MRI. Sensitive indices of
      diastolic contractile function can be obtained in this rodent transplant model
      that correlate well with histologic evidence of early rejection.

PMID- 10598729
TI  - New UNOS rules: historical background and implications for transplantation
      management. United Network for Organ Sharing.
AB  - The algorithm for the allocation of donor hearts used by the United Network for
      Organ Sharing (UNOS) was changed in January 1999. The new scheme alters the
      medical urgency criteria from a 2-tiered to a 3-tiered system. Blood type O and
      blood type B candidates are less disadvantaged and pediatric candidates are
      somewhat advantaged with regard to adolescent donors. The new allocation
      algorithm allows an individual with life-threatening ventricular arrhythmias to
      be listed in the highest urgency status. Increased regulation will occur with the
      establishment of a review for the highest urgency status and the establishment of
      regional review boards.

PMID- 10598730
TI  - Endothelin in coronary endothelial dysfunction early after human heart
      transplantation.
AB  - BACKGROUND: Cytokines and growth factors released as part of the immune response
      to alloantigenic stimuli are capable of regulating endothelin-1 expression in the
      allograft. Endothelin plays a significant role as a modulator of coronary
      vascular reactivity in the early stages of atherosclerosis and may be important
      as a participant in and marker for cardiac allograft vasculopathy. METHODS: We
      characterized a possible relationship between morphological and functional
      coronary changes, transcardiac plasma endothelin level and myocardial endothelin
      mRNA expression in 33 cardiac transplant recipients in the early, stable phase
      5+/-3 months after orthotopic heart transplantation. Coronary microvascular
      function was determined as endothelium-dependent with acetylcholine and
      endothelium-independent with adenosine using intracoronary Doppler-FloWire. The
      percentage of the epicardial diameter changes was measured using quantitative
      coronary angiography. Intravascular ultrasound was performed to quantify intimal
      hyperplasia. Cardiac endothelin uptake or release was determined by measuring
      plasma endothelin levels in the coronary sinus and aorta. Myocardial endothelin
      gene expression was determined using semiquantitative RT-PCR. RESULTS: The aortic
      endothelin levels were significantly increased in transplant recipients compared
      to nontransplanted patients (11.8+/-2.2 vs 7.2+/-0.9 fmol/mL; P < 0.001).
      Endothelin uptake was noticed in the majority of patients, and the amount of
      endothelin uptake was correlated to microvascular (r = 0.37; P < 0.05) and
      epicardial (r = 0.41; P < 0.03) endothelium-dependent vasodilatation. High mRNA
      signal intensity was associated with significantly reduced coronary flow response
      to acetylcholine compared to patients with low myocardial gene expression
      (coronary flow reserve 2.4+/-0.9 vs 3.4+/-0.8, respectively; P < 0.005).
      Morphological coronary changes early after transplantation were not correlated to
      endothelin plasma levels or myocardial gene expression. CONCLUSION: Coronary
      endothelial vasomotor dysfunction after cardiac transplantation is associated
      with an increased myocardial endothelin mRNA expression and decreased endothelin
      uptake by the heart. We postulate that early activation in the endothelin system
      may have a pivotal role in the acceleration of the atherosclerotic process in
      transplant patients.

PMID- 10598731
TI  - Acute native lung hyperinflation is not associated with poor outcomes after
      single lung transplant for emphysema.
AB  - BACKGROUND: Single-lung transplantation for emphysema may be complicated by acute
      native lung hyperinflation (ANLH) with hemodynamic and ventilatory compromise.
      Some groups advocate the routine use of independent lung ventilation, double-lung
      transplant, or right-lung transplant with or without contralateral lung volume
      reduction surgery in high-risk patients. The goal of this study was to determine
      the incidence of ANLH and identify its potential predictors. METHODS: We reviewed
      51 consecutive single-lung transplants for emphysema. Symptomatic ANLH was
      defined as mediastinal shift and diaphragmatic flattening on chest x-ray with
      hemodynamic or respiratory failure requiring cardiopressor agents or independent
      lung ventilation. Preoperative and postoperative physiologic and hemodynamic data
      were analyzed from both recipients and donors. RESULTS: Sixteen patients
      developed radiographic ANLH; 8 were symptomatic, 2 severely so. We could not
      identify high-risk patients before transplant by pulmonary function tests,
      predicted donor total lung capacity (TLC)/actual recipient TLC ratio, pulmonary
      artery pressures, or the side transplanted. There was a trend toward an increased
      incidence of symptomatic ANLH in patients with bullous emphysema on chest
      computed tomography, but this was accounted for primarily by patients with alpha1
      antitrypsin deficiency (4/13 vs 4/38 with chronic obstructive pulmonary disease,
      P = 0.10). No patient required cardiopulmonary bypass or inhaled nitric oxide
      intraoperatively. Patients with acute native lung hyperinflation did not have
      increased reperfusion edema as measured by chest x-ray score or PaO2/F(I)O2
      ratio. Compared to patients without ANLH, symptomatic patients had longer
      ventilator times (64.9+/-14.6 hours vs 40.4+/-3.9, P = 0.02, ANOVA) and longer
      lengths of stay (19.3+/-2.1 days vs 13.7+/-1.3, P = 0.07), but 30-day survival
      was 100%. Two symptomatic patients required independent lung ventilation or
      inhaled nitric oxide; the others were managed with decreased minute ventilation,
      early extubation, and cardiopressor agents. No patient required early lung volume
      reduction surgery or retransplantation. Acute native lung hyperinflation had no
      effect on FEV1 or 6-minute walk results at 1 year; survival at 1, 2, or 3 years;
      or the rate of acute rejection, infection, or bronchiolitis obliterans syndrome
      greater than grade 2. CONCLUSION: Acute native lung hyperinflation is common
      radiographically but is rarely clinically severe. Although there was a trend
      toward an increase in symptomatic ANLH in patients with bullous emphysema, a high
      risk group could not be identified preoperatively. Our results do not support the
      routine use of bilateral lung transplant, the exclusive use of right single-lung
      transplant, simultaneous lung volume reduction surgery, or independent lung
      ventilation for patients with emphysema. Management strategies should be employed
      that limit overdistension of the native lung and lead to early extubation.

PMID- 10598732
TI  - Sulfasalazine inhibits reperfusion injury and prolongs allograft survival in rat
      cardiac transplants.
AB  - INTRODUCTION: Reperfusion injury is an inflammatory cell-mediated response that
      causes tissue damage immediately following transplantation, and has been
      implicated in the development of acute and chronic rejection. NF-kappaB is a
      transcription factor that upregulates adhesion molecules ICAM-1, VCAM-1, and ELAM
      1 following reperfusion. We hypothesized that treatment with sulfasalazine, a
      potent inhibitor of NF-kappaB, would decrease adhesion molecule expression,
      decrease reperfusion injury, and prolong allograft survival in rat cardiac
      transplants. METHODS: Heterotopic rat heart transplants were performed. Donor
      allografts were treated with saline, sulfasalazine (SSA), or lipopolysaccharide
      (LPS), a potent inducer of NF-kappaB activity. Reperfusion injury was assessed
      with cardiac edema (percent wet weight), neutrophil infiltration (MPO activity),
      and histologic damage (contraction band necrosis). Immunohistochemistry was
      performed to analyze protein expression. Acute rejection was determined by daily
      palpation. RESULTS: Treatment with a single 100 mg/kg intraperitoneal injection
      of sulfasalazine decreased reperfusion injury compared to saline controls (MPO
      activity, saline: 2.1+/-0.3, SSA: 1.2+/-0.31, P < 0.005; % wet weight, saline
      77.6+/-1.1%; SSA 75.8+/-1.0%, P < 0.005; contraction band necrosis, saline:
      13.1+/-2.5%, SSA: 6.1+/-3.4%, P < 0.001). LPS administration increased all
      parameters of reperfusion injury. Treatment with sulfasalazine prior to LPS also
      decreased reperfusion injury compared to LPS and saline groups. Sulfasalazine
      treatment decreased ICAM-1 and VCAM-1 protein expression. Administration of 500
      mg/kg sulfasalazine increased graft survival to 15.4+/-1.8 days compared to
      saline (6.8+/-1.4 days, P < 0.005). CONCLUSION: Treatment with sulfasalazine is
      an effective method to decrease reperfusion injury and prolong allograft survival
      in a rat cardiac transplantation model.

PMID- 10598733
TI  - Alveolar recruitment prevents rapid-reperfusion-induced injury of lung
      transplants.
AB  - BACKGROUND: Physical factors play an important role in ischemia-reperfusion
      induced injury of lung transplants. For example, rapid restoration of reperfusion
      resulted in severe pulmonary edema and deterioration of pulmonary function of
      lung explants in an ex vivo reperfusion system. This type of injury can be
      prevented by a stepwise increase in the perfusion flow rate, or by adding
      prostaglandin E1 (PGE1) to the blood perfusate during the first 10 minutes.
      However, the mechanisms of these protective effects are unknown. We noted a
      dramatic decrease in airway pressure rather than pulmonary arterial pressure in
      these studies, suggesting that lung recruitment may be an important factor in
      minimizing injury. METHODS: In the present study, we examined the importance of
      alveolar recruitment in preventing rapid-reperfusion-induced lung injury. Rat
      lungs were flushed preserved with low potassium dextran solution for 12 hours at
      4 degrees C. Lung explants were randomly divided into three groups: 1) untreated
      control; 2) lungs inflated to total lung capacity for 2 minutes; and 3) lungs
      ventilated for 10 minutes prior to reperfusion. Postpreservation lung function
      was assessed in an isolated rat lung reperfusion model. RESULTS: Rapid initiation
      of reperfusion led to severe pulmonary edema and significant pulmonary
      dysfunction. In inflation or ventilation groups, the injury was significantly
      attenuated. The PaO2 and shunt fractions in these lungs were comparable to normal
      lungs. A significant drop in airway pressure was observed in these two groups and
      the lung compliance in the inflation group was significantly better than other
      two groups. CONCLUSIONS: These results suggest that overcoming alveolar collapse
      with inflation or ventilation, may protect the lung from mechanical-stress
      induced injury during reperfusion.

PMID- 10598734
TI  - Development of an infection-resistant LVAD driveline: a novel approach to the
      prevention of device-related infections.
AB  - BACKGROUND: Infection remains the single most important challenge to extended
      left ventricular assist device (LVAD) use and often arises from the percutaneous
      driveline exit site. We evaluated the ability of an LVAD driveline prototype
      impregnated with chlorhexidine, triclosan, and silver sulfadiazine to resist
      bacterial and fungal colonization. METHODS: The spectrum and duration of
      antimicrobial activity were evaluated in vitro by daily transfer of driveline
      segments embedded on agar plates inoculated with 10(8) colony-forming units (CFU)
      of Staphylococcus aureus (S. aureus), Staphlococcus epidermidis, Enterobacter
      aerogenes, Psuedomonas aeruginosa, and Candida albicans, and then measuring zones
      of inhibition around the sample subsequent to 24 hours of incubation at 37
      degrees C. Antimicrobial activity was demonstrated against all organisms for
      greater than 14 days, and for over 21 days for gram-positive bacteria. To
      demonstrate in vivo efficacy of the treated driveline, 3-cm segments of driveline
      were implanted in the dorsal and ventral surface of rats. The exit site was
      inoculated with 10(6) CFU of S. aureus. After 7 days, driveline segments were
      aseptically explanted and assayed for bacterial colonization and retention of
      antimicrobial activity. One hundred percent of control segments were colonized
      (10(5) CFU S. aureus/cm) as against 13% of the test explants (< or = 330 CFU/cm;
      p < 0.0001). RESULTS: Subcultures of the insertion site and driveline pocket
      tissue resulted in 10(3) to 10(5) CFU per swab culture for control rats and 0 to
      10(2) CFU/swab for test animals. Test drivelines retained 80% of anti-S. aureus
      activity. Gross and histological examination of the driveline and surrounding
      pocket revealed minimal tissue reactivity with positive signs of tissue ingrowth.
      CONCLUSION: An antimicrobial driveline may prevent early infections and
      facilitate ingrowth of tissue to provide long-term stability and protection
      against late infection.

PMID- 10598735
TI  - Native heart complications after heterotopic heart transplantation: insight into
      the potential risk of left ventricular assist device.
AB  - BACKGROUND: In heterotopic heart transplantation, the donor heart is connected
      parallel to the recipient's diseased heart. Recipients continue to have risks,
      such as arrhythmia, thromboembolism, valvular heart disease, and ischemic heart
      disease which can develop in the native heart. It may serve as a clinical model
      to study long-term pathophysiologic processes in the native heart of patients
      with a left ventricular assist device. METHOD: We analyzed the prevalence of long
      term complications related to the native heart in the heterotopic heart
      transplant and attempted to gain insight into the potential risk to a native
      heart after receiving a left ventricular assist device. RESULTS: Between December
      1984 and December 1994, 16 patients (13 men, 3 women, ranging in age from 37 to
      60 years) underwent heterotopic heart transplant at the University of Pittsburgh.
      The 1- and 5-year survival rate after the transplant was 81% and 44%,
      respectively. Actuarial freedom from complications related to the native heart
      after 1 year and 4 years was ventricular arrhythmia: 85%, 75%; ischemic disease:
      85%, 64%; valvular disease: 100%, 88%; and thromboembolism: 85%, 58%. Of these
      complications, thromboembolism was not considered in determining actuarial
      freedom from complications because thromboembolism should be regarded as a device
      related complication rather than as a native-heart-related complication for left
      ventricular assist device recipients. Consequently, actuarial freedom from all
      complications excluding thromboembolism was 70% after 1 year and 50% after 4
      years. In addition, the hazard function curve remains constant up to 80 months
      after the operation without significant differences among the yearly ratios.
      CONCLUSIONS: This analysis suggests that cautious observation of the native
      heart's long-term performance is necessary for the left ventricular assist device
      recipient.

PMID- 10598736
TI  - Chronic aortic counterpulsation with latissimus dorsi in heart failure: clinical
      follow-up.
AB  - BACKGROUND: Dynamic aortomyoplasty is an alternative technique to heart
      transplantation. The goal of our study was to evaluate the benefits of aortic
      counterpulsation obtained by dynamic thoracic aortomyoplasty in patients with
      heart failure refractory to pharmacologic treatment and contraindications to
      heart transplant or cardiomyoplasty. METHODS: In this study we compared
      preoperative and postoperative data from five out of six carefully selected
      patients who were treated with dynamic thoracic aortomyoplasty. This surgical
      technique wraps the right latissimus dorsi muscle flap around the ascending
      aorta. This muscle flap was electrically stimulated during diastole, following a
      muscle-conditioning protocol, to obtain diastolic augmentation. At the 6-month
      follow-up period we evaluated, invasively and noninvasively, the hemodynamic and
      clinical effects of aortomyoplasty. RESULTS: We observed a significant decrease
      in the number of hospitalizations (P = 0.01), NYHA functional class (P = 0.01),
      cardiothoracic ratio (P = 0.02), right ventricular diameter (P = 0.03), left
      atrial diameter (P = 0.04), and pulmonary artery systolic pressure (P = 0.04);
      and a significant increase in the 6-minute walking test (P = 0.01), cardiac index
      (P = 0.04), noninvasive evaluation of diastolic augmentation (P = 0.01), left
      ventricular shortening fraction (P = 0.01), and radioisotopic left ventricular
      ejection fraction (P = 0.02). We also found a nonsignificant decrease in the left
      ventricular diameter (P = 0.08) and wedge pressure (P = 0.19); and a
      nonsignificant increase in peak oxygen consumption (P = 0.13). CONCLUSIONS:
      Dynamic thoracic aortomyoplasty in heart failure resulted in an important
      improvement of hemodynamic parameters, heart functional data, and clinical
      functional class, when comparing preoperative data with the 6-month follow-up
      data.

PMID- 10598737
TI  - Relationship between right and left-sided filling pressures in 1000 patients with
      advanced heart failure.
AB  - BACKGROUND: Elevated left ventricular filling pressures present a major target of
      therapy for symptomatic heart failure but are difficult to assess directly.
      Because the relationship of left- and right-sided pressures remains ill defined
      in chronic heart failure, this study compared 3 right-sided measurements (right
      atrial [RA] pressure, pulmonary artery systolic [PAS] pressure, and severity of
      tricuspid regurgitation [TR]) to the pulmonary capillary wedge (PCW) pressure.
      METHODS: Hemodynamic measurements and echocardiography were available from 1000
      patients undergoing transplant evaluation. Right atrial and PAS pressure, and TR
      severity were compared to PCW pressure. For 754 patients undergoing repeat
      measurements, changes in RA and PAS pressures were compared to PCW changes.
      RESULTS: Right atrial pressure correlated with PCW pressure (r = 0.64),
      regardless of etiology or TR severity. Right atrial pressure changes correlated
      with PCW changes (r = 0.62). Discordance was defined as either RA > or = 10 mm Hg
      despite PCW < 22 mm Hg (6%) or RA < 10 mm Hg despite PCW > or = 22 mm Hg (15%).
      For detection of PCW > or = 22 mm Hg, positive predictive values were 88% for RA
      > or = 10 mm Hg, 95% for PAS > or = 60 mm Hg, and 79% for > or = moderate TR.
      Pulmonary artery systolic pressure correlated very closely with PCW (r = 0.79),
      and could be estimated as 2 x PCW. Reduction in PAS pressure during therapy was
      strongly determined by PCW pressure reduction (r = 0.67). CONCLUSIONS: Accurate
      estimation of RA pressure can potentially guide therapy of left ventricular
      filling pressures in approximately 80% of chronic heart failure patients without
      obvious non-cardiac disease. In this population, elevated PAS pressures are
      largely determined by elevated left-sided filling pressures.

PMID- 10598738
TI  - Sexuality of patients with advanced heart failure and their spouses or partners.
AB  - BACKGROUND: Sexuality is an important aspect of quality of life for patients with
      advanced heart failure and their spouses or partners. Therefore, we conducted a
      study to determine the types of sexual problems and concerns of patients and
      their spouses/partners, their level of interest in receiving information on this
      topic, and the relationship between their need for information and the degree of
      sexual problems. METHODS: Sixty-three couples were recruited from a university
      affiliated, outpatient, heart failure program during their initial visit.
      RESULTS: The most important sexual relationship issue of both patients and
      spouses/partners was related to decreased frequency in sexual relations. They
      reported the need to receive specific information about sexual activity as
      moderate to very high, but it was unrelated to the level of need for education
      and counseling. CONCLUSIONS: Nurses and physicians need to assume interest and
      provide instruction related to the sexual activity needs of patients and their
      spouses/partners.

PMID- 10598739
TI  - Cyclophosphamide rescue therapy for chronic rejection after lung transplantation.
AB  - BACKGROUND: Obliterative bronchiolitis remains the leading cause of late
      mortality after heart-lung and lung transplantation. Although several treatment
      options have been advocated, none has proven to be very successful.
      Cyclophosphamide is effective in the treatment of idiopathic pulmonary fibrosis,
      and chronic rejection after lung transplantation is also a fibroproliferative
      process. We therefore conducted an open, uncontrolled study to look at the effect
      of cyclophosphamide rescue therapy in the treatment of chronic rejection in lung
      transplant recipients. METHODS: Between October 1996 and March 1998
      cyclophosphamide was prescribed to 7 patients with chronic and persistent
      rejection who failed to respond to conventional therapy (pulse steroids or
      antilymphocyte products or both). RESULTS: Cyclophosphamide therapy was initiated
      on postoperative day 478+/-366. At that time 2 patients were in bronchiolitis
      obliterans syndrome stage 0, 3 patients in stage 1, and 2 patients in stage 2.
      Their best postoperative forced expiratory volume in one second (FEV1) was 2.19+/
      0.75 L. Three months before the start of cyclophosphamide the FEV1 had declined
      to 1.90+/-0.83 L, with a further decline to 1.63+/-0.64 L at the time of
      initiating cyclophosphamide. In 6 of the 7 patients the FEV1 stabilized or
      increased after cyclophosphamide had been started (mean FEV1 3 and 6 months after
      cyclophosphamide of 1.77+/-0.58 L and 1.79+/-0.48 L, respectively). One patient
      died 18 months after the introduction of cyclophosphamide due to progressive
      obliterative bronchiolitis. In one patient cyclophosphamide had to be stopped
      because of persistent leucopenia. CONCLUSIONS: Cyclophosphamide might be a
      promising therapeutic alternative for the treatment of chronic persistent
      rejection after lung transplantation.

PMID- 10598740
TI  - Pressure-wire guided balloon angioplasty in allograft coronary vasculopathy.
AB  - We report a case of successful percutaneous transluminal coronary angioplasty
      guided from pressure-wire measurements in a transplanted patient. Fractional flow
      reserve, a lesion-specific, pressure-independent index of functional stenosis
      severity, was used to guide the intervention.

PMID- 10598741
TI  - Hematoma of the interventricular septum following right ventricular
      endomyocardial biopsy for the detection of allograft rejection after heart
      transplantation.

PMID- 10598742
TI  - Correlation of the intrinsic clearance of donepezil (Aricept) between in vivo and
      in vitro studies in rat, dog and human.
AB  - 1. Donepezil hydrochloride (Aricept) is used for the treatment of Alzheimer's
      disease. Here the correlation of the intrinsic clearance (Cl(int)) of donepezil
      between the in vivo and in vitro states was studied in rat, dog and human. 2. In
      an experiment with 14C-donepezil and human microsomes the routes of metabolism
      were identified as N-dealkylation and O-demethylation, and no unknown metabolites
      were detected. 3. The Cl(int) of donepezil in the male rat, female rat, dog and
      human liver microsomes were 33.7, 13.4, 37.0 and 6.35 microl/min/mg microsomal
      protein respectively, and sex difference in rat and interspecies difference in
      the estimated Cl(int) were found. 4. After a single intravenous administration to
      the male rat, female rat and dog, total plasma clearance (ClP(total)) was 78.6,
      29.5 and 88.3 ml/min/kg respectively, and a sex difference was observed in rat.
      5. After a single oral administration to the male rat, dog and healthy volunteer,
      ClP(total) was 140, 105 and 2.35 ml/min/kg respectively, and remarkable
      differences were observed between animals and man. 6. The contribution of renal
      clearance to blood clearance (Cl(r)) was low in all species. The predicted in
      vitro hepatic clearance (Cl(h-pre)) was in the rank order: male rat (15.91
      ml/min/kg) > dog (7.96) > female rat (7.67) > human (1.04). Although Cl(h-pre)
      was underestimated, Cl(h-pre) was significantly correlated with that of
      ClB(total) in the different animal species and in man, indicating that the in
      vitro-in vivo ranking order was conserved.

PMID- 10598743
TI  - Isolation and identification of major metabolites of rifalazil in mouse and
      human.
AB  - 1. Three metabolites of rifalazil have been isolated from dog urine and
      identified as 25-deacetyl-rifalazil, 30-hydroxy-rifalazil and 25-deacetyl-30
      hydroxy-rifalazil. In the current study major metabolites of rifalazil in mouse
      and human were isolated and identified, and their antimicrobial activities
      determined. 2. Urinary excretion of rifalazil and its metabolites in six mouse
      strains, CD-1 (ICR), BALB/c, C57BL/6, C3H/He, DBA/2 and CBA/J, was examined. Two
      major metabolites were detected in mouse urine obtained after several oral doses,
      and the proportion of rifalazil metabolites against total urinary excretion
      varied over a 2-fold range (4.8-8.7%) in the different mouse strains. 3. One of
      two major metabolites in mouse urine was 25-deacetyl-rifalazil and the other was
      unknown: it was isolated from mouse urine and identified by ms and 1H- and 13C
      nmr as 32-hydroxy-rifalazil. 4. In human, two major metabolites of rifalazil were
      detected in urine obtained after administration of a single oral dose. These
      metabolites were also produced by incubation of rifalazil with pooled human liver
      microsomes, and identified by lc/ms and lc/ms/ms as 25-deacetyl-rifalazil and 32
      hydroxy-rifalazil. 5. The antimicrobial activities of 32-hydroxy-rifalazil
      against gram-positive bacteria and mycobacteria were similar with those of the
      parent compound.

PMID- 10598744
TI  - In vitro metabolism of mifepristone (RU-486) in rat, monkey and human hepatic S9
      fractions: identification of three new mifepristone metabolites.
AB  - 1. In vitro metabolism of the antiprogestin drug mifepristone (RU-486) was
      studied after incubation with rat, monkey and human hepatic S9 fractions in the
      presence of an NADPH-generating system. 2. Unchanged mifepristone (approximately
      45% of the sample(s) in rat; approximately 70% in monkey; approximately 65% in
      human) plus six metabolites, three known and three new, were profiled, quantified
      and tentatively identified on the basis of MS and MS/MS data. 3. The proposed
      metabolic pathways for mifepristone are proposed, and the two metabolic steps are
      (A) N-demethylation and (B) methyl oxidation. 4. Step A formed N-desmethyl
      mifepristone (M1) in major amounts (approximately 35% s in rat, 16% in monkey and
      human) and N,N-didesmethyl mifepristone (M2) in minor amounts (< 5% s in all
      species). Step B, or in conjunction with step A, produced four minor/trace
      metabolites, namely hydroxymethyl mifepristone (M3), hydroxymethyl M1 (M4),
      hydroxymethyl M2 (M5) and formyl mifepristone (M6).

PMID- 10598745
TI  - Metabolism of ethyl methyl sulphide and sulphoxide in rat microsomal fractions.
AB  - 1. Gas chromatographic (GC) methods for the analysis of ethyl methyl sulphide
      (EMS) and its corresponding sulphoxide (EMSO) and sulphone (EMSO2) in rat
      microsomes and aspects of the in vitro metabolism of EMS and EMSO are described.
      2. EMS and the internal standard (dimethyl sulphide) were extracted by a
      headspace procedure and separated satisfactorily using a column packed with 4%
      Carbowax 20 M/0.8% KOH on Carbopack B. EMSO, EMSO2 and the internal standard n
      propyl sulphone were separated satisfactorily using a 2-m column packed with 10%
      Carbowax 20 M on Chromosorb W. 3. Under the optimum conditions (incubation of 10
      min and microsomal protein content of approximately 4 mg/ml), 10% of the initial
      EMS concentration (2.5 mM) was converted to the corresponding sulphoxide in rat
      liver microsomal incubations. However, < 0.1% of the sulphone was detected when
      rat liver microsomes were incubated with EMS. Similarly, 2.5% of the initial EMSO
      concentration (2.5 mM) was converted to the corresponding sulphone by rat liver
      microsomes (approximately 4 mg/ml protein) during an incubation of 30 min.
      However, no EMS was detected after incubation with EMSO under these conditions.
      4. The estimated apparent Vmax and Km for the sulphoxidation of EMS were 3.8+/
      0.02 nmol/mg protein/min and 1.9+/-0.10 mM respectively. Vmax1, Vmax2 and Km1 and
      Km2 for the S-oxidation of EMSO were 0.5+/-0.01 and 0.2+/-0.01 nmol/mg
      protein/min and 0.7+/-0.02 and 0.1+/-0.00 mM respectively. 5. Studies with
      selective inducers and inhibitors of microsomal monooxygenases indicated that the
      sulphoxidation of EMS is mediated mainly by FMO, whereas both FMO and cytochrome
      P450 are involved in the S-oxidation of EMSO.

PMID- 10598746
TI  - Rat cytochromes P450 (CYP) specifically contribute to the reductive bioactivation
      of AQ4N, an alkylaminoanthraquinone-di-N-oxide anticancer prodrug.
AB  - 1. The bioreductive activation of the alkylaminoanthraquinone di-N-oxide prodrug
      AQ4N has been characterized in rat hepatic tissue using HPLC. 2. AQ4N was shown
      to be metabolized to two products, namely AQM, the two electron reduced mono-N
      oxide, and AQ4, the four electron reduced active cytotoxic agent. 3. Metabolism
      was shown to occur in microsomes with an apparent Km = 30.29 microM and Vmax =
      1.05 nmol/mg/min. 4. Bioreduction was dependent on anaerobic conditions and the
      presence of the reduced cofactor NADPH. Ketoconazole (100 microM) and carbon
      monoxide both inhibited AQ4N metabolism inferring a role for cytochrome P450
      (CYP). 5. Microsomes from phenobarbitone and isoniazid-pretreated animals
      significantly (p < 0.05) enhanced the formation of AQ4 from AQ4N indicating a
      role for CYP2B and 2E respectively. The involvement of both CYP2B and 2E was
      confirmed by the use of CYP-specific inhibitors. 6. In conclusion, the
      involvement of rat hepatic CYP in the reductive bioactivation of the novel
      antitumour prodrug AQ4N has been established in detail for the first time. These
      findings highlight an important interspecies difference between the metabolism of
      AQ4N in rat and man which was shown earlier to be mediated by CYP3A enzymes. The
      pharmacological significance of this is discussed.

PMID- 10598747
TI  - Metabolism of CP-195,543, a leukotriene B4 receptor antagonist, in the Long-Evans
      rat and Cynomolgus monkey.
AB  - 1. The fate of [14C]CP-195,543, a novel leukotriene B4 receptor antagonist, was
      studied following oral administration to the Long-Evans rat and Cynomolgus
      monkey. 2. Most of the radioactivity was primarily excreted in the faeces, and
      urine was a minor route of excretion. 3. CP-195,543 was extensively metabolized
      in the two species, primarily by two metabolic pathways: glucuronidation of
      unchanged CP-195,543 and oxidative metabolism, presumably by cytochrome P450. 4.
      The sites of glucuronidation were the carboxylic acid moiety and the hydroxy
      group. The ester glucuronide was the predominant glucuronide conjugate detected
      in the rat, whereas the monkey generated the ether as well as the ester
      glucuronide. 5. The structures of oxidative metabolites were elucidated using
      mass spectrometry (in the positive- and negative-ion mode) and 1H-NMR. The sites
      of hydroxylation were the benzylic group and the 3-position of the benzopyran
      ring. 6. This study has indicated that CP-195,543 was mainly eliminated by Phase
      II metabolism in both species.

PMID- 10598748
TI  - Role of sialylation in determining the pharmacokinetics of neutrophil inhibitory
      factor (NIF) in the Fischer 344 rat.
AB  - 1. Recombinant neutrophil inhibitory factor (NIF) is a glycoprotein. Its amino
      acid sequence remains constant and has a molecular weight of 28.9 kD. However,
      approximately 40% of the total molecular weight consists of glycans with variable
      structure. 2. The pharmacokinetics of 11 different NIF batches with varying
      extents and patterns of sialylation have been investigated in the Fischer 344 rat
      following intravenous administration. These data indicate that reducing the
      extent of NIF sialylation reduces the half-life of the molecule due to an
      increase in the systemic clearance. Also, an increase in the number of
      unsialylated or neutral glycans may increase the volume of distribution of NIF,
      although this effect is marginal. 3. Isolated perfused rat liver (IPRL)
      investigations have shown that sialylated NIF has a low hepatic extraction (<
      1%), while asialo NIF has an extraction that is > 20-fold higher. Co
      administration of asialo NIF with asialo fetuin (a protein cleared by hepatic
      asialoglycoprotein receptor (possibly galactose)-mediated uptake reduced the
      hepatic extraction of asialo NIF. 4. These data suggest that NIF molecules that
      have free sugar moieties (possibly galactose) interact with an asialoglycoprotein
      receptor (possibly galactose-mediated) in the liver (parenchymal
      cells/hepatocytes). Interaction with this receptor leads to cellular
      internalization and degradation.

PMID- 10598749
TI  - Metabolism of furazolidone: alternative pathways and modes of toxicity in
      different cell lines.
AB  - 1. The metabolism and cytotoxicity of the antimicrobial nitrofuran drug
      furazolidone have been studied in Caco-2, HEp-2 and V79 cell lines. Free radical
      production, metabolite pattern, formation of bound residues, inhibition of
      cellular replication and protection by the antioxidant glutathione were compared
      for the three cell lines. 2. All three cell lines produced the same nitro-anion
      radical with similar kinetics. Little further metabolic breakdown was observed in
      V79 cells, whereas Caco-2 and HEp-2 cells showed extensive degradation of
      furazolidone, but with different end patterns. 3. Under hypoxic conditions, the
      colony-forming ability was extensively impaired in HEp-2 cells whereas the other
      two cell lines were less affected, suggesting that irreversible damage to DNA
      occurred prevalently in HEp-2 cells. In V79 cells the absence of oxygen caused a
      25-fold increase in the formation of protein-bound residues. 4. Brief exposure to
      furazolidone caused a 50% loss of endogenous glutathione in Caco-2 cells, but no
      loss could be detected in V79 and HEp-2 cells. Consistently, when glutathione was
      depleted by buthionine-[S,R]-sulphoximine (BSO) and diethylmaleate (DEM)
      treatment, the viability of V79 and HEp-2 cells was minimally affected by
      furazolidone, whereas that of Caco-2 cells was substantially reduced. 5. It is
      concluded that the cytotoxicity of furazolidone in these cell lines can be
      exerted by a number of different mechanisms, possibly related to different
      metabolic pathways. The cytotoxicity of nitrofuran drugs, therefore, cannot be
      ascribed to a single toxic intermediate, but in Caco-2 cells furazolidone is
      extensively metabolized and detoxified by GSH, in V79 is only partially activated
      and then bound to proteins, whereas in HEp-2, once activated, may react with DNA.

PMID- 10598750
TI  - Association of cytochrome P450 induction with oxidative stress in vivo as
      evidenced by 3-hydroxylation of salicylate.
AB  - 1. Previous studies have shown that formation of 2,3-dihydroxybenzoate (2,3-DHB)
      from salicylate in vivo is a sensitive and specific marker of *OH radical
      generation, since 2,3-DHB is formed exclusively by *OH radicals, whereas both *OH
      radicals and cytochrome P450 (CYP) contribute to the production of 2,5-DHB. In
      the present study the salicylate-hydroxylation assay was used to examine whether
      CYP induction by the administration of dexamethasone, phenobarbital or beta
      naphthoflavone to the male rat led to oxidative stress in vivo. 2. Dexamethasone
      was used under conditions that induced an approximately 50-fold induction of CYP
      P4503A expression in liver microsomal protein. Treatment with dexamethasone
      caused a 17.2-fold increase in 2,3-DHB plasma concentration compared with control
      animals. An increase in total hydroxylated salicylate (2,3-DHB plus 2,5-DHB) of
      133.5 micromol/l plasma was produced, of which--assuming that the attack by *OH
      in position 3 or 5 of salicylate occurs at a similar rate--10.9 micromol/l were
      due to *OH radical attack and 122.6 micromol/l due to metabolism by CYP. 3.
      Phenobarbital led to a 4.7-fold increase in 2,3-DHB plasma concentration under
      conditions that induced CYP P4502B and 3A. An increase in total hydroxylated
      salicylate of 34.3 micromol/l plasma was observed, 2.0 micromol/l due to *OH
      radical attack and 32.3 micromol/l due to metabolism by cytochrome P450. 4. In
      contrast to dexamethasone and phenobarbital, beta-naphthoflavone did not cause a
      significant increase in 2,3-DHB plasma concentrations. 5. SKF 525A, a mixed
      function oxidase inhibitor, caused a significant reduction of mean 2,5-DHB plasma
      concentration by 35% (p < 0.001), whereas 2,3-DHB was not significantly reduced,
      indicating that in contrast to the situation after induction by dexamethasone or
      phenobarbital, *OH radical generation by constitutive CYP contributes only to a
      minor degree to total in vivo *OH radical generation. 6. This study shows for the
      first time, to the authors' knowledge, that induction of some (but not all) P450s
      is associated with the production of hydroxyl radicals in vivo.

PMID- 10598751
TI  - 'Metabonomics': understanding the metabolic responses of living systems to
      pathophysiological stimuli via multivariate statistical analysis of biological
      NMR spectroscopic data.

PMID- 10598752
TI  - Glycerol accelerates recovery of barrier function in vivo.
AB  - Two studies were performed to evaluate the influence of glycerol on the recovery
      of damaged stratum corneum barrier function. Measurements of transepidermal water
      loss and capacitance were conducted in a 3-day follow-up after tape stripping
      (study 1) and a 7-day follow-up after a barrier damage due to a repeated washing
      with sodium lauryl sulphate. In study 1 a faster barrier repair (transepidermal
      water loss) was monitored in glycerol-treated sites. Significant differences
      between glycerol open vs. untreated and glycerol occluded vs. untreated were
      observed at day 3. Stratum corneum hydration showed significantly higher values
      in the sites treated with glycerol+occlusion, compared with all other sites. In
      study 2 a faster barrier repair was seen in glycerol-treated sites, with
      significant differences against untreated and base-treated sites 7 days after the
      end of the treatment. Stratum corneum hydration showed highest values in the
      glycerol treated sites after 3 days of treatment. Glycerol creates a stimulus for
      barrier repair and improves the stratum corneum hydration; stratum corneum
      hydration is not strictly related to barrier homeostasis and can be optimized by
      different mechanisms and pathways. The observed effects were based on the
      modulation of barrier repair and were not biased by the humectant effect of
      glycerol. As the glycerol-induced recovery of barrier function and stratum
      corneum hydration were observed even 7 days after the end of treatment, glycerol
      can be regarded as a barrier stabilizing and moisturizing compound.

PMID- 10598753
TI  - Increased expression of vascular endothelial growth factor in pyogenic
      granulomas.
AB  - The expression of vascular endothelial growth factor (VEGF) was analysed in
      biopsy samples from patients with pyogenic granuloma. The results disclosed the
      presence of a strong VEGF signal in pyogenic granulomas, which are constituted by
      a vast majority of cells of endothelial lineage. A marked positivity was evident
      in areas of proliferating endothelial cells without vessel lumen formation. In
      the same respect, staining for VEGF was less marked in the vessels with a well
      developed lumen. The fact that VEGF production appears to be limited to
      endothelial cell precursors or immature endothelial cells prior to the complete
      development of the vessels, leads to the possibility that VEGF may act as an
      autocrine factor in circumstances of endothelial cell stimulation.

PMID- 10598754
TI  - Sunscreen protection against cis-urocanic acid production in human skin.
AB  - Commercial sunscreens may offer some protection from immunosuppression induced by
      ultraviolet (UV) radiation, but agreement concerning the degree of protection is
      lacking. Cis-urocanic acid, formed by the photoisomerization of transurocanic
      acid is considered an important mediator of the cutaneous immunomodulation
      resulting from exposure to UV radiation. We investigated the effect of sunscreens
      on the isomerization of urocanic acid in 17 human subjects. Two sunscreens
      containing chemical filters, sun protection factor (SPF) 4 and SPF 10, and a SPF
      10 sunscreen with a physical filter were applied at a thickness of 2 mg/cm2. The
      effect of a thin layer (0.5 mg/cm2) of the chemical SPF 10 sunscreen was also
      evaluated, as the amount of sunscreen applied in practice may be considerably
      less than recommended. All areas were irradiated with a single UV dose of 3.6 SED
      (standard erythema doses). In irradiated unprotected skin the median net
      production of cis-urocanic acid was 52% (relative amount). In the sites treated
      with the chemical sunscreens, the production of cis-urocanic acid was 7.4% (SPF
      4) and 3.5% (SPF 10), and isomerization was thus reduced more efficiently at a
      higher SPF (p<0.01). The physical sunscreen reduced the formation of cis-UCA to
      15%, and was significantly less effective than both the chemical SPF 10 sunscreen
      (p<0.01) and the SPF 4 sunscreen (p<0.01). The production of cis-urocanic acid in
      the area treated with the thin layer of the chemical SPF 10 sunscreen was 22%.
      The protection against the production of cis-urocanic acid was therefore reduced
      significantly (p<0.01) when the sunscreen was applied in an amount lower than
      recommended.

PMID- 10598755
TI  - Early events in ultraviolet light-induced skin lesions in lupus erythematosus:
      expression patterns of adhesion molecules ICAM-1, VCAM-1 and E-selectin.
AB  - In our previous study, photoprovocation induced lupus erythematosus (LE) and
      polymorphous light eruption-like lesions in photosensitive LE patients. In this
      new study we examined the expression of ICAM-1, VCAM-1 and E-selectin, in early
      lesions in particular. A total of 32 patients with cutaneous LE, 25 with
      "classic" discoid LE, and 7 with systemic LE, including 3 patients with subacute
      cutaneous LE, were provoked with UVA and UVB on normal appearing skin. Induced
      lesions were followed up with serial biopsies. LE-like histopathology was seen
      within 1 week of provocation in some cases. Adhesion molecule expression was
      statistically significantly affected by the factors clinical diagnosis and
      wavelength (UVA or UVB). Strong keratinocyte ICAM-1 expression was found 1 week
      after provocation in reactions that eventually developed into long-standing ones.
      It is possible that these early changes reflect an underlying defect in the
      mechanisms that regulate adhesion molecule expression in LE.

PMID- 10598756
TI  - Distribution of naive and memory T-cells in photoprovoked and spontaneous skin
      lesions of discoid lupus erythematosus and polymorphous light eruption.
AB  - Immune response to ultraviolet radiation-modified skin antigens has been
      suggested as a pathomechanism of skin lesions in discoid lupus erythematosus and
      polymorphous light eruption. In order to elucidate the role of T-lymphocyte
      subsets in this response, we studied the distribution of CD45RO+, CD45RA+ and
      CD31+ cells and the endothelial expression of adhesion molecules E-selectin/P
      selectin, intercellular adhesion molecule-1 and CD31 antigen in photoprovoked and
      spontaneous skin lesions. Typically, CD45RA+ cells were the prevailing
      inflammatory cell population of discoid lupus erythematosus, whereas CD45RO+
      cells prevailed in both diseases and in healthy controls. Epidermotrophism of any
      T-cell subsets was more typical of discoid lupus erythematosus, whereas no major
      differences in endothelial adhesion molecule expression was found between the 2
      diseases. Strong keratinocyte ICAM-1 expression was associated with adjacent
      CD45RO+ cell infiltrates, not with CD45RA+ or CD31+ cell infiltrates. We conclude
      that the cellular immune response to UV radiation is dissimilar in discoid lupus
      erythematosus and polymorphous light eruption.

PMID- 10598757
TI  - Validity study for the stigmatization experience in atopic dermatitis and
      psoriatic patients.
AB  - A central experience of patients with atopic dermatitis and psoriasis is the
      feeling of stigmatization. This can be estimated by the "Questionnaire on
      Experience with Skin Complaints" (QES), based on the "Feelings of Stigmatization
      Questionnaire" by Ginsburg & Link. This study was designed to evaluate the
      psychometric properties of the QES, especially the validity of this
      questionnaire, and to supply more information about the stigmatization
      experiences of patients with atopic dermatitis and psoriasis. Three groups of
      patients were analysed: 76 with atopic dermatitis, 81 and 217 with psoriasis,
      respectively. The comparison of subgroups with different affected regions
      revealed that the genital region is especially relevant for the stigmatization
      experience in these patients. In addition, the feeling of stigmatization
      (estimated by the QES) is relatively independent of the different dimensions of
      the "Trier Scales of Coping with Diseases", except for the depressive coping
      style "Rumination" measuring a high amount of inner concern with the afflicting
      disease. It can be concluded that the QES is a valid and reliable instrument for
      examining the stigmatization experience of patients with atopic dermatitis and
      psoriasis.

PMID- 10598758
TI  - Atopic disease among adults in Northern Russia, an area with heavy air pollution.
AB  - The cumulative incidence of atopic disease among adults was assessed in the
      heavily polluted Russian town Nikel on the Kola peninsula. The study was
      conducted in spring 1994 using a self-administered questionnaire. A total of
      3,368 (93.6%) of the 3,600 subjects returned a completed questionnaire.
      Information about atopic diseases, smoking habits and living conditions in the
      family was also obtained. A cumulative incidence of atopic diseases of 11% was
      reported in 377 adults. This was significantly more frequent in women (12.7%)
      than in men (9.7%). Smoking habits differed from other western countries, as 53%
      of males and only 10% of females smoked. Indoor damp was reported by 13% and the
      keeping of dogs and cats by 52%. Our study indicates that atopic diseases is less
      frequent among adults in a heavily polluted Arctic Russian town than in western
      industrialized countries.

PMID- 10598759
TI  - Improved response of plaque psoriasis after multiple treatments with topical 5
      aminolaevulinic acid photodynamic therapy.
AB  - We investigated the clinical response of 10 patients with plaque psoriasis to
      multiple treatments with photodynamic therapy, using topical application of 5
      aminolaevulinic acid followed by exposure to broad-band visible radiation.
      Treatment was performed up to 3 times per week, with a maximum of 12 treatments,
      using a light dose of 8 Jcm(-2) delivered at a dose-rate of 15 mW cm(-2). Eight
      patients showed a clinical response. Out of 19 treated sites, 4 cleared, 10
      responded but did not clear and 5 showed no improvement. Of the 4 sites that
      cleared only 1 did so fully, after 7 treatments, 45 days after the start of
      therapy. Of the 10 sites that responded partially, the greatest reduction in
      scale, erythema and induration index occurred after a minimum of 3 and a maximum
      of 8 treatments. The intensity of 5-aminolaevulinic acid-induced protoporphyrin
      IX fluorescence, recorded prior to the first treatment, varied between sites on
      the same patient as well as between patients. There was also a variation in
      fluorescence intensity recorded from the same site immediately prior to
      subsequent treatments, although the pretreatment levels generally decreased as
      the study progressed and then increased as psoriasis relapsed. Biopsies confirmed
      that fluorescence was localized throughout the epidermis and stratum corneum, but
      the level was not consistent between sections taken within the same biopsy. We
      also observed fluorescence at sites distant from the ones that received 5
      aminolaevulinic acid, which was not present prior to the start of the treatment
      programme, but found no evidence of elevated levels of plasma porphyrins. The
      level of discomfort associated with this therapy increased with increasing values
      of the calculated photodynamic dose, defined as the product of the initial
      photosensitizer concentration and the percentage reduction in fluorescence
      following irradiation. Therefore, although clinical efficacy improved with
      multiple treatments, unpredictable response and patient discomfort make ALA-PDT
      unsuitable for the treatment of psoriasis.

PMID- 10598760
TI  - Double-blind comparison of azelaic acid 20% cream and its vehicle in treatment of
      papulo-pustular rosacea.
AB  - Previous investigations have indicated that topical azelaic acid has beneficial
      effects in rosacea. This 3-month randomized, double-blind, multicentre study
      compared the efficacy and safety of azelaic acid 20% cream with its vehicle, in
      the treatment of papulo-pustular rosacea. A total of 116 patients were enrolled
      in the study and medication was applied twice daily. Azelaic acid cream produced
      significantly greater mean reductions in total inflammatory lesions than did
      vehicle (azelaic acid: 73.4%; vehicle: 50.6%; (p = 0.011), and erythema severity
      score (azelaic acid: 47.9%; vehicle: 37.9%; (p = 0.031). Azelaic acid cream
      treatment also resulted in significantly more favourable overall improvements
      than vehicle in both physician (p = 0.020) and patient ratings (p = 0.042).
      Neither azelaic acid cream nor vehicle produced any clinically relevant
      improvement in telangiectasia. Local adverse events were transient and mainly
      mild or moderate, and rates were similar for azelaic acid cream (39.5%) and
      vehicle (38.5%). Burning was the symptom most frequently reported. More than 90%
      of patients rated the overall local tolerability of their treatment as good or
      acceptable. In conclusion, azelaic acid 20% cream is effective and well tolerated
      in the treatment of papulo-pustular rosacea.

PMID- 10598762
TI  - Soluble E-selectin as a marker of disease activity in pustulosis palmaris et
      plantaris.
AB  - In this study, we investigated a possible correlation between adhesion molecules
      and activity of pustulosis palmaris et plantaris (PPP). Serum levels of soluble E
      selectin (sE-selectin), soluble intercellular adhesion molecules 1 (sICAM-1) and
      tumour necrosis factor alpha (TNF-alpha) in 30 untreated PPP patients were
      examined, and compared with those in 20 healthy subjects. Values in 10 PPP
      patients were re-examined after treatment. Serum levels of sE-selectin and TNF
      alpha in untreated PPP patients were significantly higher than those in healthy
      subjects. There was a statistically significant correlation between the disease
      activity and serum levels of sE-selectin in untreated PPP patients. Furthermore,
      disease activity of PPP was higher in patients who smoked and during the summer,
      with elevation of serum sE-selectin levels. Serum levels of sE-selectin were
      downregulated with the recovery from PPP. These results suggest that sE-selectin
      may play a role in the pathogenesis of PPP and could be a reliable marker of its
      disease activity.

PMID- 10598761
TI  - Stinging and rosacea.
AB  - A total of 32 rosacea patients (25 with the papulopustular type of rosacea and 7
      with the erythematotelangiectatic type) and 32 healthy persons were single-blind
      tested with a solution of 5% lactic acid and pure water applied to their cheeks.
      Twenty-four patients and 6 controls reacted positively as "stingers" (p<0.001) in
      this objective test of sensitive skin. All 7 of the patients with
      erythematotelangiectatic rosacea, but only 17/25 with the papulopustular type,
      were stingers (n.s.). The reason why some patients react with subjective
      symptoms, such as itching, burning, stinging, prickling or tingling, is unclear.
      The findings in this study are not surprising, but do support the theory that
      impairment due to different stimuli, most likely because of vascular sensitivity,
      is a central mechanism in the aetiology of rosacea. The correlation between
      sensitive vessels and sensitive skin has, however, not yet been determined.

PMID- 10598763
TI  - Skin pigmentation and texture changes after hair removal with the normal-mode
      ruby laser.
AB  - Promising clinical results have been obtained with the normal mode ruby laser for
      removal of unwanted hair. Melanin within the hair follicles is thought to act as
      target for the ruby laser pulses, whereas epidermal melanin is thought to be a
      competitive chromophore, responsible for potential side effects. This study aimed
      (i) to objectify postoperative changes in skin pigmentation and texture and (ii)
      to evaluate the importance of variations in preoperative skin pigmentation for
      the development of side effects 12 weeks after 1 treatment with the normal-mode
      ruby laser. A total of 17 volunteers (skin types I-IV) were laser-treated in the
      hairy pubic region (n = 51 test areas). A shaved test area served as control.
      Skin reflectance spectroscopical measurements, 3-dimensional surface contour
      analysis and ultrasonography objectified postoperative changes in skin
      pigmentation and texture. Blinded clinical assessments revealed postoperative
      hyperpigmentation (2% of test areas) and hypopigmentation (10%), whereas no
      textural changes were seen. Reflectance spectroscopically-determined pigmentary
      changes depended on the degree of preoperative skin pigmentation, fairly
      pigmented skin types experiencing subclinical hyperpigmentation and darkly
      pigmented skin types experiencing subclinical hypopigmentation. Three-dimensional
      surface profilometry documented similar pre- and postoperative surface contour
      parameters, indicating that the skin surface texture is preserved after laser
      exposure. Ultrasonography revealed similar skin thicknesses in laser-exposed and
      untreated control areas. It is concluded that normal-mode ruby laser treatment is
      safe for hair removal in skin types I-IV.

PMID- 10598764
TI  - The dermatoscopic ABCD rule does not improve diagnostic accuracy of malignant
      melanoma.
AB  - The dermatoscopic ABCD rule has been suggested to improve diagnostic performance
      regarding cutaneous malignant melanoma. Using this rule, a total dermatoscopy
      score is calculated from the presence of various dermatoscopic elements. A total
      dermatoscopy score above 4.75 signifies possible and 5.45 probable melanoma. We
      compared the diagnostic accuracy of dermatoscopy with and without the use of the
      ABCD rule. Furthermore, receiver operating characteristic analysis was performed
      for the ABCD rule. The area under the receiver operating characteristic curve was
      0.854 (range 0.777-0.906) demonstrating that in 85.4% of the cases, cutaneous
      malignant melanomas were rated higher than the non-melanoma skin lesions.
      Sensitivity for the melanoma diagnosis was higher for simple dermatoscopy than
      when the ABCD rule was used (p<0.05). There was no difference in specificity when
      a total dermatoscopy score of 4.75 was used as cut-off point, but specificity was
      lower for simple dermatoscopy than when the total dermatoscopy score of 5.45 was
      used. Diagnostic accuracy was higher for simple dermatoscopy than for the ABCD
      rule (p<0.01). In conclusion, the dermatoscopic ABCD rule was not superior to
      simple dermatoscopy, and fewer malignant melanomas were identified with this
      rule.

PMID- 10598765
TI  - Direct or referral microscopy of vaginal wet smear for bacterial vaginosis:
      experience from an STD clinic.
AB  - A new wet smear diagnostic criterion for bacterial vaginosis was applied to 124
      consecutive female patients attending an STD clinic located in the centre of
      Copenhagen. Bacterial vaginosis was detected in 54 (44%) women, making bacterial
      vaginosis the most prevalent pathological condition encountered. A total of 47
      (87%) of the women were symptomatic. Concomitant genital infections were found in
      13 (24%) of these women, most often as vulvo-vaginal candidiasis. A correct
      microscopic diagnosis could also be obtained by sending the vaginal smear to the
      local microbiologist for rehydration and phase contrast microscopy. It is
      suggested that the previously described vaginal wet smear criteria are used in
      place of Amsel's criteria for routine diagnosis of bacterial vaginosis.

PMID- 10598766
TI  - Sudden death secondary to mycosis fungoides of the midbrain.

PMID- 10598767
TI  - Pilomatrix carcinoma in a child.

PMID- 10598768
TI  - Topical calcipotriol in childhood psoriasis.

PMID- 10598769
TI  - High-resolution magnetic resonance imaging for determination of thickness and
      depth of invasion of skin tumours.

PMID- 10598770
TI  - Bullous pemphigoid with permanent loss of the nails.

PMID- 10598771
TI  - Dapsone hypersensitivity syndrome in a patient with cutaneous lupus
      erythematosus.

PMID- 10598772
TI  - A unique case of localized pemphigus vulgaris.

PMID- 10598773
TI  - Interferon alpha-2a monotherapy for necrobiotic xanthogranuloma.

PMID- 10598774
TI  - Pyoderma gangrenosum after augmentation mammoplasty.

PMID- 10598775
TI  - Non-invasive monitoring of the mechanical properties of keloids during
      cryosurgery.

PMID- 10598776
TI  - Treatment of solar lentigo with cryosurgery.

PMID- 10598777
TI  - UVA1 for treatment of keloids.

PMID- 10598778
TI  - Failure of colchicine in the treatment of severe acne vulgaris.

PMID- 10598779
TI  - A juvenile case of classic Kaposi's sarcoma.

PMID- 10598780
TI  - Generalized severe lichen planus treated with azathioprine.

PMID- 10598781
TI  - Ichthyosis vulgaris and X-linked ichthyosis: simultaneous segregation in the same
      family.

PMID- 10598782
TI  - Post-herpes zoster scar sarcoidosis.

PMID- 10598783
TI  - Giant cafe au lait spot in a patient with neurofibromatosis.

PMID- 10598784
TI  - Vitiligo at the site of radiotherapy for malignant thymoma.

PMID- 10598785
TI  - No case against Mohs' surgery.

PMID- 10598786
TI  - Herpetic infection on the vulva associated with eccrine squamous
      syringometaplasia in malignant lymphoma.

PMID- 10598787
TI  - Experimental and theoretical comparisons between the classical Schild analysis
      and a new alternative method to evaluate the pA2 of competitive antagonists.
AB  - The Schild analysis is undoubtedly the most frequently used powerful diagnostic
      tool to investigate the nature of an antagonist and, consequently, to evaluate
      its potency, often expressed as pA2. Nevertheless, different reasons often
      prevent the experimenter from applying this analysis, leading to use an
      inhibition curve for the antagonist and to evaluate its potency by means of
      several approaches, which are generally considered theoretically invalid. In a
      recent work, a new theoretical approach, mathematically analogous to the Schild
      one, has been shown. By means of a simplified experimental protocol based on an
      antagonist inhibition curve (following a control concentration-response curve for
      the agonist), this method allows a linear regression analysis, giving a slope
      value absolutely equivalent to the Schild slope and a reliable estimation of the
      pA2 of a competitive antagonist. In this paper, this new method has been compared
      with the Schild analysis, to determine the parameters of potency relative to well
      known competitive antagonists, on different in vitro isolated preparations. In
      strips of guinea pig isolated gastric smooth muscle, pirenzepine antagonised the
      effects of bethanechol. In guinea pig isolated ileum, atropine blocked the
      contracturant effects of carbamylcholine, while in electrostimulated ileum
      segments, the inhibitory responses to alpha-methylnoradrenaline were reduced by
      idazoxan. Finally, in guinea pig isolated spontaneously beating atria, the
      negative inotropic effects of 5'-N-ethylcarboxamidoadenosine were antagonised by
      8-cyclopentyl-1,3-dipropylxanthine. The parameters of potency, relative to all
      the above competitive antagonists and expressed as pA2, resulted almost
      equivalent, when calculated by the Schild analysis or by the alternative method.
      Furthermore, when tested also for the well-known irreversible alkylating agent
      dibenamine in rat aortic rings stimulated by noradrenaline, the alternative
      method furnished a profile of clear nonlinearity, unmasking the nature of the
      antagonism. Finally, the relationships between the results calculated by the
      alternative analysis or by the Schild analysis and different levels of computer
      generated "random noise" (affecting the shape and the position of theoretical
      curves) were also evaluated, in order to know the robustness of the new method.
      The two methods proved reliable and almost equivalent in robustness, when applied
      with different levels of "random noise". These results confirm the Schild
      analysis as the most accurate tool to study antagonists, since this analysis can
      furnish the highest number of information and observations on the behaviour of an
      antagonist. Nevertheless, when limiting conditions prevent a classical Schild
      analysis and impose the use of an inhibition curve, the new method probably
      represents the most preferable experimental approach. Indeed, it allows to
      calculate the antagonist potency, after the evaluation of a slope parameter
      giving an important information about the possible nature of the antagonism.

PMID- 10598788
TI  - Characterisation of human recombinant somatostatin receptors. 1. Radioligand
      binding studies.
AB  - Human somatostatin receptor subtypes 1-5 (sst1-5) were characterised using the
      agonist radioligands [125I]LTT-SRIF28, [125I][Tyr10]CST14, [125I]CGP 23996 and
      [125I][Tyr3]octreotide in stably transfected Chinese hamster lung fibroblast
      cells (CCL39 cells). The radioligands used labelled saturable and high-affinity
      populations of sites in each instance; at sst1-4 receptors maximum binding (Bmax)
      was roughly equivalent. By contrast, at sst5 receptors Bmax determined with
      [125I]CGP 23996 and [125I][Tyr3]octreotide was significantly lower (two-and
      eightfold) compared with [125I]LTT-SRIF28 and [125I][Tyr10]CST14. Experiments
      were performed with the stable GTP-analogue guanylylimidodiphosphate (GppNHp) to
      establish guanine nucleotide sensitivity of agonist binding to sst1-5 receptors.
      The sensitivity towards GppNHp was quite variable depending on receptor and/or
      ligand. At sst1 and sst4 receptors, GppNHp produced little effect overall,
      whereas binding to sst3 and sst2 receptors was reduced by 70 and >80%,
      respectively. At sst5 receptors, the binding of [125I]LTT-SRIF28 and
      [125I][Tyr10]CST14 was only slightly affected by GppNHp, while [125I]CGP 23996
      and [125I][Tyr3]octreotide binding was almost entirely inhibited. Thus,
      [125I][Tyr3]octreotide labelled about 26-fold less sst5 receptors than [125I]LTT
      SRIF28, in the presence of 10 microM GppNHp. These discrepancies in guanine
      nucleotide sensitivity, were confirmed in GppNHp competition experiments.
      Competition studies were performed at the five receptors labelled with the
      different radioligands to establish their respective pharmacological profiles:
      the rank order of affinity was largely radioligand-independent at sst1-4
      receptors, in contrast to sst5 receptors where it was radioligand-dependent.
      Thus, the pharmacological profile of [125I]LTT-SRIF28- and [125I][Tyr10]CST14
      labelled sst5 sites correlated highly significantly, but did not correlate with
      the affinity profiles defined with [125I]CGP 23996 and [125I][Tyr3]octreotide
      binding to sst5 receptors. Depending on the agonist radioligand used and the
      receptor studied, it would appear that binding can be essentially to a guanine
      nucleotide-sensitive state (e.g. sst2 or sst3), a guanine nucleotide-insensitive
      state (sst1 or sst4) or a mixture of both (sst5); in the latter case, each
      radioligand defining a more or less different rank order of affinity at the same
      receptor. In summary, the differences in agonist receptor binding and guanine
      nucleotide sensitivity cannot be explained by the ternary complex model or its
      variations, but rather suggest the existence of multiple agonist-specific
      receptor states which vary from one receptor to another.

PMID- 10598789
TI  - Characterisation of human recombinant somatostatin receptors. 2. Modulation of
      GTPgammaS binding.
AB  - G protein activation by somatostatin (somatotropin release inhibiting factor,
      SRIF), cortistatin (CST) and analogues of these neuropeptides was investigated at
      human somatostatin receptor subtypes 1-5 (sst1-5) stably expressed in CCL39
      Chinese hamster lung fibroblast cells by measuring agonist-stimulated
      [35S]guanosine 5'-O-(3-thiotriphosphate) ([35S]GTPgammaS) binding. [35S]GTPgammaS
      binding was assessed in the presence of 100 mM NaCl and 1 microM GDP, although
      higher Emax and/or pEC50 values may have been obtained under other conditions,
      but at the expense of lower absolute stimulation or signal/noise ratio. SRIF14
      stimulated [35S]GTPgammaS binding to 162, 220, 148 and 266% of control levels via
      sst2, sst3, sst4 and sst5 receptors, respectively. At sst1 receptors, SRIF14
      produced only a limited stimulation (Emax 115%). Hence sst1 receptors were not
      subjected to further [35S]GTPgammaS binding experiments. [35S]GTPgammaS binding
      assays were then performed with sst2-5 receptors. Most of the peptide analogues
      stimulated [35S]GTPgammaS binding in sst2-5 receptor-expressing cells. BIM 23056
      behaved as an antagonist on SRIF14-induced [35S]GTPgammaS binding with an
      apparent pKBs of 6.33 and 5.84 at hsst3 and hsst5 receptors respectively, whereas
      neither agonism nor antagonism could be shown (at 1 microM) at sst2 or sst4
      receptors. The effect at sst5 receptors was not surmountable and needs further
      investigations. The so-called "antagonist" SA, was devoid of antagonist activity
      at sst2 or sst3 receptors, whereas it was almost a full agonist at sst4 and sst5
      receptor-mediated [35S]GTPgammaS binding. The [35S]GTPgammaS-binding profiles of
      hsst2-5 receptors were compared with their respective radioligand binding
      profiles. For sst4 and sst5 receptors, the rank order of affinity of all tested
      radioligands correlated highly significantly with [35S]GTPgammaS binding (r =
      0.814-0.897). At sst3 receptors, [35S]GTPgammaS binding correlated somewhat less
      with binding profiles obtained with [125I][Tyr10]CST14 and [125I]CGP 23996 than
      with [125I]LTT-SRIF28 (r = 0.743, 0.757 and 0.882, respectively). At sst2
      receptors, [35S]GTPgammaS binding correlated with [125I]LTT-SRIF28, [125I]CGP
      23996 and [125I][Tyr3]octreotide binding profiles (r = 0.596-0.699), but not with
      [125I][Tyr10]CST14 binding. The present [35S]GTPgammaS binding data combined to
      previous radioligand binding results obtained in cells expressing human SRIF
      receptors, suggest that at any given receptor, agonists' rank orders of potency
      (not to mention absolute affinity values which vary profoundly) are not as
      strictly ordered as may be anticipated. We are investigating these aspects
      further by analysing additional signalling pathways.

PMID- 10598790
TI  - Characterisation of human recombinant somatostatin receptors. 3. Modulation of
      adenylate cyclase activity.
AB  - The five human somatostatin receptor subtypes (hsst1-5) were stably expressed in
      CCL39 cells (Chinese hamster lung fibroblast cells) to study the inhibition of
      forskolin-stimulated adenylate cyclase (FSAC) activity induced by somatostatin
      (somatotropin release inhibiting factor, SRIF), cortistatin (CST) and SRIF
      peptide analogues. Inhibition of FSAC was observed with all five receptors,
      although the maximal effects produced by SRIF14 varied from around 40% (sst1,
      sst2, sst4) to 67% (sst3, sst5) reflecting to some extent differences in receptor
      density (Bmax values published in accompanying paper, this journal). SRIF28 was
      slightly more potent than SRIF14 to inhibit FSAC at all five receptors, although
      the potency of the natural peptides SRIF14, SRIF28 and CST17 was generally
      similar with pEC50-values ranging from 7.5 to 8.7 depending on receptor and
      peptide. At SRIF1 receptors (sst2, sst3, sst5) most of the peptide analogues
      displayed full agonism (with some exceptions e.g. BIM 23056 at sst1-3 and sst5
      receptors, and L362,855 and cycloantagonist SA at sst3 receptors), whereas at
      SRIF2 receptors these analogues tended to behave as partial agonists. BIM 23056
      was an antagonist at sst3 receptors (antagonist binding constant pKB = 6.33), but
      not at other receptors. The AC inhibition profiles of sst1-5 receptors were
      compared with the different radioligand binding profiles as well as with
      [35S]guanosine 5'-O-(3-thiotriphosphate) ([35S]GTPgammaS) binding profile for
      sst2-5 receptors. High correlations were observed between FSAC inhibition,
      radioligand binding and [35S]GTPgammaS binding profiles at sst3, sst4 and sst5
      receptors; by contrast, correlation coefficients at sst1 and sst2 receptors were
      low, and the binding profiles of [125I][Tyr10]CST14 correlated poorly. In line
      with these findings, the FSAC inhibition and [35S]GTPgammaS binding correlated
      poorly at sst2 receptors (sst1 receptors show no significant induction of
      [35S]GTPgammaS binding). The apparent lack of, or only weak, relationship between
      FSAC, radioligand or [35S]GTPgammaS binding observed for some SRIF receptors
      suggests that different active states may exist for these receptors, which may
      favour one transduction cascade over others.

PMID- 10598791
TI  - Characterisation of human recombinant somatostatin receptors. 4. Modulation of
      phospholipase C activity.
AB  - Total [3H]phosphoinositide (IPx) accumulation, a measure of phospholipase C (PLC)
      activity, induced by somatostatin (somatotropin release-inhibiting factor, SRIF)
      and cortistatin (CST) analogues was studied at human somatostatin receptor
      subtypes 1-5 (hsst1-5) recombinantly expressed in CCL39 (Chinese hamster lung
      fibroblast) cells. SRIF14 (10 microM) stimulated total [3H]-IPx production 200%
      and 1070% over basal levels, and increased intracellular Ca2+ ([Ca2+]i) 1600% and
      2790%, in cells expressing hsst3 and hsst5 receptors, respectively. The SRIF14
      stimulated IPx production was partly blocked by 100 ng/ml pertussis toxin (PTX)
      (30% and 15% inhibition, respectively). At hsst1, hsst2, and hsst4 receptors,
      only weak or no stimulation of PLC activity was found (Emax = 114%, 122%, and
      102%, respectively). Consequently, hsst3 and hsst5 receptors were subjected to
      more detailed studies to establish pharmacological profiles of PLC stimulation.
      At hsst3 receptors, the relative efficacies of most ligands were in the same
      range (maximum response Emax = 218-267%). At hsst5 receptors Emax varied over a
      broad range, seglitide, CST17, SRIF28 displaying almost full agonism compared to
      SRIF14, whereas octreotide and BIM 23052 showed very low partial agonism. BIM
      23056 behaved as an antagonist on SRIF14-induced total [3H]-IPx accumulation with
      a pKB (negative logarithm of antagonist binding constant) of 6.74 at hsst3
      receptors, and of 6.94 at hsst5 receptors. The putative cycloantagonist SA showed
      weak antagonist activity on SRIF14-induced total [3H]-IPx levels at hsst3 (pKB =
      5.85), but not at hsst5 receptors. The [3H]-IPx accumulation profiles at
      sst3/sst5 receptors were compared to their respective radioligand binding
      ([125I]LTT-SRIF28, [125I][Tyr10]CST14, [125I]CGP 23996, [125I][Tyr3]octreotide
      binding), to [35S]GTPgammaS binding, and to forskolin-stimulated adenylate
      cyclase (FSAC) inhibition profiles determined previously in CCL39 cells. The
      different affinity profiles correlated relatively well at both receptor subtypes
      with PLC activation (sst3: r = 0.90-0.97; sst5: r = 0.80-0.87). However,
      [35S]GTPgammaS binding correlated only minimally with stimulation of [3H]-IPx
      levels at sst5 receptors (r = 0.59), but rather well at sst3 receptors (r =
      0.80). A moderate correlation was also observed between inhibition of FSAC
      activity and stimulation of PLC activity for hsst3 and hsst5 receptors with
      correlation coefficients of 0.85 and 0.70, respectively. In summary, most SRIF
      analogues behave as full agonists at hsst3 receptors and agonist-induced
      phosphoinositide turnover correlates well with radioligand binding,
      [35S]GTPgammaS binding and inhibition of adenylate cyclase activity, all measured
      in CCL39 cells. By contrast, at hsst5 receptors, most SRIF analogues behave as
      intermediate or very low partial agonists (although receptor levels are
      comparatively high, 7000 vs. 400 fmol/mg), and the agonist-induced
      phosphoinositide turnover correlates rather poorly with radioligand binding,
      [35S]GTPgammaS binding or inhibition of adenylate cyclase activity, all measured
      in the same cell line. Agonist-induced phosphoinositide turnover, [35S]GTPgammaS
      binding and inhibition of adenylate cyclase activity, show differences both in
      the rank orders of potency and relative efficacy at hsst3 and markedly at hsst5
      receptors, suggesting either that PLC activity is functionally irrelevant or,
      more probably, that agonist-dependent receptor trafficking is taking place in
      CCL39 cells.

PMID- 10598792
TI  - Characterisation of alpha1B-adrenoceptors linked to inositol phosphate formation
      and calcium mobilisation in human astrocytoma U373 MG cells.
AB  - The human U373 MG astrocytoma cell line has been widely used as a model system
      for the investigation of astrocyte function. The aim of this study was to
      establish which alpha1-adrenoceptors are present on these cells. The specific
      binding of [3H]prazosin to membranes of U373 MG cells (Bmax 32+/-3 fmol mg(-1)
      protein, Kd 0.27+/-0.03 nM) was inhibited in a monophasic manner by alpha1
      antagonists that have different affinities for alpha1A-, alpha1B- and alpha1D
      adrenoceptors. Estimates for pKi values were: prazosin 9.69+/-0.06, 5
      methylurapidil 7.10+/-0.21; (+)-niguldipine 7.06+/-0.26; WB 4101 8.26+/-0.16; and
      BMY 7378 6.60+/-0.21. The specific binding of [3H]prazosin was reduced to low
      levels by pretreatment of cells with 10 microM chloroethylclonidine for 15 min.
      In the presence of 30 mM LiCl, 100 microM noradrenaline stimulated [3H]inositol
      phosphate accumulation by 2.1+/-0.1-fold of basal after 30-min incubation. The
      EC50 for the accumulation of [3H]IP1, the major product detected (85+/-2% of
      total [3H]IP1 + [3H]IP2 + [3H]IP3), was 0.38+/-0.05 microM. Noradrenaline-induced
      [3H]IP1 accumulation was also inhibited by alpha1-antagonists. Estimates for pKi
      values were: 5-methylurapidil 6.95+/-0.01; WB 4101 8.31+/-0.07; and BMY 7378
      6.71+/-0.28. The accumulation of [3H]IP1 in response to 100 microM noradrenaline
      was not significantly affected by raising the extracellular Ca2+ concentration
      from 1.3 to 4 mM. Noradrenaline (100 microM) also produced an increase in
      intracellular Ca2+ (mean peak 86+/-5 nM above basal). Pretreatment with
      chloroethylclonidine (10 microM, 15 min) abolished noradrenaline-induced [3H]IP1
      accumulation and Ca2+ mobilisation. Activation of the alpha1B-adrenoceptors by 10
      microM phenylephrine increased [3H]thymidine uptake to 140+/-5% of control
      uptake. Taken together, these results indicate that U373 MG cells express a
      single class of alpha1-adrenoceptors, the alpha1B-subtype, which are coupled to
      phosphoinositide hydrolysis and calcium mobilisation, and which mediate a
      mitogenic response to alpha1-agonists.

PMID- 10598793
TI  - Occurrence, pharmacology and function of presynaptic alpha2-autoreceptors in
      alpha2A/D-adrenoceptor-deficient mice.
AB  - The occurrence, pharmacological properties and function of alpha2-autoreceptors
      were studied in hippocampal slices, occipito-parietal cortex slices, segments of
      heart atria and segments of the vas deferens of wildtype (WT) mice and mice in
      which the alpha2 A/D-adrenoceptor gene had been disrupted (alpha2 A/D(KO)).
      Tissues were preincubated with [3H]-noradrenaline and then superfused and
      stimulated electrically. Stimulation periods for brain slices consisted either of
      1 pulse or of 2-64 pulses delivered at 1-s intervals; stimulation periods for
      peripheral tissues consisted either of 1 POP (pseudo-one-pulse; brief burst of 20
      pulses/50 Hz) or of 2-4 POPs delivered at 1-s intervals. Single pulses or POPs
      were used to study the effect of medetomidine and its interaction with
      antagonists. One or more pulses or POPs per stimulation period were used to study
      alpha2-autoinhibition. Medetomidine decreased the evoked overflow of tritium in
      WT tissues. In alpha2 A/D(KO) tissues, the inhibition was slightly (peripheral
      tissues) or greatly (brain slices) attenuated but not abolished. Phentolamine,
      rauwolscine, spiroxatrine, 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4
      benzodioxane (WB 4101), tolazoline and prazosin antagonized the effect of
      medetomidine in all tissues. Their pKd values against medetomidine were compared
      with pKd values at prototypical alpha2 binding sites by means of a correlation
      analysis. For WT brain and atrial autoreceptors, the correlations indicated an
      alpha2D pharmacology, whereas for WT vas deferens autoreceptors they favoured an
      alpha2B pharmacology. In the KO tissues, any correlation with alpha2D was lost,
      and the non-alpha2 A/D-autoreceptors displayed alpha2B or alpha2C pharmacology.
      When 2 or more pulses or POPs were applied to WT tissues per stimulation period,
      the pulse number-overflow curve (POP number-overflow curve) was flat, indicating
      that overflow elicited by p pulses (POPs) was much smaller than p times the
      overflow elicited by a single pulse (POP); moreover, rauwolscine caused a pulse
      (POP) number-dependent and, at high pulse (POP) numbers, large increase in evoked
      tritium overflow. In alpha2 A/D(KO) tissues, the pulse (POP) number-overflow
      curve was much steeper, indicating that overflow elicited by p pulses (POPs) was
      closer to p times the overflow elicited by a single pulse (POP); moreover,
      rauwolscine caused no (atria) or only a small increase in overflow, and did so in
      brain slices only at high pulse numbers (16 and 64). In conclusion, the
      predominant alpha2D pharmacology of the autoreceptors in WT tissues supports the
      idea that the main mammalian presynaptic alpha2-autoreceptors belong to the
      alpha2 A/D subtype. However, alpha2 A/D-deficient animals also possess
      autoreceptors. As expected, these non-alpha2 A/D-autoreceptors display alpha2B or
      alpha2C pharmacology. In WT animals, alpha2B- or alpha2C-autoreceptors or both
      may coexist with alpha2 A/D-autoreceptors, at least in peripheral tissues. Little
      autoinhibition by released noradrenaline in trains of pulses remains when the
      alpha2 A/D-adrenoceptor is lacking, again in accord with a predominance of alpha2
      A/D-autoreceptors.

PMID- 10598794
TI  - Histaminergic neurons modulate acetylcholine release in the ventral striatum:
      role of H1 and H2 histamine receptors.
AB  - To investigate whether H1 and H2 histamine receptors are implicated in the
      modulation of acetylcholine release by endogenous histamine, the ventral striatum
      of the conscious, freely moving rat was superfused by the push-pull superfusion
      technique with drugs and the release of acetylcholine was determined in the
      superfusate. Superfusion with the H1 receptor agonist 2-thiazolylethylamine (TEA,
      50 micromol/l) enhanced the release of acetylcholine, while the H1 receptor
      antagonist triprolidine (50 micromol/l) reduced acetylcholine outflow and
      abolished the TEA-evoked release of the neurotransmitter. The inhibitory effect
      of triprolidine was not influenced either on simultaneous superfusion with 10
      micromol/l (+/-)-7-bromo-1-(fluoresceinylthioureido)phenyl-8-hydroxy-3-methyl 
      2,3,4,5-tetrahydro-1H-benzazepine (SKF-83566, D1 dopamine receptor antagonist)
      and 50 micromol/l quinpirole (D2/D3 dopamine receptor agonist) or on superfusion
      with the GABAA receptor antagonist bicuculline (50 micromol/l). The H2 receptor
      antagonists ranitidine or famotidine (50 micromol/l each) greatly enhanced
      acetylcholine release rate in the ventral striatum. Presuperfusion with alpha
      fluoromethylhistidine (FMH, 1 mmol/l), which inhibits neuronal synthesis of
      histamine, abolished the famotidine-induced release of acetylcholine. The
      releasing effect of famotidine was also abolished on simultaneous superfusion
      with 10 micromol/l SKF-83566 and 50 micromol/l quinpirole. The release of
      acetylcholine elicited by famotidine was reversed to a decreased acetylcholine
      outflow when the striatum was superfused with the GABA(A) receptor antagonist
      bicuculline (50 micromol/l) prior to famotidine. Superfusion with the H2 receptor
      agonist impromidine (1 micromol/l) decreased acetylcholine outflow, while the H2
      agonist dimaprit (50 micromol/l) exerted the opposite effect. The releasing
      effect of dimaprit was not influenced by FMH (1 mmol/l), but it was abolished in
      the presence of SKF-83566 (10 micromol/l) and quinpirole (50 micromol/l). In the
      presence of bicuculline the release of acetylcholine by dimaprit was enhanced and
      prolonged. It seems possible that dimaprit and impromidine stimulate different
      subtypes of H2 receptors. The findings suggest that the release of acetylcholine
      in the striatum is modulated by neighbouring histaminergic neurons in a complex
      way. Stimulation of H1 histamine receptors, probably located on cholinergic
      neurons, enhances acetylcholine release. Stimulation by histamine of H2 receptors
      located on cholinergic or GABAergic neurons enhances the release of
      acetylcholine, while stimulation of H2 receptors located on dopaminergic neurons
      exerts the opposite effect.

PMID- 10598796
TI  - The benzodiazepine receptor partial agonist Ro 19-8022 suppresses generalized
      seizures without impairing motor functions in developing rats.
AB  - The action of a partial benzodiazepine receptor agonist Ro 19-8022 [(R)-1-[(10
      chloro-4-oxo-3-phenyl-4H-benzo[a]quinolizin-1-yl)carbo nyl] -2-pyrrolidine
      methanol] in doses from 0.01 to 150 mg/kg was studied using motor seizures
      induced by pentylenetetrazol (PTZ) in rats 7, 12, 18, 25 and 90 days old.
      Generalized tonic-clonic seizures were suppressed in all age groups, the three
      youngest groups being more sensitive than older animals. The highest dose of Ro
      19-8022 did not exhibit anticonvulsant action in the 25-day-old rats. The other
      types of seizures (minimal clonic) induced by PTZ were suppressed by Ro 19-8022
      only in 18-day-old and older rats in which PTZ reliably elicited these types of
      seizures. The doses of 50, 100 and 150 mg/kg were ineffective against minimal
      seizures. On the contrary, incidence of minimal seizures was significantly
      increased by Ro 19-8022 in 7-and 12-day-old rat pups. Motor performance of rat
      pups was not compromised by Ro 19-8022 (0.5 and 50 mg/kg) in contrast to the full
      agonist midazolam (1 and/or 2 mg/kg). The duration of anticonvulsant effects
      studied with a dose of 0.5 mg/kg was longer in 12-day-old than in adult rats.
      This dose of Ro 19-8022 resulted in a rebound proconvulsant effect 24 and 48 h
      after the administration in 12-day-old rats only. Ro 19-8022 exhibited an
      excellent anticonvulsant action especially against generalized tonic-clonic
      seizures; this action was lost with very high doses. It did not compromise the
      motor system, but in some tests motivation was probably lost.

PMID- 10598795
TI  - Histaminergic neurons modulate acetylcholine release in the ventral striatum:
      role of H3 histamine receptors.
AB  - To investigate whether histaminergic neurons influence the activity of
      cholinergic neurons, the ventral striatum was superfused through a push-pull
      cannula and the release of endogenous acetylcholine was determined in the
      superfusate. Local inhibition of histamine synthesis by superfusion with alpha
      fluoromethylhistidine (FMH) gradually decreased the release rate of
      acetylcholine. Superfusion with histamine increased the release of acetylcholine.
      The releasing effect of histamine was greatly inhibited when the striatum was
      simultaneously superfused with the D2/D3 agonist quinpirole and the D1 antagonist
      (+/-)-7-bromo-1-(fluoresceinylthioureido)phenyl-8-hydroxy-3-methyl -2,3,4,5
      tetrahydro-1H-3-benzapine (SKF 83566). The effect of histamine on acetylcholine
      release was abolished by the GABA(A) receptor antagonist bicuculline. Superfusion
      with the H3 receptor agonists imetit or immepip increased acetylcholine release
      rate in the striatum. The releasing effects of the two H3 agonists were FMH
      resistant, while superfusion with quinpirole and SKF 83566 abolished the H3
      receptor agonist-induced acetylcholine release. Superfusion with the H3 receptor
      antagonist thioperamide enhanced acetylcholine release rate. The releasing effect
      of thioperamide was abolished after inhibition of histamine synthesis by FMH. The
      release of acetylcholine by thioperamide was also abolished on simultaneous
      superfusion with quinpirole and SKF 83566. The findings show that, in the
      striatum, the activity of cholinergic neurons is permanently modulated by
      neighbouring histaminergic nerve terminals and axons. The release of
      acetylcholine is also permanently inhibited by neighbouring GABAergic neurons.
      The enhanced release of acetylcholine by the H3 receptor agonists imetit and
      immepip is due to stimulation of H3 heteroreceptors, while the increase of
      acetylcholine release by the H3 receptor antagonist thioperamide is elicited via
      blockade of H3 autoreceptors. Histamine released from histaminergic nerve
      terminals increases the release of acetylcholine in part by inhibition of
      dopamine release which, in turn, decreases GABAergic transmission. A dopamine
      independent way seems also to be involved in the histamine-evoked acetylcholine
      release.

PMID- 10598797
TI  - Influence of a Na+-H+ exchange inhibitor ethylisopropylamiloride, a Na+-Ca2+
      exchange inhibitor KB-R7943 and their combination on the increases in
      contractility and Ca2+ transient induced by angiotensin II in isolated adult
      rabbit ventricular myocytes.
AB  - In rabbit, ventricular myocytes loaded with indo-1/AM, angiotensin II (0.1 nM-0.1
      microM) exerted a positive inotropic effect with a significant increase in the
      amplitude of Ca2+ transients. For a given increase in cell shortening, the
      increase in Ca2+ transients induced by angiotensin II was less than that induced
      by elevation of extracellular Ca2+ concentration ([Ca2+]0) or isoprenaline, an
      indication that both the increase in mobilization of intracellular Ca2+ ions and
      myofibrillar sensitivity to Ca2+ ions contribute to the positive inotropic effect
      of angiotensin II. The effects of angiotensin II on Ca2+ transients and cell
      shortening were inhibited by the AT1 receptor antagonist losartan. A Na+ -H+
      exchange inhibitor EIPA [5-(N-ethyl-N-isopropyl)amiloride] at 1 and 3 microM did
      not affect the Ca2+ transients and cell shortening, but it inhibited the
      angiotensin-II-induced responses in a concentration-dependent manner more
      effectively than the responses to elevation of [Ca2+]0, indicating that EIPA
      elicited a selective inhibitory action on the effects of angiotensin II. The
      observation that EIPA at 10 microM abolished the positive inotropic effect of
      angiotensin II without a significant depression of the inotropic response to
      elevation of [Ca2+]0 supports the selective action of EIPA at the high
      concentration on the response to angiotensin II. A novel selective Na+ -Ca2+
      exchange (reverse mode) inhibitor KB-R7943, 2-[2-[4-(
      nitrobenzyloxy)phenyl]ethyl] isothiourea methanesulphonate, at 0.3 and 1 microM
      inhibited also the responses to angiotensin II more effectively than the response
      to elevation of [Ca2+]0; however, over the same concentration range it suppressed
      significantly the amplitude of Ca2+ transients and cell shortening. Combination
      of EIPA (3 microM) and KB-R7943 (0.3 microM), each of which attenuated partially
      the angiotensin-II-induced responses, abolished the positive inotropic effect and
      the increase in Ca2+ transients induced by angiotensin II with much less
      depressant effect on the responses to elevation of [Ca2+]0. Thus, these ion
      exchange inhibitors exerted selective actions on the respective targets. The
      results with these selective inhibitors indicate that the activation of Na+ -H+
      exchanger and subsequent modulation of the activity of Na+ -Ca2+ exchanger may be
      responsible for the increase in [Ca2+]i and the myofilament Ca2+ sensitization
      induced by stimulation of AT1 receptors by angiotensin II in rabbit ventricular
      myocytes.

PMID- 10598798
TI  - Cardiac profile of EGIS-9377, a novel cardiotonic agent as a Ca2+ sensitizer with
      bradycardiac activity.
AB  - The cardiac profile of EGIS-9377 ?2-(1-methylthio)-5-(2-morpholinoethylamino)-8,9
      dihydro-7H-thi opyrano[3,2-d][1,2,4]triazolo[1,5-a]pyrimidine dihydrochloride?, a
      newly synthesized cardiotonic agent, was compared with those of pimobendan and
      isoprenaline in cardiac preparations isolated from guinea pigs. The positive
      inotropic potency and efficacy of EGIS-9377 were equal to those of pimobendan in
      electrically paced papillary muscles, with each agent maximally increasing force
      of contraction by 30-35% of the maximum effect of isoprenaline. The positive
      inotropic effects of EGIS-9377 and pimobendan were accompanied by an increase in
      the relaxation time of the isometric contraction curve, whereas that of
      isoprenaline was associated with an abbreviation of this parameter. Pimobendan
      significantly increased the spontaneously beating frequency of right atria, and
      its positive chronotropic effect amounted to 40% of the maximum effect of
      isoprenaline. In contrast, EGIS-9377 exerted a significant negative chronotropic
      action, which resulted in a 30% decrease in the basal frequency. In beta-escin
      skinned trabecular muscles, both EGIS-9377 and pimobendan substantially enhanced
      contractions induced by Ca2+. EGIS-9377 at concentrations to cause a significant
      negative chronotropic action produced a marked prolongation of action potential
      duration (APD) in guinea pig papillary muscle and greatly inhibited the delayed
      rectifier potassium current (I(K)) in guinea pig ventricular single cells. This
      suggests that the negative chronotropic effect of EGIS-9377 may, at least in
      part, be due to the prolongation of APD as a result of the I(K) inhibition. The
      present results indicate that EGIS-9377 efficiently increases myocardial
      contractile force possibly due to its Ca2+ -sensitizing activity, and yet
      produces a substantial negative chronotropic action. This cardiac profile of EGIS
      9377 is suggested to be a clinically favorable feature compared with the
      inotropic agents having cyclic AMP generation or phosphodiesterase inhibition as
      their action mechanisms.

PMID- 10598799
TI  - Bovine isolated middle cerebral artery contractions to antimigraine drugs.
AB  - Ergot alkaloids, sumatriptan and the newer 5-HT1B/1D receptor agonists all
      contract cranial blood vessels and this effect seems to be primarily responsible
      for their efficacy in migraine. We have compared the contractile effects of a
      number of ergot and triptan derivatives on the bovine isolated middle cerebral
      artery and characterised the 5-hydroxytryptamine (5-HT) receptors involved by
      using 5-HT2A (ketanserin: 10, 30, 100 nM) and 5-HT1B/1D (GR127935: 30, 100, 300
      nM) receptor antagonists. The rank order of agonist potency (pD2) was ergotamine
      (8.0+/-0.1) approximately dihydroergotamine (8.0+/-0.1) > avitriptan (7.4+/-0.3)
      >5-HT (7.0+/-0.1) > naratriptan (6.8+/-0.1) > methylergometrine (major metabolite
      of methysergide; 6.5+/-0.2) > rizatriptan (6.3+/-0.3) approximately zolmitriptan
      (6.2+/-0.1) approximately sumatriptan (6.0+/-0.2) approximately methysergide
      (5.9+/-0.3). The rank order of efficacy (Emax expressed as % of contraction to
      100 mM K+) was 5-HT (127+/-11) > sumatriptan (56+/-5) > ergotamine (48+/-5)
      approximately dihydroergotamine (44+/-8) approximately methyl-ergometrine (44+/
      7) > avitriptan (37+/-7) approximately rizatriptan (33+/-5) approximately
      methysergide (29+/-10) approximately zolmitriptan (28+/-3) approximately
      naratriptan (23+/-2). The concentration-response curve to 5-HT appeared to be
      biphasic in the presence of 100 nM ketanserin, which hardly affected sumatriptan
      induced contractions, but clearly antagonised the second more efficacious phase
      of the curve to 5-HT. On the other hand, GR127935 caused a rightward shift of the
      concentration-response curves to 5-HT (in the presence of 10 microM ketanserin)
      and sumatriptan with pA2 values of 7.0 and 8.1, respectively. In conclusion, all
      acutely acting antimigraine drugs contract the bovine isolated middle cerebral
      artery. Whereas sumatriptan contracts the artery via the 5-HT1B/1D receptor, the
      5-HT-induced contraction is mediated partly by the 5-HT2A receptor and partly by
      another, possibly novel receptor differing from the 5-HT1B/1D receptor. This
      receptor may be a target for the development of future antimigraine drugs.

PMID- 10598800
TI  - Mediators in hyperpnea-induced bronchoconstriction of guinea pigs.
AB  - Both tachykinins and leukotrienes (LTs) have been demonstrated to be the
      mediators for hyperpnea-induced bronchoconstriction (HIB) of guinea pigs. We
      tested the hypothesis that leukotrienes modulate HIB indirectly by triggering
      tachykinin release. Ninety nine young guinea pigs were divided into four groups:
      control; LTC4; FPL 55712 (a LT receptor antagonist); and MK-886 (an inhibitor of
      LT synthesis). Each animal was anesthetized, cannulated, paralyzed, and
      artificially ventilated. The protocol included the baseline, hyperpnea, and
      recovery periods. Thus, animals in each group were further divided into three
      subgroups: baseline; recovery-3 min; and recovery-8 min. We measured dynamic
      respiratory compliance (Crs), forced expiratory volume in 0.1 s (FEV0.1) and
      maximal expiratory flow at 30% total lung capacity (Vmax30), as well as
      determined substance P (SP) and LT levels in plasma and bronchoalveolar lavage
      (BAL) during either the baseline or the recovery (3 or 8 min) period. Hyperpnea
      caused decreases in Crs, FEV0.1 and Vmax30, indicating HIB, in the control group
      at 3 min and 8 min of the recovery period. Both FPL 55712 and MK-886
      significantly attenuated HIB. In the control group, hyperpnea caused significant
      increases in SP and LT levels in both plasma and BAL. These increases in SP
      levels were significantly suppressed, however, by FPL 55712 and MK-886. Compared
      to the control group, infusion of LTC4 did not significantly alter either HIB, SP
      or LT levels in most cases. An additional group of 24 animals treated with
      neurokinin-2 receptor antagonist, SR 48968, demonstrated that SR 48968
      significantly suppressed hyperpnea-induced increases in plasma, but not in BAL,
      LT levels. Since FPL 55712 and MK-886 first suppress LT activities, these results
      suggest that suppressed LT activities attenuate HIB indirectly via reducing
      tachykinin release.

PMID- 10598801
TI  - Mapping of a gene for May-Hegglin anomaly to chromosome 22q.
AB  - May-Hegglin anomaly (MHA) is a rare autosomal dominant platelet disorder
      characterized by the triad of giant platelets, thrombocytopenia and leukocyte
      inclusions. Both the molecular and the genetic defects responsible for this
      disorder remain unknown. In order to map the gene responsible for MHA, we
      performed a genome-wide linkage study using highly polymorphic short tandem
      repeat markers in a single Japanese MHA family. Significant linkage was obtained
      for the markers on the long arm of chromosome 22 (22q12.3-q13.2), with a maximum
      two-point lod score of 4.52 at a recombination fraction of 0.00 for the markers
      D22S1142 and D22S277. Haplotype analysis mapped a critical region for the disease
      locus to a 13.6-centimorgan region, between D22S280 and D22S272. The relative
      proximity of the platelet GPIbbeta gene (22q11.2) to this region, as well as its
      involvement in an isolated giant platelet disorder, suggested a possible
      involvement of GPIbbeta mutations in MHA. However, DNA-sequencing analysis in two
      patients revealed no abnormality in the sequence of the GPIbbeta gene. This is
      the first report of linkage for MHA, and further analysis of this locus may lead
      to the identification of a gene the product of which regulates platelet and
      leukocyte morphology.

PMID- 10598802
TI  - Investigation of a cryptic interstitial duplication involving the Prader
      Willi/Angelman syndrome critical region.
AB  - A 3-year-old female referred with developmental delay, hypotonia and seizures was
      found to have a cryptic interstitial duplication of the Prader-Willi/Angelman
      critical region (PWACR). Her clinical features form part of a common phenotype
      characteristic of PWACR duplications including developmental delay, behavioural
      problems and speech difficulties. Microsatellite analysis showed that the
      duplication had arisen de novo, was maternal in origin and involved the entire 4
      Mb PWACR between the common deletion breakpoints. The existence of cryptic
      rearrangements emphasises the need for molecular tests alongside conventional
      cytogenetics when investigating abnormalities involving this imprinted region.

PMID- 10598803
TI  - The identical 5' splice-site acceptor mutation in five attenuated APC families
      from Newfoundland demonstrates a founder effect.
AB  - Inherited mutations of the APC gene predispose carriers to multiple adenomatous
      polyps of the colon and rectum and to colorectal cancer. Mutations located at the
      extreme 5' end of the APC gene, however, are associated with a less severe
      disease known as attenuated adenomatous polyposis coli (AAPC). Many individuals
      with AAPC develop relatively few colorectal polyps but are still at high risk for
      colorectal cancer. We report here the identification of a 5' APC germline
      mutation in five separately ascertained AAPC families from Newfoundland, Canada.
      This disease-causing mutation is a single basepair change (G to A) in the splice
      acceptor region of APC intron 3 that creates a mutant RNA without exon 4 of APC.
      The observation of the same APC mutation in five families from the same
      geographic area demonstrates a founder effect. Furthermore, the identification of
      this germline mutation strengthens the correlation between the 5' location of an
      APC disease-causing mutation and the attenuated polyposis phenotype.

PMID- 10598805
TI  - Genomic organisation of the spinocerebellar ataxia type 7 (SCA7) gene responsible
      for autosomal dominant cerebellar ataxia with retinal degeneration.
AB  - Autosomal dominant cerebellar ataxia with retinal degeneration (ADCA type II) is
      a progressive neurodegenerative disorder caused by a CAG expansion in the
      spinocerebellar ataxia 7 (SCA7) gene. Here, we describe the genomic organisation
      of the human SCA7 gene. The exon-intron boundaries were identified by sequencing
      plasmid subclones of a P1 artificial chromosome (PAC) clone containing the entire
      SCA7 gene. We found 13 exons, ranging in size from 69 to 979 bp, with all exon
      intron boundaries following the GT-AG rule. The ATG initiation codon at position
      554 of the cDNA occurs in exon 3 at position 12 and the coding region extends to
      the first five codons of exon 13, with the CAG repeat being located in exon 3
      starting at codon 30. The intron sizes were determined by long-distance
      polymerase chain reaction with primers from neighbouring exons and by restriction
      mapping of the SCA7 PAC clone. The introns varied in size from 233 bp to about 40
      kb, resulting in an overall size estimate for the SCA7 gene of 140 kb. Sequence
      analysis of intron 7 (491 bp) revealed a polymorphic GT/AC repeat, a useful
      intragenic marker for SCA7 in segregation studies.

PMID- 10598806
TI  - Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12.2
      13.1.
AB  - Allelic association methods are better suited than linkage analysis for mapping
      of susceptibility genes that confer modest increases in risk in complex diseases.
      In both family- and population-based association studies, it is very useful to
      have prior knowledge of all sequence variants and the degree of linkage
      disequilibrium in a candidate gene region. In this study, we scanned sequence
      variants in a 2.2-kb promoter sequence and all 13 exons (totalling 3.3 kb) of the
      matrix metalloproteinase-9 gene, which is associated with coronary heart disease
      and a candidate for other diseases involving connective tissue remodelling, such
      as cancer metastasis. The sequences had a total of ten variable sites, four in
      the promoter, five in the coding region (three of which alter the amino acid
      encoded) and one in the 3' untranslated sequence. Sequence inspection suggests
      that some of the variants will have a functional impact on either level of
      expression or enzymatic activity. Tight linkage disequilibrium was detected
      between variants across the entire length of the gene (approximately 9 kb), and
      frequencies of different haplotypes were determined. The data provide an
      essential tool for studies of the possible contribution of genetic variation at
      the matrix metalloproteinase-9 locus to genetically determined susceptibility to
      a number of important diseases. The results also provide experimental data on the
      extent of linkage disequilibrium in the general population, which is yet to be
      resolved.

PMID- 10598804
TI  - A testis-specific gene, TPTE, encodes a putative transmembrane tyrosine
      phosphatase and maps to the pericentromeric region of human chromosomes 21 and
      13, and to chromosomes 15, 22, and Y.
AB  - To contribute to the creation of a transcription map of human chromosome 21
      (HC21) and to the identification of genes that may be involved in the
      pathogenesis of Down syndrome, exon trapping was performed from HC21-specific
      cosmids covering the entire chromosome. More than 700 exons have been identified
      to date. One such exon, hmc01a06, maps to YAC 831B6 which contains marker D21Z1
      (alphoid repeats) and had previously been localized to the pericentromeric region
      of HC21. Northern-blot analysis revealed a 2.5-kb mRNA species strongly and
      exclusively expressed in the testis. We cloned the corresponding full-length
      cDNA, which encodes a predicted polypeptide of 551 amino acids with at least two
      potential transmembrane domains and a tyrosine phosphatase motif. The cDNA has
      sequence homology to chicken tensin, bovine auxilin and rat cyclin-G associated
      kinase (GAK). The entire polypeptide sequence also has significant homology to
      tumor suppressor PTEN/MMAC1 protein. We termed this novel gene/protein TPTE
      (transmembrane phosphatase with tensin homology). Polymerase chain reaction
      amplification, fluorescent in situ hybridization, Southern-blot and sequence
      analysis using monochromosomal somatic cell hybrids showed that this gene has
      highly homologous copies on HC13, 15, 22, and Y, in addition to its HC21 copy or
      copies. The estimated minimum number of copies of the TPTE gene in the haploid
      human genome is 7 in male and 6 in female. Zoo-blot analysis showed that TPTE is
      conserved between humans and other species. The biological function of the TPTE
      gene is presently unknown; however, its expression pattern, sequence homologies,
      and the presence of a potential tyrosine phosphatase domain suggest that it may
      be involved in signal transduction pathways of the endocrine or spermatogenetic
      function of the testis. It is also unknown whether all copies of TPTE are
      functional or whether some are pseudogenes. TPTE is, to our knowledge, the gene
      located closest to the human centromeric sequences.

PMID- 10598807
TI  - Haplosufficiency of the melancortin-4 receptor gene in individuals with deletions
      of 18q.
AB  - The melanocortin-4 receptor (MC4R) is a seven, transmembrane G-protein-coupled
      receptor whose ligand, alpha-melanocyte-stimulating hormone (alpha-MSH), is a
      post-translational derivative of pro-opiomelanocortin (POMC). The regulatory
      pathway, of which MC4R is a part, has become an area of intense interest because
      of its potential role in obesity. Three studies have identified individuals with
      dominantly inherited obesity segregating with mutations in the MC4R gene. It has
      been hypothesized that the mutation found in these subjects resulted in a loss of
      gene function resulting in obesity due to haploinsufficiency of the MC4R gene. We
      have been studying the molecular basis of the phenotype of individuals with large
      deletions of chromosome 18q. Due to its location at 18q21.3, the MC4R gene is
      hemizygous in approximately one-third of the individuals in our study. If
      hemizygosity of the MC4R gene results in haploinsufficiency-induced obesity, then
      individuals with deletions of 18q whose deletions include the MC4R gene should be
      obese in comparison with those individuals whose deletion does not include the
      gene. Our data indicate no difference in obesity among those deleted and not
      deleted for the gene. This supports the hypothesis that the MC4R gene product is
      haplosufficient and the involvement of MC4R in obesity may reflect a dominant
      negative effect.

PMID- 10598808
TI  - Analysis of segregation and aneuploidy in two reciprocal translocation carriers,
      t(3;9)(q26.2;q32) and t(3;9)(p25;q32), by triple-color fluorescence in situ
      hybridization.
AB  - Meiotic segregation patterns of chromosomes 3 and 9 were analyzed in sperm of two
      translocation carriers (t(3;9)(q26.2;q32) and t(3;9)(p25;q32)) by triple-color
      fluorescent in situ hybridization (FISH) with a telomeric DNA probe in addition
      to two centromeric probes. The frequencies of each sperm product resulting from
      alternate or adjacent I, adjacent II and 3:1 segregation in a t(3;9)(q26.2;q32)
      translocation carrier were 88.35%, 5.44% and 5.94%, respectively. On the other
      hand, the frequencies of each sperm product in a t(3;9)(p25;q32) translocation
      carrier were 89.23%, 6.02% and 4.48%, respectively. Of all the sperm products,
      the frequency of normal or chromosomally balanced sperm in a t(3;9)(q26.2;q32)
      and a t(3;9)(p25;q32) were 52.49% and 47.25%, respectively. The frequencies of
      each sperm product resulting from various segregations were different between
      both carriers and significantly deviated from the expected frequencies.
      Additional dual-color and triple-color FISH were performed to analyze aneuploidy
      rates for chromosomes 12, 17, 18, X and Y in order to detect any interchromosomal
      effect; no evidence of an interchromosomal effect was found.

PMID- 10598809
TI  - Missense mutations in hMLH1 associated with colorectal cancer.
AB  - One of the most prevalent hereditary syndromes associated with colorectal cancer
      is hereditary nonpolyposis colorectal cancer (HNPCC). The inherited gene defects
      in HNPCC have been shown to reside in DNA mismatch repair genes, mostly hMSH2 or
      hMLH1. Most HNPCC patients are heterozygous with regard to the relevant mismatch
      repair gene; they have one normal and one mutated allele, and mismatch repair in
      normal somatic cells is functional. Cancer predisposition in HNPCC is believed to
      be associated with the loss of the wild-type allele in somatic cells, resulting
      in defective DNA mismatch repair. This gives rise to DNA microsatellite
      instability (MSI), an increased somatic mutation rate, and eventually, to the
      accumulation of mutations in genes involved in colorectal carcinogenesis. In
      support of this theory, colorectal tumors in HNPCC patients and in mice deficient
      for hMSH2 or hMLH1 show MSI. Here, we describe two missense mutations in hMLH1
      exon 16 associated with colorectal cancer. Interestingly, the tumors do not show
      MSI. This raises some potentially important issues. First, even microsatellite
      negative colorectal tumors can be associated with germline mutations and these
      will be missed if an MSI test is used to select patients for mutation screening.
      Second, the lack of MSI in these cases suggests that the mechanism involved in
      carcinogenesis could be different from that generally hypothesized.

PMID- 10598810
TI  - Absence of the deltaccr5 mutation in indigenous populations of the Brazilian
      Amazon.
AB  - Carriers of the deltaccr5 allele, which contains a deletion of 32 bases in
      relation to the normal allele of the beta-chemokine receptor gene (CCR5), have
      increased resistance to HIV-1 infection. The higher frequency of this mutation in
      Europeans than in Blacks and Asians, has generated interest in determining its
      distribution in other populations. The population of this study involved 300
      Amerindians from four Brazilian Amazon tribes (Tikuna, Baniwa, Kashinawa, and
      Kanamari). All of the individuals were homozygous for the normal allele, which
      corroborates the hypothesis that the deltaccr5 allele has a European origin, and
      that its occurrence in urban populations in South America is the result of
      immigration.

PMID- 10598811
TI  - Detection of DNA copy number changes in human endometriosis by comparative
      genomic hybridization.
AB  - Endometriosis is characterized by infertility and pelvic pain in 10-15% of women
      of reproductive age. The genetic events involved in endometriotic cell expansion
      remain in large part unknown. To identify genomic changes involved in development
      of this disease, we examined a panel of 18 selected endometriotic tissues by
      comparative genomic hybridization (CGH), a molecular cytogenetic method that
      allows screening of the entire genome for chromosomal gains and/or losses. The
      study was performed on native, nonamplified DNA extracted from manually dissected
      endometriotic lesions. Recurrent copy number losses on several chromosomes were
      detected in 15 of 18 cases. Loss of chromosome 1p and 22q were detected in 50% of
      the cases. Additional common losses occurred on chromosomes 5p (33%), 6q (27%),
      7p(22%), 9q (22%), 16 (22%) as well as on 17q in one case. Gain of DNA sequences
      were seen at 6q, 7q and 17q in three cases. To validate the CGH data, selective
      dual-color FISH was performed using probes for the deleted regions on chromosomes
      1, 7 and 22 in parallel with the corresponding centromeric probes. Cases showing
      deletion by CGH all had two signals at 1p36, 7p22.1 and 22q12 in less than 30% of
      the nuclei in comparison to the double centromeric labels found in more than 85%
      of the cells. These findings indicate that genes localized to previously
      undescribed chromosomal regions play a role in development and progression of
      endometriosis.

PMID- 10598812
TI  - Complex patterns of intragenic polymorphism at the PDGFA locus.
AB  - The human platelet-derived growth factor A chain gene (PDGFA) on chromosome 7p22
      encodes an important mitogen. Within PDGFA lies a complex minisatellite structure
      that results in partial duplications of exon 4 and the IVS4 splice donor site.
      Here, we show that the PDGFA genes of four ape species and an Old-World monkey
      all have similar complex minisatellites at this position. Comparison of their
      structures suggests evolutionary constraints resulting from the protein-coding
      function of the minisatellite. Nonetheless, the IVS4 minisatellite seems to have
      undergone independent expansion events in different primate lineages. Within the
      human IVS4 minisatellite, an embedded pentanucleotide repeat, based on the
      sequence (CCTCC)n, shows frequent subunit sequence variation but only rare length
      polymorphism. In contrast, within IVS3 of human PDGFA, we have discovered a
      second minisatellite which, unlike the IVS4 minisatellite, is highly polymorphic.
      The subunit sequences of these two minisatellites, which lie less than 0.5 kb
      apart, are non-identical, but share a CnT-rich core. Two new single nucleotide
      polymorphisms (SNPs), in exon 3 and IVS4, are in linkage disequilibrium, despite
      flanking the two minisatellite regions. Reverse transcription-polymerase chain
      reaction analysis of the exon 3 SNP in human foetal tissues demonstrated
      biallelic expression of PDGFA in all tissues examined. The unusual location of
      PDGFA exon 4 between two minisatellite sequences, together with its partial
      duplication, may have functional implications, particularly for the splicing of
      the gene. The high level of polymorphism demonstrated in this region will also be
      valuable for disease-association and linkage studies of the PDGFA locus.

PMID- 10598813
TI  - Autosomal recessive chronic granulomatous disease caused by novel mutations in
      NCF-2, the gene encoding the p67-phox component of phagocyte NADPH oxidase.
AB  - Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency disease
      that leads to severe recurrent infections. CGD is caused by defects in the
      phagocyte NADPH oxidase, a multiprotein enzyme that reduces oxygen to superoxide,
      a precursor of microbicidal oxidants. Less than 6% of CGD patients have an
      autosomal recessive form of the disease caused by mutations in NCF-2. This gene
      encodes p67-phox, a cytosolic oxidase subunit that associates with membrane-bound
      flavocytochrome b558 and regulates electron transfer. We studied six patients
      from five families with p67-phox deficiency and identified seven different mutant
      alleles. Patients from three of the kindreds were homozygous for their respective
      mutation, although the parents of only one family were known to be related. Five
      of the mutations have not previously been identified: (1) a missense mutation
      (383C-->T) in exon 5, (2) a nonsense mutation (196C-->T) in exon 3, (3) a
      missense mutation (230G-->A) in exon 3, (4) a nonsense mutation (298C-->T) in
      exon 4, and (5) a dinucleotide deletion (835-836 AC) from exon 9. Phagocytes from
      each of the patients analyzed failed to generate a measurable respiratory burst
      and had no detectable p67-phox protein. Our results further demonstrate that
      there is great heterogeneity among the mutations in p67-phox-deficient CGD
      patients, with no evidence for mutational hot-spots or a founder effect. Our data
      also support the hypothesis that the stability of p67-phox is particularly
      sensitive to missense mutations that cause amino acid substitutions within its N
      terminal domain. In contrast, mutations predicting single amino acid changes
      elsewhere in the protein generally represent benign polymorphisms.

PMID- 10598814
TI  - Mutational spectrum of phenylalanine hydroxylase deficiency in the population
      resident in Catalonia: genotype-phenotype correlation.
AB  - Hyperphenylalaninemia (HPA) is a group of diseases characterized by the
      persistent elevation of phenylalanine levels in tissues and biological fluids. It
      is an autosomal recessive disorder affecting 1 in 10,000 individuals in Caucasian
      populations and about 1 in 6,600 in Catalonia. We report the mutational spectrum
      of phenylalanine hydroxylase deficiency in the population living in Catalonia and
      the genotype-phenotype correlation. The molecular study was performed in 383
      samples corresponding to 115 patients from 99 unrelated families and 268
      relatives. We have characterized 90% of the mutant alleles; there were 57
      different mutations, 49 of which have previously been described, 8 being novel
      mutations and two being large deletions. The 57 mutations detected corresponded
      to: five nonsense, seven frameshift, and eight splice defects, the remainder
      being missense mutations. These mutations cause 72 different genotypes in the 83
      families characterized, confirming the mutational heterogeneity of
      phenylketonuria (PKU) in the Mediterranean population. According to our
      biochemical classification, our HPA population is composed of 40 PKU (35%), 36
      variant PKU (31%), and 39 non-PKU HPA (34%). Mutations such as IVS 10, A403 V,
      and E390G correlated as expected with the phenotype and the predicted residual
      activity in vitro. However, in four cases (165 T, V388 M, R261Q, and Y414 C), the
      observed metabolic phenotype was not consistent with the predicted genotypic
      effect. The identification of the mutations in the PAH gene and the genotype
      phenotype correlation should facilitate the evaluation of metabolic phenotypes,
      diagnosis, implementation of optimal dietary therapy, and determination of
      prognosis in the patients and genetic counselling for the patient's relatives.

PMID- 10598815
TI  - Alstrom syndrome: further evidence for linkage to human chromosome 2p13.
AB  - Alstrom syndrome is a rare autosomal recessive disorder characterized by retinal
      degeneration, sensorineural hearing loss, early-onset obesity, and non-insulin
      dependent diabetes mellitus. The gene for Alstrom syndrome (ALMS1) has been
      previously localized to human chromosome 2p13 by homozygosity mapping in two
      distinct isolated populations - French Acadian and North African. Pair-wise
      analyses resulted in maximum lod (logarithm of the odds ratio) scores of 3.84 and
      2.9, respectively. To confirm these findings, a large linkage study was performed
      in twelve additional families segregating for Alstrom syndrome. A maximum two
      point lod score of 7.13 (theta = 0.00) for marker D2S2110 and a maximum
      cumulative multipoint lod score of 9.16 for marker D2S2110 were observed, further
      supporting linkage to chromosome 2p13. No evidence of genetic heterogeneity was
      observed in these families. Meiotic recombination events have localized the
      critical region containing ALMS1 to a 6.1-cM interval flanked by markers D2S327
      and D2S286. A fine resolution radiation hybrid map of 31 genes and markers has
      been constructed.

PMID- 10598816
TI  - Preimplantation diagnosis of the beta1 integrin knockout mutation as a model for
      aneuploid gene testing.
AB  - The autosomal beta1 integrin knockout mouse mutation was selected as a model to
      experimentally determine preimplantation diagnosis test reliability for autosomal
      gene deletions and duplications. In experiment 1, which analyzed 198 individually
      disaggregated single blastomeres, the observed test frequencies matched the
      mathematically predicted frequencies calculated from the independently derived
      values of 90% normal allele amplification, 92% mutant allele amplification, 4%
      alternate allele contamination, and 4% failure to transfer amplifiable target DNA
      into the PCR reaction mix. This experiment correctly predicted a normal embryonic
      phenotype in 143 (99.3%) of the 144 phenotypically normal autosomal recessive
      results. Experiment 2 compared single biopsied blastomere test results to test
      results on the remaining embryonic cells cultured 1 week until trophoblast
      outgrowth. Single biopsied blastomere analysis correctly predicted a normal
      autosomal recessive phenotype in 87 (98%) of the 89 embryos that would have been
      selected for implantation. Experiment 3 compared the PCR results of two biopsied
      blastomeres tested independently to the PCR result from the remaining cultured
      blastomeres to improve test reliability. Given that embryos would have been
      implanted only when two normal results were obtained, 17 of 17 phenotypically
      normal embryos would have been implanted from among the 44 embryos tested. These
      experiment 3 results are consistent with the mathematical prediction that about
      99.9% of embryos implanted with two unaffected biopsied blastomere results would
      have had a phenotypically normal genotype.

PMID- 10598817
TI  - Structure of the human Lanosterol synthase gene and its analysis as a candidate
      for holoprosencephaly (HPE1).
AB  - Holoprosencephaly (HPE) is the most common birth defect of the brain in humans.
      It involves various degrees of incomplete separation of the cerebrum into
      distinct left and right halves, and it is frequently accompanied by craniofacial
      anomalies. The HPE1 locus in human chromosome 21q22.3 is one of a dozen putative
      genetic loci implicated in causing HPE. Here, we report the complete gene
      structure of the human lanosterol synthase (LS) gene, which is located in this
      interval, and present its mutational analysis in HPE patients. We considered LS
      an excellent candidate HPE gene because of the requirement for cholesterol
      modification of the Sonic Hedgehog protein for the correct patterning activity of
      this HPE-associated protein. Despite extensive pedigree analysis of numerous
      polymorphisms, as well as complementation studies in yeast on one of the missense
      mutations, we find no evidence that the LS gene is in fact HPE1, implicating
      another gene located in this chromosomal region in HPE pathogenesis.

PMID- 10598818
TI  - Truncating ribosomal protein S19 mutations and variable clinical expression in
      Diamond-Blackfan anemia.
AB  - Diamond-Blackfan anemia (DBA) is a rare constitutional erythroblastopenia
      characterized by a specific defect in erythroid differentiation. Recently,
      mutations in the gene encoding ribosomal protein (RP) S19 were found in a subset
      of patients with the disease. To characterize further RPS19 mutations and to
      investigate genotype-phenotype relationships, we screened this gene for mutations
      in patients with DBA by direct sequencing and Southern-blot analysis. Four novel
      mutations were identified. A G120A nonsense mutation resulting in a stop at codon
      33, a C302T nonsense mutation introducing a premature stop at codon 84, and a
      327delG which results in a frame shift at codon 103. A fourth and more complex
      mutation (TT157-158AA, 160insCT) resulting in a Leu45Gln and a frame shift from
      codon 47 was found in three affected family members with variable phenotypes. The
      different clinical expression for identical mutations suggest the presence of
      other modulating factors for the disease. The mutations presented here further
      support the role of RPS19 in erythropoietic differentiation and proliferation.

PMID- 10598819
TI  - SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients.
AB  - X-linked lymphoproliferative disease (XLP) is a rare inherited immunodeficiency
      to Epstein-Barr virus (EBV). The gene responsible for XLP has recently been
      identified as the four-exon SH2D1A gene encoding a 128-amino-acid protein that
      contains an SH2-domain. Functional studies indicate the SH2D1A protein acts as a
      regulator of at least two signal transduction pathways initiated by the cell
      surface molecules SLAM and 2B4, respectively, and possibly related to the host
      immune response to EBV infection. We have carried out a systematic mutation study
      of the SH2D1A gene in our series of 19 typical and 8 atypical XLP patients by
      polymerase chain reaction (PCR), reverse transcription/PCR, and sequencing, and
      have reconstructed the haplotypes of the patients. Four out of the 13 mutations
      detected are previously unreported. The identification of SH2D1A mutations in
      carriers from all three XLP families screened and the detection of mutations in
      two out of eight atypical patients indicates the usefulness of a DNA-based
      diagnosis for XLP disease.

PMID- 10598820
TI  - Identification, mapping, and genomic structure of a novel X-chromosomal human
      gene (SMPX) encoding a small muscular protein.
AB  - Reciprocal probing has been used to identify a cDNA clone (xh8H11) representing a
      gene preferentially expressed in striated muscle. The gene maps close to DXS7101
      31.9 cM from the short arm telomere of the X-chromosome at Xp22.1. On searching
      expressed and genomic databases, 21 expressed sequence tags were found that
      allowed the assignment of a human extended consensus sequence of 887 bp,
      suggesting a completely expressed gene symbolized as SMPX. By using the human
      consensus sequence, the orthologous mouse Smpx and rat SMPX genes could be
      aligned and confirmed by complete sequencing of additional SMPX-related clones
      obtained by library screening. An open reading frame was identified encoding a
      peptide of 88-86 and 85 amino acids in human and rodents, respectively. The
      predicted peptide had no significant homologies to known structural elements. The
      human consensus cDNA sequence was used to define the genomic structure of the
      human SMPX that had been missed by a previous large scale sequencing approach.
      The gene consists of five exons (> or =172, 57, 84, 148, > or =422 bp) and four
      introns (3639, 10410, 6052, 31134 bp) comprising together 52.1 kb and is
      preferentially and abundantly expressed in heart and skeletal muscle. Thus, a
      novel human gene encoding a small muscular protein that maps to Xp22.1 (SMPX) has
      been identified and structurally characterized as a basis for further functional
      analysis.

PMID- 10598821
TI  - Haplotype-matched controls as a tool to discriminate polymorphisms from
      pathogenic mutations in mtDNA.
AB  - We have studied the pathogenic role of 10044A-->G, a heteroplasmic mitochondrial
      DNA (mtDNA) mutation that has been suggested to be pathogenic in one family with
      severe pediatric morbidity. We found the mutation at an average frequency of 1.9%
      among 259 individuals including healthy controls. The mutation appeared to be
      heteroplasmic by restriction fragment analysis but analysis of subcloned
      polymerase chain reaction fragments confirmed homoplasmy. The polymorphic nature
      of 10044A-->G was verified by demonstrating exclusive association with a rare
      mtDNA haplotype within haplogroup H. We suggest that the evaluation of putatively
      pathogenic mutations in mtDNA should include the analysis of a sufficient number
      of haplotype-matched control samples and that the heteroplasmy should be verified
      by cloning.

PMID- 10598822
TI  - Type-1c glycogen storage disease is not caused by mutations in the glucose-6
      phosphate transporter gene.
AB  - Glycogen storage disease type 1 (GSD-1) is a group of autosomal recessive
      disorders caused by deficiencies in glucose-6-phosphatase (G6Pase) and the
      associated substrate/product transporters. Molecular genetic studies have
      demonstrated that GSD-1a and GSD-1b are caused by mutations in the G6Pase enzyme
      and a glucose-6-phosphate transporter (G6PT), respectively. While kinetic studies
      of G6Pase catalysis predict that the index GSD-1c patient is deficient in a
      pyrophosphate/phosphate transporter, the existence of a separate locus for GSD-1c
      remains unclear. We have previously shown that the G6Pase gene of the index GSD
      1c patient is intact; we now show that the G6PT gene of this patient is normal,
      strongly suggesting the existence of a distinct GSD-1c locus.

PMID- 10598823
TI  - Streptozotocin-diabetes impairs prolactin binding to Leydig cells in prepubertal
      and pubertal rats.
AB  - Prolactin (PRL) binding to Leydig cells in prepubertal and pubertal
      streptozotocin (STZ)-diabetic and insulin-treated rats was studied. Prepubertal
      (30-day-old) and pubertal (50-day-old) rats were made diabetic by single
      injection of STZ (120 and 100 mg/kg b.wt, respectively). After 3 days of STZ
      administration, a group of rats was given insulin injections subcutaneously (3
      U/100 g b.wt/day in 2 equally divided doses). Animals of prepubertal and pubertal
      groups were killed on postnatal days 51 and 71, respectively. Age-dependent
      increase in serum testosterone, PRL levels and PRL receptors on Leydig cells were
      prevented by STZ-diabetes. Insulin administration partly or completely prevented
      these changes. These results suggest that steroidogenic defects in Leydig cells
      of prepubertal and pubertal diabetic rats may be associated with decrease in
      serum PRL levels and its receptors on Leydig cells. Insulin probably has a role
      in the maintenance of PRL receptor numbers on Leydig cells during pubertal
      maturation.

PMID- 10598824
TI  - Expression of C-20, 22 desmolase activity by the human fallopian tube in vitro:
      evidence for steroidogenesis.
AB  - With a view to establishing whether cells of the human Fallopian tubes possess
      the cholesterol side-chain cleavage activity, homogenates of the tubes, obtained
      from 6 women (39-45 years) following abdominal hysterectomy for benign
      conditions, were incubated with (7n-3H)-cholesterol as substrate. Controls (n=6,
      age 40-44 years) were homogenates heated in a boiling water bath for 10 min.
      Using the reverse-isotope dilution technique, (3H)-pregnenolone was isolated and
      characterized. No such metabolite was evident in control incubations of heat
      denatured enzymes. The extent of enzymic conversion varied from 1.9 x 10(-3) to
      1.3 x 10(-2)%. The results reveal for the first time the existence of an active
      cholesterol-specific C-20, 22 desmolase system in the viable tissues. It is
      suggested that there exists a potential for substantial pregnenolone synthesis in
      vivo. This rate-limiting steroid biosynthetic conversion provides a new dimension
      to the functional capacity of the Fallopian tubes in the synthesis of steroids,
      which may be necessary for modulating ciliary beat frequency and in maintenance
      of hormonal milieu essential for embryogenesis.

PMID- 10598825
TI  - 5'-deiodinase activity in cultured glial and fibroblastic cells from the
      cerebella of newborn rats.
AB  - The cerebellum of young rats contains significant 5'-deiodinase (5'-D) activity,
      but technical difficulties have made it impossible to identify the enzyme in
      cultured cerebellar astrocytes. We have developed a culture method which allows
      cerebellar astrocytes from 6-day-old rats to grow and develop 5'-D activity.
      Astrocytes cultured for 2 weeks in medium containing 3.25 microM reduced
      glutathione (GSH) and 0.21 microM vitamin E (VitE) as alpha-tocopherol had 5'-D
      activity which was stimulated by 1 mM dibutyryl cyclic adenosine monophosphate
      (dBcAMP) given 16 hours before measuring enzyme activity. Cells cultured without
      GSH and VitE showed little 5'-D activity, which was not stimulated by dBcAMP
      Primary cultures of cerebellar astrocytes were cultured for four weeks with or
      without GSH+VitE, and stimulated by dBcAMP had high 5'-D activity, but were also
      sometimes contaminated with fibroblasts. The effect of such contamination on the
      astrocyte 5'-D activity was assessed by preparing primary cultures of fibroblasts
      from the meninges surrounding 6-day-old rat cerebella. They were grown in the
      same media and under the same conditions as the astrocytes. The cultured
      fibroblasts had 5'-D activity independent of GSH+VitE or culture time. The 5'-D
      activity of both cell populations could be type II 5'-deiodinase (5'-DII) because
      it was not inhibited by 6-n-propylthiouracil (PTU). Thus, cerebellar astrocytes
      cultured for 2 weeks in medium containing GSH and VitE have 5'-DII activity.
      Prolonged cultures favor enzyme activity, but also enhance contamination with
      fibroblasts, which may also show 5'-DII activity.

PMID- 10598826
TI  - Distribution of oleoyl-estrone in rat plasma lipoproteins.
AB  - Pooled adult normal rat plasma was used for the separation of lipoprotein
      fractions: VLDL, LDL and HDL, from which a total lipids extract was obtained. The
      presence of fragments with the MW of estrone and oleoyl-estrone in the
      lipoprotein fractions was analyzed by HPLC-MS. The results show that oleoyl
      estrone is the major estrone component in lipoproteins; this molecular species
      was present in all three lipoprotein lipid extracts. The lipoprotein fractions
      were used for the analysis of protein and lipid classes: triacylglycerols, total
      and esterified cholesterol and phospholipids as well as acyl-estrone. About half
      of the total acyl-estrone was in the HDL fraction and only about 10% in the VLDL
      fraction. HDLs contained about one molecule in 50 particles, LDLs one molecule
      per particle and VLDLs 15 molecules per particle, i.e. given their size, the
      larger lipoproteins contained more oleoyl-estrone than the HDLs. The distribution
      of this hormone suggests that oleoyl-estrone is lost with other lipids as the
      lipoproteins shrink. The results presented show that oleoyl-estrone is a molecule
      found naturally in rat lipoproteins in low concentrations - the lowest in HDLs -
      that are consistent with its postulated role in the control of body weight.

PMID- 10598828
TI  - Effects of orexin A on thyrotropin-releasing hormone and thyrotropin secretion in
      rats.
AB  - Effects of orexin A on secretion of thyrotropin-releasing hormone (TRH) and
      thyrotropin (TSH) in rats were studied. Orexin A (50 microg/kg) was injected iv,
      and the rats were serially decapitated. The effects of orexin A on TRH release
      from the rat hypothalamus in vitro and on TSH release from the anterior pituitary
      in vitro were also investigated. TRH and thyroid hormone were measured by
      individual radioimmunoassays. TSH was determined by the enzyme-immunoassay
      method. The hypothalamic TRH contents increased significantly after orexin A
      injection, whereas its plasma concentrations tended to decrease, but not
      significantly. The plasma TSH levels decreased significantly in a dose-related
      manner with a nadir at 15 min after injection. The plasma thyroid hormone levels
      showed no changes. TRH release from the rat hypothalamus in vitro was inhibited
      significantly in a dose-related manner with the addition of orexin A. TSH release
      from the anterior pituitary in vitro was not affected with the addition of orexin
      A. The findings suggest that orexin A acts on the hypothalamus to inhibit TRH
      release.

PMID- 10598827
TI  - Increased urinary phosphate excretion in pseudohypoparathyroidism type II with
      long-term treatment with phosphodiesterase inhibitor.
AB  - A 58-year-old woman was diagnosed to have pseudohypoparathyroidism (PHP) type II
      because of the absence of an increase of urinary phosphate secretion, despite a
      marked increase in urinary cAMP excretion on the Ellsworth-Howard test. We
      treated the patient with a cyclic-nucleotide phosphodiesterase inhibitor,
      theophylline, resulting in increased urinary phosphate and cAMP excretions.
      Dibutyl cAMP administration induced the increase in the urinary phosphate
      excretion. In this case, the unresponsiveness of the urinary phosphate secretion
      to cAMP was recovered by a high dose of cAMP or long-term administration of a
      phosphodiesterase inhibitor. These data imply that cAMP responsiveness to renal
      tubular phosphate reabsorption should be more strictly elucidated in the patient
      with PHP type II.

PMID- 10598829
TI  - In Zucker diabetic fatty rats plasma leptin levels are correlated with plasma
      insulin levels rather than with body weight.
AB  - The obese (ob) gene product leptin, secreted from adipose tissue, acts in the
      hypothalamus to regulate body energy stores. In vitro experiments showed that
      insulin increases both leptin mRNA expression and leptin secretion by adipocytes.
      Here, we report on the relationship between plasma insulin and plasma leptin in a
      longitudinal in vivo study. In Zucker diabetic fatty (ZDF) rats, an animal model
      for non-insulin-dependent diabetes mellitus (NIDDM), and in ZDF control rats,
      blood glucose, body weight, plasma insulin and plasma leptin levels were measured
      from 10 to 25 weeks of age. In ZDF control rats, body weight, plasma leptin and
      plasma insulin levels increased gradually during the study period. In ZDF rats,
      the time course of plasma leptin was similar to that of plasma insulin, but did
      not parallel that of body weight. Calculation of partial correlation coefficients
      revealed that in ZDF control rats plasma leptin correlated with body weight
      rather than with plasma insulin. However, in ZDF rats, plasma leptin correlated
      with plasma insulin rather than with body weight, suggesting an important role
      for insulin in the modulation of leptin secretion in this animal model for NIDDM.

PMID- 10598830
TI  - Leptin concentrations and their relation to body fat distribution and weight loss
      -a prospective study in individuals with impaired glucose tolerance. DPS-study
      group.
AB  - Leptin is proposed to be involved in regulation of body weight. Only little
      information is available on leptin concentrations in individuals with impaired
      glucose tolerance (IGT). The aim of the present study was to assess the effect of
      body fat distribution and weight reduction on serum leptin levels in a
      prospective setting in IGT subjects. Sixty-nine individuals with impaired glucose
      tolerance aged 45-64 years participated in this prospective study. Serum leptin
      levels were about 300% higher among females than among males, despite an only 30%
      higher fat percentage in females. A close association between degree of obesity
      and leptin concentrations was observed in both sexes. The correlation coefficient
      between fat mass and leptin concentration ranged between r = 0.467- 0.817 (p<
      0.001 - 0.01). A close correlation between degree of weight loss and decrease in
      leptin concentrations was observed in both sexes. A 10.1 kg (9.6%) decrease in
      body weight among females was associated with a 32% decrease in leptin
      concentrations. The corresponding value among males for an 8.0 kg (8.6%) decrease
      was 29%. Changes in leptin concentrations were best explained by changes in fat
      mass among both males and females. Body fat distribution was also of importance,
      especially among females. Gender associated differences in leptin concentrations
      appear to be largely influenced by gender differences in body fat distribution.

PMID- 10598832
TI  - Neurobiological bases of behavioral development in the second year.
AB  - We discuss selected psychological competences that develop and become noticeable
      between one and two years of age and are temporally correlated to structural,
      biochemical and physiological changes in the brain. The psychological competences
      are: Language development, a sense of "right" and "wrong", self-awareness, and
      the ability to make inferences. The accompanying changes in the brain involve the
      prefrontal cortex, language-related cortical areas, hippocampus, cerebellum,
      basal ganglia and an increase in the connectivity of the network. Of special
      interest are the maturational changes in layers III-IV of the prefrontal cortex.
      Layer III is the origin and target of callosal and commissural axons linking the
      two hemispheres and the target of associational axons linking ipsilateral areas
      within each hemisphere. Layer IV, the target for axons from the mediodorsal
      nucleus of the thalamus, conveys information from other associational cortices,
      cerebellum, basal ganglia, and the reticular and limbic systems. In the second
      year, intensive dendritic growth and synaptogenesis in these layers increase the
      linking of these two layers and form a neural basis for a more efficient
      convergence and integration of information from the two hemispheres, which are
      functionally asymmetric. It is our hypothesis that these changes, together with
      the maturational changes in the cortico-subcortical network, are a basis for the
      observed emergence of the psychological competences. We are aware that temporal
      correlations cannot prove firm causal relationships. However, knowledge of these
      correlations is useful in generating specific hypotheses that can be tested
      directly.

PMID- 10598831
TI  - Oxidative stress and anti-oxidant metabolites in patients with hyperthyroidism:
      effect of treatment.
AB  - OBJECTIVE: Oxygen free radicals (OFR) play a role in the pathogenesis of tissue
      damage in many pathological conditions via the peroxidation of membrane
      phospholipids. Experimental studies showed an elevated oxidative stress during
      hyperthyroidism, which is reduced by treatment. Therapy per se might decrease
      oxidative stress. DESIGN: Fasting plasma levels of thiobarbituric acid reacting
      substances (TBARS), vitamin E and coenzyme Q10 were measured in 22 hyperthyroid
      patients, before treatment for their thyroid disease, after 13.9 [SD 9.2] weeks,
      when they achieved an euthyroid state on thyrostatic drugs, and again after 47.7
      [21.0] weeks, off therapy. No patient presented additional risk factors for
      increased lipoperoxidation and/or increased OFR levels. Smokers were asked to
      abstain from smoking overnight. METHODS: All analytes were measured by HPLC.
      RESULTS: In hyperthyroidism, plasma levels of TBARS were increased, whereas
      vitamin E and coenzyme Q10 were reduced. Average levels of TBARS and antioxidant
      agents returned to normal in euthyroid patients, without differences in relation
      to stop of thyrostatic therapy. CONCLUSIONS: Our data confirm the presence of
      oxidative stress and decreased anti-oxidant metabolites in hyperthyroid patients,
      which are corrected in euthyroidism, without any influence of thyrostatic drugs
      per se. Nutritional support with antioxidant agents, which are defective during
      hyperthyroidism, is warranted.

PMID- 10598833
TI  - Predictive value of neonatal MRI as compared to ultrasound in premature infants
      with mild periventricular white matter changes.
AB  - A follow-up study was performed in 42 premature infants in whom serial neonatal
      ultrasound and a single neonatal MRI of the brain was normal, or showed mild
      periventricular white matter changes. The aim of the study was to evaluate the
      clinical significance of periventricular signal intensity changes on MRI and to
      compare the predictive value of neonatal MRI with that of ultrasound. The infants
      underwent repeated standardised motor assessments and developmental tests. MRI
      was repeated at the corrected age of 12 months. Pronounced periventricular signal
      intensity changes on neonatal MRI and periventricular echodensities (flaring) on
      ultrasound were associated with a high incidence of transient motor problems
      during infancy. The degree of echogenicity carried the highest predictive value,
      as compared to duration of flaring on ultrasound and degree of periventricular
      signal intensity change on MRI. It is concluded that signal intensity changes on
      neonatal MRI represent the same ischaemic change of the periventricular white
      matter as flaring on ultrasound and that routine neonatal MRI screening is not
      warranted in premature infants without clinical evidence of neurological problems
      and with normal or mildly abnormal ultrasound scans. Recording of the degree of
      echogenicity should become a routine procedure in neonatal cerebral
      ultrasonography.

PMID- 10598834
TI  - Apoptosis in brain biopsies of subacute sclerosing panencephalitis patients.
AB  - Subacute sclerosing panencephalitis (SSPE) is associated with inflammatory
      infiltration, neuronal loss, and demyelination. The pathogenesis of these changes
      is unclear. We examined DNA fragmentation and Bcl-2 expression in brain biopsies
      of nineteen SSPE patients to investigate the role of apoptosis in tissue damage.
      DNA fragmentation was present in oligodendroglia, and, in tissues with neuronal
      loss, in neurons. Reactive astrocytes had no DNA fragmentation, but strong Bcl-2
      expression. These results suggest apoptosis as one of the mechanisms for
      oligodendroglial and neuronal death in SSPE.

PMID- 10598835
TI  - Clinical spectrum and diagnostic difficulties of infantile ponto-cerebellar
      hypoplasia type 1.
AB  - We present the clinical and histopathological features and the diagnostic
      difficulties encountered in five children affected by a motor neuron disorder
      other than spinal muscular atrophy. Investigations performed suggested the
      diagnosis of ponto-cerebellar hypoplasia type 1 (PCH-1). Severe respiratory
      difficulty was present at birth in two of these children; hypotonia,
      arthrogryposis, microcephaly and nystagmus were present in all. Early and
      progressive bulbar involvement with swallowing difficulties and stridor was also
      a common feature in these infants. Severe cognitive delay was invariably present.
      Brain magnetic resonance imaging showed ponto-cerebellar hypoplasia in four
      children while striking atrophy of the cerebellar vermis and cerebellar
      hemispheres were present in the fifth child. Electrophysiological and
      pathological investigations of proximal muscles performed at presentation in all
      these children were not conclusive, while the post-mortem studies, or the study
      of distal muscles during life, showed a clear neurogenic picture. Genetic studies
      excluded involvement of the SMN gene, or of other genes located on chromosome 5q,
      confirming that ponto-cerebellar hypoplasia type 1 is a different entity from
      typical proximal spinal muscular atrophy.

PMID- 10598836
TI  - MRI and clinical characteristics of children with hemiplegic cerebral palsy.
AB  - Magnetic resonance imagings of 91 children with hemiplegic cerebral palsy were
      analysed with the aim of clustering their features into fairly homogeneous forms.
      In addition, the different clinical patterns of each form were described. Four
      main types of lesion were distinguished: form 1 (13 cases), which comprised brain
      malformations, form 2 (41 subjects), which grouped abnormalities of the
      periventricular white matter, form 3 (27 children), which was represented by
      cortical-subcortical lesions, and form 4 (10 subjects), which grouped non
      progressive postnatal brain injuries. None of the children had normal MRI and a
      high incidence of bilateral lesions was found, especially in form 2. A left motor
      involvement was prevalent in the sample and was noted in all but the third form.
      The severity of impairment was mainly moderate in forms 1 and 3, mild in the
      others. The upper limb was found to be more affected in all forms except the
      second one, which presented a greater involvement of the lower limb. Mental
      retardation occurred in about one-third of the children with forms 1 and 4, less
      often in the other two. Seizures occurred in about half of the children with
      forms 1 or 3, while the incidence was lower in forms 4 and 2. A strong
      correlation between the presence of seizures and mental retardation was observed.
      The results of this study show the importance of MRI in the evaluation of
      children with hemiplegic cerebral palsy.

PMID- 10598837
TI  - Quantitative proton magnetic resonance spectroscopy of cerebral metabolic
      disturbances in patients with MELAS.
AB  - Four patients with clinically and genetically defined MELAS were examined using
      quantitative localized proton magnetic resonance spectroscopy of the brain. Acute
      and chronic lesions were located in the occipital lobe and mostly characterized
      by strongly elevated concentrations of lactate (Lac) and glucose (GIc) as well as
      severely reduced concentrations of total N-acetylaspartyl compounds (tNAA,
      neuroaxonal markers), glutamate (Glu), and total creatine. These findings
      indicate a high degree of nonoxidative glycolysis reflecting either impaired
      oxidative energy metabolism or the use of anaerobic metabolism by infiltrating
      macrophages as well as damage or loss of viable neuroaxonal tissue. In contrast,
      glial cell populations, in particular astrocytes, seem to remain unaffected as
      evidenced by unchanged concentrations of myo-inositol (glial marker). In
      addition, all patients including one who never experienced a stroke-like episode
      showed elevated Lac and Glc as well as reduced tNAA and Glu in tissues appearing
      normal on MRI. These disturbances were stronger in cortical gray matter and
      cerebellum than in white matter and indicate that neuroaxonal damage is not
      restricted to structural lesions. The steady presence of Lac is consistent with a
      reduced capacity of the mitochondrial oxidative energy metabolism resulting from
      impaired respiratory chain function.

PMID- 10598838
TI  - Late primary unilateral thalamic hemorrhage in infancy: report of two cases.
AB  - We report on two infants with primary unilateral thalamic hemorrhage which
      occurred at two months of age. Both infants were normal prior to the onset of
      hemorrhage. Both children presented with seizures and subsequently developed
      epilepsy. These cases suggest that primary unilateral thalamic hemorrhage can
      occur in seemingly well infants outside the neonatal period.

PMID- 10598839
TI  - Circulating antineutrophil autoantibodies in a child with isolated central
      nervous system vasculitis.
AB  - An 8-year old girl with history of twisted neck and painful swelling on the left
      side of the neck was found to have malfunction of glossopharyngeal and
      hypoglossal nerves on the left side. Magnetic resonance angiography revealed a
      giant aneurysm of the internal carotid artery surrounded by a widespread
      inflammatory tumor. Cerebral angiography disclosed a large, false aneurysm with
      almost complete compression of the internal carotid artery. Circulating
      antineutrophil cytoplasmic autoantibodies (titer 1:2560) and high levels of
      antibodies against antiproteinase 3 were detectable. This observation indicates
      that these autoantibodies may be a diagnostic tool in children in whom an
      undiagnosed central nervous system inflammatory disease is present.

PMID- 10598840
TI  - Clinical and neuroradiological follow-up in mucopolysaccharidosis type III
      (Sanfilippo syndrome).
AB  - Mucopolysaccharidosis type III (Sanfilippo syndrome) is an autosomal recessive
      disorder characterised by progressive nervous system involvement with mental
      retardation, behavioural problems and seizures. Three patients, of 20 months to
      12 years of age, were followed up for 3 years both clinically and by using brain
      magnetic resonance imaging (MRI). Our results suggest that in MPS III patients
      MRI findings, including atrophy and abnormal or delayed myelination, may precede
      the onset of overt neurological symptoms. The increasing neurological morbidity
      is accompanied by different degrees of progressive atrophic changes, mainly
      affecting the cerebral cortex and the corpus callosum. However, it appears that,
      across subjects, the rate of MRI changes is unrelated to the severity of the
      clinical phenotype. On this basis it could be argued that in MPS III the
      worsening of the neurological symptoms might not necessarily reflect only the
      progressive cerebral abnormalities detectable by MRI.

PMID- 10598841
TI  - Biventricular diastolic cardiac function assessed by MR flow imaging using a
      single angulation.
AB  - PURPOSE: To evaluate whether one single angulation is reliable for biventricular
      diastolic MR flow measurements across both the mitral and tricuspid valves.
      MATERIAL AND METHODS: MR flow imaging was performed in 14 healthy volunteers and
      14 patients with pulmonary fibrosis. Flow curve parameters were calculated from
      the mitral valve in mitral valve angulation, the tricuspid valve in tricuspid
      valve angulation, and also from the mitral valve in tricuspid valve angulation
      and the tricuspid valve in mitral valve angulation. RESULTS: For flow through the
      mitral valve, there were no significant differences between angulation set
      parallel to the mitral valve and angulation set parallel to the tricuspid valve
      for the diastolic inflow volume, the E-peak and the E:A ratio as measured in
      healthy volunteers and patients. The tricuspid valve flow was imaged well when
      the angulation was set parallel to the tricuspid valve, but not when angulation
      was set parallel to the mitral valve. The results indicate that the inflow
      volumes, the E-peak, and the E:A peak ratios across the mitral valve and
      tricuspid valve can be obtained using one single angulation which is set parallel
      to the tricuspid valve. CONCLUSION: Biventricular diastolic flow measurements can
      be obtained using one single angulation set parallel to the tricuspid valve.

PMID- 10598842
TI  - Motion artifacts in cardiac CT. The Novacor left ventricular assist device and
      its implications for clinical imaging.
AB  - PURPOSE: Cardiovascular applications of CT are primarily limited by temporal
      resolution of the scanner. Recent development in scanner technology has greatly
      increased temporal resolution. We here describe a standardized method of
      assessing temporal properties of various CT techniques. MATERIAL AND METHODS: The
      Novacor left ventricular assist device was mounted in a water-filled circulation
      phantom and scanned at different pump rates with a spiral CT unit and an electron
      beam unit. We also evaluated the use of ECG-triggered subsecond scanning on a
      spiral CT unit. RESULTS: Using the fastest conventional scanning protocol, severe
      motion artifacts occurred. These artifacts could not be reproduced from image to
      image, even if the pump rate was adjusted to scan rate (l/s). Electron beam
      tomography (EBT) reproducibly yielded few artifacts at 100 ms and practically no
      artifacts at 50 ms scanning time. Even without ECG-triggering, pump motion could
      be reproduced as a cine-cycle. With the ECG-triggered partial scanning CT
      technique, limited motion artifacts could be reproduced during diastole at a
      heart rate of 70-80 beats/min. CONCLUSION: The Novacor ventricular assist device
      may serve as a benchmark test in the evaluation of new scanning techniques for
      cardiovascular CT. While EBT presently remains the only CT technique to freeze
      cardiac motion throughout its cycle, ECG-triggered subsecond scans may, under
      certain conditions, capture cardiac anatomy in diastole.

PMID- 10598843
TI  - Bronchopulmonary arterial anastomosis at the precapillary level in human lung.
      Visualization using CT angiography compared with microangiography of autopsied
      lung.
AB  - PURPOSE: To investigate the interrelationships between the bronchial and
      pulmonary circulations including the existence of precapillary bronchopulmonary
      arterial anastomoses. MATERIAL AND METHODS: CT of bronchial arteriography (BAG
      CT) was performed in 10 patients and BAG-CT during a pulmonary artery block test
      (PA-block) in 5 patients with lung cancer. Bronchial and pulmonary circulations
      were evaluated in 5 autopsied normal lungs by injecting silicone rubber with
      different colors into the bronchial and pulmonary arteries. RESULTS: BAG-CT
      correlated well with the findings at silicone rubber injection into lung autopsy
      samples. BAG-CT demonstrated inflow of contrast medium into the pulmonary artery
      during PA-block in all cases, while no inflow was observed before and following
      reversal of PA-block. Mixed silicone rubber was observed in the lobar to
      subsubsegmental bronchial arteries in all cases and in the subsubsegmental
      pulmonary artery in one case. CONCLUSION: Precapillary bronchopulmonary arterial
      anastomoses may exist at the level of the lobar bronchi to the periphery. If
      either the pulmonary or bronchial circulation is disturbed, flow occurs inside
      the anastomoses to supplement the other flow, especially flow from the bronchial
      to the pulmonary arteries via the anastomoses, which occurs within 30 min.

PMID- 10598844
TI  - Characterization of breast masses by dynamic enhanced MR imaging. A logistic
      regression analysis.
AB  - PURPOSE: To identify features useful for differentiation between malignant and
      benign breast neoplasms using multivariate analysis of findings by MR imaging.
      MATERIAL AND METHODS: In a retrospective analysis, 61 patients with 64 breast
      masses underwent MR imaging and the time-signal intensity curves for precontrast
      dynamic postcontrast images were quantitatively analyzed. Statistical analysis
      was performed using a logistic regression model, which was prospectively tested
      in another 34 patients with suspected breast masses. RESULTS: Univariate analysis
      revealed that the reliable indicators for malignancy were first the appearance of
      the tumor border, followed by the washout ratio, internal architecture after
      contrast enhancement, and peak time. The factors significantly associated with
      malignancy were irregular tumor border, followed by washout ratio, internal
      architecture, and peak time. For differentiation between benignity and
      malignancy, the maximum cut-off point was to be found between 0.47 and 0.51. In a
      prospective application of this model, 91% of the lesions were accurately
      discriminated as benign or malignant lesions. CONCLUSION: Combination of contrast
      enhanced dynamic and postcontrast-enhanced MR imaging provided accurate data for
      the diagnosis of malignant neoplasms of the breast. The model had an accuracy of
      91% (sensitivity 90%, specificity 93%).

PMID- 10598845
TI  - Optimising imaging parameters for post mortem MR imaging of the human brain.
AB  - PURPOSE: MR imaging of post mortem brains has the potential to yield volumetric
      information and define the extent of structural changes prior to pathological
      examination. Although standard T2-weighted clinical imaging sequences have been
      used for the examination of formalin-fixed brains, these protocols may not yield
      optimum contrast. We examined the effect of varying durations of formalin
      fixation on the transverse relaxation time (T2) and the tissue spin density.
      MATERIAL AND METHODS: Three post mortem brains were examined weekly during
      formalin fixation from the unfixed state to 35 days fixation. Standard MR spin
      echo imaging was used at 5 echo times (20-100 ms) to calculate transverse
      relaxation time (T2) and spin density. RESULTS: T2 decreased significantly
      (ANOVA, p<0.001) in both grey and white matter by 7 days fixation and there was a
      further (but non-significant) trend towards lower values between 7 and 35 days.
      Grey and white matter T2 times converged with fixation. Conversely, the grey to
      white matter spin density ratio increased from 1.19+/-0.01 to 1.54+/-0.06 over
      five weeks of fixation. CONCLUSION: Our results suggest that spin density
      weighted imaging sequences would provide improved grey to white matter contrast
      over T2-weighted sequences.

PMID- 10598846
TI  - Postoperative nerve root displacement and scar tissue. A prospective cohort study
      with contrast-enhanced MR imaging one year after microdiscectomy.
AB  - PURPOSE: To investigate the association between postoperative nerve root
      displacement and epidural scar tissue. MATERIAL AND METHODS: One hundred patients
      who had undergone lumbar microdiscectomy were included in a prospective cohort
      study with a 1-year follow-up. The patients were classified as failures or
      successes at the 12-month follow-up according to a clinical score. Patients with
      signs of recurrent disc herniation on MR were excluded from the study. All the 13
      patients classified as failures were investigated with MR at the 1-year follow
      up, and 40 patients classified as successes were picked at random for MR imaging;
      thus MR was performed in 53 patients. The MR images were independently evaluated
      by two neuroradiologists. The images were rated according to the presence or
      absence of nerve root displacement at the surgically treated disc interspace.
      Scar formation was rated according to two different classification systems.
      RESULTS: Nerve root displacement was observed in 13 patients. No evidence of scar
      formation was found in 4 patients, a small amount in 11, intermediate in 37 and
      extensive scar formation in 1 patient. No association between nerve root
      displacement and the amount of scar tissue was found. CONCLUSION: Postoperative
      nerve root displacement seems to be an independent clinical entity not associated
      to postoperative scar tissue.

PMID- 10598847
TI  - 110 subfascial lipomatous tumors. MR and CT findings versus histopathological
      diagnosis and cytogenetic analysis.
AB  - PURPOSE: To evaluate whether liposarcoma, atypical lipomatous tumors and lipoma
      can be differentiated radiologically. MATERIAL AND METHODS: We have
      retrospectively analyzed CT and/or MR images of 110 subfascial lipomatous
      lesions. The amount of fat within the tumors was visually graded from the images
      as: none, 1-75%, 75-95% or 95-100%. The structure of non-fatty tumor components
      was compared. The images were compared to histopathology and in 37 cases to
      cytogenetic findings. RESULTS: Only 4 of 20 liposarcomas contained fat. All 4
      lesions, histopathologically diagnosed as atypical lipomatous tumors, contained
      fat but less than 75% of tumor volume. All lesions with more fat than 75% of
      tumor volume were histologically diagnosed as lipomas. However, one-third of the
      karyotyped lipomas had ring chromosomes which are considered typical for atypical
      lipomatous tumors. CONCLUSION: When a tumor is composed more or less solely of
      fat, the diagnosis of a lipoma or atypical lipomatous tumor with a phenotype
      simulating a lipoma can be assumed. When the fat content is less than 75% of the
      tumor volume or non-fatty nodules are found, biopsies from different tumor
      components have to be performed to exclude malignancy. When no fat is found,
      imaging does not help in differentiating lipoma or liposarcoma from other soft
      tissue tumors.

PMID- 10598848
TI  - MR assessment of movement and morphologic change in the menisci during knee
      flexion.
AB  - PURPOSE: To examine movement and morphologic alteration in the menisci during
      knee flexion. MATERIAL AND METHODS: Twenty healthy knees were imaged at 0
      degrees, 45 degrees, and 90 degrees of passive non-weight-bearing flexion in the
      sagittal plane with MR. In each meniscus, posterior movement distance during knee
      flexion and the ratio of anteroposterior (a.p.) diameter at flexion to that at
      extension were calculated. RESULTS: Each meniscus moved posteriorly during knee
      flexion. Movement was greater in the anterior horn than in the posterior horn,
      and greater in the medial meniscus than in the lateral meniscus (p<0.05). The
      a.p. diameter of each meniscus was reduced at flexion (p<0.05). CONCLUSION: Knee
      flexion normally leads to posterior movement and shortening of the a.p. diameter
      of the menisci, which may be related to the positioning and curvature of femoral
      condyles at the femorotibial contact point at knee flexion.

PMID- 10598849
TI  - MR imaging in suspected acute trauma of wrist bones.
AB  - OBJECTIVE: The purpose of this study was to evaluate the findings of MR imaging
      compared to plain radiography in acute wrist trauma. METHODS: Radiography and MR
      imaging (obtained at 1.5 T) of 67 patients (38 female, 29 male, aged 15-80 years)
      were analysed by three senior radiologists in a blinded random fashion. RESULTS:
      One-third (n= 13) of the 37 fractures observed on MR images were missed on the
      radiographs. The McNemar test indicated significant differences in diagnoses
      between radiography and MR. CONCLUSION: We recommend that MR imaging should be
      considered in the diagnosis of acute wrist trauma when: 1) There is a clear
      discrepancy between the clinical status and a negative radiography and when
      splint treatment would increase cost by causing occupational restrictions; and 2)
      Healing of trauma diagnosed as contusion or distension does not occur within the
      expected time.

PMID- 10598850
TI  - Reliability of ultrasonography in the follow-up of hip dysplasia in children
      above 2 years of age.
AB  - PURPOSE: The aim of the present study was to assess whether ultrasonography (US)
      was reliable in the follow-up of children above 2 years of age who had previously
      been treated for congenital or developmental hip dislocation or dysplasia (HD).
      MATERIAL AND METHODS: As part of the routine follow-up, we examined 53 children
      (106 hips), aged 2-12 years (mean 6 years). Using US, the coverage of the femoral
      head was assessed by the distance from the lateral tangent of the ossified
      femoral head to the lateral bony acetabular rim (lateral head distance, LHD). The
      corresponding distance was measured on radiographs (LHDR). The radiographic
      femoral head coverage was assessed by the migration percentage (MP) and the
      center-edge (CE) angle. RESULTS: We found a good accordance between sonographic
      LHD and the radiographic parameters MP and CE in all age groups, indicating that
      femoral head coverage was reliably assessed by US. There was also a high
      correlation between LHD and LHDR (r=0.85). All hips with subluxation were
      detected by US. In 11 hips that appeared normal on US, but with dysplasia or
      uncertain findings by radiography, the condition spontaneously normalized in 9
      out of 9 examined hips with further follow-up. CONCLUSION: Because a reliable
      assessment of the hip is obtained, we recommend that US should be used as the
      primary imaging technique in the routine follow-up of children above 2 years of
      age with previous HD. Radiography should be omitted when US shows normal findings
      and is only needed when the US LHD is above the upper normal limit or the hip
      looks abnormal or suspicious by subjective evaluation.

PMID- 10598851
TI  - Ultrasonographic localization of a displaced screw in the carpal canal. A case
      report.
AB  - We present a case of a 65-year-old patient with a surgically treated distal
      radius fracture. At 5-month follow-up, conventional radiography revealed breakage
      of the plate and a screw displaced into the volar soft tissue. Preoperative
      ultrasonography including dynamic assessment of the tendons showed the screw
      intratendinously as a hyperechogenic structure with repetitive echoes. This
      unusual localization was proven by surgery. Dynamic ultrasonography played an
      important diagnostic role in the localization of the loosened and displaced
      osteosynthetic material.

PMID- 10598852
TI  - SPIO-MR imaging versus double-phase spiral CT in detecting malignant lesions of
      the liver.
AB  - PURPOSE: To assess the diagnostic performance of superparamagnetic iron oxide MR
      (SPIO-MR) imaging compared with double-phase spiral CT in detecting liver
      metastases and hepatocellular carcinoma. MATERIAL AND METHODS: Thirty-eight
      patients with a total of 144 malignant lesions of the liver were examined by CT
      and SPIO-MR. After definition of a gold standard by a panel of experts, the
      patient images were randomized and presented to a blinded jury of 5 independent
      observers whose task was to identify as many lesions as possible. The results
      were tested for statistical significance using multifactorial analysis of
      variance (alpha=5%). RESULTS: SPIO-MR produced the highest detection rate and was
      significantly superior (p<0.05) to unenhanced MR imaging and double spiral-phase
      contrast-enhanced CT (DPS-CECT). Maximum performance in DPS-CECT was obtained
      during the portal venous contrast phase but was significantly inferior to SPIO-MR
      imaging. The scores for unenhanced CT and unenhanced MR were significantly lower
      than for the corresponding enhanced procedures. SPIO-MR imaging produced a higher
      incidence of false-positive findings (n=39). CONCLUSION: SPIO-MR produced a
      significantly better detection rate for malignant focal liver lesions compared
      with double-phase spiral DPS-CECT but was associated with a higher rate of false
      positive findings.

PMID- 10598853
TI  - Single-session alcohol sclerotherapy in symptomatic benign hepatic cysts. Long
      term results.
AB  - PURPOSE: To evaluate the long-term results of single-session alcohol
      sclerotherapy of symptomatic benign liver cysts. MATERIAL AND METHODS: 23 cysts
      in 19 patients were treated by single-session percutaneous catheterization and
      injection of 96% ethanol. Evaluation of long-term results was possible in 11
      cysts (volume 200-2,700 ml, mean 1,317 ml) in 11 patients. Time of observation
      was 12-67 months, mean 38.3 months. RESULTS: The reduction of volume was 93-100%
      (mean 98%). The re-accumulation of fluid after therapy seen in 9 patients proved
      to be transitory. Except for pain there were no complications. CONCLUSION: Single
      session sclerotherapy resulted in satisfactory cyst volume reduction in all 11
      long-term follow-up patients.

PMID- 10598854
TI  - Power Doppler sonography of hepatocellular carcinoma treated by transcatheter
      arterial chemoembolization. Assessment of the therapeutic effect.
AB  - PURPOSE: To evaluate the usefulness of power Doppler sonography (PDS) in
      assessing the therapeutic effect of transcatheter arterial chemoembolization
      (TACE) in hepatocellular carcinoma (HCC). MATERIAL AND METHODS: TACE was
      performed in 43 patients (48 lesions) with HCC. All patients were examined with
      both PDS and color Doppler sonography (CDS) to assess the therapeutic results 1
      week after TACE. Follow-up hepatic angiography was performed in 39 patients 3-4
      months after TACE and then CT after iodized oil reinjection was also performed 3
      4 weeks after a repeat TACE; in the remaining 4 patients, hepatectomy was
      performed within one month after chemoembolization and histologic study was
      undertaken to confirm the Doppler findings. RESULTS: Determination of therapeutic
      results with PDS and CDS were in agreement with those of follow-up findings in 37
      and 29 of the 48 lesions, respectively. There was a significant difference in
      overall accuracy (p=0.038) between PDS and CDS results. CONCLUSION: PDS is more
      effective than CDS for evaluating changes in tumor vascularity after TACE. PDS
      may also replace angiography in assessing the therapeutic effects of TACE for
      HCCs, except in deep-seated areas.

PMID- 10598855
TI  - Localization of pancreatic insulinomas with MR imaging at 0.5 T.
AB  - OBJECTIVE: To determine the role of MR imaging in the localization of pancreatic
      insulinomas in patients with clinical and laboratory diagnosis of insulin
      producing tumor. MATERIAL AND METHODS: Thirty-one patients presenting with signs
      and symptoms of pancreatic insulinomas were prospectively included in our study.
      Twenty-six patients underwent surgery, and pathologic specimens were examined: 5
      patients, in whom the initial diagnosis of insulinoma was excluded, were also
      studied and then followed up. All patients were studied with a high gradient
      power 0.5 T magnet. Images were evaluated by 2 radiologists blinded to previous
      investigations, tests and results. RESULTS: MR imaging correctly localized 24 of
      the 26 insulinomas (2 were false-negative and 1 false-positive) and was correctly
      negative in the 5 control patients. The interobserver agreement had a kappa value
      of 0.89. CONCLUSION: MR imaging was accurate in localizing pancreatic insulinomas
      and as a consequence, patients in our institution are now submitted to surgery
      directly after the MR examination. Invasive methods are considered only in cases
      in which, despite clear biochemical results, MR imaging has not demonstrated a
      pancreatic focal lesion.

PMID- 10598856
TI  - Transcatheter embolization of a superior mesenteric artery pseudoaneurysm. A case
      report.
AB  - A 61-year-old man, with pseudoaneurysm of the superior mesenteric artery
      presenting with gastrointestinal bleeding, was successfully treated by
      transcatheter embolization using interlocking detachable coils. During the
      following observation time of 10 months, the patient had no sign of
      gastrointestinal bleeding. We underline the importance and feasibility of
      transcatheter embolization as the first-line treatment in such pseudoaneurysms.

PMID- 10598857
TI  - Radiological demonstration of gastroesophageal reflux. Diagnostic value of barium
      and bread studies compared with 24-hour pH monitoring.
AB  - PURPOSE: To correlate gastroesophageal reflux (GER), demonstrated by a
      radiological method using food, with the reflux events, as determined by 24-h pH
      monitoring. MATERIAL AND METHODS: One hundred and seventeen patients with a
      median age of 47 years (86 male and 31 female) were examined. In the supine left
      position, the patient consumed 360 ml of barium contrast. Fluoroscopy was
      performed with the patient in the supine right oblique position during
      mastication and swallowing a piece of rye bread with liver pate and barium. The
      test was positive if barium was observed > or =5 cm proximal to the
      gastroesophageal junction. An antimony pH-probe was placed 5 cm above the lower
      esophageal sphincter, previously determined by manometry. The position was
      controlled by radiography after positioning and before removal. The total time of
      esophageal pH<4 exceeding 5.0% was considered pathological. RESULTS: The
      radiological method had a specificity of 100% and a sensitivity of 52% compared
      to 24-h pH monitoring. CONCLUSION: The high specificity of this radiological
      method justify direct therapeutic consequence of a positive test. However, a
      negative test still renders the problem unsolved.

PMID- 10598859
TI  - Single-cell volume estimation by three-dimensional wide-field microscopy applied
      to astroglial primary cultures.
AB  - Astrocytes, which constitute a prominent part of the number and volume of brain
      cells, have a high capacity for controlling their volume, and astrocytic swelling
      is associated with a number of pathological states affecting the CNS. In order to
      understand the mechanisms for regulating cell volume in astrocytes better, it is
      of utmost importance to develop technical instrumentation and analysis methods
      capable of detecting and characterizing dynamic cell shape changes in a
      quantitative and robust way. For this purpose, a new method was developed to
      quantify changes in cell volume at the single-cell level. This method is based on
      three-dimensional (3D) fluorescence imaging obtained by optical sectioning. An
      automated image acquisition system was developed for the collection of two
      dimensional (2D) microscopic images. A deblurring algorithm was implemented in
      order to restore the originally unfocused image content. Advanced image analysis
      techniques were applied for accurate and automated determination of cell volume.
      The sensitivity and reproducibility of the method was evaluated by using
      fluorescent beads. The techniques were applied to fura-2-labeled astroglial cells
      in primary culture exposed to hypo- or hyperosmotic stress. The results show that
      this method is valuable for determining volume changes in cells or parts thereof.

PMID- 10598858
TI  - Predicting the effect of gonadotropin-releasing hormone (GnRH) analogue treatment
      on uterine leiomyomas based on MR imaging.
AB  - PURPOSE: To test the hypothesis that the simple assessment of signal intensity on
      T2-weighted MR images is predictive of the effect of hormonal treatment with
      gonadotropin-releasing hormone (GnRH) analogue. MATERIAL AND METHODS: The
      correlation between T2-weighted MR imaging of uterine leiomyomas and histologic
      findings was evaluated using 85 leiomyomas from 62 females who underwent
      myomectomy or hysterectomy. We also correlated the pretreatment MR images
      features obtained in 110 women with 143 leiomyomas with the effect of GnRH
      analogue treatment. The size (length x width x depth) of the leiomyoma was
      evaluated before and at 6 months after treatment by ultrasound. RESULTS: The
      proportion of leiomyoma cell fascicles and that of extracellular matrix affected
      signal intensities of uterine leiomyomas on T2-weighted MR images. The amount of
      extracellular matrix was predominant in hypointense leiomyomas on T2-weighted
      images, while diffuse intermediate signal leiomyomas were predominantly composed
      of leiomyoma cell fascicles. Marked degenerative changes were noted in leiomyomas
      with heterogenous hyperintensity. The homogeneously intermediate signal intensity
      leiomyomas showed significant size reduction after treatment (size ratio;
      posttreatment volume/pretreatment volume 0.29+/-0.11). The size ratio for the
      hypointense tumors was 0.82+/-0.14, and 0.82+/-0.18 for the heterogeneously
      hyperintense tumors. There was a significant difference in the response to
      treatment between the homogeneously intermediate signal intensity leiomyomas and
      the hypointense or heterogeneously hyperintense leiomyomas (both p<0.01).
      CONCLUSION: Signal intensity on T2-weighted MR images depends on the amount of
      leiomyoma cell fascicles and extracellular matrix. Simple assessment of the MR
      signal intensity is useful in predicting the effect of GnRH analogue on uterine
      leiomyomas.

PMID- 10598860
TI  - Vital imaging and ultrastructural analysis of individual axon terminals labeled
      by iontophoretic application of lipophilic dye.
AB  - We describe a method for in vivo confocal fluorescence imaging of synaptic
      terminals and subsequent electron microscopic reconstructions of the same
      terminals. By iontophoretically applying lipophilic dye to nerve terminals at a
      single neuromuscular junction with a sharp microelectrode in living neonatal
      mice, we were able to quickly label other synaptic terminals of the same motor
      unit. This vital labeling technique allows the same synapses to be imaged in
      living animals for several days. By using two dyes applied to separate junctions
      we could visualize competing axons converging at the same site. We also show that
      similar approaches can be used to study synaptic inputs to neurons. Following
      photoconversion, the dye labeled axons and synapses were easily identified and
      distinguished from unlabeled synapses of other axons ultrastructurally. This new
      labeling technique thus provides a useful means to study reorganization of
      synaptic structure at high temporal and spatial resolution.

PMID- 10598861
TI  - A novel fluorescent GSH-adduct binds to the NMDA receptor.
AB  - In an attempt to develop various fluorescent probes to label glutathione (GSH)
      receptors, we have serendipitously synthesized a probe that binds to and
      antagonizes the NMDA receptor. Probe 1, a GSH adduct, displaces the competitive
      NMDA antagonist [3H]-CGP 39653 with a higher affinity than NMDA or cysteine in
      rat synaptic membranes. In recording experiments from a rat cortical 'wedge'
      preparation, Probe 1 reversibly blocks both NMDA- and cysteine-induced
      depolarization. In mixed astrocyte-neuron tissue culture preparations, Probe 1
      labels parts of both cell bodies as well as processes. The present data suggest
      that Probe 1 binds to the NMDA receptor and antagonizes channel function.

PMID- 10598862
TI  - A multielectrode implant device for the cerebral cortex.
AB  - A new class of brain implant technology was developed that allows the
      simultaneous recording of voltage signals from many individual neurons in the
      cerebral cortex during cognitive tasks. The device allows recording from 49
      independent positions spanning a 2 x 2-mm region of neural tissue. The recording
      electrodes are positioned in a square grid with 350 microm spacing, and each
      microelectrode can be precisely independently vertically positioned using a
      hydraulic microdrive. The device utilizes ultrafine, sharp iridium
      microelectrodes that minimize mechanical disturbance of the region near the
      electrode tip and produce low noise neuronal recordings. The total weight of this
      device is less than 20 g, and the device is reusable. The implant device has been
      used for transdural recordings in primary somatosensory and auditory cortices of
      marmosets, owl monkeys, and rats. On a typical day, one-third of the
      microelectrodes yield well-discriminated single neuron action potential
      waveforms. Additional array electrodes yield lower amplitude driven multiunit
      activity. The average signal-to-noise ratio of discriminated action potential
      waveforms 6 months after implantation was greater than 9. Simple design
      alternatives are discussed that can increase the number of electrodes in the
      array and the depths at which dense array recordings can be achieved.

PMID- 10598863
TI  - A versatile microporation technique for the transfection of cultured CNS neurons.
AB  - The application of molecular techniques to cultured central nervous system (CNS)
      neurons has been limited by a lack of simple and efficient methods to introduce
      macromolecules into their cytosol. We have developed an electroporation technique
      that efficiently transfers RNA, DNA and other large membrane-impermeant molecules
      into adherent hippocampal neurons. Microporation allowed the use of either in
      vitro transcribed RNA or cDNA to transfect neurons. While RNA transfection
      yielded a higher percentage of transfected neurons and produced quantitative co
      expression of two proteins, DNA transfection yielded higher levels of protein
      expression. Dextran-based calcium indicators also were efficiently delivered into
      the cytosol. Microporated neurons appear to survive poration quite well, as
      indicated by their morphological integrity, electrical excitability, ability to
      produce action potential-evoked calcium signals, and intact synaptic
      transmission. Furthermore, green fluorescent protein (GFP)-tagged marker proteins
      were expressed and correctly localized to the cytosol, plasma membrane, or
      endoplasmic reticulum. The microporation method is efficient, convenient, and
      inexpensive: macromolecules can be introduced into most adherent neurons in a 3
      mm2 surface area while requiring as little as 1 microl of the material to be
      introduced. We conclude that the microporation of macromolecules is a versatile
      approach to investigate signaling, secretion, and other processes in CNS neurons.

PMID- 10598864
TI  - Adaptive phase estimation and its application in EEG analysis of word processing.
AB  - Oscillations are a general phenomenon of neuronal activity during information
      processing. Mostly, widespread networks are involved in brain functioning. In
      order to investigate network activity coherence analysis turned out to be a
      useful tool for examining the functional relationship between different cortical
      areas. This parameter allows the investigation of synchronisation phenomena with
      regard to defined frequencies or frequency bands. Coherence and cross phase are
      closely connected spectral parameters. Coherence may be understood as a measure
      of phase stability. Whereas coherence describes the amount of information
      transfer, the corresponding phase, from which time delays can be computed, hints
      at the direction of information transfer. Mental processes can be very brief and
      coupling between different areas may be highly dynamic. For this reason a two
      dimensional approach of adaptive filtering was developed to estimate coherence
      and phase continuously in time. Statistical and dynamic properties of
      instantaneous phase are discussed. In order to demonstrate the value of this
      method for studying higher cognitive processes the method was applied to EEG
      recorded during word processing. During visual presentation of abstract nouns an
      information transfer from visual areas to frontal association areas in the Alpha1
      frequency band could be verified within the first 400 ms. The Alpha1 band
      predominately seems to reflect sensory processing and attentional processes. In
      addition to conventional coherence analyses during word processing phase
      estimations may yield valuable new insights into the physiological mechanisms
      during word processing.

PMID- 10598865
TI  - A new planar multielectrode array for extracellular recording: application to
      hippocampal acute slice.
AB  - The present paper describes a new planar multielectrode array (the MED probe) and
      its electronics (the MED system) which perform electrophysiological studies on
      acute hippocampal slices. The MED probe has 64 planar microelectrodes, is covered
      with a non-toxic, uniform insulation layer, and is further coated with
      polyethylenimine and serum. The MED probe is shown to be appropriate for both
      stimulation and recording. In particular, multi-channel recordings of field EPSPs
      obtained by stimulating with a pair of planar microelectrodes were established
      for rat hippocampal acute slices. The recordings were stable for 6 h. Finally a
      spatial distribution of long-term potentiation was studied using the MED system.

PMID- 10598866
TI  - Immunohistochemistry of neural markers for the study of the laminar architecture
      in celloidin sections from the human cerebral cortex.
AB  - Morphometric studies of the cerebral cortex in celloidin sections provide
      reliable quantitative estimates of cytoarchitectural features in individual brain
      regions. To increase our knowledge about the morphology and distribution of
      neuronal and glial cell types using specific cellular markers, we compared two
      methods of celloidin removal/antigen recovery, and subsequent immunohistochemical
      staining of free floating sections with specific antibodies. The method based on
      methanol and NaOH for celloidin removal was the most adequate for optimal
      recovery of immunoreactivity of the neural markers NF200, MAP2, GFAP, calretinin,
      parvalbumin, calbindin-D28kD, and synaptophysin. The other method, based on a
      treatment with ethanol/ether and formic acid, gave good results in the
      immunostaining of NF200, GFAP and MAP2, but not the other markers named above.
      The immunostained sections were compared with nearby sections stained with cresyl
      violet in order to assign the immunoreactive structures to individual layers in
      the prefrontal cortex. Sections from blocks not embedded in celloidin showed a
      comparable distribution of all the antigens included in the present study. The
      present paper provides an antigen recovery technique for celloidin sections that
      can be applied to optimize studies on the cytoarchitecture and distribution of
      specific neural elements in the human cerebral cortex.

PMID- 10598867
TI  - A rapid method for determination of cell survival in primary neuronal DRG
      cultures.
AB  - A simple and rapid enzyme-linked immunosorbent assay (ELISA) has been developed
      to provide an alternative to cell counting to detect increases in cell survival
      in primary neuronal cultures. This sensitive assay has the advantage of being
      less time consuming and labour intensive than cell counting, can be used to
      quantify cell survival and is more accurate than estimation methods of counting.
      The ELISA uses an antibody raised to GAP-43, a growth-associated protein which is
      strongly expressed by developing and regenerating neurones. The effects of nerve
      growth factor (NGF), neurotrophin-3 (NT-3) and brain-derived neurotrophic factor
      (BDNF) on GAP-43 immunoreactivity in dissociated primary cultures of rat and
      chick dorsal root ganglia have been compared to results obtained by cell
      counting. Data show that human NGF produced the greatest increase in GAP-43
      immunoreactive neurones in both species; this increase in immunoreactivity
      correlated well with the increased survival shown by cell count data. Results
      prove that the ELISA can also be used to accurately detect small changes in cell
      survival as seen with NT-3 and BDNF, or potentiation of the effects obtained with
      the trophic factor NT-3. In conclusion, this ELISA may be a useful tool to detect
      neurotrophic effects of unknown agents or novel neurotrophins.

PMID- 10598868
TI  - Lactoferrin: a multifunctional glycoprotein.
AB  - Lactoferrin is an iron-binding glycoprotein found in milk, exocrine secretions of
      mammals, and in secondary granules from polymorphonuclear neutrophils. This
      review describes the wide spectrum of functions ascribed to lactoferrin, with
      special emphasis on the antimicrobial properties of this protein, and its derived
      peptides.

PMID- 10598869
TI  - Tyrosinase gene expression in clear cell sarcoma indicates a melanocytic origin:
      insight from the first reported canine case.
AB  - The aim of this study was to characterize a metastasizing soft tissue tumor in a
      dog, which clinically, grossly and histologically showed a close resemblance to
      human clear cell sarcoma, a soft tissue variant of malignant melanoma.
      Ultrastructurally, melanosomes were found, indicating a melanocytic origin of the
      tumor. Using reverse-transcription polymerase chain reaction, expression of the
      gene encoding tyrosinase was determined in tumor cells. With this first case of
      canine clear cell sarcoma, as well as the earlier report from our laboratory on
      amelanotic melanomas in the cat, we demonstrate that expression of the tyrosinase
      gene may occur in a broader range of less differentiated melanocytic tumors in
      different species, including man.

PMID- 10598870
TI  - High antibiotic consumption in Danish intensive care units?
AB  - Decreased antibiotic susceptibility among microorganisms isolated from intensive
      care unit (ICU) patients is found to be associated with high total antibiotic
      consumption or inappropriate use of antibiotics in the ICUs. The aims of this
      study were: 1) to characterize the antibiotic consumption in Danish ICUs, and in
      four ICUs with expectedly large differences in levels of antibiotic consumption,
      2) to estimate the association between antibiotic susceptibility among isolated
      microorganisms and antibiotic consumption. This was done by: 1) a retrospective
      questionnaire study of the annual supply of antibiotics in 1995 to 30 ICUs in
      Denmark, and 2) a 2-month prospective study of patients and microbiological
      samples in four Danish ICUs in 1996. We found that the supply of antibiotics to
      Danish ICUs was substantial, with a median value of 124 DDD/100 patient days. No
      association was found between high consumption of antibiotics and decreased
      antibiotic susceptibility in the four ICUs.

PMID- 10598871
TI  - The terminal complement complex is generated in chronic leg ulcers in the absence
      of protectin (CD59).
AB  - Loss of membrane complement regulators accompanied by complement activation is
      suggested to be involved in the pathophysiological processes leading to tissue
      damage in myocardial ischaemia. In the present study we have investigated whether
      the same phenomenon may occur in ischaemic and/or venous hypertension leg ulcers.
      The deposition of complement, plasma complement regulators and expression of
      membrane regulators were detected by immunohistochemical methods, including
      immunofluorescence with antibodies against C3d, the terminal complement complex
      (TCC), vitronectin, clusterin, decay-accelerating factor (CD55) and protectin
      (CD59). Eleven frozen biopsies from ischaemic leg ulcers, 10 biopsies from venous
      hypertension leg ulcers, and 10 biopsies from normal skin were studied. In 9 of
      11 ischaemic and in 5 of 10 venous hypertension leg ulcers, marked staining for
      TCC was found around the capillaries, most often at the ulcer margin. No TCC
      staining was found in normal skin. Staining for TCC was always accompanied by
      staining for clusterin and vitronectin and C3d. In normal skin, CD59 was found on
      the elastic fibers in the dermis, on the muscle coat, the Schwann sheath and
      acinar cells. Semiquantitative measurement of CD59 showed marked increased
      staining intensity in the endothelium in venous hypertension ulcers and
      diminished intensity in ischaemic ulcers compared to normal skin. No such
      difference could be observed for CD55. When TCC was positive in the capillary
      walls, weak or no staining for CD59 was found. A significantly higher ratio of
      TCC/CD59 was found in the ischaemic compared to venous ulcers (p = 0.018). This
      was due to a marked difference between the ulcer margins (p = 0.013). Localized
      areas in the venous ulcers had the same pattern as that seen in the ischaemic
      ulcers. Our results suggest that loss of CD59 may enhance deposition of TCC and
      that complement-dependent inflammation may be an important factor in the tissue
      damaging processes seen in chronic leg ulcers.

PMID- 10598872
TI  - In situ localization of S-phase-specific histone (H3) mRNA in Bowen's disease.
AB  - PCNA and Ki-67 immunohistochemistry has been used to assess cell proliferation in
      place of tritiated thymidine or BrdU labeling of S-phase cells. Recently, it has
      been possible to reliably demonstrate histone H3 mRNA by in situ hybridization in
      formalin-fixed and paraffin-embedded tissue sections. We have compared this new
      proliferation marker with Ki-67 and PCNA with regard to distribution of positive
      cells and labeling indices (LI%) for 22 cases of Bowen's disease. In normal skin,
      Ki-67-IHC positive cells and histone mRNA positive cells were observed in the
      basal and suprabasal layers of the epidermis. In Bowen's disease, positive cells
      with each marker were more frequent in upper neoplastic epidermis than in
      suprabasal layers, and the average LI%s were markedly elevated with all markers,
      the scores decreasing in the following order: PCNA-IHC, Ki-67-IHC and H3mRNA-ISH.
      However, the results of double staining demonstrated that S-phase cells do not
      necessarily show exactly the same distributions as with PCNA and Ki-67-IHC
      labeling. H3mRNA-ISH showed three different degrees of reaction with
      significantly different LI%s, whereas PCNA and Ki-67 LI% did not vary essentially
      in the same areas. These results strongly suggest that Bowen's disease, which is
      well known as a low-grade neoplastic state with malignant potential, also
      demonstrates clear intratumoral heterogeneity of S-phase cells using the H3mRNA
      ISH method.

PMID- 10598873
TI  - Immunohistochemical analysis of Fas ligand expression in normal human tissues.
AB  - Cross-linking of Fas and Fas ligand (FasL) induces apoptosis in Fas-bearing cells
      and regulates apoptosis. Fas is widely expressed in normal human tissues, but
      FasL expression has been considered to be restricted to lymphoid tissues. Recent
      studies have demonstrated that FasL is also expressed in some nonlymphoid
      tissues. To screen the in situ expression of FasL in normal human tissues,
      immunohistochemistry was performed using paraffin-embedded human tissues. FasL
      immunostaining was easily detected in testis, neurons, trophoblasts, tonsil,
      lymph node, Paneth cells, hepatocytes, renal tubular epithelium and bronchial
      epithelium, consistent with previous reports. Surprisingly, FasL was also
      expressed in many other cell types, including thymic medulla, skeletal muscle,
      cardiac muscle, pituitary gland, parathyroid gland, prostate glands, oocytes,
      epithelium of fallopian tube, endometrial glands, and gastric parietal cells.
      These findings demonstrate that FasL is widely expressed in human tissues and
      suggest that wide but cell-type specific expression of FasL may not only be
      implicated in the regulation of immune homeostasis but also in the regulation of
      cell death and life in many cell types in vivo.

PMID- 10598874
TI  - In vitro effect of fibrinogen on Candida albicans germ tube formation.
AB  - Pseudohyphae formation by Candida albicans blastoconidia, as seen in vaginal
      smears, is a phenotypical change commonly assumed to mean fungal invasiveness,
      i.e. not mere colonization. C. albicans forms germ tubes in vitro in the presence
      of serum. In our search for inhibitory components of germ tube formation, we
      decided to study fibrinogen. The inhibition of germ tube formation by clinical
      isolates of C. albicans was evaluated in the presence of serial concentrations of
      fraction I, type IV and fraction I, type Is of fibrinogen from bovine plasma.
      Fibrinogen showed a dose-dependent, pH-independent inhibitory effect on the germ
      tube formation by C. albicans.

PMID- 10598875
TI  - Functional differentiation of acute myeloid leukaemia blast cells.
AB  - Little is known of the functional status of blast cells from patients with acute
      myeloid leukaemia (AML). We have studied phagocytosis and membrane receptors by
      flow cytometry (FCM), and secretory activities in blast cells from 24 AML
      patients prior to treatment. Blast cells from 11/16 patients attached N.
      meningitidis, and internalization occurred in 7/14. The phagocytosis of zymosan
      particles and N. meningitidis correlated linearly (r = 0.9, p<0.01, n = 11).
      Surface membrane expression of CD32 and CD11b was sufficient to account for
      opsonin-dependent attachment in all except one patient. A significant fraction of
      the blast cells attached, but did not internalize meningococci. CD32 and CD11b
      were non-functional in all the blasts from five patients, and in a subpopulation
      from seven additional patients. Significantly more large than small blasts
      expressed CD32, CD35 and CD11b (p<0.001). Phagocytosis was unrelated to the
      secretion of IL-1alpha, IL-1beta, and TNFalpha. In conclusion, AML blast cell
      function is related to receptor expression, cell size and granularity, and to FAB
      type.

PMID- 10598876
TI  - The relationship between the acid and alkaline phosphatase activity and the
      adherence of clinical isolates of Candida parapsilosis to human buccal epithelial
      cells.
AB  - Candida parapsilosis is an emerging fungal pathogen implicated in many diseases,
      especially in compromised hosts. Candidal colonization and infection depends on
      the initial ability to adhere to host surfaces, which in turn depends upon the
      cell wall components and the allied structures of both the host and the fungus.
      Examination of a miscellaneous collection of 24 C. parapsilosis isolates, from
      both superficial and deep infections, for their potential pathogenic traits
      displayed a relationship between the phosphatase activity measured with p
      nitrophenol phosphate and adhesion of the yeasts to human buccal epithelial cells
      (BECs). Significant intraspecies differences were seen in both the alkaline and
      acid phosphatase activity as well as in their adhesion to BECs (p<0.0001). The
      acid phosphatase activity of the superficial isolates was significantly greater
      (152%) than that of the systemic isolates (p = 0.0352). A highly significant
      positive correlation was also established between the yeast adhesion to BECs and
      both the acid (r = 0.88, p<0.0001) and alkaline (r = 0.9, p<0.0001) phosphatase
      activity. These relationships, described here for the first time, imply that
      phosphatases of Candida species may play a crucial role in potentiating their
      virulence.

PMID- 10598877
TI  - Apoptosis and expression of caspases 3, 6 and 8 in malignant non-Hodgkin's
      lymphomas.
AB  - In this study we investigated the immunohistochemical expression of caspases 3, 6
      and 8 in 85 malignant non-Hodgkin's lymphomas and in 4 hyperplastic lymph nodes.
      The extent of apoptosis and the immunohistochemical expression of bcl-2 and bax
      was also studied. Caspase 3 immunoreactivity was seen in 84/85 (99%), caspase 6
      in 46/85 (54%), and caspase 8 in 66/85 (78%) lymphomas. The immunoreactivity for
      caspase 3 was diffuse cytoplasmic while antibodies to caspase 6 and 8 showed
      granular and fragmented, sometimes also nuclear immunopositivity. High-grade non
      Hodgkin's lymphomas expressed strong caspase 6 and 8 immunoreactivity
      significantly more often than low-grade lymphomas (p = 0.016 and p = 0.0002,
      respectively). Strong caspase 3 immunoreactivity was also seen more often in high
      grade lymphomas, but the association did not reach statistical significance (p =
      0.14). There was a strong association between the expression of caspase 3 and 6
      (p = 0.032), caspase 3 and 8 (p = 0.042), and especially between caspase 6 and 8
      (p = <0.00001). There was a significant difference in the apoptotic index between
      low-grade (0.59+/-0.44%) and high-grade lymphomas (1.96+/-1.92%) (p<0.001).
      Strong bcl-2 expression was seen in 35/80 (44%) and strong bax expression in
      20/80 (25%) lymphomas. No significant association was found between the
      expression of bcl-2 or bax and the expression of the caspases. According to the
      results the expression of caspases 6 and 8 is upregulated in high-grade compared
      with low-grade lymphomas and probably contributes to the execution of apoptosis
      in them. A similar tendency could also be seen with caspase 3. The expression of
      the three caspases is significantly associated, suggesting that it is mutually
      regulated. Finally, the results suggest that the expression of bcl-2 or bax does
      not influence the expression of caspases 3, 6 and 8 in malignant lymphomas to a
      significant degree.

PMID- 10598878
TI  - Effect of the anti-neoplastic agents edelfosine (ET-18-OCH3), ilmofosine (BM
      41.440) and the hexadecylphosphocholine analogues D-20133 and D-21266 on
      histamine release from isolated rat mast cells.
AB  - The ether phospholipid AMG-PC (1-O-hexadecyl-2-O-methyl-rac-glycero-3
      phosphocholine, ET-16-OCH3) affects rat mast cell responses in a dual manner. A
      powerful synergistic interaction with the ionophore A23187 and the phorbol ester
      TPA indicated an involvement of mechanisms relating to activation of protein
      kinase C. In contrast, the related hexadecylphosphocholine (miltefosine) only
      causes inhibition. Here, the investigation is extended to include the
      antineoplastic ether phospholipids ET-18-OCH3 (edelfosine) and BM 41.440
      (ilmofosine) as well as the heterocyclic hexadecylphosphocholine analogues D
      20133 and D-21266. The four test drugs had an influence very similar to that of
      AMG-PC on mast cell responses to selected secretagogues, i.e., they both enhanced
      and inhibited antigen-induced histamine release whereas only inhibition was
      observed with compound 48/80. They significantly amplified the response to A23187
      alone as well as in combination with TPA and, under certain conditions,
      inhibitory effects were observed with ET-18-OCH3, D-20133 and D-21266 but not
      with BM 41.440. The latter was more effective in enhancing A23187 mediated
      responses and had a wider concentration range of activity than the other three
      drugs. D-20133 and D-21266 influenced mast cells in a manner distinct from that
      of hexadecylphosphocholine and may share cellular targets with the ether
      phospholipids. The results raise speculation of an involvement of mast cells in
      the immunomodulatory action of these drugs.

PMID- 10598880
TI  - Activation of cellular responses to interleukin 6 is blocked by staurosporine.
AB  - Interleukin 6 (IL-6) acts on a wide spectrum of cells and can regulate
      differentiation or growth in these different cells. The effects of the microbial
      alkaloid staurosporine (SS) on IL-6 signaling through gp130, and also on the
      internalization of the IL-6 receptor complex, were studied using HepG2 cells
      which are well-characterized in their ability to respond to IL-6 by upregulating
      acute-phase protein production. SS was found effective in the blockade of the
      signaling cascade of IL-6: phosphorylation of both gp130 and Stat3 was eliminated
      by SS treatment and the production of IL-6 stimulated haptoglobin by the cells
      was abolished. In addition, SS reduced the internalization rate of 125I-IL-6 by
      50%, resulting in a retention of 125I-IL-6 on the cell surface and a
      corresponding decrease in degraded 125I-IL-6 in the extracellular medium. SS is
      commonly employed as an apoptosis inducing agent but the mechanism of its action
      is not clear. The ability of SS to void the capacity of IL-6, and IL-6-related
      cytokines such as Oncostatin M, to deliver growth and differentiation signals may
      be one process by which this agent could promote apoptosis in a variety of cell
      types.

PMID- 10598879
TI  - Accelerated recovery from cyclophosphamide-induced leukopenia in mice
      administered a Japanese ethical herbal drug, Hochu-ekki-to.
AB  - The effect of a Japanese ethical herbal drug, Hochu-ekki-to (HOT), on recovery
      from leukopenia induced by cyclophosphamide (CY) was investigated. Daily oral
      administration of 1000 mg/kg HOT into CY-treated mice significantly prevented
      decrease of leukocyte numbers in the peripheral blood and accelerated recovery
      from leukopenia. Ginsenoside Rgl extracted from Ginseng radix, a major herb of
      HOT, was one of the active ingredients. HOT increased numbers of neutrophils and
      monocytes in the peripheral blood compared with CY-treated control. Moreover, HOT
      augmented the resistance against Pseudomonas aeruginosa infection. The number of
      colony-forming units in the spleen (CFU-S) also increased in HOT-treated mice.
      The frequencies of IL-3-, GM-CSF- and IFN-gamma-producing cells increased in the
      spleen, bone marrow, liver and IEL on HOT treatment, and HOT clearly augmented
      the expressions of IL-3, GM-CSF and IFN-gamma mRNA in the spleen, bone marrow,
      liver and IEL except IL-3 and IFN-gamma mRNA in the IEL. These results suggest
      that HOT enhances the production of hematopoietic lymphokines, stimulates the
      proliferation of hematopoietic progenitor cells and consequently accelerates
      recovery from leukopenia in CY-treated mice. Additionally, IFN-gamma which HOT
      augmented the production may contribute the protective effect against the
      bacterial infection by activating of phagocyte cells.

PMID- 10598881
TI  - Inhibition of human B cell activation by a novel nonsteroidal anti-inflammatory
      drug, indometacin famesil.
AB  - Indometacin farnesil (INF) is a prodrug of indomethacin (IND) designed to reduce
      the occurrence of side-effects by esterification of the carboxyl group on IND
      with farnesol. Previous studies have shown that INF has the characteristics of
      disease-modifying anti-rheumatic drug (DMARD) in that it has a component of slow
      acting effect in treatment of rheumatoid arthritis (RA), in which abnormal B cell
      functions are considered to be involved. The current studies therefore examined
      the effects of INF on human B cells. Ig production was induced from highly
      purified B cells obtained from healthy donors by stimulation with Staphylococcus
      aureus Cowan I (SA) plus IL-2. T cell proliferation and IFN-gamma production were
      induced from highly purified T cells by stimulation with immobilized mAb to CD3.
      At pharmacologically attainable concentrations, INF, but not IND, suppressed the
      production of IgM and IgG of B cells, whereas neither suppressed the T cell
      proliferation and IFN-gamma production. The inhibition of Ig production by INF is
      not due to its IND structure, but is most likely due to its farnesil component,
      since farnesol alone comparably suppressed the Ig production. INF and farnesol
      did not suppress the expression of early activation markers, including CD98,
      CD25, and CD71, on SA-stimulated B cells, but appeared to inhibit the maturation
      of B cells following the initial activation. These results indicate that INF
      preferentially suppresses the human B cell functions. Thus, the data suggest that
      INF may have more beneficial effects than IND in treatment of RA.

PMID- 10598883
TI  - Burkholderia cepacia is resistant to the antimicrobial activity of airway
      epithelial cells.
AB  - There has been much interest recently in the antimicrobial properties of cationic
      peptides called beta-defensins from epithelial cells. Human beta-defensin (hBD)-1
      and -2 have been particularly implicated in cystic fibrosis (CF) patients, where
      their inhibition by high salt concentrations may explain in part the
      susceptibility of the CF lung to bacterial infection. In this work, we have
      employed a simple co-culture system using the 16-HBE human bronchial epithelial
      cell line to assess growth inhibitory activity against Pseudomonas aeruginosa and
      Burkholderia cepacia. In medium alone, P. aeruginosa proliferated more than
      100,000-fold, whereas in the presence of 16-HBE cells or 16-HBE-conditioned
      medium, bacterial proliferation was less than 100-fold. Raising the salt
      concentration of cell-free 16-HBE conditioned medium to approximately 200 mM
      significantly reduced this growth inhibitory activity. In contrast, there was no
      evidence of epithelial-derived growth inhibitory activity against two strains of
      B. cepacia. RT-PCR analysis indicated expression of the hBD-2 mRNA in 16-HBE
      cells, but not hBD-1. These data demonstrate for the first time that B. cepacia
      is resistant to epithelial-derived antimicrobial substances and argue against
      them being important in the defense against this organism in the lung.

PMID- 10598882
TI  - Hypothemycin inhibits the proliferative response and modulates the production of
      cytokines during T cell activation.
AB  - Hypothemycin, a resorcylic acid lactone antibiotic, was identified as active in a
      screen for inhibitors of T cell activation. It was found to inhibit the
      proliferation of mouse and human T cells stimulated with anti-CD3 mAb + PMA and
      of human PBMC stimulated with anti-CD3 mAb alone. This inhibition was partially
      reversed by exogenous IL-2 indicating that it is not due to non-specific
      toxicity. Hypothemycin potently suppressed the production of IL-2 (IC50: 9 nM)
      but affected IL-2-induced proliferation to a lesser extent (IC50: 194 nM).
      Hypothemycin also inhibited IL-6, IL-10, IFN-gamma and TNF-alpha production. By
      contrast, it markedly enhanced the production of IL-4, IL-5 and IL-13. These
      effects were seen both at the mRNA and protein secretion levels. Analysis of the
      effect of hypothemycin on CD69 induction suggested that it disrupts calcineurin
      independent rather than calcineurin-dependent signaling. Furthermore,
      hypothemycin was able to inhibit the phosphorylation of ERK1/2 induced by PMA
      treatment of T cells. Therefore, hypothemycin represents an inhibitor of T cell
      activation with a novel mode of action and unique modulatory activity on cytokine
      production.

PMID- 10598884
TI  - Multiple interleukin-2 signaling pathways differentially regulated by
      microgravity.
AB  - Defects in innate immunity have been demonstrated in astronauts after space
      flight. To investigate the role of microgravity on innate immune function, we
      evaluated NK and LAK activity of human PBMC stimulated with IL-2 under conditions
      of simulated microgravity, by using a rotating wall vessel (RWV) culture system.
      Under these conditions, both NK and LAK activity were generated at levels
      comparable to those found in static flask cultures. The phenotype of the
      activated PBMC was similar between the two culture conditions, with one notable
      exception: the IL-2 receptor alpha chain (CD25), which failed to be upregulated
      in simulated microgravity. To further investigate this change in IL-2 signaling,
      we examined the ability of IL-2 to induce secondary cytokines. The production of
      IFNgamma, IL-1beta, and TNFalpha was almost completely abrogated in the
      microgravity cultures, suggesting that the IL-2 signaling pathways leading to
      various IL-2-mediated effects are differentially regulated under bioreactor
      culture conditions.

PMID- 10598885
TI  - Improvement of murine immune functions in vitro by thioproline.
AB  - Previous studies have shown that several immune functions were improved in mice
      after the ingestion of a thioproline (thiazolidine-4-carboxylic acid) enriched
      diet. In the present work, we have studied the in vitro effects of several
      concentrations of this thiol compound (0.1, 0.5, 1, 2.5 and 5 mM) on the most
      relevant functions of three pivotal immune cells, namely, macrophages,
      lymphocytes, and natural killer (NK) cells from BALB/c mice. The results show
      that thioproline stimulates the phagocytic process of macrophages, increasing the
      mobility directed to the inflammatory focus (chemotaxis) and the phagocytosis of
      inert particles. It increases the adherence and the chemotaxis capacities of
      lymphocytes, their proliferative activity and favours the natural cytotoxic
      activity that could improve the capacity to destroy malignant cells. Thioproline
      concentrations of 0.5 and 1 mM were the most effective regarding the different
      functions analysed. These results suggest that the improvement of immune
      functions, observed in previous work, after thioproline-enriched diet ingestion
      is due to a direct action of this thiol compound on immune cells.

PMID- 10598886
TI  - Standard and new treatments for abdominal aortic aneurysms: the value of the
      Montefiore endovascular grafts for difficult aneurysms.
AB  - The mortality rate following rupture of an abdominal aortic aneurysm (AAA) is 80
      90% and the main goal of treatment is to prevent rupture. Treatment of the
      aneurysm is generally recommended for patients with an aneurysm larger than 5 cm
      in diameter, and the only effective treatment has been to replace the aneurysm
      with a prosthetic graft. Traditionally, this is performed through a major
      laparotomy; that is, open surgical repair, which itself carries a mortality rate
      of 4-8% and requires a hospital stay of 7-10 days. In addition, some sick
      patients are deemed a prohibitive risk for such major surgery and, therefore,
      treatment may be deferred. Endovascular grafts (EVGs) that enable treatment of
      patients with AAA without the need for laparotomy were developed in the hope of
      improving on the shortcomings of the standard repair technique. In addition to
      the various industry-made EVGs the authors have been using a surgeon-made
      Montefiore Endovascular Grafting System (MEGS). The recent introduction of
      several industry-made devices has prompted some to postulate that MEGS is no
      longer required. The 60 patients with AAA treated from 1 July 1997 to 30 June
      1998 were evaluated for the inclusion criteria for industry-made EVG protocols.
      Those excluded from these protocols were evaluated for the MEGS. Open surgical
      repair was reserved for those unsuitable for any EVG repair or those not
      consenting to EVG repair. Thirty-seven percent of all cases could be treated with
      an industry-made device. By using the MEGS, an additional 43% of the cases could
      be treated endovascularly. In total, 80% of AAAs were able to be treated
      endovascularly. The reasons for excluding patients from industry-made devices
      were a combination of the following factors: (1) Short (<1.5 cm) or angulated
      (>60) proximal necks, (2) iliac artery aneurysms, (3) small, diseased or tortuous
      access arteries, and (4) small distal aortas. The mean length of stay for those
      treated endovascularly was 2.3 days, whereas it was 9 days for those treated by
      open surgery. There was no difference in the morbidity and mortality rates. EVG
      repair is feasible and safe for the majority of patients with AAAs; however, long
      term durability is yet to be shown. Despite the availability of industry-made
      devices, there appears to be a continuing role for MEGS, especially for difficult
      aneurysms including those patients with complex anatomy and those with ruptured
      AAAs.

PMID- 10598887
TI  - Thrombolytic therapy can reduce the arrhythmogenic substrate after acute
      myocardial infarction: a study using the signal-averaged electrocardiogram,
      endocardial catheter mapping and programmed ventricular stimulation.
AB  - Thrombolytic therapy improves survival after acute myocardial infarction (AMI)
      primarily by preserving left ventricular function. Its influence on the
      arrhythmogenic substrate remains uncertain. To investigate the electrophysiologic
      effects of thrombolytic therapy, signal-averaged electrocardiography, endocardial
      catheter mapping and programmed stimulation were performed in 93 consecutive
      patients with their first AMI who underwent thrombolytic therapy. Early
      reperfusion was achieved in 75 patients (group 1), but not in 18 patients (group
      2). The incidence of the signal-averaged electrocardiogram abnormality was 11% in
      group 1 (8 of 75 patients) and 33% in group 2 (6 of 18 patients) (p<0.02).
      Catheter mapping detected delayed endocardial electrograms in 30 group 1 patients
      and 10 group 2 patients (p=NS). The spatial distribution of these electrograms
      was smaller, and the longest duration of endocardial electrograms was shorter in
      group 1 than in group 2 (p<0.01). Sustained monomorphic ventricular tachycardia
      was induced less commonly in group 1 (20%) than in group 2 (44%) (p<0.05). In
      conclusion, thrombolytic therapy can reduce the arrhythmogenic substrate and
      improve electrical stability after AMI. This antiarrhythmic effect may
      contribute, in part, to the improved survival of patients treated with
      thrombolytic drugs.

PMID- 10598888
TI  - Effects of exercise training on the recovery of the autonomic nervous system and
      exercise capacity after acute myocardial infarction.
AB  - This study investigated the effects of aerobic exercise training on the early
      phase of the recovery process following acute myocardial infarction (AMI) in
      terms of the autonomic nervous system, cardiac function and exercise capacity.
      Twenty-eight patients in the first week after the onset of AMI were assigned
      randomly to either a training group or a control group. The training group
      performed aerobic exercise for 2 weeks. Cardiopulmonary exercise testing was
      performed 3 times during the 3 months after the onset. Heart rate variability,
      plasma norepinephrine (NE) levels, and cardiac index (CI) during exercise were
      measured. In the training group, plasma NE level and deltaCI (peak CI-rest CI)
      were significantly improved from 1 to 3 weeks after the onset, and the high
      frequency of heart rate variability and peak oxygen uptake were significantly
      increased up to 3 months after the onset. In the control group, the plasma NE
      level and the deltaCI during the 1-3 weeks post-AMI, the high frequency of heart
      rate variability and the peak oxygen uptake showed a tendency to improve up to 3
      months after the onset. These results indicate that sympathetic nervous activity
      improves soon after the onset of AMI, in conjunction with improvement in cardiac
      function, and that this improvement is not affected by exercise training. In
      contrast, the recovery of parasympathetic nervous activity requires a longer
      period, along with the recovery of exercise capacity, which is facilitated by
      even short-term aerobic exercise training.

PMID- 10598889
TI  - Relation between coronary thrombus and angiographic no-flow during primary
      angioplasty in patients with acute myocardial infarction.
AB  - No flow is an unsolved issue in primary percutaneous transluminal coronary
      angioplasty (PTCA) for patients with acute myocardial infarction (AMI), and the
      pathophysiology of no-flow is undetermined. To evaluate the potential
      participation of coronary thromboembolism in no-flow during primary PTCA, the
      present study reviewed cinefilms of 256 consecutive patients who underwent
      primary PTCA for AMI within 24h after the onset of chest pain between January
      1992 and June 1998, focusing on the thrombus size. Angiographic no-flow was
      defined as the cessation of flow into the distal coronary circulation of the
      treated vessel with a to-and-fro contrast movement, not attributable to high
      grade stenosis or spasm of the original target lesion. The coronary thrombus size
      was determined by using the 2-cm balloon catheter as a reference after crossing
      the infarct-related occluded artery with a guide wire. Angiographic no-flow was
      observed in 37 patients (37/256, 14%): 14 of 29 cases (48%) with a large thrombus
      (> or =2cm) versus 23 of 227 cases (9%) with a small thrombus (<2cm, 14/29 vs
      23/227, p<0.01). Among 37 patients who experienced angiographic no-flow, overt
      distal emboli were observed in 14 patients. A thrombolytic agent was used through
      a guiding catheter in 102 cases prior to or after balloon dilatation to prevent
      or attenuate distal embolism, particularly in all those cases with a large
      thrombus (29/29 100%), and angiographic no-flow was seen in 27 cases of this
      subgroup (27/102, 26%). It is suggested that distal thromboembolism plays an
      important role in the mechanism of angiographic no-flow during primary PTCA
      performed for AMI.

PMID- 10598890
TI  - Effects of unilateral stellate ganglion block on the spectral characteristics of
      heart rate variability.
AB  - The effect of unilateral stellate ganglion block on cardiovascular regulation
      remains controversial, so the present study used power spectral analysis of heart
      rate variability to investigate its effect on the autonomic neural control of the
      heart. In 20 young healthy volunteers (mean age: 25 years), heart rate
      variability was determined before and after unilateral stellate ganglion block
      (right side 11, left side 9) using 8 ml of 1% mepivacaine during supine rest.
      Using autoregressive spectrum analysis, power spectra were quantified by
      measuring the area in 3 frequency bands: high-frequency power (lnHF,
      parasympathetic influence) from 0.15 to 0.40 Hz, low-frequency power (lnLF,
      predominantly sympathetic influence) from 0.04 to 0.15 Hz, and total-frequency
      power (lnTF) less than 0.40 Hz. Right stellate ganglion block decreased not only
      the lnLF component from 6.55+/-0.84 to 5.77+/-0.47 but also the lnHF component
      from 4.40+/-0.95 to 3.42+/-1.12 (p<0.05). In contrast, left stellate ganglion
      block changed neither the lnLF nor the lnHF component. The lnTF component was
      also decreased significantly by right stellate ganglion block from 7.80+/-0.95 to
      7.01+/-0.36 (p<0.05), but was unchanged following left stellate ganglion block.
      Neither right nor left stellate ganglion block induced any significant change in
      both the RR and corrected QT intervals. However, changes in the RR interval
      induced by right stellate ganglion block showed significant positive correlation
      with changes in lnHF (p<0.005) and lnTF (p<0.05). These results suggest that (1)
      autonomic innervation to the sinus node is mainly through the right-sided
      stellate ganglion, (2) pharmacological right-sided stellate ganglion block may
      attenuate not only sympathetic but also parasympathetic activity and (3)
      following right stellate ganglion block the decrease in both the sympathetic and
      parasympathetic influence on the sinus node may inconsistently counterbalance and
      change the RR interval.

PMID- 10598891
TI  - Gender differences in the presentation of adult obstructive hypertrophic
      cardiomyopathy with resting gradient: a study of 122 patients.
AB  - The present study investigated gender differences among adult patients with
      obstructive hypertrophic cardiomyopathy (OHCM) and resting gradient. Using
      outflow gradients >10 mmHg and the presence of asymmetrical septal hypertrophy of
      the left ventricle as inclusion criteria, 122 patients were identified among
      patients referred for echocardiographic examinations between May 1990 and October
      1996. Clinical, echocardiographical and follow-up data were compared between male
      and female patients. The female patients were significantly older than male
      patients (mean age +/-SD 66.7+/-10.5 vs 54.8+/-12.5 years). The female patients
      had a smaller interventricular septal wall thickness, less frequent systolic
      anterior movement of the mitral valve, more frequent association with
      hypertension, and less frequent association with ischemic heart disease (IHD) and
      giant T wave inversion. In this study population, adult female patients presented
      with OHCM 12 years later than males. Whether this represents female patients'
      reluctance to seek medical attention early, a different disease process that
      affects predominantly elderly females, or a gender-specific end organ response to
      aging, hypertension, IHD and other processes, or the protective effects of
      estrogen remains to be determined.

PMID- 10598892
TI  - Incidence and clinical significance of junctional rhythm remaining after
      termination of radiofrequency current delivery in patients with atrioventricular
      nodal reentrant tachycardia.
AB  - The aim of this study was to elucidate the electrophysiologic characteristics and
      clinical significance of the accelerated junctional rhythm (JR) that remains
      after termination of radiofrequency (RF) current delivery during catheter
      ablation (CA) for atrioventricular nodal reentrant tachycardia (AVNRT). Fifty
      consecutive patients with AVNRT (21M, 29F, age 48 years) underwent RF-CA
      targeting the slow pathway. JR occurred at 124 out of a total of 236 ablation
      sites (53%) during the RF delivery. With 15 RF deliveries (6.4%, n=10), JR
      remained after termination of the RF delivery (Post-JR). The mean cycle length of
      the Post-JR immediately after termination of the RF delivery was 639+/-124 ms and
      its duration was widely distributed from 3 s to more than 1 h. The Post-JR
      exhibited a spontaneous rate deceleration and overdrive suppression by rapid
      atrial pacing. The JR during the RF delivery followed by Post-JR had a greater
      time span in which the JR appeared, compared with that without Post-JR. The Post
      JR had less sensitivity(18 vs 96%), but greater specificity (97 vs 59%) and a
      positive predictive value (60 vs 39%) in predicting successful ablation compared
      with JR seen only during the RF delivery. It is concluded that the presence of
      Post-JR might be a reflection of the intense effect of RF energy on the nodal or
      peri-nodal tissue.

PMID- 10598893
TI  - Angiographic and clinical significance of 'transient' ST-segment depression in
      the lateral chest leads in anterior wall acute myocardial infarction.
AB  - This study aimed to clarify the significance of ST-segment depression in the
      lateral chest leads in anterior wall acute myocardial infarction (AMI) with ST
      segment elevation. A total of 196 patients with their first anterior wall AMI (<
      or =6h) were divided into 2 groups according to the presence (group A, n=39) or
      absence (group B, n=157) of ST-segment depression > or =0.1 mV in V5 and/or V6 on
      the admission electrocardiogram. Patients with electrocardiographic confounding
      factors were excluded. No patients had persistent ST-segment depression in the
      lateral chest leads. Emergency coronary angiography revealed that group A had
      higher incidences of occlusion of the left anterior descending coronary artery
      (LAD) proximal to its first septal branch (77% vs 51%, p<0.01) and good
      collateral circulation than group B (46% vs 25%, p<0.05). Peak creatine kinase
      levels were significantly lower in group A than in group B (2060+/-1099 vs 2873+/
      2077 IU/L, p<0.01). Left ventricular ejection fraction in the chronic phase was
      significantly greater in group A than in group B. Regional wall motion in the
      infarct region in the chronic phase was better in group A than in group B. These
      results indicate that patients with 'transient' ST-segment depression in the
      lateral chest leads in anterior wall AMI had a relatively smaller infarct size,
      despite their higher incidence of occlusion of the LAD proximal to its first
      septal branch, because of their higher incidence of good collateral circulation.

PMID- 10598895
TI  - Influence of exercise on QT dispersion in hypertensive patients with left
      ventricular hypertrophy without coronary artery disease.
AB  - In hypertensive patients with left ventricular hypertrophy (LVH), the influence
      of exercise on the regional variations in ventricular repolarization is not well
      understood. The present study compared dispersions of QT and QT apex (QTD and
      QTaD), which are indices of regional variations in ventricular repolarization,
      between hypertensive patients with echocardiographic evidence of LVH and those
      without LVH. Seventy essential hypertensive patients underwent a modified Bruce
      protocol exercise test, and QTD and QTaD were measured at rest and at peak
      exercise level. All subjects had undergone coronary angiography and did not have
      coronary artery disease. None of them showed ST-segment depression during or
      after exercise. There were 20 patients with LVH and 50 patients without LVH. The
      QTD and QTaD at rest were not different between the patients with LVH and those
      without LVH (56+/-32 vs 57+/-28 ms, 52+/-20 vs 49+/-23 ms). At peak exercise
      level, QTaD was significantly decreased compared with the baseline in
      hypertensive patients without LVH (49+/-23 to 42+/-16ms, p<0.05), whereas in
      patients with LVH QTaD increased (52+/-20 to 67+/-17ms, p<0.05). QTaD at peak
      exercise level was positively correlated with the left ventricular mass index
      (r=0.357, p=0.0024). These data were unchanged after correction for heart rate
      using Bazett's equation. In conclusion, QTaD increased after exercise in
      hypertensive patients with LVH. Inhomogeneity of repolarization is induced by
      exercise stress in hypertensives with LVH.

PMID- 10598894
TI  - Cardiac abnormalities in diabetic patients with mutation in the mitochondrial
      tRNA(Leu(UUR)) gene.
AB  - An A-to-G transition at position 3243 of the mitochondrial DNA is known to be a
      pathogenic factor for mitochondrial myopathy, encephalopathy, lactic acidosis and
      stroke-like episodes (MELAS), diabetes and cardiomyopathy. This mutation causes
      dysfunction of the central nervous system in MELAS. Because the heart, as well as
      the brain and nervous system, is highly dependent on the energy produced by
      mitochondrial oxidation, these tissues are more vulnerable to mitochondrial
      defects. Cardiac abnormalities were assessed in 10 diabetic patients associated
      with this mutation using echocardiography and 123I-metaiodobenzylguanidine (MIBG)
      scintigraphy, and compared with 19 diabetic patients without the mutation.
      Duration of diabetes, therapy, control of blood glucose and diabetic
      complications, such as diabetic retinopathy and nephropathy, were not different
      between the 2 groups. Diabetic patients with the mutation had a significantly
      thicker interventricular septum (16.8+/-3.7 vs 11.0+/-1.6mm, p<0.001) than those
      without the mutation. Fractional shortening was lower in diabetic patients with
      the mutation than those without it (30.7+/-7.0 vs 42.5+/-6.6, p<0.001). MIBG
      uptake on the delayed MIBG image was significantly lower in diabetic patients
      with the mutation than in those without the mutation (mean value of the heart to
      mediastinum ratio: 1.6+/-0.2 vs 2.0+/-0.4, p>0.05). In conclusion, left
      ventricular hypertrophy with or without abnormal wall motion and severely reduced
      MIBG uptake may be characteristic in diabetic patients with a mutation in the
      mitochondrial tRNA(Leu(UUR)) gene.

PMID- 10598896
TI  - Aortic valve replacement for aortic regurgitation caused by aortitis.
AB  - Between January 1984 and December 1998, 19 patients (16 with Takayasu's
      arteritis, 3 with non-Takayasu's aortitis) underwent surgical treatment for
      aortic regurgitation resulting from the aortitis. Of the 19 patients, 14 had
      aortic valve replacement (AVR) and 5 had aortic root replacement. One patient
      (5.3%) died of graft infection during the hospital stay. During the follow-up
      period, 1 (5.6%) of the 18 postoperative patients died of paravalvular leakage
      due to valve detachment, which also required redo-operations in 2 patients with
      non-Takayasu's aortitis. Both patients were operated on during the active phase
      of the inflammation without perioperative steroid therapy. Although transmural
      pledgeted sutures were used for replacement of the detached prosthetic valve in 1
      of these 2 patients, disruption of the aortic wall resulted in recurrence of
      valve detachment. In the other patient, aortic root replacement was successfully
      performed with the Cabrol technique in the second operation. Perioperaitve
      steroid therapy plays an important role in preventing complications after AVR
      when the valve replacement is carried out during the active phase of the
      inflammation, and for patients with non-Takayasu's aortitis, aortic root
      replacement should be considered to reduce the tension on the suture line and the
      native aortic valve annulus.

PMID- 10598897
TI  - Complete atrioventricular septal defect associated with tetralogy of fallot:
      surgical indications and results.
AB  - Complete atrioventricular septal defect (AVSD) associated with tetralogy of
      Fallot is a rare condition that still has problems in the postoperative period.
      The authors report their surgical experiences over the past 10 years. Nine
      children underwent total correction. The defect was repaired by the 2-patch
      technique and the ATrioventricular valve was reconstructed by suturing the cleft
      and annuloplasty. A transannular right ventricular outflow patch was used in 5
      patients. All patients had Down syndrome and a free-floating superior bridging
      lEAflet. One patient died from cardiac failure. Although there was no reoperation
      or death in the late postoperative periods, mild mitral regurgitation occurred in
      4 patients and there was moderate or severe pulmonary regurgitation in 2
      patients. All survivors currently have no critical symptoms in their daily lives.
      With the standard of patient selection used, the optimal body weight was around 8
      kg and PA index was 200 or more. Right ventriculotomy provided a better view for
      complete closure of the ventricular septal defect (VSD). In order to avoid re
      regurgitation of the atrioventricular valve, the 2-patch technique is the most
      suitable procedure for total repair.

PMID- 10598898
TI  - Correlation between atrial natriuretic peptide and baroreflex sensitivity in
      patients with congestive heart failure.
AB  - The aim of this study was to investigate the relationship between baroreflex
      sensitivity (BRS) and humoral factors in patients with congestive heart failure
      (CHF). BRS was assessed by the phenylephrine method in 16 patients with CHF and
      in 13 healthy controls. The CHF group was subdivided into 2 groups according to
      BRS (group A: <6 ms/mmHg, n=9; group B: > or =6 ms/mmHg, n=7). BRS was markedly
      depressed in CHF than in the controls (4.8+/-2.0 vs 8.3+/-3.6 ms/mmHg, p<0.01),
      and lower in group A than group B (3.3+/-1.3 vs 6.7+/-0.6 ms/mmHg, p<0.01). The
      plasma human atrial natriuretic peptide (h-ANP) level in group A was
      significantly higher than in group B (54.6+/-27.6 vs 18.0+/-7.4 pg/ml, p<0.01),
      and a significant inverse correlation was observed between plasma h-ANP and BRS
      (r=-0.635, p<0.01). However, there were no significant differences between the 2
      groups in plasma catecholamine concentration, plasma renin activity and cardiac
      function by echocardiogram. These findings suggest that the elevation of
      endogenous ANP may also serve to compensate for impaired BRS in patients with
      CHF, in addition to its principal actions, such as diuresis and vasodilation.

PMID- 10598899
TI  - Development and evaluation of a new canine myocardial infarction model using a
      closed-chest injection of thrombogenic material.
AB  - A new canine myocardial infarction model using thrombi induced by closed-chest
      injection of thrombin and autogenous blood with fibrinogen into coronary arteries
      was developed. Occlusive thrombi were formed in all treated animals. Occluded
      vessels did not spontaneously reperfuse 1 day after occlusion, but did so within
      3 days. Infarction was confirmed by increased levels of creatine kinase-MB,
      glutamate-oxaloacetate transaminase and a-hydroxybutyrate dehydrogenase.
      Additionally, the left ventricular ejection fraction (LVEF) decreased within 0.5
      h after occlusion and had not improved 4 weeks later. After 1 week, extensive
      transmural anteroinferior myocardial infarction was observed and heart mass had
      increased. By 4 weeks after occlusion, pulmonary capillary wedge pressure and
      central venous pressure were increased, and oxygen pressure was decreased.
      Dropout of nuclei in cardiomyocytes and increased amount of collagen fiber were
      observed in myocardial infarct regions of hearts excised 4 weeks after occlusion.
      This canine model may be useful and convenient in evaluating treatment efficacy
      and the long-term outcome of acute myocardial infarction.

PMID- 10598900
TI  - Sequential changes of hepatocyte growth factor in the serum and enhanced c-Met
      expression in the myocardium in acute myocardial infarction.
AB  - A 68-year-old male with acute myocardial infarction (AMI) was admitted to the
      hospital with chest pain that had started 1 day earlier. The serum levels (ng/ml)
      of hepatocyte growth factor (HGF) were 1.06, 1.22, 1.05, 0.72 and 0.64 on days 2,
      3, 4, 5 and 6 postinfarction, respectively. He died suddenly due to
      cardiopulmonary arrest on day 6. At autopsy, approximately 400 ml of bloody
      pericardial fluid, caused by rupture of the left ventricle, was detected and the
      c-Met expression in the myocardium was immunohistochemically found to be most
      intense in the border zone of the infarcted and non-infarcted region. Although
      there was no c-Met expression in the infarcted myocardium, it was increased in
      the myocardial cells surrounding the blood vessels. This is the first report to
      show sequential changes of HGF in the serum, as well as c-Met expression in the
      myocardium, in a patient with AMI.

PMID- 10598901
TI  - Pulmonary embolism due to right ventricular thrombus in a case of Behcet's
      disease.
AB  - Right ventricular thrombus is a very rare manifestation of cardiovascular
      Behcet's disease. A 25-year-old man was admitted to hospital due to cough and
      fever of unknown origin. He experienced repetitive pulmonary embolism due to a
      right ventricular thrombus, which was surgically removed. A diagnosis of Behcet's
      disease was made based on his clinical course and the histological findings of
      the right ventricular wall and the skin lesion. He was quickly relieved of his
      symptoms after warfarinization and cyclosporine therapy.

PMID- 10598902
TI  - Coronary dissection due to overdilatation of an elastic membrane of the multi
      link stent delivery system caused by balloon rupture.
AB  - A 65-year-old male with unstable angina underwent coronary angiography, which
      revealed a significant stenotic lesion in the right coronary artery. This
      narrowing was subsequently treated with the Multi-Link stent. During the balloon
      inflation associated with stent deployment, balloon rupture occurred and resulted
      in overdilatation of an elastic membrane in the stent delivery system. This, in
      turn, resulted in coronary dissection, which required treatment with further
      stenting.

PMID- 10598903
TI  - Unusual complications in an inflammatory abdominal aortic aneurysm.
AB  - An unusual case of an inflammatory abdominal aortic aneurysm (IAAA) associated
      with coronary aneurysms and pathological fracture of the adjacent lumbar
      vertebrae. The associated coronary lesions in cases of IAAA are usually
      occlusions. In the present case, it was concluded that a possible cause of the
      coronary aneurysm was coronary arteritis and the etiology of the pathological
      fracture of the lumbar vertebrae was occlusion of the lumbar penetrating arteries
      due to vasculitis resulting in aseptic necrosis. Inflammatory AAA can be
      associated with aneurysms in addition to occlusive disease in systemic arteries.
      The preoperative evaluation of systemic arterial lesions and the function of
      systemic organs is essential.

PMID- 10598905
TI  - Secretory leukocyte protease inhibitor (SLPI): oxidation of SLPI does not explain
      its variable anti-HIV activity.
AB  - Secretory leukocyte protease inhibitor (SLPI) has been proposed as a potential
      inhibitor of HIV-1 infection in human saliva. Although the ability of recombinant
      (r) SLPI to inhibit HIV-1 infection of macrophages and primary T-cells has been
      demonstrated by two independent laboratories, evidence to the contrary has also
      been reported. This study re-examines the anti-HIV effect of rSLPI and
      investigates the effects of repeated freeze-thawing and oxidation on the anti-HIV
      activity of rSLPI. rSLPI inhibited HIV-1BaL infection of human macrophages in a
      highly variable manner. HPLC and electrospray ionization mass spectrometry (ESI)
      analyses indicated that variability in our inhibition data could not be
      attributed to the degradation or oxidation of rSLPI. These results suggest that
      the variable anti-HIV effect of rSLPI may be due to differential expression of
      the cell-surface molecule(s) to which SLPI binds rather than to changes in the
      rSLPI molecule.

PMID- 10598904
TI  - Development of experimental oral carcinogenesis and its impact on current oral
      cancer research.

PMID- 10598906
TI  - Association between extent of periodontal attachment loss and self-reported
      history of heart attack: an analysis of NHANES III data.
AB  - Coronary heart disease is responsible for one of every five deaths in the United
      States. Recent epidemiological studies have shown an association between
      periodontal disease and coronary heart disease. The purpose of this cross
      sectional study was to verify this association using data from the third National
      Health and Nutrition Examination Survey (NHANES III). Data for 5564 people 40
      years of age and older who had complete periodontal assessments and information
      on heart attack were evaluated. The outcome was the self-reported history of
      heart attack (yes vs. no). The main independent variable was the percent of
      periodontal sites per person with attachment loss of 3 mm or greater (categorized
      as 0%, > 0-33%, > 33-67%, and > 67%). Periodontal attachment loss was measured at
      two sites per tooth in randomly assigned half-mouths, one upper and one lower
      quadrant. The covariables included sociodemographic variables and established
      risk factors for cardiovascular disease. Relative to the 0% category, the
      unadjusted odds of heart attack increased with each higher category of attachment
      loss-2.2 (95% confidence interval = 1.3-3.8), 5.5 (3.4-9.1), and 9.8 (4.5-21.0),
      respectively. Adjustment for age, sex, race, poverty, smoking, diabetes, high
      blood pressure, body mass index, and serum cholesterol decreased these odds to
      1.4 (0.8-2.5), 2.3 (1.2-4.4), and 3.8 (1.5-9.7), respectively. This study
      supports findings from previous studies of an association between periodontal
      disease and coronary heart disease.

PMID- 10598908
TI  - Expression of syndecan-2, -4, and fibroblast growth factor receptor type 1 in
      human periodontal ligament fibroblasts and down-regulation of these membrane
      proteins during maturation in culture.
AB  - Syndecans are transmembrane heparan sulfate proteoglycans. They are known to
      interact with basic fibroblast growth factor (bFGF), and it has been suggested
      that they play important roles in the growth, morphology, and migration of a
      variety of cell types. We examined the expression of syndecans and fibroblast
      growth factor receptor type 1 (FGFR1) in periodontal ligament (PDL) cells,
      because these membrane proteins may play roles in the control of growth and
      differentiation during regeneration of PDL. Reverse-transcription/polymerase
      chain-reaction (RT-PCR) showed that PDL cells expressed syndecan-2 and -4 mRNAs.
      This was confirmed by sequence analysis of the PCR products. When PDL cells were
      maintained for 25 days, alkaline phosphatase (ALPase) activity gradually
      increased and reached a maximal level on day 20. Northern blotting analysis
      showed that PDL cells expressed 2.3-kb syndecan-2, 2.6-kb syndecan-4, and 2.8-kb
      FGFR1 mRNAs throughout the entire culture period, whereas no syndecan-1 mRNA was
      detectable by this method. Maximal levels of syndecan-2, -4, and FGFR1 mRNAs were
      observed on day 5. However, their levels were markedly decreased on days 20 and
      25. Accordingly, the inhibitory effect of bFGF on ALPase activity was less on day
      20 than on day 5. When PDL cells were pre-treated with heparitinase, a mitogenic
      response of PDL cells to bFGF was decreased. These observations indicate that PDL
      cells express syndecan-2, -4, and FGFR1 mRNAs, and that those levels are changed
      with the increase in ALPase activity in culture. The reductions in syndecan-2, 
      4, and FGFR1 levels may be involved in the control of growth and differentiation
      of PDL cells during development and regeneration.

PMID- 10598907
TI  - TGFbeta isoforms and decorin gene expression are modified in fibroblasts obtained
      from non-syndromic cleft lip and palate subjects.
AB  - Interaction between extracellular matrix (ECM) and cytokines is thought to be
      crucial for palatal development. The localization of transforming growth factors
      (TGFalpha and TGFbeta isoforms) in craniofacial tissues suggests that they carry
      out multiple functions during development. In the present report, we studied
      TGFalpha, TGFbeta1, and TGFbeta3 expressions and their effects on ECM
      macromolecule production of normal and cleft palatal fibroblasts in vitro, to
      investigate the mechanisms by which the phenotypic modulation of fibroblasts
      occurs during the cleft palate process. The results indicated that, while
      TGFalpha mRNA was not evidenced in CLP or normal fibroblasts, a reduced TGFbeta1
      hybridization signal was detected in CLP fibroblasts. In addition, these secreted
      more active TGFbeta3 than TGFbeta1, as evaluated in a biological assay. The CLP
      phenotype, which differed from the normal one because of its higher PG decorin
      expression and greater production of GAG and collagen, was further modified by
      the addition of growth factors. In fact, in CLP fibroblasts, TGFalpha and
      TGFbeta1 down-regulated PG decorin transcript, TGFbeta1 increased collagen and
      GAG in both cellular and extracellular compartments, and TGFbeta3 promoted
      secretory processes of cells. In conclusion, the data represent the first report
      in a human model in vitro that TGFbeta1 and beta3 are differently expressed and
      are correlated to the CLP phenotype. Thus, strength is given to the hypothesis
      that TGFbeta isoforms are the potential inducers of phenotypic expression in
      palatal fibroblasts during development and that an autocrine growth factor
      production mechanism may be responsible for the phenotypic modifications.

PMID- 10598909
TI  - The diversity and distribution of the predominant ribotypes of Actinomyces
      naeslundii genospecies 1 and 2 in samples from enamel and from healthy and
      carious root surfaces of teeth.
AB  - The bacterial communities associated with root caries are highly diverse and
      undergo succession during lesion formation. Consequently, root caries is said to
      have a polymicrobic etiology, typified by variation in the predominant species
      among samples from different lesions. Despite the polymicrobic etiology, A.
      naeslundii genospecies 1 and 2 (previously A. viscosus) have consistently been
      shown to be associated with root caries in humans; they predominate in some
      lesions and have been suggested to play a significant role in the disease.
      Several genetic variants of A. naeslundii are known to be present among the oral
      A. naeslundii population of an individual. The current study was initiated to
      explore the possibility that a variant in these A. naeslundii populations had
      characteristics which made it best fitted to colonize or promote root-surface
      caries lesions. Using ribotyping to detect variants, we tested the hypothesis
      that 'a ribotype of A. naeslundii best fitted to the environment would be
      selected and predominate in the A. naeslundii population of lesions'. Samples of
      plaque from enamel, normal root surfaces, plaque overlying the lesion, and
      material from within the lesion were taken from nine patients with soft root
      caries. The flora from 14 lesions and 9 enamel sites was analyzed on selective
      and non-selective media, and A. naeslundii genospecies were identified by
      serology. We ribotyped 972 isolates, showing 54 different patterns. Between 6 and
      20 ribotypes were isolated from eight of nine patients. In general, each site
      from a patient showed a similar distribution of ribotypes. These results do not
      support the hypothesis and suggest that any phenotypic characters that allow A.
      naeslundii genospecies 1 and 2 to colonize or contribute to the formation of root
      caries lesions are common among strains identified by ribotyping.

PMID- 10598910
TI  - Masticatory force and function in patients with hemispheric brain infarction and
      hemiplegia.
AB  - Recent functional animal studies have reported that the motor control of
      masticatory muscle function is bilaterally guided by both hemispheres, which may
      fundamentally differ from the cortical control of limb muscle function. In this
      study, we investigated whether unilateral cortical brain infarction induces
      different impairments in masticatory and upper limb motor performance. Evidence
      of the importance of both hemispheres in controlling masticatory movements would
      be greater if the masticatory function were shown to be unimpaired in patients
      with severe hemiplegia. The masticatory function of 16 patients with severe
      hemiparesis caused by brain infarction in the region of the middle cerebral
      artery was studied by means of interview, clinical examination, and bite-force
      measurements. Finger-thumb grip-force measurements and clinical examination of
      the upper limbs were also performed for evaluation of the effect of infarction on
      upper limb motor function. Localization of the infarction was confirmed with
      computer tomography and magnetic resonance imaging. The Scandinavian Stroke Scale
      demonstrated that each patient had a major unilateral cortical infarction which
      had caused a marked handicap with a serious impairment of upper limb function on
      the contralateral side. The clinical examination revealed no major signs of
      temporomandibular disorders, and the masticatory muscles, when examined by
      palpation, contracted symmetrically. None of the patients with unilateral brain
      infarction showed any differences in bite forces between the healthy and
      paralyzed sides. These results indicate that, in hemiparetic patients, great
      differences may exist between the motor performances of the masticatory and upper
      limb muscles. The present investigation clinically illustrates the importance of
      both hemispheres in the control of masticatory function and movements.

PMID- 10598911
TI  - The intra-articular distance within the TMJ during free and loaded closing
      movements.
AB  - Previous studies on free opening and closing movements of the mandible have
      demonstrated that the opening movement traces of the condylar kinematic center
      (i.e., the condylar point for which the protrusive and the opening movement
      traces coincide) lie closer to the articular eminence than the closing traces.
      This indicates the presence of an intra-articular distance within the joint
      during free closing. Since the mandible behaves like a class III biomechanical
      lever, a counteracting mechanical load on the mandible during closing will press
      the condyle-disc complex against the articular eminence. Therefore, in this study
      the hypothesis was tested that the difference between opening and closing
      movement traces of the kinematic center is reduced when the closing movements are
      counteracted by a mechanical load. From 10 healthy participants, 20-second
      movement recordings were obtained by a six-degrees-of-freedom opto-electronic jaw
      movement recording system (OKAS-3D) for three types of movements: (1) free
      opening and closing movements, (2) free opening and loaded closing movements
      (i.e., the participants closed against a small or high manually applied downward
      directed force to the chin), and (3) gum chewing. Off-line, the opening and
      closing movement traces of the kinematic center were reconstructed, and the
      average difference between the traces (the intra-articular distance) was
      calculated. The average intraarticular distance was significantly smaller during
      loaded closing than during free closing, whereas no significant differences were
      found in the intra-articular distances between the loaded situations of low and
      high manual loading and contralateral chewing (ANOVA and post hoc Bonferroni
      multiple comparisons of means test, p<0.005). In conclusion, loading of the
      mandible during closing movements reduces the intra-articular distance within the
      temporomandibular joint.

PMID- 10598912
TI  - Thickness of acquired salivary pellicle as a determinant of the sites of dental
      erosion.
AB  - Dental erosion shows a typical distribution pattern within the dental arches.
      Tooth protection from erosion by salivary pellicle has been shown in vitro, but
      the hypothesis that pellicle may differ quantitatively at sites of erosion has
      not been investigated. This study aimed to determine the thickness of acquired
      salivary pellicle within the dental arches, investigate the possible relationship
      of this thickness to the distribution and severity of erosion within the arches,
      and confirm the protective effect of pellicle against dental erosion. Eight
      enamel blocks were produced from each of 5 bovine incisors assigned to five
      volunteers. Each block was further cut into 2 slabs, producing control and
      experimental slabs. Pellicle developed on experimental slabs located on 8 intra
      oral sites after 1 hr of exposure was stained by "sheep anti-human IgGAM-FITC".
      Slabs were then visualized, and pellicle thickness measured, by confocal laser
      scanning microscopy. Eroded enamel lesions were produced in experimental and
      control slabs by means of pure orange juice. The degree of erosion was quantified
      by transverse microradiography. Pellicle thickness varied significantly within
      the dental arches and among individuals. An inverse relationship (r = -0.96,
      p<0.001) was observed between the degree of erosion and pellicle thickness.
      Significant differences in erosion were observed between slabs with and those
      without pellicle. This study has shown that the thickness of acquired salivary
      pellicle varies within the dental arches, which may be responsible for the site
      specificity of dental erosion, and that pellicle does protect the teeth from
      erosion.

PMID- 10598913
TI  - Ultrastructural properties of laser-irradiated and heat-treated dentin.
AB  - Previous studies using scanning electron microscopy and infrared absorption
      spectroscopy reported that laser irradiation causes compositional changes in
      enamel. The purpose of this study was to evaluate the ultrastructural and
      compositional changes in dentin caused by irradiation with a short-pulse laser (Q
      switched Nd:YAG). The irradiated and non-irradiated areas of the lased dentin
      samples were investigated by scanning (SEM) and transmission electron microscopy
      (TEM), micro-micro electron diffraction, and electron microprobe analysis of
      dispersive energy (EDX). Heat-treated dentin was similarly investigated. This
      study demonstrated that laser irradiation resulted in the recrystallization of
      dentin apatite and in the formation of additional calcium phosphate phases
      consisting of magnesium-substituted beta-tricalcium phosphate, beta-TCMP, beta
      (Ca,Mg)3(PO4)2, and tetracalcium phosphate, TetCP, Ca4(PO4)O. TEM analyses of the
      modified and unmodified zones of the irradiated areas showed two types of crystal
      populations: much larger crystals from the modified zone and crystals with size
      and morphology similar to those of dentin apatite in the unmodified zone. The
      morphology of crystals in the modified zones in the irradiated dentin resembled
      those of dentin sintered at 800 or 950 degrees C. In the irradiated areas
      (modified and unmodified zones), the Ca/P ratio was lower compared with that in
      the non-irradiated dentin. The Mg/Ca ratio in the modified zones was higher than
      that in the unmodified zones and in the non-irradiated dentin. In sintered
      dentin, the Mg/Ca ratio increased as a function of sintering temperature. The
      ultrastructural and compositional changes observed in laser-irradiated dentin may
      be attributed to high temperature and high pressure induced by microplasma during
      laser irradiation. These changes may alter the solubility of the irradiated
      dentin, making it less susceptible to acid dissolution or to the caries process.

PMID- 10598914
TI  - Images in infectious diseases in obstetrics and gynecology. Human papillomavirus
      infection and cervical dysplasia.

PMID- 10598915
TI  - Gram stain method shows better sensitivity than clinical criteria for detection
      of bacterial vaginosis in surveillance of pregnant, low-income women in a
      clinical setting.

PMID- 10598916
TI  - Puerperal and intrapartum group A streptococcal infection.
AB  - OBJECTIVE: To determine the demographic and clinical variables characteristic of
      non-epidemic intrapartum or puerperal group A streptococcal (GAS) infection.
      METHODS: The records of 47 patients diagnosed with intrapartum or puerperal GAS
      infection over a 6 1/2 year period at Hadassah-University Hospital-Mt. Scopus,
      Jerusalem were reviewed. Data regarding 25,811 women, the general population of
      women that delivered during that period, were obtained from their computerized
      medical records. Frequency distributions, t-test, chi-square, and Spearman's Rank
      Correlation were used, as appropriate, to analyze and compare demographic and
      clinical variables associated with development of GAS infection, its clinical
      course and subsequent development of septic shock. RESULTS: Mean age of mothers
      with GAS infection was higher than that of our general pregnant population (30.4
      versus 27.4 years, P = 0.0019), and a higher proportion of GAS infected patients
      (30% versus 12%, P < 0.005) experienced PROM. Thirty-one (66%) women had fever as
      their sole presenting symptom, eight (17%) had fever and abdominal pain, seven
      (15%) had fever and abnormal vaginal bleeding, and one patient (2%) presented
      with a rash. Three patients (6%) developed a septic shock. Two of these patients
      presented with symptoms more than 14 days after delivery. CONCLUSIONS: We
      describe the characteristics of non-epidemic intrapartum or puerperal GAS
      infection. Data from our study and review of the literature suggest that some
      patients who develop septic shock may present later in the puerperium than
      patients with an uncomplicated GAS infection.

PMID- 10598917
TI  - Risk of hepatitis B transmission after amniocentesis in chronic hepatitis B
      carriers.
AB  - OBJECTIVE: To measure the risk of perinatal transmission of HBV in chronic
      carriers who undergo amniocentesis. METHODS: This was a prospective, longitudinal
      study from 1990 to 1995 of women who were HBV carriers and underwent
      amniocentesis. The infants of these women were followed from birth to one year of
      age. Maternal data examined included HBV antigen and antibody status, liver
      function tests (LFTs) and the amniocentesis report. RESULTS: Twenty-eight women
      were identified. Two of 28 neonates were stillborn unrelated to hepatitis. Five
      infants were lost to follow-up leaving 21 mother-child pairs to evaluate. All 21
      women were chronic HBV carriers at the time of amniocentesis for delivery. No
      mother had abnormal LFTs, and only one of 21 women was positive for hepatitis B e
      antigen (HBeAg). Thirteen amniocenteses were for advanced maternal age, and four
      were for abnormal maternal serum alphafetoprotein (MSAFP) screening. None of the
      amniocenteses were recorded as bloody, and the placenta was anterior in 6 of 21
      procedures. None of the 21 infants (95% CI: 0-16.8%) were positive for HbsAg
      during the first month of life or at 12 months of age. All infants received HBV
      vaccine and HBIG immunoprophylaxis. CONCLUSION: The risk of transmission of HBV
      to the fetus after amniocentesis in women who are HBV carriers is low.
      Immunoprophylaxis in these infants was successful.

PMID- 10598919
TI  - Thrombolysis for acute stroke.
AB  - Thrombolysis for acute stroke is effective if administered according to the
      approved protocol. Since the initial report of success in 1995, a number of
      subsequent reports confirmed the safety and efficacy of this treatment. There is
      no particular subgroup of patients at increased likelihood of benefit or
      hemorrhage that can be identified at baseline. Unlike many expensive therapies,
      thrombolysis for acute stroke saves the health care system considerable long-term
      costs. The search for even safer and more effective thrombolytics continues.

PMID- 10598918
TI  - Pattern of parvovirus B 19 infection during different trimesters of pregnancy in
      Kuwait.
AB  - OBJECTIVE: Aims of this study were to determine the IgG and IgM seropositivity to
      parvovirus B19 during the three trimesters of pregnancy. METHODS: Initially, a
      total of 1,047 pregnant women were included in a prospective study. Blood samples
      were obtained from 343, 406 and 298 cases in the first, second and third
      trimesters, respectively. To study the incidence of seroconversion, a second
      sample of blood was obtained 2-4 weeks later from the first 100 cases, who were
      IgG and IgM negative in the first trimester. RESULTS: The seroprevalence of
      parvovirus B19 IgG and IgM was 53.3% and 2.2%, respectively. The incidence of
      seroconversion was 16.5%. The rate of fetal loss was 15.4% in patients with acute
      infection, all of which occurred in the first two trimesters. CONCLUSIONS: The
      percentage of IgG positive cases is significantly higher in first and second
      trimesters compared to the third trimester. The seroconversion rate was 16.5%.

PMID- 10598921
TI  - Ischemic brain edema.
AB  - Brain edema is a life-threatening complication of cerebral infarction. The
      molecular cascade initiated by cerebral ischemia includes the loss of membrane
      ionic pumps and cell swelling. Secondary formation of free radicals and proteases
      disrupts brain-cell membranes, causing irreversible damage. New diagnostic
      methods based on magnetic resonance imaging have markedly improved diagnostic
      accuracy. Cytotoxic and vasogenic edema is maximal by 24 to 72 hours after the
      ischemic event. Thrombolytics reperfuse tissue and improve outcome; when
      treatment is delayed, they can increase edema and blood-brain barrier opening.
      Although osmotherapy reduces brain water, and is used to treat ischemic edema,
      its efficacy remains to be proven. As the molecular events become clearer, novel
      treatments that block different stages of the injury cascade will be available
      for clinical testing.

PMID- 10598922
TI  - Cerebral hemorrhagic complications of thrombolytic therapy.
AB  - Thrombolytic therapy is well established in the management of a select group of
      atherothrombotic and thromboembolic diseases at the expense of definite but
      increased risk of intracranial hemorrhage. The incidence of intracranial
      hemorrhage is higher (6.4% to 20%) in the thrombolytic treatment of acute
      ischemic stroke, whereas the cerebral hemorrhagic complications of thrombolytic
      treatment in acute myocardial infarction, acute pulmonary embolism, deep venous
      thrombosis, and arterial and graft occlusion is less than 2%. Although systemic
      fibrinolysis after thrombolysis is responsible for hemorrhagic complications,
      many factors are implicated in predisposition to cerebral hemorrhagic
      complications such as old age, untreated or chronic hypertension, history of
      cardiac disease, hyperglycemia, patients with small body mass, previous stroke,
      longer therapeutic treatment window, increasing neurological deficit or severity
      of neurological deficit, higher thrombolytic dose and computed tomography
      findings of mass effect, edema, or extended infarct sign involving more than one
      third of the territory of the middle cerebral artery. Although the knowledge of
      different factors associated with intracranial hemorrhage is important, it is the
      judicious use and strict adherence of appropriate clinical protocols in different
      clinical settings of thrombolytic treatment and avoidance of the contra
      indications that will minimize the rate of hemorrhagic complication to achieve
      good clinical outcome and desired benefit.

PMID- 10598920
TI  - Biology of ischemic cerebral cell death.
AB  - With the approval of alteplase (tPA) therapy for stroke, it is likely that
      combination therapy with tPA to restore blood flow, and agents like glutamate
      receptor antagonists to halt or reverse the cascade of neuronal damage, will
      dominate the future of stroke care. The authors describe events and potential
      targets of therapeutic intervention that contribute to the excitotoxic cascade
      underlying cerebral ischemic cell death. The focal and global animal models of
      stroke are the basis for the identification of these events and therapeutic
      targets. The signalling pathways contributing to ischemic neuronal death are
      discussed based on their cellular localization. Cell surface signalling events
      include the activities of both voltage-gated K+, Na+, and Ca2+ channels and
      ligand-gated glutamate, gamma-aminobutyric acid and adenosine receptors and
      channels. Intracellular signalling events include alterations in cytosolic and
      subcellular Ca2+ dynamics, Ca2+ -dependent kinases and immediate early genes
      whereas intercellular mechanisms include free radical formation and the
      activation of the immune system. An understanding of the relative importance and
      temporal sequence of these processes may result in an effective stroke therapy
      targeting several points in the cascade. The overall goal is to reduce disability
      and enhance quality of life for stroke survivors.

PMID- 10598923
TI  - Limited field irradiation for medically inoperable patients with peripheral stage
      I non-small cell lung cancer.
AB  - The outcome of limited field irradiation for medically inoperable patients with
      peripheral stage I non-small cell lung cancer (NSCLC) was analyzed to discuss the
      elective irradiation of regional lymph nodes. From 1976 through 1994, 36 patients
      with peripheral stage I NSCLC were treated with definitive radiation therapy (RT)
      alone at Gunma University hospital. The total dose ranged from 60 to 81 Gy with a
      2 Gy-daily standard fractionation, although only one patient received 48 Gy. Ten
      patients received elective irradiation of the regional lymph nodes with a total
      dose of 40 Gy or more. The overall response rate was 97% with 31% complete
      responses. The overall survival rates at 3 and 5 years were 42 and 23%, and
      disease-specific survival rates were 56 and 39% at 3 and 5 years, respectively.
      In 26 patients without the elective regional irradiation, disease-specific
      survival rates at 3 and 5 years were 53 and 40%, respectively, whereas they were
      64 and 39% in 10 patients with the regional nodal irradiation. The cumulative 5
      year local progression rate was 28%, and the overall progression rate was 60% at
      5 years. Four patients had a local recurrence as the only site of initial tumor
      progression. Combined local and regional progression was seen in two patients,
      and one patient had a local recurrence in combination with distant metastasis.
      Twelve patients had distant failure without evidence of local or regional
      progression. Only one patient without regional nodal irradiation developed an
      isolated regional failure. No patient had serious complications related to RT.
      High-dose limited field RT is justified for medically inoperable patients with
      peripheral stage I NSCLC. The regional nodal irradiation can be omitted in these
      pulmonary compromised patients because of the low regional relapse rate. Dose
      escalation by a conformal RT with a small target volume can be expected to
      provide a better local control rate and better survival.

PMID- 10598925
TI  - An evaluation of the tumour markers, carcinoembryonic antigen (CEA), cytokeratin
      marker (CYFRA 21-1) and neuron-specific enolase (NSE) in the differentiation of
      malignant from benign solitary pulmonary lesions.
AB  - PURPOSE: The aim of this prospective study was to assess the diagnostic value of
      the tumour markers carcinoembryonic antigen (CEA), cytokeratin 19 fragment marker
      (CYFRA 21-1) and neuron-specific enolase (NSE) in the differentiation of
      malignant (MSPLs) from benign solitary pulmonary lesions (BSPLs). METHODS:
      Solitary pulmonary lesions (SPLs) were diagnosed using plain radiography and
      spiral computed tomography (SCT) and then completely removed by surgery in 104
      consecutive patients (MSPLs; n = 81, BSPLs; n = 23). The serum concentrations of
      the tumour markers were determined 1-3 days prior to surgery by ELISA for CEA and
      CYFRA 21-1 and by IRMA for NSE using commercially available assay kits. The cut
      off values were set at 3 ng/ml (for non-smokers) and 5 ng/ml (for smokers) for
      CEA, at 3.3 ng/ml for CYFRA 21-1 and at 12.5 ng/ml for NSE. RESULTS: MSPLs were
      identified with a sensitivity between 13.6 and 45.7%, a specificity between 87.0
      and 100% and an accuracy between 32.7 and 54.8%. Using the tumour markers alone,
      the highest sensitivity (27.2%) and accuracy (40.4%) was found with CEA, the
      highest specificity (100%) with CYFRA 21-1 and with NSE. Primary lung cancers (n
      = 39) were identified with a sensitivity between 17.9 and 61.5%, a specificity
      between 87.0 and 100% and an accuracy between 48.4 and 71.0%. Using the tumour
      markers alone, the highest sensitivity (35.9%) and accuracy (59.7%) was found
      with CYFRA 21-1, the highest specificity (100%) with CYFRA 21-1 and with NSE. The
      combination of all three tumour markers resulted in a greater sensitivity and
      greater diagnostic accuracy but a loss in specificity compared with CYFRA 21-1
      and NSE. CONCLUSION: The use of the tumour markers alone or in combination showed
      a low sensitivity and low accuracy for the diagnostic differentiation of MSPLs
      from BSPLs and primary lung cancers from BSPLs. However, both CYFRA 21-1 and NSE
      exhibited a specificity of 100% and may be useful complements to standard
      clinical imaging methods.

PMID- 10598924
TI  - Postoperative adjuvant adoptive immunotherapy with lymph node-LAK cells and IL-2
      for pathologic stage I non-small cell lung cancer.
AB  - We conducted a clinical trial of adoptive immunotherapy with lymph node
      lymphokine-activated killer (LN-LAK) cells and recombinant interleukin 2 (rIL-2)
      for a surgical adjuvant therapy of pathologic stage I non-small cell lung cancer.
      The regimen consisted of the subcutaneous administration of low-dose rIL-2 for 6
      consecutive days and the transfer of ex vivo generated LAK cells from regional
      lymph node lymphocytes, obtained at the time of surgical operation. A group of 19
      patients with primary lung cancer received the immunotherapy about 2 weeks after
      surgery (pulmonary lobectomy). The regimen was postoperatively well tolerated by
      the patients. In peripheral blood lymphocytes (PBL) obtained after the treatment,
      the proportion of CD3+ T cells predominantly increased with the increase of CD4+
      T cell subsets. On the other hand, the proportion of CD20+ B cells decreased.
      Both NK and LAK activity of PBL significantly increased. However, the
      immunomodulatory effects did not result in a prolongation of the postoperative
      survival time in comparison to the postoperative survival of patients (n = 21)
      with surgery alone during the same period. These results suggested that the
      treatment with low-dose LN-LAK cells and concurrent low-dose IL-2 could,
      therefore, neither reduce nor eradicate minimal micrometastatic diseases.

PMID- 10598926
TI  - Evidence that thrombin present in lungs of patients with pulmonary metastasis may
      contribute to the development of the disease.
AB  - Early cellular events in the lung which may lead to the development of pulmonary
      metastases (PM) are still poorly understood. Thrombin, a key component of the
      coagulation cascade, may be involved in the development of PM as it has been
      shown to be an enhancer of platelet-tumor interaction in vitro and metastasis in
      vivo, and because it has been found in high levels in lungs from patients with
      PM. In this study, we assessed the potential role of thrombin in promoting PM by
      inducing an enhancement of tumor cell adhesion to platelets and tumor cell
      chemoinvasion and proliferation. We used bronchoalveolar lavage fluid (BALF) from
      20 patients with PM. Results were compared with those from healthy controls. We
      found an enhancement of adhesion of PM-BALF-treated tumor cells to untreated
      platelets. BALF from patients with PM significantly increased chemoinvasion and
      proliferation in three human tumor cell lines. These activities were attenuated
      significantly by a thrombin inhibitor: hirudin. These results indicate that the
      thrombin present in the lungs of patients with PM is, at least in part,
      responsible for their adhesive, invasive and mitogenic activity on three
      different tumor cell lines. They also suggest that thrombin may be involved in
      the development of PM.

PMID- 10598927
TI  - Increased intensity of lung infiltrates at the side of lung cancer in patients
      with lung cancer associated with pulmonary fibrosis.
AB  - It has been reported that lung cancer is frequently associated with idiopathic
      pulmonary fibrosis (IPF). The purpose of this study was to compare the intensity
      of lung infiltrates between the side associated with lung cancer and the side
      without lung cancer. Twenty-three patients (24 lung cancers) with primary lung
      cancer associated with pulmonary fibrosis were retrospectively evaluated. Chest
      CT findings were evaluated by three expert radiologists using the intensity
      scores. In 16 of the 23 patients, it was possible to compare the intensity of
      lung infiltrates between both sides of the lungs. As a result, increased
      intensity at the side in which lung cancer developed was demonstrated in 12 of 16
      patients (75%). In the remaining four patients, intensity of lung infiltrates was
      the same in both lungs. In operated patients as well as autopsied patients, it
      was possible to evaluate the pathological findings of lung tissues around cancer
      cells. This study clearly demonstrates that the intensity of lung infiltrates
      increased at the side in which lung cancer developed.

PMID- 10598928
TI  - Phase II study of paclitaxel and carboplatin for advanced non-small-cell lung
      cancer.
AB  - A prospective phase II study was conducted to determine the response, toxicity
      and survival rate of lung cancer patients treated with combination paclitaxel and
      carboplatin in stage IIIB and IV NSCLC. Eligible patients required measurable
      and/or evaluable diseases; performance status (ECOG) 0-2; no previous
      chemotherapy; adequate hepatic, renal and bone marrow function. Paclitaxel was
      administered at a dose of 200 mg/m2, 3 h infusion, followed by carboplatin at an
      AUC of 6. Treatment was repeated every 3 weeks for six courses. G-CSF 5
      microgram/kg was subcutaneously injected during subsequent courses if there was
      grade 3-4 leucopenia or granulocytopenia in the previous course. From April 1996
      through July 1997, 53 patients were enrolled; all are assessable for toxicity and
      response. The median age was 56 years (range, 20-77 years). Sixty four percent
      were male, 64% had adenocarcinoma and 62% had stage IV disease. Two hundred and
      seventy two courses were administered; 36 patients (68%) completed all six
      cycles. Two patients achieved a complete response (4%) and 27 patients achieved a
      partial response (51%), for an overall response rate of 55%. Sixteen patients had
      stable disease (30%) and 8 patients had progressive disease (15%). The median
      progression free survival time for all patients, stage IIIB and stage IV patients
      was 28 weeks (range, 18-37 weeks), 31 weeks (range 21-41 weeks) and 22 weeks
      (range 16-29 weeks), respectively. The median survival time and 1 year survival
      rate for all patients was 55 weeks (range, 51-59 weeks) and 55%, respectively.
      Stage IIIB patients had better median survival time and 1-year survival rate than
      stage IV patients (75 vs. 46 weeks, P = 0.007; 80% vs. 42%, P = 0.003). Grade 3
      and 4 granulocytopenia, anemia and thrombocytopenia were observed in 25, 3, and
      1%, respectively, of the 272 courses administered. G-CSF was required in 28% of
      the 272 courses. There were four episodes of febrile neutropenia (1.5%), three
      episodes of angina pectoris (1%) and one episode of anaphylaxis (0.4%). Other
      common toxicities, generally mild, included myalgia, arthralgia, peripheral
      neuropathy and asthenia. Most toxicities showed cumulative effect. Paclitaxel
      plus carboplatin is a moderately active regimen in advanced NSCLC. Toxicities of
      this regimen are well tolerated.

PMID- 10598929
TI  - The cyclin-dependent kinase inhibitor p27 as a prognostic factor in advanced non
      small cell lung cancer: its immunohistochemical evaluation using biopsy
      specimens.
AB  - The expression of p27, which is known as a cyclin-dependent kinase inhibitor, on
      surgically resected specimens has considerable value for the prognosis of non
      small cell lung cancer (NSCLC) patients. We immunohistochemically investigated
      the expression of the p27 protein in the biopsy specimens taken from 69 advanced
      NSCLC patients and assessed its clinical value. There was no significant
      correlation between p27 positivity and clinical parameters, including sex, age,
      histological type, clinical stage, smoking index and performance status.
      Furthermore, p27 positivity was not associated with response to chemotherapy.
      However, the Kaplan-Meier curve demonstrated that low p27 expression was
      significantly related to poor prognosis (P = 0.0019, by the log-rank test). Using
      multivariate analysis, p27, age and serum total protein level were found to be
      the independent prognostic parameters. The p27 positivity in the biopsy specimens
      of advanced NSCLC appears to be a useful prognostic marker.

PMID- 10598930
TI  - Cavitary lung cancer with an aspergilloma-like shadow.
AB  - A 66-year-old man who complained of cough and haemoptysis had a cavitary lesion
      with the meniscus sign in the right lower lung field on his chest X-ray and CT
      scan. He had smoked 40 cigarettes daily, for about 46 years. Initially, he was
      diagnosed with aspergilloma and given an antifungal agent. After 2 months, the
      cavitary lesion showed a slight irregularity of the inner border. The walls were
      irregularly thickened and were surrounded by infiltrative densities compared with
      the previous chest radiograph. Enlargement of right hilar and mediastinal lymph
      nodes was also observed. The fungus ball-like shadow was fixed on the anterior
      wall of the cavity and its position was not altered with the patient's movements.
      These radiographic findings led to suspicion that the lesion might be malignant.
      Transbronchial lung biopsy of the cavity wall and CT guided needle aspiration
      biopsy of the fungus ball-like lesion were performed. Microscopic examination
      revealed a squamous-cell carcinoma in both the cavity wall and the fungus ball
      like lesion. There was no evidence of fungal elements. In conclusion, the
      meniscus sign is most often associated with benign diseases such as aspergilloma,
      however, one should remember that carcinoma may be a cause.

PMID- 10598931
TI  - Management of lung cancer--Chiangmai, Thailand, 24-26 February, 1999.

PMID- 10598932
TI  - Determination of oxygen extraction ratios by magnetic resonance imaging.
AB  - The oxygen extraction ratio (OER) of a tissue describes the interplay between
      oxygen delivery and consumption and, as such, directly reflects the viability and
      activity of any organ. It is shown that OER can be quantified using a single
      magnetic resonance imaging observable, namely the relaxation time T2 of venous
      blood draining from the tissue. This principle is applied to study local OER
      changes in the brain on visual stimulation in humans, unambiguously demonstrating
      a mismatch between changes in blood flow and oxygen metabolism on activation.

PMID- 10598933
TI  - Mutually protective actions of kainic acid epileptic preconditioning and
      sublethal global ischemia on hippocampal neuronal death: involvement of adenosine
      A1 receptors and K(ATP) channels.
AB  - Preconditioning with sublethal ischemia attenuates the detrimental effects of
      subsequent prolonged ischemic insults. This research elucidates potential in vivo
      cross-tolerance between different neuronal death-generating treatments such as
      kainate administration, which induces seizures and global ischemia. This study
      also investigates the effects of a mild epileptic insult on neuronal death in rat
      hippocampus after a subsequent, lethal epileptic stress using kainic acid (KA) as
      a model of epilepsy. Three preconditioning groups were as follows: group 1 was
      injected with 5 mg/kg KA before a 6-minute global ischemia; group 2 received a 3
      minute global ischemia before 7.5 mg/kg KA; and group 3 was injected with a 5
      mg/kg dose of KA before a 7.5-mg/kg KA injection. The interval between treatments
      was 3 days. Neuronal degeneration, revealed by the silver impregnation method and
      analysis of cresyl violet staining, was markedly reduced in rats preconditioned
      with a sublethal ischemia or a 5-mg/kg KA treatment. Labeling with terminal
      deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'triphosphate-biotin nick
      end labeling and DNA laddering confirmed the component of DNA fragmentation in
      the death of ischemic and epileptic neurons and its reduction in all
      preconditioned animals. The current study supports the existence of bidirectional
      cross-tolerance between KA excitotoxicity and global ischemia and suggests the
      involvement of adenosine A1 receptors and sulfonylurea- and ATP-sensitive K+
      channels in this protective phenomenon.

PMID- 10598934
TI  - Relationship between inward rectifier potassium current impairment and brain
      injury after cerebral ischemia/reperfusion.
AB  - Functional alterations of barium-sensitive potassium inward rectifier (KIR)
      current, which is involved in the vasodilation of middle cerebral arteries (MCA)
      in rat brain, have been described during brain ischemia/reperfusion (I/R). The
      authors investigate the effects of I/R on KIR current recorded in isolated
      myocytes from MCA of control rats and from contralateral and ipsilateral MCA of
      ischemic rats by the whole-cell patch-clamp technique, and the relationship
      between its alteration and the severity of brain injury. The vascular smooth
      muscle cells exhibited similar morphologic features in all conditions, and the
      KIR was present in the three groups of myocytes, exhibiting a characteristic
      inward rectification and a normal external potassium dependence. The KIR density
      was significantly reduced in cell of MCA ipsilateral to occlusion with a maximum
      at -135 mV, whereas there was no difference between control and contralateral
      cells. This alteration in KIR density in occluded MCA was significantly
      correlated with severity of brain injury and brain edema. These results suggest
      that the alteration of KIR density in MCA myocytes after I/R and the consecutive
      impaired dilation of MCA may contribute to aggravation of the brain injury.

PMID- 10598935
TI  - Effects of tissue type plasminogen activator in embolic versus mechanical models
      of focal cerebral ischemia in rats.
AB  - Tissue type plasminogen activator (tPA) can be effective therapy for embolic
      stroke by restoring cerebral perfusion. However, a recent experimental study
      showed that tPA increased infarct size in a mouse model of transient focal
      ischemia, suggesting a possible adverse effect of tPA on ischemic tissue per se.
      In this report, the effects of tPA in two rat models of cerebral ischemia were
      compared. In experiment 1, rats were subjected to focal ischemia via injection of
      autologous clots into the middle cerebral artery territory. Two hours after clot
      injection, rats were treated with 10 mg/kg tPA or normal saline. Perfusion
      sensitive computed tomography scanning showed that tPA restored cerebral
      perfusion in this thromboembolic model. Treatment with tPA significantly reduced
      ischemic lesion volumes measured at 24 hours by >60%. In experiment 2, three
      groups of rats were subjected to focal ischemia via a mechanical approach in
      which a silicon-coated filament was used intraluminally to occlude the origin of
      the middle cerebral artery. In two groups, the filament was withdrawn after 2
      hours to allow for reperfusion, and then rats were randomly treated with 10 mg/kg
      tPA or normal saline. In the third group, rats were not treated and the filament
      was not withdrawn so that permanent focal ischemia was present. In this
      experiment, tPA did not significantly alter lesion volumes after 2 hours of
      transient focal ischemia. In contrast, permanent ischemia significantly increased
      lesion volumes by 55% compared with transient ischemia. These results indicate
      that in these rat models of focal cerebral ischemia, tPA did not have detectable
      negative effects. Other potentially negative effects of tPA may be dependent on
      choice of animal species and model systems.

PMID- 10598936
TI  - Evolution of microcirculatory disturbances after permanent middle cerebral artery
      occlusion in rats.
AB  - Nonischemic brain capillaries show a continuous and heterogeneous plasma
      perfusion. In the current study, plasma perfusion was investigated in rats during
      2 to 168 hours of permanent middle cerebral artery occlusion. Perfused
      capillaries were detected in brain cryosections by fluorescein isothiocyanate
      (FITC) dextran after 10 minutes of circulation time. Heterogeneity of capillary
      perfusion was identified by Evans blue (EB), which circulated for 3 seconds. In
      this setting, the heterogeneity of intracapillary EB concentrations reflects
      heterogeneities in capillary flow velocities. The CBF was quantified by
      simultaneous iodo[14C]antipyrine autoradiography. When moving from normal flow to
      low-flow areas in the ischemic hemisphere, three states of capillary filling
      could be distinguished: state 1--fast perfusion, filling by FITC dextran and EB
      (CBF 0.33 mL x g(-1) x min(-1)); state 2--delayed perfusion, only FITC dextran
      filling (CBF 0.104 mL x g(-1) x min(-1)); state 3--minimal perfusion, no dye
      filling (CBF 0.056 mL x g(-1) x min(-1)). In tissue of state 1 at the borderline
      to ischemic tissue, a higher heterogeneity of intracapillary EB concentration
      (85.7%) was found than in the contralateral nonischemic hemisphere (76.4%) (P <
      0.05), indicating a compromised microcirculation. The adjacent ischemic areas
      were filled by FITC dextran (state 2) 2 to 4 hours after middle cerebral artery
      occlusion, indicating a maintained, although slow, perfusion at this time. Later,
      minimal perfused areas (state 3) progressively replaced the delayed perfused
      areas (state 2). This study shows, for the first time, the evolution of
      microvascular disturbances in relation to CBF. In the low-flow areas, an early
      residual plasma perfusion is later followed by a lack of perfusion or minimal
      perfusion. In areas of higher, although reduced flow at the border between normal
      and ischemic tissue, an extreme capillary perfusion heterogeneity indicates
      permanent microcirculatory abnormalities.

PMID- 10598937
TI  - Transplantation of fetal kidney tissue reduces cerebral infarction induced by
      middle cerebral artery ligation.
AB  - The authors, and others, have recently reported that intracerebral administration
      of glial cell line-derived neurotrophic factor (GDNF) or osteogenic protein-1
      protects against ischemia-induced injury in the cerebral cortex of adult rats.
      Because these trophic factors are highly expressed in the fetal, but not adult,
      kidney cortex, the possibility that transplantation of fetal kidney tissue could
      serve as a cellular reservoir for such molecules and protect against ischemic
      injury in cerebral cortex was examined. Fetal kidneys obtained from rat embryos
      at gestational day 16, and adult kidney cortex, were dissected and cut into small
      pieces. Adult male Sprague-Dawley rats were anesthetized with chloral hydrate and
      placed in a stereotactic apparatus. Kidney tissues were transplanted into three
      cortical areas adjacent to the right middle cerebral artery (MCA). Thirty minutes
      after grafting, the right MCA was transiently ligated for 90 minutes. Twenty-four
      hours after the onset of reperfusion, animals were evaluated behaviorally. It was
      found that the stroke animals that received adult kidney transplantation
      developed motor imbalance. However, animals that received fetal kidney grafts
      showed significant behavioral improvement. Animals were later sacrificed and
      brains were removed for triphenyltetrazolium chloride staining, Pax-2
      immunostaining, and GDNF mRNA expression. It was noted that transplantation of
      fetal kidney but not adult kidney tissue greatly reduced the volume of infarction
      in the cerebral cortex. Fetal kidney grafts showed Pax-2 immunoreactivity and
      GDNF mRNA in the host cerebral cortex. In contrast, GDNF mRNA expression was not
      found in the adult kidney grafts. Taken together, our data indicate that fetal
      kidney transplantation reduces ischemia/reperfusion-induced cortical infarction
      and behavioral deficits in adult rats, and that such tissue grafts could serve as
      an unique cellular reservoir for trophic factor application to the brain.

PMID- 10598938
TI  - Adenovirus-mediated gene transfer of glial cell line-derived neurotrophic factor
      prevents ischemic brain injury after transient middle cerebral artery occlusion
      in rats.
AB  - To examine a possible protective effect of exogenous glial cell line-derived
      neurotrophic factor (GDNF) gene expression against ischemic brain injury, a
      replication-defective adenoviral vector containing GDNF gene (Ad-GDNF) was
      directly injected into the cerebral cortex at 1 day before 90 minutes of
      transient middle cerebral artery occlusion (MCAO) in rats. 2,3,5
      Triphenyltetrazolium chloride staining showed that infarct volume of the Ad-GDNF
      injected group at 24 hours after the transient MCAO was significantly smaller
      than that of vehicle- or Ad-LacZ-treated group. Enzyme-linked immunosorbent assay
      (ELISA) for immunoreactive GDNF demonstrated that GDNF gene products in the Ad
      GDNF-injected group were higher than those of vehicle-treated group at 24 hours
      after transient MCAO. Immunoreactive GDNF staining was obviously detected in the
      cortex around the needle track just before or 24 hours after MCAO in the Ad-GDNF
      group, whereas no or slight GDNF staining was detected in the vehicle group. The
      numbers of TUNEL, immunoreactive caspase-3, and cytochrome c-positive neurons
      induced in the ipsilateral cerebral cortex at 24 hours after transient MCAO were
      markedly reduced by the Ad-GDNF group. These results suggest that the successful
      exogenous GDNF gene transfer ameliorates ischemic brain injury after transient
      MCAO in association with the reduction of apoptotic signals.

PMID- 10598939
TI  - A transforming growth factor-beta antagonist unmasks the neuroprotective role of
      this endogenous cytokine in excitotoxic and ischemic brain injury.
AB  - Various studies describe increased concentrations of transforming growth factor
      beta (TGF-beta) in brain tissue after acute brain injury. However, the role of
      endogenously produced TGF-beta after brain damage to the CNS remains to be
      clearly established. Here, the authors examine the influence of TGF-beta produced
      after an episode of cerebral ischemia by injecting a soluble TGF-beta type II
      receptor fused with the Fc region of a human immunoglobulin (TbetaRIIs-Fc).
      First, this molecular construct was characterized as a selective antagonist of
      TGF-beta. Then, the authors tested its ability to reverse the effect of TGF-beta1
      on excitotoxic cell death in murine cortical cell cultures. The addition of 1
      microg/mL of TbetaRIIs-Fc to the exposure medium antagonized the neuroprotective
      activity of TGF-beta1 in N-methyl-D-aspartate (NMDA)-induced excitotoxic cell
      death. These results are consistent with the hypothesis that TGF-beta1 exerts a
      negative modulatory action on NMDA receptor-mediated excitotoxicity. To determine
      the role of TGF-beta1 produced in response to brain damage, the authors used a
      model of an excitotoxic lesion induced by the intrastriatal injection of 75 nmol
      of NMDA in the presence of 1.5 microg of TbetaRIIs-Fc. The intrastriatal
      injection of NMDA was demonstrated to induce an early upregulation of the
      expression of TGF-beta1 mRNA. Furthermore, when added to the excitotoxin,
      TbetaRIIs-Fc increased (by 2.2-fold, P < 0.05) the lesion size. These
      observations were strengthened by the fact that an intracortical injection of
      TbetaRIIs-Fc in rats subjected to a 30-minute reversible cerebral focal ischemia
      aggravated the volume of infarction. In the group injected with the TGF-beta1
      antagonist, a 3.5-fold increase was measured in the infarction size (43.3 +/- 9.5
      versus 152.8 +/- 46.3 mm3; P < 0.05). In conclusion, by antagonizing the
      influence of TGF-beta in brain tissue subjected to excitotoxic or ischemic
      lesion, the authors markedly exacerbated the resulting extent of necrosis. These
      results suggest that, in response to such insults, brain tissue responds by the
      synthesis of a neuroprotective cytokine, TGF-beta1, which is involved in the
      limitation of the extent of the injury. The pharmacologic potentiation of this
      endogenous defensive mechanism might represent an alternative and novel strategy
      for the therapy of hypoxic-ischemic cerebral injury.

PMID- 10598940
TI  - Secondary reduction in the apparent diffusion coefficient of water, increase in
      cerebral blood volume, and delayed neuronal death after middle cerebral artery
      occlusion and early reperfusion in the rat.
AB  - It has been reported recently that very delayed damage can occur as a result of
      focal cerebral ischemia induced by vascular occlusion of short duration. With use
      of diffusion-, T2-, and contrast-enhanced dynamic magnetic resonance imaging
      (MRI) techniques, the occlusion time dependence together with the temporal
      profile for this delayed response in a rat model of transient focal cortical
      ischemia have been established. The distal branch of the middle cerebral artery
      was occluded for 20, 30, 45, or 90 minutes. Twenty minutes of vascular occlusion
      with reperfusion exhibited no significant mean change in either the apparent
      diffusion coefficient of water (ADC) or the T2 relaxation time at 6, 24, 48, or
      72 hours after reperfusion (P = 0.97 and 0.70, respectively). Ninety minutes of
      ischemia caused dramatic tissue injury at 6 hours, as indicated by an increase in
      T2 relaxation times to 135% of the contralateral values (P < 0.01). However, at
      intermediate periods of ischemia (30 to 45 minutes), complete reversal of the ADC
      was seen at 6 hours after reperfusion but was followed by a secondary decline
      over time, such that a 25% reduction in tissue ADC was seen at 24 as compared
      with 6 hours (P < 0.02). This secondary response was accompanied by an increase
      in cerebral blood volume (CBV), as shown by contrast-enhanced dynamic MRI (120%
      of contralateral values; P < 0.001), an increase in T2 relaxation time (132%; P <
      0.01), together with clear morphological signs of cell death. By day 18, the mean
      volume of missing cortical tissue measured with high-resolution MRI in animals
      occluded for 30 and 45 minutes was 50% smaller than that in 90-minute occluded
      animals (P < 0.005). These data show that ultimate infarct size is reduced after
      early reperfusion and is occlusion time dependent. The early tissue recovery that
      is seen with intermediate occlusion times can be followed by cell death, which
      has a delayed onset and is accompanied by an increase in CBV.

PMID- 10598941
TI  - Cerebral functional magnetic resonance imaging activation modulated by a single
      dose of the monoamine neurotransmission enhancers fluoxetine and fenozolone
      during hand sensorimotor tasks.
AB  - Fluoxetine inhibits the reuptake of serotonin, and dextroamphetamine enhances
      presynaptic release of monoamines. Although the excitatory effect of both
      noradrenaline and dopamine on motor behavior generally is accepted, the role of
      serotonin on motor output is under debate. In the current investigation, the
      authors evidenced a putative role of monoamines and, more specifically, of
      serotonin in the regulation of cerebral motor activity in healthy subjects. The
      effects on cerebral motor activity of a single dose of fluoxetine (20 mg), an
      inhibitor of serotonin reuptake, and fenozolone (20 mg/50 kg), an amphetamine
      like drug, were assessed by functional magnetic resonance imaging. Subjects
      performed sensorimotor tasks with the right hand. Functional magnetic resonance
      imaging studies were performed in two sessions on two different days. The first
      session, with two scan experiments separated by 5 hours without any drug
      administration, served as time-effect control. A second, similar session but with
      drug administration after the first scan assessed drug effects. A large increase
      in evoked signal intensity occurred in the ipsilateral cerebellum, and a
      parallel, large reduction occurred in primary and secondary motor cortices (P <
      10(-3)). These results are consistent with the known effects of habituation. Both
      drugs elicited comparable effects, that is, a more focused activation in the
      contralateral sensorimotor area, a greater involvement of posterior supplementary
      motor area, and a widespread decrease of bilateral cerebellar activation (P < 10(
      3)). The authors demonstrated for the first time that cerebral motor activity can
      be modulated by a single dose of fluoxetine or fenozolone in healthy subjects.
      Drug effects demonstrated a direct or indirect involvement of monoamines and
      serotonin in the facilitation of cerebral motor activity.

PMID- 10598942
TI  - Assessment of extrastriatal vesicular monoamine transporter binding site density
      using stereoisomers of [11C]dihydrotetrabenazine.
AB  - Previous studies have demonstrated the utility of [11C]dihydrotetrabenazine
      ([11C]DTBZ) as a ligand for in vivo imaging of the vesicular monoamine
      transporter system. The (+)-isomer has a high affinity (approximately 1 nmol/L)
      for the vesicular monoamine transporter (VMAT2) binding site, whereas the (-)
      isomer has an extremely low affinity (approximately 2 micromol/L). Efforts to
      model dynamic (+)-[11C]DTBZ data demonstrate the difficulty in separating the
      specific binding component from the free plus nonspecific component of the total
      positron emission tomography (PET) measure. The authors' previous PET work, as
      well as in vitro studies, indicate that there is little specific VMAT2 binding in
      neocortical regions. However, precise determination of in vivo binding levels
      have not been made, leaving important questions unanswered. At one extreme, is
      there sufficient specific binding in cortex or other extrastriate regions to be
      estimated reliably with PET? At the other extreme, is there sufficiently little
      binding in cortex so that it can be used as a reference region representing
      nonsaturable tracer uptake? The authors address these questions using paired
      studies with both active (+) and inactive (-) stereoisomers of [11C]DTBZ. Six
      normal control subjects were scanned twice, 2 hours apart, after injections of 16
      mCi of (+)- and (-)-[11C]DTBZ (order counter-balanced). Three-dimensional PET
      acquisition consisted of 15 frames over 60 minutes for each scan. Arterial
      samples were acquired throughout, plasma counted, and corrected for radiolabeled
      metabolites. Analysis of specific binding was assessed by comparison of total
      distribution volume measures from the (+)- and (-)-[11C]DTBZ scans. The authors'
      findings indicate that only approximately 5% of the cortical signal in (+)
      [11C]DTBZ scans results from binding to VMAT2 sites. The strongest extrastriatal
      signal comes from the midbrain regions where approximately 30% of the PET measure
      results from specific binding. The authors conclude that (1) the density of VMAT2
      binding sites in cortical regions is not high enough to be quantified reliably
      with DTBZ PET, and (2) binding does appear to be low enough so that cortex can be
      used as a free plus nonspecific reference region for striatum.

PMID- 10598943
TI  - Estimated number of children with cancer eligible for hyperthermia based on
      population- and treatment-related criteria.
AB  - Patients with recurrent, progressed or otherwise, therapy resistant malignancies,
      whose diseases are not amenable to standard therapies, may benefit from
      hyperthermia (HT). Based on the number of 1600 newly diagnosed malignancies, in
      patients < 15 years of age, per annum of which 70% are successfully treated on
      the standard treatment protocols of the German Society of Pediatric Oncology and
      Hematology (GPOH) and allowing for various drop-outs for reasons such as lack of
      established protocols, insufficient state of health and others, this means that
      as many as 100 children per annum can be expected to be enrolled into phase I/II
      trials in Germany. In view of the promising results in adults, phase I/II HT
      studies have also been performed in children and adolescents with recurrent or
      advanced malignancies including Ewing's tumours, aggressive fibromatosis, and
      germ cell tumours. Recent results in paediatric studies indicate the feasibility
      of both regional deep HT and whole body HT, and the best case analysis reveals
      promising response rates (CR + PR) as well as some long-term remissions.
      Technical modifications, due to the smaller body diameters, led to mean
      intratumoural temperatures in paediatric patients similar to those reported for
      adults in whom an improved outcome was demonstrated. The results in children and
      adolescents even suggest that introduction of HT into standard treatment
      protocols may be promising to improve tumour response and event-free survival in
      patients with poor risk malignancies of childhood.

PMID- 10598944
TI  - Water-filtered infrared-A radiation: a novel technique for localized hyperthermia
      in combination with bacteriochlorophyll-based photodynamic therapy.
AB  - A novel application of an infrared-A (IR-A) radiation source equipped with a
      water-filter in the radiation path is described, which allows for tumour
      treatment with a simultaneous combination of localized hyperthermia (HT) and
      bacteriochlorophyll-serine (Bchl-ser) based photodynamic therapy (PDT). Using
      this system, the IR-A radiation was used to heat tumours to 43 degrees C for 60
      min, while at the same time activating the Bchl-ser which was injected i.v. at a
      dose of 20 mg/kg, 10 min following commencement of HT. The growth of tumours
      undergoing this combined therapy was compared to that of tumours undergoing HT
      alone or sham-treated controls. Within the 90 day observation period, 100% of
      tumours in sham-treated animals, 80% in HT-treated animals and only 17% in HT +
      Bchlser-treated animals reached the end point target volume of 3.5 ml. Thus, the
      tumour growth inhibition effect of HT can be substantially enhanced by
      combination with Bchl-ser-PDT. This novel technique has proved to be well
      tolerated, easy to apply and should be suitable for treatment of superficial
      malignancies, especially where hypoxic tumour areas are present.

PMID- 10598945
TI  - Tumour cell kinetics as predictors of response in canine lymphoma treated with
      chemotherapy alone or combined with whole body hyperthermia.
AB  - Kinetic parameters including potential doubling time (Tpot), duration of S phase
      (Ts), labelling index (LI), and DNA index (DI) were obtained from 42 dogs with
      previously untreated lymphoma. Standard flow cytometric techniques using BrdUrd
      were employed. All dogs were treated with L-asparaginase and remission was
      induced in 26 dogs, which were then randomized to receive chemotherapy only
      (doxorubicin [DOX] alone or with lonidamine) or chemotherapy plus whole body
      hyperthermia (WBH). Dogs were treated every 3 weeks for up to five treatments and
      evaluated every 3 weeks for evidence of tumour recurrence. Within this subset of
      animals there was no difference in outcome based on treatment group. Median
      values for Tpot, Ts and LI were 3.4 days, 7.23 h and 12.49%, respectively. Dogs
      that had tumours with LI > or = 20% had a shorter time until recurrence than dogs
      with tumours characterized by LI < 20%. In dogs treated only with chemotherapy,
      dogs bearing tumours with longer than median Tpot and Ts values and lower than
      median LI had significantly longer remission duration than dogs with more rapidly
      proliferating tumours. Dogs treated only with chemotherapy, which had longer than
      median Tpot and Ts values and lower than median LI, had significantly longer
      remission duration than all other dogs in the study. The mechanisms in which
      kinetics are associated with response to chemotherapy are not clear and vary
      depending on tumour type and treatment regimen. More work is needed to understand
      factors involved in cell killing during in vivo hyperthermia.

PMID- 10598947
TI  - Pre-clinical evaluation of a two-channel microwave hyperthermia system with
      adaptive phase control in a large animal.
AB  - A pre-clinical assessment of the heating capabilities of a two-channel 915 MHz
      Microfocus-1000 hyperthermia system, with adaptive phase control, was carried out
      in a series of experiments using a large animal model. The results of the
      experimental measurements of specific absorption rate (SAR) and tissue
      temperature show that when muscle tissue of the hind legs of pigs was compressed
      to 6.5-7 cm, then a pair of parallel opposed, coherently driven, transverse
      electromagnetic wave applicators could elevate the temperature in deep tissue to
      therapeutic levels without overheating superficial tissues when the phase
      difference between applicators was determined by the adaptive phase control
      algorithm.

PMID- 10598946
TI  - Appendicitis during locoregional thermoradiotherapy of advanced or recurrent
      rectal and cervical cancer, a report of two cases.
AB  - INTRODUCTION: Local tumour control after irradiation alone for advanced,
      inoperable carcinomas of the bladder and rectum or inoperable recurrent cervical
      carcinoma is usually disappointing. Both preclinical and clinical studies
      reported improvements by adding hyperthermia to radiotherapy. Reports for phase
      II/III trials do not indicate any enhanced side effects. However, two cases of
      acute suppurating appendicitis were observed in a series of patients treated with
      deep regional hyperthermia. MATERIALS, METHODS AND RESULTS: Eighty patients with
      advanced, inoperable, or recurrent rectal or recurrent cervical tumours were
      treated with deep regional hyperthermia (313 sessions) in addition to
      radiotherapy between September 1995 and October 1998. The treatment for two of
      these patients (2.5%) had to be discontinued after the fourth/second hyperthermia
      treatments at 19.8/10.8 Gy total dose, respectively, for symptoms of pain in the
      right pelvis and elevated rectal temperature. Both patients underwent laparotomy
      and were found to have suppurative appendicitis. In addition to the retrocoecal
      location in both patients, evidence of preexisting chronic appendicitis, and
      appendiceal faecalith were observed in each patient. CONCLUSION: The development
      of acute appendicitis in 2.5% of patients during a course of deep regional
      thermoradiotherapy for pelvic tumour is much higher than the expected incidence
      of appendicitis in the general population (< 1/1000) (Korner et al. 1997). An
      enhanced risk of suppurative appendicitis in patients undergoing pelvic
      thermoradiotherapy cannot be excluded, especially in retrocoecal located
      appendices with obstructed appendix lumen from preexisting chronic appendicitis
      or faecalith.

PMID- 10598948
TI  - Experimental evaluation of the thermal properties of two tissue equivalent
      phantom materials.
AB  - Tissue equivalent radio frequency (RF) phantoms provide a means for measuring the
      power deposition of various hyperthermia therapy applicators. Temperature
      measurements made in phantoms are used to verify the accuracy of various
      numerical approaches for computing the power and/or temperature distributions.
      For the numerical simulations to be accurate, the electrical and thermal
      properties of the materials that form the phantom should be accurately
      characterized. This paper reports on the experimentally measured thermal
      properties of two commonly used phantom materials, i.e. a rigid material with the
      electrical properties of human fat, and a low concentration polymer gel with the
      electrical properties of human muscle. Particularities of the two samples
      required the design of alternative measuring techniques for the specific heat and
      thermal conductivity. For the specific heat, a calorimeter method is used. For
      the thermal diffusivity, a method derived from the standard guarded comparative
      longitudinal heat flow technique was used for both materials. For the 'muscle'
      like material, the thermal conductivity, density and specific heat at constant
      pressure were measured as: k = 0.31 +/- 0.001 W(mK)(-1), p = 1026 +/- 7 kgm(-3),
      and c(p) = 4584 +/- 107 J(kgK)(-1). For the 'fat'-like material, the literature
      reports on the density and specific heat such that only the thermal conductivity
      was measured as k = 0.55 W(mK)(-1).

PMID- 10598949
TI  - Influence of patient models and numerical methods on predicted power deposition
      patterns.
AB  - BACKGROUND: A hyperthermia planning system has been developed for generating
      patient and applicator models as well as calculating and visualizing E-field and
      temperature distributions. Significant dependencies on models and algorithms have
      been found. METHODS: Computerized tomography (CT) data sets are first transformed
      into so called 'labelled CT-volume'-data sets of equal resolution, which are used
      for segmentation. The first type of patient model obtained subsequently is based
      on regions with specified electrical properties representing tissues or organs
      (so called 'region-based model'). The second patient model renders a direct
      transformation of Hounsfield Units (HU) to electrical constants (so called 'HU
      based model'). The FDTD-method (finite difference time domain) is then applied on
      a cubic lattice employing either an auxiliary 'sub-cubic lattice' (for HU-based
      segmentation) or a tetrahedron grid (for region-based segmentation) to assign the
      electrical properties, both representing the anatomy of the patient. E-field
      distributions are corrected by a post-processing procedure with respect to the
      geometry of interfaces defined by the tetrahedron grid. For comparison, the VSIE
      method (volume surface integral equation) is performed on the same tetrahedron
      grid. The applicator model assumes eight half-wavelength dipole antennas fed with
      constant voltages with water as background medium. RESULTS: For both numerical
      methods (FDTD, VSIE) the resulting antenna input impedances as well as the
      current distributions along the antennas were quite similar and almost
      insensitive to the particular geometry model (region-based, HU-based). In
      contrast to that, the power deposition patterns in the interior of the patient
      depended strongly on those models. Major differences can be related to different
      labels of the tissue type bone in the HU-based model in comparison to the
      definition via regions. Conversely, comparable results were obtained using the
      VSIE method and the FDTD method on the region-based patient model with a
      posteriori correction at the tetrahedron grid points. SAR (specific absorption
      rate) elevations up to a factor of 10 were predicted when employing region-based
      models. Those peaks might correspond to specific toxicity of electromagnetic
      radiation clinically known as hot spot phenomena or musculo-skeletal syndromes.
      Conversely, HU-based models generated quite homogeneous power deposition patterns
      with fluctuations of at most factor 2. CONCLUSION: The methods employing region
      based geometry models such as the VSIE method and FDTD method in conjunction with
      a posteriori correction at tissue interfaces result in comparable E-field
      distributions for regional hyperthermia. Due to its shorter calculation time, the
      FDTD method is currently used in the clinic. Predictions derived from HU-based
      models without prior corrections of tissue specifications are not always
      supported by clinical experience.

PMID- 10598950
TI  - Inhibition and recovery of GM-CSF production in the lung after hyperthermia.
AB  - The purpose of this work was to study the response that is invoked by
      hyperthermia in the production of Granulocyte-Macrophage colony-stimulating
      factor (GM-CSF) by the lung. Rats were heated regionally at chest area by a RF
      generator operating at 27.397 MHz for 1 h at various temperatures and then
      allowed to recover or repair in various periods of time after heat application.
      Lung tissue from these animals was then removed and cultured for the production
      of GM-CSF. GM-CSF was assayed by the production of colonies in the semi-solid
      agar cultures of bone marrow cells. Immediately after heat treatment hyperthermia
      had no significant effect on the production of GM-CSF by the lung. A delayed
      effect was observed about 3.5 h after heat treatment. This effect consisted of a
      temperature dependent decrease in GM-CSF production. The damage was recoverable
      and required 1-50 days of post heat treatment time for animals to reach normal
      level of GM-CSF production. The results suggest that in-vivo application of
      hyperthermia invokes temporary reduction in GM-CSF production by the lung, which
      has not been reported previously.

PMID- 10598952
TI  - Effects of diesel exhaust particles (DEP), carbon black, and silica on macrophage
      responses to lipopolysaccharide: evidence of DEP suppression of macrophage
      activity.
AB  - The effects of diesel exhaust particle (DEP) exposure on alveolar macrophage (AM)
      response to ex vivo and in vivo lipopolysaccharide (LPS) challenge were
      determined by monitoring LPS-stimulated production of interleukin-1 (IL-1) and
      tumor necrosis factor-alpha (TNF-alpha). The roles of the insoluble particulate
      and the organic compounds of DEP in altering pulmonary responses were evaluated
      by comparing the DEP-induced pulmonary responses to those of carbon black (CB), a
      carbonaceous particle with few adsorbed organic compounds, or to silica, a known
      pneumotoxic dust. Male Sprague-Dawley rats were exposed to a single intratracheal
      dose (5 or 35 mg/kg body weight) of DEP, CB, or silica, or to saline vehicle.
      Rats were sacrificed 1, 3, or 7 d postexposure. To study the responsiveness to
      the bacterial product LPS, AM isolated from particle-exposed rats were challenged
      ex vivo with LPS (0.1 microg/10(6) AM) and LPS-stimulated cytokine release was
      monitored. In addition, rats were exposed intratracheally to a single dose of DEP
      (5 mg/kg) and 3 d later exposed in vivo to 1 mg/kg LPS for 3 h prior to
      measurement of cytokine production by AM. DEP exposure resulted in neutrophil
      infiltration and elevated levels of albumin and lactate dehydrogenase (LDH)
      activity in the bronchoalveolar lavage fluid; these responses were not
      substantially different from those elicited by CB or silica exposure. AM from DEP
      exposed rats showed increased spontaneous production of IL-1, but not TNF-alpha,
      while the opposite was true for CB or silica. Upon ex vivo challenge with LPS, AM
      from DEP-exposed rats showed a significant decrease in the secretion of TNF-alpha
      and, to a lesser extent, IL-1, compared to the sum of the DEP and LPS effects. In
      contrast, AM from CB- or silica-exposed rats did not show this decreased
      responsiveness to subsequent LPS challenge. This inhibitory action of DEP on LPS
      stimulated AM production of IL-1 and TNF-alpha was further confirmed by the
      results obtained from rats exposed to both DEP and LPS in vivo. In summary, these
      results indicate that while DEP, CB, and silica all induce pulmonary inflammatory
      responses due to particle stimulation, only DEP suppress AM cytokine release in
      response to LPS stimulation. The contrasting cellular response with respect to
      DEP and CB exposures may be due to the presence of adsorbed organic compounds on
      DEP, which may contribute to the increased susceptibility of hosts to pulmonary
      infections after DEP exposure.

PMID- 10598951
TI  - Effectiveness of 2',2'difluorodeoxycytidine (Gemcitabine) combined with
      hyperthermia in rat R-1 rhabdomyosarcoma in vitro and in vivo.
AB  - PURPOSE: To investigate the schedule-dependency of 2',2'difluorodeoxycytidine
      (dFdC, Gemcitabine) combined with hyperthermia (HT), in vitro as well as in vivo.
      MATERIALS AND METHODS: Rat R-1 rhabdomyosarcoma cells were treated with various
      concentrations of dFdC for 70 min, 4 h and 24 h. After various time intervals HT
      (60 min at 43 degrees C) was applied. Cell survival was determined by clonogenic
      assays. Female Wag/Rij rats bearing R-1 tumours on the hind limbs were treated
      with dFdC (20 mg/kg), with locally applied HT (60 min at 43 degrees C) or with a
      combined treatment using different time intervals (0, 24 and 48 h). Tumour growth
      delay (TGD) and normal tissue toxicity were assessed. RESULTS: With dFdC alone,
      significant cytotoxicity was observed after a 24 h-exposure. Except for the 24 h
      exposure, HT reduced the cytotoxicity of dFdC in simultaneous applications. An
      enhanced cytotoxic effect was found when HT was applied 20 h after a 4 h
      incubation with dFdC. In vivo, HT applied 48 h after dFdC-administration resulted
      in potentiation of the effect of dFdC with respect to TGD without an increase in
      toxicity. CONCLUSIONS: The efficacy of dFdC combined with HT is schedule
      dependent both in vitro and in vivo. The addition of HT enhances the
      effectiveness of dFdC in the R-1 tumour model.

PMID- 10598953
TI  - Role of iron in asbestos-body-induced oxidant radical generation.
AB  - Asbestos bodies (AB) were harvested from human lung tissue digests and isolated
      from uncoated asbestos fibers. Samples containing 1000 AB were added to a
      reactive solution to investigate the ability of AB to oxidize deoxy-D-ribose and
      generate reactive oxygen species (ROS) in the presence of ascorbate and hydrogen
      peroxide as determined by formation of thiobarbituric acid (TBA)-reactive
      products. Three types of asbestos fibers were tested for comparison, since they
      are known to be able to produce ROS. The absorbance values measured with 1000 AB
      were significantly higher than those observed with 1000 fibers of the three types
      of asbestos. Since in our reaction system the only source of transition metals
      was the iron-rich AB, data suggest iron derived from the ferritin coating of AB
      was involved in oxidant generation. Addition of iron to AB enhanced TBA-reactive
      product formation, while chelation of Fe with deferoxamine reduced this reaction.
      Hydroxyl radical scavengers 1,3-dimethyl-2-thiourea (DMTU) and mannitol (MN) also
      effectively blocked TBA-reactive product generation. Data indicate the importance
      of Fe in AB-induced oxidant damage. With the addition of polymorphonuclear
      leukocytes (PMN) to AB, incubation in the reactive solution gave very high
      amounts of TBA-reactive products, but using a reactive solution devoid of
      ascorbate, very low amounts of TBA-reactive products were generated. In the
      latter condition, the superoxide of cell membranes probably reduced and removed
      iron from AB-coating ferritin, but less effectively than ascorbate. Further after
      the possible reoxidation of Fe2+, Fe3+ could be coordinated by lactoferrin. Since
      such availability of reductant is never approached in living systems, the iron in
      the AB coating is unlikely to function as a catalyst of Fenton-type reactions in
      vivo.

PMID- 10598954
TI  - Protective role of germanium-132 against paraquat-induced oxidative stress in the
      livers of senescence-accelerated mice.
AB  - The effects of the synthetic antioxidant germanium (Ge-132) were studied on liver
      oxidant damage induced by paraquat (PQ) in senescence-accelerated mice (SAM). PQ
      administered intravenously to SAM-P/8 (susceptible) or SAM-R/1 (resistant) mice
      increased liver DNA strand breakage and malondialdehyde (MDA) levels, indicators
      of oxidant damage. Ge-132 effectively blocked the PQ-induced effects on liver DNA
      strand breaks and MDA levels. In addition, Ge-132 significantly elevated the
      activities of hepatic superoxide dismutase (SOD) and catalase following PQ
      pretreatment. Histopathologically, Ge-132 inhibited PQ-induced hepatic
      mitochondrial injury in both strains, but more effectively in the susceptible
      strain. Data suggest that Ge-132 may be useful as an antioxidant in view of its
      ability to prevent PQ-induced hepatic oxidant injury.

PMID- 10598955
TI  - Effect of low-level short-term o-xylene inhalation of benzo[a]pyrene (BaP)
      metabolism and BaP-DNA adduct formation in rat liver and lung microsomes.
AB  - o-Xylene is a commonly used solvent that alters mixed-function oxidase (MFO)
      activity in an organ- and isozyme-specific pattern following intraperitoneal (ip)
      administration. Similar MFO alterations have been observed after ip or inhalation
      exposure to other methyl benzenes. These MFO alterations shifted the metabolism
      of the carcinogen benzo[a]pyrene (BaP) toward formation of toxication metabolites
      in lung. The purpose of this study was to determine whether o-xylene inhalation
      caused similar MFO changes and whether these alterations were reflected in
      altered BaP metabolism and BaP-DNA adduct formation. o-Xylene (300 ppm, 6 h)
      decreased the activity of arylhydrocarbon hydroxylase (AHH) in lung. CYP2B1
      activity (benzyloxyresorufin O-dealkylase; BROD), which is responsible for
      metabolism of BaP to relatively nontoxic metabolites, was decreased in lung, as
      was, to a lesser extent, CYP1A1 (ethoxyresorufin O-dealkylase; EROD), which is
      responsible for metabolism of BaP to reactive/toxic metabolites. The BROD/EROD
      ratio, an indirect indicator of the pattern of BaP toxication/detoxication, was
      decreased in lung, suggesting that BaP metabolism is shifted toward toxication.
      No MFO alterations were observed in liver. In lung microsomes, o-xylene increased
      formation of 7,8-BaP-diol, while 9,10-BaP-diol, 3-OH BaP, and 9-OH BaP were
      decreased. In liver, o-xylene increased 9-OH BaP formation, while 4,5- and 9,10
      diols as well as total diols were decreased. The toxication/detoxication ratios
      for BaP individual and total metabolite groups were increased in lung microsomes
      and unaltered in liver. The major BaP-DNA adduct, BaP diol epoxide-N2
      deoxyguanosine, was increased in lung but decreased in liver microsomes from o
      xylene-exposed rats. Four minor BaP-DNA adducts were formed in lung and three in
      liver, only one of which (liver adduct 3) was decreased. The o-xylene-induced
      increase in BaP adduct formation in lung and decrease in liver indicate that
      coexposure to organic solvents such as the methyl benzenes may alter the
      carcinogenesis of BaP, or other PAHs, in an organ-specific fashion.

PMID- 10598956
TI  - Effects of cadmium on metallothionein levels in human peripheral blood
      leukocytes: a comparison with zinc.
AB  - Metallothioneins (MT) are low-molecular-weight, cysteine-rich proteins that are
      induced in response to a variety of chemical stresses and therefore can be used
      to assess human exposure to environmental agents. In the current study, flow
      cytometry was used to characterize the basal and cadmium-induced expression of MT
      in the three major leukocyte populations of human peripheral blood. In the
      analysis, monocytes were the most sensitive leukocytes to this toxic metal, with
      significant increases in cellular MT levels being detected at concentrations of
      cadmium as low as 0.1 microM (24 h). The lymphocyte population also exhibited
      pronounced treatment-associated elevations in cellular MT, while the granulocyte
      population was found to be nonresponsive. Although both CdCl2 (3 microM) and
      ZnCl2 (50 microM) induced MT expression in monocytes to a similar degree and did
      not affect the expression of this protein in granulocytes, cadmium but not zinc
      treatment induced dramatic increases in MT levels of lymphocytes. Our results
      indicate that cellular MT protein levels, as determined by this flow cytometric
      method, may be used to characterize the differential responsiveness of the major
      human leukocyte subpopulations to transitional metals. It is evident from the
      current work that the responsiveness of all peripheral blood leukocyte
      populations should be analyzed in exposure assessment studies.

PMID- 10598957
TI  - Left ventricular endocardial pacing: don't try this at home.

PMID- 10598958
TI  - Left ventricular lead insertion using a modified transseptal catheterization
      technique: A totally endocardial approach for permanent biventricular pacing in
      end-stage heart failure.
AB  - This article describes a new technique of LV lead insertion, using transseptal
      catheterization performed through the right internal jugular vein, to obtain a
      totally endocardial biventricular chronic pacing in end-stage heart failure.
      Three patients with QRS widening (> 180 ms) linked to complete left bundle branch
      block (n = 2) or right ventricular pacing (n = 1) were included in this
      preliminary study. Catheterization was performed under fluoroscopy and
      transesophageal echocardiography guidance. Transseptal catheterization was
      achieved by puncture of the right internal jugular vein at the base of the neck
      and by using a Brockenbrough needle, the tip curve of which was more curved than
      the standard model. A flexible long sheath was advanced in the left atrium
      through the interatrial septum and then a unipolar electrode was placed easily in
      the LV. The proximal tip of the LV lead was tunneled from the neck to the
      subclavian area and connected to the ventricular channel of a dual (n = 1) or
      simple (n = 2) chamber pacemaker. Efficient acute sensing (V wave amplitude = 13
      +/- 3 m V) and pacing (acute pacing threshold = 0. 7 +/- 0.4 V) were obtained in
      the three patients. Early loss of capture occurred in two patients requiring lead
      replacement. Functional status dramatically improved in all three patients. At 6
      month follow-up, biventricular pacing was maintained in all patients (mean
      threshold 1.4 V) who were free of clinical embolic event with oral
      anticoagulation therapy. This modified technique of jugular transseptal
      catheterization appears promising for the development of left heart pacing.

PMID- 10598959
TI  - Driving safety among patients with neurocardiogenic (vasovagal) syncope.
AB  - Neurocardiogenic syncope is one of the most common causes of syncope. However,
      the important issue of driving related injury due to syncope in this population
      is not well defined. Risk of injury due to syncope while driving and driving
      behavior was evaluated in 155 consecutive patients (92 women and 63 men; mean age
      49 +/- 19 years) with history of syncope in whom hypotension and syncope or
      presyncope could be provoked during head-up tilt testing. Patients with syncope
      and positive head-up tilt table test were treated with pharmacological therapy.
      All participants were asked to fill out a detailed questionnaire regarding any
      driving related injuries and their driving behavior before tilt table testing and
      during follow-up. Prior to head-up tilt testing two patients had syncope while
      driving, and one of these patients had syncope related injury during driving. The
      mean duration of syncopal episodes was 50 +/- 14 months (range 12-72 months). Of
      the 155 patients, 52 (34%) had no warning prior to syncope, while 103 (6%) had
      warning symptoms such as dizziness prior to their clinical syncope. Following a
      diagnosis of neurocardiogenic syncope established by head-up tilt testing, six
      patients stopped driving on their own. During a median follow-up of 22 months
      recurrent syncope occurred in five (3.2%) patients. No patient had syncope or
      injury during driving. In conclusion, syncope and injury while driving in
      patients with neurocardiogenic syncope is rare. The precise mechanism of this is
      unclear but may be related to posture during driving. Consensus among the medical
      community will be needed to provide specific guidelines in these patients.

PMID- 10598960
TI  - Beat-to-Beat repolarization variability in LQTS patients with the SCN5A sodium
      channel gene mutation.
AB  - Current techniques evaluating beat-to-beat variability of repolarization rely on
      accurate determination of T wave endpoints. This study proposes a T wave endpoint
      independent method to quantify repolarization variability in a standard 12-lead
      ECG using a wavelet transformation. Our method was used to identify
      repolarization variability in long QT syndrome patients (LQTS) with the SCN5A
      sodium channel gene mutation. Using wavelet transformations based on the second
      Gaussian derivative, we evaluated repolarization variability in 11 LQTS patients
      with the mutation, 13 noncarrier family members, and 28 unrelated healthy
      subjects. Time-domain repolarization variability parameters (SDRTo, SDRTm) and
      wavelet parameters describing temporal (beat-to-beat) variability of
      repolarization in time (TVT) and in amplitude (TVA) were analyzed.
      Reproducibility of wavelet parameters and relationship of wavelet-based
      variability with heart rate and preceding RR interval were investigated. The
      wavelet-based method quantified beat-to-beat variability of the entire
      repolarization segment (regardless of QT interval identification) providing
      insight into variability in repolarization morphology. Our method showed that
      SCN5A carriers have significantly increased repolarization variability in
      amplitude (23% +/14% vs 8 +/- 4%, P < 0.001) and in time (14 +/- 17 ms vs 3 +/-2
      ms, P < 0.004) compared to noncarriers. Variability of repolarization amplitude
      was found to be heart rate dependent with variability decreasing with increasing
      heart rate. Relative error describing reproducibility of TVA and TVT was < or =
      5% and < or =10%, respectively. Our method quantifies repolarization variability
      in amplitude and in time without the need to identify T or U wave endpoints.
      Wavelet-detected repolarization variability contributes to phenotypic
      identification of SCN5A carriers, with more pronounced beat-to-beat variability
      in repolarization amplitude than in time.

PMID- 10598961
TI  - Intravenous nitrates for pharmacological stimulation during head-up tilt testing
      in patients with suspected vasovagal syncope and healthy controls.
AB  - Nitrates may be used for pharmacological stimulation during tilt testing for the
      diagnosis of vasovagal syncope. In this study we assessed the diagnostic value of
      intravenous nitrates during tilt testing in patients with a typical history of
      vasovagal syncope. Twenty patients and 23 controls were tilted at 700 for a
      maximum duration of 30 minutes. After a 10-minute baseline supine phase, the test
      started with a continuous nitrate infusion at 1 microg/kg/min and increased every
      5 minutes by 1 microg/kg/min, to a maximum of 6 microg/kg/min at the end of the
      test. The test was ended if the subjects developed a positive response (syncope
      or presyncope). Nineteen patients (95%) and 17 (74%) of the controls had a
      positive response. At test end sensitivity was 95%, but specificity was 26% and
      accuracy was 58%. Receiver operator characteristics (ROC) analysis revealed a
      maximum accuracy of 79% at 18 minutes, with a sensitivity of 80% and a
      specificity of 78%. Intravenous nitrates during tilt testing in patients with
      typical clinical criteria of vasovagal syncope is highly effective in provoking
      vasovagal syncope. Based on the ROC analysis, a maximum accuracy of 79% was
      attained at 18 minutes (at a dose of 4 microg/kg/min), suggesting a good
      diagnostic performance when tilt duration is limited to this point. A positive
      result requiring more than 18 minutes of stimulated tilting should be interpreted
      with caution, due to the accompanying considerable decrease of specificity.

PMID- 10598962
TI  - Stable electrical performance of high efficiency pacing leads having small
      surface, steroid-eluting pacing electrodes.
AB  - Previous experience with steroid-eluting small electrode designs have described
      their increased pacing efficiency, yet some reports have questioned their
      electrical stability. We report our experience with a new pacing lead design
      incorporating small surface (i.e. 1.2 mm2), high impedance pacing electrodes.
      Medtronic Model 5034 ventricular pacing leads were implanted by a single
      physician in 167 patients. Of those, 96 patients had an additional Model 5534
      atrial lead implanted. All patients were followed for at least 9 months.
      Microdislodgment, as defined by a sudden increase in pacing threshold accompanied
      by radiographic stability, was observed in 6 of 263 (2.3%) leads implanted. Of
      the 4/167 (2.4%) ventricular leads that exhibited electrical instability, only 2
      were sustained. Importantly, neither was significant enough to result in loss of
      capture. The other two cases of ventricular electrode instability manifested as a
      transient threshold rise with eventual return to near the original values. By
      comparison, the atrial lead model exhibited a sudden and sustained pacing
      threshold rise 5 which was evident in two patients (2.1%) with neither requiring
      invasive intervention. For all remaining chronic leads, clinically acceptable
      electrical performance profiles were demonstrated. We conclude that low
      microdislodgment rates and stable electrical performance profiles can be achieved
      with the small electrode steroid-eluting pacing electrodes as long as careful
      lead positioning and securing techniques are followed during implantation. We
      further suggest that successful high impedance lead design is critically
      dependent on its stiffness and mass characteristics.

PMID- 10598963
TI  - Bipolar ventricular far-field signals in the atrium.
AB  - In an attempt to evaluate the prevalence and predisposing factors of bipolar
      ventricular far-field oversensing, 57 patients were studied who had a Medtronic
      dual chamber pacemaker implanted (models 7940: n = 6; 7960i: n = 41; 401: n = 3;
      8968i: n = 7) and bipolar atrial leads with a dipole spacing from 8.6 to 60 mm
      attached to various parts of the atrial wall (lateral/anterior: n = 30;
      appendage: n = 10; atrial septum: n = 10; floating: n = 7). Median bipolar
      sensing threshold for P waves was 4.0 mV (2.8-4.0 mV, lower and upper quartile)
      with standard leads and 0.35 (0.25-1.4) mV with single pass (VDD) devices. At the
      highest sensitivity available, 43 of 50 DDD pacemakers but only two of seven VDD
      systems detected intrinsic R waves in the atrium (P < 0.01). Ventricular far
      field oversensing occurred at 0.5 mV in 28 (56%) and at 1.0 mV in 16 of 50 DDD
      units (32%), respectively, and there was one observation in a septal implant at a
      sensitivity of even 2.8 mV. With ventricular pacing, VDD systems were as
      susceptible to far-field signals as DDD pacemakers. Outside the postventricular
      blanking period (100 ms), evoked R waves were detected by 27 of 57 systems (47%)
      at maximum atrial sensitivity, by 10 (18%) at 0.5 mV, and by 2 (4%) at a setting
      of 1.0 up to 1.4 mV, respectively. There was no definite superiority of any lead
      position, there was a trend in favor of the atrial free wall for better intrinsic
      R wave rejection, but just the opposite was the case for paced ventricular beats.
      Bipolar signal discrimination tended to be higher with short tip-to-ring spacing
      (1 7.8 mm) but the difference to larger dipole lengths (30-60 mm) was not
      significant in terms of the R to P wave ratio and the overall far-field
      susceptibility. In summary, bipolar ventricular far-field oversensing in the
      atrium is common with short postventricular blanking times and high atrial
      sensitivity settings that may be warranted for tachyarrhythmia detection and mode
      switching. A potentially more discriminant effect of shorter dipole lengths (< or
      = 10 mm) remains to be tested.

PMID- 10598965
TI  - Midodrine hydrochloride in the treatment of vasovagal syncope.
AB  - Therapy of vasovagal syncope is still a subject of debate. Various
      pharmacotherapies were proposed. However, they are often not tolerated or
      ineffective. The purpose of this prospective, nonrandomized study was to evaluate
      the usefulness of alpha-agonist midodrine hydrochloride in the treatment of
      vasovagal syncope. Forty-one patients (mean age 34 years, 18 men) with history of
      recurrent syncope and positivity of head-up tilt testing were included (28
      patients with type 1, 10 patients with type 2, 3 patients with type 3 according
      to VASIS classification). In all patients oral therapy with midodrine was
      started. Initial dose was 2.5 mg two times daily. When necessary, the dose was
      increased to 5 mg two times daily. Efficacy of treatment was assessed by repeated
      head-up tilt testing after 1-2 weeks of therapy and by long-term follow-up. After
      midodrine hydrochloride treatment, 39 of 41 patients (95%) had no inducible
      presyncope or syncope on repeated tilt table testing. Effective dose was 2.5 mg
      two times daily in 25 patients and 5 mg two times daily in 16 patients. During a
      mean follow-up period 19+/-9 months, 38 of 39 patients (97%) with negative
      repeated tilt table test remained free of syncope recurrence.

PMID- 10598964
TI  - Early recurrence of atrial fibrillation after external cardioversion.
AB  - Early recurrence of atrial fibrillation (AF) has been reported to occur in a
      significant number of patients after internal cardioversion. However, information
      about early recurrence of AF after external cardioversion has never been
      reported. The present study was conducted to investigate the clinical and
      electrophysiological characteristics of early recurrence of AF and its role in
      failure of cardioversion in patients with chronic AF. METHODS AND RESULTS: The
      study included 50 consecutive patients, age 69+/-9, with a history of chronic AF
      for more than 3 months duration and electrical cardioversion. They were divided
      into two groups according to the presence (group 1) or absence (group 2) of early
      recurrence of AF. There were 13 (26%) patients in group 1 and 37 (74%) patients
      in group 2. The age, gender, duration of AF, left ventricular function, left
      atrial dimension, and underlying heart disease were similar between group 1 and
      2. Forty-five patients were successfully converted to sinus rhythm with a mean
      energy of 158+/-57 . Among those who failed to be converted to sinus rhythm, 4
      (80%) belonged to group 1 and 1 (20%) belonged to group 2. The early recurrences
      of AF were initiated with consecutive APDs; but the numbers of APD in the first
      30 seconds after cardioversion were similar between group 1 and 2. However, the
      coupling interval of the second APD was shorter in group 1 than group 2 (188+/-22
      vs 324+/-59 ms, P = 0.003). Nine of the 13 early recurrences were prevented by an
      increase of shock energy (n = 3) or intravenous amiodarone infusion (n = 6).
      There were no differences in duration of follow-up, recurrence rate, and time
      interval to recurrence between group 1 and group 2. Early recurrence of AF
      occurred in 26% of chronic AF patients who underwent external electrical
      cardioversion and was a major cause of failure in cardioversion. Early recurrence
      of AF was initiated by APDs with decreasing coupling intervals and could be
      prevented with an increase of shock energy or amiodarone.

PMID- 10598966
TI  - Neuromuscular function of the latissimus dorsi muscle in goats after dynamic
      cardiomyoplasty.
AB  - Skeletal muscle deterioration is emerging as a limitation to long-term cardiac
      assist by dynamic cardiomyoplasty. Chronic electrical stimulation of in situ
      skeletal muscle showed that ischemia, decreased muscle preload, muscle overuse,
      and chronic electrical stimulation are factors for muscle deterioration.
      Transposition around the heart has been associated with signs of muscle
      denervation after chronic electrical stimulation. To evaluate latissimus dorsi
      muscle neuromuscular function after longterm dynamic cardiomyoplasty, we
      performed neuromuscular functional analysis and histology on the latissimus dorsi
      muscle and thoracodorsal nerve of six normal goats and six goats after 6 months
      of dynamic cardiomyoplasty. Electromyographic analysis showed positive sharp
      waves and fibrillation potentials in the latissimus dorsi of three goats from the
      dynamic cardiomyoplasty group. Conduction velocity of the thoracodorsal nerve of
      goats from the dynamic cardiomyoplasty group (58.32+/-9.80 m/s) was reduced
      compared to the goats from the control group (71.48+/-5.71 m/s, P = 0.02).
      Histologic changes in skeletal muscle were compatible with denervation. Loss of
      myelin sheaths, collapse of endoneurial connective tissue, and solitary foci of
      axonophagia and myelinophagia further documented severe injury to the
      thoracodorsal nerve in goats from the dynamic cardiomyoplasty group. The
      latissimus dorsi muscle wrap was denervated after long-term dynamic
      cardiomyoplasty. Traction on the neurovascular pedicle at each contraction of the
      transposed muscle may induce afferent axonal injury of the thoracodorsal nerve
      resulting in diminished muscular function.

PMID- 10598968
TI  - Effects of ischemia on P wave dispersion and maximum P wave duration during
      spontaneous anginal episodes.
AB  - P wave dispersion (P dispersion), defined as the difference between the maximum
      and the minimum P wave duration, and maximum P wave duration (P maximum) are
      electrocardiographic (ECG) markers that have been used to evaluate the
      discontinuous propagation of sinus impulses and the prolongation of atrial
      conduction time, respectively. To study the effects of myocardial ischemia on P
      dispersion and P maximum, 95 patients with coronary artery disease (CAD) and
      typical angina pectoris and 15 controls with angina like symptoms underwent 12
      lead surface ECG during and after the relief of pain. During pain and during the
      asymptomatic period, P maximum and P dispersion were calculated from the averaged
      complexes of all 12 leads. P dispersion increased significantly during
      spontaneous angina (45+/-17 ms) compared to the asymptomatic period (40+/-15 ms),
      P < 0.001 only in the patient group. Both P maximum and P dispersion showed
      higher values during angina in those patients who developed diffuse ischemia, as
      estimated with ST segment changes in multiple ECG leads. P dispersion showed
      higher values during the anginal episode in patients with left ventricular
      dysfunction, independently of the presence of a previous myocardial infarction.
      Atrial conduction abnormalities, as estimated with P maximum and particularly P
      dispersion, are significantly influenced by myocardial ischemia in patients with
      CAD and spontaneous angina.

PMID- 10598967
TI  - AV node ablation and pacemaker implantation after withdrawal of effective rate
      control medications for chronic atrial fibrillation: effect on quality of life
      and exercise performance.
AB  - We assess whether AV node ablation and pacemaker implantation after
      discontinuation of effective rate-control medical therapy for chronic atrial
      fibrillation had a positive impact on quality of life and exercise performance.
      To assess the possibility of a placebo effect following pacemaker implantation,
      the study included three groups of patients. Group 1 underwent an echocardiogram,
      treadmill exercise, and quality of life measurement 1 month prior to and 6 months
      following AV node ablation and pacemaker implantation associated with
      discontinuation of rate-control medications. Group 2 underwent AV node ablation
      and pacemaker implantation without discontinuation of antiarrhythmic rate-control
      drugs. Group 3 underwent pacemaker implantation without performing AV node
      ablation and continuing rate-control medical therapy. At the 1- and 6-month
      evaluation, the patients in group 1 showed a significant improvement of left
      ventricular ejection fraction, quality of life, and activity scores. The exercise
      duration and the maximal VO2 consumption, however, did not change significantly.
      A slight improvement of the quality of life and physical activity scores was
      observed in the group undergoing AV node ablation without withdrawal of
      medications. However, no significant changes were observed in the group receiving
      only the pacemaker without modification of medical therapy and with intact AV
      node conduction. In conclusion, in patients with chronic atrial fibrillation,
      discontinuation of effective rate-control medical therapy followed by AV node
      ablation and permanent pacing appeared to improve quality of life and activity
      scores despite no change in exercise duration. The improvement observed does not
      seem to reflect a placebo effect.

PMID- 10598969
TI  - Initial clinical experience with a fully automatic in-hospital external
      cardioverter defibrillator.
AB  - Sudden cardiac death due to ventricular tachyarrhythmia remains a significant
      problem in the in-hospital setting. Although the probability of survival is
      closely correlated with the rapidity of a response by qualified personnel,
      response times can be prolonged, even in specialized care units. In an effort to
      decrease response time, a fully automatic external cardioverter defibrillator was
      recently devised. This device was evaluated in the in-hospital setting to assess
      safety and efficacy. A total of 79 patients were studied in a multicenter trial.
      Patients were monitored with fully functional devices in the electrophysiology
      laboratory (51 patients) and in the cardiac care unit (28 patients). Performance
      of the device was assessed by comparing automatic responses to any sustained
      change in cardiac rhythm, either spontaneous or induced, to a retrospective
      review of stored ECG data and programmed parameters. During a total duration of
      964 hours of monitoring, there were 99 episodes of sustained tachycardia. Therapy
      was appropriately delivered or advised in all episodes. Therapy was advised in
      one episode of supraventricular tachycardia. There were no episodes of
      inappropriate therapy delivery. There were no complications or adverse events.
      The device performed with a sensitivity of 100% and specificity of 98.8% with an
      average response time of 22 seconds. In conclusion, this automatic external
      defibrillator was safe, effective, and functioned as designed. Significant
      improvement in response time to life-threatening ventricular tachyarrhythmia in
      the in-hospital setting would be expected if this technology was widely adopted.

PMID- 10598970
TI  - Tachycardia induced electrical remodeling of the atria and the autonomic nervous
      system in goats.
AB  - Atrial fibrillation (AF) shortens the atrial effective refractory period (AERP).
      To investigate the role of the autonomic nervous system during this so-called
      electrical remodeling of the atria (ERA) and during recovery from ERA we analyzed
      heart rate variability (HRV). In 12 goats atrioventricular (300:150 beats/min)
      pacing was performed for 24 hours, interrupted at 4, 8, 16, and 24 hours for
      recording of 500 atrial (AA) intervals during sinus rhythm and measurement of the
      AERP(430ms) at 7.4 +/- 0.6 sites. After 24 hours, pacing was stopped and the
      electrophysiological study and recording of the AA intervals was repeated at 4,
      8, 16, and 24 hours after cessation of pacing. Time- and frequency-domain
      parameters were computed from each 500 AA interval recording. After 24 hours of
      rapid pacing the AERP had shortened significantly (147 +/- 5.6 to 102+/- 6.4 ms,
      P < 0.0001). No significant changes in HRV and dispersion of refractoriness
      (AAERP) (47 +/- 7.1 to 44 +/- 4.2 ms) were observed. After cessation of pacing,
      the AERP prolonged again (102 +/-6.4 to 135+/-8.8 ms, P < 0.0001) and was
      paralleled by a significant increase in AAERP (44 +/- 4.2 to 63+/- 7.1 ms, P =
      0.01). Furthermore, HRV increased significantly. At each time point an inverse
      relation between the logarithmically transformed vagal parameter HF (InHF) and
      AERP was observed. We calculated the mean InHF for each goat using all time
      points and used the median value to divide the 12 goats into high and low vagal
      tone groups. We compared the degree of ERA and recovery from ERA for both groups.
      The AERP shortened 47.4 +/- 6.5 versus 43.0+/-5.0 ms (NS) for goats with high and
      low vagal tone, respectively. During recovery from ERA the AERP lengthened 23.6
      +/- 4.0 versus 42.5 +/- 1.7 ms (P = 0.001) for goats with high and low vagal
      tone, respectively. Multivariate regression analysis indicated a short AERP as
      the single independent determinant of the inducibility of AF during ERA and
      recovery from ERA (P < 0.0001). During recovery from ERA, the AERP prolonged and
      vagal tone and AAERP increased. A high vagal tone during recovery from ERA was
      associated with a short AERP and an attenuated recovery of ERA.

PMID- 10598971
TI  - Safety seat belt use in Japanese patients with a pacemaker.
AB  - The aim of this study was to evaluate whether the rate of seat belt use is
      influenced by the interaction between the seat belt shoulder strap and pacemaker
      generator. The participants (1,942 Japanese patients with pacemakers) were asked
      to respond to a questionnaire about their seating position in the vehicle, their
      actual use of seat belts, and the reasons for not wearing seat belts. Front seat
      occupants (drivers and front seat passengers) were divided into two groups
      according to the relation between the site of the seat belt shoulder strap and
      the pacemaker implantation site: group-1--seat belt ipsilateral to the pacemaker,
      and group-2--seat belts contralateral to the pacemaker. Of the 1,942
      questionnaires sent by mail, 1,486 (76.5%) were completed and returned. The
      actual rates of seat belt use were as follows: drivers (n = 428), 67.4% in group
      1 versus 81.0% in group 2 (P < 0.01):front seat passengers (n = 403), 63.7% in
      group 1 versus 70.1 % in group 2 (NS); rear seat passengers (n = 655), 26.6%.
      Among the front seat occupants, pain or an uncomfortable sensation were stated in
      59.0% of group 1 versus 30.7% of group 2 (P < 0.01). The interaction between seat
      belts and pacemaker lowers the rate of seat belt use in patients with pacemakers.
      Pain or discomfort from seat belt-pacemaker contact was noted as the reason for
      not wearing a seat belt. Physicians should inquire about and take into account a
      patient's seating location in the vehicle and the location of the seat belt
      shoulder restraint. The pacemaker implantation site should be placed, if
      possible, contralateral to the seat belt.

PMID- 10598972
TI  - Cardiac memory.

PMID- 10598973
TI  - Repetitive ICD discharges during an ambulance ride: an unusual pacemaker-ICD
      interaction.

PMID- 10598974
TI  - "Optimum" formulae for heart rate correction of the QT interval.
AB  - The study investigated the performance of several generic QT/RR regression models
      in a dataset of QT and RR intervals obtained from resting electrocardiograms of
      1,100 healthy subjects (913 male, mean age 33+/-12 years). All the investigated
      models have three degrees of freedom and included the hyperparabolic and hyper
      hyperbolic models, algorithmic models, negative exponential models, and models
      involving inverse tangent, hyperbolic tangent, and inverse hyperbolic sign
      functions. For each generic model, the combination of parameters leading to the
      lowest regression residuum was found. The results of the study show that the
      goodness of the optimum fit is practically independent of the generic form of the
      regression model and that different datasets lead to different combinations of
      the numerical values of parameters of the corresponding regression models. The
      study concludes that the search for a universally applicable QT/RR regression
      model that would provide the best fit in all circumstances is most likely
      fruitless. Rather, individual studies such as those investigating drug related QT
      prolongation might benefit from establishing a best-fit regression that would
      provide the optimum model for each particular dataset.

PMID- 10598975
TI  - Recurrent atrial electrode displacement complicating a single lead VDD pacing
      system.
AB  - We describe an unusual complication of single-lead VDD pacing: recurrent
      advancement of the atrial bipole into the right ventricle. As a consequence, the
      patient experienced symptomatic pacemaker-mediated tachycardia and underwent two
      revision operations to achieve adequate fixation of the lead.

PMID- 10598976
TI  - Microwave ablation of atrial flutter.
AB  - Radiofrequency (RF) ablation of the isthmus between the inferior vena cava and
      the tricuspid ring has proven to be a safe and successful method of treating
      atrial flutter (AF). However, RF ablation lesions are small in size requiring a
      considerable number of energy applications to ablate the AF circuit. The aim of
      this study was to evaluate the feasibility and efficacy of microwave energy for
      AF ablation. We report a case of sustained typical AF treated successfully and
      safely by 1 pulse of microwave (MW) energy. This showed it is possible to treat
      AF with a small number of pulse applications.

PMID- 10598977
TI  - Left posteroseptal Mahaim fiber associated with marked longitudinal dissociation.
AB  - We report a patient who underwent radiofrequency catheter ablation of a left
      posteroseptal atrioventricular (AV) Mahaim fiber with a marked longitudinal
      dissociation. During atrial pacing, Wenckebach-type atrioventricular block over
      the accessory pathway was observed with progressive preexcitation and no change
      in polarity of the delta waves. The AV conduction curve was discontinuous, with a
      distinct "jump-up" in local AV conduction time of 84 ms. The earliest ventricular
      activation was recorded from the posteroseptal portion of the mitral annulus, and
      the unipolar electrogram from a distal electrode had a high, steep deflection
      with uniphasic QS-like activity with 62 ms of local AV conduction time.

PMID- 10598978
TI  - Video-assisted endoscopic removal of infected endocardial pacemaker lead with
      large floating vegetation.
AB  - The best management of pacemaker lead related endocarditis is complete surgical
      or percutaneous removal of the pacemaker system. Although the traditional
      surgical approach is via median sternotomy, we present two cases in which the
      lead and vegetations were removed using a video-assisted endoscopic technique
      through a limited right submammary incision. In each case the patient was
      supported by partial extracorporeal perfusion. Additional tricuspid valve repair
      and atrial septal defect closure was performed in one case. The postoperative
      courses were uneventful, illustrating that, when compared to the conventional
      open heart surgical approach, the less invasive approach can be a safe and
      effective way to remove an infected foreign body from the right heart with
      increased comfort, fast recovery, and a better cosmetic result.

PMID- 10598979
TI  - Pseudofracture of an ICD lead.
AB  - A proximal pseudofracture of a Medtronic 6936 defibrillating lead adjacent to the
      ICD pulse generator was found on X ray. At this site, the multifilar metallic
      connector joins the stimulating lead before coiling around it. Conventional X ray
      of the abdomen does not visualize this connection. During ICD replacement, lead
      impedance should be routinely measured.

PMID- 10598980
TI  - Interelectrode (Accufix) lead fracture.
AB  - An interelectrode fracture was diagnosed 7 years after the implantation of an
      Accufix lead. The lead body separated from the tip with the helix screwed into
      the atrial wall. The retention wire was intact and may have contributed to the
      lead rupture.

PMID- 10598981
TI  - Threshold behavior.

PMID- 10598982
TI  - Stimulation threshold behavior by means of a high-resolution automatic
      measurement algorithm constitutes an important contribution to our understanding
      of threshold performance.

PMID- 10598983
TI  - The Stimarec Bulletin. 26th Year-No 5&6--June 30, 1999.

PMID- 10598984
TI  - Anterior surgery with short fusion using the Zielke procedure for thoracic
      scoliosis: focus on the correction of compensatory curves.
AB  - Anterior instrumentation is recommended to correct idiopathic thoracolumbar or
      lumbar scoliosis through short fusion within the major curve. Only a few reports
      exist of anterior surgical correction for thoracic scoliosis. This study assessed
      the results of Zielke instrumentation for thoracic curve and analyzed the three
      dimensional correction of deformity, especially correction of the uninstrumented
      compensatory curve. Seventeen patients, who had undergone selective thoracic
      correction and fusion using the Zielke procedure to treat thoracic scoliosis, had
      been followed for at least 3 years. Three-dimensional correction was evaluated
      radiographically. Furthermore, three-dimensional back deformities were evaluated
      using a topographic body scanner. Twelve patients with a single thoracic curve
      and five with a double curve were all female, with a mean age of 14.6 years. The
      preoperative main thoracic curve was 54.8 degrees +/- 10.5 degrees (range, 40-78
      degrees), and it was 23.8 degrees +/- 10.5 degrees (range, 7-40 degrees) at the
      final follow-up examination (p < 0.0001). The average correction rate of the main
      curves was 56.6%. By correcting the thoracic curve, the upper and lower
      compensatory curves were corrected spontaneously without surgical
      instrumentation, with average correction rates of 45.1% and 50.2%, respectively.
      The average correction loss of the main curve was 2.3 degrees. The hump angle
      measured using a topographic body scanner decreased from 12.8 degrees +/- 4.5
      degrees to 8.4 degrees +/- 4.3 degrees after surgery (p = 0.0001). Of the three
      patients in whom the rod broke up, only one showed a correction loss of 10
      degrees; however, bony fusion was obtained. Anterior short fusion for thoracic
      scoliosis appears to offer significant correction, stabilization, and spontaneous
      correction of the compensatory lumbar curve without limiting lumbar motion.

PMID- 10598985
TI  - Laminectomy with posterior wiring and fusion for cervical ossification of the
      posterior longitudinal ligament, spondylosis, ossification of the yellow
      ligament, stenosis, and instability: a study of 5 patients.
AB  - Cervical laminectomy with posterior wiring and fusion is valuable for the
      management of cervical ossification of the posterior longitudinal ligament
      (OPLL), spondylosis, ossification of the yellow ligament (OYL), stenosis, and
      instability. Within 1.5 years, five patients averaging 73 years of age developed
      severe myelopathy. Dynamic radiographs confirmed an intact cervical lordosis with
      active subluxation and instability at one or two levels, whereas magnetic
      resonance and computed tomography scans showed OPLL, spondylosis, OYL, and
      stenosis. After multilevel laminectomy with posterior wiring and fusion and
      immobilization in cervicothoracic orthoses, patients fused in an average of 3.6
      months. All patients improved, showing mild to moderate residual postoperative
      myelopathy an average of 13 months later (range, 6-19 months). With an intact
      cervical lordosis, laminectomy with posterior wiring and fusion was used
      successfully to manage five patients with OPLL, spondylosis, OYL, stenosis, and
      instability.

PMID- 10598986
TI  - The effect of cervical plating on single-level anterior cervical discectomy and
      fusion.
AB  - The use of anterior plates for single-level cervical fusions is controversial.
      Previous studies that evaluated single and multiple-level fusions have shown
      increased and decreased fusion rates when cervical plates are used. The purpose
      of this study was to compare the clinical and radiographic success of single
      level discectomy performed with and without anterior cervical plate fixation.
      During a 6-year period, 80 patients were surgically treated with a single-level
      anterior cervical discectomy. Forty-four patients had cervical plates, whereas 36
      had fusions without plates (average follow-up, 2.3 years). The pseudarthrosis
      rates were 4.5% (2 of 44) for patients with plating and 8.3% (3 of 36) without
      plating. This difference was not significant (p = 0.653). There was no
      correlation of pseudarthrosis with sex, age, level of surgery, history of tobacco
      use, or the presence of previous anterior surgery. The amount of graft collapse
      for patients with plating was 0.75 mm compared with 1.5 mm for those without a
      plate (p = 0.026). The amount of kyphotic deformity of the fused segment was 1.2
      degrees with plating compared with 1.9 degrees for patients without plating (p =
      0.079). Ninety-one percent of the patients with plating had good or excellent
      results compared with 88% in the group without cervical plates, based on Odom's
      criteria. The addition of plate fixation for single-level anterior cervical
      discectomy and fusion is safe and not associated with a significant increase in
      complication rates. The pseudarthrosis rates are not significantly different when
      a cervical plate is used.

PMID- 10598987
TI  - Is computed tomography of nonvisualized C7-T1 cost-effective?
AB  - The authors determined the cost-effectiveness of computed tomography (CT) of the
      inadequately visualized C7-T1 level on conventional radiography in a
      retrospective cohort study. Routine cervical spine radiography was performed in
      360 trauma patients in whom the C7-T1 level was not adequately visualized, but
      there was no evidence of lower cervical spine injury. In these patients, CT of C7
      T1 was performed and reviewed for the presence, location, and pattern of
      fracture. An orthopaedic surgeon was consulted regarding his proposed treatment
      and the presumed natural history without treatment of each C7-T1 injury
      identified. Based on Medicare reimbursement data, cost-effectiveness was then
      calculated for 1) each fracture identified, 2) each fracture that required
      surgical fixation secondary to risk of further neurologic sequelae (definitely
      unstable), and 3) each fracture that required either surgical fixation or halo
      immobilization secondary to the risk of development of cervical instability and
      arthritis (potentially or definitely unstable). Eleven of 360 fractures of C7-T1
      were identified. The cost-effectiveness of CT for averting potential sequelae was
      $9,192 for each fracture identified, $16,852 identified for each potentially or
      definitely unstable fracture identified, and $50,557 for each definitely unstable
      fracture identified. Computed tomography of the inadequately visualized C7-T1
      level on plain radiography is cost-effective, especially given the relatively
      young age of the trauma population and therefore the high associated morbidity of
      the sequelae of these injuries over time.

PMID- 10598988
TI  - Smoking cessation in the spine surgeon's office: a review.
AB  - Tobacco abuse is a major health and economic problem in the world today. The
      spine practitioner has direct experience with the negative effects of the
      addiction. This review will provide an outline to assist all involved in spine
      care to help the patient overcome his or her dependence on nicotine. Every
      practitioner should participate. Even minimal intervention, if carried out at
      each office visit, can have surprisingly positive effects.

PMID- 10598989
TI  - The value of scintigraphy in the diagnosis of pseudarthrosis after spinal fusion
      surgery.
AB  - The utility of planar bone scintigraphy was evaluated for discerning bony union
      after spinal fusion surgery, especially in cases of clinically and radiologically
      suggested pseudarthrosis. Between 1991 and 1996, the authors performed bone
      scintigraphy on 42 patients (21 women, 21 men; mean age, 42 years) after spinal
      fusion surgery (32 posterolateral, 10 combined) and just before their admission
      to the hospital for material removal. The fusions consisted of 29 lumbosacral, 6
      thoracolumbar, 3 lumbar, 2 thoracolumbosacral, 1 thoracic, and 1 cervical. The
      mean fusion spanned four segments, and the mean time between spinal fusion and
      material removal was 27 months. The scintigraphy was performed using the tracer
      Tc-99m. Based on the scintigraphy data, the radiologist suspected pseudarthrosis
      in five patients (12%), and the condition was confirmed in four patients during
      operation (10%), two diagnosed and two undiagnosed. The accuracy of the method
      was 88%; sensitivity, 50%, specificity, 93%; positive predictive value, 40%; and
      negative predictive value, 95%. The sensitivity and positive predictive value of
      bone scintigraphy are low for possible instability after spinal fusion. The
      method is not sufficient to reliably diagnose pseudarthrosis after spondylodesis.

PMID- 10598990
TI  - Treatment of syringomyelia after posttraumatic paraparesis or tetraparesis.
AB  - This retrospective study of 12 patients with syringomyelia related to spinal cord
      trauma with paraplegia or tetraplegia and secondary progressive neurologic
      deficits was conducted to evaluate various surgical treatments. Judging by the
      results of postoperative neuroradiologic examinations, 75% had incomplete
      reduction of the spinal fracture at the time of initial surgery. The secondary
      neurologic deterioration occurred within a delay of 146 +/- 16 months and
      included ascending sensory deficits in 92%, deafferentation pain in 83%, and
      increased motor weakness in 33%. There was a positive correlation between the
      severity of symptoms, incomplete reduction of spinal fracture, and the degree of
      arachnoid scarring in preoperative neuroradiologic examinations.
      Syringoperitoneal shunting was performed in 83% of patients, and laminectomy with
      arachnoid lysis and dural grafting were performed in 17%. Pain was improved in
      75%, sensory deficits in 25%, and motor weakness in 8%. During the follow-up
      period of 44 +/- 25 months, 30% of patients with syringoperitoneal shunting
      required repeated operation for obstruction or infection, whereas the
      syringomyelia remained collapsed in the two patients with laminectomy with
      arachnoid lysis and dural grafting, but this did not require additional surgery.
      In conclusion, laminectomy with arachnoid lysis and dural grafting seems to be a
      promising alternative treatment for patients with secondary neurologic
      deterioration after traumatic paraplegia or tetraplegia. Syringoperitoneal
      shunting may be reserved for patients without severe arachnoid scarring.

PMID- 10598991
TI  - Restoration of thoracic kyphosis in the hypokyphotic spine: a comparison between
      multiple-hook and segmental pedicle screw fixation in adolescent idiopathic
      scoliosis.
AB  - This study verified the efficacy of segmental pedicle screw fixation in restoring
      thoracic kyphosis in persons with hypokyphotic scoliosis. Fifty-one patients were
      divided into three groups by the degree of preoperative thoracic hypokyphosis and
      fixation method used: the hypokyphosis-hook (HH), hypokyphosis-screw (HS), and
      normal kyphosis-screw (NS) group. They were compared after a minimum follow-up
      period of 2 years. Preoperative thoracic kyphosis of 4.1 degrees +/- 8.6 degrees,
      8.1 degrees +/- 5.6 degrees and 27.3 degrees +/- 9.8 degrees in the HH, HS, and
      NS groups were restored to 14.5 degrees +/- 10.2 degrees, 27.3 degrees +/- 11.3
      degrees, and 28.3 degrees +/- 13.7 degrees, respectively. The difference between
      the HH and HS groups was significant (p = 0.000). The HS and the NS groups did
      not differ (p = 0.16). This indicates that segmental pedicle screw fixation was
      more effective than multiple hooks in restoring kyphosis in patients with
      hypokyphotic scoliosis and created kyphosis similar to that in patients without
      preoperative hypokyphosis.

PMID- 10598992
TI  - Gelfoam as a barrier to prevent polymethylmethacrylate-induced thermal injury of
      the spinal cord: in vitro and in vivo studies in pigs.
AB  - Gelatin sponge (Gelfoam; Upjohn, Kalamazoo, MI, U.S.A.) is commonly used as an
      interpositional barrier to shield the spinal cord from thermal injury during
      vertebral reconstruction with polymethylmethacrylate bone cement. The aim of this
      study was to record epidural and intradural temperatures during
      polymethylmethacrylate reconstruction of vertebral corpectomy defects. Three
      surgical techniques (subtotal corpectomy, total corpectomy with insertion of a
      Gelfoam barrier, and total corpectomy with no barrier) were compared in vivo and
      in vitro in a porcine model. As expected, total corpectomy defects cemented
      without a Gelfoam barrier produced the highest epidural temperatures in vivo
      (52.8 degrees C) and in vitro (58 +/- 2 degrees C). The Gelfoam barrier provided
      some protection against heat transfer, but peak temperatures and absolute
      temperature increases were significantly higher than in defects with an intact
      posterior cortex (p < 0.05). These results indicate that an intact posterior
      cortex provides the best protection against heat transfer, whereas the use of a
      Gelfoam barrier appears to provide only partial protection against thermal
      injury.

PMID- 10598993
TI  - Mechanical properties and failure mechanics of the spine under posterior shear
      load: observations from a porcine model.
AB  - Few studies have focused on failure patterns of the entire motion segment and on
      the function of the individual structures resulting from dynamic posterior
      loading. The current study investigated the mechanical properties of the motion
      segment under posterior shear loading and documented the resulting injuries.
      Twenty-six porcine motion segments were separated into three groups (whole
      segments, no posterior ligaments, and no posterior ligaments and facet joints).
      The specimens were tested under posterior shear loading to failure in a custom
      designed jig adapted to a testing machine. Load-deformation curves were collected
      to obtain the following parameters: the energy absorbed to failure, the
      deformation at failure, the ultimate shear load, and the stiffness. The disk was
      found to carry approximately 1,540 N (74% of the intact specimen) of the ultimate
      load. Stiffness was dominated by the intervertebral disk complex, accounting for
      approximately 85% of the average stiffness. The predominant injuries resulting
      from posterior shear loading were avulsions of the end plate.

PMID- 10598994
TI  - An electromyography-assisted model to estimate trunk muscle forces during
      fatiguing repetitive trunk exertions.
AB  - During submaximal shortening muscle contraction, fatigue characteristically
      results in an increase in measured surface electromyography, whereas the maximum
      force that can be produced by muscle is reduced. This finding compromises
      researchers' ability to estimate muscle stress in a joint system such as the
      spine, which is composed of more muscles than degrees of freedom of the joint. A
      three-dimensional, electromyography-assisted, dynamic biomechanical model of
      spinal loading was developed and validated for use during fatiguing repetitive
      trunk extension exertions. A time-varying maximum muscle stress was included to
      model the effect of a change in the maximum force-producing capacity of the
      erector spinae muscle. Sixteen men performed submaximal isokinetic trunk
      extension endurance tests at 15 degrees per second. The exertion level (35% and
      70% of their maximum dynamic extension torque) and repetition rate (5 and 10
      repetitions per minute) of the tests were varied during four testing sessions.
      Using trunk muscle electromyography and the measured torque as input, the model
      predicted significant linear reductions in the maximum muscle stress in 78% of
      the endurance tests, which resulted in an estimated decrease in erector spinae
      force in 75% of the tests. Conversely, if the maximum muscle stress was assumed
      to be constant, the erector spinae force would have been predicted to increase in
      73% of the tests. The magnitude of the change in predicted erector spinae maximum
      muscle stress and force depended on the exertion level and repetition rate. This
      model will allow researchers to assess the effects of changes in recruitment
      patterns of trunk muscles during dynamic trunk extension on the estimated spinal
      loading of the lumbar spine.

PMID- 10598995
TI  - Anatomy of the cervicothoracic junction: a study of cadaveric dissection,
      cryomicrotomy, and magnetic resonance imaging.
AB  - The morphologic characteristics of the cervicothoracic junction from C6 to T2
      were examined. Gross dissection and cryomicrotomy was performed on 13 fresh
      cadavers. Four healthy volunteers underwent magnetic resonance imaging. Results
      indicated that vertebral body dimensions do not change appreciably, except for
      vertebral body heights and medial pedicular angulation, both of which increase
      from C6 to T2. Based on the findings of gross dissection and cryomicrotomy, the
      mediolateral width of the spinal canal was largest at C6 to accommodate the
      larger spinal cord at C6. The cross-sectional area ratios of the spinal cord to
      spinal canal were 1:2.3 at C6, 1:3.7 at C7, 1:4 at T1, and 1:3.7 at T2. The
      foraminal height and width were greater at C7-T1 and T1-T2 than at C6-C7. The
      thinnest lamina was at C7. The anatomy of the pedicles showed that the outer
      mediolateral diameter averaged 6.78 mm at C6, 7.5 mm at C7, 9.23 mm at T1, and
      7.9 mm at T2. The superior-inferior diameter of the pedicle increased from 7.58
      mm at C6 to 12.43 mm at T2. Medial angulations decreased from 44.5 at C6 to 23.35
      at T2. The coronal angulation of the exiting nerve was 64.83 for C7, 79.83 for
      C8, and 90.33 for T1 nerve roots based on coronal magnetic resonance imaging.
      Finally, gross dissection during the anterior approach to the cervicothoracic
      junction revealed that this approach was extensible, allowing access to the
      anterior aspect of the cervicothoracic spine. Associated vital structures must be
      protected, such as the arch of aorta, common carotid artery, innominate vein,
      thoracic duct, recurrent laryngeal nerve, stellate ganglion, trachea, and
      esophagus.

PMID- 10598996
TI  - Epidural lipomatosis complicating lumbar steroid injections.
AB  - Corticosteroid injections into the spinal epidural space are frequently used to
      effect a relief of back pain and associated radicular extremity symptoms. Spinal
      epidural lipomatosis has been documented after the use of systemic corticosteroid
      therapy. This case report documents the development of epidural lipomatosis after
      the administration of multiple epidural steroid injections. The development and
      subsequent resolution after discontinuation of the steroid injections are
      demonstrated with serial magnetic resonance imaging.

PMID- 10598997
TI  - Isolated spinal cord sarcoidosis mimicking an intramedullary tumor.
AB  - A case of cervical intramedullary sarcoidosis and its uncommon magnetic resonance
      imaging with contrast medium are reported. Spinal cord sarcoidosis is very rare.
      It is difficult to diagnose intramedullary sarcoidosis without a previous
      diagnosis of systemic sarcoidosis or other apparent symptom. The patient had
      subacute myelopathy. Contrast-enhanced images revealed intense focal enhancement
      of the C6-7 cervical cord. The preoperative diagnosis was an intramedullary
      tumor. Subtotal resection was performed after intraoperative frozen section study
      was interpreted as malignant lymphoma. Subsequent pathologic examination of the
      biopsied specimens revealed spinal cord sarcoidosis. After surgery, steroid
      therapy was performed, but the patient's symptoms hardly improved. Even if
      imaging study and intraoperative frozen section show neoplasm, the first surgery
      should be limited to decompressing the cord and biopsy in cases of suspected
      sarcoidosis.

PMID- 10598998
TI  - Thoracic epidural hematoma after spinal manipulation therapy.
AB  - Posttraumatic spinal epidural hematoma is an unusual pathology. The authors
      report the case of a 64-year-old woman who experienced thoracic epidural hematoma
      during a session of spinal manipulation therapy (SMT). In the literature, such an
      event has been reported previously only twice. This case represents the first
      spinal epidural hematoma occurring after a chiropractic manipulation in the
      lumbar region. Surgical evacuation of the spinal hematoma resulted in complete
      recovery in the patient. Complications of SMT are reviewed, and the etiology and
      features of spinal epidural hematoma are discussed.

PMID- 10598999
TI  - Complications of abdominal vagotomy in the dog.

PMID- 10599000
TI  - Lost among giants.

PMID- 10599001
TI  - Sutureless and reduced suture anastomosis of hollow vessels with fibrin glue: a
      review.
AB  - Research in reduced suture fibrin glue (FG) and sutureless FG anastomosis has
      been lagging behind FG utilization in other surgical fields. A review of the
      literature for vascular, esophageal, tracheal, gastrointestinal, common bile
      duct, ureteral, vas deferens, and Fallopian tube FG anastomosis indicates that
      reduced suture FG and sutureless FG procedures may be performed with less
      training, reduced operating time, leakage, ischemia, inflammation, and necrosis
      compared to sutured techniques. Reduced suture FG vascular anastomosis augments
      early anastomotic strength. Suture number for esophageal, tracheal, and
      tracheobronchial anastomoses can be reduced with FG. Bursting strength in pig
      small intestine and rat colon was lower at 4 days postoperatively, but returned
      to sutured strength at 7 days. Mortality was unaffected, and 18-month follow-up
      in sutureless FG intestinal anastomosis in pigs showed no stenosis. Preliminary
      ureteral studies have demonstrated successful sutureless FG and reduced suture FG
      laparoscopic techniques in pigs. Reduced suture FG and sutureless FG vas deferens
      anastomosis may reduce sperm granuloma rates, with increased patency and
      pregnancy rates. Patency and pregnancy rates have been similar for tubal FG,
      reduced suture FG, autologous fibrin glue (AFG), and sutured anastomosis. Any
      risk of viral transmission or immune response is eliminated by AFG. While there
      are few studies in many areas of FG hollow vessel anastomosis, the current
      literature illustrates many of the advantages of FG over other anastomotic
      techniques and should provide impetus for continued research in this promising
      field of surgery.

PMID- 10599002
TI  - Hydroxyapatite composites designed for antibiotic drug delivery and bone
      reconstruction: a caprine model.
AB  - The purpose of this study was to investigate the feasibility of fabricating a
      drug delivery system that serves a dual function, to eradicate infection as well
      as to provide a scaffold for osseous integration. Two porous composite systems
      were fabricated using hydroxyapatite (HA) as the carrier for gentamicin sulfate
      (GS), an aminoglycoside antibiotic. Structural and mechanical properties of
      porous HA-GS composites were characterized and the in vitro release behavior of
      GS from fabricated composites was monitored and compared with the well-known
      polymethylmethacrylate (PMMA)-GS delivery system. Scanning electron microscopy
      revealed a macropore range of 150 to 200 microm and 100 to 190 microm for the
      sintered and unsintered HA-GS composites, respectively. The effect of GS
      inclusion on bone apposition and ingrowth was assessed using a caprine model.
      Plugs 10 mm x 6 mm of cylindrical tricalcium phosphate, sintered HA, and sintered
      HA-GS were implanted in the femoral diaphysis for a period of 6 weeks. Data
      collected during the in vitro study showed that GS can successfully be
      incorporated into HA and used as a drug delivery system to eradicate
      Staphylococcus aureus. In vivo data confirmed that the inclusion of GS within a
      ceramic matrix did not stimulate or inhibit osteointegration or bone apposition.
      In conclusion, the fabricated sintered HA-GS composite may be beneficial in the
      treatment of infected osseous sites as a drug delivery system.

PMID- 10599003
TI  - Enhanced bone regeneration using porcine small intestinal submucosa.
AB  - Small intestinal submucosa (SIS) is an easily produced material that has been
      used experimentally for tissue engineering. To evaluate the ability of SIS to
      facilitate bone growth within a long-bone defect, a segment of the radius was
      surgically removed in adult, female Sprague-Dawley rats. The defect was either
      left unfilled or implanted with SIS, demineralized cortical bone (DMCB), or
      ovalbumin. The defect was evaluated radiographically and histologically after 3,
      6, 12, and 24 weeks. Tissue remodeling within the defect was evident by week 3 in
      SIS- and DMCB-treated rats. Filling was characterized initially by infiltration
      of mononuclear cells and extracellular material in SIS-implanted rats and
      multifocal remodeling bone particles and cartilage formation in DMCB-implanted
      rats. Cartilage was observed as early as 3 weeks and bone as early as 6 weeks in
      SIS-implanted rats. Filling of the defect arose from multiple foci in DMCB
      implanted rats, but was contiguous with and parallel to the ulnar shaft in SIS
      implanted rats, suggesting that defect repair by SIS may be conductive rather
      than inductive. Rats in which the defect was left unfilled demonstrated slow but
      progressive filling of the defect, characterized by mononuclear cell infiltrates
      and fibrous extracellular material. In summary, SIS facilitated rapid filling of
      a long-bone defect. These results suggest that SIS may be useful as a bone repair
      material.

PMID- 10599004
TI  - Endoscopic skull base surgery I: a new animal model for pituitary surgery.
AB  - Endoscopy has emerged as a new means to perform minimally invasive surgery of the
      skull base. Specifically, endoscopic techniques and instruments can be used to
      safely and effectively approach and resect tumors of the pituitary gland in
      humans. No animal model currently exists to serve as a template upon which to
      refine and develop endoscopic surgical technique in this region of the anatomy.
      We operated on two purpose-bred Hampshire-Yorkshire-Duroc hybrid swine to
      demonstrate the application of endoscopy to pituitary surgery. Based upon similar
      anatomical relationships in humans and swine between the oropharynx, nasopharynx,
      and skull base, we used a transoral, transpalatal approach to access the vomer of
      the swine. Under endoscopic exposure, we resected the vomer, entered the sphenoid
      sinus, and then resected the sphenoid septum, sella turcica, and adenohypophysis.
      Clear visualization of the pituitary, hypophyseal stalk, cavernous sinuses, and
      carotid prominences was achieved and documented with digital photography.
      Benefits and limitations of the technique were noted. These results have
      pertinent implications both for the study of the surgical anatomy of the swine
      craniofacial skeleton, and for future development of endoscopic surgical
      manipulation of the skull base.

PMID- 10599005
TI  - Esophagogastric anastomoses in rats--an experimental model.
AB  - Esophagectomy with esophagogastric anastomosis is not uncommonly complicated by
      anastomotic dehiscence. Although this is a major problem in clinical esophageal
      surgery, laboratory investigation of esophagogastric anastomotic wound healing
      has been hampered by the lack of a practical rodent model. Researchers have
      turned to large-animal experiments, or used various upper gastrointestinal pseudo
      anastomotic techniques in rodents. None of these approaches has proved to be
      satisfactory. We report our technique of side-to-side esophagogastric anastomosis
      in the rat. Using this technique we have overcome the problems encountered in our
      earlier studies of esophagogastric anastomotic wound healing in the rat.

PMID- 10599006
TI  - Historical declines in tuberculosis in England and Wales: improving social
      conditions or natural selection?
AB  - OBJECTIVES: A reinvestigation of the relationship between the decline of
      tuberculosis and improvement in social conditions in England and Wales during
      Victorian times. DESIGN: A retrospective study using data published in the annual
      reports of the Registrar General from 1853 to 1910. MEASURES ASSESSED: The
      diseases studied, in addition to tuberculosis were dysentery and cholera,
      including their total and infant mortality. Social conditions were evaluated from
      earnings and population density per house. RESULTS: Tuberculosis mortality
      declined at an annual average rate of 1.71% (95% confidence interval [Cl] 0.77
      2.63), whereas total mortality, infant mortality and mortality from cholera and
      dysentery and house population density showed no statistically significant
      decline over the same period. Real earnings increased by 1.05% (95% CI 0.29
      1.81). CONCLUSION: Improving social conditions do not provide the total
      explanation for the decline in tuberculosis during Victorian times. Other
      factors, principally natural selection, probably played a role. Part of the
      current increase in tuberculosis may be caused by effective drug therapy
      eliminating natural selection.

PMID- 10599007
TI  - Interpreting DNA fingerprint clusters of Mycobacterium tuberculosis. European
      Concerted Action on Molecular Epidemiology and Control of Tuberculosis.
AB  - Many studies of tuberculosis have defined clusters of patients on the basis of
      shared DNA fingerprint patterns of their Mycobacterium tuberculosis isolates.
      Clustering has been equated with recent transmission, and factors associated with
      clustering have been sought as a guide to population subgroups with high rates of
      ongoing transmission of M. tuberculosis. Considerable caution should be exercised
      in conducting and interpreting these studies. Groups of strains may be identical
      for reasons other than recent transmission, depending, for example, on the
      stability of the marker and the number of strains in the population over time.
      Cases actually due to recent transmission may not be seen as clustered if they
      are new immigrants to the population or if not all cases in the population are
      included in the study. The amount of clustering seen will depend on the duration
      of the study. Studies should give precise information on the study setting, the
      proportion of cases included, the recruitment period and the definition of
      clustering used. The data on clustering should be disaggregated at least by age,
      sex and immigration status. To be maximally informative, studies should involve a
      high proportion of all cases in a population, be conducted in conjunction with
      conventional epidemiological investigations of contacts (if possible), and should
      provide information on tuberculosis incidence in the population and on patients'
      age, sex, human immunodeficiency virus status, drug resistance and social and
      ethnic group.

PMID- 10599008
TI  - Direct observation of tuberculosis treatment by supervised family members in
      Yasothorn Province, Thailand.
AB  - SETTING: Yasothorn Province, Thailand. OBJECTIVE: To evaluate the effectiveness
      of a programme offering the option of direct observation of treatment (DOT) by a
      supervised family member. METHODS: Review of patient records and district
      registers in Yasothorn Province after implementation of the revised tuberculosis
      control strategy. RESULTS: From 1 October 1996 to 30 September 1997, the
      programme registered 779 patients: 366 smear-positive pulmonary, 357 smear
      negative pulmonary, and 56 extra-pulmonary. DOT was given in 243 (66%) smear
      positive, 83 (23%) smear-negative, and in 21 (38%) extra-pulmonary cases; the
      observer was a family member in 299 (86.2%) of the 347 cases. By December 1998,
      treatment outcomes were determined for the 695 new patients (326 smear-positive,
      321 smear-negative, 48 extra-pulmonary) of the 779 registered during the period
      under study. In new smear-positive patients, cure rates were 184/216 (85.2%, 95%
      confidence interval [CI] 80.5-89.9) with DOT versus 78/110 (70.9%, 95% CI 62.4
      79.4) with self-administration. CONCLUSION: The overall cure rate was 80.4% in a
      programme in which trained and supervised family members directly observed the
      treatment of two-thirds of sputum smear-positive patients. Supervised family
      members may contribute to more widespread effective implementation of the revised
      tuberculosis strategy in Thailand.

PMID- 10599009
TI  - High cure rates in smear-positive tuberculosis patients using ambulatory
      treatment with once-weekly supervision during the intensive phase in Sulawesi,
      Republic of Indonesia.
AB  - SETTING: The four provinces of Sulawesi, Republic of Indonesia. OBJECTIVE:
      Treatment of smear-positive pulmonary tuberculosis patients using ambulatory
      treatment with supervision once weekly during the intensive phase and once
      fortnightly during the continuation phase. DESIGN: Pilot projects with gradual
      expansion of activities according to defined quantitative criteria. RESULTS:
      During the period January 1993-December 1997, 11,879 new smear-positive and 320
      smear-positive previously treated patients, of whom 259 were relapses, were
      placed on short-course chemotherapy. At the end of the intensive phase, 87.5% of
      new patients and 80.0% of retreatment patients had become sputum smear-negative.
      During the period January 1993-December 1996, of 7,251 new smear-positive
      patients placed on treatment 85.2% were cured and an additional 7.9% had
      completed treatment, giving a total success rate of 93.1%. For 239 patients
      placed on retreatment the total success rate was 86.6%. CONCLUSION: The treatment
      results show that the policy introduced in Sulawesi is effective. In two
      provinces priority will now be given to increasing case detection, while in the
      other two provinces the emphasis will be on reaching full coverage. The reasons
      for the success of the projects are discussed, as are the prerequisites for
      introducing the policy in other areas.

PMID- 10599010
TI  - A randomised trial of the impact of counselling on treatment adherence of
      tuberculosis patients in Sialkot, Pakistan.
AB  - SETTING: Tuberculosis Department, Bethania Hospital, Sialkot, Pakistan.
      OBJECTIVE: To determine whether intensive counselling can improve treatment
      adherence. DESIGN: In a randomised controlled intervention trial of 1,019 adult
      tuberculosis patients, 49% were assigned to the intervention group and 51% to the
      control group. Baseline data were obtained through semi-structured interviews.
      Patients were followed until the end of treatment (cure, default, referral or
      death). The intervention included counselling at the start of treatment and at
      each subsequent visit for ambulatory patients, or weekly for hospitalised
      patients. Counselling combined health education with strategies to strengthen
      patients' self-efficacy. Control group patients received the usual care. The
      outcome measure was treatment default. RESULTS: The default rate was 54% in the
      control group and 47% in the intervention group: the default risk ratio was 0.87,
      implying a reduction in defaulting of 13%. The impact was stronger in women,
      ambulatory patients, re-treatment patients, women who worked in the home, and
      patients who were not the main provider, those with a poor knowledge of the
      disease or those with a short treatment delay. CONCLUSIONS: Intensive counselling
      has a significant, although limited, impact on treatment adherence.

PMID- 10599011
TI  - Who fails to complete tuberculosis treatment? Temporal trends and risk factors
      for treatment interruption in a community-based directly observed therapy
      programme in a rural district of South Africa.
AB  - SETTING: Hlabisa Tuberculosis Programme, Hlabisa, South Africa. OBJECTIVE: To
      determine trends in and risk factors for interruption of tuberculosis treatment.
      METHODS: Data were extracted from the control programme database starting in
      1991. Temporal trends in treatment interruption are described; independent risk
      factors for treatment interruption were determined with a multiple logistic
      regression model, and Kaplan-Meier survival curves for treatment interruption
      were constructed for patients treated in 1994-1995. RESULTS: Overall 629 of 3,610
      surviving patients (17%) failed to complete treatment; this proportion increased
      from 11% (n = 79) in 1991/1992 to 22% (n = 201) in 1996. Independent risk factors
      for treatment interruption were diagnosis between 1994-1996 compared with 1991
      1993 (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.6-2.4); human
      immunodeficiency virus (HIV) positivity compared with HIV negativity (OR 1.8,
      95%CI 1.4-2.4); supervised by village clinic compared with community health
      worker (OR 1.9, 95%CI 1.4-2.6); and male versus female sex (OR 1.3, 95%CI 1.1
      1.6). Few patients interrupted treatment during the first 2 weeks, and the
      treatment interruption rate thereafter was constant at 1% per 14 days.
      CONCLUSIONS: Frequency of treatment interruption from this programme has
      increased recently. The strongest risk factor was year of diagnosis, perhaps
      reflecting the impact of an increased caseload on programme performance. Ensuring
      adherence to therapy in communities with a high level of migration remains a
      challenge even within community-based directly observed therapy programmes.

PMID- 10599012
TI  - Patient and health care system delays in the diagnosis and treatment of
      tuberculosis.
AB  - SETTING: All culture-positive tuberculosis patients without previous treatment
      for tuberculosis (n = 184), New York City, April 1994. OBJECTIVE: To examine
      factors associated with delays in presenting to a health care provider (patient
      delay) and in starting antituberculosis treatment (health care system delay).
      DESIGN: Retrospective medical record review and patient interviews. RESULTS:
      Median total delay was 57 days (range 4-764), 35 for acid-fast bacilli smear
      positive patients and 79 for smear-negative patients (P < 0.001). Median patient
      delay was 25 (range 0-731). Median health care system delay was 15 days, 6 for
      smear-positive patients and 31 for smear-negative patients (P < 0.001). In
      logistic regression, age 55-64 years (adjusted odds ratio [OR(adj)] 10.6, 95%
      confidence interval [CI] 1.3-86.9), and primary language other than English
      (OR(adj) 2.5, 95%CI 1.0-5.8), were associated with longer patient delays.
      Homelessness (OR(adj) 7.1, 95%CI 1.05-33.5), not having a chest radiograph at the
      first medical visit (OR(adj) 2.4, 95%CI 1.0-5.4), negative smear (OR(adj) 10.2,
      95%CI 4.4-23.3) and absence of cough (OR(adj) 2.9, 95%CI 1.2-6.8) were associated
      with longer health care system delays. CONCLUSION: To reduce delays, patients
      should be educated to seek care more quickly, and should be provided with
      culturally appropriate health care and language services. Physicians should
      maintain a high index of suspicion for tuberculosis and perform appropriate
      diagnostic tests.

PMID- 10599013
TI  - Tuberculosis in Far North Queensland, Australia.
AB  - SETTING: Regional thoracic clinic in tropical Australia. OBJECTIVE: To document
      recent experience with tuberculosis in Far North Queensland, Australia, with
      particular reference to tuberculosis in indigenous people. METHODS: Retrospective
      survey of all cases of tuberculosis in Far North Queensland between January 1993
      and December 1997. RESULTS: There were 87 cases of tuberculosis; 54 were
      pulmonary, of which 67% were sputum smear-positive. Crude annual incidence of
      tuberculosis in indigenous people was 35.9/100,000 population compared to 2.32/
      100,000 in non indigenous people. There were 15 deaths, seven of which were felt
      to be avoidable. Nine of 11 relapses of previously treated disease occurred in
      Aboriginals. There were six cases of initial drug resistance, of which four were
      imported from overseas. Contact tracing identified four active cases of
      tuberculosis and 102 recently infected contacts. Preventive treatment in infected
      contacts was completed in only 41%, largely because of poor compliance related to
      alcohol consumption. CONCLUSION: Tuberculosis remains common in Far North
      Queensland, with excess cases observed mainly in the indigenous population.
      Aboriginals are at high risk of both death from and relapse of tuberculosis.
      Tuberculosis control in indigenous people scattered over such a vast area remains
      challenging, and the results at present are sub-optimal.

PMID- 10599014
TI  - A comparison of fluorescence microscopy with the Ziehl-Neelsen technique in the
      examination of sputum for acid-fast bacilli.
AB  - SETTING: National Tuberculosis Reference Laboratory in Dakar, Senegal.
      OBJECTIVES: Comparison of results with fluorescence and bright-field microscopy
      for acid-fast bacilli. METHODOLOGY: Two smears from 2,630 consecutive sputum
      specimens between January 1996 and June 1998 were prepared for blinded
      examination of one smear each by the Ziehl-Neelsen technique and fluorescence
      microscopy at 1,000x magnification. The time required to declare a slide as
      negative was determined for both techniques in a sample of 68 slides. RESULTS:
      Concordancewas 96.9% and 92.3% for diagnostic and follow-up examinations,
      respectively. The yield was similar with both techniques for specimens with at
      least 10 bacilli per 100 fields, but higher with fluorescence microscopy in those
      with fewer than 10 bacilli per 100 fields. The mean time required by fluorescence
      microscopy before declaring a slide as negative with the same magnification was 3
      minutes 34 seconds, compared to 7 minutes 44 seconds with the Ziehl-Neelsen
      technique. CONCLUSIONS: The results obtained with one technique are highly
      reproducible by the other. Fluorescence microscopy appears to be more likely to
      detect bacilli in paucibacillary cases than bright-field microscopy, and it more
      than halves the required examination time.

PMID- 10599015
TI  - Recognition of phenolic glycolipid-I (Mycobacterium leprae) and sulfolipid-I (M.
      tuberculosis) by serum from Mexican patients with leprosy or tuberculosis.
AB  - SETTING: Differential diagnosis of leprosy and tuberculosis in regions where both
      illnesses are endemic is a prerequisite for proper identification and treatment.
      OBJECTIVE: To evaluate the recognition of phenolic glycolipid-I (PGL-I) of
      Mycobacterium leprae and sulfolipid-I (SL-I) of M. tuberculosis by serum from
      patients with leprosy (LL) or pulmonary tuberculosis (PTB). DESIGN: Purified PGL
      I and SL-I were used as antigens in an ELISA test set up to assess recognition of
      these lipids by serum from 43 LL patients, 44 PTB patients and 38 healthy
      individuals. RESULTS: Leprosy patients gave higher IgM than IgG responses to PGL
      I and had comparable IgM and IgG responses to SL-I. A similar situation was
      observed with PTB serum. Some healthy individuals were found to contain
      significant levels of antibodies to both lipids. CONCLUSION: There is no specific
      recognition of either of the two lipid antigens tested by serum from both leprosy
      and tuberculosis patients; this rules out the possibility of using PGL-I and SL-I
      as tools for the differential diagnosis of these two mycobacterial diseases.

PMID- 10599016
TI  - Mycobacterium bovis as a zoonosis in the Kruger National Park, South Africa.
AB  - SETTING: The Kruger National Park (KNP), Mpumalanga Province, South Africa.
      OBJECTIVE: The prevalence of tuberculosis caused by Mycobacterium bovis exceeds
      70% in African buffalo in the southern region of the KNP. Inter-species
      transmission (lion, cheetah, baboon, antelope) has also been confirmed. Regular
      culling of emaciated buffalo and processing of meat and hides constitute routine
      control policy. Following extensive media coverage of the problem, public health
      concerns about the transmission of M. bovis to humans, including visitors to the
      KNP, prompted this investigation. DESIGN: The study was designed to determine the
      prevalence of infection and/or active disease due to M. bovis among KNP employees
      selected from three defined risk groups based on occupation category. RESULTS: Of
      206 persons screened for active disease by sputum bacteriology, two persons with
      disease due to M. tuberculosis were identified. No isolate of M. bovis was found.
      Differential skin testing using three antigens failed to show any degree of M.
      bovis infection risk, even among high risk occupations. Reasons for these results
      are discussed. CONCLUSIONS: Bovine tuberculosis was not indicated as an
      occupational zoonosis in the KNP, nor was aerosol transmission implicated as a
      mechanism for human infection. Concerns about the public health implications of
      tuberculosis in buffalo in the KNP have therefore not been validated.

PMID- 10599017
TI  - Prognosis for chronic obstructive pulmonary disease patients who receive long
      term oxygen therapy.
AB  - OBJECTIVE: To investigate the survival of patients with chronic obstructive
      pulmonary disease (COPD) receiving long-term oxygen therapy (LTOT). DESIGN:
      Retrospective study of 124 patients (76 males and 48 females, mean age 68 years)
      using LTOT from 1990 to 1996, studied with lifetable analyses. Seventy-six
      patients with PaO2 < or = 7.3 kPa, and 48 patients with PaO2 > or = 7.4 kPa were
      allocated to Groups I and II, respectively. RESULTS: The groups had similar FEV1
      and FVC levels. The 2- and 5-year survival rates were 73% and 50%, respectively,
      in Group I, and 78% and 40% in Group II. PaCO2 and FVC were predictors of
      survival in Group II. Women lived significantly longer than men (Group I: P <
      0.01, relative risk [RR] 0.341) but had better FEV1 (P < 0.01). Survival was
      significantly poorer for patients in the general hospital (P < 0.05, RR 2.096)
      compared with those at a university hospital. CONCLUSION: Survival during LTOT
      was similar in patients with and without severe hypoxaemia at the same level of
      loss of lung function. Survival was poorer when LTOT was not prescribed and
      followed in a department of respiratory medicine.

PMID- 10599018
TI  - Humoral immune responses to multiple antigens of Mycobacterium tuberculosis in
      tuberculosis patients co-infected with the human immunodeficiency virus.
AB  - A panel of ten protein antigens of Mycobacterium tuberculosis was used to
      evaluate serum antibody responses to tuberculosis in patients co-infected with
      the human immunodeficiency virus (HIV) and in HIV-infected control individuals
      without tuberculosis. Most (70%) of the tuberculosis patients had serum
      reactivity to at least one antigen and maintained the diverse antibody repertoire
      previously observed in HIV-negative tuberculosis patients.

PMID- 10599019
TI  - Mycobacterium avium complex causing endobronchial disease in AIDS patients after
      partial immune restoration.
AB  - OBJECTIVE: To report the development of an unusual manifestation of pulmonary
      Mycobacterium avium complex (MAC) infection in two patients with the acquired
      immune-deficiency syndrome (AIDS) after the commencement of combination
      antiretroviral chemotherapy. PATIENTS: Two Caucasian males with human
      immunodeficiency virus (HIV) infection and CD4 lymphocyte counts <0.05 x 10x9/1
      and with plasma HIV polymerase chain reaction (PCR) >100,000 copies/ml who were
      commenced on combination antiretroviral chemotherapy including a protease
      inhibitor. RESULTS: Both patients developed endobronchial polypoid tumours within
      two months of commencing antiretroviral chemotherapy. Histology demonstrated
      granuloma formation and acid-fast bacilli. Tissue from both patients grew M.
      avium. Both patients achieved significant suppression of viral replication and
      had significantly improved CD4 lymphocyte counts. Both required antimycobacterial
      therapy. CONCLUSIONS: Endobronchial polypoid tumours due to MAC infection have
      only been described in HIV-infected patients receiving antiretroviral
      chemotherapy. A degree of restored immunity is implicated in the pathogenesis of
      this unusual disease.

PMID- 10599020
TI  - Sputum induction to improve the diagnostic yield in patients with suspected
      pulmonary tuberculosis.
AB  - OBJECTIVE: To evaluate the utility of sputum induction in the large-scale
      tuberculosis control program. METHODS: Prospective study on sputum induction for
      improving the diagnostic yield of pulmonary tuberculosis, and estimation of the
      direct costs for sputum induction. RESULTS: Of 1,648 tuberculosis suspects with
      poor or absent sputum production, induced sputum was smear-positive in 558
      patients (353 previously smear-negative, 97 inadequate sputum and 108
      unproductive). The direct cost per induced sputum was US $0.37. CONCLUSION:
      Sputum induction is an effective, low-cost, and simple technique for improving
      the smear-positive case detection rate in a tuberculosis control program.

PMID- 10599021
TI  - Review of national tuberculosis programmes: the experience in Bangladesh.
AB  - Tuberculosis control efforts should be evaluated periodically to assess progress
      made by national programmes and to plan for the future. Simple and reliable tools
      are required for such assessments. This paper summarises the methodology and
      results of the review of the national tuberculosis programme in Bangladesh
      conducted in 1997. The authors conclude that similar reviews would not only help
      to verify the reports from the routine recording system, but would also assist
      policy development and future planning.

PMID- 10599022
TI  - AIDS and TB drug absorption.

PMID- 10599023
TI  - Childhood TB/HIV co-infection: correction, confusion and compliance.

PMID- 10599024
TI  - Nosocomial transmission in low-income countries.

PMID- 10599025
TI  - Prevalence and factors associated with tuberculosis infection.

PMID- 10599026
TI  - Outbreak of rifampin and streptomycin-resistant tuberculosis among homeless in
      Germany.

PMID- 10599027
TI  - The effect of Helicobacter pylori eradication on duodenal gastric metaplasia.
AB  - We investigated the incidence of duodenal gastric metaplasia and its response to
      Helicobacter pylori eradication in patients with duodenal ulcer or erosive
      duodenitis. Gastric and duodenal biopsies were taken from patients with
      endoscopically detected H. pylori positive duodenal ulcer or erosive duodenitis,
      and the presence and extent of duodenal gastric metaplasia was recorded. Patients
      were given omeprazole 20 mg twice daily for 2 weeks, and amoxicillin 1 g and
      clarithromycin 500 mg twice daily for 10 days, and then ranitidine for a further
      8 weeks. Biopsies were repeated 6 months after the start of treatment. Duodenal
      gastric metaplasia was initially present in 22 patients (52%) and was more
      frequent in ulcer patients than in duodenitis patients, but not significantly so
      (69% versus 45%). After treatment, H. pylori was eradicated in 68% of duodenal
      gastric metaplasia patients and the duodenum was normal endoscopically in 85% of
      these patients. Duodenal gastric metaplasia was improved or eliminated in 12/15
      H. pylori eradicators (80%) and in 5/7 H. pylori non-eradicators (71%), a non
      significant difference. The improvement in duodenal gastric metaplasia appeared
      to be independent of H. pylori eradication.

PMID- 10599028
TI  - Acute effects of griseofulvin on the pharmacokinetics and pharmacodynamics of
      warfarin in rats.
AB  - It has been reported that prothrombin time (PT), which is prolonged by warfarin,
      is reduced when patients on warfarin also take griseofulvin repeatedly. We
      investigated the cause of the drug interaction and the initial effects of
      griseofulvin on warfarin pharmacokinetics. Total cytochrome P-450, and the
      activities of aminopyrine N-demethylase, aniline p-hydroxylase and 7
      ethoxycoumarin O-deethylase, after repeated administration of griseofulvin (100
      mg/kg orally daily for 5 days) were examined. Acute effects of single doses of
      griseofulvin (100 mg/kg) on coagulation activity (prothrombin time) and warfarin
      pharmacokinetics after administration of warfarin were also studied. Repeated
      administration of griseofulvin induced warfarin-metabolizing enzymes. In
      contrast, a single administration of griseofulvin increased prothrombin time and
      serum warfarin concentrations. The activity of a warfarin-metabolizing enzyme (7
      ethoxycoumarin O-deethylase) was reduced when griseofulvin was added to rat liver
      microsomes. The results suggest that reduced warfarin action after repeated
      administration of griseofulvin may be due to induction of warfarin-metabolizing
      enzymes, but that there is also an initial increase in warfarin action.

PMID- 10599029
TI  - Investigation of ovum transport in the oviduct: the dynamics of oviductal fluids
      in domestic rabbits.
AB  - Ova are captured by the oviductal fimbria and rapidly transported to the
      ampullary-isthmic junction of the fallopian tube. Fertilized ova and oviductal
      fluids are then carried medially in the fallopian tube, while undergoing
      maturation in preparation for entering the uterine cavity, where nidation and
      further development take place. This movement of oviductal fluids was visualized
      in a rabbit model with human chorionic gonadotropin-induced ovulation, by
      injection of a contrast medium into the ampulla region of the oviduct. In the
      ampulla, the opaque medium was observed to oscillate at 0-85.4 mm/s. This medial
      transport of the fluid towards the uterus decreased to 0-9.6 mm/s in the isthmic
      portion of the tube. This decrease substantiates previous findings that the
      transport of material in the isthmic portion of the oviduct is more strongly
      under the control of ciliary action than under peristaltic activity.

PMID- 10599030
TI  - Influence of ageing on blastogenesis of mouse thymocytes in response to
      concanavalin A.
AB  - The influence of ageing on the blastogenic response of mouse thymocytes to a
      mitogen was investigated. Thymocytes from mice of various ages (10-70 days) were
      incubated with the mitogen, concanavalin A, to induce blastogenesis. The
      thymocytes were then incubated with [3H]thymidine, and the radioactivity of
      [3H]thymidine taken up by the cells was measured. The stimulation index (ratio of
      radioactivity uptake by cells incubated with and without mitogen) was used as a
      measure of blastogenesis of thymocytes. The stimulation index of thymocytes from
      10-day-old mice was 2.9; it increased with age, reaching a peak of 33.7 in 40-day
      old mice and then gradually decreasing to 8.2 in 70-day-old mice. The
      blastogenesis of thymocytes, an indicator of thymus function, was thus found to
      change considerably with age.

PMID- 10599031
TI  - Activity of factor VIIa and von Willebrand factor in non-insulin-dependent
      diabetic subjects with coronary artery disease.
AB  - Atherosclerosis is more extensive and occurs earlier in diabetics compared with
      the general population. The pathophysiology of atherosclerosis is not fully
      established. We compared the activity of two blood clotting agents, activated
      factor VII (VIIa) and von Willebrand factor (vWF), in diabetic and non-diabetic
      subjects with coronary artery disease. According to clinical features, subjects
      were placed in one of four groups: Group I, non-insulin-dependent diabetes
      mellitus (NIDDM) with coronary heart disease (CAD) (n = 16); Group II, NIDDM (n =
      15); Group III, CAD with no presence of diabetes (n = 17); and Group IV, healthy
      volunteers (n = 15). The level of factor VIIa was higher in Group I compared with
      all other groups, and was significantly higher in Group II compared with Group
      III and Group IV. Activity of vWF was higher in Group I compared with Group II,
      Group III and Group IV. There was no statistical difference between Group II and
      Group III. There was no significant correlation between concentration of blood
      glucose, total cholesterol or triglyceride, duration of diabetes and either
      factor VIIa or vWF activity. The results of this study suggest that increased
      activity of plasma vWF and factor VIIa may be useful markers to identify
      ischaemic heart disease risk in NIDDM subjects.

PMID- 10599032
TI  - Distribution and antimicrobial susceptibility of coagulase-negative staphylococci
      from skin lesions.
AB  - The distribution and antimicrobial susceptibility of coagulase-negative
      staphylococci from skin lesions were investigated. Staphylococcus epidermidis was
      found on all areas of the body, whereas S. capitis, S. haemolyticus and S.
      hominis were mainly found on the face/head or arm/leg. The distribution of
      coagulase-negative staphylococci in skin lesions and at the same location on
      normal skin was similar. Staphylococcus lugdunensis was the most susceptible to
      the nine tested antimicrobials (benzylpenicillin, ampicillin, piperacillin,
      cefazolin, erythromycin, minocycline, gentamicin, vancomycin and ofloxacin) and
      S. epidermidis the least susceptible. S. haemolyticus also showed low
      susceptibility to all nine antimicrobials. Low susceptibility to penicillins may
      be explained by beta-lactamase production. The existence of coagulase-negative
      staphylococci, especially concerning their potential pathogenicity and multiple
      drug resistance, should not be neglected.

PMID- 10599033
TI  - Rhabdomyosarcoma in a patient with mosaic Klinefelter syndrome and transformation
      of immature teratoma.
AB  - A 27-year-old man was found to have a mediastinal tumour and the histological
      diagnosis was immature teratoma. Remission was achieved by chemotherapy and total
      resection. However, he developed anaemia and leukoerythroblastosis after 2 years
      of remission, and was referred to our hospital. Rhabdomyosarcoma cells were
      detected in the bone marrow and pleural effusion. Moreover, karyotype analysis of
      peripheral blood and bone marrow cells revealed mosaic-type Klinefelter syndrome.
      We diagnosed the case as transformation of teratoma into rhabdomyosarcoma in
      Klinefelter syndrome. Although intensive chemotherapy was performed, the patient
      died with meningeal infiltration.

PMID- 10599034
TI  - Beneficial effect of piracetam monotherapy on post-ischaemic palatal myoclonus.
AB  - A 70-year-old hypertensive woman suffered a subarachnoid haemorrhage followed by
      delayed vasospasm in the basal cerebral arteries. This resulted in multiple
      ischaemic lesions in the right middle cerebral artery region and contralateral
      post-ischaemic palatal myoclonus. In this setting, piracetam administered in high
      doses (24-36 g/day), abolished the myoclonus observed in this patient. Although
      there is evidence from case reports and clinical trials of the therapeutic
      efficacy of piracetam in patients with skeletal myoclonus of various causes, to
      our knowledge this is the first report indicating the beneficial effect of
      piracetam monotherapy on post-ischaemic palatal myoclonus.

PMID- 10599035
TI  - One hundred years of medication: from the magistral formula to clinical
      pharmacology.

PMID- 10599036
TI  - Biotechnological products and gene therapy. What are we talking about?

PMID- 10599037
TI  - Biotechnological products on the market.

PMID- 10599038
TI  - Particularities of clinical investigation with biotechnology products.

PMID- 10599039
TI  - From clinical trials to usual practice: efficacy and effectiveness in clinical
      pharmacology.

PMID- 10599040
TI  - Assessment of effectiveness: pros and cons of the different available
      methodologies.

PMID- 10599041
TI  - The impact of clinical trials on prescriptions: the value of drug utilization
      studies.

PMID- 10599042
TI  - Financing and administration of public funds managed by FIS (Spanish Agency for
      the Promotion of Biomedical Research).

PMID- 10599043
TI  - Management and financing of the clinical research resources at the Hospital
      Clinic de Barcelona.

PMID- 10599044
TI  - Should clinical trials be financed with public funds?

PMID- 10599045
TI  - Phase I clinical trial units in Spain: the current situation.

PMID- 10599046
TI  - Phase I studies in Spain: involvement of the multinational industry.

PMID- 10599047
TI  - Methodological pitfalls in bioequivalence studies: sample size, between-subject
      and within-subject variability, single or multiple dose studies and metabolite
      determination.

PMID- 10599048
TI  - Working group on hepatotoxicity studies.

PMID- 10599049
TI  - Etidronate inhibits the production of IL-6 by osteoblast-like cells.
AB  - IL-6 is a resorbing cytokine synthesized by osteoblasts and monocytes that has
      been implicated in the pathogenesis of osteoporosis. Bisphosphonates are well
      known antiresorptive drugs, the antiosteoclastic effect of which has been
      recently suggested to be brought about at least in part through osteoblasts.
      Based on these facts, we have studied the effect of etidronate on the production
      of IL-6 by two tumoral cell lines of human osteoblastic phenotype (MG63 and SaOs
      cells), and by peripheral blood mononuclear cells (PBMC). For comparison, another
      antiresorptive drug, estradiol, was included in the study. MG63 cells were
      stimulated with LPS and IL-1 beta, SaOs cells with LPS, IL-1 beta and PMA, and
      PBMC with LPS and PMA. Etidronate was tested at 10(-7), 10(-6), 10(-5), and 10(
      4) M, and 17beta-estradiol was tested at 10(-10), 10(-9), 10(-8), and 10(-7) M.
      IL-6 was determined in supernatants by an ELISA. No significant effect of either
      etidronate or estradiol on IL-6 secretion by LPS or PMA-stimulated PBMC was
      found. However, in osteoblastic-like cells, an inhibition of IL-6 production by
      etidronate in LPS-stimulated cultures was found. At the highest concentrations
      tested, IL-6 production values were 58 +/- 9% and 53 +/- 8% of those at base line
      for MG63 and SaOs cells, respectively. Estradiol did not modify IL-6 secretion
      under any condition. In conclusion, our study supports the contention that the
      antiresorptive effect of bisphosphonates may be due in part to a decrease in IL-6
      production by osteoblasts.

PMID- 10599050
TI  - The morphine sparing effect of physostigmine.
AB  - The antinociceptive effect of morphine was studied in tail-flick- and acetic acid
      induced writhing in mice. Morphine effect was dose-related (1, 2 and 5 mg/kg
      s.c.). Physostigmine (0.05 and 0.1 mg/kg i.p.) potentiated the antinociceptive
      effect of morphine, and the anticholinergic, scopolamine (1 mg/kg i.p.), reversed
      the potentiating effect of physostigmine, indicating the involvement of the
      cholinergic system in pain. Coadministration of physostigmine would increase the
      therapeutic index of morphine thereby sparing the dose of morphine and also
      possibly the side effects including the development of tolerance and addiction.

PMID- 10599051
TI  - Cardioprotective effects of abciximab (ReoPro) in an isolated perfused rat heart
      model of ischemia and reperfusion.
AB  - Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes
      (PMNs) results in cardiac contractile dysfunction as well as myocardial injury,
      due in large part to endothelial dysfunction, upregulation of cell adhesion
      molecules and subsequent neutrophil induced cardiac injury. We studied the
      effects of abciximab (ReoPro), an anti-IIb/IIIa antibody, which has been shown to
      attenuate platelet interactions, in a neutrophil-platelet mediated isolated
      perfused rat heart model of ischemia (I) (20 min) and reperfusion (R) (45 min).
      Administration of abciximab (6.5 micrograms/kg) 10 min prior to the perfusion of
      the PMN + platelet perfused I/R heart improved post-reperfusion coronary flow and
      preserved post-reperfusion left ventricular developed pressure (LVDP) and +dP/dt
      max as indices of cardiac contractile function. Abciximab-treated hearts
      reperfused in the presence of PMNs and platelets preserved all indices of cardiac
      contractile function. I/R heart perfused with PMNs and platelets produced a
      profound injury to the hearts which was attenuated with the treatment of
      abciximab. In addition, abciximab significantly reduced PMN accumulation in the
      ischemic myocardium from 38 +/- 1 PMNs/mm2 in untreated hearts to 7 +/- 1 in rats
      given abciximab. Similar results were obtained with PMN perfused I/R rat hearts
      without platelets. These results provide evidence that abciximab is a potent and
      effective cardioprotective agent that inhibits leukocyte-endothelial cell
      interactions as well as platelet-endothelial cell interaction and preserves
      cardiac contractile function and coronary perfusion following myocardial ischemia
      and reperfusion. Therefore, IIb/IIIa may be important in attenuating both
      platelet and neutrophil-mediated myocardial dysfunction.

PMID- 10599052
TI  - Citicoline protects hippocampal neurons against apoptosis induced by brain beta
      amyloid deposits plus cerebral hypoperfusion in rats.
AB  - Citicoline is an endogenous intermediate involved in the biosynthesis of brain
      phospholipids and acetylcholine which has been extensively used for the treatment
      of several neurodegenerative conditions. The effects of citicoline on
      neurodegeneration, apoptosis and learning were investigated in male Sprague
      Dawley rats subjected to implants of the beta-amyloid fragment 1-40 (A beta 4: 3
      Mmol) into the right hippocampus and to permanent unilateral occlusion of the
      carotid artery. Citicoline (CDP; 0, 62.5, 125 and 250 mg/kg/day i.p.) was given
      during 2 days before and for 5 days after surgery, and the extension of the
      degeneration and the number of apoptotic figures (TUNEL technique) were evaluated
      in the dentate gyrus (DG) and the CA1 area of the hippocampus. Citicoline, at 125
      and 250 mg/kg, reduced the number of apoptotic neurons in the hippocampus of rats
      with A beta 4/hypoperfusion-induced neurodegeneration (CDP0 = 105.3 +/- 32.8
      apoptotic figures; CDP125 = 39.2 +/- 7.4** apoptotic figures; CDP250 = 34.5 +/-
      14.4** apoptotic figures; **p < 0.01 vs. CDP0). CDP also reduced neuronal
      degeneration in the CA1 area in a dose-dependent manner (CDP0 = 450.5 +/- 130.1
      microns; CDP62.5 = 280.6 +/- 76.3 microns; CDP125 = 86.6 +/- 37.3* microns;
      CDP250 = 121.7 +/- 85.3* microns; p < 0.05 vs. CDP0). Variability of results was
      very high in the DG, where a significant reduction in the extent of
      neurodegeneration was only observed in the group of rats receiving 62.5 mg/kg of
      citicoline. Finally, citicoline improved retention of a passive avoidance
      learning task, increasing the number of avoidances (Av) (CDP0 = 4.2 +/- 0.7 Av;
      CDP62.5 = 6.9 +/- 1.0 Av; CDP125 = 7.9 +/- 0.7** Av; CDP250 = 8.5 +/- 0.6** Av;
      **p < 0.01 vs. CDP0) in a dose-related manner. Based on these results, it was
      concluded that citicoline exerts antiapoptotic, neuroprotective and antiamnesic
      effects in conditions of neurodegeneration induced by A beta 4 plus
      hypoperfusion.

PMID- 10599053
TI  - Effect of anti-ICAM-1 on bronchial response: bronchoalveolar lavage fluid (BALF)
      and ultrastructural changes of bronchial epithelium in guinea pigs with dual
      phase bronchial response.
AB  - Eosinophils play an important role in the development of bronchial asthma, and
      the association between ICAM-1 and activation and migration of local eosinophils
      is attracting attention. Using an asthmatic model of dual phase bronchial
      response, the effects of anti-ICAM-1 antibody on the airway resistance, cell
      composition in the bronchoalveolar lavage fluid (BALF) and ultrastructure of
      bronchial ciliated epithelium were examined under the provoked response by
      inhalation of the antigen. By administration of anti-ICAM-1 antibody, the late
      asthmatic response (LAR) was suppressed. In the examination of bronchoalveolar
      lavage fluid, a significant decrease in eosinophils was found in LAR. In
      examining transmission and scanning electron microscopies, no difference was
      found in the immediate asthmatic response, but marked suppression of deciduation
      of bronchial ciliated epithelium was observed in LAR. These results indicated
      that anti-ICAM-1 antibody suppressed bronchial asthmatic attack, mainly in LAR,
      by controlling differentiation and migration of eosinophils.

PMID- 10599054
TI  - Effects of time and cholinesterase inhibitor treatment on multiple cerebrospinal
      fluid parameters in Alzheimer's disease.
AB  - Development of neuropathology in Alzheimer's disease (AD) cannot be studied
      directly in living patients. Therefore, concentrations in cerebrospinal fluid
      (CSF) of the proteins tau, A beta 42, alpha 1-ACT, apoE and other molecules have
      been analyzed to elucidate their possible role in degeneration and as biomarkers
      of the disease. To date, however, studies have not analyzed multiple markers in
      the same patients over time and as a function of pharmacological interventions.
      In the present investigation we measured CSF tau, A beta 42, alpha 1-ACT, apoE,
      total protein and electrophoretic fractions, and leukocytes, as well as MMSE, in
      12 AD patients of known APOE phenotype. Two or three CSF examinations were
      performed during periods of up to 2 1/2 years, while subjects were on and off
      treatment with the cholinesterase inhibitor (ChEI) metrifonate (MTF). CSF A beta
      42 and tau levels were in agreement with clinical diagnosis of AD in all
      patients. Abnormally high proportions of monocytes were found in CSF at baseline,
      and these proportions correlated positively with plasma alpha 1-ACT and MMSE
      scores. A small but significant increase in CSF alpha 1-ACT, which correlated
      with peripheral alpha 1-ACT, was associated with 6 months' MTF treatment, though
      alpha 1-ACT levels did not change further when treatment continued for 2 years.
      Monocyte proportions in CSF declined over time in both treated and untreated
      patients. Among 5 of 6 patients treated for 2 years or more with MTF, CSF
      measures remained relatively stable. One patient had changes in CSF parameters
      apparently associated with a transient ischemic attack. Our findings did not
      indicate that slowed cognitive decline with MTF treatment is associated with
      systematic change in any CSF marker analyzed. The results suggest that further
      investigations of the relationship of tau, A beta 42 and cellular abnormalities
      in CSF early in the course of AD are warranted.

PMID- 10599055
TI  - [Clinical aspects and treatment of dural-spinal arteriovenous fistulas with
      perimedullary venous drainage. 10 cases].
AB  - BACKGROUND AND PURPOSE: Spinal dural arteriovenous fistulas (SDAVF) are rare but
      represent the most frequent spinal arteriovenous malformation. Their clinical
      manifestations are well known, but their management can still be discussed
      between surgery and endovascular treatment. The purpose of this study is to
      emphasize the pre-eminence of surgical management for posterior and postero
      lateral fistulas, which are the most common location of the malformation.
      METHODS: We report a consecutive series of 10 patients with SDAVF treated between
      July, 1995 and July, 1997. Results are compared with other series of the
      literature. RESULTS: Clinical manifestations were not specific and the diagnosis
      was established in most cases only one year after the onset of symptoms, as a
      progressive myelopathy. Low back pain was present in 4 patients, with pseudo
      radicular pain in the lower limbs suggesting spinal degenerative disease in 3
      cases. At the time of diagnosis, 8 patients had permanent motor weakness of the
      lower limbs, usually associated with hypesthesia and sphincterial dysfunction (7
      cases). In all cases, the diagnosis was established using MRI. In most cases, the
      intradural draining spinal veins were also visible on MRI images. The location of
      the SDAVF was always precised by angiography, and was located between T5 and L1
      in our series. Seven patients were successfully operated on, with surgical
      interruption of the intradural draining vein. Three patients underwent an
      endovascular treatment, but two of them were operated on later, as control
      angiography showed recurrence of the SDAVF. The clinical status of patients
      always improved after treatment, but recovery was incomplete in patients with
      severe and long lasting neurological deficit. CONCLUSIONS: Surgical interruption
      of the intradural draining vein is a safe and effective method of treatment of
      SDAVF, especially for posterior and postero-lateral fistulas. Endovascular
      treatment is recommended for anterior locations of SDAVF.

PMID- 10599056
TI  - [Intracranial cavernoma. Surgical results of 47 cases].
AB  - We report the surgical results in a series of 47 patients with cerebral cavernous
      malformation who had undergone surgery between 1973 and 1994, with a follow up
      ranging from 12 months to 24 years (mean: 4 years). They were divided in there
      groups according to their initial clinical presentation: epilepsy (31 cases),
      hemorrhage (11 cases) and neurological deficit (5 cases). Surgery consisted of
      cavernoma resection only (11 cases) or its extension to surrounding gliotic
      tissue (36 cases). Results are satisfactory: no surgical mortality, low morbidity
      (4 cases), no recurrent hemorrhage, seizures disappearance with anticonvulsant
      therapy stop (4 cases) or alleviation (20 cases). Only one patient died far from
      surgery (6 months) consequently to his initial bleeding, while all the others
      lead a normal active life. The therapeutic management, compared to the
      literature, pleads in favour of intentionally surgical attitude and gliotic
      tissue removal as often as reasonably possible.

PMID- 10599057
TI  - [Cerebral tumors and neoangiogenesis ].
AB  - Angiogenesis, which is the development of new vessels arising from the
      preestablished arborization, plays a fundamental role in tumor growth.
      Angiogenesis is the combination of antagonistic factors: proangiogenesis and
      antiangiogenesis factors. On the basis of the concept of relationship between
      angiogenesis and tumor growth, a promising new way of research is developing with
      the aim to control angiogenesis with an antitumor goal. The results of the
      preclinical trials point out the potential of antiangiogenesis agents in the
      fight against cancer. So, it was showed that tumor growth in animal models of
      syngenic or human tumors is inhibited by inhibitors of proangiogenic factors
      (like VEGF or FGF antibody ...) or by antiangiogenic factors. Endostatin, which
      is a natural inhibitor of angiogenesis, seems to be the most powerful molecule,
      able to achieve total and final regression of preestablished tumors. However,
      there are only preliminary data. Clinical trials are on the way. They should
      bring some answers concerning the place of these antiangiogenesis agents in the
      traditional therapeutic strategy. In neurooncology, just like in general
      cancerology, clinical trials have began with different molecules like Marismastat
      or Thalidomid. A review of the principal actors, preclinical and clinical trials
      in progress is presented.

PMID- 10599058
TI  - [Post-traumatic intracranial arterial aneurysm. Two cases with review of the
      literature].
AB  - Post-traumatic intracranial aneurysms are rare entity, which can appear following
      even benign head injuries. Their clinical manifestations are various, from a
      typical SAH to an uncommon intracerebral hematoma. Medical history runs usually
      from a couple of days to several years. Two cases of intracranial aneurysm have
      been observed from 1995 to 1998. The first case presented as a cortical aneurysm
      in a cerebral contusion following a week of evolution. The second case presented
      as a cortical hematoma with a head trauma 10 years before. All patients were
      operated on with uneventful follow-up. Post-traumatic intracranial aneurysms can
      exhibit an increase in size or a spontaneous thrombosis. Diagnosis is made by
      angiography, which has to be repeated if treatment has to be delayed. Best
      results are obtained by exclusion of the lesion, if allowed by the patient's
      condition.

PMID- 10599059
TI  - A case of primary meningioma of the frontal sinus.
AB  - A case of right frontal sinus tumor which at histology turned out to be a
      psammomatous meningioma is reported. The occurrence of primary meningiomas within
      the paranasal sinuses is rare and probably related to the transformation of
      embryonic arachnoid cell remnants or ectopic meningocytes derived from
      pluripotential mesenchymal cells. A search of the literature disclosed 30 further
      cases of meningiomas primarily involving the paranasal sinuses: a short analysis
      of the latters is presented and some of the distinctive features of these unusual
      tumors, as compared to their intracranial counterpart, are emphasized.

PMID- 10599060
TI  - Cavernous hemangioma of the parietal bone. Case report and review of the
      literature.
AB  - Intraosseous cavernous hemangiomas are a rare finding in the calvarium. It is a
      benign tumor arising from the intrinsic vasculature of the bone. We report one
      case observed in a 20 year-old male. The diagnostic peculiarities and therapeutic
      implications of this lesion are discussed and the available literature on this
      subject is reviewed. These tumors do not recur once a radical surgical removal is
      performed.

PMID- 10599061
TI  - [Epidermoid cyst of the lateral ventricles].
AB  - A case of epidermoid cyst of the lateral ventricles is reported. The patient
      presented with a weakness of the left lower limb and neuropsychological
      disorders. The diagnosis was assessed by CT scan and MRI, and confirmed at the
      operation. The lesion has been largely removed through a transcallosal approach
      though incompletely. However the long term follow-up was uneventful. Twenty-nine
      cases of the literature have been reviewed.

PMID- 10599062
TI  - [Hydatid cysts of the brain stem. Two cases].
AB  - Cerebral hydatid cysts represent 2-3% of all intracranial masses in endemic
      countries. Its incidence in posterior fossa is very rare. We report two cases of
      brainstem location. Clinically, the lesion exhibited signs of brainstem tumor. In
      two patients, CT scan showed a hypodense lesion. There was no enhancement after
      contrast administration. One patient was explored by MRI; on precontrast images,
      the lesion appeared homogeneous with hyposignal intensity and smooth limits. T2
      weighted MRI and post contrast examination confirmed the cyst nature of the
      lesion. Surgery was performed in the two patients. The cyst was first aspirated
      and its membrane was then removed. Post operatively, one patient died, the other
      one is still alive but severely affected two years later. CT scan showed total
      disappearance of the cyst. The clinical presentation, radiological findings and
      surgical procedures are discussed.

PMID- 10599063
TI  - [Intracranial granuloma: a rare complication of ventricular derivation. Case
      report].
AB  - We report an unusual case of cerebral granuloma secondary to ventriculoperitonal
      shunt. A 17 year-old patient presented with choreoathetoid movements of the left
      upper limb five years after a ventriculoperitoneal shunt and cerebellar pilocytic
      astrocytoma excision procedure. MR imaging showed mass lesion in right basal
      ganglia area surrounding ventricular catheter which seems to be neoplastic.
      Stereotactic biopsy of the lesion with histologic study revealed a granuloma.
      Ventricular catheter was removed and patient improved clinically and lesion
      disappeared completely on MRI control. At literature review, we found only 4
      similar cases. Clinical and radiological findings (CT scan and IRM) are described
      as well as pathogenic mechanism involved. Therapeutic procedure should be limited
      to catheter removal without granuloma excision.

PMID- 10599064
TI  - [Frontal sinus approach to olfactory groove meningiomas].
AB  - We report on our experience of the frontal sinus approach for removing olfactory
      groove meningiomas. Five tumors were operated on, one unilateral, four bilateral.
      Osteotomy of the anterior wall of the frontal sinus was performed with an
      oscillating saw without any burr hole. The posterior wall of the sinus was
      resected and the tumor was attacked along the plane of the anterior skull base.
      Ethmoidal blood supply was controlled at the initial stage of the operation,
      allowing avascular tumor debulking. Olfactory nerves, invaded by the tumor,
      usually cannot be spared. Tumor extensions towards the sella and the optic canals
      were removed without any brain retraction, nor opening of the sylvian fissure,
      nor dissection of the carotid arteries. The frontal sinus approach is technically
      easy to achieve. Osteotomy and reconstruction of the anterior wall of the frontal
      sinus are rapidly performed. When the frontal sinus is small, image guided
      surgery allows to delineate precisely its limits and the flap includes the
      calvarial outer layer, tangenitally cut from one supra-orbital canal to the
      other. Cosmetic result is perfect. The frontal sinus approach gives access to the
      medial part of the orbital roofs and to the central anterior skull base from the
      crista galli to the tuberculum sellae and the anterior clinoids. The frontal
      sinus approach represents an alternative to conventional craniotomies for tumors
      developed in the central anterior skull base, especially for olfactory groove
      meningiomas.

PMID- 10599065
TI  - [Tonsillectomy as a treatment of Chiari I malformation with syringomyelia].

PMID- 10599066
TI  - [University reform without if and but. Official speech on the occasion of the
      anniversary of the DNG on 15 April 1999 in Ulm].

PMID- 10599067
TI  - [Efficacy of radiation synovectomy in degenerative inflammatory and chronic
      inflammatory joint diseases].
AB  - AIM: Effect of radiosynovectomy (RS) should be evaluated both by subjective and
      objective parameters in patients with osteoarthritis and in patients with
      inflammatory joint disorders not caused by rheumatoid arthritis. METHODS: A total
      of 98 joints in 61 patients were investigated. Patients were divided into two
      groups. The first group included 35 patients with therapy-resistant effusions
      caused by severe osteoarthritis (46 joints). The second group consisted of 26
      patients (52 joints) with ankylosing spondylitis, reactive arthritis,
      undifferentiated spondylarthropathy, psoriatic arthritis, pigmented villo-nodular
      synovitis, and recurrent synovitis following surgery. Effect of RS was evaluated
      by a standardized questionnaire and quantified by T/B-ratios derived from blood
      pool images prior to and after RS. RESULTS: Within the first patient group
      suffering from osteoarthritis, 40% showed a good or excellent improvement of
      clinical symptoms, 51% were unchanged, and in 9% symptoms worsened. Similar
      results were found in the second patient group. The majority of unchanged results
      were small finger joints. In contrast, wrist and knee joints showed a better
      improvement. Good correlation between results of bone scan and patients
      subjective impression was found in 38% and 67% in the first and the second
      patient group, respectively. CONCLUSION: Radiosynovectomy might be an effective
      treatment in osteoarthritis and inflammatory joint disorders not caused by
      rheumatoid arthritis.

PMID- 10599068
TI  - [Synthesis of tumor affinity label Yb-169- and Y-90- porphyrin complexes and
      animal experimental investigations with various Yb-169-porphyrins].
AB  - AIM: It should be shown, that it is possible to insert radioactive isotopes of Yb
      and Y into some selected porphyrins. Besides, first informations about the
      biodistribution of Yb-169-por-phyrin-complexes should be obtained. METHODS:
      Carrier added radioactive isotopes were used for the synthesis of the metal
      porphyrin complexes. The animal experiments were done with mamma carcinoma
      bearing mice. The activity of the organs was determined 5 and 24 h after i.v.
      injection in a well counter. RESULTS: Four Yb-169-porphyrin complexes and Y-90
      porphyrin complexes could be synthesized in non-carrier-free form. This was
      verified by absorption spectra, TLC and HPLC. Depending on the complex, the
      average tumour/background ratios were between 2 and 20. CONCLUSION: The
      synthesized radioactive metal-porphyrin complexes showed a clear tumour-affinity
      which could be used for tumour scintigraphy or perhaps therapy if the synthesis
      is improved (goal: reduction of carrier, other radionuclides).

PMID- 10599069
TI  - [A simple and rapid routine preparation of no-carrier added meta-I-123- and I-131
      iodobenzylguanidine (I-123-MIBG and I-131-MIBG) for clinical nuclear medicine
      applications].
AB  - AIM: Low specific activity meta-iodobenzylguanidine (I-123/I-131-MIBG) is
      currently used in the assessment of abnormalities in the myocardial
      neuroadrenergic function as well as in the management of neuroendocrine tumors.
      In recent studies an enhanced cardiac and tumor uptake were reported by the use
      of high specific activity radiopharmazeuticals, suggesting a potential clinical
      benefit of no-carrier-added (n.c.a.) I-123/I-131-MIBG. In this paper we describe
      a simple and improved preparation of I-123-MIBG and I-131-MIBG for routine
      clinical application, feasible in any nuclear medicine department. METHODS: N.c.a
      I-123-MIBG and n.c.a. I-131-MIBG were prepared by Cu(I)-assisted [I-123/I
      131]iodo-debromination at 170-175 degrees C with 86 +/- 6% and 80 +/- 10%
      radiochemical yield respectively and high specific activity (> or = 4.3 TBq/mumol
      and > or = 0.21 TBq/mumol), starting from meta-bromobenzylguanidine (MBBG). The
      total time of synthesis including the HPLC purification and the preparation of
      the injectable solution was less than 60 min. RESULTS: Neither rechromatography
      by HPLC nor TLC gave any indication of disintegration products in the injection
      solution up to 8 h after preparation. Moreover, biological testings confirmed
      that the buffered and sterile-filtered n.c.a. I-123-MIBG and n.c.a. I-131-MIBG
      solutions are isotonic, sterile and apyrogenic and thus suitable as injectable
      solutions for clinical use. CONCLUSION: High specific activity I-123-MIBG and I
      131-MIBG could now be prepared by a simple one-step reaction giving rise to high
      radiochemical yields and high purity for a widespread clinical applications.
      Therefore, this encourages clinical validations on a large scale to answer the
      question of whether n.c.a. I-123-MIBG and I-131-MIBG could play an important role
      in the assessment of the myocardial sympathetic nervous dysfunction as well as in
      the diagnosis and therapy of neuroendocrine tumors.

PMID- 10599070
TI  - [Role of positron emission tomography (PET) and single photon emission tomography
      (SPECT) in so-called "multiple chemical sensitivity"].
AB  - Functional imaging with SPECT and PET is increasingly used to prove evidence for
      the existence of a syndrome "Multiple Chemical Sensitivity" (MCS) and plays a
      major role in legal trials to justify compensation for the exposure to solvents.
      This paper critically reviews the literature on the use of SPECT and PET for the
      determination of MCS. The authors come to the conclusion that the current data
      are not sufficient to justify the claim of the existence of such a syndrome. The
      low specificity of the observed PET and especially SPECT-findings makes it very
      difficult to establish a cause-result relationship and therefore makes the use of
      these methods in legal trials on this issue doubtful.

PMID- 10599071
TI  - [Bone scintigraphy and rhenium radioisotope management in the course of
      metastatic prostatic cancer].
AB  - A 78-year-old patient with prostate cancer and osseous metastases had a pain
      symptomatic. In the Urology he was treated with antiandrogenes. The outcome of
      the bone scintigraphy showed a super bone scan with normalization after
      antiandrogene-therapy which seemed to be a sign of remission, before he showed a
      progressive form with multiple osseous metastases. Pain could not be treated with
      non steroidal antiphlogistics and opiates, so the indication for treatment with
      Rhenium-186-HEDP was given in this case.

PMID- 10599072
TI  - Indium-111 octreotide uptake in the surgical scar.
AB  - Indium-111 octreotide uptake has been reported in various somatostatin receptor
      positive tumors, granulomas and autoimmune diseases in which activated leucocytes
      may play a role, subcutaneous cavernous hemangioma and angiofibroma. We present
      Indium-111 octreotide uptake in a surgical abdominal scar tissue 1.5 and 6 months
      after surgery in a patient who had been treated for recurrent carcinoid tumor in
      the rectosigmoid junction. Indium-111 octreotide uptake in a surgical scar may be
      related to the binding to somatostatin receptors in the activated lymphocytes and
      fibroblasts that is previously reported.

PMID- 10599073
TI  - Decisive diagnosis of infected mandibular osteoradionecrosis with a Tc-99m
      labelled anti-granulocyte Fab'-fragment.
AB  - The accepted golden standard for detection of inflammatory bone disease is
      conventional three-phase bone scanning. Hyperperfusion, a high blood-pool
      activity and elevated bone metabolism are typical signs for an acute
      osteomyelitis. However, in case of subacute, chronic inflammation, neither
      elevated blood flow nor high blood-pool activity may be seen. This may cause
      difficulties in differentiating such cases from neoplastic or postoperative
      changes. This case report verifies the possible advantage of immunoscintigraphy
      with Tc-99m-labelled anti-granulocyte Fab'-fragments (LeukoScan) in a patient
      with infected mandibular osteoradionecrosis, who had equivocal clinical symptoms
      and questionable radiographic results. LeukoScan is shown to be more sensitive in
      case of subacute bone inflammation compared with three-phase bone scanning.
      However, acquisition of delayed images after 24 hours including SPECT is
      inevitable in case of negative scans during the first hours of investigation.

PMID- 10599074
TI  - Transmission-blocking immunity to Plasmodium falciparum in malaria-immune
      individuals is associated with antibodies to the gamete surface protein Pfs230.
AB  - Malaria-immune human sera were tested for their ability to affect the infectivity
      of Plasmodium falciparum gametocytes to Anopheles stephensi mosquitoes.
      Transmission-reducing effects of the sera were associated with the presence of
      antibodies to the gamete surface protein, Pfs230. Enhancement of transmission,
      manifest as elevated numbers of oocysts relative to controls, was observed for a
      number of sera, but was not found to be associated with antibodies against
      Pfs230. These results confirm that Pfs230 is a possible candidate for inclusion
      in a transmission-blocking malaria vaccine.

PMID- 10599075
TI  - Inoculum effect leads to overestimation of in vitro resistance for artemisinin
      derivatives and standard antimalarials: a Gambian field study.
AB  - Artemisinin (QHS) and its derivatives are new antimalarials which are effective
      against Plasmodium falciparum parasites resistant to chloroquine (CQ). As these
      drugs are introduced it is imperative that resistance is monitored. In this paper
      we demonstrate that the inoculum size used in in vitro testing influences the
      measured in vitro susceptibility to QHS and its derivative dihydroartemisinin
      (DHA) and to mefloquine (MEF) and CQ over the range of parasitaemias routinely
      used in testing with the WHO in vitro microtest. An increase in parasitaemia
      and/or haematocrit was accompanied by a decrease in the measured sensitivity of 2
      laboratory lines. In the context of a field study testing in vitro susceptibility
      of parasite isolates from patients with uncomplicated malaria in Fajara, The
      Gambia we demonstrate that failure to control for inoculum size significantly
      overestimates the level of resistance to QHS and DHA as well as MEF, halofantrine
      (HAL) and quinine (QUIN). When controlling for the inoculum effect, cross
      resistance was observed between QHS, MEF and HAL suggesting the presence of a
      multidrug resistance-like mechanism. These studies underline the importance of
      inoculum size in in vitro susceptibility testing.

PMID- 10599076
TI  - Effect of polyclonal antisera developed against dense granule-associated Neospora
      caninum proteins on cell invasion and development in vitro by N. caninum
      tachyzoites.
AB  - The effects of polyclonal antisera to 2 recombinant dense granule (DG) antigens
      of Neospora caninum on invasion and development by N. caninum tachyzoites in baby
      hamster kidney cell cultures were examined. In immunofluorescent antibody tests,
      the anti-DG sera, at dilutions of 1:100 to 1:500, reacted intensely with
      individual intracellular tachyzoites and groups of tachyzoites enclosed in
      parasitophorous vacuoles at 2 and 52 h p.i., respectively. Tachyzoites suspended
      in diluted anti-DG sera and inoculated immediately into the cell cultures invaded
      cells in significantly fewer numbers (53-68% fewer by 2 h p.i.) than tachyzoites
      suspended in similarly diluted normal rabbit serum. In contrast, tachyzoites
      suspended in anti-Eimeria tenella sporozoite serum invaded cells as efficiently
      as those suspended in normal rabbit serum. Addition of anti-DG sera at the time
      of inoculation of tachyzoites, or to the cell cultures after the parasites had
      entered cells, had little effect on either the percentage or rate of their
      subsequent development.

PMID- 10599077
TI  - A review of performance and pathogenicity of male and female Schistosoma mansoni
      during the life-cycle.
AB  - The sexual life-history traits of Schistosoma mansoni have been reviewed to
      compare male and female performance and pathogenicity against Biomphalaria
      glabrata during the life-cycle. A meta-analysis was used on pooled results from
      different experiments. In most cases, there was no difference between males and
      females but male cercariae were significantly more infectious than female
      cercariae. Conversely, cercarial production and cercarial life-span were
      significantly greater for females than for males; furthermore, females have a
      tendency to occur in molluscs of larger size. Each difference is discussed and
      interpreted when possible in terms of male and female differences in transmission
      strategies. The female strategy may consist of producing many long-living larvae.
      The male strategy may consist of producing few short-living larvae and would
      invest in the quality of these larvae instead of their quantity or their life
      span.

PMID- 10599078
TI  - Spatial and temporal distributions of parasites: can wild and domestic ungulates
      avoid African tick larvae?
AB  - Infestation of a new host is a crucial stage in the life-cycle of parasites, and
      the possibility that hosts avoid infesting contact depends, in part, on the
      predictability of infestation risk. Immature free stages of ticks (Acari,
      Ixodidae) have limited mobility and survival in the vegetation and strongly
      depend on host behaviours for their infestation. We studied spatial and temporal
      distributions of the larvae of 2 major groups of African risk species in a ranch
      in Zimbabwe. No difference in the abundance of Rhipicephalus evertsi evertsi
      larvae was found among vegetation types and during most of the seasonal cycle,
      and no reliable indicator of their presence on a given site was identified.
      Rhipicephalus appendiculatus/Rhipicephalus zambeziensis larvae are mainly found
      during the cool dry season, in vegetation types situated close to permanent water
      holes or dominated by Acacia trees, which provide key forage resources for
      ungulates; and several indicators of their presence were identified. For both
      tick groups, spatial and temporal distributions of the larvae result in an
      optimized contact with ungulate hosts: R. e. evertsi larvae are unpredictable and
      thus unavoidable by hosts, whereas R. appendiculatus/R. zambeziensis larvae are
      predictable but also unavoidable because they are associated with key-resources
      for ungulates.

PMID- 10599079
TI  - The susceptibility of Atlantic salmon (Salmo salar L.) x brown trout (Salmo
      trutta L.) hybrids to Gyrodactylus salaris Malmberg and Gyrodactylus derjavini
      Mikailov.
AB  - Salmo salar and Salmo trutta co-exist in coastal river systems in Europe and
      produce hybrids with little loss of viability or growth. This report describes
      the susceptibility of pure full-sibs of S. salar and S. trutta and their
      reciprocal half-sib hybrids to their respective gyrodactylids, Gyrodactylus
      salaris and Gyrodactylus derjavini. The pure-bred salmon and trout, and half-sib
      hybrids, were produced using eggs and sperm from wild anadromous S. salar (River
      Alta stock, North Norway) and wild anadromous S. trutta (River Fossbekk stock,
      Southwest Norway). Infections were initiated by exposing experimental fishes (0+)
      to S. salar naturally infected with G. salaris (River Lierelva strain) or S.
      trutta naturally infected with G. derjavini (River Sandvikselva strain). Fishes
      were then kept individually isolated under standardized conditions at 12 degrees
      C. Pure-bred S. salar were susceptible but frequently mounted a response to G.
      salaris without eliminating the infection, whereas pure-bred S. trutta were
      innately resistant to this species. Pure-bred S. trutta ranged from innately
      resistant to susceptible to G. derjavini but later most of the susceptible trout
      mounted a host response to G. derjavini. Pure-bred S. salar were also susceptible
      to this species, although parasite population growth rates were reduced and a
      host response frequently appeared eliminating G. derjavini. The abundance of both
      gyrodactylids was lower on the hybrids than on their respective pure-bred natural
      hosts, and a parental sire- and dam-influence on the resistance of hybrids was
      observed. When the sire was S. salar, the susceptibility of hybrids to G. salaris
      was similar to that of pure S. trutta; when the dam was S. salar both innately
      resistant, intermediately susceptible and responding individuals were present. In
      the case of G. derjavini, when the sire was S. trutta, infections on hybrids were
      similar to those on pure S. salar; when the dam was S. trutta, an increased level
      of susceptibility was observed. The present results provide evidence that: (1)
      Norwegian salmon stocks are variable in their susceptibility/resistance, with
      some fish able to control S. salaris infections; (2) trout stocks are innately
      resistant to G. salaris; (3) individual trout show a spectrum in
      susceptibility/resistance to G. derjavini, ranging from innate resistance through
      slightly susceptible to highly susceptible but with acquired resistance
      controlling infection; (4) although G. derjavini infections grow poorly on
      salmon, this host stock is susceptible to the parasite, but can limit infection
      by a host reaction; (5) susceptibility/resistance traits to gyrodactylids are
      genetically controlled and resistance can be transferred as a dominant trait
      through interspecific crosses between different salmonids; (6) interspecific
      hybrids between susceptible and resistant salmonids have a pattern of
      susceptibility to gyrodactylids intermediate to that of the parents; (7)
      resistance to gyrodactylids may be controlled by relatively few genes in
      salmonids; (8) epidemiologically, hybrids may act as a reservoir for
      gyrodactylids, may support a wider diversity of species than either parent and
      may disseminate gyrodactylids of both host species.

PMID- 10599080
TI  - Cloning and characterization of a beta-galactoside-binding protein (galectin)
      from the gut of the gastrointestinal nematode parasite Haemonchus contortus.
AB  - A cDNA encoding a beta-galactoside-binding lectin (galectin) was identified by
      immunoscreening a Haemonchus contortus cDNA library with antisera from lambs
      vaccinated with a membrane protein complex (H-gal-GP) derived from the parasites'
      gut. The cDNA sequence, exhibiting a tandem repeat structure and designated Hco
      gal-2, showed significant levels of similarity with galectins from several
      species of nematode as well as mammalian galectin type 4. Native galectin was
      preferentially extracted from the H-gal-GP complex and also from an insoluble
      membrane fraction prepared from adult worms using lactose-agarose affinity
      chromatography. The affinity-purified material had apparent molecular mass of
      around 35 kDa with 3 distinct bands visible on SDS-PAGE. All 3 bands were
      identified as galectins by reaction with antiserum raised to recombinant Hco-GAL
      2 on Western blot. To determine whether H. contortus galectins have any
      protective capacity against infection lambs were vaccinated with affinity
      purified galectin and subsequently given a single challenge infection.
      Vaccination did not confer any protection against infection with H. contortus as
      judged by faecal egg output or worm counts.

PMID- 10599081
TI  - Changing surface antigen and carbohydrate patterns during the development of
      Oesophagostomum dentatum.
AB  - Living and fixed specimen of Oesophagostomum dentatum were labelled in situ with
      serum antibodies or a panel of biotin-labelled lectins. Specific binding of
      antibodies was observed in all parasitic stages--freshly exsheathed 3rd-stage
      larvae (L3), 3rd- and 4th-stage (L4) larvae cultured in vitro and L3 and L4 and
      adults isolated from pig intestines. The shedding of the stained layer by motile
      larvae was inhibited by levamisole-induced paralysis. Larvae cultured in vitro
      exposed serum-derived proteins on their surface which could be labelled with
      secondary antibody directed against the respective serum donor species. While
      freshly exsheathed larvae were recognized by O. dentatum-positive serum only,
      older larvae and adults cross-reacted with serum from pigs infected with O.
      quadrispinulatum, a closely related species. Lectin binding varied considerably
      between stages. While binding was not observed in pre-parasitic stages,
      Concanavalin A, Soybean Agglutinin, Wheat Germ Agglutinin, Ricinus communis
      Agglutinin and Peanut Agglutinin bound to developing larvae in varying degrees.
      Dolichos biflorus Agglutinin only bound to advanced (luminal) larval stages,
      while adults generally displayed only weak or partial lectin binding (except with
      Concanavalin A and Wheat Germ Agglutinin). Ulex europaeus Agglutinin only
      labelled larvae derived from cultures containing 10% pig serum. Cleavage of the
      carbohydrate residues by sodium periodate treatment resulted in reduction of
      antibody binding to cultured larvae, but not to freshly exsheathed L3.
      Concanavalin A, Soybean Agglutinin, and Peanut Agglutinin binding was also
      reduced by periodate treatment, while binding of Wheat Germ Agglutinin and
      Ricinus communis Agglutinin was inhibited only in early L3, but not in older
      stages. The different lectin labelling patterns are related to the different
      stages of the nematode--infective, invasive, histotropic, and luminal--and may
      serve as a mode of adaptation for the parasite against the host's immune attack
      by surface glycoprotein variation, together with antigen shedding (as
      demonstrated by labelling of motile larvae) and a possible acquisition of host
      molecules at the parasite's surface. Furthermore, a possible role of this
      developmental variation in surface carbohydrates in parasite-parasite
      interactions is discussed.

PMID- 10599082
TI  - Development of patent Ascaris suum infections in pigs following intravenous
      administration of larvae hatched in vitro.
AB  - The normal tissue migration of Ascaris suum in the pig host involves larval
      development in the liver accompanied by considerable pathological changes. The
      vast majority of larvae that reach the small intestine are later expelled by
      unknown mechanisms. We show that when migration through the liver is bypassed by
      inoculation of pigs with an intravenous dose of larvae hatched in vitro, the
      larvae not only complete migration and return to the small intestine, but they
      also seem to have a greater chance of survival to adulthood. This technique
      offers new possibilities for studies on specific lung involvement in protective
      immunity, provides valuable information for the understanding of self cure by
      larval expulsion, and adds to our understanding of the evolution of migration of
      Ascaris larvae in tissues.

PMID- 10599083
TI  - Exposure of sows to Ascaris suum influences worm burden distributions in
      experimentally infected suckling piglets.
AB  - This paper reports on the influence of maternal exposure to Ascaris suum on worm
      burden distributions in experimentally infected piglets. In the first study, sows
      were inoculated before and during gestation (6 months, long-term exposure) with
      10,000 A. suum eggs twice weekly. In a second study, sows were inoculated during
      gestation only (3 months, short-term exposure) with increasing doses of eggs
      (10,000-40,000 eggs twice weekly). Helminth-naive sows served as controls in both
      studies. The third study used the same design as the short-term exposure study,
      but piglets from exposed and control sows were cross-suckled within 4 h of birth
      before colostrum uptake. All piglets were inoculated 2 or 3 times with 50 A. suum
      eggs on days 4 and 7 (and 14) after birth, and left with the sows. At 10 weeks of
      age all piglets were necropsied, and liver lesions and worm burdens were
      recorded. Surprisingly, in piglets born to long-term exposed sows, the prevalence
      of A. suum infection and the mean worm burden were significantly higher than
      those in piglets from control sows. In contrast, neither worm burdens nor
      prevalence were significantly different between piglets from short-term exposed
      sows compared with their controls. In the cross-suckling experiment, 67% of
      piglets suckling control sows harboured worms at slaughter, compared with 15% of
      piglets suckling exposed sows. Maximum likelihood analysis of worm burden
      distribution and the degree of parasite aggregation showed 3 distinctly different
      types of overdispersed distributions: worm counts in piglets from control sows,
      in piglets from short-term exposed sows and in piglets from long-term exposed
      sows. When the worm burden data were analysed including the cross-suckled piglets
      by biological mother, it appeared that the control and short-term distributions
      converged and that only the long-term exposure was significantly different.
      Overall, the degree of parasite aggregation in piglets infected with A. suum
      decreased with exposure of the sows. A non-linear relationship was observed
      between prevalence of infection and mean worm burden, which was different for
      piglets from exposed and control sows, and similar to relationships of this type
      that previously have been found in human A. lumbricoides infections. It was
      concluded that in porcine A. suum infections maternal exposure alters the
      distribution of worms in their offspring, in which the duration of exposure
      appeared to be an important influence. The results of the cross-suckling further
      suggest that maternal factors, e.g. antibodies, are transferred via colostrum.

PMID- 10599084
TI  - Intestinal parasites in swine in the Nordic countries: multilevel modelling of
      Ascaris suum infections in relation to production factors.
AB  - In Denmark, Finland, Iceland, Norway and Sweden, 413 sow herds were randomly
      selected for sampling. Faeces from pigs of 7 age groups/categories were examined
      for helminth eggs (11,233 individual samples), and an accompanying questionnaire
      was completed at each visit. In total, 1138 pigs on 230 farms were found to be
      positive for Ascaris suum. Considerable differences in the occurrence of A. suum
      could be observed directly for several of 20 independent variables at the herd or
      category level. However, given that univariate analyses may be severely affected
      by confounding of covariates resulting in spurious inference, additional
      multivariate analyses were undertaken. An ordinary logistic regression on Ascaris
      positive/negative farms showed that Denmark had the highest frequency of infected
      herds, while Iceland and Finland had the lowest frequencies and that herds using
      'late weaning' and 'Class 2' drugs (pyrantel, levamisole) were most often
      infected. Because many herds were found to be totally negative for A. suum, mixed
      hierarchical logistic-normal regression models (both the penalized quasi
      likelihood and the Markov Chain Monte Carlo methods) were developed for both a
      full (all herds) and a reduced (the 230 infected herds) data set using either a
      cut-off of > 0 eggs per gram (epg) or > 200 epg to counter for false-positive egg
      counts. Estimates for identical models, but where the animal level variance was
      constrained to the binomial assumption, were also calculated. Significant
      covariates were robust to model development with 'Age group', 'Country', 'Weaning
      age', 'Water system' and simple interactions between the latter two and 'Age
      group' being significantly associated with the occurrence of A. suum, while all
      variables concerning anthelmintic drug, anthelmintic strategy, floor type,
      bedding, dung removal, washing and disinfection were not. These findings are
      discussed in the light of the complex relationship between A. suum and its pig
      host.

PMID- 10599085
TI  - Nonrhabdomyosarcomatous soft tissue sarcoma.

PMID- 10599086
TI  - Langerhans' cell histiocytosis--still an unsolved problem.

PMID- 10599087
TI  - Clear cell sarcoma.

PMID- 10599088
TI  - Alpha-interferon therapy and peripheral neuropathy.

PMID- 10599089
TI  - Southern Alberta Children's Cancer Program.

PMID- 10599090
TI  - Relationships of cytokine (GM-CSF) serum concentration to blood cell count and
      the inflammatory parameters in children with malignant diseases.
AB  - This study examined both the endogenous and exogenous (therapy-related)
      pharmacokinetics of the cytokine granulocyte-macrophage colony-stimulating factor
      (GM-CSF) in neutropenic children with solid and systemic malignancies. The daily
      endogenous GM-CSF serum concentration before application was 29 pg/mL. During the
      10 days of examination, the concentration rose to an average value of 1351 pg/mL
      8 h after application. A significant stimulation of the neutrophils, monocytes,
      and eosinophils in peripheral blood was documented. No significant correlation
      between the GM-CSF concentration and peripheral blood cell counts could be
      documented. Paraclinically, there was no evidence for functional disturbance of
      either the liver or the kidneys, i.e., under the cytokine therapy. The therapy
      was well tolerated by all the children involved in the study.

PMID- 10599091
TI  - Ewing's sarcoma: prognosis and survival in Mexican children from a single
      institution.
AB  - A retrospective analysis of 55 patients with Ewing's sarcoma from an institution
      in Mexico was done between 1980 and 1993. The ages ranged between 2 and 16 years
      (mean 9.78); 39 were male and 16 female. The most frequent primary sites were in
      the humerus in 13 of 55 patients (23.6%), followed by the pelvis in 10 out of 55
      (18%). Sixty percent of the patients had metastasic disease at diagnosis; the
      lungs and bones were the most frequently affected sites. Patients with localized
      disease (n = 22) had a disease-free survival (DFS) of 44%, compared with 20% of
      those with pulmonary metastasic disease (n = 7) and 8% of patients with
      metastasic disease to the lungs and elsewhere (n = 26) (p = .00061). Patients in
      regimen 3 had a DFS of 47% at 36 months of follow-up compared to 20 and 25% for
      patients in regimens 1 and 2, respectively (p = .01). In those with trunk
      presentation the DFS was of 25% and in those with presentation in the extremities
      DFS was 50% (p = .01). Patients with pulmonary metastasic disease at diagnosis
      have a DFS of 20% in comparison to those without (44%) (p = .00061).

PMID- 10599092
TI  - The etiology of peripheral lymphadenopathy in children.
AB  - This prospective study evaluated 382 pediatric patients with peripheral
      lymphadenopathy (LA) presenting at the Pediatric Oncology and Hematology
      Departments of Social Security Children's Hospital and Gazi University Medical
      Faculty Hospital. The ages of the patients ranged between 2 months and 16 years
      (median 7 years); 72% of the patients were male. Of the 382 patients, 138 had
      localized LA (a single anatomic area involved), 171 had limited LA (two or three
      areas involved), and 73 had generalized LA (four or more anatomic areas
      involved). The specific etiology (either benign or malign) was defined in 79% of
      patients with generalized LA. However, in patients with localized LA and limited
      LA, specific etiology could be identified only in 43 and 53% of patients,
      respectively. Based on this study, BCG-LA and pyogenic infections are more
      frequently manifested by localized LA; LA of unknown origin, Hodgkin's disease,
      tuberculosis, nasopharyngeal carcinoma, and toxoplasmosis are frequently
      manifested by localized or limited LA; and cytomegalovirus infection (CMV),
      infectious mononucleous, rubella, acute leukemia, non-Hodgkin's lymphoma are
      frequently manifested by limited or generalized LA. Out of 382 patients, 196
      patients had a maximum lymph node diameter of less than 2 cm. A benign etiology
      was shown in 159/196 of these patients. In 37/196 of these patients LA was due to
      a malignancy, and these cases almost invariably had some apparent additional
      diagnostic clinical and laboratory findings. Based on this observation a maximum
      lymph node size of 2 cm was considered an appropriate limit to distinguish
      malignant disease from benign causes except when there is other evidence of an
      underlying malignant disease. However, lymphadenopathies located at
      supraclavicular region (27 patients) either localized or as part of generalized
      LA had a specific benign or malignant disease in etiology (malignancy in 20,
      tuberculosis in 3, CMV in 2, sarcoidosis in 1, and lipoma in 1) even though they
      were less than 2 cm in diameter.

PMID- 10599093
TI  - Malignant neoplasms after treatment for metachronous bilateral Wilms' tumor: a
      literature review.
AB  - Information regarding malignant neoplasms after treatment for metachronous
      bilateral Wilms' tumor is limited. A MEDLINE search was performed of all English
      language articles from 1950 to 1997 pertaining to metachronous bilateral Wilms'
      tumor. A total of 108 different cases were identified and analyzed. Mean follow
      up was 5.8 years after initial diagnosis of Wilms' tumor (range, 1 month to 25.6
      years). Eleven of 63 evaluable children (17.5%) had a congenital anomaly. Four
      patients (3.7%) developed a malignant neoplasm after treatment of a metachronous
      bilateral Wilms' tumor. Three of 18 patients followed for at least 10 years
      developed a solid tumor, including two sarcomas in the irradiated areas. Two of
      the 4 children who developed a malignant neoplasm had a congenital anomaly.
      Malignant neoplasms after treatment for metachronous bilateral Wilms' tumor can
      occur. Health-care professionals caring for these patients should be aware of
      this late sequelae of treatment.

PMID- 10599094
TI  - Clear cell sarcoma of soft tissues in children and young adults: the St. Jude
      Children's Research Hospital experience.
AB  - Clear cell sarcoma is a rare soft tissue neoplasm whose clinical behavior and
      outcome has not been previously characterized. This study reviewed the clinical
      characteristics and outcome of all children with clear cell sarcoma of the soft
      tissues who were treated at St. Jude Children's Research Hospital from March 1962
      through August 1998. Of 225 children with nonrhabdomyosarcomatous soft tissue
      sarcomas, 5 (2.2%) were diagnosed with clear cell sarcoma. Median age at
      diagnosis was 15 years 3 months. Primary sites included the extremities (n = 3),
      chest wall (n = 1), and abdomen (n = 1). At diagnosis 3 patients had localized
      disease. Following surgical resection (n = 3), radiotherapy (n = 2), and
      chemotherapy (n = 1) all three survive disease-free 10, 11, and 90 months after
      diagnosis, respectively. The remaining two patients with metastatic disease at
      diagnosis died 21 days and 9 months after diagnosis. Clear cell sarcoma of the
      soft tissues is rare in pediatrics. Complete surgical resection with negative
      margins is the most effective treatment for this disease. Patients with
      metastatic disease are candidates for multiinstitutional chemotherapy trials.

PMID- 10599095
TI  - Unusual late extrapulmonary metastasis in osteosarcoma.
AB  - The major site of metastasis from osteosarcoma is the lung, and over 90% of
      fatalities in patients with this disease die from pulmonary metastases.
      Extrapulmonary disease is developing in an increasing proportion of patients,
      usually after pulmonary metastasis. This study reports three cases of patients
      with osteosarcoma that metastasized to the brain, mediastinum, intramuscular
      site, and pelvic cavity. The physician must be aware that extrapulmonary
      metastases may be present at the time a pulmonary metastasis becomes evident.

PMID- 10599096
TI  - Continuous infusion of von Willebrand factor and factor VIII after elective heart
      surgery in a 12-year-old girl with von Willebrand disease type 3.
AB  - The continuous infusion of von Willebrand factor (VWF) in a 12-year-old girl with
      type 3 von Willebrand disease is described. The patient had elective heart
      surgery with cardiopulmonary bypass for closure of her atrial septum defect. The
      surgical procedure lasted 3 h. A presurgical bolus followed by a postoperative
      continuous infusion of factor VIII/VWF concentrates was administered. During the
      continuous infusion of clotting factors, stable plasma levels of hemostasis and
      avoidance of dangerously low levels of factor concentrates were achieved. No peri
      or postsurgical complications occurred. Continuous infusion of clotting factors
      allows constant and hemostatic factor concentrations to be maintained with the
      possibility of dose titration and adjustment.

PMID- 10599097
TI  - Peripheral neuropathy during alpha-interferon therapy in a child with Hodgkin's
      disease.
AB  - Peripheral neuropathy is one of the rarely reported neurological complications of
      interferon therapy. The authors report such a case in a 15-year-old boy during
      alpha-interferon therapy for Hodgkin's disease. He received alpha-interferon at a
      dose of 1.8 million units/day 5 times a week by subcutaneous injections as
      adjuvant immunotherapy post autologous stem cell transplant. Twenty months after
      the initiation of therapy, he complained of severe pain in his lower distal
      extremities. Neurological examination revealed the absence of deep tendon
      reflexes. A nerve conduction study showed a sensorial, polyneuropathic
      involvement in the lower extremities. Within 4 weeks after the stopping of
      interferon, his pain improved, and recovery was also seen by nerve conduction
      studies. Symptoms reappeared at the resumption of interferon treatment. This
      study suggests that peripheral neuropathy may rarely occur in patients given long
      term interferon treatment at high cumulative dosage.

PMID- 10599098
TI  - Postinfection purpura fulminans in a patient heterozygous for prothrombin G20210A
      and acquired protein S resistance.
AB  - Purpura fulminans usually consists of large, often symmetrical, spreading
      ecchymosis, which may later develop into extensive areas of skin necrosis and
      peripheral gangrene. Postinfectious purpura fulminans associated with an
      autoantibody directed against protein S has been described. The interaction and
      the contribution of recently described mutations such as factor V Leiden and
      prothrombin G20210A to the development and progression of postinfectious purpura
      fulminans and venous thrombosis is not known. The authors describe a patient
      heterozygous for prothrombin G20210A who developed purpura fulminans and
      extensive venous thrombosis secondary to acquired protein S deficiency.

PMID- 10599099
TI  - Coexistence of two prothrombotic mutations, factor V 1691 G-A and prothrombin
      gene 20210 G-A, and the risk of cerebral infarct in pediatric patients.

PMID- 10599100
TI  - Erroneous results due to blood sampling from a permanent intravenous port.

PMID- 10599101
TI  - A preterm infant with an extradural myxopapillary ependymona component of a
      teratoma and high levels of alpha-fetoprotein.

PMID- 10599102
TI  - [Descriptive epidemiology of the vascular risk factors in Baneres. Study group
      'Baneres Project'].
AB  - INTRODUCTION: Epidemiological studies of the risk factors of cerebrovascular
      disease are of great interest, particularly the identification of factors which
      may be modified. Previous studies carried out in the Alcoi region of Alicante
      province, showed a high prevalence of cerebrovascular disease. The town of
      Baneres was therefore chosen for confirmation of this data and identification of
      the frequency of vascular risk factors. OBJECTIVE: To compare the group of
      patients with cerebrovascular disease with the remainder of the population
      interviewed. PATIENTS AND METHODS: In a door-to-door study in Baneres 1,832
      people were interviewed as part of the Baneres Project. The population aged over
      45 years was interviewed and filled in a questionnaire for diagnosis of transient
      ischemic accidents. RESULTS: Arterial hypertension: estimated prevalence
      500/1,000 inhabitants, relative risk 3.24; diabetes mellitus: estimated
      prevalence 195/1,000, relative risk 2.18; coronary artery disease: estimated
      prevalence 58/1,000, relative risk 1.88; peptic ulcer: estimated prevalence
      75/1,000, relative risk 1.23; smoking: estimated prevalence 110/1,000, relative
      risk 0.46; complete arrhythmia: prevalence 73/1,000, relative risk 5.23. Family
      histories of cerebrovascular accident, arterial hypertension, diabetes and
      coronary artery disease were not significant. CONCLUSIONS: Arterial hypertension,
      diabetes mellitus and arrhythmia were significantly more prevalent amongst
      patients with vascular disease in our setting. We found no association with the
      other risk factors analyzed.

PMID- 10599103
TI  - [Genetic anticipation in idiopathic epilepsies].
AB  - INTRODUCTION: In extended and multigenerational pedigrees, the idiopathic
      epilepsy phenotype shows an extreme variability. OBJECTIVE: The range of
      idiopathic epilepsy onset age in multigenerational pedigrees was studied in order
      to determine if genetic anticipation play a role in the heredity of Idiopathic
      Epilepsies. PATIENTS AND METHODS: We compare the seizures onset age among
      relative-pairs of (parents-children, grandfathers-grandsons and nephew uncles).
      The mean onset age was compared using the Wilcoxon sign-rank paired-sample non
      parametrical test to determine whether or not significant differences over > 0
      exist, which refutes the null hypothesis of not anticipation. 84 pairs of
      relatives were taken from 72 extended multigenerational pedigrees. RESULTS: The
      onset age of idiopathic epilepsy of the pairs showed a difference significantly >
      0, which confirm the existence of intergenerational differences. This difference
      has a tendency to decrease in age which each successive generation. This
      difference occur in all relative pairs and therefore contradicts the
      ascertainment bias described by Penrose. CONCLUSIONS: The results outline the
      existence of unstable mutations (those produced by a nucleotidic variable number
      of tandem repeats) as a probable explanation of the susceptibility to develop
      some forms of idiopathic epilepsy.

PMID- 10599105
TI  - [Neurofibromatosis and cystic fibrosis: a case report].
AB  - INTRODUCTION AND CLINICAL CASE: We present the case of a patient attended in the
      Clinical Genetics Department of the Hospital Infantil Sur in Santiago de Cuba,
      who had 'cafe au lait' stains and persistent respiratory symptoms. 'Cafe au lait'
      stains were also found on the skin of the patient's mother, on clinical
      examination. No other members of the family were affected. Laboratory studies
      showed that both mother and son had positive sweat tests. PCR molecular study
      showed the patient to be homozygotic delta F508/delta F508 for the cystic
      fibrosis gene and both his parents to be delta F508 carriers. CONCLUSION: In this
      case there was a coincidence of two disorders of monogenic aetiology:
      neurofibromatosis and cystic fibrosis.

PMID- 10599104
TI  - [Depression and dementia: case-control study].
AB  - OBJECTIVE: To know the prevalence and risk factors for depression in demented
      patients. PATIENTS AND METHODS: From a field epidemiological study, in a double
      phase, door to door, in which 1,460 subjects older than 69 from a rural area
      participated, three groups were established: group A made up of 200 dementia
      diagnosed subjects; group B made up of 119 subjects without dementia but with
      punctuation on the screening instrument (MEC) under the cut off point; the 283
      subjects on the group C were not catalogued as demented, and the MEC punctuation
      was over the cut off point. Both the diagnoses of dementia and depression were
      made in basis of CAMDEX criteria. RESULTS: The frequency of depression in groups
      A, B and C was 26.5%, 11.76% and 4.94%, respectively. The dementia is a risk
      factor for depression (OR: 4.81; CI: 2.93-7.91). There are no differences in the
      frequency of depression according to dementia subtypes. Sex, age, marital status
      and severity of dementia do not have an influence on the prevalence of
      depression. The presence of psychiatric history is a risk factor for depression
      on groups A and B, but not for C. CONCLUSION: Depressions are more common on
      subjects with cognitive impairment.

PMID- 10599106
TI  - [Spontaneous dissection of the internal carotid artery. A report of two cases].
AB  - INTRODUCTION: Dissection of the internal carotid artery is a condition with a
      broad clinical spectrum. In absence of the classical triad of cervical pain,
      oculosympathetic ipsilateral paralysis and ischemic cerebral symptoms a
      considerable index of clinical suspicion is necessary to make a diagnosis. It is
      therefore considered to be probably underdiagnosed. The development of new
      techniques for neurovascular investigation, particularly ultrasound and magnetic
      angioresonance have improved the possibilities of diagnosis. CLINICAL CASES: In
      this paper we describe two cases of dissection of the internal carotid artery
      representing different clinical findings in the same condition. One patient
      presented with unilateral paralysis of the XI, X and XII cranial nerves and the
      other with transient ischemic cerebral accidents. In both cases the provisional
      diagnosis was made in function of the duplex findings of the supra-aortic trunks
      and confirmed by magnetic angioresonance studies. Both patients made satisfactory
      progress with complete recanalization of the vessels and no recurrence of
      symptoms after several months of follow-up. CONCLUSION: We discuss the different
      clinical characteristics and findings of the neurovascular examinations.

PMID- 10599107
TI  - [Spastic paraparesis due to long term consumption of wild cassava (Manihot
      esculenta): a neurotoxic model of motor neuron disease].
AB  - INTRODUCTION: Cassava (Manihot esculenta) is the basic foodstuff of more than 500
      million persons in developing countries. Its edible root contains a glucoside
      with a high cyanogenic content, linamarina, which is hydrolysed in the human
      intestinal tract by the resident microbial flora, with liberation of HCN.
      Inadequate preparation and cooking followed by consumption whilst half-raw,
      especially in diets based almost exclusively on cassava for a long period of
      time, may lead to a neurological syndrome of damage to the upper motor neuron and
      the appearance of spastic paraparesia. CLINICAL CASE: We present the case of a 44
      year old male agricultural worker from the Amazon region who had a predominantly
      crural spastic paraparesis which had been present for four years. His main food
      was 'mandioca brava' or wild cassava which was insufficiently cooked. Study of
      the CSF ruled out infection by HTLV and neurosyphilis. On magnetic resonance
      there was slight thoracic atrophy. CONCLUSIONS: In patients with spastic
      paraparesis, normal neuroimaging and CSF findings, and a normal family history,
      one should specifically investigate exposure to potentially toxic plants and
      foods, especially in regions in which nutrition is based on potentially
      cyanogenic roots or plants. It is necessary to improve the methods of processing
      and cooking cassava, and to avoid diets based almost entirely on this root, in
      order to reduce the potential neurotoxic damage which may be caused by this
      plant.

PMID- 10599108
TI  - [Horner's syndrome and brachial radiculopathy related to vertebral metastases].
AB  - INTRODUCTION: Horner's syndrome consists of sympathetic ocular paralysis, with
      lesions occurring at different levels. When it's associated with involvement of
      the C8-T1 roots, the commonest causes are the tumours responsible for Pancoast's
      syndrome. CLINICAL CASE: We describe the case of a patient who presented with a
      clinical condition in which a complete right Horner's syndrome was associated
      with ipsilateral C8-T1 brachial radiculopathy. On investigation, there was a
      tumour involving the vertebral segments between C8 and T5. Histological studies
      showed this to be a metastasis from an adenocarcinoma at the base of the right
      lung. CONCLUSION: We consider this case to be interesting because of its unusual
      aetiology, since metastatic vertebral lesions are an uncommon cause of Horner's
      syndrome.

PMID- 10599109
TI  - [The stroke chain: from the onset of symptoms to the emergency services].
AB  - INTRODUCTION: The treatment of stroke by thrombolysis or other methods
      (neuroprotection, basic care, etc.) is more effective the sooner it is begun. The
      main reasons for patients not receiving treatment during the acute phase of their
      illness are slowness in reaching hospital and delay in emergency assessment once
      they arrive there. It is necessary to identify the factors involved in these
      delays so as to modify what can be improved and establish guidelines.
      DEVELOPMENT: In the chain of events leading to arrival in hospital there are
      independent factors related to the social and health characteristics of the
      patients, their attitudes to illness, characteristics of the stroke itself and of
      the health district. Analysis of the system for response to stroke patients is
      extremely important before investing in measures to be applied during the acute
      phase. This analysis should be based on the different stages at which delays may
      occur. Outside the hospital, the systems to be recognized are those of the
      patient and his family, contact with prehospital care teams and transport to the
      hospital of reference. Hospital care involves making contact on arrival at the
      Emergency Department, and the response of the neurologist or stroke team who give
      the initial treatment. CONCLUSIONS: Programmes of education and improvement in
      the organization of the different protagonists at the various stages reduce the
      time lost by delay.

PMID- 10599111
TI  - [Computer tomography: selection criteria for thrombolytic treatment].
AB  - Emergency cranial computerized axial tomography (CAT) has a fundamental place in
      relation to the therapeutic options of neurologists dedicated to the thrombolytic
      treatment of cerebrovascular disease. This imaging technique may give important
      information regarding clinical evolution, subsequent tomographic findings and the
      final result of the evolution of these disorders. However, CAT has certain
      limitations concerning the reproducibility of the interpretation of the early
      signs of infarct, which nevertheless may be minimized by suitable training of the
      observers and establishment of a general consensus as to the criteria that should
      be used for this.

PMID- 10599110
TI  - [Monitoring and management of strokes in the acute phase].
AB  - INTRODUCTION: Treatment of acute strokes in a Stroke Unit reduces intrahospital
      mortality and dependence by 29%. One year later this effect is still present. It
      is not known whether the use of intermediate care in the so-called Acute Stroke
      Units, with continuous cardiovascular and neurological monitoring, provides
      further benefit in addition to that obtained by specialized care units in which
      monitoring is carried out at the usual intervals. DEVELOPMENT AND CONCLUSIONS: In
      this article we analyze the advantages of Acute Stroke Units in the application
      of new treatments and their potential benefits in the prevention of medical
      complications; we also review the general recommendations for treatment in the
      acute phase of strokes.

PMID- 10599112
TI  - [The role of magnetic resonance in acute stroke].
AB  - The combined use of different techniques of magnetic resonance, such as
      angiography by magnetic resonance, microscopic tissue diffusion, proton perfusion
      and spectroscopy, has meant a great advance in early diagnosis of cerebrovascular
      accidents. They also give relatively precise information as to the presence and
      extent of potentially reversible zones of border-line ischaemia, with their
      prognostic and therapeutic implications. Combined analysis of the different
      parameters which can be measured using magnetic resonance, may in the near
      future, permit this technique to be used for selection of patients who may
      benefit from the active treatment of cerebral ischaemia during the hyper-acute
      phase, and monitorization of the effect of this treatment.

PMID- 10599113
TI  - [How did the results of ECASS II influence clinical practice of treatment of
      acute stroke].
AB  - INTRODUCTION AND DEVELOPMENT: There appears to be a rationale for the use of
      thrombolysis in ischemic stroke. Streptokinase should no longer be used to treat
      acute ischemic stroke. However, thrombolytic treatment with recombinant tissue
      plasminogen activator (rt-PA) may have an important role in the management of
      acute stroke. The studies to-date highlight the importance of early intervention
      and careful patient selection. In the National Institute of Neurological
      Disorders and Stroke (NINDS) trial, treatment within three hours was associated
      with an improved functional outcome without an increase in mortality. In the
      European Cooperative Acute Stroke Study (ECASS), treatment of eligible patients
      resulted in improved neurologic and functional out come. In the Multicentre Acute
      Stroke Trial Europe (MAST-E) and Australian Streptokinase Trial (ASK) trials,
      later intervention was associated with an increased risk of cerebral hemorrhage
      and poor outcome. CONCLUSIONS: Successful use of thrombolytic therapy with rt-PA,
      therefore, depends on rapid assessment to exclude patients with hemorrhagic
      stroke or those at risk of hemorrhagic complications. It has been shown to be
      beneficial in patients treated within three hours who conform to the strict
      inclusion and exclusion criteria of the NINDS trial. Moreover, after the results
      of ECASS II, and the recent metaanalyses of all three major rt-PA trials, it
      seems that with strict selection criteria, expert CT-reading, adherence to the
      protocols and a stroke unit type approach, the time window for thrombolysis may
      be as long as six hours in selected patients.

PMID- 10599114
TI  - [Physician-patient relationship in neurological diseases].
AB  - INTRODUCTION: Neurological illness may lead to considerable disability with
      consequent social, work and family repercussions. Many patients with chronic
      neurological disorders consider it essential to maintain good doctor-patient
      relationships so as to be able to adapt to and face their disabilities. The
      patient needs to be understood, because he believes that since the doctor
      understands his symptoms, he will be able to establish a diagnosis and
      therapeutic approach. He also needs to be able to understand the information that
      the neurologist gives him. Therefore the doctor should use simple language with
      no terminology which may be difficult to understand. DEVELOPMENT: In this study
      we analyze the characteristics of the doctor-patient relationship in neurological
      disorders affecting young people, of which multiple sclerosis is the most
      representative, and in elderly patients in whom Parkinson's and Alzheimer's
      diseases are the commonest. We also consider important aspects of the doctor
      patient relationship, such as the style and empathy of the neurologist, and also
      the significance of the neurological disorder for the patient and his family.
      CONCLUSION: It is important that both the patient and his doctor understand what
      each expects of the other, so as to establish a satisfactory relationship between
      them.

PMID- 10599115
TI  - [The quality of health care services. A general proposal for clinical services].
AB  - INTRODUCTION: Quality is one of the strategic elements on which changes and
      improvement of modern healthcare systems is based. Study of the quality of health
      care implies several approaches, which are traditionally of different
      significance to patients, professionals and managers. The quality of healthcare
      systems depends on healthcare policy, on doing the right things correctly, of the
      impression that the givers and receivers of care have of the organization, of the
      definition of service attending to both inpatients and out patients and the
      satisfactory interaction between them. DEVELOPMENT: In this paper we give a
      synthesis of different concepts of the quality of care in recent years. We
      consider different approaches for the evaluation of quality from the practical
      aspect, and finally we propose a type of program for the quality of a clinical
      department, which within the strategic plan of the hospital, should be orientated
      towards the patient, and be based on three concepts: scientific-technical or
      physical quality, functional or interactive quality and corporate quality.

PMID- 10599117
TI  - [Neurological assistance as a product. Evaluation of the process in neurology].
AB  - INTRODUCTION: Appraisal of the process of assistance is a fundamental step in
      determination of the quality of medical assistance given. DEVELOPMENT AND
      CONCLUSIONS: In this paper we review the concept of medical assistance as a
      product, establishing a parallel between medical assistance and a process of
      industrial production. We consider the similarities and differences between them.
      From the point of view of production management we may distinguish different
      elements: the setting, structure, process of production, result and evaluation.
      All these are also found in healthcare assistance. We review the concept of the
      process of assistance both from the limited point of view of the management of
      disease and its complications, and from a broader perspective which includes the
      activities of patients in seeking and obtaining assistance. Different aspects and
      methods of appraisal of the process of assistance are considered: medical audit
      and monitoring. Finally, we approach the problem of appraisal of the process in
      outpatient assistance, the importance of this and the methods used in evaluation.
      We comment on experience of this aspect obtained in the Neurology Unit of the
      Hospital Marina Alta in Denia.

PMID- 10599116
TI  - [The quality assessment from the minimum basic hospital discharge data set].
AB  - INTRODUCTION: Risk adjustment is essential before comparing patient outcomes
      across hospitals. With this aim several risk adjustment systems have been
      developed, including the well-known diagnosis related groups. MATERIAL AND
      METHODS: Narrative review on risk assessment framework from administrative
      databases, including data quality and system pitfalls. RESULTS: The risk
      adjustment systems developed for cost-control aims to group different patient
      typologies in relation to the predicted use of resources with the aim to develop
      incentives to cost-reduction; the systems developed for measuring effectiveness
      have the objective to assess the health care quality. Both systems are useful for
      clinical, management and health public uses, but they have several pitfalls and
      their results should be interpreted cautiously. CONCLUSIONS: Managers and
      physicians should consider the risk adjustment systems as a valuable resource for
      decision-making and reducing uncertainty, but not as the scientific referee of
      hospital quality or hospital efficiency.

PMID- 10599118
TI  - [The development of ambulatory care groups in primary care].
AB  - INTRODUCTION: Ambulatory care groups (ACG) are a system of classification for
      patients in an ambulatory setting and in Primary Care (PC), based on the premise
      that by measuring the morbidity load of the population, it is possible to explain
      variations in the consumption of healthcare resources. PATIENTS AND METHODS: In
      order to study the behaviour of the ACG in our PC, we made a prospective study of
      a sample of the patients of 13 doctors and nurses working in new PC centres in
      Barcelona province. Analysis of the behaviour of the ACG was based on four
      variables of use of resources: number of episodes per patient, number of visits
      per patient, cost per patient including diagnostic procedures, prescriptions made
      and the time taken by health workers, and the total cost of PC per patient which
      also included the cost of PC, emergencies, hospital admissions and consultations
      with specialists in Outpatient Departments or Health Centres. RESULTS: It was
      confirmed that the coefficients of variation of the measurements were within
      acceptable limits, the worst performing ACG were identified and it was seen that
      the variability explained by dependent variables--apart from the total cost per
      patient--by the ACG, by multiple regression models, was fairly high. CONCLUSION:
      The ACG may be a useful classification system for our PC.

PMID- 10599119
TI  - [The need for specialist assistance in neurology].
AB  - INTRODUCTION: The need for specialist attention in neurology in a particular
      population is not constant but may vary over a period of time, depending on a
      series of changeable conditions. For this reason it is useful to make periodical
      reappraisals, so as to adapt the services available to the true needs of the
      population at any particular time. DEVELOPMENT: In this paper we consider the
      steps to be followed when carrying out a study of the need for attention, and
      analyze the variables which influence the calculation of the number of
      neurologists necessary in a particular population, and the methods of obtaining
      information and identifying requirements. Besides this, we summarize the data of
      five Spanish studies which sought to define the needs for neurological attention
      from both the point of view of Primary Care doctors (three studies in the Health
      Areas of Alcoi, Alicante and San Juan, in the Communidad Valenciana) and that of
      the specialist (two studies: one in the setting of the Sociedad Valenciana de
      Neurologia and one in that of the Sociedad Espanola de Neurologia). CONCLUSION:
      In our model of specialized neurological attention there is a great need and
      demand for specialized neurological attention, with a tendency towards direct
      neurological attention for each patient.

PMID- 10599120
TI  - [Demand for neurological services in Spain. Data for a more demanding future].
AB  - OBJECTIVES: The published data on neurological resources and the demand for
      neurological care in Spain were reviewed. Also, this demand was analysed in a
      specific health district (area 11, Hospital Universitario 12 de Octubre, Madrid).
      DEVELOPMENT: About 2.5 neurologists per 100,000 inhabitants in Spain was
      estimated to practice in the National Health Service in 1998. The published
      demand for first outpatient neurological consultations per 1,000 inhabitants/year
      in the National Health Service in Spain have a range of 8-35 consultations. The
      same demand in the health district analyzed was 14.5 consultations per 1,000
      inhabitants/year in 1996. CONCLUSIONS: The demand for neurological care is high
      in Spain and will increase in the future mainly due to the population aging; the
      resources of neurologists and neurological beds would be adequate to this
      increasing neurological demands.

PMID- 10599121
TI  - [Home hospitalization: an alternative to conventional hospitalization. Future
      outline].
AB  - INTRODUCTION: Domiciliary hospitalization (DH) is defined as the group of
      treatments and healthcare carried out in the patient's home, but of complexity,
      intensity and duration comparable to those received by a patient in a
      conventional hospital. OBJECTIVE: The aim of this article is to divulge, in the
      neurological world, the possibility of attendance by DH. DEVELOPMENT: A DH would
      act as a supporting term for the acute hospital, as a supporting team for Primary
      Care, and in some cases as a unit for assessment and placing patients in their
      best 'therapeutic setting' as required by any community health organization. In
      this paper we consider the professionals who make up the structure of DH, the
      criteria for admission to the Unit, the system for admission and the types of
      illness which may be attended in these units. With regard to the latter, we
      briefly analyse the neurological illnesses in the DH setting: cerebrovascular
      disease, meningitis and multiple sclerosis. Finally, we present data regarding
      the 13 units working in the Comunidad Valenciana. CONCLUSION: The basic mission
      of the DH is to improve the quality of assistance, and by means of specialist
      support enable the biggest possible number of persons who need and wish to remain
      or return home as soon as possible to do so.

PMID- 10599122
TI  - [Report on the surgery for epilepsy].
AB  - OBJECTIVE: We review the clinical indications and outcomes of surgical procedures
      in epilepsy which is resistant to medical treatment and the current situation and
      future possibilities of carrying out surgery for epilepsy in Spain. DEVELOPMENT:
      Search of the scientific literature included in the data base MEDLINE for the
      period 1995-1997, retrieval of reports in relation to agencies for the evaluation
      of health technology of the INAHTA network and the data base of the Cochrane
      library. The surgery of epilepsy reduces the frequency of seizures (the basic
      result analyzed) in all groups of patients, although in a very variable manner,
      depending on the clinical situation and type of operation. The results in
      patients with temporal lobe epilepsy and in those with localized lesions are
      particularly good (temporal lobe epilepsy and lesionectomy) (67-69% without
      seizures), with a follow up period of one to two years. It is estimated that in
      Spain between 75 and 300 new cases per year would benefit from surgery. The
      number of patients with drug-resistant epilepsy operated on in Spain is
      approximately 100-150 patients per year. CONCLUSIONS: Operations for epileptic
      syndromes, where there are surgically resectable lesions, should be justified by
      the gravity and impact of the disease on the psychosocial and functional
      development of the patient. Insufficiency resources are dedicated to the option
      of surgical treatment and perhaps they are also underused. These operations
      should be carried out in highly specialized centres, with adequate resources and
      an annual volume which guarantees excellence.

PMID- 10599123
TI  - [Post-traumatic enophthalmos. Physiopathologic considerations and current
      therapeutics].
AB  - The article is an overview of the available literature on post-traumatic
      enophthalmos (PTE). The PTE has a clinical definition and its diagnosis is based
      on a clinical examination. Fully assessment of the deformity requires complete
      ophthalmological examination and a measurement of the globe backward displacement
      by the mean of Hertel's ophthalmometer. Focusing on the pathophysiology, we
      insist on the role of periorbit and extraocular muscle retraction; nevertheless,
      according to most of the author's, opinion, the main pattern of the PTE seems to
      be the increased orbital post-traumatic volume, as it can be demonstrated by
      computed tomography (CT scan). In fact, thorough evaluation of the deformity
      needs at less a CT scan examination, providing horizontal and coronal slices.
      Sometimes, even a three-dimensional reconstruction can be obtained, helping the
      surgeon assessing the orbital deformity pre-operatively. We present five patients
      victims of a high-energy facial injury (motor vehicular accidents is responsible
      for an overwhelming majority of cases) leading to severe orbital lesions, and
      presenting a PTE as the main sequelae. We use homologous bone grafts to repair
      orbital fractures, especially calvarial bone. Osteotomy of the zygomatic bone
      (total or partial) can be proposed, combined with grafting of the orbit, to
      improve the correction of PTE. Most of all, patients with acute orbital trauma
      must be operated on as quick as possible: the sooner the surgery, the lower the
      probability for the PTE to occur.

PMID- 10599124
TI  - [Sebaceus nevus of Jadassohn. Apropos of 62 surgically treated cases and review
      of the literature].
AB  - The analysis of 62 cases of nevus sebaceus of Jadassohn and the study of the
      literature allows to define the clinical and histo-pathologic features of this
      benign tumor. The massive development of sebaceous glands, papillomatous
      epidermal hyperplasia, and maturation of apocrines glands, are present in a
      considerable number of cases. The lesions occurred on the scalp, face, auricular
      area and neck and are usually present at birth as a yellowish orange area. At
      puberty, the lesion becomes yellow to dark-brown and is verrucoid and
      micronodular. Almost all are hair-deficit nevi, and the final stage is the
      development of secondary tumors of the skin within the lesion. The risk of
      degeneration in basal-cell carcinoma justifies systematic surgical treatment.

PMID- 10599125
TI  - [Screening of cancerous and precancerous lesions of the oral mucosa in an at-risk
      population].
AB  - Early diagnosis of oral carcinomas allows a limitation of functional consequences
      of surgical treatment. A prospective study was designed in 270 alcoholic
      patients. We practiced a clinical examination of the oral cavity by a
      stomatologist followed by a Toluidin blue test. The clinical examination
      permitted to detect 1 carcinoma and 23 leukoplakias. The Toluidin blue test
      revealed one more carcinoma and two leukoplakias more. The early diagnosis of
      oral carcinomas in alcoholics patients gives them a better survival. The Toluidin
      blue test could be proposed as an aid to early diagnosis of these carcinomas.

PMID- 10599126
TI  - [The value of sialo-MRI in the study of salivary gland duct pathology].
AB  - Usual imaging diagnostic for salivary glands is sialography. Sialography is not
      stripped of disadvantages and failures. The MRI-sialography is an examination
      which is carried out without any injection of contrast's product (without
      catheterization or intravenous injection). It is thus noninvasive and painless.
      The complete study of salivary gland and its ducts is always possible and could
      not be blocked by local or loco-regional conditions. It allows exploration of
      several salivary glands in the same time. We think that the MRI-sialography must
      find its place in the diagnosis arsenal for salivary pathology in spite of its
      current handicaps represented by its cost and the difficulty of access to the
      apparatuses.

PMID- 10599127
TI  - [Synovial sarcoma of the mandible in children. Apropos of a case].
AB  - Synovialosarcoma is an aggressive malignant soft-tissue tumor. It's a mesenchymal
      tumor rare in the cephalic region in the children. Its occurs most frequently in
      the extremities, in the adolescents and young adults between 15 and 40 years. His
      treatment are principally a radical surgical excision. We report the case of a 10
      year old boy who had a mandibular tumor developing in the first premolar area and
      invading the submandibular region. The histologic diagnosis was biphasic
      synovialosarcoma with epithelial predominance. The staging showed a stage II
      tumor (5 cm) of the submandibular region with invading the mouth floor and the
      mandible. After the failure of the polychemotherapy we had performed a radical
      surgical excision with a functional cervical lymphadenectomy. The tumor was
      excised in one piece with the horizontal part of the left hemimandible. The
      treatment was completed by radiotherapy. In a second time a reconstructive
      surgery was performed with a fibula free flap. The result at one year show a good
      local control and a perfect esthetic and functional result of the mandible.
      CONCLUSION: Synovialosarcoma is a very aggressive malignant soft-tissue tumor
      with a high metastatic risk. Management must be rapid as soon as the diagnosis is
      made. Surgical excision is the main treatment in association with the
      chemotherapy and radiotherapy.

PMID- 10599128
TI  - ["Search or research". On the qualification for director of research].

PMID- 10599129
TI  - Studies on the respiratory disease 'sonbobe' in camels in the eastern lowlands of
      Ethiopia.
AB  - New epidemics of respiratory disease have caused 29.6 morbidity and 6.4%
      mortality in camels in the Somalia region of Ethiopia. The major clinical signs
      observed were fever of 40-41.5 degrees C, depression, cough, loss of appetite and
      a watery nasal discharge that became mucopurulent at a later stage. Finally, the
      camel became recumbent and extended its neck straight along the ground. Some of
      the animals died within 8-9 days. The major post-mortem lesions were hydrothorax,
      adhesion of the lung to the thorax, red and grey hepatization, emphysema,
      hydropericardium and fibrinous pericarditis. A treatment trial indicated that
      oxytetracycline was more effective than a combination of penicillin and
      streptomycin, the results showing a significant difference (p < 0.05) between the
      treated and control groups. The bacteria isolated from lung, thoracic fluid and
      whole blood were Pasteurella haemolytica. Further studies on the epidemiology of
      this disease, the identification of the serotypes involved, and the demonstration
      of any primary viral initiating agent are recommended to allow the development of
      preventive methods.

PMID- 10599131
TI  - Comparative parasitological and haematological changes in two breeds of sheep
      infected with Fasciola gigantica.
AB  - Twelve each of Red Masai and Dorper sheep, aged between 6 and 9 months, were
      acquired from a Fasciola-free area of eastern Kenya. Each breed was divided into
      two groups of 6. The sheep in one group of each breed were experimentally
      infected with 400 viable metacercariae of Fasciola gigantica. The other group of
      6 sheep of each breed remained as uninfected controls. The animals were monitored
      regularly for any evidence of disease. Blood samples taken weekly revealed a
      general reduction in red cell counts and packed cell volume, which was much
      faster in the infected Dorper sheep than in the Red Masai. This reduction started
      from the tenth week after infection and persisted to the end of the experiment 18
      weeks post infection (PI). The absolute eosinophil counts rose in all the
      infected animals, but the values were higher among the Dorper than among the Red
      Masai. Patency occurred at weeks 12 and 13 PI in the Red Masai and Dorpers,
      respectively, with the latter shedding significantly more fluke eggs. The worm
      recovery rates were higher among the Dorpers than among the Red Masai, though not
      significantly so. On the basis of egg counts and clinicopathology, the Dorper
      sheep were considered to be more susceptible to F. gigantica infections.

PMID- 10599130
TI  - Impact of mastitis control measures on milk production and mastitis indicators in
      smallholder dairy farms in Kiambu district, Kenya.
AB  - Bovine mastitis and mastitis control were investigated on smallholder farms in
      central Kenya. After an initial observational study, a clinical trial to assess
      the impact of three different mastitis control strategies--(1) improved udder
      hygiene, (2) treatment of subclinical cases, and (3) a combination of these--was
      conducted on 100 randomly selected farms with 332 lactating cows. Before the
      implementation of control measures, the milk yield was low (mean 6.5 kg/day;
      median 6 kg/day) and somatic cell counts (SCC) were high, with 80% and 43% of
      cows having milk with SCC greater than 250 x 10(3) cells/ml and 600 x 10(3)
      cells/ml, respectively. Infectious pathogens were also commonly isolated, with
      63% of cows being positive for pathogenic bacteria. Neither intervention strategy
      alone had any effect on mastitis indicators or milk yield. In combination, the
      measures had some impact, lowering the prevalence of contagious pathogens by 18%,
      but this was not reflected in a significantly increased milk yield, lowered SCC
      or reduced incidence of clinical mastitis.

PMID- 10599132
TI  - The concentration of faecal progestins during the oestrous cycle in Nkone cows
      and the effect of duration of storage of faecal samples at room temperature on
      faecal progestin levels.
AB  - The objectives of this study were to determine whether ovarian function in Nkone
      cows could be monitored by measuring progestin concentrations in faeces and to
      assess the effect of duration of storage at room temperature on faecal progestin
      concentrations. Faecal and blood samples were obtained once a day for 26 days
      from 21 Nkone cows whose oestrous cycles had been synchronized. Faecal samples
      from each cow were divided into five portions that were kept at room temperature
      for 0, 6, 12, 24 and 48 h, respectively, and then frozen. After centrifuging the
      blood to recover plasma and extracting steroids from the faeces, analysis of
      progesterone (P4) was carried out using solid-phase radioimmunoassay. The faecal
      progestin and plasma progesterone profiles corresponded well and were positively
      correlated (r = 0.70, p < 0.01). Faecal progestin concentrations decreased with
      increasing duration of storage at room temperature during both the follicular and
      luteal phases (p < 0.01). In both cases, the decline in faecal progestin
      concentrations followed an exponential pattern. The progestin concentrations in
      faeces after 48 h of storage at room temperature were higher (p < 0.05) during
      the peak luteal phase than in the follicular phase.

PMID- 10599133
TI  - Performance of broiler chickens fed sweet potato meal (Ipomoea batatas L.) diets.
AB  - Day-old Lohman broiler chicks (n = 120) were fed on five starting diets for 4
      weeks in groups of 24 birds. The starting diets contained 0%, 9%, 18%, 27% and
      36% sweet potato tuber as a replacement for maize. From the fifth week, the 120
      birds were tested in groups of 30 on four finishing diets containing 0%, 15%, 30%
      and 45% sweet potato tuber as a replacement for maize. The carcass quality was
      significantly (p < 0.05) improved due to a significant (p < 0.05) reduction of
      abdominal fat in the birds fed on the 45% sweet potato finisher diets. However,
      the birds on the sweet potato diet continually passed wet droppings, resulting in
      a significant (p < 0.05) reduction in body weight and feed conversion efficiency.
      The optimum levels of inclusion of sweet potato in the diets were considered to
      be 27% and 30% for starting and finishing broiler chickens, respectively. Sweet
      potato diets may be a remedy for fatty broilers.

PMID- 10599134
TI  - Dioscorea alata (water yam) as a replacement for maize in diets for laying hens.
AB  - One hundred and twenty-six point-of-lay birds were randomly alloted into six
      groups of 21 birds each and fed six diets containing 0%, 10%, 20%, 30%, 40% or
      50% of Dioscorea alata meal as a replacement for maize, corresponding to 0%, 20%,
      40%, 60%, 80% and 100% maize replacement. There were no significant differences
      (p > 0.05) in feed intake, egg weight or feed efficiency between the control diet
      and the test diets. However, the daily egg production per 100 birds (hen day
      production), differed significantly (p < 0.05) among the treatments. The birds on
      the control diet and diets with substitution rates of up to 80% laid
      significantly (p < 0.05) more eggs than those on the 100% substitution rate. This
      shows that D. alata can replace up to 80% of maize or constitute 40% of a laying
      chicken diet, provided the rations are isocaloric and isonitrogenous. For this to
      be achieved, more soybean and/or more fish scraps, and more palm oil are needed
      in the diets containing D. alata than in diets based on maize.

PMID- 10599135
TI  - Limb deformities of farmed ostrich (Struthio camelus) chicks in Botswana.
AB  - Limb deformities were detected in 135 out of 885 ostrich chicks, giving a
      prevalence of 15.3%. Tibiotarsal rotation affected 73% of the chicks with limb
      deformities, whereas rolled toes accounted for 36%. The right leg was more often
      affected than the left leg. The incidence of limb deformities was highest in 2-
      to 3-week-old ostrich chicks. The incidence of limb deformities was highest at
      the beginning of the breeding season and lowest towards the end, when it was
      relatively warmer. The mean serum manganese and zinc levels in deformed ostrich
      chicks were higher than the levels reported for normal chicks.

PMID- 10599137
TI  - [Glutamate and peroxidation in the pathogenesis of CNS diseases].
AB  - The review summarises literature data on the interrelationship between glutamate
      and oxidative stress. Certain attention is paid to nitric oxide and its
      contribution to the oxidative stress. Free radical scavenges attenuate brain
      damage caused by glutamate neurotoxicity.

PMID- 10599136
TI  - [Blood level of gamma-aminobutyric acid--"peripheral index" of the state of
      central neuromediator system].
AB  - The review summarized data on contents of the main inhibitory neurotransmitter of
      the central nervous system: gamma-aminobutyric acid (GABA) in blood of normal
      animal and humans, in blood of different animal species under experimental
      effects and modelling of pathological states, as well as in human blood in the
      presence nervous and endocrine diseases. Determination of GABA concentration in
      blood, taking into account the accessibility of study object, absence of
      significant sex, age, seasonal, diurnal fluctuations, as well as stability of
      amino acid level during the laboratory assay procedure, may be useful for the
      study of central neuromediator mechanisms, and allows, using representative
      samples and corresponding groups of comparison, to obtain data on disturbances of
      functional state of the GABAergic system under conditions of brain pathology.

PMID- 10599138
TI  - [The use of computer morphodensitometry in modern molecular diagnostic methods].
AB  - Technologies based on the use of polymerase chain reaction, in particular IS PCR
      are widely used now. However, wide introduction in clinico-laboratory practice of
      these methods requires: increase of reliability of the accepted decisions,
      improvement of the image for revealing more fine distinctions of objects,
      increase of quality of the obtained information, automated registration of
      results of the analysis. The application of original digital image analysis,
      adapted to specificity of biomedical objects--morphodensitometry--allows to solve
      successfully the following tasks: to optimisze conditions of IS PCR realisation
      on the basis of use of quantitative opticogeometrical parameters, quantitatively
      and subpopulistically to characterize a degree of infected cells with viral
      infection, and also nucleuses of cells, that is especially actual for
      introduction of molecular-genetic methods in clinico diagnostic practice and,
      automatically to register results of the analysis. Thus, employment of
      morphodensitometry can be very important in genediagnostic and also gene therapy.

PMID- 10599139
TI  - [Use of a novel hepato-protective preparation "phospholiv" for inhibition of
      development of chronic hepatitis in rats].
AB  - Protective influence of a new phospholipid preparation "Phospholiv" was studied
      using a model of chronic hepatitis. Animals were treated 45 days intraperitoneay
      with CCl4 with parallel intragastral administration of Phospholiv or--(for
      comparison)--the of other phospholipid hepatoprotector, Essential. Morphologic
      changes of liver, as well as protein and RNA biosynthesis were evaluated in the
      end of experiment--by means of measuring C14-leucine and C14-orotic acid
      incorporation into hepatocyte subcellular fractions. Both phospholipid
      preparations attenuated dystrophic liver changes, Phospholiv effect being more
      pronounced. They both prevented CCl4 induced inhibition of label incorporation
      into subcellular fraction proteins, but only Phospholiv, promoted the maintaining
      normal level of radioactivity incorporation into cytosol proteins and hepatocyte
      RNA. The results, confirming certain protective effect of Essential, show more
      pronounced hepatoprotective action of the new preparation Phospholiv (developed
      on the basis of polyunsaturated phosphatidylcholine and glycyrrhizinic acid
      salt). Data show also on possible fit hepatitis treatment.

PMID- 10599140
TI  - [Comparative study of the effects of essentiale and the novel Russian
      hepatoprotective agent "phospholiv" in a model of acute hepatitis in rats].
AB  - Curative effect of new preparation "Phospholiv", elaborated in Institute of
      Biomedical Chemistry, in acute CCl4 induced rat hepatit model was studied. The
      preparation consists of polyunsaturated phosphatidylcholine and glycyrrhizinic
      acid salt. Recovery of damaged biosynthesis of albumin and total cell liver RNA-
      by incorporation of C14-leucine and C14-orotic acid--were observed after 3 days
      Phospholiv administration, that showed on reparation of damaged protein-synthesis
      system. Label incorporation into liver fraction > 80S--that was decreased under
      CCl4 influence--was also restored after Phospholiv treatment, that may testify on
      its regenerative effect on wholeness of subcellular hepatocytes structures.
      Substantial decrease of morphologic damages of liver tissue was demonstrated as
      well. Other phospholipid preparation--known hepatoprotector Essentiale--gave some
      positive effects too, but Phospholiv influence on biochemical and morphological
      liver features were 1.5-2 fold as compared with that of Essentiale. Results show
      on efficiency of polyunsaturated phospholipids in the treatment of acute hepatit
      in rats--as a result of influence on hepatocytes cell membrane--and on
      preferential effect of new hepatoprotector Phospholiv.

PMID- 10599141
TI  - [Structural-functional changes in biomembranes during complications of diabetes
      mellitus and their pharmacological correction].
AB  - The decrease of sorbitol dehyidrogenase activity and the increase both of aldoso
      reductase activity and sorbitol concentration in aorta or eye lens under
      experimental diabetic angiopathy have been shown. The structural and functional
      alterations in erythrocytes membranes under angiopathy studied by spin- and
      luminesoense probes confirm the hypothesis on the major role of membrane
      pathology processes in the pathogenesis of diabetic mellitus. Pharmacological
      correction of diabetic angiopathy by glucophag or new antioxidant LBK-78
      normalized the studied diversions on the membranes level.

PMID- 10599143
TI  - [Dynamics of lipid peroxidation and blood antioxidant system during acute
      destructive pancreatitis].
AB  - The changes of lipid peroxidation parameters and state of blood serum antioxidant
      system in acute destructive pancreatitis were investigated. The increased content
      of blood serum diene conjugates and thiobarbituric acid reactive substances was
      found. It was shown that the blood serum antioxidant activity had correlated with
      concentration of urate (r = +0.79, p < 0.001).

PMID- 10599142
TI  - [Correction of diabetic neuropathies using aldose reductase inhibitors and
      pikamilon].
AB  - Streptosotocin-induced diabetes in rats is accompanied by the development of
      diabetic complications such as neuropathies. [2-14C]serotonin and [U-14C]GABA
      release from the neurotransmitter pre-loaded synaptosomes showed significant
      elevation. Aldose reductase inhibitors (AL-1576, sorbinil) administration leads
      to partial restoration of serotonin and GABA release, while picamilon restored
      only GABA release. It was shown that Na+,K(+)-ATPase activities decreased in
      synaptosomes, synaptic membranes and sciatic nerve of diabetic rats compared to
      control. Administration of AL-1576 normalized Na+, K(+)-ATPase activity, while
      sorbinil and picamilon less effectively. Sorbitol level are increased in
      streptozotocin-diabetic rats as compared to control. The picamilon and aldose
      reductase inhibitors administration to diabetic rats is accompanied by the
      partial reduction of brain sorbitol level. The findings confirm the important
      role of picamilon and aldose reductase inhibitors in the prevention and treatment
      of diabetic neuropathy.

PMID- 10599144
TI  - [Intensification of serum lipid peroxidationas a biochemical marker of
      concomitant pancreatitis in complicated gallstone disease].
AB  - Serum concentration of two products lipid peroxidation (LPO) of--conjugated
      dienes and dienketones--was assessed in 71 patients with exacerbation and
      remission of chronic pancreatitis, uncomplicated gallstone disease and with
      combinated pathology of pancreas and biliary tracts and in 100 healthy persons.
      During exacerbation of pathologic process in pancreas with the different
      ethiology of disease strong intensification of LPO occurs, but in period of
      remission LPO markers were found to be close to those in control. Postoperative
      complications and severe outcome in patients with gallstone disease are
      associated with a significant increase in LPO level in serum before reoperation.
      Routine clinical data in these patients detect no symptom of pancreas pathology.
      This finding evidenced that concentration of LPO products in the sera of patients
      with gallstone disease may be of great significance for diagnosis of associated
      pancreatitis and early predictor of outcome.

PMID- 10599145
TI  - [Antibodies against nerve tissue proteins S100, GFAP, and MP65 and pregnant women
      with early toxemia].
AB  - Serum levels/affinities of natural autoantibodies to proteins S100, GFAP and MP65
      in patients with physiological pregnancy are usually constant and may vary among
      individuals within relatively narrow range. In patients with early toxicosis in
      pregnancy dispersion of serum autoantibodies levels were often found beyond the
      normal range. This group includes cases with significantly elevated as well as
      abnormally decreased immunoreactivity parameters. Percent of newborns with
      different deviations from women with abnormal serum levels/affinities of
      autoantibodies to proteins S100, GFAP and MP65 was higher 1,5-2 fold compared
      with population.

PMID- 10599147
TI  - [Surgical options in heart failure].

PMID- 10599146
TI  - [Autoantibodies against NMDA-receptors in the blood of patients with acute
      disorders of cerebral circulation].
AB  - Concentration of autoantibodies to human brain NMDA-receptor in blood serum of
      patients with acute brain ischemic stroke was significantly higher than in
      healthy persons and patients with other neurological diseases. Average content of
      cholesterol, lipid peroxides and glutamate in the serum were close in all patient
      groups investigated. It was suggested that the content of autoantibodies to human
      brain NMDA-receptor could be used as biochemical criteria for acute brain stroke
      patient's condition control and their treatment efficiency.

PMID- 10599148
TI  - [Infection, sepsis and cardiac arrhythmia].
AB  - In clinical practice, the occurrence of arrhythmias in a critical ill patient is
      often assumed to be due to underlying infection or sepsis. This relationship has
      been suggested by both case reports and textbooks of Internal Medicine. Two
      scenarios are deemed possible: The occurrence of "preexisting" arrhythmias in
      susceptible patients (those with an arrhythmogenic substrate, e.g. a myocardial
      infarction scar) and the occurrence of arrhythmias mediated in some way through
      the infection/sepsis in otherwise unsusceptible patients. The present overview
      portrays the scarcity of data and shows that neither scenario is supported by
      firm data. While sinus tachycardia is among the spectrum of expected
      abnormalities during infection or sepsis, bradycardia may be observed in selected
      cases. This seems to occur relatively frequently in patients with fungemia.

PMID- 10599149
TI  - Effects of intradialytic parenteral nutrition in chronic haemodialysis patients
      with malnutrition: a pilot study.
AB  - BACKGROUND AND AIMS: Protein and calorie malnutrition is frequently observed in
      chronic haemodialysis (HD) patients. Recently it has been suggested that
      intradialytic nutritional support with amino acids may improve nutritional status
      and increase immunocompetence. The aim of this study was to evaluate the effects
      of intradialytic infusion of amino acids, lipids and glucose on body composition
      and other parameters of nutritional status in patients undergoing HD. METHODS:
      Seven patients with a mean age of 77 +/- 6 years (range, 60-86 years), a mean BMI
      of 20.1 +/- 2.8 (range, 16.1-24.4) and clinical signs of malnutrition
      participated in the study (mean time on HD, 51 +/- 36 months). HD was performed
      12 hours per week with bicarbonate as a buffer and a polysulfon capillary
      dialyzer (F-60). During the 3-month period of intervention the patients received
      an intradialytic parenteral solution during the regular scheduled dialysis
      treatment, containing amino acids (12 g s/h), a glucose 15% solution (37.5 g/h)
      and a fat emulsion (12.5 g/h). RESULTS: (mean +/- SEM) Total calorie intake
      increased from 1550 +/- 63 to 2255 +/- 114 (kcal/24 h) p < 0.01, during the
      intervention period and body weight increased from 49.9 +/- 5.9 to 51.9 +/- 5.7
      kg (p < 0.005). Fat mass and lean body mass (bioelectrical impedance analysis,
      BIA) increased from 13.2 +/- 2.6 to 14.2 +/- 2.6 (p < 0.02) and from 36.9 +/- 3.2
      to 37.9 +/- 3.2 kg (p < 0.003), respectively. Plasma concentrations of albumin,
      total protein, transferrin, leptin IGF-I, IGFBP-3 and the protein catabolic rate
      remained unchanged. CONCLUSIONS: Supplementary intravenous intradialytic
      nutrition in chronic HD patients with malnutrition increased total body weight by
      effecting equivalent increases in lean body and fat masses.

PMID- 10599150
TI  - Indoor factors and their association to respiratory symptoms suggestive of asthma
      in Austrian children aged 6-9 years.
AB  - The ISAAC (International Study of Asthma and Allergy in Childhood) was founded in
      1990 in order to maximise the value of epidemiological research into asthma and
      allergic diseases, to describe the prevalence of asthma and allergic disease in
      children living in different locations, to make comparisons within and between
      countries, to provide a framework for further etiological research and to find
      prevention strategies. We analysed a sub-sample of a population-based study (1995
      to 1997) in Upper Austria. The aim of our study was to investigate the influence
      of indoor risk factors on wheezing in children 6-9 years old. Our calculations
      were based on the results of a questionnaire answered by parents about their
      children's indoor environment at home. Smoking of the mother during pregnancy
      and/or during breastfeeding (OR 1.28; 95% CI 1.08-1.48), smoking of the mother at
      the present time (OR 1.25; 95% CI 1.12-1.41), a bird (OR 1.40; 95% CI 1.06-1.85)
      or rabbit (OR 1.37; 95% CI 1.03-1.82) as a domestic pet, synthetic bedding (OR
      1.33; 95% CI 1.18-1.49) and dampness or mould at home (OR 1.43; 95% CI 1.24-1.65)
      are associated with a significantly increased risk of childhood wheezing in the
      last 12 months. Other variables such as "smoking of the father", "cooking with
      gas", "gas central heating" and other "pets" do not achieve statistical
      significance.

PMID- 10599151
TI  - Changes in the volume of residual pituitary adenomas in patients with adult-onset
      growth hormone deficiency during replacement therapy with the recombinant human
      growth hormone.
AB  - In the course of a prospective study concerning recombinant human growth hormone
      replacement therapy in adult-onset growth hormone deficiency, we determined the
      volumes of residual tumors in six patients with pituitary macroadenomas who had
      formerly been treated with surgery alone or surgery and external radiotherapy.
      Pituitary CT scans in direct coronal views were obtained at baseline, and at 6,
      12 and 18 months. The volumes of the residual tumors were calculated from the
      tumor diameters assuming that the tumors had an ellipsoid shape. Tumor volumes
      did not change in one patient and were reduced in two patients. In three
      patients, clinically non-significant tumor expansion by a median of 23.6 +/-
      13.2% (range, 21.1-62.0%) was noted after 12 to 18 months. This tumor expansion
      did not cause signs or symptoms of a mass effect and did not influence further
      treatment. One of the six patients discontinued treatment and no further change
      in tumor size, as determined by MRT, was noted over a mean follow up of 34
      months. Treatment was continued for up to 38 months in five patients. In four of
      these five patients no further change in tumor size was detected. However,
      treatment with the growth hormone was stopped in one patient since a 30%
      expansion in tumor volume, elevating the optic chiasm, was noted on MRT. None of
      the patients developed deterioration of visual fields. Interestingly, tumor
      invasion of the cavernous sinus had been present initially in all three who
      displayed tumor expansion while on rhGH. This first study in which diameters of
      residual pituitary adenomas in patients on growth hormone replacement therapy
      were prospectively and carefully measured, permits no conclusion regarding a
      causal relationship between growth hormone and tumor expansion, owing to the
      small number of patients. However, the observed incidence is not much different
      from that in former studies without growth hormone replacement therapy.
      Nevertheless, a close observation of the pituitary by imaging studies at regular
      intervals appears to be mandatory, particularly in patients with invasive
      residual adenomas.

PMID- 10599152
TI  - Hearing loss and tinnitus in acute acoustic trauma.
AB  - Despite extensive educational and protective measures, acute acoustic trauma
      continues to be a major problem in young military recruits. This retrospective
      study concern conscripts from eastern Austria who were referred to the Central
      Military Hospital for acute acoustic trauma (AAT) during the last 18 months. The
      study was designed to provide information on the profile of hearing loss and the
      presence of tinnitus after AAT. At the time when AAT occurred, hearing protection
      was not used in the majority of cases. In more than 75% of the ears hearing loss
      was registered in the high-frequency region (above 2 kHz). In the remaining 25%
      the speech frequency range under 2 kHz was also affected. Interestingly, the
      degree of hearing loss was independent of the type of firearm used, the number of
      shots and the use of hearing protection (ear plugs). Hearing loss occurred
      asymmetrically due to one-sided noise, whereas the distribution of tinnitus was
      symmetrical. The majority of patients experienced both, tinnitus and hearing loss
      as a consequence of AAT. Yet, in 6.2% of the subjects tinnitus was the only
      symptom. These results strongly suggest that tinnitus is as important a symptom
      of AAT as is hearing loss. Therefore, we believe that a tinnitus match should be
      performed in every patient with suspected AAT.

PMID- 10599153
TI  - [Partial left ventriculectomy (Batista-procedure) as an alternative to
      transplantation and as a rescue procedure].
AB  - Partial left ventriculectomy (Batista operation) is one of several surgical
      options for the treatment of end-stage heart disease. In a 17-year-old patient
      who could not be accepted as a candidate for heart transplantation, this
      procedure was performed as an acute rescue procedure in conjunction with
      reduction of the left ventricle, single-stitch reconstruction of the mitral valve
      and removal of a ventricular thrombus. Following temporary dependence on
      mechanical circulatory support the patient was transferred to his own country.
      The clinical experience is discussed, including aspects of the surgical
      technique, postoperative complications, indication, relevance of mitral
      reconstruction and rhythm problems. It is concluded that partial left
      ventriculectomy can be used to treat end-stage dilated cardiomyopathy, even as an
      emergency operation. Further studies and experience are needed to clarify the
      long-term effects and clinical limitations of the procedure.

PMID- 10599154
TI  - [Consensus guidelines for drug therapy of bronchial asthma in children and
      adolescents. Austrian Society of Pediatrics and Adolescent Medicine and Austrian
      Society for Lung Diseases and Tuberculosis].

PMID- 10599155
TI  - [Renaissance of diuretics in the treatment of hypertension].
AB  - Diuretics and beta-blockers are the only antihypertensives known for their
      significant reduction of cardiovascular morbidity and mortality, particularly in
      the elderly. The use of low-dose diuretics can improve the efficacy-safety ratio.
      Hypokalemia, hypomagnesemia as well as disturbances of carbohydrate and lipid
      metabolism are dose-dependent side effects of diuretics but only minimal during
      the low-dose therapy. A novel low-dose formulation of indapamide was developed as
      a sustained-release (SR) coated tablet (1.5 mg/day) and compared to the immediate
      release (IR) formulation of indapamide (2.5 mg/day). A > 50% reduction in the
      number of patients with serum potassium levels < 3.4 mmol/l among hypertensive
      patients treated with indapamide SR as compared to IR was observed. Indapamide SR
      has also been shown to be effective (more than 20 mg enalapril) in the reduction
      of left ventricular mass index (LVMI) in hypertensive patients treated for one
      year (LIVE study). Therefore, low-dose diuretics are, in accordance with
      international recommendations for the low-dose antihypertensive drugs, a first
      line therapy of hypertension.

PMID- 10599156
TI  - [The clinical classification and conceptual approaches to the treatment of the
      sequelae of craniocerebral trauma].
AB  - A clinical and morphological classification of the sequelae of craniocerebral
      injury is proposed, which identifies tissue, spinal fluid dynamic, and vascular
      forms of posttraumatic pathology. The paper shows the necessity of leading
      development of present-day conceptual approaches to treating the sequelae of
      craniocerebral injury by using research knowledge of their pathogenesis and new
      medical technologies. A hundred eighty one cases of chronic subdural hematomas
      were used as an example to show a role of conceptual approaches to expanding the
      field of applying minimum invasive surgery and to substantially improving the
      results of management.

PMID- 10599157
TI  - [New possibilities in the surgical treatment of lower thoracic and lumbar spinal
      injuries].
AB  - The paper presents new current approaches to surgically treating the lower
      thoracic and lumbar spinal injuries. By using new procedures for spinal
      stabilization, the authors propose algorithms for surgical treatment of spinal
      injuries in relation to the neurological symptomatology and the severity of
      fracture and its pattern. The study was performed in the clinical setting.
      Seventy patients with lower thoracic and lumbar spinal injuries were operated on.
      The outcomes of their surgical treatment are analyzed. Indications for nerve
      structural decompression, for approaches to vertebral bodies are defined.

PMID- 10599158
TI  - [The computed and magnetic resonance tomographic anatomy of the normal
      hippocampal area and in neurosurgical pathology].
AB  - To make a correct diagnosis, a volumetric presentation of the anatomy of
      perihippocampal fluid spaces (PHFS) may be useful if there are abnormalities in
      the medial portion of the temporal region. Pathological processes in the region
      result in changes in the normal anatomy of PHFS. Hippocampal atrophy accompanied
      by enlarged PHFS is a sign of Alzheimer's disease (1081 patients). These changes
      are best detected on frontal MR images, but they can be seen at routine CT study.
      Hydrocephalus (88 patients) is characterized by dilatation of the lower horn of
      the lateral ventricles without increased dimensions of the transverse fissure.
      Normotensive hydrocephalus and Alzheimer's disease may be differentiated in
      evaluating the PHFS. The understanding of the anatomy of PHFS is useful in making
      a better assessment of the degree of both intra- and extracerebral tumors (in 296
      patients) and arterioventricular malformations (in 12 patients) in the medial
      portions of the temporal regions.

PMID- 10599159
TI  - [Single-photon emission-computed tomography of the brain in craniopharyngiomas in
      the late postoperative period].
AB  - The paper analyzes tomographic scanning images of 32 patients with
      craniopharyngiomas in the late postoperative period. Computed tomographic data
      allowed the patients to be divided into 3 groups: 1) 10 patients without signs of
      tumor recurrence or hydrocephalus; 2) 14 patients with recurrent cystic
      craniopharyngiomas; 3) 8 patients with severe hydrocephalus. Single photon
      emission computed tomography (SPECT) of the brain indicated regional disturbances
      of brain tissue blood supply in the frontobasal or frontobasotemporal regions of
      the right hemisphere (the area of an surgical access and of the removed tumor)
      and revealed them in the distal areas (frontobasotemporal regions of the left
      hemisphere, parietal and occipital cortices of the cerebral hemisphere or
      cerebellar tissue). The compensatory reserves of cerebral circulation were
      assessed by the foci of relative physiological hyperemia of brain tissue (the
      cerebellum and the medial portions of the occipital regions of the brain). The
      findings provide evidence for that the vascular factor is involved in the late
      postoperative pathological picture in patients with craniopharyngiomas.

PMID- 10599160
TI  - [Visual evoked potentials and the P300 component in different courses of the
      posttraumatic vegetative state].
AB  - The late latency components of visual evoked potentials (VEP) and the component
      P300 AEP were analyzed to evaluate their informative value in the process of
      mental function restoration in patient after long-term traumatic coma. VEP
      components with latencies of 70 to 320 msec were studied in 24 patients.
      Topographical mapping of the power of the study VEP components and components
      P300 was made by the peak amplitude. Long-term VEP components and component P300
      were examined by the method of three-dimensional localization of equivalent
      dipole sources. In 16 patients with positive tendencies in the condition there
      was a stable localization of the maximum VEP power in the parietal, sagittal, and
      occipital regions, component P300 showed its maximum amplitude in the central and
      parietal regions in the left hemisphere. Eight patients with negative tendencies
      in the status had the maximum VEP and component P300 in the frontal and temporal
      regions, predominantly in the right hemisphere. The paper shows it important to
      evaluate not only time-amplitude parameters and analyzes the tomographic features
      of its formation in dynamics.

PMID- 10599161
TI  - [Changes in the nitrite level of the blood in patients in the acute period of a
      subarachnoid hemorrhage of aneurysmatic etiology].
AB  - Subarachnoidal hemorrhage leads to impaired endothelium-dependent relaxation by
      inhibiting the synthesis of major vascular relaxation agent nitric oxide (NO).
      Nitrite, a closest product of the oxidation of NO, is responsible for the
      synthesis of the latter. The Griss reaction was used for daily measurement of
      blood nitrite levels in 32 patients with acute subarachnoidal hemorrhage of
      aneurysmal etiology. There were upward and downward changes in nitrite levels as
      compared to the levels of healthy individuals (0.26 +/- 0.06 mu/ml): the levels
      of nitrite were 1.5-3 times higher than the normal levels in the first 2 days
      after hemorrhage and its concentration was the minimum (less than 0.16 mu/ml)
      when there was the greatest likelihood of development of vascular spasm. There
      was an association of dynamic changes in nitrite levels with the course of the
      disease. If vascular spasm was absent, the concentration of nitrite returned to
      the normal range at week 2 of hemorrhage. When there was significant and
      permanent vascular spasm frequently leading to death, the levels of nitrite was
      constantly below the normal range.

PMID- 10599163
TI  - [Endoscopic ventriculocisternostomy: methods and equipment].
AB  - The paper describes endoscopic ventriculocisternostomic techniques. It discusses
      the problems associated with the optimum configuration of equipment and tools, as
      well as with the basic principles of postoperative management of patients.
      Emphasis is laid on the engineering features and on the prevention of
      complications. The paper is based on 4-year experience gained in using this
      procedure at the Academician N. N. Burdenko Research Institute of Neurosurgery,
      Russian Academy of Medical Sciences, to treat over 60 patients with acquired
      occlusive hydrocephalus.

PMID- 10599162
TI  - [2 cases of deep arteriovenous malformations combined with aneurysms of the
      anterior ciliary artery].
AB  - The paper presents two cases of high-surgical-risk deep arteriovenous
      malformations (AVM) concurrent with aneurysms of the middle portion of the
      anterior ciliary artery (a male aged 35 years and a female aged 24 years). In the
      former case, aneurysm and large AVM in the left visual tuber were causes of 4
      hemorrhages. In the latter, AVM of subcortical nodes and internal capsule were
      responsible for single hemorrhage. The patients underwent intraoperative
      embolization of the anterior ciliary artery followed by its clipping. This
      allowed the authors to exclude aneurysm and to achieve obliteration of the bulk
      of AVM. Operation were performed under intraoperative guidance of motor and
      speech functions. Residual AVM were exposed to proton beam radiation. The
      outcomes of treatment were good. After 4 months of surgery, the male had no
      neurological disorders; in the female motor and speech disorders were associated
      with prior hemorrhage.

PMID- 10599164
TI  - [The use of transcranial magnetic stimulation in medicine].

PMID- 10599165
TI  - Great expectations.

PMID- 10599166
TI  - The seal slighted?

PMID- 10599168
TI  - Extraction vs. nonextraction.

PMID- 10599167
TI  - Rheumatoid arthritis and children.

PMID- 10599169
TI  - Extracting premolars.

PMID- 10599170
TI  - Herbals may interact with anesthesia.

PMID- 10599171
TI  - New treatment for osseous defects available.

PMID- 10599172
TI  - Changing treatment patterns.
AB  - BACKGROUND AND OVERVIEW: Patterns of clinical care are closely linked to the
      nature of diseases in the population. During the past decade, the nature of both
      dental caries and periodontitis has undergone a transformation that has
      implications for dental practice. Especially in younger cohorts, the overall need
      for extensive restorative and periodontal treatment is much reduced, compared
      with that of prior generations. CONCLUSIONS: Over the next several decades, there
      will be a slowly declining per-capita need for restorative and surgical care. The
      overall mix of services will continue to shift toward diagnostic and preventive
      services. PRACTICE IMPLICATIONS: At least in terms of today's conventional dental
      care, each provider in the future should be able to manage the oral health care
      needs of larger numbers of patients than is possible today.

PMID- 10599173
TI  - Digital dentistry in the computer age.
AB  - BACKGROUND AND OVERVIEW: Computers are becoming an integral part of the practice
      of dentistry. Smaller, smarter and more ergonomic computing devices will support
      an increasing proportion of dental practice activities. Technology will make
      practice management more efficient, mainly by reducing transactional overhead.
      Educational software and intelligent assistants will increasingly support the
      needs for decision making in clinical practice. Research will benefit from
      automated tools for data acquisition, management and analysis. CONCLUSIONS:
      Dentistry must actively shape the application of technology. It can do this by
      developing a cadre of experts in dental informatics, relying on sound research
      principles, effectively disseminating best practices and developing strategic
      objectives for the implementation of technology. CLINICAL IMPLICATIONS: Computer
      technology is an essential ingredient for state-of-the-art patient care. Dentists
      must stay current with this rapidly developing field to make appropriate choices
      in their use of technology.

PMID- 10599174
TI  - Dental insurance, managed care and traditional practice.
AB  - BACKGROUND AND OVERVIEW: The author examined the impact of trends in commercial
      insurance plans and their managed care products on the traditional fee-for
      service solo or partnership model of dental practice. CONCLUSION: In response to
      rising dental expenditures, employers are passing on more costs of dental
      insurance to employees, dropping dental benefits altogether and moving from
      indemnity to managed care plans, mainly preferred provider organizations. These
      trends are likely to continue, resulting in fewer people with employer-based
      dental insurance coverage. PRACTICE IMPLICATIONS: These changes in dental
      insurance coverage are unlikely to challenge the traditional model of dental
      practice within the next five years, largely because of the growing decline in
      the supply of dental services and a lack of local market concentration of dental
      managed care companies.

PMID- 10599175
TI  - Building on our accomplishments.
AB  - BACKGROUND AND OVERVIEW: There are at least five forces--knowledge, finances,
      diversity, faculty and government--that have the potential to change the current
      model of dental education significantly in the new century. The author explores
      these forces and attempts to project their future impact on dental education and
      the profession. CONCLUSIONS: Our understanding of the etiology and pathogenesis
      of oral diseases will increase, though likely not enough to facilitate the
      elimination of either dental caries or adult-onset periodontitis. A mandatory
      year of additional formal education in the form of a postgraduate residency will
      become necessary. Current trends in the sources of revenue supporting dental
      education will continue, and dental education will face a financial crisis. The
      changing ethnic and racial diversity of the United States and the dental work
      force will require curricular changes to prepare students to meet the oral health
      needs of diverse populations. The current shortage of full-time dental faculty
      members will continue, and dental schools will need to redefine what it means to
      be a faculty member. Finally, the continuing decline in the dentist:population
      ratio and a peak in the actual number of active dentists will cause government to
      again question the adequacy of the dental work force. PRACTICE IMPLICATIONS:
      Academic dentistry faces a new century with new challenges, all of which have
      implications for current and future dental practitioners. The extent to which
      these challenges are successfully met will depend on the degree to which those
      with a vested interest in a thriving profession come together for the mutual
      benefit of all.

PMID- 10599176
TI  - How the licensure process will evolve.
AB  - BACKGROUND AND OVERVIEW: All aspects of dental licensure are continuing to
      evolve. This article describes the changes that are occurring in the licensure
      process and projects the direction and magnitude of future changes. CONCLUSIONS:
      The author predicts that national board examinations will continue to move away
      from recall of facts and toward assessment of basic science and clinical
      principles as they apply to clinical decision making and delivery of care.
      Clinical examinations will continue their evolution to become even more reliable
      and valid. Licensure by credentials will be adopted by more states, thus
      addressing concerns about mobility that are expressed by many practitioners.
      PRACTICE IMPLICATIONS: Despite all of this projected progress, the dental
      profession should expect elevated public pressure for greater accountability
      unless it takes a proactive position to ensure the continued competency of all
      practitioners.

PMID- 10599177
TI  - Trends in the dental health work force.
AB  - BACKGROUND AND OVERVIEW: Using data from various American Dental Association
      projects (Distribution of Dentists Survey, the Survey of Dental Practice, the
      Dental Workforce Model, and the Survey of Predoctoral Dental Educational
      Institutions), the authors analyzed trends and projections for the dental work
      force. The article presents work-force projections overall and by sex, when
      available, through the first 20 years of the 21st century. The number of women
      practicing dentistry has been increasing rapidly, while the increase in the
      number of male dentists has been more modest. In the future, the number of female
      dentists is projected to increase while the number of male dentists is projected
      to decrease. CONCLUSIONS: Estimates based on the ADA census data place the
      overall growth in the number of active private practitioners at 19.1 percent
      between 1982 and 1997. This growth signifies a substantial expansion of capacity
      to produce dental services in the United States. Growth will be slower in the
      future. PRACTICE IMPLICATIONS: Changes in the dental work-force capacity and
      demographic distributions merit careful monitoring and analysis, because they no
      doubt will determine the dental profession's future ability to deliver needed
      dental services and influence practitioners level of busyness.

PMID- 10599178
TI  - Minimizing patients' exposure to uncured components in a dental sealant.
AB  - BACKGROUND: The authors conducted research to examine the effectiveness of six
      surface treatments in reducing the oxygen-inhibited layer of a commercially
      available, freshly polymerized, light-cured unfilled dental sealant. METHODS:
      Surface treatments of a light-cured sealant (Delton Light Curing Pit & Fissure
      Sealant, Dentsply Ash) included no treatment (the control treatment), a 20-second
      exposure to an air/water syringe spray, 20 seconds' manual application of a wet
      or dry cotton roll, 20 seconds' manual application of pumice with a cotton
      pellet, and 20 seconds' application of a water/pumice slurry using a prophy cup
      on a slow-speed handpiece. The authors used high-pressure liquid chromatography
      to analyze the amount of monomers--bisphenol A glycidyl dimethacrylate, or Bis
      GMA; triethylene glycol dimethacrylate, or TEGDMA; and bisphenol A
      dimethacrylate, or Bis-DMA--remaining after each treatment. RESULTS: A one-way
      analysis of variance indicated that use of only an air/water spray removed the
      least (P = .0001) amount of all monomers (only 68.3 percent of the control
      value). Application of wet or dry cotton reduced equivalent amounts of monomers
      (86.1 to 88.9 percent of the control value), and the amount of monomer remaining
      was less than that for the air/water syringe treatment (P = .0001). The use of
      pumice on either a cotton ball or in a prophy cup achieved the greatest reduction
      (P = .0001) in total amount of residual monomer (92.9 to 95.3 percent of the
      control value). CONCLUSIONS: Treatment that used pumice eliminated the greatest
      amount (from 93 percent to 95 percent of the untreated control values) of any
      type of residual monomer. A slurry of pumice is significantly more effective in
      removing the oxygen-inhibited layer from freshly cured sealants than either an
      air/water spray or wet or dry cotton alone. CLINICAL IMPLICATIONS: Clinicians can
      most effectively reduce patients' exposure to the uncured components in the
      oxygen-inhibited layer of sealants by using a mild abrasive, such as pumice,
      either on a cotton applicator or in a prophy cup.

PMID- 10599179
TI  - Depressed taste and smell in geriatric patients.
AB  - BACKGROUND: Geriatric patients have a number of dental care problems that younger
      patients do not encounter. The oral changes associated with aging can have a
      significant effect on the efficacy of dental treatment. TYPES OF STUDIES
      REVIEWED: The authors reviewed studies dealing with the causes of depressed sense
      of taste and smell; the causes included aging, disease, medications and dental
      problems. Based on their findings, the authors described the location and anatomy
      of taste buds and receptor cells for smell and explored appetite, saliva, food
      seasonings, nutrition and dietary recommendations. They also discussed the
      relationship of smoking and tongue cleaning to taste sensations. RESULTS: The
      authors found that considerable differences exist between elderly people and
      young people in regards to sensory perception and pleasantness of food flavors.
      Salt and bitter taste acuity declines with age, but sweet and sour perceptivity
      does not. Olfactory acuity also declines with age. The authors found that most of
      the studies reviewed suggested that the sense of smell is more impaired by aging
      compared with the sense of taste. Smoking diminishes the taste of food and makes
      flavorful foods taste flat, while tongue brushing can increase taste sensation
      for geriatric patients. CLINICAL IMPLICATIONS: Food can become tasteless and
      unappetizing for geriatric patients as the result of declining taste and smell
      perception. Geriatric patients should be encouraged to add seasonings to their
      food instead of relying on excessive consumption of salt and sugar to give their
      food flavor. Adequate nutrition, tongue cleaning and smoking cessation are
      recommended for geriatric dental patients.

PMID- 10599180
TI  - Immediate placement of implants in extraction sites of maxillary impacted
      canines.
AB  - BACKGROUND: Treatment of asymptomatic impacted maxillary canines in adults is
      inevitable when primary canine becomes lost through extraction or exfoliation or
      when the impacted tooth becomes symptomatic. Treatment alternatives include an
      orthodontic procedure to bring the unerupted tooth to the dental arch or
      prosthetic replacement of the missing tooth. The authors describe an alternative
      treatment that involves immediate placement of implants into extraction sockets
      of the teeth. CASE DESCRIPTION: A patient with bilateral palatally impacted upper
      canines chose to have the unerupted teeth removed and replaced with implants and
      crowns. Two hydroxyapatite cylindrical implants were inserted through the
      alveolar ridge into the extraction sites. The unfilled areas in the extraction
      sites, around the dental implants, were packed and covered with demineralized
      freeze-dried bone allograft in conjunction with a collagen membrane barrier. Six
      months after implantation, computed tomography revealed complete osseous fill of
      the extraction defects and no bone loss around the implants. The implants were
      uncovered, and porcelain-fused-to-metal restorations were fabricated and placed.
      CLINICAL IMPLICATIONS: This treatment modality avoids the need for conventional
      preparation of teeth as part of prosthetic reconstruction or prolonged
      orthodontic treatment aimed at bringing the impacted canine to the dental arch.
      Combining the implantation with bone augmentation preserved the alveolar bone and
      shortened the treatment period.

PMID- 10599181
TI  - Placing directly formed Class V composite inlays.

PMID- 10599182
TI  - Effect of beta-adrenoreceptor blockade with nadolol on the duration of local
      anesthesia.
AB  - BACKGROUND: beta-adrenoreceptor blockers, or beta-blockers, are drugs commonly
      prescribed for hypertension, angina and migraine headaches. In a patient taking
      beta-blocker medication, administration of a local anesthetic containing a
      vasoconstrictor could result in an adverse interaction. METHODS: The authors
      conducted a double-blind, randomized, crossover, placebo-controlled study to test
      the hypothesis that a nonselective beta-blocker--nadolol--enhances
      vasoconstriction induced by the epinephrine contained in local anesthetic, thus
      resulting in an increased duration of anesthesia. Ten healthy male volunteers
      were given either a placebo or a single, standard oral dose of nadolol (80
      milligrams). The upper lateral incisor teeth were anesthetized using lidocaine
      with or without epinephrine. RESULTS: The mean duration of pulpal and soft-tissue
      anesthesia was increased in subjects who took nadolol compared with those who
      took placebo by 17 minutes (58 percent) and 16.5 minutes (19 percent),
      respectively, when they received 1 milliliter of lidocaine containing 1:100,000
      epinephrine. These differences were both clinically and statistically significant
      (P = .007). Using lidocaine without epinephrine produced no clinically or
      statistically significant difference in duration of pulpal or soft-tissue
      anesthesia in the two groups of subjects. The authors noted no significant
      changes in blood pressure or pulse rate. CONCLUSIONS: Administration of local
      anesthetic containing epinephrine to subjects receiving a beta-blocker increased
      the duration of pulpal and soft-tissue anesthesia. There was no difference in
      duration of anesthesia between groups when local anesthetic without epinephrine
      was used. CLINICAL IMPLICATIONS: Use of local anesthetic containing a
      vasoconstrictor should be avoided in patients taking beta-blocker medication
      because of a possible adverse drug interaction. However, when a vasoconstrictor
      is indicated for hemostasis, the local anesthetic should be administered slowly
      and in small amounts as pulse rate and blood pressure are being monitored. The
      patient should be informed that the duration of anesthesia might be prolonged.

PMID- 10599183
TI  - Educating dental staff members for optimum patient service.

PMID- 10599184
TI  - Streptococcus mutans, early childhood caries and new opportunities.

PMID- 10599185
TI  - Reporting abuse and neglect.

PMID- 10599186
TI  - Will the changing face of HIV/AIDS affect the Ryan White CARE Act reauthorization
      vote?

PMID- 10599187
TI  - Geographic variation in cardiovascular disease mortality in US blacks and whites.
AB  - Cardiovascular disease mortality rates have dropped significantly over the past
      several decades, but a shift has occurred over time in the geographic patterns of
      both coronary heart disease (CHD) and stroke mortality. This article describes
      these patterns and discusses how they vary by sex, race, age, and over time.
      Death certificate information for Health Service Areas (HSAs) in 1988-1992 was
      used to analyze the geographic patterns of CHD and stroke death rates by race,
      sex, and age. Changes in these patterns from 1979-1993 also were examined. In
      1988-1992, considerable geographic variation in both CHD and stroke mortality was
      demonstrated for each sex and race group. Coronary heart disease rates were
      particularly high in the lower Mississippi valley and Oklahoma for all four
      groups, in the Ohio River valley and New York for whites, and to a lesser extent
      for blacks. Areas of high rates among whites in the Carolinas resemble stroke
      mortality patterns. There were greater differences by racial group than by
      gender, by the definition of heart disease. Over time, rates have declined for
      both CHD and stroke, but regional differences in the rates of change give the
      appearance of a southwesternly movement of high heart disease rate clusters and a
      breakup of the "Stroke Belt." Further research is needed to elucidate the cause
      of regional variation in CHD and stroke mortality. Similar geographic patterns of
      high rates of CHD and stroke in the southeastern United States may reflect common
      risk factors. This knowledge can be used to help develop appropriate
      interventions to target these high-rate areas in the Mississippi and Ohio River
      valleys.

PMID- 10599190
TI  - Imbalance diet: a risk factor for thyroid cancer.

PMID- 10599188
TI  - Prevention of youth injuries.
AB  - There are four categories of causes responsible for the majority of injuries in
      youth 10-19 years of age: 1) motor vehicle traffic; 2) violence (intra-familial,
      extra-familial, self, pregnancy-related); 3) recreational; and 4) occupational.
      This article presents data from the National Center for Health Statistics
      mortality data and the National Pediatric Trauma Registry morbidity data.
      Nationwide, the pediatric injury death rate is highest among adolescents 15-19
      years of age. Motor vehicle-related deaths account for 41% and firearm-related
      deaths account for 36% of injury deaths in this age group. For youths aged 10-14
      years, motor vehicle-related deaths account for 38% and; firearm-related deaths
      account for 26% of injury deaths. For both age groups, occupant motor vehicle
      related deaths account for the majority of deaths and underscore the need for
      seat belt use. Using theoretical principles based on the Haddon matrix and a
      knowledge of adolescent development, proposed interventions to decrease injuries
      and deaths related to motor vehicles and firearms include graduated licensing,
      occupant restraint, speed limits, conflict resolution, and gun control.
      Occupational injuries, particularly injury associated with agricultural
      production, account for an estimated 100,000 injuries per year. Preventive
      strategies include OSHA regulations imposing standards for protective devices and
      further study for guidelines for adolescent work in agriculture. Injuries related
      to recreation include drowning and sports injuries. Preventive strategies may
      include proper supervision and risk reduction with respect to use of
      alcohol/drugs. The data presented support the use of primary prevention to
      achieve the most effective, safe community interventions targeting adolescents.

PMID- 10599189
TI  - A model for offering an International Medicine Seminar Course for US medical
      students: the 13-year experience of the New Jersey Medical School.
AB  - An International Medicine Elective Seminar Course at the New Jersey Medical
      School (NJMS) was designed in 1985 to present a description of medical education,
      medical care systems, major global health problems, and intervention programs in
      other countries. Seminars are scheduled for nine weeks in the fall semester. At
      the end of each course, the medical students complete evaluations. Almost all
      (97%) students in 1997-1998 evaluated the course as either good (55%) or
      excellent (45%). Enrollment in the International Medicine Seminar Course
      increased from 12 medical students in 1985-1986 to 62 students in 1997-1998. An
      increasing number of students have applied for a fourth-year overseas
      International Medicine Elective. This and students' evaluations indicated that
      they have been motivated toward international medicine. The atmosphere of
      informal seminars and faculty interaction with students has characterized the
      course. It has made this model of teaching an ideal forum for medical students'
      professional growth. This course offers students the opportunity and insight to
      explore facets of their professional role not explicitly covered in the formal
      medical curriculum. The International Medicine Seminar Course is a self-supported
      model and can be adopted readily by other medical schools.

PMID- 10599191
TI  - Morphological pattern and frequency of thyroid tumors.
AB  - OBJECTIVE: The present study was done to evaluate the frequency of thyroid cancer
      and to find out the prevalence of histological types of thyroid tumor with
      respect to age and sex group. SETTING: This study included consecutive cases of
      malignant tumors of thyroid gland, which were diagnosed in the Department of
      Pathology at the Aga Khan University Hospital, Karachi during the period of three
      years (1995-1997). METHODS: These cases were evaluated on H & E stained sections
      from paraffin embedded 10% buffered formalin fixed tissue blocks. Special stains
      and immunohistochemical analysis were performed whenever required. RESULTS: A
      total of 8541 malignant tumors were diagnosed in a period of 3 years which
      included 103 (1.2%) cases of thyroid cancer. Thyroid tumors were more prevalent
      in females with female to male ratio of 2.6:1. Papillary carcinoma (69%) was the
      most common histological type of thyroid tumors, followed by follicular carcinoma
      (11.6%), medullary carcinoma (9.7%), anaplastic carcinoma (5.9%), non-Hodgkin's
      lymphoma (2.9%) and unclassified tumors (0.9%) in order of frequency. CONCLUSION:
      Thyroid cancer was more common in females. Papillary carcinoma was the most
      common histological type of thyroid tumors in females as well as in males.
      Papillary carcinoma was more prevalent in third, fourth and fifth decades of life
      while follicular and anaplastic carcinomas were more frequent after the fourth
      decade of life.

PMID- 10599192
TI  - Fine needle aspiration cytology (FNAC) in the management of thyroid pathology-
      the Aga Khan University Hospital experience.
AB  - OBJECTIVE: To report the efficacy of FNAC in patients with thyroid disease.
      METHODS: Between January 1990 and December 1994 the records of all patients
      treated surgically for thyroid disease at ENT Head and Neck Surgery of Aga Khan
      University were reviewed. All the patients had pre-operative FNAC as the first
      line of evaluation and the histopathologist examined post-operative thyroid
      specimen. RESULTS: Forty-five patients (36 female and 9 male) had thyroid
      surgery. In 26 patients out of 45, FNAC was conclusive in diagnosing the nature
      of disease, while in 19 patients the FNAC was inconclusive because of the
      presence of follicular cell neoplasia. CONCLUSION: Our results indicate that the
      FNAC is very accurate and a reliable test in the diagnosis of thyroid pathology,
      however, to distinguish follicular adenoma from follicular carcinoma final
      histology is required. FNAC is cost effective method of evaluating thyroid
      pathology pre-operatively and plays a vital role in planning the surgical
      management of thyroid nodule.

PMID- 10599193
TI  - Results of faculty evaluation at the Aga Khan University, Karachi, Pakistan.
AB  - OBJECTIVE: The aim of the retrospective correlational analysis was to identify
      the attributes valued most by students for assessing the overall effectiveness of
      a teacher. METHODS: Responses of the students to the two versions of evaluation
      questionnaires, each attempting to assess 4 and 8 characteristics respectively on
      a scale of 1-5 were included in the analysis. The third and fourth year students,
      at the end of each course/module completed a total of 2110 evaluation forms,
      which were studied. RESULTS: The over all effectiveness of the teacher showed
      statistically significant correlation of .914 and .895 with ability to
      communicate ideas effectively and clarity and organisation of the lectures.
      Whereas the knowledge of subject and the successful use of teaching aids showed a
      correlation of .658 and .637 with a statistical significance of P < .01.
      CONCLUSION: Students need a basic outline of what they have to learn and guidance
      to plan their studies.

PMID- 10599194
TI  - Views about women's mental health: study in a squatter settlement of Karachi.
AB  - OBJECTIVE: Mental health of women is globally receiving particular attention.
      This study assessed community's view on certain aspects of women's mental health
      prior to introducing an intervention. SETTING: The study was conducted in an
      urban squatter settlement located in District West of Karachi in 1997 where the
      Aga Khan University has set up a Primary Health Care program in partnership with
      the communities. METHODS: Using convenient sampling, door to door household
      survey was conducted by medical students. RESULTS: Two hundred and eighty one
      residents were interviewed. Respondents were asked to list contributory factors
      which lead to mental distress in women. Two hundred and ten (75%) were able to
      list certain factors. The factors listed were; low family income (40%), dispute
      amongst spouses (30%), verbal abuse by in-laws (25%) and too many children (5%).
      When asked what women in the community did while they were mentally distressed
      35% respondents reported that women talked to their husbands and 18% said
      counselling from a health provider was sought. Main channels of social support
      desired were; revenue generation (67%), membership of a women's group (11%) and
      training of local community women in counselling skills (10%). CONCLUSION: Signs
      of awareness about mental health issues are present even in marginalized
      communities of Pakistan. In order to improve the mental health of women
      interventions should primarily focus on raising family income.

PMID- 10599196
TI  - Insular thyroid carcinoma. A case report with fine needle aspiration cytology.

PMID- 10599195
TI  - H. pylori IgG antibodies in children.
AB  - OBJECTIVE: The aim of the study was to see the exposure rate to H. Pylori (IgG)
      in apparently healthy children. METHODS: Serum samples of 100 apparently healthy
      children aged 6 months to 10 years were screened for IgG antibodies against H.
      pylori using Abbott's flexpack kit. Children were divided into two groups, group
      I included aged 6 months to less than 5 years and group II aged 5-10 years.
      RESULTS: Of 60 children in group I, 17 (28.3%) showed antibodies against H.
      Pylori indicating exposure. The exposure rate was 12.5% between 6 months to 11
      months, 28.5% in 12 months to 23 months and 38% in 24-36 months. Exposure rate
      increased with lowering of socioeconomic status; being 13.3% in upper, 26.9% in
      middle and 42.1% in lower socioeconomic group. Of 40 children aged 5 years to 10
      years, 16 (40%) showed H. Pylori antibodies. The exposure rate was 34.3% at years
      and increased to 62.5% in those aged 8-10 years. The H. pylori positivity was
      33.3% in upper and middle socioeconomic group and 62.5% in lower socioeconomic
      group. Over all exposure rate to H. Pylori in children was 33%. CONCLUSIONS: H.
      pylori exposure rate increased with the advancement of age and lowering of
      socioeconomic status. Early exposure might be related to the use of premasticated
      food by the mothers for feeding of children; dental plaque being the reservoir of
      infection in adults.

PMID- 10599197
TI  - Aspergillosis of the sphenoid sinus with the involvement of the clivus.

PMID- 10599198
TI  - Orelox (cefodoxime) in typhoid fever.
AB  - OBJECTIVE: To study the efficacy of Orelox (Cefodoxime) in Typhoid fever in
      children. SETTINGS: Open, non-comparative, multicentre study carried out in GP
      settings in various cities of Pakistan. PATIENTS: Children aged 1-15 years were
      included in the study. Positive Widal test was the only diagnostic inclusion
      criteria. RESULTS: Four centers participated in the study. Of the total 77
      patients (51 males and 26 females), 61 (79%) cured, 5 (7%) improved (less severe
      signs and symptoms) and 11 (14%) failures. CONCLUSION: Treatment of typhoid fever
      in this study showed 86% efficacy in producing clinical responses suggesting that
      this drug can be effectively and safely used in the treatment of typhoid fever in
      children.

PMID- 10599200
TI  - Medicine and information technology.

PMID- 10599199
TI  - Q wave and non-Q wave myocardial infarction: a multivariate analysis of survival
      experience and clinical outcome after first diagnosis at a tertiary care
      hospital.
AB  - INTRODUCTION: Myocardial infarction (MI) is a well-recognized clinical entity
      with a worldwide distribution. In the United States alone, 1.5 million cases of
      MI occur per year. This study compares the in-hospital mortality, 1 year
      mortality and time to death following a first Q-wave or non Q-wave myocardial
      infarction (MI). METHODS: One thousand five hundred and ninety-six patients were
      admitted at the Aga Khan University Hospital with a diagnosis of MI over a period
      of four years of whom 420 patients met our inclusion criteria. Data was collected
      from the patients' medical records and on telephone using a pretested
      questionnaire. Logistic regression and Cox proportional hazard models were used
      to analyze the data. RESULTS: The mean age +/- sd of the patients was 59 +/- 10
      years. Of the total patients, 151(36%) and 269(64%) suffered non-Q wave and Q
      wave MI respectively. A higher in hospital mortality was observed in patients
      with Q-wave MI (n = 64, 23.8%) than those with non-Q wave MI [n = 16 (10.6%);
      adjusted OR = 2.76, 95% CI: 1.5-5.01]. Similarly, patients having Q-wave MI
      experienced increased 1 year mortality (n = 77, 28.6%) compared to patients
      suffering non-Q wave MI [n = 26 (17.2%); adjusted OR = 2.04, 95% CI: 1.21-3.43].
      CONCLUSION: Patients with Q-wave MI had a worse prognosis compared with patients
      with non-Q-wave MI and therefore warrant a closer follow up. Further prospective
      studies are needed to evaluate the efficacy of early aggressive interventions in
      modifying the natural history of this disease.

PMID- 10599201
TI  - The pattern of malignancies in Karachi (1995 to 1996).
AB  - OBJECTIVE: To determine the cancer pattern of the city of Karachi for the years
      1995-1996. METHODS: The Karachi Cancer Registry, established in 1995 by the
      Government of Sindh, in collaboration with the IARC is an active registry. The
      staff collect the data pertaining to cancer patients and record it on the
      registry forms. Hospitals in Karachi, district south as well as some of the
      hospitals in other districts of the city, where patients are likely to go for
      treatment or diagnosis are visited. People residing in the district for more than
      six months prior to the onset of the malignancy were considered "residents". All
      the cases diagnosed on or after 1st January 1995 till 31st December 1996 were
      considered for analysis. RESULTS: In the years 1995-96, the most common cancer
      sites among males were cancers of the lung, oral cavity and lymph nodes. For
      females, breast cancer ranked first, followed by cancer of the oral cavity and
      ovary. The age standardized rate for all cancers was 96.3 per 100,000 in males
      and 96.9 per 100,000 in females. At this early stage of registration we assume
      that the registry has a missing rate of approximately 20-25%. CONCLUSION: The
      pattern of malignancies in Karachi is similar to the western countries, with lung
      and breast being the commonest tumors amongst the males and females respectively.
      The Asian countries have stomach/lung/oral cavity/liver as the commonest tumors
      amongst the males and cervix/breast amongst the females. Pakistan being a Muslim
      country, the incidence of cervical cancer showed an expected low figure.

PMID- 10599202
TI  - Awareness of sexually transmitted diseases in a selected sample in Karachi.
AB  - INTRODUCTION: Sexually Transmitted Diseases (STDs) are a major public health
      problem in developing countries (Adler, 1996). The purpose of this study was to
      asses women's knowledge level about STDs. METHODOLOGY: A cross sectional survey
      was done and data collected through a semi-structured interview. A convenient
      sample of 30 sexually active females between the ages of 15-45 years from an
      urban community in Karachi was selected for the study. RESULTS: The survey
      findings showed that 30% of the women reported that they had adequate knowledge
      and 20% partial knowledge. Thus almost three-quarters of the respondents
      indicated either inadequacy or lack of knowledge about STDs. CONCLUSION: Our
      results establish a need for STD clinics at Community-based Primary Health Care
      (PHC) Centers. These clinics need to address screening, treatment and health
      education issues in relation to STDs for the target population.

PMID- 10599203
TI  - Extensor mechanism sparing approach to the elbow for reduction and internal
      fixation of intercondylar fracture of the humerus.
AB  - OBJECTIVE: To evaluate the short term results of extensor mechanism sparing
      approach to the elbow for fixation of intercondylar fractures of the distal end
      of humerus and compare it with existing Surgical approaches. DESIGN: This is a
      prospective study conducted from June, 1992 to June, 1997. SETTING: Department of
      Orthopaedic Surgery, Jinnah Postgraduate Medical Centre and Mehran Clinic (Pvt.),
      Karachi. PRINCIPLE OF SURGICAL APPROACH: This approach is based upon the
      principle that by sparing the extensor mechanism, we reduce the amount of
      surgical trauma and help in early rehabilitation which can contribute in
      improving the results of this difficult fracture. RESULTS: There were nine type 2
      fractures, eight type 3 fractures and four type 4 fractures according to Rise
      borough and Radin classification. Based upon the same authors criteria, there
      were over all 57.14% good 23.81% fair and 19.04% poor results. Adequate exposure
      was achieved in all of type 2 and seven (87.5%) out of eight type 3 fractures. We
      failed in type 4 fractures. Mean operating time was 107.38 (+/- 24.67) minutes.
      CONCLUSION: The results in this series are comparable to other studies. They can
      however be improved with proper selection of cases, experience with the technique
      along with better fixation and rehabilitations.

PMID- 10599204
TI  - Sublingual human insulin for hyperglycaemia in type I diabetes.
AB  - OBJECTIVE: To investigate the hypoglycaemic effects of repeated sublingual doses
      of human insulin for the treatment of hyperglycaemia in type I diabetes. DESIGN:
      Clinical trial. SETTING: A Private clinic. METHOD: Eight insulin dependent
      diabetic males with a mean age of 27 years (range 18-32 years) presenting with
      hyperglycaemia were given 1 U/Kg body weight of human soluble insulin in 5
      equally divided doses at 15 min intervals, sublingually. Plasma glucose was
      estimated at 0, 15, 30, 45, 60, 90, 120 and 150 min. Urine examination for
      glucose was done at 45 min intervals. RESULTS: The results showed that the mean
      plasma glucose before treatment was 19.93 + 2.1 mmol/L Hypoglycaemic effect was
      recorded at 15 min and reached a peak at 120 min when plasma glucose dropped to
      10.9 + 1.2 mmol/L (p < 0.001). No side effect was reported and insulin was
      tolerated well. CONCLUSION: We concluded that sublingual human insulin in
      repeated doses has a hypoglycaemic effect and could be used to control
      hyperglycaemia in type I diabetes.

PMID- 10599205
TI  - Prevalent nosocomial gram negative aerobic bacilli and their antimicrobial
      susceptibility pattern in intensive care unit.
AB  - OBJECTIVE: To determine the type of prevalent aerobic gram-negative bacilli and
      their sensitivity pattern among nosocomial isolates. DESIGN: Prospective
      collection of clinically significant nosocomial gram negative bacilli. SETTING:
      Tertiary care hospital in Karachi. METHOD: One hundred isolates were identified
      by standard methods and minimum inhibitory concentration was checked by
      epsilometer test. RESULTS: The most frequent isolates were Eschericia coli (43%)
      followed by Klebsiella pneumoniae (18%) Acinetobacter spp. (7%) Enterobacter spp.
      (7%) and Klebsiella spp. other than pneumoniae (7%). Most of the isolates of
      dominant species (E. coli and Klebsiella pneumoniae) were multiresistant
      including third generation cephalosporins. CONCLUSION: This study indicates that
      most effective antibiotics imipenem and amikacin inhibited most of the isolates.
      Imipenem alone or amikacin in combination with one broad spectrum beta-lactam
      drug should be used in initial empiric therapy in any life threatening nosocomial
      infection.

PMID- 10599206
TI  - Aplastic anemia associated with pregnancy.

PMID- 10599207
TI  - Myelofibrosis in severe vitamin D deficiency rickets.

PMID- 10599208
TI  - Syndrome X and family practitioners.
AB  - BACKGROUND: Increased incidence of hypertension, non-insulin dependent diabetes
      (NIDDM) and coronary heart disease often cluster in the same individuals and
      there have been speculations that a common mechanism may be responsible for all
      of these pathological conditions. This risk factor constellation, which is
      associated with an enhanced risk for cardiovascular disease, is sometimes
      referred to as the "Insulin Resistance Syndrome", "Syndrome X", or the "Metabolic
      Syndrome". AIM: To find out the prevalence of Syndrome X in the population of
      patients coming to a preventive health check clinic at a tertiary care teaching
      hospital in a megacity of the developing world. METHODS: A total of 270 patients,
      above the age of 40 years, who attended preventive health check clinics of 2
      Family Physicians at the Aga Khan University from January 1996 to July 1997 were
      selected. Patients below 40 years were excluded from the study. RESULTS: The
      prevalence of Syndrome X, defined as association of obesity, NIDDM, hypertension,
      raised LDL and raised triglycerides is 2.6% in patients above 40 years, who were
      screened in this study. CONCLUSION: The significant prevalence of Syndrome X is
      alarming and we need to strengthen our existing educational programs for
      prevention of obesity, increased physical activity and better control of
      hypertension. When drugs are selected for pharmacological treatment, priority
      should be given to those, which improve the insulin sensitivity index or are at
      least neutral in this respect.

PMID- 10599209
TI  - "A little extra..".

PMID- 10599210
TI  - [Cross-contamination of Mycobacterium tuberculosis culture in clinical
      laboratories].
AB  - For many years, it has been thought that positive culture of M. tuberculosis is a
      definitive diagnostic evidence of tuberculosis and cross-contamination of M.
      tuberculosis culture in clinical laboratories is rare. However recently
      introduced RFLP analysis has enabled us to identify a strain of M. tuberculosis,
      and many cases of the cross-contamination in clinical laboratories confirmed by
      RFLP analysis have been reported. In this report, we present the first case of
      the cross-contamination confirmed by RFLP in Japan. In our case, 5 patients
      without any personal link to each other were suspected based on clinical findings
      to have cross-contaminated results of M. tuberculosis culture. All their
      specimens were processed on the same day, and were smear negative and culture
      positive with only a small number of colonies (less than 8 colonies). The sputum
      from the suspected source of contamination processed on the same day was strongly
      positive for AFB smear and heavily culture positive. The RFLP patterns of these 6
      patients were identical, so it was concluded that the positive cultures of the
      sputum from the 5 patients who were not expected to be culture positive on
      clinical findings were caused by the cross-contamination in our hospital
      laboratory. We review all the charts of patients with M. tuberculosis culture
      positive results in the same year of this case, but we didn't find no other cases
      suspected of the cross-contamination. Then we reviewed the literature of M.
      tuberculosis culture cross-contamination. The patterns of the cross-contamination
      are divided into two. One is associated with malfunction of a sampling needle in
      the BACTEC 460 system and the other associated with the initial processing of the
      specimens, mostly involving reagents such as NaOH solution. Cross-contaminated
      specimens are usually smear negative with only a few colonies (less than 5), and
      processed just after the source specimen of the contamination in most reported
      cases, but not in all. In almost half of them the cross-contamination results had
      significant influence on the clinical management. The frequency of the cross
      contamination is estimated around 1% of the patients with M. tuberculosis culture
      positive results. For early detection of the cross-contamination, not only
      clinicians but also laboratory staffs have important role and close cooperation
      between them is mandatory. To prevent the contamination, it is advisable to
      process smear positive and probable culture positive specimens separately from
      others, and not to use a large same container of reagents for processing of
      different specimens.

PMID- 10599211
TI  - [Clinical analysis of pulmonary tuberculosis in association with corticosteroid
      therapy].
AB  - In the last five years, five patients (three males and two females) among a total
      of 162 patients (3.1%) ranging from 63 to 79 years old developed pulmonary
      tuberculosis during the long-term corticosteroid therapy. The underlying diseases
      of these cases were pulmonary fibrosis in two, polyarteritis nodosa in one, RPGN
      + pulmonary bleeding in one, and mycosis fungoides in one. The total
      corticosteroid dose used until the clinical diagnosis of pulmonary tuberculosis
      was 1.16 g to 5.60 g and the term of administration was two to nine and a half
      months. Other immunosuppressive drugs were administered to two patients. Though
      chemoprophylaxis with INH was done in two patients for three months, it was
      impossible to prevent the development of pulmonary tuberculosis. Since almost all
      patients except one complained no symptoms at the onset, the follow-up with chest
      roentgenograms seemed to be most important during corticosteroid therapy, and in
      fact, four patients were detected by the follow-up. Antituberculous chemotherapy
      was effective in four patients but was not carried out for one patient due to the
      delay in the diagnosis. Careful clinical observation, such as by chest
      roentgenograms, seems to be appropriate for the early diagnosis and treatment of
      pulmonary tuberculosis in patients on corticosteroid therapy.

PMID- 10599212
TI  - [Active pulmonary tuberculosis in patients with lung cancer].
AB  - To clarify the features of the coexistence of active pulmonary tuberculosis in
      patients with lung cancer, we analyzed clinical data on 25 cases with coexisting
      lung cancer and active pulmonary tuberculosis encountered at Tokyo National Chest
      Hospital during the period from 1991 to 1998. There were 23 men and 2 women, with
      a mean age of 70 years. The incidence of lung cancer among patients with active
      pulmonary tuberculosis at our hospital was 0.7 per cent, while the incidence of
      active pulmonary tuberculosis in untreated lung cancer patients at our hospital
      was 1.9 per cent. We classified the 25 cases into 2 groups as follows: (1)
      tuberculosis sequential to lung cancer (11 cases) and (2) tuberculosis
      concurrently detected with lung cancer (14 cases). All patients in the former
      group were transferred from other hospitals after diagnosing the coexistence of
      pulmonary tuberculosis during the management of lung cancer. Histological types
      of lung cancer were squamous cell carcinoma in 12, adenocarcinoma in 9, and small
      cell carcinoma in 4, and as to the disease stage, stages III to IV were
      predominant. Analysis on relationship of chest X-ray findings between lung cancer
      and pulmonary tuberculosis revealed that in general, the location of lung cancer
      and tuberculosis seemed to be independent. Tuberculosis in the sequential group
      was more extensive and severer than in the concurrent group. In the concurrent
      group, treatment for tuberculosis was successful except for one case, and
      coexisting tuberculosis did not seem to affect the course of lung cancer among
      this group. However, in the sequential group, 5 patients died within 3 months, 2
      of them died of tuberculosis. We consider that in the management of lung cancer,
      physicians should consider the possibility of coexistent active pulmonary
      tuberculosis and should not make delay in the diagnosis of active pulmonary
      tuberculosis.

PMID- 10599213
TI  - [A case of pulmonary tuberculosis with acute renal failure caused by
      readministration of rifampicin].
AB  - We report a case of pulmonary tuberculosis with acute renal failure caused by
      readministration of Rifampicin (RFP). A 73 year-old man was admitted to a certain
      hospital complaining with dyspnea on exertion. As his sputum smear was positive
      for acid-fast bacilli, he was transferred to our hospital for the isolation and
      treatment. He was diagnosed as lung tuberculosis and was administrated RFP,
      Isoniazid (INH) and Ethambutol (EB). On the 20th day after the initiation of
      treatment, the administration of drugs were suspended, because of liver
      dysfunction. After recovery of liver dysfunction, we have readministered
      antituberculous drugs, starting with EB, then INH, and finally RFP. On the 22nd
      day after the readministration of RFP, acute renal failure was observed. All
      medications were suspended and we started treatment with hydration and
      furosemide. His renal function recovered after 7 weeks. Histopathological
      examination of the kidney revealed interstitial infiltration and tubular
      nephritis. According to the histopathological examination and the clinical
      course, we concluded acute renal failure was induced by the readministration of
      RFP. This case suggests that we have to pay attention to renal side effect of RFP
      in the course of readministration.

PMID- 10599214
TI  - [Commemorative lecture of receiving Imamura Memorial Prize. Studies on prevention
      and treatment of childhood tuberculosis].
AB  - We performed a retrospective analysis of 394 patients who were treated for active
      tuberculosis (TB) at our hospital from 1976 to 1997. We had started early BCG
      vaccination campaign in Osaka Prefecture from 1995 and the coverage of BCG
      vaccination in infants rose up to about 90%. From that experience, we studied the
      current situations and measures on prevention and treatment of childhood
      tuberculosis. Pulmonary TB in children is successfully treated with 6-month
      standard short-course chemotherapy using isoniazid, rifampin, and pyrazinamide
      daily for 2 months, followed by isoniazid and rifampin daily for 4 months.
      Prognosis of childhood tuberculous meningitis (TBM) is poor, early diagnosis and
      prevention of TBM is important. In order to promote TB control and eliminate
      childhood TB, especially in infants, the following is necessary; 1) early
      detection and treatment of adult TB patients, source of infection, 2) prompt and
      appropriate contact examination and chemoprophylaxis, 3) BCG vaccination during
      early infancy, 4) protection from MDR-TB are most important.

PMID- 10599215
TI  - [Pathogenesis of arterial hypertension in diabetes mellitus].

PMID- 10599216
TI  - [Classification of acute viral myopericarditis and its sequelae].

PMID- 10599217
TI  - [Contemporary concept of autoimmune cholestatic lesions of the liver].

PMID- 10599218
TI  - [The role of veloergometry in combined diagnosis of ischemic heart disease in
      patients with COPD].

PMID- 10599219
TI  - [Clinical characteristics of miliary tuberculosis today].
AB  - Present-day miliary tuberculosis (MT) is characterized clinically. Changes in its
      classical presentation are found, i.e. in acuteness, sudden onset, intoxication.
      Generalized process with pulmonary and extrapulmonary miliary foci is accompanied
      with monopenia indicating profound disorders of phagocytic immunity in miliary
      tuberculosis.

PMID- 10599220
TI  - [Clinical significance of myeloperoxydase and proteinase 2 antibodies in patients
      with systemic lupus erythematosus].
AB  - Content of antibodies to neutrophil cytoplasma--myeloperoxidase (MPO)--and
      proteinase-3 (PR-3) was measured in the sera of 65 patients with SLE and 20
      donors. Antibodies to MPO (a-MPO) and proteinase-3 (a-PR-3) significantly
      outnumbered those of the control. The number of a-MPO appeared elevated in 13,
      lowered in 7, moderate in 6 cases and directly correlated with anemia, pulmonary
      lesions, a-PR-3 level, inversely correlated with cerebrovasculitis and
      polyneuritis. The number of a-PR-3 was elevated in 14 cases (10 low titers and 4
      moderate titers). High levels of both a-PR-3 and a-MPO were recorded in 8 sera.
      The content of a-PR-3 correlated directly with age of SLE onset but inversely
      with leukocyte count. Neither course of the disease nor inflammation activity
      were related to level of neutrophil antibodies. Factor analysis has identified
      groups of elements influencing the value of a-MPO and a-PR-3.

PMID- 10599221
TI  - [Riboxine effectiveness in combined treatment of chronic atrophic gastritis].
AB  - The authors present results of combined treatment of 60 patients with chronic
      atrophic gastritis with riboxine. A favorable effect was registered on clinical
      symptoms, acid-forming function, ultrastructure of gastric mucosa. The above
      positive effects of riboxine make it useful in combined treatment of chronic
      atrophic gastritis.

PMID- 10599222
TI  - [Plasma fibronectin in gastric and duodenal ulcer].
AB  - Solid phase enzyme immunoassay was made to measure fibronectin in blood plasma of
      132 patients with ulcer and healthy controls. Exacerbations of ulcer occurred in
      a significant lowering of fibronectin concentration which tended to an increase
      with ulcer healing. In the scarring phase fibronectin levels returned to normal.
      A local stimulating action of a plasma fibronectin preparation on scarring of the
      ulcer defect is validated.

PMID- 10599223
TI  - [New advances in surgery of benign tumors of mucosa of the facial surfaces and
      other areas of the body].

PMID- 10599224
TI  - [Non-narcotic analgesics, alcohol and liver].

PMID- 10599225
TI  - [Sandostatin treatment of destructive pancreatitis].
AB  - Sandostatin has been used in combined treatment of 30 patients with destructive
      pancreatitis in a dose 200-600 micrograms/day subcutaneously. The drug
      significantly depressed production of enzyme toxins in the pancreas but failed to
      prevent widening of necrotic zones and progression of the process in the
      retroperitoneal fat. The duration of sandostatin treatment should not be longer
      than 5-7 days. If no response is achieved for this time, surgical treatment is
      indicated. It is not reasonable to reject conventional drugs used in acute
      destructive pancreatitis for sandostatin monotherapy.

PMID- 10599226
TI  - [Dyspepsia in patients with chronic gastritis: mechanisms of their onset and
      current treatment].

PMID- 10599227
TI  - [Thirty years of practice in treatment of ulcer].

PMID- 10599229
TI  - [A case of unusual course of recurrent polychondritis].

PMID- 10599228
TI  - [Pulmonary symptoms of the gallbladder cancer].

PMID- 10599230
TI  - [Problems of cardiac failure at the 20th European Cardiology Congress (Vienna,
      August 1998)].

PMID- 10599231
TI  - [Clinical syndromes of weak respiratory center].

PMID- 10599233
TI  - [In Process Citation]

PMID- 10599234
TI  - Pacemakers. Timing is everything.

PMID- 10599232
TI  - [Clinical education in Germany in the first half of the 19th century].

PMID- 10599236
TI  - New treatment for spinal compression fractures.

PMID- 10599235
TI  - Health tips. Preparing for a visit from the grandkids.

PMID- 10599237
TI  - Bleeding inside the head. Know the warning signs.

PMID- 10599238
TI  - Laser eye surgery. Bringing things into focus.

PMID- 10599240
TI  - I'm having more and more difficulty seeing well when I drive at night. Is there
      anything I can do?

PMID- 10599239
TI  - 'Mono' fats. One of the good guys.

PMID- 10599241
TI  - Can taking vitamin C supplements help if you have coronary artery disease?

PMID- 10599242
TI  - Epithelial salivary gland tumours. An immunohistological and prognostic
      investigation.

PMID- 10599243
TI  - [AIDS is an immediate theme].

PMID- 10599244
TI  - [Interdisciplinary Center for Clinical Research in Munster. The chronic disease].

PMID- 10599245
TI  - [The role of intravenous cholangiography in the era of laparoscopic
      cholecystectomy: is there a renaissance?].
AB  - BACKGROUND AND OBJECTIVE: The preoperative investigation for choledocholithiasis
      in patients undergoing elective laparoscopic cholecystectomy is still a matter of
      debate. PATIENTS AND METHODS: In a prospective clinical trial the accuracy of
      intravenous cholangiography (IVC), ultrasonography and liver function tests in
      the preoperative diagnosis of choledocholithiasis was assessed in 98 patients
      undergoing elective cholecystectomy. Only patients with uncomplicated
      cholecystolithiasis considered to be at low risk for having bile duct stones were
      investigated. A 2-year follow-up clinical survey (mean) was performed in 92 of
      the 98 patients to investigate the occurrence of postoperative
      choledocholithiasis (gold standard: clinically manifest choledocholithiasis).
      RESULTS: In this patient cohort the incidence of choledocholithiasis was found to
      be 5.1%. Among the three diagnostic tests IVC proved to be more accurate with
      higher sensitivity and a better positive predictive value than ultrasonography
      and liver function tests. The sensitivity for IVC was 100% compared to 20% for
      ultrasonography and 40% for liver function tests, respectively. The positive
      predictive value for IVC was 83.3% in comparison to 20% for ultrasonography and
      25% for liver function tests. Mild side effects caused by intravenous contrast
      media were observed in 2.0%. During a mean postoperative follow-up of 2 years no
      clinically manifest and initially overlooked choledocholithiasis could be
      detected in the 92 investigated patients. CONCLUSION: IVC is a reliable method to
      detect unsuspected common bile duct stones and should be used in the preoperative
      diagnosis prior to elective laparoscopic cholecystectomy. IVC may play a role in
      decreasing the rate of preoperative ERCP or intraoperative cholangiography in
      these patients.

PMID- 10599246
TI  - [Acute liver failure after therapeutic hyperthermia].
AB  - HISTORY AND ADMISSION FINDINGS: A 49-year-old women with malignant neoplasia had
      undergone whole body hyperthermia under sedation to a rectal temperature of 42.5
      to 42.7 degrees C for about one hour. She failed to awaken afterwards and was
      admitted in a coma and transferred to the intensive care unit (ICU). There was
      slight improvement in consciousness in the following 30 hours. INVESTIGATIONS:
      Clinical and laboratory findings gave a constellation indicating acute liver and
      renal failure (transaminases ca. 1400 U/l, bilirubin 7.27 mg/dl, serum creatinine
      3.15 mg/dl, Quick thromboplastin time under 3.5%, antithrombin III 57%, partial
      thromboplastin time 70.7 s, platelets 23,000/microliter). Other causes of acute
      liver failure, especially drug effects, and septicaemia were excluded. TREATMENT
      AND COURSE: Treatment consisted of infusion of fresh plasma, neomycin and
      lactulose by mouth, medication to prevent stress ulcer, and total parenteral
      nutrition which included branched-chain amino acids. The patient regained full
      consciousness on the regimen and on the 6th day after admission was transferred
      to an ordinary ward. She was discharged after a further 3 weeks, by which time
      results of laboratory tests were practically normal. CONCLUSION: The course of
      the illness as well as the exclusion of any other cause of the acute liver
      failure in a patients who, 7 days before whole-body hyperthermia had been
      induced, had shown no signs of liver disease, makes a causal relationship between
      the hyperthermia and the described abnormalities highly probable. These serious,
      not previously reported, side effects of whole-body hyperthermia treatment
      underline the importance of undertaking this form of treatment only if strictest
      specific criteria are met.

PMID- 10599247
TI  - [Noninvasive ventilation in critically ill patients. I. Mechanism of action and
      current scientific evidence].

PMID- 10599248
TI  - [German New Guinea: "Grave of the white man". Early malaria reports in the
      Deutsche Medizinische Wochenschrift].

PMID- 10599249
TI  - [DMW (Deutsche Medizinische Wochenschrift) Global Theme Issue 1999].

PMID- 10599250
TI  - [Gene technology].

PMID- 10599251
TI  - [DNA chip technology].

PMID- 10599252
TI  - [High-dose chemotherapy with stem cell transplantation].

PMID- 10599253
TI  - [Regional and whole-body hyperthermia].

PMID- 10599254
TI  - [Aerosol morphometry and aerosol bolus dispersion. Innovative technology in the
      diagnosis of emphysema. Clinical Cooperative Group "Aerosol Medicine"].

PMID- 10599255
TI  - [Computer-based training (CBT). Case-oriented learning on the PC with
      CASUS/ProMediWeb System].

PMID- 10599256
TI  - [Clinic internal hypertext information system].

PMID- 10599257
TI  - [Do networks improve physician-patient relations?].

PMID- 10599258
TI  - [Internet: its significance in the prevention, delivery of health care and
      evidence-based medicine. Work Group Cybermedicine].

PMID- 10599259
TI  - [Diagnostic value of electrocardiography using dobutamine in coronary artery
      disease].
AB  - OBJECTIVES: Assess the sensitivity and specificity of electrocardiograms
      performed during dopamine perfusion to detect coronary artery stenosis. PATIENTS
      AND METHODS: One hundred three coronary artery disease patients with a
      coronarography were studied; 23 coronarographies were normal, 59 patients were
      taking a beta blocker. An exercise test was also performed in 54 cases. A
      dobutamine perfusion was given at increasing dosage up to 50 micrograms/kg/min,
      in combination with intravenous atropine if needed to obtain a heart rate close
      to the theoretical maximum. RESULTS: The ST segment could not be analyzed
      reliably in 12 patients. There was an ST depression in 32 cases, an ST elevation
      in 20 and an isoelectric ST in 39. The sensitivity of a positive test to detect
      stenosis was 67% and specificity was 83%. Test sensitivity increases with
      increasing number of stenotic lesions. There were no false positives in patients
      with an ST elevation. Results were not related to gender nor beta blocker
      treatment. The exercise tests were globally comparable but poorer in patients
      taking beta blockers. There were no notable adverse effects. CONCLUSION:
      Dobutamine perfusion electrocardiogram is a simple well-tolerated exploration
      method for the diagnosis of coronary artery disease applicable in all patients.
      Its diagnostic value is similar to that of the exercise test and better in
      patients taking beta blockers. Specificity is excellent and sensitivity is
      acceptable, particularly in patients with mulitvessel disease.

PMID- 10599261
TI  - [Spinal tuberculosis in children: contribution of imaging to diagnostic and
      therapeutic management].
AB  - BACKGROUND: Spinal tuberculosis is an increasingly common condition, particularly
      in children. CASE REPORT: A 2-year-old boy presented with spinal tuberculosis
      with psoas abscesses. Radiological imaging played a major role in the diagnostic
      process. DISCUSSION: In children, spinal tuberculosis is a serious condition due
      to its rapid spread. Clinical symptoms are often insidious and histological and
      bacteriological studies may fail to disclose the diagnosis. Radiological
      investigations are essential in the diagnostic approach.

PMID- 10599260
TI  - [Levofloxacin in the treatment of community-acquired pneumococcal pneumonia].
AB  - OBJECTIVES: Levofloxacin is a new fluoroquinolone active against S. pneumoniae.
      Oral and intravenous administration is available. The aim of this study was to
      determine its efficacy in community-acquired pneumonia. PATIENTS AND METHODS:
      Five clinical trials included 1989 patients eligible for analysis. The dosage was
      500 mg once or twice a day depending on the studies. Levofloxacin was compared
      with amoxicillin (3 g/d), amoxicillin/clavulanic acid (1500 mg/d), ceftriaxone (1
      4 g/d combined or not with a macrolide and/or relay cefuroxime axetil). RESULTS:
      In these studies and among the patients eligible for analysis, microbiologically
      proven S. pneumoniae pneumonia occurred in 170 of the patients treated with
      levofloxacine and in 140 treated with the comparator. Bacteriemia was evidenced
      in 51/170 of the levofloxacin-treated patients (30%) and in 45/140 (32%) of the
      comparator-treated patients. At treatment end, clinical success rate was 93.5%
      (159/170) for levofloxacin and 90.7% (127/140) for comparators. S. pneumoniae
      eradication rate was comparable for levofloxacin (94.9%) and comparators (95.3%).
      In patients with bacteriemia, the clinical success rate was 86.2% (44/51) for
      levofloxacin and 84.4% (38/45) for comparators. DISCUSSION: These findings
      establish the efficacy of levofloxcin for the treatment of pneumococcal
      pneumonia, a major treatment challenge in community-acquired pneumonia. This
      compound has its place in the context of good use of antibiotics. Levofloxacin
      should be used in priority for patients with risk factors for complications with
      rapidly unfavorable course or as second intention treatment when re-evaluating
      insufficient therapeutic response.

PMID- 10599262
TI  - [Localized post-traumatic dissection of the descending aorta].

PMID- 10599263
TI  - [Frequency of pulmonary manifestations associated with visceral leishmaniasis].

PMID- 10599264
TI  - [Subcutaneous caffeine intoxication].

PMID- 10599265
TI  - [Treatment with inhaled budesonide for patients with mild obstructive lung
      diseases who continue to smoke: long-term benefits].

PMID- 10599266
TI  - [Ambulatory surgery. An interview with President Fagniez].

PMID- 10599267
TI  - [What are the current limits for prematurity?].
AB  - HIGH PREVALENCE: Over the last 15 years, there has been a 2-fold rise in the
      prevalence of early prematurity (birth before 33 weeks gestation) and very early
      prematurity (birth between 22 and 28 weeks gestation). More than 7000 infants
      weighing between 500 g and 1500 g are born alive each year. Survival rates above
      50% at 25 weeks, 86% at 29 weeks and 96% at 32 weeks are reported. These infants
      have the same right to adapted care as any other person. Nevertheless, maternal
      risks and the fact that these early and very early premature infants account for
      less than 1% of all births and yet include 50% of all neonatal deaths and 50% of
      all sequelae. A multidisciplinary approach is crucial for women with a high risk
      of delivery before 27 weeks gestation. ASSESSING PROGNOSIS: These infants
      comprise a very heterogeneous group of patients. Their survival and prognosis
      depends on many different factors. Antenatal factors include gestational age,
      estimated fetal weight, presence or not of malformations or fetal hypotrophy, and
      premature rupture of the membranes. During the perinatal period, antenatal
      corticosteroid therapy, pre-birth referral to a maternity ward with a pediatric
      intensive care unit, and care and degree of baro-trauma at delivery are
      essential. The neonatal assessment may lead to discontinuing treatment in case of
      extensive neurological damage. OPTIMAL CARE: With optimal care, achieved with an
      organized perinatal network using well-defined criteria for maternal referral, it
      should be possible to save 650 more children each year and reduce the number of
      severe handicaps by 390 among infants born before 33 weeks gestation. PREVENTION:
      Considerable progress has been made in perinatology, but simple and effective
      preventive measures must not be overlooked: reduction in the number of multiple
      pregnancies, detection of socio-demographic risk factors, treatment of
      asymptomatic bacteriuria, early diagnosis of threatening premature birth.

PMID- 10599268
TI  - [The hyperlipidemias. What remains of the Fredrickson classification?].

PMID- 10599269
TI  - [The hyperlipidemias. Role of various statins].
AB  - MECHANISM OF ACTION: Statins act by competitive inhibition of HMG-CoA reductase,
      a key enzyme regulating cholesterol synthesis. Reduction in serum LDL, the
      crucial biological expression dependent on this mechanism, varies in intensity as
      a function of the type and of the dose of statin. PLEIOTROPIC EFFECTS: Besides
      their lipid lowering effect, statins have also been demonstrated to have
      pleiotropic effects mostly directly related to HMG-CoA reductase inhibition.
      CARDIOVASCULAR IMPACT: Several clinical studies investigating prevention of
      cardiovascular disease have established that statins decrease cardiovascular
      morbidity and mortality. Results have been very coherent for both primary and
      secondary prevention with statins. The cardiovascular benefit is most likely
      partly related to its pleiotropic effects, particularly those inducing a
      stabilization of the atheromatous plaques. INDICATIONS: Interventional studies
      have clearly established the role of statins in comparison with other lipid
      lowering agents for the prevention of cardiovascular events in most situations
      although a few therapeutic choices remain a subject of debate. Globally, the
      primary indications of statins are hypercholesterolemia and mixed hyperlipidemia
      with moderately elevated triglycerides. There are still some questions concerning
      the therapeutic goals of statin therapy.

PMID- 10599270
TI  - [Hypertriglyceridemia: danger for the arteries].
AB  - AN INDEPENDENT RISK FACTOR: Although debate continues on the epidemiological
      impact, all surveys report that elevated serum triglyceride is an important risk
      factor in one-way analysis. More recent case-control studies in patients with
      premature coronary artery disease have shown that total triglyceride and VLDL
      levels discriminate better between subjects with and without coronary artery
      disease. Angiographic studies demonstrate that elevated serum triglyceride is
      found in coronary artery disease patients and that elevated VLDL or IDL is
      associated with severity. This relationship is persistently found when the serum
      cholesterol is taken into consideration but is no longer significant in most of
      the multivariate analyses. A recent meta-analysis is however in favor of an
      independent role for triglycerides, particularly in women. Two prospective
      studies published in 1998 confirmed that hypertriglyceridemia is an independent
      risk factor. VARIABLE IMPACT: Hypertriglyceridemia is a heterogeneous anomaly,
      not only due to different underlying pathophysiological mechanisms, but also in
      terms of cardiovascular risk. In familial hypertriglyceridemia, cardiovascular
      risk is apparently only moderately affected. Inversely, in combined familial
      hypertriglyceridemia and hyperapobetalipoproteinemia, the risk of premature
      cardiovascular disease is increased. ATHEROGENIC EFFECT: Unlike large VLDL rich
      in triglycerides, small VLDL rich in cholesterol ester have a strong atherogenic
      potential. Likewise, remnants are potentially atherogenic due to their relatively
      high cholesterol ester component and their accumulation on the arterial wall
      (Zilversmit postprandial atherogenesis theory). INCREASED RISK: The triglyceride
      related risk is partly the consequence of frequently associated changes in
      lipoprotein distribution (lower HDL cholesterol, principal consequence of
      hypertriglyceridemia, elevation of small dense more readily oxidizable LDL) and
      hemostasis disorders (increased factor VIIc and PAI-1). In addition,
      hypertriglyceridemia is often found with other cardiovascular risk factors,
      particularly it readily occurs in insulin resistance syndromes.

PMID- 10599271
TI  - [Hyperlipidemias. Concern with the Mediterranean diet].
AB  - THERAPEUTIC OBJECTIVES: Prevention and treatment of dyslipidemias are major aims
      in the prevention of cardiovascular diseases. The primary therapeutic objective
      in secondary prevention should be to avoid vascular and cardiac complications as
      well as reducing or normalizing lipid levels. THE MEDITERRANEAN DIET: There is no
      single definition of the Mediterranean diet. In terms of nutriments, it can be
      defined as a diet poor in saturated and polyunsaturated fats but rich in oleic
      acid. Despite their low amount in the diet, omega-3 fatty acids are
      characteristic compounds of the Mediterranean diet as antioxidants of various
      sources and vitamins of the B group, in particular folates. BENEFICIAL EFFECT:
      Adoption of a Mediterranean diet results in a significant reduction of total and
      LDL-cholesterol with also a significant effect on triglycerides and a small
      positive or no effect on HDL-cholesterol. However, the Mediterranean diet has
      been shown to be cardioprotective (for instance, prevention of sudden death)
      through biological effects (probably induced by omega-3 fatty acids) independent
      of its effect on blood lipoproteins. PUBLIC HEALTH ISSUE: The association of
      these cardioprotective and beneficial effects on blood lipids, in addition to
      gastronomic properties, renders this type of diet extremely attractive for public
      health purposes.

PMID- 10599272
TI  - [Pacemakers: an unusual radiological aspect].

PMID- 10599273
TI  - Self medication/prescribing by medical practitioners.

PMID- 10599274
TI  - Abortion--ethical obligations.

PMID- 10599275
TI  - Anthelmintic efficacy of mebendazole depends on the molecular polymorph.

PMID- 10599276
TI  - Amniocentesis--too dangerous and too late?

PMID- 10599277
TI  - Amniocentesis--too dangerous and too late?

PMID- 10599278
TI  - Complaints against scientology doctors.

PMID- 10599279
TI  - 'Yes!' to telemedicine.

PMID- 10599280
TI  - South Africa's health surveyed.

PMID- 10599281
TI  - Human origins in southern Africa?

PMID- 10599282
TI  - Sustainable HIV/AIDS managed care a reality.

PMID- 10599283
TI  - The Y2K phenomenon.

PMID- 10599284
TI  - Always running behind? Try these time-management tips.

PMID- 10599285
TI  - Following the HIV-1 trail--from source to South Africa.

PMID- 10599286
TI  - Born too soon, too small, to die--a plea for a fair innings.

PMID- 10599287
TI  - Rationing versus equity--the South African dilemma.

PMID- 10599288
TI  - Hepatocellular carcinoma in a patient with precirrhotic primary biliary
      cirrhosis.

PMID- 10599289
TI  - Hypoxic encephalopathy due to near-drowning.

PMID- 10599290
TI  - Flunitrazepam misuse and abuse in South Africa.

PMID- 10599291
TI  - AIDS education initiative.

PMID- 10599292
TI  - Very-low-birth-weight infants in South Africa.

PMID- 10599293
TI  - Blastocyst culture and transfer in a assisted reproduction programme.

PMID- 10599294
TI  - Hypertension management of medical aid patients attending private practices.

PMID- 10599295
TI  - Hypertension management of medical aid patients attending private practices.

PMID- 10599296
TI  - Technology in health care--blessing or curse?
AB  - This paper looks at technology and health care in terms of processes (here
      defined as goal-related, autonomous and self-regulated arrangement of actions)
      and their interactions. Using this approach, technology is considered to be the
      quality of the processes we are trying to achieve. However, health care and the
      life around it is a complex network of closely interacting processes, and through
      their interactions, processes can influence each other in various ways. In many
      cases such interactions can result in unwanted, inappropriate interference and
      the implementation of unsatisfactory health care technologies.

PMID- 10599297
TI  - Neuronavigation--destination unknown.

PMID- 10599298
TI  - The Internet, virtual communities and threats to confidentiality.
AB  - OBJECTIVES: To describe the role of the Internet in building virtual communities
      of doctors, to identify threats to privacy and confidentiality in this use of the
      Internet, and to suggest ways in which this threat can be managed. SUMMARY: The
      Internet is revolutionizing the medical profession. The doctor's role as medical
      expert is being challenged by patients who have immediate access to multiple
      sources of information about their diseases. Telemedicine makes use of the
      Internet to enable doctors to diagnose and treat patients far from their offices
      or hospitals. Internet list servers and chat groups gather doctors together in
      virtual space to exchange views on clinical and professional issues. This paper
      focuses on the last of these Internet applications, beginning with a description
      of the 'virtual community' that the list servers and chat groups constitute. It
      demonstrates how various Internet practices particular to virtual communities,
      namely registration, e-mail lists, and 'cookies', pose a threat to
      confidentiality. It discusses the conflicting values at stake, especially privacy
      and confidentiality on the one hand and openness and freedom on the other, and
      suggests how a balance between these can be achieved. CONCLUSIONS: The proposed
      resolution of the value conflict necessitates the implementation of effective
      registration systems, including collection of participants' personal information,
      and the monitoring of submissions to the chat groups. At the same time, the
      privacy (anonymity) of participants is maintained, except to the monitor, and the
      latter can intervene to delete uncivil submissions. Participants are also
      protected against unauthorised use of their e-mail addresses for advertising
      purposes and the like.

PMID- 10599299
TI  - Survival of low-birth-weight infants at Baragwanath Hospital--1950-1996.
AB  - OBJECTIVES: To examine changes in survival rates among low-birth-weight (LBW)
      infants between the years 1950 and 1996. METHODS: Survival figures were analysed
      for LBW infants managed at Baragwanath Hospital, a tertiary care centre in
      Soweto, Johannesburg, over four periods spanning five decades. RESULTS: The
      overall mortality rates of LBW infants decreased markedly between the early 1950s
      and the period 1995/96. By the mid-1990's approximately four times the number of
      infants with birth weight less than 1,500 g were surviving compared with the
      early 1950s. The reduction in mortality rates occurred in all LBW groups during
      the first three decades. However, since 1981 infants who weighed less than 1,500
      g at birth were the major contributors to the overall reduction in mortality.
      Between the years 1981/82 and 1995/96, survival increased significantly from 64%
      to 79% for infants with birth weight 1,000-1,499 g, and from 14% to 32% for those
      with birth weight less than 1,000 g. Since infants in the latter group were
      seldom offered mechanical ventilation or artificial surfactant, a large part of
      these increases in survival can be attributed to improvement in the general level
      of care. CONCLUSION: There have been dramatic improvements in the survival of LBW
      infants over this time period at Baragwanath Hospital. Although newer
      interventions such as mechanical ventilation and artificial surfactant have
      played a significant role, improvement in care at primary and secondary levels
      has been of major importance.

PMID- 10599301
TI  - End-to-side nerve suture--a technique to repair peripheral nerve injury.
AB  - End-to-side nerve suture (ETSNS) has until recently been extensively researched
      in the laboratory animal (rat and baboon). Lateral sprouting from an intact nerve
      into an attached nerve does occur, and functional recovery (sensory and motor)
      has been demonstrated. We have demonstrated conclusively that ETSNS in the human
      is a viable option in treating peripheral nerve injuries, including injuries to
      the brachial plexus. Among the many advantages of this new technique are: (i)
      simple and short operation; (ii) shorter recovery time--suture is done closer to
      the target organs; (iii) nerve grafts to bridge injured gaps are eliminated,
      reducing the morbidity of nerve surgery to a minimum; (iv) innervation of
      paralysed muscles, for which there was previously thought to be no hope of
      recovery, opens up many new treatment options; and (v) certain aspects of nerve
      function and regeneration, unknown until recently, open new horizons and
      understanding. ETSNS has given us new dimensions in the management of peripheral
      nerve injuries.

PMID- 10599300
TI  - Evaluation of a new type of direct digital radiography machine.
AB  - OBJECTIVE: To evaluate a recently developed low-dose, large-field, direct digital
      X-ray scanning system for medical use. METHOD: Radiation dose, image quality,
      diagnostic capability and clinical utility of the unit were compared with those
      of conventional radiography. RESULTS: Radiation doses ranged from 3% to 5% of
      conventional radiographic values, and a mean of 1 line-pair per millimetre could
      be detected. Ease of use, anatomical coverage and tolerance to patient motion
      were advantages. However, image quality was inferior to that of conventional
      radiographs, with limited fine detail visibility and penetration. Only 67 of 156
      (42.9%) pathological features seen on conventional radiographs were detected,
      including 13 of 41 fractures (31.7%) and 11 of 18 pneumothoraces (61.1%).
      CONCLUSION: Although image quality and diagnostic performance were not ideal,
      potential roles in triage, foreign body detection and possibly screening were
      promising. Radiographic factors may have affected sensitivity. This machine
      demonstrated useful attributes that may, with improvement, be beneficial in the
      imaging of trauma and other patients.

PMID- 10599302
TI  - Adult influenza vaccination guideline. SAMA-SA Pulmonology Society Working Group.
AB  - OBJECTIVE: To outline a rational cost-effective protocol for influenza
      vaccination of adults in South Africa. VACCINE DESCRIPTION: An inactivated
      (killed) virus vaccine containing three virus strains representing those most
      likely to circulate in the southern hemisphere during the upcoming winter.
      Vaccine success depends on the patient's age, immune system status, and degree of
      similarity of the virus strains contained in the vaccine to those circulating in
      the community. RECOMMENDATIONS: Vaccination is: potentially beneficial to any
      individual very effective in young otherwise healthy individuals targeted at high
      risk groups when there is limited availability and cost considerations. EVIDENCE:
      Detailed literature review with emphasis on local South African studies.
      Benefits, harms, costs. Successful vaccination may be effective in protecting
      against acute respiratory tract infection, and preventing hospitalisation,
      complicating pneumonia and death. The vaccine is safe with only occasional
      reports of anaphylaxis. Contraindications to the vaccine are anaphylactic
      hypersensitivity to eggs, allergy to other components of the vaccine, and acute
      severe febrile illness. Vaccine cost-effectiveness has been confirmed in several
      groups, including healthy working adults, elderly living in the community,
      elderly with underlying chronic medical disorders. VALIDATION: Endorsement by the
      SA Pulmonology Society, SAMA and all who attended a multidisciplinary consensus
      meeting to consider the draft guideline.

PMID- 10599304
TI  - The Epstein-Barr virus: a group 1 carcinogen?
AB  - The Epstein-Barr virus (EBV) is a human herpes virus with the ability to
      transform B-lymphocytes in vitro. EBV has been linked to the pathogenesis of a
      variety of human tumours, including Burkitt's lymphoma, immunosuppression-related
      lymphomas, Hodgkin's disease, nasal angiocentric T/NK-cell lymphoma and
      nasopharyngeal carcinoma. Based on the association of the virus with these
      tumours, EBV has been classified as a group 1 carcinogen by the WHO International
      Agency for Research on Cancer. In this article, the evidence suggesting that EBV
      is carcinogenic to humans is briefly reviewed.

PMID- 10599303
TI  - Adult pneumococcal vaccination guideline. SAMA-SA Pulmonology Society Working
      Group.
AB  - OBJECTIVE: To outline a rational cost-effective protocol for pneumococcal
      vaccination of adults in South Africa. VACCINE DESCRIPTION: A highly purified
      vaccine containing 25 micrograms of each of 23 capsular polysaccharides
      representing > or = 85% of the serotypes causing pneumonia and invasive
      pneumococcal disease in the community. Polysaccharide antigens induce type
      specific antibodies that enhance opsonisation, phagocytosis and killing of
      pneumococci by phagocytic cells. Factors influencing the efficacy of the vaccine
      include the age of the individual, the state of their immune response, the
      presence/absence of underlying medical disorders, and the level of pneumococcal
      antibodies attained. Protection is only against infection caused by pneumococci
      of a serotype included in the vaccine. RECOMMENDATIONS: Vaccination is
      potentially beneficial to any individual very effective in young otherwise
      healthy individuals targeted at high-risk groups when there are cost
      considerations. EVIDENCE: Detailed literature review with emphasis on local South
      African studies. Benefits, harms, costs. Vaccine is very effective in preventing
      pneumonia and invasive disease in young otherwise healthy individuals. Efficacy
      is greater against bacteraemic pneumonia than against non-bacteraemic pneumonia.
      Efficacy may be less in the elderly aged > 65 years and in some of the high-risk
      categories of individuals targeted for vaccination. Vaccine is safe with only
      occasional reports of anaphylaxis, although local reactions to the vaccine are
      quite common. CONTRAINDICATIONS: Exercise care when administering the vaccine to
      allergic individuals. Delay immunisation if possible in the case of fever, acute
      disease, and relapse of chronic disease until recovery. Relatively few data are
      available on cost-effectiveness of the vaccine. However, recent studies suggest
      that the vaccine is cost saving in developed countries in terms of prevention of
      bacteraemia alone. VALIDATION: Endorsement by the SA Pulmonology Society, SAMA
      and all who attended a multidisciplinary consensus meeting to consider the draft
      guideline.

PMID- 10599305
TI  - Recommendations for the reporting of tumors of the adrenal cortex and medulla.
      Association of Directors of Anatomic and Surgical Pathology.
AB  - The Association of Directors of Anatomic and Surgical Pathology has developed
      recommendations for the surgical pathology report for common malignant tumors.
      The recommendations for tumors of the adrenal cortex and medulla are reported
      herein.

PMID- 10599306
TI  - Clinical, immunohistochemical and phenotypic features of aggressive nodal
      cytotoxic lymphomas, including alpha/beta, gamma/delta T-cell and natural killer
      cell types.
AB  - Cytotoxic cells include natural killer (NK) cells and cytotoxic alpha beta and
      gamma delta T lymphocytes (CTLs). These cells express cytotoxic molecules of T
      cell restricted intracellular antigen (TIA-1), and activated cytotoxic molecules
      of perforin, granzyme B, and FasL. Recent studies suggest that most extranodal T
      cell lymphomas are derived from CTLs, and that NK cell lymphomas are extranodal.
      However, only a few nodal NK and cytotoxic lymphomas have been described so far.
      We present here the clinicopathological features of seven cases of nodal
      cytotoxic T and NK cell lymphomas. The study excluded anaplastic large-cell
      lymphomas expressing cytotoxic molecules. The neoplastic cells of all cases
      contained activated cytotoxic molecules of TIA-1, granzyme B, Fas ligand, and/or
      perforin. Phenotypically and genotypically, four cases showed alpha beta T cell
      type [CD2+, CD3+, T-cell receptor (TCR)-delta-1-, beta F1+, and TCR gene
      rearrangement], two cases showed gamma delta cell type [CD2+, CD3+, T-cell
      receptor (TCR) delta-1+, beta F1-, and TCR gene rearrangement], and one case
      showed NK cell type [CD2+, CD3-, CD56+, T-cell receptor (TCR) delta-1-, beta F1-,
      and TCR gene germline]. Using Southern blot analysis, Epstein-Barr virus (EBV)
      sequences were detected in six cases, and monoclonal terminal repeat
      proliferation was confirmed. In addition, in situ hybridization (ISH) studies for
      EBV showed EBV infection in almost all neoplastic cells. Clinically, all patients
      presented with peripheral lymphadenopathy in high clinical stages and showed an
      aggressive course. Hepatosplenomegaly was detected in six cases. During the
      course of the disease, bone marrow and extranodal invasion were noted in five
      cases. The nodal type showed an aggressive clinical course in all cases but one,
      as did the extranodal type. The nodal type varied in phenotype, but was closely
      associated with EBV infection.

PMID- 10599308
TI  - Significance of the small subtelomeric area of chromosome 1 (1p36.3) in the
      progression of malignant melanoma: FISH deletion screening with YAC DNA probes.
AB  - The short arm of chromosome 1 (1p), especially the subtelomeric region of 1p36,
      is a common site for abnormalities in malignant melanoma of the skin. In a recent
      study nodular melanomas displayed deletions of 1p36 in an augmented percentage of
      cases. To evaluate the dimension of these deletions and to study their
      significance for the progression of malignant melanoma we analyzed seven melanoma
      cell lines, 32 primary tumors, and 32 metastatic tumors by fluorescence in situ
      hybridization with the DNA probe D1Z2 in 1p36.3 and eight YAC DNA probes
      hybridizing to 1p36, 1p32, 1p31, and 1p21. All cell lines, 91% of the metastatic
      tumors and 63% of nodular melanomas showed a deletion of 1p36.3. In the YAC
      hybridization experiments, the most frequent deletions were found in 1p36 in all
      cell lines, in 13% of nodular melanoma, and in 44% of metastatic tumors.
      Deletions in 1p36 were mostly confined to a rather small area near the locus
      D1Z2. The frequent occurrence of this deletion in melanomas with a high
      metastatic potential and the abundant accumulation of this deletion in metastasis
      point to genes located on 1p36, which might be of significance for the metastatic
      capability of malignant melanoma.

PMID- 10599307
TI  - Absence of cytotoxic molecules in CD8- and/or CD56-positive adult T-cell
      leukaemia/lymphoma.
AB  - Adult T-cell leukaemia/lymphoma (ATLL) cells usually exhibit a CD4+
      (helper/inducer) phenotype (CD4+/8-/56-), and only a minority of tumours express
      the CD8 (cytotoxic/suppressor) or CD56 (natural killer [NK]-associated) antigens.
      TIA-1 is a cytotoxic granule-associated protein expressed in NK cells and
      cytotoxic T lymphocytes (CTLs). Granzyme B, perforin and Fas ligand (FasL) are
      also expressed in activated CTLs and NK cells. To clarify the cytotoxic potential
      of ATLL cells, immunohistochemistry was performed in CD8+ and/or CD56+ ATLL
      cells, using anti-TIA-1, anti-granzyme B, anti-perforin and anti-FasL antibodies.
      We studied nine cases of CD8+ and/or CD56+ ATLL, all of which exhibited
      monoclonal integration of human T-cell leukaemia virus type 1 (HTLV-1) proviral
      DNA. Four cases exhibited a CD8+/CD56- phenotype, four others had a CD8-/CD56+
      phenotype, and one was CD8+/CD56+. All but one case also expressed the surface
      antigens CD3, TCR alpha beta, and CD4. Expression of granzyme B and TIA-1 were
      demonstrated in three and two cases, respectively, but none expressed perforin or
      FasL. In the control study, 10 cases with typical CD3+/4+/8-/56- ATLL
      demonstrated no expression of those cytotoxic-associated proteins. Our findings
      suggest that CD8 and/or CD56 positivity probably confer(s) no cytotoxic function
      on ATLL cells, and it is possible that CD8 and CD56 may be simply aberrant
      surface markers in ATLL.

PMID- 10599309
TI  - Expression of transforming growth factor-alpha and epidermal growth factor
      receptor in gastrointestinal stromal tumours.
AB  - Activation of epidermal growth factor receptor (EGFR) is associated with cell
      growth and transformation. Both transforming growth factor-alpha (TGF-alpha) and
      epidermal growth factor bind to and activate EGFR. We studied the expression of
      TGF-alpha and two EGFRs (HER-1 and HER-2) in gastrointestinal stromal tumours
      (GISTs) of the stomach (n = 9) and small intestine (n = 6) using standard
      immunostaining techniques in paraffin-embedded sections. Most GISTs expressed TGF
      alpha, and a few expressed HER-1. All HER-1-positive tumours expressed TGF-alpha.
      These results suggest that a TGF-alpha/EGFR autocrine loop is present in GIST and
      that TGF-alpha promotes proliferation of GIST tumour cells through its
      interaction with HER-1 in at least some GISTs. This is the first description of
      an autocrine loop in GIST. In contrast, HER-2 is not expressed in any GIST.

PMID- 10599310
TI  - Elevated levels of p27, p21 and cyclin D1 correlate with positive oestrogen and
      progesterone receptor status in node-negative breast carcinoma patients.
AB  - The search for better prognostic indicators and new treatment modalities in node
      negative breast carcinoma patients is important. The aim of this study was to
      determine the immunohistochemical expression of central cell regulator proteins
      in relation to hormone receptor status, tumour-cell differentiation and
      prognosis. We investigated the immunoreactivity of p27, p21, cdk4, cyclin D1 and
      p53 in 77 node-negative breast carcinomas, with long-term follow-up (mean 163
      months; range 20-227). Nuclear staining for p27 was seen in 87% of the
      carcinomas, for cdk4 in 92%, for p21 in 68%, for cyclin D1 in 58% and for p53 in
      18%. Oestrogen receptor (ER) and progesterone receptor (PgR) nuclear staining was
      seen in 69% and 65% of the tumours, respectively. No correlation between the
      levels of p21 and p53 was observed. p21 overexpression was, however, associated
      with positive ER status. Elevated levels of p27 and cyclin D1 correlated with
      positive hormone status (both ER and PgR). We did find a significant correlation
      between p27 and cyclin D1 and histological grade of the tumours, with extensive
      positive immunostaining of p27 and cyclin D1 in well-differentiated carcinomas.
      The only significant prognostic factor in our series was histological grading.
      Ten-year relapse-free survival was significantly prolonged in patients with
      histological grade I tumours versus histological grade II and III tumours. Our
      results suggest that the expression of p27 and cyclin D1 is closely linked to
      hormone receptor status in breast carcinomas and to tumour differentiation, a
      finding that may be of importance in the treatment of hormone-dependent tumours.

PMID- 10599311
TI  - Interaction of hepatocytes and pancreatic islets cotransplanted in polymeric
      matrices.
AB  - Heterotopic hepatocyte transplantation (HcTx) in polymeric matrices may become an
      alternative to liver transplantation for metabolic disorders. Hepatotrophic
      stimulation by means of a portocaval shunt operation is an established, but
      invasive, procedure used to optimize hepatocyte engraftment in matrices. We
      evaluated hepatocyte and pancreatic islet cotransplantation (ICT) as an
      alternative noninvasive approach to hepatotrophic stimulation. Lewis rats served
      as donors and recipients. Hepatocytes and islets were isolated using collagenase
      digestion and seeded into polyvinylalcohol matrices. HcTx and ICT were compared
      with HcTx plus portocaval shunt and HcTx without stimulation. Matrices were
      investigated at 1, 3, and 6 months after implantation: the test methods applied
      were trichrome staining, PAS, immunohistochemistry for insulin, glucagon and
      incorporated BrdU, and in situ hybridization for albumin RNA. Hepatocytes
      expressed albumin RNA and formed conglomerates without atypias in all animals.
      ICT and portocaval shunting increased the number of hepatocytes and BrdU uptake.
      Alpha cells migrated into the islet-surrounding hepatocytes, whereas beta cells
      remained immobile. It is concluded that ICT and portocaval shunting supported
      engraftment of hepatocytes in polymeric matrices equally well. ICT did not
      interfere with recipient glucose metabolism and did not induce hyperproliferative
      premalignant foci within the transplanted hepatocytes. The technique is an
      attractive approach to hepatotrophic stimulation of bioartificial liver
      equivalents.

PMID- 10599312
TI  - Follicular thyroid carcinoma with rhabdoid phenotype.
AB  - The aim of this paper is to highlight the occurrence of an unusual histological
      variant of follicular carcinoma of the thyroid. Three cases are presented: each
      of the tumours contained a significant population of rhabdoid cells (accounting
      for 30-40% of the total tumour content). They were all found in female patients
      aged 65, 43 and 56 years, who presented with enlarged thyroid glands and were
      subjected to lobectomies. The tumours contained foci of well-differentiated
      follicular carcinoma, with areas of capsular and vascular invasion, and an
      accompanying rhabdoid cell component that merged with the neoplastic follicles.
      Immunohistochemically, the follicular component was positive with thyroglobulin,
      but the rhabdoid cells were negative in all three cases. The cytoplasmic
      aggregates in the rhabdoid cells were strongly positive for epithelial markers
      and vimentin. Two tumours pursued an aggressive biological course similar to
      other composite extrarenal rhabdoid tumours. A rhabdoid component accompanying
      thyroid follicular carcinomas is an adverse prognostic factor.

PMID- 10599313
TI  - In situ demonstration of parathyroid hormone-related protein mRNA in sclerosing
      hepatic carcinoma.
AB  - A 69-year-old man had a hepatic tumour occupying the left and half of the right
      lobe, with portal vein thrombus. There were hypercalcaemia and hypophosphataemia
      with increased nephrogenous cyclic adenosine monophosphate; bone metastases were
      excluded. Serum parathyroid hormone-related protein (PTHrP) was elevated, but no
      increase in intact parathyroid hormone (PTH) or vitamin D3 metabolites was found.
      At autopsy the histological features were typical of sclerosing hepatic
      carcinoma. By immunohistochemistry PTHrP was detected in cancer cell nests but
      not in the fibrous stroma. PTHrP transcripts were demonstrated by in situ
      hybridization using a polymerase chain reaction (PCR)-derived single-stranded DNA
      probe. Tumour cells expressed AE1 and CA19-9 (markers for cholangioepithelium)
      and CEA (for bile canaliculi). Electron microscopy revealed microvilli on the
      apical surface, and secretory granules 100 nm in diameter were observed. These
      findings indicate that this case is one of cholangiocellular sclerosing hepatic
      carcinoma. The interaction between cancer and stromal cells may be the cause of
      PTHrP overexpression.

PMID- 10599314
TI  - GANT-like gastrointestinal pacemaker cell tumours with oncocytic features.
AB  - We describe two cases of gastrointestinal stromal tumours with prominent
      oncocytic features. Both had features consistent with differentiation towards the
      interstitial cells of Cajal (CC). They were composed of nests and bundles of
      cells with abundant, deeply granular, eosinophilic cytoplasm. Immunohistochemical
      investigations revealed positivity with c-kit, vimentin and CD34 antibodies in
      both neoplasms. Ultrastructurally the neoplastic cells showed characteristic
      features of CC; they had synapse-like structures and dense core cytoplasmic
      granules. Oncocytic features were confirmed by immunohistochemistry using anti
      mitochondrion antibody in both cases and by electron microscopy in one case (case
      1). Although the CC are frequently described as mitochondrion-rich cells,
      oncocytic changes have not previously been reported as a feature of
      gastrointestinal autonomic nerve tumour (GANT)-like stromal tumours.

PMID- 10599315
TI  - Corpus-active gastritis with focal atrophy and parietal cell hyperplasia related
      to long-term use of omeprazole.

PMID- 10599316
TI  - The interface between rheumatology and dermatology. Why rheumaderm?
AB  - Although the division of medicine into specialties according to different systems
      is convenient, it is also artificial: the different systems interact and many
      diseases overlap both in their pathological features as well as their clinical
      expression. Many examples of such interactions are seen in the connective tissue
      disorders, where rheumatological and dermatological manifestations may be
      prominent features. In some of them the skin rash may be a diagnostic marker
      (e.g., systemic lupus erythematosus, dermatomyositis). Joint involvement can also
      be found in "primary" skin disorders such as psoriasis; certain infections can
      produce both skin and joint manifestations including a number of fairly common
      viral disorders as well as Lyme borelliosis and the acquired immune deficiency
      syndrome (A.I.D.S.) The skin may also be the major target of toxicity from a
      number of drugs, particularly those that are used in the management of rheumatic
      disorders.

PMID- 10599317
TI  - Nature and nurture in systemic lupus erythematosus.
AB  - Nowhere across the spectrum of rheumatic and dermatological disease is the
      interaction of nature and nurture more relevant than in the connective tissue
      diseases such as SLE. While genetic and environmental factors are clearly
      involved in both the triggering of the disease and its expression, the
      interaction is complex with different combinations of factors contributing in
      different patients. For example, while genetic factors contribute substantially
      to susceptibility to lupus, this does not follow a simple Mendelian pattern of
      inheritance and mathematical models suggest that there may be varying
      contribution from at least four genes with differing inheritances. A variety of
      candidate genes and environmental factors have been highlighted in SLE but to
      dissect out the complexity of how these might interact requires the study of
      patient groups with a better defined clinical and serological phenotype. For
      example, studies of patients with subacute cutaneous lupus (SCLE) have shown
      associations with various genes in the MHC region (including HLA, complement and
      TNF) and suggest that the biological effect of inheriting an extended MHC region
      may be greater than its individual parts. One can now speculate on how
      interaction with an environmental factor such as UV light explains pathogenesis.

PMID- 10599319
TI  - Neonatal lupus erythematosus.
AB  - Neonatal lupus is categorized by typical clinical features and the presence of
      maternal auto-antibodies. Mothers are uncommonly affected with clinical disease.
      The major clinical manifestations in neonates are cardiac, dermatological and
      hepatic, with rare instances of haemolytic anaemia and thrombocytopenia. The
      major morbidity and mortality result from complete congenital heart block.
      Dermatological manifestations occur mainly over the face and present with plaques
      of erythema with central atrophy, a mid-facial erythema, atrophy around the eyes
      and a telangiectatic variety. The long term outcome is usually excellent.

PMID- 10599318
TI  - Heritable connective tissue disorders.

PMID- 10599320
TI  - Prognosis in juvenile arthritis.
AB  - Juvenile arthritis implies an onset of disease under 16 years with arthritis
      persisting in one or more joints for at least six weeks, and with the active
      exclusion of well defined illnesses, such as systemic lupus erythematosus.
      Prognosis implies the ability to predict outcome. Its accuracy depends on many
      factors with early recognition and appropriate care being important. However,
      response to treatment may be variable. In general, those with involvement of a
      few joints do better than those with systemic disease or seropositive juvenile
      rheumatoid arthritis both with regard to persistence of disease activity and
      complications. These include not just joint deformities, but osteoporosis,
      amyloidosis, alterations in growth with overall failure and local anomalies,
      chronic iridocyclitis and psychosocial problems. More aggressive therapy was only
      introduced in the 1990's, so it is important that multicentre studies are
      properly assessed in the context of the suggested International diagnostic
      criteria. One hundred years ago, George Fredric Still drew attention to the
      systemic form of the disease as distinct from pure polyarthritis [1], but it was
      only in the 1970s, as follow-up proceeded, that the separate identity of variants
      became clinically evident [2]. At the Park City meeting [3] and at the EULAR
      meeting in 1977 [4] when three subgroups (notably systemic, polyarthritis and
      pauci-articular onset) were defined, that subclassification became regularly
      used. However, since there were no absolute diagnostic tests there had to be
      exclusions. At that time the most common medications were aspirin and
      corticosteroids, although a few patients received gold or penicillamine. In their
      large group Wallace and Levinson (1990) [5] found that at the 10 year follow-up
      between 31% and 55% still had active disease. Girls appeared to have a five-fold
      greater risk for persistent activity than boys; disease duration was probably the
      most important factor influencing disease activity at follow-up as suggested
      previously [6]. It was not until the 1990's that the more aggressive therapy in
      the form of methotrexate--which Giannini had shown to be effective when given in
      appropriate dosage [7]--and sulphasalazine [8] and the long acting local
      corticosteroid triamcinolone hexatonide became regularly employed [9, 10]. At the
      ILAR Meeting in 1993 an international task force was set up under the
      chairmanship of Dr. C. Fink [11] to develop a classification for the idiopathic
      arthritides in children, defining childhood as up to 16 years of age. Active
      exclusion of well-recognised disorders such as rheumatic fever or systemic lupus
      erythematosus, still had to be made. The first proposed types, which are mutually
      exclusive, are shown in Table 1. A more recent meeting in Durban under the
      chairmanship of Dr. R. Petty is yet to be published, but considerable advances
      have been made, particularly in the definition of subgroups.

PMID- 10599321
TI  - Scleroderma in children.

PMID- 10599322
TI  - Localized morphea in children.
AB  - We are following 60 patients with morphea and/or linear scleroderma at the
      Hospital for Sick Children, Toronto. Lesions may vary in depth from epidermal
      changes resembling lichen sclerosis, to superficial and deep dermal changes. The
      subcutaneous tissue, bone and muscle may be involved. There is no good clinical
      marker of the disease. Because of the variation in the time to cure, it is
      difficult to evaluate treatment regimens. We are currently using methotrexate
      weekly either orally or subcutaneously and monthly pulsed steroids for three
      months.

PMID- 10599323
TI  - Autoimmune thyroid disorders in juvenile chronic arthritis and systemic lupus
      erythematosus.
AB  - The appearance of autoimmune thyroiditis in the course of other autoimmune
      diseases, which do not affect specific organs (systemic lupus erythematosus,
      Sjogren syndrome, rheumatoid arthritis and others), is more frequent than is
      usually believed. Nevertheless, it is scarcely studied, especially in children.
      The purpose of this study was to look for autoimmune lesions of the thyroid gland
      in children suffering from juvenile chronic arthritis (JCA) and systemic lupus
      erythematosus (SLE). Twenty seven children having JCA and twelve children with
      SLE, aged 5 to 18 years, were enrolled into study. In all of them the disease was
      in an active phase. The serum levels of total thyroid hormones (T3, T4) and TSH,
      thyroid antibodies (TAB and MAB) and antinuclear antibodies (ANAB) were analyzed
      using respectively fluoroimmunologic, microhemagglutination and indirect
      immunofluorescention tests. According to our results, autoimmune thyroiditis was
      found in 12 out of 27 children with JCA (44.4%); 85.2% of them were euthyroid,
      11.1% had a compensated hypothyroidism, and 3.7% had Hashi-toxicosis. From a
      clinical point of view, very interesting was the combination of JCA, autoimmune
      thyroiditis and pseudoxanthoma elasticum in a 13-year old girl. Positive
      thyroglobulin antibodies (1:80-1:5120) were found in 17 out of 27 cases of JCA
      (63%). The microsomal antibodies were elevated (1:100-1:1600) in 7 out of 27
      (25.9%); antinuclear antibodies (1:80-1:640) were detected in 15 out of 27 cases
      of JCA (55.5%). A simultaneous elevation of all three kinds of antibodies was
      found in 14.8% of children with JCA, and of TAB and MAB--in 18.5%. Thyroid gland
      disorders were detected also in children suffering from SLE. Thyroglobulin
      antibodies were positive (1:80-1:5120) in 7 out of 12 cases. Antinuclear
      antibodies (1:320-1:2560) were detected in 8 out of 12 cases (66.7%). The serum
      levels of T3, T4 and TSH were in the reference limits in all children with SLE.
      The present study suggests that involvement of the thyroid gland is not uncommon
      in autoimmune disease in Autoimmune thyroiditis can occur in association with
      other autoimmune diseases, affecting some organs or systems, such as the insulin
      dependent diabetes mellitus, pernicious anaemia, thrombocytopenia, vitiligo, as
      well as some chromosomal aberrations--Turner's syndrome, Noonan's syndrome and
      Down's disease [1]. The appearance of autoimmune thyroiditis together with other
      autoimmune diseases which do not affect specific organs (such as systemic lupus
      erythematosus, Sjogren syndrome) is the reason to classify them in a common
      subgroup of the autoimmune polyendocrine syndromes--type IIID [2]. The rheumatic
      diseases are--more frequently than suspected--associated with autoimmune
      thyroiditis, but this connection is not well studied. The literature offers very
      scarce information on the problem, especially for the childhood. The purpose of
      this study was to look for autoimmune lesions of the thyroid gland in children
      suffering from juvenile chronic arthritis (JCA) and systemic lupus erythematosus
      (SLE).

PMID- 10599324
TI  - Prevalence of IgM-, IgA- and IgG-rheumatoid factors in seronegative polyarticular
      disease compared to pauciarticular disease in juvenile chronic arthritis as
      measured by ELISA.
AB  - OBJECTIVE: To determine the prevalence of the rheumatoid factor isotypes measured
      by enzyme-linked immunosorbent assay (ELISA) in polyarticular and pauciarticular
      juvenile chronic arthritis (JCA), and evaluate the diagnostic test qualities.
      PATIENTS AND METHODS: 53 patients with JCA (20 with seronegative polyarticular
      disease at onset, 21 with pauciarticular onset and course of disease and 12 with
      extended pauciarticular disease), as well as 125 control children (58 healthy
      controls and 67 patients with other diseases) were tested. ELISA for the
      detection of IgM-, IgA- and IgG-isotypes of RFs was used. The diagnostic
      characteristics of the tests were evaluated by means of clinical epidemiology
      methods. RESULTS: The prevalence of the ELISA for IgG-, IgA-, and IgM-RF for JCA
      patients vs all controls at optimal cut-off titres was 13%, 29%, and 32%,
      respectively. The test for IgG-RF was established to be of no significance. IgA
      RF had higher prevalence in the polyarticular and extended pauciarticular form,
      40% and 33%, respectively. IgM-RF showed a prevalence of 55% for the
      polyarticular and 42% for the extended pauciarticular form. No significant
      prevalence has been found in the pauciarticular form. CONCLUSION: Our results
      indicate that ELISA for IgG-RF is of no diagnostic value for JCA. The ELISAs for
      IgM- and IgA-RFs demonstrated a diagnostic significance for the polyarticular and
      extended pauciarticular form. Juvenile chronic arthritis (JCA) is a heterogeneous
      disease which encompasses different forms defined by the type of onset. There is
      evidence, supported by immunogenetic studies that the various subgroups may
      represent distinct disease entities [1, 2]. Numerous immunological abnormalities
      have been detected in JCA, but the most characteristic serological findings are
      ANA and IgM-rheumatoid factor, thought to be useful in the classification of
      patients and their management. Antinuclear antibodies are universal in JCA, most
      commonly found in children with early onset pauciarthritis and late onset
      seropositive polyarthritis [1, 2, 3]. In contrast, the IgM-rheumatoid factor,
      measured by conventional agglutination techniques, is a hallmark only of
      polyarthritis with late onset resembling adult rheumatoid arthritis. This group
      of patients with "seropositive" disease represents less than 20% of all JCA
      children. Of those patients with "seronegative" disease 20-30% have a systemic
      onset and the remainder have either a pauciarticular or polyarticular form [2,
      3]. Following the introduction of more sensitive techniques, it has already been
      established that rheumatoid arthritis (RA) patients' sera contain not only the
      "classical" 19S IgM-RF, but also other isotypes of the rheumatoid factor (RF). A
      number of studies have emphasized the presence of IgG-, IgA-, IgM- and even IgE-
      RF in patients with "seronegative" RA [4, 5, 6]. The aim of this study is to
      determine the prevalence of IgG, IgM and IgA RFs and to attempt at evaluating the
      diagnostic and prognostic qualities of the ELISA-tests for rheumatoid factor
      isotypes in polyarticular and pauciarticular forms at onset of JCA.

PMID- 10599325
TI  - Incidence and outcome of Kawasaki disease in Malta.
AB  - Kawasaki disease (KD) is an acute febrile illness of childhood of unknown origin
      which causes an arteritis of small and medium sized arteries. The arteritis may
      involve any organ, including the coronary arteries, causing diffuse dilatation,
      aneurysm formation, stenosis, infarction and death. This paper determines the
      incidence of KD in Malta and compares the incidence and morbidity of KD in Malta
      with that in other countries. The Maltese incidence is 3.2/100,000 population < 5
      years of age, similar to that reported in non-Asiatic communities, and
      significantly less than that reported in Asiatic communities. None of the Maltese
      patients had coronary arteritis or other complications. A significant decline in
      delay to diagnosis was found, which is attributed to increased awareness of the
      disease in the medical community.

PMID- 10599326
TI  - Systemic sclerosis. A clinical overview.
AB  - Systemic Sclerosis (SSc) is a multisystem disease that affects the skin and
      internal organs (i.e., gastrointestinal tract, lung, heart, kidney and peripheral
      nervous system). In the early phase, lung involvement is characterized by
      interstitial inflammatory alterations that are detected by bronchoalveolar lavage
      analysis and high resolution computed tomography (ground glass). As the disease
      progresses, fibrotic changes become evident and the diffusing capacity for carbon
      monoxide (DLCO) is impaired. Cardiac involvement in SSc can be manifested as
      myocardial disease, pericardial disease, conduction system disease, or
      arrhythmias. Cardiac involvement is a poor prognostic factor, but the diagnosis
      may be late or missing because of the frequent discrepancy between clinical
      manifestations and the real cardiac involvement. For this reason, resort to all
      the available diagnostic procedures is recommended to achieve an early diagnosis.
      The motility disorders are a major feature of gastrointestinal involvement in
      SSc, striking any part of this system (especially esophagus and anorectal
      region). Kidney involvement and scleroderma renal crisis are now considered rare
      because of the introduction of ACE inhibitors. Some patients may develop myositis
      or erosive arthropathy that complicate enormously the joint retraction induced by
      skin fibrosis. The peripheral nervous system (PNS) is also targeted by SSc: a
      distal mononeuropathy of the median nerve is a frequent and early feature;
      autonomic nerve dysfunction (parasympathetic impairment and marked sympathetic
      overactivity) seems to be a fundamental etiologic factor linked to the
      development of microvascular, cardiac and gastrointestinal alterations. The whole
      approach to the SSc patient is very complex and must consider, at the same time,
      many organs and systems. Thus, a global vision of SSc patient is needed in order
      to assure an early diagnosis of specific organ involvement as well as early
      treatment. Systemic Sclerosis (SSc) is a multisystem disease, that affects the
      skin, the gastrointestinal tract, the lung, the heart and the kidney. The extent
      and severity of internal organ involvement are the more important factors
      influencing the disease outcome and prognosis in SSc. In recent years, it has
      become evident that early diagnosis and accurate staging of visceral involvement
      are fundamental for appropriate management and therapeutic approach to the
      disease. Diagnostic procedures for specific organ and system involvement are now
      more sensitive because of the continuous technological improvement and, mostly,
      because they take advantage of the studies carried out in other diseases by other
      medical branches. This review will consider briefly the most frequent and
      important organ involvement in SSc.

PMID- 10599327
TI  - Scleroderma overlap syndromes.
AB  - The most common scleroderma overlap syndromes are mixed connective tissue disease
      (MCTD), scleromyositis and synthetase syndrome. There is controversy concerning
      MCTD as a separate entity due to heterogeneous clinical manifestations, not
      infrequent transformation into definite CTD and various classification criteria.
      Our study of 94 adult patients and 20 children, classified according to the
      criteria of Alarcon-Segovia, and especially a 5, 9-year follow-up showed
      transformation into SLE or SSc in over 20% of patients, less frequently than
      reported by others, whereas over half of the cases remained undifferentiated CTD.
      In several cases ARA criteria for both SSc and SLE were fulfilled, and there is
      no consensus whether such cases should be recognized as coexistence of both
      definite diseases or as MCTD. High titers of U1 RNP antibodies to 70 kD epitope
      were invariably present, whereas, by transformation into distinctive CTD there
      appeared, in addition, antibodies characteristic of these CTD. Of 108 cases
      positive for PM-Scl antibody, 83% were associated with scleromyositis. This
      scleroderma overlap syndrome differed from MCTD by coexistent features of
      dermatomyositis (myalgia, myositis, Gottron sign, heliotrope rash, calcinosis)
      with no component of SLE, characteristic of MCTD. The course was also chronic and
      rather benign, as in MCTD, and all cases responded to low or moderate doses of
      corticosteroids. A not infrequent complication was deforming arthritis of the
      hands. Our immunogenetic study showed an association of cases positive for PM-Scl
      antibody with HLA-DQA1x0501 alleles in 100% and with HLA-DRB1x0301 in 94% of
      cases. Synthetase syndrome, associated with anti-histidyl-tRNA synthetase
      antibodies, studied in 29 patients with myositis and interstitial lung disease
      (ILD), only in single cases had scleroderma-like features. These cases differed
      from SSc by acute onset with fever, and by response to moderate doses of
      corticosteroids. We also studied overlap of localized scleroderma with other CTD:
      21 cases of progressive facial hemiatrophy and linear scleroderma, and 55 (39.5%)
      of atrophoderma Pasini-Pierini (APP) and morphea. As in other autoimmune
      disorders, two or more connective tissue diseases (CTD) may develop concurrently
      or sequentially in the same patient. In such overlap syndromes ARA criteria must
      be fulfilled for each of the disease, and the clinical presentation has features
      of both. However more frequently overlap syndromes only combine some
      manifestations of more than one CTD, and present a highly heterogeneous group of
      disorders with prevailing clinical features of SSc.

PMID- 10599328
TI  - Raynaud's phenomenon and vascular disease in systemic sclerosis.
AB  - Raynaud's phenomenon (RP) is very often the first manifestation of SSc preceding
      the onset of all the other signs and symptoms of the disease. Two structures are
      involved in the pathogenesis of RP: the endothelium and the peripheral nervous
      system (PNS). The hypothesis is that SSc modifies consistently the activity of
      both these systems leading eventually to RP. The disease, through the injury to
      the endothelium, jeopardizes the basilar endothelial-dependent vascular tone
      control. An increase of endothelin, a potent endothelial-derived vasoconstrictor,
      and the reduction of nitric oxide, one of the main endothelial vasodilators, are
      two key events involved in the genesis of RP. The PNS is also targeted by the
      disease as demonstrated by the high incidence of neuropathy in SSc patients. A
      marked reduction of sensory fibres has been detected in SSc skin. Thus, the
      involvement of nerve terminals reduces the vasodilatory, endothelial dependent or
      independent, potential of the neuropeptides released by sensory nerve endings.
      Indeed, an increased sensitivity of alpha 2 adrenoceptors mediated
      vasoconstriction has been shown in SSc skin. The complex vasodilatory network
      formed by the interaction between the endothelium and the PNS seems greatly
      damaged by SSc leading inesorably toward vascular tone dysfunction clinically
      evident as RP.

PMID- 10599329
TI  - Linear scleroderma en Coup de Sabre. Relationship with progressive facial
      hemiatrophy (PFH).

PMID- 10599330
TI  - Scleroderma profunda. Clinicopathological studies.
AB  - Scleroderma profunda represents an unusual clinical entity. There are no unified
      criteria for its diagnosis. Seven patients with scleroderma profunda were
      studied. The clinical features can be summarised in three groups: 1.
      hyperpigmented plaques with subcutaneous induration; 2. erythematous plaques with
      induration of the skin and subcutis; 3. pale indurated plaques with atrophy and
      sometimes ulcerobullous lesions. Histology showed sclerodermiform changes in the
      deep dermis and subcutis and vasculitis in one case. Dermal lymphocytic
      infiltration was well pronounced in 5 cases and consisted of predominantly CD3+ T
      cells. Differential diagnosis from panniculitis can be difficult. Mucin
      deposition was established in all cases.

PMID- 10599331
TI  - Early diagnosis of systemic sclerosis.

PMID- 10599332
TI  - Cutaneous necrotizing vasculitis. Relation to systemic disease.
AB  - Cutaneous necrotizing vasculitis (CNV) is a complex multisystem disease generally
      involving the skin and mucous membranes, often accompanied by renal,
      gastrointestinal, pericardial, neurological, and articular signs and symptoms.
      CNV may be idiopatical or occur in association with a drug, infection, or
      underlying disease. CNV has been shown in patients with chronic infections
      (viral, bacterial, protozoa, helminthic), serum sickness, a variety of collagen
      vascular diseases (systemic lupus erythematous, Sjogren's syndrome, rheumatoid
      arthritis, Behcet's disease) hyperglobulinemic states, cryoglobulinemia, bowel
      bypass syndrome, ulcerative colitis, cystic fibrosis, primary biliary cirrhosis
      and HIV infection. Association with malignancies is not frequent.
      Lymphoproliferative disorders (Hodgkin's disease, mycosis fungoides,
      lymphosarcoma, adult T-cell leukemia, multiple mieloma) and solid tumors (lung
      cancer, colon carcinoma, renal, prostate, head and neck cancer and breast cancer)
      may be associated with CNV. Whenever possible, treatment is directed at the
      elimination of the cause. In other cases after adequate laboratory screening
      local and systemic therapy are recommended.

PMID- 10599333
TI  - Sjogren's syndrome. Autoimmune epithelitis.
AB  - Sjogren's syndrome is a chronic autoimmune disorder characterized by mononuclear
      cell infiltration proximally to epithelial cells of exocrine glands. In recent
      years, several studies have tried to address the function of the components of
      the immunopathologic lesion in Sjogren's syndrome. The majority of the
      mononuclear infiltrating cells are CD4 positive T lymphocytes (60-70%) whereas B
      cells constitute one fourth of the infiltrating cells. Macrophages and natural
      killer cells are poorly represented in the lesion. Epithelial cells of minor
      salivary glands of patients with Sjogren's syndrome express proinflammatory
      cytokines (IL-1 beta, IL-6), protooncogenes (c-myc) and costimulatory molecules
      (B71, B72). The destruction of epithelial cells of Sjogren's syndrome patients is
      probably due to activation of several apoptotic pathways since epithelial cells
      express different apoptosis related molecules such as Fas, FasL, Bax, while
      mononuclear cells express Bcl-2, Perforin and Granzymes. Finally epithelial cells
      seem to exert a regenerative effort since they express trefoil proteins (pS2).
      The above properties give epithelial cells a significant role in the
      pathophysiology of the syndrome but the exact events which drive the immune
      system towards an autoimmune reaction remain obscure.

PMID- 10599334
TI  - Behcet's syndrome. The Cerrahpasa experience. Members of the Behcet's Syndrome
      Research Centre.
AB  - Behcet's syndrome (BS) is a systemic vasculitis of unknown etiology. There are
      several reasons for doubting a primary autoimmune pathogenesis of this condition.
      Recent information suggests evidence for genetic anticipation. Although there is
      heightened inflammatory activity, as exemplified by the pathergy reaction, wound
      healing in BS is normal. BS also runs a more stormy course in adults and in the
      young. However, the amount of androgen receptors in scrotal skin have not found
      to be increased. Another unsolved problem is the nature of acne-like lesions and
      how they differ from acne vulgaris (AV). Only lesions in "non-acne" areas were
      compared between the two conditions, and no differences were detected. Mortality
      is increased in BS, especially among males. Azathioprine proved to be effective
      in disease control after 8 years of follow-up. We have also recently finished a
      24 week controlled trial of two doses of thalidomide, 100 mg and 300 mg per day.
      Both doses were superior to placebo, with no real differences in efficacy, in
      controlling the oral and genital ulcers.

PMID- 10599335
TI  - Autoantibodies in SLE. Disease associations.
AB  - Antinuclear antibodies are an almost universal feature of SLE. Over the years
      they have been the subject of intensive study to understand the underlying
      pathogenesis of the disease. It is clear that ANA in the context of lupus are
      directed against highly selected targets and are not just the result of
      nonspecific polyclonal B cell activation. Frequently they react with components
      of nucleoprotein complexes involved in important cellular processes which are
      very specific targets for autoimmunity in this condition. The antibodies
      themselves belong primarily to the IgG1 and IgG3 subclasses of immunoglobulin,
      are high affinity, occur in large amounts, have important associations with
      particular HLA class II genes and show all the features of an antigen-driven, T
      cell-dependent immune response. Although at first glance there is a wide range of
      antibody specificities associated with SLE, in the individual patient the
      autoantibody profile is much more restricted. Methods to detect these antibodies
      have provided the clinician with valuable tools to assist both in diagnosis and
      assessment of lupus patients. It has been possible to recognise distinctive
      serological subsets within the spectrum of lupus which are associated with
      certain patterns of disease expression. This can be helpful in determining both
      disease classification and prognosis.

PMID- 10599336
TI  - Polymorphisms of the xenobiotic-metabolizing enzymes CYP1A1 and NAT-2 in systemic
      sclerosis and lupus erythematosus.
AB  - The etiology of systemic autoimmune diseases, such as systemic lupus
      erythematosus (SLE) and systemic sclerosis (SSc) is still unknown. In several
      cases, however, xenobiotics (i.e. drugs and occupational agents) were identified
      as etiologic agents and associations with certain polymorphic alleles of
      xenobiotic-metabolizing enzymes have been reported. Cytochrome P4501A1 (CYP1A1)
      and N-acetyltransferase 2 (NAT-2) are xenobiotic-metabolizing enzymes of phase 1-
      and phase 2-metabolism, respectively. CYP1A1 may activate drugs and other
      chemicals to reactive metabolites. NAT-2 is the most important enzyme in
      acetylation of aromatic amines, and thus may be responsible for detoxification of
      many of these compounds. Two polymorphisms of the human CYP1A1 gene, a point
      mutation in the 3' flanking region of the gene (Msp1) and a mutation in exon 7
      leading to an isoleucine-valine-exchange in the heme-binding region of the
      enzyme, have been described and may lead to a higher basal and inducible enzyme
      activity. With respect to NAT-2, several alleles which combine for the two
      phenotypes "fast" and "slow" acetylators have been described. We analyzed the
      gene frequencies of the CYP1A1 polymorphisms and the phenotypes of NAT-2 in
      patients suffering from idiopathic SLE or SSc. CYP1A1 polymorphisms were analyzed
      in genomic DNA by PCR, whereas NAT-2 phenotypes were measured by the caffeine
      method. For CYP1A1 polymorphisms, 106 patients have been typed until now. The SLE
      group (n = 68) exhibited a significant increase (p < 0.05) in the mutant Val
      allele (OR = 2.59) when compared to controls (n = 184). However, no significant
      differences in allele frequencies for MspI in the SLE group and for both CYP1A1
      polymorphisms in the SSc group could be observed. Regarding the NAT-2 phenotype,
      patients suffering from SLE (n = 88) 75% and SSc (n = 26) 80.2%, respectively,
      were slow acetylators compared to 55% slow acetylators in the healthy German
      population (p < 0.05). The observed increased frequencies of the CYP1A1 mutant
      Val-allele and the slow actylator phenotype in idiopathic autoimmune disease
      support our concept that in slow acetylators non-acetylated xenobiotics may
      accumulate and are subsequently metabolized by other enzymes into reactive
      intermediates. Thus, enhanced formation of reactive metabolites could alter self
      proteins presented to the immune system thus stimulating autoreactive T cells
      which induce autoimmunity.

PMID- 10599337
TI  - Elevated soluble E-selectin in cutaneous lupus erythematosus.
AB  - Elevated levels of soluble adhesion molecules (sCAMs); sE-Selectin, sICAM-1, and
      sVCAM-1 have been reported in various inflammatory and autoimmune diseases such
      as systemic lupus erythematosus (SLE), but not in cutaneous LE. 1.1. PATIENTS AND
      METHODS: Sixty-nine serum samples from 51 LE patients, 24 with SLE, 19 with
      chronic cutaneous (DLE) and 8 with subacute cutaneous (SCLE) and sera from 32
      controls were examined for sE-Selectin, sICAM-1 and sVCAM-1 using commercially
      available ELISA kits. Thirty serum samples from different time points were
      available from 12 LE patients. 1.2. RESULTS: Significantly elevated levels of sE
      Selectin were found in DLE patients with wide-spread lesions. In contrast,
      patients with SLE and SCLE did not have elevated levels of sE-Selectin but in
      concordance with earlier reports, sICAM-1 and sVCAM-1 were elevated in these
      patients. In serial samples it seemed that sE-Selectin correlated significantly
      with active cutaneous skin lesions while sICAM-1 remained elevated irrespective
      of disease activity. 1.3. CONCLUSION: Since activated endothelial cells are the
      only source for sE-Selectin, our results suggest a more important role of
      endothelial cells in cutaneous LE than has previously been assumed. Further it
      might be speculated that selective inhibition of E-Selectin could have
      therapeutic implication in cutaneous LE.

PMID- 10599338
TI  - RNP positivity in Maltese SLE patients.
AB  - The SLE database at the Rheumatology Clinic, St. Luke's Hospital currently
      includes 62 patients. The presentation, clinical features, ACR criteria and
      laboratory findings in RNP positive lupus patients [14] were compared to RNP
      negative subgroup [33]. RNP positivity was significantly associated with
      Raynaud's phenomenon (p < 0.01), myalgia (p < 0.02), myositis (p < 0.05),
      neuropsychiatric features (p < 0.05) and Sm positivity (p < 0.01). RNP positive
      patients had a higher frequency of positive family history, mortality, malar and
      maculopapular rashes, nail-fold infarcts, telangiectasia, digital vasculitis,
      photo-sensitivity, arthritis, pleurisy, pericarditis, pericardial effusions,
      depression, headache, psychosis and TIA.

PMID- 10599339
TI  - Chilblain lupus erythematosus is associated with antibodies to SSA/Ro.
AB  - Chillblain Lupus Erythematosus (CL) of Hutchinson is a subtype of Lupus
      Erythematosus characterized by erythematous lesions symmetrically distributed on
      the face, nose, fingers and toes, knees and heels. The lesions are induced by
      cold, damp climates. A number of patients affected by CL eventually develop
      features of Systemic Lupus Erythematosus (SLE). We report here 7 patients, all
      but one affected by SLE, with chilblain cutaneous lesions on their hands, feet
      and face. The onset of CL preceded the diagnosis of SLE, from 1 to 10 years in 3
      cases, it was concurrent in one case and was subsequent in the other 2 cases. Six
      out of the seven patients referred typical Raynaud's phenomenon and one had
      acrocyanosis. CL lesions developed and were aggravated by the cold during autumn
      and winter, they improved during summer. Skin biopsy performed in 5 patients from
      the lesions showed, on histology, a typical pattern of alterations with granular
      deposits at the dermo-epidermal junction on direct immunofluorescence. Laboratory
      findings showed: ANA and anti-SSA/Ro were detected in all the patients, anti
      SSA/Ro were isolated in 4 patients and associated with anti-Sm in one case, anti
      U1 RNP in one case and with anti-Sm and anti-RNP in a third case. Complement
      consumption was observed in 5 patients, anti-dsDNA in the six patients with SLE,
      hypergammaglobulinemia in 4 and rheumatoid factor in one. The fine specificity of
      anti-SSA/Ro as determined by immunoblotting using a human spleen extract as a
      substrate, showed: anti-60kD and anti-52 kD in two sera, anti-60kD isolated in 2
      sera, anti-52kD isolated in one serum (from the patient without SLE) while 2 sera
      did not blotted. In conclusion, our study confirms the previous report of anti
      SSA/Ro antibodies in association with CL. This clinical and serologic association
      widens the spectrum of cutaneous disease that is associated with antibodies to
      SSA/Ro to include conditions such as to SCLE, hypergammaglobulinemic purpura and
      neonatal lupus.

PMID- 10599340
TI  - Male SLE patients in Malta.
AB  - The SLE patient database at the Rheumatology Clinic, St. Luke's Hospital includes
      62 patients, 58 of which have complete data. The patients were grouped according
      to sex (7 males vs 51 females). The presentation, clinical manifestations, ACR
      criteria and laboratory findings of the 2 groups were analyzed and compared.
      Serositis as the initial manifestation at presentation was significantly commoner
      in males (29% vs 2%; p < 0.05). Cardiorespiratory problems such as pleurisy,
      pericarditis, pericardial effusions and myocarditis were more frequent in the
      male subgroup. Female patients had more arthritis, myositis, neuropsychiatric
      manifestations (depression, psychosis and headache) anemia, leucopenia and ENA
      positivity than their male counterparts. All 6 mortalities recorded were in the
      female subgroup.

PMID- 10599341
TI  - Dermatomyositis. Diagnosis and evaluation of dermatomyositis, polymyositis, and
      inclusion-body myositis.
AB  - In diseases of an unknown etiology, such as the idiopathic inflammatory
      myopathies, we must tackle first of all the question of classification and the
      degree of disease activity before we can institute treatment. The majority of
      idiopathic inflammatory myopathies are diagnosed clinically and confirmed by
      biopsy. The presently applicable methods of diagnosis and evaluation of
      idiopathic inflammatory myopathy have certain limitations, and hence it is
      necessary to apply new methods of rating the disease activities. Magnetic
      resonance imaging (MRI) and 99m-technetium muscle-scanning are the latest
      noninvasive methods for evaluation of disease activities with myositis. Future
      laboratory methods to determine the numerous myositis-specific autoantibodies
      will probably enable identification of subsets of these diseases.

PMID- 10599342
TI  - Dermatomyositis and drugs.
AB  - Dermatomyositis (DM) is an idiopathic inflammatory disorder consisting of skin
      and skeletal muscle involvement. Patients with skeletal muscle involvement have
      polymyositis (PM), and those unresponsive to therapy and with characteristic
      findings on muscle biopsy have inclusion body myositis. Patients without muscle
      damage and typical skin lesions have amyopathic dermatomyositis. Disease in
      children (juvenile dermatomyositis) is not associated with malignancy as it may
      be in adults (paraneoplastic dermatomyositis). Overlap syndrome (OS) is mixed
      connective tissue disease combining some features of DM, SS and LES.
      Scleromyositis is overlap syndrome associated with anti-PM-Sci antibodies.
      Patients with PM, DM or OS with "interstitial lung disease" and anti-synthetase
      antibodies have an "anti-synthetase syndrome". Various drugs, including d
      penicillamine, NSAIDs, anti-infectious agents, as well as lipid lowering drugs,
      the HMG-CoA reductase inhibitors may cause myopathy and skin lesions (drug
      induced dermatomyositis). "Dermatomyositis" occurring as adverse reactions of
      drugs are rare, irregular and impossible to predict in individual patients. They
      are very interesting in that they may be keys for explaining the pathogenic
      mechanisms of the disease.

PMID- 10599343
TI  - Dermatomyositis associated with malignancy. 12 case reports.
AB  - Dermatomyositis (DM) is an idiopathic inflammatory disease of unknown etiology
      which manifests itself with symmetrical proximal muscle weakness and typical
      heliotrope skin rash. Internal malignancy is a specific trigger for some cases of
      DM. The aim of this study is to find predictive signs of cancer in
      dermatomyositis patients. Twelve (2 males and 10 females) (24%) out of 50 adult
      patients with DM (10 males and 40 females between 21 and 81 years old) had
      associated with malignancy (paraneopastic dermatomyositis, PDM). The male: female
      ratio in patients with idiopathic dermatomyositis (IDM) was 1:3.75 and for PDM it
      was 1:5. The frequency of dermatomyositis increases with age. PDM is most
      frequent between 40 and 69 years of life. Associated malignancies were
      respiratory tract carcinomas in males, genital and breast carcinomas in females.
      DM preceded the carcinoma in 5 cases (41.7%); 7 patients (58.3%) had already been
      treated for malignancy. In conclusion PDM in our country is more frequent in
      females and in the age after 40 years. Association of dermatomyositis with
      malignancy is relatively high.

PMID- 10599345
TI  - Psoriatic arthritis. Is something changing?
AB  - The definition of psoriatic arthritis may be at least inadequate. Moreover,
      diagnostic criteria proposed may be too restrictive. This may have affected the
      collection of reliable epidemiological data and may also influenced the
      classification of the disease. In this article all these aspects are discussed
      with the aim of offering an up-date on this intriguing disease. Therapeutic
      options are also examined.

PMID- 10599344
TI  - Reactive arthritis.
AB  - Reactive arthritis is one of the spondyloarthropathy family of clinical
      syndromes. The clinical features are those shared by other members of the
      spondyloarthritis family, though it is distinguished by a clear relationship with
      a precipitating infection. Susceptibility to reactive arthritis is closely linked
      with the class 1 HLA allele B27; it is likely that all sub-types pre-dispose to
      this condition. The link between HLA B27 and infection is mirrored by the
      development of arthritis in HLA B27-transgenic rats. In this model, arthritis
      does not develop in animals maintained in a germ-free environment. Infections of
      the gastrointestinal, genitourinary and respiratory tract appear to provoke
      reactive arthritis and a wide range of pathogens has now been implicated.
      Although mechanistic parallels may exist, reactive arthritis is distinguished
      from Lyme disease, rheumatic fever and Whipple's disease by virtue of the
      distinct clinical features and the link with HLA B27. As in these conditions both
      antigens and DNA of several micro-organisms have been detected in joint material
      from patients with reactive arthritis. The role of such disseminated microbial
      elements in the provocation or maintenance of arthritis remains unclear. HLA B27
      restricted T-cell responses to microbial antigens have been demonstrated and
      these may be important in disease pathogenesis. The importance of dissemination
      of bacteria from sites of mucosal infection and their deposition in joints has
      yet to be fully understood. The role of antibiotic therapy in the treatment of
      reactive arthritis is being explored; in some circumstances, both the anti
      inflammatory and anti-microbial effects of certain antibiotics appear to be
      valuable. The term reactive arthritis should be seen as a transitory one,
      reflecting a concept which may itself be on the verge of replacement, as our
      understanding of the condition develops. Nevertheless it appropriately describes
      arthritis that is associated with demonstrable infection at a distant site
      without traditional evidence of sepsis at the affected joint(s). Although several
      forms of disease could be described as "reactive", particularly acute rheumatic
      fever, post-meningococcal septicaemia arthritis and Lyme disease, in clinical
      practice the term is restricted to an acute spondyloarthritis, usually, but not
      exclusively, linked to acute genitourinary or gastrointestinal infection. A
      proportion of patients fulfil criteria for Reiter's Syndrome [1].

PMID- 10599346
TI  - Incidence of antiperinuclear factor in patients with psoriatic arthritis.
AB  - Antiperinuclear factor (APF) is considered a disease marker of rheumatoid
      arthritis (RA) and its diagnostic value is obvious in patients who are
      seronegative for rheumatoid factor (RF) activity. We have evaluated APF
      positivites in 76 patients with psoriatic arthritis, 38 uncomplicated psoriatic
      patients, 119 patients with non-inflammatory rheumatic diseases (NIRD), 36 RF-
      and 123 RF + RA patients and 204 healthy controls. APFs were investigated with an
      indirect immunofluorescence (IIF) test using epithelial cells from human buccal
      mucosa as a substrate. 6/76 (7.9%) PA patients were APF+. The incidence was
      greater than in healthy controls (2/204; p < 0.01) and similar to the incidences
      in patients with uncomplicated psoriasis (1/38; p = NS) and patients with non
      inflammatory rheumatic disease NIRD (5/119; p = NS). However, the incidence was
      much lower than in RF- (19/36; p < 0.001) as well as RF+ (111/123; p < 0.001) RA
      patients. Finally, we emphasise that 3 out of 6 APF positivities shown by PA
      patients were found in our 3 patients with pustolotic arthroosteitis, a new
      specific entity in the spectrum of PA.

PMID- 10599347
TI  - Triggered psoriasis.
AB  - There are conflicting reports in the literature concerning the use of
      antimalarials in psoriatic patients with arthropathy or coexisting systemic lupus
      erythematosus. On the basis of a review of 18 publications in English, it was
      estimated that up to 18% of patients with psoriasis would develop an exacerbation
      of their disease following antimalarial therapy. In contrast to lithium and beta
      blockers, antimalarials do not induce psoriasis de novo, but they only trigger
      already existing psoriasis, via a pharmacologic mechanism, probably due to an
      alteration of the activity of enzymes involved in the epidermal proliferation
      process. The chemical structure of the antimalarials is very similar to
      dansylputrescine, a potent transglutaminase (TGase) inhibitor. We suggested
      therefore that antimalarials trigger psoriasis through the modulation of the
      TGase activity. To verify this hypothesis, we examined the effect of
      hydroxychoroquine sulphate (HCQS) on cultured human skin and on TGase activity in
      vitro. Significant changes of epidermal morphology were seen in all explants
      cultured in the presence of HCQS. HCQS showed a concentration-dependent
      inhibition of TGase activity. We suggest that HCQS caused an initial break in the
      barrier function of the epidermis by inhibiting TGase activity; this was followed
      by a physiologic response of the epidermis aimed at barrier restoration. This
      rather non-specific stimulus to epidermal proliferation is probably sufficient to
      trigger psoriasis in predisposed individuals. Drug eruption is an age-old but
      timeless and fascinating subject. Of particular interest are those drug eruptions
      that may mimic idiopathic skin diseases. Apart from their obvious practical
      importance they are also of theoretical interest, because they provide an
      opportunity to investigate possible pathogenic mechanisms of the mimicked
      disease. In this paper, I would like to review briefly the characteristics of
      drug-induced psoriasis, and then propose a hypothesis concerning the pathogenesis
      of this phenomenon. In all, we found 258 reported cases of drug-induced psoriasis
      [1]. The drugs mainly involved are the antimalarials, lithium, beta blockers, and
      a large group of miscellaneous drugs. Three out of the four groups of drugs
      (lithium, beta blockers and miscellaneous drugs) can both induce or trigger
      psoriasis with almost equal frequency, namely they induce psoriasis de novo or
      they exacerbate an already existing psoriasis in 30-50% of the reported cases.
      Only one group of drugs, the antimalarials is an exception. In contrast to
      lithium and beta blockers, antimalarials do not induce psoriasis de novo, but
      only trigger already existing psoriasis. There are only three reported cases of
      psoriasis induced by antimalarials in patients who did not have the disease
      previously. Of these three patients, one had a seronegative arthritis and a
      family history of psoriasis, and, as stated by the author, there is evidence that
      the patient had pre-existing latent psoriasis. We believe that the other two
      cases may also have had latent psoriasis. That antimalarial drugs only trigger
      latent psoriasis and do not induce psoriasis de novo can be suspected from the
      fact that psoriasis cleared up completely after withdrawal of the drug in only
      30% of patients on antimalarials, as compared with more than 60% of those
      receiving lithium and nearly 50% of those receiving beta blockers. This is
      probably also why the incubation period of the cases induced by antimalarial
      drugs is much shorter than that of lithium and beta blockers. Possibly, in
      triggered psoriasis (as in antimalarials) the drug only sets off with a chain of
      pathologic events previously programmed and ready to be set off, whereas in true
      drug-induced cases (as in some cases of lithium and betablockers) the drug is
      supposed to cause more profound changes and, therefore, more time is needed for
      these changes to occur.

PMID- 10599348
TI  - Pyridinium crosslinks excretion in patients with rheumatoid arthritis.
      Correlation with disease activity and glucocorticoid treatment.
AB  - In patients with rheumatoid arthritis, significant positive correlations were
      found between urinary pyridinium crosslinks and C-reactive protein (CRP),
      erythrocyte sedimentation rate (ESR) and articular index. Also an inverse
      correlation was observed between pyridinium crosslinks excretion and grip
      strength. Glucocorticoid therapy, equivalent to daily doses of 7.5 mg of
      prednisolone or less, did not appear to have deleterious effect on bone
      metabolism in these patients as measured by urinary pyridinium crosslinks.

PMID- 10599349
TI  - Porphyria. From Sir Walter Raleigh to molecular biology.
AB  - The porphyrias are a group of disorders caused by deficient activity of the
      enzymes responsible for the biosynthesis of haem. The skin is one of the major
      organs involved in most of these diseases because the porphyrins which accumulate
      are phototoxic. The common cutaneous porphyrias are variegate porphyria,
      porphyria cutanea tarda, congenital erythropoietic porphyria and erythropoietic
      protoporphyria, each caused by a different enzyme deficiency causing a
      distinctive pattern of porphyrin accumulation and typical clinical features. The
      genes encoding these enzymes have all been cloned recently, enabling the genetic
      defects underlying these disorders to be elucidated. The factors triggering
      sporadic porphyria cutanea tarda in predisposed individuals are now becoming
      clear: hepatic iron overload is required to induce the hepatic enzyme defect and
      many patients are haemochromatosis gene carriers. Hepatitis B, C, and HIV virus
      infection also contribute to disease expression. In erythropoietic
      protoporphyria, up to 5% of patients develop liver failure. It is now clear that
      some of these patients suffer from a different recessively transmitted form of
      the disease: this finding may make it possible to identify these patients at an
      earlier stage. Gene therapy holds particular promise as a future therapy and has
      successfully been used to correct enzyme defects in vitro. Bone marrow
      transplantation has also been tried in patients with congenital erythropoietic
      porphyria. The joints are not involved by porphyria. However, some non-steroidal
      inflammatory drugs prescribed by rheumatologists have phototoxic properties
      similar to uroporphyrin. These drugs cause a syndrome clinically and
      histologically indistinguishable from porphyria cutanea tarda which is known as
      pseudoporphyria.

PMID- 10599350
TI  - Photosensitivity and joint dysfunction.

PMID- 10599351
TI  - Role of superantigens in dermatology.

PMID- 10599352
TI  - Intravascular lymphomatosis. A report of ten patients with central nervous system
      involvement and a review of the disease process.
AB  - The clinical, radiographic, and pathological findings in ten cases of
      intravascular lymphomatosis with central nervous system involvement seen at our
      institution over a 15-year period are presented. Nine patients presented with a
      subacute, progressive multifocal neurologic disorder. Most patients had fever,
      anemia, and elevation of the erythrocyte sedimentation rate. As the illness
      evolved, computerized tomography scanning and magnetic resonance imaging showed
      evidence of multifocal central nervous system disease. Angiography was
      nondiagnostic but suggested vasculitis in six cases. A response to empiric
      corticosteroid treatment was typical but usually transient. In six patients, the
      diagnosis was made antemortem by brain biopsy. The prognosis of patients was
      primarily dependent on early diagnosis and treatment, before massive central
      nervous system damage occurred. Treatment with chemotherapy, with or without
      radiotherapy, was associated with stabilization of the disease in three of five
      patients.

PMID- 10599353
TI  - Pemphigus and diet. Have we solved the mystery of fogo selvagem?
AB  - The role of nutrition in causing or preventing skin diseases is an ongoing
      interest to clinicians and researchers. An example is the well-established
      relationship between the exacerbation of acute gouty arthritis and high purine
      foods. A recent phenomenon of the link between diet and skin disease is that
      between certain foods--including garlic, onion and leek--and pemphigus. This
      connection is being intensively researched by us in collaboration with Ruocco and
      colleagues at the University of Naples II School of Medicine and Surgery. Case
      studies with supporting histological and immunological evidence are accumulating
      showing the role of these foods in provoking and exacerbating pemphigus.

PMID- 10599354
TI  - The treatment of systemic sclerosis.

PMID- 10599355
TI  - Enalapril (10 mg/day) in systemic sclerosis. One year, double blind, randomised
      study (ESS-1): echocardiographic substudy--three months follow-up.
AB  - The ESS-1 study was designed to evaluate the long-term effects of the angiotensin
      converting enzyme inhibitor (ACEI) enalapril (10 mg per day) on the cardio
      pulmonary system in patients with scleroderma (SSc). We estimated changes in
      heart diameters, systolic and diastolic left ventricle function and mean values
      of pulmonary artery pressure after 3 months treatment. The study group comprise
      41 patients with SSc. 18 patients received placebo and 23 ones were given
      enalapril. After 3 months of treatment we did not observe statistically
      significant differences in heart diameters and left ventricle systolic function
      parameters between treated group and placebo. Enalapril therapy did not affect
      left ventricle diastolic function, nevertheless differences in MVA were almost of
      statistical significance. Echocardiographic signs of pulmonary hypertension were
      found in 4 patients.

PMID- 10599357
TI  - Enalapril (10 mg/day) in systemic sclerosis. One year, double blind, randomised
      study (ESS-1): pulmonary substudy--effects of three month treatment.
AB  - The ESS-1 study is designed to evaluate the long-term effects of enalapril on
      cardiopulmonary system of patients with systemic sclerosis (SSc). During the one
      year study period 5 visits are scheduled at 3 months intervals. The effect of 3
      months treatment with enalapril (10 mg per day) on lung function was studied in
      18 patients with SSc (enalapril group) and compared with controls--23 patients
      with Ssc (placebo group), mean age, SSc duration, gender and % of patients with
      dcSSc did not differ significantly in both groups. We performed body
      plethysmography for total airways resistance (Rtot), and static lung volumes
      (TLC, ITGV and RV), spirometry for FEV1 and FVC and we measured flow parameters
      (PEF, FEF). We compared initial lung function (first examination) with results
      after 3 months treatment (second examination) in the enalapril and in the placebo
      group. Mean values of Rtot, ITGV and RV did not differ significantly in the
      enalapril group or in the placebo group before and after treatment but FVC, FEV1
      and FEF50 were significantly lower in the enalapril group and did not change in
      the placebo group after three months. We conclude that 3 month treatment with
      enalapril worsens spirometry of SSc patients. We did not observe any changes in
      lung functions in the control group in the same three month period.

PMID- 10599358
TI  - Enalapril (10 mg/day) in systemic sclerosis. One year, double blind, randomised
      study (ESS-1): electrocardiographic substudy--three months follow-up.
AB  - The ESS-1 study was designed to evaluate the long-term effects of enalapril (10
      mg per day) on the cardiopulmonary system of patients with systemic sclerosis
      (SSc). The 3 months follow-up was completed by 41 patients (23 patients in
      enalapril group and 18 in placebo group). We analysed conventional time domain
      signal averaged ECG (SAECG). Late potentials were considered to be present in QRS
      duration (QRS) was > 114 ms or root mean square of last 40 ms (RMS40) was < 20
      microV or terminal signal duration under 40 microV (LAS40) was > 38 ms at 40 Hz.
      At the beginning of study the prevalence of abnormal SAEG parameters was similar
      in both groups. We observed one abnormal parameter among 13% of patients in
      enalapril group and 16.7% of patients in placebo group. There were 2 abnormal
      parameters in 26.1% of patients in enalapril group and 16.7% of patients in
      placebo group. After three months of treatment we did not find any patient with 2
      parameters of late potentials in enalapril group and only 8.7% of patients with
      one such parameter. In placebo group no substantial improvement was observed.
      CONCLUSION: The 3 months enalapril treatment seems to decrease the incidence of
      late potentials in patients with systemic sclerosis.

PMID- 10599356
TI  - Enalapril (10 mg/day) in systemic sclerosis. One year, double blind, randomised
      study (ESS-1): ECG exercise testing--three months follow-up.
AB  - The ESS-1 study was designed to evaluate the long-term effects of the angiotensin
      converting enzyme inhibitor (ACEI) enalapril (10 mg per day) on cardiopulmonary
      system of patients with systemic sclerosis (SSc). Exercise testing is used not
      only for estimation of coronary reserve but also physical capacity--the major
      determinant of quality of life. In each patient included to the ESS-1 study we
      performed ECG exercise test on treadmill (5 times at intervals of 3 months). The
      first follow-up was completed by 41 patients (23 patients in enalapril group and
      18 in placebo group). The exercise duration in the placebo group was 683 +/- 295
      sec and in enalapril group 768 +/- 173 sec. After 3 months of study there were no
      significant differences in both groups (758 +/- 271 sec and 720 +/- 191 sec
      respectively). The analysis of ST segment deviation did not provide any
      significant changes after 3 months of treatment. We conclude that 3 months
      enalapril treatment did not improve exercise tolerance in patients with systemic
      sclerosis.

PMID- 10599359
TI  - Treatment of generalized morphea with oral 1,25-dihydroxyvitamin D3.
AB  - Scleroderma is a chronic connective tissue disease characterized by excessive
      collagen synthesis and its deposition in the skin and various internal organs.
      Immune system abnormalities and disturbances of connective tissue metabolism have
      been suggested to play a central role in the pathogenesis of scleroderma. 1.25
      Dihydroxyvitamin D3 (1.25(OH)2 D3 causes inhibition of fibroblast growth, has a
      role in controlling collagen synthesis and deposition and has numerous
      immunoregulatory activities. We assessed the effects of oral 1.25 (OH)2 D3 in the
      treatment of patients with generalized morphea. Three patients with generalized
      morphea, entered an open prospective study. They were treated with oral
      calcitriol (1.25 dyhidroxyvitamin D3) in an oral daily dose of 0.50-0.75
      microgram. After the treatment period of 4-6 months, a significant clinical
      improvement was observed. The mobility of the joints improved, the skin
      extensibility increased and a substantial improvement of the skin induration. No
      serious side effects were observed. The improvement persisted after
      discontinuation of therapy during a follow-up period of one year. The evolution
      of the patients' condition during the 6 months therapy with calcitriol, suggests
      that it can be used as a beneficial agent in the treatment of generalized
      morphea. Double-blind, placebo-controlled trials are needed to assess its
      therapeutic value and a larger number of patients is desirable.

PMID- 10599360
TI  - Vasospasmolytic therapy in patients with SSC.

PMID- 10599361
TI  - Biomechanical stimulation therapy. A novel physiotherapy method for systemic
      sclerosis.
AB  - To improve the mobility of joints, particularly of the finger joints and the
      mandibular joint, and to reduce the edema of the skin, various physical therapies
      have to be used in patients with SSc. As the quality of patients' life depends on
      the use of their fingers and of their mouth, these therapeutics belong to the
      basic measures in the treatment of SSc. In addition to the manually performed
      lymph drainage a new method, the biomechanical stimulation therapy, has proven to
      be efficacious to improve the mobility of the joints and to reduce the edema in
      SSc-patients. By devices of various size, longitudinal vibrations are transduced
      to patients' body: finger, hand, face, mandibular joint, the oral mucosa, the
      legs and the trunk. In 6 patients we found: significant (p < 0.05) increase of
      skin score, grip strength, mobility of joints (10-30%). No side effects were
      observed. We conclude from these data, that skin, mucosa, joints and patients'
      quality of life are improved by the biomechanical stimulation therapy in a
      clinical relevant degree.

PMID- 10599362
TI  - Reduced skin stiffness by grenz ray treatment in generalized morphea.

PMID- 10599363
TI  - NSAIDs/corticosteroids--primum non nocere.
AB  - NSAIDs/Corticosteroids are the most used and maybe misused drugs against "aches
      and pains of the musculoskeletal system". Their effectiveness to reduce (not
      cure) inflammation and related pain is without doubt. The problem is that of
      their side effects in particular of the GI-tract and other body systems. It is
      clear that these side effects occur more often and more seriously in a number of
      patients, the so-called high risk group: elderly women, patients with previous
      history of gastro-intestinal ulcer and corticosteroid users. The discovery that
      there are two pathways to influence cyclooxygenase activity and prostaglandin
      production and that some NSAIDs have a more marked COX-2 and COX-1 inhibition
      opens new perspectives. COX-1 is present in normal tissues and is responsible for
      the production of protective prostaglandins in the gastric mucosa and other
      tissues. COX-2 is induced by inflammatory cytokines and plays a role in the
      inflammatory cascade. Therefore more specific COX-2 antagonists should be safer
      for the gastro-intestinal mucosa and kidney function. The risk of hip fracture is
      50% higher in patients receiving long-term corticosteroid therapy, and 30-35% of
      corticosteroid patients have vertebral fractures. The renewed interest in
      osteoporosis and increased number of papers on bone loss in RA reflect on the one
      hand the advances in technology to measure bone mineral density (BMD) accurately
      and precisely, and on the other hand the availability of effective drugs to stop
      bone loss and reverse the process. The possible deleterious effect of low dose
      corticosteroids continues to be a subject of concern, particularly in
      rheumatology where serum levels of free cortisone may be higher because of low
      albumen and other protein changes. Recently, several editorials and conflicting
      data obtained from cross-sectional and longitudinal studies in RA on steroid
      induced osteoporosis have been published. Because the pathogenesis of steroid
      osteoporosis is distinct from that of entities such as postmenopausal
      osteoporosis, each therapy requires specific assessment in steroid treated
      patients. In recent years a wide variety of therapies, for example hormone
      replacement therapy, calcium supplements administered with vitamin D metabolites,
      thiazides, diuretics, anabolic steroids, tibolone, calcitonin and
      bisphosphonates, have been proposed to prevent osteoporosis in patients receiving
      longterm corticosteroid therapy, but there have been few carefully controlled
      trials, except for vitamin D and bisphosphonates.

PMID- 10599364
TI  - Management issues in vasculitis.
AB  - In a Congress devoted to both rheumatic disease and skin disease, vasculitis is
      an appropriate topic for discussion. Many dermatologists believe that
      rheumatology has made a mess of the classification of vasculitis and with respect
      to management it is too drug orientated. When vasculitis is uncomplicated and
      affects only a single organ it behaves benignly and needs only attention to
      protection and decreasing the vulnerability of the skin to gravitational
      'stasis', pressure, cooling and immobility. Complicated, multi-system vasculitis
      frequently needs much of the same skin care plus additional drug therapies.
      Unfortunately, there is no evidence that vasculitis of the skin is responsive to
      such drugs other than single case reports and uncontrolled trials. Where the
      cause of the vasculitis is a known infection, food or drug, autoimmune process or
      neoplasm, removal of the cause is an appropriate policy.

PMID- 10599366
TI  - Cyclosporin A and retinoids in psoriasis.

PMID- 10599365
TI  - Sulphasalazine. An alternative drug for second-line treatment of juvenile chronic
      arthritis.
AB  - Sulphasalazine has been established to be an effective drug for second line
      treatment of early mild to moderate rheumatoid arthritis. Its application for
      juvenile chronic arthritis (JCA) is limited so far and controversial results for
      the efficacy of this therapy have been published. We studied the efficacy and
      tolerance of the sulphasalazine treatment in 32 patients with JCA (10 with
      polyarthritis, 21 with pauciarthritis and 1 with systemic form). Our results
      revealed significant response of the treatment at the end of the 6th month in
      24/31 patients (77%). In one patient the treatment was discontinued because of
      transitory neutropenia at the end of the 1st month. No significant difference was
      observed between the efficacy of the treatment in the polyarticular and
      pauciarticular disease, as well as newly-diagnosed cases and those with
      longstanding disease. From the group of 17 children treated up to the end of the
      1st year 88% achieved complete remission. No serious toxic effects were observed,
      with the exception of two cases with transitory low-grade neutropenia. According
      to our results sulphasalazine is an effective and well tolerated drug for second
      line treatment of JCA-patients.

PMID- 10599367
TI  - Methotrexate.

PMID- 10599368
TI  - Azathioprine in dermatological practice. An overview with special emphasis on its
      use in non-bullous inflammatory dermatoses.
AB  - Azathioprine is employed for its immunosuppressive properties, as a steroid
      sparing agent or as monotherapy. Its most traditional clinical indications are
      connective tissue diseases, vasculitis, post-transplant, and immunobullous
      dermatoses. The main disadvantages of azathioprine therapy are a delayed onset of
      action (6-8 weeks), and rare profound bone marrow toxicity. Susceptibility to
      bone marrow toxicity is due to a genetically determined metabolic defect (1 in
      300). Patients at risk of such toxicity may be identified by a Thiopurine
      methyltransferase enzyme assay. We have undertaken a retrospective study, looking
      at the use of azathioprine as monotherapy for non-bullous inflammatory
      dermatoses. We studied a total of 24 patients (10 male, 14 female). The
      dermatoses comprised: atopic eczema (10), pompholyx (6), plaque psoriasis (6),
      and chronic actinic dermatitis (2). All patients had severe refractory disease
      warranting systemic second line therapy. The mean age was 49.4 years (range 17-86
      years). The starting dose of azathioprine was 100-150 mg/day, and the maintenance
      dose 50-100 mg/day. The mean duration of treatment was 33.5 months(range 1-132
      months). Eighteen patients (75%) showed a good to excellent sustained clinical
      response to azathioprine. This response rate was evenly represented in the 4
      dermatoses studied. The adverse reactions encountered were raised MCV (6),
      leucopenia (2), raised hepatic enzymes (6), and dyspepsia (4). Azathioprine had
      to be discontinued due to adverse reactions in 2 patients (dyspepsia, raised
      hepatic enzymes) followed by normalization. Other factors that potentially
      contributed to the observed adverse events were present in 5 patients: alcoholism
      (2), erythromycin toxicity (1), and malabsorption (2). Our study demonstrates the
      efficacy of azathioprine monotherapy for severe atopic eczema, pompholyx, plaque
      psoriasis, and chronic actinic dermatitis. Furthermore, azathioprine is a low
      cost and generally well tolerated drug.

PMID- 10599369
TI  - The effect of methylprednisolone pulse therapy in polymyositis/dermatomyositis.
AB  - The study aim was to assess the effect of corticosteroid (CS) therapy on the
      clinical and biological features of dermatomyositis (DM) or polymyositis (PM).

PMID- 10599370
TI  - Toxicity profile of methotrexate in rheumatoid arthritis. A preliminary survey.
AB  - A number of patients with rheumatoid arthritis attending the Rheumatology Clinic
      at St Luke's Hospital are currently receiving the drug methotrexate as a second
      line disease-modifying agent. A survey has been conducted to assess the toxicity
      profile of methotrexate in 33 of these patients who were followed up for at least
      1 year or until they developed side effects necessitating discontinuation of
      treatment. Adverse effects in this group of patients included haematological ones
      (6%), asymptomatic elevations of liver enzymes (57%), gastrointestinal (6%) and
      dermatological side effects (3%). These results have been compared to larger
      studies performed abroad. Regular monitoring of a complete blood count and liver
      function tests has helped to detect the more serious side effects of methotrexate
      at an early stage enabling successful intervention in these patients.

PMID- 10599371
TI  - Mucocutaneous side effects and continuation of aurotherapy in patients with
      rheumatoid arthritis.
AB  - AIM: To examine the possibility of the continuation of therapy after achieving
      clinical improvement in patients with mucocutaneous side-effects of parenteral
      gold compound therapy (Tauredon, "Byk Gulden", Germany). METHODS AND RESULTS: 40
      patients with active seropositive rheumatoid arthritis (average age 42.8 years,
      average duration of disease 2.8 years) received Tauredon in a dosage of 50
      mg/week intramuscularly. 19 patients (47.5%) developed mucocutaneous side
      effects. Four of them were excluded from the study because of severe skin
      reactions. In 15 patients with mild or moderate side-effects (local skin rash and
      stomatitis) aurotherapy was continued after the resolution of adverse reactions.
      Four out of the 15 patients were withdrawn from the study after restarting the
      lower dose treatment due to recurrence of dermatitis. 11 out of 19 patients
      finished 1 year of study with low dose Tauredon. Clinical remission occurred in 4
      patients (36.4%) while improvement was registered in 6 patients (54.5%). In one
      patient (9.1%) no clinical effect was observed. None of these 11 demonstrated any
      Tauredon toxicity. CONCLUSION: The development of mucocutaneous side-effects
      should not be considered as an absolute contraindication for the continuation of
      gold compound therapy. A low dose regimen may allow maintenance of therapeutic
      effect and improve tolerance in this group of patients. Gold salts, such as
      disodium aurothiomalate (ATMO have been used in the treatment of rheumatoid
      arthritis (RA) for over 70 years. They suppress inflammation and retard
      radiological progression of joint damage [1], but their use is limited by a high
      incidence of toxic side-effects in about 30% of patients. The commonest side
      effect of chrysotherapy is skin toxicity, accounting for up to 60% of all adverse
      reactions [2]. Rash is most frequent in the first year of therapy, but can occur
      at any time. Stomatitis occurs in 1-12% of patients and may occur concomitantly
      with skin rash. The causes of skin rash and stomatitis are still unknown. When
      mucocutaneous reactions develop, the drug should be withheld until the condition
      resolves [3]. Approximately 2-3% of patients have to stop treatment because of
      severe skin rash and mouth ulcers [4]. However we, together with other authors
      [5, 6, 7, 8, 9] consider that mild to moderate mucocutaneous reactions are not an
      absolute contraindication for the continuation of gold therapy. The aim of our
      study is to examine the possibility for the continuation of therapy after
      achieving clinical improvement in patients with skin rash and stomatitis as a
      result of treatment with ATM (Tauredon, "Byk Gulden", Germany).

PMID- 10599372
TI  - Discoid lupus erythematosus lesions treated with cryosurgery.

PMID- 10599374
TI  - Antibiotic resistance in bacteria. A current and future problem.
AB  - Bacterial pathogens have become increasingly resistant to commonly used
      antibiotics. In some cases, there are no remaining first-line options for
      therapy. Problem pathogens which may cause dermatologic and rheumatologic
      infections will be discussed, including vancomycin-resistant staphylococci and
      enterococci as well as the multiply-resistant Gram-negative bacilli. Risk factors
      for acquisition of these organisms and diagnostic studies available for their
      detection will be reviewed. The underlying mechanisms of resistance, geographic
      prevalence, potential for continued spread, and proposed strategies for
      prevention and control are examined. Finally, information on the newer topical
      and systemic antimicrobial agents, including investigational therapies, will be
      presented.

PMID- 10599373
TI  - The value of colloid dressings in psoriasis.
AB  - In a bilateral paired comparison study 39 patients with plaque psoriasis
      completed a 4 week study using hydrocolloid dressing alone, twice daily
      Betamethasone propionate cream alone, or both therapies combined and applied
      every 7 days.

PMID- 10599375
TI  - Newer concepts in antimicrobial therapy.
AB  - Antimicrobial agents continue to play a significant role in clinical practice not
      only due to their active role in the treatment of bacterially induced infections.
      The accompanying anti-inflammatory characteristics and their antagonism against
      superantigens add to their importance. The practitioner must also be aware of
      both overt and covert unwanted effects. During the past decade, the new
      quinolones, advanced macrolides, and better cephalosporins have been introduced.
      The staid penicillins have been up-graded with the addition of a beta-lactamase
      inhibitor. Many antibiotics have been available for several decades but new uses
      for them and their derivatives permit the dermatologist to have a more versatile
      armamentarium. Rifamycin has been shown to be effective in the treatment of
      leishmaniasis. The new macrolide, clarithromycin, will reduce the lesions of acne
      vulgaris and acne rosacea. Although phototoxicity was well recognised in the
      sulfonomides, several quinolones can create similar light-induced problems.
      Bullous diseases are known to be instigated by the penicillins, while vasculitis
      may be caused by a quinolone. Even porphyria has been reported to be induced by a
      tetracycline. Antimicrobial therapy has been an integral part of dermatologic
      practice since the introduction of the sulfa drugs six decades ago. Whether skin
      is affronted by more pathogenic bacteria than any other organ or whether the
      percentage of infectious etiologies is greater for cutaneous maladies than for
      other organ afflictions is not germane to this presentation. The facts remain
      that signs and symptoms of many dermatitides are diminished or even eliminated by
      antimicrobials [1, 2, 3, 4].

PMID- 10599376
TI  - Anecdotal therapies.
AB  - Traditionally, many advances in medicine have been serendipitous. Are
      serendipitous and anecdotal synonymous? Many of our materia medica today relate
      to initial probes and anecdotal reports that matured to full investigation and
      therapeutic indications. The recent situation regarding Skin Cap is one that
      highlights the downside of this scenario. Several drugs in the US continue usage
      largely related to anecdotal indications, and anecdotal extension of legend
      indications is a standard for American Dermatology. The situation with systemic
      drugs, such as Trental, zinc preparations, imidazoles for extended indications,
      lysine and melatonin, all will be discussed. Topical preparations such as skin
      cap, cantharone, Vioform, all also are included in this category. It is important
      to place this topic in perspective in regards to geographic variation and
      therapeutic need. Many diseases lacking specific therapy are important targets
      for anecdotal therapy, and this will foster continued approaches in this area.
      The growing standardization of medicine and pharmaceutical regulation, threatens
      the anecdotal approach, but it provides still an important link to the future for
      some forms of therapy in diseases that are difficult to treat. Traditionally, the
      anecdote has been the first step in the therapeutic chain. Withering discovery of
      the benefits of the common fox glove in dropsy, was followed by many other
      anecdotes arriving via folk-medicine in the New World. This approach of utilizing
      folk medicine has now reached new heights, with very active searches by major
      pharmaceutical companies throughout the third world for remedies that may have
      potential. Couched with this is the history of anecdotal "snake-oil" remedies,
      that clearly had no benefit to anyone except the huckster marketing same. The
      excesses in this area of unproven and false therapies, led to the gradual
      organization of therapeutic trials and the Food and Drug Administration in the US
      as we know it today. The biggest shot in the arm for enhancing FDA protocols was
      the thalidomide situation, an outgrowth of an ethically studied and used
      medication that perhaps had been released too soon, prior to sufficient trials to
      determine the total patient risk. As in many situations, the pendulum swings in
      both directions, and after thalidomide, the acceptance of new treatments required
      more and more rigorous studies, and studies from other countries often were not
      acceptable unless a small part of a larger, whole proposal. The AIDS crisis has
      prompted a swing back, away from such expensive and rigorous pre-marketing
      review, to more expedited processes for the relief of patients with this fatal
      disease. This has streamlined the FDA, and hopefully the swing of the pendulum
      will not go too far, to result in problems in the future. Anecdotal therapies and
      medications are the first step in many parts of the world to therapeutic trials.
      The most widely used aspects of anecdotal therapies, again, remains in the
      situation with diseases without good therapies at the present time. The so-called
      orphan drugs and orphan diseases, while a serious medical problem, do not present
      a significant volume for effective drug screening in many instances, and the FDA
      has developed some new approaches to circumvent this very expensive development
      process for patients suffering from these rare and unusual disorders. The most
      recent example of anecdotal therapy catching the public fancy in dermatology was
      the Skin-Cap Spray. This product, over the period of twelve months, got rave
      reviews in the lay press in the non-peer reviewed dermatologic periodicals, and
      amassed impressive sales figures in this period of time. It was extremely
      effective, and most dermatologists who used it have patients who consider it the
      most effective therapy in the last year. The formulation of a low concentration
      of zinc pyrithione seemed unusual, and this truly was an anecdotal approach,
      using a homeopathic dosage of a commonly used p

PMID- 10599377
TI  - Chondrocytes-ECM interactions in human osteoarthritis.

PMID- 10599378
TI  - The inverse relationship between osteoporosis and osteoarthritis.

PMID- 10599379
TI  - Osteoarthritis. New challenges in an old disease.

PMID- 10599380
TI  - Increased reduction in bone density and skin thickness in postmenopausal women on
      long-term corticosteroid therapy. A suggested role for estrogen add back therapy.
AB  - BACKGROUND: Long term steroid therapy is complicated by osteoporosis and
      generalised thinning of the skin. These two complications of long term
      corticosteroid therapy were routinely assessed at the Menopause Clinic of St.
      Luke's Hospital, Medical School, University of Malta. METHODS: A cross sectional
      study was performed on 64 postmenopausal women who had been on long term
      corticosteroids. Each woman had her skin thickness measured using high resolution
      ultrasound (22 mhz) and their bone density measured using a DEXA Norland. These
      measurements were compared to a control group (n = 557), a group of women who had
      sustained osteoporotic fractures (n = 180), and a group of women on hormone
      replacement therapy (HRT) (n = 399). A longitudinal study on 29 postmenopausal
      women on corticosteroids was also performed. In this study results were compared
      between women who in addition to their corticosteroids were on HRT and those who
      were on corticosteroids alone. RESULTS: The cross sectional study showed the
      corticosteroid therapy was associated with the thinnest skin thickness
      measurements mean 0.83 mm. Similarly, low bone density measurements lumbar spine
      mean 0.81 g/cm2 and left hip mean 0.71 g/cm2 were obtained for this group. The
      skin thickness in controls and in the HRT groups had a mean thickness of 0.93 mm
      while that of the osteoporotic fracture group was 0.88 mm. The bone density of
      the osteoporotic fractures in the fracture group was similar to that of group of
      women on long term corticosteroids. The lumbar spine had a mean density of 0.81
      g/cm2 and left hip that of 0.71 g/cm2. The bone density of the control group and
      HRT group was significantly higher. The lumbar spine had a mean density of 0.93
      g/cm2 and that of left hip was 0.82 g/cm2. The small longitudinal study compared
      postmenopausal women on long term corticosteroid therapy on HRT to another group
      who was not on HRT. The longitudinal study over four years revealed a constant
      increase in skin thickness (mean 6% per year) and bone density (left hip mean 5%
      per year, lumbar spine mean 5% per year). CONCLUSION: In postmenopausal women on
      long term corticosteroids, skin thickness and bone density were both decreased,
      but the addition of HRT as add back improved the situation dramatically. Skin
      thickness and bone density level in women on long term corticosteroids were
      comparable to that of women who had sustained osteoporotic fractures. It is
      therefore suggested that HRT be used as add back therapy in postmenopausal women
      on long term corticosteroid therapy.

PMID- 10599381
TI  - Paget's disease of bone in Malta. A preliminary survey.
AB  - We present the results of a preliminary survey carried out on 46 patients with
      Paget's disease of bone in Malta, 40 of whom were seen at a general medical
      outpatient clinic and a further 6 at a primary health care centre over the first
      6 months of 1997. Various aspects of the disease have been analysed: prevalence,
      age and sex distribution, familial aggregates, mode of presentation,
      complications, pattern of bone involvement, a semi-quantitative assay of disease
      activity as assessed by bone scintigraphy and serum alkaline phosphatase (SAP)
      levels, and the factors that influenced disease activity. The results have been
      compared to previous published surveys on Paget's disease in different countries.

PMID- 10599382
TI  - Joint replacement. The final solution?
AB  - Joint replacement is now a well established procedure that provides pain relief,
      mobility and stability to arthritic joints. The development of hip and knee
      replacement surgery is used to highlight some basic principles of joint
      replacement. The results of total knee replacements performed by the senior
      author were analysed in two separate, 2 to 5 year follow-up studies using the
      Scoring System of The Knee Society of America. Both studies confirm the
      reproducible, good results of this procedure. Indeed, the demand for this type of
      surgery has increased and in Malta, at present, the number of knee replacements
      performed out-numbers hip replacements by two to one. After total knee
      replacement rheumatoid arthritis patients have results that compare well with
      those of osteoarthritis patients. These patients, in particular, should benefit
      from early joint replacement.

PMID- 10599383
TI  - The archaeology of joint disease.

PMID- 10599384
TI  - Sun and skin. Role of phototype and skin colour.
AB  - The study of the biological effects of sun on the skin is one of the most topical
      questions in the recent dermatological literature. Interest in these effects has
      grown since it was demonstrated that the sun accelerates intrinsic skin ageing
      and is a principal factor for skin cancer. Skin damage caused by the sun is
      mainly due to UV radiation. Skin damage certainly has ancient roots, but has
      undergone sudden changes since man began to migrate to different geographical
      areas, for example when northern European populations colonised sunny areas close
      to equator. It is not a coincidence that the highest incidence of sun induced
      neoplasias is observed among white population of Australia. This epidemiological
      finding focused the interest towards the identification of phenotypic factors
      conditioning skin response to sunlight, and hence towards the definition of the
      so called phototype. After the fundamental work of Fitzpatrick based on sun
      exposure history more recent studies have shown that skin response to UV-rays can
      be predicted, to a good approximation, by skin colorimetry. Therefore this
      simple, cheap and non invasive measurement enables to predict sun reactivity skin
      type and to evaluate the melanoma risk.

PMID- 10599385
TI  - Topical retinoids in the treatment of aging of the skin.
AB  - Aging of the skin is a complex phenomenon resulting from the interaction of
      several intrinsic and extrinsic factors [1]. Due to the cosmetic disfigurement it
      produces and its psychological impact, especially to women, aging of the skin has
      become an issue of great social significance and concern. Intrinsic aging is an
      inevitable, genetically programmed process, the underlying mechanisms of which
      remain largely unknown. No prevention or effective treatment is currently
      available [1]. Among extrinsic influences (wind, heat, cigarette smoke,
      chemicals, etc.), ultraviolet radiation appears to be the single most important
      factor associated with aging of the skin [2]. Photoaging refers to gross and
      microscopic cutaneous changes induced by cumulative exposure to ultraviolet
      radiation (UVR). These changes are superimposed on the background of intrinsic
      aging [2]. Increased recreational sun exposure, including excessive sunbathing,
      the depletion of stratospheric ozone, the use of UVR in the treatment of various
      skin diseases, are some of the causes that have led to increased prevalence of
      photoaging during the last decades. The clinical importance of photoaging lies
      mostly on the potential for the development of precancerous lesions or skin
      cancer [3]. In contrast to intrinsic aging, photodamage can be prevented by sun
      avoidance and proper sun protection [2]. Furthermore, overwhelming clinical and
      histological evidence indicate that skin changes of photoaging can be reversed by
      the use of topical retinoids [4].

PMID- 10599386
TI  - Carbon dioxide laser resurfacing of the aged face.

PMID- 10599387
TI  - Melasma.
AB  - Melasma is a common disorder of macular hyperpigmentation which involves mostly
      in sun exposed areas of the face and neck. Those most affected are women.
      Multiple factors have been postulated to involve in the etiology and pathogenesis
      of melasma including pregnancy, oral contraceptives, genetics, sun exposure,
      cosmetics and race. We have conducted a clinical trial utilizing all trans
      retinoic acid (tretinoin, Retin-A) cream 0.1% q pm and hydroquinone lotion 3%
      (Melanex) applied every morning in Korean women with melasma. Our study patients
      demonstrated all three clinical patterns common to melasma: centrofacial, malar
      and mandibular. Wood's light examination was performed on all patients and
      identified two of the four types of melasma described. Most patients showed
      epidermal melasma and a few manifested a mixed type. No patients exhibited solely
      dermal or inapparent type in melasma. With open studies of tretinoin cream and
      hydroquinone lotion followed by sun screen, we have found significant improvement
      within 5 months with a few side effects. Histopathologic examination of melasma
      in the pre-trial biopsies revealed increased pigmentation of the epidermis,
      dermis or both. In addition, significant alterations of the dermis with solar
      damage was noted in all melasma patients sampled. Biopsies taken after five
      months of treatment revealed significant decreases in epidermal pigmentation and
      improvement of solar damage in the dermis. We reconfirmed that a synergistic
      mechanism between tretinoin and hydroquinone is responsible for the improvement
      seen in the female Korean melasma patients from our study.

PMID- 10599388
TI  - Skin tumours in prematurely photoaged skin after long-term immunosuppression
      treated with CO2 laser.

PMID- 10599389
TI  - An overview of classic Kaposi's sarcoma in Greece.
AB  - Classic Kaposi's sarcoma (CKS) is a rare tumor affecting mainly the elderly and
      running a chronic and indolent course. CKS in Greece is not uncommon with an
      estimated annual incidence of 0.47/1000,000 population, representing 1.35% of all
      malignant neoplasms. Furthermore, it is characterised by endemic clustering and
      clinico-epidemiological peculiaritis, supporting the speculation that it may
      represent a distinct form, the Mediterranean Kaposi's sarcoma, or a subtype of
      CKS. Kaposi's sarcoma is a multicentric angiomatous tumor of obscure
      etiopathogenesis and histogenesis. Based on clinical and epidemiological grounds,
      four distinct forms have been recognized: classic or sporadic, African or
      endemic, iatrogenic and epidemics or AIDS-associated KS [1].

PMID- 10599390
TI  - Surface evaluation of living skin.

PMID- 10599391
TI  - Raynaud's phenomenon caused by giant cell arteritis. A case report.

PMID- 10599392
TI  - Accelerated nodulosis during methotrexate therapy for refractory rheumatoid
      arthritis. A case report.
AB  - Accelerated nodulosis (AN) is a potential complication of methotrexate (MTX)
      therapy for rheumatoid arthritis (RA). We report on a 62-year old man affected by
      seropositive RA who developed AN after five months of MTX treatment. MTX-dose
      reduction was followed by rapid regression of the skin nodules. The Authors
      describe the typical features of AN and discuss on the pathogenetic mechanisms.

PMID- 10599393
TI  - Rheumatoid vasculitis associated with anticardiolipin antibodies.

PMID- 10599394
TI  - Unilateral proptosis in a 74-year-old woman.

PMID- 10599395
TI  - Naevus varicosus osteohypertrophicus. An early diagnostic approach.
AB  - Naevus varicosus osteohypertrophicus (synonym Klippel-Trenaunay Syndrome KTS) is
      relatively rare circumscribed, usually quadrant-related gigantism with vascular
      hyperplasia or malformations based on the embryonic development. The authors
      observed an 18- and a 30-year-old female with a triad of symptoms: cutaneous
      nevus flammeus, varicose and dilated veins, and bony and soft tissue hypertrophy
      of the low limb. The second patient also had two venous ulcers as a dominant
      clinical feature--a rare manifestation of Klippel-Trenaunay syndrome. A diagnosis
      of Klippel-Trenaunay syndrome was made by clinical observations, laboratory
      findings, dermoscan, radiological examination of the bones of the limb, Doppler
      ultrasonography, photopletismography and venoscan. A bone isotope scan was also
      done to the first patient. Making an early diagnosis of this sporadic congenital
      disease with unknown aetiology is important in order to be able to provide early
      prophylactic and therapeutic measures. Klippel and Trenaunay in 1900 were the
      first to describe a patient with the simultaneous appearance of osteohypertrophy,
      hemangiomas and varicose veins involving one extremity [1]. In 1907 Parkes and
      Weber reported a similar syndrome--they described a patient who had dilated and
      pulsatile arteries in the affected region including the presence of arterio
      venous communications. In 1918 they used the compromise term "haemangiectatic
      hypertrophy" to embrace all conditions which were associated with congenital
      vascular malformations including A-V anastomoses associated with bone and soft
      tissue hypertrophy. Most authors are agreed that Klippel-Trenaunay syndrome and
      the syndrome of multiple congenital arterio-venous fistulae are two separate
      features of the Parkes Weber hypertrophy. KTS is manifesting with a triad of
      symptoms: cutaneous vascular nevus (more frequently nevus flammeus type),
      superficial venous varicosities and hypertrophy of the affected limb. Usually one
      quadrant of the body is involved: quite often a leg, an arm, lateral side of the
      trunk, very rarely the face. More than one quadrant and bilateral involvement are
      rarely affected. Naevus flammeus appeared at birth. It is extremely variable both
      in extent and in color--the latter ranging from pale pink to deep purple. Veinous
      varicosities appear in childhood and adolescence. They are painful and may be
      complicated by superficial or deep venous thrombosis and rarely, ulceration.
      Hypertrophy of the affected extremities is due to bone and soft tissue
      hypertrophy. KTS can be associated with other developmental anomalies such as:
      polydactyly, syndactyly, oligodactyly [2] macrocephaly, blue nevus, epidermal
      naevus, venous malformations.

PMID- 10599396
TI  - Pyoderma gangrenosum successfully treated with cyclosporin A.
AB  - The subjects of the study are a 48-year old male and a 50-year female patient
      with the idiopathic form of pyoderma gangrenosum. Both patients were treated with
      Cyclosporin A (Sandimmun) as monotherapy. Complete resolution was achieved after
      three months' treatment. No serious side-effects were observed.

PMID- 10599397
TI  - Cardiac involvement and left ventricular failure in a patient with the Churg
      Strauss syndrome.
AB  - The Churg-Strauss syndrome is characterised by a history of asthma and paranasal
      sinus disease, eosinophilia of more than 10 per cent, non-fixed pulmonary
      infiltrates on chest radiography and vasculitis which may affect multiple organ
      systems. The condition usually manifests in the 4th decade. We present a 21-year
      old female with a history of asthma since one year of age who developed symptoms
      and signs of pneumonia, a pulmonary infiltrate on chest radiography and
      eosinophilia. This was followed a few weeks later by vasculitis which affected
      the skin and myocardium and associated with a peripheral eosinophilia of more
      than 80%. Physical examination revealed palpable purpura and signs of left
      ventricular failure. Echocardiography confirmed significant diminution of left
      ventricular contractility. A rapid improvement was observed after steroid
      therapy. Echocardiography after two months showed normal left ventricular
      function. In this presentation we review the cardiac manifestations of the Churg
      Strauss syndrome and its management.

PMID- 10599398
TI  - Plectin deficiency disease. A case report.

PMID- 10599399
TI  - Toxic epidermal necrolysis in a patient with psoriatic arthritis.

PMID- 10599400
TI  - [Detection of Helicobacter pylori by polymerase reaction in bile samples from
      gallbladder and bile stones].
AB  - Some papers report helicobacter pylori existence in bile from surgical specimens
      obtained during gallbladder or bile ducts surgery. The aim of this work was
      search by PCR, H. Pylori presence in bile specimens from patients suffering of
      gallbladder stones or by bile ducts stones. Bile samples were obtained by
      gallbladder punction during cholecystectomy in 26 patients, 19 of them with
      gallbladder stones and 7 also with gallbladder stones and bile duct stones. Age
      ranged from 22-69 years old, median 49.6 years old. Samples were sent to
      specialized biomolecular laboratory to perform PCR techniques. Two of 26 patients
      (7.6%) had positive reaction for the presence of DNA of H. Pylori in bile
      samples. Our research suggest that DNA of H. Pylori can be founded in bile
      samples patients with gallbladders and duct stones in Argentina.

PMID- 10599401
TI  - [HCV prevalence in health workers].
AB  - The risk of HBV infections in health workers and the different prevalence
      according to the hospital activities has been shown in a great number of papers.
      In order to establish the prevalence of serological HBV markers in health workers
      fron high complexity hospital, we have analyzed 730 inquiries refilled in the
      period 1994-1995 before receiving the antihepatitis B vaccine. We studied 730
      health workers, 282 (38.8%) males and 447 (61.2%) females with a mean age of 40.1
      years old. We found 75/730 (10.2) serums anticHBc reactives. The found prevalence
      was significantly larger than the one found in blood donors. The analysis of the
      prevalence according to the hospital activities showed that the infirmary
      personnel is the only with anti-HBc prevalence significantly superior to the
      blood donors, and the other health workers prevalence. Differences in the anti
      HBc prevalence between the physicians specialties were not found. Our results
      agree with other publications that clearly show that health workers are a risk
      group for HBV infection. However, what attracts attention in the analyzed
      population is that the only ones with anti-HBc prevalence significantly superior
      to the blood donors' and the other health workers prevalence were the nurses,
      suggesting that nurses are the only health workers that have risk of HBV
      infections.

PMID- 10599402
TI  - [Acute anemia in high digestive hemorrhage. Margins of security for their
      handling without transfusion of red globules].
AB  - Red cells transfusion in the patient with acute hemorrhage, must be evaluated in
      a risk/benefit rate context. The present tendencies appoint that the use of the
      hematocrit "magic" number is unsafe and uncertain to decide a red cell
      transfusion. We have conducted a prospective randomized and controlled trial in
      60 patients with acute digestive hemorrhage without haemodynamic failure. We
      realized two groups: 1) control group: the target of transfusion in these
      patients was the hematocrit value of > or = 28%. 2) treatment group: these
      patients were supported with normovolemic haemodilution with crystalloid
      solutions until a hematocrit value of 21%. All patients have endoscopic diagnosis
      and they went evaluated across the study with clinic and laboratory controls.
      Both groups were significative differences in the hematocrit value. We did not
      see differences between the groups in the hospital stay neither the rate of
      organs failure. We find difference between the groups in the amount of red cell
      units (0.61 +/- 0.87 vs. 2.14 +/- 1.10; treatment and control respectively, P <
      0.001). The APACHE score was greater in the treatment group. This supports that
      the oldest patients, who probably have least physiologic reserve, could be
      treated without complications. Acute hemorrhage-normovolemic haemodilution
      digestive hemorrhage transfusion.

PMID- 10599403
TI  - [Steatohepatic cirrhosis in a morbidly obese patient].
AB  - Sixty to ninety percent of obese subjects show histological abnormalities of the
      liver. The hepatic lesion can be classified into one of the four following
      groups: steatosis, steatohepatitis, fibrosis and cirrhosis. The incidence of
      cirrhosis among patients with fatty liver changes ranges from 1.5% to 8%. The now
      abandoned surgery procedures performed for the treatment of morbid obesity
      (jejunoileal bypass) had left a negative experience: the onset of acute hepatic
      failure in subjects with no previous hepatic disease or the development of
      cirrhosis within one year of the bypass. Very low formula diets leading to
      precipitous weight loss in morbidly obese people induce metabolic changes similar
      to those observed after jejunoileal bypass. We report the case of a morbidly
      obese patient who had lost 40 kg of weight during the 6 months previous to his
      hospitalization. He came with signs of hepatic failure. He worsened rapidly and
      died in a month-time. The hepatic tissue obtained post-mortem showed a non
      alcoholic steatohepatitic cirrhosis.

PMID- 10599404
TI  - [Carbamazepine-induced hepatitis. A case report].
AB  - A 59 years old man jaundice, haemathologic disturbances and Splenomegaly, with
      epilepsy treated by Carbamazepine in the last 3 weeks is reported. He had a
      positive response to withdrawal carbamazepine and corticotherapy.

PMID- 10599405
TI  - [Normovolemic anemia as intravascular and interstitial compartment therapy
      restitution in digestive hemorrhage].

PMID- 10599406
TI  - [Hiatal hernia and gastroesophageal reflux].

PMID- 10599407
TI  - [How much does it cost eradicating Helicobacter pylori in Argentine?].

PMID- 10599408
TI  - Overview of epithelial-mesenchymal interactions in the bladder.

PMID- 10599409
TI  - Uroplakins as markers of urothelial differentiation.

PMID- 10599410
TI  - Urothelial tissue regulation. Unraveling the role of the stroma.

PMID- 10599411
TI  - Creation of bladder tissue in vitro and in vivo. A system for organ replacement.

PMID- 10599412
TI  - Reconstruction of the urinary bladder by auto-augmentation, enterocystoplasty,
      and composite enterocystoplasty.

PMID- 10599413
TI  - Epithelial-mesenchymal interactions in the bladder. Implications for bladder
      augmentation.

PMID- 10599414
TI  - Serosal thickening, smooth muscle cell growth, and phenotypic changes in the
      rabbit bladder wall during outflow obstruction and regeneration.

PMID- 10599416
TI  - Ultrastructural smooth muscle ontogeny of the rat bladder.
AB  - The transmission electron microscope characteristics of developing rat bladder
      smooth muscle are described at 14 and 18 days of gestation, birth, and adulthood.
      Caveolae, microfilaments, and dense bodies increase during smooth muscle
      development. Collagen content in the extracellular matrix also increases. These
      changes may reflect increased bladder emptying in the rat, and also allow for
      comparison of smooth muscle cells in studies of bladder wound healing and tissue
      substitutes.

PMID- 10599415
TI  - Replicative senescence in human uroepithelial cells.
AB  - PURPOSE: Normal human uroepithelial cells (HUCs) proliferate rapidly in culture
      during early passage and then spontaneously undergo replicative senescence. We
      previously reported that the cyclin D1-CDK4/6 inhibitor, p16INK4a, is elevated at
      senescence in HUCs. Hence, we proposed that p16INK4a may play a critical role in
      mediating senescence in this cell type. In the current study, we further
      characterized the senescent state in HUCs. We also tested the possible roles of
      changes in other cell cycle proteins, including p53, p21WAF1, pRb, and cyclin D1
      in HUC senescence. METHODS: Normal HUCs cultured from explants of ureteral mucosa
      were used for these studies. Senescence associated-beta-galactosidase activity
      (SA-beta-gal) was used to identify cells in senescence. Flow cytometric analysis
      was used to determine changes in cell cycle distribution at senescence. Response
      of cells to serum stimulation was determined by Northern analysis of c-fos.
      Western analysis was used to assess changes in p53, p21WAF, p16INK4a, cyclin D1
      and plasminogen activator inhibitor-1 (PAI-1) levels at senescence. RESULTS: beta
      gal-positive HUCs were blocked at G1/S in senescence and failed to show c-fos
      induction in response to serum stimulation. As previously reported, senescent
      HUCs also showed elevated p16INK4a. However, unlike human fibroblasts, neither
      p53 nor p21WAF1 elevation accompanied HUCs senescence. PAI-1 levels were also not
      elevated in HUC senescence. CONCLUSION: These findings support a model in which
      elevation of p16INK4a, but not p53 or p21WAF1 plays a critical role in HUC
      replicative senescence. These findings elucidate the tumor suppressor mechanism
      of p16INK4a and the frequent loss of either p16INK4a or pRb in invasive human
      bladder tumors.

PMID- 10599417
TI  - Overview of muscle and extracellular matrix in the bladder.

PMID- 10599418
TI  - Fetal bladder physiology.

PMID- 10599419
TI  - Developmental aspects of the contractile smooth muscle component in small
      intestinal submucosa regenerated urinary bladder.

PMID- 10599420
TI  - Contractile protein changes in urinary bladder smooth muscle following outlet
      obstruction.

PMID- 10599421
TI  - Calcium ion homeostasis in urinary bladder smooth muscle.

PMID- 10599422
TI  - Cyclooxygenase-2. A key regulator of bladder prostaglandin formation.

PMID- 10599423
TI  - Role of angiotensin II in bladder smooth muscle growth and function.
AB  - Preliminary studies by our group and others indicate that angiotensin II may have
      an important role in the cellular regulation of smooth muscle growth and collagen
      production in the bladder. The exact mechanisms in which angiotensin II elicits
      its cellular effects are not known. Given the available information thus far, we
      hypothesize the following (see Figure 2): 1) Outlet obstruction of the bladder
      causes increased cell stretch/strain which in turn induces the local production
      of angiotensin II. Angiotensin II may also influence cell stretch/strain via its
      direct effects on bladder tone. 2) Angiotensin II then acts as a trophic factor
      in the bladder wall to cause smooth muscle cell hypertrophy/hyperplasia and
      increased collagen production via an autocrine and/or paracrine pathway. 3) The
      cellular effect(s) of angiotensin II may be mediated by secondary growth factors
      such as bFGF and TGFb Much more extensive research is certainly needed to reveal
      whether some part, or all of this hypothesis is correct. If angiotensin II is
      indeed active in regulating muscle and collagen changes in the pathologic
      bladder, then the clinical implications are extremely exciting since numerous
      pharmacologic agents are now available which can either inhibit angiotensin II
      production and/or block receptor mediated events. These agents may prove to be
      extremely useful in the clinical management of the neurogenic bladder in which
      obstructive changes may be prevented and potentially reversed. Despite this,
      caution must be exercised with regard to the potential use of any medications
      which alter the systemic renin-angiotensin system in the pediatric population
      since some research has suggested that an intact system may be necessary for the
      normal development of some organs, including the kidney.

PMID- 10599424
TI  - New concepts on the normal and abnormal developing bladder.

PMID- 10599425
TI  - Biochemical and physiological characterization of the urinary bladder in Ehlers
      Danlos syndrome.

PMID- 10599426
TI  - The role of collagen in bladder filling.
AB  - While this model is speculative, it is attractive in that it can account for the
      physiologic properties of the bladder. It also implies that connections must
      exist between the tension generating elements, i.e., the smooth muscle cells, and
      the other components of the bladder. In bladders that become noncompliant, it is
      likely that there is some interference with the ability of the collagen fibers to
      elastically and reversibly alter their tortuosity. This, predictably, would
      reduce total bladder capacity. Further studies will be required to establish the
      relationship between compliance changes and the passive mechanical elements of
      the bladder wall that comprise its structural protein matrix.

PMID- 10599427
TI  - Overview of nerves and pharmacology in the bladder.

PMID- 10599428
TI  - Pathways for relaxation of detrusor smooth muscle.

PMID- 10599429
TI  - Maturation of bladder reflex pathways during postnatal development.
AB  - Neuroanatomical and electrophysiological techniques have provided new insights
      into the organization of the spinal cord circuitry and the neurotransmitter
      mechanisms involved in primitive voiding reflexes in neonatal animals. In
      addition, studies of unitary synaptic transmission in spinal cord slice
      preparations indicate that developmental and spinal cord injury induced
      plasticity in sacral parasympathetic reflex pathways is due in part to
      alterations in glutamatergic excitatory transmission between interneurons and
      parasympathetic preganglionic neurons. It is proposed that these synaptic changes
      are due to competition between segmental and supraspinal inputs. Thus synaptic
      remodeling in the sacral parasympathetic nucleus is likely to be an important
      factor in the postnatal maturation of voiding reflexes.

PMID- 10599430
TI  - Subcellular distribution of free fatty acids, phospholipids, and endogenous
      lipase activity of rabbit urinary bladder smooth muscle and mucosa.
AB  - OBJECTIVES: The urinary bladder wall can be separated into two major
      compartments: the urothelium (mucosa) and the detrusor smooth muscle. Specific
      dysfunctions of both layers have been linked to ischemia, which may induce
      significant cellular and subcellular membrane damage via the activation of
      selective calcium dependent and independent hydrolytic enzymes. Preliminary to
      investigating changes in cell membrane composition induced by ischemia, we
      measured the free fatty acid (FFA) and phospholipid (PL) content of normal rabbit
      bladder muscle and mucosal cellular and subcellular membranes, and characterized
      the endogenous lipase activity. METHODS: Rabbit bladders were excised and the
      muscle and mucosal layers separated; each layer was homogenized, then
      fractionated by differential centrifugation. Endogenous lipase activity of the
      homogenates, and FFA and PL concentrations of the homogenates and subcellular
      fractions were measured. RESULTS: (1) The basal FFA concentration of the mucosal
      homogenates was 5 times that of the muscle homogenates. (2) The basal PL
      concentrations of the two tissues were similar. (3) Subcellular studies: FFA
      concentration was greatest in the mitochondrial fraction of both compartments. In
      the mucosa, PL concentration was significantly greater in the mitochondria and
      microsomes than in the other fractions; in the smooth muscle, the PL
      concentration was highest in the mitochondria. (4) The maximal endogenous lipase
      activity was 10 times higher in the mucosal homogenates than in the muscle
      homogenates. CONCLUSIONS: These results are consistent with those of previous
      studies which indicate that the mucosa is metabolically more active than the
      resting smooth muscle, which may cause the mucosa to be significantly more
      sensitive than the muscle to hypoxic/ischemic damage.

PMID- 10599431
TI  - Effects of glutamate receptor antagonists on lower urinary tract function in
      conscious unanesthetized rats.
AB  - OBJECTIVES: To study the effects of the intrathecal administered glutamate
      receptor antagonists on the bladder and urethral activities during isovolumetric
      bladder contraction in conscious normal and chronic spinal rats. METHODS: Twenty
      eight female Wistar rats with and without previous spinal cord transection were
      used. Before and after intrathecal administration of glutamate receptor
      antagonist, urodynamic parameters under isovolmetric condition of the bladder
      were analyzed. RESULTS: In normal rats, MK-801 (noncompetitive N-methyl-D
      aspartate [NMDA] receptor antagonist) and LY 293558 (competitive AMPA receptor
      antagonist) produced a decrease in bladder contraction pressure and urethral
      activity with dose dependent manner. In chronic spinal rats, detrusor-sphincter
      dyssynergia (DSD) was developed before drug administration. MK-801 and LY 293558
      partially inhibited bladder contraction pressure, and markedly depressed urethral
      contraction concomitant with bladder contraction. LY 293558 produced urethral
      relaxation concomitant with bladder contraction. CONCLUSIONS: In both normal rats
      and chronic spinal rats, two subtypes of glutamate receptors (NMDA and AMPA
      receptors) in the spinal cord were involved in the control of bladder and
      urethral activities. The AMPA receptor in the spinal cord seems to take an
      important role in the development of DSD.

PMID- 10599432
TI  - Observations from the spontaneously hypertensive rat. Insight into NGF regulation
      and noradrenergic hyper-innervation in the lower urinary tract.

PMID- 10599433
TI  - Role of Na(+)-K(+)-ATPase activity in regulation of detrusor contractility and
      diabetic bladder dysfunction.

PMID- 10599434
TI  - Restoration of bladder function in spastic neuropathic bladder using sacral
      deafferentation and different techniques of neurostimulation.
AB  - PURPOSE: Conventional sacral anterior root stimulation (SARS) results in
      simultaneous activation of both the detrusor muscle and the external urethral
      sphincter. We evaluated the possibilities of different neurostimulation
      techniques to overcome stimulation induced detrusor-sphincter-dyssynergia and to
      achieve a physiological voiding. MATERIAL AND METHODS: The literature was
      reviewed on different techniques of sacral anterior root stimulation of the
      bladder and the significance of posterior rhizotomy in patients with supraconal
      spinal cord injury suffering from the loss of voluntary bladder control, detrusor
      hyperreflexia and sphincter spasm. RESULTS: The achievement of selective detrusor
      activation would improve current sacral neurostimulation of the bladder,
      including the principle of "poststimulus voiding". This is possible with the
      application of selective neurostimulation in techniques of anodal block, high
      frequency block, depolarizing prepulses and cold block. Nowadays, sacral
      deafferentation is a standard therapy in combination with neurostimulation of the
      bladder because in conclusion advantages of complete rhizotomy predominate.
      CONCLUSIONS: The combination of sacral anterior root stimulation and sacral
      deafferentation is a successful procedure for restoration of bladder function in
      patients with supraconal spinal cord injury. Anodal block technique and
      cryotechnique are excellent methods for selective bladder activation to avoid
      detrusor-sphincter-dyssynergia and thus improve stimulation induced voiding.

PMID- 10599435
TI  - Overview of infection, immunology, and interstitial cystitis in the bladder.

PMID- 10599436
TI  - Pathophysiology of bacterial cystitis.

PMID- 10599437
TI  - Role of vaginal colonization in urinary tract infections (UTIs).

PMID- 10599438
TI  - Host factors in susceptibility to urinary tract infections.
AB  - In summary, a variety of intrinsic and acquired factors influence the risk of
      RUTI in otherwise normal women, including history of prior UTIs, the woman's
      genetic background, and exposures to spermicides, sexual activity and
      antibiotics. Further studies are directed towards understanding the interplay
      between these factors and their relative importance among various subpopulations
      of women with RUTI, such as otherwise healthy pre- and post-menopausal women.

PMID- 10599439
TI  - Induction of nitric oxide synthase with urinary tract infections.

PMID- 10599440
TI  - Interferon alpha for the treatment of superficial bladder cancer.

PMID- 10599441
TI  - Overview of cancer of the bladder.

PMID- 10599442
TI  - Urokinase (u-PA) and the u-PA receptor. Modulation of in vitro invasiveness of
      human bladder cancer cell lines.
AB  - BACKGROUND: Urokinase (u-PA) and the u-PA receptor (u-PAR) influence tumor
      invasion and metastasis. PURPOSE: The purpose of this study is to determine
      whether u-PAR display in 4 human bladder cancer cell lines (RT4, 253J, EJ and
      T24) can be modulated with substances including phorbol 12-myristate 13-acetate,
      interferon gamma, epidermal growth factor, and transforming growth factor beta
      and to correlate changes with u-PAR expression with the ability of these cells to
      invade artificial basement membrane (Matrigel). METHODS: u-PAR display was
      determined using flow cytometry and immunohistochemical staining with an anti-u
      PAR monoclonal antibody (Mab3936). Matrigel invasion chamber assays were used to
      assess the invasive capacity of the cell lines. RESULTS: The T24, EJ and 253J
      cells expressed the u-PAR while the RT4 cells did not. The EJ cells (expressing
      the highest u-PA antigen levels and the u-PAR) invaded Matrigel. The T24 cells,
      which expressed the u-PAR but do not produce u-PA, invaded Matrigel only when
      pretreated with high molecular weight urokinase (HMW u-PA). HMW u-PA pretreatment
      of EJ and 253J cells also enhanced their invasive potential. Blocking u-PA/u-PAR
      attachment with an anti-u-PAR monoclonal antibody (Mab3936) inhibited invasion.
      Modulation of u-PAR expression on cell lines displaying the u-PAR directly
      affected in vitro invasiveness of the cell lines. The RT4 cells which lack the u
      PAR were not invasive under conditions tested. Thus, bladder cancer cell lines
      require both u-PA and the u-PAR to invade Matrigel and modulation of u-PAR
      display directly affects their in vitro invasive capacity. CONCLUSIONS: This
      study shows that bladder tumor cells produce u-PA and express the u-PAR and
      require both for in vitro invasion to occur. When bladder cancer cells express
      the u-PAR, invasiveness can be enhanced by exogenous u-PA and inhibited by anti-u
      PAR antibodies. Modulation of u-PAR expression on the cell surface of bladder
      cancer cells can also affect their ability to invade Matrigel. IMPLICATIONS:
      Histologically similar bladder tumors show differences in their propensity to
      invade locally or metastasize. Intrinsic differences in the tumor cells such as
      the production of u-PA antigen and u-PA receptor on the cell surface and
      extrinsic differences in the tumor cell environment such as substances
      influencing u-PAR display or antibodies blocking the u-PAR may affect the
      biological potential of human bladder cancers and offer one explanation for the
      aggressive or indolent tumor behavior observed in individual patients.

PMID- 10599443
TI  - The role of matrix metalloproteinases in an in vitro model of bladder tumor
      invasion.

PMID- 10599444
TI  - DNA methylation in development of bladder cancer.

PMID- 10599445
TI  - Cellular proliferation and cell-cell cycle regulatory proteins as prognostic
      markers for transitional cell carcinoma of the bladder.

PMID- 10599446
TI  - Urothelial differentiation and bladder cancer.

PMID- 10599447
TI  - Complexity, retinoid-responsive gene networks, and bladder carcinogenesis.
AB  - Carcinogenesis involves inactivation or subversion of the normal controls of
      proliferation, differentiation, and apoptosis. However, these controls are
      robust, redundant, and interlinked at the gene expression levels, regulation of
      mRNA lifetimes, transcription, and recycling of proteins. One of the central
      systems of control of proliferation, differentiation and apoptosis is retinoid
      signaling. The hRAR alpha nuclear receptor occupies a central position with
      respect to induction of gene transcription in that when bound to appropriate
      retinoid ligands, its homodimers and heterodimers with hRXR alpha regulate the
      transcription of a number of retinoid-responsive genes. These include genes in
      other signaling pathways, so that the whole forms a complex network. In this
      study we showed that simple, cause-effect interpretations in terms of hRAR alpha
      gene transcription being the central regulatory event would not describe the
      retinoid-responsive gene network. A set of cultured bladder-derived cells
      representing different stages of bladder tumorigenesis formed a model system. It
      consisted of 2 immortalized bladder cell lines (HUC-BC and HUC-PC), one squamous
      cell carcinoma cell line (SCaBER), one papilloma line (RT4), and 4 transitional
      cell carcinomas (TCC-Sup, 5637, T24, J82) of varying stages and grades. This set
      of cells were used to model the range of behaviors of bladder cancers. Relative
      gene expression before (constitutive) and after treatment with 10 microM all
      trans-retinoic acid (aTRA) was measured for androgen and estrogen receptor; a set
      of genes involved with retinoid metabolism and action, hRAR alpha nd beta, hRXR
      alpha and beta CRBP, CRABP I and II; and for signaling genes that are known to be
      sensitive to retinoic acid, EGFR, cytokine MK, ICAM I and transglutaminase. The
      phenotype for inhibition of proliferation and for apoptotic response to both aTRA
      and the synthetic retinoid 4-HPR was determined. Transfection with a CAT
      containing plasmid containing an aTRA-sensitive promoter was used to determine if
      the common retinoic acid responsive element (RARE)-dependent pathway for retinoid
      regulation of gene expression was active. Each of the genes selected is known
      from previous studies to react to aTRA in a certain way, either by up- or down
      regulation of the message and protein. A complex data set not readily
      interpretable by simple cause and effect was observed. While all cell lines
      expressed high levels of the mRNAs for hRXR alpha and beta that were not altered
      by treatment with exogenous aTRA, constitutive and stimulated responses of the
      other genes varied widely among the cell lines. For example, CRABP I was not
      expressed by J82, T24, 5637 and RT4, but was expressed at low levels that did not
      change in SCaBER and at moderate levels that decreased, increased, or decreased
      sharply in HUC-BC, TCC-Sup and HUC-PC, respectively. The expression of hRAR
      alpha, which governs the expression of many retinoid-sensitive genes, was
      expressed at moderate to high levels in all cell lines, but in some it was
      sharply upregulated (TCC-Sup, HUC-PC and J82), remained constant (5637 and HUC
      BC), or was down-regulated (SCaBER, T24 and RT4). The phenotypes for inhibition
      of proliferation showed no obvious relationship to the expression of any single
      gene, but cell lines that were inhibited by aTRA (HUC-BC and TCC-Sup) were not
      sensitive to 4-HPR, and vice versa. One line (RT4) was insensitive to either
      retinoid. Transfection showed very little retinoid-stimulated transfection of the
      CAT reporter gene with RT4 or HUC-PC. About 2-fold enhancement transactivation
      was observed with SCaBER, HUC-BC, J82 and T24 cells and 3-8 fold with 5637, TCC
      Sup cells. In HUC-BC, a G to T point mutation was found at position 606 of the
      hRAR alpha gene. This mutation would substitute tyrosine for asparagine in a
      highly conserved domain. These data indicate that retinoid signaling is probably
      a frequent target of inactivation in bladder carcinogenesis. (ABSTRAC

PMID- 10599449
TI  - [Exploration of the genome and malignant proliferations: cytogenetics and
      cytogenomics].

PMID- 10599448
TI  - Tumor cell motility. A novel therapeutic target in bladder carcinoma,
      experimental and clinical results.
AB  - Surgery, chemotherapy and radiotherapy are the current modalities of tumor
      management. However, in systemic disease, predicted patients' cure can be
      achieved in but a few tumor diseases. Based on previous basic research we have
      highlighted that the loss of cell-cell adhesion in association with an increased
      tumor cell motility is an essential feature of the malignant potential of bladder
      tumors. Thus, we have attempted therapeutical methods differing from hitherto
      existing treatments by focusing on a tumor cell function we call cell motility.
      Characterization of so-called anti-motility drugs was performed biochemically as
      well analyzed by in vitro by using in established bladder carcinoma cell lines.
      We evaluated the potential therapeutic benefit in a model of chemically induced
      bladder carcinoma followed by a phase I/II trial applying anti-motility drugs in
      patients which were chemotherapy-resistant and having metastatic bladder cancer.
      Both basic research as well as the results of first translational clinical trials
      confirmed, that advanced bladder carcinomas can be favorably affected by
      inhibition of tumor cell motility.

PMID- 10599450
TI  - [Tissue microdissection: application to the study of cancer of the breast].

PMID- 10599451
TI  - [Evidence for genetic abnormalities in Reed-Sternberg cells by PCR of cells
      isolated by micromanipulation ("single cell PCR")].

PMID- 10599452
TI  - [Comparative genomic hybridization (CGH): application to the study of
      neuroendocrine tumors].

PMID- 10599453
TI  - [Pathologic anatomy and the clinic, in Paris, in the 19th to the 20th centuries].

PMID- 10599454
TI  - [WHO 1999 classification of lung cancers: a guided tour].

PMID- 10599455
TI  - [The lung nodule: which deduction for which diagnosis?].

PMID- 10599456
TI  - [Angiogenesis and tumor growth. Angiogenic factors and tumor growth].

PMID- 10599457
TI  - [Interactions between mechanisms of angiogenesis and epithelial carcinogenesis].

PMID- 10599458
TI  - [The liver, collagen XVIII and hepatocarcinogenesis].

PMID- 10599459
TI  - [Anti-angiogenic therapeutic strategies and inhibition of tumor growth].

PMID- 10599460
TI  - [ANAES: review of the literature on the reproducibility of low grade lesions and
      of atypical cells of indeterminate significance (ASCUS). Decision trees on
      treating abnormal cervical smears. Clinical problems engendered by the
      diagnosis].

PMID- 10599461
TI  - [False negatives in France: multicenter study from the French Society of Clinical
      Cytology].

PMID- 10599462
TI  - Low grade and ASCUS lesions of the cervix: diagnostic difficulties and
      reproducibility.

PMID- 10599463
TI  - [Reproducibility of the imaging of cervical smears in liquid media and
      presentation of the results of a multicenter study].

PMID- 10599464
TI  - [The use of HPV typing: the point of view of the virologist and the pathologist].

PMID- 10599465
TI  - [Reading the cervical smear: the future is today].

PMID- 10599466
TI  - [Experience with new technologies within the context of Swiss practice and
      conclusions].

PMID- 10599467
TI  - [What is in store for urology in an anatomic-pathologic account in a patient with
      a bladder tumor?].

PMID- 10599468
TI  - [New information in the classification of urothelial tumors of the bladder].

PMID- 10599469
TI  - [Prognostic factors and markers used in urothelial carcinoma of the bladder].

PMID- 10599470
TI  - [Limits to the extemporaneous examination of thyroid nodules].

PMID- 10599471
TI  - [Diagnosis of a vesiculobullous eruption in the newborn].

PMID- 10599472
TI  - [Hamartomas in children].

PMID- 10599473
TI  - [Vascular tumors in children: new entities, new concepts].

PMID- 10599474
TI  - [Cutaneous histiocytosis in children].

PMID- 10599475
TI  - Development and vulnerability: new perspectives for anxiety disorders.

PMID- 10599476
TI  - Neural circuits mediating stress.
AB  - Stress has been linked to the pathophysiology and pathogenesis of mood and
      anxiety disorders. Over the past few years, our understanding of the brain and
      neuroendocrine circuits that are linked to the stress response have increased
      dramatically. This article reviews a series of animal and human studies aimed at
      understanding what are the pathways by which stress is perceived, processed, and
      transduced into a neuroendocrine response. We focus on the classic stress
      circuit: the limbic-hypothalamic-pituitary-adrenal (LHPA) axis. These studies
      indicate that the LHPA stress circuit is a complex system with multiple control
      mechanisms and that these mechanisms are altered in pathological states, such as
      chronic stress and depression. These studies also suggest that the interactions
      between the LHPA and other neurotransmitters, such as serotonin, may provide the
      neurobiological substrate by which stress may affect mood.

PMID- 10599477
TI  - Stress and hippocampal neurogenesis.
AB  - The dentate gyrus of the hippocampal formation develops during an extended period
      that begins during gestation and continues well into the postnatal period.
      Furthermore, the dentate gyrus undergoes continual structural remodeling in
      adulthood. The production of new granule neurons in adulthood has been documented
      in a number of mammalian species, ranging from rodents to primates. The late
      development of this brain region makes the dentate gyrus particularly sensitive
      to environmental and experience-dependent structural changes. Studies have
      demonstrated that the proliferation of granule cell precursors, and ultimately
      the production of new granule cells, are dependent on the levels of circulating
      adrenal steroids. Adrenal steroids inhibit cell proliferation in the dentate
      gyrus during the early postnatal period and in adulthood. The suppressive action
      of glucocorticoids on cell proliferation is not direct but occurs through an NMDA
      receptor-dependent excitatory pathway. Stressful experiences, which are known to
      elevate circulating levels of glucocorticoids and stimulate hippocampal glutamate
      release, inhibit the proliferation of granule cell precursors. Chronic stress
      results in persistent inhibition of granule cell production and changes in the
      structure of the dentate gyrus, raising the possibility that stress alters
      hippocampal function through this mechanism. This review considers the unusual
      developmental profile of the dentate gyrus and its vulnerability to environmental
      perturbations. The long-term impact of developmental events on hippocampal
      function is considered.

PMID- 10599478
TI  - Corticotropin-releasing hormone receptor subtypes and emotion.
AB  - Preclinical data indicate that corticotropin-releasing hormone (CRH) has
      anxiogenic properties and a dysregulation in CRH systems has been suggested to
      play a role in a variety of stress-related psychiatric disorders, such as
      anxiety, depression, and eating disorders. Two CRH receptor subtypes have been
      identified, termed CRH1 receptor (CRH1) and CRH2 receptor (CRH2), with its splice
      variants CRH2 alpha and CRH2 beta. These receptor subtypes differ in their
      pharmacology and expression pattern in the brain. Mouse mutants in which the CRH1
      receptor subtype has been deleted show an impaired stress response, reduced
      anxiety-related behavior, and cognitive deficits. Studies using antisense
      oligodeoxynucleotides directed against CRH1 or CRH2 alpha identified the CRH1
      receptor as the main target for CRH in mediating anxiogenesis, although recent
      data also suggest a possible role for CRH2 alpha. More clearly, CRH2 alpha is
      involved in the CRH effects on food intake. Moreover, local injection of CRH into
      areas rich in CRH2 alpha also result in altered sexual female behavior.
      Therefore, it is suggested that the CRH2 alpha may primarily influence a system
      concerned with implicit processes necessary for survival, i.e., with motivational
      types of behavior including feeding, reproduction, and possibly defense, whereas
      the CRH1 may be more concerned with explicit processes, including attention,
      executive functions, the conscious experience of emotions, and possibly learning
      and memory related to these emotions. This also suggests that patients suffering
      from anxiety and depression may benefit from treatment with CRH1 antagonistic
      drugs, while drugs targeting CRH2 alpha may be of particular benefit for patients
      with eating disorders.

PMID- 10599479
TI  - The impact of early adverse experiences on brain systems involved in the
      pathophysiology of anxiety and affective disorders.
AB  - The relative contribution of genetic and environmental factors to the development
      of the major psychiatric disorders has long been debated. Recently, considerable
      attention has been given to the observations that adverse experiences early in
      life predispose individuals to the development of affective and anxiety disorders
      in adulthood. Corticotropin-releasing factor (CRF) is the central coordinator of
      the endocrinologic, autonomic, immunologic, and behavioral stress responses. When
      centrally administered, CRF produces many physiologic and behavioral changes
      reminiscent of both acute stress and depression. Moreover, CRF has also been
      implicated in the pathogenesis of a variety of anxiety disorders, mainly through
      CRF neurocircuits connecting the amygdala and the locus ceruleus. Clinical
      studies have provided convincing evidence for central CRF hypersecretion in
      depression, and, to a lesser extent, in some anxiety disorders. Evidence mainly
      from preclinical studies suggests that stress early in life results in persistent
      central CRF hyperactivity and increased stress reactivity in adulthood. Thus,
      genetic disposition coupled with early stress in critical phases of development
      may result in a phenotype that is neurobiologically vulnerable to stress and may
      lower an individual's threshold for developing depression and anxiety upon
      further stress exposure. This pathophysiologic model may provide novel approaches
      to the prevention and treatment of psychopathology associated with stress early
      in life.

PMID- 10599480
TI  - Vulnerability factors among children at risk for anxiety disorders.
AB  - BACKGROUND: The high-risk strategy is one of the most powerful approaches for
      identifying premorbid risk factors and reducing etiologic and phenotypic
      heterogeneity characteristic of the major psychiatric disorders. METHODS: This
      paper reviews the methods of high-risk research and findings from previous high
      risk studies of anxiety. The preliminary results of the 6-8 year follow-up of a
      high-risk study of 192 offspring of probands with anxiety disorders, substance
      abuse, and unaffected controls are presented. The key study measures include
      comprehensive diagnostic interviews, symptom ratings, indirect measures of brain
      functioning (neuropsychologic, neurologic and psychophysiologic function),
      developmental measures, and family functioning measures. RESULTS: The major
      findings reveal that there is specificity of familial aggregation of anxiety
      disorders among parents and children; children at high risk for anxiety have
      increased startle reflex, autonomic reactivity, and stress reactivity, higher
      verbal IQ, and deficits in paired associative learning as compared to other
      children. CONCLUSIONS: The finding that family environment and parenting do not
      differ between children at risk for anxiety disorders and other children, when
      taken together with the strong degree of specificity of transmission of anxiety
      disorders, suggests that there may be temperamental vulnerability factors for
      anxiety disorders in general that may already manifest in children prior to
      puberty.

PMID- 10599481
TI  - Early childhood predictors of adult anxiety disorders.
AB  - This paper considers the influence of temperamental factors on the development of
      anxious symptoms in children and adolescents. About 20 percent of healthy
      children are born with a temperamental bias that predisposes them to be highly
      reactive to unfamiliar stimulation as infants and to be fearful of or avoidant to
      unfamiliar events and people as young children. Experiences act on this initial
      temperamental bias and, by adolescence, about one-third of this group is likely
      to show signs of serious social anxiety. These children are also likely to have
      one or more biological features, including a sympathetically more reactive
      cardiovascular system, asymmetry of cortical activation in EEG favoring a more
      active right frontal area, more power in the EEG in the higher frequency range,
      and a narrower facial skeleton. The data imply that this temperamental bias
      should be conceptualized as constraining the probability of developing a
      consistently fearless and spontaneous profile rather than as determining an
      anxious or introverted phenotype.

PMID- 10599482
TI  - A developmental psychopathology model of childhood traumatic stress and
      intersection with anxiety disorders.
AB  - Empirical findings regarding childhood traumatic stress are placed within a
      developmental life-trajectory model that incorporates a tripartite etiology of
      posttrauma distress. This approach recognizes an intricate matrix of child
      intrinsic factors, developmental maturation and experience, life events, and
      evolving family and social ecologies. Of central developmental importance in the
      field of traumatic stress is the ontogenesis of appraisal, emotional response,
      emotional and physiological regulation, and consideration of protective action
      with regard to danger. The complexity of traumatic situations and their aftermath
      suggests the relevance of multiple stress diatheses in understanding individual
      variability in proximal and distal effects. Neurobiological systems that subserve
      danger mature over childhood and adolescence. Neurophysiological and
      neurohormonal studies among traumatized children and adolescents suggest
      potential neurodevelopmental stage-related vulnerabilities within these systems.
      Advances in child development and traumatic stress provide tools for
      investigating proximal and distal interplay of psychopathology, disturbances in
      the acquisition and maintenance of developmental competencies, and life
      trajectory outcomes. A developmental psychopathology model suggests different
      avenues by which dangerous circumstances, childhood traumatic experiences, and
      posttraumatic stress disorder (PTSD) can intersect with other anxiety disorders
      over the life span.

PMID- 10599483
TI  - Pathophysiology of childhood anxiety disorders.
AB  - Prior reviews on the pathophysiology of anxiety consistently note the need for
      more research on biological aspects of childhood social phobia, separation
      anxiety disorder, and generalized anxiety disorder. The current review summarizes
      biological research that is relevant to these three disorders. In the first part
      of the review, barriers that have prevented progress in this area are delineated,
      and recent developments are discussed that set the stage for major advances in
      research on childhood anxiety disorders. In the second part of the review,
      studies are discussed that provide insights on the pathophysiology of childhood
      social phobia, separation anxiety disorder, and generalized anxiety disorder.
      Research on each specific disorder illustrates the manner in which recent
      developments in biological research facilitate novel research approaches uniquely
      suited for answering essential clinical questions in research on both childhood
      and adult anxiety disorders. For example, in research on social phobia,
      biological studies might enhance understandings of the longitudinal associations
      between individual childhood and adult disorders. In research on separation
      anxiety disorder, biological studies might enhance understanding on family
      genetic associations between childhood and adult disorders. Finally, in research
      on generalized anxiety disorder, biological studies might enhance understandings
      of comorbidities among distinct childhood and adult disorders, particularly with
      respect to the relationship between anxiety and depressive disorders.

PMID- 10599484
TI  - The treatment of anxiety disorders in children and adolescents.
AB  - Anxiety disorders are the most common psychiatric conditions in the pediatric
      population, with prevalence estimates ranging from 5-18%. Children and
      adolescents with excessive anxiety often meet diagnostic criteria for a number of
      disorders within the DSM-IV. Unfortunately, the current diagnostic system is
      controversial because of high rates of symptom overlap, comorbidity with other
      psychiatric disorders, and lack of biological markers that would support a more
      empirical anxiety nosology. Treatment strategies for pediatric anxiety disorders
      have important historical roots. Several controlled studies of cognitive
      behavioral therapy (CBT) demonstrate efficacy for pediatric anxiety disorders. In
      contrast, no controlled psychopharmacology studies have demonstrated efficacy in
      children and adolescents with anxiety disorders, except obsessive-compulsive
      disorder; however, several large, methodologically sound psychopharmacotherapy
      trials are underway for pediatric anxiety disorders. This update will review the
      current status of psychosocial and psychopharmacologic treatment of pediatric
      anxiety disorders. In addition, a brief discussion of nosology, epidemiology, and
      developmental course of anxiety is included. Preliminary psychopharmacology
      treatment and CBT treatment algorithms are presented for pediatric anxiety
      disorders, based on the best available data. Recommendations for future research
      directions are also discussed.

PMID- 10599485
TI  - Current treatments of the anxiety disorders in adults.
AB  - The progress in developing effective treatments for the five principal anxiety
      disorders (ADs) in adults--panic disorder (PD), social phobia (SP), obsessive
      compulsive disorder (OCD), generalized anxiety disorder (GAD), posttraumatic
      stress disorder (PTSD)--has been rapid in the past 15 years. There are now well
      controlled clinical trials documenting effective pharmacological and
      psychological treatments for all of these disorders, although generally the
      evidence is better developed for some disorders than for others. Both the
      pharmacological treatments and the effective psychological treatments for each
      disorder will be briefly reviewed. The available data for combination treatment
      will be reviewed and comparisons of the two types of treatment will be made. This
      review will contain at least brief reviews of what the treatments involve and
      attempt to describe how well they work. Many studies unfortunately report only
      the percentage of patients who "improve" without quantifying the clinical
      significance of those responses. Data underlining clinical response in terms of
      the percentage of patients who have an "excellent," "marked," or "moderate"
      response, and the percentage of patients with a "clinically significant" response
      will be reported whenever available. Other clinically relevant issues such as
      length of treatment-relapse rates upon discontinuation and side effects will be
      presented. As such, this article should provide a brief but comprehensive review
      of the treatment of these disorders in adults.

PMID- 10599486
TI  - [Cellular and molecular mechanisms of atherogenesis (CD40-CD40L*-immunoregulatory
      signal)].

PMID- 10599487
TI  - [Qualitative difference in blood erythrocytes of men and women].

PMID- 10599488
TI  - [Increased expression of the sarcoplasmic reticulum Ca(2+)-ATPase gene
      participates in nitric oxide protective effect].

PMID- 10599489
TI  - [Immune resistance of the athlete body depending on the aerobic or anaerobic
      training].

PMID- 10599490
TI  - [Individual characteristics of the brain energy metabolism during local ischemia
      obtained by nuclear magnetic resonance in vivo].

PMID- 10599491
TI  - [Intracellular pH during early stages of apoptosis and necrosis of thymocytes].

PMID- 10599492
TI  - [Collagenolytic complex of proteases from the hepatopancreas of the Kamchatka
      crab: enzymologic activity of the individual components].

PMID- 10599493
TI  - [Effect of the low intensity laser irradiation on the cell].

PMID- 10599494
TI  - [Interaction of 125I-omnipaque with the rat mononuclear phagocytes].

PMID- 10599495
TI  - [Evaluation of the antimetastatic and immunomodulating activity of the
      preparation phytomix-40 in the in vivo experiment].

PMID- 10599496
TI  - [Comparative study of the cardioprotective and antiradical effects of estrogens
      and their nitro derivatives].

PMID- 10599497
TI  - [Novel endogenous dipeptide cycloprolyl-glycine is similar to pyracetam in
      selectivity of their mnemotropic effect].

PMID- 10599498
TI  - [Study of various mechanisms of anti-arrhythmia activity of phosphoenol
      pyruvate].

PMID- 10599499
TI  - [Effect of losartan on cerebrovascular circulation in normotensive rats in the
      postischemic period].

PMID- 10599500
TI  - [Detoxication of benzene and aflatoxin B1 by amino acid and peptide preparations
      in mice and chicken].

PMID- 10599501
TI  - [Immunologic response during long-term exposure to ozone].

PMID- 10599502
TI  - [Early blood system response to infectious organisms].

PMID- 10599503
TI  - [Functional macrophage activity in response to various plasmid variants of
      Yersinia pseudotuberculosis].

PMID- 10599504
TI  - [Production and characteristics of monoclonal antibodies against group-specific
      antigen determinant of Streptococcus group A polysaccharide].

PMID- 10599505
TI  - [Dynamics of the immune response to porin from the outer membrane of Yersinia
      pseudotuberculosis].

PMID- 10599506
TI  - [Cellular localization of mucin type receptors determined with novel GalNac/Gal
      specific lectin from sea mussel Crenomytilus grayanus in human colon tumors].

PMID- 10599507
TI  - [Effect of doxorubicin on oxidative phosphorylation in the brain mitochondria].

PMID- 10599508
TI  - [Mechanism of generation of slow components of the bioelectrical activity in
      diagnostics of the functional state of the gastrointestinal system].

PMID- 10599509
TI  - [Properties of human fetal ceruloplasmin].

PMID- 10599510
TI  - [Troponin component of the cardiotropic effect of levosimendan on the isolated
      myocardium from patients with chronic coronary insufficiency].

PMID- 10599511
TI  - [Complex diagnostics and treatment of patients with neurocirculatory dystonia by
      bioregulation of the heart rate].

PMID- 10599512
TI  - [Nitric oxide synthetase in the injured sensory neuron].

PMID- 10599513
TI  - [Neurosecretory cells from the amygdala].

PMID- 10599514
TI  - [Structural asymmetry of human cortical speech fields 44 and 45 during postnatal
      ontogenesis].

PMID- 10599515
TI  - [Immunoenzymatic method of detection of glycocalicin--glycoprotein fragment from
      Ib thrombocytes. Evaluation of the thrombocyte turnover in the circulation and
      differential diagnosis of thrombocytopenia].

PMID- 10599516
TI  - [Antibiosis. Therapeutic strategies in intensive care].

PMID- 10599517
TI  - Morphological and biological characteristics of varicella-zoster virus.

PMID- 10599518
TI  - Genomic structure and organization of varicella-zoster virus.

PMID- 10599519
TI  - Overview of the replication cycle of varicella-zoster virus.

PMID- 10599520
TI  - Role of glycoproteins in varicella-zoster virus infection.

PMID- 10599521
TI  - Varicella-zoster virus: latency and reactivation.

PMID- 10599522
TI  - Epidemiology of varicella infections.

PMID- 10599523
TI  - Viremic stages of different varicella-zoster virus-associated diseases.

PMID- 10599524
TI  - Chickenpox (varicella).

PMID- 10599525
TI  - Shingles (zoster).

PMID- 10599526
TI  - Postherpetic neuralgia.

PMID- 10599527
TI  - Infections during pregnancy.

PMID- 10599528
TI  - Diagnosis of varicella-zoster virus-associated diseases with special emphasis on
      infections in the immunocompromised host.

PMID- 10599529
TI  - Approaches to the treatment of varicella-zoster virus infections.

PMID- 10599530
TI  - Experience with live-attenuated varicella-zoster vaccines.

PMID- 10599531
TI  - Development of recombinant varicella-zoster virus vaccines.

PMID- 10599532
TI  - The biology of glycoprotein IIb-IIIa.

PMID- 10599533
TI  - Coronary intervention and glycoprotein IIb/IIIa integrin blockade.
AB  - In a few short years, platelet glycoprotein IIb/IIIa receptor antagonists have
      been developed from laboratory curiosities to critical treatment adjuncts to the
      successful performance of PCI. With more than 15,000 patients participating in
      trials of these agents during PCI, it is now clear that glycoprotein IIb/IIIa
      blockade reduces rates of adverse cardiovascular sequelae after PCI. Abciximab is
      the most extensively studied agent to date, but trials of other antagonists,
      particularly eptifibatide and tirofiban, support the utility of this class of
      therapeutic agents as a whole. This paper examines and interprets the results of
      large-scale clinical trials of glycoprotein IIb/IIIa inhibition during PCI and
      reviews directions for future study with this unique class of agents.

PMID- 10599534
TI  - Glycoprotein IIb/IIIa inhibitors in unstable angina and non-ST segment elevation
      myocardial infarction.

PMID- 10599535
TI  - Glycoprotein IIb/IIIa inhibitors in acute ST segment elevation myocardial
      infarction.
AB  - Limitations in the standard treatment of acute myocardial infarction have focused
      attention on inhibition of platelet activity by its final common pathway of
      activation, the glycoprotein IIb/IIIa receptor. Animal studies have suggested
      that a glycoprotein IIb/IIIa inhibitor could accelerate thrombolysis and prevent
      reocclusion after successful thrombolysis. Studies evaluating the use of a
      glycoprotein IIb/IIIa inhibitor alone without thrombolysis or percutaneous
      transluminal coronary revascularization do not suggest that isolated use of
      glycoprotein IIb/IIIa inhibitors restores TIMI 3 flow in a sufficient proportion
      of patients. Clinical studies evaluating the combination of thrombolytic therapy
      and glycoprotein IIb/IIIa inhibitors appear most promising, with evidence of
      improved angiographic outcomes. Reducing the dose of thrombolytic agents may
      result in reduction in bleeding risk. Current and future trials will investigate
      reduced-dose reteplase with abciximab and eptifibatide with reduced-dose
      alteplase. Available evidence suggests that glycoprotein IIb/IIIa inhibition may
      facilitate thrombolysis, thus adding a new element to future reperfusion
      regimens.

PMID- 10599536
TI  - Platelet glycoprotein IIb/IIIa antagonists in ischemic cerebrovascular disease.

PMID- 10599537
TI  - Oral platelet glycoprotein IIb/IIIa inhibitors.

PMID- 10599538
TI  - Influence of the human paraoxonase polymorphism (PON1 192) on the carotid-wall
      thickening in a healthy population.
AB  - BACKGROUND: Serum paraoxonase (PON1) is a high-density lipoprotein-bound enzyme
      that can prevent oxidation of low-density lipoprotein and thus exert an anti
      atherogenic effect. A polymorphism at codon 192 (Gln/Arg) of the PON1 gene gives
      rise to two isoforms that differ in substrate-dependent activity. OBJECTIVE: To
      determine any independent contribution of this polymorphism to the variability of
      intimal-medial thickness (IMT) of the common carotid artery for a sample of
      asymptomatic adult subjects from southern Italy by ultrasonography. METHODS: We
      studied 196 unrelated asymptomatic subjects (mean age 55.1 years), drawn from
      participants in a cardiovascular-disease-prevention campaign. Plasma levels of
      lipids and glucose were measured by routine methods. PON1 polymorphism was
      determined by polymerase chain reaction. IMT was measured from high-resolution B
      mode echo-Doppler ultrasonography images. RESULTS: Prevalences of alleles A (Gln)
      and B (Arg) were 0.68 and 0.32, respectively. We found no significant difference
      with regard to plasma levels of lipids and glucose and other variables among the
      PON1 genotypes, although subjects with BB had higher levels of triglycerides and
      lower levels of high-density lipoprotein cholesterol. Common carotid artery IMT
      was slightly greater in subjects with BB, although no significant association
      between PON1 genotypes and common carotid artery IMT was found, even after
      adjustment for confounding variables. CONCLUSIONS: Our findings demonstrate that
      there is no significant association between PON1 gene polymorphism at codon 192
      and common carotid artery IMT for an Italian population. However, the fact that
      we found slightly greater IMT in subjects with genotype BB would suggest that the
      study should be performed again with a larger sample.

PMID- 10599539
TI  - Variation of the factor VII gene and ischemic heart disease in Japanese subjects.
AB  - BACKGROUND: Polymorphisms of the 5' region (5'FT), an intronic mutation (IVS7),
      and the 353Arg-Gln (R353Q) substitution of the factor VII gene have been reported
      to be associated with the plasma level of factor VII. Greater than normal levels
      of factor VII have also been reported to be associated with atherothrombotic
      events. However, the significance of factor VII gene polymorphism in the
      pathogenesis of ischemic heart diseases (IHD) has not been confirmed. OBJECTIVE:
      To determine whether these three factor VII gene polymorphisms are associated
      with levels of factor VII in Japanese subjects, and whether these three
      polymorphisms of the factor VII gene are associated with the risk of myocardial
      infarction. METHODS: We studied three polymorphisms of the factor VII gene, 5'FT,
      IVS7, and R353Q polymorphisms, for 493 Japanese subjects consisting of 285
      subjects without clinical evidence of ischemic heart disease (non-IHD group) and
      208 myocardial infarction patients (myocardial infarction group). We also
      assessed the plasma levels of factor VII antigen (FVIIag) in 103 subjects in the
      non-IHD group. RESULTS: Multiple regression analysis revealed that the level of
      FVIIag was significantly associated with age, body mass index, cholesterol level
      and a polymorphism of the factor VII gene (5'FT). Logistic analysis of 493
      subjects revealed that cholesterol level [P = 0.0036, odds ratio 1.010, 95%
      confidence interval (CI) 1.003-1.017], smoking (P = 0.0001, odds ratio 5.522,
      (95% CI 2.684-11.364) and diabetes mellitus (P = 0.0001, odds ratio 6.450, (95%
      CI 2.953-14.088) were risk factors for myocardial infarction. However, the three
      polymorphisms of factor VII gene were not associated with risk of myocardial
      infarction. CONCLUSION: The polymorphisms of the factor VII gene influenced the
      levels of factor VII but were not significantly associated with risk of
      myocardial infarction in Japanese subjects.

PMID- 10599540
TI  - The phytoestrogens Genistein and Daidzein, and 17 beta-estradiol inhibit
      development of neointima in aortas from male and female rabbits in vitro after
      injury.
AB  - BACKGROUND: 17 beta-Estradiol and phytoestrogens are known to have beneficial
      effects on the cardiovascular systems of women. The exact mechanisms for how
      estrogens and phytoestrogens influence the cardiovascular system are not yet
      understood in detail. OBJECTIVE: The objective of this study was to investigate
      whether 17 beta-estradiol and the phytoestrogens Genistein and Daidzein have an
      effect on post-injury processes in vessel walls. METHODS: In this in-vitro
      experiment, the sex-specific effects of 50 micrograms/ml 17 beta-estradiol
      (equivalent to 180 mumol/l), and of the isoflavones Genistein (5 and 50
      micrograms/ml, equivalent to 18.5 and 185 mumol/l), and Daidzein (5 and 50
      micrograms/ml, equivalent to 19.7 and 197 mumol/l) on endothelium-denuded aortas
      from female and male rabbits after vascular injury were studied. Morphometry and
      immunohistochemistry were performed for quantitative and qualitative analysis.
      RESULTS: Neointimal cells were in part positive for alpha-actin staining of
      smooth muscle cells. Staining with 5'-bromo-2'deoxyuridine plus 2'-deoxycytidine
      showed that proliferative activity in the neointima had significantly decreased
      after 28 days for groups that had been treated with 50 micrograms/ml Genistein.
      Immunofluorescence staining for the expression of nuclear estrogen receptor
      protein in the arterial wall for aortic rings from female and male rabbits was
      positive. 17 beta-Estradiol, Genistein, and its analog Daidzein (with no protein
      tyrosine kinase activity) inhibited formation of neointima sex-independently at
      equivalent concentrations of 50 micrograms/ml. However, a concentration of 5
      micrograms/ml Genistein decreased formation of neointima significantly for aortic
      rings from male rabbits only, whereas 5 micrograms/ml Genistein increased
      formation of neointima in rings from female rabbits, which corresponded to the
      increase in proliferative activity detected after 28 days. CONCLUSION: Genistein
      and Daidzein both inhibited proliferation at certain concentrations, so this
      effect is supposed to be independent from Genistein's protein tyrosine kinase
      activity. The antiproliferative properties of all three estrogens were observed
      in the absence of endothelium and therefore are independent from endothelium
      mediated effects.

PMID- 10599541
TI  - Administration of adenosine during reperfusion reduces injury of vascular
      endothelium and death of myocytes.
AB  - INTRODUCTION: To test the hypothesis that administration of adenosine during
      reperfusion attenuates endothelial dysfunction and extension of infarct size by
      inhibiting polymorphonuclear neutrophil (PMN)-mediated events and apoptosis.
      METHODS: Anesthetized dogs were subjected to 1 h coronary artery occlusion and 6
      h of reperfusion with infusion of saline (vehicle, n = 8) or 140 micrograms/kg
      per min adenosine, n = 8) continuously into the left atrium starting 5 min before
      reperfusion and continuing for 2 h. RESULTS: There was no intergroup difference
      in collateral myocardial blood flow measured by using colored microspheres in the
      area at risk during ischemia. Infusion of adenosine transiently improved
      segmental shortening (4.1 +/- 3.1% versus -2.5 +/- 2.3%, P < 0.05) and segmental
      work (41.4 +/- 22 versus 15 +/- 13 mmHg/mm, P < 0.05) after 4 h of reperfusion.
      Infusion of adenosine reduced size of infarct (determined by staining with
      triphenyltetrazolium chloride) from 27 +/- 2% with vehicle to 14 +/- 1%, (P <
      0.05). This was confirmed by measuring that it lowered activity of plasma
      creatine kinase (from 19 +/- 2 versus 8 +/- 1 IU/g protein, P < 0.05). It also
      reduced the proportion of terminal deoxynucleotidyl transferase-mediated dUTP
      nick-end labeling-positive nuclei in the perinecrotic zone from 17.3 +/- 1.6 to
      10.3 +/- 1.0% (P < 0.05) and reduced the appearance of DNA ladders in gel
      electrophoresis. In addition, it significantly decreased accumulation of PMN in
      the ischemic area (determined by immunohistochemistry with anti-CD18 antibody)
      and activity of cardiac myeloperoxidase compared with vehicle (439 +/- 52 versus
      183 +/- 20 PMN/mm2 myocardium and 1.1 +/- 0.1 versus 2.4 +/- 0.2 U/100 mg tissue,
      P < 0.05, respectively). Furthermore, infusion of adenosine during reperfusion
      preserved vascular endothelial function expressed in terms of a decrease in
      adherence of PMN to postischemic coronary artery endothelium (63 +/- 3 versus 36
      +/- 4 PMN/mm2 endothelium, P < 0.05, basal function) and agonist (acetylcholine)
      induced endothelium-dependent relaxation (negative logarithm to base 10 of
      concentration (mol/l) for half-maximal effect 7.7 +/- 0.1 versus 7.2 +/- 0.1, P <
      0.05, stimulated function). Infusion of adenosine directly inhibited generation
      of superoxide radical from canine PMN in vitro dose dependently from 27.8 +/- 6.3
      to 5.8 +/- 2.1 nmol/l/5 x 10(6) PMN (P < 0.05). CONCLUSION: Intra-atrial infusion
      of adenosine during reperfusion reduced accumulation of PMN in area at risk,
      preserved vascular endothelial function after ischemia-reperfusion by inhibiting
      interaction between PMN and endothelial cells, and decreased extension of
      infarct, possibly by limiting apoptosis.

PMID- 10599542
TI  - Saline infusion via local drug delivery catheters is associated with increased
      neointimal hyperplasia in a porcine coronary in-stent restenosis model.
AB  - BACKGROUND: Catheter-based local drug delivery at the site of stent implantation
      has been proposed to reduce in-stent restenosis. We examined whether local
      delivery itself may cause additional vessel wall injury and negate the potential
      benefit of local drug delivery in a porcine coronary in-stent restenosis model.
      METHODS: Pigs were randomly assigned to no local delivery (controls, n = 10) or
      local saline infusion (5 ml) using commercially available catheters (n = 39;
      Dispatch catheter, Microporous Infusion catheter, and InfusaSleeve) prior to
      oversized (stent:artery ratio 1.2) coronary stent implantation. The amount of in
      stent neointima was evaluated 4 weeks later with angiography and histology.
      RESULTS: There was no difference in vessel size or stent: artery ratio. However,
      at follow-up the local saline delivery group had significantly greater diameter
      stenosis (50 +/- 19% versus 25 +/- 17% in the controls, P < 0.01). Histology
      revealed similar injury scores but significantly greater neointimal area in the
      local saline group (3.61 +/- 1.11 mm2 versus 1.96 +/- 0.82 mm2 in the controls, P
      < 0.01). In a multivariate linear regression analysis, the use of the local
      delivery catheter was the only independent variable which was positively
      correlated with the amount of neointima (P = 0.0001). CONCLUSIONS: In this in
      stent restenosis model, catheter-based local saline delivery was associated with
      significantly increased neointimal hyperplasia. Thus, for local drug delivery to
      reduce in-stent restenosis, the antiproliferative agent should be potent enough
      to compensate for the additional neointimal hyperplasia from the infusion itself.

PMID- 10599543
TI  - Epidemiology and treatment of left ventricular hypertrophy in the elderly.
AB  - Left ventricular hypertrophy (LVH) is an important independent risk factor for
      cardiovascular disease and is associated with an increased risk of ventricular
      dysrhythmia, coronary artery disease, myocardial infarction, stroke, heart
      failure and peripheral artery disease. The prevalence of LVH increases strongly
      with advancing age and, consequently, the prevention or reduction of LVH should
      be an important consideration in the older age-group. This review summarises
      current knowledge on LVH and discusses management issues with particular
      reference to the elderly. Evidence suggests that antihypertensive treatment can
      reverse or prevent LVH. There have been few studies of LVH in the elderly, but
      since age does not appear to be a factor in the regression of LVH, results of
      studies among younger hypertensive patients can be extrapolated to the elderly
      population. Meta-analyses of clinical studies have not established conclusively
      that angiotensin-converting enzyme inhibitors and calcium antagonists are
      necessarily more effective than diuretics and beta-adrenoceptor antagonists in
      reducing LVH.

PMID- 10599544
TI  - Bibliography. Current world literature.

PMID- 10599545
TI  - Good results of milder form of ovarian stimulation in an in vitro
      fertilization/intracytoplasmic sperm injection program.
AB  - In a prospective study, we compared two protocols of ovulation stimulation, the
      clomiphene citrate and human menopausal gonadotropin (hMG) versus D-triptorelin,
      a long-acting gonadotropin-releasing hormone (GnRH) agonist and hMG in 324
      couples having their first in vitro fertilization or intracytoplasmic sperm
      injection (IVF/ICSI) program, in terms of pregnancy rates and cost-effectiveness
      of drugs used. The GnRH agonist/hMG group was characterized by a greater mean
      number of ampoules of hMG used (31.7 versus 10.2), a larger number of oocytes
      collected (10.4 versus 4.2), and a larger number of embryos obtained (5.8 versus
      2.9). With the policy of transferring only two of the best quality embryos, the
      mean number of embryos replaced were comparable (1.8 in clomiphene citrate/hMG
      and 1.9 in GnRH agonist/hMG group). The percentage of patients reaching embryo
      transfer was lower in the clomiphene citrate/hMG than in the GnRH agonist/hMG
      group (84.1% versus 93.1%, respectively). However, the combined results of the
      IVF and ICSI procedure in terms of pregnancy rate, both per patient and per
      embryo transfer were better, though not significantly in the clomiphene
      citrate/hMG than in GnRH agonist/hMG group (25.0% and 29.7% versus 23.7% and
      25.5%, respectively). Similarly, the implantation rate was better (19.0% versus
      13.5%, respectively). With the use of clomiphene citrate/hMG, a fivefold less
      costly drug regimen, we obtained pregnancy rates equivalent to those gained using
      GnRH agonist/hMG in our IVF/ICSI program.

PMID- 10599546
TI  - Barbiturates inhibit progesterone synthesis in cultured Leydig tumor cells and
      human granulosa cells.
AB  - Screening drugs used in obstetrical practice for effects on steroid hormone
      synthesis revealed that phenobarbital inhibited progesterone synthesis in MA-10
      Leydig tumor cells. The inhibition was apparently a drug class effect since it
      could be reproduced by other barbiturates. Barbiturate blockade was reversible
      and could be bypassed in the MA-10 cells by using 22-hydroxycholesterol. Human
      granulosa cell progesterone synthesis was also inhibited in a dose dependent
      fashion by phenobarbital, secobarbital and barbituric acid. Significant
      inhibition occurred in dose ranges that would be therapeutic for treating
      epilepsy. From these data we conclude that barbiturates block steroidogenesis by
      inhibiting cholesterol transport to the cholesterol side chain cleavage enzyme.

PMID- 10599547
TI  - Serum vascular endothelial growth factor levels before starting gonadotropin
      treatment in women who have developed moderate forms of ovarian hyperstimulation
      syndrome.
AB  - The study aims to evaluate whether serum vascular endothelial growth factor
      (VEGF) levels, before treatment with gonadotropins, may be considered a
      predictive marker of moderate ovarian hyperstimulation syndrome (OHSS). At the
      University of Pisa hospital infertility unit we have retrospectively selected 10
      patients who developed moderate forms of OHSS and 30 control patients who
      presented a normal response to ovarian stimulation among 400 women undergoing in
      vitro fertilization (IVF). Serum samples were collected before starting pFSH
      administration (150-300 IU/day). VEGF levels in serum were measured. No
      statistically significant difference was found between the serum VEGF levels of
      patients who developed moderate forms of OHSS and women without any symptoms of
      the syndrome. Further, serum VEGF concentrations were not significantly
      correlated with the age of the patients, the number of international units of FSH
      administered during the cycle of stimulation, the follicle and oocyte numbers
      counted on the day of the egg retrieval or estradiol levels detected on the same
      day. This study demonstrates that serum VEGF levels, before starting gonadotropin
      treatment, are not predictive of the subsequent development of moderate forms of
      ovarian hyperstimulation syndrome.

PMID- 10599548
TI  - The pharmacological profile of a novel norpregnance progestin (trimegestone).
AB  - Trimegestone is a novel norpregnane progestin that is being developed, in
      combination with estradiol, for the treatment of menopausal symptoms. The
      pharmacological characteristics of trimegestone have been evaluated in both in
      vitro and in vivo test systems, and compared with reference progestins.
      Interaction with hormonal steroid receptors from animal tissues and with human
      recombinant receptors in vitro has demonstrated that trimegestone has a high
      specificity and potency for the progesterone receptor, no affinity for the
      estrogen receptor, and weak affinity for androgen, glucocorticoid and
      mineralocorticoid receptors. With respect to progestomimetic activity in vivo,
      trimegestone was more potent than reference progestins in the endometrial
      transformation test in the rabbit, preventing the uterotrophic effect of
      estradiol in the immature mouse bioassay, and had more effect on traumatic
      deciduoma formation and greater oral antiovulatory activity in the rat. In vivo,
      trimegestone effectively maintained pregnancy in the rat, but was devoid of any
      uterotrophic activity. Trimegestone showed no androgenic, glucocorticoid,
      antiglucocorticoid or mineralocorticoid activity, but did show some
      antiandrogenic and antimineralocorticoid activity at higher doses. Administration
      of trimegestone to ovariectomized rats, in combination with estradiol, inhibited
      the uterotrophic effects of estradiol. At doses up to 1 mg/kg intravenously and
      30 mg/kg orally, trimegestone was not associated with any unwanted
      pharmacological effects. Overall, the results show trimegestone to have a
      favorable pharmacological profile with potent progestomimetic activity.

PMID- 10599549
TI  - A substitutional mutation in the DNA binding domain of the androgen receptor
      causes complete androgen insensitivity syndrome.
AB  - DNA analysis of the androgen receptor gene in a patient with complete androgen
      insensitivity syndrome identified a substitutional mutation (tyrosine converted
      to cysteine at position 571) in the DNA binding domain. In vitro transfection
      experiments with the patients' androgen receptor gene, indicated normal
      expression of the androgen receptor in transfected COS-7 cells compared to the
      wild type gene. There was also no evidence of impaired thermal stability of the 5
      alpha-dihydrotestosterone-androgen receptor complex. However, the capacity of the
      androgen receptor to activate target gene transcription was found to be
      completely disrupted in a luciferase assay. These results confirmed that only one
      substitutional mutation in the DNA binding domain was related to the pathogenesis
      of the complete androgen insensitivity syndrome.

PMID- 10599550
TI  - Flow cytometry of porcine ovarian cells: antiprogestins play an important role in
      progesterone receptor upregulation.
AB  - To investigate the mechanism of antiprogestins in the regulation of ovarian
      function, a dual-chamber culture system was prepared with the amnion membrane of
      human placenta. Isolated porcine granulosa and thecal cells were grown on both
      sides of the amnion and co-cultured with or without RU486 and ZK98, 734. After 48
      h incubation, the progesterone receptor (PR) and estrogen receptor (ER) of both
      cells were detected by flow cytometry. Progesterone and estradiol concentrations
      in the media were measured by radioimmunoassay. The results showed that
      antiprogestins increased PR contents in both cells; no significant change was
      found for ER. At the same time the progesterone and estradiol production by
      granulosa cells was inhibited; the progesterone production by thecal cells was
      reduced also. These data suggest that progesterone regulates progesterone
      synthesis. This autocrine/paracrine action may be the approach through which
      progesterone controls PR upregulation. It could be one mechanism for the
      inhibition of follicle development and steroidogenic function by antiprogestins.

PMID- 10599551
TI  - The effect of intraventricularly administered GnRH on plasma beta-endorphin
      levels of the rat.
AB  - This study investigates the effects of intraventricularly administered
      gonadotropin-releasing hormone (GnRH) on plasma beta-endorphin levels in female
      proestrous rats. Adult female Wistar rats (220-250 g) were implanted with an
      indwelling cannula in the third ventricle. Approximately 20 days later, the
      animals which had established a regular 4-day cycle were implanted with two
      indwelling catheters, one intracarotid and one intrajugular, on the morning of
      proestrus. A single injection of 100 ng GnRH dissolved in 5 microliters distilled
      water or 5 microliters of saline (control) was infused slowly through the cannula
      in the third ventricle. Blood was withdrawn via the intracarotid catheter just
      before the infusion (12.30 h) and at 14.00, 15.30, 16.30 and 17.30 h for the
      determination of plasma beta-endorphin levels. The results indicated that
      intracerebroventricular infusion of GnRH causes a significant decline of plasma
      beta-endorphin levels at all time points. It is postulated that GnRH possibly
      causes desensitization of GnRH receptors, due to the continuous GnRH supply to
      the pituitary via the blood circulation.

PMID- 10599552
TI  - Neuropeptide Y, leptin, galanin and insulin in women with polycystic ovary
      syndrome.
AB  - It has been reported that polycystic ovary syndrome (PCOS) is very frequently
      associated with obesity, insulin resistance and hyperinsulinemia. However,
      metabolic disorders may lead to suppression of reproductive hormone secretion
      during undernutrition and in obesity. Some neuropeptides, such as neuropeptide Y
      (NPY) and galanin, modulate the control of appetite and play an important role in
      the mechanism of luteinizing hormone-releasing hormone (LHRH) secretion. NPY and
      galanin regulate appetite via both central and peripheral mechanisms. The
      interaction between central and peripheral signals for the control of food intake
      is due to leptin. Leptin can modulate the activity of NPY and other peptides in
      the hypothalamus that are known to affect eating behavior. In order to evaluate
      the relationship between NPY, galanin and leptin, 28 women with PCOS, 32 obese
      women (non-PCOS) and 19 lean healthy women (control group) were investigated.
      Obese women with PCOS were divided into two groups: PCOS (A) overweight (body
      mass index, BMI 26-30 kg/m2), and PCOS (B) obese (BMI 31-40 kg/m2). Plasma NPY,
      galanin and leptin concentrations were measured by radioimmunoassay. Plasma
      leptin levels in obese women with PCOS (groups A and B) were significantly higher
      than those in the control group (p < 0.05, p < 0.05, respectively). A significant
      positive correlation between plasma leptin and BMI in women with PCOS was found
      (r = 0.427, p < 0.01). A positive correlation was demonstrated between leptin and
      testosterone in PCOS (r = 0.461, p < 0.01). Plasma galanin concentrations in PCOS
      were higher than in the control group but the differences were not significant.
      Plasma NPY levels were significantly elevated in both non-obese (normal) and
      obese women with PCOS (group A) (p < 0.01, p < 0.005, respectively). However, in
      obese non-PCOS women plasma NPY levels gradually increased with increase in BMI.
      No significant correlations were found between galanin, NPY and percentage change
      in response of LH to LHRH, as well as between NPY and insulin, and galanin and
      testosterone. Plasma insulin concentrations in women with PCOS (group B) were
      significantly higher than in the control group (p < 0.001). Increased plasma NPY
      levels are found in both obese and non-obese women with PCOS. The increase in NPY
      is independent of the increase in BMI. In obese women with PCOS, plasma leptin is
      increased compared with control lean women. Serum insulin concentration is
      increased in obese women with PCOS. A positive correlation exists between leptin
      and BMI as well as between leptin and testosterone in women with PCOS. These
      results may suggest that the feedback system in the interaction between leptin
      and NPY is disturbed in PCOS.

PMID- 10599553
TI  - Endocrine response to pregnanolone.
AB  - Neuroendocrine effects of the neurosteroids, pregnanolone and allopregnanolone
      have been demonstrated in rats. The endocrine effects of pregnanolone in humans
      have so far not been fully elucidated. This study has evaluated the effects of
      pregnanolone administration on part of the hypothalamus-pituitary-gonadal (HPG)
      axis throughout the menstrual cycle in control subjects and patients with
      premenstrual syndrome (PMS). Intravenous pregnanolone and vehicle were given to
      eight women with, and eight women without, PMS during the mid-follicular and late
      luteal phase. Following the drug administrations, progesterone, estradiol,
      luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin
      plasma levels were measured. Intravenous pregnanolone induced a rise in
      progesterone levels in the follicular phase. In the luteal phase progesterone
      levels decreased in response to pregnanolone provocation. Pregnanolone did not
      induce any changes in estradiol, LH, FSH or prolactin plasma levels in either
      cycle phase. PMS patients and control subjects did not differ with respect to the
      endocrine effects of pregnanolone. In conclusion, our data show that
      pregnanolone, in moderate doses, appears not to have any adverse effects on the
      HPG axis, irrespective of cycle phase.

PMID- 10599555
TI  - [Therapy of psoriasis. Daily practice and special requirements].

PMID- 10599554
TI  - Association of tibolone and fluoride displays a pronounced effect on bone mineral
      density in postmenopausal osteoporotic women.
AB  - A double-blind, placebo-controlled, randomized, prospective two-center study was
      carried out to assess the effects of tibolone + fluoride versus placebo +
      fluoride therapy on trabecular and cortical bone in postmenopausal osteoporotic
      women. Ninety-four subjects (mean age 61.1 years, postmenopausal 13.5 years on
      average) with low bone mineral density (BMD) at baseline were randomized to 2.5
      mg of tibolone (Org OD 14, Livial) plus 26.4 mg of fluoride (Fluocalcic) or
      placebo plus 26.4 mg of fluoride daily over 2 years; 55 (58.5%) subjects
      completed the study, the main reason for discontinuation being untoward
      gastrointestinal effects. BMD at the lumbar spine was measured by both dual
      photon absorptiometry (DPA) and dual-energy X-ray absorptiometry (DXA), and at
      the hip by DXA at 6-month intervals. Baseline values (DXA, g/cm2) for tibolone +
      fluoride and placebo + fluoride groups were 0.733 and 0.744 for the lumbar spine,
      and 0.761 and 0.788 for the hip. Change from baseline and percentage change from
      baseline were calculated for the intent-to-treat and completers groups. An
      analysis of variance (ANOVA) model or Wilcoxon test was used for statistical
      evaluation. There was a mean increase in BMD at the lumbar spine measured by DPA
      of 25.3% and 12.3% in tibolone + fluoride and placebo + fluoride groups,
      respectively (p = 0.01); with DXA, respective changes were 32.6% and 14.0% (p =
      0.013). Data on BMD at the hip showed mean increases of 7.9% and 2.6% for the
      tibolone + fluoride and placebo + fluoride groups, respectively. We conclude that
      combined tibolone + fluoride treatment induces a highly significant increase in
      BMD at the lumbar spine without simultaneous loss of the cortical bone allowing
      for a meaningful reduction of the fluoride dose when given in combination with
      tibolone.

PMID- 10599556
TI  - Potential role of endothelin and nitric oxide in physiology and pathophysiology
      of the lower urinary tract.
AB  - Endothelium-derived vasoactive mediators (endothelin-1 with its vasoconstrictive
      and mitogenic properties and nitric oxide with its vasodilatory and
      antiproliferative properties) play an important role in the regulation of
      vascular smooth muscle tone and cellular proliferation. Several recent studies
      have now demonstrated the presence of these vasoactive agents in the urinary
      tract where they are thought to play a prominent role in urinary tract physiology
      and disease. This article reviews the synthesis, localisation and actions of
      endothelin and nitric oxide in the lower urinary tract and examines the possible
      role of these mediators in disease.

PMID- 10599557
TI  - Identification of a functional leukocyte-type NADPH oxidase in human endothelial
      cells :a potential atherogenic source of reactive oxygen species.
AB  - Cultured human endothelial cells (EC) exposed to atherogenic low-density
      lipoprotein levels have increased reactive oxygen species (ROS) generation. The
      enzyme responsible for this ROS production elevation is unknown. We have examined
      for the presence of a functional leukocyte-type NADPH oxidase in EC to elucidate
      whether this enzyme could be the ROS source. The plasma membrane fraction of
      disrupted EC showed a reduced-minus-oxidized difference spectra with absorption
      peaks identical to those observed in the spectra of the leukocyte NADPH oxidase
      component, cytochrome b558. Western-blot analysis, using anti-gp91 -phox. anti 
      p22-phox. anti -p47-phox. and anti -p67-phox antibodies, demonstrated the protein
      expression of NADPH oxidase subunits in EC. Reverse transcriptase-polymerase
      chain reaction (RT-PCR) showed the mRNA expression of gp91-phox, p22-phox, p47
      phox, and p67-phox in EC. Sonicates from unstimulated EC produced no measurable
      superoxide; whereas, exogenously applied arachidonic acid activated superoxide
      generation in a manner that was dependent upon the presence of NADPH and both
      membrane and cytosolic fractions combined. Apocynin, a specific leukocyte NADPH
      oxidase inhibitor, was shown by Western-blot analysis of membrane and cytoplasmic
      fractions to inhibit the translocation of p47-phox to the membrane of stimulated
      EC. These findings support the presence of a functionally active leukocyte-type
      NADPH oxidase in EC. NADPH oxidase could be the major cellular ROS source in EC
      perturbation, which has been hypothesized to be a major contributing factor in
      the pathogenesis of atherosclerosis.

PMID- 10599558
TI  - B1 integrin activation inhibits in vitro tube formation: effects on cell
      migration, vacuole coalescence and lumen formation.
AB  - Human endothelial cells (EC), when plated onto gels of extracellular matrix
      proteins such as Matrigel or collagen form capillary tubes in a process thought
      to mimic angiogenesis. We have shown previously that the extent of tube formation
      and the phenotype of the lumen are regulated by integrins (Gamble et al 1993) and
      lumen formation occurs through a process of vacuolization, coalescence and
      ultimate directional fusion of these vacuoles with the plasma membrane (Meyer
      1997 et al). We now show here that activation of beta1 integrins on endothelial
      cells inhibits tube formation. On collagen gels, endothelial cells treated with
      31 activating antibody 8A2 failed to migrate into the gel and tube formation was
      inhibited. Although several integrins mediate EC attachment to collagen
      alpha2beta1 is the chief determinant of EC behaviour since a blocking antibody to
      (alpha2beta1 reversed the effect of 8A2. On Matrigel tube formation was also
      inhibited by 8A2 treatment although cell alignment and sprout formation was still
      evident. Electron microscopy revealed the organisation of normal numbers of cells
      into solid sprouts and the formation of small intracellular vacuoles suggesting
      that initial stages of tube formation including cell migration were unaffected.
      However, beta1 integrin activation inhibited the coalescence of these small
      vacuoles into larger vacuoles, the recruitment of more cells into the sprout and
      the subsequent formation of mature lumen. The inhibition of capillary tube
      formation by beta1 activation was time dependent and long lasting. The critical
      time for activation of the beta1 integrin was the initial 1-2h after plating in
      order to inhibit tube formation although once activated, the beta1 mediated
      inhibition on Matrigel was still evident 4 days later. Our results suggest that
      beta1 integrins are critical in capillary tube formation in at least two phases.
      beta1 integrins are essential for migration of EC through collagen gels.
      Independently, beta1 integrins, although not involved in initial vacuole
      formation, are involved in the process of vacuole coalescence and subsequent
      lumen formation since beta1 integrin activation inhibits these processes.

PMID- 10599559
TI  - Apoptosis in vascular endothelial cells caused by serum deprivation, oxidative
      stress and transforming growth factor-beta.
AB  - Vascular endothelial cell apoptosis has previously been shown to play a role in
      the pathogenesis of hypertension-induced vessel deletion and damage. In the
      present in vitro study we analyse several possible relevant causative factors of
      vascular endothelial cell apoptosis, namely, serum deprivation and nutrient
      depletion, oxidative stress in the forms of hypoxia, hyperoxia or free radical
      damage, and altered levels of transforming growth factor-beta1 (TGF-beta1)
      protein. An established cell line, bovine aortic endothelial cells (BAEC), was
      maintained in complete growth medium (RPMI-1640 plus 15% fetal calf serum and
      antibiotics, abbreviated as RPMI) in 25cm2 flasks or in 12-well plates on glass
      coverslips. Confluent but actively-growing cultures were treated with either
      hypoxia (PO2 of RPMI = 50mmHg), serum-free media (SFM), SFM plus hypoxia,
      hyperoxia (PO2 of RPMI = 450mmHg), hydrogen peroxide (H2O2, 1mM) in SFM, or TGF
      beta1 protein (10ng/mL) in SFM. Appropriate control cultures were used. BAEC were
      collected 48h or 72h after all treatments except for TGF-beta1 and H2O2
      treatments that were collected at 16-18h. Cell death was assessed using
      morphological characteristics or in situ end labeling (ISEL), cell proliferation
      assessed using proliferating cell nuclear antigen (PCNA), and TGF-beta1
      expression assessed using transcript levels or immunohistochemistry. All
      treatments significantly increased levels of apoptosis over control cultures
      (P<0.05), and decreased levels of cell proliferation. Treatment with TGF-beta1
      protein or SFM plus hypoxia induced greatest levels of apoptosis. TGF-beta1
      protein and transcript levels were decreased in treated cultures, results
      suggesting that a paracrine source of TGF-beta1 protein would be needed as a
      cause of endothelial cell apoptosis in viva. Future therapies against
      inappropriate vessel deletion in disease states may use the known gene-driven
      nature of apoptosis to modify this sort of cell death in endothelial cells.

PMID- 10599560
TI  - Conference report: the 10th Annual Endothelium Symposium, Leiden, The
      Netherlands.

PMID- 10599561
TI  - Approaches to enhance expression after adenovirus-mediated gene transfer to the
      carotid artery.
AB  - The goal of this study was to enhance transgene expression after adenoviral
      mediated gene transfer to the carotid artery. We used an adenoviral vector with a
      transgene that expresses beta-galactosidase, driven by the human cytomegalovirus
      (CMV) promoter/enhancer. The CMV promoter drives constitutive expression, and
      response elements within the enhancer allow inducible expression through binding
      of active transcription factors, such as cAMP response element binding protein
      (CREB) and nuclear factor kappa B (NFkappaB). Rings of rabbit carotid artery were
      incubated ex vivo with a replication-deficient adenovirus that expresses beta
      galactosidase (AdCMV-betagal). Virus was removed from the medium, and forskolin
      or phorbol-12-myristate-13-acetate (PMA), which can induce activation of CREB or
      NFkappaB, respectively, were added to the medium. Pyrrolidine dithiocarbamate
      (PDTC) was used to inhibit activation of NFkappaB. Following incubation for 24
      hours, beta-galactosidase activity was assessed by chemiluminescent reporter
      assay. Forskolin and PMA enhanced transgene expression in the carotid artery.
      Activity increased from 56+/-13 mU/mg protein (mean+/-SE) in rings of carotid
      treated with virus alone (10(9) pfu) to 159+/-23 mU/mg protein (P<0.05) in rings
      treated with forskolin, and to 189+/-40 mU/mg protein (P<0.05) in rings treated
      with PMA. Phorbol didecanoate, an inactive phorbol, did not affect expression of
      beta-galactosidase. After pre-incubation with PDTC prior to PMA, expression of
      beta-galactosidase was less than in rings incubated with PMA alone (29+/-11,
      P<0.05). Histochemical staining of carotid artery for beta-galactosidase
      demonstrated enhanced endothelial expression following administration of PMA.
      These findings suggest that expression after gene transfer to the carotid artery
      using an adenoviral vector with the CMV promoter/enhancer may be enhanced by PMA
      and forskolin, perhaps by activation of transcription factors.

PMID- 10599562
TI  - The news on tobacco control: time to bring the background into the foreground.

PMID- 10599563
TI  - Trust? No--verify.

PMID- 10599564
TI  - USA: price cuts and point of sale ads follow tax rise.

PMID- 10599565
TI  - Turkey: tobacco's hard drive for ban-busting F1.

PMID- 10599566
TI  - A-rise, Sir Richard (p>0.001)

PMID- 10599567
TI  - The tobacco settlement: an analysis of newspaper coverage of a national policy
      debate, 1997-98.
AB  - OBJECTIVE: To examine the framing of tobacco policy issues in the news media
      during the national tobacco settlement debate of 1997-98. The major aims were (1)
      to describe the extent of newspaper coverage of each of the specific components
      of the proposed tobacco settlement; (2) to identify the tobacco control frames,
      and the dominant frame, appearing in each newspaper article; and (3) to examine
      trends in tobacco control frames over time. DESIGN: A content analysis was
      performed on 117 articles related to national tobacco legislation appearing in
      the Washington Post from 1 January 1997 through 18 June 1998. MAIN OUTCOME
      MEASURES: (1) Major policy themes of the settlement referred to or implied in
      each article; (2) major frames used to discuss the problem of tobacco in each
      article. RESULTS: The generation of new revenue was the dominant theme of the
      articles, appearing as a major focus in 44% (52) of the articles. Other than the
      issues of Food and Drug Administration regulation of tobacco and restrictions on
      cigarette advertising, the public health policy aspects of the tobacco settlement
      received little attention. The problem of tobacco was portrayed as one of youth
      smoking in 55% (64) of the articles, but as one of a deadly product in none of
      the articles. CONCLUSIONS: Future discussions of comprehensive tobacco policy
      should be driven by a more specific discussion of the precise programme and
      policy mechanisms by which tobacco use can be most effectively prevented and
      controlled. The public health community must find ways to frame the tobacco issue
      more broadly than simply as one of youth smoking.

PMID- 10599568
TI  - Print media coverage of research on passive smoking.
AB  - OBJECTIVE: To assess the extent and content of newspaper and magazine coverage of
      research on passive smoking. DESIGN: Content analysis of newspaper and magazine
      articles. SUBJECTS: Articles reporting on passive smoking research published in
      newspapers (n = 180) or magazines (n = 92) between January 1981 and December
      1994. MAIN OUTCOME MEASURES: Numbers of articles, conclusions of articles,
      sources quoted, numbers and characteristics of research studies cited, presence
      of tobacco advertising. RESULTS: The number of newspaper and magazine articles
      reporting on passive smoking research increased from four in 1981 to 57 in 1992
      and 32 in 1994. Sixty-two per cent (168/272) of articles concluded that the
      research on passive smoking is controversial. Tobacco industry representatives
      were quoted significantly more often in newspaper articles (52%, 94/180) than
      magazine articles (12%, 11/92) (p<0.0001). Of 121 different research studies
      cited in the lay press articles, only 15 were from tobacco-industry sponsored
      projects or publications. In magazines, acceptance of tobacco industry
      advertising was associated with the conclusion that research on passive smoking
      is controversial (p<0.0001). CONCLUSIONS: Although research on the harmful
      effects of passive smoking accumulated between 1981 and 1994, lay press coverage
      of the research maintained that the science was controversial. Few research
      studies were cited to support the industry's claim that passive smoking is not
      harmful to health. However, tobacco industry representatives who were critical of
      the research methods used to study the health effects of passive smoking were
      frequently quoted.

PMID- 10599569
TI  - The effects of household and workplace smoking restrictions on quitting
      behaviours.
AB  - OBJECTIVE: To assess the association of household and workplace smoking
      restrictions with quit attempts, six month cessation, and light smoking. DESIGN:
      Logistic regressions identified the association of household and workplace
      smoking restrictions with attempts to quit, six month cessation, and light
      smoking. SETTING: Large population surveys, United States. SUBJECTS: Respondents
      (n = 48,584) smoked during the year before interview in 1992-1993, lived with at
      least one other person, and were either current daily smokers or were former
      smokers when interviewed. MAIN OUTCOME MEASURES: The outcome measures were an
      attempt to quit during the last 12 months, cessation for at least six months
      among those who made an attempt to quit, and light smoking (< 15 cigarettes a
      day). RESULTS: Smokers who lived (odds ratio (OR) = 3.86; 95% confidence interval
      (CI) = 3.57 to 4.18) or worked (OR = 1.14; 95% CI = 1.05 to 1.24) under a total
      smoking ban were more likely to report a quit attempt in the previous year. Among
      those who made an attempt, those who lived (OR = 1.65, 95% CI = 1.43 to 1.91) or
      worked (OR = 1.21, 95% CI = 1.003 to 1.45) under a total smoking ban were more
      likely to be in cessation for at least six months. Current daily smokers who
      lived (OR = 2.73, 95% CI = 2.46 to 3.04) or worked (OR = 1.53, 95% CI = 1.38 to
      1.70) under a total smoking ban were more likely to be light smokers.
      CONCLUSIONS: Both workplace and household smoking restrictions were associated
      with higher rates of cessation attempts, lower rates of relapse in smokers who
      attempt to quit, and higher rates of light smoking among current daily smokers.

PMID- 10599570
TI  - Trends in environmental tobacco smoke restrictions in the home in Victoria,
      Australia.
AB  - OBJECTIVE: To assess the extent to which smokers and non-smokers in Victoria,
      Australia attempt to keep their homes smoke free and to determine whether the
      proportion of people attempting to do so has changed over time. DESIGN: Face to
      face surveys conducted in Victoria each year from 1989 to 1997. PARTICIPANTS:
      Approximately 2500 randomly selected adults each year. MAIN OUTCOME MEASURES:
      Proportion of respondents who discourage their visitors from smoking; proportion
      of smokers who always smoke outside their own homes; behaviour of smokers when
      they are around children. Changes in each of these measures over time. RESULTS:
      Reports of visitors being discouraged from smoking rose from 27% in 1989 to 53%
      in 1997. Smokers who reported always smoking outside the home rose from 20% in
      1995 to 28% in 1997. Not smoking in the presence of children rose from 14% in
      1989 to 33% in 1996. Indoor restrictions on smoking were associated with the
      presence of children in the household and even more strongly with the presence of
      non-smoking adults. People who worked in places where smoking was totally banned
      were more likely to ask their visitors not to smoke than those who worked where
      smoking was allowed. CONCLUSIONS: The results indicate a strong move towards
      homes and towards protecting children from smoke. Efforts to support and
      facilitate this social change should be further encouraged.

PMID- 10599571
TI  - The impact of workplace smoking bans: results from a national survey.
AB  - OBJECTIVE: To estimate the impact of workplace smoking restrictions on the
      prevalence and intensity of smoking among all indoor workers and various
      demographic and industry groups. DESIGN: Detailed cross sectional data on worker
      self reported characteristics, smoking histories, and workplace smoking policies
      were used in multivariate statistical models to examine whether workplace smoking
      policies reduce cigarette consumption. After analysing the distribution of
      policies, four main types of workplace programme were defined: (1) 100% smoke
      free environments, (2) work area bans in which smoking is allowed in some common
      areas, (3) bans in some but not all work and common areas, and (4) minimal or no
      restrictions. SETTING: After environmental tobacco smoke was identified as a
      health hazard in the mid-1980s, workplace smoking restrictions became more
      prevalent. By 1993, nearly 82% of indoor workers faced some restriction on
      workplace smoking and 47% worked in 100% smoke-free environments. PARTICIPANTS:
      The database included a nationally representative sample from the tobacco use
      supplements to the September 1992, January 1993, and May 1993 Current Population
      Surveys of 97,882 indoor workers who were not self employed. MAIN OUTCOME
      MEASURES: Prevalence of smoking and number of cigarettes smoked daily by smokers.
      RESULTS: Having a 100% smoke-free workplace reduced smoking prevalence by 6
      percentage points and average daily consumption among smokers by 14% relative to
      workers subject to minimal or no restrictions. The impact of work area bans was
      lessened by allowing smoking in some common areas. Smoke-free policies reduced
      smoking for all demographic groups and in nearly all industries. CONCLUSIONS:
      Requiring all workplaces to be smoke free would reduce smoking prevalence by 10%.
      Workplace bans have their greatest impact on groups with the highest rates of
      smoking.

PMID- 10599572
TI  - Effect of smoke-free policies on the behaviour of social smokers.
AB  - OBJECTIVE: To test the hypothesis that proposed amendments to the Occupational
      Safety and Health Act making all enclosed workplaces in Western Australia smoke
      free would result in a decrease in cigarette consumption by patrons at
      nightclubs, pubs, and restaurants without adversely affecting attendance. DESIGN:
      Cross sectional structured interview survey. PARTICIPANTS AND SETTING: Patrons of
      several inner city pubs and nightclubs in Perth were interviewed while queuing
      for admission to these venues. OUTCOME MEASURES: Current social habits, smoking
      habits; and how these might be affected by the proposed regulations. Persons who
      did not smoke daily were classified as "social smokers." RESULTS: Half (50%) of
      the 374 patrons interviewed were male, 51% currently did not smoke at all, 34.3%
      smoked every day, and the remaining 15.7% smoked, but not every day. A clear
      majority (62.5%) of all 374 respondents anticipated no change to the frequency of
      their patronage of hospitality venues if smoke-free policies became mandatory.
      One in five (19.3%) indicated that they would go out more often, and 18.2% said
      they would go out less often. Half (52%) of daily smokers anticipated no change
      to their cigarette consumption, while 44.5% of daily smokers anticipated a
      reduction in consumption. A majority of social smokers (54%) predicted a
      reduction in their cigarette consumption, with 42% of these anticipating
      quitting. CONCLUSIONS: One in nine (11.5%) of smokers say that adoption of smoke
      free policies would prompt them to quit smoking entirely without a significant
      decrease in attendance at pubs and nightclubs. There can be few other initiatives
      as simple, cheap, and popular that would achieve so much for public health.

PMID- 10599573
TI  - Measuring environmental tobacco smoke exposure in infants and young children
      through urine cotinine and memory-based parental reports: empirical findings and
      discussion.
AB  - OBJECTIVE: This study examined the reliability and potential biases of two urine
      collection methods from which cotinine measures were obtained and the validity of
      memory-based parental reports of their children's exposure to environmental
      tobacco smoke (ETS). DESIGN: Structured interviews were conducted with mothers of
      infants and young children to obtain memory-based estimates of recent ETS
      exposure. Urine samples were collected through standard and cotton roll
      collection methods for cotinine analysis. SETTING: All interviews took place at
      an off-campus research facility. Urine samples were collected at the study office
      or the subjects' homes. PARTICIPANTS: Mothers were recruited from San Diego
      county sites of the Women, Infants, and Children (WIC) Supplemental Food and
      Nutrition Program. Sample 1 (infants) consisted of eight boys and eight girls
      aged 1-44 months (mean = 12.6 months). Sample 2 (children) included 10 boys and
      10 girls aged 3-8 years (mean = 61.2 months). MAIN OUTCOME MEASURES: Urine
      cotinine and memory-based parent reports of ETS exposure from structured
      interviews. RESULTS: There was overall high reliability for urine cotinine
      measures and no effect of collection method on urine cotinine levels. Memory
      based reports obtained from smoking mothers showed moderately strong and
      consistent linear relationships with urine cotinine measures of their infants and
      children (r = 0.50 to r = 0.63), but not for reports obtained from non-smoking
      mothers. CONCLUSIONS: Memory-based parental reports of short-term ETS exposure
      can play an important role in quantifying ETS exposure in infants and children.

PMID- 10599574
TI  - Medical costs of smoking in the United States: estimates, their validity, and
      their implications.
AB  - OBJECTIVE: To compare estimates of the medical costs of smoking in the United
      States and to consider their relevance to assessing the costs of smoking in
      developing countries and the net economic burden of smoking. DATA SOURCES: A
      Medline search through early 1999 using keywords "smoking" and "cost", with
      review of article reference lists. STUDY SELECTION: Peer-reviewed papers
      examining medical costs in a single year, covering the non-institutionalised
      American population. DATA EXTRACTION: Methods underlying study estimates were
      identified, described, and compared with attributable expenditure methodology in
      the literature dealing with costs of illness. Differences in methods were
      associated with implied differences in findings. DATA SYNTHESIS: With one
      exception, the studies find the annual medical costs of smoking to constitute
      approximately 6-8% of American personal health expenditures. The exception, a
      recent study, found much larger attributable expenditures. The lower estimates
      may reflect the limitation of analysis to costs associated with the principal
      smoking-related diseases. The higher estimate derives from analysis of smoking
      attributable differences in all medical costs. However, the finding from the most
      recent study, also considering all medical costs, fell in the 6-8% range.
      CONCLUSIONS: The medical costs of smoking in the United States equal, and may
      well exceed, the commonly referenced figure of 6-8%. This literature has direct
      methodological relevance to developing countries interested in assessing the
      magnitude of their current cost-of-smoking burden and their future burdens, with
      differences in tobacco use histories and the availability of chronic disease
      treatment affecting country-specific estimates. The debate over the use of gross
      or net medical cost estimates is likely to intensify with the proliferation of
      lawsuits against the tobacco industry to recover expenditures on tobacco-produced
      disease.

PMID- 10599575
TI  - Analysis of factors related to illegal tobacco sales to young people in Ontario.
AB  - OBJECTIVE: To identify and to discuss factors influencing illegal merchant sales
      of tobacco to underage people in Ontario, Canada. DESIGN: Results were obtained
      through random retail compliance checks of tobacco merchants. A multivariate
      analysis specified the relationship between selected independent variables and
      the willingness of tobacco merchants to sell to minors. The selected independent
      variables included retail operation type, community population size, the presence
      of tobacco production, signage, sex and age of volunteers, smoking prevalence
      rates, and enforcement rates. PARTICIPANTS: A random, stratified sample of 438
      tobacco retailers in 186 communities in Ontario. MAIN OUTCOME MEASURE:
      Willingness of merchants to sell tobacco to minors. RESULTS: Older youths and
      girls were more likely to be sold tobacco products. Purchase attempts carried out
      in tobacco-producing regions were also statistically related to illegal sales.
      CONCLUSIONS: Policy efforts to control youth access to tobacco in Canada may need
      to invoke legislation requiring merchants to request proper identification from
      customers who appear to be under the age of 25, and who seek to purchase tobacco
      products. Further attention could also be directed at tobacco control policies
      and enforcement strategies that need to consider the unique challenges faced by
      jurisdictions where the tobacco industry is a powerful presence.

PMID- 10599576
TI  - Store tobacco policies: a survey of store managers, California, 1996-1997.
AB  - OBJECTIVE: To identify store tobacco policies and retailer perception and beliefs
      that may have contributed to changes in compliance with youth access laws in
      California. DESIGN: In the winter of 1996-7, a cross sectional, follow up
      telephone survey was conducted of California store managers whose stores were
      anonymously surveyed for illegal tobacco sales in the summer of 1996 (that is,
      1996 Youth Tobacco Purchase Survey, YTPS). SETTING: A simple random sample of
      stores from a list of California stores likely to sell tobacco, used in the 1996
      YTPS. PARTICIPANTS: 334 managers (77%) of the 434 stores surveyed in 1996
      responded to the survey. After eliminating stores that stopped selling tobacco or
      were under new management or ownership, 320 responses of store managers were
      included in the analysis. The stores were analysed by type of ownership: chain,
      which included corporate managed (n = 61); franchise owned (n = 56); and
      independent (n = 203). MAIN OUTCOME MEASURES: Responses of store managers were
      linked with the 1996 YTPS outcomes. Manager responses were compared by chi2
      tests. Logistic regression analyses were conducted to identify store factors
      associated with illegal tobacco sales. RESULTS: A lower likelihood of illegal
      sales rate was associated with the chain stores when compared with the
      independent stores (odds ratio (OR) = 0.4, 95% confidence interval (CI) 0.2 to
      0.9). A lower likelihood of illegal tobacco sales was found in stores that
      implemented tobacco related activities in the previous year such as changing
      tobacco displays (OR = 0.5, 95% CI 0.2 to 0.9) or adding new warning signs (OR =
      0.7, 95% CI 0.4 to 1.2). Store managers' beliefs that youth were sent to their
      stores to do compliance checks also resulted in a lower likelihood of illegal
      sales (OR = 0.7, 95% CI 0.4 to 1.1). CONCLUSIONS: Store tobacco youth access
      policies, and managers' beliefs about the extent of youth access enforcement in
      the community, are important in reducing illegal tobacco sales to minors.

PMID- 10599577
TI  - The passage and initial implementation of Oregon's Measure 44.
AB  - OBJECTIVE: To prepare a history of the passage and early implementation of Ballot
      Measure 44, "An Act to Support the Oregon Health Plan", and tobacco control
      policymaking in Oregon. Measure 44 raised cigarette taxes in Oregon by US$0.30
      per pack, and dedicated 10% of the revenues to tobacco control. METHODS: Data
      were gathered from interviews with members of the Committee to Support the Oregon
      Health Plan, Measure 44's campaign committee, as well as with state and local
      officials, and tobacco control advocates. Additional information was obtained
      from public documents, internal memoranda, and news reports. RESULTS: Although
      the tobacco industry outspent Measure 44's supporters 7 to 1, the initiative
      passed with 56% of the vote. Even before the election, tobacco control advocates
      were working to develop an implementation plan for the tobacco control programme.
      They mounted a successful lobbying campaign to see that the legislature did not
      divert tobacco control funds to other uses. They also stopped industry efforts to
      limit the scope of the programme. The one shortcoming of the tobacco control
      forces was not getting involved in planning the initiative early enough to
      influence the amount of money that was devoted to tobacco control. Although
      public health groups provided 37% of the money it cost to pass Measure 44, only
      10% of revenues were devoted to tobacco control. CONCLUSIONS: Proactive planning
      and aggressive implementation can secure passage of tobacco control initiatives
      and see that the associated implementing legislation follows good public health
      practice.

PMID- 10599578
TI  - Four beliefs that may impede progress in the treatment of smoking.
AB  - The validity of four often-cited statements about smoking cessation is reviewed
      and their misinterpretation is discussed. "Most smokers are interested in
      quitting" is true; however, more important is the fact that smokers try to quit
      only once every 3.5 years. Thus motivating attempts to quit and removing barriers
      to treatment are important. "Most smokers quit on their own" is often interpreted
      to mean that smokers are not nicotine dependent; however, most dependent
      alcoholics and drug abusers who quit, do so on their own. This statement is also
      often interpreted to mean that most smokers do not need therapy, but the same was
      said about clinical depression in the early 1900s. "Quit rates with treatment are
      low"; however, most successful interventions for chronic disorders are the result
      of a series of treatments, not just one treatment. "Medication is effective only
      when accompanied by psychosocial therapy" is a tenet of treatment for traditional
      drug abuse; however, medications such as over-the-counter nicotine replacement
      therapies double quit rates even in the absence of psychosocial therapy.

PMID- 10599579
TI  - Women and tobacco in Indonesia.
AB  - OBJECTIVES: To present a broad exploration of the relationship of women and
      tobacco in Indonesia and to describe action on tobacco and health specific to
      women taken by government and non-government agencies. DATA SOURCES: Published
      and unpublished prevalence surveys, official documents, vernacular newspapers,
      secondary sources, unstructured interviews, and personal observations. STUDY
      SELECTION: Data on smoking prevalence among women was primarily sought from
      official household surveys but several smaller scale local surveys were also
      examined. The only representative national household data on smoking prevalence
      from 1995 suggested a national prevalence for occasional and regular smoking of
      2.6% for women aged 20 years or older. Smaller, local level surveys had reported
      rates varying from 4% for junior high school girls, and 2.9% for women
      undergraduates at a provincial university, to 6.4% of women in a representative
      sample in Jakarta. Claims that the incidence of female smoking is increasing
      cannot be confirmed due to an absence of comparable national longitudinal data.
      CONCLUSION: Although Indonesian women are conspicuous in growing and processing
      tobacco, their rates of smoking are low in comparison with their male compatriots
      and internationally. Anecdotal evidence suggests that their disinclination to
      smoke is commonly attributed to cultural values, which stigmatise women smokers
      as morally flawed, while at the same time sanctioning smoking by men. Although
      there is little evidence of tobacco advertising directly targeting women,
      Indonesian health activists interviewed by the author felt that women are
      increasingly taking up smoking due to a weakening of stigma and to Western
      cultural influences. Cultural factors in the low rates of smoking among
      Indonesian women deserve closer investigation as they have proved to be a major
      source of health protection, albeit within a stigmatising context. More also
      needs to be known about the dynamics of female tobacco use in Indonesia and the
      factors contributing to marked geographical variations in smoking prevalence.

PMID- 10599580
TI  - Why we should tackle adult smoking first.

PMID- 10599581
TI  - Adults versus teenagers: a false dilemma and a dangerous choice.

PMID- 10599582
TI  - Public health priorities.

PMID- 10599583
TI  - Smoking cessation rate among outpatients at a cancer hospital.

PMID- 10599584
TI  - Tobacco-related scenes in television dramas for young Japanese audiences.

PMID- 10599585
TI  - Suicide prevention among active duty Air Force personnel--United States, 1990
      1999.
AB  - During 1990-1994, suicide accounted for 23% of all deaths among active duty U.S.
      Air Force (USAF) personnel and was the second leading cause of death (after
      unintentional injuries) (Table 1). During those years, the annual suicide rate
      among active duty USAF personnel increased significantly (p<0.01) from 10.0 to
      16.4 suicides per 100,000 members (Figure 1). In 1995, senior USAF leaders
      initiated prevention programs in several commands because of the increasing
      suicide rate. In May 1996, an in-depth study by a team of medical and nonmedical
      civilian and military experts was initiated to produce a comprehensive,
      communitywide prevention strategy that viewed suicide not only as a medical but a
      USAF problem, thus addressing overall social, behavior, and health issues (1).
      The plan was implemented across the entire USAF during 1996-1997. This report
      describes protective and prevention strategies and summarizes the study findings,
      which indicate that a substantial decline in the suicide rate was associated with
      the communitywide program.

PMID- 10599586
TI  - Progress toward poliomyelitis eradication--Eastern Mediterranean Region, 1998
      October 1999.
AB  - In 1988, the Regional Committee for the Eastern Mediterranean Region* (EMR) of
      the World Health Organization (WHO) adopted a resolution to eliminate
      poliomyelitis from the region by 2000. This report summarizes progress toward
      this goal in EMR countries through October 1999; all EMR countries, including war
      torn and other underdeveloped areas of the region, are conducting essential polio
      eradication strategies, and eradication activities to rapidly stop poliovirus
      transmission are under way in countries where polio is endemic.

PMID- 10599587
TI  - Nonfatal and fatal firearm-related injuries--United States, 1993-1997.
AB  - In 1997, 32,436 deaths resulted from firearm-related injuries, making such
      injuries the second leading cause of injury mortality in the United States after
      motor-vehicle-related incidents (1). Also in 1997, an estimated 64,207 persons
      sustained nonfatal firearm-related injuries and were treated in U.S. hospital
      emergency departments (EDs); approximately 40% required inpatient hospital care.
      National firearm-related injury and death rates peaked in 1993, then began to
      decline (2). This report presents national data from 1993 through 1997, which
      showed that the decline in nonfatal and fatal firearm-related injury rates was
      substantial and consistent by sex, race/ethnicity, age, and intent of injury.

PMID- 10599588
TI  - State-specific prevalence of current cigarette and cigar smoking among adults-
      United States, 1998.
AB  - Each year, cigarette smoking causes an estimated 430,000 deaths in the United
      States (1). In addition, the health risks for smoking cigars, which include
      mouth, throat, and lung cancers, are well documented (2). This report summarizes
      the findings from the 1998 Behavioral Risk Factor Surveillance System (BRFSS) on
      the prevalence of current cigarette and cigar smoking in the 50 states and the
      District of Columbia. The findings indicate that state-specific cigarette smoking
      prevalence among adults aged > or = 18 years varied twofold and having ever
      smoked a cigar (i.e., ever cigar smoking) varied nearly fourfold.

PMID- 10599589
TI  - Influenza activity--United States, 1999-2000 season.
AB  - Influenza activity was low during October 3-November 6, 1999; influenza virus
      isolates were reported from 30 states, and four long-term-care facility outbreaks
      were reported from three states. The predominant viruses isolated were influenza
      type A(H3N2) viruses. This report summarizes influenza activity in the United
      States during October 3-November 6, 1999. It also summarizes U.S. influenza
      surveillance methodology, including the four primary sources of surveillance
      data, a modification to pneumonia and influenza (P&I) mortality reporting, and
      discusses detection and control of institutional influenza outbreaks.

PMID- 10599590
TI  - Effect of a modified fibrate (Biniwas Retard) on hemorheological alterations in
      hyperlipemic patients.
AB  - The effect of a binifibrate (Biniwas Retard, Wasserman) on the plasma lipids and
      hemorheological profile of 30 primary hyperlipemic patients was studied. Our
      results indicate that the patients under study had evident rheological
      alterations as well as the expected lipid alterations. Treatment with Biniwas (2
      x 550 mg/day) for six months not only substantially improved the alterations in
      the lipid balance but also tended to normalize the patients' hemorheological
      alterations, and there was a statistically significant correlation between the
      two effects. Apart from the decrease in plasma viscosity (1.20 +/- 0.05 vs 1.29
      +/- 0.07 mPa.s, p < 0.001), the most noteworthy effects of Biniwas treatment were
      the decrease in red blood cell aggregability (8.7 +/- 1.2 vs 9.3 +/- 1.1, p <
      0.05) and increased deformability (55 +/- 3 vs 47 +/- 5%, p < 0.001). Both
      changes may be due to modifications in the lipid composition of the erythrocyte
      membrane due to cell-plasma lipid exchange.

PMID- 10599591
TI  - Rheological properties of red blood cells (including reticulocytes) in patients
      with chronic renal disease.
AB  - Hemodialysis is a method of treatment of patients suffering from terminal renal
      disease and consists in removing uremic toxins from blood. The influence of
      hemodialysis on rheological properties of red blood cells was ascertained. We
      studied the deformability of RBC after density gradient separation of whole blood
      drawn from patients with renal disease before and after dialysis. The improvement
      in deformability of cells from the top layers was observed in postdialysis
      samples.

PMID- 10599592
TI  - Ethanol and erythrocyte membrane interaction: a hemorheologic perspective.
AB  - Previous studies have documented structural and functional changes induced by
      ethanol-erythrocyte membrane interaction. In order to perform an in vitro study
      on the effect of different ethanol concentrations on erythrocyte hemorheologic
      properties, blood samples were collected from 21 male donors at the Hospital of
      Santa Maria. Whole blood aliquots were incubated with ethanol solutions of rising
      concentrations. The following parameters were measured: erythrocyte aggregation,
      haemoglobin, carboxyhaemoglobin and methaemoglobin concentrations, hematocrit,
      plasma osmolality and erythrocyte membrane fluidity (fluorescence polarisation
      probes TMA-DPH and DPH). With ethanol blood concentrations of 45 mM a rise in
      plasma osmolality (0.352 Osm/kg H2O vs 0.310 Osm/kg H2O; p < 0.001) was verified.
      With 67 mM concentration a decrease of erythrocyte aggregation (11.03 vs 12.81; p
      < 0.05) and an increase in plasma osmolality (0.380 Osm/kg H2O vs 0.310 Osm/kg
      H2O; p < 0.001) were obtained. In conclusion, ethanol only changes erythrocyte
      aggregation for a concentration of 67 mM. These data could lead to future changes
      in therapeutic approaches to situations such as alcoholic coma.

PMID- 10599593
TI  - Changes in viscosity of low shear rates and viscoelastic properties of oxidative
      erythrocyte suspensions.
AB  - We exposed erythrocytes in soluble hemoglobin and Fe+2, in which hydroxyl radical
      (OH*) might be generated, and measured low shear rate viscosity and
      viscoelasticity of erythrocyte suspensions at Hct of 40%. The quantities of the
      lipid peroxidation product, malonyldialdehyde (MDA), for oxidized samples were
      higher than that for control (e.g., 2.20 +/- 0.46 nmol and 1.70 +/- 0.42 nmol, n
      = 6, p = 0.01, respectively). The viscosity values of oxidized erythrocyte
      suspensions for all tested shear rates were higher than those for the control
      samples (p < 0.05 or better, n = 6). Dynamic viscosity (eta') of oxidized
      erythrocyte samples was higher than that of control samples at the tested shear
      stress of 30 mPa whereas it was not observed in elasticity values (eta"). We
      tentatively concluded from the study, that oxidized erythrocytes would be more
      prone to form aggregates and increase viscosity of blood at low shear rates.
      Therefore, they might impair blood flow in the microcirculation.

PMID- 10599594
TI  - Impaired skin microcirculation and blood rheology in patients with monoclonal
      gammapathy.
AB  - Hemorheological disturbances in patients with monoclonal gammapathies are widely
      known, but there is little information about microcirculation in these patients.
      The following study was performed to examine skin microcirculation and its
      relationship with blood rheology. We analysed both haematological and
      hemorheological parameters (blood and plasma viscosity, aggregation index and
      filterability of 1 ml of whole blood) and skin microcirculation in 46 patients
      with monoclonal gammapathy and 22 healthy controls. Microcirculation on dorsal
      aspect of the hand was examined with laser Doppler flowmeter. We measured resting
      flow and biological zero and maximal flow during postischemic hyperaemic reaction
      after one minute occlusion on the arm. The same parameters were estimated for
      CMBC (concentration of moving blood cells). Patients with monoclonal gammapathy
      are characterised by statistically higher whole blood and plasma viscosities and
      other hemorheological parameters and disturbed skin microcirculation expressed as
      statistically significant lower resting flux and impaired reaction for temporary
      occlusion.

PMID- 10599595
TI  - Microrheology of filtered autotransfusion drain blood with and without leukocyte
      reduction.
AB  - Autotransfusion of filtered knee drain blood (FKDB) is frequently practised in
      orthopaedic surgery, but questioned because it contains inflammatory cytokines,
      contaminants from lysed blood cells, debris and chemicals from the wound. We have
      studied the microrheology (5 microm pore filtration) of FKDB (n = 23) with versus
      without the addition of a leukocyte reducing filter (LRF) in line with the drain.
      As expected the whole blood clogging was reduced (p < 0.01) due to the lowered
      leukocyte number by the LRF. FKDB plasma contains clogging particles of unknown
      origin. With the LRF the increased plasma clogging was reduced (p approximately
      0.05). With resuspended erythrocytes there was an increase in clogging rate in
      FKDB at 24 hours. This increase was abolished with the addition of the LRF, which
      may indicate that the erythrocyte trauma results from the incubation together
      with leukocytes in the drain container. There is a potential for further
      improvement of the filters in autotransfusion drains.

PMID- 10599596
TI  - Rate of deoxygenation modulates rheologic behavior of sickle red blood cells at a
      given mean corpuscular hemoglobin concentration.
AB  - Although the mean corpuscular hemoglobin concentration (MCHC) plays a dominant
      role in the rheologic behavior of deoxygenated density-defined sickle red blood
      cells (SS RBCs), previous studies have not explored the relationship between the
      rate of deoxygenation and the bulk viscosity of SS RBCs at a given MCHC. In the
      present study, we have subjected density-defined SS classes (i.e., medium-density
      SS4 and dense SS5 discocytes) to varying deoxygenation rates. This approach has
      allowed us to minimize the effects of SS RBC heterogeneity and investigate the
      effect of deoxygenation rates at a given MCHC. The results show that the
      percentages of granular cells, classic sickle cells and holly leaf forms in
      deoxygenated samples are significantly influenced by the rate of deoxygenation
      and the MCHC of a given discocyte subpopulation. Increasing the deoxygenation
      rate using high K+ medium (pH 6.8), results in a greater percentage of granular
      cells in SS4 suspensions, accompanied by a pronounced increase in the bulk
      viscosity of these cells compared with gradually deoxygenated samples (mainly
      classic sickle cells and holly leaf forms). The effect of MCHC becomes apparent
      when SS5 dense cells are subjected to varying deoxygenation rates. At a given
      deoxygenation rate, SS5 dense discocytes show a greater increase in the
      percentage of granular cells than that observed for SS4 RBCs. Also, at a given
      deoxygenation rate, SS5 suspensions exhibit a higher viscosity than SS4
      suspensions with fast deoxygenation resulting in maximal increase in viscosity.
      Although MCHC is the main determinant of SS RBC rheologic behavior, these studies
      demonstrate for the first time that at a given MCHC, the rate of deoxygenation
      (hence HbS polymerization rates) further modulates the rheologic behavior of SS
      RBCs. Thus, both MCHC and the deoxygenation rate may contribute to
      microcirculatory flow behavior of SS RBCs.

PMID- 10599597
TI  - Effects of oxidative damage of membrane protein thiol groups on erythrocyte
      membrane viscoelasticities.
AB  - In three oxidative damaging systems: the diamide-mercaptoethanol redox
      modification system (DM), the pyrogallol oxygen free radicals system (PG) and the
      hypoxanthine-xanthine oxidase oxygen free radical system (HXO), the effect of
      erythrocyte membrane oxidative damage on membrane viscoelasticities was
      investigated with micropipette aspiration method. The experimental results
      indicated that erythrocyte membrane oxidative damage has a great influence upon
      the membrane mechanical properties. The oxidative damage led to decrease of
      contents of membrane protein thiol radical. The scanning of SDS-PAGE presented
      that membrane proteins form the higher molecular weight component (HMP) by the
      cross-linking of membrane protein thiol radicals that might hinder the
      conformational change of membrane protein. This might be the reason for the
      increased membrane elastic modulus and viscous coefficient upon treating
      erythrocytes with the oxidative damaging systems. A significant negative
      logarithm regression relation was found between the membrane elastic modulus, mu,
      or viscoefficient, eta, and the contents of membrane protein thiol radicals.
      These experimental results suggested that thiol radicals oxidative damage
      reaction due to the superoxides anions (*O2-) may be an important molecular
      mechanism inducing changes of membrane viscoelasticities or whole cell
      deformability of erythrocyte under physiological and pathological oxidative
      stress.

PMID- 10599598
TI  - Hemorheologic effects of a short-term ketogenetic diet.

PMID- 10599599
TI  - The fairness and effectiveness of stroke care in health maintenance
      organizations.

PMID- 10599600
TI  - HMO membership and patient age and the use of specialty care for hospitalized
      patients with acute stroke: The Minnesota Stroke Survey.
AB  - BACKGROUND: The number of older patients enrolling in health maintenance
      organizations (HMOs) is increasing. Concerns have been raised that older patients
      may be targeted by HMOs for more stringent cost-containment mechanisms, including
      reduced access to expensive specialty care. OBJECTIVES: We investigated the
      relationship between membership in an HMO and the decision to consult with a
      neurologist or admit to a neurology ward for patients hospitalized with acute
      stroke. We then compared 1-year mortality of patients who received neurology care
      to the 1-year mortality of those who did not receive neurology care. DESIGN:
      Retrospective medical record review. SUBJECTS: A sample of hospitalized acute
      stroke patients (age range, 30-79 years) who were discharged from Minneapolis-St.
      Paul metropolitan hospitals with a diagnosis code of acute cerebrovascular
      disease from 1991 to 1993. MEASURES: Trained nurses abstracted the medical
      records. Stroke events (n = 2,320) were validated using clinical criteria and
      neuroimaging reports. Mortality data were obtained from the Minnesota Death
      Index. RESULTS: Among patients enrolled in HMOs, 30% of validated stroke patients
      did not receive neurology care in comparison with 19% of patients not enrolled in
      HMOs. After adjusting for patient mix and hospital characteristics, the odds of
      receiving neurology care were half as great for patients enrolled in HMOs as
      compared with patients not enrolled in HMOs (odds ratio [OR] = 0.52, 95%
      confidence interval [CI] 0.36-0.74). The association of membership in HMOs with
      lower use of neurology care was concentrated in older patients. Within each age
      group, the odds ratios and 95% CI of receiving neurology care for patients
      enrolled in HMOs versus patients not enrolled in HMOs were: < 55 years (1.06,
      0.42-2.67), 55 to 64 years (0.54, 0.34-0.87), 65 to 74 years (0.51, 0.36-0.71),
      and >75 years (0.40, 0.24-0.68). Using Cox regression, 30-day mortality did not
      differ between patients who received neurology care and those who did not. Among
      30-day survivors, the mortality hazards ratio (HR) during the next 11 months for
      patients who received neurology care was 71% of the hazard for patients who did
      not receive neurology care (HR = 0.71, 95% CI = 0.55-0.91). CONCLUSIONS: These
      data suggest that membership in an HMO was associated with reduced access to
      neurology care for older patients with acute stroke and that patients who
      received neurology care had a lower risk of death during the year after their
      stroke. It remains to be determined if these differences in outcome are caused by
      true differences in stroke management or by unmeasured characteristics.

PMID- 10599601
TI  - Cost-effectiveness of outpatient geriatric assessment with an intervention to
      increase adherence.
AB  - BACKGROUND: Comprehensive geriatric assessment (CGA) can be effective in
      inpatient units, but such inpatient settings are prohibitively expensive. If
      similar benefits could be obtained in outpatient settings, CGA might be a more
      attractive option. OBJECTIVES: To assess the cost-effectiveness (CE) of an
      outpatient geriatric assessment with an intervention to increase adherence.
      SUBJECTS: Three hundred fifty-one community-dwelling, elderly subjects with at
      least one of four geriatric conditions. MEASURES: In addition to the measures of
      functioning, we collected data on the costs of the intervention itself and on the
      use of medical services in the 64 weeks after the intervention. RESULTS: The
      intervention, which prevented functional decline, cost $273 per participant. The
      intervention group averaged three more visits than the control group in the first
      32 weeks after the intervention, but only 1.2 extra visits in the next 32 weeks.
      We estimate that the costs of these additional medical services would be $473 for
      the 5 years after the intervention, leading to a total cost per Quality Adjusted
      Life Year (QALY) of $10,600. CONCLUSIONS: The CE of this program compares
      favorably with many common medical interventions. Whether investments should be
      made in health care resources on treatments that lead to modest improvements in
      the functioning of community-dwelling elderly people remains a societal decision.

PMID- 10599602
TI  - Measuring patient satisfaction for quality improvement.
AB  - BACKGROUND: Surveys used for health plan quality reporting are generally
      administered annually to health plan enrollees to assess satisfaction with both
      the health plan and health care services. Therefore, surveys may lack sensitivity
      to measure the effects of patient-focused, quality improvement initiatives that
      could demonstrate results in a shorter time period. OBJECTIVES: We describe the
      development and testing of a multidimensional, visit-specific measure of
      satisfaction with primary care that may be used in quality improvement. METHODS:
      Conducted in five adult and pediatric primary care sites serving a commercial,
      largely managed-care population, the survey includes the Medical Outcomes Study
      Visit-Specific Questionnaire, the American Board of Internal Medicine Patient
      Satisfaction Questionnaire, and locally developed items. We assessed the
      instrument's reliability, validity, and utility for quality improvement. RESULTS:
      For both adult and pediatric samples, three factors emerged: satisfaction with
      the provider, satisfaction with access, and satisfaction with the office.
      Satisfaction with the provider and with the office were independently correlated
      with overall satisfaction in both samples; satisfaction with access was
      significantly correlated with overall satisfaction only for adults. For adults,
      patients who disenrolled from the health plan were less satisfied with the office
      compared with patients who remained with the health plan. Finally, for adults, we
      detected significant differences across practice sites in terms of satisfaction
      with office and access; for children, there were intersite differences in terms
      of satisfaction with provider, office, and access. CONCLUSIONS: We have support
      for the reliability and validity of this instrument that has identified
      differences in satisfaction between practice sites that may be used for quality
      improvement.

PMID- 10599603
TI  - Similarity as a risk factor in drug-name confusion errors: the look-alike
      (orthographic) and sound-alike (phonetic) model.
AB  - BACKGROUND: One of every four medication errors reported in the United States is
      a name-confusion error. The rate of name-confusion errors might be reduced if new
      and confusing names were not allowed on the market and if safeguards could be put
      in place to avoid confusion between existing names. OBJECTIVES: To evaluate
      several prognostic tests of drug-name confusion, alone and in combination, with
      respect to their sensitivity, specificity, and overall accuracy. RESEARCH DESIGN:
      Case-control study. Twenty-two different computerized measures of orthographic
      similarity, orthographic distance, and phonetic similarity were used to compute
      similarity/distance scores for n = 1,127 cases (ie, pairs of names that appeared
      in published error reports or national error databases) and n = 1,127 controls.
      MAIN OUTCOME MEASURES: Mean similarity/distance scores were compared across cases
      and controls. The performance of each measure at distinguishing between cases and
      controls was evaluated by tenfold crossvalidation. Dose-response relationships
      were examined. Univariate and multivariate logistic regression models were formed
      and evaluated by 10 fold crossvalidation. RESULTS: Cases had significantly higher
      similarity scores than controls. Every measure of similarity proved to be a
      significant risk factor for error. There was a significant increasing trend in
      the odds-ratio as a function of similarity. A three-predictor logistic regression
      model had crossvalidated sensitivity of 93.7%, specificity of 95.9% and accuracy
      of 94.8%. CONCLUSIONS: A sensitive and specific test of drug-name confusion
      potential can be formed using objective measures of orthographic similarity,
      orthographic distance, and phonetic distance.

PMID- 10599604
TI  - The association between self-rated health and mortality in a well-characterized
      sample of coronary artery disease patients.
AB  - BACKGROUND: The relationship between self-rated health and mortality after
      adjustment for sociodemographic variables, physician-rated comorbidities, disease
      severity, health-related quality of life (HRQOL), and psychosocial measures
      (depression, social support, and functional ability) was examined in the
      Mediators of Social Support (MOSS) study. SUBJECTS: The sample consisted of 2,885
      individuals (mean age, 62.5 years) who had significant heart disease based upon
      heart catheterization. RESULTS. Using Cox proportional survival analysis,
      individuals who rated their health as "fair" or "poor" had a significantly
      greater likelihood of all-cause mortality (OR = 2.13; CI = 1.40-3.23; OR = 4.92;
      CI = 3.24-7.46, respectively) across follow-up (mean, 3.5 years) than those who
      rated their health as "very good" after considering sociodemographic factors.
      After adjustment for comorbidities, disease severity, HRQOL, psychosocial
      factors, and demographic variables, only those who rated their health as poor had
      a significant greater risk of mortality (OR = 2.96, CI = 1.80-4.85). A similar
      pattern was observed for coronary artery disease (CAD)-related mortality;
      increased adjustment of variables weakened the relationship between self-rated
      health and mortality. Individuals who rated their health as poor had a
      significantly greater risk of CAD-related mortality than did those who rated
      their health as very good (poor vs. very good OR = 3.58, CI = 2.13-6.02) after
      adjustment for all available mortality risk factors. CONCLUSIONS: This study
      indicates that it is important to include self-rated health when studying risk
      factors for mortality. Not adjusting for relevant factors may provide an
      overestimation of the effects of self-rated health on mortality in a sample of
      CAD patients.

PMID- 10599605
TI  - Patterns of change in self-reported oral health among dentate adults.
AB  - BACKGROUND: Although self-assessments of oral health have become useful tools in
      dental research, the use of self-reports to study changes in oral health over
      time has been limited. The aim of this investigation was to describe how oral
      disease and tissue damage, pain, functional limitation, disadvantage, and self
      rated oral health change over time. METHODS: The Florida Dental Care Study (FDCS)
      (n = 873) is a longitudinal study of oral health among dentate adults (age, > or
      = 45 years). Incidence rates and transition probabilities were used to describe
      changes in oral health over a 24-month period. RESULTS: The probability of
      reporting a specific problem during the 24-month study ranged from 0.52 for
      perceived need for dental care to 0.07 for avoided eating with others. Only
      dental sensitivity and perceived need for dental care had transition
      probabilities >0.20. Decomposition of transition probabilities revealed moderate
      probabilities of onset coupled with relatively high probabilities of recovery.
      CONCLUSION: Although oral health status is clearly dynamic, no individual measure
      exhibited profound fluctuation. Most oral health problems were episodic rather
      than chronic. Patterns of change in oral health varied across dimensional lines.

PMID- 10599606
TI  - Obtaining long-term disease specific costs of care: application to Medicare
      enrollees diagnosed with colorectal cancer.
AB  - OBJECTIVES: This study develops estimates of long-term, cancer-related treatment
      cost using a modeling approach and data from the SEER-Medicare linked database.
      The method is demonstrated for colorectal cancer. METHODS: Data on Medicare
      payments were obtained for colorectal cancer patients for the years 1990 to 1994
      from the SEER-Medicare linked database. Claims payment data for control subjects
      were obtained for Medicare enrollees without cancer residing in the same areas as
      patients. Estimates of long-term cost (< or = 25 years following the date of
      diagnosis) were obtained by combining treatment/phase-specific cost estimates
      with estimates of long-term survival from SEER. Treatment phases were defined as
      initial care, terminal care, and continuing care. Cancer-related estimates for
      each phase were obtained by subtracting costs for control subjects from the
      observed costs for cancer patients, matching on age group, gender, and registry
      area. Estimates of long-term cost < or = 11 years obtained by this method were
      compared with 11-year estimates obtained by application of the Kaplan-Meier
      sample average (KMSA) method. RESULTS: The mean initial-phase cancer-related cost
      was approximately $18,000 but was higher among patients with more advanced
      cancer. The mean continuing-phase cancer-related cost was $1,500 per year and
      declined with increasing age, but was higher on an annual basis among persons
      with later stages of cancer and shorter survival time. The mean terminal-phase
      cancer-related cost was $15,000 and declined with both age at death and more
      advanced stage at diagnosis. After the phase-specific estimates were combined,
      the average long-term cancer-related cost was $33,700 ($31,300 at 3% discount
      rate) for colon cancer compared with $36,500 ($33,800 at 3% discount rate) for
      cancer of the rectum. This represented about half of the total long-term cost for
      Medicare enrollees diagnosed with this disease. Long-term cost was highest for
      Stage III cancer and lowest for in situ cancer. Eleven-year cancer-related costs
      estimated by the KMSA method were similar to estimates using the phase-based
      approach. CONCLUSIONS: This paper demonstrates that valid estimates of cancer
      related long-term cost can be obtained from administrative claims data linked to
      incidence cancer registry data.

PMID- 10599607
TI  - Quality of care by race and gender for congestive heart failure and pneumonia.
AB  - BACKGROUND: Variations in the rates of major procedures by race and gender are
      well described, but few studies have assessed the quality of care by race and
      gender for basic hospital services. OBJECTIVE: To assess quality of care by race
      and gender. RESEARCH DESIGN: Retrospective review of medical records. SUBJECTS:
      Stratified random sample of 2,175 Medicare beneficiaries hospitalized for
      congestive heart failure or pneumonia in Illinois, New York, and Pennsylvania
      during 1991 and 1992. MEASURES: Explicit process criteria and implicit review by
      physicians. RESULTS: In adjusted analyses, black patients with congestive heart
      failure or pneumonia received lower quality of care overall than other patients
      with these conditions by both explicit process criteria and implicit review (P <
      0.05). On explicit measures, overall quality of care did not differ by gender for
      either condition, but significant differences were noted on explicit subscales.
      Women received worse cognitive care than men from physicians for both conditions,
      better cognitive care from nurses for pneumonia, and better therapeutic care for
      congestive heart failure (P < 0.05). Women received worse quality of care than
      men by implicit review (P = 0.03) for congestive heart failure but not pneumonia.
      CONCLUSIONS: Consistent racial differences in quality of care persist in basic
      hospital services for two common medical conditions. Physicians, nurses, and
      policy makers should strive to eliminate these differences. Gender differences in
      quality of care are less pronounced and may vary by condition and type of
      provider or service.

PMID- 10599608
TI  - The impact of competing subsistence needs and barriers on access to medical care
      for persons with human immunodeficiency virus receiving care in the United
      States.
AB  - OBJECTIVES: To examine whether competing subsistence needs and other barriers are
      associated with poorer access to medical care among persons infected with human
      immunodeficiency virus (HIV), using self-reported data. DESIGN: Survey of a
      nationally representative sample of 2,864 adults receiving HIV care. MAIN
      INDEPENDENT VARIABLES: Going without care because of needing the money for food,
      clothing, or housing; postponing care because of not having transportation; not
      being able to get out of work; and being too sick. MAIN OUTCOME MEASURES: Having
      fewer than three physician visits in the previous 6 months, visiting an emergency
      room without being hospitalized; never receiving antiretroviral agents, no
      prophylaxis for Pneumocystis carinii pneumonia in the previous 6 months for
      persons at risk, and low overall reported access on a six-item scale. RESULTS:
      More than one third of persons (representing >83,000 persons nationally) went
      without or postponed care for one of the four reasons we studied. In multiple
      logistic regression analysis, having any one or more of the four competing needs
      independent variables was associated with significantly greater odds of visiting
      an emergency room without hospitalization, never receiving antiretroviral agents,
      and having low overall reported access. CONCLUSIONS: Competing subsistence needs
      and other barriers are prevalent among persons receiving care for HIV in the
      United States, and they act as potent constraints to the receipt of needed
      medical care. For persons infected with HIV to benefit more fully from recent
      advances in medical therapy, policy makers may need to address nonmedical needs
      such as food, clothing, and housing as well as transportation, home care, and
      employment support.

PMID- 10599609
TI  - The relationship of residential instability to medical care utilization among
      poor mothers in New York City.
AB  - OBJECTIVES: This study examines the relationship between residential instability,
      including mobility and previous homelessness, and the use of medical care among
      previously sheltered and never-sheltered mothers in New York City. The study
      represents one of the first efforts to follow up on families after they are no
      longer homeless. METHODS: Mothers from 543 welfare families in New York City were
      interviewed, once in 1988 (Time 1) and again beginning in 1992 (Time 2). The
      sample included 251 families who first entered shelters after their 1988
      interview, and 292 families who spent no time in shelters before or after that
      point. Mothers were asked about the source and volume of medical care used in the
      year before follow-up. RESULTS: Bivariate and multivariate analyses showed that
      previously sheltered mothers had a greater reliance on emergency departments
      (EDs) and weaker ties to private physicians or health maintenance organizations
      (HMOs) than did mothers who never used shelters. Mobility before the Time 1
      interview was associated with greater reliance on EDs and absence of a usual
      source of care. More recent mobility was not associated with a usual source of
      care. Current residential stability reduced the likelihood of using an emergency
      department or having no regular source of care. None of the measures of
      residential instability were related to the volume of outpatient care used by
      mothers. CONCLUSIONS: A history of residential instability, particularly previous
      shelter use, strongly predicts where poor mothers currently seek health care.
      Further research is needed to determine whether these patterns of health care use
      existed before mothers entered shelters. The study provides evidence that upon
      leaving shelters, mothers are not being well integrated into primary care
      services.

PMID- 10599610
TI  - An epidemiologic approach to drug prescribing quality assessment: a study in
      primary care practice in France.
AB  - OBJECTIVE: To assess drug prescribing by primary care physicians in France for
      various types of conditions, and to identify patterns and risk factors for poor
      prescribing quality. METHODS: The orders (n = 23,080) written for patients with
      five target diseases (acute nasopharyngitis, acute tonsillitis, essential
      hypertension, osteoarthrosis, and back and periarticular disorders), by primary
      care physicians (n = 1,049) were extracted from a nationwide prescription
      database and analyzed according to 17 quantitative indicators of drug prescribing
      quality constructed on explicit a priori criteria. RESULTS: Ineffective drugs
      were prescribed in 32% to 88% of orders according to the target disease. Six
      percent to 40% of orders resulted in drug interactions, age problems, and
      overdosage. A consistent pattern of associations between indicators was found,
      which suggests that drug prescribing quality is multidimensional and is composed
      of at least five dimensions: placebo, novelty, exoticism, misdosage, and
      interaction. Several factors associated with indicators were also identified,
      some of them defining groups of patients at risk (women, elderly, and less
      educated), physicians at risk (women, aged, and isolated), and contexts at risk
      (patient's home and disease frequently treated by the physician) of poor drug
      prescribing quality. CONCLUSIONS: Drug prescribing by French primary care
      physicians appears nonoptimal, in terms of both risk of iatrogeny and waste of
      money. This study further documents the complexity and the multidimensionality of
      drug prescribing quality. It suggests that more attention must be paid to
      patients' and physicians' risk factors for poor drug prescribing quality if
      educational programs and regulatory processes are to succeed in promoting safer
      and more cost-effective practices.

PMID- 10599611
TI  - Effect of enhanced prenatal and HIV-focused services for pregnant women who are
      infected by human immunodeficiency virus on emergency department use.
AB  - OBJECTIVES: This study examines whether the receipt of enhanced prenatal or human
      immunodeficiency virus (HIV) medical services is associated with in-pregnancy
      emergency department (ED) utilization by HIV-infected women. METHODS: Medicaid
      and vital statistics records were linked for 1,826 women who are infected by HIV
      and who were delivered from 1993 to 1995 while receiving New York State Medicaid.
      The authors examined two types of ambulatory care--the Prenatal Care Assistance
      Program (PCAP) and enhanced care focused on HIV--that offer additional services
      in exchange for increased Medicaid reimbursement. From logistic regression
      models, the authors estimated adjusted associations of these types of care with
      ED use during pregnancy not leading directly to hospitalization. RESULTS: Fifty
      three percent of pregnant women visited the ED. Women with ED use averaged 2.0
      visits (SD = 1.1). After adjustment for demographic and substance use factors,
      enhanced care focused on HIV was not associated with any ED use (OR = 1.11, 95%
      CI 0.94, 1.30) or, among those using the ED at least once, with number of visits
      (P = 0.84). Interactions of receipt of PCAP care with the Adequacy of Prenatal
      Care Utilization Index (APNCU) and having a usual source of care in pregnancy
      improved model fit (P < 0.001 and P = 0.06, respectively). PCAP was associated
      with increased ED use only among women with inadequate APNCU or no usual source
      of prenatal care. CONCLUSION: Pregnant women infected with HIV receiving Medicaid
      relied heavily on ED care. Use of the ED was not associated with services focused
      on HIV but was positively associated with enhanced prenatal care. The association
      of enhanced prenatal care with greater ED use was curbed for women with more
      timely and adequate prenatal care visits or a usual source of prenatal care.

PMID- 10599612
TI  - Loudness discrimination of speech signals spectrally shaped by a simulated
      hearing aid.
AB  - A discrimination task was used to assess changes in the loudness of speech that
      accompanied changes in the spectral tilt of a simulated hearing aid's frequency
      response. Band-limited (0.25-4 kHz) spondaic words were spectrally shaped at
      comparison tilt-factor values of -6, 0, and +6 dB per octave and delivered
      monaurally via insert earphone to each of 10 listeners with normal hearing (NH)
      and 15 listeners with mild-to-moderate sensorineural hearing impairment (HI).
      Results for the NH listeners indicated that loudness differences among the tilt
      factors were generally perceptible and that loudness judgments were highly
      transitive across different tilt-factor comparisons. Loudness differences were
      also perceptible to many of the HI listeners when they switched among tilt
      factors. The HI listeners' data showed some evidence of transitivity, but not so
      much as was shown by the NH listeners. Intersubject variability in the loudness
      judgments was found to be comparable for the two subject groups. Results of the
      study are discussed with regard to their implications for hearing aid fitting,
      with particular emphasis on the "parameter adjustment and selection" fitting
      procedure (J. Punch & R. Robb, 1992).

PMID- 10599613
TI  - Auditory temporal processing impairment: neither necessary nor sufficient for
      causing language impairment in children.
AB  - Fourteen twin pairs, aged 8 to 10 years, were tested 3 times over 12 months; they
      included 11 children with language impairment (LI), 11 control children matched
      on nonverbal ability and age, and 6 co-twins who did not meet criteria for LI or
      control status. Thresholds were estimated for detecting a brief backward-masked
      tone (BM), detection of frequency modulation (FM), and pitch discrimination using
      temporal cues (deltaf0). Both BM and FM thresholds improved with training, and by
      the 2nd test session, FM thresholds were in the adult range. There were marked
      individual differences on BM and deltaf0 and, for both tasks, performance
      correlated with Tallal's Auditory Repetition Task administered 2 years
      previously. However, no auditory measure gave significant differences between LI
      and control groups; performance was influenced more by nonverbal than language
      ability. Some children did have a stable pattern of poor performance on certain
      auditory tasks, but their good FM detection raised questions about whether
      processing of auditory temporal information is abnormal. We found no evidence
      that auditory deficits are a necessary or sufficient cause of language
      impairments.

PMID- 10599614
TI  - Comparison of risk of conductive hearing loss among three ethnic groups of Arctic
      audiology patients.
AB  - The purpose of the study was to investigate the relative contributions of age,
      gender, ethnic background, and a history of middle ear disease on the amount of
      conductive hearing impairment among native and non-native audiology patients in
      the Canadian North. A second goal of the study was to determine risk factors for
      conductive hearing loss in the patients studied. Three ethnic groups were
      represented among the 3,094 patients: Inuit, American Indian, and non-native.
      Loglinear and logit statistical models were applied, and these data were best
      explained by a 3-way interaction of history of middle ear disease, ethnic group,
      and hearing loss, and the 2-way interaction of age and hearing loss. The Inuit
      appear to be at higher risk for conductive hearing impairment than the other
      ethnic groups. Conductive hearing loss also appears to increase as age increases
      through the teenage years for all the patients regardless of ethnic group
      membership. Preschoolers were at the lowest risk for conductive hearing loss. The
      trend for the amount of hearing impairment to increase throughout childhood
      suggests that children living in the Arctic may manifest a unique and more
      serious form of the disease not often observed in audiology patients who are
      Caucasian in southern Canada or the United States or that they may be exposed to
      additional risk factors.

PMID- 10599615
TI  - Improvements in speech perception with use of the AVR TranSonic frequency
      transposing hearing aid.
AB  - Five adults with sensorineural hearing impairment participated in a trial
      comparing the performance of the AVR TranSonic frequency-transposing hearing aid
      with that of their own conventional aids. They used the TranSonic for
      approximately 12 weeks, during which time systematic changes were made to the
      transposition parameters. Speech perception was assessed with each setting of
      those parameters and with the participants' own hearing aids. Four participants
      obtained significantly higher scores with the TranSonic than with their own aids
      on at least one of the tests. However, analysis of the consonant confusions
      suggested that the improvement resulted mostly from the TranSonic's low-frequency
      electro-acoustic characteristics. There was only limited evidence for 2 of the
      participants that the frequency-lowering function was effective at improving
      speech perception.

PMID- 10599616
TI  - Psychometrically equivalent spondaic words spoken by a female speaker.
AB  - Several studies demonstrate that thresholds for the individual CID W-1 spondaic
      words peaked at 0 vu are not equivalent. The purpose of this study was to equate
      the spondaic word thresholds psychometrically. Two studies were performed on 2
      groups of 20 listeners with normal hearing. In Experiment 1, psychometric
      functions were established for the 36 spondaic words spoken by a male (original
      recording) and female speaker. Based on the threshold data from Experiment 1, the
      words spoken by the female speaker were adjusted digitally in level to produce
      equal thresholds (equal intelligibility). In Experiment 2, psychometric functions
      then were established for the 36 spondaic words adjusted in level. The mean
      thresholds for the 2 experiments were the same (0.5 dB HL; ANSI, 1996), but the
      standard deviations for the word thresholds in Experiment 2 (0.7 dB) were
      significantly smaller than the standard deviations in Experiment 1 (1.6 dB). Both
      versions of the spondaic words spoken by the female speaker are included on the
      Speech Recognition and Identification Materials (Disc 2.0) compact disc.

PMID- 10599617
TI  - Effects of monitoring condition and frequency-altered feedback on stuttering
      frequency.
AB  - The purpose of the study was to examine stuttering frequency during speaking
      conditions that are believed to mitigate stuttering frequency both with normal
      nonaltered auditory feedback (NAF) and a known fluency-enhancing feedback.
      Specifically, stuttering frequency was examined as a function of three monitoring
      conditions under NAF and frequency-altered feedback (FAF): no monitoring (i.e.,
      speaking alone, in the absence of audio and visual recording), audiovisual
      monitoring (i.e., speaking alone with audiovisual recording), and audiovisual
      monitoring with observers (i.e., speaking with audiovisual recording in the
      presence of two observers). Seven adults and one adolescent who stutter served as
      participants. Stuttering frequency was differentially affected across monitoring
      conditions under each auditory feedback condition (p = .027). Post hoc analyses
      revealed no significant difference in stuttering frequency between the two
      conditions in the absence of the observers (i.e., no monitoring vs. audiovisual
      monitoring) under NAF (p = .45). There was, however, a significant difference in
      stuttering frequency for the no-monitoring and audiovisual-monitoring conditions
      relative to the audiovisual-monitoring-with-observers condition (p = .0002).
      There was no statistically significant difference in stuttering frequency across
      monitoring conditions under FAF (p > .05). The findings are consistent with the
      notion that during NAF stuttering frequency varies as a function of hierarchical
      socio-environmental conditions in which inanimate monitoring conditions
      constitute one entity. Such a relationship does not exist during FAF.

PMID- 10599618
TI  - Electromagnetic articulography treatment for an adult with Broca's aphasia and
      apraxia of speech.
AB  - Electromagnetic articulography (EMA) was explored as a means of remediating
      [s]/[symbol in text] articulation deficits in the speech of an adult with Broca's
      aphasia and apraxia of speech. Over a 1-month period, the subject was provided
      with 2 different treatments in a counterbalanced procedure: (1) visually guided
      biofeedback concerning tongue-tip position and (2) a foil treatment in which a
      computer program delivered voicing-contrast stimuli for simple repetition.
      Kinematic and perceptual data suggest improvement resulting from visually guided
      biofeedback, both for nonspeech oral and, to a lesser extent, speech motor tasks.
      In contrast, the phonetic contrast treated in the foil condition showed only
      marginal improvement during the therapy session, with performance dropping back
      to baseline 10 weeks post-treatment. Although preliminary, the findings suggest
      that visual biofeedback concerning tongue-tip position can be used to treat
      nonspeech oral and (to a lesser extent) speech motor behavior in adults with
      Broca's aphasia and apraxia of speech.

PMID- 10599619
TI  - A longitudinal investigation of speaking rate in preschool children who stutter.
AB  - Both clinical and theoretical interest in stuttering as a disorder of speech
      motor control has led to numerous investigations of speaking rate in people who
      stutter. The majority of these studies, however, has been conducted with adult
      and school-age groups. Most studies of preschoolers have included older children.
      Despite the ongoing theoretical and clinical focus on speaking rate in young
      children who stutter and their parents, no longitudinal or cross-sectional
      studies have been conducted to answer questions about the possible developmental
      link between stuttering and the rate of speech, or about differences in rate
      development between preschool children who stutter and normally fluent children.
      This investigation compared changes in articulatory rate over a period of 2 years
      in subgroups of preschool-age children who stutter and normally fluent children.
      Within the group of stuttering children, comparisons also were made between those
      who exhibited persistent stuttering and those who eventually recovered without
      intervention. Furthermore, the study compared two metrics of articulatory rate.
      Spontaneous speech samples, collected longitudinally over a 2-year period, were
      analyzed acoustically to determine speaking rate measured in number of syllables
      and phones per second. Results indicated no differences among the 3 groups when
      articulation rate was measured in syllables per second. Using the phones per
      second measure, however, significant group differences were found when comparing
      the control group to the recovered and persistent groups.

PMID- 10599620
TI  - Contributions of individual muscles to the submental surface electromyogram
      during swallowing.
AB  - Submental surface electromyographic recordings are commonly used in the
      investigation of swallowing disorders. The measured electromyography is thought
      to reflect the actions of floor-of-mouth muscles. Although this is a reasonable
      assumption, to date there have been no investigations to delineate which muscles
      contribute to this surface recording. The primary goal of this experiment was to
      determine which muscles contribute most to the submental surface.
      Electromyography was recorded simultaneously from the submental surface as well
      as from five individual muscles: mylohyoid, anterior belly of the digastric,
      geniohyoid, genioglossus and platysma. Three analysis methods were performed to
      estimate individual muscle contributions: correlation, numeric, and analytic. For
      the numeric and analytic analyses, a linear model was defined and used to
      represent the relationship between the surface and intramuscular recordings.
      Muscles that received a high correlation, numeric and/or analytic value were
      considered to be primary contributors to the submental recording. Regardless of
      analysis approach, the primary contributions to the submental surface recording
      were the mylohyoid, anterior belly of the digastric, and the geniohyoid muscles.
      Contributions from the genioglossus and the platysma muscles were minimal.
      Contributions as a function of bolus volume and viscosity are also discussed.

PMID- 10599622
TI  - Describing the consequences of disorders: comments on Yaruss (1998)

PMID- 10599621
TI  - Lexicalization and stuttering: comments on Prins, Main, and Wampler (1997)

PMID- 10599623
TI  - Balancing bilinguals: lexical-semantic production and cognitive processing in
      children learning Spanish and English.
AB  - The present study investigated developmental changes in lexical production skills
      in early sequential bilinguals, in both Spanish (L1) and English (L2), exploring
      the effects of age, years of experience, and basic-level cognitive processing
      (specifically the ability to resist interference) within a timed picture-naming
      task. To assess resistance to interference, naming was compared in low
      competition (blocked-single language) vs. high competition (mixed-alternating
      language) conditions. Participants were 100 individuals, 20 at each of 5
      different age levels (5-7, 8-10, 11-13, 14-16, & young adults). All had learned
      Spanish as a first language in the home, with formal English experience beginning
      at 5 years. Gains were made in both languages across age. However, there was a
      developmental crossover from Spanish dominance in the youngest children, through
      a period of relatively balanced Spanish and English skills in middle childhood,
      culminating in a clear pattern of English dominance among adolescents and young
      adults. Although all groups experienced a greater slowing of response times in
      the mixed-language condition relative to the blocked-language condition,
      developmental changes in the pattern of speed-accuracy trade-offs in the mixed
      condition can be interpreted to reflect a change in the ability to resist
      cognitive interference during word production.

PMID- 10599624
TI  - Verb agreement morphology in Hebrew-speaking children with specific language
      impairment.
AB  - Earlier reports of verb morphology use by Hebrew-speaking children with specific
      language impairment (SLI) have suggested that these children mark agreement with
      the subject as accurately as younger control children matched according to mean
      length of utterance (MLU). This issue was examined in greater detail in the
      present study by including a wider range of agreement inflections from the
      present and past tense paradigms and employing verbs of different patterns
      (binyanim). It was hypothesized that children with SLI would be more limited than
      would MLU controls in their use of agreement inflections within past tense
      because the past tense agreement paradigm of Hebrew requires the simultaneous
      manipulation of three features-person, number, and gender. Differences between
      the groups were not expected for the use of agreement inflections within present
      tense, because only two features-number and gender-must be manipulated in the
      present tense paradigm. A group of preschool-age children with SLI was found to
      have more difficulty than did MLU controls in the use of most past tense
      agreement inflections. Within present tense, the two groups differed in their use
      of agreement inflections in only one pattern. For both groups, most errant
      productions differed from the target form by only one feature, usually person or
      tense. We found no feature that was consistently problematic for the children.
      The findings are discussed within a limited processing capacity framework.

PMID- 10599625
TI  - Maternal education and measures of early speech and language.
AB  - The present study was designed to determine whether 4 measures of children's
      spontaneous speech and language differed according to the educational level of
      the children's mothers. Spontaneous language samples from 240 three-year-old
      children were analyzed to determine mean length of utterance in morphemes (MLUm),
      number of different words (NDW), total number of words (TNW), and percentage of
      consonants correct (PCC). A norm-referenced, knowledge-dependent measure of
      language comprehension, the Peabody Picture Vocabulary Test-Revised (PPVT-R), was
      also included for purposes of comparison with the spontaneous measures. Three
      levels of maternal education were compared: less than high school graduate, high
      school graduate, and college graduate. Trend analyses showed statistically
      significant linear trends across educational levels for MLUm, NDW, TNW, and PPVT
      R; the trend for PCC was not significant. The relationship of maternal education
      and other sociodemographic variables to measures of children's language should be
      examined before using such measures to identify children with language disorders.

PMID- 10599626
TI  - Metrical analysis of the speech of children with suspected developmental apraxia
      of speech.
AB  - Previous studies have shown that metrical analysis accounts for syllable
      omissions in young normally developing children better than prior perspectives.
      This approach has not yet been applied to children with disorders. Inappropriate
      sentential stress has been proposed as a diagnostic marker for a subgroup of
      children with suspected developmental apraxia of speech (SD-DAS), suggesting that
      the application of metrical perspectives to this population may be appropriate.
      This report extends the goal of identifying diagnostic markers for SD-DAS using
      analytic procedures from metrical phonology. The lexical metrical patterns of
      children with SD-DAS were compared to those of a group of children with speech
      delay (SD) to verify the applicability of metrical constructs to children with
      disorders while at the same time seeking lexical stress characteristics that
      might be useful for differential diagnosis. The lexical stress errors of children
      in both the SD and SD-DAS disorder groups were found to conform to patterns
      identified in metrical studies of younger normally developing children,
      confirming the applicability of this approach to children with disorders. Lexical
      metrical patterns did not differentiate the groups from each other. However,
      syllable omissions persisted to much later ages in the SD-DAS subjects,
      especially those children previously identified as having inappropriate phrasal
      stress. Further metrical studies of the speech of children with suspected SD-DAS
      are needed, both at the lexical and the sentential level, using both perceptual
      and acoustic measures.

PMID- 10599627
TI  - Prevalence of speech delay in 6-year-old children and comorbidity with language
      impairment.
AB  - We estimate the prevalence of speech delay (L.D. Shriberg, D. Austin, B. A.
      Lewis, J. L. McSweeny, & D. L. Wilson, 1997b) in the United States on the basis
      of findings from a demographically representative population subsample of 1,328
      monolingual English-speaking 6-year-old children. All children's speech and
      language had been previously assessed in the "Epidemiology of Specific Language
      Impairment" project (see J. B. Tomblin et al., 1997), which screened 7,218
      children in stratified cluster samples within 3 population centers in the upper
      Midwest. To assess articulation, the Word Articulation subtest of the Test of
      Language Development-2: Primary (Newcomer & Hammill, 1988) was administered to
      each of the 1,328 children, and conversational speech samples were obtained for a
      subsample of 303 (23%) children. The 6 primary findings are as follows: (a) The
      prevalence of speech delay in 6-year-old children was 3.8%; (b) speech delay was
      approximately 1.5 times more prevalent in boys (4.5%) than girls (3.1%); (c)
      cross-tabulations by sex, residential strata, and racial/cultural backgrounds
      yielded prevalence rates for speech delay ranging from 0% to approximately 9%;
      (d) comorbidity of speech delay and language impairment was 1.3%, 0.51% with
      Specific Language Impairment (SLI); (e) approximately 11-15% of children with
      persisting speech delay had SLI; and (f) approximately 5-8% of children with
      persisting SLI had speech delay. Discussion includes implications of findings for
      speech-language phenotyping in genetics studies.

PMID- 10599628
TI  - Optimality theory in phonological acquisition.
AB  - This tutorial presents an introduction to the contemporary linguistic framework
      known as optimality theory (OT). The basic assumptions of this constraint-based
      theory as a general model of grammar are first outlined, with formal notation
      being defined and illustrated. Concepts unique to the theory, including
      "emergence of the unmarked," are also described. OT is then examined more
      specifically within the context of phonological acquisition. The theory is
      applied in descriptions of children's common error patterns, observed inter- and
      intrachild variation, and productive change over time. The particular error
      patterns of fronting, stopping, final-consonant deletion, and cluster
      simplification are considered from an OT perspective. The discussion concludes
      with potential clinical applications and extensions of the theory to the
      diagnosis and treatment of children with functional phonological disorders.

PMID- 10599629
TI  - Prosodic influences on speech production in children with specific language
      impairment and speech deficits: kinematic, acoustic, and transcription evidence.
AB  - It is often hypothesized that young children's difficulties with producing weak
      strong (iambic) prosodic forms arise from perceptual or linguistically based
      production factors. A third possible contributor to errors in the iambic form may
      be biological constraints, or biases, of the motor system. In the present study,
      7 children with specific language impairment (SLI) and speech deficits were
      matched to same age peers. Multiple levels of analysis, including kinematic
      (modulation and stability of movement), acoustic, and transcription, were applied
      to children's productions of iambic (weak-strong) and trochaic (strong-weak)
      prosodic forms. Findings suggest that a motor bias toward producing unmodulated
      rhythmic articulatory movements, similar to that observed in canonical babbling,
      contribute to children's acquisition of metrical forms. Children with SLI and
      speech deficits show less mature segmental and speech motor systems, as well as
      decreased modulation of movement in later developing iambic forms. Further,
      components of prosodic and segmental acquisition develop independently and at
      different rates.

PMID- 10599630
TI  - What will the gastroenterologist do all day in the new millennium?

PMID- 10599631
TI  - Interventional endoscopic ultrasonography: current status and future direction.
AB  - Although first performed more than 20 years ago, endoscopic ultrasonography (EUS)
      has only recently been used for interventional/therapeutic purposes. The
      recognition and application of this versatile procedure by gastroenterologists
      who perform endoscopy has reached an all-time high, and the demand for symposia
      and tutorials devoted to EUS rivals that of endoscopic retrograde
      cholangiopancreatography 20 to 25 years ago. EUS has become an established part
      of the endoscopic armamentarium for many gastroenterologists. Despite its proved
      clinical utility for staging gastrointestinal (and lung) cancers, and its use in
      delineating the nature of "submucosal" tumors of the gastrointestinal tract, EUS
      has continued to evolve. Within the past 10 years, the safety and efficacy of EUS
      as a means of guiding tissue acquisition via fine-needle aspiration has been
      demonstrated, increasing its utility in gastrointestinal oncology. Newer
      indications currently under clinical investigation include the use of EUS as a
      delivery mechanism for novel immune-based and viral-based "chemo" therapeutic
      agents for patients with pancreatic cancer. Finally, the role of EUS as a
      reliable method to guide therapy to control the often refractory abdominal pain
      in patients with pancreatic cancer and/or chronic pancreatitis is being verified
      in clinical trials. The following is a brief overview of the current state-of-the
      art in interventional EUS.

PMID- 10599632
TI  - The spectrum of spontaneous and iatrogenic esophageal injury: perforations,
      Mallory-Weiss tears, and hematomas.
AB  - Esophageal perforations, Mallory-Weiss tears, and esophageal hematoma involve
      traumatic injury to the esophagus. These can be iatrogenic, in particular due to
      esophageal instrumentation, but can also occur spontaneously. The remarkable
      increase in diagnostic and therapeutic endoscopy as well as esophageal surgery
      has made instrumentation the most common cause of esophageal perforation. In many
      instances, spontaneous perforations are associated with retching and vomiting,
      which causes a sudden increase in intraesophageal pressure. A high index of
      suspicion leading to rapid diagnosis and appropriate therapy are needed to
      optimize clinical outcomes. This article focuses on esophageal perforations,
      Mallory-Weiss tears, and esophageal hematomas, with emphasis on etiology,
      pathogenesis, clinical presentation, diagnosis, management, and prevention.

PMID- 10599633
TI  - Thyroid storm presenting with liver failure.

PMID- 10599634
TI  - Relationship between iron concentration and hepatitis C virus RNA level in liver
      tissue.
AB  - Patients with chronic hepatitis C virus (HCV) infection frequently have increased
      hepatic iron stores. The role of hepatitis C in hepatic iron deposition is
      unknown. The authors examined whether there is a relation between hepatitis C
      virus level in liver tissue and hepatic iron concentration. Forty-two paired
      samples obtained from the liver explants of five patients who underwent
      transplantation for liver disease due to hepatitis C were studied. Hepatitis C
      virus levels were measured at multiple sites within each liver by a branched
      deoxyribonucleic assay. Measurements of hepatic iron concentration were made at
      adjacent sites by a colorimetric assay. Random effects modeling showed wide
      intrahepatic variation in hepatic HCV ribonucleic acid (RNA) concentration
      (variance = 1.2 x 10(4) [mEq/g]2) and hepatic iron concentration (variance = 1.3
      x 10(6) [microg/g]2). There was, however, a trend toward an association between
      the mean HCV level and the mean hepatic iron concentration for each liver (r =
      0.30, p = 0.05). In conclusion, HCV level and iron concentration varied within
      and between cirrhotic livers. Variability in intrahepatic iron concentration was
      not related to variability in intrahepatic HCV RNA concentration. More studies
      are needed to determine the cause of variability in hepatic iron and HCV RNA
      concentration within and between livers in patients with chronic hepatitis C.

PMID- 10599635
TI  - Abnormal uroporphyrin levels in chronic hepatitis C virus infection.
AB  - A strong association between hepatitis C virus (HCV) infection and porphyria
      cutanea tarda (PCT) has been observed, but the implications of the viral
      infection in the metabolism of porphyrins in patients without clinical
      manifestations of PCT are not known. The levels of porphyrin in plasma and
      uroporphyrin (URO) and coproporphyrin (COPRO) in 24-hour urine were measured in
      156 patients with chronic HCV infection showing no clinical evidence of PCT.
      Levels of URO higher than the upper limit were observed in 35 of 156 patients
      (22.4%). The range and the mean values +/- standard deviation were 26-1,196
      microg/24 hours and 82 +/- 204 microg/24 hours. Increased levels of COPRO and
      plasma porphyrin were observed in 12 of 156 patients (7.7%) and 2 of 156 patients
      (1.3%) respectively. There were no differences between patients with increased
      URO levels and patients with normal URO levels in terms of gender, age, risk
      factors for HCV infection, alcohol abuse, or hepatitis B viral infection.
      Transferrin saturation (p = 0.040), gamma glutamyl transpeptidase (p < 0.0001),
      aspartate aminotransferase (p = 0.006), and alanine aminotransferase (p = 0.040)
      were significantly higher in patients with abnormal URO than in patients with
      normal URO. The frequency of cirrhosis was higher, but not significantly
      different, in patients with increased URO (16.7%) compared with patients with
      normal URO (3.8%). The authors demonstrated that even without a clinical
      manifestation of PCT it is possible to detect abnormalities in the metabolism of
      porphyrins in patients with chronic HCV infection. The implications of these
      findings deserve additional investigation.

PMID- 10599636
TI  - The etiologic role of gastric hypersensitivity in functional dyspepsia in Korea.
AB  - To evaluate the role of gastric hypersensitivity and the relationship between
      gastric hypersensitivity and delayed gastric emptying in Korean functional
      dyspepsia (FD) patients, the authors performed gastric barostat and gastric
      emptying scintigraphy in 64 FD patients and compared these results with those of
      control subjects. Basal tones and gastric compliance were similar in control
      subjects and patients. However, threshold of abdominal discomfort was lower in FD
      patients than in control subjects (8.9 +/- 3.6 mmHg and 14.5 +/- 3.7 mmHg
      respectively; p < 0.05). Twenty-four of 64 patients (37.5%) experienced abdominal
      discomfort at a pressure less than 7 mmHg above minimal distending pressure
      (corresponding to the 95th percentile of normal values). Half time of solid-phase
      gastric emptying in patients and control subjects was not significantly
      different. Twenty-three of 64 patients (35.9%) had delayed gastric emptying
      compared with control subjects (normal ranges were mean +/- two standard
      deviations in control subjects). Thresholds of abdominal discomfort were not
      significantly different in patients with and without delayed gastric emptying
      (9.3 +/- 4.0 mL/mmHg vs. 8.6 +/- 3.3 mL/mmHg). There were also no significant
      differences in the proportion of patients with delayed gastric emptying between
      patients with and without gastric hypersensitivity. In conclusion, gastric
      hypersensitivity plays an important role in FD, and the presence of gastric
      hypersensitivity was not related to the presence of delayed gastric emptying.

PMID- 10599637
TI  - A gastroenterological list for the millennium.
AB  - To determine the 10 most significant advances in gastroenterology during this
      century as we approach the millennium, the authors polled 50 distinguished active
      clinicians and leading researchers in the field, including workers in liver
      disease and the pathology of the gut and its associated glands. Forty-five
      persons (90%) responded and listed 58 different items. These were then organized
      into four groups: group A, with 10 categories that received between 42 and 11
      votes; group B, with 10 categories that received between 10 and 3 votes; group C,
      with 3 items receiving 2 votes each; and group D, with the remaining 14 items
      receiving 1 vote each. The respondents did not indicate their choices in rank
      order. The top 10 leading choices (group A, containing between 42 and 11 votes)
      included Helicobacter pylori, fiberoptic endoscopy, gastrointestinal imaging by
      radiograph and computed tomographic scan, Australia antigen including vaccines
      for hepatitis A and B, the molecular basis of colon cancer, liver
      transplantation, laparoscopic-assisted surgery, therapy for peptic ulcer disease
      including H2-receptor antagonists and proton pump inhibitors, the discovery of
      gastrointestinal hormones beginning with secretin, and lastly the discovery of
      the role for gluten in celiac disease.

PMID- 10599638
TI  - A national survey of practice patterns of gastroenterologists with comparison to
      the past two decades.
AB  - Previous surveys on the practice of gastroenterology collected limited data on
      practice demographics. Gastroenterology practices may have changed over the past
      decade as a result of changes in health care delivery. The authors sought to
      describe the practice composition and demographics of today's gastroenterologist,
      and also to make comparisons to prior studies to determine whether changes have
      occurred. A nationwide cross-sectional survey was performed in 1997 of 900
      American Gastroenterological Association (AGA) members selected randomly from the
      AGA directory. A total of 767 AGA members were eligible for the study, and 376
      responded (response rate, 49%). The mean age was 46 years old and the mean year
      training was completed was 1982. The majority of gastroenterologists were in solo
      or group practice (57%) and in an urban setting (55%). Respondents were fairly
      equally represented from different regions of the country. The most common
      diagnosis seen was irritable bowel syndrome ([IBS] 19%), followed by esophageal
      reflux (17%) and inflammatory bowel disease (14%). Functional disorders as a
      group (IBS, nonulcer dyspepsia, and other functional disorders) were, by far, the
      most common disorders (35%), which is similar to findings in prior studies of
      gastrointestinal practices. Only 3% of gastroenterologists believed that managed
      care has made it easier to deliver quality health care to patients with IBS.
      Despite changes that have occurred in health care over the past decade, the types
      of diagnoses seen in gastroenterology practices has remained the same. Most
      gastroenterologists feel that managed care has not made it easier to deliver
      quality health care.

PMID- 10599639
TI  - Massive hemorrhagic ascites secondary to endometriosis.

PMID- 10599640
TI  - Separation of an overtube from the bite block during treatment of food impaction.

PMID- 10599641
TI  - Henoch-Schonlein purpura associated with Campylobacter enterocolitis.

PMID- 10599642
TI  - Is bleeding time measurement useful for choosing the liver biopsy route? The
      results of a pragmatic, prospective multicentric study in 219 patients.

PMID- 10599643
TI  - Sweet's syndrome in association with probable autoimmune hepatitis.

PMID- 10599644
TI  - Prothrombotic and vascular risk factors in nonarteritic anterior ischemic optic
      neuropathy.

PMID- 10599645
TI  - Tissue plasminogen activator after retinal artery occlusion.

PMID- 10599646
TI  - BK virus retinitis.

PMID- 10599647
TI  - Weight loss in idiopathic intracranial hypertension.

PMID- 10599648
TI  - Aspirin and cataract.

PMID- 10599649
TI  - Oversized grafts.

PMID- 10599650
TI  - Crowded optic discs and AION. Anterior ischemic optic neuropathy.

PMID- 10599651
TI  - Update on acute and chronic endophthalmitis.

PMID- 10599652
TI  - A prospective, randomized, double-masked trial on radiation therapy for
      neovascular age-related macular degeneration (RAD Study). Radiation Therapy for
      Age-related Macular Degeneration.
AB  - OBJECTIVE: To determine the efficacy of external beam radiation therapy on
      choroidal neovascularization (CNV) secondary to age-related macular degeneration
      (ARMD). DESIGN: Multicenter, parallel, randomized, double-masked clinical trial
      performed at nine ophthalmic and radiotherapeutic centers. PARTICIPANTS: Two
      hundred five patients were randomly assigned either to treatment with 8 fractions
      of 2 Gy external beam irradiation (n = 101) or to control with 8 fractions of 0
      Gy (sham treatment, n = 104). Both patients and ophthalmologists were masked with
      regard to applied treatment. Patients with subfoveal classic or occult CNV,
      visual acuity of 20/320 or greater on the Early Treatment Diabetic Retinopathy
      Study chart, lesion size of 6 disc areas or less, history of visual symptoms of 6
      months or less, and absence of foveal hemorrhage were recruited. INTERVENTION: In
      the treatment group, external beam irradiation with 8 fractions of 2 Gy was
      performed, whereas in the control group, sham treatment with 8 fractions of 0 Gy
      was applied. MAIN OUTCOME MEASURES: Primary outcome measure was the difference in
      visual acuity between baseline and after 1 year of follow-up. RESULTS: One
      hundred eighty-three patients (89.3%) completed the 1-year follow-up. The mean
      reduction in visual acuity was 3.5 +/- 4.7 lines in 88 patients of the 8- x 2-Gy
      treatment group and 3.7 +/- 3.8 lines in 95 patients of the 8- x 0-Gy control
      group. This difference was not statistically significant (P = 0.53, Mann-Whitney
      U test). At 1 year, 51.1% of treated patients and 52.6% of control subjects lost
      three or more lines (P = 0.88). Visual acuity in the presence of classic CNV
      dropped by 3.7 +/- 4.4 lines in 33 patients of the treatment group versus 4.3 +/-
      3.9 lines in 36 patients of the control group (P = 0.47). Visual acuity in 114
      patients with occult CNV dropped by 3.4 +/- 4.9 in the treatment group (55
      patients) versus 3.4 +/- 3.8 lines in the control group (59 patients) (P = 0.80).
      CONCLUSIONS: In this randomized study, radiation therapy at a dose of 16 Gy
      applied in 8 fractions of 2 Gy provided no benefit as a treatment for subfoveal
      CNV secondary to ARMD at 1 year.

PMID- 10599653
TI  - Radiation exposure: a new risk factor for idiopathic perifoveal telangiectasis.
AB  - OBJECTIVE: To examine the association between previous radiation exposure and
      idiopathic perifoveal telangiectasis (IPT). DESIGN: A multicentered, individually
      matched, case-control study design was used. PARTICIPANTS/CONTROLS: Sixty-five
      case subjects were matched with 175 control subjects. Individuals with
      unequivocal evidence of angiographically confirmed IPT were included as cases.
      Control subjects were matched for center, age, and gender. MAIN OUTCOME MEASURE:
      The main exposures of interest were a history of therapeutic head or neck
      irradiation and environmental radiation exposure. METHODS: A standardized
      questionnaire was administered to case and control subjects. Data were collected
      for the main exposures of interest as well as pertinent covariates. Conditional
      logistic regression was used to evaluate therapeutic and environmental radiation
      as risks for IPT. RESULTS: On univariate analysis, head or neck irradiation was
      associated with IPT (odds ratios [OR] = 4.15, 95% confidence interval [CI] = 1.30
      13.24). While controlling for diabetes and family history of diabetes, IPT was
      found to be associated with both head or neck irradiation (OR = 4.06, 95% CI =
      1.20-13.76) and with environmental irradiation (OR = 6.73, 95% CI = 1.06-42.74).
      CONCLUSIONS: This study presents a previously unreported association between
      prior radiation exposure and IPT.

PMID- 10599654
TI  - Radiation-associated choroidal neovasculopathy.
AB  - PURPOSE: To characterize a newly discovered choroidal vascular abnormality in
      patients who have received radiation therapy for subfoveal choroidal
      neovascularization (CNV) secondary to age-related macular degeneration. DESIGN:
      Two-center cross-sectional study. PARTICIPANTS: In the United States, there were
      95 patients who were treated with 10 or 12 Gy of external beam photons. In
      Belgium, 98 patients were treated with 20 Gy. These patients were examined
      retrospectively for the presence of a specific CNV abnormality. RESULTS: During
      the follow-up period, an unusual vascular growth pattern was identified in 12
      patients (12.6%) of those treated in the United States and in 7 (7.1%) of those
      treated in Belgium. These patients developed round or oval vascular blebs along
      the outer border of their neovascular lesions. These blebs profusely leaked
      fluorescein dye and could be imaged best by indocyanine green angiography.
      Patients with these blebs appeared to have a marked propensity for loss of visual
      acuity. CONCLUSION: An unusual pattern of new vessel growth occurred in 19 of the
      193 patients with CNV treated with radiation. This new entity, termed radiation
      associated choroidal neovasculopathy, is a recognizable disorder that appears to
      have a particularly poor prognosis.

PMID- 10599655
TI  - Fundus photographic, fluorescein angiographic, and indocyanine green angiographic
      signs in successful laser chorioretinal venous anastomosis for central retinal
      vein occlusion.
AB  - OBJECTIVE: To describe the fundus signs and angiographic signs that accompany
      development of a laser-induced chorioretinal venous anastomosis in central
      retinal vein occlusion and to describe the chronology of the signs. DESIGN:
      Noncomparative, consecutive case series. PARTICIPANTS: Fifteen eyes of 15
      patients were treated. INTERVENTION: The argon laser was used in the original
      method of McAllister and Constable to form an anastomosis in five eyes, and the
      modified method of McAllister involving the argon laser followed by the YAG laser
      was used for ten eyes. MAIN OUTCOME MEASURES: Changes in vessel diameters,
      retinal blood flow, and morphology of anastomosis over time as documented
      photographically and angiographically. RESULTS: The earliest fluorescein
      angiographic sign of success is a hyperfluorescent spindle at 1 week. The
      earliest indocyanine green angiographic sign is direct connection of retinal
      venous and choroidal venous circulations at 2 weeks. The earliest fundus
      photographic and, hence, ophthalmoscopic sign is asymmetry in venous diameter at
      the disc at 3 weeks. No sign is present in all successful cases. The most
      commonly observed sign is fluorescein flow around a corner in a retrograde
      direction toward the anastomosis in 80% of cases. Drainage of only a fraction of
      the retina occurred in 93% of cases. Fifteen eyes with successful anastomoses had
      mean improvement of 2.3 +/- 2.4 (standard deviation [SD]) Snellen lines of best
      corrected visual acuity compared to 0.2 +/- 2.3 (SD) lines for 9 eyes with
      unsuccessful anastomoses (P = 0.0439). CONCLUSION: Recognition of the variety and
      typical chronology of postoperative fundus and angiographic signs in laser
      induced chorioretinal anastomosis will help prevent premature retreatment and
      guide appropriately timed additional treatment for failed initial attempts.
      Fluorescein angiography and indocyanine green angiography are necessary
      components of intensive postoperative follow-up of these patients. The follow-up
      care is more difficult than the technical aspects of the surgery itself.
      Successful anastomoses help by taking part of the flow away from the compromised
      central vein, not by providing global venous bypass. This technique remains
      controversial, unproven, and in need of a randomized clinical trial to determine
      its role in the management of nonischemic central retinal vein occlusion.

PMID- 10599656
TI  - Methods for evaluation of retinal microvascular abnormalities associated with
      hypertension/sclerosis in the Atherosclerosis Risk in Communities Study.
AB  - OBJECTIVE: To develop protocols to photograph and evaluate retinal vascular
      abnormalities in the Atherosclerosis Risk in Communities (ARIC) Study; to test
      reproducibility of the grading system; and to explore the relationship of these
      microvascular changes with blood pressure. DESIGN: Population-based, cross
      sectional study. PARTICIPANTS: Among 4 examination centers, 11,114 participants
      (48-73 years of age) at their third triennial examination, after excluding
      persons with diabetes from this analysis. METHODS: One eye of each participant
      was photographed by technicians with nonmydriatic fundus cameras. Reading center
      graders evaluated focal arteriolar narrowing, arteriovenous (AV) nicking, and
      retinopathy by examining slides on a light box and measured diameters of all
      vessels in a zone surrounding the optic disc on enhanced digitized images. To
      gauge generalized narrowing, vessel diameters were combined into central
      arteriolar and venular equivalents with formulas adjusting for branching, and the
      ratio of equivalents (A/V ratio) was calculated. MAIN OUTCOME MEASURES: Retinal
      vascular abnormalities, mean arteriolar blood pressure (MABP). RESULTS: Among
      11,114 participants, photographs were obtained of 99%, with quality sufficient to
      perform retinal evaluations in 81%. In the 9040 subjects with usable photographs,
      A/V ratio (lower values indicate generalized arteriolar narrowing) ranged from
      0.57 to 1.22 (median = 0.84, interquartile range = 0.10), focal arteriolar
      narrowing was found in 7%, AV nicking in 6%, and retinopathy in 4%. Because of
      attrition of subjects and limitation of methods, prevalence of abnormality was
      likely underestimated. Controlling for gender, race, age, and smoking status,
      these retinal changes were associated with higher blood pressure. For every 10
      mmHg increase in MABP, A/V ratio decreased by 0.02 unit (P < 0.0001), focal
      arteriolar narrowing had an odds ratio (OR) of 2.00 (95% confidence interval [CI]
      = 1.87-2.14), AV nicking had an OR of 1.25 (95% CI = 1.16-1.34), and retinopathy
      had an OR of 1.25 (95% CI = 1.15-1.37). For any degree of generalized narrowing,
      individuals with focal narrowing had MABP approximately 8 mmHg higher than those
      without (P < 0.0001). Masked replicate assessment of a sample found the following
      reproducibility: for A/V ratio, correlation coefficient = 0.79 and median
      absolute difference = 0.03; for focal arteriolar narrowing, kappa = 0.45; for AV
      nicking, kappa = 0.61; and for retinopathy, kappa = 0.89. CONCLUSION: Protocols
      have been developed for nonmydriatic fundus photography and for evaluation of
      retinal vascular abnormalities. Several microvascular changes were significantly
      associated with higher blood pressure; follow-up will show whether these are
      predictive of later cerebrovascular or cardiovascular disease independently of
      other known risk factors.

PMID- 10599657
TI  - Retinal detachment after clear lens extraction for high myopia: seven-year follow
      up.
AB  - OBJECTIVE: To prospectively evaluate the incidence of complications, particularly
      retinal detachment, 7 years after clear lens extraction (CLE) for myopia greater
      than -12 diopters (D). DESIGN: Extended follow-up of noncomparative case series.
      PARTICIPANTS: Fifty-two eyes of 30 patients with preoperative myopia greater than
      -12 D, best-corrected visual acuity (BCVA) of 20/100 or better, and intolerance
      of contact lenses. INTERVENTION: Patients with lattice degeneration, retinal
      tear, or hole underwent photocoagulation before CLE. The authors performed
      phacoemulsification through a 3.2-mm-wide incision using primary irrigation and
      aspiration, widened the incision to 6.5 mm, and implanted a one-piece polymethyl
      methacrylate intraocular lens (IOL). MAIN OUTCOME MEASURES: The BCVA, uncorrected
      visual acuity (UCVA), stability of spherical equivalent (SE), neodymium:YAG
      (Nd:YAG) capsulotomy rate, and complications (especially retinal detachment).
      RESULTS: At 7 years, the SEs of 29 eyes (59.1%) were within +/-1.0 D of
      emmetropia and 42 eyes (85.7%) were within +/-2.0 D. Mean SE was -1.01 D (+/
      0.94). At 7 years, mean UCVA was 20/80 compared with 20/66 at 1 year. BCVA and
      UCVA were better in eyes with open capsules versus intact capsules. During the 7
      years, 30 eyes (61.2%) required capsulotomy for opacification. Mean time for
      capsulotomy was 48.4 months after CLE. The authors performed ten argon laser
      retinal treatments after surgery, with all but one in the first postoperative
      year. The overall incidence of posterior vitreous detachment was 16.3%. The
      incidence of retinal detachment during the 7 years was 4 of 49 eyes, or 8.1% (vs.
      2.0% at 4 years). One patient had bilateral retinal detachments. CONCLUSION:
      Despite advances in surgical technique, retinal detachment remains a major
      concern after CLE for high myopia. In the authors' series, the incidence of
      retinal detachment after CLE was nearly double that estimated for persons with
      myopia greater than -10 D who do not undergo surgery. Although CLE has
      advantages, including rapid and predictable visual rehabilitation, stable
      refraction, the ability to replace the IOL, and often superb optical quality with
      no irregular astigmatism, it is invasive and can result in severe vision loss.
      Long and continuous follow-up of the outcomes of CLE for high myopia is
      absolutely necessary before the authors can consider CLE as a routine option for
      patients with high myopia.

PMID- 10599658
TI  - Aqueous and vitreous penetration of levofloxacin after oral administration.
AB  - OBJECTIVE: To investigate the penetration of levofloxacin, an optical S-(-)isomer
      of ofloxacin, into the aqueous and vitreous humor after oral administration.
      DESIGN: Randomized, clinical trial comparing tissue levels of levofloxacin after
      one or two doses 12 hours apart. PARTICIPANTS: Forty-five patients undergoing
      initial vitrectomy between February 1997 and June 1997 at the UIC Eye Center.
      METHODS: Aqueous, vitreous, and serum samples were obtained and later analyzed
      from 45 patients after oral administration of 1 500-mg tablet (group 1, 22
      patients) or 2 500-mg tablets (group 2, 23 patients) 12 hours apart before
      surgery. MAIN OUTCOME MEASURES: Aqueous, vitreous, and serum concentrations of
      levofloxacin (micrograms/milliliter). RESULTS: Group 1 achieved mean aqueous,
      vitreous, and serum levels of 0.59 +/- 0.48 microg/ml, 0.32 +/- 0.34 microg/ml,
      and 4.34 +/- 3.59 microg/ml, respectively. Group 2 achieved mean aqueous,
      vitreous, and serum levels of 1.90 +/- 0.97 microg/ml, 2.39 +/- 0.70 microg/ml,
      and 8.02 +/- 3.14 microg/ml. CONCLUSIONS: Mean inhibitory aqueous and vitreous
      MIC90 levels were achieved against a majority of ocular pathogens, including
      Staphylococcus aureus and Staphylococcus epidermidis, Streptococcus pneumoniae
      (vitreous), Bacillus cereus (vitreous), Haemophilus influenzae, Moraxella
      catarrhalis, and most gram-negative aerobic organisms except Pseudomonas
      aeruginosa after two doses given 12 hours apart. Mean MIC90 levels were obtained
      in the vitreous for a majority of pathogens responsible for traumatic,
      postoperative, or bleb-related endophthalmitis.

PMID- 10599659
TI  - Elevated vitreous interleukin-10 level is not diagnostic of intraocular-central
      nervous system lymphoma.
AB  - OBJECTIVE: Diagnosis of intraocular-central nervous system (CNS) lymphoma is
      commonly made by identifying malignant lymphocytes in the vitreous. However, such
      cells are in the minority in the vitreous cellular infiltrate (most are reactive
      lymphocytes), and therefore lack of cytologic support from biopsied vitreous
      samples in patients suspected of having intraocular-CNS lymphoma may occur.
      Recent data suggest that interleukin-10 (IL-10) levels are elevated in the serum
      and vitreous of patients with non-Hodgkin's lymphoma, whereas IL-12 and IL-6
      levels are elevated in patients with uveitis of non-neoplastic etiology. The
      authors evaluated the usefulness of measuring vitreous levels of IL-6, -10, and 
      12 in the diagnosis of intraocular-CNS lymphoma. DESIGN: Prospective case series.
      PARTICIPANTS: Seventeen patients with intraocular inflammation who underwent a
      diagnostic or therapeutic vitrectomy: 4 patients with intraocular-CNS lymphoma
      and 13 patients with uveitis unrelated to a neoplasm. INTERVENTION: Eighteen
      vitreous specimens were obtained prospectively. Concentrations of IL-6, -10, and 
      12 were measured by enzyme immunosorbent assay, and relative ratios of the
      interleukins were calculated. Cytopathologic examination and flow cytometry of
      vitreous cells were also performed. MAIN OUTCOME MEASURES: The ratio of IL-10/IL
      12 and IL-10/IL-6 was calculated to assess any association of intraocular-CNS
      lymphoma and high vitreous IL-10 relative to IL-6 and IL-12 levels. RESULTS: The
      IL-10/IL-6 and IL-10/IL-12 ratio was greater than 1 in 8 of 14 vitreous specimens
      obtained from 13 patients with non-neoplastic uveitis. One of the four specimens
      from patients with cytologically proven intraocular-CNS lymphoma had vitreous IL
      10/IL-6 and IL-10/IL-12 ratios of less than 1. CONCLUSION: Although a helpful
      diagnostic tool, an elevated vitreous IL-10 to IL-6 or IL-12 ratio is not always
      associated with intraocular-CNS lymphoma.

PMID- 10599660
TI  - Automated scanning laser ophthalmoscope image montages of retinal diseases.
AB  - PURPOSE: To generate wide-field automated seamless retinal montage images.
      DESIGN: Prospective, observational, case series study. PARTICIPANTS: Eighteen
      eyes of 14 patients were studied. INTERVENTION: A digital scanning laser
      ophthalmoscope (SLO), the Heidelberg Retina Angiograph (HRA), was used to obtain
      overlapping images of the fundus during fluorescein angiograms, indocyanine green
      angiograms, or monochromatic retinal imaging using infrared or green light.
      Software was used to generate seamless montages. MAIN OUTCOME MEASURES: Ability
      to electronically synthesize retinal montages. Four laser wavelengths were used.
      The wide-field degrees, vertical and horizontal number of pixels, and diameter of
      the individual images were measured. RESULTS: High-resolution (pixel size, 10
      microm), wide-field, typically 100 degrees to 140 degrees, digital montages of
      the postequatorial retina can be generated from HRA images. CONCLUSIONS: The
      software automatically and rapidly aligned the retinal blood vessels and
      synthesized a montage of the entire fundus that could then be overlaid on images
      taken at different times to illustrate change. These montages will allow improved
      ability to understand and follow retinal diseases.

PMID- 10599661
TI  - Inhaled corticosteroids, family history, and risk of glaucoma.
AB  - OBJECTIVE: Until recently, inhaled corticosteroids were not considered to cause
      elevated intraocular pressure (IOP), although topical and oral corticosteroids
      have been shown to do so in susceptible individuals. The authors aimed to (1)
      identify whether an association existed between inhaled corticosteroid use and
      elevated IOP or open-angle glaucoma and (2) determine whether this effect may
      have a genetic basis. DESIGN: Cross-sectional, population-based study of 3654
      persons 49 to 97 years of age attending the Blue Mountains Eye Study, near
      Sydney, Australia. METHODS: A series of questions assessed use of inhaled and
      other corticosteroids as well as family history of glaucoma. Elevated IOP was
      assessed using applanation tonometry. Diagnosis of glaucoma was based on
      automated perimetry defects and optic disc signs but without reference to IOP.
      MAIN OUTCOME MEASURE: Statistical analysis of associations between inhaled
      corticosteroid use and elevated IOP or glaucoma, by family history, adjusting for
      other risk factors. RESULTS: Open-angle glaucoma was diagnosed in 108 subjects,
      and elevated IOP was found in 160 subjects. In persons with a glaucoma family
      history, there was a strong association between inhaled corticosteroid use and
      presence of either glaucoma or elevated IOP (odds ratio [OR], 2.6; 95% confidence
      interval, 1.2-5.8). The risk increased with higher doses (OR, 6.3; 95% CI, 1.0
      38.6) for persons who used more than four puffs per day. These findings were not
      explained by concurrent use of oral or ocular corticosteroids. In persons without
      a family history of glaucoma, no association was found between use of inhaled
      corticosteroids and glaucoma or elevated IOP. CONCLUSIONS: These findings suggest
      an association between ever use of inhaled corticosteroids and a finding of
      elevated IOP or glaucoma in subjects with a glaucoma family history. Patients
      being treated with inhaled corticosteroids need review by an ophthalmologist if
      they report a glaucoma family history.

PMID- 10599662
TI  - Axial length decrease accompanying successful glaucoma filtration surgery.
AB  - OBJECTIVE: To evaluate change in axial length measurement after successful
      glaucoma filtering surgery. DESIGN: Retrospective consecutive case series.
      PARTICIPANTS: Sixty-two patients with phakia who underwent primary
      trabeculectomy. INTERVENTION: The A-scan biometry of ocular axial length before
      and after trabeculectomy. MAIN OUTCOME MEASURES: Changes in ocular axial length
      measurement after successful trabeculectomy were analyzed. RESULTS: The mean
      decrease in axial length measurement was 0.423 mm (range, -2.8 to +0.5 mm).
      Regression analysis yielded a statistically significant association between
      decrease in axial length measurement and age (P = 0.0001) and post-trabeculectomy
      intraocular pressure decrease greater than 30 mmHg (P = 0.01). Analysis of
      variance revealed a significant association between decrease in axial length
      measurement and use of antimetabolite (P = 0.005). Pseudophakic axial length
      measurements increased an average of 0.275 mm compared to the axial length after
      trabeculectomy and before cataract surgery. CONCLUSIONS: Axial length measurement
      decreased in 32 of 62 eyes after successful initial trabeculectomy. A decrease in
      axial length measurement may have an influence on intraocular lens calculations.
      Therefore, the authors recommend that an axial length measurement be obtained on
      phakic eyes before an initial trabeculectomy to reduce the risk of an inaccurate
      intraocular lens power calculation based on post-trabeculectomy axial length
      measurements.

PMID- 10599663
TI  - Randomized clinical trial of the 350-mm2 versus the 500-mm2 Baerveldt implant:
      longer term results: is bigger better?
AB  - OBJECTIVE: To report the longer term results of a randomized, clinical trial
      comparing the 350-mm2 and the 500-mm2 Baerveldt glaucoma implants. DESIGN:
      Extended follow-up on a randomized, controlled trial. PARTICIPANTS: Between March
      1991 and April 1993, 107 patients with uncontrolled intraocular pressure (IOP)
      due to non-neovascular glaucoma associated with aphakia, pseudophakia, or failed
      filters were randomly assigned for surgical placement of either the 350-mm or the
      500-mm2 Baerveldt implant at the Doheny Eye Institute. METHODS: A random-numbers
      table was used to assign each patient to one of the two groups. Preoperative IOPs
      and visual acuities were recorded. Clinical records were reviewed to ascertain
      postoperative IOPs, visual acuities, number of medications used, and implant
      related complications that occurred throughout the follow-up period. MAIN OUTCOME
      MEASURES: Success was defined as IOP of 6 mmHg or greater and of 21 mmHg or less
      in two or more consecutive follow-up visits without further glaucoma surgery or
      loss of light perception attributable to glaucoma. RESULTS: The overall success
      rates were 87% for the 350-mm2 group and 70% for the 500-mm2 group (P = 0.05).
      Average follow-up was 37 months (range, 1-76 months) for the 350-mm2 group and 34
      months (range, 5-77 months) for the 500-mm2 group. The life-table success rates
      declined over time for both implant groups, from a high of 98% for the 350-mm2
      group and 92% for the 500-mm2 group at 1 year to a cumulative success rate of 79%
      for the 350-mm2 group and 66% for the 500-mm2 group at 5 years. Visual acuities
      were better or remained the same in 50% of the patients in the 350-mm2 group and
      46% of those in the 500-mm2 group. Complications during the 5-year follow-up were
      also statistically similar. CONCLUSIONS: The longer term results show that the
      350-mm2 Baerveldt implant is more successful than the 500-mm2 implant for overall
      IOP control. Interval comparisons indicate a higher rate of success for the 350
      mm2 implant in the first, second, third, fourth, and fifth years of implantation.
      Visual acuities, implant-related complications, and average IOPs were
      statistically indistinguishable between the two groups.

PMID- 10599664
TI  - The Micro-Reflux Test: a new test to evaluate nasolacrimal duct obstruction.
AB  - OBJECTIVE: The authors describe a new and simple procedure, the Micro-Reflux Test
      (MRT), to screen for primary acquired nasolacrimal duct obstruction (PANDO). This
      study sought to determine the reliability of this new test in the diagnosis of
      complete nasolacrimal duct obstruction. DESIGN: A nonrandomized, prospective,
      self-controlled, comparative case series. PARTICIPANTS: Two hundred eyes of 100
      patients with documented unilateral complete PANDO were examined. INTERVENTION:
      The MRT was performed by a masked examiner on both eyes of each patient. Two
      drops of 0.25% sodium fluorescein dye were instilled in the inferior cul-de-sac
      and the patient made to blink five times to activate the lacrimal pump mechanism.
      Excess fluorescein dye was blotted away using tissue paper. The patient was
      positioned at the slit lamp, and observation of the inferior punctum with the
      cobalt blue filter was done using 5x magnification. The tissue overlying the
      lacrimal sac was massaged in a counterclockwise direction with moderate pressure
      using the index finger. The test was considered positive if there was continued
      observed reflux of fluorescein-stained tears from the inferior punctum after the
      initial counterclockwise massage to empty the inferior canaliculus. The validity
      of the MRT was measured by sensitivity and specificity as well as positive- and
      negative-predictive values. MAIN OUTCOME MEASURE: The MRT was considered positive
      if there was continued reflux of fluorescein-stained tears from the inferior
      punctum after the initial digital massage to empty the dye from the inferior
      canaliculus. RESULTS: The MRT used for the evaluation of complete PANDO has a
      sensitivity of 97% and a specificity of 95%. It has a positive-predictive value
      of 95% and a negative-predictive value of 97%. CONCLUSION: The MRT is a reliable
      screening test for presence of complete nasolacrimal duct obstruction.

PMID- 10599665
TI  - Successful treatment of crocodile tears by injection of botulinum toxin into the
      lacrimal gland: a case report.
AB  - OBJECTIVE: Pathologic lacrimation (crocodile tears) is a rare but stigmatizing
      symptom after facial nerve paralysis. The aim of this pilot study was to examine
      whether botulinum toxin injection into the lacrimal gland is effective in
      reducing pathologic tear secretion. DESIGN: Case report. INTERVENTION: One
      patient who had crocodile tears after a zoster oticus infection received a
      botulinum toxin injection (2.5 mouse units) into the lacrimal gland. TESTING:
      Before injection, 1 week, 1 month, and 6 months after injection, patient's
      lacrimation was assessed by a Schirmer test. RESULTS: The lacrimation of the
      injected eye was reduced after 1 week and equal after 1 month when compared to
      the healthy side. After 6 months, hyperlacrimation reoccurred. No side effects
      were observed. CONCLUSION: Intraglandular injection of botulinum toxin into the
      lacrimal gland may serve as a sufficient therapy for crocodile tears.

PMID- 10599666
TI  - Retrograde intubation dacryocystorhinostomy for proximal and midcanalicular
      obstruction.
AB  - OBJECTIVE: Retrograde intubation of canaliculi during dacryocystorhinostomy can
      restore canalicular patency in cases otherwise managed with bypass tubes. The
      surgical technique and success for this procedure are discussed. DESIGN: A
      retrospective, noncomparative case series with clinic or telephone interview for
      long-term follow-up of patients' symptoms. PARTICIPANTS: One hundred two patients
      who had undergone this particular lacrimal drainage surgery at Moorfields Eye
      Hospital between 1992 and 1997. INTERVENTION: All patients underwent a
      dacryocystorhinostomy and retrograde canaliculostomy while under general
      anesthetic. MAIN OUTCOME MEASURES: Relief or reduction of epiphora and discharge.
      RESULTS: One hundred twenty-three lacrimal systems of 102 patients were included.
      There were 53 females and 49 males, with ages at surgery ranging from 6 to 83
      years (mean, 49 years). The etiology was idiopathic (30%), herpetic canaliculitis
      (24%), punctal agenesis (18%), and trauma (11%); less-common causes included
      dacryocystitis, Stevens-Johnson syndrome, eczema, and prior radiation therapy.
      Both upper and lower canalicular systems were involved in the majority (73%) of
      patients, and in 13 (11%) systems a dacryocystorhinostomy had previously been
      performed. The silicone tube was placed for a mean of 2 months (range, 1 week-9
      months), and the mean postoperative follow-up was 8 months (range, 2-24 months).
      Epiphora subjectively improved in 90 (73%) of 123 systems, of which 27 (22%) of
      123 were asymptomatic. In 33 systems (27%) in which epiphora persisted, 14 (11%)
      have undergone closed placement of a Jones canalicular bypass tube with control
      of symptoms. CONCLUSIONS: Retrograde canaliculostomy and intubation can spare a
      significant number of patients the long-term inconvenience of Jones tubes.
      Failure of this technique does not, however, compromise or complicate the future
      placement of a bypass tube.

PMID- 10599667
TI  - Orbital helical computed tomography in the diagnosis and management of eye
      trauma.
AB  - OBJECTIVE: To prospectively determine the accuracy of helical computed tomography
      (CT) and multiplanar reconstruction and its value in surgical planning for the
      management of ocular trauma with suspected intraocular and orbital foreign bodies
      using surgical and clinical follow-up findings as the gold standard. DESIGN:
      Prospective, observational case series. PARTICIPANTS: Thirty-six patients with
      ocular trauma and suspected foreign bodies were studied. INTERVENTION: All
      patients were examined using a standardized scanning protocol with helical CT
      direct scanning in the axial plane and multiplanar reconstruction of coronal and
      sagittal planes. MAIN OUTCOME MEASURES: The images were analyzed for the presence
      and number of intraocular and orbital foreign bodies, anatomic location, and
      foreign body size. The surgical and clinical follow-up findings (contact lens
      examination, gonioscopy, indirect ophthalmoscopy and scleral depression,
      perimetry, color testing, measurement of size) were used as the gold standard to
      which the image results were compared. RESULTS: Helical CT showed a single
      intraocular foreign body in 14 patients, a single orbital foreign body in 9
      patients, and multiple orbital foreign bodies in 2 patients. Intraocular or
      orbital foreign bodies were excluded in 11 patients. Twenty foreign bodies were
      correlated with surgical results. Surgical and clinical follow-up findings were
      in agreement with helical CT results regarding the detection and determination of
      the number of presumed foreign bodies. Localization to intraocular versus orbital
      compartment and proximity to the optic nerve was accurate in all patients.
      Determination of size of the foreign bodies on the helical CT images was reliable
      and repeatable. CONCLUSIONS: Helical CT axial scanning with multiplanar
      reconstruction is accurate at detecting and localizing intraocular and orbital
      metallic, glass, and stone foreign bodies. This imaging method aids the surgeon
      in choosing the surgical approach to retained intraocular and orbital foreign
      bodies.

PMID- 10599668
TI  - Myocysticercosis: experience with imaging and therapy.
AB  - OBJECTIVE: To compare computed tomography (CT) and B-scan ultrasonography (USG)
      in the diagnosis and to study the efficacy of a combination of oral albendazole
      and prednisolone in the management of myocysticercosis. DESIGN: Retrospective,
      noncomparative case series. PARTICIPANTS: Twenty-six consecutive patients with
      myocysticercosis. INTERVENTION: Diagnostic imaging was performed by CT scan and
      USG in 24 and 22 patients, respectively; serial USG was obtained in 7 patients
      receiving treatment. All patients received oral albendazole (15 mg/kg body weight
      per day) and prednisolone (1.5 mg/kg body weight per day) for 4 weeks. MAIN
      OUTCOME MEASURES: Presence of scolex on CT scan compared to USG and clinical
      response to medical therapy were the main outcome measures. Recovery was defined
      as complete resolution of the scolex or of the main presenting clinical feature.
      RESULTS: Presence of scolex on CT scan (11 of 24) and USG (11 of 22) was not
      different (P = 1.0; chi-square test). Recovery was seen in 24 (92%) of 26
      patients receiving medical treatment. On serial USG of patients receiving
      treatment (n = 7), cysts with scolex were seen to progress to a cyst without
      scolex before final resolution. Time to recovery on treatment (0.5-35 months)
      correlated with the duration of symptoms at presentation (correlation coefficient
      r = 0.56, P = 0.003, linear regression analysis), but not with positive serum
      enzyme-linked immunosorbent assay for anticysticercal antibodies (P = 0.57, log
      rank test) or the presence of scolex (P = 0.52, log-rank test). CONCLUSIONS:
      Treatment with a combination of oral albendazole and prednisolone is effective in
      the management of myocysticercosis. Imaging methods CT and USG are equally
      effective in identifying the cyst and the scolex; serial USG is useful in
      studying the temporal sequence of therapeutic response. The longer recovery time
      correlating with the duration of symptoms may indicate the chronicity of the
      inflammatory changes requiring longer time for recovery.

PMID- 10599669
TI  - Ocular explosions from periocular anesthetic injections: a clinical,
      histopathologic, experimental, and biophysical study.
AB  - OBJECTIVES: An increasing number of cases are being recognized in which a
      periocular anesthetic for cataract surgery has been inadvertently injected
      directly into the globe under high pressure until the globe ruptures or
      "explodes." The objectives of the current study were to (1) analyze this injury
      clinically and histopathologically through a series of seven case reports; (2)
      reproduce the injury experimentally in human eyebank eyes, live anesthetized
      rabbit eyes, and human cadaveric eyes; (3) investigate the biophysical basis of
      the injury; and (4) outline recommendations to help decrease the risk of ocular
      rupture with periocular injections. DESIGNS/PARTICIPANTS: Clinical,
      histopathologic, experimental animal, autopsy eye, and theoretical biophysical
      study. METHODS: The clinical and histopathologic findings of the patients' eyes
      were documented. Human eyebank eyes, live anesthetized rabbit eyes, and human
      cadaveric eyes were exploded via direct intraocular saline injection. The laws of
      Bernoulli, LaPlace, Friedenwald, and Pascal were used to investigate
      theoretically the biophysics of the injury. RESULTS: The findings of anterior and
      posterior scleral rupture, retinal detachment, vitreous hemorrhage, and lens
      extrusion were observed clinically and experimentally. In some clinical and
      experimental cases, the anterior segment appeared entirely normal despite a
      posterior rupture. The surgeon proceeded with and completed the cataract surgery
      in two of the seven clinical cases without knowledge of the rupture. The pressure
      required to produce such an injury is in the range of 2800 to 6400 mmHg, and this
      pressure is more easily attained with a 3-ml syringe than with a 12-ml syringe.
      CONCLUSIONS: Explosion of an eyeball during the injection of anesthesia for
      ocular surgery is a devastating injury that may go unrecognized. The probability
      of an ocular explosion can be minimized by (1) the use of a blunt needle and a 12
      ml syringe, (2) aspirating the plunger and wiggling the syringe before injection,
      (3) discontinuing the injection if corneal edema or resistance to injection is
      noted, and (4) inspecting the globe for evidence of intraocular injection before
      ocular massage or placement of a Honan balloon. On recognition of an ocular
      explosion, immediate referral to and intervention by a vitreoretinal surgeon is
      optimal.

PMID- 10599671
TI  - Pyramidal anterior polar cataracts.
AB  - OBJECTIVE: To document clinical features and subsequent management of pyramidal
      anterior polar cataracts in children. DESIGN: Retrospective, noncomparative case
      series and clinicopathologic correlation. PARTICIPANTS: Fifteen patients who
      presented to the pediatric ophthalmology clinic. INTERVENTION: All patients
      underwent measurement of visual acuity, assessment of ocular motility,
      examination of the anterior and posterior segments, and cycloplegic refraction.
      Amblyopia treatment was instituted when appropriate. When visual impairment
      occurred from cataract progression or amblyopia or both, cataract removal with or
      without lens implantation was performed. After surgery, correction of refractive
      error and treatment of amblyopia were instituted. Several pyramidal opacities
      were retrieved during cataract extraction and examined by light and electron
      microscopy. MAIN OUTCOME MEASURES: Visual acuity at initial presentation, size of
      lens opacity before surgery, amblyopia status, most recent visual acuity after
      cataract extraction, and histologic examination of lens opacity. RESULTS: Nine
      children had bilateral and six had unilateral pyramidal cataracts (24 eyes).
      There was no discernible inheritance pattern. Patients were followed for 27
      months on average. Twenty of 24 eyes developed cortical opacification that
      extended significantly beyond the base of the pyramidal lesion. Nineteen eyes
      required cataract surgery: 10 eyes underwent lensectomy with anterior vitrectomy
      and 9 had extracapsular cataract extraction, 8 of which had insertion of a
      posterior chamber intraocular lens. Amblyopia was present or developed in all six
      patients with unilateral cataract and in eight of nine patients with bilateral
      cataract. Visual acuity in many eyes remained poor despite amblyopia therapy. The
      pyramidal opacities consisted of hyperplastic lens epithelium, which exhibited a
      loss of polarity and was surrounded by a collagenous matrix. CONCLUSIONS:
      Pyramidal anterior polar cataracts are present at birth and may represent a
      variant of anterior polar lens opacities. They may be unilateral or, if
      bilateral, they may be either symmetric or asymmetric. They consist of
      hyperplastic lens epithelium in a collagenous matrix. Patients with pyramidal
      cataracts are likely to develop amblyopia. This can result from either unilateral
      occurrence or asymmetry of bilateral opacities and is often worsened by
      surrounding cortical opacification. Many patients require cataract surgery. All
      infants and young children with anterior polar opacities showing this
      configuration should be followed for cataract progression and amblyopia.

PMID- 10599670
TI  - Visual-evoked potential evidence of chiasmal hypoplasia.
AB  - PURPOSE: To show that chiasmal hypoplasia or aplasia need not be an isolated
      developmental anomaly and to examine the spectrum of associated clinical findings
      to explore the possibility that these patients may represent a phenotypic
      manifestation of a developmental gene anomaly. DESIGN: An observational case
      series. PARTICIPANTS: Five infants, between several weeks and 7 months of age, in
      whom the electrophysiologic characteristic of chiasmal hypoplasia had been noted
      were included. METHODS: Flash electroretinography and flash and pattern visual
      evoked potentials (VEPs) were elicited from all patients. Clinical ophthalmologic
      examinations, including funduscopy, were performed, and all patients had magnetic
      resonance imaging (MRI) brain scans. MAIN OUTCOME MEASURES: The occipital
      distribution of monocular VEP response peaks was studied. The symmetry of lateral
      channel responses was compared for monocular stimulation. RESULTS: All five
      patients had a crossed asymmetry in the monocular VEP occipital distribution,
      which is consistent with a paucity of fibers crossing at the chiasm. The MRI
      findings supported this electrophysiologic observation, illustrating degrees of
      chiasmal hypoplasia and variable coincidence of other midline abnormalities of
      the brain. Optic disc appearances varied from normal to hypoplastic and
      colobomatous. CONCLUSIONS: The ophthalmologic and MRI findings of five patients
      who showed a crossed asymmetry in monocular flash VEPs are consistent with a
      paucity of axons crossing at the chiasm. The similarities between achiasmia in
      humans and mice due to a Pax2 gene anomaly are discussed.

PMID- 10599672
TI  - Treatment of acute comitant esotropia in Chiari I malformation.
AB  - PURPOSE: To explore the appropriate treatment of acute comitant esotropia in
      patients with Chiari I malformation. DESIGN: Interventional case reports and
      literature review. PARTICIPANTS: Two patients with Chiari I malformation
      presenting with acute comitant esotropia are described. INTERVENTION: Strabismus
      surgery, then neurosurgical decompression of the Chiari I malformation was
      performed. MAIN OUTCOME MEASURE: Both patients were evaluated for resolution of
      esotropia and other ocular motility problems. RESULTS: After initially successful
      strabismus surgery, both patients developed recurrent esotropia with diplopia,
      which resolved on suboccipital decompression. CONCLUSION: Comitant esotropia may
      recur and other eye movement disorders may develop after initially successful
      strabismus surgery in patients with Chiari I malformation. The data suggest that
      the appropriate sequence of treatment should first be suboccipital decompression,
      then strabismus surgery if spontaneous realignment does not occur, but further
      studies are needed to confirm this impression.

PMID- 10599673
TI  - Combined resection and anterior transposition of the inferior oblique muscle for
      asymmetric double dissociated vertical deviation.
AB  - OBJECTIVE: To evaluate the efficacy of combined monocular resection and bilateral
      anterior transposition of the inferior oblique (IO) muscle for asymmetric double
      dissociated vertical deviation (DVD). DESIGN: Nonrandomized, comparative clinical
      trial. PARTICIPANTS: Twelve patients with asymmetric DVD and coexisting unequal
      IO overaction (IOOA). INTERVENTION: Six consecutive patients underwent combined
      graded monocular resection and bilateral anterior transposition of the IO muscle
      and six consecutive historical control patients underwent equal anteriorization
      of the IO muscle. MAIN OUTCOME MEASURES: Between-group comparison of the
      postoperative vertical deviation and reduction in IOOA. RESULTS: The mean
      difference of the asymmetric DVD in the primary position was reduced from 13.3 +/
      4.8 prism diopters (PD) to 2.2 +/- 1.8 PD in the study group (P = 0.001) and
      from 13.3 +/- 4.0 PD to 10.2 +/- 3.1 PD in the control group (P = 0.003). The
      difference in improvement between the groups was statistically significant (P =
      0.004). The IOOA was significantly reduced in both groups. CONCLUSIONS: Bilateral
      IO anteriorization with monocular-graded IO resection should be considered as the
      treatment of choice in patients with asymmetric DVD with IOOA.

PMID- 10599674
TI  - Episcleritis in childhood.
AB  - OBJECTIVE: To describe the characteristics and systemic disease associations of
      episcleritis in childhood. DESIGN: Retrospective, observational case series.
      PARTICIPANTS: Twelve children diagnosed with episcleritis between July 1981 and
      June 1998. METHODS/TESTING: Complete eye and systemic evaluations. MAIN OUTCOME
      MEASURES: Characteristics of episcleritis and presence and nature of concurrent
      systemic disease. RESULTS: The 12 children (10 boys and 2 girls) ranged in age
      from 13 months to 16 years. Five children had bilateral simple episcleritis, one
      had bilateral nodular episcleritis, and six had unilateral simple episcleritis.
      The eye examination was otherwise normal and recovery was uneventful in all
      cases. Six of the nine children older than 5 years of age had one of the
      following rheumatologic diseases: systemic lupus erythematosus, juvenile
      rheumatoid arthritis, spondyloarthropathy, inflammatory bowel disease, rheumatic
      fever, or polyarteritis nodosa. All three children younger than 5 years of age
      had simple episcleritis, an antecedent viral illness, and presented within 2
      months of each other. CONCLUSIONS: Episcleritis is a rare occurrence in
      childhood, especially in children younger than 5 years of age. In older children,
      it is frequently associated with rheumatologic disease.

PMID- 10599675
TI  - Posterior scleritis: clinical features, systemic associations, and outcome in a
      large series of patients.
AB  - OBJECTIVE: To document the clinical features, systemic associations, and visual
      outcome in a large number of patients with posterior scleritis. DESIGN:
      Retrospective, noncomparative case series. PARTICIPANTS: There were 137 patient
      records showing patients with a diagnosis of posterior scleritis who were
      attending or had attended the scleritis clinic at Moorfields Eye Hospital between
      1974 and 1996. Ninety-nine records were suitable for detailed analysis. METHODS:
      The medical records and B-mode ultrasound examinations were reviewed. MAIN
      OUTCOME MEASURES: The clinical features, systemic associations, treatment, and
      outcome of each patient were determined. RESULTS: Posterior scleritis occurred at
      all ages. The mean age at onset was 49.3 years. Posterior scleritis began before
      age 40 in 30% of patients and was twice as common in women as in men. The B-mode
      ultrasound examination showed diffuse and nodular changes in the posterior
      sclera. Necrotizing posterior scleritis was not identified. Twenty-nine percent
      of patients had an associated systemic disease that included systemic
      vasculidites, autoimmune diseases, and lymphoma. Such patients more commonly had
      nodular changes on B-mode ultrasound examination. Early treatment controlled
      posterior scleral inflammation and limited visual loss. Thirty-one percent of
      patients lost two or more lines of vision. Statistical analysis revealed that
      patients older than age 50 had an increased risk of having an associated systemic
      disease and were more likely to experience visual loss. Patients with associated
      systemic disease required more aggressive immunosuppressive therapy and more
      frequently had accompanying anterior scleritis. There was no association between
      unilateral, bilateral, or recurrent disease and the presence of systemic disease
      or visual loss from posterior scleritis. CONCLUSIONS: The B-mode ultrasound
      examination reveals that posterior scleritis occurs far more often than
      previously thought and can lead to rapid and permanent visual loss. All patients
      with posterior scleritis must be assumed to be at risk of visual loss. Forty
      percent of patients had no anterior scleral inflammation, and 9% had no
      detectable physical signs. All patients need to be investigated for an associated
      systemic disease and all require early treatment to minimize loss of vision.

PMID- 10599676
TI  - Orbital infarction and melting in a patient with systemic lupus erythematosus.
AB  - OBJECTIVE: To present a patient with systemic lupus erythematosus who developed
      infarction and melting of the orbit secondary to her systemic disease. DESIGN: A
      case report. PARTICIPANT: A 61-year-old white woman with a 5-year history of
      systemic lupus erythematosus. METHODS: The patient presented with left orbital
      pain, limitation of extraocular movements, and a fistula from the ethmoid sinus
      to the upper eyelid. A detailed examination with computerized tomography,
      ultrasound, and a comprehensive medical evaluation with laboratory testing was
      performed. Histopathologic analysis with special stains of the orbital tissues
      was also performed. RESULTS: Histopathologic examination of the biopsy specimens
      revealed the features of an inflammatory process involving the orbit, similar to
      a panniculitis. These include a lymphocytic reaction with a predominance of
      plasma cells, vasculitis with occlusion, and thickening of the vessel walls,
      necrosis, and hyalinization of fat. CONCLUSION: This is a unique case in which
      infarction and melting of the entire orbital structures occurred in the presence
      of systemic lupus erythematosus. The underlying disease process is a lupus
      related panniculitis. The authors stress that this is a very rare entity and that
      other diseases should be ruled out before entertaining this diagnosis.

PMID- 10599677
TI  - Outcomes of retreatment after laser in situ keratomileusis.
AB  - OBJECTIVE: To evaluate the safety and efficacy of retreatment after myopic laser
      in situ keratomileusis (LASIK). DESIGN: Retrospective, noncomparative case
      series. PARTICIPANTS: A total of 962 eyes of 566 patients underwent LASIK for up
      to -20.0 diopters (D) of myopia, of which 53 eyes (5.5%) were retreated.
      INTERVENTION: Retreatments were performed by lifting the original flap and using
      the Nidek EC-5000 excimer laser (Nidek Inc., Tokyo, Japan). MAIN OUTCOME
      MEASURES: Uncorrected visual acuity (UCVA), best spectacle-corrected visual
      acuity (BCVA), fogged manifest refraction, and complications were evaluated 6
      months after retreatment. RESULTS: Overall, 53 (5.5%) of 962 eyes underwent LASIK
      retreatment. Before retreatment, the mean spherical equivalent (MSE) was -1.7 +/-
      1.1 D (range, +0.3 to -5.0 D), UCVA ranged from 20/25 to 20/400, and BCVA ranged
      from 20/20 to 20/50. Six months after retreatment, the MSE was -0.09 +/- 0.29 D,
      48 (90.6%) eyes were within +/-0.5 D, and all eyes were within +/-1.0 D of the
      attempted correction. The UCVA improved to 20/20 or better in 21 (39.6%) eyes and
      20/40 or better in 51 (96.2%) eyes. The BCVA was maintained in 33 eyes (62.3%),
      15 eyes (28.3%) gained 1 line or more of vision, whereas 5 eyes (9.4%) lost 1
      line. All eyes had a BCVA of 20/50 or better. No retreated eye lost two or more
      lines of BCVA. No complications were observed. CONCLUSION: Retreatment for low
      amounts of residual myopia performed by lifting the original flap within the
      first year after surgery after myopic LASIK is safe, effective, and predictable.

PMID- 10599679
TI  - Opportunities and challenges in pediatric clinical research.

PMID- 10599678
TI  - Treatment strategies for postoperative Propionibacterium acnes endophthalmitis.
AB  - PURPOSE: Propionibacterium acnes endophthalmitis after cataract extraction and
      posterior chamber intraocular lens (IOL) implantation is characterized by a
      chronic indolent course, frequently associated with recurrence after standard
      endophthalmitis treatment. This study was designed to evaluate the efficacy of
      various therapeutic methods in the treatment of primary and recurrent episodes of
      postoperative P. acnes endophthalmitis. DESIGN: Retrospective, noncomparative
      case series. PARTICIPANTS: Twenty-five patients treated at Wills Eye Hospital for
      P. acnes endophthalmitis. METHODS: The authors retrospectively reviewed the
      clinical charts and microbiology files of all patients treated at Wills Eye
      Hospital between January 1991 and April 1998 with culture-proven P. acnes
      endophthalmitis after cataract extraction and posterior chamber IOL implantation.
      MAIN OUTCOME MEASURES: Results of cultures and microbiologic examinations,
      efficacy of various treatment methods in the prevention of recurrent inflammatory
      episodes, and final visual outcome. RESULTS: Twenty-five patients who met
      inclusion criteria were identified; initial therapy consisted of 1 of the
      following: intraocular antibiotic (IOAB) injections alone (2 patients); IOAB
      combined with pars plana vitrectomy (PPV) (10 patients); IOAB and PPV combined
      with partial capsulectomy (9 patients); and IOAB, PPV, total capsulectomy, and
      IOL exchange (4 patients). Nearly half of the patients (10 of 21, or 48%)
      initially treated with IOAB alone (1 of 2), IOAB and PPV (5 of 10), and IOAB
      combined with PPV and partial capsulectomy (4 of 9) required further therapeutic
      interventions for recurrent disease. Retreatment with IOAB alone or combined with
      PPV and partial capsulectomy in these patients failed to eradicate the infection
      in three (75%) of four patients. None of the patients (0 of 4) treated initially
      with total capsulectomy and IOL exchange required additional surgical
      intervention. Furthermore, none of the patients (0 of 13) who underwent total
      capsulectomy with IOL removal or exchange or IOL exchange alone as an initial,
      secondary, or tertiary treatment required further intervention. CONCLUSION: In
      the authors' series, approximately half of the patients with P. acnes
      endophthalmitis were treated successfully initially with nonsurgical or limited
      surgical intervention. All patients treated with total capsulectomy and IOL
      exchange or removal, either as an initial treatment or for recurrent disease,
      were cured. Removal of the entire capsular bag and the IOL may be performed as a
      definitive initial therapy and should be performed for recurrent inflammation.

PMID- 10599680
TI  - Four decades of growth hormone therapy for short children: what have we achieved?

PMID- 10599681
TI  - Pituitary tumors in children and adolescents.

PMID- 10599682
TI  - Long-term consequences of castration in men: lessons from the Skoptzy and the
      eunuchs of the Chinese and Ottoman courts.

PMID- 10599683
TI  - The anecdotal history of screening for congenital hypothyroidism.

PMID- 10599684
TI  - IMAGe, a new clinical association of intrauterine growth retardation, metaphyseal
      dysplasia, adrenal hypoplasia congenita, and genital anomalies.
AB  - We report three boys with adrenal hypoplasia congenita (AHC) and additional
      findings that represent a new syndrome, IMAGe: Intrauterine growth retardation,
      Metaphyseal dysplasia, AHC, and Genital anomalies. Each presented shortly after
      birth with growth retardation and severe adrenal insufficiency. Each of the three
      patients had mild dysmorphic features, bilateral cryptorchidism, a small penis,
      and hypogonadotropic hypogonadism. Skeletal surveys revealed metaphyseal
      dysplasia in all three and epiphyseal dysplasia in two. The patients had
      documented or suspected hypercalciuria and/or hypercalcemia, resulting in
      nephrocalcinosis in one and in prenatal liver and spleen calcifications in
      another. AHC presents most often either as an isolated abnormality, caused by
      mutations in the DAX1 gene, or as part of an Xp21 contiguous gene syndrome,
      caused by a deletion of the Duchenne muscular dystrophy, glycerol kinase, and
      DAX1 genes. All three patients with the IMAGe association had normal creatine
      kinase levels and no evidence of glycerol kinase deficiency. Sequence analysis of
      DNA from these patients revealed no mutation in the DAX1- or steroidogenic factor
      1-coding sequences, nor was a deletion of DAX1 detected. Identification of the
      molecular basis of the IMAGe association will give new insight into the
      pathogenesis of this syndromic relationship involving bone, adrenal cortical, and
      pituitary development.

PMID- 10599685
TI  - Glucocorticoid-remediable aldosteronism.

PMID- 10599686
TI  - Growth-promoting strategies in Turner's syndrome.

PMID- 10599687
TI  - Insulin-like growth factors and skeletal growth: possibilities for therapeutic
      interventions.

PMID- 10599688
TI  - Insulin-like growth factors in pediatric health and disease.

PMID- 10599689
TI  - Heritable disorders of pituitary development.
AB  - Basic and translational research achievements over the past 2 decades have
      disclosed the molecular mechanisms underlying several genetic forms of
      hypopituitarism. Disorders that are limited to the hypothalamic, pituitary, GH
      axis are caused by mutations in individual components of that axis. Disorders
      involving GH and one or more additional pituitary hormones are caused by
      mutations in the homeodomain transcription factors that direct embryological
      development of the anterior pituitary gland. Pit-1 has a POU-specific and a POU
      homeo DNA-binding domain. The phenotype produced by mutations in the PIT1 gene
      involves deficiencies of GH, PRL, and TSH. Pituitary glands are either small or
      normally sized. The PROP1 gene encodes a transcription factor with a single
      paired-like DNA-binding domain. Persons with inactivating mutations in PROP1 have
      deficiencies of LH and FSH, as well as GH, PRL, and TSH. Their pituitary glands
      may be small, normally sized, or extremely large and show suprasellar extension.
      Pituitary degeneration may produce acquired deficiency of ACTH. Expression of the
      HESX1 gene precedes expression of PROP1 and PIT1, and it is much more widespread.
      The protein has a paired-like domain, and it competes with the product of PROP1
      for DNA-binding. Homozygosity for inactivating mutations of HESX1 produces a
      complex phenotype that resembles septo-optic dysplasia. Much more needs to be
      learned about the role of HESX1 mutations in other forms of hypopituitarism.

PMID- 10599690
TI  - Autoimmunity and diabetes.
AB  - The face of immune-mediated (type 1) diabetes is changing. No longer considered a
      disease confined to childhood, the incidence rate in Western countries is clearly
      rising and affecting younger children. Such a secular trend can only be explained
      on the basis of increased contacts with adverse environmental factors acting on a
      background of complex genetics. Multiple defects in immunological tolerance to
      "self' predispose to immune-mediated (type 1) diabetes. Initiation of immune
      responses involves the cytokine rich natural killer T cells. Such cells appear
      deficient in both humans and the rodent models of the disease. Furthermore, the
      regulatory abilities of T cells in general seem to be compromised. Effector
      mechanisms probably are dominated by cell-mediated beta cell destruction through
      apoptosis induction. Surprisingly, the essential antigen-presenting cells in the
      autoimmune processes involved appear to be B lymphocytes. The improved
      understanding of the beta cell autoantigens involved has led to better disease
      prediction. The long prodromal phase now readily identifiable through
      autoantibodies is spawning hopes of disease prevention, notably through antigen
      based interventions or diabetes "vaccines."

PMID- 10599691
TI  - Gigantism.

PMID- 10599692
TI  - Pediatric pituitary adenomas.

PMID- 10599693
TI  - Genetically defined forms of diabetes in children.

PMID- 10599694
TI  - The essential role of IGF-I: lessons from the long-term study and treatment of
      children and adults with Laron syndrome.
AB  - Fifty patients with primary GH resistance (Laron syndrome) due to molecular
      defects of the GH receptor or post-receptor pathways were followed from infancy
      through adulthood. This condition leading to long-term insulin-like growth factor
      I (IGF-I) deprivation caused marked growth retardation (-4 to 8 height SD),
      acromicia, organomicria, retarded development of the skeletal and muscular
      systems, a small cranium, slow motor development, and impairment of intellectual
      development in some of the patients. In addition, there was progressive obesity,
      insulin resistance, a tendency for hypoglycemia, followed later in life by
      hypercholesterolemia and by glucose intolerance and even diabetes. IGF-I
      treatment of children with Laron syndrome, by our and other groups (150-240
      microg/day sc), stimulated growth (8 cm in the first year and 4-5 cm in the
      following years) and normalized the biochemical abnormalities. Overdosage led to
      adverse effects such as hypoglycemia, edema, swelling of soft tissues, and
      hyperandrogenism. It is concluded that primary IGF-I deprivation induces severe
      auxological, biochemical, and hormonal changes, the only treatment being
      biosynthetic IGF-I administration.

PMID- 10599695
TI  - Mendelian diseases among Roman Jews: implications for the origins of disease
      alleles.
AB  - The Roman Jewish community has been historically continuous in Rome since pre
      Christian times and may have been progenitor to the Ashkenazi Jewish community.
      Despite a history of endogamy over the past 2000 yr, the historical record
      suggests that there was admixture with Ashkenazi and Sephardic Jews during the
      Middle Ages. To determine whether Roman and Ashkenazi Jews shared common
      signature mutations, we tested a group of 107 Roman Jews, representing 176
      haploid sets of chromosomes. No mutations were found for Bloom syndrome, BRCA1,
      BRCA2, Canavan disease, Fanconi anemia complementation group C, or Tay-Sachs
      disease. Two unrelated individuals were positive for the 3849 + 10C->T cystic
      fibrosis mutation; one carried the N370S Gaucher disease mutation, and one
      carried the connexin 26 167delT mutation. Each of these was shown to be
      associated with the same haplotype of tightly linked microsatellite markers as
      that found among Ashkenazi Jews. In addition, 14 individuals had mutations in the
      familial Mediterranean fever gene and three unrelated individuals carried the
      factor XI type III mutation previously observed exclusively among Ashkenazi Jews.
      These findings suggest that the Gaucher, connexin 26, and familial Mediterranean
      fever mutations are over 2000 yr old, that the cystic fibrosis 3849 + 10kb C->T
      and factor XI type III mutations had a common origin in Ashkenazi and Roman Jews,
      and that other mutations prevalent among Ashkenazi Jews are of more recent
      origin.

PMID- 10599696
TI  - New insight into the molecular basis of 3beta-hydroxysteroid dehydrogenase
      deficiency: identification of eight mutations in the HSD3B2 gene eleven patients
      from seven new families and comparison of the functional properties of twenty
      five mutant enzymes.
AB  - Classical 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase (3betaHSD)
      deficiency is a form of congenital adrenal hyperplasia that impairs
      steroidogenesis in both the adrenals and gonads resulting from mutations in the
      HSD3B2 gene and causing various degrees of salt-wasting in both sexes and
      incomplete masculinization of the external genitalia in genetic males. To
      identify the molecular lesion(s) in the HSD3B2 gene in the 11 patients from the
      seven new families suffering from classical 3betaHSD deficiency, the complete
      nucleotide sequence of the whole coding region and exon-intron splicing
      boundaries of this gene was determined by direct sequencing. Five of these
      families were referred to Morel's molecular diagnostics laboratory in France,
      whereas the two other families were investigated by Peter's group in Germany.
      Functional characterization studies were performed by Simard's group in Canada.
      Following transient expression in 293 cells of each of the mutant recombinant
      proteins generated by site-directed mutagenesis, the effect of the 25 mutations
      on enzyme activity was assessed by incubating intact cells in culture with 10 nM
      [14C]-DHEA as substrate. The stability of the mutant proteins has been
      investigated using a combination of Northern and Western blot analyses, as well
      as an in vitro transcription/translation assay using rabbit reticulocyte lysates.
      The present report describes the identification of 8 mutations, in seven new
      families with individuals suffering from classical 3betaHSD deficiency, thus
      increasing the number of known HSD3B2 mutations involved in this autosomal
      recessive disorder to 31 (1 splicing, 1 in-frame deletion, 3 nonsense, 4
      frameshift and 22 missense mutations). In addition to the mutations reported here
      in these new families, we have also investigated for the first time the
      functional significance of previously reported missense mutations and or sequence
      variants namely, A82T, A167V, L173R, L205P, S213G and K216E, P222H, T259M, and
      T259R, which have not previously been functionally characterized. Furthermore,
      their effects have been compared with those of the 10 previously reported mutant
      enzymes to provide a more consistent and comprehensive study. The present results
      are in accordance with the prediction that no functional 3betaHSD type 2
      isoenzyme is expressed in the adrenals and gonads of the patients suffering from
      a severe salt-wasting form of CAH due to classical 3betaHSD deficiency. Whereas
      the nonsalt-losing form also results from missense mutation(s) in the HSD3B2
      gene, which cause an incomplete loss in enzyme activity, thus leaving sufficient
      enzymatic activity to prevent salt wasting. The functional data described in the
      present study concerning the sequence variants A167V, S213G, K216E and L236S,
      which were detected with premature pubarche or hyperandrogenic adolescent girls
      suspected to be affected from nonclassical 3betaHSD deficiency, coupled with the
      previous studies reporting that no mutations were found in both HSD3B1 and/or
      HSD3B2 genes in such patients strongly support the conclusion that this disorder
      does not result from a mutant 3betaHSD isoenzyme. The present study provides
      biochemical evidence supporting the involvement of a new molecular mechanism in
      classical 3betaHSD deficiency involving protein instability and further
      illustrates the complexity of the genotype-phenotype relationships of this
      disease, in addition to providing further valuable information concerning the
      structure-function relationships of the 3betaHSD superfamily.

PMID- 10599697
TI  - Somatostatin infusion withdrawal: studies in normal children and in children with
      growth hormone deficiency.
AB  - Withdrawal of a somatostatin infusion (SSIW) is followed by a rebound rise of GH
      in both animals and normal adult men, a phenomenon likely mediated by endogenous
      GHRH function. In the present study, we have evaluated the GH response to SSIW in
      a group of 28 prepubertal children (18 boys and 10 girls; aged 3.7-11.1 yr). Six
      children had GH deficiency [GHD; GH responses to pyridostigmine (PD)+GHRH and to
      clonidine <20 and <7 microg/L, respectively], 4 children had GH neurosecretory
      dysfunction (GHND; GH responses to PD+GHRH and to clonidine > or =20 and >7
      microg/L, respectively; mean integrated nighttime GH concentrations <3 microg/L),
      and 18 children were short normal children [normal controls (NC)]. All children
      received a constant infusion of SS at the dose of 3 microg/Kg x h for 90 min.
      SSIW elicited a clear-cut GH rise in NC children (13.7+/-1.0 microg/L), but not
      in GH-deficient children, regardless of the underlying etiology (GHD, 1.6+/-0.4
      microg/L; GHND, 2.4+/-0.3 microg/L). The GH response to SSIW was similar between
      GHD and GHND children. There was no overlapping of the maximum SSIW-stimulated GH
      peaks between NC and GHD or GHND children. In conclusion, we have demonstrated
      that SSIW elicits a significant GH rise in NC children, but not in GH-deficient
      children, regardless of the underlying etiology (GHD or GHND). This resulted in
      complete discrimination of NC from GHD or GHND children. Were these present
      findings confirmed on a larger number of children, SSIW, because of its testing
      efficaciousness and safety, procedural simplicity, and economy holds promise of
      being a useful diagnostic tool for GH-dependent growth disorders.

PMID- 10599698
TI  - Adrenal hyperandrogenism in children.

PMID- 10599699
TI  - Growth hormone receptor deficiency in Ecuador.

PMID- 10599700
TI  - Profile of the pediatric endocrine clinic at New York-Presbyterian Hospital, New
      York Weill Cornell Center.

PMID- 10599701
TI  - A new "new" syndrome in the new world: is multiple postreceptor steroid hormone
      resistance due to a coregulator defect?

PMID- 10599702
TI  - Resistance to several steroids in two sisters.
AB  - A 14-yr-old native American girl from the Iroquois Nation was referred as a
      potential patient with the syndrome of apparent mineralocorticoid excess.
      Instead, her evaluation revealed resistance to glucocorticoids,
      mineralocorticoids, and androgens, but no resistance to vitamin D or thyroid
      hormones. She lacked Cushingoid features despite significantly high cortisol
      levels. Menstruation was regular, and there was no clinical evidence of
      masculinization despite high serum androgen levels in the male range. The
      patient's sister had similar clinical features. Partial resistance to exogenous
      glucocorticoid and mineralocorticoid administration was well demonstrated in both
      patients. It is proposed that these patients represent the first cases of partial
      resistance to multiple steroids, possibly due to a coactivator defect.

PMID- 10599703
TI  - Perplexing polymorphisms: D(i)ps, Sn(i)ps, and trips.

PMID- 10599704
TI  - Sibling pair linkage and association studies between bone mineral density and the
      insulin-like growth factor I gene locus.
AB  - A major determinant of the risk for osteoporosis in later life is bone mineral
      density (BMD) attained during early adulthood. BMD is a complex trait that
      presumably is influenced by multiple genes. Insulin-like growth factor I (IGF-I)
      is an attractive candidate gene for osteoporosis susceptibility, because IGF-I
      has marked effects on bone cells and has been implicated in the pathogenesis of
      osteoporosis. The IGF-I gene contains a microsatellite repeat polymorphism
      approximately 1 kb upstream from the IGF-I gene transcription start site, and
      previous investigators have found a higher prevalence of the 192/192 genotype of
      this polymorphism among men with idiopathic osteoporosis compared to controls. In
      this study we used this IGF-I polymorphism to test for an association between
      this polymorphism and BMD in our large population of premenopausal women (1
      sister randomly chosen from 292 Caucasian and 71 African-American families). We
      also used this polymorphism to detect linkage to BMD elsewhere in the IGF-I gene
      or in a nearby gene using sibling pair linkage analysis in healthy premenopausal
      sister pairs (542 sibling pairs: 418 Caucasian and 124 African-American). Neither
      test provided any evidence of linkage or association between the IGF-I gene locus
      and spine or femoral neck BMD in Caucasians or African-Americans.

PMID- 10599705
TI  - Diagnosis of hidden central hypothyroidism in survivors of childhood cancer.
AB  - To determine how often central hypothyroidism remains undetected by routine out
      patient tests of thyroid hormone, we studied 208 pediatric cancer survivors
      referred for evaluation because of signs of subtle hypothyroidism or
      hypopituitarism. Of the 208 (68 females and 140 males), 110 had brain tumors, 14
      had other head/neck tumors, 11 had solid tumors remote from head and neck, and 73
      had leukemia. Patients were evaluated 1-16 yr (mean, 6.1+/-4.1 yr) after tumor
      diagnosis. The nocturnal TSH surge and response to TRH were measured. Of 160
      patients with free T4 in lowest third of normal, 34% had central hypothyroidism
      (blunted TSH surge or low/delayed TSH peak or delayed TSH decline after TRH); 9%
      had central hypothyroidism with mild TSH elevation (mixed hypothyroidism).
      Another 16% had mild primary hypothyroidism (TSH, 5-15 mU/L). Of 48 with free T4
      in the upper two thirds of normal, 14% had central hypothyroidism; 17% had mild
      primary hypothyroidism. Incidence of central, mixed, and mild primary
      hypothyroidism 10 yr after tumor diagnosis was significantly related to total
      cranial radiation dose (P < 0.0001). Of 62 patients with central hypothyroidism,
      34% had not developed GH deficiency. TSH surge identified 71%, and response to
      TRH identified 60% of those with central hypothyroidism. More than half of the
      slowly growing patients who have received cranial or craniospinal radiation for
      childhood cancer develop subtle hypothyroidism. In our study group, 92% of
      patients with central hypothyroidism and 27% with mixed hypothyroidism would have
      remained undiagnosed using baseline thyroid function tests alone. Both TSH surge
      and response to TRH must be evaluated to identify all of these patients.

PMID- 10599706
TI  - Is obesity an outcome of gonadotropin-releasing hormone agonist administration?
      Analysis of growth and body composition in 110 patients with central precocious
      puberty.
AB  - Concern has been raised that children with central precocious puberty (CPP) are
      prone to the development of obesity. Here we report longitudinal height, weight,
      and body mass index (BMI) data from 96 girls and 14 boys with CPP before, during,
      and after GnRH agonist (GnRHa) administration. Skinfold thickness (n = 46) and
      percent body fat by dual energy x-ray absorptiometry (n = 21) were determined in
      subsets for more accurate assessment of body composition and to validate the use
      of the BMI SD score as an index of body fatness in our subjects. Before the
      initiation of therapy (PRE), the girls with CPP had a mean BMI SD score for
      chronological age (CA) of 1.1+/-0.1 and for bone age (BA) of 0.1+/-0.1. By the
      end of the study, 12-24 months after the discontinuation of GnRHa, the mean BMI
      SD score was 0.9+/-0.1 for CA and 0.6+/-0.1 for BA. At the visit when GnRHa was
      discontinued, 41% and 22% of the girls had a BMI SD score for CA more than the
      85th and 95th percentiles, respectively, indicating that obesity was present at a
      high rate among our subjects; the BMI SD score for CA at the PRE visit was its
      strongest predictor. Indeed, 86% of the girls with BMI SD score for CA above the
      85th percentile when GnRHa was discontinued also had BMI SD score for CA above
      the 85th percentile at the PRE visit. The proportion of boys with elevated BMI SD
      score for CA was also high. Fifty-four percent and 31% of the SD scores were
      greater than the 85th and 95th percentiles after 36 months of GnRHa therapy; the
      BMI SD score for CA PRE had been above the 85th percentile in 71% of these
      overweight subjects. Obesity occurs at a high rate among children with CPP, but
      does not appear to be related to long term pituitary-gonadal suppression induced
      by GnRHa administration. Children with CPP should have a baseline BMI SD score
      calculated, and those at risk for obesity should be counseled appropriately.

PMID- 10599707
TI  - The effects of anorexia nervosa on bone metabolism in female adolescents.
AB  - Osteopenia is a frequent, often persistent, complication of anorexia nervosa (AN)
      in adolescent girls and occurs during a critical time in bone development. Little
      is known about bone metabolism in this patient population. Therefore, we measured
      bone density (BMD) and body composition by dual energy x-ray absorptiometry,
      nutritional status, bone turnover, calcium, and hormonal status in 19 adolescent
      girls with AN (mean +/- SEM, 16.0+/-0.4 yr) and 19 bone age-matched controls. The
      mean duration of AN was 19+/-5 months. Spinal (L1-L4) osteopenia was common in
      AN. Lumbar anterioposterior BMD was more than 1 SD below the mean in 42% of
      patients, and lateral spine BMD was more than 1 SD below in 63% of patients
      compared with controls. Lean body mass significantly predicted lumbar bone
      mineral content (r = 0.75; P < 0.0001) in controls only. In AN, duration of
      illness was the most significant predictor of spinal BMD (lumbar: r = -0.44; P =
      0.06; lateral: r = -0.59; P = 0.008). AN adolescents with mature BA (15 yr and
      greater) were hypogonadal [estradiol, 16.2+/-1.9 vs. 23.3+/-1.6 pg/mL (P = 0.01);
      free testosterone, 0.70+/-0.17 vs. 1.36+/-0.14 pg/mL (P = 0.01)] although
      dehydroepiandrosterone sulfate and urinary free cortisol levels did not differ.
      Leptin levels were reduced in AN (2.9+/-2.1 vs. 16.5+/-1.8 ng/mL; P < 0.0001).
      Insulin-like growth factor I (IGF-I) was reduced in AN to 50% of control levels
      (219+/-41 vs. 511+/-35 ng/mL; P < 0.0001) and correlated with all measures of
      nutritional status, particularly leptin (r = 0.80; P < 0.0001). Surrogate markers
      of bone formation, serum osteocalcin (OC) and bone-specific alkaline phosphatase
      (BSAP), were significantly (P = 0.02) reduced in AN vs. controls (OC, 39.1+/-6.4
      vs. 59.2+/-5.2 ng/mL; BSAP, 27.9+/-4.0 vs. 40.6+/-3.4 U/L). The majority of the
      variation in bone formation in AN was due to IGF-I levels (OC: r2 = 0.72; P =
      0.002; BSAP: r2 = 0.53; P = 0.01) in stepwise regression analyses. Bone
      resorption was comparable in patients and controls. These data demonstrate that
      bone formation is reduced and uncoupled to bone resorption in mature adolescents
      with AN in association with low bone density. Lean body mass was a significant
      predictor of BMD in controls, but not AN patients. The major correlate of bone
      formation in AN was the nutritionally dependent bone trophic factor, IGF-I.
      Reduced IGF-I during the critical period of bone mineral accumulation may be an
      important factor in the development of osteopenia in adolescents with AN.

PMID- 10599708
TI  - Mutational analysis of DAX1 in patients with hypogonadotropic hypogonadism or
      pubertal delay.
AB  - Although delayed puberty is relatively common and often familial, its molecular
      and pathophysiologic basis is poorly understood. In contrast, the molecular
      mechanisms underlying some forms of hypogonadotropic hypogonadism (HH) are
      clearer, following the description of mutations in the genes KAL, GNRHR, and
      PROP1. Mutations in another gene, DAX1 (AHC), cause X-linked adrenal hypoplasia
      congenita and HH. Affected boys usually present with primary adrenal failure in
      infancy or childhood and HH at the expected time of puberty. DAX1 mutations have
      also been reported to occur with a wider spectrum of clinical presentations.
      These cases include female carriers of DAX1 mutations with marked pubertal delay
      and a male with incomplete HH and mild adrenal insufficiency in adulthood. Given
      this emerging phenotypic spectrum of clinical presentation in men and women with
      DAX1 mutations, we hypothesized that DAX1 might be a candidate gene for mutation
      in patients with idiopathic sporadic or familial HH or constitutional delay of
      puberty. Direct sequencing of DAX1 was performed in 106 patients, including 85
      (80 men and 5 women) with sporadic HH or constitutional delay of puberty and
      patients from 21 kindreds with familial forms of these disorders. No DAX1
      mutations were found in these groups of patients, although silent single
      nucleotide polymorphisms were identified (T114C, G498A). This study suggests that
      mutations in DAX1 are unlikely to be a common cause of HH or pubertal delay in
      the absence of a concomitant history of adrenal insufficiency.

PMID- 10599709
TI  - X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic
      spectrum in males and females.
AB  - X-linked adrenal hypoplasia congenita (AHC) is a disorder associated with primary
      adrenal insufficiency and hypogonadotropic hypogonadism (HH). The gene
      responsible for X-linked AHC, DAX1, encodes a member of the nuclear hormone
      receptor superfamily. We studied an extended kindred with AHC and HH in which two
      males (the proband and his nephew) were affected with a nucleotide deletion
      (501delA). The proband's mother, sister, and niece were heterozygous for this
      frameshift mutation. At age 27 yr, after 7 yr of low dose hCG therapy, the
      proband underwent a testicular biopsy revealing rare spermatogonia and Leydig
      cell hyperplasia. Despite steadily progressive doses of hCG and Pergonal
      administered over a 3-yr period, the proband remained azoospermic. The proband's
      mother, sister (obligate carrier), and niece all had a history of delayed
      puberty, with menarche occurring at ages 17-18 yr. Baseline patterns of pulsatile
      gonadotropin secretion and gonadotropin responsiveness to exogenous pulsatile
      GnRH were examined in the affected males. LH, FSH, and free alpha-subunit were
      determined during 12.5-24 h of frequent blood sampling (every 10 min). Both
      patients then received pulsatile GnRH (25 ng/kg) sc every 2 h for 6-7 days.
      Gonadotropin responses to a single GnRH pulse iv were monitored daily to assess
      the pituitary responsiveness to exogenous GnRH. In the proband, FSH and LH levels
      demonstrated a subtle, but significant, response to GnRH over the week of
      pulsatile GnRH therapy. Free alpha-subunit levels demonstrated an erratic pattern
      of secretion at baseline and no significant response to pulsatile GnRH. We
      conclude that 1) affected males with AHC/HH may have an intrinsic defect in
      spermatogenesis that is not responsive to gonadotropin therapy; 2) female
      carriers of DAX1 mutations may express the phenotype of delayed puberty; and 3)
      although affected individuals display minimal responses to pulsatile GnRH, as
      observed in other AHC kindreds, subtle differences in gonadotropin patterns may
      nevertheless exist between affected individuals within a kindred.

PMID- 10599710
TI  - Final height of patients with Turner's syndrome treated with growth hormone (GH):
      indications for GH therapy alone at high doses and late estrogen therapy. Italian
      Study Group for Turner Syndrome.
AB  - We report final height data of patients with Turner's syndrome collected by the
      Italian Study Group for Turner's Syndrome. One hundred and thirty-five patients
      reached their final height during GH therapy with different therapeutic regimens
      (dose and combination). They were divided into 3 groups: group A, 74 patients
      with high doses of GH (1 IU/kg/week) for at least 2 yr; group A1, GH alone and
      estrogen therapy added not before 14 yr of chronological age (47 patients, of
      whom 30 were treated for >4 yr and 10 for >6 yr); group A2, GH plus ethinyl
      estradiol (17 patients) or GH plus oxandrolone (10 patients); group B, 51
      patients with low doses of GH (0.5 IU/kg-week) and high doses of GH for less than
      2 yr; and group C, 10 patients with high doses of GH with spontaneous menarche.
      In contrast to the patients of groups B and C, the patients of group A showed a
      significantly higher final height (mean, 147.5+/-6.5 cm) than their projected
      height (mean, 142.9+/-6.4 cm). They showed also a significantly higher final
      height compared to the subjects of groups B (mean, 145.6+/-5.7 cm) and C (mean,
      143.0+/-5.3). Among the patients of group A, the best results were obtained in
      the patients of group A1 treated with GH alone at high doses and for a longer
      period (4 yr, 149.3+/-6.4 cm; 6 yr, 153.8+/-4.0 cm). Karyotype, GH secretion, and
      birth weight did not influence the efficacy of GH therapy. A low target height
      and a high prevalence of a spontaneous ovarian activity or menarche may
      negatively influence the effect of GH therapy. Estrogens did not improve final
      height when added to GH therapy. The use of small doses of oxandrolone was not
      effective in our experience. GH therapy provides a satisfactory auxological
      result, especially with high doses of GH alone, given for a long period of time.
      Optimization of the treatment would seem to require the identification of the
      ideal age for starting therapy, and this is only possible with a specially
      designed multicenter study.

PMID- 10599711
TI  - Discontinuation of growth hormone (GH) treatment: metabolic effects in GH
      deficient and GH-sufficient adolescent patients compared with control subjects.
      Swedish Study Group for Growth Hormone Treatment in Children.
AB  - The need for continuing GH replacement in patients with childhood-onset GH
      deficiency continuing into adulthood has been recognized. The metabolic
      consequences of discontinuing GH in adolescent patients with childhood-onset GH
      deficiency and short stature were examined over a period of 2 yr. Forty
      adolescents (aged 16-21 yr) receiving GH treatment for more than 3 yr and 16
      closely matched healthy controls were studied. After a baseline visit, GH
      treatment was discontinued. The patients were then examined with the same
      protocol once a year for 2 yr. Twenty-one patients had severe GH deficiency (GHD)
      into adulthood, whereas 19 patients were regarded as having sufficient endogenous
      GH secretion (GHS). After 2 yr without GH treatment, the serum insulin-like
      growth factor I level was lower in GHD than in both GHS and control subjects.
      Both before and 2 yr after GH treatment was discontinued, serum concentrations of
      total cholesterol (C), low density lipoprotein C, and apolipoprotein B were
      higher in the GHD than in both GHS and control subjects. Serum concentrations of
      high density lipoprotein C decreased in the GHD group and increased in the other
      2 study groups. The amount of total body and abdominal fat mass throughout the
      study and the increment in these masses were more marked in the GHD than in the
      GHS and control subjects when GH treatment was discontinued. The discontinuation
      of GH therapy in adolescents with severe GHD continuing into adulthood results
      over a period of 2 yr in the accumulation of important cardiovascular risk
      factors that are associated with GHD in adults.

PMID- 10599712
TI  - Growth and pubertal development in elite female rhythmic gymnasts.
AB  - Optimal growth depends upon both environmental and genetic factors. Among
      environmental factors that could alter growth and sexual maturation are stress
      and intensive physical training. The influence of these factors has been
      documented in a variety of sports, but there is limited information on rhythmic
      gymnasts, who have entirely different training and performance requirements. The
      study was conducted during the 13th European Championships in Patras, Greece, and
      included 255 female rhythmic gymnasts, aged 11-23 yr. The study included
      measurement of height and weight, assessment of breast and pubic hair
      development, estimation of body fat and skeletal maturation, and registration of
      menarcheal age and parental height. Gymnasts were taller than average height for
      age, with mean height above and mean weight below the 50th percentile. Actual
      height SD score was positively correlated to weight SD score (P < 0.001), number
      of competitions (P = 0.01), and body mass index (BMI; P < 0.001). Predicted adult
      height SD score was positively correlated to weight SD score (P < 0.001) and
      negatively to body fat (P = 0.004). There was a delay in skeletal maturation of
      1.3 yr (P < 0.001). Pubertal development was following bone age rather than
      chronological age. The mean age of menarche was significantly delayed from that
      of their mothers and sisters (P = 0.008 and P = 0.05, respectively), was
      positively correlated to the intensity of training and to the difference between
      chronological age and bone age (P < 0.001 and P = 0.002, respectively), and was
      negatively correlated to body fat (P < 0.001). In the elite female rhythmic
      gymnasts, psychological and somatic efforts have profound effects on growth and
      sexual development. Despite these aberrations, adult height is not expected to be
      affected.

PMID- 10599713
TI  - Effects of postnatal estradiol and progesterone replacement in extremely preterm
      infants.
AB  - The fetus is supplied from the placenta with estradiol (E2) and progesterone (P)
      in increasing amounts during gestation. After delivery of a premature infant,
      placental supply is disrupted, resulting in a rapid decrease in E2 and P.
      Replacement of these placental hormones may restore intrauterine conditions and
      may be beneficial for bone mineral accretion, clinical course, and outcome.
      Thirty female infants with a median gestational age of 26.6 weeks (between 24.1
      28.7) and a birth weight of 675 g (370-990) were randomized to receive E2 and P
      replacement, aiming to maintain plasma levels equaling the intrauterine levels,
      or no replacement. The E2 and P replacement was started iv and was followed by
      transepidermal administration for a total duration of 6 weeks. Repeated
      measurements included plasma levels of E2, P, FSH, and LH; uterine volume;
      calcium and phosphorus in spot urine specimens; and bone mineral accretion by
      single photon absorption densitometry. Further, the incidence of chronic lung
      disease and various clinical outcome data were recorded. The plasma levels of E2
      and P were within the intrauterine range with median replacements of 2.30 mg/kg x
      day E2 (1.13-6.23) and 21.20 mg/kg x day P (11.23-27.36), iv. Three- and 6-fold
      higher doses of E2 and P were needed via the transepidermal route. The uterine
      volumes increased, and FSH and LH as indicators for biological effectiveness were
      significantly lowered with replacement. The bone mineral accretion rates tended
      to be higher, and the incidence of chronic lung disease tended to be lower (0%
      vs. 29%; P = 0.097). E2 and P replacement via iv and transepidermal routes is
      capable of maintaining plasma levels as high as those in utero with biological
      effectiveness. Trends toward improved postnatal bone mineral accretion and less
      chronic lung disease were found with the hormone replacement. Further and more
      extensive studies are warranted to address the role of this new approach in the
      care of extremely premature infants.

PMID- 10599714
TI  - A single sample subcutaneous luteinizing hormone (LH)-releasing hormone (LHRH)
      stimulation test for monitoring LH suppression in children with central
      precocious puberty receiving LHRH agonists.
AB  - The effectiveness of LHRH agonist therapy in central precocious puberty depends
      upon suppression of LH secretion. The iv LHRH stimulation test is the gold
      standard for evaluating LH suppression, but is difficult to administer because it
      requires an iv line and multiple blood samples. We hypothesized that a sc LHRH
      test followed by a single LH measurement 40 min later would be as accurate in the
      assessment of LH suppression in children receiving LHRH analogs. Eleven children
      received the sc test 1 month before or after their regularly scheduled iv LHRH
      treatment. Each child was receiving Lupron to suppress central puberty. Twenty
      five comparisons of the iv and sc LHRH tests were completed over 14 months. We
      developed a clinical score for pubertal suppression using Tanner staging,
      skeletal maturation, and growth velocity. The best correlation between this
      clinical score and the iv LHRH test was achieved when biochemical suppression was
      defined as peak LH less than 2 IU/L (100% sensitivity, 95% specificity). Using
      this definition, the sc LHRH test was 96% accurate (in 24 of 25 subjects), with a
      sensitivity of 75% and a specificity of 100% compared to the iv LHRH test. We
      conclude that the single sample sc LHRH test can accurately determine LH
      suppression and adequacy of LHRH agonist therapy in central precocious puberty.

PMID- 10599715
TI  - Vitamin D supplementation during infancy is associated with higher bone mineral
      mass in prepubertal girls.
AB  - The objective of this study was to determine whether vitamin D supplementation of
      breast-fed infants during the first year of life is associated with greater bone
      mineral content and/or areal bone mineral density (aBMD) in later childhood. The
      design was a retrospective cohort study. One hundred and six healthy prepubertal
      Caucasian girls (median age, 8 yr; range, 7-9 yr) were classified as vitamin D
      supplemented or unsupplemented during the first year of life on the basis of a
      questionnaire sent to participating families and their pediatricians. Bone area
      (square centimeters) and bone mineral content (grams) were determined by dual
      energy x-ray absorptiometry at six skeletal sites. Vitamin D receptor (VDR) 3'
      gene polymorphisms (BsmI) were also determined. The supplemented (n = 91) and
      unsupplemented (n = 15) groups were similar in terms of season of birth, growth
      in the first year of life, age, anthropometric parameters, and calcium intake at
      time of dual energy x-ray absorptiometry. The supplemented group had higher aBMD
      at the level of radial metaphysis (mean +/- SEM, 0.301+/-0.003 vs. 0.283+/-0.008;
      P = 0.03), femoral neck (0.638+/-0.007 vs. 0.584+/-0.021; P = 0.01), and femoral
      trochanter (0.508+/-0.006 vs. 0.474+/-0.016; P = 0.04). At the lumbar spine level
      aBMD values were similar (0.626+/-0.006 vs. 0.598+/-0.019; P = 0.1). In a
      multiple regression model taking into account the effects of vitamin D
      supplementation, height, and VDR genotype on aBMD (dependent variable), femoral
      neck aBMD remained higher by 0.045 g/cm2 in the supplemented group (P = 0.02).
      Vitamin D supplementation in infancy was found to be associated with increased
      aBMD at specific skeletal sites later in childhood in prepubertal Caucasian
      girls.

PMID- 10599716
TI  - Changes in plasma leptin during the treatment of diabetic ketoacidosis.
AB  - To test the hypothesis that insulin regulates leptin, we measured the plasma
      leptin concentration before and during treatment of diabetic ketoacidosis (DKA),
      a condition characterized by extreme insulin deficiency. The study included 17
      patients with type 1 diabetes (7 males and 10 females), aged 10+/-1 yr (mean +/-
      SE), with a body mass index of 17.6+/-1.9 kg/m2. Patients were treated with
      continuous insulin infusion and fluid and electrolyte replacement. Plasma leptin
      was measured every 6 h in the first 24 h, during which patients received a total
      insulin dose of 0.6-2.0 U/kg. Plasma leptin concentrations were also measured in
      a control group of 29 stable type 1 diabetic children (12 males and 17 females)
      and 25 healthy children (11 males and 14 females), aged 11+/-1 yr, with a body
      mass index of 18.5+/-1.1 kg/m2. Before treatment, plasma leptin concentrations
      were significantly lower in patients with DKA than those in diabetic and healthy
      controls (4.9+/-1.2 vs. 9.0+/-1.8 and 11.2+/-2.1 ng/mL, respectively; P < 0.05).
      In the DKA patients, plasma leptin increased to 6.4+/-1.5, 7.5+/-1.9, 9.1+/-2.7,
      and 8.9+/-2.5 at 6, 12, 18, and 24 h, respectively, after starting treatment (P =
      0.001). Thus, leptin levels increased by 38+/-10% and 92+/-38% within 6 and 24 h
      of starting treatment. There was no difference in the change in plasma leptin by
      24 h between subjects who could eat (n = 7) and those who could not (n = 10). The
      plasma leptin increase was paralleled by a rise in insulin level and a decline in
      glucose and cortisol levels at 6 and 24 h. In conclusion, DKA was associated with
      decreased plasma leptin concentrations. Treatment resulted in a significant
      increase in plasma leptin, which may be due to the effect of insulin on leptin
      production. Our data lend support to the hypothesis that insulin is the link
      between caloric intake and plasma leptin.

PMID- 10599717
TI  - Levothyroxine suppression of thyroglobulin in patients with differentiated
      thyroid carcinoma.
AB  - For patients with differentiated thyroid carcinoma, the appropriate degree of TSH
      suppression by levothyroxine (L-T4) is still unknown. To find the target level of
      TSH suppression, we analyzed the relationship between the degree of TSH
      suppression determined by third generation assay and thyroglobulin (Tg) response
      during the titration of the dosage of L-T4. Ninety-two patients with
      differentiated thyroid carcinoma (19 males and 73 females; age, 40.5+/-13.5, mean
      +/- SD) were included. All of the recruited patients had near-total
      thyroidectomy, 30-150 mCi 131I thyroid ablation, and negative Tg autoantibodies.
      They were classified into 3 groups. Group A was composed of 25 patients with
      local or distant relapse. Group B was composed of 12 patients without clinically
      detectable relapse, but Tg levels either above 2 ng/mL under L-T4 suppression or
      above 3 ng/mL off L-T4 therapy. Group C included 55 patients who had no active
      disease and Tg levels below 2 and 3 ng/mL during and off L-T4 suppression,
      respectively. Serum TSH and Tg were measured simultaneously at the end of 8-12
      weeks of a certain dose of L-T4 therapy during dosage titration and also after
      withdrawal of L-T4 for 4-6 weeks for the total body scan. Wilcoxon signed ranks
      test was used to compare paired samples of Tg, and Spearman rank correlation was
      used to determine the correlation of relative changes in TSH to changes in Tg
      calculated by individual. The results showed that 1) Tg levels were significantly
      higher during the period off L-T4 therapy than on L-T4, therapy in all 3 groups
      (P < 0.01); 2) during L-T4, therapy, within the same treatment course, mean Tg
      levels were higher when TSH levels were normal than when TSH levels were
      suppressed, statistically significant in group A (P = 0.001), nonsignificant in
      group B (P = 0.09), and nonsignificant in group C (P = 0.30); and 3) when TSH was
      suppressed below normal, there was no correlation between the relative changes in
      TSH and Tg by individual in all 3 groups (P > 0.05). The data suggest a
      stratified postoperative thyroid hormone management of patients with
      differentiated thyroid carcinoma. TSH should be lowered to below normal in
      patients with active disease. If patients are clinically disease free with Tg
      levels below 2 ng/mL, TSH can be kept within the normal range. For the most
      controversial group B patients, it is recommended that the TSH be suppressed and
      be closely followed up.

PMID- 10599718
TI  - Prevalence and causes of hypergastrinemia in primary hyperparathyroidism: a
      prospective study.
AB  - Gastrin levels have been reported to be often increased in patients with primary
      hyperparathyroidism (PHPT) considered to be caused by hypercalcemia. To determine
      the prevalence of increased basal gastrin and to investigate its causes, 52
      consecutive patients with PHPT were studied prospectively, undergoing a clinical,
      biochemical, and gastric morphofunctional assessment before any parathyroid
      surgical procedure. This included evaluation of basal and secretin-stimulated
      gastrin, basal and pentagastrin-stimulated gastric acid secretion, upper
      gastrointestinal endoscopy, with histological evaluation for gastritis and
      Helicobacter pylori infection. Twenty of the 52 PHPT patients (38.5%) had
      increased fasting gastrin. Further investigation allowed us to clearly
      demonstrate the causes of hypergastrinemia in 16 of these 20 patients. In 7 of 20
      (35%), hypergastrinemia was caused by gastric fundus atrophy; in 3 patients
      (15%), Zollinger-Ellison syndrome with Multiple Endocrine Neoplasia type I was
      diagnosed; whereas in another 20% of patients, mild hypergastrinemia was ascribed
      to Helicobacter pylori gastritis. Finally, in 2 patients, additional clinical
      history revealed an occasional use of the gastric antisecretory drug omeprazole a
      few days before the serum gastrin determination. This study shows that the
      hypercalcemic status per se is not sufficient to produce an increase in fasting
      gastrin levels. Furthermore, gastric fundus atrophy, and not gastrinoma, is the
      major cause of relevant (>160 pg/mL) hypergastrinemia.

PMID- 10599719
TI  - Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone
      acetate is associated with increased epithelial proliferation in the normal
      postmenopausal breast.
AB  - The relative effects of postmenopausal hormone replacement therapy (HRT) with
      estrogen alone vs. estrogen+progestin on breast cell proliferation and on breast
      cancer risk are controversial. A cross-sectional observational study was carried
      out to examine the proliferative effects of HRT with estrogen or estrogen plus
      the progestin, medroxyprogesterone acetate, in breast tissue of postmenopausal
      women. Benign breast biopsies from 86 postmenopausal women were analyzed with
      antiproliferating cell nuclear antigen (anti-PCNA) and Ki67 antibodies to measure
      relative levels of cell proliferation. Epithelial density and estrogen and
      progesterone receptor status were also determined. The women were categorized
      either as users of: 1) estrogen (E) alone; 2) estrogen+medroxyprogesterone
      acetate (E+P); or 3) no HRT. Compared with no HRT, the breast epithelium of women
      who had received either E+P or E alone had significantly higher PCNA
      proliferation indices, and treatment with E+P had a significantly higher index
      (PCNA and Ki67) than treatment with E alone. Breast epithelial density was
      significantly greater in postmenopausal women treated with E and E+P, compared
      with no HRT. Thus, the present study shows that postmenopausal HRT with E+P was
      associated with greater breast epithelial cell proliferation and breast
      epithelial cell density than E alone or no HRT. Furthermore, with E+P, breast
      proliferation was localized to the terminal duct-lobular unit of the breast,
      which is the site of development of most breast cancers. Further studies are
      needed to assess the possible association between the mitogenic activity of
      progestins and breast cancer risk.

PMID- 10599720
TI  - Changes in thyroid nodule volume caused by fine-needle aspiration: a factor
      complicating the interpretation of the effect of thyrotropin suppression on
      nodule size.
AB  - The effectiveness of TSH suppression therapy for thyroid nodules remains
      controversial. Prior studies have assumed that the fine-needle aspiration biopsy
      (FNAB), used to confirm a benign condition before the establishment of control
      and treatment groups, has no effect on nodule volume. Seventeen untreated
      euthyroid patients with clinical solitary thyroid nodules that were solid (on
      high-resolution ultrasound) and a colloid goiter (on cytologic examination) had
      ultrasound measurements of nodule volume before a FNAB, immediately thereafter,
      and 1 month and 6 months later. Size differences and individual variability at
      each time period were analyzed. No significant difference in mean thyroid nodule
      volume was present at any point after the FNAB; however, the changes in nodule
      volume were quite marked and bidirectional among patients masking the cumulative
      effect. The variability of the change in individual nodule volume was
      statistically significant when comparisons were made across time (P = 0.0032).
      FNAB of thyroid nodules results in significant individual changes in volume after
      the procedure. Studies, such as the effect of TSH suppression on thyroid nodule
      volume, that incorporate the FNAB in both control and treatment arms of the
      experimental design, need to take these changes into account, less erroneous
      conclusions result.

PMID- 10599721
TI  - Measures of submaximal aerobic performance evaluate and predict functional
      response to growth hormone (GH) treatment in GH-deficient adults.
AB  - The impact of GH on functional performance in GH-deficient adults is not well
      understood. To investigate the effects of GH on skeletal muscle, physical, and
      functional capacity, we randomized 28 GH-deficient adults to receive 3 months of
      recombinant human GH [rhGH: somatotropin, 6.25 microg/kg lean body mass (LBM) for
      1 month, 12.5 microg/kg LBM thereafter] in a double-blind placebo-controlled
      crossover trial. We measured muscle fiber type, size, and insulin-like growth
      factor I messenger RNA, aerobic capacity [maximal oxygen uptake (VO2max),
      ventilation threshold (VeT)], isokinetic strength, oxygen-cost-of-walking at
      normal and fast speeds, and fatigue determined by the profile of mood states
      questionnaire. As expected, GH treatment decreased body fat, increased LBM,
      increased muscle fiber size, and increased muscle insulin-like growth factor-I
      messenger RNA 5-fold; however, muscle strength remained unchanged. At baseline,
      VeT occurred at a high percentage of maximal VO2max (73.3% +/-2.6) because of low
      VO2max (1.74+/-0.1 L/min or 20.7+/-1.3 mL/ kg x min). Walking required high
      oxygen consumptions representing from 83+/-4% of VeT at normal speeds to 120+/-5%
      of VeT at fast speeds. After rhGH, there was a significant (P = 0.03) increase in
      VeT (18%), compared with placebo. This was paralleled by a nonsignificant rise in
      VO2max. Functionally, rhGH treatment decreased the oxygen cost of walking,
      relative to VeT, at normal (14% decrease, P = 0.019) and fast (21% decrease, P =
      0.004) SPW speeds. A 3-variable model (baseline fast SPW speed, VeT/VO2max, and
      VeT) accounted for 39% of the variance of change in self-reported fatigue. These
      data indicate that GH-deficient adults require a high fraction of VeT for daily
      activities, explaining the perception of increased fatigue and impaired physical
      performance. The actions ofrhGH on muscle fiber size translate into physiological
      improvement in submaximal aerobic capacity and result in functional improvement
      in walking ability but do not necessarily alter strength. Thus, measures of
      effort-independent submaximal aerobic performance provide novel objective
      determinants of functional impairment and fatigue and can be used to evaluate and
      predict response to GH treatment.

PMID- 10599722
TI  - Growth retardation in Turner syndrome: aneuploidy, rather than specific gene
      loss, may explain growth failure.
AB  - The etiology of short stature (SST) in Turner syndrome (TS) is still a subject of
      speculation. A variety of hypotheses have been put forward, from SST as a result
      of increased intrauterine tissue pressure after fetal lymphedema to
      haploinsufficiency of a specific growth gene(s). These hypotheses have various
      statistical-auxological implications on the growth distribution in TS. Empirical
      research has provided no clear evidence for any of these theories, but the well
      known correlation between patients' and midparental height (MPH) could be
      established. The influence of undetected mosaic status has often been cited as a
      major problem in the investigation of growth in TS. However, an assessment of
      mosaic status (simultaneous analysis of karyotype and phenotype) and its effect
      on growth with inclusion of MPH has been not yet carried out for a large sample.
      The aim of this study was to evaluate growth and its complex relationship to
      mosaic status and MPH in TS. In a mixed cross-sectional and longitudinal study we
      retrospectively analyzed the auxological and clinical data of 447 patients with a
      pure loss of X-chromosomal material (n = 381 with 45,X0; n = 66 mosaics). The 447
      patients were selected from a series of 609 consecutive patients with TS. To
      assess the effect of mosaic status on growth, we computed a bifactorial analysis
      of variance (phenotype, karyotype), including MPH as a covariate. In line with
      the mosaic hypothesis, we found a correlation between individual loss of X
      chromosomal material and phenotypical expressivity. In contrast, no correlation
      was found with respect to growth. With respect to MPH, we found growth
      retardation (GR) even in those patients with "normal" height above the third
      percentile (-2 or more SD score). The interindividual variance of GR in TS
      (comparable to growth variance in the normal population) seems to be unrelated to
      other TS-specific factors (e.g. mosaic status or single gene loss). Instead, both
      interindividual variance and the global growth shift distribution are best
      explained by the presence of an unspecific aneuploidic effect. Furthermore,
      consideration of patient height in relation to MPH should lead to a better
      understanding of the nature of GR in TS than the commonly used, strictly
      qualitative definition of SST.

PMID- 10599723
TI  - Long-term outcome after depot gonadotropin-releasing hormone agonist treatment of
      central precocious puberty: final height, body proportions, body composition,
      bone mineral density, and reproductive function.
AB  - A considerable number of patients with central precocious puberty (CPP) treated
      with depot GnRH agonists have reached final height (FH). The aim of this
      prospective, multicentric study was the evaluation of the benefits, side-effects,
      and long term outcome of depot GnRH agonist therapy. We investigated 50 young
      women (mean +/- SD age, 16.7+/-2.6 yr; range, 12.9-23.4 yr) at FH. They received
      depot triptorelin over a period of 4.4+/-2.1 yr (range, 1.0-9.7 yr). Target
      height (TH) and predicted adult height (PAH) at the start of treatment were
      163.6+/-6.2 and 154.9+/-9.6 cm, respectively (P < 0.05). FH was 160.6+/-8.0 cm
      (FH vs. TH, P = NS; FH vs. PAH, P < 0.05). Young patients showed the highest
      height gain (FH minus initial PAH). Seventy-eight percent of all patients reached
      a FH within their TH range. Even in young patients and those with an unfavorable
      initial PAH below the TH range, 60% reached a FH within their individual TH
      range. Standardized bone mineral density and standardized bone mineral density SD
      score investigated by dual energy x-ray absorptiometry of the lumbar spine (L1
      L4) were 1040.9+/-124.2 mg/cm2 and 0.0+/-1.0; those of the femoral neck were
      902.2+/-115.4 mg/cm2 and 0.2+/-1.0, respectively. The SD score of the ratio of
      sitting height over lower leg length was normal (0.3+/-1.2). Body mass index SD
      scores at pretreatment, at the end of treatment, and at FH were not significantly
      different (2.0+/-2.0, 2.0+/-2.0, and 1.7+/-2.2, respectively). Menarche or
      remenarche started at age 12.3+/-1.4 yr (range, 9.3-15.8 yr) in all patients. In
      conclusion, long term depot GnRH agonist treatment of CPP girls preserved genetic
      height potential and improved FH significantly combined with normal body
      proportions. No negative effect on bone mineral density and reproductive function
      was seen. Treatment neither caused nor aggravated obesity.

PMID- 10599724
TI  - Degree of fatness after treatment for acute lymphoblastic leukemia in childhood.
AB  - Excessive fatness is considered a frequent late complication of treatment for
      childhood acute lymphoblastic leukemia. Most previous studies, however, were
      based on body mass index (BMI) rather than more direct fat mass measurements. We
      studied 95 survivors of childhood acute lymphoblastic leukemia a median of 11 yr
      (range, 3-23 yr) after diagnosis. BMI values at diagnosis, at cessation of
      therapy, yearly thereafter for up to 10 yr, and at follow-up were compared with
      French reference values. Whole body percent fat was measured at follow-up by dual
      energy x-ray absorptiometry and compared with data from 463 local controls.
      Adjusted for sex and age, the mean BMI increased significantly during therapy and
      remained largely unchanged thereafter. At follow-up, BMI did not differ
      significantly between patients and local controls. On the other hand, the whole
      body percent fat was significantly increased (mean observed/predicted value,
      21.8/19.0%; P < 0.0002). Twenty-five patients (26%) had a percent fat above the
      90th percentile of the reference values, which indicates excessive fatness.
      Adjusted for sex and age, a higher percent fat was related to cranial irradiation
      or GH insufficiency, but not to sex, the cumulative doses of anthracyclines or
      corticosteroids, or the type of corticosteroid used. BMI was a poor measure of
      body fatness.

PMID- 10599725
TI  - Estrogen receptor gene polymorphism, but not estradiol levels, is related to bone
      density in healthy adolescent boys: a cross-sectional and longitudinal study.
AB  - The purpose of the present study was to investigate the influence of estrogen
      receptor alpha gene polymorphism and estradiol on height and bone density during
      and after puberty in males. Using the restriction enzymes XbaI and PvuII, the
      allelic variants XX, Xx, xx, PP, Pp, and pp were identified in 90 Caucasian boys
      16.9+/-0.3 yr of age (mean +/- SD). Bone mineral density (BMD; g/cm2) of the
      total body, head, femoral neck, and lumbar spine was measured using dual-energy x
      ray absorptiometry. Volumetric BMD (vBMD; mg/cm3) was estimated for the spine.
      The XbaI or PvuII genotypes were not related to the levels of estradiol, and the
      levels of estradiol were not related to BMD (P > 0.05). The xx allelic variant
      was associated with a higher spine vBMD than the Xx allelic variant (361 vs. 340
      mg/cm3, P = 0.04). In a multivariate analysis including pubertal development,
      physical activity, and body weight, the XbaI genotype independently predicted
      total body BMD, head BMD, and spine vBMD (P < 0.05). The PvuII genotype
      independently predicted spine vBMD (pp > PP, P = 0.01). The 20 boys with the PP
      allelic variant were found to have a greater body height than the other 70 boys
      (182 cm vs. 179 cm, P = 0.03). At a 2-yr follow-up the XbaI genotype was still
      independently related to total body BMD, head BMD, and spine vBMD. In conclusion,
      estrogen receptor gene polymorphism is related to bone density and height during
      late puberty and at attainment of peak bone density in young men.

PMID- 10599726
TI  - Corticotropin-releasing hormone: a potent androgen secretagogue in girls with
      hyperandrogenism after precocious pubarche.
AB  - CRH is an adrenal androgen secretagogue in men and has been proposed as a
      candidate regulator of adrenarche. CRH also affects androgen production by theca
      cells and may be involved in the pathogenesis of ovarian hyperandrogenism (OH).
      Precocious pubarche (PP) in girls can precede adolescent OH, a condition
      characterized by a high ovarian 17-hydroxyprogesterone (17-OHP) response 24 h
      after GnRH agonist challenge. In adolescent girls with a history of PP, we
      assessed the early androgen response to CRH, as well as the CRH effect on the
      late ovarian response to GnRH agonist. Within a randomized cross-over design,
      saline or CRH (human CRH 1 microg/kg x h in saline) was infused over 3-h (1100
      1400 h) into 12 adolescent girls (age 17+/-2 yr; body mass index 21.4+/-0.9
      Kg/m2) who had been pretreated with dexamethasone (1 mg at 0 h) and GnRH agonist
      (leuprolide acetate 500 microg sc at 0800 h = time 0). All adolescents had
      hirsutism, irregular menses, hyperandrogenemia, and hyperinsulinemia after PP.
      Serum LH, FSH, androstenedione, dehydroepiandrosterone (DHEA), and DHEA-sulfate
      (DHEAS) were measured at time 0, 3, 6, and 24 h, and ACTH and 17-OHP were
      measured at time 0, 6, and 24 h. ACTH concentrations at the end of saline or CRH
      infusions were less than 45 pg/mL; neither saline nor CRH infusions evoked early
      changes in 17-OHP levels. Within 3 h of CRH infusion, DHEAS increased by 46%, on
      average; androstenedione increased 2.5-fold and DHEA increased 5-fold duringCRH
      infusion (all P < 0.0001 compared with saline). There was no detectable CRH
      effect on the responses of LH, FSH, DHEA, DHEAS, 17-OHP, androstenedione,
      testosterone, and estradiol 24 h after GnRH agonist administration; five of 12
      girls had elevated 17-OHP responses suggestive of OH. In conclusion, CRH was
      found to be a potent adrenal androgen secretagogue in adolescent girls with
      hyperandrogenism after PP. In this study, CRH failed to detectably affect the
      ovarian androgen response to gonadotropins.

PMID- 10599727
TI  - Normalization of height in girls with Turner syndrome after long-term growth
      hormone treatment: results of a randomized dose-response trial.
AB  - Short stature and ovarian failure are the main features in Turner syndrome (TS).
      To optimize GH and estrogen treatment, we studied 68 previously untreated girls
      with TS, age 2-11 yr, who were randomly assigned to one of three GH dosage
      groups: group A, 4 IU/m2 day (approximately 0.045 mg/kg x day); group B, first yr
      4, thereafter 6 IU/m2 x day (approximately 0.0675 mg/kg/day); group C, first yr
      4, second yr 6, thereafter 8 IU/m2 x day (approximately 0.090 mg/kg x day). In
      the first 4 yr of GH treatment, no estrogens for pubertal induction were given to
      the girls. Thereafter, girls started with 17beta-estradiol (5 microg/kg bw x day,
      orally) when they had reached the age of 12 yr. Subjects were followed up until
      attainment of adult height or until cessation of treatment because of
      satisfaction with the height achieved. Seven-year data of all girls were
      evaluated to compare the growth-promoting effects of three GH dosages during
      childhood. After 7 yr, 85% of the girls had reached a height within the normal
      range for healthy Dutch girls. The 7-yr increment in height SD-score was
      significantly higher in groups B and C than in group A. In addition, we evaluated
      the data of 32 of the 68 girls who had completed the trial after a mean duration
      of treatment of 7.3 yr (range, 5.0 - 8.75). Mean (SD) height was 158.8 cm (7.1),
      161.0 cm (6.8), and 162.3 cm (6.1) in groups A, B, and C, respectively. The mean
      (SD) difference between predicted adult height before treatment and achieved
      height was 12.5 cm (2.1), 14.5 cm (4.0), and 16.0 cm (4.1) for groups A, B, and
      C, respectively, being significantly different between group A and group C. GH
      treatment was well tolerated in all three GH dosage groups. In conclusion, GH
      treatment starting in relatively young girls with TS results in normalization of
      height during childhood, as well as of adult height, in most of the individuals.
      With this GH and estrogen treatment regimen, most girls with TS can grow and
      develop much more in conformity with their healthy peers.

PMID- 10599728
TI  - Skeletal features and growth patterns in 14 patients with haploinsufficiency of
      SHOX: implications for the development of Turner syndrome.
AB  - We report on clinical features in 14 Japanese patients (4 males and 10 females)
      with partial monosomy of the short arm pseudoautosomal region involving SHOX (n =
      11) or total monosomy of the pseudoautosomal region with no involvement of
      disease genes on the sex-differential regions (n = 3). Skeletal assessment showed
      that three patients had no discernible skeletal abnormalities, one patient
      exhibited short 4th metacarpals and borderline cubitus valgus, and the remaining
      10 patients had Madelung deformity and/or mesomelia characteristic of Leri-Weill
      dyschondrosteosis (LWD), together with short 4th metacarpals and/or cubitus
      valgus. Skeletal lesions were more severe in females and became obvious with age.
      Growth evaluation revealed that patients without LWD grew along by the -2 SD
      growth curve before puberty and showed a normal or exaggerated pubertal growth
      spurt, whereas those with LWD grew along by the standard growth curves before
      puberty but exhibited an attenuated pubertal growth spurt and resultant short
      stature. Maturational assessment indicated a tendency of relatively early
      maturation in patients with LWD. There was no correlation between the clinical
      phenotype and the deletion size. These findings suggest that haploinsufficiency
      of SHOX causes not only short stature but also Turner skeletal anomalies (such as
      short 4th metacarpals, cubitus valgus, and LWD) and that growth pattern is
      primarily dependent on the presence or absence of LWD. Because skeletal lesions
      have occurred in a female-dominant and age-influenced fashion, it is inferred
      that estrogens exert a maturational effect on skeletal tissues that are
      susceptible to premature fusion of growth plates because of haploinsufficiency of
      SHOX, facilitating the development of skeletal lesions.

PMID- 10599729
TI  - Body proportions during long-term growth hormone treatment in girls with Turner
      syndrome participating in a randomized dose-response trial.
AB  - To assess body proportions in girls with Turner syndrome (TS) during long term GH
      treatment, height, sitting height (SH), hand (Hand) and foot (Foot) lengths, and
      biacromial (Biac) and biiliacal (Biil) diameters were measured in 68 girls with
      TS participating in a GH dose-response trial. These previously untreated girls
      with TS, aged 2-11 yr, were randomly assigned to 1 of 3 GH dosage groups: group
      A, 4 IU/m2 x day; group B, first year 4 and thereafter 6 IU/m2 x day; group C,
      first year 4, second year 6, and thereafter 8 IU/m2 x day. Seven-year data were
      evaluated to assess the effect of GH treatment on body proportions during
      childhood. In addition, data from all girls who had reached adult height were
      evaluated to determine the effect on the adult body proportions. All results were
      adjusted for age and sex and expressed as SD scores using reference values of
      healthy Dutch girls. To describe the proportions of SH, Hand, Foot, Biac, and
      Biil to height, these values were adjusted for the SD score of height and were
      expressed as shape values, using the formula, e.g. for SH: shape SH = (SH SD
      score - height SD score)/square root(2 - 2 x correlation coefficient between SH
      and height in the reference population). Furthermore, SD scores using references
      of untreated girls with TS were calculated for height and SH. Values less than -2
      or more than +2 were considered outside the normal range. At baseline, the shape
      values of all measurements were significantly higher than zero, but most mean
      shape values were still within the normal range. Seven-year data of 64 girls and
      adult height data of 32 girls showed that an increase in height was accompanied
      by an even higher increase in Foot, resulting in mean SD scores above zero and
      shape values of +2 and higher. The increase in the shape value of Foot was
      significantly higher in groups B and C compared to that in group A after 7 yr of
      GH treatment, but there were no significant differences between the GH dosage
      groups in the girls who had reached adult height. The shape values of SH had
      decreased to values closer to zero after reaching adult height, especially in
      group A. A similar pattern in the relationship of SH to height was seen using
      references of girls with TS. No significant changes in the other proportions were
      found after reaching adult height. In conclusion, on the average, untreated girls
      with TS have relatively large trunk, hands, and feet, and broad shoulders and
      pelvis compared to height. The increase in height after long term GH treatment is
      accompanied by an even higher increase in Foot and a moderate improvement of the
      disproportion between height and SH. Recently published reference data from
      untreated adults with TS and the results of a different patient group receiving a
      comparable GH dosage suggest that the disproportionate growth of feet has to be
      considered a part of the natural development in TS, but might be influenced by
      higher GH dosages. The development of large feet can play a role in the decision
      of the girl to discontinue GH treatment in the last phase of growth.

PMID- 10599730
TI  - A preponderance of basic luteinizing hormone (LH) isoforms accompanies
      inappropriate hypersecretion of both basal and pulsatile LH in adolescents with
      polycystic ovarian syndrome.
AB  - We recently demonstrated that adolescent girls with polycystic ovarian syndrome
      (PCOS) exhibit augmented LH secretion due to an increase in immunofluorometric
      and deconvolution-estimated LH secretory burst mass and pulse frequency.
      Concurrently, we inferred either a prolongation of apparent (endogenous) LH half
      life or elevated basal (nonpulsatile) LH release in PCOS. The in vivo half-life
      of LH molecules can be affected by the oligosaccharide side-chains, which also
      modify in vitro bioactivity and electrostatic change. Accordingly, as a surrogate
      estimator of altered endogenous LH half-life and/or biopotency in PCOS, we
      characterized the isoelectric properties of secreted LH isoforms and determined
      their in vitro biological activity in adolescent girls with PCOS compared with
      healthy age-matched eumenorrheic controls. To this end, 12-h (overnight) serum
      samples from PCOS patients (n = 12) and normal adolescents (n = 10) were pooled
      by subject. Bioactive LH concentrations were then quantitated in a rat Leydig
      cell in vitro bioassay, and immunological activity was determined by
      immunofluorometry. The distribution of LH isoforms was evaluated by preparative
      chromatofocusing (pH window, 10.5 to <4.0) of samples further combined to yield
      three independent serum pools for each of the patient and control groups. Fasting
      serum concentrations of 17-hydroxyprogesterone (17-OHP), androstenedione,
      testosterone, estrone, estradiol, and sex hormone-binding globulin were
      determined as possible endocrine correlates of LH isotypes. Mean serum
      concentrations of immunoreactive and bioactive LH in adolescents with PCOS were 3
      and 2 times higher than values in controls: immunoreactive: PCOS, 7.8+/-0.9;
      controls: 2.6+/-0.3 IU/L (P < 0.001); and bioactive: PCOS, 52+/-10; controls,
      25+/-4.1 IU/L (P = 0.002), respectively. Bioactive LH concentrations correlated
      positively with 17-OHP (P = 0.022), androstenedione (P = 0.012), and testosterone
      (P = 0.046) concentrations in PCOS. Chromatofocusing of LH isoforms disclosed
      greater LH immunoreactivity at pI values greater than 8 and 7.99-7.0 in
      adolescents with PCOS compared with controls (P = 0.031). The percentage of basic
      LH isoforms was related positively to serum concentrations of 17-OHP (P = 0.032),
      androstenedione (P = 0.046), and testosterone (P = 0.040). In conclusion, the
      present isotype analysis demonstrates elevated in vitro LH bioactivity and a
      preponderance of basic LH isoforms in girls with PCOS. Since previously reported
      heterologous in vivo assays of LH kinetics point toward accelerated removal of
      such alkaline isotypes, our findings would favor the earlier alternative
      hypothesis of inappropriate hypersecretion of basal (interpulse) LH rather than
      prolongation of the LH half-life as the mechanism for elevated interpulse serum
      LH concentrations in adolescents with PCOS. In ensemble, the foregoing data thus
      suggest 3-fold amplification of basal LH secretion as well as both a heightened
      amplitude and frequency of the pulsatile mode of LH release in PCOS.

PMID- 10599731
TI  - Vasopressin and oxytocin neurons of the human supraoptic and paraventricular
      nucleus: size changes in relation to age and sex.
AB  - The hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei consist of
      arginine vasopressin (AVP)- and oxytocin (OT)-synthesizing neurons that send
      projections to the neurohypophysis, whereas the PVN also projects to other brain
      areas. A growing body of evidence in animals suggests the presence of sex
      differences in the vasopressinergic and oxytocinergic systems. The present study
      was aimed at determining whether the sizes of AVP and OT neurons in the human SON
      and PVN show sex differences, as earlier studies demonstrated that a change in
      neuronal size is a sensitive parameter for activity. The minimal and maximal
      diameters were determined to estimate the volumes of cell somata and cell nuclei
      in AVP and OT neurons stained with an antibody against human glycoprotein-(22
      39), a part of the AVP precursor, and a monoclonal anti-OT antibody in 15 men and
      17 women ranging in age from 29-94 yr. The AVP neurons appeared to be larger in
      young men than in young women (< or =50 yr old). In elderly women (>50 yr old)
      AVP cell size considerably exceeded that in young women. In elderly men AVP
      neurons were larger than in young men and elderly women, although these
      differences were not significant. In addition, AVP cell size correlated
      positively with age in women but not in men. No significant differences were
      found in the AVP cell nucleus volumes among all four groups studied. Sex
      differences in the size of the PVN vasopressin neurons were pronounced at the
      left side (P = 0.048) and absent at the right side (P = 0.368), indicating the
      presence of functional lateralization in this nucleus. No difference was found in
      any morphometric parameter of OT neurons in the PVN among the 4 groups studied.
      Thus, our data demonstrate sex differences in the size of the AVP neurons, and
      thus in their function, that are age and probably also side dependent and the
      absence of such changes in OT neurons in the PVN. These data provide a basis for
      the reported higher AVP plasma levels in men compared to women.

PMID- 10599732
TI  - Interleukin-10 modifies the effects of interleukin-1beta and tumor necrosis
      factor-alpha on the activity and expression of prostaglandin H synthase-2 and the
      NAD+-dependent 15-hydroxyprostaglandin dehydrogenase in cultured term human
      villous trophoblast and chorion trophoblast cells.
AB  - The concentrations of tumor necrosis factor-alpha (TNFalpha) and interleukin
      1beta (IL-1beta), two inflammatory cytokines in amniotic fluid, have been shown
      to rise during chorioamnionitis. This is probably related to activation of the
      immune system in order to intensify the inflammatory process and to protect the
      maternal and fetal organism from infectious agents. These cytokines activate the
      PG biosynthetic pathway in several tissues, but few studies have examined effects
      on PG-metabolizing enzymes. When PGs are produced by increased synthesis and/or
      decreased metabolism at the chorio-decidual interface, labor can be induced.
      Interleukin-10 (IL-10) is known to act as an antiinflammatory cytokine. The goals
      of this study were to evaluate the interaction of IL-10 with IL-1beta and
      TNFalpha on PG synthesis and to determine the effects of IL-10, IL-1beta, and
      TNFalpha on PG metabolism using purified cultures of villous trophoblast and
      chorion trophoblast cells prepared from placentas of patients at term. Cells were
      treated with IL-1beta and TNFalpha with or without IL-10 for various times up to
      24 h. Levels of messenger ribonucleic acid (mRNA) encoding PGH synthase-2 (PGHS
      2) and NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) were
      quantified by Northern blotting, and PGE2 and 13,14-dihydro-15-keto-PGF2alpha
      (PGFM) output in the medium was measured by RIA. IL-1beta increased PGHS-2 mRNA
      and PGE2 output from villous and chorion trophoblasts and decreased PGDH mRNA in
      villous trophoblasts (all P < 0.05). These effects were reversed by IL-10. We
      found no change in PGHS-2 mRNA or PGE2 output in either trophoblast type treated
      with TNFalpha, but TNFalpha reduced PGDH mRNA in villous trophoblast, and this
      effect was reversed by IL-10 (both P < 0.05). We conclude that proinflammatory
      cytokines can influence PG output through effects on PG synthesis and metabolism
      and that these effects may be opposed by an antiinflammatory cytokine. These
      interactions may be important in the progression of preterm labor with underlying
      infection and in term labor in regions of the uterus where cytokine production is
      increased.

PMID- 10599733
TI  - Expression of prolactin-releasing peptide and its receptor messenger ribonucleic
      acid in normal human pituitary and pituitary adenomas.
AB  - The recently identified PRL-releasing peptide (PrRP) is the first hypothalamic
      peptide hormone that specifically stimulates PRL production from the pituitary
      gland. Similar to other hypothalamic regulatory hormones, it acts through its
      specific seven-transmembrane domain, G protein-coupled receptor. Using RT-PCR, we
      examined messenger ribonucleic acid (mRNA) expression of PrRP and its receptor in
      normal human pituitary tissue and in pituitary tumors. PrRP mRNA was expressed in
      all five normal pituitary glands examined. In contrast, PrRP mRNA was detected in
      only 5 of 11 of the human prolactinomas. All 5 prolactinomas expressing PrRP were
      responsive to dopamine agonist treatment, whereas PrRP-negative prolactinomas
      were non- or partially responsive. PrRP mRNA was also detected in 6 of 13 GH
      secreting tumors and 5 of 10 clinically nonfunctioning tumors investigated. PrRP
      receptor mRNA was found in all the normal and neoplastic human pituitary samples
      studied. The production of PrRP and its receptor by normal and neoplastic
      pituitary tissue raises the question of whether it may regulate PRL production in
      an autocrine/paracrine manner in pituitary tissue. Further investigation of PrRP
      and its receptor expression and function will be needed to clarify its potential
      role in regulating PRL secretion in normal human lactotrophs and pituitary
      tumors.

PMID- 10599734
TI  - Mapping the major susceptibility loci for familial Graves' and Hashimoto's
      diseases: evidence for genetic heterogeneity and gene interactions.
AB  - The autoimmune thyroid diseases (AITDs), comprising Graves' disease (GD) and
      Hashimoto's thyroiditis (HT), appear to develop as a result of a complex
      interaction between predisposing genes and environmental triggers. The goals of
      the present study were to identify the susceptibility loci for GD and HT and to
      study the relationships between them. We performed a whole genome linkage study
      on a dataset of 56 multiplex, multigenerational AITD families (354 individuals),
      using 387 microsatellite markers. We identified 6 loci that showed evidence for
      linkage to AITD. Only one locus, on chromosome 6 [AITD-1; 80 centimorgans (cM)],
      was linked with both GD and HT [maximum LOD score (MLS), 2.9]. This locus was
      close to, but distinct from, the human leukocyte antigen region. One locus on
      chromosome 13 (HT-1; 96 cM) was linked to HT (MLS, 2.1), and another locus on
      chromosome 12 (HT-2; 97 cM) was linked to HT in a subgroup of the families (MLS,
      3.8). Three loci showed evidence for linkage with GD: GD-1 on chromosome 14 (99
      cM; MLS, 2.5), GD-2 on chromosome 20 (56 cM; MLS, 3.5), and GD-3 on chromosome X
      (114 cM; MLS, 2.5). Since GD-2 showed the strongest evidence for linkage to GD we
      fine-mapped this locus to a 1-cM interval between markers at 55 and 56 cM on
      chromosome 20. These results demonstrated that 1) Graves' and Hashimoto's
      diseases are genetically heterogeneous, with only one locus in common to both
      diseases on chromosome 6; 2) only one HT locus was identified in all families,
      probably due to heterogeneity of the HT phenotype; and 3) three loci were shown
      to induce genetic susceptibility to GD by interacting with each other. One of
      them (GD-2) was fine-mapped to a 1-cM interval.

PMID- 10599735
TI  - Balanced translocation of 10q and13q, including the PTEN gene, in a boy with a
      human chorionic gonadotropin-secreting tumor and the Bannayan-Riley-Ruvalcaba
      syndrome.

PMID- 10599736
TI  - The discovery of growth hormone-releasing hormone.

PMID- 10599737
TI  - Estrogen: consequences and implications of human mutations in synthesis and
      action.
AB  - Recent developments have advanced our knowledge of the role of estrogen in the
      male. Studies of the mutations in CYP19, the gene encoding aromatase, in six
      females and two males and a mutant estrogen receptor alpha in a man are
      described. These observations provide illuminating new insights into the critical
      role of estrogen in the male (as well as female) in the pubertal growth spurt and
      skeletal maturation, and in the importance of estrogen sufficiency in the accrual
      and maintenance of bone mass. The weight of evidence supports an effect of
      androgens on the latter processes, but this effect has not been quantitated.
      There is a discordance in the estrogen-deficient male between skeletal growth and
      skeletal maturation and the accrual of bone mass and density. Estrogen synthesis
      by the testis is limited before puberty, and estrogen deficiency does not affect
      the age of pubertal onset. Estrogen deficiency in men leads to
      hypergonadotropism, macroorchidism, and increased testosterone levels. Estrogen
      lack has a significant effect on carbohydrate and lipid metabolism, and estrogen
      resistance was associated with evidence of premature coronary atherosclerosis in
      a man. These observations have highlighted the role of extraglandular estrogen
      synthesis and intracrine and paracrine actions. In the human, in contrast to
      nonprimate vertebrates, aromatase deficiency and estrogen resistance (alpha) does
      not seem to affect gender identity or psychosexual development. The clinical
      repercussions of mutations in CYP19 on the fetal-placental unit have highlighted
      the major role of placental aromatase in the protection of the female fetus from
      androgen excess, thus preventing androgen-induced pseudohermaphrodism and
      virilization of the mother. These features are compared with the virilization
      that occurs in utero in the female spotted hyena. The novel features of the
      aromatase deficiency syndrome in the affected female--in the fetus, during
      childhood, and at puberty--are discussed, including virilization at puberty and
      development of polycystic ovaries. The severity of the syndrome correlates with
      the severity of impairment of aromatase formation in expression systems. Finally,
      the structural consequences of missense mutations in CYP19 are described in
      accordance with a model of the structure of human aromatase.

PMID- 10599738
TI  - Some hypothalamic hamartomas contain transforming growth factor alpha, a puberty
      inducing growth factor, but not luteinizing hormone-releasing hormone neurons.
AB  - Activation of LH-releasing hormone (LHRH) secretion, essential for the initiation
      of puberty, is brought about by the interaction of neurotransmitters and
      astroglia-derived substances. One of these substances, transforming growth factor
      alpha (TGFalpha), has been implicated as a facilitatory component of the glia-to
      neuron signaling process controlling the onset of female puberty in rodents and
      nonhuman primates. Hypothalamic hamartomas (HH) are tumors frequently associated
      with precocious puberty in humans. The detection of LHRH-containing neurons in
      some hamartomas has led to the concept that hamartomas advance puberty because
      they contain an ectopic LHRH pulse generator. Examination of two HH associated
      with female sexual precocity revealed that neither tumor had LHRH neurons, but
      both contained astroglial cells expressing TGFalpha and its receptor. Thus, some
      HH may induce precocious puberty, not by secreting LHRH, but via the production
      of trophic factors--such as TGFalpha--able to activate the normal LHRH neuronal
      network in the patient's hypothalamus.

PMID- 10599739
TI  - Bone mineral acquisition in healthy Asian, Hispanic, black, and Caucasian youth:
      a longitudinal study.
AB  - Ethnic and gender differences in bone mineral acquisition were examined in a
      longitudinal study of 423 healthy Asian, black, Hispanic, and white males and
      females (aged 9-25 yr). Bone mass of the spine, femoral neck, total hip, and
      whole body was measured annually for up to 4 yr by dual energy x-ray
      absorptiometry. Age-adjusted mean bone mineral curves for areal (BMD) and
      volumetric (BMAD) bone mineral density were compared for the 4 ethnic groups.
      Consistent differences in areal and volumetric bone density were observed only
      between black and nonblack subjects. Among females, blacks had greater mean
      levels of BMD and BMAD at all skeletal sites. Differences among Asians,
      Hispanics, and white females were significant for femoral neck BMD, whole body
      BMD, and whole body bone mineral content/height ratio, for which Asians had
      significantly lower values; femoral neck BMAD in Asian and white females was
      lower than that in Hispanics. Like the females, black males had consistently
      greater mean values than nonblacks for all BMD and BMAD measurements. A few
      differences were also observed among nonblack male subjects. Whites had greater
      mean total hip BMD, whole body BMD, and whole body bone mineral content/height
      ratio than Asian and Hispanic males; Hispanics had lower spine BMD than white and
      Asian males. The tempo of gains in BMD varied by gender and skeletal site. In
      females, total hip, spine, and whole body BMD reached a plateau at 14.1, 15.7,
      and 16.4 yr, respectively. For males, gains in BMD leveled off at 15.7 yr for
      total hip and at age 17.6 yr for spine and whole body. Black and Asian females
      and Asian males tended to reach a plateau in BMD earlier than the other ethnic
      groups. The use of gender- and ethnic-specific standards is recommended when
      interpreting pediatric bone densitometry data.

PMID- 10599740
TI  - 17Beta-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic
      variability, population genetics, and worldwide distribution of ancient and de
      novo mutations.
AB  - 17Beta-hydroxysteroid dehydrogenase-3 (17betaHSD3) deficiency is an autosomal
      recessive form of male pseudohermaphroditism caused by mutations in the HSD17B3
      gene. In a nationwide study on male pseudohermaphroditism among all pediatric
      endocrinologists and clinical geneticists in The Netherlands, 18 17betaHSD3
      deficient index cases were identified, 12 of whom initially had received the
      tentative diagnosis androgen insensitivity syndrome (AIS). The phenotypes and
      genotypes of these patients were studied. Endocrine diagnostic methods were
      evaluated in comparison to mutation analysis of the HSD17B3 gene. RT-PCR studies
      were performed on testicular ribonucleic acid of patients homozygous for two
      different splice site mutations. The minimal incidence of 17betaHSD3 deficiency
      in The Netherlands and the corresponding carrier frequency were calculated.
      Haplotype analysis of the chromosomal region of the HSD17B3 gene in Europeans,
      North Americans, Latin Americans, Australians, and Arabs was used to establish
      whether recurrent identical mutations were ancient or had repeatedly occurred de
      novo. In genotypically identical cases, phenotypic variation for external sexual
      development was observed. Gonadotropin-stimulated serum
      testosterone/androstenedione ratios in 17betaHSD3-deficient patients were
      discriminative in all cases and did not overlap with ratios in normal controls or
      with ratios in AIS patients. In all investigated patients both HSD17B3 alleles
      were mutated. The intronic mutations 325 + 4;A-->T and 655-1;G-->A disrupted
      normal splicing, but a small amount of wild-type messenger ribonucleic acid was
      still made in patients homozygous for 655-1;G-->A. The minimal incidence of
      17betaHSD3 deficiency in The Netherlands was shown to be 1: 147,000, with a
      heterozygote frequency of 1:135. At least 4 mutations, 325 + 4;A-->T, N74T, 655
      1;G-->A, and R80Q, found worldwide, appeared to be ancient and originating from
      genetic founders. Their dispersion could be reconstructed through historical
      analysis. The HSD17B3 gene mutations 326-1;G-->C and P282L were de novo
      mutations. 17betaHSD3 deficiency can be reliably diagnosed by endocrine
      evaluation and mutation analysis. Phenotypic variation can occur between families
      with the same homozygous mutations. The incidence of 17betaHSD3 deficiency is
      0.65 times the incidence of AIS, which is thought to be the most frequent known
      cause of male pseudohermaphroditism without dysgenic gonads. A global inventory
      of affected cases demonstrated the ancient origin of at least four mutations. The
      mutational history of this genetic locus offers views into human diversity and
      disease, provided by national and international collaboration.

PMID- 10599741
TI  - Involvement of the angiotensin II type 2 receptor in apoptosis during human fetal
      adrenal gland development.
AB  - The aim of this study was to establish a link between the highly expressed
      angiotensin II (Ang II) type 2 receptor (AT2) in human fetal adrenal cells and
      the proposed apoptotic activity in the center of the gland. There was an
      important increase in apoptotic DNA fragmentation with age in adrenal glands of
      fetuses from 15-20 weeks gestation. Adrenal cells showing the characteristic
      apoptotic internucleosomal DNA fragmentation were localized in the central
      portion of the fetal zone. In cells cultured for 24 h, Ang II, via the AT2
      receptor, induced DNA fragmentation and cleavage of the DNA repair enzyme, poly
      (ADP-ribose) polymerase. Furthermore, characteristic membrane blebbing was
      observed specifically on cells of the fetal zone. Immunofluorescence studies
      demonstrated that stimulation with Ang II or CGP 42112 (an agonist of the AT2
      receptor) strongly modified the actin network, now localized exclusively along
      the plasma membrane, with a predominance of labeling at the base of the bleb
      formation. This rearrangement of actin distribution was different in cells from
      the definitive zone, corroborating the observation that these cells express many
      more Ang II type 1 receptors (AT1) than AT2 receptors. Taken together, our data
      indicate that the AT2 receptor is involved in the apoptotic process observed in
      the human fetal adrenal gland and could participate in the morphological changes
      occurring after birth, leading to involution of the fetal zone.

PMID- 10599742
TI  - Tension pneumocranium, a rare complication of transsphenoidal pituitary surgery:
      Mayo Clinic experience 1976-1998.
AB  - We describe four cases of symptomatic pneumocranium, a rare, potentially life
      threatening complication of transsphenoidal pituitary surgery. Symptomatic
      pneumocranium manifested as impaired mental status, headaches, and grand mal
      seizures, early in the postoperative course after transsphenoidal pituitary
      surgery. Furthermore, a Cushing response, including systemic hypertension and
      bradycardia (secondary to intracranial hypertension) was seen, which has not been
      previously described in association with symptomatic pneumocranium. We describe a
      previously unreported risk factor for tension pneumocranium, untreated
      obstructive sleep apnea. Other factors predisposing to tension pneumocranium in
      our patients included: cerebrospinal fluid leaks, postoperative positive-pressure
      mask ventilation, large pituitary tumors, and intraoperative lumbar drainage
      catheters. Surgical drainage of the pneumocranium and repair of any coexistent
      cerebrospinal fluid leak markedly improved neurologic status. Symptomatic
      pneumocranium occurring early in the postoperative course after transsphenoidal
      pituitary surgery is rare, but prompt recognition and treatment of this condition
      can be life-saving.

PMID- 10599743
TI  - Prevalence of mild apparent mineralocorticoid excess in Mennonites.
AB  - We have studied an unusual patient with mild low-renin hypertension due to a
      homozygous mutation in the HSD11B2 gene (PNAS 95:10200-10205, 1998). The patient
      came from an inbred Mennonite family, and though the mutation identified her as
      an AME patient, she had a normal birth weight and did not demonstrate the typical
      features of AME, such as hypokalemic alkalosis, low birth weight, failure to
      thrive, poor growth, and in many cases nephrocalcinosis. Biochemically, typical
      patients with AME have abnormal cortisol metabolites and an exceedingly
      diminished ability to convert [11-3H]cortisol to cortisone. In this patient with
      mild AME, the conversion of cortisol to cortisone was 58% compared to 0 to 6% in
      typical AME patients, while the normal conversion is 90 to 95%. Molecular
      analysis of the HSD11B2 gene of this patient showed a homozygous mutation in
      codon 227 (P227L). We studied this Mennonite population for the prevalence of the
      P227L mutation. Our hypothesis was that this mild form of AME would be prevalent
      in the somewhat inbred Mennonite population to which the patient belongs. Our
      proposed study was 1) to determine if there are other cases of this mild form of
      AME, and 2) to establish the heterozygote frequency of the mutation in the
      Mennonites. RESULTS: We did not detect any additional cases of mild AME. We
      detected 15 carriers of the P227L mutation out of 445 Mennonites, resulting in a
      heterozygote frequency of 0.03. CONCLUSION: Since this is an inbred population,
      the chance of two heterozygotes marrying would be 0.001, which is 1 in 1000
      people. This population is known to have large families and therefore the
      possibility of having an affected child is high. The population consists of 2000
      members and we have discovered one affected patient. Thus, there might be one
      other patient in this population.

PMID- 10599744
TI  - Exaggerated adrenarche and hyperinsulinism in adolescent girls born small for
      gestational age.
AB  - Serum dehydroepiandrosterone-sulfate (DHEAS) is a classic marker for adrenarche
      and, subsequently, for the individual hormonal milieu. We have tested the
      hypothesis that prenatal growth reduction is followed by exaggerated adrenarche.
      Serum DHEAS, androstenedione and insulin concentrations were determined together
      with fasting glycemia in matched populations of asymptomatic, non-obese, post
      menarcheal girls (mean age 14 yr) who were born either with a strictly
      appropriate weight for gestational age (AGA) or small for gestational age (SGA).
      When compared to AGA girls, the SGA girls had identical glucose levels, higher
      values for insulin and androstenedione (p<0.01), and a two-fold rise of DHEAS
      concentrations (p<0.0001). In conclusion, girls with prenatal growth reduction
      were found to be prone to develop, besides hyperinsulinism, a variant of
      exaggerated adrenarche. It remains to be verified whether the exaggerated
      adrenarche in adolescence is followed by adrenal hyperandrogenism throughout
      adulthood and senescence.

PMID- 10599745
TI  - Evidence that the insulin-like growth factor binding protein-4 protease in human
      ovarian follicular fluid is pregnancy associated plasma protein-A.
AB  - Ovarian insulin-like growth factor binding protein-4 (IGFBP-4) proteolysis is
      involved in the regulation of follicular development, but until now the identity
      of the responsible enzyme was unknown. In this study, we identify the IGFBP4
      protease in human follicular fluid as pregnancy associated plasma protein-A (PAPP
      A) based on distinctive IGFBP-4 cleavage pattern, the same protease inhibitor
      profile, specific inhibition and immunodepletion of IGFBP-4 protease activity
      with PAPP-A polyclonal antibodies, and immunorecognition by PAPP-A monoclonal
      antibodies in ELISA. Furthermore, PAPP-A levels in estrogen-dominant and androgen
      dominant follicular fluids reflect their IGFBP-4 proteolytic activity. PAPP-A was
      also secreted by human granulosa cells, the reputed source of IGFBP-4 protease
      activity in follicular fluid. We have the molecular and biochemical tools to
      begin to delineate the regulation and biological function of PAPP-A in normal and
      dysregulated follicular development and atresia.

PMID- 10599746
TI  - Polycystic ovary syndrome, gestational diabetes, and bulimia nervosa.

PMID- 10599747
TI  - Toward the establishment of a clinical prediction rule for response of
      prolactinomas to cabergoline.

PMID- 10599748
TI  - Toward the establishment of a clinical prediction rule for response of
      prolactinomas to cabergoline.

PMID- 10599749
TI  - Comment on spironolactone, but not flutamide, administration prevents bone loss
      in hyperandrogenic women treated with gonadotropin-releasing hormone agonist.

PMID- 10599750
TI  - DHEA: efficacy supported by testing and model studies.

PMID- 10599751
TI  - The C494F variant in the CYP11B1 gene is a sequence polymorphism in the Spanish
      population.

PMID- 10599752
TI  - Single-strand conformation polymorphism analysis for the detection of mutations
      in the CYP11B1 gene.

PMID- 10599753
TI  - Effect of growth hormone (GH) therapy on endothelial function in GH-deficient
      adults.

PMID- 10599754
TI  - Comment on health issues for women athletes: exercise-induced amenorrhea.

PMID- 10599755
TI  - Multiple prion types in the same brain: is a molecular diagnosis of CJD possible?

PMID- 10599756
TI  - To test or not to test? That is the question.

PMID- 10599757
TI  - Diabetes and dementia: is the brain another site of end-organ damage?

PMID- 10599758
TI  - Evaluation of surgery for Parkinson's disease: a report of the Therapeutics and
      Technology Assessment Subcommittee of the American Academy of Neurology. The Task
      Force on Surgery for Parkinson's Disease.

PMID- 10599759
TI  - Gene therapy using viral vectors for acute neurologic insults.
AB  - Enormous knowledge has emerged concerning the cellular and molecular events
      underlying necrotic neuron death after seizure, hypoxia-ischemia, or
      hypoglycemia. This has allowed the design of rational therapies to protect
      neurons at such times. One of the most exciting arenas of such interventions is
      the use of viral vectors to deliver neuroprotective genes. This review considers
      the progress in this nascent discipline. Neuroprotection has been demonstrated
      against a variety of in vitro and in vivo rodent models of necrotic insults with
      vectors overexpressing genes that target various facets of injury. These have
      included the energetic components, calcium excess, accumulation of reactive
      oxygen species, protein malfolding, inflammation, and triggering of apoptosis
      (i.e., programmed cell death) in a subset of cells. A number of caveats,
      subtleties, and pressing questions concerning this literature then are
      considered. These include whether these gene therapy interventions actually
      prevent, rather than merely delay, neuron death; the extent to which the effects
      of such vectors on neuronal cell biology is actually understood; the potential
      adverse effects of the use of such vectors; and whether sparing a neuron from
      death with one of these interventions spares function as well. Finally, we
      consider the likelihood of such gene therapy becoming relevant to clinical
      neurology in the near future.

PMID- 10599760
TI  - A novel sodium channel mutation in a family with hypokalemic periodic paralysis.
AB  - OBJECTIVE: To identify the cause of hypokalemic periodic paralysis (HOKPP) in a
      family whose disease is not caused by a mutation in the dihydropyridine-sensitive
      (DHP) receptor alpha1-subunit gene (CACNA1S). BACKGROUND: Hypokalemic periodic
      paralysis is primarily caused by mutations within CACNA1S. Genetic heterogeneity
      for HOKPP has been reported, but no other locus has been identified. METHODS:
      Single-stranded conformational polymorphism (SSCP) analysis and PCR direct
      sequencing were used to screen the skeletal muscle alpha1-sodium channel gene
      (SCN4A) for a mutation in our family. RESULTS: SSCP analysis showed an abnormally
      migrating conformer in exon 12. Direct sequencing of the conformer showed a
      guanine to adenine transition at position 2006 in the cDNA sequence; this results
      in an amino acid substitution of a highly conserved arginine (Arg) to histidine
      (His) at position 669. This sequence alteration segregated only with the affected
      members of the kindred and was not found in a panel of 100 DNA samples from
      healthy controls. The amino acid substitution alters the outermost positive
      charge in the membrane spanning segment DII/S4, which is involved in voltage
      sensing. CONCLUSIONS: The first arginine in DII/S4 and in DIV/S4 within the
      skeletal muscle sodium channel and the L-type calcium channel genie CACNA1S
      appear to be critical for normal function. In all four cases, Arg to His
      mutations result in a disease phenotype. The identification of a mutation within
      the skeletal muscle sodium channel resulting in hypokalemic periodic paralysis
      represents a novel finding.

PMID- 10599761
TI  - Diabetes mellitus and the risk of dementia: The Rotterdam Study.
AB  - OBJECTIVE: To determine the influence of type 2 diabetes mellitus on the risk of
      dementia and AD. BACKGROUND: Both dementia and diabetes are frequent disorders in
      elderly people. METHODS: Prospective population-based cohort study among 6,370
      elderly subjects. At baseline study participants were examined for presence of
      diabetes mellitus. Nondemented participants were followed up, on average, for 2.1
      years. Incident dementia was diagnosed using a three-step screening and
      comprehensive diagnostic workup. To complete the follow-up, medical files were
      studied of persons who could not be reexamined. We estimated relative risks with
      proportional hazard regression, adjusting for age, sex, and possible confounders.
      RESULTS: During the follow-up, 126 patients became demented, of whom 89 had AD.
      Diabetes mellitus almost doubled the risk of dementia (relative risk [RR] 1.9
      [1.3 to 2.8]) and AD (RR 1.9 [1.2 to 3.1]). Patients treated with insulin were at
      highest risk of dementia (RR 4.3 [1.7 to 10.5]). CONCLUSION: The diabetes
      attributable risk for dementia of 8.8% suggests that diabetes may have
      contributed to the clinical syndrome in a substantial proportion of all dementia
      patients.

PMID- 10599762
TI  - Rate of memory decline in AD is related to education and occupation: cognitive
      reserve?
AB  - OBJECTIVE: To determine whether the rate of decline in performance on a memory
      test is more rapid in AD patients with higher versus lower educational and
      occupational attainment. BACKGROUND: Epidemiologic and imaging studies have
      suggested that, given comparable clinical severity of dementia, AD pathology is
      more advanced in patients with higher educational and occupational attainment.
      Because educational and occupational attainment should not influence the
      progression of AD pathology, and because severe AD pathology will eventually
      produce a mortality-causing condition, people with higher attainment might
      experience clinical AD for a shorter time and have a more rapid clinical
      progression. METHODS: A total of 177 AD patients were tested yearly for up to
      four study visits with the Selective Reminding Test (a memory test). Analysis of
      prospective change in the total recall score was performed by applying
      generalized estimating equations to regression analyses with repeated measures.
      RESULTS: At the initial visit, scores were comparable in the high- and low
      education and the high- and low-occupation groups. Overall, memory scores
      declined by approximately 1 point yearly (p<0.01). There was a more rapid decline
      in memory scores in patients with higher educational (p<0.057) and higher
      occupational attainment (p<0.02). The authors then stratified patients based on
      their initial memory scores. The more rapid decline in memory scores associated
      with higher educational and occupational attainment was noted only in the group
      with low initial scores (p<0.05 for both). The full group and stratified group
      analyses were also repeated controlling for other potentially relevant variables
      including age, gender, race, ethnicity, and the presence of extrapyramidal signs,
      stroke, or at least one apolipoprotein E-epsilon4 allele. The results remained
      unchanged. CONCLUSIONS: Memory declined more rapidly in AD patients with higher
      educational and occupational attainment. This adds support to the idea that the
      discontinuity between the degree of AD pathology and the observed clinical
      severity of AD is mediated through some form of reserve.

PMID- 10599763
TI  - Cognitive decline in individuals with high blood pressure: a longitudinal study
      in the elderly. EVA Study Group. Epidemiology of Vascular Aging.
AB  - OBJECTIVE: To examine whether baseline high blood pressure and antihypertensive
      treatment predicts cognitive decline in elderly individuals. METHODS: A
      longitudinal population-based study of elderly individuals (n = 1,373) in Nantes
      (western France) was undertaken. Individuals 59 to 71 years of age were selected
      from electoral rolls. High blood pressure at baseline was defined as systolic
      blood pressure > or =160 mm Hg or diastolic blood pressure > or =95 mm Hg.
      Cognitive decline was defined as a drop of 4 points or more on the Mini-Mental
      State Examination between baseline and the 4-year assessment. RESULTS: There is
      an association between high blood pressure at baseline and cognitive decline at
      the 4-year assessment (odds ratio, 2.8; 95% CI, 1.6 to 5.0). In participants with
      high blood pressure, the risk of cognitive decline was 4.3 (95% CI, 2.1 to 8.8)
      in those without antihypertensive therapy and 1.9 (95% CI, 0.8 to 4.4) in those
      being treated. In participants with high blood pressure both at baseline and at
      the 2-year assessment, the risk for untreated participants was 6.0 (95% CI, 2.4
      to 15.0) compared with 1.3 (95% CI, 0.3 to 4.9) in treated participants.
      CONCLUSIONS: High blood pressure was associated with cognitive decline. In
      individuals with high blood pressure, cognitive decline occurred in a relatively
      short time period and the risk was highest in untreated hypertensive patients.

PMID- 10599764
TI  - Marital status and risk of Alzheimer's disease: a French population-based cohort
      study.
AB  - OBJECTIVE: To analyze the relationship between marital status and risk of AD or
      dementia. METHODS: This study was carried out from the Personnes Agees QUID
      (PAQUID) cohort, an epidemiologic study on normal and pathologic aging after age
      65 years. The PAQUID cohort began in 1988. Individuals were followed up at 1, 3,
      and 5 years, with an active detection of dementia. Marital status was divided
      into four categories: widowed, never married, divorced or separated, and the
      reference category, married or cohabitant. The longitudinal relationship between
      marital status and risk of incident AD or dementia was analyzed by a Cox model
      with delayed entry. RESULTS: Among the 3,675 individuals initially not demented,
      2,106 were married or cohabitants, 1,287 were widowers, 179 were never married,
      and 103 were divorced or separated. Among the 2,881 individuals reevaluated at
      least once for the risk of dementia during the 5-year follow-up, 190 incident
      cases of dementia were identified, including 140 with AD. The relative risks
      (RRs) of dementia (RR = 1.91, p = 0.018) and of AD (RR = 2.68, p<0.001) were
      increased for the never-married individuals compared with those who were married
      or cohabitants. This excess of risk was specifically associated with AD.
      Adjustment for other risk factors of dementia (education, wine consumption), or
      for factors reflecting social environment, leisure activities, and depression,
      did not modify the risk of AD for never-married individuals (RR = 2.31, p =
      0.02). CONCLUSIONS: We confirmed an association between marital status and AD,
      with an excess risk observed among never-married individuals. This association
      may provide clues about the pathogenesis of AD.

PMID- 10599765
TI  - Head trauma and risk of dementia and Alzheimer's disease: The Rotterdam Study.
AB  - OBJECTIVE: To investigate the relation between head trauma and incidence of
      dementia in a prospective population-based study. BACKGROUND: Whether head trauma
      increases the risk of dementia and AD remains controversial. It has been
      suggested that the risk might be particularly increased for carriers of the APOE
      epsilon4 allele. METHODS: The study population included 6645 participants of the
      prospective population-based Rotterdam Study, aged 55 years or older, who were
      free of dementia at baseline. Head trauma with loss of consciousness was measured
      at baseline by a self-report to a physician and detailed the number of head
      traumas, time since head trauma, and duration of loss of consciousness. The
      cohort was followed for incident dementia that was diagnosed according to
      international criteria. Logistic regression was used to calculate the risk of
      dementia after adjusting for age, gender, and education. RESULTS: No increased
      risk of dementia or AD was found for persons with a history of head trauma with
      loss of consciousness (relative risk [RR] for dementia = 1.0, 95% CI, 0.5-2.0; RR
      for AD = 0.8, 95% CI, 0.4-1.9). Multiple head traumas, time since head trauma,
      and duration of unconsciousness did not significantly influence the risk of
      dementia. In addition, the APOE-epsilon4 allele did not modify the relationship.
      CONCLUSIONS: This study suggests that mild head trauma is not a major risk factor
      for dementia or AD in the elderly. In addition, this study does not concur with
      previous cross-sectional studies suggesting an interaction with the APOE
      genotype.

PMID- 10599766
TI  - Functional anatomy of neuropsychological deficits after severe traumatic brain
      injury.
AB  - BACKGROUND: Neurobehavioral disorders after severe traumatic brain injury (TBI)
      are poorly correlated with focal lesions detected by structural neuroimaging
      techniques such as CT scan or MRI. OBJECTIVE: To explore the relationships
      between regional cerebral glucose metabolism at rest, as measured by PET, and
      neurobehavioral status after severe TBI at the subacute stage. METHODS: Thirteen
      patients without focal structural lesion on MRI were studied. Neuropsychological
      assessment included tests of memory, attention and speed of information
      processing, and executive functions, and a global neurobehavioral assessment.
      Regional cerebral glucose metabolism at rest was measured with (18F)
      fluorodeoxyglucose and PET. RESULTS: A close link was found between cognitive and
      behavioral disorders and decreased cortical metabolism in prefrontal and
      cingulate cortex. Tests of memory and executive functions significantly
      correlated with regional metabolism in the mesial and lateral prefrontal cortex
      and the cingulate gyrus. Behavioral disorders correlated significantly with
      mesial prefrontal and cingulate metabolisms. CONCLUSION: These results suggest a
      predominant role of prefrontal and cingulate dysfunction in cognitive and
      behavioral disorders of patients with severe traumatic brain injury, even in the
      absence of focal structural lesion of the brain. Further cognitive functional
      activation research using PET or functional MRI might help clarify the relative
      contributions of both areas to dysfunction.

PMID- 10599767
TI  - Dementia as the most common presentation of cortical-basal ganglionic
      degeneration.
AB  - OBJECTIVE: To evaluate the clinical presentations and dominant symptoms of
      patients with postmortem proven cortical-basal ganglionic degeneration (CBGD)
      from one neuropathology center. BACKGROUND: CBGD is a rare but increasingly
      recognized condition with clinical and pathologic features that continue to
      evolve. Attempts have been made to develop clinical criteria to enhance the
      specificity of diagnosis, but it is not clear what proportion of patients
      harboring CBGD disease present in the "classical" fashion versus other
      presentations. Previous large-case series that emphasize a parietal/perceptual
      motor presentation may be biased because the cases mainly originate from movement
      disorder centers. METHODS: Thirteen cases of pathologically confirmed CBGD with
      sufficient clinical data were identified from a single neuropathology center
      between 1981 and 1996. RESULTS: Before death, only 4 of the 13 patients had a
      clinical diagnosis of CBGD, 6 had a clinical diagnosis of Alzheimer's disease
      (AD), 1 had AD and parkinsonism, and 2 had an atypical dementia of the
      frontotemporal type. Nine of 13 cases had early dementia. CONCLUSIONS: Dementia
      was the most common presentation of CBGD in this study. Despite the best efforts
      to define criteria to enhance the specificity of a diagnosis of CBGD, it is
      becoming clear that the clinical syndrome that accompanies this disease is quite
      varied. Unfortunately, patients fulfilling classical diagnostic criteria may
      represent a minority of those with this pathologic diagnosis.

PMID- 10599768
TI  - Validity of clinical criteria for the diagnosis of dementia with Lewy bodies.
AB  - OBJECTIVE: To assess the clinical validity of clinical diagnostic criteria for
      dementia with Lewy bodies (DLB). METHODS: We assessed the sensitivity,
      specificity, and positive and negative predictive values of the clinical criteria
      of the Consortium on dementia with Lewy Bodies (CDLB) in 18 patients with autopsy
      proven DLB and in 76 patients with dementia not associated with Lewy bodies,
      using postmortem diagnosis as a gold standard. RESULTS: CDLB criteria had either
      high sensitivity or high specificity, but no set of criteria simultaneously
      provided both high sensitivity and high specificity. Clinical criteria had higher
      predictive validity in patients with pure DLB than in patients with DLB and AD.
      Seventy-eight percent of patients with pure DLB had two or more major criteria,
      compared with 44% of patients with DLB and AD (p<0.02). If the nine patients with
      DLB and AD were excluded from the DLB group, the CDLB criteria for probable DLB
      had sensitivity of 78% and specificity of 85%. CDLB criteria for probable DLB
      (two or more major criteria) distinguished DLB from AD with a sensitivity of 78%
      and a specificity of 64%. CONCLUSIONS: The proposed CDLB criteria have high
      negative predictive value and thus do well at excluding patients with DLB.
      Positive predictive value of 75% can be achieved by a combination of any three
      major or minor criteria, providing the analysis is confined to patients with mild
      to moderate dementia. Criteria were most accurate if confined to patients with
      pure DLB who had mild to moderate dementia.

PMID- 10599769
TI  - Error behaviors associated with loss of competency in Alzheimer's disease.
AB  - OBJECTIVE: To investigate qualitative behavioral changes associated with
      declining medical decision-making capacity (competency) in patients with AD.
      BACKGROUND: Qualitative measures can yield clinical information about functional
      changes in neurologic disease not available through quantitative measures.
      METHODS: Normal older controls (n = 21) and patients with mild and moderate
      probable AD (n = 72) were compared using a standardized competency measure and
      neuropsychological measures. A system of 16 qualitative error scores representing
      conceptual domains of language, executive dysfunction, affective dysfunction, and
      compensatory responses was used to analyze errors produced on the competency
      measure. Patterns of errors were examined across groups. Relationships between
      error behaviors and competency performance were determined, and neurocognitive
      correlates of specific error behaviors were identified. RESULTS: AD patients
      demonstrated more miscomprehension, factual confusion, intrusions, incoherent
      responses, nonresponsive answers, loss of task, and delegation than controls.
      Errors in the executive domain (loss of task, nonresponsive answer, and loss of
      detachment) were key predictors of declining competency performance by AD
      patients. Neuropsychological analyses in the AD group generally confirmed the
      conceptual domain assignments of the qualitative scores. CONCLUSIONS: Loss of
      task, nonresponsive answers, and loss of detachment were key behavioral changes
      associated with declining competency of AD patients and with neurocognitive
      measures of executive dysfunction. These findings support the growing linkage
      between executive dysfunction and competency loss.

PMID- 10599770
TI  - Gender differences in the incidence of AD and vascular dementia: The EURODEM
      Studies. EURODEM Incidence Research Group.
AB  - OBJECTIVE: To study the difference in risk for dementing diseases between men and
      women. BACKGROUND: Previous studies suggest women have a higher risk for dementia
      than men. However, these studies include small sample sizes, particularly in the
      older age groups, when the incidence of dementia is highest. METHODS: Pooled
      analysis of four population-based prospective cohort studies was performed. The
      sample included persons 65 years and older, 528 incident cases of dementia, and
      28,768 person-years of follow-up. Incident cases were identified in a two-stage
      procedure in which the total cohort was screened for cognitive impairment, and
      screen positives underwent detailed diagnostic assessment. Dementia and main
      subtypes of AD and vascular dementia were diagnosed according to internationally
      accepted guidelines. Sex- and age-specific incidence rates, and relative and
      cumulative risks for total dementia, AD, and vascular dementia were calculated
      using log linear analysis and Poisson regression. RESULTS: There were significant
      gender differences in the incidence of AD after age 85 years. At 90 years of age,
      the rate was 81.7 (95% CI, 63.8 to 104.7) in women and 24.0 (95% CI, 10.3 to
      55.6) in men. There were no gender differences in rates or risk for vascular
      dementia. The cumulative risk for 65-year-old women to develop AD at the age of
      95 years was 0.22 compared with 0.09 for men. The cumulative risk for developing
      vascular dementia at the age of 95 years was similar for men and women (0.04).
      CONCLUSION: Compared with men, women have an increased risk for AD. There are no
      gender differences in risk for vascular dementia.

PMID- 10599771
TI  - The occurrence of depressive symptoms in the preclinical phase of AD: a
      population-based study.
AB  - OBJECTIVE: To examine preclinical depressive symptoms 3 years before the
      diagnosis of AD. METHODS: The authors compared incident AD patients and
      nondemented individuals in terms of baseline mood- and motivation-related
      symptoms of depression, and assessed whether depressive symptoms in preclinical
      AD are related to self-perceived memory problems. Participants came from a
      population-based longitudinal study on aging and dementia in Stockholm, Sweden.
      The sample consisted of 222 persons older than 74 years who were followed for a 3
      year interval. Thirty-four individuals had developed AD at follow-up, whereas 188
      remained nondemented. Dementia diagnosis was made according to the criteria of
      the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised.
      Depressive symptoms were assessed by the Comprehensive Psychopathological Rating
      Scale. RESULTS: The incident AD patients had more depressive symptoms than the
      nondemented persons at baseline. There was a dominance of motivation-related
      symptoms of depression (e.g., lack of interest, loss of energy, concentration
      difficulties) in preclinical AD. This association remained when adjusting for
      subjective memory complaints. CONCLUSIONS: Depressive symptoms are elevated
      preclinically in AD, and this elevation is not merely a by-product of self
      perceived cognitive difficulties. Thus, depressive symptoms may be part of the
      preclinical phase in AD.

PMID- 10599772
TI  - Clinicopathologic correlates in temporal cortex in dementia with Lewy bodies.
AB  - OBJECTIVE: To address the relationship between dementia and neuropathologic
      findings in dementia with Lewy bodies (DLB) in comparison with AD. METHODS: We
      evaluated the clinical presentation of autopsy-confirmed DLB in comparison with
      AD according to new Consortium on DLB criteria and compared the two conditions
      using quantitative neuropathologic techniques. This clinicopathologic series
      included 81 individuals with AD, 20 with DLB (7 "pure" DLB and 13 "DLB/AD"), and
      33 controls. We counted number of LB, neurons, senile plaques (SP), and
      neurofibrillary tangles (NFT) in a high order association cortex, the superior
      temporal sulcus (STS), using stereologic counting techniques. RESULTS: The
      sensitivity and specificity of Consortium on DLB clinical criteria in this series
      for dementia, hallucinations, and parkinsonism are 53% and 83%, respectively, at
      the patient's initial visit and 90% and 68%, respectively, if data from all
      clinic visits are considered. In pathologically confirmed DLB brains, LB
      formation in an association cortical area does not significantly correlate with
      duration of illness, neuronal loss, or concomitant AD-type pathology. Unlike AD,
      there is no significant neuronal loss in the STS of DLB brains unless there is
      concomitant AD pathology (neuritic SP and NFT). CONCLUSIONS: The evaluation of
      new Consortium on DLB criteria in this series highlights their utility and
      applicability in clinicopathologic studies but suggests that sensitivity and
      specificity, especially at the time of the first clinical evaluation, are modest.
      The lack of a relationship of LB formation to the amount of Alzheimer-type
      changes in this series suggests that DLB is a distinct pathology rather than a
      variant of AD.

PMID- 10599773
TI  - Metrifonate treatment of AD: influence of APOE genotype.
AB  - OBJECTIVE: To investigate whether an interaction exists between APOE genotype and
      the response of AD patients to metrifonate treatment and whether APOE genotype
      independently affects the rate of AD progression. BACKGROUND: Metrifonate is a
      new acetylcholinesterase inhibitor for the treatment of AD symptoms. METHODS:
      Data were pooled from four prospective, randomized, double-blind, placebo
      controlled clinical trials and analyzed retrospectively. A total of 959 patients
      who received once-daily placebo (n = 374) or metrifonate (30 to 60 mg based on
      weight or a 50-mg fixed dose, n = 585) for up to 26 weeks agreed to APOE
      genotyping. RESULTS: Metrifonate clearly improved the cognitive performance of
      the AD patients when compared with placebo (Alzheimer's Disease Assessment Scale
      Cognitive Subscale [ADAS-Cog], p = 0.0001). The interaction of APOE genotype and
      the metrifonate effect on cognitive performance were not significant (p = 0.25).
      Metrifonate also clearly improved the global function of the AD patients when
      compared with placebo (Clinician's Interview-Based Impression of Change with
      Caregiver Input [CIBIC-Plus], p = 0.0001). The interaction of APOE genotype with
      the metrifonate effect on global function also was not significant (p = 0.70). No
      significant three-way interactions were observed among APOE genotype, gender, and
      response to metrifonate treatment (ADAS-Cog, p = 0.68; CIBIC-Plus, p = 0.26).
      APOE genotype did not influence disease progression as evaluated by either
      cognitive performance (ADAS-Cog, p = 0.93) or global function (CIBIC-Plus, p =
      0.64). CONCLUSIONS: The findings from these studies of up to 26 weeks' duration
      do not clearly support an interaction between APOE genotype and metrifonate
      treatment effects. They suggest that APOE genotypes do not necessarily predict an
      AD patient's response to metrifonate treatment and that APOE genotype may not
      influence the rate of disease progression for patients with mild to moderate AD.

PMID- 10599775
TI  - Left unilateral neglect or right hyperattention?
AB  - BACKGROUND: Contradictory interpretations of left unilateral neglect suggest that
      it reflects either decreased attention toward the left or increased attention
      toward the right. According to the right-hyperattention postulate, increasing
      severity of neglect should result from an increasingly stronger bias toward the
      right. Thus, response times to right-sided targets should become progressively
      faster as neglect increases in severity across patients. The left-hypoattention
      postulate predicts that as neglect increases, progressively less-attentional
      resources are deployed in both hemispaces. Thus, response times to right targets
      should progressively increase with increasing neglect. METHODS: We analyzed the
      distribution of manual response times to left- and right-sided targets in 24
      patients with right hemisphere lesions and varying degrees of left neglect.
      RESULTS: Not only the responses to left targets but also those to right targets
      became progressively slower as neglect increased, consistent with the
      hypoattention account. However, the two regression lines were not parallel. With
      increasing neglect, responses to left targets increased more steeply than those
      to right targets did. CONCLUSIONS: A rightward attentional bias is present in
      patients with left neglect, together with left hypoattention. However, this
      rightward bias is one of defective, and not enhanced, attention.

PMID- 10599774
TI  - Ipsilesional intentional neglect and the effect of cueing.
AB  - BACKGROUND: Contralesional hemispatial neglect may be induced by an attentional
      deficit where patients are inattentive to or unaware of stimuli in contralesional
      hemispace, an intentional deficit where patients are unable to act in or towards
      contralesional hemispace, or both. The deficits associated with ipsilesional
      neglect have not been as well characterized. Because cueing may be used as a
      rehabilitative assistive device, we wanted to learn whether the efficacy of an
      attentional or intentional cue was related to the type of bias. METHODS: We
      studied a patient with a right frontotemporal stroke who had ipsilesional neglect
      by using a video apparatus that dissociates sensory-attentional and motor
      intentional systems. We also performed a cueing experiment with primarily sensory
      attentional cues (i.e., read the letter at the end of the line) and primarily
      motor-intentional cues (i.e., touch the end of the line). RESULTS AND
      CONCLUSIONS: Ipsilesional neglect was primarily a motor-intentional deficit with
      a motor-action bias to the left and a secondary sensory-attentional bias for
      stimuli to the right. With cueing we found a double dissociation: the rightwards
      motor-intentional cue improved the primary left-sided intentional bias and the
      leftwards sensory-attentional cue improved the secondary right-sided attentional
      bias. Effective rehabilitation strategies need to address both sensory
      attentional and motor-intentional deficits in patients with neglect.

PMID- 10599776
TI  - Cerebral lateralization: relationship of language and ideomotor praxis.
AB  - OBJECTIVE: To determine the relationship of language lateralization and hand
      preference to praxis performance following left and right hemispheric amobarbital
      induced inactivations. BACKGROUND: Patients who are aphasic from left cerebral
      dysfunction also frequently exhibit ideomotor apraxia in which they make
      temporal, spatial, and postural errors of learned skilled movements. However,
      hemispheric lateralization of the systems mediating ideomotor praxis in patients
      with atypical cerebral language dominance (i.e., bilateral or right hemispheric
      language function) remains uncertain. METHODS: Subjects included 90 patients with
      intractable seizures who were undergoing the intracarotid amobarbital procedure
      (IAP) as part of their preoperative evaluation for epilepsy surgery. Hand
      preference was determined by the Benton Handedness Questionnaire. Praxis was
      assessed by the subject's performance when pantomiming the use of four pictured
      tools. RESULTS: During left IAP, patients with typical language dominance made
      more ideomotor apraxic errors than did patients with atypical language dominance.
      During right IAP, patients with atypical language dominance made more ideomotor
      apraxic errors than did patients with typical language dominance. Overall,
      patients with atypical language dominance made fewer ideomotor apraxic errors
      than did patients with typical language dominance. These relationships were
      present irrespective of hand preference. CONCLUSIONS: Language dominance is more
      closely associated with the laterality of temporal and spatial movement
      representations (i.e., ideomotor praxis dominance) than is hand preference.
      Patients with atypical language dominance exhibit more bilateral cerebral
      distribution of both language and praxis function.

PMID- 10599777
TI  - Does HHV-8 have a protective role on the development of HIV encephalopathy?
      Italian HIV-Seroconversion Study.
AB  - OBJECTIVE: To evaluate risk factors for HIV encephalopathy and whether Kaposi's
      sarcoma (KS) and coinfection with human herpesvirus 8 (HHV-8) protect against
      this disease in a cohort of HIV seroconverters. METHODS: Individuals with known
      dates of HIV seroconversion belonging to different HIV exposure categories
      (intravenous drug users, homosexual men, heterosexual contacts) were recruited by
      17 clinical centers throughout Italy. Antibodies to HHV-8 lytic antigens were
      detected in a subgroup of participants using an immunofluorescence assay. Risk
      factors for HIV encephalopathy were evaluated using Cox proportional models. The
      association between KS or HHV-8 infection and HIV encephalopathy was evaluated
      using standard statistical techniques. RESULTS: During the study period, 485 of
      the 1,520 participants developed acquired immunodeficiency syndrome, 38 of whom
      developed HIV encephalopathy. HHV-8 serologic status was determined for 390
      participants. Male gender, injecting drug use, and low CD4 T-cell count were
      associated with HIV encephalopathy; none of the 63 participants with KS developed
      this disease. The risk of HIV encephalopathy did not differ significantly by HHV
      8 serologic status. CONCLUSIONS: HIV encephalopathy was found to be associated
      with male gender and intravenous drug use. The risk increased at lower CD4 T-cell
      counts. Although HIV encephalopathy occurred less frequently in patients with KS,
      no association with HHV-8 infection was found.

PMID- 10599778
TI  - Glucose and [11C]flumazenil positron emission tomography abnormalities of
      thalamic nuclei in temporal lobe epilepsy.
AB  - OBJECTIVES: To analyze interictal patterns of thalamic nuclei glucose metabolism
      and benzodiazepine receptor binding in patients with medically intractable
      temporal lobe epilepsy (TLE) using high-resolution 2-deoxy-2-[18F]fluoro-D
      glucose (FDG) and [11C]flumazenil (FMZ) PET. BACKGROUND: Structural and glucose
      metabolic abnormalities of the thalamus are considered important in the
      pathophysiology of TLE. The differential involvement of various thalamic nuclei
      in humans is not known. METHODS: Twelve patients with TLE underwent volumetric
      MRI, FDG and FMZ PET, and prolonged video-EEG monitoring. Normalized values and
      asymmetries of glucose metabolism and FMZ binding were obtained in three thalamic
      regions (dorsomedial nucleus [DMN], pulvinar, and lateral thalamus [LAT]) defined
      on MRI and copied to coregistered, partial-volume-corrected FDG and FMZ PET
      images. Hippocampal and amygdaloid FMZ binding asymmetries and thalamic volumes
      also were measured. RESULTS: The DMN showed significantly lower glucose
      metabolism and FMZ binding on the side of the epileptic focus. The LAT showed
      bilateral hypermetabolism and increased FMZ binding. There was a significant
      correlation between the FMZ binding asymmetries of the DMN and amygdala. The PET
      abnormalities were associated with a significant volume loss of the thalamus
      ipsilateral to the seizure focus. CONCLUSIONS: Decreased [11C]flumazenil (FMZ)
      binding and glucose metabolism of the dorsomedial nucleus (DMN) are common and
      have strong lateralization value for the seizure focus in human temporal lobe
      epilepsy. Decreased benzodiazepine receptor binding can be due to neuronal loss,
      as suggested by volume loss, but also may indicate impaired gamma-aminobutyric
      acid (GABA)ergic transmission in the DMN, which has strong reciprocal connections
      with other parts of the limbic system. Increased glucose metabolism and FMZ
      binding in the lateral thalamus could represent an upregulation of GABA-mediated
      inhibitory circuits.

PMID- 10599779
TI  - Postictal in situ MRS brain lactate in the rat kindling model.
AB  - OBJECTIVE: To determine the temporal and spatial extent of the lactate (Lact)
      changes as correlated with seizure characteristics and EEG changes in the rat
      kindling model. BACKGROUND: Prior studies using MRS have detected cerebral Lact
      postictally in animal models of seizures and in patients with intractable focal
      epilepsy. METHODS: We performed MRS in sham control rats (n = 4) and in rats
      stimulated in the right hippocampus at two different stages of the kindling and
      at three time points after the seizures: <2 hours (n = 8 and 5, stage 0 and stage
      5), 2 to 3 hours (n = 5 and 6), and >3 hours (n = 4 and 2). Lact/creatine (Cr)
      and N-acetylaspartate (NAA)/Cr ratios were measured in six contiguous voxels
      (three left, three right) covering the hippocampi, anterior and posterior
      regions, and compared with EEG and ictal behavior. Lact/Cr ratios were measured
      at a very low level in the sham control rats and in the >3-hour group. RESULTS:
      In the <2-hour group, Lact/Cr increase was higher in stage-5 rats as compared
      with stage-0 rats (p = 0.001, unpaired t-test) and sham control rats when all the
      voxels were considered. Lact/Cr ratios were higher in the stimulated area as
      compared with all other brain areas in stage-0 rats (p = 0.05, paired t-test) but
      not in the stage-5 rats. Similar results with more inter-animal variability were
      measured in the 2- to 3-hour group. NAA/Cr ratios increased significantly after
      stage-0 kindling in the stimulated hippocampus but not after stage-5 kindling.
      CONCLUSIONS: Postictal Lact increase as assayed by MRS correlates with EEG and
      behavioral seizures and suggests that it would be an additional noninvasive
      technique for seizure localization during the presurgical evaluation of patients
      with intractable focal epilepsy.

PMID- 10599780
TI  - Cognitive correlates of 1H MRSI-detected hippocampal abnormalities in temporal
      lobe epilepsy.
AB  - OBJECTIVES: To examine associations between 1H magnetic resonance spectroscopic
      imaging (1H MRSI)-detected hippocampal creatine to N-acetylaspartate (Cr/NAA)
      ratios and neuropsychological measures sensitive to mesial temporal lobe
      function. BACKGROUND: The measurement of 1H MRSI-detected hippocampal metabolites
      has proved effective in determining extent and lateralization of neuronal damage.
      However, relationships between 1H MRSI-detected hippocampal metabolic
      abnormalities and specific areas of cognitive functioning have received limited
      attention compared to other studies using MRI volumetry or cerebral blood flow
      techniques. METHODS: We analyzed right and left hippocampal Cr/NAA ratios in 46
      adult mesial temporal lobe epilepsy patients (32 left, 14 right) by 1H MRSI at
      high magnetic field (4.1 T). We examined the relationship between the right and
      left Cr/NAA hippocampal ratios to measures of verbal and visual memory,
      intelligence, attention, visuoperception, and confrontation naming. RESULTS:
      Measures of episodic verbal memory (n = 33) and visual confrontation naming (n =
      46) were selectively associated with left hippocampal metabolic function
      (p<0.004), whereas neuronal function of the right hippocampal region was strongly
      associated with performance on a measure of facial recognition (n = 46; p<0.02).
      CONCLUSIONS: This study shows that specific areas of cognitive function are
      related to hippocampal neuronal metabolic abnormalities as detected by
      spectroscopic imaging. The current study indicates that 1H MRSI offers a
      complimentary technique to structural imaging studies in the study of mesial
      temporal lobe epilepsy and may enhance understanding of the role of hippocampal
      function in complex cognitive systems.

PMID- 10599781
TI  - Methodologic issues in assessing risk factors for epilepsy in an epidemiologic
      study in India.
AB  - OBJECTIVES: To test a field questionnaire for epilepsy risk factors in rural
      India. BACKGROUND: Case-control studies are necessary to plan appropriate
      prevention and intervention strategies against epilepsy but difficult to mount in
      developing countries for various logistic and cultural reasons. Recent studies
      have proposed nutritional and infective risk factors not reported in Western
      studies. METHODS: A structured questionnaire including known and putative risk
      factors was administered to parents of 61 children with epilepsy and 59 randomly
      selected population control subjects in rural West Bengal. ORs of effect were
      calculated using a multiple logistic regression model with 95% CIs. RESULTS:
      Socioeconomic status, febrile convulsions, and reproductive history were easily
      assessable. Ages, dates, and some proxy infection markers were unreliable.
      Febrile convulsions were an independent risk factor (OR 6.45; 95% CI, 1.45 to
      28.66). Associations with family history and infective symptoms were suggested.
      No association was demonstrated with socioeconomic status or reproductive
      factors. CONCLUSIONS: Known risk factors were confirmed, and novel factors were
      suggested. A retrospective questionnaire does not allow accurate study of
      infective exposures. Greater statistical power is needed to study weaker
      associations and interacting effects.

PMID- 10599782
TI  - Prevalence of epilepsy in rural Bolivia: a door-to-door survey.
AB  - OBJECTIVE: To carry out a door-to-door survey in rural areas of the Cordillera
      Province, Santa Cruz Department, Bolivia, to determine the prevalence of
      neurologic diseases (epilepsy, stroke, parkinsonism, and peripheral neuropathy)
      in a sample of approximately 10,000 inhabitants. METHODS: A team of nondoctor
      health workers administered a standard screening instrument for neurologic
      diseases-a slightly modified version of the World Health Organization protocol.
      All subjects found positive during the screening underwent a neurologic
      examination. RESULTS: On screening, the authors found 1,130 positive subjects, of
      whom 1,027 were then investigated by neurologists. On the basis of the definition
      proposed by the International League Against Epilepsy, we detected 124 epileptic
      patients (prevalence, 12.3/1,000), 112 of whom had active epilepsy (prevalence,
      11.1/1,000) on the prevalence day (November 1, 1994). Peak age-specific
      prevalence occurred in the 15 to 24-year age group (20.4/1,000). Sex-specific
      prevalence was higher in women (13.1/1,000) than men (11.4/1,000). Eighty-nine
      patients (71.8%) underwent a standard EEG recording. Considering both EEG and
      clinical data, partial seizures were the most common type (53.2%) based on the
      classification of the International League Against Epilepsy. The mean age at
      onset was 20.7 years for partial seizures and 13.6 years for generalized
      seizures. Only 10.5% of patients had received specific treatment for more than 2
      months of their life. CONCLUSION: This report on epilepsy prevalence in Bolivia
      confirms that epilepsy is a major health problem in rural areas of developing
      countries.

PMID- 10599783
TI  - Menstrual cycle effects on cortical excitability.
AB  - OBJECTIVE: To determine whether there are menstrual cycle-related effects on
      cortical excitability in normal women. BACKGROUND: Ovarian steroid hormones
      affect neurotransmission in the brain. Data from animal experiments have shown
      that progesterone metabolites enhance the action of gamma-aminobutyric acid
      (GABA), the main inhibitory neurotransmitter in the cortex, producing
      benzodiazepine-like (e.g., diazepam and lorazepam) physiologic and behavioral
      effects. Estradiol has excitatory effects on measures of neuronal excitability,
      possibly acting through the glutamate system. These effects have been difficult
      to detect in women using conventional techniques. However, recently, paired
      transcranial magnetic stimulation (TMS) has been used to detect the effects of
      GABAergic and glutamatergic drugs in humans. We used this method to measure the
      effects of the menstrual cycle in normal women. METHODS: We tested 13 healthy
      women during the follicular (low-progesterone) and luteal (high-progesterone)
      phases of the menstrual cycle using paired TMS. The effect of a subthreshold
      conditioning pulse on the cortex was tested by measuring the response to a second
      suprathreshold test pulse and comparing it with the response elicited by the test
      pulse administered alone. RESULTS: Conditioning TMS produced more inhibition in
      the luteal phase than in the follicular phase (p = 0.01), of similar magnitude to
      the reported effect of benzodiazepine drugs. CONCLUSIONS: This study provides the
      first direct evidence of changes in the excitability of a cortical network with
      the menstrual cycle. The results also show a potential confound for studies using
      transcranial magnetic stimulation in populations that include menstruating women.

PMID- 10599784
TI  - Brief bursts of pulse stimulation terminate afterdischarges caused by cortical
      stimulation.
AB  - OBJECTIVE: To determine whether cortical electrical stimulation can terminate
      bursts of epileptiform activity in humans, we used afterdischarges (ADs) as a
      model of epileptiform activity. METHODS: Cortical stimulation was performed for
      clinical localization purposes using subdural electrodes implanted in patients
      undergoing preresection evaluations for treatment of medically intractable
      seizures. We used 0.3-millisecond pulses of alternating polarity, repeated at 50
      pulses/second. When stimulation produced AD, we often applied short additional
      brief bursts of pulse stimulation (BPS). We examined the effectiveness of BPS in
      aborting ADs in 17 patients using survival analysis. RESULTS: With BPS, ADs
      stopped within 2 seconds in 115 cases, 2 to 5 seconds in 22 cases, and in more
      than 5 seconds in 89 cases. Without BPS, ADs stopped within 2 seconds in 21
      cases, 2 to 5 seconds in 114 cases, and in more than 5 seconds in 340 cases. BPS
      was an effective method to abort ADs (Cox proportional hazards model: p<0.0001).
      At any time during the course of ADs, the instantaneous rate of stopping ADs
      within 2 seconds after BPS was applied was 4.6 times greater than when BPS was
      not applied (95% CI = 3.7, 5.7). In eight cases, ADs progressed to the occurrence
      of clinical seizures, always when BPS was not applied. CONCLUSIONS:
      Afterdischarges significantly decreased in duration after we applied brief bursts
      of pulse stimulation. Although afterdischarges are not identical to spontaneous
      epileptiform activity, these results support the idea that electrical
      stimulation, applied in an appropriate manner at seizure onset, could abort
      seizures in humans.

PMID- 10599785
TI  - Visual dysfunction in patients receiving vigabatrin: clinical and
      electrophysiologic findings.
AB  - BACKGROUND: Vigabatrin is an antiepileptic drug that, although relatively well
      tolerated, is associated with visual field constriction and other visual
      disturbances of unclear origin. METHODS: We performed a complete
      neuroophthalmologic examination and electrophysiologic studies on 39 patients
      receiving vigabatrin and on 11 control patients. RESULTS: Nearly 50% of patients
      receiving vigabatrin had constricted visual fields compared with control
      patients. Some of the vigabatrin patients also had reduced visual acuity and
      abnormal color vision. In addition, most vigabatrin patients had abnormal
      electroretinographic results, the severity of which correlated strongly with the
      degree of visual field constriction. CONCLUSIONS: Vigabatrin can cause
      electrophysiologic evidence of retinal dysfunction and clinically detectable
      disturbances of visual sensory function.

PMID- 10599786
TI  - Bradykinin B1 receptor expression and function on T lymphocytes in active
      multiple sclerosis.
AB  - BACKGROUND: Lesion development in MS is initiated by migration of inflammatory
      cells into the central nervous system, a process dependent on endothelial cell
      lymphocyte interaction. Bradykinin B1 receptor is a membrane-bound G protein
      coupled receptor shown to be upregulated on the surface of various cells types
      during inflammation. OBJECTIVE: To assess the expression and function of the
      bradykinin B1 receptor on T lymphocytes from MS patients. METHODS: The authors
      used multiplex polymerase chain reaction amplification and Western blot
      techniques to demonstrate B1 receptor expression by T cells. A modified Boyden
      chamber assay also was used to assess the effect of B1 agonist and antagonist on
      T cell migration. RESULTS: The authors demonstrated that the expression of B1
      receptor was upregulated on T cells derived from peripheral blood of MS patients.
      Expression of this receptor was upregulated on T cells from patients with
      secondary progressive MS and relapsing-remitting patients in active relapse.
      Expression was lower in relapsing remitting patients in remission and least in
      control subjects, including patients with epilepsy, chronic inflammatory
      demyelinating polyneuritis, and systemic lupus erythematosus. In vitro treatment
      of cells from healthy control subjects with tumor necrosis factor-alpha and
      interferon-gamma also induced the expression of B1 receptors. The authors also
      found that the significantly higher rate of migration of MS T lymphocytes,
      compared with control subjects in the Boyden chamber assay, could be prevented by
      the addition of the selective and stable B1 agonist Sar (D-Phe8) desArg9-BK.
      CONCLUSION: The authors demonstrate that B1 receptors are upregulated by T
      lymphocytes during the course of MS and that signaling through this receptor with
      a B1 agonist can negatively regulate T-cell migration in vitro.

PMID- 10599787
TI  - Gastric tolerance of high-dose pulse oral prednisone in multiple sclerosis.
AB  - BACKGROUND: Prednisone and methylprednisolone are well absorbed orally and have
      lower treatment costs than IV methylprednisolone, but concern that low-dose
      corticosteroid may cause increased disease activity and that high oral doses may
      cause gastric ulceration inhibits use of oral therapy for MS attacks. METHODS:
      Gastric mucosal injury, detected by measurement of gastric permeability, was
      examined after five alternate day doses of IV methylprednisolone (1 g) or oral
      prednisone (1,250 mg) in 21 patients with MS. A triple sugar test solution was
      consumed at bedtime, and urine was collected overnight. Urine sugar
      concentrations were determined by high-pressure liquid chromatography. Gastric
      permeability was expressed as total mg of sucrose excreted. RESULTS: Seventeen
      patients completed the protocol (12 oral, 5 IV). Baseline sucrose excretion was
      normal in all. Both groups demonstrated an increase in gastric permeability after
      steroid treatment, but there was no difference between the two groups (95% CI 95
      to 91 mg, p = 0.96). After treatment, three (25%) patients in the oral group, and
      two (40%) patients the IV group, had modestly abnormal gastric permeability (95%
      CI 34 to 64%, P = 0.6). CONCLUSIONS: Short-term high-dose oral prednisone is not
      associated with greater gastric damage, as measured with permeability tests, than
      IV methylprednisolone. High-dose oral prednisone should be considered a first
      line treatment option for MS attacks.

PMID- 10599788
TI  - PET studies of parkinsonism associated with mutation in the alpha-synuclein gene.
AB  - OBJECTIVE: To assess the pattern of dopaminergic abnormalities in a Greek
      American kindred (family H) with autosomal dominantly inherited, levodopa
      responsive parkinsonism caused by a mutation of the gene encoding alpha
      synuclein. BACKGROUND: Mutations of alpha-synuclein have been associated recently
      with dominantly inherited, levodopa-responsive parkinsonism. The pattern of
      dopamine deficiency and status of postsynaptic dopamine receptors in this
      condition have not been reported previously. The authors followed a large, six
      generation family in whom the affected members carry the recently reported G209A
      mutation in the gene encoding alpha-synuclein. METHODS: The authors studied four
      affected and two clinically unaffected gene-negative members of family H using
      [18F]-6-fluoro-L-dopa (FD) and [11C]-raclopride (RAC) PET to assess presynaptic
      dopaminergic function and dopamine D2 receptors. The results were compared with
      normal subjects and patients with sporadic, idiopathic PD (IP). RESULTS: In
      affected individuals, FD uptake was reduced in both the caudate and the putamen,
      but the putamen was affected more severely than the caudate, as seen in IP. RAC
      binding was within the normal range, but the ratio of RAC binding in the putamen
      to that in the caudate was increased in affected members of family H. This
      pattern is similar to that seen in IP. CONCLUSIONS: PET of the nigrostriatal
      system in parkinsonism associated with a mutation in the ac-synuclein gene
      indicates that it results in a pattern of dopamine deficiency, with preserved D2
      binding, indistinguishable from IP.

PMID- 10599789
TI  - Botulinum toxin A in patients with oromandibular dystonia: long-term follow-up.
AB  - OBJECTIVE: To study the safety and efficacy of botulinum toxin A (BTX) in
      patients with oromandibular dystonia (OMD) and to compare the treatment results
      of the various subtypes of OMD. BACKGROUND: OMD is one of the most challenging
      forms of dystonia to treat. Pharmacologic therapies are generally not effective,
      and there are no surgical alternatives. METHODS: Of 202 patients diagnosed
      clinically to have OMD in a movement disorders clinic over a period of 10 years,
      162 patients satisfied the study inclusion criteria. The masseters and
      submentalis complex were the only two muscle groups injected with BTX in this
      group of patients. RESULTS: The mean age was 57.9+/-15.3 years and the mean
      follow-up period was 4.4+/-3.8 years. More than half the patients had jaw-closing
      (JC) dystonia. A total of 2,529 BTX treatments were administered into the
      masseter muscles, submentalis complex, or both during a total of 1,213 treatment
      visits. The mean doses of BTX (per side) were 54.2+/-15.2 U for the masseters and
      28.6+/-16.7 U for the submentalis complex. The mean total duration of response
      was 16.4+/-7.1 weeks. The mean global effect of BTX was 3.1+/-1.0 (range, 0 to 4,
      where 4 equals the complete abolition of the dystonia), with the JC dystonia
      patients responding best. Fifty-one patients (31.5%) reported adverse effects
      with BTX in at least one visit. Complications such as dysphagia and dysarthria
      were reported in 135 (11.1%) of all treatment visits. CONCLUSIONS: BTX is a safe
      and effective long-term treatment for OMD. JC dystonia responds better than jaw
      opening or mixed dystonias, and the treatment of the latter types of OMD are more
      likely associated with dysphagia and dysarthria. Jaw-opening dystonia can be
      treated successfully by injecting the submentalis complex.

PMID- 10599790
TI  - The Tourette syndrome diagnostic confidence index: development and clinical
      associations.
AB  - BACKGROUND: The clinical characteristics of Tourette syndrome (TS) present
      challenges for the systematic determination of whether individuals are affected
      and severity. Vocal and motor tics wax and wane, decrease over time, and may be
      voluntarily suppressible, and therefore may be absent at interview. Current
      instruments measure symptoms at interview or rate symptom severity only. METHOD:
      To minimize error in case ascertainment and produce an instrument measuring
      lifetime likelihood of having had TS, clinical members of the American Tourette
      Syndrome Association International Genetic Collaboration developed the Diagnostic
      Confidence Index (DCI). The expert group worked collaboratively with progressive
      revision in consensus workshops using existing diagnostic criteria as guidelines.
      The DCI produces a score from 0 to 100 that is a measure of the likelihood of
      having or ever having had TS. RESULTS: The DCI was administered to 280
      consecutive patients with TS attending a TS clinic; 264 (94%) completed it,
      indicating high feasibility and acceptability. Its correlation with other
      instruments and associations with psychopathology provide support for its being a
      lifetime measure of TS. CONCLUSIONS: The DCI is a useful, practicable instrument
      in the clinic or research practice allowing an assessment of lifetime likelihood
      of TS. Further work is needed to test the DCI's psychometric properties, such as
      its validity and reliability in populations of interest.

PMID- 10599791
TI  - Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy.
AB  - OBJECTIVE: To determine whether microscopic vasculitis explains the clinical and
      pathologic features of diabetic lumbosacral radiculoplexus neuropathy (DLSRPN).
      BACKGROUND: DLSRPN is usually attributed to metabolic derangement or ischemic
      injury, but microscopic vasculitis as the sole cause needs consideration.
      METHODS: We prospectively studied the clinical, laboratory, and EMG features as
      well as the pathology of distal cutaneous nerve biopsy specimens of patients with
      DLSRPN. RESULTS: Study of DLSRPN nerve biopsy specimens (n = 33) compared with
      those from healthy controls (n = 14) and those with diabetic polyneuropathy (n =
      21) provided strong evidence for ischemic injury (axonal degeneration, multifocal
      fiber loss, focal perineurial necrosis and thickening, injury neuroma,
      neovascularization, and swollen fibers with accumulated organelles), which we
      attribute to microscopic vasculitis (epineurial vascular and perivascular
      inflammation, vessel wall necrosis, and evidence of previous bleeding). Segmental
      demyelination was significantly associated with multifocal fiber loss.
      CONCLUSIONS: 1) This severe, debilitating neuropathy begins with symptoms
      unilaterally and focally in the leg, thigh, or buttock and spreads to involve the
      other regions of the same and then opposite side and is due to multifocal
      involvement of lumbosacral roots, plexus, and peripheral nerve (i.e., diabetic
      lumbosacral radiculoplexus neuropathy). 2) Motor, sensory, and autonomic fibers
      are all involved. 3) Ischemic injury explains the clinical features and
      pathologic abnormalities of nerve. 4) The proximate cause of the ischemic injury
      appears to be microscopic vasculitis. 5) The segmental demyelination is probably
      secondary to ischemic axonal dystrophy, thus providing a unifying hypothesis for
      both axonal degeneration and segmental demyelination.

PMID- 10599792
TI  - Rapidly progressive, predominantly motor Guillain-Barre syndrome with anti-GalNAc
      GD1a antibodies.
AB  - OBJECTIVE: To investigate the presence of anti-GalNAc-GD1a antibodies in patients
      with Guillain-Barre syndrome (GBS) and to determine the relation of anti
      ganglioside antibodies with clinical features. BACKGROUND: The GBS is
      heterogeneous with regard to clinical manifestations, antecedent infections, and
      the presence and specificity of anti-ganglioside antibodies. Recently, antibodies
      to minor gangliosides have been identified in serum from GBS patients. METHODS:
      The authors used ELISA to detect anti-ganglioside antibodies in 132 GBS patients
      and then correlated results with a database containing information on antecedent
      infections and clinical parameters. RESULTS: Anti-GalNAc-GD1a antibodies could be
      detected in 19 (14%) GBS patients. The presence of anti-GalNAc-GD1a antibodies
      was related to antecedent Campylobacter jejuni infection (p<0.001). GBS patients
      with anti-GalNAc-GD1a antibodies had a rapidly progressive, more severe, and
      predominantly distal weakness. Furthermore, they had less sensory loss,
      paresthesia, and cranial nerve involvement. In most patients, this reactivity was
      independent of reactivity to GM1. Dividing patients into separate groups based on
      their reactivity to GalNAc-GD1a and GM1 enabled the authors to delineate more
      homogeneous subgroups with regard to clinical features. CONCLUSIONS: This study
      provides further evidence for the hypothesis that antecedent infections and the
      specificity of subsequent anti-neural antibody responses determine the clinical
      manifestations in GBS patients.

PMID- 10599793
TI  - Benign acute childhood myositis: laboratory and clinical features.
AB  - BACKGROUND: Benign acute myositis of childhood is a disorder of midchildhood,
      typically affecting boys. Symptoms include calf pain and difficulty walking after
      a viral illness. There is an epidemiologic association with influenza.
      OBJECTIVES: To describe the clinical and laboratory features of benign acute
      myositis. RESULTS: Thirty-eight children (32 boys, 6 girls) were seen with 41
      episodes of myositis between 1978 and 1997. Two were siblings and three had
      recurrent episodes. Mean age at onset of symptoms was 8.1 years. Children
      remained ambulant during 33 of 41 episodes. Two characteristic gaits were noted:
      toe-walking in 13, with a wide-based stiff-legged gait in another 7. Muscle
      tenderness was isolated to the gastrocnemius-soleus muscles in 82% of episodes.
      Recovery occurred within 1 week. Creatine kinase levels were elevated during all
      episodes. Viral studies were positive in 10 of 24 episodes, 5 because of
      influenza B. CONCLUSION: Benign acute myositis is a syndrome of midchildhood that
      can be differentiated from more serious causes of walking difficulty by the
      presence of calf tenderness, normal power, intact tendon reflexes, and elevated
      creatine kinase. The gait patterns noted may minimize power generation of the
      calf muscles by splinting the ankles. Onset in childhood may reflect an age
      related response to viral infection, and occurrence primarily in boys may reflect
      a genetic predisposition or an as-yet unknown metabolic defect.

PMID- 10599794
TI  - A case-controlled MRI/MRA study of neurovascular contact in hemifacial spasm.
AB  - BACKGROUND: Neurovascular contact (NVC) with the root exit zone (REZ) of the
      ipsilateral facial nerve is associated with hemifacial spasm (HFS), but
      unresolved issues remain. OBJECTIVES: To 1) determine the frequency of
      symptomatic and nonsymptomatic NVC, 2) determine the features of NVC associated
      with HFS, and 3) correlate severity of HFS to these features. METHODS: Two
      independent, blinded, prospective assessments of high-resolution MR and MR
      angiography (MRA) images were performed on Chinese cases (HFS: n = 44; age
      matched control subjects: n = 20). RESULTS: Over 88% of 44 symptomatic sides in
      patients with HFS had NVC of the ipsilateral facial nerve. At least 80% of
      symptomatic sides involved NVC at the anterior aspect of the REZ [REZ(ant.)].
      Although NVC was observed in approximately half of nonsymptomatic sides, at least
      70% of them were not at REZ(ant.). NVC at the cisternal and intracanalicular
      portions of the facial nerve were not associated with HFS. Half of our patients
      with HFS had bilateral NVC, but none had bilateral symptoms. Most of our MR/MRA
      images showed that the size and position of the arterial branches of the
      vertebrobasilar system were markedly asymmetric. Of patients with bilateral NVC,
      over 83% had asymmetric NVC sites. The anterior inferior cerebellar artery was
      the most common vessel involved in NVC, but was not significantly associated with
      HFS. Most of the NVC involved one vessel at one contact point with no
      indentation. The development of HFS was significantly associated with nerve
      indentation in NVC. The development and severity of HFS were not associated with
      multiple contact points in NVC. No significant interobserver variability existed
      between the blinded assessments. CONCLUSIONS: MRI/MR angiography are accurate,
      fast, and safe in characterizing neurovascular contact (NVC) at the brainstem.
      The site of NVC and ipsilateral facial nerve indentation in NVC are significant
      determinants for the development of hemifacial spasm (HFS). The lack of bilateral
      NVC at the anterior aspect of the root exit zone of the facial nerve could
      explain in part the lack of bilateral symptoms. The development and severity of
      HFS are not associated with a specific blood vessel or multiple contact points in
      NVC.

PMID- 10599795
TI  - Reduction of intracerebral hemorrhaging in a rabbit embolic stroke model.
AB  - OBJECTIVE: To study the effects of a spin trap agent and a CD18 antibody
      administered after stroke induction on intracerebral hemorrhaging. The drugs can
      prevent leukocyte adhesion. METHODS: A rabbit embolic stroke model that produces
      intracerebral hemorrhage was used. RESULTS: A time course study showed that
      hemorrhaging was grossly apparent in approximately 50% of the subjects at 5 hours
      and in 75% at 24 hours after embolization. MDL 101,002, a spin trap agent,
      administered IV 5 minutes after embolization, significantly decreased the volume
      of hemorrhage. It also improved the behavior score relative to vehicle-treated
      rabbits. The CD18 antibody tended to decrease hemorrhage volume. CONCLUSION: The
      beneficial effect of MDL 101,002 may be caused by inhibition of free radical
      injury to brain tissue, thereby protecting brain microvessel integrity. Acute
      therapy for intracerebral hemorrhage may be feasible.

PMID- 10599796
TI  - MRI volumes of amygdala and hippocampus in non-mentally retarded autistic
      adolescents and adults.
AB  - OBJECTIVE: To determine whether volumes of hippocampus and amygdala are abnormal
      in people with autism. BACKGROUND: Neuropathologic studies of the limbic system
      in autism have found decreased neuronal size, increased neuronal packing density,
      and decreased complexity of dendritic arbors in hippocampus, amygdala, and other
      limbic structures. These findings are suggestive of a developmental curtailment
      in the maturation of the neurons and neuropil. METHODS: Measurement of
      hippocampus, amygdala, and total brain volumes from 1.5-mm coronal, spoiled
      gradient-recalled echo MRI scans in 14 non-mentally retarded autistic male
      adolescents and young adults and 14 individually matched, healthy community
      volunteers. RESULTS: Amygdala volume was significantly smaller in the autistic
      subjects, both with (p = 0.006) and without (p = 0.01) correcting for total brain
      volume. Total brain volume and absolute hippocampal volume did not differ
      significantly between groups, but hippocampal volume, when corrected for total
      brain volume, was significantly reduced (p = 0.04) in the autistic subjects.
      CONCLUSIONS: There is a reduction in the volume of amygdala and hippocampus in
      people with autism, particularly in relation to total brain volume. The
      histopathology of autism suggests that these volume reductions are related to a
      reduction in dendritic tree and neuropil development, and likely reflect the
      underdevelopment of the neural connections of limbic structures with other parts
      of the brain, particularly cerebral cortex.

PMID- 10599797
TI  - The treatment of neurogenic orthostatic hypotension with 3,4-DL-threo
      dihydroxyphenylserine: a randomized, placebo-controlled, crossover trial.
AB  - OBJECTIVE: To study the therapeutic effect and mechanism of action of 3,4-DL
      threodihydroxyphenylserine (DL-DOPS) in neurogenic orthostatic hypotension.
      METHODS: The blood pressure (BP) response to an orthostatic challenge on DL-DOPS
      was compared with that of placebo in a randomized, double-blind, placebo
      controlled, crossover trial in 10 patients. The mechanism of action of DOPS was
      studied by measuring forearm vascular resistance and changes in supine and
      upright plasma DL-DOPS and norepinephrine levels. The effect of DL-DOPS on the
      quality of life was determined by questionnaire. RESULTS: DL-DOPS increased the
      supine (p<0.001) and upright (p<0.05) systolic blood pressure (SBP) and diastolic
      blood pressure (DBP) (both p<0.01). The peak SBP on DL-DOPS in the supine
      position occurred 300 minutes after ingestion of the medication. The increase in
      BP was accompanied by an increase in plasma levels of norepinephrine and DL-DOPS
      in both the supine and upright positions after DL-DOPS ingestion (p<0.0001).
      There was a trend toward improvement in symptoms of orthostatic intolerance.
      CONCLUSION: DL-DOPS improved features of neurogenic orthostatic hypotension in
      patients with central and peripheral autonomic nervous system disease. There was
      an increase in plasma norepinephrine. No major side effects occurred.

PMID- 10599798
TI  - Hyperventilation-induced nystagmus in patients with vestibular schwannoma.
AB  - OBJECTIVE: To analyze the nystagmus evoked by hyperventilation in patients with
      unilateral vestibular schwannoma and to use this information to predict the
      effects of hyperventilation on individual ampullary nerves. METHODS: Three
      dimensional scleral search coil eye movement recording techniques were used to
      record the magnitude and time course of eye movements in six patients with
      unilateral vestibular schwannoma and hyperventilation-induced nystagmus. The
      presenting complaints in five of these patients were vertigo or dysequilibrium.
      RESULTS: The eye movement response to hyperventilation was a "recovery" nystagmus
      with slow-phase components corresponding to excitation of the affected vestibular
      nerve. Projection of the eye velocity vector into the plane of the semicircular
      canals revealed that fibers arising from the ampulla of the horizontal canal were
      most affected by hyperventilation with lesser activation of fibers to the
      superior canal and smaller, more variable responses from posterior canal fibers.
      CONCLUSIONS: The three-dimensional characteristics of the nystagmus evoked by
      hyperventilation in patients with vestibular schwannoma provide insight into the
      vestibular end organs affected by the tumor and the mechanism responsible for the
      nystagmus. This finding indicates that hyperventilation resulted in a transient
      increase in activity from these partially demyelinated axons.

PMID- 10599799
TI  - Relicts of dancing mania: the dancing procession of Echternach.
AB  - In the small town of Echternach in Luxembourg, remnants of chorea St. Vitii can
      be found every year when pilgrims gather at the grave of St. Willibrord (658-739)
      to take part in the so-called Dancing Procession on Whit Tuesday. Miracles and
      healings are reported to have taken place in front of Willibrord's sarcophagus in
      the late eighth century. News of the miraculous healings inspired the celebratory
      folkdances in Echternach. Willibrord became the patron saint of patients with
      movement disorders. Important annual pilgrimages to the grave of Saint
      Willibrord, with pilgrims from Gallic and Teutonic provinces, were reported
      around 1100. The Dancing Procession is first mentioned in the Echternach city
      archives in 1497. In 1900, Henri Meige, a neurologist with a special interest in
      movement disorders, visited Echternach to observe the annual Dancing Procession.
      Although Meige was disappointed with the lack of hysteria, he concluded that the
      Dancing Procession of Echternach was not without grandeur. Outbreaks of mass
      hysteria with a background of religious fervor, pagan traditions, or superstition
      are the most likely explanation for the medieval dancing mania. This view is
      supported by the religious motivation behind the present-day Dancing Procession
      in Echternach, a ritual with mixed pagan-Christian origins related to Saint
      Vitus' dance.

PMID- 10599800
TI  - Sporadic Creutzfeldt-Jakob disease: co-occurrence of different types of PrP(Sc)
      in the same brain.
AB  - Phenotypic heterogeneity of sporadic Creutzfeldt-Jakob disease (CJD) has been
      linked to biochemically distinct types of the protease-resistant form of the
      prion protein (type 1 and type 2 PrP(Sc)). We investigated 14 cases of sporadic
      CJD and found that both type 1 and type 2 PrP(Sc) coexisted in 5 subjects. The
      distinct PrP(Sc) isoforms were associated with different patterns of PrP
      deposition and severity of spongiform changes, suggesting that the PrP(Sc) type
      plays a central role in determining the neuropathologic profile of CJD.

PMID- 10599801
TI  - Intracerebral hemorrhage outcome: apolipoprotein E genotype, hematoma, and edema
      volumes.
AB  - We investigated whether early hematoma or edema volumes could explain the adverse
      association between APOE epsilon4 and survival in intracerebral hemorrhage. Among
      102 patients, epsilon4 carriers had a higher mortality rate than non-epsilon4
      carriers (38 versus 24%, p = 0.05). Nonsurvivors had larger hematoma (75.5 cm3
      versus 27.1 cm3, p<0.001) and edema volumes (37.5 cm3 versus 17.1 cm3, p<0.01),
      but these were not associated with epsilon4 after adjusting for race, age, and
      type of hemorrhage.

PMID- 10599802
TI  - No evidence of hypoxic tissue on 18F-fluoromisonidazole PET after intracerebral
      hemorrhage.
AB  - We studied six patients after intracerebral hemorrhage (ICH) and eight controls
      using positron emission tomography (PET) with to determine whether a zone of
      tissue hypoxia, possibly representing "penumbral" tissue, exists surrounding an
      intracerebral hemorrhage. None of the stroke patients, studied 24 to 43 hours
      after symptom onset, nor any of the controls exhibited areas of tissue hypoxia on
      18F-fluoromisonidazole PET images. These findings may have implications for the
      treatment of intracerebral hemorrhage with neuroprotective strategies.

PMID- 10599803
TI  - Vasogenic edema on MELAS: a serial study with diffusion-weighted MR imaging.
AB  - The authors performed a serial study of a patient with mitochondrial myopathy,
      encephalopathy, lactic acidosis, and stroke-like syndrome (MELAS) who presented
      with diffusion-weighted MRI (DWI). DWI demonstrated a higher apparent diffusion
      coefficient in the lesion than in the control region during the acute stage of
      stroke. Vasogenic edema is present in stroke-like episodes in MELAS.

PMID- 10599804
TI  - Cultured inclusion-body myositis muscle fibers do not accumulate beta-amyloid
      precursor protein and can be innervated.
AB  - Cultured muscle fibers from patients with sporadic inclusion-body myositis (s
      IBM), similar to normal control muscle fibers, 1) did not have beta-amyloid
      precursor protein (betaAPP) immunoreactivity; and 2) became normally innervated,
      as evidenced by the following features: full cross-striation, continuous
      contraction, and acetylcholinesterase and acetylcholine receptors accumulated
      only at neuromuscular junctions. Thus, factors responsible for betaAPP
      accumulation and denervation-like changes in s-IBM muscle biopsies are not
      operative in the relatively short-term, non-aged, cultured s-IBM muscle fibers.

PMID- 10599805
TI  - Autosomal dominant familial spinal and bulbar muscular atrophy with gynecomastia.
AB  - The proband, a 53-year-old man, developed progressive spinal and bulbar muscular
      atrophy and gynecomastia at the age of 50. His father had weakness of lower
      limbs, and his son had a nasal voice, ocular movement abnormalities, and
      gynecomastia, whereas two of the proband's brothers showed either gynecomastia or
      tongue fasciculations. None of the patients showed any expansion of CAG repeat in
      the androgen receptor gene or any hormonal abnormality. Thus, this family is
      affected by a form of autosomal dominant spinal and bulbar muscular atrophy with
      gynecomastia.

PMID- 10599806
TI  - Neuroimaging study in autosomal dominant cerebellar ataxia, deafness, and
      narcolepsy.
AB  - Four patients affected with autosomal dominant cerebellar ataxia, deafness, and
      narcolepsy underwent brain CT and MRI. Radiologic findings were supratentorial
      atrophy (more pronounced than infratentorial atrophy), pronounced dilatation of
      the third ventricle, low T2 signal intensity in the basal ganglia, loss of
      cerebral cortex-white matter differentiation, and periventricular high-signal
      rims. 2-[18F]Fluoro-2-deoxy-D-glucose PET was done with one patient, without
      specific findings. Genetic analyses excluded SCA-1, SCA-2, SCA-3, SCA-6, SCA-7,
      DRPLA, and huntingtin gene mutations.

PMID- 10599807
TI  - Silent functional magnetic resonance imaging demonstrates focal activation in
      rapid eye movement sleep.
AB  - Functional imaging of human sleep has been performed with nuclear medicine
      methods, but MRI has been difficult to implement, in part because of the noise
      associated with echo-planar imaging as well as the difficulty in reading
      physiologic signals in the MRI environment. We describe a silent MR sequence that
      can record brain activation over many hours with simultaneous acquisition of an
      EEG. This shows activation of occipital cortex and deactivation of frontal cortex
      during REM sleep, in agreement with previous studies using other techniques. MRI
      Sleep-REM sleep.

PMID- 10599808
TI  - Soleus H-reflex tests in causalgia-dystonia compared with dystonia and mimicked
      dystonic posture.
AB  - Dystonia in the causalgia-dystonia syndrome is characterized by a fixed dystonic
      posture. To identify involvement of central pathophysiologic mechanisms, we
      analyzed soleus H-reflex tests in five patients with causalgia-dystonia. Soleus H
      reflex test results in these patients differed from those in healthy controls but
      were similar to those in purely dystonic patients and healthy controls mimicking
      dystonic posture. The results suggest involvement of supraspinal mechanisms in
      the abnormal posture of causalgia-dystonia.

PMID- 10599809
TI  - [11C](R)-PK11195 positron emission tomography imaging of activated microglia in
      vivo in Rasmussen's encephalitis.
AB  - This study was designed to explore the feasibility of PET using [11C](R)-PK11195
      as an in vivo marker of activated microglia/brain macrophages for the assessment
      of neuroinflammation in Rasmussen's encephalitis (RE). [11C](R)-PK11195 PET was
      carried out in four normal subjects, two patients with histologically confirmed
      RE, and three patients with clinically stable hippocampal sclerosis and low
      seizure frequency. Binding potential maps showing specific binding of [11C](R)
      PK11195 were generated for each subject. Regional binding potential values were
      calculated for anatomically defined regions of interest after coregistration to
      and spatial transformation into the subjects' own MRI. In one patient with RE who
      underwent hemispherectomy, the resected, paraffin-embedded brain tissue was
      stained with an antibody (CR3/43) that labels activated human microglia. Whereas
      specific binding of [11C](R)-PK11195 in clinically stable hippocampal sclerosis
      was similar to that in normal brain, patients with RE showed a focal and diffuse
      increase in binding throughout the affected hemisphere. In RE, [11C](R)-PK11195
      PET can reveal in vivo the characteristic, unilateral pattern known from
      postmortem neuropathologic study. PET imaging of activated microglia/brain
      macrophages offers a tool for investigation of a range of brain diseases where
      neuroinflammation is a component and in which conventional MRI does not
      unequivocally indicate an inflammatory tissue reaction. [11C](R)-PK11195 PET may
      help in the choice of appropriate biopsy sites and, further, may allow assessment
      of the efficacy of antiinflammatory disease-modifying treatment.

PMID- 10599810
TI  - Optic nerve edema as a consequence of respiratory disease.
AB  - The authors describe a patient with bilateral papilledema, visual field
      abnormalities, poorly reactive pupils, meningeal enhancement on cranial MRI, and
      diffuse brain parenchymal hypervascularity. The opening pressure at the time of
      lumbar puncture was normal, and results of other CSF studies were normal. All
      abnormalities resolved with home oxygen therapy.

PMID- 10599811
TI  - Marginally improved detection of GM1 antibodies by Covalink ELISA in multifocal
      motor neuropathy.

PMID- 10599812
TI  - Meningeal metastases from malignant melanoma presenting with gaze-evoked
      tinnitus.

PMID- 10599813
TI  - A practical method to predict rate of cognitive decline in mild to moderate
      Alzheimer's disease.

PMID- 10599814
TI  - Gabapentin-induced anorgasmia.

PMID- 10599815
TI  - Suppression of pendular nystagmus by smoking cannabis in a patient with multiple
      sclerosis.

PMID- 10599816
TI  - Oxcarbazepine in a monotherapy trial for partial seizures--placebo-controlled
      studies in neurology: where do they stop?

PMID- 10599817
TI  - Oxcarbazepine in a monotherapy trial for partial seizures--placebo-controlled
      studies in neurology: where do they stop?

PMID- 10599818
TI  - Potential source of cerebral embolism in migraine with aura: a transcranial
      Doppler study.

PMID- 10599819
TI  - Risk factors for seizure-related motor vehicle crashes in patients with epilepsy.

PMID- 10599820
TI  - Risk factors for seizure-related motor vehicle crashes in patients with epilepsy.

PMID- 10599821
TI  - Withdrawal of life support in the neurologic intensive care unit.

PMID- 10599822
TI  - Practicing neurology: a delicate balance.

PMID- 10599823
TI  - Contemporary challenges and new directions in psychotherapy: an introduction.

PMID- 10599824
TI  - Future directions in the treatment of anxiety disorders: an examination of
      theory, basic science, public policy, psychotherapy research, clinical training,
      and practice.
AB  - This article represents a transcribed roundtable discussion on anxiety disorders
      that took place at the 1998 Society for Psychotherapy Research in Snowbird, Utah.
      Eminent experts in the field of anxiety disorders took part in a discussion that
      focused on issues related to theory, basic science, public policy, therapy
      research, clinical training, and practice. Important topics addressed by the
      panel included the role of theory in research and clinical practice, the
      importance of psychopharmacological interventions, efficacy versus effectiveness
      research, the impact of public policy on research advancement, and the interface
      between basic science, research, and clinical practice.

PMID- 10599825
TI  - Psychotherapy for depression: current and future directions in research, theory,
      practice and public policy.
AB  - This article is based on a symposium held at the 1998 Annual Meeting of Society
      for Psychotherapy Research (Snow Bird, Utah). Recognized experts addressed
      current and future directions in psychotherapy for depression from the
      perspectives of process and outcome research, basic research, theoretical models,
      clinical practice and training, and public policy. The specific issues discussed
      at the symposium included the strengths and limitations of major forms of
      psychotherapy; the therapeutic factors common and unique to different approaches;
      the future viability of current theories of depression; the role of treatment
      manuals in clinical practice and training; the development of new interventions
      based on basic research; and the priorities that should guide federal funding.

PMID- 10599826
TI  - Personality disorders: a discussion of current status and future directions for
      research, practice, and policy.
AB  - This article is the result of a panel discussion on future directions in
      personality disorders held at the 1998 Meeting of the Society for Psychotherapy
      Research in Snowbird Utah. Three experts in the field of personality disorders
      were invited to participate in a dialogue on priorities and directions for
      research, practice, and policy in this area. Topics discussed amongst the
      panelists included the following: 1) relevance of psychotherapy process research
      for treatments of personality disorders, and potential fruitful directions for
      such research; 2) what has been learned from outcome research in treatment of
      personality disorders, and directions for such research that are likely to be
      most productive in improving treatments; 3) the extent to which research has
      influenced clinical practice and how existing gaps might be addressed; 4) policy
      questions related to payment for treatment of personality disorders.

PMID- 10599827
TI  - Toward the development of a clinically useful approach to psychotherapy research.
AB  - The controversial move toward the development of a consensus on evidence-based or
      empirically supported therapies may be seen as an international crisis facing
      psychotherapists. Researchers long have complained that practicing therapists all
      too often continue to guide what they do therapeutically on the basis of their
      clinical experience and not the available research findings. Practicing
      therapists long have complained that therapy research bears only a remote
      resemblance to what goes on in actual clinical practice and that research reports
      are written for other researchers, not for clinicians. In the hope of turning our
      current crisis into an opportunity, this panel involved a dialogue that was
      designed to bridge this clinical-research gap.

PMID- 10599828
TI  - Reflecting on current challenges and future directions in psychotherapy: what can
      be learned from dialogues between clinicians, researchers, and policy makers?

PMID- 10599829
TI  - Incidences of asymmetries for the palmar grasp reflex in neonates and hand
      preference in adults.
AB  - It was hypothesized that adult handedness might be predicted from the neonatal
      grasp reflex. Grasp reflex was measured from right and left hand (10 trials for
      each hand) in neonates. According to significance for the difference between the
      mean grasp reflex strength from the right and left hands, the subjects were
      designated as right-, left-, and mixed-handers. Adult hand preference was
      assessed by Edinburgh Handedness Inventory. The percentage of left-handedness
      (8.3%) in neonates coincided with adult left-handedness (6.3-9.2%). The
      percentage of consistent right-hand preference in adults coincided with
      percentage of right-handedness in neonates (25.7%). The high percentage of
      neonatal mixed-handedness was similar to that to be expected from the right shift
      model of hand preference. It was concluded that left-handedness and consistent
      right-handedness may be determined prenatally, under genetic and/or hormonal
      control, and that a large majority of neonatal handedness, mixed-handers, might
      change their hand preference in favor of right-handed-ness under socio-cultural
      and developmental influences of speech centres.

PMID- 10599830
TI  - Functional recruitment of red blood cells to rat brain microcirculation
      accompanying increased neuronal activity in cerebellar cortex.
AB  - Scanning laser-Doppler flowmetry (SLDF) combines laser-Doppler flowmetry and
      laser scanning to provide images of cerebral blood flow (CBF) with high spatial
      and temporal resolution. We investigated the contribution of single vascular
      elements to the local increase of CBF accompanying increased neuronal activity in
      halothane-anesthetized rats. CBF was examined in the cerebellar cortex under
      control conditions and in response to electrical stimulation of parallel and
      climbing fibers. At rest, arterioles contributed 9%, venules 11-13% and small
      vessels (< 20 microm) 8-14%, while the background constituted 64-72% of the total
      SLDF signal. During activation the background signal decreased to 55-60% while
      the signal from arterioles increased to 11-12%, from venules to 14-15% and from
      small vessels to 14-19%. The signal increase in small vessels that did not give
      any laser-Doppler signal at rest was due to functional recruitment of red blood
      cells to the capillary bed. We conclude that functional recruitment may be an
      integral part of the hemodynamic response accompanying neuronal activity.

PMID- 10599831
TI  - Cholecystokinin CCK(B) receptor mRNA isoforms: expression in schizophrenic
      brains.
AB  - In the light of earlier findings of reduced cholecystokinin (CCK) peptide and CCK
      mRNA levels in the cerebral cortex, we have used in situ hybridization to examine
      possible regulation of mRNAs coding for two isoforms of the CCK(B) receptor in
      frontal cortex (Brodmann's area 10) of schizophrenic patients. The hybridizations
      revealed a 51% decrease of the full length CCK(B) receptor mRNA in the outer
      layers (II-III) of the frontal cortex. The corresponding alterations for the
      truncated isoform were a 65% reduction in the outer layers and a 62% reduction in
      the inner layers (IV-VI) of the frontal cortex. This strengthens the hypothesis
      that CCKergic transmission in this part of the brain is involved in the
      pathophysiology of schizophrenia.

PMID- 10599832
TI  - Thrombolysis of cerebral clot embolism in rat: effect of treatment delay.
AB  - Rats submitted to focal cerebral ischemia by middle cerebral artery clot embolism
      were treated with recombinant tissue plasminogen activator (rt-PA) at increasing
      delays (1.5, 3 and 4.5 h) after the onset of ischemia. Treatment efficacy was
      evaluated by NMR imaging of the apparent diffusion coefficient of water (ADC). In
      untreated animals the size of the ADC-detectable lesion gradually increased after
      clot embolism, expanding over 8 h to 174 +/- 17% of the volume visible at 30 min.
      Thrombolysis initiated 1.5 h after embolism did not reverse the ischemic lesion
      but reduced its growth to 113 +/- 19% (p < 0.05). Lesion size increased to 135 +/
      14% after 3 h (NS) and to 214 +/- 35% after 4.5 h delay (NS). Thrombolysis with
      rt-PA attenuates infarct expansion but does not reverse ischemic injury.

PMID- 10599833
TI  - Antidepressant-like properties of prepro-TRH 178-199: acute effects in the forced
      swim test.
AB  - This study examined the central effects of rat prepro-TRH 178-199, a peptide with
      corticotropin release inhibiting activity at the pituitary, on the Porsolt forced
      swim test (FST) of depressive behavior in rats. Subacute intracerebroventricular
      administration of prepro-TRH 178-199 dose-responsively reduced floating and
      increased active behaviors in the FST. Chronic administration of 6 microg/kg
      prepro-TRH 178-199 decreased floating more than subacute treatment, but there
      were no significant differences between chronic and subacute treatment effects on
      active behavior. Biological activity of this peptide resides in the C-terminal
      fragment as prepro-TRH 178-199 and prepro-TRH 191-199 were equally potent in the
      FST. These data suggest that endogenous prepro-TRH 178-199 with its
      antidepressant-like activity might contribute to the etiology or manifestation of
      depressive behavior.

PMID- 10599834
TI  - Inward rectifier potassium channel Kir 2.3 is inhibited by internal sulfhydryl
      modification.
AB  - Regions of the hippocampal inward rectifier potassium channel Kir 2.3 that
      contact the aqueous environment were investigated by identification of native
      cysteine residues that confer sulfhydryl reagent sensitivity to the channel
      conductance. Kir 2.3 currents were inhibited by N-ethylmaleimide (NEM), whereas
      currents of Kir 2.1 were unaffected. The reactive residues were identified as Kir
      2.3 Cys28 and Cys50 using chimeric constructs and mutagenesis. These sites were
      not accessible to p-chloromercuriphenylsulfonate (pCMPS) applied extracellularly.
      However, both Cys28 and Cys50 were accessible to 2-(trimethylammoniumethyl)
      methanethiosulfonate (MTSET) applied to the intracellular surface of the
      membrane. These studies demonstrate that Cys28 and Cys50 lie in a cytoplasmic
      aqueous accessible region of the channel, and suggest that the channel N-terminus
      is a key constituent of the internal vestibule of the pore and/or modulates
      channel gating.

PMID- 10599835
TI  - Galvanic stimulation in bilateral vestibular failure: 3-D ocular motor effects.
AB  - Bilateral galvanic vestibular stimulation (GVS) with current intensity of 3 mA
      was applied at mastoid level in 11 patients with chronic bilateral vestibular
      failure, in order to determine ocular motor responses by 3-D video-oculography.
      The following abnormal features were found: (1) a predominantly torsional or
      mixed torsional-horizontal nystagmus at the onset of stimulation with lower
      current intensities (1.0-3.0 mA) in nine patients; (2) a reduced amplitude of
      tonic ocular torsion by about 50% in nine patients (1.3 +/- 0.6 degrees at 3 mA);
      (3) a nystagmus in the opposite direction at stimulation offset in five patients
      (rebound); (4) no eye movements at all in a patient with bilateral nerve failure.
      GVS stimulates the vestibular nerve, thus allowing differentiation of nerve
      failure from labyrinthine failure. The low thresholds for initiating nystagmus
      and the rebound, which appear to be the most typical features of bilateral
      labyrinthine failure, can be explained by central compensation mechanisms.

PMID- 10599836
TI  - Glutamate receptors mediate regulation of Na pump isoform activities in neurons.
AB  - Rat cerebral neurons matured in culture were stimulated with glutamate analogues,
      and the K+ uptake activities of Na pump isoforms were measured. Ionotropic
      receptor agonists, kainate, AMPA, and NMDA, increased total K+ uptake activity
      via activation of the alpha2/alpha3 isoforms and an inhibition of the alpha1
      isoform as reported previously for glutamate. The effects of kainate or AMPA were
      antagonized by CNQX and those of NMDA were by APV or MK-801. In contrast,
      metabotropic receptor agonist ACPD had no effects on the Na pump isoform
      activities. Glutamate transporter substrate, PDC, was effective, but NMDA
      receptor antagonists abolished the effects of PDC. These results suggest that the
      ionotropic glutamate receptors mediate the regulation of Na pump isoform
      activities in neurons.

PMID- 10599837
TI  - A transient geniculo-extrastriate pathway in macaques? Implications for
      'blindsight'.
AB  - Both monkeys and cats receiving primary visual cortex lesions in infancy show
      better residual vision than animals sustaining similar damage in adulthood. In
      cats, the better recovery has been explained in part by stabilization of a
      transient pathway from the dorsal lateral geniculate nucleus (dLGN) to cortical
      visual area PMLS. To test the hypothesis that a similar transient pathway from
      the dLGN to dorsal extrastriate areas exists in primates and thus serves as a
      candidate for recruitment after early V1 damage, retrograde tracers were injected
      into areas MT, MST, and/or 7a of infant macaques. No evidence of a transient
      pathway from the dLGN to these areas was obtained, despite projections from the
      pulvinar and other extrastriate areas in all cases.

PMID- 10599838
TI  - Different neural substrates for Kanji and Kana writing: a PET study.
AB  - To investigate the neural substrate underlying the mechanisms of Kanji and Kana
      writing, we conducted a PET activation study during mental writing task in eight
      right-handed normal Japanese subjects. During scans subjects were required to
      mentally write a Kanji or three Kana letters with their right hand, for each
      stimulant word presented auditorily. The direct comparisons between Kanji writing
      and Kana writing revealed that the left posterior inferior temporal gyrus was
      activated in Kanji writing while the left angular gyrus was activated in Kana
      writing. In addition, more extensive areas were activated in Kanji writing
      compared with Kana writing. These results suggest that different respective
      neural substrates are involved in Kanji and Kana writing respectively.

PMID- 10599839
TI  - Sex differences in the refractory period of the 100 ms auditory evoked magnetic
      field.
AB  - The 100 ms latency auditory evoked magnetic response (M100) has been implicated
      in the earliest stage of acoustic memory encoding in the brain. Sex differences
      in this response have been found in its location within the brain and its
      functional properties. We recorded the M100 in 25 adults in response to changes
      in interstimulus interval of an auditory stimulus. Response amplitudes of the
      M100 were used to compute a measure of the M100 refractory period, which has been
      proposed to index the decay time constant of echoic memory. This time constant
      was significantly longer in both hemispheres of the female participants when
      compared to the male participants. Possible implications of this for behavioral
      sex differences in human memory performance are discussed.

PMID- 10599840
TI  - Biochemical markers of cognition: a proton MR spectroscopy study of normal human
      brain.
AB  - In the current study we explored the relationship between neurometabolites
      measured by proton magnetic resonance spectroscopy (1H-MRS) and cognitive ability
      assessed with a battery of neuropsychological tests. Forty-five participants were
      recruited from the local college community, and examined utilizing
      neuropsychological testing and 1H-MRS. Our central finding was that N
      acetylaspartate (NAA) was associated with overall neuropsychological performance
      (F(1,42) = 23.16, p < 0.0001], r2 = 0.35. We found an even stronger association
      between timed neuropsychological measures and NAA (F(1,42) = 31.15, p < 0.0001],
      r = 0.43. These results reveal the specific relationship of NAA to
      neuropsychological functioning in normal human brain. The current observations in
      healthy individuals are consistent with the hypothesis that variability in NAA
      levels and neuropsychological performance may be related to mitochondrial
      function.

PMID- 10599841
TI  - Changes in protein expression in the vestibular nuclei during vestibular
      compensation.
AB  - In the guinea pig, labyrinthectomy induces an immediate depression of the resting
      discharges in the neurons of the ipsilateral vestibular nuclei. Later on, in
      spite of the persistent deprivation of their ipsilateral labyrinthine input, a
      spontaneous restoration of activity, which is complete within 1 week, occurs in
      these neurons. Here, by using computer-assisted quantitative two-dimensional gel
      analysis, we have detected three proteins whose expressions were increased in the
      ipsilateral vestibular nuclei 1 week after unilateral labyrinthectomy. The spatio
      temporal pattern of this phenomenon was compatible with a role for it in the
      restoration of activity in the vestibular neurons deprived of their ipsilateral
      labyrinthine input. Furthermore, the N-terminal amino acid sequences of two of
      these expressed proteins were obtained.

PMID- 10599842
TI  - Reduced mismatch negativity (MMN) suggests deficits in pre-attentive auditory
      processing in distractible children.
AB  - Mismatch negativity (MMN) event-related brain potential reflects the brain's
      automatic auditory change detection mechanism that depends on integrity of the
      auditory sensory memory. We studied MMN in easily distractible (n = 20) and in
      non-distractible (n = 20) healthy 9-year-old children. Two MMN phases were
      revealed in both groups: an earlier MMN peak at approximately 220 ms and a later
      negative slope approximately 300-500 ms after stimulus presentation. The results
      suggested a strong frontal lobe contribution in the generation of the later MMN
      phase, and this response was significantly reduced in amplitude in the
      distractible children. The present findings suggest that distractible children
      may have deficits in the frontally mediated aspects of auditory sensory memory.

PMID- 10599843
TI  - Neuronal death in nigral grafts in the absence of poly (ADP-ribose) polymerase
      activation.
AB  - The exact causes of the extensive cell death in nigral transplants are still
      unknown. Since poly-(ADP-ribose) polymerase (PARP) overactivation has been
      implicated in neuronal death, we examined the effects of PARP on the survival of
      nigral grafts by using donor tissue from PARP knock-out or wild-type mice. Eight
      hours after preparation of the nigral cell suspension, cell damage was quantified
      by measurement of lactate dehydrogenase release, DNA fragmentation and caspase
      activation. At this stage, PARP deletion had no protective effect. Moreover,
      neither the survival of transplanted dopaminergic neurons, nor the functional
      recovery of hemiparkinsonian graft recipients were improved by the absence of
      PARP. We conclude that cell death in embryonic nigral grafts is not affected by
      the absence of PARP activation.

PMID- 10599844
TI  - Facilitation instead of inhibition for repeated right-sided events in left
      neglect.
AB  - When two visual events appear consecutively in the same spatial location, our
      response to the second event is slower than that to the first. This inhibition
      for repeated events may reflect a bias toward sampling novel locations, a bias
      useful for exploring the visual space. Patients with right hemisphere damage and
      left neglect explore asymmetrically a visual scene. They are initially attracted
      by right-sided items and become stuck to them, being unable to reorient their
      attention toward the left. Here we show that neglect patients show facilitation
      instead of inhibition for repeated events on the right, non-neglected side.
      Patients without neglect showed normal inhibition. Our observation may explain
      why neglect patients' exploration of space cannot extend beyond a few right-sided
      objects.

PMID- 10599845
TI  - Biosensor binding assay of BmK AS-1, a novel Na+ channel-blocking scorpion ligand
      on rat brain synaptosomes.
AB  - The pharmacological binding of BmK AS-1, a novel Na+ channel-specific ligand
      purified from Chinese scorpion Buthus martensi Karsch (BmK), has been
      investigated by biosensor assay. The results showed a fast association rate
      constant (1.14 x 10(4) M(-1) s(-1)) but a very slow dissociation rate constant
      (3.24 x 10(-5) s(-1)) for BmK AS-1 binding to the Na+ channel on rat brain
      synaptosomes. The binding of BmK AS-1 to rat brain synaptosomes could be
      partially competed by BmK IT2, a depressant insect-selective toxin, but not by
      BmK I, an alpha-like toxin from the same venom. It was thus further demonstrated
      that BmK AS-1 might bind to a distinct receptor site, which was partially
      overlapping that for BmK IT2, but different from that of BmK I on rat brain Na+
      channels.

PMID- 10599846
TI  - Mismatch negativity in the visual modality.
AB  - In the auditory system, the automatic detection of stimulus change provides a
      mechanism for switching attention to biologically significant events. It gives
      rise to the mismatch negativity (MMN) event related potential. It is unclear
      whether a similar mechanism exists in vision. To investigate this issue, evoked
      potentials were recorded to target stimuli in the centre of the visual field, and
      to frequent standard and infrequent deviant stimuli presented outside the focus
      of attention, in the peripheral field. Deviants evoked a more negative potential
      than standards 250-400 ms after the stimulus. The negativity, distributed over
      supplementary visual areas of occipital and posterior temporal cortex, was
      associated with the rarity of the deviants and not the physical features which
      distinguished them from standards. This negativity shares a number of
      characteristics with auditory MMN.

PMID- 10599847
TI  - 5-HT1A autoreceptor desensitization by chronic ultramild stress in mice.
AB  - Electrophysiological and biochemical approaches were used to assess possible
      changes in central 5-HT neurotransmission in mice that had been subjected to
      chronic ultramild stress for 8 weeks. This treatment produced a significant
      decrease in the potency of the 5-HT1A agonist ipsapirone to inhibit the
      electrical activity of serotoninergic neurons in the dorsal raphe nucleus,
      without modifying 5-HT1A receptor binding in various brain areas. These data
      demonstrate that chronic ultramild stress triggers a long term and durable
      functional desensitization of somatodendritic 5-HT1A autoreceptors in mice.

PMID- 10599849
TI  - Expression in paradoxical sleep of a conditioned heart rate response.
AB  - After a session of habituation to a tone, awake rats underwent two conditioning
      sessions during which the tone was paired with footshock. The tone alone was
      presented during paradoxical sleep (PS) following each session; it never awakened
      the animal. Heart rate (HR) was recorded at each tone presentation in wakefulness
      and PS. During conditioning in wakefulness, tone presentation elicited HR
      accelerative responses. Tone-evoked HR accelerations were also detected in PS
      following the two conditioning sessions. Such changes were not observed in rats
      that received unpaired presentations of tone and footshock. These results
      demonstrate that an HR conditioned response acquired in wakefulness can be
      expressed during PS.

PMID- 10599848
TI  - Immunohistochemical localization of CDK5 activator p39 in the rat brain.
AB  - We examined the immunohistochemical localization of p39, the regulatory subunit
      of cyclin-dependent kinase 5 (Cdk5), in the adult rat brain. Cdk5 requires either
      p39 or p35 to assume its active form in the mammalian CNS. We developed a
      specific antibody against p39, and localized p39-immunoreactivity in the rat
      brain. p39-immunoreactivity was observed in the neuronal somata of the cerebral
      cortex, hippocampus and basal ganglia, and also in the Purkinje cells.
      Immunopositive astrocytes and oligodendrocytes were scattered throughout the rat
      brain. p35 immunoactivity has been observed exclusively in neurons and was never
      detected in glial cells. The present results suggest that p39 and p35 may have
      different functional roles in the regulation of Cdk5 in the rat CNS.

PMID- 10599850
TI  - Restoration of vision III: soma swelling dynamics predicts neuronal death or
      survival after optic nerve crush in vivo.
AB  - Predicting neuron death or survival after axonal injury is important in
      neurotrauma research. We now used in vivo confocal neuroimaging microscopy to
      repeatedly visualize retinal ganglion cells after optic nerve crush and studied
      their morphological alterations and ultimate fate. An intracollicular injection
      of a retrograde fluorescent tracer was made before or after optic nerve crush.
      Retinal ganglion cell sizes were then determined at different time points up to
      post-surgery day 75. Cell death was inevitable when soma swelling was fast and
      massive (86% above baseline or higher), but when it was slower and moderate (32%
      above baseline) long-term neuron survival could be predicted with high accuracy
      as early as post-operative day 5. Moderate swelling continued until day 15 (64%)
      and after about 3 weeks these cells started shrinking again, as a sign of
      recovery. We propose that moderate soma swelling is an adaptive rather than
      pathogenic post-traumatic reaction to axonal injury.

PMID- 10599851
TI  - Identification and distribution of Parkin in rat brain.
AB  - Mutations within the amino acid sequence of Parkin, the encoded protein of the
      parkin gene, appear to trigger the degeneration of dopaminergic neurons in the
      substantia nigra. Here, the presence and anatomical distribution of Parkin within
      the rat was examined. Immunoblot analysis of tissue homogenates showed two major
      bands at 50 and 44kDa. Within the brain, Parkin-containing neurons were
      identified in the basal ganglia, including the substantia nigra and caudate
      putamen. Parkin was visualized in the raphe nucleus, which as in the substantia
      nigra, was closely localized to monoaminergic-encoding neurons. In addition,
      Parkin was detected in laminar structures such as the cortex and hippocampus; a
      substantial number of Parkin-immunoreactive neurons was seen in the cerebellum as
      well. Parkin therefore is widely distributed in brain pathways implicated in the
      pathology of Parkinson's disease.

PMID- 10599852
TI  - Anxiogenic-like effect induced by substance P injected into the lateral septal
      nucleus.
AB  - The lateral septal nucleus is known to modulate aversive reactions and to receive
      a strikingly dense substance P (SP) innervation. In the present study, after
      determining the optimal intracerebroventricular dose (10 pmol) to induce aversive
      responses, we applied SP directly into the lateral septal nucleus, and quantified
      anxiogenic responses using the elevated plus-maze (EPM) test. Notably, when
      placed in the EPM these animals presented clear aversive behaviors expressed
      either as jumps and bursts of running (darting responses) or freezing. However,
      we observed an effective increase in the anxiogenic responses evaluated in the
      EPM test uniquely in the animals that presented freezing. Animals expressing
      darting responses, in turn, were likely to have a stronger aversive condition, in
      which anxiogenic-like responses were hindered when measured in the EPM test.
      Overall, the present results support the idea that SP may have an important
      modulatory role on anxiogenic responses mediated by the lateral septal nucleus.

PMID- 10599853
TI  - Persistent frontal P300 brain potential suggests abnormal processing of auditory
      information in distractible children.
AB  - The P300 event-related potential (ERP) was studied at the beginning, in the
      middle, and at the end of an auditory stimulus discrimination task in 70 normal 9
      year-old children. Easily distractible children showed frontally a short-latency
      P300 response to target stimuli throughout the task, whereas in the non
      distractible children the corresponding response was distinctly smaller and also
      showed a tendency to decrease in size towards the end of the task. The short
      latency frontal P300 response reflects activation of the brain's orienting
      networks, and it normally decreases in size when stimuli lose their 'novelty
      value' with stimulus repetition. Persistent frontal P300 suggest that
      distractible children continued to show enhanced orienting to stimuli that should
      have already been well encoded and/or categorized.

PMID- 10599854
TI  - Spatiotemporal progression of neurodegeneration and glia activation in the
      wobbler neuropathy of the mouse.
AB  - The wobbler mouse (phenotype WR; genotype wr/wr) has been investigated as a model
      for neurodegenerative diseases like SMA and ALS. A new diagnostic marker based on
      a polymorphism in the closely linked chaperonine gene Cct4 enabled us to diagnose
      the allelic status at the wr locus within the original background strain C57BL/6.
      Using this marker, we investigated the spatiotemporal progression of
      neuropathology in WR mice from postnatal day (d.p.n.) 10 to 60. Neurodegeneration
      starts at 13 d.p.n. in the thalamus (N. ventralis), in deep cerebellar nuclei,
      brain stem (N. vestibularis) and spinal cord interneurons. The motor nuclei of
      spinal nerves and motoneurons degenerate from 15 d.p.n. onward. Reactive
      astrocytes are observed around 17 d.p.n. in the white and grey matter of the
      spinal cord. Microgliosis occurs only from 23 d.p.n. onward. Our data demonstrate
      that in the WR disease, neurodegeneration in thalamus, cerebellum, and brain stem
      precedes motoneuron degeneration, astrogliosis and microgliosis.

PMID- 10599855
TI  - Red nucleus neurons of Bcl-2 over-expressing mice are protected from cell death
      induced by axotomy.
AB  - The Bcl-2 proto-oncogene regulates apoptosis and prevents cell death. We studied
      the effect of Bcl-2 gene over-expression on the survival of axotomized red
      nucleus (RN) neurons after unilateral hemisection at cervical segment 4/5 (C4/5)
      in mice. Seventy-five percent of RN neurons survived in Bcl-2 over-expressing
      mice 1 or 2 months after surgery compared with only 55% of RN neurons in wild
      type mice. However, Bcl-2 gene over-expression does not prevent lesion-induced
      shrinkage of RN neurons.

PMID- 10599856
TI  - EEG signs of vigilance fluctuations preceding perceptual flips in multistable
      illusionary motion.
AB  - This EEG study was performed to clarify the time course of brain electrical
      events and possible vigilance changes associated with perceptual flips during
      multistable perception. 13 healthy subjects (28.5 3.8 years) were recorded with a
      21-channel digital EEG during a stroboscopic alternative motion paradigm implying
      illusionary motion with ambiguous direction. Perceptual flips were preceded by a
      significant decrease of EEG frequencies, and followed by a significant frequency
      increase with a trend to overshoot. EEG slowing is a reliable sign of vigilance
      decrease and can be related to thalamic deactivation. This is consistent with a
      recent fMRI study, which showed thalamic deactivation associated with perceptual
      flips. The study added important chronological information about this phenomenon
      and allows the conclusion that reduced vigilance facilitates perceptual
      discontinuities during multistable perception.

PMID- 10599857
TI  - Temporal and speech processing deficits in auditory neuropathy.
AB  - Auditory neuropathy affects the normal synchronous activity in the auditory
      nerve, without affecting the amplification function in the inner ear. Patients
      with auditory neuropathy often complain that they can hear sounds, but cannot
      understand speech. Here we report psychophysical tests indicating that these
      patients' poor speech recognition is due to a severe impairment in their temporal
      processing abilities. We also simulate this temporal processing impairment in
      normally hearing listeners and produce similar speech recognition deficits. This
      study demonstrates the importance of neural synchrony for auditory perceptions
      including speech recognition in humans. The results should contribute to better
      diagnosis and treatment of auditory neuropathy.

PMID- 10599858
TI  - Over-expression of P-glycoprotein in malformations of cortical development.
AB  - Drug resistance in epilepsy due to malformations of cortical development (MCD) is
      unexplained. P-glycoprotein is a mediator of drug resistance, and we propose that
      MCD lesions over-express P-glycoprotein. Because P-glycoprotein expression may be
      induced by some antiepileptic drugs (AEDs), we studied brain samples from MCD
      cases before the onset of seizures or treatment with AEDs. Sixteen MCD cases and
      16 age-matched controls were examined using immunohistochemistry. Glial
      labelling, representing over-expression, was seen in 10 of 16 MCD samples and in
      two of 16 control samples (p = 0.003). Semiquantitative assessment showed many
      immunoreactive glia in five of 16 MCD and one of 16 controls. We conclude that
      there is constitutive over-expression of P-glycoprotein in many MCD.

PMID- 10599859
TI  - Does your gaze direction and head orientation shift my visual attention?
AB  - The effects of another person's gaze direction and head orientation on the
      observer's attentional processes were investigated. Subjects responded to visual,
      laterally presented reaction signals. The presentation of the reaction signal was
      preceded by a facial cue stimulus signaling a direction which was either
      congruent, neutral, or incongruent with the laterality of the reaction signal. A
      head (front and profile views) with an averted gaze affected the response times
      in comparison to the front view of a face with a straight gaze. In contrast, a
      profile view of a head with a compatible gaze direction did not result in such an
      effect. The results indicate that visual information from the other individual's
      gaze direction and head orientation is integrated, and the integrated information
      is fed to the brain areas subserving visual attention orienting.

PMID- 10599861
TI  - Localization of cerebral activity during simple singing.
AB  - Cerebral blood flow (CBF) was measured with PET during rudimentary singing of a
      single pitch and vowel, contrasted to passive listening to complex tones. CBF
      increases in cortical areas related to motor control were seen in the
      supplementary motor area, anterior cingulate cortex, precentral gyri, anterior
      insula (and the adjacent inner face of the precentral operculum) and cerebellum,
      replicating most previously seen during speech. Increases in auditory cortex were
      seen within right Heschl's gyrus, and in the posterior superior temporal plane
      (and the immediately overlying parietal cortex). Since cortex near right Heschl's
      has been linked to complex pitch perception, its asymmetric activation here may
      be related to analyzing the fundamental frequency of one's own voice for feedback
      guided modulation.

PMID- 10599860
TI  - Mesolimbic gender differences in peptide CART mRNA expression: effects of
      cocaine.
AB  - The putative neurotransmitter peptide CART has been suggested to be involved in
      the actions of psychostimulants. We analyzed the CART mRNA expression in
      mesolimbic brain areas of male and ovariectomized 17beta-estradiol- (30 microg)
      and vehicle-treated female rats. A gender difference was noted in the accumbens
      shell during basal conditions; male rats expressed higher levels of CART mRNA
      than both female groups. Following binge cocaine injections (3 x 15 mg/kg),
      elevated levels were found in the central amygdala of male but not female rats.
      In the medial accumbens shell CART mRNA was elevated after cocaine, but only in
      the non-treated females. The present results support a role of mesolimbic CART in
      psychostimulant drug action.

PMID- 10599862
TI  - fMRI during word processing in dyslexic and normal reading children.
AB  - The present study addresses phonological processing in children with
      developmental dyslexia. Following the hypothesis of a core deficit of assembled
      phonology in dyslexia a set of hierarchically structured tasks was applied that
      specifically control for different kinds of phonological coding (assembled versus
      addressed phonological strategies). Seventeen developmental dyslexics and 17
      normal reading children were scanned during four different tasks: (1) passive
      viewing of letter strings (control condition), (2) passive reading of non-words,
      (3) passive reading of legal words, and (4) a task requiring phonological
      transformation. Statistical analysis of the data was performed using statistical
      parametric mapping (SPM96). Comparison of patterns of activation in dyslexic and
      normal reading children revealed significant differences in Broca's area and the
      left inferior temporal region for both, non-word reading and the phonological
      transformation task. The present data provide new evidence for alteration of the
      phonological system in dyslexic children, and in particular, the system that
      mediates assembled phonological coding.

PMID- 10599863
TI  - Dopamine release in the prefrontal cortex in response to memantine following sub
      chronic NMDA receptor blockade with memantine: a microdialysis study in rats.
AB  - Memantine is an uncompetitive N-methyl-D-aspartate receptor antagonist which
      blocks the NMDA receptor with moderate-affinity in a use- and voltage dependent
      manner. In clinical practice it is used chronically in the treatment of dementia
      and does not induce psychotomimetic effects as, high affinity, uncompetitive
      antagonists. Thus, it was of interest to determine dopamine (DA) and metabolite
      (DOPAC - dihydroxyphenylacetic acid and HVA - homovanillic acid) concentrations
      in the prefrontal cortex (PFC) in response to 14 days administration of memantine
      (20 mg/kg/day). It was previously determined that in rats this treatment induces
      sensitization to the locomotor effect and tolerance to the learning impairing
      properties of high doses of memantine. Acute administration of memantine (20
      mg/kg, i.p.) did not affect dopamine levels in the PFC. It did however increase
      DA metabolite (DOPAC and HVA) concentrations. Administration of memantine (20
      mg/kg/day) for 14 days before the acute challenge only slightly changed
      memantine's effect on PFC neurochemistry even though pharmacokinetic tolerance
      was observed. When memantine was administered to the sham group, which had been
      repeatedly treated with Hypnorm (including neuroleptic), an increase in PFC
      dopamine and metabolite content was seen. In accordance with the fact that
      memantine does not possess psychotomimetic activity at therapeutically relevant
      doses, these experiments showed that it does not affect the prefrontal cortex
      dopamine levels.

PMID- 10599864
TI  - Expression of human tyrosine hydroxylase type I in Escherichia coli as a protease
      cleavable fusion protein. Short communication.
AB  - Wild-type and N-terminal 35-, 38-, and 44-amino acid-deleted mutants of human
      tyrosine hydroxylase type 1 (hTH1) fused to maltose-binding protein via the
      target sequence for a restriction protease were expressed in Escherichia coli and
      purified. The fused protein was treated with the restriction protease factor Xa
      or enterokinase to isolate hTH1 from the fused form. The treatment of fused wild
      type and 35-amino acid-deleted mutant with factor Xa and enterokinase caused non
      specific cleavages in the vicinity of the phosphorylation sites, Ser19 and Ser40,
      due to the flexible conformation of the N-terminus of hTH1.

PMID- 10599865
TI  - The effect of a subchronic post-lesion treatment with (-)-deprenyl on the
      sensitivity of 6-OHDA-lesioned rats to apomorphine and d-amphetamine.
AB  - The effects of a subchronic post-lesion treatment of 14 days with (-)-deprenyl or
      its solvent on the rotational response to apomorphine (0.1 mg/kg) and d
      amphetamine (2.5 mg/kg) in 6-OHDA- and SHAM-lesioned rats were investigated. Rats
      received a local injection of 6-OHDA (9 microg/0.7 microl) or its solvent into
      the medial forebrain bundle. Following the (SHAM or 6-OHDA) lesion the animals
      were randomly assigned to one of the two post-lesion treatment groups, viz.
      vehicle or (-)-deprenyl (0.1 mg/kg, 2 x day, i.p.) and treated for 14 days. After
      a wash out period of 6 weeks the number of rotations in response to apomorphine
      (0.1 mg/kg) and d-amphetamine (2.5 mg/kg) were compared. Seven days following the
      final behavioural experiments the animals were sacrificed and the striatal
      dopamine, DOPAC and HVA levels were determined. The (-)-deprenyl-treated 6-OHDA
      lesioned rats responded with a reduced number of rotations in response to
      apomorphine but not to d-amphetamine as compared to vehicle-treated 6-OHDA
      lesioned rats. However the two lesion groups did not differ in striatal dopamine,
      DOPAC and HVA concentrations; the levels were below or close to the detection
      limit ipsilateral to the 6-OHDA injections. Thus a post-lesion treatment with (-)
      deprenyl reduced the dopaminergic supersensitivity without a concomitant increase
      in striatal dopamine content. The data are discussed in the light of the
      previously described neurorescue properties of (-)-deprenyl.

PMID- 10599866
TI  - Protective effect of nitric oxide against iron-induced neuronal damage.
AB  - We investigated the effect of nitric oxide (NO) on iron-induced neuronal damage.
      Incubation of PC12 cells after the addition of FeCl2 induced rapid increases
      (within 1 hr) in lipid peroxidation and a concentration (0.1-2 mM)-dependent
      decrease in cell viability at 48 hr, both of which were blocked by deferoxamine
      and 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1,2-a]pyrazine-3-o ne
      hydrochloride (MCLA) (a superoxide scavenger) but not by mannitol (a hydroxyl
      radical scavenger). Iron-induced cytotoxicity was also antagonized by superoxide
      dismutase with catalase. On the other hand, the NO donors S-nitroso-N
      acetylpenicillamine (SNAP), 3-?(+/-)-(E)-ethyl-2'-[(E)-hydroxylamino]-5-nitro-3
      hexenecarbo moyl?-pyridine (NOR-4), and 2,2'-(hydroxynitrosohydrazono)bis
      ethanamine (NOC-18) decreased cell viability 48 hr after addition without
      increasing lipid peroxidation. However, when added with 1 mM FeCl2, NO donors
      including NOC-18, SNAP and NOR-4 (0.1-1 mM) inhibited lipid peroxidation in a
      concentration-dependent manner and suppressed cell death at lower concentrations.
      Addition of MCLA and NOC-18 also suppressed decreases in iron-induced
      [3H]thymidine incorporation. In rat brain homogenate, NOC-18 and SNAP both
      suppressed iron-induced lipid peroxidation. These findings suggest that NO has a
      dual effect on neuronal viability and can act as an antioxidant which protects
      neurons from iron-induced damage.

PMID- 10599867
TI  - Biphasic effect of sigma receptor ligands on the extracellular concentration of
      dopamine in the striatum of the rat.
AB  - The extracellular concentration of dopamine in the striatum of the rat was
      determined following the intrastriatal infusion of sigma ligands. The
      administration of (+)-pentazocine (0.3 and 1.0 mM) through a microdialysis probe
      for 120 min resulted in a biphasic effect on the extracellular concentration of
      dopamine: a brief increase of approximately 70% followed by a prolonged decrease
      of approximately 65%. A similar effect on dopamine release was elicited by the (
      )-isomer of pentazocine, as well as by di-o-tolylguanidine. In addition, the
      infusion of the NMDA antagonist 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic
      acid (CPP) (100 microM) through the dialysis probe significantly attenuated the
      initial increase but not the subsequent decrease in dopamine release produced by
      the intrastriatal infusion of (+)-pentazocine. These data are suggestive that
      dopamine release in the striatum may be modulated by multiple sigma receptor
      subtypes and that NMDA receptors may mediate the stimulatory effect of sigma
      ligands on dopamine release in the striatum.

PMID- 10599868
TI  - Flupirtine shows functional NMDA receptor antagonism by enhancing Mg2+ block via
      activation of voltage independent potassium channels. Rapid communication.
AB  - The spectrum of action of flupirtine includes analgesia, muscle relaxation and
      neuroprotection. N-methyl-D-aspartate (NMDA) receptor antagonism has been
      discussed as a possible mechanism of action of this compound with little direct
      evidence. The objective of the present study was to develop a plausible model to
      explain flupirtine's spectrum of action. A four-stage strategy was selected for
      this purpose: Firstly, the serum concentration of flupirtine under therapeutic
      conditions was determined on the basis of the current literature. The second
      stage involved assessing the known in-vitro effects in light of the therapeutic
      active concentration. Using whole cell patch clamp recordings from cultured rat
      superior colliculus neurones interactions between flupirtine and NMDA receptors
      were assessed. Only very high concentrations of flupirtine antagonized inward
      currents to NMDA (200 microM) at -70 mV with an lC50 against steady-state
      responses of 182.1+/-12.1 microM. The effects of flupirtine were voltage
      independent and not associated with receptor desensitization making actions
      within the NMDA receptor channel or at the glycine modulatory site unlikely. NMDA
      receptor antagonism probably has little relevance for the clinical efficacy of
      flupirtine as the concentrations needed were far higher than those achieved in
      clinical practice. However, the activation of a G-protein-regulated inwardly
      rectifying K+ channel was identified as an interesting molecular target site of
      flupirtine. In the next stage, the central nervous spectrum of action of
      experimental K+ channel openers (PCO) was considered. As far as they have been
      studied, experimental K+ channel openers display a spectrum of action comparable
      to that of flupirtine. In the final stage, a global model was developed in which
      flupirtine stabilizes the resting membrane potential by activating inwardly
      rectifying K+ channels, thus indirectly inhibiting the activation of NMDA
      receptors. The model presented here reconciles the known functional NMDA receptor
      antagonism of flupirtine with the activation of K+ channels that occurs at
      therapeutic concentrations, thus providing an understanding of flupirtine's
      spectrum of action. This makes flupirtine the prototype of a clinically
      applicable substance group with analgesic, muscle-relaxant and neuroprotective
      properties.

PMID- 10599869
TI  - Maternal photoperiodic exposures alter the neonatal growth, pineal functions and
      sexual development of the Indian palm squirrel F. pennanti. Short communication.
AB  - The phenomenon of maternal transfer of photic information to their young ones is
      still an enigma. Existing reports in some rodents of temperate zone suggest that
      photoperiodic condition experienced by mother during their gestation period
      influences the pineal physiology of fetus, but nothing has been reported about
      the growth and sexual development of pups. Present experiment for the first time
      explains the effect of gestational photoperiod on the growth and sexual
      development of pups from a seasonally breeding tropical rodent F. pennanti. The
      results suggest that, constant light (LL; 24L: OD) and long day length (LDL; 14L:
      10D) experiencing mother conveyed the photic information to young ones to inhibit
      the pineal function, while short day length (SDL; 10L: 14D) stimulated the pineal
      function in pups. Altered pineal functions of pups ultimately interfered with
      their growth and sexual maturation. Most interestingly, the pups delivered by DD
      experiencing mothers and then reared under same condition, at the age of 40 days
      attained a level of growth and sexual maturity equivalent to the growth and
      sexual maturation of 60 days old pups under natural day length (NDL) condition.
      Therefore, we may suggest that the photic information perceived by the mother
      alter her normal melatonin level, hence, passing through placenta melatonin
      influences the growth and sexual maturation of the young ones.

PMID- 10599870
TI  - Serum and cerebrospinal fluid concentrations of melatonin: a pilot study in
      healthy male volunteers.
AB  - Melatonin was determined in serum and cerebrospinal fluid (CSF) obtained from 13
      healthy males lumbar-punctured in the sitting position without preceding bed
      rest. There was a significant correlation between the levels of melatonin in
      serum and the CSF. The serum concentration was lower than that in the CSF, a
      finding that calls in question the theory that melatonin is mainly released from
      the pineal gland into the bloodstream. In conclusion, serum levels of melatonin
      in healthy male volunteers, mirror the CSF concentrations when lumbar puncture is
      carried out using the described technique.

PMID- 10599871
TI  - Effects of co-administration of anticonvulsant and putative anticonvulsive agents
      and sub/suprathreshold doses of L-dopa upon motor behaviour of MPTP-treated mice.
AB  - The effects of co-administration of the dopamine precursor, L-Dopa, with
      anticonvulsant and putative anticonvulsive agents upon the motor activity of
      hypoactive MPTP-treated C57 BL/6 mice were measured in six experiments. In each
      case, MPTP (2 x 40 mg/kg, s.c., separated by a 24-hr interval) was administered
      four to six weeks prior to behavioural testing. Thus, the effects of these agents
      combined with either a single acute, subthreshold dose (5 mg/kg, s.c.) of L-Dopa,
      or, with chronically-administered, suprathreshold doses (20 mg/kg, s.c.) of L
      Dopa were studied. In the former, lamotrigine, FCE 26743 and L-Deprenyl, injected
      60 min before subthreshold L-Dopa (5 mg/kg), each induced an antiparkinsonian
      action in MPTP-treated mice that consisted of dose-specific, as opposed to dose
      related, elevations of locomotion and rearing behaviour. In the latter,
      lamotrigine (all three measures of activity at 3 mg/kg), FCE 26743 (locomotion
      and total activity at 3; rearing at 1 and 3 mg/kg) and L-Deprenyl (locomotion and
      total activity at 1 and 3mg/kg), but not phenytoin (neither at 1 nor 3 mg/kg),
      reinstated the motor activity-stimulating effects of the threshold dose of L-Dopa
      (20 mg/kg) in L-Dopa-tolerant, MPTP-treated mice. Neurochemical analyses
      confirmed severe DA depletions in MPTP-treated mice. Since neither lamotrigine,
      FCE 26743 nor L-Deprenyl, nor subthreshold L-Dopa, by themselves increased the
      motor behaviour of MPTP-treated mice, a synergistic effect of the co
      administration is concluded. Further, since the suprathreshold dose of L-Dopa by
      itself failed to stimulate motor activity in the MPTP mice following chronic (25
      daily injections) administrations of the compound, it is suggested that a
      restorative effect, in combination with lamotrigine, FCE 26743 or L-Deprenyl was
      evidenced. The potential therapeutic benefits of anticonvulsant or putative
      anticonvulsive compounds for parkinsonian symptoms are discussed.

PMID- 10599872
TI  - A trial of L-deprenyl for the treatment of neuroleptic-induced parkinsonism.
AB  - This study examined the potential of L-Deprenyl, a selective monoamine oxidase-B
      (MAO-B) inhibitor, for the treatment of neuroleptic-induced parkinsonism (NIP).
      Thirty-one consecutive schizophrenic or schizophreniform patients were treated
      with haloperidol in a flexible dose design. Nineteen of them developed NIP and
      were administered adjunctive L-Deprenyl 10 mg/d for six weeks in an open fixed
      dose design. One patient had to be withdrawn from the study because of
      exacerbation of the NIP. Severity of NIP was mild to moderate throughout the
      whole study period in all other cases. Five patients were considered to require
      biperiden 2-4 mg/d in addition to L-Deprenyl after two weeks of treatment,
      although they did not differ from the other 13 patients in any of the variables
      studied. A significant improvement in NIP was found in both groups of patients,
      with no psychotic exacerbation or a change in the dosage of haloperidol. These
      findings suggest that selective MAO-B inhibitors may be effective in some
      patients with mild to moderate NIP.

PMID- 10599873
TI  - Respiratory chain enzyme activities in spermatozoa from untreated Parkinson's
      disease patients.
AB  - We studied respiratory chain enzyme activities in spermatozoa homogenates from 12
      untreated Parkinson's disease (PD) male patients and from 23 age matched healthy
      male controls. When compared with controls, PD patients showed significantly
      lower specific activities for complexes I+ III, II+III, and IV. However, citrate
      synthase corrected activities were similar in patients and controls. Values for
      enzyme activities in the PD group did not correlate with age at onset, duration,
      scores of the Unified Parkinson's Disease Rating Scales and Hoehn and Yahr
      staging. These results suggest that this tissue cannot be used to develop a
      diagnostic test for PD.

PMID- 10599874
TI  - An overnight switch to ropinirole therapy in patients with Parkinson's disease.
      Short communication.
AB  - Patients with Parkinson's disease (n = 68) switched from pergolide or
      bromocriptine to ropinirole overnight (dose equivalence ratios 1:6 and 10:6,
      respectively). The activities of daily living score for the Unified Parkinson's
      Disease Rating Scale (UPDRS) was significantly improved 4 weeks after the
      bromocriptine-ropinirole switch. All other UPDRS scores, including that for the
      side-effect component, were not significantly different after either switch.
      Overnight switching may be a safe therapeutic approach that may reduce
      hospitalisation and related socio-economic costs.

PMID- 10599875
TI  - Clinimetric issues of screening for responsiveness to intrathecal baclofen in
      dystonia.
AB  - OBJECTIVES: In this study we address clinimetric issues that pertain to the
      screening of responsiveness to intrathecal baclofen (ITB) in dystonia. METHODS:
      Eight patients with severe dystonia, who did not respond to oral medication, were
      evaluated in a double-blind placebo controlled ascending dose screening
      procedure, which included a randomised sequence of injections of 25, 50 and 75
      microg baclofen and placebo. Self-assessments of dystonia severity on a visual
      analogue scale (VAS) and the Dyskinesia Rating Scale (DRS) were carried out at
      baseline 1, 4 and 8 hours after a bolus injection. RESULTS: Compared to the VAS,
      the DRS lacked responsiveness in all patients. Baseline scores of the VAS scores
      varied considerably between and within patients and underscore the need to
      express response scores in relation to the baseline. After placebo administration
      some patients showed a persistent improvement of about 30% across the day, while
      at some assessments improvements of >50% were noted. Based on the aforementioned
      findings, a responsiveness coefficient was used which relates the baclofen effect
      size to the non-specific score changes that may occur as a placebo effect or as
      random fluctuations in dystonia. Four patients with a responsiveness coefficient
      >2 received pump implantation and did well on continuous infusion of ITB. Several
      side effects occurred during the screening procedure, but none interfered with
      the execution of the screening procedure. CONCLUSIONS: This study demonstrates
      important clinimetric issues that need to be taken into account when screening
      for responsiveness to ITB.

PMID- 10599876
TI  - Increased cerebrospinal fluid levels of substance P in patients with amyotrophic
      lateral sclerosis. Short communication.
AB  - To clarify the mechanism of brain and spinal cord impairment in amyotrophic
      lateral sclerosis (ALS), we measured the cerebrospinal fluid (CSF) levels of
      substance P (SP) in 11 patients with sporadic ALS. Findings were compared with
      those obtained in controls and diseased controls. The CSF SP levels of patients
      with ALS, and particularly in patients with a disease duration of less than 2.5
      years, were significantly higher than those in controls. These findings strongly
      suggested that SP may play an important role in the pathophysiology of ALS.

PMID- 10599877
TI  - Extrapontine myelinolysis with parkinsonism after rapid correction of
      hyponatremia: high cerebrospinal fluid level of homovanillic acid and successful
      dopaminergic treatment.
AB  - Extrapontine myelinolysis (EPM) is a demyelinating process of the brain. We
      report the case of an 11-year-old girl who developed EPM with parkinsonism.
      Magnetic resonance imaging revealed demyelinating patterns in the basal ganglia
      without central pontine lesions. The cerebrospinal fluid levels of homovanillic
      acid and 5-hydroxyindoleacetic acid were high at the time of onset and normalized
      upon complete recovery from extrapyramidal symptoms after a dopaminergic
      treatment. We speculated that demyelination of nerve fibers containing dopamine
      receptors in the striatum might be a main cause of these symptoms.

PMID- 10599878
TI  - Diminished neuronal metabolic activity in Alzheimer's disease. Review article.
AB  - An increasing number of studies have appeared in the literature suggesting that
      Alzheimer's disease (AD) is a hypometabolic brain disorder. Decreased metabolism
      in AD has been revealed by a variety of in vivo and postmortem methods and
      techniques including positron emission tomography and glucose metabolism. We used
      the size of the Golgi apparatus (GA) and cell profile area as indicators of
      neuronal activity in postmortem material. Using an antibody against MG-160, a
      sialoglycoprotein of the medial cisternae of the GA, we were able to visualize
      and quantify the GA area. In a series of experiments, we tried to relate neuronal
      metabolism to different hallmarks of AD, i.e. plaques and tangles, and also to
      genetic risk factors for AD like age and (apolipoprotein E) ApoE polymorphism.
      Our results showed that in AD there is indeed a clear reduction in brain
      metabolism in several severely affected brain regions including the nucleus
      basalis of Meynert (NBM), the CA1 area of the hippocampus and the hypothalamic
      tuberomamillary nucleus. However, the reduction in neuronal activity did not seem
      to be caused by the presence of neuropathological hallmarks of AD, i.e. plaques
      and tangles. There was, however, a clear relationship between the presence of
      ApoE epsilon4 alleles and a decrease in GA size. Our data suggest that decreased
      neuronal activity and neuropathological hallmarks of AD, such as plaques and
      tangles, are basically independent phenomena. Moreover, ApoE epsilon4 may
      participate in the pathogenesis of AD by decreasing neuronal metabolism. The main
      implication of these findings is that therapeutic strategies in AD should be
      focussed on reactivation of neuronal metabolism.

PMID- 10599879
TI  - Ventral hippocampal glutamate receptors in the rat: possible involvement in
      learning mechanisms of an active avoidance response.
AB  - The role of ventral hippocampus glutamate receptors on learning mechanisms and
      memory was studied in the rat. Adult male rats were unilaterally implanted in the
      ventral hippocampus with microinjection cannulas. The general experimental
      procedure used was the chemical stimulation of hippocampal neurons with glutamic
      acid alone or in combination with glutamate receptor antagonists during learning
      of an active avoidance response. The one-way active response consisted in
      avoiding an electric shock applied to the feet while an ultrasonic tone of 40 KHz
      was on. Two series of experiments were performed. In Experiment 1, the possible
      effect of glutamate on the evocation of the learned avoidance response was
      studied. In Experiment 2, the possible effect of glutamate on the acquisition of
      the avoidance response was analyzed. Experiment 1 showed that glutamate in the
      range 1-10 nmol did not interfere with the recall of the avoidance response,
      suggesting that glutamate has no effect on the hippocampal evocation processes.
      Experiment 2 showed that glutamic acid inhibits the acquisition process,
      increasing the latency time of escape and deteriorating the learning efficiency.
      This effect was antagonized by AP7, the NMDA-glutamate receptor antagonist, and
      increased by AP3, the metabotropic glutamate receptor antagonist. Present data
      suggest that metabotropic glutamate receptors facilitate and NMDA-glutamate
      receptors inhibit the learning hippocampal mechanisms in the rat.

PMID- 10599880
TI  - Antipsychotic-like effect of the AMPA receptor antagonist LY326325 as indicated
      by suppression of conditioned avoidance response in the rat.
AB  - The effect of LY326325, a novel AMPA receptor antagonist, on the conditioned
      avoidance response and catalepsy was investigated in the rat. The conditioned
      avoidance response is a behavioral methodology which is regarded to predict
      potential antipsychotic efficacy of experimental drugs. Catalepsy ratings were
      utilized to assess the putative propensity of LY325326 to induce extrapyramidal
      side effects. Systemic administration of LY326325, 18 mg/kg subcutaneously,
      caused a selective suppression of conditioned avoidance response, without effect
      on escape behavior or intertrial crosses. In addition, no catalepsy was observed.
      Our present and previous results support an antipsychotic effect of AMPA receptor
      antagonists with a low liability for extrapyramidal side effects, i.e.
      pharmacological effects consonant with an atypical antipsychotic profile.

PMID- 10599881
TI  - Low CSF soluble interleukin 2 receptor levels in acute depression. Short
      communication.
AB  - Thirteen patients with DSM-III-R diagnosis of either major depression or bipolar
      I depression participated in the study. The control group consisted of 10
      subjects evaluated for headache or suspected meningitis, none of whom were found
      to suffer from any organic disease. CSF was withdrawn from all subjects for the
      measurement of soluble interleukin 2 receptor (sIL-2R). CSF sIL-2R levels were
      found to be lower in patients as compared to controls (df = 1, 20; F = 84;
      p<0.000001).

PMID- 10599882
TI  - The 5' region of the tryptophan hydroxylase gene: mutation search and association
      study with alcoholism.
AB  - A deficiency in the serotonergic system has been suggested as a negative
      reinforcer in alcoholism. Tryptophan hydroxylase (TPH) is critical in the fine
      tuning of serotonergic neurotransmission. We observed a significantly high
      frequency of the A allele of the IVS7+218A>C polymorphism in intron 7 of the TPH
      gene in Japanese alcoholics with histories of drinking-related antisocial
      behaviors compared with that of Japanese controls (p = 0.006). However, this
      polymorphism is intronic, and a study of TPH mRNA did not detect aberrant splice
      products or polymorphic nucleotides linked to this polymorphism. Therefore, we
      screened for variations in the promoter and 5'-untranslated region of the gene.
      Three novel variants/polymorphisms, -1066G>A in the 5' flanking region,
      IVS1B+23(GTTTT)4-5 in intron 1B, and IVS1C+50T>C in intron 1C, were identified.
      The -1066G>A and IVS1C+50T>C polymorphisms were in modest linkage disequilibrium
      with the IVS7+218A>C polymorphism. However, no significant association was found
      between the three novel polymorphisms and alcoholism. Although our findings
      reiterate that TPH may play some role in the genetic predisposition to
      alcoholism, the mechanism remains unknown.

PMID- 10599883
TI  - Corneodesmosin gene polymorphism demonstrates strong linkage disequilibrium with
      HLA and association with psoriasis vulgaris.
AB  - Corneodesmosin (CD) is thought to play a key role in corneocyte cohesion, and its
      proteolysis appears to be a major event in the process of desquamation. Recently
      it was shown that CD is encoded by the S-gene, which is located approximately 160
      kb telomeric of HLA-C. In the present study, the role of CD in the genetics of
      psoriasis vulgaris was studied in greater detail. The second exon of the CD gene
      was sequenced in 86 HLA-typed individuals from 13 psoriasis multiplex families. A
      total of 11 silent dimorphisms and 7 variants resulting in amino acid
      substitutions were found. Pedigree analysis showed that these variants could be
      grouped into 7 alleles, encoding 6 different amino acid sequences. These alleles
      are in strong linkage disequilibrium with HLA-B and -C, indicating that the
      polymorphism of the CD gene is ancient and well conserved rather than sporadic.
      One allele at the CD locus, designated CD2, displayed strong linkage
      disequilibrium with HLA-Cw6, the HLA allele most prominently associated with
      psoriasis. CD2 demonstrated a greater relative risk than Cw6 (3.4 vs. 2.5, not
      significant) and higher significant transmission disequilibrium with psoriasis
      than any of the investigated HLA-alleles. Due to its biologic function, cellular
      location and disease association, the CD gene appears to be an excellent
      candidate gene for PSORS1, the HLA-linked determinant of psoriasis vulgaris.

PMID- 10599884
TI  - Alpha-2 domain polymorphism and HLA class I peptide loading.
AB  - Diversity within the class I HLA antigen binding groove is positioned to moderate
      the presentation of peptide ligands. Polymorphism is widely dispersed about the
      peptide binding groove, and unravelling the functional significance of a given
      polymorphism requires comparative analysis of peptides presented by class I
      subtypes differing at the position(s) in question. Previous studies have
      demonstrated that not all class I polymorphisms act equally, and to determine the
      impact of substitutions specifically located in the alpha2 domain, peptides
      purified from B*1501, B*1512, B*1510, and B*1518 were examined by pooled Edman
      sequencing and comparative mass spectrometric analysis. Molecule B*1512 differs
      from B*1501 at residues 166 (Glu to Asp) and 167 (Trp to Gly) of the alpha2
      domain. The pooled motif and ion mass ligand maps for B*1512 tightly matched
      those of B*1501, demonstrating that the 166/167 polymorphism between B*1501 and
      B*1512 has little impact upon ligand presentation. Although the 166/167
      polymorphism minimally affects peptide binding preferences, this polymorphism
      makes B*1512 and B*1501 quite distinct by serology. We then compared the B70
      molecules B*1510 and B*1518. The two are almost indistinguishable by serology and
      differ only by an alpha2 polymorphism at 116. Comparative peptide mapping shows
      that a Tyr to Ser polymorphism at 116 drastically changes the ligands bound by
      B*1510 and B*1518; no overlaps could be found. Polymorphisms in alpha2 therefore
      vary from subtle to extreme in the manner by which they moderate ligand
      presentation, and serologic crossreactivity did not reflect the ligands presented
      by these B15 subtypes.

PMID- 10599885
TI  - LPS upregulates MHC class II I-A expression in B lymphocytes at transcriptional
      and at translational levels.
AB  - Major histocompatibility complex (MHC) class II molecules are expressed in a
      limited number of cell types, including B lymphocytes, dendritic cells and
      macrophages. Lipopolysaccharide (LPS) increases the surface expression of class
      II molecules in a murine B-cell line by inducing an increase in I-A protein and I
      A mRNA levels. LPS does not modify the rate of mRNA degradation; therefore, the
      increase in mRNA is due to an increase in transcription. In addition, LPS
      increases the levels of I-Aalpha protein, which correlates with an increase in
      ribosome loading for I-Aalpha but not for I-Abeta mRNA after treatment with LPS.
      Interestingly, in non-induced cells, I-Aalpha messenger RNA shows a significant
      peak of free mRNA. Therefore, LPS regulates the expression of MHC class II
      molecules at translational level in B cells, in addition to the transcriptional
      control. The actual mechanism implies changes of translation initiation rates, as
      shown by an increase ribosome loading in polysome gradients.

PMID- 10599886
TI  - The IL-4 receptor alpha-chain variant Q576R is strongly associated with decreased
      kidney allograft survival.
AB  - The involvement of the interleukin-4 (IL-4) pathway in B-lymphocyte activation
      and induction of a T helper 2 (Th2) cell response prompted us to investigate the
      influence of a recently described gain-of function mutation in the IL-4 receptor
      alpha-chain gene (IL-4R alpha; CD 124) on renal allograft survival. We developed
      a genotyping assay for the IL-4R alpha variant Q576R and investigated 203 renal
      transplant patients, all of whom underwent transplantation surgery at a single
      institution. The overall frequency of the IL-4R alpha variant Q576R in this group
      was 38.9% (79/203). The Kaplan-Meier method was used to estimate the graft
      survival of 156 patients with complete follow-up time of 24 months. Significantly
      higher graft survival rates (P=0.012, log-rank test) were found in patients with
      the wild-type IL-4 receptor (2-year graft survival 78.8%) as compared to patients
      with the IL-4R alpha variant Q576R (2-year graft survival 60.6%). Multifactorial
      cox regression analysis showed that this effect was independent of HLA matching,
      sex of donor and recipient, age of recipient, year of transplantation and
      preformed antibodies (P=0.017). These results indicate a strong association of
      the IL-4R alpha variant Q576R with kidney allograft loss. Genotyping of kidney
      allograft recipients for the IL-4R alpha variant may offer a simple method to
      identify high-risk patients in the post-transplantation period.

PMID- 10599887
TI  - Allele typing of human TNFA 5'-flanking region using polymerase chain reaction
      preferential homoduplex formation assay (PCR-PHFA): linkage disequilibrium with
      HLA class I and class II genes in Japanese.
AB  - Tumor necrosis factor alpha plays a substantial role in a number of conditions
      such as inflammation, autoimmunity, insulin resistance and sleep. Three new
      single nucleotide polymorphisms, -1,031 T/C, -863 C/A and -857 T/C, were recently
      identified in the upstream 5'-flanking region of TNFA in the Japanese population.
      In the present study, we developed polymerase chain reaction (PCR)-preferential
      homoduplex formation assay for the single-step allele typing of TNFA, and
      determined the genotypes of 271 healthy unrelated Japanese individuals. Four
      haplotypes, -1,031/-863/-857 TCC, TCT, CAC and CCC, were found to constitute the
      majority, if not all, of the TNFA alleles of healthy Japanese population. These
      alleles were designated as TNFA-U01, -U02 -U03 and -U04, respectively, in the
      order of frequency. Based on HLA-A, -B and -DRB1 genotypes together with TNFA
      genotypes, multi-locus haplotypes were analyzed. Significant positive
      associations were observed between TNFA-U01 and A*3303, B*5201, B*4403, B*4601,
      B*0702, DRB1*1502, DRB1*0101, DRB1*1302, between TNFA-U02 and B*5401, B*3501,
      DRB1*0405, DRB1*0407, between TNFA-U03 and B*4006, B*4002, DRB1*0803, DRB1*0802,
      DRB1*0403, DRB1*0901, and between TNFA-U04 and B*4801. Four-locus haplotype
      estimation revealed that A*3303-B*4403-TNFA-U01-DRB1*1302, A*2402-B*5201-TNFA-U01
      DRB1*1502 and A*2402-B*5401-TNFA-U02-DRB1*0405 constitute major extended
      haplotypes in Japanese. Interestingly, TNFA alleles previously shown to have a
      higher promoter activity (U02, U03) were found to form haplotypes with certain
      DRB1 alleles associated with T helper 1 (Th1)-dominant diseases such as
      rheumatoid arthritis, insulin dependent diabetes mellitus and Crohn's disease in
      Japanese. In contrast, TNFA allele with a low promoter activity (U01) is in
      linkage disequilibrium with the DRB1 alleles associated with T helper 2 (Th2)
      dominant diseases such as atopic dermatitis and ulcerative colitis. These
      observations raise the possibility that TNFA upstream promoter region
      polymorphisms contribute to some of the HLA-disease associations.

PMID- 10599888
TI  - Expression of the membrane protein tyrosine phosphatase CD148 in human tissues.
AB  - CD148, a receptor-like protein tyrosine phosphatase also known as HPTP-eta/DEP-1,
      is involved in signal transduction in leucocytes and is thought to contribute to
      mechanisms of cellular differentiation. We have investigated the in situ
      expression of CD148 in various fresh-frozen tissues by immunohistology and
      analyzed its expression on subpopulations of activated peripheral blood
      leucocytes by flow cytometry. In lymphoid organs, CD148 was found to be widely
      expressed on B and T cells, granulocytes, macrophages, certain dendritic cells as
      well as mature thymocytes. The cellular level of CD148 was increased after in
      vitro activation of peripheral blood leucocytes. Comparative analysis of tissue
      samples from normal gut and from patients with active Crohn's disease showed that
      leucocytes expressing CD148 are significantly upregulated in inflamed tissues and
      that a subset of these cells co-express the activation marker CD25. In non
      lymphoid tissues, CD148 was found to be present on many epithelial cell types
      with glandular and/or endocrine differentiation as well as on fibrocytes,
      melanocytes and Schwann cells. CD148 expression was maintained also in malignant
      counterparts of such tissues. However, a marked loss of CD148 immunoreactivity
      was apparent in some of the investigated high-grade carcinomas. In summary, our
      results confirm a role of CD148 as a leucocyte activation marker. Among non
      hematopoietic cells, CD148 is expressed by characteristic types of epithelial and
      non-epithelial cells. Downregulation of CD148 might promote dedifferentiation and
      autonomous growth of such cells in malignant tumors.

PMID- 10599889
TI  - Expression of homing receptors and related molecules on human mast cells and
      basophils: a comparative analysis using multi-color flow cytometry and toluidine
      blue/immunofluorescence staining techniques.
AB  - Mast cells (MC) and blood basophils (Ba) are multifunctional effector cells of
      the immune system and accumulate in areas of ongoing disease. However, despite of
      similar morphology, MC and Ba differ from each other in terms of cell surface
      receptor expression, mediator content, and tissue distribution. In order to gain
      new insights into mechanisms and molecules responsible for the distribution and
      accumulation of MC and Ba, we have investigated expression of homing receptors on
      primary human MC (lung, n=28; uterus, n=17), Ba (healthy donors, n=64), the mast
      cell line HMC-1, and the basophil line KU-812. Expression of cell surface
      antigens on MC and Ba was analyzed by mAb and indirect immunofluorescence
      staining techniques. In addition to previous findings, Ba were found to react
      with mAb against the selectin-ligands sLe(x) (CD15s) and PSGL-1 (CD162), L
      selectin (CD62L), beta7-integrin, the 'matrix-receptor' neurothelin (CD147),
      platelet-endothelial cell tetraspan antigen-3 (PETA-3=CD151), and BST-1 (CD157).
      Novel antigens detectable on MC (lung and uterus) were CD147, CD151, CD157 and
      CD49c (VLA-3alpha). By contrast, MC were not recognized by mAb to sLe(x), PSGL-1,
      L-selectin, or beta7 integrin. No reactivity of Ba or MC with mAb to syndecan-1
      (CD138), VE-cadherin (CD144), MUC18/MCAM (CD146), MGC-24 (CD164), or ALCAM
      (CD166) was found. The cell lines HMC-1 and KU-812 expressed a similar profile of
      antigens when compared to primary cells. In summary, Ba and MC express a unique
      profile of homing molecules. Apparently, Ba differ from MC in expression of
      recognition receptors relevant for binding to endothelium and consecutive
      transmigration.

PMID- 10599890
TI  - High-resolution typing for HLA-DRB1*15 amd -DRB1*16 by fluorescence-marked
      sequence-specific priming (TaqMan assay).
AB  - Sequence-specific primed polymerase chain reaction (PCR-SSP) is widely used in
      HLA laboratories. The TaqMan method, which is described here for high-resolution
      typing of HLA-DRB1*15 and -DRB1*16, does not require elaborate and time-consuming
      post-PCR detection steps. In this one-tube assay, conventional PCR-SSP and
      fluorescence detection of the amplicon with a doubly labeled fluorescent probe
      are combined: a fluorogenic hybridization probe (FHP) labeled with a spectral
      resolvable fluorescent reporter dye (FAM or TET) at its 5' terminus and a common
      quencher dye (TAMRA) at its 3' terminus is cleaved by the 5' nuclease activity of
      Taq DNA polymerase only if the target sequence is amplified. An increase of
      fluorescence intensity indicates a successful amplification. For high-resolution
      typing of HLA-DRB1*15 and -DRB1*16 alleles we designed two FHPs and 14 specific
      primer mixes (7 for DR15 and 7 for DR16). Amplification of the specific sequence
      was detected by a FAM-labeled FHP, whereas amplification of the internal control
      was detected by a TET-labeled FHP. We were able to type all heterozygous
      DRB1*15/DRB1*16 subtype combinations. For evaluation, 60 HLA-DRB1*15-positive and
      40 HLA-DRB1*16-positive individuals were typed and the results were compared with
      conventional PCR-SSP DR15/16 subtyping. There were no discrepancies between the
      two methods. The TaqMan method is an alternative to conventional PCR-SSP typing
      which is suitable for routine use in HLA laboratories.

PMID- 10599891
TI  - HLA class II molecular polymorphisms in healthy Slavic individuals from North
      Western Russia.
AB  - Polymerase chain reaction (PCR)-based genotyping was used to characterize the
      features of HLA class II molecular polymorphisms in a Slavic population of North
      Western Russia. Two hundred individuals were analyzed for the DRB1 gene, and 100
      persons randomly selected from this cohort were additionally typed for DQA1, DQB1
      and DPB1 genes. Allele and haplotype frequencies were found to be similar to
      those observed in other Caucasian populations, with the exception of considerably
      high prevalence of the DPB1*0301 allele (16.0%) in the group studied. The high
      rate of diversity was observed within DRB1*04 and DRB1*14 specificities, as well
      as for extended DR-DQ haplotypes. In addition, significant number of "unusual" DR
      DQ linkage patterns have been detected. The data seem to reflect the complexity
      of ethnic background of "European" Russians and may be helpful for the
      development of international network between donor registries.

PMID- 10599892
TI  - New HLA class II alleles in the Indonesian population.
AB  - This paper describes two new class II alleles of the major histocompatibility
      complex (MHC), DRB1*1431 and DRB3*0303, that have been found in the Indonesian
      population. In addition, the identification of DRB1*0819 is presented as a
      confirmatory report.

PMID- 10599893
TI  - DQB1*0602 confers genetic susceptibility to multiple sclerosis in Afro
      Brazilians.
AB  - We studied the distribution of the HLA-DRB1, -DQA1 and -DQB1 alleles in 44 Afro
      Brazilian patients with multiple sclerosis and 88 controls. Although no
      significant differences were found between the patients and controls for the DRB1
      and DQA1 alleles, the HLA-DQB1*0602 allele was positively associated with
      multiple sclerosis (45.0% vs. 17.0%, Pc=0.024, RR=3.31). The positive extended
      haplotypes for DQB1*0602 were more frequent in patients than controls, although
      the differences were not statistically significant in any of them. These results
      in Afro-Brazilians are in line with other studies which have found DQB1*0602 to
      be associated with the disease in the absence of the DRB1*1501 allele. We
      therefore think that the association with the disease in this ethnic group is
      more allelic than haplotypic.

PMID- 10599894
TI  - Linkage and association study of the CTLA-4 region in coeliac disease for Italian
      and Tunisian populations.
AB  - Coeliac disease (CD) is a multifactorial disease for which there is an intensive
      search for genetic risk factors. Some authors found an association between the
      CTLA-4 region and CD. In the present work, we investigate the possible
      implication of the CTLA-4 region as a genetic risk factor for CD, through two
      statistical approaches: the maximum likelihood score (MLS) test in a large
      Italian sample of affected sib-pairs using polymorphic genetic markers on
      chromosome 2, and the transmission disequilibrium test (TDT) in continental
      Italian and Tunisian families using the CTLA-4 exon 1 49 A/G polymorphism. None
      of these approaches provides evidence for linkage or association between the CTLA
      4 region and CD. This might result from a difference in the CTLA-4 region from
      population to population, either in its involvement as a risk factor or in the
      strength of linkage disequilibrium.

PMID- 10599895
TI  - Nomenclature for factors of the HLA system, update July/August 1999. WHO
      Nomenclature Committee for Factors of the HLA System.

PMID- 10599896
TI  - The relationships between spinal sagittal configuration, joint mobility, general
      low back mobility and segmental mobility in female homecare personnel.
AB  - The aim of this study was to investigate joint mobility, segmental and general
      spinal mobility and their interrelationship in 607 women working as homecare
      personnel. Joint mobility (mainly peripheral) was estimated using the "Beighton"
      score. Spinal posture and mobility were measured by Debrunner's kyphometer.
      Passive segmental mobility and pain provocation were estimated manually.
      Reliability tests between two physiotherapists of segmental mobility and pain
      provocation (n = 150 subjects) were performed. Positive correlations were found
      between joint mobility, sagittal thoraco-lumbar mobility and segmental mobility.
      Hyperlordosis (>39 degrees) was associated with greater lumbar mobility. The
      reliability of manual segmental mobility and segmental pain provocation was good,
      especially in the lowest back segments (kappa approximately 0.7). Joint mobility,
      general mobility and segmental spinal mobility intercorrelated. Segmental
      mobility manually estimated showed intertester reliability. The good positive
      correlation between sagittal lumbar mobility and manually tested segmental
      mobility indicates criterion validity for the latter.

PMID- 10599897
TI  - Long-term effects of a pulmonary rehabilitation programme in outpatients with
      chronic obstructive pulmonary disease: a randomized controlled study.
AB  - Fifty patients with severe chronic obstructive pulmonary disease (FEV1 < 50%
      pred.) were randomized to a rehabilitation group and a control group. The
      rehabilitation group took part in an individualized multidisciplinary, outpatient
      12-month rehabilitation programme. Exercise training was intensive during the
      first 6 weeks and was then gradually replaced by an individual home-training
      programme and booster sessions. Controls received the usual outpatient care.
      Positive effects were found in terms of maximum symptom-limited exercise
      tolerance and walking distance (13.5 and 12.1% increase, respectively) in the
      rehabilitation group compared with the controls. Quality of life measurements
      showed minor beneficial effects on the Sickness Impact Profile, indicating a
      higher level of activity. No effect was seen on the St George's Respiratory
      Questionnaire or the Mood Adjective Check List. Patients expressed their
      enthusiasm for the rehabilitation programme in a study-specific questionnaire.

PMID- 10599898
TI  - Long-term effects of heart transplantation: the gap between physical performance
      and emotional well-being.
AB  - The purpose of our study was to assess physical and emotional factors in heart
      transplant patients. A prospective design was used to compare patients' physical
      symptoms, emotional complaints, and restrictions at admission to the waiting
      list, immediately after, and 1 and 5 years after heart transplantation. Thirty
      three patients were included (30 male, 3 female) in the study. Their mean age at
      admission was 48 +/- 10.2 years. Of these, 23 suffered from cardiomyopathy, 8
      from coronary heart disease, and 2 from valvular insufficiency. At admission, the
      patients suffered from symptoms of cardiac insufficiency, and were restricted in
      sports, gardening, hobbies, sexual life, job, food-intake, and mobility. More
      than three-fourths rated their physical and emotional status as moderate to poor.
      Emotionally, they suffered from irritability, restlessness, depression, psychic
      lability, lowered drive, lack of social contact, low self-esteem, and anxiety. At
      the end of rehabilitation (4-8 weeks after the operation), all physical and
      emotional complaints, as well as restrictions had significantly decreased (p <
      0.0001 to p < 0.001), except for trembling, numbness of hands/feet, and food
      intake. One year postoperatively, patients reported even fewer physical
      complaints (p < 0.01). Three-fourths rated their physical and emotional status
      good or excellent. Five years postoperatively--in contrast to physical status,
      restrictions, and physical complaints--the emotional complaints had increased
      significantly (p < 0.0001). Patients reported excellent physical performance up
      to 5 years postoperatively. On the other hand, the study revealed that their
      emotional well-being had significantly deteriorated from 1 to 5 years
      postoperatively. Attention should, therefore, not only be paid to the good
      physical health of the survivors, but also to the worsening of their emotional
      status.

PMID- 10599899
TI  - Quality of life in patients with chronic heart failure: a randomized controlled
      trial of changes induced by a regular exercise program.
AB  - The aim of this study was to evaluate the impact of a three-month exercise
      program on the perception of quality of life in patients with severe chronic
      heart failure. In a randomized controlled setting, 27 patients with a left
      ventricular ejection fraction of 18.1 +/- 8.0% were entered into the study. The
      training group performed aerobic exercises for three hours/week while the control
      group continued their usual activities of daily living. Quality of life was
      measured using the German version of the MOS SF-36. Two patients required a
      change in their drug regimen and were therefore withdrawn from the study. Twenty
      five patients completed the study. In the exercise group the perception of
      quality of life improved significantly in the domains of vitality (p = 0.0001),
      physical role fulfillment (p = 0.001), physical (p = 0.02) and social (p =
      0.0002) functioning. Exercise was effective in increasing peak oxygen uptake and
      exercise time (p < 0.01). Only weak correlations were registered between
      parameters of physical performance and quality of life domains. The results of
      the study indicate that aerobic exercise can improve the perception of quality of
      life in patients with severe chronic heart failure.

PMID- 10599900
TI  - Reliability of isokinetic ankle dorsiflexor strength measurements in healthy
      young men and women.
AB  - The purposes of this study were: (i) to determine the test-retest reliability of
      isokinetic ankle dorsiflexor strength measurements in young healthy adults using
      the Biodex dynamometer, and (ii) to examine several statistical measures for the
      interpretation of reliability. Thirty men and women (mean age 23 +/- 3 years)
      performed three maximal concentric contractions at 30 degrees/s, 60 degrees/s, 90
      degrees/s, 120 degrees/s and 150 degrees/s. Reliability of peak torque, work and
      torque at a specific time were assessed by calculating the intraclass correlation
      coefficient (ICC 2,1), Pearson product moment correlation coefficient (r),
      standard error of the measurement (SEM), method error (ME) and coefficient of
      variation (CV), and by plotting the differences between observations against
      their means. Isokinetic tests of ankle dorsiflexor strength in healthy young
      adults using the Biodex dynamometer were highly reliable (ICC 0.61-0.93). It is
      recommended that test-retest reliability analyses include the ICC and assessments
      of measurement errors (SEM, ME or CV), as well as graphs to indicate any
      systematic variations in the data.

PMID- 10599901
TI  - Inter-rater reliability of the Sodring Motor Evaluation of Stroke patients
      (SMES).
AB  - The Sodring Motor Evaluation of Stroke patients is an instrument for
      physiotherapists to evaluate motor function and activities in stroke patients.
      The rating reflects quality as well as quantity of the patient's unassisted
      performance within three domains: leg, arm and gross function. The inter-rater
      reliability of the method was studied in a sample of 30 patients admitted to a
      stroke rehabilitation unit. Three therapists were involved in the study; two
      therapists assessed the same patient on two consecutive days in a balanced
      design. Cohen's weighted kappa and McNemar's test of symmetry were used as
      measures of item reliability, and the intraclass correlation coefficient was used
      to express the reliability of the sumscores. For 24 out of 32 items the weighted
      kappa statistic was excellent (0.75-0.98), while 7 items had a kappa statistic
      within the range 0.53-0.74 (fair to good). The reliability of one item was poor
      (0.13). The intraclass correlation coefficient for the three sumscores was 0.97,
      0.91 and 0.97. We conclude that the Sodring Motor Evaluation of Stroke patients
      is a reliable measure of motor function in stroke patients undergoing
      rehabilitation.

PMID- 10599902
TI  - Physical performance in individuals with late effects of polio.
AB  - The aim of this study was to evaluate physical performance in individuals with
      late effects of polio; specifically, to evaluate the effects of reduced muscle
      strength in the lower limbs. Thirty-two individuals seen at the polio clinic at
      Sahlgrenska University Hospital, Goteborg, Sweden, participated in the study.
      Each subject performed a bicycle exercise test in which peak oxygen uptake and
      anaerobic threshold were determined. Muscle strength in the quadriceps and the
      hamstrings were measured on an isokinetic dynamometer. Reductions in peak
      workload, peak oxygen uptake and predicted heart rate were seen. The anaerobic
      threshold was within or slightly lower than normal limits in relation to
      predicted maximal oxygen uptake, indicating that the cardio-respiratory system
      was not limiting performance. The muscle testing demonstrated a significantly
      lower ability to perform muscle actions compared with individuals from a
      reference group, and strong correlations were found between muscle strength peak
      VO2 and peak workload, respectively. Adjusted peripheral muscle endurance
      training might improve the work capacity in those individuals with weak leg
      muscles and low oxygen uptake, while individuals with relatively good muscle
      strength would improve their aerobic fitness in a general fitness program.

PMID- 10599903
TI  - Repetitive sensorimotor training for arm and hand in a patient with locked-in
      syndrome.
AB  - The locked-in syndrome is characterized by quadriplegia, preserved consciousness
      and inability to respond to the outside world. In recent years, the repetitive
      execution of identical movements has been demonstrated to be crucial for the
      recovery of arm and hand function in stroke patients. The present study aimed at
      investigating the efficiency of repetitive training in a patient suffering from
      locked-in syndrome due to an occlusion of the basilar artery. Seven months after
      the brainstem lesion and after a 15-week period of standard inpatient therapy,
      the repetitive training was applied to the (most affected) right upper extremity
      in addition to usual therapy. After 42 weeks of the repetitive training for the
      right arm, it was applied to the left arm. The ranges of active motion as well as
      functional motor capacity and muscle tone were regularly assessed. During those
      phases when the repetitive sensorimotor training was applied to the right or left
      arm, the ranges of active motion, muscle strength and functional motor capacity
      of the trained arm increased significantly accompanied by a continuous
      normalization of muscle tone in the flexor muscle groups. Since the prominent
      functional improvements of the right and left arms were observed during those
      phases when the repetitive training was applied, these effects were likely to be
      due to the training rather than to the standard rehabilitation program or
      extraneous influences. The repetitive sensorimotor training, therefore, appears
      to be appropriate to improve motor function of the arm and hand and to accelerate
      the time course of recovery even in patients with almost complete central
      paralysis of both arms.

PMID- 10599904
TI  - Systemic doxycycline administration in the treatment of periodontal infections
      (I). Effect on the subgingival microbiota.
AB  - Systemic doxycycline is one of the more common antimicrobial agents used in the
      treatment of periodontal infections and yet little is known of its effect on
      subgingival plaque composition during and after its administration. The purpose
      of the present investigation was to evaluate changes in subgingival plaque
      composition during and after 14 days of doxycycline administration. 20 subjects
      with adult periodontitis were randomly assigned to test (n = 10) and control (n =
      10) groups. The subjects received full mouth clinical assessment of pocket depth,
      attachment level, BOP, gingival redness, suppuration and plaque accumulation at
      baseline and 90 days. All subjects received full mouth SRP at baseline and,
      additionally, the test group received 100 mg doxycycline daily for 14 days.
      Subgingival plaque samples were taken from the mesial surface of up to 28 teeth
      in each subject at baseline and 90 days. In addition, plaque samples were taken
      from 2 randomly selected teeth at 3, 7 and 14 days during and after antibiotic
      administration. Control subjects were sampled at the same time points. Counts of
      40 subgingival species were determined using checkerboard DNA-DNA hybridization
      and fluorescent detection. Significance of differences between test and control
      groups was determined at each time point using the Mann Whitney test.
      Significance of changes over time within test and control groups was determined
      using the Quade test. A modest but significant reduction in mean pocket depth
      from baseline to 90 days occurred in both test and control groups. A significant
      decrease in the % of sites with gingival redness occurred in the test group.
      There were no significant differences in proportions between test and control
      groups for 33 of the test species at any time point. Test subjects exhibited
      lower proportions of 4 Actinomyces species and an increase in 3 Streptococcus
      species during antibiotic administration. After cessation of doxycycline,
      Actinomyces sp. increased while Streptococcus sp. returned to baseline
      proportions. The relationship between these 2 genera appeared to be reciprocal;
      an increase in one was accompanied by a decrease in the other. Periodontal
      pathogens including B. forsythus, P. gingivalis, T. denticola and A.
      actinomycetemcomitans were not significantly altered by oral administration of
      doxycycline using conventional therapeutic dosage.

PMID- 10599905
TI  - Systemic doxycycline administration in the treatment of periodontal infections
      (II). Effect on antibiotic resistance of subgingival species.
AB  - The purpose of this investigation was to determine the proportion and prevalence
      of doxycycline resistant species in subgingival plaque samples taken during and
      after doxycycline administration. 20 subjects with adult periodontitis were
      randomly assigned to test (n = 10) or control groups (n = 10). Saliva samples as
      well as subgingival plaque samples taken from the distal surface of 6 posterior
      teeth were collected at baseline. All subjects received full mouth SRP and the
      test group systemic doxycycline at the dosage of 100 mg/day for 14 days. Saliva
      samples and plaque samples from the distal surface of 2 randomly selected teeth
      were taken at 3, 7 and 14 days during and after antibiotic administration.
      Control subjects were sampled at the same time points. Samples were anaerobically
      dispersed and serially diluted in PRAS Ringer's solution and plated on enriched
      Trypticase soy blood agar plates with or without 4 microg/ml doxycycline. After 7
      days of anaerobic incubation, colonies were counted on both sets of plates.
      Microbial growth was washed from the doxycycline-containing media and the species
      identified using 40 DNA probes and checkerboard DNA-DNA hybridization.
      Differences in proportions of resistant species between test and control groups
      were tested for significance at each time point using the Mann Whitney test and
      over time within each group using the Quade test. The mean % (+/-SEM) of isolates
      resistant to 4 microg/ml doxycycline in the plaque samples of the test subjects
      increased from 6+/-2 to 48+/-9% during doxycycline administration, decreasing to
      25+/-6% 2 weeks later and 9+/-2% at 90 days. In saliva, the % of resistant
      isolates rose from 13+/-1% to 81+/-10% during doxycycline administration falling
      to 46+/-8% 2 weeks later and 22+/-5% at 90 days. The % of resistant isolates did
      not change significantly in plaque or saliva samples of the control subjects at
      the same time points. For all subject visits combined, the most prevalent
      resistant species were: Streptococcus anginosus, Streptococcus oralis,
      Streptococcus intermedius, Streptococcus sanguis, Streptococcus mitis,
      Veillonella parvula, Actinomyces gerencseriae, Streptococcus constellatus,
      Actinomyces naeslundii genospecies 2, Streptococcus gordonii, Eikenella corrodens
      and Actinomyces naeslundii genospecies 1. Doxycycline resistant strains of these
      species were detected in both plaque and saliva samples prior to therapy and in
      the control group. Despite the finding of increased resistance, approximately 50%
      of the organisms present at periodontal sites at the end of 14 days of
      doxycycline administration tested sensitive to the agent.

PMID- 10599906
TI  - Localized adhesion molecule expression and circulating LFA-3 levels in adult and
      early onset forms of periodontitis.
AB  - Because of their importance in mediating cellular interactions in chronic
      inflammatory diseases, this study has examined the expression of a number of
      adhesion molecules in adult (n=11), generalized early onset (n=5) and localized
      early onset (n=2) forms of periodontitis. In comparison with immunostaining
      profiles of cryostat sections of healthy gingival tissue (n=7), the beta 1
      integrins VLA-1, VLA-2 and VLA-4 were found to be up-regulated in periodontitis,
      with VLA-6 being markedly elevated. Although only small differences were observed
      in ICAM-1 and LFA-3 expression in the gingival epithelium, there was particularly
      notable up-regulation of these adhesion molecules within the inflammatory
      infiltrates of the diseased tissues. However, there were no statistically
      significant differences between the serum levels of a soluble form of LFA-3 in
      periodontitis patients (n=47) compared with healthy control subjects (n=40),
      although the generalized early onset and adult periodontitis groups exhibited
      wider ranges of circulating LFA-3. These findings show that there is localized
      modulation of adhesion molecule expression in the chronic inflammatory
      periodontal diseases studied, but that the levels of LFA-3 in the circulation
      nevertheless remain unaffected.

PMID- 10599907
TI  - The effect of multiple anticonvulsant therapy on the expression of phenytoin
      induced gingival overgrowth.
AB  - The potential effect of co-medication with phenobarbitone, primidone and
      carbamazepine on plasma and saliva concentrations of 5-(4-hydroxyphenyl)-5
      phenylhydantoin (4-HPPH), the major metabolite of phenytoin in man and on the
      incidence of phenytoin-induced gingival overgrowth was investigated in a group of
      36 adult epileptic patients. There were no significant differences in plasma or
      saliva concentrations of 4-HPPH or phenytoin in patients prescribed phenytoin
      alone, compared to those who received phenytoin with either phenobarbitone,
      primidone, or carbamazepine. In addition, the extent and the incidence of
      gingival overgrowth were similar in the 2 groups. The results suggest that
      chronic co-medication with other anti-convulsant drugs which induce phenytoin
      metabolism, does not affect the plasma or saliva 4-HPPB steady-state levels, nor
      the degree of gingival overgrowth in adult epileptic patients on therapy with
      phenytoin.

PMID- 10599908
TI  - Unusual peripheral odontogenic tumors in the differential diagnosis of gingival
      swellings.
AB  - Differential diagnosis of gingival mass lesions includes several conditions and
      causes. Peripheral odontogenic tumors may mimic gingival swellings and, although
      rare, must be included in the differential diagnosis. The purpose of this article
      is to describe 3 different cases of peripheral odontogenic tumors and to discuss
      the differential diagnosis of gingival swelling. Histologic examination is
      mandatory when localized gingival swellings are surgically removed.

PMID- 10599909
TI  - Interleukin-1 haplotype and periodontal disease progression following therapy.
AB  - The purpose of this study was to assess the prognostic value of the IL-1
      haplotype on the progression of periodontal disease following therapy. 48 adult
      patients with untreated periodontitis harboring Actinobacillus
      actinomycetemcomitans and/or Porphyromonas gingivalis were randomly assigned to
      receive full-mouth scaling alone (control) or in combination with systemic
      metronidazole plus amoxicillin and supragingival irrigation with chlorhexidine
      digluconate (test). All patients received supportive periodontal therapy at 3 to
      6 months intervals. In 33 patients, lymphocyte DNA was analyzed for polymorphism
      in the IL-1A gene at position -889 and IL-1B gene at position +3953. Overall, 16
      of 33 patients (7 of 17 test and 9 of 16 control) carried the IL-1 haplotype. 2
      years following initial periodontal therapy, no differences in the survival rates
      of sites or teeth not exhibiting probing attachment loss of 2 mm or more compared
      to baseline, were found between patients who tested positive (85% sites, 53%
      teeth) and patients who tested negative (89% sites, 56% teeth) for the IL-1
      haplotype. The results indicated that the IL-1 haplotype may be of limited value
      for the prognosis of periodontal disease progression following non-surgical
      periodontal therapy.

PMID- 10599910
TI  - The prevalence of BANA-hydrolyzing periodontopathic bacteria in smokers.
AB  - Smoking has been identified as a risk factor for development of periodontal
      disease and a strong indicator for treatment failure in periodontal patients.
      This study examined 172 patients categorized as current smokers (n=55), previous
      smokers (n=38) or individuals that had never smoked (n=79). A total of 670
      interproximal plaques collected with a wooden toothpick were analyzed for
      hydrolysis of the synthetic trypsin substrate benzoyl-DL-arginine naphthylamide
      (BANA). About 95% of the BANA hydrolysis by plaque is due to the presence of one
      or more of the periodontopathogens, P. gingivalis, T. denticola or B. forsythus.
      Gingival health was measured using the papillary bleeding score (PBS). Current
      smokers had less gingival bleeding than previous smokers or those who had never
      smoked (20% versus 41% and 25%, respectively). Plaque removed from non-bleeding
      sites in current smokers were 11x more likely to have a positive BANA reaction
      when compared to plaque removed from non-bleeding sites in individuals who never
      smoked. A significant positive relationship exists between smoking and
      colonization by the BANA periodontopathogens. Smoking may select for these
      periodontopathic species in the plaque and may be one reason why smoking is a
      risk factor in periodontal disease development.

PMID- 10599911
TI  - Pre- and post-implantation microbiota of the tongue, teeth, and newly placed
      implants.
AB  - OBJECTIVES: This investigation sought intra-oral sources of species colonizing
      dental implants. MATERIALS AND METHODS: Plaque samples were taken pre- and post
      successful osseointegration from implants, teeth, and from tongues of 10
      edentulous and 11 partially dentate subjects. Samples were assayed using whole
      genomic DNA probes in a checkerboard assay to 42 subgingival species. RESULTS:
      Similar prevalences and mean levels (10(3) to 10(4)) of microorganisms colonized
      implants and teeth. Species levels from tongue samples were higher than those of
      teeth and implants, although species prevalence was similar, suggesting that
      larger samples were obtained from the tongue. No significant differences were
      observed between the microbiota from the tongue of edentulous and partially
      dentate subjects. Most implant species were detected on tongue pre-implantation.
      In individual edentulous subjects, there were positive associations between
      Capnocytophaga ochracea and Campylobacter rectus from tongue and implant samples.
      In individual partially dentate subjects, there were positive associations
      between Fusobacterium nucleatum subsp. vincentii from tongue and implant samples,
      and Treponema denticola from implant and tooth samples taken at the same visit.
      CONCLUSION: This study indicated that the tongue, in addition to teeth, can be a
      source for species colonizing new implants.

PMID- 10599912
TI  - The use of barrier membranes and enamel matrix proteins in the treatment of
      angular bone defects. A prospective controlled clinical study.
AB  - In the present prospective clinical trial, the effect of various regenerative
      procedures performed at sites with angular bone defects were evaluated. The main
      outcome variable was probing attachment alteration. MATERIAL AND METHODS: 40
      subjects, aged 32-61 years participated. They met the following inclusion
      criteria: (i) presence of generalized, advanced periodontal tissue destruction;
      (ii) presence of 2 similar, contralateral, angular bone defects (experimental
      sites) located in either the maxilla or the mandible; (iii) the defect site must
      exhibit a probing pocket depth (PPD) of > or = 6 mm, a probing attachment level
      (PAL) of > or = 7 mm, and a depth of the intrabony component of > or = 3 mm. All
      subjects had a good oral hygiene standard, were in good general health and did
      not use any medication. Prior to the start of the study, all subjects received
      non-surgical treatment for periodontal disease. Baseline clinical measurements
      (plaque, gingivitis, PPD, PAL and soft tissue recession) of the selected
      experimental sites were obtained 6 months after the completion of basic therapy.
      The 40 subjects were randomly divided into 4 treatment groups including 10
      subjects each: 3 membrane groups and one Emdogain group. 1 h before surgery, the
      patients were given 3 g of Amoxicillin. No other antibiotics were prescribed. The
      test and control sites were treated during the same surgical session. Full
      thickness flaps were elevated and the exposed root surfaces were planed. Membrane
      placement: The root surface was rinsed with saline. A barrier membrane (Guidor or
      Resolut or Periodontal (e-PTFE) material) was positioned to cover the defect and
      the adjacent 2-3 mm of bone tissue. The control treatment was identical to the
      test treatment with the exception of barrier placement. Emdogain placement: The
      exposed root surfaces at both the test and control sites were, during a 2-min
      period, conditioned with a 24% EDTA gel. Emdogain was applied to the exposed root
      surface of the test site. In the control site, the vehicle, the PGA gel, was used
      as placebo control. The flaps were closed and sutured to obtain a complete
      coverage of the intrabony defect. RESULTS: Re-examinations, which were performed
      12 months after surgery, disclosed that regenerative therapy, including either
      the use of barrier membranes or application of enamel matrix proteins to an
      instrumented root surface in an angular, intrabony defect, enhanced outcome
      variables such as probing pocket depth and probing attachment gain. It was
      furthermore demonstrated that clinical improvements were better at sites with
      deep, than at sites with shallow, intrabony defects. CONCLUSION: The 4
      regenerative modalities tested appeared to be equally effective in terms of PPD
      reduction and PAL gain, and superior to open flap curettage alone.

PMID- 10599913
TI  - Histological observations of a bilateral maxillary sinus floor elevation 6 and 12
      months after grafting with osteogenic protein-1 device.
AB  - OBJECTIVE: The purpose of this case study was to analyze the tissue formed in a
      maxillary sinus, 6 and 12 months after grafting with recombinant human osteogenic
      protein-1 (OP-1) linked to a collagen carrier of bovine origin. PATIENT AND
      METHODS: A 49-year-old woman referred for bilateral sinus floor elevation, was
      grafted with an OP-1 device. After 6 months, a biopsy was taken from one of the
      grafted areas. After 12 months, during implant placement, 5 biopsies were taken
      from the grafted area and the maxillary host bone. Biopsies were processed
      without decalcification for histological analyses. RESULTS: The biopsy taken
      after 6 months contained newly formed bone, fibrotic tissue and device remnants.
      After 12 months, however, bone was absent from all biopsies which were taken from
      the grafted area, while particles of the collagen carrier were still abundant.
      Inflammatory cells were observed between remnants of the collagen carrier in the
      grafted area. CONCLUSION: This study indicates that an onset of new bone
      formation, which was observed after 6 months, did not persist. 12 months after
      grafting no bone was present in the biopsies from the grafted area, while the
      collagen carrier had remained. Lack of mechanical loading, as a result of
      postponing implant placement from 6 to 12 months, may have resulted in resorption
      of the emerging bone which was present 6 months after grafting.

PMID- 10599914
TI  - Combined systemic and local antimicrobial therapy of periodontal disease in
      Papillon-Lefevre syndrome. A report of 4 cases.
AB  - 4 patients, 2 pairs of siblings, suffering from Papillon-Lefevre syndrome were
      treated for periodontal disease. Following extraction of hopeless teeth, the
      children received scaling and adjunctive systemic antibiotics (metronidazole and
      amoxicillin for 7 to 10 days). In addition, they performed supragingival pulsated
      jet irrigation with 0.06% chlorhexidine digluconate 1 x daily. In 2 siblings, A.
      actinomycetemcomitans was suppressed subgingivally below detectable levels,
      pocket probing depths were reduced to 4 mm or less, and plaque and bleeding
      indices were low. No further disease progression was seen over a 3-year-period.
      Another female patient also showed clinical improvement and suppression of
      subgingival A. actinomycetemcomitans and B. forsythus up to the 9-month-follow
      up, while her sister showed further attachment loss over the course of 4 years.
      The present case reports indicated that in some patients suffering from Papillon
      Lefevre syndrome periodontal disease may be arrested by means of (i) oral hygiene
      instruction, (ii) extraction of severely diseased teeth, (iii) scaling, (iv)
      systemic antibiotics and (v) long-term antimicrobial irrigation.

PMID- 10599915
TI  - Periodontal tissue alterations following Emdogain treatment of periodontal sites
      with angular bone defects. A series of case reports.
AB  - The aim of the present study was to assess the predictability of probing
      attachment gain and probing pocket depth reduction following Emdogain treatment
      at sites with deep angular bone defects. MATERIAL AND METHODS: 108 consecutively
      treated periodontal patients (mean age 55.8 years) were included. Each subject
      exhibited at least 1 deep interproximal intrabony defect that could be identified
      as an experimental site based on the inclusion criteria: (i) probing pocket depth
      > or = 5 mm, (ii) probing attachment loss > or = 6 mm, (iii) radiographic
      evidence of an interproximal bone defect with a > or = 3 mm intrabony component.
      A total of 145 defects met the criteria for inclusion. All subjects received non
      surgical periodontal therapy. This included subgingival instrumentation in all
      parts of the dentition. At least 6 months after the completion of this treatment,
      a baseline examination was performed to characterise the experimental site.
      Reconstructive therapy was subsequently performed. Full-thickness periodontal
      flaps were elevated, and the root surface scaled and planed. No bone recontouring
      was performed. A gel containing 24% EDTA was applied on the exposed root and was
      kept in place for 2 min. A preparation of enamel matrix proteins was applied to
      the root surface and adjacent defect space. The flaps were replaced and closed
      with sutures. The experimental sites were re-examined 12 months after
      reconstructive surgery. RESULTS: The re-examination demonstrated that a treatment
      including the application of enamel matrix proteins at periodontal sites with
      angular defects resulted in a mean probing attachment level gain of 4.6 mm and a
      probing pocket depth reduction of 5.2 mm. 87% of all sites treated exhibited a
      probing attachment gain of > 2 mm. One site suffered probing attachment loss. The
      radiographic assessments revealed that the bone defect had been reduced in depth
      by 2.9 mm on average. The reduction in defect size corresponded to an average
      bone fill of 69% of the original defect. In 43% of the defects, the bone fill
      amounted to > or = 80%. CONCLUSION: The overall probing pocket depth reduction,
      probing attachment level gain, and soft tissue recession, that results following
      Emdogain therapy, is similar to the corresponding outcome variables following
      GTR.

PMID- 10599916
TI  - Presence of a protrusion on the ventral disk of adhered trophozoites of Giardia
      lamblia.
AB  - About 30% of the trophozoites of Giardia lamblia, fixed while adherent to the
      substrate using fixative solutions designed to better preserve cytoskeletal
      elements, showed the presence of a ventral disk. This structure varied in shape
      and size and could be seen by scanning and transmission electron microscopy, as
      well as by confocal laser scanning microscopy of cells incubated with 3-3'
      dihexyloxacarbocyanine iodide, which labels cisternae of the endoplasmic
      reticulum. It could also be observed in living adherent cells. A row of
      microtubules, a large number of glycogen particles, peripheral vesicles and
      concentric membranes were seen within the protrusion.

PMID- 10599917
TI  - Cloning and characterization of a new asparagine-rich protein in Plasmodium
      falciparum.
AB  - A cDNA clone that encodes a Plasmodium falciparum asparagine (N)-rich protein
      (PfARP) was isolated through immunoscreening of an expression library. A 9.4 kb
      PfARP transcript was identified by Northern blot hybridization and the gene was
      localized on chromosome 1. The complete coding sequence (6666 bp) revealed a
      protein that contains clustered as well as randomly distributed N residues
      (24.3%), seven copies of a repeat sequence [DNT(D/N)(K/N)(V/L/M)] and multiple
      copies of tripeptide repeats within a 101 amino acid region containing 89 D/E
      residues. The PfARP was immunogenic in inbred and outbred mice and endemic sera
      revealed the presence of low-titer antibodies against PfARP. Anti-PfARP sera
      showed cytoplasmic and surface localization of apparently cross-reactive malarial
      antigens in different life-cycle stages (ring, trophozoite, schizont, and
      gametocytes). Although the biological function(s) of PfARP are not known, the
      observation that it is present in multiple parasite stages and that it is a
      target of natural immune response warrants further study of PfARP as an immune
      target.

PMID- 10599918
TI  - Ultrastructural study of the papillae and presumed sensory receptors in the
      scolex of the Gymnorhynchus gigas plerocercoid (Cestoda: Trypanorhyncha).
AB  - The ultrastructure of the papillae and presumed sensory receptors in the tegument
      of the scolex of Gymnorhynchus gigas plerocercoid were investigated by scanning
      and transmission electron microscopy. Four distinct types of putative sense
      receptor (including three uniciliated and one nonciliated) are described for the
      first time in G. gigas, and this investigation is the first detailed
      ultrastructure study of tegumental receptors carried out in trypanorhynch
      cestodes. Microtriches arranged in clusters with a dome-shaped pattern seemed to
      be papillae that contained a ciliated sensory receptor (type I). The density of
      these papillae was greater in the center of the bothridial adherent surface near
      the tentacle orifice than in the lateral margins of the bothridia or in the pars
      post-bothridialis. The type I receptor is characterized by a long cilium anchored
      in the nerve bulb by a dense basal body but lacks rootlets. The bulb contains one
      or two electron-dense collars, numerous electron-lucent neurovesicles, and some
      mitochondria. The type II receptor presents a short cilium retracted into an
      invagination of the tegument that arises from the basal body. The bulb contains
      one electron-dense collar and numerous electron-lucent vesicles, but the rootlets
      are absent. The type III receptor is also a ciliated receptor embedded in a bulb
      wider than that of types I and II, and it differs from type II in that it
      possesses two electron-dense collars and small rootlets associated with the basal
      body. No electron-lucent vesicle was found in the bulb of this type III receptor.
      The type IV receptor is a nonciliated receptor localized under the surface with
      no contact to the outside. It consists of a flattened bulb that contains two
      electron-dense collars and striated rootlets associated with a band of
      microfilaments. A comparison of the ultrastructural features of receptors in
      different cestodes is presented.

PMID- 10599919
TI  - Scanning electron microscopy of the surface coat of Blastocystis hominis.
AB  - Scanning electron microscopy of Blastocystis hominis showed that its outer coat
      has a fibrillar structure and individual fibrils may extend up to 5 microm from
      the periphery of the parasite. The surface coat remains intact during cell
      division. Bacteria are often seen adhering to it, but for the first time a
      trophozoite of Chilomastix mesnili was also seen in this position. It is
      postulated that breakdown of attached organisms may provide nutrients for
      Blastocystis.

PMID- 10599920
TI  - A revised description of Haplosporidium armoricanum, parasite of Ostrea edulis L.
      from Galicia, northwestern Spain, with special reference to the spore-wall
      filaments.
AB  - Haplosporidian spores from Ostrea edulis, previously described as Minchinia
      armoricana, were reexamined by light and electron microscopy. These spores were
      either free among host cells or enclosed in sporocysts. They contained two long
      epispore cytoplasm extensions (ECE), each possessing cytoskeletal structures
      corresponding to the filaments. After lysis and degradation of the ECE, these
      extensions disappeared and the spores became devoid of membrane-bound extensions.
      However, 2 long filaments (approximately 130 microm long) persisted that were
      closely attached, in opposition to the spore wall, by a bundle of 9-13 fibers
      each. Thus, we propose a revised description of M. armoricana (= H. armoricana)
      to confirm its placement in the genus Haplosporidium as H. armoricanum.

PMID- 10599921
TI  - Identification and localization of an adhesin on the surface of Tritrichomonas
      foetus.
AB  - Tritrichomonas foetus is a mucosal parasite of the urogenital-vaginal tract of
      cattle that strongly adheres to erythrocytes, which suggests that it presents an
      adhesin that recognizes red blood cells from different animal species and blood
      groups. In the present report we describe a cell-fractionation method for
      obtainment of a membrane fraction of T. foetus, which adhered to red blood cells.
      The T. foetus adhesin was obtained after parasite lysis and fractionation
      followed by ultracentrifugation, whereby a 100,000-g pellet fraction showed a
      strong hemagglutinating activity. Sodium dodecyl sulfate-polyacrylamide gel
      electrophoresis of this fraction, of erythrocyte ghosts, and of ghosts allowed to
      interact with the parasite membrane fraction revealed the presence of a 100-kDa
      protein as the putative adhesin. Polyclonal antibodies obtained in rabbits
      immunized with this protein recognized proteins of 100 and 90 kDa as determined
      by immunoblotting. Confocal laser scanning microscopy and transmission electron
      microscopy of cells incubated first in the presence of the antibody and
      subsequently in the presence of fluorescein- or gold-labeled goat anti-rabbit IgG
      showed labeling of the protozoan surface as well as of some cytoplasmic vesicles.

PMID- 10599922
TI  - The distribution of excretory/secretory antigens during the muscle phase of
      Trichinella spiralis and T. pseudospiralis infections.
AB  - The in situ distribution of excretory/secretory (ES) antigens of the infective
      stage larvae of Trichinella spiralis and T. pseudospiralis was compared at
      various periods of development by immunofluorescent laser confocal microscopy and
      the immunoperoxidase method. In the former infection, epitopes of the ES antigens
      were always confined exclusively within the nurse cell, i.e., in the cytoplasmic
      region, hypertrophic nuclei, stichocytes, and cuticular surface of worms. In the
      latter infection, as early as at day 15 postinfection, ES epitopes were located
      along the infected myofibers, in the adjacent muscles, hypertrophic nuclei,
      stichocytes, and cuticular surface of worms. By day 30 postinfection there was a
      marked increase in both the distribution and the intensity of ES antigens in
      infected as opposed to uninfected myofibers. A new method was also developed to
      reveal the number of hypertrophic nuclei, small cells, and larvae in intact nurse
      cells. As many as four worms could be accommodated within a single complex. The
      number of hypertrophic nuclei within each complex varied from 15 to 81.

PMID- 10599923
TI  - Echinococcus granulosus: praziquantel treatment against the metacestode stage.
AB  - The efficacy of praziquantel against the metacestode of Echinococcus granulosus
      was studied by means of in vitro incubations or in vivo experiments. The results
      of in vitro incubations indicated that the effectiveness of praziquantel was
      higher when the parasite material comprised cysts from cyst masses than in the
      case of intact cysts that retained their adventitial layer. Ultrastructural
      alterations in the germinal layer of collapsed cysts incubated in vitro were
      detected. The results obtained in mice after 4 months of treatment demonstrated
      no significant difference between the control and treated groups with regard to
      the number and wet weight of developed cysts. However, ultrastructural
      alterations were detected in the cyst tissue that were similar to those described
      in the in vitro experiment. In contrast, the effect of chemoprophylaxis on the
      number and the wet weight of developed cysts was extremely significant as
      compared with the control value, the efficacy being 99.41% and 98.32%,
      respectively. Moreover, ultrastructural observations of the cyst tissue revealed
      loss of its integrity, and no intact cyton was observed in the germinal layer of
      the developed cyst.

PMID- 10599924
TI  - Effects of the multidrug-resistance-reversing agents verapamil and CL 347,099 on
      the efficacy of ivermectin or moxidectin against unselected and drug-selected
      strains of Haemonchus contortus in jirds (Meriones unguiculatus).
AB  - The development of anthelmintic resistance is making parasite control in small
      ruminants problematic. Following the discovery that the drug transporter P
      glycoprotein may be involved in macrocyclic lactone resistance in Haemonchus
      contortus, we determined the effect of two multidrug-resistance modulators,
      verapamil and CL347,099, on the efficacy of ivermectin and moxidectin against
      unselected and drug-selected strains of H. contortus. CL347,099 is an analog of
      verapamil that has multidrug-resistance properties but weaker calcium-channel
      blocking activity than the parent drug. The combinations of verapamil with either
      ivermectin or moxidectin significantly reduced worm counts of the selected
      strains as compared with the untreated controls, whereas ivermectin or moxidectin
      alone did not significantly reduce worm counts as compared with the untreated
      controls. The CL347,099 plus moxidectin combination was significantly more
      efficacious than moxidectin alone against the ivermectin-selected strain. The
      drug-combination regimes were without adverse effect on the jirds. However,
      higher levels of verapamil (> or =40 mg/kg) produced some toxicity.

PMID- 10599925
TI  - Trypanosoma cruzi: lack of T cell abnormalities in mice vaccinated with live
      trypomastigotes.
AB  - We have previously shown that inoculation of Trypanosoma cruzi clone-CL-14
      generates efficient protective immunity against virulent T. cruzi and no
      infection or histopathology per se, indicating that it induces an immune state
      different from that exhibited by infected animals. To understand the basis of
      this difference, we screened CL-14-vaccinated mice for T cell abnormalities
      thought to be involved in the genesis of pathology. Lymphocytes from vaccinated
      mice present normal proliferative responses to concanavalin A; enhanced responses
      to T. cruzi antigens; do not show evidence of polyclonal activation (increased
      blast transformation and lymphocyte numbers) or changes in the density of CD4,
      CD8 and TCR-beta expression. Also, vaccinated mice display transient expansion of
      CD8+ lymphocytes expressing activated phenotypes (CD11a(hi) CD45RBlo CD62Llo). In
      view of the absence of pathology in vaccinated animals, the absence of
      immunosuppression and the restoration of a resting immune state reinforce the
      benign nature of this immunization.

PMID- 10599926
TI  - Cloning and characterization of iron-containing superoxide dismutase from the
      human malaria species Plasmodium ovale, P. malariae and P. vivax.
AB  - The iron-containing superoxide dismutase (FeSOD) gene from three human malaria
      species, namely Plasmodium ovale, P. malariae and P. vivax, was amplified by
      polymerase chain reaction, cloned and then sequenced. Comparisons of their
      deduced amino acid sequences with that of the FeSOD from P. falciparum revealed a
      very low polymorphism at the FeSOD locus in human malaria species. One P. ovale
      and the P. vivax FeSOD genes presented the same nucleotide sequence as that of
      the P. falciparum strain HB3 whereas the second P. ovale and the P. malariae
      genes exhibited two punctual mutations. These mutations did not affect the
      function and structure of the enzyme. The FeSOD polymorphism was so low that no
      phylogenetic relationship among human malaria species could be proposed, but this
      conservative structure strengthened the potentiality of this enzyme as a possible
      target for antimalarial drugs.

PMID- 10599927
TI  - Taenia crassiceps cysticercosis: a role for prostaglandin E2 in susceptibility.
AB  - Several biological factors are involved in susceptibility and resistance to
      murine cysticercosis. A substantial body of evidence implies prostaglandins as
      potent regulators of immune responses during parasitic diseases. Here we
      evaluated the role played by prostaglandin E2 in cysticercosis. Mice were treated
      in vivo with prostaglandin E2 or with indomethacin (a prostaglandin E2 synthesis
      inhibitor) before infection. Parasite growth was enhanced by prostaglandin
      treatment, which provoked poor Con-A responses, low Th1-type cytokines secretion,
      and high levels of IL-6 and IL-10. In contrast, mice receiving indomethacin
      showed a reduction in parasite load parallel to a strong Con-A response and high
      levels of IL-2 and IFN-gamma, concomitantly with a decrease in IL-4, IL-6 and IL
      10 production. Indirect in vitro studies suggest that an important source of
      prostaglandin E2 production could be related to host's adherent cells. However,
      prostaglandin E2 from parasite origin cannot be discarded.

PMID- 10599928
TI  - Blastocystis in animal handlers.
AB  - The present study investigated whether people working closely with animals were
      at higher risk of getting infected with Blastocystis hominis. The prevalence of
      the parasite was determined in two population groups, i.e., animal handlers and
      normal healthy individuals who did not work with animals. In all, 105 stool
      samples were collected from animal handlers from 2 local research institutions, a
      local zoo, and a local abattoir and 163 stool samples were collected from normal
      healthy individuals residing in high-rise flats in the city. The in vitro culture
      method used in the study detected that 41% of 105 animal handlers and 17% of 163
      flat-dwellers in the city were positive for Blastocystis. This statistically
      significant finding (P = 0.0000313) shows that people who work closely with
      animals do stand at risk of acquiring Blastocystis infection.

PMID- 10599929
TI  - Immunomodulative effect of muramyldipeptide in mice with larval toxocarosis.
AB  - The phagocytic ability of polymorphonuclear leukocytes, the metabolic activity of
      peritoneal macrophages, the proliferative response of T- and B-cells, and the
      production of specific anti-Toxocara antibodies were studied in paratenic hosts
      with experimental larval toxocarosis after treatment with the immunomodulator
      muramyldipeptide for 119 days. Peroral infection of mice with 2,500 Toxocara
      canis eggs partially reduced the numbers of cells and inhibited the activity of
      all cellular immune-response parameters studied. During most of the experiment
      the greatest suppression was recorded for the peritoneal-macrophage metabolic
      activity. Parenteral administration of muramyldipeptide to mice at two doses
      prior to and after infection restored and significantly stimulated the parasite
      inhibited phagocytic ability of blood polymorphonuclear leukocytes, metabolic
      activity of macrophages, and T-lymphocyte proliferative response. It also
      elevated the production of specific circulating anti-Toxocara antibodies. The
      immunomodulator significantly reduced the count of migrating T. canis larvae in
      the host organism (30.6%) and decreased by half the percentage of larvae in the
      brain.

PMID- 10599930
TI  - Neurobiological and anthropological aspects of compulsions and rituals.
AB  - Obsessions and compulsions frequently accompany motor and vocal tics in Gilles de
      la Tourette syndrome (GTS). The occurrence of motor tics and compulsions helps to
      understand the neurobiological foundation of repetitive behavior patterns. Based
      on a review of the literature and our own studies in GTS, we suggest that simple
      motor tics are caused by a stimulus-dependent disinhibition of stereotypies
      encoded in the head of the caudate, while more complex compulsions are associated
      with a serotonergic disinhibition of frontocortical-striatal circuits in GTS and
      obsessive-compulsive disorder. These findings indicate that obsessions and
      compulsions do not simply result from a lack of cortical control of
      phylogenetically primitive behavior patterns. Rather, an activation of the
      orbitofrontal cortex seems to be essential for the induction of anxiety and the
      disinhibition of subcortical stereotypies. The neurobiological findings may help
      to clarify why compulsions differ from cultural rituals. Cultural rituals are
      performed cyclically, represent important social conflicts and are usually not
      accompanied by fear or anxiety. Obsessions, on the other hand, seem to be
      generated in a self perpetuating cycle of cortico-subcortical activation and are
      associated with anxiety and ineffective repetition of stereotypies.

PMID- 10599931
TI  - Evidence report: treatment of depression - newer pharmacotherapies. Agency for
      Health Care Policy and Research (AHCPR).

PMID- 10599932
TI  - Citalopram: an interaction study with clomipramine in a patient heterozygous for
      CYP2D6 genotype.
AB  - A pharmacokinetic interaction between the selective serotonin reuptake inhibitor
      citalopram and a tricyclic antidepressant, clomipramine, was noted in a patient
      treated for major depression and obsessive-compulsive disorder. After the
      addition of citalopram, a desmethylclomipramine plasma level increase and an 8
      hydroacy-desmethylclomipramine plasma level decrease were observed. The CYP2D6
      phenotype, determined when the patient received the antidepressant comedication,
      characterized a poor metabolizer status (dextromethorphan metabolic ratio >0.3),
      despite a heterozygous genotype containing a wild-type allele with extensive
      metabolic capacity and a mutant non-functional allele (CYP2D6*1A/CYP2D6*4A). This
      case seems to be one of the first descriptions of the clinical relevance of a
      CYP2D6 heterozygous genotype in a patient treated with antidepressant.

PMID- 10599933
TI  - The influence of valerian treatment on "reaction time, alertness and
      concentration" in volunteers.
AB  - A randomised, controlled, double-blind trial was performed on 102 male and female
      volunteers to determine whether reaction time, alertness and concentration might
      be impaired by treatment with a native valerian root extract (VRE). The effect
      was first examined the morning after a single evening dose of VRE (600 mg LI 156)
      vs. flunitrazepam (FNZ) (1 mg) and placebo (PL) (trial section A), and then after
      two weeks of evening administration of VRE (600 mg LI 156) vs. PL (trial section
      B). 99 volunteers were analysed in section A and 91 in section B. The primary
      criterion was the median of reaction time (MRT) measured with the Vienna
      Determination Test. Secondary criteria were cognitrones (alertness test),
      tracking test (two-handed co-ordination), sleep quality (VIS-A, Vis-M), further
      VDT parameters, and safety criteria. The single administration of LI 156 did not
      impair the reaction abilities, concentration and co-ordination. After 14 days of
      treatment, the equivalence of VRE and PL was proven by confirmative analysis
      concerning the improvement of MRT (p = 0.4481). Evaluation of the secondary
      criteria were consistent with the results of the primary criterion. It is
      concluded that neither single nor repeated evening administrations of 600 mg of
      VRE have a relevant negative impact on reaction time, alertness and concentration
      the morning after intake.

PMID- 10599934
TI  - Synergistic effects of tetrahydroaminoacridine and lithium on cholinergic
      function after excitotoxic basal forebrain lesions in rat.
AB  - Effects of lithium and tetrahydroaminoacridine (THA), either alone or in
      combination, were tested in an animal model of excitotoxic cholinergic
      deafferentation of the cerebral cortex. Rats received ibotenic acid lesions of
      cholinergic basal forebrain nuclei resulting in a 30% to 40% depletion of both
      cortical choline acetyltransferase (ChAT) and acetylcholinesterase (AChE)
      activity. Lithium as well as THA, given separately either prior or subsequently
      to the development of the lesion, had small but significant effects on the
      recovery of cortical ChAT and AChE activity. Applied in combination, these drugs
      clearly showed synergistic effects. These potentiating actions might be due to
      neuroprotective/ neurotrophic mechanisms as well as to effects on acetylcholine
      turnover and muscarinic receptor-coupled phosphoinositide turnover. Similar
      approaches of combination therapy might prove useful for the management of mental
      disorders associated with cholinergic dysfunction.

PMID- 10599935
TI  - Neuropsychometric tests in cross sectional and longitudinal studies - a
      regression analysis of ADAS - cog, SKT and MMSE.
AB  - INTRODUCTION: In clinical and drug studies, different neuropsychometric tests are
      used. So far, no empirical data have been published to compare studies using
      different tests. The purpose of this study was to calculate a regression formula
      allowing a comparison of cross-sectional and longitudinal data from three
      neuropsychometric tests that are frequently used in drug studies (Alzheimer's
      Disease Assessment Scale, ADAS-cog; Syndrom Kurz Test, SKT; Mini Mental State
      Examination, MMSE). METHOD: 177 patients with dementia according to ICD10
      criteria were studied for the cross sectional and 61 for the longitudinal
      analysis. Correlations and linear regressions were calculated between tests.
      Significance was proven with ANOVA and t-tests using the SPSS statistical
      package. RESULTS: Significant Spearman correlations and slopes in the regression
      occurred in the cross sectional analysis (ADAS-cog-SKT r(s) = 0.77, slope = 0.45,
      SKT-ADAS-cog slope = 1.3, r2 = 0.59; ADAS-cog-MMSE r2 = 0.76, slope = -0.42, MMSE
      ADAS-cog slope = -1.5, r2 = 0.64; MMSE-SKT r(s) = -0.79, slope = -0.87, SKT-MMSE
      slope = -0.71, r2 = 0.62; p<0.001 after Bonferroni correction; N = 177) and in
      the longitudinal analysis (SKT-ADAS-cog, r(s) = 0.48, slope = 0.69, ADAS-cog-SKT
      slope = 0.69, p<0.001, r2 = 0.32, MMSE-SKT, r(s) = 0.44, slope = -0.41, SKT-MMSE,
      slope = -0.55, p<0.001, r2 = 0.21). CONCLUSIONS: The results allow calculation of
      ADAS-scores when SKT scores are given, and vice versa. In longitudinal studies or
      in the course of the disease, scores assessed with the ADAS-cog and the SKT may
      now be statistically compared. In all comparisons, bottom and ceiling effects of
      the tests have to be taken into account.

PMID- 10599936
TI  - Gabapentin leads to remission of somatoform pain disorder with major depression.
AB  - Gabapentin, a novel antiepileptic drug, is effective in the treatment of partial
      seizures with and without secondary generalization. Evidence suggests that it may
      have mood-stabilizing and possibly antidepressant properties in bipolar
      depression. We report on a 48-year-old woman who had recurrent major depressive
      disorder. Following inguinal herniorrhaphy, she developed severe stabbing pain in
      the lower abdomen and inguinal area that progressed to constant pain in her whole
      body. She was depressive, hopeless, and had given up her social activities. A
      diagnosis of major depressive disorder and somatoform pain disorder was made.
      Antidepressants and carbamazepine were ineffective, and she had attempted
      suicide. Gabapentin resulted in remission of both the pain and the depressive
      mood at a dose of 1.800 mg/day.

PMID- 10599937
TI  - Hypothermia developing during neuroleptic treatment.

PMID- 10599938
TI  - Hsp72 antigen expression in the proliferative compartment of involved psoriatic
      epidermis.
AB  - Oxidative damage to growth regulatory proteins has been implicated in the
      aetiology of psoriasis. However, the transient synthesis of heat shock proteins
      has been shown to protect cells against the adverse effects of oxidative and
      other forms of physiological stress. This study has used an hsp72 monoclonal
      antibody to measure inducible 72 kDa heat shock protein expression in heat
      stressed normal human skin and established plaque psoriasis. Hsp72 was detected
      in the basal and suprabasal layer cells of heat-stressed normal skin, and in 12
      involved psoriasis lesions. Hsp72 expression was not detected in unstressed
      normal skin or in 12 cases of uninvolved psoriasis. Immunoprecipitation and
      Western blotting of cell lysates from heat stressed normal skin and involved
      psoriasis lesions confirmed the presence of a 72 kDa polypeptide with hsp72
      immunoreactivity. The MIB-1 monoclonal antibody was used to determine the
      proliferative fraction of normal and involved psoriastic epidermis. The Ki67
      antigen was localised to the nuclei of basal and suprabasal layer cells of normal
      and involved psoriatic epidermis. Involved psoriatic epidermis contained a higher
      number of proliferating keratinocytes when compared with normal skin. The study
      has also demonstrated a strong correlation between hsp72 expression and
      keratinocyte proliferation in involved psoriatic epidermis (r=0.864, p<0.001). We
      believe that the 72 kDa inducible heat shock protein performs a protective
      function in the proliferative compartment of normal and involved psoriatic skin.

PMID- 10599939
TI  - Subcutaneous trichoblastoma.
AB  - We have recently observed three examples of solitary trichoblastomas (TB) with
      unusual histopathologic features characterized mainly by numerous aggregations of
      basaloid cells limited to the subcutis. The three trichoblastomas with unusual
      features were identified from a large series of 38 solitary TB cases collected
      over a period of 20 years. Clinically, all three neoplasms presented in men (49,
      52, and 62 years old) as solitary, 1- to 1.5-cm skin-colored nodules situated on
      the scalp, face, and lower arm, respectively. Histopathologically, they showed
      numerous, smooth-bordered aggregations of basaloid cells limited to the subcutis
      and surrounded by a sclerotic and partly hyalinized stroma. Multiple sections
      revealed no connections of basaloid aggregations to the overlying epidermis or
      pre-existing follicular structures. All three cases displayed rather unusual
      morphologic growth patterns, including areas of variously sized, nodular
      aggregations of basaloid cells and extensive foci of elongated, thin columns and
      branching cords of basaloid cells. A striking feature in the stromal component in
      two cases was the presence of large, prominent areas of hyalinization and
      sclerosis. Characteristically, all three neoplasms showed numerous foci with
      rudimentary follicular germs and papillae. Cytomorphologically, the basaloid
      cells exhibited dark staining nuclei with large prominent nucleoli and scanty,
      pale or eosinophilic cytoplasm. Variable number of mitotic figures (2-4 mitoses
      per high-power field) and single necrotic cells were noted. In one case, small,
      foci of necrosis en masse were observed. Follow-up data after total excision in
      all three cases (80, 69, and 6 months) revealed no local recurrences. In light of
      our observations, we suggest that subcutaneous TB represents a rare variant of
      solitary TB. Besides the exclusive subcutaneous location, this neoplasm also
      displays a constellation of particular histopathologic features, namely, rather
      complex epithelial growth patterns and stroma with prominent foci of sclerosis
      and hyalinization.

PMID- 10599940
TI  - CD56+ blastic transformation of chronic myeloid leukemia involving the skin.
AB  - We report on two patients with chronic myeloid leukemia (CML) who presented
      blastic transformation involving the skin, with leukemic infiltrates showing
      unusual morphologic and immunohistologic characteristics. Both patients were
      elderly men with a 36-month and a 40-month history of CML, respectively. They
      presented with disseminated, reddish to violaceous papules and plaques (case 1),
      and with localized reddish nodules on the left temporal area (case 2). Concurrent
      features of blastic transformation in the bone marrow were observed in one
      patient (case 1). Histopathologic examination of skin lesions revealed similar
      features in both cases. There was a moderate to dense dermal infiltrate composed
      mainly of medium-sized atypical mononuclear myeloid precursor cells with only few
      relatively well-differentiated cells of the granulocytic series. Histochemical
      staining for naphthol-ASD-chloroacetate esterase revealed strong positivity (>50%
      of neoplastic cells) in case 2 and only scattered positivity (< 10% of neoplastic
      cells) in case 1. Immunohistologic analysis performed on paraffin-embedded
      sections showed in both cases variable reactivity of neoplastic cells for
      leucocyte common antigen (CD45), lysozyme, myeloperoxidase, CD11c, CD15, CD43,
      CD66, CD68, HLA-DR, and the neural cell adhesion molecule (NCAM) CD56. A negative
      reaction was observed for CD3, CD34, and TdT. The immunohistologic findings were
      remarkably similar to those reported for acute myeloid leukemia (AML) with
      monocytic differentiation (French-American-British [FAB] classification, subtype
      M4). Examination of blasts from the bone marrow performed in one patient (case 1)
      revealed a similar phenotype also with CD56 expression. In conclusion, our
      observations show that specific cutaneous infiltrates in CML may show morphologic
      and immunohistochemical characteristics similar to those observed in AML with
      monocytic differentiation. Moreover, specific cutaneous manifestations of CML may
      express CD56.

PMID- 10599941
TI  - In vivo abnormal keratinazation in Darier-White's disease as viewed by real-time
      confocal imaging.
AB  - Darier-White's disease is a rare autosomal-dominant disorder of keratinization.
      The underlying pathology for the clinical presentation is acantholysis, and
      various types of dyskeratosis and acanthosis. In this study, we utilized a non
      invasive optical imaging modality, confocal reflectance microscopy, to identify
      specific histologic features of Darier-White's disease in vivo. Micrographic
      findings in the confocal images were corps ronds, suprabasal clefts, acantholytic
      suprabasal keratinocytes, and villi. Real-time confocal images are illustrative
      and can be well correlated with known light microscopic phenomena, particularly
      in the case of keratinization abnormalities in Darier-White's disease.

PMID- 10599942
TI  - Malignant rhabdoid tumor beside benign skin mesenchymal neoplasm with
      myofibromatous features.
AB  - Only a few reports of primary cutaneous rhabdoid tumors have been published. We
      describe the case of a 3-month-old female patient who developed a rhabdoid type
      cutaneous sarcomatoid neoplasm in her upper back, close to a benign
      myofibromatous proliferation of infancy. The lesion was studied both by light
      microscopy and immunohistochemically. Flow cytometry was performed showing a DNA
      diploid profile of the malignant tumor. The pathological findings suggest a
      mesenchymal origin (hemangiopericytic or myofibroblastic type) for both tumors.
      The patient was surgically treated, but she died nine months later.

PMID- 10599943
TI  - Dermatofibroma parasitized by Leishmania in HIV infection: a new morphologic
      expression of dermal Kala Azar in an immunodepressed patient.
AB  - Visceral leishmaniasis is a protozoan infection that may complicate the course of
      patients with human immunodeficiency virus (HIV). Dermatofibroma is a cutaneous
      fibrohistiocytic lesion considered neoplastic by some authors and inflammatory by
      others. Eruptive dermatofibromas have been described in patients with HIV
      infection or with other altered immunity situations. We present the case of a 32
      year-old, HIV-positive man with visceral leishmaniasis who complained of the
      appearance of a cutaneous lesion in the leg formed by the coexistence of
      dermatofibroma and Leishmania parasitic colonization. As far as we know, this
      type of association has not been reported previously. We consider that the
      dermatofibroma could have developed as an unusual form of fibrohistiocytic
      reaction to leishmania. From a practical approach, we recommend the search of
      leishmaniasis in dermatofibroma in immunosuppressed patients.

PMID- 10599944
TI  - Infection with parapoxvirus induces CD30-positive cutaneous infiltrates in
      humans.
AB  - Expression of CD30 is a distinct feature of B- or T-cell activation, found in
      Hodgkin's disease, large cell anaplastic lymphoma, lymphomatoid papulosis, as
      well as in certain viral infections such as human T-lymphotropic virus type I,
      HIV, hepatitis B and C virus, and Epstein-Barr virus. Here, we report highly
      proliferative CD30-positive cutaneous infiltrates in 3 patients with Milkers's
      nodules, adding parapoxvirus infection to the spectrum of CD30-positive benign
      lympho-proliferations.

PMID- 10599945
TI  - Glial heterotopia in the subcutaneous tissue overlying T-12.
AB  - Heterotopic glial nodules occur most commonly in the head and neck area, and are
      theorized to arise following abnormalities in the development of the facial and
      skull bone plates. However, in spite of the fact that some of these lesions are
      associated with communication with the central nervous system (CNS), the lack of
      a meningeal component, argues against simple herniation and separation of brain
      tissue through a defect in the skull. We present an infant with a nodule directly
      over the spine present in the T-12 region with no skin abnormalities. Magnetic
      resonance imaging (MRI) and computerized axial tomography (CT) showed no spinal
      abnormalities with an overlying fibrotic soft tissue mass. The patient had no
      other associated clinical findings. Histologic findings showed a cellular
      component arising within the reticular dermis with a deep circumscribed margin.
      The nodule contained irregularly shaped cells containing abundant cytoplasm and
      indistinct cellular margins with bland nuclei. These cells were clustered around
      and between a fibro-mucinous stroma. Immunohistochemical stains showed positive
      staining for S-100 protein, vimentin, GFAP, NSE, and CD57, and negative staining
      for Ki-67, CD34, Neurofilament protein, cytokeratin, and EMA. The spindle cells
      showed positive staining for CD34 and vimentin. The clinical and histologic
      features and immunohistochemical profiles are used to separate this lesion from
      the closely related, ependymal rests, ependymomas, and primary cutaneous
      chorodomas.

PMID- 10599946
TI  - Basal cell carcinoma with prominent central palisading of epithelial cells
      mimicking schwannoma.
AB  - Basal cell carcinoma (BCC), the most common malignant neoplasm of skin, may show
      a wide spectrum of histologic appearances. The presence of peripheral palisades
      is a very characteristic feature of BCC but, to our knowledge, central nuclear
      palisading has never been described. We report two cases of BCC exhibiting
      striking central nuclear palisading with Verocaylike bodies, in a pattern
      reminiscent of schwannoma. Peripheral palisades and clefts were also present in
      most tumor nodules and lobules, giving the neoplasms the overall configuration of
      otherwise typical solid BCC. In addition, foci of conventional BCC could be found
      adjacent, and in transition, to schwannoid areas. The immunohistochemical study
      showed strong reactivity for keratins (AE1 and AE3) in tumor cells, whereas no
      immunostaining for S-100 or muscle-specific actin was found. This previously
      undescribed histological feature of BCC should lead us to include BCC in the list
      of tumors to be considered in the differential diagnosis of a cutaneous neoplasm
      with schwannoid features.

PMID- 10599948
TI  - Announcement of the winner of the 1998 Munksgaard and Journal of Cutaneous
      Pathology Prize.

PMID- 10599947
TI  - Primary invasive signet-ring cell melanoma.
AB  - The histopathological variants of malignant melanoma include the common type
      (lentigo maligna, superficial spreading melanoma, nodular melanoma,
      acrolentiginous melanoma), spindle cell, desmoplastic, balloon cell, pleomorphic
      (fibrohistiocytic), myxoid, small cell melanoma and malignant blue nevus.
      Recently, signet-ring cell melanoma was introduced as an additional cytologic
      variant. We describe a 72-year-old patient with a primary signet-ring cell
      melanoma of the skin located on the upper arm. Histopathologic examination
      disclosed a melanocytic tumor extending from the epidermis to the deep reticular
      dermis. Numerous pleomorphic tumor cells showed large, intracellular vacuoles and
      oval to spindle-shaped nuclei at their periphery. Mitotic figures and
      multinucleated melanocytes were also observed. Some of the signet-ring cells
      exhibited cytoplasmatic periodic acid-Schiff (PAS)-positivity.
      Immunohistochemistry showed positive reaction of the tumor cells for S-100, HMB
      45 protein and vimentin, confirming their melanocytic differentiation. Tumor
      cells were negative for cytokeratins, epithelial membrane antigen (EMA), and
      carcinoembryonic antigen (CEA). The signet-ring cell melanoma disclosed an
      invasion to Clark Level IV and tumor thickness of 2.2 mm. Signet-ring cell
      melanoma is a rare morphologic variant of melanoma. Its recognition is important
      for differentiation from other tumors featuring signet ring cells.

PMID- 10599949
TI  - Alternative strategies in drug development: clinical pharmacological aspects.
AB  - Due to the continuous increase in time and cost of drug development and the
      considerable amount of resources required by the traditional approach, companies
      can no longer afford to continue to late phase 3 with drugs which are unlikely to
      be therapeutically effective. The future challenge must be for the pharmaceutical
      industry to slash its research and development costs by achieving a significant
      cut in the attrition rate for drugs entering preclinical and clinical
      development, and to reduce the development time and to increase the probability
      of success in later clinical trials by streamlining the development processes. In
      the 100 years to 1995, the pharmaceutical industry worked on about 500 targets
      with a limited number of compounds, whereas now, using new technologies like
      genomics, high throughput screening and combinatorial chemistry, drug companies
      will see an explosion in the number of targets and leads it can explore.
      Therefore, a tough selection process for picking candidate compounds out of
      research and a quick kill process for the candidate, which does not measure up in
      advanced trials, is mandatory to avoid wasting time, energy and money. To improve
      the transition from research to development it is necessary to validate new
      targets, define success criteria for research, integrate bioinformation at every
      stage in drug discovery, define prerequisites for development, identify the
      "losers" and select the "winners" early and concentrate efforts on them, and to
      automate the research and development (R&D) process to optimize resource
      requirements versus time lines and to ensure effective flow of information from
      drug discovery to late phase of development. In drug development a deeper
      understanding of a drugs' action is necessary from animal models and phase I, IIa
      studies prior to taking the drug further in development. Instead of moving from
      discovery thorough development phases in sequential steps, drug development
      should be streamlined combining preclinical and early clinical development as an
      exploratory stage and phases IIb, III as a confirmatory stage. Preclinical and
      clinical-pharmacological studies in the exploratory stage of drug development
      should be designed for decision making in contrast to later clinical trials that
      require power for proof-of-safety and efficacy. Strategies to improve the quality
      of decisions in drug development are: the use and integration of new tools and
      technologies such as pharmacogenomics to improve our knowledge about the origin
      of the disease and to identify new therapeutic strategies; modelling and
      simulation of preclinical and clinical trials to bridge the gap between the early
      stages of the development of a new drug and its potential effects in humans; more
      sophisticated clinical pharmacokinetics to answer the question if the drug is
      present at the disease site for a sufficient time and to provide information on
      concentration-effect-relationships; selecting and evaluating
      surrogates/biomarkers for safety and efficacy; involvement of the target
      population as soon as possible; using information technologies to make better use
      of existing data. The more thorough and profound studies have been carried out
      during this exploratory stage of development, the earlier a decision can be made
      on the continuation or discontinuation of further development, thus saving
      development time and money and assessing and considerably reducing the risk for
      the patients and increasing the success-rate of the project in the later
      confirmatory effectiveness trial. Taking responsibility as the link between
      research and development gives clinical pharmacology a major opportunity to
      assume a pivotal role in research and development of new drugs. To reach this
      goal, clinical pharmacology must be fully integrated in the whole process from
      the candidate selection to its approval.

PMID- 10599950
TI  - Inhibition of platelet aggregation after intake of acetylsalicylic acid detected
      by a platelet function analyzer (PFA-100).
AB  - OBJECTIVE: The aim of the investigation was to determine the inhibition of
      platelet aggregation detected by the platelet function analyzer PFA-100 in
      patients with coronary artery disease who routinely take 100 mg acetylsalicylic
      acid once daily. METHOD: The PFA-100 (Dade International Inc., Miami, USA) is a
      new device for in vitro measurement of platelet function in citrated whole blood.
      The time needed to form a platelet plug occluding the aperture cut into a
      collagen/epinephrine- or collagen/ADP-coated membrane is determined under high
      shear conditions. Typically, acetylsalicylic acid-induced inhibition of platelet
      aggregation is detected by prolonged closure time in collagen/epinephrine or and
      normal values for collagen/ADP. Blood samples of 48 patients were investigated,
      the control group consisted of 10 healthy volunteers without intake of
      acetylsalicylic acid. The upper limits of normal values of the control group were
      137 sec closure time for collagen/epinephrine and 150 sec for collagen/ADP (mean
      + 2 SD). RESULTS: Statistical analysis (Wilcoxon test) did not show a significant
      difference (p = 0.46) between the patient group (129 +/- 11 sec) and the control
      group (92 +/- 7 sec) for collagen/epinephrine (mean +/- SEM). Only 31% of
      patients had closure time values above those upper limits defined above.
      CONCLUSION: The effect of 100 mg acetylsalicylic acid daily appears to be too
      small and too variable to detect a sufficient inhibition of platelet aggregation
      by the PFA-100 in all patients with coronary artery disease.

PMID- 10599951
TI  - Pharmacokinetics and safety of deramciclane during multiple oral dosing.
AB  - Deramciclane is a new putative non-benzodiazepine-type anxiolytic compound. It is
      a selective serotonin 5-HT(2A) and 5-HT(2C) receptor antagonist and has also
      inverse agonist properties. The aim of this study was to reveal the
      pharmacokinetics and tolerability of deramciclane during repeated oral dosing in
      healthy male volunteers. SUBJECTS, MATERIAL AND METHODS: A randomized double
      blind, placebo-controlled design was used. The study had three consecutive groups
      that received first a single oral dose of 10, 30 and 60 mg of deramciclane
      followed by twice a day administration for seven days. The total number of
      subjects was 28. The pharmacokinetic parameters were calculated for a single dose
      and after repeated administration. Tolerability was assessed by monitoring safety
      laboratory variables, electrocardiogram, heart rate, blood pressure and adverse
      events. RESULTS: The steady-state was reached during the seven-day
      administration. The pharmacokinetics of deramciclane was dose-proportional at
      steady-state at each dose level. Deramciclane accumulated about three-fold during
      repeated administration. The relative bioavailability of deramciclane increased
      about 1.4-fold compared to that of a single dose at each dose level. The mean
      elimination half-life of deramciclane for 10, 30 and 60 mg doses prolonged from
      24.3, 20.9 and 22.9 h after a single dose to 30.5, 25.6 and 28.7 h at steady
      state, respectively. Only few adverse events were reported, all mild and
      transient in nature. The most frequently reported adverse drug reactions were
      tiredness and headache. There were no deramciclane-induced changes in the
      clinical chemistry or hematology variables, blood pressure, heart rate or in
      electrocardiogram. CONCLUSIONS: In conclusion, the pharmacokinetics of
      deramciclane is linear over the dose range of 10 - 60 mg at steady-state. The
      slight non-linearity within the dose levels during repeated administration of
      seven days was regarded as clinically irrelevant. Deramciclane was safe and well
      tolerated up to doses of 60 mg b.i.d. for seven days.

PMID- 10599952
TI  - Similar motor block effects with different disposition kinetics between lidocaine
      and (+ or -) articaine in patients undergoing axillary brachial plexus block
      during day case surgery.
AB  - AIM: The aim of this investigation was to compare the clinical effects and
      pharmacokinetics of lidocaine and articaine in two groups of 15 patients
      undergoing axillary brachial plexus anesthesia. METHOD: The study had a
      randomized design. Thirty patients were allocated to one of the two groups. Each
      patient received either lidocaine (600 mg = 2.561 mMol + 5 microg/ml adrenaline)
      or articaine (600 mg = 2.113 mMol + 5 microg/ml adrenaline), injected via the
      axilla of the brachial plexus over a period of 30 seconds. Onset of surgical
      analgesia was defined as the period from the end of the injection of the local
      anesthetic to the loss of pinprick sensation in the distribution of all three
      nerves. RESULTS: The mean onset time of sensory block of the median nerve of both
      lidocaine and articaine were approximately 10 min. Lidocaine is biexponentially
      eliminated with a t1/2alpha of 9.95 +/- 14.3 min and a t1/2beta of 2.86 +/- 1.55
      h. Lidocaine is metabolized into MEGX (mono-ethyl-glycyl-xilidide) (t(max) 2.31
      +/- 0.84 h; C(max) 0.32 +/- 0.13 mg/l; t1/2beta 2.36 +/- 2.35 h). Lidocaine total
      body clearance was 67.9 +/- 28.9 l/h. Articaine is rapidly and monoexponentially
      eliminated with a t1/2beta of 0.95 +/- 0.39 h. The total body clearance of
      articaine is higher than that of lidocaine, 1,133 +/- 582 l/h vs 67.9 +/- 28.9
      l/h, respectively (p < 0.0001). The volume of distribution (V(d)), of articaine
      is a factor 16 higher times than that of lidocaine (p < 0.0001). CONCLUSION: For
      the axillary administration, lidocaine and articaine show similar
      pharmacodynamics with a different pharmacokinetic behavior and can therefore be
      used to the clinical preference for this regional anesthetic technique.

PMID- 10599954
TI  - Black death, smallpox, and continuity in nature: philosophies in generating new
      knowledge from clinical experiences.

PMID- 10599953
TI  - Nifedipine is not feasible for biliary pain in patients with gallbladder stones.
AB  - OBJECTIVE: Biliary pain is generally treated with NSAIDs and spasmolytics, but
      some patients do not tolerate them. Nifedipine has been suggested to have some
      analgesic effect and it has been used successfully in many painful smooth muscle
      disorders. Our aim was to evaluate the effect of nifedipine for biliary colics
      and gallbladder volume. PATIENTS AND METHODS: Twenty-seven patients suffering
      from uncomplicated symptomatic gallbladder stones were prospectively randomized
      to receive either oral nifedipine (10 mg 3 times daily) or placebo in a double
      blind manner. Liver chemistry and ultrasonography were examined before and after
      the 8-week study period. The patients completed each day a diary of their pain,
      headache, palpitation, burning feeling in skin, dizziness, and their use of
      painkillers. RESULTS: Biliary pain seemed to be less intensive and shorter in
      duration, but without statistical significance, whereas headache tended to be
      more common (p = 0.077) in nifedipine group than that in placebo group. This
      difference would have reached statistical significance with over 155 patients
      randomized. Overall additional drug use was similar in both groups, and was
      increased in nifedipine group for headache (p = 0.05). The fasting gallbladder
      volume tended to decrease (p = 0.085) during the nifedipine treatment but not
      with placebo. Serum liver chemistry remained within normal range. CONCLUSIONS:
      This small study shows that nifedipine may decrease slightly biliary pain
      intensity and duration, and contrary to previous findings in healthy volunteers,
      it seems to decrease resting gallbladder volume in patients with symptomatic
      uncomplicated gallbladder stones, but did not reduce the need of traditional pain
      medication partly because of increased need for headache. Thus it is not a
      feasible choice for routine use against biliary pain in symptomatic gallbladder
      stones, which is why the study was not continued to reach statistical
      significance in respect to biliary pain.

PMID- 10599955
TI  - Thoracoscopic reduction pneumoplasty for severe emphysema: do pleural adhesions
      affect outcome?
AB  - BACKGROUND: Pleural adhesions are frequently encountered in patients undergoing
      reduction pneumoplasty. We evaluated the impact that pleural adhesions had on the
      surgical technique and outcome of thoracoscopic reduction pneumoplasty. METHODS:
      59 operated patients were divided into 2 groups depending on the presence (group
      A) or absence (group B) of pleural adhesions. RESULTS: At inter-group comparison
      (A versus B) a significant difference was found for mean duration of operation
      (128+/-55 min versus 73+/-33 min; p<0.005), morbidity (14 versus 9 patients;
      p<0.05), and hospital stay (14.1+/-11.8 days versus 12.0+/-7.4 days; p<0.001).
      Complications occurred less frequently in the last 29 patients than in the first
      30 patients (11 versus 24; p<0.03). At histopathologic analysis subpleural
      (p<0.005) and interstitial fibrosis (p<0.001), and interstitial granulomas
      (p<0.012) were more frequent in group A specimens. At six months dyspnea index,
      six-minute-walk test, FEV1, FVC, PaO2, and prednisone and oxygen independence
      improved significantly in both groups. However FEV1 increased less in group A
      (1.20+/-0.2L vs 1.31+/-0.3L; p < 0.01). CONCLUSIONS: Pleural adhesions may be
      associated with increased morbidity and less improvement in FEV1 but they do not
      contraindicate thoracoscopic reduction pneumoplasty.

PMID- 10599956
TI  - Transmyocardial laser revascularization with the Holmium:YAG laser does not
      improve myocardial perfusion in the acutely ischemic heart: an experimental study
      measuring myocardial perfusion by a thermal imaging camera.
AB  - BACKGROUND: Transmyocardial laser revascularization (TMLR) is a new surgical
      therapy for patients with end-stage coronary artery disease refractory to
      conventional therapy. TMLR should act by improvement of perfusion of the lasered
      myocardium. Blood should be delivered from the cavity of the heart to the surface
      of the myocardium. The aim of this study was to measure perfusion of normal,
      ischemic, and ischemic myocardium after TMLR. METHOD: We used a new method of
      perfusion measurement by an infrared thermal imaging system in an open-chested
      adult sheep model with temporary and permanent occlusion of the dominant diagonal
      branch. RESULTS: A significant fall from normal perfusion of the myocardium to
      reduced after inducing ischemia (p<0.01) and a significant rise again after
      reperfusion (p<0.001) could be shown. Perfusion measurements after TMLR did not
      significantly differ from perfusion measurements after inducing ischemia (p=0.2).
      CONCLUSION: In the presented sheep model, laser revascularization could not
      improve myocardial perfusion after acute ischemia as seen by the infrared thermal
      imaging system.

PMID- 10599957
TI  - Effectiveness of preoperatively obtained autologous platelet concentrates in open
      heart surgery.
AB  - BACKGROUND: Autologous blood components have been widely introduced in open heart
      surgery. However, the effectiveness of autologous platelet products remains
      controversial. METHODS: Autologous platelet concentrates (PC) were collected from
      patients (n = 35) scheduled for primary valvular heart surgery 1 to 3 days before
      the operation and were transfused immediately after cardiopulmonary bypass. Blood
      loss and platelet-related factors were compared with the control patients who had
      no PC (n=35). RESULTS: There were no serious complications in harvesting,
      preservation, and transfusion of autologous PC. The maximal platelet aggregation
      response significantly improved after its transfusion and tended to be higher
      with autologous PC stored 1 day than with ones stored 2-3 days. Activation of
      coagulation and fibrinolytic factors did not significantly differ between the
      groups. Postoperative blood loss was significantly less in autologous PC group,
      and seemed to have a negative correlation with platelet aggregation response.
      CONCLUSIONS: Autologous PC can be safely prepared and are clinically effective in
      reduction of postoperative blood loss in open heart surgery.

PMID- 10599958
TI  - Hypocalcemia in piglets reduces cardiac and pulmonary vascular disturbance after
      hypoxemia and reoxygenation during cardiopulmonary bypass.
AB  - BACKGROUND: Placing cyanotic newborns on cardiopulmonary bypass (CPB) and
      performing abrupt reoxygenation affects myocardial performance. This study tests
      the hypothesis that hypocalcemia is beneficial in this circumstance of
      reoxygenation. METHODS: Twenty-one newborn piglets (anesthetized, open-chests)
      were placed for one hour on CPB. Seven piglets under normoxic and normocalcemic
      conditions were the controls. The other piglets underwent hypoxemia and
      subsequent reoxygenation, for periods of 30 minutes each, under normo-calcemic
      (Normo-Ca++, n= 7) or hypocalcemic conditions (Hypo-Ca++, n=7). Thirty minutes
      after discontinuation of CPB, the hemodynamic function was assessed taking into
      account stroke work indices (SWI), end systolic elastance (EES), pulmonary
      vascular resistance index (PVRI), cardiac release of conjugated dienes (CD) and
      creatine phosphokinase (CK), and myocardial oxygen consumption (MVO2). These
      parameters were expressed as a percentage of the pre-CPB value. The endogenous
      antioxidant reserve capacity (AORC) of ventricular wall specimens was determined
      by in-vitro lipid peroxidation forming malondealdehyde (nmol MDA/g protein).
      RESULTS: After one hour of CPB the cardiac performance returned to normal range
      without any functional or metabolic disturbance. The normocalcemic condition
      resulted in a hardly impaired cardiac performance (42%**SWI; 67%**EES), an
      augmented PVRI (more than 4-fold**), and highly elevated release of CD and CK (3
      fold** each). The Normo-Ca++ group's MVO2 (95 +/- 14%) was unaltered. The
      hypocalcemic condition improved the myocardial function to near control value
      (85% SWI; 91 % EES) and attenuated the augmentation of the PVRI (n.s. vs. Control
      group) down to 64% of the Normo-Ca++ group's level. The release of CD and CK in
      the Hypo-Ca++ group (both n. s. vs. Control group) only minimally increased. The
      Hypo-Ca++ group's MVO2 improved (137+/-8%*). The MDA formation was worse (344+/
      38**) in the Normo-Ca++ group, but unaltered in the Hypo-Ca++ group (203+/-9;
      n.s. vs. Control group (218+/-20)). * =p<0.05 vs. Controls and Normo-Ca++, **
      =p<0.05 vs. Controls and Hypo-Ca++, using ANOVA. CONCLUSIONS: Hypocalcemia during
      hypoxemia and subsequent reoxygenation highly attenuates myocardial and pulmonary
      vascular disturbance in newborn piglets. This condition of low blood calcium
      protects cardiac function and metabolism as well as the pulmonary vascular tone
      due to diminished myocyte membrane damage, reduced cellular membrane lipid
      peroxydation, and improved endogenous antioxidant reserve capacity.

PMID- 10599959
TI  - Effective gene transfer in the rat myocardium via adenovirus vectors using a
      coronary recirculation model.
AB  - BACKGROUND: Gene therapy promises to play an important role in the treatment of
      heart disease and in transplantation. The limited effectiveness of gene transfer,
      however, remains an unresolved problem. The aim of the study was to create a
      model for more effective gene transfer using adenovirus vectors carrying the lacZ
      reporter gene (AdV-lacZ). METHODS: Beating Lewis rat hearts perfused with
      oxygenated Krebs-Henseleit solution were harvested, after which an atrial septal
      defect (ASD) was created. All vessels were tied and AdV-lacZ was injected into
      the aortic root. The solution was recirculated through the ASD to the left side
      of the heart and pumped back to the coronary arteries by the left ventricle.
      Incubation was allowed for 20 min at 15 degrees C and the hearts were
      subsequently transplanted heterotopically in syngeneic rats. This method was
      compared to AdV-lacZ injection into cardioplegic hearts. The hearts were
      harvested after 2, 7, or 14 days and evaluated histologically for expression of
      the lacZ gene. RESULTS: Maximal gene expression was achieved after 7 days by the
      recirculation model. There was less efficient gene expression at day 2 and at day
      14. No evidence of ischemic injury of the myocardium was noticed histologically.
      Almost no successful gene expression was seen in the arrested hearts. CONCLUSION:
      This novel recirculation method lets the vector be repeatedly exposed to the
      endothelium, resulting in an effective gene expression after 7 days incubation
      time rather than after 14, when a decline has set in presumably due to
      immunologic response.

PMID- 10599960
TI  - Composite graft replacement of the aortic root: long-term results, incidence of
      reoperations.
AB  - BACKGROUND: Long-term results after composite graft replacement of the aortic
      root may depend on the insertion technique. METHODS: 181 consecutive patients
      (mean age 53 years; 153 men) operated on between 1983 and 1993 were studied.
      Indications for surgery were annuloaortic ectasia (n=98), acute aortic dissection
      (n = 46), other indications (n = 12), and various indications after previous
      aortic valve replacement (n = 25). Mean follow-up was 28 months. The open-button
      technique was performed in 74 patients (41 %) and the Bentall inclusion technique
      in 107 patients (59%), with a Cabrol shunt to the right atrium in 16 patients.
      RESULTS: Overall survival was 75% after 7 years, significantly decreased in acute
      aortic dissection (p = 0.0019) and without difference between the two surgical
      techniques (p = 0.3166). Reoperation-free survival was 69% at 7 years and
      significantly decreased after acute dissection (p = 0.0421 ). Pseudoaneurysm
      formation only occurred in 3 patients operated with the Bentall technique not
      including a Cabrol shunt. CONCLUSIONS: Long-term results are satisfactory. In
      acute aortic dissection survival is decreased and late reoperations more
      frequent. The open technique is safe in non-dissection and in acute dissection
      and avoids pseudoaneurysm formation. The Bentall technique combined with Cabrol
      shunt is indicated if there is a high risk of hemorrhage. Long-term monitoring of
      the aorta is mandatory in patients with acute dissection and/or Marfan disease.

PMID- 10599961
TI  - Hemostasis management by use of Hepcon/HMS: increased bleeding without increased
      need for blood transfusion.
AB  - BACKGROUND: Extracorporeal circulation forces complete anticoagulation, most
      frequently achieved by complete heparinization. Activated clotting time (ACT) is
      the gold standard for monitoring, although there is a lack of correlation between
      heparin plasma level and ACT. Several systems for the estimation of free heparin
      have been developed: in this study we focused investigating on the influence of
      the Hepcon/HMS system on postoperative bleeding and transfusion requirements.
      METHODS: 114 patients were randomly assigned to one group monitored by use of
      Hepcon/HMS (group hepcon) and another group by use of ACT (ACT group); 7 patients
      were excluded due to re-exploration. 12 patients did not receive aprotinin; this
      part of the study was stopped early due to massive increased bleeding. 46 and 49
      patients of groups hepcon and ACT, respectively, received aprotinin. RESULTS:
      Using aprotinin, in group hepcon total administered heparin was elevated by 13 %
      in contrast to group ACT while administered protamine was reduced by 20%. The
      ratio of antagonization was 82 +/- 17 % and 51 +/- 12 %, respectively.
      Coagulation parameters were not influenced except for increased postoperative ACT
      and PTT in the hepcon group. Bleeding of patients in that group was significantly
      increased during the first 6 hours, which led to an increased autologous
      retransfusion. Need for substitution of other blood components was not increased
      postoperatively. CONCLUSIONS: Use of the Hepcon/HMS-system for monitoring of
      heparinization during extracorporeal circulation is possible without increased
      risk of thromboembolism. Postoperative blood loss was slightly but significantly
      increased but there was no need for more heterogenous transfusion.

PMID- 10599962
TI  - Simultaneous carotid and coronary artery surgery: indications and perioperative
      outcome.
AB  - BACKGROUND: A significant number of patients with coronary artery disease is
      diagnosed with additional carotid artery disease. This subset of patients has
      been identified as a high-risk group for cardiac and cerebral complications
      following surgical intervention. METHODS: In a retrospective analysis we
      investigated the perioperative outcome of combined single-stage carotid
      endarterectomy (CEA) and coronary artery bypass grafting (CABG) in 63 patients
      operated between January 1989 and August 1998. In all of these patients, CEA was
      performed prior to CABG and before initiation of cardiopulmonary bypass. RESULTS:
      Perioperative mortality rate was 7.9% (5/63) for simultaneous CEA and CABG and
      was due to cardiac complications in all patients. Postoperative unilateral
      neurological symptoms were diagnosed in 1 patient (1.7%) and were completely
      reversible. No neurologic events suggestive for permanent cerebral damage were
      observed during the 30 d postoperative period. CONCLUSIONS: In our study combined
      single-stage CEA and CABG was associated with low cerebral morbidity and patient
      outcome was mainly determined by cardiac complications. In this subset of
      patients, simultaneous CEA and CABG appears to be a safe method.

PMID- 10599963
TI  - Descending necrotizing mediastinitis: mediastinal drainage with or without
      thoracotomy.
AB  - Descending necrotizing mediastinitis (DNM) is a lethal process originating from
      odontogenic, pharyngeal, or cervical infections that descends along the fascial
      planes into the mediastinum. The surgical management ranges from cervical
      drainage to routine thoracotomy but remains controversial. We here describe two
      patients treated successfully who underwent cervical drainage alone or cervical
      drainage combined with thoracotomy. Wide cervical exploration with postural
      drainage was effective in one patient with limited DNM above the carina.
      Mediastinal exploration through thoracotomy was required to salvage the other
      with DNM extending below the carina and associated with pericardial invasion.

PMID- 10599964
TI  - Aorta-cutaneous fistula as a rare complication of localized chronic
      mediastinitis.
AB  - A 35-year-old man was admitted 5 years after congenital heart surgery complicated
      by Staphylococcus aureus and a cutaneous fistula located at the left fourth
      intercostal space. He was febrile (40 degrees C), suffering from sternal pain and
      suppuration from the old fistula. During examination arterial blood suddenly
      discharged from the fistula, so that surgery was immediately instituted. An
      infected Dacron tube implanting on the ascending aorta for a central aorto
      pulmonary shunt was at the origin of a false aneurysm: this had led to the repeat
      formation of an aorta-cutaneous fistula and outbreak of external bleeding.

PMID- 10599965
TI  - Multicentric metachronous central carcinoid of the lung: a case report.
AB  - A 51-year-old female patient with metachronous multiple central typical carcinoid
      represents the subject of the case discussed. The patient underwent
      bronchoplastic surgery in order to remove the first carcinoid tumor twelve years
      ago. She was readmitted to the hospital following a long tumor-free period of
      disease when two new central carcinoids were diagnosed. The carcinoids were first
      treated by rigid bronchoscopical removal of the tumors followed by laser
      coagulation of the bases. Bronchoscopic follow-up one year after the treatment
      did not reveal any pathological findings.

PMID- 10599966
TI  - Pulmonary aspergilloma - clinical findings and surgical treatment.
AB  - The management of pulmonary aspergilloma is still a topic of discussion.
      Demonstrating several cases of pulmonary aspergilloma, their clinical course and
      their follow-up, we try to contribute some arguments for the preference of an
      early operation. Between 1992 and 1998, 18 patients underwent thoracotomy for
      treatment of pulmonary aspergilloma. The most common indication for operation
      were hemoptysis [6] and indeterminate mass [6]. Lobectomy was the most frequent
      operation [11]. Underlying diseases were bronchiectasis [10], tuberculosis [3],
      carcinoma [2], blebs [2], and epitheloid granuloma. Two patients had
      postoperative complications, another three died later in the clinical course
      because of liver failure, septicemia, and persisting air leakage and sepsis. We
      recommend early resection of symptomatic, cavitating aspergilloma in the simple
      form and even with an inflammatory reaction of the surrounding tissue. Especially
      low-risk patients profit highly from an early operation. High-risk patients
      should be operated on only in cases of life-threatening complications.

PMID- 10599967
TI  - Sunscreens for melanoma prevention.

PMID- 10599968
TI  - Role of UVA in the pathogenesis of melanoma and non-melanoma skin cancer. A short
      review.
AB  - It is well established, at least in mice, that not only ultraviolet C (UVC) or
      ultraviolet B (UVB), but also ultraviolet A (UVA) is able to induce squamous cell
      carcinomas. Results from animal models, epidemiological studies, and clinical
      observations suggest that UVA might play an important role in the pathogenesis of
      malignant melanoma as well. In contrast to UVC or UVB, UVA is hardly able to
      excite the DNA molecule directly and produces only few pyrimidine dimers.
      Oxidative DNA base damage, generated indirectly through photosensitizers, might
      be responsible for the mutagenic and carcinogenic properties of UVA. This is
      supported by differences in mutation spectra induced by UVA and UVB in mammalian
      cells and tumors. Avoidance of natural and artificial UVA sources is recommended,
      especially for melanoma-prone individuals.

PMID- 10599969
TI  - Photosensitivity in the Smith-Lemli-Opitz syndrome.

PMID- 10599970
TI  - The related DNA repair deficient photosensitive diseases.

PMID- 10599971
TI  - Sunscreens: photoprotection of non-erythema endpoints relevant to skin cancer.

PMID- 10599972
TI  - In vitro phototoxicity of new quinolones: production of active oxygen species and
      photosensitized lipid peroxidation.
AB  - To elucidate photosensitization potentials of new quinolone antibacterial agents,
      production of active oxygen species and peroxidation of squalene after
      ultraviolet A exposure were investigated. Production of singlet oxygen and/or
      hydrogen peroxide was estimated by bleaching of p-nitroso-N,N-dimethylaniline.
      Lomefloxacin showed the greatest ability to produce active oxygen species, and
      this ability was reduced by the addition of the singlet oxygen quencher sodium
      azide. Ciprofloxacin and fleroxacin also had strong activity. Photosensitized
      peroxidation of squalene was evaluated by measurement of thiobarbituric acid
      reactive substances. Lomefloxacin was the strongest sensitizer, followed by
      fleroxacin and ciprofloxacin. These results suggest that certain new quinolones
      are involved in phototoxicity via the mechanism of active oxygen species.

PMID- 10599973
TI  - Relationship between constitutive skin color and ultraviolet light sensitivity in
      Koreans.
AB  - The assessment of skin sensitivity to ultraviolet (UV) radiation is important in
      treating a variety of skin diseases and preventing the deleterious effects of UV.
      Although there are many ways to predict the sensitivity to UVR, controversies
      exist over their objectivity, correlation, and applicability in various races.
      For the purpose of evaluating the relationship of skin color and UV
      responsiveness, this study was performed to assess the validity of constitutive
      skin color for an individual's UV sensitivity in 80 healthy Korean volunteers.
      The subjects were divided into two groups: a young-aged group with 40 subjects
      aged 20-39 years and an old-aged group with 40 subjects aged 43-63 years. A
      minimal erythema dose (MED) of UVB and minimal immediate pigment darkening dose
      (MIPDD) of UVA were assessed using a fluorescent lamp (Panasol II, National
      Biologic Co., Twinberg, USA) and a metal-halide lamp (Dermalight 2001, Mutzhas,
      Munich, Germany), respectively. The constitutive skin color of buttock was
      measured with a Minolta Chroma Meter CR-300 (Osaka, Japan), using the CIE
      (Commission International de l'Eclairege) L*a*b* system. Of the three L*a*b*, we
      used the L* value to estimate the skin color. For the MED and L* values, the
      values were inversely proportionate (P<0.05) in the young-aged group; however, no
      correlation existed in the old-aged group. No relationships existed among
      Fitzpatrick skin type and MED, skin type and MIPDD. The results of this study
      indicated that the constitutive skin colors in the young-aged group can be an
      objective and adequate predictor of cutaneous UV sensitivity.

PMID- 10599974
TI  - Suppression of immediate-type hypersensitivity elicitation in the skin prick test
      by ultraviolet B irradiation.
AB  - Reproducibility of skin prick testing (SPT) and its modulation by ultraviolet B
      (UVB) radiation is of clinical interest. Sensitized atopic volunteers (groups A
      and B, n=21) were prick tested with common commercial allergen solutions
      (undiluted, diluted 1:10 and diluted 1:100) before, 24 h after one and 24 h after
      three suberythematous UVB irradiations. Volunteers in group A (n=8) received
      local UVB irradiation of prick test areas, whereas volunteers in group B (n=13)
      received whole body UVB irradiation, with prick test areas covered. In group A,
      the wheal intensities, expressed as the ratio allergen wheal size to histamine
      wheal size, were decreased by 28% (1:10 dilution) (P=0.01) and 45% (1:100
      dilution) (P=0.02) after one UVB irradiation. Flare intensities were decreased by
      48% (1:10 dilution) (P=0.03) after three UVB irradiations. In group B, the wheal
      and flare responses tended to decrease. Possible mechanisms of this short-term
      suppressive effect of UVB irradiation on SPT reactions include a direct effect on
      mast cells. It is concluded that UV irradiation, even a single exposure, prior to
      skin testing may compromise the validity of SPT testing.

PMID- 10599975
TI  - Sunscreen product performance.

PMID- 10599976
TI  - The susceptibility of red blood cells to autoxidation in type 2 diabetic patients
      with angiopathy.
AB  - We examined the in vitro susceptibility of red blood cell (RBC) lipids to
      oxidation in type 2 diabetic patients with or without angiopathy. Lipid
      peroxidation was assessed by quantifying thiobarbituric acid (TBA) reactivity as
      malondialdehyde (MDA). We also examined the RBC antioxidant status by determining
      glutathione (GSH) levels. Before in vitro oxidation, RBC MDA levels were
      significantly higher in both diabetic groups than in the controls (P < .001), and
      a significant difference was found between the two diabetic groups (P < .05).
      After in vitro treatment of RBCs with hydrogen peroxide, the degree of lipid
      peroxidative damage was significantly higher in diabetic patients with angiopathy
      versus diabetics without angiopathy (P < .001). Diabetic patients have low RBC
      GSH levels compared with controls, and after in vitro oxidation, the levels were
      significantly decreased in diabetics (P < .001). There was not a significant
      correlation between RBC MDA levels and glycated hemoglobin (GHb), plasma
      cholesterol, and triglyceride. The correlation between RBC MDA and GSH was weak
      (P < .001). We suggest that the results of this study might help to clarify the
      role of oxidative mechanisms as an in vitro model of degenerative damage in type
      2 diabetic angiopathic complications.

PMID- 10599977
TI  - Tumor necrosis factor alpha signaling pathway and apoptosis in pancreatic beta
      cells.
AB  - Cytokines induce apoptosis in pancreatic beta cells, but the exact mechanisms and
      sequence of events are not clear. Here, we investigate a role for tumor necrosis
      factor alpha (TNF-alpha) in the apoptosis of beta cells. Using the ribonuclease
      (RNase) protection assay and the reverse transcriptase-polymerase chain reaction
      (RT-PCR) method, we confirmed that TNF receptor 1 (TNFR1), TNFR1-associated death
      domain protein (TRADD), Fas receptor-associated intracellular protein with death
      domain (FADD), and FADD-like interleukin-1beta-converting enzyme (FLICE) were
      expressed in the pancreatic beta cell line, MIN6 cells. Fluorescent microscopic
      examination using Hoechst 33342 dye (Sigma, St Louis, MO) demonstrated that TNF
      alpha induced time- and dose-dependent apoptotic nuclear changes in these beta
      cells. In situ end-labeling (ISEL) DNA analysis revealed that 10 nmol/L TNF-alpha
      generated new 3'-OH DNA strand breaks. Moreover, qualitative assessment of the
      induced DNA damage on agarose gels showed that 10 nmol/L TNF-alpha produced
      characteristic apoptotic patterns of DNA fragments formed by internucleosomal
      hydrolysis of static chromatin. In addition, C2-ceramides and natural ceramides
      dispersed in a solvent mixture of ethanol and dodecane induced characteristic
      features of apoptosis in MIN6 cells, mimicking TNF-induced DNA damage. We also
      determined endosomal ceramide production after TNF-alpha (10 nmol/L) treatment in
      MIN6 cells using the diacylglycerol kinase assay. These results suggest that TNF
      alpha can cause apoptosis in pancreatic beta cells through TNFR1-linked apoptotic
      factors, TRADD, FADD, and FLICE, and TNF-induced ceramide production may be
      involved in the pathways.

PMID- 10599978
TI  - Strength training does not alter the effects of testosterone propionate
      injections on high-density lipoprotein cholesterol concentrations.
AB  - The purpose of the study was to examine the long-term effects of a high-volume
      strength training program (vertical ladder climbing) and testosterone propionate
      injections (intraperitoneal) on serum lipid and lipoprotein concentrations in
      male Sprague-Dawley rats. The animals were randomly divided into a testosterone
      (T)-treated group (dose per injection, 2.5 mg/kg testosterone propionate
      solubilized in 1 mL safflower oil) and a control (C) group (injected with an
      isovolumic amount of safflower oil alone). Animals were further divided into a
      strength-trained group (E) and a sedentary group (S). The 10-week resistance
      training program consisted of weights (100% of body mass) appended to the tail as
      the animal climbed an 85-cm ladder to volitional fatigue. Following 10 weeks of
      strength training and testosterone injections, body weight was not significantly
      different between the main effects of strength training exercise (TE + CE v TS +
      CS) and testosterone injections (TE + TS v CE + CS) or between groups. Testicular
      mass (mean +/- SE) was measured as a relative indicator of testosterone effects.
      Both TE and TS had significantly reduced testicular mass (2.56 +/- 0.04 and 2.38
      +/- 0.03 g, respectively) compared with CE and CS (3.49 +/- 0.03 and 3.49 +/-
      0.04 g, respectively). No significant differences were observed between groups
      for total serum cholesterol, serum triglycerides, or serum low-density
      lipoprotein cholesterol (LDL-C). In contrast, significant decreases in high
      density lipoprotein cholesterol (HDL-C) were observed for both TE (26.7 +/- 1.6
      mg/dL) and TS (27.5 +/- 1.3 mg/dL) compared with CE (48.7 +/- 2.9 mg/dL) and CS
      (43.5 +/- 2.6 mg/dL). As a result, the total cholesterol to HDL-C ratio was
      significantly greater for TS + TE (4.7 +/- 0.1) compared with CS + CE (2.9 +/-
      0.2). These observations suggest that in animals, a 10-week program of high
      volume strength training does not elicit any beneficial effect on the lipid or
      lipoprotein status, nor does it attenuate the altered lipoprotein profile induced
      by testosterone propionate injections.

PMID- 10599979
TI  - The narrow therapeutic window of glycated hemoglobin and assay variability.
AB  - Glycated hemoglobin is measured by a variety of assays, each of which has a
      unique normal level. Our purpose is to show that among the different assays
      available in the United States, using the same patient's blood sample, assay
      results may vary widely and may more or less easily achieve a glycated hemoglobin
      value within the normal range. The following assays were compared using the same
      patient's blood sample for each pair of assays: glycohemoglobin affinity assay
      (GHB Reader; Isolab, Akron, OH) versus gel electrophoresis assay (n = 76); Isolab
      versus ion capture assay (IMX; Abbott Laboratories, Irving, TX) (n = 57);
      monoclonal antibody assay (DCA2000; Bayer Diagnostics, Pittsburgh, PA) versus IMX
      (n = 100); and high-performance liquid chromatography (HPLC) assay (Bio-Rad
      Variant A1c; Bio-Rad Laboratories, Richmond, CA) versus IMX assay (n = 55). Our
      analyses indicate that a relative ranking can be established for the ease of
      achieving a normal glycated hemoglobin level. The ranking indicates that the most
      stringent or difficult assays for achieving a normal level are the Isolab and
      DCA2000 assays. The intermediate assays are the IMX and Bio-Rad Variant, and the
      easiest method for achieving a normal value is the gel electrophoresis assay. Our
      results indicate that various glycated hemoglobin assays vary widely and are
      associated with more or less difficulty for an individual patient to achieve a
      glycated hemoglobin level within the normal range. These results are especially
      significant with respect to (1) the clinically narrow therapeutic window of
      glycated hemoglobin values in type 1 diabetes to avoid rapidly advancing severe
      hypoglycemia rates and chronic microvascular complication rates, and (2) the
      glycated hemoglobin threshold for rapidly advancing macrovascular disease in both
      type 1 and type 2 patients.

PMID- 10599980
TI  - Meal-induced oxidative stress and low-density lipoprotein oxidation in diabetes:
      the possible role of hyperglycemia.
AB  - Oxidative stress and its contribution to low-density lipoprotein (LDL) oxidation
      have been implicated in the pathogenesis of vascular diabetic complications.
      However, the relationship between hyperglycemia, hyperinsulinemia,
      hyperlipidemia, and oxidative stress is still debated. If plasma glucose and/or
      insulin and/or lipid are some of the most important determinants of oxidative
      stress in diabetes, then their typical postprandial elevations in diabetes would
      be expected to favor oxidative stress and LDL oxidation. To test this hypothesis,
      in type 2 diabetic patients, we evaluated the effects of two different standard
      meals designed to produce different levels of postprandial hyperglycemia on the
      plasma oxidative status and LDL oxidation. The meals were administered in
      randomized order to each of 10 type 2 diabetic patients. Blood samples were
      collected at baseline and 60 and 120 minutes after the meals. In every sample,
      plasma levels of glucose, insulin, cholesterol, triglycerides, nonesterified
      fatty acids (NEFAs), malondialdehyde (MDA), and the total radical-trapping
      antioxidant parameter (TRAP) were measured. LDL susceptibility to oxidation was
      evaluated at baseline and after 120 minutes. Plasma glucose, insulin,
      triglycerides, and MDA increased and NEFAs and TRAP significantly decreased after
      either meal. The variations in plasma glucose, MDA, and TRAP were significantly
      greater and LDL was more susceptible to oxidation after the meal that produced a
      significantly higher degree of hyperglycemia. These results suggest that
      postprandial hyperglycemia may contribute to oxidative stress in diabetic
      patients, providing a mechanistic link between hyperglycemia and diabetic
      vascular disease.

PMID- 10599981
TI  - Metabolic adaptations to a high-fat diet in endurance cyclists.
AB  - We examined the time course of metabolic adaptations to 15 days of a high-fat
      diet (HFD). Sixteen endurance-trained cyclists were assigned randomly to a
      control (CON) group, who consumed their habitual diet (30% +/- 8% mJ fat), or a
      HFD group, who consumed a high-fat isocaloric diet (69% +/- 1% mJ fat). At 5-day
      intervals, the subjects underwent an oral glucose tolerance test (OGTT); on the
      next day, they performed a 2.5-hour constant-load ride at 70% peak oxygen
      consumption (VO2peak), followed by a simulated 40-km cycling time-trial while
      ingesting a 10% 14C-glucose + 3.44% medium-chain triglyceride (MCT) emulsion at a
      rate of 600 mL/h. In the OGTT, plasma glucose concentrations at 30 minutes
      increased significantly after 5 days of the HFD and remained elevated at days 10
      and 15 versus the levels measured prior to the HFD (P < .05). The activity of
      carnitine acyltransferase (CAT) in biopsies of the vastus lateralis muscle also
      increased from 0.45 to 0.54 micromol/g/min over days 0 to 10 of the HFD (P < .01)
      without any change in citrate synthase (CS) or 3-hydroxyacyl-coenzyme A
      dehydrogenase (3-HAD) activities. Changes in glucose tolerance and CAT activity
      were associated with a shift from carbohydrate (CHO) to fat oxidation during
      exercise (P < .001), which occurred within 5 to 10 days of the HFD. During the
      constant-load ride, the calculated oxidation of muscle glycogen was reduced from
      1.5 to 1.0 g/min (P < .001) after 15 days of the HFD. Ingestion of a HFD for as
      little as 5 to 10 days significantly altered substrate utilization during
      submaximal exercise but did not attenuate the 40-km time-trial performance.

PMID- 10599982
TI  - Combined hyperlipidemia is associated with increased exercise-induced muscle
      protein release which is improved by triglyceride-lowering intervention.
AB  - Although myopathy is considered an adverse effect of treatment with 3-hydroxy-3
      methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors and fibrates in combined
      hyperlipidemia, the present study was performed to investigate whether combined
      hyperlipidemia itself is associated with skeletal muscle pathology and whether
      lipid-lowering intervention has beneficial effects. To investigate whether
      combined hyperlipidemia is associated with skeletal muscle pathology, 10 male
      patients and 15 normolipidemic controls underwent a 45-minute standardized
      bicycle ergometer test at a load of 2 W/kg lean body mass (parallel study). One-
      and 8-hour postexercise increments in the plasma level of the muscle proteins
      creatine kinase (CK), myoglobin (Mb), and fatty acid-binding protein (FABP) were
      assessed as parameters for (subclinical) skeletal muscle pathology. The 8-hour
      postexercise increments in CK and Mb and 1-hour postexercise increment in Mb were
      significantly higher in patients than in controls, thus indicating increased
      exercise-induced muscle membrane permeability in combined hyperlipidemia. To
      investigate the effects of lipid-lowering intervention on skeletal muscle in
      combined hyperlipidemia, 21 subjects with combined hyperlipidemia were randomized
      double-blindly to receive 6 weeks of treatment with fluvastatin 40 mg/d,
      gemfibrozil 600 mg twice daily, or combination therapy. All subjects underwent an
      ergometer test before and after treatment. Gemfibrozil treatment alone reduced
      the CK increments 8 hours postexercise by 47% and the FABP increments 1 and 8
      hours postexercise by 83% and 101%, respectively (all P < .05). Combined
      treatment reduced Mb increments 1 hour postexercise by 54% and FABP increments 8
      hours postexercise by 44% (all P < .05). A highly significant correlation existed
      between therapy-induced changes in plasma triglycerides and changes in
      postexercise increments of FABP and Mb. In conclusion, combined hyperlipidemia is
      associated with an increased exercise-induced release of muscle proteins, which
      is ameliorated by triglyceride-lowering intervention. As FABP is an indicator for
      ischemia-induced skeletal muscle pathology, a possible explanation is the
      impaired muscle blood flow during hypertriglyceridemia, which may be reversed by
      triglyceride-lowering intervention. The mechanism and clinical relevance of these
      findings remain to be investigated.

PMID- 10599983
TI  - Plasma platelet-activating factor acetylhydrolase activity in human
      immunodeficiency virus infection and the acquired immunodeficiency syndrome.
AB  - Platelet-activating factor (PAF) acetylhydrolase (PAF-AH) catalyzes the
      hydrolysis of PAF, a mediator of inflammation, as well as other biologically
      active oxidized phospholipids. In humans, plasma PAF-AH activity is bound to low
      density lipoprotein (LDL) and high-density lipoprotein (HDL). Higher levels of
      plasma PAF-AH activity have been found in a variety of diseases, and are thought
      to be a defense mechanism against the toxic effects of PAF and oxidized
      phospholipids. We studied plasma PAF-AH activity in patients with human
      immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome
      (AIDS), a disease characterized by chronic HIV infection and a systemic host
      response. Plasma PAF-AH activity was significantly greater in AIDS patients
      compared with control subjects (25.2 +/- 2.0 v 17.0 +/- 0.8 nmol/min/mL, P <
      .001). The higher levels of plasma PAF-AH activity were found in LDL (28.2 +/-
      2.2 v 18.3 +/- 1.0 nmol/min/mL for AIDS v controls, respectively, P = .0005), but
      not in HDL. Plasma PAF-AH activity in AIDS correlated with circulating interferon
      alfa (r = .575, P = .005) and plasma triglycerides (r = .556, P < .0025). The
      presence of secondary infection in AIDS did not significantly change plasma PAF
      AH activity. The initiation of a new antiretroviral regimen with either a
      protease inhibitor or the nucleoside analog lamivudine did not significantly
      decrease plasma PAF-AH activity, despite successful suppression of HIV RNA
      levels. Plasma PAF-AH activity may be a sensitive marker of the host response to
      infection, and the higher levels of plasma and LDL-associated PAF-AH activity in
      patients with HIV infection and AIDS may be a physiological response to protect
      the host against oxidative injury from PAF and oxidized phospholipids.

PMID- 10599984
TI  - Effects of evodiamine on the secretion of testosterone in rat testicular
      interstitial cells.
AB  - Evodiamine, a bioactive component isolated from the Chinese medicine Wu-chu-yu,
      exhibits vasodilative and antianoxic action. Although evodiamine indeed has many
      biological effects, its effects on the endocrine system are not clear. The
      present study explored the effects of evodiamine on testosterone secretion in
      vitro. Rat collagenase-dispersed testicular interstitial cells (TICs) were
      incubated with evodiamine (0 to 10(-4) mol/L) in the presence or absence of human
      chorionic gonadotropin (hCG), forskolin, 8-bromo-adenosine 3':5'-cyclic
      monophosphate (8-Br-cAMP), or steroidogenic precursors (including 25
      hydroxycholesterol, pregnenolone, progesterone, 17alpha-hydroxyprogesterone, and
      androstenedione) at 34 degrees C for 1 hour. The testosterone concentration in
      the media samples was measured by radioimmunoassay. Evodiamine 10(-4) mol/L was
      effective to reduce both basal and hCG-stimulated testosterone secretion in rat
      TICs after 1, 2, or 4 hours of incubation. The stimulatory effect of forskolin on
      testosterone release in TICs was prevented by administration of evodiamine.
      Evodiamine 10(-4) mol/L also decreased 8-Br-cAMP- and androstenedione-stimulated
      testosterone secretion. These results suggest that evodiamine reduces
      testosterone secretion in rat TICs via a mechanism involving reduced activity of
      cAMP-related pathways and 17beta-hydroxysteroid dehydrogenase (17beta-HSD).

PMID- 10599985
TI  - Heightened norepinephrine-mediated vasoconstriction in type 2 diabetes.
AB  - Adrenergic responsiveness (AR) appears to be increased in subjects with diabetes,
      but measurement of arterial AR in normotensive people with type 2 diabetes
      mellitus has not been previously reported. We sought to determine whether,
      compared with control subjects, there is increased arterial AR in type 2 diabetes
      mellitus and its relationship to the level of systemic sympathetic nervous system
      activity (SNSa). We studied 15 type 2 diabetic subjects aged 57 +/- 3 years
      without hypertension or clinical signs of autonomic neuropathy and 13 age-matched
      control subjects aged 55 +/- 2 years. We assessed vascular alpha-AR by measuring
      forearm blood flow (FABF) by venous occlusion plethysmography during
      intrabrachial artery norepinephrine (NE) and phentolamine infusions, as well as
      arterial plasma NE levels and the extravascular NE release rate (NE2) derived
      from 3H-NE kinetics, as estimates of systemic SNSa. The vasoconstricting effect
      of NE during intrabrachial artery NE infusion was greater in type 2 diabetes
      compared with control subjects (P = .02). The vasodilating effect of phentolamine
      was greater in type 2 diabetics compared with control subjects (P = .05),
      suggesting increased endogenous arterial alpha-adrenergic tone. Arterial plasma
      NE levels (control v type 2, 1.8 +/- 0.10 v 1.84 +/- 0.14 nmol/L, P = .86) and
      NE2 (control vtype 2, 11.8 +/- 1.54 v 13.3 +/- 0.89 nmol/min/m2, P = .39) were
      similar in the two groups. In summary, in type 2 diabetes compared with control
      subjects, (1) the vasoconstriction response to intraarterial NE is greater, (2)
      plasma NE and NE2 are similar, suggesting similar levels of systemic SNSa, and
      (3) arterial alpha-adrenergic tone is greater. We conclude that subjects with
      type 2 diabetes demonstrate inappropriately increased alpha-AR for their level of
      systemic SNSa.

PMID- 10599987
TI  - Changing pattern of prevalence of insulin resistance in Psammomys obesus, a model
      of nutritionally induced type 2 diabetes.
AB  - Psammomys obesus (a desert gerbil, nicknamed the "sand rat") with innate insulin
      resistance was transferred to a high-energy (HE) diet at a young (8 to 20 weeks)
      and older (38 to 45 weeks) age. The young Psammomys progressed to in vivo insulin
      resistance, followed by pronounced hyperglycemia and hyperinsulinemia, as
      described previously. Analysis of the time dependency of these changes in
      response to the HE diet showed that the increase in serum glucose preceded the
      increase in insulin and plateaued earlier, reverting to normal together with
      insulin in the older Psammomys. Implants releasing insulin 2 IU/24 h did not
      induce appreciable hypoglycemia, a decrease in free fatty acids (FFAs), or a
      suppression of hepatic phosphoenolpyruvate carboxykinase (PEPCK) activity in
      young animals after 5 hours, despite a markedly increased circulating insulin.
      However, in the older Psammomys, the exogenous hyperinsulinemia produced a
      significant decline in serum glucose and FFA and a suppression of hepatic PEPCK
      activity. A euglycemic-hyperinsulinemic clamp confirmed that hepatic glucose
      production (HGP) was lower in older Psammomys versus the young and was almost
      completely abolished by insulin (from 5.6 +/- 0.6 to 0.2 +/- 0.1 mg x min(-1) x
      kg(-1) v 10.9 +/- 0.8 to 3.9 +/- 0.5 mg x min(-1) x kg(-1)). This indicates that
      HGP, rather than glucose underutilization, was the main contributor to the
      hyperglycemia and that the hepatic insulin resistance in Psammomys is attenuated
      with age. In relation to the human condition, these findings point out that while
      the type 2 diabetes prevalence in Western populations generally increases with
      age, the excessive nutritional intake in high-risk populations produces a pattern
      of diabetes prevalence that tapers off with age. As such, the nutritionally
      induced diabetes in Psammomys represents a similar model for a differing pattern
      of the age-related prevalence of diabetes.

PMID- 10599986
TI  - Comparative regulation of hepatic sterol 27-hydroxylase and cholesterol 7alpha
      hydroxylase activities in the rat, guinea pig, and rabbit: effects of cholesterol
      and bile acids.
AB  - The regulation of the classic and alternative bile acid synthetic pathways by key
      hepatic enzyme activities (microsomal cholesterol 7alpha-hydroxylase and
      mitochondrial sterol 27-hydroxylase, respectively) was examined in bile acid
      depletion and replacement and cholesterol-feeding experiments with rats, guinea
      pigs, and rabbits. The bile acid pool was depleted by creating a bile fistula
      (BF) and collecting bile for 2 to 5 days, and it was replaced by intraduodenal
      infusion of the major biliary bile acids (taurocholic acid [TCA],
      glycochenodeoxycholic acid [GCDCA], and glycocholic acid [GCA] in the rat, guinea
      pig, and rabbit, respectively) at rates equivalent to the measured hepatic flux
      of the bile acids. To study the effects of cholesterol, the animals were fed for
      7 days on a basal diet with and without 2% cholesterol. Cholesterol 7alpha
      hydroxylase and sterol 27-hydroxylase activities, measured by isotope
      incorporation assays, were related to bile acid output and composition and
      hepatic cholesterol concentrations. Intraduodenal infusion of bile acids
      increased the output of the tested bile acids, but did not significantly change
      hepatic cholesterol concentrations and had no effect on sterol 27-hydroxylase
      activity. Neither bile acid depletion nor replacement affected sterol 27
      hydroxylase activity when three different substrates (cholesterol, 5beta
      cholestane-3alpha,7alpha-diol, and 5beta-cholestane-3alpha,7alpha,12alpha-triol)
      were tested. In contrast, feeding 2% cholesterol increased hepatic cholesterol
      concentrations in rats, guinea pigs, and rabbits threefold, twofold, and
      eightfold, respectively, and increased hepatic mitochondrial sterol 27
      hydroxylase activity (conversion of cholesterol to 27-hydroxycholesterol) in all
      three animal models. The stimulation and feedback inhibition of cholesterol
      7alpha-hydroxylase activity by bile acid depletion and replacement were observed
      in all three animal models, whereas the effect of cholesterol feeding was species
      dependent (cholesterol 7alpha-hydroxylase activity increased in the rat, did not
      change in the guinea pig, and was inhibited in the rabbit). Thus, in contrast to
      sterol 27-hydroxylase, which was upregulated by cholesterol but not affected by
      bile acid depletion and replacement in all three animal models, cholesterol
      7alpha-hydroxylase activity was controlled consistently and inversely by the
      hepatic flux of bile acids, but was species-dependent in its response to a 1-week
      feeding with 2% cholesterol.

PMID- 10599988
TI  - Splanchnic bed utilization of enteral alpha-ketoisocaproate in humans.
AB  - The branched-chain ketoacids (BCKAs) are used as dietary supplements to spare
      essential amino acid nitrogen, yet little is known about their absorption and
      utilization in the body. To study the fate of enterally delivered alpha
      ketoisocaproate (KIC), seven healthy adults were infused in the postabsorptive
      state with [1-(13)C]KIC and [phenyl-2H5]phenylalanine intravenously (NGI) and
      with [5,5,5-2H3]KIC by nasogastric tube (NG). After 3.5 hours, the routes of
      tracer infusion were switched for an additional 3.5 hours. Each subject received
      a second infusion study on a different day with the order of tracer infusion
      reversed. KIC and phenylalanine kinetics and first-pass uptake and disposal of
      the enteral tracer by the splanchnic bed were calculated from the tracer
      enrichments measured in plasma KIC, leucine, and phenylalanine and breath CO2.
      Phenylalanine flux was 39.5 +/- 1.2 micromol/kg/h during the i.v. infusion
      periods. KIC flux was 33.1 +/- 1.8 and 30.4 +/- 1.4 micromol/kg/h measured with
      13C- and 2H3-KIC, respectively, and these values were significantly different.
      The fraction of enterally delivered tracer sequestered by the splanchnic bed on
      the first pass was 30.9% +/- 2.0%, 30.0% +/- 1.4%, and 30.7% +/- 2.7% for 13C
      KIC, 2H3-KIC, and 2H5-phenylalanine, respectively. The fraction of infused 13C
      KIC tracer recovered as 13CO2 was 27.1% +/- 1.2% and 24.0% +/- 0.9% during i.v.
      and NG infusion, respectively. From these data, the fraction of ng KIC tracer
      extracted and oxidized on the first pass was calculated to be 5.1% +/- 1.1%. This
      fraction was greater than that previously reported for leucine extraction and
      oxidation (2%), but it was still only a small fraction of the overall extraction
      (5/30 = 16%). Because the only two fates of the KIC tracer extracted by the
      splanchnic bed are oxidation or transamination to leucine, the majority (84%) of
      the KIC tracer was extracted and converted to leucine. These results demonstrate
      that KIC delivered enterally to postabsorptive humans is rapidly extracted and
      predominantly converted to leucine by the splanchnic bed. This leucine appears to
      be available for use by both the splanchnic bed and the whole body.

PMID- 10599989
TI  - Differences in estimates of forearm protein synthesis between leucine and
      phenylalanine tracers following unbalanced amino acid infusion.
AB  - We compared the leucine (Leu) and phenylalanine (Phe) tracer-determined response
      of forearm protein synthesis (PS) before and after stimulation of protein
      anabolism by intravenous infusion of Leu-enriched, Phe-deficient amino acids and
      insulin (increased to approximately 100 microU/mL) with the euglycemic clamp. Six
      healthy subjects received primed-constant infusions of L-[ring-2H5]-Phe and L-[1
      (14)C]-Leu, and steady-state forearm Phe and Leu kinetics were determined.
      Following the combined infusion, the arterial Leu concentration increased
      approximately 70% (P < .001), whereas Phe decreased about 15% (P < .01). Forearm
      PS and net balance (NB) increased (P < .05 or less v basal) using both amino acid
      tracers. However, the relative increments observed with the Leu tracer were more
      than 75% larger (P < .05 or less) than those observed with the Phe tracer, even
      when the data were corrected for the standard relative abundance of these two
      amino acids in forearm protein(s). Thus, the calculated changes of forearm PS and
      NB in response to an unbalanced amino acid infusion with hyperinsulinemia were
      affected by the plasma level of leucine and phenylalanine, whose tracers were
      used to estimate forearm protein turnover. Since these two essential amino acids
      share the same transport system, a competition at this level cannot be excluded.

PMID- 10599991
TI  - Effect of local sympathetic blockade on forearm blood flow and glucose uptake
      during hypoglycemia.
AB  - During hypoglycemia, hepatic glucose production increases and peripheral glucose
      utilization decreases. Systemic beta-adrenergic blockade during hypoglycemia
      increases peripheral glucose utilization. To explore the local effects of
      increased alpha- and beta-adrenergic activity on skeletal muscle glucose
      utilization, we measured arterial and venous plasma glucose concentrations,
      forearm blood flow (FBF), and forearm glucose uptake (FGU) during a
      hyperinsulinemic (40 mU/m2/min) stepped-hypoglycemic clamp with intrabrachial
      artery infusion of saline, phentolamine, propranolol, or combined phentolamine
      and propranolol. A control study was also performed with a euglycemic clamp and
      intraarterial saline. During hypoglycemia with saline and phentolamine, there
      were significant increases in FBF (130% +/- 38% and 180% +/- 35%, respectively)
      and FGU (120% +/- 51% and 230% +/- 150%, respectively). During hypoglycemia with
      propranolol and phentolamine + propranolol, FBF remained constant. FGU during
      hypoglycemia with propranolol was not different versus hypoglycemia with saline.
      No differences were found in these studies for forearm lactate output (FLO) or
      venous free fatty acid concentrations. These results demonstrate that local, as
      opposed to systemic, blockade during hypoglycemia does not alter peripheral
      glucose utilization.

PMID- 10599990
TI  - Thyrotropin decreases leptin production in rat adipocytes.
AB  - Leptin, which is secreted from adipocytes, has a role in the regulation of
      appetite and energy expenditure. The thyrotropin receptor (TSH-R) was recently
      found in adipocytes. We examined the effects of TSH on leptin production and
      lipolysis in rat epididymal adipocytes. TSH decreased the concentration of leptin
      in the medium time (approximately 24 hours)- and dose (approximately 10(-7)
      mol/L)-dependently (half-maximal inhibition [IC50] approximately 10(-9) mol/L).
      TSH also decreased the ob mRNA level approximately 55% in adipocytes. We
      confirmed the presence of TSH-R mRNA in the adipocytes by reverse transcription
      polymerase chain reaction (RT-PCR). TSH stimulated glycerol release dose
      dependently (IC50 approximately 10(-8) mol/L) in adipocytes. This TSH-induced
      glycerol release was further enhanced by adenosine deaminase (ADA). In summary,
      TSH reduced leptin production and stimulated lipolysis in rat epididymal
      adipocytes. Although the pathophysiological relevance of the regulation of leptin
      production and lipolysis by TSH is unknown, we speculate that TSH may affect the
      regulation of appetite and energy expenditure in pathophysiological states.

PMID- 10599992
TI  - Influence of placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD)
      inhibition on glucose metabolism and 11beta-HSD regulation in adult offspring of
      rats.
AB  - Placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) converts
      glucocorticoids to 11-keto-products and is believed to play an important role in
      protecting fetuses from higher maternal glucocorticoid levels. Recent reports
      have speculated that prenatal glucocorticoid exposure leads to fetal growth
      retardation and adult offspring hypertension and hyperglycemia. To investigate
      the effects of placental 11beta-HSD2 inhibition on glucose metabolism and the
      11beta-HSD system in adult offspring, pregnant rats were treated with daily
      injections of carbenoxolone (CBX), an inhibitor of 11beta-HSD. The offspring of
      the maternal CBX treatment group showed reduced birth weight (treated v control,
      5.6 +/- 0.5 v 6.4 +/- 0.4 g, P < .0001). In adult offspring of the maternal CBX
      treatment group, plasma hemoglobin A1c was significantly increased (7.3% +/- 1.8%
      v 4.8% +/- 0.3%, P < .01) and glucose intolerance was shown on the oral glucose
      tolerance test. The gene expression of hepatic 11beta-HSD1 and renal 11beta-HSD2
      was decreased 87.6% (P < .05) and 52.3% (P < .01) in adult offspring of the
      maternal CBX treatment group, whereas renal 11beta-HSD1 was not significantly
      altered. The change in 11beta-HSD activity corresponded to the change in the gene
      expression. These results suggest that inhibition of placental 11beta-HSD2 causes
      growth retardation, glucose intolerance, and partial suppression of the 11beta
      HSD system in the offspring.

PMID- 10599993
TI  - Plasminogen activator inhibitor activity: an independent risk factor for the high
      miscarriage rate during pregnancy in women with polycystic ovary syndrome.
AB  - In 41 women with at least one pregnancy drawn from a group of 149 (108 never
      pregnant) women with polycystic ovary syndrome (PCOS), our specific aim was to
      determine whether hypofibrinolysis mediated by high plasminogen activator
      inhibitor activity (PAI-Fx) is an independent risk factor for miscarriage. The 41
      women had 77 total pregnancies with 34 miscarriages (44%) and 42 live births
      (55%). There were 12 women with at least one pregnancy, at least one miscarriage,
      and no live births (16 pregnancies and 16 miscarriages). There were 15 women with
      at least one pregnancy, no miscarriages, and at least one live birth (25
      pregnancies and 28 live births). Of 12 women with only miscarriages and no live
      births, 67% had PAI-Fx greater than 16.4 U/mL (normals' 95th percentile), versus
      29% of 15 women with no miscarriages and all live births (chi2 = 3.8, P = .052).
      By stepwise logistic regression, the number of pregnancies (P = .0001) and PAI-Fx
      (P = .016) were significant positive explanatory variables for the number of
      miscarriages. Age, 4G/5G polymorphisms of the PAI gene, factor V Leiden,
      methylenetetrahydrofolate reductase (MTHFR) gene mutations, androstenedione,
      testosterone, sex hormone-binding globulin, the Quetelet index, and fasting serum
      insulin and glucose were not significant variables in the logistic regression
      model. In a separate stepwise logistic regression, three nonoverlapping groups of
      women (12 with > or = 1 pregnancy, > or = 1 miscarriage, and 0 live births, 10
      with > or = 1 pregnancy, > or = 1 miscarriage, and > or = 1 live births, and 15
      with > or = 1 pregnancy, 0 miscarriages, and > or = 1 live births) were the
      dependent variables. PAI-Fx was positively associated (P = .05) with the group
      with the worst pregnancy outcome (> or = 1 pregnancy, > or = 1 miscarriage, and 0
      live births). The 41 women with PCOS and at least one pregnancy were more likely
      than healthy normal controls to have heterozygosity and homozygosity for the
      4G/5G polymorphism of the PAI-1 gene (P = .028), but did not differ from normals
      for factor V Leiden (P > .10) or MTHFR (P > .09) mutations. PAI-Fx is a
      predominant independent significant positive reversible risk factor for
      miscarriage in women with PCOS.

PMID- 10599994
TI  - Effects of dietary composition and exercise timing on substrate utilization and
      sympathoadrenal function in healthy young women.
AB  - The effects of dietary composition (high-fat [FAT] or high-carbohydrate [CHO])
      and exercise timing (preprandial exercise [Ex-] or postprandial exercise [-Ex])
      on postprandial substrate utilization and sympathoadrenal function were studied
      in seven women aged 20 to 21 years. The experimental protocol included four
      different sessions (Ex-FAT, FAT-Ex, Ex-CHO, and CHO-Ex). The FAT and CHO diets
      provided 48% and 5% fat, respectively. On the experimental days, subjects ate a
      meal containing the same caloric energy at lunchtime, and they exercised for 30
      minutes on a bicycle ergometer at an intensity of 60% maximal oxygen consumption
      (VO2max) before and after the meal, followed by rest for 3 hours. The resting
      respiratory quotient (RQ) was significantly lower (P < .05) with the FAT diet or
      postprandial exercise. The mean RQ during the experimental period was 0.78, 0.75,
      0.81, and 0.77 in Ex-FAT, FAT-Ex, Ex-CHO, and CHO-Ex groups, respectively. The
      total area under the curve of serum norepinephrine (NE) as an index of NE
      secretion was significantly higher (P < .05) with the FAT diet or postprandial
      exercise (130.2, 175.8, 33.0, and 136.9 ng x mL(-1) x min, respectively). A
      negative correlation was observed between the RQ and the total area of NE (r =
      .49, P < .05). The serum thyroid hormone level was not influenced by dietary
      composition and exercise timing. These results suggest that postprandial
      exercise, especially after intake of a FAT diet, increases fat utilization via a
      slightly larger decrease in the RQ. This might be related to the sympathoadrenal
      system at rest and during exercise.

PMID- 10599995
TI  - Regulation of leptin by thyroid hormone in humans: studies in vivo and in vitro.
AB  - The influence of thyroid hormones on human adipose tissue leptin production and
      leptin gene expression was investigated in vitro and in vivo. Twelve women
      received 60 microg triiodothyronine (T3) per day for 7 days, which increased
      total T3 by 195% (1.78 +/- 0.07 to 5.25 +/- 0.39 mU/L, P < .001), significantly
      decreased thyrotropin ([TSH] 1.57 +/- 0.40 to 0.03 +/- 0.01 mU/L, P < .01), and
      increased energy expenditure (1,602 +/- 32 to 1,754 +/- 34 kcal/24 h, P < .05).
      However, serum leptin did not change (9.36 +/- 1.6 v 8.90 +/- 1.3 microg/L,
      nonsignificant). Human subcutaneous adipose tissue biopsies from eight healthy
      women were incubated in vitro as small fragments with T3 in concentrations from 1
      to 50 nmol/L. Leptin production was inhibited dose-dependently. After 24 hours of
      incubation, a T3 concentration of 50 nmol/L reduced basal leptin production by
      42% (P < .05) and the stimulated leptin production (dexamethasone 10 nmol/L) by
      52% (P < .05). Leptin mRNA expression was measured by a semiquantitative
      multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) method. Fifty
      nanomolars T3 decreased basal leptin mRNA expression by 47% compared with
      controls (P < .001), and the stimulated leptin mRNA expression was reduced to a
      similar degree (53%). In conclusion, in human adipose tissue, T3 (>20 nmol/L)
      inhibited leptin production and leptin gene expression in vitro, whereas an
      elevation of T3 corresponding to a moderate thyrotoxic state (T3 5.25 +/- 0.39
      nmol/L) was without any impact on serum leptin levels in vivo.

PMID- 10599996
TI  - Tissue distribution and turnover of [3H]riboflavin during respiratory infection
      in mice.
AB  - Studies in children and mice suggest that respiratory infections cause a
      mobilization of riboflavin from the tissues to the blood, resulting in increased
      urinary loss of this vitamin. To verify this observation, the tissue distribution
      and turnover of [3H]riboflavin were investigated in control and low-riboflavin
      fed mice infected with Klebsiella pneumoniae. Infection significantly reduced
      [3H]riboflavin levels in the liver and kidney of low-riboflavin-fed mice and in
      the liver of control mice. Such changes were not observed in tissues such as
      muscle, small intestine, and brain. Urinary excretion of [3H]riboflavin increased
      significantly during the acute phase of infection and the biological half-life of
      [3H]riboflavin was shorter in the low-riboflavin-fed group. The results confirm
      that the mobilization of riboflavin from tissues to blood during infection
      results in a deterioration of riboflavin status. Thus, the study supports the
      hypothesis that respiratory infection is a nondietary factor contributing to the
      high prevalence of subclinical riboflavin deficiency in children of developing
      countries like India.

PMID- 10599997
TI  - Immunization with the HBV core 18-27 epitope elicits CTL responses in humans
      expressing different HLA-A2 supertype molecules.
AB  - The human leukocyte antigen (HLA)-A2 restricted HBV core 18-27 epitope is
      immunodominant in the context of HLA-A2.1 and subdominant in the context of the
      other HLA-A2 supertype molecules, as defined by frequency of recognition by
      memory cytotoxic T lymphocyte (CTL) responses from acute hepatitis B virus (HBV)
      patients, and on the basis of its binding affinity to purified HLA molecules in
      vitro. Herein, we show that immunization with a lipopeptide containing HBV core
      18-27 epitope induces CTL responses in patients expressing different HLA-A2
      supertype molecules, with indistinguishable frequency and magnitude. No
      difference in responses was noted between patients expressing either one or two
      different HLA-A2 supertype molecules. Thus, complexes of HBV core 18-27 bound to
      different HLA-A2 supertype alleles do not appear to act as altered peptide
      ligands, and do not cross antagonize CTL responses. These results substantiate
      the immunological relevance of the HLA supertypes concept, and illustrate its
      potential usefulness for the development of vaccines.

PMID- 10599999
TI  - Monocytes confer CD14 antigenicity on activated lymphocytes.
AB  - In the present study, exposure of human peripheral blood mononuclear cells (PBMC)
      to phorbol 12-myristate 13-acetate (PMA) was found to elicit the expression of
      CD14 on lymphocytes. Less than 3% of the lymphocytes present among freshly
      isolated PBMC were stained with 63D3 anti-CD14 monoclonal antibody (mAb). Within
      two days of exposure of PBMC to PMA, up to 30% of the lymphocytes reacted with
      the 63D3 anti-CD14 mAb, though not with the LeuM3 and My4 anti-CD14 mAbs. The
      appearance of CD14 on lymphocytes was also elicited by exposure of PBMC to
      phytohemagglutinin (PHA), concanavalin A (Con A), or agarose-bound
      phytohemagglutinin but not by exposure to lipopolysaccharide, interferon-alpha,
      or interleukin-2. Purified lymphocyte preparations did not acquire CD14 following
      stimulation with PMA. Monocytes lost their reactivity with CD14 mAbs (63D3,
      LeuM3, and My4) within a few hours after exposure to PMA. The level of soluble
      CD14 was higher in supernatant fluids of cultures of untreated PBMC than of PMA
      stimulated PBMC. The addition of PMA to cultures of T cells and monocytes
      separated by Millipore filters lead to the expression of CD14 on the lymphocytes.
      The present study indicates that activation of lymphocytes in the presence of
      monocytes leads to the appearance of CD14 on lymphocytes, and raises the
      possibility that the expression of CD14 on lymphocytes may result from the
      transfer of CD14 molecules from monocytes to lymphocytes.

PMID- 10599998
TI  - Co-cultivation of CD4+ and CD8+ human T-cells leads to the appearance of CD4
      cells expressing CD8 through de novo synthesis of the CD8 alpha-subunit.
AB  - The appearance of a population of dual-staining CD4+CD8+ cells in human T
      lymphocyte cultures has been reported by various authors, including our own
      observation that they are always seen in simple phytohaemagglutinin-stimulated
      cultures from several different donors. The purpose of the present study was to
      investigate factors involved in the dual-staining (DS) phenotype, and to clarify
      some apparent inconsistencies between published observations. Our findings can be
      summarised as follows. 1. A population of DS CD4+CD8+ cells always appears in PHA
      stimulated T-cell cultures if they contain both CD4 and CD8 subsets. The
      incidence of DS cells is related to PHA concentration, but other factors are
      involved since DS cells are not seen in PHA-stimulated cultures of purified CD4+
      or CD8+ cells. Stimulation with PHA is not a prerequisite since very similar
      results are seen with ConA. 2. Direct physical contact between CD4+ and CD8+
      cells is required for the appearance of the DS phenotype; soluble factors alone,
      including IL-4, appear nor to be responsible. 3. The DS phenotype in these
      conditions is always CD4+ cells weakly expressing CD8 and is a consequence of de
      novo synthesis of the CD8alpha molecule by the CD4+ cells.

PMID- 10600000
TI  - Expression of the costimulator molecules, CD80, CD86, CD28, and CD152 on
      lymphocytes from neonates and young children.
AB  - The expression of CD80, CD86, CD28, and CD152 were examined on peripheral blood
      lymphocytes from adults, neonates (cord blood lymphocytes) and young children (2
      20 months of age). There was no difference in the expression of CD80 or CD86
      between adult and neonatal B cells, either resting or activated. A higher
      percentage of resting T cells expressed CD28 in neonates and young children
      compared to adults. CD28 expression was similar on adult and neonatal T cells
      activated with PMA and ionomycin. However, CD28 was expressed at greater
      intensity on a higher percentage of neonatal T cells than adult T cells
      stimulated with CD3. CD152 expression was lower on neonatal T cells than adult T
      cells stimulated with PMA and ionomycin and undetectable on neonatal T cells
      stimulated with CD3. In contrast, intracellular CD152 was equivalent in adult and
      neonatal T cells stimulated with PMA and ionomycin, suggesting trafficking of
      CD152 to the cell surface may be differentially regulated in neonatal T cells.
      Since the T cell response is determined by the balance of signals received from
      CD28 and CD152, high levels of CD28 expression and lower surface expression of
      CD152 on neonatal T cells may represent specialisation to promote activation of
      neonatal T cells.

PMID- 10600001
TI  - Further characterization of memory T cells existing in a case of CD8 deficiency.
AB  - CD8 deficiency is a rare primary immunodeficiency caused by a defect of ZAP-70,
      which plays a pivotal role in T cell activation. We previously reported the
      existence of memory phenotype-CD4+ T cells in a case of CD8 deficiency, which
      demonstrates that activation signals through ZAP-70 are not essential to the
      phenotypic conversion of T cells from "naive" to "memory." In this study, we
      further characterized CD45RO+ T cells in a CD8 deficient patient. We showed that
      the patient's CD45RO+ T cell population had a wide variety of T cell receptor
      Vbeta-chain gene usage, and contained few clonally expanded T cells, while many
      clonally expanded T cells were present in the memory T cell population of age
      matched healthy children. These results suggest that various kinds of antigens
      were involved in the differentiation of the patient's T cells, and that the
      differentiation into memory T cells was not accompanied by profound T cell
      proliferation. Moreover, our findings confirmed that the patient's CD45RO+CD4+ T
      cells had acquired effector-cytokine producing ability, indicating that there
      exists an alternative activation pathway which is independent of ZAP-70 for the
      acquisition of effector-cytokine producing ability.

PMID- 10600002
TI  - Non-classic sHLA class I in human oocyte culture medium.
AB  - Soluble human leukocyte antigen (sHLA) class I molecules have been described in
      all human fluids. These molecules play a significant role in immune function.
      sHLA has been shown to produce tolerance and to induce apoptosis in cytotoxic
      alloreactive T cells. They are also present in the supernatant of many cultured
      cells. Similarly, non-classic HLA class I antigens in soluble form are present in
      human fluids. Among these, HLA-G is the most important because of its location in
      fetal tissue that suggests maternal immunological tolerance of the fetal
      semiallograft. In our present study we show that using two monoclonal antibodies,
      w6/32 and TP25.99, in the enzyme-linked immunosorbent assay allows the detection
      of non-classic sHLA class I molecules in the medium from human embryo cultures.
      The sample were collected from oocytes cultures. Oocyte donors were 11 women
      attending the in vitro fertilization program. The results showed a significant
      association (chi2 = 9.66, p = 0.002) between sHLA antigens and the oocyte
      cleavage rate measured 48 h after fertilization.

PMID- 10600003
TI  - Serum levels of beta-2-microglobulin-free heavy chain of HLA class I antigen in
      healthy individuals: relationship to their class I allotype.
AB  - An ELISA-based double determinant immunoassay has been established to measure the
      soluble beta2-microglobulin (beta2m)-free heavy chain (FHC) of the HLA-B, -C (and
      HLA-A3, -A28 and -A30) class I molecular complex in sera from 212 HLA-typed
      healthy unrelated individuals. FHC was calculated by means of a standard curve
      constructed using serial concentrations of beta2m-associated HLA-class I heavy
      chain (HLA-I)/FHC purified from cultured human lymphoid cell C1R-sB7-supernatant.
      The mean FHC concentration (+/-SD) was 0.25 mg/l (+/-0.2). Its median
      concentration did not statistically differ between males and females, though the
      male/female ratio was greater in the high secretor (FHC >0.45 mg/l; mean + 1SD)
      than in the low secretor group (FHC < 0.05 mg/l; mean - 1SD). FHC < 0.05 mg/l was
      statistically (Fisher's exact test) associated with HLA-B17 (p = 0.003); FHC >
      0.45 mg/l was statistically associated with HLA-B35 (p = 0.003) and -Cw4 (p =
      0.002). None of these allele-positive groups showed a mean FHC concentration 1.5
      times higher than that of the corresponding allele-negative ones. This allotype
      dependent HLA-B and C FHC enhancement was less marked than that previously
      reported for HLA-I in individuals carrying HLA-A9 (and its splits). These results
      indicate that FHC could be a more valuable marker when its levels are compared
      among individuals carrying different allotypes. Moreover the lack of correlation
      between FHC and HLA-I levels measured in 52 HLA-A3, -A28 or -A30 positive
      individuals suggests that the two molecules may be regulated by different
      metabolic pathways and their serum expression may have a different biological
      significance.

PMID- 10600004
TI  - Parasitic infection with Trichuris trichiura influences plasma levels of soluble
      HLA class I.
AB  - High levels of sHLA-I (soluble HLA--class I) have been correlated with rejection
      episodes in solid organ transplant recipients and with graft versus host disease
      in bone marrow recipients. Studies of human infection with parasitic worms of the
      gut have suggested that certain individuals may be genetically predisposed to
      intense infection. In this study, the influence of parasitic helminth infection
      on levels of sHLA-I in plasma was investigated in 155 HLA typed individuals from
      St. Lucia, exposed to the gut parasite Trichuris trichiura. The results confirmed
      previous findings showing increased levels of sHLA-I in HLA-A9, and in this case
      HLA-A23 positive individuals. However, HLA-A9 positive individuals with high worm
      burden had significantly lower levels of sHLA-I in their plasma compared with HLA
      A9 positive subjects with low worm burden. These results suggest that the
      intensity of T. trichiura infection influences the ability of HLA-A9 positive
      subjects to maintain high levels of sHLA-I.

PMID- 10600005
TI  - Occurrence of gamma-aminobutyric acid-transaminase activity in nerve fibers of
      human thymus.
AB  - The specific localization of gamma-aminobutyric acid-transaminase (GABA-t) in the
      thymus of young and elderly men was studied. Our results show a specific vascular
      localization of GABA-t in the human thymus, and deal with the amount and
      distribution of GABA-t and its changes with age. Samples of human thymus were
      harvested throughout of 12 autopsies in infants (n = 3), as well as young (n =
      3), adult (n = 3) and elderly (n = 3) men. Histologic staining of the human
      thymus was performed with eosin-orange, while histologic staining of nerve fibers
      was performed with the Bodian method. Histochemical and biochemical demonstration
      of GABA-t, including protein dosage, was performed by the methods of Van Gelder
      and Jung, respectively. Finally, quantitative analysis of images was performed.
      Staining with eosin-orange reveals the micro-anatomical details of the thymic
      micro-environment. The Bodian method shows the nerve fibers and neurofibrils.
      Histochemical staining for GABA-t shows an increase of this enzyme with age and a
      marked localization in the nerve fibers of the thymus in infant, young, adult,
      and elderly men, as well as specific vascular localization of this enzyme. These
      biochemical data are in accordance with the histoenzymatic results and confirm
      all of our previous observations. Finally, quantitative analysis of images
      performed on slices let us confirm all the morphological changes induced by age.
      We can conclude that GABA is an inhibitory neurotransmitter of the human thymus,
      while GABA-t plays an important role in GABA metabolism.

PMID- 10600006
TI  - Noncanonical Valpha24JalphaQ T cells with conservative alpha chain CDR3 region
      amino acid substitutions are restricted by CD1d.
AB  - Human NKRP-1A (CD161)+ T cells include members of a family of CD4+ or CD4-/CD8-
      lymphocytes that utilize an invariant alpha chain in the T-cell receptor (TCR).
      The alpha chain consists of the Valpha24 segment joined to Jalpha18 (JalphaQ)
      (TCRAV24/AJ18). These families of T cells rapidly produce both interleukin-4 and
      interferon-gamma upon TCR cross-linking, and are restricted by CD1d. To determine
      the spectrum of allowable V/J rearrangements in the Valpha24+ CD4-/CD8- family,
      TCR Valpha24 chain transcripts derived from the total CD4-/CD8- population in
      peripheral blood mononuclear cells were sequenced. A second invariant
      rearrangement, Valpha24Jalpha45, was found in two donors. In addition, a subset
      of 15 clones with single amino acid substitutions in the CDR3 were identified and
      used to define CD1d restriction. All 15 variant clones were indistinguishable
      from invariant clones on the basis of surface phenotype and response to CD3 cross
      linking. However, CD1d was the restriction element only for those clones with the
      conservative substitution of threonine or asparagine for serine at the V/J
      junction. Thus, the family of human CD161+ T cells can be extended to include a
      subset of Valpha24-JalphaQ rearrangements with a single amino acid substitution
      that defines a Valpha24 CDR3 residue critical for CD1d restriction.

PMID- 10600007
TI  - Non-productive human TCR beta chain genes represent V-D-J diversity before
      selection upon function: insight into biased usage of TCRBD and TCRBJ genes and
      diversity of CDR3 region length.
AB  - The aim of the study was to assess the influence of constraints of V-D-J
      rearrangement on the nonrandom junctional diversity of productive T-cell receptor
      beta-chain genes in peripheral T-cells. Mature peripheral T lymphocytes are
      expected to display a biased repertoire of T cell receptors (TCRs), enriched for
      those that can recognize peptides presented by the major histocompatibility
      complex (MHC) molecules. Therefore, functional TCR rearrangements of peripheral T
      cells are unsuitable to reveal the bias of the TCR repertoire, introduced by V-D
      J rearrangement. To overcome this problem, we have studied nonfunctional TCR
      genes representing a repertoire of rearranged TCR gene sequences without any
      known post-rearrangement selection. Detailed molecular analysis of a database
      generated from more than 500 functional (TCRBV20S1) and nonfunctional (TCRBV10S1P
      and TCRBV19S1P) T-cell receptor genes from peripheral blood T-cells permitted a
      comparative analysis of recombination frequencies of each germline-encoded V, D,
      and J-segments, as well as exonucleolytic nibbling and addition of nucleotides in
      functional and nonfunctional transcripts. Our data demonstrate that V-D-J
      recombination generates a more diverse CDR3 length distribution than found among
      productive TCRBV genes, suggesting that selection constrains the CDR3 to an
      optimal junctional region length. Furthermore, the well established biased
      patterns of D- and J-usage in the rearranged TCRBV genes in human peripheral
      blood lymphocytes were also present in nonfuncrional transcripts. Therefore, V-D
      J diversity is biased mainly by constraints of the rearrangement process rather
      than intrathymic T-cell selection and peripheral expansion of particular T-cell
      clones.

PMID- 10600008
TI  - Intracellular and cell surface heterotypic associations of human leukocyte
      antigen-DR and human invariant chain.
AB  - The intracellular and cell-surface heterotypic associations of HLA-DR in the
      presence and absence of the invariant chain were investigated. Simultaneous
      confocal microscopy imaging of the Golgi apparatus and HLA-DR molecules revealed
      that cells transfected only with HLA-DR and not the invariant chain or HLA-DM,
      accumulate class II molecules mostly in the Golgi apparatus, proximal to the cell
      nucleus. In contrast, in cells transfected with both HLA-DR and the invariant
      chain, or HLA-DR, the invariant chain and HLA-DM, the class II molecules are more
      evenly distributed in intracellular compartments. Confocal microscopy and flow
      cytometry revealed that in the absence of the invariant chain, a greater number
      of HLA-DR molecules are transported to the cell surface. Biochemical experiments
      and nonequilibrium pH gradient electrophoresis revealed that HLA-DR associates
      with surface invariant chain in the presence of HLA-DM. In cells that lack HLA
      DM, no cell-surface association of HLA-DR and Ii was observed. Taken together,
      these results reveal two separate and distinct functions for surface and
      intracellular invariant chain subsets. The intracellular invariant chain
      "arrests" the class II molecules in the endocytic pathway. In contrast, cell
      surface invariant chain associates with class II molecules at the cell surface,
      possibly playing a role in recycling empty class II molecules or as an accessory
      molecule.

PMID- 10600009
TI  - A candidate interferon-gamma activated site (GAS element) in the HLA-G promoter
      does not bind nuclear proteins.
AB  - The HLA-G gene is highly expressed at the maternal-fetal interface, where it is
      believed to participate in the generation and maintenance of maternal tolerance
      to the fetal semiallograft. This gene has two elements through which interferon
      gamma (IFN-gamma) could act to enhance its rate of transcription, an Enhancer
      A/ICS region and a candidate IFN-gamma activated site (GAS). In this study we
      investigated functionality of this candidate HLA-G GAS. Two HLA-G-expressing cell
      lines were tested, the human myelomonocytic cell line, U937, and a mouse
      fibroblast cell line, S14/8, which is stably transfected with the full length HLA
      G gene. Nuclear proteins from IFN-gamma-treated U937 and S14/8 cells bound the
      interferon regulatory factor-1 (IRF-1) gene GAS sequence (TTC CCCGAA) but not the
      HLA-G gene's candidate GAS sequence (TTTCGAGAA). Excess unlabeled HLA-G-GAS
      oligonucleotide failed to inhibit binding of the IRF-1-GAS using the same nuclear
      extracts. These data indicate that a sequence in the HLA-G gene which would
      normally permit cytokine enhancement of gene expression, the GAS element, is
      nonfunctional. This is also true of another regulatory sequence, the Enhancer
      A/ICS element, suggesting that defects in IFN-gamma response elements prevent
      inappropriate up-regulation of HLA-G gene expression at the maternal-fetal
      interface.

PMID- 10600010
TI  - Definition of human interleukin-4 receptor alpha chain haplotypes and allelic
      association with atopy markers.
AB  - Cumulative evidence indicates that the human interleukin-4 receptor alpha chain
      gene (IL-4Ralpha, CD124) is highly polymorphic in contrast to other cytokine
      receptor genes. Our group recently identified the IL-4Ralpha variant R551 as
      being strongly associated with decreased kidney allograft survival. Due to the
      key immunoregulatory role of IL-4 and controversial reports on the association of
      IL-4Ralpha variants with atopy, we present here the development of polymerase
      chain reaction-primer sets for sequence-specific amplification of all seven
      hitherto described amino acid polymorphisms, and we investigated 158 blood donors
      prospectively. By using an Expectation-Maximization algorithm, we calculated the
      presence of 11 putative human IL-4Ralpha haplotypes and identified 4 putative IL
      4Ralpha haplotypes with a cumulative frequency of >90%. None of the polymorphisms
      showed a significant association with the phenotype atopy. All mutant alleles
      showed a trend toward decreased total IgE levels. This association was only
      significant (p < 0.05; Mann-Whitney U-test) for the A375, R406, and P478 variants
      in non-atopic blood-donors (n = 90), presumably due to the high variance of IgE
      levels among the smaller group of atopic individuals. We postulate that IL
      4Ralpha mutations are associated to different extents with a decrease in function
      of the receptor but do not present a major atopy locus.

PMID- 10600011
TI  - TNF-alpha and TNF-beta gene polymorphisms in systemic sclerosis.
AB  - Tumor necrosis factor (TNF)-alpha and TNF-beta, mediators of inflammatory
      responses, have been implicated in the pathogenesis of autoimmune diseases. The
      aim of this investigation was to determine whether two promoter region
      polymorphisms of the TNF-alpha gene (TNF-alpha -308 and TNF-alpha -238) and a
      determinant in the first intron of the TNF-beta gene (TNF-beta +252) affect
      susceptibility to systemic sclerosis (scleroderma) (SSc). Fifty patients and 60
      healthy blood donors from Japan were genotyped for these markers by polymerase
      chain reaction-based methods. Fisher's exact test was used to test for
      significant associations. Because of very limited variation at the TNF-alpha -308
      and TNF-alpha -238 loci in the Japanese people, statistical analyses with
      sufficient power could not be done for these genotypes. However, the two
      homozygous genotypes of the TNF-beta +252 locus were found to be significantly
      associated with SSc. Compared to controls, the frequency of the TNF-1 genotype
      was decreased, whereas that of TNF-2 was increased in SSc patients. The former
      implies an association with resistance, while the latter suggests an association
      with susceptibility to the disease. These results show that the TNF-beta +252
      locus plays an important role in the etiopathogenesis of SSc.

PMID- 10600012
TI  - The influence of age at onset and gender on the HLA-DQA1, DQB1 association in
      Chinese children with insulin dependent diabetes mellitus.
AB  - Certain alleles of human leukocyte antigen (HLA)-DR and -DQ genes have been
      strongly associated with susceptibility and resistance to insulin- dependent
      diabetes mellitus (IDDM). To further clarify the association of HLA DQ alleles
      with IDDM and the influence of age at onset and gender on the association with
      IDDM, we investigated the association of HLA-DQA1, -DQB1 in 54 childhood onset
      Chinese (21 male) IDDM patients and 65 normal controls by using polymerase chain
      reaction-sequence specific primer (PCR-SSP). The mean age plus or minus SD at
      onset of IDDM patients was 8.37+/-3.54 year old. Our results revealed that the
      frequencies of DQA1 *0301, *0302, DQB1 *0201, and *0302 in IDDM patients were
      significantly higher than that in the control group (p < 0.025, < 0.005, < 0.001,
      and < 0.001, respectively). The frequency of DQA1 *0301, *0302, DQB1 *0201, and
      *0302 were susceptible alleles to IDDM with relative risks of 2.0, 3.5, 5.0 and
      4.3, respectively. The protective alleles to IDDM were DQA1 *0101, *0103, DQB1
      *0301, *0503, and *0602. We divided IDDM patients into three groups according to
      age at onset (1-5, 6-10, and 11-15 years old). The frequency of DQA1 *0302
      decreased as age increased, and the frequency of DQA1 *0501 increased as age
      increased. Our results also showed that male IDDM patients had higher frequencies
      of DQA *0501, DQB1 *0201 than female IDDM patients (p < 0.025 and < 0.025,
      respectively), while female IDDM patients had higher frequencies of DQB1 *0502
      than male IDDM patients (p < 0.05). In our study significant susceptibility
      haplotypes to IDDM were DQA1 *0301-DQB1 *0302, DQA1 *0501-DQB1 *0201, DQA1 *0301
      DQB1 *0201, and DQA *0302-DQB1 *0201.

PMID- 10600013
TI  - Evolution of HLA-class I compared to HLA-class II polymorphism in Terena, a South
      American Indian tribe.
AB  - We have studied the HLA alleles of 60 unrelated healthy Terena and 10 Terena
      families. They are members of an isolated Brazilian tribe located in Mato Grosso
      do Sul (South Central Brazil). Six novel alleles were found in this population:
      HLA-A*0219 (gf = 0.02), A*0222 (gf = 0.15), HLA-B* 3520 (gf = 0.01), B*3521 (gf =
      0.03), B*3912 (gf = 0.03) and B*4803 (gf = 0.16). Five of the six novel alleles
      differ from their putative progenitors by amino acid replacements in residues
      that contribute to the pockets of the peptide-binding site. Many of the variants
      defined by molecular methods were not identified correctly by serological typing.
      We calculated heterozygosity values (H) for HLA-A, -B, -C, DRB1, DQB1 and DPB .
      The highest values were observed at the HLA-B locus, followed by HLA-A, -DRB1 and
      DQB1. Residue positions 9, 24, 45, 62, 67, 95, 114, 116, 156, and 163 of HLA
      class I showed heterozygosity values greater than 0.50. Nine of them contribute
      to the peptide-binding specificity pockets and one to the T cell receptor binding
      site. If HLA antigens are useful for defense against pathogenic agents,
      heterozygosity would offer an advantage by allowing binding of a larger
      repertoire of peptides to the class I molecules. Individuals that are
      heterozygous at these positions would probably have a wider repertoire of peptide
      presentation to T cells. The observed results including the presence of novel
      alleles in the class I HLA loci suggest a functionally significant, more rapid
      evolution of class I compared to class II loci in this South American isolated
      population.

PMID- 10600015
TI  - Nomenclature for factors of the HLA system, update July/August 1999. WHO
      Nomenclature Committee for Factors of the HLA System.

PMID- 10600014
TI  - Shared cadaver donor-husband HLA class I mismatches as a risk factor for renal
      graft rejection in previously pregnant women.
AB  - During the last few years, we have observed four cases in which accelerated
      rejection of a cadaver donor kidney in a previously pregnant woman could be
      clearly attributed to the rapid emergence of anti-human leukocyte antigen (HLA)
      antibodies that had been stimulated by mismatched paternal antigens but were
      completely undetectable at the time of transplantation. In addition to reviewing
      those cases, we also reviewed data on 19 other women with a history of at least
      one pregnancy who underwent transplantation with a first cadaveric kidney since
      1991 and were followed for at least six months. The HLA antigens of the husbands
      had to have been determined and all accelerated rejection or early graft losses
      due to confirmed or presumed immunological causes were considered. Of the 19
      additional women meeting these inclusion criteria, three suffered early
      immunological graft loss. As in our index cases, two of these women had also
      received kidneys from donors who shared at least one major immunogenic mismatched
      antigen with the respective husband for a total of six of seven women with early
      immunological graft loss. Only one of the 16 women without accelerated rejection
      or early immunological graft loss had a donor who shared a mismatched antigen
      with her husband. The difference between the two groups is statistically
      significant (p = 0.0005). These findings, considered with individual cases
      reported by other groups, indicate that transplantation from a cadaver donor with
      immunogenic mismatched class I HLA antigen(s) shared with the husband should be
      avoided in women with a previous history of pregnancy even when anti-HLA
      antibodies are not currently detected.

PMID- 10600017
TI  - EEG coherence: an introduction.

PMID- 10600018
TI  - Corticomuscular coherence: a review.
AB  - Corticomuscular coherence measured between electroencephalography (EEG),
      magnetoencephalography, or local field potentials and electromyography (EMG)
      should be helpful in understanding the cortical control of movement. EEG-EMG
      coherence and phase spectra depend on the types of EEG derivation and current
      source density function of EEG appears to be the most appropriate for computation
      of EEG-EMG coherence. A new model for the interpretation of the phase spectra
      ("constant phase shift plus constant time lag model") shows that cortical surface
      negative potentials are phase-locked to EMG firing. There are functional
      differences of EEG-EMG coherence among the alpha, beta, and gamma bands
      suggesting differences in their possible generator mechanisms. Since
      corticomuscular coherence is a noninvasive measure of corticomotoneuronal
      function in a specific frequency range, clinical application of this method might
      be very fruitful in tremor research.

PMID- 10600016
TI  - The HLA dictionary 1999: a summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles
      and their association with serologically defined HLA-A, -B, -C, -DR, and -DQ
      antigens.
AB  - This report presents serologic equivalents of 90 HLA-A, 190 HLA-B, and 145 HLA
      DRB1 alleles. The equivalents cover over 70% of the presently identified HLA-A, 
      B, and -DRB1 alleles. The dictionary is an update of the one published in 1997
      and now also includes equivalents for HLA-C, DRB3, DRB4, DRB5, and DQB1 alleles.
      The data summarize information obtained by the WHO HLA Nomenclature Committee,
      the International Cell Exchange (UCLA), the National Marrow Donor Program (NMDP),
      and by individual laboratories. In addition, a listing is provided of alleles
      that are expressed as antigens with serologic reaction patterns that differ from
      the well-established HLA specificities and that often lack official WHO
      nomenclature. The provided equivalents will be useful in guiding searches for
      unrelated donors in which patients and/or potential donors are typed by either
      serology or DNA-based methods. These equivalents will also serve typing and
      matching procedures for organ transplant programs where HLA typings from donors
      and from recipients on waiting lists represent mixtures of serologic and
      molecular typings. Some guidelines are provided for the use of appropriate WHO
      HLA nomenclature for serologic typings and for generic and allele specific
      typings obtained with molecular methods. The tables with HLA equivalents and the
      questionnaire for submission of serology on poorly identified alleles will also
      be available at the WMDA web page: www.bmdw.org/wmda.

PMID- 10600019
TI  - Event-Related changes of band power and coherence: methodology and
      interpretation.
AB  - Event-related calculation of band power changes can be used to quantify event
      related desynchronization, event-related synchronization, and event-related
      coherence (ERCoh). It is shown that in the case of a motor task especially, the
      ERCoh time course depends on the type of EEG derivation used, whereby referenced
      EEG data can result in a bilateral coherence increase, although both hemispheres
      generate independent sensorimotor rhythms. It is further shown that not only
      Rolandic mu rhythms but also central beta rhythms display a lack of
      interhemispheric linear phase coupling.

PMID- 10600020
TI  - Coherence of sequential movements and motor learning.
AB  - The analysis of oscillatory EEG phenomena such as interregional coherence (task
      related coherence [TRCoh] or event-related coherence) has advanced our knowledge
      of neurophysiological processes underlying the performance and learning of
      skilled finger movements. It has become clear that various types of higher task
      demands are reflected by changes in the functional coupling of different cortical
      areas and not only by changes in regional activation. Neuroscientists are merely
      starting to understand how coherent oscillations might encode information in the
      human motor system ("sensorimotor binding") and how well this can be measured
      from the surface EEG. However, interregional coherence is a potentially
      independent mechanism that can, up to now, only be investigated with
      electrophysiological techniques such as EEG and MEG. The studies reviewed below
      focus on coherence of finger movements and motor learning: increasing complexity
      of a movement sequence, internal rhythm generation, visuomotor integration,
      deficits in interhemispheric coupling, and bimanual coordination. Evidence is
      presented for a special functional significance of TRCoh in the beta frequency
      range (13 to 21 Hz) for information processing in large-scale sensorimotor
      networks during motor tasks.

PMID- 10600021
TI  - Electrocorticographic coherence patterns.
AB  - The availability of implantable subdural electrode arrays has made systematic
      studies of electrocorticographic (ECoG) coherence possible. Studies of coherence
      patterns recorded directly from human cortex are reviewed along with the
      presentation of original human clinical data, which reveal reliable and
      characteristic patterns of coherence. A data-driven technique for discriminating
      between reliable and unreliable coherence and phase values is described and used
      to reveal the relationship between coherence and cortical anatomy, such as in the
      region of the central sulcus, where low phase coherence declines and high phase
      shifted coherence increases. Analysis of coherence magnitude and phase makes it
      possible to determine which signals likely arise from the cortical surface, and
      which arise from the depths of a sulcus. Alterations in coherence patterns caused
      by tumors or epilepsy are described and may be used to identify normal and
      pathological functional relationships between distant cortical areas. Some
      electrophysiologic/pathologic correlations indicate at least two types of
      epileptic abnormality, implying a sequence in breakdown of epileptic tissue. The
      relationship between coherence patterns and behavior and cognition is introduced
      and compared to similar studies of single-unit binding in animals.

PMID- 10600022
TI  - EEG coherence in pathological conditions.
AB  - Coherence analysis of the electroencephalogram is considered an indicator of
      functional cortico-cortical connections, which makes it suitable for the
      neurophysiologic investigation of brain connectivity in normal and pathological
      conditions. In the clinical environment, coherence analysis has been applied in
      the study of brain development and in the assessment of diseases potentially
      involving brain connectivity, such as cortical and subcortical dementia,
      schizophrenia, and corpus callosum lesions. Whereas coherence decrease, at least
      for the high-frequency bands, is considered the expression of decreased
      functional cortico-cortical connections, more work needs to be performed in
      interpreting coherence increases. A special consideration is also required by
      technical aspects, such as the recording conditions and the reference used, which
      may greatly influence the results and need to be accounted for when drawing
      physiopathological interpretations. At present, whereas coherence analysis
      resulted successful in differentiating patients groups from the normal
      population, the specificity of coherence changes in various pathological
      conditions is questionable at the best. The same limits apply to the diagnostic
      value of the technique in individual patients.

PMID- 10600023
TI  - Task-dependent effects on motor-evoked potentials and on the following silent
      period.
AB  - The silent period (SP) after transcranial stimulation is used as a diagnostic
      tool in various central nervous system disorders although no standardized
      experimental setup has been established. The aim of this study was to demonstrate
      the influence of an isotonic compared to an isometric experimental condition. The
      SP after transcranial magnetic brain stimulation in the biceps brachii and
      brachioradialis muscle was up to 130% longer when elicited during a maintain
      position (isotonic) task as compared to a maintain-force task (isometric) when
      stimulus intensities of 5% to 25% above threshold were used. The mean SP duration
      in these muscles was positively correlated to the mean contraction time in both
      tasks. However, no such relationship was observed for the trials within the
      individual subjects. We speculate that the invariably longer SP of the maintain
      position task was due to the different "motor set" which predictively determined
      the muscle behavior after the stimulus. In the maintain-position trials, the
      stimulus-induced long-lasting flexion movement is counteracted by a motor set
      aiming to relax the elbow flexors immediately after the stimulus. In the maintain
      force task the contraction twitch is short and a force drop below the preset
      level must be prevented by a motor set aiming to contract the elbow flexors
      immediately after the stimulus. The latter may increase the synaptic input to the
      motoneuron pool and facilitate the reoccurrence of the electromyogram terminating
      the SP. At high-stimulus intensities the SP duration increased in both tasks, and
      the task-dependent differences disappeared. Therefore, when using the SP duration
      for diagnostic purposes, isometric conditions and high-stimulus intensities
      should be used.

PMID- 10600024
TI  - Timing of disease progression by quantitative EEG in Alzheimer' s patients.
AB  - This prospective study was planned to assess whether quantitative EEG (qEEG) can
      give an estimate of the timing of achievement of three endpoints (loss of
      activities of daily living, incontinence, and death) in 72 consecutive patients
      (53 females, 19 males; mean age, 70.8) affected with probable Alzheimer's
      disease, as defined according to the NINCDS-ADRDA criteria. Power-weighted, log
      transformed relative values of the four conventional EEG bands were considered in
      a central-posterior temporal region for each hemisphere. The hypothesis was
      tested by the lifereg procedure of the Statistical Analysis System package (first
      significance level accepted, P < or = 0.01). Because patients were in different
      stages of the disease, the statistical analysis was performed in the entire group
      as well as in the subgroup of 41 patients (mean age, 69.6) with mild dementia
      (scoring 3 or 4 on the global deterioration scale). In the whole group, the loss
      of activities of daily living was predicted by delta power in either side (P =
      0.01), incontinence was predicted by alpha power in the right side (P < 0.01),
      whereas the statistical significance was not reached for death (P < 0.05). In the
      subgroup of mild demented patients, the loss of activities of daily living was
      predicted by delta power in the left side (P = 0.01), incontinence by both delta
      (P < 0.01) and alpha (P < 0.001) power in the right side, and death was not
      significantly predicted (P = 0.08). Quantitative EEG is a low-cost, discomfort
      free technique which may be used to obtain information on the timing of disease
      evolution. The results showed in mild Alzheimer's disease appear especially
      interesting to attempt a prediction of the future time course of the disease from
      its beginning.

PMID- 10600025
TI  - Epitopes and functional responses defined by a panel of anti-Fas (CD95)
      monoclonal antibodies.
AB  - Fas (CD95) is a cell surface glycoprotein that mediates apoptotic cell death when
      cross-linked with agonistic anti-Fas monoclonal antibodies (MAbs) or the
      endogenous Fas ligand. In this study, we investigated the in vitro biological
      properties of a panel of anti-human Fas MAbs. We found that five anti-Fas MAbs of
      IgG1 subclass (B.E28, B.G30, B.L25, DX2, and B.G34) induced marked apoptotic cell
      death in Fas-expressing leukemia cells, although this killing was delayed when
      compared to the cytolytic effect mediated by the prototypic anti-Fas MAb of IgM
      subclass (clone CH-11). On the other hand, four clones (ZB4, B.G27, B.D29, and
      B.K14) efficiently blocked apoptotic cell death induced by the CH-11 MAb or Fas
      ligand. The ability of these MAbs to inhibit cell death appeared to correlate
      with their relative affinity for the Fas molecule. Furthermore, different clones
      recognized the same epitope and elicited different effects (induction or
      inhibition of cell killing); conversely, different clones elicited the same
      effect but recognized different epitopes. These results suggest that the
      different biological effects of anti-Fas MAbs would not be mediated in an epitope
      restricted manner. The relative binding affinity might correlate to some extent
      with the biological properties of the MAb.

PMID- 10600026
TI  - Functional characterization of monoclonal antibodies to interferon-tau.
AB  - Interferon tau (IFNtau) produces an array of biological effects, including
      antiluteolytic, antiviral, antiproliferative and immunomodulatory activities,
      without the consequent cytotoxicity associated with other type I IFNs. Four anti
      IFNtau monoclonal antibodies (MAbs) have been characterized by determining
      regional epitopes and observation of their effects on IFNtau binding, antiviral
      and antiproliferative activity. Using an enzyme-linked immunoadsorbent assay
      (ELISA) developed against six overlapping synthetic peptides representing the
      entire linear sequence of IFNtau, three antibodies, HL-98, HL-100 and HL-127,
      were found to react with the carboxy terminal peptide, while HL-129 bound the
      penultimate amino terminal peptide. Binding studies indicated that MAbs directed
      against either region could effectively inhibit the binding of alkaline
      phosphatase labeled IFNtau to cells expressing type I IFN receptors. While only
      two of the MAbs significantly reversed IFNtau-induced growth inhibition, the
      antiviral activity of IFNtau was significantly inhibited by MAbs that bound the
      amino and carboxy termini, confirming the functional importance of these domains
      in the binding and subsequent activity of IFNtau.

PMID- 10600027
TI  - Development of class-switched, affinity-matured monoclonal antibodies following a
      7-day immunization schedule.
AB  - Previously we reported making high-affinity monoclonal antibodies (MAbs) 13 days
      after the onset of Repetitive Immunizations Multiple Sites (RIMMS) strategy. The
      Ig subclass variety and affinity of these antibodies suggested that maturational
      processes had already begun within draining lymph nodes. We now demonstrate that
      this diversity can in fact be captured as early as Day 7. In the work reported
      here, somatic fusion of immune lymphocytes isolated from peripheral lymph nodes
      resulted in the isolation of affinity-matured MAbs reactive with cytosine
      deaminase. This model further demonstrates and substantiates at a cellular level
      the rapid development and maturation of T-cell-dependent B-cell responses
      occurring within draining lymph nodes following antigen challenge.

PMID- 10600028
TI  - Development of a functional monoclonal single-chain variable fragment antibody
      against Venezuelan equine encephalitis virus.
AB  - We have generated a single-chain variable fragment (ScFv) antibody, from a
      previously well-characterized monoclonal antibody (MAb) to Venezuelan equine
      encephalitis (VEE) virus, 5B4D-6. The variable regions of the heavy (V(H)) and
      light (V(L)) chain antibody genes, were connected by a DNA linker and cloned in
      the phagemid vector pCANTAB5E. The ScFv clone in Escherichia coli strain TG-1,
      5B4D-6-6, was expressed as a approximately 30 kDa ScFv protein and higher
      molecular weight fusion products which were functional in recognizing VEE virus
      by enzyme-linked immunosorbent assay (ELISA). Results were reproduced in
      Escherichia coli strain HB2151, where clone D66 was expressed mainly as soluble
      periplasmic protein. The D66 ScFv antibody bound VEE virus strongly as determined
      by ELISA. Nucleotide sequence analysis of 5B4D-6-6 ScFv indicated that the Vkappa
      gene belonged to family XVI, subgroup V, while the V(H) gene was unique in its
      sequence, though its amino acid sequence could be subgrouped as IA. The deduced
      protein sequence of D66 was highly homologous to published murine ScFv protein
      sequences. This work demonstrates, for the first time, cloning of a functional
      ScFv antibody against VEE virus.

PMID- 10600029
TI  - Generation of a monoclonal antibody that recognizes a polymorphic epitope of
      C57BL/6 Ly-49G2.
AB  - To facilitate the study of natural killer (NK) cell functions, we have generated
      a panel of hybridomas that secrete antibodies recognizing B6 NK cell surface
      markers. One of these hybridomas, Cwy-3, secretes a mouse IgG1 specific for the
      B6 allele of Ly-49G2 (Ly-49G2B6). In addition, this monoclonal antibody (MAb)
      fails to stain A-LAKs derived from all other mouse strains tested. This suggests
      that Cwy-3 recognizes a polymorphic epitope of Ly-49G2B6. More importantly, this
      MAb exhibits no cross-reactivity to other known B6 Ly-49 family members.
      Therefore, Cwy-3 is in sharp contrast to the two known anti-Ly-49G2 MAbs, which
      are reported to recognize a nonpolymorphic epitope of Ly-49G2, and react with
      other Ly-49 members. In this regard, Cwy-3 will offer significant advantages over
      the cross-reactive anti-Ly-49G2 MAbs in fully defining the specificity and
      function of the Ly-49G2B6 NK cell receptor. With this novel Ly-49G2-specific MAb,
      we have isolated an EL-4 subline expressing a significant density of Ly-49G2
      receptors.

PMID- 10600030
TI  - Production and characterization of mouse monoclonal antibodies to human zinc
      finger OZF protein overexpressed in pancreatic carcinomas.
AB  - Mouse monoclonal antibodies (MAbs) were raised against the human OZF protein, a
      zinc finger protein of the Kruppel family, consisting of 10 amino acids followed
      by 10 zinc finger motives. The OZF gene is amplified in 15-25% of pancreatic
      carcinomas and protein overexpression occurs in more than half of the tumors. Six
      MAbs effective in detecting the recombinant and the cellular protein by enzyme
      linked immunoadsorbent assay (ELISA), Western immunoblotting, and
      immunofluorescence were purified and characterized. Five MAbs belong to the IgG1
      subclass and one to the IgG3 subclass. In contrast to polyclonal antibodies,
      which detect many related proteins, they recognize an epitope unique to the human
      OZF protein. The sequence of the epitope, located at the junction between the
      first 10 amino acids and the zinc finger domain, is not present in other Kruppel
      proteins, including mouse and bovine OZF proteins. The MAbs are highly specific
      to the endogenous OZF protein in its denatured and native form. Therefore, they
      should be useful for OZF functional study and clinical diagnosis of tumors with
      aberrant OZF expression.

PMID- 10600031
TI  - Production and characterization of monoclonal antibodies against pigtailed
      macaque (Macaca nemestrina) cell adhesion molecules.
AB  - Our previous in vitro studies indicate a significant role for cell adhesion
      molecules in the biology of HIV-1 and HTLV-1. Confirmation of the involvement of
      these molecules in the pathogenesis of retrovirus infection in vivo will require
      a suitable animal model. The SIV/pigtailed macaque (Macaca nemestrina) model of
      acquired immunodeficiency syndrome (AIDS) is an ideal system in which to study
      adhesion molecules and viral pathogenesis. The monoclonal antibodies (MAbs)
      against human adhesion molecules previously produced in our laboratory either do
      not react with or fail to block function of pigtailed macaque adhesion molecules.
      We have used papiovirus-transformed pigtailed macaque B cells as immunogen to
      generate murine MAbs against macaque adhesion molecules including ICAM-1, VCAM-1,
      and LFA-1. The specificity of the MAbs was confirmed by immunoprecipitation from
      lysates of vectorially iodinated cells, flow cytometry analysis of transfected
      cell lines and primary cells, binding assays on recombinant soluble human VCAM-1
      and ICAM-1, and by inhibition of adhesion functions. MAbs against ICAM-1 and VCAM
      1 showed positive staining of fixed tissue in immunohistochemistry studies. The
      same antibodies also blocked the function of these two adhesion molecules. The
      new MAbs can be used to study the tissue expression of adhesion molecules in SIV
      infected animals as well as to test the involvement of these molecules in virus
      infection. Thus they should prove invaluable as probes of the role of cell
      adhesion molecules in AIDS pathogenesis in an animal model.

PMID- 10600032
TI  - A monoclonal antibody against hamster tracheal mucin, which recognizes N-acetyl
      galactosamine containing carbohydrate chains as an epitope.
AB  - Airway mucin that is present in airway secretion, plays an important role in host
      defense by trapping airborne particles and removing them by mucociliary transport
      system. For the study of mucin, it is crucially important to have antibodies
      specific against mucin because other commonly used methods such as histologic
      stain for the detection of mucin usually suffer from varying levels of
      nonspecificity. In this study, we produced a monoclonal antibody (MAb) against
      hamster airway mucin, which is one of the most commonly used animal species for
      the study of mucin in vitro, and characterized its immunological properties along
      with the determination of the epitope it recognizes. The MAb, which was named MAb
      HTA, was IgM isotype and specific against mucin from both in vitro cell culture
      and in vivo airway secretion. In Western blot, MAb HTA specifically recognized
      high molecular weight airway mucin, which was also confirmed by the appearance of
      peak profile of immunological signal only on void volume fraction in Sepharose CL
      4B gel filtration chromatography. It also immunoprecipitated high molecular
      weight hamster airway mucin with the aid of antimouse IgM agarose. In
      immunohistochemical stain of hamster trachea, it showed strong signal on airway
      epithelium and also on the mucin secreting goblet cell granules. The
      immunological signal was greatly increased by the treatment of endotoxin, which
      has been reported to cause airway secretory cell metaplasia. The MAb HTA
      recognized carbohydrate chains containing N-acetyl-galactosamine, one of the
      linking sugars of airway mucin, as an epitope. Treatment of mucin with N-acetyl
      galactosaminidase caused great reduction of immunological signal. To the best of
      our knowledge, this is the first to report a MAb that recognizes N
      acetylgalactosamine, a linking sugar of airway mucin. The specificity of MAb HTA
      against airway mucin and the clear demonstration of the epitope it recognizes
      should greatly aid the pharmacological and biochemical study of mucin in various
      physiological and pathological situations.

PMID- 10600033
TI  - Production and characterization of monoclonal antibodies against human airway
      mucins.
AB  - The objective of this study was to generate and characterize monoclonal
      antibodies (MAbs) against human airway mucins, and therefore, should serve as a
      useful tool in studying the regulation of airway mucins in various physiological
      or pathological situations of human airway. As an antigen, we used a high
      molecular mass mucin preparation purified from the sputum of normal human
      subjects. Two monoclonal hybridomas, namely MAbs HM02 and HM03 were obtained and
      they showed strong immunoreactivity against purified or crude mucin in sputum or
      bronchial washing of normal human subject. With the high immunoreactivity of
      these MAbs, mucin contents could be analyzed with more than 100-fold dilution of
      human airway secretion. The antibodies recognized carbohydrate epitopes because
      their immunoreactivity was completely abolished by treatment of the mucin with 5
      mM periodate. Further characterization of MAbs HM02 and HM03 showed that: (1)
      they belong to the IgM type; (2) they bind to high molecular mass mucins based on
      Western blot; (3) they could indirectly immunoprecipitate human airway mucin and
      as we know, this is the first to demonstrate immunoprecipitation of human airway
      mucin with anti-human mucin antibodies; and (4) they bind to the goblet cell in
      airway epithelium as well as some submucosal glands based on
      immunohistochemistry. Therefore, MAbs HM02 and HM03 should be able to serve as an
      invaluable tool in studying the regulation of airway mucins in various
      physiological and pathological situations of human airway.

PMID- 10600034
TI  - Detection of bone marrow micrometastasis.
AB  - The detection of metastasizing single tumor cells has so far been difficult.
      Using a monoclonal antibody (MAb A45-B/B3) recognizing human cytokeratin, we
      identified immunocytochemically single tumor cells and micrometastases in
      patients (n = 24) with nonsmall cell lung cancer at the time of surgery of the
      primary tumor. The cytokeratin-positive cells (1-14/5 x 10(5) cells) in the bone
      marrow samples of 9 (9/24) patients were found. We also found a garland-like
      cluster, which consists of seven cancer cells and two closely connected tumor
      cells from one bone marrow sample. These results indicate that this technique can
      be used as a early diagnostic technique of bone marrow micrometastasis in the
      patient with the nonsmall cell lung cancer.

PMID- 10600035
TI  - Liposome-based drug delivery systems.
AB  - Liposomes are spherical lipid bilayers from 50 nm to 1000 nm in diameter, and
      serve as a convenient delivery vehicle for biologically active molecules.
      Lipid/drug aggregates are easy to form and vulnerable to structural
      manipulations, allowing for the adjustment of their properties for particular
      purposes. In selected cases, the application of liposomes in pharmacological
      therapy improves drug pharmacokinetics compared to its free form. The major
      advantages of the liposome application are: the protection of active compounds
      from degradation; the increase in circulation time and the possibility to achieve
      partial or total selectivity. Selectivity alone improves drug potency, eliminates
      side effects and allows for dosage reduction. Selected liposome formulations are
      presented along with their present and potential applications. Also, the
      perspectives for further development of the technique are discussed.

PMID- 10600036
TI  - Clinically available NMDA antagonist, memantine, attenuates tolerance to
      analgesic effects of morphine in a mouse tail flick test.
AB  - Converging lines of evidence indicate that N-methyl-D-aspartate (NMDA) receptor
      antagonists attenuate the development of morphine tolerance tested in
      antinociception assays in rodents. The present study extends these findings to
      the effects of clinically available NMDA receptor antagonist, memantine. Male
      Albino Swiss mice were tested for analgesia using the tail-flick apparatus.
      Preliminary experiment was designed to find out the optimal dose of morphine and
      the number of injections that would produce tolerance to its analgesic effects.
      In the main experiment, during the development of tolerance period (6 days), mice
      received 10 mg/kg sc b.i.d. morphine injections in the animal room (non
      associative tolerance). This treatment resulted in 5.8 fold rightward shift of
      morphine cumulative dose-response effect from 3.39 mg/kg on day 1 to 16.19 mg/kg
      on day 8 of the experiment. Memantine pretreatment (5 and 10 mg/kg, but not 2.5
      mg/kg), given 30 min prior to each morphine dose during the development of
      tolerance period, inhibited the rightward shift of morphine cumulative dose
      response curve. Thus, pretreatment with memantine at doses of 2.5, 5 and 10 mg/kg
      resulted in ED50 values of 12.13, 4.74 and 1.95 mg/kg, respectively,
      corresponding to 3.35, 1.02 and 0.94 fold changes. These data indicate that low
      affinity, clinically available NMDA receptor antagonist, memantine, may be used
      to inhibit the development of morphine tolerance.

PMID- 10600037
TI  - Gene transfer of vascular endothelial growth factor and endothelial nitric oxide
      synthase--implications for gene therapy in cardiovascular diseases.
AB  - Gene therapy is based on the delivery of exogenous genetic material in order to
      influence the endogenous genetic components involved in disease development. This
      new therapeutic approach has been suggested to have great potential in the
      treatment of insufficient angiogenesis or in prevention of restenosis after
      balloon angioplasty of atherosclerotic arteries. As both vascular endothelial
      growth factor (VEGF) and nitric oxide (NO) exert beneficial effects on vascular
      physiology, we studied the generation of both compounds after in vitro
      transfection of relevant genes. The plasmid vectors, containing VEGF cDNA were
      constructed and lipotransfected into vascular smooth muscle cells (VSMC).
      Transfected cells generated up to a few nanograms of VEGF, which induced
      proliferation of endothelial cells. VSMC transfected with another plasmid,
      containing endothelial constitutive NO synthase (ecNOS) cDNA generated micromolar
      quantities of nitrite. Moreover, such NO-producing cells synthesized
      significantly more VEGF than VSMC transfected with control plasmids. Thus, the
      study demonstrated that transfer of VEGF and/or NOS genes to VSMC led to the
      production of measurable amounts of both VEGF protein and NO. Additionally, we
      evidenced that NO can enhance the endogenous generation of VEGF. A new protective
      mechanism of NO has been thus revealed.

PMID- 10600038
TI  - Effects of doxycycline on the development of bone damage caused by prednisolone
      in rats.
AB  - The aim of the present study was to investigate the effects of doxycycline on the
      development of bone damage caused by prednisolone in rats. The experiments were
      carried out on male WAG rats (200-260 g), divided into 2 control and 6
      experimental groups receiving prednisolone (5 mg/kg im daily) or/and doxycycline
      (100 mg/kg po daily) for 2 or 4 weeks. The animals were sacrificed on the 15th or
      29th day of the experiment and the following characteristics were examined: mass,
      length, mechanical properties, mineral and calcium content in the tibia and
      femur, width of endosteal and periosteal osteoid, endosteal and periosteal
      transverse growth, transverse cross-section area of the diaphysis and of the
      marrow cavity in the tibia, width of epiphyseal cartilage and width of trabeculae
      in the femur. Prednisolone caused features of osteopenia (inhibition of bone
      formation and intensification of bone resorption), which were stronger after 4
      weeks of the experiment. Doxycycline administered alone for 2 or 4 weeks
      intensified the processes of bone formation and resorption. Doxycycline to some
      degree attenuated the influence of prednisolone on rat bones.

PMID- 10600039
TI  - Analgesic activity of thioureido derivatives of arylsemicarbazones.
AB  - The synthesis of a series of novel arylsemicarbazones derived from 4
      aminoacetophenone and their evaluation for analgesic activity are described. The
      p-chloro-substituted derivatives (12-15) are extremely potent compounds as
      compared to standard drugs currently being used.

PMID- 10600040
TI  - Immunological activity of new heterocyclic amides of 5-amino-3-methylisoxazole-4
      carboxylic acid.
AB  - In the present study, some new amides of 5-amino-3-methylisoxazole-4-carboxylic
      acid were obtained. All new structures possessed markedly different groups of
      electron acceptor character, different spatial structure and they contained
      nitrogen heteroatom, enabling formation of salts and, at the same time, higher
      biological availability. They were examined for immunomodulating activity in
      comparison with cyclosporine A (CsA). We investigated effects of the compounds on
      the lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha
      (TNF-alpha) and interleukin-6 (IL-6) by human peripheral blood cells. Some
      compounds exhibited suppressory action which corresponded with increasing
      electronoacceptor nature of the amide substituent. Two compounds, characterized
      by flat aromatic rings, demonstrated quite different properties. Much higher
      activity was expressed by compounds which contained -NH group, the group which
      conditioned immunostimulatory activity in other compounds described previously.

PMID- 10600041
TI  - Drugs used in physician-assisted death.
AB  - Epidemiological studies, case reports, and recommendations concerning the drugs
      used in physician-assisted death are reviewed in this paper. Using a MEDLINE and
      Cancerlit search, we found a total of 20 relevant publications. Recent research,
      mainly from the Netherlands, has shown that high doses of barbiturates are
      usually effective for physician-assisted suicide, while a combination of a
      barbiturate and a derivative of curare are effective for euthanasia. Opioids are
      less reliable drugs for physician-assisted death because of the unpredictable
      duration of the dying process even after high doses. The same applies to
      benzodiazepines. The most frequent undesired effect is an unexpectedly long dying
      process due to impaired uptake of the drugs. Although the evidence base is
      incomplete, the Dutch recommendations issued in 1994 and renewed in 1998 do not
      seem inappropriate.

PMID- 10600042
TI  - Coronary artery stents: appropriate use of adjunctive pharmacotherapy to prevent
      stent thrombosis.
AB  - In 1986, the first metallic stent was implanted inside a human coronary artery in
      order to reduce the incidence of abrupt vessel occlusion and restenosis after
      percutaneous coronary balloon angioplasty. Little was known at that time
      regarding the adequate anticoagulation regimen needed and the initial enthusiasm
      was soon marred by a high rate of thrombotic stent closure that usually occurred
      2 days to 4 weeks after stent implantation. Antithrombotic drugs such as heparin,
      aspirin (acetylsalicylic acid), low molecular weight heparins, dextran,
      dipyridamole and warfarin (coumadin) were incorporated in a series of trials
      which reduced the risk of stent thrombosis, but increased substantially the rate
      of bleeding complications and the length of hospitalisation. The greatest
      breakthrough came with the improvement in stent deployment techniques using
      intravascular ultrasound-guided, high-pressure balloon inflation inside the
      stent, and the understanding of the central role of platelet activation in stent
      thrombosis. These 2 factors have led to 'optimal stent deployment' with high
      pressure ballooning after stent deployment and the simultaneous use of more
      potent antiplatelet agents in conjunction with aspirin. Newly developed selective
      inhibitors of the platelet glycoprotein IIb/IIIa receptor and new stent designs
      have also recently been integrated into clinical practice and are currently being
      evaluated in clinical trials.

PMID- 10600043
TI  - Pharmacological management of osteoporosis in postmenopausal women: a comparative
      review.
AB  - Optimising lifestyle and diet are important in the management of osteoporosis,
      however, they cannot completely prevent postmenopausal bone loss. Calcium
      supplementation significantly retards but does not completely arrest bone loss,
      but several small controlled studies suggest that it reduces fracture incidence.
      Thiazide diuretics slow bone loss similarly but their effects on fracture
      incidence remain to be determined. Hormone replacement therapy (HRT) increases or
      maintains bone density, prevents height loss and prevents vertebral fractures.
      There is observational evidence that HRT decreases cardiovascular disease and
      increases the risks of thromboembolic disease and breast cancer. The selective
      estrogen receptor modulator (SERM) raloxifene also slows postmenopausal bone loss
      although it is less effective that HRT. It also increases the risk of
      thromboembolic disease but is associated with a significantly reduced risk of
      breast cancer. The bisphosphonates are of comparable efficacy to HRT in the
      prevention of bone loss and have been shown to halve the risk of fractures of the
      vertebrae, forearm and hip. The maintenance of normal vitamin D (colecalciferol)
      status is important, particularly in the elderly. HRT, the bisphosphonates and
      raloxifene are all suitable for use in the prevention of postmenopausal bone
      loss, but the former 2 are to be preferred in the treatment of established
      disease. The most comprehensive long term safety data are available for HRT.
      Clinical trials are underway at present with more potent bisphosphonates which
      may make possible longer dose intervals and alternative routes of administration.
      There is a need for an effective bone anabolic factor but those which have been
      trialled to date have not proceeded because of significant adverse effects.

PMID- 10600044
TI  - Worldwide prevalence and incidence of dementia.
AB  - Dementia is a common and disabling disorder in the elderly. Because of the
      worldwide aging phenomenon, existing in both developed and developing countries,
      dementia has a growing public health relevance. This article reviews the
      prevalence and incidence data for dementia reported in the international
      literature in the last 10 years. Results from 36 prevalence and 15 incidence
      studies have been examined. Prevalence is equal to 0.3 to 1.0 per 100 people in
      individuals aged 60 to 64 years, and increases to 42.3 to 68.3 per 100 people in
      individuals 95 years and older. The incidence varies from 0.8 to 4.0 per 1,000
      person years in people aged 60 to 64 years, and increases to 49.8 to 135.7 per
      1,000 person years when the population was older than 95 years. The international
      comparison allows the following conclusions: (i) both prevalence and incidence
      show little geographical variation, as differences between countries seem to
      reflect methodological rather than real differences [the low prevalence of
      dementia in Africa needs to be confirmed by incidence data]; (ii) both incidence
      and prevalence figures increase with age even in the advanced ages; (iii)
      regarding dementia types, most of the inconsistency in results from different
      studies is due to vascular dementia rather than to Alzheimer's disease (AD); (iv)
      it is still unclear if the reported higher frequency of vascular dementia in
      Asian populations is due to differential distribution of genetic and/or
      environmental factors, or due to methodological differences; (v) different
      dementia types might have different age distributions.

PMID- 10600045
TI  - Efficacy and adverse effects of medications used in the treatment of glaucoma.
AB  - With the advent of several new topically active medications for glaucoma therapy,
      intraocular pressure (IOP) can be reduced to target levels in more patients
      before resorting to surgery. Some of these newer agents have a number of
      advantages over some of the older medications, several of which are seldom used
      now. The topically active carbonic anhydrase inhibitors are better tolerated than
      oral formulations, which are infrequently used despite their greater efficacy
      compared with the topical formulations. The alpha2-adrenergic agonists
      effectively reduce IOP with few systemic adverse effects. The prostaglandin
      analogues are even more effective and well tolerated when applied once daily
      without known systemic adverse effects. The variety of glaucoma medications
      forces the physician to be selective with various combinations before proceeding
      with surgery. This article critically reviews the literature pertaining to the
      newer glaucoma medications, thereby providing guidelines to make rational choices
      from among the available options.

PMID- 10600047
TI  - Suicidality in panic disorder: a comparison with schizophrenic, depressed, and
      other anxiety disorder outpatients.
AB  - Recent findings by Weissman, Klerman, Markowitz, and Ouellette (1989) that
      subjects with panic disorder, with and without comorbid conditions, may be at
      increased risk for suicide attempts have been controversial. In an attempt to
      further investigate this finding, we utilized the original National Institute of
      Mental Health Epidemiological Catchment Area (ECA) suicide questions in an
      outpatient psychiatric clinic. We examined patients with panic disorder (n =
      101). other anxiety disorders (n = 47), schizophrenia (n = 22). and major
      depression (n = 19). No significant differences were found among all four groups
      on any of the ECA suicide ideation questions. Only two (2%) of the panic disorder
      patients and none of the other groups made a suicide attempt in the past year.
      While 17% of patients with panic disorder and 9% of patients with other anxiety
      disorders reported having made a suicide attempt at some other time in their
      life, the schizophrenic (33%) and depressed groups (40%) reported significantly
      greater histories of suicide attempts. In a forward stepwise regression analysis
      for panic disorder patients, a history of substance abuse and comorbid depression
      predicted suicidality. The actual clinical risk for suicide attempts in panic
      disorder patients appears to occur when they suffer with comorbid diagnoses.
      These results highlight the need to aggressively treat panic disorder patients so
      they do not suffer the all-too-common sequelae of depression and substance abuse.

PMID- 10600046
TI  - Epirubicin: a review of its efficacy as adjuvant therapy and in the treatment of
      metastatic disease in breast cancer.
AB  - Epirubicin is a semisynthetic derivative of doxorubicin which has been
      extensively evaluated in patients with breast cancer. It is effective in the
      management of metastatic disease and as adjuvant therapy in patients with early
      breast cancer. In the adjuvant setting, epirubicin-based therapy appears to have
      efficacy at least equivalent to that of the standard therapy cyclophosphamide,
      methotrexate and fluorouracil (CMF), with the most recent trials, predominantly
      in premenopausal patients, reporting significant gains in relapse-free survival
      and overall survival for epirubicin-based vs CMF therapy. In a single trial, the
      5-year relapse-free survival of postmenopausal patients receiving long term
      hormonal therapy (tamoxifen) was significantly increased when epirubicin was
      added as single-agent chemotherapy and compared with tamoxifen alone. In patients
      with metastatic disease, epirubicin- and doxorubicin-containing regimens (with
      cyclophosphamide and fluorouracil; FEC and FAC) are therapeutically equivalent.
      Increasing the dose of epirubicin appears to improve response rates in patients
      with either metastatic or early disease but, with the exception of 1 adjuvant
      study, improved overall survival has not been demonstrated. Quality of life (QOL)
      has yet to be adequately evaluated with epirubicin. The major adverse effects of
      epirubicin are acute dose-limiting haematotoxicity and cumulative dose-related
      cardiotoxicity. Other important adverse effects include mucositis, nausea and
      vomiting, reversible alopecia and local cutaneous reactions. However, the
      tolerability of epirubicin is better than that of doxorubicin at equimolar doses.
      CONCLUSION: Epirubicin has been extensively investigated in patients with breast
      cancer and has been found to be a highly effective agent, both for the treatment
      of patients with metastatic disease and as an adjuvant therapy. Recent trials
      have confirmed that, in selected patients requiring adjuvant therapy, FEC therapy
      is at least as effective as CMF, a standard treatment. FEC is also
      therapeutically equivalent to FAC in patients with metastatic breast cancer, and
      because the therapeutic index appears to be better the opportunity exists to
      increase dose intensity in an effort to improve efficacy. Such trials, and those
      of combinations of epirubicin with newer or alternative agents, should result in
      the introduction of more effective and better tolerated epirubicin-based
      protocols for adjuvant therapy and the management of patients with advanced
      breast cancer. In the meantime there is sufficient evidence to justify
      consideration of epirubicin for inclusion in first-line therapies for patients
      with early or metastatic breast cancer.

PMID- 10600048
TI  - Retrospective versus prospective self-rating of anxiety symptoms and cognitions.
AB  - The discrepancy between retrospective and prospective rating of anxiety symptoms
      and cognition was examined in 20 agoraphobics. Subjects were required to complete
      a checklist of symptoms and cognitions during exposure to an agoraphobic
      situation. and then to complete a similar set retrospectively. More cognitions
      were rated retrospectively than prospectively, with the discrepancy especially
      evident for cognitions about physical catastrophe. In contrast, there was no
      discrepancy between anxiety symptoms rated prospectively versus retrospectively.
      This may be because anxiety symptoms are easier for patients to identify than
      cognitions. require less introspection. or are less affected by context than
      cognition. Implications of the findings are discussed and suggestions for future
      research are made.

PMID- 10600049
TI  - High-Level cognition in phobics: abstract anticipatory memory is associated with
      the attenuation of physiological reactivity to threat.
AB  - The extent to which anxious people benefit from exposure-based treatments seems
      to depend on the degree to which they activate their fear network during
      exposure. This study was designed to investigate whether the cognitive processing
      of threat in anxious individuals is dominated by abstract anticipatory memory,
      and whether this abstract memory mode is related to the incomplete activation of
      the fear network. Activation of the fear network was assessed during phobic
      exposure, as evidenced by the initial autonomic reaction. Spider phobics and
      controls were presented with a threatening imagery script. Half of them were
      exposed to a real-life spider. Spider phobics memorized relatively more abstract
      anticipatory descriptions than concrete sensory descriptions when compared with
      the control subjects. Only in phobic subjects. higher recognition of abstract
      anticipatory descriptions was inversely related to heart rate reactivity during
      exposure. A preferential memory mode for abstract information was related to an
      attenuated heart rate reactivity to threat in spider phobics. It is suggested
      that the preferential memory mode for abstract information may inhibit the
      activation of the subcortical affective memory system, which is crucial for the
      complete activation of the fear network. The absence of complete fear network
      activation may play a role in the persistence of anxiety disorders by hindering
      anxious individuals to learn that the stimuli they fear are not as dangerous as
      they assumed.

PMID- 10600050
TI  - Somatic symptoms of generalized anxiety disorder from the DSM-IV: associations
      with pathological worry and depression symptoms in a nonclinical sample.
AB  - The present study investigates specificity of the six somatic symptoms that are
      associated with generalized anxiety disorder (GAD), according to the fourth
      edition of the Diagnostic and Statistical Manual of Mental Disorders. A
      nonclinical sample of 183 students provided severity ratings for (a)
      restlessness, (b) easily fatigued, (c) difficulty concentrating, (d)
      irritability, (e) muscle tension, and (f) sleep disturbance. In addition, they
      responded to questionnaires assessing pathological worry and depression symptoms.
      Partial correlations and multiple regression analyses indicated that only muscle
      tension showed a unique relation to pathological worry. In contrast, difficulty
      concentrating was exclusively related to depression symptoms. Present findings
      corroborate psychophysiological findings that elevated muscle tension is a
      specific characteristic of pathological worriers. Moreover, they suggest that the
      problem of unclear boundaries between GAD and major depression may be reduced if
      future revisions of the somatic symptom list for GAD emphasize muscle tension
      while de-emphasizing difficulty concentrating.

PMID- 10600051
TI  - Coronary artery bypass grafting: long-term psychological and social outcomes.
AB  - Long-term psychosocial outcomes were examined in 132 patients 7 to 22 years (M =
      9.4 years) after coronary artery bypass grafting. The control group comprised 145
      medically treated patients with coronary heart disease of 7 to 22 year duration
      (M = 9.2). Significantly more medically than surgically treated patients were
      scored in the clinically significant range for anxiety, and for depression on the
      hospital anxiety and depression scale. Significantly more medically than
      surgically treated patients reported a definite, considerable, or very severe
      impairment of family relationships, social activities, leisure activities, home
      management, and work on the social functioning scale. Work status did not
      significantly differ between surgical and medical patients. This study shows
      previously unreported long-term favorable psychosocial outcomes in patients who
      underwent coronary artery bypass grafting.

PMID- 10600052
TI  - Family dimensions in anxious-depressed school refusers.
AB  - The Family Adaptability and Cohesion Evaluation Scale II (FACES II) was
      administered to 46 adolescents with comorbid anxiety and major depressive
      disorders and to their parents in a treatment study of school refusal. FACES II
      measures cohesion and adaptability dimensions, as well as family type (balanced
      to extreme). Generally, adolescents and parents reported low cohesion (i.e..
      disengagement) and low adaptability (i.e.. rigidity) on FACES II. Adolescents and
      parents described their ideal families as significantly less disengaged and less
      rigid than their own families. Fifty percent of adolescents, 38% of fathers, and
      24% of mothers classified their families as the extreme type. Adolescents in
      extreme families, when compared with adolescents in more balanced families,
      reported significantly higher scores on two of three depression instruments and
      on a measure of somatic symptoms. Family therapy to improve cohesion and
      adaptability and treatments focused on improving depression and somatic symptoms
      may improve family functioning and decrease the severity and course of school
      refusal.

PMID- 10600053
TI  - Health concerns in patients with obsessive-compulsive disorder.
AB  - In the present study, individuals with obsessive-compulsive disorder (OCD) who
      also had excessive health concerns (n = 56) were compared with OCD individuals
      without such concerns (n = 343) regarding their OCD symptom severity, types of
      obsessions and compulsions, insight into the irrationality of their obsessions,
      and prevalence of generalized anxiety disorder. While the presence of health
      concerns did not affect the severity of OCD symptoms, the groups differed with
      respect to the types of symptoms displayed: those with health concerns had more
      somatic and harm obsessions, and checking compulsions: whereas those without such
      concerns had more contamination obsessions and washing compulsions. The insight
      of both groups ranged from poor to excellent, yet the number of individuals with
      poor insight was greater among those with health concerns than those without.
      Generalized anxiety disorder was also more prevalent among OCD individuals with
      excessive health concerns.

PMID- 10600054
TI  - Refining strategies for the prevention and control of hypertension and related
      complications.
AB  - Hypertension is the leading preventable cause of premature morbidity and
      mortality from coronary heart disease, chronic heart failure, stroke and kidney
      failure. Despite the remarkable advances made in the design, development, and
      distribution of antihypertensive drugs and the plethora of published guidelines
      for hypertension treatment over the last two decades, blood pressure control
      rates remain rather disappointing. In the United States, Canada, and the United
      Kingdom, as well as in countries with far less resources devoted to health care,
      fewer than one in four hypertensives are controlled. This observation remains a
      major source of frustration for clinicians and health policy makers alike and
      serves as a constant reminder for more refined strategies for hypertension
      treatment and control. The 14th International Interdisciplinary Conference on
      Hypertension in Blacks (ISHIB99), held in Toronto, Canada on July 10-14, 1999
      provided a unique forum for the discussion of this issue. The recommendations
      discussed are summarized herein under 10 specific headings that include: (1)
      Renewed emphasis on health education for patients and their families; (2)
      Increased involvement of non-physician health care providers; (3) Aggressive
      detection, evaluation and control of attendant cardiovascular risk factors; (4)
      Renewed determination for clinicians to set and achieve blood pressure targets;
      (5) Increased patient involvement in management decisions; (6) Improved access to
      quality care for the "working poor" and indigent; (7) Renewed commitment to
      community participation; (8) Partnership with managed care and professional
      organizations; (9) Renewed emphasis on the importance of psychosocial factors;
      (10) Enhanced communication and networking among hypertension care providers and
      between providers and patients.

PMID- 10600055
TI  - Representation of blacks, women, and the very elderly (aged > or = 80) in 28
      major randomized clinical trials.
AB  - OBJECTIVE: The purpose of this manuscript is to precisely quantify the
      representation of women, blacks, and very old (aged 80 or more) participants in
      28 past or ongoing randomized clinical trials on hypertension, cardiovascular
      disease, renal disease, and diabetes mellitus. METHODS: Selection of the 28
      studies was arbitrary, based primarily on the reference being often quoted or
      cited as relevant data for women, blacks, the elderly, or persons with diabetes
      mellitus. RESULTS: Twenty-three of the 28 studies enrolled a majority of men.
      Many of the completed trials had an under-representation of blacks (0% to 8%). An
      adequate number (1,091) of very old (aged 80 or more) persons have been studied
      for isolated systolic hypertension, but the number of such patients thus far
      studied for diastolic hypertension is too small to allow evidence-based
      recommendations for therapy. Reported studies in diabetes have included a
      majority of men (average, 58%) and four of the five trials reviewed enrolled
      relatively few blacks (average, 4.6%). CONCLUSIONS: Women, blacks, and the very
      old (aged 80 or more) have been under-represented in many past randomized
      clinical trials, but ongoing studies will resolve this discrepancy in most
      instances. The Women's Health Initiative (WHI) will provide data on 161,861 multi
      ethnic postmenopausal women. ALLHAT results will include 15,133 hypertensive
      blacks, and AASK will have 1,094 hypertensive blacks with nephrosclerosis.
      ALLHAT, STOP-2, and HYVET will include more than 5,000 persons aged 80 or more.
      Future trials on diabetes mellitus must be designed to improve the representation
      of women and blacks.

PMID- 10600056
TI  - Effects of the chronotherapeutic delivery of verapamil on circadian blood
      pressure in African-American patients with hypertension.
AB  - OBJECTIVE: To evaluate the effects of COER-verapamil on circadian blood pressure
      (BP) and heart rate in African-American patients with hypertension. DESIGN:
      Retrospective pooled analyses of efficacy and tolerability data from three
      prospective, randomized, double-blind, placebo-controlled trials with COER
      verapamil in hypertension. PATIENTS/PARTICIPANTS: Sixty-eight African-American
      patients with stages I-III hypertension (seated diastolic BP, 95-114 mm Hg) were
      randomized to receive placebo or treatment with 180-540 mg of COER-verapamil once
      daily at bedtime for 4 to 8 weeks. METHODS: Using ambulatory monitoring, efficacy
      was assessed by measuring change from baseline in systolic and diastolic BP,
      heart rate, and the heart rate-systolic pressure product during three time
      intervals: early morning (0600 to 1000), daytime (0800 to 2200), and nighttime
      (2200 to 0800). Changes also were compared to data from the non-African-American
      population. Adverse effects were tabulated at each visit. RESULTS: Mean changes
      from baseline in early-morning BP, heart rate, and rate-pressure product for
      patients treated with COER-verapamil were -13.8/-11.2 mm Hg, -6.2 beats/minute,
      and -1960 mm Hg-beats/min, respectively (P<0.01 for all parameters compared to
      placebo). Significant and similar reductions also were observed for daytime and
      nighttime BP, heart rate, and the rate-pressure product. The incidence of side
      effects in the COER-verapamil-treated patients was similar to placebo and the
      African-American patients had similar incidences to the non-African-American
      patients. CONCLUSIONS: The chronotherapeutic delivery of verapamil significantly
      reduced circadian BP, heart rate, and the rate-pressure product. The side effect
      profile of COER-verapamil was similar to that of placebo. Thus, this therapy for
      delivery of a heart-rate lowering calcium channel blocker is a useful
      antihypertensive strategy for African-American patients with hypertension.

PMID- 10600057
TI  - The prevalence of salt sensitivity in an African-American adolescent population.
AB  - This study examined the prevalence of salt-sensitivity (SS) in 140 healthy
      African-American adolescents. SS was defined as an increase in mean blood
      pressure > or =5 mm Hg from a 5-day low salt (Na+) diet (50 mmol/24 hr) to a 10
      day high Na+ diet (150 mmol/24 hr NaCl supplement); remaining subjects were
      classified as salt-resistant (SR). Dietary compliance was defined as Na+
      excretion < or =50 mmol/24 hr for the low Na+ diet and > or =165 mmol/24 hr for
      the high NaCl supplement diet. 31 (22%) subjects were classified as SS and 109
      (78%) as SR. There were no significant differences between SS and SR subjects on
      baseline characteristics, family history of hypertension, or on resting blood
      pressure or heart rate measures. As expected, SS subjects showed a greater
      increase in mean, systolic, and diastolic blood pressures (P<.001 for all) than
      SR subjects in response to the high NaCl supplement. There was a greater increase
      in weight (P<.01) and Quetelet Index (P<.05) for SS than SR subjects in response
      to Na+ loading. These results are the first to show that SS is prevalent in a
      subgroup of healthy African-American adolescents.

PMID- 10600058
TI  - The relationship among John Henryism, hostility, perceived stress, social
      support, and blood pressure in African-American college students.
AB  - African Americans' rates of hypertension-related morbidity and mortality are
      several times that of white Americans. A number of behavioral and psychological
      variables may influence these differences. John Henryism, characterized by active
      coping to overcome obstacles, is one such variable. Prior research indicates that
      among highly educated individuals, high levels of John Henryism may be associated
      with decreased hypertension risk. The purpose of this study was to identify a
      cohort of well-educated African Americans to establish a baseline examination of
      the relationships between John Henryism, hostility, perceived stress, social
      support and resting systolic and diastolic blood pressures (SBP and DBP,
      respectively). Participants completed measures of study variables and resting
      blood pressures were taken. Results indicated that high family and friendship
      support were related to reports of lowered levels of stress (P<.001). Family
      support was associated with decreased risk for elevated DBP (P<.05). A positive
      association between hostility and DBP was found (P<.01). Perceived stress was
      negatively associated with SBP (P<.05), but did not have an independent effect on
      DBP. Similarly, no interactive effects of John Henryism and perceived stress were
      found on blood pressure. Examination of this cohort over time will reveal the
      impact of John Henryism and other variables on blood pressure elevations and
      hypertension.

PMID- 10600059
TI  - The influence of maternal hypertension on low birth weight: differences among
      ethnic populations.
AB  - OBJECTIVE: To determine the influence of maternal hypertension on the risk of low
      birth weight among white, black, and Hispanic residents of New York City.
      METHODS: New York City birth certificates, 1988 through 1994, provided data on
      maternal and infant characteristics. Hypertension was self-reported on birth
      certificates, and was categorized as chronic or pregnancy-related hypertension.
      The complication of preeclampsia/eclampsia was also noted. The risk of low birth
      weight (<2500 grams) for maternal hypertension was determined. RESULTS: The
      prevalence of hypertension during pregnancy was 3.8% overall, and was highest for
      blacks and lowest for whites. Low birth weight rates for white, black, and
      Hispanic babies were 5.0%, 12.8%, and 7.5%, respectively. Low birth weight rates
      among hypertensive mothers for whites, blacks and Hispanics were 16.8%, 24.4% and
      19.5% respectively. The trends were similar for chronic and pregnancy-related
      hypertension, as well as for preeclampsia/eclampsia. The relative risk of low
      birth weight offspring among all hypertensive mothers was highest among whites
      (3.58, 95% CI = 3.39-3.79), and lowest among blacks (1.99, 95% CI = 1.93-2.06).
      This trend persisted for chronic and pregnancy-related hypertensive mothers, and
      those with preeclampsia/eclampsia, after adjusting for other maternal
      socioeconomic characteristics. Due to the higher prevalence of hypertension among
      black mothers, the population attributable risk of low birth weight was highest
      among black babies (557 per 100,000 live births) and lowest among whites (309 per
      100,000 live births). CONCLUSION: Maternal hypertension is an important risk
      factor for low birth weight. Its impact, however, differed by race/ethnicity
      groups.

PMID- 10600060
TI  - Body image preferences among urban African Americans and whites from low income
      communities.
AB  - OBJECTIVE: The purpose of this study was to determine (1) how African-American
      and white men and women from similar low income communities perceive their body
      mass relative to others in the population; and (2) whether ethnic and gender
      differences exist in the selection of ideal body image sizes for the same and
      opposite sex. DESIGN: A street survey of African-American and white men and women
      was conducted using a census tract sampling schema. Participants (N = 927) were
      interviewed and asked to provide their height and weight and to select body size
      images from a standardized ethnic-specific Figure Rating Scale to represent their
      current self, ideal self, and their estimation of ideals for the opposite sex.
      Sociodemographics and co-morbidity were assessed by self-report. RESULTS: All
      ethnic and gender groups showed a significant correlation between their body mass
      index and selected body image size, r = .63 to .74, all P<.001. Average ideal
      body image size for self was the same for African-American and white men, while
      African-American women had a significantly greater ideal image size compared with
      white women (P = .004). Ideal body image size preferences for members of the
      opposite sex were greater for African-Americans. White women had a notable
      preference for the smallest body image sizes. Multiple linear regression analyses
      showed that, independent of sociodemographic variables and co-morbidity, body
      image sizes for current self, ideal self, and ideal for the opposite sex were all
      significantly greater in African-Americans. CONCLUSION: Strategies to ameliorate
      overweight and its attendant diseases may require a shift in social norms,
      particularly among African-American women in low socioeconomic communities. This
      has implications for the design of community-based interventions and suggests a
      need for ethnic-specific interventions.

PMID- 10600061
TI  - Compliance with post-hospitalization follow-up visits: rationing by
      inconvenience?
AB  - OBJECTIVES: Appointment-keeping after hospitalization is a poorly understood link
      between inpatient and outpatient care. We investigated how health care system and
      patient characteristics influence appointment-keeping after discharge from an
      acute care hospitalization. DESIGN: Prospective cohort study. SETTING: Urban
      public teaching hospital. SUBJECTS: All 372 consecutive eligible patients
      admitted over a 15 week period to medicine wards. METHODS AND MEASURES: We
      interviewed patients during hospitalization and after discharge, searched the
      hospital's electronic databases, and reviewed charts. We measured medication
      compliance, health care access and use, health status (SF-36), previous
      appointment compliance, and physician recommended follow-up appointments. Main
      outcome was appointment adherence after discharge. RESULTS: Patients were
      primarily African American (71%), uninsured (64%), female (53%), and had a mean
      age of 48 years; 64% of first appointments after discharge were kept. Adjusted
      odds ratios (95% confidence intervals) for appointment-keeping were 3.3 (1.7,
      6.5) for receiving a written appointment at discharge, and 0.50 (0.27, 0.90) for
      previous difficulty with obtaining health care. Readmission rates were not
      associated with appointment adherence. CONCLUSION: Modifiable system, as well as
      patient, characteristics are associated with follow-up appointment-keeping. The
      practice of not giving patients written appointments at the time of discharge may
      constitute an implicit form of "rationing by inconvenience." Further studies
      should also evaluate potential associations between appointment-keeping and re
      hospitalization.

PMID- 10600062
TI  - Diminished socioeconomic and racial disparity in the detection of early-stage
      breast cancer, Connecticut, 1986-1995.
AB  - Annual counts, proportional distributions, and age-adjusted incidence rates of
      disease by stage at diagnosis are reported for 27,970 in situ and invasive breast
      cancers from the Connecticut Tumor Registry, 1986-1995. Odds ratios for the
      likelihood of late-stage disease by year of diagnosis, age category,
      race/ethnicity, and the socioeconomic level of community of residence are
      presented. More breast cancer is diagnosed today at earlier, treatable stages
      than was previously the case. Nonetheless, young women, non-whites, and residents
      of low-to-moderate income census tracts were all at increased risk of being
      diagnosed with late-stage disease than were their respective reference groups.
      From 1986 through 1990, there was little change in the greater likelihood that
      non-whites and disadvantaged women would be diagnosed with late-stage disease.
      For 1990-95, however, the disparity in late-stage diagnosis by race/ethnicity and
      socioeconomic standing was greatly decreased.

PMID- 10600063
TI  - American Indian and Alaska Native health behavior: findings from the behavioral
      risk factor surveillance system, 1992-1995.
AB  - OBJECTIVE: The purpose of this study was to evaluate differences between American
      Indian and white adults in behavioral risk factors for chronic disease and
      injury. METHODS: Data were drawn from the 1992-1995 Behavioral Risk Factor
      Surveillance System, an ongoing telephone survey of health behaviors of adults.
      Prevalence estimates by sex were calculated for American Indian and white
      respondents in 15 states and the significance of their differences evaluated by
      chi-square tests. RESULTS: American Indians were found to be at significantly
      higher risk than whites for fair to poor general health status, medical cost
      difficulties, binge drinking, cigarette smoking, not always using safety belts,
      being diagnosed as diabetic, and obesity. CONCLUSIONS: To reduce the gap in
      behavioral risk factors between American Indians and whites, more resources need
      to be dedicated to American Indian health. Note. The term "American Indian"
      henceforth refers to those who identify themselves as American Indian or Alaska
      Native.

PMID- 10600064
TI  - Determinants of birth-weight outcomes among Mexican-American women: examining
      conflicting results about acculturation.
AB  - In this article, we describe a comprehensive model for exploring the determinants
      of birth-weight outcomes among Mexican-American women from the Arizona Perinatal
      Acculturation Project. Data for this article came from a longitudinal study
      consisting of two phases. In phase one, a detailed prenatal survey was
      administered to 500 pregnant women. Phase two consisted of a postnatal survey
      administered to the women at least three months after they delivered (N = 269).
      Subjects who provided data were recruited from two health care agencies. Separate
      model building processes were conducted for a continuous measure of birth weight,
      and a dichotomous indicator of low-moderate birth weight (<2900 grams) using
      multiple linear and logistic regression analyses, respectively. The potential
      predictor variables for the models were divided into twelve predictor sets. The
      results showed that both final models included a combination of
      biological/behavioral factors, as well as protective sociocultural factor
      indicators. Acculturation status, one of the primary variables of interest in the
      study was found to be important for predicting birth weight and low-moderate
      birth weight. This result did not change when low birth weight (<2500 grams)
      infants were removed from the analyses. Low acculturation status was found to be
      associated with better birth-weight outcomes than high acculturation status.
      Surprisingly, length of US residence had an opposite effect in predicting both
      birth-weight indicators when compared to acculturation status. These results
      suggest that the relationships between acculturation and birth outcomes should be
      redefined to take into account the complexity of the phenomenon of acculturation
      in addition to the measurement of an array of family and sociocultural factors.

PMID- 10600065
TI  - Mortality among US adult Asians and Pacific Islanders: findings from the National
      Health Interview Surveys and the National Longitudinal Mortality Study.
AB  - OBJECTIVES: To assess the mortality of the adult Asian and Pacific Islander
      population in the United States. METHODS: Cohort study using data from the
      National Health Interview Survey (1986 to 1994) and the National Longitudinal
      Mortality Study. Deaths were ascertained by matching the National Death Index
      with average follow-ups of 5.3 and 9 years, respectively, for the two studies.
      RESULTS: Respondents from the pooled National Health Interview Surveys included
      532,794 non-Hispanic whites, 94,242 blacks, 52,725 Hispanics, and 16,936 Asians
      and Pacific Islanders, all of whom were at least 18 years of age at baseline. The
      National Longitudinal Mortality Study included 373,397 non-Hispanic whites,
      41,262 blacks, 23,356 Hispanics, and 8,390 Asians and Pacific Islanders. Overall
      age-standardized mortality was the lowest in Asians/Pacific Islanders, whose risk
      of death was about 40% lower than whites'. Adjustment for differences in
      education levels had a minimal influence on the mortality advantage in
      Asians/Pacific Islanders. CONCLUSIONS: Longitudinal cohorts provide an important
      source of health status information on Asians and Pacific Islanders. These two
      studies from representative national samples suggest that overall mortality is
      substantially lower among Asians and Pacific Islanders than in all other major
      ethnic groups.

PMID- 10600066
TI  - Smoking, acculturation and family cohesion in Mexican-American women.
AB  - OBJECTIVE: To compare the characteristics of smokers and non-smokers in a setting
      that includes predominately Mexican-American women, with particular attention to
      acculturation, nativity and family cohesion. DESIGN: Cross-sectional survey in a
      public hospital women's clinic. METHODS: A self-administered survey was completed
      by gynecologic patients. It assessed: demographics, acculturation, birthplace and
      family cohesion. Comparisons of ever/never smokers and current/non-smokers were
      made using chi-square tests. Stratified analysis was used to assess for
      confounding. RESULTS: Smoking was very common in the white non-Hispanic group
      (ever smoking 86%, current smoking 70%). High rates were also seen among certain
      subgroups of Mexican-American women: US-born (ever smoking 65%, current smoking
      44%), high acculturation (ever smoking 57%, current smoking 40%) and those with
      less cohesive families (ever smoking 67%, current smoking 67%). Stratified
      analysis revealed that place of birth and family cohesion, controlling one for
      the other, had adjusted prevalence ratios for current smoking of 3.7 (95% CI 1.5,
      9.0) and 3.2 (95% CI 1.3, 8.1) respectively. CONCLUSION: Very high rates of
      smoking were observed among white non-Hispanic patients and certain subgroups of
      Latino subjects in this population. In Latinos, being US-born and having
      membership in a less cohesive family unit were independently associated with
      smoking.

PMID- 10600067
TI  - Treatment status and experiences of hypertension patients at a large health
      center in Cape Town.
AB  - OBJECTIVE: This study was undertaken at a community health center (CHC) in the
      Cape Peninsula in order to assess the treatment status, knowledge and experiences
      of hypertensive patients. In addition, a health indicator sheet for hypertension
      was evaluated and an attempt was made to identify predictors of blood pressure
      (BP) control at this clinic. METHODS: Two hundred two hypertensive patients were
      selected by interviewing the first available hypertensive patients. The patients'
      BP was measured electronically and by sphygmomanometer, and was compared to that
      recorded by the clinician on their clinic folders; heights and weights were also
      determined. RESULTS: Of the hypertensives, 41.6% had a BP above 160/95 mm Hg and
      only 42.1% had a BP below 140/90 mm Hg. Patients had little knowledge of either
      the consequences of hypertension or the actions needed to ensure that
      complications were prevented; 31% suggested home remedies for hypertension. The
      majority of the patients were satisfied with the service they received, but 47%
      complained about long waiting times, 37% felt that the doctor did not examine
      them adequately, and 15.5% reported that insufficient medication was provided
      when filling prescriptions. Urine and eye tests had been conducted infrequently
      during the previous two years. Thirty percent of the patients requested the
      return of the dedicated hypertension clubs. Conditional logistic regression
      models identified that patients who expressed the need to make proposals to the
      clinic staff about their care had better BP control than those who did not.
      CONCLUSIONS: The BP of hypertensive patients is not optimally controlled at this
      CHC and both non-drug and drug management of hypertension need to be improved.
      Steps should be taken to help hypertensive patients become more knowledgeable so
      that they may play more active and compliant roles in their hypertension care.
      Patients also suggested that dedicated hypertension clubs be reinstituted at the
      CHCs.

PMID- 10600068
TI  - Stress, stress reduction and hypercholesterolemia in African Americans: a review.
AB  - Psychological stress may directly contribute to the disproportionately high rates
      of coronary heart disease morbidity and mortality and its etiologic risk factors
      in African Americans. Specifically, acute and chronic stress have been shown to
      raise serum lipids and are associated with clinical coronary events. The
      mechanisms by which stress contributes to alterations in lipid levels are not
      fully known, but various pathways (ie, hormonal, dietary, etc) have been
      implicated. Traditional methods for reducing blood serum lipids include diet,
      drugs or both. These methods have been criticized because of issues of
      compliance, side effects, and cost. Because of these limitations, nondrug
      behavioral methods are recommended by the National Cholesterol Education Program
      as the first line of prevention and treatment for hypercholesterolemia and other
      risk factors. Research shows that CHD morbidity and mortality and major risk
      factors may be modifiable by behavioral intervention. Specifically, the
      Transcendental Meditation technique, an effective antidote to stress, reduces
      levels of major CHD risk factors including hypercholesterolemia, as well as blood
      pressure and smoking. Using an effective stress reduction approach for prevention
      and treatment of CHD and its risk factors in African Americans may prove to be a
      valuable asset for this underserved population.

PMID- 10600069
TI  - Pattern of renal diseases among adults in Saudi Arabia: a clinicopathologic
      study.
AB  - In order to delineate the pattern of renal diseases among the adult population in
      Saudi Arabia, a retrospective study of 166 kidney biopsies performed between 1989
      and 1997 at Asir Central Hospital, Abha, Southern Saudi Arabia was conducted.
      Primary glomerular disease accounted for 66.8% of all cases. Mesangiocapillary
      glomerulonephritis (MCGN) was found to be the most common histological lesion
      accounting for 25.9% of all cases and 38.7% of the primary nephritis. This was
      followed by immunoglobulin A nephropathy (IgA) (18.9%), and focal segmental
      glomerulosclerosis (17.1%), minimal change disease (9.9%), membranous
      glomerulonephritis (9.0%) and mesangioproliferative glomerulonephritis (4.5%).
      Lupus nephritis was the leading cause of the secondary glomerulonephritis
      (61.5%). Clinical evidence of schistosomiasis was seen in 4.2% of all the cases
      and in 11.6% of the mesangiocapillary cases. Schistosomal infection may play a
      role in the pathogenesis of glomerulonephritis in the Saudi population, and
      further studies are needed to confirm such an association.

PMID- 10600070
TI  - Cardiovascular risk factors in South America and the Caribbean.
AB  - Facing the conclusion of the twentieth century, cardiovascular disease (CVD)
      remains a major cause of morbidity and a leading contributor to mortality
      worldwide. Developing countries, including those in South America and the
      Caribbean, contribute substantially to the global burden of CVD. Indeed, 8 to 9
      million deaths attributable to CVD (63% of world total) occurred in developing
      countries in 1990, compared to 5.3 million deaths in developed nations. Over the
      next 25 years, it is projected that there will be a rise in CVD mortality rates
      in the developing countries, linked not only to demographic changes (expansion
      and aging of the population), but also to progressive urbanization and lifestyle
      modifications. As such, the ratio of deaths from CVD to deaths from infectious
      disease is likely to triple during the next 20 years in South America and the
      Caribbean. The identification of major risk factors and the implementation of
      control strategies (eg, community education and target of high risk individuals)
      have contributed to the fall in CVD mortality rates observed in industrialized
      nations. Most countries of South America and the Caribbean lack an efficient
      health care system, and the medical and socio-economic consequences of the
      projected rise in CVD will further strain financial resources. Therefore,
      appropriate strategies based on knowledge extrapolated from research among other
      populations should be initiated. The agenda of any lifestyle-related disease
      control program should include the promotion of healthy diet, exercise, and
      should encourage decreasing tobacco and alcohol usage.

PMID- 10600071
TI  - Risks in risk definitions.
AB  - Exact definitions of epidemiological concepts are necessary tools for exact
      studies. The present paper, stimulated by Beck's article in this journal
      (Community Dent Oral Epidemiol 1998; 26: 220-5), includes some further comments
      on this topic. For detailed risk analyses, one has to know a) whether the
      subjects are disease free or not at baseline in the groups to be compared, and b)
      whether the follow-up period is fair for all the study groups in prevention
      studies. An epistemological aspect is presented in a discussion of the roles of
      empirical evidence and theory in identifying evidence for or against some
      suspected risk factors.

PMID- 10600072
TI  - Smokeless tobacco (shamma) and oral cancer in Saudi Arabia.
AB  - Oral use of smokeless tobacco has been associated with the development of oral
      cancer. Shamma is a preparation of smokeless tobacco. Previous investigators in
      the Kingdom of Saudi Arabia (KSA) have reported a relationship between their
      patients with oral cancer and a history of using shamma. The purpose of this
      study was to explore the possible relationship between a smokeless tobacco
      preparation (shamma) and oral cancer, among the provinces of the KSA. Tumor
      Registry (TR) data from the King Faisal Specialist Hospital and Research Centre
      (KFSH&RC) were reviewed for the period from 1976 to 1995. A total of 26510 Saudi
      cancer patients were referred over this 20-year period. The frequency of oral
      cancer was investigated, specifically for those primary sites located near the
      habitual placement of this smokeless tobacco product. Notably, 35.4% of these
      oral cancers were referred from one province - Jizan. The percentage of oral
      cancer cases from this province is significantly higher than the percentage of
      total malignant cases referred to KFSH&RC from this province, and the Saudi
      population of this province when compared to the whole of the KSA. These data
      suggest that there is a relationship between the factors smokeless tobacco
      product (shamma), frequency of oral cancer, and Jizan province: oral cancer
      appears to be more common in this province where shamma is also common.

PMID- 10600073
TI  - Salivary mutans streptococci and caries development in the primary and mixed
      dentitions of children.
AB  - OBJECTIVES: For more than 25 years, both cross-sectional and longitudinal studies
      of dental caries have focused on the role of salivary mutans streptococci (SMS)
      as a predictor of caries risk. This study examined the relationship between SMS
      and longitudinal caries development in the primary and mixed dentitions. METHODS:
      Eighty-five children, initial mean age 3.8 years, were examined for dental caries
      at baseline and once annually for 6 years. Children's SMS were sampled with a
      tongue blade, which was impressed onto plates containing a medium selective for
      SMS. After incubation, colony forming units of SMS were determined semi
      quantitatively and categorized as low, moderate or high. RESULTS: Children
      classified as high caries risk at baseline had significantly greater (P<0.05)
      dmfs scores for all teeth, and in the primary molars, than children classified as
      moderate or low caries risk at every age but 9 (P<0.10). Children classified as
      high risk at age 3 had the greatest DMFS increment through age 8. Based on annual
      examinations, there was a trend towards increasing mean dmfs/DMFS scores among
      children classified as high risk in every year. CONCLUSIONS: The current study is
      among the first to report on the ability of annual measurements of SMS to
      identify long-term caries risk in both the primary and the mixed dentitions.
      Despite limitations in predicting caries risk using microbiological methods, this
      longitudinal study supports the overall benefits of this type of testing.

PMID- 10600074
TI  - Socio-economic status and orthodontic treatment need.
AB  - OBJECTIVES: This study aimed to examine the relationship between socio-economic
      status and both normatively assessed and self perceived need for orthodontic
      treatment. METHODS: More than six thousand 14-year-old children were assessed for
      orthodontic treatment by trained and calibrated examiners. The Index of
      Orthodontic Treatment Need was the measuring instrument along with a
      questionnaire which asked: "Do you think your teeth need straightening?" RESULTS:
      Normative need for orthodontic treatment (IOTN >3) was more common amongst
      deprived children than among their affluent counterparts. The same was found for
      perceived need. However, the children who wanted treatment were not necessarily
      those who needed it and vice versa. CONCLUSIONS: Socio-economic status affects
      normatively measured orthodontic treatment need through, as yet, undefined
      mechanisms. It also affects a person's perception of need for orthodontic
      treatment, but these two associations are separate. The mismatch of need and
      desire for treatment is a problem for orthodontists.

PMID- 10600075
TI  - Introduction--ART from a global perspective.

PMID- 10600076
TI  - How effective is ART in the management of dental caries?
AB  - The ART approach involves excavating cavitated dentine caries with hand
      instruments, then restoring the cavity and sealing any associated fissures and
      pits with an adhesive restorative material, resulting in a sealant restoration.
      Until recently, ART has mainly been used under field conditions, and thus the
      adhesive restorative material used has been glass ionomer which does not require
      mixing machines and curing lights. Since the inception of ART, a growing number
      of studies world-wide have taken place. A total of four studies have reported 3
      year survival percentages for one-surface ART restorations. The highest 3-year
      survival percentage in permanent teeth was 88%, which is comparable to the 85%
      survival of one-surface amalgam restorations placed under the same field
      conditions after 3 years. The outcomes depend to some extent on the material
      used, operator experience and presence of caries. The presence of caries as a
      reason for failure was higher in the early than in the most recent studies. Only
      one study has reported on the use of ART restorations in the deciduous dentition.
      It is concluded that: a very large proportion of dentine lesions in the permanent
      teeth can be treated using the ART approach; the 3-year survival rate of the more
      recently placed one-surface ART restorations in permanent teeth was higher than
      that of ART restorations placed in the beginning; the survival of one-surface ART
      restorations in the permanent dentition with newer glass ionomers is comparable
      to that of one-surface conventional restorations placed using amalgam in a
      comparable setting after 3 years; more studies of longer duration are needed to
      confirm these findings; ART should be considered a caries treatment modality that
      benefits people; and educational courses need to be organised before the approach
      is applied in the clinic.

PMID- 10600077
TI  - Is ART really atraumatic?
AB  - Atraumatic restorative treatment (ART) is an approach to the management of
      carious lesions that uses only hand instruments to remove carious tissue and to
      restore the tooth involved. The name ART implies that the approach is atraumatic
      to both the patient and the tooth. This study set out to evaluate whether ART is
      atraumatic in terms of both patient discomfort and tooth tissue conservation.
      Three hundred and fifty-nine patients were divided in two groups: one group was
      treated with hand instruments and the other with rotary equipment. Each patient
      received two restorations: one using amalgam and one using glass ionomer as the
      restorative material, placed without the use of anaesthesia. Less discomfort was
      reported with the ART approach compared to conventional restorations made using
      rotary instruments and amalgam. Moreover, preparations with hand instruments were
      smaller than those produced with rotary instruments. Reported discomfort was
      associated with the size of the preparation, although the influence of the
      operator on both criteria was considerable. A patient effect was also observed
      since patients who reported discomfort during the first treatment were more
      likely to report discomfort after the second treatment. In conclusion, the choice
      of the term "ART" as an atraumatic procedure is defensible.

PMID- 10600078
TI  - The residual caries dilemma.
AB  - Restorative dentistry is based on the assumption that bacterial infection of
      demineralized dentine should prompt operative intervention. One of the concepts
      of practical dentistry is to create a favourable environment for caries arrest
      with minimal operative intervention. The progress of remaining primary caries is
      key to any discussion of this concept. This discussion is important for the
      atraumatic restorative treatment (ART) approach, since the removal of all carious
      dentine is sometimes difficult using hand instruments only. In this paper the
      results of possible measures to guard against the effects of residual carious and
      its consequences are reviewed, in order to obtain an impression of the
      justification for (in)complete excavation of occlusal dentinal caries. Three
      types of measure are considered: isolating the caries process from the oral
      environment, excavating the carious dentine, and using a cariostatic filling
      material. Each of these measures contributes to the arrest of the caries process.
      However, none of these measures can arrest this process by itself. A combination
      of all three seems necessary. It is concluded that although residual caries does
      not seem to be the criterion for rerestoration, one has to strive for as complete
      caries removal as possible. If this cannot be fulfilled the sealing capacities of
      the filling material seem to be more important than its cariostatic properties.

PMID- 10600079
TI  - Does ART have a place in preservative dentistry?
AB  - The ART technique consists of hand excavating carious tissue and placing a highly
      viscous glass ionomer cement as a restoration material and as a sealant. Although
      the results of several studies are promising, the retention rates of these
      restorations for primary teeth are not impressive. Materials and methods that
      yield greater success rates are needed to improve long-term caries management
      outcomes. In principle, ART should yield outcomes similar to those associated
      with preservative dentistry, including the potential for minimal surgical
      intervention, conservation of sound tooth structure, avoidance of pain and need
      for local anesthetic injections, reduced risk for subsequent endodontics and
      tooth extraction, and increased survival time of the affected teeth. The ideal
      direct-filling ART material would be biocompatible and tooth colored; "forgiving"
      in its handling properties; insensitive to moisture or desiccation; hardenable
      without special equipment; able to form stable bonds to enamel and dentin; able
      to seal marginal gaps against bacteria; capable of releasing fluoride or
      remineralization and antibacterial agents when demineralization is most likely;
      and resistant to chemical attack. The highly viscous glass ionomer materials
      currently used for ART meet several of this criteria, though they may be
      deficient in their ability to seal marginal gaps against bacteria and in their
      sensitivity to desiccation. Furthermore, although they release fluoride over the
      lifetime of the restoration, this fluoride release alone may not prevent caries
      progression in all cases. It is necessary for cases of high caries risk to use
      chlorhexidine in conjunction with fluoride to achieve caries arrest and
      remineralization of adjacent areas of the affected teeth. Thus, while the ART
      technique offers some benefits in restoring function and reducing the rate of
      caries progression, it is unlikely that current materials will be able to arrest
      caries progression completely in high-risk persons.

PMID- 10600080
TI  - Painting the future for ART.
AB  - The objective of this paper is to review recent research and developments with
      respect to the atraumatic restorative treatment (ART) approach and to outline
      future areas of research and development. Areas identified as requiring further
      investigation include the evaluation of: ART restorations for longer than 3 years
      duration using recognised evaluation criteria, multi-surface ART restorations,
      ART restorations in primary teeth and ART sealants. In addition, the possibility
      and potential dangers of caries remaining after cavity cleaning with hand
      instruments must be investigated and the findings balanced against the known
      damage to sound tooth tissue caused by more routine cavity preparation
      techniques. New bioactive restorative materials which offer the possibility of
      healing dentinal caries lesions should be developed and evaluated. Finally,
      behavioural and educational aspects of the ART approach should be investigated.

PMID- 10600081
TI  - We've been shown the money, and we now know how to spend it.

PMID- 10600082
TI  - Clinical pharmacy saves money and lives--so what's new?

PMID- 10600083
TI  - Clinical pharmacy services, pharmacist staffing, and drug costs in United States
      hospitals.
AB  - We evaluated direct relationships and associations among clinical pharmacy
      services, pharmacist staffing, and drug costs in United States hospitals. A
      database was constructed from the 1992 American Hospital Association's Abridged
      Guide to the Health Care Field and the 1992 National Clinical Pharmacy Services
      database. Multiple regression analysis, controlling for severity of illness, was
      employed to determine the associations. The study population consisted of 934
      hospitals. Four clinical pharmacy services were associated with lower drug costs:
      in-service education, $77,879.19+/-$56,203.42 (a total of $48,518,735.37 for the
      623 hospitals offering this service, p=0.016); drug information, $430,579.84+/
      $299,232.76 ($90,852,346.24 for the 211 hospitals offering this service,
      p=0.015); drug protocol management, $137,333.67+/-$98,617.83 ($45,045,443.76 for
      the 328 hospitals offering this service, p=0.049); and admission drug histories,
      $213,388.21+/-$201,537.85 ($5,548,093.46 for the 26 hospitals offering this
      service, p=0.011). As staffing increased for hospital pharmacy administrators
      (p<0.0001), dispensing pharmacists (p<0.0001), and pharmacy technicians
      (p<0.0001), drug costs increased. As staffing increased for clinical pharmacists,
      drug costs decreased (p=0.018). The results of this study show that increased
      staff levels of clinical pharmacists and some clinical pharmacy services are
      associated with reduced hospital drug costs.

PMID- 10600084
TI  - Malaria epidemiology and economics in a pharmacist-managed international travel
      clinic.
AB  - With high rates of travel and low adherence to malaria prophylaxis, targeting
      educational efforts to high-risk travelers is vital. We assessed risk factors for
      acquiring malaria, and resource use and outcomes of these patients in a managed
      care environment. Patients were identified from January 1, 1994, to December 31,
      1997, using microbiology and pharmacy databases, chart reviews, and interviews.
      Sixteen patients acquired malaria during the study; although only 50% contacted
      the travel clinic. Only 31% (5) of them had documented adherence. Fifty percent
      were hospitalized at a cost of $3881/patient. Travelers at greatest risk for
      nonadherence appear to be expatriates and those visiting Africa. Providers should
      target these groups with more intensive counseling in an effort to improve
      therapy adherence and reduce the risk for malaria.

PMID- 10600085
TI  - A randomized, prospective study measuring outcomes after antibiotic therapy
      intervention by a multidisciplinary consult team.
AB  - Our aim was to identify financial and outcome benefits of therapeutic
      intervention by a multidisciplinary antimicrobial treatment team composed of
      pharmacists, a clinical microbiologist, and an infectious disease specialist. Of
      252 consecutive inpatients receiving suboptimal intravenous antibiotics
      identified by the clinical pharmacist, 127 were prospectively randomized to
      intervention and 125 to a control group. The groups were similar with regard to
      severity of illness, infection type, and time from admission to randomization.
      Physicians received timely, detailed reviews of relevant microbiologic and
      clinical data with recommendations of possible optimal antibiotic choices,
      dosages, and rationales. Median length of stay after randomization for control
      and intervention groups was 9.0 days and 5.7 days, respectively (3.3-day
      difference, p=0.0001). Fifteen (12.0%) and eight patients (6.3%), respectively,
      died, although the time-specific mortality risk was not significantly different
      when length of postrandomization follow-up and time to death were taken into
      account. Physician acceptance of suggestions was 89%. Median patient charges for
      radiology, laboratory, pharmacy, and room were reduced by $4404/intervention, and
      median hospital costs were reduced by $2642/intervention. A multidisciplinary
      antimicrobial therapy team can be a useful information source for physicians,
      improve outcomes in hospitalized patients receiving intravenous antimicrobials,
      and result in substantial cost savings.

PMID- 10600086
TI  - Pharmacokinetic interaction between ketoconazole and amprenavir after single
      doses in healthy men.
AB  - STUDY OBJECTIVE: To determine the effects of coadministration of amprenavir and
      ketoconazole on the pharmacokinetics of both drugs, and to assess the utility of
      the erythromycin breath test (ERMBT) to predict and explain these effects.
      DESIGN: Open-label, randomized, balanced, single-dose, three-period crossover
      study. SETTING: University research center. SUBJECTS: Twelve healthy men.
      INTERVENTION: Subjects received amprenavir 1200 mg, ketoconazole 400 mg, and
      amprenavir 1200 mg plus ketoconazole 400 mg. Each treatment was separated by 14
      days. MEASUREMENTS AND MAIN RESULTS: Serial plasma samples for amprenavir and
      ketoconazole concentrations were measured by high-performance liquid
      chromatography. Coadministration of the drugs increased amprenavir area under the
      curve extrapolated to infinity (AUCinfinity) by 31% and reduced its maximum
      concentration (Cmax) by 16%. Amprenavir increased the AUCinfinity of ketoconazole
      by 44% and increased the drug's half-life and Cmax by 23% and 19%, respectively.
      Both agents resulted in substantial inhibition of ERMBT. CONCLUSION:
      Coadministration of ketoconazole and amprenavir results in a statistically
      significant increase in AUC for both agents, but the changes are not likely to be
      clinically important.

PMID- 10600087
TI  - Influence of warfarin regimen type on clinical and monitoring outcomes in stable
      patients in an anticoagulation management services.
AB  - Options for dosing warfarin include same daily dosing, such as 7 mg/day, and
      alternate-day dosing, such as 5 mg Monday and Thursday, and 7.5 mg all other
      days. Some practitioners favor same daily dosing because it is simple, whereas
      others prefer alternate-day dosing because it requires a single tablet size.
      Computerized records of patients followed by an anticoagulation management
      service were reviewed retrospectively to identify those whose anticoagulation was
      stable with one of these two dosing methods. Clinical and monitoring outcomes
      were compared between groups. Rates of hemorrhagic and thromboembolic
      complications were similar in the two groups, as were monitoring outcomes,
      including clinic visits/year, warfarin dosage adjustments/year, and percentage of
      international normalized ratios within range. Patients receiving the same daily
      dose reported lower rates of confusion (0% vs 7%) and dosing errors (3.3% vs 14%)
      that those receiving alternate-day dosing, and expressed a stronger preference
      for their regimen (40% vs 1.5%). When selecting a regimen, consideration must be
      given to patient-specific risk of confusion and dosing errors, associated costs,
      practicality and precision of dosing adjustments, and patient preference.

PMID- 10600088
TI  - Comparison of five beta-lactam antibiotics against common nosocomial pathogens
      using the time above MIC at different creatinine clearances.
AB  - STUDY OBJECTIVE: To compare the time above the minimum inhibitory concentration
      (T>MIC) for five parenteral beta-lactam antibiotics against common nosocomial
      bacterial pathogens at different creatinine clearances (Clcr). INTERVENTIONS:
      Serum concentration-time profiles were simulated for cefepime, ceftazidime,
      piperacillin, piperacillin-tazobactam, and imipenem at Clcr ranging from 120-30
      ml/minute. The MIC data for 90% of organisms (MIC90) were collected for
      Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Citrobacter
      freundii, Enterobacter aerogenes, Enterobacter cloacae, Pseudomonas aeruginosa,
      and oxacillin-susceptible Staphylococcus aureus, and a weighted geometric mean
      MIC90 was calculated. The T>MIC was calculated as percentage of the dosing
      interval in which free concentrations exceeded the weighted geometric mean MIC90.
      A T>MIC of 70% or greater was considered desirable for all organisms except S.
      aureus (> or = 50%). MEASUREMENTS AND MAIN RESULTS: Cefepime 2 g every 12 hours
      (Clcr > or = 70 ml/min) and every 24 hours (Clcr < or = 60 ml/min) achieved
      desirable T>MIC for all Enterobacteriaceae and S. aureus at every Clcr. Imipenem
      0.5 g achieved desirable T>MIC for E. coli, K. pneumoniae, C. freundii, and S.
      aureus at every Clcr. However, imipenem T>MIC was less than 70% for the following
      regimens and organisms: S. marcescens 0.5 g every 6 hours (Clcr > or = 90
      ml/min), E. aerogenes 0.5 g every 6 hours (Clcr > or = 80 ml/min), E. cloacae 0.5
      g every 6 hours (Clcr > or = 100 ml/min), S. marcescens 0.5 g every 8 hours (Clcr
      60-70 ml/min), E. cloacae 0.5 g every 8 hours (Clcr 60-70 ml/min), and E.
      aerogenes 0.5 g every 8 hours (Clcr 50-70 ml/min). Ceftazidime 2 g every 8 hours
      (Clcr 60-100 ml/min) and every 12 hours (Clcr 40-50 ml/min) achieved desirable
      T>MIC for E. coli, K. pneumoniae, S. marcescens, and S. aureus only. At every
      dose and Clcr, piperacillintazobactam achieved desirable T>MIC for S. aureus but
      not for any Enterobacteriaceae at Clcr > 50 ml/minute. Piperacillin did not
      achieve desirable T>MIC for any organism, and none of the beta-lactams attained a
      T>MIC of 70% or above for P. aeruginosa at any Clcr. CONCLUSION: At every Clcr,
      cefepime achieved a desirable T>MIC for more nosocomial pathogens than any other
      beta-lactam evaluated. Based on pharmacodynamic data, cefepime is an appropriate
      empiric choice for treatment of nosocomial infections. However, when P.
      aeruginosa is a potential pathogen, empiric combination therapy should be
      considered.

PMID- 10600089
TI  - Vitamins for the management of cardiovascular disease: a simple solution to a
      complex problem?
AB  - Attention is focusing on the relationship between homocysteine and cardiovascular
      disease and the role of vitamins in the management of this prevalent ailment.
      Epidemiologic studies have shown that a relationship between elevated
      homocysteine concentrations and cardiovascular disease may exist; however, a
      cause-and-effect relationship has not been proven. The B vitamins are key
      components of homocysteine metabolism, and the trend is toward their being
      increasingly prescribed for cardiovascular disease. Prescribing of antioxidant
      vitamins, vitamin E in particular, has increased as well. Vitamin E may decrease
      the risk of nonfatal myocardial infarction in patients with coronary artery
      disease, but its benefit in preventing fatal myocardial infarction has not been
      shown. Vitamin supplements are not warranted in all patients with cardiovascular
      disease but may have a place in therapy for selected patients.

PMID- 10600090
TI  - Vitamin K to reverse excessive anticoagulation: a review of the literature.
AB  - We conducted an extensive literature review to evaluate the appropriate use,
      route, and dose of vitamin K to reverse excessive anticoagulation. Issues such as
      sample size, study design, different patient populations, and various study end
      points confounded results. Of 18 studies published, 8 enrolled 229 patients to
      evaluate parenteral vitamin K administration. Nine studies with 288 patients
      evaluated oral administration, and only 2 retrospective studies (280 patients)
      compared routes of administration. Reductions in international normalized ratios
      at 24 hours ranged from 21-42%, 47-86%, 25-67%, and 40-75% for temporary warfarin
      discontinuation alone, and intravenous, subcutaneous, and oral routes of vitamin
      K administration, respectively. Methodologically weak studies and indeterminate
      results plague interpretation of the literature on vitamin K. In general, results
      of this review support current guidelines for reversing excessive warfarin
      anticoagulation. However, it is important to realize that the quality of
      literature on which these recommendations are based is poor and that optimal dose
      and route of vitamin K administration remain unclear. Large, well-designed,
      randomized, controlled trials are necessary to define optimum management
      strategies for excessively anticoagulated patients.

PMID- 10600091
TI  - A pilot study of estrogen's effects on bronchial myocyte adhesion molecule
      expression.
AB  - We examined the effects of estrogen on tumor necrosis factor alpha (TNF-alpha)
      induced expression of intracellular adhesion molecule (ICAM-1) and vascular
      adhesion molecule (VCAM-1) in cultured human bronchial smooth muscle cells
      (BSMC). Experiments were performed in triplicate in T-75 tissue culture flasks
      containing normal human BSMC. Four experiments were carried out: untreated BSMC
      cells (control); TNF-alpha 1000 U/ml stimulation of BSMC; forskolin 5 microM
      before TNF-alpha stimulation of BSMC; and estradiol 30 microM before TNF-alpha
      stimulation of BSMC. Cyclic adenosine monophosphate was measured by a
      commercially available radioimmunoassay kit. Cell expression of ICAM-1 and VCAM-1
      was quantified by flow cytometry Incubation of cells with TNF-alpha 1000 U/ml for
      24 hours elicited a 27-fold increase in basal expression of ICAM-1 and a 2-fold
      increase in VCAM-1 (p>0.05). Incubation of BSMC with forskolin 5 microM, for 1
      hour before TNF-alpha, decreased TNF-alpha-induced expression of ICAM-1 by 62%
      and VCAM-1 slightly by 17%. The BSMC incubated with estradiol 30 microM, 1 hour
      before TNF-alpha, decreased TNF-alpha-induced expression of ICAM-1 by 21%; VCAM-1
      remained unchanged (p>0.05). We found a trend toward inhibition of TNF-alpha
      stimulated ICAM-1 expression in cultured BSMC with pretreatment with estradiol.
      However, due to large variability within the cell culture model, statistical
      significance was not reached.

PMID- 10600092
TI  - Effect of recombinant human growth hormone and insulin-like growth factor-1
      administration on IGF-1 and IGF-binding protein-3 levels in brain injury.
AB  - STUDY OBJECTIVE: To assess the effect of recombinant human growth hormone (rhGH)
      on the insulin-like growth factor-1 (IGF-1) plasma concentration versus time
      profile during continuous infusion of recombinant human (rh)IGF-1 to patients
      with traumatic brain injury (TBI). SETTING: University of Kentucky Chandler
      Medical Center. PATIENTS: Twenty-three patients with TBI (aged 18-59 yrs) with
      Glascow Coma Scale scores of 4-10. INTERVENTION: Patients were randomized to
      receive rhIGF-1 0.01 mg/kg/hour and daily subcutaneous doses of rhGH 0.05
      mg/kg/day or saline for 14 days. MEASUREMENTS AND MAIN RESULTS: Plasma
      concentrations of IGF-1 and IGF-binding protein (BP)-3 were quantified by
      radioimmunoassay. Patients receiving rhIGF-1/rhGH reached a peak IGF-1
      concentration (1199.3+/-84.0 microg/L) at 72 hours and maintained it throughout
      the study. Levels of IGF-1 in the control group did not change significantly
      above baseline throughout the study. Concentrations of IGFBP-3 were significantly
      higher after 48 hours in the treated group (5.1+/-0.4 mg/L) than in controls
      (2.9+/-0.5 mg/L) and continued until the end of the study (p<0.05). CONCLUSION:
      Infusion of rhIGF-1 in conjunction with rhGH effectively achieved and maintained
      supraphysiologic IGF-1 plasma concentrations throughout the dosing period in
      patients with TBI. It appears that rhGH alters the IGF-1 plasma concentration
      versus time profile during continuous administration. Although speculative,
      changes in protein binding of IGF-1 are the most likely mechanism.

PMID- 10600093
TI  - Treatment of Parkinson's disease with ropinirole after pergolide-induced
      retroperitoneal fibrosis.
AB  - Pergolide is a dopaminergic agonist used to treat Parkinson's disease but is
      associated with the development of retroperitoneal fibrosis (RPF). Newer nonergot
      agents (pramipexole, ropinirole) may not carry this same risk. A patient with a
      history of pergolide-induced RPF was treated successfully with ropinirole for 1
      year without complications.

PMID- 10600094
TI  - Potential interaction between itraconazole and clarithromycin.
AB  - Three patients negative for human immunodeficiency virus infection were admitted
      for pulmonary Mycobacterium avium complex (MAC) and aspergillosis infections.
      They were treated with different drug combinations, but all regimens included
      clarithromycin for MAC and itraconazole for aspergillosis. All patients
      experienced an increase in clarithromycin concentrations and clarithromycin: 14
      OH-clarithromycin ratio compared with expected range values. They had no clinical
      side effects. The time course suggested a possible interaction between
      clarithromycin and itraconazole, presumably through itraconazole's effects on
      cytochrome P450 3A4 activity. A bidirectional interaction cannot be ruled out.
      The data suggest that, when necessary, these two drugs can be administered
      together safely. Further investigation is necessary to determine the extent and
      clinical consequences of coadministration in humans.

PMID- 10600095
TI  - Warfarin-5-FU interaction--a consecutive case series.
AB  - Five patients from a single institution received concomitant warfarin and 5
      fluorouracil (5-FU) during a 3-year period. The mean weekly warfarin dose before
      starting chemotherapy was 40.66 mg and during chemotherapy it was 24 mg
      (p=0.0026). All patients required a warfarin dosage reduction (range 18-74%, mean
      44%). Two patients were hospitalized, one with a major retroperitoneal bleed, the
      other for fresh-frozen plasma administration and observation. Maximum
      international normalized ratios (INRs) ranged from 3.66-23.7. This series
      confirms a common, clinically significant interaction between warfarin and 5-FU.
      An interaction between capecitabine, the orally available prodrug of 5-FU, and
      warfarin also has been reported. We recommend weekly monitoring of prothrombin
      time and INR for all patients receiving concomitant warfarin and 5-FU or
      capecitabine.

PMID- 10600096
TI  - Suspected ifosfamide-induced neurotoxicity.
AB  - Ifosfamide is an antineoplastic agent that requires hepatic activation to the
      cytotoxic active metabolite ifosforamide mustard. During metabolism, the
      byproduct, chloroacetaldehyde, which is structurally similar to both chloral
      hydrate and acetaldehyde, is produced. Secondary to its ability to cross the
      blood-brain barrier, this metabolite may be responsible for the neurotoxicity
      observed with ifosfamide. Any case of suspected ifosfamide-induced neurotoxicity,
      together with a decision to treat, must be determined on an individual patient
      basis. The differential diagnosis should include infection, laboratory
      abnormalities, and concomitant drugs. At this time, literature to support
      treatment modalities such as intravenous albumin and methylene blue is minimal.

PMID- 10600097
TI  - Trimethoprim-sulfamethoxazole-induced tremor in an immunocompetent patients.
AB  - Trimethoprim-sulfamethoxazole (TMP-SMX) is a widely administered antibiotic that
      is well tolerated by most patients. Hypersensitivity reactions and
      gastrointestinal intolerance are the most common adverse events associated with
      it. Central nervous system adverse effects such as tremors are less common and
      occur primarily in patients with acquired immune deficiency syndrome. A 29-year
      old immunocompetent man developed a tremor while taking TMP-SMX. The tremor
      resolved within 2 days after the drug was discontinued.

PMID- 10600098
TI  - Hydroxyurea in two pregnant women with sickle cell anemia.
AB  - Hydroxyurea is classified as an S-phase antineoplastic agent (pregnancy category
      D). Two women became pregnant while taking hydroxyurea for sickle cell anemia and
      delivered live infants with no congenital anomalies. Although teratogenic effects
      of hydroxyurea were reported in animal studies, several case reports suggest the
      agent may have minimal teratogenic effects on the developing fetus. Fourteen
      cases of hydroxyurea therapy in pregnant patients with acute or chronic
      myelogenous leukemia, primary thrombocythemia, or sickle cell disease are
      reported in the literature. Three pregnancies were terminated by elective
      abortion; one woman developed eclampsia and delivered a phenotypically normal
      stillborn infant. All other patients delivered live, healthy infants without
      congenital anomalies. Further studies with larger numbers of patients receiving
      hydroxyurea during pregnancy, with longer follow-up of exposed children and more
      careful assessment of fetotoxic effects, are required before the agent can be
      promoted as safe in pregnancy.

PMID- 10600099
TI  - Amiodarone-induced pulmonary toxicity.
AB  - Amiodarone-induced pulmonary toxicity (AIPT) is one of the most serious adverse
      effects of amiodarone therapy and can be fatal. Therefore, vigilant monitoring is
      advised. Baseline chest radiograph and pulmonary function tests and follow-up
      chest films at 3-month intervals are advocated. However, since abnormalities on
      these two examinations do not always precede symptoms, patient self-reports of
      respiratory symptoms appear to be the best method for early detection of AIPT.

PMID- 10600100
TI  - Crystalline degradation product cross-reactivity with vancomycin fluorescence
      polarization immunoassays.

PMID- 10600101
TI  - Potentiometric analysis of the flavin cofactors of neuronal nitric oxide
      synthase.
AB  - Midpoint reduction potentials for the flavin cofactors in the reductase domain of
      rat neuronal nitric oxide synthase (nNOS) in calmodulin (CaM)-free and -bound
      forms have been determined by direct anaerobic titration. In the CaM-free form,
      the FMN potentials are -49 +/- 5 mV (oxidized/semiquinone) -274 +/- 5 mV
      (semiquinone/reduced). The corresponding FAD potentials are -232 +/- 7, and -280
      +/- 6 mV. The data indicate that each flavin can exist as a blue (neutral)
      semiquinone. The accumulation of blue semiquinone on the FMN is considerably
      higher than seen on the FAD due to the much larger separation (225 mV) of its two
      potentials (cf. 48 mV for FAD). For the CaM-bound form of the protein, the
      midpoint potentials are essentially identical: there is a small alteration in the
      FMN oxidized/semiquinone potential (-30 +/- 4 mV); the other three potentials are
      unaffected. The heme midpoint potentials for nNOS [-239 mV, L-Arg-free; -220 mV,
      L-Arg-bound; Presta, A., Weber-Main, A. M., Stankovich, M. T., and Stuehr, D. J.
      (1998) J. Am. Chem. Soc. 120, 9460-9465] are poised such that electron transfer
      from flavin domain is thermodynamically feasible. Clearly, CaM binding is
      necessary in eliciting conformational changes that enhance flavin to flavin and
      flavin to heme electron transfers rather than causing a change in the driving
      force.

PMID- 10600102
TI  - Engineering a thermostable protein via optimization of charge-charge interactions
      on the protein surface.
AB  - A simple theoretical model for increasing the protein stability by adequately
      redesigning the distribution of charged residues on the surface of the native
      protein was tested experimentally. Using the molecule of ubiquitin as a model
      system, we predicted possible amino acid substitutions on the surface of this
      protein which would lead to an increase in its stability. Experimental validation
      for this prediction was achieved by measuring the stabilities of single-site
      substituted ubiquitin variants using urea-induced unfolding monitored by far-UV
      CD spectroscopy. We show that the generated variants of ubiquitin are indeed more
      stable than the wild-type protein, in qualitative agreement with the theoretical
      prediction. As a positive control, theoretical predictions for destabilizing
      amino acid substitutions on the surface of the ubiquitin molecule were considered
      as well. These predictions were also tested experimentally using correspondingly
      designed variants of ubiquitin. We found that these variants are less stable than
      the wild-type protein, again in agreement with the theoretical prediction. These
      observations provide guidelines for rational design of more stable proteins and
      suggest a possible mechanism of structural stability of proteins from
      thermophilic organisms.

PMID- 10600103
TI  - Hydrodynamic radii of native and denatured proteins measured by pulse field
      gradient NMR techniques.
AB  - Pulse field gradient NMR methods have been used to determine the effective
      hydrodynamic radii of a range of native and nonnative protein conformations. From
      these experimental data, empirical relationships between the measured
      hydrodynamic radius (R(h)) and the number of residues in the polypeptide chain
      (N) have been established; for native folded proteins R(h) = 4.75N (0.29)A and
      for highly denatured states R(h) = 2.21N (0.57)A. Predictions from these
      equations agree well with experimental data from dynamic light scattering and
      small-angle X-ray or neutron scattering studies reported in the literature for
      proteins ranging in size from 58 to 760 amino acid residues. The predicted values
      of the hydrodynamic radii provide a framework that can be used to analyze the
      conformational properties of a range of nonnative states of proteins. Several
      examples are given here to illustrate this approach including data for partially
      structured molten globule states and for proteins that are unfolded but
      biologically active under physiological conditions. These reveal evidence for
      significant coupling between local and global features of the conformational
      ensembles adopted in such states. In particular, the effective dimensions of the
      polypeptide chain are found to depend significantly on the level of persistence
      of regions of secondary structure or features such as hydrophobic clusters within
      a conformational ensemble.

PMID- 10600104
TI  - Comparison of local and global stability of an analogue of a disulfide-folding
      intermediate with those of the wild-type protein in bovine pancreatic
      ribonuclease A: identification of specific regions of stable structure along the
      oxidative folding pathway.
AB  - We have identified specific regions of the polypeptide chain of bovine pancreatic
      ribonuclease A (RNase A) that are critical for stabilizing the oxidative folding
      intermediate des-[40-95] (with three native disulfide bonds but lacking the
      fourth native Cys40-Cys95 disulfide bond) in an ensemble of largely disordered
      three-disulfide precursors (3S if des-[40-95]). A stable analogue of des-[40-95],
      viz., [C40A, C95A] RNase A, which contains three out of four native disulfide
      pairings, was previously found to have a three-dimensional structure very similar
      to that of the wild-type protein. However, it is determined here from GdnHCl
      denaturation experiments to have significantly reduced global stability, i.e., =
      4.5 kcal /mol at 20 degrees C and pH 4.6. The local stability of [C40A, C95A]
      RNase A was also examined using site-specific amide (2)H/(1)H exchange
      measurements at pD 5.0 to determine the individual unfolding free energy of
      specific residues under both strongly native (12 degrees C) and more
      destabilizing (20 degrees C) conditions. Comparison of the relative stabilities
      at specific amide sites of [C40A, C95A] RNase A at both temperatures with the
      corresponding values for the wild-type protein at 35 degrees C corroborates
      previous experimental evidence that unidentified intramolecular contacts in the
      vicinity of the preferentially formed native one-disulfide (C65-C72) loop are
      crucial for stabilizing early folding intermediates, leading to des-[40-95].
      Moreover, values of for residues at or near the third alpha-helix, and in part of
      the second beta-sheet of [C40A, C95A] RNase A, indicate that these two regions of
      regular backbone structure contribute to stabilizing the global chain fold of the
      des-[40-95] disulfide-folding intermediate in the wild-type protein. More
      significantly, we have identified numerous specific residues in the first alpha
      helix and the first beta-sheet of the protein that are stabilized in the final
      step of the major oxidative regeneration pathway of RNase A (des-[40-95] --> N).

PMID- 10600105
TI  - Crystal structure of d(GGCCAATTGG) complexed with DAPI reveals novel binding
      mode.
AB  - The single-crystal X-ray structure of the complex between the minor groove binder
      4',6-diamidino-2-phenylindole (DAPI) and d(GGCCAATTGG) reveals a novel way of off
      centered binding, with an unique hydrogen bond between the minor groove binder
      and a CG base pair. Application of crystal engineering and cryocooling techniques
      helped to extend the resolution to 1.9 A, resulting in an unambiguous
      determination of drug conformation and orientation. The structure was refined to
      completion using SHELXL-93, resulting in a residual factor R of 18. 0% for 3562
      reflections with F(o) > 4sigma(F(o)) including 81 water molecules. As the bulky
      NH(2)-group on guanine is believed to prevent drug binding in the minor groove,
      the nature and stability of the CG-DAPI contact was further addressed in full
      detail using ab initio quantum chemical methods. The amino groups involved in the
      guanine-drug interaction are substantially nonplanar, resulting in an energy gain
      of about 5 kcal/mol. The combined structural and theoretical data suggest that
      the guanine NH(2)-group does not destabilize the drug binding to an extent that
      it prevents complexation.

PMID- 10600106
TI  - Structure and recognition of sheared tandem G x A base pairs associated with
      human centromere DNA sequence at atomic resolution.
AB  - G x A mismatched base pairs are frequently found in nucleic acids. Human
      centromere DNA sequences contain unusual repeating motifs, e.g. , (GAATG)n x
      (CATTC)n found in the human chromosome. The purine-rich strand of this repeating
      pentamer sequence forms duplex and hairpin structures with unusual stability. The
      high stability of these structures is contributed by the "sheared" G x A base
      pairs which present a novel recognition surface for ligands and proteins. We have
      solved the crystal structure, by the multiple-wavelength anomalous diffraction
      (MAD) method of d(CCGAATGAGG) in which the centromere core sequence motif GAATG
      is embedded. Three crystal forms were refined to near-atomic resolution. The
      structures reveal the detailed conformation of tandem G x A base pairs whose
      unique hydrogen-bonding surface has interesting interactions with bases, hydrated
      magnesium ions, cobalt(III)hexaammine, spermine, and water molecules. The results
      are relevant in understanding the structure associated with human centromere
      sequence in particular and G x A base pairs in nucleic acids (including RNA, like
      ribozyme) in general.

PMID- 10600107
TI  - Guanine-rich telomeric sequences stimulate DNA polymerase activity in vitro.
AB  - Guanine-rich oligonucleotides and short telomeric DNA sequences can self
      associate into G-quartet stabilized complexes. We discovered that this self
      association can occur in sequencing reactions and that higher-order structures
      stimulate DNA polymerase to synthesize extended DNA strands. Base analogues were
      used to identify Hoogsteen base pairings as stabilizing forces in these
      stimulatory DNA structures. Scanning force microscopy confirmed that quartet-DNA
      was formed from these oligomers and that these extended, four-stranded structures
      could be bound by DNA polymerase. Since guanine quartet-stabilized structures are
      proposed to exist in vivo, such structures may stimulate DNA polymerization in
      vivo.

PMID- 10600109
TI  - Hydrogen-exchange stabilities of RNase T1 and variants with buried and solvent
      exposed Ala --> Gly mutations in the helix.
AB  - Hydrogen-exchange rates were measured for RNase T1 and three variants with Ala -
      > Gly substitutions at a solvent-exposed (residue 21) and a buried (residue 23)
      position in the helix: A21G, G23A, and A21G + G23A. These results were used to
      measure the stabilities of the proteins. The hydrogen-exchange stabilities
      (DeltaG(HX)) for the most stable residues in each variant agree with the
      equilibrium conformational stability measured by urea denaturation (DeltaG(U)),
      if the effects of D(2)O and proline isomerization are included [Huyghues
      Despointes, B. M. P., Scholtz, J. M., and Pace, C. N. (1999) Nat. Struct. Biol.
      6, 210-212]. These residues also show similar changes in DeltaG(HX) upon Ala -->
      Gly mutations (DeltaDeltaG(HX)) as compared to equilibrium measurements
      (DeltaDeltaG(U)), indicating that the most stable residues are exchanging from
      the globally unfolded ensemble. Alanine is stabilizing compared to glycine by 1
      kcal/mol at a solvent-exposed site 21 as seen by other methods for the RNase T1
      protein and peptide helix [Myers, J. K., Pace, C. N., and Scholtz, J. M. (1997)
      Proc. Natl. Acad. Sci. U.S.A. 94, 3833-2837], while it is destabilizing at the
      buried site 23 by the same amount. For the A21G variant, only local NMR chemical
      shift perturbations are observed compared to RNase T1. For the G23A variant,
      large chemical shift changes are seen throughout the sequence, although X-ray
      crystal structures of the variant and RNase T1 are nearly superimposable. Ala -->
      Gly mutations in the helix of RNase T1 at both helical positions alter the native
      state hydrogen-exchange stabilities of residues throughout the sequence.

PMID- 10600108
TI  - Crystal structure of wild-type tryptophan synthase complexed with the natural
      substrate indole-3-glycerol phosphate.
AB  - We used freeze trapping to stabilize the Michaelis complex of wild-type
      tryptophan synthase and the alpha-subunit substrate indole-3-glycerol phosphate
      (IGP) and determined its structure to 1. 8 A resolution. In addition, we
      determined the 1.4 A resolution structure of the complex with indole-3-propanole
      phosphate (IPP), a noncleavable IGP analogue. The interaction of the 3'-hydroxyl
      of IGP with the catalytic alphaGlu49 leads to a twisting of the propane chain and
      to a repositioning of the indole ring compared to IPP. Concomitantly, the
      catalytic alphaAsp60 rotates resulting in a translocation of the COMM domain
      [betaGly102-betaGly189, for definition see Schneider et al. (1998) Biochemistry
      37, 5394-5406] in a direction opposite to the one in the IPP complex. This
      results in loss of the allosteric sodium ion bound at the beta-subunit and an
      opening of the beta-active site, thereby making the cofactor pyridoxal 5'
      phosphate (PLP) accessible to solvent and thus serine binding. These findings
      form the structural basis for the information transfer from the alpha- to the
      beta-subunit and may explain the affinity increase of the beta-active site for
      serine upon IGP binding.

PMID- 10600110
TI  - Determination of Fe-ligand bond lengths and the Fe-N-O bond angles in soybean
      ferrous and ferric nitrosylleghemoglobin a using multiple-scattering XAFS
      analyses.
AB  - The NO adducts of leghemoglobin (Lb) are implicated in biological processes, but
      only the adduct with ferrous Lb (Lb(II)NO) has been characterized previously. We
      report the first characterization of ferric nitrosylleghemoglobin (Lb(III)NO) and
      XAS experiments performed on frozen aqueous solutions of Lb(II)NO and Lb(III)NO
      at 10 K. The XANES and electronic spectra of the NO adducts are similar in shape
      and energies to the myoglobin (Mb) analogues. The environment of the Fe atom has
      been refined using multiple-scattering (MS) analyses of the XAFS data. For
      Lb(II)NO, the MS analysis resulted in an averaged Fe-N(p)(pyrrole) distance of
      2.02 A, an Fe-N(epsilon)(imidazole) distance of 1.98 A, an Fe-N(NO) distance of
      1.77 A, and an Fe-N-O angle of 147 degrees. The Fe-N(NO) distance and Fe-N-O
      angle obtained from the analysis of Lb(II)NO are in good agreement with those
      determined crystallographically for [Fe(TPP)(NO)] (TPP, tetraphenylporphyrinato),
      with and without 1-methylimidazole (1-MeIm) as the sixth ligand, and the MS XAFS
      structures reported previously for the myoglobin (Mb(II)NO) analogue and
      [Fe(TPP)(NO)]. The MS analysis of Lb(III)NO yielded an average Fe-N(p) distance
      of 2.00 A, an Fe-N(epsilon) distance of 1.89 A, an Fe-N(NO) distance of 1.68 A,
      and an Fe-N-O angle of 173 degrees. These bond lengths and angles are consistent
      with those determined previously for the myoglobin analogue (Mb(III)NO) and the
      crystal structures of the model complexes, [Fe(III)(TPP)(NO)(OH(2))](+) and
      [Fe(OEP)(NO)](+) (OEP, octaethylporphyrinato). The final XAFS R values were 16.1
      and 18.2% for Lb(II)NO and Lb(III)NO, respectively.

PMID- 10600111
TI  - Preference of Cd(II) and Zn(II) for the two metal sites in Bacillus cereus beta
      lactamase II: A perturbed angular correlation of gamma-rays spectroscopic study.
AB  - Cd-substituted forms of the Bacillus cereus metallo-beta-lactamases (BCII) were
      studied by perturbed angular correlation of gamma-rays (PAC) spectroscopy. At
      very low [Cd]:[apo-beta-lactamase] ratios, two nuclear quadrupole interactions
      (NQI) were detected. For [Cd]:[apo-beta-lactamase] ratios between 0.8 and 3.0,
      two new NQIs appear, and the spectra show that up to 2 cadmium ions can be bound
      per molecule of apoenzyme. These results show the existence of two interacting Cd
      binding sites in BCII. The relative populations of the two NQIs found at low
      [Cd]:[apo-beta-lactamase] ratios yielded a 1:3 ratio for the microscopic
      dissociation constants of the two different metal sites (when only one cadmium
      ion is bound). X-ray diffraction data at pH 7.5 demonstrate that also for Zn(II)
      two binding sites exist, which may be bridged by a solvent molecule. The measured
      NQIs could be assigned to the site with three histidines as metal ligands (three
      His site) and to the site with histidine, cysteine, and aspartic acid as metal
      ligands (Cys site), respectively, by PAC measurements on the Cys168Ala mutant
      enzyme. This assignment shows that cadmium ions preferentially bind to the Cys
      site. This is in contrast to the preference of Zn(II) in the hybrid Zn(II)Cd(II)
      enzyme, where an analysis of the corresponding PAC spectrum showed that Cd(II)
      occupied the Cys site, whereby Zn(II) occupied the site with three histidines.
      The difference between Zn(II) and Cd(II) in affinity for the two sites is
      combined with the kinetics of hydrolysis of nitrocefin for different metal ion
      substitutions (Zn(2)E, ZnE, Cd(2)E, CdE, and ZnCdE) to study the function of the
      two metal ion binding sites.

PMID- 10600112
TI  - Reduction of furin-nicked Pseudomonas exotoxin A: an unfolding story.
AB  - Upon entering mammalian cells, Pseudomonas exotoxin A (PE) is proteolytically
      processed by furin to produce an N-terminal fragment of 28 kDa and a C-terminal
      fragment of 37 kDa. Cleavage is followed by the reduction of a key disulfide bond
      (cysteines 265-287). This combination of proteolysis and reduction releases the
      37 kDa C-terminal fragment, which then translocates to the cytosol where it ADP
      ribosylates elongation factor 2 and inhibits protein synthesis. To investigate
      toxin reduction, furin-nicked PE or a hypercleavable mutant, PEW281A, was
      subjected to various treatments and then analyzed for fragment production.
      Reduction was evident only when unfolding conditions and a reducing agent were
      applied. Thermal unfolding of PE, as evidenced by changes in alpha-helical
      content and increased sensitivity to trypsin, rendered nicked toxin susceptible
      to protein disulfide isomerase- (PDI-) mediated reduction. When subcellular
      fractions from toxin-sensitive cells were incubated with nicked PE, toxin
      unfolding and reducing activities were present in the membrane fraction but not
      the soluble fraction. These data indicate that PE reduction is a two-step
      process: unfolding that allows access to the Cys265-287 disulfide bond, followed
      by reduction of the sulfur-sulfur bond by PDI or a PDI-like enzyme. With regard
      to cellular processing, we propose that the toxin's three-dimensional structure
      retains a "closed" conformation that restricts solvent access to the Cys265-287
      disulfide bond until after a cell-mediated unfolding event.

PMID- 10600113
TI  - Effect of staphylococcal delta-lysin on the thermotropic phase behavior and
      vesicle morphology of dimyristoylphosphatidylcholine lipid bilayer model
      membranes. Differential scanning calorimetric, 31P nuclear magnetic resonance and
      Fourier transform infrared spectroscopic, and X-ray diffraction studies.
AB  - We investigated the effects of various concentrations of staphylococcal delta
      lysin on the thermotropic phase behavior of large multilamellar
      dimyristoylphosphatidylcholine (DMPC) vesicles by differential scanning
      calorimetry (DSC), 31P nuclear magnetic resonance (NMR) and Fourier transform
      infrared (FTIR) spectroscopy, and X-ray diffraction. The DSC studies revealed
      that at all concentrations, the addition of delta-lysin progressively decreases
      the enthalpy of the pretransition of DMPC bilayers without significantly
      affecting its temperature or cooperativity. Similarly, the addition of smaller
      quantities of peptide has little effect on the temperature of the main phase
      transition of DMPC bilayers but does reduce the cooperativity and enthalpy of
      this transition somewhat. However, at higher peptide concentrations, a second
      phase transition with a slightly increased temperature and a markedly reduced
      cooperativity and enthalpy is also induced, and this latter phase transition
      resolves itself into two components at the highest peptide concentrations that
      are tested. Moreover, our 31P NMR spectroscopic studies reveal that at relatively
      low delta-lysin concentrations, essentially all of the phospholipid molecules
      produce spectra characteristic of the lamellar phase, whereas at the higher
      peptide concentrations, an increasing proportion exhibit an isotropic signal.
      Also, at the highest delta-lysin concentrations that are studied, the isotropic
      component of the 31P NMR spectrum also resolves itself into two components. At
      the highest peptide concentration that was tested, we are also able to effect a
      macroscopic separation of our sample into two fractions by centrifugation, a
      pellet containing relatively smaller amounts of delta-lysin and a supernatant
      containing larger amounts of peptide relative to the amount of lipid present. We
      are also able to show that the more cooperative phase transition detected
      calorimetrically, and the lamellar phase 31P NMR signal, arise from the pelleted
      material, while the less cooperative phase transition and the isotropic 31P NMR
      signal arise from the supernatant. In addition, we demonstrate by X-ray
      diffraction that the pelleted material corresponds to delta-lysin-containing
      large multilamellar vesicles and the supernatant to a mixture of delta-lysin
      containing small unilamellar vesicles and discoidal particles. We also show by
      FTIR spectroscopy that delta-lysin exists predominantly in the alpha-helical
      conformation in aqueous solution or when interacting with DMPC, and that a large
      fraction of the peptide bonds undergo H-D exchange in D(2)O. However, upon
      interaction with DMPC, the fraction of exchangeable amide protons decreases. We
      also demonstrate by this technique that both of the phase transitions detected by
      DSC correspond to phospholipid hydrocarbon chain-melting phase transitions.
      Finally, we show by several techniques that the absolute concentrations of delta
      lysin and the thermal history, as well as the lipid:peptide ratio, can affect the
      thermotropic phase behavior and morphology of peptide-lipid aggregates.

PMID- 10600114
TI  - Mechanism of inhibition of porcine leukocyte 12-lipoxygenase by the isoform
      specific inhibitor 4-(2-oxapentadeca-4-yne)phenylpropanoic acid.
AB  - The mechanism of inhibition of porcine leukocyte 12-lipoxygenase by 4-(2
      oxapentadeca-4-yne)phenylpropanoic acid (OPP) was investigated. This compound is
      selective for the leukocyte form of the 12-lipoxygenase and inhibits the purified
      recombinant enzyme with an IC(50) value of approximately 2 microM. OPP induced a
      concentration-dependent lag phase in the oxygenation of arachidonic acid and
      decreased the maximal rate of reaction. Addition of the fatty acid hydroperoxide
      13(S)-hydroperoxyoctadecadienoic acid (13-HPODE) to the reaction greatly reduced
      the OPP-induced lag. Lineweaver-Burk analysis of the effect of OPP on 12
      lipoxygenase kinetics with arachidonic acid indicated that it was a mixed-type
      inhibitor. OPP was not metabolized by 12-lipoxygenase as evidenced by its
      quantitative recovery from incubations with stoichiometric amounts of enzyme and
      13-HPODE or arachidonic acid. OPP inhibited the pseudoperoxidase activity of the
      enzyme with 13-HPODE and the reducing agent, BWA137C. Lineweaver-Burk analysis of
      the effect of OPP on pseudoperoxidase kinetics suggested that OPP was competitive
      with 13-HPODE. Single-turnover experiments indicated that OPP inhibited the
      reduction of 13-HPODE by a stoichiometric amount of ferrous 12-lipoxygenase.
      Addition of 13-HPODE shortened the OPP-induced lag phase but did not affect the
      maximal rate of enzyme activity. In addition, OPP had no effect on total product
      formation in either the presence or the absence of 5 microM 13-HPODE when the
      reaction was allowed to go to completion. All of these observations are
      consistent with a model for inhibition of 12-lipoxygenase activity in which OPP
      slows the oxidation of the inactive ferrous enzyme to the active ferric enzyme
      and competes with arachidonic acid for the ferric enzyme.

PMID- 10600115
TI  - Purification of porcine brain protein phosphatase 2A leucine carboxyl
      methyltransferase and cloning of the human homologue.
AB  - The carboxyl methyltransferase, which is claimed to exclusively methylate the
      carboxyl group of the C-terminal leucine residue of the catalytic subunit of
      protein phosphatase 2A (Leu(309)), was purified from porcine brain. On the basis
      of tryptic peptides, the cDNA encoding the human homologue was cloned. The cDNA
      of this gene encodes for a protein of 334 amino acids with a calculated M(r) of
      38 305 and a predicted pI of 5.72. Database screening reveals the presence of
      this protein in diverse phyla. Sequence analysis shows that the novel
      methyltransferase is distinct from other known protein methyltransferases,
      sharing only sequence motifs supposedly involved in the binding of
      adenosylmethionine. The recombinant protein expressed in bacteria is soluble and
      the biophysical, catalytic, and immunological properties are indistinguishable
      from the native enzyme. The methylation of PP2A by the recombinant protein is
      restricted to Leu(309) of PP2A(C). No direct effects on phosphatase activity
      changes were observed upon methylation of the dimeric or trimeric forms of PP2A.

PMID- 10600116
TI  - Phosphate ion partially relieves the cooperativity of effector binding in D-3
      phosphoglycerate dehydrogenase without altering the cooperativity of inhibition.
AB  - The binding of L-serine to phosphoglycerate dehydrogenase from E. coli displays
      elements of both positive and negative cooperativity. In addition, the inhibition
      of enzymatic activity by L-serine is also cooperative with Hill coefficients
      greater than 1. However, phosphate buffer significantly reduces the cooperative
      effects in serine binding without affecting the cooperativity of inhibition of
      activity. The maximal degree of inhibition and fluorescence quenching in Tris
      buffer occurs when an average of two serine binding sites out of four are
      occupied. This value increases to three out of the four sites at maximal levels
      of inhibition and quenching in phosphate buffer. The increase from two to three
      sites appears to be due to the ability of phosphate to reduce the site to site
      cooperative effects and render each ligand binding site less dependent on each
      other. The correlation between the level of inhibition and the fractional site
      occupancy indicates that in Tris buffer, one serine is bound to each interface at
      maximal effect. In the presence of phosphate, the order of binding appears to
      change so that both sites at one interface fill before the first site at the
      opposite interface is occupied. In each case, there is a good correlation between
      serine binding, conformational change at the regulatory site interfaces, and
      inhibition of enzyme activity. The observation that phosphate does not appear to
      have a similar effect on the cooperativity of inhibition of enzymatic activity
      suggests that there are two distinct cooperative pathways at work: one path
      between the four serine binding sites, and one path between the serine binding
      sites and the active sites.

PMID- 10600117
TI  - Human apurinic/apyrimidinic endonuclease is processive.
AB  - Apurinic/apyrimidinic endonuclease (AP endo) is believed to play a critical role
      in repair of oxidative damage of DNA and is proposed to initiate repair of most
      abasic sites in the base excision repair pathway. AP endo makes a single nick 5'
      to an abasic site in double-stranded DNA. In this study, we investigated whether
      AP endo locates an abasic site through a processive or a distributive mechanism.
      We used a linear multi-abasic site substrate (concatemer), synthesized by
      ligating together identical 25-nucleotide monomeric units (25-mers). We first
      determined that the 25-mer monomer from which the concatemers were prepared was
      nicked by AP endo in a fashion similar to that of the previously published 49-mer
      substrate with a different sequence. Steady state parameters K(m) and k(cat) and
      single-turnover parameters for substrate binding were comparable to previously
      published values. Using the multi-abasic site concatemer, we demonstrated that AP
      endo was capable of cleaving approximately seven to eight abasic sites, traveling
      at least 200 nucleotides, before dissociating from its substrate. Thus, AP endo,
      like uracil DNA glycosylase, behaves in a quasi processive fashion. Processivity
      could be separated from catalysis, since processivity was maximal at 25 mM NaCl,
      while the rate of cleavage was maximal at 125 mM salt. In short, nicking activity
      was maximized close to physiological salt molarities while processivity was
      midrange at physiological salt concentrations. The latter is likely to be subject
      to tight regulation by small changes in ionic strength.

PMID- 10600118
TI  - IscS is a sulfurtransferase for the in vitro biosynthesis of 4-thiouridine in
      Escherichia coli tRNA.
AB  - We have improved the in vitro assay for 4-thiouridine (s(4)U) biosynthesis in
      Escherichia coli tRNA by substituting an unmodified tRNA transcript as substrate
      and including recombinant ThiI protein, a known factor required for s(4)U
      synthesis. Using this assay, we have purified an enzyme from wild-type E. coli
      that is able to provide sulfur for s(4)U synthesis in vitro. The purified protein
      has a molecular weight of 45 kDa and contains pyridoxal phosphate as a cofactor.
      This protein catalyzes sulfur transfer from cysteine to tRNA and is analogous to
      factor C previously reported (Lipsett, M. N. (1972) J. Biol. Chem. 247, 1458
      1461). UV spectroscopy and HPLC analysis of thiolated tRNA and its digests
      confirm that the product of the in vitro reaction is s(4)U. N-Terminal sequence
      analysis of the purified protein identifies it as IscS, a recently characterized
      NifS-like cysteine desulfurase that mobilizes sulfur for the synthesis of [Fe-S]
      clusters. We have cloned and overexpressed iscS and show that the recombinant
      protein displayed tRNA sulfurtransferase activity equal to that of the native
      protein. We also show that, of the multiple proteins in E. coli with cysteine
      desulfurase activity as observed by native gel staining, only IscS is able to
      mobilize the sulfur for transfer to tRNA. Our identification of IscS as a tRNA
      sulfurtransferase provides support for this activity in vivo and further expands
      the role for NifS proteins as versatile sulfur-carrying enzymes.

PMID- 10600119
TI  - Identification of mammalian mitochondrial ribosomal proteins (MRPs) by N-terminal
      sequencing of purified bovine MRPs and comparison to data bank sequences: the
      large subribosomal particle.
AB  - Bovine mitochondrial ribosomes are presented as a model system for mammalian
      mitochondrial ribosomes. An alternative system for identifying individual bovine
      mitochondrial ribosomal proteins (MRPs) by RP-HPLC is described. To identify and
      to characterize individual MRPs proteins were purified from bovine liver,
      separated by RP-HPLC, and identified by 2D PAGE techniques and immunoblotting.
      Molecular masses of individual MRPs were determined. Selected proteins were
      subjected to N-terminal amino acid sequencing. The peptide sequences obtained
      were used to screen different databases to identify several corresponding MRP
      sequences from human, mouse, rat, and yeast. Signal sequences for mitochondrial
      import were postulated by comparison of the bovine mature N-termini determined by
      amino acid sequencing with the deduced mammalian MRP sequences. Significant
      sequence similarities of these new MRPs to known r-proteins from other sources,
      e.g., E. coli, were detected only for two of the four MRP families presented.
      This finding suggests that mammalian mitochondrial ribosomes contain several
      novel proteins. Amino acid sequence information for all of the bovine MRPs will
      prove invaluable for assigning functions to their genes, which would otherwise
      remain unknown.

PMID- 10600120
TI  - Mapping of peroxyl radical induced damage on genomic DNA.
AB  - We have examined the DNA damage produced by reaction of peroxyl radicals with
      human fibroblast DNA. DNA damage consisted of both strand breaks and base
      modifications. The extent of strand breaks and base modifications induced as a
      function of peroxyl radical concentration was determined by quantitation of
      fragment size distributions using denaturing glyoxal-agarose gel electrophoresis.
      Both strand breaks and base modifications increased in a log linear fashion with
      respect to peroxyl radical concentration. Oxidative base modifications were
      observed to occur to a greater extent than strand breaks at every concentration
      measured. The sequence-specific distribution of peroxyl radical induced base
      damage was mapped for 803 nucleotide positions using the method of ligation
      mediated PCR. A total of 87% of all guanine positions in the examined sequences
      was found to be significantly oxidized. The order of reactivity of DNA bases
      toward oxidation by peroxyl radicals was found to be G >> C > T. Adenine is
      essentially unreactive. The yield of oxidative base modifications at guanines and
      cytosines by peroxyl radicals depends on the exact specification of 5' and 3'
      flanking bases in a polarity dependent manner. Every guanine in the 5'XGC3' motif
      was found to be oxidized, where X is any 5' neighbor. In contrast, 5' and 3'
      purine flanks drastically reduced the extent of peroxyl radical G oxidation. The
      pattern of base modification and the influence of nearest neighbors differs
      substantially from that previously reported for hydrogen peroxide damage mediated
      by low valent transition metal ions for the identical DNA sequences.

PMID- 10600121
TI  - Relationship between hexamerization and ssDNA binding affinity in the uvsY
      recombination protein of bacteriophage T4.
AB  - In bacteriophage T4, homologous genetic recombination events are catalyzed by a
      presynaptic filament containing stoichiometric quantities of the T4 uvsX
      recombinase bound cooperatively to single-stranded DNA (ssDNA). The formation of
      this filament requires the displacement of cooperatively bound gp32 (the T4 ssDNA
      binding protein) from the ssDNA, a thermodynamically unfavorable reaction. This
      displacement is mediated by the T4 uvsY protein (15.8 kDa, 137 amino acids),
      which interacts with both uvsX- and gp32-ssDNA complexes and modulates their
      properties. Previously, we showed that uvsY exists as a hexamer under
      physiological conditions and that uvsY hexamers bind noncooperatively but with
      high affinity to ssDNA. We also showed that a fusion protein containing the N
      terminal 101 amino acid residues of uvsY lacks interactions with uvsX and gp32
      but retains both weak ssDNA-binding activity and a residual ability to stimulate
      uvsX-catalyzed recombination functions. Here, we present quantitative data on the
      oligomeric structure and ssDNA-binding properties of a closely related fusion
      protein designated uvsY. Sedimentation velocity and equilibrium results establish
      that uvsY, unlike native uvsY, behaves as a monomer in solution (M(app) = 14.2
      kDa, = 2.1). Like native uvsY, uvsY binds noncooperatively to an etheno-DNA
      (epsilonDNA) lattice with a binding site size of 4 nucleotides/monomer; however
      at physiological ionic strength, the association constant for uvsY-epsilonDNA is
      decreased 10(4)-fold relative to native uvsY. Nevertheless, the magnitude of the
      salt effect on the association constant (K) is essentially unchanged between uvsY
      and uvsY, indicating that disruption of the C-terminus does not disrupt the
      electrostatic ssDNA-binding determinants found within each protomer of uvsY.
      Instead, the large difference in ssDNA-binding affinities reflects the loss of
      hexamerization ability by uvsY, suggesting that a form of intrahexamer synergism
      or cooperativity between binding sites within the uvsY hexamer leads to its high
      observed affinity for ssDNA.

PMID- 10600122
TI  - Site-specific DNA transesterification by vaccinia topoisomerase: role of specific
      phosphates and nucleosides.
AB  - Vaccinia topoisomerase forms a covalent DNA-(3'-phosphotyrosyl)-enzyme
      intermediate at a pentapyrimidine target site 5'-CCCTTp downward arrow in duplex
      DNA. Here we present experiments that illuminate the contributions of specific
      nucleosides and phosphates to site affinity and transesterification. We find that
      the -1 phosphate and -2 nucleoside on the scissile strand (5'-CCCTTp / NpN)
      enhance the rate of transesterification by factors of 40 and 25, respectively,
      whereas the DNA segment downstream of the -2 nucleotide makes no significant
      kinetic contribution. Placement of a 5'-phosphate/3'-OH nick at position +2, +3,
      +4, or +5 within the CCCTT element results in a 5-10-fold reduction in the
      affinity of topoisomerase binding to DNA. A nick at the +2 phosphate also slows
      the rate of transesterification by approximately 500-fold. This finding, together
      with earlier studies of the effects of position-specific base and sugar
      modifications, points to the +2 Tp nucleotide as being the most critical element
      of the CCCTT target site other than the scissile phosphate itself. On the
      noncleaved strand, the segment downstream of the 3'-GGGAA element contributes
      minimally to the rate of transesterification provided that the substrate is
      otherwise fully base-paired within the 5'-CCCTT target site. By studying the
      effects of single nucleotide gaps and missing phosphate nicks within the 3'-GGGAA
      sequence, we find that the +1 and +2 adenosine nucleosides enhance the rate of
      transesterification by 20- and 1,000-fold respectively and that the +5 phosphate
      (3'-GpGGAA) is also important for cleavage. Cumulative functional analyses of the
      vaccinia topoisomerase-DNA interface are discussed in light of newly available
      structures for the vaccinia and human type IB enzymes.

PMID- 10600123
TI  - Quantitation of metal ion and DNA junction binding to the Holliday junction
      endonuclease Cce1.
AB  - Cce1 is a magnesium-dependent Holliday junction endonuclease involved in the
      resolution of recombining mitochondrial DNA in Saccharomyces cerevisiae. Cce1
      binds four-way DNA junctions as a dimer, opening the junction into an extended, 4
      fold symmetric structure, and resolves junctions by the introduction of paired
      nicks in opposing strands at the point of strand exchange. In the present study,
      we have examined the interactions of wild-type Cce1 with a noncleavable four-way
      DNA junction and metal ions (Mg(2+) and Mn(2+)) using isothermal titration
      calorimetry, EPR, and gel electrophoresis techniques. Mg(2+) or Mn(2+) ions bind
      to Cce1 in the absence of DNA junctions with a stoichiometry of two metal ions
      per Cce1 monomer. Cce1 binds to four-way junctions with a stoichiometry of two
      Cce1 dimers per junction molecule in the presence of EDTA, and one dimer of Cce1
      per junction in 15 mM magnesium. The presence of 15 mM Mg(2+) dramatically
      reduces the affinity of Cce1 for four-way DNA junctions, by about 900-fold. This
      allows an estimation of DeltaG degrees for stacking of four-way DNA junction 7 of
      -4.1 kcal/mol, consistent with the estimate of -3.3 to -4.5 kcal/mol calculated
      from branch migration and NMR experiments [Overmars and Altona (1997) J. Mol.
      Biol. 273, 519-524; Panyutin et al. (1995) EMBO J. 14, 1819-1826]. The striking
      effect of magnesium ions on the affinity of Cce1 binding to the four-way junction
      is predicted to be a general one for proteins that unfold the stacked X-structure
      of the Holliday junction on binding.

PMID- 10600124
TI  - Properties of p-cresol methylhydroxylase flavoprotein overproduced by Escherichia
      coli.
AB  - The alpha(2)beta(2) flavocytochrome p-cresol methylhydroxylase (PCMH) from
      Pseudomonas putida is composed of a flavoprotein homodimer (alpha(2) or PchF(2);
      M(r) = 119 kDa) with a cytochrome monomer (beta, PchC; M(r) = 9.3 kDa) bound to
      each PchF subunit. Escherichia coli BL21(DE3) has been transformed with a vector
      for expression of the pchF gene, and PchF is overproduced by this strain as the
      homodimer. During purification, it was recognized that some PchF had FAD bound,
      while the remainder was FAD-free. However, unlike PchF obtained from PCMH
      purified from P. putida, FAD was bound noncovalently. The FAD was conveniently
      removed from purified E. coli-expressed PchF by hydroxyapatite chromatography.
      Fluorescence quenching titration indicated that the affinity of apo-PchF for FAD
      was sufficiently high to prevent the determination of the dissociation constant.
      It was found that p-cresol was virtually incapable of reducing PchF with
      noncovalently bound FAD (PchF(NC)), whereas 4-hydroxybenzyl alcohol, the
      intermediate product of p-cresol oxidation by PCMH, reduced PchF(NC) fairly
      quickly. In contrast, p-cresol rapidly reduced PchF with covalently bound FAD
      (PchF(C)), but, unlike intact PCMH, which consumed 4 electron equiv/mol when
      titrated with p-cresol (2 electrons from p-cresol and 2 from 4-hydroxybenzyl
      alcohol), PchF(C) accepted only 2 electron equiv/mol. This is explained by
      extremely slow release of 4-hydroxybenzyl alcohol from reduced PchF(C). 4
      Hydroxybenzyl alcohol rapidly reduced PchF(C), producing 4-hydroxybenzaldehyde.
      It was demonstrated that p-cresol has a charge-transfer interaction with FAD when
      bound to oxidized PchF(NC), whereas 4-bromophenol (a substrate analogue) and 4
      hydroxybenzaldehyde have charge-transfer interactions with FAD when bound to
      either PchF(C) or PchF(NC). This is the first example of a "wild-type"
      flavoprotein, which normally has covalently bound flavin, to bind flavin
      noncovalently in a stable, redox-active manner.

PMID- 10600125
TI  - Kinetic studies on the successive reaction of neuronal nitric oxide synthase from
      L-arginine to nitric oxide and L-citrulline.
AB  - Rat neuronal nitric oxide synthase (nNOS) was heterologously expressed in
      Escherichia coliand purified. The conversion of L-arginine to N(omega)-hydroxy-L
      arginine and further to L-citrulline in one cycle of the reaction of the purified
      nNOS was measured with the reaction rapid quenching method using (3)H-L-arginine
      as the substrate. It was found that most of the produced (3)H-N(omega)-hydroxy-L
      arginine was successively hydroxylated to (3)H-L-citrulline without leaving the
      enzyme. From the analysis of time courses, the rate constants for each reaction
      step, and also for the dissociation of the intermediate, were estimated at
      various temperature in which the rates for the first and the second reactions
      were not much different each other but the rate for the dissociation of (3)H
      N(omega)-hydroxy-L-arginine from the enzyme was significantly slow. Under the
      steady-state reaction condition, almost all of the nNOS was estimated to be
      active from the amount of burst formation of L-citrulline in the pre-steady
      state. The rate constant for the dissociation of the product L-citrulline from
      nNOS was calculated from the combination of results of the rapid quenching
      experiments and the metabolism of L-arginine in the presence of an excess amount
      of substrate, which was the smallest among all the rate constants in one cycle of
      the nNOS reaction. The activation energies for all the reaction steps were
      determined from the temperature dependence of the rate constants, which revealed
      that the rate-determining step of the nNOS reaction in the steady state was the
      dissociation of the product L-citrulline from the enzyme.

PMID- 10600126
TI  - Structure-function correlations of the reaction of reduced nicotinamide analogues
      with p-hydroxybenzoate hydroxylase substituted with a series of 8-substituted
      flavins.
AB  - Structural and kinetic studies have revealed two flavin conformations in p
      hydroxybenzoate hydroxylase (PHBH), the in-position and the out-position.
      Conversion between these two conformations is believed to be essential during
      catalysis. Although substrate hydroxylation occurs while the flavin in PHBH is in
      the in-conformation, the position of the flavin during reduction by NADPH is
      uncertain. To investigate the catalytic importance of the out-conformation of the
      flavin and to clarify the mechanism of flavin reduction in PHBH, we report
      quantitative structure-reactivity relationships (QSAR) using PHBH substituted
      separately with nine derivatives of FAD modified in the 8-position and four
      dihydronicotinamide analogues as reducing agents. The 8-position of the FAD
      isoalloxazine ring was chosen for modification because in PHBH it has minimal
      interactions with the protein and is accessible to solvent. The chemical sequence
      of events during catalysis by PHBH was not altered when using any of the modified
      flavins, and normal products were obtained. Although the rate of reduction of
      PHBH reconstituted with flavin derivatives is expected to be dependent on the
      redox potential of the flavin, no strict correlation was observed. Instead, the
      rate of reduction correlated with the kappa-substituent constant, which is based
      on size and hydrophobicity of the 8-substituent on the FAD. Substituents that
      sterically hinder attainment of the out-conformation decreased the rate of flavin
      reduction much more than expected on the basis of the redox potential of the
      flavin. The results of this QSAR analysis are consistent with the hypothesis that
      the flavin in PHBH must move to the out-conformation for proper formation of the
      charge-transfer complex between NADPH and FAD that is necessary for rapid flavin
      reduction.

PMID- 10600127
TI  - Nickel and cobalt reagents promote selective oxidation of Z-DNA.
AB  - The structural characteristics of Z-DNA were used to challenge the selectivity of
      guanine oxidation promoted by nickel and cobalt reagents. Base pairing and
      stacking within all helical structures studied previously had hindered access to
      guanine and limited its reaction. However, the Z-helix uniquely retains high
      exposure of guanine N7. This exposure was sufficient to direct oxidation
      specifically to a plasmid insert -(CG)(13)AATT(CG)(13)- that adopted a Z
      conformation under native supercoiling. An alternative insert -(CG)(7)- retained
      its B-conformation and demonstrated the expected lack of reactivity. For a nickel
      salen complex made from a particularly bulky ligand, preferential reaction
      shifted to the junctions within the Z-DNA insert as is common for large reagents.
      Inactivation of the nickel reagents by high-salt concentrations prevented
      parallel investigations of Z-DNA, formed by oligonucleotides. However, the
      activity of Co(2+) was minimally affected by salt and consequently confirmed the
      high reactivity of 5'-p(CG)(4) in its Z-conformation. These reagents may now be
      applied to a broad array of targets, since their structural specificity remains
      predictable for both complex and helical assemblies of nucleic acids.

PMID- 10600128
TI  - Thermodynamics of RNA-RNA duplexes with 2- or 4-thiouridines: implications for
      antisense design and targeting a group I intron.
AB  - Antisense compounds are designed to optimize selective hybridization of an
      exogenous oligonucleotide to a cellular target. Typically, Watson-Crick base
      pairing between the antisense compound and target provides the key recognition
      element. Uridine (U), however, not only stably base pairs with adenosine (A) but
      also with guanosine (G), thus reducing specificity. Studies of duplex formation
      by oligonucleotides with either an internal or a terminal 2- or 4-thiouridine
      (s(2)U or s(4)U) show that s(2)U can increase the stability of base pairing with
      A more than with G, while s(4)U can increase the stability of base pairing with G
      more than with A. The latter may be useful when binding can be enhanced by
      tertiary interactions with a s(4)U-G pair. To test the effects of s(2)U and s(4)U
      substitutions on tertiary interactions, binding to a group I intron ribozyme from
      mouse-derived Pneumocystis carinii was measured for the hexamers, r(AUGACU),
      r(AUGACs(2)U), and r(AUGACs(4)U), which mimic the 3' end of the 5' exon. The
      results suggest that at least one of the carbonyl groups of the 3' terminal U of
      r(AUGACU) is involved in tertiary interactions with the catalytic core of the
      ribozyme and/or thio groups change the orientation of a terminal U-G base pair.
      Thus thio substitutions may affect tertiary interactions. Studies of trans
      splicing of 5' exon mimics to a truncated rRNA precursor, however, indicate that
      thio substitutions have negligible effects on overall reactivity. Therefore,
      modified bases can enhance the specificity of base pairing while retaining other
      activities and, thus, increase the specificity of antisense compounds targeting
      cellular RNA.

PMID- 10600129
TI  - Ovalbumin(323-339) peptide binds to the major histocompatibility complex class II
      I-A(d) protein using two functionally distinct registers.
AB  - Proteins of the class II major histocompatibility complex (MHC) bind antigenic
      peptides that are subsequently presented to T cells. Previous studies have shown
      that most of the residues required for binding of the chicken ovalbumin (Ova) 323
      339 peptide to the I-A(d) MHC class II protein are contained within the shorter
      325-336 peptide. This observation is somewhat inconsistent with the X-ray
      structure of the Ova peptide covalently attached to I-A(d) ( structure) in which
      residues 323 and 324 form binding interactions with the protein. A second
      register for the Ova(325-336) peptide is proposed where residues 326 and 327
      occupy positions similar to residues 323 and 324 in the structure. Two Ova
      peptides that minimally encompass the and alternate registers, Ova(323-335) and
      Ova(325-336), respectively, were found to dissociate from I-A(d) with distinct
      kinetics. The dissociation rates for both peptides were enhanced when the His81
      residue of the MHC beta-chain was replaced with an asparagine. In the structure
      the betaH81 residue forms a hydrogen bond to the backbone carbonyl of I323. If
      the Ova(325-336) peptide were also bound in the register, there would be no
      comparable hydrogen-bond acceptor for the betaH81 side chain that could explain
      this peptide's sensitivity to the betaH81 replacement. The Ova(323-335) peptide
      that binds in the register does not stimulate a T-cell hybridoma that is
      stimulated by Ova(325-336) bound in the alternate register. These results
      demonstrate that a single peptide can bind to an MHC peptide in alternate
      registers producing distinct T-cell responses.

PMID- 10600130
TI  - Characterization of a novel dUTP-dependent activity of CTP synthetase from
      Saccharomyces cerevisiae.
AB  - CTP synthetase [EC 6.3.4.2, UTP:ammonia ligase (ADP-forming)] from the yeast
      Saccharomyces cerevisiae catalyzes the ATP-dependent transfer of the amide
      nitrogen from glutamine to the C-4 position of UTP to form CTP. In this work, we
      demonstrated that CTP synthetase utilized dUTP as a substrate to synthesize dCTP.
      The dUTP-dependent activity was linear with time and with enzyme concentration.
      Maximum dUTP-dependent activity was dependent on MgCl(2) (4 mM) and GTP (K(a) =
      14 microM) at a pH optimum of 8.0. The apparent K(m) values for dUTP, ATP, and
      glutamine were 0.18, 0.25, and 0.41 mM, respectively. dUTP promoted the
      tetramerization of CTP synthetase, and the extent of enzyme tetramerization
      correlated with dUTP-dependent activity. dCTP was a poor inhibitor of dUTP
      dependent activity, whereas CTP was a potent inhibitor of this activity. The
      enzyme catalyzed the synthesis of dCTP and CTP when dUTP and UTP were used as
      substrates together. CTP was the major product synthesized when dUTP and UTP were
      present at saturating concentrations. When dUTP and UTP were present at
      concentrations near their K(m) values, the synthesis of dCTP increased relative
      to that of CTP. The synthesis of dCTP was favored over the synthesis of CTP when
      UTP was present at a concentration near its K(m) value and dUTP was varied from
      subsaturating to saturating concentrations. These data suggested that the dUTP
      dependent synthesis of dCTP by CTP synthetase activity may be physiologically
      relevant.

PMID- 10600131
TI  - Anophelin: kinetics and mechanism of thrombin inhibition.
AB  - Anophelin is a 6.5-kDa peptide isolated from the salivary gland of Anopheles
      albimanus that behaves as an alpha-thrombin inhibitor. In this paper, kinetic
      analyses and the study of mechanism of alpha-thrombin inhibition by anophelin
      were performed. Anophelin was determined to be a reversible, slow, tight-binding
      inhibitor of alpha-thrombin, displaying a competitive type of inhibition. The
      binding of anophelin to alpha-thrombin is stoichiometric with a dissociation
      constant (K(i)) of 5.87 +/- 1.46 pM, a calculated association rate constant
      (k(1)) of 2.11 +/- 0.06 x 10(8) M(-1) s(-1), and a dissociation rate constant (k(
      1)) of 4.05 +/- 0.97 x 10(-4) s(-1). In the presence of 0.15 and 0.4 M NaCl, a
      17.6- and 207-fold increase in the K(i) of anophelin-alpha-thrombin complex was
      observed, respectively, indicating that ionic interactions are important in
      anophelin-alpha-thrombin complex formation. Incubation of alpha-thrombin with C
      terminal hirudin fragment 54-65 that binds to alpha-thrombin anion binding
      exosite 1 (TABE1) attenuates alpha-thrombin inhibition by anophelin; anophelin
      also blocks TABE1-dependent trypsin-mediated proteolysis of alpha-thrombin. Using
      gamma-thrombin, an alpha-thrombin derivative where the anion binding exosite has
      been disrupted, anophelin behaves as a fast and classical competitive inhibitor
      of gamma-thrombin hydrolysis of small chromogenic substrate (K(i) = 0. 694 +/-
      0.063 nM). In addition, anophelin-gamma-thrombin complex formation is prevented
      by treatment of the enzyme with D-Phe-Pro-Arg-chloromethyl ketone (PPACK), a
      reagent that irreversibly blocks the catalytic site of thrombin. It is concluded
      that anophelin is a potent dual inhibitor of alpha-thrombin because it binds both
      to TABE1 and to the catalytic site, optimal binding being dependent on the
      availability of both domains. Finally, anophelin inhibits clot-bound alpha
      thrombin with an IC(50) of 45 nM and increases the lag phase that precedes
      explosive in vitro alpha-thrombin generation after activation of intrinsic
      pathway of blood coagulation. Because of its unique primary sequence, anophelin
      may be used as a novel reagent to study the structure and function of alpha
      thrombin.

PMID- 10600132
TI  - Folding and assembly of dimeric human glutathione transferase A1-1.
AB  - Glutathione transferases function as detoxification enzymes and ligand-binding
      proteins for many hydrophobic endogenous and xenobiotic compounds. The molecular
      mechanism of folding of urea-denatured homodimeric human glutathione transferase
      A1-1 (hGSTA1-1) was investigated. The kinetics of change were investigated using
      far-UV CD, Trp20 fluorescence, fluorescence-detected ANS binding, acrylamide
      quenching of Trp20 fluorescence, and catalytic reactivation. The very early
      stages of refolding (millisecond time range) involve the formation of structured
      monomers with native-like secondary structure and exposed hydrophobic surfaces
      that have a high binding capacity for the amphipathic dye ANS. Dimerization of
      the monomeric intermediates was detected using Trp fluorescence and occurs as
      fast and intermediate events. The intermediate event was distinguished from the
      fast event because it is limited by a preceding slow trans-to-cis isomerization
      reaction (optically silent in this study). At high concentrations of hFKBP,
      dimerization is not limited by the isomerization reaction, and only the fast
      event was detected. The fast (tau = 200 ms) and intermediate (tau = 2.5 s) events
      show similar urea-, temperature-, and ionic strength-dependent properties. The
      dimeric intermediate has a partially functional active site ( approximately 20%).
      Final reorganization to form the native tertiary and quaternary structures occurs
      during a slow, unimolecular, urea- and ionic strength-independent event. During
      this slow event (tau = 250 s), structural rearrangements at the domain interface
      occur at/near Trp20 and result in burial of Trp20. The slow event results in the
      regain of the fully functional dimer. The role of the C-terminus helix 9
      (residues 210-221) as a structural determinant for this final event is proposed.

PMID- 10600133
TI  - Electron transfer to photosystem 1 from spinach plastocyanin mutated in the small
      acidic patch: ionic strength dependence of kinetics and comparison of mechanistic
      models.
AB  - A set of plastocyanin (Pc) mutants, probing the small acidic patch (Glu59, Glu60,
      and Asp61) and a nearby residue, Gln88, has been constructed to provide further
      insight into the electron transfer process between Pc and photosystem 1. The
      negatively charged residues were changed into their neutral counterparts or to a
      positive lysine. All mutant proteins exhibited electron transfer kinetics
      qualitatively similar to those of the wild type protein over a wide range of Pc
      concentrations. The kinetics were slightly faster for the Gln88Lys mutant, while
      they were significantly slower for the Glu59Lys mutant. The data were analyzed
      with two different models: one involving a conformational change of the Pc
      photosystem 1 complex that precedes the electron transfer step (assumed to be
      irreversible) [Bottin, H., and Mathis, P. (1985) Biochemistry 24, 6453-6460] and
      another where no conformational change occurs, the electron transfer step is
      reversible, and dissociation of products is explicitly taken into account
      [Drepper, F., Hippler, M., Nitschke, W., and Haehnel, W. (1996) Biochemistry 35,
      1282-1295]. Both models can account for the observed kinetics in the limits of
      low and high Pc concentrations. To discriminate between the models, the effects
      of added magnesium ions on the kinetics were investigated. At a high Pc
      concentration (0.7 mM), the ionic strength dependence was found to be consistent
      with the model involving a conformational change but not with the model where the
      electron transfer is reversible. One residue in the small acidic patch, Glu60,
      seems to be responsible for the major part of the ionic strength dependence of
      the kinetics.

PMID- 10600134
TI  - Altering the receptor-effector ratio by transgenic overexpression of type V
      adenylyl cyclase: enhanced basal catalytic activity and function without
      increased cardiomyocyte beta-adrenergic signalling.
AB  - The limiting element in beta-adrenergic receptor (betaAR)-G(s)-adenylyl cyclase
      (AC) signal transduction in the cardiomyocyte is not known, but it has been
      proposed that the level of adenylyl cyclase expression constrains betaAR
      signaling. To alter the above equilibrium, type V AC was overexpressed in a
      myocyte-specific manner in the hearts of transgenic mice using the alpha-myosin
      heavy chain promoter. Expression of type V AC was approximately 75% over
      endogenous levels as quantitated by [(3)H]forskolin binding. Functional activity
      of the transgene product was evident in cardiac membrane AC studies, where basal
      (45 +/- 11 vs 19 +/- 5 pmol min(-)(1) mg(-)(1)) and forskolin+Mn(2+) (695 +/- 104
      vs 386 +/- 34 pmol min(-)(1) mg(-)(1)) stimulated activities were increased
      compared to activities in nontransgenic (NTG) littermates. However, while
      isoproterenol stimulated activities were higher (74 +/- 12 vs 46 +/- 9.8 pmol
      min(-)(1) mg(-)(1)), the fold stimulation over basal was not increased in ACV
      overexpressors compared to NTG (line 14.3 = 2.29 +/- 0.44-fold, line 15.1 = 1.70
      +/- 0.1-fold, NTG = 2.62 +/- 0.18-fold). Similarly, in whole cell patch-clamp
      studies, betaAR-mediated opening of L-type Ca(2+) channels was not found to be
      enhanced in transgenic ACV myocytes (225 +/- 15 vs 216 +/- 10% of basal
      currents). Basal and isoproterenol stimulated PKA activities were elevated in the
      ACV mice compared to NTG, but again the extent of stimulation over basal was not
      enhanced. Phosphorylated phospholamban was approximately 2-fold greater in
      myocytes from ACV hearts compared to NTG, indicating that distal elements of the
      contractile cascade are activated by AC overexpression. ACV mice displayed
      increased heart rates and fractional shortening as assessed by echocardiography.
      However, in vivo hemodynamic studies revealed that heart rate and contractility
      responses to agonist infusion were not enhanced in ACV mice compared to NTG. We
      conclude that at native stoichiometries, the levels of adenylyl cyclase influence
      basal activities and cardiac function, but do not constrain betaAR signaling in
      the cardiomyocyte.

PMID- 10600136
TI  - The effect of clutch cooling rate on starling, Sturnus vulgaris, incubation
      strategy.
AB  - In avian species where only one parent incubates, that parent must divide its
      time between the mutually exclusive activities of incubation and foraging in such
      a way as to maintain both body condition and clutch temperature within certain
      limits. In a uniparental incubator, the starling, we experimentally reduced the
      rate at which unattended clutches of eggs cooled down and monitored the resulting
      changes in the parent's incubation strategy. Opposite to the predictions of
      standard models of time allocation during incubation, parents spent a much
      greater percentage of each 24-h period incubating when the rate of clutch cooling
      was reduced. Incubation bouts lasted significantly longer on experimental nests
      than on control nests, both during the daytime and overnight. Mean foraging bout
      duration did not differ between the two groups of nests. These results are
      consistent with the hypotheses that parental foraging success cues the end of a
      foraging bout, and that parental energy level cues the end of an incubation bout.
      However, most previous studies suggest that parents spend less time incubating
      when the rate of clutch cooling is slow. If parental energy level cues departure,
      these results can be explained only if the amount of time available for
      incubation is constrained in these cases by the time a parent must spend foraging
      in order to maintain body condition. Such parents should take more time away from
      incubation when the unattended clutch cools slowly, as this is when the cost of
      being absent is minimized. Copyright 1999 The Association for the Study of Animal
      Behaviour.

PMID- 10600135
TI  - Herbicide-degrading alpha-keto acid-dependent enzyme TfdA: metal coordination
      environment and mechanistic insights.
AB  - TfdA is a non-heme iron enzyme which catalyzes the first step in the oxidative
      degradation of the widely used herbicide (2, 4-dichlorophenoxy)acetate (2,4-D).
      Like other alpha-keto acid-dependent enzymes, TfdA utilizes a mononuclear Fe(II)
      center to activate O(2) and oxidize substrate concomitant with the oxidative
      decarboxylation of alpha-ketoglutarate (alpha-KG). Spectroscopic analyses of
      various Cu(II)-substituted and Fe(II)-reconstituted TfdA complexes via electron
      paramagnetic resonance (EPR), electron spin-echo envelope modulation (ESEEM), and
      UV-vis spectroscopies have greatly expanded our knowledge of the enzyme's active
      site. The metal center is coordinated to two histidine residues as indicated by
      the presence of a five-line pattern in the Cu(II) EPR signal, for which
      superhyperfine splitting is attributed to two equivalent nitrogen donor atoms
      from two imidazoles. Furthermore, a comparison of the ESEEM spectra obtained in
      H(2)O and D(2)O demonstrates that the metal maintains several solvent-accessible
      sites, a conclusion corroborated by the increase in multiplicity in the EPR
      superhyperfine splitting observed in the presence of imidazole. Addition of alpha
      KG to the Cu-containing enzyme leads to displacement of an equatorial water on
      copper, as determined by ESEEM analysis. Subsequent addition of 2,4-D leads to
      the loss of a second water molecule, with retention of a third, axially bound
      water. In contrast to these results, in Fe(II)-reconstituted TfdA, the
      cosubstrate alpha-KG chelates to the metal via a C-1 carboxylate oxygen and the
      alpha-keto oxygen as revealed by characteristic absorption features in the
      optical spectrum of Fe-TfdA. This binding mode is maintained in the presence of
      substrate, although the addition of 2,4-D does alter the metal coordination
      environment, perhaps by creating an O(2)-binding site via solvent displacement.
      Indeed, loss of solvent to generate an open binding site upon the addition of
      substrate has also been suggested for the alpha-keto acid-dependent enzyme
      clavaminate synthase 2 [Zhou et al. (1998) J. Am. Chem. Soc. 120, 13539-13540].
      Nitrosyl adducts of various Fe-TfdA complexes have also been investigated by
      optical and EPR spectroscopy. Of special interest is the tightly bound NO complex
      of Fe-TfdA.(alpha-KG).(2,4-D), which may represent an accurate model of the
      initial oxygen-bound species.

PMID- 10600137
TI  - Population density influences male-male competition in guppies.
AB  - This study tested the general prediction that population density affects male
      male competition, female mate choice and the opportunity for sexual selection. By
      manipulating the density of guppies, Poecilia reticulata, while keeping the sex
      ratio constant, I found that male mating tactics were phenotypically plastic with
      respect to density. As density increased, males decreased their courtship
      displays. Male-male competition and mate searching were highest at intermediate
      densities. Population density had no significant effect on the total number of
      copulations, copulatory tactics or the percentage of postcopulatory guarding.
      Female preference for males with a higher percentage of orange coloration was
      similar at all density levels. The 'opportunity for sexual selection', which
      estimates the upper limit to which a selected trait can shift if directional
      selection is operating and was calculated as the variance in number of
      copulations per male divided by the square of the mean number of copulations, was
      negatively associated with population density. This may be due to the decrease in
      male-male competition at high density rather than female preference which was
      similar across density treatments. Copyright 1999 The Association for the Study
      of Animal Behaviour.

PMID- 10600138
TI  - Unravelling the chemical basis of competitive scent marking in house mice.
AB  - Major urinary proteins (MUPs) in the urine of male house mice, Mus domesticus,
      bind the male signalling volatiles 2- sec -butyl-4,5-dihydrothiazole (thiazole)
      and 3,4-dehydro- exo -brevicomin (brevicomin) and slowly release these volatiles
      from urinary scent marks. To examine the role of urinary proteins and volatiles,
      either attached or unattached to the proteins, in competitive scent marking, we
      fractionated urine from isolated male BALB/c laboratory mice, Mus musculus, by
      size-exclusion chromatography into three pools. Pool I contained all of the
      urinary proteins and their bound ligands while pools II and III contained lower
      molecular weight components including unbound signalling volatiles. In experiment
      1, pools I-III were streaked out on to absorbent paper (Benchkote) and introduced
      into enclosures housing single wild-caught male mice, together with a clean
      control surface. Each male was tested with fresh stimuli and with aged stimuli
      deposited 24 h previously. Only pool I stimulated significantly more
      countermarking and investigation than the control, attracting mice to investigate
      from a distance even when the rate of ligand release was considerably reduced
      after 24 h. Experiment 2 examined responses to pool I when this was fresh, aged
      by 7 days, or had been mixed with menadione to displace ligands from the
      proteins. Although all three protein stimuli were investigated and countermarked
      more than a clean control, the aged and menadione-treated pool I stimulated the
      strongest responses, despite containing the lowest levels of thiazole and
      brevicomin. Thus competitive countermarking is stimulated by proteins or by
      nonvolatile protein-ligand complexes in male urine, while release of volatile
      ligands attracts attention to a competitor's scent marks. Copyright 1999 The
      Association for the Study of Animal Behaviour.

PMID- 10600139
TI  - Size-assortative mating, male choice and female choice in the curculionid beetle
      Diaprepes abbreviatus.
AB  - In the beetle Diaprepes abbreviatus (L.) females are larger on average than
      males, as indicated by elytra length. Size-assortative matings were observed in
      wild populations in Florida and in laboratory mating experiments. We tested three
      mechanisms for this size-assortative mating: (1) mate availability; (2) mating
      constraints; and (3) mate choice. We found that mate choice influenced size
      assortative mating by: (1) large and small males preferring to mate with large
      females; (2) large males successfully competing for large females, leaving small
      males to mate with small females; and (3) females accepting large males as mates
      more readily than small males. Males increased their reproductive success by
      mating with larger, more fecund females. They transferred protein to females
      during mating. Copyright 1999 The Association for the Study of Animal Behaviour.

PMID- 10600140
TI  - Sexual selection for white tail spots in the barn swallow in relation to habitat
      choice by feather lice.
AB  - Many bird species have white spots in their tails or wing feathers, and such
      characters have been hypothesized to be either reliable signals (handicaps) or
      amplifiers that facilitate the message of a signal. In barn swallows, Hirundo
      rustica, the size of the white spots in the tail feathers is sexually dimorphic
      and positively correlated with feather length. We tested whether such spots act
      as handicaps or amplifiers. These white spots affect sexual selection in barn
      swallows, as shown by an experiment in which we randomly subjected males to (1) a
      considerable reduction of the size of all the spots by the use of a black
      permanent marker pen, (2) a small reduction of the size of the spots, or (3) no
      reduction. There was a positive association between spot size and the number of
      offspring produced per season. The white tail spots were preferred by feather
      eating Mallophaga as a feeding site: holes made by Mallophaga were more abundant
      in the white spots than expected by chance. A habitat choice experiment with
      Mallophaga on barn swallow tail feathers revealed that they preferred white spots
      over black parts of the tail feathers. We therefore expected long-tailed male
      barn swallows to have more Mallophaga than short-tailed males. However, the
      opposite relationship was observed, indicating that long-tailed males may
      reliably signal their quality by the presence of large white tail spots without
      parasite damage. Thus white tail spots in barn swallows appear to be a reliable
      signal of phenotypic quality. Copyright 1999 The Association for the Study of
      Animal Behaviour.

PMID- 10600141
TI  - Social anxiety, relationships and self-directed behaviour among wild female olive
      baboons.
AB  - Self-directed behaviour (SDB) can be used as a behavioural indicator of stress
      and anxiety in nonhuman primates (Maestripieri et al. 1992, Animal Behaviour, 44,
      967-979). We investigated the effect of nearest neighbours' relative dominance
      status on the SDB of sexually mature female olive baboons, Papio anubis. When the
      animal nearest to (within 5 m of) a female was a dominant individual, SDB rates
      (a combined measure of self-scratching, self-grooming, self-touching, body
      shaking and yawning) increased by ca. 40% over those observed when the nearest
      neighbour was a subordinate. The results indicate that (1) SDB can be used as a
      measure of uncertainty during the social interactions of cercopithecine primates
      and (2) as there was considerable variation in SDB response according to the
      nature of the dominant individual, SDB can be used to assess relationship
      security (i.e. the perceived predictability of a relationship for one partner).
      Finally, in combination with measures of affiliation rate, SDB may provide
      insight into relationship value. Copyright 1999 The Association for the Study of
      Animal Behaviour.

PMID- 10600142
TI  - Size and stability of vertebrate leks.
AB  - Lek size varies greatly among lekking species. At present there is no explicit
      theoretical explanation for this diversity. We extend an existing model of
      optimal lek size that incorporates female mating preferences and male-male
      contest competition. The model shows that variation in lek size is predicted by
      the interaction between lek size, overall copulation rate and the proportion of
      copulations accruing to males of different rank. In species where females prefer
      to mate on the largest leks and high-ranking males are able to monopolize females
      irrespective of the size of the lek, the maximum lek size will be large.
      Conversely, in species where females show weak preference for mating on large
      leks or increasing lek size quickly results in scramble competition, the maximum
      lek size will be smaller. Thus, differences between species in lek size may be
      due largely to differences in the extent to which high-ranking males can
      monopolize mating opportunities. Leks become unstable and break down when high
      ranking males can no longer get their 'expected' copulation success. Therefore,
      the mechanism that generates male clustering, that is, sexual parasitism of high
      ranking males by subordinates, also sets a limit to the largest stable lek size.
      Copyright 1999 The Association for the Study of Animal Behaviour.

PMID- 10600143
TI  - 'Friendship' for fitness in chimpanzees?
AB  - It has been repeatedly suggested that primates trade social services for fitness
      benefits in their relationships with the opposite sex. We tested this proposal in
      a colony of captive chimpanzees, Pan troglodytes, by examining behavioural data
      on grooming, agonistic support and food sharing in relation to genetically
      established paternity. We found no support for the notion of trade. First, males
      did not sire more offspring with females that they actively groomed more
      frequently, that they supported more often or with which they shared food more
      frequently. Correspondingly, females did not give birth to more offspring sired
      by males from which they received more services. Second, males that showed more
      affiliative behaviour towards females in general did not sire more progeny.
      Furthermore, females did not bear more offspring sired by males to which they
      themselves directed more sociopositive behaviour. Results from this captive
      colony are compatible with those reported for chimpanzees under natural
      conditions. Copyright 1999 The Association for the Study of Animal Behaviour.

PMID- 10600144
TI  - Geographical variation in temporal and spatial vocalization patterns of male
      harbour seals in the mating season.
AB  - In the aquatically mating harbour seal, Phoca vitulina, oestrous females show
      marked differences in spatial and temporal distribution between geographical
      areas. This suggests that the males' display behaviour may also vary between
      areas. We recorded male vocalizations in two areas, the Moray Firth and Orkney,
      U.K. In the Moray Firth, females haul out on a few intertidal sandbars and travel
      along predictable routes to forage at sea. In Orkney, female haul out sites are
      much less influenced by tidal availability and females are much more dispersed.
      In the Moray Firth, males vocalized only during a short mating season, from 1
      July to 12 August. Vocalizations varied significantly with the tide, the peak at
      high tide clearly coinciding with the period when most females were in the water.
      In contrast, vocalizations in Orkney were significantly related to both tidal and
      diel patterns. We suggest that the timing of male vocalizations reflects
      differences in female availability between sites. In the inner Moray Firth,
      vocalizations were heard throughout the females' range, whereas vocalizations in
      Orkney were heard only in two discrete areas. However, at both sites the density
      of vocalizing males was highest in narrow channels and/or along predictable
      female travel routes. Therefore, males clearly adapt their temporal and spatial
      behaviour patterns to variations in female distribution and density. These
      results suggest that male mating strategies in aquatically mating pinnipeds are
      more variable than was previously envisaged. Copyright 1999 The Association for
      the Study of Animal Behaviour.

PMID- 10600145
TI  - Asymmetry in spider orb webs: a result of physical constraints?
AB  - A typical feature of most vertical orb webs is that the upper web region is
      smaller and contains less silk than the lower web region, creating an
      asymmetrical web. The degree of web asymmetry changes during the spider's
      development: small juveniles construct more symmetrical webs, but older and
      larger individuals decrease the upper web region. This implies that weight may
      control the extent of web asymmetry. Using two species, Argiope keyserlingi and
      Larinioides sclopetarius, we tested the effect of weight increase on web
      asymmetry by naturally increasing weight through feeding and by artificially
      adding lead weights to the abdomen of the spiders. Weight increase (natural or
      artificial) resulted in more asymmetric webs through a reduction of the upper web
      region. Added weight may interfere with spiral placement in the upper region,
      because the spider has to lift its abdomen above the carapace during the process.
      In the lower region, however, the position of the spider is mostly head up during
      spiral placement. Therefore, amongst other factors, weight and gravitational
      forces may be physical constraints during web construction. Copyright 1999 The
      Association for the Study of Animal Behaviour.

PMID- 10600146
TI  - Impact of geographical origin on mating behaviour in two species of Biomphalaria
      (Planorbidae: Gastropoda).
AB  - Studies of inbreeding and outcrossing have traditionally concentrated on matings
      within populations. The influence of geographical origin on mate choice in
      animals from different populations has received less attention. We investigated
      whether planorbid snails mated preferentially within their own population or with
      snails from other populations. Snails from three Biomphalaria pfeifferi strains
      and three B. glabrata strains were allowed to mate with conspecifics in the
      laboratory. We recorded their matings at night using time-lapse video. When they
      could choose between sympatric and allopatric snails, Biomphalaria snails
      significantly preferred the former: snails of each population mated more often
      with sympatric than with allopatric snails. This tendency to avoid outcrossing
      may indicate that, in some species, local adaptations can be more valuable than
      genetic novelties. Copyright 1999 The Association for the Study of Animal
      Behaviour.

PMID- 10600147
TI  - Interactions between red-billed oxpeckers, Buphagus erythrorhynchus, and domestic
      cattle, Bos taurus, in Zimbabwe.
AB  - Many apparent interspecific mutualisms are poorly understood. Although theory has
      focused on the various evolutionary problems peculiar to mutualism, especially
      the need to identify mechanisms that protect a mutualism from cheating or
      exploitation, there are relatively few quantified examples of how organisms
      actually interact. Oxpeckers are believed to benefit their mammalian hosts by
      reducing tick loads, an assumption based on the fact that the birds include ticks
      in their diet. I watched red-billed oxpeckers foraging on domestic cattle in the
      Limpopo Valley between August 1996 and September 1997. From focal watches of 41
      individually colour-ringed oxpeckers, I found that birds fed mainly on wounds, in
      ears and by 'scissoring' with the bill (a distinctive feeding technique).
      Observable tick feeding represented a very small percentage of their foraging
      time. Based on oxpecker behaviour at feeding sites, blood from open wounds
      appeared to be the favoured food: oxpeckers displaced each other significantly
      more, and were significantly less likely to be deterred by the cows' attempts to
      remove them, when feeding on a wound than at other feeding sites. The preference
      for blood, the inability of cows to prevent oxpeckers feeding on blood and the
      relatively small amount of visible tick feeding suggest that, certainly for
      cattle, oxpeckers may not be beneficial. However, as cows have not coevolved with
      oxpeckers, these results may not be representative of oxpecker relations with
      native African mammalian hosts. Copyright 1999 The Association for the Study of
      Animal Behaviour.

PMID- 10600148
TI  - The relationship between signal quality and physical condition: is sexual
      signalling honest in the three-spined stickleback?
AB  - Honest sexual signalling requires that the level of advertisement reveals mate
      quality. In the three-spined stickleback, Gasterosteus aculeatus, females base
      their mate choice mainly on the intensity of the males' red breeding coloration.
      Different results have, however, been obtained on the relationship between red
      breeding coloration and physical condition. In this study, the relationship was
      curvilinear in a natural population, with males in good and poor condition
      (measured as lipid content) having larger red areas than males of intermediate
      condition. By manipulating food intake and thus male condition prior to breeding,
      I further show that poor condition can induce an increase in signalling effort.
      This effect was further strengthened when the predation cost of signalling was
      increased by exposing the males to predators. This suggests that the reason for
      the high signalling effort of males in poor condition is their low probability of
      future reproduction and thus lower cost of signalling in terms of loss of future
      reproductive opportunities. Males in poor condition signal as a terminal effort
      and take larger risks and invest more in current reproduction than males in good
      condition. Finally, I discuss whether an effect of decreasing residual
      reproductive value on signalling effort could result in the breakdown of the
      honesty of the signal. Copyright 1999 The Association for the Study of Animal
      Behaviour.

PMID- 10600149
TI  - Does darkening signal submission in territorial contests between juvenile
      Atlantic salmon, Salmo salar ?
AB  - Communication by means of visual signals occurs during the competitive,
      aggressive and sexual interactions of many animals. Some animals such as fish are
      able to change their body coloration rapidly, and there is evidence that this is
      used as a means of signalling. However, the precise meaning of such signals is
      rarely understood. We examined whether (1) darkness in juvenile Atlantic salmon
      is associated with submission, and (2) changing to a darker colour could act as a
      signal to the opponent and hence induce a change in its behaviour. We found that
      both the sclera of the eye and the overall body coloration tended to darken in
      fish that were losing territorial encounters, while victors retained their
      original coloration. The darkening was rapid and usually occurred during a period
      of sustained attacks by the opponent; however, the aggression level decreased as
      soon as the losing fish had become darker. We suggest that the darkening of the
      losing fish was associated with submission and may result in a change in the
      behaviour of its opponent, so minimizing the potential risk of injury during
      unnecessarily prolonged fights. Copyright 1999 The Association for the Study of
      Animal Behaviour.

PMID- 10600150
TI  - Vibrational directionality in the southern green stink bug, Nezara viridula (L.),
      is mediated by female song.
AB  - We tested the hypothesis that male southern green stink bugs, Nezara viridula
      (L.), use substrate-borne songs to locate females. We recorded the responses of
      bugs on plants to the vibrations caused by a prerecorded female song and by an
      artificial sound. The female song caused males to walk, to respond with the
      calling and courtship songs and to approach the source of the song with
      characteristic search behaviour at junctions between branches on the plants. At a
      junction, a searching male stopped, stretched his legs and antennae and compared
      the vibratory signals on the two branches, with different combinations of legs
      and antennae. The males then left the junction and approached the source of the
      vibration. Males located the loudspeaker significantly more frequently in the
      presence than in the absence of vibratory stimuli on cyperus, Cyperus
      alternifolius L., and beans, Phaseolus vulgaris L. Vibrational directionality was
      also elicited by artificial pure tones whose spectral and temporal parameters
      were similar to those of natural female song. Females showed no reaction to
      vibratory stimulation and no vibrational directionality. We discuss possible
      mechanisms underlying vibrational directionality in the light of expected signal
      changes during transmission through plants. Copyright 1999 The Association for
      the Study of Animal Behaviour.

PMID- 10600151
TI  - Song learning with audiovisual compound stimuli in zebra finches.
AB  - We investigated the effects of audiovisual compound training on song learning in
      zebra finches, Taeniopygia guttata. In the first experiment, presentation of a
      stuffed adult zebra finch male was found to be reinforcing to zebra finch males
      in an operant task. In a separate experiment, zebra finch males were reared
      without their father from day 7 after hatching onwards. Between 35 and 76 days,
      they were placed in isolation and exposed to taped songs of a zebra finch male,
      according to a random schedule (20 presentations/h). For half of the birds,
      presentation of the song coincided with presentation of a stuffed zebra finch
      male. For the remaining birds, each presentation of the song was followed by
      presentation of a stuffed male. The birds were subsequently isolated until day
      142, when their own songs were recorded and analysed. Birds in both groups shared
      significantly more song elements with their tutor songs than with an unfamiliar
      song. There was no significant difference in song learning between the groups.
      These results confirm that zebra finches can learn part of their songs from taped
      tutor songs. Furthermore, simultaneous presentation of the tutor song and a
      relevant, salient visual stimulus is not superior to sequential presentation.
      Copyright 1999 The Association for the Study of Animal Behaviour.

PMID- 10600152
TI  - Search behaviour and mate choice by female field crickets, Gryllus integer.
AB  - The search tactics that females might employ to find a suitable mate impose
      different cognitive demands on searchers and some theoretical models of search
      behaviour presuppose that females are able to recall encountered males and return
      to mate with a previously sampled individual. In this study, I exposed female
      field crickets, Gryllus integer, to male calls either sequentially or
      simultaneously from two speakers in a three-arm radial maze. Subjects that were
      exposed to the two calls in sequence and allowed to move to the location of each
      call returned, in the absence of any audible signal, to the location of the call
      initially encountered. Subjects allowed to walk to the location of only one of
      two simultaneously active speakers before playback of both calls was terminated
      were as likely to move, in the absence of any audible signal, to the never-active
      speaker as to the location of the other male call. These subjects were also more
      likely to search all three arms of the maze and searched for a longer time than
      females exposed to calls sequentially. Thus, female G. integer probably do not
      construct a spatial representation of the locations of potential mates from the
      calls of males that advertise concurrently. The results of this study suggest,
      however, that female G. integer are able to recall previously encountered males
      under some conditions and may potentially employ a search tactic that is more
      complicated than a simple instantaneous comparison of the qualities of males that
      are actively calling. Copyright 1999 The Association for the Study of Animal
      Behaviour.

PMID- 10600153
TI  - The effects of social status on food-associated calling behaviour in captive
      cotton-top tamarins.
AB  - We examined the effects of social environment on food-asociated calling of cotton
      top tamarins, Saguinus oedipus, in two experiments. In experiment 1, we compared
      the food-associated calling behaviour of six juvenile tamarins living in their
      natal groups with their calling behaviour 9 months after being removed from
      family groups and paired. In experiment 2, we studied food-associated calling
      behaviour of nine cotton-top tamarins immediately before and after removal from
      their natal groups and pairing. The tamarins underwent three separate
      developmental processes in their calling behaviour. Animals removed from their
      natal groups showed an immediate reduction in vocalizations other than food
      associated calls (C and D chirps). The development of precise adult forms of C
      and D chirps was more gradual and was a function of time since removal from their
      natal group rather than time since pairing. Finally, the postremoval tamarins
      persisted in applying C chirps to nonfood objects and showed no correlation
      between C-chirp rate and food preference, which is typical of immature tamarins.
      We conclude that social status plays an important role in the development of
      adult forms and usage of food-associated calls. Copyright 1999 The Association
      for the Study of Animal Behaviour.

PMID- 10600154
TI  - Behaviour of house mice artificially selected for high levels of voluntary wheel
      running.
AB  - We have developed a novel model to study the correlated evolution of behavioural
      and morphophysiological traits in response to selection for increased locomotor
      activity. We used selective breeding to increase levels of voluntary wheel
      running in four replicate lines of laboratory house mice, Mus domesticus, with
      four random-bred lines maintained as controls. The experiment presented here
      tested for correlated behavioural responses in the wheel-cage complex, with
      wheels either free to rotate or locked (environmental factor). After 13
      generations, mice from selected lines ran 2.2 times as many revolutions/day as
      controls on days 5 and 6 of initial exposure to wheels (10 826 versus 4890
      revolutions/day, corresponding to 12.1 and 5.5 km/day, respectively). This
      increase was caused primarily by mice from selected lines running faster, not
      more minutes per day. Focal-animal observations confirmed that the increase in
      revolutions/day involved more actual running (or climbing in locked wheels), not
      an increase in coasting (or hanging). Not surprisingly, access to free versus
      locked wheels had several effects on behaviour, including total time spent in
      wheels, sniffing and biting. However, few behaviours showed statistically
      significant differences between the selected and control lines. Selection did not
      increase the total time spent in wheels (either free or locked), the frequency of
      nonlocomotor activities performed in the wheels, nor the amount of locomotor
      activity in cages attached to the wheels; as well, selection did not decrease the
      amount of time spent sleeping. Thus, wheel running is, at the genetic level, a
      largely independent axis of behaviour. Moreover, the genetic architecture of
      overall wheel running and its components seem conducive to increasing total
      distance moved without unduly increasing energy or time-related costs. The
      selection experiment also offers a new approach to study the proximate mechanisms
      of wheel-running behaviour itself. For example, frequencies of sniffing and wire
      biting were reduced in selected females but not males. This result suggests that
      motivation or function of wheel running may differ between the sexes. Copyright
      1999 The Association for the Study of Animal Behaviour.

PMID- 10600155
TI  - Uncertainty in the reconstruction of ancestral character states and limitations
      on the use of phylogenetic comparative methods.

PMID- 10600156
TI  - Correlated-response-to-selection experiments designed to test for a genetic
      correlation between female preferences and male traits yield biased results.

PMID- 10600158
TI  - Biological and pathological functions of phospholipase A(2) receptor.

PMID- 10600159
TI  - Effects of phenylarsine oxide on expression of heme oxygenase-1 reporter
      constructs in transiently transfected cultures of chick embryo liver cells.
AB  - Heme oxygenase catalyzes the first and rate-controlling step of heme catabolism.
      Induction of heme oxygenase-1 can be caused by numerous factors, including heme,
      other metalloporphyrins, transition metal ions, heat shock, ultraviolet light,
      phorbol esters, sodium arsenite, and phenylarsine oxide (PAO). Induction of this
      enzyme may protect cells from oxidative damage. Using heme oxygenase-1
      promoter/reporter gene constructs, we have previously reported that the sodium
      arsenite-mediated induction of heme oxygenase-1 in chick embryo liver cells and
      chicken hepatoma (LMH) cells involves an AP-1 element. We have now investigated
      whether the PAO-mediated induction of heme oxygenase-1 also involves an AP-1
      element. Primary cultures of chick embryo liver cells were transiently
      transfected with heme oxygenase-1 promoter/reporter gene constructs, treated with
      PAO, and reporter gene activities were measured. We found that the PAO-mediated
      increase in reporter gene activity was dose- and time-dependent. This activity
      was decreased by prior treatment with N-acetylcysteine. Studies with mutated
      constructs showed that both an AP-1 element and a metal responsive element are
      involved in the PAO-mediated induction of the heme oxygenase-1 reporter
      construct. Electrophoretic mobility shift assays showed that nuclear proteins
      from PAO-treated cells had increased binding to an AP-1 probe, and that this
      increase was abrogated by N-acetylcysteine. These findings support the hypothesis
      that the PAO-mediated induction of heme oxygenase-1 is caused by activation of AP
      1 and MRE/cMyc elements and may involve nuclear proteins whose states of
      phosphorylation determine binding to regulatory elements, and thus the level of
      expression of heme oxygenase-1.

PMID- 10600160
TI  - Novel inhibitors of glutamyl-tRNA(Glu) reductase identified through cell-based
      screening of the heme/chlorophyll biosynthetic pathway.
AB  - The metabolite 5-aminolevulinic acid (ALA) is an early committed intermediate in
      the biosynthetic pathway of heme and chlorophyll formation. In plants, 5
      aminolevulinic acid is synthesized via a two-step pathway in which glutamyl
      tRNA(Glu) is reduced by glutamyl-tRNA(Glu) reductase (GluTR) to glutamate 1
      semialdehyde, followed by transformation to 5-aminolevulinic acid catalyzed by
      glutamate 1-semialdehyde aminotransferase. Using an Escherichia coli cell-based
      high-throughput assay to screen small molecule libraries, we identified several
      chemical classes that specifically inhibit heme/chlorophyll biosynthesis at this
      point by demonstrating that the observed cell growth inhibition is reversed by
      supplementing the medium with 5-aminolevulinic acid. These compounds were further
      tested in vitro for inhibition of the purified enzymes GluTR and glutamate 1
      semialdehyde aminotransferase as confirmation of the specificity and site of
      action. Several promising compounds were identified from the high-throughput
      screen that inhibit GluTR with an I(0.5) of less than 10 microM. Our results
      demonstrate the efficacy of cell-based high-throughput screening for identifying
      inhibitors of 5-aminolevulinic acid biosynthesis, thus representing the first
      report of exogenous inhibitors of this enzyme.

PMID- 10600161
TI  - Ligation of low-density lipoprotein receptor-related protein with antibodies
      elevates intracellular calcium and inositol 1,4, 5-trisphosphate in macrophages.
AB  - We have probed the signaling characteristics of the macrophage low-density
      lipoprotein receptor-related protein (LRP) with monoclonal antibody 8G1, its Fab
      and F(ab')(2) fragments directed against the ligand binding heavy chain, and
      monoclonal antibody 5A6 directed against the membrane-spanning light chain of
      LRP. Ligation of LRP with 8G1, its Fab and F(ab')(2) fragments, or 5A6 increased
      intracellular Ca(2+) levels two- to threefold. Prior ligation of LRP with 8G1 did
      not affect the increase in [Ca(2+)](i) observed on subsequent ligation of LRP
      with lactoferrin, P. exotoxin A, or lipoprotein lipase. Binding to LRP by 8G1,
      its Fab and F(ab')(2) fragments, or 5A6 increased inositol 1,4,5-trisphosphate
      (IP(3)) levels by 50 to 100%. Incubation of macrophages with guanosine 5', 3'
      O(thio)-triphosphate (GTP-gamma-S) before treatment with antibody potentiated and
      sustained the 8G1-induced increase in IP(3) levels. Treatment of macrophages with
      guanyl-5'-yl thiophosphate prior to GTP-gamma-S treatment abolished the GTP-gamma
      S-potentiated increase in IP(3) levels in 8G1-treated macrophages. Antibody
      induced increases in IP(3) and [Ca(2+)](i) in macrophages on ligation of LRP were
      pertussis toxin sensitive. Binding of 8G1 or its Fab or F(ab')(2) fragments to
      LRP stimulated macrophage protein kinase C (PKC) activity as evaluated by histone
      IIIs phosphorylation by about two- to sevenfold. Staurosporin inhibited the anti
      LRP antibody-induced increase in PKC activity. Ligation of LRP with 8G1 increased
      cellular cAMP levels about twofold. Preincubation of macrophage with the LRP
      binding protein receptor-associated protein suppressed the 8G1-induced increase
      in cAMP levels. Thus, binding of antibodies directed against either chain of LRP
      triggers complex signaling cascades.

PMID- 10600162
TI  - Characterization of recombinant human brain-derived neurotrophic factor variants.
AB  - The purpose of this work was the chemical characterization of variants of the
      recombinant human brain derived neurotrophic factor (rHu-BDNF), expressed in
      Escherichia coli. This paper also addresses the question of the in vitro activity
      of these variants. Chemical characterization of the variants employed peptide
      mapping using Glu-C protease and cyanogen bromide digestion on reduced and
      alkylated variants followed by the analysis of the digested peptides using mass
      spectrometry and Edman sequencing. The BDNF variants in this work have been
      designated by the order of their elution as observed from the high temperature
      RPLC assay. It was determined that Peaks 1 and 2, which eluted just before the
      predominant BDNF peak, had methionine sulfoxide instead of methionine at
      positions 31 and 61, respectively. Peak 4, which is chromatographically a single
      peak, contained three variants. Two of these variants had norleucine instead of
      methionine, at positions 61 and 92, respectively, while the third had methionine
      sulfoxide instead of methionine at position 92. Peak 5 had norleucine at position
      31 instead of methionine. All of these variants showed in vitro biological
      activity consistent with the BDNF standard, suggesting the preservation of the
      trkB receptor-ligand binding domain of the variants.

PMID- 10600163
TI  - Transcriptional regulation of 5-aminolevulinate synthase by phenobarbital and
      cAMP-dependent protein kinase.
AB  - 5-Aminolevulinate synthase (ALA-S) is a mitochondrial matrix enzyme that
      catalyzes the first and rate-limiting step of the heme biosynthesis. There are
      two ALA-S isozymes encoded by distinct genes. One gene encodes an isozyme that is
      expressed exclusively in erythroid cells, and the other gene encodes a
      housekeeping isozyme that is apparently expressed in all tissues. In this report
      we examine the mechanisms by which phenobarbital and cAMP regulate housekeeping
      ALA-S expression. We have determined that cAMP and phenobarbital effects are
      additive and the combined action is necessary to observe the cAMP effect on ALA-S
      mRNA in rat hepatocytes. The role of the cAMP-dependent protein kinase (PKA) has
      been examined. A synergism effect on ALA-S mRNA induction is observed in rat
      hepatocytes treated with pairs of selective analogs by each PKA cAMP binding
      sites. A 870-bp fragment of ALA-S 5'-flanking region is able to provide cAMP and
      phenobarbital stimulation to chloramphenicol O-acetyltranferase fusion vectors in
      transiently transfected HepG2 cells. ALA-S promoter activity is induced by
      cotransfection with an expression vector containing the catalytic subunit of PKA.
      Furthermore, cotransfection with a dominant negative mutant of the PKA regulatory
      subunit impairs the cAMP analog-mediated increase, but the phenobarbital-mediated
      induction is not modified. Our data suggest that the transcription factor cAMP
      response element binding protein (CREB) is probably involved in PKA induction of
      ALA-S gene expression. Finally, heme addition greatly decreases the basal and
      phenobarbital or cAMP analog-mediated induction of ALA-S promoter activity. The
      present work provides evidence that cAMP, through PKA-mediated CREB
      phosphorylation, and phenobarbital induce ALA-S expression at the transcriptional
      level, while heme represses it.

PMID- 10600164
TI  - Deamidation of asparagine residues in a recombinant serine
      hydroxymethyltransferase.
AB  - Serine hydroxymethyltransferase purified from rabbit liver cytosol has at least
      two Asn residues (Asn(5) and Asn(220)) that are 67 and 30% deamidated,
      respectively. Asn(5) is deamidated equally to Asp and isoAsp, while Asn(220) is
      deamidated only to isoAsp. To determine the effect of these Asn deamidations on
      enzyme activity and stability a recombinant rabbit liver cytosolic serine
      hydroxymethyltransferase was expressed in Escherichia coli over a 5-h period.
      About 90% of the recombinant enzyme could be isolated with the two Asn residues
      in a nondeamidated form. Compared with the enzyme isolated from liver the
      recombinant enzyme had a 35% increase in catalytic activity but exhibited no
      significant changes in either affinity for substrates or stability. Introduction
      of Asp residues for either Asn(5) or Asn(220) did not significantly alter
      activity or stability of the mutant forms. In vitro incubation of the recombinant
      enzyme at 37 degrees C and pH 7.3 resulted in the rapid deamidation of Asn(5) to
      both Asp and isoAsp with a t(1/2) of 50-70 h, which is comparable to the rate
      found with small flexible peptides containing the same sequence. The t(1/2) for
      deamidation of Asn(220) was at least 200 h. This residue may become deamidated
      only after some unfolding of the enzyme. The rates for deamidation of Asn(5) and
      Asn(220) are consistent with the structural environment of the two Asn residues
      in the native enzyme. There are also at least two additional deamidation events
      that occur during prolonged incubation of the recombinant enzyme.

PMID- 10600165
TI  - One- and two-photon-induced fluorescence from recombinant green fluorescent
      protein.
AB  - The fluorescence spectral properties of recombinant green fluorescent protein
      (rGFP) were examined with one- and two-photon excitations using femtosecond
      pulses from a Ti:sapphire laser. Intensity-dependent properties of the two-photon
      induced fluorescence from rGFP excited by an 800-nm, 100-fs laser beam were
      reported, and the two-photon excitation cross section of rGFP was measured at 800
      nm as about 160 x 10(-50) cm(4)s/photon. The possible excited-state proton
      transfer between two electronic states at about 400 nm in protonated (RH) species
      and 478 nm in deprotonated (R(-)) species in rGFP was confirmed by fluorescence
      and fluorescence excitation anisotropy spectra. A subelectronic state (or
      vibronic progression) at about 420 nm in RH species was identified, which was
      relatively stable and not involved in the excited state proton transfer in rGFP
      upon irradiation.

PMID- 10600166
TI  - Uric acid oxidation by peroxynitrite: multiple reactions, free radical formation,
      and amplification of lipid oxidation.
AB  - Uric acid has been considered to be an efficient scavenger of peroxynitrite but
      the reaction between urate and peroxynitrite has been only partially
      characterized. Also, previous studies have indicated that urate may increase
      peroxynitrite-mediated oxidation of low density lipoprotein (LDL). Here, we
      examined the reaction between urate and peroxynitrite by combining kinetic,
      oxygen consumption, spin trapping, and product identification studies; in
      parallel, we tested the effect of urate upon peroxynitrite-mediated lipid
      oxidation. Our results demonstrated that urate reacts with peroxynitrite with an
      apparent second order rate constant of 4.8 x 10(2) M(-1). s(-1) in a complex
      process, which is accompanied by oxygen consumption and formation of allantoin,
      alloxan, and urate-derived radicals. The main radical was identified as the
      aminocarbonyl radical by the electrospray mass spectra of its 5, 5-dimethyl-l
      pyrroline N-oxide adduct. Mechanistic studies suggested that urate reacts with
      peroxynitrous acid and with the radicals generated from its decomposition to form
      products that can further react with peroxynitrite anion. These many reactions
      may explain the reported efficiency of urate in inhibiting some peroxynitrite
      mediated processes. Production of the aminocarbonyl radical, however, may
      propagate oxidative reactions. We demonstrated that this radical is likely to be
      the species responsible for the effects of urate in amplifying peroxynitrite
      mediated oxidation of liposomes and LDL, which was monitored by the formation of
      lipid peroxides and thiobarbituric acid-reactive substances. The aminocarbonyl
      radical was not detectable during urate attack by other oxidants and consequently
      it is unlikely to be responsible for all previously described prooxidant effects
      of uric acid.

PMID- 10600167
TI  - Release of highly active Fet3 from membranes of the yeast Pichia pastoris by
      limited proteolysis.
AB  - A soluble derivative of Fet3 has been obtained from the methylotrophic yeast
      Pichia pastoris by limited proteolysis of membrane suspensions with trypsin. The
      soluble protein and the membrane-bound parent Fet3 have been purified to apparent
      homogeneity. Soluble Fet3 had molecular mass 100 kDa, while the full-length
      protein had molecular mass 110 kDa, in line with the expected decrease for
      cleavage and loss of a single transmembrane helix and a small cytoplasmic domain.
      The optical and EPR spectra of Fet3 were typical of the multicopper oxidases,
      indicating the presence of one type 1 blue copper site and a type 2/type 3 copper
      trinuclear cluster. V(max) values for iron oxidation by P. pastoris Fet3 were
      obtained similar to human ceruloplasmin and much higher than those reported for
      Saccharomyces cerevisiae Fet3.

PMID- 10600168
TI  - Saccharomyces cerevisiae expresses two genes encoding isozymes of
      methylenetetrahydrofolate reductase.
AB  - The identification, expression, and assay of two Saccharomyces cerevisiae genes
      encoding methylenetetrahydrofolate reductases (MTHFR) is described. MTHFR
      catalyzes the reduction of 5, 10-methylenetetrahydrofolate to 5
      methyltetrahydrofolate, used to methylate homocysteine in methionine synthesis.
      The MET12 gene is located on chromosome XVI and encodes a protein of 657 amino
      acids. The MET13 gene is located on chromosome VII and encodes a protein of 599
      amino acids. The deduced amino acid sequences of these two genes are 34%
      identical to each other and 32-37% identical to the human MTHFR. A phenotype for
      the single disruption of MET12 was not observed, however, single disruption of
      MET13 resulted in methionine auxotrophy. Double disruption of both MET12 and
      MET13 also resulted in methionine auxotrophy. Growth of the methionine auxotrophs
      was supported by both methionine and S-adenosylmethionine. Transcripts of both
      MET12 and MET13 were detected in total RNA from wild type cells grown in the
      presence or absence of methionine. The methionine requirement of the met12 met13
      double disruptant was complemented by plasmid-borne MET13, but not MET12 even
      when a multicopy plasmid was used. Furthermore, overexpression of the human MTHFR
      in the met12 met13 double disruptant complemented the methionine auxotrophy of
      this strain. In contrast, overexpression of the Escherichia coli metF gene did
      not complement the methionine requirement of met12 met13 cells. Assays for MTHFR
      in crude extracts and expression of the yeast proteins in Escherichia coli
      verified that both MET12 and MET13 encode functional MTHFR isozymes.

PMID- 10600169
TI  - Solution structure and dynamics of G1TE, a nonphosphorylated cyclic peptide
      inhibitor for the Grb2 SH2 domain.
AB  - The solution structure and dynamics of G1TE, a nonphosphorylated cyclic peptide
      inhibitor for the Grb2 SH2 domain, was determined using two-dimensional NMR and
      simulated annealing methods. G1TE consists of 10 amino acids and a C-terminal Cys
      cyclized through its side-chain sulfur atom by a thioether linkage to its N
      terminus. The results indicate that G1TE assumes a circle-like shape in solution
      in which all the side chains are protruding outside, and none of the residues are
      involved in intramolecular hydrogen bonding. The average root-mean-square
      deviations were found to be 0.41 +/- 0.11 A for the backbone heavy atoms C,
      Calpha, and N, and 1.03 +/- 0.14 A for all heavy atoms in a family of 10
      structures. (15)N relaxation measurements indicate that G1TE has rather
      restricted dynamics in the fast time scale within its backbone. However, residues
      Tyr3, Val6, and Gly7 may be involved in a possible conformational exchange. The
      structural comparison between G1TE in solution and the BCR-Abl phosphopeptide
      bound to Grb2 SH2 domain revealed that G1TE may form a larger circle-like binding
      surface than the BCR-Abl phosphopeptide in the bound form. Also, the restricted
      backbone dynamics of G1TE may result in a reduced loss of entropy and can
      compensate for the absence of a phosphate group at the Tyr3 position. These
      structural and dynamic properties of G1TE may provide a molecular basis for
      understanding its interactions with the Grb2 SH2 domain.

PMID- 10600170
TI  - Effect of training on H(2)O(2) release by mitochondria from rat skeletal muscle.
AB  - In this study, oxygen consumption and H(2)O(2) release rate by succinate or
      pyruvate/malate supplemented mitochondria isolated from skeletal muscle of
      trained and untrained rats were investigated. The overall mitochondrial
      antioxidant capacity and the effect of preincubation of mitochondria with GDP, an
      inhibitor of uncoupling proteins UCP1 and UCP2, on both succinate-supported
      H(2)O(2) release and membrane potential were also determined. The results
      indicate that training does not affect mitochondrial oxygen consumption with both
      complex-I- and complex II-linked substrates. Succinate-supported H(2)O(2) release
      was lower in trained than in untrained rats both in State 4 and State 3. Even the
      antimycin A-stimulated release was lower in trained rats. When pyruvate/malate
      were used as substrates, H(2)O(2) release rate was lower in trained rats only in
      the presence of antimycin A. The increase of mitochondrial protein content
      (determined by the ratio between cytochrome oxidase activities in homogenates and
      mitochondria) in trained muscle was such that the succinate-supported H(2)O(2)
      release per g of tissue was not significantly different in trained and untrained
      rats, while that supported by pyruvate/malate was higher in trained than in
      untrained animals. The lack of training-induced changes in overall antioxidant
      capacity of mitochondria indicates that the decrease in mitochondrial H(2)O(2)
      release cannot be attributed to a greater capacity of mitochondria to scavenge
      the reactive oxygen intermediates derived from univalent O(2) reduction by
      respiratory chain components. In contrast, the above decrease seems to depend on
      the drop induced by training in mitochondrial membrane potential. These training
      effects are not due to an increased level of mitochondrial uncoupling protein,
      because in the presence of GDP the increase in both membrane potential and
      H(2)O(2) release was greater in untrained than in trained rats.

PMID- 10600171
TI  - Differential glucocorticoid responses of CYP3A23 and CYP3A2 are mediated by
      selective binding of orphan nuclear receptors.
AB  - CYP3A2 and CYP3A23 are two cytochrome P450 genes in rat that are differentially
      regulated in both their constitutive activities and their responsiveness to
      glucocorticoids, the prototypic CYP3A inducers. CYP3A2 displays 20-25% of the
      response to glucocorticoids as CYP3A23 despite extensive sequence homology in
      their 5'-regulatory regions. Promoter deletion analyses revealed that the CYP3A2 
      57 to -168 region, homologous to the CYP3A23 dexamethasone-responsive region,
      mediated its low level activation. When this region was analyzed by DNase I
      footprinting, three binding sites were shown to correspond to the functional
      elements described for CYP3A23: DexRE-1, DexRE-2, and Site A (J. M. Huss and C.
      B. Kasper (1998) J. Biol. Chem. 273: 16155-16162). The CYP3A2 DexRE-2 and Site A
      elements bear two mismatches each from the CYP3A23 elements but displayed similar
      binding patterns in footprinting and gel-shift analyses as their CYP3A23
      counterparts. The region containing 3A2DexRE-1 has six mismatches and displayed
      unique footprinting and gel-shift patterns compared to 3A23DexRE-1. Functional
      assays revealed that four mismatches within the DexRE-1 and DexRE-2 elements
      accounted for the differential inducibility of the two isoforms. We propose that
      the reduced responsiveness of CYP3A2 is the result of preferential binding of
      COUP-TF at the CYP3A2 DexRE-1 site. In contrast, CYP3A23 DexRE-1 associates with
      an accessory factor(s) that acts in concert with downstream sites to mediate the
      strong glucocorticoid induction response observed for CYP3A23. Site A mismatches
      did not influence induction magnitude but were responsible for basal activity
      differences. Higher CYP3A23 basal activity appears to be due to an E-box in
      3A23SiteA that interacts with USF1, a ubiquitous bHLH/leucine zipper
      transcription factor. This site is disrupted in the corresponding 3A2SiteA.
      Hence, 4 nucleotide mismatches within two elements account for the difference in
      glucocorticoid induction, and a single mismatch is responsible for the fivefold
      difference in the basal activities of CYP3A2 and CYP3A23.

PMID- 10600172
TI  - The N-terminally acetylated form of mammalian histone H1(o), but not that of
      avian histone H5, increases with age.
AB  - We report here on the HPCE separation of two chicken H5 histones, which do not
      show the heterogeneity (Gln/Arg) at residue 15 first found by Greenaway and
      Murray [Greenaway and Murray (1971) Nat. New Biol. 229, 233-238]. The two
      subfractions obtained were identified using reversed-phase HPLC, hydrophilic
      interaction HPLC, Edman degradation, and MALDI-MS analysis. We found that the two
      H5 subcomponents differ only by an acetylated (designated H5a) and an
      unacetylated N-terminus (H5b). In contrast to the N-terminally acetylated form of
      rat kidney histone H1(o), which increased by about 40% with aging of the animal,
      the corresponding form of chicken H5 did not: the ratio N-terminally acetylated:
      unacetylated remained constant (30:70) when histone H5 was extracted from
      erythrocytes of newly hatched chickens and from adult chickens, respectively. The
      HPCE technique used in this investigation represents a quick and convenient
      method for analyzing N-terminally acetylated proteins in the presence of
      unacetylated forms.

PMID- 10600173
TI  - Cytochrome p450nor, a novel class of mitochondrial cytochrome P450 involved in
      nitrate respiration in the fungus Fusarium oxysporum.
AB  - Fusarium oxysporum, an imperfect filamentous fungus performs nitrate respiration
      under limited oxygen. In the respiratory system, Cytochrome P450nor (P450nor) is
      thought to catalyze the last step; reduction of nitric oxide to nitrous oxide. We
      examined its intracellular localization using enzymatic, spectroscopic, and
      immunological analyses to show that P450nor is found in both the mitochondria and
      the cytosol. Translational fusions between the putative mitochondrial targeting
      signal on the amino terminus of P450nor and Escherichia coli beta-galactosidase
      resulted in significant beta-galactosidase activity in the mitochondrial fraction
      of nitrate-respiring cells, suggesting that one of the isoforms of P450nor
      (P450norA) is in anaerobic mitochondrion of F. oxysporum and acts as nitric oxide
      reductase. Furthermore, these findings suggest the involvement of P450nor in
      nitrate respiration in mitochondria.

PMID- 10600174
TI  - Inhibitory effect of quercetin metabolites and their related derivatives on
      copper ion-induced lipid peroxidation in human low-density lipoprotein.
AB  - To determine the antioxidant activity of dietary quercetin (3,3',4', 5,7
      pentahydroxyflavone) in the blood circulation, we measured the inhibitory effect
      of quercetin metabolites and their related derivatives on copper ion-induced
      lipid peroxidation of human low-density lipoprotein (LDL). Conjugated quercetin
      metabolites were prepared from the plasma of rat 1 h after oral administration of
      quercetin aglycone (40 micromol/rat). The rate of cholesteryl ester hydroperoxide
      (CE-OOH) accumulation and the rate of alpha-tocopherol consumption in mixtures of
      LDL solution (0.4 mg/ml) with equal volumes of this preparation were slower than
      the rates in mixtures of LDL with preparations from control rats. The
      concentrations of CE-OOH after 2 h oxidation in the mixtures of LDL with
      preparations of conjugated quercetin metabolites were significantly lower than
      those in the control preparation. It is therefore confirmed that conjugated
      quercetin metabolites have an inhibitory effect on copper ion-induced lipid
      peroxidation in human LDL. Quercetin 7-O-beta-glucopyranoside (Q7G) and rhamnetin
      (3,3',4', 5-tetrahydroxy-7-methoxyflavone) exerted strong inhibition and their
      effect continued even after complete consumption, similarly to quercetin
      aglycone. The effect of quercetin 3-O-beta-glucopyranoside (Q3G) did not continue
      after its complete consumption, indicating that the antioxidant mechanism of
      quercetin conjugates lacking a free hydroxyl group at the 3-position is different
      from that of the other quercetin conjugates. The result that 4'-O-beta
      glucopyranoside (Q4'G) and isorhamnetin (3,4',5, 7-tetrahydroxy-3'
      methoxyflavone) showed little inhibition implies that introduction of a conjugate
      group to the position of the dihydroxyl group in the B ring markedly decreases
      the inhibitory effect. The results of azo radical-induced lipid peroxidation of
      LDL and the measurement of free radical scavenging capacity using stable free
      radical, 1,1,-diphenyl-2-picrylhydrazyl, demonstrated that the o-dihydroxyl
      structure in the B ring is required to exert maximum free radical scavenging
      activity. It is therefore likely that conjugation occurs at least partly in
      positions other than the B ring during the process of metabolic conversion so
      that the inhibitory effect of dietary quercetin is retained in blood plasma after
      absorption.

PMID- 10600175
TI  - Interaction of 1-hydroxyethyl radical with antioxidant enzymes.
AB  - There is considerable interest in the role of the 1-hydroxyethyl radical (HER) in
      the toxic effects of ethanol. The goal of this study was to evaluate the effects
      of HER on classical antioxidant enzymes. The interaction of acetaldehyde with
      hydroxylamine-o-sulfonic acid has been shown to produce 1, 1'-dihydroxyazoethane
      (DHAE); this compound appears to be highly unstable, and its decomposition leads
      to the generation of HER. Addition of DHAE into a solution of PBN led to the
      appearance of the typical EPR spectra of PBN/HER adduct. No PBN/HER spin adduct
      was detected when DHAE was incubated with 0.1 M PBN in the presence of GSH. In
      the absence of PBN, DHAE oxidized ascorbic acid to semidehydroascorbyl radical,
      presumably via an ascorbate-dependent one-electron reduction of HER back to
      ethanol. Catalase was progressively inactivated by exposure to DHAE-generated HER
      in a time and HER concentration-dependent manner. Ascorbic acid and PBN gave full
      protection to catalase against HER-dependent inactivation. The antioxidants 2
      tert-butyl-4-methylphenol, propylgallate, and alpha-tocopherol-protected catalase
      against inactivation by 84, 88, and 39%, respectively. Other antioxidant enzymes
      were also sensitive to exposure to HER. Glutathione reductase, glutathione
      peroxidase, and superoxide dismutase were inactivated by 46, 36, and 39%,
      respectively, by HER. The results reported here plus previous results showing HER
      interacts with GSH, ascorbate, and alpha-tocopherol suggest that prolonged
      generation of HER in cells from animals chronically exposed to ethanol may lower
      the antioxidant defense status, thereby contributing to mechanisms by which
      ethanol produces a state of oxidative stress and produces toxicity.

PMID- 10600177
TI  - Characterization of the glucosyltransferases that assemble the side chains of the
      Indian Leishmania donovani lipophosphoglycan.
AB  - The life cycle of Leishmania parasites within its sand fly vector involves the
      development of extracellular promastigotes from a noninfective, "procyclic" stage
      into an infective, "metacyclic" stage that is adapted for transmission in the fly
      and survival in the mammalian host. Lipophosphoglycan (LPG), the predominant
      surface glycoconjugate in both procyclic and metacyclic stages, is a critical
      virulence determinant. LPG is a multidomain molecule; the structural
      polymorphisms among species lie in branching from the backbone
      6Galbeta1,4Man(alpha1)-PO(4) repeat units and in the composition of the small
      oligosaccharide caps. We have recently demonstrated that the LPG from an Indian
      isolate of Leishmania donovani differs from a Sudanese strain by possessing one
      or two side chain beta(1,3)-linked glucose residues. We now have characterized
      the glucosyltransferase activities responsible for glucosylating the LPG. When
      incubated with UDP-[(3)H]glucose and Mn(2+), microsomal membranes from the Indian
      isolate transferred [(3)H]glucose to the repeat units of the exogenous acceptor
      Sudanese L. donovani LPG, which does not contain any side chain branching.
      Glucose addition was maximal at 28 degrees C, the optimal growth temperature of
      procyclic L. donovani. Consistent with the lack of side chain branching in its
      LPG, Sudanese L. donovani showed minimal glucosyltransferase activity. Indian
      metacyclic promastigotes, in contrast to procyclic promastigotes, express no
      glucose side chains off the repeat units. Therefore, we compared the relative
      activity of the glucosyltransferases in microsomes from procyclic and metacyclic
      promastigotes and observed approximately 80% less activity in the latter. These
      results provide evidence that the glucose side chain addition to LPG is
      developmentally regulated during the parasite's life cycle and that the
      glucosyltransferases of L. donovani are strain specific.

PMID- 10600176
TI  - Lysine 219 participates in NADPH specificity in a flavin-containing monooxygenase
      from Saccharomyces cerevisiae.
AB  - The flavin-containing monooxygenase from Saccharomyces cerevisiae (yFMO) uses
      NADPH and O(2) to oxidize thiol containing substrates such as GSH and thereby
      generates the oxidizing potential for the ER. The enzyme uses NADPH 12 times more
      efficiently than NADH. Amino acid sequence analysis suggests that Lys 219 and/or
      Lys 227 may act as counterions to the 2' phosphate of NADPH and to help determine
      the preference for pyridine nucleotides. Site directed mutations show that Lys
      219 makes the greater contribution to cosubstrate recognition. Conversion of Lys
      219 to Ala reduces NADPH dependent activity 90-fold, but has no effect on NADH
      dependent activity. Conversion of Lys 227 to Ala reduces NADPH-dependent activity
      fivefold and NADH-dependent activity threefold. Dissociation constants for
      NADP(+) to oxidized yFMO were measured spectroscopically. K(d) is 12 microM for
      the wild-type enzyme and 243 microM for the K219A mutant, consistent with the
      role of Lys 219 in pyridine nucleotide binding.

PMID- 10600178
TI  - Expression of cysteine proteases in extraembryonic tissues during mouse
      embryogenesis.
AB  - The expression of cathepsin B- and L-specific mRNAs as well as active forms of
      the enzymes was determined in mouse placenta and visceral yolk sac from 7.5
      through 17.5 days postconception, a period marked by major anatomic transitions
      in the mouse conceptus. The level of specific mRNA was determined relative to the
      28S ribosomal RNA in a series of multiprobe ribonuclease protection assays using
      high-specific-activity antisense cathepsin B and L riboprobes. The molecular
      forms of active cysteine proteases present in the tissues at the time of
      extraction were detected using a membrane-permeant radiolabeled active site
      specific inhibitor, Fmoc-[(125)I(2)]Tyr-Ala-CHN(2). The results of this study
      show that the expression of active cathepsin L relative to active cathepsin B is
      significantly higher in visceral yolk sac than in placenta, consistent with a
      higher proteolytic requirement for the former tissue. Active cathepsin L was
      highest at Day 9.5 in visceral yolk sac, a stage at which it has been shown that
      proteolysis in this organ is required for production of amino acids for embryonic
      protein synthesis. Cathepsin L mRNA was also elevated in the Day 9.5 placenta,
      but paradoxically this did not result in an increase in cellular active enzyme.
      An unknown protein, termed p14, highly expressed in placenta, also reacted with
      the inhibitor. Expression of this protein was highest early during gestation in
      the ectoplacental cone, suggesting that p14 may be important in the implantation
      process.

PMID- 10600180
TI  - Complex transcriptional initiation pattern of the thymidylate synthase promoter
      in mouse tissues.
AB  - Thymidylate synthase (TS) is an essential enzyme that must be expressed in all
      proliferating cells. The mouse TS promoter lacks a TATA box and an initiator
      element and initiates transcription over a broad region in cultured fibroblasts.
      The goal of this study was to determine if expression of the TS gene in a variety
      of cells and tissues involves the use of alternative promoters or different
      patterns of transcriptional initiation sites. The amount of TS mRNA and the
      pattern of initiation sites were determined using S1 nuclease protection assays.
      We found that even though the amount of TS mRNA varied over a wide range,
      reflecting differences in cell proliferation rates, the pattern of initiation
      sites was nearly identical in all of the cell lines and tissues that were
      examined. Therefore transcription of the TS gene is directed by a single promoter
      that is capable of being expressed in a wide variety of cellular environments.

PMID- 10600179
TI  - The cancer chemopreventive agent resveratrol is incorporated into model membranes
      and inhibits protein kinase C alpha activity.
AB  - Resveratrol is a phytoalexin found in grapes and other foods that cancer
      chemopreventive and other biological activities have been attributed recently. We
      report that resveratrol is able to incorporate itself into model membranes in a
      location that is inaccessible to the fluorescence quencher, acrylamide.
      Differential scanning calorimetry revealed that resveratrol considerably affected
      the gel to liquid-crystalline phase transition of multilamellar vesicles made of
      phosphatidylcholine/phosphatidylserine and increased the temperature at which the
      fluid lamellar to H(II) inverted hexagonal transition took place in multilamellar
      vesicles made of 1,2-dielaidoyl-sn-phosphatidylethanolamine. Such a transition
      totally disappeared at 2.5 mM of resveratrol (resveratrol/lipid molar ratio of
      2:1). This effect on 1, 2-dielaidoyl-sn-phosphatidylethanolamine polymorphism was
      confirmed through (31)P-NMR, which showed that an isotropic peak appeared at high
      temperature instead of the H(II)-characteristic peak of 42 mM of resveratrol
      (resveratrol/lipid molar ratio of 1.5:1). Finally, resveratrol inhibited PKCalpha
      when activated by phosphatidylcholine/phosphatidylserine vesicles with an IC(50)
      of 30 microM, whereas when the enzyme was activated by Triton X-100 micelles the
      IC(50) was 300 microM. These results indicate that the inhibition of PKCalpha by
      resveratrol can be mediated, at least partially, by membrane effects exerted near
      the lipid-water interface.

PMID- 10600181
TI  - Mechanistic studies of the oxidation of pyridoxalated hemoglobin polyoxyethylene
      conjugate by nitrogen monoxide.
AB  - Pyridoxalated hemoglobin polyoxyethylene conjugate (PHP), a modified human
      derived hemoglobin, is currently in clinical trials as a nitrogen monoxide
      scavenger for the treatment of shock. Stopped-flow spectroscopy studies of the
      reaction between nitrogen monoxide and PHP indicate that at pH 7 the second-order
      rate constant is (88 +/- 3) x 10(6) M(-1) s(-1), a value very similar to that for
      the unmodified human hemoglobin. At alkaline pH the reaction proceeds via the
      intermediate peroxynitrito complex PHP-Fe(III)OONO, which rapidly decomposes to
      nitrate and the iron(III) form of PHP. The rate of decay of PHP-Fe(III)OONO
      increases significantly with decreasing pH such that it does not accumulate in
      concentrations large enough to be observed spectroscopically under neutral or
      acidic conditions. Ion chromatographic analysis of the nitrogen-containing
      products of the NO(*)-mediated reaction of PHP shows that nitrate is formed
      quantitatively at both pH 7 and pH 9.

PMID- 10600182
TI  - Aging selectively decreases oxidative capacity in rat heart interfibrillar
      mitochondria.
AB  - Mitochondrial-derived oxidative injury contributes to cellular aging as well as
      to reperfusion-induced tissue damage. While the aging-heart suffers greater
      tissue damage following ischemia and reperfusion than the adult heart, the
      occurrence of aging-related alterations in mitochondrial oxidative metabolism in
      the elderly heart has remained uncertain. We determined if aging altered
      oxidative metabolism in either of the two populations of cardiac mitochondria,
      subsarcolemmal mitochondria (SSM) that reside beneath the plasma membrane or
      interfibrillar mitochondria (IFM) located between the myofibrils. SSM and IFM
      were isolated from 6-month adult and 24- and 28-month elderly Fischer 344 rat
      hearts. Aging-related alterations were limited to IFM, while SSM remained
      unaffected. Aging decreased the rate of oxidative phosphorylation in IFM,
      including when stimulated by electron donors specific for cytochrome oxidase.
      Cytochrome oxidase enzyme activity was decreased in IFM from aging hearts, while
      activity in SSM remained similar to adult controls. These findings allow future
      studies of aging-related decrements in oxidative function to focus upon IFM,
      while SSM provide an inherent control group of mitochondria that are free of
      aging-related alterations in oxidative function. The selective alteration of IFM
      during aging raises the possibility that the consequences of aging-induced
      mitochondrial dysfunction will be enhanced in specific subcellular regions of the
      senescent myocyte.

PMID- 10600184
TI  - Recent progress in the control and standardization of acellular pertussis
      vaccines

PMID- 10600183
TI  - Phospholamban reduces cardiac Ca-ATPase sensitivity to thapsigargin and
      cyclopiazonic acid.

PMID- 10600185
TI  - Development of acellular pertussis vaccines.
AB  - In 1974, the authors reported the isolation and characterization of protective
      antigens of Bordetella pertussis in mice. With this information, an acellular
      pertussis vaccine was developed, composed mainly of pertussis toxin (PT) and
      filamentous haemagglutinin (FHA). Substances causing side effects, especially
      lipopoly sacahoride (LPS) or endotoxin that cause fever, were removed, and
      detoxification of the PT by formaldehyde with retention of potency was achieved.
      In 1981, an acellular pertussis vaccine called the "Adsorbed Purified Pertussis
      Vaccine" was approved in Japan, in place of the whole-cell pertussis vaccine. The
      acellular pertussis vaccine has been widely accepted as safer and more
      efficacious in Japan. Since 1981, intense surveillance has shown that there are
      only rare adverse reactions and that pertussis has virtually been eliminated in
      Japan. Evaluation of active immunization with highly purified and
      pharmacologically inert PT and FHA and passive immunization with polyclonal and
      monoclonal antibodies, provide quantitative data about the vaccine-induced
      immunity in mice. Finally, it was discovered that the PT toxoid in the vaccine is
      the major and essential protective antigen. The toxoid of PT should be sufficient
      for protection against pertussis.

PMID- 10600186
TI  - Review of the biology of Bordetella pertussis.
AB  - Bordetella pertussis produces a complex array of adhesins, aggressins and toxins
      that are presumed to be important in the colonisation of its human host and in
      ensuring its survival and propagation. The organism also has highly sophisticated
      mechanisms for regulating virulence factor expression, in response to
      environmental signals or by reversible mutations. Despite the rapidly increasing
      knowledge of these aspects of the biology of B. pertussis, our understanding of
      the pathogenesis of whooping cough is still far from clear. In defining the role
      of individual factors, reliance has to be placed on in vitro assays or animal
      models of the human infection, particularly in the mouse, where different
      conditions may prevail. Some clues to pathogenic mechanisms may be provided by
      considering other bordetellae, especially B. parapertussis, B. bronchiseptica and
      B. avium, their similar, but not identical, range of virulence factors and the
      common features of the diseases caused by these species in their respective
      hosts. The bordetellae are usually defined as obligate, non-invasive parasites of
      the respiratory tracts of warm-blooded animals, including birds, with a
      predilection for the respiratory ciliated epithelium. This definition has been
      challenged by a number of recent observations. For example, the ability of
      Bordetella spp. to regulate virulence factor expression in response to external
      signals strongly suggests that they have alternative habitats where such
      regulation would be an advantage. These habitats may be intracellular, since it
      has been shown that B. pertussis, B. parapertussis and B. bronchiseptica can
      invade and survive within host cells, or they may be in other sites within the
      same or different hosts. Recent DNA fingerprinting studies of B. pertussis have
      revealed hitherto unsuspected heterogeneity amongst isolates which could be
      reflected in antigenic differences between strains. Some of these new
      perspectives on Bordetella pathogenicity may have implications for pertussis
      vaccine development.

PMID- 10600187
TI  - The immunology of bordetella pertussis infection.

PMID- 10600188
TI  - Overview of recent clinical trials of acellular pertussis vaccines.
AB  - The evidence from pre-licensure studies does not suggest that there are
      clinically important differences in reactogenicity between acellular vaccines.
      The merits of different acellular products will therefore have to be compared on
      efficacy criteria. Ideally, acellular vaccines with the minimum antigen content
      necessary to ensure optimum protection should be used in order to avoid
      administration of superfluous antigens to children and to simplify licensing and
      batch release procedures. On the basis of the evidence so far available it seems
      unlikely that monocomponent pertussis toxin (PT) vaccines provide optimal
      protection and that multicomponent vaccines are needed to achieve a level of
      disease control that approaches that of a good whole-cell vaccine. It is unclear
      whether all two component vaccines containing PT and filamentous haemagglutinin
      (FHA) have similar efficacy but on the available evidence the safest option for
      policy makers would seem to be to use a vaccine with at least three components,
      PT+FHA+pertactin. There is now good evidence that the five component vaccine
      which contains agglutinogens 2 and 3 in addition to PT/FHA and pertactin provides
      the best protection and is the only acellular vaccine whose efficacy matches that
      of a good whole cell vaccine. However, the public health advantage of the five
      component vaccine over other acellular vaccines may not become apparent until
      they have been in routine use for some decades and their ability to protect
      against transmission as well as clinical pertussis has emerged. The decision to
      replace an effective whole-cell vaccine by an acellular vaccine for primary
      immunisation needs careful consideration. Apart from the probable sacrifice of
      efficacy for reduced reactogenicity (at least for vaccines which do not contain
      agglutinogens 2 and 3) there is the question of value for money and the ease with
      which acellular DTP vaccines can be combined with conjugate polysaccharide
      vaccines such as Haemophilus influenzae type b. Whatever the decision of policy
      makers, the need for continued follow up of trial cohorts and active surveillance
      of the efficacy and safety of those acellular vaccines that are introduced into
      routine use must be accorded a high priority.

PMID- 10600189
TI  - Correlates of clinical performance of acellular pertussis vaccines: implications
      for development of DTaP combination vaccines.

PMID- 10600190
TI  - Protection against pertussis with a monocomponent pertussis toxoid vaccine.

PMID- 10600191
TI  - DTaP vaccines from north american vaccine (NAVA): composition and critical
      parameters.
AB  - NAVA's acellular pertussis vaccine is based on highly purified pertussis toxin
      (PT) inactivated with H(2)O(2). PT was analysed using advanced biochemical
      methodology including mass spectroscopy (LC/MS), yielding mass and peptide
      mapping information on the subunits. Pertactin, adenylate cyclase, and Fim 1, 2
      were below detection levels and only trace amounts of filamentous haemagglutinin
      (FHA) have been identified as a minor impurity. The vaccine does not induce anti
      FHA antibodies during the course of a 3-dose primary immunization series in
      infants. B and T cell epitopes are preserved to a higher extent after
      H(2)O(2)detoxification when compared with chemical inactivation with
      formaldehyde, thus providing new information explaining why vaccines employing
      formaldehyde detoxified PT may need additional pertussis components added to
      induce high levels of protection. Anti-PT antibodies generated by NAVA
      diphtheria, tetanus, and acellular pertussis vaccine (DTaP) showed a positive
      correlation with protection against WHO-defined pertussis. The safety profiles
      for these vaccines showed low reactogenicity with no serious adverse events due
      to the vaccines.

PMID- 10600192
TI  - Safety, immunogenicity and efficacy results of a 2-component DT acellular
      pertussis paediatric vaccine and its combinations with IPV and HIB antigens.

PMID- 10600193
TI  - The vaccine containing recombinant pertussis toxin induces early and long-lasting
      protection.
AB  - Most acellular pertussis vaccines contain a form of pertussis toxin (PT)
      detoxified by chemical treatment. The Chiron-Vaccines product is unique because
      it contains a genetically detoxified pertussis toxin. This molecule showed
      absolute safety, an antigenic profile similar to wild-type PT, and an
      immunogenicity that is superior to all chemically detoxified PTs. In the efficacy
      trial, the vaccine containing the genetically detoxified PT demonstrated early
      and long-lasting protection.

PMID- 10600194
TI  - Pasteur Merieux Connaught five-component acellular pertussis vaccine.

PMID- 10600195
TI  - Composition of acellular pertussis and combination vaccines: a general review.
AB  - Since the development and introduction of the acellular pertussis vaccine in
      Japan in the early eighties, we have come a long way in using this component in
      combination with other vaccines. However, the basic problem in development of an
      effective and safe pertussis vaccine is that the antigens to induce complete
      protection against clinical pertussis and the precise mechanism by which
      pertussis vaccine confers immunity is yet unknown. Hence, the composition of
      future acellular pertussis vaccine remains an open issue. Recently, acellular
      pertussis vaccine has been licensed for the booster doses in the U.S.A. and for
      primary immunization of infants in Italy and Germany. A multicentric trial has
      been carried out to compare the serological response and adverse reactions of 13
      acellular pertussis vaccines. These vaccines contained one or more of the four
      components, i.e. FHA, PT, 69 kDa OMP and fimbriae. All vaccines were associated
      with substantially fewer and less adverse reactions and were more immunogenic
      with respect to antibodies against the added antigens. DTP vaccines in the near
      future will have combinations of other components and the key antigen for
      combination will be acellular pertussis component which is going to replace whole
      cell pertussis component in DTP vaccines. In view of this, manufacturers like
      ourselves from the developing countries are still groping in the dark, uncertain
      whether we should have a single component acellular pertussis vaccine or
      multicomponent one. This will have a major impact on the cost of production, the
      final cost of the combination vaccines and the regulatory issues that we will
      have to tackle in view of the recent thinking on harmonization in the
      pharmaceutical industry.

PMID- 10600196
TI  - The effect of adsorption with aluminium hydroxide on the reactogenicity of
      pertussis vaccines.

PMID- 10600197
TI  - Poor response to hib (PRP-T) vaccine when combined with an acellular
      pertussis/diphtheria/tetanus vaccine for primary immunization of infants.

PMID- 10600198
TI  - Standardization of acellular pertussis vaccines.
AB  - In comparison with the current whole cell pertussis vaccine, the new generation
      of acellular pertussis vaccines opens new opportunities to improve the
      standardization of the product, because well defined and characterized components
      are used in these new products.However, different compositions, purification and
      inactivation methods are used by different manufacturers. Consequently the
      various acellular pertussis vaccines in the world are difficult to compare in a
      meaningful manner using simple laboratory tests. In addition, the absence of a
      reliable animal model and serological correlates with protection in children are
      other complicating factors. For that reason it seems that the consistency in
      manufacturing based on a clinically validated production process is the best way
      to ensure the safety and efficacy of routinely produced acellular pertussis
      vaccines. Laboratory tests to monitor the antigen content, purity, safety and
      immunogenicity seem to be the best approach to standardize this new generation of
      pertussis vaccines against homologous standard vaccines with known clinical
      efficacy and safety and to support the consistency in manufacture.

PMID- 10600199
TI  - Immunogenicity issues in the quality control of the new acellular pertussis
      vaccines.
AB  - Over the last few years our laboratory has been assessing the consistency of
      production of different batches of acellular pertussis vaccines to be marketed in
      Italy. Central to this is immunogenicity assay of the lots under control compared
      with those of a reference vaccine with documented clinical efficacy.However, the
      current assays based on the assessment of antibody (Ab) response in the mouse are
      unrelated to mechanisms of protection in children. The absence of a clear
      correlation between Ab responses and protection has also been documented in
      recent clinical trials. On this basis, we are currently considering the
      possibility of adding to the established criteria of immunogenicity in mice based
      on Ab responses, information from studies on cell-mediated immune responses to
      the vaccine constituents.

PMID- 10600200
TI  - Quantitation of immunogenicity In acellular pertussis vaccines.

PMID- 10600201
TI  - Assessment of assay precision: a case study of an ELISA for anti-pertussis
      antibody.
AB  - Assay evaluation and validation is essential to ensure that assays are
      sufficiently specific and provide estimates with sufficient precision for the
      required purposes. This must be an on-going process, and assays should therefore
      be designed to permit some degree of both direct and indirect measurement of
      intra- and inter-assay variation. Quality control procedures may contribute
      relevant information, but may not be sufficient. Results obtained by two
      laboratories using as nearly as possible identical reagents and samples in an
      ELISA for anti-pertussis antibodies are described. These results illustrate
      aspects of assay performance which may be overlooked once a formal "validation
      exercise" has been carried out and assays are in routine use. This study also
      illustrates the information, in addition to that available from in-house studies,
      which may be provided by appropriately designed inter-laboratory studies, such as
      the collaborative studies carried out for characterization and calibration of
      reference materials and standards.

PMID- 10600202
TI  - Approaches to the control of acellular pertussis vaccines.
AB  - The quality control of acellular pertussis vaccines presents particular problems
      related to the differences in composition and method of detoxification used in
      the various type of preparation. These vaccines are not amenable to potency assay
      by the active mouse protection test used for whole-cell pertussis vaccines and
      assurance of protective activity is problematic. In contrast, monitoring of these
      vaccines for safety is relatively straightforward and is centred on assays for
      the lipooligosaccharide endotoxin, active pertussis toxin and absence of
      reversion to toxicity of detoxified product. The absence of heat-labile toxin,
      tracheal cytotoxin and adenyl cyclase toxin is assumed provided that adequate
      validation of the process has been performed. Confirmation of the antigenic
      content of the detoxified bulk components is difficult to achieve by conventional
      binding assays based on monoclonal antibodies because of changes in accessibility
      of reactive sites post-toxoiding. However, single radial diffusion assay using
      polyclonal antisera permits estimation of pertussis toxoid (PT), filamentous
      haemagglutinin (FHA) and pertactin (P69). Dot blot immunoassay can be used for
      the fimbrial agglutinogens 2 and 3 (Fim 2 and 3) and potentially could also be
      used to check the composition of final filling lots for PT, FHA, P69 and Fim 2
      and 3. Gel electrophoresis and immunoblotting can be applied to monitor purity of
      purified bulk components and the characteristics of these change after chemical
      detoxification. Electron microscopy provides a useful semi-quantitative
      supporting method for checking purity of bulk components. Physico-chemical
      examination, particularly CD and fluorescence spectroscopy, offer a means of
      monitoring the consistency of detoxified bulk components. No completely
      satisfactory method is available for monitoring potency. Immunogenicity assays
      may be useful for checking consistency but do not necessarily correlate with
      protection. At present, active protection against aerosol challenge offers the
      best prospect of a functional assay.

PMID- 10600203
TI  - Acellular pertussis vaccines: neutralization by immune sera of the lethality of
      pertussis toxin and viable Bordetella pertussis for chick embryos.
AB  - Vaccines containing acellular pertussis components, either separate or combined
      with other microbial antigens, were evaluated for specific immune responses in
      guinea-pigs and mice. The capacity of sera to protect chick embryos from the
      lethal effect of pertussis toxin was independent of the Chinese hamster ovary
      cell clumping neutralization titre and the antigen binding ELISA anti-toxin
      titre. Direct correlations did not exist between ELISA titres to Pt, FHA, fimbria
      or 69 kDa and capacity to prevent killing of embryos by different strains of
      Bordetella pertussis. With the exception of one combination vaccine product,
      addition of foreign microbial antigens to acellular pertussis vaccines did not
      significantly alter capacity of the sera to protect embryos against toxin or
      bacteria.

PMID- 10600204
TI  - Evaluation of transmission electron microscopy for examination of components of
      acellular pertussis and combination vaccines.
AB  - New acellular pertussis and combination vaccines vary in the concentration and
      presence or absence of specific components and in extent of adsorption to
      adjuvants. There is a pressing need to develop new control methods for acellular
      pertussis vaccines. Negative staining electron microscopy has been evaluated as a
      method for assessing the purity of individual vaccine components and the amount
      of adsorption to aluminium gels. Negative staining showed the characteristic
      morphology of vaccine components and permitted detection of contaminants and
      morphological changes. Reproducible results were obtained by use of a
      standardized negative staining technique and confidence in the technique was
      increased by comparison of previously unexamined specimens with a specimen that
      had been characterized by repeated observations. The degree of adsorption to
      aluminium adjuvants could only be assessed by observation of the amount of non
      adsorbed material in the specimen. Negative staining electron microscopy can be
      used as one of a number of techniques for control of acellular pertussis
      combination vaccines.

PMID- 10600205
TI  - Physico-chemical analysis of Bordetella pertussis antigens.
AB  - Physico-chemical methods are being developed for use in the control and
      standardization of acellular pertussis vaccines and their individual components.
      We have compared native and detoxified preparations of the B. pertussis antigens,
      pertussis toxin (PT), filamentous haemagglutinin (FHA), and the 69-kDa outer
      membrane protein (P69) using circular dichroism (CD), fluorescence spectroscopy,
      SDS-PAGE and FPLC gel filtration chromatography. Upon aldehyde detoxification, PT
      underwent a large change in its intrinsic fluorescence maximum (8-10 nm red
      shift) and a large increase in its apparent size, detected by chromatography.
      Polyacrylamide gels showed individual subunits of the same apparent molecular
      weight (M(r)) as well as some polypeptides of higher M(r). FHA also changed
      conformation (5-nm red-shift in intrinsic fluorescence) upon aldehyde
      detoxification, with a resultant increase in the M(r)of its major constituent.
      The P69 protein appeared quite robust to formaldehyde treatment as measured by
      the same methods. Its near-UV CD spectrum contains a prominent tryptophan band;
      so this method may be more suitable for observing differences in conformation. We
      also examined an aluminium-desorbed DTaP preparation by these methods. When used
      in conjunction with immunochemical and toxicological assays, these methods are
      informative and useful in the characterization of candidate standards and should
      be valuable methods for ensuring the consistency of manufactured vaccines.

PMID- 10600206
TI  - Evaluation of protection conferred by several acellular pertussis vaccines in an
      intranasal model of B. pertussis infection.

PMID- 10600207
TI  - Histopathological investigations into the basis of the Kendrick test potency
      assay.

PMID- 10600208
TI  - Evaluation of a guinea pig model to assess interference in the immunogenicity of
      different components of a combination vaccine comprising diphtheria, tetanus and
      acellular pertussis (DTaP) vaccine and haemophilus influenzae type b capsular
      polysaccharide conjugate vaccine.
AB  - A guinea pig model to assess the immunogenicity of a combination vaccine
      containing diphtheria, tetanus and acellular pertussis (DTaP) vaccine and
      Haemophilus influenzae type b (Hib) capsular polysaccharide conjugated to tetanus
      toxoid (HibT) was evaluated comparatively with the mouse immunogenicity test to
      study the effect of combining these antigens on the immunogenicity of various
      components. The immunogenicity test in mice was performed by subcutaneous
      injection of groups of 10 animals twice at an interval of four weeks with 1/10 of
      a single human dose of various formulations of combination vaccines, DTaP or HibT
      vaccine. The animals were bled at 4 and 6 weeks and IgG or total antibodies to
      various components were determined by ELISA or RIA. The guinea pig immunogenicity
      model included groups of animals injected subcutaneously twice at an interval of
      six weeks with 1.5 times the single human dose of various formulations. The
      animals were bled at 4, 6 and 8 weeks and serum samples were tested for
      antibodies to various components by ELISA, RIA and/or neutralization tests.
      Additionally, potency of tetanus and diphtheria components was assessed as per
      the US Food and Drug Administration's regulations. Aluminium phosphate (AIPO(4))
      adsorbed HibT vaccine or HibT as a combination with AIPO(4)adsorbed DTaP vaccine
      showed significant increases in IgG antibodies to tetanus toxin in mice as well
      increased tetanus antitoxin levels in guinea pigs as compared to soluble HibT
      vaccine. In general, combining DTaP and HibT vaccines did not affect the antibody
      levels to tetanus and diphtheria toxoids whereas DTaP-HibT combination vaccine
      elicited significantly lower IgG antibodies to pertussis toxin and filamentous
      haemagglutinin than DTaP vaccine alone, particularly after first injection. Mice
      showed similar Hib antibody responses for the combination and HibT alone whereas
      guinea pigs consistently showed lower anamnestic responses to Hib for combination
      formulations than for HibT alone. Reducing the amount of HibT and/or tetanus
      toxoid in the combination formulations reduced this suppression of Hib antibody
      response in guinea pigs. Suppression of Hib antibody response in combination
      vaccines has also been reported from recent clinical trials. Based on the results
      from this study, it appears that the guinea pig model may be able to predict the
      human response to various components of combination vaccines.

PMID- 10600209
TI  - Non-pertussis components of combination vaccines: problems with potency testing.
AB  - Vaccines comprising combinations of diphtheria, tetanus and pertussis (DTP) with
      Haemophilus influenzae type b polysaccharide-protein conjugate (Hib), inactivated
      poliomyelitis virus (IPV) and hepatitis B virus (HBV) are already available, and
      new combinations using acellular pertussis components in a triple vaccine (DTaP)
      are under development. Evidence to date has shown that control of the efficacy,
      safety and stability of combination vaccines cannot be based on information
      already available on the individual components or existing licensed formulations.
      Several examples of immunological interference between components of a
      combination vaccine have been observed both in clinical trials and in laboratory
      tests. Examples of these for D, T and Hib components in DTP and DTaP combinations
      have been investigated.

PMID- 10600210
TI  - An approach to establishing diphtheria potency specifications for diphtheria and
      tetanus toxoid, acellular pertussis vaccine formulations linked to clinical
      efficacy.

PMID- 10600211
TI  - Factors affecting ability of experimental vaccines to protect guinea pigs against
      lethal challenge with diphtheria toxin.

PMID- 10600212
TI  - Comment: acellular pertussis and combination vaccines.

PMID- 10600213
TI  - Informal consultation with manufacturers and WHO Ad hoc working group on mouse
      protection models for acellular pertussis vaccines national institute for
      biological standards, 12 november 1998.

PMID- 10600214
TI  - Clinical significance of the neuroendocrine control of autoimmune processes: a
      important niche for psychoneuroimmunologists?

PMID- 10600215
TI  - Interactions between the sympathetic nervous system and the immune system.

PMID- 10600216
TI  - Individual behavioral characteristics of wild-type rats predict susceptibility to
      experimental autoimmune encephalomyelitis.
AB  - Neuroendocrine-immune interactions are thought to be important in determining
      susceptibility to autoimmune disease. Animal studies have revealed that
      differences in susceptibility to experimental autoimmune encephalomyelitis (EAE)
      are related to reactivity in the hypothalamo-pituitary-adrenal axis. It is known
      that there is a close relation between neuroendocrine parameters and behavioral
      characteristics, suggesting that behavior and disease susceptibility may be
      associated. In the present study we investigated whether behavioral
      characteristics of wild-type rats are related to susceptibility to disease. We
      show here that the latency of the animal to attack an intruder correlates
      significantly with the EAE disease score: animals that do not attack the intruder
      during the test period are more resistant to the disease than animals with short
      attack latency times. These data, obtained in an unselected strain of wild-type
      rats, demonstrate that behavioral response patterns of individual animals can in
      part predict susceptibility to autoimmune disease.

PMID- 10600217
TI  - Patients with systemic lupus erythematosus differ from healthy controls in their
      immunological response to acute psychological stress.
AB  - Clinical observations suggest that psychological stress induces exacerbation of
      disease activity in patients with systemic lupus erythematosus (SLE). In order to
      determine whether SLE patients differ from healthy controls in their stress
      response, we analyzed heart rate, blood pressure, catecholamine concentration,
      lymphocyte subpopulations, natural killer (NK) cell activity, and expression of
      beta-adrenoceptors on PBMC before, immediately after, and 1 h after a public
      speaking task in 15 SLE patients and 15 healthy subjects. Both groups
      demonstrated similar psychological, cardiovascular, and neuroendocrine responses
      to acute stress. However, natural killer (CD16(+)/CD56(+)) cell numbers
      transiently increased after stress exposure, with significantly less pronounced
      changes in SLE patients. In addition, NK activity increased in healthy controls
      (n = 8) but not in SLE patients (n = 4) after acute stress. Furthermore, the
      number of beta(2)-adrenoceptors on PBMC significantly increased only in healthy
      subjects (n = 8) after stress but not in SLE patients (n = 7). These data
      indicate that SLE patients differ from healthy controls in stress-induced immune
      responses.

PMID- 10600218
TI  - Increased sensitivity of prediabetic nonobese diabetic mouse to the behavioral
      effects of IL-1.
AB  - The nonobese diabetic (NOD) mouse is a model of spontaneous insulin-dependent
      diabetes mellitus (IDDM) or type I diabetes. In humans, and in animal models of
      IDDM, the progression of the disease is modulated by various environmental
      factors, particularly infectious agents. Interleukin-1 (IL-1) plays a pivotal
      role in the development of IDDM, and modulation of its synthesis may be a
      mechanism by which environmental modulation of disease progression occurs. Since
      various alterations at the level of the gene, number, and sensitivity of IL-1
      receptors have been described in different animal models of autoimmune disease,
      we investigated, in the prediabetic NOD mouse, the presence of IL-1 receptors and
      their functional behavioral characteristics. Here we present evidence that
      prediabetic NOD mice exhibit a normal distribution and density of functional
      brain IL-1 receptors, but are more sensitive to the behavioral effects of IL-1
      than the control ICR strain.

PMID- 10600219
TI  - Dual role for noradrenergic innervation of lymphoid tissue and arthritic joints
      in adjuvant-induced arthritis.
AB  - The role of noradrenergic innervation in the disease outcome of adjuvant-induced
      arthritis (AA) has been examined following (1) systemic administration of
      guanethidine and (2) local application of 6-hydroxydopamine (6-OHDA) into the
      lymph nodes that drain the hind limbs (DLN). Sympathetic denervation by these
      different neurotoxins produced directionally opposite effects on disease outcome.
      These conflicting findings could be explained from differential denervation of
      sympathetic nerves in key target tissues that result from different routes of
      neurotoxin administration. Alternatively, these conflicting data could be due to
      differences in the mechanisms by which guanethidine and 6-OHDA destroy
      sympathetic nerve terminals. In this study, we compared disease outcome in AA
      following systemic and local DLN application of 6-OHDA to determine whether the
      route of administration is important to the development and progression of AA.
      Bilateral local DLN application of 6-OHDA or vehicle was performed 1 day before
      injection of Freund's complete adjuvant (CFA) to induce arthritis. For systemic
      denervation, 6-OHDA or vehicle was given by ip injections on days 1, 3, and 5
      prior to CFA challenge and then once a week. Local DLN application of 6-OHDA
      resulted in significant increases in dorsoplantar width in arthritic rats by 27
      days following CFA treatment compared to those of non-denervated arthritic rats.
      In contrast, systemic denervation in arthritic rats significantly decreased
      dorsoplantar widths 27 days after CFA treatment compared to those in
      sympathetically intact arthritic animals. X-ray analysis confirmed these
      findings. Further, local DLN application of 6-OHDA exacerbated the disease
      regardless of whether the neurotoxin was administered prior to immunization with
      CFA or closer to the time of disease onset. Our findings indicate that the route
      of 6-OHDA administration for denervation of sympathetic innervation is an
      important parameter in determining disease outcome, presumably due to
      differential sympathetic denervation of target tissues that are involved in
      disease development and progression. 6-OHDA administration into local DLN
      denervated these lymph nodes, but spared sympathetic innervation of the hind
      limbs, a pattern of sympathetic denervation that resulted in disease
      exacerbation. In contrast, systemic 6-OHDA administration which denervated both
      the arthritic joints and the secondary lymphoid organs attenuated the severity of
      AA. This study supports a dual role for NA innervation in modulating the severity
      of AA by innervation of the arthritic joints and lymphoid organs.

PMID- 10600220
TI  - Hypothalamo-pituitary-adrenal axis responses to lipopolysaccharide in male and
      female rats with adjuvant-induced arthritis.
AB  - We have previously demonstrated that rats with adjuvant-induced arthritis (AA)
      are unable to mount a hypothalamo-pituitary-adrenal (HPA) axis response to either
      psychological or physical stress. In the present study we have taken male and
      female rats with AA and injected these with lipopolysaccharide (LPS) as an acute
      immune challenge and assessed the effects of this challenge at all levels of the
      HPA axis. We have demonstrated that, in contrast to acute stress, there is an
      activation of the HPA axis in male AA rats in response to acute immune challenge
      which occurs at all levels of the HPA axis. The hypothalamic and pituitary
      response to LPS is intact in the female AA rat. However, there appears to be an
      impaired adrenal responsiveness in the AA female given LPS. The non-AA female is
      able to respond to LPS suggesting that this defect is not inherent but is a
      reaction to the development of inflammation. This hyporesponsiveness has major
      implications for the ability of the organism to survive infections or immune
      challenges which are potentially life threatening in the absence of release of
      anti-inflammatory glucocorticoids from the adrenal cortex. The implications of
      these changes in the female on the subsequent development of the disease and the
      mechanisms mediating these effects may provide a better understanding of the
      gender differences underlying susceptibility to autoimmune diseases.

PMID- 10600221
TI  - Alterations in hypothalamic-pituitary-adrenal function correlated with the onset
      of murine SLE in MRL +/+ and lpr/lpr mice.
AB  - Systemic lupus erythematosus (SLE) is a spontaneously occurring, chronic
      autoimmune disease that can manifest neuropsychiatric abnormalities. The pathways
      mediating these central changes are not known; however, neuroendocrine
      alterations associated with inflammation may play a role. Predisposition to and
      progression of autoimmune disease has been associated with altered hypothalamic
      pituitary-adrenal (HPA) function and inflammation has been reported to alter
      hypothalamic regulation of HPA responses. We investigated whether disease
      progression in a murine model of systemic lupus erythematosus (MRL +/+. MRL
      lpr/lpr) resulted in altered expression of HPA regulatory peptides at the level
      of the hypothalamus and how these alterations related to circulating levels of
      corticosterone, corticosterone binding globulin, and autoantibody titers. We
      report that as MRL +/+ and MRL lpr/lpr mice age and circulating levels of
      autoantibodies increase, there is a decrease in hypothalamic CRH mRNA expression
      and finally an increase in AVP mRNA expression. We also report that associated
      with increased autoantibody levels, disease progression, and altered hypothalamic
      peptide expression there is an increase in circulating levels of corticosterone
      and a trend for levels of corticosterone binding globulin to decrease. Our data
      complement previous observations of altered peptidergic regulation of the HPA
      axis and increased HPA activity during chronic inflammation in exogenously
      induced rodent models of chronic inflammation and indicate that similar processes
      may occur in spontaneous murine models of SLE.

PMID- 10600222
TI  - Altered plasma levels of nerve growth factor and transforming growth factor-beta2
      in type-1 diabetes mellitus.
AB  - Nerve growth factor (NGF) and transforming growth factor-beta2 (TGF-beta2) are
      cytokines which have known immunological effects. An elevated level of NGF has
      been reported in certain autoimmune diseases, whereas TGF-beta2 is an
      immunosuppressor which is known to play a role in regulating cell proliferation.
      A role of this cytokine has been proposed in the pathogenesis of type-1 diabetes
      mellitus (IDDM), but no clinical studies have yet measured its serum level in
      this disease. In this study we measured the levels of NGF and TGF-beta2 in the
      sera of patients with IDDM (n = 26) and values were compared to those of age
      matched normal subjects (n = 27) and also to patients with type-2 diabetes
      mellitus (NIDDM) (n = 26) with similar HbA1c levels and an equal duration of
      diabetes. Serum NGF levels were significantly elevated in IDDM patients compared
      to those of age-matched controls (p <.001) and NIDDM controls (p <.01). TGF-beta2
      levels were lower in IDDM patients when compared with the healthy control (p
      <.001) and the NIDDM control (p <.05). There was no correlation between the
      levels of NGF and TGF-beta2. The duration of diabetes and the level of HbA1c did
      not affect the NGF and TGF-beta2 levels in the IDDM patients. We conclude that an
      increase in NGF and a suppression in TGF-beta2 levels are present in patients
      with type-1 diabetes mellitus and that both cytokines may play independent roles
      in the pathogenesis of this disease.

PMID- 10600223
TI  - Is a picture worth a thousand words? Evidence from concept definitions by
      patients with semantic dementia.
AB  - Nine patients with semantic dementia (the temporal lobe variant of frontotemporal
      dementia) were asked to define concrete concepts either from presentation of a
      picture of the object or from its spoken name. As expected, the patients with the
      most severe semantic impairment produced the least detailed definitions, and the
      quality of the definitions overall was significantly related to concept
      familiarity. Further analyses of the definitions were designed to assess two key
      theoretical aspects of semantic organization. (i) Do objects and their
      corresponding names activate conceptual information in two neuroanatomically
      separable (modality-specific) semantic systems? If so, then-apart from any
      expected commonality in performance attributable to factors such as concept
      familiarity-one would not predict striking item-specific similarities in a
      patient's picture- and word-elicited definitions. (ii) Do sensory/perceptual
      features and more associative/functional attributes of conceptual knowledge form
      two neuroanatomically separable subsystems? If so, then one would predict
      significant dissociations in the prominence of these two types of information in
      the patients' definitions. The results lead us to favor a model of the semantic
      system that is divided by attribute type but not by modality.

PMID- 10600224
TI  - A case study of transient dyslexia.
AB  - This paper presents a case study of a seizure-induced transient dyslexic episode
      experienced by a radio presenter while reading a script live on air. An analysis
      of the recording of the episode in conjunction with the script being read yields
      a number of interesting observations. There is, for example, a distinct temporal
      pattern of breakdown from what can be characterized as orthographic errors
      through to semantic confusions. Many of the orthographic errors can be explained
      as a form of repetition blindness. Furthermore, the pattern of lexical error
      lends support to a two-stage model lexicalization.

PMID- 10600225
TI  - Convergent cortical representation of semantic processing in bilinguals.
AB  - This study examined whether semantic processes in two languages (English and
      Spanish) are mediated by a common neural system in fluent bilinguals who acquired
      their second language years after acquiring their first language. Functional
      magnetic resonance imaging was performed while bilingual participants made
      semantic and nonsemantic decisions about words in Spanish and English. There was
      greater activation for semantic relative to nonsemantic decisions in left and
      right frontal regions, with greater left frontal activation. The locations of
      activations were similar for both languages, and no differences were found when
      semantic decisions for English and Spanish words were compared directly. These
      results demonstrate a shared frontal lobe system for semantic analysis of the
      languages and are consistent with cognitive research on bilingualism indicating
      that the two languages of a bilingual person access a common semantic system.

PMID- 10600226
TI  - The recognition potential: An ERP index of lexical access.
AB  - Recognition potential (RP) is a brain electrical response that appears when a
      subject views recognizable images of words. However, it has yet to be determined
      whether the processes reflected by RP are related to orthographic or to semantic
      analysis. This study aimed to resolve this question by studying the RP evoked by
      orthographically correct stimuli that were devoid of meaning. Results showed RP
      not only to this type of stimuli, but also to others achieving lower levels in
      the reading process. Strikingly, however, the RP amplitude significantly differed
      in parallel with the levels of the reading processes attained by the stimuli, the
      amplitude of the RP progressively increasing as the level approached the semantic
      one, which showed the highest amplitude. These results not only confirm the
      replicability of RP, but also its promise of potential usefulness in the study
      and assessment of language perception.

PMID- 10600227
TI  - Change of perspective in discourse comprehension: encoding and retrieval
      processes after brain injury.
AB  - Damage to frontal areas has been associated with nonaphasic language disturbances
      in which word and sentence level processes remain largely intact but text level
      processes are impaired. Most studies providing evidence for these language
      deficits have concentrated on text production. To study text comprehension of
      nonaphasic patients, we adopted the paradigm of Anderson and Pichert (1978) that
      was developed to separate encoding from retrieval processes. Subjects read a
      story under one of two alternative perspectives and subsequently recalled it.
      After this first recall, they were instructed to now adopt the second perspective
      and to recall the story once more. Twenty-four brain-injured patients
      participated. Each patient's lesion was evaluated with respect to the involvement
      of right- and/or left-frontal regions. Seven patients showed unilateral left
      frontal lesions, five patients unilateral right-frontal lesions, four patients
      had bilateral frontal damage, and the lesions of the remaining eight patients did
      not involve frontal areas. The only factor predicting behavioral results was the
      presence of a left-frontal lesion. For patients without frontal lesions and
      patients with unilateral right-frontal lesions, we replicated previously reported
      results. Encoding relevant information was recalled better than other
      information. Furthermore, the switch of perspective aided recall of perspective
      relevant information during the second recall. In contrast, patients with left
      frontal or bilateral frontal lesions could not make use of the perspective
      instructions. While they showed comparable recall performance, as well as
      sensitivity to the relative ease of information, neither the encoding
      instructions nor the switch instructions had an impact on the recall patterns.
      These results suggest that left-frontal damage leads to an impairment of goal
      directed text processing skills.

PMID- 10600228
TI  - Hemispheric asymmetry in lexical decisions: the effects of grammatical class and
      imageability.
AB  - It has been suggested that neural systems for lexical processing of nouns and
      verbs are anatomically distinct. The aim of the present study was to investigate
      if brain asymmetry for the processing of these two grammatical classes is also
      different. Neurologically intact adults performed a lateralized lexical decision
      task with grammatically unambiguous words of high, medium, and low degrees of
      imagery. For error scores a right visual field (RVF) advantage and an overall
      effect of imageability were obtained. For latency scores grammatical class and
      imageability modified visual field differences: in the noun class a RVF advantage
      was obtained only for low imagery nouns, while for the verbs the RVF advantage
      was present for both medium and low imagery verbs. These results suggest that the
      participation of right hemisphere neural systems in the processing of verbs is
      more limited than in the processing of nouns.

PMID- 10600229
TI  - The relation of phoneme discrimination, lexical access, and short-term memory: A
      case study and interactive activation account.
AB  - A brain-damaged patient (AP) is reported who had a strong tendency to identify
      nonwords as words on auditory lexical decision and to lexicalize nonwords in
      repetition, yet who showed a normal ability to perceive individual phonemes. It
      was initially hypothesized that these findings could be accounted for in terms of
      disrupted lexical phonological representations. This hypothesis was rejected on
      the basis of an interactive activation model of word recognition which revealed
      that modifications at the lexical level did not mimic the patient's pattern of
      results. Instead, it was found that increasing the rate of decay of activation at
      the phoneme level produced output that was consistent with the phoneme
      discrimination, lexical decision, and repetition results. This hypothesis of
      increased phoneme level decay led to the prediction that speech discrimination
      would decline with increased interstimulus interval and that short-term memory
      performance would be impaired. Both predictions were confirmed. The results of
      this study provide support for an interactive activation model of word
      recognition with feedback from the lexical to the phonemic level and for a close
      connection between the processes involved in word recognition and short-term
      memory.

PMID- 10600230
TI  - Hemispheric sensitivity to grammatical cues: evidence for bilateral processing of
      number agreement in noun phrases.
AB  - The present experiment employed a grammatical priming task to explore the
      possible contributions of the left and right cerebral hemispheres to the
      processing of grammatical agreement. Stimuli were three-word noun phrases, with
      the prime centered above the fixation point and the target presented laterally to
      one visual field after a 600-ms stimulus onset asynchrony. Number agreement
      between primes and targets was varied such that the article of the prime could be
      consistent (i.e., each narrow shoe or all narrow shoes), inconsistent (i.e., all
      narrow shoe or each narrow shoes) or neutral (i.e., the narrow shoe(s)) with
      respect to the inflection of the target. Half of the subjects provided lexical
      decision responses and the other half pronunciation. The bilateral priming
      effect, obtained only in lexical decision, suggests that both the left and the
      right hemispheres are sensitive to certain grammatical cues. In addition to the
      task difference in priming, the inclusion of a neutral condition and of pseudo
      inflected nonwords allowed these effects to be attributed to postlexical
      mechanisms.

PMID- 10600231
TI  - Left-handedness and achievements in foreign language studies.
AB  - Studies of brain lateralization lend support to the hypothesis that language
      motor functions in left-handers are differently organized from those in right
      handers. However, the implications of these differences regarding cognitive
      functioning are as yet subject to controversy. This concerns all hypotheses
      raised and empirical data collected over the years. Although it was suggested
      that left-handers are at higher risk of having language and reading deficits,
      empirical data from clinical and nonclinical populations are inconclusive at the
      present time. No effort, however, has been invested in examining possible
      differences in academic studies of foreign languages according to handedness.
      Here we report data indicating inferior achievements of left-handed native Hebrew
      speakers in studies of English as a foreign language. Left-handed pupils
      significantly more than right-handers were placed in lower level English classes
      and had more difficulties in applying orthographic-phonological mapping rules in
      reading English words and pseudowords. However, left-handers' difficulties in
      this task were not correlated with their performance in a word recognition task.
      It is thus suggested that the "common symptom" of poor word reading in left
      handers indicates different processing failures in different left-handers, some
      of which impede the buildup of an internal representational system of mapping
      orthography to phonology and some of which concern mainly the precision of word
      production.

PMID- 10600232
TI  - Epithelial sodium channels in skeletal cells; a role in mechanotransduction?

PMID- 10600233
TI  - Possible involvement of a chloride-bicarbonate exchanger in apoptosis of
      endothelial cells and cardiomyocytes.
AB  - We examined the role of ion movement in staurosporine-induced apoptosis of
      vascular endothelial cells. Cultured vascular endothelial cells from bovine
      carotid arteries were used. Apoptosis was determined by propidium iodide assay.
      Treatment of the endothelial cells with staurosporine (10 nmol/l-1 micromol/l)
      for 6 h induced nuclear fragmentation in a dose-dependent manner. Staurosporine
      (1 micromol/l) elicited apoptosis in 70.5+/-1.5% of cells. Concomitant treatment
      of endothelial cells with 1 mmol/l of 4, 4-diisothiocyanatostilbene-2,2
      disulfonic acid (DIDS), a chloride-bicarbonate exchange blocker, completely
      inhibited staurosporine-induced apoptosis. Other ion transporter inhibitors such
      as dimethyl amiloride and anthracene-9 carboxylic acid were less effective
      inhibitors of staurosporine-induced apoptosis of endothelial cells. DIDS
      prevented staurosporine-induced apoptosis of endothelial cells as well as
      cardiomyocytes. Next, we determined whether chloride ions or bicarbonate are
      involved in apoptosis. Incubation with a chloride ion removal buffer did not
      inhibit staurosporine-induced apoptosis of endothelial cells. However,
      endothelial cell apoptosis was completely suppressed by an inhibitor of caspase,
      benzyloxycarbonyl-Asp-CH(2)-O(C)O-dichlorobenzene (zD-dcb, 50 micromol/l).
      Staurosporine (1 micromol/l) increased the intracellular pH of endothelial cells,
      and DIDS (1 mmol/l), but not a caspase inhibitor, inhibited this increase in pH
      caused by staurosporine. Our findings suggest that endothelial cell apoptosis
      induced by staurosporine may be associated with the Cl(-)and bicarbonate (HCO-3)
      ions. Thus, Cl(-)efflux from cells or HCO-3 influx to cells (which increases pH)
      may play an important role in signal transduction leading events such as
      activation of caspase in staurosporine-induced apoptosis.

PMID- 10600234
TI  - PDGF-BB and IGF-I use different signaling pathways to induce NaK-ATPase subunits
      in cultured rat thoracic aortic smooth muscle cells.
AB  - (Na(+)+K(+))-adenosine triphosphatase (NaK-ATPase), an ubiquitous membrane
      transport protein consisting of alpha and beta subunits, regulates
      Na(+)/K(+)fluxes and maintains many vital physiological functions, including cell
      growth. Results have indicated that platelet-derived growth factor (PDGF) and
      insulin-like growth factor-I (IGF-I) both enhance NaK-ATPase subunits. Genistein,
      an inhibitor of tyrosine phosphorylation, inhibits serum- and PDGF-BB-induced NaK
      ATPase alpha(1)subunit protein levels without inhibiting IGF-I-induced NaK-ATPase
      alpha(1)subunit protein levels. These results indicate that PDGF-BB and IGF-I
      utilize separate signaling pathways to induce the synthesis of NaK-ATPase
      alpha(1)subunits. In addition, genistein failed to inhibit PDGF-BB-stimulated NaK
      ATPase beta(1)subunit levels, suggesting that two separate pathways are involved
      to induce the synthesis of the NaK-ATPase alpha(1)and beta(1)subunits,
      respectively.

PMID- 10600235
TI  - A mouse fibroblast line cycles between monolayer and spheroid forms, regulates
      Met and HGF expression, and releases an attachment and growth-promoting
      substance.
AB  - A subline of mesoderm-derived mouse NIH3T3 fibroblasts was selected for its
      ability to proliferate in serum-free media. This cell line (SFDH) grows as a
      monolayer at low density and spontaneously forms dense, multicellular spheroids
      at high density. Spheroid formation can also be induced by the addition of
      dexamethasone, polybrene, or heparin. Spheroids eventually detach from the
      substrate, but will reattach and re-form monolayers when transferred to fresh
      culture vessels and media, repeating the cycle again upon reaching high density.
      Thin section analysis of spheroids shows morphologically-distinct regions of
      cells, including an attenuated outer surface and a cuboidal interior with
      occasional lumen-like areas. Over time in culture, spheroids express increasing
      levels of met, the Met ligand-SF/HGF and cytokeratin, an epithelial marker, in
      comparison to monolayers. Both monolayer and spheroid-derived cells are rapidly
      tumorigenic in nude mice. Media conditioned by SFDH cells contain factors that
      stimulate growth and attachment of a variety of tumorigenic and non-tumorigenic
      cell lines, inducing cells to divide in serum-free media for up to 14 days when
      plated on tissue culture-treated and nontreated plastic surfaces pre-coated with
      SFDH conditional media. The growth-stimulating activity fractionates as a single
      peak over a sepharose column in the presence of 6 m urea, and sediments as a high
      molecular weight complex. Growth-stimulating activity can be neutralized by
      several antisera specific for hepatocyte growth factor, and the same sera
      recognize a novel approximately 37 kD protein in active supernatants. The cyclic,
      continuous nature of alternating monolayer and spheroid forms makes this cell
      line appropriate for studying changing gene expression patterns in progressive
      cell-cell/cell-matrix interactions.

PMID- 10600236
TI  - Mutations in the ATP-binding domain affect the subcellular distribution of
      mitotic centromere-associated kinesin (MCAK).
AB  - Mitotic centromere-associated kinesin (MCAK) is important for anaphase chromosome
      segregation. MCAK is diffusely localized to both the cytoplasm and the nucleus
      during interphase. At prophase MCAK is recruited to mitotic centromeres. It is
      associated with centromeres throughout mitosis and then returns to exhibiting a
      diffuse nuclear and cytoplasmic localization during interphase. MCAK has several
      predicted nuclear localization sequences. The subcellular distribution of
      expressed deletion constructs of GFP-MCAK suggest that the nucleocytoplasmic
      ratio of MCAK protein is dependent on a balance between several predicted nuclear
      localization sequences (NLS) and a putative nuclear exclusion sequence (NES) in
      the amino-terminal region of MCAK. Amino acid substitutions in the ATP-binding
      domain of the MCAK motor affect nuclear localization, which, in turn, influences
      the degree of centromere binding.

PMID- 10600237
TI  - Reduced viability of vascular endothelial cells by high concentration of ascorbic
      acid in vitreous humor.
AB  - Normal mammalian vitreous humor maintains its avascularity after regression of
      hyaloid vessels. Neovascularization in adults is only detected under pathological
      conditions which suggests that antiangiogenic factors are present in the vitreous
      humor. To elucidate the mechanism of vitreal angiogenic inhibition, we
      investigated the effect of vitreous humor on cultured vascular endothelial cells.
      When bovine aortic endothelial cells were cultured in the presence of bovine
      vitreous humor in medium, a decrease in cell viability was observed within 24 h.
      Ascorbic acid from vitreous humor has been identified as a cell death inducing
      factor with high performance liquid chromatography (HPLC) and molecular mass
      analysis. Ascorbic acid reduced endothelial cell viability at concentrations
      normally present in vitreous humor. This effect was completely inhibited by
      antioxidants, N-acetylcysteine and catalase. Amongst the ascorbic acid
      derivatives tested, ascorbic acid 2-phosphate did not induce cell death,
      suggesting that the production of ascorbyl radical is required for induction of
      cell death. Furthermore, capillary formation in three-dimensional collagen gel
      cultures characteristic of vascular endothelial cells were disrupted in the
      presence of ascorbic acid. Since ascorbic acid is highly concentrated in ocular
      tissues, especially in vitreous humor, it may function as a neovascularization
      inhibitor.

PMID- 10600238
TI  - Purification and characterization of a novel 35-kDa protein from transformed
      cardiomyocytes.
AB  - A 35-kDa protein (designated p35) showing antigenic homology with an N-terminal
      epitope on the SV-40 large T-antigen oncoprotein was purified from transformed
      cardiomyocytes. Sequence analysis of several tryptic peptides indicated that p35
      was not homologous to previously described sequences. Polyclonal antibody raised
      against synthetic peptide containing one of the tryptic fragments was used in
      Western blot analyses to ascertain the tissue-specific pattern of p35 expression.
      p35 was expressed ubiquitously in adult mouse tissues, and was detected in both
      embryonic and transformed cardiomyocyte preparations. Subcellular fractionation
      studies indicated that p35 is an integral membrane protein. Expression of p35
      appeared to be regulated by growth conditions as evidenced by a transient
      decrease in protein levels following the addition of serum to quiescent NIH 3T3
      cells.

PMID- 10600239
TI  - Scyphozoan jellyfish's mesoglea supports attachment, spreading and migration of
      anthozoans' cells in vitro.
AB  - Mechanically and enzymatically dissociated cells from five anthozoan species were
      laid on seven substrates in vitro. Cells were taken from two sea anemones
      (Aiptasia sp. and Anemonia sulcata), a scleractinian coral (Stylophora
      pistillata) and two alcyonacean corals (Heteroxenia fuscescence and Nephthea sp).
      Substrates tested: glass (coverslips), plastic (uncoated tissue culture plates),
      type IV collagen, gelatin, fibronectin, mesoglea pieces from the scyphozoan
      jellyfish Rhopilema nomadica and acetic acid extract of jellyfish mesoglea.
      Except for the mesoglea pieces, cells did not respond to any one of the other
      substrates, retaining their rounded shape. Following contact with mesoglea
      pieces, cells attached and spread. Subsequently they migrated into the mesogleal
      matrix at a rate of 5-10 microm/h during the first 2-5 h. No difference was found
      between the behavior of cells from the five different cnidarian species.

PMID- 10600240
TI  - The level and phosphorylation of Hsp70 in the rat liver cytosol after
      adrenalectomy and hyperthermia.
AB  - Hepatic heat shock protein Hsp70 synthesis and in vitro phosphorylation were
      studied in the liver cytosol of intact, adrenalectomized and dexamethasone
      administered adrenalectomized rats after 41 degrees C whole body hyperthermic
      stress. Hsp70 was detected by immunoblotting with N27F3-4 monoclonal antibody
      recognizing both constitutive and inducible forms of the protein. A comparison
      between basal and heat stress-induced levels of the protein in the liver cytosol
      of the three groups of animals suggested that glucocorticoid hormones stimulate
      the basal synthesis of Hsp70 and inhibit its induction by stress. In both
      unstressed and hyperthermia-exposed animals, hepatic Hsp70 was detected as a
      phosphoprotein. The extent of its in vitro phosphorylation was found to be
      significantly reduced by heat stress or adrenalectomy, but dexamethasone failed
      to restore it to the original level.

PMID- 10600241
TI  - A passion of the soul: an introduction to pain for consciousness researchers.
AB  - Pain is an important focus for consciousness research because it is an avenue for
      exploring somatic awareness, emotion, and the genesis of subjectivity. In
      principle, pain is awareness of tissue trauma, but pain can occur in the absence
      of identifiable injury, and sometimes substantive tissue injury produces no pain.
      The purpose of this paper is to help bridge pain research and consciousness
      studies. It reviews the basic sensory neurophysiology associated with tissue
      injury, including transduction, transmission, modulation, and central
      representation. In addition, it highlights the central mechanisms for the
      emotional aspects of pain, demonstrating the physiological link between tissue
      trauma and mechanisms of emotional arousal. Finally, we discuss several current
      issues in the field of pain research that bear on central issues in consciousness
      studies, such as sickness and sense of self.

PMID- 10600242
TI  - On the possibility of universal neural coding of subjective experience.
AB  - Various neurophysiological experiments have revealed remarkable correlations
      between cortical neuronal activity and subjective experiences. However, the mere
      presence of neuronal electrical activity does not appear to be sufficient to
      produce these experiences. It has been suggested that the explanation for the
      neural basis of consciousness might lie in understanding the reason that some
      types of neuronal activity possess subjective correlates and others do not. Here
      I propose and develop the idea that this difference may be caused by the
      existence of an elementary nonarbitrary linkage between temporal or
      spatiotemporal patterns of neuronal activity and their subjective attributes. I
      also show how cortical neural circuits capable of generating experience-coding
      patterns could emerge during evolution and brain development, due to the presence
      of spontaneous stochastic neuronal activity and activity-dependent synaptic
      plasticity. This hypothesis leads to several testable predictions, principal
      among which is the idea that the neural correlates of consciousness are
      essentially innate and universal.

PMID- 10600243
TI  - Dendritic encoding: an alternative to temporal synaptic coding of conscious
      experience.
AB  - In this commentary, arguments are made for a dendritic code being preferable to a
      temporal synaptic code as a model of conscious experience. A temporal firing
      pattern is a product of an ongoing neural computation; hence, it is based on a
      neural algorithm and an algorithm may not provide the most suitable model for
      conscious experience. Reiteration of a temporal firing code as suggested in a
      preceding article (Helekar, 1999) does not necessarily improve the situation. The
      alternative model presented here is that certain synaptic activity patterns,
      possibly those possessing universal features as suggested by Helekar, can become
      encoded in the dendritic structure. Following dendritic encoding, quantum
      phenomena in those specific dendrite sets could illuminate the static image of
      that encoded synaptic activity. It is the activation of the static image that
      would be equivalent to conscious experience; thus, conscious awareness would not
      be directly affiliated with synaptic activity. This dendrite encoding model may
      go farther than other models to explain the gestalt nature of consciousness,
      insofar as quantum entanglement could produce an interconnectedness between
      specific sets of dendrites-an interconnectedness that need not be based on neural
      computation or neural connections.

PMID- 10600244
TI  - In defense of experience-coding nonarbitrary temporal neural activity patterns

PMID- 10600245
TI  - Afterimages: a tool for defining the neural correlate of visual consciousness.
AB  - Our visual system not only mediates information about the visual environment but
      is capable of generating pictures of nonexistent worlds: afterimages, illusions,
      phosphenes, etc. We are "aware" of these pictures just as we are aware of the
      images of natural, physical objects. This raises the question: is the neural
      correlate of consciousness (NCC) of such images the same as that of images of
      physical objects? Images of natural objects have some properties in common with
      afterimages (e.g., stability of verticality) but there are also obvious
      differences (e.g., images maintain size constancy, whereas afterimages follow
      Emmert's Law: when seen while screens at different distances are observed, an
      afterimage looks larger, the greater the distance of the screen). The differences
      can be explained by differences in the retinal extent of images and afterimages,
      which favors the view that both have the same NCC. It seems reasonable to assume
      that before neural activity can produce awareness, all the computations necessary
      for a veridical representation of, e.g., an object, must be completed within the
      neural substrate and that information characteristic of a particular object must
      be available within the NCC. Given these assumptions, it can be shown that no
      retinotopic (in a strict sense) cortical areas can serve as the NCC, although
      some type of topographic representation is necessary. It seems also to be
      unlikely that neurons classified as cardinal cells alone can serve as NCC.

PMID- 10600246
TI  - Response deadline and subjective awareness in recognition memory.
AB  - Level of processing and generation effects were replicated in separate
      experiments in which recognition memory was tested using either short (500 ms) or
      long (1500 ms) response deadlines. These effects were similar at each deadline.
      Moreover, at each deadline these effects were associated with subsequent reports
      of remembering, not of knowing. And reports of both knowing and remembering
      increased following the longer deadline. These results imply that knowing does
      not index an automatic familiarity process, as conceived in some dual-process
      models of recognition, and that both remembering and knowing increase with the
      slower, more controlled processing permitted by the longer response time.

PMID- 10600247
TI  - Dissociative effects of alcohol on recollective experience.
AB  - This article reports a study comparing the effects of a single dose of alcohol
      with a matched placebo drink on recognition memory with and without conscious
      recollection. A double-blind, cross-over design was used with healthy volunteers
      who were all social drinkers. Processing depth at study was manipulated using
      generate versus read instructions. Conscious recollection at test was assessed
      using the remember-know-guess paradigm (Gardiner, 1988; Tulving, 1985). Alcohol
      significantly reduced conscious recollection (remember responses) but had no
      effect on recognition in the absence of conscious recollection (know responses).
      False alarms rates were low and unaffected by alcohol. Previous findings that
      generation effects are found only for remember responses were closely replicated.
      A further dissociation of the generation effect occurred between treatments in
      that deeper processing at study facilitated recognition on placebo but not on
      alcohol. That both alcohol and depth of processing produce dissociative effects
      on recollective experience provides further evidence that remembering and knowing
      reflect distinct memory systems.

PMID- 10600248
TI  - Attention effects of abrupt-onset precues with central, single-element, and
      multiple-element precues.
AB  - Endogenous and exogenous processes of attention have been inferred with different
      types of precues used in allocation of attention to a target location. In the
      present research, a comparison was made between the typical peripheral single
      element precue (SEP), a central precue, and a multiple-element precue (MEP) in
      order to further understanding of the processes involved in allocation of
      attention. Two precues were used on each trial in these experiments. An abrupt
      onset precue appeared with an SEP, an MEP, or a central precue and was followed
      50 or 300 ms later by a screen containing a target and two distractor characters.
      The abrupt-onset precue and the other precue each could be valid or invalid in
      indicating the location of the target, as in the study by Juola, Koshino, and
      Warner (1995). Response times to the targets showed that validity effects of the
      abrupt-onset precue and the MEP or central precue were additive, whereas those of
      the abrupt-onset precue and the SEP were interactive. These data suggest that,
      like a central precue, an MEP is an endogenous precue that guides conscious
      control of attention and has its attentional effects at a different processing
      level from an SEP, which is an exogenous precue and may compete for attentional
      resources with an abrupt-onset precue.

PMID- 10600249
TI  - Accounting for the computational basis of consciousness: a connectionist
      approach.
AB  - This paper argues for an explanation of the mechanistic (computational) basis of
      consciousness that is based on the distinction between localist (symbolic)
      representation and distributed representation, the ideas of which have been put
      forth in the connectionist literature. A model is developed to substantiate and
      test this approach. The paper also explores the issue of the functional roles of
      consciousness, in relation to the proposed mechanistic explanation of
      consciousness. The model, embodying the representational difference, is able to
      account for the functional role of consciousness, in the form of the synergy
      between the conscious and the unconscious. The fit between the model and various
      cognitive phenomena and data (documented in the psychological literatures) is
      discussed to accentuate the plausibility of the model and its explanation of
      consciousness. Comparisons with existing models of consciousness are made in the
      end.

PMID- 10600250
TI  - Color science and spectrum inversion: a reply to Nida-Rumelin.
AB  - Martine Nida-Rumelin (1996) argues that color science indicates that behaviorally
      undetectable spectrum inversion is possible and raises this possibility as an
      objection to functionalist accounts of visual states of color. I show that her
      argument does not rest solely on color science, but also on a philosophically
      controversial assumption, namely, that visual states of color supervene on
      physiological states. However, this assumption, on the part of philosophers or
      vision scientists, has the effect of simply ruling out certain versions of
      functionalism. While Nida-Rumelin is quite right to search for empirical tests
      for claims about the nature of visual states, philosophical issues remain pivotal
      in determining the correctness of these claims.

PMID- 10600251
TI  - Intrinsic phenomenal properties in color vision science: a reply to Peter Ross.

PMID- 10600252
TI  - Anisometry of space representation in unilateral neglect: empirical test of a
      former hypothesis.
AB  - When left-neglect patients are required to extend horizontal segments to double
      their original length, relative left overextension is frequently observed. Less
      frequently, relative left underextension may also be found. It was hypothesized
      that this contrast could depend on the degree of horizontal anisometry of the
      medium for the representation of spatial properties. The present paper reports an
      experiment conducted in order to test that hypothesis, on the basis of which left
      overextension should be larger with shorter than with longer segments and with
      segments lying in the right rather than in the left hemispace. Although
      supportive, the results unveiled unexpected complications: the expected effect of
      line length was found only in neglect patients with frontal damage, while the
      expected effect of side of presentation was found only in neglect patients
      without frontal damage.

PMID- 10600253
TI  - The effect of quinacrine on oxidative stress in kidney tissue stored at low
      temperature after warm ischemic injury.
AB  - Rabbit kidney cortex tissue slices were made ischemic (37 degrees C) for 60 min
      and then either reperfused in warm (37 degrees C) oxygenated physiologic buffer
      for 210 min or placed in UW Na gluconate solution (+/- quinacrine; 100
      micromol/L) for 18 h followed by warm aerobic reperfusion. Slices were sampled at
      intervals and analyzed for malondialdehyde (MDA) content by HPLC. Control
      (nonischemic) slices had no change in MDA content over the duration of the
      experiment. Hypothermic storage of nonischemic slices did not result in any
      increase in MDA during reperfusion. Ischemic slices showed significant increases
      in MDA content during the first 1.5 h of reperfusion and remained elevated for
      the remainder of the experiment. Hypothermic storage of warm ischemic kidney
      slices resulted in a significant decrease in MDA content during the storage
      period. However, MDA content in these slices increased during warm reperfusion
      and was significantly higher than that in nonischemic controls. Quinacrine added
      during hypothermic storage of warm ischemic slices significantly decreased slice
      MDA content during warm reperfusion, an effect which was lost by increasing the
      storage solution calcium content. This study shows that aerobic hypothermic
      storage can aid in reducing oxidative stress in warm ischemic kidney tissue
      during reperfusion. This study suggests that the effects of quinacrine are at the
      level of the mitochondrion and not as an antioxidant compound.

PMID- 10600255
TI  - Effects of solute methoxylation on glass-forming ability and stability of
      vitrification solutions
AB  - The effects of replacing hydroxyl groups with methoxyl (OCH(3)) groups in the
      polyols ethylene glycol (EG), propylene glycol (PG), glycerol, and threitol were
      studied by differential scanning calorimetry (DSC) during cooling of aqueous
      solutions to -150 degrees C and subsequent rewarming. For 35% (w/w) PG, 40% EG,
      and 45% glycerol, a single substitution of a terminal hydroxyl group with a
      methoxyl group reduced the critical cooling rate necessary to avoid ice on
      cooling (vitrify) from approximately 500 to 50 degrees C/min. This reduction was
      approximately equivalent to increasing the parent polyol concentration by 5%
      (w/w). The critical warming rate calculated to avoid formation of ice on
      rewarming (devitrification) was also reduced by methoxyl substitution, typically
      by a factor of 10(4) for dilute solutions. Double methoxylation (replacement of
      both terminal hydroxyls) tended to result in hydrate formation, making these
      compounds less interesting. An exception was threitol, for which substituting
      both terminal hydroxyls by methoxyls reduced the critical rewarming rate of a 50%
      solution by a factor of 10(7) without any hydrate formation. These glass-forming
      and stability properties of methoxylated compounds, combined with their low
      viscosity, enhanced permeability, and high glass transition temperatures, make
      them interesting candidate cryoprotective agents for cryopreservation by
      vitrification or freezing. Copyright 1999 Academic Press.

PMID- 10600254
TI  - A method for differentiating nonunique estimates of membrane transport
      properties: mature mouse oocytes exposed to glycerol.
AB  - Measurement of the osmotic response of a cell in the presence of cryoprotectant
      facilitates the determination of permeability coefficients which, in turn, can be
      used to design cryopreservation protocols which minimize osmotic stress. One
      problem encountered in determining permeability coefficients, using the Kedem
      Katchalsky (K-K) model of membrane permeability, is that several combinations of
      the three passive coupled transport coefficients, namely, hydraulic permeability
      (L(p), microm min(-1) atm(-1)), solute permeability (P(gly), microm s(-1)), and
      the reflection coefficient (sigma), can give a similar fit to the measured data.
      A method for determining the "correct" set of coefficients is suggested. The
      osmotic response of 10 metaphase II mouse oocytes was measured on perfusion with
      1.5 mol L(-1) glycerol at 24 degrees C. For 8 of 10 oocytes perfused, two
      combinations of L(p), P(gly), and sigma gave a predicted response which closely
      matched the measured osmotic response, depending upon the initial estimates
      supplied to the software for these parameters. For the remaining two oocytes,
      similar values for the permeability coefficients were generated regardless of the
      initial estimates. To determine the correct set of parameters, the K-K equations
      were used to predict experimental conditions for which volumetric histories would
      be distinctly different for the two sets of "best-fit parameters," and then
      additional experimental data were compared to these predictions. Thus a further
      three oocytes were perfused with 0.2 or 0.5 mol L(-1) glycerol in the absence of
      nonpermeating solute. In the presence of both 0.2 and 0.5 mol L(-1) glycerol,
      L(p) = 2.11 +/- 0.69, P(gly) = 0.0016 +/- 0.0015, and sigma = 0.44 +/- 0.11
      yielded a very poor fit to the measured response while L(p) = 0.98 +/- 0.70,
      P(gly) = 0. 0031 +/- 0.0021, and sigma = 0.91 +/- 0.15 yielded a close fit to the
      measured response. Thus the latter combination of coefficients was taken to be
      correct.

PMID- 10600256
TI  - Freeze-drying of red blood cells: how useful are freeze/thaw experiments for
      optimization of the cooling rate?
AB  - A red blood cell suspension, prepared according to a high-yield HES
      cryopreservation protocol, was frozen at selected cooling rates of 50, 220, 1250,
      4200, and 13,500 K/min. After either thawing or vacuum-drying, the cell recovery
      was determined using a modified saline stability test. As expected, the recovery
      of thawed samples followed the theory of Mazur's two-factor hypothesis. The best
      result was found at a cooling rate of 220 K/min. In contrast, the recovery of
      freeze-dried and rehydrated samples was very poor at that rate, but maximal at
      4200 K/min where thawing caused almost complete hemolysis. This discrepancy is
      attributed to different damaging mechanisms involved with the respective sample
      processing subsequent to freezing. While thawing leads to increased
      devitrification and recrystallization at supraoptimal cooling rates for
      cryopreservation, the resultant almost vitreous sample structure seems to be
      advantageous for vacuum-drying. It can be concluded that freeze/thaw experiments
      are not sufficient for optimization of the cooling rate for freeze-drying.

PMID- 10600257
TI  - The effect of partial removal of yolk on the chilling sensitivity of zebrafish
      (Danio rerio) embryos
AB  - The effect of partial removal of yolk on the survival of zebrafish embryos and
      the chilling sensitivity of yolk-reduced embryos were investigated at several
      stages of embryo development. Dechorionated embryos were punctured with a sharp
      microneedle and approximately 50 to 75% of yolk content was released following
      multiple punctures. The survival of yolk-reduced embryos was found to be stage
      dependent. Only 7.9% of 26-somite (24 h) embryos survived, whereas 56.7% of prim
      6 (27 h), 62.4% of prim-15 (34 h), and 81.3% of high-pec (49 h) embryos survived
      after partial removal of yolk. For chilling sensitivity studies the yolk-reduced
      embryos at high-pec stage were cultured in embryo medium for 2, 6, or 24 h to
      allow embryo recovery before they were chilled at 0 degrees C for 6 h. No
      significant differences (P > 0.05) were seen in normalized survivals between
      control and yolk-reduced embryos following a 2- or 6-h recovery period. However,
      when the recovery period was extended to 24 h, the yolk-reduced embryos showed
      significant (P < 0.05) higher survival than that of chilled controls and the
      significance was more pronounced (P < 0.01) after a longer period (10 h) of
      chilling. Similar results were also obtained with embryos at prim-6 stage. These
      results indicated that after partial removal of yolk, zebrafish embryos at post
      prim-6 stage can survive well and their sensitivity to chilling can be reduced.
      This may have significant implications in alleviating certain difficulties
      confronting the cryopreservation of fish embryos. Copyright 1999 Academic Press.

PMID- 10600258
TI  - Viability of deformed cells.
AB  - Most of the researchers in the field of cryobiology believe that the mechanism of
      damage during freezing with low cooling rates is chemical and related to the
      hypertonicity of the extracellular solution. However, there is some evidence to
      indicate that cells may be destroyed during freezing also by compression between
      ice crystals. We have developed an experimental procedure to study the effect of
      cell compression on viability. Using human prostate primary adenoma cancer cells
      we show that cell viability decreases steeply when cells are compressed to 30% of
      their original diameter. If uniform expansion of cell membrane is assumed, this
      corresponds to a 50% increase in the cell membrane surface area. A simple
      mathematical model shows that the temperature at which the compression effect may
      cause cell damage is related to the spacing between ice crystals. When the ice
      crystals are spaced at distances comparable to the cell diameter the model
      combined with our experimental data predicts compression damage at about -1.8
      degrees C. This is consistent with experimental observation on frozen cell
      destruction in the presence of antifreeze proteins.

PMID- 10600259
TI  - Cryopreservation of isolated fish blastomeres: effects of cell stage,
      cryoprotectant concentration, and cooling rate on postthawing survival
AB  - The toxicity of the cryoprotectant dimethyl sulfoxide (Me(2)SO) to isolated
      blastomeres was examined in three fish species representative of distinct
      environments: marine (whiting, Sillago japonica); estuarine (pejerrey,
      Odontesthes bonariensis); and freshwater (medaka, Oryzias latipes). The effects
      of embryonic stage, Me(2)SO concentration, and cooling rate on the
      cryopreservation of blastomeres were also studied. Whiting sheds small planktonic
      eggs whereas the other two species shed large demersal eggs. Isolated blastomeres
      from the three species tolerated Me(2)SO concentrations up to 9% relatively well
      for over 5 h but lost viability rapidly at 18%. Cells from later embryonic stages
      (512 or 1024 cells) were more tolerant of Me(2)SO than those from earlier stages
      (128 or 256 cells). The three factors examined, alone or in combination, had a
      significant effect on the survival of blastomeres after freezing and thawing, but
      the extent of the effect and the optimum conditions varied with the species. In
      general, the highest rates of successful cryopreservation were observed with
      older rather than younger blastomeres, slower rather than faster cooling, and
      with 9-18% rather than 0% Me(2)SO. Survival rates for blastomeres cryopreserved
      under the most effective combination of the three factors examined for each
      species were 19.9 +/- 10.1% for whiting, 34.1 +/- 8.5% for medaka, and 67.4 +/-
      12.8% for pejerrey. Copyright 1999 Academic Press.

PMID- 10600260
TI  - Thyroid cryotherapy in an experimental rat model.
AB  - In recent years cryotherapy has been more and more frequently used for the
      treatment of tumors of different organs. Until now, the use of cryotherapy for
      the treatment of thyroid lesions, as well as histopathologic changes in thyroid
      tissue after cryotherapy, has not been described. Nitrous oxide cryotherapy of
      one thyroid lobe in twenty 12-week male Wistar rats was performed. After 2 and 4
      weeks, the cryotreated thyroid lobe and the second lobe along with a part of the
      trachea, esophagus, and the subhyoid muscles adhering to the thyroid were excised
      and assessed macro- and microscopically. The macroscopic evaluation, performed 2
      and 4 weeks postcryotherapy, revealed atrophy of the cryotreated lobe in 4 and 3
      rats, respectively, and reduction of the cryotreated lobe dimensions in 6 and 7
      rats, respectively. In the specimens of the lobes excised 2 weeks following
      cryotherapy, examined microscopically, necrosis, granulomatous inflammation,
      hemorrhages, and hemosiderin deposits were found most often, whereas in the
      specimens of the lobe excised after 4 weeks lymphocytic inflammation and fibrosis
      were mainly observed. No microscopic changes were observed in the thyroid lobes
      that were not frozen or in the parathyroid glands located inside these lobes or
      extrathyroidally, either ipsilaterally or contralaterally to the cryotreated
      thyroid lobes. There was no microscopic damage to other tissues adjacent to the
      thyroid gland. No rat developed vocal cord dysfunction after cryotherapy and no
      significant changes in serum calcium level before and after cryotherapy were
      observed. The results obtained show that it is possible to cryoblate thyroid
      tissue without damaging the tissues adjacent to the thyroid, as well as to spare
      function of the recurrent laryngeal nerves and parathyroid glands.

PMID- 10600262
TI  - EDITORIAL.

PMID- 10600261
TI  - A histological analysis of liver injury in freezing storage.
AB  - As part of a more extensive study on the use of high subzero freezing for
      cryopreservation of mammalian livers we have tried to single out the effects of
      freezing and thawing on tissue damage. We compared the morphology of livers after
      freezing and thawing with what we considered an optimal high subzero
      cryopreservation protocol with the morphology of livers preserved under the same
      thermal conditions and in the same solution in a supercooled state, without
      freezing. The results show that while hepatocytes survive high subzero
      cryopreservation, detachment of endothelial cells occurs in every freezing
      experiment. On the other hand, the endothelial cells in livers that are not
      frozen are intact. This suggests that endothelial cell damage is caused by
      freezing and may be an important factor in high subzero freezing cryopreservation
      of the liver.

PMID- 10600263
TI  - Effects of local anaesthetics on the activity of the Na,K-ATPase of canine renal
      medulla.
AB  - The purpose of this study is to characterize the effects of local anaesthetics on
      Na,K-ATPase activity. The ATPase activity of Na, K-ATPase-enriched membranes from
      canine renal medulla was determined in the absence and in the presence of
      lidocaine, procaine, tetracaine, benzocaine, bupivacaine, prilocaine, and
      procainamide at 37 and 25 degrees C. All of these local anaesthetics, except
      benzocaine, inhibit the activity of the Na,K-ATPase of canine renal medulla at
      both 25 and 37 degrees C. Benzocaine inhibits Na,K-ATPase activity at 37 degrees
      C, but stimulates activity at 25 degrees C. The influence of lidocaine on
      stimulation of Na,K-ATPase activity by Na(+) and K(+) was investigated. Lidocaine
      increases the apparent K(0.5) of the Na,K-ATPase for both Na(+) and K(+) and
      decreases the V(max) values for both ions. IC(50) values for lidocaine increase
      with increasing concentrations of both Na(+) and K(+). The data indicate that
      lidocaine diminishes the affinity of the Na,K-ATPase for Na(+) and K(+) and that
      binding of Na(+) or K(+) decreases the potency of lidocaine as an inhibitor of
      the Na,K-ATPase. Lidocaine markedly decreases the affinity of the Na,K-ATPase for
      ouabain, but only slightly diminishes the maximum amount of ouabain bound.
      Unprotonated lidocaine is apparently a more potent inhibitor than is the
      protonated form.

PMID- 10600264
TI  - Effect of L-aminocarnitine, an inhibitor of mitochondrial fatty acid oxidation,
      on the exocrine pancreas and liver in fasted rats.
AB  - Fasting induces pancreatic secretory lipase, possibly through an increased
      utilization of fatty acids and/or ketone bodies by the acinar cells. To test this
      hypothesis, the effects of L-aminocarnitine (ACA), an inhibitor of mitochondrial
      beta-oxidation and ketone body formation, on the pancreatic enzyme composition
      were studied in rats. The characteristics and reversibility of the hepatic
      steatosis produced by ACA in fasted animals were also investigated. In fasted
      rats, ACA decreased the plasma levels of beta-hydroxybutyrate, glucose and
      insulin, but increased that of glucagon. Fasting for 3 days increased the
      pancreatic lipase content by 80%. Administration of ACA (3, 10 or 30 mg kg(-1)
      daily) for 3 days to fasted rats led to dose-related decreases in pancreatic
      lipase content, the fasting-induced increase was prevented even by the lowest
      dose. Nevertheless, ACA in the fasted rats likewise decreased the pancreatic
      contents of protein, amylase and trypsinogen to varying degrees, suggesting a
      general defect of protein synthesis. The 3-day treatment with ACA during fasting
      led to dose-related, marked increases in hepatic weight and triglyceride content.
      Light and electron microscopy revealed lipid vesicles of varying sizes in the
      hepatocytes; the fat deposition was predominant in the periportal zones of the
      hepatic lobules. By means of electron microscopy, lipid vacuoles were observed in
      the centroacinar cells, but not in the acinar cells of the pancreas. In rats
      treated with 30 mg kg(-1) of ACA daily for 3 days while they were fasted,
      cessation of ACA treatment and refeeding with normal chow led to normalization of
      the pancreatic enzyme contents within 6 days, and gradual and complete
      disappearance of the hepatic steatosis within 24 days. Microscopy also
      demonstrated complete recovery in both the liver and the pancreas. The results
      indicate that pancreatic secretory lipase induction during the adaptive phase of
      starvation is dependent on an unhindered mitochondrial beta-oxidation of fatty
      acids and ketogenesis. The dose-related degree of hepatic triglyceride
      accumulation which can be produced readily by administration of ACA during short
      term starvation in the rat may serve as a new, convenient experimental model for
      studies of fatty liver.

PMID- 10600265
TI  - Modulating role of Semecarpus anacardium L. nut milk extract on aflatoxin B(1)
      biotransformation.
AB  - As part of a substantial effort to curtail the adverse health effects posed by
      aflatoxin B(1), studies have been conducted to elucidate the possible mechanism
      for the anticarcinogenic action of Semecarpus anacardium nut extract against
      aflatoxin B(1)-induced hepatocellular carcinoma. Rats are monitored for levels of
      urinary, serum and liver biomarkers, namely, unmetabolised aflatoxin B(1), and
      its metabolites aflatoxin M(1), and aflatoxin Q(1), over the course of 2 weeks
      with nut extract therapy following a single-exposure to aflatoxin B(1). Due to
      the administration of nut extract, the excretion of unmetabolised aflatoxin B(1)
      was increased in day 1 urine when compared with rats without drug treatment. In
      serum and liver which were collected on day 16 and the rest of periodical urine
      samples showed aflatoxin B(1) and its metabolites in undetectable levels. The nut
      extract administration induced cytochrome P(450), glutathione, and glutathione-S
      transferase levels in liver homogenates of aflatoxin B(1)-treated rats. These
      data seem to indicate that anticarcinogenic action by Semecarpus anacardium nut
      extract is possibly via suppression of aflatoxin B(1)activation and through
      interaction with microsomal-activating components. Previous evidence from this
      laboratory about the potency of Semecarpus anacardium nut extract against
      aflatoxin B(1)-induced hepatocellular carcinoma together with the present results
      suggest that extremely effective therapeutic protection can be achieved by this
      drug against aflatoxin B(1)-mediated ill effects.

PMID- 10600266
TI  - Regulation of the renal basolateral transport system for organic anions by
      calcium channel blockers.
AB  - Calcium channel blockers have been reported to exert multiple effects on renal
      tubular function. Therefore, the effects of the calcium channel blockers
      nifedipine and verapamil on the cellular uptake of tritiated para -aminohippuric
      acid (PAH) into microdissected non-perfused rabbit kidney S2 proximal tubule
      segments were investigated to study a possible influence of calcium channel
      blockers on renal PAH transport. Since the tubules were entirely collapsed, the
      accumulated radioactivity overwhelmingly reflects the transport across the
      basolateral membrane. Tubular PAH accumulation was increased by 1 and 10 microm
      verapamil, and by 1 microm nifedipine, but it was unaffected by lower or higher
      concentrations of these calcium channel blockers. The increase in PAH
      accumulation caused by 1 microm nifedipine or 10 microm verapamil was independent
      from changes in intracellular Ca(2+) and inhibited by staurosporine (1 and 10 n
      m) a potent inhibitor of protein kinase C (PKC). Our results indicate that the
      calcium channel blockers nifedipine and verapamil increase the transport of
      organic anions across the basolateral membrane of proximal tubules, probably by
      an activation of PKC. Furthermore, the increased tubular PAH transport may
      disturb the estimation of the renal PAH-clearance.

PMID- 10600267
TI  - Effect of streptozotocin-induced hyperglycaemia on intravenous pharmacokinetics
      and acute cardiotoxicity of doxorubicin in rats.
AB  - The present study was designed to investigate the pharmacokinetics and acute
      cardiotoxicity of doxorubicin (DOX) after intravenous (i.v.) administration (15
      mg kg(-1)) to streptozotocin (STZ)-induced hyperglycaemic and normoglycaemic male
      Wistar albino rats. In STZ diabetic rats the area under the serum DOX time
      concentration curve (AUC(0-24 h)) increased (13.35+/-1.33 compared with 7.13+/
      0.71 microg h(-1) ml(-1); P<0.0001) and plasma and renal DOX clearance decreased.
      The DOX accumulation in STZ-induced diabetic rat heart (12.7+/-1.2 microg g(-1))
      was increased (P<0.05) compared with non-diabetic hearts (11.0+/-0.9 microg/g),
      24 h after DOX administration. Serum creatine phosphokinase (CPK) activity showed
      25% increase in peak level in STZ diabetic rats compared to non-diabetic rats.
      DOX produced a reduction in heart rate of anaesthetized non-diabetic (20%) and
      diabetic (14%) rats 1 and 2 h after its administration, respectively. Isolated
      atria of diabetic rats were more sensitive to the negative chronotropic effect of
      DOX (150 microm). These preliminary results indicate that hyperglycaemia may
      alter the pharmacokinetics and acute cardiotoxicity of DOX and suggest that i.v.
      doses of DOX in diabetic patients may need to be modified if the present data
      could be extrapolated to humans.

PMID- 10600268
TI  - Fluoxetine modulates norepinephrine contractile effect on rat vas deferens.
AB  - The aim of this study was to evaluate whether the antidepressant drug fluoxetine
      could modify rat vas deferens response to norepinephrine (NE), and to compare its
      effect with that of desipramine and cocaine. Results showed that 10(-5)m
      fluoxetine produced a super-sensibility of vas deferens to NE. This result was
      the same as those obtained for 10(-6)m desipramine or cocaine. Since the effect
      was Na(+)- and Cl(-)-dependent, an inhibitory mechanism of neuronal NE transport
      was suggested. Fluoxetine did not modify [(3)H]prazosin K(d) or B(max) in rat vas
      deferens, reinforcing the hypothesis of a pre-synaptic site of action. On the
      other hand fluoxetine inhibited NE maximal effect. This inhibitory effect could
      be related to an antagonism of calcium entry through the voltage-dependent
      calcium channel, since it was partially reverted by increasing calcium
      concentration and, besides, the drug was able to inhibit the calcium
      concentration-response curve also. Contractions induced by 5-hydroxytryptamine (5
      HT) were not modified in the presence of fluoxetine. It is concluded that
      fluoxetine modulates rat vas deferens response to low NE concentrations in the
      same manner as the selective inhibitor of NE neuronal uptake desipramine. This
      peripheral effect could participate in the modulation of the male reproductive
      tract observed by these drugs when used in clinical trials.

PMID- 10600269
TI  - The cannabinoid agonist HU 210 modifies rat behavioural responses to novelty and
      stress.
AB  - Experiments were performed on groups of rats after acute and sub-chronic
      treatment (once daily for 9 days) with the cannabinoid agonist HU 210 (25-100
      microg kg(-1), i.p.) as well as 24 h and 7 days after the last drug injection.
      The animals underwent three behavioural tests in novel environments. In the
      observation cages (Test 1), rat locomotor activity was found to be dose
      dependently reduced after acute and sub-chronic treatment at all doses and
      virtually unchanged during abstinence; grooming was potently inhibited by acute
      treatment but potentiated by the sub-chronic one at doses of 50 and 100 microg
      kg(-1), the effect of the higher dose persisting after 24 h and 7 days
      abstinence. Vocalization in animals in response to a tactile stimulus was highest
      after HU 210 at 100 microg kg(-1) in all experimental modes except after 7 days
      abstinence. In the X-maze (Test 2), sub-chronic HU 210 dose- dependently enhanced
      rat natural aversion for open arms, and this behaviour persisted during
      abstinence after the highest dose. Grooming in the X-maze was completely absent
      in rats acutely injected with HU 210 but potentiated in those sub-chronically
      treated or abstinent. In the swimming test (Test 3) rats sub-chronically treated
      at 50 and 100 pg kg(-1) displayed relevant wall-hugging and the same occurred 24
      h after last injection. On the whole, our results are indicative of an anxiogenic
      like effect of sub-chronic HU 210 at high doses and reflect the persistence of
      enhanced emotional response to novel environments when the treatment is
      discontinued.

PMID- 10600270
TI  - Distribution of lipid-soluble antioxidants in lipoproteins from healthy subjects.
      I. Correlation with plasma antioxidant levels and composition of lipoproteins.
AB  - The concentration of five lipid-soluble antioxidants (gamma- and alpha
      tocopherol, lycopene, beta-carotene and ubiquinol-10) was measured in plasma and
      very low-density, low-density and high-density lipoproteins (VLDL, LDL and HDL)
      isolated from young healthy normo- cholesterolemic subjects. Alpha-tocopherol was
      the exclusive antioxidant whose plasma concentration significantly correlated
      with the absolute concentration of total cholesterol (r =0.541, P<0.001). No
      correlation was found between plasma concentration and lipoprotein content of
      alpha-tocopherol and ubiquinol-10, whereas it reached statistically significant
      values for gamma-tocopherol, lycopene and beta-carotene. The alpha-tocopherol
      content in VLDL and HDL, but not in LDL, was strictly associated with the
      relative abundance of cholesterol and phospholipids in the lipoprotein particles.
      Moreover, the difference between alpha-tocopherol concentration in VLDL and LDL
      appeared to be strictly related to the differences in cholesterol, phospholipids
      and triglycerides. The percent distribution of the total plasma pool of
      antioxidant in each lipoprotein class revealed that gamma- and alpha-tocopherol
      were roughly equally distributed in LDL and HDL. On the other hand, lycopene,
      beta-carotene and ubiquinol-10 were preferentially sequestered in LDL. Finally,
      the absolute and relative concentration of alpha-tocopherol, but not that of
      other antioxidants, in HDL exhibited a statistically significant correlation with
      plasma HDL/LDL cholesterol ratio. These findings indicate that: (i) plasma
      concentrations of major lipid-soluble antioxidants are not always predictive of
      their levels in lipoproteins and that, within individual lipoprotein classes,
      (ii) the lipid composition, metabolism and relative plasma concentration may
      significantly affect their abundance.

PMID- 10600271
TI  - Distribution of lipid-soluble antioxidants in lipoproteins from healthy subjects.
      II. Effects of in vivo supplementation with alpha-tocopherol.
AB  - The effects of orally supplemented dl -alpha-tocopherol on the plasma
      concentration of lipid-soluble antioxidants and their distribution in very-low
      density, low-density and high-density lipoproteins (VLDL, LDL and HDL) was
      investigated in a cohort of control normocholesterolemic adult subjects receiving
      600 mg alpha-tocopherol daily for 2 weeks. This regimen did not modify the plasma
      lipid profile (total, LDL and HDL cholesterol and triglycerides) and chemical
      composition of VLDL, LDL and HDL. Plasma concentration of alpha-tocopherol
      increased from 19.44+/-4.77 to 38. 03+/-9.06 microm and this was associated with
      slight decrease in the concentration of gamma-tocopherol from 1.27+/-0.97 to
      0.99+/-1.17 microm, without any significant changes of either lycopene and beta
      carotene. Qualitatively similar changes were found in VLDL, LDL and HDL but the
      net increase of alpha-tocopherol in plasma did not correlate with the increase in
      alpha-tocopherol content in any of the lipoprotein types. Following
      supplementation, the percentage of total plasma alpha-tocopherol pool carried by
      VLDL increased from 20. 97+/-6.07% to 33.57+/-6.97%, whereas it decreased from
      41.85+/-7.02% to 36.36+/-5.69% in the case of LDL and from 37.17+/-6.04% to
      30.05+/-4.88% in the case of HDL. The absolute and relative enrichment of alpha
      tocopherol in either VLDL and LDL did not exhibit any statistically relevant
      correlation with the chemical composition of these lipoproteins in the different
      subjects investigated. On the other hand, the amount of alpha-tocopherol
      enriching the HDL particles was inversely related to the relative abundance of
      protein (r =0.449;P<0.05) and directly to the phospholipid/protein ratio (r
      =0.480, P<0.05).

PMID- 10600272
TI  - Influence of baseline values on lipids, lipoproteins and fibrinolytic parameters
      during amlodipine treatment of hypertension in Japanese patients.
AB  - Twenty-four Japanese hypertensive patients of both sexes, grouped as having
      'medium' and 'high' baseline total lipid values, had their serum lipids,
      lipoproteins and plasma fibrinolytic parameters, renin and noradrenaline levels
      determined after 3 months of amlodipine treatment. For the patients with 'medium
      baseline values', total plasminogen activator inhibitor-1 (PAI-1) and t-PA-PAI-1
      complex levels decreased, while the changes in lipids and lipoproteins were not
      significant after amlodipine treatment. For the patients with 'high baseline
      values', the mean triglyceride and very low density lipoprotein cholesterol
      (VLDLC) levels were reduced while the reductions in total and free PAI-1 and the
      increase in tissue plasminogen (t-PA) levels were not significant after
      amlodipine treatment. Negative correlations were observed between t-PA and high
      density lipoprotein cholesterol (HDLC) and HDLC/total cholesterol (TC) ratio in
      the patients with 'medium baseline values' while t-PA positively correlated with
      HDLC/TC ratio in patients with 'high baseline values'. The mean levels of renin
      and noradrenaline remained unchanged before and after amlodipine treatment in the
      two baseline groups. These findings show that baseline lipid levels of the
      hypertensive patients could influence lipids and fibrinolytic parameters
      differently during amlodipine treatment. The baseline lipid levels also
      influenced the metabolic association between lipids and fibrinolytic function in
      hypertensive patients during amlodipine treatment. The baseline total lipid
      values could therefore provide explanations for the complex metabolic interaction
      between lipids and fibrinolytic function as well as for the antiatherogenic
      actions of amlodipine treatment in hypertensive patients.

PMID- 10600273
TI  - Influence of baseline values on lipids, lipoproteins and fibrinolytic parameters
      during treatment of hypertension with cilnidipine.
AB  - Sixteen adult hypertensive patients of both sexes, classified as having 'medium'
      (total lipid profile 240-300 mg dl(-1)), and 'high' (total lipid profile >300 mg
      dl(-1)) baseline values, underwent serum lipids, lipoproteins and plasma
      fibrinolytic parameters evaluations after 3 months of cilnidipine treatment.
      Patients with 'medium baseline values' did not have any change in lipids,
      lipoproteins and fibrinolytic parameters while patients with 'high baseline
      values' had beneficial lipid and lipoprotein changes [decreases in total
      cholesterol (TC), triglycerides (TG), very low density lipoprotein-cholesterol
      (VLDLC) and increases in high density lipoprotein-cholesterol (HDLC), and HDLC/TC
      ratio] after cilnidipine treatment. Changes in lipids were negatively associated
      with fibrinolysis for the patients with 'medium baseline values' and positively
      associated in patients with 'high baseline values' after cilnidipine treatment.
      Reduction in blood pressure was related to fibrinolysis and reduced risk of
      coronary heart disease in the patients with 'high baseline values' after
      cilnidipine therapy. These results show that during cilnidipine treatment, the
      baseline lipid profile levels of the patients may influence the lipid altering
      actions as well as the interaction between lipids and fibrinolysis.

PMID- 10600274
TI  - Cytotoxic activity of kaempferol glycosides against human leukaemic cell lines in
      vitro.
AB  - Two kaempferol coumaroyl glycosides (i.e. platanoside and tiliroside) isolated
      from the methanolic extract of Platanus orientalis L. buds, were examined for
      their in vitro cytotoxic activity against a panel of human leukaemic cell lines.
      Platanoside (1) exhibited cytotoxic activity against most of the cell lines
      tested, while tiliroside (2) was active against two of the nine tested cell
      lines. Compound 1, was examined for its effect on the uptake of [(3)H]thymidine
      as a marker of DNA synthesis. Kaempferol was used as a control.

PMID- 10600275
TI  - Granulocyte chemiluminescence activity, antibody production and percentage of
      CD4(+) and CD8(+) lymphocytes in peripheral blood of offspring of salbutamol
      treated pregnant C3H mice.
AB  - Preterm delivery is one of the most important problems in obstetric care. One of
      commonly used treatment of such high risk cases is salbutamol-beta(2)
      adrenoceptor agonist. The aim of present study was to determine if such treatment
      causes any changes in neonatal immune system and therefore should be considered
      in newborn care. The experiments were performed in 4-5- and 6-7-week-old female
      and male offspring of salbutamol treated C3H inbred mice. In the present study
      chemiluminescent activity of peripheral blood granulocytes, percentage of CD4(+)
      and CD8(+) lymphocytes and antibody production were evaluated. A lower number of
      peripheral blood granulocytes in 6-7-week-old offspring of salbutamol treated
      mothers was observed, while in the case of younger mice's lymphocytes count in
      both groups, the differences were not significant as compared to control group.
      In 4-5-week-old mice a lower percentage of CD4(+), CD3(+) and CD8(+) was
      evaluated, while in older offspring the percentage of CD4(+) and CD3(+) was
      higher in the case of the progeny of salbutamol treated mothers. As far as
      chemiluminescent activity was concerned no differences were found in any of
      experimental groups. We showed higher IgM production both in male and female
      offspring of the experimental group and no changes in IgG levels in mice sera.
      Alterations observed in progeny of salbutamol treated mice might have influence
      on their further immune system development and function.

PMID- 10600276
TI  - Thymus and lymph node cell CD4(+) and CD8(+) marker expression and their
      angiogenic activity of offspring of salbutamol-treated pregnant C3H mice.
AB  - Salbutamol, beta(2)-adrenoceptor agonist is a first choice drug in preterm
      delivery treatment. The aim of the present study was to determine whether
      salbutamol can cause any alterations in neonatal immune systems and therefore
      should be considered in newborn care. The experiments were performed on 4-5- and
      6-7-week-old female and male offspring of salbutamol-treated C3H inbred mice.
      Thymus and lymph node weight, cellularity and lymphatic organs, lymphocytes
      phenotypes and their angiogenic activity were evaluated. We observed lower thymus
      weight in 6-7-week-old progeny of salbutamol-treated mothers and in the same time
      lower thymus cell number in both age groups. Lower lymph node weight was
      developed in older progeny while cellularity was diminished both in 4-5- and 6-7
      week-old offspring of salbutamol-treated mothers. We have not detected any
      changes in percentage of CD4, CD8, CD3 and CD4CD8 positive lymphocytes in progeny
      of salbutamol-treated mothers. As far as lymph node lymphocytes phenotype is
      considered we showed in both age groups lowering of CD4 and CD3 positive cells in
      experimental groups. In the LIA test (lymphocyte-induced angiogenesis) we showed
      lower lymph node cell angiogenic activity of salbutamol-treated mothers' progeny
      in both age groups. In the case of thymus lymphocytes we have not observed any
      alterations in their angiogenic activity. The differences in histological
      examination of thymus and lymph nodes were not detected in experimental and
      control groups.

PMID- 10600277
TI  - Immunosuppression and recovery of drug-impaired host resistance against Candida
      albicans infection by oxoglaucine.
AB  - The immunosuppressive action of aporphinoid alkaloid oxoglaucine was studied in
      experimental Candida albicans (C. albicans) infection in mice. The alkaloid
      augmented host resistance to pathogen applied to mice (6-8 weeks of age) at a low
      dose of 2 mg kg(-1) in 3 days and impaired it at a high dose of 10 mg kg(-1). The
      suppressive activity observed under the latter schedule correlated with the
      inhibited proliferative response of splenic cells to mitogens and with decreased
      popliteal lymph node (PLN) reaction to C. albicans. Treatment of mice with
      oxoglaucine (at the age of 5 days) at a dose of 5 mg kg(-1) in 3 consecutive days
      increased the susceptibility to Candida inoculation at the age of 6 weeks.
      Delayed type hypersensitivity (DTH) response to C. albicans was enhanced after
      pretreatment of adult mice and was suppressed after administration to newborn
      mice. Long-time treatment (10 days) with oxoglaucine, cyclophoshamide or
      prednisolone at a dose of 10 mg kg(-1) increased the rate of mortality of Candida
      infected mice. Combined pretreatment of mice with cyclophosphamide or
      prednisolone (5 days at a dose of 5 mg kg(-1)) followed by oxoglaucine (5 days at
      a dose of 5 mg kg(-1)), prolonged the survival of infected mice.

PMID- 10600278
TI  - Effects of some antibiotics on enzyme activity of glucose-6-phosphate
      dehydrogenase from human erythrocytes.
AB  - Inhibitory effects of some antibiotics on glucose-6-phosphate dehydrogenase from
      the erythrocytes of human have been investigated. For this purpose, at the
      beginning, erythrocyte glucose-6-phosphate dehydrogenase was purified 13.654
      times in a yield of 28% by using ammonium sulphate precipitation and 2',5'-ADP
      Sepharose 4B affinity gel. Temperature of +4 degrees C was maintained during the
      purification process. Enzyme activity was determined with the Beutler method by
      using a spectrophotometer at 340 nm. This method was utilized for all kinetic
      studies. Sodium ceftizoxime, sodium ampicillin, sodium cefuroxime, sodium
      cefazolin, sodium cefoperazone, streptomycin sulphate, gentamicin sulphate, and
      netilmicin sulphate were used as antibiotics. All the antibiotics indicated the
      inhibitory effects on the enzyme. K(i) constants for glucose-6-phosphate
      dehydrogenase were found by means of Lineweaver-Burk graphs. While sodium
      cefoperazone, gentamicin sulphate, and netilmicin sulphate showed competitive
      inhibition, the others displayed non-competitive inhibition. In addition, I(50)
      values of the antibiotics were determined by plotting activity percent vs [I]. In
      addition, in vivo studies were done for sodium sefuroxime in Sprague-Dawley type
      rats. It was found that G6PD in erythrocyte was more inhibited by the drug in 2.5
      h.

PMID- 10600279
TI  - Prevention of cisplatin-induced nephrotoxicity by methimazole.
AB  - Nephrotoxicity is a dose-limiting factor in the use of cisplatin against solid
      tumours. Methimazole, an antithyroid drug containing a free SH group, has a
      nephroprotective potential against chemically-induced nephrotoxicity. We tried to
      explore the nephrotoxic effect of the experimentally therapeutic dose of
      cisplatin (7 mg kg(-1), i.p.), particularly on the nuclear level of kidney cells
      in male albino rats, as well as the possible protective effect of methimazole.
      Furthermore, the drug interaction regarding the oncolytic effect of cisplatin was
      examined in Ehrlich ascites carcinoma (EAC)-bearing mice. A single dose of
      cisplatin caused kidney damage, 6 days after injection, manifested by 219%
      increase in serum creatinine, 384% increase in blood urea nitrogen and 170%
      increase in kidney content of lipid peroxides. Kidney DNA showed clear
      fragmentations detected by gel electrophoresis. However, kidney reduced
      glutathione was unchanged at that time period. Histological examination of kidney
      confirmed the toxic effect of cisplatin. Methimazole (40 mg kg(-1), i.p., 30 min
      before cisplatin injection) significantly protected the kidney from the
      nephrotoxic effect of cisplatin as judged from the biochemical parameters
      investigated as well as the histopathological examination. On the other hand, the
      survival data in EAC-bearing mice treated with both drugs indicated the
      persistence of an effective cytotoxic action. This study points to a promising
      use of this combination and necessitates further experimental and clinical
      studies.

PMID- 10600280
TI  - Effects of nitric oxide synthesis inhibition on the Na,K-ATPase activity in the
      kidney.
AB  - The present study was aimed at investigating the role of endogenous nitric oxide
      (NO) in regulating Na,K-ATPase activity in the kidney. The expression of alpha-1
      and beta-1 subunits; and the enzymatic activity of Na,K-ATPase were determined in
      the kidney of rats treated with an NO synthase inhibitor, N(G)-nitro-L-arginine
      methyl ester (L-NAME). Following the treatment with L-NAME in the drinking water
      for 4 weeks, Na,K-ATPase activity was increased while tissue nitrite/nitrate
      levels were decreased in the kidney. Supplementation with L-arginine prevented
      the L-NAME-induced changes. The expression of either alpha-1 or beta-1 subunit
      protein of Na,K-ATPase, assessed by Western blot analysis, was not affected by L
      NAME-treatment. An acute in vitro treatment of the kidney with L-NAME also caused
      an increase of Na,K-ATPase activity; which was again prevented by cotreatment
      with L-arginine. On the contrary, treatment with sodium nitroprusside
      significantly decreased Na,K-ATPase activity. These results suggest that the
      endogenous NO plays a direct inhibitory role on Na,K-ATPase activity in the
      kidney.

PMID- 10600281
TI  - Intestinal obstruction in advanced ovarian cancer: what does the patient want?

PMID- 10600282
TI  - Systematic review of surgery in malignant bowel obstruction in advanced
      gynecological and gastrointestinal cancer. The Systematic Review Steering
      Committee.
AB  - OBJECTIVE: The objective was to locate, appraise, and summarize evidence from
      scientific studies on intestinal obstruction due to advanced gynecological and
      gastrointestinal cancer in order to assess the efficacy of surgery. MATERIALS AND
      METHODS:  DATA SOURCES: A comprehensive list of studies was provided by an
      extensive search of electronic databases, relevant journals, bibliographic
      databases, conference proceedings, reference lists, the gray literature, personal
      contact, and the worldwide web. DATA SYNTHESIS: Two researchers extracted the
      data independently. Due to the methodological quality of the studies, only a
      qualitative assessment was possible. RESULTS: The role of surgery in malignant
      bowel obstruction remains controversial, and no firm conclusions from the many
      retrospective case series can be made. Control of symptoms varies from 42% to
      over 80%, although it is often unclear how symptoms were measured and whether the
      symptom scores used are validated. There is a large range in the rates of
      reobstruction, from 10 to 50%, although time to reobstruction was often not
      included. There is a wide range of postoperative morbidity and mortality,
      although again the definition of both of these surgical outcomes varied among
      many of the papers. CONCLUSION: The role of surgery in malignant bowel
      obstruction needs careful evaluation, using validated outcome measures on symptom
      control and quality of life scores. Further information would include
      reobstruction rates together with the morbidity associated with the various
      surgical procedures. Currently, bowel obstruction is managed empirically, and
      there are marked variations in clinical practice by different units. There needs
      to be a greater standardization of management so that comparisons between
      different series can be made.

PMID- 10600283
TI  - Lymphedema and lymphocysts following lymphadenectomy may be prevented by
      omentoplasty: A pilot study.
AB  - OBJECTIVES: Pelvic lymph node dissection as part of the staging surgery for
      cervical carcinoma interrupts the afferent lymphatics, so the lymph drains
      retroperitoneally. New surgical techniques designed to leave the peritoneum open
      after the retroperitoneal dissection, in particular the application of a pedicled
      omentoplasty along the dissection route, have been advocated to prevent the
      formation of lymphocysts and lymphedema. We investigated the possible benefit of
      pedicled omentoplasty in preventing lymphocysts and lymphedema following pelvic
      lymph node dissection. METHODS: In this pilot study with historical controls we
      compared the formation of lymphocysts and lymphedema following two different
      surgical techniques for pelvic node dissection: group I (historical controls), in
      which the dorsal peritoneum was left open, and group II, in which the dorsal
      peritoneum was left open with application of a pedicled omentoplasty. In these
      two groups of gynecologic patients, we compared the lymph flow patterns and the
      occurrence of lymphedema following systemic pelvic lymphadenectomy. The two
      groups were of comparable clinical status and consisted of 12 (group I) and 10
      (group II) patients. Lymphocysts, if any, were detected by CT scan, the lymph
      flow patterns were visualized by dynamic lymphscintography, and lymphedema was
      visualized by physical examination and magnetic resonance imaging of the groin
      and the upper leg. RESULTS: In both groups a distinct intraperitoneal absorption
      of the lymph fluid was observed. Pedicled omentoplasty seemed to facilitate the
      absorption or transport of lymph fluid, resulting in less lymphedema in the upper
      leg. CONCLUSION: It appeared that leaving the dorsal peritoneum open to give the
      lymph stream the opportunity to pour into the abdominal cavity is important in
      preventing lymphocysts and lymphedema. The dynamic lymphscintigraphy described in
      this paper showed that the intraabdominal lymph flow is absorbed by the
      peritoneum and even more quickly by the pedicled omentum.

PMID- 10600284
TI  - The prognostic factors for patients with early cervical cancer treated by radical
      hysterectomy and postoperative radiotherapy.
AB  - PURPOSE: This study was undertaken to evaluate the efficacy of postoperative
      radiotherapy (post-OP RT) and to investigate the prognostic factors for early
      stage cervical cancer patients who were treated by radical surgery, and the
      pathological findings suggested a relatively high risk of relapse with surgery
      alone. MATERIALS AND METHODS: From January 1990 to December 1995, 222 patients
      with stage IB-IIA cervical cancer, treated by radical surgery and a full course
      of post-OP RT, were included in this study. The indications for post-OP RT were
      based on pathological findings, including lymph node metastasis, positive
      surgical margins, parametrial extension, lymphovascular permeation, and invasion
      of more than two-thirds of the cervical wall thickness. The radiation dose of
      external beam was 44-45 Gy to the whole pelvis and 50-54 Gy to the true pelvis.
      One hundred seventy-two patients also received intravaginal brachytherapy as a
      local boost. The minimal follow-up period was 2 years. RESULTS: The actuarial 5
      year overall and disease-specific survival rates for all patients were 76 and
      82%, respectively. The tumor control rate within the pelvis reached 94%, and
      distant metastasis was the major cause of treatment failure. Univariate analysis
      of clinical and pathological parameters revealed that clinical stage, bulky tumor
      size, positive lymph nodes, parametrial extension, and histologic type were
      significant prognostic factors. After multivariate analysis, only positive lymph
      nodes (P = 0.01), bulky tumor size (P = 0.02), and parametrial extension (P =
      0.05) independently influenced the disease-specific survival (DSS). For patients
      with lymph node metastasis, the number and location of the nodal involvement
      significantly affected the prognosis. The 5-year DSS for patients with no, one,
      and more than one lymph node metastasis were 87, 84, and 61% (P = 0.0001),
      respectively. Patients with upper pelvic lymph node metastasis had a higher
      incidence of distant metastasis (50% vs 16% in lower pelvic node group, P =
      0.03). In the subgroup of single lower pelvic nodal metastasis, the prognosis was
      similar to that of patients without lymph node involvement (5-year DSS 85% vs
      87%, P = 0.71). CONCLUSION: Our results indicate that post-OP RT can achieve very
      good local control in stage IB-IIA cervical cancer patients whose pathological
      findings show risk features for relapse after radical surgery. The prognostic
      factors for treatment failure identified in this study can be used as selection
      criteria for clinical trials to test the effects of other adjuvant treatments,
      such as chemotherapy. Patients with a single lower pelvic lymph node metastasis
      have a relatively good prognosis and may not need adjuvant treatment beyond
      radiation therapy.

PMID- 10600285
TI  - First-line chemotherapy with paclitaxel and platinum for advanced and recurrent
      cancer of the cervix--a phase II study.
AB  - OBJECTIVE: The aim of this study was to assess the role of first-line
      chemotherapy with paclitaxel and platinum in the treatment of advanced or
      recurrent cervix cancer. METHODS: Twenty patients with advanced or recurrent
      cancer of the cervix with no prior chemotherapy and measurable disease were
      entered in a phase II trial from September 1995 to September 1998. Seventeen
      patients were treated with paclitaxel at 135 mg/m(2) over 24 h followed by
      cisplatin at 75 mg/m(2) every 4 weeks. Three patients with impaired renal
      function were treated with paclitaxel at 135 mg/m(2) over 3 h with carboplatin at
      300 mg/m(2). RESULTS: A clinical response rate of 45% was noted (two complete
      responses and seven partial responses) with a median duration of 6 months (range:
      1.5-9). The median progression-free interval and overall survival in patients
      with a clinical response was 10.5 and 13 months, respectively, compared to 4 (P =
      0.015) and 6 months in the nonresponders (P = 0. 14). Seven of nine patients
      (77.8%) with a clinical response are alive. Patients with recurrences outside the
      radiation field had twice the response rate (60%) than that of those within the
      radiated field. The chemotherapy was well tolerated; the most significant
      toxicity was grade 3/4 neutropenia (55%). No patient had discontinuation of
      chemotherapy due to toxicity. CONCLUSIONS: First-line chemotherapy with
      paclitaxel and platinum for advanced and recurrent cervix cancer is promising and
      deserves consideration for large phase III trials.

PMID- 10600286
TI  - Cytologic examination to detect clear cell adenocarcinoma of the vagina or
      cervix.
AB  - OBJECTIVE: The aim of this study was to determine the sensitivity of
      cytopathologic examination for the detection of vaginal or cervical clear cell
      adenocarcinoma (CCA). METHODS: Systematic collection in the Dutch automated
      nationwide pathology archive of all cytology and histology data of women with
      CCA, born in The Netherlands after 1947 was performed. All cytologic examinations
      within 2 years prior to histological diagnosis of CCA were included. RESULTS:
      Ninety patients with CCA have been registered. Forty-nine of these patients had
      cytologic examinations prior to histology. Eighty-five percent of cervical CCAs
      were preceded by a positive cervical smear. One hundred percent of vaginal CCAs
      were preceded by a positive vaginal smear. Cervical smears are relatively
      insensitive to detect vaginal CCA. Vaginal smears were often omitted. Only 2
      apparently false-negative smears were found. The mean numbers of smears in
      diethylstilbestrol (DES)-exposed and nonexposed women were minimally different:
      1.0 and 0.8, respectively. This suggests an only modest impact of the awareness
      of DES as a risk factor. FIGO tumor stage I was preceded more frequently by
      cytology than the higher tumor stages. CONCLUSION: The majority of CCA cases can
      be detected at an early stage by yearly clinical and cytological examinations,
      which must comprise cervical as well as vaginal sampling. Since CCA may also
      occur in postmenopausal women, for the purpose of secondary prevention of CCA
      regular cytologic examinations of DES-exposed women must be continued after
      menopause.

PMID- 10600287
TI  - Utility of the monoclonal antibody HIK1083 in the diagnosis of adenoma malignum
      of the uterine cervix.
AB  - OBJECTIVES: The aim of this study was to qualify a staining technique for the
      diagnosis of adenoma malignum. METHODS: The gastric mucin expression of adenoma
      malignum, ordinary endocervical adenocarcinoma, and normal cervical glands was
      immunohistochemically compared using the monoclonal antibody HIK1083. RESULTS:
      The three categories were clearly distinguished, with 90% (9/10) of cases with
      positive adenoma malignum, 30% (3/10) of cases with weakly positive ordinary
      cervical adenocarcinoma, and no (0/10) cases of positive normal cervical glands.
      CONCLUSIONS: This preliminary report indicates that the use of HIK1083 is
      valuable in the diagnosis of adenoma malignum.

PMID- 10600289
TI  - Randomized study comparing two techniques of conization: cold knife versus loop
      excision.
AB  - OBJECTIVE: To compare the histomorphologic and colposcopic results of cold knife
      conization and loop excision. METHODS: Sixty-six women were randomly allocated to
      have the cone specimen removed by cold knife excision (n = 38) or loop excision
      (n = 28). Subjects eligible for inclusion were those who presented histologically
      verified grade 3 cervical intraepithelial neoplasia (CIN) or grade 2 CIN with
      squamocolumnar junction not seen. RESULTS: The mean height of the cone specimens
      was greater in the cold knife group [18.9 mm (SD = 5. 5) and 12.8 mm (SD = 4.3),
      respectively; P = 0.0001], as was the frequency of clear margins (100 and 80%,
      respectively; P = 0.001). In the loop excision group, thermal injuries were
      present in half of the cone sections. The median (range) thickness of thermal
      injury was 0.98 mm (0-1.5 mm) in the ectocervix and 0.95 mm (0-1.75 mm) in the
      endocervix. Histologic evaluation of the endocervical margins was not possible in
      2 cases (7%). At follow-up colposcopy, evaluation of the entire squamocolumnar
      junction was possible in 15 (39%) and 20 (71%) women, respectively (P < 0.01).
      Four patients in the cold knife group and 6 in the loop group had histologically
      confirmed persistent dysplasia (P > 0.05), yielding success rates of 90 and 79%,
      respectively (P > 0.05). CONCLUSIONS: Loop excision provides a sample that is
      adequate for histologic evaluation in most cases, results in the same success
      rate as cold knife conization, and allows optimal colposcopic surveillance in
      significantly more cases than cold knife excision.

PMID- 10600288
TI  - Hyperfractionated radiation therapy plus chemotherapy in locally advanced
      cervical cancer: results of two phase I dose-escalation Gynecologic Oncology
      Group trials.
AB  - OBJECTIVE: The aims of this study were to assess the early and late toxicities of
      multiple-daily-fraction whole pelvic radiation plus concurrent chemotherapy with
      either hydroxyurea or 5-fluorouracil (5-FU)/cisplatin and to determine the
      maximum tolerated external radiation dose in conjunction with brachytherapy, when
      given with either of these drug regimens, as treatment for locally advanced
      carcinoma of the cervix. METHODS: The first study (GOG 8801) of 38 patients
      utilized hydroxyurea as a single oral dose of 80 mg/kg to a maximum of 6 g at
      least 2 h prior to a radiation treatment twice every week. In the second study
      (GOG 8901) of 30 patients, cisplatin and 5-FU were used concomitantly with
      radiotherapy. Fifty milligrams per square meter of cisplatin was administered on
      days 1 and 17 of external radiation. 5-FU was given by continuous intravenous
      infusion at a dose of 1000 mg/m(2)/day for 4 consecutive days on days 2, 3, 4, 5,
      and 18, 19, 20, and 21 of external radiation therapy. Both studies utilized
      external radiation given by an accelerated hyperfractionated regimen of 1.2 Gy
      per fraction, two fractions per day. All patients were treated 5 days per week
      with a minimum of 4 h between fractions. RESULTS: Acute toxicity was manageable
      on both protocols but nausea, vomiting, and myelosuppression were more severe
      with hydroxyurea. Chronic toxicity was primarily enteric and appeared to be dose
      related. There was no obvious correlation seen between pelvic failure rates and
      the radiation dose or between the chemotherapy regimens used. CONCLUSIONS: The
      defined maximal tolerated dose of whole pelvic radiation was 57.6 Gy in 48
      fractions which could be delivered in a hyperfractionated setting with
      concomitant chemotherapy, followed by brachytherapy. Follow-up is now sufficient
      that further adverse events should be rare.

PMID- 10600290
TI  - Laparoscopically assisted Schauta operation: learning experience at the
      Gynecologic Oncology Unit, Buenos Aires University Hospital.
AB  - OBJECTIVES: The aim of this study was to show the learning experience of the
      employment of laparoscopic lymphadenectomy followed by a Schauta operation to
      treat patients with cervical carcinoma at a university hospital and to evaluate
      the feasibility, complications, hospital stay, delay in return to work, and
      overall survival of this procedure. METHODS: Between June 1, 1993, and December
      30, 1997, 56 patients were selected. Surgical treatment began with a pelvic
      laparoscopic lymphadenectomy followed by a Schauta operation. Patients were
      staged according to FIGO criteria (Ia2, 10 cases; Ib1, 33 patients; Ib2, 8 cases;
      IIa, 3 cases; and IIb, 2 patients). Patients had a follow-up of 47 months.
      Overall survival was calculated with Kaplan-Meier tables. RESULTS: The procedure
      was not completed in 9 pts, in 5 cases among the first 20 pts that were entered
      on the trial due to technical problems and in 4 due to extracervical spread of
      disease (2 with gross laparoscopically unresectable lymph node metastases, 1 with
      parametrial infiltration, and 1 with rectovaginal septum involvement). In the 47
      pts in which the procedure could be completed, the laparoscopic approach was done
      in 102 min and the vaginal part in 165 min. There were 4 complications: 1
      ureteral injury, 1 abscess of the ischiorectal fossa, 1 hematoma of the
      Schuchardt incision, and 1 case of leg edema. The mean number of resected nodes
      was 17. Among the 47 cases in which the surgical procedure was completed, overall
      survival was 100% for Stage Ia, 88% for Ib1, and 85% for Ib2 after a mean follow
      up of 4 years. Four pts have relapsed and died; 3 were stage Ib1 and the other
      was stage Ib2. They had pelvic recurrences. CONCLUSIONS: This surgery is secure
      and has an excellent outcome, so it can be considered a valid approach for the
      treatment of patients with cervical carcinoma, but in our hands, 20 cases were
      needed to obtain the minimum skill needed to perform it.

PMID- 10600291
TI  - Laparoscopic staging in locally advanced cervical carcinoma: A new possible
      philosophy?
AB  - OBJECTIVES: The aim of this study was to evaluate the feasibility and efficacy of
      designing the therapeutic management of each patient, morbidity, and mortality
      using laparoscopic staging in locally advanced cervical carcinoma and to
      establish the standard procedure for a "complete" staging. METHODS: From July 10,
      1995, to June 30, 1998, 98 pts were included. Clinical staging was performed
      according to FIGO's criteria (22 Ib2; 38 IIb; 25 IIIb; and 6 IV). The Quetelet
      index was calculated for each patient. Forty-nine pts were submitted to a
      previous CT scan. Surgical steps for a complete staging were: (1) peritoneal
      washings for cytology; (2) whole abdominal cavity exploration, with a biopsy of
      all suspicious lesions; (3) exploration of the vesicocervical and rectovaginal
      septums with a biopsy of suspicious areas; (4) bilateral pelvic lymphadenectomy
      and, when macroscopically positive, paraaortic lymphadenectomy. RESULTS: Eighty
      four of 91 pts were evaluable. The average duration for the procedure was 108
      min, and blood loss was less than 200 cc. Hospitalization time ranged from 24 to
      48 h. The average number of resected pelvic nodes was 18.5 (9-31). Positive nodes
      were found in 38 cases; 19 pts had unresectable positive nodes. Paraaortic
      dissection was performed in 26 cases and 11 cases were positive. When tumor was
      <5 cm, 8/32 (25%) lymphadenectomies were positive; when it was >5 cm, 30/52 (58%)
      were positive. Thirty-eight of 49 pelvic CT scans were reported to be normal
      (18/38 had positive nodes) and 11/49 suspicious (6/11 had positive nodes). Tumor
      invasion of the vesicocervical space or of the anterior parametrium was found in
      23/84 patients. The rectovaginal septum was positive in 10 cases. Four of 84
      patients (4.7%) presented with intraperitoneal spread. Only one trauma to the
      vena cava occurred at the time of the Verres needle insertion and two
      postoperative lymphoceles were observed. All patients began curative treatment
      within 3 to 7 days. CONCLUSIONS: This method is feasible, complications are
      infrequent, and subsequent treatment is not delayed.

PMID- 10600292
TI  - Association of syndecan-1 with tumor grade and histology in primary invasive
      cervical carcinoma.
AB  - OBJECTIVES: The expression of syndecan-1, a cell surface heparan sulfate
      proteoglycan, is reduced during malignant transformation of squamous cells.
      Studies on squamous cell carcinoma of the head and neck have shown that syndecan
      1-positive tumors are associated with longer overall and recurrence-free
      survival. The purpose of this study was to analyze syndecan-1 expression in
      invasive cervical carcinoma and to examine the association of syndecan-1
      expression with prognostic factors and overall survival. METHODS: The study
      population consisted of 124 patients treated for primary invasive carcinoma of
      the uterine cervix at the Turku University Central Hospital during the years 1970
      1988. The material consisted of 102 (82.3%) squamous cell carcinomas, 16 (12.9%)
      adenocarcinomas and 1 (0.8%) adenosquamous carcinoma, 1 (0.8%) small cell
      carcinoma, 1 (0. 8%) adenoid basal carcinoma, 1 (0.8%) carcinosarcoma, and 2
      (1.6%) unclassified cervical carcinomas. Syndecan-1 expression was determined on
      paraffin-embedded tissue blocks using a human syndecan-1-specific monoclonal
      antibody B-B4 and immunohistochemistry. The expression of syndecan-1 was
      classified according to staining intensity as well as the percentage of
      positively stained tumor cells. RESULTS: Staining intensity was strong in 44
      (36%) samples, while 24 (19%) specimens remained syndecan-1-negative. In 49 (40%)
      samples, the percentage of syndecan-1-positive cells was >/=90%. Syndecan-1
      expression, as determined by >/=50% positively stained tumor cells, was
      associated with the grade of differentiation (P = 0.03) and squamous histology (P
      < 0.001), but was not associated with clinical stage (P = 0.16) or disease-free
      survival (P = 0.86). Age (P = 0.003) and clinical stage (P < 0.001) were
      significant prognostic factors, but syndecan-1 expression determined neither by
      percentage of positively stained tumor cells nor by staining intensity was
      associated with the outcome. CONCLUSIONS: In cervical carcinoma syndecan-1 is
      associated with histological differentiation grade and squamous histology, but
      does not predict clinical outcome.

PMID- 10600293
TI  - Synthesis of IFN-gamma by CD8(+) T cells is preserved in HIV-infected women with
      HPV-related cervical squamous intraepithelial lesions.
AB  - OBJECTIVE: The aim of this study was to investigate whether coinfection with HIV
      affects the synthesis of Th1 and Th2 cytokines by peripheral blood T cells of
      women infected with human papillomavirus (HPV). METHODS: Cervical swabs and
      peripheral blood were obtained from women referred for colposcopy. HPV DNA by
      Digene's hybrid capture assay, HIV RNA by Roche's Amplicor assay, and cytokine
      synthesis of T-cell subsets by flow cytometry were assessed. HPV-associated
      cervical and HIV-associated immune deficiency diseases were staged using the
      Bethesda System and the Centers for Disease Control criteria, respectively.
      RESULTS: Patients with HIV and/or HPV infections had lower percentages of IL-2(+)
      and higher percentages of IL-10(+) T cells than healthy women. Furthermore, women
      with both virus infections (HIV(+)/HPV(+)) had significantly fewer IL-2(+)
      CD4(+), IFN-gamma(+) CD4(+), and TNF-alpha(+) CD4(+) T cells than women with HPV
      infection alone (HPV(+)). Whereas HIV(+) and healthy women had similar numbers of
      IFN-gamma(+) CD8(+) T cells, HPV(+) women had significantly fewer IFN-gamma(+)
      CD8(+) T cells than healthy women. CONCLUSION: HIV infection adversely affects
      the synthesis of Th1 cytokines by CD4(+), but not IFN-gamma synthesis by CD8(+) T
      cells of women with active HPV infection. The increase in IFNgamma(+) CD8(+) T
      cells, a phenotype consistent with cytotoxic T lymphocytes, may account for the
      stable HIV disease of the women studied. However, the increase in IFN-gamma(+)
      CD8(+) T cells is less likely to be HPV-specific as there was a higher incidence
      of HPV-related cervical SIL in HIV(+)/HPV(+) women compared with HPV(+) women.

PMID- 10600294
TI  - Spread of ovarian cancer after laparoscopic surgery: report of eight cases.
AB  - OBJECTIVE: The aim of this study was to describe early occurrences of metastases
      after laparoscopy of ovarian masses later found to be malignant. METHODS: The
      hospital charts of eight women having undergone laparoscopic surgery for ovarian
      mass were reviewed and analyzed. RESULTS: The mean age of the patients was 40
      years (range 25 to 66). Size of the tumor ranged from 2 to 15 cm. In four
      patients the ovarian mass was suspected to be malignant in the laparoscopy.
      Diagnostic procedure (biopsy of the tumor) was performed in two and salpingo
      oophorectomy in six patients. Staging laparotomy was performed within the mean of
      17 days (range 7-29). In four patients (50%) the cancer had spread from a
      localized to an advanced stage during the delay. Ascites was present in the
      laparoscopy in two of the four patients with port site or abdominal wall
      metastases. CONCLUSIONS: Laparoscopic surgery of ovarian mass later found to be
      malignant can cause considerable and early spread of the cancer.

PMID- 10600295
TI  - Differential gene expression pattern between normal human trophoblast and
      choriocarcinoma cell lines: downregulation of heat shock protein-27 in
      choriocarcinoma in vitro and in vivo.
AB  - OBJECTIVE: Our purpose was to identify potential differences in gene expression
      between normal trophoblast and choriocarcinoma cells. METHODS: The Atlas human
      cDNA expression array hybridization technique was used to study the gene
      expression pattern in normal trophoblast and choriocarcinoma cell lines.
      Furthermore, to confirm heat shock protein-27 (Hsp-27) expression data, reverse
      transcriptase-PCR (RT-PCR), Western blot, and immunohistochemical analyses were
      used in vitro with cell lines and in vivo with paraffin sections. RESULTS: The
      expression of nine genes was strongly different comparing a normal trophoblast
      cell line with choriocarcinoma cells on the Atlas membranes. Compared to normal
      trophoblast cells, six genes were upregulated and three were downregulated in
      choriocarcinoma cells. Furthermore, the downregulation of Hsp-27 in
      choriocarcinoma cells was confirmed both in vitro with cell lines and in vivo
      with paraffin sections using RT-PCR, Western blot, and immunohistochemical
      techniques. CONCLUSION: cDNA expression array is a useful technique for
      identifying differentially expressed gene patterns in normal trophoblast and
      choriocarcinoma cells. The strong expression of Hsp-27 in placental villous
      trophoblast cells may play a role in trophoblast differentiation. The
      downregulation of Hsp-27 in choriocarcinoma may contribute to the extreme
      sensitivity of trophoblastic tumors to chemotherapy.

PMID- 10600296
TI  - Diagnostic and prognostic values of plasma levels of fibrinolytic markers in
      ovarian cancer.
AB  - OBJECTIVE: The aim of this study was to find out whether any of the fibrinolytic
      parameters could be used as tumor markers in predicting the prognosis of ovarian
      cancers. MATERIALS AND METHODS: In the present study, we determined the plasma
      concentrations of tissue-type plasminogen activator (tPA), urokinase-type
      plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), PAI-2,
      and uPA receptor (uPAR) in 25 patients with ovarian cancer, 16 patients with
      benign gynecologic tumor or inflammation, and 36 healthy controls in order to
      find out whether the plasma levels of these markers could be used to evaluate the
      prognostic value in patients with gynecologic cancers. We also determined two
      tissue concentrations of malignant tumor (one was at the tumor site itself and
      the other at the cut-end tissue of the tumor, which was expected to be free of
      tumor) in order to see the correlation between plasma and tissue concentrations.
      RESULTS: Plasma PAI-1 was significantly higher in patients with malignancy than
      in the healthy controls (P = 0.0001). There was no significant correlation
      between plasma and tissue concentrations, either tumor tissue or cut-end tissue,
      of the same parameters. Tissue concentrations of uPA, PAI-1, and PAI-2 were
      significantly higher and tPA significantly lower in the malignant tumor tissue
      than in the cut-end tissue in the patients with ovarian cancer (P = 0.014, 0.03,
      0.002, and 0.01, respectively). Plasma PAI-1 was significantly higher in patients
      in the late stage of ovarian cancer than in the early stages and in the controls.
      CONCLUSION: From our study, we concluded that plasma levels of PAI-1 were
      correlated with the presence of malignant ovarian cancer and higher stage of
      disease.

PMID- 10600297
TI  - Role of TSG101 in uterine cervix cancer.
AB  - OBJECTIVE: TSG101 was first described as a possible tumor suppressor gene in
      breast cancer. To determine whether TSG101 might play a role in cervical
      carcinogenesis, we examined a panel of cervical cancer cell lines and primary
      tumor specimens for transcript abnormalities and mutations in TSG101. METHODS:
      Total RNA was derived from cell line cultures or primary tumor specimens. We
      performed nested reverse transcription polymerase chain reaction (RT-PCR) with
      eight overlapping primer sets, followed by single-strand conformational
      polymorphism (SSCP) analysis, to screen for mutations in the TSG101 open reading
      frame. Representative normal and shifted SSCP bands were sequenced. To identify
      abnormal-sized transcripts, we performed RT-PCR with primers flanking the open
      reading frame followed by gel electrophoresis. RESULTS: Mutational analysis was
      performed on cDNAs from 20 primary cervical tumors and 8 cervical carcinoma cell
      lines. Two polymorphisms were identified, neither of which resulted in an altered
      amino acid sequence. Transcript analysis was performed on a subset of 16 primary
      cervix tumors and 6 cervix carcinoma cell lines. The wild-type transcript (1228
      bp) was the dominant transcript expressed in all samples. A transcript measuring
      330 bp was detected in 5 of 6 cell lines and 11 of 16 primary tumor specimens.
      CONCLUSION: Our results suggest that mutations in TSG101 rarely occur in
      carcinomas of the uterine cervix. However, the presence of minor aberrant TSG101
      transcripts is a common feature. The relationship between aberrant transcription
      and carcinogenesis should be further investigated.

PMID- 10600298
TI  - Decision making about prophylactic oophorectomy among at-risk women:
      psychological influences and implications.
AB  - OBJECTIVE: Women with a family history of ovarian cancer are confronted with
      difficult decisions regarding the management of their risk status. Currently, the
      main preventive option available is prophylactic oophorectomy. The objective of
      the present paper is to review research and theory on psychological factors that
      influence decision making about preventive surgery and discuss the implications
      for patient management. METHODS: Guided by a cognitive-social framework, the
      literature on decision making about preventive surgery is reviewed and
      integrated. RESULTS: The available studies show that women are more likely to opt
      for surgery if they feel more vulnerable to cancer, believe that surgery will
      prevent cancer, and are worried about developing cancer. Further, the response to
      ovarian risk is influenced by the individual's characteristic psychological
      style: monitors (who typically scan for and amplify threatening cues) tend to
      feel more vulnerable to cancer and more distressed about their cancer risk than
      blunters (who typically distract from threatening cues) do. CONCLUSION: On the
      basis of prior research, monitors may be more likely to choose surgical
      intervention to reduce their distress, without fully anticipating the
      psychological and medical consequences of that decision. In order to facilitate
      informed decision making, counseling protocols should be designed to enable the
      patient to understand and take account of the psychological consequences of the
      available medical options. Future studies are needed to systematically extend and
      explore the proposed theory-based relationships.

PMID- 10600299
TI  - Prognostic significance of p53 and p21(waf1/cip1) immunoreactivity in epithelial
      cancers of the ovary.
AB  - OBJECTIVES: Theprognostic value of p53 expression in epithelial ovarian cancer
      remains unresolved. We hypothesized that prognosis may relate more to expression
      of p21(waf1/cip1), the major downstream effector of p53, which can also be
      induced through p53-independent mechanisms. We therefore studied the relationship
      of p53 and p21(waf1/cip1) expression in epithelial ovarian cancers to
      clinicopathological variables and prognosis. METHODS: Fixed, embedded tumors from
      85 patients with untreated, primary epithelial ovarian cancer were immunostained
      with antibodies to p53 and p21(waf1/cip1). Expression was correlated with
      clinicopathological features and prognosis. Survival curves were calculated by
      the Kaplan-Meier method and compared using the log-rank test for p53,
      p21(waf1/cip1), and all combinations of expression of the two markers. RESULTS:
      Sixty-two percent of tumors expressed p53, and 42% expressed p21(waf1/cip1).
      There was no correlation between p53 and p21(waf1/cip1) expression. Advanced
      stage, grade, age >/=50, and p53 expression were associated with worse disease
      free survival. Patients whose tumors were p53(+)/waf1(-), however, had a
      particularly strong association with poorer disease-free survival when compared
      with other combinations of p53 and p21(waf1/cip1) expression (P = 0.003). Neither
      p53, nor p21(waf1/cip1), nor combinations of expression were independently
      related to survival when histology, age, stage, and differentiation were
      considered. CONCLUSIONS: p53 expression in the absence of p21(waf1/cip1)
      expression is a better marker of poor prognosis than either p53 or p21(waf1/cip1)
      expression status alone in univariate analysis. Absence of independent prognostic
      significance may be related to the paucity of early stage cases in the current
      study.

PMID- 10600300
TI  - Phase II trial of intraperitoneal cisplatin with intravenous doxorubicin and
      cyclophosphamide in previously untreated patients with advanced ovarian cancer
      long-term follow-up.
AB  - Forty-three patients with ovarian cancer were entered on this trial and treated
      with intravenous (iv) cyclophosphamide (C) and doxorubicin (A), and
      intraperitoneal (ip) cisplatin (DDP), every 21 days for eight cycles. Following
      iv hydration, the cisplatin was administered through an intraperitoneal catheter
      in 2 L of 0.9% normal saline with a 4-h dwell. All patients are evaluable for
      overall and progression-free survival with a median follow-up of 70 months
      (range: 3-162 months); 39 patients are evaluable for response. All complete
      responses were surgically confirmed. The median age was 59 (range 28-82 years); 3
      patients were stage IC, 5 were IIC, 14 patients were stage III (optimally
      debulked), 14 patients were stage III (suboptimally debulked), and 7 patients
      were stage IV. Two patients had received prior alkylator therapy. Six of 8
      patients with Stage IC or II remain without evidence of disease at a mean of 12
      years following chemotherapy. Of 14 optimally debulked stage III patients, there
      were 7 complete responses, 3 partial responses, 1 patient with stable disease,
      and 3 inevaluable patients. Of 14 suboptimally debulked stage III patients there
      were 4 complete responses, 4 partial responses, 3 with stable disease, 2
      progressions on treatment, and 1 inevaluable patient. Five-year progression-free
      and overall survivals for stage III optimally debulked patients are 21 and 64%,
      respectively. At 10 years, progression-free and overall survivals for this group
      are 21 and 29%, respectively. Toxicity included neutropenia (complicated by
      sepsis in 2 patients), infrequent thrombocytopenia, and mild anemia. Three
      patients developed transient serum creatinine elevations >2.0 mg/dl; however,
      decreased creatinine clearance was noted in 93/258 (36%) of evaluable courses
      which required a cisplatin dose reduction per protocol. Controllable
      hypomagnesemia, nausea, and emesis were also observed. We conclude that the
      combination of iv CA and ip DDP is an effective regimen with long-term
      progression-free and overall survivals that compare favorably with those of other
      published studies of intravenous or intraperitoneal chemotherapy. This report is
      unusual in terms of the prolonged follow-up for all patients enrolled. These long
      term results lend further support to recently published trials documenting the
      efficacy of intraperitoneal chemotherapy for patients with this disease.

PMID- 10600301
TI  - Human papillomavirus testing in primary screening for cervical cancer of human
      immunodeficiency virus-infected women, 1990-1998.
AB  - OBJECTIVE: Women infected with the human immunodeficiency virus (HIV) have an
      increased risk of cervical neoplasia while the value of cytologic screening is
      limited due to a high prevalence of inflammatory disease. The study was conducted
      to determine whether testing for human papillomavirus (HPV) DNA could improve
      primary screening for cervical cancer of these patients. METHODS: One hundred
      thirty-eight HIV-infected women were examined between 1990 and 1998. Ninety-four
      patients with a total of 279 women-years were eligible for incidence evaluation.
      Colposcopy, cytology, and HPV DNA testing with the hybrid capture I assay were
      performed at each visit. RESULTS: Seventeen cases of high-grade cervical
      neoplasia were diagnosed at study entry and 13 developed CIN II or CIN III during
      follow-up. The hybrid capture I assay detected 94.1% of prevalent and 100% of
      incident high-grade neoplasia, while the corresponding sensitivity of Pap smears
      using CIN I or worse as the referral criteria was 82.3% for prevalent and 69.2%
      for incident high-grade neoplasia. Eleven of 13 patients who progressed to
      histologically confirmed CIN II/III tested positive for HPV DNA at study entry
      compared with 5/13 women presenting with any degree of cytologic atypia at
      recruitment. The Pap smears of 36/94 women remained normal throughout the study
      while 54/94 patients remained negative for high-risk HPV types. CONCLUSION:
      Hybrid capture I identified high-grade cervical neoplasia more accurately than
      the Pap smear and appeared to be beneficial for primary cervical cancer screening
      in HIV-infected women.

PMID- 10600302
TI  - MIB-1 in endometrial carcinoma: prognostic significance with 5-year follow-up.
AB  - OBJECTIVE: MIB-1, a monoclonal antibody to the Ki-67 antigen, has presumptively
      been shown to be predictive of recurrent disease in patients with endometrial
      cancer. In order to more conclusively establish whether MIB-1 staining can be
      used as a prognostic indicator of recurrent disease or survival, a larger group
      of patients with a minimum follow-up of 5 years was analyzed. METHODS: The tumors
      from 147 consecutive patients receiving primary surgical therapy for endometrial
      carcinoma were evaluated with the MIB-1 monoclonal antibody. Proliferation index
      was quantified by image analysis. Patients were followed for a minimum of 60
      months. In addition to MIB-1 staining, histologic type, stage, grade, depth of
      invasion, lymphovascular space invasion, and peritoneal cytology were evaluated
      as prognostic indicators. RESULTS: Twenty-five of 147 patients died during the
      study period. MIB-1 staining was not significantly elevated in advanced (stage
      II, III, and IV) as opposed to early (stage I) carcinomas (P = 0.38). In patients
      whose tumor MIB-1 staining was less than 33.0%, no deaths occurred. By
      multivariate analysis, only MIB-1 staining (P < 0.001), FIGO stage (P = 0.005),
      and LVI (P = 0.005) were shown to be independent prognostic indicators predictive
      of survival. CONCLUSION: In this series of 147 consecutive patients with
      endometrial carcinoma, the monoclonal antibody MIB-1 was shown to be an
      independent prognostic indicator of 5-year survival. This follow-up further
      validates the previous work regarding the significance and potential usefulness
      of MIB-1 as a prognostic indicator.

PMID- 10600303
TI  - Gynecologic oncologic surgery in the elderly: A retrospective analysis of 213
      patients.
AB  - OBJECTIVES: The aims of the study were (1) to analyze morbidity and mortality for
      elderly women (>/=70 years) operated on for gynecological malignancies at our
      department between 1985 and 1996; and (2) to compare two periods of time (years
      1985-1990 versus years 1991-1996) to investigate whether new expedience in the
      surgical technique as well as in the perioperative management introduced by 1991
      influenced the feasibility and tolerability of surgery in elderly patients.
      METHODS: In a retrospective analysis, we evaluated tumor site, comorbidities,
      surgical features, morbidity, and mortality. By 1991, several modifications in
      management were introduced, including: (1) early postoperative mobilization; (2)
      self-donation with autologous blood transfusion; (3) intraoperative antibiotic
      prophylaxis; (4) the retroperitoneum was left open and drains were not used after
      pelvic and aortic lymphadenectomy; (5) use of coagulator forceps and hemoclips
      for meticolous hemostasis. RESULTS: In 213 patients, tumor site distribution was
      uterine corpus n = 93, ovary n = 51, vulva n = 29, cervix n = 23, breast n = 15,
      and vagina n = 2. There were advanced stage diseases in 47%, comorbid illnesses
      in 76%, and high surgical risk in 48%. Sixty-nine patients (group A) and 144
      patients (group B) were treated in the first and second study periods,
      respectively. Overall, severe postoperative morbidity and mortality were 17 and
      2.8%, respectively. Group B compared to group A showed more frequent use of major
      surgical procedures (P < 0.01) and lymphadenectomy (P < 0.04), lower transfusion
      rate (P < 0.001), reduced severe morbidity (P < 0.002), lower mortality (P =
      0.3), and shorter hospital stay (P < 0.001). CONCLUSIONS: Our study suggests that
      surgery, including very radical procedures, is reasonably feasible and well
      tolerated by elderly patients. The introduction of technical and medical advances
      in the later years of the study resulted in a significant improvement of surgical
      rates.

PMID- 10600304
TI  - Lack of efficacy of 24-h infusional topotecan in platinum-refractory ovarian
      cancer: A Gynecologic Oncology Group trial.
AB  - BACKGROUND: The aim of this study was to evaluate the efficacy of a more
      convenient topotecan administration schedule in the second-line treatment of
      advanced platinum-refractory ovarian cancer. METHODS AND MATERIALS: The
      Gynecologic Oncology Group conducted a Phase II trial of 24-h infusional
      topotecan (8.5 mg/m(2)), repeated every 3 weeks in 26 patients with platinum
      refractory ovarian cancer (failure to respond to initial platinum-based treatment
      or development of recurrent disease within 6 months of completion of
      chemotherapy). RESULTS: Grade 4 neutropenia (85% of patients) and
      thrombocytopenia (12%) were the major toxicities encountered. Of the 25 patients
      evaluable for response, only a single patient experienced an objective response
      (4%). CONCLUSIONS: When employed at this dose and schedule (24-h infusion every 3
      weeks), topotecan has minimal second-line activity in platinum-refractory ovarian
      cancer.

PMID- 10600305
TI  - Photodynamic therapy for the hypercalcemic type of the small cell carcinoma of
      the ovary in a mouse xenograft model.
AB  - OBJECTIVE: The hypercalcemic type of the small cell carcinoma of the ovary
      (HTSCCO) is a rapidly fatal ovarian tumor in young women. Photodynamic therapy
      (PDT) induces selective necrosis to malignant tissues. The aim of this study was
      to determine the sensitivity of the HTSCCO to PDT in a mouse xenograft model.
      METHODS: Tumors were obtained from a patient with a HTSCCO and were transplanted
      into nude mice. Following photosensitization with m-THPC, either superficial or
      interstitial laser light was administered to the tumors. Necroses were measured
      by morphometry. Serum calcium levels were determined prior to and after PDT.
      RESULTS: Superficial irradiation of m-THPC sensitized tumors showed over three
      times more necrosis than control tumors (P = 0.037). Interstitially irradiated
      tumors showed over seven times more necrosis than control tumors (P = 0.0012).
      All animals showed a highly significant hypercalcemia prior to PDT (P < 0.0001).
      PDT induced a significant decrease in serum calcium levels (P = 0.0297).
      CONCLUSION: This study suggests that PDT may be of therapeutic value for the
      HTSCCO.

PMID- 10600306
TI  - Frequent occurrence of loss of heterozygosity among tumor suppressor genes in
      uterine leiomyosarcoma.
AB  - OBJECTIVE: Leiomyosarcoma of the uterus is a rare smooth muscle tumor; it is
      extremely malignant and the rates of local recurrence and metastasis are high.
      Since tumor suppressor genes are commonly altered in malignant tumors, it is
      possible that mutations in such genes are involved in the development of uterine
      leiomyosarcoma. METHODS: Fifty-five patients (37-70 years of age) diagnosed as
      having smooth muscle tumors of the uterus were selected. DNA was extracted from
      four or five 8-microm-thick consecutive tissue sections of each smooth muscle
      tumor from the paraffin-embedded blocks. Loss of heterozygosity (LOH) was
      investigated at nine loci within or close to tumor suppressor genes (TP53, RB1,
      DCC, NM23, WT1, D14S267, P16, DPC4, PTCH). RESULTS: Nineteen of twenty
      leiomyosarcomas revealed at least one instance of LOH among eight of the nine
      markers tested (one locus showed no LOH at all). In fact, 11 of the 20 cases
      exhibited two or more instances of LOH and, of the remaining 9 cases, 4 showed a
      point mutation of p53 in addition to an alteration in one of the 9 markers, while
      one exhibited a p53 mutation only. CONCLUSION: An accumulation of genetic
      alterations among tumor suppressor genes may play a key role in the tumorigenesis
      and progression of uterine leiomyosarcoma.

PMID- 10600307
TI  - Cost analysis of laparoscopy versus laparotomy for early endometrial cancer.
AB  - OBJECTIVE: The purpose of this study was to determine whether the cost associated
      with treatment of early stage endometrial cancer differs on the basis of the
      surgical approach. METHODS: A retrospective analysis was performed on a series of
      women with presumed early stage endometrial cancer treated between 5/96 and 1/99
      at a single institution. The patients were grouped according to the surgical
      approach utilized. The first group consisted of 19 patients who underwent
      laparoscopic assisted vaginal hysterectomy, bilateral salpingo-oophorectomy, and
      laparoscopic pelvic and paraaortic lymph node dissection. The second group
      consisted of 17 patients who underwent a total abdominal hysterectomy, bilateral
      salpingo-oophorectomy, and pelvic and paraaortic lymph node dissection. The two
      groups were compared with a two-tailed Student t test. Variables analyzed
      included age, Quetelet index (QI), surgical stage, number of lymph nodes,
      surgical time, estimated blood loss, postoperative complications, number of days
      in the hospital, and costs. The cost analysis was divided into room and board,
      pharmacy, ancillary services, operating room equipment, operating room services,
      and anesthesia. RESULTS: Both groups were similar in age, QI, and distribution of
      stage. The laparoscopic group required more OR time (237 vs 157 min, P < 0.001);
      however, the number of lymph nodes, estimated blood loss, and postoperative
      complications were not significantly different between the groups. The
      laparoscopic group required significantly shorter hospitalization than the
      laparotomy group (3.7 vs 5.2 days, P < 0.001) resulting in less room and board
      ($299 vs $454, P < 0.001) as well as pharmacy costs ($443 vs $625, P < 0.02). The
      cost of anesthesia was higher in the laparoscopic group ($696 vs $444, P < 0.001)
      but the costs of OR equipment, OR services, and total costs were not
      statistically different between the groups. CONCLUSION: Laparoscopic surgical
      management of early stage endometrial cancer is feasible with minimal morbidity.
      The cost savings of early hospital discharge is offset by longer surgical time
      and higher anesthetic costs. The total costs for each surgical approach are not
      statistically different. The presumed advantages of less pain, early resumption
      of normal activities, and overall improvement of quality of life await further
      investigation.

PMID- 10600308
TI  - Is age a barrier to the aggressive treatment of ovarian cancer with paclitaxel
      and carboplatin?
AB  - OBJECTIVE: The objective of this study was to determine whether the toxicities
      associated with chemotherapy are age related in women treated for ovarian cancer.
      METHODS: Patients with stage II-IV epithelial ovarian cancer underwent
      cytoreductive surgery. Adjunctive therapy was given to each patient consisting of
      intravenous (IV) paclitaxel 175 mg/m(2) over 3 h with a subsequent 30-min IV
      infusion of carboplatin. Carboplatin dose was calculated to achieve a targeted
      area under the curve (AUC) of 5.0-7.5. Treatment was repeated at 21- to 28-day
      intervals for six cycles. Toxicities were graded after each dose of chemotherapy.
      Results were analyzed using the Wilcoxon rank sum test and log likelihood ratio
      to compare toxicities in women age <60 years old to women >/=60 years old.
      RESULTS: Fifty-three women, 22 of whom were >/=60 years old, were treated with
      309 cycles of chemotherapy. Forty-eight patients (92%) completed all six cycles.
      AUC dosing of carboplatin was equivalent for both groups. Carboplatin dose
      reduction occurred in 75% of patients for grade 4 neutropenia or
      thrombocytopenia. No patient required a reduction in the paclitaxel dose.
      Neutropenia was less frequent in women >/=60 years old than in women <60 years
      old (P = 0.02). There was no difference between women <60 years old and women
      >/=60 years old in the incidence of anemia, thrombocytopenia, or the use of
      growth factors. A 68% complete clinical response rate was observed in women >/=60
      years old compared to a 74% complete response rate for women under age 60 (P =
      0.22). CONCLUSION: Age is not a barrier to the aggressive treatment of ovarian
      cancer with this regimen of paclitaxel and carboplatin.

PMID- 10600309
TI  - BRCA1-related and sporadic ovarian cancer in the same family: implications for
      genetic testing.
AB  - OBJECTIVE: The aim of this study was to present a family with both BRCA1-related
      and sporadic ovarian cancer and address current difficulties in genetic testing.
      METHODS: BRCA1 mutation detection was performed on a family having four confirmed
      cases of ovarian cancer, two cases of breast cancer, and one case each of colon,
      stomach, and prostate cancer. The incidence and types of cancer were consistent
      with a BRCA1 mutation although previous linkage analysis had excluded this family
      as being due to BRCA1. RESULTS: A protein-truncating mutation in BRCA1, denoted
      2799delAA, was identified in the germline DNA of each of the women affected with
      breast and ovarian cancer in this family except the proband, who was diagnosed
      with ovarian cancer at age 65. CONCLUSIONS: In an earlier study, which sought to
      determine the proportion of site-specific ovarian cancer due to BRCA1, the family
      described in this report was wrongly identified as not being due to BRCA1 when,
      in fact, all but one of the breast and ovarian cancer cases carry a deleterious
      BRCA1 mutation. Our analysis suggests that the proband, who was the first of the
      women in this family to seek genetic counseling, developed ovarian cancer by
      chance and not as the result of an inherited mutation. We describe the results of
      our analysis in light of current issues that face clinicians who may be involved
      in genetic testing for breast and ovarian cancer predisposition.

PMID- 10600310
TI  - Dactinomycin in the treatment of recurrent or persistent endometrial carcinoma: A
      Phase II study of the Gynecologic Oncology Group.
AB  - OBJECTIVES: The search for effective systemic chemotherapy for endometrial cancer
      is ongoing. Complete responses to current drugs or regimens are infrequent, and
      overall survival for patients with disease not amenable to surgery or radiation
      therapy is poor. Dactinomycin has proven activity against a wide variety of solid
      tumors but has not been tested against endometrial cancer. Using pharmacokinetic
      data supporting an intermittent, single-dose schedule, this Phase II Gynecologic
      Oncology Group study was conducted to determine the antitumor activity and
      toxicity of dactinomycin in patients with persistent or recurrent endometrial
      adenocarcinoma. METHODS: Eligibility was limited to patients with measurable
      disease, adequate renal, hepatic, and bone marrow function, and no more than one
      prior chemotherapy regimen. Treatment consisted of 2 mg/m(2) slow intravenous
      push of dactinomycin over 15 min with courses repeated every 4 weeks. RESULTS: A
      total of 27 patients were entered in this study between April 1996 and September
      1996; all were evaluable for toxicity and 25 were evaluable for response.
      Overall, 12/25 (48%) patients had received prior radiation therapy and all had
      received prior chemotherapy. Sites of measurable disease were pelvis (9 patients)
      and distant (16 patients). There was 1 complete response and 2 partial responses
      for an overall objective response rate of 12%. Aside from emesis (grade 3, 2
      patients; grade 4, 2 patients) significant nonhematologic toxicity was rare. The
      most common toxicity was neutropenia (grade 3, 2 patients; grade 4, 10 patients).
      CONCLUSION: Toxicity was deemed acceptable but the limited effectiveness of
      dactinomycin precludes further clinical development in this patient population.

PMID- 10600311
TI  - Clinical picture of women with early stage ovarian cancer.
AB  - OBJECTIVE: The objective of this study was to review the clinical picture of
      women with early stage ovarian cancer, to examine the difference between women
      with borderline ovarian tumors (BLOT) and those with ovarian cancer (OC), and to
      estimate the average time interval between the onset of symptoms and diagnosis.
      METHODS: A retrospective review of all women with surgical stage I and II OC or
      BLOT was performed and the following information abstracted: age, parity, family
      history of cancer, personal history of previous malignancies, symptoms, signs,
      date of start of symptoms, imaging studies, CA-125 values, date of diagnosis at
      surgery, tumor stage, histology, grade, date of last follow-up, and condition at
      last follow-up. Comparison between patients with BLOT and OC was performed using
      chi(2) and two-sample t tests. RESULTS: Our search identified 72 women with
      surgical stage I and II BLOT (n = 22) or OC (n = 50). Seventy-eight percent of
      the patients had presenting symptoms, the most common of which were abdominal or
      pelvic pain (34. 7%), bloatedness (31.9%), and vaginal bleeding (19.4%). Symptoms
      were similar among women with BLOT and those with OC, with a higher proportion of
      BLOT patients reporting no symptoms (31.8% versus 18. 0%, respectively).
      Abdominal and/or pelvic masses were palpable in 72.2% of the patients and ascites
      was present in 12.5%. Ovarian masses were most commonly complex in appearance and
      CA-125 was elevated in 52.2% of the patients in whom CA-125 values were known.
      The average time interval between onset of symptoms and diagnosis was 4.6 months
      (range 0.1-24.4 months). Women with BLOT had a significantly longer average time
      interval than women with OC (8.0 +/- 7.7 versus 3.4 +/- 3.7 months, respectively,
      P = 0.03). CONCLUSIONS: The majority of women with early stage ovarian cancer
      have nonspecific symptoms. The array of symptoms is similar between women with
      BLOT and those with OC. However, women with BLOT tend to have a longer time
      interval from onset of symptoms to diagnosis.

PMID- 10600312
TI  - Sertoli cell tumor in androgen insensitivity syndrome--a case report.
AB  - A 26-year-old individual with androgen insensitivity syndrome was operated on for
      a 3200-g Sertoli cell tumor of the left gonad with retroperitoneal metastases.
      Six courses of bleomycin, etoposide, and cisplatin chemotherapy followed surgical
      treatment. Eighteen months after the initial surgery the patient is free of
      disease and in good health. The association of Sertoli cell tumor with androgen
      insensitivity syndrome is discussed and the relevant literature is briefly
      reviewed.

PMID- 10600313
TI  - Inflammatory malignant fibrous histiocytoma of the ovary producing interleukin-6:
      A case report.
AB  - OBJECTIVE: Inflammatory malignant fibrous histiocytoma (IMFH) is composed of
      fibroblastic and histiocytic elements with a marked inflammatory cell infiltrate.
      The authors examined the case of a 43-year-old woman with IMFH of the ovary.
      METHODS: The serum interleukin-6 (IL-6) levels were examined and
      immunohistochemical analysis of the tumor was performed using monoclonal
      antibodies against lysozyme, alpha 1-antitripsin, vimentin, and IL-6. RESULTS:
      The patient had marked general inflammatory reactions of fever (38.0 degrees C),
      leukocytosis with 78.3% neutrophils, elevated CRP (23.5 mg/dl), and accelerated
      ESR (166 mm/h). The serum IL-6 concentration was 499 pg/ml. The right ovary was
      occupied by the solid tumor, composed of both fibrous and histiocytic elements
      with a marked inflammatory cell infiltrate. These inflammatory reactions
      disappeared after surgical resection and recurred when the tumor reappeared. The
      immunohistochemical staining of lysozyme, alpha 1-antitrypsin, vimentin, and IL-6
      was localized to the malignant cells, suggesting their histiocytic origin.
      CONCLUSIONS: This is the first case of IMFH of the ovary producing IL-6.
      Expression of IL-6 in the IMFH may account for both the local and the systemic
      inflammatory effects of tumors with these morphological features.

PMID- 10600314
TI  - Embryonal rhabdomyosarcoma of the uterine corpus in a 76-year-old patient.
AB  - BACKGROUND: Primary embryonal rhabdomyosarcoma of the uterine corpus is an
      extremely rare tumor. A case of rhabdomyosarcoma originating in the uterine myoma
      is presented with a review of the literature. CASE: A 76-year-old female
      presented with a half-year history of abdominal swelling and fever of unknown
      origin. A 15 x 15 x 17 cm myoma-like tumor was noted on the anterior wall of the
      uterine myometrium. The patient underwent total abdominal hysterectomy and
      bilateral salpingo-oophorectomy. The histology and immunohistochemistry aided in
      the final diagnosis of a pure embryonal rhabdomyosarcoma of the uterine corpus.
      This patient received three courses of CYVADIC chemotherapy consisting of
      cyclophosphamide, vincristine, doxorubicin, and dacarbazine after the surgery and
      is now alive with no evidence of disease 10 months from her surgery. CONCLUSION:
      This case is extremely rare with respect to the uterine corpus origin, especially
      the myoma nodule and the age of the patient.

PMID- 10600315
TI  - Low-grade endometrial stromal sarcoma with cardiovascular involvement--a report
      of three cases.
AB  - BACKGROUND: In low-grade endometrial stromal sarcoma, it has been reported that
      vascular space involvement in surgical specimens is found in over 50% of
      patients. However, in contrast to intravenous leiomyomatosis, it has been thought
      that further tumor extension to large vessels is rarely observed. CASES: We
      present three cases of low-grade endometrial stromal sarcoma with cardiovascular
      involvement by recurrent tumors observed on imaging studies. Two cases
      demonstrated tumor infiltration inside the inferior vena cava while the other
      case showed tumor growth in the left ventricle. CONCLUSION: This report suggests
      that attention should be paid to the possibility of cardiovascular invasion
      during the entire course of this disease.

PMID- 10600316
TI  - Malignant transformation of an ovarian mature cystic teratoma presenting as a
      rectal mass.
AB  - BACKGROUND: Squamous cell carcinoma arising from malignant degeneration of a
      mature cystic teratoma is rare with a reported incidence of approximately 1-3%.
      The most common presenting symptoms are lower abdominal pain and increasing
      abdominal girth of several months' duration. Approximately 50% of the patients
      present with FIGO stage I while 35-38% present with stage III diseases. CASE: The
      case described herein represents an unusual presentation and initial diagnostic
      dilemma of locally aggressive squamous cell carcinoma arising in an ovarian
      dermoid cyst, with invasion into the distal rectum and anal canal causing rectal
      bleeding similar to the presentation of anal squamous cell carcinoma. Despite
      aggressive surgical management with posterior exenteration and optimal tumor
      debulking followed by 5040-cGy pelvic radiation utilizing 25-MV photons, the
      patient developed pelvic recurrence at the vaginal cuff 6 weeks after completion
      of her adjuvant radiotherapy. She subsequently failed cis-platinum single-agent
      chemotherapy and died 9 months after her initial surgery and diagnosis.
      CONCLUSION: Squamous cell carcinoma in the anal canal, diagnosed by colonoscopy
      or proctoscopy, could be an unusual presentation of that arising from malignant
      degeneration of an ovarian dermoid cyst. This tumor may behave in a locally
      aggressive manner and be resistant to pelvic radiation or single-agent
      chemotherapy of cis-platinum. The current experience of adjuvant treatment after
      comprehensive staging and cytoreductive surgery reported in the world literature
      is limited, and the optimal management of the malignancy remains unclear.

PMID- 10600317
TI  - Abdominal sacral colpopexy in patients with gynecologic cancer: report of 25
      cases with long-term follow-up and literature review.
AB  - OBJECTIVE: The aim of this study was to evaluate abdominal sacral colpopexy
      performed in conjunction with radical pelvic surgery for gynecologic cancer.
      METHODS: Over a 9-year period from 1990 to 1999 25 patients with invasive
      gynecologic cancer and concomitant uterovaginal or vaginal vault prolapse
      underwent surgery. These patients were compared to a series of 50 patients with
      no history of gynecologic cancer who underwent abdominal sacral colpopexy during
      the same period. RESULTS: All surgeries were performed without intraoperative
      complication. There was one failed vault suspension in each group and no
      postoperative mesh complications as a result of radical pelvic surgery or
      postoperative radiation or chemotherapy. CONCLUSION: Abdominal sacral colpopexy
      may be safely performed along with radical pelvic surgery for gynecologic cancer
      without an increase in intra- or postoperative morbidity even if patients require
      chemotherapy or radiation therapy after surgery.

PMID- 10600318
TI  - Uterine pleomorphic rhabdomyosarcoma in a patient receiving tamoxifen therapy.
AB  - INTRODUCTION: Tamoxifen has been used as adjuvant therapy for the treatment of
      breast cancer. Its use has been associated with the development of proliferative
      endometrial lesions such as polyps, hyperplasia, and carcinoma. Mesenchymal
      tumors including malignant mixed mullerian tumors, endometrial stromal sarcomas,
      adenosarcomas, and leiomyosarcomas have been more recently described with
      tamoxifen use. CASE REPORT: This report describes the first case of a pure
      uterine rhabdomyosarcoma in a patient receiving tamoxifen therapy. DISCUSSION:
      Although uterine rhabdomyosarcomas are rare tumors and may arise de novo, we
      discuss the possible role of tamoxifen in the development of these mesenchymal
      tumors.

PMID- 10600319
TI  - Laparoscopic radical parametrectomy and pelvic and aortic lymphadenectomy for
      vaginal carcinoma: A case report.
AB  - OBJECTIVE: The objective of this study was to examine the feasibility of
      laparoscopic radical parametrectomy after previous hysterectomy. METHODS: This
      was a prospective study of a patient with vaginal adenocarcinoma after previous
      simple hysterectomy. The technique of radical parametrectomy with vaginectomy and
      pelvic and aortic lymphadenectomy as used for open cases for years was performed
      laparoscopically. RESULTS: The operating time was 270 min, the estimated blood
      loss was 200 mL, and the duration of hospitalization was 3 days. There were no
      intraoperative or postoperative complications. CONCLUSIONS: Radical
      parametrectomy with vaginectomy and pelvic and aortic lymphadenectomy can be
      successfully accomplished laparoscopically.

PMID- 10600320
TI  - Inguinal lymph node metastasis as the only manifestation of lymphatic spread in
      ovarian cancer: A case report.
AB  - OBJECTIVE: Inguinal metastasis is a rare manifestation of ovarian cancer. Autopsy
      studies have reported inguinal metastasis in 0-3% of patients with advanced
      disease. CASE REPORT: We describe a 43-year-old patient with ovarian cancer
      limited to the adnexa who had an isolated metastasis in an enlarged inguinal
      lymph node. The patient underwent total abdominal hysterectomy, omentectomy,
      pelvic and paraaortic lymphadenectomy, and excision of the enlarged inguinal
      lymph node. All 78 pelvic and 40 paraaortic lymph nodes were negative.
      CONCLUSION: This case demonstrates that early isolated distant lymph node
      metastasis, although rare, can occur in patients with ovarian cancer and may be a
      presenting symptom.

PMID- 10600321
TI  - Tool-using strategies by early hominids at bed II, Olduvai Gorge, Tanzania.
AB  - This study examines the current prevailing model of Oldowan technology-the
      opportunistic, least-effort strategy of stone tool making and using by early
      hominids. The sample includes the MNK chert factory site and three
      contemporaneous assemblages from Olduvai Gorge, all dated between 1.65 and 1.53
      m.y.a. The analysis suggests that early hominids at Olduvai may have been
      selective, applying distinctive strategies in making and using tools depending on
      the different types of raw materials available to them. The preponderance of lava
      cores and near absence of flakes associated with the cores suggest that lava
      cores at Olduvai did not provide a source of flakes. They were primarily heavy
      duty core tools, despite the fact that the majority of Olduvai lava is of
      excellent quality for flaking. Contrary to this pattern, the abundance of chert
      flakes and the lack of large chert cores suggest that the production of flakes
      was the most important strategy applied to chert. Original forms and flaking
      mechanics of the raw materials may have been important factors in the
      simultaneous application of the different, complementary strategies. The Oldowan
      tool-using strategy was dynamic and flexible, in response to changes in raw
      material availability. The use of chert between 1.65 and 1.53 m.y.a. was
      apparently related to the drastic decrease in flake production in lava and
      quartz. Finally, lack of initial reduction episodes of lava material challenges
      the idea of the stone cache strategy at Olduvai between 1.65 to 1.53 m.y.a.

PMID- 10600322
TI  - Neandertal knees: power lifters in the Pleistocene?
AB  - It has been proposed (Trinkaus, 1983 a; Miller & Gross, 1998) that the marked
      thickness of Neandertal patellae and/or the posterior displacement of their
      tibial condyles increased their relative M. quadriceps femoris moment arms,
      thereby making their legs powerful in extension. However, it is necessary to
      compare these reflections of muscle moment arm length to appropriate measures of
      the body weight moment arm and body mass estimates, both of which are influenced
      by ecogeographically determined body proportions. Reassessment of tibial condylar
      displacement and patellar thickness, as well as patellar height, relative to an
      appropriate measure of the moment arm for the baseline load on the knee (body
      weight), to that moment arm times estimated body mass, and to that moment arm
      times a skeletal reflection of body mass (femoral head diameter) rejects the
      hypothesis that the Neandertals had exceptionally powerful knee extension.
      Relative tibial condylar displacement remains above that of a modern industrial
      society sample, but similar to that of the Broken Hill tibia, Late Pleistocene
      early modern humans and a recent human nonindustrial sample. Relative patellar
      thickness is similar to that of early modern humans, who have relatively thick
      patellae compared to the late Holocene human samples. Consequently, once body
      proportions are taken into account, there is little difference between the
      Neandertals and other later Pleistocene humans in knee extensor mechanical
      advantage, and all of these fossil hominids are similar in the more important
      proximal tibial proportions to those of nonindustrial recent humans.

PMID- 10600323
TI  - Sivapithecus dental specimens from Dhara locality, Kalgarh District, Uttar
      Pradesh, Siwaliks, northern India.

PMID- 10600324
TI  - Nomenclature of African Plio-Pleistocene hominins.

PMID- 10600325
TI  - New age estimates for the Swanscombe hominid, and their significance for human
      evolution.

PMID- 10600326
TI  - The woman from Tabun: Garrod's doubts in historical perspective.

PMID- 10600327
TI  - Contents and index

PMID- 10600328
TI  - Diagnostic guidelines--An International Consensus document.

PMID- 10600329
TI  - Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan
      American Group for Immunodeficiency) and ESID (European Society for
      Immunodeficiencies).

PMID- 10600330
TI  - Mechanism of action for leflunomide in rheumatoid arthritis.
AB  - Leflunomide (Arava) has recently been approved by the Food and Drug
      Administration for the treatment of rheumatoid arthritis (RA). This approval was
      based on data from a double-blind, multicenter trials in the United States
      (leflunomide versus methotrexate versus placebo) in which leflunomide was
      superior to placebo and similar to methotrexate (Strand et al., Arch. Intern.
      Med., in press, 1999). In a multicenter European trial, leflunomide was similar
      to sulfasalazine in efficacy and side effects (Smolen et al., Lancet 353, 259
      266, 1999). Both methotrexate and leflunomide retarded the rate of radiolographic
      progression, entitling them to qualify as disease-modifying agents (Strand et
      al., Arch. Intern. Med., in press, 1999). Leflunomide is an immunomodulatory drug
      that may exert its effects by inhibiting the mitochondrial enzyme dihydroorotate
      dehydrogenase (DHODH), which plays a key role in the de novo synthesis of the
      pyrimidine ribonucleotide uridine monophosphate (rUMP). The inhibition of human
      DHODH by A77 1726, the active metabolite of leflunomide, occurs at levels
      (approximately 600 nM) that are achieved during treatment of RA. We propose that
      leflunomide prevents the expansion of activated and autoimmune lymphocytes by
      interfering with the cell cycle progression due to inadequate production of rUMP
      and utilizing mechanisms involving p53. The relative lack of toxicity of A77 1726
      on nonlymphoid cells may be due to the ability of these cells to fulfill their
      ribonucleotide requirements by use of salvage pyrimidine pathway, which makes
      them less dependent on de novo synthesis.

PMID- 10600331
TI  - Treatment with tumor necrosis factor-alpha and granulocyte-macrophage colony
      stimulating factor increases epidermal Langerhans' cell numbers in cancer
      patients.
AB  - Dendritic cells (DCs) initiate primary and stimulate secondary T-cell responses.
      We conducted a phase I trial of tumor necrosis factor (TNF-alpha) and granulocyte
      macrophage colony-stimulating factor (GM-CSF) in patients with cancer to increase
      DCs in peripheral blood or skin based on in vitro data that showed that CD34(+)
      hematopoietic precursors require these cytokines to mature into functional
      antigen-presenting DCs. Eleven patients were treated for 7 days with GM-CSF, 125
      microg/m(2) twice daily as subcutaneous injections, and TNF-alpha as a continuous
      infusion at dose levels of 25, 50, or 100 microg/m(2)/day. The maximum tolerated
      dose of TNF-alpha was 50 microg/m(2)/day with this dose of GM-CSF; dose-limiting
      toxicities occurred in both patients treated with 100 microg/m(2)/day. One became
      thrombocytopenic and the other had transient confusion. Epidermal Langerhans'
      cells were quantitated by S100 staining of skin biopsies and DC precursors in
      peripheral blood by colony-forming unit dendritic (CFU-dendritic) assays. S100
      positive cells in the epidermis doubled after treatment (2.55 S100(+) cells/high
      power field before treatment to 6.05 after treatment, p = 0.029). CFU-dendritic
      in peripheral blood increased after treatment in 3 colorectal cancer patients but
      not in 3 patients with melanoma. CD11c(+) or CD123(+), HLA-DR(bright), lineage
      negative dendritic cell precursors were not increased in peripheral blood
      mononuclear cells. This trial demonstrates that treatment with TNF-alpha and GM
      CSF can increase the number of DCs in the skin and the number of dendritic cell
      precursors in the blood of some patients with cancer. This approach may increase
      the efficacy of vaccination to tumor antigens in cancer patients.

PMID- 10600332
TI  - The safety and efficacy of ALLERVAX CAT in cat allergic patients.
AB  - Conventional immunotherapy for cat allergy is effective in reducing cat allergy
      symptoms in many patients, but this type of immunotherapy can cause severe
      reactions, including anaphylaxis, and often requires years of injections for
      successful desensitization. To improve the efficacy of immunotherapy for cat
      allergic patients, synthetic cat allergen peptides (ALLERVAX CAT) were generated,
      based on analysis of the immunodominant T cell epitopes of cat allergen. These
      peptides lack the tertiary structure of native Fel d1 and possess a significantly
      reduced capacity to bind to Fel d1-specific IgE. Using these peptides, we
      performed a multicenter, randomized, double-blind, placebo-controlled study of
      133 cat allergic patients chronically exposed to cats or who had failed previous
      conventional cat immunotherapy. We evaluated the safety of ALLERVAX CAT treatment
      and determined whether ALLERVAX CAT treatment improved tolerance to cat allergen,
      as measured by symptom analysis and pulmonary function testing. Three of the
      ALLERVAX CAT-treated patients required systemic epinephrine for adverse
      reactions, but the frequency of all adverse reactions in both groups was not
      statistically different from that of the placebo group. The majority of adverse
      events were "late" events, most commonly associated with respiratory symptoms,
      and these events declined with successive injections. ALLERVAX CAT given at a
      dose of 750 microg/dose improved pulmonary function in patients with reduced
      baseline FEV1, and global evaluation of the subjects' ability to tolerate cats
      improved significantly in the actively treated groups relative to placebo. Thus,
      although therapy with ALLERVAX CAT is associated with some adverse events in
      patients with severe cat sensitivity, such therapy is an effective approach for
      the management of cat allergy, since it improves tolerance to cats and improves
      pulmonary function in cat allergic patients with reduced FEV1.

PMID- 10600333
TI  - Inhibition of the CD40 pathway of monocyte activation by triazolopyrimidine.
AB  - Blockade of the CD40/CD40L pathway of monocyte/macrophage activation represents a
      promising strategy for the treatment of several inflammatory disorders. So far,
      most pharmacological agents developed for that purpose target CD40L (CD154)
      expressed on activated T cells. Herein, we provide evidence that
      triazolopyrimidine, a chemical compound primarily developed for the prevention of
      arterial thrombosis, strongly inhibits the response of human monocytes to CD40
      ligation. First, we found that triazolopyrimidine inhibits the production of IL
      12, TNF-alpha, and IL-6 by monocytes activated by coculture with fibroblasts
      transfected with the CD40L gene as well as the induction of procoagulant activity
      at their membrane. This was related to a decreased expression of CD40 on
      monocytes exposed to triazolopyrimidine, an effect that was already apparent at
      the mRNA level. Furthermore, the addition of triazolopyrimidine to monocytes
      cultured with IL-4 and GM-CSF prevented their differentiation into fully
      competent dendritic cells (DC) as DC differentiated in the presence of
      triazolopyrimidine expressed less CD40 at their surface and were profoundly
      deficient in the production of IL-12 upon exposure to CD40L transfectants. We
      conclude that triazolopyrimidine strongly inhibits the CD40 pathway of monocyte
      activation at least in part by downregulating the gene expression of CD40.

PMID- 10600334
TI  - Serum sCD23 level in patients with AIDS-related non-Hodgkin's lymphoma is
      associated with absence of Epstein-Barr virus in tumor tissue.
AB  - The cytokine soluble CD23 (sCD23) acts as a B cell growth factor and is
      associated with Epstein-Barr virus (EBV) infection. To elucidate the role sCD23
      might play in the pathogenesis of AIDS-related non-Hodgkin's lymphoma (AIDS NHL),
      101 AIDS NHL patients from the Multicenter AIDS Cohort Study were studied. Serum
      sCD23 within 18 months prior to lymphoma diagnosis was measured for all patients
      and EBV in tumor tissue was ascertained for 49 patients. Tumor morphology and
      primary site were verified from pathology reports and tumor specimens. Bivariate
      tests and multivariate regression were employed to determine whether serum sCD23
      correlated with tumor EBV, morphology, and primary site. Higher levels of serum
      sCD23 were associated with the absence of tumor EBV and with small noncleaved
      cell morphology. Thus, the serum sCD23 level does not appear to be mediated by
      EBV in these patients, but could be related to a pathogenetic mechanism of small
      noncleaved cell lymphoma.

PMID- 10600335
TI  - Lymphocyte proliferation assays may underestimate antigen responsiveness in human
      immunodeficiency virus infection.
AB  - The objective of this study was to examine the relationships among lymphocyte
      proliferation, interferon-gamma (IFN-gamma) production, and apoptosis in
      peripheral blood mononuclear cells (PBMC) of HIV-1-infected patients and
      controls. PBMC were prepared from 19 HIV-1-infected patients and 16 healthy
      controls. Using tetanus toxoid (TT) as a recall antigen, we assessed lymphocyte
      proliferation using [(3)H]thymidine incorporation after 2, 4, 6, and 7 days'
      culture and IFN-gamma production in 48-h culture supernatants by ELISA. Apoptosis
      was measured using TdT-mediated dUTP nick-end labeling. Median stimulation
      indices (SIs) in HIV-1-infected patients were 2.8 and 3.7 as opposed to 24.9 and
      25.1 in healthy controls after 6 and 7 days' culture, respectively (P < 0. 001).
      Among the controls, peak proliferation was seen after 7 days in culture whereas
      in patients, SIs peaked at 4 days and fell progressively by days 6 and 7. At 2
      and 4 days of stimulation with tetanus, patients' T cells showed increased
      apoptosis (19 and 25%) vs 12 and 15% apoptosis seen in controls' cells, P < 0.05.
      Interferon-gamma in 48-h supernatants of TT-stimulated PBMC was comparable among
      patients and controls. Whereas in our system, 6 and 7 day assays of lymphocyte
      proliferation provide increasing responses to TT among healthy controls, these
      durations of culture may underestimate antigen responsiveness in HIV-1 infection.
      Cell death due to apoptosis may account for this phenomenon. Whether shorter term
      or longer term assays of lymphocyte responsiveness more accurately reflect in
      vivo immune competence is unknown. Nonetheless, shorter duration assays may
      provide a more realistic estimate of the frequency of antigen-reactive cells in
      persons with HIV-1 infection.

PMID- 10600336
TI  - Multiformic modulation of endotoxin effects by linomide.
AB  - Linomide is a potent immunomodulator that either enhances or suppresses certain
      immunological processes. Of particular interest is this compound's capacity to
      inhibit a variety of organ-specific autoimmune diseases. Here, we report on the
      effects of linomide on several immunological reactions elicited by endotoxin
      (LPS), both in vivo and in vitro. In rats and mice linomide inhibited the
      elicitation of endotoxin-induced uveitis (EIU), an acute inflammatory eye disease
      that develops within 24 h following footpad injection of LPS. Linomide also
      inhibited the production of TNF-alpha and IL-6 by LPS-stimulated rat and mouse
      macrophage monolayers. On the other hand, treatment with linomide significantly
      increased the levels of IL-1beta (mice and less in rats), IL-6 (rats), and TNF
      alpha (mice) in serum samples collected 2 h following injection with LPS. The
      increased production of proinflammatory cytokines in linomide-treated mice was
      also indicated by the enhanced lethal effect of LPS in these mice. The finding of
      elevated levels of these cytokines in animals with suppressed EIU is also in line
      with previous observations of an inverse relationship between EIU severity and
      levels of TNF-alpha. Data recorded here underscore the unique capacity of
      linomide to both enhance and suppress the immune system.

PMID- 10600337
TI  - Impaired expression of CD28 on T cells in hairy cell leukemia.
AB  - T cells from patients with active hairy cell leukemia (HCL), a chronic B cell
      malignancy, show poor proliferation in response to allogeneic peripheral blood
      mononuclear cells (PBMC). In order to study the T cell dysfunction, the
      expression of several adhesion and costimulatory molecules was analyzed by flow
      cytometry. Circulating T cells from HCL patients showed increased percentages of
      CD28(-) in all T cell subsets. In some patients the percentage of CD28(-) T cells
      within the CD4(+) subset was increased up to 80%. These CD4(+)CD28(-) T cells did
      not proliferate in a mixed lymphocyte culture (MLC) against allogeneic PBMC.
      After enrichment for CD4(+)CD28(+) T cells, the proliferative response in the MLC
      was recovered, but this response was still lower than the proliferative response
      from control T cells. In conclusion, lack of CD28 on T cells and a restricted T
      cell repertoire may contribute to immune deficiency in patients with HCL.

PMID- 10600338
TI  - A human anti-HIV autoantibody enhances EBV transformation and HIV infection.
AB  - A highly specific, human IgG mAb, F223, which reacts with both HIV-1-infected
      cells and uninfected lymphoid cells, has been derived. F223 reacts with gp120 but
      fails to neutralize viral infection. The antibody does enhance HIV-1 infection in
      a complement-dependent manner. The autoantigen recognized by F223 is expressed on
      a small percentage of T cells and NK cells and the majority of B cells.
      Immunoprecipitation demonstrates F223 reactivity with an as of yet unidentified
      159-kDa protein in uninfected lymphoid cells. This reactivity with uninfected
      cells is inhibited by free gp120 demonstrating the cross-reactive nature of this
      antibody. The F223 light chain demonstrates strong homology to VLlambda2 family
      genes whereas the heavy chain is most homologous (84%) to the germline gene VH3
      H.11. In vivo usage of VH3 family genes by F223 and an anti-HIV-1 (gp41) human
      mAb, 3D6, with related autoreactivity, suggests that VH3 sequences may be
      important components of potentially pathogenic human anti-HIV-1 envelope
      autoantibodies. F223 was isolated from an HIV-1 infected individual with lymphoma
      and in vitro F223 significantly enhances EBV transformation of normal B cells and
      increases immunoglobulin production without affecting B cell proliferation.
      Characterization of this antibody response may provide important insights and
      mechanistic information on HIV pathogenesis.

PMID- 10600339
TI  - Immune complex size and complement regulate cytokine production by peripheral
      blood mononuclear cells.
AB  - We have previously shown that immune complexes isolated from children with
      juvenile rheumatoid arthritis are heterogeneous in their size, composition, and
      proinflammatory capacities. The experiments described here were undertaken to
      clarify further the roles of size and composition in determining the
      proinflammatory effects of immune complexes. We incubated peripheral blood
      mononuclear cells (PBMCs) with different soluble immune complex preparations:
      opsonized complexes, which were formed in the presence of serum, unopsonized
      complexes, which were formed in the absence of serum, and immune precipitates
      solubilized by complement after their formation. ELISA assays showed that immune
      complexes formed in the presence of complement were less efficient than
      unopsonized complexes in inducing IL-1beta and IL-8 secretion from leukocytes.
      Solubilized immune precipitates showed intermediate capacity to stimulate the
      release of both cytokines. Complexes formed in heat-inactivated serum were as
      efficient as unopsonized complexes in eliciting cytokine secretion from the
      cells. The capacity of complement to regulate cytokine secretion from leukocytes
      was related, at least in part, to immune complex size. Sucrose density gradients
      showed unopsonized complexes and solubilized immune precipitates were larger than
      opsonized immune complexes. In contrast, fluid-phase binding of C4 to immune
      complexes, which did not appreciably change immune complex size, substantially
      increased IL-1beta secretion from PBMC.

PMID- 10600340
TI  - Specificities of multiple sclerosis cerebrospinal fluid and serum antibodies
      against mimotopes.
AB  - In order to characterize antigenic epitopes specifically targeted by the immune
      response of patients with multiple sclerosis (MS), the antibody specificities of
      cerebrospinal fluids (CSF) and sera from the same MS patients have been analyzed
      using a random pentadecapeptide library displayed on phage. The 3 peptides
      (mimotopes) selected with MS sera were not disease-specific. In contrast, the
      combination of 4 MS CSF selected mimotopes, allowed the detection of specific
      antibodies in 21 of 60 MS CSF whereas only 2 of 27 CSF from patients with other
      neurological diseases equally recognized the 4 mimotopes. Some amino acid
      similarities were found between two MS CSF selected mimotopes and two envelope
      regions (319-329 and 433-443, respectively) of MSRV (multiple-sclerosis
      associated retrovirus) and the related endogenous retrovirus HERV-W.

PMID- 10600341
TI  - Effect of glutamine on Th1 and Th2 cytokine responses of human peripheral blood
      mononuclear cells.
AB  - Decreased glutamine concentrations are found in patients with catabolic stress
      and are related to susceptibility to infections. In this study, we evaluated the
      role of glutamine in Th1/Th2 cytokine responses. Peripheral blood mononuclear
      cells were stimulated with phytohemagglutinin (PHA), live attenuated bacillus
      Calmette-Guerin (BCG), or measles virus in the presence of different glutamine
      concentrations. We found that glutamine at an optimal concentration (0.6 mM)
      significantly enhanced PHA-stimulated lymphocyte proliferation as well as Th1
      [interferon-gamma (IFN-gamma) and interleukin-2 (IL-2)] and Th2 cytokine (IL-4
      and IL-10) production. In the absence of glutamine, BCG and measles virus
      elicited minimal lymphocyte proliferation, whereas BCG enhanced Th1 cytokine
      response and measles virus promoted Th2 cytokine response. Interestingly,
      addition of glutamine promoted the BCG-elicited Th1 cytokine response (IFN
      gamma), but suppressed the measles-induced Th2 cytokine response (IL-10). These
      results suggest that appropriate glutamine levels may influence host responses to
      different antigens and microorganisms. Furthermore, predominately Th1, but not
      Th2, cytokine responses required the presence of optimal concentrations of
      glutamine.

PMID- 10600342
TI  - Recurrent respiratory papillomatosis: altered CD8(+) T-cell subsets and
      T(H)1/T(H)2 cytokine imbalance.
AB  - Human papillomaviruses (HPVs) cause benign papillomas and squamous cell
      carcinomas in the genital and respiratory tracts. Recurrent respiratory
      papillomas (RRP) generate a high level of morbidity and significant mortality
      because of their location, resistance to treatment, and relentless recurrence
      that can vary in frequency in a given patient and between patients. We have found
      that T-cells from these patients, when exposed to or isolated from autologous
      papilloma tissue, have an elevated percentage of CD8(+), CD28(-) T-cells, and
      that T-cells from many of these patients express an increase in T(H)2-like
      cytokine mRNA in response to autologous papilloma tissue. Furthermore, both of
      these immunologic findings correlate with disease severity. These observations
      suggest that patients with RRP, and possibly others with refractory HPV-induced
      lesions, are unable to manage their disease with an appropriate and effective HPV
      specific, T-cell response. This immune imbalance may be responsible for the
      development and severity of HPV-induced respiratory papillomatosis.

PMID- 10600343
TI  - Pathophysiological role of endothelins in pulmonary microcirculatory disorders
      due to intestinal ischemia and reperfusion.
AB  - BACKGROUND: This study was conducted to investigate pulmonary microcirculatory
      disorders caused by intestinal ischemia reperfusion (IIR), and the
      pathophysiological roles of endothelin (ET) in acute lung injury (ALI). METHODS:
      Male rats were pretreated with normal saline or a nonselective ET receptor
      antagonist (TAK-044) and subjected to IIR (60 min of intestinal ischemia and 180
      min of reperfusion). The right upper lobe of the lung was examined by intravital
      confocal microscopy. RESULTS: The size of arterioles and venules was not
      significantly reduced during IIR, but the functional capillary density (FCD)
      decreased significantly. TAK-044 improved the pulmonary microhemodynamics,
      inhibiting the accumulation of leukocytes, the pulmonary edema, and the decrease
      of FCD. CONCLUSIONS: In the early stage of IIR, pulmonary microhemodynamics
      seemed more likely to be disturbed by the decrease of FCD, than by arteriolar or
      venular vasoconstriction. ETs decrease the FCD, promoting the interaction between
      leukocytes and pulmonary vessels.

PMID- 10600344
TI  - Effects of gabexate mesilate (FOY) on ischemia-reperfusion-induced acute lung
      injury in dogs.
AB  - BACKGROUND: To assess the effects of gabexate mesilate (FOY), a protease
      inhibitor, on a canine model of pulmonary ischemia-reperfusion injury. FOY has
      been applied clinically to treat acute pancreatitis and disseminated
      intravascular coagulation (DIC) and has been found to suppress some leukocyte
      mediated tissue injuries in both in vitro and in vivo studies. MATERIALS AND
      METHODS:  DESIGN: Comparison of four experimental groups: group 1 (untreated
      control, n = 8), unilateral (left) pulmonary ischemia due to perfusion and
      ventilation obstruction followed by reperfusion, without receiving any specific
      treatment; group 2 (negative control, sham operation, n = 8), left pulmonary
      hilar dissection without ischemia; group 3 (FOY posttreatment, n = 8), FOY
      treatment during the reperfusion stage only; and group 4 (FOY pretreatment, n =
      8), FOY treatment before ischemia and then continued during reperfusion. SETTING:
      University animal laboratory. SUBJECTS: Heart-worm-free mongrel dogs (12 to 15 kg
      body wt) were anesthetized with pentobarbital and mechanically ventilated.
      INVESTIGATIONS: Lung ischemia was made by snaring the left pulmonary artery and
      veins and clamping the bronchus with peribronchial tissue for 90 min followed by
      reperfusion for 18 h. Animals of the two treatment groups received a 1 mg/kg
      bolus of FOY at the beginning of reperfusion, with infusion of 2 mg/kg/h of FOY
      continuously starting 30 min before ischemia (group 4) or after reperfusion
      (group 3). During this study the following were measured: hemodynamics and
      aerodynamics, blood gas, bronchoalveolar lavage (BAL) fluid neutrophil percentage
      and protein concentration, lung wet to dry weight ratio (W/D ratio),
      myeloperoxidase (MPO) activity of the lung tissue, alveolar neutrophil
      infiltration, and degree of injury. RESULTS: This model of lung ischemia
      reperfusion induced significant pulmonary hypertension, increased pulmonary
      vascular resistance, decreased pulmonary dynamic compliance and arterial
      hypoxemia, increased BAL fluid total protein amount and neutrophil percentage,
      and increased alveolar neutrophil infiltration, histological injury score, and
      lung tissue MPO assay (group 1). Animals of the sham operation (negative control,
      group 2) showed only minimal changes in the above parameters. Treatment with FOY
      significantly attenuated the injury by decreasing the lung W/D ratio, alveolar
      neutrophil infiltration, histological injury score, lung tissue MPO assay, BAL
      fluid neutrophil percentage, and protein amount. Pretreatment with FOY (group 4)
      attenuated the injury to a significantly greater degree than it did when
      administered at the reperfusion stage only (group 3), which was reflected by the
      above-mentioned parameters, and as well significantly improved gas exchange
      function. FOY treatment was found to have little effect in altering hemodynamics
      and aerodynamics at most time points in this model of lung injury. CONCLUSIONS:
      FOY can attenuate the ischemia-reperfusion-induced acute lung injury in dogs by
      ameliorating the degree of alveolar membrane permeability change, neutrophil
      aggregation, and activation. FOY treatment starting before ischemia attenuated
      this injury to a significantly higher degree than its use after ischemia.
      However, the effect of FOY may be partial because it cannot alter the
      hemodynamics or aerodynamics as prominently as other parameters in this type of
      lung injury. Concomitant use of FOY with other agents will have additive or
      synergic effects in preventing lung ischemia-reperfusion injury.

PMID- 10600345
TI  - An extended dorsal island skin flap with multiple vascular territories in the
      rat: A new skin flap model.
AB  - BACKGROUND: The use of various animal skin flap models can lead to difficulty in
      the interpretation of experimental findings. Establishment of an axial-pattern
      flap model with predictable necrosis is desirable for the study of the flap
      pathophysiology. MATERIALS AND METHODS: Twenty rats were injected with a lead
      oxide, gelatin, and water mixture through the carotid artery to investigate the
      cutaneous vascular anatomy. Each cutaneous perforator on the rat dorsum was
      dissected to its source artery. The skin was removed and radiographed to define
      its vascular architecture. On the basis of the initial angiographic data, an
      extended dorsal island skin flap (based on the unilateral deep circumflex iliac
      artery) measuring up to 8 x 9 cm was designed in 10 rats to assess the viability
      of the flap. The boundaries of the flap are defined by anatomical landmarks to
      standardize the flap for rats of different sizes. The upper margin was located at
      the level of the tip of the scapula and the lower margin at a level 2 cm below
      the iliac crest. All flaps were observed for 7 days postoperatively and the
      surviving flap area was calculated as a percentage of total flap dimensions using
      the paper template technique. RESULTS: Most of the skin of the rat dorsum is
      supplied by three arteries: the deep circumflex iliac artery (DCIA), the
      posterior intercostal arteries (PIA), and the lateral thoracic artery (LTA). The
      DCIA anastomoses with the ipsilateral PIA and the contralateral PIA and DCIA. The
      average percentage survival of the skin flap is 70.5 +/- 4.8% (mean +/- SD).
      CONCLUSIONS: The extended dorsal island skin flap has a consistent vasculature
      and has a predictable distal necrosis area. This new model is felt to be
      appropriate for skin flap physiological studies.

PMID- 10600346
TI  - Telomerase activity is a useful marker to distinguish malignant pancreatic cystic
      tumors from benign neoplasms and pseudocysts.
AB  - BACKGROUND: Pancreatic serous cystadenoma, mucinous cystic neoplasms, ductal
      adenocarcinoma with cystic change, and pseudocysts are a spectrum of pancreatic
      cystic lesions. Their management strategy and prognosis are extremely diverse.
      Imaging study, cytology, and analysis of the tumor markers of cyst fluid are not
      always reliable in differentiation of these disease entities. MATERIALS AND
      METHODS: Fifteen patients with pancreatic cystic neoplasms (including six
      mucinous cystadenocarcinomas, two mucinous cystic neoplasms with borderline
      malignancy, two mucinous cystadenomas, and five serous cystadenomas), 4 patients
      with pancreatic ductal adenocarcinomas with cystic change, and 10 patients with
      pseudocysts were studied. Echo-guided or computed tomography-guided biopsies of
      pancreatic cystic lesions and their normal counterparts were conducted on all
      patients prior to operation or other management. The specimens were assayed for
      telomerase activity by using TRAP (telomere repeat amplification protocol). The
      level of telomerase activity in each specimen was semiquantitated as strong,
      moderate, weak, and none. The final diagnoses were made from histopathological
      examination of surgically resected or biopsied specimens. The efficacy of
      telomerase activity as a tumor marker to predict malignancy of pancreatic cystic
      lesions was evaluated. RESULTS: Three of the four pancreatic ductal
      adenocarcinomas with cystic change had strong or moderate telomerase activity;
      four of the six mucinous cystadenocarcinomas had moderate or weak telomerase
      activity; one of the two mucinous cystadenomas with borderline malignancy had
      weak telomerase activity; and none of their normal counterparts had detectable
      telomerase activity. In contrast, none of the two mucinous cystadenomas, five
      serous cystadenomas, and 10 pseudocysts had detectable telomerase activity. Based
      on these results, the sensitivity of telomerase activity for prediction of
      malignancy or premalignancy of pancreatic cystic lesions was 67%, the specificity
      was 100%, and the positive and negative predictive values were 1.0 and 0.81,
      respectively. The overall accuracy was 86%. CONCLUSIONS: The differential
      expressions of telomerase activity have been detected specifically in malignant
      and premalignant pancreatic cystic tumors, but not in benign cystic neoplasms or
      pseudocysts. The implications of these results are that telomerase activation
      takes part in the malignant transformation of pancreatic cystic neoplasms and
      that telomerase activity is a useful marker to distinguish malignant pancreatic
      cystic tumors from benign neoplasms and pseudocysts.

PMID- 10600347
TI  - Heat shock preconditioning on mitochondria during warm ischemia in rat livers.
AB  - BACKGROUND: The aim of this study was to investigate the effects of stress
      tolerance from heat shock preconditioning on changes in mitochondrial functions
      during ischemia-reperfusion injury of the liver. MATERIALS AND METHODS: Rats were
      divided into a heat shock group (group HS) and a control group (group C). In
      group HS, rats received heat shock pretreatment 48 h prior to ischemia
      reperfusion. Heat shock pretreatment was performed in a water bath at 42 degrees
      C for 15 min under general anesthesia. In group C, the same treatment was done
      with the water bath at 37 degrees C instead of at 42 degrees C. A 30-min warm
      ischemia by cramping the hepatoduodinal ligament (Pringle's maneuver) followed by
      a 60-min reperfusion was administered to all rats. Changes in membrane potential
      of hepatic mitochondria (MPM); mitochondrial respiratory function before ischemia
      (n = 5), after ischemia (n = 10), and after reperfusion (n = 10); and ATP
      recovery after reperfusion were compared between the groups. RESULTS: After a 30
      min ischemia, MPM in group C decreased significantly and did not recover even
      after reperfusion. On the other hand, MPM in group HS was maintained even after a
      30-min ischemia and 60 min into reperfusion as well. The respiratory control
      ratio (RCR) of the mitochondria in group C decreased to as low as 5.06 +/- 0.72
      after a 30-min ischemia, but in group HS, RCR was maintained near a normal level.
      The ATP level recovered significantly earlier in group HS than in group C after
      reperfusion. CONCLUSIONS: Heat shock preconditioning of the liver protected
      mitochondria from loss of membrane integrity during ischemia and contributed to
      their ability to produce energy-rich phosphates during reperfusion.

PMID- 10600348
TI  - Induction of neuronal and inducible nitric oxide synthase in the motoneurons of
      spinal cord following transient abdominal aorta occlusion in rats.
AB  - BACKGROUND: Motoneurons in the spinal cord are especially vulnerable to ischemic
      injury and selectively destroyed after transient ischemia. Nitric oxide (NO) has
      been implicated in both neurodegneration and neuroprotection to ischemic insult.
      To evaluate the role of NO in pathophysiology to spinal cord ischemia, the
      expression of neuronal and inducible nitric oxide synthase (n-NOS and i-NOS) and
      nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) in the
      motoneurons of the lumbosacral spinal cord was examined in a rat model with
      transient abdominal aorta (TAA) occlusion. MATERIALS AND METHODS: Male Sprague
      Dawley rats were divided into sham-operated (n = 12) and TAA occlusion (n = 24)
      groups. TAA occlusion was induced by placement of a microvascular clamp around
      the abdominal aorta for 20 min. Three sham-operated and six TAA occlusion animals
      were sacrificed at each time interval at 4, 24, and 48 h and 7 days after
      operation. Tissue sections obtained from the lumbosacral spinal cord were
      processed for n-NOS, i-NOS, NADPH-d, and hematoxylin-eosin (HE) staining.
      Histological changes of motoneurons in ventral horn were assessed by HE staining.
      RESULTS: In sham-operated control animals, n-NOS-, i-NOS-, and NADPH-d-positive
      neurons were barely detectable in the ventral horn of the spinal cord. At 4 h
      after TTA occlusion, n-NOS and NADPH-d expression became evident in the
      motoneurons and was markedly enhanced at 24 and 48 h. i-NOS expression was also
      induced in the ventral horn motoneurons of the lumbosacral spinal cord at the
      same time points. Enzymatic expression in the motoneurons was diminished 7 days
      after operation. Hyperchromatic neurons indicative of cell death were observed in
      HE-stained specimens 7 days following TAA occlusion. CONCLUSIONS: The rapid
      induction of n-NOS, i-NOS, and NADPH-d in the motoneurons of ventral horn
      suggests that NO may be involved in the selective and delayed neuronal death in
      the spinal cord to the ischemic insult.

PMID- 10600349
TI  - Exogenous transforming growth factor beta(2) modulates collagen I and collagen
      III synthesis in proliferative scar xenografts in nude rats.
AB  - BACKGROUND: Keloid and hypertrophic scars are fibrous dermal tumors characterized
      by overabundant collagen deposition. Previous studies demonstrated that exogenous
      transforming growth factor beta (TGF-beta) might increase collagen production in
      incisional wound models and in vitro. Using an in vivo model of human scar
      xenografts maintained in congenitally athymic, asplenic "nude" rats, we examined
      endogenous TGF-beta(2), collagen I, and collagen III levels in keloids and burn
      hypertrophic scars treated with TGF-beta(2) and TGF-beta(2) antibody. METHODS:
      Fresh keloid and burn hypertrophic scar specimens excised from human subjects
      were explanted to pedicled flaps based on the superficial inferior epigastric
      vessels in athymic "nude" rats. These flaps were allowed to mature for 3 weeks,
      after which the scar explants were directly perfused with 200 ng of TGF-beta(2)
      or 250 microg of TGF-beta(2) antibody daily for 5 consecutive days, then again on
      Days 10, 15, and 20. Biopsies were taken 30 and 120 days following the initiation
      of treatment. Immunohistochemical staining was then performed for TGF-beta(2),
      collagen I, and collagen III. The intensity of staining was quantified. RESULTS:
      Our results demonstrated that treatment of human proliferative scars with
      exogenous TGF-beta(2) results in a significant increase in endogenous TGF
      beta(2), collagen I, and collagen III production. By contrast, exogenous addition
      of anti-TGF-beta(2) antibody significantly decreased endogenous TGF-beta(2),
      collagen I, and collagen III production. CONCLUSION: This study supports a
      causative role for TGF-beta(2) in the formation of proliferative scars and
      suggests that TGF-beta(2) antibody may be a new potential antiscarring agent.

PMID- 10600350
TI  - Role of sodium nitroprusside in the improvement of rat liver preservation in
      University of Wisconsin solution: A study in the isolated perfused liver model.
AB  - BACKGROUND: Long-term liver preservation is needed to transform liver
      transplantation from an emergency operation into an elective procedure and,
      therefore, to improve the results of liver transplantation. AIMS: We have studied
      the possibility of extending the period of cold ischemia of the rat liver,
      maintaining good hemodynamics and functional conditions, by adding the NO donor
      sodium nitroprusside (NPNa) to the preservation solution. MATERIALS AND METHODS:
      Rat livers were preserved for 24, 48, and 72 h in University of Wisconsin
      solution (UW) at 4 degrees C (groups I, II, and III) or UW to which 500 microM
      NPNa was added (groups IV, V, and VI). Following the preservation time, liver
      viability was assessed using the isolated perfused liver model. Lactate
      dehydrogenase (LDH) and K(+) release, bile flow, and portal resistance were
      evaluated in each group and compared with those of liver controls (group VII)
      excised and perfused without preservation. RESULTS: Some deleterious effects can
      be seen during cold storage conditions as assessed by an increment in
      intrahepatic resistance and a diminution in the capacity of the organ to produce
      bile. On histological observation, we see vacuolated hepatocytes and free
      endothelial cells (detached) in the sinusoidal lumen. Addition of 500 microM NPNa
      to UW significantly moderates these injuries, with an improvement in intrahepatic
      circulation (less intrahepatic resistance), an increment in bile production, and
      better histological appearance of the organ. We were also able to determine the
      capacity of the UW + NPNa to produce NO. CONCLUSION: We assume that the
      beneficial vascular effects of NPNa are mediated by NO production.

PMID- 10600351
TI  - Downregulation of apoptosis-related genes in keloid tissues.
AB  - BACKGROUND: Physiologically programmed cell death or apoptosis occurs during the
      natural balance between cellular proliferation and demise. MATERIALS AND METHODS:
      We compared the expression of 64 apoptosis-related genes in keloids and normal
      scars to investigate the potential role of apoptosis in keloid formation. Two
      sets of mRNA were isolated from keloids excised from four previously untreated
      patients and four normal scar patients separately. Human cDNA arrayed
      hybridization was performed to compare the apoptosis-related gene expression
      between these two groups. In addition, TUNEL assays were performed to evaluate
      the percentage of apoptotic cells in keloids (center and periphery) versus normal
      scars. RESULTS: Eight of the sixty-four apoptosis-related genes studied were
      significantly underexpressed in keloid tissue. The underexpressed genes and their
      relative expression compared with normal scar were defender against cell death 1
      (DAD-1) (34.1% of normal scar); nucleoside diphosphate kinase B (c-myc
      transcription factor) (24.7%); glutathione S-transferase (17.9%); glutathione S
      transferase microsomal (28.1%); glutathione peroxidase (47.2%); tumor necrosis
      factor receptor 1-associated protein (TRADD) (51.0%); 19-kDa interacting protein
      3 (NIP3) (36.0%); and cytoplasmic dynein light chain 1 (HDLC1) (47.7%). Spatial
      analysis of apoptosis using TUNEL assays revealed apoptosis indices of 0.83 for
      keloid periphery and 0.63 for keloid center. CONCLUSIONS: In this study we
      demonstrated underexpression of apoptosis-related genes in human keloid tissue
      and decreased apoptotic activity in fibroblasts derived from keloids versus
      normal scars. We hypothesized that keloid fibroblasts fail to undergo
      physiologically programmed cell death and, thus, continue to produce and secrete
      connective tissue beyond the period expected in normal scar formation, accounting
      for the progressive and hypertrophic nature of keloids. This mechanism leads to
      new possibilities for treatment of keloids through induction of apoptosis.

PMID- 10600352
TI  - Blockade by polyunsaturated n-3 fatty acids of endotoxin-induced monocytic tissue
      factor activation is mediated by the depressed receptor expression in THP-1
      cells.
AB  - BACKGROUND: Monocytic hypercoagulation often occurs in inflammatory conditions.
      We have previously reported that polyunsaturated n-3 fatty acids (n-3 FA)
      including eicosapentaenoic acid (20:5) and docosahexaenoic acid (22:6) prevent
      the activation of monocytic tissue factor (TF) induced by bacterial endotoxin
      [lipopolysaccharide (LPS)] in cell cultures and animals. HYPOTHESIS: We herein
      explore the mode of inhibitory action of n-3 FA to determine if LPS transmembrane
      signaling is blocked, exerting such antagonism. RESULTS: Exposure of human
      leukemia monocytic THP-1 cells to bacterial endotoxin (Escherichia coli 0111:B04,
      1.5 microg/ml) for 6 h significantly activated TF activity and the production of
      nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), and interleukin (IL)
      1beta in conditioned medium. Pretreatment with n-3 FA, 20:5 and 22:6 at 10
      microM, resulted in time-dependent suppression of not only TF activation but also
      the elicitation of NO, TNF-alpha, and IL-1beta. These LPS responses were
      substantially depressed by more than 50% after a 72-h pretreatment. FACScan
      analysis showed that n-3 FA readily prevented fluorescein isothiocyanate (FITC)
      conjugated LPS from binding to THP-1 cells by approximately 70%. The observation
      that anti-CD14 mAb diminished FITC-LPS binding in a dose-dependent fashion has
      revealed CD14 dependency in LPS recognition. LPS upregulated CD14 expression,
      which was significantly arrested by n-3 FA. Similarly, the upregulation of the
      expression of CD11b, another proposed LPS receptor, was also minimally but
      significantly depressed by n-3 FA. CONCLUSION: The present study demonstrates
      that n-3 FA are able to block LPS transmembrane signaling via suppression of the
      receptor upregulation, mediating a variety of significant antagonisms against LPS
      action.

PMID- 10600353
TI  - Heparin-binding epidermal growth factor-like growth factor protects rat intestine
      from ischemia/reperfusion injury.
AB  - BACKGROUND: We have shown previously that heparin-binding epidermal growth factor
      (EGF)-like growth factor (HB-EGF) is cytoprotective for intestinal epithelial
      cells exposed to hypoxia in vitro. We now examine the effects of HB-EGF on the
      recovery of small intestine from ischemic injury in vivo. METHODS: Segmental
      intestinal ischemia of 60-min duration was produced in adult rats by occlusion of
      a first-order branch of the superior mesenteric artery. Recombinant HB-EGF (100
      microg) was injected intraluminally into the proximal small bowel after 45 min of
      ischemia in experimental animals, and buffered saline was injected in control
      animals. Animals were sacrificed after 48 h, and the affected bowel was resected,
      processed, and examined microscopically, with histologic grading of the ischemic
      injury. Additional animals were allowed to recover for up to 1 month to evaluate
      mortality differences. RESULTS: Intraluminal administration of HB-EGF resulted in
      significantly decreased extent and severity of ischemia/reperfusion injury, with
      significantly decreased grade of injury in the HB-EGF-treated compared with
      nontreated animals (average injury grade 0.66 compared with 2.44, respectively).
      Moreover, the mortality rate was significantly lower in the HB-EGF-treated
      animals compared with nontreated animals (0% vs 25%, respectively). HB-EGF
      treated animals had increased weight gain in the postischemia recovery period.
      CONCLUSIONS: We conclude that HB-EGF, given intraluminally, reduces both the
      amount and the severity of ischemia/reperfusion injury in the small bowel,
      reduces the mortality associated with intestinal ischemia, and may enhance
      intestinal recovery. The in vitro and in vivo cytoprotective effects of this
      growth factor suggest that it may, in the future, be clinically useful in
      treating patients with intestinal ischemia.

PMID- 10600354
TI  - Effects of dextran and pentoxifylline on hemorrhagic shock-induced P-selectin
      expression.
AB  - BACKGROUND: Dextran and pentoxifylline have been shown to prevent leukocyte
      endothelium adherence encountered after hemorrhagic shock. P-Selectin is the
      first endothelial cell adhesion molecule to be upregulated after an ischemic
      insult. We investigated the effects of resuscitation with dextran 70 and
      administration of pentoxifylline during resuscitation on hemorrhagic shock
      induced P-selectin expression. MATERIAL AND METHODS: Hemorrhagic shock was
      induced in C57BL/6 mice by withdrawing blood to reduce mean arterial blood
      pressure to 30 mm Hg for 45 min. Animals were resuscitated by infusing one of the
      following solutions (each n:5): (1) Ringer's lactate, (2) 6% dextran 70, (3)
      Ringer's lactate plus 50 mg/kg pentoxifylline, (4) 5% human albumin. Afterward
      shed blood was infused. In vivo P-selectin expression was determined using dual
      radiolabeled monoclonal antibody technique in lung, heart, liver, kidney,
      mesentery, stomach, small bowel, and colon 5 h after resuscitation. RESULTS: P
      Selectin was significantly upregulated in all of the organs studied in the
      Ringer's lactate resuscitation group (P < 0.001). Resuscitation with dextran 70
      and administration of pentoxifylline during resuscitation prevented P-selectin
      upregulation. Resuscitation with human albumin caused significant attenuation but
      could not prevent P-selectin upregulation (p < 0.01). CONCLUSION: Our study
      implies that the prevention of hemorrhagic shock-induced leukocyte-endothelium
      adherence by dextran 70 and pentoxifylline observed in other studies may be
      mediated by prevention of P-selectin expression by these agents.

PMID- 10600355
TI  - A size-matching heterotopic aortic valve implantation model in the rat.
AB  - BACKGROUND: Structural failure of cardiac valve allografts may be related to
      technical factors such as size mismatch, resulting in early intimal proliferation
      and fibrosis or immunological reactions against the transplanted valves,
      featuring lymphocytic infiltration. OBJECTIVE: To develop a heterotopic aortic
      valve implantation model in the rat to study the immunological factors leading to
      graft failure in the setting of a technical adaptation for size mismatch.
      METHODS: Syngeneic (WAG-WAG or DA-DA) and allogeneic (WAG-BN or WAG-DA) rat
      strain combinations were used to study the effect of the allogeneic response on
      valve properties. An end-to-side anastomosis was made between the U-shaped aortic
      root graft and the recipient's abdominal aorta to resolve the problems of size
      matching. RESULTS: No animals suffered from ischemic or neurological
      complications during the study period. One hundred percent survival and patency
      of the aortic grafts were achieved at the end of a 21-day observation period. In
      the syngeneic group 9 of 10 valves were still competent when assessed during
      retrograde injection. In contrast, 2 of 10 allogeneic valve grafts were competent
      on postoperative Day 21. Microscopic evaluation revealed no fibrosis or intimal
      thickening in the syngeneic valve grafts while the allogeneic valve grafts
      demonstrated rejection-like morphology. CONCLUSION: The absence of fibrosis and
      intimal thickening in the syngeneic transplanted valve grafts indicates that this
      implantation model is not influenced by nonimmunological-based structural
      changes. Therefore, this new model enables us to study the association between
      donor-directed immune responses and allograft degeneration in a technically
      unbiased manner.

PMID- 10600356
TI  - Effect of INT1 gene on Candida albicans murine intestinal colonization.
AB  - BACKGROUND: Increased intestinal colonization with Candida albicans is believed
      to be a major factor predisposing immunocompromised and postsurgical patients to
      systemic candidiasis, although the mechanisms facilitating C. albicans
      colonization remain unclear. Because previous studies have linked the C. albicans
      INT1 gene to filament formation, epithelial adherence, and mouse virulence,
      experiments were designed to evaluate the effect of INT1 on intestinal
      colonization. MATERIALS AND METHODS: Mice were orally inoculated with either the
      parent strain (CAF2, INT/INT1), an int1 heterozygote (CAG1, INT1/int1), an int1
      homozygote (CAG3, int1/int1), or a reintegrant (CAG5, int1/int1 + INT1), and
      sacrificed 3 and 7 days later for quantitative analysis of cecal C. albicans.
      RESULTS: Following oral inoculation with 10(3) C. albicans, only small numbers of
      each strain were recovered from the cecal flora of normal mice. However, in mice
      pretreated with oral antibiotics, cecal colonization of each strain was increased
      (P < 0.01). In addition, cecal colonization was reduced for all int1 mutant
      strains compared with the parent strain (P < 0.05). By light microscopy, all four
      C. albicans strains were easily observed in the ileal lumen as both budding yeast
      and filamentous forms, although only occasional yeast forms appeared adherent to
      the intestinal epithelium. CONCLUSIONS: C. albicans readily colonized and
      replicated in the ceca of antibiotic-treated mice. The presence of two functional
      copies of INT1 appeared to facilitate C. albicans cecal colonization, suggesting
      that intestinal colonization may be another virulence factor associated with INT1
      and that the gene product may be an attractive target to control C. albicans
      intestinal colonization.

PMID- 10600357
TI  - Compound 48/80 suppresses monocytic tissue factor-initiated extrinsic blood
      coagulation induced by bacterial endotoxin.
AB  - BACKGROUND: Hypercoagulability is one of the commonly exhibited endotoxemia
      septic symptoms; it could contribute to the manifestation of disseminated
      intravascular coagulation presenting threats to cardiovascular functions. The
      underlying mechanism, however, remains largely complex and unknown. OBJECTIVES:
      We herein determine whether bacterial endotoxin (LPS) upregulates the activities
      of clotting factors in plasma, contributing to extrinsic hypercoagulation.
      Compound 48/80 (48/80) is also tested for its ability to suppress
      hypercoagulation. METHODS: In an in vitro infection model, we exposed whole blood
      to LPS (Escherichia coli 0111:B04; 100 ng/ml) for 2 h. Thrombin time (TT),
      prothrombin time (PT), and the activities of clotting factors ( FVII, FIX, FX )
      in plasma contributing to the extrinsic coagulation were determined. Peripheral
      blood monocytes were isolated from Histoplaque 1077 gradient centrifugation, and
      the procoagulant activity was determined by a single-stage clotting assay on a
      Fibrometer. RESULTS: LPS drastically activated monocytic procoagulant activity
      which was defined as tissue factor (TF) activity, whereas LPS had no effect on
      TT, PT, and the activities of clotting factors in plasma. 48/80 not only
      instantaneously offset LPS-induced monocytic TF activation, but also
      significantly inhibited PT including the activities of clotting factors (FVII,
      FIX, and FX) in plasma, whereas TT remained unaffected. CONCLUSIONS: Monocytic TF
      activation was solely responsible for the extrinsic hypercoagulation in response
      to LPS. 48/80 effectively suppressed LPS-induced monocyticTF-initiated extrinsic
      coagulation at multiple sites, possibly presenting a new therapy for an
      instantaneous relief of hypercoagulation under septic conditions.

PMID- 10600358
TI  - Increased risk of antibody-mediated rejection of reduced-size liver allografts.
AB  - Because of the shortage of liver allografts in children, transplantation of
      reduced-size liver allografts from adult cadaveric donors or living, related
      donors is being done more frequently. Reduced-size liver allografts may be used
      in cases of ABO incompatibility and T-cell warm cross-match positivity. This
      experimental study in inbred rats was undertaken to determine if reduced-size
      liver allografts are more sensitive to antibody-mediated rejection than full-size
      liver allografts. Brown-Norway (BN) (RT1(n)) rats were sensitized by three
      successive skin grafts at 10-day intervals. Then orthotopic Lewis (LEW) (RT1(1))
      liver grafts were transplanted into these BN rats. Full-size liver allografts
      were compared with reduced-size liver allografts (70% of donor liver). Control
      groups were composed of full-size and/or reduced-size isografts. Titers of
      specific antibodies were assayed using a complement-dependent assay before and
      after orthotopic liver transplantation. Histological and immunofluorescence
      studies (IgG, IgM, C(3), and fibrinogen deposits) were assessed. Recipients of
      reduced-size liver allografts died of hyperacute rejection at 36.6 +/- 4.1 h,
      significantly earlier than recipients receiving full-size liver allografts, which
      died of accelerated acute rejection at 259.2 +/- 25.2 h (P < 0.001). Either full
      size or reduced-size isograft recipients survived indefinitely. A decrease in the
      titers of donor-specific antibodies was observed in both groups of animals.
      Slight deposits of IgG, IgM, C(3), and fibrinogen were observed in recipients of
      reduced-size liver allografts, whereas larger deposits were observed in
      recipients of full-size liver allografts. Our data demonstrate that there is an
      increased risk of antibody-mediated rejection of reduced-size liver allografts in
      sensitized recipients. This may have important clinical implications for partial
      liver grafting in cases of ABO incompatibility and T-cell warm cross-match
      positivity.

PMID- 10600359
TI  - Ethics and surgical research: what should guide our behavior?

PMID- 10600360
TI  - A prototype model structure for mixed microbial populations in homogeneous food
      products.
AB  - An important factor which has not been included in many models in the field of
      predictive microbiology is the influence of a background of microflora in a food
      product. It is however generally known that the growth of a microorganism as a
      pure culture can be substantially different from its growth in a mixed culture,
      due to microbial interactions. Because of the importance of these interactions
      and the lack of suitable modeling techniques in the field of predictive
      microbiology to describe them, the potential of models in other research fields
      namely ecology-to deal with interactions is explored in previous work of the
      authors. However, a model structure for microbial growth in food products cannot
      simply be copied from those elaborated in ecology. The structure of a predictive
      growth model is indeed typical, primarily due to the explicit modeling of a lag
      phase. The current paper proposes a prototype model structure for growth of mixed
      microbial populations in homogeneous food products. The model is able to describe
      a lag phase and reduces to a classical predictive growth model in the special
      case of single-species growth.

PMID- 10600361
TI  - Short- vs. long-range disperser: the evolutionarily stable allocation in a
      lattice-structured habitat
AB  - The population dynamics of two types of organisms in a lattice-structured habitat
      are studied and the evolutionarily stable allocation between short- and long
      range disperser is calculated. Offsprings of short-range dispersal stay in the
      vicinity of their parent and cause local competition. Using pair approximation, I
      derive a closed system of ordinary differential equations of global and local
      densities (or mean crowding), and calculate the condition for one type to invade
      the population dominated by the other type. The evolutionarily stable strategy
      (ESS) of resource allocation is derived for the case in which there is a linear
      trade-off between short- and long-range dispersers. The maximum equilibrium
      abundance of the population may be achieved by a mixture of both types of
      dispersers, but it is in general different from the ESS resource allocation
      calculated from the invasibility condition. For the same parameter values, the
      ESS invests a larger fraction of resources to short-range disperser than the
      optimal allocation which maximizes the equilibrium population density. This
      difference can be explained by the fact that long-range disperser is more
      effective in the preoccupation of space than short-range disperser. The
      predictions are confirmed by the direct computer simulations of the lattice
      stochastic models. Copyright 1999 Academic Press.

PMID- 10600362
TI  - A quadratic discriminant analysis of protein structure classification based on
      the Helix/Strand content.
AB  - Based on the 210 non-homologous proteins (domains) classified manually by Michie
      et al. (J. Mol. Biol. 262, 168-185, 1996), a new structure classification
      criterion of globular proteins relying on the content of helix/strand has been
      proposed, using a quadratic discriminant method. Each protein is classified into
      one of the three classes, i.e. those of alpha class, beta class and alphabeta
      class (including alpha/beta and alpha+beta classes). According to the new
      structure classification criterion, of the 210 proteins in the training set, 207
      are correctly classified and thus the accuracy is 207/210=98.57%. Multiple cross
      validation tests are performed. The jackknife test shows that of the 210 proteins
      207 are correctly classified with an accuracy of 98.57%. To test the method
      further, of 3577 proteins (domains) extracted from SCOP, 91.39% of them are
      correctly reclassified by the new classification criterion. On average, the
      accuracy of the new criterion is about 8 percentage points higher than that of
      the criterion proposed by Nakashima et al. (J. Biochem. 99, 153-162, 1986). Our
      result shows that the classification based solely on structures is basically
      consistent with that combining both structural and evolutionary information.
      Further complete automated classification scheme should consider both structures
      and evolutionary relationship. The methodology presented provides an appropriate
      mathematical format to reach this goal.

PMID- 10600363
TI  - A chondral modeling theory revisited.
AB  - The mechanical environment of limb joints constantly changes during growth due to
      growth-related changes in muscle and tendon lengths, long bone dimensions, and
      body mass. The size and shape of limb joint surfaces must therefore also change
      throughout post-natal development in order to maintain normal joint function.
      Frost's (1979, 1999) chondral modeling theory proposed that joint congruence is
      maintained in mammalian limbs throughout postnatal ontogeny because cartilage
      growth in articular regions is regulated in part by mechanical load. This paper
      incorporates recent findings concerning the distribution of stress in developing
      articular units, the response of chondrocytes to mechanically induced
      deformation, and the development of articular cartilage in order to expand upon
      Frost's chondral modeling theory. The theory presented here assumes that muscular
      contraction during post-natal locomotor development produces regional
      fluctuating, intermittent hydrostatic pressure within the articular cartilage of
      limb joints. The model also predicts that peak levels of hydrostatic pressure in
      articular cartilage increase between birth and adulthood. Finally, the chondral
      modeling theory proposes that the cell-cell and cell-extracellular matrix
      interactions within immature articular cartilage resulting from mechanically
      induced changes in hydrostatic pressure regulate the metabolic activity of
      chondrocytes. Site-specific rates of articular cartilage growth are therefore
      regulated in part by the magnitude, frequency, and orientation of prevailing
      loading vectors. The chondral modeling response maintains a normal kinematic
      pathway as the magnitude and direction of joint loads change throughout ontogeny.
      The chondral modeling theory also explains ontogenetic scaling patterns of limb
      joint curvature observed in mammals. The chondral modeling response is therefore
      an important physiological mechanism that maintains the match between skeletal
      structure, function, and locomotor performance throughout mammalian ontogeny and
      phylogeny.

PMID- 10600364
TI  - Bacterial lysis by phage--a theoretical model.
AB  - The similarity to materials corrosion is invoked to develop a model for phage
      infected bacterial lysis based on the statistics of extremes. The importance of
      cell size, envelope thickness and lysozyme eclipse time on the final probability
      distribution of lysis is considered. Experiments are suggested to test the model.

PMID- 10600365
TI  - Relative advantage: a substitute for mean fitness in Fisher's fundamental
      theorem?

PMID- 10600366
TI  - Nuclear magnetic resonance solution structure of truncated human GRObeta [5-73]
      and its structural comparison with CXC chemokine family members GROalpha and IL
      8.
AB  - The three-dimensional structure of a novel four amino acid truncated form of the
      CXC chemokine GRObeta [5-73] isolated from bone marrow stromal cells with potent
      hematopoietic and anti-infective activities has been determined by two
      dimensional (1)H nuclear magnetic resonance (NMR) spectroscopy in solution. On
      the basis of 1878 upper distance constraints derived from nuclear Overhauser
      effects (NOE) and 314 dihedral angle constraints, a group of 20 conformers
      representing the solution structure of the human GRObeta [5-73] was computed with
      the program DYANA. At the concentrations used for NMR study, GRObeta [5-73] forms
      a dimer in solution that is architectured by a six-stranded antiparallel beta
      sheet (residues 25 to 29, 39 to 44, 49 to 52) and a pair of helices (residues 58
      to 68) with 2-fold symmetry, while the C terminus of the protein is disordered.
      The average of the pairwise root-mean-square deviations of individual NMR
      conformers relative to the mean coordinates for the backbone atoms N, C(alpha)
      and C' of residues 5 to 68 is 0.47 A. Overall, the global fold of GRObeta [5-73]
      is similar to that of the previously reported NMR structure of GROalpha and the
      NMR and X-ray structures of interleukin-8. Among these three CXC chemokines,
      GRObeta [5-73] is most similar in structure to GROalpha. Significant differences
      between GRObeta [5-73], GROalpha and interleukin-8 are in the N-terminal loop
      comprising residues 12 to 19. The N-terminal arm containing the conserved ELR
      motif and the loop of residues 30 to 38 containing the GPH motif are different
      among these three CXC chemokines. The structural differences in these two regions
      may be responsible for the specificity of the receptor binding and biological
      activity of different chemokines.

PMID- 10600367
TI  - A sequence in the Escherichia coli fdhF "selenocysteine insertion Sequence"
      (SECIS) operates in the absence of selenium.
AB  - The UGA codon context of the Escherichia coli fdhF mRNA includes an element
      called the selenocysteine insertion sequence (SECIS) that is responsible for the
      UGA-directed incorporation of the amino acid selenocysteine into a protein. Here,
      we describe an extended fdhF SECIS that includes the information for an
      additional function: the prevention of UGA readthrough under conditions of
      selenium deficiency. This information is contained in a short mRNA region
      consisting of a single C residue adjacent to the UGA on its downstream side, and
      an additional segment consisting of the six nucleotides immediately upstream from
      it. These two regions act independently and additively, and probably through
      different mechanisms. The single C residue acts as itself; the upstream region
      acts at the level of the two amino acids, arginine and valine, for which it
      codes. These two codons at the 5' side of the UGA correspond to the ribosomal E
      and P sites. Here, we present a model for the E. coli fdhF SECIS as a
      multifunctional RNA structure containing three functional elements. Depending on
      the availability of selenium, the SECIS enables one of two alternatives for the
      translational machinery: either selenocysteine incorporation into a polypeptide
      or termination of the polypeptide chain.

PMID- 10600368
TI  - Repression and activation of arginine transport genes in Escherichia coli K 12 by
      the ArgP protein.
AB  - In Escherichia coli K 12, arginine modulates the functioning of the arginine
      transport system. Cells grown in the presence of arginine show a 60 % reduction
      in the active incorporation of radioactive arginine. This regulation of arginine
      transport is independent of the regulation of arginine biosynthesis. Previously,
      a mutant was isolated with a 90 % reduction of arginine transport. The mutation
      affected also the transport of ornithine and lysine. It was mapped and assigned
      to a locus named argP at minute 65 of the E. coli linkage map. Genetic studies
      showed that in argP/argP(+) merodiploids, the mutated argP allele is dominant.
      The argP(+) gene was cloned and sequenced. Analysis of the sequenced gene
      revealed that it is identical with iciA, an E. coli gene that encodes an
      inhibitor of chromosomal initiation of replication in vitro. The sequence
      analysis of the mutated argP gene identified a single mutation that led to the
      substitution of proline for serine in the C-terminal domain of the ArgP protein.
      This protein has homology with a large group of prokaryotic regulatory proteins
      known as the LysR family. Proteins from this family have been shown to function
      as transcriptional regulators. Here, it is shown that the ArgP protein activates
      the formation of the ArgK protein, an ATP-binding protein essential for the
      operation of the arginine transport system. In the presence of L-arginine, ArgP
      inhibits its own synthesis.

PMID- 10600369
TI  - Similarities and differences in the RNase H activities of human immunodeficiency
      virus type 1 reverse transcriptase and Moloney murine leukemia virus reverse
      transcriptase.
AB  - Retroviral revXerse transcriptases (RTs) have an associated RNase H activity that
      can cleave RNA-DNA duplexes with considerable precision. We believe that the
      structure of the RNA-DNA duplexes in the context of RT determines the specificity
      of RNase H cleavage. To test this idea, we treated three related groups of
      synthetic RNA-DNA hybrids with either Moloney murine leukemia virus (MLV) RT or
      human immunodeficiency virus type 1 (HIV-1) RT. All of the hybrids were prepared
      using the same 81-base RNA template. The first series of RNase H substrates was
      prepared with complementary DNA oligonucleotides of different lengths, ranging
      from 6 to 20 nucleotides, all of which shared a common 5' end and were
      successively shorter at their 3' ends. The second series of oligonucleotides had
      a common 3' end but shorter 5' ends. The DNA oligonucleotides in the third series
      were all 20 bases long but had non-complementary stretches at either the 5' end,
      3' end, or both ends. Several themes have emerged from the experiments with these
      RNA-DNA duplexes. (1) Both HIV-1 RT and MLV RT cleave fairly efficiently if the
      duplex region is at least eight bases long, but not if it is shorter. (2)
      Although, under the conditions we have used, both enzymes require the substrate
      to have a region of RNA-DNA duplex, both MLV RT and HIV-1 RT can cleave RNA
      outside the region that is part of the RNA-DNA duplex. (3) The polymerase domain
      of HIV-1 RT uses certain mismatched segments of RNA-DNA to position the enzyme
      for RNase H cleavage, whereas the polymerase domain of MLV RT does not use the
      same mismatched segments to define the position for RNase H cleavage. (4) For HIV
      1 RT, a mismatched region near the RNase H domain can interfere with RNase H
      cleavage; cleavage is usually (but not always) more efficient if the mismatched
      segment is deleted. These results are discussed in regard to the structure of HIV
      1 RT and the differences between HIV-1 RT and MLV RT.

PMID- 10600370
TI  - Antisense RNA regulation in prokaryotes: rapid RNA/RNA interaction facilitated by
      a general U-turn loop structure.
AB  - Efficient gene control by antisense RNA requires rapid bi-molecular interaction
      with a cognate target RNA. A comparative analysis revealed that a YUNR motif
      (Y=pyrimidine, R=purine) is ubiquitous in RNA recognition loops in antisense RNA
      regulated gene systems. The (Y)UNR sequence motif specifies two intraloop
      hydrogen bonds forming U-turn structures in many anticodon-loops and all T-loops
      of tRNAs, the hammerhead ribozyme and in other conserved RNA loops. This
      structure creates a sharp bend in the RNA phosphate-backbone and presents the
      following three to four bases in a solvent-exposed, stacked configuration
      providing a scaffold for rapid interaction with complementary RNA. Sok antisense
      RNA from plasmid R1 inhibits translation of the hok mRNA by preventing ribosome
      entry at the mok Shine & Dalgarno element. The 5' single-stranded region of Sok
      RNA recognizes a loop in the hok mRNA. We show here, that the initial pairing
      between Sok antisense RNA and its target in hok mRNA occurs with an observed
      second-order rate-constant of 2 x 10(6) M(-1) s(-1). Mutations that eliminate the
      YUNR motif in the target loop of hok mRNA resulted in reduced antisense RNA
      pairing kinetics, whereas mutations maintaining the YUNR motif were silent. In
      addition, RNA phosphate-backbone accessibility probing by ethylnitrosourea was
      consistent with a U-turn structure formation promoted by the YUNR motif. Since
      the YUNR U-turn motif is present in the recognition units of many
      antisense/target pairs, the motif is likely to be a generally employed enhancer
      of RNA pairing rates. This suggestion is consistent with the re-interpretation of
      the mutational analyses of several antisense control systems including RNAI/RNAII
      of ColE1, CopA/CopT of R1 and RNA-IN/RNA-OUT of IS10.

PMID- 10600371
TI  - Length dependence of RNA-RNA annealing.
AB  - The association of complementary nucleic acids can be described by a second order
      rate constant k. For extended molecules, including complex nucleic acids, values
      of k were shown to be proportional to the square root of the chain length L of
      the shorter nucleic acid strand at temperatures between tm and tm-30 degrees C.
      For homopolymers this is true over a wider temperature range. Below temperatures
      of tm-30 degrees C, annealing rate constants may sharply decrease due to the
      formation of intramolecular structures. It seems to be reasonable to assume that
      the formation of intramolecular structures of nucleic acids reduces the density
      of nucleation sites for annealing and, thereby, lowers the rates of association.
      Here, we examined the relationship between RNA chain length and the kinetics of
      RNA-RNA annealing at physiological ionic strength and temperature. We used a
      complete sequence space derived from chloramphenicol acetyltransferase (cat)
      sequences to average over all structures for each given length. For groups of
      progressively longer antisense RNA species and a 800 nucleotides long
      complementary RNA, the observed annealing rate constants kobs were measured in
      vitro. The structure-averaged values for kobs of RNA-RNA annealing were not
      related to the square root of the chain length. Instead, they were found to be
      proportional to 10(alphaL) (alpha=0.0017). Here, a theoretical model is suggested
      in which the observed length dependence is mainly influenced by ionic
      interactions between complementary RNA strands. The observed length dependence
      has substantial implications for the biological behavior of long-chain
      complementary RNA including the design of antisense RNA. The efficacy of
      antisense RNA in living cells is known to be related to annealing kinetics in
      vitro. Thus, on a statistical basis and independent of individual structures,
      long-chain rather than short-chain antisense RNA should lead to stronger
      inhibition.

PMID- 10600372
TI  - The interpretation of Mg(2+) binding isotherms for nucleic acids using Poisson
      Boltzmann theory.
AB  - Magnesium ions play a crucial role in the structural integrity and biological
      activity of nucleic acids. Experimental thermodynamic descriptions of Mg(2+)
      interactions with nucleic acids in solution have generally relied on the analyses
      of binding polynomials to estimate the energetic contributions of diffuse and
      site-bound ions. However, since ion binding is dominated by long-range
      electrostatic forces, such models provide only a phenomenological description of
      the experimental Mg(2+) binding data and provide little insight into the actual
      mechanism of the binding equilibria. Here, we present a rigorous theoretical
      framework based on the non-linear Poisson-Boltzmann (NLPB) equation for
      understanding diffuse ion interactions that can be used to interpret experimental
      Mg(2+) binding isotherms. As intuitively expected, in the NLPB model binding is
      simply the total accumulation of the ion around the nucleic acid. Comparing the
      experimental data to the calculated curves shows that the NLPB equation provides
      a remarkably accurate description of Mg(2+) binding to linear polynucleotides
      like DNA and poly(A x U) without any fitted parameters. In particular, the NLPB
      model explains two general features of magnesium binding; the strong dependence
      on univalent salt concentration, and its substantial anticooperativity. Each of
      these effects can be explained by changes in the Mg(2+) distribution around the
      polyion under different solution conditions. In order to more fully understand
      these different aspects of magnesium binding, the free energy of Mg(2+) binding,
      DeltaGMg, is calculated and partitioned into several salt-dependent
      contributions: the change in the electrostatic interaction free energy of the
      charges, DeltaDeltaGE.D (including Mg(2+)-phosphate, Mg(2+)-Mg(2+), Mg(2+)-Na(+),
      Na(+)-Na(+), Na(+)-phosphate interactions, and similar contributions for Cl(-))
      and the cratic free energies of (re)organizing the MgCl2 and NaCl atmospheres,
      DeltaG(Mg)org and DeltaDeltaG(Na)org, respectively. For the systems studied here,
      DeltaGMg is strongly influenced by entropic free energy changes in the
      distributions of both NaCl and MgCl2, DeltaG(Mg)org and DeltaDeltaG(Na)org. From
      this analysis, we also raise the possibility that coions added with the magnesium
      salt might play an important role in the overall stability of nucleic acids under
      some conditions.

PMID- 10600373
TI  - C-H.O hydrogen bonds in minor groove of A-tracts in DNA double helices.
AB  - Analysis of available B-DNA type oligomeric crystal structures as well as protein
      bound DNA fragments (solved using data with resolution <2.6 A) indicates that in
      both data sets, a majority of the (3'-Ade) H2..O2(3'-Thy/Cyt) distances in AA.TT
      and GA.TC dinucleotide steps, are considerably shorter than their values in a
      uniform fibre model, and are smaller than their optimum separation distance.
      Since the electropositive C2-H2 group of adenine is in close proximity of the
      electronegative keto oxygen atoms of both pyrimidine bases in the antiparallel
      strand of the double-helical DNA structures, it suggests the possibility of intra
      base-pair as well as cross-strand C-H..O hydrogen bonds in the minor groove. The
      C2-H2..O2 hydrogen bonds within the A.T base-pairs could be a natural consequence
      of Watson-Crick pairing. However, the close cross-strand interactions between the
      bases at the 3'-ends of the AA.TT and GA.TC steps arise due to the local sequence
      dependent geometry of these steps. While the base-pair propeller twist in these
      steps is comparable to the fibre model, some of the other local parameters such
      as base-pair opening angle and inter-base-pair slide show coordinated changes,
      leading to these shorter C2-H2..O2 distances. Hence, in addition to the well
      known minor groove hydration, it appears that favourable C2-H2..O2 cross-strand
      interactions may play a role in imparting a characteristic geometry to AA.TT and
      GA.TC steps, as well as An.Tn and GAn.TnC tracts, which leads to a narrow minor
      groove in these regions.

PMID- 10600374
TI  - Brownian dynamics simulation of ion flow through porin channels.
AB  - Bacterial porins, which allow the passage of solutes across the outer bacterial
      membrane, are structurally well characterized. They therefore lend themselves to
      detailed studies of the determinants of ion flow through transmembraneous
      channels. In a comparative study, we have performed Brownian dynamics simulations
      to obtain statistically significant transfer efficiencies for cations and anions
      through matrix porin OmpF, osmoporin OmpK36, phosphoporin PhoE and two OmpF
      charge mutants. The simulations show that the electrostatic potential at the
      highly charged channel constriction serves to enhance ion permeability of either
      cations or anions, dependent on the type of porin. At the same time translocation
      of counterions is not severely impeded. At the constriction, cations and anions
      follow distinct trajectories, due to the segregation of basic and acidic protein
      residues. Simulated ion selectivity and relative conductance agree well with
      experimental values, and are dependent crucially on the charge constellation at
      the pore constriction. The experimentally observed decrease in ion selectivity
      and single channel conductance with increasing ionic strength is well reproduced
      and can be attributed to electrostatic shielding of the pore lining.

PMID- 10600376
TI  - Computer simulations of actin polymerization can explain the barbed-pointed end
      asymmetry.
AB  - Computer simulations of actin polymerization were performed to investigate the
      role of electrostatic interactions in determining polymerization rates.
      Atomically detailed models of actin monomers and filaments were used in
      conjunction with a Brownian dynamics method. The simulations were able to
      reproduce the measured barbed end association rates over a range of ionic
      strengths and predicted a slower growing pointed end, in agreement with
      experiment. Similar simulations neglecting electrostatic interactions indicate
      that configurational and entropic factors may actually favor polymerization at
      the pointed end, but electrostatic interactions remove this trend. This result
      would indicate that polymerization at the pointed end is not only limited by
      diffusion, but faces electrostatic forces that oppose binding. The binding of the
      actin depolymerizing factor (ADF) and G-actin complex to the end of a filament
      was also simulated. In this case, electrostatic steering effects lead to an
      increase in the simulated association rate. Together, the results indicate that
      simulations provide a realistic description of both polymerization and the
      binding of more complex structures to actin filaments.

PMID- 10600375
TI  - The C-terminal domain of the Pseudomonas secretin XcpQ forms oligomeric rings
      with pore activity.
AB  - The Pseudomonas secretin XcpQ forms an oligomeric complex, which is involved in
      the translocation of proteins across the outer membrane via the type II secretion
      pathway. Pseudomonas aeruginosa produces only small amounts of this complex, 50
      to 100 copies per bacterium, and overexpression is lethal to these cells.
      However, overexpression of Pseudomonas alcaligenes XcpQ could be achieved in the
      P. alcaligenes mutant strain 537. Protease protection experiments with P.
      alcaligenes XcpQ showed that the C-terminal domain of XcpQ, which is conserved in
      all the different members of the secretin family, is largely resistant to
      proteinase K. This protease-resistant fragment is embedded in the membrane and
      remains a stable complex, indicating that this domain is involved in complex
      formation. Both the intact and the protease-protected XcpQ complex showed a
      tendency to form two-dimensional crystal-like structures. Electron microscopic
      analysis of these structures showed that the overall oligomeric rings of the
      intact and of the protease-resistant complex are highly similar. The central
      cavity of the intact XcpQ complex contains structured mass. Both the intact and
      the protease-protected XcpQ complex showed pore-forming activity in planar lipid
      bilayers, consistent with their role as a translocation channel. However, the
      single-channel conductances observed were not uniform. Together, these results
      demonstrate that the C-terminal secretin homology domain of XcpQ is the
      structural domain that forms the channel through which macromolecules are being
      transported.

PMID- 10600377
TI  - Mutational analysis of the affinity maturation of antibody 48G7.
AB  - The affinity maturation of antibody 48G7 from its germline predecessor 48G7g has
      been studied at a molecular level through a combination of structural and
      biochemical means. Each of the nine somatic mutations accumulated during affinity
      maturation has been assessed for gain or loss of function in both the germline
      and affinity-matured antibodies. Individual somatic mutations were found to be
      either positive or neutral in their effects on affinity for hapten JWJ1, with a
      marked context-dependence for some sites of mutation. In a number of cases
      significant cooperativity was found between pairs of somatically mutated
      residues. Interpretation of the structural changes introduced by many of the
      point mutations has been possible due to the availability of high-resolution
      crystal structures of 48G7g and 48G7, and mechanisms by which these structural
      changes may result in enhanced affinity for hapten have been identified. Precise
      dissection of structure-function relationships in this system provides additional
      insights into the role of cooperativity in the evolution of antibody affinity.
      Comparison of 48G7 with previously characterized systems provides a varied view
      of the structure-function mechanisms by which the humoral immune system produces
      large increases in affinity.

PMID- 10600378
TI  - Kinetic analysis of peptide binding to the TAP transport complex: evidence for
      structural rearrangements induced by substrate binding.
AB  - The transporter associated with antigen processing (TAP) plays a key role in the
      class I major histocompatibility complex (MHC) mediated immune surveillance. It
      translocates peptides generated by the proteasome complex into the endoplasmic
      reticulum (ER) for loading onto MHC class I molecules. At the cell surface these
      MHC complexes are monitored for their antigenic cargo by cytotoxic T-lymphocytes.
      Peptide binding to TAP is the essential step for peptide selection and for
      subsequent ATP-dependent translocation into the ER lumen. To examine the pathway
      of substrate recognition by TAP, we employed peptide epitopes, which were labeled
      with an environmentally sensitive fluorophore. Upon binding to TAP, a drastic
      fluorescence quenching of the fluorescent substrate was detected. This allowed us
      to analyze TAP function in real-time by using a homogeneous assay. Formation of
      the peptide-TAP complex is composed of a fast association step followed by a slow
      isomerization of the transport complex. Proton donor groups moving in proximity
      to the fluorescence label cause fluorescence quenching. Taken together, this
      peptide-induced structural reorganization may reflect the crosstalk of structural
      information between the peptide binding site and both nucleotide-binding domains
      within the TAP complex.

PMID- 10600379
TI  - Crystallographic studies on damaged DNAs. I. An N(6)-methoxyadenine residue forms
      a Watson-Crick pair with a cytosine residue in a B-DNA duplex.
AB  - Oxyamines such as hydroxylamine and methoxylamine disturb DNA replication and act
      as potent mutagens, causing nucleotide transition from one purine to another or
      one pyrimidine to another. In order to investigate mismatch base-pairing in DNA
      damaged with oxyamines, a dodecamer with the sequence d(CGCGmo(6)AATCCGCG), where
      mo(6) A is 2'-deoxy-N(6)-methoxyadenosine, was synthesized and its crystal
      structure determined. No significant conformational changes are found between the
      present dodecamer and the original undamaged B-form dodecamer. Electron density
      maps clearly show that the mo(6)A residue forms a base-pair with a 2'
      deoxycytidine residue through hydrogen bonds similar to a Watson-Crick G.C base
      pair. For these hydrogen bonds to be made, N(6)-methoxyadenine must chemically
      take the imino form. The methoxylation thus enables the adenine base to mimic a
      guanine base. As a result, misincorporation of 2'-deoxycytidine instead of
      thymidine, or 2'-deoxyadenosine instead of 2'-deoxyguanosine, can occur in DNA
      replication.

PMID- 10600380
TI  - Crystallographic studies on damaged DNAs. II. N(6)-methoxyadenine can present two
      alternate faces for Watson-Crick base-pairing, leading to pyrimidine transition
      mutagenesis.
AB  - In a previous paper, 2'-deoxy-N(6)-methoxyadenosine (mo(6)A) was shown to form a
      mismatch base-pair with 2'-deoxycytidine with a Watson-Crick-type geometry. To
      fully understand the structural basis of genetic mutations with damaged DNA, it
      is necessary to examine whether the methoxylated adenine residue still has the
      ability to form the regular Watson-Crick pairing with a thymine residue.
      Therefore, a DNA dodecamer with the sequence d(CGCGmo(6)AATTCGCG) has been
      synthesized and its crystal structure determined. The methoxylation has no
      significant effect on the overall DNA conformation, which is that of a standard B
      form duplex. The methoxylated adenine moieties adopt the amino tautomer with an
      anti conformation around the C(6)-N(6) bond to the N(1) atom, and they form a
      Watson-Crick base-pair with thymine residues on the opposite strand, similar to
      an unmodified adenine residue. It is concluded that methoxylated adenine can
      present two alternate faces for base-pairing, thanks to the amino<-->imino
      tautomerism allowed by methoxylation. Based on this property, two gene transition
      routes are proposed.

PMID- 10600381
TI  - Structural analysis of an RNase T1 variant with an altered guanine binding
      segment.
AB  - The ribonuclease T1 variant 9/5 with a guanine recognition segment, altered from
      the wild-type amino acid sequence 41-KYNNYE-46 to 41-EFRNWQ-46, has been
      cocrystallised with the specific inhibitor 2'-GMP. The crystal structure has been
      refined to a crystallographic R factor of 0.198 at 2.3 A resolution. Despite a
      size reduction of the binding pocket, pushing the inhibitor outside by 1 A, 2'
      GMP is fixed to the primary recognition site due to increased aromatic stacking
      interactions. The phosphate group of 2'-GMP is located about 4.2 A apart from its
      position in wild-type ribonuclease T1-2'-GMP complexes, allowing a Ca(2+),
      coordinating this phosphate group, to enter the binding pocket. The
      crystallographic data can be aligned with the kinetic characterisation of the
      variant, showing a reduction of both, guanine affinity and turnover rate. The
      presence of Ca(2+) was shown to inhibit variant 9/5 and wild-type enzyme to
      nearly the same extent.

PMID- 10600382
TI  - Crystal structure of the purine nucleoside phosphorylase (PNP) from Cellulomonas
      sp. and its implication for the mechanism of trimeric PNPs.
AB  - The three-dimensional structure of the trimeric purine nucleoside phosphorylase
      (PNP) from Cellulomonas sp. has been determined by X-ray crystallography. The
      binary complex of the enzyme with orthophosphate was crystallized in the
      orthorhombic space group P212121 with unit cell dimensions a=64.1 A, b=108.9 A,
      c=119.3 A and an enzymatically active trimer in the asymmetric unit. X-ray data
      were collected at 4 degrees C using synchrotron radiation (EMBL/DESY, Hamburg).
      The structure was solved by molecular replacement, with the calf spleen PNP
      structure as a model, and refined at 2.2 A resolution. The ternary "dead-end"
      complex of the enzyme with orthophosphate and 8-iodoguanine was obtained by
      soaking crystals of the binary orthophosphate complex with the very weak
      substrate 8-iodoguanosine. Data were collected at 100 K with CuKalpha radiation,
      and the three-dimensional structure refined at 2.4 A resolution. Although the
      sequence of the Cellulomonas PNP shares only 33 % identity with the calf spleen
      enzyme, and almost no identity with the hexameric Escherichia coli PNP, all three
      enzymes have many common structural features, viz. the nine-stranded central beta
      sheet, the positions of the active centres, and the geometrical arrangement of
      the ligands in the active centres. Some similarities of the surrounding helices
      also prevail. In Cellulomonas PNP, each of the three active centres per trimer is
      occupied by orthophosphate, and by orthophosphate and base, respectively, and
      small structural differences between monomers A, B and C are observed. This
      supports cooperativity between subunits (non-identity of binding sites) rather
      than existence of more than one binding site per monomer, as previously suggested
      for binding of phosphate by mammalian PNPs. The phosphate binding site is located
      between two conserved beta- and gamma-turns and consists of Ser46, Arg103,
      His105, Gly135 and Ser223, and one or two water molecules. The guanine base is
      recognized by a zig-zag pattern of possible hydrogen bonds, as follows: guanine N
      1...Glu204 O(epsilon1)...guanine NH2...Glu204 O(epsilon2). The exocyclic O6 of
      the base is bridged via a water molecule to Asn246 N(delta), which accounts for
      the inhibitory, but lack of substrate, activity of adenosine. An alternative
      molecular mechanism for catalysis by trimeric PNPs is proposed, in which the key
      catalytic role is played by Glu204 (Glu201 in the calf and human enzymes), while
      Asn246 (Asn243 in the mammalian enzymes) supports binding of 6-oxopurines rather
      than catalysis. This mechanism, in contrast to that previously suggested, is
      consistent with the excellent substrate properties of N-7 substituted
      nucleosides, the specificity of trimeric PNPs versus 6-oxopurine nucleosides and
      the reported kinetic properties of Glu201/Ala and Asn243/Ala point variants of
      human PNP.

PMID- 10600383
TI  - Crystal structure of chondroitinase B from Flavobacterium heparinum and its
      complex with a disaccharide product at 1.7 A resolution.
AB  - Glycosaminoglycans (GAGs) are a family of acidic heteropolysaccharides, including
      such molecules as chondroitin sulfate, dermatan sulfate, heparin and keratan
      sulfate. Cleavage of the O-glycosidic bond within GAGs can be accomplished by
      hydrolases as well as lyases, yielding disaccharide and oligosaccharide products.
      We have determined the crystal structure of chondroitinase B, a glycosaminoglycan
      lyase from Flavobacterium heparinum, as well as its complex with a dermatan
      sulfate disaccharide product, both at 1.7 A resolution. Chondroitinase B adopts
      the right-handed parallel beta-helix fold, found originally in pectate lyase and
      subsequently in several polysaccharide lyases and hydrolases. Sequence homology
      between chondroitinase B and a mannuronate lyase from Pseudomonas sp. suggests
      this protein also adopts the beta-helix fold. Binding of the disaccharide product
      occurs within a positively charged cleft formed by loops extending from the
      surface of the beta-helix. Amino acid residues responsible for recognition of the
      disaccharide, as well as potential catalytic residues, have been identified. Two
      arginine residues, Arg318 and Arg364, are found to interact with the sulfate
      group attached to O-4 of N-acetylgalactosamine. Cleavage of dermatan sulfate
      likely occurs at the reducing end of the disaccharide, with Glu333 possibly
      acting as the general base.

PMID- 10600384
TI  - X-ray structure determination of human profilin II: A comparative structural
      analysis of human profilins.
AB  - Human profilins are multifunctional, single-domain proteins which directly link
      the actin microfilament system to a variety of signalling pathways via two
      spatially distinct binding sites. Profilin binds to monomeric actin in a 1:1
      complex, catalyzes the exchange of the actin-bound nucleotide and regulates actin
      filament barbed end assembly. Like SH3 domains, profilin has a surface-exposed
      aromatic patch which binds to proline-rich peptides. Various multidomain proteins
      including members of the Ena/VASP and formin families localize profilin:actin
      complexes through profilin:poly-L-proline interactions to particular cytoskeletal
      locations (e.g. focal adhesions, cleavage furrows). Humans express a basic (I)
      and an acidic (II) isoform of profilin which exhibit different affinities for
      peptides and proteins rich in proline residues. Here, we report the
      crystallization and X-ray structure determination of human profilin II to 2.2 A.
      This structure reveals an aromatic extension of the previously defined poly-L
      proline binding site for profilin I. In contrast to serine 29 of profilin I,
      tyrosine 29 in profilin II is capable of forming an additional stacking
      interaction and a hydrogen bond with poly-L-proline which may account for the
      increased affinity of the second isoform for proline-rich peptides. Differential
      isoform specificity for proline-rich proteins may be attributed to the
      differences in charged and hydrophobic residues in and proximal to the poly-L
      proline binding site. The actin-binding face remains nearly identical with the
      exception of five amino acid differences. These observations are important for
      the understanding of the functional and structural differences between these two
      classes of profilin isoforms.

PMID- 10600385
TI  - Crystal structure of Escherichia coli methionyl-tRNA synthetase highlights
      species-specific features.
AB  - The 3D structure of monomeric C-truncated Escherichia coli methionyl-tRNA
      synthetase, a class 1 aminoacyl-tRNA synthetase, has been solved at 2.0 A
      resolution. Remarkably, the polypeptide connecting the two halves of the Rossmann
      fold exposes two identical knuckles related by a 2-fold axis but with zinc in the
      distal knuckle only. Examination of available MetRS orthologs reveals four
      classes according to the number and zinc content of the putative knuckles.
      Extreme cases are exemplified by the MetRS of eucaryotic or archaeal origin,
      where two knuckles and two metal ions are expected, and by the mitochondrial
      enzymes, which are predicted to have one knuckle without metal ion.

PMID- 10600386
TI  - NMR structure of an F-actin-binding "headpiece" motif from villin.
AB  - A growing family of F-actin-bundling proteins harbors a modular F-actin-binding
      headpiece domain at the C terminus. Headpiece provides one of the two F-actin
      binding sites essential for filament bundling. Here, we report the first
      structure of a functional headpiece domain. The NMR structure of chicken villin
      headpiece (HP67) reveals two subdomains that share a tightly packed hydrophobic
      core. The N-terminal subdomain contains bends, turns, and a four-residue alpha
      helix as well as a buried histidine residue that imparts a pH-dependent folding.
      The C-terminal subdomain is composed of three alpha-helices and its folding is pH
      independent. Two residues previously implicated in F-actin-binding form a buried
      salt-bridge between the N and C-terminal subdomains. The rest of the identified
      actin-binding residues are solvent-exposed and map onto a unique F-actin-binding
      surface.

PMID- 10600387
TI  - Crystal structure of the histone acetyltransferase Hpa2: A tetrameric member of
      the Gcn5-related N-acetyltransferase superfamily.
AB  - We report the crystal structure of the yeast protein Hpa2 in complex with acetyl
      coenzyme A (AcCoA) at 2.4 A resolution and without cofactor at 2.9 A resolution.
      Hpa2 is a member of the Gcn5-related N-acetyltransferase (GNAT) superfamily, a
      family of enzymes with diverse substrates including histones, other proteins,
      arylalkylamines and aminoglycosides. In vitro, Hpa2 is able to acetylate specific
      lysine residues of histones H3 and H4 with a preference for Lys14 of histone H3.
      Hpa2 forms a stable dimer in solution and forms a tetramer upon binding AcCoA.
      The crystal structure reveals that the Hpa2 tetramer is stabilized by base-pair
      interactions between the adenine moieties of the bound AcCoA molecules. These
      base-pairs represent a novel method of stabilizing an oligomeric protein
      structure. Comparison of the structure of Hpa2 with those of other GNAT
      superfamily members illustrates a remarkably conserved fold of the catalytic
      domain of the GNAT family even though members of this family share low levels of
      sequence homology. This comparison has allowed us to better define the borders of
      the four sequence motifs that characterize the GNAT family, including a motif
      that is not discernable in histone acetyltransferases by sequence comparison
      alone. We discuss implications of the Hpa2 structure for the catalytic mechanism
      of the GNAT enzymes and the opportunity for multiple histone tail modification
      created by the tetrameric Hpa2 structure.

PMID- 10600388
TI  - Plant cyclotides: A unique family of cyclic and knotted proteins that defines the
      cyclic cystine knot structural motif.
AB  - Several macrocyclic peptides ( approximately 30 amino acids), with diverse
      biological activities, have been isolated from the Rubiaceae and Violaceae plant
      families over recent years. We have significantly expanded the range of known
      macrocyclic peptides with the discovery of 16 novel peptides from extracts of
      Viola hederaceae, Viola odorata and Oldenlandia affinis. The Viola plants had not
      previously been examined for these peptides and thus represent novel species in
      which these unusual macrocyclic peptides are produced. Further, we have
      determined the three-dimensional structure of one of these novel peptides,
      cycloviolacin O1, using (1)H NMR spectroscopy. The structure consists of a
      distorted triple-stranded beta-sheet and a cystine-knot arrangement of the
      disulfide bonds. This structure is similar to kalata B1 and circulin A, the only
      two macrocyclic peptides for which a structure was available, suggesting that
      despite the sequence variation throughout the peptides they form a family in
      which the overall fold is conserved. We refer to these peptides as the cyclotide
      family and their embedded topology as the cyclic cystine knot (CCK) motif. The
      unique cyclic and knotted nature of these molecules makes them a fascinating
      example of topologically complex proteins. Examination of the sequences reveals
      they can be separated into two subfamilies, one of which tends to contain a
      larger number of positively charged residues and has a bracelet-like
      circularization of the backbone. The second subfamily contains a backbone twist
      due to a cis-Pro peptide bond and may conceptually be regarded as a molecular
      Moebius strip. Here we define the structural features of the two apparent
      subfamilies of the CCK peptides which may be significant for the likely defense
      related role of these peptides within plants.

PMID- 10600389
TI  - Projection structure of a plant vacuole membrane aquaporin by electron cryo
      crystallography.
AB  - The water channel protein alpha-TIP is a member of the major intrinsic protein
      (MIP) membrane channel family. This aquaporin is found abundantly in vacuolar
      membranes of cotyledons (seed storage organs) and is synthesized during seed
      maturation. The water channel activity of alpha-TIP can be regulated by
      phosphorylation, and the protein may function in seed desiccation, cytoplasmic
      osmoregulation, and/or seed rehydration. Alpha-TIP was purified from seed meal of
      the common bean (Phaseolus vulgaris) by membrane fractionation, solubilization in
      diheptanoylphosphocholine and anion-exchange chromatography. Upon detergent
      removal and reconstitution into lipid bilayers, alpha-TIP crystallized as helical
      tubes. Electron cryo-crystallography of flattened tubes demonstrated that the
      crystals exhibit plane group p2 symmetry and c222 pseudosymmetry. Since the 2D
      crystals with p2 symmetry are derived from helical tubes, we infer that the unit
      of crystallization on the helical lattice is a dimer of tetramers. A projection
      density map at a resolution of 7.7 A revealed that alpha-TIP assembles as a 60 A
      x 60 A square tetramer. Each subunit is formed by a heart-shaped ring comprised
      of density peaks which we interpret as alpha-helices. The similarity of this
      structure to mammalian plasma membrane MIP-family proteins suggests that the
      molecular design of functionally analogous and genetically homologous aquaporins
      is maintained between the plant and animal kingdoms.

PMID- 10600390
TI  - Sequence and structure-based prediction of eukaryotic protein phosphorylation
      sites.
AB  - Protein phosphorylation at serine, threonine or tyrosine residues affects a
      multitude of cellular signaling processes. How is specificity in substrate
      recognition and phosphorylation by protein kinases achieved? Here, we present an
      artificial neural network method that predicts phosphorylation sites in
      independent sequences with a sensitivity in the range from 69 % to 96 %. As an
      example, we predict novel phosphorylation sites in the p300/CBP protein that may
      regulate interaction with transcription factors and histone acetyltransferase
      activity. In addition, serine and threonine residues in p300/CBP that can be
      modified by O-linked glycosylation with N-acetylglucosamine are identified.
      Glycosylation may prevent phosphorylation at these sites, a mechanism named yin
      yang regulation. The prediction server is available on the Internet at
      http://www.cbs.dtu.dk/services/NetPhos/or via e-mail to NetPhos@cbs. dtu.dk.

PMID- 10600391
TI  - Selective degradation of unfolded proteins by the self-compartmentalizing HtrA
      protease, a periplasmic heat shock protein in Escherichia coli.
AB  - HtrA, which has a high molecular mass of about 500 kDa, is a periplasmic heat
      shock protein whose proteolytic activity is essential for the survival of
      Escherichia coli at high temperatures. To determine the structural organization
      of HtrA, we have used electron microscopy and chemical cross-linking analysis.
      The averaged image of HtrA with end-on orientation revealed a six-membered, ring
      shaped structure with a central cavity, and its side-on view showed a two-layered
      structure. Thus, HtrA behaves as a dodecamer consisting of two stacks of
      hexameric ring. HtrA can degrade thermally unfolded citrate synthase and malate
      dehydrogenase but cannot when in their native form. HtrA degraded partially
      unfolded casein more rapidly upon increasing the incubation temperature. However,
      it hydrolyzed oxidized insulin B-chain, which is fully unfolded, at nearly the
      same rate at all of the temperatures tested. HtrA also rapidly degraded reduced
      insulin B-chain generated by treatment of insulin with dithiothreitol but not A
      chain or intact insulin. Moreover, HtrA degraded fully unfolded alpha
      lactalbumin, of which all four disulfide bonds were reduced, but not the native
      alpha-lactalbumin and its unfolded intermediates containing two or three
      disulfide bonds. These results indicate that unfolding of the protein substrates,
      such as by exposure to high temperatures or reduction of disulfide bonds, is
      essential for their access into the inner chamber of the double ring-shaped HtrA,
      where cleavage of peptide bonds may occur. Thus, HtrA with a self
      compartmentalizing structure may play an important role in elimination of
      unfolded proteins in the periplasm of Escherichia coli.

PMID- 10600392
TI  - Analysis of amylin cleavage products provides new insights into the amyloidogenic
      region of human amylin.
AB  - Human amylin is the primary component of amyloid deposits found in the pancreatic
      beta-cells of patients with type 2 diabetes mellitus. Recently, two fragments of
      amylin have been identified in vivo. One fragment contains residues 17 to 37 of
      human amylin (AMYLIN17-37) and the other contains residues 24 to 37 (AMYLIN24
      37). The secondary structure and amyloid forming ability of each peptide was
      determined at pH 5.5(+/-0.3) and pH 7.4(+/-0.3). Results at these two values of
      pH were very similar. Both peptides are predominantly unstructured in solution
      (CD) but adopt a significant amount of beta-sheet secondary structure upon
      aggregation (FTIR). Transmission electron microscopy (TEM) confirmed the presence
      of amyloid fibrils. AMYLIN24-37 was further dissected by studying peptides
      corresponding to residues 24 to 29 and 30 to 37. The AMYLIN30-37 peptide forms
      amyloid deposits. Samples of the 24 to 29 fragment which had TFA as the
      associated counterion formed ordered deposits but samples associated with HCl did
      not. Residues 20 to 29 are traditionally thought to be the amyloidogenic region
      of amylin, but this study demonstrates that peptides derived from other regions
      of amylin are capable of forming amyloid, and hence indicates that these regions
      of amylin can play a role in amyloid formation.

PMID- 10600393
TI  - Divergent allosteric patterns verify the regulatory paradigm for aspartate
      transcarbamylase.
AB  - The native Escherichia coli aspartate transcarbamoylase (ATCase, E.C. 2.1.3.2)
      provides a classic allosteric model for the feedback inhibition of a biosynthetic
      pathway by its end products. Both E. coli and Erwinia herbicola possess ATCase
      holoenzymes which are dodecameric (2(c3):3(r2)) with 311 amino acid residues per
      catalytic monomer and 153 and 154 amino acid residues per regulatory (r) monomer,
      respectively. While the quaternary structures of the two enzymes are identical,
      the primary amino acid sequences have diverged by 14 % in the catalytic
      polypeptide and 20 % in the regulatory polypeptide. The amino acids proposed to
      be directly involved in the active site and nucleotide binding site are strictly
      conserved between the two enzymes; nonetheless, the two enzymes differ in their
      catalytic and regulatory characteristics. The E. coli enzyme has sigmoidal
      substrate binding with activation by ATP, and inhibition by CTP, while the E.
      herbicola enzyme has apparent first order kinetics at low substrate
      concentrations in the absence of allosteric ligands, no ATP activation and only
      slight CTP inhibition. In an apparently important and highly conserved
      characteristic, CTP and UTP impose strong synergistic inhibition on both enzymes.
      The co-operative binding of aspartate in the E. coli enzyme is correlated with a
      T-to-R conformational transition which appears to be greatly reduced in the E.
      herbicola enzyme, although the addition of inhibitory heterotropic ligands (CTP
      or CTP+UTP) re-establishes co-operative saturation kinetics. Hybrid holoenzymes
      assembled in vivo with catalytic subunits from E. herbicola and regulatory
      subunits from E. coli mimick the allosteric response of the native E. coli
      holoenzyme and exhibit ATP activation. The reverse hybrid, regulatory subunits
      from E. herbicola and catalytic subunits from E. coli, exhibited no response to
      ATP. The conserved structure and diverged functional characteristics of the E.
      herbicola enzyme provides an opportunity for a new evaluation of the common
      paradigm involving allosteric control of ATCase.

PMID- 10600394
TI  - Intramolecular signal transmission in enterobacterial aspartate transcarbamylases
      II. Engineering co-operativity and allosteric regulation in the aspartate
      transcarbamylase of Erwinia herbicola.
AB  - The aspartate transcarbamylase (ATCase) from Erwinia herbicola differs from the
      other investigated enterobacterial ATCases by its absence of homotropic co
      operativity toward the substrate aspartate and its lack of response to ATP which
      is an allosteric effector (activator) of this family of enzymes. Nevertheless,
      the E. herbicola ATCase has the same quaternary structure, two trimers of
      catalytic chains with three dimers of regulatory chains ((c3)2(r2)3), as other
      enterobacterial ATCases and shows extensive primary structure conservation. In
      (c3)2(r2)3 ATCases, the association of the catalytic subunits c3 with the
      regulatory subunits r2 is responsible for the establishment of positive co
      operativity between catalytic sites for the binding of aspartate and it dictates
      the pattern of allosteric response toward nucleotide effectors. Alignment of the
      primary sequence of the regulatory polypeptides from the E. herbicola and from
      the paradigmatic Escherichia coli ATCases reveals major blocks of divergence,
      corresponding to discrete structural elements in the E. coli enzyme. Chimeric
      ATCases were constructed by exchanging these blocks of divergent sequence between
      these two ATCases. It was found that the amino acid composition of the outermost
      beta-strand of a five-stranded beta-sheet in the effector-binding domain of the
      regulatory polypeptide is responsible for the lack of co-operativity and response
      to ATP of the E. herbicola ATCase. A novel structural element involved in
      allosteric signal recognition and transmission in this family of ATCases was thus
      identified.

PMID- 10600395
TI  - Fluorescence in situ hybridization analysis of biomarkers in cancer.

PMID- 10600396
TI  - Fluorescence in situ hybridization analysis of HER-2/neu, c-myc, and p53 in
      endometrial cancer.
AB  - Our objective was to evaluate the association between HER-2/neu, c-myc, p53, and
      clinicopathologic variables in endometrial cancer using fluorescence in situ
      hybridization (FISH) cytogenetic analysis. FISH analysis for HER-2/neu, c-myc,
      and p53 was performed on 47 endometrial cancer specimens. Amplification of HER
      2/neu was seen in 4/47 (8.5%) cases and amplification of c-myc was seen in 7 of
      47 (15%) cases; neither was associated with adverse clinicopathologic variables
      or survival. Deletion of p53 was seen in 31/47 (66%) cases and was associated
      with poor histologic grade (P = 0.008). There was no impact of genetic
      alterations on overall survival or disease-free interval. Grade 3 tumor was
      associated with poor overall survival (P = 0.032). This study found that p53
      deletion is a common genetic alteration in endometrial cancer and is associated
      with poor-grade tumors.

PMID- 10600397
TI  - The slow induction of resistant hepatocytes during initiation of
      hepatocarcinogenesis by the nongenotoxic carcinogen clofibrate.
AB  - This study was designed to explore whether a well-known nongenotoxic liver
      carcinogen, clofibrate, would induce rare resistant hepatocytes similar to those
      seen during initiation of hepatocarcinogenesis with many genotoxic carcinogens.
      Male young adult F344 rats were exposed to a control diet containing 0.5% (w/w)
      clofibrate for 3, 6, or 10 months. After 1 month on a diet free of clofibrate,
      the animals were assayed for resistant hepatocytes by a standardized selection
      procedure using 2-acetylaminofluorene as the inhibitor and partial hepatectomy as
      a strong stimulus for cell proliferation. No resistant hepatocytes were found in
      the animals exposed to clofibrate for 3 months or in any of a series of control
      animals. However, animals on the clofibrate for 6 and 10 months contained
      resistant hepatocytes that were clonally expanded to produce hepatocyte nodules.
      These nodules were indistinguishable on gross and microscopic examination from
      hepatocyte nodules seen in animals in which nodules are induced with one of many
      different genotoxic carcinogens. Also, like those nodules, the nodules seen in
      the animals exposed to clofibrate stained positively for glutathione S
      transferase 1-1 and gamma-glutamyl transpeptidase and negatively for ATPase. The
      evidence from this study indicates that the nongenotoxic carcinogen, clofibrate,
      induces early cellular changes in the liver that are very similar to those
      induced by many different genotoxic carcinogens. These changes are manifest as a
      resistance phenotype in a few scattered hepatocytes that now can be clonally
      expanded selectively to form hepatocyte nodules. However, the resistant
      hepatocytes are induced by clofibrate much more slowly. Whether this basic
      similarity pertains to the later steps in the hepatocarcinogenic process remains
      to be studied.

PMID- 10600398
TI  - Changes in connexin 43 protein expression in human endometrial carcinoma.
AB  - The expression of connexin 43 was studied using immunohistochemical and Western
      blot analyses on cell lines of endometrial epithelial origin. Connexin proteins
      were examined because decreases in their expression and function have been
      correlated with carcinogenesis. The cell lines were chosen to represent
      increasing grades of endometrial cancer progression starting from FEEC (fetal
      endometrial epithelial cells; transformed with SV40 large T antigen) to HEC-1A
      (stage 1A endometrial carcinoma) to RL-95-2 (grade 2 endometrial carcinoma).
      Parallel studies using connexin 43 polyclonal antibodies for both Western blots
      and immunofluorescence showed that the levels of connexin 43 expression were
      normal endometrial stromal cells = FEEC > HEC-1A > RL-95-2. Consequently, we
      applied the immunofluorescence assay to analyze paraffin-embedded uterine
      sections from hysterectomy specimens of patients with normal endometrium and from
      patients diagnosed with grade 1, 2, and 3 endometrial cancer. Using five
      different cases from each category, we found an inverse correlation between
      connexin 43 expression and tumor grade. Our data indicate that connexin 43
      expression may be useful as an adjunctive marker of progression for endometrial
      carcinoma.

PMID- 10600399
TI  - Restimulation of resting autoreactive T cells by Schwann cells in vitro.
AB  - This study demonstrates that rat Schwann cells can reactivate resting
      experimental allergic neuritis generating P(2) and P(2) peptide specific CD4(+) T
      cell lines. T cell proliferation was significantly greater to P(2) than to P(2)
      peptide (SP-26) or ovalbumin (OA). Four-level analysis of variance showed that T
      cell proliferation with endogenous or exogenous P(2) was not significantly
      different for Schwann cells plus cytokine IFN-gamma (P = 0.5071) unlike P(2)
      peptide or OA specific T cells (P = 0.0056 and 0.0003, respectively). Untreated
      Schwann cells were more effective inducers than irradiated or fixed Schwann
      cells. As stimulated CD4(+) P(2) T cells produce IFN-gamma and TNF-alpha, this
      could exacerbate blood nerve barrier breakdown that has been increasingly
      implicated in inflammatory demyelinating neuropathies (IDNs). This would permit
      entry of antibodies and complement, thereby contributing to the demyelination
      process. Schwann cell induced reactivation of CD4(+) T cells may therefore play a
      role in IDNs.

PMID- 10600400
TI  - Effect of exogenous thyroxine on the development of the Purkinje cell in fetal
      alcohol effects in the rat.
AB  - The amelioration of fetal alcohol effects on the postnatal development of the
      Purkinje cell by exogenous L-thyroxine was investigated in the neonatal rat. Time
      pregnant rats were divided into three groups. Group A (n = 6) received 35% liquid
      ethanol diet; Group B (n = 6) was fed a liquid diet in which maltose dextrins
      replaced alcohol isocalorically, constituting the pair-fed group; Group C (n = 6)
      received the 35% liquid ethanol diet and, in addition, received exogenous
      thyroxine (5 microg/kg/day) subcutaneously. After the pups were born, the mothers
      were removed and the pups of each were surrogate fostered by dams who were fed
      normal rat chow and water ad libitum. An average of six pups, one from each
      litter, were killed at days 7, 14, 21, and 28 for each of the above three groups.
      Light and electron microscopic observations of lobule II/III revealed a delayed
      alignment of Purkinje cells (Pc) in alcohol-exposed pups compared to pair-fed
      pups. The Pc of the pair-fed group showed a single-layer arrangement at 7 days
      which was seen only at day 14 in the alcohol group. However, in the alcohol +
      T(4)-exposed pups a single-layer arrangement was quite often seen at 7 days.
      Morphological observations showed impaired evidence of protein synthesis at all
      time sequences in the pups of Group A compared to Group B. A most interesting
      finding was the morphological evidence of greater protein synthesis in the Pc of
      the alcohol + T(4) group at all times as indicated by a hypertrophied nucleus,
      abundant ribosomal collection, and numerous Nissl bodies.

PMID- 10600401
TI  - Proliferating cell nuclear antigen in normal and regenerating rat livers.
AB  - Immunohistochemical analysis using proliferating cell nuclear antigen (PCNA)
      antibody shows a negligible number of cells stained in normal liver, but much
      higher numbers in regenerating liver 24 and 48 h after surgery. We also verified
      different results by biochemical analysis. Two forms of PCNA, L type (eluted at
      low concentrations of KCl from a phosphocellulose column) and H type (eluted at
      high KCl concentrations), were observed in the nucleoplasm of regenerating livers
      24 and 48 h after surgery. Treatment of the H type fraction with nuclease caused
      the H type to disappear and the amount of L type to increase. PCNAs in the
      cytoplasm are P type (eluted in the pass through fraction) and L type.
      Surprisingly, the total amounts of P type and L type in cytoplasmic extracts are
      comparable to those of L type and H type in the nucleoplasm. These results
      suggest that newly synthesized PCNA is immediately converted into the P and L
      complex forms. The P type and some of the L type that lacks a nuclear
      localization signal remain in the cytoplasm; the rest of the L type with a
      nuclear localization signal is transferred into the nuclei. Then, some of the L
      type in the nucleoplasm forms the H type, which binds to DNA. These three types
      of PCNA are also found in significant amounts in the nucleoplasm and cytoplasm of
      normal rat liver despite its nonproliferating state.

PMID- 10600402
TI  - Striatal fosB expression is causally linked with l-DOPA-induced abnormal
      involuntary movements and the associated upregulation of striatal prodynorphin
      mRNA in a rat model of Parkinson's disease.
AB  - Rats with unilateral dopamine-denervating lesions sustained a 3-week treatment
      with a daily l-DOPA dose that is in the therapeutic range for Parkinson's
      disease. In most of the treated animals, chronic l-DOPA administration gradually
      induced abnormal involuntary movements affecting cranial, trunk, and limb muscles
      on the side of the body contralateral to the lesion. This effect was paralleled
      by an induction of FosB-like immunoreactive proteins in striatal subregions
      somatotopically related to the types of movements that had been elicited by l
      DOPA. The induced proteins showed both regional and cellular colocalization with
      prodynorphin mRNA. Intrastriatal infusion of fosB antisense inhibited the
      development of dyskinetic movements that were related to the striatal subregion
      targeted and produced a local specific downregulation of prodynorphin mRNA. These
      data provide compelling evidence of a causal role for striatal fosB induction in
      the development of l-DOPA-induced dyskinesia in the rat and of a positive
      regulation of prodynorphin gene expression by FosB-related transcription factors.

PMID- 10600403
TI  - AMPA and kainate receptors each mediate excitotoxicity in oligodendroglial
      cultures.
AB  - Recent studies indicate that oligodendrocytes are vulnerable to excitotoxic
      insults mediated by glutamate receptors. The present study was carried out to
      characterize the type of glutamate receptors triggering cell death in optic nerve
      oligodendrocyte cultures. Acute activation of either AMPA or kainate receptors
      was toxic to oligodendrocytes, an effect that was prevented by CNQX. However,
      exposure to agonists of the NMDA and metabotropic glutamate receptors did not
      impair cell viability. Dose-response curves showed that toxicity was mediated by
      three distinct populations of receptors: an AMPA-type receptor and high- and low
      affinity kainate-type receptors. Expression and immunocytochemical studies
      suggested that the glutamate receptor subunits give rise to the native receptors
      in each population. In all instances, Ca(2+) entry was a major determinant of
      glutamate receptor excitotoxicity. However, its influence varied for each
      receptor subtype. These results indicate that aberrantly enhanced activation of
      AMPA and/or kainate receptors may be involved in demyelinating diseases.

PMID- 10600404
TI  - Microglial activation and neurological symptoms in the SIV model of NeuroAIDS:
      association of MHC-II and MMP-9 expression with behavioral deficits and evoked
      potential changes.
AB  - HIV-1 causes cognitive and motor deficits and HIV encephalitis (HIVE) in a
      significant proportion of AIDS patients. Neurological impairment and HIVE are
      thought to result from release of cytokines and other harmful substances from
      infected, activated microglia. In this study, the quantitative relationship
      between microglial activation and neurological impairment was examined in the
      simian immunodeficiency model of HIVE. Macaque monkeys were infected with a
      passaged, neurovirulent strain of simian immunodeficiency virus,
      SIV(mac)239(R71/17E). In concurrent studies, functional impairment was assessed
      by motor and auditory brainstem evoked potentials and by measurements of
      cognitive and motor behavioral deficits. Brain tissue was examined by
      immunohistochemistry using two markers of microglia activation, MHC-II and matrix
      metalloproteinase-9 (MMP-9). The inoculated animals formed two groups: rapid
      progressors, which survived 6-14 weeks postinoculation, and slow progressors,
      which survived 87-109 weeks. In the rapid progressors, two patterns of MHC-II
      expression were present: (1) a widely disseminated pattern of MHC-II expressing
      microglia and microglial nodules in cortical gray matter and subcortical white
      matter, and (2) a more focal pattern in which MHC-II expressing microglia were
      concentrated into white matter. Animals exhibiting both patterns of microglial
      activation showed mild to severe changes in cognitive and motor behavior and
      evoked potentials. All rapid progressors showed expression of MMP-9 in microglia
      located in subcortical white matter. In the slow progressors MHC-II and MMP-9
      staining was similar to uninoculated control macaques, and there was little or no
      evidence of HIVE. These animals showed behavioral deficits at the end of the
      disease course, but little changes in evoked potentials. Thus, increases in MHC
      II and MMP-9 expression are associated with development of cognitive and motor
      deficits, alterations in evoked potentials, and rapid disease progression.

PMID- 10600405
TI  - Nitric oxide and l-arginine cause an accumulation of utrophin at the sarcolemma:
      a possible compensation for dystrophin loss in Duchenne muscular dystrophy.
AB  - Duchenne muscular dystrophy (DMD), a severe X-linked recessive disorder which
      results in progressive muscle degeneration, is due to a lack of dystrophin, a
      membrane cytoskeletal protein. An approach to treatment is to compensate for
      dystrophin loss with utrophin, another cytoskeletal protein with over 80%
      homology with dystrophin. Utrophin is expressed, at the neuromuscular junction,
      in normal and DMD muscles and there is evidence that it may perform the same
      cellular functions as dystrophin. So, the identification of molecules or drugs
      that could up-regulate utrophin is a very important goal for therapy. We show
      that in adult normal and mdx mice (an animal model of Duchenne myopathy) treated
      with l-arginine, the substrate of nitric oxide synthase (NOS), a pool of utrophin
      localized at the membrane appeared and increased, respectively. In normal and mdx
      myotubes in culture, l-arginine, nitric oxide (NO), or hydroxyurea increased
      utrophin levels and enhanced its membrane localization. This effect did not occur
      with d-arginine, showing the involvement of NOS in this process. The NO-induced
      increase in utrophin was prevented by oxadiazolo-quinoxalin-1-one, an inhibitor
      of a soluble guanylate cyclase implicated in NO effects. These results open the
      way to a potential treatment for Duchenne and Becker dystrophies.

PMID- 10600406
TI  - Apolipoprotein E expression by neurons surviving excitotoxic stress.
AB  - In the adult brain, apolipoprotein E (apoE) mRNA is thought to be expressed by
      nonneuronal cells. Yet, when a brain damage has occurred, the protein is found in
      neurons. We have studied apoE expression following systemic kainic acid (KA),
      injected in rats to induce hippocampal neurodegeneration. We describe two
      effects. First, a moderate increase of apoE levels in astrocytes. Second, and
      unexpected, a very strong increase of apoE mRNA levels in clusters of CA1 and CA3
      pyramidal neurons. Neuronal identity of these cells is supported by a series of
      observations. First, apoE hybridization signals were found in cells with
      morphological characteristics of pyramidal neurons. Second, the cells were
      positive for the neuronal marker MAP2. Third, the cells were negative for the
      astrocytic marker GFAP and for the microglia marker OX42. Fourth, the same
      distribution pattern was found with probes hybridizing to c-fos, a transcription
      factor transiently expressed in neurons under stress. At 48 and 72 h following
      KA, most of the excitotoxic cell death had already occurred. Since no
      morphological signs of programmed cell death were observed in apoE-positive
      pyramidal neurons, we suggest that expression of apoE by neurons may be part of a
      rescue program to counteract neurodegeneration.

PMID- 10600407
TI  - Altered gene expression in steroid-treated denervated muscle.
AB  - In rats treated with high-dose corticosteroids, skeletal muscle that is
      denervated in vivo (steroid-denervated) develops electrical inexcitability
      similar to that seen in patients with acute quadriplegic myopathy. To determine
      whether changes in muscle gene transcription might underlie inexcitability of
      steroid-denervated muscle we performed RNase protection assays to quantitate
      adult (SkM1) and embryonic (SkM2) sodium channel isoforms and chloride channel
      (CLC-1) mRNA levels in control, denervated, steroid-innervated, and steroid
      denervated skeletal muscle. While SkM1 mRNA levels were relatively unaffected by
      denervation or steroid treatment, SkM2 mRNA levels were increased by both. These
      effects were synergistic and high levels of SkM2 mRNA were expressed in
      denervated muscle exposed to corticosteroids. Skeletal muscle CLC-1 mRNA levels
      were decreased by denervation. To better understand the marked upregulation of
      SkM2 in steroid-denervated muscle we examined changes in myogenin and
      glucocorticoid receptor mRNA levels. However, changes in these mRNA levels cannot
      account for the upregulation of SkM2 in steroid-denervated muscle.

PMID- 10600408
TI  - Pigment epithelium-derived factor delays the death of photoreceptors in mouse
      models of inherited retinal degenerations.
AB  - Pigment epithelium-derived factor (PEDF) is a member of the serine protease
      inhibitor superfamily produced by retinal pigment epithelial cells in the
      developing and adult retina. In vitro, it induces neuronal differentiation of
      retinoblastoma cells and promotes survival of cerebellar granule neurons. The
      pedf gene is closely linked to an autosomal-dominant locus for retinitis
      pigmentosa, suggesting that PEDF could be a survival factor for photoreceptors.
      We have investigated this possibility by injecting PEDF into the eyes of
      homozygous retinal degeneration (rd) and retinal degeneration slow (rds) mice,
      two mutants displaying apoptotic photoreceptor loss. This procedure resulted in a
      transient delay of photoreceptor loss in the rd mouse and a reduction in
      apoptotic photoreceptor profiles in the rds mouse. We conclude that PEDF can act
      as a survival-promoting factor for photoreceptors in vivo and could potentially
      be useful for the treatment of photoreceptor diseases.

PMID- 10600409
TI  - Detection and statistical analysis of human cortical sulci.
AB  - Many studies dealing with the human brain use the spatial coordinate system of
      brain anatomy to localize functional regions. Unfortunately, brain anatomy, and
      especially cortical sulci, is characterized by a high interindividual
      variability. Specific tools called anatomical atlases must then be considered to
      make the interpretation of anatomical examinations easier. The work described
      here first aims at building a numerical atlas of the main cortical sulci. Our
      system is based on a database containing a collection of anatomical MRI of
      healthy volunteer brains. Their sulci have been manually drawn and labeled for
      both hemispheres. Sulci are represented as 3D superficial curves. After a
      nonlinear registration process, a statistical atlas of the cortical topography of
      a particular MRI is built from the database. It is an a priori model of cortical
      sulci, including three major components: an average curve represents the average
      shape and position of each sulcus; a search area accounts for its spatial
      variation domain; a set of quantitative parameters describes the variability of
      sulci geometry and topology. This atlas is completely individualized and adapted
      to the features of the brain under examination. The atlas is represented by a
      graph, the nodes of which represent sulci and the edges the relations between
      sulci. It can also be considered a statistical model that describes the cortical
      topography as well as its variability.

PMID- 10600410
TI  - Overt verbal responding during fMRI scanning: empirical investigations of
      problems and potential solutions.
AB  - This paper presents a pair of studies designed to empirically explore the
      severity of potential artifacts associated with overt verbal responding during
      fMRI scanning and to examine several different solutions to these artifacts. In
      Study One, we compared susceptibility artifacts, signal-to-noise ratios, and
      activation patterns when overt versus covert verbal responses were elicited
      during fMRI scanning, using both individual and group analyses. The results
      indicated that different patterns of brain activation were elicited during covert
      as compared to overt verbal responses. This suggests that covert responses cannot
      be used as a simple substitute for overt verbal responses. Further, the results
      suggested that the use of overt verbal responses during fMRI scanning can produce
      interpretable results if: (1) the primary comparison is between two conditions
      that both use overt verbal responses, and (2) analyses are conducted on pooled
      group data rather than individual participant data. In Study Two, we evaluated
      the feasibility and validity of a method for acquiring participants' overt
      responses during fMRI scanning. The results indicated that our method was very
      accurate in acquiring the content of participant's responses. Further, inspection
      of the responses demonstrated that participants do not always comply with task
      instructions and highlighted the importance of obtaining behavioral performance
      measures during fMRI scanning.

PMID- 10600411
TI  - Human movement-related potentials vs desynchronization of EEG alpha rhythm: a
      high-resolution EEG study.
AB  - Movement-related potentials (MRPs) and event-related desynchronization (ERD) of
      alpha rhythm were investigated with an advanced high-resolution
      electroencephalographic technology (128 channels, surface Laplacian estimate,
      realistic head modeling). The working hypothesis was that MRPs and alpha ERD
      reflect different aspects of sensorimotor cortical processes. Both MRPs and alpha
      ERD modeled the responses of primary sensorimotor (M1-S1), supplementary motor
      (SMA), and posterior parietal (PP, area 5) areas during the preparation and
      execution of unilateral finger movements. Maximum responses were modeled in the
      contralateral M1-S1 during both preparation and execution of the movement. The
      SMA and PP responses were modeled mainly from the MRPs and alpha ERD,
      respectively. The modeled ipsilateral M1-S1 responses were larger and stronger in
      the alpha ERD than MRPs. These results may suggest that alpha ERD reflects
      changes in the background oscillatory activity in wide cortical sensorimotor
      areas, whereas MRPs represent mainly increased, task-specific responses of SMA
      and contralateral M1-S1.

PMID- 10600412
TI  - PET mapping of extrastriatal D2-like dopamine receptors in the human brain using
      an anatomic standardization technique and [11C]FLB 457.
AB  - The Computerized Brain Atlas (CBA) transforms PET images of individual subjects
      into a standard brain anatomy. We have previously applied this to PET images with
      [(11)C]raclopride and confirmed that the D2 dopamine receptors in the striatum
      can be evaluated accurately with a standard brain anatomy. There is growing
      evidence that extrastriatal D2 receptors, in spite of their low density, have
      pathophysiological significance for schizophrenia. We used the CBA to explore the
      extrastriatal distribution of D2 receptors in 13 healthy subjects using [11C]FLB
      457, a substituted benzamide with very high affinity for D2 and D3 receptors.
      There was good agreement between the specific binding ratios from CBA
      quantification of standardized images and those from region-of-interest analyses
      of original images. The highest levels of binding were observed in the putamen
      and caudate nucleus, followed by the globus pallidus and nucleus accumbens.
      Besides the basal ganglia, the hypothalamus and nucleus ruber also showed high
      levels of binding. Intermediate levels were found in the substantia nigra,
      nucleus subthalami, amygdala, and thalamus. Interestingly, there was very
      heterogeneous binding among the thalamic nuclei. The anterior and mediodorsal
      nuclei showed relatively high binding. The cerebral cortices showed lower levels
      with significant regional differences. Binding was highest in the temporal cortex
      and hippocampus followed by the anterior cingulate gyrus, and the parietal and
      frontal cortices, but was lowest in the occipital cortex. The use of CBA for
      analysis of [11C]FLB 457 binding makes it possible to build a normal database for
      the extrastriatal D2 receptors in the living human brain. The heterogeneous
      distribution of D2 receptors provides an attractive opportunity for new research
      on the pathophysiology and drug treatment of schizophrenia.

PMID- 10600413
TI  - Regional variability of cerebral blood oxygenation response to hypercapnia.
AB  - In functional magnetic resonance imaging studies changes in blood oxygenation
      level-dependent (BOLD) signal intensities during task activation are related to
      multiple physiological parameters such as cerebral blood flow, volume, and
      oxidative metabolism, as well as to the regional microvascular anatomy.
      Consequently, the magnitude of activation-induced BOLD signal changes may vary
      regionally and between subjects. The aim of this study was to use a uniform
      global stimulus such as hypercapnia to quantitatively investigate the regional
      BOLD response in the human brain. In 10 healthy volunteers, T2*-weighted gradient
      echo images were acquired for a total dynamic scanning time of 9 min during
      alternating periods of breath holding for 30 s after expiration and self-paced
      normal breathing for 60 s. Hypercapnia-induced BOLD signal changes in the
      sensorimotor cortex, frontal cortex, basal ganglia, visual cortex, and cerebellum
      were significantly different (P < 0.001) and varied from 1.8 to 5.1%. The highest
      BOLD signal changes were found in the cerebellum and visual cortex, whereas the
      lowest BOLD signal increase was observed in the frontal cortex. These results
      demonstrate a regional dependence of the BOLD signal changes during breath hold
      induced hypercapnia, indirectly supporting the notion of regional different
      sensitivities of BOLD responses to task activation.

PMID- 10600414
TI  - The role of higher-order motor areas in voluntary movement as revealed by high
      resolution EEG and fMRI.
AB  - In the human motor cortex structural and functional differences separate motor
      areas related to motor output from areas essentially involved in higher-order
      motor control. Little is known about the function of these higher-order motor
      areas during simple voluntary movement. We examined a simple finger flexion
      movement in six healthy subjects using a novel brain-imaging approach,
      integrating high-resolution EEG with the individual structural and functional
      MRI. Electrical source reconstruction was performed in respect to the individual
      brain morphology from MRI. Highly converging results from EEG and fMRI were
      obtained for both executive and higher-order motor areas. All subjects showed
      activation of the primary motor area (MI) and of the frontal medial wall motor
      areas. Two different types of medial wall activation were observed with both
      methods: Four of the subjects showed an anterior type of activation, and two of
      the subjects a posterior type of activation. In the former, activity started in
      the anterior cingulate motor area (CMA) and subsequently shifted its focus to the
      intermediate supplementary motor area (SMA). Approximately 120 ms before the
      movement started, the intermediate SMA showed a drop of source strength, and
      simultaneously MI showed an increase of source strength. In the posterior type,
      activation was restricted to the posterior SMA. Further, three of the subjects
      investigated showed activation in the inferior parietal lobe (IPL) starting
      during early movement preparation. In all subjects showing activation of higher
      order motor areas (anterior CMA, intermediate SMA, IPL) these areas became active
      before the executive motor areas (MI and posterior SMA). We suggest that the
      early activation of the anterior CMA and the IPL may be related to attentional
      functions of these areas. Further, we argue that the intermediate part of the SMA
      triggers the actual motor act via the release of inhibition of the primary motor
      area. Our results demonstrate that a noninvasive, multimodal brain imaging
      technique can reveal individual cortical brain activity with high temporal and
      spatial resolution, independent of a priori physiological assumptions.

PMID- 10600415
TI  - Neuroanatomic overlap of working memory and spatial attention networks: a
      functional MRI comparison within subjects.
AB  - Frontal and posterior parietal activations have been reported in numerous studies
      of working memory and visuospatial attention. To directly compare the brain
      regions engaged by these two cognitive functions, the same set of subjects
      consecutively participated in tasks of working memory and spatial attention while
      undergoing functional MRI (fMRI). The working memory task required the subject to
      maintain an on-line representation of foveally displayed letters against a
      background of distracters. The spatial attention task required the subject to
      shift visual attention covertly in response to a centrally presented directional
      cue. The spatial attention task had no working memory requirement, and the
      working memory task had no covert spatial attention requirement. Subjects'
      ability to maintain central fixation was confirmed outside the MRI scanner using
      infrared oculography. According to cognitive conjunction analysis, the set of
      activations common to both tasks included the intraparietal sulcus, ventral
      precentral sulcus, supplementary motor area, frontal eye fields, thalamus,
      cerebellum, left temporal neocortex, and right insula. Double-subtraction
      analyses yielded additional activations attributable to verbal working memory in
      premotor cortex, left inferior prefrontal cortex, right inferior parietal lobule,
      precuneus, and right cerebellum. Additional activations attributable to covert
      spatial attention included the occipitotemporal junction and extrastriate cortex.
      The use of two different tasks in the same set of subjects allowed us to provide
      an unequivocal demonstration that the neural networks subserving spatial
      attention and working memory intersect at several frontoparietal sites. These
      findings support the view that major cognitive domains are represented by
      partially overlapping large-scale neural networks. The presence of this overlap
      also suggests that spatial attention and working memory share common cognitive
      features related to the dynamic shifting of attentional resources.

PMID- 10600416
TI  - Noradrenergically mediated plasticity in a human attentional neuronal network.
AB  - Noradrenaline is implicated in the modulation of attention and arousal, but the
      neuroanatomical basis of this effect in humans is unknown. A previous functional
      neuroimaging study failed to find clear effects of clonidine (alpha2 adrenoceptor
      agonist) on activity of brain regions implicated in attention. Therefore, we now
      investigate whether clonidine affects the functional integration of a
      neuroanatomical attentional network, by modulating connectivity between brain
      regions rather than activity within discrete regions. Following infusion of
      either clonidine or placebo, positron emission tomography measurements of brain
      activity were collected in 13 normal subjects while they were either resting or
      performing an attentional task. Effective connectivity analysis showed that
      during rest, clonidine decreased the functional strength of connections both from
      frontal cortex to thalamus and in pathways to and from visual cortex. Conversely,
      during the attentional task, functional integration generally increased, with
      changes being centered on parietal cortex (increased connectivity from locus
      coeruleus to parietal cortex and from parietal cortex to thalamus and frontal
      cortex). A drug-induced increase in the modulatory effects of frontal cortex on
      projections from locus coeruleus to parietal cortex was also observed.
      Collectively, these results highlight cognitively dissociable effects of
      clonidine on interactions among functionally integrated brain regions and
      implicate the noradrenergic system in mediating the functional integration of
      attentional brain systems. The context-sensitive nature of the changes are
      consistent with observations that noradrenergic drugs have differential effects
      on brain processes depending on subjects' underlying arousal levels. More
      generally, the results illustrate the dynamic plasticity of cognitive brain
      systems following neurochemical challenge.

PMID- 10600417
TI  - Laser doppler imaging of activation-flow coupling in the rat somatosensory
      cortex.
AB  - Activation-flow coupling (AFC) provides a physiological basis for mapping
      cerebral activation using cerebral blood flow (CBF) as a surrogate marker for
      neuronal function. Laser Doppler offers a minimally invasive approach for
      measuring changes in cerebral blood flow but the spatial resolution of this
      technique is limited by the number of individual probes that can be used.
      Recently, laser Doppler imaging (LDI) scanners, which use computer-driven optics
      to scan and measure LD changes in two dimensions, have successfully measured flow
      changes in the exposed cortex of animals. Here we demonstrate the use of an LDI
      device through a thinned skull to determine the spatiotemporal characteristics of
      AFC in alpha-chloralose anesthetized rats in response to electrical forepaw
      stimulation. The spatial and temporal characteristics of the AFC response
      measured by LDI are in agreement with prior results obtained using a single LD
      probe. These results suggest a promising role for LDI in the characterization of
      the spatiotemporal characteristics of AFC in animal models and possibly for
      intraoperative monitoring in the human brain.

PMID- 10600418
TI  - Accurate high-speed spatial normalization using an octree method.
AB  - The goal of regional spatial normalization is to remove anatomical differences
      between individual three-dimensional (3-D) brain images by warping them to match
      features of a standard brain atlas. Full-resolution volumetric spatial
      normalization methods use a high-degree-of-freedom coordinate transform, called a
      deformation field, for this task. Processing to fit features at the limiting
      resolution of a 3-D MR image volume is computationally intensive, limiting broad
      use of full-resolution regional spatial normalization. A highly efficient method,
      designed using an octree decomposition and analysis scheme, is presented to
      resolve the speed problem while targeting accuracy comparable to current
      volumetric methods. Translation and scaling capabilities of octree spatial
      normalization (OSN) were tested using computer models of solid objects (cubes and
      spheres). Boundary mismatch between transformed and target objects was zero for
      cubes and less than 1% for spheres. Regional independence of warping was tested
      using brain models consisting of a homogenous brain volume with one internal
      homogenous region (lateral ventricle). Boundary mismatch improved with
      successively smaller octant-level processing and approached levels of less than
      1% for the brain and 5% for the lateral ventricle. Five 3-D MR brain images were
      transformed to a target 3-D brain image to assess boundary matching. Residual
      boundary mismatch was approximately 4% for the brain and 8% for the lateral
      ventricle, not as good as with homogeneous brain models, but similar to other
      results. Total processing time for OSN with a 256(3) brain image (1-mm voxel
      spacing) was less than 10 min.

PMID- 10600419
TI  - Accuracy and limitation of functional magnetic resonance imaging for
      identification of the central sulcus: comparison with magnetoencephalography in
      patients with brain tumors.
AB  - The aim of the present study was to clarify the accuracy and limitation of
      functional magnetic resonance imaging (fMRI) for the identification of the
      central sulcus affected by brain tumors. Twelve normal volunteers and 11 patients
      with intracranial tumors adjacent to the central sulcus underwent fMRI and
      magnetoencephalography (MEG). Three patients were evaluated again after surgery.
      fMRI was performed with a 1.5 Tesla scanner during repetitive opening and closing
      of each hand. Cross-correlation function was used to identify activation areas,
      and the central sulcus was defined as the nearest sulcus to the highest
      activation spots that were determined by elevating correlation coefficient
      threshold. Somatosensory-evoked fields were measured using a whole head MEG
      system. The central sulcus was defined as the nearest sulcus to the N20m for the
      median nerve stimulus. fMRI and MEG coincided in defining the central sulcus in
      all 24 hemispheres of volunteers and all 10 examined nonaffected hemispheres of
      patients. The fMRI-defined central sulcus coincided with the MEG-defined central
      sulcus in nine (82%) but did not in two (18%) affected hemispheres of patients.
      The preoperative mismatch disappeared after surgery in one of the two patients.
      The present study indicates that fMRI successfully defined the central sulcus in
      most of the patients with brain tumors. However, in a few cases, fMRI was not
      reliable probably due to venous flow changes by tumor compression and/or
      compensational activity by brain tissues surrounding the primary sensorimotor
      cortex. For precise functional assessment of the brain affected by intracranial
      tumors, combination of fMRI and MEG will be recommended.

PMID- 10600420
TI  - LOFA: software for individualized localization of functional MRI activity.
AB  - Although PET, SPECT, and fMRI studies have led to significant advances in
      functional mapping of the human brain, precise localization and quantification of
      activity in individual brains require additional procedures. Difficulties to be
      addressed by a localization strategy are: resolution of individual anatomic
      differences, differentiation of functional activity in closely juxtaposed brain
      regions, and management of multiple intricately shaped 3D anatomic structures. In
      this paper, we describe a localization tool, LOFA, which addresses these problems
      by forming ROIs with a user-driven interface. Using LOFA, complex 3D anatomy can
      be defined through open or closed loops and anatomic landmarks. Resulting
      partitions can be overlaid on top of each other to form multiple regions of
      interest (ROIs), and functional activity in these ROIs can be extracted
      individually, one after the other. LOFA introduces important paradigmatic
      advances over the other ROI analysis methods. The toolbox is interactive, fully
      compatible with AFNI (MCW), and requires Pv-Wave (VNI Inc.) license to run.

PMID- 10600421
TI  - Robust smoothness estimation in statistical parametric maps using standardized
      residuals from the general linear model.
AB  - The assessment of significant activations in functional imaging using voxel-based
      methods often relies on results derived from the theory of Gaussian random
      fields. These results solve the multiple comparison problem and assume that the
      spatial correlation or smoothness of the data is known or can be estimated. End
      results (i. e., P values associated with local maxima, clusters, or sets of
      clusters) critically depend on this assessment, which should be as exact and as
      reliable as possible. In some earlier implementations of statistical parametric
      mapping (SPM) (SPM94, SPM95) the smoothness was assessed on Gaussianized t-fields
      (Gt-f) that are not generally free of physiological signal. This technique has
      two limitations. First, the estimation is not stable (the variance of the
      estimator being far from negligible) and, second, physiological signal in the Gt
      f will bias the estimation. In this paper, we describe an estimation method that
      overcomes these drawbacks. The new approach involves estimating the smoothness of
      standardized residual fields which approximates the smoothness of the component
      fields of the associated t-field. Knowing the smoothness of these component
      fields is important because it allows one to compute corrected P values for
      statistical fields other than the t-field or the Gt-f (e.g., the F-map) and
      eschews bias due to deviation from the null hypothesis. We validate the method on
      simulated data and demonstrate it using data from a functional MRI study.

PMID- 10600422
TI  - Ethnic variation in attitudes toward hypertension in adults ages 75 and older.
AB  - BACKGROUND: Although critical to the management of hypertension, the attitudes of
      geriatric patients and possible ethnic group differences in attitudes concerning
      the disease are poorly understood. METHODS: Data from a 1995-1996 population
      based survey of 507 Hispanic American, African American, and non-Hispanic white
      adults ages 75 and older were used to assess ethnic differences in perceptions
      regarding the cause, prevention, and treatment of hypertension, as well as
      associations between perceptions and use of preventive health services. RESULTS:
      African Americans were more likely to attribute hypertension to health behaviors
      and stress. In contrast, Hispanic Americans were more likely consider the disease
      a normal part of aging, whereas non-Hispanic whites were more likely to attribute
      hypertension to heredity or mechanistic causes. Non-Hispanic whites were less
      likely to perceive hypertension as preventable, whereas Hispanic Americans were
      less likely to feel that hypertension was treatable. The odds of having a primary
      care physician, blood pressure checked, or glaucoma checked were lower among
      older African Americans and Hispanic Americans than older non-Hispanic whites.
      The odds of having had a recent physical and of emergency room use were higher
      among African Americans and lower among Hispanic Americans, in relation to non
      Hispanic whites. CONCLUSION: Ethnic differences regarding hypertension were
      clearly evident in this sample of older adults. In addition, attitudes regarding
      the cause and treatment of hypertension were found to be associated with both the
      use and the underuse of preventive health services in all three ethnic groups.

PMID- 10600423
TI  - A message from preventive medicine and your physician

PMID- 10600424
TI  - The effect of ascorbic acid supplementation on the nicotine metabolism of
      smokers.
AB  - BACKGROUND: The relationship of serum ascorbic acid (AA) levels and excretion of
      nicotine metabolites was determined in 75 men who smoked at least one pack of
      cigarettes per day. METHODS: The subjects were randomly divided into three groups
      of 25 each who received a placebo, 200 mg of supplementation, or 1000 mg of
      supplementation of AA per day for 1 month. Baseline and weekly serum AA levels
      were determined and simultaneous estimates of urinary excretion of nicotine
      metabolites as cotinine equivalents (CE). RESULTS: The group mean serum AA levels
      in the placebo group decreased 13% after 2 weeks; the group mean serum levels of
      the supplemented groups increased significantly after 1 week (P </= 0. 001) and
      remained elevated over 100% per week from baseline throughout the study. There
      was a progressive increase in urinary CE excretion in the placebo group. In the
      supplemented groups, group mean CE excretion decreased an average of 5% weekly in
      the 200-mg group and an average of 33% weekly in the 1000-mg group. Pearson's
      correlation between serum AA and urine CE excretion was significant (r = -0.7980,
      P </= 0.0003). CONCLUSIONS: Body levels of AA affect the level of urinary
      nicotine metabolites. The results of this study indicate that dietary levels of
      AA are inversely correlated to urinary excretion of nicotine metabolites and may
      be due to suppressed: (1) nicotine intake by smokers who smoked fewer cigarettes
      or inhale less deeply, (2) nicotine metabolism, or (3) both.

PMID- 10600425
TI  - Relationship between birth weight and blood pressure in adolescence.
AB  - BACKGROUND: Several studies have found a relation ship between small size at
      birth and high blood pressure (HBP). However, this association has not been fully
      evaluated in adolescence. The aim of the present study was to evaluate the
      relation of birth weight (BW) to BP in adolescence, controlling for factors
      related to BP, to extrauterine environment, and to maternal risk of fetal
      distress. METHODS: In 1310 adolescents (ages 12-14 years), randomly selected from
      Turin school children, we evaluated BP, heart rate (HR), weight, height, familial
      risk of hypertension, parental cultural level, BW, and maternal history of
      diseases during pregnancy. The BW-BP association was tested by using multiple
      regression analysis and adjusting for the other variables mentioned above. The
      same analysis was done for the subgroup at high risk of fetal distress. RESULTS:
      The association between BW and BP was negative but weak when we adjusted for all
      confounders (= -0.07 in males; = -0.27 in females). The association was negative
      and became stronger after the inclusion of all confounders, particularly HR (= 
      3.92), in the group of children at high risk of fetal distress. CONCLUSIONS:
      Intrauterine environment, as reflected by BW, has little effect on BP in early
      adolescence without concomitant maternal diseases or environmental conditions
      leading to severe placental hypoperfusion.

PMID- 10600426
TI  - Positive and negative outcome expectations of smoking: implications for
      prevention.
AB  - BACKGROUND: To inform the development of messages for tobacco prevention
      programs, we examined seven positive and five negative outcome expectations of
      smoking as risk factors for smoking uptake. METHODS: A cross-sectional, self
      administered survey of 471 students in grades 6-12 who were never or experimental
      smokers was performed. Logistic regression was used to examine the relationship
      between outcome expectations and susceptibility to becoming a smoker in the
      future, a measure of intent and resistance to peer smoking. RESULTS: A total of
      36.1% of the sample was susceptible to smoking. All positive outcome expectations
      showed a strong and significant association with susceptibility. Students were
      most likely to be susceptible if they believed they would enjoy smoking (OR =
      29.4). Three of the five negative outcome expectations were significantly
      associated with susceptibility, but the strength of these associations was much
      lower than that observed for the positive expectations (OR = 0.5 to 0.6). A
      strong belief in the negative outcomes of smoking did not alter the association
      between susceptibility and positive outcome expectations. CONCLUSIONS: These
      findings suggest that teaching adolescents and teens about the negative
      consequences of smoking is unlikely to change their intent to smoke. Preventive
      efforts should identify ways to address the positive expectations adolescents
      have about smoking, possibly by offering alternative means for achieving these
      outcomes.

PMID- 10600427
TI  - Use of cancer screening practices by Hispanic women: analyses by subgroup.
AB  - OBJECTIVES: This study compares the use of three cancer screening practices (Pap
      smear, mammogram, and clinical breast examination) 3 years prior to interview
      among five subgroups of Hispanic women, and examines whether sociodemographic;
      access; health behavior, perception, and knowledge; and acculturation factors
      predict screening practices for any subgroup. METHODS: Descriptive and multiple
      logistic regression analyses were conducted with data pooled from the 1990 and
      1992 National Health Interview Surveys on women who reported that they were
      Hispanic. The study sample includes 2,391 respondents: 668 Mexican-American, 537
      Mexican, 332 Puerto Rican, 143 Cuban, and 711 other Hispanic women. RESULTS:
      Subgroup profiles reveal differences in education, health insurance, use of
      English language, and screening use. Mexican women were the least likely to be
      screened with any procedure. Logistic regression results for each screening
      practice show that having a usual source of care was a positive predictor for
      obtaining each of the three screening practices within the last 3 years. Being
      married, being more than 50 years of age, and having knowledge of breast self
      examination were all predictors of having a Pap smear. Having health insurance
      and ever having had a clinical breast examination and Pap smear were predictors
      of having a mammography, while age, knowledge of breast self-examination, ever
      having had a Pap smear and mammogram, and being a nonsmoker all predicted having
      a clinical breast examination. CONCLUSIONS: We conclude that access factors and
      prior screening are more strongly associated with current screening than are
      language and ethnic factors. Our data confirm that a disproportionate percentage
      of Hispanic women are low income and at risk of being underscreened. Our findings
      from a nationally representative sample of Hispanics have implications for
      provider practices, ethnic-specific community interventions, and future
      development of measures and data collection approaches.

PMID- 10600428
TI  - Randomized controlled trial of a computer strategy to increase general
      practitioner preventive care.
AB  - BACKGROUND: Previous interventions targeting primary care practitioners with the
      aim of increasing preventive care delivery have demonstrated limited
      effectiveness. The primary aim of this study was to assess the effectiveness of a
      computerized continuing medical education program to increase rates of three
      screening behaviors (cholesterol, blood pressure, and cervical screening) and to
      identify three risk behaviors (smoking, alcohol consumption, benzodiazepine use)
      in general practice. METHODS: Nineteen general practitioners were randomly
      allocated to intervention or control conditions. Those given the intervention
      received a computerized feedback system. The intervention was delivered using a
      touch-screen computer located in the surgery waiting area. The preventive
      behaviors of interest were patient smoking, alcohol use, benzodiazepine use, and
      blood pressure, cholesterol and cervical screening using the Papanicolou test.
      Differences in performance by group in each of the outcomes was measured at
      baseline and 3-month follow-up. Logistic regression analyses with generalized
      estimating equations were conducted as the main analyses. RESULT: At 3-month
      follow-up, statistically significant differences were evident in the following
      outcome measures: accurate classification of benzodiazepine users (z = 2.8540, P
      < 0.05); accurate classification of non-benzodiazepine users (z = 2.7339, P <
      0.05); accurate classification of hazardous or harmful alcohol drinkers (z =
      2.3079, P < 0.02); blood pressure screening (z = 3.4136, P < 0.001); and
      cholesterol screening (z = 6.6313, P < 0.001). CONCLUSION: A computerized system
      of performance-specific feedback was effective at increasing some preventive care
      services in general practice.

PMID- 10600429
TI  - Smoking and cancer screening for women ages 42-75: associations in the 1990-1994
      National Health Interview Surveys.
AB  - BACKGROUND: Previous studies have found an association between current smoking
      and lower rates of mammography and Pap testing. The objective of this study was
      to investigate the association of smoking status with breast and cervical cancer
      screening across the 1990-1994 National Health Interview Surveys (NHIS). The NHIS
      provides a consistent set of independent and dependent variables across several
      surveys, with data collected by a similar in-person interview methodology from
      year to year. This report employs more databases than have been used in other
      analyses that have examined associations between smoking and cancer screening.
      METHODS: Data were from the health promotion and cancer control supplements to
      the 1990-1994 NHIS. The target population was women ages 42-75. Associations were
      examined between smoking status (never, former, <1 pack/day, >/=1 pack/day) and
      three screening indicators: ever had a mammogram, mammogram in the past 2 years,
      and Pap test in the past 3 years. Sample sizes ranged from about 3,000 to over
      10,800 depending on the respective NHIS survey and dependent variable. Data
      analyses were conducted by bivariate and multiple logistic regression. RESULTS:
      Women who smoked >/=1 pack of cigarettes per day were significantly less likely
      to have had mammography screening in all NHIS surveys, compared to women who
      never smoked. Adjusted odds ratios were 0.63 to 0.74 for ever had a mammogram,
      and 0.56 to 0.66 for mammography in the past 2 years. Women who smoked >/=1 pack
      per day also had lower Pap test rates than women who never smoked in 1992-1994
      (adjusted odds ratios of 0.51-0.71). Results for lighter smokers were not as
      consistent. Former smokers often had significantly higher screening rates than
      never smokers. CONCLUSIONS: Research still needs to identify reasons for lower
      screening among women who smoke. Factors to explore include the social networks
      of smokers and broader health behavior patterns. Clinicians should consider
      heavier smoking as a marker for risk of not obtaining screening and make
      assessment of screening status a priority at each visit.

PMID- 10600430
TI  - Cross-sectional study on the relationship between smoking or smoking cessation
      and trait anxiety.
AB  - OBJECTIVE: The relationships between trait anxiety, or anxiety proneness, and
      smoking and between trait anxiety and smoking cessation, among an adult
      population were investigated. METHODS: The subjects were 2,669 male Japanese
      personnel working for a Japanese government agency. Participants completed a self
      administered questionnaire on smoking and smoking cessation status and other
      habits. Trait anxiety was evaluated with the trait anxiety part of the
      standardized Japanese version of the Spielberger State-Trait Anxiety Inventory.
      Trait anxiety is regarded as the long-term, more endogenous general type of
      anxiety. Odds ratios of the single 2 x 2 table were calculated and a logistic
      regression analysis was used to adjust for age. RESULTS: After adjusting for age,
      high trait anxiety did not increase the risk of smoking and was not related to
      success in abstaining from smoking. More subjects with high trait anxiety had
      planned to stop smoking (adjusted odds ratio: 1.39, P = 0.01) but did not
      actually succeed in doing so. CONCLUSION: The present study did not support the
      hypothesis that high trait anxiety increased the risk of having a smoking habit
      and that high trait anxiety increased the chance of abstaining from smoking.
      However, the study did show that high trait anxiety was related to the planning
      of smoking cessation, but not to actually giving up the smoking habit.

PMID- 10600431
TI  - Influence of health care, cost, and culture on breast cancer screening: issues
      facing urban American Indian women.
AB  - BACKGROUND: Breast cancer is the second leading cause of cancer death among
      American Indian women. Southwestern American Indian women are more likely to have
      distant spread of the disease, and 5-year survival from breast cancer is poor in
      comparison to U.S. whites. Mortality from breast cancer could be reduced by more
      than 30% in American Indian women if current recommendations for screening were
      followed. METHODS: A random household cross-sectional survey was conducted among
      519 adult American Indian women in Phoenix, Arizona. Logistic regression was used
      to identify predictors of recent clinical breast examination and mammogram among
      those women aged 40 years and older. RESULTS: Just more than half (53.0%) of the
      women surveyed reported they had received a clinical breast examination in the
      last year, and 35.7% indicated they had received a mammogram in the last 2 years.
      Access to care, knowledge of the examinations, and health beliefs were positively
      associated with breast cancer screening in the multivariate analyses.
      CONCLUSIONS: The cancer screening rates observed in urban American Indian women
      are far below current national estimates and Healthy People 2000 Objectives. This
      study confirms the limited access of urban Indians to preventive health services,
      and supports a role for cancer education in improving screening participation in
      this special population.

PMID- 10600432
TI  - Pap smear screening among urban Southwestern American Indian women.
AB  - BACKGROUND: American Indian women have among the highest incidence and mortality
      rates of cervix cancer in the United States. The incidence of cancer of the
      cervix among American Indians is 19.5/100,000 versus 7.8/100,000 in U.S. whites,
      and comparison by geographic region/tribe indicates that the rate is four to six
      times higher in some tribes. Papanicolaou cytological testing (Pap smear) permits
      the detection of cervical lesions before they become cancerous, effectively
      reducing the incidence of cervical cancer by 75-90%. The American Cancer Society
      recommends a Pap smear every year beginning at age 18 years or when sexually
      active, and more frequent screening in high-risk populations. METHODS: A random
      household cross-sectional survey was conducted in Phoenix, Arizona, to assess
      cervical cancer screening rates among 519 adult urban American Indian women.
      Logistic regression was used to identify predictors of Pap smear use. RESULTS:
      Three-quarters (76.1%) of urban women American Indian surveyed received a Pap
      smear within the past 3 years, but only 49.5% received a Pap smear within the
      last year. Women over age 50 years were significantly less likely to have
      received a recent Pap smear in comparison to younger women. CONCLUSIONS: The
      results of this study indicate that limited access to health care and lack of
      knowledge about the procedure were important barriers to Pap smear use. Improving
      cervix cancer screening participation rates is an important step in reducing the
      disease burden in this high-risk population.

PMID- 10600433
TI  - Impact of treatment for childhood obesity on parental risk factors for
      cardiovascular disease.
AB  - BACKGROUND: Family-based approaches using the parents as agents of change to
      treat childhood obesity are superior to programs targeting only children in
      achieving weight reduction and have a lower dropout rate. OBJECTIVE: The aim of
      this study was to compare the impact of two behavioral approaches (parents only
      vs children only) for the treatment of childhood obesity on parental weight,
      eating, and activity habits as well as cardiovascular risk factors. DESIGN: A
      randomized 1-year clinical intervention study was performed. METHODS: Sixty obese
      children (>/=20% over ideal weight for age, height, and sex), ages 6-11 years,
      were randomly allocated to the experimental (parents as sole agents of change) or
      conventional groups (children as sole agents of change). Fourteen (1-h-long)
      support/educational sessions were conducted by a clinical dietitian for the
      parents in the experimental group and 30 sessions for children in the
      conventional group. Anthropometric and biochemical measurements were determined
      at the start and end of the program. RESULTS: The experimental approach, when
      compared to the conventional intervention, was found to be superior in the
      reduction of fathers overweight (P < 0.05). The former approach resulted also in
      improved profile of risk factors for cardiovascular disease in both parents.
      These changes could be ascribed to a greater improvement in eating and activity
      behaviors observed in parents belonging to the experimental intervention group
      who participated in a family-based intervention to treat their children's
      obesity. CONCLUSIONS: Treatment of childhood obesity targeting the parents as the
      sole agent of change, which is more effective for the treatment of childhood
      obesity when compared to a children-oriented program, may in addition award
      parents with the benefit of changing their own eating and activity patterns, thus
      making this program ideal for treatment of obesity in children and their
      overweight parents.

PMID- 10600434
TI  - The effectiveness of a directly mailed smoking cessation intervention to
      Australian discharged hospital patients.
AB  - BACKGROUND: The objective was to assess the effectiveness of a directly mailed
      smoking cessation intervention to discharged hospital patients. METHODS: A
      randomized controlled trial was used. In the 2 weeks after discharge, smokers in
      the intervention group were sent by mail a personally addressed letter from their
      medical consultant urging them to quit plus a self-help quitting manual, and
      smokers in the control group received usual care. Patients were surveyed about
      their smoking status at 6 and 12 months after discharge. A total of 1858
      discharged patients responded to both questionnaires. The main outcome measures
      were self-reported smoking in past week at 6 and 12 months after discharge.
      Quitters at 12 months were biochemically tested for evidence of smoking. RESULTS:
      The results failed to show that smoking cessation advice directly mailed to a
      broad cross-section of discharged hospital patients who smoke led to smoking
      cessation. However, the intervention increased cessation among smokers with
      medical conditions for which quitting is highly relevant. In general, patients
      who were more likely to quit were older, had entered the hospital as an emergency
      case, and had a medical diagnosis for which quitting is highly relevant.
      CONCLUSIONS: This study suggests that hospital patients who smoke and are also
      diagnosed with conditions which call for quitting are more likely to quit if they
      receive from their consultant a personalized letter advising them to quit and a
      self-help manual.

PMID- 10600435
TI  - A critical review of interventions to increase compliance with medication-taking,
      obtaining medication refills, and appointment-keeping in the treatment of
      cardiovascular disease.
AB  - BACKGROUND: The aim of this study was to critically review the literature
      regarding interventions to improve cardiovascular patients' compliance with
      medication-taking, obtaining medication refills, or appointment keeping. METHODS:
      The search for relevant randomized trials involved searching the Medline,
      Healthplan, and Psychlit databases from 1985 to 1996; searching the
      bibliographies of located studies; contacting Australian government departments,
      non-government organizations, and pharmaceutical companies; and ultimate review
      of the resulting list by two field experts. The 33 located trials were critically
      appraised and classified as being of good, fair, or poor methodological quality.
      Descriptive and effectiveness data were then extracted from the 20 good and fair
      quality trials. Interrater reliability was high on the 20% of references double
      coded. RESULTS: The 20 studies reviewed evaluated the effectiveness of 18
      intervention strategies. Tentative recommendations were made for many patient
      focused and structural strategies across all three target behaviors. Physician
      focused strategies, tested only for appointment keeping, were all tentatively
      recommended against. CONCLUSIONS: The methodological quality of many of the
      located trials was less than optimal, prohibiting strong recommendations.
      Therefore, further good-quality, randomized trials are necessary in order to
      clarify the effectiveness of those strategies identified as potentially useful in
      this review.

PMID- 10600436
TI  - Support for and observance of worksite smoking restriction policies--A study of
      municipal employees at a city office in Japan.
AB  - BACKGROUND: While various types of smoking restrictions have been introduced in
      Japanese workplaces, it is not clear what restriction policies workers find
      acceptable. This study examined the relationship between the extent of worksite
      smoking restriction and worker attitudes toward these policies. METHODS:
      Municipal employees randomly selected from a city office were surveyed using a
      self-administered questionnaire concerning support for and smokers' observance of
      their present smoking restriction. A total of 2857 (88. 6%) workers responded.
      RESULTS: More than 60% of respondents regarded a work-area ban with a designated
      smoking space as the most desirable policy. Among subjects who were aware of the
      current policies in their workplaces, positive support was highest for a total
      ban (73.9%) and decreased as the extent of the restriction became milder (P for
      trend <0.001). In contrast, an inverse relation was found for negative support (P
      for trend <0.001). These trends were observed among both nonsmokers and smokers.
      Smokers subject to a work-area ban observed the policy more faithfully than those
      subject to milder policies. CONCLUSIONS: Policies prohibiting smoking in work
      areas were favorably accepted by municipal employees, irrespective of smoking
      status. These results should encourage Japanese workplaces to adopt work-area
      bans, through which nonsmokers are effectively protected from environmental
      tobacco smoke.

PMID- 10600437
TI  - Physical activity, physical fitness, and coronary heart disease risk factors in
      youth: the Quebec Family Study.
AB  - OBJECTIVE: The relationships between physical activity, fitness, and CHD risk
      factors were investigated in 342 males and 268 females 9-18 years of age.
      METHODS: Daily energy expenditure, moderate to vigorous physical activity,
      inactivity, and television viewing time were estimated. Indicators of physical
      fitness included submaximal work capacity, quadriceps muscle strength, sit-ups,
      and the sum of six skinfolds. Risk factors included mean arterial blood pressure
      and fasting blood levels of triglycerides, LDL-cholesterol, HDL-cholesterol, and
      glucose. RESULTS: Canonical correlations between activity and risk factor
      profiles range from 0.22 to 0.45, while those between fitness and risk factor
      profiles range from 0.34 to 0.55, indicating that 5 to 20% and 11 to 30% of the
      variance in the risk profile is explained by activity and fitness, respectively.
      CONCLUSION: The results suggest that both physical fitness and level of habitual
      physical activity are strongly associated with CHD risk factors in this sample of
      youth.

PMID- 10600438
TI  - Dissecting obesogenic environments: the development and application of a
      framework for identifying and prioritizing environmental interventions for
      obesity.
AB  - BACKGROUND: The "obesogenicity" of modern environments is fueling the obesity
      pandemic. We describe a framework, known as ANGELO (analysis grid for
      environments linked to obesity), which is a conceptual model for understanding
      the obesogenicity of environments and a practical tool for prioritizing
      environmental elements for research and intervention. METHODS: Development of the
      ANGELO framework. The basic framework is a 2 x 4 grid which dissects the
      environment into environmental size (micro and macro) by type: physical (what is
      available), economic (what are the costs), political (what are the "rules"), and
      sociocultural (what are the attitudes and beliefs). Within this grid, the
      elements which influence food intake and physical activity are characterized as
      obesogenic or "leptogenic" (promoting leanness). RESULTS: Application of the
      ANGELO framework. The ANGELO framework has been piloted at the population level
      (island communities) to prioritize the settings/sectors for intervention and at
      the setting level (fast food outlets) to prioritize research needs and
      interventions. Environmental elements were prioritized by rating their validity
      (evidence of impact), relevance (to the local context), and potential
      changeability. CONCLUSIONS: The ANGELO framework appears to be a flexible and
      robust instrument for the needs analysis and problem identification stages of
      reducing the obesogenicity of modern environments.

PMID- 10600439
TI  - Physician contact with older community patients: is there an association with
      physical fitness?
AB  - BACKGROUND: Contact with family physicians by older adults may be linked to their
      physical fitness in addition to other health, behavioral, and sociodemographic
      determinants. We studied a stratified random sample of urban community-dwelling
      elderly patients in London, Ontario, Canada, to describe the interaction of
      physical fitness measures and a number of health and lifestyle behaviors and
      sociodemographic outcomes with family physician contact over 1 year. We
      hypothesized that physician contact would be associated with lower indices of
      physical fitness and that association would be similar to other known
      determinants of physician utilization. METHODS: Three hundred seventy-five
      noninstitutionalized elderly men (N = 185) and women (N = 190) ages 55 to 84
      years were recruited from the municipal tax assessment list for the city of
      London (population 280,000). Four categories of independent variables were
      selected to reflect common determinants of health (physical fitness, self
      reported and clinically measured health, lifestyle behaviors, and
      sociodemographics). The association between these categories of variables and
      self-reported contact with family physicians and a variety of health
      professionals was determined for the year prior to the study. RESULTS: Forty-six
      percent of the subjects had at least one physician contact in the month prior to
      the study and 79% within the previous year. None of the other health professions
      (including nursing, chiropractic, physiotherapy, homemaking, and dentistry) were
      contacted more than once in the previous year. Lifestyle and sociodemographic
      variables including activity habits, smoking, income, marital status, and
      education were not associated with physician contact, whereas poor self-reported
      cardiovascular health and use of cardiovascular and pulmonary medications were
      associated with physician contact. Interestingly, physical fitness variables
      including maximal aerobic capacity, grip strength, and hip flexibility were not
      associated with physician contact. CONCLUSIONS: The absence of an association
      among physical fitness, lifestyle, and sociodemographic variables and physician
      contact was not anticipated and may be due to the selection of individuals who
      were independent, active community dwellers. It may be that most of the physician
      contact in this relatively healthy and physically fit sample was preventive in
      nature, for example, monitoring common chronic disease states in the elderly
      including cardiovascular and pulmonary disease. This paper reports baseline data
      from a longitudinal study of the interaction between physical fitness and health
      outcomes in groups of older community-dwelling individuals. As this group ages
      further, it would be interesting to determine the use of the health care system
      in relation to their changing functional and health status. In particular, do
      chronic health conditions such as cardiovascular disease, which increase in
      prevalence with age, become modified through maintenance of physical fitness and
      does this impact on health service use?

PMID- 10600440
TI  - Systematic differences in validity of self-reported mammography behavior: A
      problem for intergroup comparisons?
AB  - BACKGROUND: Prior studies of recall accuracy for screening mammogram behavior
      have examined relatively homogeneous groups. Data are limited on possible
      systematic group differences, so we evaluated women's recall accuracy in two
      separate care systems in one city. Methods. Women 50 to 70 years old with and
      without screening mammograms 10 to 14 months prior were identified from fiscal,
      clinic, and radiology records at a military care system (MCS) and a county-funded
      system (CFS) for indigents. Mammogram status was verified through radiology
      records. Women were excluded if mammograms were diagnostic, done for other than
      annual screening, or had abnormal results. Interviewers blinded to mammogram
      status surveyed randomly selected eligible women. RESULTS: For 62 screened/31
      unscreened MCS women and 78 screened/61 unscreened CFS women, specificity was
      similar, at 65 and 62%, respectively. In contrast, sensitivity varied
      significantly: 95% versus 79% (P = 0. 011). Primary ethonocultural groups were
      Euro-American (MCS-60%) and Mexican American (CFS-85%). Although not different in
      specificity of recall (67% versus 61%), these major subgroups significantly
      differed in sensitivity (97% versus 80%, P = 0.017), proportion of true negatives
      due to never having a mammogram (35% versus 57%, P = 0.003), and proportion with
      >/=high school education (78% versus 19%, P < 0.00001). CONCLUSION: Systematic
      differences in recall validity may exist and compromise the accuracy of
      intergroup comparisons.

PMID- 10600441
TI  - Smoking bans in the home and car: Do those who really need them have them?
AB  - BACKGROUND: This paper addresses the question of whether individuals who are most
      in need of household and car smoking bans, such as individuals with children
      living at home or who have many friends who smoke, are the ones who have them.
      METHOD: A representative sample of 6985 California adults ages 18 and older
      participated in telephone interviews. RESULTS: Overall, 76% of adults report
      having home smoking bans and 66% have car smoking bans. Being a smoker or African
      American, not having children in the home, having more friends who smoke, and
      lower household income were associated with lower prevalence of both home and car
      smoking bans (P < 0.01). In multivariate analyses, nonsmokers were 7.9 (95% CI =
      3.56, 17.31) times more likely to have a home smoking ban when none of their
      friends were smokers compared to when most of their friends were smokers. Among
      smokers, there was an interaction between having children at home and the
      proportion of friends who smoke. Only 27 to 55% of smokers had home smoking bans
      unless most of their friends were smokers, then the odds of having a ban were 6.1
      (95% CI = 2.76, 13.68) times higher for smokers with children (67% with home
      bans) than for smokers without children at home (25% with home bans).
      CONCLUSIONS: Efforts to increase home and car smoking bans for nonsmokers who
      have friends who smoke and smokers with children living at home are needed.

PMID- 10600442
TI  - Age of initiation, smoking patterns, and risk in a population of working adults.
AB  - BACKGROUND: Early age of initiation is a significant risk factor for long-term
      dependent smoking and may also relate to other unhealthy behaviors and increased
      likelihood of illness, independent of duration of smoking. METHODS: The current
      study assessed age of initiation in relation to cigarette dependence, interest in
      quitting, social environment pertaining to smoking, behavioral risk factors, and
      current health problems. Subjects were 2120 current daily smokers in 24 worksites
      in the Minneapolis/St. Paul, Minnesota, metropolitan area. RESULTS: Findings were
      surprisingly consistent with early age of initiation predicting more dependent
      smoking, less interest and confidence in ability to quit, poorer diet, less use
      of seat belts, more illness and hospitalization, and greater likelihood of
      smoking among partner/spouse, friends, and co-workers. CONCLUSIONS: The overall
      strength of the findings was unexpected. Early initiation of regular smoking
      predicted a significant constellation of risk factors throughout adulthood.
      Interventions that significantly delay smoking onset, even in the absence of
      permanent prevention, could have important public health implications.

PMID- 10600443
TI  - Plasmodium yoelii: cloning and characterization of the gene encoding for the
      mitochondrial heat shock protein 60.
AB  - Heat shock proteins are a highly conserved group of proteins required for the
      correct folding, transport, and degradation of other proteins in vivo. The Hsp70,
      Hsp90, and Hsp60 families are among the most widely studied families. Hsp60 is
      found in eubacteria, mitochondria, and chloroplasts, where, in cooperation with
      Hsp10, it participates in protein folding and translocation of proteins to the
      organelles. We have cloned and characterized the Hsp60 gene of Plasmodium yoelii
      (PyHsp60). PyHsp60 is a single-copy gene, located on chromosome 9, 10, or 11. The
      PyHsp60 cDNA sequence showed an open reading frame of 1737 nucleotides that codes
      for a polypeptide of 579 amino acids, with 93% amino acid identity to Plasmodium
      falciparum Hsp60 (PfHsp60). Cloning and sequencing of a genomic PCR clone showed
      the presence of a 201-bp intron, located 141 bp downstream of the ATG codon. A
      single, heat-inducible, 2.3-kb transcript was detected in Northern blots of RNA
      isolated from blood stage parasites. Mouse antisera raised against a DNA vaccine
      vector that expresses PyHsp60 recognized sporozoites and liver- and blood-stage
      parasites by indirect fluorescent antibody test (IFAT). By Western blot, these
      antisera reacted with the mycobacterial Hsp65 and recognized a protein of
      approximately 65 kDa in P. yoelii sporozoites and P. falciparum blood stages.
      These results show that PyHsp60 and PfHsp60 genes are homologous and that of the
      PyHsp60 gene encodes a heat-inducible, intracellular protein that is expressed in
      several of the developmental stages of P. yoelii.

PMID- 10600444
TI  - Nitric oxide is involved in the lesions of the peripheral autonomic neurons
      observed in the acute phase of experimental Trypanosoma cruzi infection.
AB  - Our aim was to investigate the possible involvement of nitric oxide (NO) in
      peripheral denervation during the acute phase of murine experimental Trypanosoma
      cruzi infection. Wistar male rats were infected with the Y strain of T. cruzi.
      One group of animals was also treated with the NO synthase inhibitor N-nitro-l
      arginine. A group of uninfected animals was the control. At the 18th day of
      infection the animals were sacrificed. Quantification of neurons in the colon and
      heart and tissue parasitism in the heart was performed. Serum concentration of
      nitrate was measured and a histochemical technique for assessing NADPH-diaphorase
      activity in the colon was also performed. The infected animals presented a
      statistically significant decrease in the number of peripheral neurons in the
      colon and heart and a 2-fold increase in serum NO(3) concentration compared with
      controls. The animals treated with N-nitro-l-arginine showed almost an absence of
      NO(3) concentration in the serum and did not show loss of neurons compared with
      controls. These treated animals displayed a 15-fold increase in tissue parasitism
      compared with nontreated infected animals. The NADPH-diaphorase activity was much
      more intense in the muscle layers of the colon of the infected animals than in
      those of the controls. Taken together, these data suggest that NO is involved in
      the peripheral denervation observed in the acute phase of experimental T. cruzi
      infection.

PMID- 10600445
TI  - Onchocerca volvulus: limited heterogeneity in the nuclear and mitochondrial
      genomes.
AB  - West African populations of Onchocerca volvulus endemic to the rain forest and
      savanna bioclimes of West Africa differ in their ability to induce ocular disease
      in infected individuals. In recent years, both clinical- and animal-model-based
      studies have implicated particular parasite antigens in the development of ocular
      onchocerciasis. To test the hypothesis that the difference in pathogenic
      potential of blinding and nonblinding parasites might be reflected in qualitative
      differences in antigens that have been implicated in the development of ocular
      onchocerciasis, we compared the sequences of two parasite antigens implicated in
      the development of ocular disease in blinding- and nonblinding-strain parasites.
      The results demonstrated a high level of homogeneity between the parasite strains
      in these genes. The study was extended to include additional nuclear genes
      encoding antigens that are commonly recognized by individuals infected with O.
      volvulus and to the mitochondrial genome of the parasite. The results demonstrate
      a high degree of homogeneity in both the nuclear and the mitochondrial genomes
      among O. volvulus isolates collected from several different sites in Africa and
      in the Americas. This high degree of genetic homogeneity may reflect the passage
      of the parasite through a recent genetic bottleneck.

PMID- 10600446
TI  - Ixodes ticks: serum species sensitivity of anticomplement activity.
AB  - Ixodid ticks feed for extended periods of up to 2 weeks or more. To complete
      engorgement, they must overcome their host's innate immune mechanisms of which
      the complement system is a major component. Using in vitro assays, salivary gland
      extracts of the ixodid ticks, Ixodes ricinus, I. hexagonus, and I. uriae, were
      shown to inhibit activity of the alternative pathway of complement. The ability
      of the different Ixodes species to inhibit complement activity varied with the
      animal species used as a complement serum source. Serum species sensitivity
      correlates to the reported host range of the tick species tested.

PMID- 10600447
TI  - Rouleaux-forming serum proteins are involved in the rosetting of Plasmodium
      falciparum-infected erythrocytes.
AB  - Excessive sequestration of Plasmodium falciparum-infected (pRBC) and uninfected
      erythrocytes (RBC) in the microvasculature, cytoadherence, and rosetting, have
      been suggested to be correlated with the development of cerebral malaria. P.
      falciparum erythrocyte membrane protein-1 (PfEMP1) is the parasite-derived
      adhesin which mediates rosetting. Herein we show that serum proteins are crucial
      for the rosette formation of four strains of parasites (FCR3S1, TM284, TM180, and
      R29), whereas the rosettes of a fifth strain (DD2) are serum independent. Some
      parasites, e.g., FCR3S1, can be depleted of all rosettes by washes in heparin and
      Na citrate and none of the rosettes remain when the parasite is grown in foetal
      calf serum or ALBUMAX. Rosettes of other parasites are less sensitive; e.g., 20%
      of TM180 and R29 and 70% of TM284 rosettes still prevail after cultivation. A
      serum fraction generated by ion-exchange chromatography and poly-ethylene-glycol
      precipitation restored 50% of FCR3S1 and approx 40 to 100% of TM180 rosettes. In
      FCR3S1, antibodies to fibrinogen reverted the effect of the serum fraction and
      stained fibrinogen bound to the pRBC surface in transmission electron microscopy.
      Normal, nonimmune IgM and/or IgG was also found attached to the pRBC of the four
      serum-dependent strains as seen by surface immunofluorescens. Our results suggest
      that serum proteins, known to participate in rouleaux formation of normal
      erythrocytes, produce stable rosettes in conjunction with the recently identified
      parasite-derived rosetting ligand PfEMP1.

PMID- 10600448
TI  - Leishmania donovani: characterization and expression of ORFF, a gene amplified
      from the LDI locus.
AB  - The LD1 locus is a 27.5-kb region of chromosome 35 that is conserved among all
      species of Leishmania and is amplified in several different isolates. Here, we
      report the genomic distribution of ORFF, a gene from the LD1 region, and its
      expression at the RNA and protein levels in two Indian isolates of Leishmania
      donovani. In both of these isolates, ORFF was present as a single copy on
      chromosome 35. Densitometric analysis of ORFF mRNA abundance revealed relative
      abundance of 0.2 and 1.0 in AG83 and S-Lal, respectively. Antiserum against
      recombinant ORFF protein detected a protein of the predicted size ( approximately
      34 kDa) in both strains. The protein is most abundant in mid-log-phase
      promastigotes and has a nuclear localization. The ORFF protein is preferentially
      expressed in L. donovani amastigotes but, in contrast, is expressed at higher
      levels in L. major promastigotes.

PMID- 10600449
TI  - Protection against lethal toxoplasmosis in mice by an avirulent strain of
      Toxoplasma gondii: stimulation of IFN-gamma and TNF-alpha response.
AB  - In this study, we examined whether the PTN strain (isolated from an AIDS patient)
      of Toxoplasma gondii could induce cross-protection in mice against infection with
      a lethal dose of the PLK strain. Mice were first infected with tachyzoites (5 x
      10(5)) of PTN and 5 days later challenged with PLK (1 x 10(5), LD(90)) parasites.
      None of these mice succumbed to infection until day 21 after infection, whereas
      100% of the mice given the same dose of PLK infection alone died between 5 and 11
      days after infection. The protection was accompanied by an increased expansion of
      NK cells and CD4 + T cells. This condition was associated by increased production
      of IFN-gamma and an augmented number of IFN-gamma-producing cells in the spleen.
      Further, PTN + PLK-infected mice showed higher production of TNF-alpha and
      nitrite compared to PLK-infected mice. Mice infected with the PTN strain had an
      enhanced capacity to activate the immune system early in infection since they
      produced higher levels of IFN-gamma, TNF-alpha, and NO than PLK-infected mice.
      Administration of anti-IFN-gamma mAb or anti-asialo GM1 antibody resulted in 100
      and 20% mortality, respectively, in PTN-infected mice but no death in PTN + PLK
      infected mice. Together, these results suggest that early production of IFN-gamma
      and NK-cell activity is important in protection against PTN infection, whereas in
      PTN + PLK infection components of adaptive immunity rapidly developed following
      elaboration of an effective early innate immune response.

PMID- 10600450
TI  - High-level expression, purification, and characterization of recombinant type A
      botulinum neurotoxin light chain.
AB  - Botulinum neurotoxin light chain (BoNT LC, 50 kDa) is responsible for the zinc
      endopeptidase activity specific for proteins of neuroexocytosis apparatus. We
      describe the expression of recombinant type A BoNT LC in Escherichia coli as well
      as the purification and characterization of the recombinant protein. A high level
      of expression of BoNT/A LC was obtained by an extended postinduction time of 15 h
      at 30 degrees C. Recombinant BoNT/A LC was isolated from an Ni(2+) column. Due to
      its high pI ( approximately 8.7), purification was achieved by a single step of
      passing the protein through anion-exchange chromatography at pH 8.0 without the
      need of elution. The purified recombinant BoNT/A LC retained proteolytic activity
      and had a secondary structure similar to that of native LC determined by CD
      measurement.

PMID- 10600451
TI  - Expression, isolation, and characterization of a chloroplast targeting peptide.
AB  - For the first time a method is described in which an N-terminal targeting peptide
      is isolated from Escherichia coli. After overexpression, purification, and
      cleavage of a fusion protein the protease-sensitive transit peptide from the
      chloroplast precursor protein preferredoxin could be isolated by HPLC. It was
      characterized by N-terminal amino acid sequencing and electrospray mass
      spectrometry. Its functionality was suggested by in vitro import competition
      experiments with isolated pea chloroplasts, in which the isolated peptide
      inhibited the import of radioactively labeled preferredoxin. Results from import
      competition experiments performed with a transit peptide deletion mutant
      suggested that the four extreme C-terminal amino acids lack information to
      interact with the chloroplast import machinery.

PMID- 10600452
TI  - Expression and purification of the transcription factor NtcA from the
      cyanobacterium Anabaena PCC 7120.
AB  - The transcription factor NtcA from the cyanobacterium Anabaena PCC 7120 was
      heterologously expressed in Escherichia coli. In order to optimize the expression
      of NtcA, random silent mutations were introduced at the 5' end of the DNA
      encoding the protein. To get as high a yield of pure protein as possible,
      different strategies of expression as well as purification conditions were used.
      Under optimal expression conditions, a high-level expression clone of NtcA was
      coexpressed with GroEL-ES at 37 degrees C. A hexahistidine tag was added to the N
      terminus of the protein in order to allow purification on an IMAC affinity
      column. Expression followed by one purification step using IMAC affinity
      chromatography gave a yield of 30-40 mg pure NtcA protein per liter of bacterial
      culture. Gel-shift experiments showed that the recombinant NtcA was active in
      binding a DNA sequence containing an NtcA-specific site.

PMID- 10600453
TI  - Expression and purification of the BmK M1 neurotoxin from the scorpion Buthus
      martensii Karsch.
AB  - The gene encoding a neurotoxin (BmK M1) from the scorpion Buthus martensii Karsch
      was expressed in Saccharomyces cerevisiae at a high level with the alcohol
      dehydrogenase promoter. SDS-PAGE of the culture confirmed expression and showed
      secretion into medium from yeast. Recombinant BmK M1 was purified rapidly and
      efficiently by ion exchange and gel filtration chromatography to homogeneity,
      produced a single band on tricine-SDS-PAGE, and processed the homologous N
      terminus. Amino acid analysis and N-terminal sequencing demonstrated that the
      recombinant toxin was processed correctly from the alpha-mating factor leader
      sequence and was chemically identical to the native form. The expressed
      recombinant BmK M1 was toxic for mice, which indicated that it was biologically
      active. Quantitative estimation showed that recombinant BmK M1 had an LD(50)
      similar to that of the native toxin.

PMID- 10600454
TI  - Molecular cloning of the arylsulfate sulfotransferase gene and characterization
      of its product from Enterobacter amnigenus AR-37.
AB  - The gene encoding the Enterobacter amnigenus AR-37 arylsulfate sulfotransferase
      (ASST) was cloned, sequenced, and expressed in Escherichia coli NM522. Sequencing
      led to the identification of three contiguous open reading frames (ORFs) on the
      same strand. Based on amino acid sequence homology, ORF1, ORF2, and ORF3 are
      designated astA, dsbA, and dsbB, respectively. A multiple sequence alignment
      revealed conserved regions in ASST. An N-terminal amino acid sequence analysis of
      the purified ASST from E. coli NM522 (pEAST72) showed that it is subject to N
      terminal processing. The specific activity of purified ASST is 436.5 U/mg of
      protein. The enzyme is a monomeric protein with a molecular mass of 64 kDa. Using
      phenol as an acceptor substrate, 4-methylumbelliferyl sulfate is the best donor
      substrate, followed by beta-naphthyl sulfate, p-nitrophenyl sulfate (PNS), and
      alpha-naphthyl sulfate. For PNS, alpha-naphthol is the best acceptor substrate,
      followed by phenol, resorcinol, p-acetaminophen, tyramine, and tyrosine. The
      enzyme has a different acceptor specificity than the enzyme purified from
      Eubacterium A-44. It is similar to Klebsiella K-36 and Haemophilus K-12. The
      apparent K(m) values for PNS using phenol as an acceptor and for phenol using PNS
      as a donor are 0.163 and 0.314 mM, respectively. The pI and optimum pH are 6.1
      and 9.0, respectively.

PMID- 10600455
TI  - Expression and purification of the hormone binding domain of the Drosophila
      ecdysone and ultraspiracle receptors.
AB  - Escherichia coli vectors were constructed for the production of a protein complex
      that mimics the native ecdysone receptor (EcR) isolated from Drosophila. The two
      steroid receptors, ultraspiracle (USP) and EcR, were expressed as truncations,
      retaining primarily the hormone binding domains. The recombinant receptor complex
      was able to mimic the pharmacology of the native receptor with respect to both
      synthetic and natural agonists. USP and EcR fusion proteins could be expressed in
      separate cell lines and then recombined following isolation to yield a ligand
      binding preparation with a dissociation constant (K(D)) for Ponasterone A of 1.5
      nM and a total yield of 1.9 pmol ligand binding sites/mg protein. Alternatively,
      the simultaneous coexpression of both receptors increased yields by several
      orders of magnitude to 6 nmol ligand binding sites/mg protein with a K(D) of 0.6
      nM. Chromatographic analysis under native conditions showed that EcR, when
      expressed alone, migrated as a variety of complexes, mostly coming out in the
      void volume as denatured, insoluble, aggregate. In contrast, purified extracts of
      coexpressed EcR and USP eluted as a single peak with a mobility indicating a
      heterodimer. The majority of the coexpressed fusion receptors, following
      purification, formed functional steroid binding sites. A detailed scheme is
      provided for the expression and isolation of milligram quantities of highly
      purified receptor dimer.

PMID- 10600456
TI  - Large-scale HPLC purification of calbindin D9k from porcine intestine.
AB  - Two efficient procedures for large-scale purification of calbindin D9k from
      porcine intestine by HPLC were developed. Both protocols start with heat
      treatment of the intestinal tissue followed by acetic acid extraction, a capture
      with alginic acid, NaCl precipitation of other proteins, and a concentration step
      on Amberlite XAD-2. In the first method, a single reverse-phase HPLC step
      completes the purification and results in milligram quantities of pure calbindin.
      In the second method, an additional ion exchange HPLC step was introduced,
      followed by a reverse-phase HPLC resulting in 100 milligram-scale preparations of
      homogeneous calbindin in a 56% yield from the Amberlite step. Both methods
      yielded a homogeneous metal-free apoprotein with a molecular weight of 8838.0 +/-
      8.8 as analyzed by MALDI TOF mass spectrometry corresponding to N-acetylated
      porcine calbindin. The isolated apocalbindin was fully reconstituted with 2 molar
      equivalents of Ca(2+) and the protein displayed UV and fluorescence spectra
      characteristic of those of native calbindin D9k.

PMID- 10600457
TI  - Expression of a recombinant Toxoplasma gondii ROP2 fragment as a fusion protein
      in bacteria circumvents insolubility and proteolytic degradation.
AB  - A 268-amino-acid-residue carboxy-terminal antigenic fragment of the Toxoplasma
      gondii rhoptry protein ROP2 (recROP2(t), residues 196-464) was expressed in
      Escherichia coli. This recombinant fragment was produced at low concentration and
      in a highly insoluble form. By contrast, the level of recROP2(t) production was
      drastically greater when the same coding sequence was fused to the C-terminus of
      thioredoxin (TRX) or to the maltose-binding protein (MBP) gene. While both fusion
      proteins were found to be mainly insoluble, solubilization could be achieved
      without significant degradation. MBP was more efficient than TRX in increasing
      the recovery of soluble protein with more than 10% of total MBP-recROP2(t) being
      readily expressed in a soluble form. Moreover, the insoluble form of MBP
      recROP2(t) could be correctly refolded with a recovery of more than 80%. Both
      forms of MBP-recROP2(t) were purified to homogeneity by amylose chromatography.
      In contrast, the refolding of TRX-recROP2(t) promoted aggregation of the protein,
      which was prevented by the use of zwitterionic detergent during the one-step
      purification by gel filtration. Subsequent proteolytic cleavages of purified TRX
      recROP2(t) and of MBP-recROP2(t) led respectively to the complete degradation or
      to the truncation of the recROP2(t) moiety. However, recROP2(t), despite the
      presence of the fusion partners, adopted a suitable conformation recognized by
      human serum-derived antibodies from T. gondii-seropositive individuals. Finally,
      both fusion proteins were able to induce specific humoral and cell-mediated
      immune response to the ROP2 fragment. Such fusions could represent an alternative
      to study the immunogenicity of T. gondii proteins which are difficult to produce
      because of insolubility and degradation.

PMID- 10600458
TI  - Purification and characterization of a recombinant Haemophilus influenzae outer
      membrane phosphomonoesterase e (P4).
AB  - Haemophilus influenzae is a common inhabitant of the upper respiratory tract and
      can cause serious infections of mucosal surfaces. Results from recent studies
      indicate that this pathogen possesses copious amounts of surface-localized
      phosphomonoesterase activity mediated by the bacterial lipoprotein e (P4). While
      the enzyme has previously been purified to apparent homogeneity, purification of
      large amounts of protein has been prevented by presence of N-terminal lipid
      modification. Recombinant DNA technology was employed to simultaneously replace
      the N-terminal lipid modification signal sequence with one for protein secretion
      without such modification and to place expression of the protein under the
      control of the T7-inducible promoter. Results from this work show that high
      levels of phosphomonoesterase activity were achieved after IPTG induction and
      purified to apparent homogeneity after two chromatography steps. Consistent with
      loss of the N-terminal lipid modification, the recombinant enzyme was easily
      extracted from the bacterial membrane and partitioned within the matrix of gel
      filtration chromatography resin while retaining a denatured molecular weight
      similar to that of wild-type e (P4). Results from physicochemical
      characterization suggest that the recombinant protein was similar to wild-type
      protein in SDS-PAGE-derived molecular weight, primary structure, substrate
      specificity, pH optimum, and sensitivity or resistance to various inhibitors.
      Acquisition of sufficient amounts of recombinant P4 was a prelude for studies to
      elucidate the structure and function of this unusual phosphomonoesterase.

PMID- 10600459
TI  - Bacterial expression and characterization of functional recombinant
      triosephosphate isomerase from Schistosoma japonicum.
AB  - The dimeric enzyme triosephosphate isomerase (TPI) converts glyceraldehyde-3
      phosphate to dehydroxyacetone phosphate, a key reaction in glycolysis. Previous
      studies of the native enzyme in the human blood-flukes belonging to the genus
      Schistosoma have indicated that TPI is a promising anti-schistosome vaccine
      antigen. However, a recombinant form of the enzyme is required as an alternative
      to the impractical option of using biochemically purified TPI obtained from worm
      tissue for large-scale vaccine use. We previously cloned and sequenced a full
      length cDNA encoding the TPI of the Asian (Chinese strain) schistosome
      Schistosoma japonicum (SjcTPI). We now report very high level bacterial
      expression of this cDNA and the subsequent purification of the recombinant
      protein to >98% homogeneity under nondenaturing conditions. The recombinant
      SjcTPI (re-SjcTPI) was shown to be enzymatically active with a specific activity
      of 7687 units/mg protein, an activity higher than that of commercially obtained
      porcine TPI tested concurrently under the same assay conditions. The K(m) value
      for the re-SjcTPI using glyceraldehyde-3-phosphate as substrate was 406.7 microM,
      which is similar to the K(m) values reported for the yeast enzyme and various
      mammalian TPIs. With the availability of substantial amounts of enzymatically
      active and readily purified re-SjcTPI made in bacteria we can now test whether
      the recombinant protein can induce a similar level of protection in
      vaccination/challenge experiments as the native, biochemically purified enzyme.

PMID- 10600460
TI  - Functional expression and characterization of the myrosinase MYR1 from Brassica
      napus in Saccharomyces cerevisiae.
AB  - Myrosinases are thioglucosidases that hydrolyze the natural plant products
      glucosinolates. We have expressed the myrosinase MYR1 from Brassica napus in
      Saccharomyces cerevisiae. The recombinant myrosinase was enzymatically active
      which shows that the MYR1, which in the plant is complex bound with myrosinase
      binding proteins and myrosinase-associated proteins, is functional in its free
      form. Characterization of the recombinant MYR1 with respect to pH optimum,
      substrate specificity, activation by ascorbic acid, and inhibitors showed similar
      characteristics as previously observed for other plant myrosinases. The
      indolizidine alkaloid castanospermine, an inhibitor of O-glycosidases, inhibited
      the hydrolysis of p-hydroxybenzylglucosinolate with a K(i) value of 0.3 microM
      and 2-deoxy-2-fluoroglucotropaeolin, a specific inhibitor of thioglucosidases,
      inhibited the enzyme with a K(i) value of 1 mM. The expression of the myrosinase
      in yeast was transient and the growth of the yeast cells was significantly
      reduced during the period of expression of the myrosinase. Immunoblot analysis
      showed that the highest level of expression of MYR1 was obtained 24 h after
      induction with galactose. The amount of myrosinase protein correlated with the
      level of enzyme activity. The transient expression of myrosinase indicates that
      myrosinase is toxic to the cells. This is the first report on successful
      heterologous expression of a myrosinase and provides an important tool for, e.g.,
      further characterization of myrosinase by site-directed mutagenesis and for
      studying the interaction between myrosinase and myrosinase-binding proteins,
      myrosinase-associated proteins, and epithiospecifier proteins.

PMID- 10600461
TI  - Use of thiophilic adsorption chromatography for the one-step purification of a
      bacterially produced antibody F(ab) fragment without the need for an affinity
      tag.
AB  - Thiophilic adsorption chromatography (TAC) was employed for the purification of a
      recombinant F(ab) fragment of the antibody IN-1 from the periplasmic protein
      fraction of Escherichia coli. Adsorption of the F(ab) fragment to the T-gel was
      achieved at a high concentration of ammonium sulfate and turned out to be
      independent of the presence of a His(6) tag or Strep tag or of the human or
      murine nature of the C(H)1 and C(L) domains (subclass IgG1/kappa). Elution was
      effected by means of a decreasing salt gradient, yielding fractions with the
      correctly assembled, heterodimeric F(ab) fragment at high purity. Interestingly,
      the single substitution of an alanine residue with phenylalanine in the CDR-L1 of
      the F(ab) fragment significantly enhanced the retention on the column so that
      quantitative elution necessitated prolonged application of a low-salt buffer. Our
      findings suggest that TAC is generally suitable for the isolation of bacterially
      produced F(ab) fragments and support the notion that aromatic side chains play an
      important role in the interaction with the affinity matrix. This method should
      prove valuable in the production of proteins for in vivo applications as might be
      the case for the F(ab) fragment of the antibody IN-1, which promotes axonal
      regeneration in the central nervous system.

PMID- 10600462
TI  - Use of carboxypeptidase Y propeptide as a fusion partner for expression of small
      polypeptides in Escherichia coli.
AB  - The carboxypeptidase Y (CPY) propeptide from Saccharomyces cerevisiae was
      developed as a fusion partner for the efficient expression of small polypeptides
      in Escherichia coli. Six consecutive histidine residues (6xHis) were fused to the
      N-terminus of the CPY propeptide for the facilitated purification of fusion
      proteins using immobilized metal ion affinity chromatography. In addition, a
      methionine or the pentapeptide (Asp)(4)-Lys linker was inserted at the junction
      between the CPY propeptide and the target polypeptide to release the target
      polypeptide by digestion with cyanogen bromide or enterokinase. Therapeutically
      valuable peptide hormones, such as salmon calcitonin precursor (sCAL-Gly), a
      fragment of human parathyroid hormone (hPTH(1-34)), and human glucagon were
      successfully expressed in E. coli as fusion polypeptides with the fusion partner.
      SDS-PAGE analyses showed that the majority of the expressed fusion sCAL-Gly and
      fusion hPTH(1-34) were present in the form of inclusion bodies, whereas about 66%
      of the expressed human glucagon was in a soluble form. Almost complete cleavage
      of the fusion polypeptides was obtained by digestion with enterokinase. Reverse
      phase HPLC analyses showed that the target polypeptides released from the fusion
      proteins were identical to their native forms.

PMID- 10600463
TI  - Expression and characterization of the HMG-CoA reductase of the thermophilic
      archaeon Sulfolobus solfataricus.
AB  - The thermostable class I HMG-CoA reductase of Sulfolobus solfataricus offers
      potential for industrial applications and for the initiation of crystallization
      trials of a biosynthetic HMG-CoA reductase. However, of the 15 arginine codons of
      the hmgA gene that encodes S. solfataricus HMG-CoA reductase, 14 (93%) are AGA or
      AGG, the arginine codons used least frequently by Escherichia coli. The presence
      of these rare codons in tandem or in the first 20 codons of a gene can complicate
      expression of that gene in E. coli. Problems include premature chain termination
      and misincorporation of lysine for arginine. We therefore sought to improve the
      expression and subsequent yield of S. solfataricus HMG-CoA reductase by expanding
      the pool size of tRNA(AGA,AGG), the tRNA that recognizes these two rare codons.
      Coexpression of the S. solfataricus hmgA gene with the argU gene that encodes
      tRNA(AGA,AGG) resulted in an over 10-fold increase in enzyme yield. This has
      provided significantly greater quantities of purified enzyme for potential
      industrial applications and for crystallographic characterization of a stable
      class I HMG-CoA reductase. It has, in addition, facilitated determination of
      kinetic parameters and of pH optima for all four catalyzed reactions, for
      determination of the K(i) for inhibition by the statin drug mevinolin, and for
      comparison of the properties of the HMG-CoA reductase of this thermophilic
      archaeon to those of other class I HMG-CoA reductases.

PMID- 10600464
TI  - Expression and purification of hexahistidine-tagged human glutathione S
      transferase P1-1 in Escherichia coli.
AB  - The bacterial expression and purification of human pi class glutathione S
      transferase (hGST P1-1) as a hexahistidine-tagged polypeptide was performed. The
      expression plasmid for hGST P1-1 was constructed by ligation of the cDNA which
      codes for the protein into the expression vector pET-15b. The expressed protein
      was purified by either glutathione or metal (Co(2+)) affinity column
      chromatography, which produced the pure and fully active enzyme in one step with
      a yield of more than 30 mg/liter culture. The activity of the purified protein
      was 130 units mg(-1) from the GSH affinity column and 112 units mg(-1) from the
      Co(2+) affinity column chromatography. The purity of the protein was assessed by
      electrospray ionization mass spectrometry and size-exclusion chromatography. It
      showed that the real molecular weight of the hexahistidine-tagged hGST P1-1
      polypeptide chain agreed with the calculated value and that the purified protein
      eluted as an apparent homodimer on the gel filtration column. Our expression
      system allows the expression and purification of active hexahistidine-tagged hGST
      P1-1 in high yield with no need of removal of the hexahistidine tag and gives
      pure protein in one purification step allowing further study of this enzyme.

PMID- 10600465
TI  - Vector engineering anomalies: impact on fusion protein purification performance.
AB  - Recombinant protein purification using IMAC is often carried out by protein
      fusion to affinity tags. We have identified several tags useful for protein
      purification on Zn(II)-IDA columns. These tags were fused to the green
      fluorescent protein (rGFPuv) using the vector pGFPuv distributed by Clontech Lab
      (Palo Alto, CA) and analyzed for purification on Zn(II)-IDA. Each fusion protein
      exhibited elution heterogeneity (elution in two distinct pHs) from Zn(II)-IDA
      columns This led us to believe that two populations of fluorescent proteins were
      being expressed: one without the tag coeluting with Escherichia coli proteins at
      pH 7.5 and one bearing the tag eluting at a pH lower than pH 7.5. Assessment of
      the constructs revealed the possibility of a ribosomal binding site and start
      codon between the fusion tag and the rGFPuv sequence which might be used as a
      secondary translation start site. This hypothesis was confirmed by changing the
      second ATG (methionine) codon to an ACG (threonine) codon. The protein produced
      from this new construct eluted in a single fraction from a Zn(II)-IDA column.
      Thus, vector irregularities (along with other possibilities) should be examined
      when searching for the cause of elution heterogeneity of a target protein.

PMID- 10600466
TI  - Heterologous expression, purification, and kinetic comparison of the cytoplasmic
      and mitochondrial glyoxalase II enzymes, Glo2p and Glo4p, from Saccharomyces
      cerevisiae.
AB  - The aims of the present study are (i) to purify a mitochondrial glyoxalase II to
      homogeneity for the first time from any organism and (ii) to compare its kinetic
      properties with those of the cytoplasmic enzyme. Both the cytoplasmic and the
      mitochondrial glyoxalases II from Saccharomyces cerevisiae, which are the
      products of two distinct genes, GLO2 and GLO4, were purified from yeast and in
      recombinant form from Escherichia coli. To obtain a higher protein yield
      (compared to wild-type expression) in yeast, the genes were placed under the
      control of the strong GAL1 promoter on a multicopy plasmid. Amino-terminal
      sequencing and molecular mass determination by MALDI-TOF mass spectrometry of the
      mitochondrial Glo4 protein revealed Met-11 of the primary translation product of
      the gene as the N-terminal amino acid. Judged by enzyme kinetic properties the
      recombinant and natural proteins were equivalent. The cytoplasmic and the
      mitochondrial enzyme differed in the pH dependence of the kinetic parameters for
      the main substrate, S-d-lactoylglutathione. Whereas the cytoplasmic protein
      showed a pronounced peak of enzyme activity between pH 7-8 and a continuous up to
      fivefold increase of the K(M) value with increasing pH (from 5. 5-9.0), the
      mitochondrial protein had a nearly constant K(M) value and an activity maximum
      over a broad pH range (6.5-9.0). The kinetic parameters (at pH 7.5) of both the
      cytoplasmic and the mitochondrial enzyme for S-D-lactoylglutathione were of the
      same order of magnitude as reported recently for the human and Arabidopsis
      thaliana enzymes which are presumably of cytoplasmic origin. However, both yeast
      enzymes showed a severalfold lower preference for the more hydrophobic substrate,
      S-d-mandeloylglutathione.

PMID- 10600467
TI  - Use of Pichia pastoris for the expression, purification, and characterization of
      rat calretinin "EF-hand" domains.
AB  - Calretinin (CR) is a calcium-binding, neuronal protein of undefined function.
      Related proteins either buffer intracellular calcium concentrations or are
      involved in calcium-signaling pathways. We transformed three CR gene fragment
      sequences, corresponding to its three complementary domains (I-II, III-IV, and V
      VI), into Pichia pastoris. High yields of extracellular expression, of more than
      200 mg/liter, were achieved. Simple purification protocols provide high yields of
      homogenous proteins: dialysis and DEAE-cellulose chromatography for domains I-II
      and III-IV or ammonium sulfate precipitation and octyl-Sepharose chromatography
      for domain V-VI. To our knowledge, this is the first report of the expression of
      an EF-hand protein using P. pastoris. Direct comparison of the purified yields of
      domain I-II indicates a approximately 20-fold improvement over Escherichia coli.
      N-terminal amino acid sequencing confirmed our gene products and two anti
      calretinin antibodies recognized the appropriate domains. All three CR domains
      bind (45)Ca and the domain containing EF-hands V and VI seems to have a lower
      calcium capacity than the other domains. Circular dichroism indicates a high
      helix content for each of the domains. Calcium-induced structural changes in the
      first two domains, followed by tryptophan fluorescence, correspond with previous
      studies, while tyrosine emission fluorescence indicates calcium-induced
      structural changes also occur in domain V-VI. The methods and expression levels
      achieved are suitable for future NMR labeling of the proteins, with (15)N and
      (13)C, and structure-function studies that will help to further understand CR
      function.

PMID- 10600468
TI  - Purification of virus-like particles of recombinant human papillomavirus type 11
      major capsid protein L1 from Saccharomyces cerevisiae.
AB  - Recombinant major capsid protein, L1 (M(r) = 55,000), of human papillomavirus
      type 11 was expressed intracellularly at high levels in a galactose-inducible
      Saccharomyces cerevisiae expression system by an HPV6/11 hybrid gene. The capsid
      protein self-assembled into virus-like particles (VLPs) and accounted for 15% of
      the total soluble protein. A purification process was developed that consisted of
      two main steps: microfiltration and cation-exchange chromatography. The purified
      VLPs were 98% homogeneous, and the overall purification yield was 10%. The final
      product was characterized by several analytical methods and was highly
      immunogenic in mice.

PMID- 10600469
TI  - Mitochondrial processing peptidase: multiple-site recognition of precursor
      proteins.
AB  - During or shortly after import of the precursor proteins into mitochondria, the
      amino-terminal extension peptides are first proteolytically removed by
      mitochondrial processing peptidase (MPP). The peptidase is a
      metalloendopeptidase, classified as a member of pitrilysin family, and forms a
      heterodimer consisting of structurally related alpha- and beta-subunits which are
      homologous to core proteins, core 2 and core 1, respectively, of mitochondrial
      ubiquinol-cytochrome c oxidoreductase complex. The enzyme specifically recognizes
      a large variety of mitochondrial precursor proteins and is cleaved at a single
      and specific site. In this review, I will focus on recognition mechanisms of
      precursor proteins by MPP. Structural characteristics of the precursor
      responsible for the recognition by MPP, role of each subunit, and amino acid
      residues of MPP involved in the recognition are discussed.

PMID- 10600470
TI  - 5-Lipoxygenase upregulation by dexamethasone in human mast cells.
AB  - In spite of intensive research, our understanding of the regulation of expression
      of 5-LO (the key enzyme in the leukotriene metabolism) remains fragmentary. We
      investigated the effects of dexamethasone on the expression of this gene in a
      binary model consisting of two clones of the human mast cell line HMC-1, one with
      a 5-LO-negative and the other with a 5-LO-positive phenotype, respectively. When
      dexamethasone was included in the culture medium at a physiologically relevant
      concentration, biosynthesis of 5-LO derivatives increased considerably not only
      in the 5-LO-negative HMC-1 cells (approx 10-fold) but also in the 5-LO-positive
      cells, characterized by an already substantial enzyme activity. Consistently,
      Northern blot analysis revealed that a dramatic increase in the abundance of 5-LO
      mRNA occurred when the cells were exposed to dexamethasone. Likewise, a
      significant increase in the immunoreactive 5-LO protein was detected by Western
      blotting. In contrast, dexamethasone seemed to have no effect on the expression
      of two other genes of pivotal importance in leukotriene biosynthesis, viz. FLAP
      and LTC(4) synthase. We conclude that in human mast cells glucocorticoids
      effectively and selectively upregulate the expression of 5-LO.

PMID- 10600471
TI  - Two interaction modes of the gp41-derived peptides with gp41 and their
      correlation with antimembrane fusion activity.
AB  - Peptides derived from gp41 effectively block the gp41-mediated cell fusion or HIV
      infection. A 36-mer (naDP178), 51-mer (C51) and 27-mer peptide (C27) from the
      membrane proximal region of gp41 have been examined their interaction modes with
      the coiled-coil motif of gp41 presented in thioredoxin (Trx-N) or the bacterially
      expressed ectodomain of gp41 (Ec-gp41ec). All of these peptides effectively
      inhibited the gp41-mediated membrane fusion, however, they showed distinct
      interaction modes with Ec-gp41ec or Trx-N. C51 peptide bound tightly to Trx-N,
      and it increased the solubility of Ec-gp41ec. naDP178 showed very weak binding
      affinity to Trx-N, however, it effectively solubilized Ec-gp41ec. In contrast,
      C27 peptide showed significant binding to Trx-N; however, it did not affect the
      solubility of Ec-gp41ec. These interaction modes of C-peptides were assumed to be
      related to their different inhibitory mechanism against gp41-mediated cell
      fusion.

PMID- 10600472
TI  - SNX5, a new member of the sorting nexin family, binds to the Fanconi anemia
      complementation group A protein.
AB  - The function of the Fanconi anemia complementation group A (FANCA) protein
      remains unclear. To investigate possible protein-protein interactions, we
      performed yeast two-hybrid screening using a FANCA fragment as bait. Sorting
      nexin 5 (SNX5), a new member of the human SNX family, was identified as a
      putative FANCA-binding protein. The interaction between FANCA and SNX5 was
      confirmed by immunoprecipitation studies. All members of the SNX family have a
      characteristic amino acid region termed the phox homology (PX) domain. Deletion
      mutant analysis indicated that the PX domain is not required for binding to
      FANCA. The SNX proteins are thought to play an important role in receptor
      trafficking between organelles. We found that overexpression of SNX5 increased
      FANCA protein levels. Northern blot analysis of SNX5 showed the presence of
      alternatively spliced transcripts and different expression patterns in various
      human cancer cell lines and normal tissues. Further studies are needed to
      elucidate the functional significance of FANCA and SNX5 binding; however, we
      speculate that FANCA may affect SNX5 traffic with cell surface receptors.

PMID- 10600473
TI  - A novel function of VEGF receptor-2 (KDR): rapid release of nitric oxide in
      response to VEGF-A stimulation in endothelial cells.
AB  - VEGF-A induces angiogenesis and regulates endothelial function via production and
      release of nitric oxide (NO), which is produced by endothelial nitric oxide
      synthase (eNOS). While the upregulation of eNOS expression has been shown to be
      mediated via VEGF receptor KDR, there is controversy about which of the VEGF
      receptors triggers the release of nitric oxide in endothelial cells. In order to
      determine the levels of NO produced in response to VEGF-A stimulation in
      different endothelial cells, a reporter assay measuring the formation of cGMP as
      the direct product of NO-induced activation of guanylate cyclase was performed.
      Using two independent experimental strategies, we were able to prove that VEGF
      receptor KDR, but not VEGF receptor Flt-1, can induce NO release in endothelial
      cells. First, we made use of porcine aortic endothelial cells (PAE) expressing
      either KDR or Flt-1. While KDR-expressing PAE/KDR cells responded to VEGF-A
      stimulation with a significant elevation of intracellular cGMP already after 2
      min, Flt-1-expressing PAE/Flt-1 cells did not show any signal in this RIA-based
      cGMP assay. In a second experimental strategy freshly isolated human umbilical
      vein endothelial cells (HUVEC) were stimulated either with the KDR-specific
      ligand VEGF-E or with the Flt-1-specific ligand PIGF-2. VEGF-E induces cGMP
      elevation in this setting, while PIGF-2 was unable to do so, clearly
      demonstrating that KDR is responsible for NO release in endothelial cells. In our
      assays cGMP formation is fully dependent on NO generation since the NOS inhibitor
      L-NAME can block this VEGF-A-induced action. These data show that the VEGF
      receptor KDR is responsible for NO release in endothelial cells, highlighting a
      new function of KDR and further supporting the importance of KDR in the
      regulation of the vasculature.

PMID- 10600474
TI  - Phosphatidylcholine-dependent phospholipase C in rat liver chromatin.
AB  - Phosphatidylcholine-dependent phospholipase C is an enzyme which hydrolyses
      phosphatidylcholine giving origin to diacylglicerol and phosphorylcholine.
      Diacylglicerol has many effect and activates also protein kinase C. Since the
      presence of protein kinase C in the hepatocyte nuclei and the existence of a
      phospholipidic fraction in the chromatin have been demonstrated, we investigated
      if phosphatidylcholine-dependent phospholipase C could be present in the nuclei.
      The results obtained have shown the presence of this enzyme in the chromatin
      fraction which differs with respect to that of nuclear membrane in pH and Km. The
      activity has been also evaluated during liver regeneration. In the chromatin an
      increase of activity has been shown 12 h and 30 h after hepatectomy, i.e. at the
      beginning of hepatocyte S-phase. No similar behaviour has been observed in the
      nuclear membrane. It has been suggested that diacylglicerol, produced by the
      hydrolysis of chromatin phosphatidylcholine, may have a role in initiating DNA
      synthesis through the prolonged activation of the nuclear form of protein kinase
      C.

PMID- 10600475
TI  - Inhibition of transcription of class II, but not class III and I, genes in
      Xenopus postblastular embryos overexpressed with the TBP-binding protein, Dr1
      (NC2beta).
AB  - Dr1 (NC2beta) is known to effectively repress transcription of class II genes,
      and much less effectively class III genes, but not class I genes through its
      binding to the TATA-binding protein (TBP), which is the major component of the
      basal transcription factor for polymerases II, III, and I. Previously, we
      isolated Xenopus Dr1 cDNA, and demonstrated that its mRNA is transcribed in
      oocytes and is inherited into early embryos, but its level decreases in later
      stages. Here, we overexpressed Xenopus Dr1 in Xenopus embryos and, found that the
      overexpression significantly reduces the levels of poly(A), cytoskeletal actin
      and histone H4 mRNAs, and the labeling of heterogeneous mRNA-like RNA in
      postblastular embryos, without affecting tRNA and rRNA syntheses. These results
      indicate that the overexpressed Dr1 specifically down-regulates the transcription
      of class II, but not class III and I, genes, and suggest that Dr1 plays an
      important role in the control of transcription in Xenopus embryogenesis.

PMID- 10600476
TI  - New insight into abnormal prion protein using monoclonal antibodies.
AB  - Studies of abnormal prion protein (PrPres) are hindered by the lack of specific
      monoclonal antibodies (mAbs), and the relationships between PrPres, infectivity,
      and strain specificity in prion diseases are still subject to debate. We have
      studied PrPres with new mAbs produced against PrP in mice using various
      immunization strategies. PrPres was analyzed by Western blot with different prion
      strains in various hosts. Differences in the electrophoretic pattern of human
      PrPres revealed by these antibodies provide new insight into PrPres cleavage by
      proteases and interpretation of strain typing. This study confirms that the N
      terminal extremity of PrPres is differentially sensitive to proteases.
      Conversely, the C-terminal extremity, which resists proteolysis, seems to be
      abnormally detectable by antibodies in ultrastructural studies. This work
      confirms the highly complex role of PrPres in prion diseases and provides new
      tools which will be made available to facilitate progress in qualitative and
      quantitative studies of PrP.

PMID- 10600477
TI  - Mice lacking Pin1 develop normally, but are defective in entering cell cycle from
      G(0) arrest.
AB  - The peptidyl prolil cis/trans isomerase Ess1/Pin1 is essential for mitosis
      progression in yeast cells and is hypothesized to perform the same role in
      mammalian cells. To investigate the function of Pin1 in mammalian cells, we
      created mice lacking Pin1. These mice underwent normal development. Although the
      embryonic Pin1-/- fibroblasts grew normally, they proved significantly deficient
      in their ability to restart proliferation in response to serum stimulation after
      G(0) arrest. These results suggest that Pin1 is required for cell cycle
      progression from G(0) arrest as well as mitosis progression in normal mammalian
      cells.

PMID- 10600478
TI  - Differential regulation of immediate early gene expression in preadipocyte cells
      through multiple signaling pathways.
AB  - Using digoxigenin (DIG)-based differential hybridization, a series of immediate
      early genes (IEG) was identified following the adipogenic stimulation in 3T3-L1
      preadipocyte cells. Most of the known IEGs were identified as well as new members
      such as zf9 and Stra13. To delineate possible signaling pathways accounting for
      these gene expression, a subset of specific kinase inhibitors, SB203580, PD98059,
      rapamycin, LY294002, and Ro-32-0432, which inhibit p38 (HOG), MEK (MAPKK), S6
      kinase, PI3 kinase, and protein kinase C (PKC), respectively, were employed. The
      IEGs were classified into three categories according to their susceptibility to
      the inhibitors. Expression of the first group (c-fos, jun-B, egr-1, tis11, tis21,
      thrombospondin-1, erp, thyroid hormone receptor [N-10], cyr61, and zf9) was
      mainly dependent on PKC and MEK pathways, while that of the second class (gene33
      and tis10) exhibited an additional dependence on PI3 kinase pathways. The third
      one (Id-3, gly96, and Stra13) was characterized in that none of these inhibitors
      interfered with gene expression. Our results suggest that the induction of IEGs
      by the adipogenic stimuli is mediated by common as well as distinct signaling
      pathways.

PMID- 10600479
TI  - Suppression of activin-induced apoptosis by novel antisense strategy in human
      prostate cancer cells.
AB  - Apoptosin, a novel gene encoding a mitotic kinase-motif protein, is stimulated by
      activin, a member of TGF-beta family, in human LNCaP prostate cancer cells and in
      patient tissues. We employed a gene knockout methodology based on the covalent
      bonding of chemically modified antisense probes to apoptosin mRNAs in LNCaP
      cells. The mRNA-antisense hybrid duplexes were neither translated nor post
      transcriptionally modified, resulting in no protein synthesis. Introducing
      antisense apoptosin into activin-induced apoptotic LNCaP cells prevented
      apoptosis, interfered with genomic DNA fragmentation and released cell cycle
      checkpoint. These findings suggest that the apoptosin, in addition to p53, is
      important in apoptotic regulation of human prostate cancers.

PMID- 10600480
TI  - Constitutive secretion of an endogenous insulin-like peptide binding protein with
      high affinity for insulin in Spodoptera frugiperda (Sf9) cell cultures.
AB  - Serum-free medium from batch cultures of Sf9 insect cells was examined for the
      occurrence of proteins related to the insulin-like growth factor family. We found
      that the Sf9 cell line constitutively produced and secreted a soluble protein
      with a MW of 27 kDa that exerted specific binding to human insulin-like growth
      factor-I (IGF-I) and -II. Moreover, the secreted protein bound human insulin and
      human proinsulin with higher affinity than IGF-I and -II. The order of affinity
      to the insulin peptides, determined by competitive inhibition of ligand binding,
      was: insulin > proinsulin > IGF-I >> IGF-II. The dissociation constant (k(d)) for
      IGF-II was 28.5 +/- 1.7 nM and for insulin 7.2 +/- 1.3 nM, as determined by
      Scatchard plot analysis. The results suggest that the Sf9 cells produce an
      insulin binding protein similar to the human insulin-like growth factor binding
      protein-related protein 1 (IGFBP-rP1).

PMID- 10600481
TI  - Localization of glycosaminoglycan substitution sites on domain V of mouse
      perlecan.
AB  - Perlecan, the predominant basement membrane proteoglycan, has previously been
      shown to contain glycosaminoglycans attached at serine residues, numbers 65, 71,
      and 76, in domain I. However, the C-terminal domains IV and V of this molecule
      may also be substituted with glycosaminoglycan chains, but the exact substitution
      sites were not identified. The amino acid sequence of mouse perlecan reveals many
      ser-gly sequences in these domains that are possible sites for glycosaminoglycan
      substitution. We expressed recombinant domain IV and/or V of mouse perlecan in
      COS-7 cells and analyzed glycosaminoglycan substitution. Both heparan sulfate and
      chondroitin sulfate chains could be detected on recombinant domain V. One site,
      ser-gly-glu (serine residue 3593), toward the C-terminal region of domain V is a
      substitution site for heparan sulfate. When this sequence was absent,
      chondroitin/dermatan sulfate substitution was deleted, and the likely site for
      this galactosaminoglycan substitution was ser-gly-ala-gly (serine residue 3250)
      on domain V.

PMID- 10600482
TI  - Transfection analysis of functional roles of complexin I and II in the exocytosis
      of two different types of secretory vesicles.
AB  - Classical neurotransmitters such as gamma-aminobutyric acid and glutamate are
      released from synaptic nerve terminals by exocytosis of synaptic vesicles. PC12
      cells also have SSVs capable of storing acetylcholine (ACh). A novel method to
      examine the effect of transient transfection of any gene of interest on the
      exocytosis of SSVs was developed. The transfection of choline acetyltransferase
      (ChAT) into PC12 cells which have lost ACh synthesizing activity resulted in the
      accumulation of a substantial amount of ACh. Synthesized ACh was released in
      Ca(2+)-dependent manner. Release was thought to occur by an exocytosis of SSVs
      because: (1) release was abolished by treating the cells with vesamicol, a
      specific inhibitor of the vesicular ACh transporter (VAChT) localizing
      specifically in SSVs; and (2) the release was further increased by cotransfecting
      rat VAChT with the ChAT. By means of this method, we showed that overexpression
      of complexin I or II with ChAT markedly suppressed high-K(+)-dependent ACh
      release of SSVs.

PMID- 10600483
TI  - Increased cytosolic Ca(2+) concentration in endothelial cells by calmodulin
      antagonists.
AB  - Many functions of endothelial cells are Ca(2+)/calmodulin dependent, whereas the
      role of calmodulin in the regulation of cytosolic Ca(2+) ([Ca(2+)](i)) remains
      largely unexplained. In the present study, effects of various calmodulin
      antagonists on [Ca(2+)](i) were investigated in cultured aortic endothelial cells
      loaded with the Ca(2+)-sensitive dye fura-2/AM, and were compared with those of
      calmodulin-dependent protein kinase II (CaM kinase II) inhibitors. The calmodulin
      antagonists W-7, calmidazolium and fendiline provoked dose-dependent increases in
      [Ca(2+)](i). However, the CaM kinase II inhibitors KN-93 and lavendustin C had no
      effect on [Ca(2+)](i). In the absence of extracellular Ca(2+), pretreatment of
      cells with bradykinin (BK) and thapsigargin completely prevented W-7-stimulated
      increase in [Ca(2+)](i). Alternatively, pretreatment with W-7 also completely
      blocked BK- and thapsigargin-stimulated increases in [Ca(2+)](i). The time course
      of the Ca(2+)-response in W-7 treated cells was identical to that in thapsigargin
      treated cells, but not that in BK-stimulated cells, suggesting that calmodulin
      antagonists could share a common signaling pathway with thapsigargin to increase
      [Ca(2+)](i) in endothelial cells. These findings indicate that calmodulin is
      involved in the regulation of [Ca(2+)](i), and may play an important role in the
      uptake of Ca(2+) to intracellular stores.

PMID- 10600484
TI  - Isolation and characterization of a mannan-binding lectin from the freshwater
      cyanobacterium (blue-green algae) Microcystis viridis.
AB  - Microcystis viridis NIES-102 strain, a unicellular freshwater bloom-forming
      cyanobacterium, showed transient hemagglutinating activity in laboratory culture
      during stationary phase under nonaeration conditions. However, the
      hemagglutinating activity which was inhibited with yeast mannan could not be
      observed during culture with aeration. A mannan-binding lectin named MVL was
      isolated with the assay of the hemagglutinating activity against rabbit
      erythrocytes from the cyanobacterium by successive hydrophobic and gel filtration
      chromatography. MVL was composed of a single polypeptide of 13 kDa. The gene
      (mvl) for MVL was cloned from a genomic DNA of NIES-102 strain as a template, and
      its sequence was determined. The deduced amino acid sequence showed that MVL
      consisted of 113 amino acid residues and was composed of two tandemly repeated
      homologous domains of 54 amino acid residues. MVL showed no sequence homology to
      any other lectins or proteins.

PMID- 10600485
TI  - Annexin V counteracts apoptosis while inducing Ca(2+) influx in human lymphocytic
      T cells.
AB  - We have previously shown that when annexin V is present during the execution of a
      cell death program, apoptosis is delayed. This is reflected by the inhibition of
      DNA cleavage and of the release of apoptotic membrane particles, and by reduction
      of the proteolytic processing of caspase-3. Here, we have studied the
      mechanism(s) through which annexin V counteracts apoptosis in the human CEM T
      cell line. The degree of apoptosis inhibition was associated with an increase of
      intracellular Ca(2+) concentration ([Ca(2+)](i)). Reduction of the extracellular
      Ca(2+) concentration by EGTA abolished the anti-apoptotic effect, suggesting that
      annexin V favors Ca(2+) influx and that Ca(2+) acts as an inhibitor rather than
      an activator of apoptosis in CEM T cells. The effects on apoptosis and
      [Ca(2+)](i) of several modified annexins with different electrophysiological
      properties indicate that the N-terminal domain of annexin V is necessary for the
      Ca(2+)-dependent anti-apoptotic action of annexin V. These results suggest that
      annexin V regulates membrane Ca(2+) permeability and is protective against
      apoptosis by increasing [Ca(2+)](i) in CEM T cells.

PMID- 10600486
TI  - Expression of full-length NBS1 protein restores normal radiation responses in
      cells from Nijmegen breakage syndrome patients.
AB  - Cells from Nijmegen breakage syndrome (NBS) display multiple phenotypes, such as
      chromosomal instability, hypersensitivity to cell killing from ionizing
      radiation, and possibly abnormal cell cycle checkpoints. NBS1, a gene mutated in
      NBS patients, appears to encode a possible repair protein, which could form the
      foci of a sensor-like molecular complex capable of detecting DNA double strand
      breaks, however, it has no kinase domain for signaling DNA damage. Here, we
      report that the stable expression of NBS1 cDNA in NBS cells after transfection
      results in the complete restoration of foci formation in the nucleus, and in
      normal cell survival after irradiation. The prolonged G2 block observed after
      irradiation was also abolished by expression of NBS1, providing additional
      confirmation that the G2 checkpoint is abrogated in NBS cells. These results
      suggest that a defective NBS1 protein could be the sole cause of the NBS
      phenotype, and that NBS1 likely interacts with another protein(s) to produce the
      entire range of NBS phenotypic expression.

PMID- 10600487
TI  - The regulation of caveolin expression and localization by serum and heparin in
      vascular smooth muscle cells.
AB  - Caveolae have been implicated in growth factor receptor and G-protein coupled
      receptor signaling in vascular cells. It has been postulated that caveolin, the
      structural protein of caveolae, may act as a general tyrosine kinase inhibitor by
      binding and inhibiting signaling molecules involved in the activation of the MAP
      kinase proliferation cascade. Using an in vitro model of VSMC proliferation, we
      found that serum stimulation caused a dose dependent decrease in both caveolin-1
      and caveolin-2 protein levels in human coronary artery smooth muscle cells.
      Heparin, an inhibitor of VSMC proliferation, inhibited the serum-induced loss of
      caveolin-1 and caveolin-2. In addition, heparin caused an increase in both
      caveolin-1 and caveolin-2 localization to caveolae-enriched sucrose gradient
      membrane fractions when compared to serum alone. Taken together, caveolin may
      play an important role in the regulation of VSMC proliferation and heparin and
      serum have opposing effects on caveolin expression and localization in VSMC.

PMID- 10600488
TI  - Phorbol ester reduces phosphorylation of epidermal growth factor receptor in
      pancreatic cancer cells by activation of a tyrosine phosphatase.
AB  - In this study we report that phorbol 12-myristate 13-acetate (PMA) transiently
      reduced the level of EGF receptor tyrosine phosphorylation in three pancreatic
      cancer cell lines (HPAC, SW1990, and UCVA-1) in response to EGF. The effect was
      maximal at 40-90 min. Pretreatment with the protein kinase C inhibitor GF 109203X
      reduced the PMA effect. Flow cytometry experiments showed that PMA produced only
      a slight reduction in the surface expression of EGF-R. The phosphotyrosine
      phosphatase inhibitor bpV(phen) returned phosphorylation to almost control
      levels. Moreover, homogenates of PMA treated pancreatic cells reduced the
      phosphorylation of activated receptor that was immunoprecipitated from A431
      epidermoid cells. A combination of orthovanadate and NaF or bpV(phen) inhibited
      the effect of the homogenates. These results suggest that PMA activates a
      phosphotyrosine phosphatase activity that reduces the steady-state level of
      tyrosine phosphorylation of the receptor that is induced by EGF.

PMID- 10600489
TI  - Synthetic phytanyl-chained glycolipid vesicle membrane as a novel matrix for
      functional reconstitution of cyanobacterial photosystem II complex.
AB  - The vesicles composed of synthetic phytanyl-chained glycolipid and natural
      sulfoquinovosyldiacylglycerol at 9:1 molar ratio were successfully applied to
      functional reconstitution of photosystem II complex (PS II) from a thermophilic
      cyanobacterium. The synthetic glycolipid employed was one of our model archaeal
      diether lipids, 1, 3-di-O-phytanyl-2-O-(beta-D-maltotriosyl)glycerol. The light
      induced oxygen-evolving activity of PS II reconstituted in the glycolipid
      vesicles was approximately 6-fold higher than that reconstituted in several
      phosphatidylcholine vesicles. The present results reveal the first evidence that
      a well-designed synthetic glycolipid is effective for the functional
      reconstitution of complicated and labile membrane protein complexes, such as PS
      II.

PMID- 10600490
TI  - Novel exons located more than 200 kb downstream of the previously described 3'
      exon of the K-sam gene for generating activated forms of KGF receptor.
AB  - The K-sam gene was first identified as an amplified gene in the poorly
      differentiated types, especially in the scirrhous type, of gastric cancers. We
      have recently found and reported that the carboxyl-terminal exons of K-sam are
      frequently deleted in the scirrhous type of gastric cancer. The deletion
      generates preferential expression of at least six novel K-sam-II mRNAs: K-sam
      IIH1, -IIH2 and -IIH3/O4, and K-sam-IIO1, -IIO2, and -IIO3, which encode novel
      proteins lacking the transformation-inhibitory sequence or activated K-sam
      proteins. In this study, we investigated expression of the previously described K
      sam-IIC1 and -IIC3 mRNAs and the novel six K-sam-II mRNAs in 14 gastric cancer
      cell lines, 7 breast cancer cell lines, and 20 human normal tissues. All the six
      novel K-sam-II mRNAs were expressed preferentially in the cell lines derived from
      the scirrhous type of gastric cancers but not in the 7 breast cancer cell lines
      and the 20 human normal tissues. We further determined the positional
      relationship of four exons of H1, O1, O2, and O3 out of the six exons of H1, H2,
      H3/O4, O1, O2, and O3, and found that these four novel K-sam exons were located
      more than 200 kb downstream of the previously described carboxyl-terminal exon of
      the K-sam gene. Expression of K-sam-IIH1, -IIO1, and -IIO2 mRNAs encoding
      activated K-sam products in the scirrhous type of gastric cancer cell lines
      HSC39, OCUM2M, HSC59, and HSC60 was not due to the deletion of the C1 exon of K
      sam.

PMID- 10600491
TI  - Formation of four isomers at the asp-151 residue of aged human alphaA-crystallin
      by natural aging.
AB  - Although proteins are generally composed entirely of l-amino acids, we have
      previously shown that Asp-151 in alphaA-crystallin from aged human lens is
      converted to the biologically uncommon d-isomer to a high degree. The formation
      of d-isomer was not simple racemization, but stereoinvertion. The reaction was
      also accompanied with isomerization to form beta-Asp (isoaspartate) residue
      simultaneously; therefore, four isomers of Asp-151, normal l-alpha-Asp and
      biologically uncommon l-beta-Asp, d-alpha-Asp, and d-beta-Asp, are formed in
      alphaA-crystallins. In the present study, we measured the ratio of the four
      isomers of Asp-151 in alphaA-crystallins obtained from total lens proteins of
      human lenses of newborn and 30-, 60-, and 80-year-olds. The isomers increased
      with age, and the total amount of three isomers was more than that of normal l
      alpha-Asp in the alphaA-crystallin of the human lenses of the 80-year-olds. These
      drastic changes started at birth, with about 45% of normal l-alpha-Asp lost by 30
      years. These modifications of the Asp residue likely affect the three-dimensional
      packing array of the lens proteins.

PMID- 10600492
TI  - Involvement of epidermal growth factor-like domain of NELL proteins in the novel
      protein-protein interaction with protein kinase C.
AB  - NELL proteins are the thrombospondin-1-like proteins that are strongly expressed
      in neural tissues, containing six epidermal growth factor (EGF)-like domains. By
      radiolabeling of the NELL protein-expressing COS-7 cells with
      [(32)P]orthophosphate, here we demonstrate that NELL proteins are synthesized as
      phosphoproteins by interacting with protein kinases in the cells. By
      immunoprecipitation and in vitro phosphorylation assays, we have also found that
      NELL proteins expressed in COS-7 cells are associated with and phosphorylated by
      protein kinase C betaI (PKCbetaI). Further analysis using various deletion
      mutants of NELL proteins by the yeast two-hybrid assay has revealed their EGF
      like domains to be involved in the isoform-specific interaction with PKC.
      Conversely, the NH(2)-terminal variable region of PKC isoforms has been found
      essential for the interaction with NELL proteins. Because NELL proteins are
      expressed mainly in the cytoplasm of neuronal cells, unlike most EGF-like domain
      containing extracellular proteins, the novel protein-protein interaction
      identified here between the EGF-like domains of NELL proteins and PKC suggests
      that EGF-like domains of intracellular proteins can be a target of PKC that
      mediates various signaling pathways.

PMID- 10600493
TI  - The early phase of apoptosis in human neuroblastoma CHP100 cells is characterized
      by lipoxygenase-dependent ultraweak light emission.
AB  - Human neuroblastoma CHP100 cells were forced into apoptosis (programmed cell
      death, PCD) or necrosis by treatment with calcium chloride or sodium
      nitroprusside (a nitric oxide donor), respectively. Cellular luminescence, a
      marker of membrane lipid peroxidation, was increased by calcium but not by
      nitroprusside, and reached a maximum of 4-fold the control value 2 hours after
      treatment. The increase in luminescence was paralleled by increased 5
      lipoxygenase (up to 250% of the control value) and decreased catalase (down to
      50%) activity within the same time window. Consistently, incubation of CHP100
      cells with inhibitors of 5-lipoxygenase (5,8,11,14-eicosatetraynoic acid and
      MK886) reduced light emission and PCD, whereas inhibition of catalase by 3-amino
      1, 2,4-triazole enhanced both processes. Treatment of CHP100 cells with retinoic
      acid or cisplatin, unrelated PCD inducers reported to activate the lipoxygenase
      pathway, also gave enhanced light emission parallel to PCD increase. Altogether,
      these results suggest that cellular luminescence is an early marker of apoptotic,
      but not necrotic, program(s) involving generation of hydrogen peroxide and
      activation of 5-lipoxygenase.

PMID- 10600494
TI  - Differential temperature dependency of chemical stressors in HSF1-mediated stress
      response in mammalian cells.
AB  - Expression of stress proteins is generally induced by a variety of stressors. To
      gain a better understanding of the sensing and induction mechanisms of stress
      responses, we studied the effects of culture temperature on responses to various
      stressors, since the induction of hsp70 in mammalian cells by heat shock is
      somehow modulated by culture temperature. Hsp70 was not induced by treatment with
      sodium arsenite, azetidine-2-carboxylic acid, or zinc sulfate at the level of
      heat shock factor (HSF) 1 activation in cells incubated at low temperature,
      although these treatments induced hsp70 in cells incubated at 37 degrees C. The
      repression of sodium arsenite or zinc sulfate-induced HSF1 activation by low
      temperature was not simply due to the inhibition of protein synthesis. On the
      other hand, heat shock and iodoacetamide induced HSF 1 activation in cells
      incubated at either temperature. Thus, there seem to be two kinds of stressors
      that induce HSF1 activation independently of or dependent on culture temperature.
      Furthermore, the reduction of glutathione level seemed to be essential for HSF1
      activation by chemical stressors.

PMID- 10600495
TI  - Distantly related cousins of MAP kinase: biochemical properties and possible
      physiological functions.
AB  - MAP kinases have been established to be key regulators of cellular signal
      transduction systems and are conserved from baker's yeast to human beings. Until
      now, three major types of mammalian MAP kinases (ERK, p38, and JNK/SAPK) have
      been reported and extensively studied. Advancement of genomic research as well as
      homology cloning techniques has revealed that there are several other protein
      kinase families that are structurally modestly related to those conventional MAP
      kinases. Indeed, most of them possess the TXY motif characteristic to MAP kinases
      in their activation loop, and can be regarded as members of the MAP kinase
      superfamily, yet some of them show closest overall similarity to Cdks. These
      kinases, all of mammalian origin, include MAK, MRK, MOK, p42KKIALRE, p56KKIAMRE,
      NLK, DYRK/Mnb, and Prp4. Although most of their physiological roles remain
      unknown, recent progress starts shedding some light on their functions.

PMID- 10600496
TI  - ROCK inhibitor Y-27632 attenuates stellate cell contraction and portal pressure
      increase induced by endothelin-1.
AB  - By using a selective ROCK inhibitor Y-27632, the role of Rho-ROCK signaling in
      the function of hepatic stellate cells in culture was studied. Stellate cells
      maintained the "star-like" configuration of the quiescent stage in the presence
      of Y-27632, while the expression of smooth muscle alpha-actin and PDGF receptor
      beta was not affected by the agent. Serum-stimulated migration of the cells was
      significantly suppressed by Y-27632. The contraction of stellate cells induced by
      5 nM endothelin-1 was attenuated by the agent in a dose-dependent manner.
      Formation of F-actin stress fibers and phosphorylation of myosin light chain was
      apparently reduced by Y-27632 even under the stimulation with endothelin-1. On
      the other hand, ex vivo liver perfusion experiment revealed that endothelin-1 (2
      nM)-induced increase of portal vein constriction was almost completely inhibited
      by 20 microM Y-27632 with a concomitant improvement of hepatocyte degeneration.
      These results suggest that ROCK is one of the key regulators of stellate cell
      motility and that the clinical application of ROCK inhibitors such as Y-27632
      should be considered in the reduction of portal hypertension in liver fibrosis
      and cirrhosis.

PMID- 10600497
TI  - A kinetic epoxidation assay for chloroperoxidase.
AB  - Chloroperoxidase exhibits a wide variety of enantioselective epoxidation
      reactions. Until now, the epoxidation activities have been mainly evaluated using
      elaborate gas chromatographic methods. This paper reports a rapid and convenient
      spectrophotometric assay for CPO. The disappearance of indene by catalytic
      epoxidation is monitored at 250 nm and this is used as an index of enzyme
      activity. This method will prove to be highly useful in large-scale screening of
      mutants.

PMID- 10600498
TI  - The role of phosphatidylinositol 3-kinase, Src kinase, and protein kinase A
      signaling pathways in insulin and glucagon regulation of CYP2E1 expression.
AB  - The signaling pathways involved in insulin and glucagon regulation of CYP2E1
      expression were examined in primary cultured rat hepatocytes. Insulin addition to
      primary cultured rat hepatocytes for 24 h resulted in an approximately 80% and
      >90% decrease in CYP2E1 mRNA levels at 1 and 10 nM insulin, respectively,
      relative to untreated cells. Addition of the phosphatidylinositol 3-kinase
      inhibitor wortmannin, or the Src kinase inhibitor geldanamycin, prior to insulin
      addition, inhibited the insulin-mediated decline in CYP2E1 mRNA. In contrast,
      treatment of cells with glucagon (100 nM), or the cAMP analogue dibutyryl-cAMP
      (50 microM), for 24 h increased CYP2E1 mRNA levels by approximately 7-fold.
      Addition of the protein kinase A inhibitor H89 prior to glucagon treatment
      attenuated the glucagon-mediated increase in CYP2E1 mRNA by approximately 70%.
      Glucagon (100 nM) opposed the effects of insulin (1 nM) on CYP2E1 mRNA expression
      and conversely, insulin blocked the effects of glucagon. These data provide
      compelling evidence for the regulation of CYP2E1 expression via mutually
      antagonistic signaling pathways involving insulin and glucagon.

PMID- 10600499
TI  - Identification of substrate sequences for membrane type-1 matrix
      metalloproteinase using bacteriophage peptide display library.
AB  - Membrane type-1 matrix metalloproteinase (MT1-MMP) has been reported to mediate
      the activation of progelatinase A (proMMP-2) which is associated with tumor
      invasion and metastasis, and also known to have an ability to digest
      extracellular matrix components. To clarify substrate specificity of MT1-MMP, we
      have searched for amino acid sequences cleaved by this protease using the hexamer
      substrate phage library consisting of a large number of randomized amino acids
      sequences. The consensus substrate sequences for MT1-MMP were deduced from the
      selected clones and appeared to be P-X-G/P-L at the P3-P1' sites. Peptide
      cleavage assay revealed that MT1-MMP preferentially digested a synthetic
      substrate containing Pro of the P1 position compared to that being substituted
      with Gly. Our results may have an important implication to identifying new target
      proteins for MT1-MMP and leading to the design of its selective inhibitors
      suitable for cancer chemotherapy.

PMID- 10600500
TI  - Eukaryotic initiation factor 4B from wheat and Arabidopsis thaliana is a member
      of a multigene family.
AB  - Clones of eukaryotic initiation factor (eIF) 4B from wheat and Arabidopsis
      thaliana were obtained from cDNA and genomic libraries. The exon/intron
      organization of the genes from wheat and A. thaliana is very similar. The deduced
      amino acid sequences for the wheat and Arabidopsis eIF4B proteins showed overall
      similarity to each other, but very little similarity to eIF4B from other
      eukaryotes. The recombinant form of eIF4B supports polypeptide synthesis in an in
      vitro translation system and reacts with antibodies to native wheat eIF4B. In
      contrast to mammalian eIF4B and eIF4A, the combination of wheat eIF4B and eIF4A
      does not stimulate RNA-dependent ATP hydrolysis activity; however, wheat eIF4B
      does stimulate eIF4F and eIF4A RNA-dependent ATP hydrolysis activity.
      Interestingly, eIF4B does not stimulate eIF(iso)4F and eIF4A hydrolysis activity.
      Gel filtration experiments indicate wheat eIF4B, like its mammalian counterpart,
      self-associates to form a homodimer.

PMID- 10600501
TI  - Characterization of 2,6-dichloro-p-hydroquinone 1,2-dioxygenase (PcpA) of
      Sphingomonas chlorophenolica ATCC 39723.
AB  - Pentachlorophenol (PCP) is a general biocide and a major environmental pollutant.
      The initial steps of PCP degradation by Sphingomonas chlorophenolica ATCC 39723
      have been studied and characterized. Two enzymes are responsible for converting
      PCP to 2, 6-dichloro-p-hydroquinone (2,6-DiCH) which is a common metabolic
      intermediate of the biodegradation of polychlorinated phenols. 2, 6-DiCH is
      degraded by PcpA from strain ATCC 39723, but the reaction end product has been
      misidentified as 6-chlorohydroxyquinol and has been elusive to detection. We
      report here the overproduction of PcpA in Escherichia coli and the demonstration
      of quantitative conversion of 2,6-DiCH to 2-chloromaleylacetate with the
      coconsumption of one equivalent O(2) and release of one equivalent Cl(-) by
      purified PcpA. On the basis of the reaction stoichiometry, the enzyme is proposed
      to be 2,6-DiCH 1,2-dioxygenase.

PMID- 10600502
TI  - Purification and characterization of a benzo[a]pyrene hydroxylase from Pleurotus
      pulmonarius.
AB  - Cytochrome P450 has been implicated in the process of biotransformation of
      polycyclic aromatic hydrocarbons and of other organic pollutants by white-rot
      fungi. We have purified and reconstituted a benzo[a]pyrene hydroxylating
      cytochrome P450 (P450) from microsomal fractions of the white rot fungus
      Pleurotus pulmonarius. The microsomal P450 was recovered using a combination of n
      aminooctyl agarose and hydroxyapatite chromatography and had an apparent
      molecular mass of 55 kDa. The purified protein exhibited moderate affinity for
      benzo[a]pyrene with a K(s) of 66 microM calculated from the Type I substrate
      binding spectra produced. Reconstitution of activity was achieved and a turnover
      of 0.75 nmol 3-hydroxybenzo[a]pyrene product/min/nmol P450 was observed,
      comparable to levels of metabolism observed by animal cytochromes P450 involved
      in xenobiotic detoxification.

PMID- 10600503
TI  - Incorporation of MAL, an integral protein element of the machinery for the
      glycolipid and cholesterol-mediated apical pathway of transport, into artificial
      membranes requires neither of these lipid species.
AB  - The MAL proteolipid, an integral membrane protein with selective residence in
      glycolipid- and cholesterol-enriched membrane (GEM) microdomains, has recently
      been identified as being an element of the integral protein machinery necessary
      for apical transport in MDCK cells. With the use of a recombinant baculovirus, we
      have expressed and purified polyhistidine-tagged MAL to determine whether MAL has
      special lipid requirements for becoming incorporated into membranes. In contrast
      with caveolin-1, a component of GEMs that requires cholesterol for its
      integration into artificial membranes, MAL incorporation took place with
      dimyristoylphosphatidylcholine as the only lipid component. The presence of
      cholesterol, sphingomyelin, or galactocerebrosides did not affect the efficiency
      of this process. These results indicated that MAL is compatible with membranes
      containing either only phospholipids or also glycolipids and cholesterol and are
      consistent with the reported requirement of a sorting event for the specific
      targeting of MAL to GEM microdomains.

PMID- 10600504
TI  - Inframolecular studies of the protonation of adenophostin A: comparison with 1-D
      myo-inositol 1,4,5-trisphosphate.
AB  - Adenophostin A is a glyconucleotide natural product with the highest known
      potency for the D-myo-inositol 1,4,5-trisphosphate receptor. Using synthetic
      adenophostin A we have investigated the macroscopic and microscopic protonation
      process of this compound by performing (31)P NMR, (1)H NMR, and potentiometric
      titration experiments. The logarithms of the first to the fourth stepwise
      protonation constants are, respectively, log K(1) = 8.48, log K(2) = 6.20, log
      K(3) = 4.96, and log K(4) = 3.80. The latter constant refers to the protonation
      equilibrium involving the N1 adenine nitrogen. From the microconstants the
      protonation fractions of each individual phosphate group can be calculated.
      Remarkably, the ionization state of the phosphates of adenophostin A at near
      physiological pH is very similar to those of inositol 1,4,5-trisphosphate,
      indicating that differences in phosphate charge cannot account for the high
      potency of this molecule. The analysis of the (1)H chemical shifts vs pH provided
      complementary conformational information. In particular, a slight "wrongway
      shift" of H1" can be related to the protonation of P2, thus indicating a short
      H1"-P2 distance. Our results are in line with a recently published model in
      which, however, a certain degree of constraint would keep the ribose 2'-phosphate
      moiety close to the glucose ring phosphates.

PMID- 10600505
TI  - Inflammatory cytokines induced down-regulation of m-calpain mRNA expression in
      fibroblastic synoviocytes from patients with osteoarthritis and rheumatoid
      arthritis.
AB  - Our previous reports revealed that calpain has proteoglycanase activity and
      exists in synovial fluid in osteoarthritis and rheumatoid arthritis. We examined
      the effects of cytokines on expression of the calpain-calpastatin system in
      fibroblastic synoviocytes (FLS). Primary cultures of human FLS from
      osteoarthritis (OA) and rheumatoid arthritis (RA) patients were stimulated with
      inflammatory cytokines and the amounts of m-calpain and calpastatin mRNAs
      expressed were determined by Northern blotting. Northern blots were subjected to
      computerized densitometer and band intensities were determined. Interleukin-1 (IL
      1) down-regulated m-calpain and tissue-type calpastatin mRNA expression in OA and
      RA FLS. In RA FLS, although IL-6 did not alter m-calpain mRNA expression, IL-1 +
      tumor necrosis factor (TNF) and IL-1 + transforming growth factor (TGF) down
      regulated m-calpain mRNA expression. These results provide new information about
      the effects of inflammatory cytokines on calpain and calpastatin system in OA and
      RA pathology.

PMID- 10600506
TI  - Identification and characterization of SorCS, a third member of a novel receptor
      family.
AB  - A novel receptor, SorCS, was isolated from murine brain. It shows homology to the
      mosaic receptor SorLA and the neurotensin receptor sortilin based on a common
      VPS10 domain which is the hallmark of this new receptor family. In the N-terminus
      of SorCS two putative cleavage sites for the convertase furin mark the beginning
      of the VPS10 domain, followed by a module of imperfect leucine-rich repeats and a
      transmembrane domain. The short intracellular C-terminus contains consensus
      signals for rapid internalization. The identified putative binding motifs for SH2
      and SH3 domains are unique in the family of VPS10 domain receptors. SorCS is
      predominantly expressed in brain, but also in heart, liver, and kidney. SorCS
      transcripts detected by in situ hybridization in the murine central nervous
      system point to a neuronal expression.

PMID- 10600507
TI  - Nitric oxide donors selectively potentiate thrombin-stimulated p70(S6k) activity
      and morphological changes in Swiss 3T3 cells.
AB  - Thrombin stimulates both DNA synthesis and cell morphological changes in Swiss
      3T3 cells, although the mechanism of signal coordination leading to these
      responses is unknown. We report here that nitric oxide (NO) donors selectively
      enhance thrombin-stimulated p70(S6k) activity by 40-60%, an effect that was
      sustained for 24 h. Potentiation of p70(S6k) also was observed with cGMP
      analogues indicating that this effect is mediated by cGMP-activated protein
      kinase. NO donors also induced morphological changes characterized by spindle
      shaped cells in confluent, nondividing cells or by extended protrusions from the
      trailing edge in subconfluent, polarized cells. NO donors had no significant
      effects on intracellular Ca(2+) mobilization, DNA synthesis, proliferation, or
      ERKs 1 and 2 and p90RSK activities, indicating that mitogenic responses and cell
      division are not altered by NO donors. We conclude that NO donors modulate the
      morphological changes associated with cellular motility in response to thrombin
      stimulation through selective enhancement of p70(S6k) activity.

PMID- 10600508
TI  - Adriamycin inhibits human RH II/Gu RNA helicase activity by binding to its
      substrate.
AB  - RNA helicases are enzymes important in RNA synthesis, processing, transport, and
      turnover. Human nucleolar RNA helicase II/Gu protein (RH II/Gu) was expressed in
      a baculovirus system. The purified recombinant RH II/Gu protein has RNA helicase
      activity on a 5' tailed ds RNA substrate in vitro. We found that Adriamycin, a
      widely used anticancer drug, inhibited RH II/Gu helicase activity in a dose
      dependent manner with an IC(50) of 40 microM. Adriamycin bound to the RNA
      substrate, and the binding was disrupted by boiling or treatment with 1% SDS,
      suggesting that the binding of Adriamycin to RNA is reversible. Adriamycin was
      also found by gel electrophoresis to bind to yeast tRNA to form slow-migrating
      complexes. These results suggest that Adriamycin can inhibit RNA synthesis or
      processing by binding to RNA substrates.

PMID- 10600509
TI  - Lysozyme association with nucleic acids.
AB  - Lysozyme is well known for the ability to hydrolyze the cell wall of bacteria.
      Based on the similarity of structure between lysozyme and histones as seen from
      the results of X-ray crystal structure determinations, we have postulated that
      binding to nucleic acids may be another biological function of lysozyme. We have
      therefore begun a systematic study of the interactions of lysozyme and related
      molecules with nucleic acids, and present here a preliminary report. Binding to
      DNA and RNA has been demonstrated from gel electrophoresis, enzyme activity, and
      coprecipitation studies. We suggest that this function of lysozyme will provide
      an explanation why Lee-Huang et al. (1999) [Proc. Natl. Acad. Sci. USA 96, 2678
      2681] were able to call lysozyme a "killer protein" against the AIDS virus, and
      may provide a new avenue of research on AIDS therapy.

PMID- 10600510
TI  - Chimeric virus-like particle formation of adeno-associated virus.
AB  - Adeno-associated virus (AAV) capsids are composed of three proteins, VP1, VP2,
      and VP3. These capsid proteins have a common amino acid sequence, being expressed
      from different initiation codons on the same open reading frame. Although VP1 is
      necessary for viral infection, it is not essential for capsid formation. The
      other capsid proteins, VP2 and VP3, are sufficient for capsid formation, but
      their functions are poorly understood. To investigate the role(s) of the capsid
      proteins in capsid formation, we used a baculovirus protein expression system to
      produce virus-like particles (VLPs). We found that varying the ratios of VP2 and
      VP3 did not affect VLP formation. Further, their physical properties were
      equivalent to those of empty wild-type particles. The function of VP3 was studied
      further by fusing a peptide tag, FLAG, to its N-terminus. This chimeric viral
      protein, in combination with VP2, could assemble into VLPs, indicating that the
      chimerism of VP3 did not affect VLP formation. Although the monomeric native form
      of the FLAG-VP3 chimera could react with anti-FLAG antibody, VLP containing the
      chimeric VP3 could not, suggesting that the N-terminal region of VP3 is located
      inside the VLP. These observations indicate that it may be possible to utilize
      AAV VLP as vectors of a broad range of drugs since fusion of the VP3 N-terminus
      with defined molecules could impose distinct physical properties onto the
      internal environment of the VLP.

PMID- 10600511
TI  - Heat-induced G1 arrest is dependent on p53 function but not on RB
      dephosphorylation.
AB  - Normal human cells were heat shocked at 43 degrees C for 2 hr and recovered at 37
      degrees C. The levels of p53 and p21 reached a maximum approximately 2 and 6 hr
      after the heat shock, respectively, and these levels were higher than the control
      level even at 24 hr. The fraction of S phase cells decreased significantly 8 hr
      after heat shock, and gradually thereafter. Heat-induced G1 arrest was not found
      in NCI-H1299 and HeLa cells, which are deficient in p53 function, indicating that
      p53 function is essential for G1 arrest after heat shock. We found little or no
      change in phosphorylation of retinoblastoma (RB) protein until 12 hr after heat
      shock, and a significant change at about 24 hr. No change in phosphorylation of
      RB at serine-780 and serine-795 occurred within 12 hr after heat shock. These
      results suggest that heat shock induces G1 arrest mediated by p53, but that G1
      arrest within 12 hr after heat shock does not require RB dephosphorylation.

PMID- 10600512
TI  - Angiotensin II and retinal pericytes migration.
AB  - Angiotensin II (Ang II) appears to participate in the regulation of
      neovascularization processes in the retina. Migration of perimural cells such as
      pericytes plays a key role in regulation of angiogenesis. We hypothesize that Ang
      II stimulates migration of retina pericytes. For this we studied the effects of
      Ang II on migration of bovine retinal pericytes using modified Boyden chambers
      and collagen IV-covered polyester membranes. Ang II stimulated migration of
      pericytes by 54.8 +/- 9.7% (n = 10, p < 0.001). This effect was blocked by an
      AT(1) receptor antagonist (Losartan) but not by an AT(2) receptor antagonist
      (PD123319). We determined using checkerboard assays (n = 3) that Ang II induces
      migration of pericytes by chemotaxis (gradient-dependent), in opposition to
      chemokinesis (nondirected). Thus, Ang II via its AT(1) receptor acts as a
      chemotactic factor and stimulates migration of retina microvascular pericytes.
      This effect may contribute to Ang II-induced regulation of neovascularization
      processes in the retina.

PMID- 10600513
TI  - Structural analysis and disulfide-bridge pairing of two odorant-binding proteins
      from Bombyx mori.
AB  - Pheromone-binding protein (PBP) and general odorant-binding proteins (GOBPs) were
      purified from the antennae of Bombyx mori and structurally characterised. The
      amino acid sequence of GOBP-2 has been corrected. The disulphide arrangements of
      PBP and GOBP-2 have been determined by a combined mass spectrometric/Edman
      degradation approach. The same cysteine pairings, Cys19-Cys54, Cys50-Cys108, and
      Cys97-Cys117, were found in both proteins, suggesting that such patterns occur
      commonly throughout this family of molecules. This arrangement of disulphide
      bonds indicates that the three-dimensional structure of insect OBPs is defined by
      three loops, rich in helical content, which can vary in size and charge
      distribution from one protein to another.

PMID- 10600514
TI  - Lipoxygenase inhibition induced apoptosis, morphological changes, and carbonic
      anhydrase expression in human pancreatic cancer cells.
AB  - Epidemiologic and animal studies have linked pancreatic cancer growth with fat
      intake, especially unsaturated fats. Arachidonic acid release from membrane
      phospholipids is essential for tumor cell proliferation. Lipoxygenases (LOX)
      constitute one pathway for arachidonate metabolism. We previously reported that 5
      LOX and 12-LOX are upregulated in human pancreatic cancer cells and that blockade
      of these enzymes abolishes pancreatic cancer cell growth. The present study was
      aimed at evaluating the effect of LOX inhibition on differentiation and apoptosis
      in pancreatic cancer cells in parallel with growth inhibition. Four human
      pancreatic cancer cell lines, PANC-1, MiaPaca2, Capan2, and HPAF, were used.
      Apoptosis was evaluated by three separate methods, including DNA propidium iodide
      staining, DNA fragmentation, and the TUNEL assay. Morphological changes and
      carbonic anhydrase activity were used to determine the effect of LOX inhibitors
      on differentiation. The general LOX inhibitor NDGA, the 5-LOX inhibitor Rev5901,
      and the 12-LOX inhibitor baicalein all induced apoptosis in all four pancreatic
      cancer cell lines, as confirmed by all three methods, suggesting that both the 5
      LOX and 12-LOX pathways are important for survival of these cells. Furthermore,
      NDGA, Rev5901, or baicalein resulted in marked cellular morphological changes in
      parallel with increased intracellular carbonic anhydrase activity, indicating
      that LOX blockade induced a more differentiated phenotype in human pancreatic
      cancer cells. Together with our previous findings, this study suggests that
      perturbations of LOX activity affect pancreatic cancer cell proliferation and
      survival. Blockade of LOX enzymes may be valuable for the treatment of human
      pancreatic cancer.

PMID- 10600515
TI  - Identical primary sequence but different conformations of the bioactive regions
      of canine CCK-8 and CCK-58.
AB  - The C-terminal bioactive regions of CCK-8 and CCK-58 are identical (DY*MGWMDF
      NH(2), Y* denotes a sulfated tyrosine residue), but these peptides have different
      patterns of bioactivity. Specifically, CCK-58 binds more avidly to the CCK(A)
      receptor while CCK-8 is more potent for stimulation of amylase secretion from
      pancreatic acini. We postulate that these seemingly contradictory observations
      reflect a stable conformational change in CCK-58 that enhances binding, but
      diminishes activation of second messenger. We used CD and NMR spectra to evaluate
      postulated structural differences between CCK-8 and the carboxy-terminus of
      synthetic CCK-58. The CD spectra indicate the presence of turns in CCK-8 but a
      mixture of helical and random coil structures for CCK-58. Comparisons of partial
      NMR chemical shift assignments of CCK-58 and full assignments for CCK-8 also
      indicate differences in the backbone conformations for these residues. The data
      support the hypothesis that these peptides have different, stable, carboxy
      terminal structures that may influence bioactivity.

PMID- 10600516
TI  - Sas3 is a histone acetyltransferase and requires a zinc finger motif.
AB  - SAS3 was originally isolated as a gene related to SAS2, which encodes a positive
      regulator of transcriptional silencing in yeast. The Sas3 protein possesses an
      evolutionally conserved domain that is shared by a group of SAS-like factors.
      This conserved domain contains an atypical zinc finger motif and a putative
      acetyl-CoA binding motif. We showed that recombinant Sas3 exhibits histone
      acetyltransferase (HAT) activity toward acetylate core histones H2A, H3, and H4.
      This substrate specificity is similar to those of Tip60 and Esa1. Analysis of a
      series of deletion mutants revealed that the minimum region required for HAT
      activity is located within amino acid residues 241-577, including the domain
      conserved in the MYST family proteins. Amino acid substitution mutant analysis
      showed that both the acetyl-CoA binding motif and the zinc finger motif are
      required for HAT activity. These results suggest that SAS3 and its family members
      require the zinc finger motif for their activity.

PMID- 10600517
TI  - Inhibition mechanism of cathepsin L-specific inhibitors based on the crystal
      structure of papain-CLIK148 complex.
AB  - Papain was used as an experimental model structure to understand the inhibition
      mechanism of newly developed specific inhibitors of cathepsin L, the papain
      superfamily. Recently, we developed a series of cathepsin L-specific inhibitors
      which are called the CLIK series [(1999) FEBS Lett. 458, 6-10]. Here, we report
      the complex structure of papain with CLIK148, which is a representative inhibitor
      from the CLIK series. The inhibitor complex structure was solved at 1.7 A
      resolution with conventional R 0.177. Unlike other epoxisuccinate inhibitors
      (E64, CA030, and CA074), CLIK148 uses both prime and nonprime sites, which are
      important for the specific inhibitory effect on cathepsin L. Also, the
      specificity for cathepsin L could be explained by the existence of Phe in the P2
      site and hydrophobic interaction of N-terminal pyridine ring.

PMID- 10600518
TI  - Hypernuclear acetylation in atherosclerotic lesions and activated vascular smooth
      muscle cells.
AB  - Recent studies have implicated acetylation of several nuclear proteins such as
      histones and p53 on their epsilon-portion of lysine residues in eukaryotic
      transcription. Here we raised a specific polyclonal antibody against epsilon
      acetylated lysine. Using the antibody, we detected hypernuclear acetylation (HNA)
      in atherosclerotic vascular smooth muscle cells (VSMCs). Thrombin, a humoral
      factor known to cause activation and proliferation of VSMCs, strongly potentiated
      HNA in cultured VSMCs. MAP kinase pathway and a signal coactivator CREB binding
      protein (CBP) were involved in thrombin-induced HNA of VSMCs. Our results suggest
      that coactivators cooperating with signal-dependent transcription activators play
      an important role in atherosclerogenesis via HNA in VSMCs.

PMID- 10600519
TI  - Transient increase of a protein kinase activity identified to CK2 during sea
      urchin development.
AB  - Using GST-EF-1 delta as an exogenous substrate, and EF-1 delta kinase activity
      was shown to increase transiently during early development of sea urchin embryos.
      The basal activity of EF-1 delta kinase in unfertilized eggs was 150
      fmoles/min/mg protein. The activity began to increase 10 h after fertilization
      and reached its maximum level (8.4 x basal) at 24 h. The activity then declined
      to twice the basal value at 72 h post-fertilization. The EF-1 delta kinase
      activity was identified to a CK2-type enzyme on the basis of its substrate
      specificity for EF-1 delta, crude casein and beta casein, its inhibition by
      heparin, DRB, 2,3-bisphosphoglycerate, and its stimulation by spermine,
      spermidine, and polylysin. Furthermore, the activity was inhibited by the
      synthetic peptide RRREEETEEE specific for CK2. DRB (200 microM) and 2,3
      bisphosphoglycerate (2.5 mM) blocked or delayed the transition from blastula to
      gastrula of the embryos, suggesting a role for the kinase in early development.

PMID- 10600520
TI  - Enhanced expression and autoimmunity of recombination signal binding protein
      jkappa in human dilated cardiomyopathy.
AB  - Dilated cardiomyopathy (DCM) is a major cause of heart failure in younger
      individuals. Its prognosis is poor with 40-50% of patients dying within 2 years
      after diagnosis. Although the etiology of DCM is poorly understood, there is
      increasing evidence that DCM may represent an autoimmune disease in a significant
      subset of patients. In order to identify candidate antigens in DCM, we applied a
      molecular strategy which combines recombinant expression cloning and
      autoimmunological screening procedures. A left ventricle from a male DCM patient
      was explanted at heart transplantation and a human DCM left ventricular cDNA
      expression library was constructed. 2 x 10(6) clones were immunologically
      screened with serum collected from the same patient prior transplantation.
      Subsequent rounds of screening and purification allowed isolation of a positive
      clone which was sequenced and identified as Recombination Signal Binding Protein
      jkappa (RBP-jkappa). RBP-jkappa is an already identified transcription factor,
      e.g., involved in Epstein-Barr-virus-induced immortalization processes.
      Radioactively labeled RBP-jkappa protein was synthesized via in vitro translation
      using the isolated RBP-jkappa cDNA. This RBP-jkappa protein was used for
      immunoprecipitation reactions to screen sera of healthy controls and patients
      suffering of DCM for the presence of RBP-jkappa autoantibodies. Analysis revealed
      that only 31% (n = 16) of healthy but 70.6% of DCM patients (n = 17) carry an
      autoantibody against RBP-jkappa. Patients suffering from ischemic cardiomyopathy
      showed a prevalence of 22% of RBP-jkappa autoantibodies. Western analysis with an
      monoclonal antibody raised against RBP-jkappa showed that RBP-jkappa was
      overexpressed to 488 +/- 140% in DCM hearts compared to non-failing controls (n =
      8). Autologous immunological screening of a cDNA expression library is a powerful
      and novel technology to gain insights into the etiology of human idiopathic DCM.
      Human DCM displays an autoimmune response against RBP-jkappa and an
      overexpression of RBP-jkappa. Since RBP-jkappa is involved in cellular
      immortalization and exerts antiapoptotic effects, the increased RBP-jkappa
      autoantibody level during DCM may inhibit this growth-regulating feature of RBP
      jkappa. In this setting, enhanced myocardial RBP-jkappa expression could
      represent a compensatory but ineffective response to counteract the increased
      rate of apoptosis in DCM. Furthermore, RBP-jkappa may be a useful diagnostic
      marker for DCM.

PMID- 10600521
TI  - Glycosaminoglycans promote HARP/PTN dimerization.
AB  - Heparin affin regulatory peptide (HARP), also called pleiotrophin (PTN), is a
      secreted polypeptide which binds to heparin and plays a key role in cellular
      growth and differentiation. In order to assess the determinants potentially
      important to its biological activity, we tested the ability of HARP to
      oligomerize, a process involved in mitogenic activity of the heparin-binding
      fibroblast growth factor. Using dissuccinimidyl suberate cross-linking
      experiments and affinity chromatography, we report that human HARP forms
      noncovalent dimers. Dimerization is dependent on the presence of heparin or other
      sulfated glycosaminoglycans, as chlorate treatment of cells inhibits this
      process. In vitro, different glycosaminoglycans, such as dermatan sulfate and
      chondroitin sulfate-C, also induce a dimer assembly of HARP. The relevance of
      this process was supported by experiments demonstrating that HARP is secreted as
      a dimer in conditioned medium of NIH-3T3 cells that overexpressed this growth
      factor and is also associated to the cell surface or to the extracellular matrix.

PMID- 10600522
TI  - Involvement of vesicle-cytoskeleton interaction in AQP5 trafficking in AQP5-gene
      transfected HSG cells.
AB  - A cDNA of rat aquaporin 5 (AQP5) was used to transfect to HSG (human salivary
      gland cells), and the trafficking mechanism was studied in vitro by confocal
      laser microscopy. The trafficking of AQP5 to the plasma membrane was induced by
      stimulation of AQP5-gene-transfected human salivary gland cells (HSGAQP5 cells)
      with thapsigargin, an inhibitor of endoplasmic Ca(2+)-ATPase, and or with A
      23187, a calcium ionophore. Pretreatment of these cells with colchicine or
      vinblastine, microtubule inhibitors, prevented the trafficking induced by
      thapsigargin or A-23187. The trafficking event was not completely inhibited by
      cytochalasin B, a microfilament inhibitor. These results demonstrate that the
      trafficking of AQP5 vesicles to the plasma membrane is triggered by an increase
      in intracellular Ca(2+) and that the interaction of AQP5-containing vesicles with
      the cytoskeleton is involved in this trafficking.

PMID- 10600523
TI  - Ca(2+) and extracellular acidification rate responses to parathyroid hormone
      fragments in rat ROS 17/2 and human SaOS-2 cells.
AB  - To examine the importance of the N- or C-termini of PTH(1-34) the effects of
      truncated fragments of PTH on human receptors in osteoblast-like SaOS-2 cells and
      rat receptors in rats ROS 17/2 cells were examined. Fura-2-loaded cells were used
      to monitor cytosolic free Ca(2+) concentration ([Ca2+]i), and the Cytosensor
      microphysiometer was used to monitor extracellular acidification rate (ECAR). C
      terminally truncated fragments (1-31) and (1-28) of hPTH(1-34)NH(2) stimulated an
      increase in [Ca(2+)](i) and ECAR in both cell lines. hPTH(3-34)NH(2) and other N
      terminally truncated fragments did not stimulate [Ca(2+)](i) or ECAR in either
      cell type. The signal transduction pathway of PTH-induced ECAR in ROS 17/2 cells
      was investigated to compare with previous results in SaOS-2 cells. Potentiation
      by IBMX, attenuation by 8Br-cAMP and lack of effect of the PKC inhibitor
      chelerythrine chloride support a cAMP/PKA-mediated signal transduction pathway in
      ROS 17/2, while the protein kinase C pathway was predominant in SaOS-2 cells. We
      conclude that the intact N-terminus of PTH is essential in PTH signaling mediated
      via either the cAMP/PKA or inositol lipid/Ca(2+)/PKC pathways in osteoblast-like
      cells.

PMID- 10600524
TI  - Expression of the human cholesterol 7alpha-hydroxylase gene in transgenic mice.
AB  - We have generated transgenic mice expressing human CYP7A1 transgenes. Only 1.5
      kilobases (kb) of 5' upstream sequence and 6.5 kb of 3' sequence were sufficient
      for hepatic transcription of the transgenes. However, the 5' end segment alone
      was not sufficient to direct liver expression, suggesting that additional hepatic
      regulatory elements reside in the 3' extension or within introns. The level of
      expression of these transgenes was low in comparison to the levels of the
      endogenous mouse CYP7A1 mRNA. To generate mice expressing higher levels of CYP7A1
      mRNA, we injected a large human genomic PAC clone, extending up to -105 kb 5' of
      the structural gene and about 50 kb 3' of the gene. These transgenic mice
      expressed CYP7A1 mRNA at higher levels, suggesting that additional hepatic
      regulatory elements are found either 5' of -1520 or beyond 6.5 kb 3' of the gene.

PMID- 10600525
TI  - The role of calcium in pre- and postmitochondrial events in tributyltin-induced T
      cell apoptosis.
AB  - Using a novel dual-channel FACS methodology, the organotin compound TBT (2
      microM) was shown to induce rapid (maximal by 3 min) and sustained elevations in
      intracellular calcium levels [Ca(2+)](i) in Jurkat T cells. This was preceded by
      mitochondrial hyperpolarization (maximal at 1 min), with subsequent loss of
      membrane potential, (Deltapsi(m)) over the next 15 min and was associated with
      the release of mitochondrial cytochrome c and the activation of type II caspases.
      The activation of the caspases was blocked by calcium chelation with EGTA and/or
      BAPTA. Interestingly, changes in Deltapsi(m) caused by TBT were not affected by
      chelation of intra- and extracellular calcium or by performing the experiments in
      a Ca(2+)-free medium. TBT also caused rapid elevation of [Ca(2+)](i) in cells
      lacking glycolytic ATP production. Despite this, the loss of Deltapsi(m) and the
      activation of type II caspases were delayed (maximal by 2 h) in these cells.
      Further, there was a failure to activate type II caspases in cells treated with
      TBT in a Ca(2+)-free medium, despite rapid release of mitochondrial cytochrome c.
      Consequently, these cells evaded the induction of apoptosis and were diverted to
      delayed necrotic deletion. Taken together, these data strongly suggest that the
      rapid rise in [Ca(2+)](i) caused by TBT in Jurkat T cells is not directly coupled
      to the induction of mitochondrial permeability transition, which rather results
      from a direct interaction of TBT with mitochondrial component(s) controlling pore
      transition. However, the rise in [Ca(2+)](i) is a prerequisite for
      postmitochondrial events involved in caspase activation prior to the induction of
      apoptosis.

PMID- 10600526
TI  - Inhibition of biotin carboxylase by a reaction intermediate analog: implications
      for the kinetic mechanism.
AB  - The first committed step in long-chain fatty acid synthesis is catalyzed by the
      multienzyme complex acetyl CoA carboxylase. One component of the acetyl CoA
      carboxylase complex is biotin carboxylase which catalyzes the ATP-dependent
      carboxylation of biotin. The Escherichia coli form of biotin carboxylase can be
      isolated from the other components of the acetyl CoA carboxylase complex such
      that enzymatic activity is retained. The synthesis of a reaction intermediate
      analog inhibitor of biotin carboxylase has been described recently (Organic Lett.
      1, 99-102, 1999). The inhibitor is formed by coupling phosphonoacetic acid to the
      1'-N of biotin. In this paper the characterization of the inhibition of biotin
      carboxylase by this reaction-intermediate analog is described. The analog showed
      competitive inhibition versus ATP with a slope inhibition constant of 8 mM.
      Noncompetitive inhibition was found for the analog versus biotin.
      Phosphonoacetate exhibited competitive inhibition with respect to ATP and
      noncompetitive inhibition versus bicarbonate. Biotin was found to be a
      noncompetitive substrate inhibitor of biotin carboxylase. These data suggested
      that biotin carboxylase had an ordered addition of substrates with ATP binding
      first followed by bicarbonate and then biotin.

PMID- 10600527
TI  - Identification and characterization of genes whose expressions are altered in rat
      6 fibroblasts transformed by mutant p53(val135).
AB  - The wild-type tumor suppressor gene p53 is known as a transcription factor in
      activating or suppressing target genes that encode proteins in regulating genome
      stability, DNA damage, cell arrest, and apoptosis. However, the role of mutant
      p53 in the process of cell transformation is still unclear. Our recent work
      indicated that overexpression of mutant p53(val135) induced high incidence of
      spontaneous transformation in prolonged cultures of Rat 6 fibroblasts. In order
      to identify genes related to neoplastic transformation induced by the mutant p53,
      the p53(val135)-overexpressor R6#13-8 and its derived spontaneously transformed
      cell line T2 were analyzed by mRNA differential display. In a systematic
      screening with 80 primer sets of RT-PCR reactions, three genes were found to be
      differentially expressed between R6#13-8 and T2 cells. Two genes, identified as
      homologues of the growth factor inducible immediate-early gene Cyr61 and the
      human nonmuscle myosin heavy chain-B, were down-regulated in T2 cells.
      Interestingly, both genes were also suppressed in Rat 6 cells transformed by c-H
      ras and v-myc, but not by v-src genes. The third gene is a homologue of the
      frizzled related protein, a gene family that acts, in some cases, as an
      antagonist to the Wnt signaling pathway. It is intriguing that the rat homologue
      of the frizzled related protein was only expressed in p53(val135)-overexpressing
      cells, but not in the parental Rat 6 cells. However, the same gene was also
      highly expressed in ras-transformed Rat 6 cells, and moderately expressed in v
      src-transformed Rat 6 cells. This is the first study in which the association of
      mutant p53 to these three genes is revealed. Our current report may provide new
      clues to the role of mutant p53 in the process of cell transformation.

PMID- 10600528
TI  - c-Src activates the DNA binding and transcriptional activity of Stat3 molecules:
      serine 727 is not required for transcriptional activation under certain
      circumstances.
AB  - Stat3 proteins are constitutively activated in cells transformed by v-Src and the
      proteins have been shown to interact directly. Subsequent studies have shown that
      Stat3 is required for cellular transformation of NIH fibroblasts by v-Src,
      suggesting a potential role for Stat3 in aberrant cell growth. Stat3 is
      phosphorylated on a single tyrosine (tyrosine 705) which is required for
      effective dimer formation. An additional phosphorylation event (serine 727) is
      believed to be required for full transcriptional activity of Stat1 and Stat3
      molecules. Here we report that c-Src activates the DNA binding activity of
      Stat3alpha, Stat3beta, and three Stat3 mutants, one in which serine 727 was
      replaced by alanine (Stat3alphaS727A) and C-terminal truncated molecules Delta48
      and Delta55. Consistent with this finding is a general increase in the tyrosine
      705-phosphorylated Stat3 in cells cotransfected with c-Src. Furthermore,
      transcription from an alpha-2 macroglobulin reporter gene is activated by
      Stat3alphaS727A to the same magnitude as compared to Stat3alpha and Stat3beta in
      the presence of c-Src. These results suggest that serine 727, contained in a
      consensus MAP kinase recognition site and shown to be the only serine in Stat3
      phosphorylated in epidermal growth factor (EGF) treated cells, is not necessary
      for transcriptional activity comparable to wild-type Stat3alpha or Stat3beta when
      activated by c-Src in COS-7 cells.

PMID- 10600529
TI  - Hannahpep: A novel fibrinolytic peptide from the Indian King Cobra (Ophiophagus
      hannah) venom.
AB  - A novel fibrinolytic peptide (Hannahpep) was isolated and purified from the venom
      of the Indian King Cobra (Ophiophagus hannah) by thin-layer chromatography
      followed by reverse-phase high-performance liquid chromatography. The MW of the
      peptide was found to be 610 Da and the amino acid sequence of Hannahpep was
      determined to be Arg, His, Ala, Arg, His, Asp. Hannahpep produced
      defibrinogenating activity in male albino mice. It exhibited significant
      fibrinolytic and fibrinogenolytic activity in vitro. Hannahpep showed plasma
      anticlotting activity. However, it lacked hemolytic, hemorrhagic, or
      phospholipase activity. This peptide may have possible therapeutic application in
      the management of thrombosis or occlusion of a blood vessel.

PMID- 10600530
TI  - Inhibition of P-glycoprotein activity and chemosensitization of multidrug
      resistant ovarian carcinoma 2780AD cells by hexanoylglucosylceramide.
AB  - In the present study we show that neutral hexanoyl-(glyco)sphingolipids inhibit P
      glycoprotein (Pgp) activity in human ovarian 2780AD cells. By contrast,
      hexanoylceramide and the gangliosides GM(3) and GM(2) had no effect on Pgp
      activity, whereas sphingosine had a stimulating effect. In the case of
      hexanoylglucosylceramide, inhibition of Pgp activity by was reflected by a
      regained doxorubicin sensitivity of cells, which were grown in medium
      supplemented with the lipid. Our results lead to the conclusion that a direct
      transmodulation of Pgp activity by glycolipids occurs, depending on lipid
      headgroup structure, which can result in reduced resistance to the
      chemotherapeutic agent doxorubicin.

PMID- 10600531
TI  - Regulation of phosphatidylserine synthesis in Jurkat T cell clones: caffeine
      bypasses CD3/TCR-induced protein tyrosine kinases and calcium signals.
AB  - Phosphatidylserine synthesis as measured by the incorporation of [(3)H]serine
      into phosphatidylserine (PtdSer) through the serine-base exchange enzyme system
      (serine-BEES) is markedly inhibited in Jurkat cells treated with caffeine. The
      caffeine-induced inhibition was compared to that observed in cells treated with
      either CD3 mAb or thapsigargin. While CD3- and thapsigargin-induced inhibition
      was related to the release of Ca(2+) from the endoplasmic reticulum (ER), a
      process that deprives the serine-BEES of its major cofactor, caffeine modified
      PtdSer synthesis in the absence of decreased Ca(2+) content of ER. Using Jurkat
      clones differing by the expression of cell surface markers or protein tyrosine
      kinases implicated in the CD3/TCR signal transmission pathway, we have shown that
      CD3 mAb-induced inhibition of PtdSer synthesis necessitates the expression of
      both the CD3/TCR and the protein tyrosine phosphatase CD45 at the cell surface as
      well as the presence of p56(lck) and ZAP-70 protein tyrosine kinases. By
      contrast, thapsigargin, a blocker of the Ca(2+)-ATPase of the ER, known for its
      Ca(2+) releasing properties, inhibited PtdSer synthesis in all the Jurkat clones
      tested, indicating that this compound bypasses the CD3/TCR-induced signals.
      Despite its lack of effect on Ca(2+) release from ER and on protein tyrosine
      phosphorylations, caffeine inhibited PtdSer synthesis in all the Jurkat clones.
      The use of several cAMP-inducing drugs and of others xanthine derivatives
      indicated that caffeine modify PtdSer synthesis either by a direct action on the
      serine-BEES or by a modification of the structure of the phospholipids used as
      substrate by the enzyme.

PMID- 10600532
TI  - Phosphatidylserine exposure during apoptosis is a cell-type-specific event and
      does not correlate with plasma membrane phospholipid scramblase expression.
AB  - Phosphatidylserine (PS) exposure on the surface of cells has been considered a
      characteristic feature of apoptosis. However, we demonstrate herein that
      externalization of PS occurs in a cell-type-specific, albeit caspase-dependent,
      manner. Moreover, we could find no correlation in six different cell lines
      between the level of expression of the phospholipid (PL) scramblase and the
      capacity of these cells to externalize PS during apoptosis. Overexpression of PL
      scramblase in Raji cells, which exhibit low constitutive expression of this
      enzyme, by retroviral transduction of PL scramblase or treatment of the cells
      with interferon-alpha, failed to confer the capacity to expose PS in response to
      apoptotic stimuli. However, the lack of PS exposure in some cell types was not
      due to their inability to translocate PS molecules to the cell surface, since
      incubation with thiol reactive agents, such as N-ethylmaleimide, disulfiram and
      diamide, yielded rapid and pronounced PS exposure in all cell lines. These data
      suggest that plasma membrane PS exposure is not an obligatory component of the
      apoptotic phenotype, and that PL scramblase is not the sole determinant of PS
      externalization in apoptotic cells when this occurs.

PMID- 10600533
TI  - Functional expression, purification, and characterization of recombinant human
      pyruvate carboxylase.
AB  - The cDNA-encoding human pyruvate carboxylase (hPC) has been assembled and cloned
      into a very high efficiency mammalian expression vector and the construct
      transfected into 293T kidney cells. Stable clones expressing very high levels of
      hPC were produced and used as a source of the enzyme. Purification of the
      recombinant hPC was performed by selective precipitation with 40% ammonium
      sulfate followed by a single step avidin affinity chromatography, with an overall
      yield of 20%. Recombinant hPC purified by this method yielded a single band on
      SDS-PAGE with a specific activity of 20 U/mg. Kinetic analysis demonstrated that
      the recombinant human PC has the same properties as the native enzyme isolated
      from liver autopsy. This is the first report of production and purification of
      recombinant PC.

PMID- 10600534
TI  - Muscle-specific up-regulation of rat UCP3 mRNA expression by long-term hindlimb
      unloading.
AB  - The effect of long-term hindlimb unloading (2 or 5 week) on the expression of
      uncoupling protein-3 (UCP3) gene was investigated in rat skeletal muscles. The
      interaction of hindlimb unloading and thyroid status was also investigated at 2
      weeks. Whatever the duration, mechanical unloading induced a similar increase in
      UCP3 mRNA relative abundance in the slow-twitch soleus (SOL) muscle (+80%, P <
      0.05), whereas no effect was observed in the fast-twitch extensor digitorum
      longus (EDL) muscle. Hypothyroidism down-regulated while hyperthyroidism up
      regulated UCP3 mRNA relative abundance in both SOL and EDL muscles, but thyroid
      status did not prevent the up-regulation of UCP3 induced by 2 weeks of
      suspension. These data therefore indicate for the first time that long-term
      hindlimb unloading up-regulates muscle UCP3 gene expression in a muscle-specific
      manner which is independent of thyroid status.

PMID- 10600535
TI  - Characterization of newly identified four isoforms for a putative cytosolic
      protein tyrosine phosphatase PTP36.
AB  - In the course of determining the expression profiles of protein tyrosine
      phosphatases in lactating mammary gland, we found the expression of an isoform
      for a putative cytosolic and cytoskeleton-associated protein tyrosine phosphatase
      PTP36. Further detailed RT-PCR and Northern blot analyses revealed the expression
      of several isoforms for PTP36 in a tissue-dependent manner. We have cloned the
      cDNAs encoding four truncated isoforms for PTP36 and designated PTP36-A, -B, -C,
      and -D, respectively. PTP36-A and -C had new sequences generated due to
      frameshift, whereas PTP36-B and -D were in-frame variants. Gly- and Glu-rich
      domains and a putative PTP domain were missing from PTP36-A, but the band 4.1
      domain remained. PTP36-B retained the band 4.1 and PTP domains but lacked Pro-,
      Gly- and Glu-rich domains. Most domain structures were lacking in PTP36-C and -D.
      Interestingly, PTP36-C contained an incomplete band 4.1 domain, but the newly
      created sequence exhibited high homology to human nebulette, which was also
      suggested to associate with cytoskeletons. When transiently expressed in COS7 and
      HEK293 cells, not only the wild type but also all the isoforms were recovered in
      Triton X-100-insoluble cytoskeleton-associated fractions and this distribution
      was not affected by mechanical cell detachment and treatment with a kinase
      inhibitor staurosporine. Such cellular distribution of PTP36 was also observed in
      stable COS7 clones. Further studies using deletion mutants suggested that the
      first 30 amino acids as well as the band 4.1 domain of PTP36 were involved in
      association with Triton X-100 insoluble cytoskeletons. Tissue-dependent
      expression and deletion in domain structures might reflect the biological
      significance of the isoforms for PTP36 in certain physiological conditions.

PMID- 10600536
TI  - A novel paired domain DNA recognition motif can mediate Pax2 repression of gene
      transcription.
AB  - The paired domain (PD) is an evolutionarily conserved DNA-binding domain encoded
      by the Pax gene family of developmental regulators. The Pax proteins are
      transcription factors and are involved in a variety of processes such as brain
      development, patterning of the central nervous system (CNS), and B-cell
      development. In this report we demonstrate that the zebrafish Pax2 PD can
      interact with a novel type of DNA sequences in vitro, the triple-A motif,
      consisting of a heptameric nucleotide sequence G/CAAACA/TC with an invariant core
      of three adjacent adenosines. This recognition sequence was found to be conserved
      in known natural Pax5 repressor elements involved in controlling the expression
      of the p53 and J-chain genes. By identifying similar high affinity binding sites
      in potential target genes of the Pax2 protein, including the pax2 gene itself, we
      obtained further evidence that the triple-A sites are biologically significant.
      The putative natural target sites also provide a basis for defining an extended
      consensus recognition sequence. In addition, we observed in transformation assays
      a direct correlation between Pax2 repressor activity and the presence of triple-A
      sites. The results suggest that a transcriptional regulatory function of Pax
      proteins can be modulated by PD binding to different categories of target
      sequences.

PMID- 10600537
TI  - Binding and processing of (125)I-ACTH by isolated rat splenic lymphocytes.
AB  - The effect of incubation temperature and ligand competition was tested for (125)I
      ACTH binding to isolated rat lymphocytes. AlphaMSH but not Agouti-like peptide
      was an effective competitive inhibitor for cell surface binding at 4 degrees C.
      Cells incubated with (125)I-ACTH at 37 degrees C rapidly associated ligand for 10
      min and then gradually lost the radioactivity with time. Cells incubated with
      (125)I-ACTH at 4 degrees C accumulated ligand to only about half the maximal
      amount when compared to cells incubated at 37 degrees C for 10 min. Temperatures
      below 20 degrees C and toxins that block lysosomal degradation blocked the loss
      of cell-associated radioactivity. These results suggest the lymphocyte ACTH
      receptor is the Melanocortin 5 receptor and the receptor is internalized by
      endocytosis to deliver ligand to the lysosome.

PMID- 10600538
TI  - Cell swelling activates stress-activated protein kinases, p38 MAP kinase and JNK,
      in renal epithelial A6 cells.
AB  - Osmotic shock is well recognized as one of the factors activating stress
      activated protein kinases (SAPKs), p38 MAP kinase and c-Jun N-terminal kinases
      (JNKs). In renal epithelial A6 cells, hypo-osmotic shock transiently activated
      SAPKs with maximal activation at 5 min. A6 cells showed a regulatory volume
      decrease (RVD) after swelling when the cells were exposed to a hypo-osmotic
      solution. In contrast, activation of SAPKs was maintained over 90 min after hypo
      osmotic shock in the presence of 5-nitro-2-(3-phenylpropylamino)benzoic acid
      (NPPB, a Cl(-) channel blocker), which completely blocked the RVD and kept the
      cells continuously swelling. Exposure of the cells to a high K(+) iso-osmotic
      solution containing nystatin, which induces continuous cell swelling, also
      continuously activated SAPKs. Furthermore, membrane deformation induced by
      chlorpromazine activated SAPKs. These results suggest that changes in membrane
      tension by cell swelling or chlorpromazine, but not osmolality, are important
      steps for activation of SAPKs in A6 cells.

PMID- 10600539
TI  - Mutations of the IL-12 receptor beta2 chain gene in atopic subjects.
AB  - Interleukin-12(IL-12) promotes cell-mediated Th1 responses and production of IFN
      gamma that downregulates IgE production. The signal of IL-12 is transduced
      through the IL-12 receptor (IL-12R) and Stat4. Twenty-four of 75 atopic
      individuals with high levels of IgE showed insufficient IFN-gamma production by
      peripheral blood mononuclear cells (PBMCs) following stimulation with IL-12 but
      not that with phytohemagglutinin (PHA). Interestingly, 10 of the above 24
      subjects were found to be heterozygous for truncated (2496 del 91) or missense
      (1577 A to G and 2799 A to G) mutations of IL-12R beta2 chain gene (IL-12R
      beta2). Insufficient phosphorylation of Stat4 was also demonstrated in these 10
      individuals. This is the first report showing that reduced IFN-gamma production
      following IL-12 stimulation is associated with the heterozygous IL-12R beta2
      mutations in atopic subjects.

PMID- 10600540
TI  - Distribution of D(5) dopamine receptor mRNA in rat ventromedial hypothalamic
      nucleus.
AB  - Estrogen induces lordosis through, in part, estrogen receptor (ER)-mediated
      synthesis of progesterone receptors (PR) in the ventromedial nucleus (VMN). In
      vitro, PR is activated by the neurotransmitter dopamine through D1-like receptors
      (1). In vivo, lordosis is induced by dopamine, an effect mediated in part by PR
      and D(5) dopamine receptors. The purpose of the present study was to determine
      mRNA distribution of D1-like receptors in the female rat brain using RT-PCR
      combined with punchout microdissection techniques. Employing specific primers to
      D(5) and D(1) dopamine receptors, we found detectable expression levels of D(5)
      dopamine receptor mRNA in VMN as well as the arcuate nucleus/median eminence
      (ArcN/ME). In contrast, D(1) dopamine receptor mRNA was detected only in VMN. By
      using this highly sensitive and specific RT-PCR methodology, we have confirmed
      the presence of D(5) dopamine receptor mRNA in an area of the brain that
      regulates reproductive behavior through PR. The data support the previous
      observation that D(5) dopamine receptors in VMN contribute to facilitation of
      female reproductive behavior by D1-like agonists.

PMID- 10600541
TI  - Mechanism of aminobisphosphonate action: characterization of alendronate
      inhibition of the isoprenoid pathway.
AB  - Alendronate (ALN), an aminobisphosphonate compound used for the treatment of
      osteoporosis and other disorders of bone resorption, has been suggested to act by
      inhibition of the formation of GGPP. In the present study we used an S(10)
      homogenate fraction of rat liver to show that ALN causes a dose-dependent
      inhibition of [(3)H]MVA incorporation into sterols and a concomitant increase in
      incorporation of radiolabel into IPP and DMAPP. We further show that ALN is a
      potent inhibitor of cytosolic trans-prenyltransferase (FPP synthase). The
      inhibition is competitive with respect to allylic pyrophosphate substrates, but
      not IPP, suggesting that ALN acts as an allylic pyrophosphate analog and binds to
      the free enzyme. The K(i) is in the 0.5 microM range.

PMID- 10600542
TI  - Structural analysis of esp-1 gene (PRSS 21).
AB  - The esp-1 gene is originally cloned from human eosinophils and encodes a membrane
      type serine protease. This gene is ubiquitously expressed in various tissues but
      not kidney or muscle, and highly expressed in testis. Among granulocytes, this
      gene is expressed in eosinophils but not neutrophils, although both are derived
      from myeloid progenitors. In the present study, we have cloned the esp-1 genome
      using a BAC library, and determined exon-intron junctions: This gene spans
      approximately 4.6 kb, and consists of 6 exons and 5 introns. On radiation hybrid
      and FISH analyses, the esp-1 gene was mapped to 16p13.3. In addition, we have
      cloned a new splicing variant form of esp-1 from a HeLa cell cDNA library, which
      contains many esp-1 clones. Both RNase protection and primer extension analyses
      revealed the transcription initiation site of the esp-1 gene is located at
      nucleotide position -106, residue G. Dual-luciferase reporter analysis revealed a
      GC-rich region between nucleotide positions, -106 and -189 containing one AP-1/Sp
      1 binding site is responsible for the minimum promoter activity in HeLa cells.

PMID- 10600543
TI  - Mutant mice lacking Crk-II caused by the gene trap insertional mutagenesis: Crk
      II is not essential for embryonic development.
AB  - Crk family adapter proteins including Crk-II, Crk-I, and Crk-L consist mostly of
      SH2 and SH3 domains. Through the interactions between SH2 domain and
      phosphotyrosine residues and/or between SH3 domain and proline-rich motifs, they
      are involved in a variety of signaling cascades. Despite their essential roles in
      the signal transductions, knock-out mice of these molecules have not been
      reported yet. We performed the gene trap insertional mutagenesis with a trap
      vector, pU-Hachi, and generated a mutant mice line, Ayu 8104, in which the trap
      vector was inserted into the c-crk gene. Homozygous Ayu 8104 mice lacked Crk-II
      and Crk-I transcripts but expressed the truncated Crk proteins retaining one SH2
      and one SH3 domain. Since the structure of the truncated proteins was similar to
      that of Crk-I, the insertion was considered to cause Crk-II-specific disruption.
      Homozygous mutant mice, however, did not exhibit any obvious abnormalities,
      suggesting that Crk-family adapters, Crk-II, Crk-I, and Crk-L would redundantly
      function in the signaling cascades and Crk-II was not apparently essential for
      embryonic development.

PMID- 10600544
TI  - Prothoracicotropic activity of SBRPs, the insulin-like peptides of the saturniid
      silkworm Samia cynthia ricini.
AB  - Synthesis and secretion of the insect molting hormone ecdysteroid in the
      prothoracic glands (PGs) are stimulated by the prothoracicotropic hormone (PTTH)
      secreted by the brain. Bombyxins, insulin-like peptides of the silkworm Bombyx
      mori, show prothoracicotropic activity when administered to the saturniid
      silkworm Samia cynthia ricini, but they are inactive to B. mori itself. Recently,
      the genes for the bombyxin homologs of S. cynthia ricini (referred to as Samia
      bombyxin-related peptides, SBRPs) were cloned. To examine the prothoracicotropic
      activity of SBRPs on S. cynthia ricini, we synthesized two representative
      molecules, SBRP-A1 and -B1. They promoted pupa-to-adult development with ED(50)
      of 50 and 10 ng/pupa (EC(50) of 5 and 1 nM), respectively.

PMID- 10600545
TI  - Negative regulatory role of the Escherichia coli hfq gene in cell division.
AB  - We found that the hfq::cat mutant strain produced minicells at high frequency.
      Minicell production by the mutant strain was more prominent in poor media and in
      the stationary phase than in rich media and in the exponentially growing phase.
      The amount of the cell division protein FtsZ increased up to two- to threefold of
      the wild-type cells in the hfq::cat mutant in the stationary phase, while such
      differences were not observed in the exponentially growing phase. Increased ftsZ
      mRNA levels were also observed in the hfq::cat mutant in the stationary phase.
      These results suggest a negative regulatory role of the DNA-, RNA-binding protein
      Hfq in cell division in the stationary phase.

PMID- 10600546
TI  - Chloroplast chaperonins: evidence for heterogeneous assembly of alpha and beta
      Cpn60 polypeptides into a chaperonin oligomer.
AB  - Higher plant chloroplasts contain two chaperonin 60 family proteins, Cpn60alpha
      and Cpn60beta, which are known to have divergent amino acid sequences. Although
      Cpn60alpha and Cpn60beta are present in roughly equal amounts and copurify in
      their native states, a heterogeneous ensemble of the chaperonin oligomer has not
      yet been demonstrated. We separately purified Cpn60alpha and Cpn60beta proteins
      from spinach leaves as the monomeric form. Either antibody raised against one
      chaperonin 60 protein could coimmunoprecipitate the other chaperonin 60 protein
      in their oligomeric state but not in its monomeric state, suggesting that the
      chloroplast Cpn60alpha and Cpn60beta polypeptides actually reside in the same
      chaperonin oligomer in the stroma. Moreover, the chaperonin oligomers migrated as
      at least two distinct bands on the native gel electrophoresis, each of which
      contained both chaperonin 60 proteins. These results suggest that chloroplast
      chaperonin oligomers might be composed of at least two distinct sets of two
      chaperonin proteins.

PMID- 10600547
TI  - Involvement of ryanodine receptor type 3 in dopamine release from the striatum:
      evidence from mutant mice lacking this receptor.
AB  - Although it is known that ryanodine receptor type 3 is expressed in the striatum,
      the function of this receptor has not been elucidated. Therefore, we examined
      whether caffeine- and ryanodine-induced dopamine release in striatal slices is
      affected in mice lacking ryanodine receptor type 3. Pretreatment with
      thapsigargin, an inhibitor of the Ca(2+) ATPase pump of the endoplasmic
      reticulum, abolished caffeine- or ryanodine-induced dopamine release in slices
      from normal mice. Dopamine concentration in the striatum and KCl-induced dopamine
      release were unaffected by a ryanodine receptor type 3 deficiency. Ryanodine
      induced dopamine release was significantly attenuated in mice lacking ryanodine
      receptor type 3, whereas caffeine-induced dopamine release was partially
      attenuated. Caffeine produced a similar hyper-motor activity in both wild and
      homozygous mice. The present results suggest the involvement of ryanodine
      receptor type 3 in dopamine release from the striatum.

PMID- 10600548
TI  - A novel epidermal growth factor-like molecule containing two follistatin modules
      stimulates tyrosine phosphorylation of erbB-4 in MKN28 gastric cancer cells.
AB  - We have isolated a gene from stomach fibroblasts encoding novel proteins
      containing two follistatin modules which might bind TGF-beta-related growth
      factors and a single epidermal growth factor (EGF)-like domain which is closely
      related to EGF/Neuregulin (NRG) family growth factors. Sequence analysis revealed
      novel cDNA clones, the protein products of which were designated tomoregulin (TR)
      and consisted of at least three isoforms which were distinguished by their
      cytoplasmic domains. The cytoplasmic domains in all isoforms were short and
      contained potential G-protein activating motifs. Precursors of TR (Pro-TR) are
      glycosylated transmembrane proteins. Two secreted soluble forms resulting from
      proteolytic cleavage were distinguished by the presence or absence of the EGF
      like domain. The EGF-like domain of TR was highly conserved compared to EGF/NRG
      family growth factors with the exception of an arginine to histidine substitution
      at position 39 (Arg --> His 39). Soluble TR stimulated erbB-4 tyrosine
      phosphorylation in MKN 28 gastric cancer cells, although it was weak compared to
      neuregulin-induced erbB-4 tyrosine phosphorylation; this suggests that TR might
      be a ligand for erbB-4- or erbB-4-related receptor tyrosine kinase. TR may have
      important roles in normal development of middle to late stages of embryos and
      maintenance of adult central nervous system tissues as high expression of TR
      mRNAs was observed in these tissues. The modular features suggest multiple roles
      for TR; these include functioning as a ligand for erbB- receptor, a regulator of
      TGF-beta-related growth factor signaling by direct interaction through the
      follistatin modules, and a G-protein-coupled receptor.

PMID- 10600549
TI  - Evidence of two populations of GABA(A) receptors in cerebellar granule cells in
      culture: different desensitization kinetics, pharmacology, serine/threonine
      kinase sensitivity, and localization.
AB  - GABA(A) receptors of rat cerebellar granule cells in culture have been studied by
      the whole cell patch clamp technique. The biphasic desensitization kinetic
      observed could be due either to different desensitization mechanisms of a single
      receptor population or to different receptor populations. The overall data
      indicate that the latter hypothesis is most probably the correct one. In fact,
      the fast desensitizing component was selectively potentiated by a benzodiazepine
      agonist and preferentially down-regulated by activation of the protein
      serine/threonine kinases A and G, as a consequence of the latter characteristic
      that receptor population was preferentially down-regulated by previous activation
      of N-methyl-d-aspartate glutamate receptors, via production of nitric oxide and
      PKG activation, most probably in dendrites. The other population is
      benzodiazepine insensitive and not influenced by activation of PKA or PKG. This
      slowly desensitizing population may correspond to the extrasynaptic delta subunit
      containing GABA(A) receptors described by other authors. Instead, the rapidly
      desensitizing population appears to represent dendritic synaptic GABA(A)
      receptors.

PMID- 10600550
TI  - Characterization of the binding of the RNA-binding protein AUF1 to the human
      AT(1) receptor mRNA.
AB  - An important mechanism of regulation of the expression of the AT(1) receptors is
      the modulation of the mRNA stability. AUF1, a human RNA-binding protein, may play
      an important role. Since AUF1 seems to bind to AU-rich regions of the 3'
      untranslated region of the mRNAs, we verified the nucleotide sequence of human
      AT(1) receptor 3'-untranslated region and we found possible binding sites. In
      addition we evaluated the expression of the AUF1 protein in human vascular smooth
      muscle cells: the administration of both isoproterenol and angiotensin II induced
      a significant increase of total anti-AUF1 immunoreactive isoforms. At the same
      time angiotensin II induced a significant decrease in the AT(1) receptor mRNA
      abundance. Moreover, we found that recombinant human AUF1 protein binds to human
      AT(1) receptor riboprobes. The protein was able to bind to the distal portion of
      the 3'-untranslated region, and also to the coding region. Since the clinically
      relevant AT(1) receptor polymorphism is located in the 3'-untranslated region, we
      created two DNAs, corresponding to the A and C polymorphism, without any
      differences. Our data demonstrate the presence of AUF1 in human vascular smooth
      muscle cells and its modulation by activation of the beta-adrenergic and the
      AT(1) pathways, a and specific binding of AUF1 to the human AT(1) receptor mRNA,
      suggesting a role of this protein in the modulation of the AT(1) receptor
      expression.

PMID- 10600551
TI  - Editorial

PMID- 10600552
TI  - Review: electron crystallography: present excitement, a nod to the past,
      anticipating the future.
AB  - From a modest beginning with negatively stained samples of the helical T4
      bacteriophage tail, electron crystallography has emerged as a powerful tool in
      structural biology. High-resolution density maps, interpretable in terms of an
      atomic structure, can be obtained from specimens prepared as well-ordered, two
      dimensional crystals, and the resolution achieved with helical specimens and
      icosahedral viruses is approaching the same goal. A hybrid approach to
      determining the molecular structure of complex biological assemblies is
      generating great interest, in which high-resolution structures that have been
      determined for individual protein components are fitted into a lower resolution
      envelope of the large complex. With this as background, how much more can be
      anticipated for the future? Considerable scope still remains to improve the
      quality of electron microscope images. Automation of data acquisition and data
      processing, together with the emergence of computational speeds of 10(12)
      floating point operations per second or higher, will make it possible to extend
      high-resolution structure determination into the realm of single-particle
      microscopy. As a result, computational alignment of single particles, i.e., the
      formation of "virtual crystals," can begin to replace biochemical
      crystallization. Since single-particle microscopy may remain limited to "large"
      structures of 200 to 300 kDa or more, however, smaller proteins will continue to
      be studied as helical assemblies or as two-dimensional crystals. The further
      development of electron crystallography is thus likely to turn increasingly to
      the use of single particles and small regions of ordered assemblies, emphasizing
      more and more the potential for faster, higher throughput.

PMID- 10600553
TI  - Animation of the dynamical events of the elongation cycle based on cryoelectron
      microscopy of functional complexes of the ribosome.
AB  - Using three-dimensional cryoelectron microscopy, the binding positions of tRNA
      and elongation factors EF-G and EF-Tu (the latter complexed with aminoacyl tRNA
      and GTP) on the ribosome were determined in previous studies. On the basis of
      these studies, the dynamical events that take place in the course of the
      elongation cycle of protein synthesis have been animated. The resulting 3-min
      movie is accessible on the website of this journal (http://www. idealibrary.com).
      The following article provides a brief annotation of those frames of the movie
      for which experimental support is available.

PMID- 10600554
TI  - Electron crystallography of bacteriorhodopsin with millisecond time resolution.
AB  - The goal of time-resolved crystallographic experiments is to capture dynamic
      "snapshots" of molecules at different stages of a reaction pathway. In recent
      work, we have developed approaches to determine determined light-induced
      conformational changes in the proton pump bacteriorhodopsin by electron
      crystallographic analysis of two-dimensional protein crystals. For this purpose,
      crystals of bacteriorhodopsin were deposited on an electron microscopic grid and
      were plunge-frozen in liquid ethane at a variety of times after illumination.
      Electron diffraction patterns were recorded either from unilluminated crystals or
      from crystals frozen as early as 1 ms after illumination and used to construct
      projection difference Fourier maps at 3.5-A resolution to define light-driven
      changes in protein conformation. As demonstrated here, the data are of a
      sufficiently high quality that structure factors obtained from a single electron
      diffraction pattern of a plunge-frozen bacteriorhodopsin crystal are adequate to
      obtain an interpretable difference Fourier map. These difference maps report on
      the nature and extent of light-induced conformational changes in the photocycle
      and have provided incisive tools for understanding the molecular mechanism of
      proton transport by bacteriorhodopsin.

PMID- 10600555
TI  - Visualizing a new binding site of ncd-motor domain on tubulin.
AB  - Ncd is a microtubule minus-end directed motor of the kinesin superfamily.
      Previously it has been shown that ncd and kinesin motor domains share the same
      major binding site on microtubules. Here we report a three-dimensional EM
      reconstruction of negatively stained two-dimensional Zn-induced tubulin crystal
      sheets (Zn-sheets) decorated with the ncd motor domain at a resolution of 16 A.
      This work has revealed a second specific binding site for the ncd motor domain.
      The motor binding site on the tubulin Zn-sheets spans both alpha and beta tubulin
      subunits. This binding site is located at a position different from the
      previously identified ncd binding site on microtubules and may play a role in
      motor function.

PMID- 10600556
TI  - The structure of aquaporin-1 at 4.5-A resolution reveals short alpha-helices in
      the center of the monomer.
AB  - Aquaporin-1 is a water channel found in mammalian red blood cells that is
      responsible for high water permeability of its membrane. Our electron
      crystallographic analysis of the three-dimensional structure of aquaporin-1 at
      4.5-A resolution confirms the previous finding that each subunit consists of a
      right-handed bundle of six highly tilted transmembrane helices that surround a
      central X-shaped structure. In our new potential map, the rod-like densities for
      the transmembrane helices show helically arranged protrusions, indicating the
      positions of side chains. Thus, in addition to the six transmembrane helices,
      observation of helically arranged side-chain densities allowed the identification
      of two short alpha-helices representing the two branches of the central X-shaped
      structure that extend to the extracellular and cytoplasmic membrane surfaces. The
      other two branches are believed to be loops connecting the short alpha-helix to a
      neighboring transmembrane helix. A pore found close to the center of the
      aquaporin-1 monomer is suggested to be the course of water flow with implications
      for the water selectivity.

PMID- 10600557
TI  - Haloarcula marismortui 50S subunit-complementarity of electron microscopy and X
      Ray crystallographic information.
AB  - The large 50S subunit of the Haloarcula marismortui 70S ribosome was solved to 19
      A using cryo-electron microscopy and single particle reconstruction techniques
      and to 9 A using X-ray crystallography. In the latter case, phases were
      determined by multiple isomorphous replacement and anomalous scattering from
      three heavy atom derivatives. The availability of X-ray and electron microscopy
      (EM) data has made it possible to compare the results of the two experimental
      methods. In the flexible regions of the 50S subunit, small differences in the
      mass distribution were detected. These differences can be attributed to the
      influence of packing in the crystal cell. The rotationally averaged power spectra
      of X-ray and EM were compared in an overlapping spatial frequency range from 60
      to 13 A. The resulting ratio of X-ray to EM power ranges from 1 to 15, reflecting
      a progressively larger underestimation of the Fourier amplitudes by the electron
      microscope.

PMID- 10600558
TI  - Scaling structure factor amplitudes in electron cryomicroscopy using X-Ray
      solution scattering.
AB  - The structure factors derived from electron cryomicroscopic images are modified
      by the contrast transfer function of the microscope's objective lens and other
      influences. The phases of the structure factors can be corrected in a
      straightforward way when the positions of the contrast transfer function rings
      are determined. However, corrected amplitudes are also essential to yield an
      accurate distribution of mass in the reconstruction. The correct scale factors
      for the amplitudes are difficult to evaluate for data that are merged from many
      different micrographs. We opt to use X-ray solution scattering intensity from a
      concentrated suspension of the specimen to correct the amplitudes of the
      spherically averaged structure factors. When this approach is applied to the
      three-dimensional image data of ice-embedded acrosomal bundles, the core of a
      filament in a three-dimensional reconstruction of the acrosomal bundle becomes
      denser and matches more closely the outer density ascribed to scruin.

PMID- 10600559
TI  - Review: resolution issues in single-particle reconstruction.
AB  - Specific factors that affect the resolution of single-particle reconstructions
      are discussed. We present reconstructions of six particles (DNA-dependent protein
      kinase catalytic subunit, alphaB-crystallin, the ribonucleoprotein vault,
      hepatitis A virus, adenovirus type 2, and the adenovirus type 12/alpha(v)beta5
      integrin complex), which have a variety of symmetries (asymmetric to 60-fold) and
      a wide range of molecular masses (470 kDa to 150 MDa). In the case of icosahedral
      viruses, we have found that applying a "soft" mask to remove regions of
      disordered density improves the resolution given by the Fourier shell correlation
      0.5 criterion. This masking procedure is also useful during refinement to improve
      the quality of the reference model and thus aid in precise alignment of the
      particle images. For asymmetric particles, we note that image classification,
      although often a necessary step to generate a first reconstruction, can limit the
      achievable resolution. The diameter of the particle and the available
      computational power can also affect the resolution, as can structural variability
      within the particle.

PMID- 10600560
TI  - Capsids of tricorn protease studied by electron cryomicroscopy.
AB  - Tricorn protease from the archaeon Thermoplasma acidophilum acts "downstream" of
      the proteasome; in conjunction with its aminopeptidase cofactors it converts
      peptides generated by the proteasome into free amino acids. The basic functional
      unit of Tricorn is a homohexamer of the 121-kDa subunit, 20 of which can assemble
      further to form an icosahedral capsid with a molecular mass of 14.6 MDa. We have
      used electron cryomicroscopy to determine the structure of the Tricorn capsids to
      a resolution of 1.3 nm.

PMID- 10600561
TI  - Review: rhinoviruses and their ICAM receptors.
AB  - The normal function of human intercellular adhesion molecule-1 (ICAM-1) is to
      provide adhesion between endothelial cells and leukocytes after injury or stress.
      ICAM-1 binds to leukocyte function-associated antigen or macrophage-1 antigen.
      However, ICAM-1 is also used as a receptor by the major group of human
      rhinoviruses and is a catalyst for the subsequent viral uncoating during cell
      entry. The three-dimensional atomic structure of the two amino-terminal domains
      (D1 and D2) of ICAM-1 has been determined to 2.2 A resolution and fitted into a
      cryoelectron microscopy reconstruction of a rhinovirus-ICAM-1 complex. Rhinovirus
      attachment is confined to the BC, CD, DE, and FG loops of the amino-terminal Ig
      like domain (D1) at the end distal to the cellular membrane. The loops are
      considerably different in structure to those of human ICAM-2 or murine ICAM-1,
      which do not bind rhinoviruses. There are extensive charge interactions between
      ICAM-1 and human rhinoviruses, which are mostly conserved in both major and minor
      receptor groups of rhinoviruses.

PMID- 10600562
TI  - Structural studies of cytoskeletal protein arrays formed on lipid monolayers.
AB  - Lipid monolayers have been widely used for the production of 2-D crystalline
      arrays of water-soluble proteins for structural analysis. Less well known is the
      utility of lipid layers for the assembly of multicomponent structures in two
      dimensions. This report summarizes current efforts and limitations to utilize a
      monolayer system composed of the quaternary ammonium surfactant
      didodecyldimethyammonium and dilaurylphosphatidylcholine to assemble 2-D
      complexes between actin and cytoskeletal proteins.

PMID- 10600563
TI  - EMAN: semiautomated software for high-resolution single-particle reconstructions.
AB  - We present EMAN (Electron Micrograph ANalysis), a software package for performing
      semiautomated single-particle reconstructions from transmission electron
      micrographs. The goal of this project is to provide software capable of
      performing single-particle reconstructions beyond 10 A as such high-resolution
      data become available. A complete single-particle reconstruction algorithm is
      implemented. Options are available to generate an initial model for particles
      with no symmetry, a single axis of rotational symmetry, or icosahedral symmetry.
      Model refinement is an iterative process, which utilizes classification by model
      based projection matching. CTF (contrast transfer function) parameters are
      determined using a new paradigm in which data from multiple micrographs are fit
      simultaneously. Amplitude and phase CTF correction is then performed
      automatically as part of the refinement loop. A graphical user interface is
      provided, so even those with little image processing experience will be able to
      begin performing reconstructions. Advanced users can directly use the lower level
      shell commands and even expand the package utilizing EMAN's extensive image
      processing library. The package was written from scratch in C++ and is provided
      free of charge on our Web site. We present an overview of the package as well as
      several conformance tests with simulated data.

PMID- 10600564
TI  - Expression, two-dimensional crystallization, and electron cryo-crystallography of
      recombinant gap junction membrane channels.
AB  - We used electron cryo-microscopy and image analysis to examine frozen-hydrated,
      two-dimensional (2D) crystals of a recombinant, 30-kDa C-terminal truncation
      mutant of the cardiac gap junction channel formed by 43-kDa alpha(1) connexin. To
      our knowledge this is the first example of a structural analysis of a membrane
      protein that has been accomplished using microgram amounts of starting material.
      The recombinant alpha(1) connexin was expressed in a stably transfected line of
      baby hamster kidney cells and spontaneously assembled gap junction plaques.
      Detergent treatment with Tween 20 and 1,2-diheptanoyl-sn-phosphocholine resulted
      in well-ordered 2D crystals. A three-dimensional density (3D) map with an in
      plane resolution of approximately 7.5 A revealed that each hexameric connexon was
      formed by 24 closely packed rods of density, consistent with an alpha-helical
      conformation for the four transmembrane domains of each connexin subunit. In the
      extracellular gap the aqueous channel was bounded by a continuous wall of protein
      that formed a tight electrical and chemical seal to exclude exchange of
      substances with the extracellular milieu.

PMID- 10600565
TI  - Methods for reconstructing density maps of "single" particles from cryoelectron
      micrographs to subnanometer resolution.
AB  - Recently the resolution attainable in density maps calculated from cryo-electron
      micrographs of free-standing virus capsids has advanced to resolutions below 1
      nm. This represents a significant milestone in that resolutions of this order
      potentially allow direct visualization of individual elements of protein
      secondary structure (i.e., alpha-helices), in addition to the shapes and
      connectivity of subdomains. We describe here a computational strategy for
      structural analyses at this level of detail: its principal innovation is a
      procedure for correcting the contrast transfer function of the electron
      microscope. Also important is the practice of combining data from pairs of
      differently defocused micrographs to improve the signal-to-noise ratio of the
      images, thereby allowing more precise determinations of the particles'
      orientations and origins and contributing to higher resolution reconstructions.
      These procedures proved instrumental in our analysis of the capsid of hepatitis B
      virus at 9-A resolution (Conway et al., 1997, Nature 386, 91-94). Finally, we
      discuss the prospects for achieving comparable resolutions for isolated
      macromolecular complexes with lower symmetry or no symmetry and for further
      extension of the resolution.

PMID- 10600567
TI  - Three-dimensional visualization of the Golgi apparatus: observation of Brunner's
      gland cells by a confocal laser scanning microscope.
AB  - The three-dimensional structure of the Golgi apparatus in cells of the Brunner's
      gland in the mouse was observed by using a confocal laser scanning microscope.
      Two lectins, FITC-labeled soybean agglutinin and Texas red-labeled Griffonia
      simplicifolia agglutinin II, were used to visualize the whole Golgi apparatus.
      Staining with the former lectin, which has been known to label the cis-stacks,
      showed a lacy dome-like structure situated in the supranuclear region. Staining
      with the latter lectin, known to label the intermediate-to-trans-stacks and the
      secretory granules, showed a dome-like structure consisting of network and
      cobblestone-like patterns in the same region and also granular stainings near the
      surface of the cobblestone-like patterns and the apical region of a cell. Double
      staining demonstrated that the soybean agglutinin-labeled network always
      surrounded the G. simplicifolia agglutinin II-stained structure. Based on these
      observations, we propose a new three-dimensional model of the Golgi apparatus: it
      forms a dome-like structure over a nucleus, a network of cis-stacks forms its
      outer boundary, and this outer boundary is lined and paved with successive
      intermediate and trans-stacks. It is thought that secretory granules are released
      toward the internal space of the Golgi apparatus and transported to the apical
      cytoplasm through the holes of the network.

PMID- 10600566
TI  - Formation of helical protein assemblies of IgG and transducin on varied lipid
      tubules.
AB  - Helical protein arrays on lipid tubules are valuable assemblies for studying
      protein structure and protein-lipid interactions through electron microscopy and
      crystallography. We describe conditions for forming such arrays from two
      proteins, IgG and transducin, the photoreceptor G protein, using a variety of
      lipid surfaces. Anti-dinitrophenyl (DNP) IgG arrays formed on DNP
      phosphatidylethanolamine (DNP-PE) mixed with either galactosyl-ceramide lipids or
      phosphatidylcholine (PC) display different pH sensitivities and dimensions, yet
      have similar helical symmetries. DNP-PE/PC mixtures formed small crystals and
      large well-ordered flattened tubules. The peripheral membrane protein transducin
      (G(t)) formed helical arrays either on a mixture of cationic and neutral lipids
      or on residual photoreceptor lipids. Despite differences in lipid composition,
      the G(t) arrays have similar structures and show similar sensitivity to
      activation and variations in ionic environment. G(t) activation causes the
      helical assemblies to collapse to small vesicles, a process resembling the
      vesiculation of activated dynamin-lipid tubules. In a preliminary three
      dimensional reconstruction, the hapten-bound IgG appears to make two contacts to
      the central lipid tubule, presumably via the F(ab) domains. The ability to
      generate a three-dimensional reconstruction without tilts illustrates one
      advantage of helical structures for two-dimensional crystallography, especially
      for visualizing protein-lipid interactions.

PMID- 10600568
TI  - Simultaneous localization of transcription and early processing markers allows
      dissection of functional domains in the plant cell nucleolus.
AB  - Nucleolar transcription in isolated onion cell nuclei was visualized, after Br
      UTP incorporation, under the conventional fluorescence microscope, the confocal
      microscope, and the transmission electron microscope. The confocal microscopy
      study of transcription was combined with immunodetection of fibrillarin, a
      component of the RNP complex involved in the early processing of pre-rRNA.
      Superposition of transcription and fibrillarin images from the same optical
      section showed some small "black holes" in the nucleolus, around which a lateral
      and radial differentiation of labeling was observed: laterally, zones
      corresponding to transcription labeling alternated with zones of fibrillarin
      labeling; radially, areas of transcription gradually became areas of
      colocalization of transcription and fibrillarin, and, further outward, of
      fibrillarin alone, which occupied the major part of the labeled nucleolar area.
      Three-dimensional reconstruction of the nucleolar transcription labeling, from
      confocal optical sections, showed clusters of foci arranged around an area of low
      or no labeling. Thin labeled extensions, connecting single foci, were observed.
      Visualization of transcription at the ultrastructural level identified the black
      holes as fibrillar centers, in view of their size and the absence of labeling in
      them. In fact, most of the labeling was observed in discrete areas of the dense
      fibrillar component, near fibrillar centers, including the transition area
      between these two components. This observation was supported by a quantitative
      study. Otherwise, the outline of fibrillar centers did not appear entirely
      surrounded by particles, and a minor proportion of particles was detected
      dispersed throughout the dense fibrillar component. As a complementary study, the
      transcription factor upstream binding factor (UBF) and the protein NopA64, a
      plant nucleolin homologue, were immunolocalized. Small foci of UBF localization
      alone and other foci in which the two protein markers overlapped were observed.
      The outer areas of the nucleolus showed the exclusive presence of NopA64. Under
      the electron microscope, UBF labeling, quantitatively assessed, appeared as
      clusters of particles, most of them surrounding fibrillar centers. A graphic
      model is presented to give a molecular interpretation of these data.

PMID- 10600569
TI  - Fast and accurate three-dimensional reconstruction from projections with random
      orientations via radon transforms
AB  - A new algorithm for three-dimensional reconstruction from randomly oriented
      projections has been developed. The algorithm recovers the 3D Radon transform
      from the 2D Radon transforms (sinograms) of the projections. The structure in
      direct space is obtained by an inversion of the 3D Radon transform. The
      mathematical properties of the Radon transform are exploited to design a special
      filter that can be used to correct inconsistencies in a data set and to fill the
      gaps in the Radon transform that originate from missing projections. Several
      versions of the algorithm have been implemented, with and without a filter and
      with different interpolation methods for merging the sinograms into the 3D Radon
      transform. The algorithms have been tested on analytical phantoms and
      experimental data and have been compared with a weighted back projection
      algorithm (WBP). A quantitative analysis of phantoms reconstructed from noise
      free and noise-corrupted projections shows that the new algorithms are more
      accurate than WBP when the number of projections is small. Experimental
      structures obtained by the new methods are strictly comparable to those obtained
      by WBP. Moreover, the algorithm is more than 10 times faster than WPB when
      applied to a data set of 1000-5000 projections. Copyright 1999 Academic Press.

PMID- 10600570
TI  - Structure of the Ni/Fe-S protein subcomponent of the acetyl-CoA
      decarbonylase/synthase complex from Methanosarcina thermophila at 26-A
      resolution.
AB  - The acetyl-CoA decarbonylase/synthase (ACDS) complex is responsible for synthesis
      and cleavage of acetyl-CoA in methanogens. The complex is composed of five
      different subunits, with a probable stoichiometry of
      alpha(8)beta(8)gamma(8)delta(8)epsilon(8). The native molecular mass of a
      subcomponent of the ACDS complex from Methanosarcina thermophila, the Ni/Fe-S
      protein containing the 90-kDa alpha and 19-kDa epsilon subunits, was determined
      by scanning transmission electron microscopy. A value of 218.6 +/- 19.6 kDa (n =
      566) was obtained, thus establishing that the oligomeric structure of this
      subcomponent is alpha(2)epsilon(2). The three-dimensional structure of
      alpha(2)epsilon(2) was determined at 26-A resolution by analysis of a large
      number of electron microscopic images of negatively stained, randomly oriented
      particles. The alpha(2)epsilon(2) subcomponent has a globular appearance, 110 A
      in diameter, and consists of two large, hemisphere-like masses that surround a
      hollow internal cavity. The two large masses are connected along one face by a
      bridge-like structure and have relatively less protein density joining them at
      other positions. The internal cavity has four main openings to the outside, one
      of which is directly adjacent to the bridge. The results are consistent with a
      structure in which the large hemispheric masses are assigned to the two alpha
      subunits, with epsilon(2) as the bridge forming a structural link between them.
      The structure of the alpha(2)epsilon(2) subcomponent is discussed in connection
      with biochemical data from gel filtration, crosslinking, and dissociation
      experiments and in the context of its function as a major component of the ACDS
      complex.

PMID- 10600571
TI  - Investigation into the acyl chain packing of endotoxins and phospholipids under
      near physiological conditions by WAXS and FTIR spectroscopy.
AB  - The acyl chain packing of various endotoxins and phospholipids was monitored via
      the main wide-angle reflection between 0.410 and 0.460 nm by wide-angle X-ray
      scattering (WAXS) and via the absorption band of the symmetric stretching
      vibration of the methylene groups v(s)(CH(2)) around 2849 to 2853 cm(-1) by
      Fourier-transform infrared spectroscopy. The lipids investigated included various
      rough mutant (R) and smooth form (S) lipopolysaccharides (LPS) differing in the
      length of the sugar portion, lipid A, the "endotoxic principle" of LPS, and
      various saturated and unsaturated phospholipids with different head groups under
      a near physiological (>/=85%) water content. The packing density of the saturated
      endotoxin acyl chains is lower than those of saturated phospholipids but similar
      to those of monounsaturated phospholipids, each in the gel phase. The hydrophobic
      moiety of endotoxins thus exhibits significant conformational disorder already in
      the gel phase. The acyl chain packing of the endotoxins decreases with increasing
      length of the sugar chain lengths, which seems to be relevant to the observed
      differences in biological activity. For Re-LPS with different counterions (salt
      forms), in the presence of externally added cations or at reduced water content
      (50%), no change of the acyl chain packing density is deduced in the X-ray data,
      although the FT-IR data indicate its increase. The position of the v(s)(CH(2))
      vibration is, thus, only a relative measure of lipid order, in particular when
      lipids with different head groups and in the presence of external agents are
      compared.

PMID- 10600572
TI  - Quantitative energy-dispersive X-ray microanalysis of calcium dynamics in cell
      suspensions during stimulation on a subsecond time scale: preparative and
      analytical aspects as exemplified with paramecium cells.
AB  - We analyzed preparative and analytical aspects of the dynamic localization of
      Ca(2+) during cell stimulation, using a combination of quenched flow and energy
      dispersive X-ray microanalysis (EDX). Calcium (or Sr, as a substitute) was
      retained as fluorides during freeze-substitution, followed by epoxide embedding.
      The quenched-flow used allowed analyses, during stimulation, in the subsecond
      time range. Sections of 500 nm were analyzed and no artificial Ca or Sr leakage
      was recognizable. We calculated a primary beam spread from 63 to 72 nm that
      roughly indicated the resolution of EDX/structure correlation. These values are
      quite compatible with the size of potential structures of interest, e.g., Ca
      stores (approximately 100-nm thickness) or cilia (approximately 250-nm diameter).
      We used widely different standards to calibrate the ratio of CaK(alpha) net
      counts in relation to actual ?Ca. Calibration curves showed a linear relationship
      and a detection limit of ?Ca = 2 mM, while ?Ca in cytosol was 3 mM and in stores
      was 43 mM, both in nonactivated cells. Eventually Sr(2+) can rapidly be
      substituted for Ca(2+) in the medium before and during stimulation, thus allowing
      one to determine Me(2+) fluxes. With our "model" cell, Paramecium, we showed
      that, upon stimulation (causing rapid Ca(2+) mobilization from subplasmalemmal
      stores), Ca was immediately exchanged for Sr in stores.

PMID- 10600573
TI  - Selective cleaning of the cell debris in human chromosome preparations studied by
      scanning force microscopy.
AB  - The chromosome structure is one of most challenging biological structures to be
      discovered. Most evidence about the structure comes from optical microscopy.
      Scanning force microscopy (SFM) can achieve molecular resolution and allows
      imaging in liquids. However, little information about the chromosome structure
      has been revealed by SFM. In this work, a mild enzymatic treatment is applied to
      the chromosomes to remove selectively the RNA and proteins coming from the cell.
      The resulting SFM images indicate that a protein film with embedded RNA molecules
      covers chromosomes in standard cytogenetic preparations. The thickness of the
      protein layer is 15-35 nm and the RNA adheres preferentially to the chromosome
      surface. The cell material film results in a quite smooth chromosome surface
      without evidence of any structural detail. After treatment, the chromosome was
      cleaned from cell residues and individual chromatin fibers at the surface were
      resolved. Furthermore, insights about the higher order structure of the
      chromosome can be inferred.

PMID- 10600574
TI  - Crystallization of a macromolecular ring assembly of tubulin liganded with the
      anti-mitotic drug podophyllotoxin.
AB  - The interaction of the anti-cancer drug podophyllotoxin with a high-molecular
      weight assembly of tubulin has been employed to produce three-dimensional
      crystals from avian erythrocyte tubulin as well as from pig brain tubulin. Avian
      erythrocyte tubulin crystals belong to the space group C2 with unit cell
      dimensions a = 740 A, b = 330 A, c = 460 A, beta = 128 degrees. The basis of
      these crystals is ring oligomers with a molecular mass of approximately 6 x 10(6)
      Da. So far, the crystals diffract to 8-A resolution and a first complete data set
      to 12-A resolution has been collected under cryogenic conditions. The crystals
      grew from conventionally purified tubulin consisting of multiple isoforms and
      different posttranslational modifications. Thus, the use of highly homogeneous
      tubulin preparations should improve the diffraction quality of these crystals.

PMID- 10600575
TI  - Crystallization and preliminary crystallographic study of stonustoxin, a protein
      lethal factor isolated from the stonefish (Synanceja horrida) venom.
AB  - Crystals of stonustoxin have been obtained and diffract to 3.4 A resolution.
      Stonustoxin is a protein lethal factor isolated from the venom of the stonefish,
      Synanceja horrida. The crystals belong to the tetragonal space group P422, with
      unit cell constants a = b = 109.0 A, c = 245.7 A. A native stonustoxin molecule
      has two subunits, designated alpha and beta, respectively, and there is one
      stonustoxin molecule per asymmetric unit.

PMID- 10600576
TI  - Crystallization and preliminary X-ray crystallographic studies on the herpes
      simplex virus 1 single-stranded DNA binding protein.
AB  - Crystals of a 60-amino-acid C-terminal deletion mutant of the herpes simplex
      virus 1 single-stranded DNA binding protein, ICP8, have been grown by hanging
      drop vapor diffusion. The colorless crystals grow as thin plates to a maximum
      size of approximately 0.3 mm x 0.3 mm x 0.05 mm. The space group is P2(1)2(1)2(1)
      with unit cell constants a = 101.2 A, b = 145.8 A, and c = 162.9 A. There are one
      or two molecules of ICP8 per asymmetric unit.

PMID- 10600577
TI  - Withdrawal of long-term antiepileptic treatment in children.

PMID- 10600578
TI  - Relapse risk analysis after drug withdrawal in epileptic children with
      uncomplicated seizures.
AB  - In an attempt to find the risk of relapse and factors predictive of risk of
      relapse, 97 children with epilepsy, withdrawn from their medication, followed in
      our outpatient clinic from 1990 to 1995 were included in this study. The overall
      relapse rate was 20.6%. All relapses occurred within 2 years after withdrawal
      started. Female gender, age at onset of seizures of more than 2 years, and the
      duration of withdrawal were found to be significant risk factors in relapse rate
      following univariate analysis. However, gender was not found to be significant in
      multivariate analysis. All other factors, including the duration of seizures
      prior to starting antiepileptic drug (AED) treatment, the number of seizure
      before the start of AED treatment, the period between AED induction and control
      of seizures, diagnostic yield from electroencephalogy (EEG) at diagnosis, the
      number of seizures after the onset of AED therapy, length of seizure-free period,
      aetiology of the seizures, a history of epilepsy in the immediate family, or
      previously experienced febrile convulsions were not significant factors in
      relapse rate. Significant risk factors for relapse rate also significantly
      affected relapse time. We conclude that when AED therapy is withdrawn from
      children with uncomplicated epilepsy, as in our patients, the two important risk
      factors, age at onset of seizures and the duration of withdrawal, can predict a
      poor prognosis with a higher relapse rate: this needs taking into consideration.

PMID- 10600579
TI  - Patterns of brain activity in patients with epilepsy and depression.
AB  - Depression is a recognized feature of epilepsy. This study tested the hypothesis
      that depression arising in patients with epilepsy would be associated with
      decreased activity in brain regions previously demonstrated to be hypoperfused
      both in primary depression and in depression secondary to movement disorders. Two
      groups of patients with temporal lobe epilepsy were studied, one of which also
      met DSM IV criteria for a major depressive episode. All underwent a SPECT scan
      using the blood flow marker,(99m)Tc-HMPAO. An automated voxel-based analysis
      demonstrated no regions of relatively decreased activity in the depressed
      compared with the non-depressed patients. Sites of relative hyperactivity in the
      depressed group were concentrated in the left hemisphere, particularly in
      dorsolateral prefrontal cortex, striatum, thalamus and temporo-parietal regions.
      Comparison of these data with normal population data revealed that in the
      depressed epilepsy group regional activities were within the normal range whilst
      corresponding results from the non-depressed group were below it. Depressed
      patients with epilepsy have cerebral regions with greater perfusion than non
      depressed people with epilepsy, although they are not hyperperfused compared with
      normals. Our results suggest that depression in people with epilepsy may arise
      from a mechanism which differs from that underlying the development of depression
      in patients with movement disorders.

PMID- 10600580
TI  - Women with epilepsy: their views about their treatment and care.
AB  - This study reports the results of a questionnaire survey of female members of the
      British Epilepsy Association. The women were asked about their epilepsy and its
      management. A questionnaire was sent to 6000 BEA women members of whom 1855 (31%)
      replied. The majority of women (89%) stated they currently take older
      antiepileptic medications, either as monotherapy or in combination with others.
      Newer antiepileptic drugs were prescribed to 30% of women. The most frequently
      mentioned antiepileptic drug side-effects were tiredness and forgetfulness.
      Seventy percent of the sample considered that the lack of energy had at least a
      moderate impact on their life. Thirty-eight percent of women would have liked
      better seizure control whilst 32% agreed that they would prefer to change to a
      medication with fewer side-effects. However, 49% were reluctant to change their
      medication. Fifty-nine percent stated that they see their hospital specialist
      regularly whilst half the sample (49%) saw their GP regularly. Hospital
      specialists on the whole, played a more active role in the management of epilepsy
      than GPs. Many women (68%) felt that their GP's main task appeared to be to write
      prescriptions and 40% felt that they knew more about their epilepsy than their
      GP. However, the women generally perceived that their GP or hospital specialists
      were sympathetic to their condition and their concerns.

PMID- 10600581
TI  - Vigabatrin and tiagabine are pharmacologically different drugs. A pre-clinical
      study.
AB  - In light of theirclosely related mechanisms of action, and preliminary clinical
      evidence suggesting that they possess similar efficacies, it has been anecdotally
      suggested that vigabatrin and tiagabine may prove to be therapeutically
      indistinguishable. As a result, we have conducted a preclinical comparison of
      their anticonvulsant profile and mechanism of action. Pentylenetetrazol and
      maximal electroshock seizures were employed to determine the experimental
      anticonvulsant profile. Mechanisms of action were investigated using assays of
      gamma -aminobutyric acid (GABA), GABA-transaminase and glutamic acid
      decarboxylase in mouse brain and GABA uptake and GABA-transaminase in rat
      astrocyte cultures. Vigabatrin was without effect on either pentylenetetrazol- or
      maximal electroshock-induced seizures, whereas tiagabine increased the latency to
      pentylenetetrazol seizures and reduced the incidence of maximal electroshock
      seizures. In mouse brain assays, tiagabine was without effect, while vigabatrin
      increased GABA concentrations and reduced GABA-transaminase and glutamic acid
      decarboxylase activities. In cortical astrocyte cultures, vigabatrin reduced the
      activities of both GABA uptake and GABA-transaminase, whereas tiagabine blocked
      GABA uptake alone. These results suggest that vigabatrin and tiagabine have
      differing efficacy in experimental seizure models and distinct neurochemical
      effects. It is possible, then, that these drugs will have different spectra of
      activity and toxicity profiles in human epilepsy.

PMID- 10600582
TI  - Epilepsy, employment and the disability discrimination act. Does legislation make
      a difference?
AB  - The Disability Discrimination Act 1995 confers limited but significant rights on
      people with disabilities in the United Kingdom. In this article we focus on the
      protection that the Act offers to people with epilepsy in the sphere of
      employment. We examine the exempt categories of employment and the extent to
      which epilepsy qualifies as a disability for statutory purposes. We go on to
      explore the impact of the new law on the recruitment and employment experience of
      people with epilepsy. The shortcomings of the legislation are highlighted and
      improvements, which would benefit people with epilepsy, are recommended. Claims
      featuring epilepsy, brought under the Act, are analysed to illustrate how the
      legislation is being interpreted and applied.

PMID- 10600583
TI  - Effects of information on parental knowledge of febrile convulsions.
AB  - The purpose of this study was to study the effects of giving information to
      parents with febrile convulsive children. All parents of children with febrile
      convulsions who are seen at Worcester Royal Infirmary are given information.
      Fifty parents of children who had had a first febrile convulsion during May 1996
      to December 1996 were interviewed by telephone from July to September 1997. The
      same questions were asked of 50 parents of children who came to a community
      health clinic and who had not had febrile convulsions. The design used open
      questions and covered medical history, general child health knowledge and
      knowledge of febrile convulsion. The answers were compared using a chi-squared
      test (significance level P < 0.05). Possible confounding factors were tested by a
      correlation test. No difference was found between the two groups in family
      structure, housing, and general child health knowledge. Information about febrile
      convulsions was retained by informed parents. Both groups thought the given
      information was useful and should be written in the child health record book.
      Information about febrile convulsions was remembered by parents.

PMID- 10600584
TI  - Headaches and other pain symptoms among patients with psychogenic non-epileptic
      seizures.
AB  - Studies of patients with psychogenic non-epileptic seizures (NES) typically focus
      upon the phenomenology and outcome of NES episodes. Little is known, however,
      about the frequency and nature of other somatic symptoms such as pain, in this
      population. To assess the frequency, location and severity of symptoms of pain
      among NES patients, we administered structured interviews to 56 patients, 6 or
      more months following the diagnosis of psychogenic non-epileptic seizures (NES).
      Patients were recruited from a tertiary hospital-based epilepsy monitoring unit.
      Seventy-seven percent of patients suffered from moderate to severe pain, most
      commonly headache (61%), while neck pain and backache were also common. Twenty
      six of 27 patients with persistent NES vs. 17 of 29 patients whose NES resolved
      experienced moderate to severe pain (P < 0.001). Pain is an under-recognized
      problem that occurs frequently and with significant severity among NES patients.
      Pain symptoms are more common among patients with persistent NES than those whose
      NES resolve.

PMID- 10600585
TI  - Limbic encephalitis and hyperactive foci on PET scan.
AB  - Two cases of patients with paraneoplastic limbic encephalitis, difficult to
      control seizures, and unilateral hippocampal hypermetabolism on positron emission
      tomography (PET) are described. Two women aged 33 and 61 presented with
      uncontrolled complex partial seizures, profound memory loss and cognitive
      decline. One was later diagnosed with breast cancer and the other with lung
      cancer. Video-EEG on the first patient recorded multifocal sharp waves and
      bilateral independent seizure onsets. The second patient had no epileptiform
      discharges and bitemporal ictal onset, even though the clinical seizures
      suggested a right temporal onset. Magnetic resonance imaging (MRI) was normal in
      both patients. PET scans obtained in the interictal state showed right
      hippocampal hypermetabolism in both patients. In the second patient, the lung
      cancer was irradiated with resolution of seizures and improvement of memory
      function. A PET scan six months later was normal. Subsequent seizure recurrence
      and worsening of memory led to the discovery of widespread metastases. Limbic
      encephalitis should be considered in the differential diagnosis of intractable
      partial epilepsy, particularly if accompanied by severe memory loss and cognitive
      decline. Treatment of the underlying cancer may be lead to improved seizure
      control. Hippocampal hypermetabolism may be a common feature on PET, and may
      indicate subclinical seizure activity.

PMID- 10600586
TI  - A unique effect of clonazepam on frontal lobe seizure control.
AB  - In a 16-year-old female, clonazepam (CZP) changed randomly occurring intractable
      tonic seizures of frontal lobe origin to a few sleep seizures when used as an
      adjunctive therapy. The significance of this change in the seizure pattern is
      discussed with an explanation of possible pathophysiologic mechanism.

PMID- 10600587
TI  - The acceptability of sleep-deprived electroencephalograms.
AB  - The aim of this study was to ascertain the acceptability of sleep-deprived EEGs
      to parents and their young child. Fifty unselected children having a sleep
      deprived EEG were recruited. Data were collected from a sleep diary, a parent
      questionnaire and the request form of the EEG. Data collected covered
      developmental, learning and behavioural problems and the acceptability of the
      sleep-deprived EEG. There were 29 males (58%) in the study group. The average age
      was 8.6 years (range 2-17 years). Fifty percent of parents found it difficult to
      keep their child awake at night and 30% of parents found it difficult to wake
      their child in the morning. Fifty-four percent of parents reported their child
      had difficult behaviour on the day of the EEG. None had seizures provoked by
      sleep deprivation.

PMID- 10600588
TI  - The burden and pharmacoeconomics of epilepsy in India.

PMID- 10600589
TI  - The primate lentivirus-encoded Nef protein can regulate several steps of the
      viral replication cycle.
AB  - The primate lentiviruses encode a protein, Nef, which is required for efficient
      viral replication in their host. Several biological activities of nef identified
      in vitro may contribute to this requirement in vivo, including receptor
      modulation and interference with cellular signaling pathways. We show that HIV-
      and SIV-encoded Nef can enhance virus production within a single viral
      replication cycle, not only by increasing viral infectivity, as previously
      reported, but also by acting through the efficiency of viral transcription and of
      viral release.

PMID- 10600590
TI  - Evolution of poliovirus type I during 5.5 years of prolonged enteral replication
      in an immunodeficient patient.
AB  - Poliovirus type 1 was isolated from an immunodeficient patient 4 days after onset
      of paresis (IS1) and after 5.5 years of prolonged enteral virus replication
      (IS2). Antigenic characterization revealed that IS1 was Sabin 1-like, whereas IS2
      reacted like poliovirus 1 Mahoney. Complete genomic sequencing demonstrated the
      phylogenetic relationship (94.9% identity) of IS1 and IS2, which differed from
      the most closely related Sabin 1 by 5.4 and 8.3%, respectively. Both isolates had
      revertant-like mutations at nucleotides 480 and 6203. Deduced amino acid
      sequences indicated significant changes between IS1 and IS2 at the neutralizing
      antigenic site 1. Prolonged enteral replication, evolution, and shedding of
      poliovirus by immunodeficient patients should be considered in the poliovirus
      eradication strategy.

PMID- 10600591
TI  - Inefficient measles virus budding in murine L.CD46 fibroblasts.
AB  - Infection of mouse L.CD46 fibroblasts with measles virus resulted in a poor virus
      yield, although no defects in the steps of virus binding, entry or fusion, were
      detected. Two days post-infection, the level of expression of the viral F protein
      was found to be similar on the surface of infected L.CD46 and HeLa cells using a
      virus multiplicity enabling an equal number of cells to be infected. After
      immunofluorescence labelling and confocal microscopy, L.CD46 cells also displayed
      a significant increase in the co-localisation of the N protein with the cell
      surface H and F proteins. Immunogold labelling and transmission electron
      microscopy demonstrated the accumulation of numerous nucleocapsids near the
      plasma membrane of L. CD46 cells with little virus budding, in contrast to
      infected HeLa cells which displayed fewer cortical nucleocapsids and more
      enveloped viral particles. Purified virus particles from infected L. CD46
      contained a reduced amount of H, F and M protein. Altogether, these data indicate
      that, in L.CD46 cells, the late stage of measles virus assembly is defective.
      This cellular model will be helpful for the identification of cellular factors
      controlling measles virus maturation.

PMID- 10600592
TI  - A mutation correcting the DNA interaction defects of a mutant phage lambda
      terminase, gpNu1 K35A terminase.
AB  - Terminase, the DNA packaging enzyme of bacteriophage lambda, is a heteromultimer
      composed of gpNu1 (181 aa) and gpA (641 aa) subunits, encoded by the lambda Nu1
      and A genes, respectively. Similarity between the deduced amino acid sequences of
      gpNu1 and gpA and the nucleotide binding site consensus sequence suggests that
      each terminase subunit has an ATP reactive center. Terminase has been shown to
      have two distinct ATPase activities. The gpNu1 subunit has a low-affinity ATPase
      stimulated by nonspecific DNA and gpA has a high-affinity ATPase. In previous
      work, a mutant terminase, gpNu1 K35A holoterminase, had a mild defect in
      interactions with DNA, such that twofold increased DNA concentrations were
      required both for full stimulation of the low-affinity ATPase and for saturation
      of the cos cleavage reaction. In addition, the gpNu1 K35A terminase exhibited a
      post-cleavage defect in DNA packaging that accounted for the lethality of the Nu1
      K35A mutation [Y. Hwang and M. Feiss (1997) Virology 231, 218-230]. In the work
      reported here, a mutation in the turn of the putative helix-turn-helix DNA
      binding domain has been isolated as a suppressor of the gpNu1 K35A change. This
      suppressor mutation causes the change A14V in gpNu1. A14V reverses the DNA
      binding defects of gpNu1 K35A terminase, both for stimulation of the low-affinity
      ATPase and for saturation of the cos cleavage defect. A14V suppresses the post
      cleavage DNA packaging defect caused by the gpNu1 K35A change.

PMID- 10600593
TI  - Structural and functional analysis of the 5' untranslated region of
      coxsackievirus B3 RNA: In vivo translational and infectivity studies of full
      length mutants.
AB  - The lengthy 5' untranslated region (5'UTR) of coxsackievirus B3 (CVB3) forms a
      highly ordered secondary structure, which plays an important role in controlling
      viral transcription and translation. Our previous work has delineated the
      internal ribosome entry site (IRES) by mutation of mono- and bicistronic plasmids
      containing the 5'UTR and subsequent cell- free translation in rabbit reticular
      lysate (D. Yang, J. E. Wilson, D. R. Anderson, L. Bohunek, C. Cordeiro, R.
      Kandolf, and B. M. McManus. (1997). Virology 228, 63-73). To further identify the
      sequence elements responsible for viral translation and infectivity in tissue
      culture cells, >30 full-length mutants of CVB3 were constructed by mutations of
      the IRES and its flanking regions. Viral RNAs were transcribed from these
      constructs and transfected into HeLa cells. When the stem-loops G and H in the
      putative IRES were deleted, viral infectivity was abolished and viral protein
      translation was also undetectable by immunoblot analysis. However, when stem
      loops A and B were deleted or stem-loop E was partially deleted, viral protein
      translation could be detected although cytopathic effect could not be observed.
      The data suggest that the crucial sequence of the IRES is located at stem-loops G
      and H. Further serial deletion mapping up and down stream of the crucial sequence
      defined more accurately the 5' and 3' boundaries of the IRES, located at
      nucleotides (nts) 309-432 and 639-670, respectively. These results indicate that
      the core sequence of the IRES should be located at nts 432-639. This IRES segment
      is much shorter and located closer to the initiation codon than that of
      poliovirus. To further define critical nucleotides within the IRES core, site
      directed mutagenesis was conducted at the IRES core sequence by PCR. A 46-nt
      deletion in the pyrimidine-rich tract of stem-loop G abolished viral translation
      and infectivity. Interestingly, five single-nt substitutions in the pyrimidine
      rich tract aimed at destabilizing the base pairing between the viral IRES and
      host 18S rRNA did not abolish CVB3 infectivity although viral protein translation
      was significantly reduced. This finding suggests that ribosomal internal
      initiation of translation and viral infectivity not only may require RNA
      secondary structure but also may need tertiary structure and perhaps the
      assistance of host protein factors.

PMID- 10600594
TI  - Possible emergence of new geminiviruses by frequent recombination.
AB  - Although exchange of genetic information by recombination plays a role in the
      evolution of viruses, the extent to which it generates diversity is not clear. We
      analyzed genomes of geminiviruses for recombination using a new statistical
      procedure developed to detect gene conversions. Geminiviruses (family,
      Geminiviridae) are a group of plant viruses characterized by a genome of circular
      single-stranded DNA (approximately 2700 nucleotides in length) encapsidated in
      twinned quasi-isometric particles. Complete nucleotide sequences of geminiviruses
      were aligned, and recombination events were detected by searching pairs of
      viruses for sequences that are significantly more similar than expected based on
      random distribution of polymorphic sites. The analyses revealed that
      recombination is very frequent and occurs between species and within and across
      genera. Tests identified 420 statistically significant recombinant fragments
      distributed across the genome. The results suggest that recombination is a
      significant contributor to geminivirus evolution. The high rate of recombination
      may be contributing to the recent emergence of new geminivirus diseases.

PMID- 10600595
TI  - The cognate coat protein is required for cell-to-cell movement of a chimeric
      brome mosaic virus mediated by the cucumber mosaic virus movement protein.
AB  - Cucumber mosaic cucumovirus (CMV) and brome mosaic bromovirus (BMV) have many
      similarities, including the three-dimensional structure of virions, genome
      organizations, and requirement of the coat protein (CP) for cell-to-cell
      movement. We have shown that a chimeric BMV with the CMV 3a movement protein (MP)
      gene instead of its own cannot move from cell to cell in Chenopodium quinoa, a
      common permissive host for both BMV and CMV. Another chimeric BMV was constructed
      by replacing both MP and CP genes of BMV with those of CMV (MP/CP-chimera) and
      tested for its infectivity in C. quinoa, to determine whether the CMV CP has some
      functions required for the CMV MP-mediated cell-to-cell movement and to exhibit
      functional difference between CPs of BMV and CMV. Cell-to-cell movement of the
      MP/CP-chimera occurred, and small local lesions were induced on the inoculated
      leaves. A frameshift mutation introduced in the CMV CP gene of the MP/CP-chimera
      resulted in a lack of cell-to-cell movement of the chimeric virus. These results
      indicate that the viral movement mediated by the CMV MP requires its cognate CP.
      Deletion of the amino-terminal region in CMV CP, which is not obligatory for CMV
      movement, also abolished cell-to-cell movement of the MP/CP-chimera. This may
      suggest some differences in cell-to-cell movement of the MP/CP-chimera and CMV.
      On the other hand, the sole replacement of BMV CP gene with that of CMV abolished
      viral cell-to-cell movement, suggesting a possibility that the viral movement
      mediated by the BMV MP may also require its cognate CP. Functional compatibility
      between MP and CP in viral cell-to-cell movement is discussed.

PMID- 10600596
TI  - SIV/HIV Nef recombinant virus (SHIVnef) produces simian AIDS in rhesus macaques.
AB  - The simian immunodeficiency virus (SIV) nef gene is an important determinant of
      viral load and acquired immunodeficiency syndrome (AIDS) in macaques. A role(s)
      for the HIV-1 nef gene in infection and pathogenesis was investigated by
      constructing recombinant viruses in which the nef gene of the pathogenic
      molecular clone SIVmac239 nef was replaced with either HIV-1sf2nef or HIV
      1sf33nef. These chimeras, designated SHIV-2nef and SHIV-33nef, expressed HIV-1
      Nef protein and replicated efficiently in cultures of rhesus macaque lymphoid
      cells. In two SHIV-2nef-infected juvenile rhesus macaques and in one of two SHIV
      33nef-infected juvenile macaques, virus loads remained at low levels in both
      peripheral blood and lymph nodes in acute and chronic phases of infection (for
      >83 weeks). In striking contrast, the second SHIV-33nef-infected macaque showed
      high virus loads during the chronic stage of infection (after 24 weeks). CD4+ T
      cell numbers declined dramatically in this latter animal, which developed simian
      AIDS (SAIDS) at 47-53 weeks after inoculation; virus was recovered at necropsy at
      53 weeks and designated SHIV-33Anef. Sequence analysis of the HIV-1sf33 nef gene
      in SHIV-33Anef revealed four consistent amino acid changes acquired during
      passage in vivo. Interestingly, one of these consensus mutations generated a tyr
      x-x-leu (Y-X-X-L) motif in the HIV-1sf33 Nef protein. This motif is
      characteristic of certain endocytic targeting sequences and also resembles a src
      homology region-2 (SH-2) motif found in many cellular signaling proteins. Four
      additional macaques infected with SHIV-33Anef contained high virus loads, and
      three of these animals progressed to fatal SAIDS. Several of the consensus amino
      acid changes in Nef, including Y-X-X-L motif, were retained in these recipient
      animals exhibiting high virus load and disease. In summary, these findings
      indicate that the SHIV-33Anef chimera is pathogenic in rhesus macaques and that
      this approach, i.e., construction of chimeric viruses, will be important for
      analyzing the function(s) of HIV-1 nef genes in immunodeficiency in vivo, testing
      antiviral therapies aimed at inhibiting AIDS, and investigating adaptation of
      this HIV-1 accessory gene to the macaque host.

PMID- 10600597
TI  - Protection of macaques against a SHIV with a homologous HIV-1 Env and a
      pathogenic SHIV-89.6P with a heterologous Env by vaccination with multiple gene
      deleted SHIVs.
AB  - To evaluate the potential of SHIVs as anti-HIV-1 live vaccines, we constructed
      two gene-deleted SHIVs, designated SHIV-drn and SHIV-dxrn. The former lacks
      vpr/nef and the latter lacks vpx/vpr/nef. Four macaques that had been vaccinated
      with SHIV-drn were challenged with SHIV-NM-3rN, which has an HIV-1 Env that is
      the same as that of SHIV-drn. No challenge virus was detected by DNA PCR in, or
      recovered from, two of the macaques. In the other two, challenge virus was
      detected once and twice, respectively. Plasma viral loads were much lower than
      those in unvaccinated controls. Another four macaques were vaccinated with SHIV
      dxrn. These macaques showed resistance but less than that of SHIV-drn-vaccinated
      macaques. When the two SHIV-drn-vaccinated macaques were challenged with
      pathogenic SHIV-89.6P, which has an HIV-1 Env that is antigenically different
      from that of SHIV-drn, replication of the challenge virus was restricted, and the
      usual decrease in the number of CD4(+) cells was prevented. In this protection,
      it is noteworthy that protection involved not only neutralizing antibodies and
      killer cell activity, but also other unknown specific and nonspecific immunity
      elicited by the infection.

PMID- 10600598
TI  - A CXC chemokine receptor, CXCR5/BLR1, is a novel and specific coreceptor for
      human immunodeficiency virus type 2.
AB  - G protein-coupled receptors serve as coreceptors in the infection process of
      human immunodeficiency virus type-1 (HIV-1), type-2 (HIV-2), and simian
      immunodeficiency virus (SIV). In this study, we showed that a CXC-CKR,
      CXCR5/BLR1, is a novel coreceptor for HIV-2, but for neither HIV-1 nor SIV. The
      expression of CXCR5 was detected by polymerase chain reaction after reverse
      transcription of cellular mRNA from S+L-HOS/CD4 cells and MT-2 human T cells, and
      the CXCR5 gene was cloned into an expression vector. S+L-HOS/CD4 cells were
      susceptible to several HIV-2 strains but not most HIV-1 strains. To examine a
      coreceptor activity of CXCR5, we used NP-2/CD4, which is a human glioma cell
      line, NP-2, transduced with the CD4 gene that shows strict resistance to
      infection with HIV-1, HIV-2, SIVmac, SIVagm, or SIVmnd strain. When CXCR5 was
      transduced into NP-2/CD4 cells, they became highly susceptible to HIV-2ROD and
      HIV-2CBL23 strains in a CD4-dependent manner but to not to HIV-1 or SIV strains.
      Anti-CXCR5 monoclonal antibody and a ligand for CXCR5, BCA-1, inhibited HIV-2
      infection to NP-2/CD4/CXCR5 cells. Our findings suggest a possibility that
      CXCR5/BLR1 serves as a coreceptor for HIV-2 strains in vivo.

PMID- 10600599
TI  - Insertional mutagenesis of AAV2 capsid and the production of recombinant virus.
AB  - The structural genes of adeno-associated virus serotype 2 (AAV2) have been
      altered by linker insertional mutagenesis in order to define critical components
      of virion assembly and infectivity. An in-frame restriction site linker was
      inserted across the capsid coding domain of a recombinant plasmid. After
      complementation in vivo, recombinant AAV2 viruses were generated and assayed for
      capsid production, packaging, transduction, heparin agarose binding, and
      morphology. Three classes of capsid mutants where identified. Class I mutants
      expressed structural proteins but were defective in virion assembly. Class II
      mutants generated intact virions that protected the viral genome from DNase, but
      failed to infect target cells. The majority of these mutants bound the heparin
      affinity matrix, suggesting that attachment to the AAV primary receptor was not
      rate limiting. One class II mutant, H2634, assembled virions and bound heparin
      using only Vp3, indicating that this subunit is responsible for mediating AAV
      receptor attachment. Finally, class III mutants assembled virions, encapsidated
      DNA, and infected target cells. Infectivity of these mutants ranged from 5 to
      100% of that of the wild-type, demonstrating for the first time the ability to
      alter capsid proteins without interfering with infectivity. These AAV virions
      with altered capsid subunits will provide critical templates for manipulating AAV
      vectors for cell-specific gene delivery in vivo. In summary, the AAV capsid
      variants described here will facilitate further study of virus assembly, entry,
      and infection, as well as advance the development of this versatile vector
      system.

PMID- 10600600
TI  - In vitro selection and characterisation of influenza B/Beijing/1/87 isolates with
      altered susceptibility to zanamivir.
AB  - We describe the in vitro selection and characterisation of virus derived from
      B/Beijing/1/87 passaged in the presence of zanamivir. During zanamivir passage,
      the phenotype of virus isolates was either drug dependent or drug resistant in
      plaque reduction assays. The susceptibility of the neuraminidase of the drug
      dependent isolates was unchanged from that of the wild-type enzyme. The drug
      dependent isolates contained two mutations in the viral haemagglutinin: V90A,
      close to the proposed secondary sialic acid-binding site, and L240Q, close to the
      primary sialic acid-binding site. Virus isolates that were drug resistant
      contained the same mutations in the haemagglutinin but also contained the
      mutation E116G in the neuraminidase. For the drug-dependent viruses, zanamivir
      susceptibility could not be measured because plaque numbers increased with
      increasing drug concentration. The in vitro zanamivir susceptibility of drug
      resistant viruses was lower than that of the wild-type virus by a factor of 275-
      to >2532-fold. Neuraminidase containing the E116G mutation has a 33-fold lower
      affinity for zanamivir than the wild-type enzyme. The finding that the same
      haemagglutinin mutations are found in both drug-dependent and drug-resistant
      viruses confirms that the same changes to the receptor binding function can
      contribute to both phenotypes. This observation demonstrates the interplay
      between the influenza virus haemagglutinin and neuraminidase in escape from
      zanamivir inhibition in vitro.

PMID- 10600601
TI  - Identification of a novel 0.7-kb polyadenylated transcript in the LAT promoter
      region of HSV-1 that is strain specific and may contribute to virulence.
AB  - Herpes Simplex virus expresses latency-associated transcripts (LATs) the function
      of which remains obscure despite increasing knowledge of their structure and
      expression. Upstream of the LAT coding region is a region of the genome that is
      poorly characterized although it lies in an area that is responsible for
      modulation of reactivation efficiency in two different animal models. Transcript
      mapping with strains 17, McKrae, KOS, and F has revealed strain differences in
      this region of the viral genome. Strain 17 and McKrae expressed a novel
      polyadenylated 0.7-kb transcript that is absent from KOS and F. This transcript
      is expressed in the LAT direction and has the kinetics of a true late gene during
      the lytic cycle of infection. A deletion mutant, 17DeltaBsa, which does not
      express the 0.7-kb RNA, is less virulent than the parental strain 17. A rescuant
      with F sequence (17DeltaBsa/RF) shows virulence similar to F, whereas a rescuant
      with strain 17 sequence (17DeltaBsa/R17) is similar to strain 17. Virulence is
      altered by deletion or substitution in the region encoding the 0.7-kb transcript
      (BsaI-BsaI); however, reactivation in the mouse explant cocultivation assay or
      the adrenergically induced rabbit reactivation model remained unchanged. The
      importance of this region for virulence is discussed.

PMID- 10600602
TI  - Bovine leukemia virus Gag particle assembly in insect cells: formation of
      chimeric particles by domain-switched leukemia/lentivirus Gag polyprotein.
AB  - A key stage in the life cycle of C-type retroviruses is the assembly of Gag
      precursor protein at the plasma membrane of infected cells. Here we report the
      assembly of bovine leukemia virus (BLV) gag gene product into virus-like
      particles (VLPs) using the baculovirus expression system. Expression of BLV
      Pr44(Gag) resulted in the assembly and release of VLPs, thereby confirming the
      ability of retroviral Gag polyprotein to assemble and bud from insect cells.
      Efficient particle formation required a myristoylation signal at the N-terminus
      of BLV Pr44(Gag). Recombinant baculoviruses expressing matrix (MA) or capsid
      nucleocapsid (CA-NC) proteins of BLV were generated but neither of these domains
      was capable of assembling into particulate structures. To assess the
      compatibility of Gag domains between leukemia and lentivirus groups three
      different recombinant chimeras each expressing MA of one virus (e.g., simian
      immunodeficiency or BLV) and CA-NC of another (e.g., BLV or human T-cell leukemia
      virus type-I) were constructed. Each of the chimeric proteins assembled
      efficiently and budded as VLPs, suggesting that the MA and CA domains of these
      two evolutionary divergent retrovirus groups can be functionally exchanged
      without perturbation of Gag VLP formation. The lenti-leukemia chimeric Gag
      approach has potential for studying protein-protein interactions in other
      retroviruses.

PMID- 10600603
TI  - Rapid and efficient cell-to-cell transmission of human immunodeficiency virus
      infection from monocyte-derived macrophages to peripheral blood lymphocytes.
AB  - Macrophages are considered of central importance in cell-to-cell transmission of
      human immunodeficiency virus (HIV) infection in vivo. In this report, we describe
      a novel cell-to-cell transmission model using HIV-infected monocyte-derived
      macrophages (MDMs) as donor cells and peripheral blood lymphocytes (PBLs) as
      recipients. Virus was transmitted during a 2-h coincubation period from
      intracellular or tightly cell-associated viral stores in adherent infected MDMs
      to nonadherent CD3(+) PBLs. Transmission required cell contact, but syncytia
      formation was not observed. HIV cell-to-cell transmission occurred in both
      allogeneic and autologous systems, and replication was higher in
      phytohemagglutinin (PHA)-stimulated than unstimulated recipient PBLs. In
      contrast, transmission of infection by cell-free virus was barely detectable
      without PHA stimulation of recipients, suggesting the cell-cell interaction may
      have provided stimuli to recipient cells in the cell-to-cell system. Viral DNA
      levels increased 5-24 h postmixing, and this increase was inhibited by
      pretreatment of cells with the reverse transcription inhibitor azidothymidine,
      indicating de novo reverse transcription was involved. Cell-to-cell transmission
      was more efficient than infection with cell-free virus released from donor MDMs,
      or 0.1 TCID(50)/cell cell-free viral challenge. This model provides a system to
      further investigate the mechanisms and characteristics of HIV cell-to-cell
      transmission between relevant primary cells that may be analogous to this
      important mode of virus spread in vivo.

PMID- 10600604
TI  - Efficient rescue of infectious bursal disease virus from cloned cDNA: evidence
      for involvement of the 3'-terminal sequence in genome replication.
AB  - To study the mechanism of replication of infectious bursal disease virus (IBDV),
      and to determine factors on the IBDV RNA which are involved in viral replication,
      we used cloned full-length cDNA of both the A- and B-segments to generate
      infectious IBDV. Infectious IBDV was rescued from plasmids that contained full
      length IBDV cDNA behind a T7 promoter, by transfecting these plasmids into cells
      which were infected with a recombinant Fowlpox virus that expressed T7 RNA
      polymerase. By using the cDNA transfection system we evaluated the effect of the
      length of the 3' terminus of the A-segment plus strand of IBDV. Although wild
      type IBDV predominantly contains four cytosines at the 3' terminus, no difference
      in virus yield was found when virus was rescued from cDNAs containing three to
      six adjacent cytosines. When the 3' terminus was shorter than three cytosines the
      efficiency to generate infectious IBDV from cDNA was reduced, but IBDV could
      still be recovered reproducibly. The rescued viruses from cDNAs containing 3'
      terminal deletions appeared to have a restored 3'-terminal sequence. The missing
      nucleotides are probably restored by using complementary bases of a stem-loop
      structure as template.

PMID- 10600605
TI  - Comparative analysis of the ability of the polymerase complexes of influenza
      viruses type A, B and C to assemble into functional RNPs that allow expression
      and replication of heterotypic model RNA templates in vivo.
AB  - Influenza viruses type A, B, and C are human pathogens that share common
      structural and functional features, yet they do not form natural reassortants. To
      determine to what extent type-specific interactions of the polymerase complex
      with template RNA contribute to this lack of genotypic mixing, we investigated
      whether homotypic or heterotypic polymerase complexes support the expression and
      replication of model type A, B, or C RNA templates in vivo. A plasmid-based
      expression system, as initially described by Pleschka et al. [(1996) J. Virol.
      70, 4188-4192] for influenza A virus, was developed for influenza viruses
      B/Harbin/7/94 and C/Johannesburg/1/66. The type A core proteins expressed
      heterotypic model RNAs with similar efficiencies as the homotypic RNA. The
      influenza B virus model RNA was efficiently expressed by all three types of
      polymerase complexes. Although no functional polymerase complex could be
      reconstituted with heterotypic P protein subunits, when the influenza A virus P
      proteins were expressed together with heterotypic nucleoproteins, significant,
      albeit limited, expression of RNA templates of all influenza virus types was
      detected. Taken together, our results suggest that less strict type-specific
      interactions are involved for the polymerase complex of influenza A compared with
      influenza B or C viruses.

PMID- 10600606
TI  - Glycans and proteoglycans are involved in the interactions of human
      immunodeficiency virus type 1 envelope glycoprotein and of SDF-1alpha with
      membrane ligands of CD4(+) CXCR4(+) cells.
AB  - We demonstrate that human immunodeficiency virus HIV-1(LAI) envelope glycoprotein
      120 (gp120(LAi)) specifically interacts with several membrane ligands on lymphoid
      CEM or monocytic U937 cells in addition to its previously identified receptor,
      CD4, and CXCR4, its coreceptor. In its native state, gp120(LAI) is able to elicit
      specific multimolecular complexes with these membrane ligands at the surface of
      the cells; most of the interactions are abolished by mannan or heparin but not by
      dextran. Similarly, stromal cell-derived factor (SDF)-1alpha interacts not only
      with CXCR4 expressed by CXCR4(+) CD4(+) U937, CEM, and HOS-CD4(+) CXCR4(+) cells
      but also with CD4 expressed by intact U937, CEM, and HOS-CD4(+) CXCR4(+/-) cells
      or electroblotted onto Immobilon. SDF-1alpha binding to CD4(+) CXCR4(+/-) cells,
      or soluble CD4 electroblotted onto Immobilon, is significantly inhibited by sCD4,
      whereas truncated sCD4 lacking D3 and D4 domains had no significant effect, which
      indicates that SDF-1 binds to CD4 but at regions different from the HIV-gp120
      binding site. Heparin and mannan also inhibit SDF-1alpha binding to intact CD4(+)
      CXCR4(+/-) cells, and electroblotted soluble CD4. Heparitinase treatment of such
      cells reduced SDF-1alpha binding. These data demonstrate that glycans and
      glycosaminoglycans are directly or indirectly involved in the interactions of HIV
      1 gp120(LAI) and of SDF-1alpha with membrane ligands of CD4(+) CXCR4(+) cells and
      thus could play a role both in HIV-1 infection and in the physiology of SDF
      1alpha.

PMID- 10600607
TI  - Naturally occurring, nonregressing canine oral papillomavirus infection: host
      immunity, virus characterization, and experimental infection.
AB  - Papillomaviruses occasionally cause severe, nonregressing or recurrent infections
      in their human and animal hosts. The mechanisms underlying these atypical
      infections are not known. Canine oral papillomavirus (COPV) typically regresses
      spontaneously and is an important model of mucosal human papillomavirus
      infections. A severe, naturally occurring, nonregressing COPV infection provided
      an opportunity to investigate some aspects of viral pathogenicity and host
      immunity. In this case, the papillomas proved refractory to surgical and medical
      treatments, including autogenous vaccination and vaccination with capsid (L1)
      virus-like particles. High levels of induced anti-L1 antibodies appeared to have
      no effect on the infection. The papillomas spread to oesophageal mucosa, perioral
      haired skin, and remote cutaneous sites. Isolation of COPV from the animal and
      sequencing of several regions of the viral genome showed no differences to the
      COPV prototype. Experimental infection of beagle dogs with this viral isolate
      resulted in the uncomplicated development and regression of oral warts within the
      usual period, indicating that the virus was not an unusual pathogenic variant.
      These findings support the hypothesis that the recurrent lesions seen in some
      human papillomavirus infections, such as recurrent laryngeal papillomatosis, are
      associated with specific defects in host immunity rather than variations in viral
      pathogenicity.

PMID- 10600608
TI  - The vaccinia virus 39-kDa protein forms a stable complex with the p4a/4a major
      core protein early in morphogenesis.
AB  - The vaccinia virus (VV) 39-kDa protein, the product of the A4L gene, is a highly
      antigenic protein of the viral core. Pulse-chase and immunoprecipitation
      experiments have shown that the 39-kDa protein interacts with p4a (encoded by the
      A10L gene), the precursor of the most abundant virion protein. This interaction
      is maintained with the processed 4a form that arises during virion maturation.
      The controlled disruption of mature viral particles showed that the 39-kDa and 4a
      proteins are tightly bound within the virion. Immunoelectron microscopy showed
      that both proteins first localize within the cytoplasm and later accumulate
      inside the viral factories, reaching these locations via a mechanism apparently
      unrelated to cellular membranes. Double labeling experiments showed a
      colocalization of both proteins in all virus-induced structures.

PMID- 10600609
TI  - Finding the Missing Link between Landscape Structure and Population Dynamics: A
      Spatially Explicit Perspective.
AB  - We construct and explore a general modeling framework that allows for a
      systematic investigation of the impact of changes in landscape structure on
      population dynamics. The essential parts of the framework are a landscape
      generator with independent control over landscape composition and physiognomy, an
      individual-based spatially explicit population model that simulates population
      dynamics within heterogeneous landscapes, and scale-dependent landscape indices
      that depict the essential aspects of landscape that interact with dispersal and
      demographic processes. Landscape maps are represented by a grid of [Formula: see
      text] cells and consist of good-quality, poor-quality, or uninhabitable matrix
      habitat cells. The population model was shaped in accordance to the biology of
      European brown bears (Ursus arctos), and demographic parameters were adjusted to
      yield a source-sink configuration. Results obtained with the spatially explicit
      model do not confirm results of earlier nonspatial source-sink models where
      addition of sink habitat resulted in a decrease of total population size because
      of dilution of high-quality habitat. Our landscape indices, which describe scale
      dependent correlation between and within habitat types, were able to explain
      variations in variables of population dynamics (mean number of females with sink
      home ranges, mean number of females with source home ranges, and mean dispersal
      distance) caused by different landscape structure. When landscape structure
      changed, changes in these variables generally followed the corresponding change
      of an appropriate landscape index in a linear way. Our general approach
      incorporates source-sink dynamics as well as metapopulation dynamics, and the
      population model can easily be modified for other species groups.

PMID- 10600610
TI  - Evolution of Size-Dependent Flowering in Onopordum illyricum: A Quantitative
      Assessment of the Role of Stochastic Selection Pressures.
AB  - We explore the evolution of delayed, size-dependent reproduction in the
      monocarpic perennial Onopordum illyricum, using a range of mathematical models,
      parameterized with long-term field data. Analysis of the long-term data indicated
      that mortality, flowering, and growth were age and size dependent. Using mixed
      models, we estimated the variance about each of these relationships and also
      individual-specific effects. For the field populations, recruitment was the main
      density-dependent process, although there were weak effects of local density on
      growth and mortality. Using parameterized growth models, which assume plants grow
      along a deterministic trajectory, we predict plants should flower at sizes
      approximately 50% smaller than observed in the field. We then develop a simple
      criterion, termed the "1-yr look-ahead criterion," based on equating seed
      production now with that of next year, allowing for mortality and growth, to
      determine at what size a plant should flower. This model allows the incorporation
      of variance about the growth function and individual-specific effects. The model
      predicts flowering at sizes approximately double that observed, indicating that
      variance about the growth curve selects for larger sizes at flowering. The 1-yr
      look-ahead approach is approximate because it ignores growth opportunities more
      than 1 yr ahead. To assess the accuracy of this approach, we develop a more
      complicated dynamic state variable model. Both models give similar results
      indicating the utility of the 1-yr look-ahead criterion. To allow for temporal
      variation in the model parameters, we used an individual-based model with a
      genetic algorithm. This gave very accurate prediction of the observed flowering
      strategies. Sensitivity analysis of the model suggested that temporal variation
      in the parameters of the growth equation made waiting to flower more risky, so
      selected for smaller sizes at flowering. The models clearly indicate the need to
      incorporate stochastic variation in life-history analyses.

PMID- 10600611
TI  - Variability and Parasitoid Foraging Efficiency: A Case Study of Pea Aphids and
      Aphidius ervi.
AB  - When a parasitoid is searching for hosts, not all hosts are equally likely to be
      attacked. This variability in attack probability may affect the parasitoid
      functional response. Using a collection of experiments, we quantified the
      functional response of Aphidius ervi (Hymenoptera: Braconidae), an insect
      parasitoid of the pea aphid Acyrthosiphon pisum (Homoptera: Aphididae). We
      measured variability in the number of hosts attacked by a foraging parasitoid
      both among plants and within plants. At the first scale, A. ervi, searching among
      plants containing different numbers of aphids, showed both aphid-density
      dependent and aphid-density-independent variability in the number of aphids
      attacked per plant. Within plants, A. ervi selectively attacked second and third
      instar aphids relative to other instars. Furthermore, there was variability in
      the susceptibility of attack among aphids independent of instar. Variability in
      attack rates among aphids both among and within plants decreased parasitoid
      foraging efficiency, with the greatest decrease caused by among-plant
      variability. Furthermore, the decrease in foraging efficiency was greatest when
      the average number of aphids per plant was low, thereby transforming a strong
      Type II functional response into one approaching Type I.

PMID- 10600612
TI  - Seed Dispersal as a Maternally Influenced Character: Mechanistic Basis of
      Maternal Effects and Selection on Maternal Characters in an Annual Plant.
AB  - Maternal influences on progeny characters affect phenotypic correlations between
      characters expressed in maternal and progeny generations and consequently
      influence evolutionary responses to selection. Net selection on maternally
      influenced characters depends on selection both on the progeny character and on
      the maternal characters that influence it. I used seed dispersal in Cakile
      edentula as a system in which to identify the mechanisms of environmentally
      mediated maternal effects and to determine how selection on maternal characters
      alters the adaptive value of dispersal. In C. edentula, maternal morphology
      responds to conspecific density experienced by the mother. Maternal morphology in
      turn affects offspring (seed) dispersal and density and thereby offspring
      morphology and fitness. I estimated the magnitude of density-mediated maternal
      effects on dispersal and identified their mechanism by characterizing the
      plasticity of maternal morphology to density. I also measured density-dependent
      selection on maternal characters that influence dispersal. Maternal plasticity to
      density was caused by both allometric and nonallometric variation in morphology,
      and this plasticity resulted in a negative correlation between maternal and
      progeny density. Such negative maternal effects are expected to retard responses
      to selection. Maternal morphology influenced maternal fitness, in part through
      the relationship of fitness to maternal plant size and in part through size
      independent fitness effects. Maternal phenotypes that promote dispersal, and
      thereby increase progeny fitness, were associated with decreased maternal
      fitness. Selection on dispersal at the level of progeny favors increased
      dispersal; maternal influences on dispersal, however, not only cause a greatly
      reduced adaptive value of dispersal but lead to the prediction of a slower
      response to selection.

PMID- 10600613
TI  - Non-native Ants Are Smaller than Related Native Ants.
AB  - I compare the sizes of non-native and native ants to evaluate how worker size may
      be related to the ability of a species to invade new habitats. I compare the size
      of 78 non-native ant species belonging to 26 genera with the size of native
      congeneric species; native ants are larger than non-native ants in 22 of 26
      genera. Ants were sorted by genera into fighting and nonfighting groups, based on
      observations of interspecific interactions with other ant species. In all of the
      genera with monomorphic worker castes that fight during competition, the non
      native species were smaller than the native species. The genera that engage in
      combat had a higher frequency of significantly smaller size in non-native ants. I
      selected Wasmannia auropunctata for further studies, to compare native and non
      native populations. Specimens of W. auropunctata from non-native populations were
      smaller than conspecific counterparts from its native habitat. I consider
      hypotheses to explain why non-native ants are smaller in size than native ants,
      including the role of colony size in interspecific fights, changes in life
      history, the release from intraspecific fighting, and climate. The discovery that
      fighting non-natives are smaller than their closest native relatives may provide
      insight into the mechanisms for success of non-native species, as well as the
      role of worker size and colony size during interspecific competition.

PMID- 10600614
TI  - Genetic Constraints and Selection Acting on Tolerance to Herbivory in the Common
      Morning Glory Ipomoea purpurea.
AB  - Tolerance to herbivory minimizes the effects of herbivory on plant fitness. In
      the presence of herbivores, maximal levels of tolerance may be expected to
      evolve. In many plant species, however, tolerance is found at an intermediate
      level. Tolerance may be prevented from evolving to a maximal level by genetic
      constraints or stabilizing selection. We report on a field study of Ipomoea
      purpurea, the common morning glory, in which we measured three types of costs
      that may be associated with tolerance and the pattern of selection acting on
      tolerance to two types of herbivore damage: apical meristem damage and folivory.
      We used genetic correlations to test for the presence of three types of costs: a
      trade-off between tolerance and fitness in the absence of herbivore damage, a
      trade-off between tolerance and resistance, and genetic covariances among
      tolerance to different types of damage. We found no evidence that tolerance to
      apical meristem damage or tolerance to folivory was correlated with resistance,
      although these two types of tolerance were positively correlated with one
      another. Tolerance to both types of damage involved costs of lower fitness in the
      absence of herbivory. Selection acting on tolerance to either type of herbivory
      was not detected at natural levels of herbivory. Selection is expected to act
      against tolerance at reduced levels of herbivory and favor tolerance at elevated
      levels of herbivory. In addition, significant correlational selection gradients
      indicate that the pattern of selection acting on tolerance depends on values of
      resistance. Although we found no evidence for stabilizing selection, fluctuating
      selection resulting from fluctuating herbivore loads may be responsible for
      maintaining tolerance at an intermediate level.

PMID- 10600615
TI  - Courtship Disruptions and Male Mating Strategies: Examples from Female-Defense
      Mating Systems.
AB  - Males frequently interrupt the copulation attempts of other males, and these
      courtship disruptions may limit the extent to which a few males are able to
      monopolize mating access to females. Males actively defend sexually receptive
      females in many species in which females form dense aggregations during the
      breeding season. Across and within such species there is considerable variation
      in the mating tactics adopted by males, with males in some cases defending groups
      of females and in other cases sequentially consorting with individual females.
      Colonial blackbirds have been central to studying this mating system, and we
      develop a conceptual model for how courtship disruption may account for variation
      in male mating tactics in this group. Our model assumes that the frequency of
      disruptions increases with greater colony size. As a consequence, successful
      copulations are less likely to occur at large colonies than at small colonies,
      and males are expected to switch from defending multiple females at the colony to
      consorting individual females away from it. Results from two species of blackbird
      support the basic assumptions of this model. In one species, the Montezuma
      oropendola, disruptions occur rarely and males defend groups of females, whereas
      in the other species, the yellow-rumped cacique, disruptions are frequent and
      males defend single females. Moreover, consistent with a key prediction, within
      each species, males associated with small colonies remain at the colony and
      defend groups of females, whereas males spend little time defending groups of
      females at large colonies and rarely attempt copulations there. This model has
      the potential to explain variation in male mating strategies and female
      monopolization for other taxa in which females form breeding aggregations.

PMID- 10600616
TI  - Density-dependent variation in lifetime breeding success and natural and sexual
      selection in Soay rams.
AB  - Variation in male lifetime breeding success (LBS) is central to understanding
      selection, yet it has rarely been measured in natural populations of large
      mammals. Here, we first describe variation in the opportunity for selection in
      cohorts of Soay rams (Ovis aries) on the archipelago of St. Kilda, Scotland, that
      were born during years of varying population density. Variation in LBS is closely
      coupled with demography, as rams born in years of low density following
      population crashes enjoy greater LBS than do those born in high-density years.
      Paradoxically, the opportunity for selection was greatest in the largest cohorts,
      those born in years of high population density, owing to low juvenile breeding
      success and overwinter survival. Variation in longevity and the contribution of
      nonbreeders were the most important components of the total variance in LBS in
      cohorts born in years of high density, while variation in fecundity was more
      important in cohorts born in low-density years. The opportunity for sexual
      selection is thus stronger in cohorts born in low-density years, as many rams in
      these cohorts survive to compete for mates as adults in subsequent ruts.
      Variation in population density in the year of birth also influenced the
      intensity of selection. Individuals born in years of high population density
      underwent strong natural selection in favor of longer hindlimbs over their first
      winter. In contrast, in cohorts born in low-density years, there was no natural
      selection on hindlimb in the first year of life. Longer hindlimbs were associated
      with increased fecundity over the entire lifetime of individuals born in low
      density years. Natural and sexual selection thus act on the same trait in the
      same direction at different life-history stages in Soay rams, depending on the
      population density experienced in the year of birth.

PMID- 10600617
TI  - New Non-Gaussian Feature in COBE-DMR 4 Year Maps.
AB  - We extend a previous bispectrum analysis of the cosmic microwave background
      temperature anisotropy, allowing for the presence of correlations between
      different angular scales. We find a strong non-Gaussian signal in the
      "interscale" components of the bispectrum: their observed values concentrate
      close to zero instead of displaying the scatter expected from Gaussian maps. This
      signal is present over the range of multipoles l = 6-18, in contrast with
      previous detections. We attempt to attribute this effect to galactic foreground
      contamination, pixelization effects, possible anomalies in the noise, documented
      systematic errors studied by the COBE team, and the effect of assumptions used in
      our Monte Carlo simulations. Within this class of systematic errors, the
      confidence level for rejecting Gaussianity varies between 97% and 99.8%.

PMID- 10600618
TI  - A Model for Structure Formation Seeded by Gravitationally Produced Matter.
AB  - This model assumes the baryons, radiation, three families of massless neutrinos,
      and cold dark matter were mutually thermalized before the baryon number was
      fixed, primeval curvature fluctuations were subdominant, and homogeneity was
      broken by scale-invariant fluctuations in a new dark matter component that
      behaves like a relativistic ideal fluid. The fluid behavior could follow if this
      new component were a single scalar field that interacts only with gravity and
      with itself by a pure quartic potential. The initial energy distribution could
      follow if this component were gravitationally produced by inflation. The power
      spectra of the present distributions of mass and radiation in this model are not
      inconsistent with the measurements but are sufficiently different from the
      adiabatic cold dark matter model to allow a sharp test in the near future.

PMID- 10600619
TI  - Zero-Metallicity Stars and the Effects of the First Stars on Reionization.
AB  - We present stellar structure and atmosphere models of metal-free stars and
      examine them from a cosmological point of view. Metal-free stars exhibit high
      effective temperatures and small sizes relative to metal-enriched stars of equal
      mass. These unique physical characteristics enhance the ionizing photon
      production by metal-free stars, particularly in the He ii (hnu>/=4 ryd)
      continuum. The star formation rate of metal-free stars necessary to reionize the
      hydrogen in the universe by z=5 is consistent with the inferred star formation
      rate at that epoch. However, the hard stellar spectra are inconsistent with the
      observations of He ii opacity in the intergalactic medium (IGM) at z
      approximately 3, indicating that the period of metal-free star formation ended
      before that epoch. We examine the effects of these stars on the ionization
      balance of the IGM, the radiative feedback of the first luminous objects, and the
      extragalactic radiation field. We comment on the prospects for detecting metal
      free stellar populations with the lambda1640 and lambda4686 recombination lines
      of He ii.

PMID- 10600620
TI  - On the Number Density of Sunyaev-Zeldovich Clusters of Galaxies.
AB  - If the mean properties of clusters of galaxies are well described by the entropy
      driven model, the distortion induced by the cluster population on the blackbody
      spectrum of the cosmic microwave background radiation is proportional to the
      total amount of intracluster gas, while temperature anisotropies are dominated by
      the contribution of 1014 M middle dot in circle clusters. This result depends
      marginally on cluster parameters, and it can be used to estimate the number
      density of clusters with enough hot gas to produce a detectable Sunyaev-Zeldovich
      effect. Comparing different cosmological models, the relation depends mainly on
      the density parameter Omegam. If the number density of clusters could be
      estimated by a different method, then this dependence could be used to constrain
      Omegam.

PMID- 10600621
TI  - Evidence for X-Ray Emission from a Large-Scale Filament of Galaxies?
AB  - Cosmological simulations predict that a large fraction of the baryonic mass of
      the universe exists as 105-107 K diffuse, X-ray-emitting gas, tracing low-density
      filament and sheetlike structures exterior to massive clusters of galaxies. If
      present, this gas helps reconcile the current shortfall in observed baryon counts
      relative to the predictions of the standard big bang model. We present here the
      discovery and analysis of a 5 sigma significance half-degree filamentary
      structure, which is present in both the I-band galaxy surface density and the
      unresolved X-ray emission in a deep ROSAT PSPC field. The estimated diffuse X-ray
      emission component of this structure has a surface brightness of approximately
      1.6x10-16 ergs s-1 cm-2 arcmin-2 (0.5-2 keV), comparable to the predictions for
      intercluster gas, and may represent a direct detection of this currently
      unconfirmed baryonic component.

PMID- 10600622
TI  - X-Raying the Star Formation History of the Universe.
AB  - The current models of early star and galaxy formation are based upon the
      hierarchical growth of dark matter halos, within which the baryons condense into
      stars after cooling down from a hot diffuse phase. The latter is replenished by
      infall of outer gas into the halo potential wells; this includes a fraction
      previously expelled and preheated because of momentum and energy fed back by the
      supernovae which follow the star formation. We identify such an implied hot phase
      with the medium known to radiate powerful X-rays in clusters and in groups of
      galaxies. We show that the amount of the hot component required by the current
      star formation models is enough to be observable out to redshifts z approximately
      1.5 in forthcoming deep surveys from Chandra and X-Ray Multimirror Mission,
      especially in case the star formation rate is high at such and earlier redshifts.
      These X-ray emissions constitute a necessary counterpart and will provide a much
      wanted probe of the star formation process itself (in particular, of the
      supernova feedback) to parallel and complement the currently debated data from
      optical and IR observations of the young stars.

PMID- 10600623
TI  - New CO and Millimeter Continuum Observations of the z = 2.394 Radio Galaxy
      53W002.
AB  - The z=2.39 radio galaxy 53W002 lies in a cluster of Lyalpha emission-line objects
      and may itself be undergoing a major burst of star formation. CO (3-2) emission,
      at 102 GHz, was detected from 53W002 in 1997 by Scoville et al., who also
      reported a possible 30 kpc extension and velocity gradient suggesting a rotating
      gaseous disk. In this Letter, we present new interferometric CO (3-2)
      observations that confirm the previous line detection with improved signal-to
      noise ratio, but show no evidence for source extension or velocity gradient. The
      compact nature of the CO source and the molecular mass found in this object are
      similar to luminous infrared galaxies and other active galactic nuclei previously
      studied.

PMID- 10600624
TI  - Radio Emission from Three-dimensional Relativistic Hydrodynamic Jets:
      Observational Evidence of Jet Stratification.
AB  - We present the first radio emission simulations from high-resolution three
      dimensional relativistic hydrodynamic jets; these simulations allow us to study
      the observational implications of the interaction between the jet and the
      external medium. This interaction gives rise to a stratification of the jet in
      which a fast spine is surrounded by a slow high-energy shear layer. The
      stratification (in particular, the large specific internal energy and slow flow
      in the shear layer) largely determines the emission from the jet. If the magnetic
      field in the shear layer becomes helical (e.g., resulting from an initial
      toroidal field and an aligned field component generated by shear), the emission
      shows a cross section asymmetry, in which either the top or the bottom of the jet
      dominates the emission. This, as well as limb or spine brightening, is a function
      of the viewing angle and flow velocity, and the top/bottom jet emission
      predominance can be reversed if the jet changes direction with respect to the
      observer or if it presents a change in velocity. The asymmetry is more prominent
      in the polarized flux because of field cancellation (or amplification) along the
      line of sight. Recent observations of jet cross section emission asymmetries in
      the blazar 1055+018 can be explained by assuming the existence of a shear layer
      with a helical magnetic field.

PMID- 10600625
TI  - The Ejection of Relativistic Bullets from Supernovae and the Generation of Gamma
      Ray Bursts.
AB  - It is generally believed that cosmological gamma-ray bursts (GRBs) are produced
      by the deceleration of relativistic objects with Gamma greater, similar100. We
      study the possibility that some GRBs are produced along with relativistic matter
      ejected from supernovae. In this model, it is quite likely that the matter has to
      travel through the progenitor's thick envelope before generating GRBs. Under the
      assumption that the ejected matter is described as a single collective piece of
      matter, we obtain constraints on the matter having Gamma greater, similar100 at
      the breakout of the progenitor. One advantage of considering this type of model
      is that the expected GRB energy is sufficiently large, in contrast to the GRB
      generation model of the shock breakout in the energetic supernova explosion. We
      find that, in general, the cross section of the matter has to be very small
      compared with the progenitor's radius, and thus the matter has to be bullet-like
      (or jetlike) rather than shell-like.

PMID- 10600626
TI  - The Rapid X-Ray Variability of V4641 Sagittarii (SAX J1819.3-2525 = XTE J1819
      254).
AB  - We report on the rapid X-ray variability of the variable star and X-ray transient
      V4641 Sagittarii (SAX J1819.3-2525 = XTE J1819-254) as observed on 1999 September
      15 by the proportional counter array (PCA) on board the Rossi X-Ray Timing
      Explorer. During the first approximately 900 s of the first PCA observation,
      V4641 Sgr showed very strong X-ray fluctuations by a factor of 4 on timescales of
      seconds to about 500 on timescales of minutes. The spectrum of the source during
      this flaring episode became harder when the count rate decreased. After this
      flaring episode, V4641 Sgr entered a quiescent state in which it remained for the
      rest of this and subsequent PCA observations. The X-ray spectrum was considerably
      softer in this quiescent state than during the flaring episode. The intrinsic X
      ray luminosity (during both the flaring episode and the quiescent state) and the
      rapid X-ray variability do not strongly constrain the nature of the compact
      object (neutron star or black hole) in the system, although a black hole seems to
      be more likely. The very short duration of the bright X-ray phase of V4641 Sgr
      and its likely close proximity suggest that many similar objects could be present
      in our Galaxy, most of which are not noticed when they are in outburst because of
      the short duration of these outbursts. A considerable number of the black holes
      present in our Galaxy might be contained in systems similar to V4641 Sgr.

PMID- 10600627
TI  - A Theoretical Light-Curve Model for the 1999 Outburst of U Scorpii.
AB  - A theoretical light curve for the 1999 outburst of U Scorpii is presented in
      order to obtain various physical parameters of the recurrent nova. Our U Sco
      model consists of a very massive white dwarf (WD) with an accretion disk and a
      lobe-filling, slightly evolved, main-sequence star (MS). The model includes a
      reflection effect by the companion and the accretion disk together with a
      shadowing effect on the companion by the accretion disk. The early visual light
      curve (with a linear phase of t approximately 1-15 days after maximum) is well
      reproduced by a thermonuclear runaway model on a very massive WD close to the
      Chandrasekhar limit (MWD=1.37+/-0.01 M middle dot in circle), in which optically
      thick winds blowing from the WD play a key role in determining the nova duration.
      The ensuing plateau phase (t approximately 15-30 days) is also reproduced by the
      combination of a slightly irradiated MS and a fully irradiated flaring-up disk
      with a radius approximately 1.4 times the Roche lobe size. The cooling phase (t
      approximately 30-40 days) is consistent with a low-hydrogen content of X
      approximately 0.05 of the envelope for the 1.37 M middle dot in circle WD. The
      best-fit parameters are the WD mass of MWD approximately 1.37 M middle dot in
      circle, the companion mass of MMS approximately 1.5 M middle dot in circle (0.8
      2.0 M middle dot in circle is acceptable), the inclination angle of the orbit (i
      approximately 80&j0;), and the flaring-up edge, the vertical height of which is
      approximately 0.30 times the accretion disk radius. The duration of the strong
      wind phase (t approximately 0-17 days) is very consistent with the BeppoSAX
      supersoft X-ray detection at t approximately 19-20 days because supersoft X-rays
      are self-absorbed by the massive wind. The envelope mass at the peak is estimated
      to be approximately 3x10-6 M middle dot in circle, which is indicates an average
      mass accretion rate of approximately 2.5x10-7 M middle dot in circle yr-1 during
      the quiescent phase between 1987 and 1999. These quantities are exactly the same
      as those predicted in a new progenitor model of Type Ia supernovae.

PMID- 10600628
TI  - eta Carinae: Binarity Confirmed.
AB  - We report the recovery of a spectroscopic event in eta Carinae in 1997/1998 after
      a prediction by Damineli in 1996. A true periodicity with P=2020+/-5 days (0.2%
      uncertainty) is obtained. The line intensities and the radial velocity curve
      display a phase-locked behavior, implying that the energy and dynamics of the
      event repeat from cycle to cycle. This rules out S Doradus oscillation or
      multiple shell ejection by an unstable star as the explanation of the
      spectroscopic events. A colliding-wind binary scenario is supported by our
      spectroscopic data and by X-ray observations. Although deviations from a simple
      case exist around periastron, intensive monitoring during the next event (mid
      2003) will be crucial to our understanding of the system.

PMID- 10600629
TI  - What Is Hatching in the Egg?
AB  - We report VLA detections at 1.3, 2, and 3.6 cm of the Egg Nebula, RAFGL 2688. We
      resolve the source and find an inner 9&arcsec; diameter core that is produced by
      approximately 0.01 M middle dot in circle of dust. It seems that the Egg Nebula
      experienced a major mass ejection, losing approximately 1 M middle dot in circle
      during the past </=1200 yr. The centimeter-wavelength emission is extended at a
      position angle of 53 degrees, while the famous jets and lobes in the Egg Nebula
      lie along a position angle of 15 degrees. The multiple symmetries in the Egg
      Nebula may occur because the rotation axis of the mass-losing star is not
      perpendicular to the orbital plane of the putative close binary. Between 3.6 cm
      and 350 um, the dust opacity appears to vary as nu0.6, which can be explained if
      there are some grains with sizes at least as large as 0.5 cm.

PMID- 10600630
TI  - Nucleosynthesis and Mixing in Cassiopeia A.
AB  - We present results from the first light observations of the Cassiopeia A
      supernova remnant (SNR) by the Chandra X-Ray Observatory. Based on representative
      spectra from four selected regions, we investigate the processes of
      nucleosynthesis and mixing in Cas A. We make the first unequivocal identification
      of iron-rich ejecta produced by explosive silicon burning in a young Galactic
      SNR. Elsewhere in the remnant, we see silicon-rich ejecta from explosive oxygen
      burning. The Fe-rich ejecta lie outside the Si-rich material, indicating that
      bulk motions were extensive and energetic enough in Cas A to cause a spatial
      inversion of a significant portion of the supernova core. It is likely that this
      inversion was caused by "Fe"-rich ejecta emerging in plumes from the rising
      bubbles in the neutrino-driven convection layer during the supernova explosion.
      In addition, the radioactive decay energy from 56Ni may have contributed to the
      subsequent evolution of the material. We have also discovered faint, well-defined
      filaments with featureless X-ray spectra that are possibly sites of cosmic-ray
      acceleration in Cas A.

PMID- 10600631
TI  - Large Proper-Motion Infrared
AB  - We report the detection of proper motions in [Fe ii] 1.644 um emission among the
      southeasternmost features in the Herbig-Haro object complex GGD 37. Imaging
      observations were made over a period of 5 yr, at epochs 1993.67, 1996.71, and
      1998.68, that reveal proper-motion velocities of 400+/-200 km s-1 at GGD 37:W2
      and 850+/-200 km s-1 at a newly identified object, designated GGD 37:RWPF 1. We
      believe the proper-motion velocity of GGD 37:RWPF 1 is the highest found to date
      for a Herbig-Haro object. The direction of GGD 37:RWPF 1's proper motion is
      almost due west, away from the nearby young stellar object complex in Cep A East.
      GGD 37:W2's direction of proper motion is north/northwest, which does not lead
      back to any of the compact objects in Cep A East.

PMID- 10600632
TI  - Comparison of Transient Network Brightenings and Explosive Events in the Solar
      Transition Region.
AB  - The relation between transient network brightenings, known as blinkers, and
      explosive events is examined based on coordinated quiet Sun observations in the
      transition region line O v lambda630 recorded by the Coronal Diagnostic
      Spectrometer (CDS), in the transition region line Si iv lambda1402 recorded by
      the Solar Ultraviolet Measurements of Emitted Radiation (SUMER) instrument, and
      in photospheric magnetograms taken by the Big Bear Solar Observatory
      videomagnetograph. From these observations, we find that (1) explosive events,
      which are traditionally defined as features with very broad UV line profiles,
      tend to keep away from the centers of network brightenings and are mostly located
      at the edges of such brightenings, (2) CDS blinkers consist of many small-scale,
      short-lived SUMER "unit brightening events" with a size of a few arcseconds and a
      lifetime of a few minutes, and most importantly (3) each SUMER unit brightening
      event is characterized by a UV line profile that is not as broad as those of
      explosive events, but still has significantly enhanced wings. Our results imply
      that, like explosive events, individual unit brightening events involve high
      velocities, and, hence, blinkers may have the same physical origin as explosive
      events. It is likely that transient network brightenings and explosive events are
      both due to magnetic reconnection-but with different magnetic geometries.

PMID- 10600633
TI  - The proteasome activator 11 S REG (PA28) and class I antigen presentation.
AB  - There are two immune responses in vertebrates: humoral immunity is mediated by
      circulating antibodies, whereas cytotoxic T lymphocytes (CTL) confer cellular
      immunity. CTL lyse infected cells upon recognition of cell-surface MHC Class I
      molecules complexed with foreign peptides. The displayed peptides are produced in
      the cytosol by degradation of host proteins or proteins from intracellular
      pathogens that might be present. Proteasomes are cylindrical multisubunit
      proteases that generate many of the peptides eventually transferred to the cell
      surface for immune surveillance. In mammalian proteasomes, six active sites face
      a central chamber. As this chamber is sealed off from the enzyme's surface, there
      must be mechanisms to promote entry of substrates. Two protein complexes have
      been found to bind the ends of the proteasome and activate it. One of the
      activators is the 19 S regulatory complex of the 26 S proteasome; the other
      activator is '11 S REG' [Dubiel, Pratt, Ferrell and Rechsteiner (1992) J. Biol.
      Chem. 267, 22369-22377] or 'PA28' [Ma, Slaughter and DeMartino (1992) J. Biol.
      Chem. 267, 10515-10523]. During the past 7 years, our understanding of the
      structure of REG molecules has increased significantly, but much less is known
      about their biological functions. There are three REG subunits, namely alpha,
      beta and gamma. Recombinant REGalpha forms a ring-shaped heptamer of known
      crystal structure. 11 S REG is a heteroheptamer of alpha and beta subunits.
      REGgamma is also presumably a heptameric ring, and it is found in the nuclei of
      the nematode work Caenorhabditis elegans and higher organisms, where it may
      couple proteasomes to other nuclear components. REGalpha and REGbeta, which are
      abundant in vertebrate immune tissues, are located mostly in the cytoplasm.
      Synthesis of REG alpha and beta subunits is induced by interferon-gamma, and this
      has led to the prevalent hypothesis that REG alpha/beta hetero-oligomers play an
      important role in Class I antigen presentation. In the present review we focus on
      the structural properties of REG molecules and on the evidence that REGalpha/beta
      functions in the Class I immune response.

PMID- 10600634
TI  - Stimulation of c-Src by prolactin is independent of Jak2.
AB  - Interaction of prolactin (PRL) with its receptor (PRLR) leads to activation of
      Jak and Src family tyrosine kinases. The PRL/growth hormone/cytokine receptor
      family conserves a proline-rich sequence in the cytoplasmic juxtamembrane region
      (Box 1) required for association and subsequent activation of Jaks. In the
      present work, we studied the mechanisms underlying c-Src kinase activation by PRL
      and the role that Jak2 plays in this process. PRL addition to chicken embryo
      fibroblasts (CEF) expressing the rat PRLR long form resulted in activation of c
      Src and Jak2 and in tyrosine phosphorylation of the receptor. Receptor
      phosphorylation was due to associated Jak2, since in cells expressing either a
      Box 1 mutated PRLR (PRLR(4P-A)), which is unable to interact with Jak2, or a
      kinase-domain-deleted Jak2 (Jak2Deltak), PRL did not stimulate receptor
      phosphorylation. Interestingly, addition of PRL to cells expressing PRLR(4P-A)
      resulted in an activation of c-Src equivalent to that observed with the wild-type
      receptor. These findings indicate that PRL-mediated stimulation of c-Src was
      independent of Jak2 activation and of receptor phosphorylation. Our results
      suggest that PRL-activated Src could send signals to downstream cellular targets
      independently of Jak2.

PMID- 10600635
TI  - Ligand-specific utilization of the extracellular membrane-proximal region of the
      gp130-related signalling receptors.
AB  - The receptor gp130 is used by the interleukin-6 (IL-6)-type cytokines, which
      include IL-6 and leukaemia-inhibitory factor (LIF). To investigate the role of
      the three extracellular membrane-proximal fibronectin-type-III-like (FNIII)
      modules of gp130 and the related receptor for granulocyte colony-stimulating
      factor (G-CSFR) in cytokine signal transduction we have transfected into murine
      myeloid M1-UR21 cells the chimaera (GR-FNIII)gp130, which contains the membrane
      proximal FNIII modules of the G-CSFR on a gp130 backbone, and its complement, the
      chimaera (gp130-FNIII)GR. Whereas the binding affinities of (125)I-labelled IL-6
      to (GR-FNIII)gp130, or of (125)I-Tyr1,3-G-CSF to (gp130-FNIII)GR, were similar to
      wild-type gp130 and wild-type G-CSFR, respectively, (125)I-LIF failed to bind
      with high affinity to (GR-FNIII)gp130. In assays measuring differentiation the
      (gp130-FNIII)GR cells were fully responsive to G-CSF, whereas the (GR-FNIII)gp130
      cells responded fully to the agonistic anti-gp130 monoclonal antibody (mAb) B
      S12, but not to IL-6 or LIF. Neutralizing mAbs that recognize the membrane
      proximal FNIII modules of gp130 or the G-CSFR differentially interfered with
      signalling by B-S12, LIF and G-CSF. The data suggest that B-S12 and G-CSF induce
      the correct orientation or conformation for signalling by the wild-type and
      chimaeric homodimeric receptors, that the membrane-proximal region of gp130 is
      important for the correct formation of the signalling IL-6-IL-6 receptor-gp130
      complex and that this region is also involved in LIF-dependent receptor
      heterodimerization and signalling.

PMID- 10600636
TI  - Mechanism of band 3 dimer dissociation during incubation of erythrocyte membranes
      at 37 degrees C.
AB  - The mechanism of dissociation of the stable dimer of band 3 was investigated
      during the incubation of isolated erythrocyte membranes or resealed ghosts at 37
      degrees C. The kinetics of changes in the structural and functional integrity of
      the membrane domain of band 3 (MDB3) were measured and correlated with the change
      in the Stokes radius of band 3. MDB3 integrity was determined as follows: (1) by
      measuring the fluorescence emission spectrum of 4, 4'-di-isothiocyanostilbene
      2,2'-disulphonate (DIDS) bound covalently to MDB3; (2) by measuring the number of
      DIDS covalent binding sites present after incubation of unlabelled resealed
      ghosts; and (3) by measuring the anion transport V(max) by using the same
      resealed ghosts. Incubation of membranes at 37 degrees C caused the dissociation
      of band 3 dimers to monomers but only after a lag period lasting approx. 50 h.
      The observation of such a lag implies that dissociation involves a sequence of
      molecular events beginning with some type of initial process. We have discovered
      that this initial process involves a conformation change in MDB3. There was a
      shift in the fluorescence spectrum for DIDS-labelled band 3 and a decrease in the
      DIDS binding capacity and transport activity of the unlabelled protein.
      Incubation of membranes at 4 degrees C inhibited the conformational change in
      MDB3 and the dissociation of dimers. Furthermore, no conformational change in
      MDB3 was observed when erythrocytes were incubated at 37 degrees C. We suggest
      that MDB3 unfolding is the molecular event responsible for the subsequent
      dissociation of stable dimers of band 3 to monomers during the incubation of
      erythrocyte membranes at 37 degrees C. The monomers so generated are either not
      functional in anion exchange or they have an attenuated functionality. The
      absence of a conformational change for band 3 in erythrocytes might imply that
      haemolysis perturbs the membrane structure and somehow predisposes band 3 to the
      conformational change that occurs during incubation at 37 degrees C.

PMID- 10600637
TI  - Molecular cloning and functional expression of bovine spleen ecto-NAD+
      glycohydrolase: structural identity with human CD38.
AB  - Bovine spleen ecto-NAD(+) glycohydrolase, an archetypal member of the mammalian
      membrane-associated NAD(P)(+) glycohydrolase enzyme family (EC 3.2.2.6), displays
      catalytic features similar to those of CD38, i.e. a protein originally described
      as a lymphocyte differentiation marker involved in the metabolism of cyclic ADP
      ribose and signal transduction. Using amino acid sequence information obtained
      from NAD(+) glycohydrolase and from a truncated and hydrosoluble form of the
      enzyme (hNADase) purified to homogeneity, a full-length cDNA clone was obtained.
      The deduced sequence indicates a protein of 278 residues with a molecular mass of
      31.5 kDa. It predicts that bovine ecto-NAD(+) glycohydrolase is a type II
      transmembrane protein, with a very short intracellular tail. The bulk of the
      enzyme, which is extracellular and contains two potential N-glycosylation sites,
      yields the fully catalytically active hNADase which is truncated by 71 residues.
      Transfection of HeLa cells with the full-length cDNA resulted in the expression
      of the expected NAD(+) glycohydrolase, ADP-ribosyl cyclase and GDP-ribosyl
      cyclase activities at the surface of the cells. The bovine enzyme, which is the
      first 'classical' NAD(P)(+) glycohydrolase whose structure has been established,
      presents a particularly high sequence identity with CD38, including the presence
      of 10 strictly conserved cysteine residues in the ectodomain and putative
      catalytic residues. However, it lacks two otherwise conserved cysteine residues
      near its C-terminus. Thus hNADase, the truncated protein of 207 amino acids,
      represents the smallest functional domain endowed with all the catalytic
      activities of CD38/NAD(+) glycohydrolases so far identified. Altogether, our data
      strongly suggest that the cloned bovine spleen ecto-NAD(+) glycohydrolase is the
      bovine equivalent of CD38.

PMID- 10600638
TI  - Carbohydrate-binding modules from a thermostable Rhodothermus marinus xylanase:
      cloning, expression and binding studies.
AB  - The two N-terminally repeated carbohydrate-binding modules (CBM4-1 and CBM4-2)
      encoded by xyn10A from Rhodothermus marinus were produced in Escherichia coli and
      purified by affinity chromatography. Binding assays to insoluble polysaccharides
      showed binding to insoluble xylan and to phosphoric-acid-swollen cellulose but
      not to Avicel or crystalline cellulose. Binding to insoluble substrates was
      significantly enhanced by the presence of Na(+) and Ca(2+) ions. The binding
      affinities for soluble polysaccharides were tested by affinity electrophoresis;
      strong binding occurred with different xylans and beta-glucan. CBM4-2 displayed a
      somewhat higher binding affinity than CBM4-1 for both soluble and insoluble
      substrates but both had similar specificities. Binding to short oligosaccharides
      was measured by NMR; both modules bound with similar affinities. The binding of
      the modules was shown to be dominated by enthalpic forces. The binding modules
      did not contribute with any significant synergistic effects on xylan hydrolysis
      when incubated with a Xyn10A catalytic module. This is the first report of family
      4 CBMs with affinity for both insoluble xylan and amorphous cellulose.

PMID- 10600639
TI  - Characterization of plasma unsaturated lysophosphatidylcholines in human and rat.
AB  - Unsaturated lysophosphatidylcholines (lysoPtdCho) bound to albumin circulate in
      blood plasma and seem to be a novel transport system for carrying polyunsaturated
      fatty acids (PUFA) to tissues that are rich in these fatty acids, such as the
      brain. The potential of these lysoPtdCho as a significant source of PUFA for
      cells has been assessed by comparing their plasma concentration with that of
      unsaturated non-esterified fatty acids (NEFA) bound to albumin. In humans, the
      PUFA concentration was 25.9+/-3.1 nmol/ml for these lysoPtdCho, compared with
      33.4+/-9.6 nmol/ml for NEFA; in rats the equivalent values are 14.2+/-0.6 and
      13.1+/-1.1 nmol/ml respectively (means+/-S.E.M.). The lysoPtdCho arachidonic acid
      content was 2-fold (human) and 5-fold (rat) higher than that of NEFA. In human
      and rat plasma, unsaturated lysoPtdCho were associated mainly with albumin rather
      than lipoproteins. The rate and extent of the acyl group shift from the sn-2 to
      sn-1 position of these lysoPtdCho were studied by the incubation of 1-lyso, 2
      [(14)C]C(18:2)n-6-glycerophosphocholine (GPC) with plasma. The rapid
      isomerization of this lipid occurred at pH 7 (20% isomerization within 2 min) and
      was not prevented by its association with albumin. The position of the acyl group
      in the lysoPtdCho circulating in plasma was studied by collecting blood directly
      in organic solvents containing 1-lyso,2-[(14)C]C(18:2)n-6-GPC as a marker of
      isomerization that occurred during sampling and analysis. Approx. 50% of the PUFA
      was located at the sn-2 position, demonstrating that substantial concentrations
      of 2-acyl-lysoPtdCho are present in plasma and are available for tissue uptake,
      where they can be reacylated at the sn-1 position to form membrane phospholipids.

PMID- 10600640
TI  - Influence of spermine on intestinal maturation of the glycoprotein glycosylation
      process in neonatal rats.
AB  - Previous work has shown an inverse evolution of the rat intestinal glycoprotein
      sialylation that decreases from birth to weaning and of fucosylation that
      increases markedly after weaning during postnatal development. At weaning time,
      an increase in the intestinal level of polyamines (and especially that of
      spermine) was observed, owing partly to the higher level of spermine found in
      solid food given to rats at this period in comparison with the level found in
      milk. To study the role of this polyamine as a possible maturation factor of the
      glycoprotein glycosylation, suckling rats were treated for 4 days with spermine
      administered orally. This treatment allowed us to mimic the spermine increase
      that was observed naturally in rat small intestine after weaning because, in
      intestines of spermine-treated suckling rats, spermine was the only polyamine to
      be increased and was at a level similar to that of weaned rats. Spermine
      treatment did not induce appreciable changes in sialyltransferase activity or in
      sialylation of the brush-border-membrane glycoproteins. On the contrary, this
      treatment induced a rise in an alpha-1, 2-fucosyltransferase activity that was
      regulated at the transcriptional level, but not by its inhibitor (fuctinin), and
      no change in the availability of substrate (GDP-fucose). As a consequence of the
      increase in alpha-1,2-fucosyltransferase level and of the decrease in alpha-l
      fucosidase level after treatment with spermine, several alpha-1,2-fucoproteins,
      naturally found in brush border membranes after weaning time, appeared
      precociously in these membranes after the treatment of the immature suckling
      rats. These results indicate that spermine is a maturation factor for the
      fucosylation of intestinal brush-border-membrane glycoproteins but not for their
      sialylation, and that this polyamine might be implicated in the increased
      fucosylation naturally occurring at weaning time during postnatal development.

PMID- 10600641
TI  - Evidence for phospholipases from Trypanosoma cruzi active on phosphatidylinositol
      and inositolphosphoceramide.
AB  - The lipid moiety in the glycosylphosphatidylinositol anchors of glycoproteins of
      Trypanosoma cruzi consists of an alkylacylglycerol, a lysoalkylglycerol or a
      ceramide. Previously, we showed that the inositolphosphoceramides (IPCs) are the
      major components in the precursor inositolphospholipids of epimastigote and
      trypomastigote forms. Using (3)H-labelled subfractions of IPC,
      phosphatidylinositol (PI) and glycoinositolphospholipids (GIPLs) as substrates
      with a cell-free system, we now demonstrate the association of at least five
      enzyme activities with the trypanosomal membranous particulate material. These
      include: phospholipase A(1) and phospholipase A(2), enzymes that release free
      fatty acid from the PI and GIPLs; an acyltransferase responsible for the
      acylation of the generated monoacyl or monoalkylglycerolipids with endogenous
      unlabelled fatty acid; two activities of phospholipase C, one releasing ceramide
      from IPC and the other alkylacylglycerol, alkylglycerol or diacylglycerol from
      PI. The neutral lipids were also generated on incubation of the GIPLs. The
      phospholipase C activities were inhibited by p-chloromercuriphenylsulphonic acid,
      as reported for other PI phospholipases C. An IPC-fatty-acid hydrolase, releasing
      fatty acid from the labelled IPC, was also observed. The enzyme activities
      reported in the present study may be acting in remodelling reactions leading to
      the anchor of the mature glycoproteins of T. cruzi.

PMID- 10600642
TI  - Characterization of class II apurinic/apyrimidinic endonuclease activities in the
      human malaria parasite, Plasmodium falciparum.
AB  - We have reported that the human malaria parasite, Plasmodium falciparum, repairs
      apurinic/apyrimidinic (AP) sites on DNA by a long-patch base excision repair
      (BER) pathway. This biology is different from that in mammalian cells, which
      predominantly repair AP sites by a DNA-polymerase-beta-dependent, one-nucleotide
      patch BER pathway. As a starting point for the identification and biochemical
      characterization of the enzymes involved in the parasite DNA BER pathway, we
      chose characterization of the AP endonuclease activity in a P. falciparum cell
      free lysate. Evidence is provided for the presence of class II, Mg(2+)-dependent
      and independent AP endonucleases in the parasite lysate. The investigation of the
      processing of AP sites in Plasmodium will provide new information about long
      patch BER pathways; if they are different from those in the human host they might
      provide a new target for anti-malarial chemotherapy.

PMID- 10600643
TI  - Both retinoic-acid-receptor- and retinoid-X-receptor-dependent signalling
      pathways mediate the induction of the brown-adipose-tissue-uncoupling-protein-1
      gene by retinoids.
AB  - The intracellular pathways and receptors mediating the effects of retinoic acid
      (RA) on the brown-fat-uncoupling-protein-1 gene (ucp-1) have been analysed. RA
      activates transcription of ucp-1 and the RA receptor (RAR) is known to be
      involved in this effect. However, co-transfection of an expression vector for
      retinoid-X receptor (RXR) increases the action of 9-cis RA but not the effects of
      all-trans RA on the ucp-1 promoter in brown adipocytes. Either RAR-specific ?p
      [(E)-2-(5,6,7,8,-tetrahydro-5,5,8, 8-tetramethyl-2-naphthalenyl)-1
      propenyl]benzoic acid? or RXR-specific [isopropyl-(E,E)-(R,S)-11-methoxy-3,7, 11
      trimethyldodeca-2,4-dienoate, or methoprene] synthetic compounds increase the
      expression of UCP-1 mRNA and the activity of chloramphenicol acetyltransferase
      expression vectors driven by the ucp-1 promoter. The RXR-mediated action of 9-cis
      RA requires the upstream enhancer region at -2469/-2318 in ucp-1. During brown
      adipocyte differentiation RXRalpha and RXRgamma mRNA expression is induced in
      parallel with UCP-1 mRNA, whereas the mRNA for the three RAR subtypes, alpha,
      beta and gamma, decreases. Co-transfection of murine expression vectors for the
      different RAR and RXR subtypes indicates that RARalpha and RARbeta as well as
      RXRalpha are the major retinoid-receptor subtypes capable of mediating the
      responsiveness of ucp-1 to retinoids. It is concluded that the effects of
      retinoids on ucp-1 transcription involve both RAR- and RXR-dependent signalling
      pathways. The responsiveness of brown adipose tissue to retinoids in vivo relies
      on a complex combination of the capacity of RAR and RXR subtypes to mediate ucp-1
      induction and their distinct expression in the differentiated brown adipocyte.

PMID- 10600644
TI  - Two zebrafish (Danio rerio) antizymes with different expression and activities.
AB  - Cellular polyamines are regulated by a unique feedback mechanism involving
      ornithine decarboxylase (ODC) antizyme. The synthesis of mammalian antizyme
      requires a programmed translational frameshift event induced by polyamines.
      Antizyme represses ODC, a key enzyme for polyamine synthesis, through
      accelerating enzyme degradation by the 26 S proteasome. Antizyme also inhibits
      the cellular uptake of polyamines. In the present study we isolated two distinct
      zebrafish (Danio rerio) antizyme cDNA clones (AZS and AZL) from an embryonic
      library. Their sequences revealed that both clones required translational
      frameshifting for expression. Taking account of +1 frameshifting, AZS and AZL
      products were 214 and 218 residues long respectively and shared 51.8% amino acid
      identity. In rabbit reticulocyte lysates, both mRNA species were translated
      through spermidine-induced frameshifting. The presence of the two antizyme mRNA
      species in embryos, adult fish and a cultured cell line was confirmed by Northern
      blot analysis. The ratio of AZS mRNA to AZL mRNA in the adult fish was 1.8-fold
      higher than in the embryos. Whole-mount hybridization in situ demonstrated that
      both mRNA species are expressed in every tissue in embryo, but predominantly in
      the central nervous system and the eyes. Bacterial expression products of both
      cDNA species inhibited ODC activity, but only the AZS product accelerated ODC
      degradation in vitro. These results show that both zebrafish antizymes are
      induced by polyamines but their mRNA species are expressed differently during
      development. The difference in activities on ODC degradation suggests their
      functional divergence.

PMID- 10600645
TI  - Oligomerization reduces heparin affinity but enhances receptor binding of
      fibroblast growth factor 2.
AB  - The biological response of cells to fibroblast growth factors (FGFs) depends on
      heparan sulphate glycosaminoglycans sharing particular structural motifs. Heparin
      induced FGF dimerization has been suggested to mediate receptor dimerization and
      activation. Here we demonstrate that heparin-derived oligosaccharides that
      promote receptor binding and activation specifically induce the dimerization of
      basic FGF (FGF2). These heparin-induced dimers of FGF2 acquire high affinity for
      receptor binding and are biologically active. Using biotinylated FGF2 bound to
      immobilized streptavidin gradually saturated with biotin, enabled a quantitative
      analysis of heparin-dependent and heparin-independent FGF2 monomers and
      oligomers. Streptavidin induced FGF2 dimers bind and activate FGF receptors only
      in the presence of heparin. An excess of streptavidin, forcing biotin-FGF2 into
      monomers, reduces receptor binding and blocks FGF-dependent cell proliferation.
      All these suggest predominant receptor binding and activation by heparin
      associated FGF2 oligomers. Unexpectedly, heparin induced dimers and higher order
      oligomers lose most of their affinity towards heparin. Direct binding of soluble
      FGF receptors (FGFRs) to either monomers or dimers of FGF2, immobilized on
      heparin, confirm the preferred association of FGFRs with dimers of FGF2.
      Computerized molecular docking predicts a cis-oriented FGF2 dimer, stabilized by
      heparin, which complies with all the experimental data.

PMID- 10600646
TI  - Molecular cloning and functional characterization of the mouse organic-anion
      transporting polypeptide 1 (Oatp1) and mapping of the gene to chromosome X.
AB  - We have cloned a murine member of the organic-anion-transporting polypeptide
      (Oatp) family of membrane-transport proteins from mouse liver. The cloned cDNA
      insert of 2783 bp with an open reading frame of 2011 bp codes for a 12
      transmembrane 670-amino-acid protein with highest amino acid identity with the
      rat Oatp1. When expressed in Xenopus laevis oocytes, the mouse Oatp exhibited the
      same substrate specificity as the rat Oatp1. Besides the common Oatp substrates
      bromosulphophthalein, taurocholate, oestrone 3-sulphate and ouabain, the new
      mouse Oatp also mediates transport of the Oatp1-specific magnetic-resonance
      imaging agent gadoxetate. The Oatp2-specific cardiac glycoside digoxin, however,
      is not transported. Kinetic analyses performed for taurocholate and oestrone 3
      sulphate revealed apparent K(m) values of 12 microM and 5 microM respectively.
      Northern-blot analysis demonstrated a predominant expression in the liver with an
      additional moderate expression in the kidney. Taken together, the amino acid
      identity, the functional characteristics and the tissue distribution suggest that
      we have isolated the murine orthologue of the rat Oatp1, and consequently the
      identified protein will be called Oatp1. Using fluorescence in situ
      hybridization, the murine Oatp1 gene was mapped to chromosome XA3-A5.

PMID- 10600647
TI  - Phosphorylation of the rat pancreatic bile-salt-dependent lipase by casein kinase
      II is essential for secretion.
AB  - Bile-salt-dependent lipase (BSDL, EC 3.1.1.-) is an enzyme expressed by the
      pancreatic acinar cells and secreted as a component of the pancreatic juice of
      all examined species. During its secretion route BSDL is associated with
      intracellular membranes. This association allows the complete glycosylation of
      the enzyme or participates in the inhibition of the enzyme activity, which can
      deleterious for the acinar pancreatic cell. Thereafter, the human BSDL is
      phosphorylated by a serine/threonine protein kinase and released from
      intracellular membranes. In the present study, we show that the rat pancreatic
      BSDL, expressed by AR4-2J cells used as a model, is phosphorylated by a protein
      kinase that is insensitive to inhibitors of protein kinases A, C or G and that
      the phosphorylation process is favoured by okadaic acid (an inhibitor of protein
      phosphatases 1 and 2A). However, 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole
      (DRB), which is a specific inhibitor of casein kinase II, abolishes the
      phosphorylation in vitro of BSDL within micro- somes of AR4-2J pancreatic cells.
      We showed further that the alpha-subunit of casein kinase II co-locates with BSDL
      within the lumenal compartment of the Golgi. Genistein, which perturbs the trans
      Golgi network, also inhibits the phosphorylation of BSDL, suggesting that this
      post-translational modification of BSDL probably occurred within this cell
      compartment. The inhibition of the phosphorylation of BSDL by DRB also decreases
      the rate at which the enzyme is secreted. Under the same conditions, the rate of
      alpha-amylase secretion was not modified. These data strongly suggest that
      phosphorylation is a post-translational event, which appears to be essential for
      the secretion of BSDL.

PMID- 10600648
TI  - The sensitivity of c-Jun and c-Fos proteins to calpains depends on conformational
      determinants of the monomers and not on formation of dimers.
AB  - Milli- and micro-calpains are ubiquitous cytoplasmic cysteine proteases activated
      by calcium. They display a relatively strict specificity for their substrates
      which they usually cleave at only a limited number of sites. Motifs responsible
      for recognition by calpains have not been characterized yet, and recently a role
      for PEST motifs in this process has been ruled out. c-Fos and c-Jun transcription
      factors are highly sensitive to calpains in vitro. They thus provide favourable
      protein contexts for studying the structural requirements for recognition and
      degradation by these proteases. Using in vitro degradation assays and site
      directed mutagenesis, we report here that susceptibility to calpains is primarily
      determined by conformational determinants of the monomers and not by the
      quaternary structure of c-Fos and c-Jun proteins. The multiple cleavage sites
      borne by both proteins can be divided into at least two classes of sensitivity,
      the most sensitive ones being easily visualized in the presence of rate-limiting
      amounts of calpains. One site located at position 90-91 in c-Fos protein is
      extremely sensitive. However, efficient proteolysis did not have any strict
      dependence on the nature of the amino acids on either side of the scissile bond
      in the region extending from P2 to P'2. The structural integrity of the monomers
      is not crucial for recognition by calpains. Rather, sensitive sites can be
      recognized independently and their recognition is dependent on the local
      conformation of peptide regions that may span several tens of amino acids and
      maybe more in the case of the identified c-Fos hypersensitive site.

PMID- 10600649
TI  - Intrinsic alcohol dehydrogenase and hydroxysteroid dehydrogenase activities of
      human mitochondrial short-chain L-3-hydroxyacyl-CoA dehydrogenase.
AB  - The alcohol dehydrogenase (ADH) activity of human short-chain l-3-hydroxyacyl-CoA
      dehydrogenase (SCHAD) has been characterized kinetically. The k(cat) of the
      purified enzyme was estimated to be 2. 2 min(-1), with apparent K(m) values of
      280 mM and 22microM for 2-propanol and NAD(+), respectively. The k(cat) of the
      ADH activity was three orders of magnitude less than the l-3-hydroxyacyl-CoA
      dehydrogenase activity but was comparable with that of the enzyme's
      hydroxysteroid dehydrogenase (HSD) activity for oxidizing 17beta-oestradiol [He,
      Merz, Mehta, Schulz and Yang (1999) J. Biol. Chem. 274, 15014-15019]. However,
      the k(cat) values of intrinsic ADH and HSD activities of human SCHAD were found
      to be two orders of magnitude less than those reported for endoplasmic-reticulum
      associated amyloid beta-peptide-binding protein (ERAB) [Yan, Shi, Zhu, Fu, Zhu,
      Zhu, Gibson, Stern, Collison, Al-Mohanna et al. (1999) J. Biol. Chem. 274, 2145
      2156]. Since human SCHAD and ERAB apparently possess identical amino acid
      sequences, their catalytic properties should be identical. The recombinant SCHAD
      has been confirmed to be the right gene product and not a mutant variant. Steady
      state kinetic measurements and quantitative analyses reveal that assay conditions
      such as pH and concentrations of coenzyme and substrate do not account for the
      kinetic differences reported for ERAB and SCHAD. Rather problematic experimental
      procedures appear to be responsible for the unrealistically high catalytic rate
      constants of ERAB. Eliminating the confusion surrounding the catalytic properties
      of this important multifunctional enzyme paves the way for exploring its role(s)
      in the pathogenesis of Alzheimer's disease.

PMID- 10600650
TI  - Palmitoylation of the 25-kDa synaptosomal protein (SNAP-25) in vitro occurs in
      the absence of an enzyme, but is stimulated by binding to syntaxin.
AB  - The neuronal N-ethylmaleimide-sensitive-factor-attachment-protein receptor
      (SNARE) proteins 25-kDa synaptosomal protein (SNAP-25), syntaxin 1 and
      synaptobrevin 2 interact to form the intermembrane SNARE complex, which mediates
      docking and fusion of synaptic vesicles with the plasma membrane. Assembly of the
      SNARE complex is accompanied by conformational changes, especially in SNAP-25.
      SNAP-25 is palmitoylated in vivo at cysteine residues located in the middle of
      the molecule. Acylation is required for membrane binding or membrane targeting of
      this intrinsically hydrophilic protein. Palmitoylation of recombinant SNAP-25 was
      studied in vitro in the absence of an enzyme source with [(3)H]palmitoyl-CoA as
      the lipid donor. [(3)H]Palmitate incorporation into unbound SNAP-25 was
      negligible, but was stimulated 100-fold when SNAP-25 was present in the SNARE
      complex. SNAP-25 in a binary complex with syntaxin 1 was palmitoylated with
      almost the same efficiency. A mutant of SNAP-25, which was not acylated in vivo,
      did not incorporate [(3)H]palmitate in this assay. [(3)H]Palmitate incorporation
      into wild-type SNAP-25 was blocked by chemical blocking of free SH groups, but
      slightly stimulated by reduction of disulfide-bonds. This shows that
      palmitoylation of SNAP-25 in vitro occurs at the same cysteine residues that are
      palmitoylated in vivo. This demonstrates that efficient palmitoylation of SNAP-25
      depends on an interaction with a physiological binding partner. It suggests
      further that palmitoylation of SNAP-25 requires the alpha-helical conformation of
      the protein, which is induced by binding to syntaxin 1.

PMID- 10600651
TI  - Reaction mechanism of recombinant 3-oxoacyl-(acyl-carrier-protein) synthase III
      from Cuphea wrightii embryo, a fatty acid synthase type II condensing enzyme.
AB  - A unique feature of fatty acid synthase (FAS) type II of higher plants and
      bacteria is 3-oxoacyl-[acyl-carrier-protein (ACP)] synthase III (KAS III), which
      catalyses the committing condensing reaction. Working with KAS IIIs from Cuphea
      seeds we obtained kinetic evidence that KAS III catalysis follows a Ping-Pong
      mechanism and that these enzymes have substrate-binding sites for acetyl-CoA and
      malonyl-ACP. It was the aim of the present study to identify these binding sites
      and to elucidate the catalytic mechanism of recombinant Cuphea wrightii KAS III,
      which we expressed in Escherichia coli. We engineered mutants, which allowed us
      to dissect the condensing reaction into three stages, i.e. formation of acyl
      enzyme, decarboxylation of malonyl-ACP, and final Claisen condensation.
      Incubation of recombinant enzyme with [1-(14)C]acetyl-CoA-labelled Cys(111), and
      the replacement of this residue by Ala and Ser resulted in loss of overall
      condensing activity. The Cys(111)Ser mutant, however, still was able to bind
      acetyl-CoA and to catalyse subsequent binding and decarboxylation of malonyl-ACP
      to acetyl-ACP. We replaced His(261) with Ala and Arg and found that the former
      lost activity, whereas the latter retained overall condensing activity, which
      indicated a general-base action of His(261). Double mutants
      Cys(111)Ser/His(261)Ala and Cys(111)Ser/His(261)Arg were not able to catalyse
      overall condensation, but the double mutant containing Arg induced
      decarboxylation of [2-(14)C]malonyl-ACP, a reaction indicating the role of
      His(261) in general-acid catalysis. Finally, alanine scanning revealed the
      involvement of Arg(150) and Arg(306) in KAS III catalysis. The results offer for
      the first time a detailed mechanism for a condensing reaction catalysed by a FAS
      type II condensing enzyme.

PMID- 10600652
TI  - Effects of angiotensin II on remodelling of the airway and the vasculature in the
      rat.
AB  - Airway remodelling occurs in chronic asthma. Angiotensin II promotes growth in
      cardiovascular remodelling. Since the renin-angiotensin system is activated in
      acute severe asthma, we hypothesized that angiotensin II has a role in airway
      remodelling. A total of 14 young male Wistar rats were randomly divided into two
      groups. All received 2-week infusions of bromodeoxyuridine, and the experimental
      group also received angiotensin II. Blood pressure rose in the angiotensin II
      infused group [mean levels: pre-infusion, 134.9 (S.D. 14.7) mmHg; post-infusion,
      197.1 (22.5) mmHg], and expression of renin mRNA in the renal juxtaglomerular
      cells was suppressed in these animals. The proportion of bromodeoxyuridine
      positive cell nuclei was no different in the airways of control and angiotensin
      II-infused animals for smooth muscle [mean bromodeoxyuridine index: control, 8.
      6% (S.E.M. 1.1%); angiotensin II, 9.3% (1.1%)], epithelium [control, 16.7%
      (2.3%); angiotensin II, 16.0% (2.2%)] and adventitia [control, 26.4% (2.2%);
      angiotensin II, 26.6% (2.4%)]. In the arteries, bromodeoxyuridine indices were
      higher in the angiotensin II-infused rats [18.4% (2.3%)] than in the control
      animals [9.4% (2.8%)], but no difference was found in the veins [12% (2.9%) and
      11.4% (2.6%) respectively]. Morphometry of the airway wall and mesenteric
      vasculature was no different in the two groups. Therefore a 2-week infusion of
      angiotensin II increases blood pressure and DNA synthesis in the mesenteric
      arteries, but does not cause airway remodelling, in the rat.

PMID- 10600653
TI  - Changes in vitreous concentrations of human hepatocyte growth factor (hHGF) in
      proliferative diabetic retinopathy: implications for intraocular hHGF production.
AB  - We measured human hepatocyte growth factor (hHGF) concentrations in the original
      vitreous and in the artificial vitreous after vitrectomy in 13 patients with
      proliferative diabetic retinopathy (PDR) undergoing repeated pars plana
      vitrectomy, in order to investigate whether the vitreous hHGF concentration is
      related to the recurrence of PDR after vitrectomy as well as to the original
      occurrence of PDR. We also examined the relationship between vitreous
      concentrations of hHGF and transforming growth factor-beta(2) (TGF-beta(2)), the
      predominant TGF-beta isoform in the vitreous, in 14 patients with PDR. For the
      original vitreous, mean hHGF concentrations were higher (P<0.05) in that from
      patients with severe PDR (vitreous haemorrhage, fibrovascular proliferation and
      tractional retinal detachment) than in that from patients with vitreous
      haemorrhage alone. In the artificial vitreous, mean vitreous hHGF concentrations
      were higher (P<0.05) in that from patients with severe PDR than in that from
      patients with vitreous haemorrhage alone or with vitreous haemorrhage plus
      fibrovascular proliferation. No correlation was found between the hHGF
      concentration in the artificial vitreous and time between vitrectomies. Vitreous
      hHGF concentrations were directly proportional to vitreous concentrations of
      latent TGF-beta(2) (r=0. 831; P=0.0002), but inversely proportional to vitreous
      concentrations of active TGF-beta(2) (r=0.495; P=0.072), which inhibits hHGF
      production. A decreased conversion of latent into active TGF-beta(2) in ocular
      disorders such as PDR is likely to result in an increased concentration of hHGF
      in the vitreous. Thus intraocular hHGF may be involved in pathological mechanisms
      causing not only the occurrence, but also the recurrence, of PDR.

PMID- 10600654
TI  - Analgesic effects of adenosine in syndrome X are counteracted by theophylline: a
      double-blind placebo-controlled study.
AB  - It has been proposed that adenosine mediates ischaemic pain in humans. Patients
      with cardiac Syndrome X are hypersensitive to potential pain stimuli, including
      adenosine. On the other hand, recent findings suggest that low-dose adenosine
      infusion may have analgesic effects. Our aim was to test two hypotheses: (1) that
      the analgesic effect of adenosine is peripheral in origin, and (2) that part of
      the hypersensitivity to pain of patients with cardiac Syndrome X results from a
      disturbed mechanism of adenosine analgesia. A total of 12 female Syndrome X
      patients and eight healthy age-matched female controls were studied in a
      randomized, double-blind and placebo-controlled study. Adenosine (70 microg/min)
      or placebo was infused into the forearm via an intra-arterial catheter. After 15
      min of infusion, a tourniquet on the upper arm was inflated to 225 mmHg to ensure
      arterial occlusion. The patient then carried out dynamic handgrip work at 60 Hz.
      Pain or discomfort in the forearm was estimated continuously according to the
      Borg CR-10 scale. After the first test, theophylline was infused for 10 min
      intravenously at a dose of 5 mg/kg body weight. The ischaemic forearm test was
      then repeated. On a second occasion, the procedure was repeated with the opposite
      treatment (adenosine/placebo). Only six of 12 Syndrome X patients completed the
      protocol because of pain during the catheterization procedure or an inability to
      establish an intra-arterial line. The time to onset of pain in the working,
      ischaemic forearm was greater for subjects treated with adenosine than for those
      treated with placebo, both in those Syndrome X patients who tolerated
      catheterization (49+/-27 s compared with 32+/-18 s; P<0.03) and in healthy
      controls (40+/-19 s compared with 16+/-8 s; P<0.02). The time to maximum pain,
      limiting ischaemic work, was also greater with adenosine pretreatment both in
      Syndrome X patients (137+/-28 s compared with 106+/-28 s; P<0.03) and in healthy
      controls (109+/-31 compared with 82+/-18 s; P<0.01). After infusion of
      theophylline there was no difference between adenosine and placebo in either
      group. Intra-arterially infused adenosine had similar peripheral analgesic
      effects on experimentally induced muscular ischaemia in those female Syndrome X
      patients who tolerated intra-arterial catheterization and in healthy controls.
      Thus adenosine analgesia is counteracted by theophylline, suggesting that the
      effect is mediated by membrane-bound peripheral adenosine receptors.

PMID- 10600655
TI  - Time course of changes in serum glucose, insulin, lipids and tissue lipase
      activities in macrosomic offspring of rats with streptozotocin-induced diabetes.
AB  - The aim of this investigation was to determine the time course of changes in
      serum glucose, insulin and lipid levels, as well as lipid and protein content and
      lipolytic activities in insulin target organs (liver, adipose tissue and muscle),
      in macrosomic offspring of streptozotocin-induced mildly hyperglycaemic rats.
      Food intake and nutritional efficiency were also evaluated. Mild hyperglycaemia
      in pregnant rats was induced by intraperitoneal injection of streptozotocin (40
      mg/kg body weight) on day 5 of gestation. Control pregnant rats were injected
      with citrate buffer. At birth, macrosomic pups (birth weight >1.7 S.D. greater
      than the mean value for the control pups) had higher serum insulin, glucose and
      lipid levels than control pups. These macrosomic rats maintained accelerated
      postnatal growth combined with high adipose tissue weight up to 12 weeks of age.
      These rats were not hyperphagic; however, they had higher food efficiency and fat
      storage capacity with higher adipocyte lipoprotein lipase activity, which
      contributed to persisting obesity. Hepatic lipase activity was increased in
      macrosomic rats at all ages. Moreover, macrosomia was associated with metabolic
      disturbances that varied according to age and sex. After 1 month, several
      alterations observed at birth had disappeared. Serum glucose, insulin and lipid
      levels in male and female macrosomic rats became similar to those of their
      respective controls. At 2 months of age, hepatic and serum triacylglycerol levels
      were higher in macrosomic females than in controls. By 3 months, macrosomic rats
      (both males and females) had developed insulin resistance with hyperinsulinaemia,
      hyperglycaemia, and higher serum and hepatic lipids. In conclusion, macrosomia
      was associated with alterations in glucose and lipid metabolism through to
      adulthood. It should be considered as an important potential risk factor for
      obesity and its metabolic complications.

PMID- 10600656
TI  - Influence of muscle temperature on the contractile properties of the quadriceps
      muscle in humans with spinal cord injury.
AB  - Low muscle temperature in paralysed muscles of individuals with spinal cord
      injury may affect the contractile properties of these muscles. The present study
      was therefore undertaken to assess the effects of increased muscle temperature on
      the isometric contractile properties of electrically stimulated paralysed
      quadriceps muscles. When muscle temperature at a depth of 3 cm was increased from
      approximately 32 degrees C to approximately 36 degrees C by ultra-short-wave
      application, the half-relaxation time shortened and low-frequency force responses
      became less fused, but the maximal rate of increase in force remained unchanged.
      Heating had no effect upon either force decline or slowing of relaxation during
      fatiguing contractions. The force-frequency relationship of the paralysed
      quadriceps muscle was shifted to the right after the muscle was heated. Despite
      this shift, however, the relationship still resembled that in muscles of non
      paralysed individuals, probably due to the unexplained high twitch forces. These
      results indicate that reduced muscle temperature in spinal-cord-injured
      individuals may lead to an underestimation of the changes in contractile
      properties in terms of relaxation rate or the degree of fusion with low-frequency
      stimulation. In addition, the force-frequency relationship of paralysed muscles
      does not accurately reflect the magnitude of these changes, even when the muscle
      is heated, and should therefore be treated with caution.

PMID- 10600657
TI  - Plasma-volume contraction and exercise-induced hypoxaemia modulate erythropoietin
      production in healthy humans.
AB  - This study examined exercise-induced hypoxaemia (EIH) and plasma volume
      contraction as modulators of serum erythropoietin (Epo) production. Five athletes
      cycled for 3 min at supra-maximal power outputs, at each of two different
      elevations (1,000 m and 2,100 m). Five subjects were exposed to normobaric
      hypoxia (F(I)O(2)=0.159), seven subjects underwent plasmapheresis to reduce
      plasma volume and eight subjects were time controls for Epo levels.
      Oxyhaemoglobin saturation was significantly reduced during exercise and during
      normobaric hypoxia. The time period of haemoglobin oxygen saturation <91% was
      24+/-29 s (mean+/-S.D., n=5) for exercise at 1000 m, 136+/-77 s (mean+/-S.D.,
      n=5) for exercise at 2100 m and 178+/-255 s (mean+/-S.D., n=5) with resting
      hypoxic exposure. However, significantly increased serum Epo levels were observed
      only following exercise (24+/-3%; mean+/-S.D., n=5 at 1,000 m and 36+/-5%; mean+/
      S.D., n=5 at 2,100 m). Volume contraction also resulted in increased serum Epo
      (35+/-6%; mean+/-S.D., n=7) in spite of a significant rise in haematocrit of
      2.2%. Despite similar degrees of arterial desaturation, only the hypoxaemia
      induced by exercise was associated with an increase in serum Epo. This finding
      indicates that other factors, in addition to hypoxaemia, are important in
      modulating the production of Epo in response to exercise. Volume depletion in the
      absence of exercise resulted in increases in Epo levels that were comparable with
      those observed in response to exercise. The paradoxical responses of the
      increased haematocrit and the increase in Epo in subjects undergoing
      plasmapheresis suggests that plasma volume may also modulate the production of
      Epo.

PMID- 10600658
TI  - Relationship between gastro-intestinal complaints and endotoxaemia, cytokine
      release and the acute-phase reaction during and after a long-distance triathlon
      in highly trained men.
AB  - The aim of the present study was to establish whether gastro-intestinal (GI)
      complaints observed during and after ultra-endurance exercise are related to gut
      ischaemia-associated leakage of endotoxins [lipopolysaccharide (LPS)] into the
      circulation and associated cytokine production. Therefore we collected blood
      samples from 29 athletes before, immediately after, and 1, 2 and 16 h after a
      long-distance triathlon for measurement of LPS, tumour necrosis factor-alpha and
      interleukin-6 (IL-6). As the cytokine response would trigger an acute-phase
      response, characteristic variables of these responses were also measured, along
      with creatine kinase (CK) to obtain an indicator of muscle damage. There was a
      high incidence (93% of all participants) of GI symptoms; 45% reported severe
      complaints and 7% of the participants abandoned the race because of severe GI
      distress. Mild endotoxaemia (5-15 pg/ml) was evident in 68% of the athletes
      immediately after the race, as also indicated by a reduction in IgG anti-LPS
      levels. In addition, we observed production of IL-6 (27-fold increase immediately
      after the race), leading to an acute-phase response (20-fold increase in C
      reactive protein and 12% decrease in pre-albumin 16 h after the race). The extent
      of endotoxaemia was not correlated with the GI complaints or the IL-6 response,
      but did show a correlation with the elevation in C-reactive protein (r(s) 0.389;
      P=0.037). Creatine kinase levels were increased significantly immediately post
      race, and increased further in the follow-up period. Creatine kinase levels did
      not correlate with those of either IL-6 or C-reactive protein. It is therefore
      concluded that LPS does enter the circulation after ultra-endurance exercise and
      may, together with muscle damage, be responsible for the increased cytokine
      response and hence GI complaints in these athletes.

PMID- 10600659
TI  - Modulation of the intrahepatic renin-angiotensin system after stimulation of the
      gastric sodium monitor in the rat.
AB  - Changes in the rate of formation of angiotensin II (ANG II) participate in
      mediating the natriuresis that occurs in direct response to a gastric sodium
      stimulus (upper-gut sodium monitor). As this natriuresis is also dependent on
      intrahepatic events, we investigated whether changes in hepatic and plasma
      angiotensinogen levels and hepatic angiotensin-converting enzyme (ACE) activity
      might explain the decrease in ANG II synthesis. Male Sprague-Dawley rats,
      equilibrated on a low-sodium diet, were anaesthetized and received a sodium load
      of 1.5 mmol/kg (using 3 x normal saline) either intragastrically or
      intravenously. Blood and livers were sampled before and at various times after
      sodium administration. ACE activity in serum and tissues was determined by
      generation of histidyl-leucine. Angiotensinogen was determined by
      radioimmunoassay of angiotensin I generated by incubation in the presence of
      exogenous renin. Plasma angiotensinogen had decreased significantly by 15 min
      after sodium administration (P<0.005), while hepatic angiotensinogen was also
      decreased significantly from 30 min after the sodium load (P<0.01). Hepatic ACE
      activity decreased in response to sodium (P<0.005) from 30 min. We conclude that
      stimulation of the gastric sodium monitor regulates angiotensinogen synthesis and
      secretion by the liver, as well as hepatic ACE activity.

PMID- 10600660
TI  - Venous endothelin receptor function in patients with chronic heart failure.
AB  - Cardiac preload reduction through venodilatation is beneficial in chronic heart
      failure. The recent development of endothelin receptor antagonists for possible
      therapeutic use in heart failure has hastened the need for a clearer
      understanding of the venoconstrictor actions of endothelin-1 in this disease. Two
      main subtypes of endothelin receptor, ET(A) and ET(B), exist in human blood
      vessels. We studied the venoconstrictor effects of endothelin-1 (a non-selective
      ET(A) and ET(B) agonist) and sarafotoxin S6c (a selective ET(B) agonist) in vivo
      in patients with chronic heart failure and in age-matched healthy controls. On
      separate days at least 1 week apart, locally active doses of endothelin-1 or
      sarafotoxin S6c were infused into a suitable dorsal hand vein for 1 h, and the
      venous internal diameter was measured using a displacement technique.
      Venoconstriction in response to endothelin-1 was significantly blunted in heart
      failure patients compared with controls (26+/-7% and 51+/-6% peak reduction in
      vein calibre respectively; P=0.013). Venoconstriction to sarafotoxin S6c was
      similar in heart failure patients and controls (17+/-5% and 17+/-4% peak
      reduction in vein calibre respectively). Both ET(A) and ET(B) receptors mediate
      venoconstriction in healthy subjects and in patients with chronic heart failure.
      Optimal inhibition of the venoconstrictor effects of endothelin-1 in chronic
      heart failure may therefore require administration of an antagonist with ET(A)-
      and ET(B)-receptor-blocking properties. Chronic heart failure may be associated
      with a selective decrease in venous ET(A) receptor sensitivity, but further
      studies are required to clarify the functional significance of this observation.

PMID- 10600661
TI  - Hip and knee arthroplasty: a comparison and the endocrine, metabolic and
      inflammatory responses.
AB  - Changes in circulating levels of catecholamines, cortisol, glucose, interleukin-6
      and C-reactive protein and in the leucocyte count were investigated for 7 days
      after surgery in 158 patients undergoing hip or knee arthroplasty. We compared
      the responses to the two operations, and also examined the effects of pathology
      (osteoarthritis and rheumatoid arthritis) on the changes associated with knee
      arthroplasty. Exploratory factor analysis was applied to the data to identify the
      variables and sampling times that could be used in future to provide a concise
      description of the response. Patients undergoing knee arthroplasty showed
      significantly greater changes in noradrenaline, adrenaline and glucose levels,
      but not in cortisol levels, compared with those undergoing hip arthroplasty.
      Interleukin-6 and C-reactive protein concentrations were also significantly
      greater in knee patients than hip patients; however, when corrected for
      pathology, many of these differences were not significant. Minimal effects of
      pathology (chronic inflammation with rheumatoid arthritis) were found on the
      hormonal changes in knee patients. In particular, there was little evidence to
      support the inference from animal data that the hypothalamic-pituitary-adrenal
      axis is impaired. The expected increases in interleukin-6 and C-reactive protein
      concentrations were found in the rheumatoid arthritis patients. Exploratory
      factor analysis showed that the response could be separated into six components,
      accounting for 60% of the total variance, and identified the variables and
      sampling times indicative of each. In conclusion, there are differences in the
      hormonal, but not inflammatory, responses to hip and knee arthroplasty. Little
      evidence was found for an important effect of pathology on the changes associated
      with knee surgery. Factor analysis provided a useful summary of the data.

PMID- 10600663
TI  - Volume acceleration as an index of respiratory drive during exercise.
AB  - In order to evaluate the applicability of volume acceleration (A(I)) at the onset
      of inspiration as an index of neuromuscular output, CO(2) rebreathing in six
      healthy subjects and incremental-load exercise in eight healthy subjects was
      performed while measuring A(I) and mouth occlusion pressure (P(0.1)). During
      CO(2) rebreathing, A(I) increased linearly with end-tidal CO(2) partial pressure
      and P(0.1). During incremental-load exercise, P(0.1) and A(I) increased
      exponentially with minute ventilation and mean inspiratory flow, and A(I)
      increased linearly with P(0.1). Dyspnoea sensation at rest and exercise with or
      without the circuit system in eight healthy subjects was examined. Dyspnoea
      sensation increased markedly with the circuit system in some subjects.
      Incremental-load exercise was carried out by 13 healthy subjects and 21 patients
      with chronic obstructive pulmonary disease (COPD) to evaluate the difference in
      A(I) as respiratory drive between the two groups in the absence of a respiratory
      circuit. In patients with COPD, A(I) responses to minute ventilation, mean
      inspiratory flow and carbon dioxide output (VCO(2)) were greater than those in
      healthy subjects. In patients with COPD, the A(I) response to VCO(2) was greater
      in those with a lower FEV(1.0) (forced expiratory volume in 1.0 s), but the
      ventilatory response to VCO(2) was lower in those with a lower FEV(1. 0). These
      data suggest that A(I) reflects neuromuscular output during CO(2) rebreathing and
      incremental-load exercise under conditions where mechanical properties of the
      respiratory system are expected to be involved. During exercise, flow increased
      markedly, and the influence of the resistance of the respiratory circuit also
      increased. Therefore the use of A(I) has the advantage of less resistance (no
      respiratory circuit) and less additional respiratory effort, in comparison with
      the use of P(0.1), especially in patients with COPD.

PMID- 10600662
TI  - 5-hydroxytryptamine- and U46619-mediated vasoconstriction in bovine pulmonary
      conventional and supernumerary arteries: effect of endogenous nitric oxide.
AB  - We compared 5-hydroxytryptamine (5-HT)- and U46619-mediated contractions in
      bovine pulmonary conventional arteries (CA) and supernumerary arteries (SA). The
      effects of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME)
      (100 microM) and the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4, 3
      a]quinoxalin-1-one (ODQ) (10 microM) on the responses of CA and SA to 5-HT and
      U46619 were also examined. In addition, the effects of the 5-HT(2B) receptor
      antagonist SB 200646 (1 nM-1 microM) on the responses to 5-HT in SA and CA were
      studied. Tissue cGMP levels were measured in the absence and presence of L-NAME,
      ODQ, 5-HT and U46619. 5-HT was approximately 30 times more potent in SA ?
      log[EC(50) (M)] (pEC(50)) 6.32+/-0.13? than in CA (5.05+/-0.14). U46619 displayed
      a similar potency in both CA (pEC(50) 7.80+/-0.07) and SA (7.75+/-0. 12). L-NAME
      did not significantly alter the resting tone of CA or SA. In contrast, ODQ
      produced a transient increase in the tone of both CA and SA. Neither L-NAME nor
      ODQ altered the responses to 5-HT or U46619 in CA. In addition, neither L-NAME
      nor ODQ altered the responses to U46619 in SA, but both L-NAME and ODQ increased
      the magnitude of the response to 5-HT in SA without changing the sensitivity.
      Inhibition of the 5-HT(2B) receptor with SB 200646 did not alter the response to
      5-HT in SA or CA. Basal levels of cGMP (pmol/mg of protein) were similar in CA
      (1.16+/-0.33) and SA (0. 8+/-0.51), and were not significantly changed in the
      presence of 5-HT or U46619. L-NAME and ODQ reduced the basal levels of cGMP in
      both SA and CA. The results suggest that endogenous NO selectively attenuates the
      vasoconstrictor response to 5-HT in SA, but not in CA. These results also suggest
      that the NO/cGMP pathway may have a role in maintaining low vascular tone, but
      that other mechanisms are able to compensate for the absence of this pathway.

PMID- 10600664
TI  - Reduced baroreflex sensitivity in elderly humans is not due to efferent autonomic
      dysfunction.
AB  - A progressive decline in baroreflex sensitivity (BRS) is a characteristic feature
      of human aging, the basis of which is poorly understood. The purpose of the
      present study was to determine whether alterations in efferent baroreflex
      function might contribute to the age-related decrease in BRS. We studied 10
      healthy young (mean age 30.5 years; age range 22-40 years; six male) and 10
      healthy elderly (mean age 70.7 years; age range 67-75 years; five male)
      volunteers. We tested efferent cardiac vagal function using the bradycardiac
      response to the cold face test, and efferent sympathetic function using heart
      rate and blood pressure responses to four stress tests: (i) low-level cognitive
      stress, (ii) high-level cognitive stress, (iii) hand immersion in ice water (cold
      pressor test) and (iv) isometric sustained hand-grip. Haemodynamic responses to
      these stresses are mediated via efferent baroreflex pathways, whereas the
      afferent components of each reflex response are independent of afferent
      baroreflex pathways. BRS was measured from simultaneous Finapres-derived
      continuous blood pressure and digital ECG R-R interval data using the sequence
      analysis paradigm. As expected, BRS was significantly reduced in the elderly
      group (7. 29+/-0.74 ms/mmHg; mean+/-S.E.M.) compared with the young group (13.
      84+/-1.13 ms/mmHg; P<0.001). However, neither the bradycardiac responses to the
      cold face test nor the efferent sympathetically mediated heart rate/blood
      pressure responses to the stress test battery were significantly different
      between the young and elderly groups. We conclude that the age-related decrease
      in BRS is not attributable to impairments in the efferent sympathetic or
      parasympathetic system components of the baroreceptor reflex pathway.

PMID- 10600665
TI  - Basal and exercise-induced skeletal muscle blood flow is augmented in type I
      diabetes mellitus.
AB  - Hyperaemia occurs early in the renal and retinal microcirculation of patients
      with type I (insulin-dependent) diabetes mellitus, and may be critical in the
      development of nephropathy and retinopathy. We therefore sought to determine
      whether resting and exercise-induced hyperaemia was also apparent in the skeletal
      muscle circulation of young subjects with type I diabetes. Blood flow was
      assessed by venous occlusion plethysmography in 18 diabetic (DM) subjects and 20
      matched controls. Exercise entailed 2 min of isotonic exercise against no load.
      Endothelium-dependent and -independent vasodilator function was assessed
      following intra-arterial infusion of acetylcholine and sodium nitroprusside
      respectively. Forearm blood flow (FBF) was higher in DM subjects than in controls
      (3.3+/-0.3 and 2.2+/-0.2 ml x min(-1) x 100 ml(-1) forearm respectively;
      P<0.005). This was not due to differences in forearm or body size, blood
      pressure, heart rate, lipid status or glycaemic control. Peripheral insulin
      levels were higher in DM subjects than in controls (48.5+/-8 and 15.5+/-1.5 micro
      units/ml respectively; P<0.005). Resting FBF was closely correlated with insulin
      levels (r(2)=0.4; P<0.005). Parameters of exercise-induced hyperaemia [including
      peak flow (16.4+/-1.4 and 12.0+/-0.7 ml x min(-1) x 100 ml(-1) forearm in DM and
      control subjects respectively; P<0.01) and the volume repaid to the forearm at 5
      min post-exercise (32.1+/-3.1 and 23.1+/-1.4 ml x 100 ml(-1) forearm
      respectively; P<0.05)] were also significantly greater in DM subjects, even when
      differences in resting FBF were taken into account. Peak hyperaemic blood flow
      and the volume repaid at 5 min were also related to insulin levels (r(2)=0.16;
      P<0.05 and r(2)=0.27; P<0.005 respectively). The vasodilator response to
      acetylcholine was reduced in DM subjects (P<0.05; analysis of variance), and the
      slope of this dose-flow relationship was inversely related to insulin levels
      (r(2)=0.2; P<0.05). These data show that both resting and exercise-induced
      skeletal muscle blood flow are augmented in young patients with type I diabetes,
      possibly due to the vasodilatory effect of increased insulin levels. Diminished
      vasodilator responses to acetylcholine may also, in part, be a consequence of
      insulin-augmented resting muscle blood flow.

PMID- 10600666
TI  - Peak expiratory flow at increased barometric pressure: comparison of peak flow
      meters and volumetric spirometer.
AB  - Increasing numbers of patients are receiving hyperbaric oxygen therapy as an
      intensive care treatment, some of whom have pre-existing airway obstruction.
      Spirometers are the ideal instruments for measuring airway obstruction, but peak
      flow meters are useful and versatile devices. The behaviour of both types of
      device was therefore studied in a hyperbaric unit under conditions of increased
      pressure. It is important to have a non-electrical indicator of airway
      obstruction, to minimize the fire risk in the hyperoxic environment. The
      hypothesis was tested that, assuming that dynamic resistance is unchanged, both
      the Wright's standard and mini-peak flow meters would over-read peak expiratory
      flow (PEF) under increased pressure when compared with a volumetric spirometer,
      as the latter is unaffected by air density. It was postulated that a correction
      factor could be derived so that PEF meters could be used in this setting. Seven
      normal subjects performed volume-dependent spirometry to derive PEF, and
      manoeuvres using both standard and mini PEF meters at sea level, under hyperbaric
      conditions at 303, 253 and 152 kPa (3, 2.5 and 1.5 atmospheres respectively; 1
      atmosphere absolute=101.08 kPa), and again at sea level. There was a progressive
      and significant decline in PEF with increasing pressure as measured by the
      spirometer (69.46+/-0.8% baseline at 303 kPa compared with 101 kPa), while the
      PEF meters showed a progressive increase in their readings (an increase of 7.86+/
      1.69% at 303 kPa with the mini PEF meter). Using these data points, a correction
      factor was derived which allows appropriate values to be calculated from the
      Wright's meter readings under these conditions.

PMID- 10600667
TI  - Rotation of F(1)-ATPase and the hinge residues of the beta subunit.
AB  - Rotation of a motor protein, F(1)-ATPase, was demonstrated using a unique single
      molecule observation system. This paper reviews what has been clarified by this
      system and then focuses on the role of residues at the hinge region of the beta
      subunit. We have visualised rotation of a single molecule of F(1)-ATPase by
      attaching a fluorescent actin filament to the top of the beta subunit in the
      immobilised F(1)-ATPase, thus settling a major controversy regarding the rotary
      catalysis. The rotation of the beta subunit was exclusively in one direction, as
      could be predicted by the crystal structure of bovine heart F(1)-ATPase. Rotation
      at low ATP concentrations revealed that one revolution consists of three 120
      degrees steps, each fuelled by the binding of an ATP to the beta subunit. The
      mean work done by a 120 degrees step was approximately 80 pN nm, a value close to
      the free energy liberated by hydrolysis of one ATP molecule, implying nearly 100%
      efficiency of energy conversion. The torque is probably generated by the beta
      subunit, which undergoes large opening-closing domain motion upon binding of
      AT(D)P. We identified three hinge residues, betaHis179, betaGly180 and
      betaGly181, whose peptide bond dihedral angles are drastically changed during
      domain motion. Simultaneous substitution of these residues with alanine resulted
      in nearly complete loss (99%) of ATPase activity. Single or double substitution
      of the two Gly residues did not abolish the ATPase activity. However, reflecting
      the shift of the equilibrium between the open and closed forms of the beta
      subunit, single substitution caused changes in the propensity to generate the
      kinetically trapped Mg-ADP inhibited form: Gly180Ala enhanced the propensity and
      Gly181Ala abolished the propensity. In spite of these changes, the mean
      rotational torque was not changed significantly for any of the mutants.

PMID- 10600668
TI  - Coupling H(+) transport to rotary catalysis in F-type ATP synthases: structure
      and organization of the transmembrane rotary motor.
AB  - H(+)-transporting F(1)F(o)-type ATP synthases utilize a transmembrane H(+)
      potential to drive ATP formation by a rotary catalytic mechanism. ATP is formed
      in alternating beta subunits of the extramembranous F(1) sector of the enzyme,
      synthesis being driven by rotation of the gamma subunit in the center of the F(1)
      molecule between the alternating catalytic sites. The H(+) electrochemical
      potential is thought to drive gamma subunit rotation by first coupling H(+)
      transport to rotation of an oligomeric rotor of c subunits within the
      transmembrane F(o) sector. The gamma subunit is forced to turn with the c(12)
      oligomeric rotor as a result of connections between subunit c and the gamma and
      epsilon subunits of F(1). In this essay, we will review recent studies on the
      Escherichia coli F(o) sector. The monomeric structure of subunit c, determined by
      nuclear magnetic resonance (NMR), is discussed first and used as a basis for the
      rest of the review. A model for the structural organization of the c(12) oligomer
      in F(o), deduced from extensive cross-linking studies and by molecular modeling,
      is then described. The interactions between the the a(1)b(2) 'stator' subcomplex
      of F(o) and the c(12) oligomer are then considered. A functional interaction
      between transmembrane helix 4 of subunit a (aTMH-4) and transmembrane helix 2 of
      subunit c (cTMH-2) during the proton-release step from Asp61 on cTMH-2 is
      suggested. Current a-c cross-linking data can only be explained by helix-helix
      swiveling or rotation during the proton transfer steps. A model that mechanically
      links helix rotation within a single subunit c to the incremental 30 degrees
      rotation of the c(12) oligomer is proposed. In the final section, the structural
      interactions between the surface residues of the c(12) oligomer and subunits
      epsilon and gamma are considered. A molecular model for the binding of subunit
      epsilon between the exposed, polar surfaces of two subunits c in the oligomer is
      proposed on the basis of cross-linking data and the NMR structures of the
      individual subunits.

PMID- 10600669
TI  - Structure and function of the F(o) complex of the ATP synthase from Escherichia
      coli.
AB  - The membrane-bound ATP synthase (F(1)F(o)) from mitochondria, chloroplasts and
      bacteria plays a crucial role in energy-transducing reactions. In the case of
      Escherichia coli, the reversible, proton-translocating ATPase complex consists of
      two different entities, F(1) and F(o). The water-soluble F(1) part carries the
      catalytic sites for ATP synthesis and hydrolysis. It is associated with the
      membrane-embedded F(o) complex, which functions as a proton channel and consists
      of subunits a, b and c present in a stoichiometry of 1:2:12. Subunit b was
      isolated by preparative gel electrophoresis, acetone-precipitated and renatured
      in a cholate-containing buffer. Reconstituted subunit b together with purified ac
      subcomplex is active in proton translocation and F(1) binding, thereby
      demonstrating that subunit b had recovered its native conformation. Circular
      dichroism spectroscopy of subunit b reconstituted into liposomes revealed a
      rather high degree of alpha -helical conformation of 80%. After addition of a
      His(6)-tag to the N terminus of subunit a, a stable ab(2) subcomplex was purified
      instead of a single subunit a, arguing in favour of a direct interaction between
      these subunits. After addition of subunit c and reconstitution into phospholipid
      vesicles, an F(o) complex was obtained exhibiting rates of proton translocation
      and F(1) binding comparable with those of wild-type F(o). The epitopes of
      monoclonal antibodies against subunit c are located in the hydrophilic loop
      region (cL31-Q42) as mapped by enzyme-linked immunosorbent assay using
      overlapping synthetic heptapeptides. Binding studies revealed that all monoclonal
      antibodies (mAbs) bind to everted membrane vesicles irrespective of the presence
      or absence of F(1). Although the hydrophilic region of subunit c, and especially
      the highly conserved residues cA40, cR41, cQ42 and cP43, are known to interact
      with subunits gamma and epsilon of the F(1) part, the mAb molecules have no
      effect on the function of F(o), either in proton translocation or in F(1)
      binding. However, the F(1) part and the mAb molecule(s) are bound simultaneously
      to the F(o) complex, suggesting that not all c subunits are involved in the
      interaction with F(1).

PMID- 10600670
TI  - Cross-linking and electron microscopy studies of the structure and functioning of
      the Escherichia coli ATP synthase.
AB  - ATP synthase, also called F(1)F(o)-ATPase, catalyzes the synthesis of ATP during
      oxidative phosphorylation. The enzyme is reversible and is able to use ATP to
      drive a proton gradient for transport purposes. Our work has focused on the
      enzyme from Escherichia coli (ECF(1)F(o)). We have used a combination of methods
      to study this enzyme, including electron microscopy and chemical cross-linking.
      The utility of these two approaches in particular, and the important insights
      they give into the structure and mechanism of the ATP synthase, are reviewed.

PMID- 10600671
TI  - Rate acceleration of ATP hydrolysis by F(1)F(o)-ATP synthase.
AB  - The rate acceleration of ATP hydrolysis by F(1)F(o)-ATP synthase is of the order
      of 10(11)-fold. We present a cyclic enzyme mechanism for the reaction, relate it
      to known F(1) X-ray structure and speculate on the linkage between enzyme
      reaction intermediates and subunit rotation. Next, we describe five factors known
      to be important in the Escherichia coli enzyme for the rate acceleration. First,
      the provision of substrate binding energy by residues lining the catalytic site
      is substantial; beta-Lys155 and beta-Arg182 are specific examples, both of which
      differentially support substrate MgATP versus product MgADP binding. Second,
      octahedral coordination of the Mg(2+) in MgATP is crucial for both catalysis and
      catalytic site asymmetry. The residues involved are beta-Thr156, beta-Glu185 and
      beta-Asp242. Third, there is stabilization of a pentacoordinate phosphorus
      catalytic transition state by residues beta-Lys155, beta-Arg182 and alpha-Arg376.
      Fourth, residue beta-Glu181 binds the substrate water and stabilizes the
      catalytic transition state. Fifth, there is strong positive catalytic
      cooperativity, with binding of MgATP at all three sites yielding the maximum rate
      (V(max)); the molecular basis of this factor remains to be elucidated.

PMID- 10600672
TI  - Steady-state and pre-steady-state kinetics of the mitochondrial F(1)F(o) ATPase:
      is ATP synthase a reversible molecular machine?
AB  - H(+)-ATP synthase (F(1)F(o) ATPase) catalyzes the synthesis and/or hydrolysis of
      ATP, and the reactions are strongly affected by all the substrates (products) in
      a way clearly distinct from that expected of a simple reversibly operating
      enzyme. Recent studies have revealed the structure of F(1), which is ideally
      suited for the alternating binding change mechanism, with a rotating gamma
      subunit as the energy-driven coupling device. According to this mechanism ATP,
      ADP, inorganic phosphate (P(i)) and Mg(2+) participate in the forward and reverse
      overall reactions exclusively as the substrates and products. However, both F(1)
      and F(1)F(o) demonstrate non-trivial steady-state and pre-steady-state kinetics
      as a function of variable substrate (product) concentrations. Several effectors
      cause unidirectional inhibition or activation of the enzyme. When considered
      separately, the unidirectional effects of ADP, P(i), Mg(2+) and energy supply on
      ATP synthesis or hydrolysis may possibly be explained by very complex kinetic
      schemes; taken together, the results suggest that different conformational states
      of the enzyme operate in the ATP hydrolase and ATP synthase reactions. A possible
      mechanism for an energy-dependent switch between the two states of F(1)F(o)
      ATPase is proposed.

PMID- 10600673
TI  - Crucial role of the membrane potential for ATP synthesis by F(1)F(o) ATP
      synthases.
AB  - ATP, the universal carrier of cell energy, is manufactured from ADP and phosphate
      by the enzyme ATP synthase using the free energy of an electrochemical gradient
      of protons (or Na(+)). The proton-motive force consists of two components, the
      transmembrane proton concentration gradient (delta pH) and the membrane
      potential. The two components were considered to be not only thermodynamically
      but also kinetically equivalent, since the chloroplast ATP synthase appeared to
      operate on delta pH only. Recent experiments demonstrate, however, that the
      chloroplast ATP synthase, like those of mitochondria and bacteria, requires a
      membrane potential for ATP synthesis. Hence, the membrane potential and proton
      gradient are not equivalent under normal operating conditions far from
      equilibrium. These conclusions are corroborated by the finding that only the
      membrane potential induces a rotary torque that drives the counter-rotation of
      the a and c subunits in the F(o) motor of Propionigenium modestum ATP synthase.

PMID- 10600674
TI  - Composition and assembly of the yeast vacuolar H(+)-ATPase complex.
AB  - The proton-translocating ATPase (H(+)-ATPase) found on the membrane of the yeast
      vacuole is the best characterized member of the V-type ATPase family. Biochemical
      and genetic screens have led to the identification of 14 genes, the majority
      designated VMA (for vacuolar membrane ATPase) encoding subunits of the enzyme
      complex. At least eight genes encode for proteins comprising the peripherally
      associated catalytic V(1) subcomplex, and six genes code for proteins forming the
      proton-translocating membrane V(o) subcomplex. Several additional genes have been
      identified that encode proteins that are not part of the final V-ATPase complex
      yet are required for its assembly. These non-subunit Vma proteins function as
      dedicated V-ATPase assembly factors since their absence appears to inhibit
      assembly of the V-ATPase only. The assembly factors designated Vma12p, Vma21p and
      Vma22p have been localized to the membrane of the endoplasmic reticulum and aid
      the association of newly synthesized V-ATPase subunits translocated into the
      endoplasmic reticulum membrane. Two of these proteins, Vma12p and Vma22p,
      function together in an assembly complex that interacts directly with nascent V
      ATPase subunits.

PMID- 10600675
TI  - Structure, mechanism and regulation of the clathrin-coated vesicle and yeast
      vacuolar H(+)-ATPases.
AB  - The vacuolar H(+)-ATPases (or V-ATPases) are a family of ATP-dependent proton
      pumps that carry out acidification of intracellular compartments in eukaryotic
      cells. This review is focused on our work on the V-ATPases of clathrin-coated
      vesicles and yeast vacuoles. The coated-vesicle V-ATPase undergoes trafficking to
      endosomes and synaptic vesicles, where it functions in receptor recycling and
      neurotransmitter uptake, respectively. The yeast V-ATPase functions to acidify
      the central vacuole and is necessary both for protein degradation and for coupled
      transport processes across the vacuolar membrane. The V-ATPases are multisubunit
      complexes composed of two functional domains. The V(1) domain is a 570 kDa
      peripheral complex composed of eight subunits of molecular mass 73-14 kDa
      (subunits A-H) that is responsible for ATP hydrolysis. The V(o) domain is a 260
      kDa integral complex composed of five subunits of molecular mass 100-17 kDa
      (subunits a, d, c, c' and c") that is responsible for proton translocation. To
      explore the function of individual subunits in the V-ATPase complex as well as to
      identify residues important in proton transport and ATP hydrolysis, we have
      employed a combination of chemical modification, site-directed mutagenesis and in
      vitro reassembly. A central question concerns the mechanism by which vacuolar
      acidification is controlled in eukaryotic cells. We have proposed that disulfide
      bond formation between conserved cysteine residues at the catalytic site of the V
      ATPase plays an important role in regulating V-ATPase activity in vivo. Other
      regulatory mechanisms that are discussed include reversible dissociation and
      reassembly of the V-ATPase complex, changes in the tightness of coupling between
      proton transport and ATP hydrolysis, differential targeting of V-ATPases within
      the cell and control of the Cl(-) conductance that is necessary for vacuolar
      acidification.

PMID- 10600676
TI  - Assembly and regulation of the yeast vacuolar H(+)-ATPase.
AB  - The yeast vacuolar H(+)-ATPase (V-ATPase) consists of a complex of peripheral
      subunits containing the ATP binding sites, termed the V(1) sector, attached to a
      complex of membrane subunits containing the proton pore, termed the V(o) sector.
      Interaction between the V(1) and V(o) sectors is essential for ATP-driven proton
      transport, and this interaction is manipulated in vivo as a means of regulating V
      ATPase activity. When yeast (Saccharomyces cerevisiae) cells are deprived of
      glucose for as little as 5 min, up to 75% of the assembled V-ATPase complexes are
      disassembled into cytoplasmic V(1) sectors and membrane-bound V(o) sectors.
      Remarkably, this disassembly is completely reversible. Restoration of glucose to
      the growth medium results in quantitative reassembly of the disassembled
      complexes in as little as 5 min, even in the absence of any new protein
      synthesis. Cells also appear to regulate the extent of V(1)V(o) assembly on a
      long-term basis. Yeast cells grown for extended periods in a poor carbon source
      contain a high proportion of free V(1) and V(o) sectors, and these sectors remain
      poised for reassembly when growth conditions improve. Parallel experiments on the
      Manduca sexta V-ATPase suggest that reversible disassembly may be a general
      regulatory mechanism for V-ATPases. These results imply that V-ATPases are
      surprisingly dynamic structures, and their unique 'regulated instability' raises
      a number of interesting physiological and structural questions. How are
      extracellular conditions such as carbon source communicated to V-ATPase complexes
      present on intracellular membranes? How are such major structural changes in the
      V-ATPase generated and how are V(1) sectors 'silenced' in vivo to prevent
      unproductive hydrolysis of cytoplasmic ATP by the dissociated enzyme? We are
      addressing these questions using a combination of genetic and biochemical
      approaches.

PMID- 10600677
TI  - The cellular biology of proton-motive force generation by V-ATPases.
AB  - The vacuolar H(+)-ATPase (V-ATPase) is one of the most fundamental enzymes in
      nature. It functions in almost every eukaryotic cell and energizes a wide variety
      of organelles and membranes. In contrast to F-ATPases, whose primary function in
      eukaryotic cells is to form ATP at the expense of the proton-motive force, V
      ATPases function exclusively as ATP-dependent proton pumps. The proton-motive
      force generated by V-ATPases in organelles and across plasma membranes of
      eukaryotic cells is utilized as a driving force for numerous secondary transport
      processes. The enzyme is also vital for the proper functioning of endosomes and
      the Golgi apparatus. In contrast to yeast vacuoles, which maintain an internal pH
      of approximately 5. 5, it is believed that the vacuoles of lemon fruit may have a
      pH as low as 2. Similarly, some brown and red algae maintain an internal pH as
      low as 1 in their vacuoles. It was yeast genetics that allowed the identification
      of the special properties of individual subunits and the discovery of the factors
      that are involved in V-ATPase biogenesis and assembly. Null mutations in genes
      encoding V-ATPase subunits of Saccharomyces cerevisiae result in a phenotype that
      is unable to grow at high pH and is sensitive to high and low metal-ion
      concentrations. Treatment of these null mutants with ethyl methanesulphonate
      causes mutations that suppress the V-ATPase null phenotype, and these cells are
      able to grow at pH 7.5. The suppressor mutants were denoted as svf (Suppressor of
      V-ATPase Function). The svf mutations are recessive: crossing the svf mutants
      with their corresponding V-ATPase null mutants resulted in diploid strains that
      were not able to grow at pH 7.5. A novel gene family in which null mutations
      cause pleiotropic effects on metal-ion resistance or on the sensitivity and
      distribution of membrane proteins in different targets was discovered. We termed
      this gene family VTC (Vacuolar Transporter Chaperon) and discovered four genes in
      S. cerevisiae that belong to the family. Inactivation of one of them, VTC1, in
      the background of V-ATPase null mutations resulted in an svf phenotype that was
      able to grow at pH 7.5. Apparently, Vtc1p is one of a few membrane organizers
      that determine the relative amounts of different membrane proteins in the various
      cellular membranes. We utilize the numerous yeast mutants generated in our
      laboratory to identify the specific organelle whose acidification is vital. The
      interaction between V-ATPase and the secretory pathway is investigated.

PMID- 10600678
TI  - Cellular role of the V-ATPase in Neurospora crassa: analysis of mutants resistant
      to concanamycin or lacking the catalytic subunit A.
AB  - Vacuolar ATPases (V-ATPases) are large complex enzymes that are structural and
      mechanistic relatives of F(1)F(o)-ATPases. They hydrolyze ATP and pump protons
      across membranes to hyperpolarize membranes and, often, to acidify cellular
      compartments. The proton gradients generated are used to drive the movement of
      various compounds across membranes. V-ATPases are found in membranes of
      archaebacteria and some eubacteria, in various components of the endomembrane
      system of all eukaryotes and in the plasma membranes of many specialized
      eukaryotic cells. They have been implicated in a wide variety of cellular
      processes and are associated with several diseases. Bafilomycin and concanamycin,
      specific inhibitors of V-ATPases, have been instrumental in implicating the V
      ATPase in many of these roles. To understand further the mechanism of inhibition
      by these antibiotics and the physiological role of the enzyme in the cell, we
      have isolated mutants of the filamentous fungus Neurospora crassa that are
      resistant to concanamycin. Concanamycin has a dramatic effect on hyphal
      morphology at acid pH and is lethal at basic pH. In the resistant mutants, the
      cells can germinate and grow, although abnormally, in basic medium. Thus far,
      none of the mutants we have characterized is mutated in a gene encoding a subunit
      of the V-ATPase. Instead, the largest class of mutants is mutated in the gene
      encoding the plasma-membrane H(+)-ATPase. Mutations in at least four
      uncharacterized genes can also confer resistance. Inactivation of the V-ATPase by
      disruption of vma-1, which encodes the catalytic subunit (A) of the enzyme,
      causes a much more severe phenotype than inhibition by concanamycin. A strain
      lacking vma-1 is seriously impaired in rate of growth, differentiation and
      capacity to produce viable spores. It is also completely resistant to
      concanamycin, indicating that the inhibitory effects of concanamycin in vivo are
      due to inhibition of the V-ATPase. How the multiplicity of ATPases within a cell
      is regulated and how their activity is integrated with other metabolic reactions
      is poorly understood. Mutant analysis should help unravel this puzzle.

PMID- 10600679
TI  - Luminal acidification of diverse organelles by V-ATPase in animal cells.
AB  - Eukaryotic cells contain organelles bounded by a single membrane in the
      cytoplasm. These organelles have differentiated to carry out various functions in
      the pathways of endocytosis and exocytosis. Their lumina are acidic, with pH
      ranging from 4.5 to 6.5. This article describes recent studies on these animal
      cell organelles focusing on (1) the primary proton pump (vacuolar-type H(+)
      ATPase) and (2) the functions of the organelle luminal acidity. We also discuss
      similarities and differences between vacuolar-type H(+)-ATPase and F-type ATPase.
      Our own studies and interests are emphasized.

PMID- 10600680
TI  - Synaptic-like microvesicles, synaptic vesicle counterparts in endocrine cells,
      are involved in a novel regulatory mechanism for the synthesis and secretion of
      hormones.
AB  - Microvesicles in endocrine cells are the morphological and functional equivalent
      of neuronal synaptic vesicles. Microvesicles accumulate various neurotransmitters
      through a transmitter-specific vesicular transporter energized by vacuolar H(+)
      ATPase. We found that mammalian pinealocytes, endocrine cells that synthesize and
      secrete melatonin, accumulate l-glutamate in their microvesicles and secrete it
      through exocytosis. Pinealocytes use l-glutamate as either a paracrine- or
      autocrine-like chemical transmitter in a receptor-mediated manner, resulting in
      inhibition of melatonin synthesis. In this article, we briefly describe the
      overall features of the microvesicle-mediated signal-transduction mechanism in
      the pineal gland and discuss the important role of acidic organelles in a novel
      regulatory mechanism for hormonal synthesis and secretion.

PMID- 10600681
TI  - Structure and regulation of insect plasma membrane H(+)V-ATPase.
AB  - H(+) V-ATPases (V-ATPases) are found in two principal locations, in endomembranes
      and in plasma membranes. The plasma membrane V-ATPase from the midgut of larval
      Manduca sexta is the sole energizer of all transepithelial secondary transport
      processes. At least two properties make the lepidopteran midgut a model tissue
      for studies of general aspects of V-ATPases. First, it is a rich source for
      purification of the enzyme and therefore for structural studies: 20 larvae
      provide up to 0.5 mg of holoenzyme, and soluble, cytosolic V(1) complexes can be
      obtained in even greater amounts of up to 2 mg. Second, midgut ion-tranport
      processes are strictly controlled by the regulation of the V-ATPase, which is the
      sole energizer of all ion transport in this epithelium. Recent advances in our
      understanding the structure of the V(1) and V(o) complexes and of the regulation
      of the enzyme's biosynthesis and ion-transport activity will be discussed.

PMID- 10600682
TI  - H(+)V-ATPase-dependent luminal acidification in the kidney collecting duct and
      the epididymis/vas deferens: vesicle recycling and transcytotic pathways.
AB  - Many vertebrate transporting epithelia contain characteristic 'mitochondria-rich'
      cells that express high levels of a vacuolar proton-pumping ATPase (H(+)V-ATPase)
      on their plasma membrane and on intracellular vesicles. In the kidney cortex, A
      cells and B-cells are involved in proton secretion and bicarbonate secretion,
      respectively, in the distal nephron and collecting duct. A-cells have an H(+)V
      ATPase on their apical plasma membrane and on intracellular vesicles, whereas the
      cellular location of the H(+)V-ATPase can be apical, basolateral, bipolar or
      diffuse in B-cells. The rat epididymis and vas deferens also contain a distinct
      population of H(+)V-ATPase-rich epithelial cells. These cells are involved in
      generating a low luminal pH, which is involved in sperm maturation and in
      maintaining sperm in an immotile state during their passage through the
      epididymis and vas deferens. In both kidney and reproductive tract, H(+)V-ATPase
      rich cells have a high rate of apical membrane recycling. H(+)V-ATPase molecules
      are transported between the cell surface and the cytoplasm in vesicles that have
      a well-defined 'coat' structure formed of the peripheral V(1) subunits of the
      H(+)V-ATPase. In addition, we propose that B-type intercalated cells have a
      transcytotic pathway that enables them to shuttle H(+)V-ATPase molecules from
      apical to basolateral plasma membrane domains. This hypothesis is supported by
      data showing that A-cells and B-cells have different intracellular trafficking
      pathways for LGP120, a lysosomal glycoprotein. LGP120 was found both on the
      basolateral plasma membrane and in lysosomes in B-cells, whereas no LGP120 was
      detectable in the plasma membrane of A-cells. We propose that the 'polarity
      reversal' of the H(+)V-ATPase in B-intercalated cells is mediated by a
      physiologically regulated transcytotic pathway that may be similar to that
      existing in some other cell types.

PMID- 10600683
TI  - Crystallization, structure and dynamics of the proton-translocating P-type
      ATPase.
AB  - Large single three-dimensional crystals of the dodecylmaltoside complex of the
      Neurospora crassa plasma membrane H(+)-ATPase (H(+) P-ATPase) can be grown in
      polyethylene-glycol-containing solutions optimized for moderate supersaturation
      of both the protein surfaces and detergent micellar region. Large two-dimensional
      H(+) P-ATPase crystals also grow on the surface of such mixtures and on carbon
      films located at such surfaces. Electron crystallographic analysis of the two
      dimensional crystals grown on carbon films has recently elucidated the structure
      of the H(+) P-ATPase at a resolution of 0.8 nm in the membrane plane. The two
      dimensional crystals comprise two offset layers of ring-shaped ATPase hexamers
      with their exocytoplasmic surfaces face to face. Side-to-side interactions
      between the cytoplasmic regions of the hexamers in each layer can be seen, and an
      interaction between identical exocytoplasmic loops in opposing hexamer layers
      holds the two layers together. Detergent rings around the membrane-embedded
      region of the hexamers are clearly visible, and detergent-detergent interactions
      between the rings are also apparent. The crystal packing forces thus comprise
      both protein-protein and detergent-detergent interactions, supporting the
      validity of the original crystallization strategy. Ten transmembrane helices in
      each ATPase monomer are well-defined in the structure map. They are all
      relatively straight, closely packed, moderately tilted at various angles with
      respect to a plane normal to the membrane surface and average approximately 3.5
      nm in length. The transmembrane helix region is connected in at least three
      places to the larger cytoplasmic region, which comprises several discrete domains
      separated by relatively wide, deep clefts. Previous work has shown that the H(+)
      P-ATPase undergoes substantial conformational changes during its catalytic cycle
      that are not changes in secondary structure. Importantly, the results of
      hydrogen/deuterium exchange experiments indicate that these conformational
      changes are probably rigid-body interdomain movements that lead to cleft closure.
      When interpreted within the framework of established principles of enzyme
      catalysis, this information on the structure and dynamics of the H(+) P-ATPase
      molecule provides the basis of a rational model for the sequence of events that
      occurs as the ATPase proceeds through its transport cycle. The forces that drive
      the sequence can also be clearly stipulated. However, an understanding of the
      molecular mechanism of ion transport catalyzed by the H(+) P-ATPase awaits an
      atomic resolution structure.

PMID- 10600684
TI  - Biogenesis and function of the yeast plasma-membrane H(+)-ATPase.
AB  - One of the most abundant proteins in the yeast plasma membrane is the P-type H(+)
      ATPase that pumps protons out of the cell, supplying the driving force for a wide
      array of H(+)-dependent cotransporters. The ATPase is a 100 kDa polypeptide,
      anchored in the lipid bilayer by 10 transmembrane alpha-helices. It is
      structurally and functionally related to the P-type Na(+),K(+)-, H(+),K(+)- and
      Ca(2+)-ATPases of animal cells and the H(+)-ATPases of plant cells, and it shares
      with them a characteristic reaction mechanism in which ATP is split to ADP and
      inorganic phosphate (P(i)) via a covalent beta-aspartyl phosphate intermediate.
      Cryoelectron microscopic images of the H(+)-ATPase of Neurospora crassa and the
      sarcoplasmic reticulum Ca(2+)-ATPase of animal cells have recently been obtained
      at 8 nm resolution. The membrane-embedded portion of the molecule, which
      presumably houses the cation translocation pathway, is seen to be connected via a
      narrow stalk to a large, multidomained cytoplasmic portion, known to contain the
      ATP-binding and phosphorylation sites. In parallel with the structural studies,
      efforts are being made to dissect structure/function relationships in several P
      type ATPases by means of site-directed mutagenesis. This paper reviews three
      phenotypically distinct classes of mutant that have resulted from work on the
      yeast PMA1 H(+)-ATPase: (1) mutant ATPases that are poorly folded and retained in
      the endoplasmic reticulum; (2) mutants in which the conformational equilibrium
      has been shifted from the E(2) state, characterized by high affinity for
      vanadate, to the E(1) state, characterized by high affinity for ATP; and (3)
      mutants with altered coupling between ATP hydrolysis and proton pumping. Although
      much remains to be learned before the transport mechanism can be fully
      understood, these mutants serve to identify critical parts of the polypeptide
      that are required for protein folding, conformational change and H(+):ATP
      coupling.

PMID- 10600685
TI  - Analysis of the membrane domain of the gastric H(+)/K(+)-ATPase.
AB  - A structure of the catalytic or alpha subunit of the H(+)/K(+)-ATPase, with ten
      transmembrane segments, and of the beta subunit, with a single such segment, was
      established using a combination of tryptic cleavage and peptide sequencing and in
      vitro translation. Sites at which covalent ligands bind to external surfaces were
      also defined by cleavage, separation and sequencing. Cys813 was found to be the
      common covalent binding site for all the substituted pyridyl methylsulfinyl
      benzimidazoles. The binding region of a K(+)-competitive reagent, the 1,2 &agr; 
      imidazo-pyridine SCH 28080, was defined by the kinetic effects of site-specific
      mutations. Amino acids substitutions in membrane-spanning segments M1, M3, M4 and
      M6 were found to influence the apparent inhibitor constant, K(i), to varying
      degrees, some having a large effect, some a moderate effect and some a slight
      effect, whereas some mutations had no effect. We interpret changes in K(i)
      without effects on the apparent Michaelis constant, K(m), as affecting SCH 28080
      binding only. Mutation of Cys813 significantly affected the K(i) for SCH 28080,
      explaining the prevention of benzimidazole inhibition by the imidazo-pyridine.A
      model of the &agr; subunit was constructed with a vestibule on the luminal
      surface of the pump bounded by M1-M6 and containing the SCH 28080 binding region.
      The cation binding site is suggested to be more towards the cytoplasmic face of
      the enzyme's membrane domain. This model predicts the membrane peptide
      associations for the catalytic subunit. Biochemical and yeast two-hybrid methods
      place the beta subunit in association with M8, whereas similar methods place M5/6
      in proximity to M9/10. These results, when combined with analysis of the two
      dimensional crystals of the sarcoplasmic reticular Ca(2+) and Neurospora crassa
      H(+)-ATPases, provide the basis for a tentative model of the arrangement of the
      six core segments of the gastric H(+)/K(+)-ATPase.

PMID- 10600686
TI  - New paradigms of signaling in the vasculature: ephrins and metalloproteases.
AB  - As our understanding of the control of vasculogenesis and angiogenesis continues
      to grow, we will be confronted with an increasing number of interacting and
      intersecting receptor-mediated signaling pathways. If we are to be successful in
      developing new and novel effective therapeutic reagents that can function as
      stimulators or inhibitors of these critically important processes, we will have
      to develop a sophisticated, full understanding of the complex interactions
      associated with ephrin-based and metalloprotease-based signaling pathways.

PMID- 10600687
TI  - Whole microbial cell processes for manufacturing amino acids, vitamins or
      ribonucleotides.
AB  - The development of recombinant DNA technology has greatly expanded whole
      microbial cell processes for manufacturing amino acids, vitamins, or
      ribonucleotides. A novel well-designed scheme with integrated enzymatic
      conversions and fermentation enables the production of even complicated
      compounds, such as sugar nucleotides and oligosaccharides.

PMID- 10600688
TI  - Peroxisome proliferator-activated receptors: three isotypes for a multitude of
      functions.
AB  - The peroxisome proliferator-activated receptors (PPARs) are fatty acid and
      eicosanoid inducible nuclear receptors, which occur in three different isotypes.
      Upon activator binding, they modulate the expression of various target genes
      implicated in several important physiological pathways. During the past few
      years, the identification of both PPAR ligands, natural and synthetic, and PPAR
      targets and their associated functions has been one of the most important
      achievements in the field. It underscores the potential therapeutic application
      of PPAR-specific compounds on the one side, and the crucial biological roles of
      endogenous PPAR ligands on the other.

PMID- 10600689
TI  - Current biology of VEGF-B and VEGF-C.
AB  - Endothelial growth factors and their receptors may provide important therapeutic
      tools for the treatment of pathological conditions characterised by defective or
      aberrant angiogenesis. Vascular endothelial growth factor (VEGF) is pivotal for
      vasculogenesis and for angiogenesis in normal and pathological conditions. VEGF-B
      and VEGF-C provide this gene family with additional functions, for example, VEGF
      C also regulates lymphangiogenesis.

PMID- 10600690
TI  - Ligand-binding domain of estrogen receptors.
AB  - Estrogen receptors are multi-domain proteins that interact with other proteins
      and DNA to fulfil their function: the regulation of transcription. During the
      past 2-3 years, our understanding of this complex process has increased
      tremendously as crystal structures of isolated ligand-binding domains in complex
      with various ligands, as well as co-activator peptides, are now available. The
      structural information, combined with new data on novel co-activators/co
      repressors, muteins and their actions, and novel ligands, allows for the first
      time the development of detailed theories for the first steps of transcription
      initiation.

PMID- 10600691
TI  - Searching for drug targets in microbial genomes.
AB  - Comparative analysis of the complete genome sequences of 10 bacterial pathogens
      available in the public databases offers the first insights into the drug
      discovery approaches of the near future. Genes that are conserved in different
      genomes often turn out to be essential, which makes them attractive targets for
      new broad-spectrum antibiotics. Subtractive genome analysis reveals the genes
      that are conserved in all or most of the pathogenic bacteria but not in
      eukaryotes; these are the most obvious candidates for drug targets. Species
      specific genes, on the other hand, may offer the possibility to design drugs
      against a particular, narrow group of pathogens.

PMID- 10600692
TI  - Nuclear receptor regulation of cholesterol and bile acid metabolism.
AB  - The metabolism of cholesterol and bile acids is transcriptionally regulated by
      classic feedforward and feedback signaling pathways. The mechanisms underlying
      this regulation have recently been elucidated by the characterization of three
      classes of orphan nuclear receptors. Furthermore, the study of these receptors
      suggests their potential as targets for new drug therapies.

PMID- 10600693
TI  - Analysis of gene expression in single cells.
AB  - A cell's structural and functional characteristics are dependent on the specific
      complement of genes it expresses. The ability to study and compare gene usage at
      the cellular level will therefore provide valuable insights into cell physiology.
      Such analyses are complicated by problems associated with sample collection,
      sample size and the limited sensitivity of expression assays. Advances have been
      made in approaches to the collection of cellular material and the performance of
      single-cell gene expression analysis. Recent development in global amplification
      of mRNA may soon permit expression analyses of single cells to be performed on
      DNA microarrays.

PMID- 10600694
TI  - Antiangiogenic agents.
AB  - A greater understanding of the complex process of tumor-induced angiogenesis,
      coupled with the notion that tumors require a blood supply to both grow and
      metastasize, has fueled the search for agents that block or disrupt the
      angiogenic process. Because normal vascular endothelial cells (ECs) turn over so
      slowly, conventional wisdom suggests that an antiangiogenic approach to cancer
      therapy should offer improved efficacy and reduced toxicity, without the
      potential for drug resistance. Numerous reports have identified small molecules
      or antibodies that can interfere with one or more key steps in EC signaling,
      migration or differentiation. Three new compounds, ZD4190, SU6668 and PD 0173073,
      have been reported during the past year to have significant and selective
      antiangiogenic activity, as well as antitumor activity.

PMID- 10600695
TI  - Production of fine chemicals using biocatalysis.
AB  - Presently, a large number of biotransformations are carried out on an industrial
      scale and are discussed in a fast increasing number of reviews. Besides this, a
      significant number of biotransformations have been investigated over the past
      year, from degrading to transforming and synthetic reactions. The development of
      more specific and stable biocatalysts, either isolated enzymes or whole cells,
      generated by the new methods of genetic engineering and improved by reaction
      engineering have led to new industrial biotransformations.

PMID- 10600696
TI  - Biocatalysis for industrial production of fine chemicals.
AB  - Chiral intermediates constitute a significant part of the fine chemicals market,
      which is strongly influenced by trends in the pharmaceutical industries, where
      approximately 70% of pharmaceuticals are expected to be enantiomerically pure in
      the next century as compared to 25% today. The main technologies by which
      enantiomerically pure ingredients are obtained today are (dynamic) resolutions of
      racemic mixtures. Asymmetric syntheses are being developed, but their
      applications in industry are still under represented. Biotechnological methods,
      resolutions as well as asymmetric syntheses, are becoming increasingly important
      in the industrial production of fine chemicals.

PMID- 10600697
TI  - Complex traits, genes, polymorphisms and the drug discovery/development process.

PMID- 10600698
TI  - Predicting protein three-dimensional structure.
AB  - The current state of the art in modeling protein structure has been assessed,
      based on the results of the CASP (Critical Assessment of protein Structure
      Prediction) experiments. In comparative modeling, improvements have been made in
      sequence alignment, sidechain orientation and loop building. Refinement of the
      models remains a serious challenge. Improved sequence profile methods have had a
      large impact in fold recognition. Although there has been some progress in
      alignment quality, this factor still limits model usefulness. In ab initio
      structure prediction, there has been notable progress in building approximately
      correct structures of 40-60 residue-long protein fragments. There is still a long
      way to go before the general ab initio prediction problem is solved. Overall, the
      field is maturing into a practical technology, able to deliver useful models for
      a large number of sequences.

PMID- 10600699
TI  - VEGF and therapeutic opportunities in cardiovascular diseases.
AB  - In the past ten years, alternative revascularization strategies have come from
      bench to bedside focusing on the growth of new vessels to replace the old.
      Hypoxia and vascular endothelial growth factor may induce capillary growth;
      however, atherosclerosis affects large conductance vessels, which can only be
      replaced by functional collateral arteries.

PMID- 10600700
TI  - Biocatalytic synthesis of oligosaccharides.
AB  - Tremendous advances in biocatalytic approaches to oligosaccharide synthesis have
      taken place in the past two years. The use of isolated enzymes, both
      glycosyltransferases and glycosidases, or engineered whole cells allows the
      preparation of natural oligosaccharides and analogs required for glycobiology
      research.

PMID- 10600701
TI  - The cell cycle and development: redundant roles of cell cycle regulators.
AB  - The existence of families of cell cycle regulators reflects the need by a
      developing organism to precisely control proliferation of its cells and also
      suggests that family members may play redundant roles. Recent advances have shown
      redundancy to be a theme in development.

PMID- 10600702
TI  - Cell adhesion molecules, signal transduction and cell growth.
AB  - Signals from dynamic cellular interactions between the extracellular matrix and
      neighboring cells ultimately input into the cellular decision-making process.
      These interactions form the basis of anchorage-dependent growth. Recent advances
      have provided the mechanistic details behind the ability of integrins, and other
      cell adhesion molecules (CAMs), to regulate both early signal transduction events
      initiated by soluble factors and downstream events more proximally involved in
      cell cycle progression. These actions appear to depend on the ability of CAMs to
      initiate the formation of organized structures that permit the efficient flow of
      information.

PMID- 10600703
TI  - Chromosome segregation during the prokaryotic cell division cycle.
AB  - Recent work has dramatically changed our view of chromosome segregation in
      bacteria. Rather than being a passive process, it involves rapid movement of
      parts of the circular chromosome. Several genes involved in chromosome
      segregation have been identified, and the analysis of their functions and
      intracellular localization are beginning to shed light on the mechanisms that
      ensure efficient chromosome segregation.

PMID- 10600704
TI  - MEF2: a transcriptional target for signaling pathways controlling skeletal muscle
      growth and differentiation.
AB  - Skeletal muscle development involves a multistep pathway in which mesodermal
      precursor cells are selected, in response to inductive cues, to form myoblasts
      that later withdraw from the cell cycle and differentiate. The transcriptional
      circuitry controlling muscle differentiation is intimately linked to the cell
      cycle machinery, such that muscle differentiation genes do not become transcribed
      until myoblasts have exited the cell cycle. Members of the MyoD and MEF2 families
      of transcription factors associate combinatorially to control myoblast
      specification, differentiation and proliferation. Recent studies have revealed
      multiple signaling systems that stimulate and inhibit myogenesis by altering MEF2
      phosphorylation and its association with other transcriptional cofactors.

PMID- 10600705
TI  - How do small GTPase signal transduction pathways regulate cell cycle entry?
AB  - A variety of studies have shown that activation of the cell cycle machinery
      requires the participation of multiple signalling pathways. These pathways
      include Ras-dependent effectors such as the extracellular-signal related kinases,
      otherwise known as mitogen-activated protein kinases (ERKs, MAPKs),
      phosphatidylinositol 3 (PI3)-kinase and p21Ral pathways, as well as other
      signalling pathways regulated by the small GTPases p21Rho, p21Rac and p21Cdc42.

PMID- 10600706
TI  - Pancreas: how to get there from the gut?
AB  - All pancreatic cell types derive from the same endodermal dorsal and ventral
      anlage that grow together to form the definitive pancreas. A number of distinct
      transcription factors operating at various levels of pancreatic development, and
      in different cell-types, have been identified and their functions have, in many
      cases, been genetically analyzed. This knowledge has given us useful information
      both on pancreas development and on various pancreatic disorders, such as
      diabetes. However, the extrinsic factors that ultimately control the process
      leading from the primitive gut endoderm to a fully developed, functional pancreas
      needs now to be identified. With such information, the prospect of using
      pancreatic stem and/or progenitor cells as a therapeutic approach towards curing
      diabetic disorders will be within reach.

PMID- 10600707
TI  - Induction and differentiation of the neural crest.
AB  - The neural crest is a population of cells that forms at the junction between the
      epidermis and neural plate in vertebrate embryos. Recent progress has elucidated
      the identity and timing of molecular events responsible for the earliest steps in
      neural crest development, particularly those involving the induction and its
      migration. Concomitantly, advances have been made in the identification,
      purification and generation of neural crest stem cells at various developmental
      stages that deepens our understanding of the plasticity and restriction of neural
      crest differentiation.

PMID- 10600708
TI  - Molecular mechanisms of liver development and differentiation.
AB  - Recent advances in identifying molecular signals that dictate liver development
      and differentiation have come from analysis of several experimental systems
      including the developing embryo, cell and tissue culture, knockout mice and
      transplantation of hepatic precursor cells. Fibroblast growth factors and several
      families of transcription factors including hepatocyte nuclear factors 1, 3 and 4
      and CCAAT/enhancer-binding protein have been shown to be important components of
      the differentiation process that culminates in the fully functional liver.

PMID- 10600709
TI  - Signaling mechanisms in pituitary morphogenesis and cell fate determination.
AB  - The development of the pituitary gland has provided an instructive model system
      for exploring the mechanisms by which differentiated cell types arise from a
      common primordium in response to extrinsic and intrinsic signals. Recent studies
      have established that organ commitment, early patterning, proliferation and
      positional determination of cell types in the developing pituitary are mediated
      through the integral actions of multiple signaling gradients acting on an
      initially uniform ectodermal cell population. Studies of the cell-autonomous
      transcriptional mediators of the transient signaling events have also provided
      insight into the molecular mechanisms by which overlapping patterns of
      transcription factor expression can positionally specify pituitary cell lineages.
      There is emerging evidence for a morphogenetic code for the development of the
      pituitary gland based on the cooperative and opposing actions of multiple
      signaling gradients, mediated by corresponding expression patterns of temporally
      and spatially induced transcription factors.

PMID- 10600710
TI  - Transcriptional activation of adipogenesis.
AB  - Studies from the past several years have revealed that adipogenesis is controlled
      by an interplay of transcription factors, including members of the CCAAT/enhancer
      binding protein family and peroxisome proliferator activated receptor gamma. In
      addition to providing a new understanding of this aspect of the energy balance
      systems, these factors provide potential new targets for therapeutic intervention
      in metabolic diseases, such as obesity and type 2 diabetes mellitus.

PMID- 10600711
TI  - Progression into and out of mitosis.
AB  - Progression through mitosis is controlled by cyclin-dependent kinases, which
      drive cells into metaphase, and by the anaphase-promoting complex/cyclosome, a
      ubiquitin ligase that triggers sister chromatid separation and exit from mitosis.
      Recent work has shown how the mutual regulation between cyclin-dependent kinases
      and the anaphase-promoting complex/cyclosome ensures that cell-cycle events occur
      in the right order. The analysis of complexes required for sister chromatid
      cohesion and chromosome condensation has revealed how cyclin-dependent kinases
      and the anaphase-promoting complex/cyclosome control the behaviour of
      chromosomes.

PMID- 10600712
TI  - Cytokinesis: an emerging unified theory for eukaryotes?
AB  - In animal and fungal cells, cytokinesis involves an actomyosin ring that forms
      and contracts at the division plane. Important new details have emerged
      concerning the composition, assembly, and dynamics of these contractile rings. In
      addition, recent advances suggest that targeted membrane addition is a central
      feature of cytokinesis in animal cells - as it is in fungi and plants - and the
      coordination of actomyosin ring function with targeted exocytosis at the cleavage
      plane is being explored. Important new information has also emerged about the
      spatial and temporal regulation of cytokinesis, especially in relation to the
      function of the spindle midzone in animal cells and the control of cytokinesis by
      GTPase systems.

PMID- 10600713
TI  - Cell proliferation and apoptosis.
AB  - Cell proliferation and cell death are essential yet opposing cellular processes.
      Crosstalk between these processes promotes a balance between proliferation and
      death, and it limits the growth and survival of cells with oncogenic mutations.
      New insights into the mechanisms by which strong signals to proliferate and
      activation of cyclin-dependent kinases promote apoptosis have recently been
      published, and a novel cell cycle regulated caspase inhibitor, Survivin, has been
      described.

PMID- 10600714
TI  - Gene and genome duplications in vertebrates: the one-to-four (-to-eight in fish)
      rule and the evolution of novel gene functions.
AB  - One important mechanism for functional innovation during evolution is the
      duplication of genes and entire genomes. Evidence is accumulating that during the
      evolution of vertebrates from early deuterostome ancestors entire genomes were
      duplicated through two rounds of duplications (the 'one-to-two-to-four' rule).
      The first genome duplication in chordate evolution might predate the Cambrian
      explosion. The second genome duplication possibly dates back to the early
      Devonian. Recent data suggest that later in the Devonian, the fish genome was
      duplicated for a third time to produce up to eight copies of the original
      deuterostome genome. This last duplication took place after the two major
      radiations of jawed vertebrate life, the ray-finned fish (Actinopterygia) and the
      sarcopterygian lineage, diverged. Therefore the sarcopterygian fish, which
      includes the coelacanth, lungfish and all land vertebrates such as amphibians,
      reptiles, birds and mammals, tend to have only half the number of genes compared
      with actinopterygian fish. Although many duplicated genes turned into
      pseudogenes, or even 'junk' DNA, many others evolved new functions particularly
      during development. The increased genetic complexity of fish might reflect their
      evolutionary success and diversity.

PMID- 10600716
TI  - Model systems for redox cofactor activity.
AB  - Numerous model studies of organic redox cofactor activity have appeared in the
      latter half of 1998 and the first half of 1999. These investigations include the
      use of solution models to explore flavin-dependent, quinone-dependent and
      pyrroloquinone-dependent redox processes, the exploration of flavin and quinone
      redox events using organized interfaces, and the application of computational
      methods to increase the understanding of flavin-catalyzed, nicotinamide-catalyzed
      and quinone-catalyzed redox processes.

PMID- 10600717
TI  - Novel approaches to molecular recognition using porphyrins.
AB  - Studies of molecular recognition using designed and synthesised molecules provide
      valuable information on the principle and possible applications of artificial
      functional molecules. Porphyrin-based receptors have been used to elucidate haem
      protein interactions and the basic mechanism of multi-point recognition.

PMID- 10600718
TI  - Model membranes: developments in functional micelles and vesicles.
AB  - Although aggregates of amphiphilic molecules have been studied for decades,
      systems are now being developed that are able to perform useful functions,
      including drug delivery, control of the availability of chemical species, sensing
      of ions or organic molecules, and, the most challenging, providing a reaction
      environment for chemical reactions that resembles that of the natural system.
      Such systems are therefore becoming more and more important in a variety of
      fields, ranging from material science to analytical chemistry and medicine.

PMID- 10600719
TI  - Carbohydrates in transplantation.
AB  - Carbohydrate materials have become increasingly utilized in transplantation and
      cell/tissue engineering within the past year. This has been well documented in
      recent applications of immobilized or soluble alpha-galactosyl epitopes (i.e.
      oligosaccharides with a terminal Galalpha1-3Gal sequence) in preventing
      hyperacute rejection in pig-to-primate xenotransplantation. In addition, alpha
      galactosyl polymers have been shown to exhibit much greater activity (up to 10(4)
      times) than alpha-galactosyl monomers in inhibiting the binding of anti
      galactosyl antibodies to pig kidney epithelial cells and assisting in the
      prevention of cytotoxicity in human serum.

PMID- 10600720
TI  - Helical peptide and protein design.
AB  - The design of dimeric coiled-coils has ultimately led to novel applications, such
      as self-replicating peptide systems, whereas the structural features of the less
      common trimeric coiled-coil continue to be elucidated. Novel topologies have been
      discovered in designed proteins, as exemplified by the right-handed tetrameric
      coiled-coil and the inverted U four-helix bundle, and a single switch of two
      amino acids within a protein has been shown to be sufficient to designate a new
      protein fold. Conformational switching from helix to sheet has been observed for
      designed peptides and transcription factors, whereas peptides designed from beta
      amino acids have been found to adopt a helical conformation in aqueous solution.

PMID- 10600721
TI  - Aminoglycoside-RNA interactions.
AB  - The structural and physico-chemical parameters promoting the binding of
      aminoglycosides to RNAs are becoming clear. The strength of the interaction is
      dominated by electrostatics, with the positively charged aminoglycosides
      displacing metal ions. Although aminoglycosides inhibit most known ribozymes,
      aminoglycosides or polyamines are able to catalyze specific RNA cleavage in the
      absence of metal ions.

PMID- 10600722
TI  - Effect of N-linked glycosylation on glycopeptide and glycoprotein structure.
AB  - Asparagine-linked glycosylation is an enzyme-catalyzed, co-translational protein
      modification reaction that has the capacity to influence either the protein
      folding process or the stability of the native glycoprotein conjugate. Advances
      in both glycoconjugate chemical synthesis and glycoprotein expression methods
      have increased the availability of these once elusive biopolymers. The
      application of spectroscopic methods to these proteins has begun to illuminate
      the various ways in which the saccharide affects the structure, function and
      stability of the proteins.

PMID- 10600723
TI  - Synthesis and catalysis by molecularly imprinted materials.
AB  - Molecularly imprinted materials have been demonstrated to possess a very high
      degree of selectivity towards targeted substrates. In addition to such tailor
      made molecular recognition, progress has been made in introducing reactive groups
      into the recognition sites. Putting teeth into imprinted matrices is one method
      of making true enzyme mimics or plastizymes, which are plastic polymer enzyme
      mimics.

PMID- 10600724
TI  - Bioinspired polymeric materials: in-between proteins and plastics.
AB  - Chemical and biological researchers are making rapid progress in the design and
      synthesis of non-natural oligomers and polymers that emulate the properties of
      natural proteins. Whereas molecular biologists are exploring biosynthetic routes
      to non-natural proteins with controlled material properties, synthetic polymer
      chemists are developing bioinspired materials with well-defined chemical and
      physical properties that function or self-organize according to defined molecular
      architectures. Bioorganic chemists, on the other hand, are developing several new
      classes of non-natural oligomers that are bridging the gap between molecular
      biology and polymer chemistry. These synthetic oligomers have both sidechain and
      length specificity, and, in some cases, demonstrate capability for folding, self
      assembly, and specific biorecognition. Continued active exploration of diverse
      backbone and sidechain chemistries and connectivities in bioinspired oligomers
      will offer the potential for self-organized materials with greater chemical
      diversity and biostability than natural peptides. Taken together, advances in
      molecular bioengineering, polymer chemistry, and bioorganic chemistry are
      converging towards the creation of useful bioinspired materials with defined
      molecular properties.

PMID- 10600725
TI  - Selectin-carbohydrate interactions in shear flow.
AB  - Hydrodynamic shear creates mechanical stresses on selectin bonds, modulating
      affinity and kinetic parameters. Chemical modification of sialyl Lewis(x)
      increases the strength of L-selectin bonds without altering recognition,
      suggesting that mechanical and biorecognition characteristics are separable. L
      selectin bond formation rates may be strongly influenced by sulfate orientation
      in sulfo sialyl Lewis(x).

PMID- 10600726
TI  - Designed molecules that fold to mimic protein secondary structures.
AB  - Molecules that fold to mimic protein secondary structures have emerged as
      important targets of bioorganic chemistry. Recently, a variety of compounds that
      mimic helices, turns, and sheets have been developed, with notable advances in
      the design of beta-peptides that mimic each of these structures. These compounds
      hold promise as a step toward synthetic molecules with protein-like properties
      and as drugs that block protein-protein interactions.

PMID- 10600727
TI  - Chemical protein synthesis.
AB  - Since the mid-1990s, chemical synthesis has emerged as a powerful technique for
      the study of structure/function relationships in proteins. During the review
      period, the applicability of chemical protein synthesis techniques has been
      significantly broadened by increases in the size of synthetically accessible
      proteins through two new techniques: solid-phase protein synthesis and expressed
      protein ligation. Also in the period under review, synthetic access to novel
      classes of proteins has been established, including metalloproteins with tuned
      properties and integral membrane proteins.

PMID- 10600728
TI  - Hydrolysis of phosphates, esters and related substrates by models of biological
      catalysts.
AB  - Why study hydrolases, and why model them? First, hydrolases themselves are of
      fundamental importance and utility. Examples of their utility in organic
      synthesis include kinetic resolutions of optical isomers. Restriction
      endonucleases (DNA hydrolases) are key tools for biotechnology and are vital
      biological catalysts. Peptidases are necessary for protein digestion and can be
      harnessed to perform the reverse reaction (peptide synthesis). Thus, for these
      and many other reasons, hydrolases receive the attention of fundamental and
      applied research. Models of hydrolases can contribute to our understanding of
      reaction mechanisms and may also supplant the enzymes as useful catalysts under
      some conditions. Altering or even increasing the specificity of natural catalysts
      are also goals of these model studies.

PMID- 10600729
TI  - RNA structure, metal ions, and catalysis.
AB  - Several new and unexpected insights into the metalloenzymology of ribozymes have
      been achieved in the past year. From a mechanistic point of view, the NMR and
      crystal structures of a small Pb(2+)-dependent ribozyme have been particularly
      revealing.

PMID- 10600730
TI  - Synergy and duality in peptide antibiotic mechanisms.
AB  - The molecular mechanisms by which peptide antibiotics disrupt bacterial DNA
      synthesis, protein biosynthesis, cell wall biosynthesis, and membrane integrity
      are diverse, yet historically have been understood to follow a theme of one
      antibiotic, one inhibitory mechanism. In the past year, mechanistic and
      structural studies have shown a rich diversity in peptide antibiotic mechanism.
      Novel secondary targeting mechanisms for peptide antibiotics have recently been
      discovered, and the mechanisms of peptide antibiotics involved in synergistic
      relationships with antibiotics and proteins have been more clearly defined. In
      apparent response to selective pressures, antibiotic-producing organisms have
      elegantly integrated multiple functions and cooperative interactions into peptide
      antibiotic design for the purpose of improving antimicrobial success.

PMID- 10600731
TI  - Sequence-specific DNA recognition by polyamides.
AB  - Sequence-specific DNA-binding small molecules that can permeate cells could
      potentially regulate transcription of specific genes. Simple pairing rules for
      the minor groove of the double helix have been developed that allow the design of
      ligands for predetermined DNA sequences. Some of these polyamides have been shown
      to inhibit specific gene expression in mammalian cell culture.

PMID- 10600732
TI  - Structure of a transcribing T7 RNA polymerase initiation complex.
AB  - The structure of a T7 RNA polymerase (T7 RNAP) initiation complex captured
      transcribing a trinucleotide of RNA from a 17-base pair promoter DNA containing a
      5-nucleotide single-strand template extension was determined at a resolution of
      2.4 angstroms. Binding of the upstream duplex portion of the promoter occurs in
      the same manner as that in the open promoter complex, but the single-stranded
      template is repositioned to place the +4 base at the catalytic active site. Thus,
      synthesis of RNA in the initiation phase leads to accumulation or "scrunching" of
      the template in the enclosed active site pocket of T7 RNAP. Only three base pairs
      of heteroduplex are formed before the RNA peels off the template.

PMID- 10600733
TI  - Phase-coherent amplification of matter waves
AB  - Phase-coherent matter-wave amplification was demonstrated using Bose- Einstein
      condensed rubidium-87 atoms. A small seed matter wave was created with coherent
      optical Bragg diffraction. Amplification of this seed matter wave was achieved by
      using the initial condensate as a gain medium through the superradiance effect.
      The coherence properties of the amplified matter wave, studied with a matter-wave
      interferometer, were shown to be locked to those of the initial seed wave. The
      active matter-wave device demonstrated here has great potential in the fields of
      atom optics, atom lithography, and precision measurements.

PMID- 10600734
TI  - Exciton storage in semiconductor self-assembled quantum dots
AB  - Storage and retrieval of excitons were demonstrated with semiconductor self
      assembled quantum dots (QDs). The optically generated excitons were dissociated
      and stored as separated electron-hole pairs in coupled QD pairs. A bias voltage
      restored the excitons, which recombined radiatively to provide a readout optical
      signal. The localization of the spatially separated electron-hole pair in QDs was
      responsible for the ultralong storage times, which were on the order of several
      seconds. The present limits of this optical storage medium are discussed.

PMID- 10600735
TI  - Experimental tunneling ratchets
AB  - Adiabatically rocked electron ratchets, defined by quantum confinement in
      semiconductor heterostructures, were experimentally studied in a regime where
      tunneling contributed to the particle flow. The rocking-induced electron flow
      reverses direction as a function of temperature. This result confirms a recent
      prediction of fundamentally different behavior of classical versus quantum
      ratchets. A wave-mechanical model reproduced the temperature-induced current
      reversal and provides an intuitive explanation.

PMID- 10600736
TI  - Three-dimensional atomic-scale imaging of impurity segregation to line defects
AB  - Clouds of impurity atoms near line defects are believed to affect the plastic
      deformation of alloys. Three-dimensional atom probe techniques were used to image
      these so-called Cottrell atmospheres directly. Ordered iron-aluminum alloys (40
      atomic percent aluminum) doped with boron (400 atomic parts per million) were
      investigated on an atomic scale along the <001> direction. A boron enrichment was
      observed in the vicinity of an <001> edge dislocation. The enriched region
      appeared as a three-dimensional pipe 5 nanometers in diameter, tangent to the
      dislocation line. The dislocation was found to be boron-enriched by a factor of
      50 (2 atomic percent) relative to the bulk. The local boron enrichment is
      accompanied by a strong aluminum depletion of 20 atomic percent.

PMID- 10600737
TI  - Deflection of the local interstellar dust flow by solar radiation pressure.
AB  - Interstellar dust grains intercepted by the dust detectors on the Ulysses and
      Galileo spacecrafts at heliocentric distances from 2 to 4 astronomical units show
      a deficit of grains with masses from 1 x 10(-17) to 3 x 10(-16) kilograms
      relative to grains intercepted outside 4 astronomical units. To divert grains out
      of the 2- to 4-astronomical unit region, the solar radiation pressure must be 1.4
      to 1.8 times the force of solar gravity. These figures are consistent with the
      optical properties of spherical or elongated grains that consist of astronomical
      silicates or organic refractory material. Pure graphite grains with diameters of
      0.2 to 0.4 micrometer experience a solar radiation pressure force as much as
      twice the force of solar gravity.

PMID- 10600738
TI  - Short-lived oxygen diffusion during hot, deep-seated meteoric alteration of
      anorthosite
AB  - Heterogeneous oxygen isotope compositions of plagioclase from the Boehls Butte
      anorthosite include some of the most oxygen-18-depleted values (to -16 per mil)
      reported for plagioclase in meta-igneous rocks and indicate high-temperature (T >
      500 degrees C) isotopic exchange between plagioclase and nearly pristine meteoric
      fluid. Retrograde reaction-enhanced permeability assisted influx of meteoric
      hydrothermal fluids into the deep-seated anorthosite. Isotopic gradients of about
      14 per mil over 600 micrometers in single crystals require short-lived (about
      10(4) years) diffusional exchange of oxygen and locally large effective
      water:rock ratios, followed by rapid loss of water and cessation of oxygen
      diffusion in the anorthosite.

PMID- 10600739
TI  - Surfactant-mediated two-dimensional crystallization of colloidal crystals
AB  - Colloidal particles can form unexpected two-dimensional ordered colloidal
      crystals when they interact with surfactants of the opposite charge. Coulomb
      interactions lead to self-limited adsorption of the particles on the surface of
      vesicles formed by the surfactants. The adsorbed particles form ordered but fluid
      rafts on the vesicle surfaces, and these ultimately form robust two-dimensional
      crystals. This use of attractive Coulomb interaction between colloidal particles
      and surfactant structures offers a potential new route to self-assembly of
      ordered colloidal structures.

PMID- 10600740
TI  - Postnatal sex reversal of the ovaries in mice lacking estrogen receptors alpha
      and beta.
AB  - Mice lacking estrogen receptors alpha and beta were generated to clarify the
      roles of each receptor in the physiology of estrogen target tissues. Both sexes
      of alphabeta estrogen receptor knockout (alphabetaERKO) mutants exhibit normal
      reproductive tract development but are infertile. Ovaries of adult alphabetaERKO
      females exhibit follicle transdifferentiation to structures resembling
      seminiferous tubules of the testis, including Sertoli-like cells and expression
      of Mullerian inhibiting substance, sulfated glycoprotein-2, and Sox9. Therefore,
      loss of both receptors leads to an ovarian phenotype that is distinct from that
      of the individual ERKO mutants, which indicates that both receptors are required
      for the maintenance of germ and somatic cells in the postnatal ovary.

PMID- 10600741
TI  - Isolation of West Nile virus from mosquitoes, crows, and a Cooper's hawk in
      Connecticut.
AB  - West Nile (WN) virus, a mosquito-transmitted virus native to Africa, Asia, and
      Europe, was isolated from two species of mosquitoes, Culex pipiens and Aedes
      vexans, and from brain tissues of 28 American crows, Corvus brachyrhynchos, and
      one Cooper's hawk, Accipiter cooperii, in Connecticut. A portion of the genome of
      virus isolates from four different hosts was sequenced and analyzed by
      comparative phylogenetic analysis. Our isolates from Connecticut were similar to
      one another and most closely related to two WN isolates from Romania (2.8 and 3.6
      percent difference). If established in North America, WN virus will likely have
      severe effects on human health and on the health of populations of birds.

PMID- 10600742
TI  - Origin of the West Nile virus responsible for an outbreak of encephalitis in the
      northeastern United States.
AB  - In late summer 1999, an outbreak of human encephalitis occurred in the
      northeastern United States that was concurrent with extensive mortality in crows
      (Corvus species) as well as the deaths of several exotic birds at a zoological
      park in the same area. Complete genome sequencing of a flavivirus isolated from
      the brain of a dead Chilean flamingo (Phoenicopterus chilensis), together with
      partial sequence analysis of envelope glycoprotein (E-glycoprotein) genes
      amplified from several other species including mosquitoes and two fatal human
      cases, revealed that West Nile (WN) virus circulated in natural transmission
      cycles and was responsible for the human disease. Antigenic mapping with E
      glycoprotein-specific monoclonal antibodies and E-glycoprotein phylogenetic
      analysis confirmed these viruses as WN. This North American WN virus was most
      closely related to a WN virus isolated from a dead goose in Israel in 1998.

PMID- 10600743
TI  - Binding of transcription termination protein nun to nascent RNA and template DNA.
AB  - The amino-terminal arginine-rich motif of coliphage HK022 Nun binds phage lambda
      nascent transcript, whereas the carboxyl-terminal domain interacts with RNA
      polymerase (RNAP) and blocks transcription elongation. RNA binding is inhibited
      by zinc (Zn2+) and stimulated by Escherichia coli NusA. To study these
      interactions, the Nun carboxyl terminus was extended by a cysteine residue
      conjugated to a photochemical cross-linker. The carboxyl terminus contacted NusA
      and made Zn2+-dependent intramolecular contacts. When Nun was added to a paused
      transcription elongation complex, it cross-linked to the DNA template. Nun may
      arrest transcription by anchoring RNAP to DNA.

PMID- 10600744
TI  - Requirement of yeast SGS1 and SRS2 genes for replication and transcription.
AB  - The SGS1 gene of the yeast Saccharomyces cerevisiae encodes a DNA helicase with
      homology to the human Bloom's syndrome gene BLM and the Werner's syndrome gene
      WRN. The SRS2 gene of yeast also encodes a DNA helicase. Simultaneous deletion of
      SGS1 and SRS2 is lethal in yeast. Here, using a conditional mutation of SGS1, it
      is shown that DNA replication and RNA polymerase I transcription are drastically
      inhibited in the srs2Delta sgs1-ts strain at the restrictive temperature. Thus,
      SGS1 and SRS2 function in DNA replication and RNA polymerase I transcription.
      These functions may contribute to the various defects observed in Werner's and
      Bloom's syndromes.

PMID- 10600745
TI  - Posttranscriptional gene silencing in Neurospora by a RecQ DNA helicase.
AB  - The phenomenon of posttranscriptional gene silencing (PTGS), which occurs when a
      transgene is introduced into a cell, is poorly understood. Here, the qde-3 gene,
      which is required for the activation and maintenance of gene silencing in the
      fungus Neurospora crassa, was isolated. Sequence analysis revealed that the qde-3
      gene belongs to the RecQ DNA helicase family. The QDE3 protein may function in
      the DNA-DNA interaction between introduced transgenes or with an endogenous gene
      required for gene-silencing activation. In animals, genes that are homologous to
      RecQ protein, such as the human genes for Bloom's syndrome and Werner's syndrome,
      may also function in PTGS.

PMID- 10600746
TI  - Evolution of shape complementarity and catalytic efficiency from a primordial
      antibody template.
AB  - The crystal structure of an efficient Diels-Alder antibody catalyst at 1.9
      angstrom resolution reveals almost perfect shape complementarity with its
      transition state analog. Comparison with highly related progesterone and Diels
      Alderase antibodies that arose from the same primordial germ line template shows
      the relatively subtle mutational steps that were able to evolve both structural
      complementarity and catalytic efficiency.

PMID- 10600747
TI  - Crystal structure of Thermotoga maritima ribosome recycling factor: a tRNA mimic.
AB  - Ribosome recycling factor (RRF), together with elongation factor G (EF-G),
      catalyzes recycling of ribosomes after one round of protein synthesis. The
      crystal structure of RRF was determined at 2.55 angstrom resolution. The protein
      has an unusual fold where domain I is a long three-helix bundle and domain II is
      a three-layer beta/alpha/beta sandwich. The molecule superimposes almost
      perfectly with a transfer RNA (tRNA) except that the amino acid-binding 3' end is
      missing. The mimicry suggests that RRF interacts with the posttermination
      ribosomal complex in a similar manner to a tRNA, leading to disassembly of the
      complex. The structural arrangement of this mimicry is entirely different from
      that of other cases of less pronounced mimicry of tRNA so far described.

PMID- 10600748
TI  - Microglial activation resulting from CD40-CD40L interaction after beta-amyloid
      stimulation.
AB  - Alzheimer's disease (AD) has a substantial inflammatory component, and activated
      microglia may play a central role in neuronal degeneration. CD40 expression was
      increased on cultured microglia treated with freshly solublized amyloid-beta
      (Abeta, 500 nanomolar) and on microglia from a transgenic murine model of AD (Tg
      APPsw). Increased tumor necrosis factor alpha production and induction of
      neuronal injury occurred when Abeta-stimulated microglia were treated with CD40
      ligand (CD40L). Microglia from Tg APPsw mice deficient for CD40L demonstrated
      reduction in activation, suggesting that the CD40-CD40L interaction is necessary
      for Abeta-induced microglial activation. Finally, abnormal tau phosphorylation
      was reduced in Tg APPsw animals deficient for CD40L, suggesting that the CD40
      CD40L interaction is an early event in AD pathogenesis.

PMID- 10600749
TI  - Cognitive modularity and genetic disorders.
AB  - This study challenges the use of adult neuropsychological models for explaining
      developmental disorders of genetic origin. When uneven cognitive profiles are
      found in childhood or adulthood, it is assumed that such phenotypic outcomes
      characterize infant starting states, and it has been claimed that modules
      subserving these abilities start out either intact or impaired. Findings from two
      experiments with infants with Williams syndrome (a phenotype selected to bolster
      innate modularity claims) indicate a within-syndrome double dissociation: For
      numerosity judgments, they do well in infancy but poorly in adulthood, whereas
      for language, they perform poorly in infancy but well in adulthood. The
      theoretical and clinical implications of these results could lead to a shift in
      focus for studies of genetic disorders.

PMID- 10600750
TI  - Mediation by a CREB family transcription factor of NGF-dependent survival of
      sympathetic neurons.
AB  - Nerve growth factor (NGF) and other neurotrophins support survival of neurons
      through processes that are incompletely understood. The transcription factor CREB
      is a critical mediator of NGF-dependent gene expression, but whether CREB family
      transcription factors regulate expression of genes that contribute to NGF
      dependent survival of sympathetic neurons is unknown. CREB-mediated gene
      expression was both necessary for NGF-dependent survival and sufficient on its
      own to promote survival of sympathetic neurons. Moreover, expression of Bcl-2 was
      activated by NGF and other neurotrophins by a CREB-dependent transcriptional
      mechanism. Overexpression of Bcl-2 reduced the death-promoting effects of CREB
      inhibition. Together, these data support a model in which neurotrophins promote
      survival of neurons, in part through a mechanism involving CREB family
      transcription factor-dependent expression of genes encoding prosurvival factors.

PMID- 10600751
TI  - Use of the cell wall precursor lipid II by a pore-forming peptide antibiotic.
AB  - Resistance to antibiotics is increasing in some groups of clinically important
      pathogens. For instance, high vancomycin resistance has emerged in enterococci.
      Promising alternative antibiotics are the peptide antibiotics, abundant in host
      defense systems, which kill their targets by permeabilizing the plasma membrane.
      These peptides generally do not act via specific receptors and are active in the
      micromolar range. Here it is shown that vancomycin and the antibacterial peptide
      nisin Z use the same target: the membrane-anchored cell wall precursor Lipid II.
      Nisin combines high affinity for Lipid II with its pore-forming ability, thus
      causing the peptide to be highly active (in the nanomolar range).

PMID- 10600752
TI  - Role of protein phosphatases in the regulation of human mast cell and basophil
      function.
AB  - Many extracellular stimuli mediate physiological change in target cells by
      altering the phosphorylation state of proteins. These alterations result from the
      dynamic interplay of protein kinases, which mediate phosphorylations, and protein
      phosphatases, which catalyse dephosphorylations. The antigen-mediated aggregation
      of high-affinity receptors for IgE on mast cells and basophils triggers rapid
      changes in the phosphorylation of many proteins and culminates in the generation
      of inflammatory mediators involved in allergic inflammatory diseases such as
      asthma. Although protein kinases have an established role in this process, less
      is known about the involvement of protein phosphatases. This imbalance has been
      redressed in recent years by the availability of phosphatase inhibitors, such as
      okadaic acid, that facilitate investigations of the role of protein phosphatases
      in intact cells. Here we review a number of studies in which inhibitors of
      protein phosphatases have been used to shed light on the potential importance of
      these enzymes in the regulation of human mast cell and human basophil function.

PMID- 10600753
TI  - HSP27 and signaling to the actin cytoskeleton focus on "HSP27 expression
      regulates CCK-induced changes of the actin cytoskeleton in CHO-CCK-A cells".

PMID- 10600754
TI  - HSP27 expression regulates CCK-induced changes of the actin cytoskeleton in CHO
      CCK-A cells.
AB  - We investigated how heat shock protein 27 (HSP27) and its phosphorylation are
      involved in the action of cholecystokinin (CCK) on the actin cytoskeleton by
      genetic manipulation of Chinese hamster ovary (CHO) cells stably transfected with
      the CCK-A receptor. In these cells, as in rat acini, CCK activated p38 mitogen
      activated protein (MAP) kinase and increased the phosphorylation of HSP27. This
      effect could be blocked with the p38 MAP kinase inhibitor SB-203580. Examination
      by confocal microscopy of cells stained with rhodamine phalloidin showed that CCK
      dose-dependently induced changes of the actin cytoskeleton, including cell shape
      changes, which were coincident with actin cytoskeleton fragmentation and
      formation of actin filament patches in the cells. To further evaluate the role of
      HSP27, CHO-CCK-A cells were transfected with expression vectors for either wild
      type (wt) or mutant (3A, 3G, and 3D) human HSP27. Overexpression of wt-HSP27 and
      3D-HSP27 inhibited the effects on the actin cytoskeleton seen after high-dose CCK
      stimulation. In contrast, overexpression of nonphosphorylatable mutants, 3A- and
      3G-HSP27, or inhibition of phosphorylation of HSP27 by preincubation of wt-HSP27
      transfected cells with SB-203580 did not protect the actin cytoskeleton. These
      results suggest that phosphorylation of HSP27 is required to stabilize the actin
      cytoskeleton and to protect the cells from the effects of high concentrations of
      CCK.

PMID- 10600755
TI  - Time-dependent changes in myosin heavy chain mRNA and protein isoforms in
      unloaded soleus muscle of rat.
AB  - Time-dependent changes in myosin heavy chain (MHC) isoform expression were
      investigated in rat soleus muscle unloaded by hindlimb suspension. Changes at the
      mRNA level were measured by RT-PCR and correlated with changes in the pattern of
      MHC protein isoforms. Protein analyses of whole muscle revealed that MHCI
      decreased after 7 days, when MHCIIa had increased, reaching a transient maximum
      by 15 days. Longer periods led to inductions and progressive increases of
      MHCIId(x) and MHCIIb. mRNA analyses of whole muscle showed that MHCIId(x)
      displayed the steepest increase after 4 days and continued to rise until 28 days,
      the longest time period investigated. MHCIIb mRNA followed a similar time course,
      although at lower levels. MHCIalpha mRNA, present at extremely low levels in
      control soleus, peaked after 4 days, stayed elevated until 15 days, and then
      decayed. Immunohistochemistry of 15-day unloaded muscles revealed that MHCIalpha
      was present in muscle spindles but at low amounts also in extrafusal fibers. The
      slow-to-fast transitions thus seem to proceed in the order MHCIbeta --> MHCIIa -
      > MHCIId(x) --> MHCIIb. Our findings indicate that MHCIalpha is transiently
      upregulated in some fibers as an intermediate step during the transition from
      MHCIbeta to MHCIIa.

PMID- 10600756
TI  - Involvement of JAK2 and MAPK on type II nitric oxide synthase expression in skin
      derived dendritic cells.
AB  - In this report, we demonstrate that a fetal mouse skin-derived dendritic cell
      line produces nitric oxide (NO) in response to the endotoxin [lipopolysaccharide
      (LPS)] and to cytokines [tumor necrosis factor-alpha (TNF-alpha) and granulocyte
      macrophage colony-stimulating factor (GM-CSF)]. Expression of the inducible
      isoform of NO synthase (iNOS) was confirmed by immunofluorescence with an
      antibody against iNOS. The tyrosine kinase inhibitor genistein decreased LPS- and
      GM-CSF-induced nitrite (NO(-2)) production. The effect of LPS and cytokines on
      NO(-2) production was inhibited by the Janus kinase 2 (JAK2) inhibitor tyrphostin
      B42. The p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB-203580 also
      reduced the NO(-2) production evoked by LPS, TNF-alpha, or GM-CSF, but it was not
      as effective as tyrphostin B42. Inhibition of MAPK kinase with PD-098059 also
      slightly reduced the effect of TNF-alpha or GM-CSF on NO(-2) production.
      Immunocytochemistry studies revealed that the transcription factor nuclear factor
      kappaB was translocated from the cytoplasm into the nuclei of fetal skin-derived
      dendritic cells (FSDC) stimulated with LPS, and this translocation was inhibited
      by tyrphostin B42. Our results show that JAK2 plays a major role in the induction
      of iNOS in FSDC.

PMID- 10600757
TI  - Epidermal growth factor regulation in adult rat alveolar type II cells of
      amiloride-sensitive cation channels.
AB  - Using the patch-clamp technique, we studied the effects of epidermal growth
      factor (EGF) on whole cell and single channel currents in adult rat alveolar
      epithelial type II cells in primary culture in the presence or absence of EGF for
      48 h. In symmetrical sodium isethionate solutions, EGF exposure caused a
      significant increase in the type II cell whole cell conductance. Amiloride (10
      microM) produced approximately 20-30% inhibition of the whole cell conductance in
      both the presence and absence of EGF, such that EGF caused the magnitude of the
      amiloride-sensitive component to more than double. Northern analysis showed that
      alpha-, beta- and gamma-subunits of rat epithelial Na(+) channel (rENaC) steady
      state mRNA levels were all significantly decreased by EGF. At the single channel
      level, all active inside-out patches demonstrated only 25-pS channels that were
      amiloride sensitive and relatively nonselective for cations (P(Na(+))/P(K(+))
      approximately 1.0:0.48). Although the biophysical characteristics (conductance,
      open-state probability, and selectivity) of the channels from EGF-treated and
      untreated cells were essentially identical, channel density was increased by EGF;
      the modal channel per patch was increased from 1 to 2. These findings indicate
      that EGF increases expression of nonselective, amiloride-sensitive cation
      channels in adult alveolar epithelial type II cells. The contribution of rENaC to
      the total EGF-dependent cation current under these conditions is quantitatively
      less important than that of the nonselective cation channels in these cells.

PMID- 10600758
TI  - Hypoxia/aglycemia increases endothelial permeability: role of second messengers
      and cytoskeleton.
AB  - The effects of hypoxia/aglycemia on microvascular endothelial permeability were
      evaluated, and the second messenger systems and the cytoskeletal-junctional
      protein alterations in this response were also examined. Monolayers of human
      dermal microvascular endothelial cells on microcarrier beads were exposed to
      either thioglycolic acid (5 mM, an O(2) chelator), glucose-free medium, or both
      stresses together. Permeability measurements were performed over a 90-min time
      course. Although neither hypoxia alone nor aglycemia alone increased endothelial
      permeability significantly, the combination of both increased significantly as
      early as 15 min. Intracellular Ca(2+) measurements with fura 2-AM showed that
      hypoxia/aglycemia treatment increased Ca(2+) influx. To determine the second
      messengers involved in increased permeability, monolayers were incubated for 30
      min with the cytosolic Ca(2+) scavenger 3,4, 5-trimethoxybenzoic acid 8
      (diethylamino)octyl ester (TMB-8, 0.1 mM), a classical protein kinase C (PKC)
      blocker, Go-6976 (10 nM), a cGMP-dependent protein kinase (PKG) antagonist, KT
      5823 (0.5 microM), or the mitogen-activated protein (MAP) kinase inhibitor PD
      98059 (20 microM). Hypoxia/aglycemia-mediated permeability changes were blocked
      by chelating cell Ca(2+), PKC blockade, PKG blockade, and by inhibiting p38 MAP
      kinase-1. Finally, changes in the binding of junctional proteins to the
      cytoskeleton under the same conditions were assessed. The concentrations of
      occludin and pan-reactive cadherin binding to the cytoskeleton were significantly
      decreased by only both stresses together. However, these effects were also
      blocked by pretreatment with TMB-8, Go-6976, KT-5823 (not in occludin), and PD
      98059. These data suggest that hypoxia/aglycemia-mediated endothelial
      permeability may occur through PKC, PKG, MAP kinase, and Ca(2+) related to
      dissociation of cadherin-actin and occludin-actin junctional bonds.

PMID- 10600759
TI  - Leukoregulin upregulation of prostaglandin endoperoxide H synthase-2 expression
      in human orbital fibroblasts.
AB  - Human orbital fibroblasts from patients with severe thyroid-associated
      ophthalmopathy are particularly susceptible to the actions of a variety of
      proinflammatory molecules. In this study, we demonstrate that the inductions of
      prostaglandin endoperoxide H synthase-2 (PGHS-2), interleukin (IL)-1alpha, and IL
      1beta by leukoregulin, a product of activated T lymphocytes, are far more robust
      in orbital fibroblasts than those observed in dermal fibroblasts. These actions
      of leukoregulin are mediated through an intermediate induction of IL-1alpha. In
      contrast, leukoregulin also induces IL-1-receptor antagonist (IL-1ra) expression
      in orbital fibroblasts, but this induction is considerably greater in dermal
      fibroblasts (2.3- vs. 8.5-fold). Interrupting the effects of IL-1alpha, either
      with a neutralizing antibody or with exogenous IL-1ra, can block the induction of
      PGHS-2 by leukoregulin. Leukoregulin increases PGHS-2 gene transcription in
      orbital fibroblasts but exerts the major effect on cyclooxygenase expression by
      enhancing the stability of mature PGHS-2 mRNA. The cytokine triggers nuclear
      translocation of nuclear factor-kappaB (NF-kappaB) p50/p50 homodimers and p50/p65
      heterodimers, and an inhibitor of this transcriptional factor,
      pyrrolidinedithiocarbamate, can attenuate the PGHS-2 induction. Thus differential
      inducibility of the members of the IL-1 family of genes in orbital fibroblasts
      would appear to underlie, at least in part, the differences in PGHS-2 induction
      observed in orbital and dermal fibroblasts. NF-kappaB plays an important role in
      mediating the effects of leukoregulin on PGHS-2 expression.

PMID- 10600760
TI  - Odor suppression of voltage-gated currents contributes to the odor-induced
      response in olfactory neurons.
AB  - Olfactory chemotransduction involves a signaling cascade. In addition to
      triggering transduction, odors suppress ion conductances. By stimulating with
      brief odorant pulses, we observed a current associated with odor-induced
      suppression of voltage-gated conductances and studied its time dependence. We
      characterized this suppression current in isolated Caudiverbera caudiverbera
      olfactory neurons. All four voltage-gated currents are suppressed by odor pulses
      in almost every neuron, and suppression is caused by odors inducing excitation
      and by those inducing inhibition, indicating a nonselective phenomenon, in
      contrast to transduction. Suppression has a 10-fold shorter latency than
      transduction. Suppression was more pronounced when odors were applied to the soma
      than to the cilia, opposite to transduction. Suppression was also present in rat
      olfactory neurons. Furthermore, we could induce it in Drosophila photoreceptor
      cells, demonstrating its independence from the chemotransduction cascade. We show
      that odor concentrations causing suppression are similar to those triggering
      chemotransduction and that both suppression and transduction contribute to the
      odor response in isolated olfactory neurons. Furthermore, suppression affects
      spiking, implying a possible physiological role in olfaction.

PMID- 10600761
TI  - CFTR upregulates the expression of the basolateral Na(+)-K(+)-2Cl(-)
      cotransporter in cultured pancreatic duct cells.
AB  - The purpose of the current experiments was 1) to assess basolateral Na(+)-K(+)
      2Cl(-) cotransporter (NKCC1) expression and 2) to ascertain the role of cystic
      fibrosis transmembrane conductance regulator (CFTR) in the regulation of this
      transporter in a prototypical pancreatic duct epithelial cell line. Previously
      validated human pancreatic duct cell lines (CFPAC-1), which exhibit physiological
      features prototypical of cystic fibrosis, and normal pancreatic duct epithelia
      (stable recombinant CFTR-bearing CFPAC-1 cells, termed CFPAC-WT) were grown to
      confluence before molecular and functional studies. High-stringency Northern blot
      hybridization, utilizing specific cDNA probes, confirmed that NKCC1 was expressed
      in both cell lines and its mRNA levels were twofold higher in CFPAC-WT cells than
      in CFPAC-1 cells (P < 0.01, n = 3). Na(+)-K(+)-2Cl(-) cotransporter activity,
      assayed as the bumetanide-sensitive, Na(+)- and Cl(-)-dependent NH(+)(4) entry
      into the cell (with NH(+)(4) acting as a substitute for K(+)), increased by
      approximately 115% in CFPAC-WT cells compared with CFPAC-1 cells (P < 0.01, n =
      6). Reducing the intracellular Cl(-) by incubating the cells in a Cl(-)-free
      medium increased Na(+)-K(+)-2Cl(-) cotransporter activity by twofold (P < 0.01, n
      = 4) only in CFPAC-WT cells. We concluded that NKCC1 is expressed in pancreatic
      duct cells and mediates the entry of Cl(-). NKCC1 activity is enhanced in the
      presence of an inward Cl(-) gradient. The results further indicate that the
      presence of functional CFTR enhances the expression of NKCC1. We speculate that
      CFTR regulates this process in a Cl(-)-dependent manner.

PMID- 10600762
TI  - Na(+)/H(+) exchangers (NHE1-3) have similar turnover numbers but different
      percentages on the cell surface.
AB  - NHE1, NHE2, and NHE3 are well-characterized cloned members of the mammalian
      Na(+)/H(+) exchanger (NHE) gene family. Given the specialized function and
      regulation of NHE1, NHE2, and NHE3, we compared basal turnover numbers of NHE1,
      NHE2, and NHE3 measured in the same cell system: PS120 fibroblasts lacking
      endogenous NHEs. NHE1, NHE2, and NHE3 were epitope tagged with vesicular
      stomatitis virus glycoprotein (VSVG). The following characteristics were
      determined on the same passage of cells transfected with NHE1V, NHE2V, or NHE3V:
      1) maximal reaction velocity (V(max)) by (22)Na(+) uptake and fluorometery, 2)
      total amount of NHE protein by quantitative Western analysis with internal
      standards of VSVG-tagged maltose-binding protein, and 3) cell surface expression
      by cell surface biotinylation. Cell surface expression (percentage of total NHE)
      was 88.8 +/- 3.5, 64.6 +/- 3.3, 20.0 +/- 2.6, and 14.0 +/- 1.3 for NHE1V, 85- and
      75-kDa NHE2V, and NHE3V, respectively. Despite these divergent cell surface
      expression levels, turnover numbers for NHE1, NHE2, and NHE3 were similar (80.3
      +/- 9.6, 92.1 +/- 8.6, and 99.2 +/- 9.1 s(-1), when V(max) was determined using
      (22)Na uptake at 22 degrees C and 742 +/- 47, 459 +/- 16, and 609 +/- 39 s(-1)
      when V(max) was determined using fluorometry at 37 degrees C). These data
      indicate that, in the same cell system, intrinsic properties that determine
      turnover number are conserved among NHE1, NHE2, and NHE3.

PMID- 10600763
TI  - Calcium transients in single fibers of low-frequency stimulated fast-twitch
      muscle of rat.
AB  - Ca(2+) transients were investigated in single fibers isolated from rat extensor
      digitorum longus muscles exposed to chronic low-frequency stimulation for
      different time periods up to 10 days. Approximately 2.5-fold increases in resting
      Ca(2+) concentration ([Ca(2+)]) were observed 2 h after stimulation onset and
      persisted throughout the stimulation period. The elevated [Ca(2+)] levels were in
      the range characteristic of slow-twitch fibers from soleus muscle. In addition,
      we noticed a transitory elevation of the integral [Ca(2+)] per pulse with a
      maximum ( approximately 5-fold) after 1 day. Steep decreases in rate constant of
      [Ca(2+)] decay could be explained by an immediate impairment of Ca(2+) uptake
      and, with longer stimulation periods, by an additional loss of cytosolic Ca(2+)
      binding capacity resulting from a decay in parvalbumin content. A partial
      recovery of the rate constant of [Ca(2+)] decay in 10-day stimulated muscle could
      be explained by an increasing mitochondrial contribution to Ca(2+) sequestration.

PMID- 10600764
TI  - Heterogeneity of pig intestinal D-glucose transport systems.
AB  - Heterogeneity of intestinal D-glucose transport is demonstrated using pig jejunal
      brush-border membrane vesicles in the presence of 100/0 (out/in) mM gradients
      each of NaCl, NaSCN, and KSCN. Two D-glucose transport systems are kinetically
      distinguished: high-affinity, low-capacity system 1, which is equivalent to the
      symporter SGLT1; and low-affinity, high-capacity system 2, which is not a member
      of the SGLT family but is a D-glucose and D-mannose transporter exhibiting no
      preference for Na(+) over K(+). A nonsaturable D-glucose uptake component has
      also been detected; uptake of this component takes place at rates 10 times the
      rate of components characterizing the classical diffusion marker L-glucose. It is
      also shown that, in this kinetic work, 1) use of D-glucose-contaminated D
      sorbitol as an osmotic replacement cannot cause the spurious appearance of
      nonexistent transport systems and 2) a large range (>/=50 mM) of substrate
      concentrations is required to correctly fit substrate saturation curves to
      distinguish between low-affinity transport systems and physical diffusion.

PMID- 10600765
TI  - Folic acid inhibition of EGFR-mediated proliferation in human colon cancer cell
      lines.
AB  - Although accumulating evidence suggests a chemopreventive role for folic acid in
      colon cancer, the regulation of this process in unknown. We hypothesize that
      supplemental folic acid exerts its chemopreventive role by inhibiting mucosal
      hyperproliferation, an event considered to be central to the initiation of
      carcinogenesis in the gastrointestinal tract. The present investigation examines
      the effect of supplemental folic acid on proliferation of Caco-2 and HCT-116
      colon cancer cell lines. Furthermore, because certain tyrosine kinases,
      particularly epidermal growth factor receptor (EGFR), play a role in regulating
      cell proliferation, we also examined the folic acid-induced changes in tyrosine
      kinase activity and expression of EGFR. In Caco-2 and HCT-116 cells, maintained
      in RPMI 1640 medium containing 1 microg/ml folic acid, we observed that the
      supplemental folic acid inhibited proliferation in a dose-dependent manner.
      Pretreatment of HCT-116 and Caco-2 cell lines with supplemental folic acid (1.25
      microg/ml) completely abrogated transforming growth factor-alpha (TGF-alpha)
      induced proliferation in both cell lines. Tyrosine kinase activity and the
      relative concentration of EGFR were markedly diminished in both cell lines
      following a 24-h exposure to supplemental folic acid. The folic acid-induced
      inhibition of EGFR tyrosine kinase activity in colon cancer cell lines was also
      associated with a concomitant reduction in the relative concentration of the 14
      kDa membrane-bound precursor form of TGF-alpha. In conclusion, our data suggest
      that supplemental folic acid is effective in reducing proliferation in two
      unrelated colon cancer cell lines and that EGFR tyrosine kinase appears to be
      involved in regulating this process.

PMID- 10600766
TI  - Epidermal and hepatocyte growth factors stimulate chemotaxis in an intestinal
      epithelial cell line.
AB  - The migration of intestinal cells is important in the development and maintenance
      of normal epithelium, in a process that may be regulated by growth factors and
      cytokines. Although a number of growth factor receptors are expressed by
      intestinal cells, little progress has been made toward assignment of functional
      roles for these ligand-receptor systems. This study compares several growth
      factors and cytokines for their chemoattraction of the mouse small intestinal
      epithelial cell line. Epidermal and hepatocyte growth factors stimulated a rapid
      30-fold chemotaxis of cells with delayed threefold migration toward transforming
      growth factor-beta1. Despite stimulating proliferation, keratinocyte, fibroblast,
      or insulin-like growth factors did not stimulate directed migration. Chemotaxis
      required tyrosine kinase and phosphatidylinositol phospholipase C activities but
      not protein kinase C or mitogen-activated protein kinase activity. These findings
      suggest that the repertoire of growth factors capable of regulating directed
      intestinal epithelial cell migration is limited and that a divergence exists in
      the signal transduction pathways for directed vs. nondirected migration.

PMID- 10600767
TI  - Actin filament organization is required for proper cAMP-dependent activation of
      CFTR.
AB  - Previous studies have indicated a role of the actin cytoskeleton in the
      regulation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion
      channel. However, the exact molecular nature of this regulation is still largely
      unknown. In this report human epithelial CFTR was expressed in human melanoma
      cells genetically devoid of the filamin homologue actin-cross-linking protein ABP
      280 [ABP(-)]. cAMP stimulation of ABP(-) cells or cells genetically rescued with
      ABP-280 cDNA [ABP(+)] was without effect on whole cell Cl(-) currents. In ABP(-)
      cells expressing CFTR, cAMP was also without effect on Cl(-) conductance. In
      contrast, cAMP induced a 10-fold increase in the diphenylamine-2-carboxylate
      (DPC)-sensitive whole cell Cl(-) currents of ABP(+)/CFTR(+) cells. Further, in
      cells expressing both CFTR and a truncated form of ABP-280 unable to cross-link
      actin filaments, cAMP was also without effect on CFTR activation. Dialysis of ABP
      280 or filamin through the patch pipette, however, resulted in a DPC-inhibitable
      increase in the whole cell currents of ABP(-)/CFTR(+) cells. At the single
      channel level, protein kinase A plus ATP activated single Cl(-) channels only in
      excised patches from ABP(+)/CFTR(+) cells. Furthermore, filamin alone also
      induced Cl(-) channel activity in excised patches of ABP(-)/CFTR(+) cells. The
      present data indicate that an organized actin cytoskeleton is required for cAMP
      dependent activation of CFTR.

PMID- 10600768
TI  - Myosin molecular motor dysfunction in dystrophic mouse diaphragm.
AB  - Cross-bridge properties and myosin heavy chain (MHC) composition were
      investigated in isolated diaphragm from 6-mo-old control (n = 12) and mdx (n =
      12) mice. Compared with control, peak tetanic tension fell by 50% in mdx mice (P
      < 0.001). The total number of cross bridges per square millimeter (x10(9)), the
      elementary force per cross bridge, and the peak mechanical efficiency were lower
      in mdx than in control mice (each P < 0.001). The duration of the cycle and the
      rate constant for cross-bridge detachment were significantly lower in mdx than in
      control mice. In the overall population, there was a linear relationship between
      peak tetanic tension and either total number of cross bridges per square
      millimeter or elementary force per cross bridge (r = 0.996 and r = 0.667,
      respectively, each P < 0.001). The mdx mice presented a higher proportion of type
      IIA MHC (P < 0.001) than control mice and a reduction in type IIX MHC (P < 0.001)
      and slow myosin isoforms (P < 0.01) compared with control mice. We concluded
      that, in mdx mice, impaired diaphragm strength was associated with qualitative
      and quantitative changes in myosin molecular motors. It is proposed that reduced
      force generated per cross bridge contributed to diaphragm weakness in mdx mice.

PMID- 10600769
TI  - Circadian regulation of uroguanylin and guanylin in the rat intestine.
AB  - Uroguanylin (UGN) and guanylin (GN) are the endogenous intestinal ligands for
      guanylyl cyclase C (GC-C). We examined the circadian expression of UGN, GN, and
      GC-C in the jejunum, ileum, and proximal colon of young adult rats by Northern
      blot analyses. These assays revealed that UGN is more abundant in the proximal
      small intestine, whereas GN and GC-C are more abundant in the proximal colon.
      mRNA levels showed significant circadian variation for UGN (3- to 18-fold
      peak/trough difference), GN (2.1- to 2.8-fold peak/trough difference), and GC-C
      (3- to 5-fold peak/trough difference). The maximal abundance occurred in the dark
      period for all three mRNAs, although peak UGN and GN expression occurred later in
      the dark period in the jejunum relative to the ileum and colon. Immunoblot
      analyses using monospecific polyclonal antibodies against UGN and GN prohormones
      confirmed the regional and circadian variation detected by Northern assays. Thus
      the expression of these genes is regulated not only by histological position but
      also by circadian time.

PMID- 10600770
TI  - Characterization of a phosphorylation event resulting in upregulation of the
      salivary Na(+)-K(+)-2Cl(-) cotransporter.
AB  - Previous studies from our laboratory have shown a close correlation between
      increased Na(+)-K(+)-2Cl(-) cotransporter activity and increased cotransporter
      phosphorylation after beta-adrenergic stimulation of rat parotid acinar cells. We
      demonstrate here that these effects are paralleled by an increase in the number
      of high-affinity binding sites for the cotransporter inhibitor bumetanide in
      membranes prepared from stimulated acini. We also show that the sensitivity of
      cotransporter fluxes to inhibition by bumetanide is the same in both resting and
      isoproterenol-stimulated cells, consistent with the hypothesis that beta
      adrenergic stimulation and the accompanying phosphorylation result in the
      activation of previously quiescent transporters rather than in a change in the
      properties of already active proteins. In addition, we demonstrate that the
      increased phosphorylation on the cotransporter resulting from beta-adrenergic
      stimulation is localized to a 30-kDa phosphopeptide obtained by cyanogen bromide
      digestion. Immunoprecipitation and Western blotting experiments demonstrate that
      this peptide is derived from the NH(2)-terminal cytosolic tail of the
      cotransporter, which surprisingly does not contain the sole protein kinase A
      consensus site on the molecule.

PMID- 10600771
TI  - Matrix free Mg(2+) and the regulation of mitochondrial volume.
AB  - Mitochondria must maintain volume homeostasis in order to carry out oxidative
      phosphorylation. It has been postulated that the concentration of free Mg(2+)
      ([Mg(2+)]) serves as the sensor of matrix volume and regulates a K(+)-extruding
      K(+)/H(+) antiport (K. D. Garlid. J. Biol. Chem. 255: 11273-11279, 1980). To test
      this hypothesis, the fluorescent probe furaptra was used to monitor [Mg(2+)] and
      free Ca(2+) concentration ([Ca(2+)]) in the matrix of isolated beef heart
      mitochondria, and K(+)/H(+) antiport activity was measured by passive swelling in
      potassium acetate. Concentrations that result in 50% inhibition of maximum
      activity of 92 microM matrix [Mg(2+)] and 2.2 microM [Ca(2+)] were determined for
      the K(+)/H(+) antiport. Untreated mitochondria average 670 microM matrix
      [Mg(2+)], a value that would permit <1% of maximum K(+)/H(+) antiport activity.
      Hypotonic swelling results in large decreases in matrix [Mg(2+)], but swelling
      due to accumulation of acetate salts does not alter [Mg(2+)]. Swelling in
      phosphate salts decreases matrix [Mg(2+)], but not to levels that permit
      appreciable antiport activity. We conclude that 1) it is unlikely that matrix
      [Mg(2+)] serves as the mitochondrial volume sensor, 2) if K(+)/H(+) antiport
      functions as a volume control transporter, it is probably regulated by factors
      other than [Mg(2+)], and 3) alternative mechanisms for mitochondrial volume
      control should be considered.

PMID- 10600772
TI  - Protein kinase D inhibits plasma membrane Na(+)/H(+) exchanger activity.
AB  - The regulation of plasma membrane Na(+)/H(+) exchanger (NHE) activity by protein
      kinase D (PKD), a novel protein kinase C- and phorbol ester-regulated kinase, was
      investigated. To determine the effect of PKD on NHE activity in vivo,
      intracellular pH (pH(i)) measurements were made in COS-7 cells by
      microepifluorescence using the pH indicator cSNARF-1. Cells were transfected with
      empty vector (control), wild-type PKD, or its kinase-deficient mutant PKD-K618M,
      together with green fluorescent protein (GFP). NHE activity, as reflected by the
      rate of acid efflux (J(H)), was determined in single GFP-positive cells following
      intracellular acidification. Overexpression of wild-type PKD had no significant
      effect on J(H) (3. 48 +/- 0.25 vs. 3.78 +/- 0.24 mM/min in control at pH(i) 7.0).
      In contrast, overexpression of PKD-K618M increased J(H) (5.31 +/- 0.57 mM/min at
      pH(i) 7.0; P < 0.05 vs. control). Transfection with these constructs produced
      similar effects also in A-10 cells, indicating that native PKD may have an
      inhibitory effect on NHE in both cell types, which is relieved by a dominant
      negative action of PKD-K618M. Exposure of COS-7 cells to phorbol ester
      significantly increased J(H) in control cells but failed to do so in cells
      overexpressing either wild-type PKD (due to inhibition by the overexpressed PKD)
      or PKD-K618M (because basal J(H) was already near maximal). A fusion protein
      containing the cytosolic regulatory domain (amino acids 637-815) of NHE1 (the
      ubiquitous NHE isoform) was phosphorylated in vitro by wild-type PKD, but with
      low stoichiometry. These data suggest that PKD inhibits NHE activity, probably
      through an indirect mechanism, and represents a novel pathway in the regulation
      of the exchanger.

PMID- 10600773
TI  - Molecular cloning and functional characterization of KCC3, a new K-Cl
      cotransporter.
AB  - We isolated and characterized a novel K-Cl cotransporter, KCC3, from human
      placenta. The deduced protein contains 1,150 amino acids. KCC3 shares 75-76%
      identity at the amino acid level with human, pig, rat, and rabbit KCC1 and 67%
      identity with rat KCC2. KCC3 is 40 and 33% identical to two Caenorhabditis
      elegans K-Cl cotransporters and approximately 20% identical to other members of
      the cation-chloride cotransporter family (CCC), two Na-K-Cl cotransporters
      (NKCC1, NKCC2), and the Na-Cl cotransporter (NCC). Hydropathy analysis indicates
      a typical KCC topology with 12 transmembrane domains, a large extracellular loop
      between transmembrane domains 5 and 6 (unique to KCCs), and large NH(2) and COOH
      termini. KCC3 is predominantly expressed in kidney, heart, and brain, and is also
      expressed in skeletal muscle, placenta, lung, liver, and pancreas. KCC3 was
      localized to chromosome 15. KCC3 transiently expressed in human embryonic kidney
      (HEK)-293 cells fulfilled three criteria for increased expression of K-Cl
      cotransport: stimulation of cotransport by swelling, treatment with N
      ethylmaleimide, or treatment with staurosporine.

PMID- 10600774
TI  - Asymmetric distribution of muscarinic acetylcholine receptors in Madin-Darby
      canine kidney cells.
AB  - We have characterized the muscarinic ACh receptors (mAChRs) expressed in Madin-
      Darby canine kidney (MDCK) strain II epithelial cells. Binding studies with the
      membrane-impermeable antagonist N-[(3)H]methylscopolamine demonstrated that
      mAChRs are approximately 2.5 times more abundant on the basolateral than on the
      apical surface. Apical, but not basolateral, mAChRs inhibited forskolin
      stimulated adenylyl cyclase activity in response to the agonist carbachol.
      Neither apical nor basolateral mAChRs exhibited detectable carbachol-stimulated
      phospholipase C activity. Carbachol application to the apical or the basolateral
      membrane resulted in a threefold increase in intracellular Ca(2+) concentration,
      which was completely inhibited by pertussis toxin on the apical side and
      partially inhibited on the basolateral side. RT-PCR analysis showed that MDCK
      cells express the M(4) and M(5) receptor mRNAs. These data suggest that M(4)
      receptors reside on the apical and basolateral membranes of polarized MDCK strain
      II cells and that the M(5) receptor may reside in the basolateral membrane of a
      subset of cells.

PMID- 10600775
TI  - Taurine prevents high-glucose-induced human vascular endothelial cell apoptosis.
AB  - Elevated blood glucose in uncontrolled diabetes is causally correlated with
      diabetic microangiopathy. Hyperglycemia-triggered accelerated endothelial cell
      apoptosis is a critical event in the process of diabetes-associated microvascular
      disease. The conditionally semiessential amino acid taurine has been previously
      shown to protect against human endothelial cell apoptosis. Therefore, this study
      was designed to investigate the role of taurine in the prevention of high-glucose
      mediated cell apoptosis in human umbilical vein endothelial cells (HUVEC) and the
      mechanisms involved. Exposure of HUVEC to 30 mM glucose for 48 h (short-term) and
      14 days (long-term) resulted in a significant increase in apoptosis, compared
      with normal glucose (5.5 mM; P < 0.05). High-glucose-induced DNA fragmentation
      preferentially occurred in the S phase cells. Mannitol (as osmotic control) at 30
      mM failed to induce HUVEC apoptosis. Taurine prevented high-glucose-induced HUVEC
      apoptosis, which correlates with taurine attenuation of high-glucose-mediated
      increased intracellular reactive oxygen species (ROS) formation and elevated
      intracellular Ca(2+) concentration ([Ca(2+)](i)) level. Antioxidants, DMSO, N
      acetyl cysteine, and glutathione, only partly attenuated high-glucose-induced
      HUVEC apoptosis. Glucose at 30 mM did not cause HUVEC necrosis. However, both
      glucose and mannitol at 60 mM caused HUVEC necrosis as represented by increased
      lactate dehydrogenase release and cell lysis. Taurine failed to prevent
      hyperosmolarity-induced cell necrosis. These results demonstrate that taurine
      attenuates hyperglycemia-induced HUVEC apoptosis through ROS inhibition and
      [Ca(2+)](i) stabilization and suggest that taurine may exert a beneficial effect
      in preventing diabetes-associated microangiopathy.

PMID- 10600776
TI  - PKC-epsilon regulates basolateral endocytosis in human T84 intestinal epithelia:
      role of F-actin and MARCKS.
AB  - Protein kinase C (PKC) and the actin cytoskeleton are critical effectors of
      membrane trafficking in mammalian cells. In polarized epithelia, the role of
      these factors in endocytic events at either the apical or basolateral membrane is
      poorly defined. In the present study, phorbol 12-myristate 13-acetate (PMA) and
      other activators of PKC selectively enhanced basolateral but not apical fluid
      phase endocytosis in human T84 intestinal epithelia. Stimulation of basolateral
      endocytosis was blocked by the conventional and novel PKC inhibitor Go-6850, but
      not the conventional PKC inhibitor Go-6976, and correlated with translocation of
      the novel PKC isoform PKC-epsilon. PMA treatment induced remodeling of
      basolateral F-actin. The actin disassembler cytochalasin D stimulated basolateral
      endocytosis and enhanced stimulation of endocytosis by PMA, whereas PMA
      stimulated endocytosis was blocked by the F-actin stabilizers phalloidin and
      jasplakinolide. PMA induced membrane-to-cytosol redistribution of the F-actin
      cross-linking protein myristoylated alanine-rich C kinase substrate (MARCKS).
      Cytochalasin D also induced MARCKS translocation and enhanced PMA-stimulated
      translocation of MARCKS. A myristoylated peptide corresponding to the
      phosphorylation site domain of MARCKS inhibited both MARCKS translocation and PMA
      stimulation of endocytosis. MARCKS translocation was inhibited by Go-6850 but not
      Go-6976. The results suggest that a novel PKC isoform, likely PKC-epsilon,
      stimulates basolateral endocytosis in model epithelia by a mechanism that
      involves F-actin and MARCKS.

PMID- 10600777
TI  - Role of microtubules in the regulation of metabolism in isolated cerebral
      microvessels.
AB  - We used (13)C-labeled substrates and nuclear magnetic resonance spectroscopy to
      examine carbohydrate metabolism in vascular smooth muscle of freshly isolated pig
      cerebral microvessels (PCMV). PCMV utilized [2-(13)C]glucose mainly for
      glycolysis, producing [2-(13)C]lactate. Simultaneously, PCMV utilized the
      glycolytic intermediate [1-(13)C]fructose 1,6-bisphosphate (FBP) mainly for
      gluconeogenesis, producing [1-(13)C]glucose with only minor [3-(13)C]lactate
      production. The dissimilarity in metabolism of [2-(13)C]FBP derived from [2
      (13)C]glucose breakdown and metabolism of exogenous [1-(13)C]FBP demonstrates
      that carbohydrate metabolism is compartmented in PCMV. Because glycolytic enzymes
      interact with microtubules, we disrupted microtubules with vinblastine.
      Vinblastine treatment significantly decreased [2-(13)C]lactate peak intensity
      (87.8 +/- 3.7% of control). The microtubule-stabilizing agent taxol also reduced
      [2-(13)C]lactate peak intensity (90.0 +/- 2. 4% of control). Treatment with both
      agents further decreased [2-(13)C]lactate production (73.3 +/- 4.0% of control).
      Neither vinblastine, taxol, or the combined drugs affected [1-(13)C]glucose peak
      intensity (gluconeogenesis) or disrupted the compartmentation of carbohydrate
      metabolism. The similar effects of taxol and vinblastine, drugs that have
      opposite effects on microtubule assembly, suggest that they produce their effects
      on glycolytic rate by competing with glycolytic enzymes for binding, not by
      affecting the overall assembly state of the microtubule network. Glycolysis, but
      not gluconeogenesis, may be regulated in part by glycolytic enzyme-microtubule
      interactions.

PMID- 10600778
TI  - Skeletal muscle reperfusion injury is mediated by neutrophils and the complement
      membrane attack complex.
AB  - The relative inflammatory roles of neutrophils, selectins, and terminal
      complement components are investigated in this study of skeletal muscle
      reperfusion injury. Mice underwent 2 h of hindlimb ischemia followed by 3 h of
      reperfusion. The role of neutrophils was defined by immunodepletion, which
      reduced injury by 38%, as did anti-selectin therapy with recombinant soluble P
      selectin glycoprotein ligand-immunoglobulin (Ig) fusion protein. Injury in C5
      deficient and soluble complement receptor type 1-treated wild-type mice was 48%
      less than that of untreated wild-type animals. Injury was restored in C5
      deficient mice reconstituted with wild-type serum, indicating the effector role
      of C5-9. Neutropenic C5-deficient animals showed additive reduction in injuries
      (71%), which was lower than C5-deficient neutrophil-replete mice, indicating
      neutrophil activity without C5a. Hindlimb histological injury was worse in
      ischemic wild-type and C5-deficient animals reconstituted with wild-type serum.
      In conclusion, the membrane attack complex and neutrophils act additively to
      mediate skeletal muscle reperfusion injury. Neutrophil activity is independent of
      C5a but is dependent on selectin-mediated adhesion.

PMID- 10600779
TI  - Normalization of muscle plasmid uptake by Southern blot: application to SERCA1
      promoter analysis.
AB  - Direct injection of plasmid DNA into muscle allows the study of promoters in a
      physiological environment. Because of the variability of reporter gene activity,
      attempts have been made to normalize activity to muscle plasmid uptake by
      coinjection of a second "control" plasmid whose reporter gene is constitutively
      expressed by a viral promoter. The purpose of this study was to evaluate the use
      of a control plasmid vs. Southern blot to normalize for differences in uptake of
      plasmids containing promoter fragments of the skeletal muscle-specific
      sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA1) gene. Results showed that the
      correlation of luciferase activity from control vs. SERCA1 plasmids is poor and
      that normalization by a virally driven control plasmid increased variability of
      SERCA1 luciferase activity. In several cases, the presence of a control plasmid
      inhibited SERCA1 reporter expression. When Southern blot analysis was used to
      normalize for differences in plasmid uptake there was less variability than with
      coinjection, and correlations between plasmid uptake and SERCA1 luciferase
      activity were better. Moreover, there were no inhibitory effects of a control
      plasmid allowing for optimization of injection conditions of the SERCA1 deletion
      constructs. The use of Southern analysis is suggested to determine whether
      plasmid uptake is differentially affected by physiological stimuli, muscle types,
      or plasmid sizes under study.

PMID- 10600780
TI  - Role of gelsolin in the actin filament regulation of cardiac L-type calcium
      channels.
AB  - The actin cytoskeleton is an important contributor to the modulation of the cell
      function. However, little is known about the regulatory role of this
      supermolecular structure in the membrane events that take place in the heart. In
      this report, the regulation of cardiac myocyte function by actin filament
      organization was investigated in neonatal mouse cardiac myocytes (NMCM) from both
      wild-type mice and mice genetically devoid of the actin filament severing protein
      gelsolin (Gsn-/-). Cardiac L-type calcium channel currents (I(Ca)) were assessed
      using the whole cell voltage-clamp technique. Addition of the actin filament
      stabilizer phalloidin to wild-type NMCM increased I(Ca) by 227% over control
      conditions. The basal I(Ca) of Gsn-/- NMCM was 300% higher than wild-type
      controls. This increase was completely reversed by intracellular perfusion of the
      Gsn-/- NMCM with exogenous gelsolin. Further, cytoskeletal disruption of either
      Gsn-/- or phalloidin-dialyzed wild-type NMCM with cytochalasin D (CD) decreased
      the enhanced I(Ca) by 84% and 87%, respectively. The data indicate that actin
      filament stabilization by either a lack of gelsolin or intracellular dialysis
      with phalloidin increase I(Ca), whereas actin filament disruption with CD or
      dialysis of Gsn-/- NMCM with gelsolin decrease I(Ca). We conclude that cardiac L
      type calcium channel regulation is tightly controlled by actin filament
      organization. Actin filament rearrangement mediated by gelsolin may contribute to
      calcium channel inactivation.

PMID- 10600781
TI  - Role of HERG-like K(+) currents in opossum esophageal circular smooth muscle.
AB  - An inwardly rectifying K(+) conductance closely resembling the human ether-a-go
      go-related gene (HERG) current was identified in single smooth muscle cells of
      opossum esophageal circular muscle. When cells were voltage clamped at 0 mV, in
      isotonic K(+) solution (140 mM), step hyperpolarizations to -120 mV in 10-mV
      increments resulted in large inward currents that activated rapidly and then
      declined slowly (inactivated) during the test pulse in a time- and voltage-
      dependent fashion. The HERG K(+) channel blockers E-4031 (1 microM), cisapride (1
      microM), and La(3+) (100 microM) strongly inhibited these currents as did
      millimolar concentrations of Ba(2+). Immunoflourescence staining with anti-HERG
      antibody in single cells resulted in punctate staining at the sarcolemma. At
      membrane potentials near the resting membrane potential (-50 to -70 mV), this
      K(+) conductance did not inactivate completely. In conventional microelectrode
      recordings, both E-4031 and cisapride depolarized tissue strips by 10 mV and also
      induced phasic contractions. In combination, these results provide direct
      experimental evidence for expression of HERG-like K(+) currents in
      gastrointestinal smooth muscle cells and suggest that HERG plays an important
      role in modulating the resting membrane potential.

PMID- 10600782
TI  - Neuroendocrine modulation of the "menopause": insights into the aging brain.
AB  - The menopause marks the permanent end of fertility in women. It was once thought
      that this dramatic physiological change could be explained simply by the
      exhaustion of the reservoir of ovarian follicles. New data from studies performed
      in women and animal models make us reassess this assumption. An increasing body
      of evidence suggests that there are multiple pacemakers that contribute to the
      transition to irregular cycles, decreasing fertility, and the timing of the
      menopause. We will present evidence that lends credence to the possibility that a
      dampening and desynchronization of the precisely orchestrated neural signals lead
      to miscommunication between the brain and the pituitary-ovarian axis, and that
      this constellation of hypothalamic-pituitary-ovarian events leads to the
      deterioration of regular cyclicity and heralds menopausal transition.

PMID- 10600783
TI  - Production of soluble tumor necrosis factor receptors by human subcutaneous
      adipose tissue in vivo.
AB  - To investigate in vivo adipose tissue production of tumor necrosis factor-alpha
      (TNF-alpha), interleukin-6 (IL-6), and their soluble receptors: TNF receptor type
      I (sTNFR-I), TNF receptor type II (sTNFR-II), and IL-6 receptor (sIL-6R), we
      determined arteriovenous differences in their levels across abdominal
      subcutaneous adipose tissue in obese subjects. Subjects had a median
      (interquartile range) age of 44.5 (27-51.3) yr, body mass index (BMI) of 32.9
      (26. 0-46.6) kg/m(2), and %body fat of 42.5 (28.5-51.2) %. Although there was not
      a significant difference in the arteriovenous concentrations of TNF-alpha (P =
      0.073) or sTNFR-II (P = 0.18), the levels of sTNFR-I (P = 0.002) were higher in
      the vein compared with artery, suggesting adipose tissue production of this
      soluble receptor. There was a significant arteriovenous difference in IL-6 (P <
      0.001) but not in its soluble receptor (P = 0.18). There was no relationship
      between TNF-alpha levels and adiposity indexes (r(s) = 0.12-0.22, P = not
      significant); however, levels of both its soluble receptor isomers correlated
      significantly with BMI and %body fat (sTNFR-I r(s) = 0.42-0.72, P < 0.001; sTNFR
      II r(s) = 0.36-0.65, P < 0.05- <0. 001). IL-6 levels correlated significantly
      with both BMI and %body fat (r(s) = 0.51, P = 0.004, and r(s) = 0.63, P < 0.001),
      but sIL-6R did not. In conclusion, 1) soluble TNFR-I is produced by adipose
      tissue, and concentrations of both soluble isoforms correlate with the degree of
      adiposity, and 2) IL-6, but not its soluble receptor, is produced by adipose
      tissue and relates to adiposity.

PMID- 10600784
TI  - Endothelium-specific activation of NAD(P)H oxidase in aortas of exogenously
      hyperinsulinemic rats.
AB  - To examine the effects of chronic hyperinsulinemia on vascular tissues, we
      examined the production of superoxide anion (O(-2)) in the aortic tissues of
      control and exogenously hyperinsulinemic rats performed by the implantation of an
      insulin pellet for 4 wk. O(-2) production by aortic segments from
      hyperinsulinemic rats was 2. 4-fold (lucigenin chemiluminescence method) and 1.7
      fold (cytochrome c method) of that of control rats without any differences in O(
      2) degrading activities in aortic tissues, respectively (P < 0.025). The
      increment was completely abolished in the presence of either 100 micromol/l
      apocynin (an inhibitor of NADPH oxidase) or 10 micromol/l diphenyleneiodonium (an
      inhibitor of flavin-containing enzyme) and was exclusively endothelium dependent.
      Consistently, NAD(P)H oxidase activities in endothelial homogenate in
      hyperinsulinemic rats were dose dependently stimulated above the values of
      control rats, although these activities in nonendothelial homogenate were not
      significantly stimulated by insulin. Furthermore, an insulin effect was also
      demonstrated 1 h after exposing aortic tissues to insulin. These results indicate
      that O(-2) production specifically increases in endothelium of aortic tissues in
      chronic hyperinsulinemic rats through the activation of NAD(P)H oxidase.

PMID- 10600785
TI  - Mechanisms by which insulin, associated or not with glucose, may inhibit hepatic
      glucose production in the rat.
AB  - We investigated the intrahepatic mechanisms by which insulin, associated or not
      with hyperglycemia, may inhibit hepatic glucose production (HGP) in the rat.
      After a hyperinsulinemic euglycemic clamp in postabsorptive (PA) anesthetized
      rats, the 70% inhibition of HGP could be explained by a dramatic decrease in the
      glucose 6-phosphate (G-6-P) concentration, whereas the glucose-6-phosphatase (G-6
      Pase) and glucokinase (GK) activities were unchanged. Under hyperinsulinemic
      hyperglycemic condition, the GK flux was increased. The G-6-P concentration was
      not or only weakly decreased. The inhibition of HGP involved a significant 25%
      inhibition of the G-6-Pase activity. Under similar conditions in fasted rats, the
      GK flux was very low. The suppression of G-6-Pase and HGP did not occur, despite
      plasma insulin and glucose concentrations similar to those in PA rats. Therefore,
      1) insulin suppresses HGP in euglycemia by solely decreasing the G-6-P
      concentration; 2) when combining both hyperinsulinemia and hyperglycemia, the
      suppression of HGP involves the inhibition of the G-6-Pase activity; and 3) a
      sustained glucose-phosphorylation flux might be a crucial determinant in the
      inhibition of G-6-Pase and of HGP.

PMID- 10600786
TI  - Effects of parathyroid hormone-related protein on human mesangial cells in
      culture.
AB  - Parathyroid hormone (PTH) and PTH-related protein (PTHrP) produce similar
      biological effects through the PTH/PTHrP receptor. Because PTHrP exhibits
      vasodilatory properties, we evaluated the hypothesis that this hormone interacts
      with human mesangial cells (HMC). The PTHrP prevented both the expected reduction
      in the planar cell surface area and the increase in myosin light-chain
      phosphorylation induced by platelet-activating factor (PAF) on HMC, in a dose
      dependent manner. This effect was completely blocked by pertussis toxin and
      dideoxyadenosine, suggesting that a G protein-coupled receptor and cAMP are
      important in the PTHrP transduction mechanism. Moreover, PTHrP increased cAMP
      synthesis and thymidine incorporation in HMC. However, whereas RT-PCR and
      Southern and Northern blot analyses demonstrated the expression of human
      PTH/PTHrP receptor in human kidney cortex, no expression could be demonstrated in
      HMC. These results show that PTH and PTHrP directly interact with mesangial
      cells. These effects might be mediated by a receptor different from the PTH/PTHrP
      receptor.

PMID- 10600787
TI  - Dose-related effects of GLP-1 on insulin secretion, insulin sensitivity, and
      glucose effectiveness in mice.
AB  - We examined the dose-related net effects of glucagon-like peptide 1 (GLP-1) on
      insulin secretion, insulin sensitivity, and glucose disposal as derived from the
      minimal model of glucose disappearance in anesthetized mice. GLP-1 dose
      dependently potentiated insulin secretion after glucose administration, with the
      half-maximal effect at 1 nmol/kg. GLP-1 also dose dependently reduced the area
      under the glucose curve (AUC(glucose)) and increased the glucose elimination rate
      (K(G)) but did not affect the glucose effectiveness (S(G)). Furthermore, the
      insulin sensitivity index (S(I)) was reduced after administration of GLP-1.
      Because insulin secretion was stimulated to a larger degree than S(I) was
      reduced, the peptide increased the global disposition index (GDI = AUC(insulin) x
      S(I)). Matching plasma insulin levels after GLP-1 by exogenous insulin reproduced
      the influences of GLP-1 on AUC(glucose), K(G), S(I), and GDI. Finally, the GLP-1
      receptor antagonist exendin-3-(9-39) inhibited the actions of GLP-1. We conclude
      that GLP-1 increases glucose tolerance in the mouse mainly by potently
      stimulating insulin secretion.

PMID- 10600788
TI  - Parathyroid hormone-parathyroid hormone-related peptide receptor expression and
      function in otosclerosis.
AB  - The aim of this study was to investigate the possibility that an abnormality
      related to parathyroid hormone (PTH) action is involved in the increased bone
      turnover observed in otosclerosis. To do so, expression and function of the PTH
      PTH-related peptide (PTHrP) receptor were studied in the involved tissue (stapes)
      and compared with that in control bone sample obtained from the external auditory
      canal (EAC) in the same patient in 10 cases of otosclerosis and in 1 case of
      osteogenesis imperfecta. PTH-PTHrP receptor expression was studied by RT-PCR of
      RNA prepared from cultured cells in three patients and RNA directly extracted
      from bone samples in four patients. PTH-PTHrP receptor function was assessed by
      measuring the stimulation of cAMP production by 0.8, 8, and 80 nM PTH in bone
      cell cultures in seven cases. Results showed that PTH-PTHrP receptor mRNA
      expression in the otosclerotic stapes was lower than that in EAC samples (P <
      0.05), whereas it was higher in stapes than that in EAC in the case of
      osteogenesis imperfecta. cAMP production after PTH stimulation was lower in bone
      cells cultured from otosclerotic stapes compared with that in cells cultured from
      EAC (range of increase in stimulation: 0.8-4.5 and 1.5-7 in stapes and EAC bone
      cells, respectively, P < 0.05). In contrast, the stimulation of cAMP production
      by forskolin was not significantly different in otosclerotic stapes and EAC bone
      cells (range of increase in stimulation: 20.7-83.1 and 4.9-99.8 in stapes and
      EAC, respectively, P > 0.05). These results show a lower stimulation of cAMP
      production in response to PTH associated with a lower PTH-PTHrP receptor mRNA
      expression in pathological stapes from patients with otosclerosis compared with
      that in control EAC samples. This difference supports the hypothesis that an
      abnormal cellular response to PTH contributes to the abnormal bone turnover in
      otosclerosis.

PMID- 10600789
TI  - High nocturnal body temperatures and disturbed sleep in women with primary
      dysmenorrhea.
AB  - Primary dysmenorrhea is characterized by painful uterine cramps, near and during
      menstruation, that have an impact on personal life and productivity. The effect
      on sleep of this recurring pain has not been established. We compared sleep,
      nocturnal body temperatures, and hormone profiles during the menstrual cycle of
      10 young women who suffered from primary dysmenorrhea, without any menstrual
      associated mood disturbances, and 8 women who had normal menstrual cycles.
      Dysmenorrheic pain significantly decreased subjective sleep quality, sleep
      efficiency, and rapid eye movement (REM) sleep but not slow wave sleep (SWS),
      compared with pain-free phases of the menstrual cycle and compared with the
      controls. Even before menstruation, in the absence of pain, the women with
      dysmenorrhea had different sleep patterns, nocturnal body temperatures, and
      hormone levels compared with the controls. In the mid-follicular, mid-luteal, and
      menstrual phases, the dysmenorrheics had elevated morning estrogen
      concentrations, higher mean in-bed temperatures, and less REM sleep compared with
      the controls, as well as higher luteal phase prolactin levels. Both groups of
      women had less REM sleep when their body temperatures were high during the luteal
      and menstrual phases, implying that REM sleep is sensitive to elevated body
      temperatures. We have shown that dysmenorrhea is not only a disorder of
      menstruation but is manifest throughout the menstrual cycle. Furthermore,
      dysmenorrheic pain disturbs sleep, which may exacerbate the effect of the pain on
      daytime functioning.

PMID- 10600790
TI  - Zonation of acetate labeling across the liver: implications for studies of
      lipogenesis by MIDA.
AB  - Measurement of fractional lipogenesis by mass isotopomer distribution analysis
      (MIDA) of fatty acids or cholesterol labeled from [(13)C]acetate assumes constant
      enrichment of lipogenic acetyl-CoA in all hepatocytes. This would not be the case
      if uptake and release of acetate by the liver resulted in transhepatic gradients
      of acetyl-CoA enrichment. Conscious dogs, prefitted with transhepatic catheters,
      were infused with glucose and [1, 2-(13)C(2)]acetate. Stable concentrations and
      enrichments of acetate were measured in artery (17 microM, 36%), portal vein (61
      microM, 5. 4%), and hepatic vein (17 microM, 1.0%) and were computed for mixed
      blood entering the liver (53 microM, 7.4%). We also measured balances of
      propionate and butyrate across gut and liver. All gut release of propionate and
      butyrate is taken up by the liver. The threefold decrease in acetate
      concentration and the sevenfold decrease in acetate enrichment across the liver
      strongly suggest that the enrichment of lipogenic acetyl-CoA decreases across the
      liver. Thus fractional hepatic lipogenesis measured in vivo by MIDA may be
      underestimated.

PMID- 10600791
TI  - Rates of small intestinal mucosal protein synthesis in human jejunum and ileum.
AB  - We investigated possible differences in the rates of mucosal protein synthesis
      between the proximal and distal regions of the small intestine. We took advantage
      of access to the gut mucosa available in otherwise healthy patients with
      ileostomy in whom the terminal ileum was histologically normal. All subjects
      received primed, continuous intravenous infusions of L-[1-(13)C]leucine after an
      overnight fast. After 4 h of tracer infusion, jejunal biopsies were obtained
      using a Crosby-Kugler capsule introduced orally; ileal biopsies were obtained via
      endoscopy via the ileostomy. Protein synthesis was calculated from protein
      labeling relative to intracellular leucine enrichment obtained by appropriate
      mass spectrometric measurements. Rates of jejunal and ileal mucosal protein
      synthesis were significantly different (P < 0.001) at 2.14 +/- 0.2 and 1.2 +/-
      0.2 %/h (means +/- SD). These are lower than rates in normal healthy duodenum
      (2.53 +/- 0.25 %/h), suggesting a gradation of rates of synthesis along the
      bowel. Together with other data, these results suggest that mucosae of the bowel
      contribute not more than 10% to whole body protein turnover.

PMID- 10600792
TI  - Aspirin inhibits androgen response to chorionic gonadotropin in humans.
AB  - Eicosanoids play an important role in the regulation of the hypothalamic
      pituitary axis; less clear is their role in testicular steroidogenesis. To
      evaluate the involvement of cyclooxygenase metabolites, such as prostaglandins,
      in the regulation of human testicular steroidogenesis, we examined the effects of
      a prostaglandin-blocker, aspirin, on plasma testosterone, pregnenolone,
      progesterone, 17OH-progesterone, androstenedione, dehydroepiandrosterone, and
      17beta-estradiol response to human chorionic gonadotropin (hCG) in normal male
      volunteers in a placebo-controlled, single-blinded study. To test the efficacy of
      aspirin, seminal prostaglandin E(2) levels were also determined. hCG stimulation
      increased peripheral levels of testosterone, 17OH-progesterone, androstenedione,
      dehydroepiandrosterone, and 17beta-estradiol, without affecting circulating
      pregnenolone and progesterone values. Aspirin significantly lowered seminal
      prostaglandin E(2) levels, whereas it did not modify steroid concentrations not
      exposed to exogenous hCG. Moreover, the drug significantly reduced the response
      of testosterone, 17OH-progesterone, androstenedione, and dehydroepiandrosterone
      to hCG, as assessed by the mean integrated area under the curve, whereas it did
      not influence 17beta-estradiol response. In conclusion, aspirin treatment
      inhibits androgen response to chorionic gonadotropin stimulation in normal
      humans. The action of aspirin is probably mediated via an effective arachidonate
      cyclooxygenase block.

PMID- 10600793
TI  - Role of a negative arterial-portal venous glucose gradient in the postexercise
      state.
AB  - Prior exercise stimulates muscle and liver glucose uptake. A negative arterial
      portal venous glucose gradient (a-pv grad) stimulates resting net hepatic glucose
      uptake (NHGU) but reduces muscle glucose uptake. This study investigates the
      effects of a negative a-pv grad during glucose administration after exercise in
      dogs. EXPERIMENTAL PROTOCOL: exercise (-180 to -30 min), transition (-30 to -20
      min), basal period (-20 to 0 min), and experimental period (0 to 100 min). In the
      experimental period, 130 mg/dl arterial hyperglycemia was induced via vena cava
      (Pe, n = 6) or portal vein (Po, n = 6) glucose infusions. Insulin and glucagon
      were replaced at fourfold basal and basal rates. During the experimental period,
      the a-pv grad (mg/dl) was 3 +/- 1 in Pe and -10 +/- 2 in Po. Arterial insulin and
      glucagon were similar in the two groups. In Pe, net hepatic glucose balance (mg x
      kg(-1) x min(-1), negative = uptake) was 4.2 +/- 0.3 (basal period) and -1.2 +/-
      0.3 (glucose infusion); in Po it was 4.1 +/- 0.5 and -3.2 +/- 0.4, respectively
      (P < 0.005 vs. Pe). Total glucose infusion (mg x kg(-1) x min(-1)) was 11 +/- 1
      in Po and 8 +/- 1 in Pe (P < 0.05). Net hindlimb and whole body nonhepatic
      glucose uptakes were similar. CONCLUSIONS: the portal signal independently
      stimulates NHGU after exercise. Conversely, prior exercise eliminates the
      inhibitory effect of the portal signal on glucose uptake by nonhepatic tissues.
      The portal signal therefore increases whole body glucose disposal after exercise
      by an amount equal to the increase in NHGU.

PMID- 10600794
TI  - Endothelin-1 stimulates heat shock protein 27 induction in osteoblasts:
      involvement of p38 MAP kinase.
AB  - We previously reported that endothelin-1 (ET-1) activates p42/p44 mitogen
      activated protein (MAP) kinase in osteoblast-like MC3T3-E1 cells and consequently
      induces synthesis of interleukin-6. In the present study, we investigated the
      effect of ET-1 on the induction of heat shock protein 27 (HSP 27) in MC3T3-E1
      cells. ET-1 time and dose dependently stimulated HSP 27 accumulation. ET-1
      induced an increase in the levels of mRNA for HSP 27. Both staurosporine and
      calphostin C, inhibitors of protein kinase C (PKC), suppressed the ET-1-induced
      HSP 27 accumulation. 12-O-tetradecanoylphorbol 13-acetate (TPA), a PKC activator,
      induced the HSP 27 accumulation and the expression of mRNA for HSP 27. The ET-1
      stimulated HSP 27 accumulation was reduced in PKC-downregulated MC3T3-E1 cells.
      The HSP 27 accumulation by ET-1 was not suppressed by PD-98059, an inhibitor of
      the upstream kinase that activates p42/p44 MAP kinase. ET-1 or TPA induced the
      phosphorylation of p38 MAP kinase. SB-203580, an inhibitor of p38 MAP kinase,
      reduced the ET-1-stimulated HSP 27 accumulation. Calphostin C and U-73122, a
      phospholipase C inhibitor, suppressed the ET-1-induced phosphorylation of p38 MAP
      kinase. U-73122 and propranolol, a phosphatidic acid phosphohydrolase inhibitor,
      reduced the ET-1-stimulated HSP 27 accumulation. SB-203580 suppressed the ET-1
      stimulated increase in the mRNA levels for HSP 27. These results strongly suggest
      that ET-1 stimulates HSP 27 induction in osteoblasts and that p38 MAP kinase
      activation is involved in the HSP 27 induction.

PMID- 10600795
TI  - Effect of short-term exercise training on insulin-stimulated PI 3-kinase activity
      in human skeletal muscle.
AB  - The purpose of this study was to determine if the improvement in insulin
      sensitivity with exercise training is associated with enhanced
      phosphatidylinositol 3-kinase (PI 3-kinase) activity. Nine sedentary men were
      studied before and after 7 days of exercise training (1 h/day, approximately 75%
      maximal oxygen consumption). Insulin sensitivity was determined with a euglycemic
      hyperinsulinemic glucose clamp in the sedentary state and 15-17 h after the final
      exercise bout. PI 3-kinase activity was determined from samples (vastus
      lateralis) obtained in the fasted condition and after 60 min of submaximal
      insulin stimulation during the clamp. After exercise, glucose infusion rate
      increased (P < 0. 05) significantly (means +/- SE, 7.8 +/- 0.5 vs. 9.8 +/- 0.8
      mg. kg(-1). min(-1)), indicating improved insulin sensitivity. Insulin-stimulated
      (insulin stimulated/fasting) phosphotyrosine immunoprecipitable PI 3-kinase
      activity also increased significantly (P < 0.05) with exercise (3.1 +/- 0.8-fold)
      compared with the sedentary condition (1.3 +/- 0.1-fold). There was no change in
      fasting PI 3-kinase activity. These data suggest that an enhancement of insulin
      signal transduction in skeletal muscle may contribute to the improvement in
      insulin action with exercise.

PMID- 10600796
TI  - A dietary intervention (high carbohydrate) during the neonatal period causes
      islet dysfunction in rats.
AB  - Artificial rearing of 4-day-old rat pups on a high-carbohydrate (HC) milk formula
      results in the immediate onset of hyperinsulinemia. To evaluate these early
      changes, studies on pancreatic function were carried out on 12-day-old HC rats
      and compared with age-matched mother-fed (MF) pups. The plasma insulin and
      glucagon contents were increased sixfold and twofold, respectively, in HC rats
      compared with MF rats. There was a distinct leftward shift in the glucose
      stimulated insulin secretory pattern for HC islets. HC islets secreted insulin in
      the absence of any added glucose and in the presence of Ca(2+) channel
      inhibitors. The activities of glucokinase, hexokinase, glyceraldehyde-3-phosphate
      dehydrogenase, and pyruvate dehydrogenase complex were significantly increased in
      HC islets compared with MF islets. The protein contents of GLUT-2 and hexokinase
      were significantly increased in HC islets. These findings indicate that a
      nutritional intervention in the form of a HC formula only during the suckling
      period has a profound influence on pancreatic function, causing the onset of
      hyperinsulinemia.

PMID- 10600797
TI  - Muscle lipid accumulation and protein kinase C activation in the insulin
      resistant chronically glucose-infused rat.
AB  - Chronic glucose infusion results in hyperinsulinemia and causes lipid
      accumulation and insulin resistance in rat muscle. To examine possible mechanisms
      for the insulin resistance, alterations in malonyl-CoA and long-chain acyl-CoA
      (LCA-CoA) concentration and the distribution of protein kinase C (PKC) isozymes,
      putative links between muscle lipids and insulin resistance, were determined.
      Cannulated rats were infused with glucose (40 mg. kg(-1). min(-1)) for 1 or 4
      days. This increased red quadriceps muscle LCA-CoA content (sum of 6 species) by
      1.3-fold at 1 day and 1.4-fold at 4 days vs. saline-infused controls (both P <
      0.001 vs. control). The concentration of malonyl-CoA was also increased (1.7-fold
      at 1 day, P < 0.01, and 2.2-fold at 4 days, P < 0.001 vs. control), suggesting an
      even greater increase in cytosolic LCA-CoA. The ratio of membrane to cytosolic
      PKC-epsilon was increased twofold in the red gastrocnemius after both 1 and 4
      days, suggesting chronic activation. No changes were observed for PKC-alpha, 
      delta, and -theta. We conclude that LCA-CoAs accumulate in muscle during chronic
      glucose infusion, consistent with a malonyl-CoA-induced inhibition of fatty acid
      oxidation (reverse glucose-fatty acid cycle). Accumulation of LCA-CoAs could play
      a role in the generation of muscle insulin resistance by glucose oversupply,
      either directly or via chronic activation of PKC-epsilon.

PMID- 10600798
TI  - Amino acid-induced stimulation of translation initiation in rat skeletal muscle.
AB  - Amino acids stimulate protein synthesis in skeletal muscle by accelerating
      translation initiation. In the two studies described herein, we examined
      mechanisms by which amino acids regulate translation initiation in perfused
      skeletal muscle hindlimb preparation of rats. In the first study, the effects of
      supraphysiological amino acid concentrations on eukaryotic initiation factors
      (eIF) 2B and 4E were compared with physiological concentrations of amino acids.
      Amino acid supplementation stimulated protein synthesis twofold. No changes were
      observed in eIF2B activity, in the amount of eIF4E associated with the eIF4E
      binding protein (4E-BP1), or in the phosphorylation of 4E-BP1. The abundance of
      eIF4E bound to eIF4G and the extent of phosphorylation of eIF4E were increased by
      800 and 20%, respectively. In the second study, we examined the effect of
      removing leucine on translation initiation when all other amino acids were
      maintained at supraphysiological concentrations. Removal of leucine from the
      perfusate decreased the rate of protein synthesis by 40%. The inhibition of
      protein synthesis was associated with a 40% decrease in eIF2B activity and an 80%
      fall in the abundance of eIF4E. eIF4G complex. The fall in eIF4G binding to eIF4E
      was associated with increased 4E-BP1 bound to eIF4E and a reduced phosphorylation
      of 4E-BP1. In contrast, the extent of phosphorylation of eIF4E was unaffected. We
      conclude that formation of the active eIF4E. eIF4G complex controls protein
      synthesis in skeletal muscle when the amino acid concentration is above the
      physiological range, whereas removal of leucine reduces protein synthesis through
      changes in both eIF2B and eIF4E.

PMID- 10600799
TI  - Cyclosporin-induced dyslipoproteinemia is associated with selective activation of
      SREBP-2.
AB  - The use of cyclosporin A has contributed greatly to the success of organ
      transplantation. However, cyclosporin-associated side effects of hypertension,
      nephrotoxicity, and dyslipoproteinemia have tempered these benefits. Cyclosporin
      induced dyslipoproteinemia may be an important risk factor for the accelerated
      atherosclerosis observed posttransplantation. Using a mouse model, we treated
      Swiss-Webster mice for 6 days with a daily dose of 20 microg/g body wt of
      cyclosporin and observed significant elevations of plasma cholesterol,
      triglyceride, and apolipoprotein B (apoB) levels relative to vehicle-alone
      treated control animals. Measurement of the rate of secretion of very low-density
      lipoprotein (VLDL) by the liver in vivo showed that cyclosporin treatment led to
      a significant increase in the rate of hepatic VLDL triglyceride secretion. Total
      apoB secretion was unaffected. Northern analysis showed that cyclosporin A
      treatment increased the abundance of hepatic mRNA levels for a number of key
      genes involved in cholesterol biosynthesis relative to vehicle-alone treated
      animals. Two key transcriptional factors, sterol regulatory element-binding
      protein (SREBP)-1 and SREBP-2, also showed differential expression; SREBP-2
      expression was increased at the mRNA level, and there was an increase in the
      active nuclear form, whereas the mRNA and the nuclear form of SREBP-1 were
      reduced. These results show that the molecular mechanisms by which cyclosporin
      causes dyslipoproteinemia may, in part, be mediated by selective activation of
      SREBP-2, leading to enhanced expression of lipid metabolism genes and hepatic
      secretion of VLDL triglyceride.

PMID- 10600800
TI  - Effect of high-altitude acclimation on NEFA turnover and lipid utilization during
      exercise in rats.
AB  - Relative exercise intensity (or %maximum O(2) consumption, VO(2 max)) controls
      fuel selection at sea level (SL) and after high-altitude acclimation (HA) in
      rats. In this context we used indirect calorimetry, [1-(14)C]palmitate infusions,
      and muscle triacylglycerol (TAG) measurements to determine 1) total lipid
      oxidation, 2) the relationship between circulatory nonesterified fatty acid
      (NEFA) flux and concentration, and 3) muscle TAG depletion after exercise in HA
      acclimated rats. Aerobic capacity is decreased in trained rats after 10 wk of
      acclimation. Both SL and HA showed the same relative use of lipids at 60% [62 +/-
      5% (HA) and 61 +/- 3% (SL) of O(2) consumption (VO(2))] and 80% [46 +/- 6% (HA)
      and 47 +/- 5% (SL) of VO(2)] of their respective VO(2 max). At 60% VO(2 max),
      plasma [NEFA] were higher in HA, but rate of appearance was essentially the same
      in both groups (at 30 min, 38 +/- 9 vs. 49 +/- 6 micromol. kg(-1). min(-1) in HA
      and SL, respectively). At this intensity SL showed no significant decrease in
      muscle TAG, but in HA it decreased by 64% in soleus and by 90% in red
      gastrocnemius. We conclude that 1) the relative contributions of total lipid are
      the same in SL and HA, contrary to differences in [NEFA], because the
      relationship between flux rate and [NEFA] is modified after acclimation, and 2)
      muscle TAG may play a more important role at HA.

PMID- 10600801
TI  - Contraction-stimulated muscle glucose transport and GLUT-4 surface content are
      dependent on glycogen content.
AB  - The influence of muscle glycogen content on basal and contraction-induced glucose
      transport and cell surface GLUT-4 content was studied in rat skeletal muscle.
      Wistar rats were preconditioned by a combination of swimming exercise and diet,
      resulting in 40% lower (LG) or threefold higher (HG) muscle glycogen content
      compared with nonexercised controls (NG). At rest and during contractions, 2
      deoxy-D-glucose uptake in perfused fast-twitch muscle, but not slow-twitch
      muscle, was significantly lower in HG compared with LG. Cell surface GLUT-4
      content in the fast-twitch plantaris was 994 +/- 180, 1,173 +/- 311, and 2,155 +/
      243 dpm/g in the basal condition and increased (P < 0.05) to 2,285 +/- 239,
      3,230 +/- 464, and 4,847 +/- 654 dpm/g during contractions with HG, NG, and LG,
      respectively, the increase being significantly smaller in HG compared with LG.
      The contraction-induced increments in glucose transport and in cell surface GLUT
      4 content were negatively correlated with the initial glycogen content (P <0.01).
      In conclusion, glucose transport and cell surface GLUT-4 content in resting and
      contracting fast-twitch muscle are dependent on the muscle glycogen content.

PMID- 10600802
TI  - Use of a single (13)C NMR resonance of glutamate for measuring oxygen consumption
      in tissue.
AB  - A kinetic model of the citric acid cycle for calculating oxygen consumption from
      (13)C nuclear magnetic resonance (NMR) multiplet data has been developed.
      Measured oxygen consumption (MVO(2)) was compared with MVO(2) predicted by the
      model with (13)C NMR data obtained from rat hearts perfused with glucose and
      either [2-(13)C]acetate or [3-(13)C]pyruvate. The accuracy of MVO(2) measured
      from three subsets of NMR data was compared: glutamate C-4 and C-3 resonance
      areas; the doublet C4D34 (expressed as a fraction of C-4 area); and C-4 and C-3
      areas plus several multiplets of C-2, C-3, and C-4. MVO(2) determined by set 2
      (C4D34 only) gave the same degree of accuracy as set 3 (complete data); both were
      superior to set 1 (C-4 and C-3 areas). Analysis of the latter suffers from the
      correlation between citric acid cycle flux and exchange between alpha
      ketoglutarate and glutamate, resulting in greater error in estimating MVO(2).
      Analysis of C4D34 is less influenced by correlation between parameters, and this
      single measurement provides the best opportunity for a noninvasive measurement of
      oxygen consumption.

PMID- 10600803
TI  - Pancreatic innervation is not essential for exercise-induced changes in glucagon
      and insulin or glucose kinetics.
AB  - The purpose of this study was to determine the role of pancreatic innervation in
      mediating exercise-induced changes in pancreatic hormone secretion and glucose
      kinetics. Dogs underwent surgery >16 days before an experiment, at which time
      flow probes were implanted on the portal vein and the hepatic artery, and
      Silastic catheters were inserted in the carotid artery, portal vein, and hepatic
      vein for sampling. In one group of dogs (DP) all nerves and plexuses to the
      pancreas were sectioned during surgery. A second group of dogs underwent sham
      denervation (SHAM). Pancreatic tissue norepinephrine was reduced by >98% in DP
      dogs. Each study consisted of basal (-30 to 0 min) and moderate exercise (0 to
      150 min, 100 m/min, 12% grade) periods. Isotope ([3-(3)H]glucose) dilution and
      arteriovenous differences were used to assess hepatic function. Arterial and
      portal vein glucagon and insulin concentrations and the rate of net extrahepatic
      splanchnic glucagon release (NESGR) were similar in DP and SHAM during the basal
      period. Arterial and portal vein glucagon and NESGR increased similarly in DP and
      SHAM during exercise. Arterial and portal vein insulin were similar during
      exercise. Arterial glucose, tracer-determined endogenous glucose production, and
      net hepatic glucose output were similar in DP and SHAM during the basal and
      exercise periods. These results demonstrate that pancreatic nerves are not
      essential to pancreatic hormone secretion or glucose homeostasis during rest or
      moderate exercise.

PMID- 10600804
TI  - Skeletal muscle fatty acid metabolism in association with insulin resistance,
      obesity, and weight loss.
AB  - The current study was undertaken to investigate fatty acid metabolism by skeletal
      muscle to examine potential mechanisms that could lead to increased muscle
      triglyceride in obesity. Sixteen lean and 40 obese research volunteers had leg
      balance measurement of glucose and free fatty acid (FFA) uptake (fractional
      extraction of [9,10 (3)H]oleate) and indirect calorimetry across the leg to
      determine substrate oxidation during fasting and insulin-stimulated conditions.
      Muscle obtained by percutaneous biopsy had lower carnitine palmitoyl transferase
      (CPT) activity and oxidative enzyme activity in obesity (P < 0.05). During
      fasting conditions, obese subjects had an elevated leg respiratory quotient (RQ,
      0.83 +/- 0.02 vs. 0.90 +/- 0.01; P < 0.01) and reduced fat oxidation but similar
      FFA uptake across the leg. During insulin infusions, fat oxidation by leg tissues
      was suppressed in lean but not obese subjects; rates of FFA uptake were similar.
      Fasting values for leg RQ correlated with insulin sensitivity (r = -0.57, P <
      0.001). Thirty-two of the obese subjects were restudied after weight loss (WL, 
      14.0 +/- 0.9 kg); insulin sensitivity and insulin suppression of fat oxidation
      improved (P < 0.01), but fasting leg RQ (0.90 +/- 0.02 vs. 0.90 +/- 0.02, pre-WL
      vs. post-WL) and muscle CPT activity did not change. The findings suggest that
      triglyceride accumulation in skeletal muscle in obesity derives from reduced
      capacity for fat oxidation and that inflexibility in regulating fat oxidation,
      more than fatty acid uptake, is related to insulin resistance.

PMID- 10600805
TI  - Insulin resistance and glucose transporter expression during the euglycemic
      hyperinsulinemic clamp in the lamb.
AB  - Three- to six-day-old lambs infused with 100 mU x kg(-1) x min(-1) insulin
      required greater amounts of glucose to maintain euglycemia during a euglycemic
      hyperinsulinemic clamp compared with 31- to 35-day-old insulin-infused lambs
      (15.87 +/- 3.47 vs. 4.30 +/- 1.11 mg x kg(-1) x min(-1), P < 0.05, respectively).
      Endogenous glucose production persisted in both groups; however, the percent
      decrease compared with age-matched lambs receiving no insulin was greater in the
      younger group compared with the older group (53%, P < 0.001, vs. 34%, P < 0.01).
      The younger animals showed greater glucose utilization compared with the older
      animals (215 vs. 96%, respectively, P < 0.01). No effect of insulin was noted on
      GLUT-4 protein expression in either group. GLUT-2 expression was increased in
      older vs. younger lambs. Older insulin-infused lambs showed lower GLUT-2
      expression than older 0 insulin-infused lambs [0.94 +/- 0.07 vs. 1.64 +/- 0.10
      (OD) units, P < 0.005]. Increased sensitivity to insulin in the younger animals
      was not related to acute changes in GLUT-4 expression. Increased GLUT-2
      expression with age, as well as decreased expression with hyperinsulinemia, is
      consistent with the development of an insulin-resistant state in the adult.

PMID- 10600806
TI  - Simultaneous indirect activity measurements of GH and PRL genes in the same,
      living mammosomatotrope.
AB  - Dynamic intracellular processes in endocrine cells are usually controlled by the
      coordinated modulation of two or more functionally related genes. Attempts to
      gain a more complete understanding of these processes would be facilitated
      greatly by a method enabling activity measurements of two genes at the same time.
      Here we describe how we developed such a system and used it to determine
      indirectly whether individual, living pituitary cells could concurrently express
      both the growth hormone (GH) and prolactin (PRL) genes. Our results demonstrate
      that coexpression of these genes is indeed possible. Moreover, our findings
      provide a general paradigm for future "real-time" analysis of other interrelated
      genes involved in the regulation of endocrine processes.

PMID- 10600807
TI  - Lessons From Genetically Engineered Animal Models VI. Liver repopulation systems
      and study of pathophysiological mechanisms in animals.
AB  - The ability to localize transplanted hepatocytes in the liver offers exciting new
      opportunities. Transplanted hepatocytes enter liver plates, form hybrid plasma
      membrane structures with adjacent hepatocytes, express liver genes correctly, and
      survive indefinitely. The transplanted cell mass is regulated, such that cell
      proliferation is limited in the normal adult liver, whereas the liver is
      repopulated extensively when proliferation rates in transplanted and host
      hepatocytes become dissociated or host hepatocytes are ablated selectively.
      Transplanted hepatocytes are susceptible to hepatitis viruses. These aspects of
      transplanted hepatocyte biology indicate that liver repopulation systems can help
      address questions concerning pathophysiological mechanisms.

PMID- 10600808
TI  - Nutrient Tasting and Signaling Mechanisms in the Gut III. Endocrine cell
      recognition of luminal nutrients.
AB  - The profile of hormone secretion from the gastrointestinal tract on food
      ingestion depends to a great extent on the composition of the meal. High levels
      of protein result in a quantitatively and qualitatively different response
      compared with a meal rich in fats. The outstanding question is whether this
      differential response is driven by the ability of gastroenteric endocrine cells
      to directly sense the contents of the lumen via apical microvilli. Alternative
      effectors would include activation of the intrinsic and extrinsic innervation or
      other epithelial cell populations. The data available indicate that the role of
      the gastrointestinal innervation is relatively limited and is probably a major
      factor only in the postprandial responses of hormones released from endocrine
      cells in the distal small intestine. However, whether nutrients directly
      stimulate gastroenteric endocrine cells or another epithelial cell type has yet
      to be established.

PMID- 10600809
TI  - The cytoskeleton of digestive epithelia in health and disease.
AB  - The mammalian cell cytoskeleton consists of a diverse group of fibrillar elements
      that play a pivotal role in mediating a number of digestive and nondigestive cell
      functions, including secretion, absorption, motility, mechanical integrity, and
      mitosis. The cytoskeleton of higher-eukaryotic cells consists of three highly
      abundant major protein families: microfilaments (MF), microtubules (MT), and
      intermediate filaments (IF), as well as a growing number of associated proteins.
      Within digestive epithelia, the prototype members of these three protein families
      are actins, tubulins, and keratins, respectively. This review highlights the
      important structural, regulatory, functional, and unique features of the three
      major cytoskeletal protein groups in digestive epithelia. The emerging exciting
      biological aspects of these protein groups are their involvement in cell
      signaling via direct or indirect interaction with a growing list of associated
      proteins (MF, MT, IF), the identification of several disease-causing mutations
      (IF, MF), the functional role that they play in protection from environmental
      stresses (IF), and their functional integration via several linker proteins that
      bridge two or potentially all three of these groups together. The use of agents
      that target specific cytoskeletal elements as therapeutic modalities for
      digestive diseases offers potential unique areas of intervention that remain to
      be fully explored.

PMID- 10600810
TI  - Copper treatment alters the permeability of tight junctions in cultured human
      intestinal Caco-2 cells.
AB  - The effects of copper on tight-junction permeability were investigated in human
      intestinal Caco-2 cells, monitoring transepithelial electrical resistance and
      transepithelial passage of mannitol. Apical treatment of Caco-2 cells with 10-100
      microM CuCl(2) (up to 3 h) produced a time- and concentration-dependent increase
      in tight-junction permeability, reversible after 24 h in complete medium in the
      absence of added copper. These effects were not observed in cells treated with
      copper complexed to L-histidine [Cu(His)(2)]. The copper-induced increase in
      tight-junction permeability was affected by the pH of the apical medium, as was
      the apical uptake of (64)CuCl(2), both exhibiting a maximum at pH 6.0. Treatment
      with CuCl(2) produced a concentration-dependent reduction in the staining of F
      actin but not of the junctional proteins zonula occludens-1, occludin, and E
      cadherin and produced ultrastructural alterations to microvilli and tight
      junctions that were not observed after treatment with up to 200 microM Cu(His)(2)
      for 3 h. Overall, these data point to an intracellular effect of copper on tight
      junctions, mediated by perturbations of the F actin cytoskeleton.

PMID- 10600811
TI  - Differentiated intestinal epithelial cells exhibit increased migration through
      polyamines and myosin II.
AB  - Early mucosal restitution is a rapid process by which differentiated intestinal
      epithelial cells migrate to reseal superficial wounds. However, most of the in
      vitro studies for restitution employ undifferentiated intestinal crypt cells as a
      model. The transcription factor, Cdx2, plays an important role in the regulation
      of intestinal epithelial differentiation. Forced expression of the Cdx2 gene in
      undifferentiated intestinal crypt cells induces the development of a
      differentiated phenotype. The current study was designed to determine changes in
      differentiated intestinal epithelial cell migration after wounding in the stable
      Cdx2-transfected IEC-6 cells and then to examine involvement of polyamines and
      nonmuscle myosin II in the process of cell motility. Cdx2-transfected IEC-6 cells
      were associated with a highly differentiated phenotype and exhibited increased
      cell migration after wounding. Migration of Cdx2-transfected IEC-6 cells were
      approximately four times that of nontransfected IEC-6 cells. Migration after
      wounding was associated with significant increases in polyamine synthesis.
      Depletion of cellular polyamines by 5 mM alpha-difluoromethylornithine (DFMO), a
      specific inhibitor of polyamine biosynthesis, inhibited cell migration without
      affecting the differentiated phenotype. DFMO also decreased levels of nonmuscle
      myosin II mRNA and protein and resulted in reorganization of myosin II, along
      with a marked reduction in stress fibers. Exogenous spermidine given together
      with DFMO not only returned nonmuscle myosin II levels and cellular distribution
      toward normal but also restored cell migration to control levels. These results
      indicate that 1) Cdx2-transfected IEC-6 cells exhibit increased cell migration
      after wounding and 2) cellular polyamines are absolutely required for stimulation
      of cell migration in association with their ability to modulate the structural
      organization of nonmuscle myosin II.

PMID- 10600812
TI  - Influence of H. pylori infection on meal-stimulated gastric acid secretion and
      gastroesophageal acid reflux.
AB  - Gastric acid secretion, gastrin release, gastric emptying, and gastroesophageal
      acid reflux were measured in asymptomatic individuals before and after
      elimination of Helicobacter pylori gastritis. After basal gastric acid secretion
      and serum gastrin concentrations were measured, meal-stimulated gastric acid
      secretion and gastrin release were assessed during in vivo intragastric titration
      to pH 3. Experiments were repeated 4 wk after treatment with lansoprazole,
      amoxicillin, and clarithromycin. Esophageal pH was also monitored for 24 h before
      and after therapy. Basal gastric acidity increased approximately 20 mmol/l in
      subjects whose infection was eradicated (P < 0.05) but not in those with
      persistent infection. Basal and meal-stimulated gastric acid secretion did not
      change after H. pylori eradication, despite a 41% reduction in meal-stimulated
      gastrin release (P < 0.05). Gastroesophageal acid reflux increased two- to
      threefold after successful treatment (P < 0. 05) but did not change in subjects
      with persistent infection. Thus elimination of H. pylori gastritis increases
      gastric acidity, probably by reducing nonparietal alkaline secretion, and this
      may facilitate gastroesophageal acid reflux.

PMID- 10600813
TI  - Role of the PI3K/PKB signaling pathway in cAMP-mediated translocation of rat
      liver Ntcp.
AB  - cAMP stimulates Na(+)-taurocholate (TC) cotransport by translocating the Na(+)-TC
      cotransporting peptide (Ntcp) to the plasma membrane. The present study was
      undertaken to determine whether the phosphatidylinositol-3-kinase (PI3K)
      signaling pathway is involved in cAMP-mediated translocation of Ntcp. The ability
      of cAMP to stimulate TC uptake declined significantly when hepatocytes were
      pretreated with PI3K inhibitors wortmannin or LY-294002. Wortmannin inhibited
      cAMP-mediated translocation of Ntcp to the plasma membrane. cAMP stimulated
      protein kinase B (PKB) activity by twofold within 5 min, an effect inhibited by
      wortmannin. Neither basal mitogen-activated protein kinase (MAPK) activity nor
      cAMP-mediated inhibition of MAPK activity was affected by wortmannin. cAMP also
      stimulated p70(S6K) activity. However, rapamycin, an inhibitor of p70(S6K),
      failed to inhibit cAMP-mediated stimulation of TC uptake, indicating that the
      effect of cAMP is not mediated via p70(S6K). Cytochalasin D, an inhibitor of
      actin filament formation, inhibited the ability of cAMP to stimulate TC uptake
      and Ntcp translocation. Together, these results suggest that the stimulation of
      TC uptake and Ntcp translocation by cAMP may be mediated via the PI3K/PKB
      signaling pathway and requires intact actin filaments.

PMID- 10600814
TI  - Nerve-mediated motility of ileal segments isolated from NK(1) receptor knockout
      mice.
AB  - Tachykinins such as substance P (SP) and neurokinin A (NKA) acting on neurokinin
      (NK) receptors modulate the nonadrenergic noncholinergic (NANC) neurotransmission
      in the gastrointestinal tract of several species, but the information about the
      mouse small intestine is scanty. Both SP and NKA induced concentration-dependent
      contractions of ileal segments isolated from wild-type mice that were blocked by
      NK(1) and NK(2) antagonists, respectively. In contrast, segments isolated from
      NK(1) receptor (NK(1)-R) knockout mice responded only to elevated concentrations
      of SP. To reveal the inhibitory NANC (iNANC) responses, tissues were pretreated
      with atropine and guanethidine. Under these conditions, a tetrodotoxin-sensitive
      relaxation in response to electrical field stimulation (EFS) was observed. NK(1)
      R knockout mice presented a trend toward an increase in iNANC responses, whereas
      the NK(1)-R antagonist significantly potentiated iNANC relaxation in tissues
      isolated from wild-type mice. N(G)-nitro-L-arginine methyl ester (100 microM)
      transformed the relaxant response to EFS into a tetrodotoxin-sensitive, frequency
      dependent contraction characteristic of an excitatory NANC (eNANC) system. A
      NK(1)-R antagonist abolished the contractile responses of the mouse ileum to EFS,
      whereas a NK(2) receptor antagonist had a trend toward reducing EFS-induced
      contraction. The eNANC component was absent in NK(1)-R knockout mice. Measurement
      of SP-like immunoreactivity indicated similar amounts of SP per gram of tissue
      isolated from wild-type and NK(1)-R knockout mice, indicating that the observed
      differences in response to EFS were not due to a differential peptide content. It
      is concluded that, in the mouse ileum, both NK(1) and NK(2) receptors modulated
      the responses to exogenous tachykinins, whereas NK(1) is the primary tachykinin
      receptor involved in both iNANC and eNANC transmission.

PMID- 10600815
TI  - Capsaicin sensitivity and voltage-gated sodium currents in colon sensory neurons
      from rat dorsal root ganglia.
AB  - DiI-labeled colon sensory neurons were acutely dissociated from S1 rat dorsal
      root ganglia (DRG) and studied using perforated whole cell patch-clamp
      techniques. Forty-six percent (54/116) of labeled sensory neurons responded to
      capsaicin (10(-8)- 10(-5) M) with an increase in inward current, which was a
      nonspecific cation conductance. Responses to capsaicin applied by puffer ejection
      were dependent on dose, with a half-maximal response at 4.9 x 10(-7) M; bath
      application was characterized by marked desensitization. Voltage-gated Na(+)
      currents in 23 of 30 DRG cells exhibited both TTX-sensitive and TTX-resistant
      components. In these cells, capsaicin induced an inward current in 11 of 17 cells
      tested. Of the cells containing only a TTX-sensitive component, none of six cells
      tested was sensitive to capsaicin. In all cells that responded to capsaicin with
      an increase in inward current, capsaicin abolished voltage-gated Na(+) currents
      (n = 21). Capsazepine (10(-6) M) significantly attenuated both the increase in
      inward current and the reduction in Na(+) currents. Na(+) currents were not
      significantly altered by adenosine, bradykinin, histamine, PGE(2), or serotonin
      at 10(-6) M and 10(-5) M. These findings may have important implications for
      understanding both the irritant and analgesic properties of capsaicin.

PMID- 10600816
TI  - Hepatic fibronectin matrix turnover in rats: involvement of the
      asialoglycoprotein receptor.
AB  - Fibronectin (Fn) is a major adhesive protein found in the hepatic extracellular
      matrix (ECM). In adult rats, the in vivo turnover of plasma Fn (pFn) incorporated
      into the liver ECM is relatively rapid, i.e., <24 h, but the regulation of its
      turnover has not been defined. We previously reported that cellular Fn (cFn) and
      enzymatically desialylated plasma Fn (aFn), both of which have a high density of
      exposed terminal galactose residues, rapidly interact with hepatic
      asialoglycoprotein receptors (ASGP-R) in association with their plasma clearance
      after intravenous infusion. With the use of adult male rats (250-350 g) and
      measurement of the deoxycholate (DOC)-insoluble (125)I-labeled Fn in the liver,
      we determined whether the ASGP-R system can also influence the hepatic matrix
      retention of various forms of Fn. There was a rapid deposition of (125)I-pFn,
      (125)I-aFn, and (125)I-cFn into the liver ECM after their intravenous injection.
      Although (125)I-pFn was slowly lost from the liver matrix over 24 h, more than
      90% of the incorporated (125)I-aFn and (125)I-cFn was cleared within 4 h (P <
      0.01). Intravenous infusion of excess nonlabeled asialofetuin to competitively
      inhibit the hepatic ASGP-R delayed the rapid turnover of both aFn and cFn already
      incorporated within the ECM of the liver. ECM retention of both (125)I-aFn and
      (125)I-cFn was also less than (125)I-pFn (P < 0.01) as determined in vitro using
      liver slices preloaded in vivo with either tracer form of Fn. The hepatic ASGP-R
      appears to participate in the turnover of aFn and cFn within the liver ECM,
      whereas a non-ASGP-R-associated endocytic pathway apparently influences the
      removal of normal pFn incorporated within the hepatic ECM, unless it becomes
      locally desialylated.

PMID- 10600817
TI  - Nitric oxide mediates hepatic arterial vascular escape from norepinephrine
      induced constriction.
AB  - The involvement of nitric oxide (NO) in the vascular escape from norepinephrine
      (NE)-induced vasoconstriction was investigated in the hepatic arterial
      vasculature of anesthetized cats. The hepatic artery was perfused by free blood
      flow or pump-controlled constant-flow, and NE (0.15 and 0.3 microg x kg(-1) x
      min(-1), respectively) was infused through the portal vein. In the free-flow
      perfusion model, the NE-induced hepatic vasoconstriction recovered from the
      maximum point of the constriction, resulting in 36.6 +/- 5. 9% vascular escape.
      Blockade of NO formation with N(omega)-nitro-L-arginine methyl ester (L-NAME, 2.5
      mg/kg ipv) potentiated NE-induced maximum vasoconstriction, and the potentiation
      was reversed by L-arginine (75 mg/kg ipv). Furthermore, NE-induced
      vasoconstriction became more stable after L-NAME, resulting in an inhibition of
      vascular escape (7.5 +/- 3.3%), and the inhibition was reversed by L-arginine
      (23.0 +/- 6.4%). Similar potentiation of NE-induced vasoconstriction and
      inhibition of hepatic vascular escape by L-NAME (40.4 +/- 4.3% control vs. 10.2
      +/- 3.7% post-L-NAME escape) and the reversal by L-arginine were also observed in
      the constant-flow perfusion model. The data suggest that NO is the major
      endogenous mediator involved in the hepatic vascular escape from NE-induced
      vasoconstriction.

PMID- 10600818
TI  - Regulation of G(1) cyclin-dependent kinases in the liver: role of nuclear
      localization and p27 sequestration.
AB  - Recent studies suggest that cyclin D1 mediates progression of hepatocytes through
      G(1) phase of the cell cycle. The present study further examines the regulation
      of cyclin D1-dependent kinase activity and the interplay between cyclin D1 and
      other G(1) phase regulatory proteins during liver regeneration. After 70% partial
      hepatectomy in rats, there was upregulation of kinase activity associated with
      cyclins (A, D1, D3, and E), cyclin-dependent kinases (Cdk2 and Cdk4), and Cdk
      inhibitory proteins (p27, p107, and p130). Although cyclin D1/Cdk4 complexes were
      more abundant in the cytoplasmic fraction after partial hepatectomy, kinase
      activity was detected primarily in the nuclear fraction. Cytoplasmic cyclin
      D1/Cdk4 complexes were activated by recombinant cyclin H/Cdk7. Because endogenous
      Cdk7 activity was found in the nucleus, this suggests that activation of cyclin
      D1/Cdk4 requires nuclear importation and subsequent phosphorylation by cyclin
      H/Cdk7. Recombinant cyclin E/Cdk2 was inhibited by extracts from quiescent liver,
      and cyclin D1 could titrate out this inhibitory activity. Induction of cyclin D1
      was accompanied by increased abundance of cyclin D1/p27 complexes, and most p27
      was sequestered by cyclin D1 after partial hepatectomy. Thus cyclin D1 appears to
      play two roles during G(1) phase progression in the regenerating liver: it forms
      a nuclear kinase complex, and it promotes activation of Cdk2 by sequestering
      inhibitory proteins such as p27. These experiments underscore the complexity of
      cyclin/Cdk regulatory networks in the regenerating liver.

PMID- 10600819
TI  - Development of a test to measure gastric accommodation in humans.
AB  - Postprandial symptoms of bloating, distension, early satiety, and nausea are
      associated with impaired postprandial gastric accommodation, which is detectable
      by means of an intragastric, barostatically controlled balloon in the proximal
      stomach and by ultrasound in the distal stomach. Our aim was to develop a
      noninvasive method to measure the entire gastric accommodation reflex. In 10
      healthy volunteers, we used single photon emission computed tomography (SPECT) to
      measure fasting and postprandial gastric volumes. This method involved
      intravenous injection of (99m)Tc pertechnetate and gastric reconstruction of
      tomographic images with Analyze software. SPECT-Analyze imaging detects the
      postprandial gastric accommodation reflex in vivo. Mean fasting gastric volume
      was 182 +/- 11 (SE) ml and mean postprandial volume was 690 +/- 32 ml (P <
      0.001). Both proximal and distal segments of stomach showed a two- to almost
      fourfold difference in volumes postprandially. Intraobserver coefficients of
      variation in estimated fasting and postprandial volumes were 9 and 8%;
      interobserver variations were 13 and 12%, respectively. SPECT-Analyze
      noninvasively measures postprandial gastric (total, proximal, and distal)
      accommodation in humans. This method appears promising to compare the
      accommodation response in health and disease and to perform mechanistic studies
      of the accommodation response.

PMID- 10600820
TI  - Evidence for Gd(3+) inhibition of membrane ATP permeability and purinergic
      signaling.
AB  - Extracellular ATP functions as an important autocrine and paracrine signal that
      modulates a broad range of cell and organ functions through activation of
      purinergic receptors in the plasma membrane. Because little is known of the
      cellular mechanisms involved in ATP release, the purpose of these studies was to
      evaluate the potential role of the lanthanide Gd(3+) as an inhibitor of ATP
      permeability and to assess the physiological implications of impaired purinergic
      signaling in liver cells. In rat hepatocytes and HTC hepatoma cells, increases in
      cell volume stimulate ATP release, and the localized increase in extracellular
      ATP increases membrane Cl(-) permeability and stimulates cell volume recovery
      through activation of P(2) receptors. In cells in culture, spontaneous ATP
      release, as measured by a luciferin-luciferase-based assay, was always detectable
      under control conditions, and extracellular ATP concentrations increased 2- to 14
      fold after increases in cell volume. Gd(3+) (200 microM) inhibited volume
      sensitive ATP release by >90% (P < 0.001), inhibited cell volume recovery from
      swelling (P < 0.01), and uncoupled cell volume from increases in membrane Cl(-)
      permeability (P < 0.01). Moreover, Gd(3+) had similar inhibitory effects on ATP
      release from other liver and epithelial cell models. Together, these findings
      support an important physiological role for constitutive release of ATP as a
      signal coordinating cell volume and membrane ion permeability and suggest that
      Gd(3+) might prove to be an effective inhibitor of ATP-permeable channels once
      they are identified.

PMID- 10600821
TI  - Cloning, expression, and vesicular localization of zinc transporter Dri 27/ZnT4
      in intestinal tissue and cells.
AB  - We have identified the Dri 27 cDNA on the basis of its upregulated expression
      during rat intestinal development. It encodes a hydrophobic protein of 430 amino
      acids that shares significant homology with members of the mammalian zinc
      transporter family ZnT. The murine homologue of Dri 27 (named ZnT4) was recently
      associated with the mouse mutation "lethal milk." The primary sequence of Dri
      27/ZnT4 displays features characteristic of polytopic membrane proteins. In this
      paper, we show that Dri 27/ZnT4 is localized in the membrane of intracellular
      vesicles, the majority of which concentrate in the basal cytoplasmic region of
      polarized enterocytes. A Dri 27/ZnT4 myc-tagged construct, transiently
      transfected in intestinal Caco-2 cells, partially colocalizes with the
      transferrin receptor and with the beta-subunits of the clathrin adaptor complexes
      AP-1 and AP-2 in a subpopulation of endosomal vesicles. By subcloning distinct
      portions of the protein in frame with glutathione-S-transferase, we also provide
      experimental evidence of their function as zinc-binding and protein-protein
      interaction domains.

PMID- 10600822
TI  - Iron primes hepatic macrophages for NF-kappaB activation in alcoholic liver
      injury.
AB  - NF-kappaB activation induced by lipopolysaccharide (LPS) in cultured hepatic
      macrophages (HM) may be abrogated by pretreatment of cells with a lipophilic iron
      chelator, 1,2-dimethyl-3-hydroxypyrid-4-one (L1, deferiprone), suggesting a role
      for iron in this molecular event [M. Lin, M., R. A. Rippe, O. Niemela, G.
      Brittenham, and H. Tsukamoto, Am. J. Physiol. 272 (Gastrointest. Liver Physiol.
      35): G1355-G1364, 1997]. To ascertain the relevance in vivo of this hypothesis,
      HM from an experimental model of alcoholic liver injury were examined for the
      relationship between nuclear factor (NF)-kappaB activation and iron storage. HM
      showed a significant increase in nonheme iron concentration (+70%), accompanied
      by enhanced generation of electron paramagnetic resonance-detected radicals
      (+200%), NF-kappaB activation (+100%), and tumor necrosis factor-alpha (+150%)
      and macrophage inflammatory protein-1 (+280%) mRNA induction. Treatment of the
      cells ex vivo with L1 normalized all these parameters. HM content of ferritin
      protein, ferritin L chain mRNA, and hemeoxygenase-1 mRNA and splenic content of
      nonheme iron were increased, suggesting enhanced heme turnover as a cause of the
      increased iron storage and NF-kappaB activation. To test this possibility,
      increased iron content in HM was reproduced in vitro by phagocytosis of heat
      treated red blood cells. Treatment caused a 40% increase in nonheme iron
      concentration and accentuated LPS-induced NF-kappaB activation twofold. Both
      effects could be abolished by pretreatment of cells with zinc protoporphyrin, a
      hemeoxygenase inhibitor. To extend this observation, animals were splenectomized
      before 9-wk alcohol feeding. Splenectomy resulted in further increments in HM
      nonheme iron storage (+60%) and NF-kappaB activation (+90%) and mononuclear cell
      infiltration (+450%), particularly around the iron-loaded HM in alcohol-fed
      animals. These results support the pivotal role of heme-derived iron in priming
      HM for NF-kappaB activation and expression of proinflammatory genes in alcoholic
      liver injury.

PMID- 10600823
TI  - Desensitization to LPS after ethanol involves the effect of endotoxin on voltage
      dependent calcium channels.
AB  - Hepatic macrophages are sensitized to alcohol in 24 h due to increases in the
      endotoxin receptor, CD14; however, desensitization to lipopolysaccharide (LPS),
      which occurred earlier, could not be explained by changes in CD14. Therefore, the
      purpose of this work was to attempt to understand factors responsible for ethanol
      induced desensitization to LPS in hepatic macrophages. Rats were given ethanol (5
      g/kg body wt) intragastrically, and hepatic macrophages were isolated 2 h later.
      After addition of endotoxin, intracellular Ca(2+) concentration ([Ca(2+)](i)) was
      measured using fura 2 and tumor necrosis factor (TNF)-alpha was measured by
      ELISA. Ethanol given 2 h before injection of LPS totally prevented liver injury
      and blunted LPS-induced increases in [Ca(2+)](i) and TNF-alpha in hepatic
      macrophages. Furthermore, the protein kinase C (PKC) agonist phorbol 12-myristate
      13-acetate and acute ethanol treatment both activated PKC and largely prevented
      the influx of [Ca(2+)](i) caused by LPS. Sterilization of the gut with
      antibiotics completely blocked all effects of ethanol on [Ca(2+)](i) and TNF
      alpha release. Thus ethanol-induced desensitization of hepatic macrophages
      correlates with gut-derived endotoxin after ethanol and involves the effect of
      PKC on voltage-dependent Ca(2+) channels.

PMID- 10600824
TI  - CYP2E1 is not involved in early alcohol-induced liver injury.
AB  - The continuous intragastric enteral feeding protocol in the rat was a major
      development in alcohol-induced liver injury (ALI) research. Much of what has been
      learned to date involves inhibitors or nutritional manipulations that may not be
      specific. Knockout technology avoids these potential problems. Therefore, we used
      long-term intragastric cannulation in mice to study early ALI. Reactive oxygen
      species are involved in mechanisms of early ALI; however, their key source
      remains unclear. Cytochrome P-450 (CYP)2E1 is induced predominantly in
      hepatocytes by ethanol and could be one source of reactive oxygen species leading
      to liver injury. We aimed to determine if CYP2E1 was involved in ALI by adapting
      the enteral alcohol (EA) feeding model to CYP2E1 knockout (-/-) mice. Female
      CYP2E1 wild-type (+/+) or -/- mice were given a high-fat liquid diet with either
      ethanol or isocaloric maltose-dextrin as control continuously for 4 wk. All mice
      gained weight steadily over 4 wk, and there were no significant differences
      between groups. There were also no differences in ethanol elimination rates
      between CYP2E1 +/+ and -/- mice after acute ethanol administration to naive mice
      or mice receiving EA for 4 wk. However, EA stimulated rates 1.4-fold in both
      groups. EA elevated serum aspartate aminotransferase levels threefold to similar
      levels over control in both CYP2E1 +/+ and -/- mice. Liver histology was normal
      in control groups. In contrast, mice given ethanol developed mild steatosis,
      slight inflammation, and necrosis; however, there were no differences between the
      CYP2E1 +/+ and -/- groups. Chronic EA induced other CYP families (CYP3A, CYP2A12,
      CYP1A, and CYP2B) to the same extent in CYP2E1 +/+ and -/- mice. Furthermore,
      POBN radical adducts were also similar in both groups. Data presented here are
      consistent with the hypothesis that oxidants from CYP2E1 play only a small role
      in mechanisms of early ALI in mice. Moreover, this new mouse model illustrates
      the utility of knockout technology in ALI research.

PMID- 10600825
TI  - Role of neuropeptide-sensitive L-type Ca(2+) channels in histamine release in
      gastric enterochromaffin-like cells.
AB  - Peptides release histamine from enterochromaffin-like (ECL) cells because of
      elevation of intracellular Ca(2+) concentration ([Ca(2+)](i)) by either receptor
      operated or voltage-dependent Ca(2+) channels (VDCC). To determine whether VDCCs
      contribute to histamine release stimulated by gastrin or pituitary adenylate
      cyclase-activating polypeptide (PACAP), the presence of VDCCs and their possible
      modulation by peptides was investigated in a 48-h cultured rat gastric cell
      population containing 85% ECL cells. Video imaging of fura 2-loaded cells was
      used to measure [Ca(2+)](i), and histamine was assayed by RIA. Cells were
      depolarized by increasing extracellular K(+) concentrations or by 20 mM
      tetraethylammonium (TEA(+)). Cell depolarization increased transient and steady
      state [Ca(2+)](i) and resulted in histamine release, dependent on extracellular
      Ca(2+). These K(+)- or TEA(+)-dependent effects on histamine release from ECL
      cells were coupled to activation of parietal cells in intact rabbit gastric
      glands, and L-type channel blockade by 2 microM nifedipine inhibited 50% of
      [Ca(2+)](i) elevation and histamine release. N-type channel blockade by 1 microM
      omega-conotoxin GVIA inhibited 25% of [Ca(2+)](i) elevation and 14% of histamine
      release. Inhibition was additive. The effects of 20 mM TEA(+) were fully
      inhibited by 2 microM nifedipine. Both classes of Ca(2+) channels were found in
      ECL cells, but not in parietal cells, by RT-PCR. Nifedipine reduced PACAP-induced
      (but not gastrin-stimulated) Ca(2+) entry and histamine release by 40%.
      Somatostatin, peptide YY (PYY), and galanin dose dependently inhibited L-type
      Ca(2+) channels via a pertussis toxin-sensitive pathway. L-type VDCCs play a role
      in PACAP but not gastrin stimulation of histamine release from ECL cells, and the
      channel opening is inhibited by somatostatin, PYY, and galanin by interaction
      with a G(i) or G(o) protein.

PMID- 10600826
TI  - NOX, a novel nitric oxide scavenger, reduces bacterial translocation in rats
      after endotoxin challenge.
AB  - Endotoxemia promotes gut barrier failure and bacterial translocation (BT) by
      upregulating inducible nitric oxide synthase (iNOS) in the gut. We hypothesized
      that administration of a dithiocarbamate derivative, NOX, which scavenges nitric
      oxide (NO), may reduce intestinal injury and BT after lipopolysaccharide (LPS)
      challenge. Sprague-Dawley rats were randomized to receive NOX or normal saline
      via subcutaneously placed osmotic pumps before or after LPS challenge. Mesenteric
      lymph nodes, liver, spleen, and blood were cultured 24 h later. Transmucosal
      passage of Escherichia coli C-25 or fluorescent beads were measured in an Ussing
      chamber. Intestinal membranes were examined morphologically for apoptosis, iNOS
      expression, and nitrotyrosine immunoreactivity. NOX significantly reduced the
      incidence of bacteremia, BT, and transmucosal passage of bacteria and beads when
      administered before or up to 12 h after LPS challenge. LPS induced enterocyte
      apoptosis at the villus tips where bacterial entry was demonstrated by confocal
      microscopy. NOX significantly decreased the number of apoptotic nuclei and
      nitrotyrosine residues. NOX prevents LPS-induced gut barrier failure by
      scavenging NO and its toxic derivative, peroxynitrite.

PMID- 10600827
TI  - Immunolocalization of anion exchanger AE2 and Na(+)-HCO(-)(3) cotransporter in
      rat parotid and submandibular glands.
AB  - Salivary glands secrete K(+) and HCO(-)(3) and reabsorb Na(+) and Cl(-), but the
      identity of transporters involved in HCO(-)(3) transport remains unclear. We
      investigated localization of Cl(-)/HCO(-)(3) exchanger isoform AE2 and of Na(+)
      HCO(-)(3) cotransporter (NBC) in rat parotid gland (PAR) and submandibular gland
      (SMG) by immunoblot and immunocytochemical techniques. Immunoblotting of PAR and
      SMG plasma membranes with specific antibodies against mouse kidney AE2 and rat
      kidney NBC revealed protein bands at approximately 160 and 180 kDa for AE2 and
      approximately 130 kDa for NBC, as expected for the AE2 full-length protein and
      consistent with the apparent molecular mass of NBC in several tissues other than
      kidney. Immunostaining of fixed PAR and SMG tissue sections revealed specific
      basolateral staining of PAR acinar cells for AE2 and NBC, but in SMG acinar cells
      only basolateral AE2 labeling was observed. No AE2 expression was detected in any
      ducts. Striated, intralobular, and main duct cells of both glands showed NBC
      expression predominantly at basolateral membranes, with some cells being apically
      stained. In SMG duct cells, NBC staining exhibited a gradient of distribution
      from basolateral localization in more proximal parts of the ductal tree to apical
      localization toward distal parts of the ductal tree. Both immunoblotting signals
      and immunostaining were abolished in preabsorption experiments with the
      respective antigens. Thus the mechanisms of fluid and anion secretion in salivary
      acinar cells may be different between PAR and SMG, and, because NBC was detected
      in acinar and duct cells, it may play a more important role in transport of HCO(
      )(3) by rat salivary duct cells than previously believed.

PMID- 10600828
TI  - Role of K+ATP channels in local metabolic coronary vasodilation.
AB  - ATP-sensitive potassium (K+ATP) channels have been shown to play a role in the
      maintenance of basal coronary vascular tone in vivo. K+ATP channels are also
      involved in the coronary vasodilator response to adenosine. The aim of this study
      was to determine the role of K+ATP channels in local metabolically mediated
      increases in coronary blood flow during cardiac electrical paired pacing without
      catecholamine effects. In 10 anesthetized closed-chest dogs, coronary blood flow
      was measured in the left circumflex coronary artery, and myocardial O2
      consumption was calculated using the arteriovenous O2 difference. Cardiac
      interstitial adenosine concentration was estimated from coronary venous and
      arterial plasma adenosine measurements using a previously described,
      multicompartmental, axially distributed, mathematical model. Paired stimulation
      increased heart rate from 57 to 120 beats/min, myocardial O2 consumption 88%, and
      coronary blood flow 76%. During K+ATP channel blockade with glibenclamide,
      baseline coronary blood flow decreased in relation to myocardial O2 consumption
      and thus coronary sinus O2 tension fell. Paired-pulse pacing with glibenclamide
      resulted in increases in myocardial O2 consumption and coronary blood flow
      similar to those during control pacing. Coronary venous and estimated
      interstitial adenosine concentration did not increase sufficiently to overcome
      the glibenclamide blockade. In conclusion, K+ATP channels are not required for
      locally mediated metabolic increases in coronary blood flow that accompany
      myocardial O2 consumption during pacing tachycardia without catecholamines, and
      adenosine levels do not increase sufficiently to overcome the glibenclamide
      blockade.

PMID- 10600829
TI  - Effects of methionine on endogenous antioxidants in the heart.
AB  - The deficiency of methionine, an essential amino acid, is associated with
      cardiovascular lesions. Because different types of cardiac pathologies are caused
      by a decrease in antioxidants, we examined the effects of methionine on
      myocardial antioxidant enzymes in hemodynamically assessed rats that were treated
      with methionine (10 mg/ml) in drinking water for 12, 24, and 48 h. Glutathione
      peroxidase (GSHPx) activity was significantly increased to 150.5 +/- 12.2 and
      191.7 +/- 13.7% of the control value at 12 and 24 h, respectively, followed by a
      decline to 120 +/- 24.6% at 48 h. The mRNA levels of GSHPx at these time points
      were 151.2 +/- 12.0, 218.7 +/- 35.3, and 173.5 +/- 25.2%, respectively.
      Superoxide dismutase (SOD) activity was 144.3 +/- 3.7, 114.3 +/- 10.1, and 143.1
      +/- 11. 2% at 12, 24, and 48 h, respectively. Catalase (Cat) activity was 272.4
      +/- 5.4, 237.8 +/- 16.6, and 224.1 +/- 17.3% of the control value. The expression
      of Cat and SOD mRNA was unchanged at 12, 24, and 48 h. The lipid peroxidation was
      decreased by 24.4 +/- 11.2, 54. 9 +/- 0.1, and 6.4 +/- 2.1% at 12, 24, and 48 h,
      respectively. Methionine had no effect on the ventricular or aortic pressures,
      heart rate, and myocardial glutathione levels at any of the time points. The
      study shows that methionine has a significant effect on the myocardial
      antioxidant enzyme activities, and only changes in GSHPx enzyme activity
      correlated with the mRNA changes. These antioxidant changes may have a role in
      the beneficial effects of methionine in pathological rather than physiological
      conditions.

PMID- 10600830
TI  - Dynamic counterbalance between direct and indirect vagal controls of
      atrioventricular conduction in cats.
AB  - The vagal system regulates the atrioventricular conduction time (TAV) via two
      opposing mechanisms: a direct effect on the atrioventricular node and an indirect
      effect through changes in heart period (TAA). To evaluate how dynamic vagal
      activation affects TAV, we stimulated the vagal nerve with frequency-modulated
      Gaussian white noise and estimated the transfer function from vagal stimulation
      to the TAV response under conditions of no pacing and constant pacing in
      anesthetized cats. The effect of changes in TAA on TAV was estimated by a random
      pacing protocol. The transfer function from vagal stimulation to TAV has low-pass
      filter characteristics. Constant pacing increased the maximum step response in
      TAV (2.4 +/- 1.2 vs. 6.3 +/- 2.2 ms/Hz, P < 0.01). The time constant did not
      differ between the vagal effect on TAV and that on TAA (2.9 +/- 1.2 vs. 2.3 +/-
      0.5 s). Because changes in TAA reciprocally affected TAV without significant
      delay, the direct and indirect effects were dynamically counterbalanced and
      exerted stable TAV transient response during vagal stimulation under normal sinus
      rhythm.

PMID- 10600831
TI  - Chronic run training suppresses alpha-adrenergic response of rat cardiomyocytes
      and isovolumic left ventricle.
AB  - The effects of endurance run training on alpha-adrenergic responsiveness of rat
      left ventricle (LV) were examined in cardiomyocytes and isovolumic LV. Female
      Sprague-Dawley rats were sedentary (Sed) or trained (Tr) for >20 wk by treadmill
      running. Cardiomyocyte shortening and fura 2 fluorescence ratio were recorded
      before and during 5-min exposure to 5 microM phenylephrine (PE) while paced at
      0.5 Hz in 2 mM extracellular Ca2+ concentration at 29 degrees C. Cardiomyocyte
      shortening and shortening velocity increased with PE, and these effects were more
      pronounced in the Sed group. The rate of cytosolic Ca2+ concentration removal was
      reduced by PE in the Sed cardiomyocytes, but was unaffected in the Tr. Isovolumic
      LV pressure was recorded immediately before and during 5-min perfusion with 5
      microM PE during pacing at 280 beats/min and 37 degrees C, and positive inotropy
      due to PE was more pronounced in the Sed than in the Tr. These data demonstrated
      that the effects of alpha-adrenergic stimulation on myocardial positive inotropy
      and calcium regulation were reduced in this rat model of run training at both the
      cellular and whole organ levels.

PMID- 10600832
TI  - Capillary recruitment in response to tissue hypoxia and its dependence on red
      blood cell deformability.
AB  - The effect of reduced red blood cell (RBC) deformability on microvessel
      recruitment attendant to a reduction in tissue PO2 was studied in rat cremaster
      muscle using indicator-dilution techniques. Transit times (TT) of fluorescently
      labeled RBCs (TTRBC) and plasma (TTPl) between functionally paired arterioles and
      venules were obtained from their dispersion throughout the microvascular network.
      Changes in PO2 were effected by superfusing the tissue with Ringer solution
      deoxygenated to different levels. Arteriolar blood flow (Q) was measured with the
      two-slit technique, and the vascular volume (V) occupied by RBCs and plasma was
      computed from the product of Q x TT during bolus infusions of rat and less
      deformable human RBCs to obtain VRBC and fluorescently labeled albumin to obtain
      VPl. Measurements of TTRBC and TTPl permitted computation of an average flow
      weighted tissue (microvascular) hematocrit (HM) relative to systemic values (HS).
      During infusions of autologous rat RBCs, Q and total V increased threefold in
      response to hypoxia, whereas normalized RBC TT (TTRBC/TTPl) and normalized tissue
      hematocrit (HM/HS) did not show a significant trend, indicating an increase in
      the number of pathways through which the RBCs can traverse the network because of
      spatial recruitment of capillaries. In contrast, during infusions of human RBCs,
      TTRBC/TTPl and HM/HS decreased significantly in response to hypoxia. Although Q
      exhibited an increase similar to that during rat RBC infusions, VRBC exhibited a
      smaller increase compared with VPl, suggesting that reduced RBC deformability
      leads to a redistribution of RBCs through larger-diameter pathways within the
      network and exclusion of these RBCs from pathways normally recruited during
      hypoxia. Hence, reduced RBC deformability may adversely affect capillary
      recruitment and physiological mechanisms that ensure adequate delivery of oxygen
      to tissue.

PMID- 10600833
TI  - A hemodynamic analysis of coronary capillary blood flow based on anatomic and
      distensibility data.
AB  - An understanding of cardiac health and disease requires knowledge of the various
      factors that control coronary capillary blood flow. An analysis of coronary
      capillary blood flow based on a complete set of actual data on the capillary
      anatomy and elasticity does not exist. Previously, a complete set of data on the
      branching pattern and the vascular geometry of the pig coronary capillary network
      were obtained in our laboratory. In the present study, we obtained distensibility
      data on the coronary capillary blood vessels on the epicardial surface in the
      form of a pressure-diameter relationship using intravital microscopy. A
      mathematical model of the coronary capillary blood flow was then constructed on
      the basis of measured anatomic and elasticity data of the coronary capillary
      network, rheology of blood, physical laws governing blood flow, and appropriate
      boundary conditions. The constructed model was used to examine the heterogeneity
      of the spatial distribution of coronary blood flow, which is an important issue
      in coronary physiology. One interesting result of the model is that the
      dispersions of pressure and flow are significantly reduced in the presence of
      capillary cross-connections, and the resistance to flow is reduced as well.
      Finally, we found that the compliance of the epicardial surface capillary vessels
      is so small that its effect on the blood pressure drop is negligible in the
      diastolic state. However, the compliance of the intramyocardial capillaries
      remains unknown, and the interaction of the muscle contraction and blood vessel
      elasticity in systole remains to be studied.

PMID- 10600834
TI  - Effects of ACE inhibition and beta-receptor blockade on energy metabolism in rats
      postmyocardial infarction.
AB  - Chronic treatment with beta-receptor blockers or angiotensin-converting enzyme
      (ACE) inhibitors in heart failure can reduce mortality and improve left
      ventricular function, but the mechanisms involved in their beneficial action
      remain to be fully defined. Our hypothesis was that these agents prevent the
      derangement of cardiac energy metabolism. Rats were subjected to myocardial
      infarction (MI) or sham operation. Thereafter, animals were treated with
      bisoprolol, captopril, or remained untreated. Two months later, cardiac function
      was measured in the isolated heart by a left ventricular balloon (pressure-volume
      curves), and energy metabolism of residual intact myocardium was analyzed in
      terms of total and isoenzyme creatine kinase (CK) activity, steady-state levels
      (ATP, phosphocreatine), and turnover rates (CK reaction velocity) of high-energy
      phosphates (31P nuclear magnetic resonance) and total creatine content (HPLC).
      Bisoprolol and partially captopril prevented post-MI hypertrophy and partially
      prevented left ventricular contractile dysfunction. Residual intact failing
      myocardium in untreated, infarcted hearts showed a 25% decrease of the total, a
      26% decrease of MM-, and a 37% decrease of the mitochondrial CK activity. Total
      creatine was reduced by 15%, phosphocreatine by 21%, and CK reaction velocity by
      41%. Treatment with bisoprolol or captopril largely prevented all of these
      changes in infarcted hearts. Thus the favorable functional effects of beta
      receptor blockers and ACE inhibitors post-MI are accompanied by substantial
      beneficial effects on cardiac energy metabolism.

PMID- 10600835
TI  - Translational mechanisms accelerate the rate of protein synthesis during canine
      pressure-overload hypertrophy.
AB  - This study examined how translational mechanisms regulate the rate of cardiac
      protein synthesis during canine pressure overload in vivo. Acute aortic stenosis
      (AS) was produced by inflating a balloon catheter in the ascending aorta for 6 h;
      sustained AS was created by controlled banding of the ascending aorta. AS caused
      significant hypertrophy as reflected by increased left ventricular (LV) mass
      after 5 and 10 days. To monitor LV protein synthesis in vivo, myosin heavy chain
      (MHC) synthesis was measured by continuous infusion of radiolabeled leucine.
      Acute AS accelerated the rate of myosin synthesis without a corresponding
      increase in ribosomal RNA, indicating an increase in translational efficiency.
      Total MHC synthesis (mg MHC/LV per day) was significantly increased at 5 and 10
      days of sustained AS. Total MHC degradation was not significantly altered at 5
      days of AS but increased at 10 days of AS in concordance with a new steady state
      with respect to growth. Translational capacity (mg total RNA/LV) was
      significantly increased after 5 and 10 days of AS and was preceded by an increase
      in the rate of ribosome formation. MHC mRNA levels remained unchanged during AS.
      These findings demonstrate that cardiac protein synthesis is accelerated in
      response to pressure overload by an initial increase in translational efficiency,
      followed by an adaptive increase in translational capacity during sustained
      hypertrophic growth.

PMID- 10600836
TI  - Alterations in contractile properties and Ca2+ handling in streptozotocin-induced
      diabetic rat myocardium.
AB  - The mechanisms of the slower time courses of Ca2+ transients (CaT) and
      contraction in diabetic (diabetes mellitus, DM) myocardium were studied. The
      aequorin method was applied to papillary muscles of streptozotocin-induced DM and
      control rats. The time courses of CaT and tension of twitch in DM were slower
      than those in control, although the magnitudes of the CaT and contraction were
      identical. The dependence of CaT decay time and relaxation time on developed
      tension in DM and control rats differed. The length-tension relation in twitch
      and the pCa-tension relation in tetanus were identical in the two groups. The
      magnitude of extra Ca2+ (transient increase in intracellular Ca2+ concentration
      induced by a quick release in tetanus) was identical in both groups. pCa-tension
      relations of skinned trabeculae at different sarcomere lengths were nearly
      identical. The cross-bridge cycling rate (CCR) in DM was slower than that in
      control. These results indicate that the tension-dependent change in the Ca2+
      affinity of troponin C in DM myocardium functions as in control myocardium. The
      slower time courses of CaT and tension in DM myocardium are caused by slower Ca2+
      uptake by the sarcoplasmic reticulum and the slower CCR.

PMID- 10600837
TI  - Effects of modest anemia on systemic and coronary circulation of septic sheep.
AB  - Although a lower transfusion trigger is generally recommended, little evidence is
      available about the physiological mechanisms of mild anemia in diseases with an
      imbalance between O2 supply and O2 demand such as sepsis. This study was
      undertaken to describe the systemic and coronary metabolic O2 reserve in an awake
      sheep model of hyperdynamic sepsis comparing two different hemoglobin levels.
      Twenty-four hours after sheep were rendered septic by cecal ligation and
      perforation (CLP), blood transfusion (n = 7, hemoglobin = 120 g/l) and isovolemic
      hemodilution (n = 8, hemoglobin = 70 g/l), respectively, were performed. Another
      24 h later, we measured hemodynamics, organ blood flows, and systemic and
      myocardial O2 metabolism variables at baseline and through four stages of
      progressive hypoxia. Maximum coronary blood flow was 766.3 +/- 87.4 ml. min(-1).
      100 g(-1) in hemodiluted sheep group versus 422.7 +/- 53.7 ml. min(-1). 100 g(-1)
      in the transfused sheep (P < 0.01). Myocardial O2 extraction was higher in the
      transfusion group (P = 0.03) throughout the whole hypoxia trial. In the
      hemodilution group, coronary blood flow increased more per increase in myocardial
      O(2) uptake than in transfused sheep (P < 0.01). This was accompanied by a lower
      left ventricular epicardial-to-endocardial flow ratio in hemodiluted sheep (1.13
      +/- 0.07) than in transfused sheep (1.34 +/- 0.02, P < 0.05). We conclude that
      the lower coronary blood flow and greater myocardial O2 extraction in transfused
      septic sheep preserves transmyocardial O2 metabolism better in comparison to
      hemodiluted sheep.

PMID- 10600838
TI  - Neuregulin activation of ErbB receptors in vascular endothelium leads to
      angiogenesis.
AB  - The ErbB, or epidermal growth factor receptor (EGF-r), family of transmembrane
      tyrosine kinase receptors has been demonstrated to play an important role in
      growth regulation and intracellular signaling in a wide variety of cell types.
      Targeted deletion of neuregulin (an ErbB ligand) in mice results in endocardial
      cushion abnormalities, suggesting that these receptor-ligand interactions have
      important effects on vascular endothelial growth and development. To study the
      role of ErbB receptor signaling in vascular endothelium, we investigated the
      expression pattern of the various receptor family members and the effect of ErbB
      receptor stimulation in human umbilical vein endothelial cells (HUVEC). We
      demonstrate that ErbB2 (neu), ErbB3, and ErbB4 are highly expressed, whereas
      ErbB1 (EGF-r) is undetectable. Stimulation of HUVEC with recombinant neuregulin
      beta (an ErbB3/4 ligand) induces rapid calcium fluxes, receptor tyrosine
      phosphorylation, and cell proliferation. We demonstrate marked in vitro and in
      vivo angiogenic responses to neuregulin-beta, which are independent of vascular
      endothelial cell growth factor. These findings support an important role for the
      ErbB family of receptors in endothelial cell signaling and function, including
      neuregulin-induced angiogenesis.

PMID- 10600839
TI  - Functional role of ionic regulation of Na+/Ca2+ exchange assessed in transgenic
      mouse hearts.
AB  - Na+/Ca2+ exchange is the primary mechanism mediating Ca2+ efflux from cardiac
      myocytes during diastole and, thus, can prominently influence contractile force.
      In addition to transporting Na+ and Ca2+, the exchanger is also regulated by
      these ions. Although structure-function studies have identified protein regions
      of the exchanger subserving these regulatory processes, their physiological
      importance is unknown. In this study, we examined the electrophysiological and
      mechanical consequences of cardiospecific overexpression of the canine cardiac
      exchanger NCX1.1 and a deletion mutant of NCX1.1 (Delta680-685), devoid of
      intracellular Na+ (Na+i)- and Ca2+ (Ca2+i)- dependent regulatory properties, in
      transgenic mice. Using the giant excised patch-clamp technique, normal ionic
      regulation was observed in membrane patches from cardiomyocytes isolated from
      control and transgenic mice overexpressing NCX1.1. In contrast, ionic regulation
      was nearly abolished in mice overexpressing Delta680-685, indicating that the
      native regulatory processes could be overwhelmed by expression of the transgene.
      To address the physiological consequences of ionic regulation of the Na+/Ca2+
      exchanger, we examined postrest force development in papillary muscles from
      NCX1.1 and Delta680-685 transgenic mice. Postrest potentiation was found to be
      substantially greater in Delta680-685 than in NCX1.1 transgenic mice, supporting
      the notion that ionic regulation of Na+/Ca2+ exchange plays a significant
      functional role in cardiac contractile properties.

PMID- 10600840
TI  - Caveolae require intact VAMP for targeted transport in vascular endothelium.
AB  - Caveolae appear to function in vesicular trafficking of specific molecular cargo
      into and across vascular endothelial and other cells. They contain the molecular
      machinery for docking and fusion, similar to other vesicular trafficking systems,
      yet the mechanisms mediating ligand internalization and targeted intracellular
      transport by caveolae remain unclear. Using immunoelectron microscopy, we show
      that caveolae in the microvascular endothelium of rat lung express vesicle
      associated membrane protein (VAMP)-2 (also called synaptobrevin) on their
      cytoplasmic surface. Immunofluorescence studies of cholera toxin B (CTB)-FITC
      internalization in toxin-treated cells demonstrate that intact VAMP-2 is
      necessary for the efficient trafficking of caveolar ligands. The CTB subunit
      binds preferentially to GM1 in caveolae, and N-ethylmaleimide treatment
      drastically inhibits the intracellular accumulation of CTB. The cleavage of
      caveolar VAMP-2 with VAMP-specific neurotoxins (botulinum D and F but not A)
      significantly inhibits CTB endocytosis and targeted intracellular accumulation in
      cultured endothelial cells. This impairment of caveolae-mediated trafficking
      provides evidence that caveolae require intact VAMP-2 for efficient targeted
      delivery via vesicle docking with target organelles.

PMID- 10600841
TI  - Effect of aging on gender differences in neural control of heart rate.
AB  - To clarify the influence of gender on sympathetic and parasympathetic control of
      heart rate in middle-aged subjects and on the subsequent aging process, heart
      rate variability (HRV) was studied in normal populations of women (n = 598) and
      men (n = 472) ranging in age from 40 to 79 yr. These groups were divided into
      eight age strata at 5-yr intervals and were clinically diagnosed as having no
      hypertension, hypotension, diabetic neuropathy, or cardiac arrhythmia. Frequency
      domain analysis of short-term, stationary R-R intervals was performed, which
      reveals very-low-frequency power (VLF; 0.003-0.04 Hz), low-frequency power (LF;
      0.04-0.15 Hz), high-frequency power (HF; 0.15-0.40 Hz), the ratio of LF to HF
      (LF/HF), and LF and HF power in normalized units (LF% and HF%, respectively). The
      distribution of variance, VLF, LF, HF, and LF/HF exhibited acute skewness, which
      was adjusted by natural logarithmic transformation. Women had higher HF in the
      age strata from 40 to 49 yr, whereas men had higher LF% and LF/HF between 40 and
      59 yr. No disparity in HRV measurements was found between the sexes in age strata
      >/=60 yr. Although absolute measurements of HRV (variance, VLF, LF, and HF)
      decreased linearly with age, no significant change in relative measurements
      (LF/HF, LF%, and HF%), especially in men, was detected until age 60 yr. We
      conclude that middle-aged women and men have a more dominant parasympathetic and
      sympathetic regulation of heart rate, respectively. The gender-related difference
      in parasympathetic regulation diminishes after age 50 yr, whereas a significant
      time delay for the disappearance of sympathetic dominance occurs in men.

PMID- 10600842
TI  - Generation of superoxide in cardiomyocytes during ischemia before reperfusion.
AB  - Although a burst of oxidants has been well described with reperfusion, less is
      known about the oxidants generated by the highly reduced redox state and low O(2)
      of ischemia. This study aimed to further identify the species and source of these
      oxidants. Cardiomyocytes were exposed to 1 h of simulated ischemia while oxidant
      generation was assessed by intracellular dihydroethidine (DHE) oxidation.
      Ischemia increased DHE oxidation significantly (0.7 +/- 0.1 to 2.3 +/- 0.3) after
      1 h. Myxothiazol (mitochondrial site III inhibitor) attenuated oxidation to 1.3
      +/- 0.1, as did the site I inhibitors rotenone (1.0 +/- 0.1), amytal (1.1 +/-
      0.1), and the flavoprotein oxidase inhibitor diphenyleneiodonium (0.9 +/- 0.1).
      By contrast, the site IV inhibitor cyanide, as well as inhibitors of xanthine
      oxidase (allopurinol), nitric oxide synthase (nitro-L-arginine methyl ester), and
      NADPH oxidase (apocynin), had no effect. Finally, DHE oxidation increased with Cu
      and Zn-containing superoxide dismutase (SOD) inhibition using
      diethyldithiocarbamate (2.7 +/- 0.1) and decreased with exogenous SOD (1.1 +/-
      0.1). We conclude that significant superoxide generation occurs during ischemia
      before reperfusion from the ubisemiquinone site of the mitochondrial electron
      transport chain.

PMID- 10600843
TI  - Human VEGF gene expression in skeletal muscle: effect of acute normoxic and
      hypoxic exercise.
AB  - Vascular endothelial growth factor (VEGF) is involved in extracellular matrix
      changes and endothelial cell proliferation, both of which are precursors to new
      capillary growth. Angiogenesis is a vital adaptation to exercise training, and
      the exercise-induced reduction in intracellular PO2 has been proposed as a
      stimulus for this process. Thus we studied muscle cell PO2 [myoglobin PO2
      (MbPO2)] during exercise in normoxia and in hypoxia (12% O2) and studied the mRNA
      levels of VEGF in six untrained subjects after a single bout of exercise by
      quantitative Northern analysis. Single-leg knee extension provided the acute
      exercise stimulus: a maximal test followed by 30 min at 50% of the peak work rate
      achieved in this graded test. Because peak work rate was not affected by hypoxia,
      the absolute and relative work rates were identical in hypoxia and normoxia.
      Three pericutaneous needle biopsies were collected from the vastus lateralis
      muscle, one at rest and then the others at 1 h after exercise in normoxia or
      hypoxia. At rest (control), VEGF mRNA levels were very low (0.38 +/- 0.04
      VEGF/18S). After exercise in normoxia or hypoxia, VEGF mRNA levels were much
      greater (16.9 +/- 6.7 or 7.1 +/- 1.8 VEGF/18S, respectively). In contrast, there
      was no measurable basic fibroblast growth factor mRNA response to exercise at
      this 1-h postexercise time point. Magnetic resonance spectroscopy of myoglobin
      confirmed a reduction in MbPO2 in hypoxia (3.8 +/- 0.3 mmHg) compared with
      normoxia (7.2 +/- 0.6 mmHg) but failed to reveal a relationship between MbPO2
      during exercise and VEGF expression. This VEGF mRNA increase in response to acute
      exercise supports the concept that VEGF is involved in exercise-induced skeletal
      muscle angiogenesis but questions the importance of a reduced cellular PO2 as a
      stimulus for this response.

PMID- 10600844
TI  - Intravenous pyruvate prolongs survival during hemorrhagic shock in swine.
AB  - Pyruvate improves cellular and organ function during hypoxia and ischemia and
      stabilizes the NADH redox state and cytosolic ATP phosphorylation potential. In
      this in vivo study, we evaluated the effects of intravenous pyruvate on
      cardiovascular and neocortical function, indexes of the cytosolic redox state
      (lactate/pyruvate ratio, L/P) and cellular energy state (adenosine and
      degradative products hypoxanthine and inosine, ADO + HX + Ino) during controlled
      arterial hemorrhage (40 mmHg) in sedated swine (45 kg). Na+ pyruvate was infused
      1 h before (1 g. kg(-1). h(-1)) and 2 h during (0.5 g. kg(-1). h(-1)) hemorrhage
      to attain arterial pyruvate levels of 6 mM. Volume (0.9% NaCl) and osmotic (10%
      NaCl) effects were matched in controls. Time to peak hemorrhage (57 min) and peak
      hemorrhage volume (43 ml/kg) were similar in all groups. The volume and osmotic
      groups experienced spontaneous cardiovascular decompensation between 60 and 90
      min, with an average time until death of 82.7 +/- 5.5 and 74.8 +/- 8.2 min. In
      contrast, survival in the pyruvate group was 151.2 +/- 10.0 min (P < 0.001).
      During hemorrhage, the pyruvate group had better cardiovascular and
      cerebrovascular function with significantly higher systemic and cerebral oxygen
      consumption and less attenuation of the amplitude and frequency of the
      electrocorticogram. In addition, pyruvate prevented metabolic acidosis and
      stabilized the L/P. Pyruvate slowed the rise in neocortical microdialysis levels
      of ADO + HX + Ino, and prevented the net efflux of ADO + HX + Ino into the
      sagittal sinus. The findings reveal considerable metabolic and functional
      enhancement by pyruvate during severe hemorrhagic shock with a 75-min delay in
      spontaneous cardiovascular decompensation and death.

PMID- 10600845
TI  - Integrin signaling, free radicals, and tyrosine kinase mediate flow constriction
      in isolated cerebral arteries.
AB  - Isolated, cannulated, and pressurized (100 mmHg) middle cerebral arteries from
      adult cats were perfused intraluminally at rates from 0 to 4 ml/min with heated
      and gassed physiological saline solution. An electronic system held pressure
      constant by changing outflow resistance. The arteries constricted 18.1 +/- 0.95%
      in response to flow and depolarized from -54 +/- 0.51 to -40 +/- 1.26 mV (P <
      0.05). Constriction was independent of a functional endothelium but was
      eliminated by superoxide dismutase or tyrosine kinase inhibitors. Luminal
      perfusion with a synthetic extracellular matrix Arg-Gly-ASP (RGD) peptide that
      binds with integrin significantly reduced constriction to flow. Neither reducing
      intraluminal pressure nor increasing tone or shear stresses altered constriction
      to flow. Flow-induced constriction did not impede the ability of the arteries to
      dilate to hypercapnia, and inhibiting flow-induced constriction did not alter
      contractile responses to other agonists. These data suggest that, in vitro,
      middle cerebral arteries constrict to flow through a mechanism involving free
      radicals and tyrosine kinase and that flow shear stresses resulting in
      constriction are transduced by integrin signaling.

PMID- 10600846
TI  - Altered central nervous system processing of baroreceptor input following
      hindlimb unloading in rats.
AB  - The effect of cardiovascular deconditioning on central nervous system processing
      of baroreceptor afferent activity was evaluated following 14 days of hindlimb
      unloading (HU). Inactin-anesthetized rats were instrumented with catheters, renal
      sympathetic nerve electrodes, and aortic depressor nerve electrodes for
      measurement of mean arterial pressure, heart rate, renal sympathetic nerve
      activity (RSNA), and aortic depressor nerve activity (ADNA). Baroreceptor and
      baroreflex functions were assessed during infusion of phenylephrine and sodium
      nitroprusside. Central processing of baroreceptor afferent input was evaluated by
      linear regression relating RSNA to ADNA. The maximum baroreflex-elicited increase
      in RSNA was significantly reduced in HU rats (122 +/- 3.8 vs. 144 +/- 4.9% of
      baseline RSNA), whereas ADNA was not altered. The slope (-0.18 +/- 0.04 vs. -0.40
      +/- 0.04) and y-intercept (121 +/- 3.2 vs. 146 +/- 4.3) of the linear regression
      relating increases in efferent RSNA to decreases in afferent ADNA during
      hypotension were significantly reduced in HU rats. There were no differences
      during increases in arterial pressure. Results demonstrate that the attenuation
      in baroreflex-mediated increases in RSNA following HU is due to changes in
      central processing of baroreceptor afferent information rather than aortic
      baroreceptor function.

PMID- 10600847
TI  - Modulation of endocardial natriuretic peptide receptors in right ventricular
      hypertrophy.
AB  - Natriuretic peptide (NP) receptors (NPRs) located at the endocardial endothelium
      are suggested to be involved in regulating myocardial contractility. However, the
      characteristics and modulation of NPRs in relation to cardiac failure are not
      well defined. This study examined the properties of NPRs in ventricular
      endocardium using quantitative receptor autoradiography, RT-PCR, Southern blot
      analysis, and activation of particulate guanylyl cyclase (GC) by NPs. In control
      rats, specific 125I-labeled rat atrial NP (rANP)(1-28) binding sites were
      localized in right (RV) and left ventricular (LV) endocardium. Binding affinities
      of 125I-rANP(1-28) were remarkably higher in RV than LV endocardium. Radioligand
      binding at these sites was mostly inhibited by des[Gln18,Ser19,Gly20,Leu21,
      Gly22]ANP(4-23), a specific NP clearance receptor ligand. mRNAs for all three
      recognized NPRs were detected in endocardial cells by RT-PCR and confirmed by
      Southern blot analysis. Production of cGMP by particulate GC in endocardial cell
      membranes was stimulated by NPs with a rank order of potency of C-type NP(1-22)
      >> brain NP (BNP)(1-26) > ANP(1-28). We also examined the modulation of these
      NPRs during cardiac hypertrophy induced by monocrotaline (MCT). In MCT-treated
      rats with pulmonary hypertension, specific (125)I-rANP(1-28) binding to
      hypertrophied RV endocardium almost disappeared and cGMP production by NPs was
      significantly decreased. In rats with pulmonary hypertension, plasma levels of
      ANP and BNP were increased by fivefold compared with controls. The results
      indicate that there is a differential distribution of NPRs in the cardiac
      chambers, with the most abundant binding sites in RV endocardium, that NPR-B is
      the predominant GC-coupled NPR in ventricular endocardium, and that endocardial
      NPRs are downregulated with ventricular hypertrophy. Downregulation of NPRs may
      be associated with an increment of endogenous NP production caused by mechanical
      overload in hypertrophied ventricle.

PMID- 10600848
TI  - Dietary fish oil promotes positive inotropy of ouabain in the rat heart.
AB  - We tested the hypothesis that a fish oil (FO) diet promotes positive inotropy of
      ouabain without increased toxicity. For 2 mo, two groups of adult male rats were
      fed 1) a regular food diet supplemented with dietary long-chain polyunsaturated
      fatty acid from FO or 2) a regular food diet (control). The responsiveness to
      ouabain was evaluated for the two groups in Langendorff-perfused hearts, by (31)P
      nuclear magnetic resonance spectroscopy, and on purified membrane-bound Na-K
      ATPase. The maximum positive inotropy achieved with ouabain was nearly two times
      higher in the FO than in the control group and was not associated with
      significant changes in energetics. Alteration of function and energetic
      metabolism and inhibition of Na-K-ATPase in response to 3 x 10(-4) M ouabain were
      delayed in the FO group. This study demonstrates that dietary FO, by a cardiac
      membrane incorporation of n-3 polyunsaturated fatty acid, promotes positive
      inotropy of ouabain without toxicity and changes in cardiac metabolism.

PMID- 10600849
TI  - PKC translocation without changes in Galphaq and PLC-beta protein abundance in
      cardiac hypertrophy and failure.
AB  - Activation of protein kinase C (PKC) has been implicated as playing a key role in
      the pathogenesis of cardiac hypertrophy. This study investigates the response of
      several signal transduction proteins responsible for PKC activation during the
      transition from compensated pressure-overload hypertrophy (POH) to congestive
      heart failure (CHF). Pressure overload was produced on male, adult, Hartley
      strain guinea pigs using a ligature around the descending thoracic aorta. Sham
      operated controls, POH, and CHF groups were identified based on left ventricular
      hypertrophy, pulmonary congestion, and isolated heart Langendorff mechanics.
      Quantitative immunoblotting revealed phospholipase C (PLC)-betaI and Galphaq were
      unchanged during POH and CHF, as were RGS2, RGS3, and RGS4 (regulators of G
      protein signaling, which are activators of intrinsic GTPase activity).
      Translocation of PKC-alpha, -epsilon, and -gamma from cytosolic to membranous
      fractions were significantly increased during POH and CHF. Cytosolic PKC activity
      was also elevated during POH. We conclude that differential PKC activation may be
      mediated by increases in Galphaq and PLC-betaI activity rather than upregulation
      of expression.

PMID- 10600850
TI  - Contribution of carotid chemoreceptors to mesenteric venoconstriction during
      acute hypercapnia in rabbits.
AB  - The contribution of carotid chemoreceptors to hypercapnia-induced mesenteric
      venoconstriction was examined in 12 alpha-chloralose-anesthetized rabbits (1.0
      1.6 kg). Surgical preparation consisted of a tracheotomy, femoral arterial and
      venous cannulation, and a midline laparotomy through which a 13-cm loop of ileum
      was exteriorized and superfused with physiological salt solution. Mesenteric vein
      diameter and intravenous pressure (using a servo-null measurement system) were
      measured in 500- to 1,000-micron mesenteric veins during 40-s periods of 15%,
      20%, and 25% CO2 inhalation. Measurements were then repeated following bilateral
      ablation of the carotid chemoreceptors. Before denervation, mesenteric vein
      diameter constricted 6.5 +/- 1.1%, 11.9 +/- 1.1%, and 17.9 +/- 2.2% during the
      15%, 20%, and 25% CO2 inhalation, respectively. After denervation, these values
      were reduced to 5.0 +/- 0.9%, 6.9 +/- 1.2%, and 8.4 +/- 1.3%, respectively. We
      conclude that activation of the carotid chemoreceptors by hypercapnia induces
      active mesenteric venoconstriction. After denervation of the carotid
      baroreceptors and chemoreceptors, there was also a small decrease in venule
      diameter proportional to the level of inspired CO2. We further conclude that
      noncarotid body chemoreceptor activation contributes to mesenteric venular
      constriction.

PMID- 10600851
TI  - Factors governing mechanical stimulation in frog hearts.
AB  - Because stretch-induced activation may be important in generating clinically
      relevant arrhythmias in the heart, we delineated the ability of different types
      of stretches to activate ventricular tissue. Geometrically simple sheets of frog
      (Rana catesbeiana) ventricular tissue were mounted to allow stretches to be
      applied perpendicular to one edge. Every heart could be activated by a stretch
      pulse (n = 25), and several parameters were varied to determine their effects on
      mechanical activation threshold. At shorter coupling intervals, a larger stretch
      was needed to excite the tissue, and activation-recovery intervals were shorter,
      similar to previously published electrically probed strength-interval and
      restitution relations. Additionally, the tissue became easier to activate as the
      speed of the stretch increased from 0.09 to 2.6% length/ms. The increment in
      stretch needed for activation decreased as the baseline stretch increased from 0
      to 6% length. Thus we show that mechanical activation is similar to electrical
      activation and that increasing uniquely mechanical parameters such as the speed
      of the applied stretch or baseline level of stretch can decrease the mechanical
      activation threshold.

PMID- 10600852
TI  - Modulation of myocardial function and [Ca2+] sensitivity by moderate hypothermia
      in guinea pig isolated hearts.
AB  - Cardiac hypothermia alters contractility and intracellular Ca2+ concentration
      ([Ca2+]i) homeostasis. We examined how left ventricular pressure (LVP) is altered
      as a function of cytosolic [Ca2+]i over a range of extracellular CaCl2
      concentration ([CaCl2]e) during perfusion of isolated, paced guinea pig hearts at
      37 degrees C, 27 degrees C, and 17 degrees C. Transmural LV phasic [Ca2+] was
      measured using the Ca2+ indicator indo 1 and calibrated (in nM) after correction
      was made for autofluorescence, temperature, and noncytosolic Ca2+. Noncytosolic
      [Ca2+]i, cytosolic diastolic and systolic [Ca2+]i, phasic [Ca2+]i, and systolic
      Ca2+ released per beat (area Ca2+) were plotted as a function of 0.3-4.5 mM
      [CaCl2]e, and indexes of contractility [LVP, maximal rates of LVP development
      (+dLVP/dt) and relaxation (-dLVP/dt), and the integral of the LVP curve per beat
      (LVParea)] were plotted as a function of [Ca2+]i. Hypothermia increased systolic
      [Ca2+]i and slightly changed systolic LVP but increased diastolic LVP and
      [Ca2+]i. The relationship of diastolic and noncytosolic [Ca2+] to [CaCl2]e was
      shifted upward at 17 degrees C and 27 degrees C, whereas that of phasic [Ca2+])
      to [CaCl2]e was shifted upward at 17 degrees C but not at 27 degrees C. The
      relationships of phasic [Ca2+]i to developed LVP, +dLVP/dt, and LVP(area) were
      progressively reduced by hypothermia so that maximal Ca2+-activated LVP decreased
      and hearts were desensitized to Ca2+. Thus mild hypothermia modestly increases
      diastolic and noncytosolic Ca2+ with little effect on systolic Ca2+ or released
      (area) Ca2+, whereas moderate hypothermia markedly increases diastolic,
      noncytosolic, peak systolic, and released Ca2+ and results in reduced maximal
      Ca2+-activated LVP and myocardial sensitivity to systolic Ca2+.

PMID- 10600853
TI  - Functional, biochemical, and molecular investigations of renal kallikrein-kinin
      system in diabetic rats.
AB  - A reduction of renal kallikrein has been found in non-insulin-treated diabetic
      individuals, suggesting that an impaired renal kallikrein-kinin system (KKS)
      contributes to the development of diabetic nephropathy. We analyzed relevant
      components of the renal KKS in non-insulin-treated streptozotocin (STZ)-induced
      diabetic rats. Twelve weeks after a single injection of STZ, rats were
      normotensive and displayed hyperglycemia, polyuria, proteinuria, and reduced
      glomerular filtration rate. Blood bradykinin (BK) levels and prekallikrein
      activity were significantly increased compared with controls. Renal kallikrein
      activity was reduced by 70%, whereas urinary BK levels were increased up to
      threefold. Renal kininases were decreased as indicated by a 3-fold reduction in
      renal angiotensin-converting enzyme activity and a 1.8-fold reduction in renal
      expression of neutral endopeptidase 24.11. Renal cortical expression of kininogen
      and B2 receptors was enhanced to 1.4 and 1. 8-fold, respectively. Our data
      suggest that increased urinary BK levels found in severely hyperglycemic STZ
      diabetic rats are related to increased filtration of components of the plasma KKS
      and/or renal kininogen synthesis in combination with decreased renal kinin
      degrading activity. Thus, despite reduced renal kallikrein synthesis, renal KKS
      is activated in the advanced stage of diabetic nephropathy.

PMID- 10600854
TI  - Estrogen improves acetylcholine-induced but not metabolic vasodilation in
      biological males.
AB  - We have previously shown that chronic estrogen therapy improves endothelium
      dependent vasodilation in the resistance vessels of biological males. Whether
      this is nitric oxide (NO) mediated and whether estrogen improves metabolic
      vasodilation is unknown. Resting forearm blood flow (FBF), ACh-induced
      vasodilation, and functional hyperemic blood flow (exercise) were assessed before
      and after the inhibition of NO with N(G)-monomethyl-L-arginine (L-NMMA) in 15
      male-to-female transsexuals prescribed estrogen and in 14 age-matched males.
      Resting FBF was similar in the two groups and was similarly (P = 0.44) but
      significantly reduced by 48% after infusion of L-NMMA (P < 0.0001). The ACh dose
      response relationship was shifted upward and to the left in the transsexual
      compared with the male group (P < 0.01). After the inhibition of NO, however, the
      difference in the ACh dose-response curve between the two groups was abolished (P
      = 0.15). Peak functional hyperemic blood flow was similar for the two groups (P =
      0.94). L-NMMA produced a significant (P < 0.01) but similar (P = 0.64) reduction
      in peak hyperemia in the two groups. The volume of blood repaid to the forearm 1
      and 5 min after exercise was also reduced by L-NMMA (P < 0.0001); however, there
      were no differences between the two groups. This suggests that ACh-mediated NO
      dependent vasodilation may be more sensitive to the effects of chronic estrogen
      than exercise-induced vasodilation. Long-term estrogen does not appear to improve
      exercise-induced metabolic vasodilation in biological males, despite the fact
      that NO contributes to this process.

PMID- 10600855
TI  - Cardiopulmonary baroreceptor control of muscle sympathetic nerve activity in heat
      stressed humans.
AB  - Whole body heating decreases central venous pressure (CVP) while increasing
      muscle sympathetic nerve activity (MSNA). In normothermia, similar decreases in
      CVP elevate MSNA, presumably via cardiopulmonary baroreceptor unloading. The
      purpose of this project was to identify whether increases in MSNA during whole
      body heating could be attributed to cardiopulmonary baroreceptor unloading
      coincident with the thermal challenge. Seven subjects were exposed to whole body
      heating while sublingual temperature, skin blood flow, heart rate, arterial blood
      pressure, and MSNA were monitored. During the heat stress, 15 ml/kg warmed saline
      was infused intravenously over 7-10 min to increase CVP and load the
      cardiopulmonary baroreceptors. We reported previously that this amount of saline
      was sufficient to return CVP to pre-heat stress levels. Whole body heating
      increased MSNA from 25 +/- 3 to 39 +/- 3 bursts/min (P < 0. 05). Central blood
      volume expansion via rapid saline infusion did not significantly decrease MSNA
      (44 +/- 4 bursts/min, P > 0.05 relative to heat stress period) and did not alter
      mean arterial blood pressure (MAP) or pulse pressure. To identify whether
      arterial baroreceptor loading decreases MSNA during heat stress, in a separate
      protocol MAP was elevated via steady-state infusion of phenylephrine during whole
      body heating. Increasing MAP from 82 +/- 3 to 93 +/- 4 mmHg (P < 0.05) caused
      MSNA to decrease from 36 +/- 3 to 15 +/- 4 bursts/min (P < 0.05). These data
      suggest that cardiopulmonary baroreceptor unloading during passive heating is not
      the primary mechanism resulting in elevations in MSNA. Moreover, arterial
      baroreceptors remain capable of modulating MSNA during heat stress.

PMID- 10600856
TI  - Intramyocardial vascular volume distribution studied by synchrotron radiation
      excited X-ray fluorescence.
AB  - We evaluated the vascular volume distribution with fine resolution (0.1-1.3 mg
      myocardial tissue) in the sagittal plane of the left ventricle by using the
      microsphere filling method in 21 dogs. The coronary arterial volume density in
      the sagittal plane did not exhibit normal distribution and was characterized by
      variability among the outer-to-inner layers and within the layers (+2SD/-2SD > 80
      times), and the median values in the layers ranged from 4.7 to 22. 9 nl/mg
      myocardial tissue. The fractal analysis of vascular volume revealed a self
      similar nature with a fractal dimension (D value) similar to that of flow
      distribution (1.20 +/- 0.05 and 1.24 +/- 0. 09 for vascular volume and flow
      distribution, respectively) and had a more marked variability than the flow. The
      correlation of the regional vascular volume between adjacent regions decreased as
      the distance increased. However, the correlation coefficients in the endocardial
      to-epicardial direction were significantly higher than those in the anterior-to
      posterior direction (P < 0.05 by paired t-test). In conclusion, we determined
      intramyocardial vascular volume density in the sagittal plane, and the
      distribution revealed considerable variability, self-similarity, and asymmetry in
      the correlation among the adjacent regions. These observations could be related
      to the characteristics of the intramural coronary vascular network.

PMID- 10600857
TI  - Role of capillaries in determining CBF reserve: new insights using myocardial
      contrast echocardiography.
AB  - To define the role of capillaries in the control of coronary blood flow (CBF)
      reserve, we developed a model of the coronary circulation and evaluated
      experimental data in its context. Our model comprised three compartments
      connected in series (arterial, capillary, and venous), each with its own
      resistance. The resistance in each vascular compartment was derived from the
      model based on hemodynamic data obtained in nine dogs during baseline and
      stenosis, both at rest and during hyperemia. The capillary hydrostatic pressure
      was assumed to be constant in all stages. Although in the absence of stenosis,
      the contribution of capillaries to total myocardial vascular resistance was only
      25 +/- 5% at rest, it increased to 75 +/- 14% during hyperemia, despite the total
      myocardial vascular resistance decreasing by 51 +/- 13%. In the presence of a
      noncritical stenosis, total myocardial vascular resistance decreased by 22 +/-
      10% at rest, with no change in capillary resistance. During hyperemia, total
      myocardial vascular resistance increased by 58 +/- 50% in the presence of the
      noncritical stenosis. In this situation, because arteriolar and venular
      resistances were already minimal, the increase in myocardial vascular resistance
      was due to increased capillary resistance, making it the predominant source (84
      +/- 8%) of total myocardial vascular resistance. Myocardial video intensity (VI)
      on myocardial contrast echocardiography (MCE), which reflects capillary blood
      volume, decreased distal to the stenosis during hyperemia. In the presence of a
      flow-limiting stenosis at rest, myocardial VI also decreased, indicating that
      decrease in CBF was associated with an increase in capillary resistance. Our
      findings also provide an alternative explanation for the critical coronary
      closing pressure. Thus, contrary to previously held notions, capillaries play a
      vital role in the regulation of CBF.

PMID- 10600858
TI  - Preconditioning reduces tissue complement gene expression in the rabbit isolated
      heart.
AB  - Both preconditioning and inhibition of complement activation have been shown to
      ameliorate myocardial ischemia-reperfusion injury. The recent demonstration that
      myocardial tissue expresses complement components led us to investigate whether
      preconditioning affects complement expression in the isolated heart. Hearts from
      New Zealand White rabbits were exposed to either two rounds of 5 min global
      ischemia followed by 10 min reperfusion (ischemic preconditioning) or 10 microM
      of the ATP-dependent K+ (KATP) channel opener pinacidil for 30 min (chemical
      preconditioning) before induction of 30 min global ischemia followed by 60 min of
      reperfusion. Both ischemic and chemical preconditioning significantly (P < 0.05)
      reduced myocardial C1q, C1r, C3, C8, and C9 mRNA levels. Western blot and
      immunohistochemistry demonstrated a similar reduction in C3 and membrane attack
      complex protein expression. The K(ATP) channel blocker glyburide (10 microM)
      reversed the depression of C1q, C1r, C3, C8, and C9 mRNA expression observed in
      the pinacidil-treated hearts. The results suggest that reduction of local tissue
      complement production may be one means by which preconditioning protects the
      ischemic myocardium.

PMID- 10600859
TI  - Comparison of SERCA1 and SERCA2a expressed in COS-1 cells and cardiac myocytes.
AB  - Cultured COS-1 cells, as well as chicken embryonic and neonatal rat cardiac
      myocytes, were infected with recombinant adenovirus vectors to define limiting
      factors in the expression and Ca2+ transport function of recombinant sarcoplasmic
      endoplasmic reticulum Ca(2+) (SERCA) isoforms. Titration experiments showed that
      all COS-1 cells and myocytes in culture could be infected by an adenovirus titer
      of 10 plaque-forming units (pfu) per seeded cell. Raising the adenovirus titer
      further yielded higher protein expression up to an asymptotic limit for
      functional, membrane-bound SERCA protein. The asymptotic behavior of SERCA
      expression was not transcription related but was due to posttranscriptional
      events. The minimal (-268) cardiac troponin T (cTnT) promoter was a convenient
      size for adenovirus vector construction and manifested tight muscle specificity.
      However, its efficiency was lower than that of the nonspecific cytomegalovirus
      (CMV) promoter. At any rate, identical maximal levels of SERCA expression were
      obtained with the CMV and the cTnT promoter, as long as the viral titer was
      adjusted to compensate for transcription efficiency. A maximal threefold increase
      of total SERCA protein expression over the level of the endogenous SERCA of
      control myocytes was reached (a sevenfold increase compared with the endogenous
      SERCA of the same infected myocytes due to reduction of endogenous SERCA after
      infection). In contrast with previous reports [Ji et al. Am. J. Physiol. 276
      (Heart Circ. Physiol. 45): H89-H97, 1999], a higher kinetic turnover was
      demonstrated for the SERCA1 compared with the SERCA2a isoform as shown by a 5.0-
      versus 2.6-fold increase in calcium uptake rate accompanying maximal expression
      of recombinant SERCA1 or SERCA2a, respectively. This information is deemed
      necessary for studies attempting to modify myocardial cell function by
      manipulation of SERCA expression.

PMID- 10600860
TI  - Intravenous angiotensinogen antisense in AAV-based vector decreases hypertension.
AB  - Angiotensinogen (AGT) has been linked to hypertension. Because there are no
      direct inhibitors of AGT, we have developed antisense (AS) inhibition of AGT mRNA
      delivered in an adeno-associated virus (AAV)-based plasmid vector. This plasmid,
      driven by the cytomegalovirus promoter, contains a green fluorescent protein
      reporter gene and AS cDNA for rat AGT. Transfection of the plasmid into rat
      hepatoma cells brought a strong expression of the transgenes and a significant
      reduction in the level of AGT. In the in vivo study, naked plasmid DNA was
      intravenously injected into adult spontaneously hypertensive rats at different
      doses (0.6, 1.5, and 3 mg/kg). Expression of AGT AS mRNA was present in liver and
      heart, and it lasted longer in the liver. All three doses produced a significant
      decrease in blood pressure (BP). BP decreased for 2, 4, and 6 days, respectively.
      The lowest dose decreased BP by 12 +/- 3.0 mmHg, whereas the higher doses
      decreased BP by up to 22.5 +/- 5.2 mmHg compared with the control rats injected
      with saline (P < 0.01). The injection of the plasmid with liposomes produced a
      more profound and longer reduction (8 days) in BP. Consistent changes in plasma
      AGT level were observed. Sense plasmid had no effect. No liver toxicity was
      observed after injection of AS plasmid with or without liposomes. Our results
      suggest that the systemic delivery of AS against AGT mRNA by AAV-based plasmid
      vector, especially with liposomes, may have potential for gene therapy of
      hypertension and that further studies with the plasmid packaged into a
      recombinant AAV vector for a longer-lasting AS effect are warranted.

PMID- 10600861
TI  - A force transducer for measuring mechanical properties of single cardiac
      myocytes.
AB  - We have described a transducer design capable of recording forces generated by
      single cardiac myocytes with sufficient temporal resolution to detect force
      responses to rapid length changes. Our force sensors were made from thin steel
      foils that act as cantilevers whose bending is monitored by reflection off a
      laser beam. Deflection of the laser beam is measured by a differential photodiode
      detector. A small, 50-micron-thick tungsten needle attached to the free end of
      the steel foil allowed us to glue single cardiac cells to the force transducer.
      The transducers have compliances of approximately 0.02 m/N and resonance
      frequencies between 2 and 3 kHz. The resolution is approximately 18 nN rms at a
      detector bandwidth of 16 kHz, so we were able to resolve 0.2% of the maximum
      isometric force ( approximately 12 microN) developed by a single cardiac myocyte.
      We have demonstrated that the transducer is well suited to analysis of mechanical
      properties of single ventricular myocytes, for example, the recording of
      isometric forces and rate constants of force redevelopment after rapid release
      restretch maneuvers.

PMID- 10600862
TI  - Novel method to estimate ventricular contractility using intraventricular pulse
      wave velocity.
AB  - We developed a novel technique for estimating ventricular contractility using
      intraventricular pulse wave velocity (PWV). In eight isolated, cross-circulated
      canine hearts, we used a fast servo pump to inject a volume pulse into the base
      of the left ventricular chamber at late diastole and at late systole. We measured
      the transit time of the volume pulse wave as it traversed the distance from base
      to apex and calculated the intraventricular PWV. The intraventricular PWV
      increased from diastole (2.3 +/- 0.4 m/s) to systole (11.7 +/- 2.4 m/s, P <
      0.0001 vs. diastole). The square of the intraventricular PWV at late systole
      correlated linearly with the left ventricular end-systolic elastance (r = 0.939,
      P < 0.0001) and with the end-systolic Young's modulus (r = 0.901, P < 0.0001).
      Moreover, the intraventricular PWV was insensitive to preload. We conclude that
      the intraventricular PWV at late systole reflects left ventricular end-systolic
      elastance reasonably well. The fact that estimation of PWV does not require
      volume measurement or load manipulation makes this technique an attractive means
      of assessing ventricular contractility.

PMID- 10600863
TI  - Prologue: ischemic preconditioning in cardiac vascular muscle.

PMID- 10600864
TI  - Glycolipid RC-552 induces delayed preconditioning-like effect via iNOS-dependent
      pathway in mice.
AB  - We recently demonstrated that monophosphoryl lipid A (MLA)-induced delayed
      cardioprotection is mediated by inducible nitric oxide synthase (iNOS) in mice.
      In the present study, we determined whether RC-552, a novel synthetic glycolipid
      related in chemical structure to MLA, could afford similar protection. Adult mice
      were pretreated with vehicle or RC-552 (350 microg/kg ip, n = 7 mice/group) 24 h
      before global ischemia and reperfusion in a Langendorff isolated, perfused heart
      model. A group of RC-552-treated mice received S-methylisothiourea (SMT), a
      selective inhibitor of iNOS (3 mg/kg ip), 30 min before heart perfusion.
      Myocardial infarct size was significantly reduced from 19.2 +/- 2.0% in vehicle
      to 8.2 +/- 2.9% in RC-552 group (P < 0.05). Treatment with SMT abolished RC-552
      induced reduction in infarct size (20.0 +/- 3.9%). In addition, RC-552 failed to
      reduce infarct size in isolated hearts from iNOS knockout mice (27.1 +/- 2.8%)
      compared with that in hearts from control knockout mice without drug treatment
      (22.9 +/- 5.4%). Acute buffer perfusion with RC-552 (0.1, 1.0, or 2.5 microg/ml)
      for 8 min immediately before ischemia-reperfusion did not reduce infarct size
      significantly. We concluded that RC-552 induces delayed cardioprotection via an
      iNOS-dependent pathway.

PMID- 10600865
TI  - Opening of mitochondrial KATP channel induces early and delayed cardioprotective
      effect: role of nitric oxide.
AB  - Opening of mitochondrial ATP-sensitive (mitoKATP) channel with diazoxide induces
      an early phase (EP) of cardioprotection. It is unknown whether diazoxide also
      induces a delayed phase (DP) of cardioprotection. Because nitric oxide (NO)
      modulates ATP sensitivity of the KATP channel, we hypothesized that NO may play a
      role in diazoxide-induced cardioprotection. Diazoxide (1 mg/kg) was administered
      either 30 min (for EP) or 24 h (DP) before 30 min of lethal ischemia. Blockers of
      mitoK(ATP) channel [5-hydroxydecanoate (5-HD)] or NO synthase [N(G)-nitro-L
      arginine methyl ester (L-NAME)] were given 10 min before ischemia-reperfusion
      performed by 30 min of left anterior descending coronary artery occlusion and 3 h
      of reperfusion. A risk area (RA) was demarcated by Evans blue dye, and infarct
      size (IS) was measured by tetrazolium staining. Diazoxide caused a decrease in IS
      (%RA) from 27.8 +/- 4.2% in the vehicle group to 12.9 +/- 1.2% during EP and from
      30.4 +/- 4. 2% in vehicle-treated rabbits to 19.6 +/- 2.4% during DP (P < 0.05).
      IS increased to 31.3 +/- 1.1% and 27.9 +/- 1.0% (EP) and 29.9 +/- 2. 3% and 35.1
      +/- 1.8% (DP) with 5-HD and L-NAME, respectively (P < 0. 05). 5-HD and L-NAME
      caused no proischemic effect in controls. Diazoxide induced both early and
      delayed anti-ischemic effects via opening of mitoK(ATP) channels, which was NO
      dependent.

PMID- 10600866
TI  - S-T segment voltage during sequential coronary occlusions is an unreliable marker
      of preconditioning.
AB  - During coronary angioplasty, a stair-step decrease in peak S-T segment elevation
      from the first to the second coronary occlusion has been assumed to indicate a
      preconditioning (PC) effect. This association was evaluated with myocardial
      electrograms in rabbits, which revealed that two sequential 5-min coronary
      occlusions resulted in a marked decrease in the area under the S-T segment
      voltage-time curve (P < 0.05) with no change during a third occlusion.
      Pretreatment with either 5-hydroxydecanoate, a mitochondrial ATP-sensitive
      potassium (K(ATP)) channel blocker, or anisomycin, an activator of stress
      activated protein kinases, had no effect on the stair-step decline in the S-T
      segment voltage between the first two occlusions. HMR-1883, a potent closer of
      sarcolemmal K(ATP) channels, abolished changes in S-T segment elevation after
      brief coronary occlusions but had no effect on the infarct-sparing property of
      the two preconditioning 5-min occlusions. Interestingly, HMR-1883 blocked
      myocardial protection from diazoxide, raising doubt that the latter opens only
      mitochondrial channels. Therefore, myocardial protection and S-T segment changes
      during ischemia are dissociated. These data suggest that it is the mitochondrial
      K(ATP) channel that protects the myocardium, and it is the sarcolemmal channel
      that is responsible for changes in S-T elevation. Therefore, it cannot always be
      inferred that changes in S-T segment elevation reflect the state of myocardial
      protection.

PMID- 10600867
TI  - Met5-enkephalin protects isolated adult rabbit cardiomyocytes via delta-opioid
      receptors.
AB  - In rats and rabbits, endogenous opioid peptides participate in ischemic
      preconditioning. However, it is not known which endogenous opioid(s) can trigger
      cardioprotection. We examined preconditioning-induced and opioid-induced
      limitation of cell death in isolated, calcium-tolerant, adult rabbit
      cardiomyocytes. Cells were subjected to simulated ischemia by pelleting and
      normothermic hypoxic incubation. Preconditioning was elicited with 15 min of
      simulated ischemia followed by 15 min of resuspension and reoxygenation. All
      cells underwent 180 min of simulated ischemia. Cell death was assessed by trypan
      blue permeability. Morphine protected cells, as did preconditioning; naloxone
      blocked the preconditioning-induced protection. Exogenous Met5-enkephalin (ME)
      induced protection, but exogenous beta-endorphin did not. ME-induced protection
      was blocked by the delta-selective antagonist naltrindole. Additionally, two
      other proenkephalin products, Leu5-enkephalin and Met5-enkephalin-Arg-Phe,
      provided protection equipotent to ME. These data suggest that one or more
      proenkephalin products interact with delta-opioid receptors to endogenously
      trigger opioid-mediated protection.

PMID- 10600868
TI  - Rabbit heart can be "preconditioned" via transfer of coronary effluent.
AB  - Brief myocardial ischemia not only evokes a local cardioprotective or
      "preconditioning" effect but also can render remote myocardium resistant to
      sustained ischemia. We propose the following hypotheses: remote protection is
      initiated by a humoral trigger; brief ischemia-reperfusion will result in release
      of the humoral trigger (possibly adenosine and/or norepinephrine) into the
      coronary effluent; and transfer of this effluent to a virgin acceptor heart will
      elicit cardioprotection. To test these concepts, effluent was collected during
      normal perfusion from donor-control hearts and during preconditioning ischemia
      reperfusion from donor-preconditioned (PC) hearts. After reoxygenation occurred
      and aliquots for measurement of adenosine and norepinephrine content were
      harvested, effluent was transfused to acceptor-control and acceptor-PC hearts.
      All hearts then underwent 40 min of global ischemia and 60 min of reperfusion,
      and infarct size was delineated by tetrazolium staining. Mean infarct size was
      smaller in both donor- and acceptor-PC groups (9% of left ventricle) than in
      donor- and acceptor-control groups (36% and 34%; P < 0.01). Protection in
      acceptor-PC hearts could not, however, be attributed to adenosine or
      norepinephrine. Thus preconditioning-induced cardioprotection can be transferred
      between rabbit hearts by transfusion of coronary effluent. Although adenosine and
      norepinephrine are apparently not responsible, these results suggest that remote
      protection is initiated by a humoral mechanism.

PMID- 10600869
TI  - Pharmacological manipulation of Ins(1,4,5)P3 signaling mimics preconditioning in
      rabbit heart.
AB  - Recent evidence revealed biphasic alterations in myocardial concentrations of the
      second messenger inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] with ischemic
      preconditioning (PC), i.e., increase during brief PC ischemia and decrease early
      during sustained test occlusion. Our aim was to determine whether an agonist and
      an antagonist of Ins(1,4,5)P(3) signaling (D-myo-inositol-1,4,5-trisphosphate
      hexasodium salt [D-myo-Ins(1,4, 5)P3] and 2-aminoethoxydiphenyl borate (2-APB),
      respectively), given such that they mimic this biphasic profile, would mimic
      infarct size reduction with PC. To test this concept, isolated, buffer-perfused
      rabbit hearts received no intervention (control), ischemic PC, D-myo
      Ins(1,4,5)P3, D-myo-Ins(1,4,5)P(3) + PC, 2-APB, or 2-APB + PC. All hearts then
      underwent 30-min coronary occlusion and 2 h reflow, and infarct size was
      delineated by tetrazolium staining. In addition, the effects of D-myo
      Ins(1,4,5)P3 and 2-APB on Ins(1,4,5)P3 signaling were evaluated in isolated fura
      2-loaded rat cardiomyocytes. Mean infarct size was reduced with PC and in all D
      myo-Ins(1,4,5)P3- and 2-APB-treated groups versus control (59 and 42-55%,
      respectively, vs. 80% of myocardium at risk, P < 0.05). Thus pharmacological
      manipulation of Ins(1,4,5)P3 signaling mimics the cardioprotection achieved with
      ischemic PC in rabbit heart.

PMID- 10600870
TI  - Endotoxin and ischemic preconditioning: TNF-alpha concentration and myocardial
      infarct development in rabbits.
AB  - Ischemic preconditioning (IP) and prior exposure to lipopolysaccharides (LPS)
      reduce infarct size (IS) and serum tumor necrosis factor-alpha (TNF-alpha)
      concentration resulting from myocardial ischemia-reperfusion in rabbits. The
      decrease in TNF-alpha might relate to an induced TNF-alpha inhibitory serum
      activity (TNF-alpha-ISA). We analyzed TNF-alpha and TNF-alpha-ISA during 30 and
      180 min ischemia and reperfusion, respectively, in anesthetized rabbits either
      untreated (group 1, n = 7), preconditioned (5 and 10 min ischemia and
      reperfusion, respectively, group 2, n = 9), or exposed to LPS 72 h before
      ischemia (group 3, n = 9). TNF-alpha-ISA was assessed by coincubating LPS
      stimulated rabbit blood with serum of groups 1-3 and measuring TNF-alpha (WEHI
      assay). With a comparable area at risk, IS in group 1 was 36.9 +/- 11.1 (SD)%,
      and it was reduced to 13.1 +/- 11.6% and 17.3 +/- 11.3% (both P < 0.05) in groups
      2 and 3, respectively. TNF-alpha was increased during ischemia-reperfusion in
      group 1 but remained unchanged in rabbits subjected to IP or LPS. TNF-alpha-ISA
      was detected during ischemia-reperfusion in group 2 (29% and 38% of maximum
      inhibition, respectively) and during baseline, ischemia and reperfusion in group
      3 (51%, 46%, 48% of maximum inhibition, respectively) but was absent in group 1.
      Cardioprotection by IP and LPS is associated with a reduced TNF-alpha and an
      induced TNF-alpha-ISA during ischemia-reperfusion.

PMID- 10600871
TI  - Ischemic preconditioning prevents postischemic P-selectin expression in the rat
      small intestine.
AB  - Ischemic preconditioning (IPC) prevents the deleterious effects of prolonged
      ischemia and reperfusion (I/R). Because leukocyte infiltration is required to
      produce the microvascular dysfunction induced by I/R in the small intestine, and
      P-selectin-dependent leukocyte rolling is a requisite step in this process, we
      hypothesized that IPC would attenuate postischemic P-selectin expression. To
      address this postulate, P-selectin expression was evaluated in nonischemic
      (control) rat jejunum and in rat jejunum subjected to I/R alone (20 min
      ischemia/60 min reperfusion), or IPC (5 min ischemia/10 min reperfusion) + I/R
      using a dual radiolabeled monoclonal antibody approach. I/R was associated with a
      sevenfold increase in jejunal P-selectin expression, an effect that was
      completely abolished by IPC. Exposing the bowel to adenosine deaminase or an
      adenosine A1, but not an A2, receptor antagonist during the period of
      preconditioning ischemia or to selective PKC antagonists during prolonged
      ischemia prevented the beneficial effect of IPC to limit I/R-induced P-selectin
      expression. Our data indicate that P-selectin expression is a novel downstream
      effector target of the adenosine-initiated, PKC-dependent, anti-inflammatory
      signaling pathway in IPC.

PMID- 10600872
TI  - AT1-receptor blockade enhances ischemic preconditioning in hypertrophied rat
      myocardium.
AB  - The purpose of this study was to determine whether ischemic preconditioning
      protects contractile function in hypertrophied rat myocardium from ischemia
      reperfusion (I/R) injury. Male salt-sensitive rats were fed a high-salt diet for
      2 wk to induce myocardial hypertrophy. Nonhypertrophied hearts were obtained from
      age-matched Sprague-Dawley (SD) rats fed a regular diet. Heart weight-to-body
      weight ratios were higher in salt-sensitive rats than in SD rats (6.9 +/- 0.2 vs.
      4.7 +/- 0.2 g/kg, P < 0.01). A second group of salt-sensitive and SD rats was
      administered losartan (10 mg. kg(-1). day(-1)), an AT(1)-receptor blocker, for 1
      wk before the study. Isolated hearts were preconditioned with transient ischemia
      before global I/R. After I/R, preconditioned hypertrophied hearts exhibited
      greater recovery of left ventricular developed pressure compared with that of
      preconditioned normal hearts (73 +/- 8 vs. 18 +/- 8%, P < 0.01). Left ventricular
      developed pressure was further enhanced by losartan in both hypertrophied and
      normal myocardium (99 +/- 5 vs. 73 +/- 8%, P < 0.05 and 97 +/- 15 vs. 18 +/- 8%,
      P < 0.01). Hypertrophied rat myocardium can be protected from I/R-induced
      contractile dysfunction by ischemic preconditioning. Losartan improves the
      ischemic tolerance of normal and hypertrophied myocardium.

PMID- 10600873
TI  - Nitroglycerin induces late preconditioning against myocardial stunning via a PKC
      dependent pathway.
AB  - Previous studies have shown that administration of nitric oxide (NO) donors
      induces a delayed cardioprotective effect indistinguishable from the late phase
      of ischemic preconditioning (PC). However, the ability of clinically relevant NO
      donors to elicit this phenomenon has not been evaluated. In this study we tested
      whether an NO-releasing agent that is nitroglycerin (NTG), which is widely used
      clinically, can mimic the late phase of ischemic PC. Four groups of conscious
      rabbits underwent six cycles of 4-min occlusion (O)/4-min reperfusion (R) for 3
      consecutive days (days 1, 2, and 3). The severity of myocardial stunning was
      assessed as the total deficit of systolic wall thickening (WTh) after the last
      O/R cycle. In the control group (group I, n = 6), the total deficit of WTh was
      reduced by 50% and 51% on days 2 and 3 vs. day 1, respectively, indicating late
      PC against stunning. Pretreatment with NTG (2 microg. kg(-1). min(-1) iv over 1
      h) on day 0 (group II, n = 6) was as effective as ischemic PC in mitigating
      myocardial stunning 24 h later (day 1); on days 2 and 3, no further reduction of
      stunning was seen. Coadministration of the PKC inhibitor chelerythrine (5 mg/kg)
      with NTG (group III, n = 6) completely abrogated the NTG-induced protection.
      Pretreatment with chelerythrine alone (group IV, n = 5) did not alter stunning.
      These results demonstrate that a relatively brief infusion of NTG induces a
      robust protective effect against stunning 24 h later via a protein kinase C (PKC)
      dependent signaling mechanism. The magnitude of NTG-induced protection is
      equivalent to that observed during the late phase of ischemic PC. Late PC induced
      by brief treatment with NTG could be a useful therapeutic strategy for myocardial
      protection in patients with ischemic heart disease.

PMID- 10600874
TI  - Nitric oxide donors attenuate myocardial stunning in conscious rabbits.
AB  - Although previous studies suggested that the protection of late preconditioning
      (PC) against myocardial stunning is mediated by nitric oxide (NO), direct
      evidence that exogenous administration of NO attenuates myocardial stunning is
      lacking. Furthermore, although exogenous NO administration was shown to elicit a
      late PC phase, it is unknown whether NO donors also induce an early PC phase.
      Therefore, conscious rabbits underwent two experimental stages (3 days of six 4
      min occlusion/4-min reperfusion cycles each) 2 wk apart. In study I, both stages
      were control stages (n = 7). In studies II and III, stage I was the control
      stage. On day 1 of stage II, seven rabbits received infusion of nitroglycerin
      (NTG; 2 microg. kg(-1). min(-1) iv) during the ischemia-reperfusion sequence,
      starting 30 min before the 1st occlusion and ending 10 min after the 6th
      reperfusion (study II). Another seven rabbits received infusion of NTG (2 microg.
      kg(-1). min(-1) iv) for 1 h followed by a 30-min washout interval and then
      underwent six 4-min occlusion/4-min reperfusion cycles (study III). In the
      control stage of all three studies, recovery of wall thickening (WTh) after
      occlusion/reperfusion cycles was markedly enhanced on days 2 and 3 compared with
      day 1, indicating late PC. In study II, infusion of NTG during the
      occlusion/reperfusion cycles on day 1 resulted in significant and sustained
      enhancement in WTh recovery. A similar attenuation of stunning was observed in
      study IV in six rabbits given intravenous infusion of S-nitroso-N
      acetylpenicillamine (SNAP) during occlusion/reperfusion cycles. The magnitude of
      the protection afforded by NTG and SNAP was comparable to that afforded by the
      late ischemic PC phase. In contrast, in study III infusion of NTG before
      occlusion/reperfusion cycles did not enhance WTh recovery, indicating that NTG
      failed to induce an early PC effect against stunning. This study demonstrates
      that administration of hemodynamically inactive doses of two unrelated NO donors
      alleviates myocardial stunning in conscious rabbits, providing direct evidence
      for a protective action of NO in this setting.

PMID- 10600875
TI  - Role of reactive oxygen species in acetylcholine-induced preconditioning in
      cardiomyocytes.
AB  - We examined the ability of ACh to mimic ischemic preconditioning in
      cardiomyocytes and the role of ATP-sensitive potassium (KATP) channels and
      mitochondrial reactive oxygen species (ROS) in mediating this effect. Chick
      embryonic ventricular myocytes were studied in a flow-through chamber while flow
      rate, pH, PO2, and PCO2 were controlled. Cell viability was quantified with
      propidium iodide (5 microM), and production of ROS was measured using 2', 7'
      dichlorofluorescin diacetate. Data were expressed as means +/- SE.
      Preconditioning with 10 min of ischemia followed by 10 min of reoxygenation or 10
      min of ACh (1 mM) followed by a drug-free period before 1 h of ischemia and 3 h
      of reoxygenation reduced cell death to the same extent [preconditioning 19 +/- 2%
      (n = 6, P < 0.05) ACh 21 +/- 5% (n = 6, P < 0.05) vs controls 42 +/- 5% (n = 9)].
      Like preconditioning, ACh increased ROS production threefold before ischemia
      [0.60 +/- 0.16 (n = 7, P < 0.05) vs. controls, 0.16 +/- 0. 03 (n = 6); arbitrary
      units]. Protection and increased ROS production during ACh preconditioning were
      abolished with 5-hydroxydecanoate (5-HD, 100 microM), a selective mitochondrial
      K(ATP) channel antagonist, and the thiol reductant 2-mercaptopropionyl glycine (2
      MPG, 1 mM), an antioxidant [cell death: 5-HD+ACh 37 +/- 7% (n = 5), 2-MPG+ACh 47
      +/- 6% (n = 6); ROS signals: 5-HD+ACh 0.09 +/- 0.03 (n = 5), 2-MPG+ACh 0.01 +/-
      0.04 (n = 4)]. In addition, ACh-induced ROS signaling was blocked by the
      mitochondrial site III electron transport inhibitor myxothiazol (0.02 +/- 0.07, n
      = 5). These results demonstrate that activation of mitochondrial K(ATP) channels
      and increased ROS production from mitochondria are important intracellular
      signals that participate in ACh-induced preconditioning in cardiomyocytes.

PMID- 10600876
TI  - Lung glutathione and oxidative stress: implications in cigarette smoke-induced
      airway disease.
AB  - Glutathione (GSH), a ubiquitous tripeptide thiol, is a vital intra- and
      extracellular protective antioxidant in the lungs. The rate-limiting enzyme in
      GSH synthesis is gamma-glutamylcysteine synthetase (gamma-GCS). The promoter (5'
      flanking) region of the human gamma-GCS heavy and light subunits are regulated by
      activator protein-1 and antioxidant response elements. Both GSH and gamma-GCS
      expression are modulated by oxidants, phenolic antioxidants, and inflammatory and
      anti-inflammatory agents in lung cells. gamma-GCS is regulated at both the
      transcriptional and posttranscriptional levels. GSH plays a key role in
      maintaining oxidant-induced lung epithelial cell function and also in the control
      of proinflammatory processes. Alterations in alveolar and lung GSH metabolism are
      widely recognized as a central feature of many inflammatory lung diseases
      including chronic obstructive pulmonary disease (COPD). Cigarette smoking, the
      major factor in the pathogenesis of COPD, increases GSH in the lung epithelial
      lining fluid of chronic smokers, whereas in acute smoking, the levels are
      depleted. These changes in GSH may result from altered gene expression of gamma
      GCS in the lungs. The mechanism of regulation of GSH in the epithelial lining
      fluid in the lungs of smokers and patients with COPD is not known. Knowledge of
      the mechanisms of GSH regulation in the lungs could lead to the development of
      novel therapies based on the pharmacological or genetic manipulation of the
      production of this important antioxidant in lung inflammation and injury. This
      review outlines 1) the regulation of cellular GSH levels and gamma-GCS expression
      under oxidative stress and 2) the evidence for lung oxidant stress and the
      potential role of GSH in the pathogenesis of COPD.

PMID- 10600877
TI  - Superoxide anion impairs Ca(2+) mobilization in cultured human nasal epithelial
      cells.
AB  - We examined the effects of superoxide anion (O(-2)) on the intracellular Ca(2+)
      concentration in cultured human nasal epithelial cells. The cells were exposed to
      O(-2) by pretreatment with xanthine (X) and xanthine oxidase (XO); control cells
      were treated with X alone. When Ca(2+)-containing Krebs solution was reperfused
      in the thapsigargin-treated, store-depleted cells, reapplication-induced
      intracellular Ca(2+) concentration elevation was significantly smaller in X/XO
      treated cells than in the control cells, suggesting that O(-2) impairs Ca(2+)
      release-activated Ca(2+) entry (CRAC). Bath application of ATP induced a steep
      Ca(2+) transient in both control and X/XO-treated cells. However, the
      concentration-response curve of the ATP-induced Ca(2+) transient was shifted to a
      higher concentration in X/XO-treated cells. The impairments of CRAC and ATP
      induced Ca(2+) transient induced by X/XO were reversed by superoxide dismutase.
      Furthermore, all these X/XO-induced effects were also observed in cells
      pretreated with pyrogallol, also an O(-2) donor. These results indicate that O(
      2) impairs at least two mechanisms involved in Ca(2+) mobilization in human nasal
      epithelial cells, i.e., CRAC and ATP-induced Ca(2+) release.

PMID- 10600878
TI  - Fluid absorption related to ion transport in human airway epithelial spheroids.
AB  - Airway epithelium explants from cystic fibrosis (CF) patients and non-CF subjects
      formed monolayered spheres, with the apical ciliated cell membrane facing the
      bath and the basolateral cell membrane pointing toward a fluid-filled lumen. With
      the use of two microelectrodes, transepithelial potential difference and changes
      in potential difference in response to passage of current pulses were recorded,
      and epithelial resistance and the equivalent short-circuit current were
      calculated. Non-CF control potential difference and short-circuit current values
      were significantly lower than the CF values, and amiloride inhibited both values.
      Fluid transport rates were calculated from repeated measurements of spheroid
      diameters. The results showed that 1) non-CF and CF spheroids absorbed fluid at
      identical rates (4.4 microl x cm(-2) x h(-1)), 2) amiloride inhibited fluid
      absorption to a lower residual level in non-CF than in CF spheroids, 3) Cl(-)
      channel inhibitors increased fluid absorption in amiloride-treated non-CF
      spheroids to a level equal to that of amiloride-treated CF spheroids, 4)
      hydrochlorothiazide reduced the amiloride-insensitive fluid absorption in both
      non-CF and CF spheroids, and 5) osmotic water permeabilities were equal in non-CF
      and CF spheroids ( approximately 27 x 10(-7) cm x s(-1) x atm(-1)).

PMID- 10600879
TI  - Surfactant protein C in fetal and ventilated preterm rabbit lungs.
AB  - The developing lung contains surfactant protein (SP) C mRNA levels comparable to
      term values before mature type II cells and alveolar surfactant lipids are
      detectable. Estimates of the amount of mature SP-C in the alveolar lavages of
      preterm lungs are not available. We used an antibody to a recombinant human SP-C
      to measure the amount of SP-C in alveolar lavages of preterm fetal rabbits,
      ventilated preterm rabbits, and term rabbits. The amounts of SP-C were compared
      with the amounts of saturated phosphatidylcholine (Sat PC). Median Sat PC amounts
      increased about 680-fold, and median SP-C values increased by over 5,000-fold in
      alveolar washes from 27 days gestation to term. There was no increase in Sat PC
      or SP-C with ventilation at 27 and 28 days gestation, but ventilation increased
      both Sat PC and SP-C at 29 days gestation. The molar percent of SP-C relative to
      Sat PC also increased with gestational age and with ventilation at 29 days
      gestation. proSP-C was abundant in a membrane fraction from lung tissue at 27 and
      28 days gestation when minimal mature SP-C was detected in alveolar washes. At 29
      days and at term, proSP-C decreased in membrane fractions. The preterm lung that
      is surfactant lipid deficient is also severely deficient in mature SP-C.

PMID- 10600880
TI  - Autocrine production of matrix metalloproteinase-2 is required for human airway
      smooth muscle proliferation.
AB  - Airway smooth muscle proliferation is important in asthma and is dependent on pro
      and antimitogenic factors and cell-matrix interactions. Here we show an
      antiproliferative effect of protease inhibitors on human airway smooth muscle due
      to inhibition of autocrine-derived matrix metalloproteinase (MMP)-2.
      Proliferation in response to fetal bovine serum, thrombin, and platelet-derived
      growth factor was inhibited by the broad-spectrum protease inhibitor Complete and
      the MMP inhibitors EDTA and Ro-31-9790 but not by cysteine or serine protease
      inhibitors. Conditioned medium from airway smooth muscle cells contained 72-kDa
      gelatinase that was secreted by growth-arrested cells and increased by fetal
      bovine serum but not by thrombin or platelet-derived growth factor.
      Immunostaining of cultured human airway smooth muscle cells and normal lung
      biopsies confirmed this gelatinase to be MMP-2. Our results suggest a novel role
      for MMP-2 as an important autocrine factor required for airway smooth muscle
      proliferation. Inhibition of MMPs could provide a target for the prevention of
      smooth muscle hyperplasia and airway remodeling in asthma.

PMID- 10600881
TI  - Quantitative trait locus mapping of airway responsiveness to chromosomes 6 and 7
      in inbred mice.
AB  - Quantitative trait locus (QTL) mapping was used to identify chromosomal regions
      contributing to airway hyperresponsiveness in mice. Airway responsiveness to
      methacholine was measured in A/J and C3H/HeJ parental strains as well as in
      progeny derived from crosses between these strains. QTL mapping of backcross
      [(A/J x C3H/HeJ) x C3H/HeJ] progeny (n = 137-227 informative mice for markers
      tested) revealed two significant linkages to loci on chromosomes 6 and 7. The QTL
      on chromosome 6 confirms the previous report by others of a linkage in this
      region in the same genetic backgrounds; the second QTL, on chromosome 7,
      represents a novel locus. In addition, we obtained suggestive evidence for
      linkage (logarithm of odds ratio = 1.7) on chromosome 17, which lies in the same
      region previously identified in a cross between A/J and C57BL/6J mice. Airway
      responsiveness in a cross between A/J and C3H/HeJ mice is under the control of at
      least two major genetic loci, with evidence for a third locus that has been
      previously implicated in an A/J and C57BL/6J cross; this indicates that multiple
      genetic factors control the expression of this phenotype.

PMID- 10600882
TI  - NADPH and heme redox modulate pulmonary artery relaxation and guanylate cyclase
      activation by NO.
AB  - The hemoprotein oxidant ferricyanide (FeCN) converts the iron of the heme on
      soluble guanylate cyclase (sGC) from Fe(2+) to Fe(3+), which prevents nitric
      oxide (NO) from binding the heme and stimulating sGC activity. This study uses
      FeCN to examine whether modulation of the redox status of the heme on sGC
      influences the relaxation of endothelium-removed bovine pulmonary arteries (BPA)
      to NO. Pretreatment of the homogenate of BPA with 50 microM FeCN resulted in a
      loss of stimulation of sGC activity by the NO donor 10 microM S-nitroso-N
      acetylpenicillamine (SNAP). In the FeCN-treated homogenate reconcentrated to the
      enzyme levels in BPA, 100 microM NADPH restored NO stimulation of sGC, and this
      effect of NADPH was prevented by an inhibitor of flavoprotein electron transport,
      1 microM diphenyliodonium (DPI). In BPA the relaxation to SNAP was not altered by
      FeCN, inhibitors of NADPH generation by the pentose phosphate pathway [250 microM
      6-aminonicotinamide (6-AN) and 100 microM epiandrosterone (Epi)], or 1 microM
      DPI. However, the combination of FeCN with 6-AN, Epi, or DPI inhibited (P < 0.05)
      relaxation to SNAP without significantly altering the relaxation of BPA to
      forskolin. The inhibitory effects of 1 microM 1H-[1,2, 4]oxadiazolo[4,3
      a]quinoxalin-1-one (a probe that appears to convert NO-heme of sGC to its Fe(3+)
      heme form) on relaxation to SNAP were also enhanced by DPI. These observations
      suggest that a flavoprotein containing NADPH oxidoreductase may influence cGMP
      mediated relaxation of BPA to NO by maintaining the heme of sGC in its Fe(2+)
      oxidation state.

PMID- 10600883
TI  - Differential signaling pathways of HO-1 gene expression in pulmonary and systemic
      vascular cells.
AB  - Heme oxygenase-1 (HO-1) is induced by oxidative stress and plays an important
      role in cellular protection against oxidant injury. Increasing evidence also
      suggests that HO-1 is markedly modulated by hypoxia in vitro and in vivo. Our
      group has previously demonstrated that the transcription factor hypoxia-inducible
      factor (HIF)-1 mediates hypoxia-induced HO-1 gene transcription and expression in
      systemic (aortic) vascular smooth muscle (AoVSM) cells (P. J. Lee, B. -H. Jiang,
      B. Y. Chin, N. V. Iyer, J. Alam, G. L. Semenza, and A. M. K. Choi. J. Biol. Chem.
      272: 5375-5381, 1997). Because the pulmonary circulation is an important target
      of hypoxia, this study investigated whether HO-1 gene expression in pulmonary
      arterial vascular smooth muscle was differentially regulated by hypoxia in
      comparison to AoVSM cells. Interestingly, hypoxia neither induced HO-1 gene
      expression nor increased HIF-1 DNA binding activity in pulmonary arterial
      vascular smooth muscle cells. Conversely, pulmonary arterial endothelial cells
      (PAECs) demonstrated a marked induction of HO-1 gene expression after hypoxia.
      Electrophoretic mobility shift assays detected an increase in activator protein-1
      rather than in HIF-1 DNA binding activity in nuclear extracts of hypoxic PAECs.
      Analyses of the promoter and 5'-flanking regions of the HO-1 gene were performed
      by transiently transfecting PAECs with either the hypoxia response element (HIF-1
      binding site) or the HO-1 gene distal enhancer element (AB1) linked to a
      chloramphenicol acetyltransferase reporter gene. Increased chloramphenicol
      acetyltransferase activity was observed only in transfectants containing the AB1
      distal enhancer, and mutational analysis of this enhancer suggested that the
      activator protein-1 regulatory element was critical for hypoxia-induced HO-1 gene
      transcription. Collectively, our data demonstrate that the molecular regulation
      of HO-1 gene transcription during hypoxia differs between the systemic and
      pulmonary circulations and also provide evidence that hypoxia-induced HO-1 gene
      expression in PAECs and AoVSM cells is regulated through two discrete signaling
      pathways.

PMID- 10600884
TI  - Developmental and glucocorticoid regulation of surfactant protein mRNAs in
      preterm lambs.
AB  - Glucocorticoid treatment increases content of surfactant protein (SP) A and SP-B
      in lung tissue and lavage fluid of preterm lambs. To investigate this process, we
      determined the ontogeny and glucocorticoid induction of SP mRNAs. In separate
      treatment protocols, each with its own controls, sheep were injected with
      betamethasone 15 h, 48 h, or weekly for 1-4 doses before preterm delivery. Using
      ovine SP cDNAs, we found an increase equal to or more than threefold in basal
      levels of all three SP mRNAs between 125 days and term. After betamethasone
      treatment, SP-B and SP-C mRNA levels increased by 15 h and all SP mRNAs were
      elevated after 24 h (>/=2-fold); mRNA levels in fetuses delivered 1-3 wk after
      betamethasone were not different from control. We conclude that in vivo
      betamethasone rapidly induces a coordinated increase in SP mRNAs, which is fully
      reversible within 7 days despite repetitive doses of betamethasone. Similar
      increases in mRNA and protein contents for SP-A and SP-B suggest that
      glucocorticoid regulation of these SPs in vivo is primarily pretranslational.

PMID- 10600885
TI  - Smoke extract stimulates lung fibroblasts to release neutrophil and monocyte
      chemotactic activities.
AB  - Accumulation of monocytes and neutrophils and fibrous distortion of the airway
      are characteristics of airway disease secondary to smoking. The presence of
      inflammatory cells and fibrosis correlate, and, therefore, we postulated that
      lung fibroblasts might release chemotactic activity for neutrophils and monocytes
      in response to smoke extract. To test this hypothesis, human fetal lung (HFL1)
      fibroblasts were cultured, and the supernatant fluid was evaluated for neutrophil
      (NCA) and monocyte (MCA) chemotactic activities with a blind well chamber
      technique. HFL1 fibroblasts released chemotactic activity in response to smoke
      extract in a dose- and time-dependent manner (P < 0.05). Checkerboard analysis
      showed that the activity was predominantly chemotactic. Partial characterization
      of the released chemotactic activity revealed that the activity was partly heat
      labile, trypsin sensitive, and ethyl acetate extractable. Lipoxygenase inhibitors
      and cycloheximide inhibited the release of both NCA and MCA. Molecular-sieve
      chromatography revealed that NCA and MCA were heterogeneous. NCA was inhibited by
      anti-human interleukin (IL)-8 and anti-granulocyte colony-stimulating factor
      antibodies and a leukotriene (LT) B(4)-receptor antagonist. Anti-granulocyte
      macrophage colony-stimulating factor (GM-CSF) and anti-monocyte chemoattractant
      protein (MCP)-1 antibodies and an LTB(4)-receptor antagonist inhibited MCA.
      Immunoreactive IL-8, granulocyte colony-stimulating factor, GM-CSF, and MCP-1
      significantly increased in culture supernatant fluid in response to smoke
      extract. Finally, smoke extract augmented the expression of mRNAs of IL-8, GM
      CSF, and MCP-1. These data demonstrate that lung fibroblasts release NCA and MCA
      in response to smoke extract and suggest that lung fibroblasts may modulate the
      inflammatory cell recruitment into the lung.

PMID- 10600886
TI  - Human lung myofibroblast-derived inducers of alveolar epithelial apoptosis
      identified as angiotensin peptides.
AB  - Earlier work from this laboratory found that fibroblasts isolated from fibrotic
      human lung [human interstitial pulmonary fibrosis (HIPF)] secrete a soluble
      inducer(s) of apoptosis in alveolar epithelial cells (AECs) in vitro [B. D. Uhal,
      I. Joshi, A. True, S. Mundle, A. Raza, A. Pardo, and M. Selman. Am. J. Physiol.
      269 (Lung Cell. Mol. Physiol. 13): L819-L828, 1995]. The cultured human
      fibroblast strains most active in producing the apoptotic activity contained high
      numbers of stellate cells expressing alpha-smooth muscle actin, a myofibroblast
      marker. The apoptotic activity eluted from gel-filtration columns only in
      fractions corresponding to proteins. Western blotting of the protein fraction
      identified immunoreactive angiotensinogen (ANGEN), and two-step RT-PCR revealed
      expression of ANGEN by HIPF fibroblasts but not by normal human lung fibroblasts.
      Specific ELISA detected angiotensin II (ANG II) at concentrations sixfold higher
      in HIPF-conditioned medium than in normal fibroblast-conditioned medium.
      Pretreatment of the concentrated medium with purified renin plus purified
      angiotensin-converting enzyme (ACE) further increased the ELISA-detectable ANG II
      eightfold. Apoptosis of AECs in response to HIPF-conditioned medium was
      completely abrogated by the ANG II receptor antagonist saralasin (50 microg/ml)
      or anti-ANG II antibodies. These results identify the protein inducers of AEC
      apoptosis produced by HIPF fibroblasts as ANGEN and its derivative ANG II. They
      also suggest a mechanism for AEC death adjacent to HIPF myofibroblasts [B. D.
      Uhal, I. Joshi, C. Ramos, A. Pardo, and M. Selman. Am. J. Physiol. 275 (Lung
      Cell. Mol. Physiol. 19): L1192-L1199, 1998].

PMID- 10600887
TI  - Regulation of connective tissue growth factor expression by prostaglandin E(2).
AB  - Transforming growth factor-beta (TGF-beta) stimulates alpha(1)(I) collagen mRNA
      synthesis in human lung fibroblasts through a mechanism that is partially
      sensitive to cycloheximide and that may involve synthesis of connective tissue
      growth factor (CTGF). Northern blot analyses indicate that TGF-beta stimulates
      time- and dose-dependent increases in CTGF mRNA. In TGF-beta-stimulated
      fibroblasts, maximal levels of CTGF mRNA (3.7-fold above baseline) occur at 6 h.
      The TGF-beta-stimulated increase in CTGF mRNA was not blocked by cycloheximide.
      Nuclear run-on analysis indicates that TGF-beta increases the CTGF transcription
      rate. The TGF-beta-stimulated increases in CTGF transcription and steady-state
      levels of CTGF mRNA are attenuated in prostaglandin E(2) (PGE(2))-treated
      fibroblasts. PGE(2) fails to attenuate luciferase activity induced by TGF-beta in
      fibroblasts transfected with the TGF-beta-responsive luciferase reporter
      construct p3TP-LUX. In amino acid-deprived fibroblasts, PGE(2) and insulin
      regulate alpha(1)(I) collagen mRNA levels without affecting CTGF mRNA levels. The
      data suggest that the regulation of alpha(1)(I) collagen mRNA levels by TGF-beta
      and PGE(2) may function through both CTGF-dependent and CTGF-independent
      mechanisms.

PMID- 10600888
TI  - Hyperoxia inhibits proliferation of Mv1Lu epithelial cells independent of TGF
      beta signaling.
AB  - High concentrations of O(2) inhibit epithelial cell proliferation that resumes on
      recovery in room air. To determine whether growth arrest is mediated by
      transforming growth factor-beta (TGF-beta), changes in cell proliferation during
      exposure to hyperoxia were assessed in the mink lung epithelial cell line Mv1Lu
      and the clonal variant R1B, which is deficient for the type I TGF-beta receptor.
      Mv1Lu cells treated with TGF-beta accumulated in the G(1) phase of the cell cycle
      as determined by propidium iodide staining, whereas proliferation of R1B cells
      was unaffected by TGF-beta. In contrast, hyperoxia inhibited proliferation of
      both cell lines within 24 h of exposure through an accumulation in the S phase.
      Mv1Lu cells treated with TGF-beta and exposed to hyperoxia accumulated in the
      G(1) phase, suggesting that TGF-beta can inhibit the S phase accumulation
      observed with hyperoxia alone. Cyclin A was detected in cultures exposed to room
      air or growth arrested by hyperoxia while decreasing in cells growth arrested in
      the G(1) phase by TGF-beta. Finally, hyperoxia failed to activate a TGF-beta
      dependent transcriptional reporter in both Mv1Lu and R1B cells. These findings
      reveal that simple growth arrest by hyperoxia involves a defect in S phase
      progression that is independent of TGF-beta signaling.

PMID- 10600889
TI  - SP-B refining of pulmonary surfactant phospholipid films.
AB  - Pulmonary surfactant stabilizes the alveoli by lining the air-fluid interface
      with films that reduce surface tension to near 0 mN/m (gamma(min)). Surfactant
      protein B (SP-B) enhances the surface activity of surfactant phospholipids. A
      captive bubble tensiometer (CBT) was used to study the properties of adsorbed
      films of dipalmitoylphosphatidylcholine (DPPC) with acidic 1-palmitoyl-2-oleoyl
      sn-glycero-3-[phospho-rac-(1-glycerol)] (POPG) or neutral 1-palmitoyl-2-oleoyl-sn
      glycerol-3-phosphocholine with (7:3) and without 1% dimeric SP-B. SP-B enhanced
      the adsorption rate of DPPC-containing neutral or acidic lipid suspensions (1
      mg/ml) to a similar extent. Quasi-static cycling of these films revealed that SP
      B significantly decreased the film area reduction required to reach gamma(min)
      for the acidic but not for the neutral system. The results obtained with DPPC
      phosphatidylglycerol (PG)-SP-B were consistent with selective DPPC adsorption
      into the surface monolayer during film formation. Film area reduction required to
      reach gamma(min) with this system (with and without calcium) approached that of
      pure DPPC, suggesting selective DPPC insertion and PG squeeze-out. Dynamic
      cycling of such films showed that larger film area reductions were required to
      reach gamma(min) for the neutral than for acidic system, even after 20 cycles.
      Fluorescence microscopy of solvent-spread DPPC-POPG-SP-B planar films revealed
      highly condensed structures at approximately 25 mN/m, although no specific PG
      phase-segregated structures could be identified. The study suggests that specific
      interactions of SP-B with acidic phospholipids of surfactant may be involved in
      the generation and maintenance of DPPC-rich films in the alveoli.

PMID- 10600890
TI  - Neutrophils enhance clearance of necrotic epithelial cells in ozone-induced lung
      injury in rhesus monkeys.
AB  - To test the hypothesis that neutrophil influx is important for the removal of
      necrotic airway epithelial cells, rhesus monkeys were treated with a function
      blocking monoclonal antibody (MAb) against CD18 followed by exposure to ozone or
      filtered air. CD18 MAb-treated, ozone-exposed monkeys showed a significant
      inhibition of neutrophil emigration and an accumulation of necrotic airway
      epithelial cells. In a subsequent experiment, monkeys were given CD18 MAb or an
      isotype control immunoglobulin before ozone or filtered-air exposure. Complement
      5a was instilled into lobes of the right lung at the end of the exposure. Lavage
      neutrophils were significantly elevated in the right lobes compared with those in
      the contralateral left lobes; consequently, there were significantly fewer
      necrotic cells in the airways of the right lung, whereas large aggregations of
      necrotic cells were observed in the contralateral airways of the left lung. These
      data indicate that neutrophil influx in ozone-induced injury in primates is CD18
      dependent and that neutrophils contribute to the repair of airway epithelium by
      removal of injured epithelial cells.

PMID- 10600891
TI  - Vascular inflammation inhibits gene transfer to the pulmonary circulation in
      vivo.
AB  - We report gene transfer to the normal and injured murine pulmonary circulation
      via systemic (intravascular) and airway (intratracheal) delivery of novel
      polycationic liposomes (imidazolium chloride, imidazolinium chloride-cholesterol,
      and ethyl phosphocholine). With use of the reporter genes chloramphenicol
      acetyltransferase (CAT) or human placental alkaline phosphatase (hpAP),
      intravascular injection of lipid-DNA complexes resulted in gene expression
      primarily in the lung, with lesser expression in the heart (11% of lung, P <
      0.05) and spleen (8% of lung, P < 0.05). Histochemical staining for the hpAP
      reporter gene showed localized transgene expression in the microvascular
      endothelium. Monocrotaline (80 mg/kg body wt sc) treatment produced endovascular
      inflammation and reduced lung CAT activity (2 days postintravascular
      transfection) by 75 +/- 8 and 86 +/- 6% at 7 and 21 days, respectively, after
      monocrotaline (P < 0. 05). Despite the apparent decrease in functional CAT
      protein, Southern blot analysis suggested maintained plasmid delivery, whereas
      quantitative PCR (TaqMan) showed decreased CAT mRNA levels in monocrotaline mice.
      In contrast, intratracheal delivery of lipid-DNA complexes showed enhanced CAT
      expression in monocrotaline mice. Transfection in alternate pulmonary vascular
      disorders was studied by inducing hypoxic pulmonary hypertension (4 wk at
      barometric pressure of 410 mmHg). Efficiency and duration of gene transfer,
      assessed by CAT activity, were similar in pulmonary hypertensive and normal
      lungs. We conclude that imidazolinium-derived polycationic liposomes provide a
      means of relatively selective and efficient gene transfer to the normal and
      injured murine microvascular circulation, although translation of transgene mRNA
      may be reduced by preexisting endothelial injury.

PMID- 10600892
TI  - TGF-beta3-null mutation does not abrogate fetal lung maturation in vivo by
      glucocorticoids.
AB  - Newborn transforming growth factor (TGF)-beta3-null mutant mice exhibit defects
      of palatogenesis and pulmonary development. Glucocorticoids, which play a central
      role in fetal lung maturation, have been postulated to mediate their stimulatory
      effects on tropoelastin mRNA expression through TGF-beta3 in cultured lung
      fibroblasts. In the present study, we analyzed the abnormally developed lungs in
      TGF-beta3-null mutant mice and compared the effects of glucocorticoids on gene
      expression and lung morphology between TGF-beta3 knockout and wild-type mice.
      Lungs of TGF-beta3-null mutant mice on embryonic day 18.5 did not form normal
      saccular structures and had a thick mesenchyme between terminal air spaces.
      Moreover, the number of surfactant protein C-positive cells was decreased in TGF
      beta3-null mutant lungs. Interestingly, glucocorticoids were able to promote lung
      maturation and increased expression of both tropoelastin and fibronectin but
      decreased the relative number of surfactant protein C-positive cells in fetal
      lungs of both genotypes. This finding provides direct evidence that
      glucocorticoid signaling in the lung can use alternative pathways and can exert
      its effect without the presence of TGF-beta3.

PMID- 10600893
TI  - Resistance of hypotransferrinemic mice to hyperoxia-induced lung injury.
AB  - Oxidative stress plays a central role in the pathogenesis of acute and chronic
      pulmonary diseases. Safe sequestration of iron, which participates in the
      formation of the hydroxyl radical, is crucial in the lung's defense. We used a
      mouse line defective in the major iron transport protein transferrin to
      investigate the effect of aberrant iron metabolism on the lung's defense against
      oxidative injury. The tolerance to hyperoxic lung injury was greater in the
      hypotransferrinemic than in wild-type mice as documented by histopathology and
      biochemical indexes for lung damage. There was no increase in the levels of
      intracellular antioxidants, inflammatory cytokines, and heme oxygenase-1 in the
      hypotransferrinemic mouse lung compared with those in wild-type mice. However,
      there were elevated expressions of ferritin and lactoferrin in the lung of
      hypotransferrinemic mice, especially in the alveolar macrophages. Our results
      suggest that pulmonary lactoferrin and ferritin protect animals against oxidative
      stress, most likely via their capacity to sequester iron, and that alveolar
      macrophages are the key participants in iron detoxification in the lower
      respiratory tract.

PMID- 10600894
TI  - Inhaled NO reaches distal vasculatures to inhibit endothelium- but not leukocyte
      dependent cell adhesion.
AB  - Nitric oxide (NO), in addition to being a potent vasodilator, also prevents
      leukocyte adhesion in the microvasculature. Based on the antiadhesive properties
      of NO and work suggesting that NO is transported by proteins in the circulation,
      we tested the possibility that inhaled NO could impart antiadhesive effects in
      peripheral microvessels. We also determined the underlying mechanisms of actions.
      Three well-established models that induce local microvascular changes (either
      endothelium or leukocyte) were used. Hydrogen peroxide (H(2)O(2); 100 microM) was
      superfused onto the cat mesentery to induce an endothelium-derived, P-selectin-
      and platelet-activating factor-dependent, oxidant-dependent leukocyte
      recruitment. In a second series of experiments, the cat mesentery was superfused
      with histamine (100 microM) to induce rapid endothelium-derived, P-selectin- and
      platelet-activating factor-dependent, oxidant-independent leukocyte recruitment.
      Finally, in a third series of experiments to target the leukocyte (but not the
      endothelium) directly in the periphery, the chemotactic molecule leukotriene B(4)
      (20 nM) was superfused onto the cat mesentery. The above experiments were
      performed with and without cats breathing NO (80 parts/million). Intravital
      microscopy was used to visualize the mesenteric microcirculation. Inhaled NO
      reduced the increased leukocyte rolling and adhesion associated with H(2)O(2)
      superfusion of the feline mesentery via a cGMP-dependent mechanism. In contrast,
      inhaled NO had no effect on the histamine-induced increase in leukocyte rolling
      flux but partially inhibited the subsequent adhesion. The leukocyte chemotactic
      mediator leukotriene B(4) induced a significant increase in leukocyte adhesion,
      but NO inhalation did not impair this chemotactically induced leukocyte
      recruitment. These data suggest that inhaled NO can reach the endothelium in the
      distal microvasculature and alter the response to an oxidative and a nonoxidative
      activator of endothelium but imparts no antiadhesive effect directly on
      circulating leukocytes.

PMID- 10600895
TI  - Alveolar sodium and liquid transport in mice.
AB  - We have developed a simple isolated lung preparation for measurement of liquid
      and solute fluxes across mouse alveolar epithelium. Liquid instilled into air
      spaces was absorbed at the rate (J(w)) of 3.7 +/- 0.32 ml x h(-1) x g dry lung
      wt(-1) x J(w) was significantly depressed by ouabain (P < 0.001) and amiloride (P
      < 0.001). Omission of glucose from the instillate or addition of the Na(+)
      glucose cotransport inhibitor phloridzin did not affect J(w). However, the low
      epithelial lining fluid glucose concentration (one-third that of plasma), the
      larger-than-mannitol permeability of methyl-alpha-D-glucopyranoside, and the
      presence of Na(+)-glucose cotransporter SGLT1 mRNA in mouse lung tissue suggest
      that there is a Na(+)-glucose cotransporter in the mouse alveolar-airway barrier.
      Isoproterenol stimulated J(w) (6.5 +/- 0.45 ml x h(-1) x g dry lung wt(-1); P <
      0.001), and this effect was blocked by amiloride, benzamil, ouabain, and the
      specific beta(2)-adrenergic antagonist ICI-118551 but not by atenolol. Similar
      stimulation was obtained with terbutaline (6.4 +/- 0.46 ml x h(-1) x g dry lung
      wt(-1)). Na(+) unidirectional fluxes out of air spaces varied in agreement with
      J(w) changes. Thus alveolar liquid absorption in mice follows Na(+) transport via
      the amiloride-sensitive pathway, with little contribution from Na(+)-glucose
      cotransport, and is stimulated by beta(2)-adrenergic agonists.

PMID- 10600896
TI  - Exacerbation of bleomycin-induced lung injury in mice by amifostine.
AB  - Bleomycin (BLM) induces lung injury and fibrosis in the murine lung and enhances
      tumor necrosis factor (TNF)-alpha and collagen mRNA expression in the murine
      lung. Amifostine is a cytoprotective agent that protects normal tissues from the
      cytotoxic effects of chemo- and radiation therapy. We investigated the effect of
      amifostine in BLM-induced lung injury in mice. Mice received intraperitoneal
      amifostine (200 mg/kg) 30 min before and/or 1, 3, and 7 days after an
      intratracheal injection of saline or BLM (4 U/kg). The animals were killed 14
      days after BLM exposure, and their lungs were studied for TNF-alpha and collagen
      mRNA expression, hydroxyproline content, and histopathology. Light microscopy
      demonstrated that amifostine exacerbated the BLM-induced lung injury in mice.
      Increased TNF-alpha mRNA expression as a result of BLM exposure was not modulated
      by amifostine treatment. In contrast, amifostine treatment enhanced the BLM
      induced expression of alpha(1)(I) procollagen mRNA in the lung. Similarly, mice
      treated with amifostine before BLM exposure accumulated significantly higher
      amounts of hydroxyproline (111 +/- 5 microg/lung) than BLM-treated animals (90 +/
      6 microg/lung). These data suggest that amifostine treatment exacerbates BLM
      induced lung injury in mice.

PMID- 10600897
TI  - Fas-induced apoptosis of alveolar epithelial cells requires ANG II generation and
      receptor interaction.
AB  - Recent works from this laboratory demonstrated potent inhibition of Fas-induced
      apoptosis in alveolar epithelial cells (AECs) by the angiotensin-converting
      enzyme (ACE) inhibitor captopril [B. D. Uhal, C. Gidea, R. Bargout, A. Bifero, O.
      Ibarra-Sunga, M. Papp, K. Flynn, and G. Filippatos. Am. J. Physiol. 275 (Lung
      Cell. Mol. Physiol. 19): L1013-L1017, 1998] and induction of dose-dependent
      apoptosis in AECs by purified angiotensin (ANG) II [R. Wang, A. Zagariya, O.
      Ibarra-Sunga, C. Gidea, E. Ang, S. Deshmukh, G. Chaudhary, J. Baraboutis, G.
      Filippatos and B. D. Uhal. Am. J. Physiol. 276 (Lung Cell. Mol. Physiol. 20):
      L885-L889, 1999]. These findings led us to hypothesize that the synthesis and
      binding of ANG II to its receptor might be involved in the induction of AEC
      apoptosis by Fas. Apoptosis was induced in the AEC-derived human lung carcinoma
      cell line A549 or in primary AECs isolated from adult rats with receptor
      activating anti-Fas antibodies or purified recombinant Fas ligand, respectively.
      Apoptosis in response to either Fas activator was inhibited in a dose-dependent
      manner by the nonthiol ACE inhibitor lisinopril or the nonselective ANG II
      receptor antagonist saralasin, with maximal inhibitions of 82 and 93% at doses of
      0.5 and 5 microg/ml, respectively. In both cell types, activation of Fas caused a
      significant increase in the abundance of mRNA for angiotensinogen (ANGEN) that
      was unaffected by saralasin. Transfection with antisense oligonucleotides against
      ANGEN mRNA inhibited the subsequent induction of Fas-stimulated apoptosis by 70%
      in A549 cells and 87% in primary AECs (both P < 0.01). Activation of Fas
      increased the concentration of ANG II in the serum-free extracellular medium 3
      fold in primary AECs and 10-fold in A549 cells. Apoptosis in response to either
      Fas activator was completely abrogated by neutralizing antibodies specific for
      ANG II (P < 0.01), but isotype-matched nonimmune immunoglobulins had no
      significant effect. These data indicate that the induction of AEC apoptosis by
      Fas requires a functional renin-angiotensin system in the target cell. They also
      suggest that therapeutic control of AEC apoptosis is feasible through
      pharmacological manipulation of the local renin-angiotensin system.

PMID- 10600898
TI  - Central nervous system regulation of reflex responses to hypotension during fetal
      life.
AB  - The ability of the fetus to survive, grow, and successfully complete the
      transition from fetal to neonatal life is critically dependent on the appropriate
      regulation of fetal blood pressure, blood volume, and fluid dynamics. This is a
      short review of the physiological mechanisms controlling the fetal cardiovascular
      system, focusing mainly on the neural and endocrine elements in the schema of
      cardiovascular function and control. The fetal cardiovascular system is arranged
      anatomically to provide for perfusion of the umbilical-placental circulation, the
      organ of gas exchange of the fetus, and to largely bypass the lungs. Fetal blood
      volume and pressure, maintained at levels that are appropriate for this function,
      are influenced by neural and endocrine control mechanisms, which are similar to,
      but quantitatively different from, the adult animal. Baroreceptors and
      chemoreceptors located in the carotid sinuses and aortic arch sense changes in
      blood pressure and blood gases and comprise the afferent limb of the major
      reflexes that maintain normal fetal blood pressure and volume. Fetal hypotension
      stimulates reflex decreases in fetal heart rate, which are apparently mediated by
      chemoreceptor input. Arginine vasopressin responses to hypotension are most
      likely mediated by baroreceptor input. Recent evidence suggests that the reflex
      responses to hypotension in the fetus are modulated by paracrine or endocrine
      factors. For example, baroreceptor or chemoreceptor reflex pathways are modulated
      by the endogenous production of prostanoids and by the preparturient changes in
      fetal plasma estrogen concentration.

PMID- 10600899
TI  - Rainbow trout (Oncorhynchus mykiss) possess two somatostatin mRNAs that are
      differentially expressed.
AB  - Previously, we isolated a 624-bp cDNA encoding for a 115-amino acid
      preprosomatostatin containing [Tyr7,Gly10]-somatostatin (SS)-14 (now designated
      PPSS-II') obtained from the endocrine pancreas (Brockmann bodies) of rainbow
      trout. In this study we have characterized a second cDNA obtained from trout
      pancreas that is 600-bp in length and encodes for a 111-amino acid precursor
      containing [Tyr7,Gly10]-SS-14 (PPSS-II''). The nucleotide and amino acid identity
      between the two cDNAs is 82.3 and 80.5%, respectively. Both PPSS-II' and PPSS
      II'' mRNA were present in esophagus, pyloric ceca, stomach, upper and lower
      intestine, and pancreas, whereas only SS-II" mRNA was present in brain. PPSS-II''
      mRNA was more abundant than PPSS-II' mRNA in pancreas, whereas PPSS-II' mRNA was
      more abundant than PPSS-II" mRNA in stomach. Fasting increased pancreatic PPSS
      II'' mRNA levels but had no effect on the levels of PPSS-II' mRNA. These results
      indicate the existence of two nonallelic pancreatic SS-II genes that are
      differentially expressed, both in terms of distribution among tissues and in
      terms of relative abundance within the tissues.

PMID- 10600900
TI  - The mudskipper, Periophthalmodon schlosseri, actively transports NH4+ against a
      concentration gradient.
AB  - Periophthalmodon schlosseri can maintain ammonia excretion rates and low levels
      of ammonia in its tissues when exposed to 8 and 30 mM NH4Cl, but tissue ammonia
      levels rise when the fish is exposed to 100 mM NH4Cl in 50% seawater. Because the
      transepithelial potential is not high enough to maintain the NH4+ concentration
      gradient between blood and water, ammonia excretion under such a condition would
      appear to be active. Branchial Na+-K+-ATPase activity is very high and can be
      activated by physiological levels of NH4+ instead of K+. Ammonia excretion by the
      fish against a concentration gradient is inhibited by the addition of ouabain and
      amiloride to the external medium. It is concluded that Na+-K+-ATPase and an
      Na+/H+ exchanger may be involved in the active excretion of ammonia across the
      gills. This unique ability of P. schlosseri to actively excrete ammonia is
      related to the special structure of its gills and allows the fish to continue to
      excrete ammonia while air exposed or in its burrow.

PMID- 10600901
TI  - Effect of endogenous kinins, prostanoids, and NO on kinin B1 and B2 receptor
      expression in the rabbit.
AB  - To determine whether kinin receptor expression is regulated by kinins,
      prostaglandins, and/or nitric oxide (NO), rabbits were treated with a B(1)
      receptor (B(1)R) antagonist, a B2 receptor (B2R) antagonist, a prostacyclin
      mimetic, or inhibitors of NO synthase, cyclooxygenase, or angiotensin-converting
      enzyme. The mRNA concentrations for B1R and B2R (multiplex RT-PCR) were measured
      in several organs. The B2R mRNA expression was not significantly upregulated by
      any of the treatments; it was notably downregulated by angiotensin-converting
      enzyme or cyclooxygenase blockade or B2R antagonism in the heart and duodenum. A
      treatment with bacterial lipopolysaccharide (LPS), known to induce B1R
      expression, has also been applied and was the most consistent in upregulating the
      expression of B1R mRNA (kidney, duodenum, and striated muscle). The contractile
      responses mediated by kinin receptors in blood vessels isolated from the treated
      rabbits also indicated that LPS was the only B1R inducer (aorta). Icatibant, a
      nonequilibrium antagonist of the rabbit B2R, was the sole tested drug to alter
      the contractions mediated by the B2R in the jugular vein or the intensity of the
      immunohistochemical B2R staining in several organs (inhibition in both cases).
      B2R mRNA expression was downregulated in some organs by several of the applied
      treatments, but the data did not support generally applicable feedback for the
      regulation of B2R expression involving endogenous kinins, prostanoids, or NO.
      There was no indication of compensatory or reciprocal regulation of B1Rs,
      relative to B2Rs, inasmuch as B1R expression was restricted to LPS-treated
      animals.

PMID- 10600902
TI  - Shivering and digestion-related thermogenesis in pigeons during dark phase.
AB  - The pigeon's main source of regulated heat production, shivering, is especially
      likely to be used for thermoregulation during the dark phase of the day when
      there is little heat from locomotor activity. However, food stored in the
      pigeon's crop is digested during the night, and digestion-related thermogenesis
      (DRT) will provide heat that should decrease the need for shivering to maintain
      body temperature (Tb). We investigated the conditions under which DRT alters the
      occurrence of nocturnal shivering thermogenesis in pigeons. In fasting
      experiments, in which DRT was minimal, variations in pectoral shivering were
      closely related to the kinetics of nocturnal Tb when the ambient temperature (Ta)
      was moderate (21 degrees C). In that case, shivering was low while Tb fell at the
      beginning of the night, moderate during the nocturnal plateau in Tb, and strong
      during the prelight increase in Tb. Similar kinetics of nocturnal Tb occurred
      when Ta = 28 degrees C, but shivering was negligible throughout the dark phase.
      In restricted feeding experiments, nocturnal DRT was varied by providing
      different amounts of food late in the light phase. When Ta = 21 degrees C, 11
      degrees C, and 1 degrees C, nocturnal Tb and O2 consumption were directly related
      to the amount of food ingested. However, nocturnal shivering tended to decrease
      as the food load increased and was significantly reduced at the higher loads.
      Because nocturnal shivering did not become more efficient in producing heat as
      the size of the food load increased, we conclude that nocturnal DRT decreased the
      need for shivering thermogenesis.

PMID- 10600903
TI  - Regulatory features of transcription in isolated mitochondria from Artemia
      franciscana embryos.
AB  - Optimal conditions were developed for an in organello transcriptional run-on
      assay using mitochondria isolated from Artemia franciscana embryos to investigate
      potential regulatory features of RNA synthesis under conditions of anoxia-induced
      quiescence. Transcription is not dependent on oxidative phosphorylation for
      maximal activity when exogenous ATP is available. Bona fide transcription
      products, as assessed by hybridization with specific mitochondrial cDNAs from A.
      franciscana, are produced in an inhibitor-sensitive manner. Transcription rate
      measured at pH 7.9 is reduced 80% when pH is lowered to 6.3, a pH range that
      mimics the in vivo change seen on exposure of embryos to anoxia. The proton
      sensitivity of mitochondrial RNA synthesis may provide a mechanism to depress
      this significant energy expenditure during quiescence. The influence of
      nucleotide concentration on kinetics is complicated by an interdependence among
      nucleotide species. ATP inhibition observed at subsaturating UTP concentrations
      is relieved when UTP is at saturating, physiologically relevant levels. Taken
      together, these data suggest that local (versus nuclear mediated) control is
      important in dictating mitochondrial transcription during rapid modulations in
      gene expression, such as those observed under anoxia-induced quiescence.

PMID- 10600904
TI  - Intermittent bright light and exercise to entrain human circadian rhythms to
      night work.
AB  - Bright light can phase shift human circadian rhythms, and recent studies have
      suggested that exercise can also produce phase shifts in humans. However, few
      studies have examined the phase-shifting effects of intermittent bright light,
      exercise, or the combination. This simulated night work field study included
      eight consecutive night shifts followed by daytime sleep/dark periods (delayed 9
      h from baseline). There were 33 subjects in a 2 x 2 design that compared 1)
      intermittent bright light (6 pulses, 40-min long each, at 5,000 lx) versus dim
      light and 2) intermittent exercise (6 bouts, 15-min long each, at 50-60% of
      maximum heart rate) versus no exercise. Bright light and exercise occurred during
      the first 6 h of the first three night shifts. The circadian phase marker was the
      demasked rectal temperature minimum. Intermittent bright-light groups had
      significantly larger phase delays than dim-light groups, and 94% of subjects who
      received bright light had phase shifts large enough for the temperature minimum
      to reach daytime sleep. Exercise did not affect phase shifts; neither
      facilitating nor inhibiting phase shifts produced by bright light.

PMID- 10600905
TI  - Purification, structural characterization, and myotropic activity of endothelin
      from trout, Oncorhynchus mykiss.
AB  - Endothelin (ET) from a nontetrapod species has never been characterized, either
      structurally or biologically. A single molecular form of trout ET with 21-amino
      acid residues was isolated in pure form from an extract of the kidney of the
      steelhead trout, Oncorhynchus mykiss and its primary structure established as Cys
      Ser-Cys-Ala-Thr-Phe-Leu-Asp-Lys-Glu10-Cys-Val-Tyr-Phe-Cys-His- L eu-Asp-Ile-Ile20
      Trp. This amino acid sequence shows only three substitutions (Ala4-->Ser, Thr5-
      >Ser, and Phe6-->Trp) compared with human ET-2, demonstrating that the structure
      of the peptide has been well conserved during evolution and that the pathway of
      posttranslational processing of preproendothelin in the trout is probably similar
      to that in mammals. Synthetic trout ET produced concentration-dependent
      constrictions of isolated rings of vascular tissue from trout efferent branchial
      artery (EBA; pD2 = 7. 90 +/- 0.06, n = 5), caeliacomesenteric artery (pD2 = 8.03
      +/- 0. 04, n = 4), anterior cardinal vein (ACV; pD2 = 8.57 +/- 0.25, n = 4), and
      rat abdominal aorta (AO; pD2 = 8.86 +/- 0.08, n = 7). Trout and rat vessels were
      more sensitive to mammalian ET-1 than to trout ET (pD(2) for human ET-1 in: EBA =
      9.12 +/- 0.14; ACV = 9.90 +/- 0.15; AO = 8.86 +/- 0.08), but there was no
      significant difference in the maximum tension produced by either peptide in these
      vessels.

PMID- 10600906
TI  - Role of metallothionein against oxidative stress in the mussel Mytilus
      galloprovincialis.
AB  - Metallothionein (MT) is a sulfhydryl-rich protein involved mainly in heavy metal
      homeostasis and detoxification. In this study, the use of the mussel as an
      experimental model allowed us to test MT antioxidant properties at the molecular,
      cellular, and organism level. MT induction was achieved by mussel exposure to Cd
      (200 microg/l) in aquaria for 7 days followed by detoxification in the sea for 28
      days. Cd-preexposed and nonexposed mussels were then treated with Fe (300-600
      microg/l) in aquaria for 3 days. Biochemical assays on digestive gland tissue
      showed that treatment with Fe led to a significant increase in oxyradical
      production and malondialdehyde level only in mussels not preexposed to Cd. The Cd
      dependent resistance to oxidative stress was ascribed to MT induction, as Cd
      produced no significant variation of reduced glutathione and major antioxidant
      enzymes. Digital imaging of isolated digestive gland cells showed lower
      oxyradical rise and higher viability in cells from Cd-preexposed mussels after
      treatments with 0.5-5 mM H2O2. Analyses on whole organisms showed that anoxic
      survival was lowered in mussels that had been treated with Fe, but such an effect
      was less pronounced in Cd-preexposed mussels compared with nonpreexposed ones. In
      conclusion, data suggest an antioxidant role for MT, which seems to occur through
      oxyradical scavenging and is able to protect both isolated cells and the entire
      organism from oxidative stress.

PMID- 10600907
TI  - Thermocyclic entrainment of lizard blood plasma melatonin rhythms in constant and
      cyclic photic environments.
AB  - We assessed how chronic exposure to 6-h cryophase temperatures of 15 degrees C in
      an otherwise 33 degrees C environment entrains the rhythm of blood plasma
      melatonin rhythms in lizards (Tiliqua rugosa) subjected to constant dark (DD),
      constant light (LL), and to 12:12-h light-dark cycles (12L:12D). The peak of the
      melatonin rhythm was entrained by the cryophase temperature of the thermocycle in
      DD and LL, irrespective of the time at which the cryophase temperature was
      applied. Comparable thermocycles of 6 h at 15 degrees C imposed on a 12L:12D
      photocycle, however, affected the amplitude and phase of the melatonin rhythm,
      depending on the phase relationship between light and temperature. Cold pulses in
      the early light period and at midday resulted, respectively, either in low
      amplitude or nonexistent melatonin rhythms, whereas those centered in or around
      the dark phase elicited rhythms of high amplitude. Supplementary experiments in
      12L:12D using two intermittent 6-h 15 degrees C cryophases, one delivered in the
      midscotophase and another in the midphotophase, elicited melatonin rhythms
      comparable to those in lizards subjected to constant 33 degrees C and 12L:12D. In
      contrast, lizards subjected to 12L:12D and a 33 degrees C:15 degrees C
      thermocycle, whose thermophase was aligned with the photophase, produced a
      threefold increase in the amplitude of the melatonin rhythm. Taken together,
      these results support the notion that there is an interaction between the
      external light and temperature cycle and a circadian clock in determining
      melatonin rhythms in Tiliqua rugosa.

PMID- 10600908
TI  - Energetic dependence of NPY-induced LH secretion in a teleost fish (Dicentrarchus
      labrax).
AB  - The purpose of this work was to examine the role of energetic status in
      neuropeptide Y (NPY)-induced luteinizing hormone (LH) secretion and glucose
      metabolism in fish. Fasted juvenile sea bass (Dicentrarchus labrax) were injected
      intraperitoneally with pig (p) NPY or pNPY + glucose, whereas fed animals were
      injected with pNPY alone and plasma glucose, insulin, and LH levels were
      examined. pNPY alone or in combination with glucose was found to induce a dose
      dependent increase in LH secretion in fasted animals. Similar LH responses to
      pNPY were observed in vitro in dispersed pituitary cells isolated from fed and
      fasted animals incubated in L-15 and restricted media. Injection of pNPY +
      glucose in fasted animals resulted in depletion of glucose. Insulin plasma levels
      decreased in fasted animals coinjected with pNPY + glucose but remained stable
      when NPY was administrated alone to fed and fasted animals. Results suggest that
      1) NPY-induced LH secretion in fish is dependent on energetic status and 2) NPY
      is capable of modifying glucose metabolism.

PMID- 10600909
TI  - Relation between complement and the febrile response of guinea pigs to systemic
      endotoxin.
AB  - We reported recently that the complement (C) system may play a role in the
      febrile response of guinea pigs to intravenous lipopolysaccharide (LPS)
      administration because C depletion abolished the LPS-induced rise in core
      temperature (T(c)). The present study was designed to investigate further the
      relation between C reduction [induced by cobra venom factor (CVF); 20, 50, 100,
      and 200 U/animal iv] and the fever of adult, conscious guinea pigs produced by
      LPS injected intravenously (2 microg/kg) or intraperitoneally (8, 16, 32
      microg/kg) 18 h after CVF; control animals received pyrogen-free saline. Serum C
      levels were measured as total hemolytic C activity before and 18 h after CVF
      injection and expressed as CH(100) units. In other experiments, serum C levels
      were determined at various intervals after the intravenous and intraperitoneal
      injections at different doses of LPS alone. LPS produced fevers generally of
      similar heights but of different onset latencies and durations, depending on the
      dose and route of administration. CVF caused dose-related reductions in serum C,
      from approximately 1,136 U to below detection. These reductions proportionately
      attenuated the fevers induced by intraperitoneal LPS, but not by intravenous LPS.
      Intravenous and intraperitoneal LPS per se caused reductions in serum C of 25 and
      40%, respectively, indicating activation of the C cascade. These decreases were
      transient, however, occurring early during the febrile rise approximately 30 min
      after LPS injection. These data thus support the notion that the C system may be
      critically involved in the febrile response of guinea pigs to systemic,
      particularly intraperitoneal, LPS.

PMID- 10600910
TI  - Measurement of force and both surface and deep M wave properties in isolated rat
      soleus muscles.
AB  - In isolated soleus muscles of 4-wk-old rats, M wave parameters were recorded with
      surface and deep recording electrodes and examined in relation to both twitch and
      tetanic force. Addition of ouabain (10(-5) M for 16 min) to isolated muscles
      caused an approximately 40% decrease in twitch amplitude and area (P < 0.01) that
      was associated with a 98% decrease in surface M wave amplitude, a 78% decrease in
      deep M wave amplitude (both P < 0.001), a 98% decrease in surface M wave area (P
      < 0.01), 48% of which occurred within 60 s of addition of ouabain (P < 0.05), and
      a 55% decrease in deep M wave area (P < 0.05). The decrease in twitch parameters
      on addition of ouabain was most closely correlated with deep M wave area (r =
      0.92). Direct tetanic stimulation at a frequency of 30 Hz resulted in an initial
      potentiation of M waves, which was not seen at a frequency of 90 Hz. Instead, 90
      Hz stimulation resulted in a prompt decrease in tetanic force that was correlated
      with a decrease in both deep M wave amplitude (r = 0.94; P < 0.01) and deep M
      wave area (r = 0.96; P < 0.01). It is concluded that simultaneous surface and
      deep recordings involving area and amplitude are fundamental to analysis of the
      effects of pharmacological agents on muscle performance and the use of M waves as
      predictors of muscle excitability.

PMID- 10600911
TI  - Regulation of L-methionine and L-lysine uptake in chicken jejunal brush-border
      membrane by dietary methionine.
AB  - In the chicken intestine, L-methionine is transported by systems that are
      specific for neutral amino acids (L- and B-like) and by systems that can also
      transport cationic amino acids (y(+)m and b(0,+)-like). These four uptake
      pathways have been investigated in brush-border membrane vesicles from the
      jejunum of chickens fed a diet enriched with 0.4% L-methionine. Methionine
      supplementation from the 1st to the 6th wk of age has no effect on body weight or
      on the efficiency of food utilization. The kinetic analysis of L-methionine
      influx across the transport systems specific for neutral amino acids shows, for
      system L, no dietary effect on the Michaelis constant (Km) and a 30% reduction in
      maximal velocity (Vmax); for system B it shows a decrease in Km (30%) and in Vmax
      (51%). Transport systems shared by cationic and neutral amino acids show no
      dietary effect on b(0,+) activity and a significant reduction in y(+)m Vmax,
      similar for L-methionine and L-lysine, both in the absence and in the presence of
      Na+ (L-methionine, 30 and 26% reduction; L-lysine, 19 and 28% reduction,
      respectively). The downregulation induced by L-methionine supplementation may be
      an adaptive response to reduce the risk of intoxication by dietary excess of L
      methionine. These results support the view that the toxicity of the supplemented
      substrate can be an important factor in the regulation of amino acid transport by
      dietary content.

PMID- 10600912
TI  - Influence of hemodilution on the renal blood flow autoregulation during acute
      expansion in rats.
AB  - Autoregulation of renal blood flow (RBF) was studied in rats that underwent
      equivalent blood volume expansion with saline (Sal; 5% body wt), 7% BSA solution
      (1.4% body wt), and reconstituted whole blood from donor rats (WBL; 1.4% body
      wt). Renal perfusion pressure (RPP) and renal neural reflexes were prevented by
      clamping RPP and sectioning the vagus, baro/chemoreceptor, and renal nerves. Sal
      and BSA expansion increased RBF by approximately 60%, whereas no effect was
      observed with WBL. RBF autoregulation was markedly attenuated after expansion
      with cell-free solutions, but no change occurred in WBL-expanded rats. Correction
      of the fall in hematocrit in Sal- and BSA-expanded rats restored RBF and its
      autoregulation to control levels. Expansion with Sal or BSA after inhibition of
      renal vascular tone with intrarenal infusion of papaverine still increased RBF
      and further changed the RBF-RPP relationship. These findings suggest that the
      hemodilution plays a central role in the reduction of renal vascular resistance
      and in the attenuation of the autoregulatory efficiency of renal circulation that
      accompany expansion with cell-free solutions.

PMID- 10600913
TI  - Restricted fetal growth and the response to dietary cholesterol in the guinea
      pig.
AB  - Epidemiological studies suggest that retarded growth before birth is associated
      with increased plasma total and low-density lipoprotein (LDL) cholesterol
      concentrations in adult life. Thus perturbations of prenatal growth may
      permanently alter cholesterol metabolism. To determine directly whether
      restriction of prenatal nutrition and growth alters postnatal cholesterol
      homeostasis, the plasma cholesterol response to cholesterol feeding (0.25%
      cholesterol) was examined in adult guinea pig offspring of ad libitum-fed or
      moderately undernourished mothers. Maternal undernutrition (85% ad libitum intake
      throughout pregnancy) reduced birth weight (-13%). Plasma total cholesterol was
      higher prior to and following 6 wk cholesterol feeding in male offspring of
      undernourished mothers compared with male offspring of ad libitum-fed mothers (P
      < 0.05). The influence of birth weight on cholesterol metabolism was examined by
      dividing the offspring into those whose birth weight was above (high) or below
      (low) the median birth weight. Plasma total cholesterol concentrations prior to
      cholesterol feeding did not differ with size at birth, but plasma total and LDL
      cholesterol were 31 and 34% higher, respectively, following cholesterol feeding
      in low- compared with high-birth weight males (P < 0.02). The response to
      cholesterol feeding in female offspring was not altered by variable maternal
      nutrition or size at birth. Covariate analysis showed that the effect of maternal
      undernutrition on adult cholesterol metabolism could be partly accounted for by
      alterations in prenatal growth. In conclusion, maternal undernutrition and small
      size at birth permanently alter postnatal cholesterol homeostasis in the male
      guinea pig.

PMID- 10600914
TI  - Flow reduces the amplitude and increases the frequency of lymphatic vasomotion:
      role of endothelial prostanoids.
AB  - Fluid dynamic forces have substantial effects on the movement of lymph and
      activity of lymph vessels. The effect of increases in intraluminal flow on
      spontaneous pumping activity of isolated collecting lymphatics has not yet been
      characterized in a condition in which the intraluminal pressure is constant.
      Thus, in afferent lymph microvessels isolated from rat iliac lymph nodes, changes
      in maximum (Dmax) and minimum (Dmin) diameter to increases in perfusate flow were
      investigated in the presence of a constant perfusion pressure of 6 cmH2O.
      Intraluminal flow was elicited by increases in the difference between outflow and
      inflow pressures (Pdiff, from 0 to 6 cmH2O). Diameters were measured by
      videomicroscopy. In response to increases in perfusate flow, Dmax and Dmin of
      lymphatics decreased from 157.5 +/- 6.1 to 90.9 +/- 5.6 micron and from 91.9 +/-
      5.3 to 66.3 +/- 3.6 micron, respectively, whereas vasomotion frequency increased
      from 18.0 +/- 0.7 min(-1) to 23.4 +/- 1.1 min(-1) (at Pdiff of 4 cmH2O). Removal
      of extracellular Ca2+ abolished spontaneous diameter oscillations; under these
      conditions the passive diameter of lymphatics was 216.0 +/- 7.1 micron and did
      not change in response to increases in perfusion. In the absence of endothelium,
      flow-induced changes in Dmax, Dmin, and oscillation frequency were eliminated.
      Nomega-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, did
      not affect flow-induced changes in diameter of lymphatics. In contrast,
      indomethacin, an inhibitor of prostaglandin synthesis, or SQ-29,548, a
      PGH2/thromboxane A2 (PGH2/TxA2) receptor blocker, inhibited the perfusion-induced
      reduction of Dmax and Dmin of lymphatics and also the increase in the frequency
      of vasomotion. These findings suggest that the sensitivity of lymphatic
      endothelium to increases in intraluminal flow could provide an important local
      intrinsic mechanism for the control of lymphatic resistance by release of
      constrictor prostanoids PGH2/TxA2.

PMID- 10600915
TI  - Muscle fiber type specificity in insulin signal transduction.
AB  - We determined the muscle fiber type-specific response of intracellular signaling
      proteins to insulin. Epitrochlearis (Epi; 15% type I, 20% type IIa, and 65% type
      IIb), soleus (84, 16, and 0%), and extensor digitorum longus (EDL; 3, 57, and
      40%) muscles from Wistar rats were incubated without or with 120 nM insulin (3-40
      min). Peak insulin receptor (IR) tyrosine phosphorylation was reached after 6
      (soleus) and 20 (Epi and EDL) min, with sustained activity throughout insulin
      exposure (40 min). Insulin increased insulin receptor substrate (IRS)-1 and IRS-2
      tyrosine phosphorylation and phosphotyrosine-associated phosphatidylinositol (PI)
      3-kinase activity to a maximal level after 3-10 min, with subsequent
      downregulation. Akt kinase phosphorylation peaked at 20 min, with sustained
      activity throughout insulin exposure. Importantly, the greatest insulin response
      for all signaling intermediates was observed in soleus, whereas the insulin
      response between EDL and Epi was similar. Protein expression of the p85alpha
      subunit of PI 3-kinase and Akt kinase, but not IR, IRS-1, or IRS-2, was greater
      in oxidative versus glycolytic muscle. In conclusion, increased function and/or
      expression of key proteins in the insulin-signaling cascade contribute to fiber
      type-specific differences in insulin action in skeletal muscle.

PMID- 10600916
TI  - Xanthine oxidase is involved in exercise-induced oxidative stress in chronic
      obstructive pulmonary disease.
AB  - In the present study, we hypothesized that exhaustive exercise in patients with
      chronic obstructive pulmonary disease (COPD) results in glutathione oxidation and
      lipid peroxidation and that xanthine oxidase (XO) contributes to free radical
      generation during exercise. COPD patients performed incremental cycle ergometry
      until exhaustion with (n = 8) or without (n = 8) prior treatment with
      allopurinol, an XO inhibitor. Reduced (GSH) and oxidized glutathione (GSSG) and
      lipid peroxides [malondialdehyde (MDA)] were measured in arterial blood. In
      nontreated COPD patients, maximal exercise (approximately 75 W) resulted in a
      significant increase in the GSSG-to-GSH ratio (4. 6 +/- 0.9% at rest vs. 9.3 +/-
      1.7% after exercise). In nontreated patients, MDA increased from 0.68 +/- 0.08
      nmol/ml at rest up to 1. 32 +/- 0.13 nmol/ml 60 min after cessation of exercise.
      In contrast, in patients treated with allopurinol, GSSG-to-GSH ratio did not
      increase in response to exercise (5.0 +/- 1.2% preexercise vs. 4.6 +/- 1.1% after
      exercise). Plasma lipid peroxide formation was also inhibited by allopurinol
      pretreatment (0.72 +/- 0.15 nmol/ml preexercise vs. 0.64 +/- 0.09 nmol/ml 60 min
      after exercise). We conclude that strenuous exercise in COPD patients results in
      blood glutathione oxidation and lipid peroxidation. This can be inhibited by
      treatment with allopurinol, indicating that XO is an important source for free
      radical generation during exercise in COPD.

PMID- 10600917
TI  - Control of pulmonary surfactant secretion from type II pneumocytes isolated from
      the lizard Pogona vitticeps.
AB  - Pulmonary surfactant, a mixture consisting of lipids and proteins and secreted by
      type II cells, functions to reduce the surface tension of the fluid lining of the
      lung, and thereby decreases the work of breathing. In mammals, surfactant
      secretion appears to be influenced primarily by the sympathetic nervous system
      and changes in ventilatory pattern. The parasympathetic nervous system is not
      believed to affect surfactant secretion in mammals. Very little is known about
      the factors that control surfactant secretion in nonmammalian vertebrates. Here,
      a new methodology for the isolation and culture of type II pneumocytes from the
      lizard Pogona vitticeps is presented. We examined the effects of the major
      autonomic neurotransmitters, epinephrine (Epi) and ACh, on total phospholipid
      (PL), disaturated PL (DSP), and cholesterol (Chol) secretion. At 37 degrees C,
      only Epi stimulated secretion of total PL and DSP from primary cultures of lizard
      type II cells, and secretion was blocked by the beta-adrenoreceptor antagonist
      propranolol. Neither of the agonists affected Chol secretion. At 18 degrees C,
      Epi and ACh both stimulated DSP and PL secretion but not Chol secretion. The
      secretion of surfactant Chol does not appear to be under autonomic control. It
      appears that the secretion of surfactant PL is predominantly controlled by the
      autonomic nervous system in lizards. The sympathetic nervous system may control
      surfactant secretion at high temperatures, whereas the parasympathetic nervous
      system may predominate at lower body temperatures, stimulating surfactant
      secretion without elevating metabolic rate.

PMID- 10600918
TI  - Relationship between intracranial pressure and cervical lymphatic pressure and
      flow rates in sheep.
AB  - Previous reports from our group demonstrated that about one-half of the total
      volume of cerebrospinal fluid (CSF) removed from the cranial vault in sheep is
      transported into extracranial lymphatics, especially cervical lymphatic vessels
      in the neck. In this study, we tested the hypothesis that an elevation of
      intracranial pressure (ICP) would increase cervical lymphatic pressure and lymph
      flow rates in anesthetized sheep. Catheters were inserted into both lateral
      ventricles, the cisterna magna, cervical lymphatics, and the jugular vein. A
      ventriculo-cisternal perfusion system was employed to regulate ICP. Mean (P =
      0.008), peak (P = 0.007), and baseline (P = 0.013) cervical lymphatic pressures
      increased as ICP was elevated from 10 to 70 cmH2O in 20-cmH2O increments.
      Similarly, cervical lymph flow rates increased (P < 0.001), with flows at 70
      cmH2O ICP observed to be approximately fourfold higher than those at 10 cmH2O
      ICP. No changes were observed in mesenteric lymph flow rates (vessels not
      expected to drain CSF). We conclude that cervical lymphatic vessels play an
      important role in the transport of CSF from the cranial vault when ICP is
      elevated.

PMID- 10600919
TI  - Inhibition of food intake in response to intestinal lipid is mediated by
      cholecystokinin in humans.
AB  - Intraduodenal fat inhibits gastric emptying and exerts early satiation in animals
      and humans, but it is not clear whether the effects are mediated by
      cholecystokinin (CCK) in humans. Here, we tested whether CCK-A receptors mediate
      the inhibition of fat on food intake. Two sequential, double-blind, crossover
      studies were performed in 24 male subjects. First, subjects received either
      intraduodenal fat or saline together with a preload of either water or banana
      shake. Second, 12 subjects received either intraduodenal fat or saline perfusion
      plus a concomitant infusion of saline or loxiglumide, a specific CCK-A receptor
      antagonist, together with a preload of banana shake. In both studies, subjects
      were free to eat and drink as much as they wished. Fat induced a reduction in
      calorie intake (P < 0.05) compared with controls. Furthermore, a decrease in
      hunger feelings was observed. Infusion of loxiglumide abolished the effects of
      fat. Duodenal fat interacts with an appetizer to modulate energy intake in
      humans. This effect is mediated by CCK-A receptors.

PMID- 10600920
TI  - Mode of activation of salt secretion by C-type natriuretic peptide in the shark
      rectal gland.
AB  - We studied the modes of activation of the salt-secreting rectal gland of the
      spiny dogfish, Squalus acanthias, by the native cardiac peptide CNP. The
      stimulatory action of CNP in isolated perfused glands is inhibited by 10 mM
      procaine, presumably by blocking release of vasoactive intestinal peptide (VIP)
      from nerves. Procaine reduces the slope of the dose-response curve of human CNP
      and that of shark CNP (each P < 0.0001). CNP increases short-circuit current in
      cultured rectal gland cells from 4.8 +/- 1.6 to 27.0 +/- 7.8 microA/cm2. It also
      stimulates the secretion of chloride in isolated perfused glands in the presence
      of 10 mM procaine from 72 +/- 31 to 652 +/- 173 microeq. h(-1). g(-1). These
      results suggest that CNP has a direct cellular action not mediated by the neural
      release of VIP. The residual stimulation of perfused glands in the presence of
      procaine was almost completely inhibited by staurosporine [10 nM; an inhibitor of
      protein kinase C (PKC)] from 652 +/- 173 to 237 +/- 61 microeq. h(-1). g(-1).
      Although CNP stimulates guanylyl cyclase in shark rectal gland, chloride
      secretion of perfused glands was not elicited by 8-bromoadenosine-cGMP (8-BrcGMP)
      alone nor by the activator of PKC phorbol ester. The combination of PKC
      activation and 8-BrcGMP infusion, however, stimulated chloride secretion in
      perfused glands from 94 +/- 30 to 506 +/- 61 microeq. h(-1). g(-1), a level
      comparable to that observed in glands blocked with procaine. Several parallel
      pathways appear to be synergistic in activating chloride secretion stimulated by
      CNP in the rectal gland.

PMID- 10600921
TI  - Biochemical and functional evidences for a GLUT-4 homologous protein in avian
      skeletal muscle.
AB  - The characteristics and modulation of glucose transport were investigated in
      skeletal muscles of 5-wk-old Muscovy ducklings (Cairina moschata). Glucose uptake
      by sarcolemmal vesicles isolated from gastrocnemius muscle followed typical
      Michaelis-Menten kinetics with a K(m) value (17 mM) similar to that described in
      equivalent mammalian preparations. Western blot analysis of duckling sarcolemma
      using antibodies directed against rat GLUT-4 transporter revealed an
      immunoreactive protein of similar molecular mass (45 kDa) to that present in
      rats. When ducklings were killed in the postabsorptive state, GLUT-4 homologous
      protein was located predominantly (80%) in intracellular membranes. Insulin
      stimulation of a perfused leg muscle preparation in vitro led to the
      translocation of GLUT-4 homologous proteins from intracellular pools to the
      sarcolemma, with a subsequent increase in glucose uptake by sarcolemmal vesicles
      and perfused muscles. Glucose transport was positively controlled by the
      metabolic needs of skeletal muscle as reflected by the increased glucose uptake
      of sarcolemmal vesicles isolated from cold-acclimated ducklings. Present results,
      therefore, demonstrate, for the first time in an avian species, the existence in
      skeletal muscle of a glucose transporter showing molecular and functional
      homologies with the mammalian GLUT-4 transporter.

PMID- 10600922
TI  - PGE2 suppresses mitogen-induced Ca2+ mobilization in T cells.
AB  - PGE2-mediated suppression of T cell proliferation during sepsis could result from
      altered Ca2+ signaling. The present study evaluated the effects of PGE2 on Ca2+
      release from intracellular stores and its influx through the plasma membrane in
      splenic T cells from Sprague-Dawley rats. Intracellular Ca2+ concentration
      ([Ca2+]i) responses in individual T cells were assessed using the Ca2+ imaging
      technique, and the release of Ca2+ from intracellular stores and Ca2+ influx were
      spectrofluorometrically quantified in T cell suspensions. Under unstimulated
      conditions, nearly 85% of T cells exhibited [Ca2+]i </=50 nM. After stimulation
      with concanavalin A (Con A), an increase in [Ca2+]i was recorded in approximately
      60% of the cells. The pretreatment of T cells with PGE2 had no apparent effect on
      [Ca2+]i in resting cells; it significantly suppressed the Con A-induced increase
      in [Ca2+]i in all of the Con A-responsive cells. Ca2+ release from the
      intracellular stores contributed to the early spike in [Ca2+]i, and the late
      phase of elevation in [Ca2+]i was dependent on Ca2+ influx through the plasma
      membrane. Our data suggest that PGE(2) causes an overall suppression of the Con A
      induced [Ca2+]i elevation in T cells via inhibiting both Ca2+ influx and its
      release from the intracellular stores.

PMID- 10600923
TI  - Corticotropin-releasing hormone-binding protein in brain and pituitary of food
      deprived obese (fa/fa) Zucker rats.
AB  - The present study was conducted to verify whether experimental conditions such as
      obesity and food deprivation, which promote food intake and reduce thermogenesis,
      could modify the expression of the corticotropin-releasing hormone (CRH)-binding
      protein (BP) in the rat brain. In situ hybridization, histochemistry, and
      immunohistochemistry were used to assess the expression of CRH-BP in lean (Fa/?)
      and obese (fa/fa) Zucker rats that were fed ad libitum, food deprived for 24 h,
      or food deprived for 24 h and refed for 6 h. In both lean and obese rats, food
      deprivation led to a reduction in body weight that was accompanied by a
      reversible increase in plasma corticosterone levels. Food deprivation and, to a
      lesser degree, obesity induced the expression of CRH-BP mRNA in the dorsal part
      of the medial preoptic area (MPOA). This induction of the CRH-BP gene led to by
      food deprivation was confirmed by the appearance in the dorsal part of the MPOA
      of neurons immunoreactive to CRH-BP. Food deprivation (in particular) and obesity
      also increased the levels of CRH-BP mRNA in the basolateral amygdala (BLA). The
      enhanced CRH-BP expression in the MPOA and BLA in response to food deprivation
      was reversed by refeeding. In lean Fa/? rats, the CRH-BP mRNA level in the
      pituitary cells was significantly decreased after food deprivation and restored
      after refeeding. When food was provided ad libitum, the number of cells
      expressing CRH-BP in the anterior pituitary was significantly higher in lean rats
      than in obese animals. Food deprivation for 24 h decreased dramatically the
      number of pituitary cells expressing CRH-BP in lean rats. Altogether, the present
      results demonstrate that food deprivation and, to a lesser extent, obesity can
      selectively affect the expression of CRH-BP. Given both the inactivating effect
      of CRH-BP on the CRH system and the potential roles played by the MPOA and BLA in
      the thermogenic and anorectic effects of CRH, it can be argued that the induction
      of the CRH-BP gene in obesity and after food deprivation occurs as a mechanism to
      reduce energy expenditure and to stimulate food intake.

PMID- 10600924
TI  - Nitric oxide is the predominant mediator of cerebellar hyperemia during
      somatosensory activation in rats.
AB  - Crus II is an area of the cerebellar cortex that receives trigeminal afferents
      from the perioral region. We investigated the mechanisms of functional hyperemia
      in cerebellum using activation of crus II by somatosensory stimuli as a model. In
      particular, we sought to determine whether stimulation of the perioral region
      increases cerebellar blood flow (BFcrb) in crus II and, if so, whether the
      response depends on activation of 2-amino-3-hydroxy-5-methylisoxazole-4-propionic
      acid (AMPA)-kainate receptors and nitric oxide (NO) production. Crus II was
      exposed in anesthetized rats, and the site was superfused with Ringer. Field
      potentials were recorded, and BFcrb was measured by laser-Doppler flowmetry. Crus
      II was activated by electrical stimulation of the perioral region (upper lip).
      Perioral stimulation evoked the characteristic field potentials in crus II and
      increased BFcrb (34 +/- 6%; 10 Hz-25 V; n = 6) without changing arterial
      pressure. The BFcrb increases were associated with a local increase in glucose
      utilization (74 +/- 8%; P < 0.05; n = 5) and were attenuated by the AMPA-kainate
      receptor antagonist 2, 3-dihydroxy-6-nitro-7-sulfamoylbenzo-[f]quinoxaline (-71
      +/- 3%; 100 microM; P < 0.01; n = 5). The neuronal NO synthase inhibitor 7
      nitroindazole (7-NI, 50 mg/kg; n = 5) virtually abolished the increases in BFcrb
      (-90 +/- 2%; P < 0.01) but did not affect the amplitude of the field potentials.
      In contrast, 7-NI attenuated the increase in neocortical cerebral blood flow
      produced by perioral stimulation by 52 +/- 6% (P < 0.05; n = 5). We conclude that
      crus II activation by somatosensory stimuli produces localized increases in local
      neural activity and BFcrb that are mediated by activation of glutamate receptors
      and NO. Unlike in neocortex, in cerebellum the vasodilation depends almost
      exclusively on NO. The findings underscore the unique role of NO in the
      mechanisms of synaptic function and blood flow regulation in cerebellum.

PMID- 10600925
TI  - Two circadian rhythms in the human electroencephalogram during wakefulness.
AB  - The influence of the circadian pacemaker and of the duration of time awake on the
      electroencephalogram (EEG) was investigated in 19 humans during approximately 40
      h of sustained wakefulness. Two circadian rhythms in spectral power density were
      educed. The first rhythm was centered in the theta band (4.25-8.0 Hz) and
      exhibited a minimum approximately 1 h after the onset of melatonin secretion. The
      second rhythm was centered in the high-frequency alpha band (10.25-13.0 Hz) and
      exhibited a minimum close to the body temperature minimum. The latter rhythm
      showed a close temporal association with the rhythms in subjective alertness,
      plasma melatonin, and body temperature. In addition, increasing time awake was
      associated with an increase of power density in the 0.25- to 9.0-Hz and 13.25- to
      20. 0-Hz ranges. It is concluded that the waking EEG undergoes changes that can
      be attributed to circadian and homeostatic (i.e., sleep-wake dependent)
      processes. The distinct circadian variations of EEG activity in the theta band
      and in the high-frequency alpha band may represent electrophysiological
      correlates of different aspects of the circadian rhythm in arousal.

PMID- 10600926
TI  - Sympathetic and cardiovascular actions of orexins in conscious rats.
AB  - The novel hypothalamic peptides orexin-A and orexin-B are known to induce feeding
      behavior when administered intracerebroventricularly, but little is known about
      other physiological functions. The renal sympathetic nerves play important roles
      in the homeostasis of body fluids and the circulatory system. We examined the
      effects of intracerebroventricularly administered orexins on mean arterial
      pressure (MAP), heart rate (HR), renal sympathetic nerve activity (RSNA), and
      plasma catecholamine in conscious rats. Orexin-A (0.3, 3. 0 nmol) provoked an
      increase in MAP (94.3 +/- 0.7 to 101.9 +/- 0.7 mmHg and 93.1 +/- 1.1 to 108.3 +/-
      0.8 mmHg, respectively) and RSNA (28.0 +/- 7.0 and 57.9 +/- 12.3%, respectively).
      Similarly, orexin-B (0.3, 3.0 nmol) increased MAP (93.9 +/- 0.9 to 97.9 +/- 0.9
      mmHg and 94.5 +/- 1.1 to 105.3 +/- 1.7 mmHg, respectively). Orexin-A and -B at
      3.0 nmol also increased HR. In other conscious rats, a high dose of orexin-A and 
      B increased plasma norepinephrine. Plasma epinephrine only increased with a high
      dose of orexin-A. These results indicate that central orexins regulate
      sympathetic nerve activity and affect cardiovascular functions.

PMID- 10600927
TI  - Potassium secretion and the regulation of distal nephron K channels.
AB  - K-selective channels in the luminal membranes of distal nephron segments form a
      key pathway for the secretion of K ions into the urine. This process is important
      to the control of K balance, particularly under conditions of normal or high K
      intake. This brief review will cover three issues: 1) the identification of
      apical K channels, 2) the role of these channels in the maintenance of K
      homeostasis, and 3) the role of aldosterone in this regulatory process. The large
      amount of literature on renal K transport has been elegantly summarized in a
      recent review in this journal [G. Giebisch. Am. J. Physiol. 274 (Renal Physiol.
      43): F817-F833, 1998]. Here I will focus on a few prominent unsolved problems.

PMID- 10600928
TI  - Regulation of the ROMK channel: interaction of the ROMK with associate proteins.
AB  - The ROMK channel plays an important role in K recycling in the thick ascending
      limb (TAL) and K secretion in the cortical collecting duct (CCD). A large body of
      evidence indicates that the ROMK channel is a key component of the native K
      secretory channel identified in the apical membrane of the TAL and the CCD.
      Although the ROMK channel shares several key regulatory mechanisms with the
      native K secretory channel in a variety of respects, differences in the channel
      modulatory mechanism are clearly present between the ROMK channel and the native
      K secretory channel. Therefore, it is possible that additional associate proteins
      are required to interact with the ROMK channel to assemble the native K secretory
      channel. This notion is supported by recent reports showing that cystic fibrosis
      transmembrane conductance regulator (CFTR) and A kinase anchoring proteins (AKAP)
      interact with the ROMK channels to restore the response to ATP sensitivity and
      protein kinase A stimulation. This review is an attempt to summarize the up-to
      date progress regarding the interaction between the ROMK channel and the
      associate proteins in forming the native K secretory channel.

PMID- 10600929
TI  - Cisplatin induces renal expression of P-glycoprotein and canalicular
      multispecific organic anion transporter.
AB  - The expression of two members of the ATP-binding cassette family of transport
      proteins, P-glycoprotein (P-gp) and the canalicular multispecific organic anion
      transporter (cMOAT or Mrp2), was evaluated in renal brush-border membranes (BBM)
      and various rat tissues after cisplatin treatment. One administration of
      cisplatin (5 mg/kg) increased P-gp expression by >200-300% in renal BBM and in
      crude membranes from liver and intestine. The increase in P-gp expression in the
      kidney was also detected in photolabeling experiments, suggesting the induction
      of functional P-gp. cMOAT expression was increased by >10-fold in renal BBM after
      cisplatin administration, although it had no effect on liver cMOAT expression.
      The increase in the levels of both proteins was maximal at 2 days after cisplatin
      treatment and lasted for at least 8 days. These results indicate that a single
      administration of cisplatin induces overexpression of P-gp and cMOAT in specific
      tissues. This may be of significant relevance to the design of clinical trials
      using cisplatin as a single chemotherapeutic agent or in combination with other
      drugs.

PMID- 10600930
TI  - Expression of rat kidney anion exchanger 1 in type A intercalated cells in
      metabolic acidosis and alkalosis.
AB  - By enzyme-linked in situ hybridization (ISH), direct evidence is provided that
      acid-secreting intercalated cells (type A IC) of both the cortical and medullary
      collecting ducts of the rat kidney selectively express the mRNA of the kidney
      splice variant of anion exchanger 1 (kAE1) and no detectable levels of the
      erythrocyte AE1 (eAE1) mRNA. Using single-cell quantification by microphotometry
      of ISH enzyme reaction, medullary type A IC were found to contain twofold higher
      kAE1 mRNA levels compared with cortical type A IC. These differences correspond
      to the higher intensity of immunostaining in medullary versus cortical type A IC.
      Chronic changes of acid-base status induced by addition of NH(4)Cl (acidosis) or
      NaHCO3 (alkalosis) to the drinking water resulted in up to 35% changes of kAE1
      mRNA levels in both cortical and medullary type A IC. These experiments provide
      direct evidence at the cellular level of kAE1 expression in type A IC and show
      moderate capacity of type A IC to respond to changes of acid-base status by
      modulation of kAE1 mRNA levels.

PMID- 10600931
TI  - Prostaglandins buffer ANG II-mediated increases in cytosolic calcium in
      preglomerular VSMC.
AB  - In order to exert an appropriate biological effect, the action of the
      vasoconstrictive hormone angiotensin II (ANG II) is modulated by vasoactive
      factors such as prostaglandins PGE2 and PGI2. The present study investigates
      whether prostaglandins alter ANG II-mediated increases in cytosolic calcium
      concentration ([Ca2+]i) in vascular smooth muscle cells (VSMC) isolated from rat
      renal preglomerular arterioles. [Ca2+]i was assessed using the calcium-sensitive
      dye fura 2 and a microscope-based photometer system. ANG II (10(-7) M) caused a
      biphasic, time-dependent [Ca2+]i response: an initial peak increase from 52 +/- 7
      to 264 +/- 25 nM, followed by a sustained plateau of 95 +/- 9 nM in cultured
      VSMC. Coadministration of PGE2 or PGI2 or synthetic mimetics caused dose
      dependent decreases in the peak [Ca2+]i response to ANG II, with attenuation of
      40-50%. This degree of inhibition was even more pronounced in individual freshly
      isolated preglomerular VSMC. Increasing cAMP levels in cultured VSMC, by using
      either a cell-permeable analog or inhibiting phosphodiesterase activity, mirrored
      the antagonistic effects of prostaglandins on ANG II-stimulated increases in
      [Ca2+]i. Radioimmunoassays demonstrate that ANG II (10(-7) M) stimulates
      production of PGI2 and PGE2; the stable prostacyclin metabolite 6-keto
      PGF(1alpha) was released in 10-fold greater concentrations than PGE(2.)
      Indomethacin blockade of prostaglandin production potentiated both the peak (264
      to 337 +/- 26 nM) and sustained [Ca2+]i responses (95 to 181 +/- 22 nM) to ANG
      II. When prostaglandin analogs were added during indomethacin treatment, the ANG
      II response was restored to the typical pattern. In conclusion, we demonstrate
      that modulation of intracellular calcium levels is one mechanism by which
      prostaglandins can buffer ANG II-mediated constriction in renal preglomerular
      VSMC. PGI2 is more potent than PGE2 in this regard.

PMID- 10600932
TI  - Nitric oxide activates PKCalpha and inhibits Na+-K+-ATPase in opossum kidney
      cells.
AB  - Nitric oxide (NO) reduces the molecular activity of Na+-K+-ATPase in opossum
      kidney (OK) cells, a proximal tubule cell line. In the present study, we
      investigated the cellular mechanisms for the inhibitory effect of NO on Na+-K+
      ATPase. Sodium nitroprusside (SNP), a NO donor, inhibited Na+-K+-ATPase in OK
      cells, but not in LLC-PK1 cells, another proximal tubule cell line. Similarly,
      phorbol 12-myristate 13-acetate, a protein kinase C (PKC) activator, inhibited
      Na+-K+-ATPase in OK, but not in LLC-PK1, cells. PKC inhibitors staurosporine or
      calphostin C, but not the protein kinase G inhibitor KT-5823, abolished the
      inhibitory effect of NO on Na+-K+-ATPase in OK cells. Immunoblotting demonstrated
      that treatment with NO donors caused significant translocation of PKCalpha from
      cytosolic to particulate fractions in OK, but not in LLC-PK1, cells. Furthermore,
      the translocation of PKCalpha in OK cells was attenuated by either the
      phospholipase C inhibitor U-73122 or the soluble guanylate cyclase inhibitor 1H
      [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one. U-73122 also blunted the inhibitory
      effect of SNP on Na+-K+-ATPase in OK cells. The phospholipase A2 inhibitor
      AACOCF3 did not blunt the inhibitory effect of SNP on Na+-K+-ATPase in OK cells.
      AACOCF3 alone, however, also decreased Na+-K+-ATPase activity in OK cells. In
      conclusion, our results demonstrate that NO activates PKCalpha in OK, but not in
      LLC-PK1, cells. The activation of PKCalpha in OK cells by NO is associated with
      inhibition of Na+-K+-ATPase.

PMID- 10600933
TI  - In rat tIMCD, NH4+ uptake by Na+-K+-ATPase is critical to net acid secretion
      during chronic hypokalemia.
AB  - The purpose of this study was to determine the magnitude of Na+ pump-mediated
      NH4+ uptake in the terminal inner medullary collecting duct (tIMCD) at K+ and
      NH4+ concentrations observed in vivo in the inner medullary interstitium of
      normal and in K+-restricted rats. Interstitial K+ and NH4+ concentrations in the
      terminal half of the inner medulla were taken to be 10 and 6 mM in K+-restricted
      rats, but 30 and 6 mM in K+-replete rats. In tubules from K+-restricted rats,
      when perfused at a K+ concentration of 10 mM, addition of ouabain to the bath
      reduced total bicarbonate flux (JtCO2) by 40% and increased intracellular pH
      (pHi), indicating significant NH4+ uptake by the Na+-K+-ATPase. In tubules from
      K+-restricted rats, JtCO2 was reduced with increased extracellular K+. At a K+
      concentration of 30 mM, ouabain addition neither reduced JtCO2 nor increased pHi
      in tubules from rats of either treatment group. In conclusion, in the tIMCD from
      hypokalemic rats, 1) acute changes in extracellular K+ concentration modulate net
      acid secretion, and 2) Na+ pump-mediated NH4+ uptake should be an important
      pathway mediating transepithelial net acid secretion in vivo.

PMID- 10600934
TI  - Estradiol suppresses mesangial cell type I collagen synthesis via activation of
      the MAP kinase cascade.
AB  - We have previously shown that estradiol suppresses the synthesis of type I
      collagen by murine mesangial cells grown in the presence of serum via activation
      of the transcription factor activator protein-1 (AP-1). We hypothesized that
      estradiol upregulates AP-1 via activation of the mitogen-activated protein (MAP)
      kinase cascade, a signal transduction pathway that regulates AP-1 activity.
      Estradiol (10(-10) to 10(-7) M) upregulated the MAP kinase pathway in murine
      mesangial cells grown in the presence of serum in a dose-dependent manner.
      Activation was evident by 1 min, peaked at 10 min, and was completely dissipated
      by 2 h. In contrast, estradiol had no significant effect on total (phosphorylated
      + unphosphorylated) p44 extracellular signal-related protein kinase (ERK) or p42
      ERK. Nuclear extracts isolated from mesangial cells treated with estradiol showed
      increased binding to a consensus sequence AP-1 binding oligonucleotide in gel
      shift assays. In contrast, nuclear extracts from cells exposed to PD-98059, a
      highly selective inhibitor of MAP kinase-ERK kinase 1 (MEK1) and MEK2, showed
      reduced binding. In addition, PD-98059 antagonizes the enhanced binding induced
      by estradiol. Estradiol (10(-9) M) suppressed mesangial cell type I collagen
      synthesis (37.8 +/- 2.4%, expressed as a percentage of control values, P < 0.001
      vs. control). In contrast, PD-98059 increased type I collagen synthesis (344.6 +/
      98.8, P < 0.01) and reversed the suppression of type I collagen synthesis
      induced by estradiol. The effects of estradiol, PD-98059, and PD-98059 plus
      estradiol on type I collagen protein synthesis were closely paralleled by their
      effects on steady-state levels of mRNA for the alpha(1) chain of type I collagen.
      These data suggest that estradiol suppresses type I collagen synthesis via
      upregulation of the MAP kinase cascade, leading to stimulation of AP-1 activity.

PMID- 10600935
TI  - Carbon monoxide induces vasodilation and nitric oxide release but suppresses
      endothelial NOS.
AB  - The vascular effects of carbon monoxide (CO) resemble those of nitric oxide (NO),
      but it is unknown whether the two messengers converge or exhibit reciprocal
      feedback regulation. These questions were examined in microdissected perfused
      renal resistance arteries (RRA) studied using NO-sensitive microelectrodes.
      Perfusion of RRA with buffers containing increasing concentrations of CO resulted
      in a biphasic release of NO. The NO response peaked at 100 nM CO and then
      declined to virtually zero at 10 microM. When a series of 50-s pulses of 100 nM
      CO were applied repeatedly (150-s interval), the amplitude of consecutive NO
      responses was diminished. NO release from RRA showed dependence on L-arginine but
      not D-arginine, and the responses to CO were inhibited by pretreatment with NG
      nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthases (NOS). CO
      (100 nM) also suppressed NO release induced by 100 microM carbachol, a potent
      agonist for endothelial NOS (eNOS). RRA from rats in which endogenous CO
      production from inducible HO was elevated (cobalt chloride 12 h prior to study)
      also showed suppressed responses to carbachol. Furthermore, responses consistent
      with these findings were obtained in juxtamedullary afferent arterioles perfused
      in vitro, where the vasodilatory response to CO was biphasic and the response to
      acetylcholine was blunted. Collectively, these data suggest that the CO-induced
      NO release could be attributed to either stimulation of eNOS or to NO
      displacement from a cellular storage pool. To address this, direct in vitro
      measurements with an NO-selective electrode of NO production by recombinant eNOS
      revealed that CO dose-dependently inhibits NO synthesis. Together, the above data
      demonstrate that, whereas high levels of CO inhibit NOS activity and NO
      generation, lower concentrations of CO induce release of NO from a large
      intracellular pool and, therefore, may mimic the vascular effects of NO.

PMID- 10600936
TI  - rOCT2 is a basolateral potential-driven carrier, not an organic cation/proton
      exchanger.
AB  - The driving forces mediating tetraethylammonium (TEA) transport were
      systematically assessed in Xenopus oocytes and MDCK cells expressing organic
      cation transporter (OCT) 2 cloned from rat kidney (rOCT2). In rOCT2 cRNA-injected
      oocytes, uptake of [14C]TEA was saturable, with an estimated Michaelis constant
      (Km) of 393 microM, and was specifically inhibited by organic cations.
      Furthermore, TEA uptake demonstrated two distinct components, one that was
      potential sensitive and one that was pH sensitive. When membrane potential was
      intact, TEA uptake was largely unaffected by changes in medium pH; when the
      oocyte membrane was depolarized (K+ in = out = 102.5 mM, plus valinomycin),
      decreasing external medium pH significantly reduced TEA uptake. Consistent with
      the potential sensitivity of uptake, electrophysiological analysis of rOCT2
      injected oocytes demonstrated movement of positive charge into the oocyte upon
      TEA addition. To further evaluate the nature of the pH effect and assess the
      properties of rOCT2 in a renal epithelium, rOCT2 was introduced into MDCK cells.
      A stably transfected single cell clone (MDCK-rOCT2) showed mediated, potential
      sensitive, pH-sensitive TEA uptake (Km = 48 microM). TEA efflux from preloaded
      MDCK-rOCT2 cells was stimulated by externally applied (trans) tetramethylammonium
      but was trans-inhibited by H+ (external pH 5.4). The effect of external H+ was to
      modulate rOCT2-mediated transport. Thus rOCT2 is a potential-driven transporter,
      not an organic cation/H+ exchanger, consistent with a physiological role in the
      basolateral entry step in renal organic cation secretion.

PMID- 10600937
TI  - Hormone-stimulated Ca2+ transport in rabbit kidney: multiple sites of inhibition
      by exogenous ATP.
AB  - Exogenous ATP markedly reduced 1-desamino-8-D-arginine vasopressin (dDAVP)
      stimulated Ca2+ transport and cAMP accumulation in primary cultures of rabbit
      connecting tubule and cortical collecting duct cells. Similarly, ATP inhibited
      the stimulatory effect of 8-bromo-cAMP. At first sight, this is in agreement with
      the "classic" concept that dDAVP exerts its stimulatory effect via cAMP. However,
      dDAVP-stimulated Ca2+ transport was markedly reduced by the protein kinase C
      (PKC) inhibitor chelerythrine, reported previously to inhibit the cAMP
      independent pathway responsible for parathyroid hormone-, [Arg8]vasopressin-,
      PGE2-, and adenosine-stimulated Ca2+ transport. Chelerythrine also inhibited the
      increase in Ca2+ transport evoked by the cAMP-independent A1 receptor agonist N6
      cyclopentyladenosine (CPA). Downregulation of phorbol ester-sensitive PKC
      isoforms by chronic phorbol ester treatment has been shown before to be without
      effect on hormone-stimulated Ca2+ transport, indicating that the chelerythrine
      inhibitable pathway consists of a phorbol ester-insensitive PKC isoform. Here,
      this maneuver did not affect ATP inhibition of dDAVP-stimulated Ca2+ transport
      and cAMP formation, while abolishing ATP inhibition of CPA-stimulated Ca2+
      transport. These findings show that ATP acts via 1) a phorbol ester-sensitive PKC
      isoform to inhibit hormonal stimulation of Ca2+ transport at the level of the
      chelerythrine-inhibitable pathway involving a phorbol ester-insensitive PKC
      isoform and 2) a phorbol ester-insensitive mechanism to inhibit V2 receptor
      mediated concomitant activation of this pathway and adenylyl cyclase.

PMID- 10600938
TI  - Insulin stimulates Mg2+ uptake in mouse distal convoluted tubule cells.
AB  - Insulin has been shown to be a magnesium-conserving hormone acting, in part,
      through stimulation of magnesium absorption within the thick ascending limb.
      Although the distal convoluted tubule possesses the most insulin receptors, it is
      unclear what, if any, actions insulin has in the distal tubule. The effects of
      insulin were studied on immortalized mouse distal convoluted tubule (MDCT) cells
      by measuring cellular cAMP formation with radioimmunoassays and Mg2+ uptake with
      fluorescence techniques using mag-fura 2. To assess Mg2+ uptake, MDCT cells were
      first Mg(2+) depleted to 0.22 +/- 0.01 mM by culturing in Mg2+-free media for 16
      h and then placed in 1.5 mM MgCl2, and the changes in intracellular Mg2+
      concentration ([Mg2+]i) were measured with microfluorescence. [Mg2+]i returned to
      basal levels, 0.53 +/- 0.02 mM, with a mean refill rate, d([Mg2+]i)/dt, of 164 +/
      5 nM/s. Insulin stimulated Mg2+ entry in a concentration-dependent manner with
      maximal response of 214 +/- 12 nM/s, which represented a 30 +/- 5% increase in
      the mean uptake rate above control values. This was associated with a 2.5-fold
      increase in insulin-mediated cAMP generation (52 +/- 3 pmol. mg protein(-1). 5
      min(-1)). Genistein, a tyrosine kinase inhibitor, diminished insulin-stimulated
      Mg2+ uptake (169 +/- 11 nM/s), but did not change insulin-mediated cAMP formation
      (47 +/- 5 pmol. mg protein(-1). 5 min(-1)). PTH stimulates Mg2+ entry, in part,
      through increases in cAMP formation. Insulin and PTH increase Mg2+ uptake in an
      additive fashion. In conclusion, insulin mediates Mg2+ entry, in part, by a
      genistein-sensitive mechanism and by modifying hormone-responsive transport.
      These studies demonstrate that insulin stimulates Mg2+ uptake in MDCT cells and
      suggest that insulin acts in concert with other peptide and steroid hormones to
      control magnesium conservation in the distal convoluted tubule.

PMID- 10600939
TI  - The rat pkd2 protein assumes distinct subcellular distributions in different
      organs.
AB  - Mutations in the PKD2 gene account for approximately 15% of all cases of
      autosomal-dominant polycystic kidney disease. In the present study the cellular
      distribution of the Pkd2 protein was investigated by immunohistochemistry in
      different rat organs. Although the Pkd2 protein showed a widespread expression, a
      strikingly different distribution of the protein was observed between individual
      organs. Whereas in renal distal tubules and in striated ducts of salivary glands
      a basal-to-basolateral distribution of Pkd2 was found, a punctate cytoplasmic
      location was detected in the adrenal gland, ovary, cornea, and smooth muscle
      cells of blood vessels. Interestingly, in the adrenal gland and ovary, the rat
      Pkd2 protein was more heavily N-glycosylated than in the kidney and salivary
      gland. These results suggest that Pkd2 accomplishes its functions by interacting
      with proteins located in different cellular compartments. The extrarenal
      expression pattern of the Pkd2 protein hints at other candidate sites of disease
      manifestations in patients carrying PKD2 mutations.

PMID- 10600940
TI  - Afferent arteriolar adenosine A2a receptors are coupled to KATP in in vitro
      perfused hydronephrotic rat kidney.
AB  - Adenosine is known to exert dual actions on the afferent arteriole, eliciting
      vasoconstriction, by activating A1 receptors, and vasodilation at higher
      concentrations, by activating lower-affinity A2 receptors. We could demonstrate
      both of these known adenosine responses in the in vitro perfused hydronephrotic
      rat kidney. Thus, 1.0 microM adenosine elicited a transient vasoconstriction
      blocked by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and 10-30 microM adenosine
      reversed KCl-induced vasoconstriction. However, when we examined the effects of
      adenosine on pressure-induced afferent arteriolar vasoconstriction, we observed a
      third action. In this setting, a high-affinity adenosine vasodilatory response
      was observed at concentrations of 10-300 nM. This response was blocked by both 4
      (2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3, 5]triazin-5-yl
      amino]ethyl)phenol (ZM-241385) and glibenclamide and was mimicked by 2
      phenylaminoadenosine (CV-1808) (IC50 of 100 nM), implicating adenosine A2a
      receptors coupled to ATP-sensitive K channels (KATP). Like adenosine, 5'-N
      ethylcarboxamidoadenosine (NECA) elicited both glibenclamide-sensitive and
      glibenclamide-insensitive vasodilatory responses. The order of potency for the
      glibenclamide-sensitive component was NECA > adenosine = CV-1808. Our findings
      suggest that, in addition to the previously described adenosine A1 and low
      affinity A2b receptors, the renal microvasculature is also capable of expressing
      high-affinity adenosine A2a receptors. This renal adenosine receptor elicits
      afferent arteriolar vasodilation at submicromolar adenosine levels by activating
      KATP.

PMID- 10600941
TI  - Role of membrane-type matrix metalloproteinase 1 (MT-1-MMP), MMP-2, and its
      inhibitor in nephrogenesis.
AB  - Extracellular matrix (ECM) proteins, their integrin receptors, and matrix
      metalloproteinases (MMPs), the ECM-degrading enzymes, are believed to be involved
      in various biological processes, including embryogenesis. In the present study,
      we investigated the role of membrane type MMP, MT-1-MMP, an activator pro-MMP-2,
      in metanephric development. Also, its relationship with MMP-2 and its inhibitor,
      TIMP-2, was studied. Since mRNAs of MT-1-MMP and MMP-2 are respectively expressed
      in the ureteric bud epithelia and mesenchyme, they are ideally suited for
      juxtacrine/paracrine interactions during renal development. Northern blot
      analyses revealed a single approximately 4.5-kb mRNA transcript of MT-1-MMP, and
      its expression was developmentally regulated. Inclusion of MT-1-MMP antisense
      oligodeoxynucleotide (ODN) in the culture media induced dysmorphogenetic changes
      in the embryonic metanephros. MMP-2 antisense ODN also induced similar changes,
      but they were relatively less; on the other hand TIMP-2 antisense ODN induced a
      mild increase in the size of explants. Concomitant exposure of MT-1-MMP and MMP-2
      antisense ODNs induced profound alterations in the metanephroi. Treatment of TIMP
      2 antisense ODN to metanephroi exposed to MT-1-MMP/MMP-2 antisense notably
      restored the morphology of the explants. Specificity of the MT-1-MMP antisense
      ODN was reflected in the selective decrease in its mRNA and protein expression.
      The MT-1-MMP antisense ODN also resulted in a failure in the activation of pro
      MMP-2 to MMP-2. These findings suggest that the trimacromolecular complex of MT-1
      MMP:MMP-2:TIMP-2 modulates the organogenesis of the metanephros, conceivably by
      mediating paracrine/juxtacrine epithelial:mesenchymal interactions.

PMID- 10600942
TI  - Cyclin kinase inhibitor p21CIP1/WAF1 limits interstitial cell proliferation
      following ureteric obstruction.
AB  - Tubulointerstitial renal injury induced by unilateral ureteric obstruction (UUO)
      is characterized by marked cell proliferation and apoptosis. Proliferation
      requires cell cycle transit that is positively regulated by cyclins and cyclin
      dependent kinases (CDKs) and inhibited by the CIP/KIP family of cyclin-dependent
      kinase inhibitors (CKIs: p21, p27, and p57). We have shown that the absence of
      p27 results in markedly increased tubular epithelial cell proliferation and
      apoptosis following UUO (V. Ophascharoensuk, M. L. Fero, J. Hughes, J. M.
      Roberts, and S. J. Shankland. Nat. Med. 4: 575-580, 1998). Since p21 mRNA is
      upregulated following UUO, we hypothesized that p21 would also serve to limit
      cell proliferation and apoptosis. We performed UUO in p21 +/+ and p21 -/- mice.
      Cell proliferation [bromodeoxyuridine (BrdU), proliferating cell nuclear antigen
      (PCNA)], apoptosis [terminal deoxynucleotidyl transferase-mediated dUTP-biotin
      nick end labeling (TUNEL) method], interstitial myofibroblast accumulation
      (actin), macrophage infiltration (F4/80), and collagen I expression were
      quantified at days 3, 7, and 14. In contrast to p27 -/- mice, there was no
      difference in tubular epithelial cell proliferation or apoptosis between p21 -/-
      and p21 +/+ mice at any time point. However, interstitial cell proliferation at
      day 3 was significantly increased in p21 -/- mice [BrdU, 40.7 +/- 1.9 cells/high
      power field (cells/hpf) vs. 28.8 +/- 2, P < 0.005], although, interestingly, no
      difference was seen in interstitial cell apoptosis. Actin/BrdU double staining
      demonstrated increased interstitial myofibroblast proliferation at day 3 in p21 
      /- animals (10 +/- 0.12 vs. 5.8 +/- 0. 11 cells/hpf, P < 0.05), which was
      followed by increased myofibroblast accumulation at day 7 in p21 -/- mice. No
      differences were detected in interstitial macrophage infiltration, collagen I
      deposition or transforming growth factor-beta1 mRNA (in situ hybridization)
      expression. In conclusion p21, unlike p27, is not essential for the regulation of
      tubular epithelial cell proliferation and apoptosis following UUO, but p21 levels
      do serve to limit the magnitude of the early myofibroblast proliferation. This
      study demonstrates a differential role for the CKI p21 and p27 in this model.

PMID- 10600943
TI  - Cellular and subcellular immunolocalization of ClC-5 channel in mouse kidney:
      colocalization with H+-ATPase.
AB  - To determine the immunolocalization of ClC-5 in the mouse kidney, we developed a
      ClC-5-specific rat monoclonal antibody. Immunoblotting demonstrated an 85-kDa
      band of ClC-5 in the kidney and ClC-5 transfected cells. Immunocytochemistry
      revealed significant labeling of ClC-5 in brush-border membrane and subapical
      intracellular vesicles of the proximal tubule. In addition, apical and
      cytoplasmic staining was observed in the type A intercalated cells in the
      cortical collecting duct. In contrast, the staining was minimal in the outer and
      inner medullary collecting ducts and the thick ascending limb. Western blotting
      of vesicles immunoisolated by the ClC-5 antibody showed the presence of H+
      ATPase, strongly indicating that these two proteins were present in the same
      membranes. Double labeling with antibodies against ClC-5 and H+-ATPase and
      analysis by confocal images showed that ClC-5 and H+-ATPase colocalized in these
      ClC-5-positive cells. These findings suggest that ClC-5 might be involved in the
      endocytosis and/or the H+ secretion in the proximal tubule cells and the cortical
      collecting duct type A intercalated cells in mouse kidney.

PMID- 10600944
TI  - Expression of peroxisomal proliferator-activated receptors and retinoid X
      receptors in the kidney.
AB  - The discovery that 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) is a ligand
      for the gamma-isoform of peroxisome proliferator-activated receptor (PPAR)
      suggests nuclear signaling by prostaglandins. Studies were undertaken to
      determine the nephron localization of PPAR isoforms and their heterodimer
      partners, retinoid X receptors (RXR), and to evaluate the function of this system
      in the kidney. PPARalpha mRNA, determined by RT-PCR, was found predominately in
      cortex and further localized to proximal convoluted tubule (PCT); PPARgamma was
      abundant in renal inner medulla, localized to inner medullary collecting duct
      (IMCD) and renal medullary interstitial cells (RMIC); PPARbeta, the ubiquitous
      form of PPAR, was abundant in all nephron segments examined. RXRalpha was
      localized to PCT and IMCD, whereas RXRbeta was expressed in almost all nephron
      segments examined. mRNA expression of acyl-CoA synthase (ACS), a known PPAR
      target gene, was stimulated in renal cortex of rats fed with fenofibrate, but the
      expression was not significantly altered in either cortex or inner medulla of
      rats fed with troglitazone. In cultured RMIC cells, both troglitazone and 15d
      PGJ2 significantly inhibited cell proliferation and dramatically altered cell
      shape by induction of cell process formation. We conclude that PPAR and RXR
      isoforms are expressed in a nephron segment-specific manner, suggesting distinct
      functions, with PPARalpha being involved in energy metabolism through regulating
      ACS in PCT and with PPARgamma being involved in modulating RMIC growth and
      differentiation.

PMID- 10600945
TI  - NBC3 expression in rabbit collecting duct: colocalization with vacuolar H+
      ATPase.
AB  - We have recently cloned and characterized a unique sodium bicarbonate
      cotransporter, NBC3, which unlike other members of the NBC family, is
      ethylisopropylamiloride (EIPA) inhibitable, DIDS insensitive, and electroneutral
      (A. Pushkin, N. Abuladze, I. Lee, D. Newman, J. Hwang, and I. Kurtz. J. Biol.
      Chem. 274: 16569-16575, 1999). In the present study, a specific polyclonal
      antipeptide COOH-terminal antibody, NBC3-C1, was generated and used to determine
      the pattern of NBC3 protein expression in rabbit kidney. A major band of
      approximately 200 kDa was detected on immunoblots of rabbit kidney.
      Immunocytochemistry of rabbit kidney frozen sections revealed specific staining
      of the apical membrane of intercalated cells in both the cortical and outer
      medullary collecting ducts. The pattern of NBC3 protein expression in the
      collecting duct was nearly identical to the same sections stained with an
      antibody against the vacuolar H+-ATPase 31-kDa subunit. In addition, the NBC3-C1
      antibody coimmunoprecipitated the vacuolar H+-ATPase 31-kDa subunit. Functional
      studies in outer medullary collecting ducts (inner stripe) showed that type A
      intercalated cells have an apical Na+-dependent base transporter that is EIPA
      inhibitable and DIDS insensitive. The data suggest that NBC3 participates in
      H+/base transport in the collecting duct. The close association of NBC3 and the
      vacuolar H+-ATPase in type A intercalated cells suggests a potential
      structural/functional interaction between the two transporters.

PMID- 10600946
TI  - A call to renew. Doctors who feel ground down can renew their spirits and their
      values.

PMID- 10600947
TI  - The NHS as a theological institution. The ideal remains strong, but the practice
      too has to measure up.

PMID- 10600948
TI  - Medicine and the marginalised. They deserve the best, not the poorest, care.

PMID- 10600949
TI  - Absinthe: what's your poison? Though absinthe is intriguing, it is alcohol in
      general we should worry about.

PMID- 10600950
TI  - Putting on the style. Journal house style is for the benefit of readers; now
      everyone can access it.

PMID- 10600952
TI  - Fin de siecle countdown

PMID- 10600951
TI  - Photographic memory, money, and liposuction: survey of medical students' wish
      lists.
AB  - OBJECTIVES: To examine whether medical students made fewer altruistic wishes and
      more money oriented wishes in later years of the medical course than students in
      earlier years. DESIGN: Anonymous questionnaire survey. SETTING: Auckland
      University School of Medicine. PARTICIPANTS: 520 medical students from 6 years of
      the course responded to the questionnaire item "If you had three wishes what
      would you wish for?" MAIN OUTCOME MEASURES: Proportion of wishes in various
      categories. RESULTS: The three most popular categories of wishes were happiness
      (34% of students), money (32%), and altruistic wishes (31%). Rates of altruistic
      wishes (odds ratio=1.05, 95% confidence interval 0.94 to 1.18; P=0.36) and wishes
      for money (odds ratio=0.96, 0.86 to 1.08; P=0.52) did not vary over the years of
      the course. Female medical students were more likely than males to make
      altruistic wishes (36% v 26%; chi(2)=5.68, P=0. 02), intimacy wishes (25% v 18%;
      chi(2)=3.74, P=0.05), and happiness wishes (42% v 26%; chi(2)=18.82, P=0.0001).
      Men were more likely than women to make sexual wishes (5% v 0.8%; chi(2)=7.34,
      P=0.01). CONCLUSIONS: We found no evidence that students were less altruistic and
      more money oriented in the later years of the medical course.

PMID- 10600953
TI  - Essential reading matter

PMID- 10600954
TI  - Magnetic resonance imaging of male and female genitals during coitus and female
      sexual arousal.
AB  - OBJECTIVE: To find out whether taking images of the male and female genitals
      during coitus is feasible and to find out whether former and current ideas about
      the anatomy during sexual intercourse and during female sexual arousal are based
      on assumptions or on facts. DESIGN: Observational study. SETTING: University
      hospital in the Netherlands. METHODS: Magnetic resonance imaging was used to
      study the female sexual response and the male and female genitals during coitus.
      Thirteen experiments were performed with eight couples and three single women.
      RESULTS: The images obtained showed that during intercourse in the "missionary
      position" the penis has the shape of a boomerang and 1/3 of its length consists
      of the root of the penis. During female sexual arousal without intercourse the
      uterus was raised and the anterior vaginal wall lengthened. The size of the
      uterus did not increase during sexual arousal. CONCLUSION: Taking magnetic
      resonance images of the male and female genitals during coitus is feasible and
      contributes to understanding of anatomy.

PMID- 10600955
TI  - Shaken, not stirred: bioanalytical study of the antioxidant activities of
      martinis.
AB  - BACKGROUND: Moderate consumption of alcoholic drinks seems to reduce the risks of
      developing cardiovascular disease, stroke, and cataracts, perhaps through
      antioxidant actions of their alcohol, flavonoid, or polyphenol contents. "Shaken,
      not stirred" routinely identifies the way the famous secret agent James Bond
      requires his martinis. OBJECTIVES: As Mr Bond is not afflicted by cataracts or
      cardiovascular disease, an investigation was conducted to determine whether the
      mode of preparing martinis has an influence on their antioxidant capacity.
      DESIGN: Stirred and shaken martinis were assayed for their ability to quench
      luminescence by a luminescent procedure in which hydrogen peroxide reacts with
      luminol bound to albumin. Student's t test was used for statistical analysis.
      RESULTS: Shaken martinis were more effective in deactivating hydrogen peroxide
      than the stirred variety, and both were more effective than gin or vermouth alone
      (0.072% of peroxide control for shaken martini, 0.157% for stirred v 58.3% for
      gin and 1.90% for vermouth). The reason for this is not clear, but it may well
      not involve the facile oxidation of reactive martini components: control martinis
      through which either oxygen or nitrogen was bubbled did not differ in their
      ability to deactivate hydrogen peroxide (0.061% v 0. 057%) and did not differ
      from the shaken martini. Moreover, preliminary experiments indicate that martinis
      are less well endowed with polyphenols than Sauvignon white wine or Scotch whisky
      (0.056 mmol/l (catechin equivalents) shaken, 0.060 mmol/l stirred v 0.592 mmol/l
      wine, 0.575 mmol/l whisky). CONCLUSIONS: 007's profound state of health may be
      due, at least in part, to compliant bartenders.

PMID- 10600956
TI  - Babes and boobs? analysis of JAMA cover art.
AB  - OBJECTIVE: To determine the representation of the sexes in JAMA cover art.
      DESIGN: Review of 50 consecutive issues. SETTING: JAMA, March 1997-March 1998.
      MAIN OUTCOME MEASURES: Numbers and nature of covers portraying men and women.
      RESULTS: Of the 50 covers, 34 depicted humans. 15 depicted women, 13 men, and 6
      were of mixed or indeterminate sex. 11 pictures of women included a child and
      five included nudity. One cover showed a man with a child (not as a father) and
      none depicted nudity. Men were depicted exclusively in authoritative roles.
      CONCLUSIONS: Much of the cover art gives strong messages about sexual stereotypes
      that are inappropriate in modern society. JAMA should consider reviewing its
      policy for choosing cover art.

PMID- 10600957
TI  - Alliteration in medicine: a puzzling profusion of p's.
AB  - PROBLEM: Puzzling, progressive profusion of alliterative "p's" in published
      papers. PURPOSE: To depict this particular "p" predominance with pinpoint
      precision. PLAN: Periodic, painstaking perusal of periodicals by a professor of
      paediatrics. PROPOSAL: The "p" plethora is positively perplexing and potentially
      perturbing.

PMID- 10600958
TI  - Questionnaire survey of post-traumatic stress disorder in doctors involved in the
      Omagh bombing.

PMID- 10600959
TI  - The lacing defence: double blind study of thresholds for detecting addition of
      ethanol to drinks.

PMID- 10600960
TI  - Surgeons swear when operating: fact or myth?

PMID- 10600961
TI  - Unsafe sax: cohort study of the impact of too much sax on the mortality of famous
      jazz musicians.

PMID- 10600962
TI  - Whither hospital linen? Two centre observational study of alien hospital linen.

PMID- 10600963
TI  - Are there excess Sharons in genitourinary clinics?

PMID- 10600964
TI  - Bangers and cash: multicentre survey of what doctors are driving.

PMID- 10600965
TI  - Always be prepared

PMID- 10600966
TI  - The next village

PMID- 10600967
TI  - On ageing: fading memory

PMID- 10600968
TI  - Seven alternatives to evidence based medicine.

PMID- 10600969
TI  - China's great famine: 40 years later.

PMID- 10600970
TI  - The price of coffins: specious arguments by eminent doctors against the dangers
      of tobacco.

PMID- 10600971
TI  - Dwale: an anaesthetic from old England.

PMID- 10600972
TI  - Alien babies

PMID- 10600973
TI  - Body piercing.

PMID- 10600974
TI  - Alternative (complementary) medicine: a cuckoo in the nest of empiricist reed
      warblers.

PMID- 10600976
TI  - The first legal cremation

PMID- 10600975
TI  - How work can be made less frustrating and conversation less boring.

PMID- 10600977
TI  - Medicine in Ulster in relation to the great famine and "the troubles".

PMID- 10600978
TI  - Conflict in Bosnia 1992-3.

PMID- 10600979
TI  - Walcheren 1809: a medical catastrophe.

PMID- 10600980
TI  - Case of chronic fatigue syndrome after Crimean war and Indian mutiny.

PMID- 10600981
TI  - Paediatrics on the peace line.

PMID- 10600982
TI  - Prisoner of war camps-memories of a remarkable evening.

PMID- 10600983
TI  - The bottlewasher and the ambassador.

PMID- 10600984
TI  - On losing your molecular privacy.

PMID- 10600985
TI  - How do you eat an elephant?

PMID- 10600986
TI  - Childhood: a public health issue.

PMID- 10600987
TI  - Guess the advert

PMID- 10600989
TI  - Paying tribute to Ireland's doctors

PMID- 10600988
TI  - Conflict, coitus, conversation: the eternals

PMID- 10600990
TI  - Survey provides no evidence that medical students turn cynical and unaltruistic

PMID- 10600991
TI  - MRI proves that leonardo da vinci got sexual anatomy wrong

PMID- 10600992
TI  - Shaken martinis may be more effective antioxidants than stirred ones

PMID- 10600994
TI  - P's predominate in published papers

PMID- 10600993
TI  - JAMA covers reflect inappropriate stereotypes of women

PMID- 10600995
TI  - What is a Cajal-Retzius cell? A reassessment of a classical cell type based on
      recent observations in the developing neocortex.

PMID- 10600996
TI  - Cajal-Retzius cell physiology: just in time to bridge the 20th century.
AB  - Cajal-Retzius (CR) cells were discovered at the end of the 19th century but,
      surprisingly, the exploration of their physiological properties is only now
      beginning, as we near the end of the 20th century. A few papers addressing these
      properties have appeared recently, but incomplete data generally give the
      arguably misleading impression that CR cells are similar to other neocortical
      neurons, and therefore may perform analogous functions. It is one of the motives
      of this review to dispel such conceptions. Although CR cells display features of
      'regular' neurons, including excitability and responsiveness to
      neurotransmitters, their function is probably limited to the primary
      implementation of cortical circuits. A strong indication in support of this idea
      is the fact that CR cells appear at the onset of neocorticogenesis and disappear
      at the end of neuronal migration.

PMID- 10600997
TI  - Comparative development of the mammalian isocortex and the reptilian dorsal
      ventricular ridge. Evolutionary considerations.
AB  - There has been a long debate about a possible homology between parts of the
      dorsal ventricular ridge (DVR) of reptiles and birds, and parts of the mammalian
      isocortex. Correspondence between these structures was originally proposed on the
      basis of connectional similarities between the DVR of birds and the mammalian
      auditory and extrastriate visual isocortical areas. Furthermore, the proposal of
      homology includes the possible embryological similarity of cells that give rise
      to the DVR and cells that give rise to the isocortex. Against this concept it has
      been claimed that the DVR and the isocortex originate in topographically
      different pallial compartments, an interpretation that is supported by recent
      developmental and molecular data. Other studies indicate that migrating cells can
      cross the borders between adjacent developmental compartments: cells that
      originate in subcortical components contribute a number of interneurons to the
      developing isocortex via tangential migration. This mechanism might reconcile the
      proposed homology with the developmental evidence, since cells originating in one
      compartment (the one corresponding to DVR) may become included in structures
      generated in a different compartment (the one corresponding to isocortex).
      However, there is no evidence in mammals of a structure homologous to the
      embryonic DVR that can produce isocortical neurons. In order to fully clarify the
      problem of isocortical origins, further comparative studies are needed of the
      embryonic development of the lateral and dorsal aspects of the cerebral
      hemispheres in amphibians, reptiles and mammals.

PMID- 10600998
TI  - Segregation and convergence of functionally defined V2 thin stripe and
      interstripe compartment projections to area V4 of macaques.
AB  - The organization of projections from V2 thin stripes and interstripes to V4 was
      investigated using a combination of physiological and anatomical techniques. The
      compartments of V2 were first characterized, in vivo, using optical recording of
      intrinsic signals. Multiple anterograde tracers were then injected into different
      V2 compartments. The distribution of labeled axons was analyzed in tangential or
      horizontal sections including V4. A small iontophoretic injection, either in a
      thin stripe or an interstripe, labeled a large primary and several secondary foci
      in V4. The primary foci from the thin stripe and interstripe were spatially
      segregated by a gap of approximately 1 mm. Furthermore, less dense regions within
      the primary foci were often 'filled-in' by secondary foci from the opposite V2
      compartment. When two injections were made both at interstripes, their
      projections to V4 were almost entirely overlapping. These anatomical patterns
      indicate that segregation and convergence of intercortical pathways are both
      important features of V4 organization. Furthermore, the size of cortical modules
      increases considerably from the blobs of V1, through the stripes of V2, to the
      afferent domains of V4.

PMID- 10600999
TI  - The effects of age on the neural correlates of episodic encoding.
AB  - Young and old adults underwent positron emission tomographic scans while encoding
      pictures of objects and words using three encoding strategies: deep processing (a
      semantic living/nonliving judgement), shallow processing (size judgement) and
      intentional learning. Picture memory exceeded word memory in both young and old
      groups, and there was an age-related decrement only in word recognition. During
      the encoding tasks three brain activity patterns were found that differentiated
      stimulus type and the different encoding strategies. The stimulus-specific
      pattern was characterized by greater activity in extrastriate and medial temporal
      cortices during picture encoding, and greater activity in left prefrontal and
      temporal cortices during encoding of words. The older adults showed this pattern
      to a significantly lesser degree. A pattern distinguishing deep processing from
      intentional learning of words and pictures was identified, characterized mainly
      by differences in prefrontal cortex, and this pattern also was of significantly
      lesser magnitude in the old group. A final pattern identified areas with
      increased activity during deep processing and intentional learning of pictures,
      including left prefrontal and bilateral medial temporal regions. There was no
      group difference in this pattern. These results indicate age-related dysfunction
      in several encoding networks, with sparing of one specifically involved in more
      elaborate encoding of pictures. These age-related changes appear to affect verbal
      memory more than picture memory.

PMID- 10601000
TI  - The functional neuroanatomy of target detection: an fMRI study of visual and
      auditory oddball tasks.
AB  - The neuronal response patterns that are required for an adequate behavioural
      reaction to subjectively relevant changes in the environment are commonly studied
      by means of oddball paradigms, in which occasional 'target' stimuli have to be
      detected in a train of frequent 'non-target' stimuli. The detection of such task
      relevant stimuli is accompanied by a parietocentral positive component of the
      event-related potential, the P300. We performed EEG recordings of visual and
      auditory event-related potentials and functional magnetic resonance imaging
      (fMRI) when healthy subjects performed an oddball task. Significant increases in
      fMRI signal for target versus non-target conditions were observed in the
      supramarginal gyrus, frontal operculum and insular cortex bilaterally, and in
      further circumscribed parietal and frontal regions. These effects were consistent
      over various stimulation and response modalities and can be regarded as specific
      for target detection in both the auditory and the visual modality. These results
      therefore contribute to the understanding of the target detection network in
      human cerebral cortex and impose constraints on attempts at localizing the
      neuronal P300 generator. This is of importance both from a neurobiological
      perspective and because of the widespread application of the physiological
      correlates of target detection in clinical P300 studies.

PMID- 10601001
TI  - Cyclin E-p27 opposition and regulation of the G1 phase of the cell cycle in the
      murine neocortical PVE: a quantitative analysis of mRNA in situ hybridization.
AB  - We have analyzed the expression patterns of mRNAs of five cell cycle related
      proteins in the ventricular zone of the neocortical cerebral wall over the course
      of the neuronogenetic interval in the mouse. One set of mRNAs (cyclin E and p21)
      are initially expressed at high levels but expression then falls to a low
      asymptote. A second set (p27, cyclin B and cdk2) are initially expressed at low
      levels but ascend to peak levels only to decline again. These patterns divide the
      overall neuronogenetic interval into three phases. In phase 1 cyclin E and p21
      levels of mRNA expression are high, while those of mRNAs of p27, cdk2 and cyclin
      B are low. In this phase the fraction of cells leaving the cycle after each
      mitosis, Q, is low and the duration of the G1 phase, TG1, is short. In phase 2
      levels of expression of cyclin E and p21 fall to asymptote while levels of
      expression of mRNA of the other three proteins reach their peaks. Q increases to
      approach 0.5 and TG1 increases even more rapidly to approach its maximum length.
      In phase 3 levels of expression of cyclin E and p21 mRNAs remain low and those of
      the mRNAs of the other three proteins fall. TG1 becomes maximum and Q rapidly
      increases to 1.0. The character of these phases can be understood in part as
      consequences of the reciprocal regulatory influence of p27 and cyclin E and of
      the rate limiting functions of p27 at the restriction point and of cyclin E at
      the G1 to S transition.

PMID- 10601002
TI  - Intracortical excitation of spiny neurons in layer 4 of cat striate cortex in
      vitro.
AB  - Recordings were made from pairs of neurons in cat striate visual cortex in vitro
      to study the AMPA-channel-mediated components of intracortical excitatory
      synaptic connections between layer 4 spiny neurons and between layer 6 and layer
      4 spiny neurons. Forty-six of the 72 cells recorded were identified
      morphologically. They consisted of spiny stellate and pyramidal cells in layer 4,
      and pyramidal cells in layer 6. Connections between layer 4 excitatory cells
      involve excitatory postsynaptic potentials (EPSPs) averaging 949 microV, with an
      average coefficient of variation of 0.21 (n = 30). The synapses operate at very
      high release probabilities (0.69-0.98). With repetitive stimulation these EPSPs
      show varying degrees of depression, largely mediated by presynaptic changes in
      release probability. Four pairs of layer 4 cells were reciprocally connected. The
      connections from layer 6 to layer 4 involve smaller, more variable EPSPs, with an
      average amplitude of 214 microV, and average coefficient of variation 0.72 (n =
      7). These synapses operate at moderately high release probabilities (0.37-0.56).
      They show facilitation with repetitive stimulation, mediated largely by
      presynaptic changes in release probability. One excitatory connection from a
      layer 4 neuron to a layer 6 pyramidal cell was also detected. Thus, layer 4 spiny
      neurons receive effective excitation from two intracortical sources that have
      different synaptic dynamics and are likely to contribute significantly to the
      temporal properties of these cells in vivo.

PMID- 10601003
TI  - Noradrenergic innervation of peptidergic interneurons in the rat visual cortex.
AB  - Previous studies have shown that cortical interneurons, presumably GABAergic, are
      among the targets of the noradrenaline (NA)-containing cortical afferents and
      that NA interacts with neuropeptides at various cellular levels. The present
      study attempts to characterize further the cortical targets of the NA afferents
      by examining, at the light and the electron microscopic level, the anatomical
      relationships of the NA fibers with three subpopulations of cortical
      interneurons, those containing somatostatin (SRIF), neuropeptide Y (NPY) or
      vasoactive intestinal polypeptide (VIP). For this purpose, a double preembedding
      immunoprocedure with antibodies against NA and SRIF, NPY or VIP was combined with
      the gold-substituted silver peroxidase method. Light microscopic examination
      showed that NA fibers contact perikarya and proximal dendrites of the SRIF, NPY
      and VIP neurons. However, NA fibers, while found to form pericellular arrays
      around NPY neurons and, to a lesser extent, around SRIF neurons, were seen to
      target VIP cortical cells with single terminal varicosities. Electron microscopy
      revealed that all peptidergic populations examined represent synaptic targets for
      the NA fibers. The NAergic synapses, localized onto the cell body and proximal
      dendrites of the peptidergic neurons, were always of the symmetrical variety.
      Results of the present study provide the morphological basis for the explanation
      of the functional interaction between the NA cortical afferent system and the
      intrinsic cortical elements.

PMID- 10601004
TI  - Timing and spatial distribution of somatosensory responses recorded in the upper
      bank of the sylvian fissure (SII area) in humans.
AB  - We studied responses of the parieto-frontal opercular cortex to electric stimuli,
      as recorded by intra-cortical electrodes during stereotactic EEG presurgical
      assessment of patients with drug-resistant temporal lobe epilepsy. After
      electrical stimulation of the median nerve at the wrist, we consistently recorded
      a negative-positive biphasic response peaking at 60 ms (N60) and 90 ms (P90) post
      stimulus in the upper bank of the sylvian fissure contralateral to stimulation.
      Talairach stereotactic coordinates of the electrode contacts recording these
      responses covered the pre- and post-rolandic part of the upper bank of the
      sylvian fissure (25<x<55 mm; -27<y<+13 mm; 0<z<21 mm), corresponding to the
      accepted localization of SII area in man. The sources of these responses were
      deeply situated in the cortex of the upper bank of the sylvian fissure at
      approximately 40 mm from the midline sagittal plane, so that some of them could
      be located in the insular cortex. Moreover this study suggests the existence of
      dipolar SII sources radial to the scalp surface, which are overlooked in magnetic
      recordings. Somatosensory evoked potentials (SEPs) recorded in SII are delayed by
      approximately 40 ms as compared with SEPs generated in the primary somatosensory
      cortex. This long delay between SI and SII responses is not fully explained
      though it is coherent with the timing of activation issued from MEG source
      modeling data.

PMID- 10601005
TI  - Development of neuronal activity and activity-dependent expression of brain
      derived neurotrophic factor mRNA in organotypic cultures of rat visual cortex.
AB  - We have analyzed in organotypic rat visual cortex cultures the way in which
      expression of brain-derived neurotrophic factor (BDNF) mRNA depends on
      synaptically generated spontaneous bioelectric activity (SBA) as monitored by
      recordings of pyramidal cells. SBA was initially low, but from the fourth week
      onwards 83% of the neurons fired action potentials at 0.2-1.2 impulses/s in a
      well-balanced state of excitation and inhibition. BDNF mRNA expression increased
      during the second week to a level surprisingly similar to the adult visual cortex
      in vivo, despite the fact that activity rates in vitro were approximately 10-fold
      lower than rates reported in vivo. Thus, SBA generated by a cortical neuronal
      network in the absence of sensory input is sufficient to elicit and maintain BDNF
      expression. The transient BDNF peak occurring after eye opening in vivo did not
      occur in vitro. A blockade of SBA seems not to alter the expression of
      neurotrophin (NT)-3 and -4/5, and tyrosine kinase receptor C and B mRNA. However,
      BDNF expression remained extremely low. A recovery of SBA after a period of
      blockade concurred with a transient hyperexcitability. BDNF immediately
      increased, driven by calcium influx through voltage-gated channels in synergy
      with NMDA receptors. Expression transiently reached high levels in neurons of
      supragranular layers. Infragranular neurons, although firing action potentials,
      recovered BDNF expression much slower. After 5 days in vitro recovery, the
      network had de novo established a balanced state of excitation and inhibition.
      Distribution and expression level of BDNF mRNA had returned to control. Even in
      'adult' cultures an acute blockade of SBA downregulated BDNF, and a subsequent
      recovery of SBA restored BDNF expression. We conclude that BDNF mRNA expression
      depends on and responds with a fast kinetic to changes of the SBA. Steady-state
      levels do not depend on the absolute levels of activity, but more likely on the
      balance between excitation and inhibition, suggesting a role for BDNF in activity
      homeostasis.

PMID- 10601006
TI  - A neural model of motion processing and visual navigation by cortical area MST.
AB  - Cells in the dorsal medial superior temporal cortex (MSTd) process optic flow
      generated by self-motion during visually guided navigation. A neural model shows
      how interactions between well-known neural mechanisms (log polar cortical
      magnification, Gaussian motion-sensitive receptive fields, spatial pooling of
      motion-sensitive signals and subtractive extraretinal eye movement signals) lead
      to emergent properties that quantitatively simulate neurophysiological data about
      MSTd cell properties and psychophysical data about human navigation. Model cells
      match MSTd neuron responses to optic flow stimuli placed in different parts of
      the visual field, including position invariance, tuning curves, preferred spiral
      directions, direction reversals, average response curves and preferred locations
      for stimulus motion centers. The model shows how the preferred motion direction
      of the most active MSTd cells can explain human judgments of self-motion
      direction (heading), without using complex heading templates. The model explains
      when extraretinal eye movement signals are needed for accurate heading
      perception, and when retinal input is sufficient, and how heading judgments
      depend on scene layouts and rotation rates.

PMID- 10601007
TI  - Sex differences in the inferior parietal lobule.
AB  - The inferior parietal lobule (IPL) - a neocortical region and part of the
      heteromodal association cortex (HASC) - has been hypothesized to exhibit sexual
      dimorphism, as do other HASC regions, particularly with regard to asymmetry.
      Using a reliable method for measuring IPL gray matter volume based upon
      individual sulcal-gyral landmarks, we measured this region on magnetic resonance
      imaging scans from a sample of 15 individually matched pairs of normal male and
      female subjects. Male subjects showed significantly larger left, but not right,
      IPL volumes when compared to females. Males also showed a leftward (left > right)
      asymmetry for the IPL, with a less marked opposite asymmetry in females. Such
      sexual dimorphisms may possibly underlie the subtle cognitive differences
      observed between the sexes.

PMID- 10601008
TI  - Wnt signaling and the activation of myogenesis in mammals.
AB  - In the amniote embryos, specification of skeletal myoblasts occurs in the
      paraxial mesoderm in response to a number of signaling molecules produced by
      neighboring tissues such as neural tube, notochord and dorsal ectoderm. Candidate
      molecules for this complex signaling activity include Sonic hedgehog, Wnts and
      Noggin as positive activators and BMP4 as a possible inhibitor. Recently, the
      receptors and the post-receptor pathways for Sonic hedgehog and Wnts have been
      characterized, and this has opened up the possibility of linking these signaling
      events to the activation of myogenic regulatory factor genes such as Myf5 and
      MyoD and functionally related genes such as Pax3. Here we focus on the role of
      Wnts, their putative receptors Frizzled and the soluble antagonist Frzb1 in
      regulating mammalian myogenesis. Although it is becoming evident that the
      signaling downstream of Frizzled receptors is much more complex than anticipated,
      it is conceivable that it may lead to transcriptional activation of Myf5 and MyoD
      and to initiation of myogenesis. However, the fact that both Wnts and Sonic
      hedgehog have a strong effect on cell proliferation and survival suggests that
      they may contribute to the overall process of myogenesis by a combination of
      these different biological activities.

PMID- 10601009
TI  - Planar polarity in the Drosophila eye: a multifaceted view of signaling
      specificity and cross-talk.
AB  - Functional tissues not only polarize their epithelia in the apical-basolateral
      axis, but also often display a polarity within the plane of the epithelium. In
      Drosophila, all adult structures are derived from epithelia called imaginal discs
      and display planar polarization; the eye and the wing are particularly well
      suited for analysis. Studies of their polarization have identified several
      conserved genes that regulate both nuclear signaling and cytoskeletal
      architecture. In particular, the Frizzled (Fz) receptor has been identified as a
      key component of polarity establishment in all tissues. The Fz signaling pathway
      and associated events are beginning to be unraveled, shedding light on a novel
      Wnt/Fz signaling cascade.

PMID- 10601010
TI  - Crystal structure of calpain reveals the structural basis for Ca(2+)-dependent
      protease activity and a novel mode of enzyme activation.
AB  - The combination of thiol protease activity and calmodulin-like EF-hands is a
      feature unique to the calpains. The regulatory mechanisms governing calpain
      activity are complex, and the nature of the Ca(2+)-induced switch between
      inactive and active forms has remained elusive in the absence of structural
      information. We describe here the 2.6 A crystal structure of m-calpain in the
      Ca(2+)-free form, which illustrates the structural basis for the inactivity of
      calpain in the absence of Ca(2+). It also reveals an unusual thiol protease fold,
      which is associated with Ca(2+)-binding domains through heterodimerization and a
      C(2)-like beta-sandwich domain. Strikingly, the structure shows that the
      catalytic triad is not assembled, indicating that Ca(2+)-binding must induce
      conformational changes that re-orient the protease domains to form a functional
      active site. The alpha-helical N-terminal anchor of the catalytic subunit does
      not occupy the active site but inhibits its assembly and regulates Ca(2+)
      sensitivity through association with the regulatory subunit. This Ca(2+)
      dependent activation mechanism is clearly distinct from those of classical
      proteases.

PMID- 10601011
TI  - Crystal structure of the ARF-GAP domain and ankyrin repeats of PYK2-associated
      protein beta.
AB  - ADP ribosylation factors (ARFs), which are members of the Ras superfamily of GTP
      binding proteins, are critical components of vesicular trafficking pathways in
      eukaryotes. Like Ras, ARFs are active in their GTP-bound form, and their duration
      of activity is controlled by GTPase-activating proteins (GAPs), which assist ARFs
      in hydrolyzing GTP to GDP. PAPbeta, a protein that binds to and is phosphorylated
      by the non-receptor tyrosine kinase PYK2, contains several modular signaling
      domains including a pleckstrin homology domain, an SH3 domain, ankyrin repeats
      and an ARF-GAP domain. Sequences of ARF-GAP domains show no recognizable
      similarity to those of other GAPs, and contain a characteristic Cys-X(2)-Cys-X(16
      17)-Cys-X(2)-Cys motif. The crystal structure of the PAPbeta ARF-GAP domain and
      the C-terminal ankyrin repeats has been determined at 2.1 A resolution. The ARF
      GAP domain comprises a central three-stranded beta-sheet flanked by five alpha
      helices, with a Zn(2+) ion coordinated by the four cysteines of the cysteine-rich
      motif. Four ankyrin repeats are also present, the first two of which form an
      extensive interface with the ARF-GAP domain. An invariant arginine and several
      nearby hydrophobic residues are solvent exposed and are predicted to be the site
      of interaction with ARFs. Site-directed mutagenesis of these residues confirms
      their importance in ARF-GAP activity.

PMID- 10601012
TI  - Crystal structure of UvrB, a DNA helicase adapted for nucleotide excision repair.
AB  - Nucleotide excision repair (NER) is a highly conserved DNA repair mechanism. NER
      systems recognize the damaged DNA strand, cleave it on both sides of the lesion,
      remove and newly synthesize the fragment. UvrB is a central component of the
      bacterial NER system participating in damage recognition, strand excision and
      repair synthesis. We have solved the crystal structure of UvrB in the apo and the
      ATP-bound forms. UvrB contains two domains related in structure to helicases, and
      two additional domains unique to repair proteins. The structure contains all
      elements of an intact helicase, and is evidence that UvrB utilizes ATP hydrolysis
      to move along the DNA to probe for damage. The location of conserved residues and
      structural comparisons allow us to predict the path of the DNA and suggest that
      the tight pre-incision complex of UvrB and the damaged DNA is formed by insertion
      of a flexible beta-hairpin between the two DNA strands.

PMID- 10601013
TI  - The monomeric homing endonuclease PI-SceI has two catalytic centres for cleavage
      of the two strands of its DNA substrate.
AB  - The monomeric homing endonuclease PI-SceI cleaves the two strands of its DNA
      substrate in a concerted manner, which raises the question of whether this enzyme
      harbours one or two catalytic centres. If PI-SceI has only one catalytic centre,
      one would expect that cross-linking enzyme and substrate should prevent
      reorientation of the enzyme required to perform the second cut after having made
      the first cut: PI-SceI, however, when cross-linked to its substrate, is able to
      cleave both DNA strands. If PI-SceI has two catalytic centres, one would expect
      that it should be possible to inactivate one catalytic centre by mutation and
      obtain a variant with preference for a substrate nicked in one strand; such
      variants have been found. The structural homology between the catalytic domain of
      PI-SceI having a pseudo 2-fold symmetry, and I-CreI, a homodimeric homing
      endonuclease, suggests that in PI-SceI active site I, which attacks the top
      strand, comprises Asp218, Asp229 and Lys403, while Asp326, Thr341 and Lys301 make
      up active site II, which cleaves the bottom strand. Cleavage experiments with
      modified oligodeoxynucleotides and metal ion mapping experiments demonstrate that
      PI-SceI interacts differently with the two strands at the cleavage position,
      supporting a model of two catalytic centres.

PMID- 10601014
TI  - Functionally different GPI proteins are organized in different domains on the
      neuronal surface.
AB  - We have investigated the organization, on the plasma membrane and in detergent
      insoluble membrane vesicles, of two neuronal glycosylphosphatidylinositol
      anchored (GPI) proteins: Thy-1, a negative regulator of transmembrane signalling;
      and prion protein, whose rapid endocytosis and Cu(2+) binding suggest that it
      functions in metal ion uptake. Prion protein occurred on the neuronal surface at
      high density in domains, located primarily at the cell body, which were
      relatively soluble in detergent. Thy-1, although much more abundantly expressed
      on neurons, occurred at lower density over much of the surface of neurites (and
      in lower abundance at the cell body) in domains that were highly resistant to
      detergent solubilization. Detergent-insoluble membrane vesicles contained Thy-1
      at a density similar to that on the neuronal surface. Vesicles containing each
      protein could be separated by immunoaffinity isolation; lectin binding showed
      that they were enriched in different glycoproteins. Our results demonstrate a
      structural diversity of the domains occupied by functionally different GPI
      proteins.

PMID- 10601015
TI  - Effects of macromolecular crowding on protein folding and aggregation.
AB  - We have studied the effects of polysaccharide and protein crowding agents on the
      refolding of oxidized and reduced hen lysozyme in order to test the prediction
      that association constants of interacting macromolecules in living cells are
      greatly increased by macromolecular crowding relative to their values in dilute
      solutions. We demonstrate that whereas refolding of oxidized lysozyme is hardly
      affected by crowding, correct refolding of the reduced protein is essentially
      abolished due to aggregation at high concentrations of crowding agents. The
      results show that the protein folding catalyst protein disulfide isomerase is
      particularly effective in preventing lysozyme aggregation under crowded
      conditions, suggesting that crowding enhances its chaperone activity. Our
      findings suggest that the effects of macromolecular crowding could have major
      implications for our understanding of how protein folding occurs inside cells.

PMID- 10601016
TI  - Identification of thermolabile Escherichia coli proteins: prevention and
      reversion of aggregation by DnaK and ClpB.
AB  - We systematically analyzed the capability of the major cytosolic chaperones of
      Escherichia coli to cope with protein misfolding and aggregation during heat
      stress in vivo and in cell extracts. Under physiological heat stress conditions,
      only the DnaK system efficiently prevented the aggregation of thermolabile
      proteins, a surprisingly high number of 150-200 species, corresponding to 15-25%
      of detected proteins. Identification of thermolabile DnaK substrates by mass
      spectrometry revealed that they comprise 80% of the large (>/=90 kDa) but only
      18% of the small (</=30 kDa) cytosolic proteins and include essential proteins.
      The DnaK system in addition acts with ClpB to form a bi-chaperone system that
      quantitatively solubilizes aggregates of most of these proteins. Efficient
      solubilization also occurred in an in vivo order-of-addition experiment in which
      aggregates were formed prior to induction of synthesis of the bi-chaperone
      system. Our data indicate that large-sized proteins are most vulnerable to
      thermal unfolding and aggregation, and that the DnaK system has central, dual
      protective roles for these proteins by preventing their aggregation and,
      cooperatively with ClpB, mediating their disaggregation. KEYWORDS:
      chaperones/heat-shock response/Hsp70/protein denaturation/thermotolerance

PMID- 10601017
TI  - Recruitment of the protein tyrosine phosphatase CSW by DOS is an essential step
      during signaling by the sevenless receptor tyrosine kinase.
AB  - The pleckstrin homology (PH) domain-containing protein Daughter of Sevenless
      (DOS) is an essential component of the Sevenless receptor tyrosine kinase (SEV)
      signaling cascade, which specifies R7 photoreceptor development in the Drosophila
      eye. Previous results have suggested that DOS becomes tyrosine phosphorylated
      during SEV signaling and collaborates with the protein tyrosine phosphatase CSW.
      We have investigated this possibility by identifying tyrosine residues 801 and
      854 of DOS as the phosphorylated binding sites for the CSW SH2 domains. We show
      that these sites become phosphorylated in response to SEV activation and that
      phosphorylation of both sites is required to allow CSW to bind DOS. Mutant DOS
      proteins in which either Y801 or Y854 of DOS has been changed to phenylalanine
      are unable to function during signaling by SEV and other receptor tyrosine
      kinases. In contrast, we find that a mutant DOS protein in which all tyrosine
      phosphorylation sites except Y801 and Y854 have been removed is able effectively
      to provide DOS function during SEV signaling and to rescue the lethality
      associated with dos loss-of-function mutations. These results indicate that a
      primary role for DOS during signaling by SEV and other receptor tyrosine kinases
      is to become phosphorylated at Y801 and Y854 and then recruit CSW.

PMID- 10601018
TI  - Ectodomain shedding of TGF-alpha and other transmembrane proteins is induced by
      receptor tyrosine kinase activation and MAP kinase signaling cascades.
AB  - A variety of transmembrane proteins, such as transforming growth factor-alpha
      (TGF-alpha), tumor necrosis factor-alpha (TNF-alpha) and L-selectin, undergo
      shedding, i.e. cleavage of the ectodomain, resulting in release of a soluble
      protein. Although the physiological relevance of ectodomain shedding is well
      recognized, little is known about the signaling mechanisms activating this
      process. We show that growth factor activation of cell surface tyrosine kinase
      receptors induces ectodomain cleavage of transmembrane TGF-alpha through
      activation of the Erk MAP kinase signaling cascade without the need for new
      protein synthesis. In addition, expression of constitutively activated MEK1 or
      its downstream target Erk2 MAP kinase was sufficient to stimulate TGF-alpha
      shedding. The basal cleavage level in the absence of exogenous growth factor
      stimulation was due to p38 MAP kinase signaling. Accordingly, a constitutively
      activated MKK6, a p38 activator, activated TGF-alpha shedding in the absence of
      exogenous stimuli. In addition to TGF-alpha shedding, these mechanisms also
      mediate L-selectin and TNF-alpha cleavage. Thus, L-selectin shedding by
      neutrophils, induced by N-formylmethionyl-leucyl-phenylalanine, was strongly
      inhibited by inhibitors of Erk MAP kinase or p38 MAP kinase signaling. Our
      results indicate that activation of Erk and p38 signaling pathways may represent
      a general physiological mechanism to induce shedding of a variety of
      transmembrane proteins.

PMID- 10601019
TI  - Cell type-specific activation of mitogen-activated protein kinases by CpG-DNA
      controls interleukin-12 release from antigen-presenting cells.
AB  - Activation of antigen-presenting cells (APCs) by invariant constituents of
      pathogens such as lipopolysaccharide (LPS) or bacterial DNA (CpG-DNA) initiates
      immune responses. We have analyzed the mitogen-activated protein kinase (MAPK)
      pathways triggered by CpG-DNA and their significance for cytokine production in
      two subsets of APCs, i.e. macrophages and dendritic cells (DCs). We found that
      CpG-DNA induced extracellular signal-regulated kinase (ERK) activity in
      macrophages in a classic MEK-dependent way. This pathway up-regulated tumor
      necrosis factor production but down-regulated interleukin (IL)-12 production.
      However, in DCs, which produce large amounts of IL-12, CpG-DNA and LPS failed to
      induce ERK activity. Consistent with a specific negative regulatory role for ERK
      in macrophages, chemical activation of this pathway in DCs suppressed CpG-DNA
      induced IL-12 production. Overall, these results imply that differential
      activation of MAP kinase pathways is a basic mechanism by which distinct subsets
      of innate immune cells regulate their effector functions.

PMID- 10601020
TI  - Direct inhibition of G(1) cdk kinase activity by MyoD promotes myoblast cell
      cycle withdrawal and terminal differentiation.
AB  - MyoD has been proposed to facilitate terminal myoblast differentiation by binding
      to and inhibiting phosphorylation of the retinoblastoma protein (pRb). Here we
      show that MyoD can interact with cyclin-dependent kinase 4 (cdk4) through a
      conserved 15 amino acid (aa) domain in the C-terminus of MyoD. MyoD, its C
      terminus lacking the basic helix-loop-helix (bHLH) domain, or the 15 aa cdk4
      binding domain all inhibit the cdk4-dependent phosphorylation of pRb in vitro.
      Cellular expression of full-length MyoD or fusion proteins containing either the
      C-terminus or just the 15 aa cdk4-binding domain of MyoD inhibit cell growth and
      pRb phosphorylation in vivo. The minimal cdk4-binding domain of MyoD fused to GFP
      can also induce differentiation of C2C12 muscle cells in growth medium. The
      defective myogenic phenotype in MyoD-negative BC3H1 cells can be rescued
      completely only when MyoD contains the cdk4-binding domain. We propose that a
      regulatory checkpoint in the terminal cell cycle arrest of the myoblast during
      differentiation involves the modulation of the cyclin D cdk-dependent
      phosphorylation of pRb through the opposing effects of cyclin D1 and MyoD.

PMID- 10601021
TI  - Interaction between developmental and cell cycle regulators is required for
      morphogenesis in Aspergillus nidulans.
AB  - In Aspergillus nidulans, mutation of the transcriptional regulator brlA arrests
      formation of asexual spore-forming structures called conidiophores but does not
      hinder vegetative hyphal growth. During conidiophore development a 6-fold, brlA
      dependent increase in the kinase activities of NIMX(cdc2) and NIMA occurs. A
      similar level of kinase induction was promoted by ectopic expression of brlA.
      Northern and Western analysis revealed marked induction of nimX(cdc2) mRNA after
      ectopic expression of brlA and increased amounts of NIMX(cdc2). Therefore,
      nimX(cdc2) is developmentally regulated by brlA indicating a direct role for brlA
      in the regulation of cell cycle genes. That correct regulation of nimX(cdc2) is
      important for normal development was further supported by analysis of
      conidiophore development and septation in cell cycle specific mutants. Most
      noticeably, the nimX(cdc2AF) mutation promoted inappropriate septation and
      hindered the switch from filamentous growth to budding growth seen during
      conidiophore development. Therefore, in contrast to the situation previously
      reported for other multicellular eukaryotes, interaction between developmental
      regulators and cell cycle regulators is essential for normal morphogenesis in
      A.nidulans.

PMID- 10601022
TI  - Serine15 phosphorylation stimulates p53 transactivation but does not directly
      influence interaction with HDM2.
AB  - The p53 tumour suppressor protein is a labile transcription factor that is
      activated and stabilized in response to a wide range of cellular stresses,
      through a mechanism involving disruption of its interaction with MDM2, a negative
      regulatory partner. Induction of p53 by DNA damage additionally involves a series
      of phosphorylation and acetylation modifications, some of which are thought to
      regulate MDM2 binding. Here we report the effects of introducing mutations at
      several known or putative N-terminal phosphorylation sites on the transactivation
      function of p53. These studies highlight phosphorylation of Ser15, a key
      phosphorylation target during the p53 activation process, as being critical for
      p53-dependent transactivation. Biochemical data indicate that the mechanism by
      which phosphorylation of Ser15 stimulates p53-dependent transactivation occurs
      through increased binding to the p300 coactivator protein. The data also indicate
      that Ser15-dependent regulation of transactivation is independent of any
      involvement in modulating MDM2 binding, and that Ser15 phosphorylation alone is
      not sufficient to block the p53-MDM2 interaction.

PMID- 10601023
TI  - RAR-independent RXR signaling induces t(15;17) leukemia cell maturation.
AB  - Although retinoic acid receptor alpha (RARalpha) agonists induce the maturation
      of t(15;17) acute promyelocytic leukemia (APL) cells, drug treatment also selects
      leukemic blasts expressing PML-RARalpha fusion proteins with mutated ligand
      binding domains that no longer respond to all-trans retinoic acid (ATRA). Here we
      report a novel RARalpha-independent signaling pathway that induces maturation of
      both ATRA-sensitive and ATRA-resistant APL NB4 cells, and does not invoke the
      ligand-induced alteration of PML-RARalpha signaling, stability or
      compartmentalization. This response involves a cross-talk between RXR agonists
      and protein kinase A signaling. Our results indicate the existence of a separate
      RXR-dependent maturation pathway that can be activated in the absence of known
      ligands for RXR heterodimerization partners.

PMID- 10601024
TI  - Mga, a dual-specificity transcription factor that interacts with Max and contains
      a T-domain DNA-binding motif.
AB  - The basic-helix-loop-helix-leucine zipper (bHLHZip) proteins Myc, Mad and Mnt are
      part of a transcription activation/repression system involved in the regulation
      of cell proliferation. The function of these proteins as transcription factors is
      mediated by heterodimerization with the small bHLHZip protein Max, which is
      required for their specific DNA binding to E-box sequences. We have identified a
      novel Max-interacting protein, Mga, which contains a Myc-like bHLHZip motif, but
      otherwise shows no relationship with Myc or other Max-interacting proteins. Like
      Myc, Mad and Mnt proteins, Mga requires heterodimerization with Max for binding
      to the preferred Myc-Max-binding site CACGTG. In addition to the bHLHZip domain,
      Mga contains a second DNA-binding domain: the T-box or T-domain. The T-domain is
      a highly conserved DNA-binding motif originally defined in Brachyury and
      characteristic of the Tbx family of transcription factors. Mga binds the
      preferred Brachyury-binding sequence and represses transcription of reporter
      genes containing promoter-proximal Brachyury-binding sites. Surprisingly, Mga is
      converted to a transcription activator of both Myc-Max and Brachyury site
      containing reporters in a Max-dependent manner. Our results suggest that Mga
      functions as a dual-specificity transcription factor that regulates the
      expression of both Max-network and T-box family target genes.

PMID- 10601025
TI  - Osa associates with the Brahma chromatin remodeling complex and promotes the
      activation of some target genes.
AB  - The yeast SWI/SNF complex and its Drosophila and mammalian homologs are thought
      to control gene expression by altering chromatin structure, but the mechanism and
      specificity of this process are not fully understood. The Drosophila osa gene,
      like yeast SWI1, encodes an AT-rich interaction (ARID) domain protein. We present
      genetic and biochemical evidence that Osa is a component of the Brahma complex,
      the Drosophila homolog of SWI/SNF. The ARID domain of Osa binds DNA without
      sequence specificity in vitro, but it is sufficient to direct transcriptional
      regulatory domains to specific target genes in vivo. Endogenous Osa appears to
      promote the activation of some of these genes. We show evidence that some Brahma
      containing complexes do not contain Osa and that Osa is not required to localize
      Brahma to chromatin. These data suggest that Osa modulates the function of the
      Brahma complex.

PMID- 10601026
TI  - SIR repression of a yeast heat shock gene: UAS and TATA footprints persist within
      heterochromatin.
AB  - Previous work has suggested that products of the Saccharomyces cerevisiae Silent
      Information Regulator (SIR) genes form a complex with histones, nucleated by cis
      acting silencers or telomeres, which represses transcription in a position
      dependent but sequence-independent fashion. While it is generally thought that
      this Sir complex works through the establishment of heterochromatin, it is
      unclear how this structure blocks transcription while remaining fully permissive
      to other genetic processes such as recombination or integration. Here we examine
      the molecular determinants underlying the silencing of HSP82, a transcriptionally
      potent, stress-inducible gene. We find that HSP82 is efficiently silenced in a
      SIR-dependent fashion, but only when HMRE mating-type silencers are configured
      both 5' and 3' of the gene. Accompanying dominant repression are novel wrapped
      chromatin structures within both core and upstream promoter regions. Strikingly,
      DNase I footprints mapping to the binding sites for heat shock factor (HSF) and
      TATA-binding protein (TBP) are strengthened and broadened, while groove-specific
      interactions, as detected by dimethyl sulfate, are diminished. Our data are
      consistent with a model for SIR repression whereby transcriptional activators
      gain access to their cognate sites but are rendered unproductive by a co-existing
      heterochromatic complex.

PMID- 10601027
TI  - C to U editing of the anticodon of imported mitochondrial tRNA(Trp) allows
      decoding of the UGA stop codon in Leishmania tarentolae.
AB  - All mitochondrial tRNAs in kinetoplastid protists are encoded in the nucleus and
      imported into the organelle. The tRNA(Trp)(CCA) can decode the standard UGG
      tryptophan codon but can not decode the mitochondrial UGA tryptophan codon. We
      show that the mitochondrial tRNA(Trp) undergoes a specific C to U nucleotide
      modification in the first position of the anticodon, which allows decoding of
      mitochondrial UGA codons as tryptophan. Functional evidence for the absence of a
      UGA suppressor tRNA in the cytosol, using a reporter gene, was also obtained,
      which is consistent with a mitochondrial localization of this editing event.
      Leishmania cells have dealt with the problem of a lack of expression within the
      organelle of this non-universal tRNA by compartmentalizing an editing activity
      that modifies the anticodon of the imported tRNA.

PMID- 10601028
TI  - The Escherichia coli trmE (mnmE) gene, involved in tRNA modification, codes for
      an evolutionarily conserved GTPase with unusual biochemical properties.
AB  - The evolutionarily conserved 50K protein of Escherichia coli, encoded by o454,
      contains a consensus GTP-binding motif. Here we show that 50K is a GTPase that
      differs extensively from regulatory GTPases such as p21. Thus, 50K exhibits a
      very high intrinsic GTPase hydrolysis rate, rather low affinity for GTP, and
      extremely low affinity for GDP. Moreover, it can form self-assemblies.
      Strikingly, the 17 kDa GTPase domain of 50K conserves the guanine nucleotide
      binding and GTPase activities of the intact 50K molecule. Therefore, the
      structural requirements for GTP binding and GTP hydrolysis by 50K are without
      precedent and justify a separate classification in the GTPase superfamily.
      Immunoelectron microscopy reveals that 50K is a cytoplasmic protein partially
      associated with the inner membrane. We prove that o454 is allelic with trmE, a
      gene involved in the biosynthesis of the hypermodified nucleoside 5
      methylaminomethyl-2-thiouridine, which is found in the wobble position of some
      tRNAs. Our results demonstrate that 50K is essential for viability depending on
      the genetic background. We propose that combination of mutations affecting the
      decoding process, which separately do not reveal an obvious defect in growth, can
      give rise to lethal phenotypes, most likely due to synergism.

PMID- 10601029
TI  - Aphid transmission of cauliflower mosaic virus requires the viral PIII protein.
AB  - The open reading frame (ORF) III product (PIII) of cauliflower mosaic virus is
      necessary for the infection cycle but its role is poorly understood. We have used
      in vitro protein binding ('far Western') assays to demonstrate that PIII
      interacts with the cauliflower mosaic virus (CaMV) ORF II product (PII), a known
      aphid transmission factor. Aphid transmission of purified virions of the PII
      defective strain CM4-184 was dependent upon added PII, but complementation was
      efficient only in the presence of PIII, demonstrating the requirement of PIII for
      transmission. Deletion mutagenesis mapped the interaction domains of PIII and PII
      to the 30 N-terminal and 61 C-terminal residues of PIII and PII, respectively. A
      model for interaction between PIII and PII is proposed on the basis of secondary
      structure predictions. Finally, a direct correlation between the ability of PIII
      and PII to interact and aphid transmissibility of the virus was demonstrated by
      using mutagenized PIII proteins. Taken together, these data argue strongly that
      PIII is a second 'helper' factor required for CaMV transmission by aphids.

PMID- 10601030
TI  - The genetic transformation of bone biology.

PMID- 10601031
TI  - Yeast autonomously replicating sequence binding factor is involved in nucleotide
      excision repair.
AB  - Nucleotide excision repair (NER) in yeast is effected by the concerted action of
      a large complex of proteins. Recently, we identified a stable subcomplex
      containing the yeast Rad7 and Rad16 proteins. Here, we report the identification
      of autonomously replicating sequence binding factor 1 (ABF1) as a component of
      the Rad7/Rad16 NER subcomplex. Yeast ABF1 protein is encoded by an essential gene
      required for DNA replication, transcriptional regulation, and gene silencing. We
      show that ABF1 plays a direct role in NER in vitro. Additionally, consistent with
      a role of ABF1 protein in NER in vivo, we show that certain temperature-sensitive
      abf1 mutant strains that are defective in DNA replication are specifically
      defective in the removal of photoproducts by NER and are sensitive to killing by
      ultraviolet (UV) radiation. These studies define a novel and unexpected role for
      ABF1 protein during NER in yeast.

PMID- 10601032
TI  - Mutational analysis of RAG1 and RAG2 identifies three catalytic amino acids in
      RAG1 critical for both cleavage steps of V(D)J recombination.
AB  - RAG1 and RAG2 initiate V(D)J recombination, the process of rearranging the
      antigen-binding domain of immunoglobulins and T-cell receptors, by introducing
      site-specific double-strand breaks (DSB) in chromosomal DNA during lymphocyte
      development. These breaks are generated in two steps, nicking of one strand
      (hydrolysis), followed by hairpin formation (transesterification). The nature and
      location of the RAG active site(s) have remained unknown. Because acidic amino
      acids have a critical role in catalyzing DNA cleavage by nucleases and
      recombinases that require divalent metal ions as cofactors, we hypothesized that
      acidic active site residues are likewise essential for RAG-mediated DNA cleavage.
      We altered each conserved acidic amino acid in RAG1 and RAG2 by site-directed
      mutagenesis, and examined >100 mutants using a combination of in vivo and in
      vitro analyses. No conserved acidic amino acids in RAG2 were critical for
      catalysis; three RAG1 mutants retained normal DNA binding, but were catalytically
      inactive for both nicking and hairpin formation. These data argue that one active
      site in RAG1 performs both steps of the cleavage reaction. Amino acid
      substitution experiments that changed the metal ion specificity suggest that at
      least one of these three residues contacts the metal ion(s) directly. These data
      suggest that RAG-mediated DNA cleavage involves coordination of divalent metal
      ion(s) by RAG1.

PMID- 10601033
TI  - Mutations of acidic residues in RAG1 define the active site of the V(D)J
      recombinase.
AB  - The RAG1 and RAG2 proteins collaborate to initiate V(D)J recombination by binding
      recombination signal sequences (RSSs) and making a double-strand break between
      the RSS and adjacent coding DNA. Like the reactions of their biochemical cousins,
      the bacterial transposases and retroviral integrases, cleavage by the RAG
      proteins requires a divalent metal ion but does not involve a covalent
      protein/DNA intermediate. In the transposase/integrase family, a triplet of
      acidic residues, commonly called a DDE motif, is often found to coordinate the
      metal ion used for catalysis. We show here that mutations in each of three acidic
      residues in RAG1 result in mutant derivatives that can bind the RSS but whose
      ability to catalyze either of the two chemical steps of V(D)J cleavage (nicking
      and hairpin formation) is severely impaired. Because both chemical steps are
      affected by the same mutations, a single active site appears responsible for both
      reactions. Two independent lines of evidence demonstrate that at least two of
      these acidic residues are directly involved in coordinating a divalent metal ion:
      The substitution of Cys for Asp allows rescue of some catalytic function, whereas
      an alanine substitution is no longer subject to iron-induced hydroxyl radical
      cleavage. Our results support a model in which the RAG1 protein contains the
      active site of the V(D)J recombinase and are interpreted in light of predictions
      about the structure of RAG1.

PMID- 10601034
TI  - The cAMP receptor protein CRP can function as an osmoregulator of transcription
      in Escherichia coli.
AB  - Transcription of the P1 promoter of the Escherichia coli proP gene, which encodes
      a transporter of osmoprotectants, is strongly induced by a shift to hyperosmotic
      media. Unlike most other osmotically regulated promoters, the induction occurs
      for a brief period of time, corresponding to the replacement of intracellular
      K(+) glutamate with osmoprotecting compounds. This burst of proP transcription is
      correlated with the osmolarity-dependent binding of the cAMP receptor protein CRP
      to a site within the proP P1 promoter. We show that CRP-cAMP functions as an
      osmotically sensitive repressor of proP P1 transcription in vitro. Binding of CRP
      to the proP promoter in vivo is transiently destabilized after a hyperosmotic
      shift with kinetics that correspond to the derepression of transcription, whereas
      Fis and Lac repressor binding is not osmotically sensitive. Similar osmotic
      regulation of proP P1 transcription by the CRP* mutant implies that binding of
      cAMP is not responsible for the unusual osmotic sensitivity of CRP activity.
      Osmotic regulation of CRP activity is not limited to proP. Activation of the lac
      promoter by CRP is also transiently inhibited after an osmotic upshift, as is the
      binding of CRP to the galdelta4P1 promoter. These findings suggest that CRP
      functions in certain contexts to regulate gene expression in response to osmotic
      changes, in addition to its  role in catabolite control.

PMID- 10601035
TI  - The homeodomain protein vax1 is required for axon guidance and major tract
      formation in the developing forebrain.
AB  - The homeodomain protein Vax1 is expressed in a highly circumscribed set of cells
      at the ventral anterior midline of the embryonic CNS. These cells populate the
      choroid fissure of the optic disk, the body of the optic stalk and nerve, the
      optic chiasm and ventral diencephalon, and the anterior midline zones that abut
      developing commissural tracts. We have generated mutant mice that lack Vax1. In
      these mice (1) the optic disks fail to close, leading to coloboma and loss of the
      eye-nerve boundary; (2) optic nerve glia fail to associate with and appear to
      repulse ingrowing retinal axons, resulting in a fascicle of axons that are
      completely segregated from optic nerve astrocytes; (3) retinal axons fail to
      penetrate the brain in significant numbers and fail to form an optic chiasm; and
      (4) axons in multiple commissural tracts of the anterior CNS, including the
      corpus callosum and the hippocampal and anterior commissures, fail to cross the
      midline. These axon guidance defects do not result from the death of normally
      Vax1(+) midline cells but, instead, correlate with markedly diminished expression
      of attractive guidance cues in these cells. Vax1 therefore regulates the guidance
      properties of a set of anterior midline cells that orchestrate axon trajectories
      in the developing mammalian forebrain.

PMID- 10601036
TI  - Vax1, a novel homeobox-containing gene, directs development of the basal
      forebrain and visual system.
AB  - The novel homeobox-containing gene Vax1, a member of the Emx/Not gene family, is
      specifically expressed in the developing basal forebrain and optic nerve. Here,
      we show that Vax1 is essential for normal development of these structures. Mice
      carrying a targeted mutation of Vax1 show dysgenesis of the optic nerve,
      coloboma, defects in the basal telencephalon, and lobar holoprosencephaly. With
      the help of molecular markers we determined that in the developing visual system,
      the absence of Vax1 results in a proximal expansion of the activity of Pax6 and
      Rx. This observation suggests that Vax1 may interfere negatively with the
      expression of Pax6 and Rx. In reciprocal gain-of-function experiments, injection
      of Xvax1 mRNA or Shh into Xenopus embryos primarily affects the brain at the
      level of the eye primordium. Consistent with the loss-of-function results, the
      injection of Xvax1 results in a down-regulation of Rx. Similarly, Shh injection
      expands the Vax1 and Pax2 territory at the expense of the Pax6 and Rx region. On
      the basis of these results, we propose a model for a molecular cascade involved
      in the establishment of structures of the visual system.

PMID- 10601037
TI  - Oppositely imprinted genes p57(Kip2) and igf2 interact in a mouse model for
      Beckwith-Wiedemann syndrome.
AB  - Beckwith-Wiedemann syndrome (BWS) is a clinically variable disorder characterized
      by somatic overgrowth, macroglossia, abdominal wall defects, visceromegaly, and
      an increased susceptibility to childhood tumors. The disease has been linked to a
      large cluster of imprinted genes at human chromosome 11p15.5. A subset of BWS
      patients has been identified with loss-of-function mutations in p57(KIP2), a
      maternally expressed gene encoding a G(1) cyclin-dependent kinase inhibitor. Some
      patients display loss of imprinting of IGF2, a fetal-specific growth factor that
      is paternally expressed. To understand how the same disease can result from
      misregulation of two linked, but unrelated, genes, we generated a mouse model for
      BWS that both harbors a null mutation in p57(Kip2) and displays loss of Igf2
      imprinting. These mice display many of the characteristics of BWS, including
      placentomegaly and dysplasia, kidney dysplasia, macroglossia, cleft palate,
      omphalocele, and polydactyly. Some, but not all, of the phenotypes are shown to
      be Igf2 dependent. In two affected tissues, the two imprinted genes appear to act
      in an antagonistic manner, a finding that may help explain how BWS can arise from
      mutations in either gene.

PMID- 10601038
TI  - Compartmentalized signaling by GPI-anchored ephrin-A5 requires the Fyn tyrosine
      kinase to regulate cellular adhesion.
AB  - Eph receptor tyrosine kinases and their corresponding surface-bound ligands, the
      ephrins, provide cues to the migration of cells and growth cones during embryonic
      development. Here we show that ephrin-A5, which is attached to the outer leaflet
      of the plasma membrane by a glycosyl-phosphatidylinositol-anchor, induces
      compartmentalized signaling within a caveolae-like membrane microdomain when
      bound to the extracellular domain of its cognate Eph receptor. The physiological
      response induced by this signaling event is concomitant with a change in the
      cellular architecture and adhesion of the ephrin-A5-expressing cells and requires
      the activity of the Fyn protein tyrosine kinase. This study stresses the
      relevance of bidirectional signaling involving the ephrins and Eph receptors
      during brain development.

PMID- 10601039
TI  - Cre-mediated gene inactivation demonstrates that FGF8 is required for cell
      survival and patterning of the first branchial arch.
AB  - In mammals, the first branchial arch (BA1) develops into a number of craniofacial
      skeletal elements including the jaws and teeth. Outgrowth and patterning of BA1
      during early embryogenesis is thought to be controlled by signals from its
      covering ectoderm. Here we used Cre/loxP technology to inactivate the mouse Fgf8
      gene in this ectoderm and have obtained genetic evidence that FGF8 has a dual
      function in BA1: it promotes mesenchymal cell survival and induces a
      developmental program required for BA1 morphogenesis. Newborn mutants lack most
      BA1-derived structures except those that develop from the distal-most region of
      BA1, including lower incisors. The data suggest that the BA1 primordium is
      specified into a large proximal region that is controlled by FGF8, and a small
      distal region that depends on other signaling molecules for its outgrowth and
      patterning. Because the mutant mice resemble humans with first arch syndromes
      that include agnathia, our results raise the possibility that some of these
      syndromes are caused by mutations that affect FGF8 signaling in BA1 ectoderm.

PMID- 10601041
TI  - INNER NO OUTER regulates abaxial- adaxial patterning in Arabidopsis ovules.
AB  - The Arabidopsis INNER NO OUTER (INO) gene is essential for formation and
      asymmetric growth of the ovule outer integument. INO encodes a member of the
      newly described YABBY family of putative transcription factors that contain
      apparent Cys(2)-Cys(2) zinc-finger domains and regions of similarity to the high
      mobility group (HMG) transcription factors. In wild-type plants, INO is expressed
      specifically on one side of the central region of each ovule primordium in the
      cells that give rise to the outer integument. Alterations in the INO expression
      pattern in mutant backgrounds implicate INO as a positive regulator of its own
      expression, and ANT, HLL, BEL1, and SUP as direct or indirect negative regulators
      that help to establish the spatial pattern of INO expression. We hypothesize that
      INO is necessary for polarity determination in the central part of the ovule.
      Maintenance of polarity in other parts of ino ovules indicates the existence of
      additional regulators and provides further evidence that the ovule is a compound
      structure.

PMID- 10601042
TI  - Hepatopulmonary syndromes.

PMID- 10601040
TI  - Wnt signaling in Xenopus embryos inhibits bmp4 expression and activates neural
      development.
AB  - We report a new role for Wnt signaling in the vertebrate embryo: the induction of
      neural tissue from ectoderm. Early expression of mouse wnt8, Xwnt8, beta-catenin,
      or dominant-negative GSK3 induces the expression of neural-specific markers and
      inhibits the expression of Bmp4 in Xenopus ectoderm. We show that Wnt8, but not
      the BMP antagonist Noggin, can inhibit Bmp4 expression at early gastrula stages.
      Furthermore, inhibition of beta-catenin activity in the neural ectoderm of whole
      embryos by a truncated TCF results in a decrease in neural development.
      Therefore, we suggest that a cleavage-stage Wnt signal normally contributes to an
      early repression of Bmp4 on the dorsal side of the embryo and sensitizes the
      ectoderm to respond to neural inducing signals from the organizer. The Wnt
      targets Xnr3 and siamois have been shown previously to have neuralizing activity
      when overexpressed. However, antagonists of Wnt signaling, dnXwnt8 and Nxfrz8,
      inhibit Wnt-mediated Xnr3 and siamois induction, but not neural induction,
      suggesting an alternative mechanism for Bmp repression and neuralization.
      Conversely, dnTCF blocks both Wnt-mediated Xnr3 and neural induction, suggesting
      that both pathways require this transcription factor.

PMID- 10601043
TI  - Informed consent.

PMID- 10601044
TI  - Immunological and genetic links in Crohn's disease.

PMID- 10601045
TI  - IBS: prime problem in primary care.

PMID- 10601046
TI  - UDCA, PBC and biochemistry: what does normal mean?

PMID- 10601047
TI  - Relative risk of dysplasia for patients with intestinal metaplasia in the distal
      oesophagus and in the gastric cardia.
AB  - BACKGROUND: Biopsy specimens obtained from the gastro-oesophageal junction can
      reveal intestinal metaplasia in patients presenting for routine upper endoscopy.
      The site of biopsy may play a critical role in determining the dysplasia risk of
      a patient. AIMS: To evaluate prospectively the dysplasia risk in patients with
      intestinal metaplasia of the distal oesophagus or within the gastric cardia.
      METHODS: Patients with short segment Barrett's oesophagus (SSBO) and cardia
      intestinal metaplasia (CIM) were followed prospectively. RESULTS: 177 patients
      with SSBO were identified (mean age 62 years, range 38-82; 91% whites). Twenty
      prevalence cases of dysplasia in SSBO were detected: 17 low grade dysplasia
      (LGD), three high grade dysplasia (HGD). Seventy six patients with CIM were
      identified (mean age 67 years, range 37-81; 81% whites). A single prevalence case
      of LGD in CIM was detected. During follow up of 78 SSBO and 34 CIM patients,
      dysplasia developed in nine (seven LGD, two HGD) with SSBO and in one (LGD) with
      CIM. There were significant differences between the two groups with respect to
      age, ethnicity, dysplasia prevalence, and incidence. Time to dysplasia
      progression was significantly longer in CIM compared with SSBO patients. Of the
      five patients with SSBO and HGD, one developed adenocarcinoma of the oesophagus
      on follow up. No HGD or cancers have been detected over this time period in CIM
      patients. CONCLUSIONS: The dysplasia risk is significantly greater in SSBO than
      in CIM patients, indicating two potentially different clinical processes. Future
      studies should separate SSBO from CIM in order to enhance the understanding of
      the pathophysiology and malignant potential of each entity.

PMID- 10601048
TI  - Expression of CD44 variants and prognosis in oesophageal squamous cell carcinoma.
AB  - BACKGROUND: The CD44 variant (CD44v) isoforms have been noted as markers for
      tumour metastasis and prognosis in several adenocarcinomas. AIMS: To investigate
      whether CD44v, especially the CD44v2 (v2) isoform, may be a useful prognostic
      factor for patients with oesophageal squamous cell carcinoma, using a recently
      developed monoclonal antibody against a v2 epitope. PATIENTS: 233 patients (211
      men and 22 women; mean age 61.9 years), with oesophageal squamous cell carcinomas
      curatively removed without additional treatment between 1987 and 1996 at the
      National Cancer Center Hospital, were analysed for CD44v expression. METHODS: The
      expression of CD44v was evaluated immunohistochemically using monoclonal
      antibodies against epitopes of the standard and variant protein, in paraffin
      embedded oesophageal squamous cell carcinoma tissue from 233 patients who had
      undergone cervical, mediastinal, and abdominal lymphadenectomy (three field
      dissection) for oesophagectomy. The data were evaluated for any correlation with
      clinicopathological indices or prognosis. RESULTS: Although total CD44 and CD44v6
      (v6) were respectively observed in 99% and 97% of the cancer specimens, the
      expression of v2 was only 30%. Patients whose tumours were v2 positive had a
      significantly better prognosis than those whose tumours were v2 negative (p =
      0.031). Furthermore, in patients without lymph node metastasis, v2 positivity
      alone was a significant independent factor of prognosis (relative risk of death
      associated with v2 negativity, 4.7; p = 0.037) in multivariate analysis.
      CONCLUSIONS: These results indicate that v2 is a useful marker for clinical
      prognosis in patients with oesophageal squamous cell carcinoma. Particularly in
      patients without lymph node metastasis, v2 status may thus have implications for
      the use of adjuvant chemotherapy and/or radiotherapy in patients with oesophageal
      cancer at an early stage.

PMID- 10601049
TI  - Changes in gastric acid secretion assayed by endoscopic gastrin test before and
      after Helicobacter pylori eradication.
AB  - BACKGROUND: It remains controversial whether or not Helicobacter pylori infection
      causes altered gastric acid secretion. A novel test for evaluating gastric acid
      secretion (endoscopic gastrin test; EGT) has recently been developed. AIM: To
      investigate by EGT the effects of H pylori eradication on the state of gastric
      acid secretion in patients with peptic ulcer. METHODS: Twenty six patients with
      duodenal ulcer and 33 with gastric ulcer, for all of whom H pylori infection had
      been documented, were studied by EGT, histological examination of gastric mucosa,
      and measurement of plasma gastrin levels before and one and seven months after H
      pylori eradication. RESULTS: In patients with duodenal ulcer, the mean EGT value
      before H pylori eradication was higher than that in H pylori negative controls,
      but it had decreased significantly seven months after the treatment. In contrast,
      the mean EGT value of patients with gastric ulcer before H pylori eradication was
      lower than that in H pylori negative controls, but it had increased one month
      after the treatment; this was followed by a slight decrease at seven months. In
      both groups, mean EGT values seven months after the treatment were not
      significantly different from the mean control value. CONCLUSIONS: The reduced
      acid secretion in gastric ulcer patients and gastric acid hypersecretion in
      duodenal ulcer patients were both normalised after the clearance of H pylori.

PMID- 10601050
TI  - Peptic ulcer bleeding: accessory risk factors and interactions with non-steroidal
      anti-inflammatory drugs.
AB  - AIMS: To determine risk factors for peptic ulcer bleeding other than non
      steroidal anti-inflammatory drugs (NSAIDs). Methods-Data on possible antecedent
      risk factors obtained in a large case control study of 1121 patients admitted to
      hospitals in Glasgow, Newcastle, Nottingham, Oxford, and Portsmouth with bleeding
      peptic ulcers were compared with the same information obtained in 989 population
      controls. Data were analysed by logistic regression with the calculation of odds
      ratios (OR) and 95% confidence intervals (CI). RESULTS: From a logistic
      regression model, oral anticoagulants (OR 7. 8; 95% CI 2.8-21.5), previous peptic
      ulcer (3.8; 2.6-4.9), treatment for heart failure (5.9; 2.3-13.1), oral
      corticosteroid use (2.7; 1. 3-4.5), treatment for diabetes (3.1; 1.2-4.3), and
      current smoking (1.6; 1.2-2.0) were all independent risk factors. No association
      was found with use of calcium channel antagonists. Odds ratios for concomitant
      NSAID usage were multiplicative with the exception of current smoking.
      CONCLUSIONS: Some 45% of admissions for peptic ulcer bleeding in England and
      Wales in those aged 60 or more are calculated to be attributable to, or
      associated with, these accessory risk factors, which, together with those
      associated with aspirin or other NSAID use will account for over 80% of
      predisposing factors to ulcer bleeding.

PMID- 10601051
TI  - Sensations induced by medium and long chain triglycerides: role of gastric tone
      and hormones.
AB  - BACKGROUND: The relative roles of gastric relaxation and the neuroendocrine
      signals released by the small intestine in the perception of nutrient induced
      sensations are controversial. The different effects of long chain (LCT) and
      medium chain (MCT) triglyceride ingestion on perception, gastric relaxation, and
      hormonal release may help to elucidate the mechanisms underlying nutrient induced
      sensations. AIMS: To compare the effects of intraduodenal LCT and MCT infusions
      on perception, gastric tone, and plasma gut hormone levels in healthy subjects.
      SUBJECTS: Nine fasting healthy volunteers. METHODS: The subjects received
      duodenal infusions of saline followed by LCTs and MCTs in a randomised order on
      two different days. The sensations were rated on a visual analogue scale. Gastric
      tone was measured using a barostat, and plasma gut hormone levels by
      radioimmunoassay. RESULTS: LCT infusion increased satiation scores, reduced
      gastric tone, and increased the levels of plasma cholecystokinin, gastric
      inhibitory polypeptide, neurotensin, and pancreatic polypeptide. MCT infusion
      reduced gastric tone but did not significantly affect perception or plasma gut
      hormone levels. LCTs produced greater gastric relaxation than MCTs. CONCLUSIONS:
      The satiation induced by intraduodenal LCT infusion seems to involve changes in
      gastric tone and plasma gut hormone levels. The gastric relaxation induced by MCT
      infusion, together with the absence of any significant change in satiation scores
      and plasma hormone levels, suggests that, at least up to a certain level, gastric
      relaxation is not sufficient to induce satiation and that nutrient induced
      gastric relaxation may occur through cholecystokinin independent mechanisms.

PMID- 10601052
TI  - Postal consent for upper gastrointestinal endoscopy.
AB  - BACKGROUND: Standards for good practice in clinical risk management issued by the
      Clinical Negligence Scheme for Trusts indicate that "appropriate information is
      provided to patients on the risks and benefits of proposed treatment, and of the
      alternatives available before a signature on a consent form is sought". AIMS: To
      investigate the practicability and patient acceptability of a postal information
      and consent booklet for patients undergoing outpatient gastroscopy. METHODS:
      Information about gastroscopy procedure, personalised appointment details, and a
      carbonised consent form were compiled into a single booklet. This was mailed to
      patients well in advance of their endoscopic procedure. Patient satisfaction for
      this new process was assessed by questionnaire. RESULTS: 275 patients received a
      patient information booklet. Of these, 150 (54.5%) returned the consent form by
      post when they confirmed their attendance; 141 (94%) had signed the form, and the
      other nine requested further information. Of the remaining 125 booklets sent out,
      115 (92%) forms were brought back on the day of the investigation having been
      previously signed. The remaining 10 (8%) required further information before
      signing the form. An audit of 168 patients was used to test reaction to the
      booklet and the idea of filling in the form before coming to hospital; 155
      patients (92. 2%) reported the information given in the booklet to be "very
      useful", and all reported it to be "clear and understandable". CONCLUSION: A
      specifically designed patient information booklet with integral consent form is
      accepted by patients, and improves the level of understanding prior to the
      investigation being carried out.

PMID- 10601053
TI  - Diversion of intestinal flow decreases the numbers of interleukin 4 secreting and
      interferon gamma secreting T lymphocytes in small bowel mucosa.
AB  - BACKGROUND/AIMS: The intestinal immune system faces large amounts of antigens,
      and its regulation is tightly balanced by cytokines. In this study, the effect of
      intestinal flow diversion on spontaneous secretion of interleukin (IL)-4 and
      interferon (IFN)- gamma was analysed. METHODS: Eight patients (two with Crohn's
      disease, four with ulcerative colitis, and two with previous colon cancer)
      carrying a double lumen small bowel stoma after a total colectomy procedure were
      included in the study. For each patient, eight biopsy samples were taken
      endoscopically from both the diverted and non-diverted part of the small bowel.
      Intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) were
      isolated separately and assayed for numbers of cells spontaneously secreting IL-4
      and/or IFN-gamma by an ELISPOT technique. RESULTS: Compared with the non-diverted
      mucosa, a significant decrease in the number of spontaneously IFN-gamma secreting
      CD3 lymphocytes was observed in the diverted small bowel mucosa among both IELs
      (p = 0.008) and LPLs (p = 0.007). The same results, although less significant,
      were obtained for IL-4, especially in LPLs (p = 0.01). CONCLUSION: The intestinal
      content influences the spontaneous secretion of IFN-gamma and IL-4 by intestinal
      lymphocytes. These results could help to elucidate the anti-inflammatory role of
      split ileostomy in patients suffering from inflammatory bowel diseases.

PMID- 10601054
TI  - Production of a panel of recombinant gliadins for the characterisation of T cell
      reactivity in coeliac disease.
AB  - BACKGROUND/AIMS: Coeliac disease is a chronic intestinal disorder most probably
      caused by an abnormal immune reaction to wheat gliadin. The identification of the
      HLA-DQ2 and HLA-DQ8 as the molecules responsible for the HLA association in
      coeliac disease strongly implicates a role for CD4 T cells in disease
      pathogenesis. Indeed, CD4 T cells specific for gliadin have been isolated from
      the small intestine of patients with coeliac disease. However, identification of
      T cell epitopes within gliadin has been hampered by the heterogeneous nature of
      the gliadin antigen. To aid the characterisation of gliadin T cell epitopes,
      multiple recombinant gliadins have been produced from a commercial Nordic wheat
      cultivar. METHODS: The alpha-gliadin and gamma-gliadin genes were amplified by
      polymerase chain reaction from cDNA and genomic DNA, cloned into a pET expression
      vector, and sequenced. Genes encoding mature gliadins were expressed in
      Escherichia coli and tested for recognition by T cells. RESULTS: In total, 16
      alpha-gliadin genes with complete open reading frames were sequenced. These genes
      encoded 11 distinct gliadin proteins, only one of which was found in the Swiss
      Prot database. Expression of these gliadin genes produced a panel of recombinant
      alpha-gliadin proteins of purity suitable for use as an antigen for T cell
      stimulation. CONCLUSION: This study provides an insight into the complexity of
      the gliadin antigen present in a wheat strain and has defined a panel of pure
      gliadin antigens that should prove invaluable for the future mapping of epitopes
      recognised by intestinal T cells in coeliac disease.

PMID- 10601055
TI  - 13C-egg white breath test: a non-invasive test of pancreatic trypsin activity in
      the small intestine.
AB  - BACKGROUND: The recent availability of egg white protein highly enriched with
      (13)C has allowed breath test technology to be adapted for the study of protein
      digestion and absorption. Pancreatic trypsin is considered to be the key enzyme
      in the proteolytic cascade. AIM: To evaluate trypsin activity in the small
      intestine of healthy volunteers and patients with pancreatic disease by a
      recently developed (13)C-egg white breath test. METHODS: A total of 48 healthy
      volunteers and 30 patients with pancreatic disease were studied after ingestion
      of a test meal consisting of 22 g (13)C-labelled egg protein. Breath samples were
      taken before and after ingestion of the meal and analysed for (13)CO(2)
      concentration. Moreover, pancreatic trypsin output after maximal stimulation was
      measured in 13 patients and nine healthy volunteers. RESULTS: The six hour
      cumulative (13)CO(2) excretion in breath was significantly lower in patients than
      controls (mean (SEM): 6.23 (0.82)% v 19.16 (0. 58)%, p<0.0001). An excellent
      correlation was found between the six hour cumulative (13)CO(2) excretion and
      trypsin activity after maximal pancreatic stimulation. CONCLUSION: The non
      invasive (13)C-egg white breath test is promising as an indirect pancreatic
      proteolytic function test.

PMID- 10601056
TI  - Familial expression of anti-Saccharomyces cerevisiae mannan antibodies in
      affected and unaffected relatives of patients with Crohn's disease.
AB  - BACKGROUND: Crohn's disease is a familial disorder, and antiglycan antibodies to
      the cell wall mannan of Saccharomyces cerevisiae (ASCA) are highly correlated
      with Crohn's disease. AIMS: To determine whether there is a familial pattern for
      expression of serum levels of anti-mannan Ig, and whether this trait is expressed
      in clinically unaffected Crohn's disease family members. METHODS: 349 patients
      with Crohn's disease, 87 Crohn's disease affected relatives, 333 inflammatory
      bowel disease (IBD) free relatives, 58 spouses, and 190 healthy control patients
      were studied. Serum IgG and IgA binding activity to S cerevisiae cell wall mannan
      was quantitated by ELISA. RESULTS: A high percentage of patients with Crohn's
      disease (51.9%) and affected family members (56.3%) were seropositive for anti
      mannan Ig, compared with the normal control population (3.7%). Seropositive and
      seronegative phenotypes of Crohn's disease probands were correlated among all
      affected relatives, and this association was stronger in affected first degree
      relatives. Statistical intraclass correlations of quantitative anti-mannan Ig
      levels revealed significantly less variation within, rather than between
      families. A significant familial aggregation was observed for affected relatives;
      this was even stronger for unaffected relatives. While a significant familial
      aggregation was observed among unaffected siblings pairs, there was no
      significant correlation among marital pairs. CONCLUSION: Results show that anti
      mannan Ig in family members affected and unaffected with Crohn's disease is a
      familial trait for both affected and unaffected relatives. The lack of
      concordance in marital pairs indicates that familiality is due in part to a
      genetic factor or childhood environmental exposure.

PMID- 10601057
TI  - The contribution of sulphate reducing bacteria and 5-aminosalicylic acid to
      faecal sulphide in patients with ulcerative colitis.
AB  - BACKGROUND: Butyrate oxidation within the colonocyte is selectively inhibited by
      hydrogen sulphide, reproducing the metabolic lesion observed in active ulcerative
      colitis. AIMS: To study generation of hydrogen sulphide by sulphate reducing
      bacteria (SRB) and the effects of 5-aminosalicylic acid (5-ASA) in patients with
      ulcerative colitis in order to identify a role of this noxious agent in
      pathogenesis. PATIENTS: Fresh faeces were obtained from 37 patients with
      ulcerative colitis (23 with active disease) and 16 healthy controls. METHODS: SRB
      were enumerated from fresh faecal slurries and measurements made of sulphate
      reducing activity, and sulphate and hydrogen sulphide concentrations. The effect
      of 5-ASA on hydrogen sulphide production was studied in vitro. RESULTS: All
      controls and patients with active ulcerative colitis carried SRB and total viable
      counts were significantly related to the clinical severity grade. SRB were of two
      distinct types: rapidly growing strains (desulfovibrios) which showed high
      sulphate reduction rates, present in 30% of patients with ulcerative colitis and
      44% of controls; and slow growing strains which had little activity. In vitro, 5
      ASA inhibited sulphide production in a dose dependent manner; in patients with
      ulcerative colitis not on these drugs faecal sulphide was significantly higher
      than in controls (0.55 versus 0.25 mM, p=0.027). CONCLUSIONS: Counts and carriage
      rates of SRB in faeces of patients with ulcerative colitis are not significantly
      different from those in controls. SRB metabolism is not uniform between strains
      and alternative sources of hydrogen sulphide production exist in the colonic
      lumen which may be similarly inhibited by 5-ASA. The evidence for hydrogen
      sulphide as a metabolic toxin in ulcerative colitis remains circumstantial.

PMID- 10601058
TI  - In vivo measurement of colonic butyrate metabolism in patients with quiescent
      ulcerative colitis.
AB  - BACKGROUND: Butyrate, a short chain fatty acid produced by bacterial
      fermentation, is a major fuel source for the colonocyte. In vitro work has shown
      that ulcerative colitis may be characterised by a metabolic defect in colonocyte
      butyrate oxidation. AIMS: To investigate the rate of metabolism of rectally
      administered butyrate in patients with quiescent colitis. METHODS: [1-(13)C]
      butyrate enemas were administered to 11 patients with long standing quiescent
      ulcerative colitis and to 10 control patients. The rate of production of
      (13)CO(2) in exhaled breath over four hours was measured by isotope ratio mass
      spectrometry combined with indirect calorimetry in order to measure CO(2)
      production. This allowed calculation of the patients' resting energy expenditure
      and respiratory quotient. RESULTS: Over a four hour period, 325 (SEM 21) micromol
      (13)CO(2) was recovered in breath samples from the colitis group compared with
      322 (17) micromol from the control group (NS). The respiratory quotient of the
      colitic group was significantly lower than that of the control group. CONCLUSION:
      There was no difference in the rate of metabolism of butyrate between the two
      groups. It is unlikely that there is a primary metabolic defect of butyrate
      metabolism in patients with quiescent ulcerative colitis.

PMID- 10601059
TI  - Irritable bowel syndrome in general practice: prevalence, characteristics, and
      referral.
AB  - BACKGROUND AND AIMS: Little is known about the prevalence, symptoms, diagnosis,
      attitude, and referral to specialists of patients with irritable bowel syndrome
      (IBS) in general practice. This study aimed to determine these characteristics.
      METHODS: 3111 patients attending 36 general practitioners (GPs) at six varied
      locations in and near Bristol, UK, were screened to identify those with a
      gastrointestinal problem. These patients (n=255) and their doctors were given
      questionnaires. Six months later the case notes were examined to reach criteria
      based diagnoses of functional bowel disorders. RESULTS: Of 255 patients with a
      gastrointestinal complaint, 30% were judged to have IBS and 14% other functional
      disorders. Compared with 100 patients with an "organic" diagnoses, those with IBS
      were more often women and more often judged by their GP to be polysymptomatic and
      to have unexplained symptoms. The majority of patients with IBS (58%) were
      diagnosed as such by the GP; 22% had other functional diagnoses. Conversely,
      among 54 patients diagnosed as having IBS by the GPs, the criteria based
      diagnosis was indeed functional in 91%; only one patient had organic disease
      (proctitis). More patients with IBS than those with organic disease feared
      cancer. In most some fear remained after the visit to the doctor. On logistic
      regression analysis, predictors of referral to a specialist (29% referred) were
      denial of a role for stress, multiple tests, and frequent bowel movements.
      CONCLUSIONS: Half the patients with gut complaints seen by GPs have functional
      disorders. These are usually recognised, and few patients are referred. In IBS,
      cancer fears often remain, suggesting unconfident diagnosis or inadequate
      explanation.

PMID- 10601060
TI  - Psychological and sex features of delayed gut transit in functional
      gastrointestinal disorders.
AB  - BACKGROUND: The relation of demographic and psychological factors to the presence
      and extent of gut transit impairment in the functional gastrointestinal disorders
      has received little attention. AIMS: To compare the psychosocial and demographic
      features of patients with functional gastrointestinal disorders and delayed
      transit in one region of the gastrointestinal tract with those displaying more
      widespread delayed transit (that is, delay in two or three regions), and those
      with normal transit in all three regions. PATIENTS: Of 110 outpatient
      participants who satisfied standardised criteria for functional gastrointestinal
      disorders, 46 had delayed transit in one region, 32 had delay in two or three
      regions, and 17 exhibited normal transit in all regions. METHODS: Transit in the
      stomach, the small intestine, and the large intestine was assessed concurrently
      using a wholly scintigraphic technique; psychological status was assessed using
      established psychometric measures. RESULTS: Patients with delayed transit
      displayed demographic and psychological features that contrasted with patients
      with normal transit in all regions. In particular, widespread delayed transit
      featured female sex, a highly depressed mood state, increased age, frequent
      control of anger, and more severe gastric stasis, while the features
      distinguishing normal transit were male sex and high levels of hypochondriasis.
      CONCLUSION: These data suggest the existence of a distinct psychophysiological
      subgroup, defined by the presence of delayed transit, in patients with functional
      gastrointestinal disorders.

PMID- 10601061
TI  - Endosonographic features predictive of benign and malignant gastrointestinal
      stromal cell tumours.
AB  - BACKGROUND/AIM: Some endoscopic ultrasonographic (EUS) features have been
      reported to be suggestive of malignancy in gastrointestinal stromal cell tumours
      (SCTs). The aim of this study was to assess the predictive value of these
      features for malignancy. METHODS: A total of 56 histologically proven cases of
      SCT studied by EUS between 1989 and 1996 were reviewed. There were 42 gastric
      tumours, 12 oesophageal tumours, and two rectal tumours. The tumours were divided
      into two groups: (a) benign SCT, comprising benign leiomyoma (n = 34); (b)
      malignant or borderline SCT (n = 22), comprising leiomyosarcoma (n = 9),
      leiomyoblastoma (n = 9), and leiomyoma of uncertain malignant potential (n = 4).
      The main EUS features recorded were tumour size, ulceration, echo pattern, cystic
      spaces, extraluminal margins, and lymph nodes with a malignant pattern. The two
      groups were compared by univariate and multivariate analysis. RESULTS: Irregular
      extraluminal margins, cystic spaces, and lymph nodes with a malignant pattern
      were most predictive of malignant or borderline SCT. Pairwise combinations of the
      three features had a specificity and positive predictive value of 100% for
      malignant or borderline SCT, but a sensitivity of only 23%. The presence of at
      least one of these three criteria had 91% sensitivity, 88% specificity, and 83%
      predictive positive value. In multivariate analysis, cystic spaces and irregular
      margins were the only two features independently predictive of malignant
      potential. The features most predictive of benign SCTs were regular margins,
      tumour size < or = 30 mm, and a homogeneous echo pattern. When the three features
      were combined, histology confirmed a benign SCT in all cases. CONCLUSIONS: The
      combined presence of two out of three EUS features (irregular extraluminal
      margins, cystic spaces, and lymph nodes with a malignant pattern) had a positive
      predictive value of 100% for malignant or borderline gastrointestinal SCT.
      Tumours less than 30 mm in diameter with regular margins and a homogeneous echo
      pattern are usually benign.

PMID- 10601062
TI  - Gastric cancer and other endoscopic diagnoses in patients with benign dyspepsia.
AB  - BACKGROUND: It has been suggested that endoscopy could be replaced with non
      invasive assessment of helicobacter status in the initial work up of young
      dyspeptic patients without sinister symptoms. AIMS: To determine the incidence of
      gastro-oesophageal malignancy in young dyspeptic patients. METHODS: The Alberta
      Endoscopy Project captured clinical and demographic data on all endoscopies
      performed from April 1993 to February 1996 at four major adult hospitals in
      Alberta. The endoscopic and histological diagnosis in a subgroup of patients
      under 45 years of age without alarm symptoms that had undergone gastroscopy was
      reviewed. In addition, a random list of 200 patients was generated and their
      medical records reviewed in order to assess the proportion with symptoms suitable
      for a non-invasive management strategy. RESULTS: Gastroscopy was performed in
      7004 patients under 45 years. In 3634 patients (56% female) alarm type symptoms
      were absent; 78.9% of patients had symptoms amenable to a non-invasive initial
      approach, giving a corrected sample size of 2867 patients (correction factor
      0.789). Three gastric cancers, one case of moderate dysplasia, 10 biopsy proved
      cases of Barrett's oesophagus, and 19 oesophageal strictures/rings were detected
      within this sample. The corrected prevalence of gastric cancer in this select
      population was 1.05 per thousand patients. DISCUSSION: Endoscopy yielded three
      gastric cancers in this sample of under 45 year old dyspeptic patients without
      sinister symptoms. While initial non-invasive screening with one-week triple
      therapy for helicobacter positive individuals is unlikely to have a detrimental
      outcome the physician is advised to consider endoscopy in patients with
      persisting, recurrent, or sinister symptoms.

PMID- 10601063
TI  - Manometry based randomised trial of endoscopic sphincterotomy for sphincter of
      Oddi dysfunction.
AB  - BACKGROUND: Endoscopic sphincterotomy for biliary-type pain after cholecystectomy
      remains controversial despite evidence of efficacy in some patients with a high
      sphincter of Oddi (SO) basal pressure (SO stenosis). AIM: To evaluate the effects
      of sphincterotomy in patients randomised on the basis of results from endoscopic
      biliary manometry. METHODS: Endoscopic biliary manometry was performed in 81
      patients with biliary-type pain after cholecystectomy who had a dilated bile duct
      on retrograde cholangiography, transient increases in liver enzymes after
      episodes of pain, or positive responses to challenge with morphine/neostigmine.
      The manometric record was categorised as SO stenosis, SO dyskinesia, or normal,
      after which the patient was randomised in each category to sphincterotomy or to a
      sham procedure in a prospective double blind study. Symptoms were assessed at
      intervals of three months for 24 months by an independent observer, and the
      effects of sphincterotomy on sphincter function were monitored by repeat
      manometry after three and 24 months. RESULTS: In the SO stenosis group, symptoms
      improved in 11 of 13 patients treated by sphincterotomy and in five of 13
      subjected to a sham procedure (p = 0.041). When manometric records were
      categorised as dyskinesia or normal, results from sphincterotomy and sham
      procedures did not differ. Complications were rare, but included mild
      pancreatitis in seven patients (14 episodes) and a collection in the right upper
      quadrant, presumably related to a minor perforation. At three months, the
      endoscopic incision was extended in 19 patients because of manometric evidence of
      incomplete division of the sphincter. CONCLUSION: In patients with presumed SO
      dysfunction, endoscopic sphincterotomy is helpful in those with manometric
      features of SO stenosis.

PMID- 10601064
TI  - Performance characteristics of magnetic resonance cholangiography in the staging
      of malignant hilar strictures.
AB  - BACKGROUND: Magnetic resonance cholangiography (MRC) is currently under
      investigation for non-invasive biliary tract imaging. AIM: To compare MRC with
      endoscopic retrograde cholangiography (ERC) for pretreatment evaluation of
      malignant hilar obstruction. METHODS: Twenty patients (11 men, nine women; median
      age 74 years) referred for endoscopic palliation of a hilar obstruction were
      included. The cause of the hilar obstruction was a cholangiocarcinoma in 15
      patients and a hilar compression in five (one hepatocarcinoma, one metastatic
      breast cancer, one metastatic leiomyoblastoma, two metastatic colon cancers). MRC
      (T2 turbo spin echo sequences; Siemens Magnetomvision 1.5 T) was performed within
      12 hours before ERC, which is considered to be the ideal imaging technique.
      Tumour location, extension, and type according to Bismuth's classification were
      determined by the radiologist and endoscopist. RESULTS: MRC was of diagnostic
      quality in all but two patients (90%). At ERC, four patients (20%) had type I,
      seven (35%) had type II, seven (35%) had type III, and two (10%) had type IV
      strictures. MRC correctly classified 14/18 (78%) patients and underestimated
      tumour extension in four (22%). Successful endoscopic biliary drainage was
      achieved in 11/17 attempted stentings (65%), one of which was a combined
      procedure (endoscopic + percutaneous). One patient had a percutaneous external
      drain, one had a surgical bypass, and in a third a curative resection was
      attempted. Effective drainage was not achieved in six patients (30%). If
      management options had been based only on MRC, treatment choices would have been
      modified in a more appropriate way in 5/18 (28%) patients with satisfactory MRC.
      CONCLUSION: MRC should be considered for planning treatment of malignant hilar
      strictures. Accurate depiction of high grade strictures for which endoscopic
      drainage is not the option of choice can preclude unnecessary invasive imaging.

PMID- 10601065
TI  - Outcome of lamivudine resistant hepatitis B virus infection in the liver
      transplant recipient.
AB  - BACKGROUND: In many transplant centres lamivudine is an important component of
      prophylaxis against, and treatment of, hepatitis B virus (HBV) graft infection.
      Drug resistant HBV species with specific polymerase mutations may emerge during
      lamivudine treatment. AIMS: To examine the clinical consequences of graft
      infection by lamivudine resistant virus. METHODS: The clinical course of four
      liver transplant patients who developed graft infection with lamivudine resistant
      virus was reviewed. The response of HBV infection to reduction of
      immunosuppression and to manipulation of antiviral therapy was assessed. For each
      patient, serum viral titre was measured and the viral polymerase gene was
      sequenced at multiple time points. RESULTS: High serum titres were observed
      following emergence of the lamivudine resistant species. Wild type HBV re-emerged
      as the dominant serum species after lamivudine withdrawal. All patients developed
      liver failure, and onset of liver dysfunction was observed when resistant virus
      was the dominant serum species. In three patients, liver recovery was observed
      when immunosuppression was stopped and when alternative antivirals were given.
      Wild type virus appeared to respond to ganciclovir, and to reintroduction of
      lamivudine. For one patient, introduction of famciclovir was associated with
      clinical, virological, and histological response. CONCLUSIONS: Failure of
      lamivudine prophylaxis may identify patients at special risk for the development
      of severe graft infection. Treatment of graft reinfection should include
      reduction of immunosuppression, and systematic exposure to alternative
      antivirals. Viral quantitation and genetic sequencing are essential components of
      therapeutic monitoring.

PMID- 10601066
TI  - Haemodynamic, renal sodium handling, and neurohormonal effects of acute
      administration of low dose losartan, an angiotensin II receptor antagonist, in
      preascitic cirrhosis.
AB  - BACKGROUND: The renin-angiotensin system may be implicated in the subtle sodium
      handling abnormality in preascitic cirrhosis. AIMS: To assess the role of
      angiotensin II in sodium homoeostasis in preascitic cirrhosis, using losartan,
      its receptor antagonist. PATIENTS: Nine male, preascitic cirrhotic patients, and
      six age matched, healthy male controls. METHODS: A dose response study using 2.5,
      5, 7.5, and 10 mg of losartan was performed on a daily 200 mmol sodium intake,
      followed by repeat studies with the optimal dose, 7.5 mg of losartan, to
      determine its effects on systemic and renal haemodynamics, renal sodium handling,
      and neurohumoral factors. RESULTS: Preascitic cirrhotic patients had
      significantly reduced baseline urinary sodium excretion compared with controls
      (154 (8) versus 191 (12) mmol/day, p<0.05), associated with significantly reduced
      systemic angiotensin II levels (6.0 (1.7) versus 39.5 (10.0) pmol/l, p=0.002).
      Losartan 7.5 mg normalised renal sodium handling in the preascitic cirrhotic
      patients (202 (12) mmol/day, p=0.05 versus baseline), without any change in
      systemic or renal haemodynamics, but with significantly increased systemic
      angiotensin II levels (7.8 (2.3) pmol/l, p=0.05 versus baseline). Losartan had no
      effect on renal sodium handling in controls. CONCLUSIONS: In preascitic cirrhotic
      patients, the subtle renal sodium retention, paradoxically associated with low
      systemic neurohumoral factor levels, is improved with low dose losartan,
      suggesting the involvement of angiotensin II via its direct action on the renal
      tubule.

PMID- 10601067
TI  - Characterisation of patients with primary biliary cirrhosis responding to long
      term ursodeoxycholic acid treatment.
AB  - BACKGROUND: In some patients with primary biliary cirrhosis, ursodeoxycholic acid
      causes full biochemical normalisation of laboratory data; in others, indexes
      improve but do not become normal. AIMS: To characterise complete and incomplete
      responders. METHODS: Seventy patients with primary biliary cirrhosis were treated
      with ursodeoxycholic acid 10-15 mg/kg/day and followed up for 6-13 years.
      RESULTS: In 23 patients (33%) with mainly stage I or II disease, cholestasis
      indexes and aminotransferases normalised within 1-5 years, except for
      antimitochondrial antibodies. Histological findings improved. Indexes were not
      normalised in 47 patients (67%) although the improvement of their biochemical
      functions parallelled the trend in the first group. In these incomplete
      responders histological findings improved to a lesser extent. The only difference
      between the two groups before treatment was higher levels of alkaline phosphatase
      and gamma glutamyl transpeptidase in the incomplete responders. At onset of
      treatment the discriminant value separating responders from incomplete responders
      was 660 U/l for alkaline phosphatase and 131 U/l for gamma glutamyl
      transpeptidase. One year later it was 239 and 27 U/l (overall predictive value
      for responders 92%, for incomplete responders 81%). There were no differences
      between the two groups concerning immune status, antimitochondrial antibody
      subtypes, liver histology, or any other data. HLA-B39, DRB1*08, DQB1*04 dominated
      in both groups. CONCLUSIONS: In patients with mainly early stages of primary
      biliary cirrhosis, higher values of alkaline phosphatase and gamma glutamyl
      transpeptidase are the only biochemical indexes which allow discrimination
      between patients who will completely or incompletely respond to ursodeoxycholic
      acid treatment.

PMID- 10601068
TI  - Somatostatin plus isosorbide 5-mononitrate versus somatostatin in the control of
      acute gastro-oesophageal variceal bleeding: a double blind, randomised, placebo
      controlled clinical trial.
AB  - BACKGROUND: Variceal bleeding is a severe complication of portal hypertension.
      Somatostatin reduces portal pressure by decreasing splanchnic blood flow, and
      nitrates by diminishing intrahepatic resistance. Experimental studies have shown
      that the combination of somatostatin and nitrates has an additive effect in
      decreasing portal pressure. AIM: To compare the therapeutic efficacy of either
      intravenous infusion of somatostatin plus oral isosorbide 5-mononitrate or
      somatostatin alone in gastro-oesophageal variceal bleeding associated with liver
      cirrhosis. METHODS: A unicentre, double blind, placebo controlled, clinical trial
      was conducted. Sixty patients bleeding from oesophageal or gastric varices were
      randomised to receive intravenous infusion of somatostatin (250 microg/hour) plus
      oral isosorbide 5-mononitrate (40 mg/12 hours) (group I) or somatostatin infusion
      plus placebo (group II) for 72 hours. RESULTS: The two groups of patients had
      similar clinical, endoscopic, and haematological characteristics. Control of
      bleeding was achieved in 18 out of 30 patients (60%) in group I and 26 out of 30
      patients (87%) in group II (p<0.05). There was no significant difference in mean
      transfusion requirements between the two groups: 2.6 (2.2) v 1.8 (1.6)
      respectively; means (SD). Mortality and side effects were similar in the two
      groups, but development of ascites was higher in group I (30%) than in group II
      (7%) (p<0.05). CONCLUSION: In cirrhotic patients with acute gastro-oesophageal
      variceal bleeding, addition of isosorbide 5-mononitrate to somatostatin does not
      improve therapeutic efficacy, induces more adverse effects, and should not be
      used.

PMID- 10601069
TI  - Regression of colonic low grade B cell lymphoma of the mucosa associated lymphoid
      tissue type after eradication of Helicobacter pylori.
AB  - BACKGROUND: Lymphoma of the mucosa associated lymphoid tissue (MALT) arising in
      the stomach has been shown to be related to Helicobacter pylori infection, and
      total regression of gastric lymphoma after successful eradication of H pylori has
      consistently been reported. MALT-type lymphoma at other localisations, however,
      has to our knowledge not been linked to H pylori, and eradication of the bacteria
      has not been studied for management of such lymphomas. PATIENT/METHOD: A 67 year
      old man was diagnosed with MALT-type lymphoma simultaneously involving the
      stomach and the colon descendens. In addition to the presence of MALT-type
      lymphoma, H pylori associated chronic gastritis was diagnosed, and treatment with
      clarithromycin, metronidazole, and omeprazole was initiated, resulting in its
      successful eradication. RESULTS: Follow up performed four months later showed
      regression of the colonic manifestation, whereas the gastric lymphoma did not
      respond to antibiotic treatment, as assessed by regular follow up for 14 months,
      in spite of its restriction to mucosa and submucosa. The patient was therefore
      treated with oral cyclophosphamide (100 mg a day) resulting in partial remission
      after seven months of continuous treatment. Because of the presence of residual
      lymphoma, additional irradiation was performed, which led to complete remission
      of the gastric lymphoma. The patient remains in complete remission 40 months
      after diagnosis and 26 months after initiation of treatment. CONCLUSION: In the
      case of concurrent gastric and intestinal low grade MALT-type lymphoma, H pylori
      eradication may cause regression of the intestinal lesion.

PMID- 10601070
TI  - Gene therapy of hepatic diseases: prospects for the new millennium.

PMID- 10601071
TI  - Proteomics in reproductive research: the potential importance of proteomics to
      research in reproduction.

PMID- 10601072
TI  - Severe OHSS: An 'epidemic' of severe OHSS: a price we have to pay?

PMID- 10601073
TI  - Problems of multiple births after ART: medical, psychological, social and
      financial aspects.

PMID- 10601074
TI  - Cryopreservation of the human female gamete: current and future issues.

PMID- 10601075
TI  - Sperm cryopreservation: is there a significant risk of cross-contamination?

PMID- 10601076
TI  - Endometrial ability to implant in ectopic sites can be prevented by interleukin
      12 in a murine model of endometriosis.
AB  - Immune dysfunctions in endometriosis are widely documented but the effectiveness
      of immunotherapies for the management of the disease is still debated. Progress
      in this field has also been limited by the lack of an appropriate animal model of
      the disease. In this study, we created a model of endometriosis in
      immunocompetent mice to verify the ability of endometrium to implant in ectopic
      sites and to investigate the potential application of the cytokine interleukin
      (IL)-12 in preventing this ectopic implantation. Endometriotic lesions were
      induced in both C57BL/6 and BALB/c mice by inoculating syngenic endometrial
      fragments through a small laparotomic incision into the peritoneal space. All the
      animals challenged with syngenic endometrium showed evidence of peritoneal
      endometriosis at 3 weeks. Histologically, endometriotic lesions consisted of
      cystic endometrial glands surrounded by a stroma. Intraperitoneal injection of IL
      12 was able to reduce total weight and total surface area of endometriotic
      lesions respectively of 77 and 61% in C57BL/6 and of 42 and 28% in BALB/c mice.
      These results demonstrate that IL-12 is able to induce a significant prevention
      of ectopic endometrial implantation in an in-vivo model of endometriosis. These
      findings support the possibility of using the immune system to generate novel
      therapies for the management of the disease.

PMID- 10601077
TI  - Endocrine and metabolic effects of octreotide, a somatostatin analogue, in lean
      PCOS patients with either hyperinsulinaemia or lean normoinsulinaemia.
AB  - The effects on insulin secretion and on the glycaemic and androgen status before
      and after short-term treatment with octreotide were evaluated in 16 normal weight
      patients with polycystic ovarian syndrome (PCOS). Hyperinsulinaemia was
      determined by measuring the insulin response after oral glucose tolerance test
      (OGTT). Seven patients (group A) were classified as normoinsulinaemic, while nine
      patients (group B) were considered hyperinsulinaemic according to insulin
      response after OGTT. Octreotide treatment did not modify either glycaemic or
      insulinaemic response after OGTT, or androgen profile, in normoinsulinaemic
      patients. On the contrary, a significant decrease in the basal concentrations of
      luteinizing hormone (LH), testosterone and androstenedione, and a significant
      increase in serum concentrations of sex hormone-binding globulin (SHBG) were
      observed in the hyperinsulinaemic group of patients, in which we observed also a
      significant decrease of insulinaemic response and a decompensation of the
      glycaemic profile after OGTT. Our study is the first report showing that: (i)
      octreotide does not appear to significantly influence pituitary release of
      gonadotrophins in this group of PCOS patients; (ii) octreotide is able to reduce
      insulin release, LH and androgen concentrations in lean PCOS patients with
      hyperinsulinaemia. Due to the presence of a decompensation of glucose homeostasis
      during treatment, octreotide does not seem advisable for long-term therapy of
      hyperandrogenism in lean PCOS patients with hyperinsulinaemia.

PMID- 10601078
TI  - Will GnRH antagonists provide new hope for patients considered 'difficult
      responders' to GnRH agonist protocols?
AB  - We have assessed the use of cetrorelix, a gonadotrophin releasing hormone (GnRH)
      antagonist, in conjunction with clomiphene citrate and gonadotrophin in 31 in
      vitro fertilization (IVF)/gamete intra-Fallopian transfer (GIFT) cycles for 25
      difficult responders. Group I included 18 poor responders (24 cycles) with no
      live birth in 23 previous IVF cycles with GnRH agonists. Group II included seven
      patients (seven cycles) with polycystic ovaries. Thirteen previous IVF/GIFT
      cycles with GnRH agonists had resulted in one live birth and three of these
      patients had developed ovarian hyperstimulation syndrome (OHSS). The treatment
      protocol involved a daily dose of clomiphene citrate 100 mg for 5 days and
      gonadotrophin injections from cycle day 2. Cetrorelix 0.25 mg/day was started
      when the leading follicle reached 14 mm. The outcome in both groups was
      favourable compared to previous treatment with GnRH agonists. In group I the
      abandoned cycle rate was 29 versus 57% (P = 0.06). More oocytes were produced
      (6.4 versus 4.7 oocytes/cycle) at a lower dose of follicle-stimulating hormone
      (FSH) (709 versus 1163 IU/oocyte; P = 0.08) and two live births resulted (11.8%).
      In group II fewer oocytes were produced (10.2 versus 14.5 oocytes/cycle), using a
      lower dose of gonadotrophin (170 versus 189 IU/oocyte) and resulted in one
      ongoing pregnancy. No patients experienced OHSS. This report is preliminary and a
      further controlled randomized study is required.

PMID- 10601079
TI  - Effects of the insulin sensitizing drug metformin on ovarian function, follicular
      growth and ovulation rate in obese women with oligomenorrhoea.
AB  - Hyperinsulinaemic insulin resistance is commonly associated with
      hyperandrogenaemia, and menstrual dysfunction. The aim of this study was to
      examine the effects of the insulin sensitizing drug, metformin, on ovarian
      function, follicular growth, and ovulation rate in obese women with
      oligomenorrhoea. Twenty obese subjects with oligomenorrhoea [polycystic ovarian
      syndrome; (PCOS)] were observed longitudinally for 3 weeks prior to and for 8
      weeks during treatment with metformin (850 mg twice per day). Fifteen patients
      completed the study. The frequency of ovulation was significantly higher during
      treatment than before treatment (P = 0.003). A significant decline in both
      testosterone and luteinizing hormone concentrations was recorded within 1 week of
      commencing treatment. Patients with elevated pretreatment testosterone
      concentrations showed the most marked increase in ovulation rate (P < 0.005), and
      significant reductions in circulating testosterone from 1.02 to 0.54 ng/ml (P <
      0.005) after only 1 week of treatment. However, the sub-group with raised fasting
      insulin showed less marked changes, and the sub-group with normal testosterone
      concentrations showed no effect of treatment. Metformin had a rapid effect upon
      the abnormal ovarian function in hyperandrogenic women with PCOS, correcting the
      disordered ovarian steroid metabolism and ovulation rate; however, there appeared
      to be no effect in cases where the circulating androgen concentration was normal.

PMID- 10601080
TI  - Ovulation induction with low dose alternate day recombinant follicle stimulating
      hormone (Puregon).
AB  - We investigated whether a recombinant follicle stimulating hormone (FSH)
      (Puregon) can be administered less frequently and at lower doses during ovulation
      induction than is current practice. Patients (20-35 years, body mass index <30
      kg/m(2)) with infertility and chronic anovulation secondary to polycystic ovarian
      syndrome and resistant to previous clomiphene treatment received (Puregon); 100
      IU, n = 17 patients, or 50 IU, n = 10 patients) on alternate days. After 2 weeks
      and in the absence of follicular recruitment, doses were increased stepwise at
      weekly intervals (50 IU/alternate days). Twenty-two cycles out of 27 were
      ovulatory. There were six pregnancies, five from Puregon (100 IU) and one from
      Puregon (50 IU); four pregnancies proceeded to term. The duration of stimulation
      (mean, range) with Puregon (100 IU) was 16.4, 7-29 and Puregon (50 IU) 19.1, 8-38
      days. The gonadotrophin doses administered (mean; range) were 689, 200-1800 IU
      (Puregon 50 IU) and 939, 400-2300 IU (Puregon 100 IU). We conclude that low dose
      alternate day Puregon treatment is suitable for this difficult patient group.

PMID- 10601081
TI  - The prognostic value of anti-paternal antibodies and leukocyte immunizations on
      the proportion of live births in couples with consecutive recurrent miscarriages.
AB  - Anti-paternal antibodies directed towards paternal leukocytes have been used to
      predict the prognosis for the subsequent pregnancy in women with consecutive
      recurrent miscarriages (CRM) and also to determine if the patient has become
      immune after paternal leukocyte immunization. The predictive value is
      controversial, as these antibodies are not essential for pregnancy to develop,
      and only occur in a minority of parous women. This study tried to determine the
      predictive value of these antibodies when assessed separately for women with five
      or more abortions and compared to women with three or four abortions. The
      patients were assessed separately so that the higher live birth rate in the
      latter group would not obscure meaningful results in the former group with a poor
      prognosis. Antibody production, whether spontaneous, or induced by immunization,
      raised the live birth rate in primary and tertiary aborters with three, four,
      five or more abortions. Anti-paternal antibodies increased the proportion of live
      births from 18.5 to 53. 7% (P </= 0.01) and from 44.4 to 67.5% (P </= 0.001) in
      primary aborters with >/= 5 CRM and 3-4 CRM respectively. Both immunization with
      paternal leukocytes per se and the ability to express anti-paternal antibodies
      were associated with an increased proportion of live births in the next
      pregnancy. Multivariate analysis showed that that the odds ratio for a live birth
      was approximately four times greater in women who were immunized and produced
      anti-paternal antibodies than in control patients. The lack of anti-paternal
      antibodies at initial testing could serve as a marker for the benefit of
      immunization with paternal leukocytes; the subsequent presence as a prognostic
      marker for the subsequent pregnancy.

PMID- 10601082
TI  - Studies on the HLA-DRB1 genotypes in Japanese women with severe pre-eclampsia
      positive and negative for anticardiolipin antibody using a polymerase chain
      reaction-restriction fragment length polymorphism method.
AB  - The human leukocyte antigen (HLA)-DR genotype was determined in 54 Japanese women
      with severe pre-eclampsia in order to elucidate the relationship between HLA-DR
      antigen systems and pre-eclampsia. The patients were divided into two groups
      according to positivity for the anticardiolipin antibody (ACA), i.e. one patient
      group negative for ACA (n = 41) and the other patient group positive for ACA (n =
      13). The frequency of each HLA-DRB1 allele in both groups was compared with that
      in 81 normally fertile Japanese women who had not experienced pre-eclampsia. The
      genotypes of HLA-DR antigens were determined using a polymerase chain reaction
      restriction fragment length polymorphism (PCR-RFLP) method. The frequency of
      DRB1*04 and DRB1*0403 in the patient group positive for the ACA was significantly
      higher compared with that in the group of normal fertile women (P< 0.05). The
      frequency of each HLA-DRB1 allele was not significantly different between patient
      group with pre-eclampsia negative for ACA and group of normal fertile women.
      These results suggest a difference in the immunogenetic background between the
      patient groups with severe pre-eclampsia positive and negative for the ACA.

PMID- 10601083
TI  - Preliminary study of the incidence of disomy in sperm fractions after MicroSort
      flow cytometry.
AB  - Using triple colour fluorescent in-situ hybridization (FISH) we have evaluated,
      on a blind basis, the disomy level for chromosome 21 and the sex chromosomes in
      flow cytometric sorted sperm samples. There were no statistically significant
      differences in the disomy rates when comparing the sorted samples (either for X-
      or Y-bearing spermatozoa) with non-sorted samples. There were no diploid
      spermatozoa observed in any sample group after MicroSort processing.

PMID- 10601084
TI  - The prognostic role of salpingoscopy in laparoscopic tubal surgery.
AB  - The present study was designed to evaluate the prognostic value of salpingoscopy
      in patients undergoing tubal laparoscopic surgery for infertility due to
      periadnexal adhesion or distal tubal occlusion. In addition, the clinical value
      of salpingoscopy was compared with a current classification system of adnexal
      adhesions and distal tubal occlusion. A total of 51 patients with either adnexal
      adhesions (24 patients) or hydrosalpinx (27 patients) were prospectively
      evaluated. Salpingoscopy was performed concomitantly with salpingo-ovariolysis or
      salpingoneostomy at the time of operative laparoscopy. There was no significant
      correlation between salpingoscopic classes and the classification system used for
      both the salpingo-ovariolysis and the salpingoneostomy groups of patients. The
      patients had a mean follow-up of 33 months. Patients with a normal tubal mucosa
      (salpingoscopic classes I and II) had a 71% cumulative term pregnancy rate in the
      salpingo-ovariolysis group and a 64% cumulative term pregnancy rate in the
      salpingoneostomy group. No intrauterine pregnancies were obtained in patients
      with intratubal damage (salpingoscopic classes III to V). There was a
      statistically significant correlation between the occurrence of a term pregnancy
      and the salpingoscopic classes, but not with the classification system used.
      These results suggest that patients with tubal infertility should be offered
      operative laparoscopy with salpingoscopy as the first step of treatment.

PMID- 10601085
TI  - Total laparoscopic hysterectomy versus total abdominal hysterectomy: an
      assessment of the learning curve in a prospective randomized study.
AB  - The present randomized study was undertaken in order to compare the short-term
      results between total laparoscopic hysterectomy and abdominal hysterectomy in a
      centre with experience in laparoscopic surgery. From January 1997 to September
      1998 inclusive, 102 women aged 44-71 years were randomly assigned to either total
      laparoscopic hysterectomy (n = 51 patients) or abdominal hysterectomy (n = 51
      patients). The patients' demographic characteristics were similar in both groups.
      Average intra-operative blood loss was lower in laparoscopic hysterectomy than in
      abdominal hysterectomy (P </= 0. 001). The average time employed for laparoscopic
      hysterectomy was 104.1 +/- 26.98 min; according to the learning curve experienced
      in this study, the range was 72-163 min and the results after the plateau was
      reached showed no statistical difference between laparoscopic and abdominal
      operating times. The mean length of hospital stay was 2.38 +/- 0.30 days in the
      laparoscopic hysterectomy group versus 6.23 +/- 1.85 days in the abdominal
      hysterectomy group (P </= 0.001). In conclusion, this study shows that total
      laparoscopic hysterectomy can be effectively performed within reasonable time
      limits, provided that operators are experienced surgeons in operative laparoscopy
      and that operating times are comparable with those of abdominal hysterectomy.

PMID- 10601086
TI  - Isolated recurrent torsion of the Fallopian tube: case report.
AB  - We report a rare clinical case of recurrent isolated torsion of the Fallopian
      tube. An 18 year old woman presented with acute right lower quadrant pain, nausea
      and vomiting. Torsion of the Fallopian tube was detected by laparoscopy and
      detorsion was performed. Two years later, a second similar episode of pelvic pain
      recurred. Having in mind the first episode, diagnosis was facilitated and
      detorsion was performed in accordance with the patient's wishes. However, the
      dilemma of ideal management of recurrent cases of torsion of the same tube
      remains open for discussion. The possibility of torsion of the Fallopian tube and
      recurrent torsion of the tube, although rare, should be considered in any patient
      with acute onset of lower abdominal pain.

PMID- 10601087
TI  - Selection of good embryos for transfer depends on embryo cohort size:
      implications for the 'mild ovarian stimulation' debate.
AB  - Embryo quality evaluated by the embryo morphology is a critical parameter in
      human in-vitro fertilization (IVF) and embryo transfer. It determines which and
      how many embryos will be replaced, as pregnancy rates are directly related to
      number and quality of transferred embryos. This retrospective analysis included
      1301 IVF and embryo transfer cycles to identify which factors influenced embryo
      quality. Embryo quality did not correlate with maternal age, causes of
      infertility, ovarian stimulation parameters or embryo cohort size. However, the
      mean score of transferred embryos was significantly higher for patients with more
      than five embryos compared to fewer than five embryos (P < 0.001), irrespective
      of maternal age. Patients tended to produce a similar embryo quality from cycle
      to cycle, r = 0.33 (P < 0.001) for the embryo cohort and r= 0.47 (P < 0.001) for
      the transferred embryos. Poor embryo morphology probably reflects oocytes with
      compromised development competence and could be an independent factor of
      infertility. Furthermore, a large embryo cohort was the main factor increasing
      the chances of at least one good embryo in the cohort.

PMID- 10601088
TI  - Screening for Chlamydia trachomatis in subfertile women.
AB  - Chlamydia trachomatis is the most common sexually transmitted disease in the UK
      and Europe. The majority of female infections are asymptomatic and recognized
      sequelae include pelvic inflammatory disease, infertility, and ectopic pregnancy.
      Women with chlamydial infection who undergo uterine instrumentation are
      recognized to be at risk of ascending infection. Most patients attending for
      infertility investigations and treatment will undergo some form of uterine
      instrumentation. Published data regarding the prevalence of chlamydial infection
      in the subfertile are few and conflicting. In this study, more than 400
      consecutive women presenting for infertility investigation and treatment at a
      single regional fertility centre were screened for Chlamydia: Half were screened
      using enzyme immunoassay (EIA) and half by ligase chain reaction (LCR).
      Prevalence by diagnostic test was 0% with EIA and 1.9% with LCR. Overall, the low
      prevalence was at least partly explained by older age. Until more evidence comes
      from studies testing consecutive subfertile patients both with EIA and a DNA
      amplification method such as LCR, centres using EIA should consider using
      prophylactic antibiotics prior to uterine instrumentation.

PMID- 10601089
TI  - Correlation of endocrine profiles with bleeding patterns during use of Nestorone
      contraceptive implants.
AB  - The relationship between ovarian hormones and bleeding patterns during continuous
      progestin contraception was studied in 29 women who used Nestorone (NES)
      releasing implants. Oestradiol and progesterone were measured in blood samples
      taken twice a week for 6 consecutive weeks, during months 6, 12, 18 and 24 of
      implant use. Retrospectively, the association between hormonal concentrations and
      bleeding patterns was evaluated. Twenty-four short (</= 24 days), 36 normal (25
      35 days), 27 long (36-90 days) and nine episodes of amenorrhoea, as well as 28
      periods of prolonged bleeding, were identified. Short cycles, periods of
      prolonged bleeding and amenorrhoea were characterized by low oestradiol
      concentrations. Bleeding after a normal or long cycle regularly occurred after a
      rise and fall of oestradiol or oestradiol and progesterone. The duration of
      bleeding was directly and significantly associated with the highest concentration
      of oestradiol in the previous 15 days in anovulatory cycles. Luteal activity was
      associated with shorter duration of bleeding. Periods of prolonged bleeding were
      usually initiated with a drop in oestradiol and over half ended with an increase
      in oestradiol. It was concluded that changes in endogenous hormone have a
      significant influence over the bleeding pattern during use of NES implants.

PMID- 10601090
TI  - An international study on the acceptability of a once-a-month pill.
AB  - Totals of 450 women attending family planning clinics in Hong Kong, Shanghai and
      Edinburgh, and 468 in Cape Town, completed a questionnaire designed to seek their
      views on a contraceptive pill which would be taken only once each month. At least
      two-thirds of the women in all centres liked the idea of a once-a-month pill. In
      Hong Kong, Cape Town and Edinburgh, women preferred a pill which inhibited
      ovulation to one which inhibited implantation, while in all centres a pill which
      worked after implantation (early menstrual inducer) was considered unacceptable
      by over half the women. A pill which was taken after a missed menstrual period
      was considered preferable in all centres, perhaps because it would not be used
      every month but rather only if pregnancy had occurred. No demographic
      characteristics, contraceptive experiences or beliefs were consistently
      correlated with attitudes towards a once-a-month pill, except that women who
      would not consider having an abortion were more likely to dislike a method that
      either prevented, or worked after, implantation. A once-a-month pill is now
      technically possible, although the major drawback is the need to determine when
      it should be taken. It is reassuring that many women from a variety of different
      cultures and with widely different experiences, would find this an attractive
      approach to contraception.

PMID- 10601091
TI  - Mice with Y chromosome deletion and reduced Rbm genes on a heterozygous Dazl1
      null background mimic a human azoospermic factor phenotype.
AB  - A subset of azoospermia or oligozoospermia patients have microdeletions in
      defined regions of their Y chromosome, namely the AZFa, b, and c regions.
      Candidate genes in humans that may cause the azoospermia factor (AZF) phenotype
      have been assigned to these regions and can include the DAZ and RBM genes. Part
      of the variability in the AZFc phenotype might be due to interaction between the
      effects of deleting the DAZ and RBM genes. We mimicked human deletions of RBM and
      DAZ in the mouse by crossing male mice with a deleted Y chromosome with a reduced
      number of Rbm genes (Y(d1)) to heterozygote Dazl1 null female mice to study the
      interaction of the Dazl1 and Rbm or other genes located in the Y(d1) deletion
      interval. Dazl-/+ Y(d1) animals showed a significant reduction in the sperm count
      (P < 0.001), an increase of abnormal sperm heads and prominent mid-piece defects
      of the tails compared to either mutation alone (P < 0.001). Hence, Dazl1 and the
      genes removed on the Y(d1) chromosome are active in different pathways
      contributing to different stages of spermatogenesis. Reduction of Dazl1 and Rbm
      genes as well as/or deletion of the Y chromosome in mice gives rise to a
      phenotype similar to the heterogeneous AZFc phenotype observed in humans.

PMID- 10601092
TI  - Testicular sperm extraction: impact of testicular histology on outcome, number of
      biopsies to be performed and optimal time for repetition.
AB  - Testicular sperm extraction (TESE) may not always be successful in patients with
      non-obstructive azoospermia, as they only have minute foci of active
      spermatogenesis from which a tiny number of spermatozoa can be extracted. The aim
      of this study was to find the percentile incidence of successful TESE in non
      obstructive azoospermia patients in relation to various histopathological
      patterns and the number of performed biopsies, and to determine the optimal time
      needed for repetition. A total of 216 patients underwent bilateral testicular
      biopsy taking a single piece from each testis for sperm retrieval and
      pathological evaluation. In another 100 patients, the same procedure was done but
      taking multiple samples (maximum four samples/testis). Spermatozoa were
      successfully retrieved from 37.5 and 49% of patients who supplied single and
      multiple samples respectively. TESE was significantly higher when multiple
      samples were taken in all histopathological groups except for Sertoli cell-only
      syndrome, tubular sclerosis and Klinefelter's pattern. Twenty-seven patients
      underwent repeated TESE for ICSI between 1 and 24 months from the first
      procedure; all of them had easy sperm retrieval during the first procedure.
      Although sperm retrieval was successful in 75 and 94.7% of patients who underwent
      the second attempt, before and after 3 months respectively, a second TESE was
      usually more difficult and necessitated multiple sampling.

PMID- 10601093
TI  - Complete mutational screening of the cystic fibrosis transmembrane conductance
      regulator gene: cystic fibrosis mutations are not involved in healthy men with
      reduced sperm quality.
AB  - Based on the analysis of the most frequent mutations responsible for cystic
      fibrosis (CF), a higher than expected frequency of CF mutations was recently
      reported in men with infertility due to reduced sperm quality. To further
      document whether this condition is associated with severe or mild abnormalities
      of cystic fibrosis transmembrane conductance regulator (CFTR) functions, we
      carried out a complete scanning of CFTR sequences using a strategy that detects
      almost all 850 mutations and 150 polymorphisms reported to date in the CFTR gene.
      We have investigated a cohort of 56 patients with severe
      oligoasthenoteratozoospermia (OAT) and 50 controls from southern France for CFTR
      gene mutations and variations. The frequencies of CF-causing mutations and CFTR
      variations identified in this OAT sample did not differ significantly from the
      frequencies found in the normal population. However, we observed a 1.7-fold
      increase in the proportion of homozygotes for a specific CFTR haplotype (TG11-T7
      G1540) in the OAT group (P = 0.025). Our results do not confirm a link between CF
      mutations and reduced sperm quality. Further studies are needed to substantiate
      the hypothesis that a combination of variants affecting expression and function
      of the CFTR protein is associated with male infertility.

PMID- 10601094
TI  - Highly sensitive quantitative telomerase assay of diagnostic testicular biopsy
      material predicts the presence of haploid spermatogenic cells in therapeutic
      testicular biopsy in men with Sertoli cell-only syndrome.
AB  - The role of a telomerase assay in the recognition of Sertoli cell-only syndrome
      with testicular foci of haploid cells was evaluated. Men with Sertoli cell-only
      syndrome (n = 23) were given a new diagnostic testicular biopsy. Part of the
      biopsy was stained and the remainder was processed for the quantitative
      telomerase assay. After 3-13 months, a therapeutic testicular biopsy was
      performed. This material was minced and then examined using confocal laser
      scanning microscopy and fluorescent in-situ hybridization. Histology of
      diagnostic testicular biopsy material confirmed the diagnosis of Sertoli cell
      only syndrome in all the participants. All seven men with a telomerase assay
      value in their diagnostic testicular biopsy of >42 total product generated (TPG)
      U/microg protein had haploid cells (i.e. spermatozoa and/or spermatids) in their
      therapeutic testicular biopsy. Among participants with telomerase assay values
      <42 TPG U/microg protein, only one man had haploid cells in his therapeutic
      testicular biopsy. Thus, telomerase assay values >42 TPG U/microg protein in the
      diagnostic biopsy identified 87.5% of the Sertoli cell-only syndrome men with
      haploid cells in their therapeutic testicular biopsy. Significantly higher values
      of the telomerase assay were found in men with testicular foci of haploid cells
      than in men without these foci. The use of a quantitative telomerase assay biopsy
      appears to be important for identifying those men with Sertoli cell-only syndrome
      who have foci of haploid cells and can be candidates for assisted reproduction
      techniques.

PMID- 10601095
TI  - The relative viability of human spermatozoa from the vas deferens, epididymis and
      testis before and after cryopreservation.
AB  - Testicular and epididymal spermatozoa are routinely used with in-vitro
      fertilization (IVF) and intracytoplasmic sperm injection (ICSI) to achieve
      pregnancies. In addition, excess cryopreserved spermatozoa can be thawed and used
      for ICSI. However, information on the recovery of epididymal and testicular
      spermatozoa after freeze-thaw is lacking. This is important to determine the
      feasibility of using previously cryopreserved aspirated spermatozoa for ICSI. We
      prospectively compared the viability of fresh and frozen-thawed spermatozoa from
      the vas deferens, epididymis and testicle by several measures. Testis spermatozoa
      were obtained from men with non-obstructive azoospermia (n = 5), epididymal
      spermatozoa from men with obstructive azoospermia (n = 8), and vasal spermatozoa
      from fertile men by vasal irrigation at vasectomy (n = 5). The viability of fresh
      spermatozoa was assessed by motility, two vital stains (carboxyfluorescein, 0.08
      mg/ml and propidium iodide, 20 mg/ml) and the hypo-osmotic swelling assay (HOS;
      100 mmol/l citrate and fructose). After cryopreservation, spermatozoa were thawed
      and all viability measures repeated. Although fresh vasal spermatozoa were the
      most motile, testicular spermatozoa exhibited similar, high viability (91 and 86%
      respectively) by vital stain. Spermatozoa from testis, epididymis and vas
      deferens survived cryopreservation equally well by vital stain, but not by
      motility. As a selection measure, the HOS assay identified significantly more
      viable epididymal and testicular spermatozoa than did motility in both fresh and
      frozen-thawed populations. It appears feasible to use frozen-thawed extracted
      spermatozoa for ICSI when motility and a selection measure such as the HOS assay
      are used. With fresh testis spermatozoa, selection methods may not be necessary
      prior to ICSI, as cell viability is high.

PMID- 10601096
TI  - Preimplantation access to maternal insulin and albumin increases fetal growth
      rate in mice.
AB  - Provision of the maternal factors, albumin and/or insulin to embryos in vitro
      restores preimplantation morphological development and cell proliferation to that
      seen in vivo. The hypothesis that the preimplantation effects of insulin or
      albumin would be reflected in increased fetal growth rate was examined. Two-cell
      embryos were cultured 48-50 h in medium supplemented with 0.17 micromol/l, 15
      micromol/l albumin or 0.17 micromol/l insulin and the resultant blastocysts
      transferred to pseudopregnant recipients. Fetal and placental mass and skeletal
      development were determined at E19 or E20 (day 19 or 20 of embryonic
      development). Preimplantation access to insulin or albumin increased fetal growth
      by 4-6%. Combining insulin and albumin did not produce a further increment in
      fetal growth. The fetal growth achieved by providing preimplantation access to
      insulin, albumin or both was equivalent to that of in-vivo developed blastocysts.
      The conclusions are that: (i) preimplantation access to maternal insulin and
      albumin is required for normal fetal growth rates in the mouse and (ii) the
      increments in inner cell mass cell number and metabolic rates induced by insulin
      (and possibly albumin) reflect a requirement for maternal growth factors during
      preimplantation stages to optimize fetal development.

PMID- 10601097
TI  - Epidermal growth factor enhances preimplantation developmental competence of
      maturing mouse oocytes.
AB  - The objective of this study was to determine whether epidermal growth factor
      (EGF) promotes nuclear and cytoplasmic maturation of mouse oocytes grown in vivo
      or in vitro. In-vivo-grown oocytes were isolated at the germinal vesicle (GV)
      stage from gonadotrophin-primed (PR) or -unprimed (UPR) 22-day-old mice before in
      vitro maturation (IVM). In-vitro-grown (IVG) oocytes were isolated from preantral
      follicles of 12-day-old mice and grown in vitro without gonadotrophins for 10
      days before maturation (IVG/IVM oocytes). IVM and IVG/IVM oocytes were matured in
      medium supplemented with either EGF (10 ng/ml), follicle stimulating hormone
      (FSH) (100 ng/ml), EGF plus FSH, or with neither ligand (control). When oocyte
      cumulus cell complexes were isolated from PR and UPR mice, IVM with EGF (10
      ng/ml), alone or in combination with FSH (100 ng/ml), increased (P < 0.05) the
      incidence of nuclear maturation to metaphase II. Cytoplasmic maturation of
      oocytes from PR females, manifested as increased frequency of cleavage to the 2
      cell stage and development to the blastocyst stage, was also enhanced with EGF (P
      < 0.05). Moreover, EGF increased the number of cells per blastocyst, but only in
      the absence of FSH (P < 0.01). In contrast, EGF, FSH, or EGF plus FSH did not
      affect the percentage of oocytes from UPR mice completing preimplantation
      development, but did increase the number of cells per blastocyst. These ligands
      also increased the proportion of IVG oocytes reaching metaphase II (53-57%)
      compared with controls (25%; P < 0.05). EGF alone or in combination with FSH
      increased (P < 0.05) the frequency of blastocyst formation (23% and 28%,
      respectively) compared with controls (13%). EGF treatment of maturing IVG oocytes
      produced blastocysts with more cells than other IVG groups (P < 0.05). It is
      concluded that gonadotrophins in vivo increase the sensitivity or responsiveness
      of cumulus cell-enclosed oocytes to EGF, thereby promoting both nuclear and
      cytoplasmic maturation. However, oocyte-granulosa cell complexes grown in vitro
      become responsive to EGF without gonadotrophin treatment. Thus, nuclear and
      cytoplasmic maturation of IVG oocytes is promoted by EGF treatment during meiotic
      maturation.

PMID- 10601098
TI  - Granulocyte-macrophage colony-stimulating factor promotes human blastocyst
      development in vitro.
AB  - The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is
      synthesized in the female reproductive tract and has been implicated in the
      growth and development of the preimplantation embryo in rodent and livestock
      species. To examine the effect of GM-CSF on human embryo development in vitro,
      surplus frozen 2-4-cell embryos were cultured in media supplemented with 2 ng/ml
      recombinant human GM-CSF. The addition of cytokine increased the proportion of
      embryos that developed to the blastocyst stage from 30 to 76%. The developmental
      competence of these blastocysts, as assessed by hatching and attachment to
      extracellular matrix-coated culture dishes, was also improved by GM-CSF. The
      period in culture required for 50% of the total number of blastocysts to form was
      reduced by 14 h, and blastocysts grown in GM-CSF were found to contain
      approximately 35% more cells, due primarily to an increase in the size of the
      inner cell mass. The beneficial effect of GM-CSF was exerted in each of two
      sequential media systems (IVF-50/S2 and G1. 2/G2.2) and was independent of the
      formulation of recombinant cytokine that was used. These data indicate that GM
      CSF may have a physiological role in promoting the development of the human
      embryo as it traverses the reproductive tract in vivo, and suggest that addition
      of this cytokine to embryo culture media may improve the yield of implantation
      competent blastocysts in human in-vitro fertilization programmes.

PMID- 10601099
TI  - Birth following vitrification of a small number of human oocytes: case report.
AB  - We report the birth of a healthy baby girl at 37 weeks gestation to a 47 year old
      recipient, after vitrification of mature oocytes from four in-vitro fertilization
      (IVF) patients. A total of 17 oocytes was vitrified in 1-2 microl of ethylene
      glycol (40%) and 0.6 mol/l sucrose (20.54%) in open pulled straws. Eleven oocytes
      survived after vitrification and five pronuclear zygotes were obtained after
      intracytoplasmic sperm injection (ICSI). Three embryos were transferred to three
      patients, two of whom were the original oocyte donors and pregnancy was not
      established. The third embryo was donated to a 47 year old infertile woman after
      preimplantation diagnosis had confirmed euploidy for chromosomes X, 13, 14, 15,
      16, 18, 21 and 22. The successfully completed pregnancy is encouraging for
      further research to explore the potential benefits of vitrification for the
      cryopreservation of human oocytes, given the relatively low success of
      conventional freezing of human oocytes by slow cooling methods.

PMID- 10601100
TI  - The effect of etonogestrel on VEGF, oestrogen and progesterone receptor
      immunoreactivity and endothelial cell number in human endometrium.
AB  - Contraceptive use often leads to disrupted endometrial bleeding patterns in
      women. In this study, two different contraceptive regimes (Mircette, a monophasic
      oral contraceptive and Implanon, a long-acting gestagen) were used and their
      effects on the immunoreactivity of vascular endothelial growth factor (VEGF),
      oestrogen receptor (ER), progesterone receptor (PR) and endothelial cell number
      were determined. During the untreated normal cycle, there was a significant
      increase (P = 0.005) in glandular VEGF immunoreactivity and a significant
      decrease (P < 0.05) in PR immunoreactivity in the mid- and late secretory phases
      compared with the proliferative phase. There was a significant positive
      correlation (gamma = 0.38, P = 0.046) between stromal VEGF immunoreactivity and
      endothelial cell number. This correlation was also apparent during treatment with
      Implanon, but not with Mircette. Disrupted bleeding patterns were associated with
      Implanon and, to a lesser extent, with Mircette. Both contraceptives
      significantly reduced glandular VEGF immunoreactivity. Implanon significantly
      increased (P = 0.016) glandular PR staining, but Mircette significantly reduced
      (P = 0.027) stromal PR staining when compared with secretory before-treatment
      biopsies. There were no changes in endothelial cell number or glandular or
      stromal ER during the normal cycle, or with use of either contraceptive. There
      was no association between the parameters measured with bleeding patterns and
      histological category.

PMID- 10601101
TI  - The effect of hormone replacement therapy on the number and the proliferation
      index of endometrial leukocytes.
AB  - This study aimed to determine the changes in endometrial leukocyte subpopulations
      under sequential hormone replacement therapy (HRT) during the late progestogenic
      phase. The number of leukocytes was determined using immunohistochemistry
      utilizing monoclonal antibodies to CD45 (total leukocytes), CD56 (endometrial
      granulated lymphocytes), CD3 (T-cells), and CD68 (macrophages). Leukocyte
      proliferation was demonstrated using in-situ hybridization with a histone probe,
      and the proliferation index was determined using double labelling for Ki67
      (Mib1). Compared to the corresponding phase of the physiological cycle,
      sequential HRT-treated endometrium exhibited a 95% increase in CD45(+) cells (P <
      0.05), a 130% increase in CD56(+) cells (P < 0.05), and a 113% increase in CD3
      cells. There was a non-statistically significant drop in the number of CD68(+)
      cells. The number of proliferating leukocytes increased in sequential HRT
      endometrium.

PMID- 10601102
TI  - Smooth muscle alpha actin and myosin heavy chain expression in the vascular
      smooth muscle cells surrounding human endometrial arterioles.
AB  - Endometrial spiral arterioles are believed to play a major role in controlling
      menstruation. These arterioles coil and grow through the secretory stages of the
      cycle, unlike the 'straight' endometrial arterioles that remain uncoiled. We
      postulate that alterations in the growth and development of spiral arterioles, in
      particular the vascular smooth muscle cells (VSMC), may contribute to
      menorrhagia. We examined smooth muscle alpha actin (alphaSMA) and myosin heavy
      chains (MHC), two VSMC differentiation markers, in the endometrial arterioles of
      64 women, comparing them in controls, menorrhagic tissues and across the
      menstrual cycle. alphaSMA and MHC expression were determined
      immunohistochemically then evaluated using computer-aided image analysis.
      alphaSMA expression in the straight arterioles of menorrhagic women was reduced
      in the early secretory stage of the cycle and significantly decreased at the mid
      secretory stage of the cycle (0.67 +/- 0.03 versus 0.55 +/- 0.04, P </= 0.05). No
      other significant differences were observed in alphaSMA and MHC expression in
      straight arterioles. MHC expression was significantly reduced in the spiral
      arterioles of menorrhagic tissues at the early secretory stage (0.57 +/- 0.01
      versus 0.38 +/- 0.04, P </= 0.05). Our results demonstrate differences in the
      VSMC of menorrhagic women compared with controls, with delayed MHC expression in
      the spiral arterioles and reduced alphaSMA expression in straight arterioles
      during the mid-secretory stage of the cycle.

PMID- 10601103
TI  - Morphological evidence for the 'implantation window' in human luminal
      endometrium.
AB  - Endometrial tissue was taken from 21 normal fertile women (aged 18-40 years)
      between 4 and 13 days after the luteinizing hormone (LH) surge. Systematic random
      samples of luminal epithelium were taken for both light and electron microscopy
      and examined morphometrically. Throughout the luteal phase there were remarkably
      few changes in the volume fraction of nucleus, mitochondria, rough endoplasmic
      reticulum and 'vesicular system' to cell. Nuclear profile dimensions and cell
      height also did not change over time. Cell and organelle volume (estimated as
      volume weighted mean volume) did not change significantly, but showed numerically
      smallest values on day LH + 13. However the ratio of desmosomes to whole cell and
      both arithmetic mean thickness and harmonic mean thickness of basement membrane
      were minimal at the time when implantation would be most likely to occur, i.e.
      approximately 6 days after the LH peak. Therefore it appears that while some
      morphometric parameters in human luminal epithelial cells change little during
      the luteal phase, specific cellular changes occur to the basement membrane and
      desmosomes which may facilitate embryo implantation. These changes occurred
      around day LH+ 6 and may be a morphological representation of the 'implantation
      window'.

PMID- 10601104
TI  - The SCID mouse: an experimental model for endometriosis.
AB  - The purpose of this study was to validate the suitability of the severe combined
      immunodeficient (SCID) mouse as an experimental model for endometriosis, by
      defining the morphological and histological features of induced endometrial
      implants, and characterizing specific biochemical properties of these implants.
      Human secretory endometrial tissues were injected into the peritoneal cavity of
      SCID/SCID CB17 mature female mice. Successful peritoneal implantation was
      observed in 55 of 57 (96.5%) SCID mice and consisted of circumscribed elevated
      nodules. Haematoxylin-eosin staining of implanting lesions demonstrated the
      presence of endometrial glandular tissue in a mixed background of stromal and
      inflammatory cells. When progesterone was administered to mice, epithelial glands
      underwent well-defined secretory changes. Immunohistochemical analysis using
      polyclonal human pan-cytokeratin antibodies demonstrated selective positive
      staining in the glandular epithelium of the human implants with none in the
      surrounding stroma. In-situ hybridization analysis using complement component 3
      cDNA radiolabelled riboprobes yielded significantly more intense signals in
      glands compared to stroma. As human endometrial implants in SCID mice were shown
      to retain specific histological, functional and biochemical properties, we
      conclude that the SCID mouse is an attractive animal model for the study of
      endometriosis.

PMID- 10601105
TI  - Activated protein C resistance shows an association with pregnancy-induced
      hypertension.
AB  - A common mutation in the factor V gene, the Leiden mutation, is the most frequent
      genetic cause of resistance to activated protein C (APC). Recent studies have
      shown that the prevalence of APC resistance is associated with severe pregnancy
      induced hypertension (PIH). Our objective was to determine whether the factor V
      Leiden mutation is more prevalent in patients who developed severe PIH than in
      normotensive pregnant women. In 70 women with a history of severe PIH, of whom 15
      had pre-eclampsia, we investigated common coagulation factors as well as APC
      resistance (factor V related). We found that seven of these 70 women showed low
      values for APC. Out of these, five were heterozygous and none was homozygous for
      factor V Leiden mutation. In a control group of normotensive pregnant women we
      found a 3.0% rate of APC resistance and a 3.0% rate of carriers of the Leiden
      mutation. These results indicate a significantly higher prevalence of both APC
      resistance and factor V Leiden mutation in women with severe PIH. Placental
      infarctions and micro-embolisms are considered to be one of the principle
      pathophysiological changes in severe PIH. Our results suggest that APC resistance
      is a risk factor for severe PIH, in addition to its well-known role in
      macrothrombo-embolism.

PMID- 10601106
TI  - Reduced male births in major Italian cities.
AB  - The downward trend in the sex ratio at birth that has occurred in several
      countries over the last 30 years was postulated to signal a deterioration in
      environmental conditions, particularly unfavourable for male conception and fetus
      survival. In Italy, in contrast, an upward trend has been observed. Assuming that
      exposure to reproductive hazards occurs mainly in the major cities, we contrasted
      the 1970-1995 sex ratio trend for the metropolitan area (defined as the four
      provinces containing the largest Italian cities) with that for the non
      metropolitan area (defined as the rest of the country). In the metropolitan area,
      the proportion of live-born males showed a negative trend significantly different
      from the positive trend observed in the rest of the country. Moreover, the
      stillbirth rate among males was constantly and significantly higher in the
      metropolitan area. Our results suggest that the decrease in the sex ratio at
      birth observed in the metropolitan area might be interpreted as a signal of
      increasing exposure to hazardous environmental conditions for male conceptions
      and neonates.

PMID- 10601107
TI  - Natural variation in the human sex ratio.
AB  - Analysis of the effect of multiple birth, birth order, age of parents and the
      sexes of preceding siblings on the secondary sex ratio was performed for 815 891
      children, born in Denmark, 1980-1993. The proportion of males was analysed as a
      function of multiple birth, birth order, age of parents and the sexes of
      preceding siblings, using contingency tables, chi(2) tests and logistic
      regression analysis. The secondary sex ratio decreased with increased number of
      children per plural birth and with paternal age, whereas no independent effect
      was observed for maternal age, birth order, the sex of the preceding child, or
      the combination of sexes of previously born children in the family.

PMID- 10601108
TI  - Anxiety and perceptive functioning of infertile women during in-vitro
      fertilization: exploratory survey of an Italian sample.
AB  - The aim of this study was to study the emotional impact of in-vitro fertilization
      (IVF) and any possible influence due to the type of diagnosis, duration of
      infertility, number of cycles and type of responses to treatment. The study was
      carried out on 200 patients admitted to hospital for the final stages of IVF
      (oocyte retrieval and embryo transfer). The psychological measures taken into
      consideration were: state and trait anxiety levels (Stait-Trait Anxiety),
      unconscious and symptomatic anxiety, perception of self and of others (EWI).
      Monitoring of anxiety levels during hospitalization highlighted significant
      differences with respect to the state anxiety values (P < 0.01) and general
      anxiety (P < 0.05), but not with respect to trait anxiety. The level of state
      anxiety of women with a diagnosis of infertility was significantly lower (P < 0.
      05). Women who have experienced infertility of medium to long duration presented
      a significantly lower state anxiety value (P < 0. 01). The failure of oocyte
      fertilization determines a significant increase in state anxiety level (P < 0.01)
      There were no significant differences in anxiety values with respect to the cycle
      number. Perceptive functioning was normal.

PMID- 10601109
TI  - Parenting stress and psychosocial well-being among parents with twins conceived
      naturally or by reproductive technology.
AB  - This study compared parenting stress and psychosocial well-being among parents
      with 1 year old twins conceived in three different ways: (i) spontaneously
      without any medical assistance (54 families), (ii) spontaneously following
      hormonal treatment (25 families) and (iii) following in-vitro fertilization (IVF)
      or artificial insemination (AI) with the semen of the social father (24
      families). The investigation included the Parenting Stress Index (PSI) and the
      General Health Questionnaire (GHQ-30). Since the presence of older children
      differed significantly between the three groups, this factor was included in the
      statistical analysis. Overall, no significant differences were found between the
      three study groups, either for the mothers or for the fathers. Nevertheless, we
      found a main effect of the presence of older children and an interaction effect
      of the presence of older children and the conception mode on some of the scales
      for the mothers: first-time mothers showed significantly higher stress related to
      parental competence, health and the partner relationship compared with mothers
      who had older children. First-time mothers with a history of infertility obtained
      significantly higher stress scores for parental competence and health and showed
      lower psychosocial well-being compared with naturally conceiving first-time
      mothers and mothers with a history of infertility who already had children.

PMID- 10601110
TI  - ESHRE Preimplantation Genetic Diagnosis (PGD) Consortium: preliminary assessment
      of data from January 1997 to September 1998. ESHRE PGD Consortium Steering
      Committee.
AB  - The first clinical application of preimplantation genetic diagnosis (PGD) was
      reported almost a decade ago. Since then, the range of genetic defects that can
      be detected at single cell level has increased dramatically. At the 13th Annual
      Meeting of ESHRE in Edinburgh in 1997, a PGD Consortium was formed to undertake
      the first systematic and long-term study of the efficacy and clinical outcome of
      PGD. We report here the first data collection covering the period of January 1997
      to September 1998. Referral data on 323 couples have been collected for a variety
      of monogenic and chromosomal disorders, providing information about which
      patients, at risk for which genetic diseases, are interested in PGD. Data were
      collected on 392 PGD cycles, resulting in 302 embryo transfers and 66 clinical
      pregnancies. Because of the importance of follow-up of the children born after
      PGD, participating centres were asked to contribute data on the pregnancies
      achieved and the children born after PGD since the start of their PGD programme.
      Data on 82 pregnancies and 110 fetal sacs were collected, and information was
      available on 79 children. Finally, biopsy, fluorescence in-situ hybridization and
      polymerase chain reaction protocols were collected, clearly showing that no
      consensus exists on technical aspects such as which culture medium to use, and
      emphasizing the role the PGD Consortium could play in setting up guidelines for
      good laboratory practice. In conclusion, it is clear that the effort of gathering
      data on PGD cycles is worthwhile and will be continued in the future, preferably
      using electronic data collection.

PMID- 10601111
TI  - Oral antioxidants and male infertility.

PMID- 10601112
TI  - Three-dimensional ultrasonographic evaluation of ovarian tumours.

PMID- 10601113
TI  - Peptide probes. 1962.

PMID- 10601114
TI  - Reappearance of the J-shaped curve.

PMID- 10601115
TI  - J-shaped relation between blood pressure and stroke in treated hypertensives.
AB  - The objective of this study was to investigate the relationship between
      hypertension and risk of stroke in the elderly. The study was performed within
      the framework of the Rotterdam Study, a prospective population-based cohort
      study. The risk of first-ever stroke was associated with hypertension (relative
      risk, 1.6; 95% CI, 1.2 to 2.0) and with isolated systolic hypertension (relative
      risk, 1.7; 95% CI, 1.1 to 2.6). We found a continuous increase in stroke
      incidence with increasing blood pressure in nontreated subjects. In treated
      subjects, we found a J-shaped relation between blood pressure and the risk of
      stroke. In the lowest category of diastolic blood pressure, the increase of
      stroke risk was statistically significant compared with the reference category.
      Hypertension and isolated systolic hypertension are strong risk factors for
      stroke in the elderly. The increased stroke risk in the lowest stratum of blood
      pressure in treated hypertensive patients may indicate that the therapeutic goal
      of "the lower the better" is not the optimal strategy in the elderly.

PMID- 10601116
TI  - Association and linkage analyses of glucocorticoid receptor gene markers in
      essential hypertension.
AB  - Suggestive evidence has been obtained in a "4-corners" study for involvement of
      the glucocorticoid receptor gene (GRL) in genetic variation in blood pressure.
      Therefore, we tested markers at the GRL locus for association and linkage with
      essential hypertension (HT). For the association study, we used a well
      characterized group of 129 white Australians of Anglo-Celtic extraction who had
      HT, a strong family history of HT (2 parents with the disease), and early-onset
      moderate-to-severe disease. Controls were 195 normotensive white subjects whose
      parents were normotensive past the age of 50 years. For the linkage study, we
      used 175 sibling pairs of similar ancestry. The case-control groups were
      genotyped for an Asn363Ser variant in exon 2, a G/T variant in intron 4, and a
      microsatellite marker (D5S207) tightly linked (<200 kb) to GRL. For the groups as
      a whole, no association or linkage was observed after analysis of data by a
      variety of statistical tests. Analysis of sibling-pair data gave an exclusion
      score of -3.8 for the logarithm of the odds for linkage, indicating significant
      nonlinkage. However, in females, weak association of the intron 4 polymorphism
      with HT (P=0.03), as well as with systolic and diastolic blood pressure in all
      subjects (P=0. 04 and 0.03), was observed, and in the case of the D5S207 marker,
      association with HT was apparent in males (P=0.0001). Thus, although our results
      provide no overall support for GRL in HT etiology, apparent gender-specific
      associations could exist in this genomic region, possibly reflecting correlated
      occurrence with (an)other metabolic syndrome disorder(s).

PMID- 10601117
TI  - Association between the C825T polymorphism of the G protein beta3-subunit gene
      and hypertension in blacks.
AB  - A polymorphism (C825T) of the G protein beta3-subunit gene has been associated
      with low renin hypertension in whites. The aim of this study was to examine the
      C825T polymorphism in relation to hypertension in a population-based study of
      black people of African origin who have high prevalence of low renin, salt
      sensitive hypertension. A total of 428 men and women, aged 40 to 59 years (270
      Caribbeans and 158 West Africans), who took part in a population-based survey
      were studied. All were blacks and first-generation immigrants. The C825T
      polymorphism was detected by polymerase chain reaction followed by restriction
      enzyme digestion. The prevalence of hypertension (supine blood pressures >/=160
      systolic and/or 95 mm Hg diastolic or on drug therapy) was 43%. The distribution
      of the genotypes (CC, CT, and TT) was in Hardy-Weinberg equilibrium with observed
      frequencies of 4.0% (n=17), 33.6% (n=144), and 62.4% (n=267), respectively.
      Allele frequencies were 20.8% for C and 79.2% for T. No difference was detected
      between Caribbeans and West Africans. A 3-fold higher risk of hypertension was
      found among the carriers of the T variant both as heterozygotes (odds ratio [OR],
      3.43 [95% CI, 0.94 to 12.4]) and homozygotes (OR, 3.87 [95% CI, 1. 09 to 13.8]).
      The estimate of effect and the blood pressure values in the groups carrying the T
      variant suggested a dominant model for the T allele. This was confirmed by a
      significant association between the T allele and hypertension (OR, 3.71 [95% CI,
      1.05 to 13. 1]), even when adjusted for age, sex, and body mass index (OR, 4.14
      [95% CI, 1.11 to 15.4]). The study shows, for the first time, a high frequency of
      the 825T allele in black people, and it provides evidence that the T allele may
      be a susceptibility factor for the development of hypertension in blacks. Given
      the high frequency of the T allele, even a 2-fold increased risk of hypertension
      among the carriers of the T allele might account for 44% of the cases of
      hypertension in blacks.

PMID- 10601118
TI  - Carvedilol and lacidipine prevent cardiac hypertrophy and endothelin-1 gene
      overexpression after aortic banding.
AB  - Carvedilol and lacidipine have been shown to exert cardioprotective effects in
      rat models of chronic hypertension. We investigated their effects in an acute
      model of pressure overload produced by suprarenal aortic constriction, in which
      enhanced myocardial production of endothelin-1 could play a crucial role. In the
      absence of drug treatment, after 1 week, aortic banding provoked an increase in
      carotid pressure associated with left ventricular hypertrophy (29%; P<0.01).
      These changes were accompanied by increased myocardial expression of
      preproendothelin-1 (2.5 times; P<0.05) and skeletal alpha-actin (3.6 times;
      P<0.05), but the expression of cardiac alpha-actin was not modified. Oral
      administration of carvedilol at a dose of 30 mg. kg(-1). d(-1) to rats with
      aortic banding normalized carotid pressure and left ventricular weight as well as
      preproendothelin-1 and skeletal alpha-actin gene expression. Carvedilol at a
      lower dose (7.5 mg x kg(-1) x d(-1)) and lacidipine 1 mg x kg(-1) x d(-1) had
      only moderate and nonsignificant effects on carotid pressure but largely
      prevented left ventricular hypertrophy (P<0.01) and preproendothelin-1
      overexpression (P<0.05). Labetalol (60 mg x kg(-1) x d(-1)) tended to exert
      similar effects but insignificantly. These results show that the antihypertrophic
      properties of carvedilol and lacidipine are partly independent of their
      antihypertensive effects and may be related to their ability to blunt myocardial
      preproendothelin-1 overexpression. Moreover, carvedilol at a dose of 7.5 mg x kg(
      1) x d(-1) did not prevent myocardial overexpression of skeletal alpha-actin,
      which suggests that, in this model, reexpression of a fetal gene can be activated
      by pressure overload independently of cardiac hypertrophy.

PMID- 10601119
TI  - Impeded alveolar-capillary gas transfer with saline infusion in heart failure.
AB  - The microvascular pulmonary endothelium barrier is critical in preventing
      interstitial fluid overflow and deterioration in gas diffusion. The role of
      endothelium in transporting small solutes in pathological conditions, such as
      congestive heart failure (CHF), has not been studied. Monitoring of pulmonary gas
      transfer during saline infusion in CHF was used to probe this issue. Carbon
      monoxide diffusion (DL(CO)), its membrane diffusion (D(M)) and capillary blood
      volume (V(C)) subcomponents, and mean right atrial (rap) and mean pulmonary wedge
      (wpp) pressures after saline or 5% D-glucose solution infusions were compared
      with baseline in 26 moderate CHF patients. Saline was also tested in 13 healthy
      controls. In patients, 750 mL of saline lowered DL(CO) (-8%, P<0.01 versus
      baseline), D(M) (-10%, P<0.01 versus baseline), aldosterone (-29%, P<0.01 versus
      baseline), renin (-52%, P<0.01 versus baseline), and hematocrit (-6%, P<0.05
      versus baseline) and increased V(C) (20%, P<0.01 versus baseline), without
      changing rap and wpp. Saline at 150 mL produced qualitatively similar results
      regarding DL(CO) (-5%, P<0.01 versus baseline), D(M) (-7%, P<0.01 versus
      baseline), V(C) (9%, P<0.01 versus baseline), rap, wpp, aldosterone (-9%, P<0.05
      versus baseline), and renin (-14%, P<0.05 versus baseline). Glucose solution (750
      mL), on the contrary, increased DL(CO) (5%, P<0.01 versus 750 mL of saline) and
      D(M) (11%, P<0.01 versus 750 mL of saline) and decreased V(C) (-9, P<0.01 versus
      750 mL of saline); aldosterone (-40%), renin (-41%), hematocrit (-3%), rap, and
      wpp behaved as they did after saline infusion. In controls, responses to both
      saline amounts were similar to responses in CHF patients regarding aldosterone,
      renin, hematocrit, rap, and wpp, whereas DL(CO), D(M), and V(C) values tended to
      rise. Hindrance to gas transfer (reduced DL(CO) and D(M)) with salt infusion in
      CHF, despite an increase in V(C) and no variations in pulmonary hydrostatic
      forces, indicates an upregulation in sodium transport from blood to interstitium
      with interstitial edema. Redistribution of blood from the lungs, facilitating
      interstitial fluid reabsorption, or sodium uptake from the alveolar lumen by the
      sodium-glucose cotransport system might underlie the improved alveolar-capillary
      conductance with glucose.

PMID- 10601120
TI  - Insulin and diastolic dysfunction in lean and obese hypertensives: genetic
      influence.
AB  - We investigated the influence of genetic predisposition to hypertension by
      studying the relation between insulin sensitivity and left ventricular (LV) mass
      and function in untreated lean and obese hypertensives. We selected 50 lean
      hypertensives with normotensive parents (negative family history of hypertension
      [F-]), 64 lean hypertensives with 1 or both parents hypertensive (positive family
      history of hypertension [F+]), 40 obese F- hypertensives, and 43 obese F+
      hypertensives. The 4 groups were comparable regarding age, gender, 24-hour blood
      pressure profile, and known duration of hypertension. We measured glucose,
      insulin, and C-peptide during fasting and during an oral glucose tolerance test;
      LV morphology and function were assessed by digitized M-mode echocardiography.
      Glucose (fasting and test) levels were normal in all and similar among the 4
      groups. Insulin and C-peptide (fasting and stimulated) levels were higher in
      obese hypertensives than in lean hypertensives; at similar body mass index,
      insulin and C-peptide levels were higher in F+ than in F- groups. Compared with
      lean hypertensives, obese hypertensives had greater LV mass index; LV systolic
      function was normal in all and similar among the groups. The indices of LV
      diastolic function were significantly lower in F+ than in F- groups. LV mass
      index did not correlate with metabolic parameters; the indices of LV diastolic
      function were inversely correlated with insulin area during test in only the 2 F+
      groups. In conclusion, genetic predisposition to hypertension is associated with
      a reduced insulin sensitivity and affects the response of the myocardium to
      increased insulin levels, inducing a greater impairment of diastolic function.
      Insulin sensitivity and genetic predisposition to hypertension seem to have no
      influence on LV mass.

PMID- 10601121
TI  - Influence of age on contractile response to insulin-like growth factor 1 in
      ventricular myocytes from spontaneously hypertensive rats.
AB  - Evidence suggests a pathophysiological role of insulin-like growth factor 1 (IGF
      1) in hypertension. Cardiac function is altered with advanced age, similar to
      hypertension. Accordingly, the effects of IGF-1 on cardiac myocyte shortening and
      intracellular Ca(2+) were evaluated in hypertension at different ages.
      Ventricular myocytes were isolated from Wistar-Kyoto rats (WKY) and spontaneously
      hypertensive rats (SHR), aged 12 and 36 weeks. Mechanical and intracellular
      Ca(2+) properties were examined by edge-detection and fluorescence microscopy. At
      12 weeks, IGF-1 (1 to 500 ng/mL) increased peak twitch amplitude (PTA) and FFI
      changes (DeltaFFI) in a dose-dependent manner in WKY myocytes, with maximal
      increases of 27.5% and 35.2%, respectively. However, IGF-1 failed to exert any
      action on PTA and DeltaFFI in the age-matched SHR myocytes. Interestingly, at 36
      weeks, IGF-1 failed to exert any response in WKY myocytes but depressed both PTA
      and DeltaFFI in a dose-dependent manner in SHR myocytes, with maximal inhibitions
      of 40.5% and 16.1%, respectively. Myocytes from SHR or 36-week WKY were less
      sensitive to norepinephrine (1 micromol/L) and KCl (30 mmol/L). Pretreatment with
      nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME,
      100 micromol/L) did not alter the IGF-1-induced response in 12-week WKY myocytes
      but unmasked a positive action in 12-week SHR and 36-week WKY myocytes. L-NAME
      also significantly attenuated IGF-1-induced depression in 36-week SHR myocytes.
      In addition, the Ca(2+) channel opener Bay K8644 (1 micromol/L) abolished IGF-1
      induced cardiac depression in 36-week SHR myocytes. Collectively, these results
      suggest that the IGF-1-induced cardiac contractile response was reduced with
      advanced age as well as with hypertension. Alterations in nitric oxide and
      intracellular Ca(2+) modulation may underlie, in part, the resistance to IGF-1 in
      hypertension and advanced age.

PMID- 10601122
TI  - Doxorubicin selectively inhibits brain versus atrial natriuretic peptide gene
      expression in cultured neonatal rat myocytes.
AB  - Doxorubicin is an antineoplastic agent with significant cardiotoxicity. We
      examined the effects of this agent on the expression of the natriuretic peptide
      (NP) genes in cultured neonatal rat atrial myocytes. Doxorubicin suppressed NP
      secretion, steady-state NP mRNA levels, and NP gene promoter activity. In each
      instance, brain NP (BNP) proved to be more sensitive than atrial NP (ANP) to the
      inhibitory effects of the drug. ICRF-187 and probucol reversed the inhibition by
      doxorubicin of ANP mRNA accumulation and ANP gene promoter activity while
      exerting no effect on BNP mRNA levels or promoter activity. This represents the
      first identification of the NP genes as targets of doxorubicin toxicity in the
      myocardial cell. This inhibition operates predominantly at a transcriptional
      locus and has more potent effects on BNP versus ANP secretion/gene expression.
      Measurement of BNP secretion/gene expression may provide a sensitive marker of
      early doxorubicin cardiotoxicity.

PMID- 10601123
TI  - Different mechanisms for testosterone-induced relaxation of aorta between
      normotensive and spontaneously hypertensive rats.
AB  - The tension in isolated ring preparations of the thoracic aortae from Wistar
      Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) was measured
      isometrically to study the differences in testosterone-induced relaxation between
      WKY and SHR aortic rings. Testosterone (9 to 300 micromol/L) induced a
      concentration-dependent relaxation in both WKY and SHR aortic rings, and the
      relaxation induced by testosterone was greater in SHR than WKY. The relaxation
      induced by testosterone was significantly reduced by denudation of endothelium in
      SHR but not WKY. Indomethacin, an inhibitor of cyclooxygenase, and N(G)-nitro-L
      arginine, an inhibitor of nitric oxide (NO) synthase, showed little influence on
      the relaxation induced by testosterone in both WKY and SHR aortic rings.
      Glibenclamide, a selective inhibitor of ATP-sensitive potassium channels,
      significantly reduced the relaxation induced by testosterone in both WKY and SHR
      aortic rings, although the extent of reduction was greater in WKY than SHR. On
      the other hand, 4-aminopyridine, a selective inhibitor of voltage-dependent
      potassium channels, and tetraethylammonium, an inhibitor of calcium-activated
      potassium channels, significantly reduced the relaxation induced by testosterone
      in SHR but not WKY. These results suggest that the mechanisms of testosterone
      induced vasorelaxation in both WKY and SHR involve, in part, ATP-sensitive
      potassium channels in the thoracic aortae and that in SHR aortic rings,
      testosterone may release endothelium-derived substances that may cause
      hyperpolarization of the cells by a mechanism that involves potassium channels.
      Moreover, the data show differences between WKY and SHR in the function of ATP
      sensitive, voltage-dependent, and calcium-activated potassium channels.

PMID- 10601124
TI  - cGMP-mediated negative-feedback regulation of endothelial nitric oxide synthase
      expression by nitric oxide.
AB  - Earlier studies have demonstrated that nitric oxide (NO) exerts a fast-acting
      inhibitory influence on endothelial NO synthase (eNOS) enzymatic activity in
      isolated vascular tissue preparations. The present study was designed to examine
      the possible effect of NO on eNOS protein expression in cultured endothelial
      cells and intact animals. Human coronary endothelial cells were incubated with S
      nitroso-N-acetyl-penicillamine (SNAP, an NO donor), oxyhemoglobin (HGB, an NO
      trapping agent), SNAP plus HGB, or inactive vehicle (control). In other
      experiments, cells were treated with 3-isobutyl-1-methylxanthine (a
      phosphodiesterase inhibitor), 1H-[1,2, 4]oxadiazolo-[4,3-2]quinoxalin-1-one (ODQ,
      a guanylate cyclase inhibitor), SNAP plus ODQ, 8-bromo-cGMP (8-Br-cGMP, a cell
      permeable cGMP compound), 8-Br-cGMP plus HGB, or inactive vehicle in order to
      discern the effect of cGMP. The incubations were conducted for 24 hours, and
      total nitrate plus nitrite production and eNOS protein abundance (Western
      analysis) were measured. To determine the effect of NO on eNOS expression in
      vivo, rats were treated with either the NO donor isosorbide dinitrate or placebo
      by gastric gavage for 48 hours, and aortic eNOS protein expression was examined.
      The NO donor SNAP markedly depressed, whereas the NO scavenger HGB significantly
      raised, eNOS protein expression. The downregulatory action of SNAP was completely
      abrogated by HGB. Phosphodiesterase inhibitor and 8-Br-cGMP downregulated,
      whereas the guanylate cyclase inhibitor ODQ upregulated eNOS protein expression.
      The downregulatory action of SNAP was completely overcome by the guanylate
      cyclase inhibitor ODQ, and the upregulatory action of the NO scavenger HGB was
      abrogated by 8-Br-cGMP. Administration of NO donor resulted in a marked
      downregulation of aortic eNOS protein expression in intact animals, thus
      confirming the in vitro findings. NO serves as a negative-feedback regulator of
      eNOS expression via a cGMP-mediated process.

PMID- 10601125
TI  - Epoxyeicosatrienoic acids increase intracellular calcium concentration in
      vascular smooth muscle cells.
AB  - Epoxyeicosatrienoic acids (EETs) are cytochrome P450-derived metabolites of
      arachidonic acid. They are potent endogenous vasodilator compounds produced by
      vascular cells, and EET-induced vasodilation has been attributed to activation of
      vascular smooth muscle cell (SMC) K(+) channels. However, in some cells, EETs
      activate Ca(2+) channels, resulting in Ca(2+) influx and increased intracellular
      Ca(2+) concentration ([Ca(2+)](i)). We investigated whether EETs also can
      activate Ca(2+) channels in vascular SMC and whether the resultant Ca(2+) influx
      can influence vascular tone. The 4 EET regioisomers (1 micromol/L) increased
      porcine aortic SMC [Ca(2+)](i) by 52% to 81%, whereas arachidonic acid,
      dihydroxyeicosatrienoic acids, and 15-hydroxyeicosatetraenoic acid (1 micromol/L)
      produced little effect. The increases in [Ca(2+)](i) produced by 14,15-EET were
      abolished by removal of extracellular Ca(2+) and by pretreatment with verapamil
      (10 micromol/L), an inhibitor of voltage-dependent (L-type) Ca(2+) channels.
      14,15-EET did not alter Ca(2+) signaling induced by norepinephrine and
      thapsigargin. When administered to porcine coronary artery rings precontracted
      with a thromboxane mimetic, 14,15-EET produced relaxation. However, when
      administered to rings precontracted with acetylcholine or KCl, 14,15-EET produced
      additional contractions. In rings exposed to 10 mmol/L KCl, a concentration that
      did not affect resting ring tension, 14,15-EET produced small contractions that
      were abolished by EGTA (3 mmol/L) or verapamil (10 micromol/L). These
      observations indicate that 14,15-EET enhances [Ca(2+)](i) influx in vascular SMC
      through voltage-dependent Ca(2+) channels. This 14,15-EET-induced increase in
      [Ca(i)(2+)] can produce vasoconstriction and therefore may act to modulate EET
      induced vasorelaxation.

PMID- 10601126
TI  - Effects of superoxide on signaling pathways in smooth muscle cells from rats.
AB  - The effects of hypoxanthine and xanthine oxidase-induced superoxide anion were
      evaluated on various signal transduction pathways in aortic smooth muscle cells
      (SMCs) from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY).
      Superoxide increased inositol 1,4,5-tris-phosphate (IP(3)) formation in a
      concentration- and time-dependent manner in both strains but more markedly in
      SMCs from SHR. Various antioxidants significantly decreased the superoxide
      induced IP(3) formation in both strains. In addition, tyrosine kinase inhibitors,
      genistein and tyrphostin A25, inhibited the superoxide-induced IP(3) formation
      more markedly in SHR than in WKY. Moreover, superoxide decreased the basal level
      of cGMP to a greater extent in SHR and also suppressed the rise in cGMP induced
      by S-nitroso-N-acetylpenicillamine. In addition, the superoxide-induced increase
      in IP(3) formation was significantly inhibited by guanylyl cyclase stimulator S
      nitroso-N-acetylpenicillamine but was potentiated by ODQ (a guanylyl cyclase
      inhibitor, 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one) and KT5823 (a cGMP
      dependent protein kinase inhibitor), with a greater effect in SHR. Finally, the
      superoxide-enhanced IP(3) formation was not accompanied by simultaneous changes
      in cAMP levels, and inhibition of the adenylyl cyclase pathway did not modify the
      superoxide-induced IP(3) formation. Our results thus demonstrate a stimulatory
      effect of superoxide on IP(3) formation, mediated by the tyrosine kinase-coupled
      phospholipase C(gamma) activity, and an inhibitory effect of superoxide on cGMP
      formation in vascular SMCs. The increased reactivity of the phospholipase C
      pathway and the decreased cross inhibition of the IP(3) pathway by cGMP in the
      presence of superoxide may underlie the altered functions of vascular SMCs in
      SHR.

PMID- 10601127
TI  - Interaction between nitric oxide and endogenous vasoconstrictors in control of
      renal blood flow.
AB  - The level of renal blood flow (RBF) is controlled by opposing vasoconstrictor and
      vasodilator influences. In a recent investigation in normotensive dogs, we found
      that combined blockade of endothelin type A (ET(A)) receptors and angiotensin II
      formation induces marked increases in RBF that were much larger than the effects
      of blocking either system alone. The aim of the present study was to determine
      the contribution of nitric oxide (NO) to this vasodilator response. Experiments
      were made in 6 conscious, chronically instrumented dogs subjected to 5 different
      experimental treatments on separate days. Blockade of ET(A) receptors alone by
      the selective antagonist LU 135252 had only minor effects on RBF compared with
      time-control experiments. Additional blockade of angiotensin II formation by
      angiotensin-converting enzyme inhibition with trandolaprilat caused a substantial
      increase of RBF by approximately 50%. This vasodilation was entirely suppressed
      when NO formation was prevented by inhibition of NO synthase with N(G)-nitro-L
      arginine methyl ester HCl. However, when during NO synthase inhibition renal
      vascular NO concentrations were clamped at control levels by infusing the NO
      donor S-nitroso-N-acetyl-D, L-penicillamine, the vasodilator response to combined
      blockade of ET(A) receptors and angiotensin II formation was completely restored
      (DeltaRBF approximately 60%). These results indicate that the vasodilation after
      combined ET(A) receptor blockade and angiotensin-converting enzyme inhibition is
      not mediated by an increase in NO release but results from the unmasking of the
      tonic influence that is normally exerted by constitutively released NO.
      Accordingly, the tonic activity of endothelial NO synthase appears to be of major
      importance in the physiological regulation of renal vascular resistance by
      determining the vasomotor responses to endothelin and angiotensin II.

PMID- 10601128
TI  - Salicylate inhibition of extracellular signal-regulated kinases and inducible
      nitric oxide synthase.
AB  - The expression of inducible nitric oxide synthase (iNOS) is a characteristic
      response to inflammation and can be inhibited with sodium salicylate. We used the
      cytokine-induced iNOS induction in cardiac fibroblasts as a model system in which
      to test the hypothesis that effects on mitogen-activated protein kinases (MAPKs)
      may explain the mechanism by which salicylate exerts its anti-inflammatory
      effects. Tumor necrosis factor-alpha (TNF-alpha) alone can induce extracellular
      signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase activity in
      a rapid and transient manner, whereas interferon-gamma (IFN-gamma) can induce
      only ERK. The inhibition of either the ERK pathway or p38 MAPK activity with
      selective inhibitors blocked cytokine-induced iNOS protein and nitrite
      production. Salicylate treatment inhibited iNOS expression induced by TNF-alpha
      and IFN-gamma and attenuated the phosphorylation of ERK by TNF-alpha and IFN
      gamma either alone or in combination. Salicylate had no obvious effect on the
      activation of p38 MAPK or c-Jun N-terminal kinase. The results showed that
      salicylate inhibited the phosphorylation of ERK and iNOS expression induced by
      cytokines in a dose-dependent manner and suggested that salicylate exerts its
      anti-inflammatory action in part through inhibition of the ERK pathway and iNOS
      induction.

PMID- 10601129
TI  - Elements of a paracrine tubular renin-angiotensin system along the entire
      nephron.
AB  - The renin-angiotensin system is a major regulator of body sodium, predominantly
      through the actions of intrarenal angiotensin II of unclear origin. We show that
      polarized epithelium of the proximal tubule synthesizes and secretes
      angiotensinogen at its apical side and that the protein can be detected in urine
      as a function of dietary sodium. Furthermore, we demonstrate that renin is
      expressed and secreted in a restricted nephron segment, the connecting tubule,
      also in a sodium-dependent fashion. A paracrine renin-angiotensin system
      operating along the entire nephron may contribute to long-term arterial pressure
      regulation by integrating distant tubular sodium-reabsorbing functions.

PMID- 10601130
TI  - Thiol protein defect in sodium-lithium countertransport in subset of essential
      hypertension.
AB  - There is probably a heterogeneous etiology for essential hypertension (EHT), and
      abnormal erythrocyte sodium-lithium countertransport (Na/Li CT) is common in a
      subgroup of patients with a strong family history of hypertension and
      cardiovascular disease (EHT-FH patients). The aim of this study was to test the
      hypothesis that altering a membrane thiol protein could mimic the abnormal Na/Li
      CT observed in the patients and that a more refined understanding of the
      mechanism of abnormal Na/Li CT would facilitate a clearer identification of a
      subgroup of patients with a homogeneous biochemical abnormality. Na/Li CT
      kinetics were determined in untreated erythrocytes and after thiol group
      alkylation with N-ethylmaleimide (NEM). Compared with normal control
      erythrocytes, untreated erythrocytes from EHT-FH patients had a low K(m) of Na/Li
      CT, with a high ratio of maximum velocity to K(m). This kinetic pattern was
      reproduced in normal erythrocytes by treatment with NEM in sodium-free medium.
      The same treatment in EHT-FH erythrocytes caused a markedly abnormal effect with
      an increase in maximum velocity, indicating an increase in transporter turnover
      in contrast to the increase in sodium affinity seen in normal control
      erythrocytes. Frequency distributions of these kinetic changes showed a subgroup
      of approximately 75% of EHT-FH patients with abnormal kinetic changes with NEM.
      Therefore, the key Na/Li CT thiol group that is very reactive to NEM and causes
      the abnormal Na/Li CT in a subgroup of hypertensive patients may be a useful
      intermediate phenotype for a disease group within the syndrome of EHT. The single
      flux assay of Na/Li CT at 140 mmol/L sodium poorly discriminates this group.
      Identification of the thiol protein involved may lead to a molecular explanation
      of the altered membrane function in this subgroup of patients.

PMID- 10601131
TI  - Effect of the HMG-CoA reductase inhibitors on blood pressure in patients with
      essential hypertension and primary hypercholesterolemia.
AB  - Certain hydroxymethylglutaryl coenzyme A reductase inhibitors, ie, statins, may
      cause vasodilation by restoring the endothelial dysfunction that frequently
      accompanies hypertension and hypercholesterolemia. Several studies have found
      that a blood pressure reduction is associated with the use of statins, but
      conclusive evidence from controlled trials is lacking. After an 8-week placebo
      and diet run-in period, 30 persons with moderate hypercholesterolemia and
      untreated hypertension (total cholesterol 6.29+/-0.52 mmol/L, systolic and
      diastolic blood pressure 149+/-6 and 97+/-2 mm Hg) were randomized in a double
      blind manner to placebo or pravastatin (20 to 40 mg/d) in a crossover design. In
      25 participants who completed the 32-week trial, pravastatin decreased total and
      LDL cholesterol (both -1.09 mmol/L, P=0.001), systolic and diastolic blood
      pressure (-8 and -5 mm Hg, both P=0.001), and pulse pressure (-3 mm Hg, P=0.011)
      and blunted the blood pressure increase caused by the cold pressor test (-4 mm
      Hg, P=0.005) compared with placebo. It also reduced the level of circulating
      endothelin-1 (P=0.001). The blood pressure results were virtually unchanged in
      stratified analyses according to gender and age and in intention-to-treat
      analyses that included the 5 patients who dropped out of the study. When the
      participants were taking either placebo or pravastatin, blood pressure was not
      significantly correlated with total or LDL cholesterol or with circulating
      endothelin-1. Pravastatin decreases systolic, diastolic, and pulse pressures in
      persons with moderate hypercholesterolemia and hypertension. This
      antihypertensive effect may contribute to the documented health benefits of
      certain statins.

PMID- 10601132
TI  - Step-down of enalapril treatment for arterial hypertension.
AB  - Enalapril treatment (20 mg every 12 hours) of 24 patients with essential
      hypertension and left ventricular (LV) hypertrophy established normal blood
      pressures after 8 weeks, and after 5 years, it had reduced LV mass index by 39%
      (from 148+/-34 to 90+/-16 g/m(2)) and had normalized LV structure and function
      and QT dispersion. Stepwise reduction of the enalapril dosage from 40 to 30, 20,
      10, and 5 mg/d during the eighth year caused no significant change in blood
      pressure, LV structure, LV systolic function, or QT dispersion, which all
      likewise remained unaltered during an additional 2-year period of the 5-mg/d
      regimen. We conclude that for hypertensive patients in whom prolonged treatment
      with high doses of enalapril has normalized blood pressure, LV structure, LV
      function, and QT dispersion, the dose may be reduced as much as 8-fold without
      detriment to cardiovascular control. The use of smaller doses is evidently
      advantageous from the point of view of health costs.

PMID- 10601133
TI  - Effects of the nonpeptide V(1) vasopressin receptor antagonist SR49059 in
      hypertensive patients.
AB  - We assessed the clinical and pharmacological profile of the orally active V(1)
      vascular vasopressin (AVP) receptor nonpeptide antagonist SR49059 (SR) during the
      osmotic stimulation of AVP release in hypertensive patients. In a double-blind
      crossover-versus-placebo study, 24 untreated stage I or II essential hypertensive
      patients (12 whites and 12 blacks) received a single 300 mg oral dose of SR 2
      hours before the stimulation of AVP secretion with a 5% hypertonic saline
      infusion. Hemodynamic, humoral, and hormonal parameters were monitored for up to
      28 hours after drug administration. SR did not alter blood pressure or heart rate
      before the saline infusion and did not reduce the blood pressure increment
      induced by the hypertonic saline infusion. However, the blood pressure peak at
      the end of the hypertonic saline infusion was slightly lower in the presence of
      SR (P=0.04). Heart rate was significantly faster between 4 and 6 hours after SR
      administration (P=0.02). The rise in plasma sodium and osmolality triggered by
      the saline infusion was not modified by SR, but AVP release was slightly greater
      in the presence of SR (P<0.0003). AVP-induced aggregation of blood platelets in
      vitro was significantly reduced by SR, with a peak effect 2 hours after drug
      administration that coincided with the SR peak plasma concentration. Plasma renin
      activity and aldosterone before and after the saline infusion were not modified
      by SR. Urine volume and osmolality were not altered by SR administration. SR
      effects were similar in the 2 ethnic groups as well as in salt-sensitive versus
      salt-resistant patients. In a situation of AVP osmotic release and volume
      expansion in hypertensive patients, a single oral dose of the V(1) vascular AVP
      receptor nonpeptide antagonist SR49059, which is able to block AVP-induced
      platelet aggregation, exerts a transient vasodilation effect that is not
      associated with a sustained blood pressure reduction. SR49059 is a pure V(1)
      vascular receptor antagonist that is devoid of V(2) renal receptor actions.

PMID- 10601135
TI  - Study duration and validity.

PMID- 10601134
TI  - AT(1) receptors mediate excitatory inputs to rostral ventrolateral medulla
      pressor neurons from hypothalamus.
AB  - Angiotensin II type 1 (AT(1)) receptors are located on pressor neurons in the
      rostral ventrolateral medulla, and their activation results in an increase in
      arterial pressure. However, the normal role of these AT(1) receptors in
      cardiovascular regulation is unknown. In this study, we tested the hypothesis
      that these receptors mediate synaptic excitation of rostral ventrolateral
      medullary pressor neurons in response to activation of the hypothalamic
      paraventricular nucleus. In anesthetized rats, microinjections of the gamma
      aminobutyric acid receptor antagonist bicuculline were made into the
      paraventricular nucleus; this injection causes activation of the nucleus as a
      consequence of disinhibition. The pressor and sympathoexcitatory responses evoked
      by paraventricular nucleus activation were significantly reduced (by
      approximately 40% to 50%) after microinjection of the specific AT(1) receptor
      antagonists losartan or L-158,809 into the rostral ventrolateral medulla on the
      ipsilateral, but not contralateral, side. These responses were reduced to a
      similar degree after microinjections of the neuroinhibitory compound muscimol
      into the ipsilateral, but not contralateral, rostral ventrolateral medulla.
      However, bilateral microinjections of the glutamate receptor antagonist kynurenic
      acid into the rostral ventrolateral medulla had no effect on the responses evoked
      from the paraventricular nucleus. Conversely, bilateral microinjections of
      kynurenic acid into the rostral ventrolateral medulla virtually abolished the
      somatosympathoexcitatory reflex, whereas bilateral microinjections of losartan or
      L-158,809 had no effect on this reflex. The results indicate that excitatory
      synaptic inputs to pressor neurons in the rostral ventrolateral medulla arising
      from activation of the paraventricular nucleus are mediated predominantly by
      AT(1) receptors.

PMID- 10601136
TI  - Vasodilator response to local hyperinsulinemia.

PMID- 10601137
TI  - Can knockout mice help dissect relevant genes in hypertension? Evidence and
      confounding factors.

PMID- 10601138
TI  - ANP bioactivity in obese hypertensives.

PMID- 10601139
TI  - Chronic salt loading and the expression of adenosine receptor subtypes.

PMID- 10601140
TI  - ACE-gene polymorphism and endothelial dysfunction in normal humans.

PMID- 10601141
TI  - Exercise-induced arterial hypoxemia.
AB  - Exercise-induced arterial hypoxemia (EIAH) at or near sea level is now recognized
      to occur in a significant number of fit, healthy subjects of both genders and of
      varying ages. Our review aims to define EIAH and to critically analyze what we
      currently understand, and do not understand, about its underlying mechanisms and
      its consequences to exercise performance. Based on the effects on maximal O(2)
      uptake of preventing EIAH, we suggest that mild EIAH be defined as an arterial
      O(2) saturation of 93-95% (or 3-4% <rest), moderate EIAH as 88-93%, and severe
      EIAH as <88%. Both an excessive alveolar-to-arterial PO(2) difference (A-a DO(2))
      (>25-30 Torr) and inadequate compensatory hyperventilation (arterial PCO(2) >35
      Torr) commonly contribute to EIAH, as do acid- and temperature-induced shifts in
      O(2) dissociation at any given arterial PO(2). In turn, expiratory flow
      limitation presents a significant mechanical constraint to exercise hyperpnea,
      whereas ventilation-perfusion ratio maldistribution and diffusion limitation
      contribute about equally to the excessive A-a DO(2). Exactly how diffusion
      limitation is incurred or how ventilation-perfusion ratio becomes maldistributed
      with heavy exercise remains unknown and controversial. Hypotheses linked to
      extravascular lung water accumulation or inflammatory changes in the "silent"
      zone of the lung's peripheral airways are in the early stages of exploration.
      Indirect evidence suggests that an inadequate hyperventilatory response is
      attributable to feedback inhibition triggered by mechanical constraints and/or
      reduced sensitivity to existing stimuli; but these mechanisms cannot be verified
      without a sensitive measure of central neural respiratory motor output. Finally,
      EIAH has detrimental effects on maximal O(2) uptake, but we have not yet
      determined the cause or even precisely identified which organ system, involved
      directly or indirectly with O(2) transport to muscle, is responsible for this
      limitation.

PMID- 10601142
TI  - Early events in stretch-induced muscle damage.
AB  - Unaccustomed exercise involving stretch of active muscle at long length causes an
      immediate loss of tension-generating capacity, a shift of optimum length, and
      changes in excitation-contraction coupling. Eventually, fiber damage may be
      observed, resulting in pain and tenderness. The subject of this review is the
      early stage in this process, particularly the cause of the immediate drop in
      tension. There is strong evidence pointing to sarcomere length instabilities and
      nonuniformities as important contributors to these changes. The evidence includes
      the influence of initial length, electron microscopy of rapidly fixed active
      fibers, the shift in optimum length in single fibers, and the effects of training
      on sacomere numbers. Experiments using Ca(2+)-sensitive dyes clearly show changes
      in excitiation-contraction coupling, but cross-species comparisons indicate that
      these are not always able to explain the consequences seen. We conclude that
      sarcomere length instabilities provide the most comprehensive explanation of the
      early consequences of eccentric exercise.

PMID- 10601143
TI  - Effects of castration and androgen treatment on androgen-receptor levels in rat
      skeletal muscles.
AB  - The effects of castration and dihydrotestosterone (DHT) treatment on levels of
      skeletal muscle androgen receptor (AR) were examined in three groups of adult
      male rats: 1) intact normal rats, 2) rats castrated at 16 wk of age, and 3) rats
      castrated at 16 wk of age and given DHT for 1 wk starting at week 17. All animals
      were killed at 18 wk of age. Castration caused a decrease (P < 0.05) in the
      weights of the levator ani and bulbocavernosus muscles. The administration of DHT
      to the castrated rats increased (P < 0.05) the weights of the levator ani and
      bulbocavernosus muscles. Castration caused a significant downregulation of AR
      levels in the bulbocavernosus (P < 0.05) but had no significant effect on AR
      levels in the levator ani muscle. DHT administration to the castrated group
      upregulated AR levels in the bulbocavernosus and levator ani muscles. The
      plantaris muscle did not significantly (P > 0.05) change for any of the
      treatments. These findings suggest that the effects of castration and androgen
      replacement differentially affect skeletal muscle mass and AR levels.

PMID- 10601144
TI  - Disruption of ET-1 gene enhances pulmonary responses to methacholine via
      functional mechanism in knockout mice.
AB  - Endothelin (ET)-1 has been shown to have various pathophysiological roles in the
      lung. Recently, it has been reported that ET-1 and a gene encoding ET-1 (Edn1)
      might be involved in airway hyperresponsiveness, which is a major feature of
      bronchial asthma. Meanwhile, it remains unclear whether ET-1 might be involved in
      airway remodeling in vivo. In the present study, we hypothesized whether ET-1
      might play a role in airway remodeling, leading to altered responsiveness. To
      test this hypothesis, we investigated airway function in vivo and airway wall
      structure in Edn1(+/-) heterozygous knockout mice, which genetically produce
      lower levels of ET-1, and Edn1(+/+) wild-type mice. In the physiological study,
      enhanced responses in lung elastance and resistance to methacholine
      administration were observed in Edn1(+/-) mice, whereas there was no difference
      in serotonin responsiveness. In the morphometric study, there were no differences
      in either lamina propria or airway smooth muscle thickness between Edn1(+/-) mice
      and Edn1(+/+) mice. These findings suggest that ET-1 gene disruption is involved
      in methacholine pulmonary hyperresponsiveness via functional mechanism, but not
      airway remodeling, in mice. The ET-1 knockout mice may provide appropriate models
      to study diseases related to ET-1 metabolism.

PMID- 10601145
TI  - Hypoxic pressor response, cardiac size, and natriuretic peptides are modified by
      long-term intermittent hypoxia.
AB  - We investigated whether the effect of long-term intermittent hypoxia (LTIH) on
      cardiovascular function may be modified by preexisting genetic traits. To induce
      LTIH experimentally, cycles of 90-s hypoxia (nadir 6%) followed by 90-s normoxia
      were applied to six Wistar-Kyoto and six spontaneously hypertensive rats during 8
      h daily. Comparison with the same number of control animals after 70 days
      revealed no alteration of intra-arterial blood pressure or heart rate. Blood
      pressure responsiveness to a brief hypoxic stimulus was enhanced in the LTIH
      animals, regardless of strain, whereas the hypoxia-induced increase in heart rate
      was abolished. In the spontaneously hypertensive but not the Wistar-Kyoto rats,
      LTIH increased left ventricular weight-to-body weight ratio and content of atrial
      natriuretic peptide mRNA. Expression of B-type natriuretic peptide was unchanged
      (Northern blot). Slightly increased right ventricular weight-to-body weight
      ratios in the LTIH animals were associated with higher right ventricular atrial
      natriuretic peptide and B-type natriuretic peptide mRNA amounts. Consequently,
      the effects of LTIH on different components of cardiovascular function appear
      incompletely related to each other and differentially influenced by
      constitutional traits.

PMID- 10601146
TI  - Electron spin resonance spectroscopy, exercise, and oxidative stress: an ascorbic
      acid intervention study.
AB  - Oxygen free radicals are highly reactive species that are produced in increased
      quantities during strenuous exercise and can damage critical biological targets
      such as membrane phospholipids. The present study examined the effect of acute
      ascorbic acid supplementation on exercise-induced free radical production in
      healthy subjects. Results demonstrate increases in the intensity of the alpha
      phenyl-tert-butylnitrone adduct (0.05 +/- 0.02 preexercise vs. 0.19 +/- 0.03
      postexercise, P = 0.002, arbitrary units) together with increased lipid
      hydroperoxides (1.14 +/- 0.06 micromol/l preexercise vs. 1.62 +/- 0.19 micromol/l
      postexercise, P = 0.005) and malondialdehyde (0.70 +/- 0.04 micromol/l
      preexercise vs. 0.80 +/- 0.04 micromol/l postexercise, P = 0.0152) in the control
      phase. After supplementation with ascorbic acid, there was no significant
      increase in the electron spin resonance signal intensity (0.02 +/- 0. 01
      preexercise vs. 0.04 +/- 0.02 postexercise, arbitrary units), lipid
      hydroperoxides (1.12 +/- 0.21 micromol/l preexercise vs. 1.12 +/- 0.08 micromol/l
      postexercise), or malondialdehyde (0.63 +/- 0.07 micromol/l preexercise vs. 0.68
      +/- 0.05 micromol/l postexercise). The results indicate that acute ascorbic acid
      supplementation prevented exercise-induced oxidative stress in these subjects.

PMID- 10601147
TI  - Purine loss after repeated sprint bouts in humans.
AB  - The influence of the number of sprint bouts on purine loss was examined in nine
      men (age 24.8 +/- 1.6 yr, weight 76 +/- 3.9 kg, peak O(2) consumption 3.87 +/-
      0.16 l/min) who performed either one (B1), four (B4), or eight (B8) 10-s sprints
      on a cycle ergometer, 1 wk apart, in a randomized order. Forearm venous plasma
      inosine, hypoxanthine (Hx), and uric acid concentrations were measured at rest
      and during 120 min of recovery. Urinary inosine, Hx, and uric acid excretion were
      also measured before and 24 h after exercise. During the first 120 min of
      recovery, plasma inosine and Hx concentrations, and urinary Hx excretion rate,
      were progressively higher (P < 0.05) with an increasing number of sprint bouts.
      Plasma uric acid concentration was higher (P < 0.05) in B8 compared with B1 and
      B4 after 45, 60, and 120 min of recovery. Total urinary excretion of purines
      (inosine + Hx + uric acid) was higher (P < 0. 05) at 2 h of recovery after B8
      (537 +/- 59 micromol) compared with the other trials (B1: 270 +/- 76; B4: 327 +/-
      59 micromol). These results indicate that the loss of purine from the body was
      enhanced by increasing the number of intermittent 10-s sprint bouts.

PMID- 10601148
TI  - Analysis of intrapulmonary O(2) concentration by MR imaging of inhaled
      hyperpolarized helium-3.
AB  - Inhalation of hyperpolarized (3)He allows magnetic resonance imaging (MRI) of
      ventilated airspaces. (3)He hyperpolarization decays more rapidly when
      interacting with paramagnetic O(2). We describe a method for in vivo
      determination of intrapulmonary O(2) concentrations ([O(2)]) based on MRI
      analysis of the fate of measured amounts of inhaled hyperpolarized (3)He in
      imaged regions of the lung. Anesthetized pigs underwent controlled
      normoventilation in a 1.5-T MRI unit. The inspired O(2) fraction was varied to
      achieve different end-tidal [O(2)] fractions (FET(O(2))). With the use of a
      specifically designed applicator, (3)He (100 ml, 35-45% polarized) was
      administered at a predefined time within single tidal volumes. During subsequent
      inspiratory apnea, serial two-dimensional images of airways and lungs were
      acquired. At least once in each animal studied, the radio-frequency excitation
      used for imaging was doubled at constant FET(O(2)). Signal intensity measurements
      in regions of interest of the animals' lungs (volume range, 54-294 cm(3)), taken
      at two different radio-frequency excitations, permitted calculation of [O(2)] in
      these regions of interest. The [O(2)] fractions in the regions of interest
      correlated closely with FET(O(2)) (R = 0.879; P < 0.0001). O(2)-sensitive (3)He
      MRI may allow noninvasive study of regional distribution of ventilation and
      alveolar PO(2) in the lung.

PMID- 10601149
TI  - Blood pressure and plasma catecholamines in acute and prolonged hypoxia: effects
      of local hypothermia.
AB  - This study measured the pressor and plasma catecholamine response to local
      hypothermia during adaptation to hypobaric hypoxia. Eight healthy men were
      studied at rest and after 10 and 45 min of local cooling of one hand and forearm
      as well as after 30 min of rewarming at sea level and again 24 h and 5 days after
      rapid, passive transport to high altitude (4,559 m). Acute mountain sickness
      scores ranged from 5 to 16 (maximal attainable score: 20) on the first day but
      were reduced to 0-8 by the fifth day. Systolic blood pressure, heart rate, and
      plasma epinephrine increased on day 1 at altitude compared with sea level but
      declined again on day 5, whereas diastolic and mean blood pressures continued to
      rise in parallel with plasma norepinephrine. With local cooling, an increased
      vasoactive response was seen on the fifth day at altitude. Very high pressures
      were obtained, and the pressure elevation was prolonged. Heart rate increased
      twice as much on day 5 compared with the other two occasions. Thoracic fluid
      index increased with cooling on day 5, suggesting an increase in pulmonary
      vascular resistance. In conclusion, prolonged hypoxia seems to elicit an
      augmented pressor response to local cooling in the systemic and most likely also
      the pulmonary circulation.

PMID- 10601150
TI  - Glucose clearance in aged trained skeletal muscle during maximal insulin with
      superimposed exercise.
AB  - Insulin and muscle contractions are major stimuli for glucose uptake in skeletal
      muscle and have in young healthy people been shown to be additive. We studied the
      effect of superimposed exercise during a maximal insulin stimulus on glucose
      uptake and clearance in trained (T) (1-legged bicycle training, 30 min/day, 6
      days/wk for 10 wk at approximately 70% of maximal O(2) uptake) and untrained (UT)
      legs of healthy men (H) [n = 6, age 60 +/- 2 (SE) yr] and patients with Type 2
      diabetes mellitus (DM) (n = 4, age 56 +/- 3 yr) during a hyperinsulinemic (
      approximately 16,000 pmol/l), isoglycemic clamp with a final 30 min of
      superimposed two-legged exercise at 70% of individual maximal heart rate. With
      superimposed exercise, leg glucose extraction decreased (P < 0.05), and leg blood
      flow and leg glucose clearance increased (P < 0.05), compared with
      hyperinsulinemia alone. During exercise, leg blood flow was similar in both
      groups of subjects and between T and UT legs, whereas glucose extraction was
      always higher (P < 0.05) in T compared with UT legs (15.8 +/- 1.2 vs. 14.6 +/-
      1.8 and 11.9 +/- 0.8 vs. 8.8 +/- 1.8% for H and DM, respectively) and leg glucose
      clearance was higher in T (H: 73 +/- 8, DM: 70 +/- 10 ml. min(-1). kg leg(-1))
      compared with UT (H: 63 +/- 8, DM: 45 +/- 7 ml. min(-1). kg leg(-1)) but not
      different between groups (P > 0.05). From these results it can be concluded that,
      in both diabetic and healthy aged muscle, exercise adds to a maximally insulin
      stimulated glucose clearance and that glucose extraction and clearance are both
      enhanced by training.

PMID- 10601151
TI  - Diversity in levels of intracellular total creatine and triglycerides in human
      skeletal muscles observed by (1)H-MRS.
AB  - We used (1)H-magnetic resonance spectroscopy to noninvasively determine total
      creatine (TCr), choline-containing compounds (Cho), and intracellular (IT) and
      extracellular (between-muscle fibers) triglycerides (ET) in three human skeletal
      muscles. Subjects' (n = 15 men) TCr concentrations in soleus [Sol; 100.2 +/- 8.3
      (SE) mmol/kg dry wt] were lower (P < 0.05) than those in gastrocnemius (Gast;
      125.3 +/- 9.2 mmol/kg dry wt) and tibialis anterior (TA; 123. 7 +/- 8.8 mmol/kg
      dry wt). The Cho levels in Sol (35.8 +/- 3.6 mmol/kg dry wt) and Gast (28.5 +/-
      3.5 mmol/kg dry wt) were higher (P < 0.001 and P < 0.01, respectively) compared
      with TA (13.6 +/- 2. 4 mmol/kg dry wt). The IT values were found to be 44.8 +/-
      4.6 and 36.5 +/- 4.2 mmol/kg dry wt in Sol and Gast, respectively. The IT values
      of TA (24.5 +/- 4.5 mmol/kg dry wt) were lower than those of Sol (P < 0.01) and
      Gast (P < 0.05). There were no differences in ET [116.0 +/- 11.2 (Sol), 119.1 +/-
      18.5 (Gast), and 91.4 +/- 19.2 mmol/kg dry wt (TA)]. It is proposed that the
      differences in metabolite levels may be due to the differences in fiber-type
      composition and deposition of metabolites due to the adaptation of different
      muscles during locomotion.

PMID- 10601152
TI  - Longitudinal distribution of chlorine absorption in human airways: a comparison
      to ozone absorption.
AB  - The bolus inhalation method was used to measure the fraction of inhaled chlorine
      (Cl(2)) and ozone (O(3)) absorbed during a single breath as a function of
      longitudinal position in the respiratory system of 10 healthy nonsmokers during
      oral and nasal breathing at respired flows of 150, 250, and 1,000 ml/s. At all
      experimental conditions, <5% of inspired Cl(2) penetrated beyond the upper
      airways and none reached the respiratory air spaces. On the other hand, larger
      penetrations of O(3) beyond the upper airways occurred as flow increased and
      during nasal than during oral breathing. In the extreme case of oral breathing at
      1,000 ml/s, 35% of inhaled O(3) penetrated beyond the upper airways and
      approximately 10% reached the respiratory air spaces. Mass transfer theory
      indicated that the diffusion resistance of the tissue phase was negligible for
      Cl(2) but important for O(3). The gas phase resistances were the same for Cl(2)
      and O(3) and were directly correlated with the volume of the nose and mouth
      during nasal and oral breathing, respectively.

PMID- 10601153
TI  - Changes in viscoelastic properties of rat lung parenchymal strips with
      maturation.
AB  - The lung extracellular matrix changes rapidly with maturation. To further our
      understanding of the mechanisms underlying lung tissue mechanics, we studied age
      related changes in mechanical properties in lung parenchymal strips from baby (10
      15 days old), young ( approximately 3 wk old), and adult ( approximately 8 wk
      old) rats. Subpleural strips were cut and suspended in a fluid-filled organ bath.
      One end of the strip was attached to a force transducer and the other to a servo
      controlled lever arm. Measurements of force (F) and length (L) were recorded
      during sinusoidal oscillations of various amplitudes and frequencies. Resistance
      modulus (R) and elastance modulus (E) were estimated by fitting the equation of
      motion to changes in stress (T) and stretch ratio (lambda). Hysteresivity (eta)
      was calculated as follows: eta = (R/E)2pif, where f is frequency. Slow-cycling T
      lambda curves were measured by applying a constant slow length change. Finally,
      quasi-static T-lambda curves were measured as stress was increased from 0 to 6
      kPa and back to 0 kPa in stepwise increments. Our results showed that lung tissue
      from immature rats was stiffer and less hysteretic than tissue from more mature
      animals. In addition, tissue from baby animals behaved in a manner compatible
      with an increased vulnerability to plastic change.

PMID- 10601154
TI  - Influence of elastic properties of tendon structures on jump performance in
      humans.
AB  - The purpose of this study was to quantify the elastic properties of tendon
      structures in vivo and to investigate the influence of the tendon properties on
      jump performance with and without countermovement. Elongation of the tendon and
      aponeurosis of vastus lateralis muscle (dL) was directly measured by
      ultrasonography while subjects (n = 31) performed ramp isometric knee extension
      up to the voluntary maximum (MVC). The relationship between muscle force and dL
      was fitted to a linear regression above 50% MVC, the slope of which was defined
      as stiffness of the tendon structures. Statistical analysis revealed no
      significant difference between duplicated measurements of stiffness, with an
      interday reliability of r = 0.88 and a coefficient of variance of 6.1%. Although
      the stiffness was not significantly related to absolute jump height in either
      vertical jump, it was inversely correlated with the difference in jump height
      between the vertical jumps performed with and without countermovement. The
      results suggested that the stiffness of tendon structures has a favorable effect
      on stretch-shortening cycle exercise, possibly due to adequate storage and recoil
      of elastic energy.

PMID- 10601155
TI  - VO(2) kinetics of mild exercise are altered by RER.
AB  - We propose that variations in fat and carbohydrate (CHO) oxidation by working
      muscle alter O(2) uptake (VO(2)) kinetics. This hypothesis provides two
      predictions: 1) the kinetics should comprise two exponential components, one fast
      and the other slow, and 2) their contribution should change with variations in
      fat and CHO oxidation, as predicted by steady-state respiratory exchange ratio
      (RER). The purpose of this study was to test these predictions by evaluating the
      VO(2) kinetic model: VO(2)(t) = alpha(R) + alpha(F)(1 - exp[(t - TD)/-tau(F)]) +
      alpha(C)(1 - exp[(t - TD)/-tau(C)]) for short-term, mild leg cycling in 38 women
      and 44 men, where VO(2)(t) describes the time course, alpha(R) is resting VO(2),
      t is time after onset of exercise, TD is time delay, alpha(F) and tau(F) are
      asymptote and time constant, respectively, for the fast (fat) oxidative term, and
      alpha(C) and tau(C) are the corresponding parameters for the slow (CHO) oxidative
      term. We found that 1) this biexponential model accurately described the VO(2)
      kinetics over a wide range of RERs, 2) the contribution of the fast (alpha(F),
      fat) component was inversely related to RER, whereas the slow (alpha(C), CHO)
      component was positively related to RER, and 3) this assignment of the fast and
      slow terms accurately predicted steady-state respiratory quotient and CO(2)
      output. Therefore, the kinetic model can quantify the dynamics of fat and CHO
      oxidation over the first 5-10 min of mild exercise in young adult men and women.

PMID- 10601156
TI  - Pixel T2 distribution in functional magnetic resonance images of muscle.
AB  - Increases in skeletal muscle (1)H-NMR transverse relaxation time (T2) observed by
      magnetic resonance imaging have been used to map whole muscle activity during
      exercise. Some studies further suggest that intramuscular variations in T2 after
      exercise can be used to map activity on a pixel-by-pixel basis by defining an
      active T2 threshold and counting pixels that exceed the threshold as "active
      muscle." This implies that motor units are nonrandomly distributed across the
      muscle and, therefore, that the distribution of pixel T2 values ought to be
      substantially broader after moderate exercise than at rest or after more intense
      exercise, since moderate-intensity exercise should recruit some motor units, and
      hence some pixels, but not others. This study examined the distribution of pixel
      T2 values in three muscles (quadriceps, anterior tibialis, and biceps/brachialis)
      of healthy subjects (5 men and 2 women, 18-46 yr old) at rest, after exercise to
      fatigue (50% 1 repetition maximum at 20/min to failure = Max), and at 1/2Max (25%
      1 repetition maximum, same number of repetitions as Max). Although for each
      muscle there was a linear relationship between exercise intensity and mean pixel
      T2, there was no significant difference in the variance of pixel T2 between
      1/2Max and Max exercise. There was a modest (10-43%) increase in variance of
      pixel T2 after both exercises compared with rest, but this was consistent with a
      Monte Carlo simulation of muscle activity that assumed a random distribution of
      motor unit territories across the muscle and a random distribution of muscle
      cells within each motor unit's territory. In addition, 40% of the pixel-to-pixel
      muscle T2 variations were shown to be due to imaging noise. The results indicate
      that magnetic resonance imaging T2 cannot reliably map active muscle on a pixel
      by-pixel basis in normal subjects.

PMID- 10601157
TI  - Effects of hindlimb unloading on rat cerebral, splenic, and mesenteric resistance
      artery morphology.
AB  - Hindlimb unloading (HU) of rats induces a cephalic shift in body fluids. We
      hypothesized that the putative increase in cranial fluid pressure and decrease in
      peripheral fluid pressure would alter the morphology of resistance arteries from
      2-wk HU male Sprague-Dawley rats. To test this hypothesis, the cerebral basilar,
      mesenteric, and splenic arteries were removed from control (C) and HU animals.
      The vessels were cannulated, and luminal pressure was set to 60 cmH(2)O. The
      resistance arteries were then relaxed with 10(-4) M nitroprusside, fixed, and cut
      into transverse cross sections (5 microm thick). Media cross-sectional area
      (CSA), intraluminal CSA, media layer thickness, vessel outer perimeter, and media
      nuclei number were determined. In the basilar artery, both media CSA (HU 17, 893
      +/- 2,539 microm(2); C 12,904 +/- 1,433 microm(2)) and thickness (HU 33.9 +/- 4.1
      microm; C 22.3 +/- 3.2 microm) were increased with hindlimb unloading (P < 0.05),
      intraluminal CSA decreased (HU 7,816 +/- 3,045 microm(2); C 13,469 +/- 5,500
      microm(2)) (P < 0.05), and vessel outer perimeter and media nuclei number were
      unaltered. There were no differences in mesenteric or splenic resistance artery
      morphology between HU and C rats. These findings suggest that hindlimb unloading
      induced increases in cephalic arterial pressure and, correspondingly, increases
      in circumferential wall stress result in the hypertrophy of basilar artery smooth
      muscle cells.

PMID- 10601158
TI  - Oxygen-conserving effects of apnea in exercising men.
AB  - We sought to determine whether apnea-induced cardiovascular responses resulted in
      a biologically significant temporary O(2) conservation during exercise. Nine
      healthy men performing steady-state leg exercise carried out repeated apnea (A)
      and rebreathing (R) maneuvers starting with residual volume +3.5 liters of air.
      Heart rate (HR), mean arterial pressure (MAP), and arterial O(2) saturation
      (Sa(O(2)); pulse oximetry) were recorded continuously. Responses (DeltaHR,
      DeltaMAP) were determined as differences between HR and MAP at baseline before
      the maneuver and the average of values recorded between 25 and 30 s into each
      maneuver. The rate of O(2) desaturation (DeltaSa(O(2))/Deltat) was determined
      during the same time interval. During apnea, DeltaSaO(2)/Deltat had a significant
      negative correlation to the amplitudes of DeltaHR and DeltaMAP (r(2) = 0.88, P <
      0.001); i.e., individuals with the most prominent cardiovascular responses had
      the slowest DeltaSa(O(2))/Deltat. DeltaHR and DeltaMAP were much larger during A
      (-44 +/- 8 beats/min, +49 +/- 4 mmHg, respectively) than during R maneuver (+3 +/
      3 beats/min, +30 +/- 5 mmHg, respectively). DeltaSa(O(2))/Deltat during A and R
      maneuvers was -1.1 +/- 0.1 and -2.2 +/- 0.2% units/s, respectively, and nadir
      Sa(O(2)) values were 58 +/- 4 and 42 +/- 3% units, respectively. We conclude that
      bradycardia and hypertension during apnea are associated with a significant
      temporary O(2) conservation and that respiratory arrest, rather than the
      associated hypoxia, is essential for these responses.

PMID- 10601159
TI  - Effects on breathing of carotid body denervation in neonatal piglets.
AB  - The purpose of these studies was to test the hypothesis that carotid
      chemoreceptor activity is necessary for postnatal maturation of the ventilatory
      control system. By using a lateral surgical access, 17 piglets were carotid body
      denervated (CBD) and 14 were sham denervated at 3-25 days of age. After surgery,
      there was no irregular breathing in any group. There was no significant
      hypoventilation when CBD was performed at less than 5 days of age (n = 5) and
      only a mild (arterial PCO(2) 5 Torr; P < 0.05) to moderate, transient (arterial
      PCO(2) 8 Torr; P < 0.5) hypoventilation in piglets denervated at 10-15 (n = 6)
      and 20-25 (n = 6) days of age, respectively. Three weeks after surgery, both
      breathing of a hypoxic gas mixture and jugular venous NaCN injections elicited a
      hyperpnea in the CBD piglets that was attenuated compared with that in sham CBD
      piglets. In the CBD piglets, there was no response to injections of NaCN in the
      carotid arteries, but there was a response to NaCN injected into the proximal
      descending aorta, suggesting the residual peripheral chemosensitivity was of
      aortic origin. Carotid chemoreceptor-intact piglets had carotid and aortic NaCN
      chemosensitivity by 2 days of age. The carotid response persisted for the 40 days
      of the study, but the aortic reflex persisted only until approximately 8 days of
      age. We conclude that 1) the major effect of CBD per se in neonatal piglets is
      age-dependent hypoventilation and 2) there is a high degree of plasticity in
      peripheral chemosensitivity in neonates that may contribute to minimizing the
      changes in breathing after CBD.

PMID- 10601160
TI  - Enhanced endothelial vasoreactivity in endurance-trained older men.
AB  - Using external vascular ultrasound, we measured brachial artery diameter (Diam)
      at rest, after release of 4 min of limb ischemia, i. e., endothelium-dependent
      dilation (EDD), and after sublingual nitroglycerin, i.e., non-endothelium
      dependent dilation (NonEDD), in 35 healthy men aged 61-83 yr: 12 endurance
      athletes (A) and 23 controls (C). As anticipated, treadmill exercise maximal
      oxygen consumption (VO(2 max)) was significantly higher in A than in C (40. 2 +/-
      6.6 vs. 27.9 +/- 3.8 ml. kg(-1). min(-1); respectively, P < 0. 0001). With regard
      to arterial physiology, A had greater EDD (8.9 +/- 4.2 vs. 5.7 +/- 3.5%; P =
      0.02) and a tendency for higher NonEDD (13.9 +/- 6.7 vs. 9.7 +/- 4.2%; P = 0.07)
      compared with C. By multiple linear regression analysis in the combined sample of
      older men, only baseline Diam (beta = -2.0, where beta is the regression
      coefficient; P = 0.005) and VO(2 max) (beta = 0.23; P = 0.003) were independent
      predictors of EDD; similarly, only Diam (beta = -4.0; P = 0.003) and VO(2 max)
      (beta = 0.27; P = 0.01) predicted NonEDD. Thus endurance-trained older men
      demonstrate both augmented EDD and NonEDD, consistent with a generalized enhanced
      vasodilator responsiveness, compared with their sedentary age peers.

PMID- 10601161
TI  - In situ SR function in postinfarction myocytes.
AB  - Previous studies have shown lower systolic intracellular Ca(2+) concentrations
      ([Ca(2+)](i)) and reduced sarcoplasmic reticulum (SR)-releasable Ca(2+) contents
      in myocytes isolated from rat hearts 3 wk after moderate myocardial infarction
      (MI). Ca(2+) entry via L-type Ca(2+) channels was normal, but that via reverse
      Na(+)/Ca(2+) exchange was depressed in 3-wk MI myocytes. To elucidate mechanisms
      of reduced SR Ca(2+) contents in MI myocytes, we measured SR Ca(2+) uptake and SR
      Ca(2+) leak in situ, i.e., in intact cardiac myocytes. For sham and MI myocytes,
      we first demonstrated that caffeine application to release SR Ca(2+) and inhibit
      SR Ca(2+) uptake resulted in a 10-fold prolongation of half-time (t(1/2)) of
      [Ca(2+)](i) transient decline compared with that measured during a normal twitch.
      These observations indicate that early decline of the [Ca(2+)](i) transient
      during a twitch in rat myocytes was primarily mediated by SR Ca(2+)-ATPase and
      that the t(1/2) of [Ca(2+)](i) decline is a measure of SR Ca(2+) uptake in situ.
      At 5.0 mM extracellular Ca(2+), systolic [Ca(2+)](i) was significantly (P </=
      0.05) lower (337 +/- 11 and 416 +/- 18 nM in MI and sham, respectively) and
      t(1/2) of [Ca(2+)](i) decline was significantly longer (0.306 +/- 0.014 and 0.258
      +/- 0.014 s in MI and sham, respectively) in MI myocytes. The 19% prolongation of
      t(1/2) of [Ca(2+) ](i) decline was associated with a 23% reduction in SR Ca(2+)
      ATPase expression (detected by immunoblotting) in MI myocytes. SR Ca(2+) leak was
      measured by a novel electrophysiological technique that did not require assigning
      empirical constants for intracellular Ca(2+) buffering. SR Ca(2+) leak rate was
      not different between sham and MI myocytes: the time constants of SR Ca(2+) loss
      after thapsigargin were 290 and 268 s, respectively. We conclude that,
      independent of decreased SR filling by Ca(2+) influx, the lower SR Ca(2+) content
      in MI myocytes was due to reduced SR Ca(2+) uptake and SR Ca(2+)-ATPase
      expression, but not to enhanced SR Ca(2+) leak.

PMID- 10601162
TI  - Skeletal muscle metabolism during short-term, high-intensity exercise in
      prepubertal and pubertal girls.
AB  - To test the hypothesis that glycolytic metabolism in muscle is attenuated in
      prepubertal children, (31)P-magnetic resonance spectroscopy was used to determine
      calf muscle intracellular pH (pH(i)) in nine prepubertal (Pre) and nine pubertal
      female swimmers (Pub). Maximal plantar flexion work capacity (100% MWC) was
      established by using a graded exercise test. Between 5 and 10 days later, calf
      muscle images (magnetic resonance imaging) and phosphorus spectra were acquired
      at rest, during 2 min of light exercise (40% MWC), and during 2 min of
      supramaximal exercise (140% MWC) in a 3.0-T NMR system. End-exercise pH(i) was
      6.66 +/- 0.11 and 6.76 +/- 0.17 for Pub and Pre, respectively. No significant
      differences in the mean values for pH(i) or the P(i)-to-phosphocreatine ratio
      were observed between groups during the protocol; however, an interaction effect
      was found for the P(i)-to-phosphocreatine ratio during the supramaximal exercise
      challenge. Cross-sectional area of gastrocnemius was 15.12 +/- 0.46 and 9.37 +/-
      0.37 cm(2) for Pub and Pre, respectively (P < 0.05). Differences in muscle size
      must be considered when interpreting the unlocalized magnetic resonance
      spectroscopy data. These results suggest that glycolytic metabolism in physically
      active children is not maturity dependent.

PMID- 10601163
TI  - Exercise-induced stimulation of K(+) transport in human erythrocytes.
AB  - The hypothesis was tested that exercise-induced changes in plasma composition
      stimulate unidirectional K(+) transport (J(in)K) in human red blood cells (RBCs).
      Ten men performed two 30-s high-intensity leg-cycling tests separated by 4 min of
      rest. Antecubital venous blood was sampled before exercise and at the end of the
      second exercise bout. RBCs were separated from true exercise plasma, (42)K was
      added to plasma, and RBC K(+) transport was studied in vitro at 37 degrees C. In
      the second part of the study, blood from nine healthy men studied in vitro at 37
      degrees C was used to test the hypothesis that exercise-simulated (ES) plasma
      stimulates net K(+) transport and J(in)K (measured using (86)Rb) in human RBCs.
      The J(in)K of resting RBCs added to true exercise plasma was 1,574 +/- 200 (SE)
      micromol. h(-1). l(-1) vs. 1,236 +/- 256 micromol. h(-1). l(-1) in true resting
      plasma at 2 min (controls). In true exercise and ES plasma, J(in)K was increased
      through activation of the ouabain-sensitive Na(+)-K(+) pump and the bumetanide
      sensitive Na(+)-K(+)-2Cl(-) cotransporter. Increases in plasma osmolality and
      K(+), H(+), and epinephrine concentrations independently and in combination
      stimulated K(+) transport into human RBCs. In a third series of experiments, in
      which ES plasma K(+) concentration was continuously measured during the first 5
      min of incubation of RBCs, a 1.6 +/- 0.3 mmol/l decrease in plasma K(+)
      concentration occurred during the first 2 min. It is concluded that RBCs
      transport K(+) at elevated rates in response to exercise-induced changes in
      plasma composition.

PMID- 10601164
TI  - Influences of thigh cuffs on the cardiovascular system during 7-day head-down bed
      rest.
AB  - Thigh cuffs, presently named "bracelets," consist of two straps fixed to the
      upper part of each thigh, applying a pressure of 30 mmHg. The objective was to
      evaluate the cardiac, arterial, and venous changes in a group of subjects in head
      down tilt (HDT) for 7 days by using thigh cuffs during the daytime, and in a
      control group not using cuffs. The cardiovascular parameters were measured by
      echography and Doppler. Seven days in HDT reduced stroke volume in both groups (
      10%; P < 0.05). Lower limb vascular resistance decreased more in the cuff group
      than in the control group (-29 vs. -4%; P < 0.05). Cerebral resistance increased
      in the control group only (+6%; P < 0.05). The jugular vein increased (+45%; P <
      0.05) and femoral and popliteal veins decreased in cross-sectional area in both
      groups (-45 and -8%, respectively; P < 0.05). Carotid diameter tended to decrease
      (-5%; not significant) in both groups. Heart rate, blood pressure, cardiac
      output, and total resistance did not change significantly. After 8 h with thigh
      cuffs, the cardiac and arterial parameters had recovered their pre-HDT level
      except for blood pressure (+6%; P < 0.05). Jugular vein size decreased from the
      pre-HDT level (-21%; P < 0.05), and femoral and popliteal vein size increased
      (+110 and +136%, respectively; P < 0.05). The thigh cuffs had no effect on the
      development of orthostatic intolerance during the 7 days in HDT.

PMID- 10601165
TI  - Extracellular calcium modulates generation of reactive oxygen species by the
      contracting diaphragm.
AB  - Recent studies have indicated that free radicals may play an important role in
      the development of muscle dysfunction in many pathophysiological conditions.
      Because the degree of muscle dysfunction observed in some of these conditions
      appears to be both free radical dependent and modulated by extracellular calcium
      concentrations, we thought that there may be a link between these two phenomena;
      i.e., the propensity of a muscle to generate free radicals may be dependent on
      extracellular calcium concentrations. For this reason, we compared formation of
      reactive oxygen species (ROS; i.e., free radicals) by electrically stimulated rat
      diaphragms (trains of 20-Hz stimuli for 10 min, train rate 0.25 trains/s)
      incubated in organ baths filled with physiological solutions containing low (1
      mM), normal (2.5 mM), or high (5 mM) calcium levels. Generation of ROS was
      assessed by measuring the conversion of hydroethidine to ethidium. We found ROS
      generation with contraction varied with the extracellular calcium level, with low
      ROS production (3.18 +/- 0.40 ng ethidium/mg tissue) for low-calcium studies and
      with much higher ROS generation for normal-calcium (18. 90 +/- 2.70 ng/mg) or
      high-calcium (19.30 +/- 4.50 ng/mg) studies (P < 0.001). Control, noncontracting
      diaphragms (in 2.5 mM calcium) had little ROS production (3.40 +/- 0.80 ng/mg; P
      < 0.001). To further investigate this issue, we added nimodipine (20 microM), an
      L-type calcium channel blocker, to contracting diaphragms (2.5 mM calcium bath)
      and found that nimodipine also suppressed ROS formation (2.56 +/- 0.85 ng
      ethidium/mg tissue). These data indicate that ROS generation by the contracting
      diaphragm is strongly influenced by extracellular calcium concentrations and may
      be dependent on calcium transport through L-type calcium channels.

PMID- 10601166
TI  - Role of nitric oxide in hypoxia inhibition of fever.
AB  - Hypoxia causes a regulated decrease in body temperature (T(b)), and nitric oxide
      (NO) is now known to participate in hypoxia-induced hypothermia. Hypoxia also
      inhibits lipopolysaccharide (LPS)-induced fever. We tested the hypothesis that NO
      may participate in the hypoxia inhibition of fever. The rectal temperature of
      awake, unrestrained rats was measured before and after injection of LPS, with or
      without concomitant exposure to hypoxia, in an experimental group treated with
      N(omega)-nitro-L-arginine (L-NNA) for 4 consecutive days before the experiment
      and in a saline-treated group (control). L-NNA is a nonspecific NO synthase
      inhibitor that blocks NO production. LPS caused a dose-dependent typical biphasic
      rise in T(b) that was completely prevented by hypoxia (7% inspired oxygen). L-NNA
      caused a significant drop in T(b) during days 2-4 of treatment. When LPS was
      injected into L-NNA-treated rats, inhibition of fever was observed. Moreover, the
      effect of hypoxia during fever was significantly reduced. The data indicate that
      the NO pathway plays a role in hypoxia inhibition of fever.

PMID- 10601167
TI  - Aerosolization of P2Y(2)-receptor agonists enhances mucociliary clearance in
      sheep.
AB  - The purpose of this study was to determine whether aerosolized INS316 (UTP)
      stimulates lung mucociliary clearance (MCC) in sheep and, if so, to compare its
      effects with INS365, a novel P2Y(2)-receptor agonist. In the first series of
      studies, we used a previously described roentgenographic technique to measure
      tracheal mucus velocity (TMV), an index of MCC, before and for 4 h after
      aerosolization of INS316 (10(-1) M and 10(-2) M) and INS365 (10(-1) M and 10(-2)
      M), or normal saline in a randomized crossover fashion (n = 6). In a second
      series of studies, we compared the ability of these agents to enhance total lung
      clearance. For these tests, the clearance of inhaled technetium-labeled human
      serum albumin was measured serially over a 2-h period after aerosolization of 10(
      1) M concentration of each agent (n = 7). Aerosolization of both P2Y(2)-receptor
      agonists induced significant dose-related increases in TMV (P < 0.05) compared
      with saline. The greatest increase in TMV was observed between 15 and 30 min
      after drug treatment. The highest dose (10(-1) M) of INS316 produced a greater
      overall stimulation of TMV than did INS365 (10(-1) M). Both compounds, compared
      with saline, induced a significant increase in MCC (P < 0.05) within 20 min of
      treatment. This enhancement in MCC began to plateau at 60 min. Although the
      response to INS316 started earlier, there was no significant difference between
      the clearance curves for the two compounds. We conclude that inhaled P2Y(2)
      receptor agonists can increase lung MCC in sheep and that for P2Y(2)-receptor
      stimulation TMV accurately reflects changes in whole lung MCC.

PMID- 10601168
TI  - Chronic recordings of hypoglossal nerve activity in a dog model of upper airway
      obstruction.
AB  - The activity of the hypoglossal nerve was recorded during pharyngeal loading in
      sleeping dogs with chronically implanted cuff electrodes. Three self-coiling
      spiral-cuff electrodes were implanted in two beagles for durations of 17, 7, and
      6 mo. During quiet wakefulness and sleep, phasic hypoglossal activity was either
      very small or not observable above the baseline noise. Applying a perpendicular
      force on the submental region by using a mechanical device to narrow the
      pharyngeal airway passage increased the phasic hypoglossal activity, the phasic
      esophageal pressure, and the inspiratory time in the next breath during non-rapid
      eye-movement sleep. The phasic hypoglossal activity sustained at the elevated
      level while the force was present and increased with increasing amounts of
      loading. The hypoglossal nerve was very active in rapid-eye-movement sleep,
      especially when the submental force was present. The data demonstrate the
      feasibility of chronic recordings of the hypoglossal nerve with cuff electrodes
      and show that hypoglossal activity has a fast and sustained response to the
      internal loading of the pharynx induced by applying a submental force during non
      rapid-eye-movement sleep.

PMID- 10601169
TI  - A three-dimensional model of the human airway tree.
AB  - A three-dimensional (3D) model of the human airway tree is proposed using a
      deterministic algorithm that can generate a branching duct system in an organ.
      The algorithm is based on two principles: 1) the amount of fluid delivery through
      a branch is proportional to the volume of the region it supplies; and 2) the
      terminal branches are arranged homogeneously within the organ. These principles
      define the basic process of branching: generation of the dimensions and
      directionality of two daughter branches is governed by the properties of the
      parent branch and the region the parent supplies. The algorithm is composed of
      nine basic rules and four complementary rules. When the contour of an organ and
      the position of the trunk are specified, branches are successively generated by
      the algorithm. Applied to the human lung, the algorithm generates an airway tree
      that consists of approximately 54,000 branches. Its morphometric characteristics
      are in good agreement with those reported in the literature. The algorithm and
      the 3D airway model are useful for studying the structure-function relationship
      in the lung.

PMID- 10601170
TI  - Adenosine contributes to hypoxia-induced forearm vasodilation in humans.
AB  - In humans, hypoxia leads to increased sympathetic neural outflow to skeletal
      muscle. However, blood flow increases in the forearm. The mechanism of hypoxia
      induced vasodilation is unknown. To test whether hypoxia-induced vasodilation is
      cholinergically mediated or is due to local release of adenosine, normal subjects
      were studied before and during acute hypoxia (inspired O(2) 10.5%; approximately
      20 min). In experiment I, aminophylline (50-200 microg. min(-1). 100 ml forearm
      tissue(-1)) was infused into the brachial artery to block adenosine receptors (n
      = 9). In experiment II, cholinergic vasodilation was blocked by atropine (0.4 mg
      over 4 min) infused into the brachial artery (n = 8). The responses of forearm
      blood flow (plethysmography) and forearm vascular resistance to hypoxia in the
      infused and opposite (control) forearms were compared. During hypoxia (arterial
      O(2) saturation 77 +/- 2%), minute ventilation and heart rate increased while
      arterial pressure remained unchanged; forearm blood flow rose by 35 +/- 6% in the
      control forearm but only by 5 +/- 8% in the aminophylline-treated forearm (P <
      0.02). Accordingly, forearm vascular resistance decreased by 29 +/- 5% in the
      control forearm but only by 9 +/- 6% in the aminophylline-treated forearm (P <
      0.02). Atropine did not attenuate forearm vasodilation during hypoxia. These data
      suggest that adenosine contributes to hypoxia-induced vasodilation, whereas
      cholinergic vasodilation does not play a role.

PMID- 10601171
TI  - Rapid force recovery in contracting skeletal muscle after brief ischemia is
      dependent on O(2) availability.
AB  - We tested the hypothesis that contracting skeletal muscle can rapidly restore
      force development during reperfusion after brief total ischemia and that this
      rapid recovery depends on O(2) availability and not an alternate factor related
      to blood flow. Isolated canine gastrocnemius muscle (n = 5) was stimulated to
      contract tetanically (isometric contraction elicited by 8 V, 0.2-ms duration, 200
      ms trains, at 50-Hz stimulation) every 2 s until steady-state conditions of
      muscle blood flow (controlled by pump perfusion) and developed force were
      attained (3 min). While maintaining the same stimulation pattern, muscle blood
      flow was then reduced to zero (complete ischemia) for 2 min. Normal blood flow
      was then restored to the contracting muscle; however, two distinct conditions of
      oxygenation (at the same blood flow) were sequentially imposed: deoxygenated
      blood (30 s), blood with normal arterial O(2) content (30 s), a return to
      deoxygenated blood (30 s), and finally a return to normal arterial O(2) content
      (90 s). During the ischemic period, force development fell to 39 +/- 6 (SE)% of
      normal (from 460 +/- 40 to 170 +/- 20 N/100 g). When muscle blood flow was
      restored to normal by perfusion with deoxygenated blood, developed force
      continued to decline to 140 +/- 20 N/100 g. Muscle force rapidly recovered to 310
      +/- 30 N/100 g (P < 0.05) during the 30 s in which the contracting muscle was
      perfused with oxygenated blood and then fell again to 180 +/- 30 N/100 g when
      perfused with blood with low PO(2). These findings demonstrate that contracting
      skeletal muscle has the capacity for rapid recovery of force development during
      reperfusion after a short period of complete ischemia and that this recovery
      depends on O(2) availability and not an alternate factor related to blood flow
      restoration.

PMID- 10601172
TI  - Modeling growth and maturation changes in peak oxygen uptake in 11-13 yr olds.
AB  - The influence of gender, growth, and maturation on peak O(2) consumption (VO(2
      peak)) in 11-13 yr olds were examined by using multilevel regression modeling.
      Subjects were 119 boys and 115 girls, aged 11.2 +/- 0.4 (SD) yr at the onset of
      the study. Sexual maturation was classified according to Tanner's indexes of
      pubic hair. VO(2 peak) was determined annually for 3 yr. The initial model
      identified body mass and stature as significant explanatory variables, with an
      additional positive effect for age and incremental effects for stage of
      maturation. A significant gender difference was apparent with lower values for
      girls, and an age-by-gender interaction indicated a progressive divergence in
      boys' and girls' VO(2 peak). Subsequent incorporation of the sum of two skinfold
      thicknesses into the model negated stature effects, reduced the gender term, and
      explained much of the observed maturity effects. The body mass exponent almost
      doubled, but the age-by-gender interaction term was consistent with the initial
      model.

PMID- 10601173
TI  - Indomethacin does not influence natural cell-mediated cytotoxic response to
      endurance exercise.
AB  - Natural cell-mediated cytotoxicity (NCMC) has been shown to be attenuated during
      recovery from high-intensity or prolonged exercise. Two theories have been
      proposed to explain the transient suppression of NCMC: prostaglandin-induced
      inhibition of natural killer (NK) cell activity or a numerical redistribution of
      NK cells. This study was designed to examine the effects of oral indomethacin (a
      prostaglandin inhibitor) on NCMC before and after 1 h of high-intensity running
      (85% maximal oxygen uptake). A secondary purpose was to compare whole blood and
      isolated peripheral blood mononuclear cell assay procedures for assessing NCMC.
      Ten male distance runners completed two trials that were preceded by either 48 h
      of indomethacin (Indo; 150 mg/day) or no treatment (control). NK (CD3(
      )/CD16(+)/CD56(+)) cell concentrations were significantly elevated postexercise
      but were not affected by Indo. NCMC was significantly suppressed at 1.5 h of
      recovery relative to preexercise only with the whole blood assay procedure. Indo
      was not found to influence NCMC, leukocyte, or lymphocyte subset concentrations.
      Mean cytotoxic response was significantly greater with the whole blood method.

PMID- 10601174
TI  - Creatine supplementation increases muscle total creatine but not maximal
      intermittent exercise performance.
AB  - This study investigated creatine supplementation (CrS) effects on muscle total
      creatine (TCr), creatine phosphate (CrP), and intermittent sprinting performance
      by using a design incorporating the time course of the initial increase and
      subsequent washout period of muscle TCr. Two groups of seven volunteers ingested
      either creatine [Cr; 6 x (5 g Cr-H(2)O + 5 g dextrose)/day)] or a placebo (6 x 5
      g dextrose/day) over 5 days. Five 10-s maximal cycle ergometer sprints with rest
      intervals of 180, 50, 20, and 20 s and a resting vastus lateralis biopsy were
      conducted before and 0, 2, and 4 wk after placebo or CrS. Resting muscle TCr,
      CrP, and Cr were unchanged after the placebo but were increased (P < 0.05) at 0
      [by 22.9 +/- 4.2, 8.9 +/- 1.9, and 14.0 +/- 3.3 (SE) mmol/kg dry mass,
      respectively] and 2 but not 4 wk after CrS. An apparent placebo main effect of
      increased peak power and cumulative work was found after placebo and CrS, but no
      treatment (CrS) main effect was found on either variable. Thus, despite the rise
      and washout of muscle TCr and CrP, maximal intermittent sprinting performance was
      unchanged by CrS.

PMID- 10601175
TI  - Exercise suppresses macrophage antigen presentation.
AB  - This study determined the effects of exercise on the ability of macrophages
      (Mphi) to present antigen to T cells. Pathogen-free male Balb/c mice (8 +/- 2 wk
      of age) were randomly assigned to either home cage control, moderate exercise
      (Mod; 18 m/min, 5% grade, 0.5 h/day), exhaustive exercise (Exh, 18-30 m/min, 3
      h/day), or treadmill control groups. The mice underwent treatments for 4 days
      during peritoneal thioglycolate inflammation. Peritoneal Mphi were harvested,
      purified, and incubated with chicken ovalbumin (C-OVA; 0-10 mg/ml) for 18 h. Mphi
      were then cocultured with C-OVA-specific T cells for 48 h, and the supernatants
      were analyzed via ELISA for interleukin-2 as an indication of Mphi antigen
      presentation (AP). Exh exhibited suppressed ( approximately 25-34%) Mphi AP
      across a wide range of C-OVA doses when measured immediately, 3, and 24 h
      postexercise. In contrast, Mod had reduced Mphi AP only at 3 h postexercise. Mphi
      AP was also lower in the treadmill control (4-27%) compared with the home cage
      control group, but was significantly higher than Exh. The reduction in Mphi AP
      was not due to exercise-induced differences in Mphi number, percentage, or
      expression of intercellular adhesion molecule-1, B7-2, or major
      histocompatability complex II, molecules important in AP. In conclusion, our data
      lend evidence that may help explain the increased incidence of infection observed
      after prolonged exhaustive exercise or overtraining.

PMID- 10601176
TI  - Arteriolar reactivity and capillarization in chronically stimulated rat limb
      skeletal muscle post-MI.
AB  - The purpose of this study was to assess whether electrical stimulation-induced
      increases in muscular activity could improve capillary supply and correct
      previously documented abnormal vasodilator and vasoconstrictor responses of
      arterioles in limb skeletal muscle post-myocardial infarction (MI). Extensor
      digitorum longus (EDL) muscle from rats with surgically induced MI (
      approximately 30% of the left ventricle) was chronically stimulated (Stim) 8
      h/day for 6 +/- 1 days, at 11 wk post-MI. Third- (3A) and fourth-order (4A)
      arterioles in EDL from nine MI rats and four MI+Stim rats were compared with
      those of 11 controls (Con). Compared with Con rats, MI alone caused a reduction
      in the resting diameter of 3A and 4A arterioles, which was completely reversed by
      MI+Stim. However, Stim did not correct the attenuated vasodilator response to 10(
      4) M adenosine seen in 4A arterioles from MI rats compared with Con. The
      constrictor response of both 3A and 4A vessels in MI rats to low doses of
      acetylcholine (10(-9) M, 10(-8) M) and norepinephrine (10(-9) M) was accentuated
      in MI+Stim. The proportion of oxidative fibers in EDL was unaffected by MI or
      MI+Stim combination. However, Stim significantly increased (P < 0.05) the
      capillary-to-fiber ratio in this muscle compared with Con. Thus, although the
      increase in muscle activity induced by chronic electrical stimulation normalized
      the reduction in resting vessel diameter seen after MI, it failed to correct the
      abnormalities in vasoreactivity of these same vessels.

PMID- 10601177
TI  - Noninvasive cardiac output measurement in orthostasis: pulse contour analysis
      compared with acetylene rebreathing.
AB  - We tested the reliability of noninvasive cardiac output (CO) measurement in
      different body positions by pulse contour analysis (CO(pc)) by using a
      transmission line model (K. H. Wesseling, B. De Wit, J. A. P. Weber, and N. T.
      Smith. Adv. Cardiol. Phys. 5, Suppl. II: 16-52, 1983). Acetylene rebreathing
      (CO(rebr)) was used as a reference method. Twelve subjects (age 21-34 yr) were
      studied: 1) six in whom CO(rebr) and CO(pc) were measured in the standing and 6
      degrees head-down tilt (HDT) postures and 2) six in whom CO was measured in the
      30 degrees HDT, supine, 30 degrees head up-tilt (HUT), and 70 degrees HUT
      postures on a tilt table. The CO(rebr)-to-CO(pc) ratio in (near) the supine
      position during rebreathing was used as the calibration factor for CO(pc)
      measurements. Calibrated CO(pc) (CO(cal sup)) consistently overestimated CO in
      the upright posture. The drop in CO with upright posture was underestimated by
      approximately 50%. CO(cal sup) and CO(rebr) values did not differ in the 30
      degrees HDT position. Changes in the CO(rebr)-to-CO(pc) ratio are highly variable
      among subjects in response to a change in posture. Therefore, CO(pc) must be
      recalibrated for each subject in each posture.

PMID- 10601178
TI  - Effect of oral DHEA on serum testosterone and adaptations to resistance training
      in young men.
AB  - This study examined the effects of acute dehydroepiandrosterone (DHEA) ingestion
      on serum steroid hormones and the effect of chronic DHEA intake on the
      adaptations to resistance training. In 10 young men (23 +/- 4 yr old), ingestion
      of 50 mg of DHEA increased serum androstenedione concentrations 150% within 60
      min (P < 0.05) but did not affect serum testosterone and estrogen concentrations.
      An additional 19 men (23 +/- 1 yr old) participated in an 8-wk whole body
      resistance-training program and ingested DHEA (150 mg/day, n = 9) or placebo (n =
      10) during weeks 1, 2, 4, 5, 7, and 8. Serum androstenedione concentrations were
      significantly (P < 0.05) increased in the DHEA-treated group after 2 and 5 wk.
      Serum concentrations of free and total testosterone, estrone, estradiol, estriol,
      lipids, and liver transaminases were unaffected by supplementation and training,
      while strength and lean body mass increased significantly and similarly (P <
      0.05) in the men treated with placebo and DHEA. These results suggest that DHEA
      ingestion does not enhance serum testosterone concentrations or adaptations
      associated with resistance training in young men.

PMID- 10601179
TI  - ET-1-induced pulmonary vasoconstriction shifts from ET(A)- to ET(B)-receptor
      mediated reaction after preconstriction.
AB  - Endothelin-1 (ET-1) has been reported to induce pulmonary vasoconstriction via
      either ET(A) or ET(B) receptors, and vasorelaxation after ET-1 injection has been
      observed. Our study investigated the effects of ET-1 in isolated rabbit lungs,
      which were studied at basal tone (part I) and after preconstriction (U-46619;
      part II). Pulmonary arterial pressure (PAP) and lung weight gain were monitored
      continuously. In part I, ET-1 (10(-8) M; n = 6; control) was injected after
      pretreatment with the ET(A)-receptor antagonist BQ-123 (10(-6) M; n = 6) or the
      ET(B)-receptor antagonist BQ-788 (10(-6) M; n = 6). The same protocol was carried
      out in part II after elevation of pulmonary vascular tone. ET-1 induced an
      immediate PAP increase (DeltaPAP 4.3 +/- 0.4 mmHg at 10 min) that was attenuated
      by pretreatment with BQ-123 (P < 0.05 at 10 min and P < 0.01 thereafter) and that
      was more pronounced after BQ-788 (P < 0.01 at 10 min and P < 0.001 thereafter).
      In part II, ET-1 induced an immediate rise in PAP with a maximum after 5 min
      (DeltaPAP 6.3 +/- 1.4 mmHg), leveling off at DeltaPAP 3.2 +/- 0.2 mmHg after 15
      min. Pretreatment with BQ-123 failed to attenuate the increase. BQ-788
      significantly reduced the peak pressure at 5 min (0.75 +/- 0.4 mmHg; P < 0.001)
      as well as the plateau pressure thereafter (P < 0.01). We conclude that ET-1
      administration causes pulmonary vasoconstriction independent of basal vascular
      tone, and, at normal vascular tone, the vasoconstriction seems to be mediated via
      ET(A) receptors. BQ-788 treatment resulted in even more pronounced
      vasoconstriction. After pulmonary preconstriction, ET(A) antagonism exerted no
      effects on PAP, whereas ET(B) antagonism blocked the PAP increase. Therefore, ET
      1-induced pulmonary vasoconstriction is shifted from an ET(A)-related to an ET(B)
      mediated mechanism after pulmonary vascular preconstriction.

PMID- 10601180
TI  - Effect of carbohydrate supplementation on postexercise GLUT-4 protein expression
      in skeletal muscle.
AB  - The effect of carbohydrate supplementation on skeletal muscle glucose transporter
      GLUT-4 protein expression was studied in fast-twitch red and white gastrocnemius
      muscle of Sprague-Dawley rats before and after glycogen depletion by swimming.
      Exercise significantly reduced fast-twitch red muscle glycogen by 50%. During a
      16-h exercise recovery period, muscle glycogen returned to control levels (25.0
      +/- 1.4 micromol/g) in exercise-fasted rats (24.2 +/- 0. 3 micro). However, when
      carbohydrate supplementation was provided during and immediately postexercise by
      intubation, muscle glycogen increased 77% above control (44.4 +/- 2.1
      micromol/g). Exercise-fasting resulted in an 80% increase in fast-twitch red
      muscle GLUT-4 mRNA but only a 43% increase in GLUT-4 protein concentration.
      Conversely, exercise plus carbohydrate supplementation elevated fast-twitch red
      muscle GLUT-4 protein concentration by 88% above control, whereas GLUT-4 mRNA was
      increased by only 40%. Neither a 16-h fast nor carbohydrate supplementation had
      an effect on fast-twitch red muscle GLUT-4 protein concentration or on GLUT-4
      mRNA in sedentary rats, although carbohydrate supplementation increased muscle
      glycogen concentration by 40% (35.0 +/- 0.9 micromol/g). GLUT-4 protein in fast
      twitch white muscle followed a pattern similar to fast-twitch red muscle. These
      results indicate that carbohydrate supplementation, provided with exercise, will
      enhance GLUT-4 protein expression by increasing translational efficiency.
      Conversely, postexercise fasting appears to upregulate GLUT-4 mRNA, possibly to
      amplify GLUT-4 protein expression on an increase in glucose availability. These
      regulatory mechanisms may help control muscle glucose uptake in accordance with
      glucose availability and protect against postexercise hypoglycemia.

PMID- 10601181
TI  - Respiratory function in lambs after in utero treatment of lung hypoplasia by
      tracheal obstruction.
AB  - Tracheal obstruction (TO) stimulates growth of hypoplastic lungs in the fetus,
      but there is little knowledge of subsequent postnatal respiratory function. We
      have determined the effectiveness of TO in fetal sheep with existing lung
      hypoplasia in restoring postnatal respiratory function. Lung hypoplasia was
      induced by lung liquid drainage from 112 days of gestation to term (
      approximately 148 days). We used an untreated group (ULH), a treated group (TLH)
      in which the trachea was obstructed for 10 days, and a control group. ULH lambs
      died within 4 h of birth. TLH lambs were hypoxic for the first week and were
      hypercapic at 2 days. Pulmonary diffusing capacity, gas volumes, and respiratory
      compliances were not different between control and TLH lambs. Minute ventilation
      was not different between the two groups; however, tidal volumes were lower and
      respiratory frequencies were higher in TLH lambs than in controls for 2 wk after
      birth. We conclude that 10 days of TO in the presence of initial lung hypoplasia
      prevents death at birth and returns most aspects of pulmonary function to normal
      by 1-2 wk after birth.

PMID- 10601182
TI  - Influence of mild exercise at the lactate threshold on glucose effectiveness.
AB  - The effect of a single bout of mild exercise on glucose effectiveness (S(G)) and
      insulin sensitivity (S(I)) was studied in six young male subjects by using a
      minimal model. An intravenous glucose tolerance test was performed under two
      conditions as follows: 1) 25 min after a bout of exercise on a cycle ergometer at
      the lactate threshold level for 60 min (Ex) and 2) without any prior exercise
      (Con). Leg blood flow (LBF) was also measured by strain-gauge plethysmography
      simultaneously with blood sampling. S(I) did not significantly change after
      exercise (18.1 +/- 1.5 vs. 17.7 +/- 1.9 x 10-(5) min/pM), whereas S(G)
      significantly increased (0.016 +/- 0.002 vs. 0.025 +/- 0.002 min(-1), P < 0.01).
      The increased blood flow after exercise remained high during the time period for
      measurement of the glucose disappearance constant and may be a determinant of
      S(G). The incremental lactate area under the curve until insulin loading was also
      significantly higher in Ex than in Con (2.6 +/- 0.9 vs. -3.5 +/- 1.5 mM/min, P <
      0.05). These results suggest that increased S(G) after mild exercise may be due,
      at least in part, to increased LBF and lactate production under a hyperglycemic
      state.

PMID- 10601183
TI  - MR measurements of muscle damage and adaptation after eccentric exercise.
AB  - The purposes of this study were, first, to clarify the long-term pattern of T2
      relaxation times and muscle volume changes in human skeletal muscle after intense
      eccentric exercise and, second, to determine whether the T2 response exhibits an
      adaptation to repeated bouts. Six young adult men performed two bouts of
      eccentric biceps curls (5 sets of 10 at 110% of the 1-repetition concentric
      maximum) separated by 8 wk. Blood samples, soreness ratings, and T2-weighted
      axial fast spin-echo magnetic resonance images of the upper arm were obtained
      immediately before and after each bout; at 1, 2, 4, 7, 14, 21, and 56 days after
      bout 1; and at 2, 4, 7 and 14 days after bout 2. Resting muscle T2 [27.6 +/- 0.2
      (SE) ms] increased immediately postexercise by 8 +/- 1 ms after both bouts. T2
      peaked 7 days after bout 1 at 47 +/- 4 ms and remained elevated by 2.5 ms at 56
      days. T2 peaked lower (37 +/- 4 ms) and earlier (2-4 days) after bout 2,
      suggesting an adaptation of the T2 response. Peak serum creatine kinase values,
      pain ratings, and flexor muscle swelling were also significantly lower after the
      second bout (P < 0.05). Total volume of the imaged arm region increased
      transiently after bout 1 but returned to preexercise values within 2 wk. The
      exercised flexor compartment swelled by over 40%, but after 2 wk it reverted to a
      volume 10% smaller than that before exercise and maintained this volume loss
      through 8 wk, consistent with partial or total destruction of a small
      subpopulation of muscle fibers.

PMID- 10601184
TI  - Role of neutrophils in xanthine/xanthine oxidase-induced oxidant injury in
      isolated rabbit lungs.
AB  - Reactive oxygen species have been shown to play an important role in the
      pathogenesis of lung injury. This study was designed to clarify the role of
      intrapulmonary neutrophils in the development of xanthine/xanthine oxidase (X/XO)
      induced lung injury in isolated buffer-perfused rabbit lungs. We measured
      microvascular fluid filtration coefficient (K(f)) and wet-to-dry weight ratio to
      assess lung injury. X/XO induced a significant increase in K(f) and wet-to-dry
      weight ratio in neutrophil-replete lungs, whereas the lung injury was attenuated
      in neutrophil-depleted lungs. A neutrophil elastase inhibitor, ONO-5046, also
      attenuated the lung injury. In addition, X/XO induced a transient pulmonary
      arterial pressure (P(pa)) increase. The thromboxane inhibitor OKY-046 attenuated
      the P(pa) increase but did not alter the increase in permeability. Neutrophil
      depletion reduced the K(f) increase but had no effect on the P(pa) increase.
      These results suggest that intrapulmonary neutrophils activated by X/XO play a
      major role in development of the lung injury, that neutrophil elastase is
      involved in the injury, and that the X/XO-induced vasoconstriction is independent
      of intrapulmonary neutrophils.

PMID- 10601185
TI  - Effects of genetic selection and voluntary activity on the medial gastrocnemius
      muscle in house mice.
AB  - In a previous study, we found that in house mice both genetic selection (10
      generations of artificial selection for high voluntary activity on running
      wheels) and access to running wheels (7-8 weeks) elicited a modest increase in
      maximal oxygen consumption. Based on these results, we hypothesized that genetic
      selection would affect the changes in endurance and oxidative capacity of the
      medial gastrocnemius (MG) muscle induced by wheel access (training response).
      Wheel access increased the isotonic endurance of the MG in both genetically
      selected and random-bred (control) mice. However, this exercise-induced
      improvement in isotonic endurance of the MG was similar between genetically
      selected and control mice. Wheel access also increased the succinate
      dehydrogenase activity of MG muscle fibers in both selected and control lines.
      However, this exercise-induced increase in succinate dehydrogenase activity was
      comparable between genetically selected and control animals. Taken together,
      these results indicate that the modest increase in maximal oxygen consumption
      associated with genetic selection is not reflected by the training-induced
      changes in oxidative capacity and endurance of MG muscle fibers.

PMID- 10601186
TI  - Cardiovascular hemodynamics with increasing exercise intensities in
      postmenopausal women.
AB  - We sought to determine the cardiovascular responses to increasing exercise
      intensities in postmenopausal women with different physical activity levels and
      hormone replacement therapy (HRT) status. Forty-four women (11 sedentary, 19
      physically active, 14 master athletes; 24 not on HRT, 20 on HRT) completed
      treadmill exercise at 40, 60, 80, and 100% of maximal oxygen consumption. Oxygen
      consumption, heart rate, blood pressure, and cardiac output, determined via
      acetylene rebreathing, were measured at each exercise intensity. HRT did not
      affect cardiovascular hemodynamics. Stroke volume (SV) decreased significantly
      between 40 and 100% of maximal oxygen consumption in all groups, and the decrease
      did not differ among groups. The greater oxygen consumption of the athletes at
      each intensity was due to their significantly greater cardiac output, which was
      the result of a significantly greater SV, compared with both of the less active
      groups. The athletes had significantly lower total peripheral resistance at each
      exercise intensity than did the two less active groups. There were no consistent
      significant hemodynamic differences between the physically active and sedentary
      women. These results indicate that SV decreases in postmenopausal women as
      exercise intensity increases to maximum, regardless of their habitual physical
      activity levels or HRT status.

PMID- 10601187
TI  - Skeletal muscle energy metabolism during prolonged, fatiguing exercise.
AB  - A depletion of phosphocreatine (PCr), fall in the total adenine nucleotide pool
      (TAN = ATP + ADP + AMP), and increase in TAN degradation products inosine 5'
      monophosphate (IMP) and hypoxanthine are observed at fatigue during prolonged
      exercise at 70% maximal O(2) uptake in untrained subjects [J. Baldwin, R. J.
      Snow, M. F. Carey, and M. A. Febbraio. Am. J. Physiol. 277 (Regulatory
      Integrative Comp. Physiol. 46): R295-R300, 1999]. The present study aimed to
      examine whether these metabolic changes are also prevalent when exercise is
      performed below the blood lactate threshold (LT). Six healthy, untrained humans
      exercised on a cycle ergometer to voluntary exhaustion at an intensity equivalent
      to 93 +/- 3% of LT ( approximately 65% peak O(2) uptake). Muscle biopsy samples
      were obtained at rest, at 10 min of exercise, approximately 40 min before fatigue
      (F-40 =143 +/- 13 min), and at fatigue (F = 186 +/- 31 min). Glycogen
      concentration progressively declined (P < 0.01) to very low levels at fatigue (28
      +/- 6 mmol glucosyl U/kg dry wt). Despite this, PCr content was not different
      when F-40 was compared with F and was only reduced by 40% when F was compared
      with rest (52. 8 +/- 3.7 vs. 87.8 +/- 2.0 mmol/kg dry wt; P < 0.01). In addition,
      TAN concentration was not reduced, IMP did not increase significantly throughout
      exercise, and hypoxanthine was not detected in any muscle samples. A significant
      correlation (r = 0.95; P < 0. 05) was observed between exercise time and glycogen
      use, indicating that glycogen availability is a limiting factor during prolonged
      exercise below LT. However, because TAN was not reduced, PCr was not depleted,
      and no correlation was observed between glycogen content and IMP when glycogen
      stores were compromised, fatigue may be related to processes other than those
      involved in muscle high-energy phosphagen metabolism.

PMID- 10601188
TI  - V-shaped cushion at the origin of bovine pulmonary supernumerary arteries:
      structure and putative function.
AB  - This study investigates the anatomic structure at the origin of pulmonary
      supernumerary arteries and their parent conventional artery. Histological
      examination showed that at the origin of each supernumerary artery the wall of
      the parent conventional artery is organized into a distinct V-shaped structure,
      which begins on the hilum side of each supernumerary artery as a funnel-shaped
      channel running into the supernumerary artery. The base of the channel is
      particularly thin walled. The lateral walls of the channel are composed of
      musculoelastic cushions that become more pronounced toward the supernumerary
      artery and fuse on its distal side, forming a baffle that projects over the
      supernumerary artery lumen. These V-shaped structures/cushions were observed with
      video stereo dissecting microscopy in both an open and closed state in isolated
      arteries in vitro. Pulmonary vasoconstriction of isolated arteries with the
      thromboxane A(2) mimetic U-46619 increased the number of V-shaped structures in
      the closed state. These studies indicate the presence of a novel anatomic
      structure at the origin of pulmonary supernumerary arteries, which may be able to
      regulate blood flow into the supernumerary artery.

PMID- 10601189
TI  - Membrane attack complex of complement and neutrophils mediate the injury of acid
      aspiration.
AB  - A significant role for the alternative complement pathway in acid aspiration has
      been demonstrated by the observation that C3 genetic knockout mice are protected
      from injury. Utilizing C5-deficient mice, we now test the role of the terminal
      complement components in mediating injury. Lung permeability in C5-deficient mice
      was 64% less than in wild-type animals and was similar to wild-type mice treated
      with soluble complement receptor type 1, which gave a 67% protection. Injury was
      fully restored in C5-deficient mice reconstituted with wild-type serum. The role
      of neutrophils was established in immunodepleted wild-type animals that showed a
      58% protection. Injury was further reduced (90%) with the addition of soluble
      complement receptor type 1, indicating an additive effect of neutrophils and
      complement. Similarly, an additional protection was noted in C5-deficient
      neutropenic mice, indicating that neutrophil-mediated injury does not require
      C5a. Thus acid aspiration injury is mediated by the membrane attack complex and
      neutrophils. Neutrophil activity is independent of C5a.

PMID- 10601190
TI  - A method of endotracheal intubation and pulmonary functional assessment for
      repeated studies in mice.
AB  - The ability to successfully intubate the trachea of mice and control their
      ventilation is important for longitudinal studies requiring recovery from
      anesthesia and repeated pulmonary function measurements or other evaluations,
      such as the use of radiological imaging (e.g., computed tomography or magnetic
      resonance imaging). We describe a method for rapid and repeated intubation of
      mice, with subsequent pulmonary function measurements at baseline and after an
      agonist challenge. We describe a simply constructed metal blade used as a
      laryngoscope to facilitate oropharyngeal exposure, transillumination of the neck
      to facilitate visualization of the trachea through the oropharynx, readily
      available polyethylene tubing to intubate the trachea, and a simple solenoid
      ventilator to maintain physiological ventilation and assess respiratory
      resistance and compliance. Brief infusions of acetylcholine through a needle into
      the jugular vein are used to assess the responsiveness of the airway smooth
      muscle.

PMID- 10601191
TI  - Errors in estimating lung liquid volume in fetal lambs when using radiolabeled
      serum albumin and blue dextran.
AB  - Fetal lung liquid volume is usually determined by using radio-iodinated serum
      albumin (RISA) or blue dextran (BD) as volume tracers. We tested the reliability
      of both tracers at 124 (G124) and 142 days of gestation (G142; term = G147) when
      the labels were employed simultaneously. We measured the proportion of label
      bound reversibly to the lung, or apparently lost from the lung compartment, by
      washing out the lung with saline and 5% albumin. At G124, volume estimates with
      the two labels were similar. At G142, the volume estimate with BD (36.3 +/- 8.7
      ml/kg of body wt) was higher (P < 0. 05) than with RISA (22.3 +/- 3.5 ml/kg).
      This difference resulted from reversible binding of BD, because 5% albumin
      washout released 38.5 +/- 4.0% of the BD added at the start of the experiment but
      a lesser amount of RISA (9.8 +/- 0.7%; P < 0.05). At G142, when RISA was used
      alone, its reversible binding was 1.3 +/- 0.2%. Background absorbance increased
      during experiments, giving rise to an apparent increase in BD concentration. We
      conclude that RISA is an effective tracer for lung liquid volume determination in
      the fetal lamb, whereas our findings of substantial epithelial binding of BD and
      large changes in background absorbance demonstrate that, under the conditions of
      our experiments, BD is a poor tracer close to term.

PMID- 10601192
TI  - Peak muscle perfusion and oxygen uptake in humans: importance of precise
      estimates of muscle mass.
AB  - The knee extensor exercise model was specifically developed to enable in vivo
      estimates of peak muscle blood flow and O(2) uptake in humans. The original
      finding, using thermodilution measurements to measure blood flow in relation to
      muscle mass [P. Andersen and B. Saltin. J. Physiol. (Lond.) 366: 233-249, 1985],
      was questioned, however, as the measurements were two- to threefold higher than
      those previously obtained with the (133)Xe clearance and the plethysmography
      technique. As thermodilution measurements have now been confirmed by other
      methods and independent research groups, we aimed to address the impact of muscle
      mass estimates on the peak values of muscle perfusion and O(2) uptake. In the
      present study, knee extensor volume was determined from multiple measurements
      with computer tomography along the full length of the muscle. In nine healthy
      humans, quadriceps muscle volume was 2.36 +/- 0.17 (range 1. 31-3.27) liters,
      corresponding to 2.48 +/- 0.18 (range 1.37-3.43) kg. Anthropometry overestimated
      the muscle volume by approximately 21-46%, depending on whether quadriceps muscle
      length was estimated from the patella to either the pubic bone, inguinal
      ligament, or spina iliaca anterior superior. One-legged, dynamic knee extensor
      exercise up to peak effort of 67 +/- 7 (range 55-100) W rendered peak values for
      leg blood flow (thermodilution) of 5.99 +/- 0.66 (range 4.15-9.52) l/min and leg
      O(2) uptake of 856 +/- 109 (range 590-1,521) ml/min. Muscle perfusion and O(2)
      uptake reached peak values of 246 +/- 24 (range 149-373) and 35.2 +/- 3.7 (range
      22.6-59. 6) ml. min(-1). 100 g muscle(-1), respectively. These peak values are
      approximately 19-33% larger than those attained by applying anthropometric muscle
      mass estimates. In conclusion, the present findings emphasize that peak perfusion
      and O(2) uptake in human skeletal muscle may be up to approximately 30% higher
      than previous anthropometric-based estimates that use equivalent techniques for
      blood flow measurements.

PMID- 10601193
TI  - Validation of fluorescent-labeled microspheres for measurement of relative blood
      flow in severely injured lungs.
AB  - The aim of the study was to validate a nonradioactive method for relative blood
      flow measurements in severely injured lungs that avoids labor-intensive tissue
      processing. The use of fluorescent-labeled microspheres was compared with the
      standard radiolabeled-microsphere method. In seven sheep, lung injury was
      established by using oleic acid. Five pairs of radio- and fluorescent-labeled
      microspheres were injected before and after established lung injury. Across all
      animals, 175 pieces were selected randomly. The radioactivity of each piece was
      determined by using a scintillation counter. The fluorescent dye was extracted
      from each piece with a solvent without digestion or filtering. The fluorescence
      was determined with an automated fluorescent spectrophotometer. Perfusion was
      calculated for each piece from both the radioactivity and fluorescence and volume
      normalized. Correlations between flow determined by the two methods were in the
      range from 0.987 +/- 0.007 (SD) to 0.991 +/- 0.002 (SD) after 9 days of soaking.
      Thus the fluorescent microsphere technique is a valuable tool for investigating
      regional perfusion in severely injured lungs and can replace radioactivity.

PMID- 10601194
TI  - Bacterial growth: constant obsession with dN/dt.

PMID- 10601195
TI  - Genome-wide transcriptional analysis of aerobic and anaerobic chemostat cultures
      of Saccharomyces cerevisiae.
AB  - The yeast Saccharomyces cerevisiae is unique among eukaryotes in exhibiting fast
      growth in both the presence and the complete absence of oxygen. Genome-wide
      transcriptional adaptation to aerobiosis and anaerobiosis was studied in assays
      using DNA microarrays. This technique was combined with chemostat cultivation,
      which allows controlled variation of a single growth parameter under defined
      conditions and at a fixed specific growth rate. Of the 6,171 open reading frames
      investigated, 5,738 (93%) yielded detectable transcript levels under either
      aerobic or anaerobic conditions; 140 genes showed a >3-fold-higher transcription
      level under anaerobic conditions. Under aerobic conditions, transcript levels of
      219 genes were >3-fold higher than under anaerobic conditions.

PMID- 10601196
TI  - Localization of synthesis of beta1,6-glucan in Saccharomyces cerevisiae.
AB  - Beta1,6-Glucan is a key component of the yeast cell wall, interconnecting cell
      wall proteins, beta1,3-glucan, and chitin. It has been postulated that the
      synthesis of beta1,6-glucan begins in the endoplasmic reticulum with the
      formation of protein-bound primer structures and that these primer structures are
      extended in the Golgi complex by two putative glucosyltransferases that are
      functionally redundant, Kre6 and Skn1. This is followed by maturation steps at
      the cell surface and by coupling to other cell wall macromolecules. We have
      reinvestigated the role of Kre6 and Skn1 in the biogenesis of beta1,6-glucan.
      Using hydrophobic cluster analysis, we found that Kre6 and Skn1 show significant
      similarities to family 16 glycoside hydrolases but not to nucleotide diphospho
      sugar glycosyltransferases, indicating that they are glucosyl hydrolases or
      transglucosylases instead of genuine glucosyltransferases. Next, using immunogold
      labeling, we tried to visualize intracellular beta1,6-glucan in cryofixed sec1-1
      cells which had accumulated secretory vesicles at the restrictive temperature. No
      intracellular labeling was observed, but the cell surface was heavily labeled.
      Consistent with this, we could detect substantial amounts of beta1,6-glucan in
      isolated plasma membrane-derived microsomes but not in post-Golgi secretory
      vesicles. Taken together, our data indicate that the synthesis of beta1, 6-glucan
      takes place largely at the cell surface. An alternative function for Kre6 and
      Skn1 is discussed.

PMID- 10601197
TI  - Characterization of a novel, antifungal, chitin-binding protein from Streptomyces
      tendae Tu901 that interferes with growth polarity.
AB  - The afp1 gene, which encodes the antifungal protein AFP1, was cloned from
      nikkomycin-producing Streptomyces tendae Tu901, using a nikkomycin-negative
      mutant as a host and screening transformants for antifungal activity against
      Paecilomyces variotii in agar diffusion assays. The 384-bp afp1 gene has a low
      G+C content (63%) and a transcription termination structure with a poly(T)
      region, unusual attributes for Streptomyces genes. AFP1 was purified from culture
      filtrate of S. tendae carrying the afp1 gene on the multicopy plasmid pIJ699. The
      purified protein had a molecular mass of 9,862 Da and lacked a 42-residue N
      terminal peptide deduced from the nucleotide sequence. AFP1 was stable at extreme
      pH values and high temperatures and toward commercial proteinases. AFP1 had
      limited similarity to cellulose-binding domains of microbial plant cell wall
      hydrolases and bound to crab shell chitin, chitosan, and cell walls of P.
      variotii but showed no enzyme activity. The biological activity of AFP1, which
      represents the first chitin-binding protein from bacteria exhibiting antifungal
      activity, was directed against specific ascomycetes, and synergistic interaction
      with the chitin synthetase inhibitor nikkomycin inhibited growth of Aspergillus
      species. Microscopy studies revealed that fluorescein-labeled AFP1 strongly bound
      to the surface of germinated conidia and to tips of growing hyphae, causing
      severe alterations in cell morphogenesis that gave rise to large spherical
      conidia and/or swollen hyphae and to atypical branching.

PMID- 10601198
TI  - The genetic switch regulating activity of early promoters of the temperate
      lactococcal bacteriophage TP901-1.
AB  - A functional analysis of open reading frame 4 (ORF4) and ORF5 from the temperate
      lactococcal phage TP901-1 was performed by mutant and deletion analysis combined
      with transcriptional studies of the early phage promoters p(R) and p(L). ORF4
      (180 amino acids) was identified as a phage repressor necessary for repression of
      both promoters. Furthermore, the presence of ORF4 confers immunity of the host
      strain to TP901-1. ORF5 (72 amino acids) was found to be able to inhibit
      repression of the lytic promoter p(L) by ORF4. Upon transformation with a plasmid
      containing both ORF4 and ORF5 and their cognate promoters, clonal variation is
      observed: in each transformant, either p(L) is open and p(R) is closed or vice
      versa. The repression is still dependent on ORF4, and the presence of ORF5 is
      needed for the clonal variation. Induction of a repressed p(L) fusion containing
      orf4 and orf5 was obtained by addition of mitomycin C, and the induction was also
      shown to be dependent on the presence of the RecA protein, even though ORF4 does
      not contain a recognizable autocleavage site. Our results suggest that the
      relative amounts of the two proteins ORF4 and ORF5 determine the decision between
      lytic or lysogenic life cycle after phage infection and that a protein complex
      consisting of ORF4 and ORF5 may constitute a new type of genetic switch in
      bacteriophages.

PMID- 10601199
TI  - Molecular analysis of the Candida albicans homolog of Saccharomyces cerevisiae
      MNN9, required for glycosylation of cell wall mannoproteins.
AB  - The fungal cell wall has generated interest as a potential target for developing
      antifungal drugs, and the genes encoding glucan and chitin in fungal pathogens
      have been studied to this end. Mannoproteins, the third major component of the
      cell wall, contain mannose in either O- or N-glycosidic linkages. Here we
      describe the molecular analysis of the Candida albicans homolog of Saccharomyces
      cerevisiae MNN9, a gene required for the synthesis of N-linked outer-chain mannan
      in yeast, and the phenotypes associated with its disruption. CaMNN9 has
      significant homology with S. cerevisiae MNN9, including a putative N-terminal
      transmembrane domain, and represents a member of a similar gene family in
      Candida. CaMNN9 resides on chromosome 3 and is expressed at similar levels in
      both yeast and hyphal cells. Disruption of both copies of CaMNN9 leads to
      phenotypic effects characteristic of cell wall defects including poor growth in
      liquid media and on solid media, formation of aggregates in liquid culture,
      osmotic sensitivity, aberrant hyphal formation, and increased sensitivity to
      lysis after treatment with beta-1,3-glucanase. Like all members of the S.
      cerevisiae MNN9 gene family the Camnn9Delta strain is resistant to sodium
      orthovanadate and sensitive to hygromycin B. Analysis of cell wall-associated
      carbohydrates showed the Camnn9Delta strain to contain half the amount of mannan
      present in cell walls derived from the wild-type parent strain. Reverse
      transcription-PCR and Northern analysis of the expression of MNN9 gene family
      members CaVAN1 and CaANP1 in the Camnn9Delta strain showed that transcription of
      those genes is not affected in the absence of CaMNN9 transcription. Our results
      suggest that, while the role MNN9 plays in glycosylation in both Candida and
      Saccharomyces is conserved, loss of MNN9 function in C. albicans leads to
      phenotypes that are inconsistent with the pathogenicity of the organism and thus
      identify CaMnn9p as a potential drug target.

PMID- 10601200
TI  - Gene disruption through homologous recombination in Spiroplasma citri: an scm1
      disrupted motility mutant is pathogenic.
AB  - To determine whether homologous recombination could be used to inactivate
      selected genes in Spiroplasma citri, plasmid constructs were designed to disrupt
      the motility gene scm1. An internal scm1 gene fragment was inserted into plasmid
      pKT1, which replicates in Escherichia coli but not in S. citri, and into the S.
      citri oriC plasmid pBOT1, which replicates in spiroplasma cells as well as in E.
      coli. Electrotransformation of S. citri with the nonreplicative, recombinant
      plasmid pKTM1 yielded no transformants. In contrast, spiroplasmal transformants
      were obtained with the replicative, pBOT1-derived plasmid pCJ32. During passaging
      of the transformants, the plasmid was found to integrate into the chromosome by
      homologous recombination either at the oriC region or at the scm1 gene. In the
      latter case, plasmid integration by a single crossover between the scm1 gene
      fragment carried by the plasmid and the full-length scm1 gene carried by the
      chromosome led to a nonmotile phenotype. Transmission of the scm1-disrupted
      mutant to periwinkle (Catharanthus roseus) plants through injection into the
      leafhopper vector (Circulifer haematoceps) showed that the motility mutant
      multiplied in the insects and was efficiently transmitted to plants, in which it
      induced symptoms similarly to the wild-type S. citri strain. These results
      suggest that the spiroplasmal motility may not be essential for pathogenicity and
      that, more broadly, the S. citri oriC plasmids can be considered promising tools
      for specific gene disruption by promoting homologous recombination in S. citri, a
      mollicute which probably lacks a functional RecA protein.

PMID- 10601201
TI  - A cyclic AMP receptor protein mutant that constitutively activates an Escherichia
      coli promoter disrupted by an IS5 insertion.
AB  - Previously an Escherichia coli mutant that had acquired the ability to grow on
      propanediol as the sole carbon and energy source was isolated. This phenotype is
      the result of the constitutive expression of the fucO gene (in the fucAO operon),
      which encodes one of the enzymes in the fucose metabolic pathway. The mutant was
      found to bear an IS5 insertion in the intergenic regulatory region between the
      divergently oriented fucAO and fucPIK operons. Though expression of the fucAO
      operon was constitutive, the fucPIK operon became noninducible such that the
      mutant could no longer grow on fucose. A fucose-positive revertant which was
      found to contain a suppressor mutation in the crp gene was selected. Here we
      identify this crp mutation, which results in a single amino acid substitution
      (K52N) that has been proposed previously to uncover a cryptic activating region
      in the cyclic AMP receptor protein (CRP). We show that the mutant CRP
      constitutively activates transcription from both the IS5-disrupted and the wild
      type fucPIK promoters, and we identify the CRP-binding site that is required for
      this activity. Our results show that the fucPIK promoter, a complex promoter
      which ordinarily depends on both CRP and the fucose-specific regulator FucR for
      its activation, can be activated in the absence of FucR by a mutant CRP that uses
      three, rather than two, activating regions to contact RNA polymerase. For the IS5
      disrupted promoter, which retains a single CRP-binding site, the additional
      activating region of the mutant CRP evidently compensates for the lack of
      upstream regulatory sequences.

PMID- 10601202
TI  - Functional domains present in the mycobacterial hemagglutinin, HBHA.
AB  - Identification and characterization of mycobacterial adhesins and complementary
      host receptors required for colonization and dissemination of mycobacteria in
      host tissues are needed for a more complete understanding of the pathogenesis of
      diseases caused by these bacteria and for the development of effective vaccines.
      Previous investigations have demonstrated that a 28-kDa heparin-binding
      mycobacterial surface protein, HBHA, can agglutinate erythrocytes and promote
      mycobacterial aggregation in vitro. In this study, further molecular and
      biochemical analysis of HBHA demonstrates that it has three functional domains: a
      transmembrane domain of 18 amino acids residing near the N terminus, a large
      domain of 81 amino acids consistent with an alpha-helical coiled-coil region, and
      a Lys-Pro-Ala-rich C-terminal domain that mediates binding to proteoglycans.
      Using His-tagged recombinant HBHA proteins and nickel chromatography we
      demonstrate that HBHA polypeptides which contain the coiled-coil region form
      multimers. This tendency to oligomerize may be responsible for the induction of
      mycobacterial aggregation since a truncated N-terminal HBHA fragment containing
      the coiled-coil domain promotes mycobacterial aggregation. Conversely, a
      truncated C-terminal HBHA fragment which contains Lys-Pro-Ala-rich repeats binds
      to the proteoglycan decorin. These results indicate that HBHA contains at least
      three distinct domains which facilitate intercalation into surface membranes,
      promote bacterium-bacterium interactions, and mediate the attachment to sulfated
      glycoconjugates found in host tissues.

PMID- 10601203
TI  - Type 1 fimbriation and phase switching in a natural Escherichia coli fimB null
      strain, Nissle 1917.
AB  - Escherichia coli Nissle 1917 has been used as a probiotic against intestinal
      disorders for many decades. It is a good colonizer of the human gut and has been
      reported to be able to express type 1 fimbriae. Type 1 fimbriae are surface
      organelles which mediate alpha-D-mannose-sensitive binding to various host cell
      surfaces. The expression is phase variable, and two tyrosine recombinases, FimB
      and FimE, mediate the inversion of the fimbrial phase switch. Current evidence
      suggests that FimB can carry out recombination in both directions, whereas FimE
      catalyzed switching is on to off only. We show here that under liquid shaking
      growth conditions, Nissle 1917 did not express type 1 fimbriae, due to a
      truncation of the fimB gene by an 1,885-bp insertion element. Despite its fimB
      null status, Nissle 1917 was still capable of off-to-on switching of the phase
      switch and expressing type 1 fimbriae when grown under static conditions. This
      phase switching was not catalyzed by FimE, by truncated FimB, or by information
      residing within the insertion element. No further copies of fimB seemed to be
      present on the chromosome of Nissle 1917, suggesting that another tyrosine
      recombinase in Nissle 1917 is responsible for the low-frequency off-to-on
      inversion of the phase switch that is strongly favored under static growth
      conditions. This is the first report documenting the non-FimB- or non-FimE
      catalyzed inversion of the fim switch.

PMID- 10601204
TI  - Genetic analysis of a chromosomal region containing genes required for
      assimilation of allantoin nitrogen and linked glyoxylate metabolism in
      Escherichia coli.
AB  - Growth experiments with Escherichia coli have shown that this organism is able to
      use allantoin as a sole nitrogen source but not as a sole carbon source. Nitrogen
      assimilation from this compound was possible only under anaerobic conditions, in
      which all the enzyme activities involved in allantoin metabolism were detected.
      Of the nine genes encoding proteins required for allantoin degradation, only the
      one encoding glyoxylate carboligase (gcl), the first enzyme of the pathway
      leading to glycerate, had been identified and mapped at centisome 12 on the
      chromosome map. Phenotypic complementation of mutations in the other two genes of
      the glycerate pathway, encoding tartronic semialdehyde reductase (glxR) and
      glycerate kinase (glxK), allowed us to clone and map them closely linked to gcl.
      Complete sequencing of a 15.8-kb fragment encompassing these genes defined a
      regulon with 12 open reading frames (ORFs). Due to the high similarity of the
      products of two of these ORFs with yeast allantoinase and yeast allantoate
      amidohydrolase, a systematic analysis of the gene cluster was undertaken to
      identify genes involved in allantoin utilization. A BLASTP search predicted four
      of the genes that we sequenced to encode allantoinase (allB), allantoate
      amidohydrolase (allC), ureidoglycolate hydrolase (allA), and ureidoglycolate
      dehydrogenase (allD). The products of these genes were overexpressed and shown to
      have the predicted corresponding enzyme activities. Transcriptional fusions to
      lacZ permitted the identification of three functional promoters corresponding to
      three transcriptional units for the structural genes and another promoter for the
      regulatory gene allR. Deletion of this regulatory gene led to constitutive
      expression of the regulon, indicating a negatively acting function.

PMID- 10601205
TI  - Vir proteins stabilize VirB5 and mediate its association with the T pilus of
      Agrobacterium tumefaciens.
AB  - Three VirB proteins (VirB1*, VirB2, and VirB5) have been implicated as putative
      components of the T pilus from Agrobacterium tumefaciens, which likely mediates
      binding to plant cells followed by transfer of genetic material. Recently, VirB2
      was indeed shown to be its major component (E.-M. Lai and C. I. Kado, J.
      Bacteriol. 180:2711-2717, 1998). Here, the influence of other Vir proteins on the
      stability and cellular localization of VirB1*, VirB2, and VirB5 was analyzed.
      Solubility of VirB1* and membrane association of VirB2 proved to be inherent
      features of these proteins, independent of virulence gene induction. In contrast,
      cellular levels of VirB5 were strongly reduced in the absence of other Vir
      proteins, indicating its stabilization by protein-protein interactions. The
      assembly and composition of the T pilus were analyzed in nopaline strain
      C58(pTiC58), its flagellum-free derivative NT1REB(pJK270), and octopine strain
      A348(pTiA6) following optimized virulence gene induction on solid agar medium. In
      all strains VirB2 was the major pilus component and VirB5 cofractionated during
      several purification steps, such as ultracentrifugation, gel filtration, and
      sucrose gradient centrifugation. VirB5 may therefore be directly involved in
      pilus assembly, possibly as minor component. In contrast, secreted VirB1* showed
      no association with the T pilus. In-frame deletions in genes virB1, virB2, virB5,
      and virB6 blocked the formation of virulence gene-dependent extracellular high
      molecular-weight structures. Thus, an intact VirB machinery as well as VirB2 and
      VirB5 are required for T-pilus formation.

PMID- 10601206
TI  - Acetone formation in the Vibrio family: a new pathway for bacterial leucine
      catabolism.
AB  - There is current interest in biological sources of acetone, a volatile organic
      compound that impacts atmospheric chemistry. Here, we determined that leucine
      dependent acetone formation is widespread in the Vibrionaceae. Sixteen Vibrio
      isolates, two Listonella species, and two Photobacterium angustum isolates
      produced acetone in the presence of L-leucine. Shewanella isolates produced much
      less acetone. Growth of Vibrio splendidus and P. angustum in a fermentor with
      controlled aeration revealed that acetone was produced after a lag in late
      logarithmic or stationary phase of growth, depending on the medium, and was not
      derived from acetoacetate by nonenzymatic decarboxylation in the medium. L
      Leucine, but not D-leucine, was converted to acetone with a stoichiometry of
      approximately 0.61 mol of acetone per mol of L-leucine. Testing various potential
      leucine catabolites as precursors of acetone showed that only alpha
      ketoisocaproate was efficiently converted by whole cells to acetone. Acetone
      production was blocked by a nitrogen atmosphere but not by electron transport
      inhibitors, suggesting that an oxygen-dependent reaction is required for leucine
      catabolism. Metabolic labeling with deuterated (isopropyl-d(7))-L-leucine
      revealed that the isopropyl carbons give rise to acetone with full retention of
      deuterium in each methyl group. These results suggest the operation of a new
      catabolic pathway for leucine in vibrios that is distinct from the 3-hydroxy-3
      methylglutaryl-coenzyme A pathway seen in pseudomonads.

PMID- 10601207
TI  - Multiple control of flagellum biosynthesis in Escherichia coli: role of H-NS
      protein and the cyclic AMP-catabolite activator protein complex in transcription
      of the flhDC master operon.
AB  - Little is known about the molecular mechanism by which histone-like nucleoid
      structuring (H-NS) protein and cyclic AMP-catabolite activator protein (CAP)
      complex control bacterial motility. In the present paper, we show that crp and
      hns mutants are nonmotile due to a complete lack of flagellin accumulation. This
      results from a reduced expression in vivo of fliA and fliC, which encode the
      specific flagellar sigma factor and flagellin, respectively. Overexpression of
      the flhDC master operon restored, at least in part, motility in crp and hns
      mutant strains, suggesting that this operon is the main target for both
      regulators. Binding of H-NS and CAP to the regulatory region of the master operon
      was demonstrated by gel retardation experiments, and their DNA binding sites were
      identified by DNase I footprinting assays. In vitro transcription experiments
      showed that CAP activates flhDC expression while H-NS represses it. In agreement
      with this observation, the activity of a transcriptional fusion carrying the
      flhDC promoter was decreased in the crp strain and increased in the hns mutant.
      In contrast, the activity of a transcriptional fusion encompassing the entire
      flhDC regulatory region extending to the ATG translational start codon was
      strongly reduced in both hns and crp mutants. These results suggest that the
      region downstream of the +1 transcriptional start site plays a crucial role in
      the positive control by H-NS of flagellum biosynthesis in vivo. Finally, the lack
      of complementation of the nonmotile phenotype in a crp mutant by activation
      deficient CAP mutated proteins and characterization of cfs, a mutation resulting
      in a CAP-independent motility behavior, demonstrate that CAP activates flhDC
      transcription by binding to its promoter and interacting with RNA polymerase.

PMID- 10601208
TI  - Differential and independent roles of a sigma(32) homolog (RpoH) and an HrcA
      repressor in the heat shock response of Agrobacterium tumefaciens.
AB  - The heat shock response in alpha proteobacteria is unique in that a combination
      of two regulators is involved: a positive regulator, RpoH (sigma(32) homolog),
      found in the alpha, beta, and gamma proteobacteria, and a negative regulator,
      HrcA, widely distributed in eubacteria but not in the gamma proteobacteria. To
      assess the differential roles of the two regulators in these bacteria, we cloned
      the hrcA-grpE operon of Agrobacterium tumefaciens, analyzed its transcription,
      and constructed deletion mutants lacking RpoH and/or HrcA. The DeltarpoH mutant
      and DeltarpoH DeltahrcA double mutant were unable to grow above 30 degrees C.
      Whereas the synthesis of heat shock proteins (e.g., DnaK, GroEL, and ClpB) was
      transiently induced upon temperature upshift from 25 to 37 degrees C in the wild
      type, such induction was not observed in the DeltarpoH mutant, except that GroEL
      synthesis was still partially induced. By contrast, the DeltahrcA mutant grew
      normally and exhibited essentially normal heat induction except for a higher
      level of GroEL expression, especially before heat shock. The DeltarpoH DeltahrcA
      double mutant showed the combined phenotypes of each of the single mutants. The
      amounts of dnaK and groE transcripts before and after heat shock, as determined
      by primer extension, were consistent with those of the proteins synthesized. The
      cellular level of RpoH but not HrcA increased significantly upon heat shock. We
      conclude that RpoH plays a major and global role in the induction of most heat
      shock proteins, whereas HrcA plays a restricted role in repressing groE
      expression under nonstress conditions.

PMID- 10601209
TI  - PRR1, a homolog of Aspergillus nidulans palF, controls pH-dependent gene
      expression and filamentation in Candida albicans.
AB  - The pH of the environment has been implicated in controlling the yeast-hypha
      transition and pathogenesis of Candida albicans. Several C. albicans genes,
      including PHR1 and PHR2, are pH dependent in their expression. To investigate the
      mechanism of pH-dependent expression, we have cloned and characterized PRR1 (for
      pH response regulator). PRR1 is homologous to palF, a component of the pH
      response pathway in Aspergillus nidulans. Expression of PRR1 was itself pH
      dependent, being maximal at acid pH but reduced severalfold at alkaline pH. In a
      prr1 null mutant the alkaline-induced expression of PHR1 was completely
      abolished. Conversely, expression of PHR2 was no longer repressed at alkaline pH.
      A prr1 null mutant exhibited no morphological abnormalities at either pH;
      however, it lost the ability to form hyphae on medium 199 and on 10% serum
      plates. The ability to filament on serum was not restored by forced expression of
      PHR1, indicating that additional PRR1-dependent genes are required for hyphal
      development. These developmental genes appear to be distinct from those
      controlled by the developmental regulator EFG1, since the EFG1-dependent gene
      HWP1 was expressed normally in the prr1 null mutant. We conclude that PRR1
      encodes a component of the pH-dependent response pathway in C. albicans and that
      this pathway regulates the expression of multiple components of hyphal
      development.

PMID- 10601210
TI  - Effect of environmental pH on morphological development of Candida albicans is
      mediated via the PacC-related transcription factor encoded by PRR2.
AB  - The ability to respond to ambient pH is critical to the growth and virulence of
      the fungal pathogen Candida albicans. This response entails the differential
      expression of several genes affecting morphogenesis. To investigate the mechanism
      of pH-dependent gene expression, the C. albicans homolog of pacC, designated PRR2
      (for pH response regulator), was identified and cloned. pacC encodes a zinc
      finger-containing transcription factor that mediates pH-dependent gene expression
      in Aspergillus nidulans. Mutants lacking PRR2 can no longer induce the expression
      of alkaline-expressed genes or repress acid-expressed genes at alkaline pH.
      Although the mutation did not affect growth of the cells at acid or alkaline pH,
      the mutants exhibited medium-conditional defects in filamentation. PRR2 was
      itself expressed in a pH-conditional manner, and its induction at alkaline pH was
      controlled by PRR1. PRR1 is homologous to palF, a regulator of pacC. Thus, PRR2
      expression is controlled by a pH-dependent feedback loop. The results demonstrate
      that the pH response pathway of Aspergillus is conserved and that this pathway
      has been adapted to control dimorphism in C. albicans.

PMID- 10601211
TI  - Genetic and functional analyses of the conserved C-terminal core domain of
      Escherichia coli FtsZ.
AB  - In Escherichia coli, FtsZ is required for the recruitment of the essential cell
      division proteins FtsA and ZipA to the septal ring. Several C-terminal deletions
      of E. coli FtsZ, including one of only 12 amino acids that removes the highly
      conserved C-terminal core domain, failed to complement chromosomal ftsZ mutants
      when expressed on a plasmid. To identify key individual residues within the core
      domain, six highly conserved residues were replaced with alanines. All but one of
      these mutants (D373A) failed to complement an ftsZ chromosomal mutant. Immunoblot
      analysis demonstrated that whereas I374A and F377A proteins were unstable in the
      cell, L372A, D373A, P375A, and L378A proteins were synthesized at normal levels,
      suggesting that they were specifically defective in some aspect of FtsZ function.
      In addition, all four of the stable mutant proteins were able to localize and
      form rings at potential division sites in chromosomal ftsZ mutants, implying a
      defect in a function other than localization and multimerization. Because another
      proposed function of FtsZ is the recruitment of FtsA and ZipA, we tested whether
      the C-terminal core domain was important for interactions with these proteins.
      Using two different in vivo assays, we found that the 12-amino-acid truncation of
      FtsZ was defective in binding to FtsA. Furthermore, two point mutants in this
      region (L372A and P375A) showed weakened binding to FtsA. In contrast, ZipA was
      capable of binding to all four stable point mutants in the FtsZ C-terminal core
      but not to the 12-amino-acid deletion.

PMID- 10601212
TI  - Cloning and characterization of the Pseudomonas fluorescens ATP-binding cassette
      exporter, HasDEF, for the heme acquisition protein HasA.
AB  - Two ATP-binding cassette (ABC) exporters are present in Pseudomonas fluorescens
      no. 33; one is the recently reported AprDEF system and the other is HasDEF, which
      exports a heme acquisition protein, HasA. The hasDEF genes were cloned by DNA
      hybridization with a DNA probe coding for the LipB protein, one of the components
      of the Serratia marcescens ABC exporter Lip system. P. fluorescens HasA showed
      sequence identity of 40 to 49% with HasA proteins from Pseudomonas aeruginosa and
      Serratia marcescens. The P. fluorescens Has exporter secreted HasA proteins from
      P. fluorescens and P. aeruginosa but not S. marcescens HasA in Escherichia coli,
      whereas the Has exporter from S. marcescens allowed secretion of all three HasA
      proteins. The P. fluorescens HasDEF system also promoted the secretion of the
      lipase and alkaline protease of P. fluorescens. Hybrid exporter analysis
      demonstrated that the HasD proteins, which are ABC proteins, are involved in the
      discrimination of export substrates. Chimeric HasA proteins containing both P.
      fluorescens and S. marcescens sequences were produced and tested for secretion
      through the Has exporters. The C-terminal region of HasA was shown to be involved
      in the secretion specificity of the P. fluorescens Has exporter.

PMID- 10601213
TI  - Separate roles of Escherichia coli replication proteins in synthesis and
      partitioning of pSC101 plasmid DNA.
AB  - We report here that the Escherichia coli replication proteins DnaA, which is
      required to initiate replication of both the chromosome and plasmid pSC101, and
      DnaB, the helicase that unwinds strands during DNA replication, have effects on
      plasmid partitioning that are distinct from their functions in promoting plasmid
      DNA replication. Temperature-sensitive dnaB mutants cultured under conditions
      permissive for DNA replication failed to partition plasmids normally, and when
      cultured under conditions that prevent replication, they showed loss of the
      entire multicopy pool of plasmid replicons from half of the bacterial population
      during a single cell division. As was observed previously for DnaA,
      overexpression of the wild-type DnaB protein conversely stabilized the
      inheritance of partition-defective plasmids while not increasing plasmid copy
      number. The identification of dnaA mutations that selectively affected either
      replication or partitioning further demonstrated the separate roles of DnaA in
      these functions. The partition-related actions of DnaA were localized to a domain
      (the cell membrane binding domain) that is physically separate from the DnaA
      domain that interacts with other host replication proteins. Our results identify
      bacterial replication proteins that participate in partitioning of the pSC101
      plasmid and provide evidence that these proteins mediate plasmid partitioning
      independently of their role in DNA synthesis.

PMID- 10601214
TI  - Regulation of sigma 54-dependent transcription by core promoter sequences: role
      of -12 region nucleotides.
AB  - The tetranucleotide core recognition sequence (TTGC) of the sigma 54 promoter -12
      recognition element was altered by random substitution. The resulting promoter
      mutants were characterized in vivo and in vitro. Deregulated promoters were
      identified, implying that this core element can mediate the response to enhancer
      binding proteins. These promoters had in common a substitution at position -12
      (consensus C), indicating its importance for keeping basal transcription in
      check. In another screen, nonfunctional promoters were identified. Their analysis
      indicated that positions -13 (consensus G) and -15 (consensus T) are important to
      maintain minimal promoter function. In vitro studies showed that the -13 and -15
      positions contribute to closed-complex formation, whereas the -12 position has a
      stronger effect on recognition of the fork junction intermediate created during
      open-complex formation. Overall the data indicate that the -12 region core
      contains specific subsequences that direct the diverse RNA polymerase
      interactions required both to produce RNA and to restrict this RNA synthesis in
      the absence of activation.

PMID- 10601215
TI  - Gradual alterations in cell wall structure and metabolism in vancomycin-resistant
      mutants of Staphylococcus aureus.
AB  - In five vancomycin-resistant laboratory step mutants selected from the highly and
      homogeneously methicillin-resistant Staphylococcus aureus strain COL (MIC of
      methicillin, 800 microg/ml; MIC of vancomycin, 1.5 microg/ml), the gradually
      increasing levels of resistance to vancomycin were accompanied by parallel
      decreases in the levels of methicillin resistance and abnormalities in cell wall
      metabolism. The latter included a gradual reduction in the proportion of highly
      cross-linked muropeptide species in peptidoglycan, down-regulation of the
      production of penicillin-binding protein 2A (PBP2A) and PBP4, and
      hypersensitivity to beta-lactam antibiotics each with a relatively selective
      affinity for the various staphylococcal PBPs; the PBP2-specific inhibitor
      ceftizoxime was particularly effective.

PMID- 10601216
TI  - Regulation of expression of the adhE gene, encoding ethanol oxidoreductase in
      Escherichia coli: transcription from a downstream promoter and regulation by fnr
      and RpoS.
AB  - The adhE gene of Escherichia coli, located at min 27 on the chromosome, encodes
      the bifunctional NAD-linked oxidoreductase responsible for the conversion of
      acetyl-coenzyme A to ethanol during fermentative growth. The expression of adhE
      is dependent on both transcriptional and posttranscriptional controls and is
      about 10-fold higher during anaerobic than during aerobic growth. Two putative
      transcriptional start sites have been reported: one at position -292 and the
      other at -188 from the translational start codon ATG. In this study we show, by
      using several different transcriptional and translational fusions to the lacZ
      gene, that both putative transcriptional start sites can be functional and each
      site can be redox regulated. Although both start sites are NarL repressible in
      the presence of nitrate, Fnr activates only the -188 start site and Fis is
      required for the transcription of only the -292 start site. In addition, it was
      discovered that RpoS activates adhE transcription at both start sites. Under all
      experimental conditions tested, however, only the upstream start site is active.
      Available evidence indicates that under those conditions, the upstream promoter
      region acts as a silencer of the downstream transcriptional start site.
      Translation of the mRNA starting at -292, but not the one starting at -188,
      requires RNase III. The results support the previously postulated ribosomal
      binding site (RBS) occlusion model, according to which RNase III cleavage is
      required to release the RBS from a stem-loop structure in the long transcript.

PMID- 10601217
TI  - The Archaeoglobus fulgidus D-lactate dehydrogenase is a Zn(2+) flavoprotein.
AB  - Archaeoglobus fulgidus, a hyperthermophilic, archaeal sulfate reducer, is one of
      the few organisms that can utilize D-lactate as a sole source for both carbon and
      electrons. The A. fulgidus open reading frame, AF0394, which is predicted to
      encode a D-(-)-lactate dehydrogenase (Dld), was cloned, and its product was
      expressed in Escherichia coli as a fusion with the maltose binding protein (MBP).
      The 90-kDa MBP-Dld fusion protein was more efficiently expressed in E. coli when
      coexpressed with the E. coli dnaY gene, encoding the arginyl tRNA for the codons
      AGA and AGG. When cleaved from the fusion protein by treatment with factor Xa,
      the recombinant Dld (rDld) has an apparent molecular mass of 50 kDa, similar to
      that of the native A. fulgidus Dld enzyme. Both the purified MBP-Dld fusion
      protein and its rDld cleavage fragment have lactate dehydrogenase activities
      specific for D-lactate, are stable at 80 degrees C, and retain activity after
      exposure to oxygen. The flavin cofactor FAD, which binds rDld apoprotein with a
      1:1 stoichiometry, is essential for activity.

PMID- 10601218
TI  - A multifunctional ATP-binding cassette transporter system from Vibrio cholerae
      transports vibriobactin and enterobactin.
AB  - Vibrio cholerae uses the catechol siderophore vibriobactin for iron transport
      under iron-limiting conditions. We have identified genes for vibriobactin
      transport and mapped them within the vibriobactin biosynthetic gene cluster.
      Within this genetic region we have identified four genes, viuP, viuD, viuG and
      viuC, whose protein products have homology to the periplasmic binding protein,
      the two integral cytoplasmic membrane proteins, and the ATPase component,
      respectively, of other iron transport systems. The amino-terminal region of ViuP
      has homology to a lipoprotein signal sequence, and ViuP could be labeled with
      [(3)H]palmitic acid. This suggests that ViuP is a membrane lipoprotein. The
      ViuPDGC system transports both vibriobactin and enterobactin in Escherichia coli.
      In the same assay, the E. coli enterobactin transport system, FepBDGC, allowed
      the utilization of enterobactin but not vibriobactin. Although the entire viuPDGC
      system could complement mutations in fepB, fepD, fepG, or fepC, only viuC was
      able to independently complement the corresponding fep mutation. This indicates
      that these proteins usually function as a complex. V. cholerae strains carrying a
      mutation in viuP or in viuG were constructed by marker exchange. These mutations
      reduced, but did not completely eliminate, vibriobactin utilization. This
      suggests that V. cholerae contains genes in addition to viuPDGC that function in
      the transport of catechol siderophores.

PMID- 10601219
TI  - IS1630 of Mycoplasma fermentans, a novel IS30-type insertion element that targets
      and duplicates inverted repeats of variable length and sequence during insertion.
AB  - A new insertion sequence (IS) of Mycoplasma fermentans is described. This
      element, designated IS1630, is 1,377 bp long and has 27-bp inverted repeats at
      the termini. A single open reading frame (ORF), predicted to encode a basic
      protein of either 366 or 387 amino acids (depending on the start codon utilized),
      occupies most of this compact element. The predicted translation product of this
      ORF has homology to transposases of the IS30 family of IS elements and is most
      closely related (27% identical amino acid residues) to the product of the
      prototype of the group, IS30. Multiple copies of IS1630 are present in the
      genomes of at least two M. fermentans strains. Characterization and comparison of
      nine copies of the element revealed that IS1630 exhibits unusual target site
      specificity and, upon insertion, duplicates target sequences in a manner unlike
      that of any other IS element. IS1630 was shown to have the striking ability to
      target and duplicate inverted repeats of variable length and sequence during
      transposition. IS30-type elements typically generate 2- or 3-bp target site
      duplications, whereas those created by IS1630 vary between 19 and 26 bp. With the
      exception of two recently reported IS4-type elements which have the ability to
      generate variable large duplications (B. B. Plikaytis, J. T. Crawford, and T. M.
      Shinnick, J. Bacteriol. 180:1037-1043, 1998; E. M. Vilei, J. Nicolet, and J.
      Frey, J. Bacteriol. 181:1319-1323, 1999), such large direct repeats had not been
      observed for other IS elements. Interestingly, the IS1630-generated duplications
      are all symmetrical inverted repeat sequences that are apparently derived from
      rho-independent transcription terminators of neighboring genes. Although the
      consensus target site for IS30 is almost palindromic, individual target sites
      possess considerably less inverted symmetry. In contrast, IS1630 appears to
      exhibit an increased stringency for inverted repeat recognition, since the
      majority of target sites had no mismatches in the inverted repeat sequences. In
      the course of this study, an additional copy of the previously identified
      insertion sequence ISMi1 was cloned. Analysis of the sequence of this element
      revealed that the transposase encoded by this element is more than 200 amino acid
      residues longer and is more closely related to the products of other IS3 family
      members than had previously been recognized. A potential site for programmed
      translational frameshifting in ISMi1 was also identified.

PMID- 10601220
TI  - Citrate synthase mutants of Sinorhizobium meliloti are ineffective and have
      altered cell surface polysaccharides.
AB  - The gltA gene, encoding Sinorhizobium meliloti 104A14 citrate synthase, was
      isolated by complementing an Escherichia coli gltA mutant. The S. meliloti gltA
      gene was mutated by inserting a kanamycin resistance gene and then using
      homologous recombination to replace the wild-type gltA with the gltA::kan allele.
      The resulting strain, CSDX1, was a glutamate auxotroph, and enzyme assays
      confirmed the absence of a requirement for glutamate. CSDX1 did not grow on
      succinate, malate, aspartate, pyruvate, or glucose. CSDX1 produced an unusual
      blue fluorescence on medium containing Calcofluor, which is different from the
      green fluorescence found with 104A14. High concentrations of arabinose (0.4%) or
      succinate (0. 2%) restored the green fluorescence to CSDX1. High-performance
      liquid chromatography analyses showed that CSDX1 produced partially succinylated
      succinoglycan. CSDX1 was able to form nodules on alfalfa, but these nodules were
      not able to fix nitrogen. The symbiotic defect of a citrate synthase mutant could
      thus be due to disruption of the infection process or to the lack of energy
      generated by the tricarboxylic acid cycle.

PMID- 10601221
TI  - Promiscuous origin of a chimeric sequence in the Escherichia coli O157:H7 genome.
AB  - A novel sequence of 2.9 kb in the intergenic region between the mutS and rpoS
      genes of Escherichia coli O157:H7 and closely related strains replaces a sequence
      of 6.1 kb in E. coli K-12 strains. At the same locus in Shigella dysenteriae type
      1, a sequence identical to that in O157:H7 is bounded by the IS1 insertion
      sequence element. Extensive polymorphism in the mutS-rpoS chromosomal region is
      indicative of horizontal transfer events.

PMID- 10601222
TI  - CDC64 encodes cytoplasmic alanyl-tRNA synthetase, Ala1p, of Saccharomyces
      cerevisiae.
AB  - The cdc64-1 mutation causes G(1) arrest in Saccharomyces cerevisiae corresponding
      to a type II Start phenotype. We report that CDC64 encodes Ala1p, an alanyl-tRNA
      synthetase. Thus, cdc64-1 might affect charging of tRNA(Ala) and thereby
      initiation of cell division.

PMID- 10601223
TI  - RNase E enzymes from rhodobacter capsulatus and Escherichia coli differ in
      context- and sequence-dependent in vivo cleavage within the polycistronic puf
      mRNA.
AB  - The 5' pufQ mRNA segment and the pufLMX mRNA segment of Rhodobacter capsulatus
      exhibit different stabilities. Degradation of both mRNA segments is initiated by
      RNase E-mediated endonucleolytic cleavage. While Rhodobacter RNase E does not
      discriminate between the different sequences present around the cleavage sites
      within pufQ and pufL, Escherichia coli RNase E shows preference for the sequence
      harboring more A and U residues.

PMID- 10601224
TI  - Spent culture supernatant of Mycobacterium tuberculosis H37Ra improves viability
      of aged cultures of this strain and allows small inocula to initiate growth.
AB  - Spent culture supernatant from early-stationary-phase Mycobacterium tuberculosis
      H37Ra cultures increased the viability of bacilli from aged cultures of this
      strain and allowed small inocula to initiate growth in liquid culture. The
      resuscitation factor was acid labile and heat stable, with a mass of less than
      1,375 Da.

PMID- 10601225
TI  - Conditional sigma factor expression, using the inducible acetamidase promoter,
      reveals that the Mycobacterium tuberculosis sigF gene modulates expression of the
      16-kilodalton alpha-crystallin homologue.
AB  - A chemically inducible acetamidase promoter-sigF fusion gene was integrated into
      the chromosome of Mycobacterium bovis BCG. Two-dimensional protein gel analysis
      permitted the identification of a number of protein spots whose expression was
      SigF related. One spot upregulated by inappropriate induction of sigF expression
      corresponded to the 16-kDa antigen alpha-crystallin.

PMID- 10601226
TI  - Mutations in catabolite control protein CcpA showing glucose-independent
      regulation in Bacillus megaterium.
AB  - We identified five single amino acid exchanges in CcpA that lead to permanent
      repression of the xylose utilization genes in the absence of glucose. Other
      proteins from the CcpA regulon also show glucose-independent regulation in the
      mutants. The mutant CcpA proteins bind to the DNA target catabolite responsive
      elements without the corepressor HPr-Ser-P.

PMID- 10601227
TI  - Evidence that expression of the Vibrio vulnificus hemolysin gene is dependent on
      cyclic AMP and cyclic AMP receptor protein.
AB  - Glucose repressed hemolysin production in Vibrio vulnificus. Promoter activity of
      the hemolysin gene, vvh, assessed with a vvh-luxCDABE transcriptional fusion,
      required cyclic AMP (cAMP) and cAMP receptor protein (CRP) in Escherichia coli.
      Hemolysin production in V. vulnificus increased after the addition of cAMP and
      was undetectable in a putative crp mutant, suggesting that vvh is also regulated
      by cAMP-CRP in V. vulnificus.

PMID- 10601228
TI  - Structural and functional analyses of the secondary cell wall polymer of Bacillus
      sphaericus CCM 2177 that serves as an S-layer-specific anchor.
AB  - Sacculi of Bacillus sphaericus CCM 2177 contain a secondary cell wall polymer
      which was completely extracted with 48% hydrofluoric acid. Nuclear magnetic
      resonance analysis showed that the polymer is composed of repeating units, as
      follows: -->3)-[4, 6-O-(1-carboxyethylidene)]( approximately 0. 5)-beta-D-ManpNAc
      (1-->4)-beta-D-GlcpNAc-(1-->. The N-terminal part of the S-layer protein carrying
      S-layer homologous motifs recognizes this polymer as a binding site.

PMID- 10601229
TI  - The periplasmic 9.6-kilodalton c-type cytochrome of Geobacter sulfurreducens is
      not an electron shuttle to Fe(III).
AB  - Geobacter sulfurreducens contains a 9.6-kDa c-type cytochrome that was previously
      proposed to serve as an extracellular electron shuttle to insoluble Fe(III)
      oxides. However, when the cytochrome was added to washed-cell suspensions of G.
      sulfurreducens it did not enhance Fe(III) oxide reduction, whereas similar
      concentrations of the known electron shuttle, anthraquinone-2,6-disulfonate,
      greatly stimulated Fe(III) oxide reduction. Furthermore, analysis of the
      extracellular c-type cytochromes in cultures of G. sulfurreducens demonstrated
      that the dominant c-type cytochrome was not the 9.6-kDa cytochrome, but rather a
      41-kDa cytochrome. These results and other considerations suggest that the 9.6
      kDa cytochrome is not an important extracellular electron shuttle to Fe(III)
      oxides.

PMID- 10601231
TI  - Lipid-assisted protein folding.

PMID- 10601232
TI  - A role for cysteine 3635 of RYR1 in redox modulation and calmodulin binding.
AB  - Oxidation of the skeletal muscle Ca(2+) release channel (RYR1) increases its
      activity, produces intersubunit disulfide bonds, and blocks its interaction with
      calmodulin. Conversely, bound calmodulin protects RYR1 from the effects of
      oxidants (Zhang, J.-Z., Wu, Y., Williams, B. Y., Rodney, G., Mandel, F.,
      Strasburg, G. M., and Hamilton, S. L. (1999) Am. J. Physiol. 276, Cell Physiol.
      C46-C53). In addition, calmodulin protects RYR1 from trypsin cleavage at amino
      acids 3630 and 3637 (Moore, C. P., Rodney, G., Zhang, J.-Z., Santacruz-Toloza,
      L., Strasburg, G. M., and Hamilton, S. L. (1999) Biochemistry 38, 8532-8537). The
      sequence between these two tryptic sites is AVVACFR. Alkylation of RYR1 with N
      ethylmaleimide (NEM) blocks both (35)S-apocalmodulin binding and oxidation
      induced intersubunit cross-linking. In the current work, we demonstrate that both
      cysteines needed for the oxidation-induced intersubunit cross-link are protected
      from alkylation with N-ethylmaleimide by bound calmodulin. We also show, using N
      terminal amino acid sequencing together with analysis of the distribution of
      [(3)H]NEM labeling with each sequencing cycle, that cysteine 3635 of RYR1 is
      rapidly labeled by NEM and that this labeling is blocked by bound calmodulin. We
      propose that cysteine 3635 is located at an intersubunit contact site that is
      close to or within a calmodulin binding site. These findings suggest that
      calmodulin and oxidation modulate RYR1 activity by regulating intersubunit
      interactions in a mutually exclusive manner and that these interactions involve
      cysteine 3635.

PMID- 10601233
TI  - Fidelity and processivity of Saccharomyces cerevisiae DNA polymerase eta.
AB  - The yeast RAD30 gene functions in error-free replication of UV-damaged DNA, and
      RAD30 encodes a DNA polymerase, pol eta, that has the ability to efficiently and
      correctly replicate past a cis-syn-thymine-thymine dimer in template DNA. To
      better understand the role of pol eta in damage bypass, we examined its fidelity
      and processivity on nondamaged DNA templates. Steady-state kinetic analyses of
      deoxynucleotide incorporation indicate that pol eta has a low fidelity,
      misincorporating deoxynucleotides with a frequency of about 10(-2) to 10(-3).
      Also pol eta has a low processivity, incorporating only a few nucleotides before
      dissociating. We suggest that pol eta's low fidelity reflects a flexibility in
      its active site rendering it more tolerant of DNA damage, while its low
      processivity limits its activity to reduce errors.

PMID- 10601234
TI  - The xenopus Suc1/Cks protein promotes the phosphorylation of G(2)/M regulators.
AB  - The entry into mitosis is controlled by Cdc2/cyclin B, also known as maturation
      or M-phase promoting factor (MPF). In Xenopus egg extracts, the inhibitory
      phosphorylations of Cdc2 on Tyr-15 and Thr-14 are controlled by the phosphatase
      Cdc25 and the kinases Myt1 and Wee1. At mitosis, Cdc25 is activated and Myt1 and
      Wee1 are inactivated through phosphorylation by multiple kinases, including Cdc2
      itself. The Cdc2-associated Suc1/Cks1 protein (p9) is also essential for entry of
      egg extracts into mitosis, but the molecular basis of this requirement has been
      unknown. We find that p9 strongly stimulates the regulatory phosphorylations of
      Cdc25, Myt1, and Wee1 that are carried out by the Cdc2/cyclin B complex.
      Overexpression of the prolyl isomerase Pin1, which binds to the
      hyperphosphorylated forms of Cdc25, Myt1, and Wee1 found at M-phase, is known to
      block the initiation of mitosis in egg extracts. We have observed that Pin1
      specifically antagonizes the stimulatory effect of p9 on phosphorylation of Cdc25
      by Cdc2/cyclin B. This observation could explain why overexpression of Pin1
      inhibits mitotic initiation. These findings suggest that p9 promotes the entry
      into mitosis by facilitating phosphorylation of the key upstream regulators of
      Cdc2.

PMID- 10601235
TI  - Intracellular signaling of angiotensin II-induced p70 S6 kinase phosphorylation
      at Ser(411) in vascular smooth muscle cells. Possible requirement of epidermal
      growth factor receptor, Ras, extracellular signal-regulated kinase, and Akt.
AB  - Activation of p70 S6 kinase (p70(S6K)) by growth factors requires multiple signal
      inputs involving phosphoinositide 3-kinase (PI3K), its effector Akt, and an
      unidentified kinase that phosphorylates Ser/Thr residues (Ser(411), Ser(418),
      Ser(424), and Thr(421)) clustered at its autoinhibitory domain. However, the
      mechanism by which G protein-coupled receptors activate p70(S6K) remains largely
      uncertain. By using vascular smooth muscle cells in which we have demonstrated
      Ras/extracellular signal-regulated kinase (ERK) activation through Ca(2+)
      dependent, epidermal growth factor (EGF) receptor transactivation by G(q)-coupled
      angiotensin II (Ang II) receptor, we present a unique cross-talk required for
      Ser(411) phosphorylation of p70(S6K) by Ang II. Both p70(S6K) Ser(411) and Akt
      Ser(473) phosphorylation by Ang II appear to involve EGF receptor transactivation
      and were inhibited by dominant-negative Ras, whereas the phosphorylation of
      p70(S6K) and ERK but not Akt was sensitive to the MEK inhibitor. By contrast, the
      phosphorylation of p70(S6K) and Akt but not ERK was sensitive to PI3K inhibitors.
      Similar inhibitory pattern on these phosphorylation sites by EGF but not insulin
      was observed. Taken together with the inhibition of Ang II-induced p70(S6K)
      activation by dominant-negative Ras and the MEK inhibitor, we conclude that Ang
      II-initiated activation of p70(S6K) requires both ERK cascade and PI3K/Akt
      cascade that bifurcate at the point of EGF receptor-dependent Ras activation.

PMID- 10601236
TI  - The role of multiubiquitination in dislocation and degradation of the alpha
      subunit of the T cell antigen receptor.
AB  - Unassembled alpha subunits of the T cell receptor (TCRalpha) are degraded by
      proteasomes following their dislocation from the endoplasmic reticulum membrane.
      We previously demonstrated that a variant of TCRalpha lacking lysines (KalphaR)
      is degraded by this pathway with kinetics indistinguishable from those of the
      wild type protein (Yu, H., Kaung, G., Kobayashi, S., and Kopito, R. R. (1997) J.
      Biol. Chem. 272, 20800-20804), demonstrating that ubiquitination on lysines is
      not required for TCRalpha degradation by the proteasome. Here, we show that
      dislocation and degradation of TCRalpha and KalphaR are suppressed by dominant
      negative ubiquitin coexpression and by mutations in the ubiquitin activating
      enzyme, indicating that their degradation requires a functional ubiquitin
      pathway. A cytoplasmic TCRalpha variant that mimics a dislocated degradation
      intermediate was degraded 5 times more rapidly than full-length TCRalpha,
      suggesting that dislocation from the endoplasmic reticulum membrane is the rate
      limiting step in TCRalpha degradation. We conclude that ubiquitination is
      required both for dislocation and for targeting TCRalpha chains to the
      proteasome.

PMID- 10601237
TI  - Membrane environment alters the conformational structure of the recombinant human
      prion protein.
AB  - The prion protein (PrP) in a living cell is associated with cellular membranes.
      However, all previous biophysical studies with the recombinant prion protein have
      been performed in an aqueous solution. To determine the effect of a membrane
      environment on the conformational structure of PrP, we studied the interaction of
      the recombinant human prion protein with model lipid membranes. The protein was
      found to bind to acidic lipid-containing membrane vesicles. This interaction is
      pH-dependent and becomes particularly strong under acidic conditions.
      Spectroscopic data show that membrane binding of PrP results in a significant
      ordering of the N-terminal part of the molecule. The folded C-terminal domain, on
      the other hand, becomes destabilized upon binding to the membrane surface,
      especially at low pH. Overall, these results show that the conformational
      structure and stability of the recombinant human PrP in a membrane environment
      are substantially different from those of the free protein in solution. These
      observations have important implications for understanding the mechanism of the
      conversion between the normal (PrP(C)) and pathogenic (PrP(Sc)) forms of prion
      protein.

PMID- 10601238
TI  - Identification and functional characterization of a novel, tissue-specific NAD(+)
      dependent isocitrate dehydrogenase beta subunit isoform.
AB  - To understand the interactions and functional role of each of the three
      mitochondrial NAD(+)-dependent isocitrate dehydrogenase (IDH) subunits (alpha,
      beta, and gamma), we have characterized human cDNAs encoding two beta isoforms
      (beta(1) and beta(2)) and the gamma subunit. Analysis of deduced amino acid
      sequences revealed that beta(1) and beta(2) encode 349 and 354 amino acids,
      respectively, and the two isoforms only differ in the most carboxyl 28 amino
      acids. The gamma cDNA encodes 354 amino acids and is almost identical to monkey
      IDHgamma. Northern analyses revealed that the smaller beta(2) transcript (1.3
      kilobases) is primarily expressed in heart and skeletal muscle, whereas the
      larger beta(1) mRNA (1.6 kilobases) is prevalent in nonmuscle tissues. Sequence
      analysis of the IDHbeta gene indicates that the difference in the C-terminal 28
      amino acids between beta(1) and beta(2) proteins results from alternative
      splicing of a single transcript. Among the various combinations of human IDH
      subunits co-expressed in bacteria, alphabetagamma, alphabeta, and alphagamma
      combinations exhibited significant amounts of IDH activity, whereas subunits
      produced alone and betagamma showed no detectable activity. These data suggest
      that the alpha is the catalytic subunit and that at least one of the other two
      subunits plays an essential supporting role for activity. Substitution of beta(1)
      with beta(2) in the co-expression system lowered the pH optimum for IDH activity
      from 8.0 to 7.6. This difference in optimal pH was analogous to what was observed
      in mouse kidney and brain (beta(1) prevalent; optimal pH 8.0) versus heart
      (beta(2) prevalent; pH 7.6) mitochondria. Experiments with a specially designed
      splicing reporter construct stably transfected into HT1080 cells indicate that
      acidic conditions favor a splicing pattern responsible for the muscle- and heart
      specific beta(2) isoform. Taken together, these data indicate a regulatory role
      of IDHbeta isoforms in determining the pH optimum for IDH activity through the
      tissue-specific alternative splicing.

PMID- 10601239
TI  - Identification of the endoplasmic reticulum targeting signal in vesicle
      associated membrane proteins.
AB  - The vesicle-associated membrane proteins (Vamp(s)) function as soluble N
      ethylmaleimide-sensitive factor attachment receptor proteins in the intracellular
      trafficking of vesicles. The membrane attachment of Vamps requires a carboxyl
      terminal hydrophobic sequence termed an insertion sequence. Unlike other
      insertion sequence-containing proteins, targeting of the highly homologous Vamp1
      and Vamp2 to the endoplasmic reticulum requires ATP and a membrane-bound
      receptor. To determine if this mechanism of targeting to the endoplasmic
      reticulum extends to other Vamps, we compared the membrane binding of Vamp1 and
      Vamp2 with the distantly related Vamp8. Similar to the other Vamps, Vamp8
      requires both ATP and a membrane component to target to the endoplasmic
      reticulum. Furthermore, binding curves for the three Vamps overlap, suggesting a
      common receptor-mediated process. We identified a minimal endoplasmic reticulum
      targeting domain that is both necessary and sufficient to confer receptor
      mediated, ATP-dependent, binding of a heterologous protein to microsomes.
      Surprisingly, this conserved sequence includes four positively charged amino
      acids spaced along an amphipathic sequence, which unlike the carboxyl-terminal
      targeting sequence in mitochondrial Vamp isoforms, is amino-terminal to the
      insertion sequence. Because Vamps do not bind to phospholipid vesicles, it is
      likely that these residues mediate an interaction with a protein, rather than
      bind to acidic phospholipids. Therefore, we suggest that a bipartite motif is
      required for the specific targeting and integration of Vamps into the endoplasmic
      reticulum with receptor-mediated recognition of specifically configured positive
      residues leading to the insertion of the hydrophobic tail into the membrane.

PMID- 10601240
TI  - Glucose regulation of free Ca(2+) in the endoplasmic reticulum of mouse
      pancreatic beta cells.
AB  - Free Ca(2+) was measured in organelles of individual mouse pancreatic beta cells
      loaded with the low affinity indicator furaptra. After removal of cytoplasmic
      indicator by controlled digitonin permeabilization the organelle Ca(2+) was
      located essentially in the endoplasmic reticulum (ER), >90% being sensitive to
      inhibition of sarco(endo)plasmic reticulum Ca(2+)-ATPases. The Ca(2+)
      accumulation in the ER of intact beta cells depended in a hyperbolic fashion on
      the glucose concentration with half-maximal and maximal filling at 5.5 and >20
      mM, respectively. Also elevation of cytoplasmic Ca(2+) by K(+) depolarization
      significantly enhanced the Ca(2+) accumulation. In permeabilized beta cells 1-3
      mM ATP caused rapid Ca(2+) filling of the ER reaching almost 500 microM. At 50
      nM, Ca(2+) ER became half-maximally filled at 45 microM ATP, whereas only 3.5
      microM ATP was required at 200 nM Ca(2+). Inositol 1,4,5-trisphosphate induced a
      rapid release of about 65% of the ER Ca(2+), and its precursor
      phosphatidylinositol 4,5-bisphosphate was found to slowly mobilize 75% by another
      mechanism. It is concluded that glucose is an efficient stimulator of Ca(2+)
      uptake in the ER of pancreatic beta cells both by increasing ATP and cytoplasmic
      Ca(2+). Because physiological concentrations of cytoplasmic ATP are in the mM
      range, Ca(2+) sequestration can be anticipated to be modulated by factors
      reducing its ATP sensitivity.

PMID- 10601241
TI  - Somatostatin increases glucocorticoid binding and signaling in macrophages by
      blocking the calpain-specific cleavage of Hsp 90.
AB  - Somatostatin has direct anti-inflammatory actions and participates in the anti
      inflammatory actions of glucocorticoids, but the mechanisms underlying this
      regulation remain poorly understood. The objective of this study was to evaluate
      whether somatostatin increases glucocorticoid responsiveness by up-regulating
      glucocorticoid receptor (GR) expression and signaling. Somatostatin promoted a
      time- and dose-dependent increase in [(3)H]dexamethasone binding to RAW 264.7
      macrophages. Cell exposure to 10 nM somatostatin for 18 h promoted a 2-fold
      increase in the number of GR sites per cell without significant modification of
      the affinity. Analysis of GR heterocomplex components demonstrated that
      somatostatin increased the level of heat shock protein (Hsp) 90, whereas the
      level of GR remained almost unchanged. The increase in Hsp 90 was associated with
      a decrease in the cleavage of its carboxyl-terminal domain. Evidence for the
      involvement of calpain inhibition in this process was obtained by the
      demonstration that 1) somatostatin induced a dose-dependent decrease in calpain
      activity and 2) calpain inhibitors, calpain inhibitor I and calpeptin, both
      abolished the cleavage of Hsp 90 and induced a dose-dependent increase in
      [(3)H]dexamethasone binding. Increases in glucocorticoid binding after
      somatostatin treatment were associated with similar increases in the ability of
      GR to transactivate a minimal promoter containing two glucocorticoid response
      elements (GRE) and to interfere with the activation of nuclear factor-kappaB (NF
      kappaB). Thus, the present findings indicate that somatostatin increases
      glucocorticoid binding and signaling by limiting the calpain-specific cleavage of
      GR-associated Hsp 90. This mechanism may represent a novel target for
      intervention to increase glucocorticoid responsiveness.

PMID- 10601242
TI  - Rescue of exocytosis in botulinum toxin A-poisoned chromaffin cells by expression
      of cleavage-resistant SNAP-25. Identification of the minimal essential C-terminal
      residues.
AB  - Botulinum neurotoxin (BoNT) types A and B selectively block exocytosis by
      cleavage of SNAP-25 and synaptobrevin, respectively; in humans, many months are
      required for full recovery from the resultant neuromuscular paralysis. To
      decipher the molecular basis for such prolonged poisoning, intoxication in adreno
      chromaffin cells was monitored over 2 months. Exocytosis from BoNT/B-treated
      cells resumed after 56 days because of the appearance of intact synaptobrevin.
      However, inhibition continued in BoNT/A-treated cells, throughout the same
      interval, with a continued predominance of cleaved SNAP-25-(1-197) over the
      intact protein. When recovery from poisoning was attempted by transfection of the
      latter cells with the gene encoding full-length SNAP-25-(1-206), no restoration
      of exocytosis ensued even after 3 weeks. To ascertain if this failure was because
      of the persistence of the toxin's protease activity, the cells were transfected
      with BoNT/A-resistant SNAP-25 constructs; importantly, exocytosis was rescued. C
      terminal truncation of the toxin-insensitive SNAP-25 revealed that residues 1
      201, 1-202, 1-203 afforded a significant return of exocytosis, unlike shorter
      forms 1-197, -198, -199, or -200; accordingly, mutants M202A or L203A of full
      length SNAP-25 rescued secretion. These findings give insights into the C
      terminal functional domain of SNAP-25, demonstrate the longevity of BoNT/A
      protease, and provide the prospect of a therapy for botulism.

PMID- 10601243
TI  - Mutational analysis of the binding site residues of the bovine cation-dependent
      mannose 6-phosphate receptor.
AB  - Mannose 6-phosphate receptors (MPRs) deliver soluble acid hydrolases to the
      lysosome in higher eukaryotic cells. The two MPRs, the cation-dependent MPR (CD
      MPR) and the insulin-like growth factor II/cation-independent MPR, carry out this
      process by binding with high affinity to mannose 6-phosphate residues found on
      the N-linked oligosaccharides of their ligands. To elucidate the key amino acids
      involved in conveying this carbohydrate specificity, site-directed mutagenesis
      studies were conducted on the extracytoplasmic domain of the bovine CD-MPR.
      Single amino acid substitutions of the residues that form the binding pocket were
      generated, and the mutant constructs were expressed in transiently transfected
      COS-1 cells. Following metabolic labeling, mutant CD-MPRs were tested for their
      ability to bind pentamannosyl phosphate-containing affinity columns. Of the eight
      amino acids mutated, four (Gln-66, Arg-111, Glu-133, and Tyr-143) were found to
      be essential for ligand binding. In addition, mutation of the single histidine
      residue, His-105, within the binding site diminished the binding of the receptor
      to ligand, but did not eliminate the ability of the CD-MPR to release ligand
      under acidic conditions.

PMID- 10601244
TI  - Cholesteryl ester transfer protein corrects dysfunctional high density
      lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol
      acyltransferase transgenic mice.
AB  - Expression of human lecithin cholesterol acyltransferase (LCAT) in mice (LCAT-Tg)
      leads to increased high density lipoprotein (HDL) cholesterol levels but
      paradoxically, enhanced atherosclerosis. We have hypothesized that the absence of
      cholesteryl ester transfer protein (CETP) in LCAT-Tg mice facilitates the
      accumulation of dysfunctional HDL leading to impaired reverse cholesterol
      transport and the development of a pro-atherogenic state. To test this hypothesis
      we cross-bred LCAT-Tg with CETP-Tg mice. On both regular chow and high fat, high
      cholesterol diets, expression of CETP in LCAT-Tg mice reduced total cholesterol (
      39% and -13%, respectively; p < 0.05), reflecting a decrease in HDL cholesterol
      levels. CETP normalized both the plasma clearance of [(3)H]cholesteryl esters
      ([(3)H]CE) from HDL (fractional catabolic rate in days(-1): LCAT-Tg = 3.7 +/-
      0.34, LCATxCETP-Tg = 6.1 +/- 0.16, and controls = 6.4 +/- 0.16) as well as the
      liver uptake of [(3)H]CE from HDL (LCAT-Tg = 36%, LCATxCETP-Tg = 65%, and
      controls = 63%) in LCAT-Tg mice. On the pro-atherogenic diet the mean aortic
      lesion area was reduced by 41% in LCATxCETP-Tg (21.2 +/- 2.0 micrometer(2) x
      10(3)) compared with LCAT-Tg mice (35.7 +/- 2.0 micrometer(2) x 10(3); p <
      0.001). Adenovirus-mediated expression of scavenger receptor class B (SR-BI)
      failed to normalize the plasma clearance and liver uptake of [(3)H]CE from LCAT
      Tg HDL. Thus, the ability of SR-BI to facilitate the selective uptake of CE from
      LCAT-Tg HDL is impaired, indicating a potential mechanism leading to impaired
      reverse cholesterol transport and atherosclerosis in these animals. We conclude
      that CETP expression reduces atherosclerosis in LCAT-Tg mice by restoring the
      functional properties of LCAT-Tg mouse HDL and promoting the hepatic uptake of
      HDL-CE. These findings provide definitive in vivo evidence supporting the
      proposed anti-atherogenic role of CETP in facilitating HDL-mediated reverse
      cholesterol transport and demonstrate that CETP expression is beneficial in pro
      atherogenic states that result from impaired reverse cholesterol transport.

PMID- 10601245
TI  - Integrin leukocyte function-associated antigen-1-mediated cell binding can be
      activated by clustering of membrane rafts.
AB  - The leukocyte function-associated antigen-1 (LFA-1) integrin (CD11a/CD18) is an
      important adhesion molecule for lymphocyte migration and the initiation of an
      immune response. At the cell surface, LFA-1 activity can be regulated by divalent
      cations that enhance receptor affinity but also by membrane clustering induced by
      treatment of cells with substances such as phorbol esters. Membrane clustering
      leads to increased LFA-1 avidity. We report here that LFA-1-mediated binding of
      mouse thymocytes or activated T lymphocytes to intercellular adhesion molecule 1
      can be rapidly induced by clustering of membrane rafts using antibodies to the
      glycosylphophatidylinositol-anchored molecule CD24 or cholera toxin (CTx). CD24
      and CD18 were found to co-localize in rafts and cross-linking with CTx lead to
      enhanced LFA-1 clustering. We observed that disruption of raft integrity by
      lowering the membrane cholesterol content abolished the CTx and the phorbol 12
      myristate 13-acetate-induced LFA-1 binding but left the ability to activate LFA-1
      with Mg(2+)/EGTA unimpaired. In contrast to activation with Mg(2+)/EGTA,
      activation via raft clustering was dependent on PI3-kinase, required cytoskeletal
      mobility, and was accompanied by Tyr phosphorylation of a 18-kDa protein. Our
      results support the notion that rafts as preformed adhesion platforms could be
      important for the rapid regulation of lymphocyte adhesion.

PMID- 10601246
TI  - Defining proximity relationships in the tertiary structure of the dopamine
      transporter. Identification of a conserved glutamic acid as a third coordinate in
      the endogenous Zn(2+)-binding site.
AB  - Recently, we have described a distance constraint in the unknown tertiary
      structure of the human dopamine transporter (hDAT) by identification of two
      histidines, His(193) in the second extracellular loop and His(375) at the top of
      transmembrane (TM) 7, that form two coordinates in an endogenous, high affinity
      Zn(2+)-binding site. To achieve further insight into the tertiary organization of
      hDAT, we set out to identify additional residues involved in Zn(2+) binding and
      subsequently to engineer artificial Zn(2+)-binding sites. Ten aspartic acids and
      glutamic acids, predicted to be on the extracellular side, were mutated to
      asparagine and glutamine, respectively. Mutation of Glu(396) (E396Q) at the top
      of TM 8 increased the IC(50) value for Zn(2+) inhibition of [(3)H]dopamine uptake
      from 1.1 to 530 microM and eliminated Zn(2+)-induced potentiation of [(3)H]WIN
      35,428 binding. These data suggest that Glu(396) is involved in Zn(2+) binding to
      hDAT. Importantly, Zn(2+) sensitivity was preserved following substitution of
      Glu(396) with histidine, indicating that the effect of mutating Glu(396) is not
      an indirect effect because of the removal of a negatively charged residue. The
      common participation of Glu(396), His(193), and His(375) in binding the small
      Zn(2+) ion implies their proximity in the unknown tertiary structure of hDAT. The
      close association between TM 7 and 8 was further established by engineering of a
      Zn(2+)-binding site between His(375) and a cysteine inserted in position 400 in
      TM 8. Summarized, our data define an important set of proximity relationships in
      hDAT that should prove an important template for further exploring the molecular
      architecture of Na(+)/Cl(-)-dependent neurotransmitter transporters.

PMID- 10601247
TI  - Substitution of pyridoxal 5'-phosphate in D-serine dehydratase from Escherichia
      coli by cofactor analogues provides information on cofactor binding and
      catalysis.
AB  - D-Serine dehydratase (DSD) is a pyridoxal 5'-phosphate-dependent enzyme that
      catalyzes the conversion of D-serine to pyruvate and ammonia. Spectral studies of
      enzyme species where the natural cofactor was substituted by pyridoxal 5'-sulfate
      (PLS), pyridoxal 5-deoxymethylene phosphonate (PDMP), and pyridoxal 5'-phosphate
      monomethyl ester (PLPMe) were used to gain insight into the structural basis for
      binding of cofactor and substrate analogues. PDMP-DSD exhibits 35% of the
      activity of the native enzyme, whereas PLS-DSD and PLPMe-DSD are catalytically
      inactive. The emission spectrum of native DSD when excited at 280 nm shows maxima
      at 335 and 530 nm. The energy transfer band at 530 nm is very likely generated as
      a result of the proximity of Trp-197 to the protonated internal Schiff base. The
      cofactor analogue-reconstituted DSD species exhibit emission intensities
      decreasing from PLS-DSD, to PLPMe-DSD, and PDMP-DSD, when excited at 415 nm.
      Large increases in fluorescence intensity at 530 (540) nm can be observed for
      cofactor analogue-reconstituted DSD in the presence of substrate analogues when
      excited at 415 nm. In the absence and presence of substrate analogues, virtually
      identical far UV CD spectra were obtained for all DSD species. The visible CD
      spectra of native DSD, PDMP-DSD, and PLS-DSD exhibit a band centered on the
      visible absorption maximum with nearly identical intensity. Addition of substrate
      analogues to native and cofactor analogue-reconstituted DSD species results in
      most cases in a decrease or elimination of ellipticity. The results are
      interpreted in terms of local conformational changes and/or changes in the
      orientation of the bound cofactor (analogue).

PMID- 10601248
TI  - ATP treatment of human monocytes promotes caspase-1 maturation and
      externalization.
AB  - Mechanisms that regulate conversion of prointerleukin-1beta (pro-IL-1beta) to its
      mature form by the cysteine protease caspase-1 are not well understood. In this
      study, we demonstrate that mature caspase-1 subunits are produced when human
      monocytes are treated with ATP and, like mature IL-1beta, are released
      extracellularly. Characterization of the pharmacological sensitivity of this
      stimulus-coupled response revealed that some caspase-1 inhibitors allow pro-IL
      1beta secretion, whereas others do not. Two nonselective alkylating agents, N
      ethylmaleimide and phenylarsine oxide, also blocked maturation and release of pro
      IL-1beta. Two inhibitors of anion transport, glyburide and ethacrynic acid,
      blocked maturation of both caspase-1 and pro-IL-1beta and prevented release of
      the propolypeptides. Procaspase-3 was detected in monocyte extracts, but its
      proteolytic activation was not efficient in the presence of ATP. Maturation of
      procaspase-1 and release of the mature enzyme subunits therefore accompany
      stimulus-coupled human monocyte IL-1 post-translational processing. Agents that
      appear to selectively inhibit mature caspase-1 do not prevent ATP-treated cells
      from releasing their cytosolic components. On the other hand, anion transport
      inhibitors and alkylating agents arrest ATP-treated monocytes in a state where
      membrane latency is maintained. The data provided support the hypothesis that
      stimulus-coupled IL-1 post-translational processing involves a commitment to cell
      death.

PMID- 10601249
TI  - A gain of superoxide dismutase (SOD) activity obtained with CCS, the copper
      metallochaperone for SOD1.
AB  - The incorporation of copper ions into the cytosolic superoxide dismutase (SOD1)
      is accomplished in vivo by the action of the copper metallochaperone CCS (copper
      chaperone for SOD1). Mammalian CCS is comprised of three distinct protein
      domains, with a central region exhibiting remarkable homology (approximately 50%
      identity) to SOD1 itself. Conserved in CCS are all the SOD1 zinc binding ligands
      and three of four histidine copper binding ligands. In CCS the fourth histidine
      is replaced by an aspartate (Asp(200)). Despite this conservation of sequence
      between SOD1 and CCS, CCS exhibited no detectable SOD activity. Surprisingly,
      however, a single D200H mutation, targeting the fourth potential copper ligand in
      CCS, granted significant superoxide scavenging activity to this metallochaperone
      that was readily detected with CCS expressed in yeast. This mutation did not
      inhibit the metallochaperone capacity of CCS, and in fact, D200H CCS appears to
      represent a bifunctional SOD that can self-activate itself with copper. The
      aspartate at CCS position 200 is well conserved among mammalian CCS molecules,
      and we propose that this residue has evolved to preclude deleterious reactions
      involving copper bound to CCS.

PMID- 10601250
TI  - Low cytoplasmic [Ca(2+)] activates I(CRAC) independently of global Ca(2+) store
      depletion in RBL-1 cells.
AB  - Release of Ca(2+) from inositol (1,4,5)-trisphosphate-sensitive Ca(2+) stores
      causes "capacitative calcium entry," which is mediated by the so-called "Ca(2+)
      release-activated Ca(2+) current" (I(CRAC)) in RBL-1 cells. Refilling of the
      Ca(2+) stores or high cytoplasmic [Ca(2+)] ([Ca(2+)](cyt)) inactivate I(CRAC).
      Here we address the question if also [Ca(2+)](cyt) lower than the resting
      [Ca(2+)](cyt) influences store-operated channels. We therefore combined patch
      clamp and mag fura-2 fluorescence methods to determine simultaneously both
      I(CRAC) and [Ca(2+)] within Ca(2+) stores of RBL-1 cells ([Ca(2+)](store)). We
      found that low [Ca(2+)](cyt) in the range of 30-50 nM activates I(CRAC) and
      Ca(2+) influx spontaneously and independently of global Ca(2+) store depletion,
      while elevation of [Ca(2+)](cyt) to the resting [Ca(2+)](cyt) (100 nM) resulted
      in store dependence of I(CRAC) activation. We conclude that spontaneous
      activation of I(CRAC) by low [Ca(2+)](cyt) could serve as a feedback mechanism
      keeping the resting [Ca(2+)](cyt) constant.

PMID- 10601251
TI  - Profilin promotes barbed-end actin filament assembly without lowering the
      critical concentration.
AB  - The mechanism of profilin-promoted actin polymerization has been systematically
      reinvestigated. Rates of barbed-end elongation onto Spectrin.4.1. Actin seeds
      were measured by right angle light scattering to avoid confounding effects of
      pyrenyl-actin, and KINSIM was used to analyze elongation progress curves. Without
      thymosin-beta4, both actin and Profilin. Actin (P.A) are competent in barbed-end
      polymerization, and kinetic simulations yielded the same bimolecular rate
      constant ( approximately 10 x 10(6) M(-1) s(-1)) for actin monomer or Profilin.
      Actin. When measured in the absence of profilin, actin assembly curves over a 0.7
      4 microM thymosin-beta4 concentration range fit a simple monomer sequestering
      model (1 microM K(D) for Thymosin-beta4. Actin). The corresponding constant for
      thymosin-beta4.pyrenyl-Actin, however, was significantly higher ( approximately 9
      10 microM), suggesting that the fluorophore markedly weakens binding to thymosin
      beta4. With solutions of actin (2 microM) and thymosin-beta4 (2 or 4 microM), the
      barbed-end assembly rate rose with increasing profilin concentration (0.7-2
      microM). Actin assembly in presence of thymosin-beta4 and profilin fit a simple
      thermodynamic energy cycle, thereby disproving an earlier claim (D. Pantaloni and
      M.-F. Carlier (1993) Cell 75, 1007-1014) that profilin promotes nonequilibrium
      filament assembly by accelerating hydrolysis of filament-bound ATP. Our findings
      indicate that profilin serves as a polymerization catalyst that captures actin
      monomers from Thymosin-beta4. Actin and ushers actin as a Profilin. Actin complex
      onto growing barbed filament ends.

PMID- 10601252
TI  - The CorA Mg(2+) transport protein of Salmonella typhimurium. Mutagenesis of
      conserved residues in the second membrane domain.
AB  - Salmonella typhimurium CorA is the archetypal member of the largest family of
      Mg(2+) transporters of the Bacteria and Archaea. It contains three transmembrane
      segments. There are no conserved charged residues within these segments
      indicating electrostatic interactions are not used in Mg(2+) transport through
      CorA. Previous mutagenesis studies of CorA revealed a single face of the third
      transmembrane segment that is important for Mg(2+) transport. In this study, we
      mutated hydroxyl-bearing and other conserved residues in the second transmembrane
      segment to identify residues involved in transport. Residues Ser(260), Thr(270),
      and Ser(274) appear to be important for transport and are oriented such that they
      would also line a face of an alpha-helix. In addition, the sequence
      (276)YGMNF(280), found in virtually all CorA homologues, is critical for CorA
      function because even conservative mutations are not tolerated at these residues.
      Finally, mutations of residues in the second transmembrane segment, unlike those
      in the third transmembrane segment, revealed cooperative behavior for the influx
      of Mg(2+). We conclude that the second transmembrane segment forms a major part
      of the Mg(2+) pore with the third transmembrane segment of CorA.

PMID- 10601253
TI  - Different regions of the immunophilin FKBP52 determine its association with the
      glucocorticoid receptor, hsp90, and cytoplasmic dynein.
AB  - FKBP52 is a high molecular mass immunophilin possessing peptidylprolyl isomerase
      (PPIase) activity that is inhibited by the immunosuppressant drug FK506. FKBP52
      is a component of steroid receptor.hsp90 heterocomplexes, and it binds to hsp90
      via a region containing three tetratricopeptide repeats (TPRs). Here we
      demonstrate by cross-linking of the purified proteins that there is one binding
      site for FKBP52/dimer of hsp90. This accounts for the common heterotetrameric
      structure of native receptor heterocomplexes being 1 molecule of receptor, 2
      molecules of hsp90, and 1 molecule of a TPR domain protein. Immunoadsorption of
      FKBP52 from reticulocyte lysate also yields co-immunoadsorption of cytoplasmic
      dynein, and we show that co-immunoadsorption of dynein is competed by a fragment
      of FKBP52 containing its PPIase domain, but not by a TPR domain fragment that
      blocks FKBP52 binding to hsp90. Using purified proteins, we also show that FKBP52
      binds directly to the hsp90-free glucocorticoid receptor. Because neither the
      PPIase fragment nor the TPR fragment affects the binding of FKBP52 to the
      glucocorticoid receptor under conditions in which they block FKBP52 binding to
      dynein or hsp90, respectively, different regions of FKBP52 must determine its
      association with these three proteins.

PMID- 10601254
TI  - The role of the Smad3 protein in phorbol ester-induced promoter expression.
AB  - The Sp1 transcription factor plays an important role in mediating the p53
      independent activation of the p21(WAF1) (WAF1) promoter by phorbol 12-myristate13
      acetate (PMA) in hematopoietic cells. Using GAL4-Sp1 fusion proteins and a
      luciferase reporter, PMA is shown to activate the transcriptional activity of Sp1
      independent of the WAF1 promoter. This activation does not require the Ser/Thr
      rich region of Sp1 and can be mediated by 41 amino acids (152-193) of Sp1 that
      are important for the interaction with human TAF130. Because transforming growth
      factor-beta enhances WAF1 promoter activity through both Sp1 and Smad proteins,
      the role of Smads in PMA transcriptional activation was examined. PMA addition to
      hematopoietic cells was found to activate a GAL4/Smad-dependent promoter and the
      transforming growth factor-beta-responsive promoter, p3TP-lux. Immunofluorescence
      data demonstrate that PMA addition to hematopoietic cells induces the
      translocation of Smad3 to the nucleus. However, Smad3 does not stimulate the WAF1
      promoter, but rather slightly inhibits the PMA-mediated induction of
      transcription from this upstream region. Additionally, transfection of Smad3 did
      not enhance the activation of GAL4/Sp1 by PMA. These results demonstrate that,
      while PMA can activate Smad-mediated transcription, Smad proteins do not appear
      to play a major role in the PMA induction of the WAF1 promoter.

PMID- 10601255
TI  - Catabolism of factor VIIa bound to tissue factor in fibroblasts in the presence
      and absence of tissue factor pathway inhibitor.
AB  - Vascular injury leads to the exposure of blood to fibroblasts and smooth muscle
      cells within the vessel wall. These cells constitutively express tissue factor
      (TF), the cellular receptor for plasma clotting factor VIIa (FVIIa). Formation of
      TF.FVIIa complexes on cell surfaces triggers the blood coagulation cascade. In
      the present study, we have investigated the fate of TF.FVIIa complexes formed on
      the cell surface of fibroblasts in the presence and absence of plasma inhibitor,
      tissue factor pathway inhibitor (TFPI). FVIIa bound to TF on the cell surface was
      internalized and degraded without depleting the cell surface TF antigen and
      activity. TFPI significantly enhanced the TF-specific internalization and
      degradation of FVIIa. TFPI-enhanced internalization and degradation of FVIIa
      requires the C-terminal domain of TFPI and factor Xa. TFPI. Xa-mediated
      internalization of FVIIa was associated with the depletion of TF from the cell
      surface. A majority of the internalized FVIIa was degraded, but a small portion
      of the internalized FVIIa recycles back to the cell surface as an intact protein.
      In addition to TF, other cell surface components, such as low density lipoprotein
      receptor-related protein (LRP) and heparan sulfates, are essential for TFPI.Xa
      induced internalization of FVIIa. Acidification of cytosol, which selectively
      inhibits the endocytotic pathway via coated pits, inhibited TFPI.Xa-mediated
      internalization but not the basal internalization of FVIIa. Overall, our data
      support the concept that FVIIa bound to cell surface TF was endocytosed by two
      different pathways. FVIIa complexed with TF in the absence of the inhibitor was
      internalized via a LRP-independent and probably noncoated pit pathway, whereas
      FVIIa complexed with TF along with the inhibitor was internalized via LRP
      dependent coated pit pathway.

PMID- 10601256
TI  - Replacement of integration host factor protein-induced DNA bending by flexible
      regions of DNA.
AB  - The Escherichia coli integration host factor (IHF) protein is required for site
      specific recombination of bacteriophage lambda DNA. Previously, we had shown that
      alternative modules of static DNA curvature could partially replace IHF in
      recombination. Now we use regions of single-stranded DNA as a flexible tether to
      address whether the function of IHF in recombination is simply to reduce
      persistence length. Although we find that these modules clearly enhance
      recombination in the absence of IHF, they are not perfect replacements. In
      addition, evidence is presented that the efficacy of a flexibility swap is
      specific to a particular IHF site. This may indicate that additional functions
      beyond simple deformation of DNA are required of IHF. During the course of these
      experiments we discovered that these flexible sequences are still specific sites
      for IHF binding and function.

PMID- 10601257
TI  - Tyrosine phosphorylation of alpha-actinin in activated platelets.
AB  - The integrin alpha(IIb)beta(3) mediates tyrosine phosphorylation of a 105-kDa
      protein (pp105) in activated platelets. We have partially purified a 105-kDa
      tyrosine-phosphorylated protein from platelets stimulated with phorbol 12
      myristate 13-acetate and obtained the sequence of an internal 12-mer peptide
      derived from this protein. The sequence was identical to human alpha-actinin
      sequences deposited in the Swiss Protein Database. alpha-Actinin, a 105-kDa
      protein in platelets, was subsequently purified from activated platelets by four
      sequential chromatographic steps. Fractions were analyzed by Western blotting and
      probed with alpha-actinin and anti-phosphotyrosine antibodies. The distribution
      of alpha-actinin and pp105 overlapped throughout the purification. Furthermore,
      in the course of this purification, a 105-kDa tyrosine-phosphorylated protein was
      only detected in fractions that contained alpha-actinin. The purified alpha
      actinin protein was immunoprecipitated with antibodies to phosphotyrosine in the
      absence but not in the presence of phenyl phosphate. alpha-Actinin resolved by
      two-dimensional gel electrophoresis of activated platelet lysates was recognized
      by the antibodies to phosphotyrosine, whereas pretreatment of the platelets with
      bisindolylmaleimide, a protein kinase C inhibitor that prevents tyrosine
      phosphorylation of pp105, inhibited the reactivity of the antibodies to
      phosphotyrosine with alpha-actinin. Taken together, these data demonstrate that a
      fraction of alpha-actinin is tyrosine-phosphorylated in activated platelets.

PMID- 10601258
TI  - Hairpin formation in Tn5 transposition.
AB  - The initial chemical steps in Tn5 transposition result in blunt end cleavage of
      the transposon from the donor DNA. We demonstrate that this cleavage occurs via a
      hairpin intermediate. The first step is a 3' hydrolytic nick by transposase. The
      free 3'OH then attacks the phosphodiester bond on the opposite strand, forming a
      hairpin at the transposon end. In addition to forming precise hairpins, Tn5
      transposase can form imprecise hairpins. This is the first example of imprecise
      hairpin formation on transposon end DNA. To undergo strand transfer, the hairpin
      must to be resolved by a transposase-catalyzed hydrolytic cleavage. We show that
      both precise and imprecise hairpins are opened by transposase. A transposition
      mechanism utilizing a hairpin intermediate allows a single transposase active
      site to cleave both 3' and 5' strands without massive protein/DNA rearrangements.

PMID- 10601259
TI  - Determination of the border between the transmembrane and cytoplasmic domains of
      human integrin subunits.
AB  - In this study we have determined the position of the C-terminal end of the
      transmembrane domains of human integrin subunits (alpha2, alpha5, beta1, beta2)
      in microsomal membranes using the glycosylation mapping technique. In contrast to
      the common view, the transmembrane helices were found to extend roughly to
      Phe(1129) in alpha2, to Phe(1026) in alpha5, to Ile(757) in beta1, and to
      His(728) in beta2. The alpha-carbon of the conserved lysine present near the C
      terminal end of the transmembrane helix (Lys(1125) in alpha2, Lys(1022) in
      alpha5, Lys(752) in beta1, and Lys(724) in beta2) is buried in the plasma
      membrane, and the charged amino group most likely reaches into the polar head
      group region of the lipid bilayer. A possible role for the conserved lysine in
      integrin function is discussed.

PMID- 10601260
TI  - The action of N-terminal acetyltransferases on yeast ribosomal proteins.
AB  - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was
      used to determine the state of N-terminal acetylation of 68 ribosomal proteins
      from a normal strain of Saccharomyces cerevisiae and from the ard1-Delta, nat3
      Delta, and mak3-Delta mutants (), each lacking a catalytic subunit of three
      different N-terminal acetyltransferases. A total 30 of the of 68 ribosomal
      proteins were N-terminal-acetylated, and 24 of these (80%) were NatA substrates,
      unacetylated in solely the ard1-Delta mutant and having mainly Ac-Ser- termini
      and a few with Ac-Ala- or Ac-Thr- termini. Only 4 (13%) were NatB substrates,
      unacetylated in solely the nat3-Delta mutant, and having Ac-Met-Asp- or Ac-Met
      Glu- termini. No NatC substrates were uncovered, e.g. unacetylated in solely mak3
      Delta mutants, consistent with finding that none of the ribosomal proteins had Ac
      Met-Ile-, Ac-Met-Leu-, or Ac-Met-Phe- termini. Interestingly, two new types of
      the unusual NatD substrates were uncovered, having either Ac-Ser-Asp-Phe- or Ac
      Ser-Asp-Ala- termini that were unacetylated in the ard1-Delta mutant, and only
      partially acetylated in the mak3-Delta mutant and, for one case, also only
      partially in the nat3-Delta mutant. We suggest that the acetylation of NatD
      substrates requires not only Ard1p and Nat1p, but also auxiliary factors that are
      acetylated by the Mak3p and Nat3p N-terminal acetyltransferases.

PMID- 10601261
TI  - Isolation and cDNA cloning of a novel galanin-like peptide (GALP) from porcine
      hypothalamus.
AB  - Galanin is a widely distributed neuropeptide with a variety of physiological
      functions. Three galanin receptor subtypes, GALR1, GALR2, and GALR3, have been
      reported. We isolated a novel galanin-like peptide (GALP) from porcine
      hypothalamus by observing its activity for increasing [(35)S]GTPgammaS binding to
      a membrane preparation of GALR2-transfected cells. The peptide had 60 amino acid
      residues and a non-amidated C terminus. The amino acid sequence of GALP-(9-21)
      was completely identical to that of galanin-(1-13). A cloned porcine GALP cDNA
      indicated that GALP was processed from a 120-amino acid GALP precursor protein.
      The structures of rat and human GALP-(1-60) were deduced from cloned cDNA, which
      indicated that the amino acid sequences 1-24 and 41-53 were highly conserved
      between humans, rats, and pigs. Receptor binding studies revealed that porcine
      GALP-(1-60) had a high affinity for the GALR2 receptor (IC(50) = 0.24 nM) and a
      lower affinity for the GALR1 receptor (IC(50) = 4.3 nM). In contrast, galanin
      showed high affinity for the GALR1 (IC(50) = 0.097 nM) and GALR2 receptors
      (IC(50) = 0.48 nM). GALP is therefore an endogenous ligand that preferentially
      binds the GALR2 receptor, whereas galanin is relatively non-selective.

PMID- 10601262
TI  - The neurite retraction induced by lysophosphatidic acid increases Alzheimer's
      disease-like Tau phosphorylation.
AB  - The bioactive phospholipid lysophosphatidic acid (LPA) causes growth cone
      collapse and neurite retraction in neuronal cells. These changes are brought
      about by the action of a cell surface receptor coupled to specific G proteins
      that control morphology and motility through the action of a group of small
      GTPases, the Rho family of proteins. Many studies have focused on actin
      reorganization modulated by Rho-GTPases, but almost no information has been
      obtained concerning microtubular network reorganization after LPA-induced neurite
      retraction. In the present study, we demonstrate an increase in site-specific
      Alzheimer's disease-like Tau phosphorylation during LPA-induced neurite
      retraction in differentiated SY-SH5Y human neuroblastoma cells. The
      phosphorylation state of Tau was inferred from its immunoreactivity with
      antibodies that recognize phosphorylation-sensitive epitopes. The effects of
      specific kinase inhibitors indicate that this phosphorylation is mediated by
      glycogen synthase kinase-3 (GSK-3). In support of this idea, we observed an
      increase of GSK-3 activity upon growth cone collapse. Our results are consistent
      with the hypothesis that activation of GSK-3 occurs in the Rho pathway and may
      represent an important link between microtubules and microfilaments dynamics
      during neuritogenesis and in pathological situations such as Alzheimer's disease.

PMID- 10601263
TI  - Performance of selected microbial pectinases on synthetic monomethyl-esterified
      di- and trigalacturonates.
AB  - Two monomethyl esters of alpha-(1-4)-linked D-galacturonic dimers and three
      monomethyl esters of alpha-(1-4)-linked D-galacturonic acid trimers were
      synthesized chemically and further used as substrates in order to establish the
      substrate specificity of six different endopolygalacturonases from Aspergillus
      niger, one exopolygalacturonase from Aspergillus tubingensis, and four selected
      Erwinia chrysanthemi pectinases; exopolygalacturonan hydrolase X (PehX),
      exopolygalacturonate lyase X (PelX), exopectate lyase W (PelW), and
      oligogalacturonan lyase (Ogl). All A. niger endopolygalacturonases (PGs) were
      unable to hydrolyze the two monomethyldigalacturonates and 2
      methyltrigalacturonate, whereas 1-methyltrigalacturonate was only cleaved by PGI,
      PGII, and PGB albeit at an extremely low rate. The hydrolysis of 3
      methyltrigalacturonate into 2-methyldigalacturonate and galacturonate by all
      endopolygalacturonases demonstrates that these enzymes can accommodate a
      methylgalacturonate at subsite -2. The A. tubingensis exopolygalacturonase
      hydrolyzed the monomethyl-esterified digalacturonates and trigalacturonates
      although at lower rates than for the corresponding oligogalacturonates. 1
      Methyltrigalacturonate was hydrolyzed at the same rate as trigalacturonate which
      demonstrates that the presence of a methyl ester at the third galacturonic acid
      from the nonreducing end does not have any effect on the performance of
      exopolygalacturonase. Of the four E. chrysanthemi pectinases, Ogl was the only
      enzyme able to cleave digalacturonate, whereas all four enzymes cleaved
      trigalacturonate. Ogl does not cleave monomethyl-esterified digalacturonate and
      trigalacturonate in case the second galacturonic acid residue from the reducing
      end is methyl-esterified. PehX did not hydrolyze any of the monomethyl-esterified
      trigalacturonates. The two lyases, PelX and PelW, were both only able to cleave 1
      methyltrigalacturonate into Delta4,5-unsaturated 1-methyldigalacturonate and
      galacturonate.

PMID- 10601264
TI  - Poliovirus RNA-dependent RNA polymerase (3D(pol)). Divalent cation modulation of
      primer, template, and nucleotide selection.
AB  - We have analyzed the divalent cation specificity of poliovirus RNA-dependent RNA
      polymerase, 3D(pol). The following preference was observed: Mn(2+) > Co(2+) >
      Ni(2+) > Fe(2+) > Mg(2+) > Ca(2+) > Cu(2+), and Zn(2+) was incapable of
      supporting 3D(pol)-catalyzed nucleotide incorporation. In the presence of Mn(2+),
      3D(pol) activity was increased by greater than 10-fold relative to that in the
      presence of Mg(2+). Steady-state kinetic analysis revealed that the increased
      activity observed in the presence of Mn(2+) was due, primarily, to a reduction in
      the K(M) value for 3D(pol) binding to primer/template, without any significant
      effect on the K(M) value for nucleotide. The ability of 3D(pol) to catalyze RNA
      synthesis de novo was also stimulated approximately 10-fold by using Mn(2+), and
      the enzyme was now capable of also utilizing a DNA template for primer
      independent RNA synthesis. Interestingly, the use of Mn(2+) as divalent cation
      permitted 3D(pol) activity to be monitored by following extension of 5'-(32)P-end
      labeled, heteropolymeric RNA primer/templates. The kinetics of primer extension
      were biphasic because of the enzyme binding to primer/template in both possible
      orientations. When bound in the incorrect orientation, 3D(pol) was capable of
      efficient addition of nucleotides to the blunt-ended duplex; this activity was
      also apparent in the presence of Mg(2+). In the presence of Mn(2+), 3D(pol)
      efficiently utilized dNTPs, ddNTPs, and incorrect NTPs. On average, three
      incorrect nucleotides could be incorporated by 3D(pol). The ability of 3D(pol) to
      incorporate the correct dNTP, but not the correct ddNTP, was also observed in the
      presence of Mg(2+). Taken together, these results provide the first glimpse into
      the nucleotide specificity and fidelity of the poliovirus polymerase and suggest
      novel alternatives for the design of primer/templates to study the mechanism of
      3D(pol)-catalyzed nucleotide incorporation.

PMID- 10601265
TI  - Cytosolic chaperonin is up-regulated during cell growth. Preferential expression
      and binding to tubulin at G(1)/S transition through early S phase.
AB  - The chaperonin containing t-complex polypeptide 1 (CCT) is a heterooligomeric
      molecular chaperone assisting in the folding of actin, tubulin, and other
      cytosolic proteins. The expression levels of CCT subunits varied among seven
      mouse cell lines tested but showed a close correlation with growth rate. Both the
      CCT protein and mRNA levels in the human promyelolytic cell HL60 decreased
      concomitant with growth arrest during differentiation. More rapid decrease in CCT
      level occurred when the mouse interleukin (IL)-3-dependent myeloid DA3 cells were
      starved for IL-3. Readdition of IL-3 caused rapid resumption of CCT synthesis
      during synchronous growth: the maximum CCT protein and mRNA levels were observed
      at G(1)/S transition through early S phase. The turnover rate of CCT was nearly
      constant regardless of growth. Gel filtration and immunoprecipitation analyses
      indicated that CCT in vivo is associated with tubulin at early S phase, but not
      at G(0)/G(1) phase. These results demonstrated that CCT expression is strongly up
      regulated during cell growth especially from G(1)/S transition to early S phase
      and is primarily controlled at the mRNA level. CCT appears to play important
      roles for cell growth by assisting in the folding of tubulin and other proteins.

PMID- 10601266
TI  - The herpes simplex virus type 1 origin-binding protein. sequence-specific
      activation of adenosine triphosphatase activity by a double-stranded DNA
      containing box I.
AB  - Origin-dependent replication of the herpes simplex virus type 1 genome requires
      the virally encoded origin-binding protein, UL9. UL9 binds specifically to the
      herpes simplex virus type 1 replication origin at two high affinity binding sites
      on the DNA, Boxes I and II. UL9 also has ATP-dependent DNA helicase and DNA
      stimulated ATPase activities that are used to unwind the origin DNA. Origin
      specific binding is mediated by the C-terminal domain (C-domain) of the enzyme.
      ATPase and helicase activities are mediated by the N-terminal domain (N-domain).
      Previous studies have shown that single-stranded DNA is a good coeffector for
      ATPase activity. We have analyzed several DNAs for their ability to stimulate the
      ATPase activity of UL9 and of a truncated UL9 protein (UL9/N) consisting only of
      the N-domain. We report here that duplex Box I DNA specifically and potently
      stimulates the ATPase activity of UL9 but not of UL9/N. We also find that removal
      of the C-domain significantly increases the ATPase activity of UL9. We have
      incorporated these results into a model for initiation in which the C-domain of
      UL9 serves to regulate the enzymatic activity of the N-domain.

PMID- 10601268
TI  - Identification of discriminator base atomic groups that modulate the alanine
      aminoacylation reaction.
AB  - Specific aminoacylation of tRNAs involves activation of an amino acid with ATP
      followed by amino acid transfer to the tRNA. Previous work showed that the
      transfer of alanine from Escherichia coli alanyl-tRNA synthetase to a cognate RNA
      minihelix involves a transition state sensitive to changes in the tRNA acceptor
      stem. Specifically, the "discriminator" base at position 73 of minihelix(Ala) is
      a critical determinant of the transfer step of aminoacylation. This single
      stranded nucleotide has previously been shown by solution NMR to be stacked
      predominantly onto G(1) of the first base pair of the alanine acceptor stem
      helix. In this work, RNA duplex(Ala) variants were prepared to investigate the
      role of specific discriminator base atomic groups in aminoacylation catalytic
      efficiency. Results indicate that the purine structure appears to be important
      for stabilization of the transition state and that major groove elements are more
      critical than those located in the minor groove. This result is in accordance
      with the predicted orientation of a class II synthetase at the end of the
      acceptor helix. In particular, substitution of the exocyclic amino group of A(73)
      with a keto-oxygen resulted in negative discrimination at this site. Taken
      together, these new results are consistent with the involvement of major groove
      atomic groups of the discriminator base in the formation of the transition state
      for the amino acid transfer step.

PMID- 10601267
TI  - Chemoattractant receptors activate distinct pathways for chemotaxis and
      secretion. Role of G-protein usage.
AB  - Human leukocyte chemoattractant receptors activate chemotactic and cytotoxic
      pathways to varying degrees and also activate different G-proteins depending on
      the receptor and the cell-type. To determine the relationship between G-protein
      usage and the biological and biochemical responses activated, receptors for the
      chemoattractants formyl peptides (FR), platelet-activating factor (PAFR), and
      leukotriene B(4) (BLTR) were transfected into RBL-2H3 cells. Pertussis toxin
      (Ptx) served as a Galpha(i) inhibitor. These receptors were chosen to represent
      the spectrum of G(i) usage as Ptx had differential effects on their ability to
      induce calcium mobilization, phosphoinositide hydrolysis, and exocytosis with
      complete inhibition of all responses by FR, intermediate effects on BLTR, and
      little effect on PAFR. Ptx did not affect ligand-induced phosphorylation of PAFR
      and BLTR but inhibited phosphorylation of FR. In contrast, chemotaxis to
      formylmethionylleucylphenylalanine, leukotriene B(4), and platelet-activating
      factor was completely blocked by Ptx. Wortmannin, a phosphotidylinositol 3-kinase
      inhibitor, also completely blocked ligand-induced chemotaxis by all receptors but
      did not affect calcium mobilization or phosphoinositide hydrolysis; however, it
      partially blocked the exocytosis response to formylmethionylleucylphenylalanine
      and the platelet-activating factor. Membrane ruffling and pseudopod extension via
      the BLTR was also completely inhibited by both Ptx and wortmannin. These data
      suggest that of the chemoattractant receptors studied, G-protein usage varies
      with FR being totally dependent on G(i), whereas BLTR and PAFR utilize both G(i)
      and a Ptx-insensitive G-protein. Both Ptx-sensitive and -insensitive G-protein
      usage can mediate the activation of phospholipase C, mobilization of
      intracellular calcium, and exocytosis by chemoattractant receptors. Chemotaxis,
      however, had an absolute requirement for a G(i)-mediated pathway.

PMID- 10601269
TI  - Survival and proliferation of cells expressing caspase-uncleavable Poly(ADP
      ribose) polymerase in response to death-inducing DNA damage by an alkylating
      agent.
AB  - To determine whether caspase-3-induced cleavage of poly(ADP-ribose) polymerase
      (PARP), a DNA damage-sensitive enzyme, alters the balance between survival and
      death of the cells following DNA damage, we created stable cell lines that
      express either caspase-uncleavable mutant or wild type PARP in the background of
      PARP (-/-) fibroblasts. The survival and apoptotic responses of these cells were
      compared after exposure to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a DNA
      damaging agent that activates PARP, or to tumor necrosis factor-alpha, which
      causes apoptosis without initial DNA damage. In response to MNNG, the cells with
      caspase-uncleavable PARP were very resistant to loss of viability or induction of
      apoptosis. Most significantly, approximately 25% of these cells survived and
      retained clonogenicity at a level of DNA damage that eliminated the cells with
      wild type PARP or PARP (-/-) cells. Expression of caspase-uncleavable PARP could
      not protect the cells from death induced by tumor necrosis factor, although there
      was a slower progression of apoptotic events in these cells. Therefore, one of
      the functions for cleavage of PARP during apoptosis induced by alkylating agents
      is to prevent survival of the extensively damaged cells.

PMID- 10601270
TI  - Multiple modes of repression by the Smad transcriptional corepressor TGIF.
AB  - TGIF is a DNA-binding homeodomain protein that has been demonstrated to play a
      role in transforming growth factor beta-regulated transcription and implicated in
      the control of retinoid-responsive transcription. We investigated the intrinsic
      transcriptional activity of TGIF fused to a heterologous DNA-binding domain. Our
      results demonstrate that TGIF is a transcriptional repressor able to repress
      transcription from several different promoters. Repression by TGIF is insensitive
      to the distance at which it is bound from the promoter. Moreover, the wild type
      TGIF effectively represses transcription when bound to its cognate DNA-binding
      site via its homeodomain. Deletion analysis revealed the presence of at least two
      separable repression domains within TGIF. Repression by one of these is dependent
      on the activity of histone deacetylases (HDACs), whereas the other appears not to
      require HDAC activity. Finally, we demonstrate that TGIF interacts with HDACs via
      its carboxyl-terminal repression domain. Together, these results suggest that
      TGIF is a multifunctional transcriptional repressor, which acts in part by
      recruiting HDAC activity.

PMID- 10601271
TI  - Cu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free
      hydrogen peroxide production and metal reduction.
AB  - Oxidative stress markers as well as high concentrations of copper are found in
      the vicinity of Abeta amyloid deposits in Alzheimer's disease. The neurotoxicity
      of Abeta in cell culture has been linked to H(2)O(2) generation by an unknown
      mechanism. We now report that Cu(II) markedly potentiates the neurotoxicity
      exhibited by Abeta in cell culture. The potentiation of toxicity is greatest for
      Abeta1-42 > Abeta1-40 >> mouse/rat Abeta1-40, corresponding to their relative
      capacities to reduce Cu(II) to Cu(I), form H(2)O(2) in cell-free assays and to
      exhibit amyloid pathology. The copper complex of Abeta1-42 has a highly positive
      formal reduction potential ( approximately +500-550 mV versus Ag/AgCl)
      characteristic of strongly reducing cuproproteins. These findings suggest that
      certain redox active metal ions may be important in exacerbating and perhaps
      facilitating Abeta-mediated oxidative damage in Alzheimer's disease.

PMID- 10601272
TI  - Cooperative regulation of CYP2C12 gene expression by STAT5 and liver-specific
      factors in female rats.
AB  - The purpose of this study was to clarify the mechanism(s) responsible for the
      growth hormone (GH)-induced expression of the CYP2C12 gene. To identify a
      functional GH-responsive element (GHRE) in vivo, we performed the direct
      injection of promoter-luciferase chimeric genes into female rat livers. The
      results showed that the luciferase activity was decreased to approximately 20% by
      the deletion of the sequence between nucleotides -4213 and -4161. Within this
      region, two copies of a possible GHRE were present. The sequence of the GHRE was
      overlapped with that of an interferon-gamma-activated sequence, known to be
      recognized by the signal transducer and activator of transcription (STAT)
      proteins. In fact, a supershift assay showed that STAT5 was capable of binding to
      the core sequence of the GHRE. Furthermore, a luciferase assay with reporter
      plasmids, Delta-4161/-3781, mutated hepatocyte nuclear factor-4 (HNF-4), and
      mutated HNF-6, revealed that the GH-stimulated expression of the CYP2C12 gene was
      regulated cooperatively by STAT5, HNF-4, HNF-6, and the factor(s) that binds to
      the elements, 2C12-I (-4095 to -4074) and 2C12-II (-4072 to -4045). The
      cooperative regulation by STAT5 and the liver-enriched transcription factors
      account for the GH-dependent and the liver-specific expression of the CYP2C12
      gene in female rats.

PMID- 10601273
TI  - Nuclear import of hepatic glucokinase depends upon glucokinase regulatory
      protein, whereas export is due to a nuclear export signal sequence in
      glucokinase.
AB  - Hepatic glucokinase (GK) moves between the nucleus and cytoplasm in response to
      metabolic alterations. Here, using heterologous cell systems, we have found that
      at least two different mechanisms are involved in the intracellular movement of
      GK. In the absence of the GK regulatory protein (GKRP) GK resides only in the
      cytoplasm. However, in the presence of GKRP, GK moves to the nucleus and resides
      there in association with this protein until changes in the metabolic milieu
      prompt its release. GK does not contain a nuclear localization signal sequence
      and does not enter the nucleus in a GKRP-independent manner because cells treated
      with leptomycin B, a specific inhibitor of leucine-rich NES-dependent nuclear
      export, do not accumulate GK in the nucleus. Instead, entry of GK into the
      nucleus appears to occur via a piggy-back mechanism that involves binding to
      GKRP. Nuclear export of GK, which occurs after its release from GKRP, is due to a
      leucine-rich nuclear export signal within the protein ((300)ELVRLVLLKLV(310)).
      Thus, GKRP appears to function as both a nuclear chaperone and metabolic sensor
      and is a critical component of a hepatic GK translocation cycle for regulating
      the activity of this enzyme in response to metabolic alterations.

PMID- 10601274
TI  - Transcriptional anti-repression. Thyroid hormone receptor beta-2 recruits SMRT
      corepressor but interferes with subsequent assembly of a functional corepressor
      complex.
AB  - Thyroid hormone receptors (T3Rs) are hormone-regulated transcription factors.
      Different T3R isoforms are expressed in a tissue-specific and developmentally
      regulated manner. The T3Ralpha-1, beta-0, and beta-1 isoforms typically repress
      target gene expression in the absence of hormone and activate transcription in
      the presence of hormone. Intriguingly, however, the T3Rbeta-2 isoform fails to
      repress, and instead is able to activate transcription in both the absence and
      presence of hormone. We investigated the molecular mechanism behind this absence
      of repression by T3Rbeta-2. Repression by T3Ralpha-1, beta-0, and beta-1 is
      mediated by the ability of these isoforms to physically recruit a SMRT/N-CoR
      corepressor complex. We determined that the unliganded T3Rbeta-2 also recruits
      the SMRT corepressor; in contrast to the alpha-1, beta-0, and beta-1 isoforms,
      however, the T3Rbeta-2 protein interacts not only with the C-terminal "receptor
      interaction domain" of SMRT, but also makes additional contacts with the N
      terminal "silencing domain" of the SMRT corepressor. These additional, T3Rbeta-2
      specific contacts interfere with the subsequent association of SMRT with mSin3, a
      crucial second subunit of the corepressor holo-complex. Our results suggest that
      T3Rbeta-2 regulates transcription through a novel anti-repression mechanism,
      recruiting SMRT, but preventing the subsequent formation of a functional
      corepressor complex.

PMID- 10601275
TI  - Casein kinase I-dependent phosphorylation and stability of the yeast multidrug
      transporter Pdr5p.
AB  - The pleiotropic drug resistance protein, Pdr5p, is an ATP-binding cassette
      transporter of the plasma membrane of Saccharomyces cerevisiae. Overexpression of
      Pdr5p results in increased cell resistance to a variety of cytotoxic compounds, a
      phenotype reminiscent of the multiple drug resistance seen in tumor cells. Pdr5p
      and two other yeast ATP-binding cassette transporters, Snq2p and Yor1p, were
      found to be phosphorylated on serine residues in vitro. Mutations in the plasma
      membrane-bound casein kinase I isoforms, Yck1p and Yck2p, abolished Pdr5p
      phosphorylation and modified the multiple drug resistance profile. We showed
      Pdr5p to be ubiquitylated when overexpressed. However, instability of Pdr5p was
      only seen in Yck1p- and Yck2p-deficient strains, in which it was degraded in the
      vacuole via a Pep4p-dependent mechanism. Our results suggest that casein kinase I
      activity is required for membrane trafficking of Pdr5p to the cell surface. In
      the absence of functional Yck1p and Yck2p, Pdr5p is transported to the vacuole
      for degradation.

PMID- 10601276
TI  - Insulin-like growth factor (IGF)-I regulates IGF-binding protein-5 gene
      expression through the phosphatidylinositol 3-kinase, protein kinase B/Akt, and
      p70 S6 kinase signaling pathway.
AB  - Expression of the insulin-like growth factor-binding protein 5 (IGFBP-5) gene in
      vascular smooth muscle cells is up-regulated by IGF-I through an IGF-I receptor
      mediated mechanism. In this study, we studied the possible involvement of the
      mitogen-activated protein kinase (MAPK) and PI 3-kinase signaling pathways in
      mediating IGF-I-regulated IGFBP-5 gene expression. The addition of Des(1-3)IGF-I,
      an IGF analog with reduced affinity to IGFBPs, resulted in a transient activation
      of p44 and p42 MAPK. Inhibition of the MAPK activation by PD98059, however, did
      not affect IGF-I-stimulated IGFBP-5 expression. Des(1-3)IGF-I treatment also
      strongly activated PI 3-kinase. This activation was probably mediated through IRS
      1, because IGF-I stimulation resulted in a significant increase in IRS-1- but not
      IRS-2-associated PI 3-kinase activity. This activation occurred within 5 min and
      was sustained at high levels for over 6 h. Likewise, Des(1-3)IGF-I caused a long
      lasting activation of PKB/Akt and p70(s6k). When LY294002 and wortmannin, two
      specific inhibitors of PI 3-kinase, were added with Des(1-3)IGF-I, the IGF-I
      regulated IGFBP-5 expression was negated. The addition of rapamycin, which
      inhibits IGF-I-induced p70(s6k) activation, significantly inhibited IGF-I
      regulated IGFBP-5 gene expression. These results suggest that the action of IGF-I
      on IGFBP-5 gene expression requires the activation of the PI 3-kinase-PKB/Akt
      p70(s6k) pathway but not the MAPK pathway in vascular smooth muscle cells.

PMID- 10601277
TI  - Purification and identification of a tissue-specific repressor involved in serum
      amyloid A1 gene expression.
AB  - We have previously demonstrated that the 5'-flanking regions from the rat serum
      amyloid A1 (SAA1) promoter are necessary and sufficient to confer specific
      cytokine-induced expression in cultured hepatoma cells. Deletion analysis
      identified a tissue-specific repressor (TSR) regulatory element, located between
      bp -289 and -256, that functioned as a silencer, contributing to the
      transcription repression on SAA1 promoter in nonliver cells. When this 34-base
      pair TSR-binding element was used as a probe in electrophoretic mobility shift
      assays, an intense DNA-protein complex was detected in nuclear extracts from HeLa
      and several other nonliver tissues. This TSR binding activity, however, was
      undetectable in extracts from liver or liver-derived cells. The distribution of
      TSR binding activity is therefore consistent with its regulatory role in
      repressing SAA1 expression in a tissue-specific manner. In this study, we
      purified TSR protein from HeLa nuclear extracts and showed that it has a
      molecular mass of approximately 50 kDa. Surprisingly, protein sequencing and
      antibody supershift experiments identified TSR as transcription factor AP-2.
      Subsequent functional analysis showed that forced expression of AP-2 in HepG2
      cells could indeed inhibit conditioned medium-induced SAA1 promoter activation.
      Moreover, expression of a dominant-negative mutant of AP-2 in HeLa cells or
      mutation of the AP-2-binding site led to derepression of the SAA1 promoter,
      presumably by neutralizing the inhibitory effects of the endogenous wild-type AP
      2. Our results therefore demonstrate a novel function for AP-2 in the
      transcriptional repression of SAA1 promoter. Together with its tissue
      distribution, AP-2 may contribute to SAA1's highly liver-specific expression
      pattern by restricting its expression in nonliver cells.

PMID- 10601278
TI  - A novel human hepatic organic anion transporting polypeptide (OATP2).
      Identification of a liver-specific human organic anion transporting polypeptide
      and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor
      transporters.
AB  - A novel human organic transporter, OATP2, has been identified that transports
      taurocholic acid, the adrenal androgen dehydroepiandrosterone sulfate, and
      thyroid hormone, as well as the hydroxymethylglutaryl-CoA reductase inhibitor,
      pravastatin. OATP2 is expressed exclusively in liver in contrast to all other
      known transporter subtypes that are found in both hepatic and nonhepatic tissues.
      OATP2 is considerably diverged from other family members, sharing only 42%
      sequence identity with the four other subtypes. Furthermore, unlike other
      subtypes, OATP2 did not transport digoxin or aldosterone. The rat isoform oatp1
      was also shown to transport pravastatin, whereas other members of the OATP
      family, i.e. rat oatp2, human OATP, and the prostaglandin transporter, did not.
      Cis-inhibition studies indicate that both OATP2 and roatp1 also transport other
      statins including lovastatin, simvastatin, and atorvastatin. In summary, OATP2 is
      a novel organic anion transport protein that has overlapping but not identical
      substrate specificities with each of the other subtypes and, with its liver
      specific expression, represents a functionally distinct OATP isoform.
      Furthermore, the identification of oatp1 and OATP2 as pravastatin transporters
      suggests that they are responsible for the hepatic uptake of this liver-specific
      hydroxymethylglutaryl-CoA reductase inhibitor in rat and man.

PMID- 10601279
TI  - SarA, a global regulator of virulence determinants in Staphylococcus aureus,
      binds to a conserved motif essential for sar-dependent gene regulation.
AB  - The expression of many virulence determinants in Staphylococcus aureus including
      alpha-hemolysin-, protein A-, and fibronectin-binding proteins is controlled by
      global regulatory loci such as sar and agr. In addition to controlling target
      gene expression via agr (e.g. alpha-hemolysin), the sar locus can also regulate
      target gene transcription via agr-independent mechanisms. In particular, we have
      found that SarA, the major regulatory protein encoded within sar, binds to a
      conserved sequence, homologous to the SarA-binding site on the agr promoter,
      upstream of the -35 promoter boxes of several target genes including hla (alpha
      hemolysin gene), spa (protein A gene), fnb (fibronectin-binding protein genes),
      and sec (enterotoxin C gene). Deletion of the SarA recognition motif in the
      promoter regions of agr and hla in shuttle plasmids rendered the transcription of
      these genes undetectable in agr and hla mutants, respectively. Likewise, the
      transcription activity of spa (a gene normally repressed by sar), as measured by
      a XylE reporter fusion assay, became derepressed in a wild type strain containing
      a shuttle plasmid in which the SarA recognition site had been deleted from the
      spa promoter region. However, DNase I footprinting assays demonstrated that the
      SarA-binding region on the spa and hla promoter is more extensive than the
      predicted consensus sequence, thus raising the possibility that the consensus
      sequence is an activation site within a larger binding region. Because the sar
      and agr regulate an assortment of virulence factors in S. aureus, we propose,
      based on our data, a unifying hypothesis for virulence gene activation in S.
      aureus whereby SarA is a regulatory protein that binds to its consensus SarA
      recognition motif to activate (e.g. hla) or repress (e.g. spa) the transcription
      of sar target genes, thus accounting for both agr-dependent and agr-independent
      mode of regulation.

PMID- 10601280
TI  - Transcriptional induction of stromelysin-3 in mesodermal cells is mediated by an
      upstream CCAAT/enhancer-binding protein element associated with a DNase I
      hypersensitive site.
AB  - Stromelysin-3 (ST3) is a matrix metalloproteinase whose synthesis is markedly
      increased in stromal fibroblasts of most invasive human carcinomas. In the
      present study, we have investigated the molecular mechanisms by which high levels
      of ST3 expression can be induced. In contrast to the early and transient
      induction of interstitial collagenase by 12-O-tetradecanoylphorbol-13-acetate
      (TPA), the fibroblastic induction of ST3 was found to be delayed and to require
      protein neosynthesis. We demonstrated that this induction is transcriptional and
      does not result from changes in RNA stability. By looking next to promoter
      regions accessible to DNase I upon gene induction, we have identified two distal
      elements and have characterized their role in the transcriptional regulation of
      ST3. The first one is a TPA-responsive element that controls the base-line ST3
      promoter activity but is not required for its activation. We demonstrate that ST3
      gene induction is actually mediated by the second element, a C/EBP-binding site,
      by showing: (i) that this element becomes accessible in cells induced to express
      ST3, (ii) that endogenous C/EBPbeta binds to the ST3 promoter, and (iii) that
      this binding leads to ST3 transcriptional activation. Our study provides new
      insights into the regulation of ST3 and suggests an additional role for C/EBP
      transcription factors in tissue remodeling processes associated with this MMP.

PMID- 10601281
TI  - Differential ganciclovir-mediated cell killing by glutamine 125 mutants of herpes
      simplex virus type 1 thymidine kinase.
AB  - The therapeutic combination of the herpesvirus simplex virus type 1 (HSV-1)
      thymidine kinase (TK) gene and the prodrug, ganciclovir (GCV), has found great
      utility for the treatment of many types of cancer. After initial phosphorylation
      of GCV by HSV-1 TK, cellular kinases generate the toxic GCV-triphosphate
      metabolite that is incorporated into DNA and eventually leads to tumor cell
      death. The cellular and pharmacological mechanisms by which metabolites of GCV
      lead to cell death are still poorly defined. To begin to address these
      mechanisms, different mutated forms of HSV-1 TK at residue Gln-125 that have
      distinct substrate properties were expressed in mammalian cell lines. It was
      found that expression of the Asn-125 HSV-1 TK mutant in two cell lines, NIH3T3
      and HCT-116, was equally effective as wild-type HSV-1 TK for metabolism and
      sensitivity to GCV, bystander effect killing and induction of apoptosis. The
      major difference between the two enzymes was the lack of deoxypyrimidine
      metabolism in the Asn-125 TK-expressing cells. In HCT-116 cells expressing the
      Glu-125 TK mutant, GCV metabolism was greatly attenuated, yet at higher GCV
      concentrations, cell sensitivity to the drug and bystander effect killing were
      diminished but still effective. Cell cycle analysis, 4', 6'-diamidine-2'
      phenylindoledihydrochloride staining, and caspase 3 activation assays indicated
      different cell death responses in the Glu-125 TK-expressing cells as compared
      with the wild-type HSV-1 TK or Asn-125 TK-expressing cells. A mechanistic
      hypothesis to explain these results based on the differences in GCV-triphosphate
      metabolite levels is presented.

PMID- 10601282
TI  - Expression and characterization of wild type and mutant recombinant human
      sulfamidase. Implications for Sanfilippo (Mucopolysaccharidosis IIIA) syndrome.
AB  - Mucopolysaccharidosis IIIA (MPS-IIIA) is an autosomal recessive lysosomal storage
      disorder caused by the deficiency of sulfamidase (NS; EC 3.10.1.1), resulting in
      defective degradation and storage of heparan sulfate. This paper reports the
      production and characterization of monoclonal and polyclonal antibodies against
      recombinant human sulfamidase (rhNS) to quantitate and characterize normal and
      mutant sulfamidase produced from the wild type NS expression vector.
      Glycosylation and phosphorylation studies of immunoprecipitated rhNS show that
      all five potential glycosylation sites are utilized, with three high
      mannose/hybrid oligosaccharides and two simpler chains, with at least one
      functional mannose 6-phosphate group. An NS quantification system was developed
      to determine the effect of the three most common and severe patient mutations:
      S66W (Italy), R74C (Poland), and R245H (The Netherlands). The quantity and
      specific activity of expressed mutant rhNS was significantly lower than expressed
      normal rhNS, with 0.3, 0.2, and 0.05% of normal rhNS produced and 15, 17, and 83%
      of normal specific activity for S66W, R74C, and R245H observed, respectively. The
      recent structural elucidation of N-acetylgalactosamine-4-sulfatase was utilized
      to postulate the effect on the structure-function relationship of NS. The
      characterization of normal and mutated rhNS has relevance for efficient diagnosis
      and therapeutic developments for MPS-IIIA patients.

PMID- 10601283
TI  - The hydrophilic isoform of glutamate decarboxylase, GAD67, is targeted to
      membranes and nerve terminals independent of dimerization with the hydrophobic
      membrane-anchored isoform, GAD65.
AB  - GAD67, the larger isoform of the gamma-aminobutyric acid-synthesizing enzyme
      glutamic acid decarboxylase, is a hydrophilic soluble molecule, postulated to
      localize at nerve terminals and membrane compartments by heterodimerization with
      the smaller membrane-anchored isoform GAD65. We here show that the dimerization
      region in GAD65 is distinct from the NH(2)-terminal membrane-anchoring region and
      that a membrane anchoring GAD65 subunit can indeed target a soluble subunit to
      membrane compartments by dimerization. However, only a fraction of membrane-bound
      GAD67 is engaged in a heterodimer with GAD65 in rat brain. Furthermore, in GAD65
      /- mouse brain, GAD67, which no longer partitions into the Triton X-114 detergent
      phase, still anchors to membranes at similar levels as in wild-type mice.
      Similarly, in primary cultures of neurons derived from GAD65-/- mice, GAD67 is
      targeted to nerve terminals, where it co-localizes with the synaptic vesicle
      marker SV2. Thus, axonal targeting and membrane anchoring is an intrinsic
      property of GAD67 and does not require GAD65. The results suggest that three
      distinct moieties of glutamate decarboxylase localize to membrane compartments,
      an amphiphilic GAD65 homodimer, an amphiphilic GAD65/67 heterodimer, tethered to
      membranes via the GAD65 subunit, and a hydrophilic GAD67 homodimer, which
      associates with membranes by a distinct mechanism.

PMID- 10601284
TI  - Cysteine mutagenesis and homology modeling of the ligand-binding site of a
      kainate-binding protein.
AB  - Glutamate receptors comprise the most abundant group of neurotransmitter
      receptors in the vertebrate central nervous system. Cysteine mutagenesis in
      combination with homology modeling has been used to study the determinants of
      kainate binding in a glutamate receptor subtype, a low molecular weight goldfish
      kainate-binding protein, GFKARbeta. A construct of GFKARbeta with no cysteines in
      the extracellular domain was produced, and single cysteine residues were
      introduced at selected positions. N-Ethylmaleimide or derivatized
      methanethiosulfonate reagents (neutral or charged) were used to modify the
      introduced cysteines covalently, and the effect on [(3)H]kainate binding was
      determined. In addition, cysteine mutants of GFKARbeta transiently expressed in
      HEK293 cells were labeled with a membrane-impermeable biotinylating reagent
      followed by precipitation with streptavidin beads and specific detection of
      GFKARbeta by Western blot analysis. The results are consistent with the proposal
      that the energy driving kainate binding is contributed both from residues within
      the binding site and from interactions between two regions (i.e. two lobes) of
      the protein that are brought into contact upon ligand binding in a manner
      analogous to that seen in bacterial amino acid-binding proteins.

PMID- 10601285
TI  - Activation function 2 in the human androgen receptor ligand binding domain
      mediates interdomain communication with the NH(2)-terminal domain.
AB  - Activation function 2 in the ligand binding domain of nuclear receptors forms a
      hydrophobic cleft that binds the LXXLL motif of p160 transcriptional
      coactivators. Here we provide evidence that activation function 2 in the androgen
      receptor serves as the contact site for the androgen dependent NH(2)- and
      carboxyl-terminal interaction of the androgen receptor and only weakly interacts
      with p160 coactivators in an LXXLL-dependent manner. Mutagenesis studies indicate
      that it is the NH(2)-/carboxyl-terminal interaction that is required by
      activation function 2 to stabilize helix 12 and slow androgen dissociation
      critical for androgen receptor activity in vivo. The androgen receptor recruits
      p160 coactivators through its NH(2)-terminal and DNA binding domains in an LXXLL
      motif-independent manner. The results suggest a novel function for activation
      function 2 and a unique mechanism of nuclear receptor transactivation.

PMID- 10601286
TI  - The effect of matrix metalloproteinase complex formation on the conformational
      mobility of tissue inhibitor of metalloproteinases-2 (TIMP-2).
AB  - The backbone mobility of the N-terminal domain of tissue inhibitor of
      metalloproteinases-2 (N-TIMP-2) was determined both for the free protein and when
      bound to the catalytic domain of matrix metalloproteinase-3 (N-MMP-3). Regions of
      the protein with internal motion were identified by comparison of the T(1) and
      T(2) relaxation times and (1)H-(15)N nuclear Overhauser effect values for the
      backbone amide (15)N signals for each residue in the sequence. This analysis
      revealed rapid internal motion on the picosecond to nanosecond time scale for
      several regions of free N-TIMP-2, including the extended beta-hairpin between
      beta-strands A and B, which forms part of the MMP binding site. Evidence of
      relatively slow motion indicative of exchange between two or more local
      conformations on a microsecond to millisecond time scale was also found in the
      free protein, including two other regions of the MMP binding site (the CD and EF
      loops). On formation of a tight N-TIMP-2. N-MMP-3 complex, the rapid internal
      motion of the AB beta-hairpin was largely abolished, a change consistent with
      tight binding of this region to the MMP-3 catalytic domain. The extended AB beta
      hairpin is not a feature of all members of the TIMP family; therefore, the
      binding of this highly mobile region to a site distant from the catalytic cleft
      of the MMPs suggests a key role in TIMP-2 binding specificity.

PMID- 10601287
TI  - Differential localization of protein kinase C delta by phorbol esters and related
      compounds using a fusion protein with green fluorescent protein.
AB  - Enzyme localization often plays a controlling role in determining its activity
      and specificity. Protein kinase C (PKC) has long been known to translocate in
      response to physiological stimuli as well as to exogenous ligands such as the
      phorbol esters. We report here that different phorbol derivatives and related
      ligands, selected for differences in chemical structure and profile of biological
      activity, induce distinct patterns of redistribution of PKC delta. Localization
      of a PKC delta-green fluorescent protein (GFP) fusion construct was monitored in
      living Chinese hamster ovary cells as a function of ligand, concentration, and
      time using confocal laser scanning microscopy. delta-PKC-GFP was expressed
      predominantly in the cytoplasm, with some in the nucleus and perinuclear region.
      Phorbol 12-myristate 13-acetate (PMA) induced plasma membrane translocation
      followed by slower nuclear membrane translocation. As the concentration of PMA
      increased, the proportion of nuclear to plasma membrane localization increased
      markedly. In contrast to PMA, bryostatin 1, a unique activator of PKC that
      induces a subset of PMA-mediated responses while antagonizing others, at all
      doses induced almost exclusively nuclear membrane translocation. Like PMA, the
      complete tumor promoter 12-deoxyphorbol 13-tetradecanoate induced plasma membrane
      and slower nuclear membrane translocation, whereas the inhibitor of tumor
      promotion 12-deoxyphorbol 13-phenylacetate, which differs only in its side chain,
      induced a distinctive distribution of PKC delta-GFP. Finally, the novel
      constrained diacylglycerol derivative B8-DL-B8 induced a slow Golgi localization.
      We speculate that differential control of PKC delta localization may provide an
      interesting strategy for producing ligands with differential biological
      consequences.

PMID- 10601288
TI  - Expression of human histo-blood group ABO genes is dependent upon DNA methylation
      of the promoter region.
AB  - We have investigated the regulatory role of DNA methylation in the expression of
      the human histo-blood group ABO genes. The ABO gene promoter region contains a
      CpG island whose methylation status correlates well with gene expression in the
      cell lines tested. The CpG island was found hypomethylated in some cell lines
      that expressed ABO genes, whereas the other cell lines that did not express ABO
      genes were hypermethylated. Whereas constitutive transcriptional activity of the
      ABO gene promoter was demonstrated in both expressor and nonexpressor cell lines
      by transient transfection of reporter constructs containing the ABO gene promoter
      sequence, HhaI methylase-catalyzed in vitro methylation of the promoter region
      prior to DNA transfection suppressed the promoter activity when introduced into
      the expressor gastric cancer cell line KATOIII cells. On the other hand, in the
      nonexpressor gastric cancer cell line MKN28 cells, treatment with DNA
      methyltransferase inhibitor 5-aza-2'-deoxycytidine resulted in demethylation of
      the ABO gene promoter and appearance of A-transferase messages, as well as A
      antigens synthesized by A-transferase. Taken together, these studies suggest that
      DNA methylation of the ABO gene promoter may play an important role in the
      regulation of ABO gene expression.

PMID- 10601289
TI  - CD40 signals apoptosis through FAN-regulated activation of the sphingomyelin
      ceramide pathway.
AB  - The possibility that the sphingomyelin (SM)-ceramide pathway is activated by
      CD40, a transmembrane glycoprotein belonging to the tumor necrosis factor
      receptor superfamily and that plays a critical role in the regulation of immune
      responses has been investigated. We demonstrate that incubation of Epstein-Barr
      virus-transformed lymphoid cells with an anti-CD40 antibody acting as an agonist
      results in the stimulation of a neutral sphingomyelinase, hydrolysis of cellular
      SM, and concomitant ceramide generation. In addition, SM degradation was observed
      in acid sphingomyelinase-deficient cells, as well as after ligation by soluble
      CD40 ligand. The anti-CD40 antibody, as well as the soluble CD40 ligand induced a
      decrease in thymidine incorporation and morphological features of apoptosis,
      which were mimicked by cell-permeant or bacterial sphingomyelinase-produced
      ceramides. Stable expression of a dominant-negative form of the FAN protein
      (factor associated with neutral sphingomyelinase activation), which has been
      reported to mediate tumor necrosis factor-induced activation of neutral
      sphingomyelinase, significantly inhibited CD40 ligand-induced sphingomyelinase
      stimulation and apoptosis of transformed human fibroblasts. Transformed
      fibroblasts from FAN knockout mice were also protected from CD40-mediated cell
      death. Finally, anti-CD40 antibodies were able to co-immunoprecipitate FAN in
      control fibroblasts but not in cells expressing the dominant-negative form of
      FAN, indicating interaction between CD40 and FAN. Altogether, these results
      strongly suggest that CD40 ligation can activate via FAN a neutral
      sphingomyelinase-mediated ceramide pathway that is involved in the cell growth
      inhibitory effects of CD40.

PMID- 10601290
TI  - The structural basis for the increased immunogenicity of two HIV-reverse
      transcriptase peptide variant/class I major histocompatibility complexes.
AB  - Designing altered peptide ligands to generate specific immunological reactivity
      when bound to class I major histocompatibility complexes is important for both
      therapeutic and prophylactic reasons. We have previously shown that two altered
      peptides, derived from human immunodeficiency virus (HIV)-reverse transcriptase
      (RT) residues 309-317, are more immunogenic in vitro than the wild-type peptide.
      One peptide variant, I1Y, was able to stimulate RT-specific cytotoxic T cells
      from the blood of three HIV-infected individuals better than the wild-type RT
      peptide. Both I1Y and I1F peptide variants increase the cell surface half-life of
      the peptide-class I complex approximately 3-fold over that of the RT peptide but
      have different immunological activities. These peptides are candidates for the
      design of vaccines for HIV due to their increased immunogenicity. To understand
      the basis for the increased cell surface stability compared with wild-type
      peptide and to understand the differences in T cell recognition between I1Y and
      I1F, we determined the x-ray crystal structures of the two class I MHC-peptide
      complexes. These structures indicate that the increased cell surface half-life is
      due to pi-pi stacking interactions between Trp-167 of HLA-A2.1 and the aromatic
      P1 residues of I1F and I1Y. Comparison of the structures and modeling potential T
      cell receptor (TCR) interactions suggests that T cell interactions and
      immunogenicity are different between I1Y and I1F for two reasons. First, subtle
      changes in the steric and polar properties of the I1Y peptide affect TCR
      engagement. Second, water-mediated hydrogen bond interactions between the P1-Tyr
      and the P4-Glu peptide residues increase peptide side chain rigidity of residues
      critical for TCR engagement.

PMID- 10601291
TI  - Purification of a novel flavoprotein involved in the thyroid NADPH oxidase.
      Cloning of the porcine and human cdnas.
AB  - Hydrogen peroxide is the final electron acceptor for the biosynthesis of thyroid
      hormone catalyzed by thyroperoxidase at the apical surface of thyrocytes. Pig and
      human thyroid plasma membrane contain a Ca(2+)-dependent NAD(P)H oxidase that
      generates H(2)O(2) by transferring electrons from NAD(P)H to molecular oxygen. We
      purified from pig thyroid plasma membrane a flavoprotein which constitutes the
      main, if not the sole, component of the thyroid NAD(P)H oxidase. Microsequences
      permitted the cloning of porcine and human full-length cDNAs encoding,
      respectively, 1207- and 1210-amino acid proteins with a predicted molecular mass
      of 138 kDa (p138(Tox)). Human and porcine p138(Tox) have 86.7% identity. The
      strongest similarity was to a predicted polypeptide encoded by a Caenorhabditis
      cDNA and with rbohA, a protein involved in the Arabidopsis NADPH oxidase.
      p138(Tox) shows also similarity to the p65(Mox) and to the gp91(Phox) in their C
      terminal region and have consensus sequences for FAD- and NADPH-binding sites.
      Compared with gp91(Phox), p138(Tox) shows an extended N-terminal containing two
      EF-hand motifs that may account for its calcium-dependent activity, whereas three
      of four sequences implicated in the interaction of gp91(Phox) with the p47(Phox)
      cytosolic factor are absent in p138(Tox). The expression of porcine p138(Tox)
      mRNA analyzed by Northern blot is specific of thyroid tissue and induced by
      cyclic AMP showing that p138(Tox) is a differentiation marker of thyrocytes. The
      gene of human p138(Tox) has been localized on chromosome 15q15.

PMID- 10601292
TI  - Alternative mechanisms of vacuolar acidification in H(+)-ATPase-deficient yeast.
AB  - Acidification of the endosomal/lysosomal pathway by the vacuolar-type proton
      translocating ATPase (V-ATPase) is necessary for a variety of essential
      eukaryotic cellular functions. Nevertheless, yeasts lacking V-ATPase activity
      (Deltavma) are viable when grown at low pH, suggesting alternative methods of
      organellar acidification. This was confirmed by directly measuring the vacuolar
      pH by ratio fluorescence imaging. When Deltavma yeasts were cultured and tested
      in the acidic conditions required for growth of V-ATPase-deficient mutants, the
      vacuolar pH was 5.9. Fluid-phase pinocytosis of acidic extracellular medium
      cannot account for these observations, because the V-ATPase-independent vacuolar
      acidification was unaffected in mutants deficient in endocytosis. Similarly,
      internalization of the plasmalemmal H(+)-ATPase (Pma1p) was ruled out, because
      overexpression of Pma1p failed to complement the Deltavma phenotype and did not
      potentiate the vacuolar acidification. To test whether weak electrolytes present
      in the culture medium could ferry acid equivalents to the vacuole, wild-type and
      the Deltavma yeasts were subjected to sudden changes in extracellular pH. In both
      cell types, the vacuoles rapidly alkalinized when external pH was raised from 5.5
      (the approximate pH of the culture medium) to 7.5 and re-acidified when the
      yeasts were returned to a medium of pH 5.5. Importantly, these rapid pH changes
      were only observed when NH(4)(+), routinely added as a nitrogen source, was
      present. The NH(4)(+)-dependent acidification was not due to efflux of NH(3) from
      the vacuole, as cells equilibrated to pH 7.5 in the absence of weak electrolytes
      rapidly acidified when challenged with an acidic medium containing NH(4)(+).
      These findings suggest that although NH(3) can act as a cell-permeant proton
      scavenger, NH(4)(+) may function as a protonophore, facilitating equilibration of
      the pH across the plasma and vacuolar membranes of yeast. The high concentration
      of NH(4)(+) frequently added as a nitrogen source to yeast culture media together
      with effective NH(4)(+) transporters thereby facilitate vacuolar acidification
      when cells are suspended in acidic solutions.

PMID- 10601293
TI  - Furin-independent pathway of membrane type 1-matrix metalloproteinase activation
      in rabbit dermal fibroblasts.
AB  - We investigated the gene expression and intracellular activity of processing
      protease furin and its involvement in the process of membrane type 1-matrix
      metalloproteinase (MT1-MMP) activation in rabbit dermal fibroblasts. When the
      rabbit fibroblasts were treated with concanavalin A (ConA), pro-MMP-2 was
      converted to an active 62-kDa MMP-2 through the appearance of a 64-kDa
      intermediate MMP-2. The ConA-induced pro-MMP-2 activation resulted from
      increasing the gene expression and production of MT1-MMP in the rabbit
      fibroblasts. Reverse transcriptase-polymerase chain reaction demonstrated that in
      rabbit dermal fibroblasts furin mRNA was detected and, unlike MT1-MMP, was not
      increased by ConA. These findings are further supported by the fact that the
      intracellular furin activity also was constitutively detected and was unchanged
      by the ConA treatment. Very similar phenomena were also observed in human uterine
      cervical fibroblasts, which are known to produce MT1-MMP by ConA stimulation.
      These results suggest that the expression of the furin gene and the intracellular
      activity are not regulated by ConA. On the other hand, neither a synthetic furin
      inhibitor, decanoyl-RVKR-CH(2)Cl (25-100 microM) nor a furin antisense
      oligonucleotide (40 microM) inhibited the MT1-MMP-mediated pro-MMP-2 activation
      in ConA-treated rabbit dermal fibroblasts, whereas these compounds interfered
      with pro-MMP-2 activation in ConA-treated human uterine cervical fibroblasts.
      Nonetheless, the furin antisense oligonucleotide completely suppressed furin gene
      expression in both rabbit and human fibroblasts. These results suggest that furin
      does not participate in the process of MT1-MMP activation induced by ConA in
      rabbit dermal fibroblasts.

PMID- 10601294
TI  - Activation of epidermal growth factor receptor promotes late terminal
      differentiation of cell-matrix interaction-disrupted keratinocytes.
AB  - The biological effects of epidermal growth factor receptor (EGFR) activation may
      differ between epidermal suprabasal and basal keratinocytes, since growth factors
      are mitogenic in adherent cells only in the presence of cell-extracellular matrix
      (ECM) interaction. To investigate biological effects of EGFR activation on
      keratinocytes without cell-ECM interaction, we cultured normal human
      keratinocytes on polyhydroxyethylmethacrylate-coated plates, which disrupt cell
      ECM but not cell-cell interaction. The cells initially expressed keratin 10 (K10)
      and then profilaggrin, mimicking sequential differentiation of epidermal
      suprabasal keratinocytes. The addition of EGF or transforming growth factor-alpha
      promoted late terminal differentiation (profilaggrin expression, type 1
      transglutaminase expression and activity, and cornified envelope formation) of
      the suspended keratinocytes, while suppressing K10 expression, an early
      differentiation marker. These effects were attenuated by EGFR tyrosine kinase
      inhibitor PD153035 or an anti-EGFR monoclonal antibody, whereas protein kinase C
      inhibitors H7 and bisindolylmaleimide I or mitogen-activated protein
      kinase/extracellular signal-regulated kinase kinase inhibitor PD98059 abolished
      profilaggrin up-regulation but not K10 suppression. Since the antidifferentiative
      role of EGFR on cell-ECM interaction-conserved keratinocytes has been well
      documented, our results indicate that the biological effects of EGFR on
      keratinocytes are influenced by cell-ECM interaction and suggest that EGFR
      activation promotes rather than inhibits the terminal differentiation of
      suprabasal epidermal keratinocytes.

PMID- 10601295
TI  - Transforming growth factor-beta induces collagenase-3 expression by human
      gingival fibroblasts via p38 mitogen-activated protein kinase.
AB  - Human collagenase-3 (matrix metalloproteinase 13 (MMP-13)) is characterized by
      exceptionally wide substrate specificity and restricted tissue specific
      expression. Human skin fibroblasts in culture express MMP-13 only when they are
      in three-dimensional collagen (Ravanti, L., Heino, J., Lopez-Otin, C., and
      Kahari. V.-M. (1999) J. Biol. Chem. 274, 2446-2455). Here we show that MMP-13 is
      expressed by fibroblasts during normal human gingival wound repair. Expression of
      MMP-13 by human gingival fibroblasts cultured in monolayer or in collagen gel was
      induced by transforming growth factor-beta1 (TGF-beta1). Treatment of gingival
      fibroblasts with TGF-beta1 activated two distinct mitogen-activated protein
      kinases (MAPKs): extracellular signal-regulated kinase 1/2 (ERK1/2) in 15 min and
      p38 MAPK in 1 and 2 h. Induction of MMP-13 expression by TGF-beta1 was blocked by
      SB203580, a specific inhibitor of p38 MAPK, but not by PD98059, a selective
      inhibitor of ERK1/2 activation. Adenovirus-mediated expression of dominant
      negative p38alpha and c-Jun potently inhibited induction of MMP-13 expression in
      gingival fibroblasts by TGF-beta1. Infection of gingival fibroblasts with
      adenovirus for constitutively active MEK1 resulted in activation of ERK1/2 and
      JNK1 and up-regulation of collagenase-1 (MMP-1) and stromelysin-1 (MMP-3)
      production but did not induce MMP-13 expression. In addition, activation of p38
      MAPK by constitutively active MKK6b or MKK3b was not sufficient to induce MMP-13
      expression. These results show that TGF-beta-elicited induction of MMP-13
      expression by gingival fibroblasts is dependent on the activity of p38 MAPK and
      the presence of functional AP-1 dimers. These observations demonstrate a
      fundamental difference in the regulation of collagenolytic capacity between
      gingival and dermal fibroblasts and suggest a role for MMP-13 in rapid turnover
      of collagenous matrix during repair of gingival wounds, which heal with minimal
      scarring.

PMID- 10601296
TI  - Monomeric structure of the human EphB2 sterile alpha motif domain.
AB  - The sterile alpha motif (SAM) domain is a protein module found in many diverse
      signaling proteins. SAM domains in some systems have been shown to self
      associate. Previous crystal structures of an EphA4-SAM domain dimer (Stapleton,
      D., Balan, I., Pawson, T., and Sicheri, F. (1999) Nat. Struct. Biol. 6, 44-49)
      and a possible EphB2-SAM oligomer (Thanos, C. D., Goodwill, K. E., and Bowie, J.
      U. (1999) Science 283, 833-836) both revealed large interfaces comprising an
      exchange of N-terminal peptide arms. Within the arm, a conserved hydrophobic
      residue (Tyr-8 in the EphB2-SAM structure or Phe-910 in the EphA4-SAM structure)
      is anchored into a hydrophobic cleft on a neighboring molecule. Here we have
      solved a new crystal form of the human EphB2-SAM domain that has the same overall
      SAM domain fold yet has no substantial intermolecular contacts. In the new
      structure, the N-terminal peptide arm of the EphB2-SAM domain protrudes out from
      the core of the molecule, leaving both the arm (including Tyr-8) and the
      hydrophobic cleft solvent-exposed. To verify that Tyr-8 is solvent-exposed in
      solution, we made a Tyr-8 to Ala-8 mutation and found that the EphB2-SAM domain
      structure and stability were only slightly altered. These results suggest that
      Tyr-8 is not part of the hydrophobic core of the EphB2-SAM domain and is
      conserved for functional reasons. Cystallographic evidence suggests a possible
      role for the N-terminal arm in oligomerization. In the absence of a direct
      demonstration of biological relevance, however, the functional role of the N
      terminal arm remains an open question.

PMID- 10601297
TI  - Gab1 mediates neurite outgrowth, DNA synthesis, and survival in PC12 cells.
AB  - The Gab1-docking protein has been shown to regulate phosphatidylinositol 3-kinase
      PI3K activity and potentiate nerve growth factor (NGF)-induced survival in PC12
      cells. Here, we investigated the potential of Gab1 to induce neurite outgrowth
      and DNA synthesis, two other important aspects of NGF-induced neuronal
      differentiation of PC12 cells and NGF-independent survival. We generated a
      recombinant adenovirus encoding hemagglutinin (HA)-epitope-tagged Gab1 and
      expressed this protein in PC12 cells. HA-Gab1 was constitutively tyrosine
      phosphorylated in PC12 cells and induced the phosphorylation of Akt/protein
      kinase B and p44/42 mitogen-activated protein kinase. HA-Gab1-stimulated a 10
      fold increase in neurite outgrowth in the absence of NGF and a 5-fold increase in
      NGF-induced neurite outgrowth. HA-Gab1 also stimulated DNA synthesis and caused
      NGF-independent survival in PC12 cells. Finally, we found that HA-Gab1-induced
      neuritogenesis was completely suppressed by pharmacological inhibition of mitogen
      activated protein kinase kinase (MEK) activity and 50% suppressed by inhibition
      of PI3K activity. In contrast, HA-Gab1-stimulated cell survival was efficiently
      suppressed only by inhibition of both PI3K and MEK activities. These results
      indicate that Gab1 is capable of mediating differentiation, DNA synthesis, and
      cell survival and uses both PI3K and MEK signaling pathways to achieve its
      effects.

PMID- 10601298
TI  - Activation of c-Ha-Ras by nitric oxide modulates survival responsiveness in
      neuronal PC12 cells.
AB  - p21(c-Ha-Ras) (Ras) can be activated by the guanine nucleotide exchange factor
      mSOS1 or by S-nitrosylation of cysteine 118 via nitric oxide (NO). To determine
      whether these two Ras-activating mechanisms modulate distinct biological effects,
      a NO-nonresponsive Ras mutant (Ras(C118S)) was stably expressed in the PC12
      cells, a cell line that generates NO upon nerve growth factor treatment. We
      report here that Ras(C118S) functions indistinguishably from wild type Ras in
      activating and maintaining the mSOS1- and Raf-1-dependent mitogen-activated
      protein kinase cascade necessary for neuronal differentiation. However,
      continuous (>5 days) exposure to nerve growth factor reveals that, in contrast to
      parental or wild-type Ras-overexpressing PC12 cells, Ras(C118S)-expressing PC12
      cells cannot sustain the basal interaction between Ras and phosphatidylinositol 3
      kinase. This results in spontaneous apoptosis of these cells despite the presence
      of nerve growth factor and serum. Thus unique downstream effector interactions
      and biological outcomes can be differentially modulated by distinct modes of Ras
      activation.

PMID- 10601299
TI  - Structure and regulated expression of the delta-aminolevulinate synthase gene
      from Drosophila melanogaster.
AB  - The structure of the single copy gene encoding the putative housekeeping isoform
      of Drosophila melanogaster delta-aminolevulinate synthase (ALAS) has been
      determined. Southern and immunoblot analyses suggest that only the housekeeping
      isoform of the enzyme exists in Drosophila. We have localized a critical region
      for promoter activity to a sequence of 121 base pairs that contains a motif that
      is potentially recognized by factors of the nuclear respiratory factor-1 (NRF
      1)/P3A2 family, flanked by two AP4 sites. Heme inhibits the expression of the
      gene by blocking the interaction of putative regulatory proteins to its 5'
      proximal region, a mechanism different from those proposed for other hemin
      regulated promoters. Northern and in situ RNA hybridization experiments show that
      maternal alas mRNA is stored in the egg; its steady-state level decreases rapidly
      during the first hours of development and increases again after gastrulation in a
      period where the synthesis of several mRNAs encoding metabolic enzymes is
      activated. In the syncytial blastoderm, the alas mRNA is ubiquitously distributed
      and decreases in abundance substantially through cellular blastoderm. Late in
      embryonic development alas shows a specific pattern of expression, with an
      elevated mRNA level in oenocytes, suggesting an important role of these cells in
      the biosynthesis of hemoproteins in Drosophila.

PMID- 10601300
TI  - Spontaneous neutrophil apoptosis involves caspase 3-mediated activation of
      protein kinase C-delta.
AB  - Neutrophils are short-lived leukocytes that die by apoptosis. Whereas stress
      induced apoptosis is mediated by the p38 mitogen-activated protein (MAP) kinase
      pathway (Frasch, S. C., Nick, J. A., Fadok, V. A., Bratton, D. L., Worthen, G.
      S., and Henson, P. M. (1998) J. Biol. Chem. 273, 8389-8397), signals regulating
      spontaneous neutrophil apoptosis have not been fully determined. In this study we
      found increased activation of protein kinase C (PKC)-beta and -delta in
      neutrophils undergoing spontaneous apoptosis, but we show that only activation of
      PKC-delta was directly involved in the induction of apoptosis. PKC-delta can be
      proteolytically activated by caspase 3. We detected the 40-kDa caspase-generated
      fragment of PKC-delta in apoptotic neutrophils and showed that the caspase 3
      inhibitor Asp-Glu-Val-Asp-fluoromethylketone prevented generation of the 40-kDa
      PKC-delta fragment and delayed neutrophil apoptosis. In a cell-free system,
      removal of PKC-delta by immunoprecipitation reduced DNA fragmentation, whereas
      loss of PKC-alpha, -beta, or -zeta had no significant effect. Rottlerin and
      LY379196 inhibit PKC-delta and PKC-beta, respectively. Only Rottlerin was able to
      delay neutrophil apoptosis. Inhibitors of MAP-ERK kinase 1 (PD98059) or p38 MAP
      kinase (SB202190) had no effect on neutrophil apoptosis, and activation of p42/44
      and p38 MAP kinase did not increase in apoptotic neutrophils. We conclude that
      spontaneous neutrophil apoptosis involves activation of PKC-delta but is MAP
      kinase-independent.

PMID- 10601301
TI  - Cloning, expression, and fatty acid regulation of the human delta-5 desaturase.
AB  - Arachidonic (20:4(n-6)), eicosapentaenoic (20:5(n-3)), and docosahexaenoic
      (22:6(n-3)) acids are major components of brain and retina phospholipids,
      substrates for eicosanoid production, and regulators of nuclear transcription
      factors. One of the two rate-limiting steps in the production of these polyenoic
      fatty acids is the desaturation of 20:3(n-6) and 20:4(n-3) by Delta-5 desaturase.
      This report describes the cloning and expression of the human Delta-5 desaturase,
      and it compares the structural characteristics and nutritional regulation of the
      Delta-5 and Delta-6 desaturases. The open reading frame of the human Delta-5
      desaturase encodes a 444-amino acid peptide which is identical in size to the
      Delta-6 desaturase and which shares 61% identity with the human Delta-6
      desaturase. The Delta-5 desaturase contains two membrane-spanning domains, three
      histidine-rich regions, and a cytochrome b(5) domain that all align perfectly
      with the same domains located in the Delta-6 desaturase. Expression of the open
      reading frame in Chinese hamster ovary cells instilled the ability to convert
      20:3(n-6) to 20:4(n-6). Northern analysis revealed that many human tissues
      including skeletal muscle, lung, placenta, kidney, and pancreas expressed Delta-5
      desaturase mRNA, but Delta-5 desaturase was most abundant in the liver, brain,
      and heart. However, in all tissues, the abundance of Delta-5 desaturase mRNA was
      much lower than that observed for the Delta-6 desaturase. When rats were fed a
      diet containing 10% safflower oil or menhaden fish oil, the level of hepatic mRNA
      for Delta-5 and Delta-6 desaturase was only 25% of that found in the liver of
      rats fed a fat-free diet or a diet containing triolein. Finally, a BLAST and
      Genemap search of the human genome revealed that the Delta-5 and Delta-6
      desaturase genes reside in reverse orientation on chromosome 11 and that they are
      separated by <11,000 base pairs.

PMID- 10601302
TI  - A mixture of alpha-helical and 3(10)-helical conformations for involucrin in the
      human epidermal corneocyte envelope provides a scaffold for the attachment of
      both lipids and proteins.
AB  - Involucrin plays an important role in the lipid and protein compound envelopes of
      mammalian epidermal corneocytes. In the present study, model peptides containing
      the consensus repeating units PEQQEGQLEL and LEQQEGQLEH, found in the central
      region of human involucrin, were studied by circular dichroism spectroscopy,
      molecular modeling, and energy minimization. These peptides have intrinsic alpha
      helix-forming properties as indicated by their circular dichroic spectra obtained
      in the presence of 2,2,2-trifluoroethanol. Peptide (LEQQEGQLEH)(3) had an alpha
      helix content of 100% in 100% 2, 2,2-trifluoroethanol at 0 degrees C. The energy
      minimized alpha-helix showed that only 50% of the glutamate side chains may be
      available for the attachment of lipids. However, when a 3(10)-helix was assumed
      for the GQL or GQLE residues in LEQQEGQLEH, all of the glutamate side chains were
      arrayed on one face of the helix, and all of the glutamine side chains were
      arrayed on the opposite face. A similar result was obtained when the nonhelical
      part of PEQQEGQLEL was assumed to contain a beta-turn III, which is equivalent to
      a short portion of 3(10)-helix. The results of this study suggest that when the
      central segment of human involucrin is predominantly alpha-helical, accompanied
      by short 3(10)-helical segments, the protein can function as a scaffold for the
      attachment of both lipids and proteins.

PMID- 10601303
TI  - Shape and specificity in mammalian 15-lipoxygenase active site. The functional
      interplay of sequence determinants for the reaction specificity.
AB  - Previous mutagenesis studies along with molecular modeling using the x-ray
      coordinates of the rabbit 15-lipoxygenase have led to the suggestion that the
      size of the substrate binding pocket may play an essential role in determining
      the oxygenation specificity of 5-, 12-, and 15-lipoxygenases. Based on the x-ray
      crystal structure of rabbit 15-lipoxygenase, Ile(593) appeared to be important in
      defining size and shape of the substrate-binding site in 15-lipoxygenases. We
      found that substitution of Ile(593) with alanine shifted the positional
      specificity of this enzyme toward 12-lipoxygenation. To compare the importance of
      position 593 with previously defined determinants for the oxygenation
      specificity, we introduced small (alanine-scan) or large amino acids
      (phenylalanine-scan) at critical positions surrounding the putative fatty acid
      binding site, so that the volume of the pocket was either increased or decreased.
      Enlargement or alteration in packing density within the substrate binding pocket
      in the rabbit 15-lipoxygenase increased the share of 12-lipoxygenase products,
      whereas a smaller active site favored 15-lipoxygenation. Simultaneous
      substitution of both large and small residues in the context of either a 15- or
      12-lipoxygenase indicated that there is a functional interplay of the sequence
      determinants for lipoxygenation specificity. If the 15-lipoxygenase active site
      is enlarged excessively, however, no lipoxygenation was observed anymore.
      Together these results indicate the importance of the overall size and shape of
      the arachidonic acid binding pocket in defining the specificity of lipoxygenase
      reaction.

PMID- 10601304
TI  - Specificity of insulin and insulin-like growth factor I receptors investigated
      using chimeric mini-receptors. Role of C-terminal of receptor alpha subunit.
AB  - We have investigated the role of the C-terminal of the alpha-subunit in the
      insulin receptor family by characterizing chimeric mini-receptor constructs
      comprising the first three domains (468 amino acids) of insulin receptor (IR) or
      insulin-like growth factor I receptor (IGFIR) combined with C-terminal domain
      from either insulin receptor (IR) (residues 704-719), IGFIR, or insulin receptor
      related receptor (IRRR). The constructs were stably expressed in baby hamster
      kidney cells and purified, and binding affinities were determined for insulin,
      IGFI, and a single chain insulin/IGFI hybrid. The C-terminal domain of IRRR was
      found to abolish binding in IR and IGFIR context, whereas other constructs bound
      ligands. The two constructs with first three domains of the IR demonstrated low
      specificity for ligands, all affinities ranging from 3.0 to 15 nM. In contrast,
      the constructs with the first three domains of the IGFIR had high specificity,
      the affinity of the novel minimized IGFIR for IGFI was 1.5 nM, whereas the
      affinity for insulin was more than 3000 nM. When swapping the C-terminal domains
      in either receptor context only minor changes were observed in affinities (<3
      fold), demonstrating that the carboxyl-terminal of IR and IGFIR alpha-subunits
      are interchangeable and suggesting that this domain is part of the common binding
      site.

PMID- 10601305
TI  - Temporal separation of insulin-stimulated GLUT4/IRAP vesicle plasma membrane
      docking and fusion in 3T3L1 adipocytes.
AB  - Examination of the time and temperature dependence of insulin-stimulated
      GLUT4/IRAP-containing vesicle trafficking demonstrated an approximate 7-fold
      increase in the half-time for plasma membrane translocation at 23 degrees C
      (t((1)/(2)) = approximately 30 min) compared with 37 degrees C (t((1)/(2)) =
      approximately 4 min) without a significant change in the extent of either GLUT4
      or IRAP translocation. Localization of the endogenous GLUT4 and expressed GLUT4
      enhanced green fluorescent protein fusion protein in intact 3T3L1 adipocytes
      demonstrated that at 23 degrees C there was a time-dependent accumulation of
      discrete GLUT4-containing vesicles adjacent to the inner face of the cell surface
      membrane but that was not contiguous and/or physically incorporated into the
      plasma membrane. Together, these data demonstrate that the temperature-dependent
      decrease in the rate of GLUT4 and IRAP translocation results from a reduction in
      GLUT4/IRAP-containing vesicle fusion and not trafficking or docking to the plasma
      membrane.

PMID- 10601306
TI  - Synergistic roles of neuregulin-1 and insulin-like growth factor-I in activation
      of the phosphatidylinositol 3-kinase pathway and cardiac chamber morphogenesis.
AB  - Cardiac chamber morphogenesis requires the coordinated growth of both cardiac
      muscle and endocardial cell lineages. Paracrine growth factors may modulate the
      coordinated cellular specification and differentiation during cardiac chamber
      morphogenesis, as suggested by the essential role of endothelial-derived growth
      factors, neuregulin-1, and insulin-like growth factor-I. Using the whole mouse
      embryo culture system for delivery of diffusible factors into the cardiac
      chamber, neuregulin-1 was shown to promote trabeculation of the ventricular wall.
      Another factor, insulin-like growth factor-I, had no apparent effect by itself.
      Combined treatment with neuregulin-1 and insulin-like growth factor-I strongly
      induced DNA synthesis of cardiomyocytes and expansion of both the ventricular
      compact zone and the atrioventricular cushions leading to chamber growth and
      maturation. In cultured cardiomyocytes, combined neuregulin-1 and insulin-like
      growth factor-I also had a synergistic effect to promote DNA synthesis and
      cellular growth, which were prevented by wortmannin, an inhibitor of
      phosphatidylinositol 3-kinase. Adenoviral delivery of dominant negative Rac1,
      which acts downstream of phosphatidylinositol 3-kinase, blocked the effect of
      combined neuregulin-1/insulin-like growth factor-I treatment. These studies
      support the concept that the interaction of neuregulin-1 and insulin-like growth
      factor-I pathways plays an important role in coordinating cardiac chamber
      morphogenesis and may occur through convergent activation of phosphatidylinositol
      3-kinase.

PMID- 10601307
TI  - The zinc finger cluster domain of RanBP2 is a specific docking site for the
      nuclear export factor, exportin-1.
AB  - The Ran-binding protein 2 (RanBP2) is a large scaffold cyclophilin-related
      protein expressed in photoreceptor cells. Red/green opsin, Ran-GTPase, and the 19
      S regulatory complex of the proteasome associate with specific RanBP2 structural
      modules. Some of these play a role in chaperoning the functional expression of
      opsin. RanBP2 localization at cytoplasmic fibrils emanating from the nuclear pore
      complex and interaction with the Ran-GTPase support also its role in
      nucleocytoplasmic transport processes. The degenerate nucleoporin repeat motifs
      FXFG, GLFG, and XXFG have been proposed to mediate the movement of
      nucleocytoplasmic transport factors. In particular, RanBP2 has been implicated in
      nuclear import processes. Here, we show the zinc fingers of RanBP2 associate with
      high specificity to the nuclear export factor, exportin-1 (CRM1). The bovine
      RanBP2 transcript contained only five of the eight zinc fingers reported in the
      human counterpart and are sufficient for exportin-1 association with RanBP2. In
      contrast to Ran interaction with RanBP2-exportin-1 complex, exportin-1 binding to
      the zinc finger cluster domain of RanBP2 is insensitive to leptomycin B and
      nucleotide-bound state of Ran-GTPase. Our results indicate that the zinc finger
      rich domain of RanBP2 constitutes a docking site for exportin-1 during nuclear
      export. Thus, RanBP2 emerges as a key component of the nuclear export pathway.

PMID- 10601308
TI  - Phosphorylation of serine 916 of Ras-GRF1 contributes to the activation of
      exchange factor activity by muscarinic receptors.
AB  - The Ras-GRF1 exchange factor is strongly implicated in the control of neuronal
      Ras. The activity of Ras-GRF1 is regulated by increases in intracellular calcium
      and the release of Gbetagamma subunits from heterotrimeric G-proteins. Increases
      in Ras-GRF1 activity toward Ras that are stimulated by receptors coupled to G
      proteins are associated with enhanced phosphorylation of Ras-GRF1 on one or more
      serine residues. Co-expression of Ras-GRF1 with subtype 1 human muscarinic
      receptors in COS-7 cells allowed mapping of a carbachol-stimulated
      phosphorylation site to a region composed of residues 916-976. Site-directed
      mutagenesis replaced each of the serine residues within this region with alanine
      and demonstrated that serine 916 is a major site of in vivo phosphorylation of
      Ras-GRF1 in both COS-7 cells and NIH-3T3 fibroblasts. Serine 916 was a substrate
      for protein kinase A both in vivo and in vitro, suggesting a novel link between
      the cAMP and Ras signaling systems. Carbachol-dependent phosphorylation of serine
      916 occurred through a protein kinase A-independent pathway, however. Full-length
      Ras-GRF1 that contains an alanine 916 mutation was only partially activated by
      carbachol, suggesting that phosphorylation at residue 916 is necessary for full
      activation. Phosphorylation of serine 916 in response to forskolin treatment did
      not, however, increase the activity of Ras-GRF1, indicating that it is not
      sufficient for activation.

PMID- 10601309
TI  - Inhibitory phosphorylation site for Rho-associated kinase on smooth muscle myosin
      phosphatase.
AB  - It is clear from several studies that myosin phosphatase (MP) can be inhibited
      via a pathway that involves RhoA. However, the mechanism of inhibition is not
      established. These studies were carried out to test the hypothesis that Rho
      kinase (Rho-associated kinase) via phosphorylation of the myosin phosphatase
      target subunit 1 (MYPT1) inhibited MP activity and to identify relevant sites of
      phosphorylation. Phosphorylation by Rho-kinase inhibited MP activity and this
      reflected a decrease in V(max). Activity of MP with different substrates also was
      inhibited by phosphorylation. Two major sites of phosphorylation on MYPT1 were
      Thr(695) and Thr(850). Various point mutations were designed for these
      phosphorylation sites. Following thiophosphorylation by Rho-kinase and assays of
      phosphatase activity it was determined that Thr(695) was responsible for
      inhibition. A site- and phosphorylation-specific antibody was developed for the
      sequence flanking Thr(695) and this recognized only phosphorylated Thr(695) in
      both native and recombinant MYPT1. Using this antibody it was shown that
      stimulation of serum-starved Swiss 3T3 cells by lysophosphatidic acid, thought to
      activate RhoA pathways, induced an increase in Thr(695) phosphorylation on MYPT1
      and this effect was blocked by a Rho-kinase inhibitor, Y-27632. In summary, these
      results offer strong support for a physiological role of Rho-kinase in regulation
      of MP activity.

PMID- 10601310
TI  - New lessons for combinatorial biosynthesis from myxobacteria. The myxothiazol
      biosynthetic gene cluster of Stigmatella aurantiaca DW4/3-1.
AB  - The biosynthetic mta gene cluster responsible for myxothiazol formation from the
      fruiting body forming myxobacterium Stigmatella aurantiaca DW4/3-1 was sequenced
      and analyzed. Myxothiazol, an inhibitor of the electron transport via the bc(1)
      complex of the respiratory chain, is biosynthesized by a unique combination of
      several polyketide synthases (PKS) and nonribosomal peptide synthetases (NRPS),
      which are activated by the 4'-phosphopantetheinyl transferase MtaA. Genomic
      replacement of a fragment of mtaB and insertion of a kanamycin resistance gene
      into mtaA both impaired myxothiazol synthesis. Genes mtaC and mtaD encode the
      enzymes for bis-thiazol(ine) formation and chain extension on one pure NRPS
      (MtaC) and on a unique combination of PKS and NRPS (MtaD). The genes mtaE and
      mtaF encode PKSs including peptide fragments with homology to methyltransferases.
      These methyltransferase modules are assumed to be necessary for the formation of
      the proposed methoxy- and beta-methoxy-acrylate intermediates of myxothiazol
      biosynthesis. The last gene of the cluster, mtaG, again resembles a NRPS and
      provides insight into the mechanism of the formation of the terminal amide of
      myxothiazol. The carbon backbone of an amino acid added to the myxothiazol-acid
      is assumed to be removed via an unprecedented module with homology to
      monooxygenases within MtaG.

PMID- 10601311
TI  - Evidence that 3-phosphoinositide-dependent protein kinase-1 mediates
      phosphorylation of p70 S6 kinase in vivo at Thr-412 as well as Thr-252.
AB  - Protein kinase B and p70 S6 kinase are members of the cyclic AMP-dependent/cyclic
      GMP-dependent/protein kinase C subfamily of protein kinases and are activated by
      a phosphatidylinositol 3-kinase-dependent pathway when cells are stimulated with
      insulin or growth factors. Both of these kinases are activated in cells by
      phosphorylation of a conserved residue in the kinase domain (Thr-308 of protein
      kinase B (PKB) and Thr-252 of p70 S6 kinase) and another conserved residue
      located C-terminal to the kinase domain (Ser-473 of PKB and Thr-412 of p70 S6
      kinase). Thr-308 of PKBalpha and Thr-252 of p70 S6 kinase are phosphorylated by 3
      phosphoinositide-dependent protein kinase-1 (PDK1) in vitro. Recent work has
      shown that PDK1 interacts with a region of protein kinase C-related kinase-2,
      termed the PDK1 interacting fragment (PIF). Interaction with PIF converts PDK1
      from a form that phosphorylates PKB at Thr-308 alone to a species capable of
      phosphorylating Ser-473 as well as Thr-308. This suggests that PDK1 may be the
      enzyme that phosphorylates both residues in vivo. Here we demonstrate that PDK1
      is capable of phosphorylating p70 S6 kinase at Thr-412 in vitro. We study the
      effect of PIF on the ability of PDK1 to phosphorylate p70 S6 kinase.
      Surprisingly, we find that PDK1 bound to PIF is no longer able to interact with
      or phosphorylate p70 S6 kinase in vitro at either Thr-252 or Thr-412. The
      expression of PIF in cells prevents insulin-like growth factor 1 from inducing
      the activation of the p70 S6 kinase and its phosphorylation at Thr-412.
      Overexpression of PDK1 in cells induces the phosphorylation of p70 S6 kinase at
      Thr-412 in unstimulated cells, and a catalytically inactive mutant of PDK1
      prevents the phosphorylation of p70 S6K at Thr-412 in insulin-like growth factor
      1-stimulated cells. These observations indicate that PDK1 regulates the
      activation of p70 S6 kinase and provides evidence that PDK1 mediates the
      phosphorylation of p70 S6 kinase at Thr-412.

PMID- 10601312
TI  - Molecular cloning, characterization, and expression of a novel human neutral
      sphingomyelinase.
AB  - Neutral sphingomyelinase (N-SMase) has emerged as an important cell membrane
      associated enzyme that participates in several signal transduction and cell
      regulatory phenomena. Using expression cloning, we have identified a 3.7-kilobase
      pair cDNA transcript for N-SMase whose open reading frame predicts a 397-amino
      acid polypeptide. Transfection of COS-7 cells with cDNA for N-SMase resulted in a
      marked increase in N-SMase activity. Recombinant N-SMase (r-N-SMase) had the
      following physical-chemical properties. Mg(2+) activated and Cu(2+) and
      glutathione inhibited the activity of r-N-SMase. In contrast, dithiothreitol did
      not alter the activity of the enzyme. Of several phospholipids examined,
      sphingomyelin was the preferred substrate for r-N-SMase. The apparent molecular
      mass of r-N-SMase derived from COS-7 cells was approximately 90 kDa, similar to
      the native neutral sphingomyelinase prepared from human urine. However, upon
      expression in Escherichia coli, the apparent molecular mass of the recombinant
      enzyme was approximately 45 kDa. We speculate that this apparent difference in
      recombinant enzymes derived from COS-7 and E. coli cells may be due to extensive
      post-transcriptional changes. r-N-SMase has numerous post-transcriptional
      modification sites such as phosphorylation sites via protein kinase C, casein
      kinase II, tyrosine kinase, and cAMP- and cGMP-dependent protein kinases as well
      as sites for glycosylation and myristoylation. Amino acid sequence alignment
      studies revealed that r-N-SMase has some similarity to acid sphingomyelinase and
      significant homology to the death domains of tumor necrosis factor-alpha receptor
      1 and Fas/Apo-I. We believe that the molecular cloning and characterization of N
      SMase cDNA will accelerate the process to define its role as a key regulator in
      apoptosis, lipid and lipoprotein metabolism, and other cell regulatory pathways.

PMID- 10601313
TI  - Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated
      transcription.
AB  - SMAD and JNK cascades are essential components of the transforming growth factor
      beta (TGF-beta) signaling machinery and are implicated in common transcriptional
      responses. However, the relationship of these pathways to one another downstream
      of the TGF-beta receptor complex is unknown. We show that JNK is rapidly
      activated by TGF-beta in a SMAD-independent manner and phosphorylates Smad3
      outside its -SSXS motif. Smad3 phosphorylation by JNK facilitates both its
      activation by the TGF-beta receptor complex and its nuclear accumulation. JNK
      regulates SMAD- and TGF-beta-mediated transcriptional responses, yet JNK
      activators only partially stimulate transcriptional responses characteristic of
      TGF-beta without coincident SMAD pathway activation. These results suggest an
      interdependent relationship between the JNK and SMAD pathways in TGF-beta
      mediated transcription.

PMID- 10601314
TI  - The essential transfer protein TraM binds to DNA as a tetramer.
AB  - The TraM proteins encoded by F-like plasmids are sequence specific DNA binding
      proteins that are essential for conjugative DNA transfer. We investigated the
      quarternary structure and the DNA binding properties of the TraM wild-type
      protein of the resistance plasmid R1 and two mutant forms thereof. Size-exclusion
      chromatography and differential scanning calorimetry showed that purified TraM
      protein (amino acids 2-127) forms stable tetramers in solution. A truncated
      version of the protein termed TraMM26 (amino acids 2-56) forms dimers. Thus, the
      dimerization and tetramerization domains can be assigned to the N-terminal and C
      terminal domains of TraM, respectively. Further analyses using chemical cross
      linking and light scattering corroborated the preferentially tetrameric nature of
      the protein but also suggest that TraM has a tendency to form higher aggregates.
      Band-shift and fluorescence spectroscopy investigations of TraM-DNA complexes
      revealed that the TraM protein is also tetrameric when bound to its minimal DNA
      binding site. The deduced binding constant in the range of 10(8) M(-1)
      demonstrated a very strong binding of TraM to its preferred DNA sequence.
      Secondary structure analysis based on CD measurements showed that TraM is mainly
      alpha-helical with a significant increase in alpha-helicity (48 to 58%) upon DNA
      binding, indicating an induced fit mechanism.

PMID- 10601315
TI  - A novel interaction of cGMP-dependent protein kinase I with troponin T.
AB  - cGMP-dependent protein kinase (cGK) is a major intracellular receptor of cGMP and
      is implicated in several signal transduction pathways. To identify proteins that
      participate in the cGMP/cGK signaling pathway, we employed the yeast two-hybrid
      system with cGK Ialpha as bait. cDNAs encoding slow skeletal troponin T (skTnT)
      were isolated from both mouse embryo and human skeletal muscle cDNA libraries.
      The skTnT protein interacted with cGK Ibeta but not with cGK II nor cAMP
      dependent protein kinase. The yeast two-hybrid and in vitro binding assays
      revealed that the N-terminal region of cGK Ialpha, containing the leucine zipper
      motif, is sufficient for the association with skTnT. In vivo analysis, mutations
      in cGK Ialpha, which disrupted the leucine zipper motif, were shown to completely
      abolish the binding to skTnT. Furthermore, cGK I also interacted with cardiac TnT
      (cTnT) but not with cardiac troponin I (cTnI). Together with the observations
      that cTnI is a good substrate for cGK I and is effectively phosphorylated in the
      presence of cTnT in vitro, these findings suggest that TnT functions as an
      anchoring protein for cGK I and that cGK I may participate in the regulation of
      muscle contraction through phosphorylation of TnI.

PMID- 10601316
TI  - N-Myristoylation and betagamma play roles beyond anchorage in the palmitoylation
      of the G protein alpha(o) subunit.
AB  - Many of the alpha subunits of heterotrimeric GTP-binding regulatory proteins (G
      proteins) are palmitoylated, a modification proposed to play a key role in the
      stable anchorage of the subunits to the plasma membrane. Palmitoylation of alpha
      subunits from the G(i) family is preceded by N-myristoylation, which alone or
      together with betagamma probably supports a reversible interaction of the alpha
      subunit with membrane as a prerequisite to the eventual incorporation of
      palmitate. Previous studies have not addressed, however, the question of whether
      membrane association alone, carried out through N-myristoylation, interaction
      with betagamma, or other events, is sufficient for palmitoylation. We report here
      for alpha(o) that it is not. We found that N-myristoylation is required for
      palmitoylation at least in part because it supports events subsequent to membrane
      attachment. Mutants of alpha(o) designed to target the subunit to membrane
      without an N-myristoyl group are unable to be palmitoylated as evaluated by
      incorporation of [(3)H]palmitate. Mutants of alpha(o) unable to interact normally
      with betagamma yet still attach to membrane demonstrate that betagamma, in
      contrast, is not required for palmitoylation. betagamma becomes necessary,
      however, when the N-myristoyl group is absent. Our results suggest that N
      myristoylation and betagamma, while almost certainly relevant to the reversible
      interaction of alpha(o) with membrane, also play at least partly overlapping,
      post-anchorage roles in palmitoylation.

PMID- 10601317
TI  - His(73), often methylated, is an important structural determinant for actin. A
      mutagenic analysis of HIS(73) of yeast actin.
AB  - His(73), has been proposed to regulate the release of P(i) from the interior of
      actin following polymerization-dependent hydrolysis of bound ATP. Although it is
      a 3-methylhistidine in the vast majority of actins, His(73) is unmethylated in S.
      cerevisiae actin. We mutated His(73) in yeast actin to Arg, Lys, Ala, Gln, and
      Glu and detected no altered phenotypes associated with the mutations in vivo.
      However, they significantly affect actin function in vitro. Substitution of the
      more basic residues resulted in enhanced thermal stability, decreased rate of
      nucleotide exchange, and decreased susceptibility to controlled proteolysis
      relative to wild-type actin. The opposite effects are observed with the neutral
      and anionic substitutions. All mutations reduced the rate of polymerization.
      Molecular dynamics simulations predict a new conformation for the His(73)
      imidazole in the absence of a methyl group. It also predicts that Arg(73)
      tightens and stabilizes the actin and that Glu(73) causes a rearrangement of the
      bottom of actin's interdomain cleft leading possibly to our observed
      destabilization of actin. Considering the exterior location of His(73), this work
      indicates a surprisingly important role for the residue as a major structural
      determinant of actin and provides a clue to the impact caused by methylation of
      His(73).

PMID- 10601318
TI  - DNA fragmentation factor 45-deficient cells are more resistant to apoptosis and
      exhibit different dying morphology than wild-type control cells.
AB  - The DNA fragmentation factor 45 (DFF45) is a subunit of a heterodimeric DNase
      complex critical for the induction of DNA fragmentation in vitro. To understand
      the in vivo role of DFF45 in programmed cell death, we measured the expression of
      DFF45 during mouse development and compared DNA fragmentation and viability of
      DFF45-deficient cells with wild-type control cells after activation of apoptosis.
      We found that DFF45 is ubiquitously expressed throughout mouse development.
      Moreover, DFF45-deficient thymocytes are resistant to DNA fragmentation with in
      vivo dexamethasone treatment. Furthermore, primary thymocytes from DFF45 mutant
      mice are also more resistant to apoptosis than wild-type control cells on
      exposure to several apoptotic stimuli. Dying DFF45-deficient thymocytes exhibit
      different morphology than wild-type control cells in that they show reduced
      degree of chromatin condensation, absent nuclear fragmentation, intranuclear
      cytoplasmic invagination, and striking nuclear chromatin conglutination after
      release from disintegrating cells. These results indicate that DFF45 is essential
      during normal apoptosis.

PMID- 10601319
TI  - Transcriptional activation of the human manganese superoxide dismutase gene
      mediated by tetradecanoylphorbol acetate.
AB  - Transcriptional activation of human manganese superoxide dismutase (MnSOD) mRNA
      induced by a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), was
      examined to identify the responsive transcriptional regulator. The effect of
      various deletions and mutations within the 5'-flanking region of the human MnSOD
      gene promoter was evaluated using the luciferase reporter system in A549 human
      lung carcinoma cells. Deletion of a region between -1292 and -1202 nucleotides
      upstream of the transcription start site abolished TPA-responsive induction,
      whereas deletion of the putative binding sequence for NF-kappaB or AP-1 did not.
      The region between -1292 and -1202 contains a cAMP-responsive element-like
      sequence, TGACGTCT, which we identified as the manganese superoxide dismutase TPA
      responsive element, MSTRE. Site-specific mutation of the MSTRE abolished the TPA
      responsive induction, validating the critical role of this sequence. We detected
      specific MSTRE activity from nuclear extracts and demonstrated by antibody
      supershift assay that this activity is closely related to CREB-1/ATF-1. TPA
      treatment rapidly induced phosphorylation of the CREB-1/ATF-1-like factor via the
      protein kinase C pathway. These results led us to conclude that the human MnSOD
      gene having the promoter construct used in this study is induced by TPA via
      activation of a CREB-1/ATF-1-like factor and not via either NF-kappaB or AP-1. In
      addition, we found that this induction was blocked by inhibitors of flavoproteins
      and NADPH oxidases, indicating involvement of enhanced generation of superoxide
      radical anion as an upstream signal.

PMID- 10601320
TI  - Connective tissue growth factor induces apoptosis in human breast cancer cell
      line MCF-7.
AB  - Connective tissue growth factor (CTGF) is a member of an emerging CCN gene family
      that is implicated in various diseases associated with fibro-proliferative
      disorder including scleroderma and atherosclerosis. The function of CTGF in human
      cancer is largely unknown. We now show that CTGF induces apoptosis in the human
      breast cancer cell line MCF-7. CTGF mRNA was completely absent in MCF-7 but
      strongly induced by treatment with transforming growth factor beta (TGF-beta).
      TGF-beta by itself induced apoptosis in MCF-7, and this effect was reversed by co
      treatment with CTGF antisense oligonucleotide. Overexpression of CTGF gene in
      transiently transfected MCF-7 cells significantly augmented apoptosis. Moreover,
      recombinant CTGF protein significantly enhanced apoptosis in MCF-7 cells as
      evaluated by DNA fragmentation, Tdt-mediated dUTP biotin nick end-labeling
      staining, flow cytometry analysis, and nuclear staining using Hoechst 33258.
      Finally, recombinant CTGF showed no effect on Bax protein expression but
      significantly reduced Bcl2 protein expression. Taken together, these results
      suggest that CTGF is a major inducer of apoptosis in the human breast cancer cell
      line MCF-7 and that TGF-beta-induced apoptosis in MCF-7 cells is mediated, in
      part, by CTGF.

PMID- 10601321
TI  - Tic40, a new "old" subunit of the chloroplast protein import translocon.
AB  - The protein import translocon at the inner envelope of chloroplasts (Tic complex)
      is a heteroligomeric multisubunit complex. Here, we describe Tic40 from pea as a
      new component of this complex. Tic40 from pea is a homologue of a protein
      described earlier from Brassica napus as Cim/Com44 or the Toc36 subunit of the
      translocon at the outer envelope of chloroplasts, respectively (Wu, C., Seibert,
      F. S., and Ko, K. (1994) J. Biol. Chem. 269, 32264-32271; Ko, K., Budd, D., Wu,
      C., Seibert, F., Kourtz, L., and Ko, Z. W. (1995) J. Biol. Chem. 270, 28601
      28608; Pang, P., Meathrel, K., and Ko, K. (1997) J. Biol. Chem. 272, 25623
      25627). Tic40 can be covalently connected to Tic110 by the formation of a
      disulfide bridge under oxidizing conditions, indicating its close physical
      proximity to an established translocon component. The Tic40 protein is
      synthesized in the cytosol as a precursor with an N-terminal cleavable
      chloroplast targeting signal and imported into the organelle via the general
      import pathway. Immunoblotting and immunogold-labeling studies exclusively
      confine Tic40 to the chloroplastic inner envelope, in which it is anchored by a
      single putative transmembrane span.

PMID- 10601322
TI  - The Wilms' tumor 1 tumor suppressor gene represses transcription of the human
      telomerase reverse transcriptase gene.
AB  - Regulation of the human telomerase reverse transcriptase (hTERT) gene is the
      primary determinant for telomerase enzyme activity, which is found in tumor cells
      but is largely absent from normal somatic cells. Recent studies have shown that
      Myc protein can transcriptionally activate the hTERT gene. However, little is
      known about the repression mechanism of the hTERT gene and telomerase enzyme.
      Here, we developed an expression cloning strategy to identify cDNAs whose
      products can repress hTERT promoter activity in telomerase-positive immortal
      cells. Using this screen, we isolated the Wilms' tumor 1 suppressor gene (WT1).
      WT1 can repress hTERT promoter activity in 293 kidney cells. The WT1 binding site
      on the hTERT promoter was identified by deletional analysis. Alteration of the
      WT1 binding site markedly derepresses transcription from an isolated hTERT
      promoter by inhibiting interaction of WT1 with DNA. These specific repression
      effects of WT1 were not observed in HeLa cells, which express no endogenous WT1.
      Furthermore, we show that WT1 can repress the endogenous hTERT promoter and
      telomerase enzyme activities. These results suggest that WT1 may be a
      transcriptional repressor of the hTERT gene, at least in some specific cells.

PMID- 10601323
TI  - ATP binding properties of the nucleotide-binding folds of SUR1.
AB  - Pancreatic beta cell ATP-sensitive potassium (K(ATP)) channels regulate glucose
      induced insulin secretion. The activity of the K(ATP) channel, composed of SUR1
      and Kir6.2 subunits, is regulated by intracellular ATP and ADP, but the molecular
      mechanism is not clear. To distinguish the ATP binding properties of the two
      nucleotide-binding folds (NBFs) of SUR1, we prepared antibodies against NBF1 and
      NBF2, and the tryptic fragment of SUR1 was immunoprecipitated after photoaffinity
      labeling with 8-azido-[(32)P]ATP. The 35-kDa fragment was strongly labeled with 5
      microM 8-azido-[(32)P]ATP even in the absence of Mg(2+) and was
      immunoprecipitated with the antibody against NBF1. The 65-kDa fragment labeled
      with 100 microM 8-azido-[alpha-(32)P]ATP in the presence of Mg(2+) was
      immunoprecipitated with anti-NBF2 and anti-C terminus antibodies. These results
      indicate that NBF1 of SUR1 binds 8-azido-ATP strongly in a magnesium-independent
      manner and that NBF2 binds 8-azido-ATP weakly in a magnesium-dependent manner.
      Furthermore, the 65-kDa tryptic fragment was not photoaffinity-labeled with 8
      azido-[gamma-(32)P]ATP at 37 degrees C, whereas the 35-kDa tryptic fragment was,
      suggesting that NBF2 of SUR1 may have ATPase activity and that NBF1 has none or
      little.

PMID- 10601324
TI  - Activity of the Nurr1 carboxyl-terminal domain depends on cell type and integrity
      of the activation function 2.
AB  - Nurr1, a member of the nuclear hormone receptor superfamily, was recently
      demonstrated to be of critical importance in the developing central nervous
      system, where it is required for the generation of midbrain dopamine cells.
      Nuclear receptors encompass a transcriptional activation function (activation
      function 2; AF2) within their carboxyl-terminal domains important for ligand
      induced transcriptional activation. Since a Nurr1 ligand remains to be
      identified, the role of the Nurr1 AF2 region in transcriptional activation is
      unclear. However, here we show that the Nurr1 AF2 contributes to constitutive
      activation independent of exogenously added ligands in human embryo kidney 293
      cells and in neural cell lines. Extensive mutagenesis indicated a crucial role of
      the AF2 core region for transactivation but also identified unique features
      differing from previously characterized receptors. In addition, Nurr1 did not
      appear to interact with, and was not stimulated by, several previously identified
      coactivators such as the steroid receptor coactivator 1. In contrast, adenovirus
      protein E1A, stably expressed in 293 cells, was shown to contribute to AF2
      dependent activation. Finally, while the AF2 core of RXR is required for ligand
      induced transcriptional activation by Nurr1-RXR heterodimers, the functional
      integrity of Nurr1 AF2 core is not critical. These results establish that the
      ligand binding domain of Nurr1 has intrinsic capacity for transcriptional
      activation depending on cell type and mode of DNA binding. Furthermore, these
      results are consistent with the possibility that gene expression in the central
      nervous system can be modulated by an as yet unidentified ligand interacting with
      the ligand binding domain of Nurr1.

PMID- 10601325
TI  - The CNC basic leucine zipper factor, Nrf1, is essential for cell survival in
      response to oxidative stress-inducing agents. Role for Nrf1 in gamma-gcs(l) and
      gss expression in mouse fibroblasts.
AB  - Nrf1 is a member of the CNC-basic leucine zipper (CNC-bZIP) family of
      transcription factors. CNC bZIP factors, together with small Maf proteins, bind
      as heterodimers to the NF-E2/AP-1 element. Similarity between the NF-E2/AP-1
      element and the antioxidant response element identified in a number of promoters
      of genes involved in detoxification and antioxidant response raises the
      possibility that Nrf1 plays a role in mediating the antioxidant response element
      response. In this study, we exploited the availability of cells from Nrf1
      knockout mice to study the role of Nrf1 transcription factor in the regulation of
      antioxidant gene expression and in cellular antioxidant response. Fibroblast
      cells derived from Nrf1 null embryos showed lower levels of glutathione and
      enhanced sensitivity to the toxic effects of oxidant compounds. Our results
      indicate that Nrf1 plays a role in the regulation of genes involved in
      glutathione synthesis and suggest a basis for a correspondingly low GSH
      concentration and reduced stress response.

PMID- 10601326
TI  - Activation of PKC delta in the rat corpus luteum during pregnancy. Potential role
      of prolactin signaling.
AB  - Maintenance of pregnancy in the rat requires the corpus luteum. At a time when
      rat placental lactogens (rPLs) are required to support progesterone production by
      the corpus luteum and when relaxin expression is initiated, expression of a
      specific protein kinase C (PKC) isoform, PKC delta, is dramatically increased. We
      therefore assessed whether prolactin (PRL) receptor activation promotes
      activation of PKC delta in a luteinized granulosa cell model. We also assessed
      the activation status of PKC delta in corpora lutea obtained when the corpus
      luteum is exposed to chronically high concentrations of rPLs. The activity of PKC
      delta was assessed by two means: an immune complex (IC) assay and Western
      blotting with a phospho-epitope-specific antibody that detects PKC delta
      phosphorylated on serine 662. PKC delta activation in the IC kinase assay was
      determined by the ability of immunoprecipitated PKC delta to phosphorylate the
      PKC delta-preferential substrate small heat shock protein (HSP-27). Treatment of
      luteinized rat granulosa cells with phorbol myristate acetate, a known activator
      of PKC, promoted a 7-fold increase in HSP-27 phosphorylation by PKC delta.
      Similarly, immunoreactivity with the phospho-epitope-specific PKC delta antibody
      was increased in extracts prepared from luteinized granulosa cells treated with
      phorbol myristate acetate or following in vitro activation of recombinant PKC
      delta. Using these assays, we assessed whether PRL receptor agonists were capable
      of activating PKC delta in luteinized granulosa cells. PRL receptor agonists
      induced translocation PKC delta from the cytosolic to the Triton-soluble membrane
      fraction and increased PKC delta activity assessed by both IC kinase assay and
      Western blotting with phospho-epitope-specific PKC delta antibody. Analysis of
      PKC delta activity in corpora lutea obtained during pregnancy by both the IC
      kinase assay and Western blotting with the phospho-epitope-specific PKC delta
      antibody revealed that PKC delta activity was increased throughout the second
      half of pregnancy. These results demonstrate that PRL receptor activation
      promotes the acute activation of PKC delta in luteinized rat granulosa cells. At
      a time when the rat is exposed to chronically high concentrations of rPLs, PKC
      delta is increasingly expressed and active.

PMID- 10601327
TI  - Axonal control of oligodendrocyte development.

PMID- 10601328
TI  - A novel regulatory mechanism of MAP kinases activation and nuclear translocation
      mediated by PKA and the PTP-SL tyrosine phosphatase.
AB  - Protein tyrosine phosphatase PTP-SL retains mitogen-activated protein (MAP)
      kinases in the cytoplasm in an inactive form by association through a kinase
      interaction motif (KIM) and tyrosine dephosphorylation. The related tyrosine
      phosphatases PTP-SL and STEP were phosphorylated by the cAMP-dependent protein
      kinase A (PKA). The PKA phosphorylation site on PTP-SL was identified as the
      Ser(231) residue, located within the KIM. Upon phosphorylation of Ser(231), PTP
      SL binding and tyrosine dephosphorylation of the MAP kinases extracellular signal
      regulated kinase (ERK)1/2 and p38alpha were impaired. Furthermore, treatment of
      COS-7 cells with PKA activators, or overexpression of the Calpha catalytic
      subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38alpha by wild
      type PTP-SL, but not by a PTP-SL S231A mutant. These findings support the
      existence of a novel mechanism by which PKA may regulate the activation and
      translocation to the nucleus of MAP kinases.

PMID- 10601329
TI  - Mutations in the alpha-tubulin 67C gene specifically impair achiasmate
      segregation in Drosophila melanogaster.
AB  - Drosophila melanogaster oocytes heterozygous for mutations in the alpha-tubulin
      67C gene (alphatub67C) display defects in centromere positioning during
      prometaphase of meiosis I. The centromeres do not migrate to the poleward edges
      of the chromatin mass, and the chromatin fails to stretch during spindle
      lengthening. These results suggest that the poleward forces acting at the
      kinetochore are compromised in the alphatub67C mutants. Genetic studies
      demonstrate that these mutations also strongly and specifically decrease the
      fidelity of achiasmate chromosome segregation. Proper centromere orientation,
      chromatin elongation, and faithful segregation can all be restored by a decrease
      in the amount of the Nod chromokinesin. These results suggest that the accurate
      segregation of achiasmate chromosomes requires the proper balancing of forces
      acting on the chromosomes during prometaphase.

PMID- 10601330
TI  - Axo-glial interactions regulate the localization of axonal paranodal proteins.
AB  - Mice incapable of synthesizing the abundant galactolipids of myelin exhibit
      disrupted paranodal axo-glial interactions in the central and peripheral nervous
      systems. Using these mutants, we have analyzed the role that axo-glial
      interactions play in the establishment of axonal protein distribution in the
      region of the node of Ranvier. Whereas the clustering of the nodal proteins,
      sodium channels, ankyrin(G), and neurofascin was only slightly affected, the
      distribution of potassium channels and paranodin, proteins that are normally
      concentrated in the regions juxtaposed to the node, was dramatically altered. The
      potassium channels, which are normally concentrated in the
      paranode/juxtaparanode, were not restricted to this region but were detected
      throughout the internode in the galactolipid-defi- cient mice.
      Paranodin/contactin-associated protein (Caspr), a paranodal protein that is a
      potential neuronal mediator of axon-myelin binding, was not concentrated in the
      paranodal regions but was diffusely distributed along the internodal regions.
      Collectively, these findings suggest that the myelin galactolipids are essential
      for the proper formation of axo-glial interactions and demonstrate that a
      disruption in these interactions results in profound abnormalities in the
      molecular organization of the paranodal axolemma.

PMID- 10601331
TI  - Duplication and maintenance of heterochromatin domains.
AB  - To investigate the mechanisms that assure the maintenance of heterochromatin
      regions, we took advantage of the fact that clusters of heterochromatin DNA
      replicate late in S phase and are processed in discrete foci with a
      characteristic nuclear distribution. At the light microscopy level, within these
      entities, we followed DNA synthesis, histone H4 acetylation, heterochromatin
      protein 1 (Hp1alpha and -beta), and chromatin assembly factor 1 (CAF-1). During
      replication, Hp1alpha and -beta domains of concentration are stably maintained,
      whereas heterochromatin regions are enriched in both CAF-1 and replication
      specific acetylated isoforms of histone H4 (H4Ac 5 and 12). We defined a time
      window of 20 min for the maintenance of this state. Furthermore, treatment with
      Trichostatin A (TSA), during and after replication, sustains the H4Ac 5 and 12
      state in heterochromatin excluding H4Ac 8 and 16. In comparison, early
      replication foci, at the same level, did not display any specific enrichment in
      H4Ac 5 and 12. These data emphasize the specific importance for heterochromatin
      of the replication-associated H4 isoforms. We propose that perpetuation of
      heterochromatin involves self-maintenance factors, including local concentration
      of Hp1alpha and -beta, and that a degree of plasticity is provided by the cycle
      of H4 acetylation/deacetylation assisted by CAF-1.

PMID- 10601332
TI  - The A-kinase-anchoring protein AKAP95 is a multivalent protein with a key role in
      chromatin condensation at mitosis.
AB  - Protein kinase A (PKA) and the nuclear A-kinase-anchoring protein AKAP95 have
      previously been shown to localize in separate compartments in interphase but
      associate at mitosis. We demonstrate here a role for the mitotic AKAP95-PKA
      complex. In HeLa cells, AKAP95 is associated with the nuclear matrix in
      interphase and redistributes mostly into a chromatin fraction at mitosis. In a
      cytosolic extract derived from mitotic cells, AKAP95 recruits the RIIalpha
      regulatory subunit of PKA onto chromatin. Intranuclear immunoblocking of AKAP95
      inhibits chromosome condensation at mitosis and in mitotic extract in a PKA
      independent manner. Immunodepletion of AKAP95 from the extract or immunoblocking
      of AKAP95 at metaphase induces premature chromatin decondensation. Condensation
      is restored in vitro by a recombinant AKAP95 fragment comprising the 306-carboxy
      terminal amino acids of the protein. Maintenance of condensed chromatin requires
      PKA binding to chromatin-associated AKAP95 and cAMP signaling through PKA.
      Chromatin-associated AKAP95 interacts with Eg7, the human homologue of Xenopus
      pEg7, a component of the 13S condensin complex. Moreover, immunoblocking nuclear
      AKAP95 inhibits the recruitment of Eg7 to chromatin in vitro. We propose that
      AKAP95 is a multivalent molecule that in addition to anchoring a cAMP/PKA
      signaling complex onto chromosomes, plays a role in regulating chromosome
      structure at mitosis.

PMID- 10601333
TI  - Gemin3: A novel DEAD box protein that interacts with SMN, the spinal muscular
      atrophy gene product, and is a component of gems.
AB  - The survival of motor neurons (SMN) gene is the disease gene of spinal muscular
      atrophy (SMA), a common motor neuron degenerative disease. The SMN protein is
      part of a complex containing several proteins, of which one, SIP1 (SMN
      interacting protein 1), has been characterized so far. The SMN complex is found
      in both the cytoplasm and in the nucleus, where it is concentrated in bodies
      called gems. In the cytoplasm, SMN and SIP1 interact with the Sm core proteins of
      spliceosomal small nuclear ribonucleoproteins (snRNPs), and they play a critical
      role in snRNP assembly. In the nucleus, SMN is required for pre-mRNA splicing,
      likely by serving in the regeneration of snRNPs. Here, we report the
      identification of another component of the SMN complex, a novel DEAD box putative
      RNA helicase, named Gemin3. Gemin3 interacts directly with SMN, as well as with
      SmB, SmD2, and SmD3. Immunolocalization studies using mAbs to Gemin3 show that it
      colocalizes with SMN in gems. Gemin3 binds SMN via its unique COOH-terminal
      domain, and SMN mutations found in some SMA patients strongly reduce this
      interaction. The presence of a DEAD box motif in Gemin3 suggests that it may
      provide the catalytic activity that plays a critical role in the function of the
      SMN complex on RNPs.

PMID- 10601334
TI  - Stress-associated endoplasmic reticulum protein 1 (SERP1)/Ribosome-associated
      membrane protein 4 (RAMP4) stabilizes membrane proteins during stress and
      facilitates subsequent glycosylation.
AB  - Application of differential display to cultured rat astrocytes subjected to
      hypoxia allowed cloning of a novel cDNA, termed stress-associated endoplasmic
      reticulum protein 1 (SERP1). Expression of SERP1 was enhanced in vitro by hypoxia
      and/or reoxygenation or other forms of stress, causing accumulation of unfolded
      proteins in endoplasmic reticulum (ER) stress, and in vivo by middle cerebral
      artery occlusion in rats. The SERP1 cDNA encodes a 66-amino acid polypeptide
      which was found to be identical to ribosome-associated membrane protein 4 (RAMP4)
      and bearing 29% identity to yeast suppressor of SecY 6 protein (YSY6p),
      suggesting participation in pathways controlling membrane protein biogenesis at
      ER. In cultured 293 cells subjected to ER stress, overexpression of SERP1/RAMP4
      suppressed aggregation and/or degradation of newly synthesized integral membrane
      proteins, and subsequently, facilitated their glycosylation when the stress was
      removed. SERP1/RAMP4 interacted with Sec61alpha and Sec61beta, which are subunits
      of translocon, and a molecular chaperon calnexin. Furthermore, Sec61alpha and
      Sec61beta, but not SERP1/RAMP4, were found to associate with newly synthesized
      integral membrane proteins under stress. These results suggest that stabilization
      of membrane proteins in response to stress involves the concerted action of a
      rescue unit in the ER membrane comprised of SERP1/RAMP4, other components of
      translocon, and molecular chaperons in ER.

PMID- 10601335
TI  - ER to Golgi transport: Requirement for p115 at a pre-Golgi VTC stage.
AB  - The membrane transport factor p115 functions in the secretory pathway of
      mammalian cells. Using biochemical and morphological approaches, we show that
      p115 participates in the assembly and maintenance of normal Golgi structure and
      is required for ER to Golgi traffic at a pre-Golgi stage. Injection of antibodies
      against p115 into intact WIF-B cells caused Golgi disruption and inhibited Golgi
      complex reassembly after BFA treatment and wash-out. Addition of anti-p115
      antibodies or depletion of p115 from a VSVtsO45 based semi-intact cell transport
      assay inhibited transport. The inhibition occurred after VSV glycoprotein (VSV-G)
      exit from the ER but before its delivery to the Golgi complex, and resulted in
      VSV-G protein accumulating in peripheral vesicular tubular clusters (VTCs). The
      p115-requiring step of transport followed the rab1-requiring step and preceded
      the Ca(2+)-requiring step. Unexpectedly, mannosidase I redistributed from the
      Golgi complex to colocalize with VSV-G protein arrested in pre-Golgi VTCs by p115
      depletion. Redistribution of mannosidase I was also observed in cells incubated
      at 15 degrees C. Our data show that p115 is essential for the translocation of
      pre-Golgi VTCs from peripheral sites to the Golgi stack. This defines a
      previously uncharacterized function for p115 at the VTC stage of ER to Golgi
      traffic.

PMID- 10601336
TI  - Role for Drs2p, a P-type ATPase and potential aminophospholipid translocase, in
      yeast late Golgi function.
AB  - ADP-ribosylation factor appears to regulate the budding of both COPI and clathrin
      coated transport vesicles from Golgi membranes. An arf1Delta synthetic lethal
      screen identified SWA3/DRS2, which encodes an integral membrane P-type ATPase and
      potential aminophospholipid translocase (or flippase). The drs2 null allele is
      also synthetically lethal with clathrin heavy chain (chc1) temperature-sensitive
      alleles, but not with mutations in COPI subunits or other SEC genes tested.
      Consistent with these genetic analyses, we found that the drs2Delta mutant
      exhibits late Golgi defects that may result from a loss of clathrin function at
      this compartment. These include a defect in the Kex2-dependent processing of pro
      alpha-factor and the accumulation of abnormal Golgi cisternae. Moreover, we
      observed a marked reduction in clathrin-coated vesicles that can be isolated from
      the drs2Delta cells. Subcellular fractionation and immunofluorescence analysis
      indicate that Drs2p localizes to late Golgi membranes containing Kex2p. These
      observations indicate a novel role for a P-type ATPase in late Golgi function and
      suggest a possible link between membrane asymmetry and clathrin function at the
      Golgi complex.

PMID- 10601337
TI  - Intracellular trafficking of variant chicken kidney AE1 anion exchangers: role Of
      alternative NH(2) termini in polarized sorting and Golgi recycling.
AB  - The variant chicken kidney AE1 anion exchangers differ only at the NH(2) terminus
      of their cytoplasmic domains. Transfection studies have indicated that the
      variant chicken AE1-4 anion exchanger accumulates in the basolateral membrane of
      polarized MDCK kidney epithelial cells, while the AE1-3 variant, which lacks the
      NH(2)-terminal 63 amino acids of AE1-4, primarily accumulates in the apical
      membrane. Mutagenesis studies have shown that the basolateral accumulation of AE1
      4 is dependent upon two tyrosine residues at amino acids 44 and 47 of the
      polypeptide. Interestingly, either of these tyrosines is sufficient to direct
      efficient basolateral sorting of AE1-4. However, in the absence of both tyrosine
      residues, AE1-4 accumulates in the apical membrane of MDCK cells. Pulse-chase
      studies have shown that after delivery to the cell surface, newly synthesized AE1
      4 is recycled to the Golgi where it acquires additional N-linked sugar
      modifications. This Golgi recycling activity is dependent upon the same
      cytoplasmic tyrosine residues that are required for the basolateral sorting of
      this variant transporter. Furthermore, mutants of AE1-4 that are defective in
      Golgi recycling are unable to associate with the detergent insoluble actin
      cytoskeleton and are rapidly turned over. These studies, which represent the
      first description of tyrosine-dependent cytoplasmic sorting signal for a type III
      membrane protein, have suggested a critical role for the actin cytoskeleton in
      regulating AE1 anion exchanger localization and stability in this epithelial cell
      type.

PMID- 10601338
TI  - Botulinum neurotoxin A blocks synaptic vesicle exocytosis but not endocytosis at
      the nerve terminal.
AB  - The supply of synaptic vesicles in the nerve terminal is maintained by a
      temporally linked balance of exo- and endocytosis. Tetanus and botulinum
      neurotoxins block neurotransmitter release by the enzymatic cleavage of proteins
      identified as critical for synaptic vesicle exocytosis. We show here that
      botulinum neurotoxin A is unique in that the toxin-induced block in exocytosis
      does not arrest vesicle membrane endocytosis. In the murine spinal cord, cell
      cultures exposed to botulinum neurotoxin A, neither K(+)-evoked neurotransmitter
      release nor synaptic currents can be detected, twice the ordinary number of
      synaptic vesicles are docked at the synaptic active zone, and its protein
      substrate is cleaved, which is similar to observations with tetanus and other
      botulinal neurotoxins. In marked contrast, K(+) depolarization, in the presence
      of Ca(2+), triggers the endocytosis of the vesicle membrane in botulinum
      neurotoxin A-blocked cultures as evidenced by FM1-43 staining of synaptic
      terminals and uptake of HRP into synaptic vesicles. These experiments are the
      first demonstration that botulinum neurotoxin A uncouples vesicle exo- from
      endocytosis, and provide evidence that Ca(2+) is required for synaptic vesicle
      membrane retrieval.

PMID- 10601339
TI  - Dynein intermediate chain mediated dynein-dynactin interaction is required for
      interphase microtubule organization and centrosome replication and separation in
      Dictyostelium.
AB  - Cytoplasmic dynein intermediate chain (IC) mediates dynein-dynactin interaction
      in vitro (Karki, S., and E.L. Holzbaur. 1995. J. Biol. Chem. 270:28806-28811;
      Vaughan, K.T., and R.B. Vallee. 1995. J. Cell Biol. 131:1507-1516). To
      investigate the physiological role of IC and dynein-dynactin interaction, we
      expressed IC truncations in wild-type Dictyostelium cells. ICDeltaC associated
      with dynactin but not with dynein heavy chain, whereas ICDeltaN truncations bound
      to dynein but bound dynactin poorly. Both mutations resulted in abnormal
      localization to the Golgi complex, confirming dynein function was disrupted.
      Striking disorganization of interphase microtubule (MT) networks was observed
      when mutant expression was induced. In a majority of cells, the MT networks
      collapsed into large bundles. We also observed cells with multiple cytoplasmic
      asters and MTs lacking an organizing center. These cells accumulated abnormal DNA
      content, suggesting a defect in mitosis. Striking defects in centrosome
      morphology were also observed in IC mutants, mostly larger than normal
      centrosomes. Ultrastructural analysis of centrosomes in IC mutants showed
      interphase accumulation of large centrosomes typical of prophase as well as
      unusually paired centrosomes, suggesting defects in centrosome replication and
      separation. These results suggest that dynactin-mediated cytoplasmic dynein
      function is required for the proper organization of interphase MT network as well
      as centrosome replication and separation in Dictyostelium.

PMID- 10601340
TI  - Microtubule actin cross-linking factor (MACF): a hybrid of dystonin and
      dystrophin that can interact with the actin and microtubule cytoskeletons.
AB  - We cloned and characterized a full-length cDNA of mouse actin cross-linking
      family 7 (mACF7) by sequential rapid amplification of cDNA ends-PCR. The
      completed mACF7 cDNA is 17 kb and codes for a 608-kD protein. The closest
      relative of mACF7 is the Drosophila protein Kakapo, which shares similar
      architecture with mACF7. mACF7 contains a putative actin-binding domain and a
      plakin-like domain that are highly homologous to dystonin (BPAG1-n) at its NH(2)
      terminus. However, unlike dystonin, mACF7 does not contain a coiled-coil rod
      domain; instead, the rod domain of mACF7 is made up of 23 dystrophin-like
      spectrin repeats. At its COOH terminus, mACF7 contains two putative EF-hand
      calcium-binding motifs and a segment homologous to the growth arrest-specific
      protein, Gas2. In this paper, we demonstrate that the NH(2)-terminal actin
      binding domain of mACF7 is functional both in vivo and in vitro. More
      importantly, we found that the COOH-terminal domain of mACF7 interacts with and
      stabilizes microtubules. In transfected cells full-length mACF7 can associate not
      only with actin but also with microtubules. Hence, we suggest a modified name:
      MACF (microtubule actin cross-linking factor). The properties of MACF are
      consistent with the observation that mutations in kakapo cause disorganization of
      microtubules in epidermal muscle attachment cells and some sensory neurons.

PMID- 10601341
TI  - Vertebrate isoforms of actin capping protein beta have distinct functions In
      vivo.
AB  - Actin capping protein (CP) binds barbed ends of actin filaments to regulate actin
      assembly. CP is an alpha/beta heterodimer. Vertebrates have conserved isoforms of
      each subunit. Muscle cells contain two beta isoforms. beta1 is at the Z-line;
      beta2 is at the intercalated disc and cell periphery in general. To investigate
      the functions of the isoforms, we replaced one isoform with another using
      expression in hearts of transgenic mice. Mice expressing beta2 had a severe
      phenotype with juvenile lethality. Myofibril architecture was severely disrupted.
      The beta2 did not localize to the Z-line. Therefore, beta1 has a distinct
      function that includes interactions at the Z-line. Mice expressing beta1 showed
      altered morphology of the intercalated disc, without the lethality or myofibril
      disruption of the beta2-expressing mice. The in vivo function of CP is presumed
      to involve binding barbed ends of actin filaments. To test this hypothesis, we
      expressed a beta1 mutant that poorly binds actin. These mice showed both
      myofibril disruption and intercalated disc remodeling, as predicted. Therefore,
      CPbeta1 and CPbeta2 each have a distinct function that cannot be provided by the
      other isoform. CPbeta1 attaches actin filaments to the Z-line, and CPbeta2
      organizes the actin at the intercalated discs.

PMID- 10601342
TI  - Blood platelets are assembled principally at the ends of proplatelet processes
      produced by differentiated megakaryocytes.
AB  - Megakaryocytes release mature platelets in a complex process. Platelets are known
      to be released from intermediate structures, designated proplatelets, which are
      long, tubelike extensions of the megakaryocyte cytoplasm. We have resolved the
      ultrastructure of the megakaryocyte cytoskeleton at specific stages of
      proplatelet morphogenesis and correlated these structures with cytoplasmic
      remodeling events defined by video microscopy. Platelet production begins with
      the extension of large pseudopodia that use unique cortical bundles of
      microtubules to elongate and form thin proplatelet processes with bulbous ends;
      these contain a peripheral bundle of microtubules that loops upon itself and
      forms a teardrop-shaped structure. Contrary to prior observations and
      assumptions, time-lapse microscopy reveals proplatelet processes to be extremely
      dynamic structures that interconvert reversibly between spread and tubular forms.
      Microtubule coils similar to those observed in blood platelets are detected only
      at the ends of proplatelets and not within the platelet-sized beads found along
      the length of proplatelet extensions. Growth and extension of proplatelet
      processes is associated with repeated bending and bifurcation, which results in
      considerable amplification of free ends. These aspects are inhibited by
      cytochalasin B and, therefore, are dependent on actin. We propose that mature
      platelets are assembled de novo and released only at the ends of proplatelets,
      and that the complex bending and branching observed during proplatelet
      morphogenesis represents an elegant mechanism to increase the numbers of
      proplatelet ends.

PMID- 10601343
TI  - Keratocytes pull with similar forces on their dorsal and ventral surfaces.
AB  - As cells move forward, they pull rearward against extracellular matrices (ECMs),
      exerting traction forces. However, no rearward forces have been seen in the fish
      keratocyte. To address this discrepancy, we have measured the propulsive forces
      generated by the keratocyte lamella on both the ventral and the dorsal surfaces.
      On the ventral surface, a micromachined device revealed that traction forces were
      small and rearward directed under the lamella, changed direction in front of the
      nucleus, and became larger under the cell body. On the dorsal surface of the
      lamella, an optical gradient trap measured rearward forces generated against
      fibronectin-coated beads. The retrograde force exerted by the cell on the bead
      increased in the thickened region of the lamella where myosin condensation has
      been observed (Svitkina, T.M., A.B. Verkhovsky, K.M. McQuade, and G. G. Borisy.
      1997. J. Cell Biol. 139:397-415). Similar forces were generated on both the
      ventral (0.2 nN/microm(2)) and the dorsal (0.4 nN/microm(2)) surfaces of the
      lamella, suggesting that dorsal matrix contacts are as effectively linked to the
      force-generating cytoskeleton as ventral contacts. The correlation between the
      level of traction force and the density of myosin suggests a model for keratocyte
      movement in which myosin condensation in the perinuclear region generates
      rearward forces in the lamella and forward forces in the cell rear.

PMID- 10601344
TI  - Induction of cell scattering by expression of beta1 integrins in beta1-deficient
      epithelial cells requires activation of members of the rho family of GTPases and
      downregulation of cadherin and catenin function.
AB  - Adhesion receptors, which connect cells to each other and to the surrounding
      extracellular matrix (ECM), play a crucial role in the control of tissue
      structure and of morphogenesis. In this work, we have studied how intercellular
      adhesion molecules and beta1 integrins influence each other using two different
      beta1-null cell lines, epithelial GE11 and fibroblast-like GD25 cells. Expression
      of beta1A or the cytoplasmic splice variant beta1D, induced the disruption of
      intercellular adherens junctions and cell scattering in both GE11 and GD25 cells.
      In GE11 cells, the morphological change correlated with the redistribution of
      zonula occluden (ZO)-1 from tight junctions to adherens junctions at high cell
      confluency. In addition, the expression of beta1 integrins caused a dramatic
      reorganization of the actin cytoskeleton and of focal contacts. Interaction of
      beta1 integrins with their respective ligands was required for a complete
      morphological transition towards the spindle-shaped fibroblast-like phenotype.
      The expression of an interleukin-2 receptor (IL2R)-beta1A chimera and its
      incorporation into focal adhesions also induced the disruption of cadherin-based
      adhesions and the reorganization of ECM-cell contacts, but failed to promote cell
      migration on fibronectin, in contrast to full-length beta1A. This indicates that
      the disruption of cell-cell adhesion is not simply the consequence of the
      stimulated cell migration. Expression of beta1 integrins in GE11 cells resulted
      in a decrease in cadherin and alpha-catenin protein levels accompanied by their
      redistribution from the cytoskeleton-associated fraction to the detergent-soluble
      fraction. Regulation of alpha-catenin protein levels by beta1 integrins is likely
      to play a role in the morphological transition, since overexpression of alpha
      catenin in GE11 cells before beta1 prevented the disruption of intercellular
      adhesions and cell scattering. In addition, using biochemical activity assays for
      Rho-like GTPases, we show that the expression of beta1A, beta1D, or IL2R-beta1A
      in GE11 or GD25 cells triggers activation of both RhoA and Rac1, but not of
      Cdc42. Moreover, dominant negative Rac1 (N17Rac1) inhibited the disruption of
      cell-cell adhesions when expressed before beta1. However, all three GTPases might
      be involved in the morphological transition, since expression of either N19RhoA,
      N17Rac1, or N17Cdc42 reversed cell scattering and partially restored cadherin
      based adhesions in GE11-beta1A cells. Our results indicate that beta1 integrins
      regulate the polarity and motility of epithelial cells by the induction of
      intracellular molecular events involving a downregulation of alpha-catenin
      function and the activation of the Rho-like G proteins Rac1 and RhoA.

PMID- 10601345
TI  - Cell elongation induces laminin alpha2 chain expression in mouse embryonic
      mesenchymal cells: role in visceral myogenesis.
AB  - Bronchial smooth muscle (SM) mesenchymal cell precursors change their shape from
      round to spread/elongated while undergoing differentiation. Here we show that
      this change in cell shape induces the expression of laminin (LM) alpha2 chain not
      present in round mesenchymal cells. LM alpha2 expression is reversible and
      switched on and off by altering the cell's shape in culture. In comparison, the
      expression of LM beta1 and gamma1 remains unchanged. Functional studies showed
      that mesenchymal cell spreading and further differentiation into SM are inhibited
      by an antibody against LM alpha2. Dy/dy mice express very low levels of LM alpha2
      and exhibit congenital muscular dystrophy. Lung SM cells isolated from adult
      dy/dy mice spread defectively and synthesized less SM alpha-actin, desmin, and SM
      myosin than controls. These deficiencies were completely corrected by exogenous
      LM-2. On histological examination, dy/dy mouse airways and gastrointestinal tract
      had shorter SM cells, and lungs from dy/dy mice contained less SM-specific
      protein. The intestine, however, showed compensatory hyperplasia, perhaps related
      to its higher contractile activity. This study therefore demonstrated a novel
      role for the LM alpha2 chain in SM myogenesis and showed that its decrease in
      dy/dy mice results in abnormal SM.

PMID- 10601346
TI  - Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3,
      with the COOH termini of claudins.
AB  - ZO-1, ZO-2, and ZO-3, which contain three PDZ domains (PDZ1 to -3), are
      concentrated at tight junctions (TJs) in epithelial cells. TJ strands are mainly
      composed of two distinct types of four-transmembrane proteins, occludin, and
      claudins, between which occludin was reported to directly bind to ZO-1/ZO-2/ZO-3.
      However, in occludin-deficient intestinal epithelial cells, ZO-1/ZO-2/ZO-3 were
      still recruited to TJs. We then examined the possible interactions between ZO
      1/ZO-2/ZO-3 and claudins. ZO-1, ZO-2, and ZO-3 bound to the COOH-terminal YV
      sequence of claudin-1 to -8 through their PDZ1 domains in vitro. Then, claudin-1
      or -2 was transfected into L fibroblasts, which express ZO-1 but not ZO-2 or ZO
      3. Claudin-1 and -2 were concentrated at cell-cell borders in an elaborate
      network pattern, to which endogenous ZO-1 was recruited. When ZO-2 or ZO-3 were
      further transfected, both were recruited to the claudin-based networks together
      with endogenous ZO-1. Detailed analyses showed that ZO-2 and ZO-3 are recruited
      to the claudin-based networks through PDZ2 (ZO-2 or ZO-3)/PDZ2 (endogenous ZO-1)
      and PDZ1 (ZO-2 or ZO-3)/COOH-terminal YV (claudins) interactions. In good
      agreement, PDZ1 and PDZ2 domains of ZO-1/ZO-2/ZO-3 were also recruited to claudin
      based TJs, when introduced into cultured epithelial cells. The possible molecular
      architecture of TJ plaque structures is discussed.

PMID- 10601347
TI  - Caspases. Multifunctional proteases.

PMID- 10601348
TI  - Antisense translates into sense.

PMID- 10601349
TI  - C-reactive protein and complement are important mediators of tissue damage in
      acute myocardial infarction.
AB  - Myocardial infarction in humans provokes an acute phase response, and C-reactive
      protein (CRP), the classical acute phase plasma protein, is deposited together
      with complement within the infarct. The peak plasma CRP value is strongly
      associated with postinfarct morbidity and mortality. Human CRP binds to damaged
      cells and activates complement, but rat CRP does not activate complement. Here we
      show that injection of human CRP into rats after ligation of the coronary artery
      reproducibly enhanced infarct size by approximately 40%. In vivo complement
      depletion, produced by cobra venom factor, completely abrogated this effect.
      Complement depletion also markedly reduced infarct size, even when initiated up
      to 2 h after coronary ligation. These observations demonstrate that human CRP and
      complement activation are major mediators of ischemic myocardial injury and
      identify them as therapeutic targets in coronary heart disease.

PMID- 10601350
TI  - Commitment and differentiation of osteoclast precursor cells by the sequential
      expression of c-Fms and receptor activator of nuclear factor kappaB (RANK)
      receptors.
AB  - Osteoclasts are terminally differentiated cells derived from hematopoietic stem
      cells. However, how their precursor cells diverge from macrophagic lineages is
      not known. We have identified early and late stages of osteoclastogenesis, in
      which precursor cells sequentially express c-Fms followed by receptor activator
      of nuclear factor kappaB (RANK), and have demonstrated that RANK expression in
      early-stage of precursor cells (c-Fms(+)RANK(-)) was stimulated by macrophage
      colony-stimulating factor (M-CSF). Although M-CSF and RANKL (ligand) induced
      commitment of late-stage precursor cells (c-Fms(+)RANK(+)) into osteoclasts, even
      late-stage precursors have the potential to differentiate into macrophages
      without RANKL. Pretreatment of precursors with M-CSF and delayed addition of
      RANKL showed that timing of RANK expression and subsequent binding of RANKL are
      critical for osteoclastogenesis. Thus, the RANK-RANKL system determines the
      osteoclast differentiation of bipotential precursors in the default pathway of
      macrophagic differentiation.

PMID- 10601351
TI  - Macrophage inflammatory protein 3alpha is involved in the constitutive
      trafficking of epidermal langerhans cells.
AB  - Certain types of dendritic cells (DCs) appear in inflammatory lesions of various
      etiologies, whereas other DCs, e.g., Langerhans cells (LCs), populate peripheral
      organs constitutively. Until now, the molecular mechanism behind such
      differential behavior has not been elucidated. Here, we show that CD1a(+) LC
      precursors respond selectively and specifically to the CC chemokine macrophage
      inflammatory protein (MIP)-3alpha. In contrast, CD14(+) precursors of DC and
      monocytes are not attracted by MIP-3alpha. LCs lose the migratory responsiveness
      to MIP-3alpha during their maturation, and non-LC DCs do not acquire MIP-3alpha
      sensitivity. The notion that MIP-3alpha may be responsible for selective LC
      recruitment into the epidermis is further supported by the following
      observations: (a) MIP-3alpha is expressed by keratinocytes and venular
      endothelial cells in clinically normal appearing human skin; (b) LCs express CC
      chemokine receptor (CCR)6, the sole MIP-3alpha receptor both in situ and in
      vitro; and (c) non-LC DCs that are not found in normal epidermis lack CCR6. The
      mature forms of LCs and non-LC DCs display comparable sensitivity for MIP-3beta,
      a CCR7 ligand, suggesting that DC subtype-specific chemokine responses are
      restricted to the committed precursor stage. Although LC precursors express
      primarily CCR6, non-LC DC precursors display a broad chemokine receptor
      repertoire. These findings reflect a scenario where the differential expression
      of chemokine receptors by two different subpopulations of DCs determines their
      functional behavior. One type, the LC, responds to MIP-3alpha and enters skin to
      screen the epidermis constitutively, whereas the other type, the "inflammatory"
      DC, migrates in response to a wide array of different chemokines and is involved
      in the amplification and modulation of the inflammatory tissue response.

PMID- 10601352
TI  - Targeted gene disruption demonstrates that P-selectin glycoprotein ligand 1 (PSGL
      1) is required for P-selectin-mediated but not E-selectin-mediated neutrophil
      rolling and migration.
AB  - P-selectin glycoprotein ligand 1 (PSGL-1) is a mucin-like selectin
      counterreceptor that binds to P-selectin, E-selectin, and L-selectin. To
      determine its physiological role in cell adhesion as a mediator of leukocyte
      rolling and migration during inflammation, we prepared mice genetically deficient
      in PSGL-1 by targeted disruption of the PSGL-1 gene. The homozygous PSGL-1
      deficient mouse was viable and fertile. The blood neutrophil count was modestly
      elevated. There was no evidence of spontaneous development of skin ulcerations or
      infections. Leukocyte infiltration in the chemical peritonitis model was
      significantly delayed. Leukocyte rolling in vivo, studied by intravital
      microscopy in postcapillary venules of the cremaster muscle, was markedly
      decreased 30 min after trauma in the PSGL-1-deficient mouse. In contrast,
      leukocyte rolling 2 h after tumor necrosis factor alpha stimulation was only
      modestly reduced, but blocking antibodies to E-selectin infused into the PSGL-1
      deficient mouse almost completely eliminated leukocyte rolling. These results
      indicate that PSGL-1 is required for the early inflammatory responses but not for
      E-selectin-mediated responses. These kinetics are consistent with a model in
      which PSGL-1 is the predominant neutrophil P-selectin ligand but is not a
      required counterreceptor for E-selectin under in vivo physiological conditions.

PMID- 10601353
TI  - Invasion by Toxoplasma gondii establishes a moving junction that selectively
      excludes host cell plasma membrane proteins on the basis of their membrane
      anchoring.
AB  - The protozoan parasite Toxoplasma gondii actively penetrates its host cell by
      squeezing through a moving junction that forms between the host cell plasma
      membrane and the parasite. During invasion, this junction selectively controls
      internalization of host cell plasma membrane components into the parasite
      containing vacuole. Membrane lipids flowed past the junction, as shown by the
      presence of the glycosphingolipid G(M1) and the cationic lipid label 1. 1'
      dihexadecyl-3-3'-3-3'-tetramethylindocarbocyanine (DiIC(16)).
      Glycosylphosphatidylinositol (GPI)-anchored surface proteins, such as Sca-1 and
      CD55, were also readily incorporated into the parasitophorous vacuole (PV). In
      contrast, host cell transmembrane proteins, including CD44, Na(+)/K(+) ATPase,
      and beta1-integrin, were excluded from the vacuole. To eliminate potential
      differences in sorting due to the extracellular domains, parasite invasion was
      examined in host cells transfected with recombinant forms of intercellular
      adhesion molecule 1 (ICAM-1, CD54) that differed in their mechanism of membrane
      anchoring. Wild-type ICAM-1, which contains a transmembrane domain, was excluded
      from the PV, whereas both GPI-anchored ICAM-1 and a mutant of ICAM-1 missing the
      cytoplasmic tail (ICAM-1-Cyt(-)) were readily incorporated into the PV membrane.
      Our results demonstrate that during host cell invasion, Toxoplasma selectively
      excludes host cell transmembrane proteins at the moving junction by a mechanism
      that depends on their anchoring in the membrane, thereby creating a nonfusigenic
      compartment.

PMID- 10601354
TI  - A new antigen recognized by cytolytic T lymphocytes on a human kidney tumor
      results from reverse strand transcription.
AB  - By stimulating blood lymphocytes from a renal cell carcinoma patient in vitro
      with the autologous tumor cells, we obtained cytolytic T lymphocyte (CTL) clones
      that killed several autologous and allogeneic histocompatibility leukocyte
      antigen (HLA)-B7 renal carcinoma cell lines. We identified the target antigen of
      these CTLs by screening COS cells transfected with the HLA-B7 cDNA and with a
      cDNA library prepared with RNA from the tumor cells. The antigenic peptide
      recognized by the CTLs has the sequence LPRWPPPQL and is encoded by a new gene,
      which we named RU2. This gene is transcribed in both directions. The antigenic
      peptide is not encoded by the sense transcript, RU2S, which is expressed
      ubiquitously. It is encoded by an antisense transcript, RU2AS, which starts from
      a cryptic promoter located on the reverse strand of the first intron and ends up
      on the reverse strand of the RU2S promoter, which contains a polyadenylation
      signal. This mechanism of antigen expression is unprecedented and further
      illustrates the notion that many peptides recognized by T cells cannot be
      predicted from the primary structure of the major product of the encoding gene.
      Antisense transcript RU2AS is expressed in a high proportion of tumors of various
      histological types. It is absent in most normal tissues, but is expressed in
      testis and kidney, and, at lower levels, in urinary bladder and liver. Short-term
      cultures of normal epithelial cells from the renal proximal tubule expressed
      significant levels of RU2AS message and were recognized by the CTLs. Therefore,
      this antigen is not tumor specific, but corresponds to a self-antigen with
      restricted tissue distribution.

PMID- 10601355
TI  - Recognition of the class Ib molecule Qa-1(b) by putative activating receptors
      CD94/NKG2C and CD94/NKG2E on mouse natural killer cells.
AB  - The heterodimeric CD94/NKG2A receptor, expressed by mouse natural killer (NK)
      cells, transduces inhibitory signals upon recognition of its ligand, Qa-1(b), a
      nonclassical major histocompatibility complex class Ib molecule. Here we clone
      and express two additional receptors, CD94/NKG2C and CD94/NKG2E, which we show
      also bind to Qa-1(b). Within their extracellular carbohydrate recognition
      domains, NKG2C and NKG2E share extensive homology with NKG2A (93-95% amino acid
      similarity); however, NKG2C/E receptors differ from NKG2A in their cytoplasmic
      domains (only 33% similarity) and contain features that suggest that CD94/NKG2C
      and CD94/NKG2E may be activating receptors. We employ a novel blocking anti-NKG2
      monoclonal antibody to provide the first direct evidence that CD94/NKG2 molecules
      are the only Qa-1(b) receptors on NK cells. Molecular analysis reveals that NKG2C
      and NKG2E messages are extensively alternatively spliced and approximately 20
      fold less abundant than NKG2A message in NK cells. The organization of the mouse
      Cd94/Nkg2 gene cluster, presented here, shows striking similarity with that of
      the human, arguing that the entire CD94/NKG2 receptor system is relatively
      primitive in origin. Analysis of synonymous substitution frequencies suggests
      that within a species, NKG2 genes may maintain similarities with each other by
      concerted evolution, possibly involving gene conversion-like events. These
      findings have implications for understanding NK cells and also raise new
      possibilities for the role of Qa-1 in immune responses.

PMID- 10601356
TI  - Monocyte chemoattractant protein 1-dependent leukocytic infiltrates are
      responsible for autoimmune disease in MRL-Fas(lpr) mice.
AB  - Infiltrating leukocytes may be responsible for autoimmune disease. We
      hypothesized that the chemokine monocyte chemoattractant protein (MCP)-1 recruits
      macrophages and T cells into tissues that, in turn, are required for autoimmune
      disease. Using the MRL-Fas(lpr) strain with spontaneous, fatal autoimmune
      disease, we constructed MCP-1-deficient MRL-Fas(lpr) mice. In MCP-1-intact MRL
      Fas(lpr) mice, macrophages and T cells accumulate at sites (kidney tubules,
      glomeruli, pulmonary bronchioli, lymph nodes) in proportion to MCP-1 expression.
      Deleting MCP-1 dramatically reduces macrophage and T cell recruitment but not
      proliferation, protects from kidney, lung, skin, and lymph node pathology,
      reduces proteinuria, and prolongs survival. Notably, serum immunoglobulin (Ig)
      isotypes and kidney Ig/C3 deposits are not diminished in MCP-1-deficient MRL
      Fas(lpr) mice, highlighting the requirement for MCP-1-dependent leukocyte
      recruitment to initiate autoimmune disease. However, MCP-1-deficient mice are not
      completely protected from leukocytic invasion. T cells surrounding vessels with
      meager MCP-1 expression remain. In addition, downstream effector
      cytokines/chemokines are decreased in MCP-1-deficient mice, perhaps reflecting a
      reduction of cytokine-expressing leukocytes. Thus, MCP-1 promotes MRL-Fas(lpr)
      autoimmune disease through macrophage and T cell recruitment, amplified by
      increasing local cytokines/chemokines. We suggest that MCP-1 is a principal
      therapeutic target with which to combat autoimmune diseases.

PMID- 10601357
TI  - The Trypanosoma cruzi trans-sialidase, through its COOH-terminal tandem repeat,
      upregulates interleukin 6 secretion in normal human intestinal microvascular
      endothelial cells and peripheral blood mononuclear cells.
AB  - The Trypanosoma cruzi trans-sialidase can sensitize mice to become highly
      susceptible to T. cruzi invasion, through mechanisms that remain unknown. In
      pursuing this observation, we found that purified trans-sialidase induces the
      selective release of biologically active interleukin (IL)-6 in naive human
      intestinal microvascular endothelial cells (HIMECs), peripheral blood mononuclear
      cells (PBMCs), and bladder carcinoma cells. The trans-sialidase action was
      independent of its catalytic activity, as demonstrated with a genetically
      engineered trans-sialidase mutant, an enzymatically active polypeptide, and
      cocultures of PBMCs with epimastigotes and trypomastigotes. Instead, the trans
      sialidase action was reproduced with a recombinant COOH-terminal tandem repeat
      and with synthetic peptides modeled on the tandem repeat. Most interesting,
      HIMECs infected with a trypomastigote population expressing trans-sialidase
      effectively released IL-6, but did not upon infection with the counterpart
      trypomastigote population expressing low trans-sialidase levels. IL-6 is a key
      factor in the regulation and symptom formation of infection caused by several
      types of viruses, such as HIV and influenza A virus. However, the function of IL
      6 in protozoan and other parasitic diseases remains unclear. The unique findings
      presented here suggest that trans-sialidase is a major inducer of IL-6 secretion
      in T. cruzi infection, independently of immune cell activation. Such IL-6
      secretion might underlie some features of Chagas's disease, such as pyrexia,
      neuroprotection, and fibrosis, and might result in the undermining of normal
      acquired immunity against T. cruzi.

PMID- 10601358
TI  - Lineage-specific modulation of interleukin 4 signaling by interferon regulatory
      factor 4.
AB  - Interleukin (IL)-4 is an immunoregulatory cytokine that exerts distinct
      biological activities on different cell types. Our studies indicate that
      interferon regulatory factor (IRF)-4 is both a target and a modulator of the IL-4
      signaling cascade. IRF-4 expression is strongly upregulated upon costimulation of
      B cells with CD40 and IL-4. Furthermore, we find that IRF-4 can interact with
      signal transducer and activator of transcription (Stat)6 and drive the expression
      of IL-4-inducible genes. The transactivating ability of IRF-4 is blocked by the
      repressor factor BCL-6. Since expression of IRF-4 is mostly confined to lymphoid
      cells, these data provide a potential mechanism by which IL-4-inducible genes can
      be regulated in a lineage-specific manner.

PMID- 10601359
TI  - Dynamin 2 is required for phagocytosis in macrophages.
AB  - Cells internalize soluble ligands through endocytosis and large particles through
      actin-based phagocytosis. The dynamin family of GTPases mediates the scission of
      endocytic vesicles from the plasma membrane. We report here that dynamin 2, a
      ubiquitously expressed dynamin isoform, has a role in phagocytosis in
      macrophages. Dynamin 2 is enriched on early phagosomes, and expression of a
      dominant-negative mutant of dynamin 2 significantly inhibits particle
      internalization at the stage of membrane extension around the particle. This
      arrest in phagocytosis resembles that seen with inhibitors of phosphoinositide 3
      kinase (PI3K), and inhibition of PI3K prevents the recruitment of dynamin to the
      site of particle binding. Although expression of mutant dynamin in macrophages
      inhibited particle internalization, it had no effect on the production of
      inflammatory mediators elicited by particle binding.

PMID- 10601360
TI  - Experimental transmission of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8)
      to SCID-hu Thy/Liv mice.
AB  - Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) is a novel human
      lymphotropic herpesvirus linked to several human neoplasms. To date, no animal
      model for infection by this virus has been described. We have examined the
      susceptibility of C.B-17 scid/scid mice implanted with human fetal thymus and
      liver grafts (SCID-hu Thy/Liv mice) to KSHV infection. KSHV virions were
      inoculated directly into the implants, and viral DNA and mRNA production was
      assayed using real-time quantitative polymerase chain reaction. This revealed a
      biphasic infection, with an early phase of lytic replication accompanied and
      followed by sustained latency. Ultraviolet irradiation of the inoculum abolished
      all DNA- and mRNA-derived signals, and infection was inhibited by ganciclovir.
      Viral gene expression was most abundant in CD19(+) B lymphocytes, suggesting that
      this model faithfully mimics the natural tropism of this virus. Short-term
      coinfection with HIV-1 did not alter the course of KSHV replication, nor did KSHV
      alter levels of HIV-1 p24 during the acute phase of the infection. Although no
      disease was evident in infected animals, SCID-hu Thy/Liv mice should allow the
      detailed study of KSHV tropism, latency, and drug susceptibility.

PMID- 10601361
TI  - The selection of M3-restricted T cells is dependent on M3 expression and
      presentation of N-formylated peptides in the thymus.
AB  - The major histocompatibility complex (MHC) class Ib molecule H2-M3 binds N
      formylated peptides from mitochondria and bacteria. To explore the role of M3
      expression and peptide supply in positive and negative selection, we generated
      transgenic mice expressing an M3-restricted TCR-alpha/beta from a CD8(+) T cell
      hybridoma (D7) specific for a listerial peptide (LemA). Development of M3
      restricted transgenic T cells is impaired in both beta2-microglobulin-deficient
      and transporter associated with antigen processing (TAP)-deficient mice, but is
      not diminished by changes in the H-2 haplotype. Maturation of M3/LemA-specific
      CD8(+) single positive cells in fetal thymic organ culture was sensitive to M3
      expression levels as determined by antibody blocking and use of the castaneus
      mutant allele of M3. Positive selection was rescued in TAP(-/-) lobes by
      nonagonist mitochondrial and bacterial peptides, whereas LemA and a partial
      agonist variant caused negative selection. Thus, M3-restricted CD8(+) T cells are
      positively and negatively selected by M3, with no contribution from the more
      abundant class Ia molecules. These results demonstrate that class Ib molecules
      can function in thymic education like class Ia molecules, despite limited ligand
      diversity and low levels of expression.

PMID- 10601362
TI  - Early activation of caspases during T lymphocyte stimulation results in selective
      substrate cleavage in nonapoptotic cells.
AB  - Apoptosis induced by T cell receptor (TCR) triggering in T lymphocytes involves
      activation of cysteine proteases of the caspase family through their proteolytic
      processing. Caspase-3 cleavage was also reported during T cell stimulation in the
      absence of apoptosis, although the physiological relevance of this response
      remains unclear. We show here that the caspase inhibitor benzyloxycarbonyl (Cbz)
      Val-Ala-Asp(OMe)-fluoromethylketone (zVAD) blocks proliferation, major
      histocompatibility complex class II expression, and blastic transformation during
      stimulation of peripheral blood lymphocytes. Moreover, T cell activation triggers
      the selective processing and activation of downstream caspases (caspase-3, -6,
      and -7), but not caspase-1, -2, or -4, as demonstrated even in intact cells using
      a cell-permeable fluorescent substrate. Caspase-3 processing occurs in different
      T cell subsets (CD4(+), CD8(+), CD45RA(+), and CD45RO(+)), and in activated B
      lymphocytes. The pathway leading to caspase activation involves death receptors
      and caspase-8, which is also processed after TCR triggering, but not caspase-9,
      which remains as a proenzyme. Most importantly, caspase activity results in a
      selective substrate specificity, since poly(ADP-ribose) polymerase (PARP), lamin
      B, and Wee1 kinase, but not DNA fragmentation factor (DFF45) or replication
      factor C (RFC140), are processed. Caspase and substrate processing occur in
      nonapoptotic lymphocytes. Thus, caspase activation is an early and physiological
      response in viable, stimulated lymphocytes, and appears to be involved in early
      steps of lymphocyte activation.

PMID- 10601363
TI  - Caspase activation is required for T cell proliferation.
AB  - Triggering of Fas (CD95) by its ligand (FasL) rapidly induces cell death via
      recruitment of the adaptor protein Fas-associated death domain (FADD), resulting
      in activation of a caspase cascade. It was thus surprising that T lymphocytes
      deficient in FADD were reported recently to be not only resistant to FasL
      mediated apoptosis, but also defective in their proliferative capacity. This
      finding suggested potentially dual roles of cell growth and death for Fas and
      possibly other death receptors. We report here that CD3-induced proliferation and
      interleukin 2 production by human T cells are blocked by inhibitors of caspase
      activity. This is paralleled by rapid cleavage of caspase-8 after CD3
      stimulation, but no detectable processing of caspase-3 during the same interval.
      The caspase contribution to T cell activation may occur via TCR-mediated
      upregulation of FasL, as Fas-Fc blocked T cell proliferation, whereas soluble
      FasL augmented CD3-induced proliferation. These findings extend the role of death
      receptors to the promotion of T cell growth in a caspase-dependent manner.

PMID- 10601364
TI  - The cysteine protease activity of the major dust mite allergen Der p 1
      selectively enhances the immunoglobulin E antibody response.
AB  - The house dust mite Dermatophagoides pteronyssinus allergen Der p 1 is the most
      immunodominant allergen involved in the expression of dust mite-specific
      immunoglobulin (Ig)E-mediated hypersensitivity. The reason for this potent IgE
      eliciting property of Der p 1 remains unknown, but there is mounting in vitro
      evidence linking the allergenicity of Der p 1 to its cysteine protease activity.
      Here we demonstrate for the first time that immunization of mice with
      proteolytically active Der p 1 results in a significant enhancement in total IgE
      and Der p 1-specific IgE synthesis compared with animals immunized with Der p 1
      that was irreversibly blocked with the cysteine protease inhibitor E-64. We
      conclude that the proteolytic activity of Der p 1 is a major contributor to its
      allergenicity.

PMID- 10601365
TI  - High level expression of CD43 inhibits T cell receptor/CD3-mediated apoptosis.
AB  - In a screen designed to identify genes that regulate T cell receptor (TCR)/CD3
      mediated apoptosis, we found that high level expression of CD43 protected T cell
      hybridomas from activation-induced cell death. The protection appears to result
      from its capacity to block Fas-mediated death signals rather than from inhibition
      of the upregulation of Fas and/or Fas ligand after T cell stimulation. We found
      that peripheral CD4(+) T cells can be divided into two subsets based on the level
      of CD43 surface expression. The CD4(+)CD43(low) subset exhibits a naive T cell
      phenotype, being CD62L(high)CD45RB(high)CD44(low), whereas CD4(+)CD43(high) cells
      exhibit a memory phenotype, being CD62L(low)CD45RB(low)CD44(high). Recent studies
      have demonstrated that engagement of TCR and Fas induces naive CD4(+) T cells to
      undergo apoptosis, and the same treatment enhances the proliferation of memory
      CD4(+) T cells. We confirm here that peripheral CD4(+)CD43(high) T cells are
      resistant to TCR/CD3-mediated cell death. These results suggest that the
      expression levels of CD43 on naive and memory CD4(+) T cells determine their
      susceptibility to Fas-dependent cell death and that high level expression of CD43
      may be used as a marker to define CD4(+) memory T cells. Expression of CD43
      provides a novel mechanism by which tumor cells expressing abnormally high levels
      of CD43 may escape Fas-mediated killing.

PMID- 10601367
TI  - MEMORANDUM FOR: science writers and editors on the journal press list :
      chemotherapy plus radiation therapy improves survival in patients with
      oropharyngeal cancer

PMID- 10601366
TI  - Dynamic interactions of macrophages with T cells during antigen presentation.
AB  - We have established a method for real-time video analysis of the interaction of
      antigen-presenting cells (APCs) with T cells. Green fluorescent protein
      expression controlled by a nuclear factor of activated T cells (NFAT)-responsive
      promoter permits the visualization of productive antigen presentation in single T
      cells. The readout is rapid (within 2 h) and semiquantitative and allows analysis
      by video microscopy and flow cytometry. Using this approach, we demonstrate that
      macrophages have the capacity to simultaneously activate multiple T cells. In
      addition, the interaction of T cells with macrophages is extraordinarily dynamic:
      after initial stable contact, the T cells migrate continuously on the surface of
      the macrophage and from APC to APC during productive antigen presentation. Thus,
      T cells sum up signals from multiple interactions with macrophages during
      stimulation.

PMID- 10601368
TI  - MEMORANDUM FOR: science writers and editors on the journal press list : BRCA
      mutations should not influence adjuvant therapy decisions for breast cancer

PMID- 10601369
TI  - Radiotherapy and concurrent chemotherapy: a strategy that improves locoregional
      control and survival in oropharyngeal cancer.

PMID- 10601370
TI  - Refining breast cancer risk assessment with molecular markers: the next step?

PMID- 10601371
TI  - Beta-carotene: a miss for epidemiology.

PMID- 10601372
TI  - Celebrity's death spurs interest in rare cancers.

PMID- 10601373
TI  - Shining light on breast tumors.

PMID- 10601374
TI  - Cancer treatment and vitamin C: the debate lingers.

PMID- 10601375
TI  - ASTRO plenary session touts top new research. American Society for Therapeutic
      Radiology and Oncology.

PMID- 10601376
TI  - Stat bite: Age-specific cancer incidence among children under 15.

PMID- 10601377
TI  - Taxing the taxanes: overused or undersold?

PMID- 10601378
TI  - Randomized trial of radiation therapy versus concomitant chemotherapy and
      radiation therapy for advanced-stage oropharynx carcinoma.
AB  - BACKGROUND: We designed a randomized clinical trial to test whether the addition
      of three cycles of chemotherapy during standard radiation therapy would improve
      disease-free survival in patients with stages III and IV (i.e., advanced
      oropharynx carcinoma). METHODS: A total of 226 patients have been entered in a
      phase III multicenter, randomized trial comparing radiotherapy alone (arm A) with
      radiotherapy with concomitant chemotherapy (arm B). Radiotherapy was identical in
      the two arms, delivering, with conventional fractionation, 70 Gy in 35 fractions.
      In arm B, patients received during the period of radiotherapy three cycles of a 4
      day regimen containing carboplatin (70 mg/m(2) per day) and 5-fluorouracil (600
      mg/m(2) per day) by continuous infusion. The two arms were equally balanced with
      regard to age, sex, stage, performance status, histology, and primary tumor site.
      RESULTS: Radiotherapy compliance was similar in the two arms with respect to
      total dose, treatment duration, and treatment interruption. The rate of grades 3
      and 4 mucositis was statistically significantly higher in arm B (71%; 95%
      confidence interval [CI] = 54%-85%) than in arm A (39%; 95% CI = 29%-56%). Skin
      toxicity was not different between the two arms. Hematologic toxicity was higher
      in arm B as measured by neutrophil count and hemoglobin level. Three-year overall
      actuarial survival and disease-free survival rates were, respectively, 51% (95%
      CI = 39%-68%) versus 31% (95% CI = 18%-49%) and 42% (95% CI = 30%-57%) versus 20%
      (95% CI = 10%-33%) for patients treated with combined modality versus radiation
      therapy alone (P =.02 and.04, respectively). The locoregional control rate was
      improved in arm B (66%; 95% CI = 51%-78%) versus arm A (42%; 95% CI = 31%-56%).
      CONCLUSION: The statistically significant improvement in overall survival that
      was obtained supports the use of concomitant chemotherapy as an adjunct to
      radiotherapy in the management of carcinoma of the oropharynx.

PMID- 10601379
TI  - Clonal expansion and loss of heterozygosity at chromosomes 9p and 17p in
      premalignant esophageal (Barrett's) tissue.
AB  - BACKGROUND: Abnormalities involving the p16 (also known as cyclin-dependent
      kinase N2 [CDKN2], p16 [INK4a], or MTS1) and p53 (also known as TP53) tumor
      suppressor genes are highly prevalent in esophageal adenocarcinomas. Loss of
      heterozygosity (LOH) at 9p21 and 17p13 chromosomes (locations for p16 and p53
      genes, respectively) is frequently observed in the premalignant condition,
      Barrett's esophagus. We studied extensively the distribution and heterogeneity of
      LOH at 9p and 17p chromosomes throughout the Barrett's segment in patients who
      have not yet developed esophageal adenocarcinoma. METHODS: We evaluated 404
      samples from 61 consecutive patients enrolled in the Seattle Barrett's Esophagus
      Study from February 1995 through September 1998. All patients had high-grade
      dysplasia but no diagnosis of cancer. The samples were assayed for LOH at 9p and
      17p chromosomes after amplification of genomic DNA by use of polymerase chain
      reaction and DNA genotyping. The cell fractions were purified by flow cytometry
      on the basis of DNA content and proliferation-associated antigen labeling.
      Association between LOH at 9p and LOH at 17p with flow cytometric abnormalities
      was determined by chi-squared test, and logistic regression models were used to
      model and test for the extent to which a particular genotype was found in 2-cm
      intervals. RESULTS AND CONCLUSIONS: LOH at 9p and 17p chromosomes are highly
      prevalent somatic genetic lesions in premalignant Barrett's tissue. LOH at 9p is
      more common than LOH at 17p in diploid samples and can be detected over greater
      regions of Barrett's epithelium. In most patients with high-grade dysplasia, the
      Barrett's mucosa contains a mosaic of clones and subclones with different
      patterns of LOH. Some clones had expanded to involve extensive regions of
      Barrett's epithelium. LOH at 9p and 17p chromosomes may be useful biomarkers to
      stratify patients' risk of progression to esophageal cancer.

PMID- 10601380
TI  - Transforming growth factor-beta and breast cancer risk in women with mammary
      epithelial hyperplasia.
AB  - BACKGROUND: Transforming growth factors-beta (TGF-betas) regulate mammary
      epithelial cell division. Loss of expression of TGF-beta receptor II (TGF-beta
      RII) is related to cell proliferation and tumor progression. Breast epithelial
      hyperplastic lesions lacking atypia (EHLA) are associated with a mild elevation
      in breast cancer risk. We investigated the expression of TGF-beta-RII in EHLA and
      the risk of subsequent invasive breast cancer. METHODS: We conducted a nested
      case-control study of women with biopsy-confirmed EHLA who did not have a history
      of breast cancer or atypical hyperplasia of the breast. Case patients (n = 54)
      who subsequently developed invasive breast cancer were matched with control
      patients (n = 115) who did not. Formalin-fixed, paraffin-embedded sections of
      breast biopsy specimens of all 169 patients with EHLA were studied by
      immunohistochemical analysis with antibodies against TGF-beta-RII. All P values
      are two-sided. RESULTS: Women with breast EHLA and 25%-75% TGF-beta-RII-positive
      cells or less than 25% TGF-beta-RII-positive cells had odds ratios of invasive
      breast cancer of 1.98 (95% confidence interval [CI] = 0.95-4.1) or 3.41 (95% CI =
      1.2-10.0), respectively (P for trend =.008). These risks are calculated with
      respect to women with EHLA that had greater than 75% TGF-beta-RII expression.
      Women with a heterogeneous pattern of TGF-beta-RII expression in their normal
      breast lobular units and either greater than 75%, 25%-75%, or less than 25%
      positive cells in their EHLA had odds ratios for breast cancer risk of 0.742 (95%
      CI = 0.3-1.8), 2.85 (95% CI = 1.1-7.1), or 3.55 (95% CI = 1.0-10.0), respectively
      (P for trend =.003). These risks are relative to women with a homogeneous pattern
      of expression in their normal lobular units and greater than 75% positive cells
      in their EHLA. CONCLUSION: This study indicates that loss of TGF-beta-RII
      expression in epithelial cells of EHLA is associated with increased risk of
      invasive breast cancer.

PMID- 10601381
TI  - Beta-carotene supplementation and incidence of cancer and cardiovascular disease:
      the Women's Health Study.
AB  - BACKGROUND: In observational studies, individuals with high intakes of fruits and
      vegetables containing beta-carotene experience lower risks of developing cancer.
      However, the few randomized trials of beta-carotene supplementation show no
      overall benefits; some even suggest harm. This trial was designed to test the
      effects of beta-carotene supplementation in women. METHODS: The Women's Health
      Study is a randomized, double-blind, placebo-controlled trial originally testing
      aspirin, vitamin E, and beta-carotene in the prevention of cancer and
      cardiovascular disease among 39 876 women aged 45 years or older. The beta
      carotene component was terminated early after a median treatment duration of 2.1
      years (range = 0.00-2. 72 years). Statistical tests were two-sided. RESULTS:
      Among women randomly assigned to receive beta-carotene (50 mg on alternate days;
      n = 19 939) or placebo (n =19 937), there were no statistically significant
      differences in incidence of cancer, cardiovascular disease, or total mortality
      after a median of 4.1 years (2.1 years' treatment plus another 2.0 years' follow
      up). There were 378 cancers in the beta-carotene group and 369 cancers in the
      placebo group (relative risk [RR] = 1.03; 95% confidence interval [CI] = 0.89-1.
      18). There were no statistically significant differences for any site-specific
      cancer or during years 1 and 2 combined and years 3 and up combined. For
      cardiovascular disease, there were no statistically significant differences for
      myocardial infarction (42 in the beta-carotene group versus 50 in the placebo
      group), stroke (61 versus 43), deaths from cardiovascular causes (14 versus 12),
      or the combined end point of these three events (116 versus 102; among women with
      more than one event, only the first was counted). Deaths from any cause were
      similar in the two groups (59 versus 55). Among smokers at baseline (13% of all
      women), there were no statistically significant differences in overall incidence
      of cancer (RR = 1.11; 95% CI = 0.78-1.58) or cardiovascular disease (RR = 1.01;
      95% CI = 0. 62-1.63). CONCLUSION: Among apparently healthy women, there was no
      benefit or harm from beta-carotene supplementation for a limited period on the
      incidence of cancer and of cardiovascular disease.

PMID- 10601382
TI  - HRAS1 rare minisatellite alleles and breast cancer in Australian women under age
      forty years.
AB  - BACKGROUND: A recent meta-analysis of 23 studies supported the empirically
      derived hypothesis that women who lack one of the four common minisatellite
      alleles at the HRAS1 locus are at increased risk of breast cancer. These studies
      relied on visual sizing of alleles on electrophoretic gels and may have
      underreported rare alleles. We determined whether this hypothesis applied to
      early-onset breast cancer by using a new method to size minisatellite alleles.
      METHODS: We conducted a population-based, case-control-family study of 249
      Australian women under 40 years old at diagnosis of a first primary breast cancer
      and 234 randomly selected women, frequency matched for age. We sized HRAS1
      minisatellite alleles with an Applied Biosystems model 373 automated DNA
      sequencer and GENESCAN(TM) software. All P values are two-sided. RESULTS: We
      found no association of rare alleles with breast cancer, before or after
      adjustment for risk factors and irrespective of how their effects were modeled
      (crude odds ratio = 1.04; 95% confidence interval [CI] = 0.071-1.53; P =.8). The
      rare allele frequency was 0. 173 (95% CI = 0.149-0.197), three times the pooled
      estimate of 0.058 (95% CI = 0.050-0.066) from previous studies (P<.001), and was
      similar for case subjects, 0.177 (95% CI = 0.143-0.221), and control subjects,
      0.169 (95% CI = 0.135-0.203) (P =.7). CONCLUSION: There was no support for an
      association between rare HRAS1 alleles and the risk of early-onset breast cancer,
      despite 80% power to detect effects of the magnitude of those associations (1.7
      fold) previously suggested. IMPLICATIONS: The question of whether cancer risk is
      associated with rare minisatellite HRAS1 alleles needs to be revisited with the
      use of new methods that have a greater ability to distinguish rare alleles from
      similarly sized common alleles.

PMID- 10601383
TI  - Breast conservation therapy for invasive breast cancer in Ashkenazi women with
      BRCA gene founder mutations.
AB  - BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes are associated with
      an increased risk of breast cancer. Whether women with breast cancer who have
      inherited mutations in these genes have a different outcome after breast
      conservation therapy than women with "sporadic" cancer is unresolved.
      Consequently, we compared the outcomes after breast conservation therapy in
      Ashkenazi women with or without germline mutations in BRCA1 and/or BRCA2
      (hereafter called BRCA). METHODS: We studied 305 women of Ashkenazi Jewish
      descent undergoing breast-conserving treatment for 329 invasive breast cancers.
      We reviewed their clinical records, retrieved their archival tissue samples, and
      tested those samples for the founder mutations BRCA1 185delAG, BRCA1 5382insC,
      and BRCA2 6174delT. Genetic results were linked to clinical data and outcomes by
      univariate and multivariate analyses. All Pvalues are two-sided. RESULTS: We
      detected mutations in BRCA genes in 28 of 305 women. Women with BRCA mutations
      were more likely to be diagnosed with cancer before the age of 50 years (P<.001)
      and to have lymph node involvement (P =.04). Ipsilateral breast tumor recurrence
      was more common in women with BRCA mutations, although this did not reach
      statistical significance (relative risk [RR] = 1.79; 95% confidence interval [CI]
      = 0.64-5.03). Women with mutations were more likely to develop contralateral
      breast cancer (RR = 3.50; 95% CI = 1.78-8.74; P =.001). Distant disease-free
      survival was shorter in women with mutations (66.2% versus 84.3% at 10 years; P
      =.05), as was breast cancer-specific survival (71.9% versus 87.2% at 10 years; P
      =.02). Tumor stage and nodal status, but not mutation status, were predictive of
      distant disease-free and breast cancer-specific survival in multivariate
      analysis. CONCLUSIONS: Women with BRCA founder mutations are at increased risk
      for breast cancer-related events after breast conservation. However, mutation
      status is not an independent predictor of survival and should not influence
      decisions regarding adjuvant therapy. The increased contralateral breast cancer
      risk in women heterozygous for BRCA mutations mandates careful surveillance.

PMID- 10601384
TI  - Effect of the retinoid X receptor-selective ligand LGD1069 on mammary carcinoma
      after tamoxifen failure.
AB  - BACKGROUND: We have previously shown that a retinoid X receptor (RXR)-selective
      ligand (a rexinoid), called LGD1069, is highly efficacious in both the
      chemoprevention and the chemotherapy for N-nitrosomethylurea-induced rat mammary
      carcinomas. To evaluate a possible role for rexinoids in breast cancer therapy
      further, we have designed and characterized a novel carcinogen-induced model to
      mimic the clinical situation in which the tumors of patients stop responding to
      tamoxifen therapy and develop resistance to this drug. METHODS: Rats with
      experimentally induced mammary tumors were treated with tamoxifen to select a
      population with primary tumors that failed to respond completely to the drug.
      Once the failure of tamoxifen therapy had been established, LGD1069 was added to
      the treatment regimen, and the tumors in these animals were compared with tumors
      in a group of animals that remained on tamoxifen alone. RESULTS: LGD1069 in
      combination with tamoxifen for up to 20 weeks yielded an overall objective
      response rate of 94% (95% confidence interval [CI] = 86%-100%) (includes complete
      and partial responses) in primary tumors compared with a rate of 33% (95% CI =
      11%-56%) in primary tumors treated with tamoxifen alone, a statistically
      significant difference (two-sided P<.0001). In addition, the LGD1069 and
      tamoxifen combination was associated with a statistically significant decrease in
      total tumor burden (two-sided P =.03). In a second study, tumors that failed to
      respond to tamoxifen therapy exhibited a 51% (95% CI = 34%-71%) objective
      response rate when treated with LGD1069 alone for 6 weeks after tamoxifen therapy
      was withdrawn. CONCLUSION: We have demonstrated that the RXR-selective ligand
      LGD1069 in combination with tamoxifen is a highly efficacious therapeutic agent
      for tumors that fail to respond completely to tamoxifen. This finding suggests
      that rexinoid therapy offers a novel approach to the treatment of breast tumors
      that may have developed resistance to antihormonal therapies such as tamoxifen.

PMID- 10601385
TI  - Re: detection of Epstein-Barr virus in invasive breast cancers.

PMID- 10601386
TI  - Re: detection of Epstein-Barr virus in invasive breast cancers.

PMID- 10601387
TI  - RESPONSE: re: detection of epstein-barr virus in invasive breast cancers

PMID- 10601388
TI  - Problems in neuroscience research.

PMID- 10601389
TI  - Neurology of Whipple's disease.

PMID- 10601390
TI  - Epilepsy surgery, visual fields, and driving.

PMID- 10601391
TI  - When aliens invade: multiple mechanisms for dissociation between will and action.

PMID- 10601392
TI  - Snapshot view of emergency neurosurgical head injury care in Great Britain and
      Ireland.
AB  - OBJECTIVES: To study the availability of neurosurgical intensive care for the
      traumatically brain injured in all 36 neurosurgical centres in the United Kingdom
      and Ireland receiving head injuries, the response times to referral, and the
      advice given to the referring hospitals. METHODS: Telephone survey of receiving
      neurosurgeons regarding their bed status and their advice on three hypothetical
      case scenarios. Outcome measures included response times for an acute head injury
      to be accepted to a neurosurgical centre; the intensive care bed status;
      variations in advice given to the referring hospitals with regard to ventilation,
      use of mannitol, steroids, anticonvulsants, and antibiotics. RESULTS: There were
      43 neurosurgical intensive care beds available for an overall estimated
      population of 63.6 million. There were 1.8 beds available/million of the
      population for non-ventilated patients, 0.64 beds available/million for
      ventilated patients, and 0.55 beds available/million for ventilated paediatric
      patients. London had a shortage of beds with 0.19 adult beds for
      ventilation/million north of the Thames and 0.14 adult beds for
      ventilation/million south of the Thames. The median response time for a patient
      with an extradural haematoma to be accepted for transfer was 6 minutes and 89% of
      such a referral was accepted within 30 minutes. Clinically significant delays in
      receiving referrals (over 30 minutes) occurred in four units. Practices regarding
      the use of hyperventilation, mannitol, anticonvulsants, and antibiotics showed
      little conformity and in some cases were against the available evidence and
      advice given by published guidelines. CONCLUSIONS: There is a severe shortage of
      available emergency neurosurgical beds especially in the south east of England.
      The lack of immediately available neurosurgical intensive care beds results in
      delays of transfer that could adversely affect the outcome of surgery for
      traumatic intracranial haematoma. Advice given to the referring units by the
      receiving doctors is very variable.

PMID- 10601393
TI  - Arnold chiari, or "Cruveilhier cleland Chiari" malformation.

PMID- 10601394
TI  - Mass volume measurement in severe head injury: accuracy and feasibility of two
      pragmatic methods.
AB  - OBJECTIVE: To assess the clinical feasibility and the accuracy of two pragmatic
      methods in comparison with a conventional computer based method of measurement of
      masses from CT. METHODS: Nineteen CT scans of 11 patients with severe head
      injury, showing 34 traumatic lesions, were examined. The volume of every lesion
      was digitally measured, then a panel of three examiners independently repeated
      the measurement using the ellipsoid and the Cavalieri method in random order.
      RESULTS: All the lesions were identified by all the readers and the mean volume
      measured by each examiner differed by less than 1.5 ml. The average reading time
      for each scan was 4 minutes for the ellipsoid and 7 minutes for the Cavalieri
      method. The average volume of the lesions was 34.2 (SD 35) ml with the digital
      system, and 38.4 (SD 41) ml and 34.8 (SD 36) ml for the ellipsoid and the
      Cavalieri readings respectively. The average difference between the applied
      technique and the digital system was 0.57 (SD 9.99) ml for the Cavalieri direct
      estimator and 0.20 (SD 15.48) ml for the ellipsoid method. The 95% confidence
      interval for this difference fell between -2.75 and 3.89 ml for the Cavalieri,
      and between -4.94 and 5.35 ml for the ellipsoid method. There were 19 lesions >25
      ml; the ellipsoid method identified 16 of them, whereas 17 were classified with
      the Cavalieri method. When considering individual lesions rather than the average
      volume, discrepancies were detected with both methods. The ellipsoid method was
      less precise, especially when extracerebral lesions were measured. CONCLUSIONS:
      Both pragmatic methods are inferior to computer based reading, which is the
      choice when accurate volume estimation is necessary. However, if a digital
      volumetric determination of the lesions using a CT computer is not possible, the
      two pragmatic methods offer an alternative.

PMID- 10601395
TI  - Disruption of attention to novel events after frontal lobe injury in humans.
AB  - OBJECTIVE: To investigate whether frontal lobe damage in humans disrupts the
      natural tendency to preferentially attend to novel visual events in the
      environment. METHODS: Nine patients with chronic infarctions in the dorsolateral
      prefrontal cortex (DLPFC) and 23 matched normal controls participated in a study
      in which subjects viewed repetitive background stimuli, infrequent target
      stimuli, and novel visual stimuli (for example, fragmented or "impossible"
      objects). Subjects controlled viewing duration by a button press that led to the
      onset of the next stimulus. They also responded to targets by pressing a foot
      pedal. The amount of time spent looking at the different kinds of stimuli, and
      the target detection accuracy and speed served as dependent variables. RESULTS:
      Overall, normal controls spent significantly more time than frontal lobe patients
      looking at novel stimuli. Analysis of responses across blocks showed that
      initially frontal lobe patients behaved like normal controls by directing more
      attention to novel than background stimuli. However, they quickly began to
      distribute their viewing time evenly between novel and background stimuli, a
      pattern that was strikingly different from normal controls. By contrast, there
      were no differences between frontal lobe patients and normal controls for viewing
      duration devoted to background and target stimuli, target detection accuracy, or
      reaction time to targets. Frontal lobe patients did not differ from normal
      controls in terms of age, education, estimated IQ, or mood, but were more
      apathetic as measured by self report and informants' judgments. Attenuated
      responses to novel stimuli significantly correlated with degree of apathy.
      CONCLUSIONS: This study demonstrates that DLPFC injury selectively impairs the
      natural tendency to seek stimulation from novel and unusual stimuli. These data
      provide the first quantitative behavioural demonstration that the human frontal
      lobes play a critical part in directing and sustaining attention to novel events.
      The impairment of novelty seeking behaviour may contribute to the characteristic
      apathy found in patients with frontal lobe injury.

PMID- 10601396
TI  - Natural history of elderly patients with asymptomatic meningiomas.
AB  - OBJECTIVE: For the treatment of elderly patients with asymptomatic meningiomas,
      it is important to determine their natural history. Based on results of follow up
      examinations, the natural history of such patients was clarified and prognostic
      factors concerning the potential of tumour growth in the aged were identified.
      METHODS: The clinical records and imaging studies of 40 elderly (over 70 years)
      patients with asymptomatic meningiomas were analysed. The patients were followed
      up with repeated imaging studies, and changes in tumour size, clinical signs, and
      outcomes were evaluated. RESULTS: There were 32 women and eight men with a mean
      age of 76.1 years. The mean follow up period was 38.4 months, ranging from 6 to
      97 months. Six patients died during the follow up period from disorders other
      than the tumours, and one patient died as a result of the tumour. Twenty six
      patients (mean follow up period 41.8 months, range 10-97 months) showed no tumour
      growth. Fourteen patients showed tumour growth (mean follow up period 32.1
      months, range 6-88 months). Five (four men and one woman) of these patients
      became symptomatic. Based on imaging analysis (1) calcification of the tumour was
      associated with no tumour growth (p=0.036), and (2) the tumour size at the
      initial diagnosis was related to subsequent tumour growth (p=0.016). Other
      possible factors related to tumour growth included sex and hyperintensity on MRI
      T2 weighted images. CONCLUSION: In elderly patients with asymptomatic
      meningiomas, careful clinical follow up with imaging studies is important. The
      imaging features mentioned may contribute to prediction of tumour growth.

PMID- 10601397
TI  - Intraoperative microvascular Doppler ultrasonography in cerebral aneurysm
      surgery.
AB  - OBJECTIVES: Outcome of surgical treatment of cerebral aneurysms may be severely
      compromised by local cerebral ischaemia or infarction resulting from the
      inadvertent occlusion of an adjacent vessel by the aneurysm clip, or by
      incomplete aneurysm closure. It is therefore mandatory to optimise clip placement
      in situ to reduce the complication rate. The present study was performed to
      investigate the reliability of intraoperative microvascular Doppler
      ultrasonography (MDU) in cerebral aneurysm surgery, and to assess the impact of
      this method on the surgical procedure itself. METHODS: Seventy five patients (19
      men, 56 women, mean age 54.8 years, range 22-84 years) with 90 saccular cerebral
      aneurysms were evaluated. Blood flow velocities in the aneurysmal sac and in the
      adjacent vessels were determined by MDU before and after aneurysm clipping. The
      findings of MDU were analysed and compared with those of visual inspection of the
      surgical site and of postoperative angiography. Analysis was also made of the
      cases in which the clip was repositioned due to MDU findings. RESULTS: A relevant
      stenosis of an adjacent vessel induced by clip positioning that had escaped
      detection by visual inspection was identified by Doppler ultrasonography in 17
      out of 90 (18.9%) aneurysms. In addition, Doppler ultrasound demonstrated a
      primarily unoccluded aneurysm in 11 out of 90 (12.2%) patients. The aneurysm clip
      was repositioned on the basis of the MDU findings in 26 out of 90 (28.8%) cases.
      In middle cerebral artery (MCA) aneurysms, the MDU results were relevant to the
      surgical procedure in 17 out of 44 (38.6%) cases. Whereas with aneurysms of the
      anterior cerebral artery significant findings occurred in only five of 32 cases
      (15.6%; p<0.05). The clip was repositioned on the basis of the MDU results in 18
      out of 50 (36%) aneurysms in patients with subarachnoid haemorrhage (SAH) grade I
      V compared with only eight out of 40 (20%) aneurysms in patients without SAH
      (p<0.05). CONCLUSIONS: MDU should be used routinely in cerebral aneurysm surgery,
      especially in cases of MCA aneurysms and after SAH. Present data show that a
      postoperative angiography becomes superfluous whenever there is good
      visualisation of the "working site" and MDU findings are clear.

PMID- 10601398
TI  - Neurological stamp. Nicholas of Cusa (1401-64).

PMID- 10601399
TI  - Increased incidence of neurological complications in patients receiving an
      allogenic bone marrow transplantation from alternative donors.
AB  - OBJECTIVE: To compare the frequency and type of neurological complications after
      bone marrow transplantation (BMT) with an HLA identical unrelated donor or a
      mismatched related donor (alternative donors) to the neurological complications
      after matched sibling BMT for standard and high risk leukaemia or myelodysplastic
      syndromes. METHODS: Retrospective analysis of consecutively treated patients with
      (a) BMT from alternative donors (n=39), (b) treated with matched sibling BMT for
      standard risk leukaemia, myelodysplastic syndromes, or aplastic anaemia (n=53),
      and (c) treated with matched sibling BMT for high risk leukaemia, myelodysplastic
      syndromes, or aplastic anaemia (n=49). RESULTS: A total of 72 neurological
      complications were found. Most of these occurred within the first 6 months after
      transplant. Thirty six patients developed a severe neurological complication: 17
      Alternative donor patients (44%) by contrast with six standard risk patients
      (11%) and 13 high risk patients (27%; p<0.005). The most frequent complication
      was a metabolic encephalopathy occurring in 18% of patients. Most of the
      encephalopathies were caused by either the transplant procedure, cyclosporin,
      systemic infections, microangiopathic thrombopathy, or by complications induced
      by graft versus host disease. Infections of the CNS developed in 9% of patients,
      cerebrovascular lesions in 3%. CONCLUSIONS: Severe neurological complications are
      more frequent after BMT from alternative donors. This is mainly due to increased
      treatment related morbidity and to more profound immunosuppression after BMT from
      alternative donors.

PMID- 10601400
TI  - Affective behavioural disturbances in Alzheimer's disease and ischaemic vascular
      disease.
AB  - OBJECTIVES: To investigate affective change in Alzheimer's disease and ischaemic
      vascular disease and examine the contribution of white matter disease to
      psychopathology in these dementias. Based on earlier studies, it was predicted
      that: (1) depression would be more prevalent and severe in ischaemic vascular
      disease; (2) psychomotor slowing would be more prevalent in ischaemic vascular
      disease; (3) apathy would be more prevalent in ischaemic vascular disease; and
      (4) The degree of white matter disease would be positively correlated with the
      severity of psychomotor slowing. METHODS: Ratings of affective/behavioural states
      and white matter disease were compared in 256 patients with Alzheimer's disease
      and 36 patients with ischaemic vascular disease or mixed dementia with an
      ischaemic vascular component using analysis of variance (ANOVA) and linear
      regression models. RESULTS: The findings were: (1) decreased affect/withdrawal
      was more prevalent and severe in patients with ischaemic vascular disease and
      patients with white matter disease; (2) psychomotor slowing was more severe in
      patients with ischaemic vascular disease and patients with white matter disease;
      and (3) differences between Alzheimer's disease and ischaemic vascular dementia
      groups in the degree of psychomotor slowing were independent of the severity of
      white matter disease. CONCLUSIONS: Future studies using structural and functional
      neuroimaging techniques would be helpful for examining the relation between
      neurobiological factors and affective/behavioural disturbances in dementia.

PMID- 10601401
TI  - Emotional outcomes after stroke: factors associated with poor outcome.
AB  - OBJECTIVES: The impact of stroke on the emotional outcome of patients is large.
      The aim was to describe the emotional outcomes among a cohort of patients which
      was of sufficient size to provide a precise estimate of their frequency and help
      identify those factors which are associated with poor outcomes after an acute
      stroke. METHODS: 372 surviving patients, who had been referred to a hospital and
      entered into a randomised trial to evaluate a stroke family care worker, were
      asked to complete questionnaires at a 6 month follow up. These included measures
      of emotional distress (general health questionnaire 30 item, hospital anxiety and
      depression scale) and physical functioning (modified Rankin, Barthel index). A
      regression analysis was used to identify factors which were independently
      associated with poor outcomes. RESULTS: 184 (60%) surviving patients scored more
      than 4 on the GHQ-30, 55 (22%) more than 8 on the HAD anxiety subscale, and 49
      (20%) more than 8 on the HAD depression subscale. Patients with severe strokes
      resulting in physical disability were more likely to be depressed whereas there
      was a less strong relation between disability and anxiety. Patients with
      posterior circulation strokes had consistently better emotional outcomes than
      those with anterior circulation strokes. CONCLUSIONS: These data may help
      identify those patients at greatest risk of poor emotional outcomes and thus help
      in planning trials and delivering appropriate interventions.

PMID- 10601402
TI  - Psychiatric aspects of temporal lobe epilepsy before and after anterior temporal
      lobectomy.
AB  - OBJECTIVES: Psychopathology has been reported to be prevalent both before and
      after surgical treatment for medically intractable temporal lobe epilepsy.
      Individual patients were evaluated prospectively to assess the effect of anterior
      temporal lobectomy (ATL) on prevalence and severity of psychiatric disease.
      METHODS: Psychiatric status was assessed in a consecutive series of epilepsy
      patients before and 6 months after ATL using a structured psychiatric interview,
      psychiatric rating scales, and self report mood measures. RESULTS: A DSM-III-R
      axis I diagnosis was present in 65% of patients before and after surgery. The
      most common diagnoses were depression, anxiety, and organic mood/personality
      disorders. There was a trend for major psychiatric diagnoses to be more common in
      patients with right compared to left temporal lobe seizure focus, both before and
      after surgery. The apparent stability in the overall rate of psychiatric
      dysfunction concealed onset of new psychiatric problems in 31% of patients in the
      months shortly after surgery, and resolution of psychiatric diagnoses in 15% of
      patients. In the group as a whole, the severity of psychiatric symptoms was lower
      at 6 months postsurgery than before temporal lobectomy. CONCLUSIONS: The overall
      prevalence of psychiatric dysfunction was comparably high before and after ATL,
      but individual changes in psychiatric status and changes in severity of symptoms
      occurred in many patients in the 6 months after surgery.

PMID- 10601403
TI  - Microvascular decompression for trigeminal neuralgia: comments on a series of 250
      cases, including 10 patients with multiple sclerosis.
AB  - OBJECTIVE: To examine surgical findings and results of microvascular
      decompression (MVD) for trigeminal neuralgia (TN), including patients with
      multiple sclerosis, to bring new insight about the role of microvascular
      compression in the pathogenesis of the disorder and the role of MVD in its
      treatment. METHODS: Between 1990 and 1998, 250 patients affected by trigeminal
      neuralgia underwent MVD in the Department of Neurosurgery of the "Istituto
      Nazionale Neurologico C Besta" in Milan. Limiting the review to the period 1991
      6, to exclude the "learning period" (the first 50 cases) and patients with less
      than 1 year follow up, surgical findings and results were critically analysed in
      148 consecutive cases, including 10 patients with multiple sclerosis. RESULTS:
      Vascular compression of the trigeminal nerve was found in all cases. The
      recurrence rate was 15.3% (follow up 1-7 years, mean 38 months). In five of 10
      patients with multiple sclerosis an excellent result was achieved (follow up 12
      39 months, mean 24 months). Patients with TN for more than 84 months did
      significantly worse than those with a shorter history (p<0.05). There was no
      mortality and most complications occurred in the learning period. Surgical
      complications were not related to age of the patients. CONCLUSIONS:
      Aetiopathogenesis of trigeminal neuralgia remains a mystery. These findings
      suggest a common neuromodulatory role of microvascular compression in both
      patients with or without multiple sclerosis rather than a direct causal role. MVD
      was found to be a safe and effective procedure to relieve typical TN in patients
      of all ages. It should be proposed as first choice surgery to all patients
      affected by TN, even in selected cases with multiple sclerosis, to give them the
      opportunity of pain relief without sensory deficits.

PMID- 10601404
TI  - Urinary dysfunction and orthostatic hypotension in multiple system atrophy: which
      is the more common and earlier manifestation?
AB  - OBJECTIVES: Urinary dysfunction and orthostatic hypotension are the prominent
      autonomic features in multiple system atrophy (MSA). A detailed questionnaire was
      given and autonomic function tests were performed in 121 patients with MSA
      concerning both urinary and cardiovascular systems. METHODS: Replies to the
      questionnaire on autonomic symptoms were obtained from 121 patients including
      three clinical variants; olivopontocerebellar atrophy (OPCA) type in 48,
      striatonigral degeneration (SND) type in 17, and Shy-Drager type in 56.
      Urodynamic studies comprised measurement of postmicturition residuals, EMG
      cystometry, and bethanechol injection. Cardiovascular tests included head up tilt
      test, measurement of supine plasma noradrenaline (norepinephrine,NA), measurement
      of R-R variability (CV R-R), and intravenous infusions of NA and isoproterenol.
      RESULTS: Urinary symptoms (96%) were found to be more common than orthostatic
      symptoms (43%) (p<0.01) in patients with MSA, particularly with OPCA (p<0.01) and
      SND (p<0.01) types. In 53 patients with both urinary and orthostatic symptoms,
      patients who had urinary symptoms first (48%) were more common than those who had
      orthostatic symptoms first (29%), and there were patients who developed both
      symptoms simultaneously (23%). Post-micturition residuals were noted in 74% of
      the patients. EMG cystometry showed detrusor hyperreflexia in 56%, low compliance
      in 31%, atonic curve in 5%, detrusor-sphincter dyssynergia in 45%, and neurogenic
      sphincter EMG in 74%. The cystometric curve tended to change from hyperreflexia
      to low compliance, then atonic curve in repeated tests. Bethanechol injection
      showed denervation supersensitivity of the bladder in 19%. Cardiovascular tests
      showed orthostatic hypotension below -30 mm Hg in 41%, low CV R-R below 1.5 in
      57%, supine plasma NA below 100 pg/ml in 28%, and denervation supersensitivity of
      the vessels (alpha in 73%; beta2 in 60%) and of the heart (beta1 in 62%).
      CONCLUSION: It is likely that urinary dysfunction is more common and often an
      earlier manifestation than orthostatic hypotension in patients with MSA, although
      subclinical cardiovascular abnormalities appear in the early stage of the
      disease. The responsible sites seem to be central and peripheral for both
      dysfunctions.

PMID- 10601405
TI  - In vivo investigation of white matter pathology in schizophrenia with
      magnetisation transfer imaging.
AB  - OBJECTIVES: This study is the first to use magnetisation transfer imaging (MTI),
      a technique sensitive to myelin and axonal abnormalities, to investigate the
      white matter in vivo in patients with schizophrenia. METHODS: MTI was performed
      in 25 schizophrenic patients and 30 healthy controls. A region of interest (ROI)
      approach was used to obtain magnetisation transfer ratios (MTRs) in several
      regions of cerebral white matter. RESULTS: MTR values were significantly reduced
      in the right and left temporal regions in schizophrenic patients compared with
      controls (p<0.001). Clinical variables such as age, duration of symptoms,
      schizophrenic symptomatology, and soft neurological signs did not predict this
      reduction in MTR. There were no MTR abnormalities in the other regions sampled.
      However, the correlation between the left and right frontal MTR values was
      marginally significantly different in schizophrenic patients compared with
      controls suggesting that subtle differences in interhemispheric connections may
      be present. CONCLUSIONS: Subtle white matter pathology, most likely related to
      myelin and axonal abnormalities, can be detected in the temporal lobes in
      schizophrenic patients. MTI may be a useful tool in investigating the white
      matter in schizophrenia.

PMID- 10601406
TI  - When does the patient with a disc herniation undergo lumbosacral discectomy?
AB  - OBJECTIVES: To design a model that could accurately predict eventual lumbar disc
      surgery in the patient initially presenting with clinical findings of nerve root
      compression. METHODS: Prospective study in 183 patients with nerve root
      compression sampled from a primary care population. All patients underwent a
      standardised history, physical examination, and MRI. Surgery carried out in the
      next 6 months was recorded. Models were constructed to predict whether patients
      eventually received surgery. RESULTS: Two models were constructed. Reduced model
      A was based on baseline findings, only, and contained six variables. Model B
      incorporated change over time as well and contained 10 variables. The area under
      the curve (in a receiver operating characteristic) for these models was 0.86 and
      0.92, respectively. It was shown that at a probability cut off of 0.60, model B
      predicted eventual surgery with a sensitivity of 57% and a specificity of 100%.
      CONCLUSIONS: Given the requirement of a high specificity, eventual operation
      could be adequately predicted in a sample of 183 patients with clinical nerve
      root compression. The application of the model in patients with nerve root
      compression might lead to earlier operation in a subset of patients resulting in
      a reduction of duration of illness and associated indirect costs. An important
      prerequisite for future application would be the validation of the prediction
      rule in another population.

PMID- 10601407
TI  - Epilepsy surgery, visual fields, and driving: a study of the visual field
      criteria for driving in patients after temporal lobe epilepsy surgery with a
      comparison of Goldmann and Esterman perimetry.
AB  - Twenty four patients who had undergone temporal lobe surgery for epilepsy were
      assessed to determine (a) whether or not they had developed a visual field defect
      and (b) if a field defect was present, were the visual field criteria, as
      required by the DVLA, fulfilled using the monocular Goldmann perimeter test and
      the automated binocular Esterman method performed on a Humphrey perimeter. A
      field deficit was found in 13 of 24 (54%) using the Goldmann perimeter and 11 of
      24 (46%) by the Esterman method. The second was a more lenient assessment with
      six of 24 (25%) failing the driving criteria compared with 10 of 24 (42%) by the
      monocular Goldmann method. Three patients were seizure free but failed the
      driving criteria. This complication of surgery for temporal lobe epilepsy needs
      to be discussed with patients before surgery.

PMID- 10601408
TI  - Subjective experience, involuntary movement, and posterior alien hand syndrome.
AB  - The alien hand syndrome, as originally defined, was used to describe cases
      involving anterior corpus callosal lesions producing involuntary movement and a
      concomitant inability to distinguish the affected hand from an examiner's hand
      when these were placed in the patient's unaffected hand. In recent years,
      acceptable usage of the term has broadened considerably, and has been defined as
      involuntary movement occurring in the context of feelings of estrangement from or
      personification of the affected limb or its movements. Three varieties of alien
      hand syndrome have been reported, involving lesions of the corpus callosum alone,
      the corpus callosum plus dominant medial frontal cortex, and posterior
      cortical/subcortical areas. A patient with posterior alien hand syndrome of
      vascular aetiology is reported and the findings are discussed in the light of a
      conceptualization of posterior alien hand syndrome as a disorder which may be
      less associated with specific focal neuropathology than are its callosal and
      callosal-frontal counterparts.

PMID- 10601409
TI  - HIV antibody profiles in serum and CSF of patients with neurological disease can
      serve as predictors of outcome.
AB  - The serum and CSF antibody profiles were investigated in 100 patients with HIV in
      relation to the type and severity of neurological disease. Among them, 87 were
      positive for anti-HIV antibodies in the CSF. In 30 of 87 patients detailed
      analysis by western blot could be performed. In 20 of 30 the profiles were
      dissimilar, with more of bands being found in the serum than in the CSF. The
      correlation of western blot profiles to the clinical outcome indicated that the
      number of anti-HIV antibody bands as well as the index in the CSF of fatal cases
      were significantly less compared with non-fatal cases (p=0.019 and p=0.039
      respectively).

PMID- 10601410
TI  - Placebo controlled pilot trial to study the remyelinating potential of
      intravenous immunoglobulins in multiple sclerosis.
AB  - Currently there is no treatment available to improve a stable deficit in multiple
      sclerosis. It was shown in animal models that intravenous immunoglobulins (IVIg)
      can enhance central nervous remyelination, and the first open trials were
      promising. We therefore conducted a double blind, placebo controlled pilot study
      to evaluate the effect of IVIg treatment in patients with multiple sclerosis with
      a stable clinical deficit. The primary outcome parameter was the change in
      central motor conduction time as an indirect measure of central myelination.
      Secondary outcome parameters were neurological examinations including the
      expanded disability status scale (EDSS), neurological rating scale (NRS), and
      manual muscle testing (MMT). Ten patients were treated first with placebo and
      then with IVIg (0.4 g/kg body weight on 5 consecutive days), the two treatments
      being separated by an interval of 6 weeks. There was no difference in the central
      motor conduction times measured before and 6 weeks after each treatment.
      Clinically there was a small improvement after IVIg treatment, but there was no
      significant difference when compared with placebo. In conclusion, our data do not
      support a role for IVIg in the remyelination of stable multiple sclerosis lesions
      as measured by central conduction time. The importance of the small clinical
      benefit is currently not clear.

PMID- 10601411
TI  - Apolipoprotein E genotype and hippocampal asymmetry in Alzheimer's disease: a
      volumetric MRI study.
AB  - Asymmetry of brain structures is common to many species and is even present in
      utero. Some developmental, pathological, and dementing diseases are associated
      with alterations in normal anatomical asymmetries. Anatomical asymmetries,
      however, have been only superficially studied in Alzheimer's disease. Recent
      evidence indicates that the allele epsilon4 of the apolipoprotein E (ApoE), a
      well known risk factor for Alzheimer's disease, might play a part in determining
      some brain morphological changes both in normal carriers and in patients with
      Alzheimer's disease. This study evaluated the effect of the ApoE genotype on
      hippocampal asymmetry in patients with Alzheimer's disease carrying 0, 1, and 2
      copies of the allele. Volumetric right-left differences of the hippocampi were
      computed in 28 right handed patients with Alzheimer's disease (14 -/-, 9
      epsilon4/-, and 5 epsilon4/4) and 30 controls without detectable cognitive
      deficit. In controls, the right hippocampus was larger than the left, whereas in
      patients with Alzheimer's disease this asymmetry was progressively reduced with
      increasing gene dose of the epsilon4 allele, and the asymmetry was reversed in
      the epsilon4/4 Alzheimer's disease group. The mean right-left volume differences
      were: 1.2, 0.7, 0.2, and -1.0 in controls, -/-, epsilon4/-, and epsilon4/4
      patients, respectively (sex adjusted p for trend=0.017). The data indicate a dose
      dependent effect of the ApoE epsilon4 allele on hippocampal volume asymmetry in
      Alzheimer's disease.

PMID- 10601412
TI  - Neurological picture. Multiple hydatid cysts of the brain after surgery.

PMID- 10601413
TI  - Neurological picture. Vertebral artery dissection presenting as cerebellar
      infarction.

PMID- 10601415
TI  - Alzheimer's disease-from basic research to clinical applications

PMID- 10601414
TI  - Immunological and inflammatory disorders Of the central nervous system

PMID- 10601416
TI  - Neurologic complications in organ transplant recipients

PMID- 10601417
TI  - Stroke and Alzheimer's disease

PMID- 10601418
TI  - Healing stories-narrative in psychiatry and psychotherapy

PMID- 10601419
TI  - Women and epilepsy

PMID- 10601420
TI  - Childhood epilepsies and brain development

PMID- 10601422
TI  - The bethlem and maudsley NHS trust prescribing guidelines 1999

PMID- 10601421
TI  - Difficult clinical problems in psychiatry

PMID- 10601423
TI  - Voltage-sensitive calcium currents are acutely increased by nerve growth factor
      in PC12 cells.
AB  - Whole cell calcium currents were recorded from PC12 cells with the perforated
      patch technique. Currents were evoked by step depolarization from a holding
      potential of -90 mV. Nerve growth factor (NGF) increased calcium currents through
      L-type calcium channels by >75% within 3-5 min. This increase was inhibited by K
      252a, by nifedipine, and by inhibition or down-regulation of kinase C. Brain
      derived neurotrophic factor (BDNF) also increased calcium current, but to a
      smaller extent. Thus increases in calcium current can be linked to activation of
      either the high- or the low-affinity nerve growth factor receptor. Increases in
      presynaptic calcium uptake appear to be a crucial element in the short-term
      actions of the neurotrophins on neurotransmitter release leading to long-term
      potentiation. Also, the control of calcium uptake is likely to be an important
      factor in the long-term actions of the neurotrophins on neuronal survival and
      neuronal protection. The present data indicate that the PC12 cell may be a useful
      model for studying the effect of the neurotrophins on calcium uptake.

PMID- 10601424
TI  - Inhibition of rapid heat responses in nociceptive primary sensory neurons of rats
      by vanilloid receptor antagonists.
AB  - Recent studies demonstrated that heat-sensitive nociceptive primary sensory
      neurons respond to the vanilloid receptor (VR) agonist capsaicin, and the first
      cloned VR is a heat-sensitive ion channel. Therefore we studied to what extent
      heat-evoked currents in nociceptive dorsal root ganglion (DRG) neurons can be
      attributed to the activation of native vanilloid receptors. Heat-evoked currents
      were investigated in 89 neurons acutely dissociated from adult rat DRGs as models
      for their own terminals using the whole cell patch-clamp technique. Locally
      applied heated extracellular solution (effective temperature approximately 53
      degrees C) rapidly activated reversible and reproducible inward currents in 80%
      (62/80) of small neurons (< or = 32.5 microm), but in none of nine large neurons
      (P < 0.001, chi(2) test). Heat and capsaicin sensitivity were significantly
      coexpressed in this subpopulation of small DRG neurons (P < 0.001, chi(2) test).
      Heat-evoked currents were accompanied by an increase of membrane conductance (320
      +/- 115%; mean +/- SE, n = 7), had a reversal potential of 5 +/- 2 mV (n = 5),
      which did not differ from that of capsaicin-induced currents in the same neurons
      (4 +/- 3 mV), and were carried at least by Na(+) and Ca(2+) (pCa(2+) > pNa(+)).
      These observations are consistent with the opening of temperature-operated
      nonselective cation channels. The duration of action potentials was significantly
      higher in heat-sensitive (10-90% decay time: 4.45 +/- 0.39 ms, n = 12) compared
      with heat-insensitive neurons (2.18 +/- 0.19 ms, n = 6; P < 0.005, Student's t
      test), due to an inflection in the repolarizing phase. This property as well as
      capsaicin sensitivity and small cell size are characteristics of nociceptive DRG
      neurons. When coadministered with heat stimuli, the competitive VR antagonist
      capsazepine (1 microM to 1 mM) significantly reduced heat-evoked currents in a
      dose-dependent manner (IC(50) 13 microM, Hill slope -0.58, maximum effect 75%).
      Preincubation for 12-15 s shifted the IC(50) by approximately 0.5 log(10) units
      to an estimated IC(50) of approximately 4 microM. The noncompetitive VR
      antagonist ruthenium red (5 microM) significantly reduced heat-evoked currents by
      33 +/- 6%. The effects of both VR antagonists were rapidly reversible. Our
      results provide evidence for a specific activation of native VRs in nociceptive
      primary sensory neurons by noxious heat. The major proportion of the rapid heat
      evoked currents can be attributed to the activation of these temperature-operated
      channels, and noxious heat may be the signal detected by VRs under physiological
      conditions.

PMID- 10601425
TI  - Using response models to estimate channel capacity for neuronal classification of
      stationary visual stimuli using temporal coding.
AB  - Both spike count and temporal modulation are known to carry information about
      which of a set of stimuli elicited a response; but how much information temporal
      modulation adds remains a subject of debate. This question usually is addressed
      by examining the results of a particular experiment that depend on the specific
      stimuli used. Developing a response model allows us to ask how much more
      information is carried by the best use of response strength and temporal
      modulation together (that is, the channel capacity using a code incorporating
      both) than by the best use of spike count alone (the channel capacity using the
      spike count code). This replaces dependence on a particular data set with
      dependence on the accuracy of the model. The model is constructed by finding
      statistical rules obeyed by all the observed responses and assuming that
      responses to stimuli not presented in our experiments obey the same rules. We
      assume that all responses within the observed dynamic range, even if not elicited
      by a stimulus in our experiment, could be elicited by some stimulus. The model
      used here is based on principal component analysis and includes both response
      strength and a coarse (+/-10 ms) representation of temporal modulation. Temporal
      modulation at finer time scales carries little information about the identity of
      stationary visual stimuli (although it may carry information about stimulus
      motion or change), and we present evidence that, given its variability, it should
      not be expected to do so. The model makes use of a linear relation between the
      logarithms of mean and variance of responses, similar to the widely seen relation
      between mean and variance of spike count. Responses are modeled using truncated
      Gaussian distributions. The amount of stimulus-related information carried by
      spike count in our data are 0.35 and 0.31 bits in primary visual and inferior
      temporal cortices, respectively, rising to 0.52 and 0.37 bits for the two
      principal-component code. The response model estimates that the channel capacity
      is 1.1 and 1.4 bits, respectively, using the spike count only, rising to 2.0 and
      2.2 bits using two principal components. Thus using this representation of
      temporal modulation is nearly equivalent to adding a second independent cell
      using the spike count code. This is much more than estimated using transmitted
      information but far less than would be expected if all degrees of freedom
      provided by the individual spike times carried independent information.

PMID- 10601426
TI  - Apamin-sensitive conductance mediates the K(+) current response during chemical
      ischemia in CA3 pyramidal cells.
AB  - Pyramidal cells typically respond to ischemia with initial transient
      hyperpolarization, which may represent a neuroprotective response. To identify
      the conductance underlying this hyperpolarization in CA3 pyramidal neurons of rat
      hippocampal organotypic slice cultures, recordings were obtained using the single
      electrode voltage-clamp technique. Brief chemical ischemia (2 mM 2-deoxyglucose
      and 3 mM NaN(3), for 4 min) induced a response mediated by an increase in K(+)
      conductance. This current was blocked by intracellular application of the Ca(2+)
      chelator, bis-(o-aminophenoxy)-N,N,N', N'-tetraacetic acid (BAPTA), reduced with
      low external [Ca(2+)], and inhibited by a selective L-type Ca(2+) channel
      inhibitor, isradipine, consistent with the activation of a Ca(2+)-dependent K(+)
      conductance. Experiments with charybdotoxin (10 nM) and tetraethylammonium (TEA;
      1 mM), or with the protein kinase C activator, phorbol 12,13-diacetate (PDAc; 3
      microM), ruled out an involvement of a large conductance-type or an apamin
      insensitive small conductance, respectively. In the presence of apamin (1
      microM), however, the outward current was significantly reduced. These results
      demonstrate that in rat hippocampal CA3 pyramidal neurons an apamin-sensitive
      Ca(2+)-dependent K(+) conductance is activated in response to brief ischemia
      generating a pronounced outward current.

PMID- 10601427
TI  - Temporal properties of chronic cochlear electrical stimulation determine temporal
      resolution of neurons in cat inferior colliculus.
AB  - As cochlear implants have become increasingly successful in the rehabilitation of
      adults with profound hearing impairment, the number of pediatric implant subjects
      has increased. We have developed an animal model of congenital deafness and
      investigated the effect of electrical stimulus frequency on the temporal
      resolution of central neurons in the developing auditory system of deaf cats.
      Maximum following frequencies (Fmax) and response latencies of isolated single
      neurons to intracochlear electrical pulse trains (charge balanced, constant
      current biphasic pulses) were recorded in the contralateral inferior colliculus
      (IC) of two groups of neonatally deafened, barbiturate-anesthetized cats: animals
      chronically stimulated with low-frequency signals (< or = 80 Hz) and animals
      receiving chronic high-frequency stimulation (> or = 300 pps). The results were
      compared with data from unstimulated, acutely deafened and implanted adult cats
      with previously normal hearing (controls). Characteristic differences were seen
      between the temporal response properties of neurons in the external nucleus (ICX;
      approximately 16% of the recordings) and neurons in the central nucleus (ICC;
      approximately 81% of all recordings) of the IC: 1) in all three experimental
      groups, neurons in the ICX had significantly lower Fmax and longer response
      latencies than those in the ICC. 2) Chronic electrical stimulation in neonatally
      deafened cats altered the temporal resolution of neurons exclusively in the ICC
      but not in the ICX. The magnitude of this effect was dependent on the frequency
      of the chronic stimulation. Specifically, low-frequency signals (30 pps, 80 pps)
      maintained the temporal resolution of ICC neurons, whereas higher-frequency
      stimuli significantly improved temporal resolution of ICC neurons (i.e., higher
      Fmax and shorter response latencies) compared with neurons in control cats.
      Furthermore, Fmax and latencies to electrical stimuli were not correlated with
      the tonotopic gradient of the ICC, and changes in temporal resolution following
      chronic electrical stimulation occurred uniformly throughout the entire ICC. In
      all three experimental groups, increasing Fmax was correlated with shorter
      response latencies. The results indicate that the temporal features of the
      chronically applied electrical signals critically influence temporal processing
      of neurons in the cochleotopically organized ICC. We suggest that such plastic
      changes in temporal processing of central auditory neurons may contribute to the
      intersubject variability and gradual improvements in speech recognition
      performance observed in clinical studies of deaf children using cochlear
      implants.

PMID- 10601428
TI  - Regulation of action potential size and excitability in substantia nigra compacta
      neurons: sensitivity to 4-aminopyridine.
AB  - Slow, pacemaker-like firing is due to intrinsic membrane properties in substantia
      nigra compacta (SNc) neurons in vitro. How these properties interact with
      afferent synaptic inputs is not fully understood. In this study, intracellular
      recordings from SNc neurons in brain slices showed that spontaneous action
      potentials (APs) were attenuated when generated from lower than normal threshold.
      Such APs were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and could be
      related to non-N-methyl-D-aspartate (NMDA) receptor-mediated spontaneous
      excitatory postsynaptic potentials (EPSPs). The AP attenuation was reproduced by
      stimulus-evoked EPSPs and by current injections to the soma. APs evoked from
      holding potentials between -40 and -60 mV were reduced in width by Cd(2+) (0. 2
      mM). Tetraethylammonium chloride (TEA, 10 mM) or 4-aminopyridine (4-AP, 5 mM)
      increased the AP width. However, at more negative holding potentials, Cd(2+) and
      TEA were inefficacious, whereas 4-AP enlarged the AP, partly via induction of a
      Cd(2+)-sensitive component. A monophasic afterhyperpolarization (AHP), following
      attenuated APs, was little affected by either Cd(2+) or TEA, but inhibited by 4
      AP, which induced an additional, slow component, sensitive to Cd(2+) or apamin
      (100 nM). The AP delay showed a discontinuous relation to the amplitude or slope
      of the injected current (delay shift), which was sensitive to low doses of 4-AP
      (0. 05 mM). The initial time window before the delay shift was longer than the
      rise time of EPSPs. It is suggested that a 4-AP-sensitive current prevents or
      postpones discharge during slow depolarization's, but allows direct excitation by
      fast EPSPs. Fast excitation leads to AP attenuation, primarily due to strong
      activation of 4-AP-sensitive current. This seems to cause inhibition of the
      Ca(2+) current during the AP and reduction of Ca(2+)-dependent K(+) currents.
      Together, these properties are likely to influence the excitability and the
      local, somatodendritic effects of the AP, in a manner that discriminates between
      firing induced by the intrinsic pacemaker mechanism and fast synaptic potentials.

PMID- 10601429
TI  - Computational model of the serotonergic modulation of sensory neurons in Aplysia.
AB  - Serotonergic modulation of the sensory neurons that mediate the gill- and tail
      withdrawal reflexes of Aplysia is a useful model system for studies of neuronal
      plasticity that contributes to learning and memory. The effects of serotonin (5
      HT) are mediated, in part, via two protein kinases (protein kinase A, PKA, and
      protein kinase C, PKC), which in turn, modulate at least four membrane currents,
      including a S ("serotonin-sensitive") K(+) current (I(K, S)), a steeply voltage
      dependent K(+) current (I(K-V)), a slow component of the Ca(2+)-activated K(+)
      current (I(K,Ca-S)), and a L-type Ca(2+) current (I(Ca-L)). The present study
      investigated how the modulation of these currents altered the spike duration and
      excitability of sensory neurons and examined the relative contributions of PKA-
      and PKC-mediated effects to the actions of 5-HT. A Hodgkin-Huxley type model was
      developed that described the ionic conductances in the somata of sensory neurons.
      The descriptions of these currents and their modulation were based largely on
      voltage-clamp data from sensory neurons. Simulations were preformed with the
      program SNNAP (Simulator for Neural Networks and Action Potentials). The model
      was sufficient to replicate empirical data that describes the membrane currents,
      action potential waveform and excitability as well as their modulation by
      application of 5-HT, increased levels of adenosine cyclic monophosphate or
      application of active phorbol esters. In the model, modulation of I(K-V) by PKC
      played a dominate role in 5-HT-induced spike broadening, whereas the concurrent
      modulation of I(K,S) and I(K,Ca-S) by PKA primarily accounted for 5-HT-induced
      increases in excitability. Finally, simulations indicated that a PKC-induced
      increase in excitability resulted from decreases of I(K,S) and I(K,Ca-S), which
      was likely the indirect result of cross-talk between the PKC and PKA systems. The
      results provide several predictions that warrant additional experimental
      investigation and illustrate the importance of considering indirect as well as
      direct effects of modulatory agents on the modulation of membrane currents.

PMID- 10601430
TI  - Activity-related calcium dynamics in motoneurons of the nucleus hypoglossus from
      mouse.
AB  - A quantitative analysis of activity-related calcium dynamics was performed in
      motoneurons of the nucleus hypoglossus in the brain stem slice preparation from
      mouse by simultaneous patch-clamp and microfluorometric calcium measurements.
      Motoneurons were analyzed under in vitro conditions that kept them in a
      functionally intact state represented by rhythmic, inspiratory-related bursts of
      excitatory postsynaptic currents and associated action potential discharges.
      Bursts of electrical activity were paralleled by somatic calcium transients
      resulting from calcium influx through voltage-activated calcium channels, where
      each action potential accounted for a calcium-mediated charge influx around 2 pC
      into the somatic compartment. Under in vivo conditions, rhythmic-respiratory
      activity in young mice occurred at frequencies up to 5 Hz, demonstrating the
      necessity for rapid calcium elevation and recovery in respiratory-related
      neurons. The quantitative analysis of hypoglossal calcium homeostasis identified
      an average extrusion rate, but an exceptionally low endogenous calcium binding
      capacity as cellular parameters accounting for rapid calcium signaling. Our
      results suggest that dynamics of somatic calcium transients 1) define an upper
      limit for the maximum frequency of respiratory-related burst discharges and 2)
      represent a potentially dangerous determinant of intracellular calcium profiles
      during pathophysiological and/or excitotoxic conditions.

PMID- 10601431
TI  - Adenosine A1 and class II metabotropic glutamate receptors mediate shared
      presynaptic inhibition of retinotectal transmission.
AB  - Presynaptic inhibition is one of the major control mechanisms in the CNS.
      Previously we reported that adenosine A1 receptors mediate presynaptic inhibition
      at the retinotectal synapse of goldfish. Here we extend these findings to
      metabotropic glutamate receptors (mGluRs) and report that presynaptic inhibition
      produced by both A1 adenosine receptors and group II mGluRs is due to G(i)
      protein coupling to inhibition of N-type calcium channels in the retinal ganglion
      cells. Adenosine (100 microM) and an A1 (but not A2) receptor agonist reduced
      calcium current (I(Ca2+)) by 16-19% in cultured retinal ganglion cells,
      consistent with their inhibition of retinotectal synaptic transmission (-30%
      amplitude of field potentials). The general metabotropic glutamate receptor
      (mGluR) agonist 1S,3R-1-amino-cyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD, 50
      microM) and the selective group II mGluR receptor agonist (2S, 2'R,3'R)-2-(2',3'
      dicarboxy-cyclopropyl)glycine (DCG-IV, 300 nM) inhibited both synaptic
      transmission and I(Ca2+), whereas the group III mGluR agonist L-2-amino-4
      phosphono-butyrate (L-AP4) inhibited neither synaptic transmission nor I(Ca2+).
      When the N-type calcium channels were blocked with omega-conotoxin GVIA, both
      adenosine and DCG-IV had much smaller percentage effects on the residual 20% of
      I(Ca2+), suggesting effects mainly on the N-type calcium channels. The inhibitory
      effects of A1 adenosine receptors and mGluRs were both blocked by pertussis
      toxin, indicating that they are mediated by either G(i) or G(o). They were also
      inhibited by activation of protein kinase C (PKC), which is known to
      phosphorylate and inhibit G(i). Finally, when applied sequentially, inhibition by
      adenosine and DCG-IV were not additive but occluded each other. Together these
      results suggest that adenosine A1 receptors and group II mGluRs mediate
      presynaptic inhibition of retinotectal synaptic transmission by sharing a
      pertussis toxin (PTX)-sensitive, PKC-regulated G(i) protein coupled to N-type
      calcium channels.

PMID- 10601432
TI  - Evidence for involvement of group II/III metabotropic glutamate receptors in NMDA
      receptor-independent long-term potentiation in area CA1 of rat hippocampus.
AB  - Previous studies implicated metabotropic glutamate receptors (mGluRs) in N-methyl
      D-aspartate (NMDA) receptor-independent long-term potentiation (LTP) in area CA1
      of the rat hippocampus. To learn more about the specific roles played by mGluRs
      in NMDA receptor-independent LTP, we used whole cell recordings to load
      individual CA1 pyramidal neurons with a G-protein inhibitor [guanosine-5'-O-(2
      thiodiphosphate), GDPbetaS]. Although loading postsynaptic CA1 pyramidal neurons
      with GDPbetaS significantly reduced G-protein dependent postsynaptic potentials,
      GDPbetaS failed to prevent NMDA receptor- independent LTP, suggesting that
      postsynaptic G-protein-dependent mGluRs are not required. We also performed a
      series of extracellular field potential experiments in which we applied group
      selective mGluR antagonists. We had previously determined that paired-pulse
      facilitation (PPF) was decreased during the first 30-45 min of NMDA receptor
      independent LTP. To determine if mGluRs might be involved in these PPF changes,
      we used a twin-pulse stimulation protocol to measure PPF in field potential
      experiments. NMDA receptor-independent LTP was prevented by a group II mGluR
      antagonist [(2S)-alpha-ethylglutamic acid] and a group III mGluR antagonist [(RS)
      alpha-cyclopropyl-4-phosphonophenylglycine], but was not prevented by other group
      II and III mGluR antagonists [(RS)-alpha-methylserine-O-phosphate monophenyl
      ester or (RS)-alpha-methylserine-O-phosphate]. NMDA receptor-independent LTP was
      not prevented by either of the group I mGluR antagonists we examined, (RS)-1
      aminoindan-1,5-dicarboxylic acid and 7-(hydroxyimino)cyclopropa[b]chromen-1a
      carboxylate ethyl ester. The PPF changes which accompany NMDA receptor
      independent LTP were not prevented by any of the group-selective mGluR
      antagonists we examined, even when the LTP itself was blocked. Finally, we found
      that tetanic stimulation in the presence of group III mGluR antagonists lead to
      nonspecific potentiation in control (nontetanized) input pathways. Taken
      together, our results argue against the involvement of postsynaptic group I
      mGluRs in NMDA receptor-independent LTP. Group II and/or group III mGluRs are
      required, but the specific details of the roles played by these mGluRs in NMDA
      receptor-independent LTP are uncertain. Based on the pattern of results we
      obtained, we suggest that group II mGluRs are required for induction of NMDA
      receptor-independent LTP, and that group III mGluRs are involved in determining
      the input specificity of NMDA receptor-independent LTP by suppressing
      potentiation of nearby, nontetanized synapses.

PMID- 10601433
TI  - Gustatory neuron types in rat geniculate ganglion.
AB  - We used extracellular single-cell recording procedures to characterize the
      chemical and thermal sensitivity of the rat geniculate ganglion to lingual
      stimulation, and to examine the effects of specific ion transport antagonists on
      salt transduction mechanisms. Hierarchical cluster analysis of the responses from
      73 single neurons to 3 salts (0.075 and 0.3 M NaCl, KCl, and NH(4) Cl), 0.5 M
      sucrose, 0.01 M HCl, and 0.02 M quinine HCl (QHCl) indicated 3 main groups that
      responded best to either sucrose, HCl, or NaCl. Eight narrowly tuned neurons were
      deemed sucrose-specialists and 33 broadly tuned neurons as HCl-generalists. The
      NaCl group contained three identifiable subclusters: 18 NaCl-specialists, 11 NaCl
      generalists, and 3 QHCl-generalists. Sucrose- and NaCl-specialists responded
      specifically to sucrose and NaCl, respectively. All generalist neurons responded
      to salt, acid, and alkaloid stimuli to varying degree and order depending on
      neuron type. Response order was NaCl > HCl = QHCl > sucrose in NaCl-generalists,
      HCl > NaCl > QHCl > sucrose in HCl-generalists, and QHCl = NaCl = HCl > sucrose
      in QHCl-generalists. NaCl-specialists responded robustly to low and high NaCl
      concentrations, but weakly, if at all, to high KCl and NH(4) Cl concentrations
      after prolonged stimulation. HCl-generalist neurons responded to all three salts,
      but at twice the rate to NH(4) Cl than to NaCl and KCl. NaCl- and QHCl
      generalists responded equally to the three salts. Amiloride and 5-(N,N-dimethyl)
      amiloride (DMA), antagonists of Na(+) channels and Na(+)/H(+) exchangers,
      respectively, inhibited the responses to 0.075 M NaCl only in NaCl-specialist
      neurons. The K(+) channel antagonist, 4-aminopyridine (4-AP), was without a
      suppressive effect on salt responses, but, when applied alone in solution, it
      evoked a response in many HCl-generalists and one QHCl-generalist neuron so
      tested. Of the 39 neurons tested for their sensitivity to temperature, 23
      responded to cooling and chemical stimulation, and 20 of these neurons were HCl
      generalists. Moreover, the responses to the four standard stimuli were reduced
      progressively at lower temperatures in HCl- and QHCl-generalist neurons, but not
      in NaCl-specialists. Thus sodium channels and Na(+)/H(+) exchangers appear to be
      expressed exclusively on the membranes of receptor cells that synapse with NaCl
      specialist neurons. In addition, cooling sensitivity and taste-temperature
      interactions appear to be prominent features of broadly tuned neuron groups,
      particularly HCl-generalists. Taken all together, it appears that lingual taste
      cells make specific connections with afferent fibers that allow gustatory stimuli
      to be parceled into different input pathways. In general, these neurons are
      organized physiologically into specialist and generalist types. The sucrose- and
      NaCl-specialists alone can provide sufficient information to distinguish sucrose
      and NaCl from other stimuli, respectively.

PMID- 10601434
TI  - Activation of serotonin receptors modulates synaptic transmission in rat cerebral
      cortex.
AB  - The cerebral cortex receives an extensive serotonergic (5-hydroxytryptamine, 5
      HT) input. Immunohistochemical studies suggest that inhibitory neurons are the
      main target of 5-HT innervation. In vivo extracellular recordings have shown that
      5-HT generally inhibited cortical pyramidal neurons, whereas in vitro studies
      have shown an excitatory action. To determine the cellular mechanisms underlying
      the diverse actions of 5-HT in the cortex, we examined its effects on cortical
      inhibitory interneurons and pyramidal neurons. We found that 5-HT, through
      activation of 5-HT(2A) receptors, induced a massive enhancement of spontaneous
      inhibitory postsynaptic currents (sIPSCs) in pyramidal neurons, lasting for
      approximately 6 min. In interneurons, this 5-HT-induced enhancement of sIPSCs was
      much weaker. Activation of 5-HT(2A) receptors also increased spontaneous
      excitatory postsynaptic currents (sEPSCs) in pyramidal neurons. This response
      desensitized less and at a slower rate. In contrast, 5-HT slightly decreased
      evoked IPSCs (eIPSCs) and eEPSCs. In addition, 5-HT via 5-HT(3) receptors evoked
      a large and rapidly desensitizing inward current in a subset of interneurons and
      induced a transient enhancement of sIPSCs. Our results suggest that 5-HT has
      widespread effects on both interneurons and pyramidal neurons and that a short
      pulse of 5-HT is likely to induce inhibition whereas the prolonged presence of 5
      HT may result in excitation.

PMID- 10601435
TI  - Selective modulation of excitatory transmission by mu-opioid receptor activation
      in rat supraoptic neurons.
AB  - Opioid peptides have profound inhibitory effects on the production of oxytocin
      and vasopressin, but their direct effects on magnocellular neuroendocrine neurons
      appear to be relatively weak. We tested whether a presynaptic mechanism is
      involved in this inhibition. The effects of mu-opioid receptor agonist D-Ala(2),
      N-CH(3)-Phe(4), Gly(5)-ol-enkephalin (DAGO) on excitatory and inhibitory
      transmission were studied in supraoptic nucleus (SON) neurons from rat
      hypothalamic slices using whole cell recording. DAGO reduced the amplitude of
      evoked glutamatergic excitatory postsynaptic currents (EPSCs) in a dose-dependent
      manner. In the presence of tetrodotoxin (TTX) to block spike activity, DAGO also
      reduced the frequency of spontaneous miniature EPSCs without altering their
      amplitude distribution, rising time, or decaying time constant. The above effects
      of DAGO were reversed by wash out, or by addition of opioid receptor antagonist
      naloxone or selective mu-antagonist Cys(2)-Tyr(3)-Orn(5)-Pen(7)-NH(2) (CTOP). In
      contrast, DAGO had no significant effect on the evoked and spontaneous miniature
      GABAergic inhibitory postsynaptic currents (IPSCs) in most SON neurons. A direct
      membrane hyperpolarization of SON neurons was not detected in the presence of
      DAGO. These results indicate that mu-opioid receptor activation selectively
      inhibits excitatory activity in SON neurons via a presynaptic mechanism.

PMID- 10601436
TI  - Computational analysis of action potential initiation in mitral cell soma and
      dendrites based on dual patch recordings.
AB  - In olfactory mitral cells, dual patch recordings show that the site of action
      potential initiation can shift between soma and distal primary dendrite and that
      the shift is dependent on the location and strength of electrode current
      injection. We have analyzed the mechanisms underlying this shift, using a model
      of the mitral cell that takes advantage of the constraints available from the two
      recording sites. Starting with homogeneous Hodgkin-Huxley-like Na(+)-K(+) channel
      distribution in the soma-dendritic region and much higher sodium channel density
      in the axonal region, the model's channel kinetics and density were adjusted by a
      fitting algorithm so that the model response was virtually identical to the
      experimental data. The combination of loading effects and much higher sodium
      channel density in the axon relative to the soma-dendritic region results in
      significantly lower "voltage threshold" for action potential initiation in the
      axon; the axon therefore fires first unless the voltage gradient in the primary
      dendrite is steep enough for it to reach its higher threshold. The results thus
      provide a quantitative explanation for the stimulus strength and position
      dependence of the site of action potential initiation in the mitral cell.

PMID- 10601437
TI  - Coordinated ground forces exerted by buttocks and feet are adequately programmed
      for weight transfer during sit-to-stand.
AB  - The purpose of this study was to test the hypothesis whether weight transfer
      during sit-to-stand (STS) is the result of coordinated ground forces exerted by
      buttocks and feet before seat-off. Whole-body kinematics and three-dimensional
      ground forces from left and right buttock as well as from left and right foot
      were recorded for seven adults during STS. We defined a preparatory phase from
      onset of the first detectable anterior/posterior (A/P) force to seat-off (buttock
      forces fell to 0) and a rising phase from seat-off to the decrease of center of
      mass (CoM) vertical velocity to zero. STS was induced by an increase of vertical
      and backward directed ground forces exerted by the buttocks that significantly
      preceded the onset of any trunk movement. All ground forces peaked before or
      around the moment of seat-off, whereas all kinematic variables, except trunk
      forward rotation and hip flexion, peaked after seat-off, during or after the
      rising phase. The present study suggests that the weight transfer from sit to
      stand is induced by ground forces exerted by buttocks and feet before seat-off,
      i.e., during the preparatory phase. The buttocks generate the isometric "rising
      forces," e.g., the propulsive impulse for the forward acceleration of the body,
      while the feet apply adequate damping control before seat-off. This indicates
      that the rising movement is a result of these coordinated forces, targeted to
      match the subject's weight and support base distance between buttocks and feet.
      The single peaked, bell-shaped profiles peaking before seat-off, were seen
      beneath buttocks for the "rising drive," i.e., between the time of peak backward
      directed force and seat-off, as well as beneath the feet for the "damping drive,"
      i.e., from onset to the peak of forward-directed force and for CoM A/P velocity.
      This suggests that both beginning and end of the weight transfer process are
      programmed before seat-off. The peak deceleration of A/P CoM took place shortly (
      approximately 100 ms) after CoM peak velocity, resulting in a well controlled CoM
      deceleration before seat-off. In contrast to the view of other authors, this
      suggests that body equilibrium is controlled during weight transfer.

PMID- 10601438
TI  - Effect of phasic activation on endplate potential in rat diaphragm.
AB  - Neuromuscular junction endplate potentials (EPPs) decrease quickly and to a large
      extent during continuous stimulation. The present study examined the hypothesis
      that EPP rundown recovers rapidly, thereby substantially preserving
      neurotransmission during intermittent compared with continuous stimulation.
      Studies were performed in vitro on rat diaphragm, using mu-conotoxin to allow
      recording of normal-sized EPPs from intact fibers. During continuous 5- to 100-Hz
      stimulation, EPP amplitude declined with a biphasic time course. The initial fast
      rate of decline was modulated substantially by stimulation frequency, whereas the
      subsequent slow rate of decline was relatively frequency independent. During
      intermittent 5- to 100-Hz stimulation (duty cycle 0.33), EPP amplitude declined
      rapidly during each train, but recovered substantially by the onset of the
      following train. The intra-train declines were substantially greater than the
      inter-train declines in EPP amplitude. Intra-train reductions in EPP amplitude
      were stimulation frequency dependent, based on both the total decline and rate
      constant of EPP decline. In contrast, the degree of recovery from train to train
      was independent of stimulation frequency, indicating low frequency dependence of
      inter-train rundown. The substantial recovery of EPP amplitude in between trains
      resulted in greater cumulative EPP size during intermittent compared with
      continuous stimulation. During continuous stimulation, EPP drop-out was only seen
      during 100-Hz stimulation; this was completed mitigated during intermittent
      stimulation. Miniature EPP size was unaffected by either continuous or
      intermittent stimulation. The pattern of rapid intra-train rundown and slow inter
      train rundown of EPP size during intermittent stimulation is therefore due to
      rapid changes in the magnitude of neurotransmitter release rather than to axonal
      block or postsynaptic receptor desensitization. These findings indicate
      considerable rundown of EPP amplitudes within a stimulus train, with near
      complete recovery by the onset of the next train. This substantially attenuates
      the decrement in EPP amplitude during intermittent compared with continuous
      stimulation, thereby preserving the integrity of neurotransmission during phasic
      activation.

PMID- 10601439
TI  - Nicotine modulates evoked GABAergic transmission in the brain.
AB  - The effects of nicotine on evoked GABAergic synaptic transmission were examined
      using whole cell recordings from neurons of the lateral spiriform nucleus in
      embryonic chick brain slices. All synaptic activities were abolished by the
      GABA(A) receptor antagonist, bicuculline (20 microM). Under voltage-clamp with
      KCl-filled pipettes (holding potential -70 mV), nicotine (0.1-1.0 microM)
      increased the frequency of spontaneous GABAergic currents in a dose-dependent
      manner. Nicotine enhanced electrically evoked GABAergic transmission only at
      relatively low concentrations of 50-100 nM (but not 25 nM), which approximate the
      concentrations of nicotine in the blood produced by cigarette smoking. At higher
      concentrations nicotine had either no effect (0.25 microM) or diminished (0.5-1.0
      microM) evoked GABAergic neurotransmission. Nicotine had no significant effect on
      the postsynaptic current induced by exogenous GABA (30-50 microM). These data
      imply that nicotine levels attained in smokers are sufficient to enhance evoked
      GABAergic transmission in the brain, and that this effect is most likely mediated
      through activation of presynaptic nicotinic receptors.

PMID- 10601440
TI  - Activation of spinal wide dynamic range neurons by intracutaneous microinjection
      of nicotine.
AB  - Nicotine evokes pain in the skin and oral mucosa and excites a subpopulation of
      cutaneous nociceptors, but little is known about the central transmission of
      chemogenic pain. We have investigated the responses of lumbar spinal wide dynamic
      range (WDR)-type dorsal horn neurons to intracutaneous (ic) microinjection of
      nicotine in pentobarbital-anesthetized rats. Nearly all (97%) units responded to
      nicotine microinjected ic (1 microl) into the low-threshold region of the hind
      paw mechanosensitive receptive field in a concentration-related manner (0.01
      10%). Responses to repeated injections of 10% nicotine exhibited tachyphylaxis at
      5-, 10-, and 15-min interstimulus intervals. Significant tachyphylaxis was not
      seen with 1% nicotine. All nicotine-responsive units tested (n = 30) also
      responded to ic histamine (1 microl, 3%) and did not exhibit tachyphylaxis to
      repeated histamine. However, there was significant cross-tachyphylaxis of
      nicotine to histamine. Thus 5 min after ic nicotine, histamine-evoked responses
      were attenuated significantly compared with the initial histamine-evoked response
      prior to nicotine, with partial recovery over the ensuing 15 min. Neuronal
      excitation by ic nicotine was not mediated by histamine H1 receptors because ic
      injection of the H1 receptor antagonist, cetirizine, had no effect on ic nicotine
      evoked responses, whereas it significantly attenuated ic histamine-evoked
      responses in the same neurons. The lowest-threshold portion of cutaneous
      receptive fields showed a significant expansion in area at 20 min after ic
      nicotine 10%, indicative of sensitization. Responses to 1% nicotine were
      significantly reduced after ic injection of the nicotinic antagonist,
      mecamylamine (0.1% ic), with no recovery over the ensuing 40-60 min. These data
      indicate that nicotine ic excites spinal WDR neurons, partly via neuronal
      nicotinic acetylcholine receptors that are presumably expressed in cutaneous
      nociceptor terminals. Repeated injections of high concentrations of nicotine led
      to tachyphylaxis and cross-tachyphylaxis with histamine, possibly relevant to
      peripheral analgesic effects of nicotine.

PMID- 10601441
TI  - Attributes of quiet stance in the chronic spinal cat.
AB  - Standing is a dynamic task that requires antigravity support of the body mass and
      active regulation of the position of the body center of mass. This study examined
      the extent to which the chronic spinal cat can maintain postural orientation
      during stance and adapt to changes in stance distance (fore-hindpaw separation).
      Intact cats adapt to changes in stance distance by maintaining a constant
      horizontal orientation of the trunk and changing orientation of the limbs, while
      keeping intralimb geometry constant and aligning the ground reaction forces
      closely with the limb axes. Postural adaptation was compared in four cats before
      and after spinalization at the T(6) level, in terms of the forces exerted by each
      paw against the support, body geometry (kinematics) and electromyographic (EMG)
      activity recorded from chronic, indwelling electrodes, as well as the computed
      net torques in the fore and hindlimbs. Five fore-hindpaw distances spanning the
      preferred distance were tested before spinalization, with a total range of 20 cm
      from the shortest to the longest stance. After spinalization, the cats were
      trained on a daily basis to stand on the force platform, and all four cats were
      able to support their full body weight. Three of the four cats could adapt to
      changes in stance distance, but the range was smaller and biased toward the
      shorter distances. The fourth cat could stand only at one stance distance, which
      was 8 cm shorter than the preferred distance before spinalization. All cats
      shifted their center of pressure closer to the forelimbs after spinalization, but
      the amount of shift could largely be accounted for by the weight loss in the
      hindquarters. The three cats that could adapt to changes in stance distance used
      a similar strategy as the intact cat by constraining the trunk and changing
      orientation of the limb axes in close relation with the forces exerted by each
      limb. However, different postures in the fore- and hindlimbs were adopted,
      particularly at the scapula (more extended) and pelvis (tipped more anteriorly).
      Other changes from control included a redistribution of net extensor torque
      across the joints of the forelimb and of the hindlimb. We concluded that the
      general form of body axis orientation is relatively conserved in the spinal cat,
      suggesting that the lumbosacral spinal circuitry includes rudimentary set points
      for hindlimb geometry. Both mechanical and neural elements can contribute toward
      maintaining body geometry through stiffness regulation and spinal reflexes.

PMID- 10601442
TI  - Weight support and balance during perturbed stance in the chronic spinal cat.
AB  - The intact cat maintains balance during unexpected disturbances of stance through
      automatic postural responses that are stereotyped and rapid. The extent to which
      the chronic spinal cat can maintain balance during stance is unclear, and there
      have been no quantitative studies that examined this question directly. This
      study examined whether the isolated lumbosacral cord of the chronic spinal cat
      can generate automatic postural responses in the hindlimbs during translation of
      the support surface. Responses to 16 directions of linear translation in the
      horizontal plane were quantified before and after spinalization at the T(6) level
      in terms of forces exerted by each paw against the support, motion of the body
      segments (kinematics), and electromyographic (EMG) activity. After spinalization,
      the cats were trained on a daily basis to stand on the force platform, and all
      four cats were able to support their full body weight. The cats usually required
      assistance for balance or stability in the horizontal plane, which was provided
      by an experimenter exerting gentle lateral force at the level of the hips. Three
      of the four animals could maintain independent stance for a brief period (10 s)
      after the experimenter stabilized them. The fourth cat maintained weight support
      but always required assistance with balance. Perturbations were delivered during
      the periods of independent stance in three cats and during assisted stance in the
      fourth. A response to translation in the spinal cats was observed only in those
      muscles that were tonically active to maintain stance and never in the flexors.
      Moreover, latencies were increased and amplitudes of activation were diminished
      compared with control. Nevertheless, flexors and extensors were recruited easily
      during behaviors such as paw shake and stepping. It is concluded that centers
      above the lumbosacral cord are required for the full elaboration of automatic
      postural responses. Although the spinal cat can achieve good weight support, it
      cannot maintain balance during stance except for brief periods and within narrow
      limits. This limited stability is probably achieved through spinal reflex
      mechanisms and the stiffness characteristics of the tonically active extensors.

PMID- 10601443
TI  - Visual stimulus-dependent changes in interhemispheric EEG coherence in ferrets.
AB  - In recent years, the analysis of the coherence between signals recorded from the
      scalp [electroencephalographic (EEG) coherence] has been used to assess the
      functional properties of cortico-cortical connections, both in animal models and
      in humans. However, the experimental validation of this technique is still
      scarce. Therefore we applied it to the study of the callosal connections between
      the visual areas of the two hemispheres, because this particular set of cortico
      cortical connections can be activated in a selective way by visual stimuli.
      Indeed, in primary and in low-order secondary visual areas, callosal axons
      interconnect selectively regions, which represent a narrow portion of the visual
      field straddling the vertical meridian and, within these regions, neurons that
      prefer the same stimulus orientation. Thus only isooriented stimuli located near
      the vertical meridian are expected to change interhemispheric coherence by
      activating callosal connections. Finally, if such changes are found and are
      indeed mediated by callosal connections, they should disappear after transection
      of the corpus callosum. We perfomed experiments on seven paralyzed and
      anesthetized ferrets, recording their cortical activity with epidural electrodes
      on areas 17/18, 19, and lateral suprasylvian, during different forms of visual
      stimulation. As expected, we found that bilateral iso-oriented stimuli near the
      vertical meridian, or extending across it, caused a significant increase in
      interhemispheric coherence in the EEG beta-gamma band. Stimuli with different
      orientations, stimuli located far from the vertical meridian, as well as
      unilateral stimuli failed to affect interhemispheric EEG coherence. The stimulus
      induced increase in coherence disappeared after surgical transection of the
      corpus callosum. The results suggest that the activation of cortico-cortical
      connections can indeed be revealed as a change in EEG coherence. The latter can
      therefore be validly used to investigate the functionality of cortico-cortical
      connections.

PMID- 10601444
TI  - Visual stimulus-dependent changes in interhemispheric EEG coherence in humans.
AB  - We analyzed the coherence of electroencephalographic (EEG) signals recorded
      symmetrically from the two hemispheres, while subjects (n = 9) were viewing
      visual stimuli. Considering the many common features of the callosal connectivity
      in mammals, we expected that, as in our animal studies, interhemispheric
      coherence (ICoh) would increase only with bilateral iso-oriented gratings located
      close to the vertical meridian of the visual field, or extending across it.
      Indeed, a single grating that extended across the vertical meridian significantly
      increased the EEG ICoh in normal adult subjects. These ICoh responses were
      obtained from occipital and parietal derivations and were restricted to the gamma
      frequency band. They were detectable with different EEG references and were
      robust across and within subjects. Other unilateral and bilateral stimuli,
      including identical gratings that were effective in anesthetized animals, did not
      affect ICoh in humans. This fact suggests the existence of regulatory influences,
      possibly of a top-down kind, on the pattern of callosal activation in conscious
      human subjects. In addition to establishing the validity of EEG coherence
      analysis for assaying cortico-cortical connectivity, this study extends to the
      human brain the finding that visual stimuli cause interhemispheric
      synchronization, particularly in frequencies of the gamma band. It also indicates
      that the synchronization is carried out by cortico-cortical connection and
      suggests similarities in the organization of visual callosal connections in
      animals and in man.

PMID- 10601445
TI  - Intracellular study of excitability in the seizure-prone neocortex in vivo.
AB  - The excitability of neocortical neurons from cat association areas 5-7 was
      investigated during spontaneously occurring seizures with spike-wave (SW)
      complexes at 2-3 Hz. We tested the antidromic and orthodromic responsiveness of
      neocortical neurons during the "spike" and "wave" components of SW complexes, and
      we placed emphasis on the dynamics of excitability changes from sleeplike
      patterns to seizures. At the resting membrane potential, an overwhelming majority
      of neurons displayed seizures over a depolarizing envelope. Cortical as well as
      thalamic stimuli triggered isolated paroxysmal depolarizing shifts (PDSs) that
      eventually developed into SW seizures. PDSs could also be elicited by cortical or
      thalamic volleys during the wave-related hyperpolarization of neurons, but not
      during the spike-related depolarization. The latencies of evoked excitatory
      postsynaptic potentials (EPSPs) progressively decreased, and their slope and
      depolarization surface increased, from the control period preceding the seizure
      to the climax of paroxysm. Before the occurrence of full-blown seizures, thalamic
      stimuli evoked PDSs arising from the postinhibitory rebound excitation, whereas
      cortical stimuli triggered PDSs immediately after the early EPSP. These data shed
      light on the differential excitability of cortical neurons during the spike and
      wave components of SW seizures, and on the differential effects of cortical and
      thalamic volleys leading to such paroxysms. We conclude that the wave-related
      hyperpolarization does not represent GABA-mediated inhibitory postsynaptic
      potentials (IPSPs), and we suggest that it is a mixture of disfacilitation and
      Ca(2+)-dependent K(+) currents, similar to the prolonged hyperpolarization of the
      slow sleep oscillation.

PMID- 10601446
TI  - Spontaneous and artificial activation of neocortical seizures.
AB  - The aim of this study is to disclose the mechanisms underlying the recruitment of
      neocortical networks during slow-wave sleep oscillations evolving into spike-wave
      (SW) seizures. 1) We investigated the activation of SW seizures in a seizure
      prone neocortex by means of electrical stimuli applied within the frequency range
      of spontaneous sleep oscillations. Stimuli were grouped in bursts of 10 Hz,
      similar to sleep spindles, and repeated every 2 s, to reproduce their rhythmic
      recurrence imposed by the slow (<1 Hz) sleep oscillation. Either cortical or
      thalamic stimuli, which were applied while the cortex displayed sleeplike
      activity, gradually induced paroxysmal responses in intracellularly recorded
      neocortical neurons, which were virtually identical to those of spontaneous
      seizures and consisted of a progressive buildup of paroxysmal depolarizing shifts
      (PDSs). 2) The ability of cortical networks to follow stimuli was tested at
      various stimulation frequencies (1-3 Hz) and quantified by calculating the
      entropy of the ensuing oscillation. Rhythmic PDSs were optimally induced, and the
      lowest entropy was generated, at a stimulation frequency around 1.5 Hz. Fast runs
      at 10-15 Hz, which often override PDSs, thus contributing to the polyspike-wave
      pattern of seizures, were induced by cortical stimuli, but were disturbed by
      thalamic stimuli. Spontaneous seizures generally evolved toward an accelerated
      discharge of PDSs. It is suggested that these accelerating trends during SW
      seizures act as protective mechanisms by provoking the uncoupling of cortical
      networks and eventually arresting the seizure.

PMID- 10601447
TI  - Long-lasting increase in cellular excitability associated with the priming of LTP
      induction in rat hippocampus.
AB  - The mechanisms underlying the facilitation (priming) of long-term potentiation
      (LTP) by prior activation of metabotropic glutamate receptors (mGluRs) were
      investigated in area CA1 of rat hippocampal slices. In particular, we focused on
      whether a long-lasting increase in postsynaptic excitability could account for
      the facilitated LTP. Administration of the mGluR agonist 1S, 3R
      aminocyclopentanedicarboxylic acid (ACPD) produced rapid decreases in the
      amplitude of both the slow spike afterhyperpolarization (AHP(slow)) and spike
      frequency adaptation recorded intracellularly from CA1 pyramidal cells. These
      changes persisted after drug washout, showing only a slow decay over 20 min. ACPD
      also caused a leftward shift of the field EPSP-population spike relation and an
      overall increase in population spike amplitude, but this effect was not as
      persistent as the intracellularly measured alterations in cell excitability. ACPD
      treated cells showed increased spike discharges during LTP-inducing tetanic
      stimulation, and the amplitude of the AHP(slow) was negatively correlated with
      the degree of initial LTP induction. The beta-adrenergic agonist isoproterenol
      also caused excitability changes as recorded intracellularly, whereas in
      extracellular experiments it weakly primed the induction but not the persistence
      of LTP. ACPD primed both LTP measures. Isoproterenol administration during the
      tetanus occluded the priming effect of ACPD on initial LTP induction but not its
      effect on LTP persistence. We conclude that the persistent excitability changes
      elicited by ACPD contributes to the priming of LTP induction but that other ACPD
      triggered mechanisms must account for the facilitated persistence of LTP in the
      priming paradigm.

PMID- 10601448
TI  - Processing of gustatory information by spiking local interneurons in the locust.
AB  - Despite the importance of gustation, little is known of the central pathways
      responsible for the processing and coding of different chemical stimuli. Here I
      have analyzed the responses of a population of spiking local interneurons, with
      somata at the ventral midline of the metathoracic ganglion, during stimulation of
      chemo- and mechanoreceptors on the legs of locusts. Volatile acidic stimuli were
      used to selectively activate the chemosensory neurons. Different members of the
      population of local interneurons received depolarizing or hyperpolarizing inputs
      during chemosensory stimulation. Many of the same interneurons that received
      chemosensory input also received mechanosensory inputs from tactile hairs on the
      leg, but others received exclusively mechanosensory inputs. Chemosensory inputs
      occurred with a short and constant latency, typical of monosynaptic connections.
      The chemosensory receptive fields of the spiking local interneurons mapped the
      surface of a hind leg so that spatial information relating to the location of a
      taste receptor was preserved. The amplitude of potentials in interneurons during
      chemosensory stimulation varied in a graded manner along the long axis of the
      leg, thus creating gradients in the chemosensory receptive fields of
      interneurons. Some interneurons were depolarized to a greater extent by chemical
      stimuli applied to basiconic sensilla on distal parts of the leg, whereas others
      were depolarized more by chemical stimulation of more proximal sensilla.

PMID- 10601449
TI  - Physiological evidence for the discrimination of L-arginine from structural
      analogues by the zebrafish olfactory system.
AB  - Although it is generally assumed that fish are capable of discriminating amino
      acid odorants on the basis of differences in side-chain structure, less is known
      about their ability to discriminate amino acids with modifications to alpha
      carboxyl and alpha-amino groups. In this study, the ability of the zebrafish
      olfactory system to detect and presumably discriminate analogues of the basic
      amino acid Arg was assessed, by using cross-adaptation and activity-dependent
      labeling techniques. Electrophysiological recordings established that
      esterification (L-arginine methyl ester; AME) or deletion (agmatine or amino-4
      guanidobutane; AGB) of the alpha-carboxyl group yielded odorants more potent than
      Arg, whereas deletion of the alpha-amino group (L-argininic acid; AA) yielded a
      less potent analogue. In cross-adaptation experiments, no test-competitor odorant
      combination yielded complete cross-adaptation, suggesting the detection of these
      Arg analogues by multiple odorant receptors (ORs) with partially nonoverlapping
      specificities. Activity-dependent immunocytochemical labeling of olfactory
      receptor neurons supported this conclusion. AGB, an ion-channel-permeant probe
      (and odorant), labeled 4.9 +/- 0.4% (n = 24) of sensory epithelium, whereas the
      addition of Arg, 1-ethylguanidine sulfate, L-alpha-amino-beta
      guanidinopropionate, or AME to AGB resulted in a significant elevation of
      labeling (8-14%). This study provides evidence that the olfactory system has the
      potential to discriminate among amino acid odorants with modified alpha-carboxyl
      and alpha-amino groups.

PMID- 10601450
TI  - Gentamicin blocks both fast and slow effects of olivocochlear activation in
      anesthetized guinea pigs.
AB  - The medial olivocochlear (MOC) efferent system, which innervates cochlear outer
      hair cells, suppresses cochlear responses. MOC-mediated suppression includes both
      slow and fast components, with time courses differing by three orders of
      magnitude. Pharmacological studies in anesthetized guinea pigs suggest that both
      slow and fast effects on cochlear responses require an initial acetylcholine
      activation of alpha-9 nicotinic receptors on outer hair cells and that slow
      effects require additional intracellular events downstream from those mediating
      fast effects. Gentamicin, an aminoglycoside antibiotic, has been reported to
      block fast effects of sound-evoked OC activation following intramuscular
      injection in unanesthetized guinea pigs, without changing slow effects. In the
      present study, we show that electrically evoked fast and slow effects in the
      anesthetized guinea pig are both blocked by either intramuscular or intracochlear
      gentamicin, with similar time courses and/or dose-response curves. We suggest
      that sound-evoked slow effects in unanesthetized animals are fundamentally
      different from electrically evoked slow effects in anesthetized animals, and that
      the former may arise from effects of the lateral OC system.

PMID- 10601451
TI  - Development and role of GABA(A) receptor-mediated synaptic potentials during
      swimming in postembryonic Xenopus laevis tadpoles.
AB  - We have investigated the contribution of GABA(A) receptor activation to swimming
      in Xenopus tadpoles during the first day of postembryonic development. Around the
      time of hatching stage (37/8), bicuculline (10-50 microM) causes a decrease in
      swim episode duration and cycle period, suggesting that GABA(A) receptor
      activation influences embryonic swimming. Twenty-four hours later, at stage 42,
      GABA(A) receptor activation plays a more pronounced role in modulating larval
      swimming activity. Bicuculline causes short, intense swim episodes with increased
      burst durations and decreased cycle periods and rostrocaudal delays. Conversely,
      the allosteric agonist, 5beta-pregnan-3alpha-ol-20-one (1-10 microM) or the
      uptake inhibitor, nipecotic acid (200 microM) cause slow swimming with reduced
      burst durations and increased cycle periods. These effects appear to be mainly
      the result of GABA release from the spinal terminals of midhindbrain
      reticulospinal neurons but may also involve spinal GABAergic neurons.
      Intracellular recordings were made using KCl electrodes to reverse the sign and
      enhance the amplitude of chloride-dependent inhibitory postsynaptic potentials
      (IPSPs). Recordings from larval motoneurons in the presence of strychnine (1-5
      microM), to block glycinergic IPSPs, provided no evidence for any GABAergic
      component to midcycle inhibition. GABA potentials were observed during episodes,
      but they were not phase-locked to the swimming rhythm. Bicuculline (10-50 microM)
      abolished these sporadic potentials and caused an apparent decrease in the level
      of tonic depolarization during swimming activity and an increase in spike height.
      Finally, in most larval preparations, GABA potentials were observed at the
      termination of swimming. In combination with the other evidence, our data suggest
      that midhindbrain reticulospinal neurons become involved in an intrinsic pathway
      that can prematurely terminate swim episodes. Thus during the first day of larval
      development, endogenous activation of GABA(A) receptors plays an increasingly
      important role in modulating locomotion, and GABAergic neurons become involved in
      an intrinsic descending pathway for terminating swim episodes.

PMID- 10601452
TI  - Pattern of pulses that maximize force output from single human thenar motor
      units.
AB  - We assessed the sequence of nerve impulses that maximize force output from
      individual human thenar motor units. When these motor units were stimulated
      intraneurally by a variable sequence of seven pulses, the pattern of pulses that
      elicited maximum force always started with a short (5-15 ms) interpulse interval
      termed a "doublet. " The twitch force summation caused by this "doublet"
      elicited, on average, 48 +/- 13% (SD) of the maximum tetanic force. The peak
      amplitude of "doublet" forces was 3.5 times that of the initial twitches, and
      twitch potentiation appeared to have little influence on twitch force summation
      elicited by the "doublets." For some units, the second optimal interpulse
      interval was also short. Peak forces elicited by the third to sixth interpulse
      intervals did not change substantially when the last interpulse interval was
      varied between 5 to 55 ms, so maximum force could not be attributed to any unique
      interpulse interval. Each successive pulse contributed a smaller force increment.
      When five to seven pulses were delivered in an optimal sequence, the evoked force
      was close to that recorded during maximal tetanic stimulation. In contrast,
      maximal force-time integral was evoked with one short interpulse interval (5-15
      ms) then substantially longer interpulse intervals (>100 ms). Maximum force and
      force-time integrals were therefore elicited by different patterns of stimuli. We
      conclude that a brief initial interpulse interval (5-15 ms) is required to elicit
      maximum "doublet" force from human thenar motor units and that near-maximal
      tetanic forces can be elicited by only five or six additional post-"doublet"
      pulses if appropriately spaced in time. However, the rate at which these post
      "doublet" stimuli must be provided is fairly uncritical. In contrast, maximum
      post-"doublet" force-time integrals were obtained at intervals corresponding to
      motoneuronal firing rates of approximately 7 Hz, rates close to that typically
      used to recruit motor units and to maintain weak voluntary contractions.

PMID- 10601453
TI  - Cross talk between A(1) and A(2A) adenosine receptors in the hippocampus and
      cortex of young adult and old rats.
AB  - Adenosine modulates synaptic transmission by acting on inhibitory A(1) and
      facilitatory A(2A) receptors, the densities of which are modified in aged
      animals. We investigated how A(2A) receptor activation influences A(1) receptor
      function and whether this interaction is modified in aged rats. In hippocampal
      and cortical nerve terminals from young adult (6 wk), but not old rats (24 mo),
      the A(2A) receptor agonist, 2-[4-(2-carboxyethyl) phenethylamino]-5'-N
      ethylcarboxamidoadenosine (CGS 21680; 30 nM) decreased the binding affinity of a
      selective A(1) receptor agonist, cyclopentyladenosine (CPA), an effect prevented
      by the A(2A) antagonist, (4-(2-[7-amino-2-(2-furyl (1,2,4)-triazolo(2,3-a
      (1,3,5)triazin-5-yl-aminoethyl)phenol (ZM 241385, 20 nM). This effect of CGS
      21680 required intact nerve terminals and was also observed in the absence of
      Ca(2+). This A(2A)-induced "desensitization" of A(1) receptors was prevented by
      the protein kinase C inhibitor, chelerythrine (6 microM), and was not detected in
      the presence of the protein kinase C activator, phorbol-12,13-didecanoate (250
      nM), which itself caused a reduction in binding affinity for CPA. The protein
      kinase A inhibitor, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (10 microM),
      and the protein kinase A activator, 8-Br-cAMP (1 mM), had no effects on the A(2A)
      induced A(1) receptor desensitization. This A(2A)-induced A(1) receptor
      desensitization had a functional correlation because CGS 21680 (10 nM) attenuated
      by 40% the inhibition caused by CPA (10 nM) on CA1 area population spike
      amplitude in hippocampal slices. This A(2A)/A(1) interaction may explain the
      attenuation by adenosine deaminase (2 U/ml), which removes tonic A(1) inhibition,
      of the facilitatory effect of CGS 21680 on synaptic transmission. The requirement
      of tonic A(1) receptor activation for CGS 21680 to induce facilitation of
      synaptic transmission was reinforced by the observation that the A(1) receptor
      antagonist, 1, 3-dipropyl-8-cyclopentylxanthine (20 nM) prevented CGS 21680 (10
      nM) facilitation of population spike amplitude. The present results show the
      ability of A(2A) receptors to control A(1) receptor function in a manner mediated
      by protein kinase C, but not protein kinase A, in young adult but not in aged
      rats.

PMID- 10601454
TI  - Reorganization in the cutaneous core of the human thalamic principal somatic
      sensory nucleus (Ventral caudal) in patients with dystonia.
AB  - A wide range of observations suggest that sensory inputs play a significant role
      in dystonia. For example, the map of the hand representation in the primary
      sensory cortex (area 3b) is altered in monkeys with dystonia-like movements
      resulting from overtraining in a gripping task. We investigated whether similar
      reorganization occurs in the somatic sensory thalamus of patients with dystonia
      (dystonia patients). We studied recordings of neuronal activity and
      microstimulation-evoked responses from the cutaneous core of the human principal
      somatic sensory nucleus (ventral caudal, Vc) of 11 dystonia patients who
      underwent stereotactic thalamotomy. Fifteen patients with essential tremor who
      underwent similar procedures were used as controls. The cutaneous core of Vc was
      defined as the part of the cellular thalamic region where the majority of cells
      had receptive fields (RFs) to innocuous cutaneous stimuli. The proportion of RFs
      including multiple parts of the body was greater in dystonia patients (29%) than
      in patients with essential tremor (11%). Similarly, the percentage of projected
      fields (PFs) including multiple body parts was higher in dystonia patients (71%)
      than in patients with essential tremor (41%). A match at a thalamic site was said
      to occur if the RF and PF at that site included a body part in common. Such
      matches were significantly less prevalent in dystonia patients (33%) than in
      patients with essential tremor (58%). The average length of the trajectory where
      the PF included a consistent, cutaneous RF was significantly longer in patients
      with dystonia than in control patients with essential tremor. The findings of
      sensory reorganization in Vc thalamus are congruent with those reported in the
      somatic sensory cortex of monkeys with dystonia-like movements resulting from
      overtraining in a gripping task.

PMID- 10601455
TI  - Patterned activity in stratum lacunosum moleculare inhibits CA1 pyramidal neuron
      firing.
AB  - CA1 pyramidal cells are the primary output neurons of the hippocampus, carrying
      information about the result of hippocampal network processing to the subiculum
      and entorhinal cortex (EC) and thence out to the rest of the brain. The primary
      excitatory drive to the CA1 pyramidal cells comes via the Schaffer collateral
      (SC) projection from area CA3. There is also a direct projection from EC to
      stratum lacunosum-moleculare (SLM) of CA1, an input well positioned to modulate
      information flow through the hippocampus. High-frequency stimulation in SLM
      evokes an inhibition sufficiently strong to prevent CA1 pyramidal cells from
      spiking in response to SC input, a phenomenon we refer to as spike-blocking. We
      characterized the spike-blocking efficacy of burst stimulation (10 stimuli at 100
      Hz) in SLM and found that it is greatest at approximately 300-600 ms after the
      burst, consistent with the time course of the slow GABA(B) signaling pathway.
      Spike-blocking efficacy increases in potency with the number of SLM stimuli in a
      burst, but also decreases with repeated presentations of SLM bursts. Spike
      blocking was eliminated in the presence of GABA(B) antagonists. We have
      identified a candidate population of interneurons in SLM and distal stratum
      radiatum (SR) that may mediate this spike-blocking effect. We conclude that the
      output of CA1 pyramidal cells, and hence the hippocampus, is modulated in an
      input pattern-dependent manner by activation of the direct pathway from EC.

PMID- 10601456
TI  - Limited contributions of serotonin to long-term hyperexcitability of Aplysia
      sensory neurons.
AB  - Serotonin (5-HT) has provided a useful tool to study plasticity of nociceptive
      sensory neurons in Aplysia. Because noxious stimulation causes release of 5-HT
      and long-term hyperexcitability (LTH) of sensory neuron somata and because 5-HT
      treatment can induce long-term synaptic facilitation of sensory neuron synapses,
      a plausible hypothesis is that 5-HT also induces LTH of the sensory neuron soma.
      Prolonged or repeated exposure of excised ganglia to 5-HT produced immediate
      hyperexcitability of sensory neurons that showed little desensitization, but the
      hyperexcitability decayed within minutes of washing out the 5-HT. Prolonged or
      repeated treatment of either excised ganglia or dissociated sensory neurons with
      various concentrations of 5-HT failed to induce significant LTH even when long
      term synaptic facilitation was induced in the same preparations. Use of a high
      divalent cation solution to reduce interneuron activity during 5-HT treatment
      failed to enable the induction of LTH in excised ganglia. Pairing 5-HT
      application with nerve shock failed to enhance LTH produced by nerve shock or to
      reveal covert LTH produced by 5-HT. The induction of LTH by nerve stimulation was
      enhanced rather than inhibited by treatment with methiothepin, a 5-HT antagonist
      reported to block various 5-HT receptors and 5-HT-induced adenylyl cyclase
      activation. This suggests that endogenous 5-HT may have inhibitory effects on the
      induction of LTH by noxious stimulation. Methiothepin blocked immediate
      hyperexcitability produced by exogenous 5-HT and also inhibited the expression of
      LTH induced by nerve stimulation when applied during testing 1 day afterward. At
      higher concentrations, methiothepin reduced basal excitability of sensory neurons
      by mechanisms that may be independent of its antagonism of 5-HT receptors.
      Several observations suggest that early release of 5-HT and consequent cAMP
      synthesis in sensory neurons is not important for the induction of LTH by noxious
      stimulation, whereas later release of 5-HT from persistently activated modulatory
      neurons, with consequent elevation of cAMP synthesis, may contribute to the
      maintenance of LTH.

PMID- 10601457
TI  - Comparison of saccades perturbed by stimulation of the rostral superior
      colliculus, the caudal superior colliculus, and the omnipause neuron region.
AB  - Over the past decade, considerable research efforts have been focused on the role
      of the rostral superior colliculus (SC) in control of saccades. The most recent
      theory separates the deeper intermediate layers of the SC into two functional
      regions: the rostral pole of these layers constitutes a fixation zone and the
      caudal region comprises the saccade zone. Sustained activity of fixation neurons
      in the fixation zone is argued to maintain fixation and help prevent saccade
      generation by exciting the omnipause neurons (OPNs) in the brain stem. This
      hypothesis is in contrast to the traditional view that the SC contains a
      topographic representation of the saccade motor map on which the rostral pole of
      the SC encodes signals for generating small saccades (<2 degrees ) instead of
      preventing them. There is therefore an unresolved controversy about the specific
      role on the most rostral region of the SC, and we reexamined its functional
      contribution by quantifying and comparing spatial and temporal trajectories of 30
      degrees saccades perturbed by electrical stimulation of the rostral pole and more
      caudal regions in the SC and of the OPN region. If the rostral pole serves to
      preserve fixation, then saccades perturbed by stimulation should closely resemble
      interrupted saccades produced by stimulation of the OPN region. If it also
      contributes to saccade generation, then the disrupted movements would better
      compare with redirected saccades observed after stimulation of the caudal SC. Our
      experiments revealed two significant findings: 1) the locus of stimulation was
      the primary factor determining the perturbation effect. If the directions of the
      target-directed saccade and stimulation-evoked saccade were aligned and if the
      stimulation was delivered within approximately the rostral 2 mm (<10 degrees
      amplitude) of SC, the ongoing saccade stopped in midflight but then resumed after
      stimulation end to reach the original visually specified goal with close to
      normal accuracy. When stimulation was applied at more caudal sites, the ongoing
      saccade directly reached the target location without stopping at an intermediate
      position. If the directions differed considerably, both initial and resumed
      components were typically observed for all stimulation sites. 2) A quantitative
      analysis of the saccades perturbed from the fixation zone showed significant
      deviations from their control spatial trajectories. Thus they resembled
      redirected saccades induced by caudal SC stimulation and differed significantly
      from interrupted saccades produced by OPN stimulation. The amplitude of the
      initial saccade, latency of perturbation, and spatial redirection were greatest
      for the most caudal sites and decreased gradually for rostral sites. For
      stimulation sites within the rostral pole of SC, the measures formed a smooth
      continuation of the trends observed in the saccade zone. As these results argue
      for the saccade zone concept, we offer reinterpretations of the data used to
      support the fixation zone model. However, we also discuss scenarios that do not
      allow an outright rejection of the fixation zone hypothesis.

PMID- 10601458
TI  - Activity of the brain stem omnipause neurons during saccades perturbed by
      stimulation of the primate superior colliculus.
AB  - Stimulation of the rostral approximately 2 mm of the superior colliculus (SC)
      during a large, visual target-initiated saccade produces a spatial deviation of
      the ongoing saccade and then stops it in midflight. After the termination of the
      stimulation, the saccade resumes and ends near the location of the flashed
      target. The density of collicular projections to the omnipause neuron (OPN)
      region is greatest from the rostral SC and decreases gradually for the more
      caudal regions. It has been hypothesized that the microstimulation excites the
      OPNs through these direct connections, and the reactivation of OPNs, which are
      normally silent during saccades, stops the initial component in midflight by
      gating off the saccadic burst generator. Two predictions emerge from this
      hypothesis: 1) for microstimulation triggered on the onset of large saccades, the
      time from stimulation onset to resumption of OPN discharge should decrease as the
      stimulation site is moved rostral and 2) the lead time from reactivation of OPNs
      to the end of the initial saccade on stimulation trials should be equal to the
      lead time of pause end with respect to the end of control saccades. We tested
      this hypothesis by recording OPN activity during saccades perturbed by
      stimulation of the rostral approximately 2 mm of the SC. The distance of the
      stimulation site from the most rostral extent of the SC and the time of
      reactivation with respect to stimulation onset were not significantly correlated.
      The mean lead of reactivation of OPNs relative to the end of the initial
      component of perturbed saccades (6.5 ms) was significantly less than the mean
      lead with respect to the end of control (9.6 ms) and resumed saccades (10.4 ms).
      These results do not support the notion that the excitatory input from SC neurons
      in particular, the fixation neurons in the rostral SC-provide the major signal to
      reactivate OPNs and end saccades. An alternative, conceptual model to explain the
      temporal sequence of events induced by stimulation of the SC during large
      saccades is presented. Other OPN activity parameters also were measured and
      compared for control and stimulation conditions. The onset of pause with respect
      to resumed saccade onset was larger and more variable than the onset of pause
      with respect to control saccades, whereas pause end with respect to the end of
      resumed and control saccades was similar. The reactivated discharge of OPNs
      during the period between the end of the initial and the onset of the resumed
      saccades was at least as strong as that following control movements. This latter
      observation is interpreted in terms of the resettable neural integrator
      hypothesis.

PMID- 10601459
TI  - Passive normalization of synaptic integration influenced by dendritic
      architecture.
AB  - We examined how biophysical properties and neuronal morphology affect the
      propagation of individual postsynaptic potentials (PSPs) from synaptic inputs to
      the soma. This analysis is based on evidence that individual synaptic activations
      do not reduce local driving force significantly in most central neurons, so each
      synapse acts approximately as a current source. Therefore the spread of PSPs
      throughout a dendritic tree can be described in terms of transfer impedance
      (Z(c)), which reflects how a current applied at one location affects membrane
      potential at other locations. We addressed this topic through four lines of study
      and uncovered new implications of neuronal morphology for synaptic integration.
      First, Z(c) was considered in terms of two-port theory and contrasted with
      dendrosomatic voltage transfer. Second, equivalent cylinder models were used to
      compare the spatial profiles of Z(c) and dendrosomatic voltage transfer. These
      simulations showed that Z(c) is less affected by dendritic location than voltage
      transfer is. Third, compartmental models based on morphological reconstructions
      of five different neuron types were used to calculate Z(c), input impedance
      (Z(N)), and voltage transfer throughout the dendritic tree. For all neurons,
      there was no significant variation of Z(c) with location within higher-order
      dendrites. Furthermore, Z(c) was relatively independent of synaptic location
      throughout the entire cell in three of the five neuron types (CA3 interneurons,
      CA3 pyramidal neurons, and dentate granule cells). This was quite unlike Z(N),
      which increased with distance from the soma and was responsible for a parallel
      decrease of voltage transfer. Fourth, simulations of fast excitatory PSPs (EPSPs)
      were consistent with the analysis of Z(c); peak EPSP amplitude varied <20% in the
      same three neuron types, a phenomenon that we call "passive synaptic
      normalization" to underscore the fact that it does not require active currents.
      We conclude that the presence of a long primary dendrite, as in CA1 or
      neocortical pyramidal cells, favors substantial location-dependent variability of
      somatic PSP amplitude. In neurons that lack long primary dendrites, however, PSP
      amplitude at the soma will be much less dependent on synaptic location.

PMID- 10601460
TI  - GABA(A) receptor-mediated miniature postsynaptic currents and alpha-subunit
      expression in developing cortical neurons.
AB  - Previous studies have described maturational changes in GABAergic inhibitory
      synaptic transmission in the rodent somatosensory cortex during the early
      postnatal period. To determine whether alterations in the functional properties
      of synaptically localized GABA(A) receptors (GABA(A)Rs) contribute to development
      of inhibitory transmission, we used the whole cell recording technique to examine
      GABAergic miniature postsynaptic currents (mPSCs) in developing cortical neurons.
      Neurons harvested from somatosensory cortices of newborn mice showed a
      progressive, eightfold increase in GABAergic mPSC frequency during the first 4 wk
      of development in dissociated cell culture. A twofold decrease in the decay time
      of the GABAergic mPSCs, between 1 and 4 wk, demonstrates a functional change in
      the properties of GABA(A)Rs mediating synaptic transmission in cortical neurons
      during development in culture. A similar maturational profile observed in
      GABAergic mPSC frequency and decay time in cortical neurons developing in vivo
      (assessed in slices), suggests that these changes in synaptically localized
      GABA(A)Rs contribute to development of inhibition in the rodent neocortex.
      Pharmacological and reverse transcription-polymerase chain reaction (RT-PCR)
      studies were conducted to determine whether changes in subunit expression might
      contribute to the observed developmental alterations in synaptic GABA(A)Rs.
      Zolpidem (300 nM), a subunit-selective benzodiazepine agonist with high affinity
      for alpha1-subunits, caused a reversible slowing of the mPSC decay kinetics in
      cultured cortical neurons. Development was characterized by an increase in the
      potency of zolpidem in modulating the mPSC decay, suggesting a maturational
      increase in percentage of functionally active GABA(A)Rs containing alpha1
      subunits. The relative expression of alpha1 versus alpha5 GABA(A)R subunit mRNA
      in cortical tissue, both in vivo and in vitro, also increased during this same
      period. Furthermore, single-cell RT-multiplex PCR analysis revealed more rapidly
      decaying mPSCs in individual neurons in which alpha1 versus alpha5 mRNA was
      amplified. Together these data suggest that changes in alpha-subunit composition
      of GABA(A)Rs contribute to the maturation of GABAergic mPSCs mediating inhibition
      in developing cortical neurons.

PMID- 10601461
TI  - Internal calcium modulates apparent affinity of metabotropic GABA receptors.
AB  - The metabotropic GABA receptor (GABA(B)R) regulates calcium influx in neurons.
      Whole cell voltage-clamp techniques were employed to determine the effects of
      internal calcium on the activity of GABA(B)Rs. GABA(B)R receptor apparent
      affinity was maximal when bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA)
      maintained internal calcium below 70 nM. Apparent affinity was reduced as
      internal calcium increased. EGTA did not produce similar effects, suggesting that
      localized increases in calcium influenced GABA(B)R apparent affinity. Confocal
      imaging disclosed relatively high internal calcium just below the plasma membrane
      of isolated neurons. BAPTA, but not EGTA, reduced this ring of high calcium.
      Heparin, dantrolene, and ryanodine increased GABA(B)R apparent affinity, effects
      similar to that of BAPTA. Calmodulin inhibitors also increased receptor apparent
      affinity. These results suggest that internally released calcium activates
      calmodulin, which reduces GABA(B)R apparent affinity. This identifies a
      reciprocal system in which the metabotropic GABA receptor can reduce calcium
      influx, but internal calcium can suppress this receptor pathway. Metabotropic
      glutamate receptors linked to inositol 1,4,5 trisphosphate (InsP(3)) raised
      internal calcium and suppressed the action of GABA(B)Rs. Thus negative feedback
      systems control the balance between excitatory and inhibitory metabotropic
      receptor pathways in retinal neurons.

PMID- 10601462
TI  - Role of L-type Ca(2+) channels in transmitter release from mammalian inner hair
      cells I. Gross sound-evoked potentials.
AB  - Intracochlear perfusion and gross potential recording of sound-evoked neural and
      hair cell responses were used to study the site of action of the L-type Ca(2+)
      channel blocker nimodipine in the guinea pig inner ear. In agreement with
      previous work nimodipine (1-10 microM) caused changes in both the compound
      auditory nerve action potential (CAP) and the DC component of the hair cell
      receptor potential (summating potential, or SP) in normal cochleae. For 20-kHz
      stimulation, the effect of nimodipine on the CAP threshold was markedly greater
      than the effect on the threshold of the negative SP. This latter result was
      consistent with a dominant action of nimodipine at the final output stage of
      cochlear transduction: either the release of transmitter from inner hair cells
      (IHCs) or the postsynaptic spike generation process. In animals in which the
      outer hair cells (OHCs) had been destroyed by prior administration of kanamycin,
      nimodipine still caused a large change in the 20-kHz CAP threshold, but even less
      change was observed in the negative SP threshold than in normal cochleae. When
      any neural contamination of the SP recording in kanamycin-treated animals was
      removed by prior intracochlear perfusion with TTX, nimodipine caused no
      significant change in SP threshold. Some features of the data also suggest a
      separate involvement of nimodipine-sensitive channels in OHC function. Perfusion
      of the cochlea with solutions containing Ni(2+) (100 microM) caused no measurable
      change in either CAP or SP. These results are consistent with, but do not prove,
      the notion that L-type channels are directly involved in controlling transmitter
      release from the IHCs and that T-type Ca(2+) channels are not involved at any
      stage of cochlear transduction.

PMID- 10601463
TI  - Spinal laminae I-II neurons in rat recorded in vivo in whole cell, tight seal
      configuration: properties and opioid responses.
AB  - Using the in vivo whole cell recording procedure described previously, we
      recorded 73 neurons in laminae I and II in the lumbar spinal cord of the rat.
      Input impedances averaged 332 MOmega, which indicated that prior sharp electrode
      recordings contained a significant current shunt. Characterization of the
      adequate stimuli from the excitatory hindlimb receptive field indicated that 39
      of 73 neurons were nociceptive, 6 were innocuous cooling cells, 20 responded
      maximally to brush, and 8 cells were not excited by stimulation of the skin of
      the hindlimb. The locations of 15 neurons were marked with biocytin. Nociceptive
      neurons were mostly found in lamina I and outer II, cooling cells in lamina I,
      and innocuous mechanoreceptive cells were mostly found in inner II or in the
      overlying white matter. The mu-opioid agonist [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]
      Enkephalin (DAMGO) hyperpolarized 7 of 19 tested neurons with a conductance
      increase. This hyperpolarization was reversed by naloxone in the neurons in which
      it was applied. DAMGO also decreased the frequency of spontaneous PSPs in 13
      neurons, 7 of which were also hyperpolarized by DAMGO. Five of the seven
      hyperpolarized neurons were nociceptive, responding to both heat and mechanically
      noxious stimuli, whereas two responded to slow, innocuous brush. These results
      indicate that whole cell, tight seal recordings sample a similar population of
      lamina I and II neurons in the rat as those found with sharp electrode recordings
      in cat and monkey. They further indicate that DAMGO hyperpolarizes a subset of
      the nociceptive neurons that have input from both heat and mechanical nociceptors
      and that presynaptic DAMGO effects can be observed in nociceptive neurons that
      are not hyperpolarized by DAMGO.

PMID- 10601464
TI  - In vivo calcium accumulation in presynaptic and postsynaptic dendrites of visual
      interneurons.
AB  - In this comparative in vivo study of dendritic calcium accumulation, we describe
      the time course and spatial integration properties of two classes of visual
      interneurons in the lobula plate of the blowfly. Calcium accumulation was
      measured during visual motion stimulation, ensuring synaptic activation of the
      neurons within their natural spatial and temporal operating range. The compared
      cell classes, centrifugal horizontal (CH) and horizontal system (HS) cells, are
      known to receive retinotopic input of similar direction selectivity, but to
      differ in morphology, biophysics, presence of dendrodendritic synapses, and
      computational task. 1) The time course of motion-induced calcium accumulation was
      highly invariant with respect to stimulus parameters such as pattern contrast and
      size. In HS cells, the rise of [Ca(2+)](i) can be described by a single
      exponential with a time constant of 5-6 s. The initial rise of [Ca(2+)](i) in CH
      cells was much faster (tau approximately 1 s). The decay time constant in both
      cell classes was estimated to be at least 3.5 times longer than the corresponding
      rise time constant. 2) The voltage-[Ca(2+)](i) relationship was best described by
      an expansive nonlinearity in HS cells and an approximately linear relationship in
      CH cells. 3) Both cell classes displayed a size-dependent saturation nonlinearity
      of the calcium accumulation. Although in CH cells calcium saturation was
      indistinguishable from saturation of the membrane potential, saturation of the
      two response parameters differed in HS cells. 4) There was spatial overlap of the
      calcium signal in response to nonoverlapping visual stimuli. Both the area and
      the amplitude of the overlap profile was larger in CH cells than in HS cells.
      Thus calcium accumulation in CH cells is spatially blurred to a greater extent
      than in HS cells. 5) The described differences between the two cell classes may
      reflect the following computational tasks of these neurons: CH cells relay
      retinotopic information within the lobula plate via dendritic synapses with
      pronounced spatial low-pass filtering. HS cells are output neurons of the lobula
      plate, in which the slow, local calcium accumulation may be suitable for local
      modulatory functions.

PMID- 10601465
TI  - Cesium induces spontaneous epileptiform activity without changing extracellular
      potassium regulation in rat hippocampus.
AB  - Cesium has been widely used to study the roles of the hyperpolarization-activated
      (I(h)) and inwardly rectifying potassium (K(IR)) channels in many neuronal and
      nonneuronal cell types. Recently, extracellular application of cesium has been
      shown to produce epileptiform activity in brain slices, but the mechanisms for
      this are not known. It has been proposed that cesium blocks the K(IR) in glia,
      resulting in an abnormal accumulation of potassium in the extracellular space and
      inducing epileptiform activity. This hypothesis has been tested in hippocampal
      slices and cultured hippocampal neurons using potassium-sensitive
      microelectrodes. In the present study, application of cesium produced spontaneous
      epileptiform discharges at physiological extracellular potassium concentration
      ([K(+)](o)) in the CA1 and CA3 regions of hippocampal slices. This epileptiform
      activity was not mimicked by increasing the [K(+)](o). The epileptiform
      discharges induced by cesium were not blocked by the N-methyl-D- aspartate (NMDA)
      receptor antagonist AP-5, but were blocked by the non-NMDA receptor antagonist
      CNQX. In the dentate gyrus, cesium induced the appearance of spontaneous
      nonsynaptic field bursts in 0 added calcium and 3 mM potassium. Moreover, cesium
      increased the frequency of field bursts already present. In contrast, ZD-7288, a
      specific I(h) blocker, did not cause spontaneous epileptiform activity in CA1 and
      CA3, nor did it affect the field bursts in the dentate gyrus, suggesting that
      cesium induced epileptiform activity is not directly related to blockade of the
      I(h). When potassium-sensitive microelectrodes were used to measure [K(+)](o),
      there was no significant increase in [K(+)](o) in CA1 and CA3 after cesium
      application. In the dentate gyrus, cesium did not change the baseline level of
      [K(+)](o) or the rate of [K(+)](o) clearance after the field bursts. In cultured
      hippocampal neurons, which have a large and relatively unrestricted extracellular
      space, cesium also produced cellular burst activity without significantly
      changing the resting membrane potential, which might indicate an increase in
      [K(+)](o). Our results suggest that cesium causes epileptiform activity by a
      mechanism unrelated to an alteration in [K(+)](o) regulation.

PMID- 10601466
TI  - Mechanical and thermal hyperalgesia and ectopic neuronal discharge after chronic
      compression of dorsal root ganglia.
AB  - Chronic compression of the dorsal root ganglion (CCD) was produced in adult rats
      by implanting a stainless steel rod unilaterally into the intervertebral foramen,
      one rod at L(4) and another at L(5). Two additional groups of rats received
      either a sham surgery or an acute injury consisting of a transient compression of
      the ganglion. Withdrawal of the hindpaw was used as evidence of a nocifensive
      response to mechanical and thermal stimulation of the plantar surface. In
      addition, extracellular electrophysiological recordings of spontaneous discharges
      were obtained from dorsal root fibers of formerly compressed ganglia using an in
      vitro nerve-DRG-dorsal root preparation. The mean threshold force of punctate
      indentation and the mean threshold temperature of heating required to elicit a
      50% incidence of foot withdrawal ipsilateral to the CCD were significantly lower
      than preoperative values throughout the 35 days of postoperative testing. The
      number of foot withdrawals ipsilateral to the CCD during a 20-min contact with a
      temperature-controlled floor was significantly increased over preoperative values
      throughout postoperative testing when the floor was 4 degrees C (hyperalgesia)
      and, to a lesser extent, when it was 30 degrees C (spontaneous pain). Stroking
      the foot with a cotton wisp never elicited a reflex withdrawal before surgery but
      did so in most rats tested ipsilateral to the CCD during the first 2
      postoperative weeks. In contrast, the CCD produced no changes in responses to
      mechanical or thermal stimuli on the contralateral foot. The sham operation and
      acute injury produced no change in behavior other than slight, mechanical
      hyperalgesia for approximately 1 day, ipsilateral to the acute injury. Ectopic
      spontaneous discharges generated within the chronically compressed ganglion and,
      occurring in the absence of blood-borne chemicals and without an intact
      sympathetic nervous system, were recorded from neurons with intact, conducting,
      myelinated or unmyelinated peripheral nerve fibers. The incidence of
      spontaneously active myelinated fibers was 8.61% for CCD rats versus 0.96% for
      previously nonsurgical rats. We hypothesize that a chronic compression of the
      dorsal root ganglion after certain injuries or diseases of the spine may produce,
      in neurons with intact axons, abnormal ectopic discharges that originate from the
      ganglion and potentially contribute to low back pain, sciatica, hyperalgesia, and
      tactile allodynia.

PMID- 10601467
TI  - Enhanced excitability of sensory neurons in rats with cutaneous hyperalgesia
      produced by chronic compression of the dorsal root ganglion.
AB  - Pain and hyperalgesia can occur when the dorsal root ganglion (DRG) and its roots
      are deformed mechanically in association with injuries or diseases of the spine.
      To evaluate the electrophysiological changes that contribute to this sensory
      pathology, intracellular recordings were obtained in vitro from DRGs that had
      received a chronic mechanical compression [chronic compression of DRG (CCD)]. The
      compression was produced by inserting L-shaped rods ipsilaterally into the
      intervertebral foramina, one at L(4) and the other at L(5) in rats 1-14 days
      before the recording. Control rats received a sham operation. Postoperatively,
      the threshold force applied by punctate stimulation of the plantar surface of the
      hind paw decreased significantly on the foot ipsilateral to the CCD (mechanical
      hyperalgesia) but changed little on the contralateral foot or on either foot for
      control rats. DRG somata were viewed through a microscope during recording and
      classified as small, medium, and large according to their diameters. CCD cells in
      each size category were more excitable than those of comparable size from control
      rats as judged by the significantly lowered threshold currents and action
      potential voltage thresholds. Spontaneous activity was recorded in 11% of all the
      CCD cells tested. The spontaneous activity and/or changes in both the threshold
      currents and action potential thresholds were observed as early as one day after
      injury. The association of cutaneous hyperalgesia with changes in the
      electrophysiological properties of DRG cells suggests a possible role for
      intrinsic alterations in the membrane properties of compressed DRG cells in the
      production and persistence of chronic pain after certain spinal injuries or
      pathologies of the spine.

PMID- 10601468
TI  - FGF-2 potentiates Ca(2+)-dependent inactivation of NMDA receptor currents in
      hippocampal neurons.
AB  - Peptide growth factors such as the neurotrophins and fibroblast growth factors
      have potent effects on synaptic transmission, development, and cell survival. We
      report that chronic (hours) treatment with basic fibroblast growth factor (FGF-2)
      potentiates Ca(2+)-dependent N-methyl-D-aspartate (NMDA) receptor inactivation in
      cultured hippocampal neurons. This effect is specific for the NMDA-subtype of
      ionotropic glutamate receptor and FGF-2. The potentiated inactivation requires
      ongoing protein synthesis during growth factor treatment and the activity of
      protein phosphatase 2B (PP2B or calcineurin) during agonist application. These
      results suggest a mechanism by which FGF-2 receptor signaling may regulate
      neuronal survival and synaptic plasticity.

PMID- 10601469
TI  - Pattern generation in the buccal system of freely behaving Lymnaea stagnalis.
AB  - Central pattern generators (CPGs) are neuronal circuits that drive active
      repeated movements such as walking or swimming. Although CPGs are, by definition,
      active in isolated central nervous systems, sensory input is thought play an
      important role in adjusting the output of the CPGs to meet specific behavioral
      requirements of intact animals. We investigated, in freely behaving snails
      (Lymnaea stagnalis), how the buccal CPG is used during two different behaviors,
      feeding and egg laying. Analysis of the relationship between unit activity
      recorded from buccal nerves and the movements of the buccal mass showed that
      electrical activity in laterobuccal/ventrobuccal (LB/VB) nerves was as predicted
      from in vitro data, but electrical activity in the posterior jugalis nerve was
      not. Autodensity and interval histograms showed that during feeding the CPG
      produces a much stronger rhythm than during egg laying. The phase relationship
      between electrical activity and buccal movement changed little between the two
      behaviors. Fitting the spike trains recorded during the two behaviors with a
      simple model revealed differences in the patterns of electrical activity produced
      by the buccal system during the two behaviors investigated. During egg laying the
      bursts contained less spikes, and the number of spikes per burst was
      significantly more variable than during feeding. The time between two bursts of
      in a spike train was longer during egg laying than during feeding. The data show
      what the qualitative and quantitative differences are between two motor patterns
      produced by the buccal system of freely behaving Lymnaea stagnalis.

PMID- 10601470
TI  - Asymmetry of hindlimb muscle activity and cutaneous reflexes after tendon
      transfers in kittens.
AB  - The mechanical actions of various ankle muscles were changed by surgically
      crossing or transferring the tendons in kittens. After the kittens grew to
      adults, both hindlimbs were implanted with multiple electromyogram (EMG)
      recording and cutaneous nerve stimulation electrodes to compare the activity of
      altered and normal muscles. The tendon transfers showed a remarkable tendency to
      regrow toward normal or only slightly altered mechanical action. In these animals
      and in the sham-operation controls, the patterns of muscle activity and reflexes
      were symmetrical in corresponding muscles of the two legs, although they could
      differ substantially between animals, particularly for the cutaneous reflexes.
      Eleven animals had at least some persistent alterations in muscle action. Their
      cutaneous reflex patterns tended to be asymmetric, in some cases quite markedly.
      EMG activity during unperturbed locomotion and paw-shaking was more symmetrical,
      but there were some changes in altered muscles and their synergists. The central
      pattern generators for locomotion and paw-shaking and particularly for cutaneous
      reflexes during locomotion appear to be at least partially malleable rather than
      entirely hardwired. This may provide a tool for studying their development and
      spinal plasticity in general.

PMID- 10601471
TI  - Role of alpha-SNAP in promoting efficient neurotransmission at the crayfish
      neuromuscular junction.
AB  - In this manuscript, we address the role of the soluble N-ethylmaleimide sensitive
      factor attachment protein (alpha-SNAP) in synaptic transmission at the
      neuromuscular junction of the crayfish opener muscle. Immunochemical methods
      confirm the presence of alpha-SNAP in these preparations and show that it is
      concentrated in the synaptic areas. Microinjection and electrophysiological
      studies show that alpha-SNAP causes an increase in neurotransmitter release yet
      does not significantly affect the kinetics. More specific quantal analysis, using
      focal, macropatch, synaptic current recordings, shows that alpha-SNAP increases
      transmitter release by increasing the probability of exocytosis but not the
      number of potential release sites. These data demonstrate that the role of alpha
      SNAP is to increase the efficiency of neurotransmission by increasing the
      probability that a stimulus will result in neurotransmitter release. What this
      suggests is that alpha-SNAP is critical for the formation and maintenance of a
      "ready release" pool of synaptic vesicles.

PMID- 10601472
TI  - Interactions between GABA and glycine at inhibitory amino acid receptors on rat
      olfactory bulb neurons.
AB  - Whole cell voltage-clamp electrophysiology was used to examine interactions
      between GABA and glycine at inhibitory amino acid receptors on rat olfactory bulb
      neurons in primary culture. Membrane currents evoked by GABA and glycine were
      selectively inhibited by low concentrations of bicuculline and strychnine,
      respectively, suggesting that they activate pharmacologically distinct receptors.
      However, GABA- and glycine-mediated currents showed cross-inhibition when the two
      amino acids were applied sequentially. Application of one amino acid inhibited
      the response to immediate subsequent application of the other. In the majority of
      neurons, GABA inhibited subsequent glycine-evoked currents and glycine inhibited
      subsequent GABA-evoked currents. In a small proportion of neurons, however, GABA
      inhibited glycine-evoked currents but glycine had little effect on GABA-evoked
      currents. The reverse was true in other neurons, suggesting that alterations in
      chloride gradients alone did not account for the cross-inhibition. Furthermore,
      no cross-inhibition was observed between GABA- and glycine-evoked currents in
      some neurons. The amplitude of the current evoked by the coapplication of
      saturating concentrations of GABA and glycine in these neurons was nearly the sum
      of the currents evoked by GABA and glycine alone. In contrast, the currents were
      not additive in neurons demonstrating cross-inhibition. These results suggest
      that olfactory bulb neurons heterogeneously express a population of inhibitory
      amino acid receptors that can bind either GABA or glycine. Interactions between
      GABA and glycine at inhibitory amino acid receptors may provide a mechanism to
      modulate inhibitory synaptic transmission.

PMID- 10601473
TI  - Chemical activation of cervical cell bodies: effects on responses to colorectal
      distension in lumbosacral spinal cord of rats.
AB  - We have shown that stimulation of cardiopulmonary sympathetic afferent fibers
      activates relays in upper cervical segments to suppress activity of lumbosacral
      spinal cells. The purpose of this study was to determine if chemical excitation
      (glutamate) of upper cervical cell bodies changes the spontaneous activity and
      evoked responses of lumbosacral spinal cells to colorectal distension (CRD).
      Extracellular potentials were recorded in pentobarbital-anesthetized male rats.
      CRD (80 mmHg) was produced by inflating a balloon inserted in the descending
      colon and rectum. A total of 135 cells in the lumbosacral segments (L(6)-S(2))
      were activated by CRD. Seventy-five percent (95/126) of tested cells received
      convergent somatic input from the scrotum, perianal region, hindlimb, and tail;
      99/135 (73%) cells were excited or excited/inhibited by CRD; and 36 (27%) cells
      were inhibited or inhibited/excited by CRD. A glutamate (1 M) pledget placed on
      the surface of C(1)-C(2) segments decreased spontaneous activity and excitatory
      CRD responses of 33/56 cells and increased spontaneous activity of 13/19 cells
      inhibited by CRD. Glutamate applied to C(6)-C(7) segments decreased activity of
      10/18 cells excited by CRD, and 9 of these also were inhibited by glutamate at
      C(1)-C(2) segments. Glutamate at C(6)-C(7) increased activity of 4/6 cells
      inhibited by CRD and excited by glutamate at C(1)-C(2) segments. After
      transection at rostral C(1) segment, glutamate at C(1)-C(2) still reduced
      excitatory responses of 7/10 cells. Further, inhibitory effects of C(6)-C(7)
      glutamate on excitatory responses to CRD still occurred after rostral C(1)
      transection but were abolished after a rostral C(6) transection in 4/4 cells.
      These data showed that C(1)-C(2) cells activated with glutamate primarily
      produced inhibition of evoked responses to visceral stimulation of lumbosacral
      spinal cells. Inhibition resulting from activation of cells in C(6)-C(7) segments
      required connections in the upper cervical segments. These results provide
      evidence that upper cervical cells integrate information that modulates activity
      of distant spinal neurons responding to visceral input.

PMID- 10601474
TI  - Acoustic and current-pulse responses of identified neurons in the dorsal cochlear
      nucleus of unanesthetized, decerebrate gerbils.
AB  - In an effort to establish relationships between cell physiology and morphology in
      the dorsal cochlear nucleus (DCN), intracellular single-unit recording and
      marking experiments were conducted on decerebrate gerbils using horseradish
      peroxidase (HRP)- or neurobiotin-filled micropipettes. Intracellular responses to
      acoustic (tone and broadband noise bursts) and electric current-pulse stimuli
      were recorded and associated with cell morphology. Units were classified
      according to the response map scheme (type I to type V). Results from 19
      identified neurons, including 13 fusiform cells, 2 giant cells, and 4 cartwheel
      cells, reveal correlations between cell morphology of these neurons and their
      acoustic responses. Most fusiform cells (8/13) are associated with type III unit
      response properties. A subset of fusiform cells was type I/III units (2), type
      III-i units (2), and a type IV-T unit. The giant cells were associated with type
      IV-i unit response properties. Cartwheel cells all had weak acoustic responses
      that were difficult to classify. Some measures of membrane properties also were
      correlated with cell morphology but to a lesser degree. Giant cells and all but
      one fusiform cell fired only simple action potentials (APs), whereas all
      cartwheel cells discharged complex APs. Giant and fusiform cells all had
      monotonic rate versus current level curves, whereas cartwheel cells had
      nonmonotonic curves. This implies that inhibitory acoustic responses, resulting
      in nonmonotonic rate versus sound level curves, are due to local inhibitory
      interactions rather than strictly to membrane properties. A complex-spiking
      fusiform cell with type III unit properties suggests that cartwheel cells are not
      the only complex-spiking cells in DCN. The diverse response properties of the
      DCN's fusiform cells suggests that they are very sensitive to the specific
      complement of excitatory and inhibitory inputs they receive.

PMID- 10601475
TI  - Quantitative analysis of substantia nigra pars reticulata activity during a
      visually guided saccade task.
AB  - Several lines of evidence suggest that the pars reticulata subdivision of the
      substantia nigra (SNr) plays a role in the generation of saccadic eye movements.
      However, the responses of SNr neurons during saccades have not been examined with
      the same level of quantitative detail as the responses of neurons in other key
      saccadic areas. For this report, we examined the firing rates of 72 SNr neurons
      while awake-behaving primates correctly performed an average of 136 trials of a
      visually guided delayed saccade task. On each trial, the location of the visual
      target was chosen randomly from a grid spanning 40 degrees of horizontal and
      vertical visual angle. We measured the firing rates of each neuron during five
      intervals on every trial: a baseline interval, a fixation interval, a visual
      interval, a movement interval, and a reward interval. We found four distinct
      classes of SNr neurons. Two classes of neurons had firing rates that decreased
      during delayed saccade trials. The firing rates of discrete pausers decreased
      after the onset of a contralateral target and/or before the onset of a saccade
      that would align gaze with that target. The firing rates of universal pausers
      decreased after fixation on all trials and remained below baseline until the
      delivery of reinforcement. We also found two classes of SNr neurons with firing
      rates that increased during delayed saccade trials. The firing rates of bursters
      increased after the onset of a contralateral target and/or before the onset of a
      saccade aligning gaze with that target. The firing rates of pause-bursters
      increased after the onset of a contralateral target but decreased after the
      illumination of an ipsilateral target. Our quantification of the response
      profiles of SNr neurons yielded three novel findings. First, we found that some
      SNr neurons generate saccade-related increases in activity. Second, we found
      that, for nearly all SNr neurons, the relationship between firing rate and
      horizontal and vertical saccade amplitude could be well described by a planar
      surface within the range of movements we sampled. Finally we found that for most
      SNr neurons, saccade-related modulations in activity were highly variable on a
      trial-by-trial basis.

PMID- 10601476
TI  - Differential inhibition of glial K(+) currents by 4-AP.
AB  - Spinal cord astrocytes express four biophysically and pharmacologically distinct
      voltage-activated potassium (K(+)) channel types. The K(+) channel blocker 4
      aminopyridine (4-AP) exhibited differential and concentration-dependent block of
      all of these currents. Specifically, 100 microM 4-AP selectively inhibited a
      slowly inactivating outward current (K(SI)) that was insensitive to dendrototoxin
      (< or = 10 microM) and that activated at -50 mV. At 2 mM, 4-AP inhibited fast
      inactivating, low-threshold (-70 mV) A-type currents (K(A)) and sustained, TEA
      sensitive noninactivating delayed-rectifier-type currents (K(DR)). At an even
      higher concentration (8 mM), 4-AP additionally blocked inwardly rectifying, Cs(+)
      and Ba(2+)-sensitive K(+) currents (K(IR)). Current injection into current
      clamped astrocytes in culture or in acute spinal cord slices induced an
      overshooting voltage response reminiscent of slow neuronal action potentials.
      Increasing concentrations of 4-AP selectively modulated different phases in the
      repolarization of these glial spikes, suggesting that all four K(+) currents
      serve different roles in stabilization and repolarization of the astrocytic
      membrane potential. Our data suggest that 4-AP is an useful, dose-dependent
      inhibitor of all four astrocytic K(+) channels. We show that the slowly
      inactivating astrocytic K(+) currents, which had not been described as separate
      current entities in astrocytes, contribute to the resting K(+) conductance and
      may thus be involved in K(+) homeostatic functions of astrocytes. The high
      sensitivity of these currents to micromolar 4-AP suggests that application of 4
      AP to inhibit neuronal A-currents or to induce epileptiform discharges in brain
      slices also may influence astrocytic K(+) buffering.

PMID- 10601477
TI  - Limited functional grouping of neurons in the motor cortex hand area during
      individuated finger movements: A cluster analysis.
AB  - Primary motor cortex (M1) hand area neurons show patterns of discharge across a
      set of individuated finger and wrist movements so diverse as to preclude
      classifying the neurons into functional groups on the basis of simple inspection.
      We therefore applied methods of cluster analysis to search M1 neuronal
      populations for groups of neurons with similar patterns of discharge across the
      set of movements. Populations from each of three monkeys showed a large group of
      neurons the discharge of which increased for many or all of the movements and a
      second small group the discharge of which decreased for many or all movements.
      Two to three other small groups of neurons that discharged more specifically for
      one or two movements also were found in each monkey, but these groups were less
      consistent than the groups with broad movement fields. The limited functional
      grouping of M1 hand area neurons suggests that M1 neurons act as a network of
      highly diverse elements in controlling individuated finger movements.

PMID- 10601478
TI  - Neuronal responses in cat primary auditory cortex to electrical cochlear
      stimulation. III. Activation patterns in short- and long-term deafness.
AB  - The effects of auditory deprivation on the spatial distribution of cortical
      response thresholds to electrical stimulation of the adult cat cochlea were
      evaluated. Threshold distributions for single- and multiple-unit responses from
      the middle cortical layers were obtained on the ectosylvian gyrus in three groups
      of animals: adult, acutely implanted animals ("acute group"); adult animals, 2 wk
      after deafening and implantation ("short-term group"); adult, neonatally deafened
      animals ("long-term group") implanted after 2-5 years of deafness. For all three
      groups, we observed similar patterns of circumscribed regions of low response
      thresholds in the region of primary auditory cortex (AI). A dorsal and a ventral
      region of low response thresholds were found separated by a narrow, anterior
      posterior strip of elevated thresholds. The two low-threshold regions in the
      acute and the short-term group were arranged cochleotopically. This was reflected
      in a systematic shift of the cortical locations with minimum thresholds as a
      function of cochlear position of the radial and monopolar stimulation electrodes.
      By contrast, the long-term deafened animals maintained only weak or no signs of
      cochleotopicity. In some cases of this group, significant deviations from a
      simple tri-partition of the dorsoventral axis of AI was observed. Analysis of the
      spatial extent of the low-threshold regions revealed that the activated area in
      acute cases was significantly smaller than the long- and the short-term cases for
      both dorsal and ventral AI. There were no significant differences in the
      rostrocaudal extent of activation between long- and short-term deafening,
      although the total activated area in the short-term cases was larger than in long
      term deafened animals. The width of the narrow high-threshold ridge that
      separated the dorsal and ventral low-threshold regions was the widest for the
      acute cases and the narrowest for the short-term deafened animals. The findings
      of relative large differences in cortical response distributions between the
      acute and short-term animals suggests that the effects observed in long-term
      deafened animals are not solely a consequence of loss of peripheral innervation
      density. The effects may reflect electrode-specific effects or reorganizational
      changes based on factors such as differences in excitatory and inhibitory
      balance.

PMID- 10601479
TI  - Specificity and strength of retinogeniculate connections.
AB  - Retinal ganglion cells and their target neurons in the principal layers of the
      lateral geniculate nucleus (LGN) of the thalamus have very similar, center
      surround receptive fields. Although some geniculate neurons are dominated by a
      single retinal afferent, others receive both strong and weak inputs from several
      retinal afferents. In the present study, experiments were performed in the cat
      that examined the specificity and strength of monosynaptic connections between
      retinal ganglion cells and their target neurons. The responses of 205 pairs of
      retinal ganglion cells and geniculate neurons with overlapping receptive-field
      centers or surrounds were studied. Receptive fields were mapped quantitatively
      using a white-noise stimulus; connectivity was assessed by cross-correlating the
      retinal and geniculate spike trains. Of the 205 pairs, 12 were determined to have
      monosynaptic connections. Both the likelihood that cells were connected and the
      strength of connections increased with increasing similarity between retinal and
      geniculate receptive fields. Connections were never found between cells with <50%
      spatial overlap between their centers. The results suggest that although
      geniculate neurons often receive input from several retinal afferents, these
      multiple afferents represent a select subset of the retinal ganglion cells with
      overlapping receptive-field centers.

PMID- 10601480
TI  - Haptic stabilization of posture: changes in arm proprioception and cutaneous
      feedback for different arm orientations.
AB  - Postural sway during quiet stance is attenuated by actively maintained contact of
      the index finger with a stationary surface, even if the level of applied force
      (<1 N) cannot provide mechanical stabilization. In this situation, changes in
      force level at the fingertip lead changes in center of foot pressure by
      approximately 250 ms. These and related findings indicate that stimulation of the
      fingertip combined with proprioceptive information about the hand and arm can
      serve as an active sensor of body position relative to the point of contact. A
      geometric analysis of the relationship between hand and torso displacement during
      body sway led to the prediction that arm and hand proprioceptive and finger
      somatosensory information about body sway would be maximized with finger contact
      in the plane of body sway. Therefore, the most postural stabilization should be
      possible with such contact. To test this analysis, subjects touched a laterally
      versus anteriorly placed surface while in each of two stances: the heel-to-toe
      tandem Romberg stance that reduces medial-lateral stability and the heel-to-heel,
      toes-outward, knees-bent, "duck stance" that reduces fore-aft stability. Postural
      sway was always least with finger contact in the unstable plane: for the tandem
      stance, lateral fingertip contact was significantly more effective than frontal
      contact, and, for the duck stance, frontal contact was more effective than
      lateral fingertip contact. Force changes at the fingertip led changes in center
      of pressure of the feet by approximately 250 ms for both fingertip contact
      locations for both test stances. These results support the geometric analysis,
      which showed that 1) arm joint angles change by the largest amount when fingertip
      contact is maintained in the plane of greatest sway, and 2) the somatosensory
      cues at the fingertip provide both direction and amplitude information about sway
      when the finger is contacting a surface in the unstable plane.

PMID- 10601481
TI  - alpha-latrocrustatoxin increases neurotransmitter release by activating a calcium
      influx pathway at crayfish neuromuscular junction.
AB  - alpha-latrocrustatoxin (alpha-LCTX), a component of black widow spider venom
      (BWSV), produced a 50-fold increase in the frequency of spontaneously occurring
      miniature excitatory postsynaptic potentials (mEPSPs) at crayfish neuromuscular
      junctions but did not alter their amplitude distribution. During toxin action,
      periods of high-frequency mEPSP discharge were punctuated by periods in which
      mEPSP frequency returned toward control levels. EPSPs were increased in amplitude
      during periods of enhanced mEPSP discharge. alpha-LCTX had no effect when applied
      in Ca(2+)-free saline, but subsequent addition of Ca(2+) caused an immediate
      enhancement of mEPSP frequency even when alpha-LCTX was previously washed out of
      the bath with Ca(2+)-free saline. Furthermore removal of Ca(2+) from the saline
      after alpha-LCTX had elicited an effect immediately blocked the action on mEPSP
      frequency. Thus alpha-LCTX binding is insensitive to Ca(2+), but toxin action
      requires extracellular Ca(2+) ions. Preincubation with wheat germ agglutinin
      prevented the effect of alpha-LCTX but not its binding. These binding
      characteristics suggest that the toxin may bind to a crustacean homologue of
      latrophilin/calcium-independent receptor for latrotoxin, a G-protein-coupled
      receptor for alpha-latrotoxin (alpha-LTX) found in vertebrates. alpha-LCTX caused
      "prefacilitation" of EPSP amplitudes, i.e., the first EPSP in a train was
      enhanced in amplitude to a greater degree than subsequent EPSPs. A similar
      alteration in the pattern of facilitation was observed after application of the
      Ca(2+) ionophore, A23187, indicating that influx of Ca(2+) may mediate the action
      of alpha-LCTX. In nerve terminals filled with the Ca(2+) indicator, calcium green
      1, alpha-LCTX caused increases in the fluorescence of the indicator that lasted
      for several minutes before returning to rest. Neither fluorescence changes nor
      toxin action on mEPSP frequency were affected by the Ca(2+) channel blockers
      omega-agatoxin IVA or Cd(2+), demonstrating that Ca(2+) influx does not occur via
      Ca(2+) channels normally coupled to transmitter release in this preparation. The
      actions of alpha-LCTX could be reduced dramatically by intracellular application
      of the Ca(2+) chelator, bis-(o-aminophenoxy)-N,N,N', N'-tetraacetic acid. We
      conclude that induction of extracellular Ca(2+) influx into nerve terminals is
      sufficient to explain the action of alpha-LCTX on both spontaneous and evoked
      transmitter release at crayfish neuromuscular junctions.

PMID- 10601482
TI  - Coding of locomotor phase in populations of neurons in rostral and caudal
      segments of the neonatal rat lumbar spinal cord.
AB  - Several experiments have demonstrated that rostral segments of the vertebrate
      lumbar spinal cord produce a rhythmic motor output more readily and of better
      quality than caudal segments. Here we examine how this rostrocaudal gradient of
      rhythmogenic capability is reflected in the spike activity of neurons in the
      rostral (L(2)) and caudal (L(5)) lumbar spinal cord of the neonatal rat. The
      spike activity of interneurons in the ventromedial cord, a region necessary for
      the production of locomotion, was recorded intracellularly with patch electrodes
      and extracellularly with tetrodes during pharmacologically induced locomotion.
      Both L(2) and L(5) neurons tended to be active in phase with their homologous
      ventral root. L(5) neurons, however, had a wider distribution of their preferred
      phases of activity throughout the locomotor cycle than L(2) neurons. The strength
      of modulation of the activity of individual L(2) neurons was also larger than
      that of L(5) neurons. These differences resulted in a stronger rhythmic signal
      from the L(2) neuronal population than from the L(5) population. These results
      demonstrate that the rhythmogenic capability of each spinal segment was reflected
      in the activity of interneurons located in the same segment. In addition to
      paralleling the rostrocaudal gradient of rhythmogenic capability, these results
      further suggest a colocalization of motoneurons and their associated interneurons
      involved in the production of locomotion.

PMID- 10601483
TI  - Unilateral dopamine denervation blocks corticostriatal LTP.
AB  - The nigrostriatal dopaminergic projection is crucial for the striatal processing
      of motor information received from the cortex. Lesion of this pathway in rats
      causes locomotor alterations that resemble some of the symptoms of Parkinson's
      disease and significantly alters the excitatory transmission in the striatum. We
      performed in vitro electrophysiological recordings to study the effects of
      unilateral striatal dopamine (DA) denervation obtained by omolateral nigral
      injection of 6-hydroxydopamine (6-OHDA) in the formation of corticostriatal long
      term potentiation (LTP). Unilateral nigral lesion did not affect the intrinsic
      membrane properties of striatal spiny neurons. In fact, these cells showed
      similar pattern of firing discharge and current-voltage relationship in
      denervated striata and in naive controlateral striata. Moreover, excitatory
      postsynaptic potentials (EPSPs) evoked by stimulating corticostriatal fibers and
      recorded from DA-denervated slices showed a pharmacology similar to that observed
      in slices obtained from controlateral intact striata. Conversely, in magnesium
      free medium, high-frequency stimulation (HFS) of corticostriatal fibers produced
      LTP in slices from nondenervated striata but not in slices from 6-OHDA-denervated
      rats. After denervation, in fact, no significant changes in the amplitude of
      extra- and intracellular synaptic potentials were recorded after the conditioning
      HFS. The absence of corticostriatal LTP in DA-denervated striata might represent
      the cellular substrate for some of the movement disorders observed in Parkinson's
      disease.

PMID- 10601484
TI  - Disynaptic pyramidal excitation in forelimb motoneurons mediated via C(3)-C(4)
      propriospinal neurons in the Macaca fuscata.
AB  - In contrast to findings in the cat, it recently has been shown that disynaptic
      pyramidal EPSPs only rarely are observed in forelimb motoneurons of the macaque
      monkey in the intact spinal cord or after a corticospinal transection in C(5).
      This finding has been taken to indicate that the disynaptic pyramidal excitatory
      pathway via C(3)-C(4) propriospinal neurons (PNs) is weakened through phylogeny
      when the monosynaptic cortico-motoneuronal connection has been strengthened. We
      reinvestigate this issue with special focus on the possibility that the
      inhibitory control of the C(3)-C(4) PNs may be stronger in the macaque monkey
      than in the cat. The effect in forelimb motoneurons of electrical stimulation in
      the contralateral pyramid was investigated in anesthetized macaque monkeys
      (Macaca fuscata). We confirmed the low frequency of disynaptic pyramidal EPSPs in
      forelimb motoneurons. However, after intravenous injection of strychnine,
      disynaptic EPSPs could be evoked in 39 of 41 forelimb motoneurons recorded after
      lesion of the corticospinal fibers in C5. After a corresponding lesion in C(2),
      disynaptic pyramidal EPSPs were observed in 2 of 25 motoneurons. In contrast to
      previous reports, we conclude that C(3)-C(4) PNs can mediate disynaptic pyramidal
      excitation in high frequency of occurrence to forelimb motoneurons in the C(6)
      C(8) segments and that this transmission is under a stronger inhibitory control
      than in the cat. Thus, the hypothesis that the disynaptic excitatory cortico
      motoneuronal pathway via the C(3)-C(4) PNs is weakened in parallel with the
      strengthened monosynaptic connection through phylogeny is not supported by the
      present findings.

PMID- 10601485
TI  - Antagonistic effects of phentolamine and octopamine on rhythmic motor output of
      crayfish thoracic ganglia.
AB  - Spontaneous rhythmic motor output of crayfish thoracic ganglia consists of bursts
      of activity in antagonistic leg motor neurons (MNs), alternating with a rather
      slow cycle period (typically > or = 20 s). The most common pattern (77% of
      preparations) consists of long coxal promotor bursts, the duration of which was
      correlated strongly with cycle period, and relatively short remotor bursts
      independent of cycle period. Octopamine, at a concentration of 2-30 microM
      reversibly retarded this rhythm, increasing both cycle period and promotor burst
      duration. Higher concentrations of octopamine inhibited promotor nerve activity
      and abolished rhythmic bursting. Phentolamine (10-50 microM) had the opposite
      effect of decreasing cycle period, mainly by decreasing promotor burst duration.
      Whereas in the presence of octopamine promotor bursts were lengthened and became
      even more strongly related to cycle period, phentolamine promoted a more
      symmetrical rhythm with shorter promotor bursts that were less dependent on cycle
      period. When octopamine was applied in the presence of phentolamine, there was no
      significant increase in cycle period or burst duration, although high octopamine
      concentrations (100 microM) were still capable of inhibiting promotor nerve
      activity. To our knowledge, pharmacological modulation of a spontaneous locomotor
      rhythm by an amine antagonist (applied by itself) has not been reported
      previously. The results raise the testable possibility that phentolamine exerts
      its modulatory effects by acting as an octopamine antagonist in crayfish thoracic
      ganglia.

PMID- 10601486
TI  - Gender differences in the fatigability of human skeletal muscle.
AB  - After participating in a 4-wk intervention that reduced normal usage of the elbow
      flexor muscles, all six women, but only one of six men, experienced a marked
      increase in the endurance time during a low-force fatiguing contraction. The
      increase in endurance time was associated with an altered pattern of muscle
      activation that did not involve the commonly observed progressive increase in
      muscle activity. Rather, the muscle activity comprised intermittent motor unit
      activity. In those individuals who exhibited this behavior, the novel pattern of
      muscle activity was only present immediately after 4 wk of limb immobilization
      and not before the intervention or after 4 wk of recovery. These findings suggest
      possible differences between women and men in the adaptations of the
      neuromuscular system.

PMID- 10601487
TI  - Induction of NMDA receptor-dependent long-term depression in visual cortex does
      not require metabotropic glutamate receptors.
AB  - We tested the role of group I mGluRs in the induction of long-term depression
      (LTD) in the visual cortex, using the novel mGluR antagonist LY341495 and mice
      lacking mGluR5, the predominant phosphoinositide (PI)-linked mGluR in the visual
      cortex. We find that LY341495 is a potent blocker of glutamate-stimulated PI
      hydrolysis in visual cortical synaptoneurosomes, and that it effectively
      antagonizes the actions of the mGluR agonist 1S, 3R-aminocyclopentane-1,3
      dicarboxylic acid (ACPD) on synaptic transmission in visual cortical slices.
      However, LY341495 has no effect on the induction of LTD by low-frequency
      stimulation. Furthermore, mice lacking mGluR5 show normal NMDA receptor-dependent
      LTD. These results indicate that group I mGluR activation is not required for the
      induction of NMDA receptor-dependent LTD in the visual cortex.

PMID- 10601488
TI  - Experiments using transcranial magnetic brain stimulation in man could reveal
      important new mechanisms in motor control.

PMID- 10601489
TI  - 12-Lipoxygenase overexpression in rodent NG108-15 cells enhances membrane
      excitability by inhibiting M-type K+ channels.
AB  - 1. 12-Lipoxygenase produces 12-hydroperoxy acid from arachidonic acid released
      from membrane phospholipids. To elucidate the role of the enzyme in neuronal
      functions, mouse neuroblastoma x rat glioma hybrid NG108-15 cells were
      permanently transfected with the cDNA for human 12-lipoxygenase. 2. The number of
      action potentials evoked by depolarizing current steps in a current-clamp mode
      was strikingly increased in 12-lipoxygenase-expressing NG108-15 cells as compared
      with the wild-type cells which hardly had the enzyme activity. 3. In the
      transformed cells, the M-type voltage-dependent K+ current was significantly
      reduced with little or no change in other ion channel currents. 4. Treatment of
      the transformed cells with a 12-lipoxygenase inhibitor recovered the action
      potential frequency and the M-current amplitude to the control level. 5. These
      results indicate that 12-lipoxygenase and/or its metabolites target K+ channels
      and upregulate the membrane excitability, and thereby modulate neuronal
      signalling.

PMID- 10601490
TI  - Ca2+ sparks and Ca2+ waves in saponin-permeabilized rat ventricular myocytes.
AB  - 1. We carried out confocal Ca2+ imaging in myocytes permeabilized with saponin in
      'internal' solutions containing: MgATP, EGTA and fluo-3 potassium salt. 2.
      Permeabilized myocytes exhibited spontaneous Ca2+ sparks and waves similar to
      those observed in intact myocytes loaded with fluo-3 AM. 3. In the presence of
      'low' [EGTA] (0.05 mM), Ca2+ waves arose regularly, even at relatively low [Ca2+]
      (50-100 nM, free). Increasing [EGTA] resulted in decreased frequency and
      propagation velocity of Ca2+ waves. Propagating waves were completely abolished
      at [EGTA] > 0.3 mM. 4. The frequency of sparks increased as a function of [Ca2+]
      (50-400 nM range) with no sign of a high affinity Ca2+-dependent inactivation
      process. 5. The rate of occurrence of Ca2+ sparks was increased by calmodulin and
      cyclic adenosine diphosphate-ribose (cADPR).

PMID- 10601491
TI  - Molecular basis of transient outward K+ current diversity in mouse ventricular
      myocytes.
AB  - 1. Two kinetically and pharmacologically distinct transient outward K+ currents,
      referred to as Ito,f and Ito,s, have been distinguished in mouse left ventricular
      myocytes. Ito,f is present in all left ventricular apex cells and in most left
      ventricular septum cells, whereas Ito,s is identified exclusively in left
      ventricular septum cells. 2. Electrophysiological recordings from ventricular
      myocytes isolated from animals with a targeted deletion of the Kv1.4 gene (Kv1.4
      /- mice) reveal that Ito,s is undetectable in cells isolated from the left
      ventricular septum (n = 26). Ito,f density in both apex and septum cells, in
      contrast, is not affected by deletion of Kv1.4. 3. Neither the 4-AP-sensitive,
      slowly inactivating K+ current, IK,slow, nor the steady-state non-inactivating K+
      current, ISS, is affected in Kv1.4-/- mouse left ventricular cells. 4. In
      myocytes isolated from transgenic mice expressing a dominant negative Kv4.2 alpha
      subunit, Kv4.2W362F, Ito,f is eliminated in both left ventricular apex and septum
      cells. In addition, a slowly inactivating transient outward K+ current similar to
      Ito,s in wild-type septum cells is evident in myocytes isolated from left
      ventricular apex of Kv4.2W362F-expressing transgenics. The density of Ito,s in
      septum cells, however, is unaffected by Kv4.2W362F expression. 5. Western blots
      of fractionated mouse ventricular membrane proteins reveal a significant increase
      in Kv1.4 protein level in Kv4.2W362F-expressing transgenic mice. The protein
      levels of other Kv alpha subunits, Kv1.2 and Kv2.1, in contrast, are not affected
      by the expression of the Kv4.2W362F transgene. 6. The results presented here
      demonstrate that the molecular correlates of Ito,f and Ito,s in adult mouse
      ventricle are distinct. Kv1.4 underlies mouse ventricular septum Ito,s, whereas
      Kv alpha subunits of the Kv4 subfamily underlie mouse ventricular apex and septum
      Ito, f. The appearance of the slow transient outward K+ current in Kv4. 2W362F
      expressing left ventricular apex cells with properties indistinguishable from
      Ito,s in wild-type cells is accompanied by an increase in Kv1.4 protein
      expression, suggesting that the upregulation of Kv1.4 underlies the observed
      electrical remodeling in Kv4.2W362F-expressing transgenics.

PMID- 10601492
TI  - Inhibition of store-operated Ca2+ entry by extracellular ATP in rat brown
      adipocytes.
AB  - 1. Modulation of intracellular free Ca2+ concentration ([Ca2+]i) by extracellular
      ATP was investigated in cultured adult rat brown adipocytes using the fluorescent
      Ca2+ indicator fura-2. 2. Bath application of ATP in micromolar concentrations
      caused a large increase in [Ca2+]i in cells previously stimulated with
      noradrenaline. This ATP-induced [Ca2+]i increase exhibited a monotonic decline to
      near the resting levels within approximately 2 min, even in the continued
      presence of the agonist. 3. The magnitude and time course of the [Ca2+]i increase
      in response to ATP were not significantly affected by removal of extracellular
      Ca2+, suggesting that a mobilization of intracellular Ca2+ primarily contributes
      to the increase. 4. The [Ca2+]i increase in response to ATP was sensitive to
      inhibition by suramin, suggesting the involvement of P2 purinoceptors in the
      response. 5. Thapsigargin (100 nM) evoked a gradual and irreversible increase in
      [Ca2+]i which was entirely dependent upon extracellular Ca2+, providing
      functional evidence for the expression of store-operated Ca2+ entry in these
      brown adipocytes. 6. Extracellular ATP at a concentration of 10 microM depressed
      this thapsigargin (100 nM)-induced [Ca2+]i increase by 92 +/- 3 % (n = 8 cells),
      strongly suggesting that ATP inhibits an influx of Ca2+ across the plasma
      membrane through the store-operated pathway. Bath application of phorbol 12
      myristate 13-acetate (PMA, 5 microM) did not affect the thapsigargin-induced
      [Ca2+]i increase, indicating that the inhibitory action of ATP is not mediated by
      activation of protein kinase C (PKC). 7. These results indicate that
      extracellular ATP not only mobilizes Ca2+ from the intracellular stores but also
      exerts a potent inhibitory effect on the store-operated Ca2+ entry process in
      adult rat brown adipocytes.

PMID- 10601493
TI  - Ca2+ store-dependent potentiation of Ca2+-activated non-selective cation channels
      in rat hippocampal neurones in vitro.
AB  - 1. Potentiation of calcium-activated non-selective cation (CAN) channels was
      studied in rat hippocampal neurones. CAN channels were activated by IP3-dependent
      Ca2+ release following metabotropic glutamate receptor (mGluR) stimulation either
      by Schaffer collateral input to CA1 neurones in brain slices in which ionotropic
      glutamate and GABAA receptors, K+ channels, and the Na+-Ca2+ exchanger were
      blocked or by application of the mGluR antagonist ACPD in cultured hippocampal
      neurones. 2. The CAN channel-dependent depolarization (DeltaVCAN) was potentiated
      when [Ca2+]i was increased in neurones impaled with Ca2+-containing
      microelectrodes. 3. Fura-2 measurements revealed a biphasic increase in [Ca2+]i
      when 200 microM ACPD was bath applied to cultured hippocampal neurones. This
      increase was greatly attenuated in the presence of Cd2+. 4. Thapsigargin (1
      microM) caused marked potentiation of DeltaVCAN in CA1 neurones in the slices and
      of the CAN current (ICAN) measured in whole cell-clamped cultured hippocampal
      neurones. 5. Ryanodine (20 microM) also led to a potentiation of DeltaVCAN while
      neurones pretreated with 100 microM dantrolene failed to show potentiation of
      DeltaVCAN when impaled with Ca2+-containing microelectrodes. 6. The mitochondrial
      oxidative phosphorylation uncoupler carbonyl cyanide m-chlorophenyl hydrazone (2
      microM) also caused a potentiation of DeltaVCAN. 7. CAN channels are subject to
      considerable potentiation following an increase in [Ca2+]i due to Ca2+ release
      from IP3-sensitive, Ca2+-sensitive, or mitochondrial Ca2+ stores. This ICAN
      potentiation may play a crucial role in the 'amplification' phase of
      excitotoxicity.

PMID- 10601494
TI  - Direct demonstration of persistent Na+ channel activity in dendritic processes of
      mammalian cortical neurones.
AB  - 1. Single Na+ channel activity was recorded in patch-clamp, cell-attached
      experiments performed on dendritic processes of acutely isolated principal
      neurones from rat entorhinal-cortex layer II. The distances of the recording
      sites from the soma ranged from approximately 20 to approximately 100 microm. 2.
      Step depolarisations from holding potentials of -120 to -100 mV to test
      potentials of -60 to +10 mV elicited Na+ channel openings in all of the recorded
      patches (n = 16). 3. In 10 patches, besides transient Na+ channel openings
      clustered within the first few milliseconds of the depolarising pulses, prolonged
      and/or late Na+ channel openings were also regularly observed. This 'persistent'
      Na+ channel activity produced net inward, persistent currents in ensemble-average
      traces, and remained stable over the entire duration of the experiments (
      approximately 9 to 30 min). 4. Two of these patches contained < or = 3 channels.
      In these cases, persistent Na+ channel openings could be attributed to the
      activity of one single channel. 5. The voltage dependence of persistent-current
      amplitude in ensemble-average traces closely resembled that of whole-cell,
      persistent Na+ current expressed by the same neurones, and displayed the same
      characteristic low threshold of activation. 6. Dendritic, persistent Na+ channel
      openings had relatively high single-channel conductance ( approximately 20 pS),
      similar to what is observed for somatic, persistent Na+ channels. 7. We conclude
      that a stable, persistent Na+ channel activity is expressed by proximal dendrites
      of entorhinal-cortex layer II principal neurones, and can contribute a
      significant low-threshold, persistent Na+ current to the dendritic processing of
      excitatory synaptic inputs.

PMID- 10601495
TI  - Physiology of rat retinal pericytes: modulation of ion channel activity by serum
      derived molecules.
AB  - 1. Pericytes, which are contractile cells located on the outer wall of
      microvessels, are thought to be particularly important in the retina where the
      ratio of these cells to vascular endothelial cells is the highest of any tissue.
      Retinal pericytes are of interest since they may regulate capillary blood flow
      and because their selective loss is an early event in diabetic retinopathy, which
      is a common sight-threatening disorder associated with dysfunction of the blood
      retinal barrier. 2. Although a breakdown in the vascular endothelial barrier is a
      frequent pathophysiological event, knowledge of the effects of blood-derived
      molecules on pericyte function is limited. Based on the premise that ion channels
      play a vital role in cellular function, we examined the effect of serum on the
      ionic currents of retinal pericytes. To do this, we used the perforated-patch
      configuration of the patch-clamp technique to monitor the whole-cell currents of
      pericytes located on freshly isolated rat retinal microvessels. 3. Exposure to
      serum reversibly activated inward and outward currents in virtually all of the
      sampled retinal pericytes. Two types of sustained conductances were induced by
      serum. These were a calcium-permeable non-specific cation (NSC) current and a
      voltage-dependent potassium current. In addition, exposure to serum increased the
      activity of chloride channels which caused transient depolarizing currents. 4.
      Associated with the activation of these conductances, the membrane potential
      showed a sustained decrease of 10 +/- 2 mV from -56 mV to -46 mV and, also,
      transient depolarizations to near -30 mV. The serum-induced depolarizations can
      activate the voltage-gated calcium channels expressed by the retinal pericytes.
      5. Calcium-permeable NSC channels appear to play a critical role in the response
      of pericytes to serum-derived molecules. Consistent with this, activation of the
      chloride and potassium channels was sensitive to SK&F 96365, which is a blocker
      of NSC channels. In addition, chloride and potassium channel activation was
      dependent on extracellular calcium. 6. The effects of serum on the activity of
      channels in retinal pericytes were qualitatively mimicked by insulin-like growth
      factor-1 (IGF-1), which is a normal constituent of the blood. 7. There are
      significant differences in the effects of serum on retinal pericytes compared
      with vascular smooth muscle cells. Serum activated sustained conductances in
      retinal pericytes but not in the vascular smooth muscle cells. This suggests a
      fundamental difference in the mechanisms by which serum-derived molecules affect
      these two types of cells. 8. We conclude that serum-derived molecules, such as
      IGF-1, can activate several types of ion channels in retinal pericytes. These
      changes in channel activity are likely to influence pericyte function at sites of
      a breakdown in the blood-retinal barrier.

PMID- 10601496
TI  - Quantal analysis of 5-hydroxytryptamine release from mouse pancreatic beta-cells.
AB  - 1. A combination of patch-clamp, amperometric and fluorimetric methods were used
      to investigate the Ca2+ dependence and kinetics of secretion from pancreatic beta
      cells elicited by voltage-gated Ca2+ entry. 2. Whether measured by the change in
      cell capacitance or by amperometric detection of 5-hydroxytryptamine (5-HT)
      release, the voltage dependence of the amount of secretion mirrored that of both
      the peak Ca2+ current and Ca2+ entry. 3. The magnitude of secretion elicited by a
      single pulse could be entirely accounted for by a readily releasable pool of
      approximately 200 vesicles. Neither depression nor potentiation of release was
      observed with 0.1 Hz pulse trains. 4. Transient amperometric currents were
      detected, which occurred independently of each other and were attributed to the
      fusion of single vesicles. 5. The time course of the macroscopic amperometric
      current could be accurately reconstructed by convolution of the all-events
      latency distribution and the unitary amperometric current. 6. In response to
      membrane depolarisation, secretion was initiated with a variable latency:
      approximately 95 % of the first secretory events occurred at least 50 ms after
      the start of the voltage pulse (and Ca2+ influx). Secretion fell rapidly on
      membrane repolarisation, even though the average intracellular calcium
      concentration ([Ca2+]i) was still elevated. 7. The [Ca2+] in the locality of the
      release site was estimated from the all-events latency distribution. [Ca2+] rose
      during a voltage pulse and secretion was elicited at > 0.4 microM and peaked at
      approximately 2-10 microM.

PMID- 10601497
TI  - Flow modulates the transport of K+ through the walls of single perfused
      mesenteric venules in anaesthetised rats.
AB  - 1. We have investigated the effects of varying flow velocity (U) upon
      permeability to potassium ions (PK) of single perfused mesenteric venules in
      anaesthetised rats. PK was estimated using a development of the single bolus
      microperfusion technique at chosen flow velocities in the range of 300 to 6000
      microm s-1. 2. In an initial study on 12 vessels, there was a strong positive
      correlation between PK and U. This was described by the relation: PK = 0.0053U +
      8.86, where PK and U are both expressed in micrometres per second (microm s-1).
      3. The addition of the nitric oxide (NO) synthase inhibitors (20 micromol l-1) N
      G-monomethyl-L-arginine (L-NMMA) and N G-nitro L-arginine (L-NNA) to the
      superfusate abolished the positive correlation between PK and U. The addition of
      D-NNA (20 micromol l-1) did not change the relation between PK and U where the
      median value for the slope of the relation was 57.7 (+/- 58.7 interquartile
      (IQR)) x 10-4 (n = 4). The addition of L-arginine (200 micromol l-1) restored the
      relation between PK and U where the slope of the relation was increased from 3.9
      (+/- 16.3 IQR) x 10-4 to 69.2 (+/- 13.5 IQR) x 10-4 (n = 7). 4. The addition of
      the guanylate cyclase inhibitor LY83583 (10 micromol l-1) abolished the positive
      correlation between PK and U (n = 6). 5. Our data suggest that the flow modulates
      the potassium permeability through the walls of single perfused rat mesenteric
      venules via a NO-cGMP-dependent process.

PMID- 10601498
TI  - Adenosinergic modulation of rat basal forebrain neurons during sleep and waking:
      neuronal recording with microdialysis.
AB  - 1. The cholinergic system of the basal forebrain (BF) is hypothesized to play an
      important role in behavioural and electrocortical arousal. Adenosine has been
      proposed as a sleep-promoting substance that induces sleep by inhibiting
      cholinergic neurons of the BF and brainstem. However, adenosinergic influences on
      the activity of BF neurons in naturally awake and sleeping animals have not been
      demonstrated. 2. We recorded the sleep-wake discharge profile of BF neurons and
      simultaneously assessed adenosinergic influences on wake- and sleep-related
      activity of these neurons by delivering adenosinergic agents adjacent to the
      recorded neurons with a microdialysis probe. Discharge rates of BF neurons were
      recorded through two to three sleep-wake episodes during baseline (artificial
      cerebrospinal fluid perfusion), and after delivering an adenosine transport
      inhibitor (s-(p-nitrobenzyl)-6-thioinosine; NBTI), or exogenous adenosine, or a
      selective adenosine A1 receptor antagonist (8-cyclopentyl-1, 3-dimethylxanthine;
      CPDX). 3. NBTI and adenosine decreased the discharge rate of BF neurons during
      both waking and non-rapid eye movement (NREM) sleep. In contrast, CPDX increased
      the discharge rate of BF neurons during both waking and NREM sleep. These results
      suggest that in naturally awake and sleeping animals, adenosine exerts tonic
      inhibitory influences on BF neurons, supporting the hypothesized role of
      adenosine in sleep regulation. 4. However, in the presence of exogenous
      adenosine, NBTI or CPDX, BF neurons retained their wake- and sleep-related
      discharge patterns, i.e. still exhibited changes in discharge rate during
      transitions between waking and NREM sleep. This suggests that other
      neurotransmitters/neuromodulators also contribute to the sleep-wake discharge
      modulation of BF neurons.

PMID- 10601499
TI  - Depression of muscle and cutaneous afferent-evoked monosynaptic field potentials
      during fictive locomotion in the cat.
AB  - 1. Monosynaptic extracellular field potentials evoked by electrical stimulation
      of ipsilateral hindlimb nerves carrying muscle group I, II and cutaneous
      afferents were examined during fictive locomotion. Fifty-eight field potentials
      were recorded in the dorsal and intermediate laminae throughout the mid-lumbar to
      first sacral segments and fictive locomotion was evoked by mesencephalic
      locomotor region (MLR) stimulation in paralysed decerebrate cats. 2. The majority
      (96 %) of group I, II and cutaneous-evoked field potentials were decreased during
      fictive locomotion. Group I, cutaneous and dorsal group II potentials were
      reduced on average to about 80 % of control values. Group II field potentials
      recorded in the intermediate laminae were reduced to a mean of 49 % of control
      values. Cyclic variations in field potential amplitude between the flexion and
      extension phases were observed in 24 of 45 cases analysed. Of those 24 field
      potentials, the two group I and four cutaneous field potentials were smaller
      during the flexion phase. All eleven group II and the remaining seven cutaneous
      fields were smaller during extension. In all but two cases, these cyclic
      variations were smaller than the tonic depression upon which they were
      superimposed. 3. In 7/9 group II field potentials examined, reductions (on
      average to 85 % of control) began with the onset of MLR stimulation that produced
      tonic activity in the motor nerves before the onset of rhythmic alternating,
      locomotor discharges. In six of the seven cases the field potential depression
      increased with the establishment of fictive locomotion. This observation and the
      cyclic modulation of field potentials during fictive locomotion suggests that the
      depression was strongly linked to the operation of the spinal locomotor
      circuitry. 4. Depression of the monosynaptic components of the field potentials
      suggests a reduction in synaptic transmission from primary afferents to first
      order spinal interneurones during fictive locomotion. Accordingly, the larger
      depression of intermediate group II field potentials may indicate a preferential
      reduction in transmission from group II afferents to interneurones located in
      intermediate spinal laminae. 5. Flexion reflexes evoked by group II and cutaneous
      afferents were also depressed during MLR-evoked fictive locomotion. The
      possibility that this depression results from a reduction in transmission from
      primary afferents, and in particular from group II afferents, ending on
      interneurones in the intermediate laminae is discussed.

PMID- 10601500
TI  - Expression of nitric oxide synthase isoforms in pregnant human myometrium.
AB  - 1. Endogenous nitric oxide has been proposed to play a role in the control of
      myometrial contractility in pregnancy. In this study, the expression,
      localisation and regulation of nitric oxide synthase (NOS) isoforms have been
      examined in human pregnant myometrium and cultured human myometrial smooth muscle
      cells, by immunoblotting, immunohistochemistry and reverse transcription
      polymerase chain reaction. 2. Immunoblotting of extracts from freshly isolated
      myometrial tissue, affinity-enriched for NOS proteins by precipitation with ADP
      sepharose, revealed expression of endothelial NOS (eNOS or NOS3) in tissues from
      preterm, term non-labour and active labour at term. Inducible NOS (iNOS or NOS2)
      and neuronal NOS (nNOS or NOS1) proteins were not detected at any stage of
      pregnancy. 3. Immunohistochemical detection showed that expression of eNOS
      protein was restricted to the endothelium of the myometrial vasculature, with no
      staining detected in myometrial smooth muscle cells. 4. Messenger RNA for all
      three NOS isoforms was detected, although iNOS and nNOS mRNAs were detectable
      only with high cycle number, implying a low copy number. 5. NOS isoforms were not
      detectable in human myometrial smooth muscle cells cultured from term non-labour
      pregnancies. Cytokine stimulation of cultured myometrial cells did not induce
      iNOS expression or nitrite accumulation in the culture medium, although both iNOS
      protein and nitrite release were detected in the human pulmonary epithelial cell
      line A549. 6. Levels of eNOS protein and of NOS mRNA expression were not
      correlated with gestational stage, suggesting that endogenously produced NO is
      not likely to be a modulator of myometrial tone during human pregnancy.

PMID- 10601501
TI  - Voltage-gated and resting membrane currents recorded from B-cells in intact mouse
      pancreatic islets.
AB  - 1. The perforated patch whole-cell configuration of the patch-clamp technique was
      applied to superficial cells in intact pancreatic islets. Immunostaining in
      combination with confocal microscopy revealed that the superficial cells
      consisted of 35 % insulin-secreting B-cells and 65 % non-B-cells (A- and D
      cells). 2. Two types of cell, with distinct electrophysiological properties,
      could be functionally identified. One of these generated oscillatory electrical
      activity when the islet was exposed to 10 mM glucose and had the
      electrophysiological characteristics of isolated B-cells maintained in tissue
      culture. 3. The Ca2+ current recorded from B-cells in situ was 80 % larger than
      that of isolated B-cells. It exhibited significant (70 %) inactivation during 100
      ms depolarisations. The inactivation was voltage dependent and particularly
      prominent during depolarisations evoking the largest Ca2+ currents. 4. Voltage
      dependent K+ currents were observed during depolarisations to membrane potentials
      above -20 mV. These currents inactivated little during a 200 ms depolarisation
      and were unaffected by varying the holding potential between -90 and -30 mV. 5.
      The maximum resting conductance in the absence of glucose, which reflects the
      conductance of ATP-regulated K+ (KATP) channels, amounted to approximately 4 nS.
      Glucose produced a concentration-dependent reduction of KATP channel conductance
      with half-maximal inhibition observed with 5 mM glucose. 6. Combining voltage-
      and current-clamp recording allowed the estimation of the gap junction
      conductance between different B-cells. These experiments indicated that the input
      conductance of the B-cell at stimulatory glucose concentrations ( approximately 1
      nS) is almost entirely accounted for by coupling to neighbouring B-cells.

PMID- 10601502
TI  - Sodium nitroprusside increases human skeletal muscle blood flow, but does not
      change flow distribution or glucose uptake.
AB  - 1. The role of blood flow as a determinant of skeletal muscle glucose uptake is
      at present controversial and results of previous studies are confounded by
      possible direct effects of vasoactive agents on glucose uptake. Since increase in
      muscle blood flow can be due to increased flow velocity or recruitment of new
      capillaries, or both, it would be ideal to determine whether the vasoactive agent
      affects flow distribution or only increases the mean flow. 2. In the present
      study blood flow, flow distribution and glucose uptake were measured
      simultaneously in both legs of 10 healthy men (aged 29 +/- 1 years, body mass
      index 24 +/- 1 kg m-2) using positron emission tomography (PET) combined with
      [15O]H2O and [18F]fluoro-2-deoxy-D-glucose (FDG). The role of blood flow in
      muscle glucose uptake was studied by increasing blood flow in one leg with sodium
      nitroprusside (SNP) and measuring glucose uptake simultaneously in both legs
      during euglycaemic hyperinsulinaemia (insulin infusion 6 pmol kg-1 min-1). 3. SNP
      infusion increased skeletal muscle blood flow by 86 % (P < 0.01), but skeletal
      muscle flow distribution and insulin-stimulated glucose uptake (61.4 +/- 7. 5 vs.
      67.0 +/- 7.5 micromol kg-1 min-1, control vs. SNP infused leg, not significant),
      as well as flow distribution between different tissues of the femoral region,
      remained unchanged. The effect of SNP infusion on blood flow and distribution
      were unchanged during infusion of physiological levels of insulin (duration, 150
      min). 4. Despite a significant increase in mean blood flow induced by an intra
      arterial infusion of SNP, glucose uptake and flow distribution remained unchanged
      in resting muscles of healthy subjects. These findings suggest that SNP, an
      endothelium-independent vasodilator, increases non-nutritive, but not nutritive
      flow or capillary recruitment.

PMID- 10601503
TI  - Rapidly adapting receptors in a rabbit model of mitral regurgitation.
AB  - 1. Unlike in normal rabbits, pulmonary rapidly adapting receptors (RARs) in
      rabbits with chronic mitral regurgitation (MR) do not respond to small changes in
      extravascular fluid (EVF) volume in major airways. The present study examined the
      effect of shrinking the EVF volume in rabbits with chronic MR by infusing
      hypertonic albumin, to see whether this response of RARs is restored. The effect
      of raising the left atrial pressure (LAP) acutely above 25 mmHg (to cause
      pulmonary oedema) on RARs was also investigated. 2. Mean RAR activities in
      rabbits with MR (n = 6) at initial control, LAP +5 mmHg, LAP +10 mmHg and final
      control periods were 20.9 +/- 9. 5, 18.8 +/- 11.3, 27.0 +/- 11.2 and 17.2 +/- 9.8
      action potentials min-1, respectively (P > 0.05, ANOVA). After infusion of 35 %
      bovine serum albumin i.v. these values were 9.4 +/- 3.2, 30.6 +/- 14.6, 48. 9 +/-
      10.1 and 18.4 +/- 7.3 action potentials min-1, respectively (P < 0.01, ANOVA). In
      rabbits with chronic MR (n = 7) raising the LAP above 25 mmHg stimulated RARs. 3.
      EVF content of the airways and lungs was measured in rabbits with MR and in
      control rabbits, at baseline and after elevation of the LAP by 10 or 25 mmHg for
      20 min. In control rabbits the EVF contents in the lower trachea, carina and
      bronchi at baseline and at LAP +10 mmHg were 52.1 +/- 1.2 and 57.8 +/- 1.7 %,
      respectively (P < 0.05, Student's t test). In rabbits with MR these values were
      58.3 +/- 1.5 and 56.9 +/- 1.9 %, respectively. When the LAP was elevated by 25
      mmHg the EVF content increased to 62.4 +/- 1.1 % (P < 0.05, t test compared with
      baseline and LAP +10 mmHg). 4. We concluded that in rabbits with chronic MR, RARs
      are unable to respond to acute, small elevations of LAP because there is no
      concomitant increase in EVF content in the vicinity of these receptors.
      Furthermore, these receptors can be activated in these animals by elevating the
      LAP above 25 mmHg or can be made sensitive to acute small elevations of LAP by
      shrinking the chronically expanded EVF compartment.

PMID- 10601504
TI  - Impaired response of human motoneurones to corticospinal stimulation after
      voluntary exercise.
AB  - 1. Activation of descending corticospinal tracts with transmastoid electrical
      stimuli has been used to assess changes in the behaviour of motoneurones after
      voluntary contractions. Stimuli were delivered before and after maximal voluntary
      isometric contractions (MVCs) of the elbow flexor muscles. 2. Following a
      sustained MVC of the elbow flexors lasting 5-120 s there was an immediate
      reduction of the response to transmastoid stimulation to about half of the
      control value. The response recovered to control levels after about 2 min. This
      was evident even when the size of the responses was adjusted to accommodate
      changes in the maximal muscle action potential (assessed with supramaximal
      stimuli at the brachial plexus). 3. To determine whether the post-contraction
      depression required activity in descending motor paths, motoneurones were
      activated by supramaximal tetanic stimulation of the musculocutaneous nerve for
      10 s. This did not depress the response to transmastoid stimulation. 4. Following
      a sustained MVC of 120 s duration, the response to transcranial magnetic
      stimulation of the motor cortex gradually declined to a minimal level by about 2
      min and remained depressed for more than 10 min. 5. Additional studies were
      performed to check that the activation of descending tracts by transmastoid
      stimulation was likely to involve excitation of direct corticospinal paths. When
      magnetic cortical stimuli and transmastoid stimuli were timed appropriately, the
      response to magnetic cortical stimulation could be largely occluded. 6. This
      study describes a novel depression of effectiveness of corticospinal actions on
      human motoneurones. This depression may involve the corticomotoneuronal synapse.

PMID- 10601505
TI  - Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir
      plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults.
      Study 006 Team.
AB  - BACKGROUND: Efavirenz is a nonnucleoside reverse-transcriptase inhibitor of human
      immunodeficiency virus type 1 (HIV-1). We compared two regimens containing
      efavirenz, one with a protease inhibitor and the other with two nucleoside
      reverse-transcriptase inhibitors, with a standard three-drug regimen. METHODS:
      The study subjects were 450 patients who had not previously been treated with
      lamivudine or any nonnucleoside reverse-transcriptase inhibitor or protease
      inhibitor. In this open-label study, patients were randomly assigned to one of
      three regimens: efavirenz (600 mg daily) plus zidovudine (300 mg twice daily) and
      lamivudine (150 mg twice daily); the protease inhibitor indinavir (800 mg every
      eight hours) plus zidovudine and lamivudine; or efavirenz plus indinavir (1000 mg
      every eight hours). RESULTS: Suppression of plasma HIV-1 RNA to undetectable
      levels was achieved in more patients in the group given efavirenz plus nucleoside
      reverse-transcriptase inhibitors than in the group given indinavir plus
      nucleoside reverse-transcriptase inhibitors (70 percent vs. 48 percent, P<0.001).
      The efficacy of the regimen of efavirenz plus indinavir was similar (53 percent)
      to that of the regimen of indinavir, zidovudine, and lamivudine. CD4 cell counts
      increased significantly with all combinations (range of increases, 180 to 201
      cells per cubic millimeter). More patients discontinued treatment because of
      adverse events in the group given indinavir and two nucleoside reverse
      transcriptase inhibitors than in the group given efavirenz and two nucleoside
      reverse-transcriptase inhibitors (43 percent vs. 27 percent, P=0.005).
      CONCLUSIONS: As antiretroviral therapy in HIV-1-infected adults, the combination
      of efavirenz, zidovudine, and lamivudine has greater antiviral activity and is
      better tolerated than the combination of indinavir, zidovudine, and lamivudine.

PMID- 10601506
TI  - Combination therapy with efavirenz, nelfinavir, and nucleoside reverse
      transcriptase inhibitors in children infected with human immunodeficiency virus
      type 1. Pediatric AIDS Clinical Trials Group 382 Team.
AB  - BACKGROUND: Consistent long-term viral suppression has been difficult to achieve
      in children with human immunodeficiency virus type 1 (HIV-1) infection. We tested
      the safety and antiviral efficacy of a novel combination consisting of efavirenz,
      nelfinavir, and one or more nucleoside reverse-transcriptase inhibitors in 57
      children previously treated with only nucleoside reverse-transcriptase
      inhibitors. METHODS: The children were monitored for 48 weeks after the
      initiation of therapy. We assessed plasma concentrations of efavirenz and
      nelfinavir, plasma HIV-1 RNA levels, and lymphocyte subpopulations. RESULTS: At
      base line, the 57 HIV-1-infected children (age range, 3.8 to 16.8 years) had a
      median of 699 CD4 cells per cubic millimeter and 10,000 copies of HIV-1 RNA per
      milliliter of plasma. The most common treatment-related effects of at least
      moderate severity were rash (in 30 percent of children), diarrhea (in 18
      percent), neutropenia (in 12 percent), and biochemical abnormalities (in 12
      percent). Serious side effects were uncommon. The mean values for the area under
      the curve for efavirenz and nelfinavir corresponded to expected values. In an
      intention-to-treat analysis, 76 percent of children had plasma HIV-1 RNA levels
      of less than 400 copies per milliliter after 48 weeks of therapy and 63 percent
      had levels of less than 50 copies per milliliter. A high plasma HIV-1 RNA level
      at base line significantly decreased the likelihood that plasma levels of HIV-1
      RNA would become undetectable during treatment. CONCLUSIONS: In HIV-1-infected
      children who were previously treated with nucleoside reverse-transcriptase
      inhibitors, the combination of efavirenz, nelfinavir, and nucleoside reverse
      transcriptase inhibitors was generally well tolerated and had a potent and
      sustained antiviral effect.

PMID- 10601507
TI  - A randomized study of the prevention of sudden death in patients with coronary
      artery disease. Multicenter Unsustained Tachycardia Trial Investigators.
AB  - BACKGROUND: Empirical antiarrhythmic therapy has not reduced mortality among
      patients with coronary artery disease and asymptomatic ventricular arrhythmias.
      Previous studies have suggested that antiarrhythmic therapy guided by
      electrophysiologic testing might reduce the risk of sudden death. METHODS: We
      conducted a randomized, controlled trial to test the hypothesis that
      electrophysiologically guided antiarrhythmic therapy would reduce the risk of
      sudden death among patients with coronary artery disease, a left ventricular
      ejection fraction of 40 percent or less, and asymptomatic, unsustained
      ventricular tachycardia. Patients in whom sustained ventricular tachyarrhythmias
      were induced by programmed stimulation were randomly assigned to receive either
      antiarrhythmic therapy, including drugs and implantable defibrillators, as
      indicated by the results of electrophysiologic testing, or no antiarrhythmic
      therapy. Angiotensin-converting-enzyme inhibitors and beta-adrenergic-blocking
      agents were administered if the patients could tolerate them. RESULTS: A total of
      704 patients with inducible, sustained ventricular tachyarrhythmias were randomly
      assigned to treatment groups. Five-year Kaplan-Meier estimates of the incidence
      of the primary end point of cardiac arrest or death from arrhythmia were 25
      percent among those receiving electrophysiologically guided therapy and 32
      percent among the patients assigned to no antiarrhythmic therapy (relative risk,
      0.73; 95 percent confidence interval, 0.53 to 0.99), representing a reduction in
      risk of 27 percent). The five-year estimates of overall mortality were 42 percent
      and 48 percent, respectively (relative risk, 0.80; 95 percent confidence
      interval, 0.64 to 1.01). The risk of cardiac arrest or death from arrhythmia
      among the patients who received treatment with defibrillators was significantly
      lower than that among the patients discharged without receiving defibrillator
      treatment (relative risk, 0.24; 95 percent confidence interval, 0.13 to 0.45;
      P<0.001). Neither the rate of cardiac arrest or death from arrhythmia nor the
      overall mortality rate was lower among the patients assigned to
      electrophysiologically guided therapy and treated with antiarrhythmic drugs than
      among the patients assigned to no antiarrhythmic therapy. CONCLUSIONS:
      Electrophysiologically guided antiarrhythmic therapy with implantable
      defibrillators, but not with antiarrhythmic drugs, reduces the risk of sudden
      death in high-risk patients with coronary disease.

PMID- 10601508
TI  - Images in clinical medicine. Cutaneous zygomycosis (Mucormycosis).

PMID- 10601509
TI  - Risk factors for injury to women from domestic violence.
AB  - BACKGROUND: Domestic violence is the most common cause of nonfatal injury to
      women in the United States. To identify risk factors for such injuries, we
      examined the socioeconomic and behavioral characteristics of women who were
      victims of domestic violence and the men who injured them. METHODS: We conducted
      a case-control study at eight large, university-affiliated emergency departments.
      The 256 intentionally injured women had acute injuries resulting from a physical
      assault by a male partner. The 659 controls were women treated for other
      conditions in the emergency department. Information was collected with a
      standardized questionnaire; no information was obtained directly from the male
      partners. RESULTS: The 256 intentionally injured women had a total of 434
      contusions and abrasions, 89 lacerations, and 41 fractures and dislocations. In a
      multivariate analysis, the characteristics of the partners that were most closely
      associated with an increased risk of inflicting injury as a result of domestic
      violence were alcohol abuse (adjusted relative risk, 3.6; 95 percent confidence
      interval, 2.2 to 5.9); drug use (adjusted relative risk, 3.5; 95 percent
      confidence interval, 2.0 to 6.4); intermittent employment (adjusted relative
      risk, 3.1; 95 percent confidence interval, 1.1 to 8.8); recent unemployment
      (adjusted relative risk, 2.7; 95 percent confidence interval, 1.2 to 6.5); having
      less than a high-school-graduate's education (adjusted relative risk, 2.5; 95
      percent confidence interval, 1.4 to 4.4); and being a former husband, estranged
      husband, or former boyfriend (adjusted relative risk, 3.5; 95 percent confidence
      interval, 1.5 to 8.3). CONCLUSIONS: Women at greatest risk for injury from
      domestic violence include those with male partners who abuse alcohol or use
      drugs, are unemployed or intermittently employed, have less than a high-school
      graduate's education, and are former husbands, estranged husbands, or former
      boyfriends of the women.

PMID- 10601510
TI  - Violent injuries among women in an urban area.
AB  - BACKGROUND: Although the rate of death from injuries due to violent acts is much
      higher among black women than among white women in the United States, little is
      known about the nature and correlates of violent injuries among black women
      living in urban areas. METHODS: In this case-control study conducted at three
      emergency departments in one inner-city community (in west Philadelphia), we
      studied 405 adolescent girls and women who had been intentionally injured and 520
      adolescent girls and women (control subjects) who had health problems not related
      to violent injury. Data were collected by conducting standardized interviews with
      use of questionnaires and by screening urine for illicit drugs. Individual
      logistic-regression models were constructed to identify factors associated with
      violent injuries inflicted by partners and those inflicted by persons other than
      the partners of the victims. RESULTS: The male partners of the injured women were
      much more likely than the male partners of control subjects to use cocaine (odds
      ratio, 4.4; 95 percent confidence interval, 2.3 to 8.4) and to have been arrested
      in the past (odds ratio, 3.1; 95 percent confidence interval, 1.8 to 5.2). Fifty
      three percent of violent injuries to the women had been perpetrated by persons
      other than their partners. Women's use of illicit drugs and alcohol abuse were
      factors associated with both violence on the part of partners and violence on the
      part of other persons. Neighborhood characteristics, including low median income,
      a high rate of change of residence, and poor education, were independently
      associated with the risk of violent injuries among women. CONCLUSIONS: Women in
      this urban, low-income community face violence from both partners and other
      persons. Substance abuse, particularly cocaine use, is a significant correlate of
      violent injuries. Standard Census data may help identify neighborhoods where
      women are at high risk for such violence and that would benefit from community
      level interventions.

PMID- 10601511
TI  - Infections in patients with diabetes mellitus.

PMID- 10601512
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 38-1999. A 62-year-old woman with an infected right foot and
      aneurysmal dilatation of a femoral artery.

PMID- 10601513
TI  - Caring for the dying--congressional mischief.

PMID- 10601514
TI  - Choosing the best initial therapy for HIV-1 infection.

PMID- 10601515
TI  - Violence against women--a challenge to the Supreme Court.

PMID- 10601516
TI  - Correction: Chest Pain with a Surprising Course.

PMID- 10601517
TI  - Executives with white coats--the work and world view of managed-care medical
      directors. First of two parts.

PMID- 10601518
TI  - Techniques for MR Imaging of Joints in Sports Medicine.
AB  - Technical advances in MR imaging of sports-related bone and joint derangement
      have improved our ability to evaluate these problems. This article discusses
      current utilization of MR imaging, advances in local coils, pulse sequences and
      parameters, and reviews current aspects and indications for MR arthrography.

PMID- 10601519
TI  - Laparoscopic colon and rectal surgery.
AB  - There are disparate variables available to appraise the quality of the
      laparoscopic colorectal surgery. Currently available data suggest that
      laparoscopic colectomy can be completed safely in most cases. It is feasible and
      offers patient-related benefits similar to those described for other laparoscopic
      procedures. The framework, within which the quality of laparoscopic colon and
      rectum surgery is appraised and judged, is discussed with an emphasis on diverse
      outcomes used to measure quality.

PMID- 10601520
TI  - The surgeon as a prognostic factor in endocrine surgical diseases.
AB  - As with all subspecialties, the endocrine surgeon offers more than just improved
      technical expertise in the treatment of endocrine surgical disease. An
      understanding of the disease, and an ability to interpret investigations and
      surgically intervene with minimal morbidity allow for better patient care.
      Outcomes of endocrine surgical diseases are measured by the success of the
      operation at relieving the endocrinopathy and the ability of the surgeon to find
      the tumor, while at the same time minimizing the postoperative morbidity. Each of
      these factors has been considered when assessing the role of specialized
      expertise in endocrine surgical disease. The recurrence and survival data for
      these tumors, however, are not forthcoming and, therefore, the limitations of the
      existing literature must be acknowledged.

PMID- 10601521
TI  - Quality of follow-up of the cancer patient affecting outcome.
AB  - It has been traditional to follow up patients after surgery for primary
      colorectal cancer for approximately 5 years. The indications and rationale for
      this type of follow-up are early detection of recurrent disease while still at a
      presymptomatic stage, recognition of a metachronous tumor that might develop in
      the remaining large bowel, psychological support for the patient, and
      facilitation of audit to determine outcome in patients randomized into clinical
      trials. This article reviews the evidence supporting the benefits or otherwise
      careful follow-up following surgery for colorectal cancer. A possible
      surveillance regimen involving liver scanning is suggested.

PMID- 10601522
TI  - Outcome after resection of a solid tumor: volume, specialization, or both?
AB  - The outcome following surgery for resection of a solid tumor depends on a number
      of factors including patient comorbidity, stage of the disease, and surgical
      expertise. Each of these aspects must be considered when outcome data are being
      assessed. This multifactorial concept makes the relative importance of volume and
      specialization difficult to assess for individual patients. This article
      investigates the role of volume and specialization in determining outcome
      following solid tumor resection.

PMID- 10601523
TI  - The German experience: the surgeon as a prognostic factor in colon and rectal
      cancer surgery.
AB  - The data of the German prospective multicenter study of the Study Group for Colo
      Rectal Carcinoma (SGCRC) were analyzed by uni- and multivariate methods with
      regard to surgeon-related prognostic factors. The parameters were frequency of
      intraoperative local tumor spillage, surgical volume, and department and surgical
      quality group. The results obtained from the data of the SGCRC implicate
      consequences for analyses and comparisons of therapy results and studies on
      adjuvant therapy in colon and rectal cancer. All identified prognostic factors
      must be regarded and respectively considered in study designs. Colon and rectal
      cancer patients must also be distinguished and separate analyses are necessary
      for these.

PMID- 10601524
TI  - Quality of cancer surgery: challenges and controversies.
AB  - It is generally accepted that the quality of cancer surgery delivered to a
      patient impacts the patient's overall prognosis significantly. Often, the fact
      that all surgery and surgeons are not equal is not considered. Furthermore, it
      should not be assumed that surgeons who perform a particular operation frequently
      perform it better. Using breast cancer, melanoma, and colorectal cancer as
      examples, this article illustrates that proper surgical education and training
      are paramount in assuring that both the selection and delivery of a particular
      procedure is appropriate in the management of cancer.

PMID- 10601525
TI  - Virtual reality in surgical training.
AB  - Virtual reality in surgery and, more specifically, in surgical training, faces a
      number of challenges in the future. These challenges are building realistic
      models of the human body, creating interface tools to view, hear, touch, feel,
      and manipulate these human body models, and integrating virtual reality systems
      into medical education and treatment. A final system would encompass simulators
      specifically for surgery, performance machines, telemedicine, and telesurgery.
      Each of these areas will need significant improvement for virtual reality to
      impact medicine successfully in the next century. This article gives an overview
      of, and the challenges faced by, current systems in the fast-changing field of
      virtual reality technology, and provides a set of specific milestones for a truly
      realistic virtual human body.

PMID- 10601526
TI  - How does human error affect safety in anesthesia?
AB  - Anesthesia morbidity and mortality, while acceptable, are not zero. Most mishaps
      have a multifactorial cause in which human error plays a significant part. Good
      design of anesthesia machines, ventilators, and monitors can prevent some, but
      not all, human error. Attention to the system in which the errors occur is
      important. Modern training with simulators is designed to reduce the frequency of
      human errors and to teach anesthesiologists how to deal with the consequences of
      such errors.

PMID- 10601527
TI  - Influence of surgery on outcomes in gastric cancer.
AB  - Surgery is the only possible curative treatment for gastric cancer. Although
      outcomes over the years have improved, there are still many controversies in the
      treatment of gastric cancer. One highly controversial topic is the extent of the
      operation. Results of recently performed large randomized studies may cause some
      policies to change. This article addresses the influence of surgery on outcomes
      of D1-D2 dissections, total versus subtotal gastrectomy, and pancreas and spleen
      resection and staging. Furthermore, several aspects of patient selection, the
      surgeon as a prognostic factor, noncurative treatment, and chemotherapy are
      discussed.

PMID- 10601528
TI  - The surgeon's role in outcome in contemporary breast cancer.
AB  - Details of surgical removal of invasive breast cancer do not govern survival or
      cure. They do, however, control local recurrence rates and regional recurrence
      risk. The surgeon's role in breast cancer in the new millennium is to produce a
      cosmetic and functional result that is as good as possibly can be achieved while
      minimizing recurrence. Guidelines for incision placement, tissue volume removal,
      and nodal removal are critical determinants of cosmetic and functional outcome
      and need to be appreciated by surgeons.

PMID- 10601529
TI  - The surgeon as a prognostic factor in the management of pancreatic cancer.
AB  - Improved results for pancreatic resection have been attributed to the
      concentration of pancreatic surgery in high-volume centers. The evidence
      supporting a relationship between hospital case volume and operative mortality
      for pancreatectomy is reviewed. The surgeon's case volume does not appear to
      influence mortality independently, but other surgeon-related characteristics,
      like specialized training, have not been examined. More research is needed to
      elucidate the factors that have contributed to reduced mortality for this complex
      surgery.

PMID- 10601530
TI  - Index

PMID- 10601531
TI  - TNF-alpha and hypermetabolism in chronic obstructive pulmonary disease.

PMID- 10601532
TI  - The impact of malnutrition on the quality of life in the elderly.
AB  - Malnutrition is a frequent condition, both widely represented in geriatric
      population and underestimated in diagnostic and therapeutic work-up, and is known
      to affect health status and life expectancy of elderly people. The unexpected
      weight loss is a pathological condition, recently classified in three different
      ways (sarcopenia, wasting and cachexia) according to criteria of nutritional
      intake, functional abilities and age-related body composition modifications, that
      is caused by social psychological and medical factors. In this review, the
      authors highlight the ways that, through malnutrition, could lead to an
      impairment of quality of life in elderly people. Notwithstanding the great
      impreciseness and confusion that surrounds the term 'quality of life', the
      authors focus their attention on the correlation existing with the recently
      occurring changes to patients' health status and life-style, analysing the
      relationship with frailty, failure to thrive and homeostatic balance failure
      syndrome. With the latter term, the authors introduce a pathological condition
      widely represented in the late stages of malnutrition that often evolves in
      multiple organ failure and lastly in the death.

PMID- 10601533
TI  - Increased resting energy expenditure is related to plasma TNF-alpha concentration
      in stable COPD patients.
AB  - The objective of this study was to test whether increased resting energy
      expenditure (REE) in chronic obstructive pulmonary disease (COPD) patients is
      related to increased cost of breathing and/or to increased cytokine production.
      In 36 non-inflammatory (CRP: 17.6 +/- 13.1 mg.l(-1), mean +/- SD; orosomucoid:
      0.71 +/- 0.18 g.l(-1)), non-malnourished (BMI: 23.6 +/- 4.3 kg.m(-2)), clinically
      stable, non severely hypoxic COPD patients (60.5 +/- 8.9 years) we measured REE,
      pulmonary function and plasma cytokine concentrations (TNF-alpha, IL1 and IL6).
      REE was increased by 10 +/- 11% (P< 0.001) above predicted values. Plasma TNF
      alpha concentration was increased in all patients (mean value 26.3 +/- 14.3
      pg.ml(-1)). Excess REE (with respect to values predicted by Harris-Benedict
      equations) was correlated with plasma TNF-alpha concentration (P< 0.005), but not
      with the degree of airway obstruction, lung overinflation, or with oxygen cost of
      breathing. Theophylline treatment resulted in a significant increase in REE by
      15%. IN CONCLUSION: non-malnourished, clinically stable, non-severely hypoxic
      COPD patients display an increased REE that is related with plasma TNF-alpha
      concentration (without apparent systemic inflammation) and to theophylline
      treatment, but that is independent of parameters of respiratory function.

PMID- 10601534
TI  - Different patterns of chronic tissue wasting among patients with chronic
      obstructive pulmonary disease.
AB  - BACKGROUND & AIMS: Nutritional depletion is frequently present in patients with
      chronic obstructive pulmonary disease, but it is unknown whether a difference
      exists between the two subtypes. The aim of this study was to determine whether
      patterns of tissue depletion were different between emphysema and chronic
      bronchitis patients and whether these were related to pulmonary function.
      METHODS: In 99 severe COPD patients and 28 healthy volunteers, body weight and
      composition were assessed by dual-energy X-ray absorptiometry. Patients were
      stratified into chronic bronchitis (n=50) and emphysema (n=49) by high-resolution
      computed tomography. RESULTS: Lean mass depletion was found in 37% of the
      emphysema patients and in 12% of the chronic bronchitis patients. The emphysema
      patients had lower values for body mass index than the other groups (P< 0.01),
      mainly due to a lower lean mass (P< 0.01) and bone mineral content (P< 0.01). Fat
      mass was also lower in the emphysema group compared to the chronic bronchitis
      group (P< 0.001). The chronic bronchitis patients had a higher fat mass (P< 0.05)
      and a lower bone mineral content (P< 0.01) than the healthy volunteers.
      CONCLUSIONS: Substantial differences in body composition were found not only
      between chronic obstructive pulmonary disease patients and healthy volunteers,
      but also between chronic bronchitis and emphysema patients.

PMID- 10601535
TI  - Lifestyle changes in free-living patients with peripheral vascular disease
      (Fontaine stage II) related to plasma and LDL lipid composition: a 15 month
      follow-up study.
AB  - Peripheral vascular disease (PVD) is characterized by arteriosclerosis and lower
      extremity ischemia which cause intermittent claudication. Patients grouped in the
      Fontaine stage II have more than 75% organic stenosis in their large coronary
      arteries and exhibit a number of alterations in blood coagulation and plasma
      lipids. The aim of this study was to evaluate an intervention program of
      lifestyle habits including dietary recommendations, moderate exercise and
      decreased smoking in a population of patients with PVD for a period of 15 months,
      with respect to plasma-lipid and lipoprotein composition as well as LDL
      susceptibility to peroxidation. These parameters are well known risk indicators
      of arteriosclerosis and coronary heart disease. A total 13 subjects diagnosed
      with PVD (Fontaine stage II) were selected, while a healthy age-matched group
      (n=20) was used as a reference. This study design was an uncontrolled trial of
      lifestyle interventions. The group of patients was examined at 0, 3, 6, 9, 12 and
      15 months. Patients smoking one or more packets of cigarettes per day at the
      beginning of the study (54.2%) decreased smoking by as much as 7.7% 15 months
      later. In addition, physical activity intensified significantly (walking > 1 km:
      13.1-77%) and treadmill running increased over the study period while the energy
      intake decreased by 10%. The percentage of saturated fat in the diet decreased by
      10% while the intake of polyunsaturated fat rose, and monounsaturated-fat intake
      showed a parallel trend to increase; the average intake of cholesterol also fell
      by 10% and plasma triglycerides and HDL-cholesterol showed a trend to decrease
      and increase, respectively. No permanent changes in LDL lipid fractions for
      patients were detected during the follow-up period and no differences between
      patients and the age-matched reference group were found. The macrophage uptake of
      plasma-oxidized LDL was significantly higher in patients than in the reference
      group and no differences due to the intervention period were detected. In
      conclusion, the education in lifestyle and nutritional habits of patients with
      PVD led to reduced energy intake parallel with augmented physical activity as
      well to a fall in plasma triglycerides and a rise in HDL-cholesterol, which are
      good indicators of a reduced risk of vascular and myocardial complications.

PMID- 10601536
TI  - Trophic response of the intestinal mucosa to inflammation in rats injected with
      turpentine: a study using pair-fed controls.
AB  - The effects of restricted food intake and acute inflammation on the small bowel
      were studied, Wistar rats (250 g) were given subcutaneous injections of
      turpentine (TR) and compared to two control groups, at 18, 42 and 66 h. One was
      fed ad libitum (C), the other was pair fed (PF) with TR. The TR and PF rats
      showed hypoplasia of the jejunal mucosa with decreased protein and DNA contents
      at 42 h and 66 h. The hypoplasia resulted in a reduced villus height that was
      significantly different from the controls at 66 h (C: 468 +/- 17, TR[66] : 376 +/
      20, PF[66] : 258 +/- 2.9 microm, P<0.001). This decrease in villus height was
      significantly greater in the PF rats than in the TR rats at 66 h. The crypt
      height/villus height (C/V) ratio in the PF rats was greater than in the TR group
      at all times. However, the protein and DNA contents in the TR group were
      significantly higher than in the PF group at 42 h and 66 h (TR/PF[42] : 29.5 +/-
      1.9 vs 20.5 +/- 2.0, P< 0.001, [66]: 25.8 +/- 2.0 vs 16.6 +/- 1.3 mg/10 cm, P,<
      0.001). Disaccharidase activities (sucrase and glucoamylase) per 10 cm jejunum at
      66 h were significantly lower in the PF group than in the control and TR groups
      (sucrase mU/10cm[66] C : 3090 +/- 144, TR 2683 +/- 479, PF 1969 +/- 144, P,<
      0.001; glucoamylase mU/10 cm[66] 237 +/- 25, TR 169 +/- 40, PF 123 +/- 5, P<
      0.01). The N-aminopeptidase patterns in the TR and PF groups were similar. These
      data suggest that dietary restriction during acute inflammation is the main
      factor causing hypoplasia of the jejunal mucosa. However, acute inflammation has
      a trophic effect on the morphological and function of the mucosa. This effect is
      probably due to inflammatory mediators, whose synthesis is stimulated by
      turpentine.

PMID- 10601537
TI  - Effect of glucose to fat ratio on energy substrate disposal in children with
      cystic fibrosis fed enterally.
AB  - High fat containing diets lower VCO(2)in patients with impaired pulmonary
      function fed at a high level of energy intake. We tested the effect of a high fat
      enteral nutrition on VCO(2)and substrate oxidation in cystic fibrosis patients
      fed enterally 130% RDA. VCO(2)and substrate oxidation were studied in a group of
      eight 6-19 year old patients while receiving for 1 month and in a random order
      isocaloric (1000 kcal/m(2)), isonitrogenous enteral diet with a normal fat and a
      high fat content (40% and 67% of non-protein energy intake). Substrate oxidation
      and net balance were estimated using indirect calorimetry at the end of each
      study period. Overnight high fat enteral infusion resulted in no significant
      change in VCO(2)and VO(2)but lowered RQ (0.84 +/- 0.01 vs 0.88 +/- 0.01, P= 0.02)
      and non-protein RQ (0.83 +/- 0.01 vs 0.88 +/- 0.01). In spite of a higher glucose
      oxidation rate (8.1 +/- 0.5 vs 6.3 +/- 0.5 g. h(-1), P= 0.04), glucose net
      balance was significantly higher during normal fat formula administration (+2.5
      +/- 0.8 v -0.3 7plusmn; 0.7 g/h, P< 0.05). The present study failed to show any
      benefit of a high fat diet on VCO(2)in non oxygenodependant cystic fibrosis
      children and adolescents fed slightly above RAD. Normal fat enteral formula led
      to higher glycogen repletion.

PMID- 10601538
TI  - Glutamine effects on permeability and ATP content of jejunal mucosa in starved
      rats.
AB  - INTRODUCTION: Starvation induces an increase in intestinal permeability that can
      be of importance to intestinal integrity. Glutamine is the principal energy
      source for intestinal enterocytes and is considered essential for gut metabolism,
      structure and function. The aim of this study was to investigate whether
      glutamine could improve the ATP content of the mucosa of starved rats and
      attenuate the permeability perturbation during incubation in vitro in Ussing
      chamber. METHODS: Segments of jejunum from rats starved for 48 h were mounted in
      Ussing chambers. Glutamine was added to Krebs-buffer at 0.6mM, 3mM, 6mM and 30mM
      concentrations on the mucosal side. Cr-EDTA permeation, ATP content of the
      epithelium mucosa and electrophysiology were studied during 180 min of incubation
      in Ussing chambers. RESULT: These was a negative linear correlation between ATP
      content and(51)Cr-EDTA permeability in stripped mucosa. ATP content was reduced
      in all groups during the experiment. When 30 mM glutamine was added on the
      mucosal side there was an increase in(51)Cr-EDTA permeability (P< 0.001). There
      was no effect of glutamine on transepithelial resistance but higher
      concentrations of glutamine (>3mM) significantly increased the short circuit
      current. CONCLUSION: Supplementing glutamine to the mucosal side in the Ussing
      chamber led to an increase in ion pump activity and to an increase in
      paracellular permeability at the 30mM glutamine concentration. Glutamine did not
      restore the intracellular ATP level. The increase in permeability was inversely
      correlated to the mucosal ATP content.

PMID- 10601539
TI  - Nutritional and clinical efficacy of ornithine alpha-ketoglutarate in severe burn
      patients.
AB  - Ornithine alpha-Ketoglutarate (OKG) displays anabolic and anticatabolic
      properties in situations of stress. However, studies including both biological
      and clinical end points are scarce. In this prospective, randomized and double
      blind study, 60 patients who had undergone severe burns (20-60% of body surface
      area) received either ornithine alpha-ketoglutarate (20 g/day) or an isocaloric
      placebo, for 21 days, starting mean 4 days after injury. In the OKG group,
      nitrogen balance reached positive values at d5 and stabilized at higher levels vs
      controls (P< 0.05 or less from day 3 to day 21), resulting in a strongly positive
      cumulated nitrogen balance at day 21 (mean +/- SEM, OKG group: +127 +/- 13;
      CONTROL GROUP: -63 +/- 18g nitrogen). As measured at day 21, transthyretin and
      RBP levels were higher in the OKG group (respectively 259 +/- 9 vs 161 +/- 10,
      and 45 +/- 1 vs 33 +/- 1 mg/l, P< 0.001). Body weight loss was counteracted at
      d21 in the OKG group (-2.6% vs -6.3%, P< 0.001). Assessment of the quality of
      wound healing using objective scoring showed better performances in the OKG group
      (P< 0.05). The results suggest that improvement in nutritional parameters
      observed during the treatment of burn-injured patients with ornithine a
      ketoglutarate allows better clinical recovery.

PMID- 10601540
TI  - Low levels of glutathione in endoscopic biopsies of patients with Crohn's
      colitis: the role of malnutrition.
AB  - BACKGROUND AND AIMS: During active Crohn's disease, generation of free radicals
      is increased, and nutritional depletion is frequent. We investigated the
      glutathione concentration of the colonic mucosa in biopsies from patients with
      active Crohn's colitis depending on nutritional status. METHODS: Endoscopic
      biopsies were taken in 10 well-nourished control patients, and 18 patients with
      active Crohn's disease (11 well-nourished, seven malnourished with a recent
      weight loss > 10 %). Colonic biopsies were taken from healthy and inflamed mucosa
      and analysed for total glutathione concentration. RESULTS: Mucosal glutathione
      concentration (nmol/mg wet tissue) was lower in patients with active colitis both
      in diseased and healthy mucosa as compared with controls (1.89 +/- 0.39, 2.08 +/-
      0.4 and 6.69 +/- 4. 94, respectively, P< 0.05). Mucosal glutathione was lower in
      healthy mucosa from malnourished versus well-nourished patients: 1.8 +/- 0.2 vs
      2.3 +/- 0.37 (P= 0.02). CONCLUSIONS: Mucosal glutathione is markedly lower in
      active Crohn's colitis, even in healthy mucosa; glutathione depletion tends to be
      more severe in malnourished patients. Glutathione depletion may be related in
      part to malnutrition and contribute to a prolonged evolution of disease and could
      be a target for pharmacological and nutritional support.

PMID- 10601541
TI  - Lipoprotein(a) and other lipoproteins in hypothyroid patients before and after
      thyroid replacement therapy.
AB  - AIMS: To analyse the influence of thyroid hormones on serum lipoprotein(a)
      (Lp(a)) concentration and other lipid parameters, and hence potentially on
      coronary artery disease (CAD) risk. METHODS: Thirty-six patients with
      hypothyroidism and 165 age-matched control euthyroid subjects were evaluated in a
      cross- sectional study, determining thyroid function tests and fasting serum
      lipids and lipoproteins. In a follow-up study for those hypothyroid patients the
      same determinations were repeated after normalization of thyroid state by
      levothyroxine (L-T(4)) replacement therapy. Patients needing other treatments
      were excluded. At baseline, patients with hypothyroidism had significantly higher
      levels of Lp(a), total cholesterol (TC), low-density lipoprotein cholesterol (LDL
      C), apolipoprotein (apo) A-I and apo B, and a higher TC/high-density lipoprotein
      cholesterol (HDL-C) ratio than control subjects. RESULTS: Severity of the
      hypothyroid state, expressed by serum thyroid-stimulating hormone, was correlated
      with serum levels of Lp(a), LDL-C, and TC (r= 0.64, 0.52, 0.49, P= 0.005, P=
      0.033, P= 0. 048, respectively). The pretreatment Lp(a) levels were also
      correlated with those of posttreatment Lp(a)(r= 0.68, P= 0.002). All patients,
      who presented basal Lp(a) levels higher than 30 mg/dl, showed a decrease in Lp(a)
      concentrations by L-T(4)therapy, and these normalized in eight cases (22.2%).
      Euthyroid state gave rise to a significant reduction of serum Lp(a) by 32.3%, of
      LDL-C by 22. 8%, of TC by 17%, of apo A-I by 9.6%, and of apo B by 9.3%. After L
      T(4)therapy, CAD risk, expressed as TC/HDL-C ratio, decreased by 19.9%.
      CONCLUSIONS: These results show that hypothyroidism is associated not only with
      elevated serum levels of LDL-C but also with elevated serum Lp(a) concentrations.
      Lp(a) levels may be at least partially modulated by thyroid hormone-dependent
      mechanisms, thus increasing the risk of developing premature atherosclerosis in
      hypothyroid state, that might be reduced by L-T(4)therapy.

PMID- 10601542
TI  - Sensitivity and limitations of high throughput fluorescent microsatellite
      analysis for the detection of allelic imbalance: application in lung tumors.
AB  - We have used two hexaplex fluorescent microsatellite assays and analysis on an
      automatic sequencer to determine allelic imbalance in lung tumors. The markers
      used are located close to tumor-suppressor genes, DNA repair genes and regions
      frequently lost in lung cancer. We present a reference interval and quantify the
      reproducibility of the assays as assessed by multiple repeat reactions for normal
      DNAs. The cut-off value was calculated to 0.77 (23% reduction of one allele
      intensity) which, to the best of our knowledge, is currently the lowest reported
      cut-off. Using these parameters we analysed 85 lung carcinomas. Eighty-three
      samples (97.6%) showed allelic imbalance in at least one locus. It is of note
      that by using a selection of only 6 markers, imbalance was detected in 81 (95.2%)
      of the samples. Loci 9p21 and 9p23 exhibited the greatest imbalance (77% and 75%
      respectively). The fractional allele loss (FAL) for the 3p markers examined was
      greater in squamous cell carcinomas than adenocarcinomas (t-test, p=0.0001) while
      no such difference was observed for 9p. The degree of imbalance of different
      markers within the same sample was divergent, indicating heterogeneity of genomic
      status (losses, amplifications, aneuploidy) in these tumors. In conclusion, we
      have established a robust experimental platform with high throughput, sensitivity
      and specificity for the detection of allelic imbalance in lung tumors. Such
      assays may be useful for the detection of allelic imbalance in clinical samples
      to trace genetically abnormal cells and thus assist in the identification of
      individuals at a high risk for developing lung cancer.

PMID- 10601543
TI  - Aneuploidy of sex chromosomes in basal cell carcinoma: its clonality and
      involvement in the development of carcinogenesis.
AB  - Although basal cell carcinoma (BCC) is a major skin cancer, the mechanism of
      carcinogenesis with regard to cytogenetic abnormalities has not been fully
      investigated. In the present study, we carried out cytogenetic analyses of 18
      patients (9 male and 9 female) with BCC. Aneuploidy was seen by Q-banding method
      in more than half of the cases and was mostly loss of the sex chromosome. We also
      performed FISH to the interphase nuclei of various tissues and short-term
      cultured BCC cells. The frequency of sex chromosomal aneuploidy was significantly
      higher in all samples from BCC patients (peripheral blood lymphocytes, non
      lesional tissues, BCC tumor tissues and cultured BCC cells) than in age-matched
      normal controls. In addition, we analyzed clonality of BCC tissues using a human
      androgen receptor gene assay and found uniparental pattern of inactive X
      chromosomes. This indicates that BCC cells were monoclonal in origin and the
      development of BCC might be correlated with sex chromosomal aneuploidy, which
      acquired accumulation of genetic mutations.

PMID- 10601544
TI  - A pilot study of the effects of short-term tamoxifen therapy on Ki-67 labelling
      index in women with primary breast cancer.
AB  - In this study we demonstrate the change in estrogen receptor (ER) level and cell
      proliferation in human breast cancer after a short-term tamoxifen therapy. Ten
      pre- and post-treatment breast tumor samples were examined immunohistochemically
      using ER and Ki-67 antibodies. Before tamoxifen treatment, six (60%) of ten
      patients were positive for ER. Tamoxifen increased the ER level in one patient
      and decreased the level in 4 patients. There was no significant change in ER
      level by tamoxifen therapy. On the other hand, Ki-67 labelling index (LI)
      significantly decreased after tamoxifen treatment. When Ki-67 LI was analyzed
      according to ER level, there was no difference between pre- and post-tamoxifen
      treatment in ER-negative patients, however, a significant decrease of Ki-67 LI by
      tamoxifen treatment was seen in ER-positive patients. Patients who showed down
      regulation of ER expression tended to show a decrease of Ki-67 LI after tamoxifen
      therapy. In conclusion, short-term tamoxifen therapy decreased the proliferation
      of breast cancer, in ER-positive breast tumor samples.

PMID- 10601545
TI  - Association of telomerase expression with successful heterotransplantation of
      lung cancer.
AB  - This study analyzed whether the expression of telomerase may serve as prognostic
      factor for the aggressiveness of human non-small cell lung carcinomas. To this
      purpose the expression of telomerase measured by immunohistochemistry was
      compared with the take rate of the primary tumors that were heterotransplanted
      into nude mice. Formalin-fixed, paraffin-embedded specimens of 97 non-small cell
      lung carcinomas from primarily untreated patients were analyzed for the
      expression of telomerase by a goat polyclonal antibody (clone C-20). Moderate or
      strong telomerase-staining was found in 78 (80%) cases. Age, gender, stage and
      histology had no influence on the telomerase expression. It was discovered that
      of the 19 telomerase-negative carcinomas only five (26%) exhibited growth in nude
      mice while of the 78 telomerase-positive cases 37 (47%) were successfully
      transplanted. To confirm these results, alcohol-fixed, paraffin-embedded cancer
      specimens from another group of patients (n=58) were analyzed for telomerase
      expression by a rabbit polyclonal antibody (clone H-231). Corresponding results
      were obtained. The take rate of telomerase-negative carcinomas was only 36%; the
      take rate of telomerase-positive carcinomas was 59%. These data suggest that high
      telomerase expression does indeed correlate with the aggressiveness of non-small
      cell lung carcinomas.

PMID- 10601546
TI  - Auto-induction and growth stimulatory effect of betacellulin in human pancreatic
      cancer cells.
AB  - Betacellulin (BTC) was identified in mouse pancreatic beta cell tumors as a
      member of the epidermal growth factor (EGF) family, and was found to bind and
      activate the EGF receptor. BTC is also expressed in some human malignancies and
      may have an important role in tumor growth progression. We examined whether BTC
      and EGF have a growth stimulatory effect on human pancreatic cancer cell lines
      both in vitro and in vivo. We also investigated the BTC expression and autonomous
      induction of BTC in pancreatic cancer cells. in vitro, both BTC and EGF had
      almost the same proliferative effect on Panc-1, MIA PaCa-2 and AsPC-1. in vivo,
      in a Panc-1 inoculated athymic mice model, BTC-treated tumors grew approximately
      five times larger than in control. Immunocytochemistry showed that BTC expression
      occurred in three pancreatic cancer cell lines, with MIA PaCa-2 showing the
      strongest intensity. Semi-quantitative RT-PCR of MIA Paca-2 showed that mRNA
      levels of BTC gradually increased after treatment with 1 nM BTC.
      Immunocytochemistry also demonstrated that the intensity of BTC-like
      immunoreactivity was increased when treated with 1 nM BTC but was reduced after
      treatment with 100 nM of AG1478, an EGF receptor tyrosine kinase inhibitor. BTC
      has thus a significant growth stimulatory effect on pancreatic cancer cells and
      might function as an autocrine and paracrine growth factor. BTC expression in
      pancreatic cancer cells is, at least in part, controlled by an auto-induction
      mechanism.

PMID- 10601547
TI  - Inhibition of azoxymethane-induced rat colon carcinogenesis by potassium hydrogen
      D-glucarate.
AB  - While calcium D-glucarate was shown to inhibit chemical carcinogenesis in various
      animal models, the effect of potassium hydrogen D-glucarate has not been
      extensively investigated. In the present study, potassium hydrogen D-glucarate
      markedly inhibited azoxymethane (AOM)-induced colon carcinogenesis in male F344
      rats. Potassium hydrogen D-glucarate (PHG) or potassium hydrogen carbonate (PHC)
      were administered to rats in a diet (140 mmol/kg). Continual post-initiation
      treatment with potassium hydrogen D-glucarate reduced both tumor incidence and
      multiplicity at sacrifice by ca. 60%, while PHC had no effect. amelioration of
      overexpression of the betaG gene in rat colon carcinomas was observed using RT
      PCR and Northern blot analysis. We hypothesize that previously demonstrated
      conversion of PHG to D-glucaro-1,4-lactone, a potent inhibitor of beta
      glucuronidase (betaG), may be responsible for this effect. The mechanism of PHG
      inhibition of colon carcinogenesis may also involve suppression of cell
      proliferation and possibly alterations in cholesterol synthesis or cholesterol
      metabolism to bile acids. In conclusion, PHG possesses excellent potential as a
      natural, apparently non-toxic inhibitor to prevent colon cancer.

PMID- 10601548
TI  - CEA immunohistochemical localization is correlated with growth and metastasis of
      human gallbladder carcinoma.
AB  - Carcinoembryonic antigen (CEA) is a good marker of colorectal cancer. Recent
      studies have demonstrated that CEA may function as a metastatic potentiator by
      different pathways; i.e., modulation of immune responses, facilitation of
      intercellular adhesion and cellular migration. However, expression patterns of
      CEA have not yet been established in human gallbladder carcinomas. In this study,
      we examined CEA expression in human gallbladder adenocarcinomas and its
      clinicopathological significance. CEA immunoreactivity was detected not only in
      the cancer cells (cytoplasmic type: 63.0%, 34/54) but also in the cancer stroma
      (stromal type: 29.6%, 16/54). According to TNM classification, 75.0% (30/40) of
      T2-4 gallbladder cancers showed cytoplasmic CEA, while 28.6% (4/14) of the T1
      cancers were cytoplasmic CEA-positive (p<0.05). Stromal CEA expression was
      detected in 40.0% (16/40) and none (0/14) of the T2-4 and T1 cancers,
      respectively (p<0.05). Lymph node metastasis was frequently found in the
      cytoplasmic CEA- and stromal CEA-positive gallbladder cancers (44.1% and 62.5%,
      respectively). These observations suggested that CEA expression plays important
      roles in cancer cell growth and metastasis of human gallbladder adenocarcinomas.

PMID- 10601549
TI  - Clinical significance of MUC1 and E-cadherin expression, cellular proliferation,
      and angiogenesis at the deepest invasive portion of colorectal cancer.
AB  - We examined MUC1 and E-cadherin expression, cellular proliferation, and tumor
      vascularization at the deepest invasive portion of colorectal cancer in relation
      to prognosis. One hundred and ten surgically resected specimens of advanced
      colorectal carcinoma were studied. E-cadherin and MUC1 expression and Ki-67
      labeling index (Ki-67 LI) were examined immunohistochemically at the site of
      deepest tumor invasion. Tumor vascularization was also examined
      immunohistochemically using anti-CD34 antibody to determine the microvessel count
      (MVC). In curative resection, patients with a high Ki-67 LI, reduced E-cadherin
      expression, MUC1-positive and high MVC lesion showed a significantly poorer
      prognosis than those with a low Ki-67 LI, E-cadherin normal, MUC1-negative and
      low MVC lesion, respectively. Furthermore, patients with both a high Ki-67 LI and
      MVC lesion showed a significantly poorer prognosis than those with other Ki-67 LI
      and MVC relations. Patients with both a MUC1-positive and E-cadherin reduced
      lesion showed a significantly poorer prognosis than those with both a MUC1
      negative and E-cadherin normal lesion. The significant risk factors in order of
      poorer prognosis by the multivariate analysis among these factors including
      routinely used clinicopathologic factors were the high MVC, E-cadherin reduced
      expression, and lymph node metastasis. These findings indicate a high MVC at the
      site of deepest tumor invasion to be the most important predictor of colorectal
      cancer prognosis among the factors studied here.

PMID- 10601550
TI  - Differentiation of human breast carcinoma cells by a novel vitamin D analog:
      1alpha-hydroxyvitamin D5.
AB  - The active metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D3, can induce
      differentiation in breast cancer cells; however, it is hypercalcemic in vivo.
      Therefore, development of non-calcemic analogs of vitamin D has received
      considerable attention. Recently, we synthesized an analog of vitamin D
      [1alpha(OH)D5] that exhibits much less calcemic activity than 1alpha,25
      dihydroxyvitamin D3. In this study, we evaluated the cell-differentiating action
      of 1alpha(OH)D5 in breast cancer cells. Following 10 days treatment with
      1alpha(OH)D5 [(10-7 M) in UISO-BCA-4], we observed induction of intracytoplasmic
      casein, intracytoplasmic lipid droplets, ICAM-1, nm23, and specific biomarkers
      associated with breast cell differentiation. 1alpha(OH)D5 treatment also showed
      induction of vitamin D receptor and TGFbeta1 proteins. UISO-BCA-4 cells
      pretreated for 10 days in vitro with 1 microM 1alpha(OH)D5 failed to form tumors
      when transplanted into athymic mice. Similarly, 4 and 8 ng 1alpha(OH)D5 treatment
      three times weekly inhibited the growth of UISO-BCA-4 cells injected into athymic
      mice. These results suggest that this new vitamin D analog may be of significant
      therapeutic value for breast cancer.

PMID- 10601551
TI  - Aberrant transcripts of FHIT, TSG101 and PTEN/MMAC1 genes in normal peripheral
      mononuclear cells.
AB  - Aberrant transcripts of FHIT and TSG101 using nested RT-PCR were reported in many
      human tumours. The role of these aberrant transcripts in tumourigenesis is not
      clear. We, therefore, analyzed the aberrant transcripts of FHIT, TSG101 and
      PTEN/MMAC1 in peripheral mononuclear cells of normal individuals using nested RT
      PCR to explore the role of these genes in cancer development. The results showed
      that there are at least five types of aberrant transcripts: type I is the
      deletion at junction located in-between normal exon and intron; type II has
      deletion of some bases and subsequent insertion of several bases in the deletion
      area; type III accommodates splicing donor or acceptor site-like sequence; type
      IV has homologous sequences near the deleted junction; and type V comprises the
      homologous sequences at the deletion junction. A normal healthy person can have
      more than one aberrant transcripts of FHIT, TSG101 and PTEN/MMAC1 genes. The size
      and the number of the transcripts vary and the diversity is unconstrained. It is
      not depended on the time, condition of the reaction, or the isolation method.
      From these results, we suggested that the aberrant transcripts of FHIT, TSG101
      and PTEN/MMAC1 genes may be the imperfect products of splicesome which occur one
      in every thousands, ten thousands or more. As a result, these data implied no
      direct association between the aberrant transcripts and tumourigenesis.

PMID- 10601552
TI  - Vaccination against human cancers (review).
AB  - Classical and molecular immunological means of active tumor-specific immunization
      against human cancers yielded whole cell or tumor cell lysate vaccines of
      preventive value (reduced relapse rates) and dendritic cell-peptide or
      genetically engineered vaccines that may induce remissions even in metastatic
      disease. Active tumor-specific immunization was often successful in the past 50
      years against experimental tumors maintained in the laboratory. During the epochs
      of classical and molecular immunology several vaccines were generated and used
      for the reduction of relapse rates of human cancer after surgical removal of the
      primary or metastatic tumors. Whole cell vaccines consist of X-irradiated
      autologous or allogeneic tumor cells coadministered with immunostimulants (BCG,
      Detox). Tumor cells haptenized biologically (as in viral oncolysates) or
      chemically were also used. Dendritic cell vaccines are prepared by transfection
      or transduction with tumor antigen-encoding DNA or by pulsing the cells with
      antigenic peptides in vitro; or collecting dendritic cells that engulfed
      apoptotic tumor cell DNA and/or peptide antigens in vivo for reinjection into the
      patient. Genetically engineered tumor cells are prepared in vitro to express MHC
      and peptides, costimulatory molecules (B7.1) and cyto- or lymphokines
      (interferons, interleukins, hematopoietic growth factors) for vaccination of
      patients. Antibody- and immune T cell-mediated immune reactions to autologous
      tumor cells are newly generated and/or quantitatively increased in immunized
      patients but do not always correlate with clinical response. Most vaccines are
      claimed to have reduced relapse rates presumably by inducing effective host
      immunity against micrometastases. Dendritic cell-peptide vaccines could induce
      partial or occasionally complete remissions in metastatic disease. The wrong
      antigenic presentation may result in tolerance induction toward the tumor;
      occasionally tumor enhancement may occur. Human tumor antigens when presented
      appropriately (with costimulatory molecules and with IL-2, IL-12) break the
      host's natural tolerance toward its tumor and induce rejection strength immune
      reactions even in patients with metastatic disease. Immune T cells thus generated
      could be collected for adoptive immunotherapy. For successful active specific
      immunization against human cancers the understanding of the immunoevasive
      maneuvers of the tumor cell (through FasL --> Fas; TRAIL; CD40L --> CD40; TGFbeta
      etc. systems) is essential.

PMID- 10601553
TI  - Electrochemotherapy with bleomycin against colorectal carcinoma in a mouse model:
      evaluations of the dose and administration route of the drug and the electric
      field intensity.
AB  - Effectiveness of electrochemotherapy against colorectal carcinoma (CRC) was
      evaluated in a mouse model. When mice with a subcutaneously established CRC tumor
      were administered intratumorally, intravenously or intraperitoneally with
      bleomycin (BLM) ranging from 1/50 to 1/2 of the 50% lethal dose, significant
      suppression of tumor development and even some cures were observed. When various
      electric field intensities ranging from 500 to 2,000 V/cm were applied for
      electrochemotherapy with BLM, all treatment protocols were similarly effective.
      Furthermore, when electrochemotherapy with the lowest dose of BLM and the lowest
      electric field intensity was repeated, complete cures of CRC were achieved in all
      animals.

PMID- 10601554
TI  - Cloning of a human hepatocyte growth factor/scatter factor transcription variant
      from a gastric cancer cell line HSC-39.
AB  - A new transcription variant of hepatocyte growth factor/scatter factor (HGF/SF)
      was cloned from human gastric cancer cell line HSC-39. Northern blot analysis of
      eight human gastric cancer cell lines (TMK-1, MKN-1, MKN-7, MKN-28, MKN-45, MKN
      74, KATO-III and HSC-39) demonstrated that HSC-39 cells expressed a 1.3 kb
      abnormal HGF/SF transcript. Screening of 1 x 10(6) colonies of cDNA library from
      HSC-39 constructed in pAP3neo mammalian expression vector selected four positive
      clones containing HGF/SF transcript. Among them, two contained a 1.3 kbp insert
      detecting the identical transcript to that obtained with HGF/SF probe by Northern
      blotting. Deoxynucleotide sequencing of the 1.3 kbp insert revealed that it was
      composed of a part of HGF/SF cDNA from exon 14 to exon 18, corresponding to the
      whole sequence of HGF/SF light chain, with 5' 75 nucleotides unrelated to any
      sequence involved in HGF/SF.

PMID- 10601555
TI  - Nitric oxide-mediated apoptosis in human breast cancer cells requires changes in
      mitochondrial functions and is independent of CD95 (APO-1/Fas).
AB  - We have previously shown that nitric oxide (NO) induces apoptosis in different
      human neoplastic lymphoid cells through caspase activation. Here we studied the
      NO-mediated apoptosis in human breast cancer cell lines derived from primary
      tumor (BT-20) or from metastasis (MCF-7). NO donor glycerol trinitrate (GTN)
      induced apoptosis in both cell lines which was completely abrogated after
      pretreatment with the broad spectrum caspase inhibitor zVAD-fmk. NO triggered
      also a time-dependent activation of caspase-1, caspase-3, and caspase-6 in these
      cells. Moreover, NO caused a release of mitochondrial protein cytochrome c into
      the cytosol, an increase in the number of cells with low mitochondrial
      transmembrane potential and with high level of reactive oxygen species
      production. However, NO did not induce mRNA expression of CD95 (APO-1/Fas)
      ligand. FAS-associated phosphatase-1 (FAP-1) molecule was constitutively
      expressed at the mRNA level and did not show any changes upon NO treatment in
      both breast cancer cell lines. The expression of the pro-apoptotic protein Bax
      and of the anti-apoptotic protein Bcl-2 remained unchanged in MCF-7 and BT-20
      cells upon GTN treatment. We suggest that the mechanism of NO-mediated activation
      of the caspase cascade and subsequent apoptosis in human breast cancer cells
      required mitochondrial damage (in particular, cytochrome c release, disruption of
      mitochondrial transmembrane potential and generation of reactive oxygen species)
      but not the activation of the CD95/CD95L pathway.

PMID- 10601556
TI  - Suppression of metastasis by tissue inhibitor of metalloproteinase-1 in a newly
      established human oral squamous cell carcinoma cell line.
AB  - We have established a highly-metastatic cell line (designated as HNOS) and a non
      metastatic cell line (designated as SAT) derived from human oral cavity squamous
      cell carcinoma (SCC). Both lines were transplantable in nude mice. The invasive
      activity through Matrigel-coated membrane of HNOS cells was also higher than that
      of SAT cells. mRNA of TIMP-1 was expressed in SAT cells but not in HNOS cells.
      Metastatic and invasive abilities were suppressed by the overexpression of TIMP-1
      in HNOS cells. These results suggest that TIMP-1 may have an important role in
      inhibiting invasion and metastasis of human oral cavity SCC.

PMID- 10601557
TI  - Comparison of action of paclitaxel and poly(L-glutamic acid)-paclitaxel conjugate
      in human breast cancer cells.
AB  - The new anticancer agent poly(L-glutamic acid)-paclitaxel (PG-TXL) is a conjugate
      of paclitaxel and the water-soluble polyglutamate carrier. The observation that
      PG-TXL appears to possess antitumor activity superior to free paclitaxel in
      preclinical studies suggests that PG-TXL might possess favorable pharmacokinetic
      properties and/or have a mechanism of action different from that of paclitaxel.
      The purpose of this study was to compare the pharmacological action of PG-TXL and
      free paclitaxel in a panel of breast cancer cell lines with emphasis on their
      ability to induce apoptosis, their effects on cell cycle progression, and their
      cellular uptake. Morphological analysis and biochemical characterizations
      demonstrated that both compounds have similar abilities to induce apoptosis in
      cells expressing wild-type p53 (MCF-7) or mutant p53 (MDA-MB435 and MDA-MB453).
      Although MCF-7 cells were less sensitive to each compound than MDA-MB435 and MDA
      MB453 cells, transfection experiments demonstrated that p53 did not appear to
      play a significant role in drug-induced cell death with either agent. Flow
      cytometry analysis further revealed that both free paclitaxel and PG-TXL induced
      a characteristic G2/M arrest in the cell cycle, consistent with the disturbance
      of microtubule polymerization as their mechanism of action. Western blot analysis
      showed that paclitaxel and PG-TXL downregulated HER2/neu expression in a similar
      fashion. HPLC analysis revealed that paclitaxel was released from the PG-TXL
      conjugate in vitro. The released paclitaxel, not the glutamic acid polymer, was
      subsequently transported into the cells. These results suggest that PG-TXL exerts
      its anticancer activity by continuous release of free paclitaxel, and that the
      favorable pharmacokinetics and drug distribution of the PG-TXL conjugate in vivo
      are likely the main factors contributing to its superior anticancer activity.

PMID- 10601558
TI  - The effect of mismatch repair deficiency on tumourigenesis; microsatellite
      instability affecting genes containing short repeated sequences.
AB  - We have investigated microsatellite instability (MSI) in colorectal, gastric,
      endometrial and ovarian cancer as a result of mismatch repair (MMR) deficiency.
      We detected frameshift mutations in several genes that carry short repeated
      sequences and are important in cell fidelity and growth control; hMSH3, hMSH6,
      BAX, IGFIIR, TGFbetaIIR, E2F4 and BRCA2. Accumulation of mutations was
      heterogeneous and mainly restricted to tumours showing MSI at several loci (MSI
      H). Both insertions and deletions were evident and occasional intratumour
      heterogeneity was evident with more than one different additional allele in the
      tumour. Most MSI-H tumours had acquired mutations in more than one gene and
      longer repeated sequences were more frequently targets for mutations. The
      TGFbetaIIR gene was mutated in 62%, the hMSH3 gene in 43%, the E2F4 gene in 35%,
      the hMSH6 in 32%, the BAX gene in 32%, the IGFIIR gene in 26%, and the BRCA2 gene
      in 2% of the MSI-H tumours. Homozygous mutations or mutation of both alleles were
      evident in all genes except BRCA2, in total 23/105 mutated cases, varying from 7%
      for BAX to 50% for E2F4. E2F4 mutations were exclusively found in colon tumours
      and E2F4 polymorphisms was found in 8% of cases. No difference in mutation
      prevalence was noted between cancer types apart from TGFbetaIIR mutations, which
      were frequently found in colon and gastric tumours but not in endometrial
      tumours, suggesting that endometrial tumours progress by a different route where
      TGFbetaIIR mutations are less favourable.

PMID- 10601559
TI  - Estrogen enhances induction of cytochrome P-4501A1 by 2,3,7, 8-tetrachlorodibenzo
      p-dioxin in liver of female Long-Evans rats.
AB  - A human carcinogen, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces liver
      tumors in female rats. In this study, we examined the effects of estrogen on an
      arylhydrocarbon receptor (AhR)-responsible protein, CYP1A1 expression induced by
      TCDD in female rat livers. The induction of CYP1A1 by a dose of 300 ng TCDD/kg
      and its resultant enzymatic activity were significantly enhanced by 5 microg
      17beta-estradiol/kg body weight treatment to both intact and ovariectomized rats.
      Immunoblot analysis showed a increase in nuclear AhR due to estrogen, TCDD or
      both, suggesting that estrogen is involved in the activation of CYP1A1 gene after
      the formation of AhR-TCDD complex.

PMID- 10601560
TI  - CEOP-B/VIMB vs. promace-CytaBOM in the treatment of intermediate or high grade
      non-Hodgkin's lymphoma: A randomised multicenter study of Southern Italy
      Cooperative Group.
AB  - From January 1992 to December 1995, 129 patients with previously untreated non
      Hodgkin's lymphoma were randomised in a phase III multicenter trial to receive
      CEOP-B/VIMB or ProMACE-CytaBOM. Eligibility criteria included intermediate or
      high grade lymphoma (follicular large cell, diffuse small cleaved-cell, diffuse
      mixed, diffuse large-cell and immunoblastic) with an Ann Arbor stage II bulky,
      III or IV. All patients entered into the study were considered evaluable
      according to intent to treat analysis. At a median follow-up of 60 months there
      were no significant differences between the treatment response rates [82% (60%CR)
      for CEOP-B/VIMB vs. 81% (69% CR) for ProMACE-CytaBOM]. Conversely, with regard to
      disease-free survival, a significant difference was observed between the two
      treatment arms (42% for CEOP-B/VIMB vs. 24% for ProMACE-CytaBOM at 5 years;
      p=0.046). However, this difference did not translate in a significant difference
      in overall survival (45% vs. 39% at 5 years). Moreover, when response rates and
      outcome were analysed for different prognostic subgroups according to
      International Prognostic Index, no significant differences were observed between
      the treatment groups. It is important to note that neither regimen was able to
      improve outcome of poor risk patients who fared badly with both treatments
      (median survival 9 and 8 months respectively). Toxicity was also similar in both
      treatments with grade 3-4 leukopenia observed in 39% and 47% of cases and grade 3
      4 thrombocytopenia in 24% and 27% of cases respectively. In conclusion, in this
      study CEOP-B/VIMB was not superior to ProMACE-CytaBOM in aggressive lymphomas and
      the alternating strategy failed to improve outcome of poor risk patients in which
      newer more aggressive treatments are needed.

PMID- 10601561
TI  - TGF-beta1 and IGF-1 expression are differently regulated by serum in metastatic
      and non-metastatic human breast cancer cells.
AB  - Transforming growth factor-beta (TGF-beta) exerts an inhibitory effect on
      epithelial cell proliferation while insulin-like growth factor-1 (IGF-1) is a
      positive regulator of proliferation and together they may participate in driving
      neoplastic progression. The regulation of TGF-beta1 and IGF-1 gene expression was
      analyzed in an in vitro model of an estrogen receptor positive (ER+), non
      metastatic (MCF-7) and an (ER-), metastatic (MDA-MB-435) breast cancer cell line,
      respectively. Our results indicate a loss of the regulation of TGF-beta1 and the
      gain of the expression and upregulation of IGF-1 pathways during malignant
      progression. These data demonstrate that two factors, convergent on cell growth,
      can have divergent roles in the regulation of the expression of TGF-beta1.

PMID- 10601562
TI  - Elevated GM-CSF levels in tumor bearing mice upregulate IL-6 production by B
      cells via a mechanism independent of TNF-alpha.
AB  - During mammary tumorigenesis a profound dysregulation of cytokine production by
      various lymphoreticular cells has been documented. B lymphocytes from tumor
      bearers have an increased production of tumor necrosis factor alpha (TNF-alpha).
      We now report that these lymphocytes have elevated levels of interleukin 6 (IL-6)
      at the transcriptional and translational levels, that are reflected systemically.
      The mammary tumor used in our study constitutively produces several factors
      including granulocyte-macrophage colony stimulating factor (GM-CSF),
      prostaglandin E2 (PGE2) and phosphatidyl serine (PS), which directly or
      indirectly can affect the cells of the immune system. in vitro addition of GM-CSF
      resulted in a dramatic increase in IL-6 levels from B cells from normal mice.
      This effect does not appear to be due to elevated levels of TNF-alpha, known to
      upregulate IL-6. Rather, GM-CSF activates IL-6 production independently of TNF
      alpha as demonstrated by neutralization studies using anti-TNF-alpha antibodies.
      Furthermore, the effect exerted by GM-CSF on IL-6 production by B lymphocytes
      appears to be direct since pretreatment of cultures with anti-GM-CSF completely
      abrogated the elevated production of IL-6. The elevated levels of IL-6 and TNF
      alpha in tumor bearers may contribute to the cachectic state observed in tumor
      bearing mice.

PMID- 10601563
TI  - Molecular profiling of sporadic colorectal tumors by microsatellite analysis.
AB  - To investigate the prognostic value of multiple genetic alterations, individual
      molecular tumor profiles were established in 79 sporadic colorectal carcinomas
      (41 stage II and 38 stage III). Tumors were analyzed for allelic loss (LOH) and
      genetic instability (MSI) using 14 microsatellites intragenic to or associated
      with tumor suppressor or DNA mismatch repair genes. Molecular profiling
      identified tumors with LOH at multiple loci without microsatellite instability
      (MSS), tumors with high levels of LOH and low level microsatellite marker
      instability (MSI-L), and tumors with high levels of MSI (MSI-H), but rare LOH. K
      ras mutations occurred more frequently in MSS/MSI-L carcinomas (26%) than in MSI
      H colorectal tumors (10%), the latter showing a high frequency of TGFbeta type II
      frameshift mutations (82%). Correlation of molecular and clinical data revealed a
      better prognosis for stage III tumor patients displaying 5q12 loss rather than
      retention of heterozygosity. Thus, molecular profiling allows the identification
      of new prognostic markers and might facilitate the stratification of colorectal
      cancer patients.

PMID- 10601564
TI  - Differential expression and allelotyping of the p73 gene in neuroblastoma.
AB  - p73 has recently been identified as a candidate imprinted tumor suppressor gene
      in neuroblastoma. To determine the possible involvement of this gene in the
      pathogenesis of neuroblastoma, we analyzed allelic expression, screened for
      mutations and determined MYCN copy numbers in 31 primary neuroblastoma tumor
      samples. Interestingly, the gene was biallelically expressed in 50% (4/8) of
      informative neuroblastomas, which suggests that activation of the normally
      silenced allele of this gene plays an important role in the tumorigenesis of
      neuroblastoma. However, no tumor-specific mutations were identified although 15
      polymorphisms were detected in this gene. We also detected a very strong
      association between a C91T polymorphism and MYCN copy number in this tumor. The T
      allele was detected in 8/17 (47%) neuroblastomas without MYCN amplifications but
      not detected in cases with MYCN amplifications (0/14). The biological
      significance of this association, however, is unknown. Overall the data suggest
      that p73 may play an important role in the pathogenesis of neuroblastoma but that
      the true tumor suppressor gene localized to this area still remains to be
      identified.

PMID- 10601565
TI  - Isolation of human colorectal tumour reactive antibodies using phage display
      technology.
AB  - Few highly specific anti-colorectal tumour antibodies exist. Here, we describe
      the isolation of a panel of colorectal tumour reactive antibodies, using
      bacteriophage-antibody display technology. A whole-cell based panning protocol
      has been used to isolate antibodies. panning against a cell type related to the
      colorectal tumour cells was used to remove antibodies reacting with common
      antigens. The 11 antibodies studied possess different levels of specificity, all
      bound to protein or glycoprotein molecules, and 2 of them recognised tunicamycin
      sensitive epitopes. None of the antibodies recognise the commonly expressed
      colorectal-markers CEA or EP-CAM. Our work demonstrates the potential of this
      technology for the development of new anti-tumour reagents.

PMID- 10601566
TI  - Molecular mechanism of action of parathyroid hormone related peptide in
      hypercalcemia of malignancy: therapeutic strategies (review).
AB  - Parathyroid hormone related peptide (PTHRP) was identified and characterized from
      tumors manifesting the syndrome of hypercalcemia of malignancy (HM). These
      hypercalcemic effects are due to the strong sequence homology between parathyroid
      hormone (PTH) and PTHRP in the bioactive amino terminal region and its ability to
      interact with G-protein linked seven transmembrane PTH/PTHRP receptor. However,
      due to the expression of PTHRP in several fetal and adult tissues, it also has a
      variety of physiological actions including the ability to play an important role
      in cell growth and differentiation. Since the isolation and characterization of
      PTHRP gene, intense efforts have been made to study its circulating forms in
      health and disease, regulation of PTHRP gene expression and molecular mechanism
      of PTHRP action in normal and in tumor cells. Various in vivo models of HM were
      developed which mimicked the human syndrome. Mice homozygous for PTHRP deletion
      died at birth due to impaired chondrocyte differentiation resulting in skeletal
      deformities and respiratory failure. Since HM continues to be a major cause of
      cancer associated morbidity and mortality there is an urgent need to develop
      strategies to control the syndrome of HM. This review describes the biosynthesis
      and secretion of various molecular forms of PTHRP, regulation of PTHRP gene
      expression and discusses the molecular pathways involved in its actions. Based on
      this information, various therapeutic strategies which are currently under
      development are discussed. These studies will form the basis of future efforts
      aimed at optimization of these approaches for further clinical development.

PMID- 10601567
TI  - Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in
      models of motor neuron death (Review).
AB  - Amyotrophic lateral sclerosis (ALS), also referred to as motor neurone disease,
      is a fatal neurological disease that is characterized clinically by progressive
      muscle weakness, muscle atrophy, and eventual paralysis. The neuropathology of
      ALS is primary degeneration of upper (motor cortical) and lower (brainstem and
      spinal) motor neurons. The amyotrophy refers to the neurogenic atrophy of
      affected muscle groups, and the lateral sclerosis refers to the hardening of the
      lateral white matter funiculus in spinal cord (corresponding to degeneration of
      the corticospinal tract) found at autopsy. Because the mechanisms for the motor
      neuron degeneration in ALS are not understood, this disease has no precisely
      known causes and no effective treatments. Very recent studies have identified
      that the degeneration of motor neurons in ALS is a form of apoptotic cell death
      that may occur by an abnormal programmed cell death (PCD) mechanism. In order to
      treat ALS effectively, we need to understand the mechanisms for motor neuron
      apoptosis more completely. Future studies need to further identify the signals
      for PCD activation in neurons as they relate to the pathogenesis of ALS and to
      clarify the molecular pathways leading to motor neuron apoptosis in animal and
      cell culture model systems. These studies should lead to a better understanding
      of motor neuron death and to the design of new therapeutic experiments critical
      for the future treatment of ALS.

PMID- 10601568
TI  - Molecular approach in cancer epidemiology: early detection of carcinogen-induced
      mutations in a whole genome (Review).
AB  - Chronic exposure of organisms to endo- or exogenous genotoxic products results in
      the accumulation of mutations in the genome and eventually to the development of
      cancers. Early detection of these mutations would allow the identification of at
      risk individuals who present a high load of mutations either because of an
      occupational or environmental exposure, or because of less efficient DNA repair
      processes. However, highly specific and sensitive assays are required to allow
      the detection of point mutations in a whole genome. We review a long-term study
      on the mutagenesis induced in E.coli by an aromatic amide, the N-2
      acetylaminofluorene. A major contribution of this work was to reveal the presence
      of specific mutation hot spot sequences. Taking advantage of this observation, we
      designed a specific, sensitive and semi-quantitative in vitro assay allowing the
      detection of carcinogen induced mutations. This assay has been validated in vivo
      and demonstrate the sensitivity of the technique in early detection of mutations
      and its usefullness in molecular epidemiology, early diagnostic and prognosis.

PMID- 10601569
TI  - Increased expression of alpha2beta1-integrin in the peritoneal dissemination of
      human gastric carcinoma.
AB  - The prognosis of advanced gastric cancer remains poor, given the frequent
      incidence of peritoneal metastasis. beta1-integrin is known to be associated with
      metastasis, though few reports have addressed the expression of beta1-integrin
      subunits in gastric cancer at primary and peritoneal lesions from the perspective
      of individual cases. We studied specimens from primary tumors from 50 patients
      and from metastatic peritoneal lesions from 27 patients with gastric carcinoma,
      including specimens from 22 metastatic lesions taken from the same patients whose
      primary tumors were sampled. Expression of beta1-integrin subunits, alpha2
      alpha6beta1 integrins, was studied using an immunohistochemical method.
      alpha2beta1-integrin was significantly expressed on a larger proportion of tumor
      cells in peritoneal metastasis (70.4%) than in primary tumors (48%) (p<0.05),
      though alpha3beta1, alpha4beta1, alpha5beta1 and alpha6beta1-integrins did not
      demonstrate significant discrepancy. The expression of alpha2beta1-integrin in
      peritoneal lesions was significantly increased compared with its expression in
      the primary lesion in the same individual. In contrast, no relationship was found
      between the expression level of beta1 integrins and clinicopathological
      parameters. Peritoneal implantation of gastric carcinoma might be closely
      associated with alpha2beta1-integrin.

PMID- 10601570
TI  - Molecular characterization of mesoderm-restricted basic helix-loop-helix protein,
      POD-1/Capsulin.
AB  - Members of the basic helix-loop-helix (bHLH) family of transcription factors have
      been implicated in the regulation of cell proliferation and differentiation. Here
      we describe molecular characterization of mesoderm-specific bHLH protein, POD
      1/Capsulin. Northern blot analysis showed that POD-1/Capsulin are preferentially
      expressed in human vascular smooth muscle cells, and are enriched in mouse heart,
      kidney, testis, spleen, and lung. Ectopic expression of the HA-tagged POD
      1/Capsulin in 293T cells revealed that this protein has an apparent molecular
      mass of 26 kDa and localized in the nucleus. Furthermore, in order to identify
      possible interactants of the bHLH protein, we performed yeast two-hybrid screen
      in a human kidney cDNA library, and identified alternative-splicing form of HEB,
      as potential heterodimeric partner of POD-1/Capsulin. Our results provide the
      molecular basis for cell type-specific transcriptional regulation by POD
      1/Capsulin.

PMID- 10601571
TI  - Modulating IGFBP-3 expression by trichostatin A: potential therapeutic role in
      the treatment of hepatocellular carcinoma.
AB  - The Hep3B cell line analyzed in the present study is a widely used in vitro model
      in studies characterizing pathogenetic, functional, and therapeutic aspects of
      human hepatocellular carcinoma (HCC). Here we have determined the chromosomal
      composition using a combination of cytogenetic techniques. In agreement with the
      original description for this cell line, Hep3B was found to have a hypotriploid
      chromosome content carrying 59-63 chromosomes and no cytogenetic differences were
      demonstrated between early and late passages suggesting that this cell line has
      remained stable after repeated subculturing. Mutations and alterations of the IGF
      axis as well as of chromosome 1p34, where the genes for histone deacetylase 1
      (HDAC1) and transforming growth factor beta receptor interacting protein-1 (TRIP
      1) map, are frequent events in hepatocarcinogenesis. This study characterizes the
      Hep3B cell line in detail at the karyotypic level, using comparative genomic
      hybridization (CGH), spectral karyotyping (SKY), G-banding and FISH techniques.
      We have also examined the effects of the histone deacetylase inhibitor
      trichostatin A (TSA) on members of the IGF-axis, and analysed them with regard to
      the karyotype. The results show that expression of one member of the IGF-axis,
      IGFBP-3, is greatly upregulated by treatment of Hep3B cells with TSA. As IGFBP-3
      has been shown to induce apoptosis, these results suggest a possible use for
      histone deacetylase inhibitors and/or IGFBP-3 in the treatment of HCC.

PMID- 10601572
TI  - Comparison of the signaling mechanisms involved in the ETB receptor-mediated
      secretagogue action of endothelin-1 on dispersed zona glomerulosa cells and
      capsule-zona glomerulosa preparations of the rat adrenal gland.
AB  - Endothelin-1 (ET-1) is a hypertensive peptide, which is expressed in the rat
      adrenal gland, where it stimulates aldosterone secretion from zona glomerulosa
      (ZG) by activating the ETb receptor subtype. A higher effectiveness of ET-1 has
      been frequently observed when the integrity of adrenal tissue is preserved.
      Hence, we compared the aldosterone secretagogue action of ET-1 on dispersed rat
      ZG cells and capsule-ZG strips. ET-1 concentration-dependently raised aldosterone
      output by both preparations with similar potency. However, the efficacy of the
      maximal effective concentration of ET-1 (10-8 M) was about 2.7-fold higher in
      capsule-ZG strips. The ETb-receptor antagonist BQ-788 (10-7 M) abolished
      aldosterone response to 10-8 M ET-1 in both ZG preparations, while the ETa
      receptor antagonist BQ-123 was ineffective. The aldosterone secretagogue action
      of 10-8 M ET-1 on dispersed ZG cells was concentration-dependently suppressed by
      the protein kinase (PK) inhibitor calphostin-C. Conversely, both calphostin-C and
      the nitric oxide (NO) synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester
      (L-NAME) evoked a concentration-dependent partial reversal of the aldosterone
      response to 10-8 M ET-1 of capsule-ZG strips. The NO donor L-arginine enhanced
      basal aldosterone yield of capsular strips, but not dispersed ZG cells. The PKA,
      cyclooxygenase and lipoxygenase inhibitors H-89, indomethacin and phenidone, as
      well as the beta-adrenoceptor antagonist l-alprenolol, were ineffective.
      Collectively, these findings allow us to conclude that in the rat i) the ETb
      receptor-mediated PKC activation is the main signaling mechanism involved in the
      direct stimulatory effect of ET-1 on ZG cells; and ii) the higher responsiveness
      of capsular strips to ET-1 may be accounted for by the ETb receptor-mediated
      release by stromal elements of NO, which in turn increases aldosterone secretion
      from ZG cells in a paracrine manner.

PMID- 10601573
TI  - Microsomal epoxide hydrolase genotypes and chronic obstructive pulmonary disease
      in Japanese.
AB  - Polymorphisms in the gene for microsomal epoxide hydrolase (mEPHX), an enzyme
      involved in the protective mechanism against oxidative stress, have been reported
      to be associated with individual susceptibility to the development of chronic
      obstructive pulmonary disease (COPD). The polymorphisms in exons 3 and 4 in the
      mEPHX gene were examined in a total of 358 Japanese individuals, including 40
      patients with COPD and 71 patients with lung cancer. The overall frequencies of
      variant allele for mEPHX codons 113 (exon 3) and 139 (exon 4) were 44% and 14%,
      respectively. Moreover, a novel single nucleotide polymorphism (estimated allele
      frequency: 0.29) was identified in Japanese at 20 bp downstream of the codon 113
      polymorphism with strong linkage disequilibrium with the wild allele for codon
      113. While the frequencies of variant allele and proportions of individuals
      homozygous variant for codon 113, assumed having very slow mEPHX activity, were
      similar among COPD or lung cancer patients and the control population, they were
      significantly higher in patients with severe COPD than in those with mild COPD
      [P=0.0225, odds ratio 2.9 (95%CI 1.1-7.4); P=0.0350, respectively]. Thus, we
      found that the frequency of the variant allele for mEPHX codon 113 is higher in
      Japanese than that in Caucasians (P=0.0028), a novel silent polymorphism exists
      in exon 3 and shows strong linkage disequilibrium with the wild allele for codon
      113, and individual homozygous variants for codon 113 may be associated with
      development of advanced COPD rather than the susceptibility to COPD.

PMID- 10601574
TI  - Serum LDL cholesterol concentration and lipoprotein electrophoresis pattern in
      patients with small cell lung cancer.
AB  - Epidemiological studies show that people with low level of total cholesterol have
      a greater risk of death due to cancer, predominantly lung cancer. The aim of our
      study was to evaluate serum level of LDL cholesterol and lipoprotein
      electrophoresis pattern in patients with small cell lung cancer and their
      dependence on clinical stage of the neoplasm. The studied group consisted of 34
      patients with newly diagnosed small cell lung cancer and 39 healthy controls.
      Fasting level of LDL cholesterol was analyzed and lipoprotein electrophoresis was
      performed. There were no statistically significant differences of evaluated serum
      lipid parameters between lung cancer patients and controls, and between the
      clinical stages of small cell lung cancer.

PMID- 10601575
TI  - Growth inhibitory effects of ATP and its derivatives on human fibroblasts
      immortalized with 60Co-gamma rays.
AB  - In our previous study (Katayama B et al, Int J Mol Med 2: 603-606, 1998), cell
      growth inhibition caused by ATP added to cultures was found to be greater in
      immortalized human fibroblasts than in the normal human fibroblasts. Since it has
      been reported that ATP affects cells via P2-purinergic receptors, growth
      inhibitory effects of ATP and its derivatives on immortalized human fibroblasts
      were investigated in the present study in order to learn what type of receptors
      are involved in ATP cytotoxicity. The ATP derivatives used in this study were:
      ATP, ADP, beta, gamma-methyleneadenosine 5'-triphosphate (MeATP), 2' & 3'-o-(4
      benzoylbenzoyl) adenosine, triethylammonium salt (BzATP), adenosine 5'-o-(3
      thiotriphosphate) (ATPgammaS), 2-methylthioadenosine 5'-triphosphate (2-MeSATP)
      and UTP. The extent of cytotoxicity induced by these drugs was found to be in the
      order of: ATP=ADP>ATPgammaS>MeATP=BzATP. On the other hand, neither 2-MeSATP nor
      UTP showed any cytotoxicity. These findings indicate that ATP may exert the cell
      growth inhibition by certain kinds of signal transduction via P2x or P2y
      purinergic receptors which affect intrinsic channels/pores of cell membrane
      and/or G protein activation. As a result, intracellular elevation in the
      concentrations of ions such as calcium and potassium, membrane depolarization,
      loss of endogenous ions/metabolites, and activation of inositol phospholipid
      specific phospholipase C may occur. Actually, a dihydropyridine calcium channel
      blocker, nifedipine, and an ATP-sensitive K+-channel blocker, glybenclamide,
      reduced the growth inhibitory effects of ATP on the cells to some extent. The
      growth inhibition caused by ATP was not due to apoptosis or induction of a
      cyclin/CDK kinase inhibitor, P21.

PMID- 10601576
TI  - Stimulation of insulin release in hereditarily diabetic rats by mixed molecules
      formed of nateglinide and a succinic acid ester.
AB  - Hereditarily diabetic Goto-Kakizaki rats were infused for 5 min with saline,
      containing as required nateglinide or mixed molecules (HD154 and HD166) with both
      a nateglinide moiety and a succinic acid ester moiety. The dose of these agents
      given intravenously amounted to 5.0 nmol/g body weight in all cases. All agents
      provoked a comparable early increase in plasma insulin concentration. However,
      HD154 and HD166, but not nateglinide itself, also caused a secondary rise in
      plasma insulin concentration 30 min after their infusion. It is proposed that
      mixed molecules formed of both a hypoglycemic sulfonylurea or meglitinide analog
      and a succinic acid ester may be better able than the antidiabetic agents
      themselves to evoke a sustained stimulation of insulin release in non-insulin
      dependent diabetes.

PMID- 10601577
TI  - FRAXE mutation in mentally retarded patients using the OxE18 probe.
AB  - The folate-sensitive fragile site FRAXE is located in proximal Xq28 of the human
      X chromosome and lies approximately 600 kb distal to the fragile X syndrome
      (FRAXA) fragile site at Xq27.3. Although FRAXA and FRAXE are indistinguishable by
      means of conventional cytogenetics, they can now be delineated at the molecular
      level and provides the basis for a proper diagnosis. The screening for CGG
      amplifications in the FMR1 gene was based on standard protocols using EcoRI
      digests on Southern blots and hybridization with the StB12.3 probe. The FRAXE
      mutation was analyzed by digestion with HindIII and the filters were probed with
      OxE20. We present the results of 144 patients referred for fragile X testing but
      negative for the FMR1 gene trinucleotide expansion, that were also screened for
      the FMR2 expansion. For FRAXE mutation a molecular protocol for OxE18 probe was
      used, in the DNA samples digested with EcoRI on the same blots as those used for
      detection of FRAXA. None of the patients tested were positive for the FRAXE
      expansion. This technique was successfully established into our laboratory
      routine showing the practical use of testing for FRAXA and FRAXE in a large
      series of patients.

PMID- 10601578
TI  - The role of potassium in the regulation of adenosine production by ATP
      diphosphohydrolase on the endothelial cell membrane.
AB  - Endothelial cells have ectonucleotidases that catabolize extracellular
      nucleotides and are sensitive to the presence of cations. Our aim was to
      determine whether the metabolism of extracellular nucleotides is influenced by
      exposure of endothelial cells to high potassium relevant to human
      pathophysiology. Human umbilical vein endothelial cells were incubated with 25 mM
      potassium and without potassium. The metabolism of radioactive substrates was
      measured and activities were 7.0+/-1.3 and 12.2+/-1.4 microM P/h/mg of protein
      with and without potassium. Also incubation with membrane pellet from endothelial
      cells was used, this assay showed 15.5+/-1.9 and 20.9+/-0.7 microM P/ h/mg of
      protein with and without potassium, respectively. HPLC analysis of supernatant
      showed that AMP production was lower in the presence of 25 mM potassium. Analysis
      of different potassium levels showed that a progressive reduction occurred above
      10 mM potassium. We conclude those potassium levels above 10 mM, which can be
      found in ischemia, inhibit the catabolism of extracellular adenine nucleotides by
      the ectonucleotidases of endothelial cells and may thus modify the
      pathophysiology of ischemia-reperfusion injury.

PMID- 10601579
TI  - Identification and characterization of opioid growth factor receptor in human
      pancreatic adenocarcinoma.
AB  - Pancreatic cancer is the fourth most common cancer-related mortality in the
      United States, and the ninth most common cause of death from cancer worldwide.
      The opioid growth factor (OGF), [Met5]-enkephalin, inhibits the growth of human
      pancreatic adenocarcinoma in vitro and in vivo, and acts in a receptor-mediated
      fashion. Ligand binding assays using PANC-1 human pancreatic tumor cells and [3H]
      [Met5]-enkephalin were performed to identify and characterize the receptor
      responsible for the growth-regulatory effects of OGF in pancreatic cancer.
      Specific and saturable binding was detected, and a Scatchard analysis revealed
      that the data were consistent for a single binding site with a binding affinity
      of 1.2+/-0.3 nM and a binding capacity of 36.4+/-4.1 fmol/mg protein. Subcellular
      fractionation studies showed that binding was restricted to the nuclear fraction.
      Competition experiments revealed that cold [Met5]-enkephalin was the most
      effective ligand at displacing [3H]-[Met5]-enkephalin; ligands for mu, delta, and
      kappa opioid receptors exhibited little or no competition. Binding was detected
      in 3 other human pancreatic tumor cell lines. Receptor number in xenografts of
      Capan-1 was decreased 8.6-fold compared to the same cells grown in tissue
      culture. Binding to radiolabeled [Met5]-enkephalin was detected in pancreatic
      cancers obtained from surgical resections. Binding capacity, but not binding
      affinity, was 7.1-fold greater in normal pancreatic tissues than in pancreatic
      neoplasia. The function, pharmacological and biochemical characteristics,
      distribution, and subcellular location of OGF binding in human pancreatic cancer
      were consistent with the OGF receptor (OGFr). In addition, human pancreatic
      cancer appears to have a low number of receptors for OGF, having the net effect
      of diminishing control of cellular replicative events.

PMID- 10601580
TI  - Bradykinin-induced inhibition of cell proliferation and tyrosine kinase activity
      in rat mesangial cells.
AB  - The relationship between cell proliferation, protein tyrosine phosphorylation,
      phosphotyrosine kinase activity and bradykinin receptor activation in rat
      mesangial cells was investigated. We demonstrated that bradykinin (BK), through
      the B2 receptor, induced a dose-dependent inhibition of mesangial cell
      proliferation stimulated by fetal calf serum. We next found that BK induced a
      dose-dependent inhibition of phospho-tyrosine kinase activity. Treatments with
      pertussis-toxin, inhibition of phospholipase C and protein kinase C inhibitors
      and chelation of free cytosolic calcium did not change the bradykinin-induced
      inhibition of phosphotyrosine kinase. Western blot analysis of phosphotyrosinated
      proteins demonstrated that BK reduced tyrosine phosphorylation of several
      proteins among which we identified the 125-focal adhesion kinase. Taken together,
      these data suggest for the first time that, in proliferating rat mesangial cells,
      B2 receptor stimulation is able to induce, via a pertussis insensitive pathway,
      the inhibition of tyrosine kinase activity and mesangial cell proliferation.

PMID- 10601581
TI  - Nitric oxide production by BCG-infected pleural macrophages from C57Bl/6 and DBA
      2 mice.
AB  - We studied the kinetics of in vivo nitrite production in the inflammatory
      reaction induced by M. bovis BCG into the pleural space. Pleural macrophages
      harvested from C57Bl/6 mice after acute BCG infection produced high levels of
      nitric oxide (NO). Enhanced production was obtained upon stimulation with LPS
      plus IFN-gamma. In sharp contrast, macrophages from DBA-2 mice produced low
      levels of NO, as nitrite, at the same time interval (24 h after BCG infection),
      being completely refractory to further stimulation. After the third day, NO
      production was similar in both strains. There was a close relationship between
      nitrite levels in the pleural exudate in vivo and those produced by harvested
      macrophages in vitro. In this in vivo system, the pattern of NO production by
      pleural macrophages one day after BCG infection was discrepant and unexpected in
      the response of C57Bl/6 and DBA-2 mice. However, this early response did not
      affect the late progressive NO production in both mice strains, that may be
      responsible to the late control of the mycobacteria growth.

PMID- 10601582
TI  - Effects of genistein and structurally related phytoestrogens on cell cycle
      kinetics and apoptosis in MDA-MB-468 human breast cancer cells.
AB  - We have studied the effects of phytoestrogens (genistein, quercetin, daidzein,
      biochanin A and kaempferol) on proliferation, cell cycle kinetics, and apoptosis
      of MDA-MB-468 breast cancer cells. Genistein and quercetin inhibited cell growth
      with IC50 values of 8.8 and 18.1 muM, respectively, while the other
      phytoestrogens were less effective. Flow cytometric analysis showed G2/M cell
      cycle arrest with 25 muM and higher concentrations of genistein. At 100 muM,
      genistein, quercetin and kaempferol caused accumulation of 70, 60 and 35% of
      cells, respectively, in G2/M phase by 24 h. In contrast, biochanin A and daidzein
      were ineffective. APO-BRDU analysis revealed apoptosis with 10 muM genistein
      (19.5%), reaching 86% at 100 muM. Apoptosis by genistein was confirmed by Hoechst
      33342 staining and fluorescence microscopy. With 100 muM quercetin, 47% of the
      cells were apoptotic, while the other bioflavonoids had little effect. Genistein
      treatment resulted in a biphasic response on cyclin B1: 70% increase in cyclin B1
      level at 25 muM, and 50 and 70% decrease at 50 and 100 muM, respectively. In
      contrast, the action of quercetin involved an increase in cyclin B1 level.
      Genistein had no effect on cdc2 level up to 50 muM concentration; however, there
      was a decrease in the phosphorylated form of the protein at 100 muM. Quercetin
      had no effect on cdc2 levels. Our results suggest that the action of genistein
      and quercetin involves G2/M arrest and apoptosis in MDA-MB-468 cells. Biochanin A
      and daidzein, although structurally related to genistein, did not share this
      mechanism. Thus, structurally related phytoestrogens have discrete target sites
      and mechanisms in their growth inhibitory action on breast cancer cells.

PMID- 10601583
TI  - Expression of the alpha6beta4 integrin provides prognostic information in bladder
      cancer.
AB  - Integrins are cell surface receptors for extracellular matrix components that may
      participate in metastatic processes. Normal urothelial tissues show a polarized
      expression of alpha6beta4 integrin on basal cells at their junction with the
      lamina propria. We have previously shown that bladder cancers frequently
      overexpress one member of the integrin family, the alpha6beta4 integrin. In this
      study, we evaluated the level of alpha6beta4 integrin expression in bladder
      cancer specimens from 57 patients and correlated the expression level with
      patient survival. Expression was evaluated by immunoperoxidase staining. Three
      patterns of alpha6beta4 expression were observed: negative (13 patients); strong
      overexpression throughout the tumor cells (21 patients); and weak expression that
      most closely resembled expression in normal urothelium (23 patients). Individuals
      with weak staining tumors had a statistically significantly better survival
      (p=0.041) than patients whose tumors exhibited either no expression or strong
      overexpression. These data indicate that evaluation of the expression of
      alpha6beta4 integrin may provide valuable prognostic information on clinical
      outcome in patients with bladder cancer.

PMID- 10601584
TI  - Estrogen and progesterone receptors can be maintained in normal human breast
      epithelial cells in primary culture and after transplantation into nude mice.
AB  - The estrogen and progesterone receptor expression was determined in breast
      epithelial cells from reduction mammoplasty specimens. Only a subset of the
      luminal epithelial cell population was found to be positive for these receptors.
      When these cells were subsequently cultured in 3-dimensional collagen gel system
      (in vitro model) or transplanted into nude mice (in vivo model), the cells
      retained their ability to express both receptors in these experimental systems.
      The maintenance of primary normal human breast epithelial cells expressing the
      estrogen and progesterone receptors in experimental systems has not been reported
      previously.

PMID- 10601585
TI  - In vivo efficacy and pharmacokinetics of a new hypoxic cell radiosensitizer
      doranidazole in SUIT-2 human pancreatic cancer xenografted in mouse pancreas.
AB  - A new 2-nitroimidazole radiosensitizer doranidazole is now undergoing clinical
      evaluation in combination with intraoperative radiotherapy for unresectable
      pancreatic cancer. However, there have been no laboratory data on its effect
      against pancreatic cancer. This study was undertaken to clarify the efficacy and
      pharmacokinetics of doranidazole in a human pancreatic cancer SUIT-2 xenografted
      in the pancreas of nude mice. The tumor-bearing mice were irradiated to the upper
      abdomen using electron beams with or without prior administration of
      doranidazole. The tumors were excised 3-6 days later and their weight was
      measured. Doranidazole given alone had no antitumor effect, but it had
      radiosensitizing effects when 100, 150, or 200 mg/kg of the drug was combined
      with single 5 Gy irradiation. The tumor/serum ratios for doranidazole
      concentration were 0.3-0.4, but the concentrations in the tumor were similar to
      those in the surrounding normal pancreas. At doses of 100 mg/kg or higher,
      concentrations of doranidazole in the pancreatic tumor appeared to be sufficient
      to obtain definite radiosensitization.

PMID- 10601586
TI  - Expression of cathepsin B and cystatin C in the human adenohypophysis and in
      pituitary adenomas.
AB  - The localization of cathepsin B, a potential promoter of prolactin (PRL) release
      via extra renal renin-angiotensin system in the adenohypophysis, and its
      inhibitor cystatin C in the human adenohypophysis and in pituitary adenomas were
      examined using single and dual immunohistochemical staining. In the
      adenohypophysis, cathepsin B was expressed in about 50% of the ACTH-producing
      cells, and in 5% or less of the GH- and PRL-producing cells. In contrast,
      cystatin C was expressed in about 70% of the GH- and PRL-producing cells, but in
      only 5% or less of the ACTH-producing cells. PRL-producing adenomas strongly
      expressed cathepsin B, but only weakly expressed cystatin C, a pattern of
      staining contrary to the expression in normal PRL-producing cells. The above
      results suggest that cathepsin B may play a role in promoting PRL release
      especially in PRL-producing adenomas.

PMID- 10601587
TI  - A human B-cell CLL model established by transplantation of JOK-1 cells into SCID
      mice and an anti-leukemia efficacy of fludarabine phosphate.
AB  - The present study was carried out to establish a human chronic lymphocytic
      leukemia (CLL) mouse model by transplantation of a JOK-1 human CLL cell line into
      SCID (severe combined immunodeficient) mice and to examine anti-leukemic effects
      of fludarabine phosphate, a prodrug of 9-beta-D-arabinofuranosyl-2-fluoroadenine
      (2F-ara-A). In vitro cytotoxic screening pattern of 2F-ara-A differed from those
      of other anticancer agents. Intraperitoneal inoculation with JOK-1 cells in SCID
      mice allowed the cells to infiltrate into a variety of organs including the liver
      and thymus, and resulted in the death of the mice with a median survival time of
      29.5 days, associated with hepatomegaly, splenomegaly and enlarged lymph nodes.
      The ascitic cells expressing the human B-lymphocytic cell surface antigen CD19
      actually grew after a latent period of 15 days. In this model, twice daily
      administration of fludarabine phosphate at a dose of 135 mg/kg for 5 days
      prolonged the survival time of the mice for considerably longer period than once
      a-day treatment. Fludarabine phosphate in the doubled course of twice daily
      increased life span of 32.9%, which was in a similar range to that of
      doxorubicin. Thus, intraperitoneal inoculation of the human JOK-1 CLL cells into
      SCID mice seems to serve as an animal model potentially for human leukemia,
      suggesting that transplantation and subsequent infiltration processes of human
      CLL cells is useful measures to explore mechanistic aspects for drug-induced
      modulation of the tumor progression.

PMID- 10601588
TI  - Microsatellite instability and MLH1 and MSH2 germline defects are related to
      clinicopathological features in sporadic colorectal cancer.
AB  - Clinical and pathological features were evaluated to predict tumor microsatellite
      instability (MSI) and germline mutations in MLH1 and MSH2 DNA mismatch repair
      genes in two patient groups with sporadic colorectal cancer (CRC): 38 young
      patients (age </=45 years) and 31 old patients (age >/=60 years). Nine (25.7%)
      young patients out of 35 and five (16%) old patients out of 31 exhibited MSI in
      their cancers. MSI+ cancers were related to proximal cancer and mucinous
      carcinoma independently of the age at cancer onset. Three (7.9%) out of 38 young
      patients had mutations in MLH1 and MSH2 genes that led to truncated protein
      products; they were all at age <35 years and showed MSI in their tumors, with
      mucinous histotype in two cases. In conclusion, histopathological and clinical
      features of CRC allow identification of cancers showing DNA microsatellite
      instability. MSI in CRC at very early onset (age <35 years) appears useful to
      predict germline MMR gene defects.

PMID- 10601589
TI  - Evidence for Fas counter attack in vivo from a study of colorectal cancer.
AB  - Peritumoural cytotoxic lymphocytic infiltrates in colorectal carcinoma may attack
      tumour cells by expressing Fas ligand and inducing tumour cell apoptosis.
      However, tumours may mount a by down regulating their Fas pathway and expressing
      Fas ligand themselves to induce apoptosis of lymphocytes. This study used
      immunohistochemistry to demonstrate the presence of CD8+ lymphocytes and Fas
      ligand. The score of CD8+ peritumoural lymphocytes was negatively correlated with
      the Fas ligand score of the tumour. The results provide evidence for the Fas
      theory, but further work would be required to determine if this is a significant
      factor in the tumour-host interaction.

PMID- 10601591
TI  - Early diagnosis and evaluation of therapy in postoperative recurrent cervical
      cancers by positron emission tomography.
AB  - Positron emission tomography (PET) using 2-[18F]fluoro-2 deoxy-D-glucose (FDG)
      was performed on two uterine cervical cancer patients in whom recurrent tumors,
      one pelvic and the other at the vaginal wall had not been precisely diagnosed
      using the usual imaging examinations. One recurrence was confirmed by the
      acccumulation of FDG to the pelvic mass as detected by magnetic resonance imaging
      (MRI). During chemotherapy, changes in FDG-PET findings were detected earlier
      than those in MRI. In the other, PET detected a recurrent tumor that could not be
      found by MRI, and was also useful for evaluating chemotherapeutic effects. These
      cases suggest that PET with FDG can be a useful examination not only for
      diagnosing recurrent cervical cancer after radical hysterectomy, especially
      pelvic recurrence, but also for evaluating chemotherapeutic effects on recurrent
      cancers.

PMID- 10601590
TI  - Selective beta2-adrenoceptor agonist enhances sensitivity to cisplatin in non
      small cell lung cancer cell line.
AB  - Cisplatin is a key drug in chemotherapy for lung cancer. It has been reported
      that intracellular accumulation of cisplatin is an important step as a
      determinant for resistance to cisplatin, which may be modulated by Na+, K+-ATPase
      activity. And it has been reported that isoproterenol, a beta-adrenoceptor
      agonist, enhances sensitivity to cisplatin in non-small cell lung cancer (NSCLC)
      cell lines. In this study, the effects of the selective beta1, beta2, and beta3
      adrenoceptor agonists on membrane Na+, K+-ATPase activity and sensitivity to
      cisplatin were evaluated using human non-small cell lung cancer cell line. In the
      NSCLC cell line, sensitivity to cisplatin was improved by treatment with
      procaterol, a selective beta2-adrenoceptor agonist. Na+, K+-ATPase was activated
      and intracellular accumulation of cisplatin increased with the treatment.
      However, beta1 or beta3-adrenoceptor agonist did not modulate sensitivity to
      cisplatin or Na+, K+-ATPase activity. These results suggest that beta2
      adrenoceptor may be one of the determinants for sensitivity to cisplatin in
      NSCLC. Exogenous beta2-adrenoceptor agonists may improve the antitumor effect of
      chemotherapy involving cisplatin.

PMID- 10601592
TI  - Endoscopic prediction of tumor depth of gastric carcinoma for assessing the
      indication of its limited resection.
AB  - Limited surgery for an early gastric carcinoma is advocated, since certain
      carcinomas have no nodal involvement. However, the endoscopic accuracy of
      distinguishing each cancer-depth has not been detailed from the standpoint of
      limited surgery. We retrospectively reviewed a total of 2,628 patients to assess
      the diagnostic accuracy of their endoscopic infiltration-depth with the nature of
      the tumors. Endoscopic distinction of early from advanced carcinomas was
      satisfactory with a reliability of 86.5%, sensitivity of 87.1%, and specificity
      of 85.9%. In the 1,354 early gastric carcinomas the microscopic infiltration
      depth was significantly related to macroscopic appearance, histologic
      differentiation and tumor size. Accompanying ulcer or scar significantly
      suggested that the carcinoma had spread vertically and horizontally.
      Macroscopically elevated and differentiated carcinomas without ulcer are usually
      limited to the mucosa, and undifferentiated and/or ulcer-positive carcinomas are
      more invasive than predicted by most present clinical standards. Endoscopically
      differential diagnosis of the infiltration-depth of gastric carcinomas is
      reliable, and the indication for limited surgery can be endoscopically determined
      in many individual patients.

PMID- 10601593
TI  - Signal transduction in adherent and non-adherent human cell lines after
      fibronectin stimulation.
AB  - It is shown that adherent and non-adherent human ovarian carcinoma cells (OVP 10)
      secrete MMPs and their production was stimulated by fibronectin as documented by
      gelatinise zymography. These cells also presented an increase of ERK
      phosphorylating activity following fibronectin stimulation, regardless of their
      adhesion. Contrary to OVP 10 cells, the human urothelial cells (HCV-29) are more
      anchorage-dependent. They only secreted the MMPs under adherent conditions and
      they revealed a lower level of basal and fibronectin stimulated ERK
      phosphorylation activity. In addition, non-adhering HCV-29 cells showed post
      translational down-regulation of focal adhesion kinase.

PMID- 10601594
TI  - The role of interleukin-6 in inhibition of lung metastasis in subcutaneous tumor
      bearing mice.
AB  - Metastasis is the most important factor for prognosis in cancer patients, and its
      occurrence is largely associated with host immune response. We found that the
      presence of a growing tumor of colon 26, a mouse colon cancer cell line,
      completely inhibited lung colony formation in a mouse injected with colon 26
      intravenously, whereas depletion of effector cells, such as natural killer and T
      cell subsets, did not affect antimetastasis of colon 26. Since colon 26 releases
      large amounts of interleukin-6 (IL-6) spontaneously, we studied the association
      of IL-6 with lung metastasis. Serum IL-6 level increased gradually and reached
      12.6 pg/ml five days after inoculation of colon 26 in the back of mice, while at
      the same time, lung colony formation was inhibited. Moreover, expression of IL-6
      mRNA in lung was observed to be associated with elevated serum IL-6 level. We
      show the first evidence that inhibition of lung metastases in tumor-bearing mice
      by colon 26 is closely associated with an increase in serum IL-6, but not in
      cellular immunity.

PMID- 10601595
TI  - Bladder carcinoma evaluated by transvaginal ultrasonography.
AB  - Transvaginal ultrasonography is a less invasive examination method than
      transrectal and transurethral ultrasonography for women. However, in spite of the
      use of transrectal and transurethral ultrasound for the detection of a bladder
      tumor being well known to urologists, we found no previous studies on
      transvaginal ultrasonography as a method to evaluate bladder carcinoma. We report
      a case in which transvaginal ultrasonography contributed to the screening and
      evaluation of bladder carcinoma.

PMID- 10601596
TI  - Cytotoxicity of docosahexaenoic acid and eicosapentaenoic acid in tumor cells and
      the dependence on binding to serum proteins and incorporation into intracellular
      lipids.
AB  - Docosahexaenoic acid (DHA) inhibited the DNA synthesis in Ehrlich ascites tumor
      cells more markedly than eicosapentaenoic acid (EPA), which was more inhibitory
      than oleic-, linoleic-, linolenic-, and arachidonic acids. Their activities
      augmented according to the increase of number of double bonds in the molecule. To
      correlate the cytotoxicity with lipid syntheses in the cells, distribution of EPA
      and DHA incorporated into cellular lipids was assessed. EPA was incorporated into
      triglycerides (TG) and DHA into phosphatidylcholine (PC). These synthesis into TG
      and PC etc., which shattered from cytotoxicity, may be involved in tumor-cellular
      protecting actions against EPA or DHA. EPA and DHA involved in cytotoxicity
      exhibition are their free acid forms. Thus, as an anticancer reaction,
      intracellular accumulation in the free acid form of DHA was more marked than that
      of EPA.

PMID- 10601597
TI  - Preoperative evaluation by whole-body 18F-fluorodeoxyglucose positron emission
      tomography in patients with primary colorectal cancer.
AB  - Whole-body positron emission tomography (WB PET) was performed preoperatively in
      24 patients with primary colorectal cancer, and the results were compared with
      the histopathological findings. The PET positive rate was 95.8% (23/24 patients)
      for the primary tumor. Among nine patients with histologically confirmed lymph
      node metastasis, two (22.2%) were positive by PET, including one with n1 and one
      with n4 disease. Among 15 patients without lymph node metastasis
      histopathologically (n0), two (13.3%) showed false-positive nodes on PET, being
      diagnosed as n1 and n3 disease, respectively. These results suggest that
      preoperative PET is useful for the diagnosis of primary colorectal cancer, but it
      is of limited value for detecting metastasis to the regional lymph nodes
      surrounding the primary lesion.

PMID- 10601598
TI  - A case-control study of uterine endometrial cancer of pre- and post-menopausal
      women.
AB  - Endometrial cancers are generally divided into at least two different
      pathogenetic types. One occurs from the proliferative endometrium, depending on
      continuous estrogen stimulation, while the other is not related to the
      stimulation and occurs from the atrophic endometrium of older post-menopausal
      women. In order to assess the risk factors for endometrial carcinoma (EC), a case
      control study with 136 Japanese women having EC and with 376 healthy controls for
      ECs in Japan, together with an immunohistochemical analyses on p53, estrogen (ER)
      and progesterone receptors (PR) of EC patients was undertaken. Nulliparity,
      increased BMI, hypertension, diabetes mellitus, later age at menopause and
      personal cancer history were all seen predominantly in the EC group. Frequency of
      irregular menses, polycystic ovary syndrome (PCOS) and obesity in the EC patients
      under 40-year old was significantly higher than the control group.
      Immunohistochemical expressions of ER (P<0.05) and PR (P<0. 01) were more
      frequently recognized in the EC of the pre-menopausal than in the post-menopausal
      patients. On the other hand, p53 overexpression was detected in 27.2% of the post
      menopausal EC group, while only found in 7.1% of the pre-menopausal EC group.
      These findings indicate that possible factors related to endometrial
      carcinogenesis are different between the pre- and post-menopausal EC patients.
      Namely, untreated ovarian dysfunction such as PCOS with unopposed estrogenic
      action in the endometrium may be associated with development and growth of EC in
      younger women, yet abnormality of p53 gene may be more concerned with the
      development of the post-menopausal EC, independently of sex steroid influence.

PMID- 10601599
TI  - Prognostic relevance of c-Myc and caspase-3 for patients with non-small cell lung
      cancer.
AB  - This analysis attempted to ascertain whether combining the expression of c-Myc
      and caspase-3 can improve the available prognostic information for patients with
      non-small cell lung carcinomas. To this purpose, the expression of c-Myc and
      caspase-3 was determined in 128 cases of non-small cell lung carcinoma. The
      median survival time for patients with c-Myc-negative carcinomas was 89 weeks; it
      was only 43 weeks for patients with c-Myc-positive tumors (p=0.03). The estimated
      increased relative risk for patients with c-Myc-positive tumors was 1.6. The
      median survival time for patients with caspase-3-negative carcinomas was 41 weeks
      while patients with caspase-3-positive carcinomas survived for 79 weeks (p=0.06).
      The relative risk for patients with caspase-3-negative tumors was 1.5. A
      significant inverse relationship between the expression of c-Myc and caspase-3
      was observed (p=0.04). To determine whether the combination of c-Myc and caspase
      3 expression has a higher prognostic significance, patients were grouped based on
      their expressions of both variables. Patients with c-Myc-negative and caspase-3
      positive tumors had the most favorable prognosis (102 weeks) while c-Myc-positive
      and caspase-3-negative carcinomas had the most unfavorable prognosis (22 weeks;
      p=0.01).

PMID- 10601600
TI  - Aberration of p53 and DCC in gastric and colorectal cancer.
AB  - We investigated the expression of p53 protein by immunohistochemistry and the
      expression of deleted in colorectal carcinoma (DCC) mRNA by the reverse
      transcription-polymerase chain reaction (RT-PCR) method in surgically resected
      tumors of gastric and colorectal cancers and compared these results to the
      clinicopathological features. Positive immunoreactions of p53 were observed in 21
      of 42 gastric cancers (50%) and 25 of 37 colorectal cancers (67.6%). Decreased
      expression of DCC mRNA was observed in 15 of 38 gastric cancers (39.5%) and 10 of
      28 colorectal cancers (35. 7%). There was a significant correlation between the
      immunoreaction of p53 and the depth of tumor invasion in gastric cancer, as well
      as between the decreased expression of DCC mRNA and nodal metastasis in
      colorectal cancer. In early cases without metastasis and invasion beyond
      muscularis propria, none of six gastric cancers showed a p53 immunoreaction,
      while seven of 9 colorectal cancers showed positive immunoreactions. On the other
      hand, two of 4 gastric cancers showed decreased expression of DCC mRNA; whereas,
      none of the seven colorectal cancers did. Alteration of p53 might occur at a
      later stage in gastric cancer than in colorectal cancer and be associated with
      the acquisition of an invasive character. In contrast to gastric cancer,
      decreased expression of DCC mRNA might be present in a later stage in colorectal
      cancer than in gastric cancer, and be related to the acquisition of metastatic
      character to the lymph nodes. In conclusion, alterations of p53 or DCC may play
      different roles in the progression of gastric cancers as compared to colorectal
      cancers, and the occurrence of both p53 and DCC genes mutations may cause these
      cancers to become more malignant.

PMID- 10601601
TI  - Breast cancer shortly after the diagnosis of interstitial pneumonia associated
      with polymyositis.
AB  - Polymyositis is sometimes associated with pulmonary fibrosis or malignant
      diseases, however, rarely with both simultaneously. For such patients, no
      criterion for initial treatment and tapering of steroid has been reported. We
      describe a patient who had breast cancer and interstitial pneumonia associated
      with polymyositis. In this case, slow tapering of the steroid was an important
      aspect of the treatment, and close clinical follow-up was necessary to monitor
      for disease exacerbation.

PMID- 10601602
TI  - Utility of liposomes coated with polysaccharide bearing 1-amino-lactose as
      targeting chemotherapy for AH66 hepatoma cells.
AB  - The cell recognition element is very important for drug delivery systems. We
      synthesized cholesteryl pullulan (CHP) bearing 1-aminolactose (1-AL) and
      introduced a saccharide, cholesteryl pullulan bearing 1-aminolactose (1-AL/CHP),
      to an outer layer of the conventional liposome as a cell recognition element.
      Lectin recognized the beta-galactose by aggregation of 1-AL/CHP coated liposome
      (1-AL/CHP liposome). The uptake of this liposome to AH66 rat hepatoma cells was
      greater than in liposomes without 1-aminolactose in vitro. Furthermore, 1-AL/CHP
      liposomal adriamycin showed a stronger antitumor effect in comparison with other
      types of liposomal adriamycin in vitro. When in vivo tumor-targeting efficacy was
      investigated in AH66 tumor transplanted mice using 3H-liposome, the tumor/serum
      radioactivity ratio in mice injected with 1-AL/CHP liposome was higher than that
      of mice injected with other liposomes. These observations suggest that 1-AL is
      effective as a cell recognition element. As a result, 1-AL/CHP liposome is
      considered to be a good carrier of anticancer drugs for the active targeting of
      tumor cells.

PMID- 10601603
TI  - Genetic heterogeneity and progression in different areas within high-grade
      diffuse astrocytoma.
AB  - The primary objective of this study was to determine loss of heterozygosity (LOH)
      in various portions of 9 high-grade diffuse astrocytomas, 8 glioblastomas and 1
      anaplastic astrocytoma. LOH was observed on chromosomes 9, 10, 17 and 19 in 8, 3,
      4 and 2 cases, respectively. Genetic heterogeneity and a multistep process were
      identified in 4 glioblastomas explaining the diverse morphological
      characteristics, a common feature of diffuse astrocytomas. In 2, 2, 3 and 1
      cases, the allele losses were found within part of grade IV astrocytomas but not
      grades II or II/III, on chromosomes 9, 10, 17 and 19, respectively. In one of
      these, while genetic heterogeneity was observed on chromosome 17 between the area
      of grade II and grade IV, 9pLOH was found within both areas and occurred on the
      same allele. The other 5 cases did not demonstrate genetic heterogeneity and the
      LOH was on the same allele, irrespective of grade, suggesting clonal origin. In
      conclusion, at the molecular level, the diverse morphological features of
      astrocytoma develops by a multistep mechanism of genetic alterations from one
      cell via low-grade and more malignant tumors towards glioblastoma.

PMID- 10601604
TI  - Enhancement of gene transfer efficiency into human cancer cells by modification
      of retroviral vectors and addition of chemicals.
AB  - Retroviral vectors have recently experienced limited use in cancer gene therapy
      mainly due to poor transduction efficiency. To overcome this drawback, we
      attempted to enhance the transduction efficiency by employing different
      retroviral packaging cell lines and chemical additives. The retrovirus from the
      PG13 packaging cell line gave mostly higher or similar transduction efficiencies
      in a variety of human cancer cell lines compared to the retrovirus from the
      PA317, Bing, or FLYRD18 packaging cell line. A cationic liposome, especially
      Lipofectamine, significantly enhanced the transduction efficiency of a
      retrovirus. However, the retrovirus derived from the PG13 cell line could not
      infect the murine cell line efficiently even after Lipofectamine treatment.
      Furthermore, chloroquine did not improve the transduction efficiency regardless
      of the presence of chemical additives. These results, therefore, suggested that
      the transduction efficiency of a retrovirus in human cancer cells can certainly
      be improved when a proper packaging cell line is chosen. In addition, this study
      implied that Lipofectamine is a superb additive to enhance the transduction
      efficiency of a retrovirus via a specific virus envelope protein-receptor
      interaction for virus entry, and that receptor-mediated endocytosis does not seem
      to be the leading route of virus delivery to liberate a virus genome.

PMID- 10601605
TI  - Alternative gonadotropin-releasing hormone processing products secreted from
      endometrial carcinoma.
AB  - Gonadotropin-releasing hormone (GnRH) receptor is demonstrated in uterine
      endometrial carcinoma. The endometrial carcinoma also produces GnRH or -like
      peptide, which prompted us to examine whether the intratumoral serves as natural
      ligand for its receptor. Endometrial carcinomas surgically removed had been
      screened for GnRH receptor expression before analysis. The in endometrial
      carcinoma cell-enriched culture media was characterized by immunoblots in tricine
      supplied electrophoresis system and subsequent amino acid sequencing. Three major
      proteins of 10.0 kDa, 7.6 kDa and 1.1 kDa corresponding to pre-proGnRH, proGnRH
      and decapeptide GnRH, respectively, were detected in all of the ten endometrial
      carcinoma specimens tested. Immunoreactive contents in the culture media,
      assessed by RIA, ranged from 0.08 to 0.1 nM. In chorionic cell-conditioned media,
      only 1.1-kDa protein was detected. Endometrial carcinoma cells secrete
      alternative GnRH processing products in addition to natural GnRH. The GnRH
      variants may compete with mature GnRH at the level of its receptors, perhaps
      counteracting the GnRH signaling pathway to retard cell proliferation.

PMID- 10601606
TI  - The influence of inspiratory hyperoxia on ischemia-reperfusion-induced tumour
      growth delay.
AB  - We investigated the ischemia-reperfusion-induced tumour growth delay as a
      function of ischemic time, tumour temperature, and the amount of inspired oxygen
      during reperfusion. The rhabdomyosarcoma R1H growing on the right flank of male
      WAG/Rij rats was clamped for 2 or 4 h at 20 degrees C or 37 degrees C. Five
      minutes prior to and 10 min during reperfusion the animals respired air, pure
      oxygen or carbogen (95% O2, 5% CO2). Comparison of single treatment modalities
      with untreated controls revealed significant tumour growth delays after clamping
      times of 4 h at 37 degrees C for air and pure oxygen, but not for carbogen.

PMID- 10601607
TI  - Regulation of estrogen receptor and epidermal growth factor receptor by tamoxifen
      under high and low estrogen environments in MCF-7 cells grown in athymic mice.
AB  - The purpose of this study was to investigate whether tamoxifen (TAM) treatment
      causes a downregulation of estrogen receptor (ER) and whether TAM induces
      epidermal growth factor receptor-1 (EGFR). We investigated the expression of ER
      and EGFR after the treatment of TAM in MCF-7 tumors grown in athymic mice under
      high and low estrogen environments. MCF-7 tumors were grown in ovariectomized
      athymic mice by implanting a sustained release 17beta-estradiol (E2) pellet. The
      E2 pellets were removed after 3 weeks of E2 treatment. Animals were then divided
      into the following 4 groups: i) an E2 (0. 72 mg/pellet) pellet [E2(+)]; ii) an E2
      and a TAM (5 mg/pellet) pellets [E2(+)TAM]; iii) no treatment [E2(-)]; iv) a TAM
      pellet [E2(-)TAM]. A significant reduction in tumor size was observed in the
      estrogen-depleted group [E2(-) and E2(-)TAM] compared with the estrogen-completed
      group [E2(+) and E2(+)TAM]. TAM inhibited estrogen-stimulated growth in the
      estrogen-completed mice. No additional reduction of the tumor by TAM was observed
      in the estrogen-depleted mice. Both ER and EGFR protein levels in the tumors of
      the estrogen-depleted mice were higher than in the estrogen-completed mice.
      Expression of ER and EGFR protein was increased by TAM in the estrogen-completed
      mice, however it was decreased by TAM in the estrogen-depleted mice. Changes of
      ER and EGFR protein levels were similar in all treatments. Transforming growth
      factor-alpha (TGF-alpha) in tumors, which is known as a ligand of EGFR and as an
      estrogen-inducible protein in ER positive MCF-7 cells, was decreased by TAM in
      the estrogen-completed mice, by contrast, it was increased by TAM in the estrogen
      depleted mice. Downregulation of ER was observed in TAM-treated mice in an
      estrogen-depleted environment, this action of TAM was similar to E2. These
      results suggest that increase of EGFR expression does not lead to a loss of ER
      after short-term TAM treatment in MCF-7 tumors.

PMID- 10601608
TI  - Balloon-occluded arterial infusion chemotherapy, simple total hysterectomy, and
      radiotherapy as a useful combination-therapy for advanced cancer of the uterine
      cervix.
AB  - We first performed 3 or 4 courses of balloon-occluded arterial infusion (BOAI)
      chemotherapy in 19 patients with advanced cancer of uterine cervix classified as
      stage III-IV according to the International Federation of Gynecology and
      Obstetrics. In the patients in whom the first BOAI resulted in insufficient drug
      accumulation in tumor tissue, the ovarian arteries and veins were ligated to
      improve the therapeutic effect. Ultimately simple total hysterectomy and
      radiotherapy were performed in 9 patients in whom the uterus was resectable (the
      combination group), and radiotherapy alone was conducted in the other 10 patients
      in whom hysterectomy was not practicable (the incomplete group). The survival
      rates were significantly higher in the combination group (2-year survival 88. 9%;
      5-year survival 66.7%) than in the incomplete group (p=0.0013).

PMID- 10601609
TI  - Interferon alpha-2b at low doses as long-term antiangiogenic treatment of a
      metastatic intracranial hemangioendothelioma: a case report.
AB  - We describe a case of intracranial haemangioendothelioma in a 20-year old female
      patient who presented severe neurological symptoms and relapsed after two
      surgical interventions. The patient was treated with low doses of recombinant
      interferon alpha-2b (1 MUI three times a week) after surgical resection which led
      to recovery of daily function and work activity. To our knowledge, this is the
      ninth patient reported with intracranial hemangioendothelioma, but the only one
      having diffuse and painful bone metastases resolved by treatment with interferon.
      After 30 months the patient is free from symptoms and recurrence. The
      effectiveness shown by recombinant interferon alpha-2b against vascular neoplasms
      prompted us to look for the possible biological basis of such a property.

PMID- 10601610
TI  - NK cells mediate the anti-tumor effects of E1-deleted, type 5 adenovirus in a
      human tumor xenograft model.
AB  - SCH58500 (ACN53) is a recombinant adenovirus expressing human p53 for gene
      therapy of cancer. In preclinical studies, SCH58500 has shown efficacy against
      many tumor-types with non-functional p53. This activity arises from both p53
      mediated and adenovirus vector-mediated mechanisms. The importance of NK cells
      for adenovirus-mediated tumor suppression after intratumoral dosing was
      demonstrated using MDA-MB-231 human breast cancer xenografts in scid (defective T
      and B cell response) and scid-beige (defective T, B, and NK cell response) mice.
      There was no adenovirus vector-mediated anti-tumor activity in scid-beige mice.
      Dexamethasone (Dex) is a potent suppressor of the cellular immune response to
      recombinant adenovirus in mice and rats. Dex abolished growth suppression caused
      by adenovirus vector, but did not interfere with the anti-tumor efficacy of p53.
      Supression of NK cell activity in scid mice using intravenous administration of a
      neutralizing antibody had the same effect as Dex. These data support a role for
      NK cells in adenovirus vector-mediated anti-tumor efficacy.

PMID- 10601611
TI  - Expression and regulation of estrogen receptor beta in human breast tumors and
      cell lines.
AB  - Expression of estrogen receptor beta (ER-beta) and its regulation by estradiol
      and anti-estrogens was analyzed in breast cancer cells. We determined that ER
      beta is expressed in normal and tumor human breast tissue as well as in breast
      cancer cell lines. We observed moderate levels of ER-beta expression in both T47D
      and T47D-V22 (a T47D variant cell line) cells, in contrast with T47DCo (a T47D
      variant cell line) cells when compared to ER-alpha expression. While T47DCo (a
      T47D variant cell line), BT474, MDA-MB-231, MDA-MB-453, MDA-MB-468 and MCF-7
      express low levels of ER-beta, other cell lines including the T47D-Y (a T47D
      variant cell line), MDA-MB-435, BT-549, and SKBr-3 cells express undetectable
      levels of ER-beta. Interestingly, ER-beta and ER-alpha are apparently not co
      expressed in the breast tissue analyzed. Estradiol induced 30-40-fold increased
      ER-beta mRNA expression in T47D cells over control untreated cells. Moreover, the
      anti-estrogen, 4-hydroxy-tamoxifen (4OH-Tam) strongly inhibited estradiol
      induction of ER-beta expression, but had little or no effect on estradiol
      induction of ER-alpha. A pure anti-estrogen, ICI-182,780, completely abolished
      the ability of estradiol to up-regulate the expression of ER. In addition, both
      actinomycin D and cyclohexymide inhibited estradiol induction of ER-beta mRNA,
      indicating that de novo mRNA and protein synthesis are probably required for this
      induction. In summary, this study demonstrates that ER-beta is expressed in
      breast cancer, and it is regulated by estradiol. Moreover, the studies
      demonstrate that estradiol up-regulation of ER-beta mRNA in T47D cells can be
      abolished by anti-estrogens. Thus, ER-beta expression may serve as a prognostic,
      diagnostic and/or therapeutic marker for breast cancer. To the best of our
      knowledge, this is the first report regarding hormonal regulation of ER-beta in
      human mammary cells.

PMID- 10601612
TI  - Inverse association of prostate cancer and non-steroidal anti-inflammatory drugs
      (NSAIDs): results of a case-control study.
AB  - We examined the association of prostate cancer and non-steroidal anti
      inflammatory drugs (NSAIDs) in a case control study of 417 prostate cancer
      patients and 420 group-matched control subjects. Regular daily use of over the
      counter NSAIDs, ibuprofen or aspirin, was associated with a 66% reduction in
      prostate cancer risk (odds ratio = 0.34, 95% confidence interval = 0.23-0.58,
      p<0.01). The risk of prostate cancer was also significantly reduced in men who
      reported taking prescription NSAIDs (odds ratio = 0.35, 95% confidence interval =
      0.15-0.84, p<0.05). These results suggest that NSAIDs may have value in the
      chemoprevention of prostate cancer.

PMID- 10601613
TI  - Pharmacokinetics of intrapleural cisplatin for the treatment of malignant pleural
      effusions.
AB  - We determined the toxicity and pharmacokinetics of high-dose intrapleural
      cisplatin (CDDP) as a treatment of malignant pleural effusions (MPE). Fourteen
      patients with MPE were enrolled in this study. After complete drainage of the
      fluid, a catheter was inserted into the pleural cavity during a thoracoscopy.
      CDDP (300 mg) was administered via the catheter in a 6-h infusion. Peak levels,
      the areas under the concentration curve (AUC), and drug half-lives were measured
      in pleural fluid and plasma samples collected at 0 (baseline), 6, and 24 h as
      well as 4, 14, and 21 days after intrapleural administration. The dosage of CDDP
      ranged from 153 to 203 mg/m2. The time interval between infusion was prolonged
      until a maximum of 109 days. Only 7/40 infusions were associated with adverse
      effects in 4 patients (18%). Residual concentrations in pleural fluid (0.66+/
      0.07 microgram /ml) were three-fold higher than in plasma (0.13+/-0.07
      microgram/ml). In pleural fluid, maximal concentration (Cmax) varied from 19 to
      900 microgram/ml and in plasma from 0.34 to 3.65 microgram/ml. AUC in plasma
      during the three courses was 112+/-49 microgram/ml/d. The T1/2 was 31+/-33 days
      higher than that previously reported after intravenous administration (8-15
      days). Although intrapleural CDDP has the potential advantage of treating the
      underlying malignancy in addition to controlling the malignant effusion with a
      good tolerance, it cannot be recommended for the standard control of malignant
      pleural effusion. Indeed we observed a great variability of intrapleural CDDP
      concentration depending on the extent of pleural invasion and plasma diffusion.
      Further studies are needed to determine the value of high-dose intrapleural CDDP
      for the treatment of MPE.

PMID- 10601614
TI  - Potentiatied anti-tumor effectiveness of combined therapy with interleukin-12 and
      mitoxantrone of L1210 leukemia in vivo.
AB  - In previous studies we have shown that combined chemo-immunotherapy of L1210
      leukemia with IL-12 and doxorubicin results in striking anti-tumor effects
      producing 100% of long-term survivors. In this study we investigated the efficacy
      of a combination of IL-12 and mitoxantrone in murine L1210 leukemia. Mice
      inoculated with 1x105 leukemia cells were treated with a single dose of
      mitoxantrone and seven daily doses of IL-12, and were daily observed for
      survival. Treatment with IL-12 or mitoxantrone given alone produced moderate anti
      leukemic effects. However, combination of both drugs resulted in a significant
      prolongation of mouse survival time. Importantly, there were almost 50% of long
      term (>60 days) survivors among the mice treated with both agents. This
      therapeutic effect was completely abrogated by sub-lethal, whole-body X
      irradiation, and significantly reduced after macrophage depletion.

PMID- 10601615
TI  - Lack of effect by prostaglandin F2alpha on the proliferation of the HCT-8 and HT
      29 human adenocarcinoma cell lines.
AB  - A variety of studies have supported the finding that regular intake of aspirin or
      non-steroidal anti-inflammatory drugs can affect colorectal cancer carcinogenesis
      by decreasing the synthesis of prostaglandins (PGs). We report that PG F2alpha,
      in the presence of indomethacin, did not stimulate the proliferation in HCT-8 and
      HT-29 human colon adenocarcinoma cells. Moreover, in both cell lines
      fluprostenol, a specific agonist of FP receptors, did not increase intracellular
      Ca2+ concentration, monitored with the fluorescent dye fura-2. These results
      indicate that in HCT-8 and HT-29 cells: i) proliferation is not sensitive to PG
      F2alpha; ii) functional FP receptors are absent. Therefore, either PG F2alpha is
      not necessarily involved in the proliferation of colorectal mucosa or cell lines
      other than HCT-8 and HT-29 should be used to assess the role played by PG F2alpha
      in promoting cell proliferation in colon cancer.

PMID- 10601616
TI  - Local and systemic treatment in small cell carcinoma of the esophagus.
AB  - Primary small cell carcinoma of the esophagus is a rare and aggressive disease.
      We report on our experience with two patients having a small cell cancer of the
      esophagus, being treated with photodynamic therapy combined with irradiation and
      induction-chemotherapy as well as a review of literature. Both patients were
      admitted with severe dysphagia, weight loss and a Karnovsky performance status of
      90. Diagnostic work-up revealed tumor-stenosis in the proximal third in one and
      in the distal third in the other case. Clinical staging showed T4N2M0 and T3N2M0,
      pure small cell carcinoma. Due to dysphagia and lymph node enlargement, local and
      systemic therapy were considered as first-line treatment. Restaging after three
      cycles of induction-chemotherapy revealed partial response in both cases.
      Esophagectomy as a second-line treatment was considered. However, in the
      preoperative period, one patient developed motorical aphasia. The CT-scan of the
      brain showed multiple brain metastases. External beam irradiation and further
      chemotherapy was initiated. The patient died 12 months after admission. The other
      patient revealed anatomical inoperability at the staging laparoscopy. External
      beam irradiation and a second session of PDT was performed. The patient is still
      alive, 12 months after his first admission. The biological behavior of this
      aggressive disease and metastases in about 50% of patients at admission, as well
      as significant dysphagia makes combined systemic and local treatment necessary.
      Nevertheless, after reviewing the literature, esophagectomy and adjuvant
      chemotherapy may have an advantage pertaining to survival time when anatomical
      and functional operability is given.

PMID- 10601617
TI  - Clofazimine and B4121 sensitize an intrinsically resistant human colon cancer
      cell line to P-glycoprotein substrates.
AB  - The potential of B4121 to sensitize three intrinsically resistant human colon
      cancer cell lines (CaCo2, ATCC HTB 37; COLO 32 DM, ATCC CCL 220; HT-29, ATCC HTB
      38) to vinblastine, doxorubicin, daunorubicin, paclitaxel, taxotere and cisplatin
      at a non-toxic, therapeutically relevant concentration of 0.25 microg/ml was
      compared with that of clofazimine at a similar concentration. The cell line
      expressing high levels of P-glycoprotein (P-gp), COLO 320 DM, was susceptible to
      chemosensitization by the experimental agents for the P-gp substrates
      (paclitaxel, taxotere, daunorubicin, vinblastine and doxorubicin) but not for
      cisplatin. CaCo2 cells expressed lower levels of P-gp and were only marginally
      susceptible to sensitization by any one of these drugs, except in the case of
      sensitization by B4121 for doxorubicin and taxotere, whereas the HT-29, a P-gp
      negative cell line, was unaffected. The riminophenazines, especially B4121, might
      prove useful as combination treatment in circumventing P-gp mediated resistance
      of colon cancers.

PMID- 10601618
TI  - Concordance between tumour cell activation by epidermal growth factor and
      alteration of cell sensitivity to cisplatin and lymphokine-activated killer cell
      activity.
AB  - In this study the impact of epidermal growth factor (EGF) on chemosensitivity and
      susceptibility to lymphokine-activated killer (LAK) cytolysis on six cell lines
      (one super expressing EGFr i.e. HN5, three high expressing i.e. Hep2, KB and MCF
      7 and two low expressing i.e. Fen and HN15) was investigated using the
      tetrazolium salt reduction assay (MTT) as measured by optical density (OD). Hep2,
      KB, MCF-7 and Fen lines showed a dose-related inhibition to cisplatin (from 19%
      to 80%). Treatment of EGFr positive cell lines, Hep2, KB and MCF-7 but not EGFr
      negative Fen by EGF prior to exposure to cisplatin inhibited the cells by between
      10-15% (p<0.05). Exposure of HN5 line to EGF (0.1 ng/ml) prior to LAK assay, led
      to a decrease in tumour killing (13%, p<0.05). However, at 0.01 ng/ml the pre
      treatment enhanced tumour sensitivity. These data indicated that pre-exposure of
      tumour cells to EGF altered their response to cisplatin and LAK killing and this
      depended on the degree of EGFr expression. These data may prove helpful for pre
      selection of patients for an appropriate therapy.

PMID- 10601619
TI  - Carcinomatous meningitis and solid tumours.
AB  - This retrospective study concerning patients with a carcinomatous meningitis (CM)
      associated with solid tumour aimed at identifying risk markers of CM which could
      be used in the future in order to prevent from this neurological complication.
      From 1976 to 1996, the patients whose CSF sampling was positive cytologically,
      were registered recording baseline clinical data, tumour histology with grade,
      tumour dissemination, treatments and follow-up. Simultaneously to the recruitment
      of the patients the incidence of CM was derived at each 5-year period. The
      variables were analysed by uni- and multivariate statistics. Among the 41 cases,
      the first three sites of the primary were breast, lung, essentially small cell
      lung cancer, and urinary tumours. At their initial presentation, 22 patients
      revealed an M1 dissemination and 22 tumours were undifferentiated. Over the 20
      years, the incidence of CM has significantly increased for urinary cancers,
      decreased for breast cancer while the administration of neoadjuvant chemotherapy
      was increasing, and remained unchanged for lung cancer. M1 and/or
      undifferentiated tumours shortened the time-to-CM whereas bone metastases, that
      were the most frequent site for secondary deposits, did not. Breast, lung and
      urinary cancers produced 80% of the CM in the series. Neoadjuvant chemotherapy
      possibly could save patients from the meningeal dissemination. M1 and
      undifferentiated tumours appeared to be independent risk factors, as well as
      osseous metastases. Other risk factors of CM should be identified in prospective
      trials.

PMID- 10601625
TI  - Structural parsimony in endonuclease active sites: should the number of homing
      endonuclease families be redefined?
AB  - Homing endonucleases are classified into four families based on active site
      sequence motifs. Through structural comparisons we have found structural
      similarities between the endonuclease domain of colicin E9, an H-N-H motif
      containing enzyme, and both the non-specific nuclease from Serratia and I-PpoI, a
      His-Cys box-containing homing endonuclease. Our comparison identifies
      conservation at the heart of all three enzyme active sites and so argues for a re
      classification of H-N-H and His-Cys box homing endonucleases as a single family.
      We suggest the 'betabetaalpha-Me family' of homing enzymes to reflect the three
      elements of secondary structure and the metal ion that define the motif.

PMID- 10601626
TI  - Complementary packing of alpha-helices in proteins.
AB  - The packing of alpha-helices in proteins is restricted by both the principle of
      close packing and the chemical nature of side chains. As a result, (1) alpha
      helical surfaces forming the interface should be complementary to each other, (2)
      hydrophobic stripes of the alpha-helices should fit together like pieces of a
      jigsaw puzzle, and (3) buried polar side chains (if there are any) should be
      arranged in a complementary fashion.

PMID- 10601627
TI  - Disulfide cross-linking of subunits F(1)-gamma and F(0)I-PVP(b) results in
      asymmetric effects on proton translocation in the mitochondrial ATP synthase.
AB  - A study is presented on the effect of diamide-induced disulfide cross-linking of
      F(1)-gamma and F(0)I-PVP(b) subunits on proton translocation in the mitochondrial
      ATP synthase. The results show that, upon cross-linking of these subunits, whilst
      proton translocation from the A side to the B F(1) side is markedly accelerated
      with decoupling of oxidative phosphorylation, proton translocation in the reverse
      direction, driven by either ATP hydrolysis or a diffusion potential, is
      unaffected. These observations reveal further peculiarities of the mechanism of
      energy transfer in the ATP synthase of coupling membranes.

PMID- 10601628
TI  - Isolation of a glycosylated form of the chicken eggshell protein ovocleidin and
      determination of the glycosylation site. Alternative
      glycosylation/phosphorylation at an N-glycosylation sequon.
AB  - Ovocleidin, a major protein of the avian eggshell calcified layer, occurs in the
      eggshell soluble organic matrix in at least two forms. The major form is a
      phosphoprotein with two phosphorylated serines (OC-17) which was sequenced
      recently. A minor form is a glycosylated protein with identical sequence and only
      one phosphorylated serine (OC-23). The site of glycosylation is Asn(59), the only
      asparagine in the amino acid sequence contained in the N-glycosylation site
      consensus sequence, N-A-S. Ser(61), which is part of this site, is phosphorylated
      in OC-17 but not in OC-23 indicating that the two modifications are mutually
      exclusive. This is the first example of alternative glycosylation/phosphorylation
      occurring at an N-glycosylation site.

PMID- 10601629
TI  - Changes in myosin heavy chain mRNA and protein isoforms in single fibers of
      unloaded rat soleus muscle.
AB  - Changes in myosin heavy chain (MHC) mRNA and protein isoforms were investigated
      in single fibers from rat soleus muscle unloaded by hindlimb suspension for 4 and
      7 days. Dramatic changes were seen after 4 days, when all fibers co-expressed
      slow and fast MHC mRNAs. Most fibers contained mRNAs for MHCIbeta, MHCIIa,
      MHCIId(x), and MHCIIb. The up-regulation of the fast isoforms was only partially
      transmitted to the protein level. Atypical combinations of MHC mRNA isoforms,
      which deviated from the 'next-neighbor rule', were frequent in fibers from
      unloaded soleus. These atypical combinations increased with time and were not
      observed in the controls. The results suggest that hindlimb suspension elicits in
      soleus muscle pronounced perturbations in the expression of MHC isoforms by
      disrupting transcriptional and translational activities.

PMID- 10601630
TI  - Dynamic character of the complex of human blood coagulation factor VIIa with the
      extracellular domain of human tissue factor: a normal mode analysis.
AB  - As an attempt to investigate the dynamic interactions between plasma serine
      protease, coagulation factor VIIa (VIIa) and its cofactor, tissue factor (TF), we
      performed normal mode analysis (NMA) of the complex of VIIa with soluble TF (the
      extracellular part of TF; sTF). We compared fluctuations of Calpha atoms of VIIa
      or sTF derived from NMA in the VIIa-sTF complex with those of VIIa or sTF in an
      uncomplexed condition. The atomic fluctuations of the Calpha atoms of sTF
      complexed with VIIa did not significantly differ from those of sTF without VIIa.
      In contrast, the atomic fluctuations of VIIa complexed with sTF were much smaller
      than those of VIIa without sTF. These results suggest that domain motions of VIIa
      molecule alone are markedly dampened in the VIIa-sTF complex and that the sTF
      molecule is relatively more rigid than the VIIa molecule. This may indicate
      functions of TF as a cofactor.

PMID- 10601631
TI  - The central interactive region of human MxA GTPase is involved in GTPase
      activation and interaction with viral target structures.
AB  - To define domains of the human MxA GTPase involved in GTP hydrolysis and
      antiviral activity, we used two monoclonal antibodies (mAb) directed against
      different regions of the molecule. mAb 2C12 recognizes an epitope in the central
      interactive region of MxA, whereas mAb M143 is directed against the N-terminal G
      domain. mAb 2C12 greatly stimulated MxA GTPase activity, suggesting that antibody
      mediated crosslinking enhances GTP hydrolysis. In contrast, monovalent Fab
      fragments of 2C12 abolished GTPase activity, most likely by blocking
      intramolecular interactions required for GTPase activation. Interestingly, intact
      IgG molecules and Fab fragments of 2C12 both prevented association of MxA with
      viral nucleocapsids and neutralized MxA antiviral activity in vivo. mAb M143 had
      no effect on MxA function, indicating that this antibody binds outside functional
      regions. These data demonstrate that the central region recognized by 2C12 is
      critical for regulation of GTPase activity and viral target recognition.

PMID- 10601632
TI  - LDL binds to surface-expressed human T-cadherin in transfected HEK293 cells and
      influences homophilic adhesive interactions.
AB  - T-cadherin (T-cad) is an unusual glycosylphosphatidylinositol-anchored member of
      the cadherin family of cell adhesion molecules. Binding of low density
      lipoproteins (LDLs) to T-cad can be demonstrated on Western blots of smooth
      muscle cell lysates, membranes and purified proteins. Using HEK293 cells
      transfected with human T-cad cDNA (T-cad+), we have investigated the adhesion
      properties of expressed mature and precursor proteins and examined the postulate
      that LDL represents a physiologically relevant ligand for T-cad. T-cad+ exhibits
      an increased Ca(2+)-dependent aggregation (vs. control) that was reduced by
      selective proteolytic cleavage of precursor T-cad and abolished after either
      proteolytic or phosphatidylinositol-specific phospholipase C (PI-PLC) cleavage of
      both mature and precursor proteins, indicating that both proteins function in
      intercellular adhesion. T-cad+ exhibited a significantly increased specific cell
      surface-binding of [(125)I]-LDL that was sensitive to PI-PLC pre-treatment of
      cells. Ca(2+)-dependent intercellular adhesion of T-cad+ was significantly
      inhibited by LDL. Our results support the suggestion that LDL is a
      physiologically relevant ligand for T-cad.

PMID- 10601633
TI  - The gamma subunit in chloroplast F(1)-ATPase can rotate in a unidirectional and
      counter-clockwise manner.
AB  - Rotation of the gamma subunit in chloroplast F(1)-ATPase (CF(1)) was investigated
      by using a single molecule observation technique, which is developed by Noji et
      al. to observe the rotation of a central gamma subunit portion in the
      alpha(3)beta(3)gamma sub-complex of F(1)-ATPase from thermophilic Bacillus PS3
      (TF(1)) during ATP hydrolysis [Noji, H. et al. (1997) Nature 386, 299-302]. We
      used two cysteines of the gamma subunit (Cys-199 and Cys-205) of CF(1)-ATPase,
      which are involved in the regulation of this enzyme, to fix the fluorochrome
      labeled actin filament. Then we successfully observed a unidirectional, counter
      clockwise rotation of the actin filament with the fluorescent microscope
      indicating the rotation of the gamma subunit in CF(1)-ATPase. We conclude that
      the rotation of the gamma subunit in the F(1)-motor is a ubiquitous phenomenon in
      all F(1)-ATPases in prokaryotes as well as in eukaryotes.

PMID- 10601634
TI  - Hypertrophic stimuli augment expression of cMG1/ERF-1, a putative zinc-finger
      motif transcription factor, in rat cardiomyocytes.
AB  - We isolated the gene for cMG1/ERF-1, a known putative zinc-finger transcription
      factor, by differential display of mRNA extracted from cardiomyocytes with and
      without leukemia inhibitory factor (LIF) stimulation. LIF induced cMG1/ERF-1 mRNA
      at 15 min, and levels peaked at 10-fold initial levels at 30 min. cMG1/ERF-1
      expression was inhibited by AG490 (JAK2 inhibitor) and genistein, but was
      unaffected by PD98059 or wortmannin. Phenylephrine, angiotensin II and endothelin
      1 also induced cMG1/ERF-1 expression. Mechanical stretch in vitro and acute
      pressure overload in vivo increased cMG1/ERF-1 expression. To our knowledge, this
      is the first report showing that the cMG1/ERF-1 gene can be induced by various
      hypertrophic stimuli, and that Janus kinase 2 is involved in this process.

PMID- 10601635
TI  - The aspartic proteinase from the rodent parasite Plasmodium berghei as a
      potential model for plasmepsins from the human malaria parasite, Plasmodium
      falciparum.
AB  - The gene encoding an aspartic proteinase precursor (proplasmepsin) from the
      rodent malaria parasite Plasmodium berghei has been cloned. Recombinant P.
      berghei plasmepsin hydrolysed a synthetic peptide substrate and this cleavage was
      prevented by the general aspartic proteinase inhibitor, isovaleryl pepstatin and
      by Ro40-4388, a lead compound for the inhibition of plasmepsins from the human
      malaria parasite Plasmodium falciparum. Southern blotting detected only one
      proplasmepsin gene in P. berghei. Two plasmepsins have previously been reported
      in P. falciparum. Here, we describe two further proplasmepsin genes from this
      species. The suitability of P. berghei as a model for the in vivo evaluation of
      plasmepsin inhibitors is discussed.

PMID- 10601636
TI  - Reduced extractability of the XPA DNA repair protein in ultraviolet light
      irradiated mammalian cells.
AB  - The XPA protein is essential for both of the known modes of nucleotide excision
      repair (NER) in human cells: transcription-coupled repair (TCR) and global genome
      repair (GGR). In TCR, this protein is thought to be recruited to lesion sites in
      DNA at which RNA polymerase II is blocked and in GGR, by direct recognition of
      damages by repair protein complex containing XPC/HR23B or DNA damage-binding
      protein. However, details of the recruitment of the XPA protein in vivo are
      unknown. It was shown earlier that a portion of another NER protein, PCNA, which
      is completely extractable from non-S-phase mammalian nuclei, becomes insoluble
      after ultraviolet (UV) light irradiation and cannot be extracted by methanol or
      buffer containing Triton X-100. In the present study, we have found that UV light
      irradiation of human or Chinese hamster cells leads to decrease of extractability
      of the XPA protein by Triton X-100. Maximal insolubilization of the XPA protein
      is observed 1-4 h after irradiation but it is not detectable by 22 h. This effect
      is dose-dependent for UV light from 2.5 to 15 J/m(2) and is unaffected by the pre
      treatment of cells with sodium butyrate, an inhibitor of histone deacetylation.
      The UV light-induced insolubilization of the XPA protein was also observed in two
      lines of Cockayne syndrome complementation group A cells, indicating that the
      effect is not dependent upon TCR. The results are discussed in relation to
      possible mechanisms of NER.

PMID- 10601637
TI  - Inhibitory effect of pax4 on the human insulin and islet amyloid polypeptide
      (IAPP) promoters.
AB  - Pax4 is a paired-box transcription factor that plays an important role in the
      development of pancreatic beta-cells. Two Pax4 cDNAs were isolated from a rat
      insulinoma library. One contained the full-length sequence of Pax4. The other,
      termed Pax4c, was identical to Pax4 but lacked the sequences encoding 117 amino
      acids at the COOH-terminus. Pax4 was found to inhibit the human insulin promoter
      through a sequence element, the C2 box, located at -253 to -244, and the islet
      amyloid polypeptide promoter through a sequence element located downstream of 
      138. The inhibitory activity of Pax4 was mapped to separate regions of the
      protein between amino acids 2-230 and 231-349.

PMID- 10601638
TI  - SMAP-29: a potent antibacterial and antifungal peptide from sheep leukocytes.
AB  - SMAP-29 is a cathelicidin-derived peptide deduced from sheep myeloid mRNA. The C
      terminally amidated form of this peptide was chemically synthesized and shown to
      exert a potent antimicrobial activity. Antibiotic-resistant clinical isolates
      highly susceptible to this peptide include MRSA and VREF isolates, that are a
      major worldwide problem, and mucoid Pseudomonas aeruginosa associated with
      chronic respiratory inflammation in CF patients. In addition, SMAP-29 is also
      active against fungi, including Cryptococcus neoformans isolated from
      immunocompromised patients. SMAP-29 causes significant morphological alterations
      of the bacterial surfaces, as shown by scanning electron microscopy, and is also
      hemolytic against human, but not sheep erythrocytes. Its potent antimicrobial
      activity suggests that this peptide is an excellent candidate as a lead compound
      for the development of novel antiinfective agents.

PMID- 10601639
TI  - GDNF triggers a novel ret-independent Src kinase family-coupled signaling via a
      GPI-linked GDNF receptor alpha1.
AB  - Glial cell line-derived neurotrophic factor (GDNF) has potentially great clinical
      importance in the treatment of Parkinson's disease and several other
      neurodegenerative diseases, however its intracellular signaling mechanisms are
      poorly understood. Here we show that upon GDNF binding glycosyl
      phosphatidylinositol (GPI)-linked GDNF receptor alpha1 (GFRalpha1) activates
      cytoplasmic Src family tyrosine kinase(s) in Ret tyrosine kinase-deficient
      cultured mouse dorsal root ganglion neurons and in two Ret-negative cell lines.
      GFRalpha1-mediated Src-type kinase activation subsequently triggers
      phosphorylation of mitogen-activated protein kinase, cAMP response element
      binding protein and phospholipase Cgamma. We therefore conclude that GDNF can
      activate intracellular signaling pathways Ret-independently via GPI-linked
      GFRalpha1.

PMID- 10601640
TI  - Unique sequence of a high molecular weight myosin light chain kinase is involved
      in interaction with actin cytoskeleton.
AB  - Myosin light chain kinase (MLCK) is the key regulator of cell motility and smooth
      muscle contraction in higher vertebrates. We searched for the features of the
      high molecular weight MLCK (MLCK-210) associated with its unique N-terminal
      sequence not found in a more ubiquitous lower molecular weight MLCK (MLCK-108).
      MLCK-210 demonstrates stronger association with the Triton-insoluble
      cytoskeletons than MLCK-108, suggesting the role for this sequence in subcellular
      targeting. Indeed, the expressed unique domain of MLCK-210 binds and bundles F
      actin in vitro and colocalises with the microfilaments in transfected cells
      reproducing endogenous MLCK-210 distribution. Thus, MLCK-210 features an
      extensive actin binding interface and, perhaps, acts as an actin cytoskeleton
      stabiliser.

PMID- 10601641
TI  - Drosophila melanogaster protein phosphatase inhibitor-2: identification of a site
      important for PP1 inhibition.
AB  - A database search with human protein phosphatase inhibitor-2 (I-2) identified a
      Drosophila melanogaster cDNA that encoded a protein identical in length and
      sharing 39% amino acid identity (58% similarity) with human I-2. The mRNA
      encoding this protein is expressed in both sexes and throughout development,
      unlike Drosophila inhibitor-t. The bacterially expressed protein was a specific
      inhibitor of protein phosphatase 1 with an IC(50) of <1 nM, confirming that it is
      the Drosophila homologue of mammalian inhibitor-2. Mutation of Phe residues
      conserved in I-2 from lower and higher eukaryotes showed that Phe-33 is important
      for inhibition of PP1c.

PMID- 10601642
TI  - A profile of differentially expressed genes in primary colorectal cancer using
      suppression subtractive hybridization.
AB  - As a step towards understanding the complex differences between normal cells and
      cancer cells, we have used suppression subtractive hybridization (SSH) to
      generate a profile of genes overexpressed in primary colorectal cancer (CRC).
      From a 35? omitted?000 clone SSH-cDNA repertoire, we have screened 400 random
      clones by reverse Northern blotting, of which 45 clones were scored as
      overexpressed in tumor compared to matched normal mucosa. Sequencing showed 37
      different genes and of these, 16 genes corresponded to known genes in the public
      databases. Twelve genes, including Smad5 and Fls353, have previously been shown
      to be overexpressed in CRC. A series of known genes which have not previously
      been reported to be overexpressed in cancer were also recovered: Hsc70, PBEF,
      ribophorin II and Ese-3B. The remaining 21 genes have as yet no functional
      annotation. These results show that SSH in conjunction with high throughput
      screening provides a very efficient means to produce a broad profile of genes
      differentially expressed in cancer. Some of the genes identified may provide
      novel points of therapeutic intervention.

PMID- 10601643
TI  - Dietary and hypothyroid hypercholesterolemia induces hepatic apolipoprotein E
      expression in the rat: direct role of cholesterol.
AB  - Apolipoprotein E (apo E) exerts a protective effect against atherosclerosis,
      related to its role in intracellular cholesterol removal and remnants clearance.
      In this study we investigated the effect of dietary and hypothyroid
      hypercholesterolemia, induced respectively by a high cholesterol diet and by
      propylthiouracil, on hepatic apo E expression in Wistar male rats. The Northern
      and Western blot analysis of hepatic mRNA and protein levels showed a 2-3-fold
      increase of apo E in hypercholesterolemic rats compared to controls. The
      incubation of FAO rat hepatoma cells with 25-OH cholesterol and mevalonate led to
      a three-fold increase of apo E mRNA, demonstrating a direct role of cholesterol
      on apo E expression. This effect was completely abolished by elevating
      intracellular cAMP levels with forskolin. Immunoblot and immunofluorescence
      analysis revealed that 25-OH cholesterol/mevalonate strongly increased also apo E
      protein synthesis and secretion in FAO cells. Our data demonstrate that
      hypercholesterolemia, apart of the cause (diet or hypothyroidism) induces liver
      apo E expression in the rat and that this effect can be directly related, via
      cAMP, to cholesterol.

PMID- 10601644
TI  - New ice-binding face for type I antifreeze protein.
AB  - Type I antifreeze protein (AFP) from winter flounder is an alanine-rich, 37 amino
      acid, single alpha-helix that contains three 11 amino acid repeats (Thr-X(2)-Asx
      X(7)), where X is generally Ala. The regularly spaced Thr, Asx and Leu residues
      lie on one face of the helix and have traditionally been thought to form hydrogen
      bonds and van der Waals interactions with the ice surface. Recently, substitution
      experiments have called into question the importance of Leu and Asn for ice
      binding. Sequence alignments of five type I AFP isoforms show that Leu and Asn
      are not well conserved, whereas Ala residues adjacent to the Thr, at right angles
      to the Leu/Asn-rich face, are completely conserved. To investigate the role of
      these Ala residues, a series of Ala to Leu steric mutations was made at various
      points around the helix. All the substituted peptides were fully alpha-helical
      and remained as monomers in solution. Wild-type activity was retained in A19L and
      A20L. A17L, where the substitution lies adjacent to the Thr-rich face, had no
      detectable antifreeze activity. The nearby A21L substitution had 10% wild-type
      activity and demonstrated weak interactions with the ice surface. We propose a
      new ice-binding face for type I AFP that encompasses the conserved Ala-rich
      surface and adjacent Thr.

PMID- 10601645
TI  - A novel glycosyltransferase with a polyglutamine repeat; a new candidate for
      GD1alpha synthase (ST6GalNAc V)(1).
AB  - The fifth type GalNAcalpha2,6-sialyltransferase (mST6GalNAc V) was cloned from a
      mouse brain cDNA library. mST6GalNAc V exhibited type II transmembrane topology
      containing a polyglutamine repeat, which showed 42.6% and 44.8% identity to mouse
      ST6GalNAc III and IV, respectively. Northern blot analysis revealed that the
      mST6GalNAc V gene was specifically expressed in forebrain and cerebellum.
      mST6GalNAc V exhibited GD1alpha synthetic activity from GM1b the same as
      mST6GalNAc III and IV. The activity ratio of GM1b toward fetuin and the
      expression pattern were completely different among the three ST6GalNAcs.
      Interestingly, the polyglutamine repeat number was different from that of inbred
      mice. We report the first glycosyltransferase with a polymorphic polyglutamine
      repeat.

PMID- 10601646
TI  - Purification and two-dimensional crystallization of highly active cytochrome
      b(6)f complex from spinach.
AB  - The purification and two-dimensional crystallization of highly active cytochrome
      b(6)f complex from spinach is described. The preparation shows all spectroscopic
      characteristics of the pure complex. The electron transfer activity of 450+/-60
      electrons per s is the highest in vitro activity reported to date. Using dimethyl
      sulfoxide (DMSO) as a solvent for the electron donor enhanced the performance and
      reproducibility of the assay. The high yield and the high activity of the protein
      make it an ideal candidate for biophysical and structural studies. Preliminary
      two-dimensional crystallization experiments yielded several different forms of
      two-dimensional and thin three-dimensional crystals, exhibiting varying degrees
      of order.

PMID- 10601647
TI  - Sarcoplasmic reticulum vesicles embedded in agarose gel exhibit propagating
      calcium waves.
AB  - In different cell types, activation of signal transduction pathways leads to the
      generation of calcium oscillations and/or waves. Due to this important impact for
      cellular function, calcium waves are the subject of intensive investigations. To
      study interactions of cell organelles with no influence of the cell membrane,
      sarcoplasmic reticulum (SR) vesicles and well-coupled mitochondria were
      reconstituted. For the first time, we demonstrate the generation and propagation
      of calcium waves in a suspension of sarcoplasmic reticulum vesicles, embedded in
      an agarose gel. The propagation dynamics resemble those of calcium waves in
      living cells. Moreover, the addition of well-coupled mitochondria leads to more
      pronounced and significantly faster propagating waves, demonstrating the
      importance of the mitochondrial Ca(2+) transport. The experimental and simulation
      results indicate the resemblance of the in vitro system to an excitable medium.

PMID- 10601648
TI  - Adrenomedullin suppresses interleukin-1beta-induced tumor necrosis factor-alpha
      production in Swiss 3T3 cells.
AB  - We demonstrated that adrenomedullin (AM) inhibited interleukin-1beta-induced
      tumor necrosis factor-alpha (TNF-alpha) secretion and gene transcription in Swiss
      3T3 fibroblasts maximally to 23% and 18% of control, while the other peptides
      elevating intracellular cAMP levels elicited much weaker effects. AM rapidly
      reduced the gene transcript level of TNF-alpha, inducing a maximal effect within
      1 h. The inhibitory effect of AM was restored with an AM receptor antagonist as
      well as a cAMP-dependent protein kinase inhibitor. These findings indicate that
      AM is a potent and quick suppressor of TNF-alpha production in Swiss 3T3 cells
      acting through the cAMP protein kinase A pathway. As TNF-alpha is a major
      inflammatory cytokine and stimulates AM production in fibroblasts, AM is deduced
      to be an autocrine or paracrine factor suppressing inflammation through the
      inhibition of TNF-alpha production.

PMID- 10601649
TI  - Selection of phage-displayed fab antibodies on the active conformation of ras
      yields a high affinity conformation-specific antibody preventing the binding of c
      Raf kinase to Ras.
AB  - The Ras proteins cycle in the cell between an inactive state and an active state.
      In the active state, Ras signals via the switch I region to effectors like c-Raf
      kinase, leading to cell growth. Since Ras mutations in cancer are often
      associated with the presence of permanently active Ras, molecules that prevent
      downstream signaling may be of interest. Here, we show that by selection on the
      active conformation of Ras, using a recently described large phage antibody
      repertoire [de Haard et al. (1999) J. Biol. Chem. 274, 18218-18230], a Fab
      antibody (Fab H2) was identified that exclusively binds to active Ras, and not to
      inactive Ras. Using surface plasmon resonance (SPR) analysis, the interaction was
      demonstrated to be of high affinity (7.2 nM). In addition, the interaction with
      Ras is specific, since binding to the homologous Rap1A protein in BIAcore
      analysis is at least three orders of magnitude lower, and undetectable in an
      enzyme-linked immunosorbent assay. The antibody fragment prevents the binding of
      active Ras to the immobilized Ras-binding domain of c-Raf kinase (Raf-RBD) at an
      IC(50) value of 135 nM. This value compares well to the K(D) of active Ras
      binding to immobilized Raf-RBD using SPR, suggesting identical binding sites.
      Like the IgG Y13-259, which does not demonstrate preferential binding to either
      inactive or active Ras, Fab H2 inhibits intrinsic GTPase activity of Ras in
      vitro. Mapping studies using SPR analysis demonstrate that the binding sites for
      the antibodies are non-identical. This antibody could be used for dissecting
      functional differences between Ras effectors. Due to its specificity for active
      Ras, Fab H2 may well be more selective than previously used anti-Ras antibodies,
      and thus could be used for gene therapy of cancer with intracellular antibodies.

PMID- 10601650
TI  - Heparin binding peptides co-purify with glycosaminoglycans from human plasma.
AB  - Glycosaminoglycans (GAGs) are complexed with plasma proteins and proteolysis of
      plasma reduced the protein-GAG ratio about 140-fold. After dialysis, analysis by
      gradient PAGE revealed heparinase-1-sensitive GAGs, thus suggesting that heparin
      could be among the plasma GAGs. However, after dialysis most of the plasma GAGs
      were still not 'free'. PAGE of peptides resistant to proteolysis showed high
      molecular weight bands on the two sides of the dialysis membrane despite the 3.5
      kDa molecular weight cut-off. Progressive dilution of the sample allowed passage
      of peptides appearing as high molecular weight bands in the diffusate. We
      interpret this phenomenon as the presence of low molecular weight peptides that
      aggregate when concentrated. Peptides on both sides of the membranes bound
      heparin.

PMID- 10601651
TI  - Simultaneous core 2 beta1-->6N-acetylglucosaminyltransferase up-regulation and
      sialyl-Le(X) expression during activation of human tonsillar B lymphocytes.
AB  - We have investigated the regulation mechanism of the surface sialyl-Le(X)
      (sLe(X)) expression level in tonsillar B cells during activation. sLe(X) antigen
      became strongly positive after activation, while resting B cells were weakly
      positive. sLe(X) structures were mainly located on O-linked oligosaccharide
      chains of glycoprotein. Transcripts of FucT-VII and core 2 GlcNAc transferase
      (C2GnT) were up-regulated after activation, while those of ST3GalIV and beta1-
      >4GalT-I were expressed constitutively. However, the up-regulation of C2GnT was
      more dramatic than that of FucT-VII. These results suggest that sLe(X) expression
      level is regulated by C2GnT during tonsillar B cell activation.

PMID- 10601652
TI  - A heuristic approach of maximum likelihood method for inferring phylogenetic tree
      and an application to the mammalian SOX-3 origin of the testis-determining gene
      SRY.
AB  - Applying the tree bisection and reconnection (TBR) algorithm, we have developed a
      heuristic method (maximum likelihood (ML)-TBR) for inferring the ML tree based on
      tree topology search. For initial trees from which iterative processes start in
      ML-TBR, two cases were considered: one is 100 neighbor-joining (NJ) trees based
      on the bootstrap resampling and the other is 100 randomly generated trees. The
      same ML tree was obtained in both cases. All different iterative processes
      started from 100 independent initial trees ultimately converged on one optimum
      tree with the largest log-likelihood value, suggesting that a limited number of
      initial trees will be quite enough in ML-TBR. This also suggests that the optimum
      tree corresponds to the global optimum in tree topology space and thus probably
      coincides with the ML tree inferred by intact ML analysis. This method has been
      applied to the inference of phylogenetic tree of the SOX family members. The
      mammalian testis-determining gene SRY is believed to have evolved from SOX-3, a
      member of the SOX family, based on several lines of evidence, including their
      sequence similarity, the location of SOX-3 on the X chromosome and some aspects
      of their expression. This model should be supported directly from the
      phylogenetic tree of the SOX family, but no evidence has been provided to date. A
      recently published NJ tree shows implausibly remote origin of SRY, suggesting
      that a more sophisticated method is required for understanding this problem. The
      ML tree inferred by the present method showed that the SRYs of marsupial and
      placental mammals form a monophyletic cluster which had diverged from the
      mammalian SOX-3 in the early evolution of mammals.

PMID- 10601653
TI  - Molecular cloning and biological activity of ecdysis-triggering hormones in
      Drosophila melanogaster.
AB  - Ecdysis-triggering hormones (ETH) initiate a defined behavioral sequence leading
      to shedding of the insect cuticle. We have identified eth, a gene encoding
      peptides with ETH-like structure and biological activity in Drosophila
      melanogaster. The open reading frame contains three putative peptides based on
      canonical endopeptidase cleavage and amidation sites. Two of the predicted
      peptides (DrmETH1 and DrmETH2) prepared by chemical synthesis induce premature
      eclosion upon injection into pharate adults. The promoter region of the gene
      contains a direct repeat ecdysteroid response element. Identification of eth in
      Drosophila provides opportunities for genetic manipulation of endocrine and
      behavioral events underlying a stereotypic behavior.

PMID- 10601654
TI  - The gene distribution in the genomes of pea, tomato and date palm.
AB  - The vast majority of genes of maize, rice, barley and wheat are contained in long
      gene-rich regions (collectively called the 'gene space') separated by long gene
      empty regions. The gene space covers a narrow, 0.8-1.6%, GC range, possibly
      because of the presence of abundant transposons. Here we report that the gene
      space is not an exclusive property of Gramineae, because it also exists in the
      large genome of pea (5000 Mb). Moreover, the gene space is not just dependent
      upon genome size, since a gene space is found in rice (415 Mb), but not in
      Arabidopsis (120 Mb), nor in two other plants investigated in the present work,
      date palm (250 Mb) and tomato (1000 Mb).

PMID- 10601655
TI  - Uptake of [(3)H]bilirubin in freshly isolated rat hepatocytes: role of free
      bilirubin concentration.
AB  - Hepatocytic transport of physiological concentrations of unconjugated bilirubin
      (UCB) has not been determined in isolated liver cells. Initial uptake of highly
      purified [(3)H]UCB was measured in rat hepatocytes in the presence of human serum
      albumin at various free, unbound UCB concentrations, [UCB]. At [UCB]=42 nM (below
      aqueous solubility of 70 nM), uptake was strictly temperature dependent; this was
      much less evident at [UCB]=166 nM (supersaturated). At low, physiological UCB
      concentrations, specific UCB uptake showed saturative kinetics with an apparent
      K(m) of 41 nM, indicating carrier-mediated transport. With aqueous
      supersaturation, UCB entered hepatocytes mainly by passive diffusion.

PMID- 10601656
TI  - Smooth muscle alpha-tropomyosin crosslinks to caldesmon, to actin and to myosin
      subfragment 1 on the muscle thin filament.
AB  - To obtain proximity information between tropomyosin (Tm) and caldesmon (CaD) on
      the muscle thin filament, we cloned gizzard alphaTm and created two single Cys
      mutants S56C/C190S (56Tm) and D100C/C190S (100Tm). They were labeled with
      benzophenone maleimide (BPM) and UV-irradiated on thin filaments. One chain of
      BPM-56Tm and two chains of BPM-100Tm crosslinked to CaD. Only BPM-100Tm
      crosslinked to actin in the absence and presence of CaD and binding of low ratios
      of myosin subfragment 1 (S1) prevented the crosslinking. Tm-S1 crosslinks were
      produced when actin.Tm was saturated with S1. Thus, CaD on the actin.Tm filament
      is located <10 A away from Tm amino acids 56 and 100; in the closed state of the
      actin.Tm filament, Tm residue 100 is located close to the actin surface and is
      moved further away in the S1-induced open state; in the open state, S1 binds
      close to Tm.

PMID- 10601657
TI  - Translocation of cytochrome c from the mitochondria to the cytosol occurs during
      heat-induced programmed cell death in cucumber plants.
AB  - In mammals mitochondria play a critical role in the activation of programmed cell
      death (PCD). One mechanism by which mitochondria can commit a cell to death is by
      translocating cytochrome c into the cytosol where it activates cell death
      caspases. However, release of cytochrome c does not appear to be a feature of
      caspase activation in nematodes or insects, similarly, there is no evidence for
      cytochrome c release during the caspase-independent PCD that can occur in
      Dictyostelium cells. In an attempt to understand the underlying regulation of PCD
      in plants we investigated if mitochondrial components were released into the
      cytosol when plant cells are induced to undergo PCD. PCD was triggered in
      cucumber cotyledons by subjecting them to a short 55 degrees C heat treatment.
      This heat treatment has previously been shown to trigger PCD in other plant
      species and cell death was confirmed in cucumber using morphological (cellular
      condensation) and molecular (DNA 'laddering') markers of PCD. We present evidence
      that, unlike Dictyostelium and invertebrate PCDs, cytochrome c release is an
      early event in plant PCD. The mitochondrial release of cytochrome c following a
      PCD-inducing stimulus in both plants and mammals suggests the pathways have been
      conserved during evolution, having been derived from ancestral unicellular death
      programmes.

PMID- 10601658
TI  - Increased leukotriene A(4) hydrolase expression in the heart of angiotensin II
      induced hypertensive rat.
AB  - Leukotriene A(4) (LTA(4)) hydrolase is essential for the conversion of LTA(4) to
      LTB(4), an inflammatory lipid mediator. We investigated whether LTA(4) hydrolase
      was regulated in the heart by angiotensin II (ang II) infusion. Continuous ang II
      infusion via an osmotic minipump for up to 7 days upregulated mRNA and protein
      levels of LTA(4) hydrolase ( approximately 3.5-fold of control) in the heart in a
      pressor-dependent manner. Immunohistochemistry demonstrated intense LTA(4)
      hydrolase staining in the myofibroblast as well as migrated
      monocytes/macrophages. These data suggest that the cardiac LTA(4) hydrolase
      LTB(4) system plays a positive role in the promotion of cardiac inflammation in
      hypertension.

PMID- 10601659
TI  - Cloning of bovine RANTES mRNA and its expression and regulation in ovaries in the
      periovulatory period.
AB  - RANTES may be one of the chemoattractants involved in stimulating eosinophils and
      macrophages to migrate selectively into bovine dominant follicles and into
      developing corpora lutea. We sequenced a 736 bp fragment of the bovine RANTES
      mRNA encoding the complete protein and defined the ovarian source of RANTES mRNA.
      As demonstrated by competitive RT-PCR, follicle-derived macrophages showed a 100
      1000 times higher RANTES mRNA level compared to unpurified granulosa cells or
      follicle-derived fibroblasts. By means of in situ hybridization, RANTES mRNA
      positive macrophages were located in the former thecal layer of the developing
      corpora lutea.

PMID- 10601660
TI  - Photosensitive liposomes as 'cages' for laser-triggered solute delivery: the
      effect of bilayer cholesterol on kinetics of solute release.
AB  - Liposomes containing acyl chains incorporating azobenzene chromophores have been
      investigated as potential 'caging' agents for fast solute release. On photolysis,
      trapped marker dye can be released from gel-phase liposomes within milliseconds.
      Solute release is markedly sensitive to the presence of cholesterol in the
      bilayer. Phospholipids bearing one saturated acyl chain and an azobenzene
      substituted chain are ineffective as sensitisers unless cholesterol is present,
      while doubly substituted phospholipids sensitise release in its absence.
      Cholesterol markedly affects the temperature profile of solute release depending
      on the host phospholipid chain length. Solute release is not seen for lipid hosts
      with unsaturated acyl chains.

PMID- 10601661
TI  - Identification of a hydrogen bond in the phe M197-->Tyr mutant reaction center of
      the photosynthetic purple bacterium Rhodobacter sphaeroides by X-ray
      crystallography and FTIR spectroscopy.
AB  - In bacterial reaction centers the charge separation process across the
      photosynthetic membrane is predominantly driven by the excited state of the
      bacteriochlorophyll dimer (D). An X-ray structure analysis of the Phe M197-->Tyr
      mutant reaction center from Rhodobacter sphaeroides at 2.7 A resolution suggests
      the formation of a hydrogen bond as postulated by Wachtveitl et al. [Biochemistry
      32, 12875-12886, 1993] between the Tyr M197 hydroxy group and one of the 2a
      acetyl carbonyls of D. In combination with electrochemically induced FTIR
      difference spectra showing a split band of the pi-conjugated 9-keto carbonyl of
      D, there is clear evidence for the existence of such a hydrogen bond.

PMID- 10601662
TI  - Human rhinovirus HRV14 uncoats from early endosomes in the presence of
      bafilomycin.
AB  - Determination of infectious progeny virus and in vivo labelling with
      [(35)S]methionine followed by immunoprecipitation demonstrates that the major
      receptor group human rhinovirus HRV14 is able to infect HeLa cells in the
      presence of the V-ATPase inhibitor bafilomycin A1. However, host cell shut off is
      delayed and viral yield is decreased in the presence of the drug. Uncoating can
      thus take place under conditions that prevent endosomal acidification indicating
      that it is catalysed by the viral receptor alone. Since transport is arrested in
      early endosomes upon inhibition of vesicle acidification, the data also suggest
      that productive uncoating takes place from early endocytic compartments.

PMID- 10601663
TI  - Biochemical characterization of different conformational states of the Sf9 cell
      purified p53His175 mutant protein.
AB  - In this study, we expressed and purified the p53 mutant encoded by the His175
      allele (p53His175) in a baculovirus expression system in order to study the
      folding and the DNA binding activity of the protein. A two-site ELISA revealed
      that purified p53His175 protein preferentially displayed a PAb1620 conformation,
      which appeared to be not sufficient to interact specifically with DNA. The
      cryptic DNA binding activity of this mutant was then investigated by
      electrophoretic mobility shift assay in the presence of anti-p53 antibodies, and
      shown to be refractory to significant activation by PAb421 (a potent allosteric
      activator of wild-type p53's DNA binding activity). Nevertheless, p53His175 DNA
      binding was regulated by antibodies targeting the N-terminal region of the
      protein. Furthermore, while the protein preferentially displayed a PAb1620
      conformation, our data suggested the existence of an equilibrium between at least
      two folding states of the protein (PAb1620 and PAb240 conformations). A model
      rationalizing the conformation, antibody-interacting ability and DNA binding
      regulation potential of p53His175 is presented.

PMID- 10601664
TI  - The T3(b) gene promoter directs intestinal epithelial cell-specific expression in
      transgenic mice.
AB  - Although a few promoters that direct intestinal epithelial cell-specific
      expression in transgenic animals have been reported, they are not necessarily
      appropriate for transgenic studies in terms of activity and tissue specificity.
      Here, we examined the tissue specificity of transgene expression directed by the
      2.8-kb promoter region of the T3(b) gene, which encodes one of the non-classical
      major histocompatibility complex class I molecules. The transgene was expressed
      exclusively in the epithelial cells of the small and large intestines at high
      levels. The results indicate that the T3(b) promoter is useful for directing
      transgene expression specifically in intestinal epithelial cells.

PMID- 10601665
TI  - Core alpha1-->3-fucose is a common modification of N-glycans in parasitic
      helminths and constitutes an important epitope for IgE from Haemonchus contortus
      infected sheep.
AB  - Synthesis of parasite specific IgE plays a critical role in the defence against
      helminth infections. We report here that IgE from serum from Schistosoma mansoni
      infected mice and Haemonchus contortus infected sheep recognizes complex-type N
      glycans from Arabidopsis thaliana, which contain R-GlcNAcbeta1-->4(Fucalpha1-
      >3)GlcNAcbeta1-Asn (core alpha1-->3-Fuc) and Xylbeta1-->2Manbeta1-->4GlcNAcbeta1
      R (core beta1-->2-Xyl) modifications, and honeybee phospholipase A2, which
      carries N-glycans that contain the core alpha1-->3-Fuc epitope. Evidence is
      presented that core alpha1-->3-fucosylated N-glycans bind a substantial part of
      the parasite specific IgE in serum of H. contortus infected sheep. These results
      suggest that the core alpha1-->3-Fuc antigen may contribute to induction of a Th2
      response leading to the production of IgE. In addition we show here that N
      glycans carrying core alpha1-->3-Fuc and beta1-->2-Xyl antigens are synthesized
      by many parasitic helminths and also by the free living nematode Caenorhabditis
      elegans. Since N-glycans containing the core alpha1-->3-Fuc have also been
      implicated in honeybee and plant induced allergies, this conserved glycan might
      represent an important common IgE epitope.

PMID- 10601666
TI  - Detection and regulation of leptin receptor mRNA in ovine mammary epithelial
      cells during pregnancy and lactation.
AB  - Adipocyte-epithelial cell interactions and their secretions are critical
      determinants of mammary gland development. In this present study, we examined the
      possible involvement of leptin and its receptors in the process of
      mammogenesis/lactogenesis. We demonstrated by reverse transcription and
      polymerase chain reaction analysis that long and short forms of leptin receptors
      were expressed in the ovine mammary gland during pregnancy and lactation.
      Furthermore, quantitative determinations, via ribonuclease protection assays,
      provided evidence that the level of leptin receptor expression was greatest
      during mid-pregnancy when active growth of the mammary gland is initiated.
      Location of the leptin receptors, as determined by in situ hybridization
      analysis, revealed that leptin receptor transcripts were expressed specifically
      in mammary epithelial cells. These data provide evidence that leptin, with its
      receptors, could be an important mediator in regulating mammary gland growth and
      development.

PMID- 10601667
TI  - The role of corticotropin-releasing factor in pain and analgesia.
AB  - Corticotropin-releasing factor (CRF) is a peptide that is released from the
      hypothalamus and in widespread areas of the brain following exposure to
      stressors. It is considered to be a mediator of many of the effects of stress,
      and its analgesic properties have been demonstrated in many studies. However, for
      primarily methodological reasons, the effects of CRF in the central nervous
      system have been neglected whereas the peripheral effects of CRF have been
      overemphasized. We present evidence that: (1) CRF can act at all levels of the
      neuraxis to produce analgesia; (2) the release of beta-endorphin does not explain
      the analgesia following intravenous or intracranial CRF administration; (3)
      inflammation must be present for local CRF to evoke analgesia and (4) the
      analgesic effects of CRF show specificity for prolonged pain. These findings
      suggest that CRF may have a significant role in chronic pain syndromes associated
      with hypothalamic-pituitary-adrenal axis abnormalities. Furthermore, CRF may
      represent a new class of analgesics that merits further study. Implications for
      the relationship between stress and pain are discussed.

PMID- 10601668
TI  - Moxonidine, a selective imidazoline/alpha(2) adrenergic receptor agonist,
      synergizes with morphine and deltorphin II to inhibit substance P-induced
      behavior in mice.
AB  - The alpha(2) adrenergic receptor (AR) class of catecholamine/imidazoline (I)
      agonists, such as norepinephrine and clonidine, produce spinal antinociceptive
      synergy when co-administered with opioids. We have observed that intrathecally
      administered moxonidine, a selective I(1)/alpha(2) (AR) agonist, produces
      antinociception. The present experiments tested moxonidine for ability to
      synergize with morphine, deltorphin II, and DAMGO (Tyr-D-Ala-NMe-Phe-Gly(ol)) to
      inhibit substance P-elicited nociceptive behavior in Institute of Cancer Research
      mice. Moxonidine, morphine, deltorphin II, and DAMGO inhibited substance P
      elicited nociceptive behavior with full efficacy. Effective dose 50% (ED(50))
      values were calculated and equi-effective dose ratios of the combinations
      moxonidine-morphine, moxonidine-deltorphin II, and moxonidine-DAMGO were
      determined. The interactions were tested by isobolographic analysis. The observed
      ED(50) values of the combinations were statistically compared against their
      respective calculated theoretical additive ED(50) values. The combinations of
      moxonidine-morphine and moxonidine-deltorphin II resulted in significant leftward
      shifts in the dose-response curves compared to those of each agonist administered
      separately. The ED(50) values of the dose-response curves of these combinations
      were significantly less than the corresponding calculated theoretical additive
      ED(50) values; these results indicated that moxonidine synergizes with both
      morphine and deltorphin II. In contrast, combining moxonidine with DAMGO did not
      increase the potencies of the agonists (in combination) when compared to the
      potencies of each agonist administered separately. These results indicated that
      the moxonidine-DAMGO interaction is subadditive. Collectively, these data
      demonstrate that moxonidine combined with some opioid agonists produces spinal
      antinociceptive synergy. Spinally administered moxonidine-opioid combinations may
      prove an effective therapeutic strategy to manage pain.

PMID- 10601669
TI  - Increased spinal cholecystokinin activity after systemic resiniferatoxin:
      electrophysiological and in situ hybridization studies.
AB  - The present study assessed the effect of a single subcutaneous injection of
      resiniferatoxin (RTX), an ultrapotent capsaicin analogue, on the activity of
      spinal cholecystokinin (CCK) systems, by using electrophysiological and in situ
      hybridization techniques. Subcutaneous RTX at 0.3 mg/kg, but not vehicle,
      produced marked thermal hypoalgesia in rats on the hot plate and tail flick
      tests. Partial recovery from hypoalgesia occurred in some (<50%), but not all,
      RTX-treated rats after 2 weeks. The flexor reflex in response to activation of
      high threshold afferents was recorded 15-35 days after RTX- or vehicle-treatment.
      There was no obvious difference between RTX- and vehicle-treated rats in the
      baseline flexor reflex. Intravenous morphine at 1 mg/kg caused a depression of
      the flexor reflex in vehicle- and in RTX-treated rats. The reflex depressive
      effect of morphine was significantly briefer in RTX-treated, non-recovered rats
      than vehicle-treated rats. Furthermore, CI-988, a high affinity antagonist of
      CCKB receptors, caused a minor depression of the reflex in vehicle- and RTX
      treated rats that had partially recovered, whereas the reflex depressive effect
      of CI-988 was significantly enhanced in RTX-treated, non-recovered rats. In situ
      hybridization showed that RTX treatment caused a marked and significant increase
      in the number of dorsal root ganglion (DRG) neurone profiles expressing CCKB
      receptor mRNA, whereas only a small increase was observed for CCKA receptor mRNA
      expressing neurone profiles. Significantly more DRG neurone profiles expressed
      CCKB receptor mRNA in RTX-treated, non-recovered rats compared to partially
      recovered rats. RTX-treatment did not influence the expression of CCK mRNA in
      DRGs. Since CCK functions as a physiological antagonist of morphine, it is
      suggested that RTX treatment enhances the activity of spinal CCK systems, leading
      to the reduced effect of morphine and increased effect of the CCKB receptor
      antagonist CI-988. This may mainly be due to upregulation of CCKB receptors in
      DRG neurones.

PMID- 10601670
TI  - Interaction between cutaneous and muscle afferent activity in polysynaptic reflex
      pathways: a human experimental study.
AB  - Interactions between the input from cutaneous and nociceptive muscle afferents in
      polysynaptic reflex pathways were investigated in man. Interaction was tested by
      evoking reflexes before, during, and after a period of muscle pain induced by
      intramuscular injection of hypertonic saline. Muscle pain was induced either in
      the ankle flexor (tibialis anterior, TA) or in the extensor (soleus, SOL) muscles
      by injection of 1 ml hypertonic saline. Electrical skin stimulation (1.1 x
      initial reflex threshold) at the dorsum of the foot over the tarsal joint was
      used to elicit cutaneo-muscular polysynaptic reflexes in the knee flexor
      semitendinosus (ST). The injected hypertonic saline evoked a robust muscle pain
      (the subjects made a continuous score of the muscle pain on a 0-10 cm VAS scale,
      and the mean VAS area was 1229+/-251 cm x s and lasting 390+/-30 s). In five of
      12 subjects, the infusion of hypertonic saline into TA evoked referred pain to
      the dorsal aspect of the ankle. A significant inhibition (17+/-8.2%, P<0.05) of
      the ST-reflex by pain in SOL was observed. Pain in TA facilitated (92+/-36%,
      P<0.05) the short-latency part (50-70 ms post stimulation) of the reflex. The
      muscle pain did not modulate the perceived sensory intensity of the electrical
      stimuli. The findings indicate an interaction of input from thin muscle afferents
      and cutaneous group A-fibre afferents in polysynaptic segmental reflex pathways,
      which seems to depend on the location of the muscle pain.

PMID- 10601671
TI  - Pain measurement with evoked potentials: combination of subjective ratings,
      randomized intensities, and long interstimulus intervals produces a P300-like
      confound.
AB  - Evoked potentials in response to painful stimuli have been studied as objective
      measures of pain. Bromm has advocated experimental conditions in which, (1)
      stimulus intensities are randomized, and (2) subjects rate each stimulus.
      However, a cognitive, i.e. information processing, 'late positive component'
      (LPC), e.g. the P300, may be elicited by these same conditions, whether or not
      the stimuli are painful. The LPC may overlap, and interfere with the measurement
      of, responses that are only seen with painful stimuli. We compared the LPC in two
      experimental protocols using ten subjects and electrical stimuli. In the 'Rating
      Protocol', shocks of different intensity levels were randomly presented and
      subjects rated the intensity of each stimulus. In the 'Oddball Standards
      Protocol', the same levels were used, but each was presented in a separate block
      of a single level. Stimuli were presented more rapidly and subjects had to push a
      button in response to occasional double shocks (oddball targets), but not to
      single shocks (oddball standards). The oddball targets served to direct subjects'
      attention to the stimuli, but only the evoked potential responses to the oddball
      standards were used for data analysis. To look at the difference between
      protocols, we computed a difference condition (Rating protocol responses minus
      Oddball Standards protocol responses) which we called Incremental activity. The
      Incremental LPC (average amplitudes from 350 to 650 ms) had a more parietal
      topography (amplitude at electrode Pz greater than at Cz) than the Oddball
      Standards LPC (Cz > Pz; protocol x electrode interaction P<0.001). This implies
      that the Rating Protocol LPC included P300-like activity. The parietal
      Incremental activity began as early as 250-350 ms after the stimulus in the
      responses to the most painful stimuli and therefore can confound the measurement
      of pain activity in the evoked potential.

PMID- 10601672
TI  - Predicting responses to self-management treatments for chronic pain: application
      of the pain stages of change model.
AB  - Psychological treatments emphasizing a self-management approach have become
      commonly accepted alternatives to medical interventions for chronic pain.
      Unfortunately, these approaches often fail to engage a significant portion of
      targeted individuals and are associated with high drop-out and relapse rates.
      Informed by the transtheoretical model of behavior change and the cognitive
      behavioral perspective on chronic pain, the Pain Stages of Change Questionnaire
      (PSOCQ) was developed to assess readiness to adopt a self-management approach to
      chronic pain. Initial studies supported the reliability and validity of four
      distinct scales, Precontemplation, Contemplation, Action and Maintenance. The
      current study was designed to assess the ability of the PSOCQ to predict self
      management participation and outcome. The PSOCQ and several relevant outcome
      measures were assessed before and after self-management treatment by 109 chronic
      pain patients. Profile analysis revealed that treatment completers and non
      completers differed significantly across the four PSOCQ scales. Post-hoc
      comparisons indicated that pretreatment PSOCQ Precontemplation and Contemplation
      scores discriminated these two groups. Separate analyses revealed that Action and
      Maintenance scores increased over the course of treatment, and that changes in
      the PSOCQ scales were associated with improved outcomes. These findings suggest
      that increased commitment to a self-management approach to chronic pain may serve
      as a mediator or moderator of successful treatment. This study supports the
      predictive validity and utility of the PSOCQ, as well as the relevance of the
      stages of change model to self-management of chronic pain.

PMID- 10601673
TI  - Relative potency of epidural to intrathecal clonidine differs between acute
      thermal pain and capsaicin-induced allodynia.
AB  - Clonidine is approved in the US for epidural administration in the treatment of
      intractable neuropathic cancer pain, but is also administered intrathecally for
      this indication and both epidurally and intrathecally in the treatment of acute,
      postoperative pain. The purpose of the current study was to estimate the relative
      potency of clonidine by epidural and intrathecal routes in the treatment of
      capsaicin-induced hyperalgesia and allodynia as a model of central
      hypersensitivity and of noxious heat as a model of acute pain. Twenty-four
      healthy volunteers were randomized to receive either intrathecal clonidine (75,
      150, or 300 micrograms) or epidural clonidine (150, 300, or 600 micrograms) and
      rated pain from a Peltier-controlled thermode at a lumbar, thoracic, and cervical
      dermatomal site before and after drug administration. In addition, they rated
      pain from intradermal capsaicin injections at a lumbar dermatome before and 60
      min after clonidine injection and described areas of hyperalgesia and allodynia
      to mechanical stimuli. Clonidine's effect differed with route of administration
      and modality of sensory testing. For acute thermal pain, intrathecal clonidine
      produced a dose-dependent analgesia with a lumbar>thoracic>cervical gradient,
      whereas only one dose of epidural clonidine reduced thermal pain and this was at
      the thoracic testing site. In contrast, the potency of clonidine to reduce
      capsaicin-induced allodynia was similar between the two routes of injection, and
      for hyperalgesia, clonidine was only slightly more potent after intrathecal than
      epidural injection. These data support clinical studies from non-comparative
      trials and suggest there is a >6-fold potency ratio of intrathecal:epidural
      administration of clonidine for acute pain, but a <2-fold potency ratio for these
      routes for mechanical hypersensitivity.

PMID- 10601674
TI  - Fear and anxiety: divergent effects on human pain thresholds.
AB  - Animal studies suggest that fear inhibits pain whereas anxiety enhances it;
      however it is unclear whether these effects generalize to humans. The present
      study examined the effects of experimentally induced fear and anxiety on radiant
      heat pain thresholds. Sixty male and female human subjects were randomly assigned
      to 1 of 3 emotion induction conditions: (1) fear, induced by exposure to three
      brief shocks; (2) anxiety, elicited by the threat of shock; (3) neutral, with no
      intervention. Pain thresholds were tested before and after emotion induction.
      Results suggest that findings from animal studies extend to humans: fear resulted
      in decreased pain reactivity, while anxiety led to increased reactivity. Pain
      rating data indicated that participants used consistent subjective criteria to
      indicate pain thresholds. Both subjective and physiological indicators (skin
      conductance level, heart rate) confirmed that the treatment conditions produced
      the targeted emotional states. These results support the view that emotional
      states modulate human pain reactivity.

PMID- 10601675
TI  - Parietal and cingulate processes in central pain. A combined positron emission
      tomography (PET) and functional magnetic resonance imaging (fMRI) study of an
      unusual case.
AB  - Parietal, insular and anterior cingulate cortices are involved in the processing
      of noxious inputs and genesis of pain sensation. Parietal lesions may generate
      central pain by mechanisms generally assumed to involve the 'medial' pain system
      (i.e. medial thalamic nuclei and anterior cingulate cortex (ACC)). We report here
      PET and fMRI data in a patient who developed central pain and allodynia in her
      left side after a bifocal infarct involving both the right parietal cortex (SI
      and SII) and the right ACC (Brodmann areas 24 and 32), thus questioning the
      schematic representation of cortical pain processing. No rCBF increase was found
      in any part of the residual cingulate cortices, neither in the basal state (which
      included spontaneous pain and extended hypoperfusion around the infarct), nor
      during left allodynic pain. Thus, as previously observed in patients with lateral
      medullary infarct, neither spontaneous pain nor allodynia reproduce the cingulate
      activation observed after noxious pain in normal subjects. Conversely, both PET
      and fMRI data argue in favour of plastic changes in the 'lateral discriminative'
      pain system. Particularly, allodynia was associated with increased activity
      anteriorly to the infarct in the right insula/SII cortex. This response is likely
      to be responsible for the strange and very unpleasant allodynic sensation
      elicited on the left side by a non-noxious stimulation.

PMID- 10601676
TI  - Remembering an everyday pain: the role of knowledge and experience in the recall
      of the quality of dysmenorrhoea.
AB  - The ability to describe the quality of a previous pain may be thought to be
      better if one had experienced that particular pain because information stored in
      episodic and/or semantic memory is available rather than if one had not and could
      only guess what the pain may be like on the basis of information stored in
      semantic memory. However research has shown that not only is the quality of
      labour pain poorly recalled by women who have given birth but also it is no
      better described by them than by women who have never given birth at all. In
      order to replicate this effect for an everyday pain, the ability to recall the
      quantity and the quality of dysmenorrhoea was measured in two groups of women.
      One group regularly experienced dysmenorrhoea, the other had never experienced
      it. Analysis of the pain intensity scores revealed that the 'pain' group reported
      significantly less pain 2 weeks later whereas the 'no-pain' group did not
      significantly differ in their rating over time. Analysis of the MPQ Descriptors
      chosen by subjects using Cohen's kappa resulted in 'fair' recall for both groups
      with no significant advantage for the 'pain' group. These results suggest that
      the episodic memory system plays a limited role in facilitating the recall of the
      quality of an often experienced pain. However the semantic memory system allows
      both previous pain sufferers and pain guessers to describe the core qualities of
      a pain to the same extent. Further research is required to explain why
      remembering the quality of a pain experience is not advantaged by episodic memory
      and what facilitates the transfer of a pain experience into semantic event
      memory.

PMID- 10601677
TI  - The economic burden of back pain in the UK.
AB  - This paper reports the results of a 'cost-of-illness' study of the socio-economic
      costs of back pain in the UK. It estimates the direct health care cost of back
      pain in 1998 to be pound1632 million. Approximately 35% of this cost relates to
      services provided in the private sector and thus is most likely paid for directly
      by patients and their families. With respect to the distribution of cost across
      different providers, 37% relates to care provided by physiotherapists and allied
      specialists, 31% is incurred in the hospital sector, 14% relates to primary care,
      7% to medication, 6% to community care and 5% to radiology and imaging used for
      investigation purposes. However, the direct cost of back pain is insignificant
      compared to the cost of informal care and the production losses related to it,
      which total pound10668 million. Overall, back pain is one of the most costly
      conditions for which an economic analysis has been carried out in the UK and this
      is in line with findings in other countries. Further research is needed to
      establish the cost-effectiveness of alternative back pain treatments, so as to
      minimise cost and maximise the health benefit from the resources used in this
      area.

PMID- 10601678
TI  - Oral naloxone reverses opioid-associated constipation.
AB  - Opioid-related constipation is one of the most frequent side effects of chronic
      pain treatment. Enteral administration of naloxone blocks opioid action at the
      intestinal receptor level but has low systemic bioavailability due to marked
      hepatic first-pass metabolism. The aim of this study was to examine the effects
      of oral naloxone on opioid-associated constipation in an intraindividually
      controlled manner. Twenty-two chronic pain patients with oral opioid treatment
      and constipation were enrolled in this study. Constipation was defined as lack of
      laxation and/or necessity of laxative therapy in at least 3 out of 6 days.
      Laxation and laxative use were monitored for the first 6 days without
      intervention ('control period'). Then, oral naloxone was started and titrated
      individually between 3x3 to 3x12 mg/day depending on laxation and withdrawal
      symptoms. After the 4-day titration period, patients were observed for further 6
      days ('naloxone period'). The Wilcoxon signed rank test was used to compare
      number of days with laxation and laxative therapy in the two study periods. Of
      the 22 patients studied, five patients did not reach the 'naloxone period' due to
      death, operation, systemic opioid withdrawal symptoms, or therapy-resistant
      vomiting. In the 6 day 'naloxone' compared to the 'control period', the mean
      number of days with laxation increased from 2.1 to 3.5 (P<0.01) and the number of
      days with laxative medication decreased from 6 to 3.8 (P<0.01). The mean naloxone
      dose in the 'naloxone period' was 17.5 mg/day. The mean pain intensity did not
      differ between these two periods. Moderate side effects of short duration were
      observed in four patients following naloxone single dose administrations between
      6 and 20 mg, resulting in yawning, sweating, and shivering. Most of the patients
      reported mild or moderate abdominal propulsions and/or abdominal cramps shortly
      after naloxone administration. All side effects terminated after 0.5-6 h. This
      controlled study demonstrates that orally administered naloxone improves symptoms
      of opioid associated constipation and reduces laxative use. To prevent systemic
      withdrawal signs, therapy should be started with low doses and patients carefully
      monitored during titration.

PMID- 10601679
TI  - Pain in the new millennium

PMID- 10601680
TI  - Chitosan and its derivatives: potential excipients for peroral peptide delivery
      systems.
AB  - In the 1990s chitosan turned out to be a useful excipient in various
      pharmaceutical formulations. By modifications of the primary amino group at the 2
      position of this poly(beta1-->4 D-glucosamine), the features of chitosan can even
      be optimised according to a given task in drug delivery systems. For peroral
      peptide delivery these tasks focus on overcoming the absorption (I) and enzymatic
      barrier (II) of the gut. On the one hand, even unmodified chitosan proved to
      display a permeation enhancing effect for peptide drugs. On the other hand, a
      protective effect for polymer embedded peptides towards degradation by intestinal
      peptidases can be achieved by the immobilisation of enzyme inhibitors on the
      polymer. Whereas serine proteases are inhibited by the covalent attachment of
      competitive inhibitors such as the Bowman-Birk inhibitor, metallo-peptidases are
      inhibited by chitosan derivatives displaying complexing properties such as
      chitosan-EDTA conjugates. In addition, because of the mucoadhesive properties of
      chitosan and most of its derivatives, a presystemic metabolism of peptides on the
      way between the dosage form and the absorption membrane can be strongly reduced.
      Based on these unique features, the co-administration of chitosan and its
      derivatives leads to a strongly improved bioavailability of many perorally given
      peptide drugs such as insulin, calcitonin and buserelin. These polymers are
      therefore useful excipients for the peroral administration of peptide drugs.

PMID- 10601681
TI  - 3'-deoxyribonucleosides and their derivatives as anti-amoebic agents.
AB  - In general nucleoside analogues were found to possess in vitro amoebicidal
      property against trophozoites of Entamoeba histolytica. The acid-labile nature of
      these compounds completely destroyed their ability to cure caecal amoebiasis of
      rats. However the therapeutic efficacy of one of these compounds yielded most
      promising results, with 10% cures when it was administered as enteric coated
      formulation.

PMID- 10601682
TI  - Formation of HDL-like complexes from apolipoprotein A-I(M) and DMPC.
AB  - Conditions for the preparation of reconstituted high density lipoproteins (HDLs)
      by incubation of the synthetic lipid dimyristoylphosphatidylcholine (DMPC) and
      recombinant apolipoprotein A-I(M) have been investigated as a function of ratio
      of incubation lipid to protein, incubation temperature and the lipid form
      (multilamellar (MLV) or small unilamellar (SUV) vesicles). The size distributions
      of the resultant lipid-protein complex particles from various incubations have
      been evaluated by native gel electrophoresis. Structural changes of the protein
      after incorporation into these complex particles have been estimated by CD.
      Thermal characteristics of the particles has been examined by DSC and correlated
      with CD results. Titration calorimetry has been used to obtain interaction
      parameters based on a simplified binding model. It is hypothesized that the major
      enthalpic step in the production of rHDLs is the primary association step between
      protein and lipid vesicles. It has been shown that by raising the temperature and
      incubation ratio, the formation of rHDL particles can be directed towards smaller
      size and a narrower size distribution. The results have been described on the
      basis of a model where formation of discoidal particles requires prior saturation
      of vesicle surface area by adsorbed protein, thus explaining differences between
      particles formed from MLVs and SUVs.

PMID- 10601683
TI  - In vitro assessment of archaeosome stability for developing oral delivery
      systems.
AB  - The in vitro stability of archaeosomes made from the total polar lipids of
      Methanosarcina mazei, Methanobacterium espanolae or Thermoplasma acidophilum, was
      evaluated under conditions encountered in the human gastrointestinal tract. At
      acidic pH, multilamellar vesicles (MLV) prepared from T. acidophilum lipids were
      the most stable, releasing approximately 80, 20, 10 and 5% of encapsulated 14C
      sucrose at pH 1.5, 2.0, 2.5 and 6.2, respectively, after 90 min at 37 degrees C.
      Archaeosomes from M. mazei lipids were the least stable. For each type of total
      polar lipid, unilamellar vesicles (ULV) were less stable than the corresponding
      MLV vesicles. Pancreatic lipase had relatively minor effect on the stability of
      archaeosomes made from either of the three types of total polar lipids, causing
      the release of 12-27% of the encapsulated 5(6)-carboxyfluorescein (CF) from ULV
      and MLV after 90 min at 37 degrees C. In simulated human bile at pH 6.2, MLV from
      M. mazei total polar lipids lost 100% of the encapsulated CF after 90 min at 37
      degrees C, whereas those from the polar lipids of M. espanolae or T. acidophilum
      lost approximately 85% of the marker. Pancreatic lipase and simulated human bile
      had no synergistic effect on the release of carboxyfluorescein from ULV or MLV
      prepared from any of the total polar lipids. After 90 min in the combined
      presence of these two stressors at pH 6.2, the leakage of fluorescein conjugated
      bovine serum albumin from MLV prepared from T. acidophilum lipids was similar to
      that of CF, and 13% of the initially present vesicles appeared to be intact.
      These results indicate that archaeosomes show stability properties indicative of
      potential advantages in developing applications as an oral delivery system.

PMID- 10601684
TI  - Pulsatile protein release from a laminated device comprising polyanhydrides and
      pH-sensitive complexes.
AB  - A laminated device comprising of polyanhydrides as isolating layers and pH
      sensitive complexes as protein-loaded layers was designed to deliver proteins in
      a pulsatile manner. Poly(sebacic anhydride)-b-polyethylene glycol (PSA-b-PEG) and
      poly(trimellitylimidoglycine-co-sebacic anhydride)-b-polyethylene glycol (P(TMA
      gly-co-SA)-b-PEG) were synthesized as isolating layers for their good processing
      properties at room temperature and suitable erosion duration. During the erosion
      period, pH of the dissolution fluid decreases to a low value (3.8-5.8).
      Poly(methacrylic acid)/polyethoxazoline (PMAA/PEOx) complex was used as protein
      loaded layers, which could dissociate and release model proteins, Myoglobin (Mb)
      and Bovine Serum Albumin (BSA), at pH 7.4 while become stable and retained the
      drugs below pH 5.0. The protein release from the device showed a typical
      pulsatile fashion. The lag time prior to the pulsatile protein release correlated
      with the hydrolytic duration of the polyanhydrides, which varied from 30 to 165 h
      by selecting polyanhydride type and isolating layer thickness. In addition, the
      pulse duration could be adjusted from 18.5 to 40 h by varying the mass of the
      complex. The results can be attributed to the synergistic effects between the
      degrading polyanhydrides, pH-sensitive complexes and proteins.

PMID- 10601685
TI  - Synthesis and characterisation of a new class of stable S-adenosyl-L-methionine
      salts.
AB  - S-adenosyl-L-methionine (SAM) is an important metabolic intermediate that serves
      as a donor of methyl and aminopropyl groups to a variety of acceptor molecules.
      The molecule in vitro is unstable both in solution and in crystalline form
      undergoing irreversible conversion to 5'-methyltioadenosine (MTA) and homoserine
      lactone. Since this form of instability seems to be prevented in the cell of the
      living organism by bonds with macromolecules, we designed and developed a novel
      class of salts of SAM with large size anions to improve the stability of the
      sulfonium compound outside the cell. For this purpose we synthesised and
      characterised by NMR and IR spectroscopy anions consisting of amidic derivatives
      of taurine with fatty acids. Stability studies performed with the new SAM salts
      indicate that SAM becomes much more stable when it interacts with large size
      anions and in fact, more than 84% of the SAM is recovered after 36 months in
      lyophilized samples. The high stability of the new products widens the
      possibility of new therapeutic applications of SAM in human therapy.

PMID- 10601686
TI  - Recombinant factor VIII SQ--the influence of formulation parameters on structure
      and surface adsorption.
AB  - The main aim of this paper was to investigate the influence of temperature, pH
      and ionic interactions on the structural stability and surface adsorption of a
      recombinant factor VIII product, r-VIII SQ. The interaction of r-VIII SQ with
      glass and air interfaces, and possible means of increasing the stability of the
      formulation, were also investigated. The stability of r-VIII SQ was followed by
      measuring the biological activity (VIII:C), by circular dichroism (CD) studies
      and by the measurement of surface tension using the pendant drop method. The
      results show that the surface tension decreased exponentially with time; this
      decrease was more pronounced above 20 degrees C, indicating increased
      conformational flexibility of the protein with increased temperatures. Far UV CD
      spectra were not influenced in the range 5-55 degrees C and near UV CD
      measurements did not indicate structural changes below 45 degrees C. During
      agitation at 25 degrees C, VIII:C was lost rapidly in formulations without a
      macromolecular additive. Nonionic surfactants such as polysorbate 80 and
      polysorbate 20 protected VIII:C to an equally high degree against surface
      adsorption. Albumin was less effective, but it is possible that this is because
      it is a protein itself and may have been affected by the agitation. The addition
      of 300 mg/ml of sucrose improved the long term stability of VIII:C, a finding
      most likely explained by the theory of preferential hydration. Near UV CD spectra
      at acidic or basic pH mainly indicated changes around 242 nm, especially at low
      ionic strength. Addition of 10 mM EDTA at pH 7 resulted in similar changes. This
      effect was completely reversed by the addition of an excess of Ca(2+), Sr(2+) or
      Mg(2+) ions. In conclusion, CD spectra and surface tension measurements of r-VIII
      SQ did not reveal any temperature-induced conformational changes in the
      temperature range 5-20 degrees C; changes were first noted at elevated
      temperatures. Surface adsorption of r-VIII SQ during agitation was prevented by
      the addition of a nonionic surfactant. Preferential hydration improved the
      storage stability of the protein but did not directly prevent its surface
      adsorption. The structural integrity of the molecule was preserved at pH 7, at an
      increased ionic strength and in the presence of some divalent metal ions (Ca(2+),
      Sr(2+) or Mg(2+)).

PMID- 10601687
TI  - Enhanced absorption of indomethacin after oral or rectal administration of a self
      emulsifying system containing indomethacin to rats.
AB  - A self-emulsifying system (SES), a mixture of an oil and a surfactant which forms
      an oil-in-water emulsion, is expected to improve the in vitro drug dissolution
      and enhance the in vivo drug absorption. In this study, a poorly water-soluble
      drug, indomethacin (IDM) was incorporated into the SES to increase
      bioavailability. The SES with 30% of Tween 85 and 70% of ethyl oleate, EO (w/w)
      was selected as an optimized formulation (high drug loading, low surfactant
      concentration, and small particle size). After an oral administration of the SES
      containing IDM and IDM suspension, (IDM was suspended in methyl cellulose), 22.5
      mg/kg as IDM, to rats, the area under the plasma concentration-time curve from
      time zero to the last measured time in plasma, 12 h (AUC(0-12 h)) was
      significantly greater (57% increase) in the SES, suggesting that oral absorption
      of IDM increased significantly by the SES. After a rectal administration of
      gelatin hollow type suppositories, filled with the SES containing IDM and IDM
      powder physically mixed with the SES, 22. 5 mg/kg, to rats, the AUC(0-12 h) also
      increased significantly (41% increase) by the SES, suggesting that rectal
      absorption of IDM also increased significantly by the SES.

PMID- 10601688
TI  - Desolvation process and surface characterisation of protein nanoparticles.
AB  - The objective of the present study was to characterise and optimise the
      desolvation process of human serum albumin (HSA) for the preparation of
      nanoparticles and to characterise the resulting colloidal system. Following the
      desolvation of the protein, the resulting nanoparticles were stabilised by the
      addition of varying amounts of glutaraldehyde or by heat denaturation. The
      particle size, zeta potential, and the number of available amino groups on the
      surface of the nanoparticles were determined. The amino groups were quantified by
      a spectrophotometric method using 2,4, 6-trinitrobenzenesulfonic acid (TNBS). The
      results indicated that the particle size depended mainly on the amount of
      desolvating agent added, but not on the amount of cross-linker or the kind of
      cross-linking procedure. Increasing amounts of glutaraldehyde reduced the number
      of amino groups on the surface of HSA nanoparticles and also decreased the zeta
      potential of the carrier system. The temperature and heat denaturation time only
      had an influence on the stability of the nanoparticles but not on the amount of
      amino groups or the particle size. It was shown that heat denatured HSA
      nanoparticles possessed the greatest number of amino groups on their surface.
      Additional experiments for the characterisation of gelatin A and B nanoparticles
      were performed.

PMID- 10601689
TI  - Thermosetting microemulsions and mixed micellar solutions as drug delivery
      systems for periodontal anesthesia.
AB  - In the present study, thermosetting microemulsions and mixed micellar solutions
      were investigated as drug delivery systems for anesthetizing the periodontal
      pocket. The structure of the systems, consisting of the active ingredients
      lidocaine and prilocaine, as well as two block copolymers (Lutrol F127 and Lutrol
      F68), was investigated by NMR spectroscopy and photon correlation spectroscopy
      (PCS). The results obtained for dilute (1-3% w/w) solutions show discrete
      micelles with a diameter of 20-30 nm and a critical micellization temperature of
      25-35 degrees C. Gel permeation chromatography (GPC) was used to study the
      distribution of the active ingredients, and indicates a preferential
      solubilization of the active components in micelles over unimers. Analogous to
      the Lutrol F127 single component system these formulations display an abrupt
      gelation on increasing temperature. The gelation temperature was found to depend
      on both the drug ionization and concentration. These systems have several
      advantages over emulsion-based formulations including good stability, ease of
      preparation, increased drug release rate, and improved handling due to the
      transparency of the formulations.

PMID- 10601690
TI  - The modified extended Hansen method to determine partial solubility parameters of
      drugs containing a single hydrogen bonding group and their sodium derivatives:
      benzoic acid/Na and ibuprofen/Na.
AB  - Sodium salts are often used in drug formulation but their partial solubility
      parameters are not available. Sodium alters the physical properties of the drug
      and the knowledge of these parameters would help to predict adhesion properties
      that cannot be estimated using the solubility parameters of the parent acid. This
      work tests the applicability of the modified extended Hansen method to determine
      partial solubility parameters of sodium salts of acidic drugs containing a single
      hydrogen bonding group (ibuprofen, sodium ibuprofen, benzoic acid and sodium
      benzoate). The method uses a regression analysis of the logarithm of the
      experimental mole fraction solubility of the drug against the partial solubility
      parameters of the solvents, using models with three and four parameters. The
      solubility of the drugs was determined in a set of solvents representative of
      several chemical classes, ranging from low to high solubility parameter values.
      The best results were obtained with the four parameter model for the acidic drugs
      and with the three parameter model for the sodium derivatives. The four parameter
      model includes both a Lewis-acid and a Lewis-base term. Since the Lewis acid
      properties of the sodium derivatives are blocked by sodium, the three parameter
      model is recommended for these kind of compounds. Comparison of the parameters
      obtained shows that sodium greatly changes the polar parameters whereas the
      dispersion parameter is not much affected. Consequently the total solubility
      parameters of the salts are larger than for the parent acids in good agreement
      with the larger hydrophilicity expected from the introduction of sodium. The
      results indicate that the modified extended Hansen method can be applied to
      determine the partial solubility parameters of acidic drugs and their sodium
      salts.

PMID- 10601691
TI  - New topical antiandrogenic formulations can stimulate hair growth in human bald
      scalp grafted onto mice.
AB  - The purpose of this study was to test the ability of topical formulations of
      finasteride and flutamide to re-enlarge hair follicles in male-pattern baldness.
      This was evaluated by an experimental model of human scalp skin graft
      transplanted onto SCID mice. A comparison was made between formulations
      containing finasteride and flutamide, and a vehicle formulation in terms of the
      mean hairs per graft, length, diameter of the shafts, and structures of the
      growth stages of the hair. Flutamide and finasteride had a significantly higher
      effect (P<0.05) than the placebo in all the tested parameters, but flutamide
      demonstrated more hair per graft and longer hair shafts than finasteride
      (P<0.05). The number of hairs per graft for flutamide and finasteride groups were
      1.22+/-0. 47 and 0.88+/-0.95 hairs/0.5 mm2 graft, respectively, versus 0. 35+/
      0.6 hairs/graft for vehicle-treated graft. Similarly, hair lengths for flutamide
      and finasteride were 5.82+/-0.50 and 4.50+/-0. 32 mm, respectively, versus 2.83+/
      0.18 mm for the vehicle-treated grafts. An in vitro diffusion study of flutamide
      gel using hairless mouse skin demonstrated the beneficial effect of the vehicle
      composition in comparison with a hydroalcoholic solution or a gel containing no
      penetration enhancer. It is therefore suggested that this topical composition
      containing flutamide or finasteride may effectively result in regression of male
      pattern baldness.

PMID- 10601692
TI  - Stories about acyl chains.

PMID- 10601693
TI  - Molecular basis of exchangeable apolipoprotein function.

PMID- 10601694
TI  - Mobilisation of triacylglycerol stores.
AB  - Triacylglycerol (TAG) is an energy dense substance which is stored by several
      body tissues, principally adipose tissue and the liver. Utilisation of stored TAG
      as an energy source requires its mobilisation from these depots and transfer into
      the blood plasma. The means by which TAG is mobilised differs in adipose tissue
      and liver although the regulation of lipid metabolism in each of these organs is
      interdependent and synchronised in an integrated manner. This review deals
      principally with the mechanism of hepatic TAG mobilisation since this is a
      rapidly expanding area of research and may have important implications for the
      regulation of plasma very-low-density lipoprotein metabolism. TAG mobilisation
      plays an important role in fuel selection in non-hepatic tissues such as cardiac
      muscle and pancreatic islets and these aspects are also reviewed briefly.
      Finally, studies of certain rare inherited disorders of neutral lipid storage and
      mobilisation may provide useful information about the normal enzymology of TAG
      mobilisation in healthy tissues.

PMID- 10601695
TI  - A metabolic path for the degradation of lysophosphatidic acid, an inhibitor of
      lysophosphatidylcholine lysophospholipase, in neuronal nuclei of cerebral cortex.
AB  - Neuronal nuclei isolated from rabbit cerebral cortex were found to be enriched in
      an NEM-insensitive lysophosphatidic acid (lysoPA) phosphohydrolase activity.
      LysoPA is an inhibitor of the nuclear lysophosphatidylcholine (lysoPC)
      lysophospholipase, and by preserving lysoPC levels, lysoPA boosted the nuclear
      production of the acyl analogue of platelet-activating factor by promoting the
      acetylation of lysoPC (Baker and Chang, Mol. Cell Biochem., 1999, in press). The
      nuclear phosphohydrolase converts lysoPA to 1-monoacylglycerol, and thus
      eliminates this lysoPA inhibition of lysoPC lysophospholipase. The nuclear lysoPA
      phosphohydrolase specific activity was more than three times that observed for
      the nuclear lysoPA lysophospholipase (Baker and Chang, Biochim. Biophys. Acta
      1438 (1999) 253-263) and represents a more active route for nuclear lysoPA
      removal. The neuronal nuclear lysoPA phosphohydrolase was inhibited at acidic pH,
      and also inhibited by calcium ions. The 1-monoacylglycerol product of the
      phosphohydrolase is rapidly degraded by neuronal monoacylglycerol lipase, an
      enzyme some sevenfold more active than the phosphohydrolase and sensitive to
      inhibition by arachidonoyl trifluoromethyl ketone (AACOCF(3)). Both acidic pH and
      free fatty acid inhibited the lipase. In the absence of AACOCF(3), production of
      fatty acid from lysoPA substrate could be largely attributed to the sequential
      actions of the nuclear phosphohydrolase and lipase. This facilitates fatty acid
      recycling back into phospholipid by lysophospholipid acylation when ATP levels
      are restored following periods of brain ischemia. At relatively low
      concentrations, sphingosine-1-phosphate, and alkylglycerophosphate were the most
      effective phosphohydrolase inhibitors while phosphatidic acid,
      alkylacetylglycerophosphate and ceramide were without effect. LysoPA is an
      interesting regulatory molecule that can potentially preserve
      lysophosphatidylcholine within the nuclear membrane for use in acetylation
      reactions. Thus conditions relevant to brain ischemia such as falling pH, falling
      ATP concentrations, rising fatty acid and intracellular calcium levels may, by
      slowing this metabolic path for lysoPA loss, promote the production of acyl PAF
      and contribute to the increased levels of the acetylated lipids noted in
      ischemia.

PMID- 10601696
TI  - Role of exogenous inositol and phosphatidylinositol in
      glycosylphosphatidylinositol anchor synthesis of GP49 by Giardia lamblia.
AB  - Although Giardia lamblia trophozoites are unable to carry out de novo
      phospholipid synthesis, they can assemble complex glycophospholipids from simple
      lipids and fatty acids acquired from the host. Previously, we have reported that
      G. lamblia synthesizes GP49, an invariant surface antigen with a
      glycosylphosphatidylinositol (GPI) anchor. It is therefore possible that myo
      inositol (Ins), phosphatidylinositol (PI) and other GPI precursors are obtained
      from the dietary products of the human small intestine, where the trophozoites
      colonize. In this report, we have investigated the role of exogenous Ins and PI
      on GPI anchor synthesis by G. lamblia. The results demonstrate that [(3)H]Ins and
      PI internalized by trophozoites, metabolically transformed into GlcN(acyl)-PI and
      downstream GPI molecules. Further investigations suggest that G. lamblia
      expresses cytidine monophosphate (CMP)-dependent (Mg(2+)-stimulated) and
      independent (Mn(2+)-stimulated) inositol headgroup exchange enzymes, which are
      responsible for exchanging free Ins with cellular PI. We observed that 3-deoxy-3
      fluoro-D-myo-inositol (3-F-Ins) and 1-deoxy-1-F-scyllo-Ins (1-F-scyllo-Ins),
      which are considered potent inhibitors of Mn(2+)-stimulated headgroup exchange
      enzyme, inhibited the incorporation of [(3)H]Ins into PI and GPI molecules
      significantly, suggesting that CMP-independent (Mn(2+)-stimulated) exchange
      enzyme may be important for these reactions. However, 3-F-Ins and 1-F-scyllo-Ins
      were not effective in blocking the incorporation of exogenously supplied [(3)H]PI
      into GPI glycolipids. Thus, it can be concluded that G. lamblia can use
      exogenously supplied [(3)H]PI and [(3)H]Ins to synthesize GPI glycolipids of
      GP49; while PI is directly incorporated into GPI molecules, free Ins is first
      converted into PI by headgroup exchange enzymes, and this newly formed PI
      participates in GPI anchor synthesis.

PMID- 10601697
TI  - Amyloid precursor protein in unique cholesterol-rich microdomains different from
      caveolae-like domains.
AB  - To determine the localization of the amyloid precursor protein (APP) on the
      cellular membrane, we performed membrane fractionation of cultured cells
      including that of Madin-Darby canine kidney (MDCK) and P19 cells transfected with
      human APP cDNA, non-transfected SH-SY5Y cells, and rat cerebral cortices. In MDCK
      cells, APP was exclusively present in abundance in the supernatant following
      solubilization of the plasma membranes using Triton X-100, and in high-density
      fractions of sucrose density gradient fractionation (SDGF) following Triton X-100
      solubilization of whole cellular membranes. Caveolin-1 was not cofractionated
      with APP. In experiments using P19 cells and rat cerebral cortices, we detected
      two isoforms of APP. The APP with the apparently lower molecular weight (immature
      type) coexisted in abundance with integrin in the high-density fractions, whereas
      the APP with the apparently higher molecular weight (mature type) was recovered
      predominantly in the low-density fractions with cholesterol and GM1 gangliosides,
      the concentrations of which were higher than those in the bulk plasma membranes,
      but lower than those in caveolae-like domains (CLDs), following SDGF of Triton X
      100-solubilized cellular membranes. The results of this study suggest the
      following; first, APP is not present in abundance in caveolae or CLDs, but is in
      unique cholesterol-rich microdomains; second, the targeting of APP to these
      unique microdomains may be linked to the maturation of APP in some cells.

PMID- 10601698
TI  - Mechanism of thiyl radical-catalyzed isomerization of unsaturated fatty acid
      residues in homogeneous solution and in liposomes.
AB  - NMR spectroscopy and gas chromatography were used on methanolic solutions of
      fatty acid methyl esters and on small bilayer liposomes to study the radical
      induced denaturation of the fatty acid residues from the natural cis
      configuration into trans-isomers. To analyze the mechanism of the thiyl radical
      catalyzed lipid isomerization, we compared the effects of thiols on oleic and
      linoleic fatty acid residues using pulse radiolysis, gamma-radiolysis and
      chemolysis (AAPH) to generate thiyl radicals. The isomerization step takes place
      within the adduct of the thiyl radical to an olefinic group of unsaturated fatty
      acids, but not within the pentadienyl radical. The stability of the adduct can be
      described by an equilibrium constant of (12+/-5) mol(-1) dm(3). The isomerization
      rate depends on the structure of the thiol. However, the resulting isomeric
      equilibrium (trans-fraction: 81%) does not depend on the structure of the thiyl
      radical or the organization of the lipids. Quantum chemical calculations were
      performed to estimate the barriers for rotation, the geometry and the enthalpy
      difference between cis- and trans-thiyl radical adducts.

PMID- 10601699
TI  - Dietary docosahexaenoic acid ameliorates, but rapeseed oil and safflower oil
      accelerate renal injury in stroke-prone spontaneously hypertensive rats as
      compared with soybean oil, which is associated with expression for renal
      transforming growth factor-beta, fibronectin and renin.
AB  - We have noted that n-3 fatty acid-rich oils, such as fish oil, perilla oil and
      flaxseed oil as well as ethyl docosahexaenoate (DHA) prolonged the survival time
      of stroke-prone spontaneously hypertensive rats (SHRSP) rats by approximately 10%
      as compared with linoleate (n-6)-rich safflower oil. Rapeseed oil with a
      relatively low n-6/n-3 ratio unusually shortened the survival time by
      approximately 40%, suggesting the presence of minor components unfavorable to
      SHRSP rats. This study examined the effects of dietary oils and DHA on renal
      injury and gene expression related to renal injury in SHRSP rats. Rats fed
      rapeseed oil- and safflower oil-supplemented diets developed more severe
      proteinuria than those fed soybean oil-supplemented diet used as a control, but
      there were no significant differences in blood pressure. In contrast, the DHA
      supplemented diet inhibited the development of proteinuria and suppressed
      hypertension. The mRNA levels for renal TGF-beta, fibronectin and renin were
      higher in the rapeseed oil and safflower oil groups after 9 weeks of feeding of
      the experimental diet than in the soybean oil and DHA groups. The fatty acid
      composition of kidney phospholipids was markedly affected by these diets. These
      results indicate that the renal injury observed in the groups fed safflower oil
      with a high n-6/n-3 ratio and rapeseed oil with presumed minor components is
      accompanied by increased expression of the TGF-beta, renin and fibronectin genes,
      and that dietary DHA suppresses renal injury and gene expression as compared with
      soybean oil.

PMID- 10601700
TI  - Induction of apoptosis by novel synthesized acylamides of human lymphocytes.
AB  - To investigate a pathway to apoptosis which may involve ceramides and to
      elucidate the minimum structure which leads to apoptosis, we synthesized several
      novel acylamides. Although the four synthesized compounds were different in
      structure from C2-ceramide, they caused Jurkat cells to undergo apoptosis. The
      most effective of them was N-myristoyl-D-alaninol (D-MA), as shown by DNA
      fragmentation (detected with propidium iodide) and a decrease in the
      mitochondrial transmembrane potential (DeltaPsi(m)) (detected with rhodamine
      123). Nevertheless, peripheral blood leukocytes exhibited no change after D-MA
      exposure, like after C2-ceramide or anti-Fas antibody treatment. The DNA
      fragmentation and DeltaPsi(m) caused by D-MA were blocked by a caspase-3 specific
      inhibitor as in the case of anti-Fas antibody stimulation. Quantification of
      ceramides by metabolic labeling with [(14)C]palmitic acid and HPTLC showed no
      increases in the ceramide levels on stimulation with D-MA, C2-ceramide or anti
      Fas antibodies. Furthermore, D-MA had an apoptosis-inducing effect on an anti-Fas
      resistant subline of Jurkat cells. These data suggest that D-MA may cause
      apoptosis of Jurkat cells without distinct ceramide formation and that this
      apoptotic pathway is very comparable, i.e. not identical, to that induced by anti
      Fas antibodies.

PMID- 10601701
TI  - The pathway from arachidonic to docosapentaenoic acid (20:4n-6 to 22:5n-6) and
      from eicosapentaenoic to docosahexaenoic acid (20:5n-3 to 22:6n-3) studied in
      testicular cells from immature rats.
AB  - The concentration-dependent metabolism of 1-(14)C-labelled precursors of 22:5n-6
      and 22:6n-3 was compared in rat testis cells. The amounts of [(14)C]22- and 24
      carbon metabolites were measured by HPLC. The conversion of [1-(14)C]20:5n-3 to
      [3-(14)C]22:6n-3 was more efficient than that of [1-(14)C]20:4n-6 to [3
      (14)C]22:5n-6. At low substrate concentration (4 microM) it was 3.4 times more
      efficient, reduced to 2.3 times at high substrate concentration (40 microM). The
      conversion of [1-(14)C]22:5n-3 to [1-(14)C]22:6n-3 was 1.7 times more efficient
      than that of [1-(14)C]22:4n-6 to [1-(14)C]22:5n-6 using a low, but almost equally
      efficient using a high substrate concentration. When unlabelled 20:5n-3 was added
      to a cell suspension incubated with [1-(14)C]20:4n-6 or unlabelled 22:5n-3 to a
      cell suspension incubated with [1-(14)C]22:4n-6, the unlabelled n-3 fatty acids
      strongly inhibited the conversion of [1-(14)C]20:4n-6 or [1-(14)C]22:4n-6 to
      [(14)C]22:5n-6. In the reciprocal experiment, unlabelled 20:4n-6 and 22:4n-6 only
      weakly inhibited the conversion of [1-(14)C]20:5n-3 and [1-(14)C]22:5n-3 to
      [(14)C]22:6n-3. The results indicate that if both n-6 and n-3 fatty acids are
      present, the n-3 fatty acids are preferred over the n-6 fatty acids in the
      elongation from 20- to 22- and from 22- to 24-carbon atom fatty acids. In vivo
      the demand for 22-carbon fatty acids for spermatogenesis in the rat may exceed
      the supply of n-3 precursors and thus facilitate the formation of 22:5n-6 from
      the more abundant n-6 precursors.

PMID- 10601702
TI  - An active-site titration method for lipases.
AB  - A method for active-site titration of lipases has been developed based on
      irreversible inhibition by methyl p-nitrophenyl n-hexylphosphonate. This method
      was applied to five lipases displaying from minor to pronounced interfacial
      activation. Soluble and immobilized lipases were successfully titrated in aqueous
      media. A low concentration of sodium dodecyl sulfate was needed for lipases
      displaying pronounced interfacial activation. The carrier of some of the
      immobilized preparations adsorbed part of the produced p-nitrophenolate. This
      problem could be solved by extracting the p-nitrophenolate after inhibition. The
      method was extended to apolar organic solvents in the case of immobilized lipase
      preparations.

PMID- 10601703
TI  - Effects of dietary protein type on oxidized cholesterol-induced alteration in age
      related modulation of lipid metabolism and indices of immune function in rats.
AB  - Exogenous oxidized cholesterol disturbs both lipid metabolism and immune
      functions. Therefore, it may perturb these modulations with ageing. Effects of
      the dietary protein type on oxidized cholesterol-induced modulations of age
      related changes in lipid metabolism and immune function was examined using
      differently aged (4 weeks versus 8 months) male Sprague-Dawley rats when casein,
      soybean protein or milk whey protein isolate (WPI) was the dietary protein
      source, respectively. The rats were given one of the three proteins in diet
      containing 0.2% oxidized cholesterols mixture. Soybean protein, as compared with
      the other two proteins, significantly lowered both the serum thiobarbituric acid
      reactive substances value and cholesterol, whereas it elevated the ratio of high
      density lipoprotein-cholesterol/cholesterol in young rats, but not in adult.
      Moreover, soybean protein, but not casein and WPI, suppressed the elevation of
      Delta6 desaturation indices of phospholipids in both liver and spleen,
      particularly in young. On the other hand, WPI, compared to the other two
      proteins, inhibited the leukotriene B4 production of spleen, irrespective of age.
      Soybean protein reduced the ratio of CD4(+)/CD8(+) T-cells in splenic
      lymphocytes. Therefore, the levels of immunoglobulin (Ig)A, IgE and IgG in serum
      were lowered in rats given soybean protein in both age groups except for IgA in
      adult, although these observations were not shown in rats given other proteins.
      Thus, various perturbations of lipid metabolism and immune function caused by
      oxidized cholesterol were modified depending on the type of dietary protein. The
      moderation by soybean protein on the change of lipid metabolism seems to be
      susceptible in young rats whose homeostatic ability is immature. These
      observations may be exerted through both the promotion of oxidized cholesterol
      excretion to feces and the change of hormonal release, while WPI may suppress the
      disturbance of immune function by oxidized cholesterol in both ages. This
      alleviation may be associated with a large amount of lactoglobulin in WPI. These
      results thus showed a possibility that oxidized cholesterol-induced perturbations
      of age-related changes of lipid metabolism and immune function can be moderated
      by both the selection and combination of dietary protein.

PMID- 10601704
TI  - Sphingosine 1-phosphate induces arachidonic acid mobilization in A549 human lung
      adenocarcinoma cells.
AB  - In the present paper, the effect of sphingosine 1-phosphate (Sph-1-P) on
      arachidonic acid mobilization in A549 human lung adenocarcinoma cells was
      investigated. Sph-1-P provoked a rapid and relevant release of arachidonic acid
      which was similar to that elicited by bradykinin, well-known pro-inflammatory
      agonist. The Sph-1-P-induced release of arachidonic acid involved Ca(2+)
      independent phospholipase A(2) (iPLA2) activity, as suggested by the dose
      dependent inhibition exerted by the rather specific inhibitor bromoenol lactone.
      The Sph-1-P-induced release of arachidonic acid was pertussis toxin-sensitive,
      pointing at a receptor-mediated mechanism, which involves heterotrimeric Gi
      proteins. The action of Sph-1-P was totally dependent on protein kinase C (PKC)
      catalytic activity and seemed to involve agonist-stimulated phospholipase D (PLD)
      activity. This study represents the first evidence for Sph-1-P-induced release of
      arachidonic acid which occurs through a specific signaling pathway involving Gi
      protein-coupled receptor(s), PKC, PLD and iPLA2 activities.

PMID- 10601705
TI  - Phosphatidylinositol 3'-kinase-mediated calcium mobilization regulates chemotaxis
      in phosphatidic acid-stimulated human neutrophils.
AB  - Phosphatidylinositol 3'-kinase (PI 3'-kinase) plays an important role in the
      migration of hepatocytes, endothelial cells and neoplastic cells to agonists
      which activate cellular tyrosine kinases. We examined the PI 3'-kinase-dependent
      chemotactic responses of neutrophilic leukocytes induced by phosphatidic acid
      (PA) in order to clarify mechanisms by which the enzyme potentially influences
      cellular migration. Western analysis of immunoprecipitates indicated that PA
      induced the tyrosine phosphorylation of three distinct proteins involved in
      functional activation which co-immunoprecipitated in PA-stimulated cells. These
      proteins were identified as lyn, syk and the 85 kDa regulatory subunit of PI 3'
      kinase. Chemotactic responses to PA but not to several other neutrophil agonists
      were inhibited by the PI 3'-kinase inhibitors wortmannin and LY294002.
      Chemotactic inhibition resulted from upstream inhibition of calcium mobilization.
      Chelation of extracellular calcium by ethylene glycol-bis(beta-aminoethyl ether)
      N,N,N',N'-tetraacetic acid (EGTA) did not affect the PA-induced chemotaxis,
      whereas chelation of intracellular calcium by 1, 2-bis(2-aminophenoxy)-ethane
      N,N,N',N'-tetraacetic acid (BAPTA) attenuated this response. Thus, changes in
      intracellular Ca(2+) levels that can be effected by Ca(2+) mobilized from
      intracellular stores in the absence of Ca(2+) influx regulate PA-induced
      chemotaxis. Furthermore, PI 3'-kinase inhibition blunted the agonist-dependent
      generation of inositol 1,4,5-trisphosphate (IP(3)), suggesting that PI 3'-kinase
      exerted its effects on calcium mobilization from intracellular sources by
      mediating activation of phospholipase C (PLC) in PA-stimulated cells. Moreover,
      the PI 3'-kinase inhibitor LY294002 also inhibited phosphorylation of syk in PA
      stimulated cells. We, therefore, propose that products of PI 3'-kinase confined
      to the inner leaflet of the plasma membrane play a role in activation of syk,
      calcium mobilization and induction of chemotactic migration.

PMID- 10601706
TI  - Fatty acids specifically related to the anisotropic properties of plasma membrane
      from rat urothelium.
AB  - Four different luminal surfaces of rat urothelium differing in their fatty acid
      composition were prepared by dietary induction. In order to induce lipid changes,
      each of four groups of rat received a basal diet rich in one of the unsaturated n
      3, n-6 or n-9 fatty acid families and a commercial (control) diet. The effects of
      the dietary regime on the fatty acid composition of luminal urothelial membranes
      and their relation to the mobility of fluorescent probes were studied. In
      comparison with the control diet membrane, all three fatty acid-rich diets
      induced a decrease of the percentage amount of saturated fatty acid while that of
      the unsaturated fatty acids was increased. Accordingly, all three diets increased
      the unsaturation index in comparison with the control diet. The anisotropy across
      each membrane fraction was assessed using the n-(9-anthroyloxy) fatty acid
      fluorescent probes 3-AS, 7-AS and 12-AS, which locate at different depths in the
      membrane. Two different anisotropy profiles were observed. One profile showed the
      highest anisotropy at the C7 depth, whereas the other exhibited a continuous
      decrease of the anisotropy from the surface to the center of the bilayer. The
      molecular properties (isomerization) of 18:2n-9 fatty acid may account, at least
      in part, for the observed V-shaped profile (the ascending trend) of the membrane
      anisotropy values as a function of the respective 18:2n-9 fatty acid contents.
      Nevertheless, the minimum value of the profile did not correspond to the minimum
      18:2n-9 fatty acid content, but rather to the higher amount of docosahexaenoic
      (22:6n-3) fatty acid. Thus, a modulating role of the 22:6n-3 fatty acid on the
      rigidifying effect of 18:2n-9 fatty acid is suggested, possibly mediated by
      relationships between fatty acid composition, saturated and unsaturated chain
      lengths, and freedom of motion of the phospholipid acyl chains.

PMID- 10601707
TI  - Microsomal fatty acyl-CoA transacylation and hydrolysis: fatty acyl-CoA species
      dependent modulation by liver fatty acyl-CoA binding proteins.
AB  - arachidonoyl-CoA. In summary, the data established for the first time a role for
      both L-FABP and ACBP in microsomal phosphatidic acid biosynthesis. By
      preferentially stimulating microsomal transacylation of unsaturated long chain
      fatty acyl-CoAs while concomitantly exerting their differential protection from
      microsomal acyl-CoA hydrolase, L-FABP and ACBP can uniquely function in
      modulating the pattern of fatty acids esterified to phosphatidic acid, the de
      novo precursor of phospholipids and triacylglycerols. This may explain in part
      the simultaneous presence of these proteins in cell types involved in fatty acid
      absorption and lipoprotein secretion.

PMID- 10601708
TI  - Changes to low-frequency components of the TEOAE following acoustic trauma to the
      base of the cochlea.
AB  - Several studies have shown that acoustic trauma to the base of the cochlea can
      result in loss of transient-evoked otoacoustic emission (TEOAE) energy at
      frequencies much lower than those affected in the audiogram. We have extended
      these studies to show that the low-frequency emission energy was substantially
      affected if the transient stimulus included frequencies within the range affected
      by the trauma, otherwise the change observed was small. In keeping with the
      suggestion that TEOAEs are predominantly comprised of intermodulation distortion
      energy (Yates and Withnell, Hear. Res. 136 (1999) 49-64), trauma to the basal
      region of the cochlea was found to affect emission energy across a broad
      frequency range in response to a wide-band acoustic stimulus. Further, group
      delay measurements demonstrated that the dominant contribution to the TEOAE
      originated from the basal region of the cochlea.

PMID- 10601709
TI  - Histopathological differences between temporary and permanent threshold shift.
AB  - The structural changes associated with noise-induced temporary threshold shift
      (TTS) were compared to the damage associated with permanent threshold shift
      (PTS). A within-animal paradigm involving survival-fixation was used to minimize
      problems with data interpretation from interanimal variability in response to
      noise. Auditory brainstem response thresholds for clicks and tone pips were
      determined pre- and 1-2 h post-exposure in 11 chinchillas. The animals were
      exposed for 24 h to an octave band of noise with a center frequency of 4 kHz and
      a sound pressure level of 86 dB. Three animals (0/0-day) had both cochleas
      terminal-fixed 2-3 h post-exposure. Two animals (27/27-day) had threshold shifts
      determined every other day for 1 week, every week thereafter, and underwent
      terminal-fixation of both cochleas 27 days after exposure. Six animals (0/n-day)
      had threshold shifts determined in both ears upon removal from the noise; their
      left cochlea was then survival-fixed 2-3 h post-exposure. Threshold shifts were
      determined in their right ear every 2-3 days until their hearing either returned
      to pre-exposure values or stabilized at a reduced level at which time their right
      cochlea was terminal-fixed (4-13 days post-exposure). All cochleas were prepared
      as plastic-embedded flat preparations. Missing hair cells were counted and
      supporting cells and nerve fibers were evaluated throughout the organ of Corti
      using phase-contrast microscopy. Post-exposure, all animals had moderate TTSs in
      their left and right ears which averaged 43 dB for 4-12 kHz. In the 0/0-day
      animals, the only abnormality which correlated with TTS was a buckling of the
      pillar bodies. In the 0/n-day animals, their left cochlea (survival-fixed 2-3 h
      post-exposure) had outer hair cell (OHC) stereocilia which were not embedded in
      the tectorial membrane in the region of the TTS whereas OHC stereocilia were
      embedded in the tectorial membrane throughout the cochleas of non-noise-exposed,
      survival-fixed controls. Three of six right cochleas (terminal-fixed 4-13 days
      post-exposure) from the 0/n-day animals developed a PTS and two of these cochleas
      had focal losses of inner and outer hair cells and afferent nerve fibers at the
      corresponding frequency location. The other cochlea with PTS had buckled pillars
      in the corresponding frequency region. These results suggest that with moderate
      levels of noise exposure, buckling of the supporting cells results in an
      uncoupling of the OHC stereocilia from the tectorial membrane which results in a
      TTS. The mechanisms resulting in TTS appear to be distinct from those that
      produce permanent hair cell damage and a PTS.

PMID- 10601710
TI  - Tubulin expression in the developing and adult gerbil organ of Corti.
AB  - In the late stages of inner ear development, the relatively undifferentiated
      cells of Kollicker's organ are transformed into the elaborately specialized cell
      types of the organ of Corti. Microtubules are prominent features of adult cells
      in the organ of Corti, particularly supporting cells. To test the possible role
      of microtubules in organ of Corti development, the microtubule organization in
      the organ of Corti has been examined using indirect immunofluorescence to beta
      tubulin in the developing gerbil cochlea. Tubulin first appears at post-natal day
      0 (P0) as filamentous asters in inner hair cells and by P2, asters are also seen
      in outer hair cells. Tubulin appears at P3 in inner pillar cells in a tooth crown
      like figure. By P6, tubulin expression is also evident in outer pillar cells and
      by P9, it is seen in Deiters cells. Elaboration of microtubules in pillar cells
      was observed to proceed from the reticular lamina towards the basilar membrane.
      The pattern of tubulin expression in the apical organ of Corti lags the base by
      about 3 days until P6, but by P9, apical and basal organ of Corti appear
      substantially the same.

PMID- 10601711
TI  - Expression of EphA4 in developing inner ears of the mouse and guinea pig.
AB  - The expression of EphA4, an Eph-class receptor tyrosine kinase, was determined by
      immunohistochemistry in developing inner ears of the mouse and the guinea pig. In
      the mouse, EphA4 expression was visible in the fibroblasts of the spiral ligament
      and in the structures that were to become the osseous spiral lamina. Cochlear
      nerve ganglion cells expressed ephrin-B2, and the modiolus expressed mRNA coding
      for ephrin-B3, both transmembrane ligands for EphA4. In contrast, in the guinea
      pig, cells of the cochlear nerve ganglion expressed EphA4, as did supporting
      cells of the organ of Corti (Hensen's cells and inner pillar cells). There was
      also some expression in fibroblasts of the spiral ligament but none in the
      structures that were to become the osseous spiral lamina. It is suggested that in
      the mouse, EphA4 may help direct the cochlear innervation towards the organ of
      Corti by a repulsive interaction, but that this is highly species dependent.

PMID- 10601712
TI  - C-type natriuretic peptide-like immunoreactivity in the rat inner ear.
AB  - C-type natriuretic peptide (CNP) is a member of the atrial natriuretic peptide
      family (ANP family). The family also includes ANP and brain natriuretic peptide
      (BNP). These peptides regulate the homeostasis of body fluid and blood pressure
      as a neuropeptide in the central nervous system as well as a cardiac hormone in
      the periphery. We have recently reported the expression of CNP mRNA in the inner
      ear. To assess the possible physiological role of CNP in the inner ear, we
      investigated the localization of CNP peptide in the rat inner ear by
      immunohistochemistry at the light and electron microscopic level. CNP-like
      immunoreactivity was widely distributed in the secretory and the neuronal portion
      of the inner ear, i.e. the spiral ligament, the dark cell region of the
      utriculus, the epithelium of the endolymphatic sac, the spiral ganglion cells and
      the vestibular ganglion cells. The results suggest that CNP may play a role in
      the homeostasis of the perilymph and endolymph and may also influence nerve
      activities in the inner ear.

PMID- 10601713
TI  - Threshold shifts and enhancement of cortical evoked responses after noise
      exposure in rats.
AB  - The effect of exposure to various types of noise (broadband, high-frequency or
      low-frequency) was studied in adult pigmented rats. Thresholds and amplitudes of
      middle latency responses (MLR) recorded from electrodes implanted on the surface
      of the auditory cortex were analyzed before and after noise exposure. Exposure to
      noise with intensities ranging from 105 to 120 dB for 1 h produced only temporary
      threshold shifts (TTS). Exposure to broadband noise produced TTS throughout the
      whole frequency range of the rat's hearing, mostly expressed at frequencies of
      maximal hearing sensitivity (16-32 kHz). Hearing loss produced by high- or low
      frequency noise exposure was related to the spectral characteristics of the
      noise. The exposure to high-intensity noise may also result in amplitude
      enhancement of the MLR. This phenomenon was seen mainly after broadband noise
      exposure and occurred in response to both low-frequency and high-frequency test
      stimuli. High-frequency and low-frequency noise produced amplitude enhancement
      mainly at frequencies which corresponded to the maximum exposure energy. In
      contrast to the relatively similar values of TTS obtained in different rats under
      the same conditions of noise exposure, great inter-individual variability was
      found in the MLR amplitude enhancement. In all rats the dynamics of recovery
      functions for amplitude enhancement were different from those for MLR thresholds.
      The data indicate that whereas post-exposure TTS are related to peripheral
      changes, the post-exposure MLR amplitude enhancement is most probably connected
      with a change in the processing of auditory information in the central nervous
      system.

PMID- 10601714
TI  - Responses of cells to stationary and moving sound stimuli in the anterior
      ectosylvian cortex of cats.
AB  - The azimuthal, directional and angular speed sound selectivities of single units
      were examined in the posterior part of the anterior ectosylvian cortex. Broadband
      noise bursts and simulated moving sounds were delivered from 16 loudspeakers
      fixed on the horizontal plane in a quasi-anechoic sound-isolation chamber. The
      activity of 78 neurons was recorded and quantitatively analyzed. Most cells
      responded to at least the static sound. The relative strengths of their responses
      suggested that the cells could be classed as omnidirectional (37.2%),
      contralateral hemifield (29.5%), ipsilateral hemifield (2.5%) and azimuth (7.7%)
      selective. The remaining 23.1% could not be classified. All cells responded to a
      simulated moving sound displaced at five different speeds. A majority (88%) of
      them showed some directional preference in that they discharged at least twice as
      strongly for one direction as for the other for at least one speed. 14.7%
      displayed angular speed selectivity. Different patterns of neuronal discharges
      were evoked. For static sounds, most of the cells gave ON-type responses. A large
      proportion (60%) of the cells responded in a sustained manner to maintained
      stimulation. Among these, 68% also gave sustained discharges to moving sounds.
      The spatial tuning and the directional and angular speed selectivity of neurons
      in the posterior part of the AEC suggest that this area is involved in the
      processing of static and moving sounds.

PMID- 10601715
TI  - Combined effects of noise and styrene exposure on hearing function in the rat.
AB  - Combined exposure to both noise and aromatic solvents such as styrene is common
      in many industries. In order to study the combined effects of simultaneous
      exposure to both noise and styrene on hearing, male adult Long-Evans rats were
      exposed either to 750 ppm styrene alone, to a 97 dB SPL octave band of noise
      centered at 8 kHz, or to a combination of noise and styrene. The exposure
      duration was 6 h/day, 5 days/week, for 4 consecutive weeks. Auditory function was
      tested over a frequency range from 2 to 32 kHz by recording near field potentials
      from the inferior colliculus, whereas histopathological analyses of the cochleae
      were performed with conventional morphometric approaches. Whereas both noise and
      styrene each caused permanent threshold shifts, the mechanisms of cochlear damage
      were different. Noise-induced hearing loss was mainly related to injuries of the
      stereocilia, whereas styrene-induced hearing loss was related to outer hair cell
      losses. Following the combined exposure, the threshold elevations as well as the
      cell losses exceeded the summed loss caused by noise and by styrene alone in the
      range of 8-16 kHz. Therefore, these results suggest that the two ototoxicants can
      cause a permanent synergistic loss of auditory sensitivity.

PMID- 10601716
TI  - Apoptotic death of hair cells in mammalian vestibular sensory epithelia.
AB  - Hair cell death was examined in cultured explants of vestibular organs from
      mature guinea pigs and gerbils. The effects of gentamicin were compared with
      those of staurosporine, a membrane-permeable kinase inhibitor that induces
      programmed cell death in almost all cell types. Under the conditions used
      staurosporine killed hair cells but supporting cells appeared unaffected, and a
      topographic pattern of differential sensitivity to staurosporine amongst hair
      cells, similar to that described for aminoglycoside antibiotics, was revealed.
      This suggests such differential sensitivity is an inherent property of the hair
      cell population. Thin sectioning, and examination of whole mount preparations
      after application of the TUNEL procedure or after double fluorescent labelling
      with phalloidin and with propidium iodide, which labels nuclei, revealed that
      hair cells after exposure to gentamicin show features identical to those of
      apoptotic cells after exposure to staurosporine. Furthermore, cells showing
      features of apoptosis constitute a major proportion of the hair cells that are
      ultimately lost following exposure to gentamicin. Incubation of cultures with
      gentamicin in the presence of broad-spectrum inhibitors of caspases, proteases
      involved specifically in the cell death pathway, prevented almost all of the hair
      cell deaths normally triggered by gentamicin. This confirms that apoptosis is the
      predominant mode of hair cell death after gentamicin exposure. Hair cells exposed
      to gentamicin in the presence of caspase inhibitors appeared to be preserved
      intact. This, and the thin section observations, suggests that apoptotic death is
      the fate of the majority of hair cells affected by that drug and that any sub
      lethal damage to hair cells exposed to gentamicin does not result in significant
      morphological alterations. Hair cell death was also prevented by deferoxamine
      which has been shown to protect cochlear hair cells in vivo from the effects of
      gentamicin. Explant cultures of mature vestibular organs may be, therefore, a
      useful model system for examining putative hair cell protecting agents.

PMID- 10601717
TI  - Age-related changes in the murine cochlear lateral wall.
AB  - Cochleas from C57BL/6 mice were investigated electrophysiologically and
      histochemically to evaluate the pathology of presbycusis. The average auditory
      brainstem response thresholds from 6-week-old mice were significantly lower than
      those of 6-month-old mice and those of 1-year-old mice. Histologic observation
      revealed changes in the cochlea after age 6 months. Conventional hematoxylin and
      eosin (H&E) staining showed disorganization of the organ of Corti, a decrease in
      the number of spiral ganglion cells, and atrophy of the stria vascularis.
      Although H&E staining and type II collagen immunolabeling did not show obvious
      changes in the spiral ligament (SL), the density of connexin 26 staining was
      reduced in this region. Sodium-potassium-adenosinetriphosphatase immunolabeling
      was increased in the SL, whereas its average density was not significantly
      altered in the stria vascularis. These results suggest that the SL could be among
      the regions responsible for cochlear malfunction with aging.

PMID- 10601718
TI  - A quantitative study of cochlear afferent axons in birds.
AB  - This paper is a comparative study of auditory-nerve morphology in birds. The
      chicken (Gallus gallus), the emu (Dromaius novaehollandiae) and the starling
      (Sturnus vulgaris) were chosen as unspecialised birds that have already been used
      in auditory research. The data are discussed in comparison to a similar earlier
      study on the barn owl, a bird with highly specialised hearing, in an attempt to
      separate general avian patterns from species specialisations. Average numbers of
      afferent fibres from 8775 (starling) to 12? omitted?406 (chicken) were counted,
      excluding fibres to the lagenar macula. The number of fibres representing
      different frequency ranges showed broad maxima in the chicken and emu,
      corresponding to hearing ranges of best sensitivity and/or particular behavioural
      relevance. Mean axon diameters were around 2 microm in the chicken and starling,
      and around 3 microm in the emu. Virtually all auditory afferents were myelinated.
      The mean thickness of the myelin sheaths was between 0.33 microm (starling) and
      0.4 microm (emu). There was a consistent pattern in the diameters of axons
      deriving from different regions. Axons from very basal, i.e. highest-frequency,
      parts of the basilar papilla were always the smallest. In the emu and the
      chicken, axons from the middle papillar regions were, in addition, larger than
      axons innervating apical regions.

PMID- 10601719
TI  - Neurogenesis in the superior olivary complex in the rat.
AB  - In a previous paper we provided evidence that crossed projection neurons are
      generated earlier than uncrossed projection neurons in the lateral superior
      olive. The aim of the present study was to determine if other major nuclei of the
      superior olivary complex (SOC), the medial superior olivary (MSO), the superior
      paraolivary (SPN) and the medial trapezoid (MTB) nuclei, are distinguished by
      their neuronal constitutions of birthdates. Pregnant rats were injected
      intraperitoneally with 5-bromodeoxyuridine (BrdU), the thymidine analogue, to
      label the neurons on one of the embryonic (E) days E11-E16. When the progeny rats
      reached adulthood, the brains were processed for BrdU immunohistochemistry. The
      MSO was mostly composed of neurons generated on E12 (95%). The remaining neurons
      in the MSO completed their neurogenesis by E13. The SPN neurons were generated
      from E12 to E14 with a peak on E13 (80%). Regardless of the morphological
      heterogeneity, the SPN consisted of a single population of neurons in terms of
      neurogenesis. The MTB neurons were generated from E13 to E16 with a peak on E14
      (73%). In contrast to the previous assumption, no topographical relationship
      existed between neurogenesis and tonotopicity within each nucleus of the SOC.

PMID- 10601720
TI  - Inner hair cell loss leads to enhanced response amplitudes in auditory cortex of
      unanesthetized chinchillas: evidence for increased system gain.
AB  - Carboplatin preferentially destroys inner hair cells (IHCs) in the chinchilla
      inner ear, while retaining a near-normal outer hair cell (OHC) population. The
      present study investigated the functional consequences of IHC loss on the
      compound action potential (CAP), inferior colliculus potential (ICP) and auditory
      cortex potential (ACP) recorded from chronically implanted electrodes. IHC loss
      led to a reduction in CAP amplitude that was roughly proportional to IHC loss.
      The ICP amplitude was typically reduced by IHC loss, but the magnitude of this
      reduction was generally less than that observed for the CAP. In contrast to the
      CAP and ICP, ACP amplitudes were generally not reduced following IHC loss. In
      some animals, the ACP amplitude remained at pre-carboplatin values despite
      substantial IHC loss. However, in other animals, IHC loss led to an increase
      ('enhancement') of ACP amplitude. ACP enhancement was greatest at 1-2 weeks post
      carboplatin, returning towards baseline amplitudes at 5 weeks post-carboplatin.
      In other animals, the ACP remained enhanced up to 5 weeks post-carboplatin. We
      interpret the transient and sustained enhancement of ACP amplitude following
      partial IHC loss as evidence of functional reorganization occurring at or below
      the level of the auditory cortex. These results suggest that the gain of the
      central auditory pathway increases following IHC loss to compensate for the
      reduced input from the cochlea.

PMID- 10601721
TI  - Floating drug delivery systems: an approach to oral controlled drug delivery via
      gastric retention.
AB  - In recent years scientific and technological advancements have been made in the
      research and development of rate-controlled oral drug delivery systems by
      overcoming physiological adversities, such as short gastric residence times (GRT)
      and unpredictable gastric emptying times (GET). Several approaches are currently
      utilized in the prolongation of the GRT, including floating drug delivery systems
      (FDDS), also known as hydrodynamically balanced systems (HBS), swelling and
      expanding systems, polymeric bioadhesive systems, modified-shape systems, high
      density systems, and other delayed gastric emptying devices. In this review, the
      current technological developments of FDDS including patented delivery systems
      and marketed products, and their advantages and future potential for oral
      controlled drug delivery are discussed.

PMID- 10601722
TI  - Chemical and enzymatic stability as well as transport properties of a Leu
      enkephalin analogue and ester prodrugs thereof.
AB  - The Leu-enkephalin analogue (Tyr-D-Ala-Gly-Phe-Leu-NH(2)) was synthesized
      together with three esters prodrugs hereof. The prodrugs synthesized were the O
      acetyl, O-propionyl and O-pivaloyl99%) and in good yields (60-75%). The chemical
      and enzymatic stability of the prodrugs has been investigated in detail. The
      prodrugs studied are quite chemically stable and the degradation of the prodrugs
      follows the pattern previously shown for similar esters (U-shaped pH-profile;
      maximal stability at pH 4-5). The prodrugs are degraded quantitatively in plasma
      to the parent peptide with half-lives in the range 2.9 min-2.6 h. Type B
      esterases were shown to be involved in the degradation as the half-lives
      increased in the presence of paraoxon. No significant stabilization was seen in
      10% porcine gut homogenate. Half-lives in the same order were seen for the
      analogue and the prodrugs in pure Leucine aminopeptidase solution. The analogue
      was stable in Carboxypeptidase A solution whereas a faster degradation of the
      prodrugs was seen in this media. Furthermore the transport properties of the
      compounds has been studied. A P(app) value of 0.284x10(-6) cm/s for the analogue
      was obtained for the transport across Caco-2 cell monolayers in the BL-AP
      direction. The P(app) values were increased by a factor of 2, 7 and 18 for the
      acetyl-, propionyl- and pivaloylprodrug. The increase could be explained by
      higher lipofilicities of the prodrugs compared to the analogue.

PMID- 10601723
TI  - Polycaprolactone-b-poly(ethylene oxide) copolymer micelles as a delivery vehicle
      for dihydrotestosterone.
AB  - Block copolymer micelles formed from copolymers of poly(caprolactone)-b
      poly(ethylene oxide) (PCL-b-PEO) were investigated as a drug delivery vehicle for
      dihydrotestosterone (DHT). The physical parameters of the PCL-b-PEO micelle
      incorporated DHT were measured, including the loading capacity of the micelles
      for DHT, the apparent partition coefficient of DHT between the micelles and the
      external medium and the kinetics of the release of DHT from the micelle solution.
      The MTT survival assay was used to assess the in vitro biocompatibility of PCL-b
      PEO micelles in HeLa cell cultures. The biological activity of the micelle
      incorporated DHT was evaluated in HeLa cells which had been co-transfected with
      the expression vectors for the androgen receptor and the MMTV-LUC reporter gene.
      The PCL-b-PEO micelles were found to have a high loading capacity for DHT and the
      release profile of the drug from the micelle solution was found to be a slow
      steady release which continued over a 1-month period. The biological activity of
      the micelle-incorporated DHT was found to be fully retained.

PMID- 10601724
TI  - Controlled release from solid dispersion composed of poly(ethylene oxide)
      Carbopol interpolymer complex with various cross-linking degrees of Carbopol.
AB  - Solid dispersion composed of the poly(ethylene oxide) (PEO)-Carbopol((R)) (CP)
      interpolymer complex containing phenacetin (PHE) was prepared by using six grades
      of CP having various cross-linking degrees. We attempted to control the medicine
      release from the PEO-CP solid dispersion by varying the CP grade. The powder X
      ray diffraction pattern and differential scanning calorimetry curves suggested
      that PHE existed in the amorphous state, and PEO in the crystalline state
      disappeared in the solid dispersions. The release profile of PHE varied depending
      on the CP grade. A small release rate was observed at CP910 and CP971P that are
      cross-linked at low and middle degrees, respectively. The Fourier transform
      infrared (FT-IR) spectra showed that the amount of the PEO-CP complex formed by
      hydrogen bonding changed depending on the CP grade. With the cross-linked CP, a
      good correlation was observed between the hydrogen bonding percent and the
      percent released of the PHE after 60 min (D(60 min)), indicating that PHE release
      was controlled by the amount of PEO-CP complex formation in the solid dispersion.
      These results show that it is feasible to control the medicine release from PEO
      CP solid dispersion by varying the CP grade.

PMID- 10601725
TI  - Development of oral controlled release preparations, a PVA swelling controlled
      release system (SCRS). I. Design Of SCRS and its release controlling factor.
AB  - Polyvinyl alcohol (PVA) is hydrophilic and swells easily by absorbing water. Some
      grades of PVA, whose degree of hydrolysis is 96.0 and 97.5 mol%, showed volume
      expansion of 500% by swelling at 37 degrees C. This expansion was inhibited by
      swelling controlling agents, namely salts. Based on this unique property of PVA,
      a new type of controlled release system was developed. The release rate was
      controlled by the content of PVA and a swelling controlling agent in the core
      tablet, and the composition and coating level of the film. Emedastine difumarate
      was incorporated into the system. At the initial stage of drug release, the rate
      of release was determined by the permeation through the membrane - a mixture of
      ethylcellulose and hydroxypropyl methylcellulose. After the membrane burst by the
      swelling of PVA, the release rate was controlled by the PVA matrix. Release
      patterns of zero-order, two phase zero-order, and rapid release after lag-time
      were obtained with this system.

PMID- 10601726
TI  - Investigation of the in vitro release of gentamicin from a polyanhydride matrix.
AB  - Septacin?trade mark omitted? is a sustained release formulation consisting of
      gentamicin sulfate dispersed in a biodegradable polyanhydride matrix. The
      polyanhydride matrix is a copolymer of erucic acid dimer (EAD) and sebacic acid
      in a 1:1 weight ratio. In vitro drug release was performed in both water and pH
      7.4 phosphate buffer. The drug release in water was faster than that in the
      buffer, which was the opposite of what would be expected based upon a faster
      polymer hydrolysis rate in the buffer. Theoretical treatment of the data using
      the Peppas model revealed that release in water was anomalous, while the release
      in pH 7.4 phosphate buffer was diffusion-controlled. Profound bead morphology
      differences were observed between beads in these two in vitro release media.
      Cracking was observed in beads in water and swelling with no apparent cracking
      was seen in beads in buffer. Concurrent monitoring of drug and sebacic acid
      release indicated that drug release is not via surface erosion. Osmotic effects
      were found to play little role in the in vitro drug release. There was no
      spectroscopic evidence of amide formation between the drug and copolymer. Sulfate
      release was monitored along with drug release and the results indicate that there
      is ion-exchange occurring during the pH 7.4 in vitro release. It was subsequently
      demonstrated that gentamicin can form an insoluble salt with EAD. This salt
      formation explains the slower drug release in pH 7.4 phosphate buffer.

PMID- 10601727
TI  - Novel sustained-release dosage forms of proteins using polyglycerol esters of
      fatty acids.
AB  - In order to develop a novel delivery system for proteins based on polyglycerol
      esters of fatty acids (PGEFs), we studied a model system using interferon-alpha
      (IFN-alpha) as the test protein. A cylindrical matrix was prepared by a heat
      extrusion technique using a lyophilized powder of the protein and 11 different
      types of synthetic PGEFs, which varied in degree of glycerol polymerization (di-
      and tetra-), chain length of fatty acids (myristate, palmitate and stearate) and
      degree of fatty acid esterification (mono-, di- and tri-). In an in-vitro release
      study using an enzyme-linked immunosorbent assay (ELISA) as a detection method,
      the matrices prepared from a monoglyceride (used for comparison) and from
      diglycerol esters exhibited a biphasic release pattern with a large initial burst
      followed by slow release. In contrast, the matrices prepared from tetraglycerol
      esters showed a steady rate of release without a large initial burst. In an in
      vivo release study, initial bursts of IFN-alpha release were, also, dramatically
      reduced when the matrices were prepared from the tetraglycerol esters of
      palmitate and stearate, and the mean residence time (MRT) of IFN-alpha was
      prolonged, whereas the matrices prepared from monoglyceride and from diglycerol
      esters showed large initial bursts of IFN-alpha release. Since the release rates
      from the matrices prepared from the tetraglycerol esters of palmitate and
      stearate were governed by Jander's equation modified for a cylindrical matrix,
      the release from those matrices was concluded to be a diffusion-controlled
      process. The bioavailability of IFN-alpha after implantation of the matrix
      formulation prepared using all types of PGEFs, except for tetraglycerol
      triesters, was almost equivalent to that after injection of IFN-alpha solution;
      consequently, IFN-alpha in these matrices appears to remain stable during the
      release period.

PMID- 10601728
TI  - Intradermal microdialysis: kinetics of iontophoretically delivered propranolol in
      forearm dermis.
AB  - Intradermal microdialysis permits us to measure the concentration in dermis of
      drugs applied to the skin. Microdialysis is especially efficient in sampling
      water-soluble molecules. Consequently, it appears particularly suitable to study
      current based delivery systems like iontophoresis that deliver ions or highly
      polar molecules. The purpose of this work was to evaluate the adequacy of a skin
      microdialysis technique to characterize and quantify the dermatopharmacokinetics
      of iontophoretically delivered propranolol in the dermis of healthy human
      volunteers. Linear microdialysis probes were inserted in the subject's forearm
      skin and an iontophoresis device was installed above them. Constant current was
      applied for two periods of 1 h each separated by a 1-h interval. Dialysate
      samples were collected every 6 min for 4.4 h and analyzed by HPLC. Probes were
      always placed in the dermis as measured by ultrasonography. Propranolol was
      detectable in the dialysate. It was possible to build detailed concentration vs.
      midtime profiles that mirrored the current applied. Elimination rate from the
      dermis had first-order kinetics and was similar in all subjects. Quantification
      of the absorption process, indexed by lag-time and area under the concentration
      curve showed a high inter- and intrasubject variability that did not correlate
      with probe depth.

PMID- 10601729
TI  - Regulation of extracellular matrix gene expression by mechanical stress.
AB  - Extracellular matrix (ECM) is the substrate for cell adhesion, growth, and
      differentiation, and it provides mechanical support to tissues. It is well known
      that connective tissue cells adapt their ECM to changes in mechanical load, as
      seen, e.g. during bone remodeling or wound healing. A feedback mechanism must
      exist by which cells that sense mechanical stress via their substrate respond by
      an altered pattern of protein expression, and thus remodel the ECM to meet
      changing mechanical requirements. What signals are triggered in connective tissue
      cells by mechanical stress, and how do such stimuli affect the expression of
      specific ECM proteins? The evidence will be reviewed that integrins, the
      transmembrane adhesion and signaling receptors which physically link ECM to the
      cytoskeleton, might be key players in transducing mechanical signals, presumably
      via MAP kinase and NF-kappaB pathways. At the far end of the response, there is
      evidence for regulation at the level of gene transcription. For example, the
      production of tenascin-C and collagen XII, two ECM proteins typical of tendons
      and ligaments, is high in fibroblasts attached to a stretched collagen matrix,
      but suppressed in cells on a relaxed matrix. The response to a change in stretch
      is rapid and reversible, and is reflected on the mRNA level. Both the tenascin-C
      and the collagen XII gene promoters contain 'stretch-responsive' enhancer regions
      with similarity to 'shear stress response elements' in other genes. The precise
      signal pathways converging on these mechano-responsive enhancer elements remain
      to be elucidated.

PMID- 10601730
TI  - How does the hyaluronan scrap-yard operate?
AB  - Hyaluronan is an extracellular polysaccharide found throughout the extracellular
      matrix, especially in soft connective tissue. It has an unusual feature, in that
      its turnover rate is much greater than that of other extracellular matrix
      components. The mechanisms of its synthesis at the plasma membrane (by hyaluronan
      synthases) and lysosomal degradation (by hyaluronidases) are well documented.
      However, the mechanisms by which it enters those cells primarily involved in its
      degradation remain a mystery. Recent work now suggests that a novel scavenger
      receptor expressed on the surface of liver endothelial cells is responsible for
      part of this degradative process. Further study is required to fill the remaining
      gaps in our knowledge about this process in other tissues.

PMID- 10601731
TI  - Cell adhesion to a population of laminin isoforms isolated from normal renal
      tissue.
AB  - To assess whether cells react differently towards a population of several laminin
      isoforms, as found in vivo, vs. a single isoform, we have compared the biological
      activity of kidney laminins to that of pure laminin 1. The kidney laminin
      preparation contained laminin 1 and further isoforms. Both substrates induced
      adhesion of a large spectrum of cell types, with kidney laminins being the most
      active. Unfolding of the coil-coiled conformation of the kidney isoforms
      negatively affected cell adhesion-promoting activity, which indicated that
      conformation-dependent cell binding is a characteristic feature of many or all
      laminins. Cellular interactions with kidney laminins were mediated by alpha3beta1
      and alpha6beta1 integrins, with the contribution of alpha3beta1 being apparently
      lower than that of alpha6beta1 integrins. Immunofluorescence staining of vinculin
      and integrin subunits decorated focal adhesions on kidney laminins which differed
      in morphology from those formed on laminin 1 alone, in spite of the presence of
      the latter in the kidney preparation. These observations collectively indicate
      that tissue specific but often overlapping expression of laminin isoforms might
      modulate cell behavior by the activation of distinct sets of integrins and by the
      induction of distinct molecular assemblies within the cell adhesion signaling
      complexes.

PMID- 10601732
TI  - The human CILP gene: exon/intron organization and chromosomal mapping.
AB  - The human cDNA for cartilage intermediate layer protein (CILP) codes for a larger
      precursor protein that consists of CILP and a homologue to porcine Nucleotide
      pyrophosphohydrolase (NTPPHase) [Lorenzo et al. 1998a. J. Biol. Chem. 273, 23469
      23475]. The human gene has now been isolated and characterized. Southern blot
      analysis indicated a single copy of the CILP gene in the human genome. The gene
      spans approximately 15.3 kbp of genomic DNA, and is organized in nine exons. The
      5' flanking region contains a putative promoter region with a TATA-like box
      localized from -29 to -23 bp upstream of the transcription start site. Analysis
      of the putative promoter region revealed potentially cis-regulatory eukaryotic
      elements such as GATA-1, MyoD, MZF1, and CdxA. The protein coding region begins
      in exon 2 with the putative signal peptide. CILP is encoded from exon 3 to exon
      9. In addition, exon 9 also codes for the entire NTPPHase homologue and contains
      the 3' untranslated region of the gene. All the introns follow the 'gt-ag' rule,
      except the last intron, intron 8, that belongs to the minor class of pre-mRNA
      introns that contain 'at-ac' at their 5' and 3' ends, respectively. The CILP gene
      was mapped to human chromosome 15q22.

PMID- 10601734
TI  - Sequence, recombinant expression and tissue localization of two novel
      extracellular matrix proteins, fibulin-3 and fibulin-4.
AB  - Fibulin-1 and fibulin-2 have previously been identified as basement membrane and
      microfibrillar proteins with a broad binding repertoire for other extracellular
      ligands. Here we report on the cloning and sequence analysis of human fibulin-3
      (487 residues), also known as protein S1-5, and fibulin-4 (443 residues). These
      novel members of this protein family are most closely related to fibulin-1C. They
      consist of a C-terminal globular domain III, also shared by the fibrillins, a
      central rod-like element composed of five calcium-binding epidermal growth factor
      like (EG) modules (domain II) and an N-terminal interrupted EG module (domain I)
      which replaces the anaphylatoxin-like modules of the other fibulins. This
      predicted domain structure was supported by electron microscopy of fibulin-4,
      which demonstrated short rods. Northern blots showed that both novel fibulins are
      expressed in several human tissues to a variable extent and that they are up
      regulated in quiescent fibroblasts. Specific antibodies which were raised against
      each of the novel fibulins did not cross-react with fibulin-1. Immunohistology of
      adult mouse tissues showed that fibulin-3, fibulin-4 and fibulin-1 have
      overlapping but distinct extracellular tissue localizations. A particularly
      prominent feature was the staining of variable sets of large and small blood
      vessels.

PMID- 10601733
TI  - Transcriptional regulation of stromelysin-1 gene expression is altered during
      progression of mouse mammary epithelial cells from functionally normal to
      malignant.
AB  - The matrix metalloproteinase stromelysin-1 plays a central role during mammary
      gland development and tumor progression. To gain insight into the regulation of
      stromelysin-1 gene expression, the murine stromelysin-1 promoter was cloned and
      transfected into mouse mammary epithelial cells displaying various degrees of
      malignancy. A reconstituted basement membrane inhibited stromelysin-1 promoter
      activity in functionally normal cells, had little effect on moderately malignant
      cells and up-regulated the promoter in highly malignant cells. Spreading of
      normal and malignant cells was reduced by a reconstituted basement membrane,
      compared to a plastic substratum. Preventing spreading by maintenance of cells in
      suspension culture, regulated stromelysin-1 promoter activity in a manner similar
      to that on a reconstituted basement membrane. Conversely, increasing spreading by
      augmenting substratum adhesivity up-regulated stromelysin-1 promoter activity in
      tumor cells. In cells with reduced spreading in the presence of reconstituted
      basement membrane and in suspension culture, actin stress fibers were replaced by
      cortical actin bundles. In tumor cells, but not in functionally normal cells,
      treatment with phorbol diesters also resulted in accumulation of cortical actin
      and increased stromelysin-1 promoter activity. Consistent with an epithelial-to
      mesenchymal conversion, regulation of stromelysin-1 gene expression in highly
      malignant cells was similar to its regulation in mammary fibroblasts. We conclude
      that the switch in transcriptional regulation of stromelysin-1 expression that
      occurs during epithelial-to-mesenchymal transition and conversion to
      tumorigenicity is related to altered regulation of signals from the
      cytoarchitecture.

PMID- 10601735
TI  - Complete primary structure of the chicken alpha1(V) collagen chain.
AB  - Chicken alpha1(V) collagen cDNAs have been cloned by a variety of methods and
      positively identified. We present here the entire translated sequence of the
      chick polypeptide and compare selected regions to other collagen chains in the
      type V/XI family.

PMID- 10601736
TI  - Distribution of cartilage molecules in the developing mouse joint.
AB  - This study describes the precise spatial and temporal patterns of protein
      distribution for aggrecan, fibromodulin, cartilage oligomeric matrix protein
      (COMP) and cartilage matrix protein (CMP) in the developing mouse limb with
      particular attention to those cells destined to form articular chondrocytes in
      comparison to those cells destined to form a mineralized tissue and become
      replaced by bone. Mouse glenohumeral joints from fetal mice (12-18 days post
      coitus (dpc) to the young adult (37 days after birth) were immunostained with
      antibodies specific for these molecules. Aggrecan staining defined the general
      chondrocytic phenotype, whether articular or transient. Fibromodulin was
      associated with prechondrocytic mesenchymal cells in the interzone prior to joint
      cavitation and with the mesenchymal cells of the perichondrium or the periosteum
      encapsulating the joint elements of the maturing and young adult limb. Staining
      was most intense around developing articular chondrocytes and much less abundant
      or absent in those differentiating cells along the anlage. CMP showed an almost
      reciprocal staining pattern to fibromodulin and was not detected in the matrix
      surrounding articular chondrocytes. COMP was not detected in the cells at the
      articular surface prior to cavitation but by 18 dpc, as coordinated movement of
      the mouse forelimb intensifies, staining for COMP was most intense around the
      maturing articular chondrocytes. These results show that the cells that
      differentiate into articular chondrocytes elaborate an extracellular matrix
      distinct from those cells that are destined to form bone. Fibromodulin may
      function in the early genesis of articular cartilage and COMP may be associated
      with elaboration of a weight-bearing chondrocyte matrix.

PMID- 10601737
TI  - Immunochemical and tissue analysis of protease generated neoepitopes of BM-40
      (osteonectin, SPARC) which are correlated to a higher affinity binding to
      collagens.
AB  - Proteolytic cleavage at single sites in the extracellular calcium-binding module
      of BM-40/SPARC/osteonectin either by an unknown endogenous protease (L197-L198)
      or several matrix metalloproteinases (E196-L197) was previously shown to enhance
      collagen binding activity 10-fold. Polyclonal rabbit antibodies were now obtained
      against synthetic peptide antigens containing either an N-terminal L197 or L198
      and characterized by radioimmunoassay, ELISA, immunoblots and immunohistology.
      These neoepitope-specific antibodies reacted with proteolytically processed but
      not with uncleaved mouse and human BM-40. The cross-reaction between the two
      different neoepitopes was < 1%, indicating the immunodominant role of the N
      terminal residues. Analysis of a basement membrane producing mouse tumor
      demonstrated extensive cleavage at the L198 site, which correlated with a calcium
      dependent binding to the matrix. A variable degree of this cleavage was also
      detected in BM-40 obtained from adult mouse bone and several other tissues.
      Negligible or much lower levels of conversion were detected at the MMP-specific
      L197 site, however. Immunogold staining of mouse heart and a basement membrane
      producing mouse tumor showed a distinct extracellular labeling for BM-40 and the
      L198 neoepitope but only a very weak reaction for the L197 neoepitope. This
      strongly indicates that these neoepitopes are generated in vivo and emphasizes a
      specific biological role for the proteolytic activation of BM-40.

PMID- 10601738
TI  - Expression and characterization of the IPM 150 gene (IMPG1) product, a novel
      human photoreceptor cell-associated chondroitin-sulfate proteoglycan.
AB  - The interphotoreceptor matrix (IPM) occupies the extracellular space between the
      apical surface of the retinal pigmented epithelium and the external limiting
      membrane of the neural retina. This space contains two chondroitin sulfate
      proteoglycans, designated IPM 150 and IPM 200, which are likely to effect retinal
      adhesion and photoreceptor survival. In an effort to characterize human IPM 150,
      several cDNA clones encoding its core protein have been isolated from a human
      retinal cDNA library. Translation of overlapping cDNA sequences yields a novel
      core protein with a predicted molecular mass of 89.3 kDa. Northern and dot-blot
      analyses as well as the isolation of expressed sequence tags demonstrate that IPM
      150 mRNA is expressed not only in the neural retina but also in several other non
      ocular tissues. In situ hybridization analyses indicate that, in the eye, IPM 150
      mRNA is expressed specifically by cone and rod photoreceptor cells.
      Characterization of IPM 150 proteoglycan core protein and identification of its
      site of synthesis are important steps towards understanding the architecture and
      biology of the IPM.

PMID- 10601739
TI  - Coexpression with collagen markedly increases the half-life of the recombinant
      human prolyl 4-hydroxylase tetramer in the yeast Pichia pastoris.
AB  - Recent coexpression studies of the subunits of human prolyl 4-hydroxylase (4-PH)
      in the yeast Pichia pastoris have indicated that only a minor fraction of them
      were present in the alpha2beta2 tetramer, while coexpression with type III
      procollagen markedly increased their assembly level. We report here that the half
      life of the recombinant 4-PH tetramer in Pichia when studied by pulse-chase
      experiments was only 50 min. Coexpression with the pro alpha1(III) chains
      increased this half-life to 12.5 h. Coexpression with the pro alpha1(I) chains,
      which were produced at half the level of the pro alpha1(III) chains, gave a half
      life of 6.5 h. Coexpression with collagen thus markedly increases the half-life
      of the 4-PH tetramer, and the half-life may be related to the level of collagen
      expression.

PMID- 10601740
TI  - "What"-Then-Where" in visual working memory: an event-related fMRI study.
AB  - Behavioral studies indicate that spatial and object working memory are computed
      by dissociable subsystems. We investigated the neural bases of this dissociation
      with a whole-brain fMRI design and analysis technique that permitted direct
      assessment of delay-period activity, uncontaminated by other components of the
      trial. The task employed a "what"-then-"where" design, with an object and a
      spatial delay period incorporated in each trial; within-trial order of delay
      conditions was balanced across each scan. Our experiment failed to find evidence,
      at the single-subject level and at the group level, for anatomical segregation of
      spatial and object working memory function in the frontal cortex. Delay-period
      activity in the caudate nucleus revealed a sensitivity to position in the trial
      in the spatial, but not the object, condition. In posterior regions, spatial
      delay-period activity was associated with preferential recruitment of
      extrastriate areas falling within Brodmann's area 19 and, less reliably, the
      superior parietal lobule. Object-specific delay-period activity was found
      predominantly in ventral regions of the posterior cortex and demonstrated more
      topographic variability across subjects than did spatial working memory activity.

PMID- 10601741
TI  - Frontal brain activity during episodic and semantic retrieval: insights from
      event-related potentials.
AB  - Previous neuropsychological and neuroimaging results have implicated the
      prefrontal cortex in memory retrieval, although its precise role is unclear. In
      the present study, we examined patterns of brain electrical activity during
      retrieval of episodic and semantic memories. In the episodic retrieval task,
      participants retrieved autobiographical memories in response to event cues. In
      the semantic retrieval task, participants generated exemplars in response to
      category cues. Novel sounds presented intermittently during memory retrieval
      elicited a series of brain potentials including one identifiable as the P3a
      potential. Based on prior research linking P3a with novelty detection and with
      the frontal lobes, we predicted that P3a would be reduced to the extent that
      novelty detection and memory retrieval interfere with each other. Results during
      episodic and semantic retrieval tasks were compared to results during a task in
      which subjects attended to the auditory stimuli. P3a amplitudes were reduced
      during episodic retrieval, particularly at right lateral frontal scalp locations.
      A similar but less lateralized pattern of frontal P3a reduction was observed
      during semantic retrieval. These findings support the notion that the right
      prefrontal cortex is engaged in the service of memory retrieval, particularly for
      episodic memories.

PMID- 10601742
TI  - Preferences for visual stimuli following amygdala damage.
AB  - Bilateral damage to the human amygdala impairs retrieval of emotional and social
      information from faces. An important unanswered question concerns the specificity
      of the impairment for faces. To address this question, we examined preferences
      for a broad class of visual stimuli in two subjects with complete bilateral
      amygdala damage, both of whom were impaired in judgments of faces. Relative to
      controls, the subjects showed a positive bias for simple nonsense figures, color
      patterns, three-dimensional-looking objects and landscapes. The impairment was
      most pronounced in regard to those stimuli that are normally liked the least. The
      human amygdala thus appears to play a general role in guiding preferences for
      visual stimuli that are normally judged to be aversive.

PMID- 10601743
TI  - Differential contributions of the left and right inferior parietal lobules to
      number processing.
AB  - We measured cerebral activation with functional magnetic resonance imaging at 3
      Tesla while eight healthy volunteers performed various number processing tasks
      known to be dissociable in brain-lesioned patients: naming, comparing,
      multiplying, or subtracting single digits. The results revealed the activation of
      a circuit comprising bilateral intraparietal, prefrontal, and anterior cingulate
      components. The extension and lateralization of this circuit was modulated by
      task demands. The intraparietal and prefrontal activation was more important in
      the right hemisphere during the comparison task and in the left hemisphere during
      the multiplication task and was intensely bilateral during the subtraction task.
      Thus, partially distinct cerebral circuits with the dorsal parietal pathway
      underlie distinct arithmetic operations.

PMID- 10601744
TI  - Set- and code-specific activation in frontal cortex: an fMRI study of encoding
      and retrieval of faces and words.
AB  - The frontal cortex has been described as playing both "set-specific" and "code
      specific" roles in human memory processing. Set specificity refers to the finding
      of goal-oriented differences in activation patterns (e.g., encoding relative to
      retrieval). Code specificity refers to the finding of different patterns of
      activation for different types of stimuli (e.g., verbal/nonverbal). Using a two
      (code: verbal, nonverbal) by two (set: encoding, retrieval) within-subjects
      design and fMRI, we explored the influence of type of code and mental set in two
      regions in the frontal cortex that have been previously shown to be involved in
      memory. A region in the dorsal extent of the inferior frontal gyrus (BA 6/44)
      demonstrated code-specific effects. Specifically, an interaction of material type
      with hemisphere was obtained, such that words produced predominantly left
      lateralized activation, whereas unfamiliar faces elicited predominantly right
      lateralized activation. A region of the right frontal polar cortex (in or near BA
      10), which has been activated in many memory retrieval studies, showed set
      specific activation in that it was more active during retrieval than encoding.
      These data demonstrate that distinct regions in the frontal cortex contribute in
      systematic yet different ways to human memory processing.

PMID- 10601745
TI  - Target selection for pursuit and saccadic eye movements in humans.
AB  - Eye movements were recorded from three subjects as they initiated tracking of a
      small circle ("target") moving leftward or rightward, above or below the
      horizontal meridian, either alone or in the presence of a small square
      ("distractor") moving leftward or rightward on the other side of the horizontal
      meridian. At the start of each trial, subjects were provided with either a "form"
      cue (always centrally positioned and having the circular shape and color of the
      upcoming moving target) or a "location" cue (a small white square positioned
      where the upcoming target would appear). The latency of pursuit increased in the
      presence of an oppositely moving distractor when subjects were provided the form
      cues but not when they were provided the location cues. The latency of saccades
      showed similar, but smaller, increases when subjects were given the form cues. On
      many trials with the form cues, pursuit started in the direction of the
      distractor and then reversed to follow the target. On these trials, the initial
      saccade often, but not always, also followed the distractor. These results
      indicate that the mechanisms of target selection for pursuit and saccades are
      tightly coordinated but not strictly yoked. The shared effects of the distractor
      on the latencies of pursuit and saccades probably reflect the common role of
      visual attention in filtering the inputs that guide these two types of eye
      movements. The differences in the details of the effects on pursuit and saccades
      suggest that the neural mechanisms that trigger these two movements can be
      independently regulated.

PMID- 10601746
TI  - Words without mind.
AB  - A woman (LR), unconscious for 20 years, spontaneously produces infrequent,
      isolated words unrelated to any environmental context. Fluorodeoxy-glucose
      positron emission tomography (FDG-PET) imaging coregistered with magnetic
      resonance imaging (MRI) revealed a mean brain metabolism equivalent to deep
      anesthesia. Nevertheless, PET imaging demonstrated islands of modestly higher
      metabolism that included Broca's and Wernicke's areas. Functional brain imaging
      with magnetoencephalographic (MEG) imaging, a technique providing a temporal
      resolution of better than 1 msec, identified preserved dynamic patterns of
      spontaneous and evoked brain activity in response to sensory stimulation.
      Specifically, we examined spontaneous gamma-band activity (near 40 Hz) and its
      reset or modification during early auditory processing, a measure that correlated
      with human perception of sensory stimuli (Joliot, Ribary, & Llinas, 1994).
      Evidence of abnormal and incomplete gamma-band responses appeared in the left
      hemisphere only in response to auditory or somatosensory stimulation. MEG single
      dipole reconstructions localized to the auditory cortex in the left hemisphere
      and overlapped with metabolically active regions identified by FDG-PET. The
      observation demonstrates that isolated neuronal groups may express well-defined
      fragments of activity in a severely damaged, unconscious brain. The motor fixed
      action pattern character of her expressed words supports the notion of brain
      modularity in word generation.

PMID- 10601747
TI  - Semantic integration in sentences and discourse: evidence from the N400.
AB  - In two ERP experiments we investigated how and when the language comprehension
      system relates an incoming word to semantic representations of an unfolding local
      sentence and a wider discourse. In Experiment 1, subjects were presented with
      short stories. The last sentence of these stories occasionally contained a
      critical word that, although acceptable in the local sentence context, was
      semantically anomalous with respect to the wider discourse (e.g., Jane told the
      brother that he was exceptionally slow in a discourse context where he had in
      fact been very quick). Relative to coherent control words (e.g., quick), these
      discourse-dependent semantic anomalies elicited a large N400 effect that began at
      about 200 to 250 msec after word onset. In Experiment 2, the same sentences were
      presented without their original story context. Although the words that had
      previously been anomalous in discourse still elicited a slightly larger average
      N400 than the coherent words, the resulting N400 effect was much reduced, showing
      that the large effect observed in stories depended on the wider discourse. In the
      same experiment, single sentences that contained a clear local semantic anomaly
      elicited a standard sentence-dependent N400 effect (e.g., Kutas &Hillyard, 1980).
      The N400 effects elicited in discourse and in single sentences had the same time
      course, overall morphology, and scalp distribution. We argue that these findings
      are most compatible with models of language processing in which there is no
      fundamental distinction between the integration of a word in its local (sentence
      level) and its global (discourse-level) semantic context.

PMID- 10601748
TI  - Role of the cerebellum in tuning anticipatory and reactive grip force responses.
AB  - The aim of our study was to determine if load perturbations that could
      destabilize grasp control are adequately controlled by cerebellar patients. We
      examined patients with unilateral cerebellar lesions who had largely recovered
      from their initial symptoms and compared grip force regulation for the affected
      and unaffected hand during a drawer-opening task. Two experimental paradigms were
      included: (1) a brief load perturbation during a self-stopped drawer pull and (2)
      a loading impact when the drawer was pulled out to the mechanical stop. The
      results showed that when a self-stopped movement was perturbed during its
      trajectory, anticipatory grip force increase was smaller for the affected than
      for the unaffected hand, illustrating a disturbed gain control due to cerebellar
      dysfunction. When the mechanical stop arrested the movement, the amount of grip
      force did not differ significantly between the affected and unaffected side;
      however, both hands used different control strategies. Whereas the unaffected
      hand anticipated the load perturbation by a ramp-like increase of grip force
      toward the impending impact, the affected hand increased grip force at movement
      onset to a default level and maintained this value until the task was ended. In
      addition, the latency between impact and reactive peak in grip force was
      prolonged for the affected hand, suggesting a delayed cerebellar transmission of
      reactive responses. In conclusion, these findings demonstrate that the cerebellum
      is involved in anticipatory and reactive mechanisms dealing with load
      perturbations during goal-directed behavior.

PMID- 10601749
TI  - Memory lost and regained following bilateral hippocampal damage.
AB  - We present a longitudinal neuropsychological study (31 examinations over a period
      of 18 months) of patient DE DF demonstrated bilateral atrophy of the hippocampal
      formation and globus pallidus resulting from carbon monoxide poisoning. Eighteen
      months after the event, the volume of the hippocampal formation was reduced by
      42% on the left side and 28% on the right. The patient initially presented with a
      severe global amnesia. Then, he showed a gradual, yet selective recovery of
      episodic memory function. Verbal free recall and spatial memory performance
      remained reduced, whereas immediate word recall and recognition memory, as well
      as picture learning and memory, improved to levels at the lower range of normal
      performance. Interestingly, nonspatial associative learning was never much
      impaired and recovered completely by the end of testing. These data are taken as
      evidence that the human hippocampal formation does not equally support different
      forms of episodic memory.

PMID- 10601750
TI  - Q&A about this issue

PMID- 10601751
TI  - Benzodiazepines: the science and the myths.

PMID- 10601752
TI  - Second generation antipsychotics for schizophrenia.
AB  - OBJECTIVE: To provide a narrative review based on clinically relevant evidence
      specific to the issues surrounding the use of the second generation
      antipsychotics in schizophrenia. METHOD: MEDLINE and Cochrane Library searches
      were performed to identify literature pertinent to the available and anticipated
      novel antipsychotics in North America. Articles that were selected included
      clinical trials, clinical practice guidelines, reviews and pharmacoeconomic
      analyses researching the efficacy and safety of the second generation
      antipsychotics including comparative studies among these agents. Related
      editorials, letters and newsletter commentaries were reviewed from a variety of
      sources to provide enhanced depth. RESULTS: Following the advent of clozapine in
      the 1980s, three other second generation antipsychotics (risperidone, olanzapine
      and quetiapine) have become available, with others (eg, ziprasidone) expected in
      the near future. The single major advance with these agents is their reduced
      propensity for extrapyramidal side effects and tardive dyskinesia. However,
      clinicians should be aware of the differential risk for these side effects. The
      purported advantage for negative symptoms compared with conventional agents has
      been inconsistent and may not be clinically important. CONCLUSIONS: The
      availability of a wide selection of antipsychotics has heralded the possibility
      of more effective management of the complex symptoms of schizophrenia. However,
      this has also made the choice of optimal treatment difficult. It is essential
      that practitioners understand how these agents compare with each other and with
      conventional antipsychotics.

PMID- 10601753
TI  - Selection of treatment of cefaclor-associated urticarial, serum sickness-like
      reactions and erythema multiforme by emergency pediatricians: lack of a uniform
      standard of care.
AB  - BACKGROUND: Serum sickness-like reactions (SSLR) and erythema multiforme are
      common adverse effects of cefaclor therapy and can be associated with significant
      morbidity. No standardized evidence-based protocol for the optimal treatment of
      drug-induced SSLR exists. OBJECTIVES: To define the standard of care used by
      physicians treating adverse reactions associated with cefaclor. METHODS: A
      retrospective review of the medical records of children discharged from a
      pediatric emergency room with a diagnosis of adverse events to cefaclor was
      conducted. Charts of patients were reviewed to determine which therapy was
      prescribed. RESULTS: During the study period, 74 cases of adverse events
      attributed to cefaclor presented to the emergency department. SSLR were the most
      common pattern of adverse events seen (31 cases, 42%), followed by urticarial
      reactions (26 cases, 35%) and erythema multiforme (17 cases, 23%). An
      antihistamine was the treatment most often prescribed (88%) for erythema
      multiforme. Significantly more children with SSLR than with erythema multiforme
      or urticaria were treated with prednisone, either alone or in combination
      (P<0.05). CONCLUSIONS: The treatment most often prescribed for serious cefaclor
      associated erythema multiforme was an antihistamine. In the case of SSLR, an
      antihistamine and prednisone were most commonly used. Prospective randomized,
      controlled trials are needed to define the role of various therapeutic agents and
      to determine the optimal therapy for SSLR and other serious adverse drug
      reactions.

PMID- 10601754
TI  - [Accuracy of a self-administered questionnaire on the use of antibiotics].
AB  - BACKGROUND: To document the ambulatory use of drugs and the indications for that
      use, investigators often rely on self-administered questionnaires of questionable
      accuracy. The present study assessed the accuracy of a French Canadian self
      administered questionnaire with regard to documenting current antibiotic drug
      use. METHODS: The information independently obtained from physicians and
      pharmacists was compared with the information reported by 340 patients. Patients
      were asked to participate in the study by their pharmacist at the time that their
      prescribed antibiotic was dispensed. The proportion of agreement between the data
      sources was calculated with regard to antibiotic regimen characteristics and
      indications for use and the nature of the treated infection. RESULTS: Self
      reported information demonstrated a high level of agreement with data provided by
      physicians (k = 0.87) and pharmacists (k = 0.94), with regard to antibiotic
      names. Regarding the nature of the treated infection, the agreement between self
      reported information and data obtained from physicians was substantial (k =
      0.63). A total of 242 patients completed the questionnaire twice at two-week
      intervals. Test-retest reliability was high regarding both the antibiotic name (k
      = 0.72) and the nature of the treated infection (k = 0.86). CONCLUSIONS: The self
      administered questionnaire assessed in this study can reliably and accurately
      document the name of antibiotics used and the nature of the treated infections.
      Further work is needed to improve the accuracy of the questionnaire with regard
      to other components of antibiotics use.

PMID- 10601755
TI  - Octreotide for orthostatic hypotension.
AB  - A patient suffering from multiple system atrophy (Shy-Drager syndrome) with
      severe symptomatic postprandial orthostatic hypotension was treated. Because the
      disease was progressively refractory to fludrocortisone and midodrine, octreotide
      was introduced subcutaneously (25 micrograms before meals). Beneficial effects
      were clearly noted by the patient and documented by repeated tilt table testing
      with and without the octreotide. The literature on the physiological actions of
      octreotide and the clinical evidence supporting its use are reviewed briefly.
      Octreotide mainly mediates splanchnic venoconstriction, which explains its
      beneficial effects. It is a useful adjunct for the short term treatment of
      orthostatic hypotension associated with dysautonomia. Its long term efficacy and
      safety need to be studied.

PMID- 10601756
TI  - Interferon-alpha in patients with chronic hepatitis C and normal transaminase
      levels.
AB  - OBJECTIVE: to assess the response to interferon-alpha therapy in patients with
      chronic hepatitis C and normal alanine transferase levels. METHODS: 16 patients
      with normal transaminases (group A) and 36 patients with elevated ALT levels
      (group B) were treated with interferon-alpha-2b at a dose of 3 MU for 6 months.
      The biochemical, virological (HCV RNA in serum, liver and peripheral blood
      mononuclear cells) and histological responses were analyzed. RESULTS: no
      significant differences were observed between the two groups in age, sex,
      parenteral or sporadic transmission, hepatic lesion, Knodell index or HCV
      genotype, except for the higher proportion of women in group A. We found no
      significant differences between the groups in rates of patients with normal ALT
      in the follow-up period (6 months post-interferon, group A 44%, group B 17%) or
      in post-therapy negativization of HCV RNA levels (group A 31%, group B 17%). In 7
      patients (44%) in group A, ALT remained normal throughout the study, whereas in
      the rest of the patients we observed some elevation during or after interferon
      treatment. Post-therapy mean Knodell index was 6 +/- 3 in group A versus 9 +/- 4
      in group B (p < 0.05). CONCLUSIONS: the response to interferon was similar in
      patients with normal or elevated transaminases.

PMID- 10601757
TI  - Diagnosis and percutaneous treatment of gastrointestinal hemorrhage. Long-term
      experience.
AB  - OBJECTIVE: to report our experience in the diagnosis and treatment of
      gastrointestinal hemorrhage. METHOD: from April 1987 to April 1997, 196 patients
      with gastrointestinal hemorrhage (134 men and 62 women) were studied. 165 (84%)
      were diagnosed as presenting upper gastrointestinal hemorrhage, and 31 (16%)
      presented lower gastrointestinal hemorrhage. The patients were studied with
      endoscopy and arteriography, and embolization was prescribed in 131 (67%).
      Patients with bleeding from esophageal varices were excluded from this study.
      RESULTS: a bleeding point was identified angiographically in 33% (n = 65)
      patients. 131 (67%) patients were treated with therapeutic embolization, which
      was successful in 89% (n = 116) patients. The bleeding was resolved in 80% (n =
      93) of the patients. Complications included arterial spasm (n = 12), pain (n =
      24), coil migration (n = 8), allergic reaction (n = 2) and celiac trunk
      dissection (n = 2). During follow-up 16 patients presented rebleeding that
      stopped after reembolization in 9 cases, whereas in 7 cases surgery was needed.
      CONCLUSIONS: in our experience, diagnostic angiography and percutaneous
      therapeutic embolization are effective, less aggressive methods that lead to few
      complications. Both methods have become indispensable tools in managing patients
      with gastrointestinal hemorrhage that does not respond to conservative therapy.
      Even in patients with no evidence of angiographic bleeding, embolization in
      selected patients is successful.

PMID- 10601758
TI  - Five-year analysis of endoscopic retrograde cholangiopancreatography in the
      Hospital del Bierzo.
AB  - OBJECTIVES: endoscopic retrograde cholangiopancreatography (ERCP) is a widely
      available endoscopic modality, that is not without risks, but is no longer
      limited to tertiary referral centers. We evaluated the procedure in terms of
      imaging success, overall therapeutic failure, complications and mortality.
      METHODS: this retrospective study ran from January 1992 to December 1997. The
      following data were collected: 1) cannulation rate, 2) failure to obtain images
      of the duct, 3) type of ERCP, 4) overall therapeutic failure rate and stone
      extraction, 5) overall complication rate, 6) immediate complications, 7) late
      complications (within the first 30 days), and 8) mortality. RESULTS: of 425 ERCP
      procedures performed, all data for 393 were obtained and included in the
      analysis. The cannulation success was 94%. Failure to obtain a suitable image
      occurred in 10%. ERCP was diagnostic in 60% and therapeutic in 40%.
      Sphincterotomy was performed in 83% of the patients. The therapeutic failure rate
      was 15%. Stone extraction was successful in 69%. The overall complication rate
      was 8.6%; 2.2% of these complications were severe or fatal. Immediate
      complications occurred in 4% and late complications in 5.9%. Immediate
      complications were less frequent in diagnostic ERCP (p < 0.01). Late
      complications were: pancreatitis (3. 5%), bleeding (1.4%), perforation (0.3%) and
      cholangitis (0.8%). There was no difference in the frequency of severe
      pancreatitis between the types of ERCP procedure. Bleeding occurred more
      frequently in sphincterotomy (p < 0.05). The overall mortality rate was 1.6%.
      CONCLUSIONS: a continuous audit in each endoscopy unit should be performed to
      improve ERCP procedures. Diagnostic and therapeutic ERCP carry a similar risk of
      severe pancreatitis. The bleeding rate was higher in therapeutic ERCP and
      sphincterotomy.

PMID- 10601759
TI  - Concordance between breath test and histologic damage in Helicobacter pylori
      associated infections in infancy.
AB  - OBJECTIVE: the purpose of this study was to investigate the concordance between
      urea breath test values and the histological severity of gastric mucosa lesions
      in children. METHOD: forty children ranging in age from 3 to 17 years were
      examined endoscopically because of abdominal pain and positive breath test
      results. Histological status was determined by the intensity of the inflammatory
      infiltrate and by the depth of the damage. Histologically, four groups were
      considered: normal-appearing gastric mucosa (group 0), mild antrum gastritis
      (group 1), moderate antrum gastritis (group 2), and severe antrum gastritis
      (group 3). RESULTS: normal-appearing gastric mucosa was observed in 8 children
      with a mean breath test value of 44.07; mild chronic gastritis was observed in 17
      children with a mean breath test value of 36.15; moderate gastritis was
      demonstrated in 10 children with a mean breath test value of 48.50, and severe
      gastritis was observed in 5 children with a mean breath test value of 52.31.
      CONCLUSION: we conclude that there is no concordance between urea breath test
      values and histological severity of gastric mucosa lesions in children.

PMID- 10601760
TI  - [Role of deglutitive inhibition in the pathophysiology of esophageal primary
      motor disorders].
AB  - The esophageal primary motor disorders like achalasia, diffuse esophageal spasm
      or the nutcracker can involve the upper esophageal sphincter, the esophageal
      body, the lower esophageal sphincter or a combination of them. This article will
      focus on the esophageal body and abnormal peristalsis. A normal esophageal
      peristaltic contraction occurs after a latency period following a swallow and
      requires a minimum amplitude to be propulsive. Abnormal latencies may generate
      simultaneous contractions whereas low amplitude contractions may be inefficient
      i.e. GERD and high amplitude contractions my provoke chest pain or dysfagia i.e.
      diffuse spasm. The latency period between deglutition and contraction is due to a
      muscle inhibition immediately after the swallow. This inhibition is due to
      release of NO by an inhibitory neurone located in the myenteric plexus. At the
      end of the inhibition, the contraction occurs due to release of acetyl choline by
      an excitatory cholinergic neurone. The exact interplay between these two neurones
      will determine the <<timing>> or propagation velocity and the amplitude of
      esophageal contractions. Patients with achalasia have a predominant loss of
      inhibitory neurones (VIP and NOS) with a relative preservation of excitatory
      cholinergic neurones. The histophatologic and immunohistochemical status in
      patients with esophageal primary motor disorders other than achalasia is poorly
      characterised Examples of deglutitive inhibition in the esophagus can be observed
      during the relaxation of the lower esophageal sphincter or when a subject
      swallows very frequently. In order to quantify deglutitive inhibition we
      developed a method that induces an artificial high pressure zone in the mid
      esophageal body. During the latency period after a swallow, the high pressure
      zone relaxes (is inhibited). With this method, we could measure the magnitude and
      duration of the inhibitory phenomenon. There is a very good correlation between
      the degree of deglutitive inhibition and propagation velocity of esophageal
      contractions. The less inhibition, the faster the propagation velocity of
      contractions. Simultaneous contractions are the consequence of absent inhibition.
      Patients with esophageal primary motor disorders may have very fast propagating
      contractions and a small percentage of simultaneous contractions or up to 100% of
      simultaneous contractions. The correlation between the degree of inhibition and
      propagation velocity of contractions suggests that the different primary motor
      disorders are the expression of a progressive failure in esophageal inhibition.

PMID- 10601761
TI  - [Ornidazole in the treatment of liver dysfunction associated to long-term
      parenteral nutrition].
AB  - AIM: to reduction the TPN-related hepatic toxicity with an anaerobicidal therapy
      (ornidazole in our case). PATIENT: a 24-year-old male surgically treated for
      intestinal occlusion. He had been treated with abdominal radiotherapy for
      rabdomyosarcoma of embryonic urogenital sinus when he was five months old. It was
      found a great abdominal radiotherapy sequelae and occluded and perforated small
      bowel loop that was resected. Postoperative time developed pelvic abscess and
      reoperation was performed. Severe intraabdominal inflammatory-adhesive process
      was noticed which included all the intestinal loops with multiple perforations.
      Attempts to release this situation was unsuccessful and several anastomoses, with
      some loop exclusions and a diverting loop jejunostomy were performed. In
      postoperative period he developed an enterocutaneous fistula and TPN was
      initiated. Higher and higher hepatic marker values were detected suggesting a
      progressive hepatotoxicity. METHODS: anaerobicidal agent (ornidazole) and cyclic
      total parenteral nutrition as a therapy design were prescribed. RESULTS: there
      were satisfactory showing a reduction in hepatic marker values (72.5% fall in
      alanine aminotransferase). CONCLUSIONS: bearing in mind that some theories
      suggest that total parenteral nutrition may cause atrophic changes in the gut
      mucosa so giving rise to bacterial translocation, this anaerobicidal treatment
      designed could be assumed effective for attenuating TPN-related liver damage.

PMID- 10601762
TI  - [About the usefulness of ultrasonography in the diagnosis of portal
      hypertension].

PMID- 10601763
TI  - [The authors reply] [In Process Citation]

PMID- 10601764
TI  - [Spontaneous internal biliary fistula].

PMID- 10601765
TI  - [Celiac sprue and autoimmunity].

PMID- 10601766
TI  - [Bile leak after removal of Kehr' s tube: diagnosis with HIDA 99m Tc].

PMID- 10601767
TI  - Our experience with Wallstent self-expanding metal prostheses in 65 patients with
      malignant dysphagia.
AB  - OBJECTIVE: to document the usefulness of self-expanding metal stents in patients
      with malignant dysphagia. METHOD: from January 1992 to January 1997 we implanted
      75 Wallstent prostheses (28 uncovered AV, 20 uncovered Unistep, 15 covered
      Telestep, and 2 covered double-mesh Permalume stents) in 65 patients with
      malignant dysphagia. RESULTS: mean survival time was 100 days in patients with
      uncovered stents, and 215 days in patients with covered stents. Oral feeding was
      possible throughout the post-implantation course in 58 of 65 patients. Only two
      severe complications occurred: esophageal perforation with mediastinitis, and
      migration of the stent from the distal esophagus into the stomach. All
      implantation procedures were done under radiological guidance. For AV and Unistep
      prostheses we used a nasal approach without sedation, and for Telestep and
      Permalume stents we used an oral approach with sedation. CONCLUSIONS: Wallstent
      self-expanding metal stents are useful in palliating malignant dysphagia. The
      placement and implantation of these stents are straightforward.

PMID- 10601768
TI  - Roux-en-Y syndrome after surgical treatment of alkaline reflux gastritis.
AB  - OBJECTIVE: to evaluate the possible existence of the so-called <<Roux-en-Y
      syndrome>> in a group of 21 patients who underwent surgery to correct
      postoperative alkaline reflux gastritis. METHODS: the study group consisted of 15
      men and 6 women (mean age 39.2 years). All had undergone Billroth II subtotal
      gastrectomy (20 for ulcer and 1 for gastric cancer). Alkaline diversion was done
      with the Roux-en-Y technique 50-60 cm away from the gastrojejunal anastomosis. In
      all patients bilateral truncal vagotomy at the hiatus was also done. No
      mechanical alterations in the gastrojejunal anastomosis were found during
      surgery. Mean follow-up period was 8.2 years (range 6.5-10.7 years), during which
      clinical, radiological and endoscopic studies were obtained. Gammagraphic study
      of gastric remnant emptying was done on postoperative day 30. RESULTS: none of
      the patients had clinical, radiological or endoscopic manifestations that
      indicated the presence of Roux-en-Y syndrome. Gammagraphic studies of gastric
      remnant emptying did not demonstrate significant differences between preoperative
      (T1/2: 7.3 min) and postoperative values (T1/2: 10.1 min). CONCLUSIONS: we found
      no evidence of disturbances in gastric remnant emptying after Roux-en-Y
      gastrojejunostomy to treat postoperative alkaline gastric reflux.

PMID- 10601769
TI  - Collateral biliary circulation in portal hypertension syndrome.
AB  - OBJECTIVE: to describe collateral circulation in the gallbladder wall in relation
      with portal hypertension syndrome, and to determine whether this syndrome is
      frequently associated portal vein thrombosis. METHODS: images were
      retrospectively reviewed for 9 patients with previously diagnosed portal
      hypertension syndrome, in whom ultrasound results suggested the presence of
      varices of the cystic vein. RESULTS: four patients showed signs suggesting portal
      vein thrombosis. The gallbladder wall showed diffuse hypoechoic thickening in all
      patients, 7 of whom had intramural dilation of tubular, tortuous appearance.
      Ultrasound findings, however, were not very specific, and differential diagnosis
      with a large number of other entities is required to rule out other possible
      causes of focal and diffuse thickening of the gallbladder wall. The use of
      Doppler sonographic techniques made it possible to determine the cause of the
      varices, and to confirm suspicions of portal thrombosis. This method was found to
      be just as sensitive as ultrasound imaging, and much more specific. Angiograms
      obtained in 3 patients for different reasons confirmed the ultrasonographic
      findings in all cases. CONCLUSIONS: this study confirms the association between
      thromboses and varices, and analyzes the physiopathological hypotheses invoked to
      explain this association. We emphasize the need for correct diagnosis, given the
      frequency of surgical iatrogenic bleeding or misdiagnosis resulting from
      confusion with other possible causes of gallbladder wall thickening. Doppler
      ultrasound is considered the ideal diagnostic method as it is harmless, sensitive
      and specific.

PMID- 10601770
TI  - Epidemiological aspects of inflammatory bowel disease in the Pamplona area.
AB  - OBJECTIVES: to analyze retrospectively our hospital records on patients diagnosed
      during the period from 1983 to 1993 as having Crohn's disease or ulcerative
      colitis, and to estimate the incidence and epidemiological characteristics of
      these diseases in the Pamplona health administration area. METHODS: 246 patients
      were diagnosed has having inflammatory bowel disease (147 with ulcerative
      colitis, 97 with Crohn's disease, and 2 with indeterminate colitis. RESULTS: mean
      incidence was 2.47 +/- 0.96 per 100 000 inhabitants for Crohn's disease, and 3.75
      +/- 1.5 per 100 000 inhabitants for ulcerative colitis (p < 0.05). There was a
      nonsignificant increase in incidence during the study period. Age, sex, alcohol
      intake, smoking habit and familial aggregation were analyzed. CONCLUSIONS: mean
      estimated incidence of Crohn's disease and ulcerative colitis in our setting
      during 1983-1993 was similar to that reported more recently for other parts of
      Spain. In our setting, ulcerative colitis was significantly more frequent that
      Crohn's disease, and familial aggregation was lower among patients who had the
      former disease. Crohn's disease was diagnosed at earlier ages, and cigarette
      smoking was more frequent among patients with this disease.

PMID- 10601771
TI  - [Helicobacter pylori infection. The Spanish consensus report. The Spanish
      Consensus Conference Group].
AB  - OBJECTIVES: taking into account the small amount of infection eradication
      treatments carried out in our country and some characteristics arising from the
      resistances to some antibiotics, the Spanish Club for the Study of Helicobacter
      pylori decided to organize a Spanish Consensus Conference to clarify the use of
      the different infection diagnostic tests, to establish the exact indications of
      its diagnosis and treatment, to recommend the best treatment guidelines for our
      country and to promote the use of eradication treatments in adequate indications.
      DESIGN: on April 23, 1999 in Madrid, physicians who were experts in infection by
      Helicobacter pylori representing the different Scientific Societies of our
      country were gathered. Prior to this, three work areas, diagnosis, indications
      and treatments, were created and the participants freely joined them. One month
      before the conference, all of the participants were sent the questions which
      would be debated. An 80% consensus level, always based on scientific evidence,
      was required for a recommendation. In the first session, a meeting by work areas
      was held and in a second session, all of the recommendations were voted on in the
      meeting of the representatives. CONCLUSIONS: the conference recommends the
      eradication of the infection in all the gastric or duodenal ulcers, in the
      erosive duodenitis, in the MALT lymphomas and in gastrectomized patients due to
      gastric cancer with residual stomach. In the de novo diagnoses of gastroduodenal
      ulcer, the rapid test of urease is recommended, and a histological study is
      recommended only if it is negative. In the case of a history of ulcers and also
      to know the eradication treatment result, the C13 urea breath test is
      recommended. The culture is reserved for primary treatment and rescue treatment
      failures so as to select the adequate antibiotic. The primary treatment regimes
      recommended for our country mean the combination of amoxicillin, clarithromycin
      and any proton pump inhibitor or with Ranitidine bismuth citrate. If there is
      allergy to penicillin, amoxycillin will be substituted by metronidazol.

PMID- 10601772
TI  - [Persistent leucocytosis as initial manifestation of Whipple's disease and
      development of gastric cancer in the follow up].
AB  - We report the case of a 57 year old male with Whipple's disease. The patient was
      asymptomatic and an unexplained peripheral leucocytosis was found in a routine
      examination. It persisted as the only abnormality for one year and then he
      developed articular symptoms, diarrhoea and weight loss. The diagnosis was
      confirmed by duodenal biopsy five years later. The leucocyte count ranged between
      14,000 and 22,000 leuc/mm3. Response to cotrimoxazole was favourable with
      disappearance of all signs and symptoms, including leucocytosis. In the last
      endoscopic control, eight years after initial manifestations, an intramucosal
      gastric adenocarcinoma was diagnosed.

PMID- 10601773
TI  - [The complete expulsion of a biodegradable anastomosis ring (BAR) ring is not
      synonym of anastomotic leak].

PMID- 10601774
TI  - [Acute pancreatitis and retroperitoneal fibrosis].

PMID- 10601775
TI  - [Subtotal colectomy: treatment for recurrent colonic perforation in Ehlers-Danlos
      syndrome].

PMID- 10601776
TI  - [Klippel-Trenaunay syndrome. A rare cause of lower gastrointestinal bleeding].

PMID- 10601777
TI  - [Systemic mastocytosis, portal hypertension and ascites].

PMID- 10601778
TI  - Prevalence of dental caries in Latvian 11- to 15-year-Old children and the
      enhanced diagnostic yield of temporary tooth separation, FOTI and electronic
      caries measurement.
AB  - The aim of this study was to test the feasibility of employing clinical visual
      examination at the D(1) (enamel and dentine caries) diagnostic threshold, fibre
      optic transillumination (FOTI), elective temporary tooth separation (ETTS) and
      electronic caries measurement (ECM) in the environment of an epidemiological
      study or clinical trial. It also aimed to compare the diagnostic yield of these
      diagnostic aides and methods. The sample consisted of 182 Latvian children, mean
      age 13.3 years (range = 10.6-15.7). For 12-year-old subjects the mean D(3)MFS was
      10.58 (SD 6.05) and the mean D(1)MFS was 19.97 (SD 10.47). The additional
      diagnostic yield from FOTI examination of approximal sites was 40.0% at the D(1)
      threshold. The additional apparent yield for ETTS was 52.8% at the D(1)
      threshold. ETTS detected 38.3% more carious surfaces than FOTI at the D(1)
      threshold. Conversely 57 surfaces thought to be carious on FOTI examination were
      judged sound following ETTS. Although the ECM appeared practical to use, it broke
      early in the trial and the results obtained prior to breakdown appeared
      inaccurate. In conclusion, all diagnostic methods were feasible under the
      conditions of an epidemiological study or clinical trial.

PMID- 10601779
TI  - Two and a half-year outcome of caries-preventive programs offered to groups of
      children in the Solntsevsky district of Moscow.
AB  - This study examined the 2.5-year outcome of preventive programs - based on the
      Nexo method - offered to three groups of children from Solntsevsky, a district of
      Moscow. Study group A consisted of 45 3-year-olds, study group B of 50 6-year
      olds, and study group C of 50 11-year-olds. A similar number of children were
      selected as control groups and they followed the normal dental service provided
      by the local Health Service System in the district. The caries-preventive
      programs offered to the study groups were based on: (1) education of the child,
      parents and teachers in the caries disease, (2) training in toothbrushing. In
      addition, the children in study groups B and C were offered professional plaque
      removal, applications of sodium fluoride (2%) and sealant applications according
      to individual needs. The children in groups B and C were clinically examined in
      March 1994 (baseline) after 1 and 2.5 years, respectively. Because of the age of
      the children in group A, these children were only examined once, after the study
      had been completed. After 2.5 years the children in all three study groups had
      improved their oral health status significantly compared to the children in the
      control group. The caries experience among the children in study group A was
      about half of that observed among children in the control group (4.91 def-s
      versus 8.60 def-s). The program was highly effective in controlling dental caries
      in the permanent dentition among the children in the study groups, who finished
      with a mean DMF-S of 0.28 (group B) and 3.12 (group C) compared to 2.24 and 6.35
      among the children in the corresponding control groups. Nearly all the children
      used fluoridated toothpaste. The mean number of visits to the clinic decreased
      from year 1 to year 2 (5 versus 3.4 in study group B and 4.5 versus 3.3 in study
      group C). In conclusion, the preventive programs were highly effective with
      regard to improving the level of oral hygiene, and thereby reducing or even
      controlling the plaque-induced disease activity.

PMID- 10601780
TI  - Caries prevalence after cessation of water fluoridation in La Salud, Cuba.
AB  - In the past, caries has usually increased after cessation of water fluoridation.
      More recently an opposite trend could be observed: DMFT remaining stable or even
      decreasing further. The aim of the present study conducted in La Salud (Province
      of Habana) in March 1997 was to analyse the current caries trend under the
      special climatic and nutritional conditions of the subtropical sugar island Cuba,
      following the cessation, in 1990, of water fluoridation (0.8 ppm F). Diagnostic
      evaluations were carried out using the same methods as in 1973 and 1982. Boys and
      girls aged 6-13 years (N = 414), lifelong residents in La Salud, were examined.
      Between 1973 and 1982 the mean DMFT had decreased by 71.4%, the mean DMFS by 73.
      3% and the percentage of caries-free children had increased from 26. 3 to 61.6%.
      In 1997, following the cessation of drinking water fluoridation, in contrast to
      an expected rise in caries prevalence, DMFT and DMFS values remained at a low
      level for the 6- to 9-year-olds and appeared to decrease for the 10/11-year-olds
      (from 1. 1 to 0.8) and DMFS (from 1.5 to 1.2). In the 12/13-year-olds, there was
      a significant decrease (DMFT from 2.1 to 1.1; DMFS from 3.1 to 1. 5), while the
      percentage of caries-free children of this age group had increased from 4.8
      (1973) and 33.3 (1982) up to 55.2%. A possible explanation for this unexpected
      finding and for the good oral health status of the children in La Salud is the
      effect of the school mouthrinsing programme, which has involved fortnightly
      mouthrinses with 0.2% NaF solutions (i.e. 15 times/year) since 1990.

PMID- 10601781
TI  - Inhibiting action of carbohydrates on the growth of fluorapatite crystals.
AB  - Hydroxyapatite (HAp) and fluorapatite (FAp) were synthesized in the presence of
      carbohydrates (glucose, fructose, galactose and sucrose). X-ray diffraction
      analysis showed that the crystallinity of two FAp groups that were synthesized in
      the presence of glucose or sucrose decreased with the increase in carbohydrate
      content. In SEM photographs we found that the size of their crystals was small
      and the shape changed. However, FAp groups that were snythesized in the presence
      of fructose or galactose showed little change in their crystallinity and shape.
      Four carbohydrates had some influence on size, but not on shape or crystallinity
      when synthesizing HAp. These results suggest that glucose and/or sucrose has a
      chemical affinity to FAp and inhibits the growth of FAp crystals.

PMID- 10601782
TI  - Rates of mineral loss in human enamel during in vitro demineralization
      perpendicular and parallel to the natural surface.
AB  - Human enamel is a structurally anisotropic material. The aim of this study was to
      investigate whether this structural anisotropy is reflected in the
      demineralization behaviour of enamel. Kinetics of demineralization of in vitro
      caries lesions with the direction of acid attack perpendicular to the natural
      surface of dental enamel from human premolar teeth were compared with kinetics
      when demineralized parallel to this surface. Pairs of enamel samples from the
      same tooth were demineralized under identical conditions. Loss of mineral with
      time was very nearly linear for both directions (consistent with the rate
      controlling step being reaction at the advancing front rather than transport
      processes), but the perpendicular rate was, on average, about 14% higher than the
      parallel rate. The rate of demineralization parallel to the surface increased
      from the natural surface to the enamel-dentine junction by 10-25%, depending on
      sample. The origin of fine structure and slight departures from linearity in the
      loss of mineral with time plots are discussed. Mineral masses per unit area were
      determined from absorption of a 15-microm diameter X-ray beam using photon
      (AgKalpha) counting methods.

PMID- 10601783
TI  - Microradiographic and microscopic studies on in situ induced initial caries in
      irradiated and nonirradiated dental enamel.
AB  - The objective of this study was to evaluate the onset of initial demineralization
      in irradiated and nonirradiated human enamel. Enamel specimens were prepared from
      the lingual and buccal surfaces of 48 freshly extracted, caries-free third
      molars. Either the lingual or the buccal enamel specimen of each tooth was
      irradiated with 60 Gy. The remaining enamel sample was not irradiated. Two
      irradiated and two nonirradiated enamel specimens were inserted into both buccal
      aspects of each 12 intraoral mandibular appliances. The appliances were worn by
      12 persons for 6 weeks throughout day and night. One side was brushed daily with
      a fluoride-free toothpaste. On the other side plaque was allowed to grow.
      Individual oral hygiene techniques were performed without any fluorides. During
      meals, the appliance was stored in 10% sucrose solution. The enamel specimens
      were cut perpendicular to the enamel surface. Subsequently, the slabs were ground
      to a thickness of 90 microm, and studied by means of TMR and microscopic
      techniques. Evaluated data did not show any differences between irradiated and
      nonirradiated enamel lesions (ANOVA). The onset of caries in irradiated enamel
      can be hampered by regularly performed oral hygiene techniques.

PMID- 10601784
TI  - Use of variable remineralization periods to improve the abrasion resistance of
      previously eroded enamel.
AB  - The objective of the study was to evaluate the period of remineralization needed
      to re-establish the resistance of eroded enamel against brushing abrasion. Enamel
      specimens were prepared from 84 polished bovine incisors. The samples were evenly
      distributed among 7 groups (A-G) and submitted to ten alternating de- and
      remineralization cycles which included abrasion by toothbrushing.
      Demineralization was accomplished by immersing the specimens in the erosive soft
      drink Sprite Light((R)) for 1 min. Remineralization was performed by storing the
      samples in artificial saliva for either 0 min (A), 10 min (B), 60 min (C) or 240
      min (D). After each remineralization, the specimens were brushed in an automatic
      brushing machine. Group E (erosion and 240 min remineralization, but no brushing)
      group F (erosion, but no remineralization and no brushing), and group G
      (brushing, but no erosion and no remineralization) served as controls. After
      performing the cycles, loss of enamel was determined by profilometry. The
      following values (mean +/- SD) were obtained and statistically analyzed (p<0.05):
      group A (5.16+/-1.26 microm), B (2.47+/-0.68 microm), C (1.72+/-0.75 microm), D
      (1.11+/-0.42 microm), E (0.81+/-0. 23 microm), F (1.04+/-0.31 microm), G (0.22+/
      0.15 microm). Only the differences between groups D, E, and F were statistically
      not significant. Under the chosen in vitro conditions, it is concluded that
      abrasion resistance of eroded enamel continuously increases with remineralization
      time. However, even after a period of 1 h of remineralization, abrasion of
      previously eroded enamel is increased

PMID- 10601785
TI  - Application of magnetic resonance microimaging to the study of dental caries.
AB  - Magnetic resonance microimaging (MRM) of teeth has continued to be developed. Two
      ways in which data can be presented have been investigated, 112-microm-thick
      image slices and pseudo-three-dimensional surface rendered images. Limitations of
      the latter have been demonstrated; the possible absence of structures having low
      intensity or incompleteness of the image at regions from which the signal
      intensity is low. This has implications for the MRM investigation of dental
      caries. However, all intensities are recorded and are available. Structures which
      give a low-intensity signal can be seen in image slices. MRM appears well suited
      to studying the development of dental caries, ideally in combination with other
      techniques. As MRM is non-destructive and non-invasive, it can be used in
      experiments which follow the progress of the disease, yet leaves the tissue
      intact for other investigations.

PMID- 10601786
TI  - Polarization-sensitive optical coherence tomography of dental structures.
AB  - Optical coherence tomography (OCT) has been developed during the last 10 years as
      a new noninvasive imaging tool and has been applied to diagnose different ocular
      and skin diseases. This technique has been modified for cross-sectional imaging
      of dental structures. In this first preliminary study the technique was applied
      to obtain tomographic images of extracted sound and decayed human teeth in order
      to evaluate its possible diagnostic potential for dental applications. Classical
      OCT images based on reflectivity measurements and phase retardation images using
      polarization-sensitive OCT were recorded. It was demonstrated that polarization
      sensitive OCT can provide additional information which is probably related to the
      mineralization status and/or the scattering properties of the dental material.
      One of the attractive features of OCT is that it uses near-infrared light instead
      of ionizing radiation. Furthermore, high transversal and depth resolution on the
      order of 10 microm can be obtained. Present limitations, e.g. the limited
      penetration depth, and possible solutions are discussed.

PMID- 10601787
TI  - Effect of four dental varnishes on the colonization of cariogenic bacteria on
      exposed sound root surfaces.
AB  - The aim of this study was to evaluate the effect of four different dental
      varnishes on the colonization of mutans streptococci, total streptococci and
      lactobacilli on exposed sound root surfaces. Sixty-five individuals were randomly
      allotted to one of four groups for treatment with Cervitec((R) ) varnish
      containing 1% chlorhexidine and 1% thymol, a thymol varnish or one of two
      different fluoride varnishes, Fluor Protector and Duraphat. The varnish was
      applied to three buccal root surfaces in each patient at baseline and after 1
      week. Dental plaque from the root surfaces was collected and analysed on four
      different occasions: at baseline, after 1 week, 1 month and 6 months. The
      Cervitec varnish caused a statistically significant reduction in the number of
      mutans streptococci over time. The reduction was significant at 1 week and 1
      month relative to baseline. The numbers of total streptococci and lactobacilli
      were not significantly affected by treatment with Cervitec. No statistically
      significant difference over time was found for mutans streptococci, lactobacilli
      or total streptococci after treatment with the fluoride varnishes or the thymol
      varnish.

PMID- 10601788
TI  - The relationship between plaque pH and glycemic index of various breads.
AB  - Plaque pH was studied during 60 min in situ in 10 subjects after eating various
      breads. The pH response was then compared to glycemic index (GI; calculated from
      the incremental blood glucose area) obtained from our earlier investigations. The
      following four products were tested: (1) barley kernel bread (BKB), (2) BKB,
      sourdough-fermented (BKBS), (3) white wheat bread (WWB), and (4) syrup-sweetened
      wheat-rye bread (SWRB). BKB was also tested with more intensive chewing and SWRB
      with the addition of fat. A 5% sucrose solution served as a control. The pH drops
      with all the breads were considerably smaller than with the sucrose solution
      during the first 15 min. From 30 min and onwards the breads gave similar, or even
      lower (SWRB) pH than sucrose. There was a great difference in pH response among
      the four breads, with the most pronounced pH fall for SWRB, followed by WWB
      (based on the AUC values). Intensive chewing of BKB increased, while the addition
      of fat to SWRB reduced the pH fall, in both cases by about 0.2 pH units. A high
      correlation (r = 0.94) between plaque pH and GI was found, i. e. the more
      pronounced the pH drop in plaque, the higher the GI in blood. Therefore, both
      from a cariogenic and from a metabolic point of view, breads with a low GI should
      be recommended.

PMID- 10601789
TI  - Salivary factors affecting dental erosion in children.
AB  - Dental erosion is becoming a major dental problem in both children and adults.
      The aim of this study was to measure the salivary flow rates, buffering capacity
      and mutans streptococci counts in children with erosion, and compare them to age-
      and sex-matched caries-free and caries-active individuals to establish which
      factors may be important in erosion. The study was conducted as a case-control
      study with standard methods of salivary and mutans streptococci measurement. The
      results showed significant differences for mutans streptococci counts (p = 0.05),
      unstimulated and stimulated salivary pH and buffering capacity (p = 0.001). These
      results suggest that although individuals with erosion have caries experience
      similar to a caries-free individual, their salivary characteristics more closely
      match those of a caries-active subject. The tests described are simple to carry
      out and may be useful in explaining individual patient susceptibility.

PMID- 10601790
TI  - The effects of milk and kappa-casein on salivary pellicle formed on
      hydroxyapatite discs in situ.
AB  - The effects of milk and kappa-casein rinses on the salivary pellicle formed on
      hydroxyapatite discs carried in the mouth were studied. SDS-PAGE analyses
      revealed an increase in the number of proteins deposited onto the discs carried
      after the water and milk rinses only. Scanning electron microscopy studies
      revealed the deposition of an amorphous material, small, micelle-like structures,
      cocci and rods on discs carried in the mouth after the water rinse. Large,
      micelle-like structures were seen on discs carried in the mouth after the milk
      and kappa-casein rinses; bacteria were not seen. Glucosyltransferase (Gtf)
      activity on discs carried in the mouth after the milk and kappa-casein rinses
      were 45+/-5 and 67+/-2% lower than the activity of Gtf on discs carried in the
      mouth after a water rinse, respectively. These data suggest that milk and kappa
      casein may influence pellicle formation in vivo.

PMID- 10601791
TI  - Anticaries effect of a component from shiitake (an edible mushroom).
AB  - The caries-inhibiting effect of the extract from shiitake (Lentinus edodes), the
      most popular edible mushroom in Japan, was studied both in vitro and in vivo.
      Shiitake extract showed an inhibitory effect on water-insoluble glucan formation
      from sucrose by crude glucosyltransferases of Streptococcus mutans JC-2 and
      Streptococcus sobrinus OMZ-176. The firmly adherent plaque in the artificial
      plaque formation test was strongly inhibited by shiitake extract. The reduction
      of firmly adherent plaque caused an increase in the incidence of non- and loosely
      adherent plaque and a decrease in total plaque formation. A significantly lower
      caries score was observed in specific pathogen-free rats infected with S. mutans
      JC-2 and fed with a cariogenic diet containing 0.25% shiitake extract as compared
      with controls fed the cariogenic diet without shiitake extract.

PMID- 10601792
TI  - Nosocomial outbreak of cross-infection due to multiple-antibiotic-resistant
      Klebsiella pneumoniae: characterization of the strain and antibiotic
      susceptibility studies.
AB  - A multiple-antibiotic-resistant (MAR) strain of Klebsiella pneumoniae was
      introduced into a pediatric ward and subsequently colonized neonates of two wards
      with several cases of systemic infection. This strain produced an extended
      spectrum beta-lactamase and was resistant to cefotaxime, ceftazidime, and, among
      others, all aminoglycosides including amikacin. The majority of representative
      isolates examined with macrorestriction analysis of genomic DNA (pulsed-field gel
      electrophoresis) were identical. The strain was susceptible to the innate
      antibacterial systems operative in fresh defibrinated blood from two adults.
      Combined human blood/antimicrobial drug assays documented the in vitro
      bactericidal activity of carbapenems (meropenem was slightly more effective than
      imipenem), fluoroquinolones (ciprofloxacin and trovafloxacin), and polymyxin B
      against this MAR strain of K. pneumoniae.

PMID- 10601793
TI  - Detection of rokitamycin-induced morphostructural alterations in Helicobacter
      pylori by atomic force microscopy.
AB  - The subinhibitory and suprainhibitory concentrations of many antibiotics are
      capable of interfering with the morphology of bacteria, thus disrupting the
      integrity of their structures and reducing bacterial virulence. Studies of this
      type have so far been performed using optical or scanning electron microscopes,
      but a new type of lens-free microscope, the atomic force microscope (AFM), has
      recently been introduced which is capable of investigating fine three-dimensional
      surface topography. The present study made use of this new technique to
      investigate the morphological alterations in Helicobacter pylori as a bacterial
      specimen exposed or not to different concentrations of rokitamycin. The produced
      images clearly show that AFM is a very useful tool for obtaining fine-quality
      three-dimensional images of bacterial morphology. The breakthrough in applying
      this new type of microscopy is also due to the fact that the images can be
      digitally collected at very high resolution in the z-axis, without the need to
      adopt the critical point-drying method or vacuum conditions, and without the need
      to coat the surface of the sample with a metal layer, a result not otherwise
      attainable with other microscopy techniques.

PMID- 10601794
TI  - In vitro activity of moxifloxacin compared to other fluoroquinolones against
      different erythromycin-resistant phenotypes of group A beta-hemolytic
      streptococcus.
AB  - The aim of the present study was to evaluate the in vitro activity of
      moxifloxacin (BAY 12-8039) compared to ciprofloxacin, ofloxacin and sparfloxacin
      against 156 group A beta-hemolytic Streptococcus strains. Sixty strains were
      macrolide-, lincosamide- and streptogramin-B-susceptible; 16 strains exhibited a
      constitutive resistance phenotype; 32 strains exhibited an inducible phenotype,
      and 48 strains were characterized by the M-type efflux-dependent phenotype. The
      minimum inhibition concentrations were determined by an agar dilution method
      according to NCCLS-approved guidelines. Moxifloxacin showed an enhanced activity
      compared with the other fluoroquinolones against the different macrolide
      resistant phenotypes.

PMID- 10601795
TI  - Overview of SPA-S-843 in vitro activity against filamentous fungi.
AB  - In this study, we investigated the in vitro antifungal activity of a new water
      soluble partricin A derivative, N-dimethylaminoacetyl-partricin A 2
      dimethylaminoethylamide diascorbate, coded SPA-843, currently developed by
      Societa Prodotti Antibiotici. The activity of SPA-S-843 was compared to that of
      amphotericin B against 13 strains of Aspergillus spp., 4 strains of Mucor sp., 4
      strains of Rhizopus oryzae, 2 strains Paecilomyces variotii, 5 strains of
      Penicillium spp., 1 strain of Sporothrix schenkii, 7 strains of Trichophyton spp.
      and 2 strains of Microsporum spp.; the minimum inhibitory concentrations (MICs)
      and minimum fungicidal concentrations (MFCs) were measured for all the organisms.
      The in vitro susceptibility testing method employed was an adaptation of the
      macrodilution reference method for yeasts as described in the National Committee
      for Clinical Laboratory Standards document M27-A. The in vitro inhibitory
      activities of SPA-S-843 and amphotericin B against the fungi were evaluated in
      RPMI-1640 supplemented with L-glutamine and buffered with
      morpholinepropanesulfonic acid, while the in vitro fungicidal activities were
      determined by subculturing 0.1 ml from all tubes with no visible growth onto drug
      free Sabouraud dextrose agar plates. Comparison with amphotericin B showed that
      the in vitro inhibitory activity of SPA-S-843 against Aspergillus spp. was better
      than that of amphotericin B and similar against R. oryzae, P. variotii,
      Penicillium spp. and S. schenkii. Amphotericin B presented geometric means (GM)
      of the MICs lower than those of SPA-S-843 against Mucor sp., Microsporum spp. and
      Trichophyton spp. SPA-S-843 was most fungicidal against Mucor sp. and P.
      variotii; SPA-S-843 and amphotericin B showed the same fungicidal activity
      against Aspergillus spp. (GM of the MFCs 12.53 microg/ml), Penicillium spp.
      (about 12 microg/ml) and S. schenkii (MFC 19.2 microg/ml). Amphotericin B
      presented GM of the MFC values lower than those of SPA-S-843 against R. oryzae,
      Microsporum spp. and Trichophyton spp.

PMID- 10601796
TI  - Effect of clarithromycin on Pseudomonas aeruginosa biofilms.
AB  - Using an experimental in vitro culture system, we investigated the effect of
      clarithromycin on biofilm formation by a leucine-requiring Pseudomonas aeruginosa
      mutant strain (HU1). Biofilm formation on celldesks in a chemically defined
      medium was assessed by viable cell count as well as by measurement of glycocalyx
      production and scanning electron-microscopic observation. Cells proliferated
      exponentially until day 3 and remained stationary afterwards. The amount of
      glycocalyx, simultaneously semiquantified, showed a linear increase from day 1 to
      day 12. Scanning electron microscopy revealed firm biofilms on day 5. Three
      different concentrations of Clarithromycin (CAM) (minimum inhibitory
      concentration MIC 64 microg/ml) were added continuously at the early and late
      phases of biofilm formation, and the antibiofilm effect of CAM was evaluated by
      the changes in cell count and glycocalyx production. CAM was effective on
      biofilms at 100 microg/ml but neither at 1 nor at 10 microg/ml. It is suggested
      that glycocalyx production started following bacterial multiplication and
      continued even after the cells had entered the stationary phase to form mature
      biofilms. No antibiofilm effect of CAM was observed at sub-MIC.

PMID- 10601797
TI  - In vitro investigation of the antimicrobial activities of novel
      tetramethylpiperidine-substituted phenazines against Mycobacterium tuberculosis.
AB  - The intra- and extracellular activities of 5 novel tetramethylpiperidine (TMP)
      substituted phenazines against Mycobacterium tuberculosis H37Rv (ATCC 27294) were
      determined and compared with those of clofazimine and rifampicin. Two of these
      agents, together with clofazimine, were also tested for their activities against
      drug-resistant strains of M. tuberculosis. Three of the TMP-substituted phenazine
      compounds were significantly more active than clofazimine against M.
      tuberculosis, including multidrug-resistant clinical strains of this microbial
      pathogen, demonstrating a lack of cross-resistance between the riminophenazines
      and standard anti-tuberculous drugs. Using M. tuberculosis-infected monocyte
      derived macrophages, all of the TMP-substituted phenazines were found to possess
      intracellular activity which was superior to that of both clofazimine and
      rifampicin. In this model of intracellular bioactivity, the experimental
      compounds inhibited bacterial growth at concentrations which were approximately
      10-fold lower than the corresponding minimal inhibitory concentration values
      obtained using conventional in vitro sensitivity testing procedures. These
      results demonstrate that the novel TMP phenazines are active against multidrug
      resistant M. tuberculosis strains, and particularly effective intracellularly.

PMID- 10601798
TI  - Adjuvant effect of clarithromycin on chemotherapy for murine lung cancer.
AB  - Clarithromycin (CAM) increased the median survival of patients with unresectable
      non-small-cell lung cancer who had received chemotherapy and/or radiotherapy
      [Chemotherapy 1997;43:288-296]. The present study was performed to ascertain
      whether CAM alone exhibits an antitumor effect against Lewis lung carcinoma (LLC)
      and to analyze the nature of its adjuvant effect on LLC-inoculated C57BL/6 mice.
      CAM at 10 mg/kg/day retarded the growth of subcutaneously inoculated LLC cells;
      consequently, the mean survival time of mice with LLC increased. This treatment
      was also effective in reducing the number of tumor nodules in the lung after
      intravenous inoculation with LLC cells. When tumor-bearing mice received an
      intravenous injection of vindesine sulfate (7 mg/kg) and cisplatin (6 mg/kg) 7
      days after tumor inoculation, the chemotherapeutic effect was significantly
      enhanced by CAM treatment when it started 7 days after chemotherapy, but not when
      it started the day after chemotherapy. The delayed initiation of CAM treatment
      resulted in the enhancement of natural killer cell activity and CD8+ T cell
      cytotoxicity and increased the number of interferon-gamma-producing T cells and
      interleukin-4-producing T cells. These findings indicate that CAM can exhibit an
      antitumor effect by itself and also induce the well-balanced expansion of helper
      T cell subsets in tumor-bearing mice recovering from the immunosuppression caused
      by chemotherapy. CAM may therefore be a promising adjuvant drug in anticancer
      chemotherapy, and treatment with this macrolide should be initiated at some
      interval after basic cancer therapy.

PMID- 10601799
TI  - Yuehchukene, a bis-indole alkaloid, and cyclophosphamide are active in breast
      cancer in vitro.
AB  - Yuehchukene (YCK) is a novel bis-indole alkaloid with weak estrogenic activity.
      Biochemical studies showed that YCK could attenuate estrogenic action. In this
      study, the response of MCF-7, an estrogen-receptor-positive breast cancer cell
      line, under different combinations of estradiol, cyclophosphamide and YCK, was
      tested. From the dose-response curve, we discovered that 10(-2) M
      cyclophosphamide, even in its so-called 'bio-inert' form, could inhibit MCF-7
      cell growth. However, the cytotoxic effect of cyclophosphamide was lost by
      reducing its concentration to approximately 1 x 10(-3) M. On the other hand, a
      low concentration ( approximately 10(-8)-10(-9) M) of YCK was found to potentiate
      the cytotoxic effect of cyclophosphamide on the MCF-7 cell line. Such an effect
      was absent in the estrogen-receptor-negative cell line MDA-MB-231. These
      findings, together with the dual role of a mixed estrogen and anti-estrogen
      effect, suggested that YCK and cyclophosphamide can be a potential combination in
      chemo-hormonal therapy for breast cancer.

PMID- 10601800
TI  - Regulation of apoptosis reduction in the cisplatin-resistant A431 cell line by
      Bcl-2 and CPP32.
AB  - Cisplatin (cis-diamminedichloroplatinum(II), CDDP) is one of the most important
      chemotherapeutic agents; however, the mechanisms of resistance to this drug are
      still unknown. Recent reports have demonstrated that chemotherapy can induce
      apoptosis in some cancer cells, indicating that apoptosis may play a very
      important role in cancer therapy. Therefore, we used a CDDP-resistant cell line
      from the human epidermoid carcinoma cell line A431 to investigate whether the
      modulation of apoptosis influences CDDP resistance. In the CDDP-resistant cell,
      the cell cycle was not perturbed after CDDP treatment. DNA gel electrophoresis
      and ELISA of the CDDP-resistant cell showed reduced apoptosis when compared with
      A431 cells treated with CDDP. We determined the p53, Bcl-2, Bax and CPP32 protein
      levels by Western blotting. This analysis demonstrated a marked increase in Bcl-2
      protein levels and a reduction in CPP32 protein levels in CDDP-resistant cells.
      Our results indicate that the reduction of apoptosis was one of the CDDP
      resistant mechanisms, and that reduced apoptosis in CDDP-resistant cells was
      influenced by Bcl-2 and CPP32 proteins.

PMID- 10601801
TI  - Seizures and epilepsy following strokes: recurrence factors.
AB  - BACKGROUND AND PURPOSE: Though there have been many reports on poststroke
      seizures, there is still much we do not know about them. Using a large cohort of
      stroke patients we analyzed the characteristics of the seizure(s) and the rate
      and factors involved in seizure recurrence. METHODS: Out of the 3,205 patients
      admitted for a first-ever stroke to our department between 1984 and 1994, we
      retrospectively studied the data of all patients with a first-ever seizure and
      analyzed their evolution. Two types of seizure(s) were defined: 'early-onset'
      seizures (occurring within the 14 days following the stroke) and 'late-onset'
      ones (after the 14th day). RESULTS: 159 patients were included in the study, i.e.
      4.96%. There were 116 ischemic strokes and 43 primary hematomas. Cortical
      involvement was found in 87% of the patients. Early-onset seizures occurred in 57
      patients and late-onset ones in 102 patients, 76% of which were observed within 2
      years. Follow-up was performed in 135 patients with a mean follow-up period of 47
      months; 68 of them presented a seizure recurrence. A 2nd seizure occurred more
      often in the patients with late-onset seizures (p < 0.01); recurrence was either
      single (24 patients) or multiple (44 patients). Univariate analysis demonstrated
      3 factors for multiple recurrences: hemorrhagic component, low Rankin scale after
      the initial seizure and occipital involvement. Multivariate analysis determined 2
      factors: occipital involvement and late onset of the 1st seizure as a predictive
      model of multiple recurrences. CONCLUSIONS: This study confirms that poststroke
      seizures are frequent and must be divided into 2 types: early-onset (</=14 days)
      and late-onset seizures. It demonstrates that a significantly lower rate of
      patients with early-onset seizures develop another seizure, i.e. epilepsy, than
      do patients with late-onset seizures. Other factors are involved in recurrence
      suggesting that poststroke epilepsy probably occurs in a chronically injured
      brain. The problem of treatment remain unanswered.

PMID- 10601802
TI  - Low-dose treatment of cervical dystonia, blepharospasm and facial hemispasm with
      albumin-diluted botulinum toxin type A under EMG guidance. An open label study.
AB  - Several studies support the hypothesis that low-dose botulinum toxin treatment
      may be as beneficial as high-dose regimen. Therefore, we studied 115 patients
      (aged 27-84; mean 58.0, SD = 12.9 years; 68% females, 32% males) suffering from
      cervical dystonia (n = 66), blepharospasm (n = 28), and facial hemispasm (n = 21)
      over a period of 2 years in an open label, non-controlled pilot study. Patients
      received low-dose treatment with botulinum toxin type A (Dysport((R))). The toxin
      was diluted in 20 ml of 0.1% albumin solution to arrive at a concentration of 25
      MU/ml and injected under EMG control. Patients responded to the treatment about 1
      week after injection (mean 7.3 days, SD = 4.6). The mean duration of beneficial
      effects was 11.7 weeks (SD = 5.6). Patients evaluated the clinical global
      improvement on a scale ranging from 0 to 4. For the whole population, the mean
      was 2.7 points (SD = 1.1). In none of the subjects could antibodies to botulinum
      toxin type A be detected, and only a few side effects were observed. In
      conclusion, low-dose therapy with botulinum toxin A merits further controlled
      studies.

PMID- 10601803
TI  - Pontine atrophy in spinocerebellar ataxia type 6.
AB  - To investigate the clinical range of spinocerebellar ataxia type 6 (SCA6), we
      screened CAG repeat expansion in the voltage-dependent alpha 1A calcium channel
      gene (CACNL1A4) in 71 ataxic patients in 60 families; 54 patients in 43 families
      with hereditary ataxia and 17 sporadic patients. Thirteen patients with SCA6 were
      detected to have elongated CAG in CACNL1A4. Of these, 7 patients had been
      diagnosed as having hereditary cerebellar cortical atrophy, and 6 patients had
      been found to have sporadic occurrence. One patient showed distinct pontine
      atrophy with prominent horizontal or oblique gaze nystagmus which is an unusual
      feature in sporadic olivopontocerebellar atrophy. For the efficient screening of
      SCA6, we would propose testing CAG repeat expansion in CACNL1A4, in patients with
      one of two markers: (1) horizontal or oblique gaze nystagmus without other eye
      movement disorders, (2) pure cerebellar atrophy, even if occurrence is sporadic.
      We should note that the pontine atrophy could also be caused by CAG repeat
      expansion in CACNL1A4.

PMID- 10601804
TI  - Preclinical impairment of the striatal dopamine transporter system in sporadic
      olivopontocerebellar atrophy: studied with [(123)I]beta-CIT and SPECT.
AB  - We investigated whether the dopamine (DA) transporter system is impaired in
      sporadic olivopontocerebellar atrophy (sOPCA) patients without clinical
      parkinsonism using the DA transporter radiotracer [(123)I]beta-CIT [2beta
      carboxymethoxy-3beta-(4-iodophenyl)tropane] and single-photon emission computed
      tomography (SPECT). SPECT scans were acquired in 9 patients with sOPCA, 7
      multiple system atrophy (MSA) patients with parkinsonism (MSA-P), and 7 age
      matched healthy controls 20-24 h after the intravenous injection of [(123)I]beta
      CIT. [(123)I]beta-CIT-specific binding in the striatum was determined as the
      radioactivity ratio of the striatum to the occipital cortex (specific binding
      ratio, SBR). In patients with sOPCA and MSA-P, SBRs in the right and left
      striatum and the mean SBR were significantly lower than those in controls (p <
      0.05). The mean SBRs in patients with sOPCA and MSA-P were reduced to 69.0 and
      60.7% of the control mean, respectively. However, there was no significant
      difference in SBRs between sOPCA and MSA-P patients. In sOPCA patients, the mean
      SBR was significantly correlated with the score of the clinical cerebellar
      function scale (r = -0.670, p = 0.024). These results indicate that even in the
      absence of clinical parkinsonism, the striatal dopaminergic system may be
      impaired in sOPCA. The DA transporter loss in sOPCA serves as another clue for
      sOPCA being a part of the spectrum of MSA.

PMID- 10601805
TI  - Severe disability at hospital discharge in ischemic stroke survivors.
AB  - BACKGROUND: Several studies have attempted to identify criteria for predicting
      functional prognosis after stroke, but often with contradictory results. The
      purpose of this study was to predict the functional outcome at discharge of first
      time stroke patients included consecutively in the Lausanne Stroke Registry.
      METHODS: We studied 3,628 sequential patients with first-ever stroke who were
      admitted consecutively to the Centre Hospitalier Universitaire Vaudois.
      Functional status was evaluated using the Rankin disability scale at discharge.
      We studied the prognostic value of historical, clinical and instrumental
      variables related to functional outcome at discharge. The factors studied were
      age, sex, risk factors, ECG results, occurrence of transient ischemic attacks
      (TIAs), extension of cerebral infarction, presumed cause of stroke, clinical
      findings and demographic characteristics. Univariate analysis was performed on
      each variable by comparing the number of functionally independent with that of
      dependent patients at the moment of discharge. The significant variables of the
      univariate analysis were subjected to multivariate analysis with a backward
      logistic regression procedure to find those with an independent effect on the
      outcome. RESULTS: A total of 3,156 patients, excluding 117 patients with ischemic
      stroke who died during hospitalization and 355 with brain hemorrhage, were
      included; 2,867 patients belonged to the nil, mild or moderate disability groups
      (modified Rankin score 1-4; functionally at least partially independent
      patients), while 291 patients belonged to the severe disability group (modified
      Rankin score 5; functionally dependent patients). The mean duration of stay in
      hospital of the severe disability group was 31.2 days (SD = 16.2). Multivariate
      analysis showed that impaired consciousness on admission, limb weakness,
      progressive worsening, infarct in the superficial and deep territory of the
      middle cerebral artery, ischemic heart disease and cardiac arrhythmia were
      predictors of severe disability at discharge. Age was not an independent
      predictor of poor outcome. Hypercholesterolemia was significantly related to a
      better outcome. CONCLUSIONS: Some prognostic indicators associated with
      functional outcome at discharge are available during the first few hours after
      onset of stroke. This is important for the management of the individual stroke
      patient and for organizing suitable rehabilitation planning.

PMID- 10601806
TI  - Pure homonymous hemianopia due to anterior choroidal artery territory infarction.
AB  - The most consistently observed neurological deficits in the anterior choroidal
      artery (AChA) territory infarction are pure motor or sensorimotor syndromes.
      Visual field defects and higher cortical dysfunction are occasionally
      accompanied, but pure homonymous hemianopia without motor and sensory symptom has
      never been reported yet. We present 2 patients with pure homonymous hemianopia,
      whose MRI disclosed cerebral infarction in the well-known territory of the AChA.
      In most patients with ischemic stroke, pure homonymous hemianopia indicates
      infarction in the posterior circulation, particularly in the posterior cerebral
      artery territory. However, the present cases provide evidence that it can also be
      caused by infarction in the anterior circulation, i.e. the AChA.

PMID- 10601807
TI  - Simultaneous assessment of brain tissue oxygenation and cerebral perfusion during
      orthostatic stress.
AB  - Simultaneous registration of cerebral tissue oxygenation parameters obtained by
      near infrared spectroscopy (NIRS), intracranial blood flow velocity (CBFV)
      measured by transcranial Doppler sonography (TCD) and basic cardiovascular
      parameters was carried out during a passive 80 degrees head-up tilt table test in
      15 patients with a history of orthostatic syncope and 20 control subjects. In
      normals, the cardiovascular parameters showed a specific course after changing to
      a vertical position: the heart rate increased, the mean arterial blood pressure
      remained unchanged, and the CBFV decreased. The NIRS measurements showed an
      increase in deoxyhemoglobin (HHb) and a decline in oxyhemoglobin (O(2)Hb) and the
      regional oxygen saturation (RSAT). Patients had a significantly more prominent
      decline in arterial blood pressure (p < 0.001), CBFV (p < 0.001) and RSAT (p =
      0.04). Five patients experienced symptoms of (pre)syncope during the experiment,
      which were associated with a further sudden and marked (>10%) drop of O(2)Hb. The
      results indicate that the combination of TCD and NIRS increases the understanding
      of hemodynamic and metabolic changes during orthostatic stress, which may lead to
      individually suited therapeutic procedures.

PMID- 10601808
TI  - Acute brainstem symptoms associated with cervical syringomyelia.
AB  - Syringomyelia classically presents with slowly progressing dissociated sensory
      and upper and lower motor deficits. Atypical and acute manifestations have rarely
      been described. We report here on 3 patients with syringomyelia, who had acute
      and atypical brainstem symptoms with regard to the underlying disease. These
      symptoms occurred after acute elevation of the intrathoracic and intra-abdominal
      pressure, respectively, and remitted subsequently. Vertebrobasilar ischemia was
      initially suspected.

PMID- 10601809
TI  - Proximal myotonic myopathy: clinical, electrophysiological and pathological
      findings in a family.
AB  - Proximal myotonic myopathy (PROMM) is an autosomal dominant muscle disorder
      characterized by proximal weakness, myotonia, muscle pain and cataract. It
      resembles Steinert myotonic dystrophy (MD), but weakness is proximal, without
      facial muscle involvement, and the chromosome 19 CTG trinucleotide repeat
      expansion characteristic of MD is not present. We describe a further family with
      PROMM. Affected members complained of weakness of lower limbs or of myotonia. EMG
      revealed diffuse myotonic discharges. Muscle histology showed dystrophic
      abnormalities. The PROMM phenotype varies, even in the same pedigree, and may
      mimic MD or limb-girdle muscle dystrophy. EMG is particularly useful, since it
      may disclose myotonic discharges even in the absence of overt myotonia. Thus far
      it is not known whether PROMM is a single entity, or if it represents a
      heterogeneous group of disorders. This question will probably soon be settled
      through genetic analysis.

PMID- 10601810
TI  - Correction of pancreatic beta-cell dysfunction with coenzyme Q(10) in a patient
      with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes
      syndrome and diabetes mellitus.

PMID- 10601811
TI  - Multiphasic disseminated encephalomyelitis: a 4-year follow-up.

PMID- 10601812
TI  - Neurosarcoidosis presenting as cerebellar mass.

PMID- 10601813
TI  - Reward linked to increased natural killer cell activity in rats.
AB  - In rats splenic natural killer (NK) cell activity was found to be significantly
      higher following chronic uncontrollable electrical stimulation of the lateral
      hypothalamus in fully conscious rats, compared to sham-operated rats. In a pre
      test study, all rats had demonstrated that the electrode site had self
      stimulating properties, which supports the possibility that the experience of
      reward may be implicated in NK cell activity augmentation.

PMID- 10601814
TI  - Inhibitory effects of endotoxin on LH secretion in the ovariectomized monkey are
      prevented by naloxone but not by an interleukin-1 receptor antagonist.
AB  - Endotoxin (lipopolysaccharides, LPS), the pathogenic moiety of gram-negative
      bacteria, is a well-known trigger for the central release of cytokines. The
      objective of this study is to evaluate the effects of systemic endotoxin
      administration on LH and cortisol secretion in a non-human primate model and to
      investigate whether these endocrine effects are mediated by centrally released
      interleukin-1 (IL-1) using the receptor antagonist to IL-1 (IL-1ra). An
      additional objective is to investigate whether endogenous opioid peptides mediate
      these endocrine effects of LPS, using the opiate antagonist naloxone. The
      experiments were performed in long-term-ovariectomized rhesus monkeys. Blood
      samples for hormone determination were obtained at 15-min intervals for a period
      of 8 h, which included a 3-hour baseline period. Since the effective central dose
      of IL-1ra in the monkey was unknown, in the first experiment we tested the
      potency of several doses of this antagonist in preventing the effects of
      centrally administered IL-1alpha, a cytokine which is known to inhibit LH and
      stimulate cortisol release. Rhesus monkeys received a 30-min
      intracerebroventricular infusion of IL-1alpha (4.2 microg/30 min) alone or
      together with various doses of IL-1ra (30-180 microg/h i.c.v.). IL-1ra infusion
      was initiated 1 h before IL-1 and extended over the experimental period. As
      previously reported, IL-1alpha induced a significant inhibition of LH, to 36.5 +/
      3.3% (mean +/- SE) by 5 h as a percentage from the 3-hour baseline. This
      inhibitory effect was reversed by cotreatment with the 180 microg/h dose of IL
      1ra (to 82.5 +/- 3.8% by 5 h; NS vs. saline) but not with the lower doses. IL-1
      stimulated cortisol release to 165.9 +/- 7.7%, but this increase was prevented by
      IL-1ra (66.6 +/- 8.9%; p < 0.05 vs. IL-1, NS vs. saline). In the second
      experiment, LPS (50 microg) was administered intravenously, alone or in
      combination with intracerebroventricular IL-1ra infusion. LPS induced a
      significant decrease in LH secretion (to 57.1 +/- 5.2%). These effects were not
      reversed by intracerebroventricular administration of IL-1ra (52.5 +/- 9.6%).
      Cortisol secretion increased in response to LPS, but this stimulatory effect was
      not affected by IL-1ra (178.3 +/- 13.4 vs. 166.9 +/- 5.7%). There were no effects
      of IL-1ra alone. In experiment 3, we investigated whether the opiate antagonist
      naloxone reverses the endocrine effects of endotoxin. Both LPS (50 microg) and
      naloxone (5-mg bolus + 5 mg/h) were infused intravenously. Naloxone was effective
      in preventing the inhibitory effect of LPS on LH (to 124.6 +/- 22.1%, NS vs.
      saline) but not the increase in cortisol (to 166.7 +/- 16.7%; p < 0.05 vs.
      saline, NS vs. LPS). Naloxone alone has no significant effect on LH or cortisol
      secretion. These data demonstrate that, in the ovariectomized monkey, a systemic
      inflammatory/immune- like stress challenge acutely inhibits tonic LH secretion
      while concomitantly stimulating cortisol release. Although endotoxin is known to
      affect central cytokine release, these endocrine effects do not require a
      mediatory role of central IL-1 in the primate. In contrast, endogenous opioid
      pathways appear to be involved in this process.

PMID- 10601815
TI  - Maternal exposure to the synthetic cannabinoid HU-210: effects on the endocrine
      and immune systems of the adult male offspring.
AB  - Natural and synthetic cannabinoid receptor agonists have been described to exert
      profound effects on both the neuroendocrine integration and the functional
      responses of the immune system. In the present study, Wistar rats were exposed to
      the highly potent cannabinoid agonist HU-210 (1, 5 and 25 microg/kg) during
      gestation and lactation and the ensuing effects on several endocrine and immune
      parameters of the adult male offspring were analyzed. Perinatal exposure to HU
      210 partially affected the distribution of lymphocyte subpopulations in the
      spleen and peripheral blood. The major changes observed occur after maternal
      exposure to the 25 microg/kg dose of HU-210. There was a reduction in the T
      helper subpopulation in the spleen and a dose-related decrease in the rate of
      T(helper)/T(cytotoxic) in peripheral blood lymphocytes. Concanavalin-A and
      lipopolysaccharide-induced proliferation were normal in all the groups tested. In
      the same animals, perinatal exposure to HU-210 did not affect basal levels of
      growth hormone, IGF-1, prolactin, or follicle-stimulating hormone. Basal values
      of luteinizing hormone were elevated in animals given the 1 microg/kg dose of HU
      210. Corticosterone levels were reduced in the animals exposed to the higher dose
      of HU-210 during gestation and lactation. These animals exhibited a decreased
      responsiveness of the hypothalamo-pituitary-adrenal (HPA) axis to the stimulation
      with a single injection of HU-210 (20 microg/kg, i.v.) at adult ages, which may
      reflect the onset of long-lasting tolerance to the HPA-activating properties of
      cannabinoids. The opposite pattern of response was found in the animals given the
      1 microg/kg dose, in which a sensitization of the corticosterone response to
      acute HU-210 was observed. The present work reveals that maternal exposure to
      cannabinoids results in minor changes in the development of the immune system,
      but may induce long-lasting alterations in the functional status of the HPA axis.

PMID- 10601816
TI  - Olfactory bulbectomy provokes a suppression of interleukin-1beta and tumour
      necrosis factor-alpha production in response to an in vivo challenge with
      lipopolysaccharide: effect of chronic desipramine treatment.
AB  - The olfactory bulbectomized (OB) rat has been developed as an animal model of
      depression and exhibits several behavioural and neurochemical characteristics
      that are qualitatively similar to those found in clinically depressed patients.
      In addition to the behavioural and neurochemical abnormalities seen in OB rats,
      it has been reported that these animals have alterations in a number ex vivo
      measures of immune function many of which are reversed following chronic
      antidepressant treatment. In the present study we sought to examine the effects
      of olfactory bulbectomy on responsiveness to an in vivo immune challenge with
      bacterial lipopolysaccharide (LPS; 100 microg/kg, i.p.). In addition, the effect
      of chronic treatment with the tricyclic antidepressant desipramine (7.5 mg/kg,
      i.p.) on bulbectomy related behavioural changes, hypothalamic-pituitary-adrenal
      axis activity and immune responsiveness was evaluated. To our knowledge this is
      the first time that in vivo immunological responsiveness has been examined in the
      OB rat model of depression. OB rats exhibited a characteristic hyperactive
      response in a novel 'open field' environment, which was attenuated following
      chronic desipramine treatment. LPS provoked a large increase in circulating
      interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha in vehicle treated
      sham operated animals. Vehicle treated OB rats displayed a significant impairment
      in LPS-induced IL-1beta (54%) and TNF-alpha (70%) secretion compared to their
      sham operated controls, an effect that was potentiated following chronic
      desipramine treatment. Furthermore, sham animals that were chronically treated
      with desipramine displayed decreases in LPS-provoked IL-1beta (51%) and TNF-alpha
      (49%) secretion compared to vehicle treated counterparts. In addition, LPS
      induced alterations in corticosterone and adrenal ascorbic acid concentrations
      were also attenuated by bulbectomy, an effect that was further enhanced following
      chronic desipramine treatment. In conclusion, these data provide evidence that
      olfactory bulbectomy in the rat impairs the ability of macrophages to produce the
      proinflammatory cytokines IL-1beta and TNF-alpha following an in vivo challenge
      with bacterial LPS. Whilst chronic treatment with desipramine normalized the
      behavioural hyperactivity observed in OB rats, such treatment further impaired
      LPS-induced IL-1beta and TNF-alpha secretion in bulbectomized rats.

PMID- 10601817
TI  - Effects of the IL-1 receptor antagonist on the IL-1- and endotoxin-induced
      activation of the HPA axis and cerebral biogenic amines in mice.
AB  - Endotoxin (lipopolysaccharide, LPS) and interleukin-1 (IL-1) are known to
      activate the hypothalamo-pituitary- adrenocortical (HPA) axis, as well as brain
      norepinephrine (NE) and indoleamine metabolism. Because LPS administration is
      known to induce the synthesis and secretion of IL-1, it has been proposed that IL
      1 is the endogenous mediator of the response to LPS. This proposal has been
      tested using various antagonists of IL-1 with varied results. Therefore we have
      re-examined this question using a wide range of doses of the interleukin-1-
      receptor antagonist protein (IL-1ra) at various times after intraperitoneal LPS.
      The results indicate that IL-1ra at doses more than adequate to prevent responses
      to exogenously administered IL-1beta, failed to significantly attenuate the
      increases in plasma ACTH and corticosterone and the cerebral catecholamine and
      indoleamine responses induced by intraperitoneal LPS in mice. IL-1ra was also
      ineffective when plasma ACTH and corticosterone were measured at longer times
      after LPS, although some trends towards attenuations were occasionally observed
      at 4 or 6 h. The latter is consistent with the time course of IL-1 induction by
      LPS. Intracerebroventricular administration of IL-1ra attenuated the endocrine
      and neurochemical responses to intraperitoneal IL-1beta. However,
      intracerebroventricular IL-1ra failed to antagonize the HPA and neurochemical
      responses to intraperitoneal administration of LPS or to intravenous IL-1beta. In
      all of these experiments, there were very close parallels between the HPA and the
      neurochemical responses, especially that of NE. We conclude that IL-1 does not
      mediate the HPA or the neurochemical responses to intraperitoneal LPS, although
      it may contribute in a minor way to the late HPA responses. However, IL-1 within
      the CNS may contribute to the responses to intraperitoneal IL-1, but not to
      intraperitoneal LPS or intravenous IL-1.

PMID- 10601818
TI  - Interleukin-1 inhibits NMDA-stimulated GnRH secretion: associated effects on the
      release of hypothalamic inhibitory amino acid neurotransmitters.
AB  - Immune system activation is often accompanied by alterations in the reproductive
      axis. Interleukin-1 (IL-1), a polypeptide cytokine, has been postulated as a
      chemical messenger between the immune and the neuroendocrine systems. Using
      superfused hypothalamic fragments explanted from intact male rats, we evaluated
      the effects of IL-1 (0. 5 and 5 nM) on basal and N-methyl-D-aspartate (NMDA)
      stimulated release of gonadotropin-releasing hormone (GnRH), and the associated
      modifications in the output of inhibitory amino acid neurotransmitters involved
      in the control of GnRH secretion. IL-1 did not modify basal GnRH release, but
      markedly restrained the stimulatory effect of NMDA on GnRH secretion. gamma
      Aminobutyric acid, glycine and taurine concentrations significantly increased in
      the superfusion medium only after pretreatment with the higher dose of IL-1 (p <
      0.05). Our results indicate that this cytokine inhibits NMDA- stimulated GnRH
      release, affecting the activity and/or the release of hypothalamic excitatory and
      inhibitory amino acid neurotransmitters participating in the regulation of GnRH
      secretion.

PMID- 10601819
TI  - Recombinant forms of the neurotrophic factor pigment epithelium-derived factor
      activate cellular metabolism and inhibit proliferation of the RAW macrophage cell
      line.
AB  - Recombinant forms of the neurotrophic factor pigment epithelium-derived factor
      (PEDF) activate metabolism of RAW macrophage cells while simultaneously
      inhibiting their proliferation. The recombinant forms (rPEDF) acted with EC(50)s
      of 0.1-1 nM while full-length native bovine PEDF was inactive. Urea, which is the
      buffer used to extract recombinant PEDF, stimulated RAW cell proliferation, the
      first report of an effect of urea on non-kidney cells. PEDF acted within 12 h and
      its effects persisted up to 72 h with continuous exposure. Although rPEDF had no
      direct action on glioma cell lines, it increased the amount of a soluble factor
      released by RAW cells which was capable of blocking glioma cell division. Thus
      PEDF may function as a neuroimmune modulator, affecting both neural and immune
      system cells.

PMID- 10601820
TI  - Extended suicide attempt: psychopathology, personality and risk factors.
AB  - Delinquency among depressed patients plays a minor role in criminal behavior.
      Among the most tragic associations between depression and criminality are cases
      of extended suicide or suicide attempt. We studied psychopathology, personality,
      and psychosocial stressors of 9 Austrian females who committed a serious extended
      suicide attempt. They were admitted for treatment at a special department of the
      Justizanstalt Wien-Josefstadt, Aussenstelle Wilhelmshohe. Patients were diagnosed
      according to ICD-10 as severely depressed with (n = 6) or without (n = 3)
      psychotic features. After stabilization we diagnosed the following personality
      disorders: anxious-avoidant (n = 5), paranoid (n = 1), combined (n = 1) and
      borderline type (n = 1). Traits of the typus melancholicus were found in 5
      patients. Seven females were pretreated before the offence by a psychiatrist or a
      psychologist; 4 of them had committed at least one suicide attempt in the past.
      Main psychosocial stressors mentioned by patients in the context of the offence
      were overstrain, marital and/or financial problems. One female killed her child
      under the influence of acoustic hallucinations. Patients with traits of the
      melancholic type showed an altruistic and hypernomic motive for killing as well
      as a psychotic identification with the victim, whereas in the other cases
      egocentric motives were in the forefront. Potential risk factors for an extended
      suicide attempt will be discussed.

PMID- 10601821
TI  - Gaze avoidance and baby-gazing.

PMID- 10601822
TI  - Psychopathology and wisconsin card sorting test performance in young unmedicated
      schizophrenic patients.
AB  - The relationship between psychopathology and Wisconsin Card Sorting Test (WCST)
      performance was evaluated in 25 unmedicated young acute schizophrenic female
      patients (14 neuroleptic-naive and 11 neuroleptic-free) and 15 female controls.
      The schizophrenic patients (especially the neuroleptic-free) performed more
      poorly than controls in the WCST. In addition, WCST impairment correlated with
      both negative and positive symptoms. The results suggest that the
      neuropsychological dysfunction in schizophrenia is present at the onset of the
      illness, and is neither secondary to previous neuroleptic treatment nor to
      chronicity of the illness.

PMID- 10601823
TI  - Schizoid and narcissistic features in personality structure diagnosis.
AB  - OBJECTIVE: This study examines the relationship between schizoid and narcissistic
      personality features. While the schizoid personality disorder seems widely
      accepted as a diagnostic category, the utility of the narcissistic personality
      disorder construct is under discussion. We regard schizoidism as a primary,
      structural disturbance of interaction with the world, whereas narcissism appears
      as a secondary phenomenon of self-organization and self-regulation. This study
      focuses on the question, whether these features are correlated or interact with
      each other in personality structure. METHOD: A standardized narcissism inventory
      is being applied to a group of schizoid and nonschizoid patients. RESULTS: Only 1
      of 18 narcissism scales differentiates significantly between these patient
      groups. By cluster analysis, the group of schizoid patients is divided into two
      subgroups characterized by their higher or lower narcissism scores. These are
      contiguous to existing descriptions of an active/fighting and a passive/evading
      schizoid subtype. CONCLUSION: 'Schizoid' and 'narcissistic' personality features
      can be regarded as distinct, but complementary personality conditions.

PMID- 10601824
TI  - The complexity of psychiatric comorbidity: a conceptual and methodological
      discussion.
AB  - Comorbidity is widely used in psychiatry, although few studies have considered
      the conceptual and methodological problems deriving from the transposition of
      this term from medicine to psychiatry. Comorbidity should be defined as two or
      more diseases, with distinct aetiopathogenesis (or, if the aetiology is unknown,
      with distinct pathophysiology of organ or system), that are present in the same
      individual in a defined period of time. In psychiatry, comorbidity is often an
      artefact for several reasons: (a) different assessment methods; (b) improper
      utilisation of the term comorbidity to indicate the association of symptoms
      instead of diseases; (c) number and characteristics of hierarchical exclusion
      rules used in classification systems; (d) nosologic classification in disorders
      (a generic term) instead of syndromes (a more precise concept, that allows
      clinicians to consider the hierarchy and the qualitative specificity of
      symptoms); (e) excessive splitting of classical syndromes into small disorders
      with inappropriate and overlapping boundaries; (f) too frequent revision of the
      diagnostic criteria, that changes diagnostic threshold; (g) number of clinical
      entities considered. Biological and psychological hypotheses that investigate the
      complexity of comorbidity findings are here presented; it is underlined that
      comorbidity should be the epidemiological descriptive starting point to build
      hypotheses that must be clear and rigorously defined, with specified usefulness
      and limits. Finally, the hypotheses should be tested with specific methodologies.

PMID- 10601825
TI  - Stereotypies: prevalence and association with compulsive and impulsive symptoms
      in college students.
AB  - BACKGROUND: Although stereotypic behaviors have been well described in patients
      with mental retardation, there has been relatively little work on the prevalence
      and nature of these phenomena in intellectually normal subjects. Stereotypies may
      conceivably be related to obsessive-compulsive disorder, to perfectionism, or to
      impulse dyscontrol. METHODS: This study attempted to assess the prevalence of
      stereotypic behaviors in a college population and to determine their relationship
      to compulsive and impulsive symptoms and traits by means of self-rated
      questionnaires. Questionnaires assessed stereotypies as well as obsessive
      compulsive symptoms, perfectionism, and impulsive-aggressive traits. RESULTS:
      Stereotypic behaviors were common in this population, and they were time
      consuming or problematic in a subgroup of subjects. The total number of
      stereotypic behaviors was significantly associated with increased scores of
      obsessive-compulsive symptoms, of perfectionism, and of impulsive-aggressive
      traits. Other measures of the severity of stereotypic behavior were also
      associated with obsessive-compulsive symptoms and perfectionism. CONCLUSIONS:
      Although the nature of stereotypic behaviors is not well understood, these
      phenomena can be clinically important in intellectually normal subjects.
      Stereotypic behaviors deserve further attention from researchers and clinicians.

PMID- 10601826
TI  - Temperament, character and perceived parental rearing in healthy adults: two
      related concepts?
AB  - The goal of this study was to test for relationships between personality
      according to Cloninger's Temperament and Character Inventory (TCI) and perceived
      parental rearing under consideration of cognitive distortions as confounding
      variables. Five hundred and forty healthy volunteers completed the TCI, the EMBU
      questionnaire (assessing perceived parental rearing), and the Dysfunctional
      Attitude Scale. The data were subjected to Pearson correlations, partial
      correlations, multiple regression, and factor analyses. Gender-specific
      relationships were found between parental rearing and both the temperament and
      the character dimensions. The factor structure of the TCI remained unchanged
      irrespective of the inclusion of the parental rearing factors. Since
      environmental factors (e.g., parental rearing) influence both temperament
      (supposed to be genetically determined) and character dimensions, the focus
      should be on the interaction between both aspects through the life span.

PMID- 10601827
TI  - Can music alleviate cognitive dysfunction in schizophrenia?
AB  - It has recently been reported that students performed relatively better on
      cognitive tasks after listening to music. Conceivably, music might reduce the
      level of arousal in subjects who are tense, thereby improving their performance.
      A test case would be schizophrenic subjects, noted for poor performance on tasks
      demanding attention, who have been characterized as suffering from hyperarousal,
      which mediates these attentional deficits. We investigated whether cognitive task
      performance could be facilitated by music in schizophrenics and report a
      beneficial effect.

PMID- 10601828
TI  - Cognitive dysfunction at baseline predicts symptomatic 1-year outcome in first
      episode schizophrenics.
AB  - The present study addresses the consequences of cognitive disturbances on
      symptomatic outcome. Fifty-three first-episode schizophrenics were reassessed (n
      = 32) 1 year after admission. Simple regression analyses revealed that several
      self-perceived cognitive deficits at baseline as measured with the Frankfurt
      Complaint Questionnaire significantly predicted increased Brief Psychiatric
      Rating Scale global scores at follow-up (p = 0.05 to p = 0.005). A stepwise
      regression analysis proved memory dysfunction to be the strongest predictor of
      symptomatic worsening (p = 0.005). It is suggested that the exploration and
      treatment of neuropsychological deficits in schizophrenia is of great clinical
      importance with regard to its impact on both functional and symptomatic outcome
      in schizophrenia.

PMID- 10601829
TI  - Unknown people believed to be known: the 'assoziierende Erinnerungs- falschungen'
      by Kraepelin.
AB  - A male patient with epilepsy, who developed a unique form of paramnesia after an
      episode of zonisamide-induced psychosis is reported. The patient consistently
      mistook people who were quite new to him, such as staff of the hospital, for
      persons whom he had met long ago. However, he did not misidentify their names or
      other attributes, such as their occupations. This extraordinary form of
      misidentification does not fall into any known subcategory of misidentification
      syndromes. Rather, this paramnesia falls into the classical description of
      'assoziierende Erinnerungsfalschungen' by Kraepelin. The neuropsychological
      interpretation of the reported patient is difficult. However, loss of familiarity
      with environmental objects due to his long sustained epileptic history is
      supposed to be a possible mechanism of paramnesia.

PMID- 10601830
TI  - Cognitive dysfunctions in bipolar disorder: evidence of neuropsychological
      disturbances.
AB  - Although cognitive dysfunctions in psychosis have classically been associated
      with schizophrenia, there is clinical evidence that some bipolar patients show
      cognitive disturbances either during acute phases or in remission periods. The
      authors critically review the data on cognitive impairment in bipolar disorder.
      The main computerized databases (Medline, Psychological Abstracts, Current
      Contents) have been consulted crossing the terms 'cognitive deficits',
      'neuropsychology', 'intellectual impairment', 'mania', 'depression' and 'bipolar
      disorder'. Changes in the fluency of thought and speech, learning and memory
      impairment, and disturbances in associational patterns and attentional processes
      are as fundamental to depression and mania as are changes in mood and behavior.
      Moreover, a significant number of bipolar patients show persistent cognitive
      deficits during remission from affective symptoms. However, there are several
      methodological pitfalls in most studies such as unclear remission criteria,
      diagnostic heterogeneity, small sample sizes, absence of longitudinal assessment,
      practice effect and poor control of the influence of pharmacological treatment.
      Most studies point at the presence of diffuse cognitive dysfunction during the
      acute phases of bipolar illness. Most of these deficits seem to remit during
      periods of euthymia, but some of them may persist in approximately one third of
      bipolar patients. Methodological limitations warrant further research in order to
      clear up the relationship between neuropsychological functioning and clinical,
      demographic and treatment variables in bipolar disorder.

PMID- 10601831
TI  - Psychiatric and medical effects of anabolic-androgenic steroid use in women.
AB  - BACKGROUND: Although numerous studies have documented the psychiatric and
      physiological effects of anabolic-androgenic steroids (AAS) in males, virtually
      no studies have investigated the effects of illicit AAS use in women. METHODS: We
      performed psychiatric and medical evaluations of 75 dedicated women athletes,
      recruited by advertisement primarily from gymnasiums in the Boston, Mass., area.
      RESULTS: Twenty-five (33%) of the women reported current or past AAS use. Users
      were more muscular than nonusers and reported use of many other 'ergogenic'
      (performance-enhancing) drugs in addition to AAS. Some described a frank syndrome
      of ergogenic polysubstance dependence, often with significant morbidity. Fourteen
      (56%) of the users reported hypomanic symptoms during AAS use and 10 (40%)
      reported depressive symptoms during AAS withdrawal, but none met full DSM-IV
      criteria for a hypomanic or major depressive episode. Nineteen (76%) users
      reported at least one adverse medical effect associated with AAS use. Perhaps the
      most interesting findings were several unusual psychiatric syndromes reported by
      both the AAS users and nonusers. These included rigid dietary practices (which we
      have termed 'eating disorder, bodybuilder type'), nontraditional gender roles and
      chronic dissatisfaction and preoccupation with their physiques (a syndrome which
      we have termed 'muscle dysmorphia'). CONCLUSIONS: Dedicated women athletes
      exhibit not only AAS abuse, but use of many other ergogenic drugs, sometimes
      associated with significant morbidity. In addition, these athletes frequently
      display several psychiatric syndromes which have not previously been well
      described.

PMID- 10601832
TI  - Personality disorders and depressive symptoms in late luteal phase dysphoric
      disorder.
AB  - BACKGROUND: Although many significant studies of late luteal phase dysphoric
      disorder (LLPD) have been carried out, some conflicting findings on the
      relationships between personality disorders, depressive symptoms, hostility and
      LLPD deserve further investigation. METHODS: Forty-three LLPD patients and 85
      control subjects, evaluated by prospective daily ratings during two symptomatic
      cycles, received a detailed psychiatric evaluation, including the sections for
      psychotic, affective and anxiety disorders of the Structured Clinical Interview
      for DSM-III-R nonpatient version and the section for personality disorders; the
      Buss Durkee Inventory for Assessing Different Kinds of Hostility and the
      Montgomery-Asberg Depression Rating Scale. RESULTS: The odds of suffering from
      LLPD are about nine-fold (crude odds ratio, OR = 9.23, 95% confidence interval,
      CI 3.98-21.39) among women with mild or moderate depressive symptoms. When two
      age strata (below and above 30) are analyzed separately, the association between
      LLPD and depressive symptoms is strong and positive in both strata, while the
      association between LLPD and avoidant personality disorder is found only among
      older women (adjusted OR = 8.26, p < 0.05, 95% CI 1.03-66.35). CONCLUSIONS: The
      major finding from this preliminary study is the association between LLPD and
      depressive symptoms. Conversely, the association between LLPD and avoidant
      personality disorder remains controversial and seems to be dependent on age. Our
      findings support the hypothesis that LLPD and avoidant personality disorder may
      be considered as part of the spectrum of recurrent mood disorder rather than as
      qualitatively distinct nosological entities. Future studies are needed, adopting
      prospective, longitudinal assessments of personality prior to the onset of LLPD.

PMID- 10601833
TI  - Development of a brief screening instrument: the HANDS.
AB  - BACKGROUND: The present study was designed to develop a briefer screening scale
      of approximately 10 items which maintained the validity of the Zung Self-Rating
      Depression Scale in a sample similar to that attending National Depression
      Screening Day (NDSD), as well as a more general audience. METHODS: We first
      administered 70 items from a variety of existing rating scales to 40 subjects who
      answered an ad for depressed subjects and 55 who answered an ad for non-depressed
      subjects, all of whose diagnoses were confirmed by the Structured Clinical
      Interview for DSM-IV (SCID). Based on the correlation between each item and the
      diagnostic criterion, we reduced the number of items to 17 which we then
      administered to another 45 subjects who answered an ad similar to that used for
      NDSD and also underwent a SCID interview. Based on these results, we arrived at
      the final 10-item Harvard Department of Psychiatry/NDSD scale (HANDS) with the
      assistance of the item-response theory. The items are scored for frequency of
      occurrence of each symptom over the past 2 weeks. Total scores range from 0 to
      30. RESULTS: The 10-item scale (HANDS) has good internal consistency and
      validity: a cutpoint score of 9 or greater gave sensitivity of at least 95% in
      both studies. Although specificity was lower for all scales in the self-selected
      population, the HANDS performed at least as well as the 20-item Zung Scale, the
      21-item Beck Depression Inventory-II and the 15-item Hopkins Symptom Depression
      Checklist. CONCLUSION: The 10-item HANDS performs as well as other widely used
      longer self-report scales and has the advantage of briefer administration time.

PMID- 10601834
TI  - Factors affecting compliance with treatment in an outpatient child psychiatric
      practice: A retrospective study in a community mental health centre in Athens.
AB  - BACKGROUND: The literature review shows that treatment compliance in child
      psychiatric practice is a multifactorial issue that includes parameters such as
      the type of problem presented by the child, the family's functioning and the
      therapeutic team's organization and functioning. METHODS: In order to examine
      these parameters and their inter-relationship, epidemiological data from the
      files of 455 cases, representing the total number of cases admitted to our Centre
      between 1990-1994, were collected. We noted that the majority of patients (58.6%)
      failed to comply with treatment. RESULTS: The statistical analysis shows that the
      sex and age of the child, the socio-economic status of the family, the family's
      size, the parents' educational background as well as the referral source are
      unrelated to compliance. On the contrary, the type of problem presented by the
      child, the type of recommended treatment, the number of sessions attended and the
      season of admission are correlated with treatment compliance. CONCLUSIONS:
      Certain aspects of our team's techniques concerning the admission procedure,
      therapeutic contract and parental counselling have been re-examined and improved.

PMID- 10601835
TI  - Cardiovascular reactivity in adolescent boys of low socioeconomic status
      previously characterized as anxious, disruptive, anxious-disruptive or normal
      during childhood.
AB  - BACKGROUND: The purpose of the study was to compare cardiovascular reactivity, a
      potential mechanism underlying the development of cardiovascular disease (CVD),
      in boys with different behavioral characteristics. METHOD: Eighty-nine adolescent
      boys with low socioeconomic status who were classified as anxious, disruptive,
      anxious-disruptive or boys without these characteristics (i.e. control) during
      childhood were observed during a laboratory stress experiment. RESULT: No
      significant group differences were found for resting levels of diastolic or
      systolic blood pressure (SBP). Anxious and anxious-disruptive boys exhibited
      greater SBP reactivity to the social stressor (Social Competence Interview)
      compared to the disruptive and control boys. The disruptive boys tended to engage
      in compromising behaviors which are associated with health problems. The anxious
      boys were significantly more likely to have a positive family history of
      hypertension. CONCLUSIONS: Boys with different behavioral problems (anxiety,
      disruptiveness) may be at risk for CVD via different mechanisms.

PMID- 10601836
TI  - Bcl-2 expression is correlated with low apoptotic index and associated with
      histopathological grading in esophageal squamous cell carcinomas.
AB  - The aim of this study was to examine the relationship between apoptosis, protein
      expression of apoptosis mediator and inhibitor genes p53 and bcl-2 and various
      histopathological grades of squamous cell carcinoma of the esophagus. Apoptotic
      index was evaluated in thirty human esophageal squamous cell carcinomas and
      adjoining normal tissue by terminal deoxynucleotidyl transferase-mediated dUTP
      nick end labelling (TUNEL). Protein expression of bcl-2 and p53 was measured by
      immunohistochemical staining of cryocut sections and Western blotting.
      Apoptototic cells were seen mainly around areas of keratinization and the
      apoptotic index was highest in well-differentiated squamous cell carcinomas. High
      Bcl-2 expression correlated inversely with the apoptotic index. p53 protein
      expression did not correlate with the grade of the tumor or the apoptotic index.
      We propose that deregulation of apoptosis contributes to the pathogenesis of
      esophageal squamous cell carcinoma.

PMID- 10601837
TI  - Comparison of the effects of immunosuppressive factors from newly established
      colon carcinoma cell cultures on human lymphocyte proliferation and cytokine
      secretion.
AB  - Tumor cells may influence the host's immune reactivity by the production of
      immunosuppressive factors (ISFs). In this study, the effects of ISFs derived from
      nine polyclonal colorectal carcinoma (CRC) cell lines on PHA-induced lymphocyte
      proliferation and cytokine secretion was investigated. We found that most of the
      culture supernatants (8/9) from CRC cell lines contained ISFs, which inhibited T
      cell proliferation to a variable degree in a dose-dependent manner. Comparison of
      T cell proliferation in the presence or absence of monocytes showed that
      monocytes can modulate the effects of tumor-derived ISFs on lymphocyte function.
      In addition, exposure of activated PBMC to the tumor cell supernatants resulted
      in an altered secretion of cytokines by these cells, i.e. the secretion of IFN
      gamma was generally reduced while the secretion of IL-1beta, IL-2 and TNF-alpha
      was little affected. We further investigated the supernatants' inhibitory effects
      on PBMC in respect to the production of prostaglandin E(2) (PGE(2)). It was found
      that PGE(2) was secreted by all tumor cell cultures. Therefore this substance is
      probably involved in the immunosuppression in vivo. However, the secreted PGE(2)
      was shown not to be solely responsible for the observed suppression of lymphocyte
      proliferation in vitro. Our results suggest that the secretion of ISF is a common
      property of CRCs as demonstrated with newly established CRC cell cultures, and
      therefore this may also be an important immune escape mechanism of colonic
      carcinomas in vivo.

PMID- 10601838
TI  - Roles of growth factors in mediating mesenchymal influence on the
      cytodifferentiation of the Dunning prostatic adenocarcinoma.
AB  - Earlier studies have shown that seminal vesicle mesenchyme (SVM) has the ability
      to induce Dunning tumor (DT) to undergo morphogenetic changes and
      cytodifferentiation. The aim of the present study was to investigate the roles of
      growth factors and their receptors in tumor-mesenchymal interactions. Small
      pieces of DT were combined with SVM (0-day neonatal SD rat) and the tissue
      recombinants (SVM + DT) were grafted under the renal capsule of male athymic nude
      mice and allowed to grow for 4 weeks. Histopathological examination confirmed
      that SVM can induce DT to express apparently more normal morphological features,
      with the formation of large tubules lined by highly differentiated columnar
      epithelial cells and the reappearance of a fibromuscular stroma. Using
      immunohistochemistry, the results demonstrated that the tissue recombinants
      typically exhibited an overexpression of EGF, EGF-R, bFGF, TGF-beta(1) together
      with a concurrent downregulation of TGF-alpha, IGF-I, IGF-II, and VEGF receptors
      (flk-1, flt-1). The levels of these growth factors and their receptors in DT +
      SVM tissue recombinants were more similar to those of the normal prostate. These
      findings reaffirmed that SVM has the ability to reprogram DT toward a more normal
      direction on one hand, while implicating the importance of cytokines in
      mesenchyme-induced DT phenotypic changes under in vivo condition on the other
      hand. This study suggests that these factors and their receptors may be essential
      mediators in tumor-mesenchymal interactions.

PMID- 10601839
TI  - Expression of size-polymorphic androgen receptor gene in uterine leiomyoma
      according to the number of cytosine, adenine, and guanine repeats in androgen
      receptor alleles.
AB  - The amino terminus region of the androgen receptor (AR) gene in the X chromosome
      involves the cytosine, adenine, and guanine (CAG) repeats. Random X chromosome
      inactivation with AR alleles in individual cells occurs in females. Therefore,
      probably either paternal or maternal single dominant polymorphic AR mRNA must be
      expressed in neoplastic tissue originating from monoclone. This prompted us to
      determine the deviated numbers of CAG repeats in AR mRNA to understand the
      clonality of uterine leiomyoma. A solitary node of leiomyoma was macroscopically
      found in 7 cases, and multiple nodes were found in another 23 cases. Homozygous
      CAG repeats (22.0 +/- 2.3) in AR alleles were found in 5 of 30 cases, and either
      a large or small size of AR mRNA expression, were found in individual nodes of
      uterine leiomyoma, although paternal and maternal AR mRNAs from normal uterine
      myometrium were consistently expressed as AR alleles. There was no significant
      specificity in activated AR alleles related to CAG numbers in individual nodes.
      Therefore, an individual node of uterine leiomyoma might be formed from an
      independent monoclonal uterine leiomyoma cell.

PMID- 10601840
TI  - Evaluation of tumor marker S-100 in cerebrospinal fluid from subjects with
      nonischemic brain pathologies.
AB  - In order to evaluate the S-100 concentration in cerebrospinal fluid from subjects
      with nonischemic brain damage, a total of 33 samples were analyzed: 11 from
      subjects in whom no organic disease could be found; 14 from patients with a
      diagnosis of lymphocytic or bacterial-fungal meningitis, and 8 from patients with
      acute lymphatic leukemia but no demonstrable signs of meningeal involvement. In
      all cases, the subjects considered had no previous history of melanoma or
      ischemic brain damage. The mean levels +/- SEM found for each study group were
      1.00 +/- 0.11, 1.67 +/- 0.23 and 1.17 +/- 0.14 microg/l, respectively.
      Significant differences appeared between the groups when applying the Kruskal
      Wallis nonparametric test (p = 0.035). The highest levels were found in the
      meningitis group and were significantly different from those of the control group
      (p = 0.015). No significant differences were found with regard to age or sex.
      Based on the pathophysiology of meningitis and on previous studies, the results
      suggest the existence of brain damage caused by an infection as a possible cause
      of increased S-100 levels.

PMID- 10601841
TI  - Reduced stability of prostate-specific antigen after long-term storage of serum
      at -20 degrees C.
AB  - The measurement of serum prostate-specific antigen (PSA) is widely used for the
      detection and management of patients with prostate cancer. Many studies on the
      validity of PSA as a marker for prostate cancer are performed on clinical samples
      that have been stored frozen for years. We have studied the stability of free
      (F), total (T) and complexed (C) PSA immunoreactivity and the proportion of free
      to total PSA (F/T) in serum after melting sera stored at -20 degrees C for 2
      years and 2 weeks, respectively. In contrast to the decrease in PSA-F and F/T
      observed in fresh samples, PSA-C decreased and PSA-F increased in a time
      dependent fashion after thawing samples that had been kept frozen for 2 years.
      This caused a net decrease in PSA-T and an increase in F/T. These results suggest
      that even though serum PSA is fairly stable during short-term storage, long-term
      storage at -20 degrees C reduces the stability of PSA immunoreactivity. Thus,
      results obtained on samples stored for prolonged times at -20 degrees C should be
      interpreted with caution. Because of the changes in PSA-F and F/T in both fresh
      and archival samples stored unfrozen, it is recommended that sera are melted only
      for the period required for pipetting the samples.

PMID- 10601843
TI  - Editorial

PMID- 10601842
TI  - Vanadate is toxic to adherent- growing multidrug-resistant cells.
AB  - The development of multidrug resistance (MDR) is the primary cause of failure of
      cancer chemotherapy and circumventing this problem is a major challenge in
      oncology. Vanadate is known to inhibit the ATPase activity of the P-glycoprotein
      and multidrug-resistant associated protein. In the present study we show that
      adherent MDR cells are more sensitive to vanadate than adherent non-MDR ones, but
      the same is not true for suspension-growing cells. Vanadate induced stress fiber
      in the non-MDR adherent MDCK cell line, but destroyed the actin fibers of MDCK/60
      and MA104 cells, two adherent MDR cell lines, suggesting that the sensitivity of
      these cells to vanadate is related to their actin cytoskeleton. The results
      suggest that vanadate may be used as an adjuvant in the chemotherapy of solid
      tumors, not only as an ATPase inhibitor but also because of its effect in the MDR
      cell cytoskeleton.

PMID- 10601844
TI  - 3,4-Dihydrocoumarin hydrolase with haloperoxidase activity from Acinetobacter
      calcoaceticus F46.
AB  - A novel lactonohydrolase, an enzyme that catalyzes the hydrolysis of 3,4
      dihydrocoumarin, was purified 375-fold to apparent homogeneity, with a 22.7%
      overall recovery, from Acinetobacter calcoaceticus F46, which was isolated as a
      fluorene-assimilating micro-organism. The molecular mass of the native enzyme, as
      estimated by high-performance gel-permeation chromatography, is 56 kDa, and the
      subunit molecular mass is 30 kDa. The enzyme specifically hydrolyzes 3,4
      dihydrocoumarin, and the Km and Vmax for 3,4-dihydrocoumarin are 0.806 mM and
      4760 U.mg-1, respectively. The N-terminal and internal amino acid sequences of
      the enzyme show high similarity to those of bacterial non-heme haloperoxidases.
      The enzyme exhibits brominating activity with monochlorodimedon in the presence
      of H2O2 and 3, 4-dihydrocoumarin or an organic acid, such as acetate and n
      butyrate.

PMID- 10601845
TI  - Biogenesis of giant mitochondria during insect flight muscle development in the
      locust, Locusta migratoria (L.). Transcription, translation and copy number of
      mitochondrial DNA.
AB  - The biogenesis of giant mitochondria in flight muscle of Locusta migratoria (L.)
      was analyzed at the molecular level. During the 2 weeks between the beginning of
      the last larval stage and the imago capable of sustained flight, individual
      mitochondria have been shown to enlarge 30-fold and the fractional mitochondrial
      volume of muscle cells increases fourfold [Brosemer, R.W., Vogell, W. and Bucher,
      Th. (1963) Biochem. Z. 338, 854-910]. Within the same period, the activity of
      cytochrome c oxidase, containing subunits encoded on mitochondrial DNA, increased
      twofold. However, no significant change in mitochondrial DNA copy number, and
      even a threefold decrease in mitochondrial transcripts, was observed.
      Mitochondrial translation rate, measured in isolated organelles, was twofold
      higher in larval muscle, which can be explained only partly by the higher content
      of mitochondrial RNAs. Thus, rather unusually, in this system of mitochondrial
      differentiation, the mitochondrial biosynthetic capacity correlates with the rate
      of organelle biogenesis rather than the steady-state concentration of a marker
      enzyme. The copy number of mitochondrial DNA does not seem to play a major role
      in determining either mitochondrial transcript levels or functional mass.

PMID- 10601846
TI  - Slender and stumpy bloodstream forms of Trypanosoma brucei display a differential
      response to extracellular acidic and proteolytic stress.
AB  - Natural infections of mammals with African trypanosomes, such as Trypanosoma
      brucei, are generally pleomorphic, the population consisting of different forms,
      termed slender and stumpy forms, that vary in number as the parasitaemia
      develops. We show that the differentiation of slender into stumpy forms is
      characterized by the acquisition by the parasite of the ability to regulate its
      internal pH, even in the face of a large, inwardly directed gradient of H+, as
      well as a tolerance towards external proteolytic stress. These adaptations
      effectively abbrogate cellular stress-activated signalling pathways involving
      adenylate cyclase and glycosylphosphoinositol-specific phospholipase-C mediated
      release of the surface coat. Although in metabolic terms stumpy forms of the
      parasite are considered to be preadapted to life in the arthropod vector, these
      data clearly demonstrate that these forms also possess additional cellular
      adaptations designed to deal with the immediate and potentially harmful changes
      in the extracellular environment that occur upon ingestion of a bloodmeal by the
      tsetse fly vector.

PMID- 10601847
TI  - Growth factor-induced promoter activation of murine phospholipase C delta4 gene.
AB  - Phospholipase C delta4 (PLCdelta4) is one of the delta-type PLC isozymes, the
      expression of which is induced in nuclei by treatment with serum and also in some
      cancer cells. We isolated and analyzed a promoter region of the murine PLCdelta4
      gene. DNA sequence analysis showed that this region is GC-rich and has no TATA
      box, and the region from -143 to -127 was found, by luciferase activity and gel
      mobility-shift assay, to be essential for transcription of PLCdelta4. We also
      found that the promoter activity of PLCdelta4 was stimulated by treatment with
      growth factors such as bradykinin, lysophosphatidic acid, and Ca2+ ionophore in
      addition to serum. In parallel, we detected PLCdelta4 mRNA induction and an
      increase in complex formation of the promoter region and nuclear protein from
      HeLa cells on stimulation with these growth factors. Finally, we found that
      trapping the growth factor-induced cytoplasmic Ca2+-inhibited activation of the
      promoter activity and protein induction in nuclei. These results show that
      PLCdelta4 may have an important role in nuclei in response to growth factors, and
      its expression may be partially regulated by an increase in cytoplasmic Ca2+.

PMID- 10601848
TI  - Important role of membrane-associated CD14 in the induction of IFN-beta and
      subsequent nitric oxide production by murine macrophages in response to bacterial
      lipopolysaccharide.
AB  - The surface antigen CD14 is known to play a central role in the recognition of
      lipopolysaccharide by macrophages. We characterized a mutant cell line, J7.DEF.3,
      derived from a murine macrophage-like cell line, J774.1, to be defective in the
      ability to express the membrane-associated form of CD14 (mCD14) but not in the
      ability to release the soluble form of CD14 (sCD14), and used these parent and
      mutant cells to investigate the role of CD14 in lipopolysaccharide signaling. In
      response to lipopolysaccharide stimulation, mutant cells produced slightly less
      tumor necrosis factor than parent cells, and produced much less (negligible
      level) nitric oxide than parent cells. Production of both tumor necrosis factor
      and nitric oxide by parent cells upon lipopolysaccharide stimulation was
      suppressed by anti-CD14 serum. Expression of interferon-beta mRNA by stimulation
      with lipopolysaccharide, detected in parent cells, was barely detectable in
      mutant cells and in enzymatically mCD14-eliminated parent cells.
      Lipopolysaccharide-induced nitric oxide production in parent cells was suppressed
      by anti-(murine interferon-beta), and its production in the mutant cells appeared
      and increased dose dependently on exogenously supplied murine interferon-beta in
      the presence of lipopolysaccharide. These results provide new insight into the
      lipopolysaccharide signaling pathway, indicating that the lipopolysaccharide
      signal for interferon-beta production is transduced through a mCD14-dependent
      pathway and that the endogenously generated interferon-beta is an essential
      cofactor leading to nitric oxide production. Nuclear translocation of a
      transcription factor, nuclear factor kappaB, was observed in both parent and
      mutant cells following stimulation with a low dose of lipopolysaccharide, and
      mitogen-activated protein kinases were also activated in both types of cell,
      although a higher dose of lipopolysaccharide was required by the mutant cells
      than by the parent cells. These results indicate that these signaling factors may
      participate in the mCD14-independent lipopolysaccharide signaling pathway rather
      than in the mCD14-dependent interferon-beta-producing pathway.

PMID- 10601849
TI  - Characterization of a recombinant soluble form of human placental leucine
      aminopeptidase/oxytocinase expressed in Chinese hamster ovary cells.
AB  - Serum levels of human placental leucine aminopeptidase/oxytocinase (P-LAP)
      increase with gestation. cDNA cloning of P-LAP revealed that the enzyme is a type
      II membrane-bound protein containing the consensus HEXXH(X)18E motif found in the
      M1 family of zinc-metallopeptidase proteins. In this study, a recombinant soluble
      form of P-LAP found in maternal serum was expressed in Chinese hamster ovary
      cells, purified to homogeneity and then characterized. Although N-terminal
      sequencing revealed a four-amino-acid deletion, the purified enzyme was active
      and was shown to be a zinc-containing homodimeric protein with molecular mass of
      280 kDa in solution. Using artificial substrates, it was shown that the enzyme
      has broad specificity and is inhibited by several compounds known as
      aminopeptidase inhibitors. Subsequently, sequential N-terminal amino-acid
      liberation of several peptide hormones by the enzyme was monitored and structures
      of the products were determined. Among the hormones having a cysteine residue at
      their N-terminal end and intramolecular disulfide bonds, it was found that
      vasopressin and oxytocin, but not calcitonin and endothelins, were cleaved by the
      enzyme. Because the molecular properties of oxytocinase so far reported often
      conflict, our results provide an initial biochemical and enzymatic
      characterization of moleculary defined P-LAP/oxytocinase.

PMID- 10601850
TI  - alpha(1,2)-fucosylation prevents sialyl Lewis x expression and E-selectin
      mediated adhesion of fucosyltransferase VII-transfected cells.
AB  - E-selectin is a cytokine-inducible, calcium-dependent endothelial cell adhesion
      molecule that plays a critical role in the leucocyte-endothelium interaction
      during inflammation and is thought to contribute to the metastatic dissemination
      of tumour cells. Like the other selectins, E-selectin binds to ligands carrying
      the tetrasaccharide sialyl-Lewis x (NeuAcalpha2,3Galbeta1,4[Fucalpha1, 3]GlcNAc)1
      or its isomer sialyl-Lewis a (NeuAcalpha2, 3Galbeta1, 3[Fucalpha1,4]GlcNAc). We
      examined the effect of expressing the H-type alpha(1,2)-fucosyltransferase or the
      alpha(2, 6)-sialyltransferase on the synthesis of sialyl-Lewis x by alpha(1,
      3)fucosyltransferase. We found that H-type alpha(1, 2)-fucosyltransferase but not
      alpha(2,6)-sialyltransferase, strongly inhibited sialyl-Lewis x expression and E
      selectin adhesion. We assume that H-type alpha(1,2)-fucosyltransferase competes
      with the endogenous alpha(2,3)-sialyltransferase for the N-acetyllactosamine
      structures assigned to further serve as acceptors for alpha(1,
      3)fucosyltransferase.

PMID- 10601851
TI  - The prothrombin gene is expressed in the rat kidney: Implications for
      urolithiasis research.
AB  - There is considerable interest in determining the role of prothrombin fragments,
      especially urinary prothrombin fragment 1 (UPTF1), in the pathogenesis of calcium
      oxalate (CaOx) urinary calculi. This fragment is present in abundance in the
      matrix of CaOx crystals generated in human urine in vitro and has also been
      detected in human urinary stones containing calcium. More recently, prothrombin
      gene expression has been reported in the human kidney. However, studies examining
      the renal biosynthesis of prothrombin or perhaps only its fragments during
      experimental lithogenesis, and in consequence, the role of UPTF1 in stone
      formation, cannot be carried out in humans. The aim of this investigation
      therefore was to determine whether prothrombin gene expression is present in the
      rat kidney. Total RNA was isolated from the kidneys and livers of 12 rats. Using
      reverse transcriptase PCR, mRNAs corresponding to the thrombin and fragment 1 + 2
      (F1+2) regions of prothrombin were analysed by agarose gel electrophoresis. The
      expression of glyceraldehyde 3-phosphate dehydrogenase was also examined to
      determine whether the quality of the tissue mRNAs was adequate for analyses. The
      amplified products were identified by sequence analysis. All kidneys displayed
      evidence of expression of the thrombin and F1+2 domains of the prothrombin gene.
      Furthermore, the sequences of these PCR-derived products from kidney were
      identical to those from liver. This suggests that the prothrombins secreted by
      these two organs are identical. The fact that prothrombin biosynthesis occurs in
      both the human and rat kidney presents an opportunity for using established rat
      models of stone disease to evaluate the influence of lithogenic conditions on
      prothrombin gene expression, and the potential role of UPTF1 in vivo.

PMID- 10601852
TI  - The origin of 1H NMR-visible triacylglycerol in human neutrophils. Highfatty acid
      environments result in preferential sequestration of palmitic acid into plasma
      membrane triacylglycerol.
AB  - Human neutrophils incubated for 1 h in vitro with 10% commercial pooled, human
      serum containing high levels of free fatty acids (1141 microM) displayed a
      distinct lipid signal, typical of triacylglycerol, in the 1H NMR spectrum.
      Concurrently their plasma membrane triacylglycerol mass increased 4.6-fold with a
      selective rise in the content of palmitic and linoleic acids. Although
      qualitatively similar, these effects were much greater than those observed after
      incubating neutrophils with 50 microg.mL-1 of lipopolysaccharide in the presence
      of 10% AB serum with normal free fatty acid content (345 microM, LPS/S).
      Incubation of neutrophils with an artificial mixture of free fatty acids at
      concentrations found in commercial serum, or with the fatty acid fraction
      isolated from commercial serum increased the 1H NMR-detectable triacylglycerol.
      The signal intensity of the 1H NMR-detectable triacylglycerol depended on the
      triacylglycerol composition, and correlated with increased membrane
      triacylglycerol mass. Cellular uptake of 3H-labelled palmitic or oleic acids
      increased in the presence of commercial serum but not with LPS/S, with little
      contribution in either case to the triacylglycerol pool that increased in mass.
      Pulse-chase experiments demonstrated that with LPS/S and commercial serum,
      radiolabelled palmitic acid was preferentially incorporated into triacylglycerol
      located in the plasma membrane. This process could occur at the plasma membrane,
      as cytoplasts efficiently convert exogenous fatty acids into triacylglycerol. We
      propose that LPS/S and serum containing high levels of free fatty acid, important
      in conditions of sepsis and inflammation, may facilitate the sequestration of
      palmitic acid into triacylglycerol by different pathways. This triacylglycerol
      originates from exogenous and endogenous free fatty acids, is 1H NMR-visible, and
      may have a role in regulating apoptosis.

PMID- 10601853
TI  - Oriented channels reveal asymmetric energy barriers for sugar translocation
      through maltoporin of Escherichia coli.
AB  - Sugar transport through maltoporin of Escherichia coli was investigated. This
      protein facilitates maltooligosaccharide translocation via a binding site in the
      channel. Because incorporation of the protein into the bilayer results in
      randomly orientated channels, we re-examined the postulated symmetric
      translocation model by reconstitution of maltoporin under an externally applied
      field. Upon binding of bacteriophage lambda, which exploit surface-exposed loops
      of maltoporin as the receptor, sugar permeation, but not the ion current, was
      blocked. Thus using the phage-to-probe orientation we were able to show that the
      channels were approximately 80% directionally inserted into the bilayer.
      Moreover, asymmetry of the channel was revealed because sugar entrance through
      the 'open' periplasmic side of maltoporin was similarly reduced. Here a new
      asymmetrical two-barrier model is presented. Based on liposome-swelling assays
      and current-fluctuation analysis we conclude that the periplasmic side of the
      porin shows a two- to threefold higher energy barrier than the extracellular loop
      side of the channels.

PMID- 10601854
TI  - Expression in yeast and tobacco of plant cDNAs encoding acyl CoA:diacylglycerol
      acyltransferase.
AB  - During the course of a search for cDNAs encoding plant sterol acyltransferases,
      an expressed sequence tag clone presenting substantial identity with yeast and
      animal acyl CoA:cholesterol acyltransferases was used to screen cDNA libraries
      from Arabidopsis and tobacco. This resulted in the isolation of two full-length
      cDNAs encoding proteins of 520 and 532 amino acids, respectively. Attempts to
      complement the yeast double-mutant are1 are2 defective in acyl CoA:cholesterol
      acyltransferase were unsuccessful, showing that neither gene encodes acyl
      CoA:cholesterol acyltransferase. Their deduced amino acid sequences were then
      shown to have 40 and 38% identity, respectively, with a murine acyl
      CoA:diacylglycerol acyltransferase and their expression in are1 are2 or wild-type
      yeast resulted in a strong increase in the incorporation of oleyl CoA into
      triacylglycerols. Incorporation was 2-3 times higher in microsomes from yeast
      transformed with these plant cDNAs than in yeast transformed with the void
      vector, clearly showing that these cDNAs encode acyl CoA:diacylglycerol
      acyltransferases. Moreover, during the preparation of microsomes from the
      Arabidopsis DGAT-transformed yeast, a floating layer was observed on top of the
      100 000 g supernatant. This fraction was enriched in triacylglycerols and
      exhibited strong acyl CoA:diacylglycerol acyltransferase activity, whereas almost
      no activity was detected in the corresponding clear fraction from the control
      yeast. Thanks to the use of this active fraction and dihexanoylglycerol as a
      substrate, the de novo synthesis of 1,2-dihexanoyl 3-oleyl glycerol by AtDGAT
      could be demonstrated. Transformation of tobacco with AtDGAT was also performed.
      Analysis of 19 primary transformants allowed detection, in several individuals,
      of a marked increase (up to seven times) of triacylglycerol content which
      correlated with the AtDGAT mRNA expression. Furthermore, light-microscopy
      observations of leaf epidermis cells, stained with a lipid-specific dye, showed
      the presence of lipid droplets in the cells of triacylglycerol-overproducer
      plants, thus illustrating the potential application of acyl CoA:diacylglycerol
      acyltransferase-transformed plants.

PMID- 10601855
TI  - Two proteins, a goldfish 20S proteasome subunit and the protein interacting with
      26S proteasome, change in the meiotic cell cycle.
AB  - To investigate the regulatory mechanism for the proteasome in the meiotic cell
      cycle, we purified the 26S proteasome from immature (in G2-phase) and mature (in
      M-phase) oocytes, and compared its subunits by immunoblotting. At least two
      protein bands, at 30 kDa (detected by GC3beta antibody) and 62 kDa (detected by 1
      4D5 antibody), differed between 26S proteasomes. A monoclonal antibody, GC3beta
      cross-reacted with two bands in the 26S proteasome from immature oocytes,
      however, the upper band was absent in the 26S proteasome from mature oocytes. The
      62-kDa protein band detected by 1-4D5 antibody was not detected in the immature
      oocyte 26S proteasome; however, a band was detected in mature oocyte 26S
      proteasome. The cDNAs encoding these proteins were isolated by an immunoscreening
      method using the monoclonal antibodies. The 30-kDa protein was an alpha4 subunit,
      which is one of the alpha-subunit group of the 20S proteasome, and the 62-kDa
      protein was a homologue of CCTepsilon, one of the components of eukaryotic
      molecular chaperones. Phosphatase treatment of the 26S proteasome revealed that a
      part of the alpha4 subunit of goldfish 20S proteasome, alpha4_ca, is
      phosphorylated in G2-phase and dephosphorylated in M-phase. A binding assay using
      a recombinant goldfish CCTepsilon revealed that unmodified CCTepsilon interacts
      with the 26S proteasome. Fertilization triggers a transition from meiotic
      metaphase to mitotic interphase. During fertilization, a GC3beta cross-reacting
      upper band reappeared. The 62-kDa band dissociated from the 26S proteasome. As a
      result, the 26S proteasome changed to an immature type from a mature type during
      fertilization. These results suggest that the 26S proteasome is changed
      reversibly during the meiotic cell cycle by modification of its subunits and
      interactions between regulators.

PMID- 10601856
TI  - Structure and interaction of VacA of Helicobacter pylori with a lipid membrane.
AB  - In its mature form, the VacA toxin of Helicobacter pylori is a 95-kDa protein
      which is released from the bacteria as a low-activity complex. This complex can
      be activated by low-pH treatment that parallels the activity of the toxin on
      target cells. VacA has been previously shown to insert itself into lipid
      membranes and to induce anion-selective channels in planar lipid bilayers.
      Binding of VacA to lipid vesicles and its ability to induce calcein release from
      these vesicles were systematically compared as a function of pH. These two
      phenomena show a different pH-dependence, suggesting that the association with
      the lipid membrane may be a two-step mechanism. The secondary and tertiary
      structure of VacA as a function of pH and the presence of lipid vesicles were
      investigated by Fourier-transform infrared spectroscopy. The secondary structure
      of VacA is identical whatever the pH and the presence of a lipid membrane, but
      the tertiary structure in the presence of a lipid membrane is dependent on pH, as
      evidenced by H/D exchange.

PMID- 10601857
TI  - Structure-activity relationship and site of binding of polyamine derivatives at
      the nicotinic acetylcholine receptor.
AB  - Several wasp venoms contain philanthotoxins (PhTXs), natural polyamine amides,
      which act as noncompetitive inhibitors (NCIs) on the nicotinic acetylcholine
      receptor (nAChR). Effects of varying the structure of PhTXs and poly(methylene
      tetramine)s on the binding affinity have been investigated. Using the fluorescent
      NCI ethidium in a displacement assay Kapp values of these compounds have been
      determined. We found that an increase in size of the PhTX's hydrophobic head
      group significantly increased the binding affinity, while inserting positive
      charge almost completely destroyed it. Elongating the PhTX polyamine chain by
      introducing an additional aminomethylene group decreased the binding affinity,
      whereas a terminal lysine improved it. In general, poly(methylene tetramine)s
      showed higher binding affinities than PhTX analogues. The stoichiometry of PhTX
      binding was determined to be two PhTX molecules per receptor monomer. PhTXs
      appeared to bind to a single class of nonallosterically interacting binding sites
      and bound PhTX was found to be completely displaced by well-characterized luminal
      NCIs. To elucidate the site of PhTX binding, a photolabile, radioactive PhTX
      derivative was photocross-linked to the nAChR in its closed channel conformation
      resulting in labeling yields for the two alpha and the beta, gamma and delta
      subunits of 10.4, 11.1, 4.0 and 7.4%, respectively. Based on these findings we
      suggest that PhTXs and poly(methylene tetramine)s enter the receptor's ionic
      channel from the extracellular side. The hydrophobic head groups most likely bind
      to the high-affinity NCI site, while the positively charged polyamine chains
      presumably interact with the negatively charged selectivity filter located deep
      in the channel lumen.

PMID- 10601858
TI  - NADP+-dependent glutamate dehydrogenase in the Antarctic psychrotolerant
      bacterium Psychrobacter sp. TAD1. Characterization, protein and DNA sequence, and
      relationship to other glutamate dehydrogenases.
AB  - The Antarctic psychrotolerant bacterium Psychrobacter sp. TAD1 contains two
      distinct glutamate dehydrogenases (GDH), each specific for either NADP+ or NAD+.
      This feature is quite unusual in bacteria, which generally have a single GDH.
      NADP+-dependent GDH has been purified to homogeneity and the gene encoding GDH
      has been cloned and expressed. The enzyme has a hexameric structure. The amino
      acid sequence determined by peptide and gene analyses comprises 447 residues,
      yielding a protein with a molecular mass of 49 285 Da. The sequence shows
      homology with hexameric GDHs, with identity levels of 52% and 49% with
      Escherichia coli and Clostridium symbiosum GDH, respectively. The coenzyme
      binding fingerprint motif GXGXXG/A (common to all GDHs) has Ser at the last
      position in this enzyme. The overall hydrophilic character is increased and a
      five-residue insertion in a loop between two alpha-helices may contribute to the
      increase in protein flexibility. Psychrobacter sp. TAD1 GDH apparent temperature
      optimum is shifted towards low temperatures, whereas irreversible heat
      inactivation occurs at temperatures similar to those of E. coli GDH. The
      catalytic efficiency in the temperature range 10-30 degrees C is similar or lower
      than that of E. coli GDH. Unlike E. coli GDH the enzyme exhibits marked positive
      cooperativity towards 2-oxoglutarate and NADPH. This feature is generally absent
      in prokaryotic GDHs. These observations suggest a regulatory role for this GDH,
      the most crucial feature being the structural/functional properties required for
      fine regulation of activity, rather than the high catalytic efficiency and
      thermolability encountered in several cold-active enzymes.

PMID- 10601859
TI  - Assignment of a single disulfide bridge in rat liver methionine
      adenosyltransferase.
AB  - Rat liver methionine adenosyltransferase incorporated 8 mol of N-ethylmaleimide
      per mol of subunit upon denaturation in the presence of 8 M urea, whereas 10 such
      groups were labelled when dithiothreitol was also included. This observation
      prompted a re-examination of the state of the thiol groups, which was carried out
      using peptide mapping, amino acid analysis and N-terminal sequencing. The results
      obtained revealed a disulfide bridge between Cys35 and Cys61. This disulfide did
      not appear to be conserved because cysteines homologous to residue 61 do not
      exist in methionine adenosyltransferases of other origins, therefore suggesting
      its importance for the differential aspects of the liver-specific enzyme.

PMID- 10601860
TI  - Nitrilase of Rhodococcus rhodochrous J1. Conversion into the active form by
      subunit association.
AB  - Nitrilase-containing resting cells of Rhodococcus rhodochrous J1 converted
      acrylonitrile and benzonitrile to the corresponding acids, but the purified
      nitrilase hydrolyzed only benzonitrile, and not acrylonitrile. The activity of
      the purified enzyme towards acrylonitrile was recovered by preincubation with 10
      mM benzonitrile, but not by preincubation with aliphatic nitriles such as
      acrylonitrile. It was shown by light-scattering experiments, that preincubation
      with benzonitrile led to the assembly of the inactive, purified and homodimeric
      80-kDa enzyme to its active 410-kDa aggregate, which was proposed to be a
      decamer. Furthermore, the association concomitant with the activation was reached
      after dialysis of the enzyme against various salts and organic solvents, with the
      highest recovery reached at 10% saturated ammonium sulfate and 50% (v/v)
      glycerol, and by preincubation at increased temperatures or enzyme
      concentrations.

PMID- 10601861
TI  - Characterization of a sulfurtransferase from Arabidopsis thaliana.
AB  - A database search for similarities between sequenced parts of the Arabidopsis
      thaliana genome with known sulfurtransferase sequences from Escherichia coli and
      mammals was undertaken to obtain information about plant sulfurtransferase-like
      proteins. One gene and several homologous EST clones were identified. One of the
      EST clones was used for screening an Arabidopsis cDNA library. The isolated full
      length clone consists of 1134 bp and encodes a 42.6 kDa protein that includes a
      putative transit peptide sequence of about 7.1 kDa. Sequence comparisons with
      known sulfurtransferases from different organisms confirmed high homology between
      them and the existence of several highly conserved regions. Results of a Southern
      blot performed with genomic Arabidopsis DNA showed the occurrence of at least two
      sulfurtransferase-like isozymes in Arabidopsis. Recombinant proteins with and
      without the putative transit peptide were expressed in E. coli with an N-terminal
      His6-tag, purified by affinity chromatography and tested for enzyme activity
      using different sulfur donors and acceptors. Both recombinant proteins catalyzed
      the formation of SCN- from thiosulfate and cyanide as a rhodanese per definition;
      however, both recombinant proteins preferred 3-mercaptopyruvate to thiosulfate. A
      monospecific antibody produced by using the mature recombinant protein as an
      antigen recognized a single protein band in total extracts of Arabidopsis plants
      equating to the full-length protein size. A single band equating to the size of
      the mature protein was detected from purified Arabidopsis mitochondria, but there
      was no antigenic reaction with any protein from chloroplasts. The function of the
      protein is still speculative. Now tools are available to elucidate the roles and
      substrates of this sulfurtransferase in higher plants.

PMID- 10601862
TI  - Purification and primary structure of a macromolecular-translocation inhibitor II
      of glucocorticoid-receptor binding to nuclei from rat liver. Inhibitor II is the
      11.5-kDa Zn2+-binding protein (parathymosin).
AB  - The nuclear binding of the activated glucocorticoid-receptor (GR) is inhibited by
      endogenous macromolecules in vitro. Previously, we have separated the inhibitors
      into three species (MTI-I, MTI-II and MTI-III). In this study, we purified the
      most potent of the three species (MTI-II) from the livers of adrenalectomized
      rats to apparent homogeneity as judged by two-dimensional PAGE. Purified MTI-II
      inhibits GR binding to DNA containing glucocorticoid-response elements. To obtain
      the amino acid sequence of MTI-II, we digested the MTI-II with endopeptidases.
      The N-terminal amino acid sequences of the four digested fragments indicated that
      MTI-II is an 11.5-kDa Zn2+-binding protein (ZnBP, also known as parathymosin).
      Furthermore, we purified ZnBP to apparent homogeneity and found that it also
      inhibits GR binding to nuclei. ZnBP is known to be an abundant acidic protein
      involved in cell proliferation, and interacts with histone H1 or key enzymes of
      carbohydrate metabolism via its acidic domain. We also showed that the inhibition
      of GR binding to nuclei is mediated by the acidic domain of MTI-II (ZnBP,
      parathymosin) and that GR binds to the MTI-II affinity matrix. Our findings add a
      new biological function, i.e. the inhibition of GR binding to nuclei and DNA, to
      this ZnBP. Moreover, our findings suggest that the abundant acidic protein is
      involved in glucocorticoid action.

PMID- 10601863
TI  - Characterization of adhesive epitopes with the OmpS display system.
AB  - OmpS is an outer membrane protein of Vibrio cholerae where it forms trimeric
      pores that function in the uptake of maltose and maltodextrins. Based on sequence
      similarity to LamB proteins, a model of OmpS folding in the outer membrane has
      been constructed. According to this model, OmpS contains 18 transmembrane beta
      strands and nine surface-accessible loops. Adhesive epitopes can, when inserted
      into surface-accessible loop 4 (L4) and expressed in Escherichia coli, retain
      their functional characteristics. We inserted three D-repeats from the
      Staphylococcus aureus fibronectin-binding protein FnBPA into L4 of OmpS and
      showed that E. coli cells expressing these hybrids bind fibronectin. DNA
      fragments covering the N-terminal half of the globoside-binding P-fimbrial
      adhesin class II PapG of E. coli were cloned into the same surface accessible
      loop (L4) of OmpS. Fragments of papG encoding 53 or 186 amino acids from the N
      terminal end of class II PapG adhesin were found to confer bacterial adhesiveness
      to globoside. Removal of 23 amino acids from the N-terminus of PapG did not
      affect receptor binding, but removal of 31 amino acids abolished it. The newly
      developed night sky image technique was also used to demonstrate the binding
      properties of membrane vesicles carrying the hybrid proteins. We raised
      antibodies against the purified hybrid protein containing 53 amino acids from
      PapG. This antiserum recognized the P-fimbriae on E. coli cells. These data
      provide evidence that the N-terminal first 53 amino acids of class II PapG
      contain the receptor-binding domain.

PMID- 10601864
TI  - The major site of the pti1 kinase phosphorylated by the pto kinase is located in
      the activation domain and is required for pto-pti1 physical interaction.
AB  - The Pto and Pti1 serine/threonine protein kinases are key components of the
      signaling pathway leading to speck disease resistance in tomato. The two kinases
      physically interact in the yeast two-hybrid system, and Pto specifically
      phosphorylates Pti1 in vitro. In this study, we identified and characterized the
      major Pti1 site phosphorylated by Pto. Pto was expressed in Escherichia coli as a
      maltose-binding fusion protein (MBP-Pto), and used to phosphorylate in vitro a
      kinase deficient Pti1 protein fused to glutathione S-transferase (GST
      Pti1[K96N]). The major phosphopeptide derived from trypsin digestion of
      phosphorylated GST-Pti1(K96N) was partially purified by reverse-phase HPLC and
      analyzed by matrix assisted laser desorption/ionization mass spectrometry. Its
      mass corresponded to phosphopeptide LHSTR, which lies in the Pti1 kinase
      activation domain at amino acid position 230-234. By phosphoamino acid analysis,
      Thr233 was determined to be the phosphorylation site of peptide LHSTR. Mutations
      of Thr233 reduced dramatically Pti1 phosphorylation by MBP-Pto and Pti1
      autophosphorylation, providing evidence that the same Pti1 site is involved in
      the two reactions. Moreover, phosphorylation of Thr233 appeared to be required
      for Pto-Pti1 physical interaction, as a mutation of this site to alanine, but not
      to aspartate, abolished the interaction between Pto and Pti1 in the yeast two
      hybrid system.

PMID- 10601865
TI  - Homologous desensitization of the human guanylate cyclase C receptor. Cell
      specific regulation of catalytic activity.
AB  - Guanylate Cyclase C (GCC) serves as a receptor for the endogenous ligands,
      guanylin and uroguanylin, as well as the family of bacterial heat-stable
      enterotoxins (ST), which are one of the major causes of diarrhoea the world over.
      We had earlier provided evidence that GCC, present in the human colonic T84 cell
      line, is desensitized on prolonged exposure to ST, and this desensitization was
      reflected in a reduced ST-stimulated guanylate cyclase activity of GCC [Bakre,
      M.M. & Visweswariah, S.S. (1997) FEBS Lett. 408, 345-349]. In this study, we have
      investigated the mechanisms that underlie this cellular desensitization process.
      Desensitization of T84 cells was not a result of reduction in GCC present in
      membranes prepared from desensitized T84 cells, nor due to increased cGMP
      phosphodiesterase activity associated with the membrane fraction. The decrease in
      ST-stimulatable guanylate cyclase activity of GCC was due to a dramatic reduction
      in the Vmax of the cyclase, which was also seen when MnGTP was used as the
      substrate. GCC undergoes ligand-induced inactivation in vitro, which is
      alleviated in the presence of ATP. In vivo desensitized GCC could be further
      inactivated in vitro when preincubated with ST, indicating that the two
      mechanisms of GCC inactivation are distinct. Cellular refractoriness as reflected
      by a reduced responsiveness to further ST-stimulation following prior exposure to
      IST, coupled with GCC desensitization was also observed in another colonic cell
      line, Caco2. However, HEK293 cells, stably transfected with GCC cDNA, when
      exposed to ST for prolonged periods, did not result in GCC desensitization,
      indicating that desensitization of GCC appeared to be a cell specific phenomenon.
      GCC expressed in HEK293-GCC cells, however, showed in vitro ligand induced
      inactivation, suggesting that there are two independent means of ligand-induced
      desensitization of GCC, perhaps distinct from the mechanisms that have been
      described earlier for other members of the guanylate cyclase receptor family.

PMID- 10601866
TI  - The structure of the membrane-binding 38 C-terminal residues from bovine PP3
      determined by liquid- and solid-state NMR spectroscopy.
AB  - The secondary structure and membrane-associated conformation of a synthetic
      peptide corresponding to the putative membrane-binding C-terminal 38 residues of
      the bovine milk component PP3 was determined using 1H NMR in methanol, CD in
      methanol and SDS micelles, and 15N solid-state NMR in planar phospholipid
      bilayers. The solution NMR and CD spectra reveal that the PP3 peptide in methanol
      and SDS predominantly adopts an alpha-helical conformation extending over its
      entire length with a potential bend around residue 19. 15N solid-state NMR of two
      PP3 peptides 15N-labelled at the Gly7 and Ala32 positions, respectively, and
      dissolved in dimyristoylphosphatidylcholine/dimyristoylphosphatidylglycerol
      phospholipid bilayers shows that the peptide is associated to the membrane
      surface with the amphipathic helix axis oriented parallel to the bilayer surface.

PMID- 10601867
TI  - The D-loop structure of human mtDNA is destabilized directly by 1-methyl-4
      phenylpyridinium ion (MPP+), a parkinsonism-causing toxin.
AB  - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine has been reported to cause
      parkinsonism via its neurotoxic form, 1-methyl-4-phenylpyridinium ion (MPP+),
      which inhibits complex I of the mitochondrial respiratory chain. Its parkinsonism
      causing mechanisms attract a great deal of interest as a model of the disease.
      Recently, we reported that MPP+ strongly decreases the amount of mtDNA
      independent of the inhibition of complex I. Maintenance of a proper amount of
      mtDNA is essential for the normal function of mitochondria as exemplified in many
      mitochondrial diseases. The most characteristic feature in vertebral mtDNA
      replication is that H-strand synthesis proceeds displacing the parental H-strand
      as a long single strand. It forms the D-loop, a triplex replication intermediate
      composed of the parental L-strand, nascent H-strand and displaced H-strand. Here
      we show that MPP+ does not inhibit DNA synthesis by DNA polymerase gamma, but
      rather releases the nascent H-strands from mtDNA both in organello and in vitro.
      This indicates that MPP+ directly destabilizes the D-loop structure, thereby
      inhibiting replication. This study raises a new mechanism, i.e. destabilization
      of replication intermediates, for depletion of mtDNA.

PMID- 10601868
TI  - Structural analysis of photosystem II in far-red-light-adapted thylakoid
      membranes. New crystal forms provide evidence for a dynamic reorganization of
      light-harvesting antennae subunits.
AB  - We studied two-dimensional crystals of the major pigment-protein complex,
      photosystem II, in far-red-light-adapted thylakoid membranes of the viridis-zb63
      mutant of barley. Significantly larger grana membranes were produced with an
      increased synthesis of the entire photosystem II complex. These red-light-adapted
      membranes also contained two-dimensional crystals with a high frequency. Three
      different crystal forms of photosystem II were observed, providing the following
      data which further our understanding of the architecture of the native complex.
      (a) The oligomeric form of photosystem II in the membrane was monomeric in all
      crystal forms, but with a clear non-crystallographic pseudo-twofold symmetry.
      This was more apparent on the lumenal face of the complex. (b) The variability of
      unit cell contacts in different crystal forms implied that the peripheral light
      harvesting antenna complex and the core of the complex were loosely connected.
      These peripheral subunits were predicted to rearrange so that they can either
      encircle the core complex or associate in parallel channels separated by lines of
      core complexes. (c) Grana membranes were found to retain a double-layered inside
      out character, with a stromal face-to-stromal face packing. However, the presence
      of a crystal in one membrane did not necessarily impose crystallinity on its
      pair.

PMID- 10601869
TI  - Assignment of heme methyl 1H-NMR resonances of high-spin and low-spin ferric
      complexes of cytochrome p450cam using one-dimensional and two-dimensional
      paramagnetic signals enhancement (PASE) magnetization transfer experiments.
AB  - An 1H-NMR study of ferric cytochrome P450cam in different paramagnetic states was
      performed. Assignment of three heme methyl resonances of the isocyanide adduct of
      cytochrome P450 in the ferric low-spin state was recently performed using
      electron exchange in the presence of putidaredoxin [Mouro, C., Bondon, A., Jung,
      C., Hui Bon Hoa, G., De Certaines, J.D., Spencer, R.G.S. & Simonneaux, G. (1999)
      FEBS Lett. 455, 302-306]. In this study, heme methyl protons of cytochrome P450
      in the native high-spin and low-spin states were assigned through one-dimensional
      and two-dimensional magnetization transfer spectroscopy using the paramagnetic
      signals enhancement (PASE) method. The order of the methyl proton chemical shifts
      is inverted between high-spin and low-spin states. The methyl order observed in
      the ferric low-spin isocyanide complexes is related to the orientation of the
      cysteinate ligand.

PMID- 10601870
TI  - Characterization of Streptococcus pneumoniae 5-enolpyruvylshikimate 3-phosphate
      synthase and its activation by univalent cations.
AB  - The aroA gene (Escherichia coli nomenclature) encoding 5-enolpyruvylshikimate-3
      phosphate (EPSP) synthase from the gram-positive pathogen Streptococcus
      pneumoniae has been identified, cloned and overexpressed in E. coli, and the
      enzyme purified to homogeneity. It was shown to catalyze a reversible conversion
      of shikimate 3-phosphate (S3P) and phosphoenolpyruvate (PEP) to EPSP and
      inorganic phosphate. Activation by univalent cations was observed in the forward
      reaction, with NH+4, Rb+ and K+ exerting the greatest effects. Km(PEP) was
      lowered by increasing [NH+4] and [K+], whereas Km(S3P) rose with increasing [K+],
      but fell with increasing [NH+4]. Increasing [NH+4] and [K+] resulted in an
      overall increase in kcat. Glyphosate (GLP) was found to be a competitive
      inhibitor with PEP, but the potency of inhibition was profoundly affected by
      [NH+4] and [K+]. For example, increasing [NH+4] and [K+] reduced Ki(GLP versus
      PEP) up to 600-fold. In the reverse reaction, the enzyme catalysis was less
      sensitive to univalent cations. Our analysis included univalent cation
      concentrations comparable with those found in bacterial cells. Therefore, the
      observed effects of these metal ions are more likely to reflect the physiological
      behavior of EPSP synthase and also add to our understanding of how to inhibit
      this enzyme in the host organism. As there is a much evidence to suggest that
      EPSP synthase is essential for bacterial survival, its discovery in the serious
      gram-positive pathogen S. pneumoniae and its inhibition by GLP indicate its
      potential as a broad-spectrum antibacterial target.

PMID- 10601871
TI  - A spectroscopic assay for the analysis of carbohydrate transport reactions.
AB  - A carbohydrate-transport assay was developed that does not require isotopically
      labelled substrates, but allows transport reactions to be followed
      spectrophotometrically. It makes use of a membrane system (hybrid membranes or
      proteoliposomes) bearing the transport system of interest, and a pyrroloquinoline
      quinone-dependent aldose dehydrogenase [soluble glucose dehydrogenase (sGDH)] and
      the electron acceptor 2,6-dichloroindophenol (Cl2Ind) enclosed in the vesicle
      lumen. After transport across the vesicular membrane, the sugar is oxidized by
      sGDH. The accompanying reduction of Cl2Ind results in a decrease in A600. The
      assay was developed and optimized for the lactose carrier (LacS) of Streptococcus
      thermophilus, and both solute/H+ symport and exchange types of transport could be
      measured with high sensitivity in crude membranes as well as in proteoliposomes.
      To observe exchange transport, the membranes were preloaded with a nonoxidizable
      substrate analogue and diluted in assay buffer containing an oxidizable sugar.
      Transport rates measured with this assay are comparable with those obtained with
      the conventional assay using isotopically labelled substrates. The method is
      particularly suited for determining transport reactions that are not coupled to
      any form of metabolic energy such as uniport reactions, or for characterizing
      mutant proteins with a defective energy-coupling mechanism or systems with high
      affinity constants for sugars.

PMID- 10601872
TI  - A superoxide dismutase from the archaeon Sulfolobus solfataricus is an
      extracellular enzyme and prevents the deactivation by superoxide of cell-bound
      proteins.
AB  - An oxygen-induced iron superoxide dismutase was found in the culture fluid of the
      thermoacidophilic crenarchaeon Sulfolobus solfataricus during growth on glucose
      rich media. This protein was also identified as being associated with the cell
      surface, with the amount of the released and cell-bound protein fractions
      depending on the growth phase of the cells. The steady decrease in cell
      associated superoxide dismutase during continued growth correlated with the
      increase of free superoxide dismutase in the medium. Both enzyme fractions were
      purified to homogeneity and found to be active with different catalytic
      efficiency, with the released superoxide dismutase showing a fourfold lower
      specific activity. Characterization in comparison with the cytosolic superoxide
      dismutase revealed identical N-terminal sequences, electrophoretic mobility,
      isoelectric point, and molecular mass for all three differently located enzymes.
      In order to clarify the physiological role of the cell-associated superoxide
      dismutase, the prevention of cell-bound protein deactivation by oxyradicals was
      also investigated. Glucose dehydrogenase, which was chosen as a model enzyme, was
      demonstrated to be located on the cell surface and to be inactivated by potassium
      superoxide by in vivo assays. The direct protective effect of superoxide
      dismutase on glucose dehydrogenase was demonstrated by in vitro assays on the
      free released enzyme. Similarly, the prevention of deactivation by potassium
      superoxide was also demonstrated for the integral membrane protein succinate
      dehydrogenase by intact cell assay. Superoxide dismutase added to cells was shown
      to moderately reduce the critical damaging peroxidation and hence play a major
      role in maintaining the integrity of the outer cell envelope components.

PMID- 10601873
TI  - Effects of noncatalytic residue mutations on substrate specificity and ligand
      binding of Thermobifida fusca endocellulase cel6A.
AB  - The availability of a high-resolution structure of the Thermobifida fusca
      endocellulase Cel6A catalytic domain makes this enzyme ideal for structure-based
      efforts to engineer cellulases with high activity on native cellulose. In order
      to determine the role of conserved, noncatalytic residues in cellulose
      hydrolysis, 14 mutations of six conserved residues in or near the Cel6A active
      site cleft were studied for their effects on catalytic activity, substrate
      specificity, processivity and ligand-binding affinity. Eleven mutations were
      generated by site-directed mutagenesis using PCR, while three were from previous
      studies. All the CD spectra of the mutant enzymes were indistinguishable from
      that of Cel6A indicating that the mutations did not dramatically change protein
      conformation. Seven mutations in four residues (H159, R237, K259 and E263)
      increased activity on carboxymethyl cellulose (CM-cellulose), with K259H (in
      glucosyl subsite -2) creating the highest activity (370%). Interestingly, the
      other mutations in these residues reduced CM-cellulose activity. Only the K259H
      enzyme retained more activity on acid-swollen cellulose than on filter paper,
      suggesting that this mutation affected the rate-limiting step in crystalline
      cellulose hydrolysis. All the mutations lowered activity on cellotriose and
      cellotetraose, but two mutations, both in subsite +1 (H159S and N190A), had
      higher kcat/Km values (6.6-fold and 5.0-fold, respectively) than Cel6A on 2,4
      dinitrophenyl-beta-D-cellobioside. Measurement of enzyme : ligand dissociation
      constants for three methylumbelliferyl oligosaccharides and cellotriose showed
      that all mutant enzymes bound these ligands either to the same extent as or more
      weakly than Cel6A. These results show that conserved noncatalytic residues can
      profoundly affect Cel6A activity and specificity.

PMID- 10601874
TI  - The multisubunit chloroplast RNA polymerase A from mustard (Sinapis alba L.).
      Integration of a prokaryotic core into a larger complex with organelle-specific
      functions.
AB  - We previously identified two multisubunit plastid RNA polymerases termed A and B.
      The B enzyme has a bacterial-type polypeptide composition and is sensitive to the
      prokaryotic transcription inhibitor rifampicin (Rif); the A enzyme has a more
      complex subunit structure and is Rif-resistant. Here we report results of N
      terminal sequencing and MS carried out with the A enzyme, which establish that
      the latter contains rpo gene products and is structurally related to the B
      enzyme. Furthermore, evidence is provided that the A enzyme can be converted into
      a Rif-sensitive enzyme form in a phosphorylation-dependent manner in vitro by a
      treatment that results in depletion of a beta-like subunit. Database searches
      using sequence information derived from additional polypeptides that are present
      in purified A preparations revealed sequence similarity with chloroplast proteins
      involved in RNA processing and redox control. This proteomics approach thus
      points to the complexity of the chloroplast transcription apparatus and its
      interconnections with post-transcriptional and signalling mechanisms.

PMID- 10601875
TI  - The structure of the carbohydrate backbone of core-lipid A region ofthe
      lipopolysaccharides from Proteus mirabilis wild-type strain S1959 (serotype O3)
      and its Ra mutant R110/1959.
AB  - The following structure of core-lipid A region of the lipopolysaccharide (LPS)
      from Proteus mirabilis strain 1959 (serotype O3) and its rough mutant R110/1959
      (Proteus type II core) was determined using NMR and chemical analysis of the core
      oligosaccharide, obtained by mild acid hydrolysis of LPS, and of the products of
      alkaline deacylation of the LPS: Incomplete substitutions are indicated by
      italics. All sugars are in pyranose form, alpha-Hep is the residue Lglycero-alpha
      Dmanno-Hep, alpha-DD-Hep is the residue Dglycero-alpha-Dmanno-Hep. The
      differences with the previously reported structures are discussed.

PMID- 10601876
TI  - Differences in the skin peptides of the male and female Australian tree frog
      Litoria splendida. The discovery of the aquatic male sex pheromone splendipherin,
      together with phe8 caerulein and a new antibiotic peptide caerin 1.10.
AB  - The skin secretions of female and male Litoria splendida have been monitored
      monthly over a three-year period using HPLC and electrospray mass spectrometry.
      Two minor peptides are present only in the skin secretion of the male. The first
      of these is the female-attracting aquatic male sex pheromone that we have named
      splendipherin, a 25 amino acid peptide (GLVSSIGKALGGLLADVVKSKGQPA-OH). This
      pheromone constitutes about 1% of the total skin peptides during the breeding
      season (January to March), dropping to about 0.1% during the period June to
      November. Splendipherin attracts the female in water at a concentration of 10-11
      10-9 M, and is species specific. The second peptide is a wide-spectrum antibiotic
      of the caerin 1 group, a 25 residue peptide (GLLSVLGSVAKHVLPHVVPVIAEKL-NH2) named
      caerin 1.10. The neuropeptides of L. splendida are also seasonally variable, the
      change identical for both the female and male. During the period October to
      March, the sole neuropeptide present in skin secretions is caerulein
      [pEQDY(SO3)TGWMDF-NH2]; this is active on smooth muscle and is also an
      analgaesic. During the southern winter (June to September), more than half of the
      caerulein is hydrolysed to [pEQDYTGWMDF-NH2], a peptide that shows no smooth
      muscle activity. In place of caerulein, a new peptide, Phe8 caerulein
      [pEQDY(SO3)TGWFDF-NH2], becomes a major component of the skin secretion. Perhaps
      this seasonal change is involved in thermoregulation, that is, with the
      initiation and maintenance of the inactive (hibernation) phase of the animal.

PMID- 10601877
TI  - Antioxidants and oxidative stress in health and disease: introduction.

PMID- 10601878
TI  - On the role of vitamin C and other antioxidants in atherogenesis and vascular
      dysfunction.
AB  - Oxidative stress has been implicated as an important etiologic factor in
      atherosclerosis and vascular dysfunction. Antioxidants may inhibit atherogenesis
      and improve vascular function by two different mechanisms. First, lipid-soluble
      antioxidants present in low-density lipoprotein (LDL), including alpha
      tocopherol, and water-soluble antioxidants present in the extracellular fluid of
      the arterial wall, including ascorbic acid (vitamin C), inhibit LDL oxidation
      through an LDL-specific antioxidant action. Second, antioxidants present in the
      cells of the vascular wall decrease cellular production and release of reactive
      oxygen species (ROS), inhibit endothelial activation (i.e., expression of
      adhesion molecules and monocyte chemoattractants), and improve the biologic
      activity of endothelium-derived nitric oxide (EDNO) through a cell- or tissue
      specific antioxidant action. alpha-Tocopherol and a number of thiol antioxidants
      have been shown to decrease adhesion molecule expression and monocyte-endothelial
      interactions. Vitamin C has been demonstrated to potentiate EDNO activity and
      normalize vascular function in patients with coronary artery disease and
      associated risk factors, including hypercholesterolemia, hyperhomocysteinemia,
      hypertension, diabetes, and smoking.

PMID- 10601879
TI  - Antioxidants, NFkappaB activation, and diabetogenesis.
AB  - Although many risk factors can trigger the development of insulin-dependent
      diabetes (IDDM), it is likely that reactive oxygen species (ROS) play a central
      role in beta-cell death and disease progression. This review will focus on the
      role of antioxidant defense systems in the susceptibility to IDDM and on ROS as
      cellular messengers that regulate the expression of genes leading to beta-cell
      death. Accumulating evidence indicates that increased antioxidant defense systems
      reduce the susceptibility to IDDM in animal models or in human study. It is
      suggested that pancreas-specific ROS productions play a critical role in
      signaling the cellular autoimmune/inflammatory response by activating the
      transcription factor, NFkappaB. Various diabetogenic factors may lead to an
      increase in ROS production, which activates the redox-sensitive NFkappaB. This
      may be the initial event for the expression of cytokines and chemotactic agents
      involved in the autoimmune/inflammatory response. It is believed that this
      cascade results in a cyclic amplification of ROS and eventually leads to
      apoptosis and/or necrosis of beta cells. The specificity of antioxidants to
      inhibit NFkappaB activation and the hyperglycemic response emphasizes the
      importance of selectivity in antioxidant therapy. Research in this area will
      contribute significantly to our understanding of the cellular and mechanistic
      role of ROS in the etiology of IDDM and will lead to the development of better
      prevention strategies.

PMID- 10601880
TI  - Opposing effects of estrogen and progestins on LDL oxidation and vascular wall
      cytotoxicity: implications for atherogenesis.
AB  - Estrogens are widely regarded as beneficial to arterial wall health. Among the
      mechanisms of this benefit are antioxidant effects on LDL and the arterial wall.
      Because progestins oppose the effect of estrogen in several systems, we asked if
      progestins oppose the antioxidant effect of estrogen. To study this question, LDL
      and various female sex hormones were incubated alone and combined in the absence
      or presence of bovine aortic endothelial cells, placental trophoblast, or
      macrophages, and LDL oxidation and cytotoxicity were quantitated. In the absence
      of cells, LDL incubated with copper in phosphate-buffered saline enhanced the
      oxidation of LDL. When 17beta-estradiol was added to this system, an antioxidant
      effect was observed. Progestins inhibited this protective estrogenic effect. In
      endothelial cell culture, progestins also opposed the antioxidant effect of
      estrogen, with the strongest antiestrogenic effect seen with the synthetic
      progestins, levonorgestrel and medroxyprogesterone acetate (MPA). Endothelial
      cell cytotoxicity was proportional to the enhanced lipid peroxide formation
      observed with progestins or estrogen. Similar opposing effects were seen when
      estrogen and progesterone were added to primary cultures of placental trophoblast
      or macrophages. Thus, three cell culture systems modeling circulating arterial
      blood contact with cell surfaces demonstrated opposing effects of estrogens and
      progestins on LDL oxidation and cell cytotoxicity. These studies are in keeping
      with published reports that female sex steroids influence LDL oxidation in vivo
      and consequent arterial wall injury.

PMID- 10601881
TI  - Oxidative stress in the pathogenesis of preeclampsia.
AB  - The etiology and pathogenesis of the pregnancy syndrome preeclampsia remain
      poorly understood. There is substantial evidence to suggest that the diverse
      manifestations of preeclampsia, including altered vascular reactivity, vasospasm,
      and discrete pathology in many organ systems, are derived from pathologic changes
      within the maternal vascular endothelium. With the theme of endothelial cell
      dysfunction emphasized, this review focuses on the role of oxidative stress (an
      imbalance favoring oxidant over antioxidant forces) in the pathogenesis of
      preeclampsia. Data are summarized regarding 1) the role of the placenta in
      preeclampsia; 2) evidence and mechanisms of oxidative stress in the preeclampsia
      placenta; 3) markers of oxidative stress in the maternal circulation; and 4) the
      potential role of maternal dyslipidemia in generation of oxidative stress. A
      recurrent theme is that free radical reactions, promoted by "cross-talk" between
      the diseased placenta and maternal dyslipidemia, promote a vicious cycle of
      events that make cause and effect difficult to distinguish but likely contribute
      to the progression of preeclampsia.

PMID- 10601882
TI  - Antioxidants, oxidative stress, and degenerative neurological disorders.
AB  - Recently, clinical trials of several neurodegenerative diseases have increasingly
      targeted the evaluation of the effectiveness of various antioxidants. The results
      so far are encouraging but variable and thus confusing. Rationale for the
      possible clinical effectiveness of antioxidants in several degenerative
      conditions has arisen out of the many years of basic science generally showing
      that reactive oxygen species (ROS) and oxidative damage are important factors in
      the processes involved. Aging is one of the most significant risk factors for
      degenerative neurological disorders. Basic science efforts in our laboratory have
      centered on exploring the role of ROS and oxidative stress in neurodegenerative
      processes. The present review brings together some of the basic concepts we have
      learned by following this approach for the last 20 years and specifically the
      results we have obtained by following up on our serendipitous findings that a
      nitrone-based free radical trap, alpha-phenyl-tert-butylnitrone (PBN), has
      neuroprotective activity in several experimental neurodegenerative models. The
      mechanistic basis of the neuroprotective activity of PBN does not appear to rely
      on its general free radical trapping or antioxidant activity per se, but its
      activity in mediating the suppression of genes induced by pro-inflammatory
      cytokines and other mediators associated with enhanced neuroinflammatory
      processes. Neuroinflammatory processes, induced in part by pro-inflammatory
      cytokines, yield enhanced ROS and reactive nitric oxide species (RNS) as well as
      other unknown components that have neurotoxic properties. Neurotoxic amounts of
      RNS are formed by the activity of inducible nitric oxide synthase (iNOS). The
      demonstration of enhanced 3-nitro-tyrosine formation in affected regions of the
      Alzheimer's brain, in comparison to age-matched controls, reinforces the
      importance of neuroinflammatory processes. iNOS induction involves activation by
      phosphorylation of the MAP kinase p38 and can be induced in cultured astrocytes
      by IL-1beta or H2O2. The action of PBN and N-acetyl cysteine to suppress the
      activation of p38 was demonstrated in cultured astrocytes. The demonstration of
      activated p38 in neurons surrounding amyloid plaques in affected regions of the
      Alzheimer's brain attest to enhanced signal transduction processes in this
      neurodegenerative condition. The major themes of ROS and RNS formation associated
      with neuroinflammation processes and the suppression of these processes by
      antioxidants and PBN continue to yield promising leads for new therapies.
      Outcomes of clinical trials on antioxidants will become less confusing as more
      knowledge is amassed on the basic processes involved.

PMID- 10601883
TI  - Mechanisms of DNA oxidation.
AB  - Oxidative damage of DNA caused by a variety of chemical and physical agents
      appears to be linked to cancer. However, it is becoming increasingly clear that
      endogenous generation of oxidants, such as hydroxyl radical and peroxynitrite,
      lead to oxidation of DNA, and this may cause cancer in individuals where no
      obvious exposure to chemical or physical agents known to be carcinogenic has
      occurred. The mechanisms for generation of these two oxidants in living organisms
      will be discussed and their reactivities with DNA to produce oxidized products
      (e.g., 8-oxo-dG) will be presented with special emphasis on the individual
      characteristics of the generation and reactivity of each oxidant.

PMID- 10601884
TI  - Oxidants and skeletal muscle function: physiologic and pathophysiologic
      implications.
AB  - Previous studies have demonstrated that skeletal muscles generate considerable
      reactive oxygen during intense muscle contraction. However, the significance of
      this phenomenon and whether it represents normal physiology or pathology are
      poorly understood. Treatment with exogenous antioxidants suggests that normal
      redox tone during contraction is influencing ongoing contractile function, both
      at rest and during intense exercise. This could represent the influence of redox
      sensitive proteins responsible for excitation-contraction coupling or redox
      sensitive metabolic enzymes. Some conditions associated with intense exercise,
      such as local tissue hypoxia or elevated tissue temperatures, could also
      contribute to reactive oxygen production. Evidence that muscle conditioning
      results in upregulation of antioxidant defenses also suggests a close
      relationship between reactive oxygen and contractile activity. Therefore, there
      appears to be a significant role for reactive oxygen in normal muscle physiology.
      However, a number of conditions may lead to an imbalance of oxidant production
      and antioxidant defense, and these, presumably, do create conditions of oxidant
      stress. Ischemia-reperfusion, severe hypoxia, severe heat stress, septic shock,
      and stretch-induced injury may all lead to oxidant-mediated injury to myocytes,
      resulting in mechanical dysfunction.

PMID- 10601885
TI  - The antioxidant function of metallothionein in the heart.
AB  - The antioxidant function of metallothionein (MT) was first suggested in the early
      1980s. Studies in vitro have revealed that MT reacts directly with reactive
      oxygen species, including superoxide and hydroxyl radicals and hydrogen peroxide.
      These reactions have never been demonstrated in intact animal studies.
      Nevertheless, both pharmacologic and genetic studies have shown that MT functions
      in protection against oxidative injury in vivo. In particular, the antioxidant
      function of MT in the heart has been explored extensively. The data gathered from
      recent studies using a cardiac-specific, MT-overexpressing transgenic mouse model
      have provided direct evidence to support this physiological role of MT. Under
      acute and chronic oxidative stress conditions such as treatment with doxorubicin,
      ischemia-reperfusion, and dietary copper restriction, MT-overexpressing
      transgenic mouse hearts displayed a marked resistance to the injurious
      consequences, including biochemical, pathological, and functional alterations.
      This protective action of MT correlates with its inhibition of reactive oxygen
      species-induced lipid peroxidation. A critical elucidation of the mechanism of
      action of MT as an antioxidant in vivo remains to be achieved. However, the
      combination of recent understanding of the zinc cluster structure of MT and novel
      molecular genetic approaches has provided the basis for further advancement in
      this field.

PMID- 10601886
TI  - Interaction of antioxidants and their implication in genetic anemia.
AB  - The generation of reactive oxygen species (ROS) is a steady-state cellular event
      in respiring cells. Their production can be grossly amplified in response to a
      variety of pathophysiological conditions such as inflammation, immunologic
      disorders, hypoxia, hyperoxia, metabolism of drug or alcohol, exposure to UV or
      therapeutic radiation, and deficiency in antioxidant vitamins. Uncontrolled
      production of ROS often leads to damage of cellular macromolecules (DNA, protein,
      and lipids) and other small antioxidant molecules. A number of major cellular
      defense mechanisms exist to neutralize and combat the damaging effects of these
      reactive substances. The enzymic system functions by direct or sequential removal
      of ROS (superoxide dismutase, catalase, and glutathione peroxidase), thereby
      terminating their activities. Metal binding proteins, targeted to bind iron and
      copper ions, ensure that these Fenton metals are cryptic. Nonenzymic defense
      consists of scavenging molecules that are endogenously produced (GSH, ubiquinols,
      uric acid) or those derived from the diet (vitamins C and E, lipoic acid,
      selenium, riboflavin, zinc, and the carotenoids). These antioxidant nutrients
      occupy distinct cellular compartments and among them, there are active recycling.
      For example, oxidized vitamin E (tocopheroxy radical) has been shown to be
      regenerated by ascorbate, GSH, lipoic acid, or ubiquinols. GSH disulfides (GSSG)
      can be regenerated by GSSG reductase (a riboflavin-dependent protein), and
      enzymic pathways have been identified for the recycling of ascorbate radical and
      dehydroascorbate. The electrons that are used to fuel these recycling reactions
      (NADH and NADPH) are ultimately derived from the oxidation of foods. Sickle cell
      anemia, thalassemia, and glucose-6-phosphate-dehydrogenase deficiency are all
      hereditary disorders with higher potential for oxidative damage due to chronic
      redox imbalance in red cells that often results in clinical manifestation of mild
      to serve hemolysis in patients with these disorders. The release of hemoglobin
      during hemolysis and the subsequent therapeutic transfusion in some cases lead to
      systemic iron overloading that further potentiates the generation of ROS.
      Antioxidant status in anemia will be examined, and the potential application of
      antioxidant treatment as an adjunct therapy under these conditions will be
      discussed.

PMID- 10601887
TI  - Antioxidants and oxidative stress in exercise.
AB  - Strenuous exercise increases oxygen consumption and causes disturbance of
      intracellular pro-oxidant-antioxidant homeostasis. The mitochondrial electron
      transport chain, polymorphoneutrophil, and xanthine oxidase have been identified
      as major sources of intracellular free radical generation during exercise.
      Reactive oxygen species pose a serious threat to the cellular antioxidant defense
      system, such as diminished reserve of antioxidant vitamins and glutathione, and
      increased tissue susceptibility to oxidative damage. However, enzymatic and
      nonenzymatic antioxidants have demonstrated great adaptation to acute and chronic
      exercise. The delicate balance between pro-oxidants and antioxidants suggests
      that supplementation of antioxidants may be desirable for physically active
      individuals under certain physiological conditions by providing a larger
      protective margin.

PMID- 10601888
TI  - Aging: is oxidative stress a marker or is it causal?
AB  - Rapid developments in free radical biology and molecular technology have
      permitted exploration of the free radical theory of aging. Oxidative stress has
      also been implicated in the pathogenesis of a number of diseases. Studies have
      found evidence of oxidative damage to macromolecules (DNA, lipids, protein), and
      data in transgenic Drosophila melanogaster support the hypothesis that oxidative
      injury might directly cause the aging process. Additional links between oxidative
      stress and aging focus on mitochondria, leading to development of the
      mitochondrial theory of aging. However, despite the number of studies describing
      the association of markers of oxidative damage with advancing age, few, if any
      definitively link oxidative injury to altered energy production or cellular
      function. Although a causal role for oxidative stress in the aging process has
      not been clearly established, this does not preclude attempts to reduce oxidative
      injury as a means to reduce morbidity and perhaps increase the healthy, useful
      life span of an individual. This review highlights studies demonstrating enhanced
      oxidative stress with advancing age and stresses the importance of the balance
      between oxidants as mediators of disease and important components of signal
      transduction pathways.

PMID- 10601889
TI  - Heme oxygenase: who needs it?
AB  - Heme is a molecule that is synthesized by the sequential actions of eight enzymes
      and is ubiquitous throughout nature. For many years it has been known that heme
      is also catabolized to yield biliverdin (which is subsequently reduced to
      bilirubin), one atom of iron, and one molecule of carbon monoxide. There has been
      a recent explosion of interest in this degradative process that is catalyzed by
      the rate-limiting enzyme, heme oxygenase. In particular, there has been a special
      interest in the potential physiological and pathological roles that may be played
      by these breakdown products. This minireview will examine some of these potential
      functional correlates, with special emphasis on potential oxidant and antioxidant
      effects of the bilirubin, carbon monoxide, and iron that result from the activity
      of heme oxygenase.

PMID- 10601890
TI  - Closing the moments.

PMID- 10601891
TI  - Interdisciplinary teamwork for hip fracture prevention.
AB  - This article discusses the roles of various interdisciplinary team members, such
      as physicians, dietitians, physical therapists, social workers, activity
      therapists, and nursing staff, whose combined expertise is necessary to prevent
      hip fractures in nursing homes. To be successful, these professionals must be
      aware of and respect the roles of all team members, consistently identify the
      risk factors associated with hip fracture, and implement, evaluate, and modify
      interventions on an individual basis.

PMID- 10601892
TI  - Bedrails: choosing the best alternative.
AB  - This article discusses the importance of resident assessment in the decision to
      use bedrails, highlights the importance of an interdisciplinary approach to
      decision-making, and offers a compendium of care plan interventions and devices
      that serve as alternatives to bedrails.

PMID- 10601893
TI  - The BRENDA model: a psychosocial addiction model to identify and treat alcohol
      disorders in elders.
AB  - Studies have shown that up to 10% of the elderly drink daily and as much as 4%
      have alcoholism. Although many elders visit a primary care provider, the problem
      frequently is overlooked or misdiagnosed. We have found that primary care-based
      nursing is an effective treatment for older adults with alcoholism. In this
      article, we introduce the BRENDA model and show its effectiveness in retaining
      older adults in treatment. BRENDA involves biopsychosocial assessment, reporting
      the assessment to the patient, an empathetic approach, identified and stated
      patient needs, direct advice to stop or decrease alcohol consumption, and
      assessment of the compliance with or outcome of the direct advice. We also
      describe the utility of the BRENDA model for the pharmacotherapeutic treatment of
      addiction in late life.

PMID- 10601894
TI  - Restraint reduction: research utilization and case study with cognitive
      impairment.
AB  - Although great strides have been made in restraint reduction, restraints still
      present a challenge for long-term care facilities. Restraint reduction is
      particularly difficult with cognitively impaired residents. This article presents
      the implementation of a research-based approach to restraint reduction and a case
      study with a cognitively impaired resident. Two year after implementing the
      research-based approach, the restraint rate had decreased 28%. The case study
      with the cognitively impaired resident revealed an increase in nurse contacts but
      a decrease in nurse time after restraint reduction. Concern for the cognitively
      impaired resident's safety remained an issue for the staff. Discussion includes
      weighing the risk/benefit ratio of restraint use and considering dignity and
      quality of life.

PMID- 10601895
TI  - Care of the morbidly obese patient in a long-term care facility.
AB  - Morbidly obese patients in a long-term care (LTC) facility have special physical
      and emotional needs that must be considered when planning care. Special attention
      to the skin, vital sign monitoring, and rehabilitative care are among the
      interventions that must be integrated into the otherwise standard care of the
      morbidly obese patient. A case study is used to illustrate the challenges and
      special needs of such patients in an LTC facility in New York state. Morbidly
      obese people (nonambulatory people who are obese) frequently are unable to
      perform self-care. The care of the morbidly obese adult who resides in an LTC or
      postacute care facility, in particular, offers unique challenges to nursing
      staff.

PMID- 10601896
TI  - A comparison of infrared ear thermometry with electronic predictive thermometry
      in a geriatric setting.
AB  - This project had three purposes: to determine the test/retest reliability of
      three thermometers--an infrared ear thermometer, an oral electronic predictive
      thermometer, and an oral mercury-in-glass thermometer (MIGT); determine the
      validity (accuracy) of the first two thermometers using the MIGT as the gold
      standard; and calculate the thermometers' sensitivity and specificity for
      detecting fever using 37.5 degrees C on the MIGT as the criterion. The MIGT had
      the best reliability, followed by the electronic predictive and infrared ear
      thermometer (for validity, the former was more accurate than the latter). Little
      difference existed in the latter two thermometers' sensitivity and specificity.
      However, the confidence intervals were wide, and further studies with larger
      samples need to be done to elucidate the thermometers' diagnostic properties.

PMID- 10601897
TI  - When monitoring laboratory results failed: a case study.

PMID- 10601898
TI  - Two models of restorative nursing care in the nursing home: designated versus
      integrated restorative nursing assistants.
AB  - A 6-month clinical trial was conducted to evaluate two models of restorative
      nursing care designed to improve mobility in nursing home residents. The models
      were compared on number of residents enrolled, documentation of nursing assistant
      (NA) compliance, and nursing staff satisfaction. The designated model, which
      relied on one specially trained NA to perform restorative activities on the unit,
      resulted in higher rates of enrollment, compliance, and staff satisfaction
      compared with the integrated model, which relied on regular staff NAs who were
      trained to incorporate restorative activities into their daily routines.

PMID- 10601899
TI  - Making a difference: Diane M. Stanley and Eileen H. Toughill. 1999 Mosby
      Geriatric Nurse Manager Award recipients.

PMID- 10601900
TI  - Estrogen: new and old choices.

PMID- 10601901
TI  - Environmental threats in the home: home care nursing perspectives.

PMID- 10601902
TI  - Diet, complementary therapy, and arthritis.

PMID- 10601903
TI  - Mentoring in gynecology: Presidential address.

PMID- 10601904
TI  - Surgical management of recurrent stress urinary incontinence: A 12-year
      experience.
AB  - OBJECTIVE: The goal of the study was to evaluate the surgical procedures used to
      manage recurrent stress urinary incontinence in a tertiary referral center, to
      compare the procedures with respect to efficacy and failure rates, and to
      identify risk factors for failure. STUDY DESIGN: The health records of patients
      who underwent surgical treatment of recurrent stress urinary incontinence
      performed by the senior author (H.P.D.) between 1984 and 1995 were reviewed. The
      objective cure rate was evaluated by means of urodynamic studies and physical
      assessment, and the subjective cure rate was determined by means of historical
      report. In light of our selection criteria, the time to failure, the number of
      previous anti-incontinence procedures needed to give the best cure rate, and the
      risk factors for failure of the 3 predominantly used surgical techniques were
      determined. The statistical methods used were the chi(2) test with 95% confidence
      interval, the Cox proportional hazard model with logistic regression, and
      survival analysis. RESULTS: One hundred ninety-eight female patients were
      surgically treated for recurrent stress urinary incontinence between January 1,
      1984, and December 31, 1995. Four surgical techniques were used: (1) the combined
      abdominovaginal (2-team) polypropylene (Marlex; Phillips Petroleum Company,
      Bartlesville, Okla) sling (group 1, n = 70), (2) the modified urethral Marlex
      sling (group 2, n = 68), (3) Burch retropubic colpourethropexy (group 3, n = 49),
      and (4) suburethral Marlex sling (group 4, n = 11). The study population
      consisted of 118 patients. The rest of the original 198, including all the
      patients in group 4, were excluded. Objective and subjective cure rates of 69%
      and 89%, 66% and 96%, and 69% and 88% were calculated for groups 1, 2, and 3,
      respectively. By 6 years after the operation 100% of the failures in groups 1 and
      2 had occurred, and 88% of the group 3 failure occurred within 2 years after the
      operation. Cure rates of 77%, 73%, and 38% (P =.320) were achieved with the 2
      team sling procedure (group 1) after 1, 2, and 3 previous anti-incontinence
      operations, respectively, whereas cure rates of 81%, 25%, and 0% (P =.001) were
      obtained with the Burch procedure (group 3) after 1, 2, and 3 previous anti
      incontinence operations, respectively. This indicates that the Burch procedure
      should be avoided after >1 previous operation, whereas the 2-team sling can be
      used after >/=3 previous anti-incontinence procedures. Statistical significance
      could not be determined for group 2 because that procedure was not used to treat
      any patient with 3 previous operations. Age was a marginal risk factor for
      failure in group 1. No statistically significant risk factors were identified for
      group 2. The number of previous anti-incontinence procedures was the major risk
      factor for failure in group 3 when age, parity, gravidity, weight, hormone
      replacement therapy, number of previous anti-incontinence procedures, and
      urethral closure pressure were covariables. CONCLUSION: According to our data,
      both sling procedures and Burch retropubic colpourethropexy can be used to
      surgically manage recurrent stress urinary incontinence with selection criteria
      such as those that we used. In our opinion comparative prospective studies of
      different surgical techniques with similar selection criteria, long-term follow
      up of >/=10 years, and the inclusion of urodynamic studies may be the most
      ethical way to determine the right operations for recurrent stress urinary
      incontinence.

PMID- 10601905
TI  - The impact of intraoperative autologous blood transfusion during type III radical
      hysterectomy for early-stage cervical cancer.
AB  - OBJECTIVE: The aim of this study was to determine the effects on transfusion
      rates, perioperative complications, and survival of using intraoperative
      autologous blood transfusions for patients undergoing type III radical
      hysterectomy and lymphadenectomy. STUDY DESIGN: A retrospective analysis was
      conducted on 156 patients treated with type III radical hysterectomy and
      lymphadenectomy at the University of Miami School of Medicine from 1990 to 1997.
      One group of patients (n = 50) had intraoperative autologous blood transfusions
      and the other (n = 106) did not. RESULTS: The group that received intraoperative
      autologous blood transfusion had a significant reduction in homologous blood
      transfusions (12% vs 30%; P =.02). Patient demographic data, histologic
      parameters, and operative factors were similar between the 2 groups. There was a
      higher percentage of patients with positive pelvic lymph nodes in the group that
      did not receive intraoperative autologous blood transfusion (10% vs 30%; P =.02).
      Seven patients in the intraoperative autologous blood transfusion group (14%)
      died with disease present and all the recurrences in this group were local.
      CONCLUSION: The use of intraoperative autologous blood transfusions during type
      III radical hysterectomy and lymphadenectomy appears to be safe and effective
      without compromising rates and patterns of recurrence.

PMID- 10601906
TI  - A prospective cohort study of women after primary repair of obstetric anal
      sphincter laceration.
AB  - OBJECTIVE: This study was undertaken to prospectively assess subjective anorectal
      symptoms by questionnaire and to prospectively assess the integrity of the anal
      sphincter by physical and ultrasonographic examination in women with and without
      obstetric anal sphincter laceration. STUDY DESIGN: Fifteen subjects who sustained
      obstetric anal sphincter lacerations at the time of vaginal delivery were matched
      with 15 control subjects and followed up prospectively. Women underwent physical
      and ultrasonographic evaluations and answered questionnaires regarding anorectal
      symptoms at 6 weeks and at 4 months post partum. Data were evaluated with the
      Fisher exact test, the Wilcoxon exact and signed rank tests, and the McNemar
      test. RESULTS: On postpartum examination the subjects with lacerations had more
      separated sphincters and decreased anal resting and squeeze tones with respect to
      control subjects (P <.05). According to ultrasonographic evaluation the anal
      sphincters were more commonly disrupted in the laceration group than in the
      control group (external anal sphincter, 40% vs 20%; P =.43; and internal anal
      sphincter, 47% vs 7%; P =.035). Subjective rating of fecal incontinence was
      significantly greater in the laceration group than in the control group (P <.05).
      There was no correlation between fecal incontinence symptoms and the integrity of
      the external anal sphincter. At the 4-month visit, fecal incontinence was
      resolved in 36% of subjects; however, continued anorectal dysfunction was
      reported by 43% of subjects in the laceration group versus only 7% of the control
      subjects (P =.08). CONCLUSION: Reports of fecal incontinence were significantly
      greater among women with a history of primarily repaired obstetric anal sphincter
      lacerations than among control subjects. Ultrasonographic examination revealed
      separated anal sphincters in 40% of the women with obstetric anal sphincter
      lacerations, despite repair at the time of delivery.

PMID- 10601907
TI  - Use of the Pelvic Organ Prolapse staging system of the International Continence
      Society, American Urogynecologic Society, and Society of Gynecologic Surgeons in
      perimenopausal women.
AB  - OBJECTIVES: This study was undertaken to apply the standardized Pelvic Organ
      Prolapse staging system to perimenopausal women to obtain normative data and to
      determine any effects of risk factors for incontinence and prolapse on Pelvic
      Organ Prolapse staging system scores. STUDY DESIGN: Two hundred forty-one women
      aged 45 to 55 years who were seen for perimenopausal care were evaluated in the
      dorsal lithotomy position for pelvic prolapse at enrollment and again at 12
      months. Prolapse was scored according to the Pelvic Organ Prolapse staging
      system, as approved by the International Continence Society. All subjects
      completed questionnaires to obtain demographic data, reproductive history, and
      gynecologic history. Data were evaluated with the Mann-Whitney rank sum test and
      with 1-way analysis of variance on ranks. RESULTS: The subjects had a mean parity
      of 2.2 and a mean weight of 72.4 kg. Hysterectomy had been performed in 28% of
      the women. Urinary incontinence was reported by 66% of the women at enrollment.
      Mean prolapse scores that described the position of the cervix, the position of
      the posterior fornix, and the total vaginal length were significantly changed by
      the 1-year follow-up, with scores reflecting increased prolapse. The mean score
      at point Ba, which represents the proximal portion of the anterior vaginal wall,
      was significantly lower, consistent with decreased prolapse at this site. History
      of smoking, prior hysterectomy, weight, parity, and incontinence at enrollment
      did not significantly correlate with any of the 9 measured prolapse points.
      CONCLUSIONS: Normative data for the Pelvic Organ Prolapse staging system of the
      International Continence Society, American Urogynecologic Society, and Society of
      Gynecologic Surgeons were measured in a group of perimenopausal women. Apparent
      increases in prolapse at points C, D, and tvl may reflect changes in vaginal size
      rather an increase in uterine or vaginal vault prolapse. This variability may
      confound the use of the Pelvic Organ Prolapse staging system in longitudinal
      studies involving perimenopausal women.

PMID- 10601908
TI  - The effects of carbon dioxide pneumoperitoneum on seeding of tumor in port sites
      in a rat model.
AB  - OBJECTIVES: The use of laparoscopic surgical techniques for the resection of
      intraperitoneal malignancies has been rapidly increasing in recent years;
      concomitantly, tumor recurrences at trocar sites have also been reported. These
      reports bring into question the appropriateness of pneumoperitoneum and
      laparoscopic techniques for carcinoma removal. We hypothesized that the carbon
      dioxide pneumoperitoneum and instrumentation used during laparoscopic procedures
      contribute to a greater incidence of tumor implantation into the ventral
      peritoneal wall wound sites than seen with laparotomy. This study, which used
      port placement and carbon dioxide pneumoperitoneum in an animal model, was
      designed to determine the relative incidences of tumor implantation into wound
      sites of the ventral peritoneal wall for laparoscopy and laparotomy. STUDY
      DESIGN: Viable MAT B III rat mammary adenocarcinoma cells were injected into the
      lower right quadrant of the peritoneal cavity of Fisher 344 rats (1 x 10(5)
      cells/rat). The animals were then divided into 4 groups: 1 group (n = 9) served
      as a control group and received no further manipulations; another (n = 8)
      underwent a midline laparotomy; another (n = 8) had four 18-gauge trocars
      inserted into the peritoneal cavity; and the last (n = 8) underwent induction of
      a 7- to 8-mm Hg carbon dioxide pneumoperitoneum in addition to the insertion of
      four 18-gauge trocars. All animals were maintained under surgical conditions for
      2 hours. Animals were killed at 7 days, and the ventral peritoneal wall was
      examined for macroscopic evidence of tumor formation. RESULTS: A total of 32
      possible sites of tumor implantation were measured. The control group showed no
      significant macroscopic evidence of tumor translocation to the ventral peritoneal
      wall. Among the 32 measured sites the laparotomy group had an overall lower
      incidence of tumor implantation at the peritoneal wall wound sites (n = 5) than
      did the group with the trocars alone (n = 20) group (P =.003) and the group with
      trocars plus carbon dioxide insufflation (n = 29, P <.0001). The group with
      trocars alone had a lower incidence of tumor implantation than did the group with
      trocars plus carbon dioxide pneumoperitoneum (P =.02). CONCLUSIONS: Trocar use
      during laparoscopic surgical procedures led to greater translocation of free
      tumor cells to peritoneal wall wound sites than did laparotomy in this animal
      model. The addition of carbon dioxide pneumoperitoneum further increased
      implantation of tumor cells at trocar sites. These results provide evidence that
      the use of laparoscopic techniques for resection of intraperitoneal malignancy
      needs further long-term study.

PMID- 10601909
TI  - Hyaluronic acid-carboxymethylcellulose film and perianastomotic adhesions in
      previously irradiated rats.
AB  - OBJECTIVE: Postoperative intra-abdominal adhesions are a major source of
      postsurgical morbidity. Pelvic irradiation increases the likelihood of adhesion
      development. The purpose of this study was to evaluate the effects of hyaluronic
      acid-carboxymethylcellulose film, which was designed as a barrier to prevent
      adhesions, on the healing of ileal anastomoses performed on irradiated rat bowel.
      STUDY DESIGN: Sixty-eight female Sprague-Dawley rats underwent whole pelvic
      irradiation with a single fraction of 1700 cGy. Twenty weeks later the rats
      underwent exploratory laparotomy with segmental ileal resection and
      reanastomosis. Eighteen of the anastomoses were wrapped in hyaluronic acid
      carboxymethylcellulose film. Fifty anastomoses were not treated with any adhesion
      inhibiting barrier. On the fifth postoperative day the animals underwent another
      laparotomy for evaluation of the anastomotic sites. RESULTS: At the second
      laparotomy 93% of the rats treated with hyaluronic acid-carboxymethylcellulose
      film were found to have perianastomotic abscesses. In the non-hyaluronic acid
      carboxymethylcellulose film group the perianastomotic abscess rate was 24% (P
      <.0001). CONCLUSION: Among previously irradiated rats undergoing small-bowel
      resection and anastomosis, hyaluronic acid-carboxymethylcellulose film was
      associated with a markedly increased rate of abscess formation at the operative
      site.

PMID- 10601910
TI  - Functional failure of fascia lata allografts.
AB  - OBJECTIVES: Fascia lata allografts are commonly used in urogynecologic
      procedures. Functional failure of several grafts has occurred, and such failure
      has been recognized as a materials problem in 12 patients. STUDY DESIGN: Twelve
      patients with failure of an initial urogynecologic procedure performed with
      irradiated and freeze-dried donor fascia lata grafts underwent reoperation.
      Portions of the implanted fascia lata grafts could be retrieved in 7 cases. Graft
      specimens underwent histologic processing followed by hematoxylin and eosin
      staining. RESULTS: Histopathologic analyses of the retrieved material
      demonstrated several ongoing processes in the failed grafts. A few grafts showed
      areas of ideal remodeling. Most grafts, however, showed areas of disorganized
      remodeling and areas of graft degeneration. Evidence of immune reaction to the
      graft was observed in some cases. CONCLUSION: The high materials failure rate
      associated with the use of irradiated and freeze-dried donor fascia lata grafts
      suggests that such tissue should not be used for urogynecologic procedures.

PMID- 10601911
TI  - Five-year results after anti-incontinence operations.
AB  - OBJECTIVE: This study was undertaken to evaluate continence rates 5 years after
      anterior colporrhaphy, anterior colporrhaphy with needle suspension of the
      bladder neck, and Burch colposuspension. STUDY DESIGN: Among 544 women with
      stress incontinence who were operated on between 1989 and 1993, 327 women (60%)
      underwent clinical and urodynamic reevaluation 5 years after the operation.
      Choice of surgical procedure was made on the basis of clinical and urodynamic
      findings and of physician preference. Continence was defined as no loss of urine
      during cystometry or during coughing with the bladder filled to 300 mL. RESULTS:
      The 327 patients underwent a total of 334 operations. The objective overall
      continence rates at 5 years were 61% (65/107) after anterior repair, 49% (59/121)
      after anterior repair with needle suspension, and 79% (84/106) after Burch
      colposuspension. Continence rates after anterior colporrhaphy were 82% (32/39)
      among patients with mild stress incontinence but 49% (33/68) among those with
      moderate or severe incontinence (P <.02). Continence rates among patients with
      moderate or severe incontinence were 49% (59/121) after anterior repair with
      needle suspension and 79% (84/106) after the Burch operation (P <.02).
      CONCLUSION: Anterior colporrhaphy can cure mild stress incontinence but is
      inadequate to correct severe incontinence. Additional needle suspension may be of
      benefit for patients with moderate to severe incontinence. Abdominal
      colposuspension is superior to the vaginal operations for long-term cure of
      stress incontinence.

PMID- 10601912
TI  - The anatomic and functional outcomes of defect-specific rectocele repairs.
AB  - OBJECTIVE: This study was undertaken to evaluate the anatomic, functional, and
      quality-of-life effects of site-specific posterior colporrhaphy in the surgical
      management of rectocele. STUDY DESIGN: In a retrospective observational study 125
      patients were studied who had undergone site-specific posterior colporrhaphy
      between 1995 and 1996, either alone or in conjunction with other pelvic
      procedures. Physical examination was performed >/=6 months after the operation to
      assess the anatomic success of the repair. Standardized questionnaires were used
      to assess quality of life, sexual function, and bowel function. RESULTS: Surgical
      correction was found at follow-up examination to have been achieved in 82% of
      eligible patients (73/89). All daily aspects of living improved significantly (P
      <.05), including ability to do housework (56% improvement or cure), travel (58%
      improvement or cure), and social activities (60% improvement or cure). Emotional
      well-being also significantly improved after the operation, as measured by
      thoughts of embarrassment (57% improvement or cure) or frustration (71%
      improvement or cure). Sexual function was not affected; however, reports of
      dyspareunia significantly (P <.04) improved or were cured after the operation in
      73% of patients (19/26), worsened in 19% of patients (5/26), and arose de novo in
      3 patients. Results showed no other significant differences in vaginal dryness,
      orgasm ability, sexual desire, sexual frequency, or sexual satisfaction. Bowel
      symptoms were assessed subjectively and were noted to have significantly improved
      (P <.008) after the operation. The following improvement or cure rates were
      obtained: stooling difficulties, 55%; pelvic pain or pressure, 73%; vaginal mass,
      74%; and splinting, 65%. CONCLUSION: This study indicates that defect-specific
      posterior colporrhaphy is equal to or superior to traditional posterior
      colporrhaphy. This type of repair provides durable anatomic support and is
      successful in restoring bowel function. It does not detrimentally affect sexual
      function, may aid in the resumption of sexual activity, and significantly
      improves quality of life and social aspects of daily living.

PMID- 10601913
TI  - Outcome after rectovaginal fascia reattachment for rectocele repair.
AB  - OBJECTIVE: This study was undertaken to determine the effects of rectovaginal
      fascia reattachment on symptoms and vaginal topography. STUDY DESIGN:
      Standardized preoperative and postoperative assessments of vaginal topography
      (the Pelvic Organ Prolapse staging system of the International Continence
      Society, American Urogynecologic Society, and Society of Gynecologic Surgeons)
      and 5 symptoms commonly attributed to rectocele were used to evaluate 66 women
      who underwent rectovaginal fascia reattachment for rectocele repair. All patients
      had abnormal fluoroscopic results with objective rectocele formation. RESULTS:
      Seventy percent (n = 46) of the women were objectively assessed at 1 year.
      Preoperative symptoms included the following: protrusion, 85% (n = 39); difficult
      defecation, 52% (n = 24); constipation, 46% (n = 21); dyspareunia, 26% (n = 12);
      and manual evacuation, 24% (n = 11). Posterior vaginal topography was considered
      abnormal in all patients with a mean Ap point (a point located in the midline of
      the posterior vaginal wall 3 cm proximal to the hymen) value of -0.5 cm (range, 
      2 to 3 cm). Postoperative symptom resolution was as follows: protrusion, 90%
      (35/39; P <.0005); difficult defecation, 54% (14/24; P <.0005); constipation, 43%
      (9/21; P =.02); dyspareunia, 92% (11/12; P =.01); and manual evacuation, 36%
      (4/11; P =.125). Vaginal topography at 1 year was improved, with a mean Ap point
      value of -2 cm (range, -3 to 2 cm). CONCLUSION: This technique of rectocele
      repair improves vaginal topography and alleviates 3 symptoms commonly attributed
      to rectoceles. It is relatively ineffective for relief of manual evacuation, and
      constipation is variably decreased.

PMID- 10601914
TI  - Sequentially combined hormone replacement therapy reduces impedance to flow
      within the uterine and central retinal arteries in healthy postmenopausal women.
AB  - OBJECTIVE: The purpose of this study was to investigate the long-term effects of
      combined hormone replacement therapy on the impedances of the uterine, central
      retinal, and ophthalmic arteries in healthy postmenopausal women. STUDY DESIGN:
      In a prospective controlled study we randomly assigned 30 healthy postmenopausal
      women (mean age, 52 +/- 3 years) to 2 groups. Women in the hormone replacement
      therapy group (n = 15) received 1 mg micronized 17beta-estradiol daily
      sequentially combined with 5 or 10 mg dydrogesterone for 14 days of each 28-day
      cycle during 12 months and 2 mg 17beta-estradiol combined with 10 mg
      dydrogesterone thereafter for a period of 3 months. The control group (n = 15)
      received no treatment. Color Doppler ultrasonography was used to measure the
      impedance to flow (pulsatility index) within the uterine, central retinal, and
      ophthalmic arteries in the 17beta-estradiol phase at baseline and after 3, 12,
      and 15 months. RESULTS: With respect to values in the control group, 12 months of
      hormone replacement therapy was associated with a significantly lower (by 39%)
      mean pulsatility index of the uterine artery (decrease from baseline of 25% in
      hormone replacement therapy group and increase of 14% in control group) and a
      significantly lower (by 29%) mean pulsatility index of the central retinal artery
      (decrease of 9% in hormone replacement therapy group and increase of 20% in
      control group). After 3 months this effect was already evident. During hormone
      replacement therapy the reductions in mean pulsatility index values of the
      uterine and central retinal arteries with respect to baseline were larger (both P
      =.002) in the women with high pretreatment pulsatility index values than in those
      with low pretreatment values. The baseline pulsatility index of the uterine
      artery correlated positively with age and with duration of amenorrhea (r = 0.42,
      P =. 01; r = 0.48, P =.008; respectively). CONCLUSION: These results suggest that
      12 months of sequentially combined hormone replacement therapy with a low dose of
      estradiol (1 mg) lowers arterial impedance in specific vascular territories.
      These data may help in understanding the effects of hormone replacement therapy
      on the cerebral circulation.

PMID- 10601915
TI  - Effects of human immunodeficiency virus 1 infection on microbial origins of
      pelvic inflammatory disease and on efficacy of ambulatory oral therapy.
AB  - OBJECTIVE: This study was undertaken to determine the effects of human
      immunodeficiency virus 1 infection on the clinical presentation, severity, causal
      organisms, and response to ambulatory therapy of pelvic inflammatory disease.
      STUDY DESIGN: Women 18 to 40 years old with lower abdominal pain for <1 month
      were recruited. Participants underwent a standardized questionnaire, physical
      examination, screening for human immunodeficiency virus 1 and other sexually
      transmitted infections, and endometrial biopsy to detect plasma cell
      endometritis. Reevaluations were performed at 1 and 4 weeks to assess response to
      therapy. RESULTS: Among 162 women with adequate endometrial biopsy specimens 63
      (39%) had histologically confirmed endometritis. Endometritis was more frequent
      among women who were seropositive for human immunodeficiency virus 1 than among
      women who were seronegative (odds ratio, 3.0; 95% confidence interval, 1.5-5.9).
      Infections with either Neisseria gonorrhoeae or Chlamydia trachomatis, or both,
      were least common and bacterial vaginosis was most common among human
      immunodeficiency virus 1-infected women with CD4 T-lymphocyte counts <400
      cells/microL (P <. 04, P <.03, respectively). After oral antibiotic therapy,
      similar proportions of both women who were seropositive and women who were
      seronegative for human immuno-deficiency virus 1 had a >/=75% reduction in
      clinical severity score (81% vs 86%). CONCLUSION: Outpatient treatment of pelvic
      inflammatory disease was successful regardless of human immunodeficiency virus 1
      serostatus.

PMID- 10601916
TI  - Loop electrosurgical excision procedure for partial upper vaginectomy.
AB  - OBJECTIVES: Partial upper vaginectomy consists of removal of the vaginal apex and
      is indicated for the diagnosis and treatment of vaginal intraepithelial neoplasia
      and recurrent cancer. We present a novel surgical approach to partial upper
      vaginectomy by use of the loop electrosurgical excision procedure. STUDY DESIGN:
      A total of 15 consecutive patients with abnormal vaginal cytologic results were
      treated by the loop electrosurgical excision procedure for partial upper
      vaginectomy. After submucosal injection of local anesthetic, the loop electrode
      was used to resect the upper third of the vagina. An iodoform vaginal pack was
      placed for 24 hours. All patients with high-grade vaginal intraepithelial
      neoplasia received intravaginal 5-fluorouracil cream postoperatively. RESULTS:
      The mean blood loss was 0 mL, and the mean surgical time was 30 minutes. A
      complication developed in 1 patient (7%). One case of invasive carcinoma was
      diagnosed. No recurrences have developed in any patients with vaginal
      intraepithelial neoplasia after hysterectomy. CONCLUSIONS: The loop
      electrosurgical excision procedure for partial upper vaginectomy can be performed
      quickly, with minimal blood loss, minimal complications, and minimal recurrence
      of neoplasia, and it provides a histologic specimen for evaluation.

PMID- 10601917
TI  - Early pregnancy termination with intravaginally administered sodium chloride
      solution-moistened misoprostol tablets: historical comparison with mifepristone
      and oral misoprostol.
AB  - OBJECTIVE: The purpose of this study was to compare the abortifacient effect of
      intravaginally administered moistened misoprostol tablets with that of the
      combination regimen of mifepristone and oral misoprostol. STUDY DESIGN: One
      hundred women at </=56 days' gestation received 800 microg misoprostol
      intravaginally in the form of sodium chloride solution-moistened tablets. The
      dose was repeated 24 hours later if a gestational sac persisted on
      ultrasonographic examination. These 100 subjects (group 1) were then matched with
      100 subjects who had received 600 mg mifepristone followed by 400 microg
      misoprostol orally as part of a large multicenter American trial (group 2).
      Subjects were monitored for abortion success, adverse side effects, and bleeding
      characteristics. Abortion failure was defined as persistence of an intrauterine
      sac or the need to perform a surgical evacuation of the uterus for hemorrhage,
      for incomplete abortion, or at the subject's request. RESULTS: In 88 of the 100
      women in group 1 and 94 of the 100 women in group 2, abortion occurred and a
      surgical procedure was not required. Abortion rates were not influenced by
      gestational age in either group. Prostaglandin-related side effects of fever and
      chills, vomiting, diarrhea, and uterine pain were all significantly higher in
      group 1. Excessive uterine bleeding was uncommon in both groups, and no subjects
      received blood transfusions. CONCLUSION: The abortion rate with intravaginally
      administered moistened misoprostol tablets is similar to that with the
      combination of mifepristone and oral misoprostol. However, intravaginal
      administration of misoprostol is associated with significantly more prostaglandin
      related side effects.

PMID- 10601918
TI  - Observed patient compliance with a structured outpatient bladder retraining
      program.
AB  - OBJECTIVE: Our purpose was to determine patient compliance with a telephone-based
      retraining program. STUDY DESIGN: This was a retrospective study of 123 women
      with urinary urgency or urge incontinence who were offered bladder retraining
      with facsimile machine submission of a retraining diary and weekly telephone
      feedback. RESULTS: Completion was defined as having >/=4 follow-up sessions and
      >/=6 weeks of retraining. Seventy-one percent (87/123) began the retraining
      program; 63% (55/87) of them completed it, for an overall compliance rate of 45%
      (55/123). When we compared those who completed retraining with those who started
      but did not complete it, only concurrent use of pharmacologic therapy was
      significantly different (87% vs 53%, respectively; P <.001). This difference
      remained significant after we controlled for other independent variables,
      including urodynamic diagnosis and physician. CONCLUSIONS: A total of 55% of
      women to whom telephone-based bladder retraining was recommended either never
      started or were noncompliant with the treatment. Bladder retraining success in
      the "real world" may be substantially lower than that described in well-funded
      labor-intensive clinical trials.

PMID- 10601919
TI  - Positive cone biopsy specimen margins in women infected with the human
      immunodeficiency virus.
AB  - OBJECTIVES: The purpose of this study was to compare the positive margin rate
      associated with cervical conization among women who are seropositive for human
      immunodeficiency virus with that among women who are seronegative. STUDY DESIGN:
      This was a cross-sectional study of 245 women who underwent cervical conization
      for the following indications: biopsy-proven cervical intraepithelial neoplasia
      grade 2 or 3, abnormal endocervical curettage specimen, cytologic-histologic
      examination discrepancy, persistent cervical intraepithelial neoplasia grade 1,
      or abnormal cytologic characteristics with inadequate colposcopic examination.
      RESULTS: Twenty-two (47.8%) of 46 women who were seropositive for human
      immunodeficiency virus and 65 (32.7%) of 199 women who were seronegative had
      positive cone biopsy specimen margins. In a multivariable logistic regression the
      human immunodeficiency virus-seropositive women had a 2-fold increased risk of
      having a positive cone biopsy margin (odds ratio, 2.25; 95% confidence interval,
      1.07-4.76). CONCLUSION: If the presence of positive cone biopsy specimen margins
      represents the potential for disease progression, then our findings of a positive
      margin rate of nearly 50% in a human immunodeficiency virus-positive population
      may argue against the kind of conservative management of colposcopic follow-up
      that has been proposed for immunocompetent women.

PMID- 10601920
TI  - Estradiol-delivering vaginal rings for hormone replacement therapy.
AB  - OBJECTIVES: This study was undertaken to determine the relief of climacteric
      symptoms by vaginal rings delivering estradiol and to monitor estrogen levels.
      STUDY DESIGN: Rings releasing in vitro either 60 or 140 microg/d estradiol were
      used by 35 women who had undergone hysterectomy for each dose level. Hot flash
      and night sweat incidences, vaginal conditions, and complaints were recorded at
      clinic visits pretreatment and at 1 week, 2 weeks, 1 month, and monthly
      thereafter through 6 months. Serum samples were assayed for estradiol, estrone,
      and estrone sulfate. RESULTS: Hot flash incidence was reduced by about 80% with
      either ring. Vaginal conditions and mood were improved. Fourteen of 70 women
      discontinued ring use during the trial, 5 because of ring expulsions. Mean (+/
      SD) estradiol levels were 123 +/- 48 and 307 +/- 93 pmol/L for the low and high
      dosage levels, respectively. Mean estrone levels exceeded estradiol levels by 1.7
      fold for the higher dosage ring and 2.6-fold for the lower dosage ring. Increases
      in estrone sulfate concentrations were many times greater than those of estradiol
      or estrone. CONCLUSIONS: Vaginal rings are an acceptable method of delivery for
      periods of >/=6 months of doses of estradiol that reduce vasomotor symptoms and
      improve vaginal conditions. There was little difference in these responses
      between the 2 dosage levels.

PMID- 10601921
TI  - The puzzling association between smoking and hypertension during pregnancy.
AB  - OBJECTIVE: The object of this study was to examine the association between
      maternal smoking and hypertension during pregnancy. STUDY DESIGN: We used data
      from the Collaborative Perinatal Project, a large prospective cohort study that
      collected detailed information on blood pressure, proteinuria, smoking, and
      placental morphologic and histologic characteristics. A total of 9651 healthy
      primigravid women without chronic hypertension who had been enrolled in the study
      at the first or second trimester (average 18 weeks' gestation) and had had >/=3
      prenatal visits were included. Gestational hypertension was defined as diastolic
      blood pressure >/=90 mm Hg on 2 occasions from 24 weeks' gestation to 2 weeks
      post partum. Preeclampsia was defined as gestational hypertension plus >/=2 urine
      samples containing >/=1+ protein according to dipstick measurement during the
      same gestational period. RESULTS: After we controlled for prepregnancy body mass,
      age, socioeconomic status, and race, both past smoking and smoking during
      pregnancy were associated in a dose-response pattern with reduced risks of
      gestational hypertension and preeclampsia. For women who smoked >/=10
      cigarettes/d the relative risks with respect to women who had never smoked were
      0.6 (95% confidence interval, 0.4-0.9) for gestational hypertension and 0.5 (95%
      confidence interval, 0.4-0.7) for preeclampsia. This protective effect was
      observed both for mild and severe gestational hypertension and for preeclampsia.
      The more and the longer a woman had smoked previously, the lower was her risk of
      development of hypertension during pregnancy. This association could not be
      explained by confounding factors, by changes in placental morphologic or
      histopathologic characteristics, by maternal net weight gain, or by elevated
      liver enzyme bioactivity. CONCLUSION: Smoking is associated with a reduced risk
      of hypertension during pregnancy. The protective effect appears to continue even
      after cessation of smoking. Further basic research on this issue is warranted.

PMID- 10601922
TI  - Prediction of delivery among women with early preterm labor by means of clinical
      characteristics alone.
AB  - OBJECTIVE: This study was undertaken to assess whether individual clinical
      factors or combinations thereof could be used to accurately predict the risk of
      delivery within 1 week of admission among women with preterm labor and minimal
      cervical dilatation. STUDY DESIGN: We performed a case-control study of patients
      admitted to our institution with preterm labor and minimal cervical dilatation. A
      case patient was a patient who sought treatment with uterine contractions between
      24 and 34 weeks' gestation with cervical dilatation </=2 cm, who received
      tocolysis with magnesium sulfate, and who was delivered within 7 days of
      admission. Control subjects were those who had the same presentation with preterm
      labor but were not delivered within the first 7 days after admission. The medical
      records of case patients and control subjects were then abstracted, and
      information on >70 potential predictors was recorded. Statistical analysis
      consisted of bivariate and multivariable methods. We also generated a
      multivariable clinical predictive model with the purpose of detecting a
      proportion as high as possible of those destined to be delivered within 1 week
      (high sensitivity). We estimated that we would need 50 case patients and 150
      control subjects to detect an odds ratio of 2.5 for risk factors with a
      prevalence of 20%, an alpha error of.05, a beta error of.20, and a control
      subject/case patient ratio of 3:1. RESULTS: Three variables were eligible for
      inclusion in our logistic models according to the bivariate analyses-bleeding on
      admission, substance abuse, and admission white blood cell count >/=14,000
      cells/microL. The simplest and most favorable model included only 2 variables,
      bleeding and substance abuse, and yielded a sensitivity of 46% and a specificity
      of 76%. The full 3-variable model had similar test characteristics. For no model
      were we able to achieve a sensitivity >/=50%. CONCLUSION: The results of this
      case-control study suggest that combinations of clinical factors do not yield an
      adequate level of discrimination to be used alone for predicting the likelihood
      of delivery within 1 week among patients with minimal degrees of cervical
      dilatation.

PMID- 10601923
TI  - Use of various ultrasonographic criteria to evaluate the efficacy of mifepristone
      and misoprostol for medical abortion.
AB  - OBJECTIVE: This study was undertaken to determine whether applying modern
      formulas for mean sac diameter and crown-rump length to data from the recently
      published US mifepristone-misoprostol abortion trial would result in differences
      in assigned gestational ages and a higher rate of complete abortion. STUDY
      DESIGN: Data from the US mifepristone-misoprostol trial were reanalyzed. The
      ultrasonographic findings at baseline examination of the 2121 participants were
      used to estimate gestational age according to criteria established by Rossavik et
      al for mean sac diameter and by Robinson and Fleming, Hadlock et al, and
      Goldstein and Wolfson for embryonic pole. The gestational ages as assigned by the
      different criteria were then compared and the treatment outcomes at various
      gestational ages were calculated for each of the dating criteria. These findings
      were compared with those reported in the original study. RESULTS: Fourteen
      percent of study subjects were assigned to the incorrect gestational age group
      according to the criteria used for the original report. Still, outcomes according
      to gestational age group were similar regardless of which ultrasonographic
      gestational age criteria were used and were comparable to those calculated in the
      original report. Overall efficacy for subjects at </=42 days' gestation was 95%
      to 96%, compared with 91% for subjects at between 43 and 49 days' gestation, when
      the various criteria were used. CONCLUSIONS: The results from the United States
      mifepristone-misoprostol abortion study were not altered by applying modern and
      appropriate ultrasonographic dating formulas. The rate of complete abortion was
      highest among subjects at </=42 days' gestation.

PMID- 10601924
TI  - Cesarean delivery risk adjustment for regional interhospital comparisons.
AB  - OBJECTIVE: The aim of this study was to determine the effect of adjustment for
      patient population mix on observed, expected, and standardized cesarean delivery
      rates in regional hospitals. STUDY DESIGN: Multiple logistic regression was
      applied to a large regional perinatal database comprising 16 hospitals. Variables
      significantly associated with cesarean delivery were used to calculate cesarean
      delivery probabilities for individual patients. Probabilities were summed across
      hospitals to derive expected hospital cesarean delivery rates. A standardized
      rate for each hospital was then calculated by dividing the observed rate by the
      expected rate and multiplying by the regional rate. RESULTS: The regional
      cesarean delivery rate was 21.9% for 6798 women. Observed hospital rates varied
      from 17.1% to 39.2%. Twenty-two variables were associated with cesarean delivery.
      Expected cesarean delivery rates ranged from 18.1% to 26.0%. Among the 5
      hospitals with the lowest observed cesarean delivery rates only 2 had rates
      significantly lower than those of the rest of the region, and only 1 of those 2
      rates remained significantly lower after adjustment. One other hospital that had
      an adjusted rate significantly lower than the crude rate had not appeared
      statistically different from the rest of the region before standardization. Among
      the 5 hospitals with the highest cesarean delivery rates, 4 had rates
      significantly higher than the rest of the region, and 3 of them had significantly
      higher observed rates than expected rates. CONCLUSIONS: Compared with using
      observed (crude) cesarean delivery rates, adjustment for differences in patient
      risk factor mix facilitates more accurate comparison of cesarean delivery rates
      among hospitals within a region.

PMID- 10601925
TI  - Oral nicardipine versus intravenous magnesium sulfate for the treatment of
      preterm labor.
AB  - OBJECTIVE: The aim of this study was to compare the efficacy and safety of oral
      nicardipine in acute therapy for preterm labor with those of parenteral magnesium
      sulfate. STUDY DESIGN: Patients between 24 and 34 weeks' gestation with
      documented preterm labor were randomly assigned to receive oral nicardipine (n =
      57) or intravenous magnesium sulfate (n = 65) as initial tocolytic therapy.
      Patients in the nicardipine group received a 40-mg loading dose and then 20 mg
      every 2 hours as needed to stop contractions (total 80 mg). Patients in the
      magnesium sulfate group received a 6-g bolus followed by 2 to 4 g/h to provide
      uterine quiescence. Patients could be switched to another tocolytic regimen if
      they continued to have contractions after 6 hours of therapy. The main outcome
      variables examined were time to uterine quiescence, time gained in utero,
      recurrence of preterm labor, failure of tocolysis, and pertinent maternal and
      neonatal outcomes. RESULTS: There were no significant differences in maternal
      demographic characteristics between the groups. Among patients who responded with
      uterine quiescence within 6 hours, there was a significant decrease in the time
      to uterine quiescence in the nicardipine group (P <.01). Patients in the
      magnesium sulfate group were more likely to have recurrence of preterm labor
      necessitating further tocolytic attempts (P =.048). The patients in the magnesium
      sulfate group had more adverse side effects, mainly nausea and vomiting (P
      =.004). There were no differences in birth weight, estimated gestational age at
      delivery, or neonatal complications between the 2 groups. CONCLUSIONS: Oral
      nicardipine is an effective, safe, and well-tolerated tocolytic agent. In this
      prospective clinical trial patients randomly assigned to receive oral nicardipine
      had arrest of preterm labor more rapidly than did those randomly assigned to
      receive parenteral magnesium sulfate. Patients who received magnesium sulfate
      were more likely to have adverse medication effects and recurrent preterm labor.

PMID- 10601926
TI  - Efficacy of methotrexate treatment in viable and nonviable cervical pregnancies.
AB  - OBJECTIVES: This retrospective study examined the overall efficacy of
      methotrexate chemotherapy in the treatment of cervical pregnancy and attempted to
      determine whether differences in the response to methotrexate therapy exist
      between patients with viable and nonviable cervical pregnancies. STUDY DESIGN: A
      MEDLINE database search and a bibliographic review of the relevant literature
      were conducted to find reported cases of cervical pregnancy treated with
      methotrexate administration during the period from 1983 to 1997. Clinical and
      demographic characteristics, methotrexate regimen, concomitant invasive
      procedures, complications, and outcomes in viable and nonviable pregnancy groups
      were analyzed and compared. RESULTS: A total of 62 reported cases of cervical
      pregnancy were assessed. There were no statistically significant differences in
      demographic data, transfusion rate, and human chorionic gonadotropin remission
      time between viable and nonviable cervical pregnancy groups. Among the 35 cases
      of viable pregnancy 63% of women received systemic injection alone or a
      combination of systemic and local (intra-amniotic or intracervical) injection
      with methotrexate or potassium chloride and 37% had local injection of
      methotrexate (with or without potassium chloride) alone. Among the 23 cases of
      nonviable cervical pregnancy 96% of women received systemic methotrexate
      injection only. The need for >/=1 concomitant surgical procedure (such as simple
      curettage, dilation and curettage, cervical blocking, or uterine artery
      embolization) in conjunction with methotrexate therapy was significantly higher
      (P =.021) in the viable pregnancy group (43%) than in the nonviable pregnancy
      group (13%). The 94% success rate of preservation of the uterus in the viable
      pregnancy group was not significantly different from the 91% preservation rate in
      the nonviable pregnancy group. All patients who had successful uterine
      preservation returned to normal menstrual patterns. CONCLUSION: This
      retrospective study found that conservative treatment with methotrexate
      chemotherapy of patients with either viable or nonviable cervical pregnancies at
      <12 weeks' gestation carries a 91% success rate for preservation of the uterus.
      The structure of the cervix was restored and menstruation returned for all
      patients in whom the uterus was preserved after treatment. There was no evidence
      to suggest that the reproductive performance of these patients was affected by
      the treatment.

PMID- 10601927
TI  - Contractile activity, membrane potential, and cytoplasmic calcium in human
      uterine smooth muscle in the third trimester of pregnancy and during labor.
AB  - OBJECTIVE: This study was undertaken to investigate in human tissue samples the
      mechanisms underlying spontaneous and prostaglandin F(2)(alpha)-induced
      contractions during the final trimester of pregnancy and labor. STUDY DESIGN:
      Membrane potential and cytoplasmic calcium were recorded simultaneously with
      contraction in uterine strips obtained from the lower segment during cesarean
      delivery. RESULTS: Between week 28 of gestation and term there was a progressive
      increase in the frequency of spontaneous contractions and a decrease in the
      negative potential of the membrane. The response to prostaglandin F(2alpha) was
      biphasic. The initial excitatory component remained stable toward term. A later
      inhibitory component, which was underpinned by increased activity of the sodium
      potassium adenosine triphosphatase pump, decreased at the time of labor.
      CONCLUSIONS: There is a gradual increase in excitability in uterine muscle
      throughout the third trimester of human pregnancy. The initial component of the
      prostaglandin response is a large contraction that is kept brief by a subsequent
      inhibitory component of the response, which ensures that full relaxation occurs
      between contractions.

PMID- 10601928
TI  - Tryptophan metabolism in pregnant sheep: increased fetal kynurenine production in
      response to maternal tryptophan loading.
AB  - OBJECTIVE: The effects of a tryptophan load on the plasma concentration of
      kynurenine, the precursor for the production in the brain of the neuroactive
      products kynurenic acid and quinolinic acid, were determined in pregnant sheep at
      midgestation and late gestation and in nonpregnant sheep. STUDY DESIGN: Pregnant
      ewes were given an intravenous infusion of 100 mg/kg L-tryptophan during 2 hours
      at 95 to 98 days' gestation (n = 4) or 135 to 138 days' gestation (n = 10).
      Nonpregnant ewes (n = 6) were studied in late estrus. Arterial blood samples
      taken from 2 hours before to 48 hours after the start of the infusion were used
      for analysis of plasma tryptophan, kynurenine, and cortisol concentrations.
      RESULTS: Tryptophan loading at both gestational ages resulted in significantly
      greater increases in kynurenine concentrations in fetal plasma (at 95-98 days'
      gestation, from 5.7 +/- 1.2 micromol/L [baseline] to 247.9 +/- 86.7 micromol/L
      (peak); at 135-138 days' gestation, from 9.0 +/- 2.3 micromol/L [baseline] to
      289.0 +/- 194.0 micromol/L [peak]) than in maternal plasma [at 95-98 days'
      gestation, from 4.6 +/- 0.8 micromol/L [baseline] to 118.0 +/- 79.7 micromol/L
      [peak]; at 135-138 days' gestation, from 4.8 +/- 2.9 micromol/L [baseline] to
      98.3 +/- 67.8 micromol/L [peak]). It took longer for kynurenine concentrations to
      return to basal values in the fetus (24-30 hours) than in the ewe (8-12 hours).
      The kynurenine responses in pregnant and nonpregnant ewes were not different from
      each other. CONCLUSION: The production of kynurenine from tryptophan is
      significantly greater in the fetal lamb than in the pregnant or nonpregnant adult
      ewe.

PMID- 10601929
TI  - Atopy, the use of condoms, and a history of cesarean delivery: potential
      predisposing factors for latex sensitization in pregnant women.
AB  - OBJECTIVE: Our purpose was to assess the prevalence of latex sensitization among
      women admitted for delivery and the relevant risk factors. STUDY DESIGN: In a
      prospective study 333 consecutive patients admitted for delivery were screened
      for specific immunoglobulin E antibodies to latex and for atopic status. A
      questionnaire was filled in and included questions about the obstetric and
      surgical history, known contact with latex, and previous use of condoms. RESULTS:
      Nine of 333 (2.7%) women showed latex-specific immunoglobulin E. All 9 women had
      atopy (100% vs 26. 2% in the latex-negative group; P <.00001). Of 8 patients with
      specific immunoglobulin E who gave details about the use of condoms, 6 had had
      frequent contact with latex condoms (75% vs 51%). Previous cesarean delivery was
      more frequent in latex-sensitized patients (33% vs 8.4%; P <.05), whereas
      previous pregnancies, previous deliveries, and total number of operations had no
      influence. CONCLUSION: Given a prevalence of 2.7% of latex sensitization, all
      obstetric patients should be questioned about known immediate allergic reaction
      to latex, a predisposition to atopy, previous intra-abdominal operations, and the
      regular use of condoms in the past. Patients with atopy and additive risk factors
      should be treated in a latex-free environment.

PMID- 10601930
TI  - Cervical length and dilatation of the internal cervical os detected by vaginal
      ultrasonography as markers for preterm delivery: A systematic review.
AB  - OBJECTIVE: We performed a systematic review to evaluate endovaginal cervical
      ultrasonography as a predictor of preterm delivery. STUDY DESIGN: Selection
      criteria were original published English-language reports of prospective studies
      including women at <37 weeks' gestation with intact amniotic membranes.
      Parameters and outcomes were cervical length or dilatation of the internal
      cervical os and preterm delivery. RESULTS: In 3 subgroups of studies including
      patients with preterm labor or low-risk, symptom-free patients with early (20-24
      weeks) or late (27-32 weeks) ultrasonographic examination, optimal cutoff values
      for cervical lengths ranged between 18 and 30, 25 and 35, or 25 and 39 mm. At
      these cutoff values, sensitivity rates were between 68% and 100%, 33% and 54%, or
      63% and 76%, and specificity rates were between 44% and 79%, 73% and 91%, or 59%
      and 69%, respectively. Sensitivity rates for dilatation of the internal cervical
      os were 70% to 100%, 16% to 25%, or 33%, and specificity rates were 54% to 75%,
      95% to 99%, or 92%, respectively. CONCLUSION: In patients with symptoms of
      preterm labor, endovaginal cervical ultrasonography appears to be an effective
      predictor of preterm delivery.

PMID- 10601931
TI  - Perinatal outcome and amniotic fluid index in the antepartum and intrapartum
      periods: A meta-analysis.
AB  - OBJECTIVE: Our purpose was to perform a meta-analysis of studies on the risks of
      cesarean delivery for fetal distress, 5-minute Apgar score <7, and umbilical
      arterial pH <7.00 in patients with antepartum or intrapartum amniotic fluid index
      >5.0 or <5.0 cm. STUDY DESIGN: Using a MEDLINE search, we reviewed all studies
      published between 1987 and 1997 that correlated antepartum or intrapartum
      amniotic fluid index with adverse peripartum outcomes. The inclusion criteria
      were studies in English that associated at least one of the selected adverse
      outcomes with an amniotic fluid index of </=5.0 cm versus >5.0 cm. Contingency
      tables were constructed for each study, and relative risks and standard errors of
      their logs were calculated. Fixed-effects pooled relative risks were calculated
      for groups of studies that were homogeneous, whereas random-effects pooled
      relative risks were calculated for significantly heterogeneous groups of studies.
      RESULTS: Eighteen reports describing 10,551 patients met our inclusion criteria.
      An antepartum amniotic fluid index of </=5.0 cm, in comparison with >5.0 cm, is
      associated with an increased risk of cesarean delivery for fetal distress (pooled
      relative risk, 2.2; 95% confidence interval, 1.5-3.4) and an Apgar score of <7 at
      5 minutes (pooled relative risk, 5.2; 95% confidence interval, 2.4-11.3). An
      intrapartum amniotic fluid index of </=5.0 cm is also associated with an
      increased risk of cesarean delivery for fetal distress (pooled relative risk,
      1.7; 95% confidence interval, 1.1-2.6) and an Apgar score <7 at 5 minutes (pooled
      relative risk, 1.8; 95% confidence interval, 1.2-2.7). A poor correlation between
      the amniotic fluid index and neonatal acidosis was noted in the only study that
      examined this end point. More than 23,000 patients are necessary to demonstrate
      that the incidence of umbilical arterial pH <7.00 is 1.5 times higher among those
      with oligohydramnios in labor than among those with adequate amniotic fluid index
      (alpha = 0.05; beta = 0.2) CONCLUSIONS: An antepartum or intrapartum amniotic
      fluid index of </=5.0 cm is associated with a significantly increased risk of
      cesarean delivery for fetal distress and a low Apgar score at 5 minutes. There
      are few reports linking amniotic fluid index and neonatal acidosis, the only
      objective assessment of fetal well-being. A multicenter study with sufficient
      power should be undertaken to demonstrate that a low amniotic fluid index is
      associated with an umbilical arterial pH <7.00.

PMID- 10601932
TI  - Stimulated nitric oxide release and nitric oxide sensitivity in forearm arterial
      vasculature during normotensive and preeclamptic pregnancy.
AB  - OBJECTIVE: We sought to determine whether the enhanced forearm vascular activity
      of nitric oxide during pregnancy and preeclampsia is associated with altered
      smooth muscle sensitivity to nitric oxide or with stimulated nitric oxide
      release. STUDY DESIGN: Forearm blood flow responses to brachial artery infusion
      of glyceryl trinitrate (a nitric oxide donor), serotonin (an endothelium
      dependent nitric oxide-mediated agonist), and ritodrine (a beta-adrenergic
      receptor agonist) were studied in 10 nonpregnant women, 12 pregnant women, and 7
      women with preeclampsia by means of strain-gauge plethysmography. Responses to
      each drug (maximum dilator response and the sum of the percentage of dilator
      responses to each drug) were compared by analysis of variance. RESULTS: Compared
      with nonpregnant women, pregnant subjects showed reduced responses to serotonin
      (summary response, 117 +/- 19 vs 221 +/- 30; P <.05). Responses to serotonin were
      reduced in the group with preeclampsia compared with those in the nonpregnant
      group (summary response, 71 +/- 28; P <.05) but did not differ from the responses
      in pregnant women. There were no differences between responses to glyceryl
      trinitrate and responses to ritodrine in any of the groups. CONCLUSION: Vascular
      smooth muscle sensitivity to nitric oxide is not altered in normal pregnancy or
      preeclampsia, but dilator responses to serotonin appear blunted. Alterations in
      serotonin receptor coupling to nitric oxide synthase, or a limitation of
      availability of the substrate for nitric oxide synthase (L-arginine) during
      pregnancy, could account for the reduction in stimulated nitric oxide release.

PMID- 10601933
TI  - Intravenous infusion of magnesium sulfate and regional redistribution of fetal
      blood flow during maternal hemorrhage in late-gestation gravid ewes.
AB  - OBJECTIVES: Even though magnesium sulfate is commonly prescribed for women with
      preeclampsia as prophylaxis against seizure and for women with preterm labor as a
      tocolytic agent there is limited information about its effects on the fetus. It
      is of particular concern that women with preeclampsia or in premature labor are
      at high risk for abruptio placentae with consequent compromise of fetal
      oxygenation. Magnesium sulfate is a vasodilator and thus may exert cardiovascular
      effects on the fetus. The goal of this study was to evaluate the effects of
      magnesium sulfate on fetal organ blood flow, especially regional cerebral blood
      flow, during the stressful condition of maternal hemorrhage. STUDY DESIGN:
      Studies were performed with 11 long-term instrumented pregnant ewes and their
      fetuses at 121 to 128 days' gestation (term, 147 days' gestation). Animals were
      randomly allocated to either the experimental (n = 5) or the control (n = 6)
      group. After a 60-minute baseline period, experimental fetuses received
      intravenous magnesium sulfate diluted in 0.9% sodium chloride (0.3 g loading
      dose, then 0.3 g/h at a rate of 3 mL/h) and control fetuses were infused with an
      equivalent volume of intravenous 0.9% sodium chloride. After 60 minutes of this
      infusion-only period, the infusions were continued and ewes were intermittently
      bled 4 times at a rate of 5 mL/kg for 10 minutes with 5 minutes between
      hemorrhages. The total blood lost at the end of the hemorrhage-plus-infusion hour
      was 20 mL/kg. The infusions were continued and the sheep were observed for 1 hour
      after this period (posthemorrhage period). At the end of baseline, infusion-only,
      and hemorrhage-plus-infusion periods, fetal and maternal blood pressures and
      blood gas values were measured and fetal organ blood flows were determined
      through a fluorescent microsphere technique. Repeated-measures analysis of
      variance and Wilcoxon tests were used to determine the significance of changes in
      hemodynamic, blood gas, and organ blood flow parameters between different time
      points within each group. Comparisons between groups were made with rank sum
      tests (Mann-Whitney tests). RESULTS: There were no significant differences
      between groups or within groups for baseline and infusion-only measurements in
      any measured hemodynamic or hematologic factor. Mean maternal blood pressure
      decreased significantly (P <.05) after hemorrhage, with similar median decrements
      in both control and experimental groups of 41 mm Hg (interquartile range, 24-57
      mm Hg) and 41 mm Hg (interquartile range, 12-43 mm Hg), respectively. There were
      no significant differences between groups in fetal blood gas values or
      hemodynamic parameters. Fetal arterial PO(2) decreased significantly after
      hemorrhage plus infusion, with similar mean (+/-SEM) decreases in control and
      experimental groups of 5.9 +/- 1.4 mm Hg and 4.5 +/- 1.5 mm Hg, respectively.
      Fetal pH also decreased significantly in both groups. After hemorrhage plus
      infusion there were significant increases in fetal regional cerebral and
      myocardial blood flows in both groups. Adrenal blood flow increased significantly
      from baseline (214%, 183%-294%) in the control group after hemorrhage plus
      infusion but not in the experimental group. No other difference in organ blood
      flow between control and experimental groups was observed. Significant regional
      variations in cerebral blood flow were not observed in either group at any time.
      CONCLUSIONS: In these initially healthy, late-gestation fetal lambs magnesium
      sulfate exposure did not impair cardiac output redistribution, nor did it cause
      fetal death in response to maternal hemorrhage.

PMID- 10601934
TI  - A randomized clinical trial of daily nonstress testing versus biophysical profile
      in the management of preterm premature rupture of membranes.
AB  - OBJECTIVE: Our purpose was to evaluate the ability of 2 different antepartum
      testing modalities to predict infectious morbidity in patients with preterm
      premature rupture of membranes. STUDY DESIGN: During a 36-month period, patients
      with preterm premature rupture of membranes (at 23 to 34 weeks of gestation) were
      randomly assigned to either a daily nonstress test or a biophysical profile,
      after a 24-hour observational period. We used the original scoring system of
      Manning et al for the biophysical profile, with a score of </=6 considered
      abnormal. Nonstress test results were considered abnormal if the test was
      nonreactive or if the patient had late decelerations or significant variable
      decelerations; abnormal results led to further evaluation with a biophysical
      profile. Results of the last test before delivery were evaluated to determine
      whether infectious complications had been predicted. RESULTS: One hundred thirty
      five patients were enrolled in the study. Demographics, pregnancy
      characteristics, and neonatal outcomes were similar. Neither the daily nonstress
      test nor the daily biophysical profile had good sensitivity for predicting
      infectious complications (39.1% and 25.0%, respectively). However, both had good
      specificity (84.6% and 92.6%, respectively). Positive and negative predictive
      values were 52.9% and 75.9%, respectively, for the daily nonstress test and 66.7%
      and 68.4%, respectively, for the daily biophysical profile. Cost was
      significantly higher in the daily biophysical profile group. Nonstress testing of
      patients at <28 weeks' gestation generally required a backup biophysical profile.
      CONCLUSION: Neither the daily nonstress test nor the daily biophysical profile
      had good sensitivity for predicting infectious complications after preterm
      premature rupture of membranes.

PMID- 10601935
TI  - Nucleated red blood cell count at birth as an index of perinatal brain damage.
AB  - OBJECTIVE: The prognostic value of the nucleated red blood cell count at birth
      with respect to perinatal brain damage and neonatal outcome was assessed in
      infants at high risk of having neurologic damage. STUDY DESIGN: The nucleated red
      blood cell count at birth, pulsed Doppler ultrasonography in the cerebral
      arteries, cranial fontanelle sonograms, and neurodevelopmental status were
      evaluated in 337 newborn infants. RESULTS: The nucleated red blood cell count at
      birth was significantly higher (1) in neonates with abnormal Doppler
      ultrasonographic parameters for the cerebral arteries at 48 to 72 hours after
      birth than in healthy neonates, (2) in 6-month-old infants with sequelae of
      hypoxic-ischemic encephalopathy than in healthy infants, and (3) in 3-year-old
      children with abnormal developmental status than in those with no abnormalities
      at follow-up. Significant correlations were observed between the nucleated red
      blood cell count and gestational age, Apgar score at 1 and 5 minutes, pH, base
      deficit, fraction of inspired oxygen, blood oxygen content, and birth weight.
      CONCLUSIONS: The nucleated red blood cell count at birth not only reflects a
      response of the infant to perinatal hypoxia but is also a reliable index of
      perinatal brain damage.

PMID- 10601936
TI  - A randomized, controlled trial of a eutectic mixture of local anesthetic cream
      (lidocaine and prilocaine) versus penile nerve block for pain relief during
      circumcision.
AB  - OBJECTIVE: We set out to compare a eutectic mixture of local anesthetic cream
      (lidocaine and prilocaine) to dorsal penile nerve block with lidocaine for
      anesthesia during circumcision. STUDY DESIGN: In a double-blind study, term
      newborns were randomized to local anesthetic cream and sodium chloride solution
      dorsal penile nerve block (n = 31) or to placebo cream and lidocaine dorsal
      penile nerve block (n = 29). Pain was assessed by determination of heart rate,
      respiratory rate, and behavioral distress scoring. Group differences were
      evaluated with repeat-measures analyses of variance. RESULTS: Distress scores and
      heart rates were significantly higher in the eutectic mixture group than in the
      lidocaine group. Respiratory rates were higher in the eutectic mixture group but
      did not reach statistical significance. CONCLUSIONS: Distress scores and heart
      rates were significantly higher in infants treated with the anesthetic mixture
      than in infants treated with lidocaine. Dorsal penile nerve block with lidocaine
      is a more efficacious means of providing anesthesia for neonatal circumcision
      than the mixture of local anesthetics.

PMID- 10601937
TI  - Tissue-specific ontogenic expression of prostaglandin H synthase 2 in the ovine
      myometrium, endometrium, and placenta during late gestation and at spontaneous
      term labor.
AB  - OBJECTIVE: The purposes of this study were to determine (1) whether uterine
      tissues as well as the fetal placenta are involved in the development of
      prostaglandin-synthesizing capacity associated with impending labor in pregnant
      sheep and (2) whether the key enzyme of prostaglandin synthesis, prostaglandin H
      synthase 2, is differentially expressed in the different intrauterine tissues
      during late gestation and in association with labor. STUDY DESIGN: Myometrium,
      endometrium, and fetal placenta were removed from ewes at 95 days' gestation, (n
      = 3), 101 to 110 days' gestation (n = 3), 111 to 120 days' gestation (n = 3), 121
      to 130 days' gestation (n = 3), 131 to 140 days' gestation (n = 3), and 141 to
      145 days' gestation (n = 4) and from ewes in spontaneous term labor at 143 to 147
      days' gestation (n = 4). Expressions of prostaglandin H synthase 2 messenger
      ribonucleic acid and protein were determined by Northern blot and Western blot
      analyses. Prostaglandin H synthase 2 was localized in the fetal placenta by
      immunohistochemical means. RESULTS: Levels of both prostaglandin H synthase 2
      messenger ribonucleic acid and protein increased gradually from 115 days'
      gestation in the fetal placenta and from 131 days' gestation in the endometrium.
      A further and more significant increase in prostaglandin H synthase 2
      concentration occurred in the placenta and endometrium during spontaneous term
      labor. In contrast, myometrial concentrations of prostaglandin H synthase 2
      messenger ribonucleic acid and protein remained at steady basal levels during the
      course of pregnancy and increased only during labor. Prostaglandin H synthase 2
      was localized in the trophoblast cells of the fetal placenta. CONCLUSIONS: Tissue
      specific ontogenic expression of prostaglandin H synthase 2 was observed in
      myometrium, endometrium, and placenta during late ovine gestation and spontaneous
      term labor. Fetal placenta and endometrium showed increased expression of
      prostaglandin H synthase 2 messenger ribonucleic acid and protein during late
      ovine gestation, whereas myometrial prostaglandin H synthase 2 concentration
      remained low throughout late gestation. Prostaglandin H synthase 2 concentrations
      in the myometrium, endometrium, and placenta are all upwardly regulated during
      labor.

PMID- 10601938
TI  - Intermittent umbilical cord occlusion in the ovine fetus near term: effects on
      behavioral state activity.
AB  - OBJECTIVE: The purpose of this study was to determine the effects on fetal
      behavioral state activity of intermittent umbilical cord occlusion resulting in
      repetitive severe short-term hypoxemia. STUDY DESIGN: Fifteen near-term fetal
      sheep (experimental group, n = 8; control group, n = 7) were studied during 4
      days while behavioral and cardiovascular parameters were monitored. Each day
      after a 2-hour control period, cord occlusions were performed in the experimental
      group animals by complete inflation of an occluder cuff (duration, 90 seconds)
      every 30 minutes for 3 to 5 hours. Results are presented as group mean +/- SEM.
      RESULTS: During umbilical cord occlusions fetal arterial PO(2) (change of 12 mm
      Hg), oxygen saturation (change of 40%), and glucose concentration (change of 0.3
      mmol/L) fell and PCO(2) (change of 7 mm Hg) rose, but all returned toward control
      values after release of occlusion. Fetal behavioral state activity was markedly
      disrupted by 90 seconds of cord occlusion, with animals showing an abrupt
      flattening of the electrocorticogram. In >90% of instances the first identifiable
      state after cord release was the high-voltage non-rapid-eye-movement state. There
      was no apparent change in this response through the 4 days of the study. For
      experimental group animals the mean percentages of time spent in low-voltage
      electrocortical state (from 53 +/- 2 to 36 +/- 2), electro-ocular state (from 45
      +/- 3 to 28 +/- 3), and fetal breathing activity (22 +/- 4 to 12 +/- 3) were
      significantly decreased (P <.001) during occlusion hours with respect to
      nonocclusion hours. CONCLUSION: Intermittent umbilical cord occlusion with severe
      but limited hypoxemia and no cumulative acidosis in the near-term ovine fetus
      disrupts behavioral state activity, with a flattening of the electrocortical
      activity during occlusions and an overall decrease in the prominence of the low
      voltage rapid-eye-movement state. If such insults are frequent and severe enough,
      they might have an effect on growth and development of the brain during the
      perinatal period.

PMID- 10601939
TI  - Cytokine abundance in placental tissues: evidence of inflammatory activation in
      gestational membranes with term and preterm parturition.
AB  - OBJECTIVES: This study of the changes in cytokine concentrations in gestational
      tissues from women with term and preterm labor was undertaken to assess the
      extent of inflammatory activation associated with spontaneous labor and delivery.
      STUDY DESIGN: Extracts of amniotic, chorionic-decidual, and placental tissues
      from women delivered at term before labor (n = 15), at term after labor (n = 15),
      and preterm (n = 31) were assayed for interleukin 1beta, interleukin 6, and
      interleukin 8. RESULTS: In amniotic tissues of women delivered by spontaneous
      labor at term the median interleukin-6, interleukin-8, and interleukin-1beta
      concentrations were 3.8 to 5.4 times those of tissues from women delivered at
      term without labor (P <.05, Mann-Whitney U test). Interleukin-6 and interleukin-8
      concentrations were also significantly increased (3. 3-4 times) in chorionic
      decidual tissues. Marked increases (approximately 3-6 times) in the
      concentrations of all 3 cytokines were observed in both amniotic and chorionic
      decidual tissues from women with preterm deliveries with respect to those from
      women with term deliveries after labor. Cytokine concentrations were
      significantly correlated within amniotic tissues from both women with term
      delivery after labor and women with preterm delivery and also in preterm
      chorionic-decidual tissues but not preterm placental tissues. Concentrations of
      cytokines in the tissues of women delivered preterm were not significantly
      affected by mode of delivery, treatment with antibiotics, or twin birth. In
      preterm tissues with evidence of intrauterine infection only amniotic interleukin
      1beta concentrations were significantly elevated (P <. 05). Little or no labor
      related change in cytokine concentrations was seen within placental tissues.
      CONCLUSIONS: Increased cytokine abundance in gestational membranes associated
      with labor supports the view that an inflammatory process is involved in both
      term and preterm labor. This process does not, however, appear to be evident in
      the villous placenta.

PMID- 10601940
TI  - Hypoxia, the subsequent systemic metabolic acidosis, and their relationship with
      cerebral metabolite concentrations: An in vivo study in fetal lambs with proton
      magnetic resonance spectroscopy.
AB  - OBJECTIVE: The relationship among decreased fetal arterial oxygen saturation, the
      subsequent systemic metabolic acidosis, and changes in cerebral metabolite
      concentrations in the fetal lamb brain was investigated by means of quantitative
      proton magnetic resonance spectroscopy. STUDY DESIGN: Fetal hypoxia was induced
      in 6 fetal lambs by gradual reduction of the oxygen supply to the anesthetized
      pregnant ewe. In vivo proton magnetic resonance spectroscopy was performed on the
      fetal lamb brain simultaneously with repeated measurements of fetal arterial
      oxygen saturation and acid-base balance. RESULTS: Proton magnetic resonance
      spectra showed metabolites such as inositol, choline compounds, creatine, and N
      acetylaspartate. A signal for cerebral lactate was below the detection level
      under normoxic conditions and increased during hypoxia to indicate concentrations
      varying from 2.8 to 11.1 mmol/kg wet weight brain tissue. N -Acetylaspartate
      signals decreased during hypoxia, whereas signals of inositol, choline compounds,
      and creatine remained constant. CONCLUSION: These results support the view that
      fetal cerebral anaerobic metabolism in fetal lambs does not start under hypoxic
      conditions if the arterial blood pH is >7.28 or the base excess is >-8 mmol/L.

PMID- 10601941
TI  - Effect of prenatal betamethasone administration on maternal and fetal
      corticosteroid-binding globulin concentrations.
AB  - OBJECTIVE: This study was undertaken to examine the effects of prenatal
      betamethasone administration on corticosteroid-binding globulin concentrations in
      maternal and fetal plasma and amniotic fluid. STUDY DESIGN: Two groups of
      patients with preterm labor at 24 to 35 weeks' gestation who were receiving
      prenatal betamethasone (2 intramuscular doses of 12 mg) were studied. Maternal
      plasma was obtained before and at variable intervals until 1 week after
      betamethasone administration. Umbilical cord blood and amniotic fluid samples
      were collected at the time of delivery. Samples were also collected from patients
      at risk for preterm delivery who did not receive glucocorticoids. RESULTS:
      Betamethasone suppressed maternal cortisol concentration by >70% within 24 hours
      of injection but did not significantly alter corticosteroid-binding capacity or
      relative concentrations of corticosteroid-binding globulin isoforms in either
      maternal or umbilical cord plasma. Betamethasone reduced corticosteroid-binding
      capacity in amniotic fluid within 24 hours of injection, and values remained
      suppressed 1 week after treatment. CONCLUSION: Maternal and fetal plasma
      corticosteroid-binding globulin concentrations were unchanged after maternal
      betamethasone administration at 24 to 32 weeks' gestation but amniotic fluid
      corticosteroid-binding globulin concentrations decreased significantly,
      suggesting different sites of either corticosteroid-binding globulin production
      or regulation or both.

PMID- 10601942
TI  - Relationship between graded degrees of anemia and amniotic fluid volume in the
      ovine fetus.
AB  - OBJECTIVE: Severe fetal anemia is associated with polyhydramnios in both human
      and ovine fetuses. This study examined the relationship between varying degrees
      of anemia and amniotic fluid volume in fetal sheep. STUDY DESIGN: Eleven long
      term catheterized ovine fetuses at 126 +/- 1 days' gestation (mean +/- SE) were
      subjected to hemorrhage of 20 to 80 mL daily for 9 consecutive days to produce
      varying degrees of fetal anemia. Five additional animals served as time control
      animals. Statistical analysis was by least squares regression and 3-factor
      analysis of variance. RESULTS: Amniotic fluid volume was 793 +/- 147 mL and did
      not change with time in the control fetuses. In the fetuses that were subjected
      to hemorrhage the amniotic fluid volume changed little through the hematocrit
      range of 40% to 25%. As fetal hematocrit fell below approximately 25%, amniotic
      fluid volume began to increase. With greater degrees of anemia the amniotic fluid
      volume increased as an exponential function of hematocrit and approached 2000 mL
      excess fluid as hematocrit dropped to <15%. According to bivariate regression the
      increase in amniotic fluid volume was related to fetal hematocrit, PaO(2), and
      urinary flow rate as well as to plasma and amniotic fluid lactate concentrations.
      According to multivariate regression only fetal PO(2) and urinary flow rate were
      significantly related to the increase in amniotic fluid volume. CONCLUSIONS:
      Although mild anemia was not associated with increased amniotic fluid volume,
      moderate to severe fetal anemia was associated with an exponential rise in
      amniotic fluid volume. This rise may have been mediated by a hypoxemia-induced
      diuresis, by a diuresis related to a lactate-induced osmotic accumulation of
      fetal fluid, or by both mechanisms.

PMID- 10601943
TI  - The role of calcium in health and disease.
AB  - Skeletal fragility at the end of the life span (osteoporosis) is a major source
      of morbidity and mortality. Adequate calcium intake from childhood to the end of
      the life span is critical for the formation and retention of a healthy skeleton.
      High intakes of calcium and vitamin D potentiate the bone loss prevention effects
      of hormone replacement therapy in postmenopausal women. Pregnancy and lactation
      are not risk factors for skeletal fragility, although lactation is associated
      with a transient loss of bone that cannot be prevented by calcium
      supplementation. Low calcium intake has been implicated in the development of
      hypertension, colon cancer, and premenstrual syndrome, and it is associated with
      low intakes of many other nutrients. Encouragement of increased consumption of
      calcium-rich foods has the potential to be a cost-effective strategy for reducing
      fracture incidence later in life and for increasing patients' dietary quality and
      overall health.

PMID- 10601944
TI  - Diethylstilbestrol in the prevention and treatment of complications of pregnancy.
      1948.

PMID- 10601945
TI  - Does the administration of diethylstilbestrol during pregnancy have therapeutic
      value? 1953.

PMID- 10601946
TI  - Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with
      tumor appearance in young women. 1971.

PMID- 10601947
TI  - Diethylstilbestrol and adenocarcinoma of the vagina.

PMID- 10601949
TI  - Excess of male fetuses in connection with twin pregnancies resulting in very
      preterm birth.

PMID- 10601951
TI  - Laparoscopically assisted vaginal hysterectomy compared with total abdominal
      hysterectomy.

PMID- 10601953
TI  - Incidence of morbidity.

PMID- 10601955
TI  - Does the use of mean or median Z-score of the thyroid volume indices provide a
      more precise description of the iodine deficiency disorder status of a
      population?
AB  - Endemic iodine deficiency is largely an environmental problem affecting whole
      populations. Currently, thyroid volume data from a population are analyzed with
      the sole objective of obtaining an estimate of goitre prevalence using +97th
      percentile or +2 standard deviations of an appropriate reference as cut-off. This
      paper proposes an alternative approach to the analysis and presentation of
      thyroid volume data using Z-scores (standard deviation scores) of the thyroid
      volume indices such as thyroid volume-for-age or thyroid volume-for-body surface
      area. The calculation of the summary statistics of the Z-scores, such as mean or
      median, provides an alternative to the prevalence-based approach for expressing
      severity of iodine deficiency disorders (IDD). An advantage of the mean or median
      Z-score is that it describes the thyroid volume profile (and therefore the IDD
      status) of the entire population directly, unlike goitre prevalence which gives
      information only about the extremes of distribution. The frequency curve or
      histogram of the Z-scores provides a complete picture of the whole distribution.
      Although qualitatively similar conclusions on IDD severity can be drawn from both
      analytical approaches, only the Z-score system is able to capture adequately the
      trends or changes in thyroid size over time, and to establish whether a
      previously iodine-deficient community's thyroid volume profile has returned to
      'normal' (as indicated by a distribution that is not significantly different from
      that of the reference) following intervention. As a continuous variable, Z-scores
      are particularly useful for the analysis of data from populations where the
      sample size is relatively small, or where many individuals lie outside the
      extreme percentiles of the reference population. In view of its advantages in the
      context of activities based on single and multiple measurements, the Z-score
      system is to be preferred for the reporting and use of thyroid volume indices. A
      desirable consequence of this preference is that national goals will be oriented
      towards an improvement of the overall thyroid volume profile of the population,
      rather than just a reduction of the number of individuals at the extremes.

PMID- 10601956
TI  - Hope for insulin mimetic oral antidiabetic drugs.

PMID- 10601957
TI  - Multicenter study on TGPO autoantibody prevalence in various thyroid and non
      thyroid diseases; relationships with thyroglobulin and thyroperoxidase
      autoantibody parameters.
AB  - OBJECTIVE: TGPO autoantibodies (aAbs) that bind simultaneously to thyroglobulin
      (Tg) and thyroperoxidase (TPO) are present in the serum of patients with
      autoimmune thyroid diseases (AITD) and have been found to differ from
      monospecific Tg and TPO aAbs. To obtain further insights on the prevalence
      defined as the rate of occurrence and significance of TGPO aAbs in a large
      population, we carried out a collaborative study involving 15 European teams.
      METHODS: Serum samples from 3122 patients with various thyroid and non-thyroid
      diseases and normal subjects were assayed using a novel TGPO aAb detection kit.
      This test was designed so that TGPO aAbs are trapped between the Tg-coated solid
      phase and the soluble TPO labeled with a radioiodinated monoclonal antibody.
      RESULTS: Only three out of the 220 normal subjects (prevalence of 1.4%) were
      found to have positive TGPO aAb levels, which were mainly observed in the
      patients with AITD: the group of patients suffering from Hashimoto's thyroiditis
      had a TGPO aAb prevalence of 40.5% (n=437 patients), those with Graves' disease,
      a prevalence of 34.6% (n=645) and those with post-partum thyroiditis, 16.0%
      (n=243). Among the non-AITD patients with positive TGPO aAb levels, the TGPO aAb
      prevalence ranged from 20.7% among those with thyroid cancer (n=246) to 0% among
      those with toxic thyroid nodules (n=47). Among the patients with non-thyroid
      diseases, the TGPO aAb prevalence ranged from 9.8% in the case of Biermer's
      pernicious anemia (n=78) to 0% in that of premature ovarian failure (n=44). It is
      worth noting that the groups showing the highest TGPO aAb prevalence also
      contained the patients with the highest TGPO aAb titers. Statistical comparisons
      between the TGPO aAb prevalences in the various groups showed that TGPO aAb could
      be used as a parameter to distinguish between the groups of Hashimoto's and
      Graves' patients and between the women with post-partum thyroiditis and the post
      partum women with only Tg and/or TPO aAb established during early pregnancy.
      Unexpectedly, the correlations between TGPO aAbs and Tg and TPO aAbs were found
      to depend mainly on the assay kit used. CONCLUSION: High TGPO aAb titers are
      consistently associated with AITD but the reverse was not found to be true. TGPO
      aAbs are a potentially useful tool, however, for establishing Hashimoto's
      diagnosis, and would be worth testing in this respect with a view to using them
      for routine AITD investigations.

PMID- 10601958
TI  - Maternal compound W serial measurements for the management of fetal
      hypothyroidsm.
AB  - OBJECTIVE: The diagnosis of fetal hypothyroidism is based at present on
      measurements of TSH and free thyroxine (FT4) in fetal blood samples obtained by
      cordocentesis. The measurement of maternal serum and urinary concentrations of
      compound W, immunologically similar to but chromatographically distinct from
      diiodothyronine sulfate (T2S), has been advocated as a new possible marker for
      fetal hypothyroidism. DESIGN: In this paper, we measured serum compound W levels
      in 84 pregnant women, 20 with and 64 without thyroid disorders before and during
      specific treatment. Compound W was also assessed in fetal blood obtained by
      cordocentesis from 49 normal fetuses and 4 fetuses with suspected hypothyroidism
      due to transplacental passage of propylthiouracil (PTU). Compound W levels were
      measured by T2S RIA in maternal and fetal serum. To assess the possible
      usefulness of 3, 5,3'-triiodothyroacetic acid (TRIAC) for therapy of fetal
      hypothyroidism we evaluated the transplacental passage of TRIAC by administering
      the drug to four pregnant women before therapeutic abortion. RESULTS: In normal
      pregnancies, both maternal and fetal compound W levels increased progressively
      during gestation with a significant direct correlation (P<0.001, in both mothers
      and fetuses). Moreover, a significant positive correlation was observed between
      fetal compound W and fetal FT4 values (P<0.005), whereas no correlation was
      observed between maternal serum compound W and maternal FT4 in either euthyroid
      or hyperthyroid women, suggesting the fetal origin of compound W. The hypothyroid
      fetuses of PTU-treated mothers showed low compound W levels, and maternal
      compound W values were in the low normal range and did not show the typical
      increase during progression of gestation. A significant increase of maternal
      compound W was observed when the PTU dose was reduced. TRIAC was documented to
      cross the placental barrier and the treatment of a hyperthyroid pregnant woman on
      PTU caused the high fetal TSH levels and goiter to normalize. CONCLUSIONS: Serial
      measurements of 3,3'-T2S crossreactive materials (compound W and 3, 3'
      diiodothyroacetic acid sulfate) in maternal blood and the administration of TRIAC
      to the mother may represent a useful and safe alternative to invasive techniques
      for the diagnosis and therapy of fetal hypothyroidism.

PMID- 10601959
TI  - Hormonal changes during the first year of oestrogen treatment in constitutionally
      tall girls.
AB  - OBJECTIVE: Oestrogens are used to inhibit growth in girls with constitutionally
      tall stature. We studied the changes in different hormones that accompany such
      therapy. SUBJECTS AND METHODS: In this longitudinal study we examined the levels
      of total insulin-like growth factor-I (IGF-I), free thyroxine (FT(4)),
      thyrotrophin (TSH), testosterone, dehydroepiandrosterone sulphate (DHEA-S),
      cortisol and prolactin in two groups of girls receiving ethinyloestradiol at a
      dose of either 0.1mg daily (group A, n=22) or 0.2mg daily (group B, n=36).
      Hormonal measurements were performed at start of therapy and after 3, 6 and 12
      months. RESULTS: In both groups the levels of IGF-I, testosterone and DHEA-S were
      reduced while the concentrations of cortisol and prolactin were increased. The
      pituitary-thyroid axis was not significantly affected by this therapy. The girls
      receiving 0.2mg ethinyloestradiol daily had lower IGF-I levels after 12 months of
      therapy and had higher serum prolactin concentrations than the girls treated with
      0.1mg daily. The reduction in predicted height and the advancement in bone age
      were similar in both groups. CONCLUSIONS: Therapy with pharmacological doses of
      ethinyloestradiol changes the levels of several hormones including IGF-I,
      testosterone, DHEA-S, prolactin and cortisol but the role of the respective
      changes in the inhibition of growth is not clear. The suppression of DHEA-S
      levels by 40% suggests that the ovaries contribute significantly to the
      production of this hormone in pubertal girls.

PMID- 10601960
TI  - The phosphorylation status of insulin-like growth factor-binding protein-1 in
      prepubertal obese children.
AB  - OBJECTIVE: We measured the total and nonphosphorylated insulin-like growth factor
      binding protein (IGFBP)-1 concentrations in obese children to determine the
      effect of obesity on the status of IGFBP-1 phosphorylation. We also measured the
      serum levels of insulin, total and free IGF-I, and IGFBP-3 to investigate their
      relationships to the IGFBP-1 phosphorylation status in obese subjects. SUBJECTS
      AND METHODS: Nineteen prepubertal obese and 15 age-matched control children were
      included in the study. The serum levels of total and nonphosphorylated IGFBP-1
      were determined by noncompetitive RIAs. RESULTS: The serum levels of total and
      nonphosphorylated IGFBP-1 were significantly lower in the obese group (48.7+/-5.6
      microgram/l, P<0.001 and 11.1+/-1.9 microgram/l, P<0.01 respectively) than in the
      controls (86.7+/-9.0 microgram/l and 28.8+/-6.2 microgram/l respectively).
      However, the ratio of nonphosphorylated IGFBP-1 to total IGFBP-1 did not differ
      significantly between the obese and control groups. The circulating free IGF-I
      level was significantly higher in the obese children than in the controls
      (P<0.05), while the serum levels of insulin, total IGF-I and IGFBP-3 were not
      significantly different between the two groups. A stepwise regression analysis of
      the combined group revealed that only the total IGFBP-1 level was an independent
      predictor of the free IGF-I concentration (P<0.001). CONCLUSION: The present
      study shows that both total and nonphosphorylated IGFBP-1 concentrations are
      decreased in obese children and the increased free IGF-I level in obese children
      is related to the reduced total IGFBP-1 level, but unrelated to the change in the
      IGFBP-1 phosphorylation status.

PMID- 10601961
TI  - Differing effects on gall-bladder motility of lanreotide SR and octreotide LAR
      for treatment of acromegaly.
AB  - BACKGROUND: Octreotide treatment may be associated with gall stone development in
      up to 50% of patients with acromegaly. Two new sustained-release formulations of
      somatostatin analogue have been recently developed: lanreotide SR (Somatuline)
      and octreotide LAR (Sandostatin LAR). The incidence of gall-stone development in
      patients receiving these drugs has been shown to be less than 20%, but the
      duration of follow-up has been limited. OBJECTIVE: Prospectively to assess and
      compare the effects of the two new long-acting somatostatin agonists on gall
      bladder motility in patients with acromegaly. METHOD AND PATIENTS: Eleven
      patients with active acromegaly were studied. Three patients had asymptomatic
      gall stones at the start of the study. Ultrasound scans were performed before
      commencement of the treatment, and repeated during treatment with lanreotide SR
      and octreotide LAR. The presence of gall stones, fasting gall bladder volume
      (FV), residual volume (RV) and maximal percentage gall bladder emptying were
      measured. RESULTS: One patient developed asymptomatic small gall stones after
      treatment with octreotide LAR for 4 months. FV and RV were both significantly
      larger when patients received treatment with lanreotide SR or octreotide LAR
      compared with pretreatment values (P<0.05 for both). Maximal percentage gall
      bladder emptying was significantly reduced in patients receiving lanreotide SR or
      octreotide LAR compared with pretreatment (P<0.01), but was less impaired in
      patients receiving lanreotide SR than in those receiving octreotide LAR (P<0.01).
      CONCLUSIONS: Gall bladder motility is impaired in patients receiving either of
      these new long-acting preparations, and long-term follow-up will be needed to
      establish the true incidence of gall stones.

PMID- 10601962
TI  - GH deficiency in adults: an epidemiological approach.
AB  - OBJECTIVE: The prevalence of adult onset GH deficiency (GH-D) is poorly
      documented. Epidemiological data are now required to estimate the financial cost
      of GH treatment in adults. The aim of the present study was to estimate the
      prevalence of GH-D, from a cohort of 1652 adult patients with hypothalamo
      pituitary diseases. DESIGN: The hormonal status of all patients presenting with
      pituitary diseaseand observed during the year 1994 in 15 endocrine units was
      retrospectively analyzed, irrespective of the date of disease onset, of the
      nature and date of pituitary investigations, and whether or not they included
      specific testing of the GH axis. Of the whole population of 1652 patients, a
      selected group (RG2) was chosen after exclusion of patients with active
      acromegaly (n=1414). RESULTS: GH stimulation tests had been performed in 549
      patients of the RG2 group and a documented GH-D was found in 301. A relationship
      between the value of the GH peak and the number of pituitary deficits was
      evaluated. For instance, it was shown that 93% of patients with three deficits
      had GH-D. These results constituted the basis for estimating the number of GH-D
      in the group of untested patients. The number of GH-D deduced from the number of
      established GH-D (n=301) and from the number of GH-D hypothesized from other
      pituitary deficits (n=406) was 707 cases. Prevalence and annual incidence were
      calculated from data recorded in a referral center with a well-defined catchment
      area, Marseilles (Bouches du Rhone department). We projected a prevalence of 2638
      for France and an annual incidence of 12 GH-D per million of the adult
      population.

PMID- 10601963
TI  - Impact of gender and androgen status on IGF-I levels in normal and GH-deficient
      adults.
AB  - OBJECTIVE: The regulation of IGF-I levels is complex and not only dependent on GH
      status, as the diagnostic sensitivity of serum IGF-I levels for GH deficiency
      (GHD) in adults is low. Other GH-related parameters have so far not proven to be
      of additional diagnostic value in GHD adults. In the present study we evaluated
      the impact of gender and androgen status on IGF-I levels and the diagnostic value
      of IGF-I and GH-related parameters in a population of adult hypopituitary
      patients and age- and gender-matched healthy subjects. DESIGN: A cross-sectional
      study. SUBJECTS: Fifty-nine GHD patients (40 males, mean age 39.3+/-1.7 (s.e.m.)
      years, and 19 females, mean age 41.9+/-2.6 years) and 69 healthy subjects (42
      males, mean age 36. 7+/-1.5 years, and 27 females, mean age 38.9+/-2.1 years).
      RESULTS: IGF-I levels were low in the GHD patients (91+/-7 vs 173+/-7
      microgram/l, P<0.001), and lower in female patients than in male (68+/-10 vs
      100+/-8 microgram/l, P=0.03). In the control group there was no gender-related
      difference in IGF-I levels (males: 178+/-8, females: 164+/-12 microgram/l,
      P=0.23). IGF-II and IGF-binding protein-3 (IGFBP-3) were also decreased in GHD
      without any gender-related differences. GH-binding protein (GHBP) levels were
      increased in the patient group. The diagnostic sensitivity (%) of IGF-I, IGF
      I/GHBP, IGF-I/IGFBP-3, and of the combination of IGF-I plus IGF-II (both low or
      one normal and one low), was higher in female patients than in male (IGF-I: 57.8
      vs 22.0, P<0.0001; IGF-I/GHBP: 84.2 vs 48.8, P=0. 002; IGF-I/IGFBP-3: 36.8 vs 7.3
      P=0.001; IGF-I+IGF-II: 77.8 vs 52.6, P=0.01). Testosterone levels were reduced in
      the female patients compared with female controls (0.5+/-0.3 vs 2.1+/-0.2nmol/l,
      P<0.001). Forward regression analyses revealed that IGFBP-3 was a significant
      predictor of IGF-I levels in both patients and healthy subjects. In a combined
      analysis of both patients and controls, sex hormone-binding globulin (SHBG) level
      was the main contributor as an explanatory variable. Gender and prolactin also
      predicted IGF-I in patients, whereas SHBG and estradiol were significant
      predictors only in the control group. CONCLUSION: (i) Levels of IGF-I, and of IGF
      I/IGFBP-3 and IGF-I/GHBP ratios are lower in females compared with male adult GHD
      patients. (ii) IGF-I/GHBP has a high diagnostic sensitivity of adult GHD, in
      particular in women. (iii) We hypothesize that the gender difference in IGF-I
      levels among adult GHD patients are causally related to the very low androgen
      levels observed among females.

PMID- 10601964
TI  - Insulin secretion and insulin sensitivity in diabetic and non-diabetic subjects
      with hepatic nuclear factor-1alpha (maturity-onset diabetes of the young-3)
      mutations.
AB  - OBJECTIVE: To evaluate insulin secretion and sensitivity in affected (diabetes
      mellitus or impaired glucose tolerance; n=7) and in unaffected (normal glucose
      tolerance; n=3) carriers of hepatocyte nuclear factor-1alpha (maturity-onset
      diabetes of the young-3 (MODY3)) gene mutations. METHODS: Insulin secretion was
      assessed by an i.v. glucose tolerance test (IVGTT), hyperglycemic clamp and
      arginine test, and insulin sensitivity by an euglycemic hyperinsulinemic clamp.
      Results were compared with those of diabetic MODY2 (glucokinase-deficient) and
      control subjects. RESULTS: The amount of insulin secreted during an IVGTT was
      decreased in affected MODY3 subjects (46+/-24 (s.d.) pmol/kg body weight (BW)) as
      compared with values in MODY2 (120+/-49pmol/kg BW) and control (173+/-37pmol/kg
      BW; P=0.0004) subjects. The amount of insulin secreted during a 10mmol/l glucose
      clamp was decreased in affected MODY3 subjects (171+/-78pmol/kg BW) and MODY2
      subjects (302+/-104pmol/kg BW) as compared with control subjects (770+/
      199pmol/kg BW; P=0.0001). Insulin secretion in response to arginine was decreased
      in affected MODY3 subjects. Milder and heterogeneous defects were observed in the
      unaffected MODY3 subjects; the amount of insulin secreted during the
      hyperglycemic clamp was 40-79% of that of controls. The response to arginine was
      abnormally delayed. Insulin sensitivity was decreased in diabetic but not in non
      diabetic MODY3 subjects. CONCLUSIONS: Beta-cell dysfunction in response to
      glucose and arginine is observed in affected and unaffected MODY3 subjects. The
      MODY3 and MODY2 subtypes present different insulin secretion profiles. Secondary
      insulin resistance might contribute to the chronic hyperglycemia of MODY3
      patients and modulate their glucose tolerance.

PMID- 10601965
TI  - Pheochromocytoma in Italy: a multicentric retrospective study.
AB  - OBJECTIVE: To conduct an epidemiological study on pheochromocytoma in Italy.
      METHODS: Data on 284 patients with pheochromocytoma observed between 1978 and
      1997 were collected from 18 Italian centers through a questionnaire reporting
      epidemiological, clinical, laboratory, radiological and surgical data. RESULTS:
      53.6% of the patients were females and 46.4% were males. Thirty-two tumors were
      discovered as incidental adrenal masses. The most frequent referred symptoms were
      palpitations (58.1%), headache (51.9%), sweating (48. 8%) and anxiety (35.3%).
      Their association was present only in 15.5% of patients. Paroxysmal symptoms were
      reported in 67.1% and hypertensive crises in 59.7% of patients. Normal blood
      pressure (systolic and diastolic) was present both in the supine and upright
      positions in 21.1% of patients. Among laboratory assays, urinary vanylmandelic
      acid (VMA) was the most widely used (58.1%) and was the least sensitive (25% of
      false negative results). Basal plasma catecholamines were found to be normal in
      11.3% of patients but were always elevated when sampled during a hypertensive
      paroxysm. A clonidine suppression test was performed in 38 patients with no
      adverse side effects. It gave a false negative response in 2 patients. A glucagon
      test was performed in 21 patients. It was interrupted for acute hypertension in
      52.4% of patients. Only 5/21 patients were normotensive and had normal basal
      plasma catecholamines. In these patients the test gave a positive response in
      four (80%). CT (79.6%) and I-MIBG scintigraphy (68.5%) were the most widely used
      methods for tumor localization. CT sensitivity was 98.9% for intra-adrenal and
      90.9% for extra-adrenal tumors. MIBG sensitivity was 88.5%. In the 263 patients
      who underwent surgery, the tumor was intra-adrenal in 89.4%, extra-adrenal in
      8.5%, intra- and extra-adrenal in 2.1%, and bilateral in 11.0% of patients.
      Malignancy was reported in 9.9% of cases. Surgery caused remission of
      hypertension in 59.3%, improvement in 26.8%, and no changes in 13. 9% of
      patients. In the last group the interval between initial symptoms and diagnosis
      was significantly longer. CONCLUSIONS: The present study confirms that the
      clinical presentation of pheochromocytoma is variable and aspecific. Normotension
      is often present and often the tumor is discovered incidentally. An indication
      for the routine use of screening methods more sensitive than urinary VMA is
      strongly suggested. The clonidine test was found to be safe and should be
      preferred to the glucagon test which has to be restricted to very selected
      patients. CT and MIBG scintigraphy are almost always successful in localizing the
      tumor. Reversal of hypertension by surgery seems to depend on an early diagnosis.

PMID- 10601966
TI  - Dendritic cells produce interleukin-12 in hyperthyroid mice.
AB  - We previously reported that serum interleukin-12 (IL-12) levels were
      significantly increased in patients with hyperthyroid Graves' disease and in
      normal subjects after administration of thyroid hormone. In the present study, we
      investigated which cells produce IL-12 and the interactions between IL-12 and
      thyroid hormones, using a hyperthyroid mouse model. Thyroid hormones induced IL
      12 production, and IL-12 was mainly produced by dendritic cells outside the
      thyroid glands in a hyperthyroid state.

PMID- 10601967
TI  - Dual control of cytochrome-c oxidase activity by female sex steroids.
AB  - Female sex steroids modify cytochrome-c oxidase (COX) activity in brown adipose
      tissue. To check the possibility of extending this modulating effect upon
      oxidative capacity to other tissues, COX activity was measured in different
      tissues from cold-acclimated female rats that were (1) intact in proestrus and
      diestrus I, (2) ovariectomized or (3) ovariectomized and treated with oestradiol
      and/or progesterone. In intact rats, COX activity varied within the oestrous
      cycle in brown adipose tissue and soleus muscle. Ovariectomy induced an increase
      in COX activity in most of the tissues studied, an increase reversed only after
      10 days of treatment with oestradiol and/or progesterone. These results indicate
      both a short-term (oestrous cycle) and a long-term (ovariectomy) control of COX
      activity by female sex steroids, probably mediated by allosteric modulation and
      control of the enzyme synthesis respectively. In thermogenic tissues, that is
      brown adipose tissue and skeletal muscles, the short-term control is interpreted
      as a cooperation between tissues to fulfil the requirements of temperature
      maintenance.

PMID- 10601968
TI  - Thyroid hormone and retinoic acid induce the synthesis of insulin-like growth
      factor-binding protein-4 in prepubertal pig sertoli cells.
AB  - A large body of evidence suggests the existence of an intratesticular IGF system
      complete with ligands, receptors and binding proteins (IGFBPs); the aim of the
      present study was to evaluate tri-iodothyronine (T(3)) and retinoic acid (RA)
      effects on IGFBP production by Sertoli cells. A significant dose-dependent
      increase in IGFBP-4 mRNA levels was observed in Sertoli cells cultured in the
      presence of physiological concentrations of T(3) or RA. This response was
      inhibited by cycloheximide, indicating that de novo protein synthesis is
      required, as well as by actinomycin D, suggesting that the increase in mRNA
      levels requires transcriptional activation. As shown by ligand blot assays the
      stimulatory effects of both agents on IGFBP-4 mRNA expression appears to be
      consistent with an enhanced synthesis and secretion of IGFBP-4, thus suggesting
      that the transcriptional response is transduced to the protein level. Our data
      establish an important direct role for T(3) and RA in regulating IGFBP-4
      expression and consequently IGF activity at the testis level.

PMID- 10601969
TI  - Expression of Reg and cytokeratin 20 during ductal cell differentiation and
      proliferation in a mouse model of autoimmune diabetes.
AB  - OBJECTIVE: To evaluate the existence of beta-cell differentiation and
      proliferation in the low-dose streptozotocin (ld-STZ) mouse model of autoimmune
      diabetes. DESIGN: We studied the expression of Reg protein and cytokeratin 20
      (CK20), the presence of proliferative phenomena (judged by the incorporation of
      bromodeoxyuridine (BrdU)), and the co-expression of Reg, CK20 or BrdU with
      insulin. MATERIALS AND METHODS: Diabetes was induced in male C57Bl6/J mice by
      administration of ld-STZ. The animals were killed at days 10 and 23 from the
      beginning of the induction of disease. Five animals were used at each time point
      and each group was evaluated for blood glucose concentrations, insulitis,
      expression of Reg and CK20 pancreatic proteins and BrdU incorporation, together
      with staining for insulin by immunohistochemistry and laser confocal microscopy.
      RESULTS: All mice treated with ld-STZ were hyperglycemic and histological
      investigation showed a mild or severe insulitis both at day 10 and at day 23. At
      day 10, immunochemistry revealed an intense expression of Reg and CK20 in
      pancreatic ducts in ld-STZ mice, but not in control mice. Reg and CK20
      immunoreactive cells were also positive for insulin. In contrast, at day 23,
      pancreatic sections reacted weakly with anti-Reg and anti-CK20 antibody; co
      localization with insulin was observed for both Reg and CK20. The incorporation
      of BrdU was observed only in insulin-positive cells in pancreatic sections from
      mice killed at day 10. CONCLUSIONS: These observations show an islet regeneration
      mechanism in response to an autoimmune attack, and that the ld-STZ mouse is a
      suitable model in which to evaluate intervention strategies.

PMID- 10601970
TI  - Pheochromocytoma combined with unusual form of Cushing's syndrome and pituitary
      microadenoma.

PMID- 10601971
TI  - Cabergoline and gallbladder motility in healthy men.

PMID- 10601972
TI  - Nuclear receptors: coactivators, corepressors and chromatin remodeling in the
      control of transcription.
AB  - A contemporary view of hormone action at the transcriptional level requires
      knowledge of the transcription factors including the hormone receptor that may
      bind to promoters or enhancers, together with the chromosomal context within
      which these regulatory proteins function. Nuclear receptors provide the best
      examples of transcriptional control through the targeted recruitment of large
      protein complexes that modify chromosomal components and reversibly stabilize or
      destabilize chromatin. Ligand-dependent recruitment of transcriptional
      coactivators destabilizes chromatin by mechanisms including histone acetylation
      and contacts with the basal transcriptional machinery. In contrast, the
      recruitment of corepressors in the absence of ligand or in the presence of
      hormone antagonists serves to stabilize chromatin by the targeting of histone
      deacetylases. Both activation and repression require the action of other
      chromatin remodeling engines of the switch 2/sucrose non-fermentable 2
      (SWI2/SNF2) class. Here we summarize this information and integrate hormone
      action into a chromatin context.

PMID- 10601973
TI  - Complex mediation of uterine endometrial epithelial cell growth by insulin-like
      growth factor-II (IGF-II) and IGF-binding protein-2.
AB  - The coexpression of IGF (-I and -II) peptides, corresponding receptors, and IGF
      binding proteins (IGFBPs) in uterine endometrium suggests that a significant
      component of IGF action in this tissue is via autocrine or paracrine pathways, or
      both. The present study examined whether IGF-II and a major uterine-expressed IGF
      II binding protein, IGFBP-2, modulate endometrial epithelial cell mitogenesis.
      Serum-deprived porcine endometrial glandular epithelial (GE) cells of early
      pregnancy were treated with various concentrations of IGFs, recombinant porcine
      (rp) IGFBP-2, or both, and examined for changes in cellular mitogenesis by
      incorporation of [(3)H]thymidine into DNA. Recombinant human (rh) IGF-II
      stimulated DNA synthesis in a dose-dependent manner. Human [Leu(27)]-IGF-II, an
      analog with selective affinity for the IGF-II (type II) receptor, increased
      thymidine uptake by twofold compared with untreated GE cells. When added in
      combination with an equimolar concentration of rhIGF-I, [Leu(27)]-IGF-II or rhIGF
      II stimulated thymidine incorporation to a greater extent than did rhIGF-I alone.
      Ligand blot analysis of GE cell conditioned medium revealed the presence of four
      IGFBPs with molecular masses of 48, 31, 23, and 15 kDa. Physiological
      concentrations of rpIGFBP-2 (nM range) increased both basal and IGF-induced DNA
      synthesis in GE cells. At equimolar concentrations, Des(1-6)IGF-II (an IGF-II
      analog with much reduced affinity for IGFBPs) and rpIGFBP-2 had additive effects
      on GE cell mitogenesis, suggesting that the IGFBP-2 modulation of uterine cell
      growth may involve both IGF-dependent and IGF-independent pathways. Our results
      demonstrate the complex interplay of IGF system components in uterine endometrial
      epithelial growth regulation in vitro, identify IGF-II and IGFBP-2 as locally
      coexpressed uterine epithelial cell mitogens, and suggest the presence of a
      functional signaling pathway by which IGF-II stimulates epithelial cell
      proliferation via the type II receptor.

PMID- 10601974
TI  - Structural and functional analysis of the promoter of a mouse gene encoding an
      androgen-regulated protein (MSVSP99).
AB  - MSVSP99 (mouse seminal vesicle secretory protein of 99 amino acids) is a member
      of the rat and mouse seminal vesicle secretory protein family. The gene encoding
      MSVSP99 is under androgenic control and we demonstrate here that this regulation
      involves a complex interplay of positive and negative regions. First, we show
      that the promoter region (-387/+16) sufficient to mediate a full androgen
      induction is a complex enhancer organized in two regulatory regions. These two
      regions are inactive individually and must act together to confer a 40-fold
      androgen induction to the MSVSP99 gene and androgen responsiveness is not only
      dependent on the presence of functional androgen response element (ARE) sequences
      but results from complex cooperations between ARE and non-ARE sequences forming
      an androgen response unit. Secondly, we characterized a new regulatory region (
      824/-632) that decreases androgen-dependent transcriptional activity of the
      MSVSP99 promoter. This region, also able to repress the transcriptional activity
      of the heterologous thymidine kinase promoter, contains a functional promoter on
      the inverted strand (-826 to -387) and we identified a transcription initiation
      site located at position -639 with respect to the cap site of the MSVSP99
      promoter. Sequence analysis of the flanking DNA also revealed that the MSVSP99
      gene is surrounded by long interspersed repeated sequences called LINEs.

PMID- 10601975
TI  - A novel mechanism for the melatonin inhibition of testosterone secretion by rat
      Leydig cells: reduction of GnRH-induced increase in cytosolic Ca2+.
AB  - The site of inhibition, by melatonin, of GnRH-dependent testosterone secretion
      was investigated in adult rat Leydig cells cultured in vitro. The various effects
      downstream of the binding of GnRH to its own receptor were isolated and mimicked
      by specific drugs. Testosterone secretion was then evaluated after 3 h
      stimulation with GnRH, thapsigargin (1 microM), phorbol-12-myristate-13-acetate
      (100 nM), arachidonic acid (20 microM), and ionomycin (1 microM) in the presence
      or absence of melatonin (215 nM). The effect of melatonin on the GnRH-induced
      changes in cytoplasmic calcium concentration ([Ca(2+)](i)) was also studied,
      using Fura-2 as fluorescent Ca(2+) indicator. Melatonin attenuated the increase
      in [Ca(2+)](i) and inhibited the testosterone secretion induced by GnRH, but not
      that induced by ionomycin. Both ionomycin and thapsigargin potentiated GnRH
      induced testosterone secretion; however, ionomycin, but not thapsigargin,
      partially prevented the inhibitory effect of melatonin on cells stimulated with
      GnRH. The effect of melatonin was probably dependent on the binding of melatonin
      to its Gi-protein-coupled receptor, as the inhibitory effect on GnRH-induced
      secretion was supressed in cells pretreated with pertussis toxin in a
      concentration of 180 ng/ml for 20 h. Assay of 17-hydroxy-progesterone showed
      that, irrespective of the treatment, cells cultured with melatonin secreted
      greater amounts than controls. We conclude that melatonin reduces GnRH-induced
      testosterone secretion by 1) decreasing [Ca(2+)](i), through impairment of the
      GnRH-dependent release of Ca(2+) from intracellular stores and 2) blocking 17-20
      desmolase enzymatic activity, an effect that occurs irrespective of changes in
      [Ca(2+)](i).

PMID- 10601976
TI  - Effects of complexation with in vivo enhancing monoclonal antibodies on activity
      of growth hormone in two responsive cell culture systems.
AB  - We describe the properties of three monoclonal antibodies (MAbs) to ovine GH, two
      of which have previously been shown to enhance, in vivo, the biological activity
      of bovine and ovine growth hormone. We have examined the effects of these MAbs on
      GH activity in two appropriate GH-responsive cell culture systems, investigating
      both acute signalling effects (Janus-activated kinase (Jak)-2 tyrosine
      phosphorylation -5 min) and longer-term (MTT-formazan production -24 h) effects
      of hormone-antibody complexes. In the 3T3-F442A pre-adipocyte cell line (which
      has been demonstrated to be GH responsive), we show that complexation of
      recombinant bovine (rb) GH with either of the two enhancing anti-ovine GH MAbs
      (OA11 and OA15) and the non-enhancing MAb, OA14, attenuates the ability of GH to
      stimulate tyrosine phosphorylation of Jak-2 at a 5-min time point. Using the
      mouse myeloid cell line, FDC-P1, stably transfected with the full-length ovine GH
      receptor (oGHR), we demonstrate that rbGH causes a dose-dependent increase in MTT
      formazan production by these cells. Further, we demonstrate that OA11 and OA14,
      but not OA15, cause a decrease in this stimulatory activity of rbGH over a
      hormone concentration range of 5-50 ng/ml at both 24 and 48 h. We conclude that
      the different in vitro activities of the two in vivo enhancing MAbs are most
      probably related to the time-courses over which these two assays are performed,
      and also to the relative affinities between antibody, hormone and receptor. In
      addition, the in vitro inhibitory activity of the enhancing MAb OA11 in both
      short- and long-term bioassay lends further support to an exclusively in vivo
      model for MAb-mediated enhancement of GH action.

PMID- 10601977
TI  - Regulation of thyrotropin receptor protein expression in insect cells.
AB  - Expression of large quantities of conformationally intact thyrotropin receptor
      (TSHR) is essential to understand the structure-function relationship of the
      receptor. We expressed three different constructs of full-length human TSHR in
      insect cells: (a) a TSHR cDNA lacking signal sequence (TSHR-ns), (b) a TSHR cDNA
      containing human TSHR signal sequence (TSHR-hs) and (c) a TSHR cDNA with
      baculovirus envelope protein encoded signal sequence gp-67 (TSHR-gp). No unique
      protein band, corresponding to any of these recombinant proteins, was visible
      upon Coomassie Blue staining after SDS-PAGE. However, Western blot using TSHR
      specific monoclonal antibody showed unique bands around 80, 100 and 100 kDa in
      TSHR-ns, TSHR-hs and TSHR-gp virus infected insect cells respectively. All three
      full-length TSHR proteins could neutralize the TSH binding inhibitory
      immunoglobulin (TBII) activity from sera of experimental animals. However, only
      glycosylated proteins (TSHR-hs and TSHR-gp) neutralized the TBII activity of sera
      from autoimmune thyroid patients, confirming the importance of glycosylation for
      patient autoantibody reactivity. Expression levels of full-length TSHR proteins
      were much lower than the levels of similarly produced corresponding ectodomains
      of TSHR proteins. Southern blot and Northern blot analyses showed that DNA and
      RNA levels in full-length TSHR virus infected insect cells were comparable to the
      levels found in cells infected with viruses encoding only the ectodomain of TSHR.
      These data suggest that full-length TSHR expression is very low and is regulated
      at the translational level.

PMID- 10601978
TI  - Variant estrogen receptor-alpha messenger RNA expression in hormone-independent
      human breast cancer cells.
AB  - T5-PRF cells are insensitive to the growth-stimulatory effects of estrogen while
      still retaining expression of estrogen receptor-alpha (ER-alpha). In the apparent
      absence of ligand, T5-PRF cells have a 3. 6+/-0.5 (s.e.m.)-fold increased basal
      ER-alpha activity and elevated basal progesterone receptor levels compared with
      the parent, estrogen-sensitive, T5 cells. Long-range ER-alpha reverse
      transcription-PCR was performed to characterize variant ER-alpha mRNA expression
      in the two cell lines. An increased relative expression of an exon 3/4-deleted ER
      alpha mRNA variant was found in T5-PRF. Recombinant expression of this ER-alpha
      variant resulted in significantly increased estrogen responsiveness, as well as a
      trend to increased basal ligand-independent activity when expressed with wild
      type ER-alpha in ER-negative cell lines, as well as significantly increasing both
      ligand-independent and estrogen-induced ER-alpha transcriptional activity when
      expressed in parental T5 cells. These results suggest a role for altered variant
      ER-alpha in ligand-independent activation of ER-alpha which may contribute to
      hormone independence in breast tumors.

PMID- 10601979
TI  - Activation of the mouse oxytocin promoter by the orphan receptor RORalpha.
AB  - Although an increasing number of nuclear orphan receptors have recently been
      identified, the number of known naturally occurring genes that are directly
      regulated by orphan receptors is still small. We have shown previously that the
      gene encoding the neuropeptide oxytocin (OT) is negatively regulated by the
      orphan receptors chicken ovalbumin upstream transcription factor I (COUP-TFI) and
      II. Here we show that the mouse OT gene promoter is activated by RORalpha, a
      representative of the ROR/RZR orphan receptor subfamily. Using
      promoter/chloramphenicol acetyltransferase reporter constructs in heterologous
      transfection assays, we determined that RORalpha action induces a <6-fold
      increase in promoter activity. By 5' and 3' deletion analysis, DNase footprint
      analysis and electrophoretic mobility shift assays, we found that RORalpha action
      is mediated by two 14 bp regions centered at 160 and 180 nucleotides upstream of
      the transcriptional initiation site. Both sites contain significant sequence
      identities with an established ROR recognition sequence. Mutations in either or
      both of these sites reduce significantly RORalpha-induced activation of the OT
      promoter. In view of the strong transcriptional activation exerted by RORalpha on
      the OT gene promoter and the widespread distribution of different members of the
      ROR/RZR family, interactions between ROR/RZR isoforms and the OT gene may form
      part of the multifactorial regulatory mechanisms that control OT gene expression
      in different tissues.

PMID- 10601980
TI  - Analysis of binding properties between 20 kDa human growth hormone (hGH) and hGH
      receptor (hGHR): the binding affinity for hGHR extracellular domain and mode of
      receptor dimerization.
AB  - It has recently been shown that 20 kDa human growth hormone (hGH) forms the 1:2
      hGH:hGH receptor (hGHR) complex and expresses full agonistic activity, although
      it hardly forms the 1:1 GH:GHR complex as compared with 22 kDa hGH. To clarify
      this mechanism, we analyzed the mode of receptor dimerization of 20 kDa hGH using
      the intact form and mutants. Complex formation analysis between hGHR
      extracellular domain (hGHBP) and either site1 mutant (K157A) or site2 mutant
      (G105R) by gel-filtration showed that the site1 mutant apparently formed no 1:1
      complex and that the site2 mutant formed only the 1:1 complex. Cell proliferation
      analysis revealed that the activity curve (vs ligand concentration) of 20 kDa hGH
      showed a bell-shaped pattern. This indicates that the receptor dimerization of 20
      kDa hGH proceeds in a sequential manner. Based on this sequential binding we have
      produced a mathematical model for receptor dimerization as a function of [hGH],
      [hGHBP], K(d) values for the first hGHBP binding (K(d1)) and the second hGHBP
      binding (K(d2)). The result of 20 kDa hGH binding to (S201C) hGHBP immobilized on
      biosensor tip showed that the K(d1) value was 1. 6x10(-8) M. Adopting this value
      as a constant in the function described above, we have obtained calculative hGHR
      dimerization curves vs hGH concentration. Since the K(d2) value could not be
      experimentally determined, the curves were simulatively obtained with varied
      K(d2) values. The simulated curve pattern coincided with the experimental result
      of the cell proliferation in Ba/F3-hGHR when the value 2.5x10(-10) M was adopted
      as K(d2). In conclusion, although the affinity of 20 kDa hGH for the first hGHR
      binding is reduced to one-tenth, that for the second binding is increased ten
      fold in comparison with those of 22 kDa hGH, indicating that 20 kDa hGH can be an
      effective hGH isoform in the presence of hGHBP.

PMID- 10601981
TI  - Analysis of the 5'-upstream regions of the human relaxin H1 and H2 genes and
      their chromosomal localization on chromosome 9p24.1 by radiation hybrid and
      breakpoint mapping.
AB  - Relaxins are known endocrine and autocrine/paracrine hormones that play a major
      role in reproduction. In the human there are two relaxin genes, H1 and H2 which
      share 90% sequence homology within their coding region. The biological and
      evolutionary significance of two highly homologous and biologically active human
      relaxins is unknown. In order to achieve a better understanding of the regulatory
      mechanisms involved in the differential expression of these two genes and to gain
      insight into their role(s) in the preterm premature rupture of the membranes, we
      have investigated the properties of their 5'-upstream regions and mapped them
      both by radiation hybrid and breakpoint mapping into the same chromosome 9p24.1
      locus. The 5' ends of these relaxin genes could be divided into a proximal highly
      homologous segment and a distal non-homologous region. Within the proximal region
      are contained several putative regulatory elements common to both genes,
      suggesting a similar regulatory mechanism. The clustering of the relaxin genes
      within the same chromosomal locus suggests that these genes may be under a common
      regulation. On the other hand, a distinct gene-specific regulation may also exist
      for the individual relaxin genes since cis elements specific to each gene were
      identified at their 5' ends. Moreover, the observed divergence at the distal
      region of their 5'-upstream sequences may provide the structural features that
      act as gene-specific transcription regulators. Since the two genes are highly
      homologous in both their coding and flanking regions, the divergence at the
      distal region of their 5' ends may be important in the regulation of these genes
      and in their involvement in the pathology of preterm birth.

PMID- 10601982
TI  - Evolution of coalitionary killing.
AB  - Warfare has traditionally been considered unique to humans. It has, therefore,
      often been explained as deriving from features that are unique to humans, such as
      the possession of weapons or the adoption of a patriarchal ideology. Mounting
      evidence suggests, however, that coalitional killing of adults in neighboring
      groups also occurs regularly in other species, including wolves and chimpanzees.
      This implies that selection can favor components of intergroup aggression
      important to human warfare, including lethal raiding. Here I present the
      principal adaptive hypothesis for explaining the species distribution of
      intergroup coalitional killing. This is the "imbalance-of-power hypothesis,"
      which suggests that coalitional killing is the expression of a drive for
      dominance over neighbors. Two conditions are proposed to be both necessary and
      sufficient to account for coalitional killing of neighbors: (1) a state of
      intergroup hostility; (2) sufficient imbalances of power between parties that one
      party can attack the other with impunity. Under these conditions, it is
      suggested, selection favors the tendency to hunt and kill rivals when the costs
      are sufficiently low. The imbalance-of-power hypothesis has been criticized on a
      variety of empirical and theoretical grounds which are discussed. To be further
      tested, studies of the proximate determinants of aggression are needed. However,
      current evidence supports the hypothesis that selection has favored a hunt-and
      kill propensity in chimpanzees and humans, and that coalitional killing has a
      long history in the evolution of both species.

PMID- 10601983
TI  - Lemur traits and Madagascar ecology: coping with an island environment.
AB  - The last decade's lemur research includes successes in discovering new living and
      extinct species and learning about the distribution, biogeography, physiology,
      behavior, and ecology of previously little-studied species. In addition, in both
      the dry forest and rain forest, long-term studies of lemur demography, life
      history, and reproduction, have been completed in conjunction with data on tree
      productivity, phenology, and climate. Lemurs contrast with anthropoids in several
      behavioral features, including female dominance, targeted female-female
      aggression, lack of sexual dimorphism regardless of mating system, sperm
      competition coupled with male-male aggression, high infant mortality,
      cathemerality, and strict seasonal breeding. Hypotheses to explain these traits
      include the "energy conservation hypothesis" (ECH) suggesting that harsh and
      unpredictable climate factors on the island of Madagascar have affected the
      evolution of female dominance, and the "evolutionary disequilibrium hypotheses"
      (EVDH) suggesting that the recent megafauna extinctions have influenced lemurs to
      become diurnal. These hypotheses are compared and contrasted in light of recent
      empirical data on climate, subfossils, and lemur behavior. New data on life
      histories of the rain forest lemurs at Ranomafana National Park give further
      support to the ECH. Birth seasons are synchronized within each species, but there
      is a 6-month distribution of births among species. Gestation and lactation
      lengths vary among sympatric lemurs, but all lemur species in the rain forest
      wean in synchrony at the season most likely to have abundant resources. Across
      species weaning synchrony seen in Ranomafana corroborates data from the dry
      forest that late lactation and weaning is the life history event that is the
      primary focus of the annual schedule. Lemur adaptations may assure maximum
      offspring survival in this environment with an unpredictable food supply and
      heavy predation. In conclusion, a more comprehensive energy frugality hypothesis
      (EFH) is proposed, which postulates that the majority of lemur traits are either
      adaptations to conserve energy (e.g., low basal metabolic rate (BMR), torpor,
      sperm competition, small group size, seasonal breeding) or to maximize use of
      scarce resources (e.g., cathemerality, territoriality, female dominance, fibrous
      diet, weaning synchrony). Among primates, the isolated adaptive radiation of
      lemurs on Madagascar may have been uniquely characterized by selection toward
      efficiency to cope with the harsh and unpredictable island environment.

PMID- 10601984
TI  - Interpreting sex differences in enamel hypoplasia in human and non-human
      primates: Developmental, environmental, and cultural considerations.
AB  - The purpose of this review is to provide a synoptic, critical evaluation of the
      evidence of, and potential etiological factors contributing to, sex differences
      in the expression of enamel hypoplasia (EH). Specifically, this review considers
      theoretical expectations and empirical evidence bearing on two central issues.
      The first of these is the impact of a theorized inherent male vulnerability to
      physiological stress on sex differences in EH. The second issue is the potential
      contribution to sex differences in EH of intrinsic differences in male and female
      enamel composition and development. To address this first issue, EH frequencies
      by sex are examined in samples subject to a high degree of physiological stress.
      Based on the concept of inherent male vulnerability (or female buffering), males
      in stressful environments would be expected to exhibit higher EH frequencies than
      females. This expectation is evaluated in light of cultural practices of sex
      biased investment that mediate the relationship between environmental stress and
      EH expression. Defects forming prenatally afford an opportunity to study this
      relationship without the confounding effects of sex-biased postnatal investment.
      Data bearing on this issue derive from previously conducted studies of EH in
      permanent and deciduous teeth in both modern and archaeological samples as well
      as from new data on Indian schoolchildren. To address the second issue,
      fundamental male-female enamel differences are evaluated for their potential
      impact on EH expression. A large sex difference in the duration of canine crown
      formation in non-human primates suggests that male canines may have greater
      opportunity to record stress events than those of females. This expectation is
      examined in great apes, whose canines often record multiple episodes of stress
      and are sexually dimorphic in crown formation times. With respect to the first
      issue, in most studies, sex differences in EH prevalence are statistically
      nonsignificant. However, when sex differences are significant, there is a slight
      trend for them to be greater in males than in females, suggesting a weak
      influence of greater male vulnerability. Cultural practices of sex-biased
      investment in children appear to have greater impact on EH expression than does
      male vulnerability/female buffering. With respect to the second issue, sex
      differences in the composition and development of enamel were reviewed and
      determined to have limited or unknown impact on EH expression. Of these factors,
      only the duration of crown formation was expected to affect EH expression by sex
      within the great apes. The data support an association between higher defect
      counts in the canines of great ape males relative to those of females that may be
      the result of longer crown formation times in the canines of great ape males.
      This review concludes with an assessment of the nature of the evidence currently
      available to examine these issues and suggests future avenues for research
      focused on elucidating them.

PMID- 10601985
TI  - Quantitative trait linkage mapping in anthropology.
AB  - Recent years have seen rapid progress in several areas of both biomedical and
      anthropological genetics. While genetic analyses have come to play a significant
      role in biological anthropology, there has been little use of modern methods for
      linkage mapping of quantitative trait loci (QTLs). It is now feasible to design
      research studies to investigate the quantitative genetics of complex phenotypes
      that are of primary importance to traditional questions in biological
      anthropology. Complex traits such as functionally significant morphological
      features, physiological characteristics or aspects of behavior can be examined to
      estimate the influence of genetic variation on within-species phenotypic
      variation. In addition, new methods for mapping quantitative trait loci provide
      opportunities to identify the regions within chromosomes that contain the
      functional genes of interest. This review summarizes molecular genetic and
      statistical genetic approaches to QTL mapping, and presents examples of how this
      approach can expand the scope of anthropological genetics to include mapping and
      identifying individual genes that influence complex phenotypic traits relevant to
      fundamental questions in biological anthropology.

PMID- 10601986
TI  - Craniofacial morphology of the first Americans: Pattern and process in the
      peopling of the New World.
AB  - The peopling of the New World has been the focus of anthropological attention
      since the last century. Proponents of multiple migration models have claimed that
      patterns of variation among extant New World populations reflect ancient,
      discrete migrations to the Americas during the terminal Pleistocene. Although
      multiple migration models appear to explain patterns of both past and present
      craniometric variation, this interpretation rests on a number of key assumptions
      that require further investigation. We examined a series of Paleoindian (n = 11)
      and Archaic (n = 384) crania from North and South America, and compare these
      early samples to a large world-wide sample of late Holocene (n = 6,742) remains
      to assess within- and among-group variability in early samples, and to determine
      how patterns of variation could be viewed as a reflection of both population
      history and population structure. Analyses included univariate and multivariate
      analysis of variance, principal component analysis, calculation of biological
      distances, and multivariate allocation methods. We also performed model-bound
      analyses of these data, including Relethford-Blangero analysis and calculation of
      F(ST). Our results indicate that under the assumptions of migration/founder
      models, the data are consistent with Paleoindians having derived from an
      undifferentiated Asian population that was not ancestral to modern American
      Indians. This view can be accommodated into existing models of multiple founders
      (migrations) in the New World. However, the assumptions required for such an
      interpretation are not realistic, and the diversity of early populations could as
      easily reflect population structuring processes such as genetic drift,
      demographic growth, and other phenomena. When the data were analyzed controlling
      for the effects of genetic drift (i.e., with smaller long-term effective
      population sizes for Paleoindians), the Paleoindian samples were no longer
      distinct from modern Native American populations. Other factors that need to be
      considered include processes involved in craniofacial change and adaptation
      during the past 10,000 years. Finally, patterns of variation in the North and
      South American Paleoindian samples are different, suggesting that the process of
      New World colonization is more complex than previously assumed.

PMID- 10601987
TI  - The recognition and evaluation of homoplasy in primate and human evolution.
AB  - Homoplasy has been a prominent issue in primate systematics and phylogeny for as
      long as people have been studying human evolution. In the past, homoplasy, in the
      form of parallel evolution, was often considered the dominant theme in primate
      evolution. Today, it receives blame for difficulties in phylogenetic analysis,
      but is essential in the study of adaptation. This paper reviews the history of
      study of homoplasy, methods of defining homoplasy, and methodological and
      biological factors that generate homoplasy. A post hoc definition of homology and
      homoplasy, based on patterns of character distributions and their congruence or
      incongruence on a cladogram, is the most consistent method of recognizing these
      phenomena. Defined this way, homology and homoplasy are mutually exclusive.
      However, when different levels of analysis are examined, it is seen that
      homoplasy at one level, such as adult phenotype, often exists simultaneously with
      homology at a different level, such as developmental process. Thus, in some
      cases, patterns of homoplasy may point to underlying similarities that reflect
      the shared heritage of a particular clade. This is an old concept that is being
      renewed on the strength of recent trends in developmental biology. Factors that
      influence homoplasy include character definition and a host of biological
      factors, such as developmental constraints, allometry, and adaptation. These
      interact with one another to provide explanations of homoplastic patterns.
      Because of the repetition of events, explanations of homoplastic features are
      often more reliable than those for homologous features, and serve as effective
      tests for hypotheses of evolutionary process. In some cases, particular
      explanations of homoplasy lead to generalizations about the likelihood of
      homoplasy in a type of structure. The structure may be adaptive or highly
      epigenetic, or it may belong to an anatomical system considered to be more prone
      to homoplasy than others. However, our review shows that these generalizations
      are usually based on theory, and contradictory expectations can be developed
      under different theoretical models. More rigorous empirical studies are necessary
      to discover what, if any, generalizations can be made about the likelihood of
      homoplasy in different types of characters.

PMID- 10601989
TI  - Endogenously produced substance P contributes to lymphocyte proliferation induced
      by dendritic cells and direct TCR ligation.
AB  - Substance P (SP) is an immunoregulatory tachykinin which augments antigen- and
      mitogen-induced lymphocyte proliferation via signaling through the neurokinin-1
      receptor (NK1-R). Non-neuronal cells of the immune system such as monocytes, T
      lymphocytes and eosinophils can be a source of SP. We have investigated if
      antigen-presenting dendritic cells (DC) produce SP. DC were grown from bone
      marrow precursors using a cocktail of GM-CSF, IL-4 and Flt-3 ligand. Reverse
      transcriptase-PCR amplification using primers for the mouse preprotachykinin-A
      gene and direct DNA sequencing of amplified products from purified DC
      demonstrated the presence of the gamma-transcript of the gene, coding for SP and
      neurokinin A. At the protein level, mouse DC expressed SP as determined by an
      enzyme immunoassay and confirmed by immunostaining. The functional role of
      endogenous SP release was determined. During the interaction with syngeneic or
      allogeneic DC, the addition of a specific NK1-R antagonist partly reduced
      proliferation in responding T lymphocytes. This was confirmed by using responders
      derived from NK1-R-deficient mice. In the absence of DC, proliferation of T cells
      induced by direct TCR ligation and soluble CD28 was partly dependent on signaling
      through NK1-R, revealing an autocrine effect of SP production by T cells. In
      conclusion, these results demonstrate that endogenously produced SP contributes
      to T cell proliferation induced by DC or TCR / CD28 stimulation.

PMID- 10601990
TI  - Ontogeny of synonymous T cell populations with specificity for a self MHC epitope
      mimicked by a bacterial homologoue: an antigen-specific T cell analysis in a non
      transgenic system.
AB  - By means of a novel technique for identification and isolation of MHC class II
      restricted antigen-specific T cells, we describe here in non-transgenic BALB / c
      mice physiological positive selection of an oligoclonal population of T cells
      which recognizes both a self MHC-derived peptide (Ialpha52) and a bacterial
      homologoue (Hi15). The results support a model for self peptide-mediated
      generation of T cells which have specificity for microbial antigens through
      molecular mimicry. This mechanism may be a model for the ontogeny of a
      physiological T cell response to infectious agents. Loss of control of these
      circuits may be part of the inciting factors of autoimmunity.

PMID- 10601991
TI  - The structural basis for complement receptor type 2 (CR2, CD21)-mediated
      alternative pathway activation of complement: studies with CR2 deletion mutants
      and vaccinia virus complement-control protein-CR2 chimeras.
AB  - The role of complement receptor 2 (CR2) short consensus repeats (SCR) in binding
      of hydrolyzed C3 (iC3) to form an alternative pathway (AP) convertase, and
      promoting C3 fragment deposition following AP activation, was examined. We used
      (1) K562 cells transfected with CR2 constructs, where the C3d-binding site of CR2
      (SCR1+2) was replaced with the four-SCR vaccinia virus complement control protein
      (VCP), or truncation mutants thereof, and (2) COS cells transfected with wild
      type (wt) CR2, or deletion mutants thereof. AP activation required iC3 binding in
      both systems. Thus, the VCP-CR2 chimera had an iC3 binding efficiency of 11.4 %,
      compared to wtCR2, and a relative AP activity of 5.5 %, the truncation mutants
      being inactive. Of the CR2 mutants, only EK (DeltaSCR10 - 11) had AP activity
      similar to wtCR2. NN (DeltaSCR6 - 8) and NOP (DeltaSCR6-mid14) had reduced AP
      activity, but near normal iC3 binding. XB (DeltaSCR3 - 6) and PP (DeltaSCR3
      mid14) were inactive in both assays. We conclude that, whilst iC3 binding to CR2
      via SCR1 - 4 is essential for AP activation, the efficiency of C3 deposition also
      depends on the midportion of CR2.

PMID- 10601992
TI  - Characterization of TCR-induced receptor-proximal signaling events negatively
      regulated by the protein tyrosine phosphatase PEP.
AB  - The proline-, glutamic acid-, serine- and threonine-enriched protein tyrosine
      phosphatase PEP, which is expressed primarily in hematopoietic cells, was
      recently discovered to be physically associated with the 50-kDa cytosolic protein
      tyrosine kinase (PTK) Csk, an important suppressor of Src family PTK, including
      Lck and Fyn in T cells. We report that this phosphatase has an inhibitory effect
      on TCR-induced transcriptional activation of the c-fos proto-oncogene and
      elements from the IL-2 gene promoter. Catalytically inactive mutants of PEP had
      no effects in these assays. Expression of PEP also reduced activation of the N
      terminal c-Jun kinase Jnk2 in response to receptor ligation, but not in response
      to UV light. In agreement with a more receptor-proximal site of action, we found
      that PEP reduced the TCR-induced increase in tyrosine phosphorylation of an Lck
      mutant, Lck-Y505F, which is only phosphorylated on tyrosine 394, the positive
      regulatory site. Finally, we observed that PEP reduced c-fos activation in a
      synergistic manner with Csk, supporting the notion that these two enzymes form a
      functional team acting on Src family kinases involved in TCR signaling.

PMID- 10601993
TI  - Membrane-bound CD154, but not CD40-specific antibody, mediates NF-kappaB
      independent IL-6 production in B cells.
AB  - CD40, a member of the tumor necrosis factor receptor (TNF-R) superfamily, is
      expressed on the surface of B cells, where its engagement results in IL-6
      secretion. In this study, we characterize the specific molecular requirements for
      CD40-mediated IL-6 production. Engagement of CD40 on either a B cell line or
      normal mouse splenic B cells with a membrane-bound form of CD154 (also known as
      CD40L or gp39) induced IL-6 secretion as well as up-regulation of IL-6 mRNA, but
      cross-linking CD40 with agonistic anti-CD40 mAb did not, although these mAb
      induce many other CD40 activation events, including the nuclear translocation of
      the transcription factor NF-kappaB. Using a mouse B cell line stably transfected
      with various human CD40 (hCD40) cytoplasmic truncation and point mutants, we show
      that the region from amino acids 202 to 225 in the cytoplasmic domain of CD40 is
      necessary for IL-6 secretion. However, the carboxy-terminal 32 amino acids are
      not, although these residues are required for CD40-mediated NF-kappaB activation.
      In addition, CD40 mutants previously shown to lack binding to TRAF2 and -3 are
      fully capable of inducing IL-6 production. Thus, CD40-mediated IL-6 induction is
      independent of NF-kappaB activation and the binding of TRAF2 and -3, but CD40
      must be engaged by trimeric CD154 on cell membranes to activate production of IL
      6.

PMID- 10601994
TI  - Lymphocyte activation gene-3 induces tumor regression and antitumor immune
      responses.
AB  - The lymphocyte activation gene-3 (LAG-3) product is an MHC class II ligand
      related to CD4. We investigated whether LAG-3 could be used in vivo to stimulate
      MHC class II(+) antigen-presenting cells (APC), such as resident macrophages or
      dendritic cells known to play a crucial role in processing and presenting of
      antigens to the immune system. We first introduced human (h) LAG-3 or mouse LAG-3
      into three types of tumor cells (MCA 205, TS / A and RENCA) to evaluate its
      capacity to stimulate a tumor-specific immune response in vivo. In contrast to
      the progressive growth of wild-type cells in syngeneic mice, LAG-3-transfected
      tumors completely regressed or their growth was markedly reduced. Mice were
      significantly to completely protected against a rechallenge with parental tumor
      cells. Protection induced by hLAG-3(+) tumor cells involved recruitment of a
      CD8(+) T cell response since nu / nu mice and CD8-depleted mice did not reject
      tumors, and a systemic tumor-specific CTL activity was induced. Co-administration
      of soluble LAG-3 with wild-type tumor cells also markedly reduced primary tumor
      growth. Interestingly, immunization with LAG-3(+) tumor cells or co
      administration of soluble LAG-3 with irradiated wild-type tumor cells reduced the
      growth of pre-established tumors. We therefore suggest that LAG-3 could be used
      as a vaccine adjuvant for its ability to trigger APC via MHC class II molecules.

PMID- 10601995
TI  - Escherichia coli infection induces only fetal thymus-derived gamma delta T cells
      at the infected site.
AB  - Intraperitoneal infection of mice with Escherichia coli induced activated TCR
      gamma delta T cells in the peritoneal cavity. We provide evidence that the E.
      coli-induced gamma delta T cells are derived only from the fetal thymus on the
      following grounds. The gamma delta T cells were not induced in athymic nude mice
      and irradiated bone marrow-transferred mice which lack fetal thymus-derived T
      cells. However, E. coli infection of fetal thymus-grafted nude mice did induce
      fetal thymus-derived gamma delta T cells. These results suggest that the fetal
      thymus-derived gamma delta T cells colonize the periphery during early ontogeny,
      and are maintained until adult age. The E. coli-induced gamma delta T cells
      express only the Vdelta1 gene. Vgamma6 was predominantly expressed whereas anti
      Vgamma1 and anti-Vgamma4 monoclonal antibodies stained less than 3 % of the
      cells. Direct sequencing of PCR products revealed that Vgamma6 and Vdelta1 genes
      expressed by the E. coli-induced gamma delta T cells were invariant sequences
      identical to those expressed in the fetal thymus. The antigen (Ag) specificity of
      a T cell hybridoma expressing the fetal type Vgamma6 / Vdelta1(+) TCR could not
      be identified as the cells failed to respond to lipopolysaccharide, E. coli Ag,
      mycobacterial heat shock protein 65, or isopentenyl pyrophosphate. These results
      suggest that the Vgamma6 / Vdelta1(+) gamma delta T cells derived from fetal
      thymus can participate in immune responses against bacterial infection through
      recognition of a novel class of Ag which is not yet identified.

PMID- 10601996
TI  - Modulation of TCR signaling by beta1 integrins: role of the tyrosine phosphatase
      SHP-1.
AB  - When cross-linked, beta1 integrins co-activate T cells together with a TCR-CD3
      signal. Soluble anti-beta1 monoclonal antibodies, however, inhibit T cell
      activation. We report inhibition of early tyrosine kinases, including ZAP-70,
      p59(fyn), CD4-associated p56(lck) and TCR components under this condition. The
      tyrosine phosphatase SHP-1 is activated by engagement of beta1 integrins and is
      implicated in this negative regulation since no inhibition occurs in SHP-1
      dominant-negative T cells. As shown by the use of Lck-deficient cells, the
      activation of the protein tyrosine phosphatase depends on a pool of p56(lck) that
      is not associated with CD4. These cross-talk events were also observed with the
      alpha4beta1 integrin ligand, VCAM-1. We propose that these results may be
      important in terms of lymphocyte circulation; while T cells migrate through the
      vascular endothelium, they are primed for an amplified response; as inflammation
      develops, a local accumulation of soluble integrin ligands may help to turn it
      off.

PMID- 10601997
TI  - A phage antibody identifying an 80-kDa membrane glycoprotein exclusively
      expressed on a subpopulation of activated B cells and hairy cell leukemia B
      cells.
AB  - We have isolated a phage display library-derived monoclonal antibody, phab V-3,
      that identifies a membrane glycoprotein of approximately 80 kDa which is
      expressed on a subpopulation of activated B lymphocytes in secondary lymphoid
      organs. In agreement with their activated phenotype, phab V-3(+) B cells display
      a blast-like morphology, and are prone to spontaneous apoptosis in vitro, unless
      rescued by stimulation with CD40 ligand (CD40L). The expression of the phab V-3
      molecule coincides with B cells that produce high levels of IgM, IgG and IgA in
      vitro upon stimulation with CD40L in combination with IL-2 and IL-10.
      Immunofluorescent analysis of B cell malignancies unveiled that the phab V-3
      molecule was uniquely expressed on hairy cell leukemia (HCL) B cells. Similar to
      phab V-3(+) tonsils B cells, HCL B cells have been reported to express CD11c,
      CD95 and CD27, which might indicate that the phab V-3(+) B cells in HCL are the
      malignant counterpart of the phab V-3(+) B cell subpopulation.

PMID- 10601998
TI  - CD40-mediated activation of Ig-Cgamma1- and Ig-cepsilon germ-line promoters
      involves multiple TRAF family proteins.
AB  - CD40 plays a critical role in immunoglobulin (Ig) class switching in B cells, but
      the molecular events involved remain poorly understood. Using CD40 mutants with
      impairments in their ability to bind selected TNF receptor-associated factor
      (TRAF) family proteins, we observed that CD40-mediated transcriptional induction
      of the germ-line Ig-Cgamma1- and Ig-Cepsilon promoters was markedly reduced by
      mutations that prevent TRAF2, TRAF3, TRAF5 or TRAF6 binding. Moreover, co
      expression of trans-dominant inhibitory forms of TRAF2, 3, 5 or 6 with wild-type
      CD40 also suppressed induction of these promoters. Overexpression of TRAF2 or
      TRAF6 was sufficient to induce transcription of the C(H) promoters through an NF
      kappaB-dependent mechanism. In contrast, TRAF3 and TRAF5 failed to induce these
      promoters, implying a more indirect role for these TRAF family members.
      Altogether, the results demonstrate a non-redundant role for multiple TRAF in the
      signal transduction pathways by which CD40 induces transcription of germ-line
      C(H) promoters. Since C(H) germ-line transcription represents an obligatory step
      in Ig class switching in B cells, these findings suggest that interference with
      the functions of any of these TRAF might provide a means of preventing class
      switching for therapeutic purposes.

PMID- 10601999
TI  - Triggering of T cell proliferation through CD28 induces GATA-3 and promotes T
      helper type 2 differentiation in vitro and in vivo.
AB  - The relative contribution of T cell receptor-versus CD28-mediated signals in co
      stimulation of resting CD4 T cells is thought to influence their functional
      differentiation towards T helper (Th) 1 versus Th2 subsets. We have used a
      conventional and a mitogenic CD28-specific monoclonal antibody to assess the
      effect of polyclonal T cell activation through CD28 alone on CD4 subset
      differentiation. In vivo, mitogenic but not conventional anti-CD28 induces
      massive lymphocytosis, the Th2 cytokines interleukin (IL)-4 and IL-10, and Th2
      dependent immunoglobulin isotypes, most notably IgE. In vitro, it is shown that
      mitogenic anti-CD28 primes for IL-4-dependent induction of IL-4 expression much
      more efficiently than conventional co-stimulation. At the molecular level, we
      show for the first time that the activation of the "Th2 promoting" transcription
      factor GATA-3 requires co-stimulation by CD28 and is also induced by mitogenic
      anti-CD28 alone. We suggest that CD28-dependent induction of GATA-3 in concert
      with other transcription factors, which are preferentially induced by strong CD28
      signals, primes CD4 T cells for IL-4-dependent Th2 differentiaton.

PMID- 10602000
TI  - Enhanced susceptibility to cytotoxic T lymphocytes without increase of MHC class
      I antigen expression after conditional overexpression of heat shock protein 70 in
      target cells.
AB  - Antigenic peptides have been found associated with heat shock proteins (HSP)
      including cytoplasmic HSP70 and heat shock cognate protein 70 as well as the
      endoplasmic reticulum-resident glucose-regulated protein 94. Recently, HSP70
      transfection has been reported to increase MHC class I cell surface expression
      and antigen presentation on mouse melanoma B16 cells (Wells et al., Int. Immunol.
      1998. 10: 609). To analyze the effect of HSP70 on MHC class I cell surface
      expression and lysability of target cells we transfected a human melanoma cell
      line with the rat Hsp70-1 gene using the Tet-On system for conditional
      overexpression of HSP70. Induction of HSP70 did not increase cell surface
      expression of HLA class I molecules in general or individual HLA-A and B antigens
      in particular. Nonetheless, induction of HSP70 enhanced susceptibility of these
      cells to lysis by allospecific CTL. The same effect was observed using an HLA-A2
      restricted tyrosinase-specific CTL clone after pulsing the tyrosinase-negative
      target cells with the specific peptide. Thus, HSP70 induction can increase
      killing by CTL without affecting MHC class I cell surface expression or antigen
      processing. This effect of HSP70 appears to be different from the commonly found
      protection exerted by HSP70 against stress like heat shock, and might be mediated
      by improving CTL-induced apoptosis.

PMID- 10602001
TI  - Accurate intracellular localization of HLA-DM requires correct spacing of a
      cytoplasmic YTPL targeting motif relative to the transmembrane domain.
AB  - HLA-DM is an MHC class II-related heterodimer that is targeted to lysosomal
      compartments by a tyrosine-based signal YTPL, present in the cytoplasmic tail of
      the beta chain. Similar signals in other proteins control transport to different
      intracellular locations and can be recognized at several sorting sites within the
      cell including the trans-Golgi network, the plasma membrane and the early or
      sorting endosome. Therefore, in addition to recognizing the basic tyrosine motif,
      the sorting machinery must be sensitive to additional features associated with
      these elements. Here we show that efficient trafficking of HLA-DM to lysosomal
      compartments is dependent upon the proximity of its tyrosine motif to the
      transmembrane domain. Constructs in which the spacing is altered are rapidly
      internalized but are expressed at the cell surface. We conclude that the spacing
      of the HLA-DMB-encoded tyrosine motif relative to the transmembrane domain is an
      important feature controlling DM sorting in endosomes.

PMID- 10602002
TI  - IL-6 up-regulates mcl-1 in human myeloma cells through JAK / STAT rather than ras
      / MAP kinase pathway.
AB  - Mcl-1 is an anti-apoptotic member of the Bcl-2 family which is tightly regulated
      during myeloid and B cell differentiation. We have recently reported that Mcl-1
      is expressed in human myeloma cells and that Mcl-1 and Bcl-x(L) expression are
      correlated. In the current study, we demonstrate that IL-6, a survival factor for
      the human myeloma cell line MDN, rapidly up-regulates Mcl-1 whereas it has no
      effect on Bcl-2 protein level. In MDN cells, IL-6 induces both extracellular
      signal-regulated protein kinase (ERK)1,2 and STAT3 activation whereas STAT1 and
      STAT5 activation remains undetectable. Furthermore, while investigating the IL-6
      signaling pathway leading to Mcl-1 up-regulation, we show that a janus kinase
      (JAK)-2 inhibitor is able to inhibit both STAT3 activation and Mcl-1 up
      regulation whereas an MAP/ERK kinase (MEK) inhibitor has no effect. In
      conclusion, our data suggest the involvement of the JAK / STAT pathway but not of
      the Ras / mitogen-activated protein (MAP) kinase pathway in IL-6-induced Mcl-1 up
      regulation.

PMID- 10602003
TI  - CD45-associated protein is not essential for the regulation of antigen receptor
      mediated signal transduction.
AB  - CD45 is a transmembrane protein tyrosine phosphatase required for signaling
      through the T-and B-cell antigen receptors. In lymphocytes, CD45 interacts with
      CD45-associated protein (CD45AP), a 32 000 Mr phosphoprotein, through their
      respective transmembrane domains. To determine whether CD45AP affects the ability
      of CD45 to regulate antigen receptor signaling, CD45AP-deficient mice were
      generated. Thymocyte development was grossly normal. Moreover, the cellularity of
      the thymus and spleens were normal. CD45 expression on thymocytes and
      splenocytes, ascertained by flow cytometry, was comparable between CD45AP
      deficient mice and littermate controls. In contrast to a previous report (Matsuda
      et al., J. Exp. Med. 1998 187: 1863 - 1870). CD45AP-deficient and normal
      thymocytes and splenocytes proliferated similarly in response to various mitogens
      or antigen receptor cross-linking. Furthermore, thymocyte CD45-associated
      p56(lck) kinase activity was similar between CD45AP-deficient and normal cells.
      We conclude that CD45AP is not essential for the regulation of Src-family kinase
      activity by CD45.

PMID- 10602004
TI  - Biochemical and functional analysis of mice deficient in expression of the CD45
      associated phosphoprotein LPAP.
AB  - The role of the CD45-associated phosphoprotein (LPAP / CD45-AP) during an immune
      response remains unclear. To understand better the function of LPAP we generated
      LPAP-deficient mice by disrupting exon 2 of the LPAP gene. LPAP-null mice were
      healthy and did not show gross abnormalities compared to their wild-type
      littermates. However, immunofluorescence analysis of T and B lymphocytes revealed
      a reduced expression of CD45, which did not affect a particular subpopulation. In
      contrast to a recent report (Matsuda et al., J. Exp. Med. 1998. 187: 1863 - 1870)
      we neither observed significant alterations of the assembly of the CD45 / lck
      complex nor of polyclonal T-cell responses. However, lymphnodes from LPAP-null
      mice showed increased cellularity, which could indicate that expression of LPAP
      might be required to prevent expansion of lymphocytes in particular lymphatic
      organs rather than potentiating immune responses.

PMID- 10602005
TI  - Positive selection of NKT cells by CD1(+), CD11c(+) non-lymphoid cells residing
      in the extrathymic organs.
AB  - Previously, we found that NK1.1(+), TCRalpha beta(+) natural killer T (NKT) cells
      develop in cytokine-supplemented suspension cultures of fetal liver established
      from normal, but not from beta2 microglobulin-deficient [beta2m(- / -)] mice, and
      that recombination-deficient SCID fetal liver can reconstiute NKT cell
      development in beta2m(- / -) fetal liver cultures. We found here that cells of
      SCID adult liver, bone marrow, spleen and thymus were able to reconstitute NKT
      cell development in the former culture system with efficiency comparable to
      normal thymic cells. The reconstitution of NKT cells was also seen in the bone
      marrow chimeras that had been administered a combination of beta2m(- / -) and Rag
      2(- / -) bone marrow cells. Development of NKT cells was hampered by depletion of
      CD11c(+) or CD11b(+) cells, but not by removal of B220(+) or Gr-1(+) cells from
      cultures of normal fetal liver cells. Furthermore CD11c(+), CD11b(+) and / or
      CD11c(+) CD11b(-) cells (both populations were CD1-dull positive) enriched from
      Rag-2-deficient fetal livers and pulsed with alpha-galactosylceramide, a possible
      antigen for NKT cells, were shown to reconstitute the NKT cell development in
      beta2m(- / -) fetal liver cultures. Collectively, our findings suggest that non
      lymphoid cells, presumably CD11c(+), CD11b(+) and / or CD11c(+), CD11b(-)
      dendritic cells, are involved in the mechanism of positive selection of NKT cells
      in the thymus and extrathymic organs.

PMID- 10602006
TI  - CD8(+) T cell cytolytic activity independent of mitogen-activated protein kinase
      / extracellular regulatory kinase signaling (MAP kinase / ERK).
AB  - Cytotoxicity is a major effector function of CD8(+) T cells. Although mitogen
      activated protein kinase (MAP kinase) / extracellular regulatory kinase (ERK)
      activity is indispensable for cytotoxic activity of most CD8(+) T cells a portion
      of CD8(+) T cells appears resistant to MEK inhibition as cytotoxicity of bulk
      cultures was partially preserved in the presence of a MEK inhibitor. We have also
      identified a long-term CD8(+) T cell line with unaltered cytolytic activity after
      prevention of ERK activation. Antigen-induced microtubule organizing center
      (MTOC) reorientation was not prevented in this CD8(+) cell line by MEK
      inhibition, in sharp contrast to the MTOC reorientation prevention in a CD8(+) T
      cell clone with MEK inhibition-sensitive cytolytic activity. These findings
      suggest that resistance of lysis to MEK inhibition may be due to a lack of ERK
      control over MTOC reorientation in some CD8(+) T cells. Thus, there appears to be
      a heterogeneity of ERK-regulated cytolytic activity in CD8(+) T cells, most
      likely resulting from a differential control of ERK over MTOC motility.

PMID- 10602007
TI  - Memory phenotype CD8(+) T cells persist in livers of mice protected against
      malaria by immunization with attenuated Plasmodium berghei sporozoites.
AB  - Natural exposure to Plasmodium parasites induces short-lived protective immunity.
      In contrast, exposure to radiation-attenuated sporozoites (gamma spz) promotes
      long-lasting protection that is in part mediated by CD8(+) T cells that target
      exoerythrocytic stage antigens. The mechanisms underlying the maintenance of long
      lasting protection are currently unclear. The liver is a repository of Plasmodium
      antigens and may support the development and / or homing of memory T cells. While
      activated CD8(+) T cells are presumed to die in the liver, the fate of anti
      Plasmodium CD8(+) T cells remains unknown. We propose that inflammatory
      conditions in the liver caused by Plasmodium parasites may allow some effector
      CD8(+) T cells to survive and develop into memory cells. To support this
      hypothesis, in this initial study we demonstrate that liver mononuclear cells
      from P. berghei gamma spz-immune mice transferred protection to naive recipients
      and moreover, that CD4(+) and CD8(+) T cells responded to Plasmodium antigens by
      up-regulating activation / memory markers. While CD4(+) T cells under went a
      transient activation following immunization with gamma spz, CD8(+) T cells
      expanded robustly after spz challenge and exhibited stable expression of CD44(hi)
      and CD45RB(lo) during protracted protection. These results establish a key role
      for intrahepatic T cells in long-lasting protection against malaria.

PMID- 10602008
TI  - CD45 isoform phenotypes of human T cells: CD4(+)CD45RA(-)RO(+) memory T cells re
      acquire CD45RA without losing CD45RO.
AB  - We have studied the alterations in CD45R phenotypes of CD4(+)CD45RA(-)RO(+) T
      cells in recipients of T cell-depleted bone marrow grafts. These patients are
      convenient models because early after transplantation, their T cell compartment
      is repopulated through expansion of mature T cells and contains only cells with a
      memory phenotype. In addition, re-expression of CD45RA by former CD4(+)CD45RA(-)
      T cells can be accurately monitored in the pool of recipient T cells that, in the
      absence of recipient stem cells, can not be replenished with CD45RA(+) T cells
      through the thymic pathway. We found that CD4(+)CD45RA(-)RO(+) recipient T cells
      could re-express CD45RA but never reverted to a genuine CD4(+)CD45RA(+)RO(-)
      naive phenotype. Even 5 years after transplantation, they still co-expressed
      CD45RO. In addition, the level of CD45RA and CD45RC expression was lower (
      approximately 35 %) than that of naive cells. In contrast, the level of CD45RB
      expression was comparable to that of naive cells. We conclude that CD4(+)CD45RA(
      )RO(+) T cells may re-express CD45(high) isoforms but remain distinguishable from
      naive cells by their lower expression of CD45RA / RC and co-expression of CD45RO.
      Therefore, it is likely that the long-lived memory T cell will be found in the
      population expressing both low and high molecular CD45 isoforms.

PMID- 10602009
TI  - Presentation of epstein-barr virus latency antigens to CD8(+), interferon-gamma
      secreting, T lymphocytes.
AB  - Epstein-Barr virus (EBV) infects more than 95 % of the human population and
      causes an asymptomatic life-long infection in the majority of EBV carriers. Cell
      mediated immunity provides resistance to EBV, as demonstrated by the occurrence
      of EBV-induced post-transplant lymphoproliferative disease in immunosuppressed
      patients. Here we looked for IFN-gamma-producing T lymphocytes in the blood of
      healthy donors with a rapid enzyme-linked immunospot (ELISPOT) assay, comparing
      as antigen presenting cells monocytes and dendritic cells (DC) infected with
      recombinant vaccinia virus (rVV). We found a strong CD8(+) ELISPOT response to
      one or more of the EBNA 3A, 3B and 3C antigens in the PBMC from 14 / 18 donors.
      The sensitivity of the overnight ELISPOT assay was increased using DC as antigen
      presenting cells, including 3 / 3 individuals who lacked ELISPOT in PBMC. In
      addition, DC could markedly expand EBV-specific spots after a 7-day culture. In a
      smaller number of donors, we documented recognition of the subdominant LMP 1, LMP
      2 and EBNA 1 antigens that are expressed in a variety of EBV-associated
      malignancies. Therefore our data provide more evidence for the efficacy of DC in
      eliciting rapid responses to EBV latency antigens in circulating CD8(+) T cells.

PMID- 10602010
TI  - A role for lymphotoxin beta receptor in host defense against Mycobacterium bovis
      BCG infection.
AB  - To investigate the role of membrane lymphotoxin (LT)alpha1 / beta2 and its LTbeta
      receptor (LTbetaR) in the protective immune response to Mycobacterium bovis
      bacillus Calmette-Guerin (BCG) infection, we have used a soluble fusion molecule
      (LTbetaR-IgG1). LTbetaR-Ig treatment interferes with granuloma formation mainly
      in the spleen by inhibiting macrophage activation and nitric oxide synthase
      activity. In addition, a large accumulation of eosinophils was observed in the
      spleen of LTbetaR-Ig-treated infected mice. Decreased blood levels of IFN-gamma
      and increased IL-4 were also observed, suggesting that the LTbetaR pathway is
      important in BCG infection to favor a Th1 type of immune response. The treatment
      of transgenic mice expressing high blood levels of a soluble TNFR1-IgG3 fusion
      protein with LTbetaR-Ig resulted in a still higher sensitivity to BCG infection,
      and extensive necrosis in the spleen. In conclusion, these results suggest that
      the LTbetaR and the TNFR pathways are not redundant in the course of BCG
      infection and protective granuloma formation: the LTbetaR pathway appears to be
      important in spleen granuloma formation, whereas the TNFR pathway has a
      predominant role in other tissues.

PMID- 10602011
TI  - Somatic hypermutation of VkappaJkappa rearrangements: targeting of RGYW motifs on
      both DNA strands and preferential selection of mutated codons within RGYW motifs.
AB  - Productive and nonproductive VkappaJkappa gene rearrangements from individual
      peripheral blood B cells were analyzed for the pattern and distribution of
      mutations. The eight RGYW motifs and their inverse repeats, WRCY, were present in
      germ-line Vkappa genes significantly more often than anticipated by random chance
      (1.6-fold and 1.4-fold, respectively) and were also mutated in nonproductive
      rearrangements significantly more often than expected, with a frequency 1.96 fold
      greater than that of non-RGYW / WRCY motifs. As a result, 50 % of all mutations
      in nonproductive VkappaJkappa rearrangements occurred in RGYW / WRCY motifs. Each
      RGYW tetramer and its corresponding WRCY contained mutations at comparable
      frequencies. Furthermore, mutations of G and C were significantly more frequent
      in RGYW / WRCY but not in other tetranucleotides. Finally, mutations in codons
      contained within RGYW / WRCY were significantly more frequent in complementarity
      determining regions but not framework regions of productive compared to
      nonproductive rearrangements and were increased by a factor that was
      significantly greater than for mutations in other motifs. These results indicate
      that the mutational machinery targets the overrepresented RGYW motifs in Vkappa
      genes on both DNA strands and that the resulting replacement mutations are
      preferentially selected into the productive repertoire.

PMID- 10602012
TI  - Recognition of autologous dendritic cells by human NK cells.
AB  - NK cells can recognize and kill tumor as well as certain normal cells. The
      outcome of the NK-target interaction is determined by a balance of positive and
      negative signals initiated by different target cell ligands. We have previously
      shown that human NK cells kill CD40-transfected tumor targets efficiently, but
      the physiological significance of this is unclear. We now demonstrate that human
      NK cells can kill dendritic cells (DC), known to express CD40 and other co
      stimulatory molecules. The killing was observed with polyclonal NK cells cultured
      short term in IL-2 as well as with NK cell clones as effectors, and with
      allogeneic as well as autologous DC as targets. NK cell recognition could be
      inhibited, but only partially, by preincubation of target cells with monoclonal
      antibodies against CD40, suggesting that this molecule may be one of several
      ligands involved. Addition of TNF-alpha of the cultures stimulated the
      development of a more mature DC phenotype, while addition of IL-10 resulted in a
      less mature phenotype, with lower expression of CD40 and other co-stimulatory
      molecules. Nevertheless, such DC were more NK susceptible than the differentiated
      DC. This may be partly explained by a reduced MHC class I expression observed on
      such cells, since blocking of MHC class I molecules on differentiated DC or CD94
      receptors of NK cells led to increased NK susceptibility. The results show that
      NK cells may interact with DC, and suggest that the outcome of such interactions
      depend on the cytokine milieu.

PMID- 10602013
TI  - A ubiquitin-like protein which is synergistically inducible by interferon-gamma
      and tumor necrosis factor-alpha.
AB  - A means of regulating the fate of intracellular proteins is their covalent
      conjugation to ubiquitin-like proteins. A recently discovered ubiquitin-like
      protein is called "diubiquitin" because it consists of two ubiquitin-like domains
      in head-to-tail arrangement. Human diubiquitin is encoded at the telomeric end of
      the MHC class I locus and was previously found to be expressed in dendritic cells
      and mature B cells. We have extended the expression analysis of diubiquitin by
      reverse transcriptase-PCR and Northern blotting in primary endothelial cells and
      human cancer cell lines derived from nine different tissues. Diubiquitin
      expression was found to be generally and synergistically inducible with the
      cytokines IFN-gamma and TNF-alpha but not with IFN-alpha. Diubiquitin mRNA
      expression was induced within 2 h after cytokine stimulation and was independent
      of protein neosynthesis but dependent on proteasome activity. The mouse homologue
      of diubiquitin which is also encoded in the MHC class I locus was likewise
      induced with IFN-gamma and TNF-alpha. A general and synergistic induction with
      IFN-gamma and TNF-alpha suggests that diubiquitin may exert its functions in
      antigen presentation or other cellular processes controlled by these two
      cytokines.

PMID- 10602014
TI  - Dendritic cells up-regulate immunoproteasomes and the proteasome regulator PA28
      during maturation.
AB  - Dendritic cells (DC) are highly specialized professional antigen presenting cells
      which are pivotal for the initiation and control of the cytotoxic T cell
      response. Upon stimulation by cytokines, bacteria, or CD40L DC undergo a
      maturation process from an antigen-receptive state to a state of optimal
      stimulation of T cells. We investigated the composition of proteasomes of DC
      derived from human peripheral blood monocytes before and after stimulation by
      CD40L, LPS, or proinflammatory cytokines (TNF-alpha + IL-6 + IL-1beta).
      Immunoprecipitation of proteasomes and analysis on two-dimensional gels revealed
      that during maturation the inducible proteasome subunits LMP2, LMP7, and MECL-1
      are up-regulated and that the neosynthesis of proteasomes is switched exclusively
      to the production of immunoproteasomes containing these subunits. The proteasome
      regulator PA28 is markedly up-regulated in mature DC and in addition a so - far
      unidentified 21-kDa protein co-precipitates with the proteasome in LPS -
      stimulated DC. These changes in proteasome composition may be functionally linked
      to special properties of DC like MHC class I up-regulation or cross-priming. Our
      findings imply that the spectrum of class I-bound peptides may change after DC
      maturation which could be relevant for the design of DC - based vaccines.

PMID- 10602015
TI  - Resting small B cells present endogenous immunoglobulin variable-region
      determinants to idiotope-specific CD4(+) T cells in vivo.
AB  - Antigenic determinants localized within the highly diversified V-regions of Ig
      are called idiotopes (Id). Processed Id-peptides can be presented on MHC class II
      molecules to CD4(+) T cells. If B cells present their endogenous Id-peptides, T
      cell activation could occur in the absence of nominal antigen, a potentially
      important process in T-B cooperation and immune regulation. To test this idea, we
      used mice made transgenic for a lambda2 L-chain (Id(+) mice). Another transgenic
      mouse strain expresses TCR transgenes with specificity for the Id (lambda2),
      presented on MHC class II molecules. When highly purified sorted Id(+) B cells
      and Id-specific T cells were sequentially injected into MHC syngeneic SCID host,
      T cell became blastoid, CD69(+) and proliferated. To exclude any role of host
      APC, MHC incompatible Rag2(- / -) mice (H-2(b)) were used as recipients for the
      Id(+) B and Id-specific T cells, with similar results. Exposure to extracellular
      Id(+) immunoglobulin (Ig) was not sufficient for Id priming of B cells in vivo,
      highlighting the preferential presentation of Id peptides derived from endogenous
      Ig, by B cells. The results suggest that B cells presenting Id self-peptides
      generated by V(D)J recombinations or somatic mutations may directly stimulate T
      cell in vivo in the absence of conventional antigen.

PMID- 10602016
TI  - Enrichment and detection of live antigen-specific CD4(+) and CD8(+) T cells based
      on cytokine secretion.
AB  - Following appropriate antigen-specific stimulation, CD4(+) and CD8(+) T
      lymphocytes rapidly express cytokines. Based on this stimulation-induced cytokine
      secretion and using cell surface affinity matrix technology we have developed a
      new method that permits specific, rapid and efficient detection, isolation and
      characterization of live antigen-specific CD4(+) and CD8(+) T lymphocytes. The
      power of this technique is demonstrated here for HLA-A0201-restricted influenza
      matrix protein peptide 58-66-specific CD8(+) cytotoxic T lymphocytes, influenza A
      virus- and recombinant tetanus toxin C fragment-specific Th1 cells and tetanus
      toxoid-specific Th2 cells.

PMID- 10602017
TI  - Decreased severity of myelin oligodendrocyte glycoprotein peptide 33 - 35-induced
      experimental autoimmune encephalomyelitis in mice with a disrupted TCR delta
      chain gene.
AB  - Immunization of C57BL / 6 mice with myelin oligodendrocyte glycoprotein (MOG)
      peptide (p) 35 - 55 induces chronic experimental autoimmune encephalomyelitis
      (EAE). The role of gamma delta T cells in the regulation of EAE is unclear. We
      investigated gamma delta T cells in C57BL / 6 wild-type mice and C57BL / mice
      with a disrupted TCRdelta chain gene (delta(- / -) mice) using MOG p35 - 55. We
      found significantly less disease in delta(- / -) mice immunized with MOG /
      complete Freund's adjuvant (mean maximal EAE score 4.3 +/- 0.8 in wild-type vs.
      2.3 +/- 0.5 in delta(- / -) mice). Transfer of wild-type spleen cells restored
      the ability of delta(- / -) mice to develop equally severe EAE as wild-type mice.
      In addition to IFN-gamma, IL-2, IL-5 and IL-10 was decreased in delta(- / -)
      mice. Decreased immune responses were also seen in delta(- / -) animals immunized
      with OVA peptide or protein and in concanavalin A-stimulated splenocytes from
      delta(- / -) mice. Enriched dendritic cells from delta(- / -) mice secreted
      significantly less TNF-alpha in response to lipopolysaccharide stimulation.
      Furthermore, when EAE was induced by adoptive transfer of an anti-MOG p35 - 55
      alpha beta T cell line, there was a striking reduction of disease incidence (0 %)
      and severity in delta(- / -) as compared to wild-type mice (83 % incidence).
      delta(- / -) mice showed no cellular infiltration in the spinal cord whereas wild
      type animals had infiltration of macrophages, B cells, alpha beta- and gamma
      delta T cells. In adoptive transfer EAE, there was reduced IL-2 and IFN-gamma
      secretion in delta(- / -) mice. These results demonstrate an impaired immune
      response in the delta(- / -) mouse that is associated with a defect in developing
      both actively induced and adoptively transferred EAE.

PMID- 10602018
TI  - RORgammaT, a thymus-specific isoform of the orphan nuclear receptor RORgamma /
      TOR, is up-regulated by signaling through the pre-T cell receptor and binds to
      the TEA promoter.
AB  - TEA (T early alpha) is a genetic element located upstream of the TCR-Jalpha
      cluster. Thymocytes from mice carrying a targeted deletion of TEA do not
      rearrange their TCRalpha locus on a window spanning the first nine Jalpha
      segments. This led us to the hypothesis of TEA having a "rearrangement focusing"
      activity on the 5' side of the TCR-Jalpha region. We analyzed DNAseI and
      "phylogenetic" footprints within the TEA promoter in an attempt to identify trans
      acting factors that could account for its regulatory function on DNA
      accessibility. One of these footprints corresponded to a putative DNA-binding
      site for an orphan nuclear receptor of the ROR / RZR family. The RORgammaT cDNA
      clone was isolated from a thymus library using a probe corresponding to the DNA
      binding domain of RORgamma / TOR. RORgammaT is a thymus-specific isoform of
      RORgamma, expressed almost exclusively in immature double-positive thymocytes.
      RORgammaT binds, to the TEA promoter in vitro. Lastly, the expression of
      RORgammaT is stimulated in two situations that mimic activation through the pre
      TCR and in which the thymocytes have their TCR-alpha locus in an "open", yet
      unrearranged DNA configuration. We propose that the expression of RORgammaT may
      be part of the pre-TCR activation cascade leading to the maturation of alpha /
      beta T cells and may participate in the regulation of DNA accessibility in the
      TCR-Jalpha locus.

PMID- 10602019
TI  - Overexpression of CD82 on human T cells enhances LFA-1 / ICAM-1-mediated cell
      cell adhesion: functional association between CD82 and LFA-1 in T cell
      activation.
AB  - We previously demonstrated that CD82, expressed on both T cells and antigen
      presenting cells (APC), plays an important role as a co-stimulatory molecule
      especially in the early phase of T cell activation. We also showed that the CD82
      expression level is up-regulated on activated T cells and memory T cells. This up
      regulation enhances both T cell-T cell and T cell-APC interactions. In this
      study, we further investigated the mechanism of CD82-mediated cell-cell adhesion.
      The enhanced adhesion between CD82-overexpressing Jurkat cells was completely
      blocked by anti-ICAM-1 / LFA-1 monoclonal antibodies. Increased interaction of
      LFA-1 with ICAM-1 was further confirmed by enhanced adhesion of CD82
      overexpressing Jurkat cells to immobilized ICAM-1-Ig. CD82 co-immunoprecipitated
      with LFA-1 from Jurkat cells and CD82 and LFA-1 colocalized at an adhesion foci.
      These results suggest that the T cell stimulation via anti-CD3 cross-linking or
      phorbol myristate acetate treatment up-regulates CD82 expression, leading to the
      colocalization of CD82 and LFA-1, and results in enhanced interaction between LFA
      1 and ICAM-1. In addition, a blocking experiment using monoclonal antibodies
      suggested that CD82 and LFA-1 molecules on APC are also important for the optimal
      activation of T cells. This is the first report that describes the enhancement of
      cell-cell interaction through LFA-1 and ICAM-1 by the overexpression of another
      cell surface molecule, CD82.

PMID- 10602020
TI  - The interplay between the duration of TCR and cytokine signaling determines T
      cell polarization.
AB  - Development of Th1 and Th2 effector lymphocytes is driven primarily by IL-12 or
      IL-4, but is also influenced by the strength of antigenic stimulation. However,
      the mechanism by which TCR signaling contributes to T cell polarization remains
      elusive. We show that in the presence of IL-12 a short TCR stimulation can lead
      to efficient Th1 polarization and IL-12 exerts its effect when present during, as
      well as after, TCR signaling. In contrast, Th2 polarization requires a prolonged
      TCR stimulation and IL-4 is effective only when present during the period of TCR
      triggering. The simultaneous stimulation by TCR and IL-4 is required to induce
      demethylation of IL-4 and IL-13 genes that accompanies the stochastic generation
      of Th2 cells producing either or both cytokines. Thus, the duration of TCR
      stimulation represents a crucial parameter that influences the response to
      polarizing cytokines and the acquisition of T cell effector functions.

PMID- 10602021
TI  - In vivo application of RNA leads to induction of specific cytotoxic T lymphocytes
      and antibodies.
AB  - To study the efficiency of RNA-based vaccines, RNA coding for the model antigen
      beta-galactosidase (beta-gal) was transcribed in vitro from a lacZ gene flanked
      by stabilizing Xenopus laevis beta-globin 5' and 3' sequences and was protected
      from RNase degradation by condensation with the polycationic peptide protamine.
      The liposome-encapsulated condensed RNA-peptide complex, the condensed RNA
      peptide complex without liposome or naked, unprotected RNA, was injected into
      BALB/c (H-2(d)) mice. All preparations led to protein expression in the local
      tissue, activation of L(d)-restricted specific cytotoxic T lymphocytes (CTL) and
      production of IgG antibodies reactive against beta-gal. RNA-triggered CTL were as
      efficient in the lysis of lacZ-transfected target cells as CTL triggered by a
      lacZ-DNA eukaryotic expression vector. Immunization with RNA transcribed from a
      cDNA library from the beta-gal-expressing cell line P13.1 again led to beta-gal
      specific CTL and IgG induction. Thus, both naked and protected RNA can be used to
      elicit a specific immune response in vivo, whereby the protected RNA is stable in
      vitro for a longer period of time. RNA vaccines can be produced in high amounts
      and have the same major advantages as DNA vaccines but lack the potentially
      harmful effect of DNA integration into the genome.

PMID- 10602022
TI  - Co-ordination of the expression of the protein tyrosine kinase p56(lck) with the
      pre-T cell receptor during thymocyte development.
AB  - The protein tyrosine kinase p56(lck) is essential for the regulation of early
      thymocyte development by transducing pre-T cell receptor (pre-TCR) mediated
      signals. Here we have investigated the developmental timing of expression of
      p56(lck) in the thymus. We show that p56(lck) transcripts are detectable in each
      CD4(-)CD8(-) double-negative (DN) thymocyte subset defined by CD25 and CD44. The
      steady-state level of p56(lck) mRNA with these four DN subsets is similar,
      varying by less than 2-fold. However, p56(lck) protein levels are undetectable in
      DN subsets 1 and 2, but are at least 20-fold up-regulated between DN subsets 2
      and 3. Analysis of independent transgenic mouse lines in which the proximal
      p56(lck) promoter was used to drive expression of a green fluorescent protein
      (GFP) reporter gene revealed a lack of correlation between GFP mRNA expression
      and transgene copy number and variable expression of GFP protein in different
      lines. Taken together these results show that the expression of the p56(lck) gene
      is developmentally regulated at the post-transcriptional level at the precise
      developmental stage at which its upstream receptor complex, the pre-TCR, is
      expressed. These results also have implications for the interpretation of the
      phenotype of transgenic mice which utilize the p56(lck) proximal promoter.

PMID- 10602023
TI  - HIV-1 Tat mutants in the cysteine-rich region downregulate HLA class II
      expression in T lymphocytic and macrophage cell lines.
AB  - Human macrophage and T cell lines were stably transfected with HIV-1 wild-type
      Tat or Tat mutants in the cysteine-rich region displaying trans-dominant negative
      effects on HIV-1 life cycle. The expression of HLA class I and class II molecules
      was not affected by wild-type Tat. Tat mutants, instead, profoundly down
      regulated in a dose-dependent fashion the expression of class II, but not of
      class I, in both cell types by acting at the transcriptional level. Down
      regulation was manifested on constitutive and IFN-gamma-induced class II gene
      expression and did not correlate with reduced transcription of the AIR-1 gene
      product CIITA, the major transcriptional activator of class II genes, indicating
      that Tat mutants did not act by inhibiting AIR-1 gene expression. Class II down
      modulation had important functional implications in macrophages, as both antigen
      processing and presenting capacity were inhibited. These results represent the
      first evidence that a modified HIV-1 Tat product can act as a potent
      immunosuppressor by inhibiting the HLA class II expression necessary for
      triggering both cellular and humoral responses against pathogens. The use of
      these HIV-1 Tat mutants also discloses new opportunities to investigate the
      molecular mechanisms underlying the coordinate HLA class II gene transcription.

PMID- 10602024
TI  - IL-12 receptor regulation in IL-12-deficient BALB/c and C57BL/6 mice.
AB  - Immunization with protein antigen in complete Freund's adjuvant (CFA) induces Th1
      cells in BALB/c and C57BL/6 (B6) mice. Pretreatment with the same protein in
      soluble form induces Th2 cells in BALB/c but not in B6 mice and inhibits Th1 cell
      development in both. We have previously shown that inhibition of Th1 in BALB/c
      mice correlates with the down-regulation of transcripts encoding the IL-12
      receptor beta2 (IL-12Rbeta2) chain, which is required for IL-12 signaling and Th1
      cell development. We now demonstrate that IL-12-deficient BALB/c mice, when
      primed with antigen in CFA, mount a Th2 instead of the Th1 response which
      develops in wild-type mice. Conversely, IL-12-deficient B6 mice fail to develop
      Th2 cells. Thus, a default Th2 development is induced by antigen priming in IL-12
      deficient BALB/c but not B6 mice. IL-12Rbeta2 transcripts are still expressed in
      antigen-restimulated CD4(+) T cells from IL-12-deficient BALB/c and B6 mice and
      they are similarly reduced by pretreatment with soluble antigen, suggesting that
      intrinsic strain differences in IL-12R regulation do not account for the
      differential polarization to the Th2 pathway. IL-4 is not required for down
      regulation of IL-12Rbeta2 transcripts and inhibition of Th1 development in mice
      pretreated with soluble protein, as shown by their reduction in IL-4-deficient
      BALB/c mice.

PMID- 10602025
TI  - Activation-dependent changes in soluble fibronectin binding and expression of
      beta1 integrin activation epitopes in T cells: relationship to T cell adhesion
      and migration.
AB  - The relationship between activation-dependent changes in beta1 integrin
      conformation, T cell adhesion to immobilized fibronectin, and T cell migration in
      vitro was analyzed in this study. Stimulation of Jurkat T cells and peripheral T
      cells with Mn(2+), the activating beta1 integrin-specific monoclonal antibody
      (mAb) TS2 /16, CD2, or CD28 stimulation led to increased adhesion, soluble
      fibronectin (FN) binding and expression of the activation epitope defined by the
      beta1 integrin mAb HUTS-21. Phorbol 12-myristate 13-acetate treatment increased
      adhesion, but not soluble FN binding or HUTS-21 epitope expression. In peripheral
      T cells, CD3 or CD7 stimulation also led to increased adhesion, soluble FN
      binding and HUTS-21 epitope expression. Soluble FN blocked peripheral T cell
      adhesion induced by Mn(2+) or TS2/16, but had no effect on adhesion induced by
      the other integrin-activating signals. In contrast, migration induced by TS2/16,
      CD2, CD3, CD7 or CD28 stimulation was blocked by excess soluble FN.
      Phosphoinositide 3-OH kinase (PI 3-K) inhibitors blocked receptor-mediated
      increases in cell adhesion, but not soluble FN binding or HUTS-21 expression.
      Migration was similarly unaffected by PI 3-K inhibitors, with the exception of
      CD7- and CD28-induced migration, which was specifically blocked by LY294,002.
      These results suggest that activation-dependent changes in beta1 integrin
      conformation are PI 3-K-independent and are involved in T cell migration but not
      adhesion.

PMID- 10602026
TI  - TCR antagonist peptides induce formation of APC-T cell conjugates and activate a
      Rac signaling pathway.
AB  - T cell receptor antagonists inhibit T cell activation by antigen, and by
      themselves fail to induce phenotypic changes associated with T cell activation.
      However, they can induce limited tyrosine phosphorylation of TCRzeta chain. Here
      we show that TCR antagonists are potent inducers of APC-T cell conjugates,
      cytoskeletal reorganization, and capping of certain T cell proteins. These events
      are associated with a signaling pathway involving tyrosine phosphorylation of Vav
      and SLP-76, activation and capping of Rac-1, a protein previously linked with
      cytoskeletal reorganization, and activation of JNK. The finding that antagonist
      peptides stimulate this pathway, while failing to stimulate other TCR-mediated
      signaling pathways, indicates the presence in T cells of a hierarchy of signaling
      that is sensitive to the avidity of Ag / MHC-TCR interaction.

PMID- 10602027
TI  - Association of STAT1, STAT3 and STAT5 proteins with the IL-2 receptor involves
      different subdomains of the IL-2 receptor beta chain.
AB  - Upon IL-2 stimulation of T lymphocytes, the IL-2 receptor (IL-2R) becomes
      phosphorylated on specific tyrosine residues which serve as docking sites for
      proteins containing SH2 or phosphotyrosine binding domains. To study the
      interaction of the IL-2Rbeta chain with Shc and STAT proteins, subdomains of the
      IL-2Rbeta chain were expressed as tyrosine-phosphorylated glutathione S
      transferase fusion proteins and used to pull-down interacting proteins from Kit
      225 cell lysates. These experiments provide direct biochemical evidence that
      binding to the IL-2R of the adaptor protein Shc requires phosphorylation of Tyr
      338 in the IL-2Rbeta acidic subdomain. In addition, we report that STAT proteins
      that are activated by IL-2, i.e. STAT1, STAT3 and STAT5, indeed associate with
      the IL-2Rbeta chain. Both the A and B isoforms of STAT5 were found to associate
      with Tyr-510 of the IL-2Rbeta C-terminal region, depending on its
      phosphorylation. In contrast, STAT1 and STAT3 associated with the IL-2Rbeta chain
      through its acidic subdomain. These results indicate that the interaction between
      IL-2Rbeta and STAT1 or 3 does not require either phosphorylation of the receptor
      or even the presence of tyrosine residues of IL-2Rbeta. Thus, the IL-2R recruits
      STAT proteins through different modes of interaction.

PMID- 10602028
TI  - Critical role for mitochondria in B cell receptor-mediated apoptosis.
AB  - Antigen-induced apoptosis of B cells serves to deplete the immune repertoire of
      anti-self specificities leading to central and peripheral B cell tolerance.
      However, the mechanism of B cell receptor (BCR)-mediated apoptosis is widely
      unknown. By using the human Burkitt lymphoma cell line BL60 as a model system for
      human germinal center B cells we show here that BCR-mediated apoptosis requires
      transcriptional activity but, in contrast to activation-induced T cell apoptosis,
      is neither mediated via known death receptor systems nor does it involve initial
      activation of caspase-8. Moreover, during BCR-induced apoptosis cytochrome c
      release and mitochondrial permeability transition (PT) precedecaspase activation.
      Although caspase inhibition after BCR stimulation blocks cleavage of caspase
      substrates and DNA fragmentation it does not prevent mitochondrial PT, cytochrome
      c release and cell death. Thus, BCR-mediated apoptosis is initiated by the
      caspase-independent induction of mitochondrial PT resulting in release of
      cytochrome c and subsequent activation of caspase-9, downstream caspases and
      apoptosis.

PMID- 10602029
TI  - ZAP-70 is required for calcium mobilization but is dispensable for mitogen
      activated protein kinase (MAPK) superfamily activation induced via CD2 in human T
      cells.
AB  - Stimulation with specific pairs of anti-CD2 antibodies can induce T cell
      activation and proliferation. In this study, we investigate the significance of
      ZAP-70 in CD2 signaling using ZAP-70-deficient T cells derived from a CD8
      deficient patient and show that ZAP-70 is necessary for cellular proliferation
      and cytokine production in T cells stimulated via CD2. Biochemical analyses show
      that CD2 stimulation induces activation of mitogen-activated protein kinase
      (MAPK) superfamily in ZAP-70-deficient T cells, indicating that a ZAP-70
      independent pathway(s) exists for MAPK superfamily activation via CD2. In
      contrast, intracellular Ca(2+) mobilization and activation of nuclear factor of
      activated T cells (NFAT) upon CD2 triggering were impaired in T cells lacking ZAP
      70. Furthermore, we found that pharmacological Ca(2+) elevation combined with CD2
      stimulation restored NFAT activation and subsequent cytokine production in ZAP-70
      deficient T cells. These results indicate that in CD2 signaling, ZAP-70 plays an
      essential role in Ca(2+) mobilization and NFAT activation.

PMID- 10602030
TI  - Fractalkine receptor expression by T lymphocyte subpopulations and in vivo
      production of fractalkine in human.
AB  - Expression and function of the fractalkine receptor CX3CR1 by T lymphocyte
      subpopulations was evaluated in healthy individuals. In CD8(+) T lymphocytes,
      CX3CR1 was expressed by and functional in both CD45RO(-) and CD45RO(+) cells. In
      CD4(+) T lymphocytes, CX3CR1 was expressed mainly by CD45RO(+) cells, and almost
      exclusively by activated HLA-DR(+) T lymphocytes. This receptor was functional in
      CD45RO(+) cells, but not in CD45RO(-) cells. Expression of fractalkine was
      detected by in situ hybridization and immunohistochemistry in endothelial cells
      of normal lung and thymus. In hyperplastic lymph nodes, fractalkine was expressed
      by endothelial cells of high endothelial venules and of subcapsular vessels, by
      follicular dendritic cells (FDC) and by some follicle lymphocytes. Fractalkine
      mRNA was constitutively present in the HK FDC-like cell line, and it was induced
      in vitro in B lymphocytes stimulated by an anti-micro or by a CD40 mAb. These
      findings indicate that fractalkine may contribute to the recruitment of effector
      T helper lymphocytes, either in peripheral tissues or in lymphoid organs. In
      these tissues, fractalkine and its receptor may favor contact within follicles
      between activated T helper lymphocytes, activated B lymphocytes and FDC, thus
      contributing to the maturation of the B lymphocyte response.

PMID- 10602031
TI  - Traffic of L-selectin-negative T cells to sites of inflammation.
AB  - T cells responding to antigen in vivo down-regulate L-selectin, the lymph node
      homing receptor, as they develop into activated effector cells. The concomitant
      up-regulation of the proinflammatory adhesion molecules LFA-1, CD44, and VLA-4
      suggests that, after their release into the circulation, they traffic to sites of
      antigen deposition and inflammation. Previous evidence, however, has suggested a
      role for L-selectin in the recruitment of both neutrophils and lymphocytes into
      sites of inflammation, which would indicate that these L-selectin(-) effector
      cells could not be the precursors of inflammatory cells. We therefore directly
      tested whether L-selectin(-) T cells activated in vivo are capable of homing to
      model inflammatory sites. L-selectin(-) cells isolated from mice primed with
      alloantigen or with a contact sensitizer migrated to inflammation markedly better
      than L-selectin(+) cells from the same animals. Furthermore, the analogous
      population of CD44(hi)integrin(hi) cells from intravenously primed L-selectin
      knockout mice traffic efficiently to inflammatory sites and reject allogeneic
      skin grafts with normal kinetics. These data demonstrate that the previously
      described L-selectin(-) population of T cells that differentiate into effectors
      in spleen and lymph nodes subsequently traffic to inflammatory sites, due in part
      to their increased expression of other proinflammatory adhesion molecules.

PMID- 10602032
TI  - Positive and negative regulatory elements contribute to CpG oligonucleotide
      mediated regulation of human IL-6 gene expression.
AB  - Oligonucleotides (ODN) expressing immunostimulatory "CpG motifs" activate human
      RPMI 8226 myeloma cells to secrete IL-6. Using deletion and site-directed
      mutagenesis of the human (h)IL-6 promoter region, two positive regulatory
      elements (the binding sites for the 5'-CCAAT / enhancer binding protein-beta and
      NF-kappaB) were identified. Two negative regulatory elements, the 3'
      retinoblastoma control element (RCE) and the binding site for Epstein-Barr virus
      C-promoter binding factor 1 (CBF1), also contributed to CpG ODN induction of hIL
      6 gene expression. Of interest, CpG ODN treatment induced the dissociation of a
      repressor protein from its 3'-RCE binding site. Thus, CpG ODN regulation of hIL-6
      gene expression involves both enhancer and derepression mechanisms.

PMID- 10602033
TI  - Association between HIV-specific T helper responses and CTL activities in
      pediatric AIDS.
AB  - We examined the relationship between the profile of HIV-specific T helper (Th)
      cell responses, cytotoxic T lymphocyte (CTL) activity, HIV viral load, and CD4(+)
      T cell counts during longitudinal studies in children with perinatal HIV
      infection. Patients with AIDS demonstrated undetectable or low levels of HIV
      specific Th and CTL activities, and exhibited almost exclusively Th0 type of
      responses with low IFN-gamma and IL-4 production. The levels of IL-2 expression
      in the envelope (env) peptide-stimulated peripheral blood mononuclear cells were
      increased in children with a slowly progressive disease, concomitant with higher
      numbers of CD45RO(+) memory T cells and increased proportions of Th1 clones. In
      these patients, high levels of env peptide-specific IL-2 expression correlated
      with increases in HIV-specific CTL responses, whereas a delay in the generation
      of HIV-specific CTL activity was associated with lower IL-2 production and
      elevated Th2 responses. Patients with slow disease progression produced higher
      levels of beta-chemokines than those detected in children with AIDS. These
      results suggest that an impaired development of HIV-specific cellular responses
      and inhibition of T cell differentiation during infancy are associated with fast
      disease progression. They also point to a protective role of noncytotoxic
      antiviral activity that might complement HIV-specific CTL responses in children
      with a slowly progressive disease.

PMID- 10602034
TI  - Oral anti-IgE immunization with epitope-displaying phage.
AB  - An essential requirement for oral vaccines is the ability to survive the harsh
      environment of the stomach in an antigenically intact form. As bacteriophages are
      adapted to this environment we used epitope-displaying M13 bacteriophages as
      carriers for an experimental oral anti-IgE vaccine. The feasibility of this
      approach was tested in a simulated gastric fluid using two different mimotopes as
      well as an anti-idiotypic Fab of the non-anaphylactogenic monoclonal anti-IgE
      antibody BSW17. All phage clones remained infective after this treatment.
      However, only epitopes displayed on the pVIII protein were still recognized by
      BSW17 whereas pIII-expressed epitopes were rapidly inactivated. Surprisingly,
      when used for oral immunization of mice all phage clones induced anti-IgE
      antibodies. In contrast, oral immunization with the purified, pVIII protein
      displaying the mimotope induced anti-phage but no anti-IgE antibodies. After
      feeding a single dose of mimotope-displaying bacteriophage, phage DNA could be
      detected in mouse feces for 10 days. Our results show that epitope-displaying
      bacteriophages can be used to induce an epitope-specific antibody response via
      the oral route.

PMID- 10602035
TI  - Anergy and suppression regulate CD4(+) T cell responses to a self peptide.
AB  - To examine the role of cognate peptide in establishing CD4(+) T cell tolerance,
      we have mated transgenic mice that express the major I-E(d)-restricted
      determinant (S1) from the influenza virus PR8 hemagglutinin (HA28 mice) with mice
      expressing a S1-specific T cell receptor (TS1 mice). Surprisingly, S1-specific
      CD4(+) T cells were not substantially deleted in TS1xHA28 mice; indeed, lymph
      node cells expressing the S1-specific TCR were as abundant in TS1xHA28 mice as in
      TS1 mice. The S1-specific T cells in TS1xHA28 mice were, however, impaired in
      their ability to respond to S1 peptide both in vitro and in vivo, and contained
      two distinct populations. Approximately half expressed a unique cell surface
      phenotype (CD25(hi)/CD45RB(int)) and had been anergized by the neo-self S1
      peptide. The remainder responded normally to the S1 peptide if purified away from
      the anergic T cells, but their proliferation was suppressed when the anergic T
      cells were also present in unfractionated lymphnode cells or in mixed cultures.
      These findings establish that anergy and suppression are coordinated mechanisms
      by which autoreactive CD4(+) T cells are regulated and that anergic/suppressor
      CD4(+) T cells can develop in response to self peptides.

PMID- 10602036
TI  - Redistribution of Bruton's tyrosine kinase by activation of phosphatidylinositol
      3-kinase and Rho-family GTPases.
AB  - Bruton's tyrosine kinase (Btk) is a member of the Tec family of protein tyrosine
      kinases (PTK) characterized by an N-terminal pleckstrin homology domain (PH)
      thought to directly interact with phosphoinositides. We report here that wild
      type (wt) and also a gain-of-function mutant of Btk are redistributed following a
      wide range of receptor-mediated stimuli through phosphatidylinositol 3-kinase (PI
      3-K) activation. Employing chimeric Btk with green fluorescent protein in
      transient transfections resulted in Btk translocation to the cytoplasmic membrane
      of live cells through various forms of upstream PI 3-K activation. The
      redistribution was blocked by pharmacological and biological inhibitors of PI 3
      K. A gain-of-function mutant of Btk was found to be a potent inducer of
      lamellipodia and/or membrane ruffle formation. In the presence of constitutively
      active forms of Rac1 and Cdc42, Btk is co-localized with actin in these regions.
      Formation of the membrane structures was blocked by the dominant negative form of
      N17-Rac1. Therefore, Btk forms a link between a vast number of cell surface
      receptors activating PI 3-K and certain members of the Rho-family of small
      GTPases. In the chicken B cell line, DT40, cells lacking Btk differed from wt
      cells in the actin pattern and showed decreased capacity to form aggregates,
      further suggesting that cytoskeletal regulation mediated by Btk may be of
      physiological relevance.

PMID- 10602037
TI  - Inhibition of Fas-mediated apoptosis by the B cell antigen receptor through c
      FLIP.
AB  - Cross-linking of the B cell antigen receptor (BCR) induces resistance to Fas (APO
      1 / CD95)-dependent apoptosis and thereby regulates one mechanism of B cell
      selection during antigen stimulation. To investigate the molecular mechanism by
      which BCR signaling regulates the Fas pathway, we examined the expression of
      constituents of the death-inducing signaling complex (DISC), including Fas, FADD,
      caspase-8 and cellular FLICE-inhibitory protein (c-FLIP). No significant changes
      in the cellular levels of Fas, FADD or caspase-8 were observed after BCR cross
      linking. By contrast, the long isoform of c-FLIP (c-FLIP(L)) was significantly up
      regulated by BCR cross-linking in primary B cells and in two B cell lines, A20
      and WEHI-279. Moreover, transfection of c-FLIP(L) into A20 cells inhibited Fas
      dependent apoptosis and suppressed recruitment of caspase-8 to the DISC. BCR
      cross-linking or FLIP overexpression also protects B cells from TRAIL-induced
      apoptosis. Thus, BCR signaling up-regulates c-FLIP(L) and suppresses the Fas- and
      TRAIL-receptor apoptosis pathways which could be important for tolerance and
      selection of antigen-specific B cells.

PMID- 10602038
TI  - Molecular modeling and site-directed mutagenesis of CCR5 reveal residues critical
      for chemokine binding and signal transduction.
AB  - The CC chemokine receptor CCR5 is the receptor for several chemokines and
      coreceptor for the entry of HIV-1. Whereas many studies focus on CCR5 interaction
      with HIV-1, residues in CCR5 important for chemokine binding and subsequent
      signal transduction remain poorly understood. Here we use an approach combining
      protein structure modeling and site-directed mutagenesis to probe the structure
      of CCR5 and its interactions with chemokine ligands and HIV-1. Structural models
      of CCR5 rationalize extensive biological data about the role of CCR5 in HIV-1
      envelope glycoprotein gp120 binding and HIV-1 entry. Furthermore, we carry out
      site-directed mutagenesis guided by structural analysis of the complex of CCR5
      and a chemokine. This leads to the novel observation that certain residues, such
      as Tyr10 and Lys26, in the N terminus of CCR5 play a critical structural role for
      ligand binding and signaling. Single glycine substitution of these residues
      significantly decreases chemokine binding and signal transduction. These results
      provide new insight into the structural basis for CCR5 receptor-ligand
      interaction and may guide the design of novel inhibitors.

PMID- 10602039
TI  - Interaction and functional interference of C/EBPbeta with octamer factors in
      immunoglobulin gene transcription.
AB  - The ubiquitous transcription factor C/EBPbeta functions as an activator or
      inhibitor depending on the ratios of three isoforms translated from in-frame AUG.
      We have identified C/EBP binding sites in both light and heavy chain
      immunoglobulin (Ig) promoters. Of the two C/EBP sites present in the light chain
      promoter, the upstream site is essential for promoter function. Mutation of this
      element drastically decreases promoter activity, despite the presence of an
      intact octamer element. Both light and heavy chain promoters were activated or
      inhibited by C/EBPbeta isoforms in transfected cells according to the
      transactivation ability of these isoforms. Endogenous IgM mRNA and protein were
      repressed by the inhibitory form, C/EBPbeta-3, indicating a general role of
      C/EBPbeta in the regulation of Ig genes. We show that C/EBPbeta-3 forms ternary
      complexes with Oct-1 and Oct-2 on heavy and light chain promoters, and also
      interacts with both octamer-binding proteins in the absence of DNA. This suggests
      that interference of Oct-1/Oct-2 function by C/EBPbeta-3 may account for the
      observed repression. Inhibition by C/EBPbeta-3 occurs not only through a C/EBP
      site, but also through the octamer element, as shown by co-transfection
      experiments with heterologous promoter constructs. Thus, C/EBPbeta regulates Ig
      promoter transcription by modulating octamer factor activity.

PMID- 10602040
TI  - Induction of optimal anti-viral neutralizing B cell responses by dendritic cells
      requires transport and release of virus particles in secondary lymphoid organs.
AB  - Dendritic cells (DC) are sentinels of the immune system, transporting antigens
      from the periphery to secondary lymphoid organs. This study investigates the
      interactions of DC with B cells for the induction of anti-viral neutralizing
      antibody responses. Using the vesicular stomatitis virus glycoprotein (VSV-G) as
      a model antigen, we show that DC contain infection with cytopathic VSV in the
      presence of a functional IFN system, facilitating transport and release of low
      levels of live virus in secondary lymphoid organs. DC exposed to live virus
      induced efficient neutralizing anti-viral B cell responses. In contrast, DC
      transporting UV-inactivated viral antigens were poor activators of anti-viral B
      cells, although they were capable of very efficiently inducing virus-specific Th
      cells. Transgenic DC expressing a membrane-bound form of VSV-G induced
      neutralizing B cell responses; however, this DC-induced, Th-dependent B cell
      response was significantly slower than the anti-viral B cell response induced by
      DC infected with live VSV, and was strongly dependent on concomitant priming of T
      help. These results suggest that DC may play a double role during infection with
      cytopathic virus: they transport and release live virus in secondary lymphoid
      tissues for optimal direct B cell induction and offer MHC class II-associated
      determinants for induction of T help.

PMID- 10602041
TI  - Deficiency of IL-2 or IL-6 reduces lymphocyte proliferation, but only IL-6
      deficiency decreases the contact hypersensitivity response.
AB  - We evaluated the importance of IL-2 and IL-6 in primary antigen-induced
      proliferation of lymph node cells (LNC) and the induction of contact
      hypersensitivity (CH). These responses were examined in cytokine-deficient mice
      following application of the contact sensitizer, oxazolone (OX). Proliferation
      and induction of IL-6 by LNC from IL-2-deficient (IL-2(-/-)) mice were reduced by
      approximately 95 %, relative to the proliferation of LNC from IL-2(+/+) mice,
      although induction and elicitation of CH responses was not significantly
      affected. In contrast, the proliferation of LNC from sensitized IL-6(- /-) mice
      was reduced by approximately 50% and the CH response was significantly reduced,
      relative to responses of IL-6(+/+) mice. Although nonspecific inflammatory
      responses induced by croton oil were similar in IL-6(+/+) and IL-6(-/-) mice,
      both the acute inflammatory response to OX and the second phase of the
      inflammatory response were significantly reduced. Thus IL-2 and IL-6 play a
      significant role in the total proliferative response of LNC following primary
      contact sensitization. However, the proliferation they promote is not critical
      for priming the antigen-specific effector cells responsible for eliciting CH
      responses and IL-6 appears to be more important for expression of the later
      phases of acute inflammation and the CH induced by OX.

PMID- 10602042
TI  - Macrophage-derived chemokine production by activated human T cells in vitro and
      in vivo: preferential association with the production of type 2 cytokines.
AB  - Macrophage-derived chemokine (MDC), a potent chemoattractant for chronically
      activated Th2 lymphocytes, is constitutively expressed by dendritic cells, B
      cells, macrophages, and thymic medullary epithelial cells, whereas monocytes, NK
      cells, and T lymphocytes produce MDC only upon appropriate stimulation. In this
      study, we show in vitro MDC production also by activated T cells, which
      preferentially associate with the production of Th2 cytokines, IL-4, IL-5, and IL
      6, and inversely correlate with the production of the Th1 cytokine, IFN-gamma.
      Moreover, high levels of MDC were detected in the sera of the great majority of
      subjects suffering from mycosis fungoides/Sezary syndrome or atopic dermatitis,
      which are considered as disorders characterized by the predominant expansion and
      activation of Th2 cells, respectively. By contrast, serum MDC levels in subjects
      with multiple sclerosis or Crohn's disease, which are characterized by a Th1
      predominance, did not differ significantly from those of healthy controls.
      Finally, MDC expression was detected in the skin biopsy specimens of subjects
      with atopic dermatitis, where it was expressed by both dendritic cells and T
      lymphocytes. Taken together, these findings suggest that MDC production by
      activated T cells may occur both in vitro and in vivo, particularly in
      association with Th2 cytokines, thus providing an important amplification circuit
      for Th2-mediated responses.

PMID- 10602043
TI  - Binding of lipopolysaccharide (LPS) to CHO cells does not correlate with LPS
      induced NF-kappaB activation.
AB  - Activation of myeloid cells by lipopolysaccharide (LPS) is a key event in the
      development of gram-negative sepsis. One crucial step within this process is the
      binding of LPS to CD14. CD14 is a glycosylphosphatidylinositol (GPI)-anchored
      membrane protein requiring at least one additional membrane-spanning molecule for
      signal transduction. It is not clear whether the function of CD14 is to merely
      catalyze LPS binding, followed by the interaction of LPS with the signal
      transducer, or whether CD14 has a more specific function and may be a part of the
      signaling complex. To address this question we generated Chinese hamster ovary
      (CHO) cells expressing a human GPI-anchored form of LPS-binding protein (mLBP) to
      substitute for CD14 as LPS acceptor molecule. By comparison of CHO / mLBP with
      CHO / vector and CHO / CD14 cells we found that expression of GPI-linked LBP
      results in an enhanced binding of LPS but not in an increase in cell activation
      as determined by translocation of NF-kappaB. Furthermore, excess of recombinant
      soluble LBP resulted also in increased LPS binding without affecting NF-kappaB
      translocation. These data show that LPS binding alone is not sufficient to induce
      signaling. We conclude that CD14 is more than a catalyst for LPS binding: it
      seems to be directly involved in LPS signaling and thus appears to be an
      essential part of the signaling complex.

PMID- 10602044
TI  - An IgE-dependent secretory response of mast cells can be induced by a
      glycosphingolipid-specific monoclonal antibody.
AB  - The signal transduction pathway of the type 1 Fcepsilon receptor (FcepsilonRI)
      has been proposed to be spatially constrained to plasma membrane microdomains
      enriched in glycosphingolipids and cholesterol. These domains are proposed to
      serve as platforms that enhance the efficiency of the antigen-receptor stimulus
      response coupling process. Here we describe a monoclonal antibody (mAb)
      designated 2B5, raised by immunizing mice with rat mucosal-type mast cell (line
      RBL-2H3) membranes, which binds to glycosphingolipids and causes a dose-dependent
      secretory response of these cells. This secretory response to mAb 2B5 requires
      binding of IgE to the FcepsilonRI on these cells, although direct interactions
      between IgE and mAb 2B5 are excluded. The bound IgE- or FcepsilonRI-specific mAb
      did not affect binding of mAb 2B5 or its Fab fragments to the RBL-2H3 cells and
      only a limited interference with the binding of IgE to the FcepsilonRI by mAb 2B5
      was observed. Binding of mAb 2B5 to the RBL-2H3 cells induced a distribution of
      fluorescently labeled IgE similar to that produced by antigen-induced aggregation
      of the IgE-FcepsilonRI. Thus we suggest that mAb 2B5 binds to cell surface
      glycosphingolipids that are probably associated with the FcepsilonRI-IgE
      complexes and causes their aggregation, thereby initiating the cascade leading to
      the cell's secretory response.

PMID- 10602045
TI  - Identification of a novel mechanism for endotoxin-mediated down-modulation of CC
      chemokine receptor expression.
AB  - In the present study, we explored the molecular mechanisms by which bacterial
      endotoxin (LPS) mediates the down-regulation of CCR2 receptors on human
      monocytes. We found that LPS induced a marked reduction in CCR2 cell surface
      protein levels which was blocked by pretreatment with the tyrosine kinase
      inhibitors genistein and herbimycin A. The effector mechanism underlying LPS
      induced CCR2 down-modulation appears to involve the enzymatic activity of
      proteinases since Western blot analysis of LPS-stimulated monocytes revealed the
      degradation of a 38-kDa species corresponding to the CCR2B monomer. In RBL cells
      expressing the CCR2B-green fluorescent protein (GFP) fusion chemokine receptor,
      LPS stimulated the internalization and degradation of CCR2. The serine proteinase
      inhibitor N-alpha-p-tosyl-L-lysine chloromethyl ketone blocked LPS-induced down
      modulation of CCR2 in monocytes and CCR2B-GFP in RBL cells. This work describes a
      previously uncharacterized mechanism for CC chemokine receptor down-modulation
      that is dependent upon tyrosine kinase activation and serine proteinase-mediated
      receptor degradation and may provide further insight into the mechanisms of
      leukocyte regulation during immunological and inflammatory responses.

PMID- 10602046
TI  - Memory CD8 T lymphocytes express inhibitory MHC-specific Ly49 receptors.
AB  - Natural killer (NK) cells survey potential targets using an array of receptors
      specific for major histocompatibility complex class I molecules. In mice, members
      of the Ly49 receptor gene family are expressed on overlapping subsets of NK cells
      and on CD1-restricted NK1 T cells. Here we characterize a population of memory
      cytotoxic (CD8(+)) T lymphocytes which also express inhibitory Ly49 family
      members. This cell population increases steadily with age; by 11 months, over one
      third of memory CD8(+) T cells express Ly49 molecules. These cells appear to
      express a normal TCR repertoire, and share several traits with previously
      activated T cells. Analysis of mutant mouse strains reveals that normal
      development of these cells depends upon the presence of the transporter
      associated with antigen presentation (TAP), classical class I molecules, and
      class II molecules. As a functional consequence of Ly49 expression, we
      demonstrate that T cell receptor-mediated activation of CD8(+) T cells is
      inhibited by Ly49 interactions with cognate class I molecules. We hypothesize
      that conventional memory CD8(+) T cells initiate Ly49 expression as a means of
      dampening an immune response and / or inhibiting T cell autoreactivity.

PMID- 10602047
TI  - The role of the CD44 cytoplasmic and transmembrane domains in constitutive and
      inducible hyaluronan binding.
AB  - The role of the CD44 cytoplasmic domain in cells displaying constitutive or
      inducible hyalu ronan (HA) binding mediated by wild-type CD44 was investigated
      using mutant CD44 constructs with the cytoplasmic domain truncated or replaced by
      foreign sequences. In cell lines in which wild-type CD44 bound HA constitutively,
      chimeric constructs consisting of the CD44 external domain and the transmembrane
      plus cytoplasmic domains of beta5 integrin bound as well as wild-type CD44,
      arguing that the specific sequence of the cytoplasmic and transmembrane domains
      was not critical for HA binding by the external domain. The cytoplasmic domain
      sequence did not contribute to the 'inducible' phenotype in cell lines which did
      not bind HA constitutively, but which could be induced to bind by CD44-specific
      mAb. Tailless CD44 was inducible in these cells, as was chimeric CD44 with the
      integrin beta5 cytoplasmic domain. Dimer- or oligomerization of CD44 by addition
      of AP1510 to cells containing CD44 / FKBP chimeric constructs caused a modest
      enhancement of HA binding in cells that bound constitutively, but did not alter
      the inducible phenotype. This result suggests that clustering of CD44 from inside
      the cell is not a sufficient 'inside-out' signal to activate HA binding in
      inducible cells.

PMID- 10602048
TI  - Comparable heavy and light chain pairings in normal and systemic lupus
      erythematosus IgG(+) B cells.
AB  - Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized
      by the presence of high immunoglobulin serum titers, but the mechanism by which
      these arise remains unclear. It has been suggested that the disease is associated
      with specific antibody features, including variable gene use, the presence of
      charged complementarity-determining region residues and/or an aberrant process of
      secondary light chain rearrangement. To study this in more detail, we compared
      variable, diversity and joining gene segment use, somatic mutation, and heavy and
      light chain pairings in single peripheral IgG(+) B cells between one normal (209
      B cells) and two SLE (156 B cells) donors. In contrast to others, we found no
      systematic differences, indicating that the memory B cell repertoires in normal
      and SLE donors are shaped in a similar way.

PMID- 10602049
TI  - The chemokine TECK is expressed by thymic and intestinal epithelial cells and
      attracts double- and single-positive thymocytes expressing the TECK receptor
      CCR9.
AB  - Chemokines are key regulators of migration in lymphoid tissues. In the thymus,
      maturing thymocytes move from the outer capsule to the inner medulla and thereby
      interact with different types of stromal cells that control their maturation and
      selection. In the process of searching for molecules specifically expressed at
      different stages of mouse thymic differentiation, we have characterized the cDNA
      coding for the thymus-expressed chemokine (TECK) and its receptor CCR9. The TECK
      receptor gene was isolated and shown to be localized on the mouse chromosome 9F1
      F4. Thymic dendritic cells have been initially thought to be a prevalent source
      of TECK. In contrast, our results indicate that thymic epithelial cells
      constitute the predominant source of TECK. Consistent with the latter
      distribution, the TECK receptor is highly expressed by double-positive
      thymocytes, and TECK can chemoattract both double-positive and single-positive
      thymocytes. The TECK transcript is also abundantly expressed in the epithelial
      cells lining the small intestine. In conclusion, the interplay of TECK and its
      receptor CCR9 is likely to have a significant role in the recruitment of
      developing thymocytes to discrete compartments of the thymus.

PMID- 10602050
TI  - Transgenic expression of an immunologically privileged retinal antigen
      extraocularly enhances self tolerance and abrogates susceptibility to autoimmune
      uveitis.
AB  - Interphotoreceptor retinoid-binding protein (IRBP) is an immunologically
      privileged retinal antigen that can elicit experimental autoimmune uveitis (EAU).
      The nature and extent of tolerance to immunologically privileged self antigens is
      poorly understood. To investigate whether transgenic expression of IRBP
      extraocularly enhances tolerance and protects from EAU we prepared mice that
      express half of the mouse IRBP gene, containing a potent uveitogenic epitope
      (residues 161 - 180), under control of MHC class II promoter. Transgene mRNA was
      detectable in many tissues. Transgenic protein was undetectable by conventional
      assays, but was detected in thymic tissue by lymphocyte proliferation assay after
      induction of the promoter. Transgenic mice challenged with p161 - 180 did not
      develop EAU and had reduced immunological responses, but remained susceptible to
      EAU induced by whole IRBP, that contains additional uveitogenic epitopes. Disease
      was also induced by wild type T cells specific to p161 - 180. Thus, extraocular
      expression of a privileged retinal antigen enhances self tolerance, supporting
      the notion that sequestration contributes to immune privilege. Exceedingly low
      levels of transgene expression result in tolerance that is both profound and
      epitope specific, implying anergy or deletion of the endogenous uveitogenic
      repertoire. The same level of expression is, however, insufficient to tolerize
      wild-type effector T cells in the periphery.

PMID- 10602051
TI  - Human CD4 residue Phe 43 is critical for repertoire development and maturation of
      MHC class II restricted CD4 single-positive T lineage cells in vivo.
AB  - To determine the functional significance of structural alteration of CD4-MHC
      class II interaction in vivo, two human (h)CD4-transgenic (tg) mice were
      established on a murine (m)CD4(-/-) H-2(b) background. The MHC class II binding
      competent hCD4 (R240AhCD4) rescues the number and helper activity of hCD4(+)CD8(
      ) single-positive (SP) mature T cells in mCD4(-/-) mice. In contrast, the MHC
      class II binding-deficient F43I hCD4 mutant cannot facilitate normal
      differentiation of double-positive thymocytes to CD4(+)CD8(-) SP thymocytes.
      Hence, only 20 - 25% of CD4(+)CD8(-) SP T cells found in wild-type or R240A
      hCD4tg mice are generated, with resultant diminished helper responses.
      Differentiation of F43I hCD4 SP T cells is MHC class II but not class I dependent
      as demonstrated by crossing F43I hCD4tg mice onto MHC-deficient mice. These cells
      show a different pattern of TCR Valpha and Vbeta gene usage relative to
      comparable R240A hCD4 SP T cells from R240 AhCD4tg animals. Expression of
      activation markers including CD25 and CD69 on F43I hCD4 SP T cells suggests that
      autoreactive specificites may not have been eliminated intrathymically.
      Collectively, the results show that CD4-MHC class II interaction significantly
      influences intrathymic repertoire selection.

PMID- 10602052
TI  - Major T cell epitope-containing peptides can elicit strong antibody responses.
AB  - Peptides containing major T cell epitopes have the capacity to induce T cell
      anergy and have therefore been proposed for the treatment of allergic and
      autoimmune diseases. Such peptides should not be immunogenic, i. e. should not
      contain a B cell recognition site. We have evaluated in BALB/c mice the
      therapeutic potential of a 15-mer peptide (p21 - 35) derived from Der p2, a major
      allergen of the house dust mite Dermatophagoides pteronyssinus, which contains a
      dominant T cell epitope but is not recognized by antibodies to Der p2.
      Unexpectedly, p21 - 35 elicited strong immune responses, suggesting the presence
      of a cryptic B cell epitope. Similar results were obtained with mice of three
      additional MHC haplotypes. A core sequence of four amino acids (Ile-Ile-His-Arg)
      corresponding to residues 28 - 31 was shared by the B and T cell epitopes.
      Critical residues for B cell recognition were Arg31 and Lys33, while Ile28 was
      essential for T cell recognition. A Lys33Ala mutant of p21 - 35 still activated T
      cells but had much reduced immunogenic properties, making it a suitable
      alternative peptide for T cell anergy induction. Careful investigation of the
      immunogenic potential of peptides used to induce T cell anergy should be carried
      out prior to their clinical application.

PMID- 10602053
TI  - Visualization of inhibitory Ly49 receptor specificity with soluble major
      histocompatibility complex class I tetramers.
AB  - Murine natural killer (NK) cells are inhibited from killing their targets by the
      interaction between inhibitory, C-type lectin like Ly49 receptors and major
      histocompatibility complex (MHC) class I molecules. The receptors have
      overlapping specificity, and it has been difficult to analyze specific aspects of
      the interaction between different Ly49 receptors and their respective ligands. We
      have addressed this problem using tetramers of bacterially expressed, non
      glycosylated, MHC class I molecules refolded with different peptides. Our results
      indicate that this technology is useful for analysis of Ly49 receptor specificity
      as well as for monitoring of NK cell subsets, with the following major
      conclusions emerging from this study: (1) tetramers of H-2D(d) bound the Ly49A
      receptor; the MHC associated glycan, previously suggested to be involved in
      recognition by this receptor, is thus not required for Ly49A receptor binding;
      (2) in support and extension of a recent report indicating peptide selectivity in
      the recognition of H-2K(b) by Ly49C(+) cells, H-2K(b) tetramer binding to Ly49C
      receptors was strongly influenced by the peptide presented by the MHC class I
      molecule; (3) tetramer binding allowed visualization of interactions that have
      not previously been detected in functional studies, such as the recognition of H
      2D(b) by Ly49A and Ly49C.

PMID- 10602054
TI  - Expression of Fas ligand improves the effect of IL-4 in collagen-induced
      arthritis.
AB  - The present study was aimed at investigating whether the expression of Fas ligand
      (FasL) by CHO cells transfected with IL-4 (CHO/IL-4) or IL-10 (CHO/IL-10) genes
      would improve the effect of the cytokine. DBA/ 1 mice immunized with type II
      collagen were treated with suboptimal doses of transfected CHO cells (a single s.
      c. injection of 2 x 10(5) cells) around onset of arthritis. Severe collagen
      induced arthritis (CIA) developed in the control groups injected with PBS, CHO
      /beta-galactosidase/FasL, CHO/IL-4 or CHO/IL-10 cells. In contrast,
      administration of CHO/IL-4/FasL, but not CHO/IL-10/FasL, cells significantly
      reduced the clinical severity and resulted in rapid and sustained suppressive
      effect. Amelioration of CIA was not due to a prolonged in vivo secretion of IL-4
      since expression of FasL by CHO cells shortened the in vivo survival of the
      xenogeneic cells. In fact, administration of FasL(+) cells was associated with a
      decreased proportion of Mac1(+) neutrophils in the blood and an increased
      expression of myeloperoxidase at the site of engineered cell engraftment. These
      findings suggest that the mechanism underlying the beneficial effect of IL-4
      delivered by cells expressing FasL involves the combination of the anti
      inflammatory properties of IL-4 and the apoptosis of Fas(+) Mac1(+) granulocytes
      participating in the pathogenic process.

PMID- 10602055
TI  - Dendritic cells are associated with augmentation of antigen sensitization by
      influenza A virus infection in mice.
AB  - To study the mechanisms responsible for enhanced sensitization of inhaled antigen
      in respiratory viral infections, we examined the contribution of dendritic cells
      (DC) and T lymphocytes to the development of inhalation sensitization during
      infection with influenza A virus in mice. BALB/c mice were sensitized by
      inhalation of ovalbumin (OA) from 3 to 7 days after the inoculation with
      influenza A virus, and were challenged with OA 3 weeks later. Airway
      responsiveness and serum OA-specific IgE were increased. The numbers of
      eosinophils and CD4(+) and CD8(+) T cells in bronchoalveolar lavage fluid were
      also increased. These changes were not observed in animals only sensitized with
      OA or only inoculated with the virus. In animals only inoculated with the virus,
      DC were immunohistochemically detected on the bronchial epithelium on days 2-5.
      With OA inhalation after virus inoculation, DC with high expression of MHC class
      II were retained for 5 weeks. These results show that influenza virus infection
      induces the migration of DC to the bronchial epithelium, and that simultaneous
      inhalation of antigen causes the loading of antigen-peptide / class II molecule
      complex on DC. Thus, the migration of DC in viral infection may play some role in
      the augmentation of antigen sensitization.

PMID- 10602056
TI  - A role for lymphatic endothelium in the sequestration of recirculating gamma
      delta T cells in TNF-alpha-stimulated lymph nodes.
AB  - TNF-alpha is one of the most potent immunoregulatory molecules in vivo. In
      addition to important regulatory effects, it is also a potent inducer of
      extravascular lymphocyte infiltration. To examine the dynamic changes that are
      induced in local lymphocyte migration through regional lymph nodes following TNF
      alpha injection, we used a protocol of direct lymphatic cannulation to
      quantitatively and qualitatively examine the traffic of lymphocytes through
      regional lymph nodes. We observed that local TNF-alpha injection reduced the
      output of lymphocytes from lymph nodes up to 90% within 6-10 h following
      stimulation. TNF-alpha also altered the specificity of migration of lymphocyte
      traffic through subcutaneous lymph nodes. In addition to the decreased output,
      phenotypic analysis demonstrated decreases in the concentration of gamma delta T
      cells by up to 30% following TNF-alpha injection. Histological examination showed
      that the gamma delta T cells were found in close association with VCAM-1
      expressing cells in TNF-stimulated lymph nodes, at least some of which appeared
      to be lymphatic endothelium. These data indicate that TNF-alpha is capable of
      altering the number and specificity of lymphocytes recirculating through
      stimulated lymph nodes by selectively altering the entry of lymphocytes into the
      efferent lymphatics of inflamed lymph nodes in vivo.

PMID- 10602057
TI  - From the outgoing editor-in-chief.

PMID- 10602058
TI  - UICC symposium on testicular cancer: Guidelines for standard care and future
      prospects.

PMID- 10602059
TI  - Erratum: Estimates of the worldwide mortality from 25 cancers in 1990. Int. J.
      Cancer, 83, 18-29 (1999).
AB  - Pisani, P., Parkin, D.M., Bray, F. and Ferlay, J. Estimates of the worldwide
      mortality from 25 cancers in 1990. Int. J. Cancer, 83, 18-29 (1999). Due to a
      printer's error, incorrect table headings were entered in Tables II-IV after the
      proofs of the article had been approved by the author. The correct tables are
      reprinted on the following pages. The publisher regrets this error.

PMID- 10602060
TI  - Erratum: Increased DNA methyltransferase expression in rhabdomyosarcomas. Int. J.
      Cancer, 83, 10-14 (1999).
AB  - Chen, B., Liu, X., Savell, V.H., Dilday, B.R., Johnson, M.W., Jenkins, J.J., and
      Parham, D.M., Increased DNA methyltransferase expression in rhabdomyosarcomas.
      Int. J. Cancer, 83, 10-14 (1999). Due to a printer's error, the bottom of Figure
      3 was cut off after the proofs had been approved by the author. The correct
      figure and legend is reprinted below. The publisher regrets this error.

PMID- 10602061
TI  - Systemic anti-IFN-gamma treatment and role of macrophage subsets in the foreign
      body reaction to dermal sheep collagen in rats.
AB  - The application of a biomaterial induces a foreign body reaction. By controlling
      this reaction, biocompatibility could be improved. We previously demonstrated
      that impregnation of a biodegradable biomaterial with antibodies against
      interferon-gamma (IFN-gamma) inhibits the foreign body reaction. In this study we
      investigate whether systemic administration of the antibody can induce similar
      reactions. Several parameters are compared between control and anti-IFN-gamma
      treated rats: cellular ingrowth; degradation of the biomaterial; ingrowth of
      macrophage (MO) subsets, T cells, B cells, NK cells, and granulocytes; and
      expression of the major histocompatibility complex class II (MHC class II)
      molecule on antigen presenting cells. Treatment with anti-IFN-gamma results in
      increased cellular ingrowth and biomaterial degradation and a decreased
      expression of MHC class II. Overall, systemic treatment with anti-IFN-gamma is
      insufficient to modulate the foreign body reaction. This suggests an alternative
      mechanism for MO activation besides IFN-gamma. The role of T cells and MO subsets
      in the foreign body reaction is discussed.

PMID- 10602062
TI  - Matrix-mixed culture: new methodology for chondrocyte culture and preparation of
      cartilage transplants.
AB  - For cartilage engineering a variety of biomaterials were applied for 3
      dimensional chondrocyte embedding and transplantation. In order to find a
      suitable carrier for the in vitro culture of chondrocytes and the subsequent
      preparation of cartilage transplants we investigated the feasibility of a
      combination of the well-established matrices fibrin and alginate. In this work
      human articular chondrocytes were embedded and cultured either in alginate, a
      mixture of alginate and fibrin, or in a fibrin gel after the extraction of the
      alginate component (porous fibrin gel) over a period of 30 days.
      Histomorphological analysis, electron microscopy, and immunohistochemistry were
      performed to evaluate the phenotypic changes of the chondrocytes, as well as the
      quality of the newly formed cartilaginous matrix. Our experiments showed that a
      mixture of 0.6% alginate with 4.5% fibrin promoted sufficient chondrocyte
      proliferation and differentiation, resulting in the formation of a specific
      cartilage matrix. Alginate served as a temporary supportive matrix component
      during in vitro culture and can be easily removed prior to transplantation. The
      presented tissue engineering method on the basis of a mixed alginate-fibrin
      carrier offers the opportunity to create stable cartilage transplants for
      reconstructive surgery.

PMID- 10602063
TI  - Use of bone-bonding hydrogel copolymers in bone: an in vitro and in vivo study of
      expanding PEO-PBT copolymers in goat femora.
AB  - Polyactive(R) [polyethylene oxide-polybuthylene terephtalate (PEO-PBT)] refers to
      a group of copolymers with bone-bonding properties. In reference to these
      properties, PEO-PBT copolymers are currently being investigated for their
      possible use in orthopedic surgery and dentistry. PEO-PBT copolymers exhibit
      hydrogel behavior. When swelling in fluid is prohibited by mechanical
      confinement, the copolymers exert a swelling pressure on surrounding structures.
      In the first part of this study, these swelling pressures were measured in vitro.
      Polymers with different ratios of PEO-PBT exerted a swelling pressure of more
      than 2 MPa when tested in fluid between the cross-heads of a Hounsfield test
      bench. In the second part of the study, the biocompatibility of PEO-PBT 55-45 and
      the effect of continuous intramedullary pressure of these copolymers on bone was
      investigated. Large cylinders of dry PEO-PBT 55-45 were implanted with a tight
      fit in the distal part of goat femora. Preswollen cylinders of PEO-PBT implanted
      in the opposite femur served as a control. Although it was assumed that the
      pressure of dry PEO-PBT on the bone would reach more than 2 MPa with press-fit
      insertion, no immediate hazardous effects of the expanding polymer were noticed
      within the first days postoperatively. The goats were sacrificed after 3, 9, and
      25 weeks. Histological examination showed good implant-bone contact at different
      follow-up times in the distal femora with the dry implanted implants. The femora
      in which the preswollen cylinders had been implanted showed a thin layer of soft
      tissue between the PEO-PBT implant and bone. The swelling pressure exerted by dry
      press-fit implanted PEO-PBT implants is an important factor in creating a strong
      interface bond between PEO-PBT and bone.

PMID- 10602064
TI  - Alumina powder/Bis-GMA composite: effect of filler content on mechanical
      properties and osteoconductivity.
AB  - Three composites consisting of alumina powder dispersed in a bisphenol-a-glycidyl
      methacrylate (Bis-GMA) matrix were prepared and evaluated to assess the effect of
      alumina powder content on the mechanical properties and osteoconductivity of the
      composite. The alumina powder composites (APC) consisted of alumina powder (AL-P)
      as the inorganic filler dispersed in a Bis-GMA matrix that was solidified by a
      radical polymerization process. Prior to polymerization the AL-P was mixed with
      the monomers in proportions of 50%, 70%, and 80% by weight (APC50, APC70, and
      APC80). A fused silica-glass-filled composite containing 70% glass by weight
      (SGC70) was used as a control. The compressive and bending strengths, the elastic
      modulus in bending, and the bending strain of the composites increased as the AL
      P content increased. We also evaluated the composites in vivo by implanting them
      into the medullary canals of rat tibiae. To compare the osteoconductivity of the
      composites, an affinity index was calculated for each composite; the affinity
      index equals the length of a bone in direct apposition to the composite and is
      expressed as a percentage of the total length of the composite surface.
      Microradiographic examination for periods of up to 26 weeks after implantation
      revealed that APC50, APC70, and APC80 all exhibited excellent osteoconductivity
      and made direct contact with the bone with no interposed soft tissues. However,
      the higher the AL-P content of the composite, the higher the osteoconductivity,
      especially at 4 weeks after the operation. Moreover, the amount of bone directly
      apposed to the composite surface increased with time. In contrast, little bone
      formation was seen on the surface of SGC70, even after 26 weeks. Observation by
      scanning electron microscope-energy dispersive X-ray microanalysis demonstrated
      that bone made direct contact with the APC surface through a layer containing
      calcium, phosphorus, and alumina powder. These results suggest that APC shows
      promise as a basis for developing mechanically strong and highly osteoconductive
      composites.

PMID- 10602065
TI  - Autologous bone marrow stromal cells loaded onto porous hydroxyapatite ceramic
      accelerate bone repair in critical-size defects of sheep long bones.
AB  - The ability of marrow-derived osteoprogenitor cells to promote repair of critical
      size tibial gaps upon autologous transplantation on a hydroxyapatite ceramic
      (HAC) carrier was tested in a sheep model. Conditions for in vitro expansion of
      sheep bone marrow stromal cells (BMSC) were established and the osteogenic
      potential of the expanded cells was validated. Ectopic implantation of sheep BMSC
      in immunocompromised mice led to extensive bone formation. When used to repair
      tibial gaps in sheep, cell-loaded implants (n = 2) conducted a far more extensive
      bone formation than did cell-free HAC cylinders (n = 2) over a 2-month period. In
      cell-loaded implants, bone formation was found to occur both within the internal
      macropore space and around the HAC cylinder while in control cell-free implants,
      bone formation was limited mostly to the outer surface and was not observed in
      most of the inner pores. As tested in an indentation assay, the stiffness of the
      complex HAC-bone material was found to be higher in cell-loaded implants compared
      to controls. Our pilot study on a limited number of large-sized animals suggests
      that the use of autologous BMSC in conjunction with HAC-based carriers results in
      faster bone repair compared to HAC alone. Potentially this combination could be
      used clinically in the treatment of extensive long bone defects.

PMID- 10602066
TI  - Citric acid etching of cervical sclerotic dentin lesions: an AFM study.
AB  - Atomic force microscopy (AFM) has been used to determine microstructural changes,
      etching rates of peritubular dentin, and intertubular dentin recession during
      demineralization in dilute acidic solutions. These studies have not included many
      forms of altered dentin, including noncarious sclerotic root dentin associated
      with Cl V (abfraction) lesions. We sought to determine microstructural changes
      and recession rates during demineralization in citric acid (pH 2.5, 0.018M) for
      the transparent/sclerotic zone. Highly polished dentin disks were prepared from
      teeth with noncarious C1 V lesions (n = 3) and compared with normal root dentin
      (n = 3). Samples were etched at 5-s intervals for 1 min and at longer intervals
      up to 30 min. The depth changes in various portions of the dentin with respect to
      the reference layer were measured and changes in microstructure observed in
      solution in the wet cell of the AFM. In sclerotic dentin, most tubule lumens were
      occluded with crystalline deposits that etched more slowly than the other dentin
      components, but etching rates could not be determined due to their irregular
      geometry. The intertubular dentin recession quickly reached a plateau after a
      depth change of <1 microm for all dentin types, in agreement with prior work.
      Mixed linear regression models indicated an important difference between the
      etching of sclerotic intertubular dentin and that of non-sclerotic root dentin
      that became apparent after 600 s (p = 0.037). The sclerotic intertubular dentin
      underwent less depth change at the plateau (558 nm) compared to normal root
      dentin (744 nm). In addition, normal root dentin underwent significantly greater
      recession than coronal dentin (p = 0.002). The results of this study indicate
      that intertubular sclerotic dentin from Cl V lesions etches differently than
      normal root dentin, and this may help explain the difficulties in restoring such
      lesions with current bonding procedures.

PMID- 10602067
TI  - Calcium phosphate deposition on titanium surfaces in the presence of fibronectin.
AB  - Titanium implants are known to nucleate spontaneously a calcium phosphate
      (apatite-like) layer when in contact with biological model fluids. The presence
      of proteins either in solution or pre-adsorbed on the titanium surface may
      influence the process of calcium phosphate deposition. The role of fibronectin, a
      protein known to promote cell adhesion in spite of its low concentration in
      biological fluids, was dissolved in Hanks' balanced salt solution (HBSS) and
      investigated. Several techniques of surface analysis, namely wettability, XPS,
      and SEM studies, were applied. The concentration of fibronectin in the HBSS
      solution was an important parameter in the process of calcium phosphate
      deposition. Concentrations as low as 0.01 mg/mL did not significantly affect the
      ionic precipitation; however, if the protein concentration was increased to 0.05
      mg/mL, a value still far below the concentration in blood (0.2 mg/mL), the
      formation of a calcium phosphate layer was strongly inhibited. The influence of
      fibronectin pre-adsorbed on titanium surface also was investigated. It was found,
      as in the first case, that the extent of ionic precipitation that occurred during
      the immersion in HBSS depended on the protein concentration in the NaCl solution
      used to pre-immerse the titanium sample.

PMID- 10602068
TI  - Systemic metal-protein binding associated with total joint replacement
      arthroplasty.
AB  - The distribution of titanium [Ti] and chromium [Cr] in serum protein fractions of
      patients with and without total joint replacements containing Cr and Ti was
      studied. Three groups were evaluated: 10 patients with cobalt-chromium [CoCr]
      alloy prostheses and known elevated levels of Cr; 10 patients with Ti containing
      implants and known elevated levels of Ti; and 10 age matched controls without
      prostheses. Metal-protein binding was also examined by adding various
      concentrations of Cr(+3) (CrCl(3)) to control serum. Cr and Ti were bound to
      serum proteins within specific molecular weight ranges in both patient groups.
      Two molecular weight ranges were found to bind Cr (at approximately 70 and
      approximately 180 kDa) in patients with CoCr alloy prostheses, whereas a single
      molecular weight range (at approximately 70 kDa) was found to bind Ti in patients
      with Ti alloy implants. This metal-protein binding was reproduced in vitro by
      adding CrCl(3) at concentrations of approximately 100 and 1000 ppb Cr, which is
      orders of magnitude higher than that contained in the serum of patients with CoCr
      alloy implants ( approximately 3 ppb Cr). This suggests that protein binding is
      initiated in the periprosthetic space where metal concentrations are typically 2
      3 orders of magnitude higher than that observed systemically in the serum. In
      vitro, high molecular weight proteins including immunoglobulins demonstrated the
      highest affinity to Cr. Determination of specific protein carriers of metal
      degradation products is an essential component in the assessment of the long-term
      biological affects of total joint replacement devices.

PMID- 10602069
TI  - Relationships among cell attachment, spreading, cytoskeletal organization, and
      migration rate for anchorage-dependent cells on model surfaces.
AB  - Many research and commercial applications use a synthetic substrate which is
      seeded with cells in a serum-containing medium. The surface properties of the
      material influence the composition of the adsorbed protein layer, which
      subsequently regulates a variety of cell behaviors such as attachment, spreading,
      proliferation, migration, and differentiation. In this study, we examined the
      relationships among cell attachment, spreading, cytoskeletal organization, and
      migration rate for MC3T3-E1 osteoblasts on glass surfaces modified with -SO(x), 
      NH(2), -N(+)(CH(3))(3), -SH, and -CH(3) terminal silanes. We also studied the
      relationship between cell spread area and migration rate for a variety of
      anchorage-dependent cell types on a model polymeric biomaterial,
      poly(acrylonitrile-vinylchloride). Our results indicated that MC3T3-E1 osteoblast
      behavior was surface chemistry dependent, and varied with individual functional
      groups rather than general surface properties such as wettability. In addition,
      cell migration rate was inversely related to cell spread area for MC3T3-E1
      osteoblasts on a variety of silane-modified surfaces as well as for different
      anchorage-dependent cell types on a model polymeric biomaterial. Furthermore, the
      data revealed significant differences in migration rate among different cell
      types on a common polymeric substrate, suggesting that cell type-specific
      differences must be considered when using, selecting, or designing a substrate
      for research and therapeutic applications.

PMID- 10602070
TI  - Fluorine ion-implanted polystyrene improves growth and viability of vascular
      smooth muscle cells in culture.
AB  - Vascular smooth muscle cells derived from the rat aorta were cultured on
      unmodified or F(+) ion-implanted polystyrene (5 x 10(12) or 5 x 10(14)
      ions/cm(2), energy 150 keV). In 1-day-old cultures, the cells adhered to the
      modified polystyrene in higher numbers and over larger contact areas. Increased
      resistance of the cells to trypsin-mediated detachment from the growth support
      indicated an improved adhesion of cells to the modified polymer at later culture
      intervals. The cells cultured on ion-modified polymers also were larger and had a
      higher total protein content. By use of immunocytochemistry, several specific
      protein species were increased, including the cytoskeletal alpha-actin and
      vimentin and the plasma membrane-associated vinculin, talin, alpha-v integrins,
      ICAM-1, and VCAM-1, which account for stronger cell-cell and cell-extracellular
      matrix adhesion. The lower number of cells found floating in the medium suggests
      that the spontaneous detachment of cells from the modified polystyrene was lower
      and that the viability of the adhered cell population was higher. As was shown by
      the two-parameter flow-cytometric measurements of BrdU incorporation and DNA
      content, as well as by (3)H-thymidine autoradiography, the cell proliferation on
      samples modified by the dose of 5 x 10(12) ions/cm(2) was similar to that in
      controls; and at the dose of 5 x 10(14) ions/cm(2), it tended to be even lower.
      The cells grown on the polymer implanted with the dose of 5 x 10(12) ions/cm(2)
      responded to a new artificially created cell-free area in a confluent cell layer
      by more intense migration whereas at the dose of 5 x 10(14) ions/cm(2), the
      migration ability of cells was similar to that on the unmodified polymer. The
      data revealed a higher biocompatibility of ion-implanted polystyrene with
      vascular smooth muscle cells in culture. There was better adhesion,
      differentiation, and survival, and there was neither excessive migration nor
      proliferation.

PMID- 10602071
TI  - Fracture toughness is dependent on bone location--a study of the femoral neck,
      femoral shaft, and the tibial shaft.
AB  - The fracture toughness of the right femoral neck, femoral shaft, and tibial shaft
      of matched cadaveric bones, ages 50 to 90 years, was compared. Results of this
      study indicate that tensile (G(Ic)) and shear (G(IIc)) fracture toughness vary
      depending on bone location. The femoral neck has the greatest resistance to crack
      initiation for both tension and shear loading while the femoral shaft has the
      least. The relationship between age and the fracture toughness of the femoral
      neck and shaft was investigated. G(c) of the femoral shaft significantly
      decreased with age for mode I and was nearly significant for mode II. Fracture
      toughness of the femoral neck did not change with age for the later decades of
      life. Implications of these findings are discussed.

PMID- 10602072
TI  - Gd(3+)-loaded polyion complex for pH depiction with magnetic resonance imaging.
AB  - In clinical diagnosis, gadolinium (Gd) ion/low molecular weight chelater
      complexes have been used as MRI contrast agents that disperse throughout a
      particular tissue and cause a brighter appearance in MRI. In order to provide a
      novel imaging concept for MRI, a contrast agent in which the T(1)-relaxation
      shortening activity (R(1) relaxivity) changes in response to the pH differences
      was studied. We prepared a polyion complex (PIC) consisting of a polyanionic Gd
      chelater, poly(diethylenetriamine-N,N,N',N", N"-pentaaceto, DTPA) (1,3
      propanediamide) (denoted as 1a) loaded with Gd ions at a [Gd]/[DTPA unit] ratio
      of 0.2 (denoted as 1b), and a polycation, poly[2-(diethylamino)ethyl
      methacrylate] (denoted as 2). The stoichiometric (based on ionic groups) mixture
      of 1b and 2 formed complex coacervates from pH 5 to pH 8. The R(1) relaxivity of
      Gd(3+) in the complex was considerably influenced by the pH, and the relative
      signal intensity changed from 4 at pH 7.2 to 11 at pH 5.0, as determined by an
      MRI phantom study. The pH responsivity of the complex solution varied with the
      composition of the PIC (i.e., the mixing ratio of 1b and 2), allowing us to
      modulate the pH sensibility. The ionic charge balance and swelling of PIC
      seemingly were related to the pH-dependent R(1) relaxivity change. It is expected
      that the PIC-based MRI contrast agent may provide a novel category of MRI methods
      and be useful in improving the detectability of an MRI-based diagnosis.

PMID- 10602073
TI  - Endothelial cell expression of monocyte chemotactic protein-1, tissue factor, and
      thrombomodulin on hydrophilic plasma polymers.
AB  - Endothelial cells (EC) from human aortas, microvessels, and pulmonary arteries
      were examined for their expression and activity of monocyte chemotactic protein-1
      (MCP-1), tissue factor, and thrombomodulin in response to tumor necrosis factor
      alpha (TNFalpha) on the hydrophilic plasma polymers gamma-butyrolactone (GBL) and
      N-vinyl-2-pyrrolidone (NVP), along with a fibronectin (FN) control. RNAs isolated
      from EC grown on these substrates were subjected to reverse transcription
      polymerase chain reaction (RT-PCR) and dot-blot analysis. EC expression of MCP-1
      and tissue factor was very low in the absence of TNFalpha but high for
      constitutively expressed thrombomodulin. TNFalpha induced EC expression and
      activity of MCP-1 and tissue factor and suppressed that of thrombomodulin on all
      substrates. Greater differences were seen with regard to cell origin, but little
      difference was seen among substrates. Basal secretion of MCP-1 was very low in
      aortic and pulmonary artery EC and even less in microvascular EC. TNFalpha
      increased MCP-1 secretion significantly in aortic and pulmonary artery EC but to
      a lesser extent in microvascular EC. In contrast, tissue factor expression was
      greater in pulmonary artery EC compared to microvascular and aortic EC. Basal
      expression of thrombomodulin was largely comparable for all three cell types
      grown on different surfaces, but TNFalpha suppressed thrombomodulin to different
      extents depending on the origin of the EC. The activity of tissue factor and
      thrombomodulin and the secretion of MCP-1 by EC were largely correlated with the
      expression of these genes. We conclude that EC origin may be an important
      determinant of cellular function on hydrophilic plasma polymer substrates.
      However, the differences in cellular function due to variations in substrate
      surface hydrophilicity could have been masked by the extracellular matrix
      remodeling that presumably occurred during EC growth to confluence.

PMID- 10602074
TI  - Adsorption of plasminogen from human plasma to lysine-containing surfaces.
AB  - The objective of this work is to develop blood-contacting surfaces that will
      dissolve nascent clots that may begin to form on them. Surfaces were prepared
      consisting of a polyurethane to which a coating reagent was attached covalently
      by photochemical methods. The coating reagent was a polyacrylamide with lysine
      and benzophenone (for photochemical attachment) moieties pendant to the chains.
      It was hypothesized that via the lysine moieties such surfaces would show
      specific binding affinity for plasminogen, the principal component of the
      fibrinolytic system in blood. Surfaces of varying lysine content in which the
      lysine was bound through the alpha-amino groups, leaving the epsilon-amino groups
      free, were investigated. A control surface in which the lysine was bound through
      the epsilon-amino groups was also examined. Advancing water contact angles showed
      the surfaces to be hydrophilic. Hydrophilicity was found to decrease as the
      lysine content increased. Adsorption of plasminogen from plasma was studied using
      radioiodinated plasminogen as a tracer. For the epsilon-lysine surfaces,
      adsorption increased with increasing lysine content and reached a value of 1.2
      microg/cm(2) for the surface with the highest lysine content, that is, in the
      range expected for a compact monolayer of plasminogen. The control surfaces,
      which contained either no lysine or lysine in which the epsilon-amino groups were
      unavailable, adsorbed very small amounts of plasminogen. Immunoblots were
      obtained for the proteins eluted from the surfaces after incubation with plasma.
      For the control surfaces, most of the proteins tested for (some 20 in all) were
      present. However, for the surface containing the highest concentration of epsilon
      lysine, only plasminogen was detected in a significant amount. It is concluded
      that the epsilon-lysine surface adsorbs plasminogen to the exclusion of the other
      plasma proteins. Studies to examine the fibrinolytic properties of these surfaces
      will constitute the next phase of this work.

PMID- 10602075
TI  - Adsorption and release of insulin-like growth factor-I on porous tricalcium
      phosphate implant.
AB  - In order to develop bone substitutes, the design of biomaterials like calcium
      phosphate ceramic loaded with bone growth factor are of great interest. However,
      it is necessary to control the amount of growth factor adsorbed onto ceramics and
      the kinetics of its release. Radiolabeling of insulin-like growth factor-I (IGF
      I) with 125-iodine ([(125)I]-IGF-I) and its adsorption onto porous tricalcium
      phosphate (TCP) cylinders enabled us to establish the time-adsorption and time
      release curves using various concentrations of IGF-I. The adsorption curve
      increased rapidly and then flattened out at 72 h; 90% of the maximum was already
      reached at 24 h; and 20% of the adsorbed IGF-I was released in water within 4
      days. In human serum the release was faster at 82% within 4 days. In vivo
      evaluation on an animal model was then performed. Rabbits' bilateral femoral
      cylindrical bone defects were filled with the TCP cylinders, which were either
      carrying IGF-I or implanted alone as a control in each rabbit. Bone turnover and
      ceramic resorption were stimulated by IGF-I loaded TCP according to standard
      radiography, dual-energy X-ray absorptiometry, histology, and histomorphometry.

PMID- 10602076
TI  - In vitro bone formation on a bone-like apatite layer prepared by a biomimetic
      process on a bioactive glass-ceramic.
AB  - In this study we have investigated the behavior of fetal rat osteoblasts,
      cultured up to 23 days, on a bioactive apatite-wollastonite (AW) glass-ceramic
      and on the same material on which a carbonated apatite layer had been formed by a
      biomimetic process (AWa). At the last day of culture, the specific activity of
      alkaline phosphatase activity, as determined biochemically, was about 30% greater
      on AWa compared with AW disks. After the cell layers had been scraped off,
      scanning electron microscopic (SEM) observations of the materials' surfaces
      revealed that mineralized bone nodules remained attached to both surfaces but in
      larger amounts on AWa. X-ray microanalysis indicated the presence of calcium (Ca)
      and phosphorus (P) in the bone tissue throughout the AWa surface and Ca, P, and
      silicon (Si) on the AW surface. The AW/ and AWa/bone interfaces also were
      analyzed after fracturing of the disks. The interfacial analysis showed firm bone
      bonding to the AW and AWa surfaces, confirmed by the X-ray microanalytic
      mappings. These results indicate the importance of surface composition in
      supporting differentiation of osteogenic cells and the subsequent apposition of
      bone matrix, which allows a strong bond of the bioactive materials to the bone.
      Furthermore, prefabrication of a biologic apatite layer by a method that mimics
      biomineralization could find application to bone-repairing materials.

PMID- 10602077
TI  - Adsorbed serum proteins responsible for surface dependent human macrophage
      behavior.
AB  - Substrate specific cellular responses are the result of a complex biological
      system that includes protein adsorption, receptor-ligand binding, and signal
      transduction. This investigation attempted to identify specific proteins adsorbed
      from human serum that may be responsible for the previously reported in vitro
      surface dependent behavior of human macrophages and foreign body giant cells
      (FBGCs). The adsorption of human albumin, alpha(2)-macroglobulin, complement
      factor 3b, fibronectin, IgG, thrombospondin, vitronectin (VN), and von Willebrand
      factor (vWF) from a 25% serum solution was quantified with (125)I-labeled
      protein. Adsorption substrates included clean glass, alkyl-silane modified glass,
      amino-silane modified glass, poly(ethylene oxide) (PEO)-coupled glass, and the
      reference biomaterials poly(etherurethane urea), Silastic(R), and
      poly(tetrafluoroethylene) (PTFE). Following quantification of 2-h adsorption,
      surfaces were treated with sodium dodecyl sulfate (SDS) and the level of adsorbed
      proteins remaining was quantified. The pre- and post-SDS adsorption were both
      compared to previously reported surface dependent in vitro macrophage and FBGC
      behavior on the same surfaces; however, no correlations could be made. Adsorption
      strength, defined as the percentage of initially adsorbed protein that remained
      adsorbed after SDS treatment, correlated well with previously reported in vitro
      cellular behavior indicating that adsorbed vWF, IgG, and VN may be involved in
      the modulation of adherent macrophage and FBGC behavior. Those surfaces that
      strongly adsorbed vWF also inhibited long-term macrophage adhesion, while those
      surfaces that strongly adsorbed IgG promoted long-term macrophage adhesion. In
      addition, the highest levels of FBGC formation had been observed only on those
      surfaces that strongly adsorbed VN. Subsequent human monocyte cultures on protein
      preadsorbed substrates confirmed the inhibitory effect of adsorbed vWF and the
      promoting effect of IgG on longterm macrophage adhesion as predicted by
      adsorption strength correlations. However, preadsorbed VN was not observed to
      modulate FBGC formation, which is in contrast to the conclusions of the
      adsorption correlations.

PMID- 10602078
TI  - Mouse fibroblasts in long-term culture within collagen three-dimensional
      scaffolds: influence of crosslinking with diphenylphosphorylazide on matrix
      reorganization, growth, and biosynthetic and proteolytic activities.
AB  - With the rapid development of tissue engineering and gene therapy, collagen-based
      biomaterials frequently are used as cell transplant devices. In this study we
      determined the behavior of mouse fibroblasts cultured for up to 6 weeks in
      control sponges treated by severe dehydration and used commercially as hemostatic
      agents and in two sponges (DPPA 2 and 3) crosslinked by diphenylphosphorylazide,
      a method developed in our laboratory. Growth capacity, biosynthetic and
      proteolytic activities, and matrix reorganization were followed over time in
      cultures and compared with similar data for fibroblasts in monolayer culture on
      plastic and in floating or attached collagen gels. Control sponges with and
      without seeded mouse fibroblasts showed rapid partial denaturation or
      contraction, weight loss, and severe calcification (13-18% Ca) after 6 weeks. In
      contrast, the crosslinked sponges showed only slightly decreased size and weight,
      and the calcification was inhibited (0.2% Ca) in the presence of cells. Mouse
      fibroblasts seeded on the crosslinked sponge surface at 50,000-200,000
      cells/cm(2) progressively penetrated the matrix and proliferated to give the same
      constant cell density after 3 weeks (around 600,000 cells/sponge). A specific,
      two- to threefold decrease in collagen synthesis was observed between 1 and 3 or
      6 weeks, due mainly to a decrease in the fraction secreted into the medium (25
      30% instead of 45-50%). No collagenase 3 activity was detected in the culture
      medium under any condition or time whereas 25% gelatinase A was found by gelatin
      zymography to be in an active form in cultures within sponges as compared with
      less than 10% in monolayers and more than 50% in floating collagen gel. A small
      amount of gelatinase B was observed after 1 week in sponge cultures and was
      completely absent thereafter. These results show that the biosynthetic and
      proteolytic behavior of mouse fibroblasts cultured in crosslinked collagen
      scaffolds is different from that in monolayers or in floating collagen gels and
      more similar to that previously described in attached collagen gels.

PMID- 10602079
TI  - Assessing acute platelet adhesion on opaque metallic and polymeric biomaterials
      with fiber optic microscopy.
AB  - The degree of platelet adhesion and subsequent thrombus formation is an important
      measure of biocompatibility for cardiovascular biomaterials. Traditional methods
      of quantifying platelet adhesion often are limited by the need for direct optical
      access, limited spatial resolution, or the lack of temporal resolution. We have
      developed a new imaging system that utilizes fiber optics and fluorescence
      microscopy for the quantification of platelet adhesion. This fiber optic remote
      microscope is capable of imaging individual fluorescently labeled platelets in
      whole blood on opaque surfaces. Using this method, platelet adhesion was
      quantified on a series of metallic [low-temperature isotropic carbon (LTIC);
      titanium alloy (Ti); diamond-like carbon (DLC); oxidized titanium alloy (TiO);
      and polycrystalline diamond (PCD)] and polymeric [woven Dacron (WD)] collagen
      impregnated Dacron (HEM), expanded polytetrafluoroethylene (ePTFE), and
      denucleated ePTFE (dePTFE)] biomaterials designed for use in cardiovascular
      applications. These materials were perfused with heparinized whole human blood in
      an in vitro parallel plate flow chamber. Platelet adhesion after 5 min of
      perfusion ranged from 3.7 +/- 1.0 (dePTFE) to 16.8 +/- 1.5 (WD) platelets/1000
      micrometer. The temporal information revealed by these studies provides a
      comparative measure of the acute thrombogenicity of these materials as well as
      some insight into their long-term hemocompatibilities. Also studied here were the
      effects of wall shear rate and axial position on platelet adhesion. A predicted
      increase in platelet adhesion with increased wall shear rate and a trend toward a
      decrease in platelet adhesion with increased axial distance was observed with the
      fiber optic microscope. Future applications for this imaging technique may
      include the long-term evaluation of thrombosis in blood-contacting devices in
      vitro and, in animal models, in vivo.

PMID- 10602080
TI  - Macrophage cytokine response to particles and lipopolysaccharide in vitro.
AB  - Several investigators have suggested that biologic molecules adsorbed onto
      particles may play a key role in determining macrophage response. Adsorbed
      endotoxins (bacterial debris) may be of particular importance since they are
      widely present exogenously and endogenously and adhere strongly to many
      materials. Murine-transformed peritoneal macrophages (IC-21) were used in this in
      vitro study. Secretions of IL-1 beta, TNF alpha, and IL-6 were used as a measure
      of macrophage response to micron-range particles of high-density polyethylene and
      Co-Cr-Mo alloy, with and without adsorbed lipopolysaccharide (LPS) endotoxin.
      Little cytokine secretion was measured in response to particles (and to
      polypropylene experimental chambers) cleaned with ethanol and saline and not
      exposed to LPS. The lack of macrophage response to cleaned particles has been
      reported by others and may help reconcile conflicting reports in the literature.
      Cytokine secretion levels were high in all cases if the chambers (with or without
      particles) were exposed to LPS (and rinsed to minimize nonbound LPS). Secretion
      patterns were different with particles present and for polymer versus metal
      particles. Overall, these results suggest that (1) adsorbed molecules on material
      surfaces strongly affect macrophage response and (2) particle surface chemistry
      and microstructure affect the concentration and configuration of adsorbed
      molecules, further influencing particle interaction with macrophage surface
      receptors.

PMID- 10602081
TI  - Elastic and physicochemical relationships within cortical bone.
AB  - The purpose of this study was to examine the relationships that exist between the
      elastic properties and the physicochemical properties of cortical bone in two
      groups of experimental animals. The animal model was the immature mutant dwarf
      rat, and the groups consisted of rats treated and not treated with recombinant
      human growth hormone (rhGH). The objective was to establish and broaden the
      quantifiable link between the three-dimensional form and function of bone beyond
      the typical unidirectional measures. This study was based on previously reported
      work that refined the ultrasonic elasticity technique for use with small
      specimens (<1.0 mm) and determined that the administration of rhGH can counter
      the degenerative effects produced by hormone-suppressed downregulation on the
      elastic and physicochemical characteristics of cortical bone. Ultrasonic wave
      propagation and density measurements were used previously to determine the three
      dimensional (orthotropic) material properties of rat femoral cortical bone. X-ray
      powder diffraction, microscopic, morphometric, and biochemical analysis
      techniques have been used to describe physicochemical properties, including
      mineral crystal size, cortical porosity, mineral and nonmineral content, and
      microstructural characteristics. In this study, mathematical relationships
      between the local physicochemical (independent variable) and elastic (dependent
      variable) properties were formulated via linear and nonlinear regression
      analyses. In general, apparent density was found to have the highest level of
      correlation with most of the longitudinal and shear moduli (R(2) = 0.300 to
      0.800). Concomitantly, mineral crystal width and cortical porosity offered the
      best correlations with the Poisson's ratios (R(2) up to 0.600). Wilcoxon t tests
      verified a significant decrease in the elastic properties in dwarf rat cortical
      bone after rhGH treatments (p < 0.05). Physicochemical measures of bone quality
      (density, crystal size) generally decreased while measures of bone quantity
      (cortical area, moments of inertia) generally increased (p < 0.05) after rhGH
      treatments. Some mineral and nonmineral properties were unchanged. This study
      presents a quantifiable link between cortical bone elasticity and its composite
      construction as measured across two dramatically different experimental groups.

PMID- 10602082
TI  - Cellular proliferation and macrophage populations associated with implanted
      expanded polytetrafluoroethylene and polyethyleneterephthalate.
AB  - The chronic inflammatory response associated with the abluminal surface of
      polymeric vascular grafts has been suggested to affect adversely graft
      neovascularization, the cellular response at the luminal surface of vascular
      grafts, and overall graft patency. To better understand the source for this
      chronic inflammation, this study examined two types of macrophages and the amount
      of cellular proliferation around two widely used graft materials, expanded
      polytetrafluoroethylene (ePTFE) and polyethyleneterephthalate (PET or Dacron)
      implanted in the rat for 3 and 5 weeks. Serial sections of explants were analyzed
      for recruited macrophages (ED1), resident macrophages (ED2), and proliferating
      cells (PCNA). Results show that Dacron is more inflammatory than ePTFE and that
      there is a segregated macrophage response; the first 54 micrometer of perigraft
      tissue were composed predominantly of recruited macrophages (ED1+) while the more
      distal tissue consisted of resident macrophages (ED2+). Proliferating cells were
      located predominantly in this same 54 micrometer perigraft region. In
      subcutaneous tissue they accounted for 23% of all cells present around Dacron
      after 3 weeks of implantation and 8% after 5 weeks. Conversely, cellular
      proliferation around ePTFE increased from 4% at 3 weeks to 21% at 5 weeks. In
      adipose tissue, proliferation levels around the implanted polymers were lower and
      more similar after 3 and 5 weeks. Serial sections revealed the coordinate
      expression of PCNA and ED1 antigens by the same individual cells, suggesting that
      proliferation is a mechanism used to perpetuate the chronic inflammatory
      response. These results suggest a new target for designing treatments to alter
      inflammation and improve the healing associated with these biomaterials.

PMID- 10602083
TI  - Use of alpha-tricalcium phosphate (TCP) as powders and as an aqueous dispersion
      to modify processing, microstructure, and mechanical properties of
      polymethylmethacrylate (PMMA) bone cements and to produce bone-substitute
      compounds.
AB  - Addition of tricalcium phosphate (alpha-TCP) powders as an aqueous dispersion to
      a polymethylmethacrylate (PMMA) bone cement is shown to produce a class of
      composites that due to their microstructure and mechanical properties may be
      suitable for application as bone substitutes. The PMMA forms a solid cellular
      matrix with open cells about 100 micrometer in size and incorporating TCP
      clusters. The TCP aggregates inside the cells form a porous network, with average
      mesopore diameters of about 0.1 micrometer, that is accessible from the outer
      surface. If TCP is added to PMMA in the form of dried powders, the composites are
      not applicable as bone substitutes. The dynamic elastic modulus (DEM) and
      compressive and tensile strengths were measured and discussed for both classes of
      composites. The mechanical properties of the bone-substitute composites, although
      lower than the other class of composites, are still competitive with those
      properties of a porous ceramic matrix of hydroxyapatite and with those of natural
      bones.

PMID- 10602084
TI  - Use of recombinant human osteogenic protein-1 for the repair of subchondral
      defects in articular cartilage in goats.
AB  - The objective of this pilot study was to examine in vivo the potential of
      recombinant human osteogenic protein-1 (rhOP-1, also called bone morphogenetic
      protein-7, BMP-7) for treatment of subchondral lesions by induction of new
      hyaline cartilage formation. Subchondral left knee defects in 17 mature goats
      were treated with fresh coagulated blood mixed with (1) rhOP-1 combined with
      collagen (OP-1 device, 400 microgram/mL); (2) rhOP-1 alone (OP-1 peptide, 200
      microgram/mL); (3) OP-1 device with small particles of autologous ear
      perichondrium; (4) OP-1 peptide with small particles of autologous ear
      perichondrium; or (5) autologous ear perichondrium alone (controls). rhOP-1 was
      combined with either collagen (OP-1 device) or not (OP-1 peptide). The defects
      were closed with a periosteal flap. The formation of cartilage tissue was studied
      by histologic and biochemical evaluation at 1, 2, and 4 months after
      implantation. One and 2 months after implantation there were no obvious
      differences between control and rhOP-1-treated defects. Four months after
      implantation, only one out of three controls (without rhOP-1) showed beginning
      signs of cartilage formation while all four rhOP-1-treated defects were
      completely or partly filled with cartilage. A significant linear relationship was
      found between rhOP-1 concentration and the total amount of aggrecan in the
      defects. These results suggest that implantation of rhOP-1 promotes cartilage
      formation in subchondral defects in goats at 4 months after implantation.
      Therefore, rhOP-1 could be a novel factor for regeneration of cartilage in
      articular cartilage defects.

PMID- 10602085
TI  - Synthesis and characterization of dextran-methacrylate hydrogels and structural
      study by SEM.
AB  - The objectives of this study were to develop a simple and reproducible method for
      the preparation of the hydrogel precursor dextran-methacrylate and to conduct a
      visual observation of the interior structure of the swollen dextran-methacrylate
      hydrogel with minimum artifacts. A dextran-methacrylate hydrogel precursor was
      synthesized by reacting dextran with methacrylic anhydride in the presence of
      triethylamine as a catalyst. The effects of reaction time, temperature,
      concentration, and catalyst amount were studied to obtain a wide range of degree
      of substitution (DS) in dextran by methacrylate. The dextran-methacrylate
      synthesized showed an enhanced solubility in water and common organic solvents.
      UV irradiation of dextran-methacrylate by a long-wave UV lamp (365 nm) generated
      a photocrosslinked hydrogel. This dextran-methacrylate hydrogel showed a range of
      swelling ratio from 67 to 227% and exhibited an increase in swelling ratio with a
      decrease in methacrylate substitution. The pH of the swelling media did not
      affect the swelling behavior of the dextran-methacrylate hydrogels at all the
      degrees of substitution used. Special cryofixation and cryofracturing techniques
      were used to prepare aqueous swollen dextran-methacrylate hydrogel samples for
      SEM observation of their surface and interior structures. A unique three
      dimensional porous structure was observed in the swollen hydrogel but was absent
      in the unswollen hydrogel. Different pore sizes and morphologies between the
      surface and the interior of swollen hydrogels also were observed.

PMID- 10602086
TI  - Reconstruction of rat peripheral nerve gap without sutures using freeze-dried
      alginate gel.
AB  - Many materials have been used for artificial tubular prostheses to assist
      peripheral nerve gap reconstruction. However, the clinical use of these devices
      has been restricted because a microsurgical procedure requires specialized
      techniques and expensive equipment, such as operating microscope systems.
      Therefore the authors developed a new gluing method, without sutures, that uses
      freeze-dried alginate gel. A 7-mm gap in the sciatic nerve of rats was bridged
      with freeze-dried alginate gel. Regeneration was evaluated by electrophysiologic
      testing and histologic study. Eighteen weeks after surgery, functional
      reinnervation of motor and sensory nerves had occurred, as demonstrated by
      recovery of compound muscle action potentials (CMAP), compound nerve action
      potentials (CNAP), and somatosensory-evoked potentials (SEP). Histologically,
      many regenerated nerve fasciculi, including myelinated and unmyelinated fibers,
      were observed and the implanted alginate gel had disappeared. In conclusion, a
      gluing technique using alginate gel is a potential alternative to the
      conventional nerve autograft technique. Advantages include simple application and
      rapid repair. Freeze-dried alginate gel is a promising material for artificial
      nerve guides for peripheral nerves and also could be used for repair of disrupted
      pathways in central nervous tissue that is amorphous and cannot be sutured.

PMID- 10602087
TI  - GAG-augmented polysaccharide hydrogel: a novel biocompatible and biodegradable
      material to support chondrogenesis.
AB  - The quality of articular cartilage engineered using a cell-polymer construct
      depends, in part, on the chemical composition of the biomaterial and whether that
      biomaterial can support the chondrocytic phenotype. Acknowledging the supportive
      influence of tissue-specific matrix molecules on the chondrocytic phenotype, we
      have combined chondroitin sulfate-A (CSA) and chitosan, a glycosaminoglycan (GAG)
      analog, to develop a novel biomaterial to support chondrogenesis. Chitosan is a
      polycationic repeating monosaccharide of beta-1,4-linked glucosamine monomers
      with randomly located N-acetyl glucosamine units. Chitosan may be combined with
      the polyanionic CSA such that ionic crosslinking results in hydrogel formation.
      Bovine primary articular chondrocytes, when seeded onto a thin layer of CSA
      chitosan, form discrete, focal adhesions to the material and maintain many
      characteristics of the differentiated chondrocytic phenotype, including round
      morphology, limited mitosis, collagen type II, and proteoglycan production. Our
      findings suggest CSA-chitosan may be well suited as a carrier material for the
      transplant of autologous chondrocytes or as a scaffold for the tissue engineering
      of cartilage-like tissue.

PMID- 10602088
TI  - Ultrastructure of substance P-immunoreactive terminals and their relation to
      vascular smooth muscle cells of rat small mesenteric arteries.
AB  - Mesenteric arteries of the rat are surrounded by a plexus of primary afferent
      nerve terminals which contain both substance P (SP) and calcitonin gene-related
      peptide (CGRP). The ultrastructural arrangement of the innervation was studied in
      second-order branches of the rat mesenteric artery using immunohistochemical
      labelling with antibodies against SP. The structure and distribution of SP
      immunoreactive (SP+) and SP-negative (SP-, i.e., virtually all noradrenergic)
      axons and their terminals within the adventitia of the artery have been
      determined. Sixteen percent of axons and 22% of varicosities in the perivascular
      plexus were SP+. Most of the SP+ varicosities lay between 0.4 and 2 microm from
      the smooth muscle cells, whereas most SP- varicosities lay much closer to the
      vessel (i.e., <1 microm). SP+ varicosities typically contained the same number
      and size of small synaptic vesicles and mitochondria as SP- varicosities, but
      there were more large dense-cored vesicles in the SP+ varicosities. Unlike SP-
      varicosities, the peptidergic varicosities did not show clustering of synaptic
      vesicles toward one part of the axon membrane, and none of them formed junctions
      with the smooth muscle cells. Close relationships between SP+ and SP-
      varicosities lacked any detectable structural specialization. The arrangement of
      SP+ (primary afferent) terminals and their association with vascular smooth
      muscle cells indicates that peptide released from afferent terminals must diffuse
      further than noradrenaline from sympathetic terminals to reach the vascular
      smooth muscle.

PMID- 10602089
TI  - CART peptide immunoreactivity in the hypothalamus and pituitary in monkeys:
      analysis of ultrastructural features and synaptic connections in the
      paraventricular nucleus.
AB  - Cocaine and amphetamine regulated transcript (CART) has been identified as one of
      the most abundant mRNAs in the rat hypothalamus. The objective of the present
      study was to elucidate the distribution of CART peptide immunoreactive (CARTir)
      neurons in the monkey hypothalamus and characterize their ultrastructural
      features and synaptic connections in the paraventricular nucleus (PVN). CARTir
      neurons were particularly abundant in the PVN, supraoptic nucleus (SON),
      infundibular nucleus, and premammillary nucleus, whereas the anterior, lateral,
      and posterior hypothalamic areas as well as the posterior nucleus displayed
      moderate immunoreactivity. Dense bundles of CARTir fibers exited the PVN and SON
      and followed a trajectory to the infundibulum similar to that previously shown
      for vasopressin and oxytocin fibers. The posterior pituitary was densely packed
      with large CARTir varicosities which, in some cases, were apposed to labeled
      pituicytes. The external/palisade zone of the median eminence contained rich
      plexuses of small CARTir varicose fibers, and the internal/fibrous zone was
      enriched in large axon-like processes. Electron microscope analysis of the PVN
      revealed (1) that CART peptide immunoreactivity is found in neurosecretory and
      non-neurosecretory neurons contacted predominantly by unlabelled terminals
      forming asymmetric synapses, (2) that CARTir terminals resemble glutamatergic
      and/or noradrenergic boutons and form asymmetric synapses with non-neurosecretory
      dendrites, and (3) that neuropeptide Y (NPY)-containing terminals are apposed to
      CARTir neurons in the medial part of the nucleus. In conclusion, our findings
      demonstrate that CART peptide is abundant in neuronal perikarya and axon
      terminals throughout the monkey hypothalamus and along the hypothalamopituitary
      axis. This strengthens the idea that CART peptides may act as putative
      neurotansmitters/neuromodulators that mediate various neuroendocrine and
      autonomic functions in primates.

PMID- 10602090
TI  - Neurotrophin expression by spinal motoneurons in adult and developing rats.
AB  - Expression of the neurotrophins NT-4, brain-derived neurotrophic factor (BDNF),
      and NT-3 in adult rat lumbosacral spinal cord motoneurons is reported. A
      sensitive in situ hybridization procedure demonstrates localization of the mRNA
      for each of these neurotrophins within spinal motoneurons of the adult and in
      early postnatal development. A majority of adult rat spinal cord lumbar
      motoneurons (approximately 63%) express NT-4 mRNA as assessed by counting
      motoneurons in the L4 and L5 segments of two adult rat spinal cords on adjacent
      cresyl violet-stained and in situ hybridization sections. Similarly, a majority
      of lumbar motoneurons (approximately 73%) express BDNF mRNA. Further analyses of
      adjacent lumbar spinal cord sections revealed that many, although not all
      motoneurons coexpress both NT-4 and BDNF mRNAs. At birth, the mRNA encoding NT-3
      is expressed in motoneurons, but BDNF mRNA is not apparent until postnatal day 5
      (P5) and NT-4 mRNA first appears at P9. The potential biological significance of
      neurotrophin mRNA expression in spinal motoneurons is supported by
      immunohistochemical localization of each neurotrophin protein in adult
      motoneurons. We discuss the potential role of spinal cord neurotrophins as
      autocrine or paracrine factors involved in modulating motoneuron synaptic
      function.

PMID- 10602091
TI  - LIM kinase 1 accumulates in presynaptic terminals during synapse maturation.
AB  - LIM kinase 1 (LIMK1) is a cytoplasmic protein kinase that is highly expressed in
      neurons. In transfected cells, LIMK1 binds to the cytoplasmic tail of neuregulins
      and regulates the breakdown of actin filaments. To identify potential functions
      of LIMK1 in vivo, we have determined the subcellular distribution of LIMK1
      protein within neurons of the rat by using immunomicroscopy. At neuromuscular
      synapses in the adult hindlimb, LIMK1 was concentrated in the presynaptic
      terminal. However, little LIMK1 immunoreactivity was detected at neuromuscular
      synapses before the 2nd week after birth, and most motoneuron terminals were not
      strongly LIMK1 immunoreactive until the 3rd week after birth. Thus, LIMK1
      accumulation at neuromuscular synapses coincided with their maturation. In
      contrast, SV2, like many other presynaptic terminal proteins, can be readily
      detected at neuromuscular synapses in the embryo. Similar to its late
      accumulation at developing synapses, LIMK1 accumulation at regenerating
      neuromuscular synapses occurred long after these synapses first formed. In the
      adult ventral spinal cord, LIMK1 was concentrated in a subset of presynaptic
      terminals. LIMK1 gradually accumulated at spinal cord synapses postnatally,
      reaching adult levels only after P14. This study is the first to implicate LIMK1
      in the function of presynaptic terminals. The concentration of LIMK1 in adult,
      but not nascent, presynaptic terminals suggests a role for this kinase in
      regulating the structural or functional characteristics of mature synapses.

PMID- 10602092
TI  - Expression of a synapse-associated membrane protein, P84/SHPS-1, and its ligand,
      IAP/CD47, in mouse retina.
AB  - P84 and integrin associated protein (IAP) are heterophilic binding partners that
      are expressed in the central nervous system in addition to a variety of other
      tissues. Both molecules are known to be involved in cell signaling in nonneural
      tissues. In the retina, both molecules are expressed prominently in plexiform
      layers, suggesting a possible association with synapses. Here, we examined the
      cellular expression and ultrastructural localization of the two molecules in the
      developing mouse retina. Both appeared to be expressed at one or both sides of
      synaptic sites, although the expression of IAP in the retina precedes that of
      P84. Examination of transgenic IAP-null retinae revealed a failure of P84 to
      become associated with synaptic sites, suggesting the interaction of P84 with IAP
      was necessary for P84's synaptic localization. These findings suggest that the
      signaling activities of P84 and IAP are localized to sites of synaptic contact in
      the retina. Thus this pair of synapse-associated molecules represents a
      bidirectional signaling system that could function to modify synaptic activity or
      possibly trophic interactions between central neurons.

PMID- 10602093
TI  - Cytochemical evidence that acetylcholine is a neurotransmitter of neurons that
      make excitatory and inhibitory outputs in the locust ocellar visual system.
AB  - Three different cytochemical methods were used to detect acetylcholine in large,
      second-order neurons of locust ocelli (L-neurons). The first method used
      polyclonal antibodies raised against choline cleaved from acetylcholine and then
      conjugated with native protein, and this revealed strong staining for
      acetylcholine in axons whose number, size, and location indicated that they were
      of L-neurons. A corresponding staining pattern was found using the second method
      with a polyclonal antiserum against choline acetyltransferase (ChAT). The third
      method was the histochemical detection at the electron microscope level of
      acetylcholinesterase, the enzyme responsible for the breakdown of acetylcholine.
      We found that this enzyme is located in synaptic clefts of L-neurons in both of
      the brain regions where L-neurons are known to make excitatory and inhibitory
      output synapses. Acetylcholinesterase was confined to synaptic sites, which is
      consistent with a role in synaptic transmission at these synapses. Taken
      together, the findings suggest that L-neurons use acetylcholine as a
      neurotransmitter.

PMID- 10602094
TI  - Cell mosaic patterns in the native and regenerated inner retina of zebrafish:
      implications for retinal assembly.
AB  - In part because of its laminar organization and morphologically distinct cell
      populations, the vertebrate retina has often been used as a system for
      investigating the assembly of neural structures. The retinas of adult teleost
      fish, because they grow throughout life and can regenerate following an injury,
      provide an especially attractive model system for such investigations. In an
      effort to provide a quantitative foundation for testing hypotheses regarding the
      mechanisms of pattern formation during growth and regeneration of the vertebrate
      retina, nearest neighbor and auto-correlation analyses were used to examine the
      mosaic patterns of eight inner retinal cell groups in the native and regenerated
      retina of adult zebrafish. In both native and regenerated retina, the mosaic
      patterns of most inner retinal cells are non-random. However, regenerated mosaics
      tend toward significantly lower nearest neighbor distances, less orderly
      patterns, and more variable radial locations than their native retina
      counterparts. The individual cell groups in both native and regenerated inner
      retina are likely to be spatially distributed independently. The results support
      the hypotheses that, in the adult zebrafish: 1) distinct inner retinal cell
      groups of native retina are also present in regenerated retina; 2) the assembly
      of inner retinal cell mosaics is controlled by non-random spatial organizing
      mechanisms during development, growth, and regeneration; and 3) the spatial
      organization of cell mosaics is disrupted during regeneration. The results
      suggest that retinal regeneration may represent a spatially disrupted
      recapitulation of retinal developmental mechanisms.

PMID- 10602095
TI  - Development of afferent patterns in the inferior colliculus of the rat:
      projection from the dorsal nucleus of the lateral lemniscus.
AB  - The inferior colliculus (IC) receives a variety of layered afferent projections.
      The purpose of the present study was to determine the development of the
      projection from the dorsal nucleus of the lateral lemniscus (DNLL) to the IC in
      rat prior to the onset of hearing (postnatal day 12/13). Lipophilic carbocyanine
      dye, DiI (1, 1'-dioctodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate),
      was used to trace the crossed inhibitory projection of DNLL in a developmental
      series of rat embryos and pups between ages embryonic day 15 (E15) and postnatal
      day 12 (P12). Dye-coated pins were positioned in paraformaldehyde-fixed brains
      either unilaterally in DNLL (embryonic cases), or in the commissure of Probst
      where DNLL fibers cross the midline (postnatal cases). By E15, pioneer fibers
      have left DNLL and crossed the midline. A few fibers have nearly reached the
      contralateral IC by E19. At birth (E22 = P0), the projection has invaded
      ventromedial, high-frequency layers of the IC. The vast majority of DNLL axons
      parallel the presumptive IC layers by P4, and by P8 the projection has segregated
      into a pattern of bands (afferent dense) and interband (afferent sparse) spaces
      that encompasses the entire frequency axis of the IC. Adult-like patches, regions
      along afferent bands that exhibit the heaviest labeling, develop by P12. These
      results indicate that some mature projection patterns are in place prior to the
      onset of hearing. Such findings suggest that evoked activity may not be required
      for the initial organization of patterned projections in the ascending auditory
      pathway.

PMID- 10602096
TI  - Constitutive expression of the 25-kDa heat shock protein Hsp25 reveals novel
      parasagittal bands of purkinje cells in the adult mouse cerebellar cortex.
AB  - Despite the reported absence of the 25-kDa heat shock protein Hsp25 in the rodent
      cerebellum, we have determined that Hsp25 is constitutively expressed in a subset
      of Purkinje cells in the adult cerebellum of the mouse. No other cerebellar
      neurons are Hsp25 immunoreactive, but there is weak staining associated with
      blood vessels. In the vermis, Hsp25-immunoreactive Purkinje cells are confined to
      two regions: one in lobules VI/VII, the other in lobules IX/X. In each region,
      only a subset of the Purkinje cells is immunoreactive. These cells are grouped in
      five parasagittal bands arranged symmetrically about the midline. The boundaries
      of these expression domains correspond to transverse zones previously inferred
      from other expression patterns. A third Hsp25-immunopositive domain is seen in
      the paraflocculus and flocculus. Again, only a subset of Purkinje cells within
      the paraflocculus and flocculus express Hsp25, revealing three distinct bands.
      Previous descriptions of compartmentation antigens have not differentiated
      between adult populations of Purkinje cells in these regions, suggesting that
      Hsp25 is a novel compartmentation antigen in the adult cerebellum.

PMID- 10602097
TI  - Expression of neurotrophin-3 in the mouse forebrain: insights from a targeted
      LacZ reporter.
AB  - To obtain insights into the expression of neurotrophin-3 (NT-3) in the mouse, we
      have utilized mice in which the Escherichia coli lacZ gene is integrated into the
      neurotrophin-3 locus (NT-3(lacZneo), Farinas et al. [1994] Nature 369:658-661).
      In this mouse strain, beta-galactosidase production is under control of the NT-3
      promoter in its normal chromosomal environment, and histochemical measurement of
      beta-galactosidase provides a simple, sensitive method to determine which cells
      express NT-3. Our data correlate well with previous in situ mRNA and
      immunocytochemical studies reporting the localization of NT-3. For example, in
      adult NT-3(lacZneo)/+ mice, beta-galactosidase is expressed in high amounts in
      limbic areas of the cortex (cingulate, retrosplenial, piriform, and entorhinal),
      in the visual cortex, in the hippocampal formation (dentate granule cells, CA2
      cells, fasciola cinereum, induseum griseum, tenia tecta, presubiculum, and
      parasubiculum), and in the septum (septohippocampal nucleus and lateral dorsal
      septum). In contrast with other studies, our results suggest more extensive
      expression of NT-3 in adult and aged mouse brains with cortical expression
      apparent at 4.5 months. To further define the cell populations expressing NT-3 in
      adult mice, we have combined immunocytochemistry with histochemical staining and
      found that beta-galactosidase is coexpressed with a neuronal marker (NeuN) and
      with parvalbumin and neuropeptides, markers for GABAergic interneurons. Our
      studies of embryonic beta-galactosidase expression in NT-3(lacZneo)/+ mice
      suggest sites of NT-3 expression not previously described, including embryonic
      piriform cortical cells and dentate granule cell precursors.

PMID- 10602098
TI  - Erratum
AB  - Johnson PT, Williams RR, Cusato K, Reese BE. 1999. Rods and cones project to the
      inner plexiform layer during development. J Comp Neurol 414:1-12. Numerous errors
      were introduced during the production of the above cited article after receipt of
      the corrected proofs. The correct text is as follows: The citation "Bowes, 1988"
      on page 2 should read "Bowes et al., 1988". The subsection under Materials and
      Methods entitled "DI labelling" should read "DiI labeling". The reference to
      "(Fig. 3, arrows)" at the top of page 9 should read "(Fig. 3i, arrows)". The
      final sentence on page 10 should read: "Many photoreceptors are generated long
      before an OPL has formed, and so it might be expected that the terminals of these
      cells would overshoot their future target stratum." Lastly, the final sentence of
      the text on page 11 should read: "The source of this environmental signal is
      unclear but since the retraction is coincident with the maturation of bipolar and
      horizontal cells, processes within the OPL are promising candidates." The
      Publisher regrets these errors.

PMID- 10602099
TI  - Clinical evaluation of contrast-enhanced color Doppler sonography in the
      differential diagnosis of liver tumors.
AB  - PURPOSE: We investigated the value of contrast-enhanced color Doppler sonography
      in the differential diagnosis of liver tumors. METHODS: We prospectively examined
      105 focal liver lesions in 100 patients by real-time gray-scale sonography, color
      Doppler sonography, and contrast-enhanced color Doppler sonography with galactose
      based microbubbles (SH U 508A; Levovist). The final diagnoses of the liver
      lesions as confirmed by pathology or additional imaging techniques were 31
      metastases, 25 hemangiomas, 19 hepatocellular carcinomas, 19 focal nodular
      hyperplasias, 2 cholangiocellular carcinomas, and 9 other lesions. RESULTS:
      Vascularity could be detected in 43 (41%) of the 105 lesions by conventional
      color Doppler sonography compared to 67 (64%) by contrast-enhanced color Doppler
      sonography. Contrast-enhanced color Doppler sonography identified moderate or
      extensive vascularity in all 19 focal nodular hyperplasias, moderate or extensive
      vascularity in 16 hepatocellular carcinomas and both cholangiocellular
      carcinomas, and no or minor vascularity in all but 3 hemangioma. The combination
      of gray-scale, conventional color Doppler, and contrast-enhanced color Doppler
      sonography led to the correct diagnosis in 81% of cases (85 of 105), compared to
      57% (60/105) for gray-scale and conventional color Doppler sonography and 31%
      (33/105) for gray-scale sonography alone. CONCLUSIONS: Contrast-enhanced color
      Doppler sonography improves the detection of tumor vascularity and is useful in
      the differential diagnosis of liver lesions.

PMID- 10602100
TI  - Value of sonography in the assessment of space-occupying lesions of the anterior
      nasal fossa.
AB  - PURPOSE: This study was conducted to define the gray-scale, color, and power
      Doppler sonographic appearances and spectral analysis patterns of anterior nasal
      masses. METHODS: Eight patients with anteriorly located nasal masses were
      referred to our hospital for CT of the paranasal sinuses. Subsequently, they were
      examined with a high-frequency linear-array ultrasound transducer. We performed
      gray-scale sonography and color and power Doppler imaging. RESULTS: Five masses
      were nasal hemangiomas. The three remaining masses were a submucosal glandular
      cyst, a nasolabial cyst, and tuberculum septi hypertrophy. Three of the
      hemangiomas were histopathologically confirmed. Sonography identified the
      anatomic origin of all 8 lesions. On color and power Doppler imaging, the 5
      hemangiomas exhibited intense vascularity that decreased with compression.
      Spectral analysis demonstrated arterial and venous flow within the hemangiomas,
      with resistance indices of 0.60-0.66 and peak systolic velocities of 6.4-18.4
      cm/second. The other 3 lesions were avascular or had vascularity only at the
      periphery. CONCLUSIONS: Anterior nasal fossa tumors can frequently be diagnosed
      by clinical examination, but specific sonographic and Doppler patterns can help
      to establish the anatomic origin, the local extension, and the correct diagnosis
      in indeterminate cases, obviating other diagnostic imaging or surgical
      procedures.

PMID- 10602101
TI  - Monitoring of fracture calluses with color Doppler sonography.
AB  - PURPOSE: Fracture callus formation is closely associated with vascular invasion,
      and the use of color Doppler sonography has been suggested as a means to monitor,
      earlier than gray-scale sonography, the first stages of the healing process. We
      report the findings in a series of patients with tibial fractures in whom both
      gray-scale sonography and color Doppler imaging were employed to monitor new bone
      formation at the fracture site. METHODS: Twenty patients with tibial fractures
      treated with external fixator frames were examined sonographically about 10 days
      after surgery and then about every 25 days until radiographic demonstration of
      consolidation. RESULTS: Eighteen of 20 patients had a well-developed callus,
      while the remaining 2 patients showed delayed fracture healing. In patients with
      normal callus development, color Doppler imaging demonstrated the progressive
      formation of new vessels until about 100 days from the surgery; at subsequent
      examinations, flow signals decreased, and bone remodeling was confirmed by
      conventional radiography and gray-scale sonography. The resistance indices in
      these patients tended to decrease in the early weeks after surgery and then
      slightly increased. In contrast, lack of development of flow signals and
      persistence of high resistance indices were observed in the 2 patients with
      delayed fracture healing. CONCLUSIONS: Color Doppler sonography seems to have the
      capability to predict whether the development of fracture calluses will be normal
      or delayed.

PMID- 10602102
TI  - Initial color Doppler findings in retinal vein occlusion.
AB  - PURPOSE: We assessed early hemodynamic characteristics of various types of
      retinal vein occlusion using color Doppler imaging and spectral analysis.
      METHODS: We measured the maximum systolic and diastolic blood flow velocities and
      the resistance index (RI) in the central retinal artery and the maximum and
      minimum blood flow velocities in the central retinal vein of affected eyes and
      contralateral unaffected eyes in 102 adults (63 men and 39 women; mean age, 61 +/
      14.6 years) who presented with retinal vein occlusion. Sixty-three control
      subjects (27 men and 36 women; mean age, 50 +/- 22.1 years) were also
      investigated. RESULTS: No significant differences in hemodynamic characteristics
      were found between the control subjects' eyes and the patients' unaffected eyes.
      In the 18 cases of ischemic central retinal vein occlusion, the mean diastolic
      arterial flow velocity (p = 0.005) and venous flow velocity (p < 0.04) were lower
      and the mean RI was higher (p = 0. 0002) in the affected eyes than in the
      unaffected contralateral eyes. In the 51 cases of nonischemic central retinal
      vein occlusion, the mean diastolic arterial flow velocity (p < 0.0001) and venous
      flow velocity (p < 0.0001) also were lower and the mean RI (p < 0.0001) was
      higher in the affected eyes than in the unaffected contralateral eyes. These
      variables were different in the ischemic versus nonischemic types of central
      retinal vein occlusion. In the 33 cases of branch retinal vein occlusion, no
      significant differences were observed in arterial or venous blood flow velocities
      in the affected versus unaffected eyes. The mean RI in the affected eyes was
      significantly higher (p = 0.009) in patients with central versus branch retinal
      vein occlusion. CONCLUSIONS: These results suggest that previous arterial
      disorders were not involved in the pathogenesis of central retinal vein occlusion
      in these patients. The findings also support the value of Doppler imaging and
      spectral analysis in the diagnosis and evaluation of retinal vein occlusion and
      confirm the involvement of arterial flow in venous occlusion.

PMID- 10602103
TI  - Sonographic findings in grade III dengue hemorrhagic fever in adults.
AB  - PURPOSE: Sonography has been used to evaluate children with dengue hemorrhagic
      fever, but to our knowledge no such studies have been conducted with adults. We
      present the sonographic findings in 40 adults with severe (grade III) dengue
      hemorrhagic fever (DHF). METHODS: Forty patients (30 men and 10 women, aged 16-65
      years) given a presumptive diagnosis of grade III dengue hemorrhagic fever during
      a documented regional epidemic underwent abdominal sonography. Ten also underwent
      chest radiography. Serologic confirmation was obtained in 5 patients, and in the
      rest the diagnosis was based on epidemiologic and clinical findings. RESULTS:
      Sonographic findings included pleural effusion in 21 patients (53%), thickening
      of the gallbladder wall in 17 (43%), and mild ascites in 6 (15%). These findings
      were similar to those of previous studies of severe DHF in children, although the
      incidence of pleural effusion and ascites was slightly lower in our series.
      Neither pleural effusion nor ascites was apparent on clinical examination. Of the
      10 patients who underwent both sonography and chest radiography, sonography
      detected pleural effusion in all 10, whereas radiography detected it in only 3.
      CONCLUSIONS: Sonographic findings in DHF in adults (pleural effusions, ascites,
      and gallbladder wall thickening) were similar to those described for children but
      seem to be of lesser severity. Abdominal sonography is a useful diagnostic tool
      for confirming suspected cases of DHF. Sonography was found to be superior to
      chest radiography in detecting pleural effusions in the 10 patients in whom
      radiographs were available.

PMID- 10602104
TI  - Prenatal sonographic diagnosis of ellis-van creveld syndrome.
AB  - Ellis-van Creveld syndrome (chondroectodermal dysplasia) is a rare autosomal
      recessive disorder characterized by a narrow thorax with short ribs, short
      extremities with polydactyly, and heart defects. A woman underwent sonographic
      examination at 27 weeks' menstrual age to rule out anomalies because of premature
      labor. Sonography revealed a live fetus with short long bones, polydactyly in the
      hands and feet, a narrow thorax with short ribs, and an atrial septal defect. All
      bony structures were of normal hyperechogenicity. The placenta appeared normal
      and was located at the posterior uterine wall; the amniotic fluid volume was also
      normal. These findings led to the diagnosis of short-rib dysplasia, most likely
      Ellis-van Creveld syndrome. The preterm labor stopped but spontaneously recurred
      at 35 weeks, when a 2,320-g female infant was vaginally delivered. The infant
      died of pulmonary insufficiency shortly after birth. Postmortem examination
      confirmed the prenatal findings. We conclude that Ellis-van Creveld syndrome can
      be readily diagnosed by prenatal sonography in the third trimester.

PMID- 10602105
TI  - Color Doppler sonography in the diagnosis of neonatal intrahepatic portosystemic
      shunts.
AB  - Intrahepatic portosystemic shunts are infrequent in children. We report 3 cases
      of neonates who presented with jaundice during the first month of life. Color
      Doppler sonography in the first 2 cases showed direct communication between the
      right portal and hepatic veins. Both infants were asymptomatic, and the shunts
      disappeared spontaneously. The third case involved several shunts and an aberrant
      medial portal vein. This patient developed heart failure and died after surgery.
      Color Doppler sonography was useful in the diagnosis and follow-up of the shunts
      in all 3 cases.

PMID- 10602106
TI  - Intrahepatic spontaneous portosystemic venous shunt: value of color and power
      Doppler sonography.
AB  - Spontaneous portosystemic venous shunts (SPVSs) within the hepatic parenchyma are
      rare. Fewer than 50 cases have been reported, and most of them were diagnosed by
      angiography. We present a case of SPVS diagnosed by color Doppler sonography in a
      5-year-old boy admitted for bleeding due to rupture of esophageal varices.
      Conventional color and power Doppler sonography as well as CT showed a large
      shunt between the posterior branch of the right portal vein and the inferior vena
      cava. We believe that accurate diagnosis and follow-up of SPVS can be done with
      color Doppler sonography without resorting to angiography.

PMID- 10602107
TI  - Sonographic diagnosis of a ruptured primary hydatid cyst of the gallbladder.
AB  - We report an unusual case of a ruptured primary hydatid cyst of the gallbladder.
      The sonographic appearance-a distended gallbladder containing an intraluminal
      mass with undulating membranes in the neck and body-led to the diagnosis of this
      extremely rare condition.

PMID- 10602108
TI  - Sonographic diagnosis of subcapsular liver hematoma mimicking tumor in a neonate.
AB  - Subcapsular hematomas of the liver in neonates uncommonly present as an abdominal
      mass without clinical signs of bleeding. We report a case in which sonography 10
      days after birth demonstrated 2 large hepatic lesions that were initially
      considered to be tumors. The diagnosis of subcapsular liver hematoma was es
      tablished by serial ultrasound examinations, which demonstrated rapid diminution
      of the lesions. A history of difficult umbilical venous catheter insertion was
      then obtained retrospectively.

PMID- 10602109
TI  - The days of our age: the American Journal of Medical Genetics in the next
      millenium.

PMID- 10602110
TI  - Amniotic fluid homocysteine levels, 5,10-methylenetetrahydrafolate reductase
      genotypes, and neural tube closure sites.
AB  - A specific gene mutation leading to altered homocysteine metabolism has been
      identified in parents and fetuses with neural tube defects (NTDs). In addition,
      current animal and human data indicate that spine closure occurs simultaneously
      in five separate sites that then fuse. We sought to determine whether either this
      mutation or abnormal amniotic fluid homocysteine levels are associated with all
      five neural tube closure sites. We retrieved stored amniotic fluid from cases of
      isolated fetal neural tube defect diagnosed from 1988 to 1998 (n = 80) and from
      normal controls matched for race, month and year of amniocentesis, and maternal
      age. Cases were categorized according to defect site by using all available
      medical records. The presence or absence of the 677C-->T mutation of 5, 10
      methylenetetrahydrafolate reductase (MTHFR) gene was determined, and homocysteine
      levels were measured; case and controls were compared. Significantly more cases
      than controls were heterozygous or homozygous for the 677C-->T MTHFR mutation
      (44% vs. 17%, P < or = 0. 001). Likewise, cases were significantly more likely
      than controls to have amniotic fluid homocysteine levels >90th centile (>1.85
      micromol/L), 27% vs. 10%, P = 0.02. Most (83%) of control cases had both normal
      MTHFR alleles and normal amniotic fluid homocysteine levels (normal/normal),
      whereas only 56% of NTD case were normal/normal (P = 0.001). When evaluated by
      defect site, only defects involving the cervical-lumbar spine, lumbosacral spine,
      and occipital encephalocele were significantly less likely to be normal/normal
      than controls (P = 0.007, 0.0003, and 0.007, respectively), suggesting a strong
      association with the 677C-->T allele. In contrast, anencephaly, exencephaly, and
      defects confined to the sacrum included many cases that had both normal MTHFR
      alleles and normal homocysteine and were not significantly different from
      controls. The 677C-->T MTHFR mutation and elevated homocysteine levels appear to
      be disproportionately associated with defects spanning the cervical-lumbar spine,
      lumbosacral spine, and occipital encephalocele. In contrast, anencephaly,
      exencephaly, and defects confined to the sacrum may not be related to altered
      homocysteine metabolism.

PMID- 10602111
TI  - Role of amniotic fluid homocysteine level and of fetal 5, 10
      methylenetetrahydrafolate reductase genotype in the etiology of neural tube
      defects.
AB  - A mutation in the gene 5,10-methylenetetrahydrofolate reductase (MTHFR), leading
      to altered homocysteine metabolism, has been identified in parents and fetuses
      with fetal neural tube defects. We sought to determine which is of greater
      importance in fetal neural tube defect formation: the fetal MTHFR mutation or
      elevated amniotic fluid homocysteine level. We retrieved stored amniotic fluid
      from cases of isolated fetal neural tube defect diagnosed from 1988 to 1998 (n =
      80), and from normal controls matched for race, month and year of amniocentesis,
      and maternal age. The presence or absence of the 677C-->T mutation of MTHFR was
      determined and homocysteine levels were measured; cases and controls were
      compared. Significantly more cases than controls were heterozygous or homozygous
      for the 677C-->T MTHFR mutation (44% vs 17%, P < or = 0.001). Cases were also
      significantly more likely than controls to have an amniotic fluid homocysteine
      level above the 90th centile (>1.85 micromol per liter); 27% vs 10%, P = 0.02.
      Thirty one cases and 12 controls had an abnormal genotype; however, amniotic
      fluid homocysteine levels were not significantly different between these two
      groups (6/31, or 19% of cases had an elevated homocysteine compared to 1/12, or
      8% of controls; P = 0.65). In contrast, 40 cases and 60 controls had a normal
      genotype; the neural tube defect cases had significantly higher homocysteine
      levels (13/40, or 32% of cases had an elevated homocysteine level compared to
      only 6/60, or 10% of controls; P = 0.008). Although both abnormal fetal MTHFR
      genotype and abnormal amniotic fluid homocysteine concentration are significantly
      associated with neural tube defects, the association with amniotic fluid
      homocysteine concentration is significant regardless of the fetal MTHFR genotype.
      The relationship between maternal and fetal homocysteine metabolism is complex.

PMID- 10602112
TI  - Nonsyndromic cleft lip and palate is not associated with cancer or other birth
      defects.
AB  - Nonsyndromic cleft lip with or without cleft palate (NSCLP) is one of the most
      common human malformations with an average prevalence of 1 in 1,000 live births.
      The cause(s) of NSCLP remain unclear as the relative roles of genes, of the
      environment, and/or of chance alone are unknown. The purpose of this study was to
      evaluate the potential role of environmental factors in the cause of NSCLP, to
      determine if other birth defects aggregate in families with at least one
      individual affected with NSCLP, and to investigate the frequency of cancer in the
      first- and second-degree relatives of NSCLP index-cases. Included in this study
      were 196 index-cases and their families. Information pertaining to environmental
      factors and pedigree information was obtained on each family. Analysis showed
      that no single environmental factor could explain the occurrence of NSCLP in this
      population. The frequency of other birth defects in these families was 1.2%,
      which is not increased over that in the general population. One hundred seven
      cancers were reported in 72 of the 196 families included in the study. The
      frequency of cancer was not significantly increased in the first- or second
      degree relatives of the NSCLP index cases or in those families with a positive
      family history of NSCLP. No childhood or adult cancers were reported in any of
      the 196 NSCLP index cases.

PMID- 10602113
TI  - SRY gene transferred to the long arm of the X chromosome in a Y-positive XX true
      hermaphrodite.
AB  - Yp-specific sequences, including the testicular determinant gene SRY, have been
      detected and located in a 46,XX true hermaphrodite individual, using PCR
      amplification and fluorescent in situ hybridization (FISH). Among different Y
      chromosome loci tested, it was only possible to detect Yp sequences. The Y
      centromere and Yq sequences were absent. Unexpectedly, the Y fragment was
      translocated to the long arm of one of the X chromosomes, at the Xq28 level, and
      the derivative (X) chromosome of the patient lacked q-telomeric sequences. To our
      knowledge, this is the first Yp/Xq translocation reported. The coexistence of
      testicular and ovarian tissue in the patient may have arisen by differential
      inactivation of the Y-bearing X chromosome, in which Xq telomeric sequences are
      missing. The possible origin of the Yp/Xq translocation, during paternal meiosis
      or in somatic paternal cells, is discussed.

PMID- 10602114
TI  - Variation in microdeletions of the cyclic AMP-responsive element-binding protein
      gene at chromosome band 16p13.3 in the Rubinstein-Taybi syndrome.
AB  - Most reported microdeletions of the CREB-binding protein (CBP) gene in the
      Rubinstein-Taybi syndrome (RTS) were detected by fluorescence in situ
      hybridization (FISH) with a single cosmid probe specific to the 3' region of the
      gene. In order to test the hypothesis that the rate of microdeletion-positive
      cases would be greater if the entire gene was evaluated, we performed FISH on 66
      patients with an established diagnosis of RTS, using a panel of five cosmids that
      span the CBP gene. Five of 66 patients had deletions by FISH (9%), consistent
      with those rates reported in various series that ranged between 3-25%. Among our
      cases, different deletions were observed; one was deleted for the 5' but not the
      3' region of the CBP gene (case 055). Other deletions included a total CBP
      deletion extending from the 5' through the 3' region (case 017), a deletion of
      all but the 5' region (cases 006 and 060), and an interstitial deletion in the 3'
      region (case 028). Fine breakpoint mapping with additional cosmid and yeast
      artificial chromosome (YAC) constructs was performed on these patients. The
      findings of a partial 5' deletion and of interstitial deletions of the CBP gene
      add to the known spectrum of mutations of this gene in RTS and demonstrate the
      need for evaluation of the entire CBP gene region for deletions rather than only
      the 3' region in RTS patients. These results further suggest that the true rate
      of microdeletion across the CBP gene detectable by FISH has yet to be established
      firmly. No phenotypic differences between partial deletion, complete deletion,
      and nondeletion patients were observed, supporting a haploinsufficiency model for
      RSTS.

PMID- 10602115
TI  - FISH analysis in detecting 9p duplication (p22p24).
AB  - Authors report on a case of partial 9p duplication, involving the 9p22-9p24
      region. This represents the second case of such duplication in which the
      breakpoints were precisely defined using fluorescence in situ hybridisation
      (FISH) with chromosome 9 specific painting and YAC DNA probes, localised onto
      9p22-9p24 region. FISH analysis pinpointed chromosome breakpoints in
      dup(9)(p22p24) and excluded an insertion or a translocation from other
      chromosomes. The present report supports the segment 9p22-9p24 as the critical
      region for the observed phenotype of the duplication 9p syndrome.

PMID- 10602116
TI  - Pendred syndrome: phenotypic variability in two families carrying the same PDS
      missense mutation.
AB  - Pendred syndrome comprises congenital sensorineural hearing loss, thyroid goiter,
      and positive perchlorate discharge test. Recently, this autosomal recessive
      disorder was shown to be caused by mutations in the PDS gene, which encodes an
      anion transporter called pendrin. Molecular analysis of the PDS gene was
      performed in two consanguineous large families from Southern Tunisia comprising a
      total of 23 individuals affected with profound congenital deafness; the same
      missense mutation, L445W, was identified in all affected individuals. A widened
      vestibular aqueduct was found in all patients who underwent computed tomography
      (CT) scan exploration of the inner ear. In contrast, goiter was present in only
      11 affected individuals, who interestingly had a normal result of the perchlorate
      discharge test whenever performed. The present results question the sensitivity
      of the perchlorate test for the diagnosis of Pendred syndrome and support the use
      of a molecular analysis of the PDS gene in the assessment of individuals with
      severe to profound congenital hearing loss associated with inner ear
      morphological anomaly even in the absence of a thyroid goiter.

PMID- 10602117
TI  - Truncus arteriosus and other lethal internal anomalies in Goltz syndrome.
AB  - An infant girl of 36 weeks gestational age was found to have cardiovascular and
      other lethal internal anomalies in addition to characteristic external
      abnormalities of focal dermal hypoplasia (Goltz syndrome). The internal anomalies
      included truncus arteriosus type II with truncal origin of hypoplastic pulmonary
      arteries, cardiac ventricular septal defect, severe hypoplasia of lungs and
      pulmonary veins, massive diaphragmatic hernia, and absence of the right kidney.
      Such a combination of severe anomalies has not been reported previously in Goltz
      syndrome.

PMID- 10602118
TI  - Impact of genetic testing for Huntington disease on the family system.
AB  - The psychological impact of DNA predictive testing on asymptomatic individuals at
      risk for Huntington disease (HD) has received considerable attention since the
      advent of the procedure in 1993. This study examined the impact of such testing
      on families from the families' perspective. Individuals asymptomatic at the time
      of testing, together with their families, were interviewed in their homes with a
      semi-structured interview. Eighteen families with a total of 55 individuals
      participated. Defining the family as the unit of analysis was consistent with
      Systems Theory that links interactions of individuals, families, and the social
      environment. Areas of affected family functioning noted by the respondents
      included: 1) family membership; 2) family patterns of communication; and 3)
      future care giving concerns as they influenced current relationships. Eighty-one
      percent of families experienced changes in family membership. Members in 50% of
      families experienced changes in patterns of communication, and 56% percent of
      persons reported changes in current relationships in response to test results and
      their implications for future caregiving. The data support the conclusion that
      genetic testing is a family, as opposed to an individual, matter and that family
      involvement in the decision making process should be strongly encouraged in order
      to help families adjust. The data imply that families will benefit in pre-test
      sessions from an examination of their patterns of dealing with illness issues,
      both past and present.

PMID- 10602119
TI  - Outcome of the routine assessment of patients with mental retardation in a
      genetics clinic.
AB  - This study reviewed hospital and genetics clinic records of 411 patients
      evaluated in our department from 1986 to 1997 inclusive. Major objectives were to
      establish how often and under what circumstances a specific genetic/syndrome
      diagnosis was made and to determine the value of laboratory tests in the hope of
      gaining a more selective approach to referral, evaluation, and use of the
      laboratory. A specific genetic/syndrome diagnosis was made in 19.9% of cases, and
      in a further 4.4% the referring diagnosis was eliminated but no new diagnosis
      made. There was a significant excess of affected males (277:134) and of affected
      male sib pairs over expectation, suggesting an additional, potentially important,
      contribution from nonspecific X-linked mental retardation (MR). Factors
      associated with making a diagnosis included referral from a pediatrician or
      neurologist, absence of cerebral palsy, presence of more than three minor
      anomalies and/or an unusual appearance, a recognizable Gestalt or key anomaly.
      There was a linear relationship between the likelihood of making a diagnosis and
      the number of minor anomalies. Factors not associated with making a diagnosis
      included the year when the patient was seen, degree of MR, number of prior
      specialists seen, presence of a major malformation, occurrence of seizures, and a
      head circumference either <3rd or >97th centile. Although chromosome studies were
      somewhat less likely to be ordered in patients with less severe MR, the positive
      rate was unaffected by the severity of the MR. The rate of abnormal results was
      positively correlated with the presence of minor anomalies and/or an unusual
      appearance. None of 134 studies carried out on patients with </=3 minor anomalies
      alone were positive. Fragile X studies were less likely to be ordered with
      increasing levels of MR and 10 of 14 positive test results were among those with
      mild delay. Thirteen of 14 diagnoses were based on Gestalt. Molecular and
      fluorescence in situ hybridization studies had a positive rate of >60% when
      ordered by a clinical geneticist compared with 0% when ordered by other
      physicians. Results showed that use of the laboratory was inconsistent and not
      clearly based on the findings in a particular child. Significant changes in
      patterns of referral and the evaluation process could be made that would result
      in significant economies of time and laboratory use and a minimum level of missed
      diagnoses.

PMID- 10602120
TI  - Candidate gene analysis in Rett syndrome and the identification of 21 SNPs in Xq.
AB  - Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that
      affects females. Exclusion mapping studies using a new family with maternal
      inheritance of RTT defined Xq28 as the candidate region for the RTT gene. Six
      candidate genes were selected for mutation analysis based on their established
      expression patterns and known functions in the CNS. These are: Glutamate receptor
      subunit 3 (GLUR3), GABA receptor subunit alpha 3 (GABRA3), GABA receptor subunit
      e1 (GABRE1), Vacuolar ATPase subunit 1 (VATPS1, XAP3), the human homologue of
      plexin 3-SEX (XAP6) and the Synaptobrevin-like protein (SYBL1). Major
      rearrangements involving these genes were excluded by Southern analysis. No
      disease-causing mutations were found, but several single-nucleotide polymorphisms
      (SNPs) were detected. These SNPs will be useful in future linkage analysis and
      whole-genome association studies for other diseases. The genomic characterization
      of GLUR3 and GABRA3 will allow mutational analysis of these genes as candidates
      for other X-linked neurological disorders mapping to Xq25-Xq26 and Xq28.

PMID- 10602121
TI  - Compound heterozygosity for a disease-causing G1489E [corrected] and disease
      modifying G530S substitution in COL5A1 of a patient with the classical type of
      Ehlers-Danlos syndrome: an explanation of intrafamilial variability?
AB  - The classical type of Ehlers-Danlos syndrome (EDS) is an autosomal dominant
      connective tissue disorder characterized by skin hyperelasticity, tissue
      fragility, and joint hypermobility. We investigated the molecular defect of EDS
      in a three-generation family. Cultured dermal fibroblasts from the propositus and
      his daughter produced abnormal alpha1(V) and alpha2(V) collagen molecules.
      Mutation analysis by means of RNase cleavage and direct sequencing of reverse
      transcription-polymerase chain reaction products showed in both the presence of a
      heterozygous G1489E [correction] mutation in the COL5A1 gene, which represents
      the first report of a glycine substitution in the main triple-helical region of
      alpha1(V) collagen. In the propositus, his unaffected daughter, and mother we
      identified a further newly recognized G530S substitution in the NH2-terminal
      domain, which did not cosegregate with the EDS phenotype and was found in only
      one of 51 unrelated control individuals. Because the NH2-terminal domain plays a
      crucial role in modulating fibril formation, the G530S substitution may alter the
      structure and function of this region and consequently the formation of collagen
      fibrils. Indeed, indirect evidence supports our hypothesis: (1) the EDS phenotype
      in the compound heterozygous propositus is more severe than that of his affected
      daughter with the G1489E [correction] mutation only; (2) his unaffected daughter
      and mother with the G530S substitution present with thin skin and delayed wound
      healing; (3) as does the only control individual with the same substitution.
      Thus, in the compound heterozygous propositus the EDS phenotype is caused by the
      G1489E [correction] mutation and possibly aggravated by the G530S substitution,
      which may explain intrafamilial variability.

PMID- 10602122
TI  - Situs inversus and hirschsprung disease: two uncommon manifestations in Bardet
      Biedl syndrome.

PMID- 10602123
TI  - Epidemiology and genetics of craniosynostosis.

PMID- 10602125
TI  - Young-Simpson syndrome comprising transient hypothyroidism, normal growth,
      macular degeneration and torticolis.

PMID- 10602126
TI  - Trisomy 13 with bilateral hand oligodactyly.

PMID- 10602127
TI  - Long-lasting patent channels created by transmyocardial laser revascularization.

PMID- 10602128
TI  - Reply

PMID- 10602129
TI  - Laser thrombolysis using long pulse frequency-doubled Nd:YAG lasers.
AB  - BACKGROUND AND OBJECTIVE: Laser thrombolysis is a means for clearing blood clots
      in occluded arteries. Many researchers have studied the mechanisms of clot
      ablation, and research clinicians have used the technique to treat myocardial
      infarction with a number of different laser systems. Specifically, a 1-microsec
      pulsed dye laser has been used clinically to remove blood clots in coronary
      arteries. As a comparative study, the ablation characteristics of lasers with
      pulse durations in the ranges of 50-150 microsec and 2-10 msec were investigated.
      Two frequency-doubled Nd:YAG lasers at 532 nm were used in this study. Ablation
      threshold and ablation efficiency of gel phantoms and thrombus using these two
      lasers were measured and compared with the results of the pulsed dye laser. The
      pulsed dye laser in this study operated at 522 nm. STUDY DESIGN/MATERIALS AND
      METHODS: Gelatin samples with 150 cm(-1) absorption coefficient at 532 nm and
      animal clot were confined to 3-mm silicone tubes to measure ablation parameters.
      Additional samples with 150 cm(-1) absorption coefficient at 522 nm were prepared
      for use with the pulsed dye laser. A fluorescence technique and photographic
      bubble detection were used to determine ablation threshold. A spectrophotometric
      technique was used to determine ablation efficiency. RESULTS: The ablation
      threshold of the gel phantoms for all three lasers was determined to be 17 +/- 2
      mJ/mm(2). Ablation efficiency for the gel phantoms was 1.7 +/- 0.1 microg/mJ.
      Clot had an ablation efficiency of 2.9 +/- 1.0 microg/mJ. CONCLUSIONS: Ablation
      threshold and efficiency are independent of laser pulse duration for 1-microsec,
      50-150-microsec, and 2-10-msec pulses (P < 0.05).

PMID- 10602130
TI  - Endoscopic lithotripsy with the holmium:YAG laser.
AB  - BACKGROUND AND OBJECTIVE: The holmium:YAG (Ho:YAG) laser can be used not only for
      soft tissue but also for hard tissue such as urinary calculi. The objective of
      this study was to assess the usefulness of the Ho:YAG laser for endoscopic
      lithotripsy in patients with urinary tract stone. STUDY DESIGN/MATERIASL AND
      METHODS: Of 102 procedures performed among 96 patients, 88 were transurethral
      ureterolithotripsy (TUL), seven were percutaneous nephrolithotripsy, and seven
      were transurethral cystolithotripsy. Six patients had bilateral stones. The
      fragments were reduced as much as possible with the Ho:YAG laser. RESULTS: The
      efficacy rate of the 102 lithotripsy procedures was 93%. With respect to the
      effect of TUL, the efficacy rates of 40 procedures for the proximal ureter, 18
      procedures for the midureter, and 30 procedures for the distal ureter were 85%,
      94%, and 100%, respectively. CONCLUSION: The Ho:YAG laser produced a sufficiently
      strong lithotripsy force on all stones. The results of this study indicate that
      lithotripsy of urinary tract stones with the Ho:YAG laser can achieve a clinical
      outcome equivalent to or exceeding that of pulsed dye laser lithotripsy. The
      Ho:YAG laser is a multipurpose laser and thus is a cost effective and very useful
      means for endoscopic lithotripsy of urinary tract stones.

PMID- 10602131
TI  - In vitro tissue effects of a combined Ho:YAG/Nd:YAG laser: sprinkling of tissue
      fragments by Ho:YAG laser light may be problematic for oncological interventions.
AB  - BACKGROUND AND OBJECTIVE: Surgery of soft tissue, for example, of the tongue or
      the liver, requires a cutting and coagulating device. Therefore, a combined
      Ho:YAG/Nd:YAG laser providing the laser beam of both systems together in one bare
      fiber seems to be useful. STUDY DESIGN/MATERIALS AND METHODS: We studied the
      effect of such a laser system in vitro on tongues of pigs. RESULTS: Combined
      application of both lasers results in vitro in a thicker coagulation zone in soft
      tissue (tongue). Tissue fragments possibly containing vital cells are sprinkled
      by the pulsed energy of the Ho:YAG laser up to a distance of 20 cm. CONCLUSION:
      Using the pulsed Ho:YAG laser for oncologic interventions seems to be
      problematic. Combined laser effect in vivo may result in better hemostasis.

PMID- 10602132
TI  - Effects on oral soft tissue produced by a diode laser in vitro.
AB  - BACKGROUND AND OBJECTIVES: This investigation determined incision characteristics
      and soft-tissue damage resulting from standardized incisions using a wide range
      of laser modes and parameters of a diode laser at 810 nm. STUDY DESIGN/MATERIALS
      AND METHODS: Histologic examinations were performed to verify vertical and
      horizontal tissue damage as well as incision depth and width. RESULTS: Incision
      depth and width correlated strongly with average powers, but not with laser
      parameters or the used tips. No laser damage was visible to the naked eye in the
      bone underlying the incisions in the range between 0.5-4.5 W. CONCLUSION: The
      remarkable cutting ability and the tolerable damage zone clearly show that the
      diode laser is a very effective and, because of its excellent coagulation
      ability, useful alternative in soft-tissue surgery of the oral cavity.

PMID- 10602133
TI  - Laser-tissue interaction with a high-power 2-microm fiber laser: preliminary
      studies with soft tissue.
AB  - BACKGROUND AND OBJECTIVE: Recent developments in fiber laser technology have
      introduced highly efficient, compact sources with high output beam quality. The
      first laser-tissue interaction studies with a high-power 2-microm fiber laser
      were conducted. STUDY DESIGN/MATERIALS AND METHODS: Chicken breast and porcine
      muscle tissue samples were subjected to continuous wave (cw) irradiation at 800
      mW and 5-W output power levels, with spot sizes of approximately 150 microm.
      After laser irradiation, samples were inspected with an optical microscope and
      prepared for histologic processing. RESULTS: Evaluation of surface changes in
      tissue samples indicated an interaction similar in nature to those previously
      demonstrated with other cw lasers, but with photothermal ablation characteristics
      typical of strongly absorbed lasers operating in the infrared wavelength region.
      An ablation velocity of 0.27 mm.sec(-1) in porcine tissue was determined at 800
      mW incident power. Histopathologic analysis demonstrated the formation of lesions
      with minimal damage at boundaries and no evidence of carbonization. CONCLUSIONS:
      Results indicate that this fiber laser has the potential to fulfill applications
      in the medical field.

PMID- 10602134
TI  - Fluorescence staining of laryngeal neoplasms after topical application of 5
      aminolevulinic acid: preliminary results.
AB  - BACKGROUND AND OBJECTIVE: The prognosis of patients suffering from laryngeal
      carcinomas can be improved by early diagnosis. Exact demarcation of tumor margins
      could contribute to an optimum preservation of the larynx. Therefore, the aim of
      the present study was the evaluation of 5-aminolevulinic acid (5-ALA)-induced
      protoporphyrin IX (PPIX) fluorescence as a new diagnostic procedure for the
      detection of laryngeal cancer. STUDY DESIGN/MATERIALS AND METHODS: Sixteen
      patients with suspected malignancies of the larynx received 0.6 wt% 5-ALA-NaCl
      solution by means of a medical nebulizer. After a period of 1-2 hours, the
      patients underwent microlaryngoscopy under white light and fluorescence
      illumination (lambda(ex) = 375-440 nm). A quantitative analysis of the
      fluorescence contrast between neoplastic and surrounding tissue was performed
      using an optical multichannel analyzer. RESULTS: Carcinoma, carcinoma in situ,
      and dysplasia showed red fluorescence that could be attributed to the 5-ALA
      induced formation of PPIX. The surrounding normal tissue exhibited
      autofluorescence in the green spectral range, which was greatly reduced within
      the tumor. The results of macroscopic red fluorescence staining were correlated
      with the histologic diagnosis. CONCLUSION: According to these preliminary
      results, the presented method seems to be a promising adjunct diagnostic
      procedure for the early identification of malignant neoplasms in the larynx. The
      aim of further investigations is the assessment of sensitivity and specificity
      and an evaluation of fluorescence-guided laser resections of laryngeal cancer.
      Lasers Med. Surg. 25:414-420, 1999.

PMID- 10602135
TI  - Comparison of cortical bone ablations by using infrared laser wavelengths 2.9 to
      9.2 microm.
AB  - BACKGROUND AND OBJECTIVE: The purpose of this study was to compare the ablation
      of cortical bone at wavelengths across the near and midinfrared region. STUDY
      DESIGN/MATERIALS AND METHODS: An free electron laser generating 4-micros
      macropulses at specific wavelengths between 2.9 and 9.2 microm was used to ablate
      cortical bone. The same pulse intensity, repetition rate, radiant exposure,
      number of pulses, and delivery was used for each wavelength. Tissue removal,
      collateral thermal injury, and morphologic characteristics of the ablation sites
      were measured by light and scanning electron microscopy, and compared with the
      infrared absorption characteristics of cortical bone. RESULTS: Within the
      parameters used, bone ablation was found to be wavelength dependent. Incisions
      were deepest where protein has strong absorption, and were most shallow where
      mineral is a strong absorber. No char was observed on ablation surfaces where
      3.0, and 5.9-6.45 microm wavelengths were used. CONCLUSIONS: The use of
      wavelengths in the 6.1-microm amide I to 6.45-microm amide II region, with the
      pulse characteristics described, were the most efficient for cutting cortical
      bone and produced less collateral thermal injury than cutting with a surgical
      bone saw. This study confirms previous observations that the ablation mechanism
      below plasma threshold is consistent with an explosive process driven by internal
      vaporization of water in a confined space and demonstrates that ablation is
      enhanced by using wavelengths that target the protein matrix of cortical bone.

PMID- 10602136
TI  - Conventional instrument vs. laser-assisted arthroscopic meniscectomy.
AB  - BACKGROUND AND OBJECTIVES: Lasers have been advocated for use in arthroscopy;
      however, results do not show significantly different outcomes from conventional
      instrument arthroscopy. This study assesses outcomes and cost to patients treated
      with conventional arthroscopic instrumentation vs. holmium laser. STUDY
      DESIGN/MATERIALS AND METHODS: Sixty-seven men and 26 women, average age 41 years
      (range, 15-76 years), were divided into two groups: patients who underwent
      conventional arthroscopic partial meniscectomies (43 patients) vs. those who
      underwent the procedure with holmium:yttrium-aluminum-garnet laser (50 patients).
      Hospital and clinic records were reviewed for demographic data, medical and
      operative histories, operative data, and follow-up examinations. Tourniquet time,
      range of motion, effusion, pain, and total cost were compared. RESULTS: No
      significant differences existed in range of motion and effusions between the two
      groups. The mean cost of conventional arthroscopic partial meniscectomy was
      significantly lower, at $1,102 (range, $538-1,586) vs. laser arthroscopic partial
      meniscectomy, at $1,536 (range, $851-2,894) (p < 0.001). Each patient of the
      laser group was billed an additional $420 to offset the rental of laser equipment
      (value, $150,000). All other costs in the laser and conventional groups were
      similar. CONCLUSION: We recommend conventional arthroscopic instrumentation for
      routine partial meniscectomy.

PMID- 10602137
TI  - Effect of laser welding with human serum albumin on the expression of P-selectin
      on platelets.
AB  - BACKGROUND AND OBJECTIVE: Artery repair by means of laser energy induces
      activation of platelets with a risk of thrombosis and local inflammatory
      reactions. The aim of this study was to investigate the effect of human serum
      albumin, the most common solder in laser surgery, on platelet activation. STUDY
      DESIGN/MATERIALS AND METHODS: Platelet activation was evaluated in canine blood
      by using two-color flow cytometry with a phycoerythrin-labeled antibody to a
      common platelet marker, glycoprotein IIb/IIIa and fluorescein isothiocyanate
      labeled antibody to a platelet activation molecule, P-selectin. Human serum
      albumin was applied in vitro and in vivo, as a solder during laser reconstruction
      of canine arteries. RESULTS: In vitro, albumin significantly (P < 0.01) reduces
      the expression of P-selectin on platelets. This is most likely related to the
      blockage of P-selectin by albumin, which binds to the platelet surface, as
      confirmed by flow cytometry with fluorescein isothiocyanate-labeled albumin. In
      vivo, application of albumin solder tended to result in a lower percentage of P
      selectin-expressing platelets in laser-repaired arteries compared to suture
      repaired arteries. CONCLUSION: Albumin decreases the percentage of P-selectin
      expressing platelets in vitro. Further research may allow the platelet activation
      inhibiting properties of albumin to be further optimized in vivo.

PMID- 10602138
TI  - Use of Q-switched alexandrite laser (755 nm, 100 nsec) for removal of traumatic
      tattoo of different origins.
AB  - BACKGROUND AND OBJECTIVES: Q-switched laser systems have been used for removal of
      tattoo-related carbon, graphite, and other particles. We assessed elimination of
      traumatic tattoos of different origin with Q-switched alexandrite laser in nine
      patients. STUDY DESIGN/MATERIALS AND METHODS: Fluence threshold was determined
      and a spot test was made. Q-switched alexandrite laser, with a fluence range 4.5
      8.0 J/cm(2) (mean, 7.16 +/- 1.18), was used at 4-5-week intervals. Total
      treatment ranged from 3-12 sessions (mean, 6.1 +/- 3.6 sessions). Double-pulse
      technique was used in black/black-bluish areas, but single-shot was applied to
      slate-gray pigment. RESULTS: More than 95% lightening was achieved in five
      patients after 5.2 +/- 2.3 sessions, and >75% lightening in six subjects after
      6.1 +/- 3.1 sessions of treatment. Blacktop, surgical pen, and gravel tattoos
      presented a better response than gunpowder/fireworks tattoos (>95% vs. 68.7 +/-
      23.9% clearance), or tattoos of unknown origin (>95% vs. 62.5 +/- 53% clearance).
      Epidermal splattering and pinpoint bleeding were observed in one case. No
      pigmentary alteration or scarring was seen. CONCLUSION: The Q-switched
      alexandrite laser is a useful system for removal of traumatic tattoos of diverse
      origin. The best response (>95% clearance) was achieved in blacktop, surgical
      pen, and gravel tattoos, although an acceptable degree of lightening may be
      obtained in tattoos due to gunpowder or fireworks.

PMID- 10602139
TI  - Histologic effects of ruby laser hair removal in Japanese patients.
AB  - BACKGROUND AND OBJECTIVE: Hair removal by lasers has recently become a popular
      method to remove unwanted hair. However, histologic changes in human skin before
      and after exposure to lasers have not been thoroughly investigated. The aim of
      this study was to clarify the differences that occur immediately after laser
      exposure and 1 month after laser exposure. STUDY DESIGN/MATERIALS AND METHODS:
      Eight adult Japanese volunteers were recruited for this study. They were treated
      with a long pulsed ruby laser at 20 J/cm(2). A single 3-mm punch biopsy of the
      laser-treated sites was obtained immediately after laser irradiation and at the 1
      month follow-up visit, and they were analyzed using hematoxylin and eosin, PAM,
      and immunohistological staining. RESULTS: Immediately after laser exposure, hair
      follicles were very damaged and had extensive eosinophilic degeneration. One
      month after laser therapy, one type of hair follicle showed cystlike formations
      with negative proliferating cell nuclear antigen reactions (PCNA). Another type
      of hair follicle showed follicular mitotic figures with cytoplasmic halos. Early
      anagen hair follicles were apparently not treated effectively by ruby laser.
      CONCLUSION: Ruby laser leads to extensive follicular damage, and hair follicles
      considered to be at early anagen phase were not effectively treated. This may be
      the reason several courses of laser therapy are required to obtain satisfactory
      results.

PMID- 10602141
TI  - Symposium on Statistical Bases for Public Health Decision Making: From
      Exploration to Modelling. Proceedings.

PMID- 10602142
TI  - Symposium on Statistical Bases for Public Health Decision Making: From
      Exploration to Modelling. Introduction and welcome.

PMID- 10602143
TI  - Simultaneous smoothing and adjusting mortality rates in U.S. counties: melanoma
      in white females and white males.
AB  - Detecting patterns in health-related data for geographic areas is facilitated
      with the use of exploratory methods, especially smoothing. In addition, these
      data often must be adjusted for known prognostic factors such as age and gender.
      The analysis in this paper focuses on mortality rates due to malignant melanoma
      in White males and White females; these data are adjusted for both age and
      latitude, separately for males and females, and then smoothed using (a) a non
      linear smoother known as weighted head-banging, and (b) a new method that
      incorporates the adjustment and the smoothing simultaneously. Maps of the
      continental United States show regions of high rates, even after having adjusted
      for age and latitude, and suggest the possibility of other variables that may
      influence the rates.

PMID- 10602144
TI  - Model-based small area estimates of overweight prevalence using sample selection
      adjustment.
AB  - Using a hierarchical model with an adjustment for sample selection, we estimate
      the overweight prevalence for adults, by states, using data from the Third
      National Health and Nutrition Examination Survey (NHANES III). A two-stage
      hierarchical model was selected to account for geographic variability of outcomes
      and to model possible overdispersion of estimates due to cluster sampling. We
      compare our model-based estimates with design-based estimates at the national
      level and obtain excellent agreement. We also provide a check of our model at the
      state level by comparing estimates with design-based and synthetic estimates.

PMID- 10602145
TI  - Application of a weighted head-banging algorithm to mortality data maps.
AB  - Smoothed data maps permit the reader to identify general spatial trends by
      removing the background noise of random variability often present in raw data. To
      smooth mortality data from 798 small areas comprising the contiguous United
      States, we extended the head-banging algorithm to allow for differential
      weighting of the values to be smoothed. Actual and simulated data sets were used
      to determine how head-banging smoothed spike and edge features in the data, and
      to observe the degree to which weighting affected the results. As expected,
      spikes were generally removed while edges and clusters of high rates near the
      U.S. borders were maintained by the unweighted head-banging algorithm.
      Incorporating weights inversely proportional to standard errors had a substantial
      effect on smoothed data, for example determining whether observed spikes were
      retained or removed. The process used to obtain the smoothed data, including the
      choice of head-banging parameters, is discussed. Results are considered in the
      context of general spatial trends. Published in 1999 by John Wiley & Sons, Ltd.
      This article is a U.S. Government work and is in the public domain in the United
      States.

PMID- 10602146
TI  - Exploring spatial patterns of mortality: the new atlas of United States
      mortality.
AB  - The National Center for Health Statistics, CDC, has produced an Atlas of United
      States Mortality which includes maps of rates for the leading causes of death in
      the United States for the period 1988-1992. As part of this project, many aspects
      of statistical mapping have been re-examined to maximize the atlas's
      effectiveness in conveying accurate mortality patterns to epidemiologists and
      public health practitioners. Because recent cognitive research demonstrated that
      no one map style is optimal for answering many different map questions, maps and
      graphs of several different mortality statistics are included for each cause of
      death. New mixed effects models were developed to provide predicted rates and
      improved variance estimates. Results from these models were smoothed using a
      weighted head-banging algorithm to produce maps of general spatial trends free of
      background noise. Maps of White female lung cancer rates from the new atlas are
      presented here to illustrate how this innovative combination of maps and graphs
      permits greater exploration of the underlying mortality data than is possible
      from previous single-map atlas designs. Published in 1999 by John Wiley & Sons,
      Ltd. This article is a U.S. Government work and is in the public domain in the
      United States.

PMID- 10602147
TI  - All maps of parameter estimates are misleading.
AB  - Maps are frequently used to display spatial distributions of parameters of
      interest, such as cancer rates or average pollutant concentrations by county. It
      is well known that plotting observed rates can have serious drawbacks when sample
      sizes vary by area, since very high (and low) observed rates are found
      disproportionately in poorly-sampled areas. Unfortunately, adjusting the observed
      rates to account for the effects of small-sample noise can introduce an opposite
      effect, in which the highest adjusted rates tend to be found disproportionately
      in well-sampled areas. In either case, the maps can be difficult to interpret
      because the display of spatial variation in the underlying parameters of interest
      is confounded with spatial variation in sample sizes. As a result, spatial
      patterns occur in adjusted rates even if there is no spatial structure in the
      underlying parameters of interest, and adjusted rates tend to look too uniform in
      areas with little data. We introduce two models (normal and Poisson) in which
      parameters of interest have no spatial patterns, and demonstrate the existence of
      spatial artefacts in inference from these models. We also discuss spatial models
      and the extent to which they are subject to the same artefacts. We present
      examples from Bayesian modelling, but, as we explain, the artefacts occur
      generally.

PMID- 10602148
TI  - Modelling for cost-effectiveness analysis.
AB  - A model creates the framework for a cost-effectiveness analysis, allowing
      decision makers to explore the implications of using an intervention in different
      ways and under different conditions. To serve its purpose a model must produce
      accurate predictions and allow for substantial variation in the factors that
      influence costs and effects. This paper considers three aspects of modelling:
      validating effectiveness estimates; modelling costs; and the implications of
      common statistical forms. Validation procedures similar to those for
      effectiveness estimates are proposed for costs. Modellers need to pay more
      attention to ensuring that the pathway of events described by a model represents
      costs as well as it does effects. Modellers can also help improve the
      epidemiological and clinical research on which cost-effectiveness analyses depend
      by showing the implications for resource allocation of the statistical forms
      conventionally used in these fields.

PMID- 10602149
TI  - Constructing confidence intervals for cost-effectiveness ratios: an evaluation of
      parametric and non-parametric techniques using Monte Carlo simulation.
AB  - The statistic of interest in most health economic evaluations is the incremental
      cost-effectiveness ratio. Since the variance of a ratio estimator is intractable,
      the health economics literature has suggested a number of alternative approaches
      to estimating confidence intervals for the cost-effectiveness ratio. In this
      paper, Monte Carlo simulation techniques are employed to address the question of
      which of the proposed methods is most appropriate. By repeatedly sampling from a
      known distribution and applying the different methods of confidence interval
      estimation, it is possible to calculate the coverage properties of each method to
      see if these correspond to the chosen confidence level. As the results of a
      single Monte Carlo experiment would be valid only for that particular set of
      circumstances, a series of experiments was conducted in order to examine the
      performance of the different methods under a variety of conditions relating to
      the sample size, the coefficient of variation of the numerator and denominator of
      the ratio, and the covariance between costs and effects in the underlying data.
      Response surface analysis was used to analyse the results and substantial
      differences between the different methods of confidence interval estimation were
      identified. The methods, both parametric and non-parametric, which assume a
      normal sampling distribution performed poorly, as did the approach based on
      simply combining the separate intervals on costs and effects. The choice of
      method for confidence interval estimation can lead to large differences in the
      estimated confidence limits for cost-effectiveness ratios. The importance of such
      differences is an empirical question and will depend to a large extent on the
      role of hypothesis testing in economic appraisal. However, where it is suspected
      that the sampling distribution is skewed, normal approximation methods produce
      particularly poor results and should be avoided.

PMID- 10602150
TI  - Evaluating the cost-effectiveness of vaccination programmes: a dynamic
      perspective.
AB  - Although there are many models which are used to calculate the health benefits
      (and thus the cost-effectiveness) of vaccination programmes, they can be divided
      into two groups: those which assume a constant force of infection, that is a
      constant per-susceptible rate of infection; and those which assume that the force
      of infection (at time t) is a function of the number of infectious individuals in
      the population at that time (dynamic models). In constant force of infection
      models the per-susceptible rate of infection is not altered, whereas in dynamic
      models mass immunization results in fewer infectious individuals in the community
      and thus a lower force of infection acting on those who were not immunized. We
      take an example of each of these types of model, examine their underlying
      assumptions and compare their predictions of the cost-effectiveness of a mass
      immunization programme against a hypothetical close contact infection, such as
      measles. We show that if cases of infection are the outcome of interest then the
      constant force of infection model will always underestimate the cost
      effectiveness of the immunization programme except at the extremes when no one or
      everyone is immunized. However, unlike the constant force of infection model, the
      dynamic model predicts an increase in the average age at infection after
      immunization which could impact on the estimate of the cost-effectiveness of the
      programme if the risk of developing serious disease is a function of the age at
      infection (as, for instance, is the case for congenital rubella syndrome). Taking
      cases of infection as the outcome measure and using the dynamic model, the
      undiscounted cost-effectiveness ratio will tend to decline over time and approach
      a constant value, as the system moves from pre- to post-immunization equilibrium.
      We go on to show how the cost-effectiveness of a fixed-term immunization
      programme might change over time, and discuss why, under most circumstances,
      decision makers should not assume that elimination (permitting termination of
      mass immunization) will occur.

PMID- 10602151
TI  - A monitoring system for detecting aberrations in public health surveillance
      reports.
AB  - Routine analysis of public health surveillance data to detect departures from
      historical patterns of disease frequency is required to enable timely public
      health responses to decrease unnecessary morbidity and mortality. We describe a
      monitoring system incorporating statistical 'flags' identifying unusually large
      increases (or decreases) in disease reports compared to the number of cases
      expected. The two-stage monitoring system consists of univariate Box-Jenkins
      models and subsequent tracking signals from several statistical process control
      charts. The analyses are illustrated on 1980-1995 national notifiable disease
      data reported weekly to the Centers for Disease Control and Prevention (CDC) by
      state health departments and published in CDC's Morbidity and Mortality Weekly
      Report. Published in 1999 by John Wiley & Sons, Ltd. This article is a U.S.
      Government work and is in the public domain in the United States.

PMID- 10602152
TI  - The cumulative q interval curve as a starting point in disease cluster
      investigation.
AB  - Statistical analyses aimed at detection and investigation of clustering are
      associated with inherent difficulties. Both types of statistical errors are large
      in these analyses. The results of the analyses should indicate whether or not at
      least some of the cases are clustered, and if they are, whether or not the
      cluster is related to an exposure. The temporal changes in the incidence rate of
      the disease may alleviate the difficulties associated with the large statistical
      errors. Because of the sparse data, estimates of the incidence rates over time
      are not reliable. In this study we present the q interval statistic that has the
      uniform (0,1) distribution. It can be viewed as a standardized time interval
      between consecutive diagnoses of the disease. As such, it reflects the reciprocal
      of the incidence rates. Since it is measured for each diagnosis, it is sensitive
      to gradual change in the incidence rate, and in general to a true clustering that
      is due to exposure, even when the test result is not significant. When clustering
      is detected, it may indicate which of the possible reasons leading to a cluster
      has a sound basis. As a result, the epidemiological search for exposure is
      limited to situations indicated by the q intervals. In addition, the q interval
      presents a useful survival statistic in a follow-up study when no control group
      is available. Software programs in SAS and in SYSTAT are available.

PMID- 10602153
TI  - A study of the average run length characteristics of the National Notifiable
      Diseases Surveillance System.
AB  - This study examines the statistical properties (that is, false positive and
      negative signals) in detecting unusual patterns of reported cases of diseases
      from the Centers for Disease Control and Prevention's National Notifiable
      Diseases Surveillance System. Control charts are applied to the residuals of one
      step ahead forecasts based on Box-Jenkins models of reported cases of disease.
      Simulation and analytical techniques are used to study the average run length
      characteristics of these control charts for various types of changes in the
      levels of the series, including spike, trend and step changes. The average run
      lengths for the highly correlated disease series are much longer than for the
      usual independent data case. This increase in the average run lengths is strongly
      influenced by the type of change in the level of the series and by the type of
      control chart. Understanding the average run length characteristics of the
      control charts can lead to timely detection of changes in the levels of disease
      series, and subsequent timely public health actions to decrease unnecessary
      morbidity and mortality.

PMID- 10602154
TI  - Estimating genetic influence on disease from population-based case-control data:
      application to cancers of the breast and ovary.
AB  - We describe genetic mixture models and goodness-of-fit statistics for evaluating
      the joint effects of genetic and environmental factors on the risk of chronic
      diseases. We focus particularly on situations wherein the gene(s) of interest
      play roles in several diseases, and death due to one disease can censor the
      occurrence of others. We use the methods to investigate the risks of cancers of
      the breast and ovary associated with germline mutations of BRCA1, using data
      pooled from three population-based U.S. case-control studies of ovarian cancer.
      We evaluate the goodness-of-fit of the genetic models by comparing the predicted
      numbers of diseased mother-daughter and sister-sister pairs to the numbers
      observed. We also use simulations to examine the performance of estimates
      obtained from such complex mixture models, and the contribution of control
      families to the precision of parameter estimates.

PMID- 10602155
TI  - An application of lifetime models in estimation of expected length of stay of
      patients in hospital with complexity and age adjustment.
AB  - Expected length of stay (ELOS) of patients in hospital is an important measure in
      hospital resource utilization management. Previous work has shown that estimation
      of ELOS is improved using complexity and age adjustment. These improved estimates
      have the potential to improve the accuracy of estimates of resource use. Recently
      other authors have applied the linear regression model to make complexity and age
      adjustments in the estimation of ELOS. However, these estimates using linear
      regression estimates are likely flawed on the basis that the assumptions
      regarding the distribution of data for the linear regression model are
      unjustifiable. The non-normal distributions of most hospital patient discharge
      data demand that an alternative method be described to provide accurate estimates
      of ELOS. The purpose of this paper is to describe an alternative method which
      uses lifetime models to initially estimate the expected length of stay. The paper
      then provides an approach to estimate the adjusted expected length of stay
      (AELOS) using several influencing factors by application of lifetime models.
      Depending on whether or not the proportional hazards assumption is appropriate
      for the data, the Cox proportional hazards model or the Kaplan-Meier adjustment
      is recommended.

PMID- 10602156
TI  - Multi-criteria decision making--an approach to setting priorities in health care.
AB  - The objective of this paper is to present a multi-criteria decision making (MCDM)
      approach to support public health decision making that takes into consideration
      the fuzziness of the decision goals and the behavioural aspect of the decision
      maker. The approach is used to analyse the process of health technology
      procurement in a University Hospital in Rio de Janeiro, Brazil. The method, known
      as TODIM, relies on evaluating alternatives with a set of decision criteria
      assessed using an ordinal scale. Fuzziness in generating criteria scores and
      weights or conflicts caused by dealing with different viewpoints of a group of
      decision makers (DMs) are solved using fuzzy set aggregation rules. The results
      suggested that MCDM models, incorporating fuzzy set approaches, should form a set
      of tools for public health decision making analysis, particularly when there are
      polarized opinions and conflicting objectives from the DM group.

PMID- 10602157
TI  - Recurrent injury event-time analysis.
AB  - Public health decision making based on data sources that are characterized by a
      lack of independence and other complicating factors requires the development of
      innovative statistical techniques. Studies of injuries in occupational cohorts
      require methods to account for recurrent injuries to workers over time and the
      temporary removal of workers from the 'risk set' while recuperating. In this
      study, the times until injury events are modelled in an occupational cohort of
      employees in a large power utility company where employees are susceptible to
      recurrent events. The injury history over a ten-year period is used to compare
      the hazards of specific jobs, adjusted for age when first hired, and
      race/ethnicity differences. Subject-specific random effects and multiple event
      times are accommodated through the application of frailty models which
      characterize the dependence of recurrent events over time. The counting process
      formulation of the proportional hazards regression model is used to estimate the
      effects of covariates for subjects with discontinuous intervals of risk. In this
      application, subjects are not at risk of injury during recovery periods or other
      illness, changes in jobs, or other reasons. Previous applications of proportional
      hazards regression in frailty models have not needed to account for the changing
      composition of the risk set which is required to adequately model occupational
      injury data. Published in 1999 by John Wiley & Sons, Ltd. This article is a US
      Government work and is in the public domain in the United States.

PMID- 10602158
TI  - Symposium on Statistical Bases for Public Health Decision Making: From
      Exploration to Modelling. Closing remarks.

PMID- 10602159
TI  - Cancer risk in patients with monoclonal gammopathy of undetermined significance.
AB  - To assess the cancer risk of monoclonal gammopathy of undetermined significance
      (MGUS) we identified 1229 cases of MGUS in the period 1978 to 1993. Data on
      cancer occurrence in the MGUS cohort were obtained from the Danish Cancer
      Registry. The expected numbers of cancer cases were calculated from age-, sex-,
      county-, and period-specific cancer incidence rates. In the MGUS cohort 64 new
      cancers with a known association with M-components were diagnosed versus 5.0
      expected giving a standardized incidence ratio (SIR) of 12.9 (95% confidence
      interval, 9.9-16.5). The relative risks of developing multiple myeloma (SIR
      34.3), Waldenstrom's macroglobulinemia (SIR 63.8), and non-Hodgkin's lymphoma
      (SIR 5.9) were significantly increased and independent of time passed from
      detection of the M-component. The relative risk of chronic lymphocytic leukemia
      was not significantly increased, SIR 2.7 (0.5-7. 7). Among cancer sites without
      known association with M-components 141 cases were observed versus 94.6 expected
      giving a SIR of 1.5 (1. 3-1.8). This enhanced risk was seen for several non
      hematological cancer sites but for most cancer sites the risk was dependent on
      time passed from detection of the M-component, indicating a bias rather than a
      causal role of MGUS.

PMID- 10602160
TI  - Laparoscopic splenectomies for idiopathic thrombocytopenic purpura: experience of
      sixty cases.
AB  - We performed a laparoscopic splenectomy (LS) in 60 patients (age 9-83, 45
      females) with idiopathic thrombocytopenic purpura (ITP) who did not achieve
      sustained remission on steroid therapy. Using a modified procedure, the mean
      duration of LS was 78 min (range 25-240 min) and surgery was associated with only
      5% major and 5% minor complications. Ten patients had a platelet count less than
      50 x 10(9)/l during surgery despite the administration of immune globulin (0.4
      g/kg x 3-5 days) or pulsed oral dexamethasone (40 mg/day x 4 days). Three
      patients were refractory to these therapies and underwent LS with a platelet
      count less than 5 x 10(9)/l. Bleeding complications during or after surgery were
      rare (5%). Accessory spleens were removed in eight patients. Convalescence was
      rapid and the mean hospital stay was 2.3 days (range 1-7 days). The patients were
      followed for a mean of 16 months (range 1-36 months), and 49 patients (84%) are
      in complete remission. Seven patients (12.5%) relapsed despite an initial good
      response in 6 of them. Two patients underwent laparoscopic removal of accessory
      spleens with excellent response. We conclude that LS for ITP is safe and
      effective and associated with low morbidity and fast recovery. Thus, LS may be
      considered earlier in the course of ITP.

PMID- 10602161
TI  - Spectrum of beta thalassemia mutations and their linkage to beta-globin gene
      haplotypes in the Indo-Mauritians.
AB  - The beta thalassemia alleles in 53 thalassemic Indo-Mauritian patients and their
      families consisting of 23 homozygous beta-thalassemia, 9 HbE/beta-thalassemia, 18
      HbS/beta-thalassemia, 1 HbD/beta-thalassemia, 1 deltabeta/beta-thalassemia and 1
      HbH/beta-thalassemia from the island of Mauritius were studied. Characterization
      by polymerase chain reaction-based reverse dot blot hybridization technique
      revealed that the IVS1-5 (G-->C) mutation accounted for 74% of the beta
      thalassemic alleles, while six other mutations occurred at much lower
      frequencies: HbE codon 26 (G-->A); 10.4%, codon 8/9 (+G); 3.5%, codon 30 (AGG-
      >ACG) also called IVSI (-1).G-->C; 3.5%, codon 15 (G-->A); 3.5%, codon 41/42 (
      CTTT); 2.4% and -28 (A-->G); 2.4%. Association of these mutations to specific
      beta globin gene sequence framework and haplotype allowed to trace their
      ancestral link. These data are useful in future molecular screening of the
      population in view of implementing a thalassemia prevention and control program
      in Mauritius.

PMID- 10602162
TI  - A novel four base-pair deletion within the Agamma-GLOBin gene promoter associated
      with slight increase of Agamma expression in adult.
AB  - We studied a Chinese family and revealed 5.4% and 3.2% fetal hemoglobin (HbF)
      with advantageously Agamma type in the mother and the daughter, respectively,
      using alkali denaturation assay and urea-Triton-acrylamide gel electrophoresis
      and high-performance liquid chromatography. The father's HbF was less than 0.5%.
      Large deletion was not observed within the beta-globin gene cluster by
      restriction endonuclease mapping. Characterization by the polymerase chain
      reaction (PCR) and DNA sequencing demonstrated the mother is a homozygote with a
      novel four base-pair "AAGC" (-226 to -223) deletion within the Agamma-globin gene
      promoter and the daughter is a heterozygote with this deletion. The deletion was
      not detected in the father. No any mutations were identified in the Ggamma
      promoter of all the subjects studied. We propose that the small deletion is
      associated with the slight increase of Agamma gene expression in adult.

PMID- 10602163
TI  - Downregulation of CD43 in RAEB and RAEB-T patients. Report of 3 cases.
AB  - CD43 (leukosialin, sialophorin) is a cell surface mucin expressed at high levels
      on most leukocytes and is reported to be involved in adhesion, anti-adhesion, and
      signal transduction prodders. Regulation of its expression is thought to take
      place through methylation of the DNA in the nonproducing cells, and the
      methylation inhibitor 5-azacytidine induces expression of the sialophorin gene.
      Here we report three cases of patients with myelodysplastic syndromes in which
      acquired severe deficiency of the CD43 antigen on the surface of most hemopoietic
      cells was observed. Peripheral blood mononuclear (PBMC) cells from 32 MDS
      patients and 20 healthy individuals were analyzed by flow cytometry after
      labeling with an anti-CD43 (DF-T1) monoclonal antibody. In 1 patient with
      refractory anemia with excess of blasts (RAEB) and 2 patients with refractory
      anemia with excess of blasts in transformation (RAEB-t), the percentages of
      CD43(+) PBMC were 3.8%, 6%, and 9.9%, respectively. The deficiency was observed
      at protein and RNA level as confirmed by western and southern blot, while
      analysis of the DNA by single-strand conformation polymorphism and sequencing did
      not reveal any difference in the gene sequence between the CD43(+) and CD43(-)
      cells of these patients. It is known that patients with MDS may have normal and
      dysplastic population of hemopoietic cells. Further studies are needed to reveal
      the mechanism of downregulation of the gene in these 3 patients and whether the
      phenomenon is related to the dysplastic population only or not.

PMID- 10602164
TI  - Ciprofloxacin-warfarin coagulopathy: a case series.
AB  - Ciprofloxacin, when given to patients previously anticoagulated with warfarin,
      can occasionally cause an exaggerated hypoprothombinemic response and bleeding
      diatheses. Two such cases encountered at our institution are presented and data
      is combined with 64 cases reported to the Food and Drug Administration's (FDA)
      Spontaneous Reporting System (SRS) database, which included all cases reported
      from 1987 through 1997. Of 66 total cases the median age was 72 (range 36-94).
      The mean time to detection of the coagulopathy following the ciprofloxacin
      challenge was 5.5 days (n = 50). Hospitalization was reported in 15 cases,
      bleeding in 25 cases, and death in one case. The median prothrombin time (PT) and
      International Normalized Ratio (INR) was 38.0 (n = 13) and 10.0 (n = 23),
      respectively. The mean number of medications taken was 6.5 (n = 45). The mean
      time to correction was significantly shorter between the treated (2.5 days) and
      the untreated (4.0 days) groups (P < 0. 008). The ciprofloxacin-warfarin
      coagulopathy occurred most commonly in patients in their seventh decade and in
      those who require polypharmacy. Active treatment of the coagulopathy results in
      more rapid resolution than observation alone. Clinicians should be aware of the
      potential bleeding complications that can occur with the ciprofloxacin-warfarin
      drug-drug interaction.

PMID- 10602165
TI  - Haemorrhagic cystitis associated with adenovirus in a patient with AIDS treated
      for a non-Hodgkin's lymphoma.
AB  - Adenovirus-induced haemorrhagic cystitis has been reported chiefly in bone marrow
      or kidney transplant recipients. We report here on an HIV-positive patient
      treated for a Burkitt's lymphoma who developed gross haematuria associated with
      fever and burning urination. Usual causes of haematuria were ruled out:
      lithiasis, urinary tract lesions, glomerulonephritis, mycobacterium and
      schistosoma infections, and drug toxicity. Adenovirus was detected by cellular
      cultures and BK/JC virus DNA sequences were detected using a polymerase chain
      reaction method. Because BK/JC virus shedding is very common (75%) in HIV
      patients receiving chemotherapy, our data strongly suggest that adenovirus was
      responsible for the haemorrhagic cystitis in our patient. In conclusion,
      adenovirus should be considered as a potential cause of haemorrhagic cystitis in
      AIDS patients whose immunosuppression is aggravated by cytotoxic drugs.

PMID- 10602166
TI  - Long-term remission in an elderly patient with mantle cell leukemia treated with
      low-dose cyclophosphamide.
AB  - We present an elderly patient with mantle cell leukemia who was successfully
      treated with low-dose cyclophosphamide (CY). A 76-year-old female was diagnosed
      as mantle cell leukemia based on abnormal lymphocytosis and splenomegaly without
      lymphadenopathy. She was orally treated with 50 mg of CY daily and had continuous
      remission over 4 years. Rearrangements of BCL1 and immunoglobulin heavy chain
      genes in the peripheral blood lymphocytes were detected at diagnosis, but not 1
      or 4 years later. Further studies are required to confirm the role of low-dose CY
      therapy for patients with mantle cell leukemia and lymphoma.

PMID- 10602167
TI  - Macrocytic anemia and thrombocytosis associated with thymoma: a case report.
AB  - Thymomas are often associated with autoimmune disorders. We report on a 45-year
      old female patient with thymoma and hypogammaglobulinemia (Good's syndrome) who
      developed symptomatic macrocytic anemia (Hb 4.4 g/dl, MCV 112 fl) and
      thrombocytosis (Plt 442 G/l). Besides hypogammaglobulinemia (IgG 589 mg/dl), an
      inverted ratio of CD4(+)/CD8(+) cells was seen. The bone marrow biopsy showed a
      slightly hypercellular bone marrow with normal granulopoiesis, normal
      megakaryopoiesis and a mild dyserythropoiesis without any ring-sideroblasts. The
      in-vitro stem cell culture from the bone marrow revealed an atypical growth of
      macroclusters, reduced BFU-E and CFU-GEMM colony growth, whereas the CFU-GM
      colony growth was within the normal range. The chromosomal analysis showed a
      normal karyotype. The plasma vitamin B(12) and folate levels were within normal
      ranges, and we could not detect any autoantibodies. These findings excluded the
      differential diagnoses pure red cell aplasia (PRCA) and pernicious anemia. After
      resection of the thymoma of mixed cell type, the macrocytic anemia and
      thrombocytosis disappeared. The clinical course was complicated by a cerebral
      palsy and a life-threatening fungal septicemia after surgery. In the third year
      after thymectomy, hyporegenerative macrocytic anemia and thrombocytosis
      reappeared and an immunosuppressive treatment with prednisolone (1 mg/kg BW) was
      started. After initiation of the prednisolone therapy, reticulocyte counts
      increased and macrocytic anemia as well as thrombocytosis disappeared. The
      normalization of these laboratory parameters during glucocorticoid therapy
      suggests that in rare cases the constellation of macrocytic anemia,
      thrombocytosis and hypogammaglobulinemia may be due to an underlying immunologic
      mechanism.

PMID- 10602168
TI  - Choroidal infiltrates simulating fundal changes of acute leukemia during
      hematological recovery following high-dose chemotherapy in acute myelomonocytic
      leukemia in remission.
AB  - A young female patient of 18 who was diagnosed to have acute myelomonocytic
      leukemia (AML M4) developed choroidal infiltrate and fundal changes suggestive of
      acute leukemia deposits while she was in remission and was recovering from
      chemotherapy induced myelosuppression. The choroidal infiltrates were associated
      with peripheral blood and CSF monocytosis. The choroidal lesion resolved on its
      own in 2 week's time, when the peripheral and CSF monocytosis subsided.
      Interestingly this patient had pseudo-Chediak Higashi inclusions in leukemic
      blasts with normal karyotype.

PMID- 10602169
TI  - Donor cell leukemia: report of a case occurring 11 years after allogeneic bone
      marrow transplantation and review of the literature.
AB  - We report the case of a man with chronic myelocytic leukemia (CML) and a
      46,XY,t(5;9;22) karyotype who developed acute myelocytic leukemia (AML) with a
      45,X,t(8;21) karyotype 11 years after bone marrow transplantation (BMT) from his
      HLA-matched sister. Fluorescent in situ hybridization (FISH) studies and
      molecular analysis using short tandem repeat (STR) sequences proved the new
      leukemia to be of donor cell origin. Donor cell leukemia (DCL) after BMT is rare.
      Our review of the literature found 15 cases following BMT for leukemia and 2
      cases after BMT for benign hematological disorders. In fewer than half the
      reported cases were molecular studies available to confirm the cytogenetic
      evidence for DCL, and the longest previously reported interval between BMT and
      DCL was 6 years.

PMID- 10602170
TI  - PCR-based diagnosis of the Filipino (--(FIL)) and Thai (--(THAI)) alpha
      thalassemia-1 deletions.
AB  - In southeast Asia, the carrier frequency of two-gene alpha-thalassemia deletions
      is quite high, ranging from 4% to 14% depending on the population. The most
      common alpha-thalassemia-1 deletion is the so-called southeast Asian deletion (-
      (SEA)). In addition, a significant proportion of cases involve two other
      deletions, the Filipino (--(FIL)) and Thai (--(THAI)) deletions. In this report,
      we identify the deletion breakpoints for the (--(FIL)) and (--(THAI)) deletions,
      and describe PCR-based protocols for rapid and reliable DNA diagnosis of these
      deletions.

PMID- 10602171
TI  - Advanced Hodgkin's disease in a pregnant HIV seropositive woman: favorable mother
      and baby outcome following combined anticancer and antiretroviral therapy.
AB  - We describe a 33 y/o HIV(+) woman who developed advanced Hodgkin's disease (HD)
      during the 2nd trimester of her pregnancy. Combination chemotherapy and
      antiretroviral treatment along with opportunistic infection prophylaxis were
      administered. At term, while in partial remission, she delivered by a Caesarian
      section a healthy baby, PCR-negative for HIV. A complete remission was later
      achieved upon completion of the chemotherapy regimen. Since both the incidence of
      HD and the proportion of young women among the HIV(+) individuals are increasing,
      it seems important to recognize that successful completion of pregnancy with no
      deterioration of accepted surrogate parameters of HIV disease progression is
      achievable in a carefully treated HIV(+) pregnant woman with advanced HD.

PMID- 10602172
TI  - Disseminated histoplasmosis following prolonged low-dose methotrexate therapy.

PMID- 10602173
TI  - Antiphospholipid syndrome during chronic myelomonocytic leukemia.

PMID- 10602174
TI  - Hyperacute graft-versus-host disease and NKT cells.

PMID- 10602175
TI  - Protease inhibitors and haptoglobin for treatment of renal failure in paroxysmal
      nocturnal hemoglobinuria.

PMID- 10602176
TI  - Open-Framework Inorganic Materials.
AB  - Aluminosilicate zeolites such as UTD-1 (structure shown) belong to a family of
      nanoporous inorganic materials that find utility in catalysis, separation, and
      ion exchange. During the last decade, the rate of discovery of new open-framework
      materials based, for example, on phosphates, sulfides, halides, nitrides, and
      coordination compounds has increased dramatically. The synthesis, structures, and
      properties of this remarkable class of materials are reviewed.

PMID- 10602177
TI  - A Critical Appraisal of the Experimental Data on the Molecular Structure and
      Spectra of Halides, Oxides, and Hydrides of the s-, d-, and f-Block Elements.
AB  - Evidence for unusual shapes of simple MX(n) molecules that are not stable under
      normal conditions is critically appraised in this review, which assesses current
      knowledge of the spectra and structures of many simple binary halides, oxides,
      and hydrides. It emphasizes the need for more high-resolution gas-phase
      spectroscopic data, summarizes the current state of knowledge in many fields, and
      suggests key experiments that should be carried out to resolve conflicting
      results obtained in earlier studies.

PMID- 10602178
TI  - Take the Right Catalyst: Palladium-Catalyzed C-C, C-N, and C-O Bond Formation on
      Chloroarenes.
AB  - Unreactive chloroarenes have been outwitted: The key to successful C-C, C-N, and
      C-O bond formation on chloroarenes is the development and optimization of
      suitable catalysts. Electron-rich alkylphosphanes are mandatory as ligands in
      these palladium-catalyzed reactions.

PMID- 10602179
TI  - The First Nitride Spinels-New Synthetic Approaches to Binary Group 14 Nitrides.
AB  - A significant breakthrough in the nitride chemistry of main group elements has
      been achieved: Surprisingly Sn(3)N(4), for which there had been no proof of
      existence until now, as well as the isotypic high-pressure polymorphs gamma
      Si(3)N(4) and gamma-Ge(3)N(4) have been synthesized. All three compounds
      crystallize in a spinel structure type (see picture) that previously has not been
      found for nitrides, and may have a high relevance for practical applications in
      the context of ultrahard materials.

PMID- 10602180
TI  - Self-Assembly of Trisoligonucleotidyls: The Case for Nano-Acetylene and Nano
      Cyclobutadiene.
AB  - Rapid cooling is the recipe for the self-assembly of nanostructures from
      trisoligonucleotidyls, a novel class of branched oligonucleotides whose 3'
      termini are connected by a trifunctional linker. The topology of the smallest
      complex is formally equivalent to the topology of acetylene, if a DNA double
      strand is envisioned as a C-C bond. The model of nano-acetylene is shown.

PMID- 10602181
TI  - Reaction of Hypercoordinate Dichlorosilanes Bearing 8-(Dimethylamino)-1-naphthyl
      Group(s) with Magnesium: Formation of the 1,2-Disilaacenaphthene Skeleton.
AB  - Migration of NMe(2) from C(naphthyl) to Si and Si-Si and Si-C bond formation to
      give a 1,2-disilaacenaphthene skeleton occurred in the reaction of
      hypercoordinate dichlorosilanes bearing the 8-(dimethylamino)-1-naphthyl group
      with two equivalents of magnesium [e.g., Eq. (a)]. The intermediate was isolated
      as the 1-isopropoxy derivative after quenching the reaction mixture with
      isopropyl alcohol.

PMID- 10602182
TI  - Organotitanium Fluorides as Matrices for Trapping Molecular ZnF(2) and MeZnF.
AB  - Trapped as molecular solids, the transition metal fluorides ZnF(2) and MeZnF-the
      latter isolated for the first time-exist as adducts in
      [(Cp*TiF(3))(8)(ZnF(2))(3)] (1) and [(Cp*TiF(3))(4)(MeZnF)(2)] (2), respectively.
      Compounds 1 and 2 were obtained in reactions of [Cp*TiF(3)] (Cp*=C(5)Me(5)) with
      ZnMe(2) and Me(3)SnF in various molar ratios. The single-crystal structure of 1
      is shown here; the unlabeled circles are F atoms.

PMID- 10602183
TI  - Rhodium-Catalyzed Formation of Phosphorus-Boron Bonds: Synthesis of the First
      High Molecular Weight Poly(phosphinoborane).
AB  - An inorganic analogue of polystyrene, poly(phenylphosphinoborane) represents the
      first high molecular weight, well-characterized polymer with a backbone of
      alternating phosphorus and boron atoms. It is accessible by metal-catalyzed
      "dehydrocoupling" of a primary phosphane-borane adduct (see scheme).

PMID- 10602184
TI  - Preparation of a Completely Oriented Molecular Sieve Membrane.
AB  - Growth of oriented seed crystals on a substrate led to a completely oriented and
      continuous membrane of LTA-type zeolite. The seed crystals of cubic morphology
      were dip-coated onto a tilted substrate (see schematic diagram) with the zeolite
      channels normal to the surface. The substrate was hydrothermally treated in a
      reaction mixture containing the organic ligand 2,2-bis(hydroxymethyl)-2,2',2"
      nitrilotriethanol, which lowers the degree of supersaturation of [Al(OH)(4)](-)
      ions and preferentially facilitates the intergrowth of the seed crystals.

PMID- 10602185
TI  - Nickel-Assisted Carbon-Fluorine Bond Activation of 2,4,6-Trifluoropyrimidine:
      Synthesis of New Pyrimidine and Pyrimidinone Derivatives.
AB  - Rapid and regioselective activation of the C-F bond of 2,4,6-trifluoropyrimidine
      occurs on reaction with [Ni(cod)(2)] (cod=1,5-cyclooctadiene) in the presence of
      PEt(3) to give 1, which can be converted into complex 2, containing a further
      N(3)-metalated pyrimidin-4-one unit. The novel pyrimidin-4-one 3 is released on
      protonation of 2.

PMID- 10602186
TI  - Strong P=P pi Bonds: The First Synthesis of a Stable Phosphanyl Phosphenium Ion.
AB  - A 35-fold excess of methyl triflate (2) is required to quantitively prepare 3,
      the first phosphanyl phosphenium ion, from diphosphene 1. Experimental data and
      calculations indicate that the P=P bond becomes stronger upon alkylation.

PMID- 10602187
TI  - Polyoxometalates as Reduction Catalysts: Deoxygenation and Hydrogenation of
      Carbonyl Compounds.
AB  - Excellent deoxygenation of ketones and aldehydes is achieved with Keggin-type
      polyoxometalates in the presence of hydrogen (see Equation (1) for an example).
      The mixed addenda phosphovanadomolybdate [PV(2)Mo(10)O(4)](5-) was found to be
      the best catalyst. X-ray diffraction and IR studies suggest that the
      polyoxometalates are structurally stable under the strongly reducing conditions.

PMID- 10602188
TI  - Total Synthesis of Everninomicin 13,384-1-Part 1: Synthesis of the A(1)B(A)C
      Fragment.
AB  - The powerful antibiotic everninomicin 13,384-1 (1, Ziracin) has been prepared for
      the first time through a total synthesis. The 1-->1'-disaccharide and the two
      orthoesters of this target molecule were introduced by new methodologies using a
      tin acetal and 1,2-phenylseleno migrations. The reaction sequence also relies on
      stereoselective glycosidations and subtle manipulations of protecting groups. In
      addition to the introduction of new synthetic methodologies, this total synthesis
      should allow the preparation of combinatorial libraries of semisynthetic
      analogues of this highly promising antibiotic for biological screening purposes.

PMID- 10602189
TI  - Total Synthesis of Everninomicin 13,384-1-Part 2: Synthesis of the FGHA(2)
      Fragment.

PMID- 10602190
TI  - Total Synthesis of Everninomicin 13,384-1-Part 3: Synthesis of the DE Fragment
      and Completion of the Total Synthesis.

PMID- 10602191
TI  - Shaping Solid-State Supramolecular Cavities: Chemically Induced Accordionlike
      Movement of gamma-Zirconium Phosphate Containing Polyethylenoxide Pillars.
AB  - The hydrophilic oxygen atoms of polyethylenoxide chains inserted as pillars in
      gamma-zirconium phosphate form hydrogen bonds with the acid groups of the host.
      As a result the pillars are almost perpendicular to the gamma layers. Upon
      changing the pH level of the supernatant solution the hydrogen bonds are broken
      and the pillars become almost perpendicular to the layers (shown schematically).
      Thus there is a reversible enlargement-shortening of the interlayer space.

PMID- 10602192
TI  - Laser-Induced "Regeneration" of Colloidal Particles: The Effects of Thermal
      Inertia on the Chemical Reactivity of Laser-Heated Particles.
AB  - A size reduction of the suspended particles is observed upon irradiation of
      colloidal metal solutions by a high-power, pulsed laser, resulting in dramatic
      changes in their optical properties. The mechanism of change involves rapid
      production of ions as a consequence of laser heating, followed by diffusion and
      chemical reduction on a long time scale to form new colloidal particles. The
      process, by which large particles are differentially consumed relative to small
      ones, depends on the "thermal inertia" of the particles, which governs the
      temperature of the particles and hence their reactivity.

PMID- 10602193
TI  - The First Catalytic Enantioselective Nozaki-Hiyama Reaction.
AB  - The Nozaki-Hiyama reaction can be performed in an enantioselective catalytic way!
      The catalytic system utilizes 10 mol % of an inexpensive chiral [Cr(salen)]
      complex. The [Cr(salen)]/Mn/Me(3)SiCl system effectively promotes the
      enantioselective addition of allyl chloride to aliphatic and aromatic aldehydes
      at room temperature (65-89 % ee, 40-60 % yield).

PMID- 10602194
TI  - N-Confused Calix
AB  - Next to the "normal" calix[4]pyrrole 1, the N-confused calix[4]pyrrole 2 is
      formed in substantial amounts (up to 22 % yield) as side product in the acid
      catalyzed condensation reaction of ketones and pyrrole. In some cases, doubly N
      confused calix[4]pyrroles are also formed.

PMID- 10602195
TI  - Treatment of Naphthols with B(C(6)F(5))(3): Formation and Characterization of the
      Lewis Acid Adducts of Their Keto Isomers.
AB  - With the strong Lewis acid B(C(6)F(5))(3), the keto tautomers from a variety of
      naphthol derivatives are obtained (e.g. alpha-naphthol, see scheme). The adducts
      of the tautomers were characterized by X-ray structure analysis, and the first
      attempts at hydrozirconation of the adducts were made.

PMID- 10602196
TI  - Palladium-Catalyzed Hydroalkoxylation of Methylenecyclopropanes.
AB  - Hydroalkoxylations proceed by a different path than transition metal catalyzed
      hydrostannations and hydrosilylations. In the reaction of methylenecyclopropanes
      1 with alcohols 2 in the presence of Pd(0), the distal bond in the cyclopropane
      ring is cleaved, and allyl ether 3 is formed selectively. R(1)=n-C(7)H(15),
      PhCH(2)CH(2); R(2)=H, PhCH(2)CH(2); R(3)=PhCH(2), CF(3)CH(2), Et(3)Si, n
      C(4)H(9), etc.

PMID- 10602197
TI  - The First Molecular Main Group Metal Species Containing Interstitial Hydride.
AB  - Lithium cages containing hydride: The reaction of tBuLi with Me(2)AlN(2-Pyr)Ph in
      toluene gave [Li(8)(H){N(2-Pyr)Ph}(6)](+)[Li(Me(2)AltBu(2))(2)](-), whose cation
      is the first molecular main group metal species to contain interstitial hydride
      (the cluster core is shown in the picture). Treatment of the reaction mixture
      with THF gave the neutral hydride Li(7)(H)[N(2-Pyr)Ph](6), which has a capped
      octahedral (Li(+))(7) cluster core. 2-Pyr=2-pyridyl.

PMID- 10602198
TI  - First and Highly Diastereoselective Synthesis of Palladepanes.
AB  - Unexpected stability is observed for the palladacycloheptane rac-2, which is
      obtained as major product and single diastereomer from the cyclization of 1 and
      Pd(0). Up to a temperature of 50 degrees C 2 shows neither reductive elimination
      nor intramolecular insertion of another olefin.

PMID- 10602200
TI  - Controlled Self-Assembly of Cyclic Gold(I) Complexes: The First Family of
      Organometallic Catenanes.
AB  - The value of n in Ph(2)P(CH(2))(n)PPh(2) controls whether a simple ring or a
      [2]catenane is formed in the reaction with a digold(I) diacetylide. Simple
      macrocyclic gold complexes are obtained for n=2 and the family of organometallic
      [2]catenanes for n=4 and 5 (see structure); a mixture of these products as well
      as a third isomer results when n=3.

PMID- 10602199
TI  - Stereoselective Mukaiyama-Michael/Michael/Aldol Domino Cyclization as the Key
      Step in the Synthesis of Pentasubstituted Arenes: An Efficient Access to Highly
      Active Inhibitors of Cholesteryl Ester Transfer Protein (CETP).
AB  - Seemingly heartbreaking for a stereochemist, the one-step selective construction
      of a stereopentad and its prompt destruction by aromatization has been proven to
      be an efficient strategy for the synthesis of fivefold substituted,
      pharmacologically highly active arenes (see scheme).

PMID- 10602201
TI  - Specific Alkylation of Guanine Opposite to a Single Nucleotide Bulge: A Chemical
      Probe for the Bulged Structure of DNA.
AB  - Remarkable enhancement of guanine alkylation just opposite a bulged site by 13R-1
      compared with those in normal duplex DNA is ascribable to the formation of a
      unique intercalated complex that is attainable only at the bulged sites (see
      picture). This observation suggests that 13R-1 can be used as a chemical probe
      for the bulged structure of DNA.

PMID- 10602202
TI  - Ga(22)
AB  - A metal-rich intermediate was captured prior to metal formation by means of a
      substitution reaction during the disproportionation of a metastable Ga(I) bromide
      solution. In the thus obtained Ga(22) cluster (see structure), the central
      gallium atom displays the unusual coordination number of 13.

PMID- 10602203
TI  - Diastereoselective Synthesis of C-Glycosylated Amino Acids with Lactams as
      Peptide Building Blocks.
AB  - Readily available by lipase-catalyzed kinetic resolution or from a chiral pool,
      beta-, gamma-, and delta-lactams can be used as peptide building blocks for the
      synthesis of C-glycosylated amino acids 1. By reaction with glycosyl dianions,
      metabolic stable glycosylated amino acids can be prepared diastereoselectively.
      Ac=acetyl; Bn=benzyl; Boc=tert-butoxycarbonyl; R=Et, Bn; R'=H, alkyl; n=1-3.

PMID- 10602204
TI  - Nickel(0)-Catalyzed Three-Component Connection Reaction of Dimethylzinc, 1,3
      Dienes, and Carbonyl Compounds.
AB  - Linear 1:1:1 coupling of dimethylzinc, 1,3-dienes, and carbonyl compounds in this
      order is facilitated by catalytic amounts of [Ni(acac)(2)] to give (E)-3-hexen-1
      ols in good yields under mild conditions [Eq. (a)]. Increasing steric hindrance
      at the carbonyl group favors formation of the 1:2:1 adduct, and this is the sole
      product when the carbonyl compound is acetone. acac=acetylacetonate.

PMID- 10602205
TI  - Intermolecular Hydroamination of Alkynes Catalyzed by Dimethyltitanocene.
AB  - A completely new application of dimethyltitanocene as catalyst for the
      intermolecular hydroamination of alkynes is presented. With this inexpensive and
      readily available catalyst, alkynes can be easily converted into imines, amines,
      and ketones (see reaction scheme).

PMID- 10602206
TI  - Catalytic, Regiospecific End-Functionalization of Alkanes: Rhenium-Catalyzed
      Borylation under Photochemical Conditions.
AB  - Approaching a Holy Grail? A regioselective functionalization of alkanes occurs
      with commercially available rhenium catalysts and borane reagents under
      photochemical conditions [Eq. (1)]. Mechanistic studies indicate that the
      regioselectivity results from a direct thermal reaction of a photochemically
      generated 16-electron boryl complex with alkane.

PMID- 10602207
TI  - Absolute Asymmetric Synthesis: The Origin, Control, and Amplification of
      Chirality.
AB  - Biomolecular homochirality, the origin of which is still a puzzle, has challenged
      scientists to design chemical systems that provide chiral molecules through
      absolute asymmetric synthesis and to amplify a small stereochemical bias in such
      systems. The photoresolution of the enantiomers of helical-shaped, sterically
      overcrowded alkene 1 with circularly polarized light and the transduction of the
      stereochemical information by triggering the helical arrangement of a large
      collection of achiral molecules in a twisted nematic liquid crystalline phase (2)
      are examples of control and amplification of chirality.

PMID- 10602208
TI  - Concomitant Polymorphs.
AB  - The simultaneous appearance of polymorphs of a substance has long been recognized
      but rarely noted or systematically studied. This phenomenon can be useful in the
      investigation of solid materials and in understanding the relative crystal
      energetics of polymorphic materials. This review covers the thermodynamic and
      kinetic factors that govern competitive and concomitant polymorphic
      crystallization. One of the many examples surveyed is a cyanine/oxonol complex,
      for which different relative molecular orientations in two of the many reported
      polymorphs are shown.

PMID- 10602209
TI  - Into the Next Dimension: Nanometer-Sized, Oligonuclear Coordination Compounds
      with C(3)-Symmetric Ligands.
AB  - Nanometer-sized cavities are present in oligonuclear coordination compounds
      formed in molecular self-assembly processes from C(3)-symmetric ligands and
      appropriate metal complex fragments. The structures obtained can be described as
      basic polyhedra such as tetrahedron, hexahedron, or octahedron (see picture).

PMID- 10602210
TI  - Chemically Modified Antisense Oligonucleotides-Recent Improvements of RNA Binding
      and Ribonuclease H Recruitment.
AB  - The incorporation of rationally designed sugar or nucleobase modifications into
      oligonucleotides gives remarkable improvements of the antisense activity. For
      example, the cytosine analogue 1 recognizes both the Watson-Crick and the
      Hoogsteen site of a guanine nucleotide 2, which dramatically enhances the RNA
      binding affinity and selectivity.

PMID- 10602211
TI  - At Last, 1,10-Phenanthroline-N,N'-dioxide, A New Type of Helicene, has been
      Synthesized using HOF small middle dotCH(3)CN.
AB  - For more than 50 years the synthesis of 1,10-phenanthroline-N,N'-dioxide (2) has
      been sought. The reason for the failure of all the earlier attempts is that the
      limited space in the bay area of the starting material 1,10-phenanthroline (1)
      cannot accommodate two oxygen atoms. The oxidation has now been achieved with the
      oxygen-transfer agent HOF small middle dotCH(3)CN, and X-ray studies have
      revealed that the product is not planar but is a new type of helicene-in this way
      the "space problem" for the two oxygen atoms has been solved.

PMID- 10602212
TI  - The First Enantiomerically Pure Triangulane (M)-Trispiro
AB  - A remarkably high specific rotation, even at 589 nm, is shown by (M)-1, the first
      enantiomerically pure unbranched [4]triangulane, although it has no chromophore
      that would lead to any significant absorption above 200 nm. This outstanding
      rotatory power is in line with a helical arrangement of its sigma bonds, as
      confirmed by high-level computations. Thus, it is appropriate to call (M)-1 a
      "sigma-[4]helicene", the first sigma-bond analogue of the aromatic [n]helicenes.

PMID- 10602213
TI  - A One-Pot, High-Yield Synthesis of a Paramagnetic Nickel Square from Divergent
      Precursors by Anion Template Assembly.
AB  - A paramagnetic Ni-containing molecular square has been synthesized in high yield
      from divergent precursors. An X-ray structure (shown in the picture) reveals the
      presence of an encapsulated tetrafluoroborate anion, which appears to be a
      requisite condition for the formation of the cyclic oligomer.

PMID- 10602214
TI  - Amine Phosphates as Intermediates in the Formation of Open-Framework Structures.
AB  - Chain, ladder, layer, and three-dimensional metal phosphates were obtained by the
      reaction of amine phosphates with metal ions under mild hydrothermal conditions.
      The role of amine phosphates as intermediates in hydrothermal syntheses was
      corroborated by in situ NMR spectroscopy and X-ray diffraction studies. The
      picture shows a simple corner-shared linear chain structure formed in the
      reaction of piperazine phosphate with Zn(II) ions.

PMID- 10602215
TI  - Self-Assembly of a Radially Functionalized Hexagonal Molecule: Hexakis(4
      hydroxyphenyl)benzene.
AB  - Two different porous hydrogen-bonded networks are formed by self-assembly of the
      radially substituted host 1. In the network of type A, formed by 1 small middle
      dot4 Et(2)O, all OH groups of 1 are involved in hydrogen bonding, and the
      molecular sheets are stacked without translation to generate extended channels
      that accommodate the Et(2)O molecules. Four OH groups of 1 are involved in the
      type B network of 1 small middle dot4 DMF, and lateral translation of the sheets
      in an ABAB sequence generates large chambers, each of which contains four DMF
      molecules.

PMID- 10602216
TI  - [Re]
AB  - A chair conformation comparable to that observed for six-membered rings composed
      of tetrahedral carbon atoms is found for the cluster anion [Re(6)(u
      H)(5)(CO)(24)](-) (see picture; black spheres: Re, white spheres: u-H; CO ligands
      omitted for clarity) in spite of the octahedral coordination at the Re centers.
      This is the first example of a carbonyl cluster exhibiting a cyclohexane-like
      geometry of the metallic framework.

PMID- 10602217
TI  - Interpenetrated and Noninterpenetrated Three-Dimensional Networks in the
      Polymeric Species Ag(tta) and 2 Ag(tta) small middle dotAgNO(3)
      (tta=tetrazolate): The First Examples of the u(4)-eta(1):eta(1):eta(1):eta(1)
      Bonding Mode for Tetrazolate.
AB  - A twofold interpenetrated neutral three-dimensional network with rectangular
      channels (left) and a noninterpenetrated three-dimensional cationic framework
      (right) are the stuctural motifs observed in the simple salt Ag(tta) and in the
      double salt 2 Ag(tta) small middle dotAgNO(3), respectively. These compounds
      exhibit the first examples of the u(4)-eta(1):eta(1):eta(1):eta(1) bonding mode
      for tetrazolate (tta).

PMID- 10602218
TI  - Novel Ternary Alkali Metal Silver Acetylides M(I)AgC(2) (M(I)=Li, Na, K, Rb, Cs).
AB  - Three different packings of (1)(infinity)[Ag(C(2))(2/2)(-)] chains (represented
      by rods in the picture) have been found in the crystal structures of the first
      ternary alkali metal silver acetylides, which were obtained by the reaction of
      M(I)C(2)H (M(I)=Li-Cs) with AgI in liquid ammonia and subsequent heating of the
      remaining residue to 120 degrees C.

PMID- 10602220
TI  - Thermal Conversion of a Helical Coil into a Three-Dimensional Chiral Framework.
AB  - Thermal dehydration results in the solid-state supramolecular conversion of the
      helical coordination polymer [{[Cu(sala)](2)(H(2)O)}(n)] into the chiral three
      dimensional covalent open network [{Cu(sala)}(n)] (shown schematically). X-ray
      crystallography reveals that hydrogen bonding plays a key role in this process.
      H(2)sala=N-(2-hydroxybenzyl)-L-alanine

PMID- 10602219
TI  - A Two-Directional and Highly Convergent Approach for the Synthesis of the Tumor
      Associated Antigen Globo-H.
AB  - The assembly of six readily available building blocks in five glycosylation steps
      affords the tumor-associated Globo-H hexasaccharide 1 without the need for any
      intermediate protecting group manipulations. The aminopropyl spacer is employed
      for conjugation to carrier proteins.

PMID- 10602221
TI  - Reductive Activation of a Hydroxylamine Hemiacetal Derivative of
      Dehydromonocrotaline: The First Reductively Activated Pyrrolizidine Alkaloid
      Capable of Cross-Linking DNA.
AB  - The acute hepatotoxicity displayed by the pyrrolizidine alkaloids, which obviates
      their clinical utility, is a result of activation in vivo by cytochrome P450
      mediated oxidation. Now the first reductively activated progenitor of the highly
      cytotoxic dehydropyrrolizidine alkaloid dehydromonocrotaline has been synthesized
      and demonstrated to mediate interstrand DNA cross-link formation (see scheme);
      pyrrolizidine alkaloids exert their cytotoxicity through the formation of DNA-DNA
      interstrand and DNA-protein cross-links.

PMID- 10602222
TI  - The First Catalytic Asymmetric Nitro-Mannich-Type Reaction Promoted by a New
      Heterobimetallic Complex.
AB  - The best ratio is 1:1:3 for the components Yb, K, and binaphthol in the new
      heterobimetallic complex, which efficiently catalyzes an asymmetric nitro-Mannich
      type reaction. The desired nitro-Mannich products 2 are obtained with up to 91 %
      ee starting from N-phosphinoyl imines 1.

PMID- 10602223
TI  - Mesoporous Magnetic Materials Based on Rare Earth Oxides.
AB  - A novel family of mesoporous oxides of rare earth metals (Gd, Tb, Dy, Ho, Er, Tm,
      Yb, Lu) were synthesized with specific surface areas of 253-348 m(2) g(-1) and
      pore diameters of 2.5-3.0 nm (see Scheme). The mesoporous solids and their
      surfactant mesophase precursors are paramagnetic and exhibit a magnetic anomaly
      due to the mesostructured atomic arrangement.

PMID- 10602224
TI  - On the "Rebound" Mechanism of Alkane Hydroxylation by Cytochrome P450: Electronic
      Structure of the Intermediate and the Electron Transfer Character in the Rebound
      Step.
AB  - Two electromeric forms, a and b (a is the ground state in a solvent) exist for
      the hydroxo-iron complex 1, an intermediate in the rebound mechanism of alkane
      hydroxylation by cytochrome P450. Results of density functional and model solvent
      calculations of various species are in agreement with experimental findings, and
      imply the role of 1 a in the rebound mechanism.

PMID- 10602225
TI  - Experimental Evidence for the Existence of Neutral P(6): A New Allotrope of
      Phosphorus.
AB  - High-energy collisions of Cp*P(6)(+) cations yield neutral P(6) molecules (see
      reaction), thus providing the first experimental evidence for the existence of
      this new allotrope of phosphorus.

PMID- 10602226
TI  - A Titanacycle-to-Carbocycle Relay Leading to an Expedient Synthesis of
      Cyclopentadienols.
AB  - Tandem addition of the two carbon-titanium bonds of a titanacyclopentadiene to
      the ester group of the same molecule affords carbocycles (shown schematically):
      The metal portion of the metallacycle has been replaced with a carbon fragment.
      Depending on the starting diyne, mono-, bi-, or tricyclic compounds can be
      obtained.

PMID- 10602227
TI  - Development of New Chiral P,N Ligands and Their Application in the Cu-Catalyzed
      Enantioselective Conjugate Addition of Diethylzinc to Enones.
AB  - High enantioselectivity (up to 98 % ee) has been achieved for the conjugate
      addition of diethylzinc to acyclic enones utilizing Cu(I) complexes of the novel
      chiral P,N ligands 1. The high enantioselectivities are best achieved using
      [Cu(OTf)](2) small middle dotC(6)H(6) as the copper catalyst precursor in
      nonpolar solvents such as toluene or Cl(CH(2))(2)Cl. R=H, CH(3); Tf=F(3)CSO(2).

PMID- 10602228
TI  - Catalytic Aerobic Oxidation of Cycloalkanes with Nanostructured Amorphous Metals
      and Alloys.
AB  - Under mild conditions (40 atm O(2), 28 degrees C, 10-15 h), an efficient aerobic
      oxidation of cycloalkanes to cycloalkanols can be achieved using nanostructured
      amorphous metals such as Fe and Co and an amorphous alloy like Fe(20)Ni(80) as
      catalysts. For example, cyclohexane is oxidized to cyclohexanol with 32-41 %
      conversion, while 1-adamantanol is formed from adamantane with 52-57 %
      conversion.

PMID- 10602229
TI  - Enantioselective Single-Crystal-to-Single-Crystal Photodimerization of Coumarin
      and Thiocoumarin in Inclusion Complexes with Chiral Host Compounds.
AB  - An intermolecular enantioselective photoreaction by a single-crystal-to-single
      crystal transformation has been carried out for the first time, as is evident
      from X-ray structure analysis and X-ray powder diffractometric studies. This
      reaction, the dimerization of the title compound to cyclobutane derivative 1
      (X=O, S), provides a good example for studying the mechanism of topochemical
      reactions in the crystal.

PMID- 10602230
TI  - A Pentacoordinated Di-N-carboxamido-dithiolato-O-sulfinato-iron(III) Complex
      Related to the Metal Site of Nitrile Hydratase.
AB  - Postcoordination oxidation by dioxygen of one of the thiolate groups in a
      pentadentate N(2)S(3) ligand results in an iron(III) complex with two N
      carboxamido, two thiolato, and one O-sulfinato ligands (see the CAMERON
      representation). This novel mixed coordination is similar to that determined for
      the inactive form of the nitrile hydratase from Rhodococcus sp. N-771, but
      differs by the O versus S binding of the sulfinato ligand.

PMID- 10602231
TI  - The First Cyclodiasteromeric
AB  - A mechanically linked molecule, consisting of an axle and two equivalent wheels,
      shows an analogous stereochemistry to the classical example tartaric acid. Though
      the components are not chiral themselves, a (cyclo)diastereomeric species is
      obtained, the enantiomers (shown schematically) and the meso form of which were
      completely separated and chiroptically characterized.

PMID- 10602232
TI  - A Stereospecific, Intermolecular Biaryl-Coupling Approach to Korupensamine A En
      Route to the Michellamines.
AB  - By what means and how well can axial chirality be controlled in an intermolecular
      Suzuki biaryl cross-coupling reaction? The directionality of reductive
      elimination [Eq. (1)] is completely controlled by using a strategically
      positioned internal ligand L to afford a single biaryl atropisomer corresponding
      to the korupensamine A skeleton. TIPS=iPr(3)Si, Ts=H(3)CC(6)H(4)SO(2).

PMID- 10602233
TI  - Isomerization of Aldehydes Catalyzed by Rhodium(I) Olefin Complexes.
AB  - A mixture of isomeric aldehydes is formed in a catalytic isomerization of alkyl
      aldehydes with [C(5)Me(5)Rh(olefin)(2)] complexes. This process offers an
      indirect method for altering the n:iso ratio of aldehydes formed in
      hydroformylation reactions. For example the reaction of n-butanal with
      [C(5)Me(5)Rh(CH(2)=CHMe)(2)] (1) results in the formation of a bis-alkyl carbonyl
      rhodium complex 2 which is the resting state during the isomerization of n
      butanal to a mixture of n- and iso-butanals (see scheme). In the presence of
      other olefins transfer formylation is observed.

PMID- 10602234
TI  - Total Synthesis of (+)-Deoxypyrrololine: A Potential Biochemical Marker for
      Diagnosis of Osteoporosis.
AB  - The collagen cross-link (+)-deoxypyrrololine (Dpl, 1), a potential biochemical
      marker for diagnosis of osteoporosis, has been obtained by a general and
      convergent total synthesis. The key synthetic features involve utilization of a L
      glutamic acid derivative as a source for all three chiral centers in (+)-1, and
      construction of the pyrrole ring by condensation of an alpha-acetoxynitro
      compound with benzyl isocyanoacetate.

PMID- 10602235
TI  - Silica-Supported Tantalum Catalysts for Asymmetric Epoxidations of Allyl
      Alcohols.
AB  - Tantalum good, titanium bad: This appears to be the case for silica-supported
      catalysts for the asymmetric epoxidation of allyl alcohols. Complexes such as
      [SiO-Ta(OEt)(4)] were prepared from silica and [Ta(=CHCMe(3))(CH(2)CMe(3))(3)],
      and in the presence of a tartrate and an alkyl hydroperoxide, these surface
      tantalum compounds lead to efficient and convenient catalysts for the asymmetric
      epoxidation of 2-propen-1-ol (R=H) and trans-2-hexen-1-ol (R=nPr; see reaction).

PMID- 10602236
TI  - Total Synthesis of (+)-Halichlorine: An Inhibitor of VCAM-1 Expression.
AB  - The diastereoselective addition of the highly functionalized organozinc compound
      1 to the aldehyde 2 in the presence of the chiral amino alcohol 3 (-->4) is a key
      step in the first total synthesis of (+)-halichlorine. A series of
      protections/deprotections and a macrolaconization complete the synthesis.
      Halichlorine selectively inhibits the expression of the cell adhesion molecule
      VCAM-1. TBS=tert-butyldimethylsilyl.

PMID- 10602237
TI  - Asymmetric Total Synthesis of Fluvirucinine A(1).
AB  - Diastereoselective vinyl addition to an amide carbonyl group and amide enolate
      induced aza-Claisen rearrangement are the key steps in the first asymmetric total
      synthesis of fluvirucinine A(1) (1), the aglycon of fluvirucin A(1). Fluvirucins
      are a class of macrolactam antibiotics produced by actinomycete strains that show
      promising biological properties.

PMID- 10602238
TI  - Micropore Decoration with Bidentate Lewis Acids: Spontaneous Assembly of 1,2
      Bis(chloromercurio)tetrafluorobenzene.
AB  - Dimethyl sulfoxide templates the assembly of 1,2
      bis(chloromercurio)tetrafluorobenzene (1) into an internally Lewis acidic
      microporous solid of composition 1 small middle dot(DMSO)(3) (2). The channels of
      2 contain both chelated and solvate DMSO molecules (omitted in the drawing for
      clarity), which can be partly exchanged with water molecules. The hydration
      dehydration of the resulting compound is reversible.

PMID- 10602239
TI  - X-Ray Structure of a Heterochiral, Sulfoximine-Stabilized Dilithiomethane
      Derivative.
AB  - A distorted Li(6)O octahedron in the center and four geminal dilithiated
      sulfoximine units characterize a tetrameric aggregate of the chiral sulfoximine
      stabilized dilithiomethane derivative 3, a previously unknown reaction
      intermediate in asymmetric dianion chemistry. A comparison with the crystal
      structure of the monolithiated parent 2, formed by the treatment of 1 with nBuLi,
      allows a rationalization of the second lithiation.

PMID- 10602240
TI  - Molecular Nanocapsules Based on Amphiphilic Hyperbranched Polyglycerols.
AB  - Polar dyes can be solubilized in apolar media-molecular nanocapsules with
      hydrophilic interiors have been prepared (see schematic representation) using
      polyglycerols with narrow polydispersity and simple esterification with fatty
      acids. These unimolecular micelles offer attractive potential for a variety of
      applications ranging from controlled drug release to the design of microreactors
      and catalysts.

PMID- 10602241
TI  - Biomimetic Explorations Towards the Bisorbicillinoids: Total Synthesis of
      Bisorbicillinol, Bisorbibutenolide, and Trichodimerol.
AB  - Strikingly simple cascade dimerization sequences can be used to assemble the
      complex frameworks of bisorbicillinoids such as bisorbicillinol (1),
      bisorbibutenolide (2), and trichodimerol (3). The mechanistic facets of the
      biomimetic total syntheses of these bioactive natural products were also
      explored. Inspection of the unique molecular architecture of these compounds
      reveals that they are likely to be assembled in nature by a dimerization of two
      oxidized forms of sorbicillin.

PMID- 10602242
TI  - Physician, heal thyself: caveat emptor.

PMID- 10602243
TI  - Do posture and straining influence urinary-flow parameters in normal women?
AB  - The influence of posture of the pelvis and straining on urinary flow was
      investigated in 21 normal women, mainly physiotherapists, who were asked to
      urinate on an uro-flow chair at their usual time and frequency. Subjects were at
      random instructed to urinate in five different test situations: anteversion,
      anteversion with straining, retroversion, retroversion with straining, and
      forward bending without straining. The urinary-flow parameters investigated were
      volume, peak flow, time to peak, peak-to-end time, total time, and mean flow. The
      analysis was done by means of analysis of variance but only for micturition
      volumes >150 mL. The morphology of the urinary-flow curves was examined for the
      presence of irregularities and increasing (after top) or decreasing (for top)
      curve tops and after-dribbling. Results demonstrated no significant differences
      for peak flow, total time, and mean flow in the anteversion, retroversion, and
      the forward-bending position. This holds for test situations and re-test
      controls. However, straining increased the peak flow and mean flow rates in all
      positions and in all women, whereas it reduced the total voiding time. The voided
      volumes were lowest in anteversion. Irregularities were less frequent in the
      forward-bending position. It can be concluded that the forward-bending position
      is the most preferable urinating position to relax the pelvic floor muscles.
      Neurourol. Urodynam. 19:3-8, 2000.

PMID- 10602244
TI  - Evaluation of a simple, non-surgical concept for management of urinary
      incontinence (minimal care) in an open-access, interdisciplinary incontinence
      clinic.
AB  - Our objective was to evaluate a new concept for assessment and treatment of
      urinary incontinence in an open-access, interdisciplinary incontinence clinic. A
      standardized program for investigation and treatment of incontinence was based on
      minimal relevant investigations, primarily non-surgical treatment with a limited
      consumption of resources ("minimal care"). This was a prospective observational
      study of 408 consecutive women examined and treated in the clinic. The main
      characteristics of the women were a high median age and a high prevalence of
      severe concomitant diseases with possible influence on lower urinary tract
      function. More than half of the patients had urge or mixed incontinence. Most of
      the patients were managed with conservative treatment. Fifteen percent were
      referred to in-hospital treatment, with 5% to incontinence surgery. In total 44%
      felt cured or very much improved. Before and after treatment one third of the
      women completed quality-of-life questions and voiding charts, while 43% completed
      the pad tests. Quality of life improved significantly. Objectively leakage on pad
      test and voiding charts was significantly improved. The patients were in general
      very satisfied with clinic's program. Almost one fourth of the women were
      followed up for 6 months after discharge. No significant deterioration in the
      subjective results were found compared to status at discharge. In conclusion, the
      results highlight the need for advice and treatment of patients with
      incontinence. The minimal care program and interdisciplinary structure in the
      incontinence clinic offer effective and low cost treatment for urinary
      incontinence. The open-access, interdisciplinary incontinence clinic model is
      recommended. Neurourol. Urodynam. 18:9-17, 2000.

PMID- 10602245
TI  - Bladder-pumping therapy for the treatment of low-capacity or low-compliance
      bladders.
AB  - The walls of low-capacity or low-compliance bladders are thought to be less
      elastic than normal. Pumping of the bladder was found to disrupt collagen-fiber
      bundles in the rat bladder wall, offering the promise of potential clinical
      application. This result prompted us to use bladder-pumping therapy to soften the
      bladder wall in patients with low-capacity or low-compliance bladders to restore
      bladder elasticity. CO(2) gas or air, at a volume below the maximum bladder
      capacity (</=200 mL), was repeatedly pumped in and out of the bladder through a
      catheter under caudal anesthesia in 26 patients with low-capacity or low
      compliance bladders and without uninhibited bladder contractions, who presented
      with urinary frequency or incontinence. A respirator was used to control the
      pumping at 0.5 cycles/s for a duration of 15 minutes. No serious adverse effects
      were encountered during or after the procedure. Overall subjective improvement
      was noted 4 weeks after the procedure in 11 of 18 patients with a low capacity
      bladder (<300 mL) and in five of eight patients with a low-compliance bladder
      (<20 mL/cm H(2)O). The procedure significantly increased the maximum bladder
      capacity, single voided volume, and average urinary flow rate after 4 weeks. In
      the responding patients, subjective improvement lasted from 3 months to over 6
      years. Bladder-pumping therapy is an easy and safe procedure and exerts a
      beneficial effect for a long period, in patients with low-capacity or low
      compliance bladders and without uninhibited bladder contractions. Neurourol.
      Urodynam. 19:19-28, 2000.

PMID- 10602246
TI  - Effects of partial bladder outlet obstruction and its relief on types I and III
      collagen and detrusor contractility in the rat.
AB  - Bladder outlet obstruction induces a rapid hypertrophy characterized by increased
      bladder mass and collagen deposition. An increase in collagen is likely to reduce
      the contractility and compliance of bladder wall. This study was undertaken to
      investigate the effects of partial bladder outlet obstruction and its relief on
      types I and III collagen, and the relationship between detrusor contractility and
      collagen types. A total of 40 female rats was used for experiment and divided
      into one control, one obstruction, and three recovery groups. The contractility
      to field stimulation was recorded; total collagen and collagen concentration were
      quantified. The localization of types I and III collagen and the expression of
      pro-alpha1(I) and alpha1(III) collagen mRNA were determined by
      immunohistochemical staining and Northern blot hybridization, respectively.
      Contractile response to field stimulation was reduced after obstruction and
      recovered following relief. The total amount of collagen increased after
      obstruction and decreased after relief; however, collagen concentration decreased
      after obstruction and increased following relief. Contractility correlated
      negatively with total collagen but positively with collagen concentration. The
      protein deposition of types I and III collagen was localized in lamina propria
      and muscle bundles in all groups. The expression of types I and III collagen gene
      was up regulated after obstruction, but down regulated after relief. Negative
      correlation between contractility and gene expressions of collagen types was
      significant. These data suggest that the change in localization and quantity of
      collagen types leads to morphologic changes of bladder and can have an impact on
      the contractility of detrusor. Neurourol. Urodynam. 19:29-42, 2000.

PMID- 10602247
TI  - Isoprostane 8-epi PGF2alpha, a product of oxidative stress, is synthesized in the
      bladder and causes detrusor smooth muscle contraction.
AB  - Isoprostane 8-epi PGF2alpha is a product of oxidative stress that causes potent
      smooth muscle contraction. Its production increases in conditions associated with
      oxidative stress such as in diabetes, smoking, and aging. The aim was to study
      whether the urinary bladder synthesizes isoprostane 8-epi PGF2alpha and releases
      to the urine and whether isoprostane 8-epi PGF2alpha causes bladder smooth muscle
      contraction. Urine samples were obtained transurethrally from 12 male New Zealand
      white rabbits for measurement of isoprostane 8-epi PGF2alpha levels. To examine
      whether bladder synthesizes isoprostane 8-epi PGF2alpha, both ureters were
      ligated, then the bladder was washed 5 times by filling and emptying with normal
      saline. Bladder was refilled with normal saline, and at 5 minutes a bladder
      washout sample was taken. After this, the bladder was contracted by nerve
      stimulation periodically for 30 minutes, and then another washout sample was
      taken. Strips of bladder tissues were processed for study of isoprostane 8-epi
      PGF2alpha production in tissue culture chambers and for isometric tension
      measurements in the organ bath. Enzyme immunoassay (EIA) revealed a remarkable
      amount of isoprostane 8-epi PGF2alpha in the rabbit urine. EIA of washout samples
      showed that the bladder synthesizes isoprostane 8-epi PGF2alpha and its
      production increases with nerve stimulation-induced contractions. EIA of samples
      from the tissue culture media showed that bladder strips synthesize isoprostane 8
      epi PGF2alpha in vitro. Electrical field stimulation (EFS) significantly
      increased the synthesis and release of isoprostane 8-epi PGF2alpha by the bladder
      strips. In the organ bath, isoprostane 8-epi PGF2alpha caused concentration
      dependent contraction of bladder tissue. While the threshold contraction required
      smaller concentration of isoprostane 8-epi PGF2alpha (3 nmol) than carbachol (10
      nmol), the amplitude of contraction to carbachol was greater than isoprostane 8
      epi PGF2alpha. Our studies show that the rabbit bladder synthesizes isoprostane 8
      epi PGF2alpha and releases it to the urine. Production of isoprostane 8-epi
      PGF2alpha in the bladder increases with nerve stimulation-induced contraction.
      Exogenous isoprostane 8-epi PGF2alpha causes significant bladder smooth muscle
      contraction. Our findings necessitate further studies to evaluate the possible
      role of oxidative stress and increased isoprostane 8-epi PGF2alpha production in
      bladder dysfunction. Neurourol. Urodynam. 19:43-51, 2000.

PMID- 10602248
TI  - Effects of pudendal nerve injury in the female rat.
AB  - To test a neurogenic hypothesis for external urethral sphincter (EUS) dysfunction
      associated with urinary incontinence, the proximal pudendal nerve was crushed in
      anesthetized retired breeder female rats (n = 5) and compared with a sham lesion
      group (n = 4). Outcome measures included concentric needle electromyograms (EMGs)
      from the target EUS, voiding patterns during a 2-hour dark period, and
      micturition data over a 24-hour period. Fast Blue (FB) was introduced to the
      crush site at the time of injury and Diamidino Yellow (DY) to the EUS at the time
      the rats were killed (3 months post-operative), when histological analysis of the
      nerve and urethra was also performed. EMG records indicated the EUS motor units
      undergo typical denervation changes followed by regeneration and recovery.
      Voiding patterns from the crush group show a significant increase of small urine
      marks in the front third of the cage. At 1-2 weeks post-op, the frequency of
      voids was significantly increased in the crush group compared to pre-op and late
      post-op time periods. The mean volume voided in the light phase at the early post
      op time was significantly increased in the sham group. Light and electron
      microscopic patterns seen in nerve and muscle suggest the regenerating motor
      units maintain a structural integrity. Motoneurons in the lower lumbar cord were
      labeled with either DY (14. 5 +/- 6.8), FB (31.7 +/- 23.7), or both (35.0 +/-
      17.5) tracers, indicating approximately 54% of the crushed pudendal neurons
      regenerated to the EUS. In conclusion, several measures suggest this reversible
      crush lesion induces mild urinary incontinence. This animal model is promising
      for further development of hypotheses regarding neural injury, the pathogenesis
      of incontinence, and strategies aimed at prevention and treatment. Neurourol.
      Urodynam. 19:53-69, 2000.

PMID- 10602249
TI  - Developmental aspects of endothelin receptors in rabbit lower urinary tract.
AB  - Since evidence of development/age-related alterations of endothelin receptors in
      circulation and respiration systems has been increasing, we attempted to
      investigate the pharmacological characterization of endothelin receptors in
      neonatal, premature, and mature male rabbit lower urinary tract. The biochemical
      properties of ET receptors were examined in the lower urinary tracts of 1-day
      (neonatal)-, 6-week (premature)-, and 1-year(mature)-old male rabbits with
      binding technique utilizing [(125)I]ET-1. The rank orders of the densities
      (B(max) values) of endothelin receptors in the bladder dome, bladder base, and
      urethra of different aged rabbits were bladder dome, 1 day > 6 week &vbar;Ls 1
      year, bladder base, 1 day > 6 week &vbar;Ls 1 year, and urethra, 1 day > 6 week >
      1 year. The pharmacological profiles of these binding sites inhibited by various
      kinds of endothelin receptor compounds showed similar K(i) values and similar
      proportions of endothelin receptor subtypes in the same regions of 1-day-, 6-week
      , and 1-year-old animals. Our data clearly demonstrated the presence of regional
      difference and development-related changes in the density and subtype specificity
      of endothelin receptors in the lower urinary tract of the male rabbit. Neurourol.
      Urodynam. 19:71-85, 2000.

PMID- 10602250
TI  - Effect of anesthetics on reflex micturition in the chronic cannula-implanted rat.
AB  - It is well known that urethane is a suitable anesthetic for acute studies and has
      been extensively recommended for investigations related to micturition
      physiology. This is mainly because of the capability of urethane anesthesia to
      spare reflex micturition as well as its easily established long-lasting and
      stable anesthetic level. However, urethane anesthesia is usually restricted to
      acute experiments due to its potential toxicity. This study searched for an
      alternative to urethane that would be suitable for studies in which recovery from
      anesthesia was needed. The list of administered drugs was as follows:
      pentobarbital, thiobutabarbital, ketamine-acepromazine, ketamine-diazepam,
      tiletamine-zolazepam, fentanyl-droperidol, alphaxalone-alphadolone, propofol,
      isoflurane, methoxyflurane, azaperone, tribromoethanol, and buprenorphine. Among
      these drugs, only tiletamine-zolazepam spared the reflex micturition
      contractions. However, the duration of this anesthesia was too short
      (approximately 30 minutes) to complete the necessary testing and additional
      dosing of the anesthetic generally obliterated the micturition reflex. On the
      other hand, rats given i.v. urethane infusion (10% solution in 0.9% saline, 3.2
      4.0 mg/kg/min, total dose 0.56-1.03 g/kg) maintained a stable anesthesia that
      permitted both reflex micturition and stereotaxic procedures. Rats moved
      spontaneously 3-16 hours after cessation of i.v. urethane anesthesia and
      completely recovered in 2 days without significant after-effects. Bladder
      function was normal. No pathological changes were seen 1 week later. The present
      results suggest that urethane is the most suitable anesthetic for acute and
      chronic physiological experiments that require demonstration of reflex
      micturition. Neurourol. Urodynam. 19:87-99, 2000.

PMID- 10602251
TI  - Role of supraspinal tachykinins for volume- and L-dopa-induced bladder activity
      in normal conscious rats.
AB  - To clarify the roles of tachykinins in volume-induced micturition and in bladder
      hyperactivity, presumed to originate from supraspinal structures, normal, female
      Sprague-Dawley rats were investigated cystometrically before and after
      intracerebroventricular (i.c.v) administration of RP 67,580, a selective
      antagonist of NK-1 receptors, and/or SR 48,968, a selective antagonist of NK-2
      receptors. The effects of RP 67,580 and SR 48,968 on intra-peritoneal (i.p.) L
      dopa-induced bladder hyperactivity were also investigated. I.c.v. administration
      of RP 67,580 (20 nmol) SR 48,968 (20 nmol) suppressed micturition. Combination of
      i.c.v. RP 67, 580 (2 nmol) and SR 48,968 (2 nmol) significantly decreased
      micturition pressure (18%), and increased bladder capacity (26%), micturition
      volume (18%), and residual volume (223%). In rats pretreated with i.p. carbidopa
      50 mg/kg, i.p. L-dopa 50 mg/kg caused bladder hyperactivity that was attenuated
      by the combination of i.c. v. RP 67,580 (2 nmol) and SR 48,968 (2 nmol). The
      results suggest that tachykinins, via stimulation of NK receptors in supraspinal
      structures, are involved in both volume and L-dopa-induced stimulation of bladder
      activity. This may imply that tachykinins can influence both the supraspinal and
      spinal control of the urinary bladder. It also implies that supraspinal NK
      receptors are a possible target for drugs aimed for elimination of bladder
      hyperactivity mediated via these pathways. Neurourol. Urodynam. 19:101-109, 2000.

PMID- 10602252
TI  - Shaping up for shipping out: PLCgamma signaling of morphology changes in EGF
      stimulated fibroblast migration.
AB  - For effective migration, cells must establish an asymmetry in cell/substratum
      biophysical interactions permitting cellular protrusive and contractile motive
      forces to produce net cell body translocation; often this is superficially
      manifested as a polarized cell shape. This change is most easily noted for
      epithelial cells, which typically undergo a mesenchymal transition prior to rapid
      motility, and for hematopoietic cells, which must transition from non-adherent to
      adherent states. These two situations entail dramatic changes that also involve
      cell-cell contact and differentiation-related changes, and thus introduce
      confounding events and signals in defining control elements. Hence, a simpler
      biochemical and biophysical model system may be useful for gaining fundamental
      insights into the underlying mechanisms. Fortunately, even relatively "uniform"
      fibroblasts also undergo an initial shape change to commence locomotion.
      Investigators have recently begun to probe underlying signals that contribute to
      the reorganization of the actin cytoskeleton. We describe here a model for
      fibroblast shape changes involved in epidermal growth factor (EGF) stimulation of
      motility, focusing on signals through EGF receptor (EGFR) -mediated pathways
      influencing cytoskeletal organization and cell/substratum adhesion. We present
      new data addressing specifically phospholipase C-gamma (PLCgamma) pathway
      activation of actin-modifying proteins, including gelsolin, that contributes to
      these changes and promotes cell migration by increasing the fraction of cells in
      a motility-permissive morphology and the time spent in such a state.

PMID- 10602253
TI  - Periodic formation of nascent lamellae is driven by changes in the stable F-actin
      pool of polymorphonuclear neutrophils after stimulation with chemotactic peptide
      and cross-linking of CD18 or CD61.
AB  - Cell motility and changes in cell shape are largely powered by actin
      polymerization and depolymerization. Eight to ten second periodic changes in
      human polymorphonuclear neutrophil (PMN) shape were detected by video-image
      analysis of PMN crawling on a surface and by right angle light scattering (RALS)
      in suspended PMN. However, sustained RALS oscillations in suspended PMN requires
      pre-treatment with an inhibitor of phosphatidylinositol 3-kinase or an activator
      of protein kinase C. Here, we show that cross-linking of the beta(2) (CD18) or
      beta(3) (CD61), but not beta(1) (CD 29) integrins in the presence of a low dose
      of formyl-Methionyl-Leucyl-Phenylalanine (fMLP) enables similar 8-s periodic RALS
      oscillations in suspended PMN in response to stimulation with two consecutive
      doses of chemoattractants. This effect did not appear to be due to increased
      surface expression of CD18 or CD61. RALS oscillations occurred in phase with 8-s
      oscillations in the stable F-actin pool and peaks in F-actin correlated with
      predominance of cells exhibiting a nascent lamella. Thus, simulation of surface
      attachment by CD18 and CD61 cross-linking after exposure to fMLP in suspended
      cells supports shape oscillations that are the result of actin-driven cyclic
      extension/retraction of nascent lamellae at the same frequency as the shape
      changes previously observed in crawling PMN.

PMID- 10602254
TI  - Stimulation-induced changes in filopodial dynamics determine the action radius of
      growth cones in the snail Helisoma trivolvis.
AB  - Filopodia on neuronal growth cones constantly extend and retract, thereby
      functioning as both sensory probes and structural devices during neuronal
      pathfinding. To better understand filopodial dynamics and their regulation by
      encounters with molecules in the environment, we investigated filopodial dynamics
      of identified B5 neurons from the buccal ganglion of the snail Helisoma trivolvis
      before and after treatment with nitric oxide (NO). We have previously
      demonstrated that treatment with several NO-donors caused a transient, cGMP
      mediated elevation in [Ca(2+)](i), which was causally related to an increase in
      filopodial length and a reduction in the number of filopodia on growth cones. We
      demonstrate here that these effects were the result of distinct changes in
      filopodial dynamics. The NO-donor SIN-1 induced a general increase in filopodial
      motility. Filopodial elongation after treatment with SIN-1 resulted from a
      significant increase in the rate at which filopodia extended, as well as a
      significant increase in the time filopodia spent elongating. The reduction in
      filopodial number was caused by a significant decrease in the frequency with
      which new filopodia were inserted into the growth cone. With the exception of the
      back where filopodia appeared less motile, filopodial dynamics appeared to be
      mostly independent of the location on the growth cone. These results suggest that
      NO can regulate filopodial dynamics on migrating growth cones and might function
      as a messenger to adjust the action radius of a growth cone during pathfinding.

PMID- 10602255
TI  - Polyglutamylation of atlantic cod tubulin: immunochemical localization and
      possible role in pigment granule transport.
AB  - In higher organisms, there is a large variety of tubulin isoforms, due to
      multiple tubulin genes and extensive post-translational modification. The
      properties of microtubules may be modulated by their tubulin isoform composition.
      Polyglutamylation is a post-translational modification that is thought to
      influence binding of both structural microtubule associated proteins (MAPs) and
      mechano-chemical motors to tubulin. The present study investigates the role of
      tubulin polyglutamylation in a vesicle transporting system, cod (Gadus morhua)
      melanophores. We did this by microinjecting an antibody against polyglutamylated
      tubulin into these cells. To put our results into perspective, and to be able to
      judge their universal application, we characterized cod tubulin polyglutamylation
      by Western blotting technique, and compared it to what is known from mammals. We
      found high levels of polyglutamylation in tissues and cell types whose functions
      are highly dependent on interactions between microtubules and motor proteins.
      Microinjection of the anti-polyglutamylation antibody GT335 into cultured
      melanophores interfered with pigment granule dispersion, while dynein-dependent
      aggregation was unaffected. Additional experiments showed that GT335-injected
      cells were able to aggregate pigment even when actin filaments were
      depolymerized, indicating that the maintained ability of pigment aggregation in
      these cells was indeed microtubule-based and did not depend upon actin filaments.
      The results indicate that dynein and the kinesin-like dispersing motor protein in
      cod melanophores bind to tubulin on slightly different sites, and perhaps depend
      differentially on polyglutamylation for their interaction with microtubules. The
      binding site of the dispersing motor may bind directly to the polyglutamate
      chain, or more closely than dynein.

PMID- 10602256
TI  - Molecular chaperones in cilia and flagella: implications for protein turnover.
AB  - The mechanisms of protein incorporation and turnover in 9+2 ciliary axonemes are
      not known. Previous reports of an HSP70-related protein, first in Chlamydomonas
      flagella and then in sea urchin embryonic cilia, suggested a potential role in
      protein transport or incorporation. The present study further explores this and
      other chaperones in axonemes from a representative range of organisms. Two
      dimensional gel electrophoresis proved identity between the sea urchin ciliary 78
      kDa HSP and a constitutive cytoplasmic HSP70 cognate (pI = 5.71). When isolated
      flagella from mature sea urchin sperm were analyzed, the same total amount and
      distribution of 78 kDa protein as in cilia were found. Antigens of similar size
      were detected in ctenophore comb plate, molluscan gill, and rabbit tracheal
      cilia. Absent from sea urchin sperm flagella, TCP-1alpha was detected in sea
      urchin embryonic and rabbit tracheal cilia; the latter also contained HSP90,
      detected by two distinct antibodies. Tracheal cilia were shown to undergo
      axonemal protein turnover while tracheal cells mainly synthesized ciliary
      proteins. TCP-1alpha progressively appeared in regenerating embryonic cilia only
      as their growth slowed, suggesting a regulatory role in incorporation or
      turnover. These results demonstrate that chaperones are widely distributed
      ciliary and flagellar components, potentially related to axonemal protein
      dynamics.

PMID- 10602258
TI  - Acknowledgment

PMID- 10602257
TI  - Lethal level overexpression of gamma-tubulin in fission yeast causes mitotic
      arrest.
AB  - gamma-Tubulin is a member of the tubulin superfamily and plays essential roles in
      microtubule nucleation. While the level of other tubulins, alpha- and beta
      tubulin, is strictly regulated in higher eukaryotes and overexpression of beta
      tubulin is toxic in yeasts, gamma-tubulin can be overexpressed by fivefold in
      fission yeast without any obvious defect in growth. Extreme overexpression of
      gamma-tubulin in mammalian cells caused growth arrest; however, the exact level
      of gamma-tubulin and the critical level of gamma-tubulin necessary for growth
      defect were undetermined. We have constructed strains that over- or underexpress
      gamma-tubulin by placing the gamma-tubulin gene under the control of the
      inducible nmt1 promoter and its variants. Among these, the weakest promoter was
      able to produce enough gamma-tubulin to support normal growth when its expression
      was induced. A strain in which the gamma-tubulin gene was placed under the
      control of the strongest inducible promoter achieved 160-fold overexpression of
      gamma-tubulin and its growth was suppressed. Normal cytoplasmic microtubules were
      mostly lost in gamma-tubulin overexpressing cells and gamma-tubulin was
      accumulated around the periphery of nuclei. Many of the cells were arrested in
      mitosis. A small fraction of cells did proceed to undergo nuclear division;
      however, its process looked either significantly deterred or abnormal. Our
      results presented here suggest that excess gamma-tubulin disrupts the microtubule
      array and significantly deters the formation of the mitotic spindle, most likely
      because of random nucleation of microtubules from excess gamma-tubulin in the
      cytoplasm.

PMID- 10602259
TI  - Professor Andre collet 1945-1999

PMID- 10602260
TI  - Unprecedented crystallization and X-ray crystal structure of racemic N(alpha)-(t
      butyloxycarbonyl)-L-L-phenylalanine N-methoxy-N-methylamide.
AB  - Weinreb amide 3 was synthesized using isobutyl chloroformate,
      carbonyldiimidazole, or ethylcarbodiimide as the coupling agent in the reaction
      of Boc-phenylalanine with O,N-dimethylhydroxylamine hydrochloride. An optically
      active oil was isolated along with an optically inactive solid irrespective of
      the type of coupling agent used. Single crystal X-ray analysis of the solid
      revealed that it is a racemate. The molecular packing of the crystals reflect the
      stability of the racemate as opposed to an enantiomerically pure solid.

PMID- 10602261
TI  - Enantiodiscrimination by a quinine-based chiral stationary phase: a computational
      study.
AB  - A detailed computational study of a derivatized quinine chiral stationary phase
      (CSP) interacting with enantiomeric 3, 5-dinitrobenzoyl derivatives of leucine
      was carried out to understand where and how chiral discrimination takes place.
      The most stable structure of the CSP derived from a conformer search gave a
      structure whose geometry agrees with an X-ray structure (rmsd 0.6 A). The
      computed retention order and enantiodiscriminating free energy differences also
      agree with chromatographic data. The location and characteristics of the analyte
      binding site were assessed. An evaluation of total energies and intermolecular
      energies responsible for complex formation and for chiral discrimination was
      performed. Molecular dynamics trajectories of those intermolecular forces as well
      as distributions of the stabilizing and destabilizing forces are presented. A
      partitioning of the CSP into molecular fragments and the role each fragment plays
      in complexation and chiral recognition is also described.

PMID- 10602262
TI  - Discrimination in resolving systems. V. Pseudoephedrine - fluoromandelic acid
      diastereomers.
AB  - Resolution of the isomeric 2'-, 3'-, and 4'-fluoromandelic acids with (+)-(1S;2S)
      pseudoephedrine in 95% ethanol produces both well and poorly discriminating,
      hydrated and unsolvated binary salts. Seven observed diastereomeric phases are
      represented by five crystal structure types including three of the four types
      observed in the pseudoephedrine mandelates. Type a: monoclinic hemihydrate less
      soluble (L) (R)-3'-fluoromandelate and more-soluble (M) (R)-4'-fluoromandelate
      (I); type b: orthorhombic unsolvated M (S)-2'-fluoromandelate; type c:
      orthorhombic unsolvated L (R)-2'-fluoromandelate; type d: orthorhombic dihydrate
      M (S)-3'-fluoromandelate and L (S)-4'-fluoromandelate; type e: monoclinic
      unsolvated M (R)-4'-fluoromandelate (II). Largest (15-fold) discriminating
      solubilities in 95% ethanol are found between the diastereomers with 2'
      fluoromandelic acid, 50% more than in the corresponding ephedrine system.
      Principle interionic interactions are hydrogen-bonds between protonated secondary
      ammonium ions and carboxylates. Infinite chains of these are found in type c,
      with a four-atom repeating unit H-N(+)-H.O(-C(-)-O) [C(2)(1)(4)], and in types b
      and d, with a six-atom repeating unit H-N(+)-H.O-C(-)-O [C(2)(2)(6)]. Water of
      crystallization intervenes in the chains of type a but not of type d hydrated
      salts, according with higher average dehydration temperatures in the former.
      Hydrated salts in general are excessively soluble in 95% ethanol.

PMID- 10602263
TI  - Chemo-enzymatic synthesis of the antidepressant duloxetine and its enantiomer.
AB  - Sodium borohydride reduction of 3-chloro-1-(2-thienyl)-1-propanone gave the
      corresponding racemic alcohol which was kinetically resolved with lipase B from
      Candida antarctica as catalyst to yield the chiral building blocks (S)-3-chloro-1
      (2-thienyl)-1-propanol and the corresponding (R)-butanoate. The enantiopure
      chiral building blocks were converted into Duloxetine and its enantiomer.

PMID- 10602264
TI  - Dysprosium(III)-diethylenetriaminepentaacetate complexes of aminocyclodextrins as
      chiral NMR shift reagents.
AB  - A metal chelating ligand is bonded to alpha-, beta-, and gamma-cyclodextrin by
      the reaction of diethylenetraminepentaacetic dianhydride with the corresponding 6
      mono- and 2-mono(amine)cyclodextrin. Adding Dy(III) to the cyclodextrin
      derivatives causes shifts in the (1)H-NMR spectra of substrates such as
      propranolol, tryptophan, aspartame, carbinoxamine, pheniramine, doxylamine, and 1
      anilino-8-naphthalenesulfonate. The Dy(III)-induced shifts enhance the
      enantiomeric resolution in the NMR spectra of several substrates. Enhancements in
      enantiomeric resolution using cyclodextrin derivatives with the amine tether are
      compared to previously described compounds in which the chelating ligand is
      attached through an ethylenediamine tether. In general, the Dy(III) complex of
      the 6-beta-derivative with the amine tether is a more effective chiral resolving
      agent than the complex with the ethylenediamine tether. The opposite trend is
      observed with the 2-beta-derivatives. The presence of the chelating ligand in the
      2-beta-derivative hinders certain substrates from entering the cavity. For
      cationic substrates, evidence suggests that a cooperative association involving
      inclusion in the cavity and association with the Dy(III) unit occurs.
      Enhancements in enantiomeric resolution in the spectrum of tryptophan are greater
      for the secondary alpha- and gamma-derivatives than the beta-derivative.

PMID- 10602265
TI  - Stereoselective pharmacokinetics of indobufen from tablets and intramuscular
      injections in man.
AB  - The influence of administration route (oral or intramuscular (i.m.)) on the
      pharmacokinetics of total indobufen (INDB) enantiomers was studied in healthy
      volunteers after a 200 mg dose as a single oral tablet or i.m. injection.
      Enantiospecific reversed phase (RP) HPLC with UV detection was used for the
      determination of INDB enantiomers in serum. INDB enantiomers were isolated from
      serum by solid phase extraction (SPE) procedure using C(18) columns. INDB
      enantiomers were converted to their L-leucinamide diastereoisomers and separated
      on a C(18) HPLC column. INDB from i.m. injections is absorbed faster (t(max) =
      0.6-0.9 h) than from tablets (t(max) = 1.3-1.8 h). The area under curve (AUC)
      after administration of the tablet was slightly higher than after i.m. injection.
      The pharmacokinetic behaviour of (+)-S- and (-)-R-INDB after administration of
      the tablet was different from i.m. injection of racemic INDB. The (+)-S
      enantiomer is more rapidly eliminated than its (-)-R-antipode. Statistically
      significant differences also occurred between enantiomers in AUC, first order
      elimination rate constant (k), clearance (Cl). The ratio AUC(R):AUC(S) was
      similar for the tablet (1.57-1.62) and i.m. injection (1.59-1.62). It was
      concluded that the formulation and extent of ionisation of rac-INDB (acid or
      sodium salt of INDB) do not significantly influence its stereoselective
      pharmacokinetics.

PMID- 10602266
TI  - Absolute stereochemistry of the strevertenes.
AB  - The CD exciton chirality method was applied to determine the absolute
      stereochemistry of the strevertenes, antifungal pentaene macrolides produced by
      Streptoverticillium sp. LL-30F848. The CD difference spectrum of strevertene A
      methyl ester 15-dimethylaminobenzoate showed a positive couplet between the
      dimethylaminobenzoate and the pentaene chromophores, and therefore established
      the 15R configuration. Thus, by considering the relative configurations of the
      remaining stereogenic centers as derived from X-ray crystallography and ROESY
      experiments, the absolute stereochemistry of the strevertenes is established as
      2R, 3S, 5S, 7S, 11R, 13R, 14R, 15R, 26S and 27R.

PMID- 10602267
TI  - Expression of the organizer specific homeobox gene goosecoid (gsc) in porcine
      embryos.
AB  - The homeobox gene goosecoid is one of the first genes expressed in the organizer
      region of vertebrates and specifies future dorsal regions along the
      anterior/posterior axis of the embryo. Goosecoid (gsc) expression marks the
      posterior end of the anterior/posterior axis and might be a good marker to
      visualise early events in embryonic axis formation and differentiation processes
      in the epiblast at the onset of gastrulation. The aim of the present study was to
      evaluate gsc expression in porcine embryos. For this the homeobox containing
      region of the porcine gsc was isolated using RT-PCR. The sequence of the PCR
      product appeared to be highly homologous to the sequence in the mouse, human, and
      chicken. We concluded that the isolated region represents part of the porcine gsc
      messenger. Relative levels of gsc expression were estimated in porcine embryos
      from day 9 to day 12 of pregnancy. Gsc was expressed in embryos of all ages and
      localisation on one side of the embryoblast was demonstrated with in situ
      hybridisation on whole- mount embryos at day 10 of pregnancy. In embryos
      collected at day 13 of pregnancy gsc expression was localised anterior to the
      primitive streak. The correlation between embryo size and level of gsc expression
      was low. Levels and pattern of expression varied within and between litters
      collected at similar days of pregnancy. It is concluded that gsc expression can
      be used as an early marker of differentiation and to describe embryo diversity in
      the pig.

PMID- 10602269
TI  - Characterization of a bovine cDNA encoding citrate synthase, and presence of
      citrate synthase mRNA during bovine pre-attachment development.
AB  - Citrate synthase is a key regulatory metabolic enzyme that catalyzes the first
      step in the tricarboxylic acid (TCA) cycle, the synthesis of citrate from acetyl
      coenzyme A and oxaloacetate. Aerobic metabolism via the TCA cycle is high in
      bovine embryos at the 4-cell stage then decreases until the compact morula stage
      before increasing at the expanded blastocyst stage. This study characterizes the
      presence of citrate synthase mRNA in bovine pre-attachment embryos to determine
      if a variation in mRNA transcript expression patterns is associated with previous
      reports of the patterns of TCA cycle activity. The reverse transcription
      polymerase chain reaction (RT-PCR) method was used to detect citrate synthase
      mRNA from the 1-cell to blastocyst stage of bovine embryo development, and in
      embryos cultured under either an atmosphere of 5% CO(2) in air or 5% CO(2)/5%
      O(2)/90%N(2). The nucleotide sequence encoding citrate synthase was determined
      from bovine heart cDNA by the rapid amplification of cDNA ends (RACE) technique.
      This 1455-bp nucleotide fragment contained an open reading frame that encoded a
      deduced protein of 466 amino acids. The bovine nucleotide sequence was 92.1% and
      93.8% identical to the human and porcine coding sequence, respectively. The amino
      acid sequence predicted from the bovine sequence is 95.1% identical to the human
      sequence and 96.3% identical to the porcine sequence. The porcine sequence
      contains a stop codon that results in a peptide truncated by 2 amino acids. The
      detection of citrate synthase transcripts from the 1-cell to blastocyst stage
      demonstrates that the decrease in TCA cycle activity observed following the 4
      cell stage is not associated with an absence of citrate synthase mRNA.

PMID- 10602268
TI  - Glowing zebrafish: integration, transmission, and expression of a single
      luciferase transgene promoted by noncovalent DNA-nuclear transport peptide
      complexes.
AB  - The development of vehicles driving foreign DNA into the cell nucleus is
      essential for effective cellular gene transfer applications. We report that
      noncovalent binding of nuclear localization signal (NLS) peptides to plasmid DNA
      enhances nuclear uptake of the DNA and promotes germline integration,
      inheritance, and expression of a single copy of a luciferase reporter gene in
      zebrafish. As few as 10 DNA-NLS complexes (0.06 fg plasmid DNA) cytoplasmically
      injected are sufficient to produce germline-transgenic zebrafish bearing a single
      copy of the transgene. This corresponds to a 10(5)-fold reduction in DNA
      concentration compared to commonly used procedures. Use of 10(3) or 10(4) DNA-NLS
      complexes augments the number of transgene integrations, which occur mostly
      within 1-4 distinct insertion sites in the genome. In situ hybridization analyses
      and transmission studies show that transgene integration into the germline and
      somatic tissues is mosaic, and that the extent of mosaicism is negatively
      correlated with the amount of DNA-NLS injected. In addition, a larger proportion
      of zebrafish harboring a single copy of the transgene expresses luciferase,
      albeit at a 10-fold lower level than those containing numerous transgene
      insertions. The data demonstrate the potential use of nuclear targeting peptides
      noncovalently bound to vector DNA to enhance the efficiency of biotechnological
      nonviral gene transfer applications.

PMID- 10602270
TI  - Sex differentiation and mRNA expression of P450c17, P450arom and AMH in gonads of
      the chicken.
AB  - The present study was conducted to reveal effects of in ovo injection of
      nonsteroidal aromatase inhibitor (Fadrozole) or estradiol at day 3 of incubation
      on mRNA levels of P45017alphahydroxylase (P450c17), P450 aromatase (P450arom) and
      anti-Mullerian hormone (AMH) in the chicken gonads. The mRNA levels in the gonads
      at days 4-8 of incubation were assessed by in situ hybridization analysis using
      digoxigenin labeling method. The in situ hybridization data were analyzed by
      relative expression of specific hybridizable signals of each mRNA corrected by
      the non-specific background by employing an image analyzer. P450c17 mRNA
      expression increased rapidly at day 6 of incubation in the male but decreased
      thereafter. In contrast to the transient expression in the male, the expression
      was gradually increased in the female. P450arom mRNA was not expressed in the
      male but was detectable in the female as early as day 6 and increased
      subsequently with days of incubation. AMH mRNA was expressed as early as day 5 of
      incubation followed by a sharp increase on day 6, which was maintained in the
      male thereafter. In contrast, the female showed very little expression. The
      injection of Fadrozole caused no effect on P450c17 mRNA expression, while it
      suppressed P450arom mRNA expression but increased AMH mRNA expression in the
      female. In contrast, the injection of estradiol induced P450arom mRNA expression
      significantly but suppressed AMH mRNA expression in the male. These results
      indicate that expression of P450arom and AMH is sexually dimorphic and is
      reciprocally regulated during early ontogenic life in chicken gonads.

PMID- 10602271
TI  - Systematic identification of genes expressed during early oogenesis in medaka.
AB  - Subtractive hybridization was used to identify differences in gene expression
      between medaka (Oryzias latipes) males and females during sex differentiation.
      Fifty female-specific cDNA fragments were cloned. They can be classified into
      three groups by virtue of whether their earliest expression is at 1, 5, or 30
      days after hatching. All 15 near full-length cDNAs belonging to the first two
      groups were cloned. Many of these female-specific genes are coordinately
      expressed in oocytes at the earliest stages of oogenesis. Some of the genes that
      were identified by their sequences include egg envelope proteins, oocyte-specific
      RNA binding proteins, and a transcription factor containing a basic helix-loop
      helix motif.

PMID- 10602272
TI  - Herpes simplex virus transcriptional activator VP16 is detrimental to
      preimplantation development in mice.
AB  - The herpes simplex virus transactivator protein VP16 is frequently used to
      regulate gene expression in several experimental systems, including transgenic
      mice. It has been suggested that high levels of VP16 expression in mice may be
      lethal. In order to systematically address this issue, we linked the VP16 gene to
      promoters that are active early and in a variety of tissues throughout
      development, such as the human beta-actin promoter or the rat nestin gene
      enhancer. VP16 expression was assayed using a LacZ reporter gene linked to a VP16
      responsive immediate early gene promoter. We show here that expression of VP16 at
      high levels is detrimental to pre-implantation development. By culturing embryos
      in vitro, we demonstrate that this effect is exerted at the transition from the 2
      cell to the 4-cell stage, reducing survival to the blastocyst stage dramatically.
      On the other hand, transgenic mice expressing VP16 transgenes at postimplantation
      stages are viable. These results suggest a differential sensitivity to VP16
      expression in different cell types and stages of development. The reduction of
      embryo survival by VP16 implicates herpes virus infection as a potential cause of
      infertility.

PMID- 10602273
TI  - Proteases with plasminogen activator activity in hamster oviduct.
AB  - At present the physiological role of most oviductal proteins remains unknown. In
      this work, we present evidence that the oviductal secretion as well as the crude
      oviductal tissue-extract show proteolytic-like esterase and amidase activity. The
      proteolytic activity of the oviductal enzymes was higher in the oviducts of
      superovulated hamster females than in those of normal ones, indicating that
      gonadotrophic hormones would stimulate the synthesis and secretion of these
      enzymes. Some of their properties were analyzed in the 15,600-g supernatant of
      both oviductal tissue extracts (OE) and oviductal fluid (OF). The enzymatic
      activity toward the synthetic substrates p-tosyl-l-arginine methyl ester-HCl
      (TAME) and alpha-N-benzoyl-dl-arginine-p-nitroanilide HCl (BAPNA) was activated
      by calcium ions, reached a maximum at pH 7.5, and was inhibited by soybean
      trypsin inhibitor (SBTI), N-alpha-p-tosyl-l-lysine chloromethyl ketone HCl
      (TLCK), phenyl methyl sulfonyl fluoride (PMSF), and benzamidine. The OE
      glycoprotein fraction recognized by WGA-Sepharose affinity columns (37% total
      proteins) showed proteolytic activity with properties similar to the OE and OF
      enzymes. The protease activity could be ascribed to a plasminogen activator (PA)
      detected in the Triton X-100 treated tissue crude membrane fraction (Triton-CMF)
      and in the oviductal secretion of the superovulated females. In the Triton-CMF
      fraction, 100% of the proteolytic activity was plasminogen-dependent. The use of
      amiloride, a selective urokinase-type plasminogen activator (uPA) inhibitor,
      shows that 90% of this activity was due to a tissue-type plasminogen activator
      (tPA) and 10% to uPA whereas in the uterus 100% of the activity was tPA. Only a
      small percentage of the OF proteolytic activity was plasminogen-dependent,
      probably due to the presence of PA inhibitors in this medium.

PMID- 10602274
TI  - Kit ligand actions on ovarian stromal cells: effects on theca cell recruitment
      and steroid production.
AB  - Factors that control recruitment of theca cells from ovarian stromal-interstitial
      cells are important for early follicle development in the ovary. During
      recruitment, theca cells organize into distinct layers around early developing
      follicles and establish essential cell-cell interactions with granulosa cells.
      Recruitment of theca cells from ovarian stromal stem cells is proposed to involve
      cellular proliferation, as well as induction of theca cell-specific functional
      markers. Previously, the speculation was made that a granulosa cell-derived
      "theca cell organizer" is involved in theca cell recruitment. Granulosa cells
      have been shown to produce kit-ligand/stem cell factor (KL). KL is known to
      promote stem cell proliferation and differentiation in a number of tissues.
      Therefore, the hypothesis was tested in the current study that granulosa cell
      derived KL may help recruit theca cells from undifferentiated stromal stem cells
      during early follicle development. The actions of KL were examined using adult
      bovine ovarian fragment organ culture and isolated ovarian stromal-interstitial
      cells. In organ culture KL significantly increased the number of theca cell
      layers around primary follicles. Experiments using purified stromal-interstitial
      cell cultures showed that KL stimulated ovarian stromal cell proliferation in a
      dose-dependent manner. Stromal cell differentiation into theca cells was analyzed
      by the induction of theca cell functional markers (i.e., androstenedione and
      progesterone production). Bovine ovarian stromal cells produced low levels of
      androstenedione (5-40 ng/microg DNA) and progesterone (5-30 ng/microg DNA) in
      vitro that were approximately 20-fold lower than theca cells under similar
      conditions. Treatment with KL did not affect ovarian stromal cell androstenedione
      or progesterone production. Interestingly, hormones such as estrogen and hCG did
      stimulate stromal cell steroid production. The results in this study suggest that
      granulosa cell-derived KL appears to promote the formation of theca cell layers
      around small (i.e., primary) ovarian follicles. KL directly stimulated ovarian
      stromal cell proliferation but alone did not induce functional differentiation
      (i.e., high steroid production). Therefore, KL is proposed to promote early
      follicle development by inducing proliferation and organization of stromal stem
      cells around small follicles. Observations suggest that KL may act as a granulosa
      derived "theca cell organizer" to promote stem cell recruitment of ovarian
      stromal cells in a manner similar to the way that KL promotes hematopoietic and
      lymphoid stem cells in bone marrow and the thymus.

PMID- 10602276
TI  - Xenopus laevis embryo development: arrest of epidermal cell differentiation by
      the chelating agent 1,10-phenanthroline.
AB  - The embryonic epidermis of stage 35 Xenopus laevis embryos is a highly
      differentiated structure composed of four cell types arranged in a regular
      architecture. Each type is distinguished by its distinct morphological
      characteristics. Some cells are ciliated (type 1); others have their surfaces
      covered by abundant, secreted vesicles of 0.1 microm diameter (type 2), or
      multiple linear aggregates of spherical subunits on their apical surfaces (type
      3) or large secreted vesicles that emanate from prominent apical holes of 1
      microm diameter (type 4). In contrast, the macroscopic appearance of embryos
      exposed to 10 microM 1,10-phenanthroline (OP) as well as the ultramicroscopic
      structure and organization of their epidermal cells are markedly altered. The
      most predominant cells of the embryonic epidermis are undifferentiated and of
      heterogeneous size. They lack any characteristic morphology and are arranged
      irregularly. Ghost cells are also identified. The recognizable differentiated
      cells are decreased in number and present in a scattered arrangement. These are
      identified as either type 1 or 2 cells but with ciliae that are shorter and
      thicker than control or with only a few vesicles larger than 0.1 microm in
      diameter on their surface. No cells with linear aggregates or prominent apical
      holes are identified. Except for the altered epidermis, the embryos do not
      develop any other major organs and exhibit axial abnormalities with an average
      dorso-anterior index of three. Thus, the chelating agent OP perturbs metal
      dependent processes essential for terminal differentiation that may likely
      account for the resultant abnormalities of embryo organogenesis and
      morphogenesis.

PMID- 10602275
TI  - In vitro culture of rat pre-antral follicles with emphasis on follicular
      interactions.
AB  - The present study was designed to determine whether rat pre-antral follicles can
      grow under in-vitro conditions. Emphasis is on whether follicular interaction is
      involved in in-vitro follicle culture, and furthermore its role in follicular
      development has been assessed. Pre-antral follicles were isolated mechanically
      from 10-day old rat ovaries. They were divided into small (50 microm < diameter <
      100 microm) and large (120 microm < diameter < 200 microm) pre-antral follicles
      and cultured individually or in groups for 6 days in medium with or without fetal
      calf serum (FCS). Based on morphological criteria, large pre-antral follicles
      cultured in groups in serum-free medium had significantly higher survival rates
      than those cultured individually. In the presence of FCS, no significant
      difference was detected with respect to the survival. However, the large pre
      antral follicles cultured in groups had a significantly greater increase in
      diameter than those cultured individually. Furthermore, follicles cultured in
      groups in FCS-containing medium exhibited significantly more follicular cell
      proliferation than those in serum-free medium, based on DNA measurement. The
      present culture system (with or without FCS) proved to be insufficient for small
      pre-antral follicles to stimulate growth comparable to that of large pre-antral
      follicles. The transmission electron microscopical (TEM) study revealed the
      ultrastructural differences between follicles cultured in FCS-containing and
      serum-free media. Taken together, the results suggest that interfollicular
      factors are involved in follicle development in vitro, which especially at the
      early folliculogenesis stage plays a positive role in terms of follicular growth
      as well as survival. The present culture model allows further investigation of
      factors that regulate early folliculogenesis.

PMID- 10602277
TI  - Estrogen receptor is expressed in pig embryos during preimplantation development.
AB  - Although estrogen is recognized as essential for embryonic development and
      maintenance of pregnancy, it remains unclear whether it has a direct role in the
      embryos themselves. The aim of this study was to investigate whether estrogen can
      have any effect in pig embryos during preimplantation development. Since the
      function of estrogen is mediated through its specific receptor, estrogen receptor
      (ER), the presence of ER mRNA and protein in pig embryos collected in vivo at
      different stages of preimplantation development was determined and compared.
      Using reverse transcription polymerase chain reaction, ER RNA was detected at the
      one-cell, two-cell, and four-cell stages. The level became undetectable at the
      five- to eight-cell stages and the morula stages and then reappeared again at the
      blastocyst stage. To determine whether the ER message observed in the embryos was
      translated into ER protein, immunocytochemical analysis was performed and the
      presence of ER protein was detected in oocytes at one-cell and four-cell stages.
      However, the amount of ER protein in porcine embryos at the blastocyst stage was
      still below the detection limit. The presence of ER mRNA at the blastocyst stages
      suggests that estrogen may start to act directly on pig embryos afterwards, and
      our results provide a basis for determining the direct role of estrogen in
      preimplantation pig embryos.

PMID- 10602278
TI  - High developmental competence of cattle oocytes maintained at the germinal
      vesicle stage for 24 hours in culture by specific inhibition of MPF kinase
      activity.
AB  - Roscovitine, a potent inhibitor of M-phase Promoting Factor (MPF) kinase
      activity, was used to maintain cattle oocytes at the germinal vesicle stage for a
      24-hr culture period. A concentration of 25 microM of roscovitine was sufficient
      to reach the maximum level of meiotic resumption inhibition with 83 +/- 6% of the
      oocytes remaining at the germinal vesicle stage after the 24 hr of culture. The
      histone H1 kinase activity was maintained at a basal level after culture under
      roscovitine inhibition at any of the concentrations tested (12.5, 25, 50, and 100
      microM). This inhibitory effect of roscovitine was fully reversible since 89 +/-
      4% of the oocytes cultured for 24 hr in the presence of 25 microM of roscovitine
      reached the metaphase II stage after a further culture of 24 hr in permissive
      medium (TCM199 supplemented with 10 ng/ml EGF). The cleavage rate as well as the
      development to the blastocyst stage was not different for oocytes cultured for 24
      hr under roscovitine (25 microM) inhibition and then matured for 24 hr in the
      presence of EGF as compared to oocytes not submitted to prematuration culture (82
      +/- 8% cleavage and 41 +/- 4% blastocysts at 8 days post insemination for control
      oocytes compared to 90 +/- 7% and 36 +/- 7% respectively for roscovitine-treated
      oocytes). Roscovitine meiotic inhibition was also effective in the presence of
      EGF, and the final developmental potential as well as the kinetics of blastocyst
      formation were not affected after such prematuration treatment. The EGF induced
      cumulus expansion was also inhibited by roscovitine. These results indicate for
      the first time the feasibility of culturing cattle oocytes under meiotic
      inhibition without decreasing their resulting developmental potential.

PMID- 10602279
TI  - Biochemical characterization of sialoprotein "anti-agglutinin" purified from boar
      epididymal and seminal plasma.
AB  - Sialoprotein "anti-agglutinin," previously shown to inhibit sperm head-to-head
      agglutination, is found in both boar epididymal and seminal plasma. The present
      report characterizes anti-agglutinin by mass spectrometry, by N-terminal amino
      acid sequence analysis, and by sodium dodecyl sulfate (SDS)-polyacrylamide gel
      electrophoresis (PAGE) and Western blotting techniques to assess phosphate
      content of the molecule. Anti-agglutinin had the SDS-PAGE mobility of
      approximately 25 kDa. By electrospray ionization-mass spectrometry, however, mass
      spectra of anti-agglutinin were characterized by two major peaks (19,379-19,382
      Da and 19,395-19,397 Da) and several minor peaks. Mass spectrometry of tryptic
      peptide fragments of deglycosylated anti-agglutinin and amino acid sequence
      analysis revealed that the protein has a unique peptide-mass fingerprinting of
      fragments (12,668 Da, 5,209 Da, 1,226 Da, and 1,168 Da) and a novel N-terminal
      amino acid sequence (KTDDY AISGA KEEEF YDYME ELYAV), respectively. Additionally
      Western blot techniques, using commercially available monoclonal antibodies, were
      used to detect presence of phosphothreonine and phosphoserine substituents, but
      two different monoclonal antibodies did not detect phosphotyrosine. Moreover,
      treatment with two different alkaline phosphotases converted the molecule, as
      assessed by SDS-PAGE and detection by silver stain, from the parent form of about
      25 kDa to forms of approximately 19 kDa (similar to that assigned by mass
      spectrometry) and/or 15 kDa. Original antiserum generated toward, and reacting
      with native anti-agglutinin, reacted only with 19 kDa form. These results are
      consistent with the conclusion that the native anti-agglutinin may be a novel
      protein that is phosphorylated at serine and/or threonine residues.

PMID- 10602280
TI  - Effects of hyperstimulation with gonadotrophins and age of females on oocytes and
      their metaphase II status in rats.
AB  - The present study was undertaken to evaluate the effects of hyperstimulation and
      aging on the number and proportion of oocytes in the metaphase II stage in female
      Wistar rats. It explored the validity of the hypothesis that a combination of
      hyperstimulation with pregnant mare serum gonadotrophins (PMSG) and age could
      compromise, to a greater extent, the oocyte quality as indicated by the
      proportion of ovulated oocytes in the metaphase II stage. Female Wistar rats were
      stimulated with varying doses of PMSG and human chorionic gonadotrophins (hCG)
      and the number and proportion of ovulated oocytes in the metaphase II stage were
      examined and compared between different groups of young adult (8-10 weeks old)
      and aging (30-32 weeks old) female rats. While spontaneous ovulation occurred in
      all young adult rats, only 50% of the aging rats did. The ovulation rate in aging
      rats was increased from 50 to 93% when non-PMSG-stimulated rats were given a dose
      of 10 IU of hCG at proestrus. The lower number of ovulated oocytes noted, even in
      those hyperstimulated with high doses of PMSG/hCG, also indicated a reduction in
      fertility in aging rats. Under the influence of high doses of PMSG, all aging
      rats ovulated, but as with the young adult rats, a higher dose of hCG was needed
      to achieve the maximum number of ovulated oocytes from the PMSG-induced expanded
      pool of preovulatory follicles. However, the average number of ovulated oocytes
      in aging rats was, nevertheless, still significantly lower than in young adult
      rats even when approximation of weight was considered. No consistent significant
      difference in proportion of normal oocytes was noted within groups and between
      young adult and aging rats. A lower proportion of ovulated oocytes was arrested
      at the metaphase II stages when rats, whether they were young adult or aging,
      were hyperstimulated with 40 IU of PMSG. However, this proportion was restored to
      normal (about 100%) when a higher dose of hCG, which is a signal responsible for
      initiating oocyte maturation, was used. Results of the present study showed that
      there appears to be an age-related reduction of sensitivity of the preovulatory
      follicles to the ovulation induction signal of hCG and thus higher doses of hCG
      were needed to ovulate the PMSG-induced expanded pool of dominant follicles. In
      older rats, apart from the obvious depletion of the pool of follicles, the
      evidence from the present study suggests that some of these older rats do have
      follicles, but that these were unable to develop to preovulatory follicles,
      probably because of the absence of sufficiently high levels of gonadotrophins
      essential for the initiation of folliculogenesis. PMSG-hyperstimulation can
      affect nuclear maturation; the proportion of ovulated oocytes not arrested at the
      metaphase II stage was higher. However, the proportion of ovulated oocytes at the
      metaphase II was restored to normal by increasing the dose of hCG use. Hence,
      meiotic aberration in rats is not age-dependent but rather dependent on the
      amplitude of the luteinizing hormone (LH)/hCG surge present. The results from
      this study nullified the hypothesis that hyperstimulation in combination with
      aging would lead to a higher proportion of abnormality in ovulated oocytes with
      respect to their being at inappropriate meiotic stages.

PMID- 10602281
TI  - Mechanism of the block to hybridization and selfing between the sympatric
      ascidians Ciona intestinalis and Ciona savignyi.
AB  - The solitary ascidians Ciona intestinalis and Ciona savignyi co-occur in southern
      California harbors, but no hybrids have been recognized in nature. Numerous
      differences in their egg morphology were detected. Homologous (normal outcross)
      fertilization yielded 96-99% cleavage, where autologous (self) fertilization
      showed 3% and heterologous (hybrid) fertilization showed 0-1%. Acid treatment (pH
      3.2) removed the block to selfing (P < 0.0001) but not hybridization for both
      species. Heterologous sperm bind to the vitelline coat (VC), but fail to
      penetrate. Enzymatic removal of the VC resulted in 91-97% cleavage with
      autologous and heterologous sperm (P < 0.0001). The vitelline coats of the two
      species differ in lectin binding to surface glycosides. Fertilization in both
      species is significantly inhibited by the lectins, fucose binding protein (P <
      0.0001) and concanavalin A (P < 0.0001), and wheat germ agglutinin inhibits
      fertilization in C. intestinalis (P < 0.0001) but is without effect on C.
      savignyi fertilization. Self and hybrid blocks employ different mechanisms
      including glycoside composition and acid sensitivity.

PMID- 10602283
TI  - Introduction to interstitial cells of Cajal.

PMID- 10602282
TI  - Both fertilization promoting peptide and adenosine stimulate capacitation but
      inhibit spontaneous acrosome loss in ejaculated boar spermatozoa in vitro.
AB  - Both fertilization promoting peptide (FPP) and adenosine stimulate capacitation
      and inhibit spontaneous acrosome loss in epididymal mouse spermatozoa; these
      responses involve modulation of the adenylyl cyclase (AC)/cAMP signal
      transduction pathway. However, it was unclear whether these responses were
      restricted to the mouse or possibly common to many mammalian species. To address
      this question, the response of boar spermatozoa to FPP and/or adenosine was
      evaluated. FPP is found in nanomolar concentrations in seminal plasma of several
      mammals, but not the pig. When cultured in caffeine-containing Medium 199 for 2
      hr, chlortetracycline fluorescence evaluation indicated that neither FPP nor
      adenosine stimulated boar sperm capacitation per se but did inhibit spontaneous
      acrosome loss. However, in caffeine-free medium, FPP and adenosine both
      stimulated capacitation and inhibited spontaneous acrosome loss, suggesting that
      boar spermatozoa have receptors for both FPP and adenosine. Gln-FPP, a
      competitive inhibitor of FPP in mouse spermatozoa, has recently been shown to
      inhibit mouse sperm responses to adenosine as well, suggesting that FPP receptors
      and adenosine receptors interact in some way. Used with boar spermatozoa, Gln-FPP
      also significantly inhibited responses to both FPP and adenosine. These responses
      suggest that mechanisms whereby FPP and adenosine can regulate sperm function,
      via AC/cAMP, are of considerable physiological significance. Mouse, human, and
      now boar spermatozoa have been shown to respond to FPP, suggesting that these
      mechanisms may be common to many mammalian species. We also suggest that the
      effects of FPP and adenosine could also be exploited to maximize monospermic
      fertilization in porcine in vitro fertilization.

PMID- 10602284
TI  - One hundred years of interstitial cells of Cajal.
AB  - This review is a portrayal of the evolution of ideas involving the interstitial
      cells of Cajal in changing disguises as dull fibroblasts, not very exciting
      Schwann cells, or perhaps quite important, though primitive neurons. However,
      today unmasked (we believe), they reveal themselves as myoid cells, a role that,
      judging by current interest, is far more exciting than former ones. Close to 500
      publications from 1860-1999 have contributed to the discussion in one way or the
      other. This literature contains a wealth of correct observations but obviously
      also wrong interpretations, which are seen as a result of too blind a belief in
      specificities of visualization methods, combined with a desire to interpret even
      the hidden detail. It has been my objective to attempt to trace the origins of
      viable ideas, and I have therefore focused on relatively few authors. The most
      recent development from 1980 until today is so well covered by easily accessible
      reviews that I have resorted to a mere, but hopefully complete, list of them.
      Modern ICC'ists have so far been caught in the external muscle of the gut and
      kept their hands off its internal affairs. However, while working my way through
      the literature it struck me that a number of recent studies may provide the
      elements of a plausible model for the villous contraction mechanism. In the
      present context, an important point is that the very first published interstitial
      "neurons" from Cajal's hand-of the intestinal villus, 1889-may achieve new
      significance as a possible correlate to the regulatory ICC of the intestinal
      muscularis. Partly to make this point, I have taken the liberty of giving a short
      account of recent results from our lab.

PMID- 10602285
TI  - Gastrointestinal peristalsis: joint action of enteric nerves, smooth muscle, and
      interstitial cells of Cajal.
AB  - Peristalsis is a propulsive motor pattern orchestrated by neuronal excitation and
      inhibition in cooperation with intrinsic muscular control mechanisms, including
      those residing in interstitial cells of Cajal (ICC). Interstitial cells of Cajal
      form a network of cells in which electrical slow waves originate and then
      propagate into the musculature initiating rhythmic contractile activity upon
      excitaton by enteric nerves. Interstitial cells of Cajal have now been isolated
      and their intrinsic properties reveal the presence of rhythmic inward currents
      not found in smooth muscle cells. In tissues where classical slow waves are not
      present, enteric cholinergic excitation will evoke slow wave-like activity that
      forces action potentials to occur in a rhythmic manner. Intrinsic and induced
      slow wave activity directs many of the peristaltic motor patterns in the gut.

PMID- 10602286
TI  - Guide to the identification of interstitial cells of Cajal.
AB  - The interstitial cell of Cajal, abbreviated ICC, is a specific cell type with a
      characteristic distribution in the smooth muscle wall throughout the alimentary
      tract in humans and laboratory mammals. The number of publications relating to
      ICC is rapidly increasing and demonstrate a rich variation in the structure and
      organization of these cells. This variation is species-, region-, and location
      dependent. We have chosen to define a "reference ICC," basically the ICC in the
      murine small intestine, as a platform for discussion of variability. The growing
      field of ICC markers for light and electron microscopy is reviewed. Although
      there is a rapidly increasing number of approaches applicable to bright field and
      fluorescence microscopy, the location of markers by electron microscopy still
      suffers from inadequate preservation of ultrastructural detail. Finally, we
      summarize evidence related to ICC ultrastructure under conditions differing from
      those of the normal, adult individual (during differentiation, in pathological
      conditions, transplants, mutants, and in cell culture).

PMID- 10602288
TI  - Reflection contrast microscopy for high resolution detection of (3)H-estradiol in
      ultrathin sections of human stratum corneum.
AB  - A single autoradiographical method for light and electron microscopy (LM and EM)
      is presented. Human skin, containing (3)H-estradiol ((3)H-E2) after an in vitro
      permeation experiment, was processed via a non-extractive tissue preparation
      protocol, comprising cryo-fixation, freeze-drying, osmium tetroxide vapor
      fixation, and Spurr resin embedding. Semithin sections were processed for LM
      autoradiography, while ultrathin sections were processed both for high-resolution
      LM and EM autoradiography. The autoradiographs were visualized by bright-field
      microscopy (BFM), reflection contrast microscopy (RCM), and transmission electron
      microscopy to evaluate the potentials of RCM visualization in high-resolution LM
      autoradiography. RCM visualization of ultrathin vs. semithin resin sections
      showed an improved stratum corneum morphology. Histological staining was
      superfluous. The localization of (3)H-E2 in human stratum corneum using high
      resolution LM autoradiography and RCM was as accurate as with high-resolution EM
      autoradiography.

PMID- 10602287
TI  - Comparative morphology of interstitial cells of Cajal: ultrastructural
      characterization.
AB  - The shape, distribution, and ultrastructural features of interstitial cells of
      Cajal (ICC) of different tissue layers and organs of the rat and guinea-pig
      digestive tract were described and compared with the corresponding cells in other
      species including mice, dogs, and humans, as reported in the literature. By light
      microscopy, the best marker for ICC appeared to be immunoreactivity for c-Kit.
      Ultrastructurally, ICC were characterized by the presence of many mitochondria,
      bundles of intermediate filaments, and gap junctions, which linked ICC with each
      other. However, ICC were morphologically heterogeneous and had particular
      features, depending on their tissue and organ location and species. ICC in the
      deep muscular plexus of the small intestine and in the submuscular plexus of the
      colon were the most like smooth muscle cells, and had a distinct basal lamina and
      numerous caveolae. In contrast, ICC of Auerbach's plexus at all levels of the
      gastrointestinal tract were the least like smooth muscle cells. They most closely
      resembled unremarkable fibroblasts. ICC within the circular muscle layer were
      intermediate in form. In addition to the tissue specificity, some organ and
      species specificity could be distinguished. The structural differences between
      ICC may be determined by their microenvironment, including the effects of
      mechanical force, type of nerve supply, and spacial relationship with smooth
      muscle cells.

PMID- 10602289
TI  - Embryological origin of interstitial cells of Cajal.
AB  - Until recently, the embryological origin of the interstitial cells of Cajal (ICC)
      within the intestine was unclear. An origin from the neural crest or from the
      mesenchyme was considered possible because ICC possess some characteristics in
      common with neural crest-derived cells, and some characteristics in common with
      cells derived from the mesenchyme. Experiments in both mammalian and avian
      species, in which segments of embryonic gut were removed prior to the arrival of
      neural crest cells and grown in organ culture, have now shown that ICC do not
      arise from the neural crest. It appears that ICC and smooth muscle cells arise
      from common mesenchymal precursor cells. From mid-embryonic stages, ICC
      precursors express Kit, which is a receptor tyrosine kinase. Both ICC and many
      smooth muscle cell precursors initially express Kit, and then the cells destined
      to become smooth muscle cells down-regulate Kit and up-regulate the synthesis of
      myofilament proteins, whereas cells destined to differentiate into ICC maintain
      their expression of Kit. Adult mice with mutations that block the activity of Kit
      have disrupted arrays of ICC, whereas normal ICC are present until shortly after
      birth in such mice. It, therefore, appears that the Kit signalling pathway in not
      necessary for the embryonic development of ICC, but rather the post-natal
      proliferation of ICC.

PMID- 10602290
TI  - Gap junctions in intestinal smooth muscle and interstitial cells of Cajal.
AB  - This manuscript reviews gap junctions' roles in control of intestinal motility.
      Gap junctions (GJs) of small intestine (SmIn) are found between circular muscle
      (CM) cells, between interstitial cells of Cajal (ICC) of deep muscular plexus
      (DMP) and between them and adjacent outer circular muscle (OCM). GJs between
      longitudinal muscle (LM) cells or between cells of inner circular muscle (ICM)
      have not been reported. Occasional GJs have been reported between ICC of the
      myenteric plexus (MyP) and rarely between these ICC and adjacent LM or CM cells,
      or between ICC within CM and smooth muscle cells. In the colon (Co) of several
      species a special network of ICC lines the inner border of CM, the submuscular
      plexus (SP). GJs are found between ICCs and between them and CM cells. The ICC of
      MyP of Co are associated with LM and CM; occasional GJs exist between ICC and
      each muscle layer. Small GJs are missed by electron microscopy or light
      microscopic Immunocytochemistry. Therefore, GJ coupling may exist without
      demonstrated GJs. The consequences for the pacemaking functions of ICC networks
      of varied densities of GJ between ICC and between ICC of MyP or DMP or of SP and
      CM are considered. Connexins (Cxs) that compose intestinal GJs may affect
      coupling, but are incompletely known. Understanding of the role of GJs in
      coordinating intestinal motility requires knowing: (1) what passes through gap
      junctions to couple ICC to smooth muscle cells; (2) what Cx with what
      conductances and what modulatory controls connect ICC and smooth muscle cells;
      (3) whether smooth muscles can generate slow waves independent of ICC networks;
      and (4) what happens to motility, slow waves, and IJPs when GJs are selectively
      uncoupled.

PMID- 10602291
TI  - Heme oxygenase, carbon monoxide, and interstitial cells of Cajal.
AB  - Interstitial cells of Cajal play a central role in the control of
      gastrointestinal motility. The mechanisms of communication between interstitial
      cells of Cajal and smooth muscle cells are to a large extent unknown. This
      article reviews the potential role of carbon monoxide as a messenger molecule
      between interstitial cells of Cajal and gastrointestinal smooth muscle cells. The
      machinery required for the formation of carbon monoxide is present in
      interstitial cells of Cajal and gastrointestinal smooth muscle cells express a
      target site of action for carbon monoxide, a potassium channel. Carbon monoxide
      may, therefore, be produced in interstitial cells of Cajal and function as a
      messenger molecule between interstitial cells of Cajal and gastrointestinal
      smooth muscle cells.

PMID- 10602292
TI  - Receptors in interstitial cells of Cajal: identification and possible
      physiological roles.
AB  - Interstitial cells of Cajal (ICCs) are specialized cells of the gastrointestinal
      tract forming distinct populations depending on their location in the gut wall.
      Morphological observations and functional data have led to the hypothesis of two
      functions for the ICCs: (1) as pacemakers of the rhythmic activity; (2) as
      intermediaries in neural inputs to the muscle. The identification of specific
      receptors on the ICCs has represented an important step in the knowledge of these
      cells. Immunohistochemical labeling of these receptors provided information on
      both ICC morphology and contacts (particularly those with nerve endings) and on
      the functions of these cells. All ICC possess the Kit receptor, which represents
      the best tool to identify these cells under the light microscope. It has been
      demonstrated that this receptor is essential for ICC differentiation, and, by
      using mutant mice lacking the Kit-related gene, it has been possible to
      discriminate among all the ICC those with a primary role as pacemakers. The ileal
      ICC, in particular those at the deep muscular plexus, express the tachykinin
      receptor NK1 and a subtype of somatostatin receptors and contain nitric oxide
      synthase. All these data support a primary role of these ICC in neural
      transmission.

PMID- 10602293
TI  - Visualization of interstitial cells of Cajal in living, intact tissues.
AB  - Interstitial cells of Cajal (ICC) appear to be a major element in pacing and
      signal transmission in the gastrointestinal tract. A prominent problem in the
      study of ICC has been the difficulty in observing them in intact tissues. We used
      several methods to visualize living ICC in freshly-dissected tissues: (1) Placing
      small crystals of the lipophilic dye DiI in the submucosal-circular muscle border
      in the mouse colon resulted in the labeling of living ICC-like cells. Two main
      morphological cell types, bipolar and multipolar, were noted. The DiI stain could
      be converted into a stable, electron-opaque product. Electron-microscopic
      observations showed that the labeled cells had the typical appearance of ICC
      reported in previous studies. (2) Living ICC in the region of the myenteric
      plexus (ICC-MP) in the small intestines of mice and guinea-pigs were observed
      with Nomarski optics. This enabled the visualization of ICC in living tissues,
      and the impalement of the cells with Lucifer yellow-filled microelectrodes. The
      dye-labeled cells had the morphological features of ICC-MP, and about 30% of them
      were found to be dye coupled to 1-21 other ICC. The identity of the cells as ICC
      was verified by electron-microscopy following photoconversion, and by c-kit
      immunohistochemistry. (3) Living ICC were labeled with a c-kit antibody that does
      not require tissue fixation. This resulted in the fluorescent staining of the
      entire ICC network. Single cells were labeled by dye injection, which provided a
      detailed picture of ICC morphology. This method was found to be suitable for a
      wide range of tissues. We expect that these three methods for identifying ICC in
      intact, living tissues will be useful for physiological and pharmacological
      investigations of ICC in a variety of gastrointestinal tissues.

PMID- 10602295
TI  - Editorial

PMID- 10602294
TI  - Interstitial cells of Cajal in human gut and gastrointestinal disease.
AB  - This paper reviews the distribution of interstitial cells of Cajal (ICC) in the
      human gastrointestinal (GI) tract, based on ultrastructural and
      immunohistochemical evidence. The distribution and morphology of ICC at each
      level of the normal GI tracts is addressed from the perspective of their
      functional significance. Alterations of ICC reported in achalasia of cardia,
      infantile hypertrophic pyloric stenosis, chronic intestinal pseudoobstruction,
      Hirschsprung's disease, inflammatory bowel diseases, slow transit constipation,
      and some other disorders of GI motility as well as in gastrointestinal stromal
      tumors are reviewed, with emphasis on the place of ICC in the pathophysiology of
      disease.

PMID- 10602296
TI  - Practical methods for detection of nitric oxide.
AB  - Nitric oxide (NO), which is generated in vivo through conversion of L-arginine to
      L-citrulline by NO synthase (NOS), mediates many physiological and
      pathophysiological processes. At least two distinct isoforms of NOS have been
      identified, constitutive NOS (cNOS) and inducible NOS (iNOS). The cNOS, which is
      constitutively expressed in endothelial cells and central and peripheral neuronal
      cells, requires both calcium and calmodulin for its activation. Cells expressing
      cNOS generally produce small amounts of NO, because of their low levels of cNOS
      protein. On the other hand, iNOS, which is induced in cells stimulated with
      endotoxins, produced larger amounts of NO. Because of the short half-life, it is
      difficult to detect NO in situ directly, especially from cells expressing cNOS.
      In this review, we discuss practical methods for NO detection, which are useful
      for the detection of small amounts of NO from cNOS and for the bioimaging of
      living cells and cultured tissues.

PMID- 10602297
TI  - Bioluminescent monitoring of intracellular ATP during fermentation.
AB  - The luciferase gene was introduced as a probe into a cell in order to develop a
      bioluminescent monitoring of intracellular ATP during fermentation. Two plasmids
      were constructed with two types of promoters. One was pLac-Luc, which had the
      luciferase gene under the lac promoter to be expressed at a high level. The other
      was pTet-Luc, which had the luciferase gene under the tetracycline promoter to be
      stably expressed. A threonine-overproducing strain of Escherichia coli (No. 29-4)
      was transformed with each plasmid. The recombinant E. coli strains were
      characterized in their growth, threonine production and luciferase expression.
      The bioluminescence produced intracellularly from expressed luciferase was
      detected during fermentation -in a non-destructive manner. The bioluminescent
      intensity reflected both intracellular ATP and luciferase levels, and the results
      indicate that stable expression of a luciferase reporter is essential for
      monitoring intracellular ATP.

PMID- 10602299
TI  - Investigation of cyclomaltooligosaccharide-bound 6-(4-methoxyphenyl)imidazo[1,2
      a]pyrazin-3(7H)-one for enhanced chemiluminescence.
AB  - The chemiluminescence compound 2-methyl-6-(4-methoxyphenyl)imidazo[1, 2-a]pyrazin
      3(7H)-one (MCLA) was attached to cyclomaltooligosaccharides (cyclodextrins)
      through a single spacer by the formation of an amide bond. The properties of
      oxygen-induced chemiluminescence of the synthesized cyclodextrin-bound MCLA were
      investigated in an aqueous phosphate buffer, pH 8.0. The light-emitting
      efficiency was remarkably dependent on the kind of bound cyclodextrin, spacer
      length between the MCLA and cyclodextrin, and the binding site in cyclodextrin.
      The light-emitting efficiencies of cyclomaltooctaose (gamma-cyclodextrin)-bound
      compounds were higher than those of cyclomaltohexaose- or cyclomaltoheptaose
      bound compounds. Especially, compounds in which MCLA attached to the secondary
      side of gamma-cyclodextrin through a short chain showed an up to 44-fold
      enhancement over that of a non-cyclodextrin compound. In the current case, the
      efficiency of single excited-state formation was 23 times greater than that of
      the non-cyclodextrin compound and significantly responsible for greater light
      emitting efficiency. The chemiluminescence spectra indicated the wide entrance of
      the secondary side of gamma-cyclodextrin, and the short spacer allowed suitable
      intramolecular affinity between the singlet excited-state chromophore moiety and
      the cyclodextrin.

PMID- 10602298
TI  - Chemiluminescence of 2-methyl-6-arylimidazo-[1,2-a]pyrazin-3(7H)-one in protic
      solvents: electron-donating substituent effect on the formation of the neutral
      singlet excited-state molecule.
AB  - 2-Methyl-6-arylimidazo[1,2-a]pyrazin-3(7H)-ones with a substituent such as
      phenyl, 4-methoxyphenyl or 4-trifluoromethoxyphenyl at the 6-position of the
      imidazo[1,2-a]pyrazin-3(7H)-one ring system, produced chemiluminescence emission
      in mixtures of water and DMF and in several mixtures of MeOH and DMF under
      neutral conditions. Under these protic luminescence conditions, the respective
      light emissions were generated from neutral singlet excited-state molecules. The
      electron-donating effect of the 4-methoxy substituent on the phenyl group
      increased the efficiency of the neutral singlet excited state formation, whereas
      non-substitution and a 4-trifluoromethoxy group having no electron donating
      ability decreased the efficiency. The compound having the electron-donating
      methoxy group substituent showed two chemiluminescence emitters, which generated
      light at lambda(max) 410-420 nm and 460 nm. It was determined that the neutral
      molecules in the excited state generating light emission at the shorter
      wavelengths are neutral singlet excited-state molecules suitable for highly
      efficient singlet excited-state formation. A role of the electron-donating effect
      of the methoxy group is postulated to be generation of the special neutral
      singlet excited-state molecules.

PMID- 10602300
TI  - Chemiluminescence properties of soybean protein fraction in the hydroperoxide and
      hydrogen donor system.
AB  - Whey fraction, a constituent of soybean protein, produced a photon emission in
      the presence of gallic acid and hydrogen peroxide. Identification of the
      chemiluminescence agent from the whey fraction indicated the participation of
      lipoxygenase in the emission. The reactivity of lipoxygenase with peroxides in
      the gallic acid solidus hydroperoxide system was in the order of methylethyl
      hydroperoxide (MEK-OOH, 4800 cps) > tert-butyl hydroperoxide (tert-BuOOH, 607
      cps) > hydrogen peroxide (H(2)O(2), 455 cps) > cumene hydroperoxide (cumene-OOH,
      261 cps). Emission maxima for H(2)O(2) and cumene-OOH were 670 nm, and emission
      maxima for MEK-OOH and tert-BuOOH were at 510 nm. The photon intensity from the
      gallic acid lipoxygenase system corresponded to the linoleic acid hydroperoxide
      value. A high correlation of photon intensity with hydroperoxide, including
      linoleic hydroperoxide was useful as a simple and sensitive method for the direct
      detection of hydroperoxides in biomaterials.

PMID- 10602301
TI  - Detection of free radicals generated from hydrogen peroxide, gallic acid and
      haemoprotein chemiluminescence system by electron spin resonance spectroscopy.
AB  - Low-level chemiluminescence is produced in a hydrogen peroxide (H(2)O(2))/gallic
      acid/haemoprotein system with single broad peaks around 520 nm, regardless of the
      biological role of the haemoprotein. The free haem iron systems (haemin and
      haematin systems) gave a higher photon intensity (1.5 x 10(4) and 2.0 x 10(4)
      cps) than that of the H(2)O(2)/gallic acid/haematoporphyrin system. These results
      indicated that haem iron plays a significant role in the photon emission of
      haemoprotein systems. A free radical with a g value of 2. 0058 was detected
      through a direct electron spin resonance (ESR) method. The photon intensity of
      the H(2)O(2)/gallic acid/haemoprotein system decreased in the order: HRP >
      cytochrome c > myoglobin > haemoglobin, and this corresponded to the decrease in
      radical intensity. These results indicated that the formation of the free radical
      with a g value of 2.0058 may be the key step for chemiluminescence in the
      H(2)O(2)/gallic acid/haemoprotein system. A quartet line similar to DMPO-OH
      adducts and uncomplexed free radicals (g = 2.0058) was detected using the ESR
      spin-trapping method in the H(2)O(2)/gallic acid/cytochrome c system.

PMID- 10602302
TI  - Effect of decaglycerol mono-oleate on chemiluminescence of human neutrophils.
AB  - Decaglycerol mono-oleate (DGMO), a type of food additive (a polyglycerol ester of
      fatty acids), was evaluated for its in vitro effect on reactive oxygen species
      (ROS) generation by human neutrophils using a luminol-dependent chemiluminescence
      assay. Neutrophils were isolated by the Histopaque-1077/1119 double density
      gradient technique. Opsonized zymosan (OZ) and phorbol 12-myristate 13-acetate
      (PMA) were employed as artificial stimuli. DGMO inhibited the chemiluminescence
      response of OZ-stimulated neutrophils by 58% (p < 0.01) at a concentration of 0.5
      mg/mL. DGMO inhibited the PMA-induced chemiluminescence by 40% (p < 0.01) at a
      concentration of 0.01 mg/mL. The inhibition phenomena could not be attributed to
      light absorption by DGMO alone, because the percentage chemiluminescence in the
      presence of DGMO is lower than the percentage transmittance of DGMO at 425 nm.
      These results suggest that DGMO downregulates ROS generation by human
      neutrophils.

PMID- 10602303
TI  - Applicability of chemiluminescence to assess the degree of operative stress in
      patients undergoing spinal surgery.
AB  - This study examined the applicability of luminol-dependent chemiluminescence (CL)
      response of neutrophils to assess the degree of stress of spinal surgery by
      measuring the capacity of circulating neutrophils to produce reactive oxygen
      species and the levels of serum cytokines: interleukin(IL)-1beta, IL-6, IL-8,
      tumour necrosis factor (TNF)-alpha and granulocyte colony stimulating factor (G
      CSF). Ten male patients underwent spinal surgery. Peripheral blood samples,
      collected before and after the operation and the next morning, were used for
      measuring the CL response of neutrophils stimulated with opsonized zymosan and
      measuring the levels of serum cytokines. The operative stress induced
      leukocytosis, particularly granulocytosis, and increased serum IL-6 and G-CSF
      significantly. However, there was no significant change in the luminol-dependent
      CL response of neutrophils or the levels of serum IL-1beta, IL-8 and TNF-alpha
      throughout the experimental period. These results suggest that, at least in the
      early postoperative period, operative stress does not prime the circulating
      neutrophils, and thus the CL response of neutrophils is not appropriate to assess
      the degree of stress of spinal surgery.

PMID- 10602304
TI  - Contribution of nitric oxide synthase to human neutrophil chemiluminescence.
AB  - A chemiluminescence (CL) assay has been used to measure the reactive oxygen
      species (ROS)-generating capacity of phagocytes. Primed neutrophils produce ROS
      and nitric oxide (NO) upon induction of nitric oxide synthase (NOS) activity. NO
      and superoxide (O(2)(-)) form peroxynitrite (ONOO(-)), and emit CL. We examined
      the involvement of NOS in the CL response of neutrophils using a method based on
      the modulation of enzyme activity of NOS by the substrate L-arginine and an
      inhibitor; L-NAME. We used lipopolysaccharide (LPS) as the neutrophil-priming
      agent. Addition of sodium azide (NaN(3)) with horseradish peroxidase (HRP) to
      luminol-dependent CL, gave a CL response that was significantly enhanced when 10
      mmol/L L-arginine was present (p <0.05), suggesting that NOS activity contributed
      to the CL response of human neutrophils. LPS-primed luminol-dependent CL was
      significantly inhibited by L-NAME compared with D-NAME. The proportion of the
      difference between the two inhibitors in luminol-dependent CL was 12.3 +/- 15.0%.
      Therefore, approximately 12% of the LPS-primed luminol-dependent CL decrease
      induced by L-NAME indicated the contribution of NOS activity to the CL response.

PMID- 10602305
TI  - Synthesis and chemiluminescent decomposition of spiro[1, 2-dioxetane-3,6'
      benzo(c)chromene]s.
AB  - Two spiro[1,2-dioxetane-3,6'-benzo(c)chromene]s bearing a t-butyldimethylsiloxy
      as a trigger at the 10'- or 2'-position were synthesized. On treatment with
      tetrabutylammonium fluoride in DMSO at 25 degrees C, the 10'-siloxyspiro[1,2
      dioxetane-3, 6'-benzo(c)chromene] decomposed rapidly to afford a flash of blue
      light. The CIEEL decay of this spirochromenedioxetane was also induced by basic
      silica gel in hexane. By contrast, TBAF-induced decomposition of an analogous
      spiro[1,2-dioxetane-3, 6'-benzo(c)chromene] with a trigger at the 2'-position,
      resulted in emission of yellow light with very low efficiency.

PMID- 10602306
TI  - Synthesis of 3-ethoxy-4,4-diisopropyl-1,2-dioxetanes bearing a benzo(b)furan-2-yl
      or a benzo(b)thiophen-2-yl group: CIEEL-active dioxetanes emitting red light.
AB  - Low-temperature singlet oxygenation of 1-ethoxy-2, 2-diisopropylethylenes
      substituted with a benzo(b)furanyl or a benzo(b)thiophenyl group bearing a t
      butyldimethylsiloxy at the 5-, 6- or 7-position of the aromatic ring afforded the
      corresponding 1, 2-dioxetanes in moderate to high yields. On treatment with
      tetrabutylammonium fluoride in DMSO, dioxetanes with a trigger (siloxy group) at
      the 5- or 7-position of the aromatic ring decomposed to emit red light
      (lambda(max) = 615-628 nm), irrespective of the aromatic ring being benzofuran or
      benzothiophene. For both series of benzofuran-analogues and benzothiophene
      analogues, an 'odd/even' relationship between the position of an oxyanion on the
      aromatic ring relative to the attachment point to the dioxetane and the
      chemiluminescent properties, lambda(max), Phi(CL), and t(1/2), is observed, as in
      the case for dioxetanes bearing a phenolic or naphtholic substituent.

PMID- 10602307
TI  - Selectivity and sensitivity in the measurement of reactive oxygen species (ROS)
      using chemiluminescent microspheres prepared by the binding of acridinium ester
      or ABEI to polymer microspheres.
AB  - Two kinds of chemiluminescent microspheres were prepared as tools for measuring
      reactive oxygen species (ROS) released into phagosomes in phagocytizing cells, by
      chemically binding acridinium ester or ABEI (isoluminol derivative) to polymer
      microspheres, and were examined from the viewpoint of specificity and sensitivity
      to ROS. Acridinium ester-bound microspheres (AE-ms) were found to be a sensitive
      probe to superoxide anion and hydrogen peroxide under a neutral condition (pH
      7.2). AE-ms emitted strong chemiluminescence (CL) by hypoxanthine (HPX)/xanthine
      oxidase (XOD) or hydrogen peroxide. The CL by HPX/XOD was initially inhibited by
      superoxide dismutase. At pH 5.6, the CL intensity from AE-ms in the presence of
      HPX/XOD was reduced to about one-eighth of that at pH 7.2. ABEI-bound
      microspheres (ABEI-ms) were found to be a selective probe for singlet oxygen
      although not highly sensitive. ABEI-ms emitted CL of moderate intensity with
      hydrogen peroxide/myeloperoxidase (MPO), but not with hydrogen peroxide alone or
      with hypochlorite/MPO at pH 5.6. The CL from ABEI-ms with hydrogen peroxide/MPO
      was completely inhibited by azide. ABEI-ms did not emit CL in the presence of
      HPX/XOD or by potassium superoxide at pH 5.6. The result of supplemental
      experiments using dissolved chemiluminescent probes and non-enzymatically
      generated ROS supported the above-described selectivity and sensitivity of
      chemiluminescent microspheres.

PMID- 10602308
TI  - Development of novel high-sensitivity chemiluminescence assay for luminol using
      thiourea derivatives.
AB  - We have screened about 100 thiourea derivatives in order to develop a sensitive
      chemiluminescence detection for luminol derivatives. Among these derivatives, we
      found a new compound, 2-(3-methylthioureido) thiazole, that could be used to
      measure luminol in the presence of hydrogen peroxide (H(2)O(2)). The detection
      limits of luminol and N-(4-aminobutyl)-N-ethylisoluminol (ABEI) were 10 fmol and
      100 fmol, respectively. The mechanism of proposed chemiluminescence reaction was
      studied by electron spin resonance (ESR) with and without superoxide dismutase
      (SOD) and the addition of ethanol. The results showed that 2-(3-methylthioureido)
      thiazole has the ability to generate hydroxyl radical from H(2)O(2), and produces
      intense chemiluminescence in the presence of luminol. The proposed novel
      chemiluminescence reaction for luminol and luminol derivatives was applied to a
      high performance liquid chromatography (HPLC) assay for amino compounds.

PMID- 10602309
TI  - New phenylboronic acid derivatives as enhancers of the luminol-H(2)O(2)
      horseradish peroxidase chemiluminescence reaction.
AB  - The preparation of three new types of phenylboronic acid derivatives and their
      evaluation as enhancers on the luminol-H(2)O(2)-horseradish peroxidase (HRP)
      chemiluminescence (CL) reaction are described. After optimizing the CL reaction
      conditions, the CL system was applied to the HRP determination. Among the three
      phenylboronic acid derivatives, i.e. 4-(4, 5-diphenyl-1H-imidazol-2
      yl)phenylboronic acid (DPA), 4-[4(or 5)-(4-dimethylaminophenyl)-5(or 4)-phenyl-1H
      imidazol-2-yl]phenylboronic acid (DAPA) and 4-[4, 5-di(2-pyridyl)-1H-imidazol-2
      yl]phenylboronic acid (DPPA), DPPA was found to be the most potent enhancer. The
      sensitivity obtained with DPPA was about 180 times higher than that without an
      enhancer. The detection limit of HRP obtained with DPPA was 0.15 ng/assay (ca.
      3.5 fmol), which is comparable to that with 4-iodophenol under the conditions
      examined. All the phenylboronic acid derivatives examined had the effect of
      prolonging light emission compared to 4-iodophenol.

PMID- 10602310
TI  - Aminopyrazine analogues as chemiluminescence derivatization reagents for pyruvic
      acid.
AB  - Aminopyrazine analogues were studied as sensitive and selective chemiluminescence
      derivatization reagents for pyruvic acid. These analogues reacted with pyruvic
      acid under acidic conditions at 100 degrees C to produce Cypridina luciferin
      derivatives, which exhibit chemiluminescence by reaction with hydrogen peroxide
      in the presence of potassium t-butoxide in dimethylformamide. Of the four
      aminopyrazine analogues (2-amino-5-phenylpyrazine, 2-amino-5-(4
      hydroxyphenyl)pyrazine, 2-amino-5-(3,4, 5-trimethoxyphenyl)pyrazine, and 2
      aminoquinoxaline), in the present test 2-amino-5-(3,4,5-trimethoxyphenyl)
      pyrazine was the most sensitive for pyruvic acid, and the chemiluminescence
      intensity was about four times higher than that obtained with aminopyrazine.

PMID- 10602311
TI  - Total free catecholamines assay by identification of its two functional groups
      and micro-flow injection chemiluminescence.
AB  - We have developed a novel method of assaying total free catecholamines using
      sulphuric acid-derivatized beads for extracting and identifying catecholamine
      (CA) on the surface, and assaying the peroxide produced from CA by
      chemiluminescence (CL). Current assay methods for CA by electrochemical
      determination, fluorescence and chemiluminescence need a time-consuming
      separation by high-performance liquid chromatography. We eliminated this
      separation step by identifying the two functional groups of CA using a
      derivatized bead and this resulted in a highly specific CA assay. The principle
      is as follows: the amino group of CA was trapped by ion binding with a sulphuric
      acid derivative immobilized on a bead, and the diol of the CA bound to the bead
      was converted to peroxide with imidazole under alkaline conditions. The peroxide
      produced was assayed by microflow injection-horseradish peroxidase-catalysed
      luminol chemiluminescence. We synthesized three types of sulphuric acid
      derivative immobilized beads (6.5 mm i.d.). The types of immobilized sulphuric
      acid derivative used were straight-chain, branched chain and benzenesulphonic,
      respectively. The order of the three types of beads for extracting CA was:
      bezenesulphonic type > branched type > straight-chain type. The optimal
      incubation time for generating peroxide was 30 min. The peroxide generated in the
      reaction solution was stable with within-run reproducibility of CV 5. 7% after
      incubation for 80 min. The regression equation of a standard curve for dopamine
      was Y = 12.8 X(2) + 476X - 373 (where Y = light intensity (RLU), X =
      concentration of dopamine (micromol/L)). The minimum detection limit of dopamine
      was 0.1 micromol/L, and the within-run reproducibility of dopamine (10.5
      micromol/L) was CV 4.7% (n = 5). This method is applicable to assay of total free
      CA without use of HPLC.

PMID- 10602312
TI  - A study of the fluorescence measurement using a 96-well microplate by a
      remodelled parallel luminescent measuring system.
AB  - To develop an index to measure alveolar macrophage activity, the fluorescent
      technique for detection of calcium flux was paid special attention. In this
      study, a parallel luminescence measuring system was remodelled for fluorescence
      measurement using a 96-well microplate. The fluorescence indicators widely used
      to measure cytosolic free calcium ion concentration require excitation at
      ultraviolet (UV) wavelengths. Instruments to produce UV wavelengths are expensive
      compared to those used to produce visible wavelengths, and UV wavelengths are
      potentially injurious to cells. To avoid these problems, Fluo 3 (excitation
      wavelength in the visible range) was used as the fluorescent dye for detecting
      calcium ions. The parallel luminometer was remodelled successfully for
      fluorescent measurement as assessed by the results obtained from the measurements
      of a common fluorescent dye, fluorescein. Concentrations of free calcium ions
      were measured using Fluo 3 at 37 degrees C to consider the measurement of calcium
      flux in living cells. Although a linear relationship between concentrations of
      free calcium ions and fluorescence were observed, a diminution of fluorescence
      over time was also observed. To measure calcium flux in living cells, further
      instrumental and experimental improvements are thus needed.

PMID- 10602313
TI  - Inhibition of nuclear factor kappa B and induction of apoptosis in T-lymphocytes
      by sulfasalazine.
AB  - 1. Chronic inflammatory diseases have been shown to be associated with NF-kappaB
      activation and impaired apoptosis of immune cells. The aim of the present study
      was to investigate if sulfasalazine and its colonic metabolites 5-aminosalicylic
      acid (5ASA) and sulfapyridine affect NF-kappaB/Rel activation and viability of T
      lymphocytes. 2. Sulfasalazine inhibits NF-kappaB/Rel activation in the murine T
      lymphocyte cell line RBL5 using electrophoretic mobility shift assays. In
      transfection assays sulfasalazine treatment for 4 h inhibits kappaB-dependent
      transcription with an IC50 value of approximately 0.625 mM. 3. Higher doses or
      prolonged treatment result in cell death of T-lymphocytes in a dose- and time
      dependent manner. Cell death is caused by apoptosis as judged by DNA
      fragmentation, annexin V and Apo 2.7 staining. Induction of apoptosis is a fast
      event with 50% apoptotic cells after a 4 h incubation with 2.5 mM sulfasalazine.
      The ED50 value for apoptosis induction after 24 h treatment was approximately
      0.625 mM. 4. In contrast, 5ASA and sulfapyridine neither inhibit NF-kappaB/Rel
      activation nor induce apoptosis in T-lymphocytes at doses up to 5.0 mM. 5. These
      results demonstrate that sulfasalazine, but not 5ASA or sulfapyridine, strongly
      inhibits NF-kappaB activation and potently induces apoptosis in T-lymphocytes.
      Inhibition of NF-kappaB/Rel activation and subsequent clearance of activated T
      lymphocytes by apoptosis might thus explain the beneficial effects of
      sulfasalazine in the treatment of chronic inflammatory disorders.

PMID- 10602314
TI  - Functional pharmacology of cloned heterodimeric GABAB receptors expressed in
      mammalian cells.
AB  - 1. In this study we report a new assay of heterodimeric gamma-amino-butanoic acid
      subtype B (GABAB) receptors where either GABABR1a or GABABR1b are co-expressed
      with GABABR2 and the chimeric G-protein Galphaq-z5 in tsA cells. In this manner
      we obtained a robust response to GABAB agonists measured as increase in
      phosphoinositide hydrolysis. 2. We used this assay to characterize a number of
      commonly used GABAB receptor ligands. Both splice variants displayed the same
      rank order of agonist potency; 3-aminopropyl(methyl)phosphinic acid (SKF
      97541)>GABA>(R)-4-amino-3-(4-chlorophenyl)butanoic acid ((R)-baclofen)>(RS)-4
      amino-3-(5-chloro-2-thienyl)butanoic acid (BCTG)>3-aminopropylphosphonic acid (3
      APPA) and furthermore, the absolute agonist potency values were very close to
      each other. 3. 3-APPA was a partial agonist displaying maximal responses of 41
      and 61% compared to GABA at GABABR1a and GABABR1b, respectively. The antagonist
      (RS)-3-amino-2-(4-chlorophenyl)-2-hydroxypropylsulphonic acid (2-OH-saclofen)
      displayed KB values of 15 and 7.8 microM at GABABR1a and GABABR1b, respectively.
      4. The rank order of agonist potency as well as the absolute ligand potencies
      correspond very well with those previously reported in different tissues, and
      this study thus provides a functional assay of cloned GABAB receptors which
      should be a valuable tool for further characterization of GABAB ligands. Finally,
      we can conclude that the functional pharmacological profiles of the two GABABR1
      splice variants are very similar.

PMID- 10602315
TI  - Effects of the gap junction uncoupler palmitoleic acid on the activation and
      repolarization wavefronts in isolated rabbit hearts.
AB  - 1. The heart normally acts as an electrical syncytium coupled via gap junctional
      channels. Since closure of these channels has been considered arrhythmogenic, we
      wanted to elucidate, how activation and repolarization wavefronts are altered
      during progressive pharmacological gap junctional uncoupling. 2. We used the well
      known gap junction uncoupler palmitoleic acid (PA). The specificity of PA was
      tested in rabbit papillary muscles, which exhibited slowed conduction without
      affecting action potential morphology. We submitted isolated rabbit hearts
      (Langendorff-technique) to increasing concentrations of palmitoleic acid (0.2, 1,
      2, 5, 10, 20 microM), while 256 channel epicardial potential mapping was carried
      out. 3. In presence of PA activation recovery intervals (ARI) at the 256
      electrodes became highly inhomogeneous with a dramatic increase in the dispersion
      of activation recovery intervals (from 6 to 35 ms, P>0.01; EC50=7 microM), while
      the mean ARI-duration at 256 sites remained stable. PA led to marked alterations
      of the activation pattern, expressed as percentage of unchanged activation
      vectors (reduction from 32 to 10%, P<0.01, EC50=3.3 microM), to prolongation of
      atrioventricular conduction time (from 58 to 107 ms, P<0.01; EC50=8 microM) of
      total activation time (from 7 to 14 ms, P<0.05, EC50=11 microM) and of QRS
      complex-duration. 4. In additional experiments the ventricle was paced via a
      bipolar electrode during the mapping procedure. From the isochrones longitudinal
      and transversal velocities were assessed showing that PA reduced transversal
      conduction velocity more distinctly than longitudinal. 5. With regard to maximum
      effects and EC50 values we conclude that gap junction uncoupling by PA mainly
      affects atrioventricular conduction, ARI-dispersion and ventricular activation
      pattern. As important arrhythmogenic effects of uncoupling enhancement of
      dispersion with concomitant disturbation of the normal activation pattern and
      slowing of conduction might be considered.

PMID- 10602316
TI  - Effect of the nonpeptide neurotrophic compound SR 57746A on the phenotypic
      survival of purified mouse motoneurons.
AB  - 1. Neurotrophic factors have been used for the treatment of several
      neurodegenerative diseases. However, their use is limited by their inability to
      cross the blood-brain barrier, their short half life and their side effects. SR
      57746A is a new orally active compound that exhibits in vivo and in vitro
      neurotrophic effects in several experimental models. 2. We show here that SR
      57746A (1 microM) increases the phenotypic survival of embryonic purified mouse
      motoneurons in vitro to the same extent as brain-derived neurotrophic factor (100
      ng ml-1), and increases the outgrowth and number of their neurites. It acts in a
      dose-dependent manner up to 1 microM which is the optimal concentration. Above
      this concentration, its neurotrophic effect decreases. 3. Genistein (10 microM),
      a protein tyrosine kinase inhibitor, also increases the phenotypic survival and
      differentiation of mouse motoneurons. It does not act in a synergistic or
      additive manner with SR 57746A. However, at concentrations equal or superior to
      25 microM, it decreases the survival of motoneurons. This suggests that the
      neurotrophic effect of genistein is due to a favourable alteration of equilibrium
      between phosphorylated and dephosphorylated states of proteins involved in
      survival and differentiation of motoneurons. 4. Like genistein, SR 57746A should
      be used at a critical concentration (1 microM) to exert its optimal effects.
      Since SR 57746A does not act synergistically with genistein, it is likely that
      its mechanism of action involves a pathway similar to that affected by this
      tyrosine kinase inhibitor. 5. At the present time, SR 57746A is the only orally
      active compound and the only synthetic compound shown to be active on motoneurons
      in vitro. It should thus be considered as a good candidate for the treatment of
      motoneuron diseases.

PMID- 10602317
TI  - Suppression of human inflammatory cell function by subtype-selective PDE4
      inhibitors correlates with inhibition of PDE4A and PDE4B.
AB  - 1. Of the four major phosphodiesterase 4 (PDE4) subtypes, PDE4A, PDE4B and PDE4D
      are widely expressed in human inflammatory cells, including monocytes and T
      lymphocytes. We explored the functional role of these subtypes using ten subtype
      selective PDE4 inhibitors, each belonging to one of two classes: (i) dual
      PDE4A/PDE4B inhibitors or (ii) PDE4D inhibitors. 2. These compounds were
      evaluated for their ability to inhibit antigen-stimulated T-cell proliferation
      and bacterial lipopolysaccharide (LPS)-stimulated tumour necrosis factor alpha
      (TNFalpha) release from peripheral blood monocytes. 3. All compounds inhibited T
      cell proliferation in a concentration-dependent manner; with IC50 values
      distributed over an approximately 50 fold range. These compounds also inhibited
      TNFalpha release concentration-dependently, with a wider ( approximately 1000
      fold) range of IC50 values. 4. In both sets of experiments, mean IC50 values were
      significantly correlated with compound potency against the catalytic activity of
      recombinant human PDE4A or PDE4B when analysed by either linear regression of log
      IC50 values or by Spearman's rank-order correlation. The correlation between
      inhibition of inflammatory cell function and inhibition of recombinant PDE4D
      catalytic activity was not significant in either analysis. 5. These results
      suggest that PDE4A and/or PDE4B may play the major role in regulating these two
      inflammatory cell functions but do not rule out PDE4D as an important mediator of
      other activities in mononuclear leukocytes and other immune and inflammatory
      cells. Much more work is needed to establish the functional roles of the PDE4
      subtypes across a broader range of cellular functions and cell types.

PMID- 10602318
TI  - Desensitization and resensitization of beta 1- and putative beta 4-adrenoceptor
      mediated responses occur in parallel in a rat model of cardiac failure.
AB  - 1. Cardiostimulant effects of the non-conventional partial agonist, CGP 12177A,
      are mediated by a receptor distinct from the beta3-adrenoceptor and termed the
      putative beta4-adrenoceptor. Using a rat model of cardiac failure, induced by
      myocardial infarction (MI), we compared the desensitization and resensitization
      of responses to CGP 12177A with those to isoprenaline and RO 363 in left (LA) and
      right atria (RA). We also examined the ability of beta-adrenoceptor antagonists
      to block responses to CGP 12177A. 2. MI reduced the maximum inotropic response to
      isoprenaline by 48% (sham 4.1+/-0.6 mN, n=10; MI 2.1+/-0.4 mN, n=8, P<0.02), RO
      363 by 61% (sham 4.2+/-0.5 mN, n=10; MI 1.8+/-0.3 mN, n=8, P<0.005) and CGP
      12177A by 49% (sham 1.4+/-0.1 mN, n=5; MI 0.7+/-0.2 mN, n=7, P<0.05) in
      electrically stimulated LA. MI also reduced the sensitivity to isoprenaline
      (pEC50: sham 8.79+/-0.08, n=10; MI 8.30+/-0.10, n=8; P=0.001) and RO 363 (pEC50:
      sham 8.69+/-0.07, n=10; MI 8.33+/-0.10, n=8; P<0.01). The maximum chronotropic
      responses to isoprenaline, RO 363 and CGP 12177A in RA were unaffected. 3.
      Pertussis toxin treatment (10 microg kg-1, i.p.) restored the maximum inotropic
      response and sensitivity to isoprenaline (sham 3.5+/-0.5 mN, n=9; MI 3.2+/-0.6
      mN, n=11, P=0.702) and CGP 12177A (sham 1.6+/-0.3 mN, n=6; MI 1.9+/-0.4 mN, n=7,
      P=0.537) in MI animals to levels similar to those in the sham group. 4. CGP
      20712A (pKB: LA 6.7+/-0.2, n=6; RA 7. 1+/-0.1, n=4), ICI 118,551 (pKB: LA 6.4+/
      0.1, n=5; RA 6.3+/-0.1, n=6), propranolol (pKB: LA 6.6+/-0.1, n=5; RA 6.8+/-0.1,
      n=6) and bupranolol (pKB: LA 7.2+/-0.1, n=6; RA 7.7+/-0.1, n=8), showed moderate
      affinity for the putative beta4-adrenoceptor. 5. Desensitization after MI and
      resensitization (after pertussis toxin treatment) to isoprenaline and CGP 12177A
      therefore occur in parallel, suggesting that the beta1- and putative beta4
      adrenoceptor use the same signalling pathway. Antagonist affinity studies
      confirmed that drugs acting at beta1-adrenoceptors also interact with putative
      beta4-adrenoceptors with approximately 100 times lower affinity. We suggest that
      CGP 12177A produces its cardiac effects by interacting with a low affinity state
      of the beta1-adrenoceptor.

PMID- 10602319
TI  - Perindopril, an angiotensin converting enzyme inhibitor, in pulmonary
      hypertensive rats: comparative effects on pulmonary vascular structure and
      function.
AB  - 1. Hypoxic pulmonary hypertension in rats (10% O2, 4 weeks) is characterized by
      changes in pulmonary vascular structure and function. The effects of the
      angiotensin converting enzyme inhibitor perindopril (oral gavage, once daily for
      the 4 weeks of hypoxia) on these changes were examined. 2. Perindopril (30 mg kg
      1 d-1) caused an 18% reduction in pulmonary artery pressure in hypoxic rats. 3.
      Structural changes (remodelling) in hypoxic rats included increases in (i)
      critical closing pressure in isolated perfused lungs (remodelling of arteries <50
      microm o.d.) and (ii) medial wall thickness of intralobar pulmonary arteries,
      assessed histologically (vessels 30 - 100 and 101 - 500 microm o.d.). Perindopril
      10 and 30 mg kg-1 d-1 attenuated remodelling in vessels < or = 100 microm (lungs
      and histology), 30 mg kg-1 d-1 was effective in vessels 101 - 500 microm but
      neither dose prevented hypertrophy of main pulmonary artery. 3 mg kg-1 d-1 was
      without effect. 4. Perindopril (30 mg kg-1 d-1) prevented the exaggerated hypoxic
      pulmonary vasoconstrictor response seen in perfused lungs from hypoxic rats but
      did not prevent any of the functional changes (i.e. the increased contractions to
      5-HT, U46619 (thromboxane-mimetic) and K+ and diminished contractions to
      angiotensins I and II) seen in isolated intralobar or main pulmonary arteries.
      Acetylcholine responses were unaltered in hypoxic rats. 5. We conclude that, in
      hypoxic rats, altered pulmonary vascular function is largely independent of
      remodelling. Hence any drug that affects only remodelling is unlikely to restore
      pulmonary vascular function to normal and, like perindopril, may have only a
      modest effect on pulmonary artery pressure.

PMID- 10602320
TI  - Vasodilator effects of sodium nitroprusside, levcromakalim and their combination
      in isolated rat aorta.
AB  - 1. The endothelial modulation of the relaxant responses to the nitric oxide (NO)
      donor sodium nitroprusside (SNP) and the KATP channel opener levcromakalim (LEM)
      and the interactions between these agents were analysed in isolated rat aorta. 2.
      LEM-induced relaxation was unchanged by endothelium removal or by the presence of
      L-NAME (10-4 M) or ODQ (10-6 M). In contrast, in KCl- (25 mM), but not in
      noradrenaline- (NA, 10-6 M) contracted arteries, SNP-induced relaxation was
      augmented by endothelium removal but not by L-NAME, indomethacin, glibenclamide
      nor charybdotoxin plus apamin. 3. The isobolographic analysis of the interactions
      between exogenously activated KATP channels and cyclic GMP using mixtures of SNP
      and LEM revealed that there were no interactions between both drugs at the
      proportions at which both drugs were active. However, the points for the SNP :
      LEM mixtures in proportions 10:1 and 1:10,000 (i.e. at concentrations at which
      LEM and SNP were inactive, respectively) fell significantly above the line of
      additivity indicating that there were negative interactions between both drugs at
      these selected proportions (about 5- and 2 fold inhibition, respectively). The
      former interaction was sensitive to glibenclamide, whereas the latter was
      insensitive ODQ. The magnitude of the 10:1 SNP:LEM interaction was smaller in
      endothelium-intact arteries and was absent in arteries stimulated by NA. 4. In
      conclusion, the relaxations induced by LEM and SNP were additive. However, the
      presence of endothelium and low concentrations of LEM inhibited SNP-induced
      relaxation. Both inhibitory effects were not additive and were only observed in
      KCl- and not in NA-contracted aortae.

PMID- 10602321
TI  - Direct myocardial anti-ischaemic effect of GTN in both nitrate-tolerant and
      nontolerant rats: a cyclic GMP-independent activation of KATP.
AB  - 1. We have recently demonstrated that glyceryl trinitrate (GTN) exerts a direct
      myocardial anti-ischaemic effect in both GTN-tolerant and nontolerant rats. Here
      we examined if this effect is mediated by GTN-derived nitric oxide (NO) and
      involves guanosine 3'5' cyclic monophosphate (cyclic GMP) and ATP-sensitive K+
      channels (KATP). 2. Rats were treated with 100 mg kg-1 GTN or vehicle s.c. three
      times a day for 3 days to induce vascular GTN-tolerance or nontolerance. Isolated
      working hearts obtained from either GTN-tolerant or nontolerant rats were
      subjected to 10 min coronary occlusion in the presence of 10-7 M GTN or its
      solvent. 3. GTN improved myocardial function and reduced lactate dehydrogenase
      (LDH) release during coronary occlusion in both GTN-tolerant and nontolerant
      hearts. 4. Cardiac NO content significantly increased after GTN administration in
      both GTN-tolerant and nontolerant hearts as assessed by electron spin resonance.
      However, cardiac cyclic GMP content measured by radioimmunoassay was not changed
      by GTN administration. 5. When hearts from both GTN-tolerant and nontolerant rats
      were subjected to coronary occlusion in the presence of the KATP-blocker
      glibenclamide (10-7 M), the drug itself did not affect myocardial function and
      LDH release, however, it abolished the anti-ischaemic effect of GTN. 6. We
      conclude that GTN opens KATP via a cyclic GMP-independent mechanism, thereby
      leading to an anti-ischaemic effect in the heart in both GTN-tolerant and
      nontolerant rats.

PMID- 10602322
TI  - Effect of Gd3+ on bradykinin-induced catecholamine secretion from bovine adrenal
      chromaffin cells.
AB  - 1. The effects of Gd3+ on bradykinin- (BK-) induced catecholamine secretion,
      45Ca2+ efflux and cytosolic [Ca2+] were studied using bovine adrenal chromaffin
      cells. 2. BK increased secretion in a Ca2+-dependent manner. From 1 - 100 microM,
      Gd3+ progressively inhibited secretion induced by 30 nM BK to near-basal levels,
      however from 0.3 - 3 mM Gd3+ dramatically enhanced BK-induced secretion to above
      control levels. Gd3+ also increased basal catecholamine secretion by 2 - 3 fold
      at 1 mM. These effects were mimicked by Eu3+ and La3+. 3. Gd3+ enhanced secretion
      induced by other agonists that mobilize intracellular Ca2+ stores, but simply
      blocked the response to K+. 4. Gd3+ still enhanced basal and BK-induced secretion
      in Ca2+-free solution or in the presence of 30 microM SKF96365, however both
      effects of Gd3+ were abolished after depleting intracellular Ca2+ stores. 5. Gd3+
      (1 mM) reduced the rate of basal 45Ca2+ efflux by 57%. In Ca2+-free buffer, BK
      transiently increased cytosolic [Ca2+] measured with Fura-2. The [Ca2+] response
      to BK was substantially prolonged in the presence of Gd3+ (1 mM). 6. The results
      suggest that Gd3+ greatly enhances the efficacy of Ca2+ released from
      intracellular stores in evoking catecholamine secretion, by inhibiting Ca2+
      extrusion from the cytosol. This suggests that intracellular Ca2+ stores are
      fully competent to support secretion in chromaffin cells to levels comparable to
      those evoked by extracellular Ca2+ entry. Drugs that modify Ca2+ extrusion from
      the cell, such as lanthanide ions, will be useful in investigating the mechanisms
      by which intracellular Ca2+-store mobilization couples to Ca2+-dependent
      exocytosis.

PMID- 10602323
TI  - Putative beta 4-adrenoceptors in rat ventricle mediate increases in contractile
      force and cell Ca2+: comparison with atrial receptors and relationship to (-)
      [3H]-CGP 12177 binding.
AB  - 1. We identified putative beta4-adrenoceptors by radioligand binding, measured
      increases in ventricular contractile force by (-)-CGP 12177 and (+/-)
      cyanopindolol and demonstrated increased Ca2+ transients by (-)-CGP 12177 in rat
      cardiomyocytes. 2. (-)-[3H]-CGP 12177 labelled 13 - 22 fmol mg-1 protein
      ventricular beta1, beta2-adrenoceptors (pKD approximately 9.0) and 50 - 90 fmol
      mg-1 protein putative beta4-adrenoceptors (pKD approximately 7.3). The affinity
      values (pKi) for (beta1,beta2-) and putative beta4-adrenoceptors, estimated from
      binding inhibition, were (-)-propranolol 8.4, 5.7; (-)-bupranolol 9.7, 5.8; (+/-)
      cyanopindolol 10.0,7.4. 3. In left ventricular papillary muscle, in the presence
      of 30 microM 3-isobutyl-1-methylxanthine, (-)-CGP 12177 and (+/-)-cyanopindolol
      caused positive inotropic effects, (pEC50, (-)-CGP 12177, 7.6; (+/-)
      cyanopindolol, 7.0) which were antagonized by (-)-bupranolol (pKB 6.7 - 7.0) and
      (-)-CGP 20712A (pKB 6.3 - 6.6). The cardiostimulant effects of (-)-CGP 12177 in
      papillary muscle, left and right atrium were antagonized by (+/-)-cyanopindolol
      (pKP 7.0 - 7.4). 4. (-)-CGP 12177 (1 microM) in the presence of 200 nM (-)
      propranolol increased Ca2+ transient amplitude by 56% in atrial myocytes, but
      only caused a marginal increase in ventricular myocytes. In the presence of 1
      microM 3-isobutyl-1-methylxanthine and 200 nM (-)-propranolol, 1 microM (-)-CGP
      12177 caused a 73% increase in Ca2+ transient amplitude in ventricular myocytes.
      (-)-CGP 12177 elicited arrhythmic transients in some atrial and ventricular
      myocytes. 5. Probably by preventing cyclic AMP hydrolysis, 3-isobutyl-1
      methylxanthine facilitates the inotropic function of ventricular putative beta4
      adrenoceptors, suggesting coupling to Gs protein-adenylyl cyclase. The receptor
      mediated increases in contractile force are related to increases of Ca2+ in
      atrial and ventricular myocytes. The agreement of binding affinities of agonists
      with cardiostimulant potencies is consistent with mediation through putative
      beta4-adrenoceptors labelled with (-)-[3H]-CGP 12177.

PMID- 10602324
TI  - Pharmacological characterization of antagonists of the C5a receptor.
AB  - 1. Potent and highly selective small molecule antagonists have recently been
      developed by us for C5a receptors (C5aR) on human polymorphonuclear leukocytes
      (PMN). In this study we compared a new cyclic antagonist, F-[OPdChaWR], with an
      acyclic derivative, MeFKPdChaWr, for their capacities to bind to C5aR on human
      PMN and human umbilical artery membranes. We also compared their inhibition of
      myeloperoxidase (MPO) secretion from human PMNs and their inhibition of human
      umbilical artery contraction induced by human recombinant C5a. 2. In both PMNs
      and umbilical artery, the cyclic and acyclic C5a antagonists displayed
      insurmountable antagonism against C5a. There were differences in selectivities
      for the C5aR with F-[OPdChaWR] (pKb 8.64+/-0.21) being 30 times more potent than
      MeFKPdChaWr (pKb 7.16+/-0.11, P<0.05) in PMNs, but of similar potency (pKb 8.19+/
      0.38 vs pKb 8.28+/-0.29, respectively) in umbilical artery. This trend was also
      reflected in their relative binding affinities, both antagonists having similar
      affinities (-logIC50 values) for C5aR in umbilical artery membranes (F
      [OPdChaWR], 7.00+/-0.46; MeFKPdChaWr, 7.23+/-0.17), whereas in PMN membranes the
      C5aR affinity of the cycle F-[OPdChaWR] (7.05+/-0. 06) was four times higher than
      that of acyclic MeFKPdChaWr (6.43+/-0. 24, P<0.05). 3. In summary, the results
      reveal that these antagonists are insurmountable in nature against C5a for C5aR
      on at least two human cell types, and the differences in relative receptor
      binding affinities and antagonistic potencies against C5a are consistent with
      differences in receptors within these cell types. The nature of these differences
      is yet to be elucidated.

PMID- 10602325
TI  - Activation of muscle nicotinic acetylcholine receptor channels by nicotinic and
      muscarinic agonists.
AB  - 1. The dose-response parameters of recombinant mouse adult neuromuscular
      acetylcholine receptor channels (nAChR) activated by carbamylcholine, nicotine,
      muscarine and oxotremorine were measured. Rate constants for agonist association
      and dissociation, and channel opening and closing, were estimated from single
      channel kinetic analysis. 2. The dissociation equilibrium constants were (mM):
      ACh (0. 16)<oxotremorine M (0.6)<carbamylcholine (0.8)<nicotine (2.6). 3. The
      gating equilibrium constants (opening/closing) were: ACh (45)>carbamylcholine
      (5.1)>oxotremorine M (0.6)>nicotine (0. 5)>muscarine (0.15). 4. Rat neuronal
      alpha4beta2 nAChR can be activated by all of the agonists. However, detailed
      kinetic analysis was impossible because the recordings lacked clusters
      representing the activity of a single receptor complex. Thus, the number of
      channels in the patch was unknown and the activation rate constants could not be
      determined. 5. Considering both receptor affinity and agonist efficacy, muscarine
      and oxotremorine are significant agonists of muscle-type nAChR. The results are
      discussed in terms of structure-function relationships at the nAChR transmitter
      binding site.

PMID- 10602326
TI  - Novel cardiac protective effects of urea: from shark to rat.
AB  - 1. This study was carried out to investigate novel cardioprotective effects of
      urea and the underlying mechanisms. The cardiac functions under oxidative stress
      were evaluated using Langendorff perfused isolated heart. 2. Isolated dogfish
      shark hearts tolerated the oxidative stress generated by electrolysis (10 mA, 1
      min) of the perfusion solution (n=4), and also showed normal cardiac functions
      during post-ischaemia reperfusion (n=4). The high concentration of urea (350 mM)
      in the heart perfusate was indispensable for maintaining the normal cardiac
      functions of the shark heart. 3. Urea at 3 - 300 mM (n=4 for each group)
      protected the isolated rat heart against both electrolysis-induced heart damage
      and post-ischaemia reperfusion-induced cardiac injury. 4. A concentration
      dependent scavenging effect of urea (3 - 300 mM, n=4 for each group) against
      electrolysis-induced reactive oxygen species was also demonstrated in vitro. 5.
      Urea derivatives as hydroxyurea, dimethylurea, and thiourea had antioxidant
      cardioprotective effect against the electrolysis-induced cardiac dysfunction of
      rat heart, but were not as effective as urea in suppressing the post-ischaemia
      reperfusion injury. 6. Our results suggest that urea and its derivatives are
      potential antioxidant cardioprotective agents against oxidative stress-induced
      myocardium damage including the post-ischaemia reperfusion-induced injury.

PMID- 10602327
TI  - Inducible expression and pharmacology of the human excitatory amino acid
      transporter 2 subtype of L-glutamate transporter.
AB  - 1. In this study we have examined the use of the ecdysone-inducible mammalian
      expression system (Invitrogen) for the regulation of expression of the
      predominant L-glutamate transporter EAAT2 (Excitatory Amino Acid Transporter) in
      HEK 293 cells. 2. HEK 293 cells which were stably transformed with the regulatory
      vector pVgRXR (EcR 293 cells) were used for transfection of the human EAAT2 cDNA
      using the inducible vector pIND and a clone designated HEK/EAAT2 was selected for
      further characterization. 3. Na+-dependent L-glutamate uptake activity (3.2 pmol
      min-1 mg-1) was observed in EcR 293 cells and this was increased approximately 2
      fold in the uninduced HEK/EAAT2 cells, indicating a low level of basal EAAT2
      activity in the absence of exogenous inducing agent. Exposure of HEK/EAAT2 cells
      to the ecdysone analogue Ponasterone A (10 microM for 24 h) resulted in a > or =
      10 fold increase in the Na+-dependent activity. 4. L-glutamate uptake into
      induced HEK/EAAT2 cells followed first-order Michaelis-Menten kinetics and Eadie
      Hofstee transformation of the saturable uptake data produced estimates of kinetic
      parameters as follows; Km 52.7+/-7.5 microM, Vmax 3.8+/-0.9 nmol min-1 mg-1
      protein. 5. The pharmacological profile of the EAAT2 subtype was characterized
      using a series of L-glutamate transport inhibitors and the rank order of
      inhibitory potency was similar to that described previously for the rat homologue
      GLT-1 and in synaptosomal preparations from rat cortex. 6. Addition of the EAAT2
      modulator arachidonic acid resulted in an enhancement (155+/-5% control in the
      presence of 30 microM) of the L-glutamate transport capacity in the induced
      HEK/EAAT2 cells. 7. This study demonstrates that the expression of EAAT2 can be
      regulated in a mammalian cell line using the ecdysone-inducible mammalian
      expression system.

PMID- 10602328
TI  - Levcromakalim causes indirect endothelial hyperpolarization via a myo-endothelial
      pathway.
AB  - 1. Effects of K+ channel opener, levcromakalim, on vascular endothelial cells
      were examined. Under voltage- and current-clamp conditions, application of
      acetylcholine to dispersed endothelial cells isolated from rabbit superior
      mesenteric artery (dispersed RMAECs) produced hyperpolarization and outward
      currents. On the other hand, dispersed RMAECs did not respond to levcromakalim.
      2. When membrane potential was recorded from endothelium in a mesenteric arterial
      segment, exposure to levcromakalim in a concentration range of 0.1 to 3 microM
      caused concentration-dependent hyperpolarization. The hyperpolarization was
      observed in the absence of external Ca2+ and was inhibited by 10 microM
      glibenclamide. 3. The presence of 1 mM heptanol did not affect the levcromakalin
      induced hyperpolarization, whereas treatment of the mesenteric arterial segment
      with 20 microM 18 beta-glycyrrhetinic acid significantly reduced the
      hyperpolarization. The response to acetylcholine of RMAECs in an arterial segment
      with 18 beta-glycyrrhetinic acid was, however, similar to that without 18 beta
      glycyrrhetinic acid. 4. These suggest that although RMAECs themselves are
      functionally insensitive to levcromakalim, those in an arterial segment are
      hyperpolarized by levcromakalim via myo-endothelial electrical communication.

PMID- 10602329
TI  - Evidence for the involvement of spinal endogenous ATP and P2X receptors in
      nociceptive responses caused by formalin and capsaicin in mice.
AB  - 1. The aim of the present study is to characterize the role of spinal endogenous
      ATP and P2X receptors in the generation of neurogenic and inflammatory pain. We
      examined the effects of intrathecal treatment with P2X receptor antagonists on
      the formalin- and capsaicin-induced nociceptive behaviours in mice. 2.
      Intrathecal pretreatment with the general P2 receptor antagonist, pyridoxal
      phosphate-6-azophenyl-2', 4'-disulphonic acid (PPADS), significantly suppressed
      both the first and second phases of the formalin-induced nociceptive behaviour.
      The second phase of the nociceptive response was also suppressed by intrathecal
      treatment with PPADS after the first phase. Furthermore, pretreatment with the
      selective antagonist for the P2X1, P2X3 and P2X2+3 receptors, 2',3'-O-(2,4,6
      trinitrophenyl)adenosine 5'-triphosphate (TNP-ATP), significantly reduced the
      first phase, but not the second phase. The second phase was also not suppressed
      by intrathecal TNP-ATP after the first phase. 3. Capsaicin-induced nociceptive
      behaviour that has been shown to be a model for neurogenic pain, was also
      significantly suppressed by intrathecal pretreatment with PPADS or TNP-ATP. 4.
      Nociceptive behaviour in the first phase of the formalin test and in the
      capsaicin test were significantly inhibited by intrathecal pretreatment with
      alpha, beta-methylene ATP (alpha,betameATP: 5 microg mouse-1) 15 min prior to
      injection of formalin or capsaicin. This treatment has been previously shown to
      desensitize spinal P2X3 receptor subtypes in vivo. 5. These findings suggest that
      spinal endogenous ATP may play a role in (1) the formalin- and capsaicin-induced
      neurogenic pain via the PPADS- and TNP-ATP-sensitive P2X receptors which are also
      desensitized by alpha,betameATP (perhaps the P2X3 receptor subtype) and (2)
      formalin-induced inflammatory pain via PPADS-sensitive, TNP-ATP- and
      alpha,betameATP-insensitive P2X (and/or P2Y) receptors.

PMID- 10602330
TI  - Characterization of excitatory prostanoid receptors in the human umbilical artery
      in vitro.
AB  - 1. 5-HT and the prostanoid TP receptor agonists, U46619 and I-BOP, constricted
      the human umbilical artery with pEC50 values of 7.3+/-0. 2, 6.7+/-0.1, and 7.3+/
      0.2, respectively. The selective TP receptor antagonist, GR32191 (0.1 microM),
      shifted the concentration-effect curves to U46619 and I-BOP to the right, but had
      no effect on the response to 5-HT. 2. The natural prostaglandins, PGF2alpha and
      PGE2, caused concentration-dependent contraction with pEC50 values of 5.2+/-0.2
      and 4.9+/-0.2, respectively. PGD2 was a partial agonist with a pEC50 of 5.24+/
      0.03. GR32191 (0.1 microM) inhibited the responses to all of these compounds
      suggesting that they produce contraction by acting at TP receptors. 3.
      Sulprostone failed to elicit contraction in the human umbilical artery at
      concentrations up to 4.4 microM suggesting the absence of EP1 and EP3 receptors.
      Despite this, 17-phenyltrinor PGE2 and GR63799 both induced contraction at
      concentrations above 1 microM, but the effects were sensitive to GR32191 (0.1
      microM). 4. Fluprostenol had no effect on the human umbilical artery at
      concentrations up to 17 microM suggesting the absence of FP receptors.
      Cloprostenol was ineffective in two tissues, but caused contraction in one tissue
      at the highest concentration tested (1.7 microM). However, this response was
      abolished in the presence of GR32191 (0.1 microM). 5. The effects of four TP
      receptor antagonists were assessed by global non-linear regression analysis.
      GR32191, SQ29548, SQ30741, and ICI192605 competitively inhibited responses to
      U46619 with pKb values of 8.0+/-0.1, 7.6+/-0.1, 7.0+/-0. 2 and 8.1+/-0.1,
      respectively. 6 These results suggest that the human umbilical artery
      functionally expresses TP receptors, but not EP1, EP2 or FP receptors.

PMID- 10602331
TI  - Effect of nitro-L-arginine on electrical and mechanical responses to
      acetylcholine in the superior mesenteric artery from stroke-prone hypertensive
      rat.
AB  - 1. High salt diet is known to aggravate the vascular pathology in spontaneously
      hypertensive stroke-prone rats (SHR-SP). The aim of the present study was to
      assess the involvement of endothelial dysfunction in this effect. Contractile
      tension and membrane potential were simultaneously recorded in superior
      mesenteric artery rings of untreated and NaCl-loaded (1% NaCl in the drinking
      water) SHR-SP and normotensive Wistar Kyoto rats (WKY). 2. In unstimulated
      artery, hyperpolarization evoked by acetylcholine was not different in WKY and in
      NaCl-loaded WKY; it was reduced in SHR-SP and further reduced in NaCl-loaded SHR
      SP. Hyperpolarization was unaffected by N(omega)-nitro-L-arginine (L-NA) but was
      abolished in high-KCl solution. 3. In noradrenaline-stimulated artery, ACh-evoked
      hyperpolarization and relaxation were not different in WKY and in SHR-SP. NaCl
      treatment did not affect the responses to ACh in WKY but decreased maximum
      relaxation in SHR-SP from 93+/-2% to 72+/-7% of the contraction. In WKY, in NaCl
      loaded WKY and in SHR-SP, L-NA similarly shifted the concentration-relaxation
      curve to ACh to the right and depressed its maximum but L-NA did not affect the
      hyperpolarization to ACh. In NaCl-loaded SHR-SP, L-NA blunted the effects of ACh
      on membrane potential and on contraction. 4. The NO donor SNAP abolished the
      depolarization and the contraction evoked by noradrenaline with the same potency
      in WKY and in untreated SHR-SP but was more potent in NaCl-loaded SHR-SP. 5. In
      KCl-contracted arteries the relaxations to ACh were not different in WKY and SHR
      SP but NaCl-loaded SHR-SP were more sensitive to ACh. 6. The results showed that
      NaCl-rich diet markedly reduced the L-NA-resistant responses to ACh and increased
      the sensitivity to NO in SHR-SP.

PMID- 10602332
TI  - Operational correlates of prostanoid TP receptor expression in human non-pregnant
      myometrium are unaffected by excision site or menstrual cycle status of the
      donor.
AB  - 1. Cumulative concentration-effect curves for the selective prostanoid TP
      receptor agonist, U46619, were constructed in strips of human non-pregnant
      myometrium grouped according to tissue excision site (top, lateral wall, lower
      uterine segment, sub-serosal or sub-endometrial), tissue orientation (strips cut
      either parallel or perpendicular to the serosa) and donor menstrual status
      (proliferative or secretory phase). 2. U46619 was excitatory in all tissues.
      There was no significant difference in either pEC50 or maximum response between
      groups (P<0.05). The range of pEC50 values was 6.8+/-0.1 (lateral wall,
      proliferative phase, n=5) to 7.1+/-0.3 (lateral wall, secretory phase, n=5). The
      range of maximum response values was 0.9+/-0.8 N cm-2 (lateral wall,
      proliferative phase, n=5) to 3.1+/-1.0 N cm-2 (lateral wall, secretory phase,
      n=5). 3. Saturation binding analyses were conducted using the radiolabelled TP
      receptor agonist, [125I]-BOP. Binding parameters were estimated for membranes
      prepared from human non-pregnant myometrium excised from the lateral wall and
      grouped according to donor menstrual status. 4. There were no significant
      differences in the mean pKd and [R]tot values for [125I]-BOP binding between the
      two groups (proliferative phase: pKd=8.3+/-0.3, [R]tot=412+/-319 fmol mg protein
      1, n=5; secretory phase: pKd=8.5+/-0.4, [R]tot=369+/-192 fmol mg protein-1, n=6;
      P<0.05). 5. These data indicate that U46619-mediated responses in human non
      pregnant myometrium are not influenced by tissue excision site, tissue
      orientation or donor menstrual status and that [125I]-BOP binding is not
      influenced by donor menstrual status. This suggests that the TP receptor
      population is homogeneous throughout the human non-pregnant myometrium, and not
      subject to hormonal regulation.

PMID- 10602333
TI  - Leukotrienes are involved in leukocyte recruitment induced by live Histoplasma
      capsulatum or by the beta-glucan present in their cell wall.
AB  - 1. The inflammatory cell influx towards the peritoneal cavity in mice inoculated
      i.p. with live or dead Histoplasma capsulatum or with its subcellular
      preparations was studied. We also evaluated the effects of dexamethasone (Dexa)
      or MK886, an inhibitor of leukotriene (LT) biosynthesis, on the recruitment of
      leukocytes. 2. Live yeast form of fungus (LYH) induced an increase in neutrophils
      (NE) which was highest 4 to 24 h after inoculation. Mononuclear cell (MN)
      migration beginning at 24 h with a gradual increase over 48 and 168 h, and an
      eosinophil (EO) recruitment occurs between 24 and 48 h. 3. NE and EO recruitment
      induced by dead mycelial form of fungus (DMH) was greater than that observed for
      dead yeast form of fungus (DYH). A similar leukocyte migration pattern was seen
      after i.p. injection of the alkali-insoluble fraction (F1) from DYH (F1Y) and F1
      from DMH (F1M) this being more active than former. The difference in
      concentration of beta-glucan in DYH and DMH could explain the different
      inflammatory capacity exhibited by the two forms of H. capsulatum. 4. LT seems to
      be the principal mediator of leukocyte migration in response to LYH, DYH or DMH
      or to beta-glucan. However, other mediators appear to contribute to NE and EO
      migration since the treatment with Dexa was more effective in inhibiting cell
      migration than MK886. Complement dependent leukocyte migration may participate in
      this recruitment. Treatment with MK886 completely abolished MN cell migration,
      indicating its dependence on the presence of LT.

PMID- 10602334
TI  - Antiplatelet effect of the anaesthetic drug propofol: influence of red blood
      cells and leucocytes.
AB  - 1. The present study was designed to investigate the mechanism of the
      antiplatelet action of the anaesthetic propofol in vitro. 2. Human whole blood
      was incubated with different concentrations of propofol and its solvent
      Intralipid(R). We determined, platelet aggregometry in whole blood, platelet
      enriched plasma (PRP), PRP plus red blood cells (RBC), and PRP plus leucocytes
      (LC); platelet production of thromboxane B2 (TxB2), ATP release by platelet dense
      granules, adenosine uptake by RBC, intraplatelet levels of cyclic adenosine
      monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP), and
      LC production of nitric oxide (NO). 3. Propofol-induced inhibition of platelet
      aggregation was greater in whole blood (IC50 80 - 136 microM) than in PRP
      (IC50>600 microM), except when aggregation was induced by arachidonic acid, in
      which case the antiaggregatory effect of the anaesthetic was similar in both
      media (IC50 72 - 85 microM). Inhibition of platelet aggregation correlated
      significantly with inhibition of TxB2 synthesis (r2=0.83). Propofol also
      inhibited granular ATP release; this effect was greatest in whole blood. 4. The
      presence of RBC or LC increased the antiaggregatory effect of propofol, mainly
      when collagen was used as aggregating agent. Intralipid inhibited the uptake of
      adenosine by RBC, however this effect probably does not contribute significantly
      to its antiaggregatory effect. 5. The anaesthetic potentiated the NO-cyclic GMP
      pathway, mainly by increasing the synthesis of NO by LC. Intralipid had no effect
      on the NO-cyclic GMP pathway in the LC-platelet interaction. 6. Propofol
      inhibited platelet aggregation in human whole blood, possibly through the sum of
      the effects of Intralipid on the platelet-RBC interaction and the increased
      synthesis of NO by LC in the platelet-LC interaction.

PMID- 10602335
TI  - Histamine H1-receptor-mediated modulation of the delayed rectifier K+ current in
      guinea-pig atrial cells: opposite effects on IKs and IKr.
AB  - 1. Histamine receptor-mediated modulation of the rapid and slow components of the
      delayed rectifier K+ current (IK) was investigated in enzymatically-dissociated
      atrial cells of guinea-pigs using the whole cell configuration of the patch clamp
      technique. 2. Histamine at a concentration of 10 microM enhanced IK recorded
      during strong depolarization to potentials ranging from +20 to +40 mV and
      inhibited IK recorded during mild depolarization to potentials ranging from -20
      to -10 mV. The increase of IK was more prominent with longer depolarizing pulses,
      whereas the inhibition of IK was more marked with shorter depolarizing pulses,
      suggesting that histamine enhances IKs (the slow component of IK) and inhibits
      IKr (the rapid component of IK). 3. The histamine-induced enhancement of IKs and
      inhibition of IKr were abolished by 3 microM chlorpheniramine but not by 10
      microM cimetidine, suggesting that these opposite effects of histamine on IKr and
      IKs are mediated by H1-receptors. 4. In the presence of 5 microM E-4031, an IKr
      blocker, histamine hardly affected IK during mild depolarization although it
      enhanced IK during strong depolarization in a concentration-dependent manner.
      Histamine increased IKs with EC50 value of 0.7 microM. In the presence of 300
      microM indapamide, an IKs blocker, histamine hardly affected IKs but inhibited
      IKr in a concentration-dependent manner. Histamine decreased IKr with IC50 value
      of 0.3 microM. 5. Pretreatment with 100 nM calphostin C or 30 nM staurosporine,
      protein kinase C inhibitors, abolished the histamine-induced enhancement of IKs,
      but failed to affect the histamine-induced inhibition of IKr. 6. We conclude that
      in guinea-pig atrial cells H1-receptor stimulation enhances IKs and inhibits IKr
      through different intracellular mechanisms.

PMID- 10602336
TI  - Effects of antisense oligonucleotides on brain delta-opioid receptor density and
      on SNC80-induced locomotor stimulation and colonic transit inhibition in rats.
AB  - 1. To reduce the density of delta-opioid receptor protein, five antisense
      phosphorothioate oligodeoxynucleotides (aODN), targeting the three exons of rat
      delta-opioid receptor mRNA (DOR), were injected twice daily for 4 days or
      continuously infused for 7 days into brain lateral ventricles (i.c.v.) of Sprague
      Dawley rats. Rats acting as controls were infused or injected with a mismatch
      sequence (mODN) of each aODN. The density of opioid receptors in rat brain
      membranes was measured by saturation binding experiments using selective ligands
      for delta, mu and kappa opioid receptors. 2. aODNs injected twice a day for 4
      days left rat brain delta-opioid receptor density unchanged. The ODN targeting
      the DOR nucleotide sequence 280 - 299 (aODN280 - 299, exon 2), decreased brain
      delta-opioid receptor density significantly more than aODNs targeting exon 1
      (aODN239 - 258), exon 2 (aODN361 - 380), or exon 3 (aODN741 - 760) (to 52% vs 79,
      72, and 68%). None of the aODNs to the DOR changed the brain density of mu- or k
      opioid receptors. 3. When in a novel environment (but not when kept in their home
      cages), the locomotor activity of aODN280 - 299 treated rats was significantly
      lower than that of saline or mODN treated rats. The delta-opioid agonist SNC80 (5
      mg kg-1, s.c.) significantly and potently stimulated locomotion and delayed
      colonic propulsion in saline- and mODN-infused rats, but left motor behaviour and
      colonic transit of delta-knockdown rats unchanged. 4. The baseline nociceptive
      threshold and the antinociceptive response to morphine were unchanged in delta
      knockdown rats.

PMID- 10602337
TI  - Continued morphine modulation of calcium channel currents in acutely isolated
      locus coeruleus neurons from morphine-dependent rats.
AB  - 1. The actions of the opioid agonists morphine and methionine-enkephalin (met
      enkephalin) on the calcium channel currents (IBa) of acutely isolated locus
      coeruleus (LC) neurons from morphine-dependent and vehicle-treated rats were
      examined using whole cell patch clamp techniques. 2. In LC neurons maintained in
      5 microM morphine, co-superfusion of naloxone (1 microM) or the mu-opioid
      receptor antagonist CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 1 microM) with
      morphine resulted in a significant increase in the amplitude of IBa. The
      increases in IBa were not different in neurons from morphine-dependent or vehicle
      rats. The increase in IBa was mimicked by washing off morphine, but not by co
      superfusion of the kappa-receptor antagonist norbinaltorphimine (300 nM) or the
      delta-receptor antagonist ICI-174864 (1 microM). 3. In spontaneously withdrawn LC
      neurons from morphine-dependent rats, met-enkephalin (pD2 7.1, maximum inhibition
      49%) and morphine (pD2 6.5, maximum inhibition 33%), inhibited IBa in all cells.
      In cells from vehicle rats the pD2 for met-enkephalin was 7.3, maximum inhibition
      52%, while the pD2 for morphine was 6.6 and the maximum inhibition 43% (P<0.05
      versus cells from morphine-dependent rats). 4. IBa in LC neurons was mostly
      comprised of omega-conotoxin GVIA- (N-type) and omega-agatoxin IVA- (P/Q-type)
      sensitive components, with lesser amounts of nimodipine-sensitive current and
      current resistant to all three blockers. Neither the density of IBa nor the
      proportion of any of the components of IBa differed between neurons from morphine
      dependent or vehicle-treated rats. 5. This study demonstrates that in morphine
      dependent rats, morphine and met-enkephalin modulation of somatic IBa in LC
      neurons displays modest tolerance compared with untreated rats. Further, chronic
      morphine treatment does not alter the type or density of IBa in LC neurons. These
      results provide more evidence that functional mu-opioid receptor coupling is not
      dramatically altered in the LC in morphine-dependent rats.

PMID- 10602338
TI  - Therapeutic index for rosiglitazone in dietary obese rats: separation of efficacy
      and haemodilution.
AB  - 1. The blood glucose-lowering efficacy of rosiglitazone (RSG) and the mechanisms
      of associated weight gain were determined in dietary obese rats (DIOs). DIO and
      chow-fed rats received RSG 0.3-30 mg kg-1 daily for 21 days. 2. In DIOs, plasma
      glucose and insulin concentrations were reduced by RSG at dosages of 3 and 10 mg
      kg-1, respectively. Homeostasis model assessment (HOMA) indicated the threshold
      for a reduction of insulin resistance was 1 mg kg-1. Neither glucose nor insulin
      levels were affected by treatment in chow-fed rats. 3. RSG 0.3 mg kg-1 lowered
      free fatty acids (FFAs) in DIOs, whereas for plasma triglycerides (TGs), the
      threshold was 3 mg kg-1. By contrast, the threshold for reducing packed red cell
      volume (PCV) and increasing cardiac mass was 10 mg kg-1. Thus, the therapeutic
      index for RSG in DIOs was >3 and < or = 10. 4. Energy intake and weight gain
      increased in treated DIOs (by 20% and 50 g, at 30 mg kg-1) and chow-fed rats (by
      25% and 35 g, at 30 mg kg-1). In DIOs, these increases coincided with falls in
      plasma leptin (40% lower at 30 mg kg-1) and insulin (43% lower at 30 mg kg-1). By
      contrast, in chow-fed rats, weight gain and hyperphagia occurred without changes
      in either leptin or insulin. However, reductions in FFAs below 0.4 - 0.3 mM were
      associated with hyperphagia and weight gain in DIO and chow-fed rats. 5. We
      conclude that increased energy intake and body weight did not attenuate the
      improved metabolism evoked by RSG in DIO rats, and that insulin action was
      enhanced at a dose >3 fold below the threshold for causing haemodilution and
      cardiac hypertrophy in DIO rats.

PMID- 10602339
TI  - The adrenergic receptor agonist, clonidine, potentiates the anti-parkinsonian
      action of the selective kappa-opioid receptor agonist, enadoline, in the
      monoamine-depleted rat.
AB  - 1. The treatment of Parkinson's disease relies predominantly upon dopamine
      replacement therapy, usually with l-dihydroxyphenylalanine (L-DOPA). However,
      side-effects of long-term treatment, such as L-DOPA-induced dyskinesias can be
      more debilitating than the disease itself. Non-dopaminergic treatment strategies
      might therefore be advantageous. 2. The aim of this study was to investigate the
      potential anti-parkinsonian efficacy of the kappa-opioid receptor agonist,
      enadoline, and the alpha-adrenoreceptor agonist, clonidine, both alone or in
      combination, in the reserpine-treated rat model of Parkinson's disease. 3. Rats
      were treated with reserpine (3 mg kg-1), and experiments carried out 18 h later,
      at which time they exhibited profound akinesia (normal animals 1251+/-228 mobile
      counts h-1, reserpine-treated animals 9+/-2 mobile counts h-1). Both enadoline
      and clonidine increased locomotion in reserpine-treated rats in a dose-dependent
      manner. The maximum locomotor-stimulating effect of enadoline alone was seen at a
      dose of 0.2 mg kg-1 (208+/-63 mobile counts h-1). The maximum effect of clonidine
      was seen at a dose of 2 mg kg-1 (536+/-184 mobile counts h-1). 4. Co
      administration of enadoline (0.1 mg kg-1) and clonidine (0.01 - 0.1 mg kg-1) at
      sub-threshold doses, synergistically increased locomotion. 5. The synergistic
      stimulation of locomotion in the reserpine-treated rat involved activation of
      kappa-opioid receptors and a combination of both alpha1 and alpha2
      adrenoreceptors. 6. The results presented suggest a need for further studies on
      the potential of stimulating kappa-opioid and/or alpha-adrenoreceptors as a
      therapy for Parkinson's disease. Furthermore, the studies may offer potential
      mechanistic explanations of the ability of alpha2-adrenergic receptor antagonist
      to reduce L-DOPA-induced dyskinesia in Parkinson's disease.

PMID- 10602340
TI  - Sustained improvement in glucose homeostasis in lean and obese mice following
      chronic administration of the beta 3 agonist SR 58611A.
AB  - 1. Acute SR 58611A (0.25 mg kg-1), was effective in reducing the blood glucose
      response to a glucose tolerance test (GTT) in normal lean (control) and
      spontaneously obese/diabetic CBA/Ca mice and to be equipotent to 1.25 mg kg-1
      glibenclamide in lean mice. 2. Neither brown (BAT) nor white (WAT) adipose tissue
      lipogenesis was altered by acute SR 58611A (2 - 8 mg kg-1) in lean mice, but both
      increased significantly at the higher doses in the obese mice. 3. Acute SR 58611A
      produced a hypoglycaemia 40 min after dosing in lean and obese animals, the
      duration and potency of which was less than that of glibenclamide. Plasma insulin
      levels increased 20 min after acute SR 58611A and glibenclamide in lean and obese
      mice. 4. Chronic treatment (0.25 mg kg-1, 15 days) with SR 58611A increased its
      effectiveness in improving glucose tolerance, but did not affect the body weight
      (BW) or food intake of either lean or obese mice. 5. Acute and chronic SR 58611A
      prolonged the hypoglycaemic effect of exogenous insulin in lean but not obese
      mice. 6. In fed and fasted lean mice and in fasted obese mice chronic SR 58611A
      produced an acute hypoglycaemia 30 min post administration which was greater than
      after a single dose. 7. SR 58611A maintained its effectiveness in improving
      glucose tolerance in lean and obese mice over a dosing period of 15 days. The
      improvement in glucose tolerance was achieved at a dose less than that required
      to stimulate adipose tissue lipogenesis and which did not affect food intake or
      body weight.

PMID- 10602341
TI  - Tetrandrine ameliorates ischaemia-reperfusion injury of rat myocardium through
      inhibition of neutrophil priming and activation.
AB  - 1. We have previously shown that tetrandrine (TTD), a
      bisbenzyltetrahydroiosquinoline isolated from the Chinese herb Stephania
      tetrandra, inhibits neutrophil adhesion, Mac-1 expression, and reactive oxygen
      species (ROS) production. To examine whether inhibition of neutrophil function
      may confer upon TTD the ability to prevent myocardial ischaemia-reperfusion
      (MI/R) injury, experiments were performed on rats subjected to coronary ligation
      followed by reperfusion for induction of MI/R injury. 2. Intravenous
      administration of TTD (0.1 and 1.0 mg kg-1) 15 min prior to coronary ligation
      completely prevented MI/R-associated mortality. TTD pretreatment also
      significantly reduced MI/R-induced ventricular tachyarrhythmia, myocardial
      infarct size, and neutrophil infiltration. 3. However, TTD pretreatment did not
      influence mean arterial blood pressure, heart rate, or product of pressure-rate,
      indicating that TTD extenuated MI/R through mechanisms independent of modulating
      haemodynamics or myocardial oxygen demand. 4. Peripheral blood neutrophils were
      isolated for ex vivo examination of shape change and Mac-1 upregulation of
      neutrophils, two sensitive indicators of proinflammatory priming, as well as N
      formyl-methionyl-leucyl-phenylalanine (fMLP)-induced adhesion and ROS production,
      parameters commonly used for the assessment of neutrophil activation. 5.
      Neutrophils from MI/R animals showed significant shape change and Mac-1
      upregulation, both of which were prevented by TTD-pretreatments. On the other
      hand, fMLP-induced adhesion and ROS production of neutrophils were markedly
      enhanced by MI/R but diminished in TTD-pretreated animals. 6. These data suggest
      that the protective effect of TTD against MI/R injury can be accounted for by
      inhibition of neutrophil priming and activation, thereby abolishing subsequent
      infiltration and ROS production that cause MI/R injury.

PMID- 10602342
TI  - Significant role of neuronal non-N-type calcium channels in the sympathetic
      neurogenic contraction of rat mesenteric artery.
AB  - 1. The possible involvement of pre-junctional non-N-type Ca2+ channels in
      noradrenaline (NA)-mediated neurogenic contraction by electrical field
      stimulation (EFS) was examined pharmacomechanically in the isolated rat
      mesenteric artery. 2. EFS-generated contraction of endothelium-denuded mesenteric
      artery was frequency-dependent (2 - 32 Hz) and was abolished by tetrodotoxin
      (TTX, 1 microM), guanethidine (5 microM) or prazosin (100 nM), indicating that NA
      released from sympathetic nerve endings mediates the contractile response. 3. NA
      mediated neurogenic contractions to lower frequency stimulations (2 - 8 Hz) were
      almost abolished by an N-type Ca2+ channel blocker, omega-conotoxin-GVIA (1
      microM) whereas the responses to higher frequency stimulations (12 - 32 Hz) were
      less sensitive to omega-conotoxin-GVIA. The omega-conotoxin-GVIA-resistant
      component of the contractile response to 32 Hz stimulation was inhibited partly
      (10 - 20%) by omega-agatoxin-IVA (10 - 100 nM; concentrations which are
      relatively selective for P-type channels) and to a greater extent by omega
      agatoxin-IVA (1 microM) and omega-conotoxin-MVIIC (3 microM), both of which block
      Q-type channels at the concentrations used. 4. omega-Agatoxin-IVA (10 - 100 nM)
      alone inhibited 32 Hz EFS-induced contraction by 10 approximately 20% whereas
      omega-conotoxin-MVIIC (3 microM) alone inhibited the response by approximately
      60%. 5. These omega-toxin treatments did not affect the contractions evoked by
      exogenously applied NA. 6. These findings show that P- and Q-type as well as N
      type Ca2+ channels are involved in the sympathetic neurogenic vascular
      contraction, and suggest the significant role of non-N-type Ca2+ channels in NA
      release from adrenergic nerve endings when higher frequency stimulations are
      applied to the nerve.

PMID- 10602343
TI  - Inhibition of neuronal KV potassium currents by the antidepressant drug,
      fluoxetine.
AB  - 1. The effect of the antidepressant drug, fluoxetine on neuronal delayed
      rectifier (KV) potassium (K) currents was investigated using perforated-patch
      whole-cell electrophysiological recording methods. 2. Fluoxetine was an effective
      inhibitor of KV currents in cerebellar granule neurons (CGNs) and also inhibited
      recombinant KV1.1 channels expressed in Chinese hamster ovary (CHO) cells. 3.
      Fluoxetine had an IC50 of 11 microM in CGNs but was slightly less potent on KV1.1
      channels (IC50=55 microM). Interestingly, fluoxetine was a much more potent
      inhibitor of KV1.1 expressed in mammalian cells than has been found previously
      for the same homomeric channel expressed in Xenopus oocytes. 4. At concentrations
      that produced around 50% block, the shape of the KV currents in the presence of
      fluoxetine was simply scaled down when compared to control currents. 5. The
      effect of fluoxetine on KV currents in CGNs was neither voltage-dependent nor
      dependent on the channels being in their open state. Both of these observations
      suggest that fluoxetine does not act as a simple open channel blocking agent. 6.
      It is concluded that block of KV currents in mammalian neurons can occur at
      therapeutic levels of fluoxetine. This could lead to an increase in neuronal
      excitability and this effect may contribute to the therapeutic antidepressant
      action of fluoxetine.

PMID- 10602344
TI  - Modulation of mPer1 gene expression by anxiolytic drugs in mouse cerebellum.
AB  - 1. The mPer1 and mPer2 genes are putative mouse clock genes that regulate
      circadian oscillator present in the suprachiasmatic nucleus (SCN) neuron. While
      they are also expressed in the granular cell layer in the cerebellum, their
      function is unknown. In a first step to verify the physiological roles of mPer1
      and mPer2 genes in the cerebellum, we examined the effects of benzodiazepines on
      the expression of the mPer1 and mPer2 genes. 2. mPer2 mRNA expression was higher
      at ZT16 than ZT4 in the mouse cerebellum. 3. High-dose administration of diazepam
      (10 mg kg-1) or triazolam (1 mg kg-1) reduced mPer1 mRNA level 1 h after
      treatment in the cerebellum. 4. Reduced expression of mPer1 by diazepam treatment
      was transient. No difference of mPer1 mRNA level between diazepam (10 mg kg-1)-
      and vehicle-treated group was observed 6 h after treatment. 5. Administration of
      high doses of tandospirone (30 mg kg-1), a non-benzodiazepine anxiolytic also
      reduced mPer1 mRNA expression 1 h after treatment. 6. Administration of high
      doses of clozapine (5 mg kg-1) or haloperidol (1 mg kg-1) impaired the rota-rod
      performance without affecting on mPer1 mRNA level. 7. Diazepam and tandospirone
      inhibited the expression of mPer1 mRNA in the primary cultured cerebellum granule
      cells. 8. Transient reductions of mPer1 mRNA levels by various benzodiazepines
      and tandospirone is associated with impairment of coordinated movement, such as
      rota-rod performance and equilibrium.

PMID- 10602345
TI  - Functional studies in atrium overexpressing A1-adenosine receptors.
AB  - 1. Adenosine and the A1-adenosine receptor agonist R-PIA, exerted a negative
      inotropic effect in isolated, electrically driven left atria of wild-type mice.
      2. In left atria of mice overexpressing the A1-adenosine receptor, adenosine and
      R-PIA exerted a positive inotropic effect. 3. The positive inotropic effect of
      adenosine and R-PIA in transgenic atria could be blocked by the A1-adenosine
      receptor antagonist DPCPX. 4. In the presence of isoprenaline, adenosine exerted
      a negative inotropic effect in wild-type atria but a positive inotropic effect in
      atria from A1-adenosine receptor overexpressing mice. 5. The rate of beating in
      right atria was lower in mice overexpressing A1-adenosine receptors compared with
      wild-type. 6. Adenosine exerted comparable negative chronotropic effects in right
      atria from both A1-adenosine receptor overexpressing and wild-type mice. 7. A1
      adenosine receptor overexpression in the mouse heart can reverse the inotropic
      but not the chronotropic effects of adenosine, implying different receptor
      effector coupling mechanisms.

PMID- 10602346
TI  - Height and body weight in the elderly. I. A 25-year longitudinal study of a
      population aged 70 to 95 years.
AB  - OBJECTIVE: To describe longitudinal changes in height and body weight between the
      ages of 70 and 95 y. DESIGN: Longitudinal cohort study with representative sample
      of 70-y-olds. SETTING: Department of Geriatric Medicine, Goteborg University,
      Sweden. SUBJECTS: 449 males and 524 females, aged 70 y, living in Goteborg were
      examined in 1971-72 and this study population participated on 11 occasions during
      a 25-year follow-up. RESULTS: Mean height decreased 4 and 4.9 cm in males and
      females respectively and the trend was significant between the ages of 70 and 95
      y in both sexes. Between 70 and 75 y of age, a significant difference was found
      between quintiles of body height where in the highest quintile height was lowered
      by 0.4 and 0. 3 cm/y, in males and females respectively, and in the lowest
      quintile by 0.1 cm/y in both sexes. Mean body weight decreased 3.2 and 5.1 kg in
      males and females respectively, from age 70 to 95 y. The trend was significant
      over 22 and 20 y for males and females, respectively. Between the ages of 70 and
      80 y, individuals in highest quintile of body weight decreased at a rate of 0.8
      and 0.6 kg/y, three times higher than those in lowest quintile. Due to the
      decrease in both height and weight over time, body mass index (BMI) was less
      affected. CONCLUSION: Height, body weight and BMI decreased significantly in both
      sexes after age 70 y, and there was a gender difference in the trend. The results
      can be used as reference data for Swedish elderly and might be of importance to
      the understanding of anthropometry with the ageing process. SPONSORSHIP: See
      acknowledgements.

PMID- 10602347
TI  - The nutritional status of disabled children in Nigeria: a cross-sectional survey.
AB  - OBJECTIVE: To compare the nutritional status of disabled children in Nigeria with
      their non-disabled siblings and neighbours. A second aim was to investigate
      anthropometric techniques appropriate for disabled children in this situation.
      DESIGN: A cross-sectional survey. SETTING: Nasarawa and Plateau States and the
      Federal Capital Territory in Central Nigeria. SUBJECTS: 311 children under 10
      years of age were studied: 112 with various disabilities, 87 siblings and 112
      neighbours. METHODS: Selected anthropometric measurements, (height, weight, mid
      upper arm circumference (MUAC), demispan and halfspan), and blood haemoglobin
      levels were assessed by trained personnel. All measurements of disabled subjects
      were compared to the non-disabled controls. RESULTS: The disabled subjects had
      mean height for age (ht/age) and weight for age (wt/age) significantly lower than
      the control group (P<0.05). These differences were due largely to the very low Z
      scores in children with neurological impairments, (ht/age= 3.07 (s.d.=1.6);
      wt/age= 2.0 (s.d.=1.2)). Measurement difficulties contributed to low height
      values in disabled children and halfspan was found to be a useful proxy for
      height in these children. MUAC results were higher for the children with
      disabilities due to polio than for controls. The mean haemoglobin levels were
      slightly but significantly higher (P<0.05) in the disabled and sibling groups
      compared to the neighbourhood group. CONCLUSION: Disabled children with
      neurological impairments and consequent feeding difficulties are nutritionally at
      risk, but others are no worse off than their non-disabled peers in this area.
      Halfspans may serve as a useful proxy indicator for estimating height in some
      children with physical impairments. SPONSORSHIP: The study was funded by a TEAR
      fund grant to JT for her MSc studies.

PMID- 10602348
TI  - The influence of smoking on vitamin D status and calcium metabolism.
AB  - OBJECTIVE: To assess the influence of smoking on serum parathyroid hormone (PTH),
      serum vitamin D metabolites, serum ionized calcium, serum phosphate, and
      biochemical markers of bone turnover in a cohort of 510 healthy Danish
      perimenopausal women. DESIGN: A cross-sectional study. SETTING: Copenhagen,
      Denmark. SUBJECTS: Five-hundred-and-ten healthy women aged 45-58 y, included 3-24
      months after last menstrual bleeding. None were using hormone replacement
      therapy. METHODS: The women were grouped according to their current smoking
      status. The two groups were compared with regard to serum levels of 25
      hydroxyvitamin D (25OHD) and 1, 25-dihydroxyvitamin D (1,25-(OH)2D), intact PTH,
      ionized calcium and phosphate, osteocalcin, as well as urine pyridinolines. Bone
      mineral density (BMD) was measured with DEXA-scans. Multiple regression analyses
      were performed to detect the effect of potentially confounding lifestyle factors,
      such as calcium and vitamin D intakes, alcohol and coffee consumption,
      sunbathing, and physical exercise. RESULTS: Fifty percent were current smokers.
      Smokers had significantly reduced levels of serum 25OHD (P=0.02), 1,25(OH)2D
      (P=0.001), and PTH (P<0.001). There was no difference in serum ionized calcium
      between smokers and non-smokers. We found a negative effect of smoking on serum
      osteocalcin (P=0.01), while urinary pyridinolines were similar in the two groups.
      The small differences in lifestyle between the two groups could not explain these
      findings. Smokers had small but significant reductions in bone mineral density.
      CONCLUSIONS: Smoking has a significant effect on calcium and vitamin D
      metabolism, which is not likely to be explained by other confounding lifestyle
      factors. The depression of the vitamin D-PTH system seen among smokers may
      represent another potential mechanism for the deleterious effects of smoking on
      the skeleton, and may contribute to the reported risk of osteoporosis among
      smokers. SPONSORSHIP: Grants from the Karen Elise Jensens Foundation.

PMID- 10602349
TI  - Effect of low-saturated fat, low-cholesterol dietary intervention on fatty acid
      compositions in serum lipid fractions in 5-year-old children. The STRIP project.
AB  - OBJECTIVE: To evaluate the effect of dietary low-saturated fat, low-cholesterol
      intervention on fat intake and fatty acid compositions in serum cholesterol ester
      (CE), phospholipid (PL) and triglyceride (TG) fractions in five-year-old
      children. DESIGN AND SUBJECTS: The STRIP project is a prospective, randomised
      intervention project in which 1062 seven-month-old infants were recruited from
      the well-baby clinics. 764 children participated in the 5-year follow-up; 202 of
      them were randomly selected for this study. Diet was assessed with 4-d dietary
      records. Serum CE, PL and TG fatty acid compositions were analysed with gas
      liquid chromatography. RESULTS: Saturated fat intake of intervention children
      (mean (confidence interval)) (girls 11.9 (11.2-12.6) % of energy intake (E%);
      boys 12.5 (11.9-13.1)) was lower than that of the control children (girls 14.4
      (13.7-15.2) E%; boys 15.0 (14.3-15. 8) E%) (P=0.0001 for the difference between
      intervention and control groups). The intake of unsaturated fat differed only
      slightly. Dietary ratios of polyunsaturated to saturated fatty acids (PS ratios)
      of the intervention and control diets were 0.44 and 0.33, respectively
      (P=0.0001). Furthermore, serum cholesterol concentrations of the intervention and
      control children differed (4. 28 (4.13-4.43) mmol/L vs 4.49 (4.35-4.63) mmol/L;
      P=0.04). Relative proportion of saturated fatty acids in serum TG was lower
      (34.9% vs 36.3%; P=0.04) and that of n-6 polyunsaturated fatty acids higher
      (13.9% vs 12.4%; P=0.0004) in the intervention than in the control children,
      whereas serum CE and PL fatty acid compositions of intervention and control
      groups were closely similar. However, intake of linoleic acid correlated better
      with serum linoleic acid relative content in the CE fraction (r=0.36; P=0.0001)
      than in the PL (r=0.27; P=0.0002) or in the TG (r=0.23; P=0.0016) fraction.
      CONCLUSIONS: Intervention resulted in decreased intake of saturated fatty acids
      and lowered serum total and LDL cholesterol concentrations. Of serum lipid
      fractions, TG fatty acid composition was the most sensitive and parallelled the
      findings in dietary food records.

PMID- 10602350
TI  - Dual-energy X-ray absorptiometry for body composition estimation in Chinese
      women.
AB  - OBJECTIVE: To determine whether dual-energy X-ray absorptiometry (DXA) is a valid
      method for body composition assessment of obese and non-obese subjects. DESIGN:
      Cross-sectional study. SUBJECTS: Chinese women living in Hong Kong; 66 of 91
      subjects had body mass index (BMI) of >25 kg/m2. MEASUREMENTS: Anthropometrics,
      including body weight, body height, waist and hip girth. Percentage body fat
      (%BF) and fat-free mass (FFM) from DXA (Hologic 2000 plus, Enhanced Array Whole
      Body Version 5.63) were compared with that based on a tracer dose of deuterium
      oxide for the determination of total body water (TBW). RESULTS: In both obese and
      non-obese subjects, FFMDXA was similar to FFMTBW. The Bland and Altman-type
      analysis indicated that comparable between-methods differences (mean bias) and
      limits of agreement were obtained in obese and non-obese subjects for FFM (0.4,
      between -4.4 and 5.2 kg vs 0.5, between -3.1 and 4.1 kg) and %BF (-0.6, between 
      7.6 and 6.4% vs -1.2, between -8.6 and 6.2%). The %BF bias was independent of
      age, BMI, hip circumference, and waist-to-hip ratio, but correlated with waist
      girth (r=0.24, P=0. 021). CONCLUSION: The sources of bias are methodological and
      anthropometric in nature. The between-methods differences, however, are small and
      clinically insignificant. DXA is a valid method for assessing the body
      composition of obese patients. SPONSORSHIP: This study was supported by a HKU
      CRCG grant.

PMID- 10602351
TI  - Association of maternal short stature with stunting in Mexican children: common
      genes vs common environment.
AB  - OBJECTIVE: To evaluate the association between stunting in children and maternal
      short stature, controlling for potential environmental confounders. DESIGN: 1988
      Mexico National Nutrition Survey. SETTING: Mexico SUBJECTS: The final sample size
      was 4663 pairs of children (<5 y) and their mothers (12-49 y) from a total of 13
      236 surveyed houses. MAIN OUTCOME MEASURES: Stunting (height-for-age Z-scores <
      2). RESULTS: The prevalence of stunting in children was 19%, and 10% of the
      mothers exhibited short stature (<145 cm). In the crude analysis, mothers with
      short stature were significantly more likely to have stunted children (odds ratio
      (OR)=4.0; 95% confidence interval (CI)=3.2-4.8; P-value <0.001). In a multiple
      logistic regression model the OR for child stunting was reduced, but remained
      significant OR=2.0; 95% CI=1.6-2.6; P-value <0.001) after adjustment for region,
      urban/rural residence, socio-economic status, household size, child age and
      presence of infection in the past 14 d, and maternal age, body mass index (BMI),
      and educational level. Adjusted ORs varied between regions (Mexico City, OR=3.9;
      North Mexico, OR=3. 1; Central Mexico, OR=2.0; South Mexico, OR=1.6. Comparison
      of crude vs adjusted estimates pointed to regional differences in the proportion
      of association between maternal and child short statures explained by
      environmental determinants. CONCLUSIONS: Maternal stature, reflecting her
      potential height and early environment, appeared to contribute to child height
      independently of the shared risk factors that could affect stature. Nonetheless,
      we could explain much of the association between stunting in children and
      maternal short stature by environmental factors, and part of the residual
      variability may be due to unmeasured determinants. Regional differences pointed
      to a predominance of environmental factors in explaining child stunting in poorer
      regions.

PMID- 10602352
TI  - Variation in fruit and vegetable consumption among adults in Britain. An analysis
      from the dietary and nutritional survey of British adults.
AB  - OBJECTIVES: Using a national representative sample to examine variation in fruit
      and vegetable consumption among adults in the UK, with particular reference to
      consumers with high and low reported intakes. DESIGN: National representative
      dietary survey using 7-d weighed diet records of men and women aged 16-64 y
      living in private households in the UK in 1986-1987. SETTING: The UK. SUBJECTS:
      1087 men and 1110 women. The sample was selected by a multi-stage random
      probability design. The response was 70%. Subjects with low energy intake were
      subsequently excluded. MAIN OUTCOME MEASURES: Food group, nutrient intake,
      physiological measures socio-economic, demographic and behavioural
      characteristics. RESULTS: Consumption of fruit and vegetables was estimated. The
      sample was divided by sex into four quarter groups according to fruit and
      vegetable consumption. There were significant similarities between quarter groups
      in fruit and vegetable and other food intake, nutrient intake, physiological
      measures, and socioeconomic, demographic and behavioural variable. The lowest
      consumers of fruit and vegetables had a mean intake of 738 g/week (men) and 630
      g/week (women), equivalent to 1.3 and 1.1 portion/d, respectively. Conversely,
      the mean intake of both men women with the highest consumption was 3137 g/week
      (5.6 portions day). There were more than twice as many adults in the age group 16
      24 located in Q1 than in Q4. The Manual social class and those in receipt of
      benefits were negatively associated with fruit and vegetable consumption. Smokers
      were significantly associated with low fruit and vegetable intake. Being married
      was associated with increased fruit and vegetable intake and being single or
      divorced/separated was associated with low fruit and vegetable intake. Eating
      home grown produce was associated with high intake. Consumers who lived in London
      or the South-East were associated with higher fruit and vegetable intake.
      CONCLUSIONS: The analysis draws attention to the wide variation in reported fruit
      and vegetable consumption among British adults. High consumers merit further
      investigation to elucidate practical strategies for increasing fruit and
      vegetable consumption. Strategies to increase consumption should be targeted at
      groups most likely to include low consumers of fruits and vegetables.
      SPONSORSHIP: London School of Hygiene and Tropical Medicine.

PMID- 10602353
TI  - Food consumption patterns in a Palestinian West Bank population.
AB  - OBJECTIVE: To describe the food consumption patterns in relation to wealth status
      and age groups in a Palestinian West Bank village population. DESIGN: Community
      based cross-sectional survey of both households and individuals. A list recall
      method was used at the household level. At the individual level, a short food
      frequency questionnaire was used in addition to a 24-h recall without estimates
      of portion sizes. SETTING: A Palestinian semi-rural village in the central West
      Bank. SUBJECTS: All households and all men and women aged 30-65 y in the study
      village were invited. All 368 households and 85% (n=500) of eligible individuals
      participated. RESULTS: The mean energy consumption from 25 selected food items on
      household level was about 13.8 MJ (3300 kcal)/consumption unit/d (a consumption
      unit corresponds to the expected energy requirement for an adult male). The
      proportion of dietary energy from fat and the consumption of most animal products
      was highest among the wealthiest households, and the opposite trend was seen for
      the consumption of wheat flour and lentils. There seems to be an ongoing trend of
      increasing consumption of processed products rich in sugar among the younger age
      groups. CONCLUSION: Shortage of dietary energy on the household level did not
      seem to be a problem in this population, even among the poorest. Differences in
      food consumption patterns between the poor and the wealthy, including a higher
      percentage of energy from fat among the wealthy, may be to the disadvantage of
      the wealthy with respect to some diet-related chronic diseases. SPONSORSHIP: The
      Norwegian Universities' Committee for Development Research (NUFU).

PMID- 10602354
TI  - Varying the protein source in mixed meal modifies glucose, insulin and glucagon
      kinetics in healthy men, has weak effects on subjective satiety and fails to
      affect food intake.
AB  - OBJECTIVE: To evaluate the influence of three dietary protein types (casein,
      gelatin, soy protein) on satiety and food intake, at two levels of loading (total
      energy of test meals: 3.6 or 1.8 MJ). DESIGN: The study employed a repeated
      measures design. Test meals were controlled for energy, macronutrients, fiber and
      palatability, and contained about 23% energy as protein (of which about 65% was
      experimentally manipulated). Postprandial subjective satiety and hunger, plasma
      glucose, insulin and glucagon were assessed for 8 h, and energy and macronutrient
      intakes were monitored for 24 h. SUBJECTS: Nine healthy normal-weight men.
      RESULTS: No effect of the type of protein on 24 h energy and macronutrient
      intakes was observed despite a significant effect of protein source on the
      kinetics of peripheral metabolic responses (but only after 3.6 MJ lunches), and
      inconsistent effects on subjective hunger and satiety responses A casein-enriched
      lunch delayed glucose and insulin responses for 1.5 h, compared with soy protein,
      probably due to a lag in gastric emptying. CONCLUSION: Varying the protein source
      in a mixed meal modifies glucose, insulin and glucagon kinetics in healthy men,
      but these variations in satiety-implicated factors have inconsistent effects on
      subjective satiety and fail to affect food intake. SPONSORSHIP: Eridania Beghin
      Say, Vilvoorde, Belgium and Association Nationale de la Recherche Technique,
      France (Convention CIFRE no 537/94).

PMID- 10602355
TI  - Effects of low-fat stanol ester enriched margarines on concentrations of serum
      carotenoids in subjects with elevated serum cholesterol concentrations.
AB  - OBJECTIVE: To investigate the effects of low-fat stanol ester margarines on
      concentrations of serum carotenoids. DESIGN: A randomized parallel double-blind
      study design consisting of a 4-week run-in (high-fat diet) and an 8-week
      experimental (low-fat, low-cholesterol diet) period. During the experimental diet
      period subjects consumed low-fat wood stanol ester (WSEM), vegetable oil stanol
      ester (VOSEM) or control (no stanol esters) margarine daily. The daily mean total
      stanol intake was 2.31 and 2.16 g in the WSEM and VOSEM groups, respectively.
      SETTING: Outpatient clinical trial with free-living subjects. SUBJECTS:
      Altogether, 60 hypercholesterolaemic subjects were selected for the study out of
      91 originally screened. The study was completed by 55 subjects. MAIN OUTCOMES
      MEASURES: Serum alpha- and beta-carotene and lycopene determined by the HPLC.
      RESULTS: Serum alpha-carotene concentration did not change significantly in
      either of the experimental groups, whereas beta-carotene concentration decreased
      significantly in the WSEM and VOSEM groups (P<0.01), and the change differed
      significantly (P<0.05 and P <0.01, respectively) from that of the control group.
      Decrease in alpha+beta-carotene concentration was significantly greater (P <0.05)
      in both experimental groups than in the control group. However, the change in
      alpha-, beta- or alpha+beta-carotene/total cholesterol ratio did not differ
      significantly among the groups. No significant changes were found in serum
      lycopene or lycopene/total cholesterol ratio in both experimental groups.
      CONCLUSIONS: Low-fat stanol ester margarines appeared to have little effect on
      serum concentrations of alpha-, beta- or alpha + beta-carotene, or lycopene.
      SPONSORSHIP: Grant to the University of Kuopio by Raisio Benecol Ltd, Raisio,
      Finland.

PMID- 10602356
TI  - Nutritional interventions to prevent intrauterine growth retardation: evidence
      from randomized controlled trials.

PMID- 10602358
TI  - Keyword index to volume 53

PMID- 10602359
TI  - MtDNA-related idiopathic dilated cardiomyopathy.

PMID- 10602360
TI  - Genetic, cytogenetic and physical refinement of the autosomal recessive CMT
      linked to 5q31-q33: exclusion of candidate genes including EGR1.
AB  - Charcot-Marie-Tooth disease is an heterogeneous group of inherited peripheral
      motor and sensory neuropathies with several modes of inheritance: autosomal
      dominant, X-linked and autosomal recessive. By homozygosity mapping, we have
      identified, in the 5q23-q33 region, a third locus responsible for an autosomal
      recessive form of demyelinating CMT. Haplotype reconstruction and determination
      of the minimal region of homozygosity restricted the candidate region to a 4 cM
      interval. A physical map of the candidate region was established by screening
      YACs for microsatellites used for genetic analysis. Combined genetic, cytogenetic
      and physical mapping restricted the locus to a less than 2 Mb interval on
      chromosome 5q32. Seventeen consanguineous families with demyelinating ARCMT of
      various origins were screened for linkage to 5q31-q33. Three of these seventeen
      families are probably linked to this locus, indicating that the 5q locus accounts
      for about 20% of demyelinating ARCMT. Several candidate genes in the region were
      excluded by their position on the contig and/or by sequence analysis. The most
      obvious candidate gene, EGR1, expressed specifically in Schwann cells, mapped
      outside of the candidate region and no base changes were detected in two families
      by sequencing of the entire coding sequence.

PMID- 10602361
TI  - Genes homologous to the autosomal dominant polycystic kidney disease genes (PKD1
      and PKD2).
AB  - Autosomal Dominant Polycystic Kidney Disease (ADPKD), a common inherited disease
      leading to progressive renal failure, can be caused by a mutation in either the
      PKD1 or PKD2 gene. Both genes encode for putative transmembrane proteins,
      polycystin-1 and polycystin-2, which show significant homology to each other and
      are believed to interact at their carboxy termini. To identify genes that code
      for related proteins we searched for homologous sequences in several databases
      and identified one partial cDNA and two genomic sequences with significant
      homology to both polycystin-1 and - 2. Further analysis revealed one novel gene,
      PKD2L2, located on chromosome band 5q31, and two recently described genes, PKD2L
      and PKDREJ, located on chromosome bands 10q31 and 22q13.3, respectively. PKD2L2
      and PKD2L, which encode proteins of 613 and 805 amino acids, are approximately
      65% similar to polycystin-2. The third gene, PKDREJ, encodes a putative 2253
      amino acid protein and shows about 35% similarity to both polycystin-1 and
      polycystin-2. For all the genes expression was found in testis. Additional
      expression of PKD2L was observed in retina, brain, liver and spleen by RT-PCR.
      Analyses of five ADPKD families without clear linkage to either the PKD1 or PKD2
      locus showed no linkage to any of the novel loci, excluding these genes as the
      cause of ADPKD in these families. Although these genes may not be involved in
      renal cystic diseases, their striking homology to PKD2 and PKD1 implies similar
      roles and may contribute to elucidating the function of both polycystin-1 and
      polycystin-2.

PMID- 10602362
TI  - Recombinant balanced and unbalanced translocations as a consequence of a balanced
      complex chromosomal rearrangement involving eight breakpoints in four
      chromosomes.
AB  - We report on a family with a balanced complex chromosomal rearrangement (CCR)
      involving eight breakpoints between chromosomes 6, 7, 18, and 21 in the father.
      All three sons inherited one derivative chromosome from the father and in
      addition each inherited a different recombinant chromosome resulting in a partial
      trisomy 6q in the first, an apparently balanced karyotype in the second, and a
      partial trisomy 7q in the third son. Fluorescence in situ hybridisation (FISH)
      and microsatellite analysis were essential for the identification of the
      breakpoints. In addition, the results were confirmed by a 24-colour FISH
      experiment using the spectral karyotyping (SKYtrade mark) system. Paternal origin
      of the de novo CCR in the father was demonstrated for the first time by haplotype
      analysis. This is the second report of a CCR leading to simpler but unbalanced
      translocations in offspring as a consequence of recombination during
      gametogenesis, and the first report of a family case of CCR exhibiting as many as
      eight breakpoints in the transmitting carrier. The initial prediction that viable
      offspring would be quite unlikely had to be revised after the birth of three
      children. Genetic counselling of carriers of balanced complex rearrangements has
      to consider a higher probability for unbalanced recombinations than has been so
      far commonly assumed.

PMID- 10602363
TI  - Carbohydrate-deficient glycoprotein syndrome type 1A: expression and
      characterisation of wild type and mutant PMM2 in E. coli.
AB  - We have identified the PMM2 genotypes of 22 unrelated Danish patients with
      carbohydrate-deficient glycoprotein syndrome type 1A: R141H/F119L (18),
      R141H/C192G (1), F119L/F119L (1), F119L/G117R (1) and D223E/T237R (1). The lack
      of patients homozygous for R141H is statistically highly significant, but
      unexplained. In order to investigate the effect of PMM2 mutations on
      phosphomannomutase (PMM2) activity, PMM2-cDNA was cloned into a pET3a vector.
      Following introduction of mutations into PMM2-cDNA by site-specific mutagenesis,
      wild type and mutant PMM2-cDNA were expressed in E. coli Bl21(DE3) cells, and the
      activity of PMM2 was determined by an enzymatic assay using mannose 1-phosphate
      as substrate. Recombinant R141H, G117R, and T237R PMM2 had no detectable
      catalytic activity, and the F119L PMM2 had 25% of the activity of the wild type.
      The activity of the C192G and D223E PMM2 was in the normal range, but the
      affinity for their substrate was lower, and the proteins were more sensitive to
      increased temperatures. Each patient has at least one mutation which retains
      residual PMM2 activity. Our results support the hypotheses that a genotype
      conveying residual PMM2 catalytic activity is required for survival, and that
      homozygosity for R141H impairs PMM2 to a degree incompatible with life.

PMID- 10602364
TI  - Multiple origins of the spinocerebellar ataxia 7 (SCA7) mutation revealed by
      linkage disequilibrium studies with closely flanking markers, including an
      intragenic polymorphism (G3145TG/A3145TG).
AB  - Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease characterised by
      the association of cerebellar ataxia and, in most patients, progressive macular
      degeneration leading to loss of autonomy and blindness. The patients die after 5
      30 years of evolution. The cause of the disease has been identified as a (CAG)n
      repeat expansion in the coding sequence of the SCA7 gene on chromosome 3p. De
      novo mutations occur on intermediate-sized alleles carrying from 28 to 35 CAG
      repeats. Neomutations explain the persistence of the disease in spite of the
      great instability of the repeat sequence which results in the appearance of
      juvenile onset patients and the extinction of the disease within families. This
      rare disorder has been reported in a wide variety of countries and ethnic groups.
      In a large number of SCA7 families (n = 41) of different origins, we have
      determined the haplotypes segregating with the mutation of several microsatellite
      markers close to the SCA7 gene and of a new intragenic polymorphism
      (G3145TG/A3145TG). Four different haplotypes were found for centromeric markers
      (G3145TG/A3145TG-D3S1287-D3S3635) in the majority of the kindreds from four
      different geographic regions: A-2-4 in Korea; A-3-6 in North Africa, B-3-6 in
      continental Europe and A-4-6 in the UK and USA. The haplotypes in the Jamaican,
      Filipino, Brazilian and German families were different, suggesting that
      independent regional founders are at the origin of the SCA7 mutation in each
      population. Two different haplotypes were observed, however, in two families from
      the same rural area in central Italy in which de novo SCA7 mutations on
      intermediate alleles have been observed, suggesting the existence of different
      pools of at-risk chromosomes in this population.

PMID- 10602365
TI  - The 11 kb FGA deletion responsible for congenital afibrinogenaemia is mediated by
      a short direct repeat in the fibrinogen gene cluster.
AB  - Congenital afibrinogenaemia is an autosomal recessive disorder characterised by
      the complete absence of detectable fibrinogen. We previously identified the first
      known causative mutations for this disorder in a non-consanguineous Swiss family.
      The four affected male individuals (two brothers and their first two cousins)
      were shown to have homozygous deletions of approximately 11 kb of the fibrinogen
      alpha chain (FGA) gene. Haplotype data suggested that the deletions occurred on
      three distinct ancestral chromosomes, implying that the FGA region of the
      fibrinogen locus is susceptible to deletion by a common mechanism, but the
      sequences responsible for the recombination remained to be identified. Here, we
      report the detailed characterisation of the deletion by nucleotide sequence
      analysis of all three deletion junctions and comparison with normal sequences. We
      found that all three deletions were identical to the base-pair and probably
      resulted from non-homologous (illegitimate) recombination. The centromeric and
      telomeric deletion junctions featured both a 7 bp direct repeat, AACTTTT,
      situated in FGA intron 1 and in the FGA-FGB intergenic sequence and a number of
      inverted repeats which could be involved in the generation of secondary
      structures. Analysis with closely linked flanking polymorphic markers revealed
      the existence of at least two haplotypes, further suggesting independent origins
      of the deletions in this family.

PMID- 10602366
TI  - Atypical deletions suggest five 22q11.2 critical regions related to the
      DiGeorge/velo-cardio-facial syndrome.
AB  - Deletions of chromosome 22q11.2 have been associated with distinct phenotypes
      including DiGeorge syndrome (DGS) and velo-cardio-facial (VCFS) syndrome. These
      diseases result from a failure to form derivatives of the third and fourth
      branchial arches during development. DGS/VCFS deletions usually encompass about 3
      Mb of genomic DNA in more than 90% of patients. However, deletion mapping studies
      have failed to demonstrate the existence of a single small region of overlap
      (SRO) and ruled out any obvious correlation between site or size of deletion and
      severity of clinical phenotype. We describe three patients carrying 'atypical'
      deletions presenting the DGS/VCFS phenotype. A comparative analysis of deletions
      in our patients and those previously published has suggested the existence of
      five distinct critical regions within the 22q11.2 locus. This observation argues
      that DGS/VCFS results from haploinsufficiency secondary to a complex and as yet
      unexplained molecular mechanism, probably involving chromatin effects in
      mediating gene expression throughout the entire region.

PMID- 10602367
TI  - Probing the gene expression database for candidate genes.
AB  - We report on a strategy for the identification of candidate genes for multiple
      malformation syndromes using expression data available in public databases. The
      basis for this pilot study was the assumption that, for a multiple malformation
      syndrome, the expression pattern of the causative gene should at least cover the
      organs or tissues affected by the syndrome. Twenty malformation syndromes were
      selected from the OMIM and defined by three to five main symptoms. These key
      symptoms were translated into anatomical terms that were used to query the Gene
      eXpression Database (GXD). The searches covered 65% of the database and yielded
      an average of 16 candidate genes per syndrome. Of these, 23% were ubiquitously
      expressed or housekeeping genes. Further database evaluation of these potential
      candidate genes was based on positional information and on information from mouse
      knockouts. In a first experiment, the correct gene was identified as a candidate
      in four of seven syndromes for which the causative gene is already known. In
      addition, this strategy identified new candidate genes for disorders for which
      the genetic basis is unknown. We identified candidate genes for the Walker
      Warburg, DOOR, C, scalp-ear-nipple and oculocerebral hypopigmentation syndromes.
      Our results suggest that it may ultimately be feasible to identify disease genes
      by probing gene expression databases with simple syndrome descriptions.

PMID- 10602368
TI  - Genetic refinement of the hereditary neuralgic amyotrophy (HNA) locus at
      chromosome 17q25.
AB  - Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant, recurrent focal
      neuropathy. HNA is characterised by episodes of painful brachial plexus
      neuropathy with muscle weakness and atrophy, as well as sensory disturbances.
      Single episodes are commonly preceded by non-specific infections, immunisations
      or parturition. Mild dysmorphic features and short stature are present in some
      HNA families, but absolute co-segregation with HNA has not been described. To
      refine the previously described HNA locus on chromosome 17q25, we performed a
      genetic linkage study in five HNA families with different geographic origins.
      Significant linkage was obtained with chromosome 17q24-q25 short tandem repeat
      (STR) markers in three HNA families and suggestive linkage was found in the other
      two HNA families. Analysis of the informative recombinations in affected
      individuals allowed us to reduce the HNA linkage interval to a candidate region
      of 3.5 cM.

PMID- 10602369
TI  - Multiple APC mutations in sporadic flat colorectal adenomas.
AB  - Adenomas are established pre-malignant lesions in colorectal carcinogenesis. To
      date the adenoma-carcinoma sequence for the development of colorectal carcinoma
      (CRC) has been based largely on molecular data of exophytic, polypoid-type
      adenomas. Subsequently, a different type of adenoma has been identified: the flat
      adenoma, so called for its flat, non-exophytic appearance, making it less likely
      to be detected during conventional endoscopy. However, due to technological
      advances in endoscopic methods, flat-type adenomas can now frequently be detected
      and are no longer considered rare colorectal lesions. The phenotype of flat
      colorectal adenomas differs macroscopically and histologically from exophytic
      adenomas. Flat colorectal adenomas, as a rule, are tubular structures often
      revealing high-grade dysplasia, irrespective of the size or villous component.
      Flat adenomas have also been recognised as pre-cancerous lesions in gastric
      cancer. Unlike the wealth of clinical and molecular information available for
      polypoid (exophytic) adenomas, molecular profiles of flat-type lesions have not
      yet been characterised systematically and the full clinical significance hereto
      realised. Previous molecular investigation of the K-ras gene in flat colorectal
      adenomas suggests a distinct pathway in their development. In this study,
      mutation analysis of the adenomatous polyposis coli (APC) gene using the protein
      truncation test (PTT) in 20 flat colorectal adenomas in a selected group of 16
      patients without hereditary predisposition to colorectal cancer, revealed double
      truncations of the APC gene in four adenomas. In one of these adenomas a third
      mutation was detected by DNA sequence analysis.

PMID- 10602370
TI  - Germline and gonosomal mosaicism in the ATR-X syndrome.
AB  - We have identified two females who are mosaic for an ATRX mutation. One case, in
      whom the mutation was undetectable in peripheral blood and buccal cells, has two
      affected sons and is therefore presumed to be a germline mosaic. In another case,
      the ATRX mutation is weakly detectable in the peripheral blood but only one of
      her three children who share the disease-associated haplotype carries the
      mutation and therefore it is concluded that she is a gonosomal mosaic. These
      cases provide the first molecular evidence for the occurrence of post-zygotic
      mutation in X-linked alpha thalassaemia mental retardation syndrome. The
      possibility of germline mosaicism must therefore be considered in the genetic
      counselling of ATR-X families.

PMID- 10602371
TI  - Smith-Lemli-Opitz syndrome: evidence of T93M as a common mutation of delta7
      sterol reductase in Italy and report of three novel mutations.
AB  - The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of
      cholesterol biosynthesis characterised by facial dysmorphisms, mental retardation
      and multiple congenital anomalies. SLOS is caused by mutations of the human
      Delta7-sterol reductase (DHCR7) gene and, so far, 19 different mutations have
      been described. Among these, mutations impairing the activity of the C-terminus
      appear to be the most severe. Here we report the mutational analysis of the DHCR7
      gene in nine Italian SLOS patients. The T93M mutation, previously reported in one
      patient, results the most frequent one (7/18 alleles) in our survey. Furthermore,
      we identified three novel mutations, two missense mutations (N407Y and E448K),
      and a 33 bp deletion spanning part of exon 5 and the donor splice site of intron
      5.

PMID- 10602372
TI  - Spell-checking our genes: report from the symposium Mutation Detection in Large
      Genes, 14 May 1999, Vicoforte, Italy.

PMID- 10602373
TI  - Antiangiogenic gene therapy.

PMID- 10602374
TI  - Gene manipulation in the induction of anti-tumour immunity.

PMID- 10602375
TI  - Mechanisms of gene transfer mediated by lipoplexes associated with targeting
      ligands or pH-sensitive peptides.
AB  - Association of a targeting ligand such as transferrin, or an endosome disrupting
      peptide such as GALA, with cationic liposome-DNA complexes ('lipoplexes') results
      in a significant enhancement of transfection of several cell types (Simoes S et
      al, Gene Therapy 1998; 5: 955-964). Although these strategies can overcome some
      of the barriers to gene delivery by lipoplexes, the mechanisms by which they
      actually enhance tranfection is not known. In studies designed to establish the
      targeting specificity of transferrin, we found that apo-transferrin enhances
      transfection to the same extent as transferrin, indicating that internalization
      of the lipoplexes is mostly independent of transferrin receptors. These
      observations were reinforced by results obtained from competitive inhibition
      studies either by preincubating the cells with an excess of free ligand or with
      various 'receptor-blocking' lipoplexes. Transfection of cells in the presence of
      drugs that interfere with the endocytotic pathway provided additional insights
      into the mechanisms of gene delivery by transferrin- or GALA-lipoplexes. Our
      results indicate that transferrin-lipoplexes deliver transgenes by endocytosis
      primarily via a non-receptor-mediated mechanism, and that acidification of the
      endosomes is partially involved in this process.

PMID- 10602376
TI  - Stable gene transfer to the nervous system using a non-primate lentiviral vector.
AB  - We have constructed a non-primate lentiviral vector system based on the equine
      infectious anaemia virus (EIAV). This system is able to transduce both dividing
      and non-dividing cells, including primary cultured hippocampal neurons and
      neurons and glia in the adult rat central nervous system (CNS), at efficiencies
      comparable with HIV-based vectors. We demonstrate that the only EIAV proteins
      required for this activity are gag/pol and that the only accessory protein
      required for vector production is rev. In addition, we show that the pol encoded
      dUTPase activity that is found in all non-primate lentiviruses is not required.
      The vectors can be pseudotyped with a range of envelopes including rabies G and
      MLV 4070A and can be concentrated to high titres. The ability of EIAV to infect
      mitotically inactive cells makes this vector an attractive alternative to the
      immunodeficiency viruses for gene therapy.

PMID- 10602377
TI  - Capture of a recombination activating sequence from mammalian cells.
AB  - We have developed a genetic trap for identifying sequences that promote
      homologous DNA recombination. The trap employs a retroviral vector that normally
      disables itself after one round of replication. Insertion of defined DNA
      sequences into the vector induced the repair of a 300 base pair deletion, which
      restored its ability to replicate. Tests of random sequence libraries made in the
      vector revealed a putative recombination signal (CCCACCC). When this heptamer or
      an abbreviated form (CCCACC) were reinserted into the vector, they stimulated
      vector repair and other DNA rearrangements. Mutant forms of these oligomers (eg
      CCCAACC or CCWACWS) did not. Our data suggest that the recombination events
      occurred within 48 h after transfection.

PMID- 10602378
TI  - C-terminal extension of the MHC class II-associated invariant chain by an
      antigenic sequence triggers activation of naive T cells.
AB  - In vitro and in vivo activation of T cells was investigated with invariant chain
      antigen fusion protein. The CD4 T cell epitope amino acid 52-61 of hen egg
      lysozyme (HEL) was attached to the C-terminal end of invariant chain (Ii).
      Expression of this recombinant Ii HEL directs the T cell epitope to the class II
      processing pathway. Class II molecules of transfected antigen presenting cells
      (APC) are charged with this HEL epitope. The endogenously provided epitope
      competes with processing and presentation of exogenously added antigen. APC
      expressing recombinant Ii HEL stimulate a maximal IL-2 response of HEL-specific T
      hybridoma cells. Nonprofessional APC expressing recombinant Ii HEL and H2-Ak are
      also able to activate naive T cells from 3A9 TCR transgenic mice, a result not
      achieved with peptide pulsed APC. To elicit an in vivo immune response dendritic
      cells (DC) were transfected with rIi HEL cDNA: following immunization of CBA mice
      with transfected DC, a primary T cell response against the HEL epitope was
      induced. Thus the procedure described here could be used to introduce antigens
      into the class II processing pathway and to elicit T cell activation both in
      vitro and in vivo.

PMID- 10602379
TI  - Taking lessons from dendritic cells: multiple xenogeneic ligands for leukocyte
      integrins have the potential to stimulate anti-tumor immunity.
AB  - Expression of large numbers of different costimulatory integrin ligands (CILs)
      attributes dendritic cells with an ability to induce primary anti-tumor immune
      responses. Here, we show that optimized gene transfer of the xenogeneic (human)
      CILs VCAM-1, MAdCAM-1 and ICAM-1 causes rapid and complete rejection of
      established mouse EL-4 tumors, and generates prolonged systemic anti-tumor
      immunity; whereas human E-cadherin weakly slows tumor growth. In each case the
      immune response was mediated by CD8+ T cells and NK cells, accompanied by
      augmented tumor-specific cytolytic T cell (CTL) activity involving both the
      perforin and Fas-ligand pathways. Adoptive transfer of splenocytes from cured
      mice rapidly cleared established tumors in recipients. The mechanism for CIL
      mediated immunity is unknown, but may involve CTL-facilitated tumor lysis, since
      CTLs were generally twice as efficient at killing CIL-transfected tumor cells
      than parental tumor cells. Optimized CIL-based gene therapy may provide an
      approach to complement or replace conventional DC adoptive cell therapy for
      suppressing tumor growth.

PMID- 10602380
TI  - Mechanism by which calcium phosphate coprecipitation enhances adenovirus-mediated
      gene transfer.
AB  - Delivery of a normal copy of CFTR cDNA to airway epithelia may provide a novel
      treatment for cystic fibrosis lung disease. Unfortunately, current vectors are
      inefficient because of limited binding to the apical surface of airway epithelia.
      We recently reported that incorporation of adenovirus in a calcium phosphate
      coprecipitate (Ad:CaPi) improves adenovirus-mediated gene transfer to airway
      epithelia in vitro and in vivo. To understand better how coprecipitation improves
      gene transfer, we tested the hypothesis that incorporation in a CaPi
      coprecipitate increases the binding of adenovirus to the apical surface of
      differentiated human airway epithelia. When a Cy3-labelled adenovirus was
      delivered in a coprecipitate, binding increased 54-fold as compared with
      adenovirus alone. Moreover, infection by Ad:CaPi was independent of fiber knob
      CAR and penton base-integrin interactions. After binding to the cell surface, the
      virus must enter the cell in order to infect. We hypothesized that Ad:CaPi may
      stimulate fluid phase endocytosis, thereby facilitating entry. However, we found
      that neither adenovirus nor Ad:CaPi coprecipitates altered fluid phase
      endocytosis. Nevertheless, Ad:CaPi preferentially infected cells showing
      endocytosis. Thus, CaPi coprecipitation improves adenovirus-mediated gene
      transfer by coating the epithelial surface with a layer of virus which enters
      cells during the normal process of endocytosis.

PMID- 10602381
TI  - BDNF gene transfer to the mammalian brain using CNS-derived neural precursors.
AB  - Neural stem cell lines represent a homogeneous source of cells for genetic,
      developmental, and gene transfer and repair studies in the nervous system. Since
      both gene transfer of neurotrophic factors and cell replacement strategies are of
      immediate interest for therapeutical purposes, we have generated BDNF-secreting
      neural stem cell lines and investigated to what extent different endogenous
      levels of BDNF expression affect in vitro survival, proliferation and
      differentiation of these cells. Also, we have investigated the in vivo effects of
      such BDNF gene transfer procedure in the rat neostriatum. Hippocampus- and
      cerebellum-derived cell lines reacted differently to manipulations aimed at
      varying their levels of BDNF production. Over-expression of BDNF enhanced
      survival of both cell types, in a serum-deprivation assay. Conversely, and ruling
      out unspecific effects, expression of an antisense version of BDNF resulted in
      compromised survival of cerebellum-derived cells, and in a lethal phenotype in
      hippocampal progenitors. These data indicate that endogenous BDNF level strongly
      influences the in vitro survival of these cells. These effects are more
      pronounced for hippocampus- than for cerebellum-derived progenitors. Hippocampus
      derived BDNF overproducers showed no major change in their capacity to
      differentiate towards a neuronal phenotype in vitro. In contrast, cerebellar
      progenitors overproducing BDNF did not differentiate into neurons, whereas cells
      expressing the antisense BDNF construct generated cells with morphological
      features of neurons and expressing immunological neuronal markers. Taken
      together, these results provide evidence that BDNF controls both the in vitro
      survival and differentiation of neural stem cells. After in vivo transplantation
      of BDNF-overproducing cells to the rat neostriatum, these survived better than
      the control ones, and induced the expected neurotrophic effects on cholinergic
      neurons. However, long-term (3 months) administration of BDNF resulted in
      detrimental effects, at this location. These findings may be of importance for
      the understanding of brain development, for the design of therapeutic neuro
      regenerative strategies, and for cell replacement and gene therapy studies.

PMID- 10602382
TI  - LPD lipopolyplex initiates a potent cytokine response and inhibits tumor growth.
AB  - Our laboratory has recently developed a lipopolyplex consisting of
      DOTAP:cholesterol liposomes, protamine sulfate, and plasmid DNA (LPD) that
      provides improved systemic gene delivery compared with lipoplex following tail
      vein injection in mice. Because endothelial cells are the primary cells
      transfected in the lung, it was hypothesized that LPD might be an effective
      vector for gene therapy of pulmonary metastases. This hypothesis was examined by
      testing the efficacy of cytokine (IL-12) and tumor suppressor (p53) strategies
      for treatment of an experimental model of pulmonary metastasis in C57Bl/6 mice.
      Surprisingly, all LPD complexes including those containing an 'empty' plasmid
      provided a potent (>50% inhibition) and dose-dependent antitumor effect, compared
      with dextrose-treated controls. In addition, i.v. injections of LPD containing
      'empty' plasmid also inhibited tumor growth in a subcutaneous model of C3
      fibrosarcomma. The antitumor effect correlated well with a strong and rapid
      proinflammatory cytokine (TNF-alpha, IL-12 and IFN-gamma) response. Naked plasmid
      DNA did not elicit a cytokine response and the response required assembly of DNA
      into a lipoplex or the LPD lipopolyplex. Except for the heart, elevated levels of
      cytokine were observed in all organs (lung, liver, kidney and spleen) where LPD
      is known to have gene transfer activity. Methylation of immune-stimulatory CpG
      motifs in the plasmid component of LPD inhibited the proinflammatory cytokine
      response as well as the antitumor effect of LPD in both tumor systems. This
      suggests that i. v. administration of LPD elicits a systemic proinflammatory
      cytokine response that mediates the antitumor activity of the lipopolyplex. In
      addition, the antitumor activity was not observed in SCID mice suggesting a
      possible role for B or T lymphocytes in the antitumor response initiated by LPD.
      This represents the first demonstration that an intravenously administered
      cationic liposome-based nonviral vector can promote a systemic, Th1-like innate
      immune response. The immune adjuvant properties of LPD might prove to be suitable
      for delivering tumor-specific antigens in the context of DNA vaccination.

PMID- 10602383
TI  - High efficiency in vitro gene transfer into vascular tissues using a pseudotyped
      retroviral vector without pseudotransduction.
AB  - Murine leukemia virus (MuLV)-derived retroviral vectors have had limited
      application in vascular gene therapy because of low transduction efficiency of
      vascular tissues, both in vitro and in vivo. In this study, we compared the gene
      transfer efficiency of two retroviral vectors: amphotropic MuLV and a MuLV vector
      pseudotyped with the vesicular stomatitis virus G glycoprotein (VSV-G) envelope.
      Target vascular tissues included human endothelial cells (EC), smooth muscle
      cells (SMC) and saphenous veins (SV). Transduction efficiency of human EC and SMC
      was significantly higher for VSV-G pseudotyped MuLV vector (90%) than for
      Amphotropic MuLV (20%). Luminal surface en face analysis of transduced cultured
      SV showed a six- to 10-fold greater transduction efficiency with VSV-G
      pseudotyped MuLV. The tissue plasminogen activator (tPA) gene was transduced into
      EC using each vector. Four days following transduction, a 12-fold higher tPA
      antigen concentration and a 38-fold higher tPA enzymatic activity was measured
      from cells transduced with the VSV-G pseudotyped vectors as compared with the
      amphotropic MuLV. There was no detectable pseudotransduction (protein transfer)
      associated with the VSV-G MuLV vector. Both AZT inhibition of reverse
      transcriptase and cell division arrest by gamma irradiation inhibited
      transduction, indicating that viral transduction correlated with RNA reverse
      transcription and cell proliferation. MuLV pseudotyped with the VSV-G envelope
      glycoprotein is an effective retroviral vector for vascular gene therapy.

PMID- 10602384
TI  - Efficient gene transfer and long-term expression in neurons using a recombinant
      adenovirus with a neuron-specific promoter.
AB  - Adenoviruses are highly efficient vectors for gene transfer into brain cells.
      Restricting transgene expression to specific cell types and maintaining long-term
      expression are major goals for gene therapy in the central nervous system. We
      targeted gene expression to neurons by constructing an adenoviral vector that
      expressed the E. coli LacZ reporter gene under the control of the rat neuron
      specific enolase promoter (Ad-NSE). Expression from Ad-NSE was compared with that
      from an adenoviral vector encoding the same reporter gene under the control of
      the Rous sarcoma virus LTR promoter (Ad-RSV). Both recombinant adenoviruses were
      injected stereotactically into rat hippocampus, cerebellum and striatum.
      Anatomical and immunohistochemical analyses of the Ad-NSE-stained cells showed
      that neurons were preferentially transduced. More neurons were stained in the
      hippocampus following infection with Ad-NSE than with Ad-RSV. Cytotoxicity from
      Ad-NSE was lower than from Ad-RSV. beta-Galactosidase gene expression after Ad
      NSE infection remained stable for 3(1/2) months, and was detectable for 6 months.
      Thus, the NSE-adenoviral vector can be used to transfer potentially therapeutic
      genes into neuronal cells. The use of a cell-specific promoter also resulted in
      high in vivo efficiency and long-term transgene expression.

PMID- 10602385
TI  - Retrovirus-mediated IL-4 gene therapy in spontaneous adenocarcinomas from MMTV
      neu transgenic mice.
AB  - Gene therapy approaches to the treatment of experimental cancer are usually based
      on established neoplastic cell lines which are manipulated in vitro and
      subsequently transplanted in host animals. However, the relevance of these
      artificial models to the biology and therapy of human tumors is uncertain. We
      have previously validated an experimental model based on MMTV-neu transgenic mice
      in which breast tumors arise spontaneously in 100% of animals and have many
      features in common with their human counterpart, including the involvement of the
      neu oncogene and the ability to metastatize. In this article we report the effect
      of intratumoral, retrovirus-mediated, IL-4 expression on the growth of breast
      tumors arising in these mice. The size of IL-4 inoculated tumors on the right
      side was significantly smaller than that of controlateral untreated tumors,
      suggesting a local effect of IL-4. In addition, the non-injected tumors on the
      left side of treated animals were significantly smaller than those arising in
      control transgenic mice, suggesting that IL-4 can also inhibit tumor growth
      systemically. These findings suggest that IL-4 gene transfer can significantly
      reduce the growth rate of spontaneously arising breast tumors and that immune
      based gene therapy could efficiently complement other approaches based on
      different mechanisms, such as suicide gene transfer or antisense technology.

PMID- 10602387
TI  - Anti-tumour activity against B16-F10 melanoma with a GM-CSF secreting allogeneic
      tumour cell vaccine

PMID- 10602386
TI  - Restoration of adrenal steroidogenesis by adenovirus-mediated transfer of human
      cytochromeP450 21-hydroxylase into the adrenal gland of21-hydroxylase-deficient
      mice.
AB  - 21-Hydroxylase deficiency, a potentially fatal disease due to deletions or
      mutations of the cytochrome P450 21-hydroxylase gene (CYP21), causes congenital
      adrenal hyperplasia (CAH) with low or absent glucocorticoid and mineralocorticoid
      production. The feasibility of gene therapy for CAH was studied using 21OH
      deficient mice (21OH-) and a replication-deficient adenovirus containing the
      genomic sequence of human CYP21 (hAdCYP21). Intra-adrenal injection of hAdCYP21
      in 21OH- mice induced hCYP21 mRNA with the highest expression from 2 to 7 days
      before a gradual decline. 21OH activity measured in adrenal tissue increased from
      undetectable to levels found in wild-type mice 2 to 7 days after AdhCYP21
      injection. Adrenal morphology of 21OH- mice showed lack of zonation, and
      hypertrophy and hyperplasia of adrenocortical mitochondria with few
      tubulovesicular christae. These morphological abnormalities were markedly
      improved 7 days after hAdCYP21 gene therapy. Plasma corticosterone increased from
      undetectable levels to values similar in wild-type mice by 7 and 14 days,
      declining over the next 40 days. This is the first demonstration that a single
      intra-adrenal injection of an adenoviral vector encoding CYP21 can compensate for
      the biochemical, endocrine and histological alterations in 21OH-deficient mice,
      and shows that gene therapy could be a feasible option for treatment of CAH.

PMID- 10602388
TI  - Fluoride-induced interleukin-6 and interleukin-8 synthesis in human epithelial
      lung cells.
AB  - Exposure to fluorides has been associated with asthmatic symptoms among workers
      in the aluminium industry. In a recent experimental study hydrogen fluoride (HF)
      was found to induce a weak inflammatory response in humans. In the present study
      the potential of sodium fluoride (NaF) and HF to induce cytokine response was
      examined and how these responses are modulated by Al3+ in a human epithelial lung
      cell line (A549). Dose-response experiments showed a maximal release of IL-6 and
      IL-8 at a concentration of 5 mM NaF 24 h after addition. The responses to HF were
      of a similar magnitude as for NaF. Time-course experiments showed a NaF-induced
      IL-6 response at 5 h, whereas an IL-8 response was observed after 10 h.
      Cycloheximide treatment completely abolished the NaF-induced cytokine responses.
      A marked increase in the mRNA level for IL-6 was observed already 2 h after
      exposure to 5 mM NaF, and presumably is a prerequisite for the subsequent
      increase of IL-6. The fluoride-induced effects on IL-6 and IL-8 release were
      strongly reduced by pretreatment with deferoxamine (an Al3+-chelator), and
      enhanced by addition of Al3+. This indicates that an AlF4-- complex, a known
      activator of GTP-binding proteins, is involved in fluoride-induced IL-6 and IL-8
      responses in A549 cells.

PMID- 10602389
TI  - Detoxification of organophosphates by A-esterases in human serum.
AB  - 1. In vitro detoxification of the organophosphate (OP) insecticides paraoxon,
      chlorpyrifos-oxon and malaoxon has been investigated in human serum. 2. Specific
      A-esterase activity to each OP substrate was measured in the serum of 100
      individuals using established spectrophotometric methods for paraoxonase and
      chlorpyrifos-oxonase and a novel assay for malaoxonase activity. 3. Dose-effect
      inhibition of serum cholinesterase by the three OPs was measured in pooled human
      serum. Inhibition of calcium dependent A-esterases by addition of EDTA resulted
      in increased inhibition of cholinesterase at a given OP concentration. 4. Data
      from both the direct spectrophotometric measurement of A-esterase activity and
      inhibition of serum cholinesterase in the presence and absence of A-esterase
      activity indicated that human serum A-esterase catalysed detoxification of
      chlorpyrifos-oxon> paraoxon> malaoxon. Our data also confirms the wide variation
      in potency to inhibit cholinesterase between the three OPs. 5. Malaoxonase
      activity in human serum does not appear to be polymorphic, however, there is
      large inter-individual variation as has been previously found for other A
      esterases. 6. This study has demonstrated two approaches to investigate the inter
      individual variation towards specific OPs and the relative ability of human serum
      A-esterase to detoxify specific OP compounds.

PMID- 10602390
TI  - The effect of perfluoroisobutene and phosgene on rat lavage fluid surfactant
      phospholipids.
AB  - 1. This study investigated whether the reactive organohalogen gases
      perfluoroisobutene (PFIB) and phosgene, which cause death by overwhelming
      pulmonary oedema, affect the surfactant system or type II pneumocytes of rat
      lung. 2. The progression and type of pulmonary injury in Porton Wistar-derived
      rats was monitored over a 48 h period following exposure to either PFIB or
      phosgene (LCt30) by analyzing the inflammatory cells and protein in
      bronchoalveolar lavage fluid. Six rat lung phospholipids were measured by high
      performance liquid chromatography, following solid phase extraction from lavage
      fluid. 3. Alterations in the cell population and lung permeability occurred
      following both gases, indicating that the injury was a permeability-type
      pulmonary oedema. Changes in the total amount of phospholipid and in the
      percentage composition of the surfactant were different for the two gases. PFIB
      produced increases in phosphatidylglycerol and phosphatidylcholine over the first
      hour, similar to that seen following air exposure, followed by substantial
      decreases in these phospholipids. Phosgene caused late increases in all
      phospholipids from 6 h post-exposure. 4. Differences in the response of the
      surfactant system to exposure to PFIB and phosgene suggest different mechanisms
      of action at the alveolar surface although the final injurious response is
      pulmonary oedema for both gases.

PMID- 10602391
TI  - Serum cytotoxin and oxidant stress markers in N-acetylcysteine treated
      thioacetamide hepatotoxicity of rats.
AB  - N-acetylcysteine (NAC) is a glutathione precursor used to treat several clinical
      conditions where intracellular oxidant-antioxidant balance is disturbed, among
      which, acetaminophen induced hepatotoxicity may be counted. In this study,
      administering thioacetamide (TAA) as a hepatotoxic agent, a rat model of
      hepatotoxicity has been established, to investigate some of the immune mediated
      basic oxidant-antioxidant homeostatic mechanisms involved, and potential serum
      markers for follow-up of disease and treatment. To do this, four experimental
      groups receiving saline/saline, saline/NAC, saline/TAA and NAC/TAA as
      intraperitoneal injections, have been formed. Rat serum tumor necrosis factor
      alpha (TNF-alpha), Interleukin1-beta (IL1-beta), malondialdehyde (MDA) as a
      measure of final oxidant damage and the antioxidant enzymes superoxide dismutase
      (SOD) and glutathione peroxidase (GSH-Px) have been assayed. Hepatocellular
      damage has been measured via the biochemical estimates ALT, AST and LDH as well
      as histopathological grading. It was found that both TNF-alpha and IL1-beta were
      significantly elevated in saline/TAA receivers (P<0.01) when compared to NAC/TAA
      receivers. Serum MDA was also increased in TAA receivers in addition to SOD
      (P<0.05) and GSH-Px (P<0.05). Serum nitrite levels have also been assayed to give
      an estimate of nitric oxide that is suggested as a counter-balancer of oxidant
      stress. NAC/saline receivers had the highest levels of nitrites in the serum
      (P<0.05). Our results indicate that part of the hepatocellular injury to rat
      liver, induced by TAA is mediated by oxidative stress caused by the action of
      cytokines imparted by the enzymatic SOD and GSH-Px and non-enzymatic gaseous
      nitric oxide mechanisms causing an alleviation on administration of NAC. In
      addition, TNF-alpha, IL1-beta, MDA, SOD, GSH-Px and nitrites are potential
      candidates of serum indicators for monitorization of pathophysiological stage of
      liver disease.

PMID- 10602392
TI  - Identification of acrolein from the ozone oxidation of unsaturated fatty acids.
AB  - By-products of lipoperoxidation reactions may be associated with the genesis or
      the progression of several diseases as arteriosclerosis, diabetes and cancer,
      among many others. Acrolein, at first a widely distributed environmental
      pollutant, is currently known as a compound capable of being generated as a
      result of metabolic reactions within biological systems, highly toxic and the
      most electrophilic of the alpha, beta-unsaturated aldehydes formed during
      lipoperoxidation. In the present study: 1. The separation of acrolein and
      malondialdehyde was achieved at alkaline pH with the use of high voltage
      capillary electrophoresis in uncoated fused-silica capillaries. 2. It was
      demonstrated how the oxidation of fatty acids (arachidonic/linoleic) with ozone
      generates, in dose-dependent form, acrolein as one of the by-products of the
      lipoperoxidation process. The oxidation of open human erythrocyte membranes with
      ozone also generated acrolein. 3. After aldolic condensation, aldol-acrolein
      derivative has a positive reaction with 2-thiobarbituric acid (TBA) and shows a
      maximum absorption at 498 nm. This novel characteristic is used in its
      identification after the separation of the by-products. 4. It is possible to
      suggest that in the classic reaction of the denominated thiobarbituric acid
      reactive substances (TBARS), when used as an indicator of the degree of
      peroxidation in biological systems, a portion of acrolein could be present but
      dwarfed by the TBA-MDA adduct.

PMID- 10602393
TI  - Male reproductive toxicity and beta-luteinizing hormone gene expression in
      sexually mature and immature rats exposed to 2-bromopropane.
AB  - 1. The reproductive effects of 2-bromopropane (2-BP) in sexually mature and
      immature male Sprague-Dawley rats were investigated. The animals were randomly
      divided into three treatment groups and one control group each of which comprised
      six mature and six immature rats. The treated groups were injected s.c. 200, 600
      and 1800 mg/kg of 2-BP on 5 days a week for 5 - 7 weeks and the control group
      received the vehicle. 2. The absolute and relative testis weights were
      significantly reduced in 600 and 1800 mg/kg b.w. dose groups in both mature and
      immature rats. The absolute epididymis, prostate, seminal vesicle, and pituitary
      weights and the relative epididymis weights, however, were significant only at
      the highest dose level used in both mature and immature rats. 3. The sperm
      concentration and sperm viability in epididymal duct decreased and the percentage
      of abnormal sperm increased in a dose-dependent manner in both mature and
      immature rats. Additionally, serum testosterone level was significantly decreased
      in all dose groups in mature rats, and was significantly reduced only in the
      group treated with the middle and highest dose in immature rats. 4. In both
      mature and immature rats treated with 200 and 600 mg/kg, the seminiferous tubules
      were atrophied and all types of germ cells were decreased in number. At the
      highest dose level, the effect was more marked showing severely atrophied
      seminiferous tubules and a complete loss of all types of germ cells. 5. The
      mating, pregnancy and fertility indices were significantly reduced in the 600 and
      1800 mg/kg groups. Additionally, at the highest dose group the number of
      implantations and viable fetuses per litter were reduced and the resorption rate
      was increased significantly. 6. In the mature rats, the beta-LH gene expression
      increased significantly in the 1800 mg/kg group when compared to the control
      group. 7. It can be concluded that 2-BP induces alterations in both neuro
      endocrine axis and the reproductive tract under the present experimental
      conditions. The no observed adverse effect level (NOAEL) in this study could be
      estimated to be lower than 200 mg/kg/b.w. based on the alteration in testicular
      morphology as well as on sperm parameters observed at the dose level of 200
      mg/kg.

PMID- 10602394
TI  - Ellagic acid ameliorates nickel induced biochemical alterations: diminution of
      oxidative stress.
AB  - Nickel, a major environmental pollutant is known for its clastogenic, toxic and
      carcinogenic potentials. The present investigation shows that ellagic acid proves
      to be exceptional in the amelioration of the nickel-induced biochemical
      alterations in serum, liver and kidney. Administration of nickel (250 micromol
      Ni/kg body wt) to female Wistar rats, resulted in increase in the reduced
      glutathione (GSH) content [kidney (*P<0.05) and liver (**P<0.001)] and
      Glutathione-S-transferase (GST) and glutathione reductase (GR) activities [kidney
      and liver, (**P<0.001)]. Ellagic acid treatment to the intoxicated rats leads to
      the formation of soluble ellagic acid-metal complex which facilitates excretion
      of nickel from the cell or tissue, thus ameliorating nickel-induced toxicity, as
      evident from the down regulation of GSH content, GST and GR activities with
      concomitant restoration of glutathione peroxidase (GPx) activity in liver and
      kidney. Our data shows that ellagic acid maintains cell membrane integrity
      through sequestration of metal ions from the extracellular fluid, as evident from
      the alleviated levels of serum glutamate oxaloacetate transaminase, (SGOT), serum
      glutamate pyruvate transaminase (SGPT) and lactate dehydrogenase (LDH) when
      compared to nickel treated group. Similarly, the enhanced blood urea nitrogen
      (BUN) and serum creatinine levels that are indicative of renal injury showed a
      reduction of about 45 and 40%, respectively. The data also show that treatment of
      ellagic acid after 30 min of nickel administration exhibits maximum inhibition in
      a dose-dependent manner. In summary, our data suggests that ellagic acid act as
      an effective chelating agent in suppressing nickel-induced renal and hepatic
      biochemical alterations.

PMID- 10602395
TI  - Species differences in arsenic-mediated renal copper accumulation: a comparison
      between rats, mice and guinea pigs.
AB  - 1. Administration of arsenite leads to an accumulation of copper in the rat
      kidney. Owing to the high retention of arsenic in the erythrocytes, however, the
      rat is considered to possess special toxicokinetics of arsenic and is therefore
      considered less comparable with other species in this respect. 2. Therefore, we
      compared the effect of dietary arsenite in mice and guinea pigs with that in
      rats. Each species was divided into four groups of animals according to the diets
      fed which contained increasing concentrations of sodium arsenite (NaAsO2; 0, 10,
      30 and 60 mg As/kg of diet). Animals were killed after 1, 2 and 3 weeks. Tissues
      were sampled and analyzed for arsenic and other trace metals (Cu, Fe, Zn and Mn).
      3. Compared to controls with copper levels of about 10 microg Cu/g wet wt. in the
      renal cortex, dietary administration of arsenite up to 60 mg As/kg of diet for 3
      weeks to rats increased cortical levels to 65 microg Cu/g wet wt. An increase of
      renal copper levels similar to that in rats, was only observed in guinea pigs but
      not in mice. Renal copper accumulation in guinea pigs was time- and concentration
      dependent as in rats. Feeding a diet with 60 mg As/kg for 3 weeks increased
      cortical copper levels from about 6 - 40 microg Cu/g wet wt. Renal copper levels
      in mice as well as other trace metal levels in guinea pigs and mice were not
      essentially altered by dietary arsenite. 4. The study shows that the renal copper
      arsenic interaction is not restricted to the rat. Since in rats and guinea pigs,
      but not in mice, arsenic accumulated in the kidney rather similarly, a common
      mechanism is suggestive. As it was previously shown in rats that only inorganic
      arsenic is involved in this interaction, a rapid conversion of the inorganic form
      into methylated metabolites as in mice may diminish the extent of the renal
      copper accumulation whereas the lack of, or a less efficient, methylation as in
      guinea pigs or rats increases it.

PMID- 10602396
TI  - Physiology and pathology of the blood-brain barrier: implications for microbial
      pathogenesis, drug delivery and neurodegenerative disorders.
AB  - The blood-brain barrier (BBB) regulates the passage of solutes between the CNS
      and the blood. The BBB not only restricts the entry of serum proteins into the
      CNS, but it also controls the passage of nutrients, electrolytes, vitamins,
      minerals, free fatty acids, peptides, and regulatory proteins in both the brain
      to blood and blood to brain direction. The BBB performs these functions through a
      number of saturable and non-saturable mechanisms. For example, efflux (CNS to
      blood) mechanisms regulate the levels of nutrients and minerals in the CSF,
      detoxify the CNS, reinforce the impermeability of the BBB against circulating
      toxins and many drugs, secrete CNS-originating substances into the blood, and
      drain substances directly into the cervical lymphatic nodes. Influx mechanisms
      control the homeostatic environment of the CNS, supply the brain with nutrients,
      and help to integrate CNS and peripheral functions. These mechanisms are altered
      in and can be the basis for disease and many of these systems are altered in
      neuroAIDS. We review here examples of several diseases in which the functions of
      the BBB are altered, and some conditions, such as alcoholism, multiple sclerosis,
      obesity, and a subtype of mental retardation, where those altered functions may
      underlie the pathophysiology. Finally, we consider some of the ways in which
      these aspects of the BBB could be active in neuroAIDS, including the efflux of
      anti-virals, the transport of virus by adsorptive endocytosis, egress routes for
      HIV-1 via brain lymphatics, and the release of neurotoxins from brain endothelial
      cells.

PMID- 10602397
TI  - Blood-brain barrier biology and methodology.
AB  - The blood-brain barrier (BBB) is formed by epithelial-like high resistance tight
      junctions within the endothelium of capillaries perfusing the vertebrate brain.
      Because of the presence of the BBB, circulating molecules gain access to brain
      cells only via one of two processes: (i) lipid-mediated transport of small
      molecules through the BBB by free diffusion, or (ii) catalyzed transport. The
      latter includes carrier-mediated transport processes for low molecular weight
      nutrients and water soluble vitamins or receptor-mediated transport for
      circulating peptides (e.g., insulin), plasma proteins (e.g., transferrin), or
      viruses. While BBB permeability, per se, is controlled by the biochemical
      properties of the plasma membranes of the capillary endothelial cells, overall
      brain microvascular biology is a function of the paracrine interactions between
      the capillary endothelium and the other two major cells comprising the
      microcirculation of brain, i.e., the capillary pericyte, which shares the
      basement membrane with the endothelial cell, and the astrocyte foot process,
      which invests 99% of the abluminal surface of the capillary basement membrane in
      brain. Microvascular functions frequently ascribed to the capillary endothelium
      are actually executed by either the capillary pericyte or the capillary astrocyte
      foot process. With respect to BBB methodology, there are a variety of in vivo
      methods for studying biological transport across this important membrane. The
      classical physiologic techniques may now be correlated with modern biochemical
      and molecular biological approaches using freshly isolated animal or human brain
      capillaries. Isolated brain capillary endothelial cells can also be grown in
      tissue culture to form an 'in vitro BBB' model. However, BBB research cannot be
      performed using only the in vitro BBB model, but rather it is necessary to
      correlate observations made with the in vitro BBB model with in vivo studies.

PMID- 10602398
TI  - Immunobiology of the blood-brain barrier.
AB  - The brain microvessel endothelial cells (BMVEC) that form the blood-brain barrier
      are uniquely positioned to influence immune responses within the central nervous
      system. As the biological interface separating the blood from the brain
      extracellular fluid, BMVEC regulate the entry of leukocytes into the brain. In
      addition, through the release of various soluble factors that affect immune
      responses, BMVEC may modulate immune responses in the brain. This review
      addresses the interplay between the immune system and the blood-brain barrier as
      it relates to the regulation of CNS defense and immunity.

PMID- 10602399
TI  - Model systems for studies of leukocyte migration across the blood - brain
      barrier.
AB  - The blood - brain barrier (BBB) plays a crucial role in central nervous system
      (CNS) homeostasis. Serving as the brain's protective shield it regulates soluble
      factor and cellular exchanges from blood to brain. Critical to its function, the
      BBB is composed of brain microvascular endothelial cells (BMVEC), a collagen
      matrix, and astrocytes. Astrocytic endfeet surround the BMVEC abluminal surface
      and influence the 'tightness' and trafficking role of the barrier. In
      neurodegenerative disorders (for example stroke, multiple sclerosis and HIV
      encephalitis) the BBB becomes compromised. This is, in part, immune mediated. An
      accumulating body of evidence demonstrates that the cellular components of the
      BBB are themselves immunocompetent. Perivascular cells (astrocytes, macrophages
      and microglial cells) and BMVEC produce inflammatory factors that affect BBB
      permeability and expression of adhesion molecules. These affect cell trafficking
      into the CNS. Leukocyte BBB migration can be influenced by cytokines and
      chemokines produced by glia. Astrocytes and macrophages secrete a multitude of
      factors that affect brain immune responses. Interactions between BMVEC,
      leukocytes and/or glia, immunological activation and noxious (infectious, toxic
      and immune-mediated) brain insults all appear to play important roles in this BBB
      cell trafficking. New information gained into the mechanisms of leukocyte-brain
      penetration may provide novel insights in the pathogenesis and treatment
      strategies of neurodegenerative disorders.

PMID- 10602400
TI  - Molecular and cellular mechanisms for microbial entry into the CNS.
AB  - A number of pathogenic microbes including neuroinvasive viruses, bacteria and
      parasites are capable of entry into the central nervous system (CNS) and cause a
      variety of clinical manifestations. The cellular and molecular mechanisms for the
      CNS invasion have been extensively studied in the last two decades. Viruses
      invade neurons and thereby cause encephalitis or peripheral neuritis, while
      bacteria enter the cerebrospinal fluid (CSF) and cause meningitis. In contrast,
      the mechanisms for parasitic neuroinvasion are much more complex and less clear.
      The capabilities that enable these elite subsets of pathogens to engineer uptake
      into the CNS will be the subject of this review.

PMID- 10602401
TI  - Bornavirus immunopathogenesis in rodents: models for human neurological diseases.
AB  - Although the question of human BDV infection remains to be resolved, burgeoning
      interest in this unique pathogen has provided tools for exploring the
      pharmacology and neurochemistry of neuropsychiatric disorders potentially linked
      to BDV infection. Two animal models have been established based on BDV infection
      of adult or neonatal Lewis rats. Analysis of these models is already yielding
      insights into mechanisms by which neurotropic agents and/or immune factors may
      impact developing or mature CNS circuitry to effect complex disturbances in
      movement and behavior.

PMID- 10602402
TI  - Measles virus in the CNS: the role of viral and host factors for the
      establishment and maintenance of a persistent infection.

PMID- 10602403
TI  - Sentries at the gate: chemokines and the blood-brain barrier.

PMID- 10602404
TI  - Central nervous system chemokine expression during Theiler's virus-induced
      demyelinating disease.
AB  - Theiler's murine encephalomyelitis virus is an endemic murine pathogen that
      induces a demyelinating disease of the central nervous system in susceptible
      mouse strains. The disease is characterized by central nervous system mononuclear
      cell infiltration and presents as chronic, progressive paralysis. The expression
      of CC and C-x-C chemokines in the central nervous system of Theiler's murine
      encephalomyelitis virus-infected mice was examined throughout the disease course
      by ELISA and RT - PCR analysis. Central nervous system expression of MCP-1 and
      MIP-1alpha protein was evident by day 11 post Theiler's murine encephalomyelitis
      virus infection of SJL mice and continued throughout disease progression. MIP
      1alpha, RANTES, MCP-1, C10, IP-10, and MIP-1beta mRNA was specifically expressed
      in the central nervous system and not the periphery following Theiler's murine
      encephalomyelitis virus infection. This was associated with development of
      clinical disease. These data suggest that the expression of multiple chemokines
      at particular times following viral infection is associated with demyelinating
      disease.

PMID- 10602405
TI  - Chemokine receptors and virus entry in the central nervous system.
AB  - Several members of the chemokine receptor family are used as coreceptors together
      with CD4 for HIV and SIV entry in the central nervous system (CNS). CCR5 is the
      major coreceptor for HIV-1 infection of macrophages and microglia, the major
      target cells for HIV-1 infection in the CNS. CXCR4 and CCR3 are also expressed on
      microglia and can mediate infection by certain HIV-1 isolates but at lower
      efficiency than CCR5. Additional chemokine receptors that can function as HIV-1
      and SIV coreceptors for a subset of viruses are expressed in the brain (i.e. Apj,
      CX3CR1, STRL33/BONZO, and gpr1), but their role in CNS infection has not been
      defined. The expression of CXCR4, and possibly other chemokine receptors, on
      subpopulations of neurons and glial cells may contribute to mechanisms of CNS
      injury that are independent of viral infection. Understanding the role of
      chemokine receptors and their chemokine ligands in HIV-1 and SIV infection of the
      CNS will elucidate mechanisms of viral tropism and pathogenesis and advance the
      development of new therapeutic strategies.

PMID- 10602406
TI  - Interactions between macrophages and brain microvascular endothelial cells: role
      in pathogenesis of HIV-1 infection and blood - brain barrier function.
AB  - Monocytes have been shown to infiltrate in brain tissue during various
      neurological disorders including AIDS dementia complex. The presence of an excess
      of activated macrophages in brain tissue is accompanied by tissue damage
      resulting in a loss in neuronal function and viability. Therapeutic options
      against such neurological disorders could therefore be aimed at the prevention of
      monocyte infiltration across the blood - brain barrier. Therefore, a better
      understanding of these processes is needed. Recent insights in cellular processes
      between monocytes/macrophages and brain microvascular endothelial cells in the
      neuropathogenesis of HIV-1 infection demonstrate that monocytes roll on
      endothelial cells via the inducible endothelial adhesion molecule E-selectin.
      Binding of these cells are mainly mediated via the endothelial adhesion molecule
      vascular cell adhesion molecule-1. The transmigration through the blood - brain
      barrier is facilitated by both endothelial and monocyte/macrophage-derived nitric
      oxide and by the increased production of gelatinase B activity by HIV-infected
      monocytes/macrophages. Chemokines produced within the brain regulate the traffic
      of the infiltrating monocytes through the brain parenchyma. In addition,
      endothelial cells also produce monocyte attracting chemokines during their first
      interactions with HIV-infected monocytes/macrophages thus promoting additional
      influx of phagocytes into the brain. Furthermore, excessive infiltration of
      monocytes is accompanied by endothelial damage resulting in the loss of tight
      junctions. Thus, in toto, brain microvascular endothelial cells might contribute
      to the neuropathogenesis of HIV-1 infection.

PMID- 10602407
TI  - HIV infection of choroid plexus in AIDS and asymptomatic HIV-infected patients
      suggests that the choroid plexus may be a reservoir of productive infection.
AB  - The choroid plexus (CPx) may be an important site of viral dissemination since
      monocytes and dendritic cells in its stroma are infected with HIV in AIDS
      patients and since the ratio of CPx to brain infection is more than 2 : 1. In
      order to see if CPx infection also develops in asymptomatic (ASY) HIV-infected
      patients, we examined archival formalin-fixed brain and CPx from 14 AIDS and
      seven ASY cases, using routine histology, immunohistochemistry for HIV gp41, and
      DNA extraction and gene amplification for HIV DNA. Eight of 14 AIDS (57%) had HIV
      positive cells in the CPx and four (29%) had HIV encephalitis. Two of seven ASY
      cases (29%) had HIV-positive cells in the CPx but none had HIV encephalitis.
      Extracted DNA from brain, CPx and systemic organs of five ASY cases was amplified
      by nested PCR with or without Southern blotting for HIV env gene. It was positive
      in systemic organs in five cases; in CPx in four cases; and in brain in one case.
      This study shows that the CPx is a site of HIV infection in ASY patients and that
      the frequency of CPx infection is higher than seen in brain in both AIDS and ASY
      cases. The results are consistent with the hypothesis that the CPx may be a site
      for hematogeneous spread and a reservoir for HIV infection during the period of
      clinical latency.

PMID- 10602408
TI  - Human immunodeficiency virus type 1 TAT protein induces adhesion molecule
      expression in astrocytes.
AB  - AIDS encephalitis is a frequent consequence of CNS HIV infection, especially in
      children. One of its many characteristics is a leukocyte infiltrate that is
      believed to contribute to the production of cytokines, chemokines and neurotoxic
      factors resulting in CNS damage. Entry of such leukocytes into the CNS is
      mediated in part by the expression of adhesion molecules by blood - brain barrier
      (BBB) endothelial cells. Expression of these proteins by astrocytes, the other
      main component of the BBB, also serves to target leukocytes to the CNS
      parenchyma. We now demonstrate that HIV-1-derived Tat, a soluble protein secreted
      by infected cells, induced astrocyte VCAM-1 and ICAM-1 expression in a dose- and
      time-dependent manner. The functional role of Tat in monocyte binding in vitro
      was also demonstrated. These data suggest that the presence of extracellular Tat
      may be a significant factor in the trafficking of HIV-infected and inflammatory
      cells into the CNS via its effect on adhesion molecule expression by astrocytes.

PMID- 10602409
TI  - Role of HIV-1 Tat and CC chemokine MIP-1alpha in the pathogenesis of HIV
      associated central nervous system disorders.
AB  - Two syndromes affecting cognitive and motor function in the setting of AIDS have
      been described as HIV encephalopathy (HIVE) and progressive multifocal
      leukoencephalopathy (PML). HIVE is characterized by the presence of microglial
      nodules with accompanying astrocytosis. PML is a fatal demyelinating disease of
      the white matter induced by the human papovavirus JCV which causes cytolytic
      destruction of glial cells. In addition to the effect of HIV-1 induced immune
      suppression, HIV may act directly as a co-factor for stimulation of JCV
      replication in AIDS patients, in part due to Tat-induced activation of JCV gene
      transcription. Since Tat has been implicated in CNS pathogenesis, we examined its
      localization in CNS specimens from HIV infected patients with HIVE and PML as
      well as controls. Based on the observation of CC chemokine induction in monocytes
      by Tat, we also examined the cellular localization of the CC chemokine Macrophage
      Inflammatory Protein-1alpha (MIP-1alpha) and its cognate receptor CCR-5 in these
      samples. In HIVE, Tat was primarily localized in astrocytes and microglia, within
      the nodular lesions. In PML, a marked increase in the number of Tat positive
      astrocytes was observed. In both HIVE and PML, prominent expression of MIP-1alpha
      and CCR-5 was found within areas containing histopathological lesions. CCR-5
      positivity of microglia was localized primarily to nodular lesions in HIVE. In
      PML, increased numbers of cells with monocyte/microglial morphology were observed
      relative to HIVE. The increased MIP-1 alpha positivity, and potentially other
      chemokines, may contribute to the pathogenesis of PML in the setting of HIV
      infection. Tat may play an important role in the pathogenesis of both HIV
      associated CNS disease states, acting indirectly through cytokine and chemokine
      dysregulation.

PMID- 10602410
TI  - Alterations in blood-brain barrier glucose transport in SIV-infected macaques.
AB  - The neurological manifestations of HIV infection may be in part due to
      alterations in the blood-brain barrier. These may be caused by structural changes
      in the barrier or may consist of subtle metabolic or biochemical disturbances in
      barrier function. In the CNS, the family of glucose transporter proteins plays a
      key role in controlling movement of glucose across cell membranes. The 55 kDa
      isoform of glucose transporter 1 (GLUT1) regulates import of glucose from blood
      to brain across the endothelial cells of the blood-brain barrier (BBB), whereas
      the 45 kDa form of GLUT1 predominantly regulates nonvascular glial glucose
      uptake. In this study, expression of 55 and 45 kDa forms of GLUT1 in different
      regions of the brain from 18 SIV-infected macaques was measured by quantitative
      immunoblot and then compared with the severity of SIV encephalitis to determine
      whether neurologic disease is related to altered glucose metabolism at the BBB
      and in brain parenchyma. An inverse relationship was found between severity of
      SIV encephalitis and expression of the endothelial 55 kDa isoform of GLUT1 at the
      BBB in cortical grey matter, caudate nucleus, and cerebellum. A similar
      relationship also was found for the glial 45 kDa GLUT1 isoform in cortical grey
      matter. In addition, a significant increase in 55 kDa GLUT1 expression was found
      in caudate nucleus during the early stages of infection. In the brains of
      macaques with moderate to severe encephalitis, 55 kDa GLUT1 expression had
      declined to pre-infection levels. These GLUT1 alterations at the BBB and in glial
      cells may reflect severe disturbances in the CNS microenvironment that contribute
      to CNS dysfunction.

PMID- 10602411
TI  - Standardized RT-PCR analysis of fusion gene transcripts from chromosome
      aberrations in acute leukemia for detection of minimal residual disease. Report
      of the BIOMED-1 Concerted Action: investigation of minimal residual disease in
      acute leukemia.
AB  - Prospective studies on the detection of minimal residual disease (MRD) in acute
      leukemia patients have shown that large-scale MRD studies are feasible and that
      clinically relevant MRD-based risk group classification can be achieved and can
      now be used for designing new treatment protocols. However, multicenter
      international treatment protocols with MRD-based stratification of treatment need
      careful standardization and quality control of the MRD techniques. This was the
      aim of the European BIOMED-1 Concerted Action 'Investigation of minimal residual
      disease in acute leukemia: international standardization and clinical evaluation'
      with participants of 14 laboratories in eight European countries (ES, NL, PT, IT,
      DE, FR, SE and AT). Standardization and quality control was performed for the
      three main types of MRD techniques, ie flow cytometric immunophenotyping, PCR
      analysis of antigen receptor genes, and RT-PCR analysis of well-defined
      chromosomal aberrations. This study focussed on the latter MRD technique. A total
      of nine well-defined chromosome aberrations with fusion gene transcripts were
      selected: t(1;19) with E2A-PBX1, t(4;11) with MLL-AF4, t(8;21) with AML1-ETO,
      t(9;22) with BCR-ABL p190 and BCR-ABL p210, t(12;21) with TEL-AML1, t(15;17) with
      PML-RARA, inv (16) with CBFB-MYH11, and microdeletion 1p32 with SIL-TAL1. PCR
      primers were designed according to predefined criteria for single PCR (external
      primers A <--> B) and nested PCR (internal primers C <--> D) as well as for
      'shifted' PCR with a primer upstream (E5' primer) or downstream (E3' primer) of
      the external A <--> B primers. The 'shifted' E primers were designed for
      performing an independent PCR together with one of the internal primers for
      confirmation (or exclusion) of positive results. Various local RT and PCR
      protocols were compared and subsequently a common protocol was designed, tested
      and adapted, resulting in a standardized RT-PCR protocol. After initial testing
      (with adaptations whenever necessary) and approval by two or three laboratories,
      the primers were tested by all participating laboratories, using 17 cell lines
      and patient samples as positive controls. This testing included comparison with
      local protocols and primers as well as sensitivity testing via dilution
      experiments. The collaborative efforts resulted in standardized primer sets with
      a minimal target sensitivity of 10-2 for virtually all single PCR analyses,
      whereas the nested PCR analyses generally reached the minimal target sensitivity
      of 10-4. The standardized RT-PCR protocol and primer sets can now be used for
      molecular classification of acute leukemia at diagnosis and for MRD detection
      during follow-up to evaluate treatment effectiveness.

PMID- 10602412
TI  - Autologous stem cell transplantation for AL amyloidosis: a standard therapy?
AB  - Autologous stem cell transplantation (ASCT) is a new treatment option in patients
      with systemic AL amyloidosis (AL). The purpose of this review is to summarize the
      clinical experience of ASCT for AL, and to discuss the feasibility and the future
      developments of this new approach.

PMID- 10602413
TI  - Leukemogenesis by CBF oncoproteins.
AB  - The AML1 and CBFbeta subunits of core binding factor (CBF) are involved in
      several chromosomal abnormalities frequently associated with acute leukemias. As
      a result, the CBFbeta-SMMHC, AML1-ETO and AML1-MDS1/EVI1 fusion proteins are
      expressed in subsets of acute myeloid leukemia, and TEL-AML1 is expressed in B
      lineage acute lymphocytic leukemia. These CBF oncoproteins likely contribute to
      leukemogenesis in part by inhibiting endogenous CBF. As a result they are
      expected to inhibit differentiation and perhaps apoptosis. In addition, the
      domains unique to each fusion protein may also contribute to leukemogenesis via
      unique mechanisms.

PMID- 10602414
TI  - Clinical significance of CD95, Bcl-2 and Bax expression and CD95 function in
      adult de novo acute myeloid leukemia in context of P-glycoprotein function,
      maturation stage, and cytogenetics.
AB  - Resistance to chemotherapy-induced apoptosis and a multidrug-resistance (MDR)
      phenotype, mainly mediated by P-glycoprotein (P-gp), contribute to chemotherapy
      failure in hematologic malignancies. To study apoptosis-regulating factors in
      acute myeloid leukemia (AML), we investigated cell samples of adults with de novo
      AML by flow cytometry for constitutive expression levels of the apoptosis-related
      molecules CD95 (n = 135), Bcl-2 (n = 131), and Bax (n = 66), as well as
      spontaneous apoptosis in vitro (n = 104) and susceptibility to anti-CD95-induced
      apoptosis (CD95 sensitivity) (n = 93). We correlated these findings with P-gp
      function as detected by the rhodamine123-efflux test (n = 121), immunophenotype,
      FAB morphology, cytogenetics, and clinical data of the examined patients.
      Immature FAB M0/1 AML cells expressed significantly more Bcl-2 (P < 0.0002) and
      less CD95 (P < 0.0003) compared with AML cells of the more mature FAB M2-5
      subtypes. No maturation-dependent difference in Bax expression was observed. FAB
      M2-5 AML cells were more susceptible to anti-CD95-induced apoptosis (P < 0.008)
      and showed a lower P-gp function (P < 0.002) than FAB M0/1 AML cells. Leukemic
      cells of AML patients who achieved a complete remission (CR) after induction
      chemotherapy expressed less Bcl-2 than non-responder (NR) (69 CR, 23 NR; P =
      0.05). CR was associated with a higher extent of spontaneous apoptosis in vitro
      (58 CR, 17 NR; P=0.05) and a tendency towards a higher CD95 expression (73 CR, 23
      NR; P = 0.08) compared to NR. CR also correlated with a low P-gp function (70 CR,
      21 NR; P = 0.008) and a tendency towards CD34 negativity (73 CR, 23 NR; P =
      0.08). No correlation between Bax expression and response to induction
      chemotherapy (49 CR, 12 NR) was observed. In stepwise logistic regression
      analyses, P-gp function and the extent of spontaneous apoptosis in vitro as well
      as CD95 sensitivity but not Bcl-2, CD95, Bax, and CD34 expression levels emerged
      as significant markers for response to induction chemotherapy. We conclude that
      the constitutive expression of CD95 and Bcl-2, as well as CD95 sensitivity and P
      gp function but not constitutive Bax expression depend on the maturation stage of
      leukemic cells in adult de novo AML. P-gp function, the extent of spontaneous
      apoptosis in vitro and CD95 sensitivity are more predictive for response to
      induction chemotherapy in adult de novoAML than the constitutive expression
      levels of the apoptosis-related molecules CD95, Bcl-2 and Bax.

PMID- 10602415
TI  - Overexpression of the chemokine receptor CXCR4 in B cell chronic lymphocytic
      leukemia is associated with increased functional response to stromal cell-derived
      factor-1 (SDF-1).
AB  - The chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1 (SDF-1)
      play an important role in trafficking of normal lymphocytes, monocytes, as well
      as hematopoietic stem- and progenitor cells. SDF-1 constitutively produced by
      bone marrow stromal cells acts as a chemoattractant supporting the homing of stem
      cells and may also contribute to the tropism of malignant cells for the bone
      marrow. Low-grade lymphoproliferative disorders, particularly B cell chronic
      lymphocytic leukemia (B-CLL), are characterized by the presence of bone marrow
      infiltration. Therefore, we analyzed expression of the chemokine receptor CXCR4
      in B-CLL, and investigated the functional effect of SDF-1 on the malignant cells.
      By flow cytometry, CXCR4 was consistently expressed on circulating CLL cells at a
      fluorescence intensity four-fold greater than that of normal B cells, and three
      fold greater than that of CD19+/CD5+ cells from the normal bone marrow. CXCR4 was
      functionally active as demonstrated by a rapid flux of intracellular free calcium
      in response to SDF-1, which was significantly reduced by the partially blocking
      CXCR4 antibody 12G5. Moreover, transendothelial migration of B-CLL cells in vitro
      was stimulated by conditioned medium from bone marrow stromal cells due to its
      content of SDF-1, as suggested by reduced migration after addition of the CXCR4
      antibody 12G5. In accordance with the CXCR4 overexpression, migration of CLL
      cells was more efficiently stimulated by recombinant SDF-1 compared to migration
      of normal B cells. We conclude that CXCR4 is overexpressed and functionally
      active in B-CLL, and may therefore contribute to the tropism of B-CLL cells for
      the bone marrow stroma.

PMID- 10602416
TI  - Lack of IRF-1 expression in acute promyelocytic leukemia and in a subset of acute
      myeloid leukemias with del(5)(q31).
AB  - One allele of interferon regulatory factor-1 (IRF-1), a transcriptional activator
      of genes critical for growth suppression, differentiation, and apoptosis, is
      usually deleted in acute myeloid leukemias (AML) and myelodysplasias (MDS) with
      deletion of chromosome 5q31. Accelerated exon skipping of IRF-1, resulting in
      transcripts lacking a translation initiation site, has been hypothesized as a
      means of functional inactivation of IRF-1 in AML/MDS. To test this hypothesis, we
      developed quantitative competitive RT-PCR assays to measure levels of full length
      and exon-skipped IRF-1 transcripts and measured IRF-1 proteins by Western
      blotting in a series of 45 samples of AML (13: -5/del5(q); 11: t(15;17); 7:
      t(8;21); and 7: inv(16)), normal blood and marrow, and myeloid cell lines. In
      contrast to AMLs with inv(16) or t(8;21), two AML samples with del(5q) had
      accelerated exon skipping and relatively low levels of full-length transcripts,
      while a third sample had very low transcript levels; IRF-1 proteins were not
      expressed and could not be induced by interferon gamma (IFNgamma). An additional
      six AML cases with -5/del(5q) had moderate exon-skipping and lacked constitutive
      IRF-1 proteins; however IRF-1 proteins were IFNgamma-inducible. Unexpectedly, all
      primary acute promyelocytic leukemia (APL) samples lacked IRF-1 protein and most
      exhibited accelerated exon skipping; furthermore, IRF-1 could not be induced by
      IFNgamma or all-trans retinoic acid (ATRA) which both induce IRF-1 in the NB4 APL
      cell line. Thus, accelerated exon skipping results in a loss of IRF-1 expression
      and function that cannot be overcome by exposure to inducing agents in a subset
      of AML patients with -5/del(5q) and in APL.

PMID- 10602417
TI  - Mapping of chromosome 20 for loss of heterozygosity in childhood ALL reveals a
      1,000-kb deletion in one patient.
AB  - The long arm of chromosome 20 displays recurrent loss of heterozygosity (LOH) for
      microsatellite markers in blast cells from children with acute lymphoblastic
      leukemia. To further characterize the region of deletion and to precisely
      establish its frequency, we searched for LOH in 103 children with ALL using
      polymorphic markers in the previously described region of interest, namely
      between D20S101 and D20S887. LOH was detected in nine patients (ie with a
      frequency of 8.7%). Interestingly, in one patient, a small deletion was found,
      flanked proximally by D20S850 and distally by M201, a dinucleotide repeat
      identified from chromosome 20 sequences. The distance between these two markers
      is approximately 1000 kb. The occurrence of non-random deletions of the long arm
      of chromosome 20 has previously been observed in myeloid malignancies
      (myeloproliferative disorders and myelodysplastic syndromes) in 5-10% of
      patients. The small deletion in our patient is located within the common region
      of deletion of myeloproliferative disorders suggesting that a tumor suppressor
      gene may be the common target of the deletions in various types of hematological
      malignancies.

PMID- 10602418
TI  - Fluorescence in situ hybridization analysis of chromosome 1 abnormalities in
      hematopoietic disorders: rearrangements of DNA satellite II and new recurrent
      translocations.
AB  - Using fluorescence in situ hybridization analysis, breakpoints involving the long
      arm of chromosome 1 (1q) were localized in 36 patients with various hematopoietic
      disorders and rearrangements of the proximal part of 1q, as ascertained with
      banding techniques. The breakpoint was localized within the satellite II (sat II)
      domain in 14 patients with various abnormalities, between the sat II domain and
      the BCL9 locus in eight, between the BCL9 and ARNT loci in two, between sat II
      and ARNT in two others, and distal to ARNT in seven. A dicentric chromosome 1 was
      present in two patients. A high incidence of heterochromatin heteromorphism of
      chromosome 1 was present in this series. Two recurrent translocations were
      identified, t(1;2)(q12;q37) in three patients suffering from three different
      acute leukemia subtypes, and t(1;16)(q12;q24) in two patients with different
      diseases. Two patients had jumping translocations. Most of the rearrangements of
      1q were secondary abnormalities, included in complex karyotypes. The roles of
      methylation, interactions with the proteins interfering with heterochromatin and
      possible gene silencing due to heterochromatin rearrangements are discussed.

PMID- 10602419
TI  - JEM-1, a novel nuclear co-factor: localisation and functional interaction with AP
      1.
AB  - JEM-1 is a novel gene whose mRNA expression in acute promyelocytic leukemia (APL)
      is induced by retinoid treatments. The gene product, a 45 kDa basic nuclear
      factor containing a leucine repeat, was transiently expressed in HeLa or COS-7
      cells and immunocharacterized within the nuclei in fine punctuated structures
      which increase in size after cell transfection. Jem-1 was not expressed in the
      nucleoli. Experimental deletion of peptide domains of Jem-1 (JemDelta331-400 and
      Jem DeltaL179-206) showed that its C-terminal sequence (Thr331 --> Leu400) is
      required for nuclear translocation, while the leucine repeat domain (Arg179 -->
      Glu206) has no influence on subcellular localization. The Jem-1 protein was not
      detected in the PML-containing nuclear bodies or in speckled structures
      containing the splicing factor SC-35. In contrast it was localized in the nucleus
      in structures containing activator protein-1 (AP-1). DNA mobility shift assays
      showed that the in vitro translated Jem protein interacts neither with the DNA
      binding site of AP-1, nor directly with in vitro co-translated c-Fos or/and c-Jun
      proteins bound to this specific sequence. Interestingly, Jem-1-1 increased
      substantially the transcriptional activity of c-Jun (three-fold) and more
      strongly that of ectopically co-expressed c-Fos and c-Jun (five- to six-fold), as
      measured by a CAT reporter gene driven by a heterologous promoter containing the
      AP-1 binding site of the human collagenase gene. These synergistic effects were
      strongly Jem-1 dose-dependent. However, Jem-1 alone showed no activity on the
      collagenase promoter. A deletion of the leucine repeat of Jem-1 (Arg179 -->
      Glu206) did not diminish the enhancer capacity of Jem-1 on AP-1 activity. In
      contrast, the enhanced AP-1 activity was abrogated when Jem-1 was deleted of its
      C-terminus (Thr331 --> Leu400). We conclude that the 45 kDa nuclear product of
      the JEM-1 gene has features of a novel transcription cofactor, which is enhancing
      AP-1 activity without directly interacting with c-Jun or c-Fos proteins. Possible
      implications of these findings for APL cell maturation are discussed.

PMID- 10602420
TI  - Frequent co-expression of the HOXA9 and MEIS1 homeobox genes in human myeloid
      leukemias.
AB  - There is increasing evidence that HOX homeobox genes play a role in
      leukemogenesis. Recent studies have demonstrated that enforced co-expression of
      HOXA9 and MEIS1 in murine marrow leads to rapid development of myeloid leukemia,
      and that these proteins exhibit cooperative DNA binding. However, it is unclear
      whether co-activation of HOXA9 and MEIS genes is a common occurrence in human
      leukemias. We surveyed expression of HOXA9 and MEIS1 in 24 leukemic cell lines
      and 80 patient samples, using RNase protection analyses and immunohistochemistry.
      We demonstrate that the expression of HOXA9 and MEIS1 in leukemia cells is
      uniquely myeloid, and that these genes are commonly co-expressed in myeloid cell
      lines and in samples of acute myelogenous leukemia (AML) of all subtypes except
      in promyelocytic leukemia. While HOXA9 is expressed in most cases of chronic
      myelogenous leukemia, MEIS1 is weakly expressed or not at all.
      Immunohistochemical staining of selected AML samples showed moderate to high
      levels of HOXA9 protein, primarily cytoplasmic, in leukemic myeloblasts, with
      weaker and primarily nuclear staining for MEIS1. These data support the concept
      that co-activation of HOXA9 and MEIS1 is a common event in AML, and may represent
      a common pathway of many different oncogenic mutations.

PMID- 10602421
TI  - Investigation of clonal involvement of myeloid cells in Philadelphia-positive and
      high hyperdiploid acute lymphoblastic leukemia.
AB  - Acute lymphoblastic leukemia (ALL) with a high hyperdiploid clone has a good
      prognosis for both childhood and adult patients while patients with Philadelphia
      positive (Ph) ALL do badly at all age groups. It has been suggested that
      different responses to treatment might be related to the cell of origin of the
      leukemia with 'stem cell' cases responding less well than those arising in a
      lymphoid committed progenitor cell. The clonal involvement of different cell
      lineages in 12 patients with acute lymphoblastic leukemia has been examined by
      applying fluorescence in situ hybridization (FISH) to detect chromosomal
      abnormalities in bone marrow cells previously identified by morphology and/or
      immunology. The karyotype of the malignant clone was either high hyperdiploid or
      Philadelphia translocation (Ph) positive with a breakpoint in the minor
      breakpoint cluster region of the BCRgene (m-BCR) or in the major breakpoint
      cluster region of the BCR gene (M-BCR). The high hyperdiploid clone, in each
      case, was found in cells of the B-lymphoid (CD19+) lineage but not in T cells
      (CD3+) or in cells of the myeloid (CD13+) or erythroid (glycophorin A+) lineages,
      indicative of a lymphoid committed progenitor cell. Heterogeneity of lineage
      involvement was found in Ph+ ALL: the m-BCR Ph+ clone was found in lymphoid/blast
      cells but not in neutrophils or eosinophils. In contrast both M-BCR Ph+ clones
      were detected in myeloid as well as lymphoid lineages, indicative of a stem cell
      origin.

PMID- 10602422
TI  - Pre-B acute lymphoblastic leukemia with b3a2 (p210) and e1a2 (p190) BCR-ABL
      fusion transcripts relapsing as chronic myelogenous leukemia with a less
      differentiated b3a2 (p210) clone.
AB  - The Philadelphia chromosome translocation t(9;22)(q34;q11) may give rise to
      different BCR/ABL fusion mRNAs due to different genomic breakpoints and
      alternative splicing. The e1a2, b2a2 or b3a2 and c3a2 fusion mRNAs encode
      distinct fusion proteins (p190, p210 and p230, respectively), which are
      associated with different forms of leukemogenesis in humans and animal models.
      Our patient presented with acute pre-B cell lymphoblastic leukemia (ALL) with
      normal cytogenetics. After 3 years of standard ALL therapy, he relapsed with
      t(9;22)-positive chronic myelogenous leukemia (CML). Retrospective molecular
      analyses of the pre-treatment pre-B cell ALL sample showed the b3a2 (p210) and
      e1a2 (p190) BCR/ABL fusion transcripts. Only the b3a2 (p210) transcript was
      detected at relapse. Southern and immunoglobulin heavy chain (IgH) analyses of
      the presentation and relapse samples revealed an identical BCR rearrangement in
      both samples. However, only the ALL sample harbored an IgH gene rearrangement.
      These findings show a clonal relationship between the more differentiated pre-B
      cell and less differentiated CML clones and that the p210 and p190 fusion mRNAs
      were alternatively spliced from a single genomic breakpoint. Our patient's
      unusual molecular findings provide circumstantial evidence that the p190 protein
      may promote a more differentiated phenotype in a comparatively less
      differentiated p210-transformed precursor cell.

PMID- 10602423
TI  - Characterisation of the differential response of normal and CML haemopoietic
      progenitor cells to macrophage inflammatory protein-1alpha.
AB  - The clonogenic cells of chronic myeloid leukaemia (CML), unlike normal
      haemopoietic colony forming cells (CFC), are resistant to the growth inhibitory
      effects of the chemokine, macrophage inflammatory protein-1alpha (MIP-1alpha).
      Here, we tested the hypothesis that MIP-1alpha protects normal, but not CML, CFC
      from the cytotoxic effects of the cell-cycle active drug cytosine arabinoside
      (Ara-C). Using a 24-h Ara-C protection assay we showed that MIP-1alpha confers
      protection to normal CFC but also sensitizes CML CFC to Ara-C. The differential
      MIP-1alpha responsiveness was not due to a down-regulation of MIP-1alpha
      receptors on CML CD34+ cells as flow cytometric analysis showed similar binding
      of a biotinylated MIP-1alpha molecule to normal and CML CD34+ cells. Flow
      cytometric analysis of the MIP-1alpha receptor subtype CCR-5 revealed comparable
      CCR-5 expression levels on normal and CML CD34+ cells. Furthermore, culture of
      CD34+ cells for 10 h in the presence of TNF-alpha resulted in an increased MIP
      1alpha receptor expression on both normal and CML CD34+ cells. Our data suggest
      that the unresponsiveness of CML CFC to the growth inhibitory effect of MIP
      1alpha is not caused by a lack of MIP-1alpha receptor or total uncoupling of the
      MIP-1alpha responsiveness but may be due to an intracellular signalling defect
      downstream of the receptors.

PMID- 10602424
TI  - Relationship between the intracellular daunorubicin concentration, expression of
      major vault protein/lung resistance protein and resistance to anthracyclines in
      childhood acute lymphoblastic leukemia.
AB  - In vitro resistance to anthracyclines is related to a poor prognosis in childhood
      acute lymphoblastic leukemia (ALL), but the underlying mechanisms are poorly
      understood. Using flow cytometry, we studied the contribution of daunorubicin
      (DNR) accumulation and retention, cell size, expression of the major vault
      protein/lung resistance protein (LRP), P-glycoprotein (P-gp) and multidrug
      resistance-associated protein (MRP) to the cytotoxicity of DNR (by MTT assay) in
      childhood ALL. The accumulated and retained DNR content was not related to the
      degree of DNR resistance, nor did the content differ between 53 initial and 20
      relapse ALL samples (P >0. 05), although the latter were median two-fold more
      resistant to DNR (P = 0.004). Leukemic cell volume correlated with resistance to
      the anthracyclines DNR (Rs 0.32, P = 0.012) and idarubicin (Rs 0.46, P = 0.011)
      but not to other classes of drugs such as prednisolone, vincristine, L
      asparaginase and etoposide. Relapsed patients had 1. 5-fold larger cells than
      patients at initial diagnosis of ALL (P = 0. 001). After cell volume correction,
      the intracellular DNR concentration was lower in relapsed compared with initial
      ALL cells (eg 60 min accumulation, P = 0.003). Moreover, the intracellular DNR
      concentration inversely correlated with DNR resistance, both in the accumulation
      (Rs -0.44, P < 0.001) and retention (Rs -0.33, P = 0. 016) test condition. The
      accumulated DNR concentration inversely correlated with expression of LRP (Rs 
      0.36, P = 0.012) but not with P-gp and MRP. Expression of LRP, but not of P-gp
      and MRP, significantly correlated with DNR resistance in childhood ALL (Rs 0. 33,
      P = 0.03). In conclusion, the intracellular DNR concentration and the expression
      level of LRP may contribute to DNR resistance in childhood ALL. The strength of
      the correlations also indicates that resistance to anthracyclines can not be
      explained by one single mechanism.

PMID- 10602425
TI  - Drug-resistance enables selective killing of resistant leukemia cells: exploiting
      of drug resistance instead of reversal.
AB  - Drug resistance is a well recognized problem in cancer therapy. Despite the
      current dogma that drug resistance is always an obstacle for treatment, here I
      show that it provides opportunities for selective protection of non-resistant
      cells with killing of drug-resistant cancer cells. According to the proposed 'two
      drug' strategy, the first drug should be ineffective against a target drug
      resistant cell (ie the drug is a substrate of MRP or Pgp pumps). In addition, it
      must be cytostatic but not cytotoxic. The second drug, which is applied in
      sequence, must be a cycle-dependent apoptotic drug to which the target cell is
      not cross-resistant. Thus, low doses of adriamycin, etoposide and actinomycin D,
      used as the first drugs, were cytostatic to parental HL60 cells. Therefore, these
      drugs precluded Bcl-2/Raf-1 phosphorylation, PARP cleavage and cell death which
      are otherwise induced by paclitaxel, a mitosis-selective apoptotic drug for HL60
      cells. In contrast, HL60/ADR cells which express MRP, a transporter which pumps
      out the first drugs from a cell, were insensitive to the first drugs and
      therefore readily underwent apoptosis following the second drug. This strategy
      also allowed a selective killing of HL60/TX cells which express MDR-1, with the
      only difference being that the second drug, paclitaxel, was substituted for
      epothilones, non-Pgp substrates. Lack of protection by the first drug, a Pgp
      substrate, resulted in HL60/TX killing by the second drug, whereas parental HL-60
      cells were fully protected. Therefore, drug resistant cells can be selectively
      killed by a combination of drugs not killing sensitive cells. Lack of toxicity
      against normal cells will be clinically translated in reduction of adverse side
      effects of chemotherapy against drug-resistant malignancies.

PMID- 10602426
TI  - Gp130-signaling synergizes with FL and TPO for the long-term expansion of cord
      blood progenitors.
AB  - We investigated the effect of a new fusion protein of IL-6 and the soluble IL-6R,
      H-IL-6, on the long-term ex vivo expansion of hematopoietic progenitors derived
      from AC133+cord blood cells. H-IL-6, which acts on both IL-6Ralpha-positive and
      IL-6Ralpha-negative cells, effectively synergized with FL and TPO with or without
      SCF for the propagation of primitive progenitors. However, IL-6 showed a greater
      synergistic effect with FL and TPO than H-IL-6 for long-term progenitor
      propagation. During the first 6 weeks of culture under stroma-free serum
      containing conditions, IL-6 induced a 1.96 +/- 0.64-fold higher expansion of
      nucleated cells, a 2.28 +/- 0.33-fold higher expansion of CD34+ cells and a 2.74
      +/- 0. 28-fold higher expansion of CD34+ AC133+ cells than H-IL-6 in combination
      with FL and TPO. The propagation of week 6 CAFC was up to four-fold higher in the
      presence of IL-6 than with H-IL-6. While the expansion of CD34+ and CD34+ AC133+
      cells dropped after 5-7 weeks in the stroma-free cultures with FL, TPO and H-IL
      6, a sustained expansion for 12 weeks was obtained in the presence of FL, TPO and
      IL-6. Stroma-contact greatly enhanced the progenitor expansion induced by FL and
      TPO or FL, TPO and H-IL-6 although the highest proliferation was again obtained
      in the presence of IL-6. In contrast, the presence of SCF resulted in increased
      differentiation. Since the majority of primitive progenitors are proposed to be
      IL-6Ralpha-negative, the results suggest that the synergistic effect of IL-6 is
      mediated by accessory cells, which have been more effectively stimulated by IL-6
      than by the fusion peptide, H-IL-6, in this culture system.

PMID- 10602427
TI  - Allelic loss and promoter hypermethylation of the p15INK4b gene features in mouse
      radiation-induced lymphoid - but not myeloid - leukaemias.
AB  - Mouse radiation-induced acute myeloid leukaemias (AMLs) which arose in a (CBA/H x
      C57BL/6) genetic background have a 45% incidence of loss of heterozygosity (LOH)
      on chromosome 4. Frequent chromosome 4 LOH in mouse radiation-induced (C57BL/6 x
      RF/J) thymic lymphomas (TLs) is associated with promoter/exon 1 region
      hypermethylation of the remaining p15INK4b and p16INK4a alleles, so this may be
      common to mouse radiation myeloid and lymphoid leukaemogenesis. We addressed the
      question of p15INK4b/p16INK4a/p19ARF gene promoter hypermethylation in radiation
      induced AMLs by comparison to TLs which arose in a similar (C57BL/6 x CBA/H)
      genetic background as a consequence of the same initiating dose of 3 Gy X-rays.
      Only one homozygous deletion was detected in the approximately 100 leukaemias
      analysed. p15INK4b gene promoter/exon 1 hypermethylation was readily detected
      (21%) in the lymphoid but not myeloid (3.1%) leukaemias, and p16INK4a and p19ARF
      gene promoter/exon 1 methylation was rare (<3%) in both. Thus, allelic loss and
      promoter hypermethylation of the p15INK4b gene is particular to radiation-induced
      lymphoid leukaemias and is independent of p16INK4a and p19ARF gene promoter/exon
      1 hypermethylation.

PMID- 10602428
TI  - Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute
      lymphoblastic leukemia treated with allogeneic bone marrow transplant in first
      complete remission.
AB  - Between 1984 and 1997, 23 consecutive patients with Philadelphia chromosome
      positive acute lymphoblastic leukemia in first complete remission were treated
      with allogeneic bone marrow transplants from HLA-matched siblings. All patients
      but one were conditioned with fractionated total body irradiation (1320 cGy) and
      high-dose etoposide (60 mg/kg). One patient received high-dose cyclophosphamide
      instead of etoposide, and another patient received both drugs. Nine patients died
      following BMT, two from relapsed leukemia, and seven from transplant-related
      causes. The 3-year probabilities of disease-free survival and relapse are 65% and
      12%, respectively. For patients transplanted after 1992, these probabilities are
      81% (48-95%, 95% confidence interval) and 11% (2-50%), respectively. The
      relatively low relapse rate in this group of patients compared to published
      reports may reflect the enhanced anti-leukemic activity of etoposide in
      combination with FTBI compared to other conditioning regimens. The enhancement in
      overall survival for patients transplanted after 1992 may reflect improvements in
      supportive care, in particular, the prophylaxis of serious fungal and viral
      infections.

PMID- 10602429
TI  - Chimerism testing after allogeneic stem cell transplantation: importance of
      timing and optimal technique for chimerism testing in different clinical
      biological situations

PMID- 10602430
TI  - Kinetics of chimerism during the early post-transplant period in pediatric
      patients with malignant and non-malignant hematologic disorders: implications for
      timely detection of engraftment, graft failure and rejection.
AB  - The monitoring of chimerism by PCR has become a routine diagnostic approach in
      patients after allogeneic bone marrow or peripheral blood stem cell
      transplantation. Nevertheless, a temporal correlation between molecular and
      hematologic assessment of engraftment has not been clearly established. To
      address this issue, and to determine the potential clinical implications of early
      kinetics of mixed chimerism, we have investigated 66 allogeneic stem cell
      transplantations (SCTs) in 58 pediatric patients suffering from different types
      of leukemia (n = 44) or non-malignant hematologic disorders (n = 14) by close
      molecular monitoring during the first days and weeks after transplantation.
      Patient- and donor-derived hematopoiesis were assessed at 1- to 3-day intervals
      in peripheral blood samples by PCR analysis of highly polymorphic microsatellite
      loci (STR-PCR). Detection of an increasing, and ultimately dominant donor
      specific allelic pattern, which we defined as molecular engraftment, preceded
      hematologic engraftment by a median of 7 days (range 1-17 days) in all patients
      investigated. PCR analyses during the first days after transplantation
      facilitated detection of molecular engraftment according to the above definition
      by day +14 (range day +2 to day +14), thus permitting prediction of successful
      engraftment (upper limit of the two-sided confidence interval po = 6%) while the
      peripheral leukocyte counts were mostly below 200/microl. In three cases,
      however, the criteria for molecular engraftment were not fulfilled by day +14.
      These patients also failed to show hematologic engraftment, and required a second
      transplantation. Close monitoring by STR-PCR showed that graft rejection and
      autologous recovery can occur early and with very rapid dynamics. Molecular
      analysis of specific leukocyte subsets isolated by flow-sorting enabled sensitive
      assessment of changes in the pattern of chimerism which had escaped detection in
      assays using whole white blood cell (WBC) samples. This approach facilitated the
      identification of expanding or decreasing recipient cells, and permitted early
      detection of impending rejection or relapse. Moreover, monitoring of the dynamics
      of chimerism allowed rapid assessment of the response to therapy. Our
      observations provide support for the concept of initiating genotype analyses
      early after SCT and monitoring at rather short intervals to permit timely
      evaluation of clinically relevant processes, and to provide a basis for early
      implementation of treatment.

PMID- 10602431
TI  - Transplantation of highly purified peripheral blood CD34+ cells from HLA
      mismatched parental donors in 14 children: evaluation of early monitoring of
      engraftment.
AB  - HLA-mismatched family members may represent an important cell source for patients
      that require stem cell transplantation but lack both a matched sibling donor and
      a closely matched unrelated donor. We report the outcome of 19 transplantations
      from HLA two- or three- loci mismatched parental donors in which 14 pediatric
      patients with hematological malignancies or other disorders, received a median of
      21.5 x 106 (range, 5.4-58) highly purified CD34+peripheral blood stem cells
      (PBSC), as well as 4.7 x 104 (range, 0.4-12) donor T cells per kg body weight. T
      cell depletion was performed using a two-step CD34-positive selection on two
      different magnetic beads devices. Ten of 14 patients presented with rapid myeloid
      engraftment. The four patients who presented with graft failure (two non
      engraftments, two rejections) received a second stem cell graft and one a third.
      Graft rejection was detected early by polymerase chain reaction (PCR) analysis of
      FACS-sorted T cells. Eight of the 14 patients are still alive after a median
      observation period of 15. 6 months (range, 3-31.3) with full donor chimerism in
      all hematopoietic cell lineages. No acute organ graft-versus-host disease (GVHD)
      and no chronic GVHD have occurred. One patient experienced relapse of leukemia.
      We conclude that transplantation of allogeneic PBSC from haploidentical donors
      will open new perspectives for pediatric patients for whom an HLA-matched stem
      cell graft is not available. Close monitoring of recipient and donor
      hematopoiesis might be of clinical value, to recognize early engraftment or
      rejection.

PMID- 10602432
TI  - Prevention of relapse in pediatric patients with acute leukemias and MDS after
      allogeneic SCT by early immunotherapy initiated on the basis of increasing mixed
      chimerism: a single center experience of 12 children.
AB  - The success of allogeneic stem cell transplantation (allo-SCT) in children is
      mainly affected by relapse or graft rejection. We have recently shown in a study
      of 55 patients with acute leukemias (ALL 21, AML 20 and MDS 14), that patients
      who demonstrate increase amounts of autologous marrow repopulation (increasing
      mixed chimerism) have a significantly enhanced risk of relapse (P < 0. 0001).
      Based on these findings, we asked whether post-transplant relapse can be
      prevented by withdrawal of immunosuppression and/or by donor lymphocyte infusion
      (DLI). We describe the results of a pilot study where adoptive immunotherapy was
      used to treat 12 patients (five ALL, three AML, four MDS) who showed increasing
      mixed chimerism (MC) post-transplant. A response to immunotherapy, defined as the
      re-establishment of complete chimerism (CC) and continuous complete remission
      (CCR), was achieved in four patients (two ALL, two AML) following withdrawal of
      CsA and in a further six patients (three ALL, three MDS) after additional DLI.
      One ALL patient, who initially responded to DLI, developed severe GVHD that
      required further immunosuppression. GVHD was controlled but this patient
      subsequently relapsed. Another patient with ALL became a CC but developed an
      isolated relapse in the bone marrow 260 days later. One patient with MDS
      developed severe GVHD after DLI and died. Two children (one AML and one MDS) did
      not show any response to interventional treatment and died due to relapse. Of the
      12 patients treated, seven remain in CCR at a median follow-up of 747 days (range
      351-1109 days). In summary, these results provide evidence that increasing MC can
      be used to guide adoptive immunotherapy strategies and that these treatment
      modalities can be used to prevent relapse in children with acute leukemias or MDS
      after allo-SCT.

PMID- 10602433
TI  - c-myc mRNA expression and genomic alterations in mantle cell lymphomas and other
      nodal non-Hodgkin's lymphomas.
AB  - Cyclin D1 is a weak oncogene that cooperates with c-myc activation in the
      development of B cell lymphomas in transgenic animals. Cyclin D1 is constantly
      overexpressed in human mantle cell lymphomas (MCL). However, the status of c-myc
      gene in these tumors is not known. We have examined the c-myc mRNA expression and
      genomic alterations, including mutational analysis of exon 1, intron 1, and exon
      2 regulatory elements, in a series of 33 MCL, 22 typical and 11 blastoid
      variants. In addition, c-myc alterations were also examined in 56 nodal non
      Hodgkin's lymphomas (NHL). c-myc mRNA overexpression was found in 38% (11/29) of
      MCL with a slightly higher frequency in blastoid variants (5/10, 50%) than in
      typical cases (6/19, 31%). Genetic alterations were only found in one blastoid
      MCL showing a three-fold c-myc gene amplification. In other nodal NHL, c-myc
      overexpression was found in 24% (7/29) of indolent tumors but in 70% (19/27) of
      aggressive variants. c-myc Genetic alterations detected in these cases were gene
      rearrangement and hypermutations in one Burkitt's lymphoma, and individual point
      mutations in intron 1 or exon 2 in 1/19 (5%) indolent and 7/16 (44%) aggressive
      variants. These results indicate that c-myc is overexpressed in a subset of MCL,
      but structural gene alterations are less frequent than in other nodal NHL.

PMID- 10602434
TI  - Primary non-Hodgkin's lymphoma of bone: a clinicopathological investigation of 60
      cases.
AB  - A retrospective analysis of patients presenting with primary lymphoma of bone
      (PLB) was performed to determine clinical factors affecting prognosis in relation
      to histological subtype and treatment outcome. Data from 106 patients, presenting
      with a PLB between 1943 and 1996, were retrieved from the files of the
      Netherlands Committee on Bone Tumours and Leiden University Medical Centre. The
      lymphomas were reclassified according to the REAL and updated Kiel
      classification. The clinical presentation, survival and prognostic factors were
      investigated. Sixty patients had sufficient clinical information and adequate
      follow-up to be included in the study. All 33 PLB that could be immunophenotyped
      were of B cell origin. According to the REAL classification, most PLB were large
      (B) cell lymphomas (92%) and according to the Kiel classification 45% of the
      tumours were centroblastic multilobated. PLB presented most often in the long
      bones (48%), with Ann Arbor stage I (46%), II (16%), IV (16%) and unknown (20%).
      Stage IV disease was exclusively caused by the presence of multiple bone lesions.
      Notwithstanding the heterogeneous treatment, the 5-year overall survival was 61%;
      46% of patients were progression free at 5 years. Patients at presentation older
      than 60 had a worse overall survival (76% vs 37%, P = 0.0002) and a worse
      progression-free period (58% vs 28%, P = 0.0073). Patients with the immunoblastic
      subtype had a worse survival than the centroblastic mono/polymorphic subtype or
      the centroblastic multilobated subtype (P = 0.015). Primary lymphoma of bone
      represents an uncommon bone tumour with a relatively homogeneous morphology and
      clinical behaviour. Compared to other aggressive lymphomas, PLB have a favourable
      prognosis.

PMID- 10602435
TI  - Analysis of p73 and p53 gene deletions in multiple myeloma.
AB  - Recently, p73, a protein with structural and functional similarities to p53, an
      extensively studied tumor suppressor gene, has been cloned. After being mapped to
      the chromosomal region 1p35-1p36, it has been postulated to act as a tumor
      suppressor gene, too, as this region is altered in several human malignancies.
      Deletions of the short arm of chromosome 1 have frequently been described in
      multiple myeloma (MM) whereas structural abnormalities of the 17p13 region
      including p53 are rare events in this disease. Since it has been proposed that
      especially neoplasias lacking p53 alterations might show a loss of heterozygosity
      at 1p35-1p36, we studied the frequency of p53 and p73 deletions in bone marrow
      mononuclear cells of 68 patients with MM, two patients with monoclonal gammopathy
      of undetermined significance and four patients with plasma cell leukemia. Dual
      color fluorescence in situ hybridization (FISH) for p53 and p73 was performed
      using commercially available DNA probes for 17p13.3 and the microsatellite marker
      D1Z2, respectively. Centromeric DNA probes served to distinguish gene deletions
      from whole chromosome losses. In contrast to recently published FISH results, we
      only detected heterozygous p53 deletions in eight out of the 74 patients, three
      of them showing a monosomy 17. Heterozygous deletions of the D1Z2 region at 1p36
      were found in six cases with one patient having a monosomy 1. Neither homozygous
      deletions of either chromosomal region nor nullisomies 1 or 17 could be detected.
      These results argue against a major role of p73 deletions in MM. As MM patients
      with 1p structural abnormalities have a significantly poorer survival rate than
      those with normal karyotypes, the role of other putative tumor suppressor genes
      located at the chromosomal region 1p36 in the pathogenesis of MM has to be
      determined.

PMID- 10602436
TI  - Fluorescent BAT-25 and BAT-26 analysis of T cell prolymphocytic leukaemia.
AB  - T cell prolymphocytic leukaemia (T-PLL) is a chronic mature T cell malignancy
      with many random cytogenetic abnormalities. These imply that maintenance of
      genomic integrity is impaired. This is supported by the recent finding that the
      ataxia telangiectasia gene, ATM, which contributes to maintaining genomic
      integrity, is frequently mutated in this disease. To evaluate in T-PLL the role
      of other genes with comparable function, a fluorescence-based semi-automated
      assay was developed for BAT-25 and BAT-26. These markers contain sequences that
      are particularly unstable in cells with DNA mismatch repair defects. Application
      of the assay to 20 T-PLL cases found no evidence for such defects.

PMID- 10602437
TI  - Rapid and sensitive detection of all types of MLL gene translocations with a
      single FISH probe set.
AB  - The MLL gene on chromosome 11 band q23 is frequently involved in chromosome
      translocations in acute lymphoblastic leukemia and acute myeloid leukemia. The
      translocation results in the formation of a fusion gene on the derivative 11
      chromosome consisting of the 5' part of the MLL gene and the 3' part of another
      gene; already more than 30 different partner chromosome regions have been
      described. MLL gene rearrangements are generally correlated with a poor
      prognosis. Therefore the presence of an 11q23 aberration has direct implications
      for treatment stratification, making early and rapid detection of utmost
      importance. In this study, we developed a FISH probe set for detection of MLL
      gene rearrangements according to strict design criteria. The cosmid probes are
      derived from the flanking regions of the MLL breakpoint region on chromosome 11
      and when used in dual colored FISH experiments give rise to a split of the
      normally colocalizing (fused) signals in case of a translocation. This split
      signal was observed in seven out of 10 cases with an 11q23 translocation with
      various partner chromosomes. In the three other cases, a deletion of the 3' part
      of the MLL gene, downstream of the breakpoint region was also found. A low false
      positive value of only 1.7% was obtained for interphase cells in contrast to
      conventional dual colored FISH where the creation of a fusion signal has cut off
      values of at least 5-10%. A major advantage of our type of probe set is the
      application of a single FISH experiment to detect all types of MLL
      translocations. Moreover, since this cosmid probe set can be used for either
      interphase or metaphase studies, metaphases are no longer a prerequisite for
      detecting the presence of an 11q23 translocation. Nevertheless, metaphase FISH
      with the new probe set is helpful in determining the partner chromosome and
      therefore may lead to the identification of new partner genes.

PMID- 10602438
TI  - Molecular assessment of clonality in a pre-B ALL unusually relapsing as a mature
      B ALL.

PMID- 10602439
TI  - Therapy-related T cell lymphoblastic lymphoma with t(11;19)(q23;p13) and MLL gene
      rearrangement.

PMID- 10602440
TI  - Extensive bone marrow necrosis associated with multiple myeloma.

PMID- 10602441
TI  - A study of 20 SLE patients with intravenous immunoglobulin--clinical and
      serologic response.
AB  - OBJECTIVE: To test the clinical response of systemic lupus erythematosus (SLE)
      patients to intravenous immunoglobulins (IVIg), and whether the clinical response
      of IVIg treatment in SLE is accompanied by modification of SLE-associated
      autoantibodies/antibodies (Abs) and complement levels. METHODS: Twenty SLE
      patients were treated with high-dose (2 g/kg) IVIg monthly, in a 5-d schedule.
      Each patient received between 1-8 treatment courses. They were evaluated for the
      clinical response, Systemic Lupus Activity Measure (SLAM) score before and after
      IVIg, levels of antinuclear antibody (ANA), dsDNA (double-stranded DNA), SS-A or
      SS-B, ENA (extractable nuclear antigens), C3 and C4 levels before and after the
      treatment, and before and after each treatment course. RESULTS: A beneficial
      clinical response following IVIg treatment was noted in 17 out of 20 patients
      (85%). Few clinical manifestations responded more to treatment: arthritis, fever,
      thrombocytopenia, and neuropsychiatric lupus. In 9 patients evaluated before and
      after IVIg, mean SLAM score decreased from 19. 3+/-4.7 to 4+/-2.9 (P<0.0001).
      There was a tendency towards abnormal levels of complement and Abs before IVIg
      courses among the treatment responders compared with the non-responders, and
      similarly the former tended to have normalization of their abnormal levels more
      than the latter. These differences were found statistically significant only with
      respect to C4 and SS-A or SS-B levels before IVIg courses. CONCLUSION: IVIg has a
      high response rate among SLE patients. A combination of clinical manifestations,
      Abs and complement levels may aid in the future in predicting who among SLE
      patients will benefit more from IVIg treatment.

PMID- 10602442
TI  - Systemic lupus erythematosus in Lebanon.
AB  - The present study describes the clinical characteristics of patients with
      systemic lupus erythematosus (SLE) from the American University of Beirut Medical
      Center (AUBMC), one of the largest teaching hospitals in Lebanon. This is a
      retrospective chart review of 100 SLE patients seen over a 20 y period. There
      were 86 females and 14 males, with a median age of 26 y. 85 patients were
      Lebanese and 15 patients were Palestinians. The main clinical features were
      arthritis and/or arthralgias seen in 95% of our patients, followed by malar rash
      (52%), and renal involvement (50%). Of the hematological manifestations,
      thrombocytopenia was most commonly seen in 33% of patients, followed by
      leucopenia in 17% and hemolytic anemia in 10% Oral ulcers and serositis were both
      seen in 40% of patients. Less frequent manifestations included discoid lupus
      (19%), neuropsychiatric manifestations (19%), and photosensitivity (16%).
      Antinuclear antibodies were detected in 87% of patients, whereas anti-DNA
      antibodies were seen in 50% of cases. 25 patients (25%) had a false-positive
      VDRL. A comparison between our findings and 3 other Arab SLE groups revealed a
      higher incidence of oral ulcers, discoid lupus, articular manifestations,
      thrombocytopenia and false-positive VDRL, and a lower incidence of
      photosensitivity, leucopenia, neuropsychiatric manifestations, and anti-DNA
      antibodies.

PMID- 10602443
TI  - Systemic lupus erythematosus into the next millennium: looking into the crystal
      ball.

PMID- 10602444
TI  - Effects of anti-CD4 antibodies on the release of IL-6 and TNF-alpha in whole
      blood samples from patients with systemic lupus erythematosus.
AB  - Anti-CD4 antibodies have been recently introduced into the therapy of various
      autoimmune diseases, among them systemic lupus erythematosus (SLE). Their modes
      of action are not yet fully understood. Interference with cytokine release may be
      one possible mechanism. Therefore, the effects of anti-CD4 antibodies on the
      cytokine release of IL-6 (interleukin-6) and TNF-alpha (tumor necrosis factor
      alpha) were investigated in a whole blood culture system. Basal and
      phytohemagglutin/lipopolysaccharide (PHA/LPS)-stimulated cytokine patterns were
      compared to cytokine release after the addition of anti-CD4 antibodies (MAX.16H5)
      or methylprednisolone in short time whole blood cell culture systems from 12
      patients with active SLE, 23 patients with inactive SLE and 12 healthy
      volunteers. TNF-alpha and IL-6 concentrations were determined in the supernatants
      by ELISA. High disease activity correlated with an increased production of
      proinflammatory cytokines. Cell cultures of patients with inactive SLE showed a
      diminished capacity to respond to mitogenic stimulation. Anti-CD4 antibodies
      added in vitro suppressed significantly the unstimulated production of IL-6
      (P<0.02) in the cell cultures of patients with active SLE and in the PHA/LPS
      stimulated cell cultures from both groups of SLE patients (both P<0.001) and
      healthy volunteers (P<0.01). However, MAX.16H5 did not affect the release of TNF
      alpha. In control samples methylprednisolone considerably reduced stimulated and
      unstimulated IL-6 and TNF-alpha production in all SLE patients, irrespective of
      the disease state, and in all healthy controls. These data indicate that the
      proinflammatory cytokines are involved in the pathogenesis of SLE. It is assumed
      that anti-CD4 antibodies, which can be effective in the treatment of highly
      active lupus patients, may act via their influence on cytokine release. The
      decrease of the proinflammatory cytokines IL-6 under therapy with MAX.16H5 could
      explain the observations of clinical trials and animal studies which showed a
      reduction of inflammatory parameters and diminished production of autoantibodies
      following treatment with anti-CD4 antibodies.

PMID- 10602445
TI  - Mycophenolate mofetil for the treatment of systemic lupus erythematosus: an open
      pilot trial.
AB  - OBJECTIVE: To investigate the effectiveness and safety of mycophenolate mofetil
      in patients with systemic lupus erythematosus who were inadequately controlled
      with corticosteroids, antimalarials, and other immunosuppressive agents. METHODS:
      Ten patients with systemic lupus erythematosus (SLE) were treated with 1500-2000
      mg mycophenolae mofetil (MMF) daily for a median observation time of 11. 2+/-2.4
      (8-16) months in an open clinical trial. The effectiveness and safety of
      treatment were analyzed using an established disease activity score, clinical
      status, and laboratory parameters. RESULTS: All patients improved under treatment
      with no or only minor side effects. The disease activity score (SLAM) decreased
      statistically significantly from a median of 15.6+/-5.5 to 9.9+/-4.1 after three
      months (P<0.01) and to 8.0+/-3.3 after six months (P<0.01). Hematologic
      parameters did not change significantly whereas a reduction of inflammatory
      markers was observed. Four patients with SLE-nephritis already treated with
      cyclophosphamide pulse therapy continuously showed a slight improvement of renal
      function. Prednisolone dosages could be reduced significantly from a median level
      of 10.0+/-5.1 mg/d before treatment to 4.6+/-3.5 mg/d after six months (P<0.01).
      CONCLUSION: Mycophenolate mofetil is a promising option in immunosuppressive
      treatment of patients with moderate and severe systemic lupus erythematosus who
      did not show a satisfactory response to other immunosuppressives.

PMID- 10602446
TI  - Clinical significance of hemostatic markers and thrombomodulin in systemic lupus
      erythematosus: evidence for a prothrombotic state.
AB  - Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder with
      overwhelming thrombotic states. The precise pathogenetic mechanisms underlying
      the prethrombotic state in SLE is not fully understood, but interactions between
      the antiphospholipid antibodies and antigen targets on the coagulation components
      have been incriminated to play fundamental roles. To evaluate this issue, 34
      women with antiphospholipid antibody negative SLE were investigated for molecular
      markers of blood coagulation and fibrinolytic activity: prothrombin fragment1+2
      (PF1+2), thrombin-antithrombin complex (TAT), plasmin-alpha2-antiplasmin
      inhibitor complex (PAP), and tissue factor pathway inhibitor (TFPI). We also
      analysed plasma soluble thrombomodulin (sTM) levels. SLE disease activity was
      determined using the SLE Disease Activity Index (SLEDAI). Concentrations of TAT,
      PAP, PF1+2 and sTM were significantly elevated (P<0.0001, P=0.0002, P<0.0001, and
      P<0.0001, respectively), while TFPI antigen levels were found to be reduced
      (P<0.0001) in patients with SLE compared to the control group. In patients with
      active SLE, anti-ds DNA levels were correlated positively with plasma TAT
      (P<0.05), PF1+2 (P<0.05), and sTM (P<0.01) concentrations and negatively with
      plasma TFPI levels (P<0.05). SLEDAI scores were correlated positively with plasma
      TAT (P<0.01), PF1+2 (<0.01), and sTM (P<0.01) levels. This study illustrates that
      both a prethrombotic state and a compensatory fibrinolytic process secondary to
      subclinical intravascular coagulation might coexist in SLE with elevated sTM
      levels, indicating impaired endothelial functions.

PMID- 10602447
TI  - Genetic variation in apolipoprotein H (beta2-glycoprotein I) affects the
      occurrence of antiphospholipid antibodies and apolipoprotein H concentrations in
      systemic lupus erythematosus.
AB  - Apolipoprotein H (apoH, protein; APOH, gene) is a required cofactor for the
      production of antiphospholipid antibodies (APA). In this study we have examined
      whether genetic variation in the APOH gene affects variation in risk for systemic
      lupus erythematosus (SLE), occurrence of antiphospholipid antibodies (APA), anti
      apoH, and plasma apoH concentrations. A total of 222 white SLE women were
      screened for four APOH polymorphisms (codons 88, 247, 306, and 316) by polymerase
      chain reaction, and for plasma apoH concentrations by ELISA. Of these, 29.3% were
      positive for APA (APA-positive group) and 31.1% for anti-apoH. None of the four
      APOH polymorphisms were significantly associated with variation in risk for SLE.
      The codons 306 and 316 polymorphisms showed significant, gene-dosage effects on
      plasma apoH concentrations (P<0.0001) and explained 30% and 13%, respectively, of
      the residual variation in apoH concentrations. No significant association was
      observed between anti-apoH status and APOH polymorphisms or plasma apoH levels.
      However, plasma apoH concentrations were significantly higher in patients
      positive for APA than in patients negative for APA (18.5+/-4.0 mg/dl vs 17.1+/-3.
      8 mg/dl; P=0.02). The distribution of the Trp316Ser polymorphism was
      significantly different between the APA-positive and APA-negative groups. The
      frequency of the mutant allele (Ser316) was significantly lower in the APA
      positive group than the APA-negative group (3.1% vs 12.1% P<0.04), indicating
      that the Ser316 mutation is protective against the production of phospholipid
      apoH dependent APA. Our data indicate that common genetic variation in the APOH
      gene is a significant determinant of plasma apoH variation in SLE patients, and
      the Trp316Ser polymorphism appears to provide protection against the production
      of APA in SLE patients.

PMID- 10602448
TI  - Neonatal lupus erythematosus: analysis of HLA class I genes in Japanese
      child/mother pairs.
AB  - Neonatal lupus erythematosus (NLE), characterized by two major symptoms of
      congenital heart block (CHB) and transient cutaneous lesions, is an antibody
      mediated disorder due to placentally transmitted maternal autoantibodies to
      Ro/SSA and/or La/SSB. We genotyped 14 mothers, 9 children with CHB, 8 with
      cutaneous NLE only and 5 asymptomatic siblings at HLA class I loci, by the
      polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)
      combined with sequence-specific amplification. Mothers of children with NLE
      exhibited a very high polymorphism of HLA class I genes. Significant increases of
      HLA-B*1501 (B62) and Cw*0303 (Cw9) with absence of HLA-A1/B8 haplotype in
      Japanese mothers differed from the serologically defined HLA class I profiles
      among NLE mothers in white and North American black populations. Child/mother
      heterozygous HLA-A/B/C haplotype identity, which extended to HLA-class II DR/DQ
      loci, was observed in only one of 9 cases with CHB. No association was found
      between HLA class I alleles of children and the symptoms of NLE. These findings
      provide for the opportunity to investigate the primary genetic associations with
      NLE/CHB in different ethnic groups.

PMID- 10602449
TI  - The composition of the lupus band test (LBT) on the sun-protected non-lesional
      (SPNL) skin in patients with cutaneous lupus erythematosus (CLE).
AB  - The objective of this study was to analyse the different immunoreactants at the
      dermo-epidermal junction (DEJ) of patients with cutaneous lupus erythematosus
      (CLE). Sun-protected non lesional (SPNL) skin biopsies from 65 patients with
      specific cutaneous manifestations of LE and from 18 patients with other
      dermatologic diseases were tested using the direct immunofluorescence (DIF)
      technique. Nineteen out of 65 patients with CLE were affected by systemic LE
      (SLE). We used the conventional chi-squared test to analyse statistical
      differences between CLE-SLE and CLE-non-SLE groups in the immunological
      composition of lupus band test (LBT). C3 was the most common component while IgM
      were the most frequent immunoglobulins (Igs) of LBT in LE patients. No
      immunoreactants could be demonstrated at the DEJ in patients with other
      dermatologic diseases. No statistical differences could be found between CLE-SLE
      and CLE-non-SLE groups as regards the detection of the different immunoreactants
      at the DEJ. A positive LBT (even for the presence of only one immunoreactant at
      the DEJ) performed on SPNL skin represents a useful and specific criterion to
      distinguish patients with lupus erythematosus (LE) from those without LE. We also
      believe in a prognostic value of a positive LBT on SPNL skin when the deposition
      of at least two immunoreactants is demonstrated, and especially if the deposits
      are composed of IgG.

PMID- 10602450
TI  - Relationship between clinical features and binding domains of anti-prothrombin
      autoantibodies in patients with systemic lupus erythematosus and antiphospholipid
      syndrome.
AB  - Autoantibodies against prothrombin, including lupus anticoagulant antibodies
      (LAC), have been identified in patients with systemic lupus erythematosus (SLE)
      and antiphospholipid syndrome (APS). To identify the epitopes of LAC in patients
      with SLE and APS, we analyzed B cell epitopes of anti-prothrombin Abs.
      Prothrombin was purified from fresh plasma samples from healthy subjects, and
      fragmented by thrombin. Two fragments (prethrombin-1, 50 kDa, and fragment-1, 22
      kDa) were separated and used for further experiments. The two fragments were
      coated on irradiated plate and the binding activities of sera from 13 patients
      with anti-prothrombin Abs (SLE, 7; APS, 4; SLE+APS, 2) were determined by using
      ELISA. The assay was conducted under the following conditions: use of irradiated
      plates, and TBS containing Tween-20. We detected two types of anti-prothrombin
      Abs. The first was anti-prethrombin-1 (n=5) while the other was Ab against
      fragment-1 (n=8). There were no patients with Abs that showed binding activities
      to both fragments. A higher proportion of patients with thrombosis were positive
      for anti-prethrombin-1 Abs (80%) than for anti-fragment-1 Abs (25%). Two patients
      with anti-prethrombin-1 Ab were positive for LAC and negative for anti
      cardiolipin-beta2 glycoprotein I antibody (aCL-beta2GPI). Our results strongly
      support the notion that both prethrombin-1 and fragment-1 on prothrombin molecule
      are B cell epitopes.

PMID- 10602451
TI  - Successful treatment of lupus with fludarabine.
AB  - We describe a 58-year old patient with chronic lymphocytic leukemia (CLL) who
      developed systemic lupus erythematosus (SLE) with severe joint involvement.
      Dilated myocardiopathy precluded the use of high corticoid doses and a 15 days of
      prednisone (15mg/d) had no effect on the polyarthritis. Therefore, fludarabine
      (25mg/m2) was administered for 5 d. One month after the first cycle, fever,
      muscle stiffness and polyarthritis resolved. A total of 6 cycles were
      administered. The evolution was complicated by herpes zoster infection and left
      pneumococcal pneumonia. At this time of writing (July 1999), the patient is
      symptom free but is profoundly lymphopenic.

PMID- 10602452
TI  - Generalized periodontal involvement in a young patient with systemic lupus
      erythematosus.
AB  - Inflammation is considered to be a leading cause of morbidity in systemic lupus
      erythematosus (SLE), yet inflammatory periodontal involvement is rarely
      encountered. A young lady suffering from active SLE accompanied by severe
      periodontal loss, manifested by gingival recession of all her teeth, was referred
      to our clinic for treatment. The association between periodontal involvement and
      connective tissue diseases is unclear, and the literature dealing with
      periodontal involvement in patients suffering from Sjogren's syndrome and
      rheumatoid arthritis is comprised of studies showing both normal and pathological
      periodontal status. We discuss the possible underlying mechanisms.

PMID- 10602453
TI  - Minocycline-induced clinical and biological lupus-like disease.
AB  - A 14-year-old girl developed maculopapular rash, myalgias, arthralgias and
      myocarditis with elevated anti-nuclear and anti-double-stranded DNA antibodies.
      She was taking minocycline for acne and all symptoms resolved when this treatment
      was stopped. The patient has no evidence of disease one year after onset of
      symptoms. Clinicians should be aware of minocycline's responsibility in inducing
      lupus-like disease.

PMID- 10602454
TI  - Hughes syndrome associated with cytomegalovirus infection.
AB  - We report the case of a patient with an acute cytomegalovirus (CMV) infection who
      developed Hughes syndrome, manifested by a common iliac vein thrombosis. IgM
      anticardiolipin antibodies (aCL) appeared with the onset of the infection,
      followed later by IgG aCL. Five months later, both IgM and IgG aCL levels
      disappeared from the serum. This is the second case of Hughes syndrome associated
      with CMV infection to be reported in the literature.

PMID- 10602455
TI  - Sickle cell/beta0-thalassemia and systemic lupus erythematosus.

PMID- 10602456
TI  - Transient thyrotoxicosis in primary anti-phospholipid syndrome.

PMID- 10602458
TI  - Keyword index volume 8 1999

PMID- 10602459
TI  - The Rel/NF-kappaB signal transduction pathway: introduction.

PMID- 10602460
TI  - Regulation of DNA binding by Rel/NF-kappaB transcription factors: structural
      views.
AB  - Rel/NF-kappaB transcription factors form homo- and heterodimers with different
      DNA binding site specificities and DNA binding affinities. Several intracellular
      pathways evoked by a wide range of biological factors and environmental
      conditions can lead to the activation of Rel/NF-kappaB dimers by signaling
      degradation of the inhibitory IkappaB protein. In the nucleus Rel/NF-kappaB
      dimers modulate the expression of a variety of genes including those encoding
      cytokines, growth factors, acute phase response proteins, immunoreceptors, other
      transcription factors, cell adhesion molecules, viral proteins and regulators of
      apoptosis. The primary focus of this review is on structural and functional
      aspects of Rel/NF-kappaB:DNA complexes and their formation. The salient features
      of the Rel/NF-kappaB dimer:DNA structure are described, as are modes of
      transcriptional regulation by phosphorylation, altered DNA binding properties,
      varying protein conformations, and interactions with IkappaB proteins.

PMID- 10602461
TI  - Activators and target genes of Rel/NF-kappaB transcription factors.
AB  - The vertebrate transcription factor NF-kappaB is induced by over 150 different
      stimuli. Active NF-kappaB, in turn, participates in the control of transcription
      of over 150 target genes. Because a large variety of bacteria and viruses
      activate NF-kappaB and because the transcription factor regulates the expression
      of inflammatory cytokines, chemokines, immunoreceptors, and cell adhesion
      molecules, NF-kappaB has often been termed a 'central mediator of the human
      immune response'. This article contains a complete listing of all NF-kappaB
      inducers and target genes described to date. The collected data argue that NF
      kappaB functions more generally as a central regulator of stress responses. In
      addition, NF-kappaB activation blocks apoptosis in several cell types. Coupling
      stress responsiveness and anti-apoptotic pathways through the use of a common
      transcription factor may result in increased cell survival following stress
      insults.

PMID- 10602462
TI  - How NF-kappaB is activated: the role of the IkappaB kinase (IKK) complex.
AB  - Rel/NF-kappaB transcription factors are primarily regulated by association with
      inhibitor IkappaB proteins. Thus, in most cells NF-kappaB exists in the cytoplasm
      in an inactive complex bound to IkappaB. Most agents that activate NF-kappaB do
      so through a common pathway based on phosphorylation-induced, proteasome-mediated
      degradation of IkappaB. The key regulatory step in this pathway involves
      activation of a high molecular weight IkappaB kinase (IKK) complex, whose
      catalysis is generally carried out by a heterodimeric kinase consisting of
      IKKalpha and IKKbeta subunits. This review describes the identification of
      proteins in the IKK complex, and the regulation and physiological functions of
      IKK.

PMID- 10602463
TI  - Control of development and immunity by rel transcription factors in Drosophila.
AB  - The Drosophila Rel/NF-kappaB transcription factors - Dorsal, Dif, and Relish -
      control several biological processes, including embryonic pattern formation,
      muscle development, immunity, and hematopoiesis. Molecular-genetic analysis of 12
      mutations that cause embryonic dorsal/ventral patterning defects has defined the
      steps that control the formation of this axis. Regulated activation of the Toll
      receptor leads to the establishment of a gradient of nuclear Dorsal protein,
      which in turn governs the subdivision of the axis and specification of ventral,
      lateral and dorsal fates. Phenotypic analysis of dorsal-ventral embryonic mutants
      and the characterization of the two other fly Rel proteins, Dif and Relish, have
      shown that the intracellular portion of the Toll to Cactus pathway also controls
      the innate immune response in Drosophila. Innate immunity and hematopoiesis are
      regulated by analogous Rel/NF-kappaB-family pathways in mammals. The elucidation
      of the complex regulation and diverse functions of Drosophila Rel proteins
      underscores the relevance of basic studies in Drosophila.

PMID- 10602464
TI  - Genetic approaches in mice to understand Rel/NF-kappaB and IkappaB function:
      transgenics and knockouts.
AB  - Rel/NF-kappaB transcription factors have been implicated in regulating a wide
      variety of genes important in cellular processes that include cell division, cell
      survival, differentiation and immunity. Here genetic models in which various
      Rel/NF-kappaB and IkappaB proteins have either been over-expressed or deleted in
      mice will be reviewed. Although expressed fairly ubiquitously, homozygous
      disruption of individual Rel/NF-kappaB genes generally affects the development of
      proper immune cell function. One exception is rela, which is essential for
      embryonic liver development. The disruption of genes encoding the individual
      subunits of the IkappaB kinase, namely IKKalpha and IKKbeta, has demonstrated
      that IKKbeta transmits the response to most common NF-kappaB inducing agents,
      whereas IKKalpha has an unexpected role in keratinocyte differentiation. Future
      studies will no doubt focus on the effect of multiple gene disruptions of members
      of this signaling pathway, on tissue-specific disruptions of these genes, and on
      the use of these mice as models for human diseases.

PMID- 10602465
TI  - Diverse agents act at multiple levels to inhibit the Rel/NF-kappaB signal
      transduction pathway.
AB  - Rel/NF-kappaB transcription factors regulate several important physiological
      processes, including developmental processes, inflammation and immune responses,
      cell growth, cancer, apoptosis, and the expression of certain viral genes.
      Therefore, they have also been sought-after molecular targets for pharmacological
      intervention. As details of the Rel/NF-kappaB signal transduction pathway are
      revealed, it is clear that modulators of this pathway can act at several levels.
      Inhibitors of the Rel/NF-kappaB pathway include a variety of natural and designed
      molecules, including anti-oxidants, proteasome inhibitors, peptides, small
      molecules, and dominant-negative or constitutively active polypeptides in the
      pathway. Several of these molecules act as general inhibitors of Rel/NF-kappaB
      induction, whereas others inhibit specific pathways of induction. Inhibitors of
      Rel/NF-kappaB are likely to gain stature as treatments for certain cancers and
      neurodegenerative and inflammatory diseases.

PMID- 10602466
TI  - Control of apoptosis by Rel/NF-kappaB transcription factors.
AB  - Apoptosis is a physiological process critical for organ development, tissue
      homeostasis, and elimination of defective or potentially dangerous cells in
      complex organisms. Apoptosis can be initiated by a wide variety of stimuli, which
      activate a cell suicide program that is constitutively present in most vertebrate
      cells. In diverse cell types, Rel/NF-kappaB transcription factors have been shown
      to have a role in regulating the apoptotic program, either as essential for the
      induction of apoptosis or, perhaps more commonly, as blockers of apoptosis.
      Whether Rel/NF-kappaB promotes or inhibits apoptosis appears to depend on the
      specific cell type and the type of inducer. An understanding of the role of
      Rel/NF-kappaB transcription factors in controlling apoptosis may lead to the
      development of therapeutics for a wide variety of human diseases, including
      neurodegenerative and immune diseases, and cancer.

PMID- 10602467
TI  - Multiple mutations contribute to the oncogenicity of the retroviral oncoprotein v
      Rel.
AB  - The avian Rev-T retrovirus encodes the v-Rel oncoprotein, which is a member of
      the Rel/NF-kappaB transcription factor family. v-Rel induces a rapidly fatal
      lymphoma/leukemia in young birds, and v-Rel can transform and immortalize a
      variety of avian cell types in vitro. Although Rel/NF-kappaB transcription
      factors have been associated with oncogenesis in mammals, v-Rel is the only
      member of this family that is frankly oncogenic in animal model systems. The
      potent oncogenicity of v-Rel is the consequence of a number of mutations that
      have altered its activity and regulation: for example, certain mutations decrease
      its ability to be regulated by IkappaBalpha, change its DNA-binding site
      specificity, and endow it with new transactivation properties. The study of v-Rel
      will continue to increase our knowledge of how cellular Rel proteins contribute
      to oncogenesis by affecting cell growth, altering cell-cycle regulation, and
      blocking apoptosis. This review will discuss biological and molecular activities
      of v-Rel, with particular attention to how these activities relate to structure -
      function aspects of the Rel/NF-kappaB transcription factors.

PMID- 10602468
TI  - Aberrant rel/nfkb genes and activity in human cancer.
AB  - Rel/NF-kappaB transcription factors are key regulators of immune, inflammatory
      and acute phase responses and are also implicated in the control of cell
      proliferation and apoptosis. Remarkable progress has been made in understanding
      the signal transduction pathways that lead to the activation of Rel/NF-kappaB
      factors and the consequent induction of gene expression. Evidence linking
      deregulated Rel/NF-kappaB activity to oncogenesis in mammalian systems has
      emerged in recent years, consistent with the acute oncogenicity of the viral
      oncoprotein v-Rel in animal models. Chromosomal amplification, overexpression and
      rearrangement of genes coding for Rel/NF-kappaB factors have been noted in many
      human hematopoietic and solid tumors. Persistent nuclear NF-kappaB activity was
      also described in several human cancer cell types, as a result of constitutive
      activation of upstream signaling kinases or mutations inactivating inhibitory
      IkappaB subunits. Studies point to a correlation between the activation of
      cellular gene expression by Rel/NF-kappaB factors and their participation in the
      malignant process. Experiments implicating NF-kappaB in the control of the
      apoptotic response also support a role in oncogenesis and in the resistance of
      tumor cells to chemotherapy. This review focuses on the status of the rel, nfkb
      and ikb genes and their activity in human tumors and their association with the
      onset or progression of malignancies.

PMID- 10602469
TI  - Persistent activation of NF-kappaB by the tax transforming protein of HTLV-1:
      hijacking cellular IkappaB kinases.
AB  - Biochemical coupling of transcription factor NF-kappaB to antigen and co
      stimulatory receptors is required for the temporal control of T-cell
      proliferation. In contrast to its transitory activation during normal growth
      signal transduction, NF-kappaB is constitutively deployed in T-cells transformed
      by the type 1 human T-cell leukemia virus (HTLV-1). This viral/host interaction
      is mediated by the HTLV-1-encoded Tax protein, which has potent oncogenic
      properties. As reviewed here, Tax activates NF-kappaB primarily via a pathway
      leading to the chronic phosphorylation and degradation of IkappaBalpha, a
      cytoplasmic inhibitor of NF-kappaB. To access this pathway, Tax associates stably
      with a cytokine-inducible IkappaB kinase (IKK), which contains both catalytic
      (IKKalpha and IKKbeta) and noncatalytic (IKKgamma) subunits. Unlike their
      transiently induced counterparts in cytokine-treated cells, Tax-associated forms
      of IKKalpha and IKKbeta are persistently activated in HTLV-1-infected T cells.
      Acquisition of the deregulated IKK phenotype is contingent on the presence of
      IKKgamma, which functions as a molecular adaptor in the assembly of pathologic
      Tax/IkappaB kinase complexes. These findings highlight a key mechanistic role for
      IKK in the Tax/NF-kappaB signaling axis and define new intracellular targets for
      the therapeutic control of HTLV-1-associated disease.

PMID- 10602470
TI  - Epstein-barr virus transformation: involvement of latent membrane protein 1
      mediated activation of NF-kappaB.
AB  - Epstein-Barr virus (EBV) transforms resting primary human B lymphocytes into
      indefinitely proliferating lymphoblastoid cell lines in vitro and is associated
      with several human malignancies in vivo. Recombinant EBV genetic analyses
      combined with in vitro B lymphocyte transformation assays demonstrate that latent
      infection membrane protein 1 (LMP1) is essential for EBV-mediated lymphocyte
      transformation. LMP1 has no intrinsic enzymatic activity but instead aggregates
      cellular proteins of the tumor necrosis factor receptor signaling pathway to
      activate transcription factor NF-kappaB. Mutants rendering LMP1 defective in
      these protein interactions are impaired in their abilities to activate NF-kappaB
      in reporter gene assays. Concordantly, EBV recombinants with LMP1 mutations that
      are compromised for NF-kappaB activation are impaired for growth transformation.
      Thus, EBV-mediated growth transformation is genetically and biochemically linked
      to LMP1-mediated activation of NF-kappaB.

PMID- 10602471
TI  - Oncogenic mutant of Galpha12 stimulates cell proliferation through cycloxygenase
      2 signaling pathway.
AB  - Expression of the GTPase-deficient, activated mutant alpha-subunit of the
      heterotrimeric G protein G12 (Galpha12QL) leads to the neoplastic transformation
      of fibroblast cell lines. The mitogenic pathway regulated by Galpha12QL includes
      an extensive signaling network involving several small GTPases and various
      kinases. In addition, Galpha12QL has been shown to potentiate the serum-induced
      phospholipase-A2 activity in NIH3T3 cells. In the present study, we demonstrate
      that cycloxygenase-2 (COX-2) pathway is involved in the mitogenic pathway
      activated by Galpha12QL. Expression of Galpha12QL and not Galpha13QL, stimulates
      the serum-induced release of arachidonic acid in NIH3T3 cells. Furthermore,
      expression of Galpha12QL or the stimulation of wild-type Galpha12 induces the
      expression of COX-2. Our results also indicate that the COX-2 inhibitor acutely
      disrupts the DNA-synthesis stimulated by Galpha12QL in NIH3T3 cells. These
      studies, for the first time, identify the crucial role of COX-2 in Galpha12
      mediated regulation of cell proliferation and suggest a role for prostaglandin
      derived autocrine loop in Galpha12-mediated signaling pathways.

PMID- 10602472
TI  - Myeloproliferative disorder and leukaemia in mice induced by different classes of
      constitutive mutants of the human IL-3/IL-5/GM-CSF receptor common beta subunit.
AB  - Several constitutively active mutant forms of the common beta subunit of the
      human IL-3, IL-5 and GM-CSF receptors (hbetac), which enable it to signal in the
      absence of ligand, have recently been described. Two of these, V449E and I374N,
      are amino acid substitutions in the transmembrane and extracellular regions of
      hbetac, respectively. A third, FIDelta, contains a 37 amino acid duplication in
      the extracellular domain. We have shown previously that when expressed in primary
      murine haemopoietic cells, the extracellular mutants confer factor-independence
      on cells of the neutrophil and monocyte lineages only, whereas V449E does so on
      all cell types of the myeloid and erythroid compartments. To study the in vivo
      effects and leukaemic potential of these mutants, we have expressed all three in
      mice by bone marrow reconstitution using retrovirally infected donor cells.
      Expression of the extracellular mutants leads to an early onset, chronic
      myeloproliferative disorder marked by elevations in the neutrophil, monocyte,
      erythrocyte and platelet lineages. In contrast, expression of V449E leads to an
      acute leukaemia-like syndrome of anaemia, thrombocytopaenia and blast cell
      expansion. These data support the possibility that activating mutations in hbetac
      are involved in haemopoietic disorders in man.

PMID- 10602473
TI  - DNA binding of USF is required for specific E-box dependent gene activation in
      vivo.
AB  - Although USF-1 and -2 are the major proteins that bind to Myc-regulated E-box
      (CACGTG) elements in many cells, there is no clear role for USF during Myc
      dependent gene regulation. Using dominant negative alleles of USF-1 we now show
      that DNA binding by USF at a Myc-regulated E-box limits the ability of another E
      box binding factor, TFE-3, to activate a target gene of Myc in vivo and to
      stimulate S phase entry in resting fibroblasts. Similarly, dominant negative
      alleles of USF-1 relieve the restriction that prevents activation of the IgH
      enhancer by TFE-3 in non B-cells. DNA binding activity of USF complexes is
      abundant in primary human B-cells and is significantly downregulated during B
      cell immortalization. Re-expression of USF-1 in immortalized B-cells retards
      proliferation. Our data establish an essential role for USF in restricting E-box
      dependent gene activation in vivo and suggest that this control is relaxed during
      cellular immortalization.

PMID- 10602474
TI  - C-terminal truncation of Dlk/ZIP kinase leads to abrogation of nuclear transport
      and high apoptotic activity.
AB  - Dlk (also termed ZIP kinase) is a novel serine/threonine kinase with a unique C
      terminal domain that is rich in arginine and contains three putative NLS motifs
      and a functional lecuine zipper. Dlk is indeed localized in the nucleus where it
      shows a speckled distribution. To elucidate the biological functions of Dlk, we
      wanted to identify the signals relevant for nuclear transport and further the
      nuclear structures which Dlk binds to. Expression of various deletion and point
      mutations of Dlk as GFP fusion proteins revealed that the leucine zipper is
      required for association with speckles and the most C-terminal NLS is necessary
      and sufficient for nuclear transport. Interestingly, a C-terminal deletion mutant
      defective for nuclear transport exhibited a pronounced colocalization with actin
      filaments and, even more strikingly, was a very potent inducer of apoptosis. This
      apoptotic activity was abrogated, however, when this mutant was retargeted to the
      nucleus via a heterologous NLS from large T, indicating that Dlk only exerts an
      apoptotic activity in the cytoplasm. To identify the speckle like structures to
      which Dlk binds we performed immunofluorescence analyses with antibodies directed
      against representative marker proteins of replication, transcription, or splicing
      centers. None of these marker proteins revealed a colocalization with Dlk.
      Instead, we found a partial colocalization with PML bodies which seem to play a
      key role in regulation of apoptosis. Taken together, these data strongly suggest
      a functional role for Dlk in control of cell survival which is dependent on its
      subcellular localization.

PMID- 10602475
TI  - Dysregulated expression of beta-catenin marks early neoplastic change in Apc
      mutant mice, but not all lesions arising in Msh2 deficient mice.
AB  - We have analysed the pattern of beta-catenin expression by immunohistochemistry
      in mice singly or multiply mutant for Apc, p53 and Msh2. We observed increased
      expression of beta-catenin in all intestinal lesions arising on an ApcMin+/-
      background. In all categories of lesion studied mosaic patterns of beta-catenin
      expression were observed, with the proportion of cells showing enhanced
      expression decreasing with increasing lesion size. p53 status did not alter these
      patterns. We also show that beta-catenin dysregulation marks pancreatic
      abnormalities occurring in ApcMin+/- and (ApcMin+/-, p53-/-) mice. In these mice
      both adenomas and adenocarcinomas of the pancreas arose and were characterized by
      increased expression of beta-catenin. We have extended these analyses to
      intestinal lesions arising in mice mutant for the mismatch repair gene Msh2. In
      these mice, increased expression of beta-catenin was again observed. However, in
      contrast with ApcMin+/- mice, a subset of lesions retained normal expression.
      Taken together, these findings show that increased expression of beta-catenin is
      an efficient marker of early neoplastic change in both murine intestine and
      pancreas in Apc mutant mice. However, we also show that dysregulation of beta
      catenin is not an obligate step in the development of intestinal lesions, and
      therefore that genetic events other than the loss of Apc function may initiate
      the transition from normal to neoplastic epithelium.

PMID- 10602476
TI  - v-Myb can transform and regulate the differentiation of melanocyte precursors.
AB  - The activity of the c-Myb transcription factor is essential for the development
      of definitive multi- and uni-lineage progenitors of the haemopoietic system.
      Reflecting this requirement, c-Myb has been oncogenically activated by
      transduction in the E26 avian retrovirus which elicits an acute leukaemia by
      transforming haemopoietic progenitors. Here, we report the novel finding that Myb
      in cooperation with EGF receptor signalling can be used to generate clonally
      expanded populations of transformed cells which have the phenotype of melanocyte
      precursors. Through the use of a conditional temperature sensitive mutant of Myb,
      we show that in the transformed cells Myb regulates commitment to melanocyte
      differentiation and possibly proliferation. These results add to our
      understanding of the roles of c-Myb beyond the haemopoietic system and to our
      knowledge and means of investigating the importance of transcription factors in
      the melanocyte lineage.

PMID- 10602477
TI  - Tumour suppressive properties of fibroblast growth factor receptor 2-IIIb in
      human bladder cancer.
AB  - FGFRs (fibroblast growth factor receptors) are encoded by four genes (FGFR1-4).
      Alternative splicing results in various receptor isoforms. The FGFR2-IIIb variant
      is present in a wide variety of epithelia, including the bladder epithelium.
      Recently, we have shown that FGFR2-IIIb is downregulated in a subset of
      transitional cell carcinomas of the bladder, and that this downregulation is
      associated with a poor prognosis. We investigated possible tumour suppressive
      properties of FGFR2-IIIb by transfecting two human bladder tumour cell lines, J82
      and T24, which have no endogenous FGFR2-IIIb expression, with FGFR2-IIIb cDNA. No
      stable clones expressing FGFR2-IIIb were isolated with the J82 cell line. For the
      T24 cell line, stable transfectants expressing FGFR2-IIIb had reduced growth in
      vitro and formed fewer tumours in nude mice which, in addition, grew more slowly.
      The potential mechanisms leading to decreased FGFR2-IIIb mRNA levels were also
      investigated. The 5' region of the human FGFR2 gene was isolated and found to
      contain a CpG island which was partially methylated in more than half the cell
      lines and tumours which do not express FGFR2-IIIb. No homozygous deletion was
      identified in any of the tumours or cell lines with reduced levels of FGFR2-IIIb.
      Mutational analysis of the entire coding region of FGFR2-IIIb at the transcript
      level was performed in 33 bladder tumours. In addition to normal FGFR2-IIIb mRNA,
      abnormal transcripts were detected in two tumour samples. These abnormal mRNAs
      resulted from exon skipping which affected the region encoding the kinase domain.
      Altogether, these results show that FGFR2-IIIb has tumour growth suppressive
      properties in bladder carcinomas and suggest possible mechanisms of FGFR2 gene
      inactivation.

PMID- 10602478
TI  - Evidence for interaction between human PRUNE and nm23-H1 NDPKinase.
AB  - We have isolated a human and murine homologue of the Drosophila prune gene
      through dbEST searches. The gene is ubiquitously expressed in human adult
      tissues, while in mouse developing embryos a high level of expression is confined
      to the nervous system particularly in the dorsal root ganglia, cranial nerves,
      and neural retina. The gene is composed of eight exons and is located in the
      1q21.3 chromosomal region. A pseudogene has been sequenced and mapped to
      chromosomal region 13q12. PRUNE protein retains the four characteristic domains
      of DHH phosphoesterases. The synergism between prune and awdK-pn in Drosophila
      has led various authors to propose an interaction between these genes. However,
      such an interaction has never been supported by biochemical data. By using
      interaction-mating and in vitro co-immunoprecipitation experiments, we show for
      the first time the ability of human PRUNE to interact with the human homologue of
      awd protein (nm23-H1). In contrast, PRUNE is impaired in its interaction with nm
      23-H1-S120G mutant, a gain-of-function mutation associated with advanced
      neuroblastoma stages. Consistently, PRUNE and nm23-H1 proteins partially
      colocalize in the cytoplasm. The data presented are consistent with the view that
      PRUNE acts as a negative regulator of the nm23-H1 protein. We discuss how PRUNE
      regulates nm23-H1 protein and postulate possible implications of PRUNE in
      neuroblastoma progression.

PMID- 10602479
TI  - Serine phosphorylation of paxillin by heregulin-beta1: role of p38 mitogen
      activated protein kinase.
AB  - The mechanisms through which heregulin (HRG) regulates the progression of breast
      cancer cells to a more invasive phenotype are currently unknown. Recently we have
      shown that HRG treatment of breast cancer cells leads to the formation of
      lamellipodia/filopodia, and increased cell migration and invasiveness through the
      phosphatidylinositol 3-kinase (PI-3 kinase). Since the process of cell migration
      must involve changes in adhesion, we explored the potential HRG regulation of
      paxillin, a major cytoskeletal phosphoprotein of focal adhesion. We report that
      HRG stimulation of non-invasive breast cancer cells resulted in stimulation of
      p38 mitogen-activated protein kinase (p38MAPK), extracellular signal-regulated
      kinases (ERK) and PI-3K, and a concurrent unexpected increase in the level of
      paxillin phosphorylation on serine residue which was sensitive to protein
      phosphatase 2b but not to protein tyrosine phosphatase 1. In addition, HRG
      triggered a rapid redistribution of paxillin to the perinuclear regions from the
      tyrosine-phosphorylated focal adhesions, and increased cell scattering. There was
      no effect of HRG on the state of phosphorylation and localization of focal
      adhesion kinase. The HRG-induced increase in serine phosphorylation of paxillin
      and cell scattering were selectively inhibited by a specific inhibitor of p38MAPK
      or a dominant-negative p38MAPK mutant, but not by inhibitors of p42/44MAPK or PI
      3 kinase pathways. For the first time our results have shown that HRG, a potent
      migratory growth factor stimulates serine phosphorylation of paxillin. These
      findings suggest a role of p38MAPK-dependent signal transduction pathway(s) in
      serine phosphorylation and disassembly of the paxillin from the focal complexes
      during HRG-induced cell shape alterations and motility.

PMID- 10602480
TI  - Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4
      results in cytoplasmic retention and apoptosis.
AB  - Dlk/ZIP kinase is a newly discovered serine/threonine kinase which, due to its
      homology to DAP kinase, was named DAP like kinase, Dlk. This kinase is tightly
      associated with nuclear structures, it undergoes extensive autophosphorylation
      and phosphorylates myosin light chain and core histones H3, H2A and H4 in vitro.
      Moreover, it possesses a leucine zipper which mediates interaction with
      transcription factor ATF-4, therefore it was called ZIP kinase. We employed the
      yeast two-hybrid system to identify interaction partners of Dlk that might serve
      as regulators or targets. Besides ATF-4 and others we found Par-4, a modulator of
      transcription factor WT1 and mediator of apoptosis. Complex formation between Dlk
      and Par-4 was confirmed by GST pull-down experiments and kinase reactions in
      vitro and coexpression experiments in vivo. The interaction domain within Dlk was
      mapped to an arginine-rich region between residues 338 - 417, rather than to the
      leucine zipper. Strikingly, coexpression of Dlk and Par-4 lead to relocation of
      Dlk from the nucleus to the cytoplasm, particularly to actin filaments. These
      interactions provoked a dramatic reorganization of the cytoskeleton and
      morphological symptoms of apoptosis, thus suggesting a functional relationship
      between Dlk and Par-4 in the control of apoptosis.

PMID- 10602481
TI  - Extinction of E-cadherin expression in breast cancer via a dominant repression
      pathway acting on proximal promoter elements.
AB  - Inactivation of the E-cadherin cell adhesion molecule is believed critical in the
      development and behavior of many epithelial cancers, though mutations in the E
      cadherin gene account for inactivation in only a fraction of cases. In many
      breast cancer lines, E-cadherin transcription is extinguished, but the role and
      significance of alterations in trans-acting transcription factors, promoter
      hypermethylation, and chromatin changes remain unresolved. To gain further
      insights into mechanisms underlying E-cadherin inactivation in breast cancer, we
      analysed somatic cell hybrids resulting from pairwise fusions between breast
      cancer lines with intact E-cadherin transcription (E-cad+) and lines lacking E
      cadherin transcription (E-cad-). All hybrid lines failed to express E-cadherin
      transcripts and protein, despite the fact that E-cadherin alleles from E-cad+
      lines were present in the hybrids. Elements in the proximal 108 bp of the E
      cadherin promoter, when present in reporter gene constructs, were sufficient to
      direct strong transcription in E-cad+ breast lines, but displayed weak activity
      in E-cad- parental lines and hybrids. E-cadherin expression could not be restored
      in E-cad- lines or hybrids by treatment with a DNA demethylating agent and/or a
      histone deacetylase inhibitor. Our findings suggest loss of E-cadherin expression
      in some breast cancers may be due to dominant repression of the trans-acting
      pathways that regulate E-cadherin transcription.

PMID- 10602482
TI  - Transcriptional repression of the transforming growth factor-beta type I receptor
      gene by DNA methylation results in the development of TGF-beta resistance in
      human gastric cancer.
AB  - The transforming growth factor-beta (TGF-beta) signaling pathway subserves an
      essential tumor suppressor function in various cell types. A heteromeric complex
      composed of TGF-beta type I (RI) and type II (RII) receptors is required for TGF
      beta signaling. We have identified a subset of human gastric cancer cell lines
      which are insensitive to TGF-beta and which express a low level of TGF-beta type
      I receptor mRNA relative to a gastric cancer cell line which is highly responsive
      to TGF-beta. Using these cells, we show that hypermethylation of a CpG island in
      the 5' region of the TGF-beta RI gene provides another potentially important
      mechanism of escape from negative growth control by TGF-beta. This
      hypermethylation was found in four of five human gastric cancer cell lines and
      five out of 40 (12.5%) primary tumors examined. In human gastric cancer cell
      lines, treatment with the demethylating agent, 5-aza-2'-deoxycytidine, resulted
      in increased expression of the TGF-beta RI gene, but not the RII gene. Transient
      transfection of an RI expression vector into the TGF-beta resistant SNU-601 cell
      line restores TGF-beta responsiveness. These findings suggest that one of the
      mechanisms of escape from autocrine or paracrine growth control by TGF-beta
      during carcinogenesis could involve aberrant methylation of CpG islands in the 5'
      region of the TGF-beta RI gene.

PMID- 10602483
TI  - Damage-induced apoptosis in intestinal epithelia from bcl-2-null and bax-null
      mice: investigations of the mechanistic determinants of epithelial apoptosis in
      vivo.
AB  - The influence of bcl-2 and bax expression on apoptotic cell death in mouse
      intestinal epithelia was assessed using homozygously null mice. Apoptosis was
      induced in vivo by the enterotoxin 5-fluorouracil (5FU) or by gamma-irradiation
      and its cell positional incidence was assessed. 5FU and gamma-radiation treated
      bax-null mice surprisingly showed no reductions in apoptotic yield in the small
      intestine or midcolon at 4.5 h at cell positions in which both agents had
      previously been shown to strongly induce p53 protein expression. The colonic
      epithelia of 5FU treated bcl-2-null mice showed elevated levels of apoptosis at
      4.5 h: from 48 apoptotic events in wild-type mice to 273 in the nulls, scoring
      200 half crypts. The increase occurred specifically in the cell positions
      considered to harbour colonic stem cells, at the base of crypts, where there is
      selective expression of bcl-2. There was a modest but significant increase in
      apoptosis in the small intestine of the bcl-2-null mice although the epithelia of
      wild-type mice here are not immunohistochemically positive for bcl-2 protein.
      These findings show that bcl-2 plays a key role in determining the sensitivity of
      colonic stem cells to damage-induced death but that bax is not responsible for
      the p53-dependent induction of apoptosis in this context.

PMID- 10602484
TI  - Consequences of Stat6 deletion on Sis/PDGF- and IL-4-induced proliferation and
      transcriptional activation in murine fibroblasts.
AB  - Aberrant communication among growth factors and cytokines that regulate tissue
      homeostasis often results in malignancy. Among the many cell types that
      participate in this process, stromal fibroblasts communicate in a paracrine and
      juxtracrine manner with cells of epithelial, endothelial, and hematopoietic
      origin. For fibroblasts, platelet-derived growth factor (PDGF) is a major
      proliferative and differentiation agent. Interleukin-4 (IL-4), however, possesses
      only modulating functions in this cell type. Here, we investigated the
      consequences of deleting Stat6 on PDGF and IL-4 signaling, proliferation, and
      transcriptional activation by establishing and characterizing early passage
      fibroblasts from wild-type and Stat6 null mice. Both wild-type and Stat6-/-
      fibroblasts showed nearly identical PDGFR and IL-4R activation, gross substrate
      tyrosine phosphorylation, PI 3-kinase activation, as well as Stat1, 3 and 5 DNA
      binding activities. Unexpectedly, IL-4's enhancement of PDGF-induced
      [3H]thymidine incorporation was greatly diminished in Stat6-/-, but not wild-type
      fibroblasts. PDGF-induced [3H]thymidine uptake was largely unaffected.
      Strikingly, IL-4, but not PDGF induction of the proinflammatory gene products, IL
      6 and MCP-1 was markedly reduced in Stat6-/- fibroblasts. Thus, Stat6 is an
      important and specific mediator of IL-4-enhanced PDGF-induced proliferation as
      well as IL-4's transcriptional activation of IL-6 and MCP-1.

PMID- 10602485
TI  - A role of inhibin as a tumor suppressor in Sertoli cells: down-regulation upon
      aging and repression by a viral oncogene.
AB  - Inhibin, a member of the TGF-beta superfamily, is synthesized in the testis by
      Sertoli cells and exerts an endocrine regulatory function on pituitary hormone
      synthesis. A distinct local function has been proposed, negatively controlling
      cellular growth in the testis (tumor suppressor activity). A critical test for
      the identification of a tumor suppressor is the reversal of transformed growth
      properties upon re-expression of the gene in tumor-derived cell lines. Sertoli
      cell-derived tumoral lines were previously established from tumors that develop
      in elderly transgenic males which express in the testis the large T antigen of
      polyoma virus. Both the tumors and the cells in culture exhibited reduced levels
      of the inhibin alpha subunit mRNA. Stable transfectants were generated, in which
      this subunit was expressed from a heterologous promoter. All of them exhibited a
      strict inhibition of growth at confluency. On the other hand, in addition to an
      aging-related decrease in inhibin synthesis, the alpha subunit gene was down
      regulated in vivo in cells expressing the viral protein. The conjunction of these
      two factors accounts for the age-related occurrence of testicular cancers in the
      transgenic model, again pointing to inhibin as a potent cell growth regulator in
      the seminiferous epithelium.

PMID- 10602486
TI  - Influence of promoter DNA topology on sequence-specific DNA binding and
      transactivation by tumor suppressor p53.
AB  - Transcriptional activation by the tumor suppressor p53 is regulated at multiple
      levels, including posttranslational modifications of the p53 protein, interaction
      of p53 with various regulatory proteins, or at the level of sequence-specific DNA
      binding to the response elements in p53's target genes. We here propose as an
      additional regulatory mechanism that the DNA topology of p53-responsive promoters
      may determine the interaction of p53 with its target genes. We demonstrate that
      sequence-specific DNA binding (SSDB) and transcriptional activation by p53 of the
      mdm2 promoter is inhibited when this promoter is present in supercoiled DNA,
      where it forms a non-B-DNA structure which spans the p53-responsive elements.
      Relaxation of the supercoiled DNA in vitro resulted in conversion of the non-B
      DNA to a B-DNA conformation within the mdm2 promoter, and correlated with an
      enhanced SSDB of p53 and an elevated expression of a reporter gene. In contrast,
      sequence specific DNA binding and transcriptional activation of the p21 promoter
      were not inhibited by DNA supercoiling. We propose that conformational
      alterations within p53-responsive sites, which either promote or prohibit
      sequence specific DNA binding of p53, are an important feature in orchestrating
      the activation of different p53 responsive promoters.

PMID- 10602487
TI  - Expression of the SRF gene occurs through a Ras/Sp/SRF-mediated-mechanism in
      response to serum growth signals.
AB  - Serum Response Factor (SRF) plays a central role in the transcriptional response
      of mammalian cells to a variety of extracellular signals. It is a key regulator
      of many cellular early response genes which are believed to be involved in cell
      growth, differentiation, and development. The mechanism by which SRF activates
      transcription in response to mitogenic agents has been extensively studied,
      however, less is known about regulation of the SRF gene itself. Previously, we
      identified distinct regulatory elements in the SRF promoter that play a role in
      activation, including an ETS domain binding site, an overlapping Sp1/Egr-1
      binding site, and two SRF binding sites. We further showed that serum induces the
      SRF gene by a mechanism that requires an intact SRF binding site, also termed a
      CArG box. In the present study we demonstrate that in response to stimulation by
      cells by lysophosphatidic acid (LPA) or whole serum, the SRF promoter is
      upregulated by a bipartite pathway that requires both an Sp1 factor binding site
      and the CArG motifs for maximal stimulation. The CArG box-dependent component of
      this pathway is targeted by Rho mediated signals, and the Sp1 binding site
      dependent component is targeted by Ras mediated signals.

PMID- 10602488
TI  - Regulation of the forkhead transcription factor FKHR, but not the PAX3-FKHR
      fusion protein, by the serine/threonine kinase Akt.
AB  - Akt, a proto-oncogene that encodes a cytosolic serine/threonine kinase, can
      phosphorylate and modulate the activity of several proteins involved in cellular
      metabolism and survival. Recently, two mammalian highly related forkhead
      transcription factors FKHRL1 and AFX and their nematode homologue Daf-16 have
      been found to be targets of this kinase. Here we show that Akt, but not inactive
      Akt, represses the transcriptional activity of FKHR, another member of the
      forkhead family. FKHR mutants with alanine substitutions at three Akt
      phosphorylation consensus sites (T24, S256 and S319) were inhibited by Akt, but
      mutation of all three sites rendered FKHR resistant to suppression. By contrast,
      the transcriptional activity of the oncogenic PAX3-FKHR fusion protein,
      containing two consensus phosphorylation sites, was not inhibited by Akt.
      Importantly, Akt inhibited the translocation of FKHR to the nucleus, providing a
      mechanism by which Akt might regulate the transcriptional activity of FKHR.
      Consistent with this model, the localization of the PAX3-FKHR fusion protein was
      nuclear and was not altered by Akt. These results provide evidence that Akt
      inhibits the transcriptional activity of FKHR by controlling its trafficking into
      the nucleus and that oncogenic PAX3-FKHR can escape this negative regulation by
      Akt.

PMID- 10602489
TI  - Gamma-rays-induced death of human cells carrying mutations of BRCA1 or BRCA2.
AB  - There is now evidence to suggest that BRCA1 and BRCA2 are involved in the
      response of cells to DNA damage and cell cycle checkpoint control. This report
      examines the death pathways of human cells with various BRCA1 and BRCA2 genotypes
      after exposure to gamma-rays. A lack of functional BRCA1 and BRCA2 led to
      defective repair of DNA double-strand breaks in irradiated cells. This impairment
      resulted in a relaxation of cell cycle checkpoints, production of micronuclei,
      and a loss of proliferative capacity. Heterozygous BRCA1 and BRCA2 mutations also
      led to enhanced radiosensitivity, with an impaired proliferative capacity after
      irradiation. The existence of a phenotype related to radiosensitivity in BRCA1+/-
      and BRCA2+/- cells raises the question of the response of heterozygous women to
      radiation.

PMID- 10602490
TI  - Different functions are required for initiation and maintenance of
      immortalization of rat embryo fibroblasts by SV40 large T antigen.
AB  - We have used two different, but complementary assays to characterize functions of
      SV40 T antigen that are necessary for its ability to immortalize rat embryo
      fibroblasts. In accordance with previous work, we found that several functions
      were required. These include activities that map to the p53 binding domain and
      the amino terminal 176 amino acids which contain the J domain as well as the CR1
      and CR2 domain required for binding and sequestering the RB family of pocket
      proteins. Moreover, we found that even though activities dependent only upon the
      amino terminus were sufficient for immortalization they were unable to maintain
      it. This suggests that immortalization by these amino terminal functions requires
      either additional events or immortalization of a subset of cells within the
      heterogeneous rat embryo fibroblast population. We further found that an activity
      dependent upon amino acids 17 - 27 which remove a portion of the CR1 domain and
      the predicted alpha-1 helix of the J domain was not necessary to maintain growth
      but was required for direct immortalization suggesting that at least one of the
      functions required initially was not required to maintain the immortal state.
      This represents the first demonstration that some of the functions required for
      maintenance of the immortal state differ from those required for initiation of
      immortalization.

PMID- 10602491
TI  - Cyclin D3 accumulation and activity integrate and rank the comitogenic pathways
      of thyrotropin and insulin in thyrocytes in primary culture.
AB  - The proliferation of most normal cells depends on the synergistic interaction of
      several growth factors and hormones, but the cell cycle basis for this combined
      requirement remains largely uncharacterized. We have addressed the question of
      the requirement for insulin/IGF-1 also observed in many cell culture systems in
      the physiologically relevant system of primary cultures of dog thyroid epithelial
      cells stimulated by TSH, which exerts its mitogenic activity only via cAMP. The
      induction of cyclin A and cdc2, the phosphorylation of cdk2, the nuclear
      translocation of cdk4 and the assembly of cyclin D3-cdk4 complexes required the
      synergy of TSH and insulin. Cyclin D3 (the most abundant cyclin D) was necessary
      for the proliferation stimulated by TSH in the presence of insulin as shown by
      microinjection of a neutralizing antibody. Cyclin D3 accumulation and activity
      were differentially regulated by insulin and TSH, which points out this cyclin as
      an integrator that ranks these comitogenic pathways as supportive and activatory,
      respectively. Paradoxically TSH alone strongly repressed cyclin D3 accumulation.
      This inhibition was overridden by insulin, which markedly stimulated cyclin D3
      mRNA and protein accumulation, but failed to assemble cyclin D3-cdk4 complexes in
      the absence of TSH. TSH unmasked the DCS-22 epitope of cyclin D3 and assembled
      cyclin D3-cdk4 in the presence of insulin. These data demonstrate that cyclin D
      synthesis and cyclin D-cdk assembly can be dissociated and complementarily
      regulated by different agents and signalling pathways.

PMID- 10602492
TI  - Transcriptional elongation of c-myb is regulated by NF-kappaB (p50/RelB).
AB  - High levels of c-myb expression are necessary for the proliferation of
      hematopoietic precursor cells whereas down-regulation of c-myb is required for
      terminal differentiation; this down-regulation occurs through a conditional block
      to transcriptional elongation in intron I. We previously observed that cAMP
      analogs prevented the late down-regulation of c-myb during hexamethylene
      bisacetamide (HMBA)-induced differentiation of murine erythroleukemia (MEL) cells
      and blocked differentiation; this correlated with the induction of NF-kappaB
      (p50/RelB) complexes which were shown to bind to NF-kappaB recognition sites
      flanking the transcriptional pause site of c-myb. We now selected stably
      transfected MEL cells which overexpressed p50, RelB or both at levels similar to
      those induced by cAMP to determine whether these NF-kappaB proteins regulate c
      myb expression in intact cells. We demonstrate that transcriptionally active NF
      kappaB (p50/RelB) complexes, but not p50 or RelB alone, prevented the early and
      late down-regulation of c-myb mRNA and increased c-myb transcriptional elongation
      in HMBA-induced MEL cells. The increase in c-myb expression was sufficient to
      block erythroid differentiation and allow continuous proliferation of cells in
      the presence of HMBA. Steady-state c-myb mRNA levels in untreated cells were not
      affected by overexpression of NF-kappaB, suggesting that p50/RelB specifically
      modulated the efficiency of transcriptional attenuation during MEL cell
      differentiation.

PMID- 10602493
TI  - Caspase-mediated cleavage and functional changes of hematopoietic progenitor
      kinase 1 (HPK1).
AB  - Activation of c-Jun N-terminal kinase (JNK) by Fas ligation is caspase-dependent,
      suggesting that caspases may regulate activators of the JNK pathway. Here, we
      report that an upstream activator of JNK, hematopoietic progenitor kinase 1
      (HPK1), was cleaved during apoptosis. Cleavage of HPK1 was blocked by peptide
      inhibitors for caspases. HPK1 was efficiently processed by recombinant caspase 3
      in vitro. A conserved caspase recognition site, DDVD (amino acids 382 - 385), was
      found in the HPK1 protein sequence. By testing HPK1 proteins with in vivo and in
      vitro cleavage assays, we showed that aspartic acid residue 385 is the target for
      caspases. HPK1 cleavage separated the amino N-terminal kinase domain from the
      carboxyl C-terminal regulatory domain, and enhanced HPK1 kinase activity. Unlike
      the full-length HPK1, the N-terminal cleaved product failed to bind adaptor
      molecules Grb2 (growth factor receptor-bound protein 2) and Crk (CT10 regulator
      of kinase). The C-terminal fragment, although having three proline-rich domains,
      bound to Grb2 and Crk less efficiently than the full-length HPK1 protein. Taken
      together, the cleavage of HPK1 by caspase profoundly changed its biochemical
      properties.

PMID- 10602494
TI  - Effects on normal fibroblasts and neuroblastoma cells of the activation of the
      p53 response by the nuclear export inhibitor leptomycin B.
AB  - p53 tumour suppressor protein levels and p53-dependent transcriptional activity
      have been recently shown to increase in cells treated with leptomycin B (LMB), an
      inhibitor of nuclear export. Experiments presented here show that LMB treatment
      leads to growth arrest and a senescence-like phenotype in human normal fibroblast
      cultures. This effect is reversible after removal of the drug and further passage
      by trypsinization. Instead, LMB has a strong cytotoxic effect on human
      neuroblastoma cell lines even at nanomolar concentrations. In both these cell
      types the effects of LMB are attenuated when the activity of the endogenous wild
      type p53 protein is abrogated by overexpression of a dominant negative p53
      mutant. We conclude that the induction of the p53 response by LMB plays an
      important role in the effects of this drug on cultured cells.

PMID- 10602495
TI  - Identification of three distinct regions of deletion on the long arm of
      chromosome 11 in childhood acute lymphoblastic leukemia.
AB  - Cytogenetic analysis of childhood acute lymphoblastic leukemia (ALL) identified
      deletions of chromosome arm 11q. These observations led us to analyse the loss of
      heterozygosity (LOH) of chromosome arm 11q in 113 primary childhood ALL samples
      using 14 microsatellite markers. LOH was found in 18 (16%) patients. Detailed
      examination identified three distinct regions of deletion. The first region is
      flanked by D11S901 and D11S1391 at 11q22-23 containing the ATM gene. Mutational
      analysis suggested that the altered gene in this region is not the ATM gene. The
      second region is flanked by D11S614 and D11S924 at 11q23 containing the MLL gene.
      The third region is flanked by D11S1356 and D11S614 at 11q23 containing the MLL
      gene. All the cases with LOH at MLL locus lacked detectable MLL gene
      rearrangements. In addition, 20 children have been studied both at initial
      diagnosis and relapse; none of the individuals who relapsed acquired LOH of 11q,
      suggesting that 11q deletions were infrequently involved in the progression of
      childhood ALL. Children with 11q LOH had a good response to induction
      chemotherapy (P=0.015). These data suggest that alterations of putative tumor
      suppressor genes on 11q are important events in development of childhood ALL. Our
      map provides important information toward cloning putative tumor suppressor genes
      associated with childhood ALL.

PMID- 10602496
TI  - Constitutive activation of IkappaB kinase alpha and NF-kappaB in prostate cancer
      cells is inhibited by ibuprofen.
AB  - Apoptotic pathways controlled by the Rel/NF-kappaB family of transcription
      factors may regulate the response of cells to DNA damage. Here, we have examined
      the NF-kappaB status of several prostate tumor cell lines. In the androgen
      independent prostate tumor cells PC-3 and DU-145, the DNA-binding activity of NF
      kappaB was constitutively activated and IkappaB-alpha levels were decreased. In
      contrast, the androgen-sensitive prostate tumor cell line LNCaP had low levels of
      NF-kappaB which were upregulated following exposure to cytokines or DNA damage.
      The activity of the IkappaB-alpha kinase, IKKalpha, which mediates NF-kappaB
      activation, was also measured. In PC-3 cells, IKKalpha activity was
      constitutively active, whereas LNCaP cells had minimal IKKalpha activity that was
      activated by cytokines. The anti-inflammatory agent ibuprofen inhibited the
      constitutive activation of NF-kappaB and IKKalpha in PC-3 and DU-145 cells, and
      blocked stimulated activation of NF-kappaB in LNCaP cells. However, ibuprofen did
      not directly inhibit IkappaB-alpha kinase. The results demonstrate that NF-kappaB
      is constitutively activated in the hormone-insensitive prostate tumor cell lines
      PC-3 and DU-145, but not in the hormone responsive LNCaP cell line. The
      constitutive activation of NF-kappaB in prostate tumor cells may increase
      expression of anti-apoptotic proteins, thereby decreasing the effectiveness of
      anti-tumor therapy and contributing to the development of the malignant
      phenotype.

PMID- 10602497
TI  - Persistence of p53 mutations and resistance of keratinocytes to apoptosis are
      associated with the increased susceptibility of mice lacking the XPC gene to UV
      carcinogenesis.
AB  - Like xeroderma pigmentosum (XP) patients, transgenic mice lacking nucleotide
      excision repair (NER) genes such as XPA and XPC are extremely susceptible to
      ultraviolet (UV)-induced skin cancer. Because the p53 gene is an important target
      for UV carcinogenesis and because the p53 protein modulates NER, we investigated
      the consequences of NER deficiency on UV-induced p53 mutations in XPC-/- mouse
      skin tumors. Thirty-eight (76%) of 50 UV-induced XPC-/- skin tumor analysed
      displayed C-->T or CC-->TT transitions at dipyrimidine sites on the untranscribed
      strand of the p53 gene. A major hot spot for p53 mutation occurred at codon 270,
      which is also a hot spot in UV-induced skin tumors from NER-proficient C3H and
      SKH-hr 1 mice. Interestingly, codon 270 mutations were induced in both XPC-/- and
      +/+ mouse skin after 1 week of UV irradiation, but the mutations persisted only
      in XPC-/- mouse skin after 3 - 4 weeks of chronic UV. The persistence of UV
      induced p53 mutations in XPC-/- mouse skin was associated with decreased
      apoptosis and increased proliferation of keratinocytes, suggesting that these
      events may contribute to the accelerated development of UV-induced skin tumors in
      XPC-/- mice.

PMID- 10602498
TI  - Involvement of protein tyrosine phosphatases in activation of the trimeric G
      protein Gq/11.
AB  - A variety of receptors coupled to the heterotrimeric guanine nucleotide-binding
      protein Gq/11 stimulate intracellular Ca2+ release through inositol (1,4,5)
      trisphosphate (IP3) formation. We previously reported that tyrosine
      phosphorylation of the alpha subunit of the Gq/11 protein by protein tyrosine
      kinases (PTKs) regulates the activation of Gq/11 protein. Here we show that
      protein tyrosine phosphatases (PTPs) are also essential for Gq/11 protein
      activation. We find that Gq/11 protein-coupled receptor-mediated formation of IP3
      is blocked by PTP inhibitors as well as PTK inhibitors. These inhibitors act
      prior to Gq/11 protein activation. Tyrosine phosphorylation of the alpha subunit
      of Gq/11 appears to inhibit its interaction with receptors. Thus, PTP is required
      for controlling the level of tyrosine phosphorylation of the alpha subunit of
      Gq/11 to promote its interaction with receptors. Therefore, we conclude that PTKs
      and PTPs co-operate to proceed activation cycle of the Gq/11 protein through
      tyrosine phosphorylation and de-phosphorylation of the alpha subunit of Gq/11.

PMID- 10602499
TI  - HPV-18 E6*I protein modulates the E6-directed degradation of p53 by binding to
      full-length HPV-18 E6.
AB  - We have previously demonstrated that ectopic expression of the HPV-18 E6*I
      protein has an antiproliferative effect in cells derived from HPV-containing
      cervical tumours. This effect correlated with the ability of E6*I to inhibit the
      E6-mediated degradation of p53 both in vitro and in vivo and with an increase in
      p53 transcriptional trans-activation. The observation that the E6*I protein can
      interact with both full-length HPV-18 E6 and E6-AP proteins in vitro indicated
      the mechanism by which this activity was mediated. In this study we describe a
      mutational strategy to attempt to differentiate between the E6-AP and full-length
      HPV-18 E6 interactions, with respect to the biological function of E6*I. We
      identify regions of the E6*I protein essential for its interaction with full
      length E6 and important for its interaction with E6-AP. We show that a mutant of
      E6*I which is unable to bind to full-length HPV-18 E6 protein is unable to
      inhibit the E6-directed degradation of p53 and is also unable to inhibit the
      proliferation of a cervical tumour-derived cell line. Finally, we show that
      inhibition of transformed cell growth by E6*I protein correlates with its ability
      to induce apoptosis in a p53-dependent manner. These results raise the intriguing
      possibility of using E6*I as a basis for therapeutic intervention in HPV
      associated tumours.

PMID- 10602500
TI  - Potent inhibitors of cyclin-dependent kinase 2 induce nuclear accumulation of
      wild-type p53 and nucleolar fragmentation in human untransformed and tumor
      derived cells.
AB  - The cdk2 gene has been identified as a human cdc2/CDC28-related gene that encodes
      a protein kinase essential for the G1/S transition in mammalian cells, but not
      for the G2/M transition, which requires Cdk1, another p34cdc2/CDC28 homolog.
      Novel potential functions of Cdk2 have been uncovered by using two potent and
      specific inhibitors of its kinase activity, roscovitine and olomoucine, on human
      wt p53-expresser untransformed and tumor-derived cells. At concentrations equal
      or superior to respectively 30- and 20-fold their in vitro IC50 values for cyclin
      B/Cdk1, cyclin A/Cdk2 and cyclin E/Cdk2, the Cdk inhibitors precipitately induce
      a dramatic nuclear accumulation of wt p53 and a delocalization of nucleolin from
      the nucleolus in all interphase cells, whatever their cell cycle status, acting
      in this way like the DNA-damaging drug, mitomycin C (7 microg/ml). These early
      events are soon followed by a nucleolar fragmentation in both normal and tumor
      cells in the presence of the Cdk inhibitors but not in the presence of the DNA
      damaging drug. Yet, treatment with either type of compounds eventually triggers
      rapidly the death of the tumor cells and, much more slowly, that of the normal
      cells. The Cdk inhibitors, however, stimulate cell death from any stage of the
      cell cycle, whereas the DNA-damaging drug kills more efficaciously S phase cells.
      These observations provide a hint that the Cdk2 kinase might be involved in
      controlling the nuclear levels of the tumor suppressor wt p53 protein and in
      maintaining the nucleolar integrity and function, linking in this way the cell
      division cycle machinery to survival functions and overall cell metabolism via
      the control of nucleocytoplasmic transport and of ribosome production.

PMID- 10602501
TI  - Increased expression of p50-NF-kappaB and constitutive activation of NF-kappaB
      transcription factors during mouse skin carcinogenesis.
AB  - To elucidate the possible role of NF-kappaB in mouse skin carcinogenesis we
      studied the expression of p50 (NF-kappaB1), p52 (NF-kappaB2), p65 (RelA) and
      IkappaB-alpha inhibitor as well as kappaB-binding activity in adult SENCAR mouse
      skin, skin papillomas, and squamous cell carcinomas (SCC) generated by a two
      stage carcinogenesis protocol. We found that in normal epidermis all of the above
      proteins were mostly expressed in the cytoplasm of basal cells. Western blot
      analysis revealed a dramatic increase of p50 and p52 expression in mouse skin
      tumors starting from the middle stage of promotion. We also found that the level
      of IkappaB-alpha protein in many late papillomas and SCC was lower than in normal
      epidermis. Results of EMSA showed an increase in kappaB-binding activity in mouse
      skin tumors and suggested that p50 is the major component of constitutive kappaB
      binding complexes in normal epidermis and in tumors. It has been shown that
      nuclear IkappaB protein Bcl-3 is able to increase p50/p50 homodimer binding to
      the different kappaB sites in mouse thymocytes. Our finding on Bcl-3
      overexpression in late papillomas and SCC could explain the selective increase of
      p50-related kappaB-binding in mouse skin tumors. Thus, our results strongly
      suggest the important role of p50 in skin carcinogenesis.

PMID- 10602502
TI  - Tob2, a novel anti-proliferative Tob/BTG1 family member, associates with a
      component of the CCR4 transcriptional regulatory complex capable of binding
      cyclin-dependent kinases.
AB  - Human cDNAs encoding a novel member of Tob/BTG1 anti-proliferative family
      proteins were cloned. The putative protein product termed Tob2 consisted of 344
      amino acids with high similarity to the Tob protein. The tob2 mRNA was 4.1 kb
      long and was ubiquitously expressed in human adult tissues, as was revealed by
      Northern blot hybridization. However, further in situ hybridization analysis
      showed a characteristic expression of the tob2 mRNA in oocytes, suggesting a
      unique role of Tob2 in oogenesis. Like the Tob protein, Tob2 inhibited cell cycle
      progression from the G0/G1 to S phases. Intriguingly, the amino-terminal half of
      Tob2 as well as that of Tob was associated with a human homologue of yeast Caf1,
      a component of the CCR4 transcription factor complex. Moreover, Caf1 was
      associated with cyclin dependent kinases. These data suggested that both Tob and
      Tob2 were involved in cell cycle regulation through their interaction with Caf1.
      Finally, the tob2 gene was mapped to human chromosome 22q13.1-q13.31.

PMID- 10602503
TI  - The cloning, mapping and expression of a novel gene, BRL, related to the AF10
      leukaemia gene.
AB  - The MLL gene is reciprocally translocated with one of a number of different
      partner genes in a proportion of human acute leukaemias. The precise mechanism of
      oncogenic transformation is unclear since most of the partner genes encode
      unrelated proteins. However, two partner genes, AF10 and AF17 are related through
      the presence of a cysteine rich region and a leucine zipper. The identification
      of other proteins with these structures will aid our understanding of their role
      in normal and leukaemic cells. We report the cloning of a novel human gene (BRL)
      which encodes a protein containing a cysteine rich region related to that of AF10
      and AF17 and is overall most closely related to the previously known protein
      BR140. BRL maps to chromosome 22q13 and shows high levels of expression in testis
      and several cell lines. The deduced protein sequence also contains a bromodomain,
      four potential LXXLL motifs and four predicted nuclear localization signals. A
      monoclonal antibody raised to a BRL peptide sequence confirmed its widespread
      expression as a 120 Kd protein and demonstrated localization to the nucleus
      within spermatocytes.

PMID- 10602504
TI  - Expression of DNA methyl-transferase (DMT) and the cell cycle in human breast
      cancer cells.
AB  - Estrogen receptor (ER)-negative breast cancer cells display extensive methylation
      of the ER gene CpG island and elevated DNA methyltransferase (DMT) expression
      compared to ER-positive cells. The present study demonstrates that DMT protein
      levels tightly correlate with S phase fraction in ER-positive cells, whereas ER
      negative cells express DMT throughout the cell cycle. In addition, levels of
      p21CIP1, which disrupts DMT binding to PCNA, are inversely correlated with DMT
      levels. Therefore increased DMT expression in ER-negative cells is not simply due
      to elevated S-phase fraction, but rather to more complex changes that allow cells
      to escape normal cell cycle-dependent controls on DMT expression. Because ER
      negative breast tumors often have activated growth factor pathways, the impact of
      these pathways on DMT expression was examined in ER-positive cells. Stable
      transfection with fibroblast growth factors (FGFs) 1 and 4 led to increased DMT
      expression that could not be accounted for by a shift in S phase fraction.
      Elevated DMT protein expression in FGF-transfectants was accompanied by a
      significant decrease in p21, again suggesting a reciprocal relationship between
      these two proteins. However, acquisition of an estrogen-independent phenotype,
      even in conjunction with elevated DMT levels, was not sufficient to promote ER
      gene silencing via methylation. These results indicate that multiple steps are
      required for de novo methylation of the ER CpG island.

PMID- 10602505
TI  - PTEN tumour suppressor is linked to the cell cycle control through the
      retinoblastoma protein.
AB  - The tumour suppressor PTEN, also named MMAC1 or TEP1, is associated with a number
      of malignancies in human populations. This protein has a dual protein phosphatase
      activity, being also capable to dephosphorylate phosphatidylinositol 3,4,5
      triphosphate. We have studied the mechanism of growth suppression attributable to
      PTEN. We observed that PTEN overexpression inhibits cell growth in a variety of
      normal and transformed, human and murine cells. Bromodeoxyuridine (BrdU)
      incorporation and TUNEL labelling experiments in transiently transfected cells
      demonstrate that this inhibition is due to a cell cycle arrest rather than
      induction of apoptosis. Given that PTEN is unable to cause cell growth arrest in
      retinoblastoma (Rb)-deficient cell lines, we have explored the possible
      requirement for pRb in the PTEN-induced inhibition of cell proliferation. We
      found that the co-expression of SV40 antigen, but not a mutant form (which binds
      exclusively to p53), and cyclin D1/cdk4 are able to overcome the PTEN-mediated
      growth suppression. In addition, the reintroduction of a functional pRb, but not
      its relatives p107 or p130, in Rb-deficient cells restores the sensitivity to
      PTEN-induced arrest. Finally, the hyperphosphorylation of transfected pRb is
      inhibited by PTEN co-expression and restored by PI-3K co-expression. Accordingly,
      PTEN gene is mostly expressed, in parallel to Akt, in mid-late G1 phase during
      cell cycle progression prior to pRb hyperphosphorylation. Finally, we have
      studied the signal transduction pathways modulated by PTEN expression. We found
      that PTEN-induced growth arrest can be rescued by the co-expression of active PI
      3K and downstream effectors such as Akt or PDK1, and also certain small GTPases
      such as Rac1 and Cdc42, but not by active Ha-ras, raf or RhoA. Collectively, our
      data link the tumour suppressor activities of PTEN to the machinery controlling
      cell cycle through the modulation of signalling molecules whose final target is
      the functional inactivation of the retinoblastoma gene product.

PMID- 10602506
TI  - Activation of p38 MAP kinase and ERK are required for ultraviolet-B induced c-fos
      gene expression in human keratinocytes.
AB  - The effects of p38 MAP kinase and ERK on UVB induced c-fos gene expression were
      studied in a human keratinocyte cell line, FL30. UVB significantly increased c
      fos gene expression at both the transcriptional and protein levels. p38 and ERK
      were also significantly activated after UVB irradiation. Treating the cells with
      p38 inhibitor SB202190 inhibited p38 activation, but not ERK; treating the cells
      with MEK-1 inhibitor PD98059 inhibited ERK activation without suppressing p38
      activation. The kinase activation was determined by Western blots using phospho
      p38 or ERK antibodies, or an in vivo p38 activity assay. Further studies
      demonstrated that blocking p38 almost completely abrogated UVB induced c-fos gene
      transcription and c-Fos protein synthesis. Inhibiting ERK partially abrogated UVB
      induced c-fos transcriptional and protein levels. Suppression of both p38 and ERK
      not only completely blocked UVB induced c-fos expression, but also decreased c
      fos gene basal expression. Our data indicated that p38 may play a more important
      role than ERK in UVB induced c-fos expression in human keratinocytes. Since c-fos
      expression may play an important role in UVB induced AP-1 activation, and AP-1
      activation is known to play a role in tumor promotion, both p38 and ERK could be
      potential targets for chemoprevention of skin cancer.

PMID- 10602507
TI  - CSF-1 activates MAPK-dependent and p53-independent pathways to induce growth
      arrest of hormone-dependent human breast cancer cells.
AB  - The CSF-1 receptor (CSF-1R) is expressed in >50% of human breast cancers. To
      investigate the consequence of CSF-1R expression, hormone-dependent human breast
      cancer cell lines, MCF-7 and T-47D, were transfected with CSF-1R. Unexpectedly,
      CSF-1 substantially inhibited estradiol (E2) and insulin-dependent proliferation
      of MCF-7 transfectants (MCF-7fms) and prevented cyclin E/cdk2 and cyclin A/cdk2
      activation, consistent with a G1 arrest. In contrast, CSF-1 increased DNA
      synthesis in T-47D transfectants (T-47Dfms) alone and with E2 or insulin. In
      response to CSF-1, there was a marked and sustained upregulation of the cyclin
      dependent kinase inhibitor, p21Waf1/Cip1, in MCF-7fms but not T-47Dfms. CSF-1
      also markedly upregulated cyclin D1 in MCF-7fms. The coordinate increase in
      cyclin D1 and p21 had the effect of decreasing the specific but not absolute
      activity of cyclin D1/cdk4. p53 was not involved since CSF-1 induction of p21 was
      unaffected by dominant-negative p53 expression. ERK activation by CSF-1 was
      robust and sustained in MCF-7fms and to a much lesser extent in T-47Dfms. Using
      pharmacological and transient transfection approaches, we showed that ERK
      activation was necessary and sufficient for p21 induction in MCF-7fms. Moreover,
      activated MEK inhibited E2-stimulated cdk2 activity. Our findings indicate that
      the consequence of CSF-1R-mediated signals in human breast cancer cells is
      dependent on the genetic background of the particular tumor.

PMID- 10602508
TI  - Ku80 can translocate to the nucleus independent of the translocation of Ku70
      using its own nuclear localization signal.
AB  - Ku antigen is a complex of Ku70 and Ku80 subunits and plays an important role in
      not only DNA double-strand breaks (DSB) repair and V(D)J recombination, but also
      in growth regulation. Ku is generally believed to always form and function as
      heterodimers on the basis of in vitro observations. Here we demonstrate that the
      localization of Ku80 does not completely coincide with that of Ku70. Ku70 and
      Ku80 were colocalized in the nucleus in the interphase but not in the late
      telophase/early G1 phase of the cell cycle. Since the in vivo function of Ku
      might be partially regulated by the control of its transport, we attempted to
      investigate the molecular mechanisms underlying the nuclear translocation of Ku.
      The nuclear translocation of Ku80 started during the late telophase/early G1
      phase after the nuclear envelope was formed and this was preceded by the nuclear
      translocation of Ku70. Furthermore, we found that the Ku80 protein was
      transported to the nucleus without heterodimerization with Ku70. To understand in
      detail the mechanism of transport of Ku80, we attempted to identify the nuclear
      localization signal (NLS) of Ku80 and defined to a region spanning nine amino
      acid residues (positions 561 - 569). The Ku80 NLS was demonstrated to be mediated
      to the nuclear rim by two components of PTAC58 and PTAC97. All these findings
      support the idea that Ku80 can translocate to the nucleus using its own NLS
      independent of the translocation of Ku70.

PMID- 10602509
TI  - HBV transcription repression in response to genotoxic stress is p53-dependent and
      abrogated by pX.
AB  - Transcription of hepatitis B Virus (HBV), an important risk factor of
      hepatocellular carcinoma (HCC), is controlled by cellular transcription
      activators including some of the cellular signaling targets. Consequently, HBV
      transcription rate changes in response to the cellular physiological conditions.
      In this report we investigated HBV gene expression and the role of physiological
      levels of the viral X protein (pX) under cisplatin induced genotoxic stress. We
      show that under these conditions the RNA level of an HBV mutant which does not
      express pX is sharply reduced. Studies revealed that transcription repression is
      responsible for the observed reduction in HBV RNA level. Repression of HBV
      transcription was obtained only in the p53 proficient cells. Furthermore, HBV
      transcription rate is recovered by the cotransfected p53 dominant negative
      plasmid, indicating that p53 is directly responsible for HBV transcription
      repression. Unexpectedly, p73, the recent p53 homologue, does not repress but
      rather activates HBV transcription. Interestingly, pX produced either by the HBV
      genome or by a cotransfected plasmid, relieves the p53 mediated repression.
      Collectively, these results attribute a physiological role to p53-inactivation by
      pX, and explain how pX may support HCC development.

PMID- 10602510
TI  - Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is
      mediated by a combination of anti-proliferative, pro-apoptotic and anti
      angiogenic effects.
AB  - While 25% of human cancers harbor oncogenic Ras mutations, such mutations are not
      found in astrocytomas. We have previously demonstrated that the activation of
      receptor tyrosine kinases expressed by malignant human astrocytoma cells and
      specimens results in functional upregulation of the Ras signalling pathway and
      increased levels of activated Ras*GTP. Farnesyl transferase inhibitors (FTIs) are
      promising anti-cancer agents in early clinical trials, which may exert their
      effect through pharmacological inhibition of the Ras signalling pathway. In this
      study we establish the anti-tumorigenic properties of the FTI L-744,832 against a
      panel of malignant human astrocytoma cell lines. Furthermore, we demonstrate the
      multiple mechanisms by which L-744,832 exerts its effect. L-744,832 demonstrates
      both cytostatic and cytotoxic effects on astrocytoma cells, and cells expressing
      a truncated constitutively phosphorylated Epidermal Growth Factor Receptor common
      in high-grade astrocytomas (EGFRvIII/p140EGF-R) demonstrate increased sensitivity
      to the agent. L-744,832 is capable of inducing apoptosis in astrocytoma cells
      under anchorage-dependent conditions; this process occurs in a p53-independent
      manner and is associated with increased expression of Bax and Bak. L-744,832 also
      induces cell cycle arrest at both the G1/M and G2/S checkpoints; this process is
      also independent of p53 mutational status. Cell cycle arrest in drug-treated
      cells can be accompanied by induction of p21WAF1/CIP1, but this induction is not
      necessary for the cell cycle inhibitory effects, nor is it dependent on
      functional p53. Finally, angiogenesis in astrocytomas has been shown to be
      dependent on secretion of Vascular Endothelial Growth Factor (VEGF) by tumour
      cells, particularly under hypoxic conditions. L-744,832 potently inhibits the
      secretion of VEGF under hypoxic conditions. These combinations of mechanisms
      suggest that these tumours, despite the absence of oncogenic Ras mutations, will
      be amenable to growth inhibition by FTIs, through a combination of anti
      proliferative, pro-apoptotic, and anti-angiogenic effects.

PMID- 10602511
TI  - Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes
      in IGF2 methylation.
AB  - Relaxation of IGF2 imprinting occurs in Wilms tumours and many other cancers, but
      the mechanism of loss of imprinting (LOI) remains unknown. To investigate the
      role of altered DNA methylation in LOI, we examined the pattern of methylation of
      the human insulin-IGF2 region in Wilms tumours and the normal kidney. The
      analysis included regions homologous to three 'differentially methylated regions'
      of the mouse Igf2 gene (dmrs 0, 1 and 2). In tumours displaying normal IGF2
      imprinting, and in the normal kidney, maternal allele-specific DNA methylation
      was identified spanning exons 2 and 3. This region is homologous to dmr 0, a site
      of maternal-specific differential methylation in the mouse. In Wilms tumours with
      relaxed imprinting or 11p15.5 LOH this region was unmethylated. No other
      differential methylation was identified. In particular, two sites of paternal
      methylation in the mouse (dmrs 1 and 2), and all three imprinted IGF2 promoters
      were not methylated in the kidney or in Wilms tumours. We postulate that LOI in
      Wilms tumours is associated with loss of maternal allele-specific methylation
      from a region located upstream of the imprinted IGF2 promoters. This region may
      contain cis acting sequences that coordinately influence imprinting.

PMID- 10602512
TI  - Protein tyrosine phosphatase epsilon increases the risk of mammary hyperplasia
      and mammary tumors in transgenic mice.
AB  - Accurate phosphorylation of tyrosine residues in proteins plays a central role in
      regulation of cellular function. Although connections between aberrant tyrosine
      kinase activity and malignancy are well-established, significantly less is known
      about the roles of protein tyrosine phosphatases (PTPases) in tumorigenesis. We
      have previously shown that the transmembranal form of PTPase Epsilon (PTPepsilon)
      is upregulated in mouse mammary tumors initiated specifically by ras or neu,
      suggesting that PTPepsilon may play a role in transformation by these two
      oncogenes. In order to test this notion in vivo, we created transgenic mice that
      express elevated levels of PTPepsilon in their mammary epithelium by use of the
      MMTV promoter/enhancer. Following several cycles of pregnancy female MMTV
      PTPepsilon mice uniformly developed pronounced and persistent mammary hyperplasia
      which was accompanied by residual milk production. Solitary mammary tumors were
      often detected secondary to mammary hyperplasia. The sporadic nature of the
      tumors, the long latency period prior to their development, and low levels of
      transgene expression in the tumors indicate that PTPepsilon provides a necessary,
      but insufficient, signal for oncogenesis. The results provide genetic evidence
      that PTPepsilon plays an accessory role in production of mammary tumors in a
      manner consistent with its upregulation in mammary tumors induced by ras or neu.

PMID- 10602513
TI  - Susceptibility of HIV-1-TAT transfected cells to undergo apoptosis. Biochemical
      mechanisms.
AB  - The effects of HIV-1 Tat protein on mitochondria membrane permeability and
      apoptosis were analysed in lymphoid cells. In this report we show that stable
      transfected HIV-Tat cells are primed to undergo apoptosis upon serum withdrawal.
      This effect was observed in both the Jhan T cell line and the K562 cells, the
      latter expressing the bcr-abl chimeric gene, which confers resistance to
      apoptosis induced by different stimuli. Using a cytofluorimetric approach we have
      determined that serum withdrawal induces a disruption of the transmembrane
      mitochondrial potential (Deltapsim) followed by an increase of reactive oxygen
      species (ROS) and the subsequent DNA nuclear loss in K562-Tat cells but not in
      the K562-pcDNA cell line. These pre-apoptotic events were associated with the
      cleavage of the caspase-3, while the expression of Bcl-2, Bcl-XL and Bax proteins
      was not affected by the presence of Tat. Regardless of the steady state of the
      Bax protein, we found that in both K562 and K562-Tat cells, this protein is
      located in the nucleus, but after serum withdrawal its localization was mainly in
      the cytoplasm. The activity of caspase-3 detected in K562-Tat cells after serum
      withdrawal paralleled with the mitochondria permeability transition.
      Nevertheless, in Jhan-Tat cells the inhibition of this caspase with the specific
      inhibitor, z-DEVD-cmk, did not affect the disruption of the mitochondria
      potential induced by serum withdrawal. Interestingly, we found that HIV-Tat
      protein accumulates at the mitochondria in the K562-Tat cells cultured under low
      serum conditions, and this mitochondrial localization correlated with the
      Deltapsim disruption detected in these cells. In addition, HIV-1 Tat protein
      synergies with protoporphyrin IX (PPIX), a ligand of the mitochondrial
      benzodiazepine receptor, in the induction of apoptosis in both Jhan and K562
      cells. Thus, HIV-1 Tat protein may induce apoptosis by a mechanism that involves
      mitochondrial PT and may contribute to the lymphocyte depletion seen in AIDS
      patients.

PMID- 10602514
TI  - Protein stabilization: a common consequence of mutations in independently derived
      v-Myc alleles.
AB  - Myc is overexpressed in many cancers as a result of gene rearrangement or
      amplification, but coding sequence changes which cluster in the N-terminal
      transactivation domain also appear to play a role in tumour progression. The
      prototypic v-Myc gene of MC29 virus differs from avian c-Myc by a series of
      mutations, including a change at a regulatory phosphorylation site within the
      mutational hotspot (thr-61) which is known to potentiate transformation in vitro.
      We now show that the mutation at thr-61 stabilizes the v-Myc protein (turnover
      difference) and that this single mutation is both necessary and sufficient for
      the phenotype. A major involvement of the proteasome in Myc degradation was
      confirmed, but surprisingly, a dilysine motif adjacent to thr-61 proved not to be
      the ubiquitin target. Two other v-Myc genes which carry a mutation at thr-61
      (avian MH2) or a large deletion encompassing this domain (feline T17) were found
      to be stabilized to a similar extent as MC29, showing that stabilization is a
      common feature of independently derived Myc oncogenes. These results suggest a
      common selective process in the genesis of these three viral oncoproteins and a
      mechanistic link with Jun, Fos and Myb oncoproteins which are also stabilized
      relative to their cellular counterparts.

PMID- 10602515
TI  - Alteration of hSNF5/INI1/BAF47 detected in rhabdoid cell lines and primary
      rhabdomyosarcomas but not Wilms' tumors.
AB  - The organization of genomic DNA into chromatin aids in the regulation of gene
      expression by limiting the access of transcriptional binding domains. The SWI/SNF
      family of chromatin-remodeling complexes, which are conserved from yeast to
      humans, open the chromatin to facilitate the transcriptional machinery to access
      their targets. The gene encoding the BAF47/hSNF5 subunit of the complex has been
      found mutated in both rhabdoid cell lines and in primary rhabdoid tumors. Since
      the pediatric tumors rhabdomyosarcoma (RMS) and Wilms' tumor (WT) share a similar
      genetic link with rhabdoid tumors, it was hypothesized that they may also show
      alterations of the BAF47 gene. Using primary tumors, the BAF47 protein was
      detected in all WT but less than 75% of the RMS tested. In cell lines, the BAF47
      protein was missing in all rhabdoid cell lines and one RMS cell line. Analysis of
      sample DNA displayed either a mutation or deletion of the BAF47 gene in all
      samples negative for the protein. Several other subunits of the human SWI/SNF
      complex, including BRG1 which is the subunit directly interacting with the Rb
      tumor suppressor gene, were detected in all tumor samples. Alteration of BAF47
      may be a genetic marker associated with the poor prognosis seen in all rhabdoid
      tumors but only some RMS.

PMID- 10602516
TI  - Induction of apoptosis by SLK, a Ste20-related kinase.
AB  - We have cloned and characterized a novel murine Ste20-related kinase designated
      SLK. SLK displays high homology to the Ste20-related kinase LOK, and is more
      distantly related to MST1 and 2, both Ste20-like kinases. In addition, SLK
      displays high homology to microtubule and nuclear associated protein (M-NAP) and
      AT1-46, both of unknown function. SLK is ubiquitously expressed as multiple mRNAs
      in tissues and cell lines and is downregulated by mitogen depletion in
      differentiating myoblasts. Biochemical characterization showed that SLK
      overexpression activates c-Jun amino-terminal kinase 1 (JNK1). However, in vitro
      kinase assays indicated that SLK was not activated in response to various growth
      factors or stress-inducing agents. Immunofluorescence studies revealed that SLK
      colocalized to distinct cytosolic domains, preferentially at the periphery of the
      cells. In addition, prolonged overexpression of SLK in cultured fibroblasts
      resulted in apoptosis as demonstrated by annexin-V and TUNEL staining. Our
      results suggest that SLK belongs to a new family of protein kinases, mediating
      activation of the stress response pathway through a novel signaling cascade.

PMID- 10602517
TI  - Limiting the location of a putative human prostate cancer tumor suppressor gene
      at chromosome 13q14.3.
AB  - We studied loss of heterozygosity (LOH) on human chromosome 13q in prostate
      cancer specimens to determine the location of a putative tumor suppressor gene
      (TSG) and to correlate these losses with the clinicopathological stage of the
      disease. Overall 13 (21%) of 61 specimens analysed had an allele loss on the long
      arm of chromosome 13. The most frequent (37%) LOH among the informative cases
      with allele losses was detected at the D13S284 locus on chromosome 13q14. 3. A
      portion of the DNA segment that spans this locus and is flanked by the
      microsatellite loci D13S153 and D13S163 was lost in 85% of the specimens with
      allele losses and was designated as a LOH cluster region (LCR). The LCR spans
      more than 6 Mbp of DNA. The results suggest that a TSG relevant for the
      development of prostate cancer is located telomeric to the RB locus. There was a
      significant correlation (P=0.0024) between chromosome 13q LOH and advanced
      metastatic disease, suggesting that loss of 13q14.3 region is associated with
      prostate cancer progression. However, further research must be conducted to
      establish the identity and function of this putative TSG.

PMID- 10602518
TI  - Both FGF1 and bcl-x synthesis are necessary for the reduction of apoptosis in
      retinal pigmented epithelial cells by FGF2: role of the extracellular signal
      regulated kinase 2.
AB  - Retinal pigmented epithelial (RPE) cells are of central importance in the
      maintenance of neural retinal function. Changes in the RPE cells associated with
      repair activities have been described as metaplasia, while RPE cell apoptosis is
      responsible for the development of a variety of retinal degenerations. We
      investigated the regulation of the anti-apoptotic properties of the fibroblast
      growth factors (FGF) 2 in serum-free cultures of RPE cells. In the absence of
      serum, confluent stationary RPE cells died by apoptosis via a caspase 3-dependent
      pathway. The addition of FGF2 greatly reduced apoptosis over a 7-day culture
      period. We demonstrated the involvement of an autocrine loop involving endogenous
      FGF1 in the mechanisms that govern FGF2-induced resistance to apoptosis by
      showing: (1) higher levels of apoptosis in cells treated with antisense FGF1
      oligonucleotide or after neutralization of excreted FGF1; (2) the long-term
      activation of FGFR1 and of ERK2, (3) the inhibition of FGFR1 and ERK2 activation
      and an increase in apoptosis if excreted FGF1 was neutralized. FGF2 also
      increased the de novo synthesis and the production of Bcl-xl before the onset of
      apoptosis. Both inhibition of ERK2 activation, which decreased Bcl-xl synthesis,
      and downregulation of Bcl-x by antisense oligonucleotide treatment inhibited the
      survival-promoting activity of FGF2. Thus, FGF2-induced cell survival is a
      progressive adaptive phenomenon involving ERK2 activation by excreted FGF1 and
      ERK2-dependent Bcl-x production.

PMID- 10602519
TI  - Fusion of the RBP56 and CHN genes in extraskeletal myxoid chondrosarcomas with
      translocation t(9;17)(q22;q11).
AB  - Although most extraskeletal myxoid chondrosarcomas (EMC) are cytogenetically
      characterized by the translocation t(9;22)(q22;q12), another subset has recently
      been identified carrying a t(9;17)(q22;q11). Whereas the t(9;22) is known to
      result in fusion of the CHN (TEC) gene from 9q22 with the EWS gene from 22q12,
      creating a chimeric EWS/CHN, the genes involved in the t(9;17) of EMC are
      unknown. We examined two EMC with t(9;17)(q22;q11) and found that the CHN gene
      was recombined with the RBP56 gene from 17q11 to generate a chimeric RBP56/CHN.
      RBP56 has not previously been shown to be involved in tumorigenesis but it
      encodes a putative RNA-binding protein similar to the EWS and FUS (TLS) proteins
      known to play a pathogenetic role in several sarcomas. The presence of the
      RBP56/CHN chimeric gene in EMC with t(9;17)(q22;q11) shows that the N-terminal
      parts of EWS and RBP56 have similar oncogenic potential making them
      pathogenetically equivalent in oncoproteins arising from fusions with certain
      transcription factors.

PMID- 10602520
TI  - Identification of a novel fusion gene involving hTAFII68 and CHN from a
      t(9;17)(q22;q11.2) translocation in an extraskeletal myxoid chondrosarcoma.
AB  - A proportion of extraskeletal myxoid chondrosarcomas (EMC) have been shown to
      have a characteristic translocation t(9;22)(q22;q12) involving the EWS gene at
      22q12 and the CHN orphan nuclear receptor gene at 9q22. This translocation
      appears to be largely specific for EMC, but has not been detected in all such
      tumours. We report here a case of EMC with a t(9;17)(q22;q11.2) as the sole
      chromosome abnormality. We have determined that the translocation results in the
      fusion of the entire coding region of CHN to the N-terminal transactivation
      domain of RBP56/hTAFII68. This is the first report of a translocation involving
      RBP56/hTAFII 68, a protein with sequence homology to both EWS and TLS/FUS. The
      involvement of RBP56/hTAFII68 may explain some unusual features of the tumour.

PMID- 10602521
TI  - Phosphorylation of murine p53, but not human p53, by MAP kinase in vitro and in
      cultured cells highlights species-dependent variation in post-translational
      modification.
AB  - The p53 tumour suppressor protein is tightly regulated by protein-protein
      association, protein turnover and a variety of post-translational modifications.
      Multisite phosphorylation plays a major role in activating and in finely tuning
      p53 function. The proline rich domain of murine p53 is a substrate for
      phosphorylation, in vitro and in cultured cells, by the p42ERK2 and p44ERK1
      mitogen-activated protein (MAP) kinases. However, to date there have been no
      reports of attempts to determine whether p53 from any other species is a
      substrate for MAP kinase. In this paper we confirm that murine p53 is targeted by
      recombinant MAP kinase and by MAP kinases in extracts of both murine and human
      cells. In contrast, human p53 is not a substrate for recombinant MAP kinase nor
      are there any detectable levels of protein kinase activity in stimulated human
      cell extracts which phosphorylate the proline rich domain of human p53 in vitro.
      Finally, although stimulation of murine fibroblasts with o-tetradecanolylphorbol
      13-acetate (TPA), an indirect activator of the MAP kinase pathway, leads to site
      specific phosphorylation of murine p53, similar treatment of human fibroblasts
      and epithelial cells showed no significant changes in the phosphorylation
      pattern. These data are consistent with accumulating evidence that significant
      species-dependent differences exist in the post-translational modification of
      p53.

PMID- 10602522
TI  - Inhibition of the putative tumor suppressor gene TIMP-3 by tumor-derived p53
      mutants and wild type p53.
AB  - The p53 gene is a tumor suppressor that regulates the expression of genes
      required for cell cycle arrest or apoptosis. Mutations in p53 have been observed
      in over 60% of all human cancers. Certain classes of mutant p53 proteins maintain
      some of their activities or acquire novel activities and thus may contribute to
      the transformed phenotype. By carrying out an analysis of differential gene
      expression using cDNA expression arrays, we compared the expression patterns of
      cells expressing no p53 to isogenic lines expressing the codon 248 Arg to Trp
      mutant p53 allele (R248W). In this report, we show that the R248W and D281G p53
      mutants, two of the more commonly occurring mutations, as well as wild type p53,
      repress transcription of the tissue inhibitor of metalloproteinases type 3 (TIMP
      3) gene by greater than tenfold. TIMP-3 expression has been observed to be
      repressed in many tumors and its reduced expression is thought to contribute to
      tumor metastasis and invasiveness by allowing increased activity of
      metalloproteinases in the extracellular matrix. Since mutant forms of p53 tend to
      be expressed at greatly elevated levels in many human tumors, the retention of
      their ability to repress TIMP-3 illustrate one mechanism by which mutant forms of
      the p53 gene may contribute to tumorigenesis.

PMID- 10602523
TI  - Axon regeneration of spinal motoneurons following a lesion at the cord-ventral
      root interface.
AB  - Those insults to the spinal cord which occur when ventral or dorsal roots are
      avulsed from the surface of the cord have been considered unfavourable with
      regard to both survival and axon regeneration of lesioned neurons. In this
      review, we describe the development of a surgical procedure aiming at a
      restoration of motor function after ventral root avulsion lesions. This
      development includes a series of investigations in animals, where an unexpected
      capacity for cell survival and axon regeneration of motoneurons after a cut
      lesion in the spinal cord was demonstrated and analyzed in great detail. Based on
      these findings, a surgical technique was tested, where avulsed ventral roots were
      replanted into the cord. After confirmation that such implanted roots could serve
      as a conduit for outgrowing motor axons in animals, the technique has been
      evaluated in a limited number of human cases of root avulsion lesions. We
      conclude that surgical intervention may indeed lead to return of motor function
      also in human cases of ventral root avulsion lesions. Interestingly, the
      procedure also seems to have an attenuating effect on the pain that develops in
      cases with a combined dorsal root avulsion. Lastly, we conclude that the cut
      lesion in the ventral part of the spinal cord, followed by axon regeneration in
      motoneurons may serve as a model for axon regeneration in the central nervous
      system.

PMID- 10602524
TI  - Effects of MK801 on evoked potentials, spinal cord blood flow and cord edema in
      acute spinal cord injury in rats.
AB  - OBJECTIVES: To determine whether MK801, an NMDA receptor antagonist, blocks
      glutamate excitotoxicity directly or via other mechanisms such as improving blood
      supply at the injury site in a rat model of spinal cord injury (SCI). In the
      present study, the effects of pre- and posttreatment with MK801 on axonal
      function, spinal cord blood flow (SCBF) and cord water content were studied after
      acute SCI in rats. METHODS: Somatosensory evoked potentials (SSEPs) and
      cerebellar evoked potentials (CEPs) were used to quantify electrophysiological
      function, and the hydrogen clearance technique and wet-dry weight measurements
      were used to measure SCBF and cord water content, respectively. Twenty rats
      received a 21 g clip compression injury of the cord at T1, and were then randomly
      and blindly allocated to either MK801 or saline groups. Each rat received an
      intravenous infusion of drug or saline four times during the experiment (16
      min/infusion) with the first infusion (MK801 3 mg/kg) beginning 8 min pre-injury,
      and the other infusions (MK801 1. 5 mg/kg) at 1 h intervals after injury. Control
      experiments on uninjured rats were performed in 10 rats using the same procedure
      as above except the clip compression injury of the cord was omitted. RESULTS: In
      the MK801 groups with or without SCI, the amplitude of the evoked potential
      peaks, especially the SSEPs, was significantly lower than in the saline group.
      There were no differences in SCBF or cord water content between the MK801 and
      saline groups. CONCLUSION: Pre- and posttreatment with MK801 inhibits evoked
      potentials, but does not improve SCBF or cord edema after acute compression SCI
      in rats. For the first time it has been shown that MK801 produced a blockade of
      glutamate excitatory transmission in afferent pathways after SCI. Further work is
      required to determine whether this inhibition is reversible and related to
      neuroprotection and functional recovery after SCI.

PMID- 10602525
TI  - Magnetic resonance imaging and neurological recovery in acute spinal cord injury:
      observations from the National Acute Spinal Cord Injury Study 3.
AB  - STUDY DESIGN: Data are from a multicenter, randomized, double blind clinical
      trial of acute spinal cord injury. OBJECTIVES: To evaluate the prognostic value
      of magnetic resonance imaging (MRI) for randomized patients in the National Acute
      Spinal Cord Injury Study 3 (NASCIS). SETTING: Sixteen spinal cord injury centers
      throughout the United States and Canada. METHODS: Of 499 patients randomized in
      NASCIS 3 between December 1991 and September 1995, MRI was electively done on 191
      patients within 72 h of injury. Indications of hemorrhage, edema, and contusion
      were recorded by standard protocol. Neurological impairment as determined by
      motor function, response to pin prick and light touch was assessed at admission
      to the participating center and 6 weeks after injury. Change in neurological
      function was obtained by subtracting the score of each neurological parameter at
      admission from that measured at 6 weeks. Spinal cord surgery performed within the
      3 days after injury was noted. Data were analyzed by: chi square, analysis of
      variance, multiple logistic regression and linear regression models. RESULTS:
      Patients with hemorrhage were much more likely to have a complete injury
      (OR=2.88, 95 Cl 1.32, 6.23); however this association was much reduced when the
      initial neurological examination was taken into account (AOR=1.43, 95% Cl 0.55,
      3.73) and was no longer a significant predictor of injury. MRI evidence of cord
      edema was the strongest predictor of reduced improvement in motor function (-3.34
      points, P=0.06) and light touch sensation (-3.41 points, P=0.05) at 6 weeks.
      CONCLUSIONS: Cord hemorrhage, contusion, and edema on MRI were not associated
      with diagnosis of a complete cord injury after neurological assessment from the
      initial clinical examination was taken into account. Prediction of a worse 6 week
      neurological status was weakly associated with the presence of edema diagnosed by
      MRI. As MRI technology improves, these diagnostic and predictive capabilities
      need to be re-assessed. SPONSORSHIP: NASCIS 3 was funded by the National
      Institute of Neurological Disorders and Stroke at the National Institutes of
      Health, Washington, DC, USA. Pharmacia and Upjohn provided study drugs and
      placebos; they also monitored data quality, and funded additional tests, in
      accordance with Food and Drug Administration regulatory requirements. Dr Bracken
      has served as an occasional paid consultant to Pharmacia and Upjohn.

PMID- 10602526
TI  - The effect of childhood spinal cord injury on skeletal development: a
      retrospective study.
AB  - STUDY DESIGN: Cross-sectional clinical review. OBJECTIVES: To assess the
      relationship between late spinal deformity in childhood onset spinal cord injury
      (SCI) and level of spinal cord lesion, severity of lesion, age at onset, duration
      of paralysis and pelvic deformities. SETTING: People with spinal cord injury
      (onset in childhood) treated and followed up at the National Spinal Injuries
      Center (identified from case notes review, contacted and agreed to participate).
      METHOD: One hundred and eighty-nine subjects satisfying study inclusion criteria
      (acute onset SCI before the 16th birthday) were identified by case note review of
      8200 records. Eighty formed the group attending for clinical review including
      whole spine radiographs (AP and lateral). Clinical examination included
      neurological status and joint range of movements. Demographic data was recorded.
      RESULTS: Scoliosis occurred more frequently and was more severe in those injured
      at a younger age, 38 degrees, compared with 24 degrees in those injured later
      (P<0.05), in paraplegia, 33 degrees, versus tetraplegia, 17 degrees, (P<0.01) and
      in complete, 36 degrees, versus incomplete lesions, 18 degrees, (P<0.001).
      Lordosis angulation in paraplegic subjects was significantly greater than in
      tetraplegic subjects in both seated, 50 degrees versus 25 degrees (P<0.014) and
      standing subjects 78 degrees versus 59 degrees (P<0.017) respectively and for
      kyphosis in standing subjects, 52 degrees versus 31 degrees (P<0.01). Sagittal
      measurements were influenced by habitual posture (which also corresponded to the
      severity of the lesion). CONCLUSION: Younger age at onset was shown to be
      associated with more severe scoliosis, as has been reported by others. Subjects
      with paraplegia and complete lesions demonstrated a greater and more frequently
      occurring scoliosis than those with tetraplegia and incomplete lesions
      respectively. Lordosis was greater in those with paraplegia than with tetraplegia
      and in those with very incomplete lesions compared with complete lesions. However
      the influence of the severity of the lesion cannot be separated from the postural
      position when analyzing spinal deformity.

PMID- 10602527
TI  - Spinal cord injuries and attempted suicide: a retrospective review.
AB  - STUDY DESIGN: A retrospective review examining the cases of 137 individuals with
      spinal cord injury (SCI) as a result of a suicide attempt between 1951 - 1992.
      OBJECTIVE: To ascertain demographic details of this participant sample, explore
      and identify the type of psychiatric condition evident around the time of injury,
      and to review outcome information of this sample with specific focus on
      mortality, especially further evidence of deliberate self harm. SUMMARY OF
      BACKGROUND DATA: Research examining suicide rates in SCI populations has found
      such numbers to be significantly higher than in the general population. However,
      these studies have typically relied on small samples of individuals and have
      often failed to distinguish between those individuals who sustained SCI as a
      result of attempted suicide, and those who first attempted suicide following SCI.
      METHODS: An established database comprising details of 137 people with SCI as a
      result of attempted suicide was reviewed and updated using patient admission
      records. The subsequent database comprised: cause, level and completeness of
      injury; height fallen; psychiatric history; psychiatric diagnosis; date of last
      contact; further suicide attempts; religious affiliation; previous and present
      employment; date and cause of death; date and place of discharge; and any other
      relevant details. From this database the three primary objectives of the study
      were ascertained: demographic detail; psychiatric condition; and outcome
      information. RESULTS: The ratio of males to females was 1 : 1 with a mean age of
      32. Almost half (48.9%) were single, around a third (32.8%) had children and 42.
      3% were employed. Schizophrenia and depression were evident in 32.8% and 27% of
      cases respectively. Previous suicide attempts had been made by 23% (n=32). The
      cause of injury in 85% of cases was 'falls'. Thirty-three people are known to
      have died, of whom eight (24%) committed suicide. During the period between the
      first and last spinal cord injury examined within this study (1951 - 1992) 1.6%
      (n=137) of the total sample of patients treated at the rehabilitation centre
      (n=8347) sustained a spinal cord injury as a result of a suicide attempt.
      CONCLUSION: Significant findings include; a high proportion of patients with
      schizophrenia; similar findings concerning age profile and level of injuries with
      previous research, but different sex ratio; and information on longer-term
      outcomes. Recommendations for further research include an adaptation of the
      psychological autopsy approach which would provide information beyond that
      normally available in actual suicides.

PMID- 10602528
TI  - Radiological pathogenesis of cervical myelopathy in 60 consecutive patients with
      cervical ossification of the posterior longitudinal ligament.
AB  - STUDY DESIGN: The radiological pathogenetic factors for cervical myelopathy in 60
      consecutive patients with cervical ossification of the posterior longitudinal
      ligament (OPLL) were investigated retrospectively. OBJECTIVE: To clarify which
      patients with OPLL will develop cervical myelopathy. METHODS: Sixty consecutive
      patients with OPLL were radiologically assessed comparing the myelopathic patient
      group (M group, n=41) and the mild or non-myelopathic patient group (non-M group,
      n=19). RESULTS: The narrowing ratio of the spinal canal in the M group (47.1%)
      was significantly greater (P=0.026) than that in the non-M group (38.3%). The two
      groups showed a significant difference (P=0.0016) with regard to the Pavlov ratio
      (M group, 0.73; non-M group, 0.84). The total range of motion of the cervical
      spine did not differ between the two groups but the per cent range of motion was
      significantly greater (P=0.037) in the M group than in the non-M group.
      CONCLUSION: This study suggests that factors important in the onset or
      aggravation of myelopathy are factors related to pathological compression by
      OPLL, cervical soft disc herniation, developmentally narrow spinal canal, and
      local or non-proportional hypermobility.

PMID- 10602529
TI  - Spinal cord lesions in Bangladesh: an epidemiological study 1994 - 1995.
AB  - OBJECTIVES: Spinal Cord Lesions are a major public health problem in Bangladesh.
      This epidemiological study was undertaken in order to identify the causes of
      spinal cord lesions and thus to allow prevention and control programs to be
      developed. MATERIALS AND METHODS: The records of 247 patients with spinal cord
      lesions admitted to The Centre for the Rehabilitation of the Paralysed (CRP),
      Savar, Dhaka from January 1994 to June 1995 were reviewed retrospectively.
      Comparisons were made with the reports of studies from other countries, both
      developing and developed. RESULTS: The most common cause of traumatic lesions was
      a fall from a height followed by falling when carrying a heavy weight on the head
      and road traffic accidents. Most of the patients were between 20 - 40 years old
      and the overall age group ranged from 10 - 70 years. The male:female ratio was
      7.5 : 1.0. Among the traumatic spinal cord lesions, 60% were paraplegics and 40%
      tetraplegics. Among the non-traumatic spinal cord lesions cases 84% were
      paraplegics and 16% tetraplegics. The leading cause of death resulted from
      respiratory complications and these deaths occurred in the very early period of
      admission. CONCLUSION: From the results it can be deduced that the high incidence
      of spinal cord lesion as a result from falls from a height, and from falling when
      carrying a heavy weight on the head, can be explained by the mainly agricultural
      based economy of Bangladesh. The most common age group (10 - 40 years) of
      patients reflects the socio-economic conditions of Bangladesh. The male:female
      ratio (7.5 : 1.0) of patients with a spinal cord lesion is due to the socio
      economic status and to the traditional culture of the society.

PMID- 10602530
TI  - Restless legs syndrome: an unusual cause for a perplexing syndrome.
AB  - Restless legs syndrome (RLS) is a well-defined symptom complex, occurring either
      as idiopathic RLS or in association with many other disorders. Although no
      definite etiology is known for this condition, several pathophysiological
      mechanisms have been proposed. There is supportive evidence that RLS is a central
      nervous system (CNS) dysfunction, suggesting involvement of the descending
      dopaminergic (DA) pathways, but it can also occur with spinal disorders. We
      present a patient suffering from RLS who eventually was diagnosed with a foramen
      magnum tumor. Based on the available evidence, we attempt to correlate the
      location of the tumor with the patient's symptoms of RLS.

PMID- 10602531
TI  - Holocord intramedullary abscess: an unusual case with review of literature.
AB  - STUDY DESIGN: A rare case of a holocord intramedullary abscess with review of
      literature. OBJECTIVES: Summary of clinical presentation, radiology,
      microbiology, etiology and management of intramedullary spinal cord abscess.
      Abscess involving the entire spinal cord is extremely rare and awareness of such
      an event could avoid delay in evacuation of the absess. METHODS: The incidence,
      clinical presentation, radiological investigations, treatment and etiology of
      intramedullary spinal cord abscess in 100 consecutive cases are discussed.
      RESULTS: Intramedullary spinal cord abscesses are rare. Presently, only five
      cases of holocord intramedullary abscess are described. In our analysis of 100
      cases of intramedullary abscess, a male preponderance was found. The first and
      the third decades were the most common age groups. Prognosis is poor if treatment
      is delayed. Contrast-enhanced MRI is the ideal investigation for diagnosis.
      Prompt surgical drainage of the abscess with appropriate antibiotic therapy is
      mandatory since the natural course of the disease has a very unfavourable
      outcome. Staphylococcus and Streptococcus were the most common causative
      organisms. CONCLUSION: Intramedullary spinal cord abscess along the entire length
      of spinal cord is rare. A thorough history with precise clinical localisation, a
      high index of suspicion, contrast-enhanced MRI at appropriate level and prompt
      surgical drainage with appropriate antibiotic therapy are key to the eventual
      outcome and prognosis.

PMID- 10602532
TI  - Leuven Consensus Conference on Ambulatory Blood Pressure Monitoring in
      Commemoration of Professor Dr A. Amery (died 2 November 1994) 23-25 September
      1999.

PMID- 10602533
TI  - Blood Pressure Monitoring. Task force I: Methodological aspects.

PMID- 10602534
TI  - Task force II: Ambulatory blood pressure monitoring in population studies.
AB  - Ambulatory blood pressure (ABP) has only rarely been employed in population
      studies because of the difficulty posed by the greater complexity of this
      technique. The cross-sectional studies that have been published, however, have
      allowed a number of conclusions to be drawn. One, 24h average blood pressure of
      populations is significantly but not closely related to office blood pressure,
      which thus can not predict accurately daily-life values of blood pressure. Two,
      24h average blood pressure is usually less than office blood pressure, the
      discrepancy increasing with the increase in office values and being of magnitude
      several mmHg at the office blood pressure of 140/90 mmHg (systolic/diastolic)
      Three, ABP in women is somewhat less than that in men and ABP for both sexes
      increases less with aging than does office blood pressure. Four, a circadian
      profile of blood pressure consisting in values that are much lower at night than
      are those during daytime characterizes both sexes and all ages with the possible
      exception of individuals aged 75 years and more, in whom the nocturnal
      hypotension appears to be attenuated. A similar attenuation has been found for
      blacks in comparison with whites. The upper limit of normality of ABP has not yet
      been defined conclusively, although 24h average values </=125/80 mmHg are almost
      invariably regarded as normal. Normality of ABP should be defined, however, by
      longitudinal population studies in which ambulatory values are related to
      prognosis. One of these studies has already been published and others will be
      completed in the near future.

PMID- 10602535
TI  - Blood Pressure Monitoring. Task force III: Target-organ damage, morbidity and
      mortality.
AB  - OBJECTIVE: To reach a consensus on ambulatory blood pressure (ABP) as a predictor
      of target-organ damage (TOD), morbidity and mortality. METHOD: The members of
      task force III wrote this article in preparation for the Seventh International
      Consensus Conference (23-25 September 1999). This article was amended after the
      meeting to reflect the consensus reached at the conference. POINTS OF CONSENSUS:
      In most studies, TOD in essential hypertension was more closely associated with
      ABP than it was with clinic blood pressure, the mean weighted correlation
      coefficients for the relationship of left ventricular mass with blood pressure
      being 0.50/0.44 (24h systolic/diastolic blood pressure) and 0.35/0.32 (clinic
      systolic/diastolic blood pressure), respectively. The above correlation
      coefficients vary among studies, possibly because of different standardizations
      of clinic blood pressure measurements and ways of selecting subjects, among other
      reasons. The closeness of the association between clinic blood pressure and left
      ventricular mass increases with the numbers of clinic measurements of blood
      pressure and visits to a clinic. Thus, the variance of left ventricular mass
      explained by ABP in addition to that explained by clinic blood pressure
      diminishes with the number of clinic blood pressure readings. The proportion of
      variability of left ventricular mass that is directly accounted for by the day
      night difference in blood pressure is 15% at the most. Thus, the advantage of ABP
      over clinic blood pressure appears to be, at least in part, a result of the
      greater number of measurements over the 24h. It might also depend, however, on
      the information offered by ambulatory blood pressure monitoring (ABPM) on daily
      life variations in blood pressure. TOD appears to be more closely associated with
      ABP than it is with clinic blood pressure for the subjects with reproducible ABP
      tracings, but not for those with poorly reproducible tracings. The probability of
      developing sustained clinic hypertension at follow-up seems to be better
      predicted by clinic blood pressure on several occasions over a 6-month period
      than it is by ABP at baseline, although, when also ABPM is repeatedly performed
      at follow-up, its ability to predict clinical outcomes of hypertensive patients
      remains superior to that of repeated clinic blood pressure measurements. ABPM of
      the elderly appears feasible and is tolerated well. A blunted day-night fall in
      blood pressure ('non-dipping') seems to be harmful, while evidence regarding the
      potentially harmful effect of extreme dipping is still limited. Authors of the
      Syst-Eur study recently demonstrated the prognostic value of ambulatory systolic
      blood pressure and in particular, of night-time blood pressure, in assessing old
      subjects with isolated systolic hypertension. The assessment of variability of
      blood pressure has been shown to provide a further prediction of cardiovascular
      risk and the potentially prognostic value of beat-to-beat variability assessed
      non-invasively (using a Finapres or Portapres device)needs further study. In the
      published event-based studies, the prognostic value of ABP recorded during a
      single session was superior to that of clinic blood pressure. Since the authors
      of published event-based prognostic studies compared ABP with only a few clinic
      measurements of blood pressure, it is not known how many visits or measurements
      of blood pressure (and at what cost) would equate to a single session of ABPM in
      terms of prediction of cardiovascular events. ABPM might allow one to identify a
      subset with 'normal' ABP (white-coat or isolated clinic hypertension). Daytime
      ABP levels <135 mmHg systolic and 85 mmHg diastolic can be defined as normal and
      values <130/80 mmHg could be defined as optimal. Cardiovascular risk for subjects
      with normal ABP seems to be lower than that for those with abnormally high ABP.
      Long-term observational and intervention studies concerning subjects with white
      coat hypertension are needed. (ABST

PMID- 10602536
TI  - Task force IV: Clinical use of ambulatory blood pressure monitoring. Participants
      of the 1999 Consensus Conference on Ambulatory Blood Pressure Monitoring.
AB  - OBJECTIVE: To reach a consensus on the clinical use of ambulatory blood pressure
      monitoring (ABPM). METHODS: A task force on the clinical use of ABPM wrote this
      overview in preparation for the Seventh International Consensus Conference (23-25
      September 1999, Leuven, Belgium). This article was amended to account for
      opinions aired at the conference and to reflect the common ground reached in the
      discussions. POINTS OF CONSENSUS: The Riva Rocci/Korotkoff technique, although it
      is prone to error, is easy and cheap to perform and remains worldwide the
      standard procedure for measuring blood pressure. ABPM should be performed only
      with properly validated devices as an accessory to conventional measurement of
      blood pressure. Ambulatory recording of blood pressure requires considerable
      investment in equipment and training and its use for screening purposes cannot be
      recommended. ABPM is most useful for identifying patients with white-coat
      hypertension (WCH), also known as isolated clinic hypertension, which is
      arbitrarily defined as a clinic blood pressure of more than 140 mmHg systolic or
      90 mmHg diastolic in a patient with daytime ambulatory blood pressure below 135
      mmHg systolic and 85 mmHg diastolic. Some experts consider a daytime blood
      pressure below 130 mmHg systolic and 80 mmHg diastolic optimal. Whether WCH
      predisposes subjects to sustained hypertension remains debated. However, outcome
      is better correlated to the ambulatory blood pressure than it is to the
      conventional blood pressure. Antihypertensive drugs lower the clinic blood
      pressure in patients with WCH but not the ambulatory blood pressure, and also do
      not improve prognosis. Nevertheless, WCH should not be left unattended. If no
      previous cardiovascular complications are present, treatment could be limited to
      follow-up and hygienic measures, which should also account for risk factors other
      than hypertension. ABPM is superior to conventional measurement of blood pressure
      not only for selecting patients for antihypertensive drug treatment but also for
      assessing the effects both of non-pharmacological and of pharmacological therapy.
      The ambulatory blood pressure should be reduced by treatment to below the
      thresholds applied for diagnosing sustained hypertension. ABPM makes the
      diagnosis and treatment of nocturnal hypertension possible and is especially
      indicated for patients with borderline hypertension, the elderly, pregnant women,
      patients with treatment-resistant hypertension and patients with symptoms
      suggestive of hypotension. In centres with sufficient financial resources, ABPM
      could become part of the routine assessment of patients with clinic hypertension.
      For patients with WCH, it should be repeated at annual or 6-monthly intervals.
      Variation of blood pressure throughout the day can be monitored only by ABPM, but
      several advantages of the latter technique can also be obtained by self
      measurement of blood pressure, a less expensive method that is probably better
      suited to primary practice and use in developing countries. CONCLUSIONS: ABPM or
      equivalent methods for tracing the white-coat effect should become part of the
      routine diagnostic and therapeutic procedures applied to treated and untreated
      patients with elevated clinic blood pressures. Results of long-term outcome
      trials should better establish the advantage of further integrating ABPM as an
      accessory to conventional sphygmomanometry into the routine care of hypertensive
      patients and should provide more definite information on the long-term cost
      effectiveness. Because such trials are not likely to be funded by the
      pharmaceutical industry, governments and health insurance companies should take
      responsibility in this regard.

PMID- 10602537
TI  - Blood Pressure Monitoring. Task force V: White-coat hypertension.
AB  - TERMINOLOGY: Two terms are in current use to describe patients whose blood
      pressures are high only in a medical setting (white-coat hypertension and
      isolated office or clinic hypertension). The term white-coat effect is also
      commonly used to describe the pressor response to the clinic setting.
      DEFINITIONS: White-coat hypertension is generally defined as a persistently
      elevated clinic blood pressure in combination with a normal ambulatory blood
      pressure (ABP). There is disagreement regarding the optimal cutoff point for ABP.
      The white-coat effect is operationally defined as the difference between the
      clinic blood pressure and daytime ABP. PREVALENCE OF WHITE-COAT HYPERTENSION:
      This varies according to the definition of white-coat hypertension and the
      population studied, but is approximately 20% among mild hypertensives, and
      increases with age. METABOLIC AND BIOCHEMICAL ASPECTS: Authors of some studies
      have suggested that white-coat hypertension is associated with metabolic
      abnormalities such as hyperlipidemia that lead to an increase in cardiovascular
      risk, but most have not found this. TARGET-ORGAN DAMAGE: Several measures of
      target-organ damage have been compared among normotensives, white-coat
      hypertensives, and sustained hypertensives; these include left ventricular mass,
      microalbuminuria, and carotid atherosclerosis. In general, target-organ damage in
      white-coat hypertension is less than that in sustained hypertension, but in some
      studies it has been found to be more prevalent than in normotensives. MORBIDITY
      AND MORTALITY: Authors of a relatively small number of prospective studies have
      concluded that white-coat hypertensives have a lower risk of morbidity than do
      sustained hypertensives, but a larger number have drawn the more general
      conclusion that, when there is a discrepancy between the clinic blood pressure
      and ABP, the prognosis is more closely related to the ABP. MANAGEMENT: When white
      coat hypertensives are prescribed antihypertensive medication there is usually a
      decrease in clinic blood pressure, but little or no change in ABP. Thus drug
      treatment is not necessarily indicated. Another issue is the follow-up of white
      coat hypertensives; there is general agreement that blood pressure outside the
      office should be monitored indefinitely. Some patient may have been wrongly
      classified as white-coat hypertensives, and others may progress to develop
      sustained hypertension.

PMID- 10602538
TI  - Task force VI: Self-monitoring of the blood pressure.
AB  - BACKGROUND: Self-monitoring of the blood pressure by patients at home or in other
      nonclinical settings has become increasingly common in recent years. This
      phenomenon has been fueled in part by the increase in availability of automatic
      sphygmomanometers, which are now both affordable and easy for patients to use.
      BENEFITS OF SELF-MONITORING: Self-monitoring of the blood pressure can be an
      important adjunct to management of hypertension. The technique allows patients to
      participate more in their care. Self-measured values of blood pressure are more
      likely to be representative of the average daily blood pressure than is a clinic
      measurement and may be better related to hypertensive involvement of target
      organs and cardiovascular morbidity than is the clinic blood pressure. Finally,
      the self-monitoring of blood pressure has the potential to reduce the costs of
      hypertension-related care. LIMITATIONS OF SELF-MONITORING: There are several
      issues that prevent the more widespread use of self-monitoring of the blood
      pressure in clinical practice. First, devices marketed for use by patients have
      advanced technically during the 1990s, but many have not been subjected to
      rigorous clinical validation for precision and reliability (e.g. in terms of
      Association for the Advancement of Medical Instrumentation and British
      Hypertension Society guidelines). It is recommended that devices for measuring
      blood pressure used by patients at home be subjected to the same validation
      processes as those that are applied to ambulatory recordings. Second, although
      the upper limits of normal for self-monitored blood pressure of a general
      population can be defined statistically (it is approximately 135/85 mmHg), it is
      not yet possible to determine the normal self-monitored blood pressure because
      these values must be linked to classical clinical cardiovascular endpoints or
      outcomes. Third, the relationships among self-monitored, clinic, and ambulatory
      blood pressures are defined for some populations but their behaviors according to
      age, sex, ethnicity, and treatment status require further study. Fourth, several
      different schedules for self-monitoring of the blood pressure by patients have
      been used in clinical research and practice. It will be necessary to determine
      the optimal schedule and number of recordings required when patients perform self
      monitoring of the blood pressure. Fifth, self-monitoring of the blood pressure in
      clinical trials of antihypertensive therapies is certainly feasible but has
      typically not been included in their design, either by investigators or by the
      pharmaceutical sponsors. Sixth, there have been data suggesting that self
      monitoring of the blood pressure reduces the comprehensive costs associated with
      hypertension care on an annual basis. However, since most work on the economic
      impact of self-monitoring of the blood pressure has been performed in managed
      care environments in the USA, it is not known whether this reduction in health
      care costs would be applicable to other types of practice environments on a
      worldwide basis. CONCLUSIONS: Self-monitoring of the blood pressure is at present
      useful as an adjunct measurement for the management of hypertensive patients and
      might provide benefits in clinical trials of antihypertensive therapy.
      Nevertheless, the available data on self-monitoring of the blood pressure are
      inadequate as grounds for clinicians to make primary diagnostic or therapeutic
      decisions and should not override the blood pressure obtained by clinical
      measurement or via ambulatory monitoring.

PMID- 10602539
TI  - Schistosoma mansoni associated glomerulopathy.

PMID- 10602540
TI  - Clinical and laboratory findings of disseminated Mycobacterium avium complex
      infection (DMAC) in a pair matched case-control study.
AB  - A pair matched case/control study was conducted from January 1991 to 30 June 1992
      in order to define clinical and laboratory findings associated with DMAC
      infection in AIDS patients. Since DMAC infection is usually associated with
      advanced immunodeficiency, and therefore also with other opportunistic illnesses,
      in addition to the number of CD4+ lymphocytes, cases and controls were matched
      using the following criteria: date of AIDS diagnosis and antiretroviral therapy,
      number and severity of associated opportunistic infections and, whenever
      possible, type of Pneumocystis carinii prophylaxis, age and gender, in this order
      of relevance. Cases (defined as patients presenting at least one positive culture
      for MAC at a normally sterile site) and controls presented CD4+ lymphocyte counts
      below 50 cel/mm3. A significantly higher prevalence of general, digestive and
      respiratory signs, increased LDH levels, low hemoglobin levels and CD4+ cell
      counts were recorded for cases when compared to controls. Increases in gammaGT
      and alkaline phosphatase levels seen in cases were also recorded for controls. In
      conclusion, the strategy we used for selecting controls allowed us to detect
      laboratory findings associated to DMAC infection not found in other advanced
      immunosupressed AIDS patients without DMAC.

PMID- 10602541
TI  - Paracoccidioides brasilienses isolates obtained from patients with acute and
      chronic disease exhibit morphological differences after animal passage.
AB  - The basis for virulence in Paracoccidioides brasiliensis is not completely
      understood. There is a consensus that the sequential in vitro subcultivation of
      P. brasiliensis leads to loss of its pathogenicity, which can be reverted by
      reisolation from animal passage. Attention to morphological and biochemical
      properties that are regained or demonstrated after animal passage may provide new
      insights into factors related to the pathogenicity and virulence of P.
      brasiliensis. We evaluated morphological characters: the percentage of budding
      cells, number of buds by cell and the diameter of 100 mother cells of yeast-like
      cells of 30 P. brasiliensis isolates, before and after animal passage. The
      isolates were obtained from patients with different clinical forms of
      paracoccidioidomycosis (PCM): acute form (group A, n=15) and chronic form (group
      C, n=15). The measurement of the yeast cell sizes was carried out with the aid of
      an Olympus CBB microscope coupled with a micrometer disc. We measured the major
      transverse and longitudinal axes of 100 viable cells of each preparation. The
      percentage of budding cells as also the number of buds by cell was not influenced
      by animal passage, regardless of the source of the strain (acute or chronic
      groups). The size values of P. brasiliensis isolates from groups A and C,
      measured before the animal passage exhibited the same behavior. After animal
      passage, there was a statistically significant difference between the cell sizes
      of P. brasiliensis isolates recovered from testicles inoculated with strains from
      groups A and C. The maximum diameter of mother cells from group A isolates
      exhibited a size of 42.1 microm in contrast with 32.9 microm exhibited by mother
      cells from group C (p<0.05). The diameter of 1500 mother cells from group A
      isolates exhibited a medium size of 16.0 microm (SD +/- 4.0), a value
      significantly higher than the 14.1 microm (SD = +/- 3.3) exhibited by 1500 mother
      cells from group C isolates (p<0.05). Our results reinforce the polymorphism
      exhibited by P. brasiliensis in biological material and the need for further
      investigations to elucidate the role of morphological parameters of the fungus in
      the natural history of the disease.

PMID- 10602542
TI  - Dermatophytosis: association between ABO blood groups and reactivity to the
      trichophytin.
AB  - The authors investigated the relationship between dermatophytosis and ABO blood
      groups through blood typing, identification of isolated dermatophytes and
      specific cellular immune response of 40 individuals carriers of this mycosis.
      They verified that the fungus Trichophyton rubrum, isolated from 54.5% of the
      patients, was more frequent in individuals belonging to blood group A. The
      cellular immune response, evaluated through the trichophytin antigen, was
      positive in 25% of the studied patients; the presence of immediate reactions (30
      minutes) was verified in 35%. The blood group distribution among patients with
      dermatophytosis and control groups was, respectively: 47.5% X 36% in group A, 40%
      X 50% in group O, 12. 5% X 11% in group B. Even though the authors have found a
      higher number of patients belonging to blood group A infected by T. rubrum, these
      results suggest that there is no statistical evidence that these individuals are
      more susceptible to dermatophytosis.

PMID- 10602543
TI  - Genetic variation between susceptible and non-susceptible snails to Schistosoma
      infection using random amplified polymorphic DNA analysis (RAPDs).
AB  - Susceptibility of snails to infection by certain trematodes and their suitability
      as hosts for continued development has been a bewildering problem in host
      parasite relationships. The present work emphasizes our interest in snail
      genetics to determine what genes or gene products are specifically responsible
      for susceptibility of snails to infection. High molecular weight DNA was
      extracted from both susceptible and non-susceptible snails within the same
      species Biomphalaria tenagophila. RAPD was undertaken to distinguish between the
      two types of snails. Random primers (10 mers) were used to amplify the extracted
      DNA by the polymerase chain reaction (PCR) followed by polyacrylamide gel
      electrophoresis (PAGE) and silver staining. The results suggest that RAPD
      represents an efficient means of genome comparison, since many molecular markers
      were detected as genetic variations between susceptible and non-susceptible
      snails.

PMID- 10602544
TI  - IgG recognizing 21-24 kDa and 30-33 kDa tachyzoite antigens show maximum avidity
      maturation during natural and accidental human toxoplasmosis.
AB  - We describe the avidity maturation of IgGs in human toxoplasmosis using
      sequential serum samples from accidental and natural infections. In accidental
      cases, avidity increased continuously throughout infection while naturally
      infected patients showed a different profile. Twenty-five percent of sera from
      chronic patients having specific IgM positive results could be appropriately
      classified using exclusively the avidity test data. To take advantage of the
      potentiality of this technique, antigens recognized by IgG showing steeper
      avidity maturation were identified using immunoblot with KSCN elution. Two
      clusters of antigens, in the ranges of 21-24 kDa and 30-33 kDa, were identified
      as the ones that fulfill the aforementioned avidity characteristics.

PMID- 10602545
TI  - A survey of congenital Chagas' disease, carried out at three health institutions
      in Sao Paulo City, Brazil.
AB  - The congenital transmission of Chagas' disease was evaluated in 57 pregnant women
      with Chagas' disease and their 58 offspring. The patients were selected from
      three Health Institutions in Sao Paulo City. The maternal clinical forms of
      Chagas' disease were: indeterminate (47.4%), cardiac (43.8%) and digestive
      (8.8%); 55 were born in endemic areas and two in Sao Paulo City. The transmission
      of Chagas' disease at fetal level was confirmed in three (5.17%) of the 58 cases
      studied and one probably case of congenital Chagas' disease. Two infected infants
      were born to chagasic women with HIV infection and were diagnosed by
      parasitological assays (microhematocrit, quantitative buffy coat-QBC or
      artificial xenodiagnosis). In both cases the placenta revealed T. cruzi and HIV
      p24 antigens detected by immunohistochemistry. In one case, a 14-week old
      abortus, the diagnosis of congenital T. cruzi infection was confirmed by
      immunohistochemistry. The other probable infection, a 30-week old stillborn, the
      parasites were found in the placenta and umbilical cord. The Western blot method
      using trypomastigote excreted/secreted antigens of T. cruzi (TESA) was positive
      for IgG antibodies in 54/55 newborns and for IgM in 1/55 newborns. One of the two
      newborns with circulating parasites had no detectable IgG or IgM antibodies. The
      assessment of IgG antibodies in the sera of pregnant women and their newborns was
      performed by ELISA using two different T. cruzi antigens: an alkaline extract of
      epimastigotes (EAE) and trypomastigote excreted/secreted antigens (TESA). The
      analysis showed a linear correlation between maternal and newborn IgG antibody
      titers at birth.

PMID- 10602546
TI  - Dermatophytosis caused by Trichophyton raubitschekii. Report of the first case in
      Sao Paulo, Brazil.
AB  - The authors report the first case of dermatophytosis caused by Trichophyton
      raubitschekii in a patient from the State of Sao Paulo with Tinea corporis
      lesions localized on the buttocks. Culture on Sabouraud-agar with cycloheximide
      permitted the isolation and identification of the fungus, and the diagnosis was
      confirmed by Dr. Lynne Sigler, University of Alberta, Canada. Systemic treatment
      with fluconazole, 150 mg/week for 4 weeks, in combination with topical treatment
      with isoconazole initially yielded favorable results, with recurrence of the
      lesions after the medication was discontinued. This is the fifth case of this
      dermatophytosis published in the Brazilian medical literature.

PMID- 10602547
TI  - Onychomycosis caused by Scytalidium dimidiatum. Report of two cases. Review of
      the taxonomy of the synanamorph and anamorph forms of this coelomycete.
AB  - The authors report two cases of onychomycosis in the dystrophic form, one of them
      involving an HIV-positive patient, provoked by Scytalidium dimidiatum, previously
      called Scytalidium lignicola. The subject is reviewed from the taxonomic
      viewpoint, considering the anamorph Hendersonula toruloidea as a synonym of
      Nattrassia mangiferae, and having Scytalidium dimidiatum as the major
      synanamorph. According to many mycologists, Scytalidium hyalinum may be a
      separate species or a hyaline mutant of Scytalidium dimidiatum. Scytalidium
      lignicola Pesante 1957 was considered to be the type-species of the genus by
      ELLIS (1971)13 and later to be a "conidial state" of Hendersonula toruloidea by
      the same author, today known as Nattrassia mangiferae. The microorganism lives
      only on the roots of certain plants (mainly Platanus and Pinus). It produces
      pycnidia and is not considered to be a pathogen, although it is considered as a
      possible emerging agent capable of provoking opportunistic fungal lesions. The
      importance of this topic as one of the most outstanding in fungal taxonomy, so
      likely to be modified over time, as well as its interest in the field of
      dermatologic mycology, are emphasized.

PMID- 10602548
TI  - Jejunal perforation caused by abdominal angiostrongyliasis.
AB  - The authors describe a case of abdominal angiostrongyliasis in an adult patient
      presenting acute abdominal pain caused by jejunal perforation. The case was
      unusual, as this affliction habitually involves the terminal ileum, appendix,
      cecum or ascending colon. The disease is caused by the nematode Angiostrongylus
      costaricensis, whose definitive hosts are forest rodents while snails and slugs
      are its intermediate hosts. Infection in humans is accidental and occurs via the
      ingestion of snail or slug mucoid secretions found on vegetables, or by direct
      contact with the mucus. Abdominal angiostrongyliasis is clinically characterized
      by prolonged fever, anorexia, abdominal pain in the right-lower quadrant, and
      peripheral blood eosinophilia. Although usually of a benign nature, its course
      may evolve to more complicated forms such as intestinal obstruction or
      perforation likely to require a surgical approach. Currently, no efficient
      medication for the treatment of abdominal angiostrongyliasis is known to be
      available. In this study, the authors provide a review on the subject,
      considering its etiopathogeny, clinical picture, diagnosis and treatment.

PMID- 10602549
TI  - Towards 2000-New Pathways for the Clinical Management of Acute Ischemic
      Syndromes: Introductory Editorial to Symposium.

PMID- 10602550
TI  - Acute Myocardial Infarction in Canada: New Epidemiologic Insights on Incidence,
      Therapy, and Risk.
AB  - Objective: To define the changing incidence, risk, and therapy of acute
      myocardial infarction (A311). Data sources: Review of contemporary AMI data from
      the University of Alberta Hospitals, six other sites of the Clinical Quality
      Improvement Network (CQIN), and other Canadian and international centers. Data
      synthesis: Ischemic heart disease is age-related and the Canadian population is
      rapidly aging. At the University of Alberta Hospitals, the incidence of Q wave
      AMI (per 100,000 population) in 1985 was 113 and has remained unchanged (NS)
      since that time (129 in 1994). In contrast, the combined incidence of non.Q-wave
      AMI and unstable angina has increased markedly, from 74 in 1985 to 226 in 1994 (p
      < 0.05). The use of proven efficacious therapies for AMI has greatly increased in
      recent years, with thrombolytic drugs being given to approximately 35;percnt; of
      all patients by 1993; and beta-blockers and aspirin to 75;percnt; and 98;percnt;
      of patients, respectively. However, females and patients older than 70 years'
      despite their greater risk, received significantly less efficacious medication
      than males and younger AMI patients. The use of calcium antagonists decreased
      from a peak utilization rate of 60;percnt; for all AMI patients in 1989 to less
      than 10;percnt; by 1993. In-hospital AMI mortality risk has also decreased in the
      last several years, particularly among higher risk older patients (35;percnt;,
      1987 vs. 19;percnt;,1993). In a population of 3896 consecutive AMI patients,
      recruited largely in 1992 and 1993 from seven CQIN sites, logistic regression
      analyses revealed aspirin was associated with the greatest relative risk
      reduction (61%); beta-blocker and thrombolytic therapy were related to risk
      reductions of 55;percnt; and 16;percnt;, respectively. Incremental age was the
      most important factor associated with increased relative risk in AMI, overall and
      in both sexes; sex was not an independent risk predictor. Qualitatively very
      similar AMI incidence, risk, and treatment data have also been recently observed
      in other centers in Canada, the United States, and elsewhere. Conclusions:
      Although widespread primary or secondary prevention is possibly contributory, the
      recent static incidence of Q-wave AMI and the marked increase in unstable angina
      and non-Q-wave AMI are more likely due to enhanced health awareness and diagnosis
      seeking behavior in the population at risk. The decline in AMI mortality, at
      least for high-risk acute care patients, is compatible with a clinically relevant
      secondary prevention effect. There are still, however, windows of opportunity to
      further improve AMI outcomes by increasing the utilization of proven efficacious
      therapy, especially among women and older patients. Another particularly
      attractive epidemiologic benefit in the immediate future would accrue from the
      further development and effective use of efficacious therapies directed against
      unstable angina and n-Q-wave AMI.

PMID- 10602551
TI  - Identifying Patient Risk: The Basis for Rational Discharge Planning After Acute
      Myocardial Infarction.
AB  - Variations in the management of patients with chest pain and acute myocardial
      infarction (MI) can significantly affect hospital length of stay and cost. Risk
      stratification of such patients, combined with data about effective therapies,
      provides the basis for developing rational guidelines for patient care that can
      improve efficiency while maintaining quality of care. Such standardized
      management approaches are often referred to as pathways or CareMaps. To be most
      effective in guiding hospital course and early discharge planning, risk
      stratification strategies must be applied early in a patient's course with
      continuous updating. The process of identifying risk in a patient with acute
      chest pain occurs in two segments: assessing the risk of acute MI at
      presentation, and subsequently assessing the morbidity and mortality risk of
      patients diagnosed with acute MI. Identification of patient risk at presentation
      has been the object of intense investigation. The history, physical exam, initial
      electrocardiogram, and cardiac enzymes are the mainstays of the process, but
      because of inherent weaknesses in this approach (>25% of acute MIs missed initial
      screening), several risk stratification models have been developed. To date these
      models have not been widely employed, however. Very sensitive early cardiac
      markers, such as troponin T, and the use of diagnostic echocardiography or
      cardiolite perfusion imaging during pain are also being investigated. Chest pain
      observation units are an alternate strategy and have obviated the need to admit
      many low- to moderate-risk chest pain patients. In these protocol-driven units,
      continuous physiologic monitoring and serial cardiac enzymes and
      electrocardiography over a 9-12 hour period refine the risk assessment. For the
      majority who "rule out," the risk of subsequent MI or death is very low. Cost
      savings due to reduced length of stay and more efficient resource utilization are
      63-76% compared with conventional word or cardiac care unit management. For
      patients with acute MI, baseline characteristics, complications, and laboratory
      and diagnostic testing help define the risk of morbidity and mortality and guide
      management through the immediate post-MI phase and long term. Many models
      incorporating these features have been proposed for risk stratification after
      acute MI, and they have implications for both timing of discharge and necessary
      diagnostic testing. Savings by employing risk stratification to guide hospital
      course and discharge planning could be 30-44% in some patient groups. In
      conclusion, risk stratification models can facilitate early discharge planning,
      potentially reducing hospital stay, improving resource utilization, and reducing
      costs.

PMID- 10602552
TI  - Time to Reperfusion: The Critical Modulator in Thrombolysis and Primary
      Angioplasty.
AB  - Rapid achievement of reperfusion with thrombolytic therapy or primary angioplasty
      has made a dramatic impact an improving the survival of patients with acute
      myocardial infarction (MI). Restoring infarct-related artery patency early after
      the onset of MI minimizes infarct size, reduces the degree of left ventricular
      dysfunction, and improves survival. Several recent studies have confirmed the
      benefit of reducing time to treatment with thrombolysis (between the onset of
      pain to initiation of thrombolysis), and that of more rapid drug reperfusion time
      with more aggressive thrombolytic regimens (between initiation of thrombolytic
      therapy and actual achievement of reperfusion). Furthermore, these effects are
      additive, confirming the benefit of rapid reperfusion. For primary angioplasty,
      the same relationship has been observed-more rapid treatment appears to be
      associated with improved outcome. The "door-to-balloon" time is a major
      determinant of overall time to reperfusion, and as such is a crucial component of
      the overall strategy. Integrating the experience in trials of thrombolytic
      therapy and primary angioplasty, a clear relationship exists between higher rates
      of early reperfusion and lower mortality. Thus, time to reperfusion appears to be
      the critical modulator in both thrombolysis and primary angioplasty.

PMID- 10602553
TI  - Potential for a New Coronary Thrombolytic Plateau.
AB  - The GUSTO-I trial provided definitive evidence that early and complete
      thrombolysis are closely associated with clinical outcome. However, in this trial
      the best thrombolytic strategy, consisting of accelerated t-PA, aspirin, and
      heparin, only yielded restoration of brisk flow (TIMI 3) in 54% of patients at 90
      minutes after therapy. There are a variety of new strategies aimed at improving
      the rate of early TIMI flow, consisting of new plasminogen activators,
      anticoagulants, and platelet inhibitors, The third generation plasminogen
      activators include reteplase (r-PA), n-PA, bat-PA, staphylokinase, and TNK. To
      date, none of these molecules have been clearly associated with superior rates of
      infarct vessel patency, but comparative trials are in progress. Potent inhibitors
      of thrombin are recombinant hirudin, the most potent naturally occurring
      anticoagulant known, and synthetic direct thrombin inhibitors such as hirulog and
      argatroban. In the years ahead, agents that block the generation of thrombin, a
      step higher up in the coagulation cascade, such as factor Xa inhibitors, will be
      clinically pursued. The platelet glycoprotein Ilb/Illa inhibitors are a potent
      class of agents directed against the final common pathway for platelet
      aggregation, and pilot studies suggest excellent potential for facilitating early
      thrombolysis. Accordingly, a multitiered strategy of improved plasminogen
      activators, thrombin inhibitors, and antiplatelets is likely to result in far
      better clinical outcomes for myocardial reperfusion therapy in the future.

PMID- 10602554
TI  - Enhancing Thrombolysis with Adjunctive Therapy.
AB  - The striking clinical benefits that can be derived from thrombolytic therapy in
      acute myocardial infarction emphasize the need for further improvement of our
      reperfusion strategies. New approaches in that direction include the development
      of more efficient thrombolytic drugs as well as an adjunctive therapy to control
      the ongoing thrombogenic stimulation. Aspirin is already useful in this regard as
      well as heparin with recombinant tissue-type plasminogen activator. The field of
      antithrombotic therapy is rapidly expanding with the development of patent drugs
      targeted at inhibiting specific steps of platelet activation and of the
      coagulation cascade. This new therapy provides opportunities to better understand
      the pathophysiological processes involved in acute ischemic syndromes and to
      modulate them. This article reviews the adjunctive antithrombotic therapy
      currently available or under clinical investigation with the potential of
      enhancing the benefits of thrombolysis.

PMID- 10602555
TI  - New Therapeutic Opportunities for Heparins: What Does Low Molecular Weight
      Heparin Offer?
AB  - New advances in antithrombotic therapy include direct thrombin inhibitors and low
      molecular weight heparins and heparinoids. Low molecular weight heparins and
      heparinoids have improved pharmacologic and pharmacokinetic properties when
      compared with unfractionated heparin. Low-molecular weight heparins are effective
      in the prevention of venous thromboembolism in general surgical patients,
      orthopedic patients, spinal cord injury patients, and general medical patients.
      At equipotent antithrombotic doses, low molecular weight heparins produce less
      bleeding. Low molecular weight heparins given in fixed doses subcutaneously have
      been shown to be as effective or more effective and safer than unfractionated
      heparin given intravenously with regular monitoring in the treatment of venous
      thromboembolic disease. Recent studies have demonstrated that low molecular
      weight heparins are effective in reducing the risk of death and myocardial
      infarction in patients with unstable angina and are as effective as intravenous
      heparin when given subcutaneously without monitoring. Preliminary data indicate
      that low molecular weight heparins may be effective in improving outcomes in
      patients with ischemic stroke.

PMID- 10602556
TI  - Economics and Quality of Life After Acute Myocardial Infarction: Insights from
      GUSTO-I.
AB  - Reperfusion therapy for acute myocardial infarction is one of the most thoroughly
      studied treatments in all of medicine. The GISSI-1 and ISIS-2 megatrials
      definitively established the superiority of intravenous streptokinase over
      conservative care for this condition. Tissue plasminogen activator (t-PA) was
      introduced with the expectation that it would be substantially more effective
      than streptokinase. It was also priced at approximately $2000, more than
      streptokinase, a cost differential that set the stage for a heated and often
      contentious debate about the added value of t-PA. Two European trials, GISSI-2
      and ISIS-3, subsequently found that t-PA and streptokinase provided equivalent
      health outcomes. It was in this setting that the GUSTO trial was conceived. The
      major result of GUSTO was the finding that accelerated t-PA saved 11 additional
      lives per 1000 patients treated. In order to address the question of whether the
      extra benefits of t-PA were worth its significant extra costs, we performed a
      detailed cost-effectiveness analysis using the empirical data from the GUSTO-I
      trial. The net incremental cost for each patient shifted from streptokinase to t
      PA in GUSTO-I was;dollar;2845. The majority of this difference was attributable
      to the difference in the cost of the thrombolytic agents. Survival modeling
      showed that accelerated t-PA added 0.14 undiscounted years per patient or,
      alternatively, that each of the 11 extra survivors per 1000 patients shifted from
      streptokinase to t-PA lived an average of 14 additional years. The incremental
      cost-effectiveness ratio for routine substitution of t-PA for streptokinase
      was;dollar;32,678 per added life year. Compared with standard benchmarks, our
      analysis shows that routine substitution of t-PA for streptokinase is
      "economically attractive." Subgroups analysis further showed that cost
      effectiveness ratios were most favorable in older patients and in anterior
      myocardial infarctions. Perhaps one of the most important results of the GUSTO-I
      trial is that it demonstrates that an expensive new biotechnology therapy can
      have a favorable economic profile if it produces sufficient additional health
      benefits.

PMID- 10602557
TI  - Costs in Perspective: Understanding Cost-Effectiveness Analysis.
AB  - This paper covers five questions: (1) What is cost-effectiveness analysis;quest;
      (2) How can cost-effectiveness analysis help policymakers allocate scarce
      resources;quest; (3) What are misconceptions about the cost effectiveness of
      health care interventions;quest; (4) What is an attractive cost-effectiveness
      ratio;quest; (5) What is the relevance of cost effectiveness to clinicians? The
      cost side of the equation includes more than simply the cost of the intervention,
      but rather the cost of all of the downstream clinical events that occur with
      either therapeutic alternative. Cost-effectiveness analyses are used to help
      decisionmakers rank programs competing for scarce resources in order to achieve
      the following objective: to maximize the net health benefits derived from a fixed
      budget for a target population. A simple example is shown. Measured cost
      effectiveness ratios for selected cardiovascular interventions are displayed. The
      systematic use of information on effectiveness and cost effectiveness should help
      those involved in setting policies to have a more rational basis for funding of
      new programs and discontinuation of funding for old programs. In Canadian health
      care it is important that we use this information to make room for innovations
      that are effective and efficient, and to remove funding from programs that are
      either known to be ineffective and costly or inefficient use of resources. More
      energy should be put toward generating the information necessary to make these
      kinds of decisions.

PMID- 10602558
TI  - Current Clinical Experience with Staphylokinase in Arterial Thrombosis.

PMID- 10602559
TI  - Hospital Protocols and Policies that may Delay Early Identification and
      Thrombolytic Therapy of Acute Myocardial Infarction Patients.
AB  - Despite the compelling relationship between early treatment and outcome from
      reperfusion therapy in patients with acute myocardial infarction, significant
      delays in early treatment are imposed by the patient, prehospital systems, and
      hospital processes and protocols used in the identification and treatment of
      patients with myocardial infarction. A survey instrument designed to determine
      the prevalence of hospital policies and protocols that might delay or expedite
      treatment with thrombolytic therapy in patients with acute myocardial infarction
      was completed by 524 hospital participating in the National Registry for
      Myocardial Infarction (NRMI). Participating hospitals had treated 17,646 patients
      with tissue plasminogen activator. The door to drug time for the entire
      population of patients treated at each hospital was available. Door to drug times
      were compared between those hospitals that had a positive response to a policy
      and those that had a negative response to that policy. Among respondent
      hospitals, thrombolysis was excluded by protocol in 34.4% for age above 75 and in
      55% for presentation after 6 hours of chest pain onset. Furthermore, 29.4% of
      hospitals required routine laboratory testing other than electrocardiography
      (ECG), including chest x-ray, prior to determination of eligibility for
      thrombolysis. Door to drug times were shorter in those hospitals with prehospital
      12-lead ECG availability, assessment of the 12-lead ECG by the emergency
      department nurse and physician as soon as it was available, and initiation of
      thrombolysis by the emergency physician (in patients with clear-cut ST elevation
      myocardial infarction) without bedside cardiology consultation. Door to drug
      times were longer in those hospitals in which predecision laboratory results were
      required, written informed consent was mandated, and drug was initiated in the
      cardiac intensive care unit rather than in the emergency department itself. Door
      to drug times were not significantly different in those hospitals with a
      designated chest pain center compared with those operating under a focused
      patient care protocol. We conclude that the earliest possible hospital treatment
      of acute myocardial infarction patients may be precluded by multiple components
      of emergency department policies and process, many of them inappropriate for
      safe, efficient, and effective identification and management of these patients.

PMID- 10602560
TI  - Current Approach to Antithrombotic Therapy: An Abbreviated Reference for
      Practicing Clinicians.

PMID- 10602561
TI  - Holmium Laser-Induced Coronary Thrombolysis.

PMID- 10602562
TI  - Dependence of Human Vascular Cell Surface Proteolysis on Expression of the
      Urokinase Receptor.
AB  - To delineate the role of binding of urokinase type plasminogen activator (uPA) to
      its receptor (uPAR) in the local generation of plasmin by endothelium, we
      transfected spontaneously transformed immortalized human vascular endothelial
      cells that express high levels of uPA but low levels of uPAR with human uPAR
      complementary DNA. Compared with nontransfected cell, the stably transformed
      clonal cell line exhibited (a) a >10-fold increase in steady-state uPAR mRNA
      levels documented with Northern blot analysis (n = 3), (b) a 2.8-fold increase in
      cell surface expression of uPAR protein quantified by enzyme linked immunosorbent
      assay (n = 3), (c) a 2.9-fold increase in specific binding of radiolabeled single
      chain uPA (n = 4), and (d) markedly increased matrix adhesion. The participation
      of uPAR in cell surface proteolysis was apparent based on a 3.0-fold increase in
      cell associated plasmin activity (n = 3) and a 2.3-fold increase in lysis of
      noncrosslinked fibrin clots (n = 5). Thus, local generation of plasmin and
      consequent degradation of fibrin are likely to be promoted by cell surface
      localization of uPA by uPAR in cellular constituents of the vessel wall.
      Furthermore, genetic engineering of endothelium to enhance expression of uPAR may
      confer resistance to thrombosis or restenosis associated with endovascular
      stents.

PMID- 10602563
TI  - A Simple, Reproducible Animal Model of Arterial Occlusion with Mixed Thrombus.
AB  - Background: Current animal models of thrombotic arterial occlusion are complex
      and difficult to perform. A more simplified model of thrombotic occlusion with
      angiographic endpoints and mixed thrombotic composition would be useful to assess
      the effectiveness of new therapeutic modalities. Methods and results: Femoral
      arteries in 38 New Zealand White rabbits were cannulated. The animal protocol
      involved denudation of one iliac artery by stripping with progressively
      increasing balloon size, followed by inflow arterial occlusion and the addition
      of thrombin. Cineangiography was performed at baseline and 10 minutes after the
      procedure to assess TIMI blood flow. Baseline angiography revealed normal TIMI 3
      flow in all arteries. A successful angiographic endpoint of TIMI 0 or TIMI 1
      blood flow was achieved in only 6 or 46% of 13 rabbits with initial use of the
      protocol, but was successful in 25 or 100% of a consecutive series of rabbits
      after the initial or repeat use of the protocol. Importantly, histologic analysis
      of thrombus revealed a mixture of platelets, erythrocytes, and fibrin. The mean
      injury index of the internal elastic lamina (IEL) was 40.7 +/- 35.16%. No
      correlation was found between TIMI flow change and intact IEL (R = -0.068, p >
      0.5). Total procedure time was about 1 hour. Conclusion: This simple and
      reproducible animal model of arterial occlusion provided a mixed thrombus that is
      comparable to human thrombus and thus may be useful to assess thrombolytic agents
      or new coronary interventional devices.

PMID- 10602564
TI  - Reduction of Platelet Thrombi and Emboli by L-Arginine during Cardiopulmonary
      Bypass in a Pig Model.
AB  - We wanted to test the hypothesis that NO generation by L-arginine (LA) infusion
      will be beneficial in increasing blood flow to all organs to counteract the
      process of global ischemia during cardiopulmonary bypass (CPB) and to reduce
      platelet emboli by platelet inhibition. The effect of LA infusion on NO
      formation, vasodilation, and reduction of thromboembolic burden in organs and
      tissues after CPB was quantified with In-111-labeled autologous platelets in two
      major groups: 180 minutes CPB (CPB) and 90 minutes CPB plus 90 minutes
      reperfusion (RP). Platelets labeled with In-111 tropolone (650-780 uCi) were
      administered 24 hours before CPB and LA infusion (bolus, 10 mg/kg and infusion at
      2 mg/kg/min, 21 pigs for 180 minutes CPB) in 8 groups of 30 Yorkshire pigs (30-35
      kg, 6 pigs; LA 2 mg/kg/min, 3 pigs; sham-thoracotomy control, 6 pigs; unoperated
      control, 6 pigs). Two groups of 9 pigs (control CPB, 6 pigs; LA 2 mg/kg/min, 3
      pigs) underwent 90 minutes of CPB and 90 minutes of reperfusion. All pigs were
      heparinized (ACT > 400 seconds); CPB was instituted with a roller pump, an
      oxygenator (OX: Bentley Univox, 1.8 m2), and an arterial filter (AF: 0.25 m2,
      Bentley) at a blood flow of 2.5-3.5 l/min. Radioactive thrombi in OX and AF and
      emboli in viscera, brain, and connective tissues were imaged with a gamma camera
      and were finally measured with an ion chamber and a gamma counter. The percent of
      injected platelets (mean +/- SD) in the organs and tissues of all pigs was
      calculated. Cerebral emboli were mapped in 25 regions of both hemispheres of pig
      brain. Flow cytometry with antibodies to CD61 (GPIIIa) and CD62P (GMP
      140:control) of porcine platelets was carried out with blood samples taken
      before, during, and after CPB. Coronary bypass with LA infusion decreased the
      amount of adherent thrombi in OX and AF (p < 0.07). The embolic burden in brain
      and lung also decreased. Regional cerebral mapping of In-111 platelets showed
      reduced emboli in almost all regions, including the medulla, hip pocampus, and
      posterior cerebral cortex in both LA-treated groups. Flow cytometry of blood
      samples demonstrated the shift of equilibria from single platelet to platelet
      aggregate-microparticle during CPB and steady-state level after the first 5-10
      minutes of initiation of CPB. The L-arginine infusion reduced thrombi and emboli
      during CPB in the pig model.

PMID- 10602565
TI  - Ultrastructural Evaluation of Postischemic Cell Death (Lethal Reperfusion Injury)
      in Porcine Hearts.
AB  - This study investigated whether reperfusion results in an increase of
      ultrastructurally determined myocardial injury in pig hearts. The left anterior
      descending coronary artery (LAD) was distally occluded in 12 pigs for 35-45
      minutes and then reperfused for 3 hours. At the end of ischemia, as well as after
      3 hours of reperfusion, one transmural biopsy was removed from the center of the
      risk region and subdivided into four-specimens, representing the subendocardial
      (I), subendo-midmyocardial (II), subepi-midmyocardial (III), and subepicardial
      layers (IV). The degree of injury was assessed by electronmicroscopy and was
      scored as reversible (1), an almost equal mixture of reversible and irreversible
      (2), and totally irreversible (3) damage. In addition, infarct size was
      determined as the ratio of infarcted (tetrazolium stain) to ischemic (dye
      technique) myocardium. Infarct sizes ranged from 29.3% to 93% (mean 61.2%). The
      scores of injury of the four tissue layers before and after reperfusion did not
      differ significantly: layer I, 2.4 +/- 0.8/2.3 +/- 0.9; layer II, 2.2 +/- 0.9/2.0
      +/- 0.9; layer III, 1.8 +/- 0.9/2.0 +/- 0.9; and layer IV, 1.6 +/- 0.9/1.3 +/-
      0.6. The means of the four layers were almost identical at the end of ischemia
      (2.1 +/- 0.8) and after 3 hours of reperfusion (2.0 +/- 0.6). A linear regression
      analysis with 95% confidence limits of the score values before and after
      reperfusion indicated that maximally 25% of a mean final infarct size of about
      50% may be due to lethal reperfusion injury. This study suggests that cell death
      in regional ischemia and reperfusion occurs predominantly during ischemia and not
      during reperfusion.

PMID- 10602566
TI  - Argatroban During Percutaneous Transluminal Coronary Angioplasty: Results of a
      Dose-Verification Study.
AB  - Background. Thrombin is a key enzyme in thrombogenesis. In animals, specific
      antithrombotic therapy at the time of coronary angioplasty reduced the incidence
      of subacute occlusion and inhibited the restenosis response. Argatroban is a
      highly selective synthetic thrombin antagonist that binds in a competitive
      manner. This is a report of a dose-verification study, assessing the safety and
      feasibility of intravenous Argatroban administration in patients undergoing
      percutaneous transluminal coronary angioplasty. Methods. Before angioplasty an
      intravenous bolus of 30 ug/kg argatroban was administered, followed by a
      continuous infusion of 3.5 ug/kg/min for 72 hours. Bolus injection was repeated,
      and the infusion rate was increased in order to achieve an activated coagulation
      time (ACT) of over 300 seconds. Following interim analysis, the bolus and initial
      infusion rate for the subsequent treatment groups was determined. Study endpoints
      were the occurrence of adverse events, coagulation tests, and qualitative
      angiogram reading. Patients were monitored by continuous 12-lead
      electrocardiographic recording over 24 hours, and underwent control angiography
      18-24 hours following angioplasty. Results. Four treatment groups, comprised of
      2, 8, 9, and 11 patients, respectively, were studied. The first two patients were
      excluded from analysis, since the initial dose was ineffective to attain an ACT
      authorizing coronary angioplasty. The group with the highest dosage received a
      250 ug/kg intravenous bolus of argatroban, followed by a 4 hour infusion of 15
      ug/kg/min. At 4 hours the infusion rate was lowered to 3.8 ug/kg/min and was
      continued for 68 hours without adjustment for catheter removal. The adverse event
      profile included myocardial infarction, aortocoronary bypass graft, bailout
      procedures, and repeat coronary angioplasty. Thrombin-time (TT), activated
      partial thromboplastin time (APTT), and prothrombin time (PT) were significantly
      related to argatroban plasma concentration, as demonstrated by regression
      analyses (R-square 0.64, 0.71, and 0.84, respectively). Prothrombin fragments 1
      and 2 and thrombin-antithrombin III complex did not fit into a mathematical
      model, but showed slightly increased levels after reduction or cessation of the
      infusion rate. Conclusions. This dose-verification study, including 30 patients
      at four dose levels, indicated that argatroban infusion in coronary angioplasty
      patients can be administered safely, and results in an adequate and predictable
      level of anticoagulation.

PMID- 10602567
TI  - Advances in the Monitoring of Oral Anticoagulation: Point-of-Care Testing,
      Patient Self-Monitoring, and Patient Self-Management.
AB  - Oral anticoagulation with warfarin sodium has proven to be an effective therapy
      for patients at risk for thromboembolic disease, but due to its high risk/benefit
      ratio, many physicians are reluctant to prescribe the drug. The development of
      capillary whole-blood prothrombin time (PT) monitors provides a potential means
      to decrease this risk/benefit ratio and to encourage the use of warfarin. Studies
      show that this technology is accurate, precise, and correlates closely with
      standard laboratory methods. Given that these monitors are simple and portable,
      investigators have conducted studies to determine their suitability for patient
      self-testing and home monitoring. Investigations show that patients can
      accurately and precisely perform the PT test at home, and that this mode of
      therapy appears to be at least as safe and effective as standard management.
      Furthermore, limited studies also suggest that patients can also manage their own
      dosing based on personalized guidelines designed by a physician. Given the
      theoretical potential for improved patient outcomes and overall cost reduction,
      patient self-monitoring and self-management are not far off. Large randomized
      prospective trials are now needed to confirm that the future of anticoagulation
      management should include patient self-monitoring and patient self-management of
      therapy.

PMID- 10602568
TI  - Comparison of the Pharmacokinetics and Effects on the Hemostatic System of
      Saruplase and Urokinase in Patients with Acute Myocardial Infarction.
AB  - The aim of the study was to compare in a single trial, using identical
      methodology, the pharmacokinetic properties and the effect on the hemostatic
      system of saruplase (unglycosylated scu-PA) and urokinase (glycosylated tcu-PA).
      Twenty-four patients with an acute myocardial infarction were either treated with
      saruplase (n = 12; 20 mg IV bolus followed by a 60 mg infusion for 60 minutes) or
      urokinase (n = 12; 1.5 million IU IV bolus followed by 1.5 million IU infusion
      for 60 minutes). Blood samples from saruplase-treated patients were analyzed for
      u-PA antigen and total u-PA and tcu-PA activities; those from urokinase-treated
      patients for u-PA antigen and tcu-PA activity. The effect of treatment on,
      including recovery of, plasma alpha2-antiplasmin, fibrinogen, and plasminogen was
      examined in both groups. The total clearance of urokinase (179 +/- 55 ml/min) is
      about half that of saruplase (406 +/- 154 ml/min), and the mean residence time of
      urokinase (59.1 +/- 22.5 minutes) is nearly twice that of saruplase (28.3 +/- 7.8
      minutes), which results in a slower elimination of urokinase from plasma. Whether
      differences in the pharmacokinetic behavior of the unglycosylated saruplase and
      the glycosylated urokinase observed in this study are due to the difference in
      glycosylation or to other factors is not resolved. The systemic effect of
      saruplase on alpha2-antiplasmin, fibrinogen, and plasminogen is similar to that
      of urokinase, although retarded.

PMID- 10602569
TI  - Prognostic Importance of Previous Myocardial Infarction in Patients Receiving
      Thrombolytic Therapy for Acute Infarction.
AB  - This study evaluated the prognostic significance of reinfarction location by
      considering the previous site or type of myocardial infarction (MI) among 1601
      patients with a history of previous MI who took part in the International (non
      Italian) tPA/STK trial and/or the Israeli GUSTO study population. These patients
      were accordingly divided and hospital mortality was compared by six location
      groups as follows: acute inferior with previous inferior (8.1% hospital
      mortality), acute inferior with previous anterior (12.8%), acute anterior with
      previous inferior (13.3%), acute anterior with previous anterior (11.1%), acute
      inferior with previous non-Q-wave MI (7.6%), and acute anterior with previous non
      Q-wave MI (11.2%) (p = 0.17 for comparison between the six groups). Hospital
      mortality tended to increase among patients with an anterior reinfarction
      compared with those with an inferior one (12.1% vs. 9.5%, p = 0.12). Among
      patients with a reinfarction at a different ECG location from the previous event,
      mortality tended to be higher compared with patients with two MIs at the same
      location (13.1% vs. 9.7%, p = 0.07). Recurrent MI following a previous Q-wave MI
      did not cause a higher mortality compared with a previous non-Q-wave type of MI
      (11.5% vs. 9.5%, p = 0.24). Among patients sustaining reinfarction, overall
      mortality did not differ between STK- and tPA-treated patients (11.0% vs. 11.4%,
      p = NS). In conclusion, the current study identified trends for higher mortality
      rates in patients with anterior compared with inferior reinfarction, with remote
      compared with the same ECG location of the two infarctions but not following a
      previous non-Q-wave compared with Q-wave MI. However, no particular combination
      of successive MIs location was significantly associated with a higher risk for
      hospital mortality.

PMID- 10602570
TI  - Noise Control Strategies for Occupational Safety and Better Working Environments.
AB  - Hearing impairment in humans due to occupational noise exposure is one of the
      significant occupational diseases in many countries. The equipment to measure
      noise levels and daily noise exposure in existing noisy environments is readily
      available and can be used to assess the risk of hearing damage. This paper
      examines the currently legislated hearing damage risk criterion and compares the
      two main noise level-time trade-off schemes being used. The engineering methods
      for controlling excessive noise levels and techniques to either bring them below
      the hearing damage risk threshold or to within an acceptable range for the
      workplace requirement are discussed, together with the expected improvements by
      such measures.

PMID- 10602571
TI  - Review: Activated Carbon Filters in Respiratory Protective Equipment.
AB  - The review considers first the nature of airflow through granular carbon filters
      and the relationship between pressure drop and airflow rate. Equilibrium
      adsorption is then summarized, with particular emphasis on the volume filling of
      micropores, on which most of the theory of activated carbon performance is based.
      The dynamics of adsorption is studied, and the analytical solution of the
      fundamental dynamic adsorption equation is given, leading to the development of
      various equations used in practice for the description of breakthrough. The most
      fundamental dynamic parameter, the rate constant for adsorption, is discussed,
      and the effects of concentration, granule diameter, and air stream velocity are
      summarized. Extracts of a number of experimental observations with reference to
      specific adsorbates are given, followed by an account of the adsorption of
      mixtures of compounds. The effect of relative humidity is discussed. This is
      followed by an account of non-destructive tests, and the review ends with a
      summary and an indication of possible fruitful areas for research.

PMID- 10602572
TI  - Approaches to the Evaluation of the Effectiveness and Reliability of Research
      Production Complexes.

PMID- 10602573
TI  - Some Applications of the Sound Intensity Technique to Noise Control in the
      Workplace.
AB  - Over a decade has elapsed since commercial sound intensity measurement systems
      became available. A literature search has shown that the sound intensity
      technique has found increasing applications in recent years. In this article, the
      principle and errors of the sound intensity technique are briefly described. Four
      case studies are given to illustrate how the sound intensity technique can be
      applied to determine sound power under both laboratory and field conditions, to
      identify noise source and to measure sound transmission loss o f composite
      partitions "in situ." It has been shown that, provided the limitations of the
      sound intensity technique are understood, results obtained by the sound intensity
      technique enable effective noise control to be implemented in the workplace.

PMID- 10602574
TI  - Subjective Annoyance Response to Diesel Engine Sound During Idling Conditions.
AB  - Subjective annoyance response to diesel engine sound during idling conditions was
      evaluated by 80 participants. Eight different sound spectra were presented to the
      participants at a constant level of 80 dB(A) in a paired comparison procedure.
      Stereo-recorded sound stimuli were played back through a pair of loudspeakers in
      an anechoic room. Four objective parameters of loudness, sharpness,
      impulsiveness, and roughness were found to be the determining factors that cause
      subjective annoyance. An annoyance prediction model for the test stimuli of an
      idling diesel engine was developed on the basis of these factors. The objective
      parameters and their interactions have a significant effect on the annoyance
      prediction model. The spectral distribution indicated by test participants to be
      pleasant can be used as a basis for appropriate modification of engine sound. A
      single microphone measurement in free field conditions can be used to estimate
      objective parameters for defining the cause of annoyance.

PMID- 10602575
TI  - Physical Workload Analysis Among Small Industry Activities Using Postural Data.
AB  - Small industry workers are often involved in manual handling operations that
      require awkward body postures, therefore, musculoskeletal disorders and
      occupational injuries are a major problem. In this study, various types of tasks
      were recorded with a video camera to chart and analyze different postures by
      computerized OWAS (Ovako Working Posture Analysing System). Collected data showed
      that poor postures were adopted not only for lifting or hammering operation but
      also for other tasks; mostly with bent and twisted back. The main aim was to
      determine the physical workload by identifying harmful postures and to develop
      recommendations for improving the existing situation. Forty-eight male workers
      from eight different units (M age = 37 years) participated. The performed
      activities were then divided into 26 subtasks. Altogether, 1,534 postures were
      selected for analysis and then classified into different OAC (OWAS Action
      Categories). From all observations, unhealthy postures, for which corrective
      measures had to be considered immediately (i.e., 10.6% classified as OAC III, and
      3.3% as OAC IV), were found. The applied method was useful in determining the
      physical workload by locating potential activities due to harmful postures,
      providing a detailed description with analysis, and suggesting successful means
      to reduce postural load.

PMID- 10602576
TI  - Quantitative Inspection of Broken Wire in Wire Ropes: Method and Apparatus.
AB  - This article introduces a complete system for automatic inspection of broken wire
      in wire ropes. The development of this technique is reviewed. It is followed by a
      description of the hardware and software of the apparatus. The hardware uses
      magnetic concentrators and Hall-effect sensors. Signal analysis is based on
      wavelet processing. Quantitative identification of broken wire in wire ropes is
      based on a pattern recognition approach of the neural network.

PMID- 10602577
TI  - Characteristics of the Workforce and Activity Optimization in the Building
      Industries of Lithuania.
AB  - The evaluation of human individual characteristics is very important for any
      ergotechnical system optimization, especially in occupational safety.
      Investigations were carried out for this purpose. An important classification of
      ergonomic characteristics for construction workers was prepared. The importance
      and relevance of the choice of those characteristics as well as their application
      are presented in the article.

PMID- 10602578
TI  - The Preventive Approaches of the Statutory Accident Insurance System and Their
      Effectiveness.
AB  - For decades, prevention has been an integral and important part of the German
      statutory accident insurance system. The very close link between prevention,
      rehabilitation, and compensation, which is so typical for the German system, had
      an extremely positive effect on the frequency of notifiable occupational
      accidents. What is more, if we compare benefits and costs of the system, it
      appears that prevention has also been successful in a strictly monetary sense.
      After a short outline of the basic principles of the German accident insurance
      system, the authors take stock of the last 33 years. The period between 1960 and
      1993 also covers the repercussions of the German reunification in 1990. The
      trends in accident and disease frequency are presented together with the trends
      in costs and benefits. To allow a realistic comparison, all figures are indicated
      in terms of 1960. It can be shown that the average contribution rate to accident
      insurance decreased in the period under consideration. This is particularly
      remarkable if we look at the enormous increase in contribution rates that took
      place in all other branches of social insurance. It is also noted that the
      contribution rates of the different industrial branches are immediately dependent
      on the accident risks in those industries. The last part of the article contains
      a qualitative and quantitative description of the prevention measures available
      to the German accident insurance institutions.

PMID- 10602579
TI  - Human Adaptation to Work in Two Different Climates.
AB  - The processes of acclimation to hot-dry and to warm-humid climates were studied
      using two approaches: a quantitative analysis of literature data and an
      experimental study in the laboratory concerning the physiological parameters of
      heart rate, rectal temperature, sweat loss, and subjective assessment. Analysis o
      f literature data: Data from 62 experiments with a total of 813 participants were
      pooled and recalculated. The experiments ranged from 6 to 24 days, air
      temperatures from 30.4 to 50.0 degrees C, water vapor pressures from 1.5 to 6.5
      kPa, and wet bulb globe temperatures (WBGT) from 27.4 to 38.6 degrees C.
      Laboratory studies: In the laboratory, 8 participants were acclimated during 15
      consecutive days to a hot-dry climate and to a warm-humid climate, which were
      equivalent in terms of the WBGT (33.5 and 33.6 degrees C, respectively). The
      participants walked four times for 25 min on a treadmill at a speed of 4 km/h.
      The hot-dry climate caused somewhat greater strain than the warm-humid condition.
      In the course of acclimation to the hot-dry climate, heart rate and rectal
      temperature started at higher levels, decreased slightly steeper but remained on
      a higher level throughout. Nevertheless, the differences between both thermal
      conditions were small, and both physiologic functions reached the point of
      acclimation almost at the same time under warm-humid and under hot-dry exposure.
      Sweat loss, which is not regarded as a valid predictor for acclimation, was
      considerably higher but increased less in the hot-dry than in the warm-humid
      climate.

PMID- 10602580
TI  - Ergodynamics in the Reliability of Power Plant Operators and Prospective Hybrid
      Intelligence Systems.
AB  - Based on ergodynamics and the hybrid intelligence theory, an analysis of the
      nuclear power plant operator's performance is given at the levels of strategies,
      tactics, and actions. Special attention is paid to the strategies used in the
      course of severe accidents at nuclear power plants. Data from Ukrainian and
      Russian power plants and training centres, and from accidents around the world
      were collected and processed. It is shown that in an emergency it is essential
      for the human operator to be flexible. This flexibility includes two main
      training and personal factors: a large set of strategies and tactics the operator
      manages to use, and quick transformations between the strategies (tactics). It
      was also found that some emergency tasks are too complicated: They require
      simultaneous use of different strategies, with time strictly limited by nuclear
      power plant dynamics. Those tasks cannot be successfully solved by any individual
      operator. Hybrid intelligence systems involving different specialists should be
      used in those cases in order to avoid failures in emergency problem solving and
      macroergonomic organizational design.

PMID- 10602581
TI  - Handgrip and Box Tilting Strategies in Handling: Effect on Stability and Trunk
      and Knee Efforts.
AB  - The purpose of this study was to evaluate the effect of four handgrip-box tilting
      strategies (right, left, backward, and no tilt of the box) on trunk and knee
      efforts, body posture, and the stability of 14 participants with limited
      experience in handling. The tasks consisted of transferring a low-lying box
      placed in front of the participant to a shelf of the same height at the
      participant's left. It was hypothesized that tilting the box could reduce trunk
      and knee efforts as well as body asymmetry, and improve stability. A
      tridimensional dynamic rigid body model was used to estimate the triaxial net
      muscular moment magnitudes at the trunk (L5/Sl) and at the knees. An approach to
      quantify the participants' dynamic stability was also included. Finally, 5 angles
      were computed to characterize body asymmetries. The results showed that tilting
      the box affected specific trunk efforts, but did not succeed in reducing trunk
      asymmetric efforts. However, the tilts were executed in a single direction, and
      it may be possible that combined tilts of the box could help reduce trunk
      asymmetric efforts. Tilting the box had little effect on knee loadings, and the
      left tilt strategy reduced participants' stability. This study showed the
      importance of considering the position of the box when assessing the risks
      encountered in asymmetrical handling.

PMID- 10602582
TI  - Permeability of Organic Solvents Through Two-Layer Safety Gloves Determined by a
      Gravimetric Method.
AB  - Organic solvents are harmful to humans and many of them are recognized as
      carcinogens. Therefore it is necessary to protect hands from contact with them.
      Most methods for testing solvent resistance of gloves use Gas Chromatography.
      However, these methods are expensive and so complex that they present application
      problems for most glove producers and users. A simple gravimetric method to test
      solvent resistance of gloves was developed. It was tested by measuring
      permeability of organic solvents such as white spirit, acetone, isopropyl
      alcohol, benzene, p-xylene, trichloroethylene, through gloves made of natural
      rubber, polivinyl chloride, neoprene, perbunan, polivinyl alcohol, and two-layer
      gloves made of natural rubber and neoprene. This method proved to be a simple,
      economical, and reliable way to examine glove permeability.

PMID- 10602583
TI  - Characteristic of Muscular Load in Computer Data Entry Workers Assessed by EMG
      and Postural Angles.
AB  - The goal of this study was to characterize the muscular load in computer data
      entry workers. EMG parameters of trapezius muscle and postural angles of head,
      arm, and back were chosen as indicators of musculoskeletal load. The examination
      was done according to the methods and protocol of international MEPS studies (the
      "Musculoskeletal, Visual, and Psychosocial Load in VDT Operators in Optimized
      Environment" international program). The musculoskeletal load during routine VDT
      data entry work performed by a group of 36 women was assessed on the basis of one
      hour physiometer recordings. Results show that the musculoskeletal load
      associated with data entry is relatively high comparing to other VDT operators'
      tasks described in the literature. An analysis of the measured parameters shows
      that most of the time women worked with muscular load higher than optimal. It is
      postulated that the main reason for the heavy musculoskeletal load was improper
      posture compelled by unergonomic spatial configuration of work stands.

PMID- 10602584
TI  - Load Acceleration and Footstep Strategies in Asymmetrical Lifting and Lowering.
AB  - Accelerated execution effects for lifting and lowering a 12-kg box using two
      footstep strategies associated with experienced workers were studied. Eight
      healthy male participants performed a normal and an accelerated execution of a
      lifting task and a lowering task, using a minimal feet displacement strategy
      (oblique-step) and a strategy with a step (crossed-step). It was hypothesized
      that the accelerated executions, as compared to the normal executions, would have
      a different effect on L5/S1 resultant moment, body posture, and other kinematic
      variables. A tridimensional dynamic rigid body model was used to compute L5/S1
      resultant moments. Results showed that the accelerated condition did not reduce
      body asymmetry of posture, but it reduced the length of the path of the global
      center of gravity and the duration of the supporting phase of the box, and it did
      not significantly affect L5/S1 maximal resultant moments for lifting but
      increased them for lowering. These results indicate that the net work production
      for accelerated strategies might be smaller, which may represent an economy of
      energy. Furthermore, the results showed that the use of an accelerated strategy
      for lowering should be avoided.

PMID- 10602585
TI  - Comparison of Two Methods for Judging Distances Near Overhead Power Lines.
AB  - Sixteen certified crane operators performed several series of boom movements
      toward a segment of a typical power line using a 100-ton lifting capacity crane
      equipped with an 18-m boom, a single lifting cable, and a hard ball hook. The
      operators were instructed to stop the crane movement when the lifting cable
      reached the edge of the danger zone located 3 m from the power line. To achieve
      each maneuver, they evaluated the distance between the nearest wire and their
      crane using two methods: free sighting and the use of highly visible markers
      delineating the edge of the danger zone. The dependent measure was the distance
      between the lifting cable and the edge of the danger zone. Results showed that
      operators were generally unreliable when judging the distance between their crane
      and the power line when sighting the power line directly, but the use of markers
      proved to be much more precise and reliable in targeting the edge of the danger
      zone.

PMID- 10602586
TI  - Optimum Design for Emergency Stop Button on Robot Teach Pendants.
AB  - This study deals with designing robot teach pendants for industrial robots. The
      emergency stop button on robot teach pendants is the primary safety device for
      industrial robots. Recommendations for the design of the emergency stop button
      were proposed based on experimental evaluations. Human performance was measured
      by the reaction time necessary to press the button on a pendant. The variation
      factors were randomly combined by seven button locations and three different
      button sizes. The results indicated that the shortest reaction time was obtained
      for the 38-mm button located on the left and left-down of the seven button
      positions on the pendant.

PMID- 10602587
TI  - Dental Workers, Musculoskeletal CumulativeTrauma, and Carpal Tunnel Syndrome: Who
      is at Risk? A Pilot Study.
AB  - A pilot study was conducted at a dental clinic to identify (a) the prevalence of
      musculoskeletal cumulative trauma disorders (MCTD), (b) associated symptoms (with
      special attention paid to carpal tunnel syndrome [CTS]), and (c) practitioners at
      risk. Videotapes, two questionnaires, a medical record review, and interviews
      were used. Forty-five dental workers participated and were classified into three
      categories: (a) dentists, (b) dental assistants and special assistants (DA/SA),
      and (c) dental hygienists and dental assistant-expanded function (DH/DAEF).
      Categorical data were analyzed using the chi- square statistic and risk ratios.
      The Fisher exact probability test was used for categorical data with a small
      cell. One or more symptoms associated with CTS were noted by 75.6% of the dental
      workers, 11% reported diagnosed CTS, and 53% reported back and shoulder pain.
      Both psychosocial factors and job demands appear to be associated with MCTD. All
      three categories of dental workers reported MCTD symptoms, and the DH/DAEF group
      was found to be at greatest risk for developing upper extremity symptoms, CTS,
      and back pain.

PMID- 10602588
TI  - A Method for Response Time Measurement of Electrosensitive Protective Devices.
AB  - A great step toward the improvement of safety at work was made when
      electrosensitive protective devices (ESPDs) were applied to the protection of
      press and robot-assisted manufacturing system operators. The way the device is
      mounted is crucial. The parameters of ESPD mounting that ensure safe distance
      from the controlled dangerous zone are response time, sensitivity, and the
      dimensions of the detection zone. The proposed experimental procedure of response
      time measurement is realized in two steps, with a test piece penetrating the
      detection zone twice. In the first step, low-speed penetration (at a speed vm)
      enables the detection zone border to be localized. In the second step of
      measurement, the probe is injected at a high speed Vd. The actuator rod position
      is measured and when it is equal to the value L registered by the earlier
      measurements, counting time begins as well as the monitoring of the state of the
      equipment under test (EUT) output relays. After the state changes, time tp is
      registered. The experimental procedure is realized on a special experimental
      stand. Because the stand has been constructed for certification purposes, the
      design satisfies the requirements imposed by Polski Komitet Normalizacyjny (PKN,
      1995). The experimental results prove the measurement error to be smaller than +/
      0.6 ms.

PMID- 10602589
TI  - Safety Management in Coal Mines-Risk Assessment.
AB  - The present state of accident hazard at work in the Polish mining industry is
      presented. A comparison is made of the accident indices in relation to other
      countries. A reference is made to the work safety management system implemented
      in the mines. Safety management is discussed in terms of risk management. On the
      basis of the natural death index and that of accidents at work, numerical scales
      are presented defining the limits of the inadmissable, tolerable, and acceptable
      risk. The course of variation of risk indices for fatal, serious, and minor
      accidents is evaluated. The results of the assessment for all kinds of accidents
      at work in the mining industry are presented.

PMID- 10602590
TI  - A Multilevel Approach to Manual Lifting in Manufacturing Industries.
AB  - Musculoskeletal injuries are often the consequences of wrong postural
      configurations used during Manual Materials Handling (MMH). This eventually leads
      to a large payout of worker's compensation and loss of production time. A
      simulated study of back injury risks has been carried out on seven selected
      manufacturing industries to identify and evaluate harmful working postures. For
      each MMH task, Ovako Working Posture Analyzing System (OWAS) codes have been
      identified with the help of motion study pictures. Also, Chaffin's biomechanical
      model was used to calculate L5/S1 load compression values on the spine during MMH
      activities. The multilevel approach adopted was a combination of OWAS and
      Chaffin's biomechanical model. The application of a digitizer enabled us to
      identify the coordinates and it made a subsequent evaluation of the angles of
      each body link possible.

PMID- 10602591
TI  - Assessment of Health Risks in Canteen Kitchens.
AB  - The ergonomic, occupational hygiene, and safety factors in canteen kitchen work
      were examined using worksite surveys and a questionnaire. Pain in the shoulders
      was found to be associated with the raised position of the upper limbs caused by
      excessively high working surfaces. Temperature, ventilation, and especially
      drafts caused the greatest disturbance at the workplace. Measurements revealed
      that variations in temperature during the day and between the neck and ankle
      caused the complaints. The most commonly occurring accident involved a wound to
      the fingers caused by a knife. However, employees reported burns to be the
      greatest accident risk. The two methods gave the most contradictory results
      concerning accidents and safety evaluations and the results corresponded best in
      ergonomic factors.

PMID- 10602592
TI  - Continuous Safety Sampling Methodology.
AB  - This research introduces a proactive methodology for accident prevention, called
      Continuous Safety Sampling Methodology, by utilizing the principles of work
      sampling and control charting. Sampling is performed to observe the occurrence of
      conditions that may become hazardous in a given system. These conditions, known
      as dendritics, may become hazards and could result in an accident or occupational
      disease. Continuous Safety Sampling Methodology performs a random sampling for
      the occurrence of these dendritics. The collected data are then used to generate
      a control chart. Based on the pattern of the control chart, a system "under
      control" is not disturbed whereas a system "out of control" is investigated for
      potential conditions becoming hazardous. Appropriate steps are then taken to
      eliminate or control these conditions to maintain a desired safe system.

PMID- 10602593
TI  - The Effect of Protective Gloves on Manual Dexterity in the Cold Environments.
AB  - This article presents a study on the effect of different protective gloves (which
      are commercially available and commonly used in the cold) on manual dexterity in
      cold environments. The experiments compared statistically four different types of
      gloves and two different types of gloving (outer or double) at +19  degrees C and
      -10  degrees C. Performance was determined both objectively and subjectively
      using two manual dexterity tasks: bolt-nut and pick-up tasks. The response
      measured was the time of performing each task. Statistical analysis showed that
      all independent factors such as glove type, participant, object size, and
      temperature had significant effects on the hand cooling reaction. A significant
      difference in the performance between the gloves was found in the bolt-nut task.
      It was also found that outer-inner combination gloving may be an approach to use
      for precision tasks.

PMID- 10602594
TI  - Torque Production Using Hand Cranks in a Simulated Gear-Operated Valve Opening
      Task.
AB  - Hand cranks are used in a variety of industries to actuate valves and in other
      gear-operated applications. In order to evaluate these types of operations and
      their compatibility with operator strength capabilities, a rotational dynamometer
      was used to measure torque production capability of operators using a hand crank
      at different heights and angles (with respect to the coronal plane). The tests
      were conducted for both clockwise and counterclockwise rotations using the
      dominant arm of each test participant. A total of 18 tests were completed by each
      of five male right-handed test participants. A 0 degrees  declination angle,
      counterclockwise operation, and both 40.65 cm and 60.96 cm heights were found to
      be associated with the greatest torque production capabilities.

PMID- 10602595
TI  - Small Business Owners' Knowledge of Their Occupational Health and Safety (OHS)
      Legislative Responsibilities.
AB  - This article reports the results of a study investigating the nature and extent
      of small manufacturing business owners' knowledge of Occupational Health and
      Safety (OHS) issues. Interviews were conducted with 33 owners of small
      manufacturing businesses in Sydney, Australia. Results showed that whereas the
      majority of owners had basic awareness of the existence of OHS legislation, they
      were often unaware about the extent of their legal OHS responsibilities. Owners
      were found to have minimal OHS training and practical OHS expertise. Lack of
      appropriate industry specific OHS information was found to be a major factor that
      inhibited the owners' ability to deal with OHS issues effectively.

PMID- 10602596
TI  - The Effectiveness of a "Break Experiment" from a Long-Term Perspective.
AB  - The study reports the results of a follow-up evaluation, conducted in 1994, of
      the impact of a training program for female unskilled metal workers that was
      implemented at the end of the 1970s. The program was designed to promote
      occupational skills development, and was first evaluated in 1979. On both
      occasions of evaluation the investment in training was examined from two
      perspectives, those of the training participants and management. Data were
      collected through semistructured personal interviews with key members of
      personnel management and through a group conversation session with a majority of
      the original course attendees. Supplementary background information was obtained
      from documents and records maintained by the organization. At some points, there
      was a convergence of views on the significance of the training program for
      occupational skills development, at others a divergence. These convergences and
      divergences are finally discussed and the findings of the study are related to
      other research on this particular kind of intervention.

PMID- 10602597
TI  - Physical Strain and Work Ergonomics in Farmers with Disabilities.
AB  - In agriculture, occupational injuries are common, and several of them lead to
      permanent physical disability. The objective of this case study was to assess the
      strain and the ergonomic needs of four farmers (aged 34-49 years) with physical
      disabilities. A maximal bicycle ergometer test or an arm-crank test was done to
      assess their maximal heart rate (HR max) and maximal oxygen consumption (V02max).
      The strain at work was analyzed by measuring heart rate (HR), muscle activity
      (EMG), and the rating of perceived exertion (RPE). The farmers were interviewed
      as to possible and impossible work tasks and the ergonomic redesign measures
      taken to improve the work environment. The work tasks performed were mainly light
      or moderate work for the cardiorespiratory system according to mean HR (88-102
      beats/min), the percentage of HR range (17-31% HRR), and the relative V02 (22-46%
      V02max). The mean activity of the trapezius muscles was 0.4-9% of the maximal
      voluntary contraction (%MVC). All the participants had work tasks they were
      unable to perform. They had made ergonomie redesign changes mainly to the
      tractor. This case study showed that some agricultural work tasks were possible
      for farmers with physical disabilities and that the physical strain associated
      with these tasks was mainly light or moderate.

PMID- 10602598
TI  - Safety Level of Acrobatic Work: A Probabilistic Study.
AB  - Acrobatic work constitutes an activity during which individuals intervene on
      buildings, cliffs, towers, and so forth, through the use of mountaineering or
      speleological techniques. The most dangerous situations occur particularly when
      ascending a rope with ascenders or roping with a descender. Any free fall or
      false manoeuvre will result in a strong shock on the belaying system that may
      cause its rupture. The fatal accident rate (FAR) of a given occupation is defined
      as the average number of fatal accidents per 108 hrs of exposure to a given
      hazard. In this study it is assumed that the FAR is proportional to the average
      number of fall-initiating events, eta, per worker and per hour of exposure to the
      fall hazard. eta is estimated to be between 10-3 and 3 * 10-3. The maximum values
      of the rupture probability of the securing systems are calculated for the FAR of
      acrobatic work to be smaller than the FAR of the three most dangerous activity
      groups of the construction industry in France. These values allow the varying
      ranges of the parameters that influence this rupture probability to be
      determined.

PMID- 10602599
TI  - Torque Production Using Handwheels of Different Size During a Simulated Valve
      Operation Task.
AB  - Opening and closing valves in industrial facilities often requires operators to
      use bars and wrenches as levers (cheaters) in order to overcome initial actuation
      forces. In order to determine more appropriate operational specifications, the
      maximum torque production capability was measured when 12 male participants used
      4 different valve handwheels at 3 different heights and 2 different angles (in
      relationship to the coronal plane). The results indicate that the participants
      produced significantly greater torque when the largest of the 4 wheels (40.6 cm
      diameter) was used than when the medium (22.9 cm), small (20.3 cm), and handled
      (17.8 cm) handwheels were used. Although the main effect of heights was found to
      be statistically significant, post-hoc analyses between the heights found them to
      be, essentially, equal. In addition, the vertical and horizontal wheel
      orientations were not found to be different. The results are applicable to all
      industries where handwheels are used and applicable to valve manufacturers for
      designing operational torque specifications below the values found in this study.

PMID- 10602600
TI  - Differences in Eye and Hand Movements of Novice and Experienced Press Operators.
AB  - Presses are very widely used in industrial and commercial companies and are often
      the source of serious accidents occurring during operation. Most of the accidents
      are due to inadequate training of novice operators. Continuous recordings of eye
      and hand movements of five novice operators and five experienced operators in
      press operation were made. Significant difference between novice and experienced
      operators was observed in eye fixation time, eye movement patterns, hand dwell
      time, and eye-hand coordination. Also, differences were observed in spatial
      distribution of eye fixations during the die-closing portion of a stroke. There
      were no significant differences between novice and experienced operators in the
      eye and the hand movement time. The results could be used as basic data to
      establish a guide determining the method and training period to train novice
      operators.

PMID- 10602601
TI  - "Hypersensitivity to Electricity" in the Office; Symptoms and Improvement.
AB  - Nineteen persons "hypersensitive" to electricity and 20 nonafflicted persons were
      studied for 1 1/2 years. The most discernible hypersensitivity symptoms were
      pricking sensations and redness in the face, but these symptoms were present in
      only half of the afflicted. Other symptoms were similar to symptoms experienced
      during office work and this study does not support the idea that
      electrosensitivity is one single syndrome. The "hypersensitive" persons improved
      significantly, mainly on neuropsychiatric symptoms, but the skin problems
      sustained- as did the belief about their cause. The afflicted persons used less
      conventional medication than the group of the nonafflicted, which suggests a
      general tendency for attribution to environmental factors.

PMID- 10602602
TI  - Investigation of Blended Fibre Filtering Materials.
AB  - Five variants of mixtures of different synthetic fibres at different area ratios
      were manufactured into needled nonwovens intended to be used as a filtering
      material for respiratory protection. Two variants were produced according to an
      earlier patent, and the contents of the other three was completely new. Samples
      of the nonwovens were tested for sodium chloride particles penetration and for
      breathing resistance. The results showed that one variant of a nonwoven,
      designated PP/PPFM, had very valuable filtering properties and that those
      properties were stable in time.

PMID- 10602603
TI  - Amalgam in Dentistry A Health Hazard for Dental Personnel?
AB  - In a cross sectional study done in 1993 among dental personnel in Norrbotten,
      self-reported prevalence of muscular pain, headache, tremor, insomnia,
      irritation, impaired memory and depression, as well as information regarding
      different mercury exposures were collected Mercury exposures were determined as
      "number of amalgam fillings in teeth," "years in practice," "insufficient
      ventilation at work," "total number of amalgam removed, produced and polished per
      day," and "working in dental clinics." As controls, physicians and nurses from
      the same geographical area were selected. The correlation between symptoms and
      different mercury exposures was calculated using logistic regression. The results
      suggested a higher prevalence of muscular fatigue and tremor for female dental
      personnel compared to controls Controls reported a lower prevalence of symptoms
      with increasing number of amalgam fillings in teeth. There was no correlation
      between the number of amalgam fillings handled per day and symptoms for dental
      personnel. Male dental personnel associated muscular fatigue headache, impaired
      memory, and depression with increased handling of amalgam in the clinic' whereas
      the female dental personnel associated the same symptoms with the number of
      amalgam fillings in teeth. The strongest correlation was found between symptoms
      and insufficient ventilation at dental clinics for dental personnel.

PMID- 10602604
TI  - Box Handling in the Loading and Unloading of Vans.
AB  - The handling of 2,306 boxes being loaded or unloaded from vans onto or from 4
      wheeled trolleys by 31 handlers in a warehouse were characterized. Handling was
      videotaped and characterized through an analysis grid completed by three trained
      observers. The following execution parameters were observed: nature of the
      exertion applied by the upper limbs, plane and direction of the exertion,
      resulting displacement of the box, grip, use of the lower limbs and the back.
      Results show that execution parameters used by handlers vary considerably from
      those usually recommended or studied. For example, symmetric grips were rarely
      used (4%). The grip was modified during the handling of half the boxes.
      Significant knee flexion was rarely observed (3% of exertions). Each box was
      moved by applying an average of 3.5 different exertions. Exertions were mostly
      applied in a plane parallel to the shoulders; they were rarely executed in a
      strict sagittal plane (11%). The implication of these observations are discussed.

PMID- 10602605
TI  - Use of Ergonomics as a Quality Improvement Tool in a Manual Assembly Task.
AB  - This study attempted to identify a direct relationship between the design
      characteristics of a manually-assembled product, exposure to work-related
      ergonomic risk factors, and improvement in product quality. The study considered
      (a) Accessibility (ease of approach) and Guidance (ease of alignment and
      positioning) as Design Variables, (b) Shoulder Abduction, Trunk Lateral Flexion,
      Rate-Normalized Percentage of Maximal Voluntary Contraction (%MVC) of the Wrist
      Flexors, Wrist Extensors, and Deltoids, and Frequency of Attachment as Ergonomics
      Variables, and (c) Percentage of Attachment Too Loose, Too Tight, and Misaligned
      as Quality Variables. Postural data, surface EMG data, and quality data were
      collected from 10 participants performing four 10-min repetitive manual assembly
      tasks with plastic threaded nuts, bolts, flat parts, and open-box parts.
      Unobstructed accessibility of manually-assembled parts was associated with
      decreased exposure to awkward trunk posture, decreased activity of the wrist
      flexors and extensors, increased frequency of repetitive motion, and a decrease
      in the tendency to attach parts too loosely. Accessibility had no effect on
      misalignment defects as measured. Part guidance decreased the number of parts
      attached too tightly and aided in increasing the rate of assembly of parts when
      there was unobstructed access to parts.

PMID- 10602606
TI  - Occupationally Oriented Medical Rehabilitation and Hairdressers' Work Techniques-
      A one-and-a-half-year follow-up.
AB  - This study examined changes in work techniques and musculoskeletal symptoms after
      occupationally oriented medical rehabilitation arranged for 21 hairdressers who
      were experiencing neck-shoulder or back pain but were still able to work. OWAS
      (Ovako Working Posture Analysing System) analyses of working postures and
      questionnaire data were obtained at the beginning of the courses and one and a
      half years later. The participants worked with their back bent and twisted or
      their arms at or over shoulder level more seldom (p <.0001) at the end of the
      follow-up than at the beginning of the rehabilitation. Subjective work-related
      physical and mental strain had decreased by 45.4% (p <.001) and 27.1% (p <.05),
      respectively, and subjective neck and back pain by 40.0% (p <.01) and 45.3% (p
      <.01), respectively. This study suggests that occupationally oriented medical
      rehabilitation can have significant and long-lasting effects on the rehabilitee's
      work techniques and subjective well-being.

PMID- 10602607
TI  - The Effects of Local Cooling on Thermophysiological Response in Participants
      Wearing Dust-Free Garments.
AB  - This study was designed to find the effects of two kinds of dust-free garments
      with (A) and without (B) frozen gel strip (FGS), and half-naked clothing
      (brassiere and shorts; C) on thermophysiological parameters and on temperature
      and humidity within clothing. The heart rate, rectal, and skin temperatures as
      well as sweat rate and clothing microclimate were measured during 140 min in 9
      healthy females. Inquiries were also made into the subjective rating of thermal,
      humidity, and comfort sensations. The main findings in our experiments are as
      follows: (a) Physiological parameters such as rectal and skin temperatures (chest
      and forehead), heart rate, and sweat rate were clearly lowest in garb C,
      intermediate in garb A, and highest in garb B throughout the experiment; (b)
      Temperature and humidity within clothing were lower in garb A than in garb B; (c)
      More than half of the 9 participants decreased thermal sensation by wearing garb
      A. These results suggest that the usage of FGS could improve the heat load in
      lightly working participants wearing dust-free garments.

PMID- 10602608
TI  - A Device for Preventing Occupational Diseases of Lower Legs.
AB  - Physiological processes characteristic of the fatigue of legs mainly appear when
      the worker's activity requires standing. If the processes are intensive and
      regular, various diseases of legs, such as varicose veins and musculoskeletal
      disorders of legs and feet, can develop. Therefore, methods of reducing the
      fatigue of legs are important in occupational health protection. Air jet massage
      technology was developed and an appropriate massage device was built by the
      authors. The massage head turning around the lower leg and moving up and down
      gradually covers the leg's surface. To determine the efficiency of the massage,
      fatigue processes were studied. These studies showed that jet massage effectively
      reduces both the subjective and objective fatigue symptoms. The device is
      convenient for use in industry, services, and at home.

PMID- 10602609
TI  - Force-Velocity Characteristics of Individual Human Skeletal Muscles: TBClat and
      TBClong--Outline of the Method.
AB  - The aim of the work is to outline a procedure of finding force-velocity (F-V)
      characteristics (F = f(V)) of individual skeletal muscles of the human locomotor
      system. The presentation is based on an example concerning extensors of the elbow
      joint: the lateral and long heads of triceps brachii (TBClat and TBClong). The
      experimental part of the procedure involves a natural movement of using the upper
      extremity to push an external object of variable, adjustable load, engaging both
      the elbow and shoulder joint. Five men aged 23 took part in the experiment. Their
      task was to push the handle of a physical pendulum whose moment of inertia could
      be adjusted within the range of 58 kg.m(2)-450 kg.m(2), so as to give it maximum
      angular velocity. During each trial the movement of the trunk, of the upper
      extremity and of the pendulum was video recorded and the force applied with the
      hand to the handle of the pendulum was measured. In order to find the F-V
      characteristics a simulation model SHOULDER was used, which is capable of solving
      the synergy problem for muscles of the arm and the shoulder girdle. It was found
      that despite considerable dispersion of experimental points the respective
      regression lines revealed a clear tendency of decreasing muscle force for
      increased shortening velocity of the monoarticular head (TBClat) and of
      increasing muscle force for increased lengthening velocity of the biarticular
      head (TBClong) of the triceps brachii muscle.

PMID- 10602610
TI  - Ventilation Flow Organization for Efficient Elimination of Contaminated Air.
AB  - Displacement ventilation and well-organized ventilation flow structures are
      emphasized. Perhaps the biggest advantage of displacement ventilation is its
      increased effectiveness in removing pollutants from a ventilated space and the
      efficient use of ventilation air. Several questions on how the systems should be
      designed to achieve optimal efficiency are still unanswered. Small variations in
      room geometries and air supply arrangements can totally change the conditions.
      Results from this investigation show the importance of an even distribution of
      the incoming supply air, numerically calculated age-of-air values and the
      influence of residual tracer concentrations on measured mean values for the age
      of air.

PMID- 10602611
TI  - Application of the Method of Organizational Congruencies in Substituting Organic
      Solvents With Vegetable Agents for the Cleaning of an Offset Printing Machine.
AB  - The aim of this research is the application of the Method of Organizational
      Congruencies before and after the substitution of organic solvents with vegetable
      agents for the cleaning of an offset printing machine in order to assess the
      organizational changes. A solvent-free process is the goal of the Subsprint
      Project (Technology Transfer Program of the European Community). This study shows
      how human and environmental health is improved by using vegetable agents, though
      this change may lead to some other organizational constraints such as an increase
      of the time needed, monotony, and repetitiveness of the technical actions
      involved. The authors underline that the knowledge of the impact of the new
      technology on health helps a better understanding of the resistance to the change
      and its further amelioration.

PMID- 10602612
TI  - Classification of the Substances on the Basis of the Acute-Toxic-Class Method
      (ATC).
AB  - The acute-toxic-class method (ATC) is an alternative to the classical LD&inf50;
      test. Four substances were tested with an ATC testing procedure. The results were
      compared with LD&inf50; data obtained from the literature. Great importance was
      attached to the observations of toxic signs following administration. The results
      of this study have shown that the ATC method allows allocation to toxicity
      classes in the same manner as on the basis of the classical LD&inf50; tests. The
      ATC method uses fewer animals and yields the same information on toxic signs.
      Introducing the ATC method into the quality system allows estimating the acute
      oral toxicity of chemicals according to the Organisation for Economic Cooperation
      and Development (OECD; OECD, 1992, 1996).

PMID- 10602613
TI  - Effect of Sweating on Insulation of Footwear.
AB  - The study aimed to find out the influence of sweating on footwear insulation with
      a thermal foot model. Simultaneously, the influence of applied weight (35 kg),
      sock, and steel toe cap were studied. Water to 3 sweat glands was supplied with a
      pump at the rate of 10 g/hr in total. Four models of boots with steel toe caps
      were tested. The same models were manufactured also without steel toe. Sweating
      reduced footwear insulation 19-25% (30-37% in toes). During static conditions,
      only a minimal amount of sweat evaporated from boots. Weight affected sole
      insulation: Reduction depended on compressibility of sole material. The influence
      of steel toe varied with insulation. The method of thermal foot model appears to
      be a practical tool for footwear evaluation.

PMID- 10602614
TI  - Effect of Footwear Insulation on Thermal Responses in the Cold.
AB  - The influence of footwear insulation on foot skin temperature in the cold at low
      activity was investigated. Simultaneously, the thermal and pain sensations, and
      the influence of steel toe cap were studied. Eight participants were exposed for
      85 min to 3 environmental temperatures ( + 3, -12, and -25 degrees C) wearing 5
      different boots. Insulation of footwear was determined with thermal foot model.
      The study showed the importance of insulation for keeping feet warm. Other
      factors, such as wetness and vasomotor response, however, modified the thermal
      response. The most affected parts were toes and heels. Cold and pain sensations
      were connected with considerably lower temperatures in these local points. No
      significant differences were observed between boots with and without steel toe
      cap.

PMID- 10602615
TI  - Sorbents for Trapping Organic Pollutants From Air.
AB  - A series of siliceous adsorbents with chemically bonded phases (CBPs) of
      different polarity were tested as sorbents for trapping air pollutants (petroleum
      ether) using controlled setup. Moreover, special attention was paid to the
      potential role of metal impurities as strong adsorption sites. Sorbents were
      characterized by various physico-chemical methods, such as porosimetry,
      inductively coupled plasma (ICP) analysis, elemental analysis, derivatography,
      and gas chromatography. Trapping tubes were utilized for sorption of toxic
      pollutants from indoor air.

PMID- 10602616
TI  - Evaluation of Grip Force Using Electromyograms in Isometric Isotonic Conditions.
AB  - The purpose of this study was to develop a relationship to evaluate the grip
      force (forcerel) using the electromyogram (EMGrel) of the flexor digitorum
      superficialis (FDS) and of the extensor digitorum (ED) according to the flexion
      extension wrist angle (thetaf.e) and to the pronation-supination forearm angle
      (thetap-s). Fifteen participants had to exert 3 levels of grip forces in 4
      positions of the wrist combined with 3 positions of the forearm. The relationship
      is: forcerel = 0.0045. thetaf-e. EMGrel(FDS) + 0.48. EMGrel(FDS)-0.0014 . thetaf
      e . EMGrel(ED) -0.0016 . thetap.s . EMGrel(ED) + 0.4. EMGrel(ED) This
      relationship can be used to estimate grip force for levels of strength lower than
      50% of the maximal voluntary contraction.

PMID- 10602617
TI  - Electromyographic Analysis of a Repetitive Hand Gripping Task.
AB  - Electromyography (EMG) has been proposed as a method for determining muscle
      effort in repetitive upper limb tasks, which are often related to cumulative
      trauma disorders. EMG activity of the finger flexor musculature was investigated
      during a repetitive hand gripping task having 5 different cycle durations (2 to 6
      s), various percentage of work time (and rest) within the work cycle (20% to
      80%), and 3 different grip force levels. Thirty healthy adult participants each
      performed 27 randomly ordered 30-s repetitive hand gripping trials as well as 3
      isometric contractions, which were used to normalize data from the hand gripping
      trials. There was a significant decrease in mean EMG as the duration of the work
      rest cycle time increased. At each force level, EMG increased as the percentage
      of work time within the work-rest cycle increased, but to a greater extent at the
      highest force level. The results of this study suggest that overall muscle
      effort, and perhaps muscle fatigue, can be reduced most effectively by modifying
      the force requirements of the repetitive task. Other variables, such as the
      percentage of work time within a cycle and overall work cycle time have less
      effect on the EMG activity level. The results of this study have implications for
      developing strategies to reduce muscle fatigue during repetitive hand gripping
      tasks in an effort to reduce the effects of cumulative trauma disorders.

PMID- 10602618
TI  - Mathematical Modelling of Muscle Effect on the Kinematics of the Head-Neck
      Complex in a Frontal Car Collision: A Parameter Study.
AB  - A 2-dimensional multibody model of the head-neck complex with muscle elements was
      developed to estimate the influence of muscles on the kinematics of the head-neck
      complex in a frontal car collision. With this model the authors evaluated how
      strongly the calculated influence of muscles depends on 3 important factors: (a)
      impact severity, (b) reflex time, and (c) parameters that determine
      characteristics of different components of the muscle model. When muscles were
      triggered at the beginning of impact, the maximum angle of the head flexion was
      decreased by the muscles by 40% in a frontal collision with an acceleration of
      15g. The influence of muscles was significant for reflex times lower than 60 (80)
      ms. The calculated influence of muscles was not sensitive to most parameters of
      the muscle model.

PMID- 10602619
TI  - A Draft of a System of Teaching Occupational Safety and Ergonomics at
      Universities in Poland.
AB  - The aim of the study was to develop a set of curricula for teaching Occupational
      Safety and Ergonomics at colleges and universities of various types, aimed at
      equipping students with knowledge and skills and at shaping active attitudes
      towards the practical application of the acquired knowledge in their future
      working lives. On the basis of the analysis of the curricula at Polish and
      foreign colleges and universities, a set (canon) of educational contents
      constituting a common practice in the academic teaching of Occupational Safety
      and Ergonomics was established. Then, a convenient for teaching this subject
      classification of university specialisations in Poland was introduced. This led
      to identifying and defining a taxonomic unit called here an educational profile.
      Next, curriculum minima for the developed profiles were defined objectively. To
      achieve this aim, the set of educational contents was ranked by university
      teachers and specialists in occupational safety and ergonomics. Each part of the
      educational contents (subject) was ranked on a 10-point scale in relation to each
      educational profile. The results of this ranking led to formulating sets of
      educational contents for each educational profile. On this basis, a repertoire of
      curricula (6 curricula, in 2 hour-by-hour versions each) was prepared, with
      methodological guidelines for lecturers. The results of the study were presented
      in the form of a manual for academic authorities.

PMID- 10602620
TI  - Risk Assessment in the Working Environment in Estonia.
AB  - The first step to chart hazards in the working environment in Estonia (labour
      force: 0.65 million) was taken by the National Board of Health Protection in the
      beginning of 1996. The existing chemical, physical, and biological agents in the
      working environment were investigated with the help of local health inspectors in
      all counties. An identification of hazards and workers at risk was carried out.
      The results of the analysis showed that 16% of Estonian industrial workers are
      exposed to different hazards: 20,000 persons are exposed to noise, 11,000 are
      working in the conditions of vibration, 10,000 are affected by unsatisfactory
      microclimate, 6,000 complain about long-lasting work in a compulsory posture, the
      overexertion of eyes is suffered by 5,500 persons, and physical overload by 3,500
      workers. In the group of chemical hazards the greatest numbers of workers are
      exposed to organic dust (6,500) and welding aerosols (5,400), followed by
      petroleum products (2,700), and oil-shale dust (4,300). The measurements of
      working conditions showed that an average of 30.3% of the results are above the
      standards. Proposals for the improvement of the situation in occupational safety
      and health are presented.

PMID- 10602621
TI  - Adaptive Process Control in Rubber Industry.
AB  - This paper describes the problems and an adaptive solution for process control in
      rubber industry. We show that the human and economical benefits of an adaptive
      solution for the approximation of process parameters are very attractive. The
      modeling of the industrial problem is done by the means of artificial neural
      networks. For the example of the extrusion of a rubber profile in tire production
      our method shows good resuits even using only a few training samples.

PMID- 10602622
TI  - Prediction of Musculoskeletal Discomfort in a Pick and Place Task (A pilot
      study).
AB  - A pilot study was conducted regarding the effects of working posture, handling
      frequency, and task duration on musculoskeletal discomfort. Participants rated
      their discomfort perceived while performing a repetitive task at 8 different
      combinations of manipulations. Pauses between the work periods lasted 15 min.
      Discomfort was rated according to Borg's category-ratio scale CR-10 and postures
      were recorded by an optoelectronic movement registration system. From linear
      multiple regression analysis equations for predicting discomfort at various body
      regions were obtained. Coefficients of determination especially point to trunk
      inclination and handling frequency as major determinants of musculoskeletal
      discomfort.

PMID- 10602623
TI  - Method for Evaluating Germicidal Ultraviolet Inactivation of Biocontaminated
      Surfaces.
AB  - Safety issues related to work-site conditions often deal with potential worker
      exposure to infectious airborne microorganisms due to their dissemination in
      indoor air and contamination of surfaces. Germicidal ultraviolet (GUV) radiation
      is used in health-care settings and other occupational environments for microbial
      inactivation. In this study, a new methodology for determining the efficiency of
      GUV microbial inactivation of surfaces was developed and evaluated. The method
      utilizes identical chambers in which test microorganisms are irradiated on agar
      surfaces at different humidity and irradiation intensity levels. The effects of
      GUV intensity and exposure time on microbial inactivation were examined for
      Micrococcus luteus and Serratia marcescens. It was found that at low humidity
      levels (20-25%) both organisms can be inactivated with at least 95% efficiency if
      the GUV intensity exceeds 50 MUW/cm2 for at least 3-5 min (corresponding to a
      dose of ~ 10 mJ/cm2). The radiation dose needed for effective inactivation of S.
      marcescens, as measured by a UV meter near the microbial sample, was found not to
      be affected by the humidity level, whereas that of M. luteus increased at higher
      humidities. The findings of this study can be used to determine sufficient GUV
      inactivation doses for occupational environments with various microbial
      contaminations.

PMID- 10602624
TI  - Identification of Ergonomic-Related Hazards in an Industrial Sample Using the
      National Occupational Exposure Survey.
AB  - The National Occupational Exposure Survey (NOES) was used to determine
      probabilities for 4 potential physical-agent and 10 potential ergonomic-related
      exposure hazards among a representative sample of U.S. industries. Potential
      physical-agent hazard exposures, principally whole-body and segmental vibration,
      were highest among railroad and heavy construction industries. Several
      construction industries had high probabilities of potential ergonomic-related
      exposure hazards, especially to the back and upper extremities. Establishments
      with 100 to 249 employees had the highest probability of potential exposures to
      the 2 types of hazards. Measures of safety and health climate did not differ
      consistently between high-hazard and low-hazard establishments. The approach
      taken in this paper may be used to help identify highrisk industries, evaluate
      interventions, and develop inspection strategies.

PMID- 10602625
TI  - Artificial Neural Networks-Modern Systems for Safety Control.
AB  - A short review of the applications of artificial neural networks in different
      fields of industry with a description of their main properties is made. Such
      systems have specific properties typical for the human brain, which can decide on
      the superiority of artificial neural networks over standard control systems.
      Basic types of such networks as well as their principles of operation and
      successful applications are described. The application of artificial neural
      networks in safety engineering is discussed with stress on their special
      properties, which are necessary in safety critical systems.

PMID- 10602626
TI  - A System for Measuring Vertical Concentration Profiles of Gaseous Pollutants,
      Using Carbon Dioxide as a Case Study.
AB  - An electronically-controlled sampling system, characterised by its organ pipe
      design, has been developed for sampling air sequentially, at different heights
      within the breathing zone. Data are automatically logged at the different
      receptor levels, for the determination of the average vertical concentration
      profile of gaseous pollutants. The system has been coupled to a carbon dioxide
      monitor and used in a brief study of the spatial and temporal variation of indoor
      carbon dioxide concentration. The system can easily be extended for different
      heights or modified for use with other types of gas monitor. The results of a
      trial run, which was carried out in a coffee room, are presented and applications
      of the Organ Pipe Sequential Sampling (OPSS) system are discussed.

PMID- 10602627
TI  - A Comparison of Skin Temperatures and Clothing Microclimate During Moderate
      Intermittent Exercise in the Cold Between One and Two Layers of Cotton and
      Polypropylene Underwear.
AB  - The purpose of this study was to compare the effects of 2 kinds of underwear made
      from hydrophobic and hydrophilic fabrics on the mean skin temperatures and
      clothing microclimate (temperature, humidity) in participants performing
      intermittent exercise in cold environmental conditions. One or 2 layers of cotton
      underwear (C1, C2) with a 2-piece long-sleeved shirt and long-legged trousers,
      and 1 or 2 layers of polypropylene underwear (P1, P2) with a 2-piece long-sleeved
      shirt and long-legged trousers were used as experimental underwear. In addition,
      the participants wore a 2-piece ski suit as 100% polyester clothing including
      100% polyester padding. Ten young adult females volunteered as participants. The
      experiments were performed in a climatic chamber at an ambient temperature (Ta)
      of 0 degrees C and an air velocity of 0.26 m s-1. The major findings are
      summarized as follows: (a) Although the clothing microclimate humidity was not
      different within the ski suit of outer clothing between C1 and P1, it was
      significantly higher in P2 than in C2; (b) Clothing microclimate temperature
      inside the ski suit did not differ between C1 and P1, whereas it was
      significantly higher in P2 than in C2; (c) The thermal gradient between innermost
      and outermost of clothing microclimate at back level did not show any difference
      between C1 and P1, but it was significantly higher in C2 than in P2. These
      results are discussed in terms of thermal physiology and clothing sciences.

PMID- 10602628
TI  - Measurement Accuracy of the Electrosensitive Protective Device Response Time When
      Using the Double Penetration Method.
AB  - The Double Penetration Method (DPM) method of measuring ESPD (Electrosensitive
      Protective Device) response time was presented by Dzwiarek (1997). Calibrating
      the measuring equipment is a crucial stage of the procedure. Experimental
      verification of theoretical predictions is also crucial. For calibration
      purposes, a device simulating real ESPD operation thus enabling a correct setting
      of the response time was designed (Dzwiarek, 1997). Theoretical analysis has
      shown that measuring ESPD response time with the DPM is subject to localisation
      errors made in the localisation of the detection zone border, rod position
      measurement errors made during highspeed penetration, and time delay measurement
      errors. The values of all those components of the total error have been
      determined experimentally using the calibrating device. Measurements have been
      taken under conditions as close to real ones as possible proving that the total
      measurement error is really enclosed within the assumed limits.

PMID- 10602629
TI  - Experimental Evaluation of the Importance of the Pulmonary Surfactant for Oxygen
      Transfer Rate in Human Lungs.
AB  - The rate of oxygen transport from atmospheric air into water and perfluorocarbon
      compound (PFC) was investigated. Static and dynamic systems with and without the
      presence of the lung surfactant monolayer were considered. For the case of water
      used as an oxygen absorbent, the monolayer activity allowed a simulation of the
      gas uptake into the lung hypophase. In the second case, a two-phase liquid system
      with water as a hypophase and PFC as the blood substitute simulated oxygen
      transport in the alveolus-blood system. Original experimental measurement devices
      gave the opportunity of determining the gas transport rate with the possibilities
      of indicating the role of the lung surfactant in the process and evaluating the
      influence of environmental conditions on the transport phenomena. Results of that
      work suggest a possible enhancing role of the lung surfactant in the oxygen
      transfer rate.

PMID- 10602630
TI  - The Correlation Between Symptoms, Frequent Use of Dental Polymers, and Evaluation
      of Health Risk.
AB  - Dental personnel are at risk as they manually handle polymer products containing
      monomers and additives that cause irritation and induce allergy. Gloves and face
      masks can be easily penetrated by monomers. A total of 587 dental personnel and a
      referent group (585) in the 2 most northern regions of Sweden were included in a
      questionnaire study (response rate 76%). Questions were asked regarding symptoms
      of atopy, asthma, conjunctivitis, atopic dermatitis, hand dermatitis, and hay
      fever/rhinitis. The dental personnel were asked to give the name of polymer
      products used in their practice and the frequency of use. They were also asked to
      risk evaluate 5 different types of polymer materials on a scale from 1 to 5.
      Analysis was done to find if the occurrence of a symptom was associated with a
      high risk evaluation of a polymer material, or with frequent use of a certain
      polymer product. Significantly more dentists reported symptoms of atopic
      dermatitis and conjunctivitis compared to referents and chair assistants. Results
      show that dental personnel with symptoms risk evaluated most materials
      significantly higher than dental personnel without symptoms. Further, the
      occurrence of some symptoms was associated with frequent use of 8 polymer
      products.

PMID- 10602631
TI  - Theoretical Analysis of Percussive Tests of Products.
AB  - The goal of theoretical research is to establish parameters, which have to be
      given in standards for percussive tests of products. Those parameters are
      essential for each user to be able to construct identical (equivalent) testing
      equipment. This would ensure identical results for identical products. The paper
      presents a detailed analysis of the distribution and the value of the forces
      generated during percussive collisions of two bodies. Elastic, plastic, and
      elastoplastic collisions are considered. Parameters determining the coefficient
      of restitution, the courses of energy, momenta, and the values of the forces in
      colliding elements are determined. The dynamic force acting on a product during a
      percussive test was studied.

PMID- 10602632
TI  - Effects of Manual Handling, Posture, and Whole Body Vibrations on Low-Back Pain.
AB  - To determine the effect of occupational stress on low-back pain (LBP), a cross
      sectional study has been carried out, by interviews, on workers exposed to 3
      stresses: manual handling (MH, 82 women and 264 men), whole body vibrations (WBV,
      274 men), and static postures (278 women). Anthropometric data, occupational
      stress, LBP severity and frequency, and a psychological evaluation of these
      groups were compared to those of a control population of 208 workers (104 men and
      104 women). The results show that 30% of the population had never suffered from
      LBP. Age and the body mass index of the workers were the parameters most closely
      associated with LBP. Women involved in MH had higher frequency and severity of
      LBP than their reference population. Men involved in MH or exposed to WBV had
      higher frequency of painful episodes than their reference population. Workers
      exposed to one of the stresses were on sick leave for LBP more often, and for
      longer periods, than workers in the reference group. The results show that
      individual factors are often decisive in the onset of LBP. Nevertheless, in the
      more serious LBP cases, occupational stress is an aggravating factor for LBP and
      its consequences.

PMID- 10602633
TI  - Job Redesign Needs for Aged Workers.
AB  - The aim of this paper is to explore and present a proposal for redesigning
      elements of the workplace for agech workers. The method of research was to
      observe, record, and measure the actions of sitting workers performing assembly
      operations on electrical products in the Kani Plant Nagoya Works of Mitsubishi
      Electric Co. (Japan). The evaluation index used in the experiment was obtained by
      measuring time motion elements, cycle time per product, and motion velocity waves
      of elderly workers. Those motion characteristics were then compared to the motion
      characteristics of young workers. The results led to job redesign elements being
      identified to reduce handling factors of high difficulty for aged workers and to
      the necessity to consider a coefficient of correction in Method Time Measurement
      (MTM) according to differences in the manufactured object's weight.

PMID- 10602634
TI  - Two-Dimensional Automatic Control Modeling of a Posture Control System.
AB  - A posture control model has been developed on the basis of the 2-dimensional
      feedback control theory. Human postural characteristics were investigated in 5
      healthy participants. Tests were performed with eyes open and eyes closed. After
      5 s of quiet standing, each participant was unexpectedly pulled forward by 30 mm
      at his pelvis height and then released. Postural sway was measured over 20 s at a
      rate of 100 per second. Transfer functions to represent the posture control
      characteristic were identified by the least squares' method. These showed good
      results of the model's fitness, predictability, and stability. The response of
      the eyes-closed condition to perturbation is more oscillatory than that of the
      eyes-open condition. It seems that the model identified could be applicable to
      ergonomics, sports, or clinical situations.

PMID- 10602635
TI  - Pressure Sensitive Mats as Safety Devices in Danger Zones.
AB  - Developing prototypes of pressure sensitive mats and testing their practical
      application were the aims of this study. Two contact plate mats were designed and
      constructed: rubber-rubber (R) and metal-metal (M). A recipe for rubber mixes and
      the production technology were prepared. Two laboratory test stands for measuring
      the actuating force, response time, static pressure resistance, and the
      durability of the mats were constructed. Computer software was written to control
      the operation of those test stands. Methods of testing pressure sensitive mats
      were based on PrDIN 31 006 (Deutsches Institut fur Normung [DIN], 1990) and EN
      1760-1 (Comite Europeen de Normalisation [CEN], 1997). Both prototypes of contact
      plate mats were tested under laboratory and industrial conditions. The test
      results proved that the design was correct, the setup requirements were
      fulfilled, and the mats were efficient and reliable in the industrial
      environment.

PMID- 10602636
TI  - Assessment of wood utility pole climbability using psychophysical and mechanical
      measurements.
AB  - The issue of climbability has been raised on several occasions for more than a
      decade in North America. Presently, climbability is estimated from the pole
      hardness measured by the Pilodyn measurements (6 J). However, the use of Pilodyn
      measurements to discriminate the pole hardness value is criticized by climbers,
      who claim that the Pilodyn hardness measurement is affected by species-treatment
      combinations and that it does not reflect gaff penetration or climbability.
      Furthermore, climbability evaluations have been conducted in which test poles
      were climbed by linemen, and corresponding subjective ratings were recorded.
      However, the ability of psychophysical measurements to accurately discriminate
      close hardness pole values and to differentiate species-treatment combinations at
      specific hardness levels have not yet been fully documented. The aim of this
      study is to evaluate the psychophysical perception of linemen and the mechanical
      measurements of gaff penetration and gaff impact during the climbing of different
      wood species and treatment combinations in order to compare these results with
      Pilodyn measurements within a precise range of pole hardnesses, to study the
      relationships between these variables, and, finally, to propose various design
      guidelines for the development of a better tool for the evaluation of
      climbability.

PMID- 10602637
TI  - Pulse nebulization in pneumatic devices.
AB  - Aerosols of a physiological salt solution and aqueous solutions of salbutamol,
      sodium cromoglicate, and dornase alfa were generated in a pneumatic nebulizer and
      analyzed in a system with controlled humidity of air as a carrier gas. Mass
      distribution of aerosol particles and yield of generation for pulse nebulization
      were measured. Pulsation of generation was realized with an attachment maintained
      by a computer program. Opening times of the valve were in the range 50-800 ms.
      The results indicate the possibility of improving aerosol particle delivery to
      the lung using a pulse generation system.

PMID- 10602638
TI  - Evaluating the potential occupational hazard of handling dental polymer products
      using the HET-CAM technique.
AB  - The irritation potencies of 8 dental polymer products, used as dental restorative
      materials, adhesives, or temporary constructions, were tested using the HET-CAM
      (hen's egg test-chorioallantoic membrane) technique. Liquid and powder
      components, and extracts of cured and freshly mixed non-cured materials of 5
      glass ionomers, 1 bonding, 1 composite, and 1 cold-cured acrylate were examined.
      Results showed that the liquid component of all products had a strong irritation
      capacity but powder suspensions and extracts from cured and freshly mixed non
      cured materials had no effect on the CAM. Thus, dental personnel who handle
      liquid and powder manually are exposed to components with a high irritation
      potential, in contrast to patients who are exposed to the cured and mixed non
      cured materials with low irritation potential. This illustrates the importance of
      safe handling procedures and practices for dental personnel who handle non-cured
      polymers manually.

PMID- 10602639
TI  - Mechanical equipment injuries in small manufacturing businesses. Knowledge,
      behavioural, and management issues.
AB  - This paper presents findings from an extensive study into factors that impact
      upon the high rate of injuries due to mechanical equipment, especially in small
      manufacturing firms. Issues relating to knowledge of health and safety issues and
      to management practices have been shown to be extremely important with regards to
      safety in small businesses. Knowledge and awareness of hazards were found to be
      relatively low and few respondents, especially managers, had received adequate
      safety training. Managers did not regard the identification and control of risks
      as a priority. Workplaces generally lacked effective safety management procedures
      such as safety rules and regulations, procedures for recording and learning from
      accidents, and clearly defined responsibilities for safety. Some issues requiring
      further investigation, and some recommendations for improving safety in small
      businesses, are presented.

PMID- 10602640
TI  - Effects of synthesized voice warning parameters on perceived urgency.
AB  - The effects of synthesized voice warning parameters on perceived urgency were
      examined in order to build a detailed and usable description of the relation
      between the parameters of synthesized voice warnings and perceived urgency. Ten
      native and 10 non-native English speakers participated in 4 experiments to
      evaluate and quantify the effects of the voice parameters. The results showed
      that speech rate, average fundamental frequency [F(0)], voice type, and
      fundamental frequency contour have clear effects on the perceived urgency of
      synthesized voice warnings. The effects of quantitative parameters on perceived
      urgency were scaled using an application of Stevens's power law (1957). In
      addition, the results showed significant differences in the perceived urgency of
      average F(0) and F(0) contour types between native and non-native English
      speakers. Implications of the results for the design and improvement of
      synthesized voice warnings are discussed.

PMID- 10602641
TI  - Computerized method for work space optimization in conditions of static work.
AB  - The aim of this research was to develop a theoretical method for the ergonomic
      optimization of the work space of the upper limb. This method is based on a model
      of the upper extremity with 7 degrees of freedom. It consists of 3 rigid elements
      modeling the arm, forearm, and hand and 34 upper extremity muscles. The trunk is
      considered immobile. The shoulder joint is modeled as a rotating kinematics pair
      of third class, the elbow and wrist joints--of fourth class. The minimum sum of
      muscle force moments in the joints and soft saturation muscle cooperation
      criterion were used as merit criteria. The developed method makes it possible to
      effectively solve, in a defined work space, the task of work space optimization.

PMID- 10602642
TI  - Experimental verification of the computerized method for work space optimization
      in conditions of static work.
AB  - The aim of this study was to verify a theoretical model for upper extremity work
      space optimization. In order to do that, experimental studies were conducted in
      which two parameters of the electromyography (EMG) signal were analyzed: AMP
      (amplitude calculated as Root Mean Square) and SZC (coefficient of the slope of
      the regression line between time and Zero Crossing values). Values of forces in
      muscles (parameter MOD) were calculated from theoretical studies. A comparison of
      experimental (AMP, SZC) and theoretical (MOD) parameters was performed by
      analyzing the coefficient of correlation between those parameters and
      differentiation of muscular load according to external load value. Analysis
      showed that the theoretical and experimental results are in step, which means
      that the developed model can be used for upper extremity work space optimization.

PMID- 10602643
TI  - Ergonomic aspects of a virtual environment.
AB  - A virtual environment is an interactive graphic system mediated through computer
      technology that allows a certain level of reality or a sense of presence to
      access virtual information. To create reality in a virtual environment,
      ergonomics issues are explored in this paper, aiming to develop the design of
      presentation formats with related information, that is possible to attain and to
      maintain user-friendly application.

PMID- 10602644
TI  - Ergonomics and quality management--humans in interaction with technology, work
      environment, and organization.
AB  - In many studies, ergonomics has been shown to influence human performance. The
      aim of this paper was to demonstrate important ergonomics influences on quality
      in industrial production, from the perspective of interactions between humans,
      technology, organization, and work environment. A second aim was to elaborate on
      the implications of these findings for the development of quality management
      strategies. This paper shows that ergonomics problems in terms of adverse work
      environmental conditions, inappropriate design of technology, and an unsuitable
      organization are important causes of quality deficiencies. Problem solving aimed
      at improving ergonomics, quality, and productivity simultaneously is likely to
      obtain support from most of the interest parties of the company, and may also
      enhance participation. Ergonomics has the potential of becoming a driving force
      for the development of new quality management strategies.

PMID- 10602645
TI  - Ergonomics oriented to processes becomes a tool for continuous improvement.
AB  - A holistic view is essential for quality initiatives such as Total Quality
      Management (TQM), Standard No. ISO 9001:1994 (International Organization for
      Standardization [ISO], 1994), Concurrent Engineering, Business Reengineering, and
      Business Process Improvement. The challenge is knowing how to transition from
      this theoretical concept to implementation. The relationship between quality
      interest and an ergonomics program will be the focus of this discussion. An
      ergonomics oriented improvement program includes (a) ergonomics or fitting the
      job to the person; (b) integration of operations management, safety engineering,
      medical management, and employees as co-owners of the process; (c) the emphasis
      of ergonomic precepts in the engineering of new processes and improvement of
      current processes; and (d) the emphasis of employees taking responsibility for
      their own well being and the improvement of their work environment. The parallel
      between the continuous improvement process delineated by the quality-system
      requirements in Standard No. ISO 9001:1994 (ISO, 1994) and the improvement
      contributions of ergonomics are very revealing (Getty, Abbott, & Getty, 1995). It
      is the contention of this approach that if the precepts of ergonomics were
      applied to the work environment, it would support the objective of world class
      quality and productivity, resulting in improved global competitiveness of
      businesses.

PMID- 10602646
TI  - Flexible management system for occupational safety and quality.
AB  - In the 10 analysed companies it is necessary to create a management for flexible
      processes and a structured flexibilisation of these processes. This represents
      the basis for the retention of existing flexibility and occupational safety. The
      strategy for a management of flexible processes leads, firstly, to a structuring
      of company procedures whilst still retaining the necessary flexibility and
      certification ability as laid down by standards No. DIN EN ISO 9000ff. and,
      secondly, to the keeping of the demands of an occupational safety management
      system. In this article the inclusion of co-workers stands in the foreground.
      This will be combined with the goal to utilise their experience and their
      acceptance of the solutions worked out.

PMID- 10602647
TI  - Macroergonomic analysis and design for improved safety and quality performance.
AB  - Macroergonomics, which emerged historically after sociotechnical systems theory,
      quality management, and ergonomics, is presented as the basis for a needed
      integrative methodology. A macroergonomics methodology was presented in some
      detail to demonstrate how aspects of microergonomics, total quality management
      (TQM), and sociotechnical systems (STS) can be triangulated in a common approach.
      In the context of this methodology, quality and safety were presented as 2 of
      several important performance criteria. To demonstrate aspects of the
      methodology, 2 case studies were summarized with safety and quality performance
      results where available. The first case manipulated both personnel and technical
      factors to achieve a "safety culture" at a nuclear site. The concept of safety
      culture is defined in INSAG-4 (International Atomic Energy Agency, 1991). as
      "that assembly of characteristics and attitudes in organizations and individuals
      which establishes that, as an overriding priority, nuclear plant safety issues
      receive the attention warranted by their significance." The second case described
      a tire manufacturing intervention to improve quality (as defined by Sink and
      Tuttle, 1989) through joint consideration of technical and social factors. It was
      suggested that macroergonomics can yield greater performance than can be achieved
      through ergonomic intervention alone. Whereas case studies help to make the case,
      more rigorous formative and summative research is needed to refine and validate
      the proposed methodology respectively.

PMID- 10602648
TI  - Synergism of ergonomics, safety, and quality--a behavioral cybernetic analysis.
AB  - This report extends a control systems or cybernetic model of behavior to the
      behavior of groups of many individuals--organizations and institutions--operating
      together with technology as complex sociotechnical (ST) systems. The premise is
      that the level of quality in performance of a complex ST system is predicated
      upon the degree to which its organizational design incorporates elements of a
      closed-loop behavioral control system: control goals and objectives, sensory
      receptors, sensory feedback, learning and memory, effectors, and sensory feedback
      control. From a control systems perspective, ergonomics is essential to effective
      organizational self-regulation. If working conditions are poorly designed, work
      performance and safety and quality outcomes cannot be closely controlled.
      Conversely, as shown by field evidence, good design promotes synergism between
      ergonomics, safety, and quality as a closed-loop consequence of effective
      employee and organizational self-control of system performance, safety, and
      quality.

PMID- 10602649
TI  - Safety and quality issues as part of a holistic (i.e., sociotechnological)
      approach.
AB  - In the past, many so-called management concepts were not very successful because
      of their fragmented approach. This is also true for topics like safety and
      quality. Here, technical aspects often predominated while disregarding the
      equally important need for a change of attitude. On the other hand, awareness was
      created by timely limited programmes. The paper deals with integrating quality
      and safety in holistic (management) concepts, which are described first before
      being discussed in detail.

PMID- 10602650
TI  - Ergonomics and work organization: the relationship between tayloristic design and
      workers' health in banks and credit cards companies.
AB  - The discussion developed in this paper is based on the results of an ergonomic
      work analysis carried out with attendants at call centers. Some critical issues
      and difficulties, like working pace, inadequate tools and workstations, and
      software inadequacies were detected in working situations. Operator-customer
      interactions are presented, attempting to put in evidence working constraints,
      working conditions, and their connection with health problems. The main
      conclusion is that serving clients, especially when the job is to provide
      information, is not a simple task, as information is not always available in the
      computerized system and is completely fragmented. The scope of workers' actions
      is very restricted and complicated and recurrent requests are redirected to
      others. Workers (individually or as groups) have limited possibilities to make
      adjustments to be able to give more adequate and personalized treatment to
      clients and, at the same time, to work in a less stressful environment. In
      periods of increased workload and work intensification, the situation is very
      much favorable to the incidence of health disorders, such as work related
      musculoskeletal disorders (WMSD) and others. Some suggestions to improve the work
      situation are discussed.

PMID- 10602651
TI  - Macroergonomics and total quality management: how to improve quality of working
      life?
AB  - In this paper, we present a macroergonomic model of work design that is applied
      and tested to examine Total Quality Management (TQM) in the public sector.
      According to the model, TQM can influence different aspects of work design and
      quality of working life (QWL). Questionnaire data collected in 2 public sector
      organizations in the USA show that TQM can have both positive and negative impact
      on work design and QWL. The main positive impact of TQM was found on job content,
      job control and participation, and social relationships. The main negative impact
      of TQM was on workload, uncertainty, and clarity of job duties. The impact of TQM
      on QWL was mixed. Our results show that the impact of TQM on work design and QWL
      varied very much across the 6 participating departments, as well as within the
      departments. Further research is warranted to assess the human impact of TQM, in
      particular research on the linkage between various aspects of TQM, on one hand,
      and work design and QWL, on the other hand.

PMID- 10602652
TI  - Heart rate variability in exposure to high altitude hypoxia of short duration.
AB  - The objective of the presented studies is to attempt an evaluation of heart rate
      (HR) and heart rate variability (HRV) regulatory mechanisms in the presence of
      autonomous nervous system (ANS) components in transient exposure to high altitude
      hypoxia. During 24 hrs including a stay in hypobaria, the participants had their
      HR continuously recorded using the Holter method. The following parameters were
      calculated at rest and during the stay in a thermobarochamber: spectral power in
      low frequency bands (LF) 0.04-0. 15 Hz and high frequency bands (HF) 0.15-0.5 Hz,
      and the sympathetic-parasympathetic balance index LF/HF. Under hypobaric
      conditions, a decrease in mean spectral power of R-R intervals was noted within
      both frequency ranges, compared with the study performed in normobaria. The
      observed differences were larger at daytime.

PMID- 10602653
TI  - Assessment of the protection efficiency and comfort of personal protective
      equipment in real conditions of use.
AB  - The lack of scientific and technical knowledge in certain complex fields,
      together with schedule constraints, have lead to adopt in EN standards
      insufficiently validated tests, relying sometimes on an empirical approach. Thus,
      even personal protective equipment (PPE) with positive results in tests required
      by the standards can nevertheless prove to be unsatisfactory when used at work.
      Several research projects have already been carried out on equipment, fall
      arresting systems, protective clothing, and gloves by several health and safety
      institutes in Europe. The results would suggest practical solutions to improve
      the representativity of several European Committee for Standardization (CEN) test
      methods and to focus more on informing and training workers on the manner of
      wearing PPE, in particular respiratory protective equipment or hearing
      protectors.

PMID- 10602654
TI  - Filtration properties of nonwovens.
AB  - This paper presents the results and conclusions from experimental investigations
      concerning filtration properties of nonwovens. The needled nonwovens were made
      from polyester fibres (PTE) with average fibre diameter 12 micrometres and
      polypropylene fibres (PP) with average fibre diameter 32 micrometres. Nonwovens
      were produced out of each of those fibres or out of a mixture of polyester and
      polypropylene fibres. This paper also presents investigations of nonwoven fabric
      made of polypropylene fibres (PP) with average fibre diameter 2.6 micrometres,
      which was formed according to melt-blown technology. Oil mist, as challenge
      aerosol, was used to evaluate the performance of filter media at various aerosol
      velocities. The average oil mist test aerosol particle diameter was 0.3
      micrometre. Filter penetration was measured at oil mist concentration 0.24
      g/m(3).

PMID- 10602655
TI  - Influence of exercise-focused group activities on the physical activity,
      functional capacity, and work ability of female farmers--a three-year follow-Up.
AB  - The objective of this randomised study was to evaluate the influence of exercise
      focused group activities on female farmers' physical activity, functional
      capacity, and work ability over a period of 3 years. Physical activity increased
      more in the intervention group (n = 62) than in the control group (n = 64) during
      the first year. By the third year physical activity had almost returned to the
      pre-intervention level. In the 3-year follow-up examination muscular endurance
      and cardio-respiratory fitness had improved in the intervention group, and
      musculoskeletal symptoms had decreased more often in the intervention group than
      in the control group. The index used to measure perceived work ability showed no
      changes over the 3-year period. It can be concluded that group activities focused
      on leisure-time physical activity and work habits can be recommended as health
      promotion measures for farmers' occupational health services.

PMID- 10602656
TI  - Achievement and social relations values as conditions of the importance of work
      aspects and job satisfaction.
AB  - One hundred and sixty-nine bank employees were investigated with the Orientation
      to Work Values Inventory by Seifert and Bergmann (values; Seifert & Bergmann,
      1983), and the Work Description Inventory by Neuberger and Allerbeck (importance
      and satisfaction with work aspects, overall job satisfaction; Neuberger &
      Allerbeck, 1978). The data show complex connections between values and the
      perceived importance of work aspects and job satisfaction. The results indicate
      that (a) the importance of achievement and social relations values influences the
      importance of aspects of work, (b) overall job satisfaction depends on social
      relations value and satisfaction with some aspects depends on this value or on
      interactions of both of the values, (c) predicting overall job satisfaction from
      satisfaction with aspects of work is modified by the interaction of the values.
      However, the hypothesis that overall job satisfaction can be predicted from
      satisfaction with most important aspects of work is not confirmed by the data.

PMID- 10602657
TI  - Participative versus assigned production standard setting in a repetitive
      industrial task: a strategy for improving worker productivity.
AB  - The participative standard with feedback condition was superior to the assigned
      difficult (140% of normal) standard with feedback condition in terms of worker
      productivity. The percentage increase in worker productivity with the
      participative standard and feedback condition was 46%, whereas the increase in
      the assigned difficult standard with feedback was 23%, compared to the control
      group (no standard, no feedback). Worker productivity also improved significantly
      as a result of assigning a normal (100%) production standard with feedback,
      compared to the control group, and the increase was 12%. The participative
      standard with feedback condition emerges as the optimum strategy for improving
      worker productivity in a repetitive industrial production task.

PMID- 10602658
TI  - Assessment of the pulmonary toxicity of inhaled gases and particles with
      physicochemical methods.
AB  - Physicochemical techniques used for evaluating the pulmonary surfactant (PS)
      quality are discussed as methods useful in assessing toxicity of inhaled gases
      and particles. Two standard devices, Langmuir-Wilhelmy film balance and pulsating
      bubble apparatus, are presented in detail, and the measured results of
      interaction between sulfuric acid and 2 models of PS materials are analyzed. The
      evident decrease in surface activity of the pulmonary surfactant after its
      contact with the acid at concentrations approaching 0.001 M may be considered as
      an indicator of the adverse effect, which can result in several health problems.
      The presented approach can be used as a method of assessing pulmonary toxicity of
      any substances present in the breathing air.

PMID- 10602659
TI  - General evaluation of risk associated with the use of pesticides and other
      chemical substances on animal breeding and plant production farms.
AB  - A general characteristic of chemical risk on plant production farms in Poland is
      presented. The paper describes risk associated with the natural occurrence of
      chemical substances (such as ammonium and hydrogen sulfide) in the process of
      animal breeding and risk connected with the use of artificial fertilizers and
      pesticides. Pesticides are briefly described taking into consideration toxicity
      classes and the toxic effect of individual compounds. Exposure to pesticides is
      presented for individual methods and related activities. Finally, the author
      discusses pesticide risk on fruit-growing farms and in greenhouses.

PMID- 10602660
TI  - Differential antibody isotype expression to the major Paracoccidioides
      brasiliensis antigen in juvenile and adult form paracoccidioidomycosis.
AB  - We investigated the relationship between antibody response to the major
      Paracoccidioides brasiliensis antigen, a 43-kDa glycoprotein, and the two
      paracoccidioidomycosis (PCM) clinical presentations, the juvenile and the adult
      forms. Total immunoglobulin G (IgG), IgG isotypes, and IgA anti-gp43 antibodies
      were determined by enzyme-linked immunosorbent assay in patients'sera. Juvenile
      PCM patients had higher (P =.003) IgG anti-gp43 levels than adult form patients.
      IgG1 subclass levels, however, were comparable between the two clinical forms.
      Patients with the juvenile form had higher (P <. 001) IgG4, but lower (P =.03)
      IgG2 levels than patients with the adult form. The IgG4 isotype, regulated by
      interleukin 4, was found in all juvenile form patients but in only 12% of the
      adult form patients. In contrast, high levels of the IgG2 isotype, regulated by
      interferon-gamma, were found in 41% of the adult PCM patients, mainly those with
      a more benign disease, but in only 12% of the juvenile patients. IgG3 was either
      absent or detected at low levels. These results demonstrate, for the first time,
      specific IgG4 antibodies in the humoral immune response of patients with an
      endemic deep mycosis and suggest that the switch to the IgG subclasses in PCM is
      regulated by the patients' T-helper subset (Th-1 or Th-2) dominant cytokine
      profile. A possible role for IgG4 in the immunopathogenesis of the juvenile, more
      severe form of the disease is discussed. Finally, IgA was found mainly in adult
      form patients, probably as a result of the chronic mucosal antigenic stimulation
      characteristic of this form.

PMID- 10602661
TI  - Human cytomegalovirus genome sequences in lymph nodes.
AB  - Human cytomegalovirus (CMV) is a major cause of morbidity in heart and lung
      transplant patients, resulting from immunosuppression-mediated reactivation of
      latent CMV originating either from the transplanted tissue, or the recipient. We
      showed that out of eight donor/recipient pairs, the lymph nodes (LNs) of three
      donors and four recipients, all CMV seropositive, harboured CMV DNA at exceeding
      levels compared with those of matched blood samples, as well as CMV RNA otherwise
      undetectable in patients' blood. On follow-up, patients positive for CMV DNA and
      RNA in LNs developed viraemia 4 to 5 weeks earlier than those initially
      polymerase chain reaction-negative for CMV. Our results indicate that LN are a
      significant site for sequestration and persistence of CMV and that LN may be
      important in seeding of CMV-infected cells into the circulation.

PMID- 10602662
TI  - Microbial interactions in the vaginal ecosystem, with emphasis on the
      pathogenesis of bacterial vaginosis.
AB  - During bacterial vaginosis (BV), populations of lactobacilli which are generally
      dominant in the vagina of overtly healthy women are replaced by other facultative
      and anaerobic microorganisms. Some Lactobacillus strains produce hydrogen
      peroxide and all produce lactic acid; however, the antagonistic role of these
      metabolites in vivo remains controversial. Positive interactions among BV
      associated organisms may contribute to the pathogenesis of BV and its sequelae.

PMID- 10602663
TI  - Pathogenicity of Cryptococcus neoformans: virulence factors and immunological
      mechanisms.
AB  - Cryptococcus neoformans is the causative agent of cryptococcosis and cryptococcal
      meningitis, which are serious pathological conditions affecting up to 10% of
      patients with AIDS. Mechanisms of pathogenicity of C. neoformans and the host
      defenses against this fungus are reviewed, incorporating recent data and
      perspectives.

PMID- 10602664
TI  - An evolutionary view of the interactions between anopheline mosquitoes and
      malaria parasites.
AB  - The transmission of malaria is governed by the mosquito vector's biting rate, its
      mortality, and the developmental period of the parasite within the mosquito. This
      review covers some data on the interactions among these parameters and describes
      possible evolutionary mechanisms underlying two aspects of the parasite's life
      cycle.

PMID- 10602665
TI  - Human retroviral sequences associated with extracellular particles in autoimmune
      diseases: epiphenomenon or possible role in aetiopathogenesis?
AB  - Publications describing retroviral sequences associated with extracellular
      particles in Sjogren's syndrome or systemic lupus erythematosus, multiple
      sclerosis, and type I diabetes present novel arguments and raise complex
      questions about eventual relationships between retroviruses and autoimmunity.
      They are presented and discussed in the present review, preceded by an overview
      of the biology of retroviral elements.

PMID- 10602666
TI  - Yersinia enterocolitica: overview and epidemiologic correlates.
AB  - Yersinia enterocolitica comprises both pathogenic and nonpathogenic members.
      Distinguished by biogrouping, serogrouping, and ecological distribution, commonly
      occurring pathogenic serobiogroups, e.g., O:3/4; O:5,27/2; O:8/1b; O:9/2, possess
      both chromosomal and plasmid-mediated virulence traits. Studies have revealed
      several (oral, blood transfusion) modes of acquisition, elucidated the putative
      role of chromosomal and plasmid-encoded virulence factors in the pathogenesis of
      human infection, and have identified major animal reservoirs, e.g., the pig.
      Diagnosis has been refined though use of selective media, monoclonal antibodies
      directed against outer membrane proteins, and of purified yersiniae outer
      membrane proteins for antibody detection. Epidemiological investigations of
      foodborne outbreaks have been advanced through the use of molecular biology
      techniques such as ribotyping and pulsed-field gel electrophoresis.

PMID- 10602667
TI  - The effect of viruses on the ability to present antigens via the major
      histocompatibility complex.
AB  - We describe viral pathogens that cause significant human disease by their ability
      to interfere with the expression of major histocompatibility complex class I and
      II molecules. Herpesviruses and papillomaviruses encode gene products that
      interfere with the class I pathway of antigen processing and/or peptide
      translocation. Adenoviruses encode unique gene products that interfere with
      transport of class I molecules. Influenza virus, measles virus, and HIV interfere
      with the class II pathway by either suppressing the production of class II
      molecules or impeding antigen trafficking. Cytomegalovirus interferes with both
      class I and class II pathways. Better understanding of these mechanisms may lead
      to further insight into the pathogenesis of viral infections and allow for
      improved treatments.

PMID- 10602669
TI  - Clinical and biological aspects of infection caused by Ehrlichia chaffeensis.
AB  - Ehrlichia chaffeensis is an obligatory intracellular bacterium that infects the
      monocyte-macrophage. E. chaffeensis, which is transmitted to humans by ticks
      primarily from infected deer, causes human monocytic ehrlichiosis, an acute
      febrile systemic illness. This paper reviews current knowledge of clinical and
      biological aspects of infections caused by E. chaffeensis.

PMID- 10602668
TI  - In vitro human immune reactivity of fast protein liquid chromatography
      fractionated Paracoccidioides brasiliensis soluble antigens.
AB  - Soluble antigens of Paracoccidioides brasiliensis yeast cells (PbAg) were
      fractionated in a fast protein liquid chromatography (FPLC) system, using Q
      Sepharose anion-exchange resin, in order to characterize antigenic fractions that
      could elicit cell reactivity and antibody recognition in human
      paracoccidioidomycosis (PCM). PbAg fractions were eluted by 20 mM Tris-HCl
      solution (pH 9.6) with an increasing gradient up to 1 M NaCl. The FPLC system was
      able to resolve 7 fractions, enumerated from 0 to VI, according to the elution on
      the NaCl gradient. The analysis of each fraction on SDS-PAGE showed that
      fractions 0 to V were constituted by multiple protein bands with molecular mass
      ranging from 18 to 114 kDa. Large amounts of nucleic acids were evidenced in
      fraction VI, as revealed by agarose gel stained with ethidium bromide. Sera from
      PCM patients presenting different clinical forms contained antibodies that
      recognized antigens in all fractions with the exception of fraction VI as
      detected by ELISA. Further studies were designed to investigate the capacity of
      these fractions to induce cell proliferation. It was demonstrated that fractions
      III and V (200 and 450 mM NaCl, respectively) stimulated a significant
      proliferative response of peripheral blood mononuclear cells, while fraction 0
      induced the lowest proliferative response among patients with PCM, in either
      acute, acute treated, or chronic forms.

PMID- 10602670
TI  - Antibiotics and Clostridium difficile.
AB  - Clostridium difficile is now established as a major nosocomial pathogen. C.
      difficile infection is seen almost exclusively as a complication of antibiotic
      therapy, and is particularly associated with clindamycin and third-generation
      cephalosporins. Depletion of the indigenous gut microflora by antibiotic therapy
      has long been established as a major factor in the disease. However, the direct
      influence of antimicrobials upon virulence mechanisms such as toxin production
      and adhesion in the bowel, and the exact mechanisms by which the organism causes
      disease remain to be elucidated.

PMID- 10602671
TI  - Molecular basis of defence against oxidative stress in Entamoeba histolytica and
      Giardia lamblia.
AB  - Gastrointestinal protozoa, viz. Entamoeba histolytica and Giardia, are able to
      survive in a microaerobic environment. The role of parasitic factors,
      particularly cysteine, cysteine-rich proteins, superoxide dismutase, and certain
      alternative mechanisms, has been described in the defence against oxidative
      stress. The role of the host-derived factors, particularly the phagocytosis of
      bacteria or host erythrocytes (intact or their enzymatic/non enzymatic
      components), in the detoxification of reactive oxygen metabolites in E.
      histolytica may provide novel approaches for the chemotherapy of invasive
      amoebiasis.

PMID- 10602672
TI  - Magic bullets need accurate guns--syphilis eradication, elimination, and control.
AB  - When cases of early syphilis are treated promptly, the spread of the bacteria
      within a population is interrupted. However, if complacency is induced by
      successful control, then upsurges in syphilis incidence can occur. The methods
      and aims of syphilis control in industrialised countries are reviewed in the
      light of the potential for regional elimination and global eradication
      programmes. While the medical means to eliminate syphilis are at hand, acceptable
      means for finding and treating cases that transmit infection need to be
      developed, particularly in the marginalized communities with limited access to
      care.

PMID- 10602673
TI  - Characterization of low-density lipoprotein uptake by murine macrophages exposed
      to Chlamydia pneumoniae.
AB  - Exposure to Chlamydia pneumoniae is correlated with atherosclerosis in a variety
      of clinical and epidemiological studies, but how the organism may initiate and
      promote the disease is poorly understood. One pathogenic mechanism could involve
      modulation of macrophage function by C. pneumoniae. We recently demonstrated that
      C. pneumoniae induces macrophages to accumulate excess cholesterol and develop
      into foam cells, the hallmark of early atherosclerotic lesions. To determine if
      C. pneumoniae-induced foam cell formation involved increased uptake of low
      density lipoprotein (LDL), the current study examined macrophage association of a
      fluorescent carbocyanine (DiI)-labeled LDL following infection. C. pneumoniae
      enhanced the association of DiI-LDL with macrophages in a dose-dependent manner
      with respect to both C. pneumoniae and DiI-LDL. Interestingly, increased
      association was inhibited by native LDL and occurred in the absence of oxidation
      byproducts and in the presence of antioxidants. However, enhanced DiI-LDL
      association occurred without the participation of the classical Apo B/E native
      LDL receptor, since C. pneumoniae increased DiI-LDL association and induced foam
      cell formation in macrophages isolated from LDL-receptor-deficient mice.
      Surprisingly, DiI-LDL association was inhibited not only by unlabeled native LDL
      but also by high-density lipoprotein, very low density lipoprotein, and oxidized
      LDL. These data indicate that exposure of macrophages to C. pneumoniae increases
      the uptake of LDL and foam cell formation by an LDL-receptor-independent
      mechanism.

PMID- 10602674
TI  - Expression and role of heat-shock protein 65 (HSP65) in macrophages during
      Trypanosoma cruzi infection: involvement of HSP65 in prevention of apoptosis of
      macrophages.
AB  - The 65-kDa heat-shock protein (HSP65) is thought to play a role in host defense
      against infections with various microbial pathogens and in autoimmune
      inflammatory disorders. We investigated the biological function and expression
      mechanism of HSP65 in macrophages of mice infected with Trypanosoma cruzi. BALB/c
      mice, which are susceptible to T. cruzi, showed high levels of parasitemia, and
      80% of these mice died within 42 days after the infection, whereas resistant
      C57BL/6 or DBA/2 mice showed low levels of transient parasitemia and all
      survived. HSP65 expression was correlated with resistance to T. cruzi infection;
      HSP65 was more strongly expressed in macrophages of resistant C57BL/6 and DBA/2
      mice than in macrophages of susceptible BALB/c mice. Immunodeficient BALB/c-nu/nu
      (nude) and C.B-17 scid/scid (SCID) mice were shown to be highly susceptible to
      this infection, and they did not express detectable levels of HSP65, suggesting
      that T cells play essential roles in the expression of HSP65 as well as in
      protective immunity against the infection. CD4(+) T cells, but not CD8(+) T cells
      or gammadelta T cells, were the cell population responsible for the induction of
      HSP65 expression in macrophages. Furthermore, depletion of asialo GM-1(+) NK
      cells made resistant C57BL/6 mice more susceptible to the infection, and HSP65
      expression in their macrophages was abolished. Semiquantitative reverse
      transcription PCR analyses showed that both interferon gamma (IFN-gamma) and
      tumor necrosis factor alpha (TNF-alpha) mRNA levels in CD4(+) T cells became low
      when resistant C57BL/6 mice were depleted of NK cells, suggesting that NK cells
      contribute to functional differentiation of CD4(+) T cells and thereby affect the
      induction of HSP65 expression. To determine the function of HSP65, macrophages
      were treated in vitro with antisense oligonucleotide for HSP65 prior to inducing
      HSP65 with IFN-gamma plus TNF-alpha or T. cruzi infection. This treatment did not
      affect the production of nitric oxide following activation, but the treated
      macrophages became susceptible to apoptosis. These results indicate that HSP65
      plays a role in preventing the apoptosis of macrophages and thereby contributes
      to host resistance against T. cruzi infection.

PMID- 10602675
TI  - The potential use of heat-shock proteins to vaccinate against mycobacterial
      infections.
AB  - Over the last few years, some of our experiments in which mycobacterial heat
      shock protein (HSP) antigens were presented to the immune system as if they were
      viral antigens have had a significant impact on our understanding of protective
      immunity against tuberculosis. They have also markedly enhanced the prospects for
      new vaccines. We now know that the mycobacterial HSP65 antigen can confer
      protection equal to that from live BCG vaccine in mice.

PMID- 10602676
TI  - The pathogenesis of Acanthamoeba keratitis.
AB  - Free-living amoebae of the genus Acanthamoeba produce a progressive, blinding
      infection of the corneal surface. The pathogenesis of Acanthamoeba keratitis
      involves parasite-mediated cytolysis and phagocytosis of corneal epithelial cells
      and induction of programmed cell death. Acanthamoeba spp. elaborate a variety of
      proteases which may facilitate cytolysis of the corneal epithelium, invasion of
      the extracellular matrix, and dissolution of the corneal stromal matrix.

PMID- 10602677
TI  - Probing the microenvironment of intracellular bacterial pathogens.
AB  - The identification of bacterial genes regulated in response to the intracellular
      environment is crucial to the understanding of host-pathogen interactions.
      Several techniques have been developed to identify and characterize bacterial
      genes that are induced during the intracellular infection and, potentially, may
      play a role in pathogenesis. This review discusses the strategies that have been
      utilized to examine differential gene expression by bacterial pathogens during
      the intracellular infection. Furthermore, a number of the differentially
      expressed genes are described.

PMID- 10602678
TI  - The epidemiology of Neisseria gonorrhoeae in Europe.
AB  - This review addresses the occurrence, the trends, and the risk groups of
      Neisseria gonorrhoeae in Europe over the past decade. A decline has been observed
      in most of Europe since the 1980s, except for an increase in the Baltic countries
      (early 1990s) and an increase among men who have sex with men (between 1989 and
      1991), and heterosexuals in some countries (between 1995 and 1997). Despite the
      overall fall in the incidence of gonorrhoea, plasmid-mediated resistance to
      penicillin and tetracycline increased in Europe. More recently, resistance to
      fluoroquinolones has been documented, mainly imported from Southeast Asia. Until
      now, no resistance to third-generation cephalosporins has been observed.

PMID- 10602679
TI  - Evolutionary genetics of Trypanosoma and Leishmania.
AB  - We review recent advances in the study of population structure and phylogenetic
      diversity of parasites belonging to the genera Trypanosoma and Leishmania. In all
      species properly analyzed, these parasites exhibit a basically clonal population
      structure, with occasional bouts of genetic exchange or hybridization, and a
      strong structuration of their populations into discrete evolutionary lineages. On
      an evolutionary scale, the impact of sex appears to be greater in African than in
      American trypanosomes. The taxonomic status of some Leishmania 'species' is
      questionable.

PMID- 10602680
TI  - Angus Reid poll finds Albertans believe health cuts have affected nursing care.

PMID- 10602681
TI  - Protecting vulnerable persons in care, Part II: Alberta Nurses and the Act.

PMID- 10602682
TI  - Review of telephone consults to the AARN practice area.

PMID- 10602683
TI  - Help stop one of Alberta's leading killers.

PMID- 10602684
TI  - Protecting vulnerable persons in care.

PMID- 10602685
TI  - Positional plagiocephaly: a community approach to prevention and treatment.

PMID- 10602686
TI  - [Air pollution by lead emitted from vehichles in the Dakar region].
AB  - The use of super carburant involves a lot of lead particles by the vehicles. This
      type of pollution specially affects the urban populations and the environment.
      This phenomenon is emphasized in the big cities like Dakar where more than 60% of
      the national car park move. This study shows that the trees can be used as
      indicator of lead pollution level. Unfortunately, the estimation of the pollution
      level isn't always easy whereas numerous factors can play a role in the
      mechanism. In this study, we have shown that the atmospheric pollution of Dakar
      by the muffler gases is a real fact.

PMID- 10602687
TI  - [Antibacterial activity of essential oils from mint in Senegal].
AB  - Three species of the Mentha gender are found in Senegal under the name of "Nana",
      and are essentially used in tea and juices as flavour. The aerial parts of the
      three species (common mint, mentholated mint and "fass" mint) have been harvested
      two months after they have been sown and the extraction of the essential oils was
      done by carrying them away with water vapour by hydrodistillation. The essential
      oils were used to study the antibacterial potency (typing of the Minimal
      Inhibitory concentrations-MIC) by the agar dilution method. This survey has been
      carried out on ten bacterial strains among which three (3) ATCC reference stubs,
      and on one fungus (Candida albicans). The MIC found was less than 25 mcg/ml;
      these results show an antibacterial potency according to the NCCLS norms (MIC <
      256 mcg/ml). The tested strains were more sensitive to the essential oil of the
      "common mint" than the "fass mint". Pseudomonas aeruginosa was the most resistant
      strain and Candida albicans the most sensitive agent.

PMID- 10602688
TI  - Neural mechanism generating firing patterns in jaw motoneurons during the food
      induced response in Aplysia kurodai. I. Identification and characterization of
      premotor neurons.
AB  - 1. In each right and left buccal ganglia of Aplysia kurodai, we identified 4
      premotor neurons impinging on the ipsilateral jaw-closing and -opening
      motoneurons. Three of them (MA1 neurons) had features of multifunctional neurons.
      Current-induced spikes in the MA1 neurons produced excitatory junction potentials
      (EJPs) in the buccal muscle fibers. In addition, tactile stimulation of the
      buccal muscle surface produced a train of spikes in the MA1 neurons without
      synaptic input. The other neuron (MA2) had only a premotor function. 2. The MA1
      and MA2 neurons had similar synaptic effects on the jaw-closing and -opening
      motoneurons. Current-induced spikes in the premotor neurons gave rise to
      monosynaptic inhibitory postsynaptic potentials (IPSPs) in the ipsilateral jaw
      closing motoneurons. Simultaneously, spikes in one of the MA1 neurons and the MA2
      also gave rise to monosynaptic excitatory postsynaptic potentials (EPSPs) in the
      ipsilateral jaw-opening motoneuron. 3. The IPSPs and the EPSPs induced by spikes
      in the premotor neurons were reversibly blocked by d-tubocurarine and
      hexamethonium, respectively, suggesting that the MA1 and MA2 neurons are
      cholinergic. 4. When depolarizing and hyperpolarizing current pulses were passed
      into one premotor neuron, attenuated but similar potential changes were produced
      in another randomly selected premotor neuron in the same ganglion, suggesting
      that they are electronically coupled.

PMID- 10602689
TI  - [Forceps, vacuum suction and cesarean section from the point of view of the
      neonatologist].

PMID- 10602690
TI  - Discovery of the first potent and selective small molecule opioid receptor-like
      (ORL1) antagonist: 1-[(3R,4R)-1-cyclooctylmethyl-3- hydroxymethyl-4-piperidyl]-3
      ethyl-1, 3-dihydro-2H-benzimidazol-2-one (J-113397).

PMID- 10602691
TI  - Alpha(2) adrenoceptor agonists as potential analgesic agents. 1.
      (Imidazolylmethyl)oxazoles and -thiazoles.
AB  - A series of (imidazolylmethyl)oxazoles and -thiazoles were prepared and evaluated
      as alpha(2) adrenoceptor agonists. These compounds were also tested in in vivo
      paradigms that are predictive of analgesic activity. Variations in both the
      imidazole and thiazole portions of the molecule were investigated. Some of the
      more potent compounds such as 22, 26, 45, and 53 displayed alpha(2) receptor
      binding in the 10-20 nM range and also had significant antinociceptive activity
      in the mouse abdominal irritant test (MAIT).

PMID- 10602692
TI  - Combining in vitro and in vivo pharmacokinetic data for prediction of hepatic
      drug clearance in humans by artificial neural networks and multivariate
      statistical techniques.
AB  - Several statistical regression models and artificial neural networks were used to
      predict the hepatic drug clearance in humans from in vitro (hepatocyte) and in
      vivo pharmacokinetic data and to identify the most predictive models for this
      purpose. Cross-validation was performed to assess prediction accuracy. It turned
      out that human hepatocyte data was the best predictor, followed by rat hepatocyte
      data. Dog hepatocyte data and dog and rat in vivo data appear to be uncorrelated
      with human in vivo clearance and did not significantly contribute to the
      prediction models. Considering the present evaluation, the most cost-effective
      and most accurate approach to achieve satisfactory predictions in human is a
      combination of in vitro clearances on human and rat hepatocytes. Such information
      is of considerable value to speed up drug discovery. This study also showed some
      of the limitations of the approach related to the size of the database used in
      the present evaluation.

PMID- 10602693
TI  - Synthesis and SAR of adatanserin: novel adamantyl aryl- and heteroarylpiperazines
      with dual serotonin 5-HT(1A) and 5-HT(2) activity as potential anxiolytic and
      antidepressant agents.
AB  - Several novel functionalized adamantyl aryl- and heteroarylpiperazine derivatives
      were prepared and examined in various receptor binding and behavioral tests to
      determine their serotonin receptor activities. Many compounds demonstrated modest
      to high affinity for 5-HT(1A) receptors, with compounds 9, 13, 23, 33, 34, and 43
      being the most potent at this site. Compound 1, 2-[4-(2-pyrimidinyl)-1
      piperazinyl]ethyl adamantyl-1-carboxylate, demonstrated relatively high affinity
      for 5-HT(1A) receptors (K(i) = 8 nM) and acceptable selectivity versus D(2)
      receptors (K(i) = 708 mM); however, it lacked in vivo activity in serotonergic
      behavioral models. In contrast, compounds 9 (WY-50,324, SEB-324, adatanserin),
      adamantyl-1-carboxylic acid 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethylamide, and
      13, adamantyl-1-carboxylic acid 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylamide,
      demonstrated high affinity for 5-HT(1A) binding sites (K(i) = 1 nM for both) and
      moderate affinity for 5-HT(2) receptors (K(i) = 73 and 75 nM, respectively). Both
      compounds also demonstrated partial 5-HT(1A) agonist activity in vivo in rat
      serotonin syndrome and 5-HT(2) antagonist activity in quipazine- and DOI-induced
      head shake paradigms. The selective 5-HT(1A) partial agonist and 5-HT(2)
      antagonist activity of 9 was accompanied by significant anxiolytic activity in an
      animal conflict model. On the basis of this profile, compound 9 entered
      development as a combined anxiolytic and antidepressant agent.

PMID- 10602694
TI  - Properties of known drugs. 2. Side chains.
AB  - We continue our study of the common features present in drug molecules by looking
      in detail at drug side chains. Using shape description methods, we divide a
      database of commercially available drugs into a list of common drug side chains.
      On the basis of the atom pair shape descriptor (taking into account atom type,
      hybridization, and bond order), there are 1,246 different side chains among the
      5,090 compounds analyzed. The average number of side chains per molecule is 4,
      and the average number of heavy atoms per side chain is 2. If we ignore the
      carbonyl side chain, then there are approximately 15,000 occurrences of side
      chains. Of these 15,000 approximately 11,000 are from the "top 20" group of side
      chains. This suggests that the diversity that side chains provide to drug
      molecules is quite low. We discuss ways that this work could be used to provide
      guidance for molecular design efforts.

PMID- 10602695
TI  - Consensus scoring: A method for obtaining improved hit rates from docking
      databases of three-dimensional structures into proteins.
AB  - We present the results of an extensive computational study in which we show that
      combining scoring functions in an intersection-based consensus approach results
      in an enhancement in the ability to discriminate between active and inactive
      enzyme inhibitors. This is illustrated in the context of docking collections of
      three-dimensional structures into three different enzymes of pharmaceutical
      interest: p38 MAP kinase, inosine monophosphate dehydrogenase, and HIV protease.
      An analysis of two different docking methods and thirteen scoring functions
      provides insights into which functions perform well, both singly and in
      combination. Our data shows that consensus scoring further provides a dramatic
      reduction in the number of false positives identified by individual scoring
      functions, thus leading to a significant enhancement in hit-rates.

PMID- 10602696
TI  - Predicting relative binding free energies of tacrine-huperzine A hybrids as
      inhibitors of acetylcholinesterase.
AB  - The binding of the 9-methyl derivative of tacrine-huperzine A hybrid to Torpedo
      californica acetylcholinesterase (AChE) has been studied by computational
      methods. Molecular dynamics simulations have been performed for the AChE-drug
      complex considering two different ionization states of the protein and two
      different orientations of the drug in the binding pocket, which were chosen from
      a previous screening procedure. Analysis of structural fluctuations and of the
      pattern of interactions between drug and enzyme clearly favor one binding mode
      for the tacrine-huperzine A hydrid, which mixes effectively some of the binding
      features of tacrine and huperzine A. The differences in inhibitory activity for a
      series of related derivatives have been successfully predicted by free energy
      calculations, which reinforces the confidence in the binding mode and its
      usefulness for molecular modeling studies. The same techniques have been used to
      make de novo predictions for a new 3-fluoro-9-ethyl derivative, which can be used
      to verify a posteriori the goodness of the binding mode. Finally, we have also
      investigated the effect of replacing Phe300 in the Torpedo californica enzyme by
      Tyr, which is present in the human AChE. The results indicate that the Phe330-
      >Tyr mutation is expected to have little effect on the binding affinities.
      Overall, the whole of results supports the validity of the putative binding model
      to explain the binding of tacrine-huperzine A hybrids to AChE.

PMID- 10602697
TI  - Design, synthesis, and evaluations of substituted 3-[(3- or 4-carboxyethylpyrrol
      2-yl)methylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGF receptor
      tyrosine kinases.
AB  - Receptor tyrosine kinases (RTKs) have been implicated as therapeutic targets for
      the treatment of human diseases including cancers, inflammatory diseases,
      cardiovascular diseases including arterial restenosis, and fibrotic diseases of
      the lung, liver, and kidney. Three classes of 3-substituted indolin-2-ones
      containing propionic acid functionality attached to the pyrrole ring at the C-3
      position of the core have been identified as catalytic inhibitors of the vascular
      endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet
      derived growth factor (PDGF) RTKs. Some of the compounds were found to inhibit
      the tyrosine kinase activity associated with isolated vascular endothelial growth
      factor receptor 2 (VEGF-R2) [fetal liver tyrosine kinase 1 (Flk-1)/kinase insert
      domain-containing receptor (KDR)], fibroblast growth factor receptor (FGF-R), and
      platelet-derived growth factor receptor (PDGF-R) tyrosine kinase with IC(50)
      values at nanomolar level. Thus, compound 1 showed inhibition against VEGF-R2
      (Flk-1/KDR) and FGF-R1 tyrosine kinase activity with IC(50) values of 20 and 30
      nM, respectively, while compound 16f inhibited the PDGF-R tyrosine kinase
      activity with IC(50) value of 10 nM. Structural models and structure-activity
      relationship analysis of these compounds for the target receptors are discussed.
      The cellular activities of these compounds were profiled using cellular
      proliferation assays as measured by bromodeoxyuridine (BrdU) incorporation.
      Specific and potent inhibition of cell growth was observed for some of these
      compounds. These data provide evidence that these compounds can be used to
      inhibit the function of these target receptors.

PMID- 10602698
TI  - Synthesis, in vitro antiproliferative activity, and DNA-binding properties of
      hybrid molecules containing pyrrolo[2,1-c][1, 4]benzodiazepine and minor-groove
      binding oligopyrrole carriers.
AB  - The synthesis, biological activity, and DNA-binding properties of a series of
      four hybrids prepared by combining polypyrrole minor groove binders and
      pyrrolo[2,1-c][1,4]benzodiazepine (PBD) 13, related to the naturally occurring
      anthramycin (3) and DC-81 (4), have been described, and structure-activity
      relationships have been discussed. These hybrids 22-25 contain from one to four
      pyrrole units, respectively. To investigate sequence selectivity and stability of
      drug/DNA complexes, DNase I footprinting and arrested polymerase chain reaction
      (PCR) were performed on human c-myc oncogene, estrogen receptor gene, and human
      immunodeficiency virus type 1 long terminal repeat (HIV-1 LTR) gene sequences.
      The antiproliferative activity of the hybrids has been tested in vitro on human
      myeloid leukemia K562 and T-lymphoid Jurkat cell lines and compared to
      antiproliferative effects of the natural product distamycin A 1, its tetrapyrrole
      homologue 17, DC 81 (4), and the PBD methyl ester 12. The results obtained
      demonstrate that the hybrids 22-25 exhibit different DNA-binding activity with
      respect to both distamycin A 1 and PBD 12. In addition, a direct relationship was
      found between number of pyrrole rings present in the hybrids 22-25 and stability
      of drug/DNA complexes. With respect to antiproliferative effects, it was found
      that the increase in the length of the polypyrrole backbone leads to an increase
      of in vitro antiproliferative effects, i.e., the hybrid 25 containing the four
      pyrroles is more active than 22, 23, and 24 both against K562 and Jurkat cell
      lines.

PMID- 10602699
TI  - Binding constants of neuraminidase inhibitors: An investigation of the linear
      interaction energy method.
AB  - The linear interaction energy (LIE) method has been applied to the calculation of
      the binding free energies of 15 inhibitors of the enzyme neuraminidase. This is a
      particularly challenging system for this methodology since the protein
      conformation and the number of tightly bound water molecules in the active site
      are known to change for different inhibitors. It is not clear that the basic LIE
      method will calculate the contributions to the binding free energies arising from
      these effects correctly. Application of the basic LIE equation yielded an rms
      error with respect to experiment of 1.51 kcal mol(-1) for the free energies of
      binding. To determine whether it is appropriate to include extra terms in the LIE
      equation, a detailed statistical analysis was undertaken. Multiple linear
      regression (MLR) is often used to determine the significance of terms in a
      fitting equation; this method is inappropriate for the current system owing to
      the highly correlated nature of the descriptor variables. Use of MLR in other
      applications of the LIE equation is therefore not recommended without a
      correlation analysis being performed first. Here factor analysis was used to
      determine the number of useful dimensions contained within the data and, hence,
      the maximum number of variables to be considered when specifying a model or
      equation. Biased fitting methods using orthogonalized components were then used
      to generate the most predictive model. The final model gave a q(2) of 0.74 and
      contained van der Waals and electrostatic energy terms. This result was obtained
      without recourse to prior knowledge and was based solely on the information
      content of the data.

PMID- 10602700
TI  - Abasic site recognition in DNA as a new strategy to potentiate the action of
      anticancer alkylating drugs?
AB  - Inhibition of abasic site repair in the cell seems an attractive strategy to
      potentiate the action of antitumor DNA alkylating drugs. Molecules that bind
      specifically and strongly to the abasic site are possible candidates to achieve
      such inhibition. We explored this strategy by preparing molecule 4 that
      incorporates (1) an aminoacridine intercalator for DNA binding, (2) an adenine
      moiety for abasic site recognition, and (3) a linker containing two guanidinium
      functions to increase binding to DNA without inducing cleavage at the base
      sensitive abasic site. Compound 4 was compared to analogues containing secondary
      amines, i.e., 1. We report on synthesis of the new heterodimer 4. We show by
      physicochemical studies-including determination of association constants with
      calf-thymus DNA, T(m) measurements, and high-field NMR examination of the
      complexes formed with abasic DNA duplexes-that 4 binds specifically and more
      strongly to the abasic site than the analogues. Compound 4 does not cleave abasic
      plasmid DNA. Compound 4 shows apparent synergy with the anticancer
      bischloroethylnitrosourea (BCNU) in L1210 and A549 cell lines in vitro. It
      potentiates BCNU in the in vivo tests. The results favor the pertinence of the
      strategy.

PMID- 10602701
TI  - Quantitative structure-metabolism relationships: steric and nonsteric effects in
      the enzymatic hydrolysis of noncongener carboxylic esters.
AB  - An attempt to quantitatively describe human blood in vitro hydrolysis data for
      more than 80 compounds belonging to seven different noncongener series of ester
      containing drugs is presented. A parameter not yet explored in pharmaceutical
      studies, the inaccessible solid angle Omega(h), calculated around different atoms
      was used as a measure of steric hindrance, and the steric hindrance around the
      carbonyl sp(2) oxygen (Omega(h)(O=)) proved the most relevant parameter. The
      obtained final equation, log t(1/2) = -3.805 + 0.172Omega(h)(O=) - 10.146q(C=) +
      0.112QLogP, also includes the AM1-calculated charge on the carbonyl carbon
      (q(C=)) and a calculated log octanol-water partition coefficient (QLogP) as
      parameters and accounts for 80% of the variability in the log half-lives of 67
      compounds. A number of structures are still mispredicted, but the equation agrees
      very well with a recently proposed mechanism for hydrolysis by carboxylesterases.
      The model, with a predictive power tested here on three unrelated structures,
      should be useful in estimating approximate rates of hydrolysis for prodrug or
      soft drug candidates ahead of their synthesis.

PMID- 10602702
TI  - Simple linear QSAR models based on quantum similarity measures.
AB  - A novel QSAR approach based on quantum similarity measures was developed and
      tested in this paper. This approach consists of replacing the usual
      physicochemical parameters employed in QSAR analysis, such as octanol-water
      partition coefficient or Hammett sigma constant, by appropriate quantum chemical
      descriptors. The methodological basis for this substitution is found in recent
      theoretical studies [J. Comput. Chem. 1998, 19, 1575-1583, J. Comput. -Aided Mol.
      Des. 1999, 13, 259-270], in which it was demonstrated that both molecular
      hydrophobic character and electronic substituent effect can be modeled by
      appropriately chosen quantum self-similarity measures (QS-SM). The most important
      aim of this study was to prove that selected QS-SM descriptors can be
      advantageously used in empirical QSAR analysis instead of classical descriptors.
      For this purpose several QSAR correlations are proposed, in which empirical
      descriptors such as Hammett sigma constants or log P values are replaced by the
      appropriate QS-SM. These examples involve: (i) a set of benzenesulfonamides which
      bind to human carbonic anhydrase, (ii) a set of benzylamines as competitive
      inhibitors of the enzyme trypsin, and (iii) a set of indole derivatives which are
      benzodiazepine receptor inverse agonist site ligands. Simple linear QSAR models
      were developed in order to obtain mathematical relationships between the
      biological activity and the pertinent quantum chemical descriptors. The validity
      of the obtained QSAR models is supported by comparison of the observed and
      predicted values of the biological activity and by a statistical analysis based
      on a randomization test.

PMID- 10602703
TI  - A series of 6- and 7-piperazinyl- and -piperidinylmethylbenzoxazinones with
      dopamine D4 antagonist activity: discovery of a potential atypical antipsychotic
      agent.
AB  - As part of a program to develop dopamine D4 antagonists for the treatment of
      schizophrenia, we discovered a series of 6- and 7-(phenylpiperazinyl)- and 
      (phenylpiperidinyl)methylbenzoxazinones through mass screening of our compound
      library. A structure-activity relationship SAR study was carried out involving
      substituents on the phenyl ring, and several selective D4 antagonists were
      identified. The 7-substituted benzoxazinones showed more activity in
      neurochemical and behavioral tests than the 6-substituted series. One of the most
      potent and selective compounds (26) was found to have potent activity in animal
      tests predictive of antipsychotic activity in humans after oral administration.
      This paper describes the SAR of the benzoxazinone series and the preclinical
      characterization of 26.

PMID- 10602704
TI  - Potential multifunctional inhibitors of HIV-1 reverse transcriptase. Novel [AZT]
      [TSAO-T] and [d4T]-[TSAO-T] heterodimers modified in the linker and in the
      dideoxynucleoside region.
AB  - In an attempt to combine the anti-HIV-inhibitory capacity of nucleoside reverse
      transcriptase (RT) inhibitors (NRTI) and non-nucleoside RT inhibitors (NNRTI),
      several heterodimer analogues of the previously reported [AZT]-(CH(2))(3)-[TSAO
      T] prototype have been prepared. In these novel series, other NRTIs, an expanded
      range of linkers with different conformational freedom and other attachment sites
      for these linkers on the base part of the NRTI analogue have been explored.
      Moreover, in order to circumvent the dependence of the NRTI moiety of the
      heterodimer on activation by cellular nucleoside kinases, novel heterodimers in
      which the NRTI is bearing a masked monophosphate group at the 5'-position are
      described. Among the novel heterodimers, several derivatives show a potent anti
      HIV-1 activity, which proved comparable, or even superior, to that of the AZT
      heterodimer prototype. The nature of the NRTI was important for the eventual anti
      HIV-1 activity. In particular, the d4T heterodimer derivative containing a propyl
      linker between the N-3 positions of the base of TSAO-T and d4T was approximately
      5- to 10-fold more inhibitory to HIV-1 than the corresponding AZT heterodimer
      prototype.

PMID- 10602705
TI  - Investigation of subsite preferences in aminopeptidase A (EC 3.4.11.7) led to the
      design of the first highly potent and selective inhibitors of this enzyme.
AB  - The study of the physiological roles of the membrane-bound zinc-aminopeptidase A
      (glutamyl aminopeptidase, EC 3.4.11.7) needs the design of efficient and
      selective inhibitors of this enzyme. An acute exploration of aminopeptidase A
      active site was performed by a combinatorial approach using (3-amino-2-mercapto
      acyl)dipeptides able to fit its S(1), S(1)', and S(2)' subsites. This analysis
      confirmed that the S(1) subsite is optimally blocked by a glutamate or isosteric
      residues and demonstrated that the S(1)' subsite is hydrophobic whereas the S(2)'
      subsite recognizes preferentially negatively charged residues derived from
      aspartic acid. The optimization of these structural parameters led to the
      synthesis of nanomolar and subnanomolar inhibitors of aminopeptidase A such as
      H(3)N(+)CH(CH(2)CH(2)SO(3)(-))CH(SH)CO-Ile-(3-COOH)Pro that exhibits a K(i) of
      0.87 nM. The best compounds were synthesized by a stereochemically controlled
      route. These first described highly potent inhibitors could allow studies about
      the role of physiological substrates of APA such as angiotensin II and
      cholecystokinin CCK(8) in the central nervous system.

PMID- 10602706
TI  - Design, synthesis, and biological evaluation of symmetrically and unsymmetrically
      substituted methoctramine-related polyamines as muscular nicotinic receptor
      noncompetitive antagonists.
AB  - The universal template approach to drug design foresees that a polyamine can be
      modified in such a way to recognize any neurotransmitter receptor. Thus, hybrids
      of polymethylene tetraamines and philanthotoxins, exemplified by methoctramine
      (1) and PhTX-343 (2), respectively, were synthesized to produce novel inhibitors
      of muscular nicotinic acetylcholine receptors. Polyamines 3-25 were synthesized
      and their biological profiles were evaluated at frog rectus abdominis muscle
      nicotinic receptors and guinea pig left atria (M(2)) and ileum longitudinal
      muscle (M(3)) muscarinic acetylcholine receptors. All of the compounds, like
      prototypes 1 and 2, were noncompetitive antagonists of nicotinic receptors while
      being, like 1, competitive antagonists at muscarinic M(2) and M(3) receptor
      subtypes. Interestingly, polyamines bearing a low number of methylenes between
      the nitrogen atoms, as in 3, 6, and 7, displayed a biological profile similar to
      that of 2: a noncompetitive antagonism at nicotinic receptors in the 7-25 microM
      range while not showing any antagonism for muscarinic receptors up to 10 microM.
      Increasing the number of methylenes separating these nitrogen atoms in
      methoctramine-related tetraamines resulted in a significant improvement in
      potency at nicotinic receptors. The most potent tetraamine was 19, bearing a 12
      methylene spacer between the nitrogen atoms, which was 12-fold and 250-fold more
      potent than prototypes 1 and 2, respectively. Tetraamines 9-11, bearing a rather
      rigid spacer between the nitrogen atoms instead of the very flexible
      polymethylene chain, displayed a profile similar to that of 1 at nicotinic
      receptors, whereas a significant decrease in potency was observed at muscarinic
      M(2) receptors. This finding may have relevance in understanding the mode of
      interaction with these receptors. Similarly, the constrained analogue 12 of
      methoctramine showed a decrease in potency at nicotinic and muscarinic M(2)
      receptors, revealing that the tricyclic system, which incorporates the 2
      methoxybenzylamine moiety of 1, does not represent a good pharmacophore for
      activity at these sites. A most intriguing finding was the observation that the
      photolabile tetraamine 22 was more potent than methoctramine at nicotinic
      receptors and, what is more important, it inhibited a closed state of the
      receptor.

PMID- 10602707
TI  - Analogues of neuroactive polyamine wasp toxins that lack inner basic sites
      exhibit enhanced antagonism toward a muscle-type mammalian nicotinic
      acetylcholine receptor.
AB  - Philanthotoxin-433 (PhTX-433), a natural polyamine wasp toxin, is a
      noncompetitive antagonist of certain ionotropic receptors. Six analogues of PhTX
      343 (a synthetic analogue of the natural product), in which the secondary amino
      groups are systematically replaced by oxygen or methylene groups, have been
      synthesized by coupling of N-(1-oxobutyl)tyrosine with 1,12-dodecanediamine, 4,9
      dioxa-1, 12-dodecanediamine, or appropriately protected di- and triamines, the
      latter being obtained by multistep syntheses. The resulting PhTX-343 analogues
      were purified and characterized, and their protolytic properties (stepwise
      macroscopic pK(a) values) were determined by (13)C NMR titrations. All analogues
      are fully protonated at physiological pH. The effects of these compounds on
      acetylcholine-induced currents in TE671 cells clamped at various holding
      potentials were determined. All of the analogues noncompetitively antagonized the
      nicotinic acetylcholine receptor (nAChR) in a concentration-, time-, and voltage
      dependent manner. The amplitudes of acetylcholine-induced currents were compared
      at their peaks and at the end of a 1 s application in the presence or absence of
      the analogues. Most of the analogues were equipotent with or more potent than
      PhTX-343. The dideaza analogue PhTX-12 [IC(50) of 0.3 microM (final current
      value)] was the most potent, representing the highest potency improvement (about
      50-fold) yet achieved by modification of the parent compound (PhTX-343). Thus,
      the presence of multiple positive charges in the PhTX-343 molecule is not
      necessary for antagonism of nAChR. In contrast, the compounds were much less
      potent than PhTX-343 at locust muscle ionotropic glutamate receptors sensitive to
      quisqualate (qGluR). The results demonstrate that the selectivity for different
      types of ionotropic receptors can be achieved by manipulating the polyamine
      moiety of PhTX-343.

PMID- 10602708
TI  - New quaternary ammonium oxicam derivatives targeted toward cartilage: synthesis,
      pharmacokinetic studies, and antiinflammatory potency.
AB  - Analogues of nonsteroidal antiinflammatory drugs (NSAIDs) oxicams, in which the
      active group was linked to a quaternary ammonium function [(4-hydroxy-2-methyl-2H
      1,2-benzothiazine-1, 1-dioxide-3-carboxamido)2-methylpyridinium iodide or
      piroxicam-N(+) and [3-(4-hydroxy-2-methyl-2H-1,2-benzothiazine-1, 1-dioxide-3
      carboxamido)propyl]trimethylammonium iodide or propoxicam-N(+)] were synthesized.
      Compounds were labeled with tritium for piroxicam-N(+) and carbon-14 for
      propoxicam-N(+). Pharmacokinetic studies conducted on rats showed that these
      molecules were able to highly concentrate in joint cartilages but their
      bioavailability by the oral way was low. Only propoxicam-N(+) exhibited a
      sufficient water solubility to be administered intravenously. This molecule was
      able to restore proteoglycans biosynthesis in cultured articular chondrocytes
      treated with Interleukin-1beta with an efficiency identical to that of
      indomethacin. These results suggest that the functionalization of oxicam
      derivatives by a quaternary ammonium group greatly increases their affinity
      toward articular cartilage without eliminating their pharmacological activity.
      New drugs synthesized according to this scheme could be useful to obtain a
      significant decrease of the efficient administered dose and consequently an
      attenuation of adverse effects such as digestive toxicity.

PMID- 10602709
TI  - Discovery and structure-activity relationships of imidazole-containing
      tetrahydrobenzodiazepine inhibitors of farnesyltransferase.
AB  - 2,3,4,5-Tetrahydro-1-(imidazol-4-ylalkyl)-1,4-benzodiazepines were found to be
      potent inhibitors of farnesyltransferase (FT). A hydrophobic substituent at the 4
      position of the benzodiazepine, linked via a hydrogen bond acceptor, was
      important to enzyme inhibitory activity. An aryl ring at position 7 or a
      hydrophobic group linked to the 8-position through an amide, carbamate, or urea
      linkage was also important for potent inhibition. 2,3,4, 5-Tetrahydro-1-(1H
      imidazol-4-ylmethyl)-7-(4-pyridinyl)-4-[2-(t rifluo romethoxy)benzoyl]-1H-1,4
      benzodiazepine (36), with an FT IC(50) value of 24 nM, produced 85% phenotypic
      reversion of Ras transformed NIH 3T3 cells at 1.25 microM and had an EC(50) of
      160 nM for inhibition of anchorage-independent growth in soft agar of H-Ras
      transformed Rat-1 cells. Selected analogues demonstrated ip antitumor activity
      against an ip Rat-1 tumor in mice.

PMID- 10602710
TI  - Potent, orally active GPIIb/IIIa antagonists containing a nipecotic acid subunit.
      Structure-activity studies leading to the discovery of RWJ-53308.
AB  - Although intravenously administered antiplatelet fibrinogen receptor (GPIIb/IIIa)
      antagonists have become established in the acute-care clinical setting for the
      prevention of thrombosis, orally administered drugs for chronic use are still
      under development. Herein, we present details from our exploration of structure
      activity surrounding the prototype fibrinogen receptor antagonist RWJ-50042
      (racemate of 1), which was derived from a unique approach involving the gamma
      chain of fibrinogen (Hoekstra et al. J. Med. Chem. 1995, 38, 1582). Our analogue
      studies culminated in the discovery of RWJ-53308 (2), a potent, orally active
      GPIIb/IIIa antagonist. To progress from RWJ-50042 to a suitable candidate for
      clinical development, we conducted a series of optimization cycles that employed
      solid-phase parallel synthesis for the rapid, efficient preparation of nearly 250
      analogues, which were assayed for fibrinogen receptor affinity and inhibition of
      platelet aggregation induced by four different activators. This strategy produced
      several promising analogues for advanced study, including 3-(3,4
      methylenedioxybenzene)-beta-amino acid analogue 3 (significant improved in vivo
      potency) and 3-(3-pyridyl)-beta-amino acid 2 (significantly improved potency,
      oral absorption, and duration of action). In dogs, 2 displayed significant ex
      vivo antiplatelet activity on oral administration at 1.0 mg/kg, 16% systemic oral
      bioavailability, minimal metabolic transformation, and an excellent safety
      profile. Additionally, 2 was found to be efficacious in three in vivo thrombosis
      models: canine arteriovenous (AV) shunt (0.01-0.1 mg/kg, iv), guinea pig
      photoactivation-induced injury (0.3-3 mg/kg, iv), and guinea pig ferric chloride
      induced injury (0.3-1 mg/kg, iv). On the basis of its noteworthy preclinical
      data, RWJ-53308 (2) was selected for clinical evaluation.

PMID- 10602711
TI  - Vasorelaxation by new hybrid compounds containing dihydropyridine and pinacidil
      like moieties.
AB  - The synthesis and pharmacological properties of a novel type of vasorelaxant
      hybrid compounds are described. The investigated compounds originate from
      fluorinated 4-aryl-1,4-dihydropyridines, which are known calcium channel
      blockers, and/or from fluorinated analogues of pinacidil, which is an opener of
      ATP-sensitive potassium channels. In particular, we studied the most potent
      hybrid, 2,6-dimethyl-3,5-dicarbomethoxy-4-(2-difluoromethoxy-5-N-(N' '-cyano-N'
      1,2,2-trimethyl-propylguanidyl)-phenyl)-1, 4-dihydropyridine (4a), together with
      its parent compounds, the dihydropyridine 1b and the pinacidil analogue 3. In
      isolated rat mesenteric arteries, micromolar concentrations of 4a relaxed
      contractions exerted by K(+)-depolarization or by norepinephrine. The latter
      effect was sensitive to the potassium channel blocker glibenclamide. Micromolar
      4a also inhibited [(3)H](+)-isradipine and [(3)H]P1075 binding to rat cardiac
      membranes, and it blocked L-type calcium channels expressed in a mammalian cell
      line. The respective parent compounds 1b and 3 were always more potent and more
      selective regarding calcium channel or potassium channel interaction,
      respectively. In contrast, 4a combined both effects within the same concentration
      range, indicating that it may represent a lead structure for a novel class of
      pharmacological hybrid compounds.

PMID- 10602712
TI  - N-deacetyl-N-aminoacylthiocolchicine derivatives: synthesis and biological
      evaluation on MDR-positive and MDR-negative human cancer cell lines.
AB  - A new series of N-deacetyl-N-(N-trifluoroacetylaminoacyl)thiocolchicine
      derivatives 9-15 have been synthesized starting from the corresponding N
      deacetylthiocolchicine (3) and the N-trifluoroacetylamino acids 5-8 which were
      used as a racemic mixture. The trifluoroacetyl protecting group has been removed
      easily, giving the corresponding N-deacetyl-N-aminoacylthiocolchicines 16-22.
      Optical pure compounds 9-22 were isolated from the diastereoisomeric mixture or
      were prepared starting from compound 3 and an optical pure amino acid derivative;
      the configuration of each compound was assigned unequivocally. The
      diastereoisomeric couples of amino acids synthesized were tested, and their
      antiproliferative activity on MDR-positive and MDR-negative human cancer cell
      lines was evaluated.

PMID- 10602713
TI  - Synthesis and biological evaluation of novel prodrugs of anthracyclines for
      selective activation by the tumor-associated protease plasmin.
AB  - New prodrugs of daunorubicin and doxorubicin designed for selective activation by
      the serine protease plasmin are described. The low toxic prodrugs 3, 4, and 5 are
      converted to the corresponding cytotoxic drugs upon proteolysis by the tumor
      associated protease plasmin. Application of a self-eliminating spacer was
      essential for enzyme activation. A prodrug containing a chloro-substituted spacer
      was synthesized with the aim of enhancing the rate of conversion by plasmin. All
      prodrugs were highly stable in buffer solution and in serum and on the average 15
      fold less cytotoxic than the parent drugs in seven human tumor cell lines. A
      marked in vitro selectivity was demonstrated by incubation of the doxorubicin
      prodrugs with a plasmin generating MCF-7 breast cancer cell line transfected with
      urokinase-type plasminogen activator (u-PA) in comparison with the nontransfected
      nonplasmin generating cell line. Prodrugs 4 and 5 showed the same cytotoxic
      effect as the free parent drug doxorubicin in the u-PA transfected cells,
      indicating complete conversion of the prodrug by plasmin. Addition of the plasmin
      inhibitor Trasylol drastically increased the ID(50) values in the u-PA
      transfected MCF-7 cells for both prodrugs 4 and 5.

PMID- 10602714
TI  - Genetic-biochemical analysis and distribution of the Ambler class A beta
      lactamase CME-2, responsible for extended-spectrum cephalosporin resistance in
      Chryseobacterium (Flavobacterium) meningosepticum.
AB  - In vitro synergy between extended-spectrum cephalosporins and either clavulanic
      acid or cefoxitin was found for Chryseobacterium meningosepticum isolates during
      a double-disk assay on an agar plate. An extended-spectrum beta-lactamase (ESBL)
      gene from a C. meningosepticum clinical isolate was cloned and expressed in
      Escherichia coli DH10B. Its protein conferred resistance to most beta-lactams
      including extended-spectrum cephalosporins but not to cephamycins or to imipenem.
      Its activity was strongly inhibited by clavulanic acid, sulbactam, and
      tazobactam, as well as by cephamycins and imipenem. Sequence analysis of the
      cloned DNA fragment revealed an open reading frame (ORF) of 891 bp with a G+C
      content of 33.9%, which lies close to the expected range of G+C contents of
      members of the Chryseobacterium genus. The ORF encoded a precursor protein of 297
      amino acids, giving a mature protein with a molecular mass of 31 kDa and a pI
      value of 9.2 in E. coli. This gene was very likely chromosomally located. Amino
      acid sequence comparison showed that this beta-lactamase, named CME-2 (C.
      meningosepticum ESBL), is a novel ESBL of the Ambler class A group (Bush
      functional group 2be), being weakly related to other class A beta-lactamases. It
      shares only 39 and 35% identities with the ESBLs VEB-1 from E. coli MG-1 and CBL
      A from Bacteroides uniformis, respectively. The distribution of bla(CME-2) among
      unrelated C. meningosepticum species isolates showed that bla(CME-2)-like genes
      were found in the C. meningosepticum strains studied but were absent from strains
      of other C. meningosepticum-related species. Each C. meningosepticum strain
      produced at least two beta-lactamases, with one of them being a noninducible
      serine ESBL with variable pIs ranging from 7.0 to 8.5.

PMID- 10602715
TI  - Ineffectiveness of topoisomerase mutations in mediating clinically significant
      fluoroquinolone resistance in Escherichia coli in the absence of the AcrAB efflux
      pump.
AB  - Fluoroquinolone-resistant mutants, selected from a wild-type Escherichia coli K
      12 strain and its Mar mutant by exposure to increasing levels of ofloxacin on
      solid medium, were analyzed by Northern (RNA) blot analysis, sequencing, and
      radiolabelled ciprofloxacin accumulation studies. Mutations in the target gene
      gyrA (DNA gyrase), the regulatory gene marR, and additional, as yet unidentified
      genes (genes that probably affect efflux mediated by the multidrug efflux pump
      AcrAB) all contributed to fluoroquinolone resistance. Inactivation of the acrAB
      locus made all strains, including those with target gene mutations,
      hypersusceptible to fluoroquinolones and certain other unrelated drugs. These
      studies indicate that, in the absence of the AcrAB pump, gyrase mutations fail to
      produce clinically relevant levels of fluoroquinolone resistance.

PMID- 10602716
TI  - Effects of atovaquone and diospyrin-based drugs on ubiquinone biosynthesis in
      Pneumocystis carinii organisms.
AB  - The naphthoquinone atovaquone is effective against Plasmodium and Pneumocystis
      carinii carinii. In Plasmodium, the primary mechanism of drug action is an
      irreversible binding to the mitochondrial cytochrome bc(1) complex as an analog
      of ubiquinone. Blockage of the electron transport chain ultimately inhibits de
      novo pyrimidine biosynthesis since dihydroorotate dehydrogenase, a key enzyme in
      pyrimidine biosynthesis, is unable to transfer electrons to ubiquinone. In the
      present study, the effect of atovaquone was examined on Pneumocystis carinii
      carinii coenzyme Q biosynthesis (rather than electron transport and respiration)
      by measuring its effect on the incorporation of radiolabeled p-hydroxybenzoate
      into ubiquinone in vitro. A triphasic dose-response was observed, with inhibition
      at 10 nM and then stimulation up to 0.2 microM, followed by inhibition at 1
      microM. Since other naphthoquinone drugs may also act as analogs of ubiquinone,
      diospyrin and two of its derivatives were also tested for their effects on
      ubiquinone biosynthesis in P. carinii carinii. In contrast to atovaquone, these
      drugs did not inhibit the incorporation of p-hydroxybenzoate into P. carinii
      carinii ubiquinone.

PMID- 10602717
TI  - Therapeutic efficacy of human macrophage colony-stimulating factor, used alone
      and in combination with antifungal agents, in mice with systemic Candida albicans
      infection.
AB  - We examined the in vivo activity of human macrophage colony-stimulating factor
      (hM-CSF) against lethal Candida albicans infection in mice. In C. albicans
      infected mice which had been immunosuppressed with cyclophosphamide, treatment
      with hM-CSF at a daily dose of 8 x 10(5) units/kg of body weight or greater
      slightly but significantly prolonged survival. Furthermore, the therapeutic
      efficacy of amphotericin B (AMPH-B) in infected mice was enhanced by its combined
      use with hM-CSF, while that of fluconazole (FLCZ) was not. The activities of
      peritoneal macrophages and neutrophils from mice administered hM-CSF plus AMPH-B
      in combination for inhibition of hyphal growth of C. albicans cells and
      intracellular phagocytosis and killing of the cells were greater than those of
      comparable phagocytic cells from control mice to which hM-CSF plus AMPH-B was not
      administered. These results suggest that intravenous administration of hM-CSF
      augments the efficacy of AMPH-B by enhancing the antifungal activities of
      macrophages and neutrophils. Therefore, it is expected that therapy with the
      combination AMPH-B and hM-CSF could improve the efficacy of AMPH-B and reduce the
      therapeutic dose of the antifungal drug that is required.

PMID- 10602718
TI  - MICs of mutacin B-Ny266, nisin A, vancomycin, and oxacillin against bacterial
      pathogens.
AB  - Peptide antibiotics, particularly lantibiotics, are good candidates for replacing
      antibiotics to which bacteria have become resistant. In order to compare two such
      lantibiotics with two antibiotics, the MICs of nisin A, mutacin B-Ny266,
      vancomycin, and oxacillin against various bacterial pathogens were determined.
      The results indicate that nisin A and mutacin B-Ny266 are as active as vancomycin
      and oxacillin against most of the strains tested. Furthermore, mutacin B-Ny266
      remains active against strains that are resistant to nisin A, oxacillin, or
      vancomycin. The wide spectrum of activity of mutacin B-Ny266, its low MICs
      against bacterial pathogens, and its activity against bacteria resistant to other
      inhibitors support the development of this substance for therapeutic use.

PMID- 10602719
TI  - Efficacies of topical formulations of foscarnet and acyclovir and of 5-percent
      acyclovir ointment (Zovirax) in a murine model of cutaneous herpes simplex virus
      type 1 infection.
AB  - The topical efficacies of foscarnet and acyclovir incorporated into a
      polyoxypropylene-polyoxyethylene polymer were evaluated and compared to that of
      5% acyclovir ointment (Zovirax) by use of a murine model of cutaneous herpes
      simplex virus type 1 infection. All three treatments given three times daily for
      4 days and initiated 24 h after infection prevented the development of the
      zosteriform rash in mice. The acyclovir formulation and the acyclovir ointment
      reduced the virus titers below detectable levels in skin samples from the
      majority of mice, whereas the foscarnet formulation has less of an antiviral
      effect. Reducing the number of treatments to a single application given 24 h
      postinfection resulted in a significantly higher efficacy of the formulation of
      acyclovir than of the acyclovir ointment. Acyclovir incorporated within the
      polymer was also significantly more effective than the acyclovir ointment when
      treatment was initiated on day 5 postinfection. The higher efficacy of the
      acyclovir formulation than of the acyclovir ointment is attributed to the
      semiviscous character of the polymer, which allows better penetration of the drug
      into the skin.

PMID- 10602720
TI  - Aminoglycoside resistance in Mycobacterium kansasii, Mycobacterium avium-M.
      intracellulare, and Mycobacterium fortuitum: are aminoglycoside-modifying enzymes
      responsible?
AB  - Aminoglycoside acetyltransferase was detected in Mycobacterium kansasii and M.
      fortuitum but not in M. avium-M. intracellulare when they were screened by a
      radioassay. Aminoglycoside phosphotransferase and nucleotidyltransferase
      activities were absent from all three species tested. Acetyltransferases from
      both M. kansasii and M. fortuitum displayed relatively high K(m)s, all at the
      millimolar level, for substrates including tobramycin, neomycin, and kanamycin A.
      The K(m) of each substrate was well above the corresponding maximum achievable
      level in serum. The low affinities of these enzymes for their substrates
      suggested that drug modification in vivo was very unlikely. Among the various
      substrates tested, no apparent positive correlation was found between substrate
      affinity and resistance level. The presence of aminoglycoside-modifying enzymes
      in these mycobacterial species was therefore not shown to confer resistance to
      aminoglycosides.

PMID- 10602721
TI  - Bacteriologic efficacies of oral azithromycin and oral cefaclor in treatment of
      acute otitis media in infants and young children.
AB  - A prospective, open-label, randomized study was conducted in order to determine
      the bacteriologic efficacies of cefaclor and azithromycin in acute otitis media
      (AOM). Tympanocentesis was performed on entry into the study and 3 to 4 days
      after initiation of treatment. Bacteriologic failure after 3 to 4 days of
      treatment with both drugs occurred in a high proportion of culture-positive
      patients, especially in those in whom AOM was caused by Haemophilus influenzae
      (16 of 33 [53%] of those treated with azithromycin and 13 of 34 [52%] of those
      treated with cefaclor). Although a clear correlation of the persistence of the
      pathogen with increased MICs of the respective drugs could be demonstrated for
      Streptococcus pneumoniae, no such correlation was found for H. influenzae. It is
      proposed that susceptibility breakpoints for H. influenzae should be considerably
      lower than the current ones for both cefaclor and azithromycin for AOM caused by
      H. influenzae.

PMID- 10602722
TI  - The CXCR4 antagonist AMD3100 efficiently inhibits cell-surface-expressed human
      immunodeficiency virus type 1 envelope-induced apoptosis.
AB  - Infection by human immunodeficiency virus type 1 (HIV-1) has been associated with
      increased cell death by apoptosis in infected and uninfected cells. The envelope
      glycoprotein complex ([gp120/gp41](n)) of X4 HIV-1 isolates is involved in both
      infected and uninfected cell death via its interaction with cellular receptors
      CD4 and CXCR4. We studied the effect of the blockade of CXCR4 receptors by the
      agonist stromal derived factor (SDF-1alpha) and the antagonist bicyclam AMD3100
      on apoptotic cell death of CD4(+) cells in different models of HIV infection. In
      HIV-infected CEM or SUP-T1 cultures, AMD3100 showed antiapoptotic activity even
      when added 24 h after infection. In contrast, other antiviral agents, such as
      zidovudine, failed to block apoptosis under these conditions. The antiapoptotic
      activity of AMD3100 was also studied in coculture of peripheral blood mononuclear
      cells or CD4(+) cell lines with chronically infected H9/IIIB cells. AMD3100 was
      found to inhibit both syncytium formation and apoptosis induction with 50%
      inhibitory concentrations ranging from 0.009 to 0.24 microg/ml, depending on the
      cell type. When compared to SDF-1alpha, AMD3100 showed higher inhibitory potency
      in all cell lines tested. Our data indicate that the bicyclam AMD3100 not only
      inhibits HIV replication but also efficiently blocks cell-surface-expressed HIV-1
      envelope-induced apoptosis in uninfected cells.

PMID- 10602723
TI  - In vitro activities of a new lipopeptide antifungal agent, FK463, against a
      variety of clinically important fungi.
AB  - The in vitro antifungal activity and spectrum of FK463 were compared with those
      of amphotericin B, fluconazole, and itraconazole by using a broth microdilution
      method specified by National Committee for Clinical Laboratory Standards document
      M27-A (National Committee for Clinical Laboratory Standards, Wayne, Pa., 1997).
      FK463 exhibited broad-spectrum activity against clinically important pathogens
      including Candida species (MIC range, <==0.0039 to 2 microg/ml) and Aspergillus
      species (MIC range, <==0.0039 to 0.0313 microg/ml), and its MICs for such fungi
      were lower than those of the other antifungal agents tested. FK463 was also
      potently active against azole-resistant Candida albicans as well as azole
      susceptible strains, and there was no cross-resistance with azoles. FK463 showed
      fungicidal activity against C. albicans, i.e., a 99% reduction in viability after
      a 24-h exposure at concentrations above 0.0156 microg/ml. The minimum fungicidal
      concentration (MFC) assays indicated that FK463 was fungicidal against most
      isolates of Candida species. In contrast, the MFCs of FK463 for A. fumigatus
      isolates were much higher than the MICs, indicating that its action is
      fungistatic against this species. FK463 had no activity against Cryptococcus
      neoformans, Trichosporon species, or Fusarium solani. Neither the test medium
      (kind and pH) nor the inoculum size greatly affected the MICs of FK463, while the
      addition of 4% human serum albumin increased the MICs for Candida species and A.
      fumigatus more than 32 times. Results from preclinical in vitro evaluations
      performed thus far indicate that FK463 should be a potent parenteral antifungal
      agent.

PMID- 10602724
TI  - The R467K amino acid substitution in Candida albicans sterol 14alpha-demethylase
      causes drug resistance through reduced affinity.
AB  - The cytochrome P450 sterol 14alpha-demethylase (CYP51) of Candida albicans is
      involved in an essential step of ergosterol biosynthesis and is the target for
      azole antifungal compounds. We have undertaken site-directed mutation of C.
      albicans CYP51 to produce a recombinant mutant protein with the amino acid
      substitution R467K corresponding to a mutation observed clinically. This
      alteration perturbed the heme environment causing an altered reduced-carbon
      monoxide difference spectrum with a maximum at 452 nm and reduced the affinity of
      the enzyme for fluconazole, as shown by ligand binding studies. The specific
      activity of CYP51(R467K) for the release of formic acid from 3beta-[32
      (3)H]hydroxylanost-7-en-32-ol was 70 pmol/nmol of P450/min for microsomal protein
      compared to 240 pmol/nmol of P450/min for microsomal fractions expressing wild
      type CYP51. Furthermore, inhibition of activity by fluconazole revealed a 7.5
      fold-greater azole resistance of the recombinant protein than that of the wild
      type. This study demonstrates that resistance observed clinically can result from
      the altered azole affinity of the fungal CYP51 enzyme.

PMID- 10602725
TI  - Activities of synthetic hybrid peptides against anaerobic bacteria: aspects of
      methodology and stability.
AB  - The increasing problem of antibiotic resistance among pathogenic bacteria
      requires development of new antimicrobial agents. One line of investigation is
      the synthesis of antimicrobial hybrid peptides. The aim of the present
      investigation was to determine the in vitro activities of 16 cecropin-melittin
      hybrid peptides (CAMEL analogues) against 60 anaerobic bacterial strains, to
      compare their activities with those of seven clinically used antimicrobial
      agents, and to compare different methods for anaerobic susceptibility testing of
      these peptides. The stability of one of the peptides, temporin B, with different
      stereoisomeric configurations was investigated in a fecal milieu. The CAMEL
      analogues showed antimicrobial activity against the anaerobic bacteria, with MICs
      ranging from 0.125 to 32 microg/ml. The overall activities (the MICs at which 90%
      of isolates are inhibited) of the CAMEL analogues against anaerobic bacteria were
      mainly inferior to those of imipenem, clindamycin, and piperacillin but were
      equal to or superior to those of metronidazole, cefoxitin, ciprofloxacin, and
      chloramphenicol. The agarose dilution method was found to be an accurate method
      for the testing of large numbers of bacterial strains. The D isomer of temporin B
      was inactivated more slowly in feces than the L isomer. This study shows that the
      CAMEL analogues are potential agents for the treatment of anaerobic infections.

PMID- 10602726
TI  - Penetration of rufloxacin into the cerebrospinal fluid in patients with inflamed
      and uninflamed meninges.
AB  - Forty-four patients scheduled for lumbar puncture (LP) were recruited to
      determine the level of penetration of orally administered rufloxacin into
      cerebrospinal fluid (CSF). The patients were divided into three clinical groups:
      those with normal CSF (groups A(1d) and A(7d)), those with aseptic meningitis
      (group B), and those with bacterial meningitis (group C). Members of group A(1d)
      received a single 400-mg rufloxacin dose, while group A(7d), B, and C
      constituents had a multiple-dose regimen (one 400-mg dose, followed by one 200-mg
      dose daily for 6 days). LP was performed on group A(1d) members 5 h after they
      had received treatment, while for group A(7d) it was undertaken 5 h after
      administration of the last dose. For group B, LP was performed 5 h after the
      first and the last doses, whereas for group C it was undertaken after the first,
      fourth, and last doses. Concentrations of rufloxacin in simultaneously collected
      CSF and plasma samples were determined. Mean CSF/plasma rufloxacin concentration
      ratios ranged from 0.57 to 0.84, depending on the study group. A higher, but not
      statistically significant, degree of penetration into CSF was observed in
      patients with bacterial meningitis than in those with normal CSF or aseptic
      meningitis. These data indicate that rufloxacin diffuses efficiently into the CSF
      of patients with either inflamed or uninflamed meninges.

PMID- 10602727
TI  - Zanamivir susceptibility monitoring and characterization of influenza virus
      clinical isolates obtained during phase II clinical efficacy studies.
AB  - Zanamivir is a highly selective neuraminidase (NA) inhibitor with demonstrated
      clinical efficacy against influenza A and B virus infections. In phase II
      clinical efficacy trials (NAIB2005 and NAIB2008), virological substudies showed
      mean reductions in virus shedding after 24 h of treatment of 1.5 to 2.0 log(10)
      50% tissue culture infective doses compared to a placebo, with no reemergence of
      virus after the completion of therapy. Paired isolates (n = 41) obtained before
      and during therapy with zanamivir demonstrated no shifts in susceptibility to
      zanamivir when measured by NA assays, although for a few isolates NA activity was
      too low to evaluate. In plaque reduction assays in MDCK cells, the susceptibility
      of isolates to zanamivir was extremely variable even at baseline and did not
      correlate with the speed of resolution of virus shedding. Isolates with apparent
      limited susceptibility to zanamivir by plaque reduction proved highly susceptible
      in vivo in the ferret model. Further sequence analysis of paired isolates
      revealed no changes in the hemagglutinin and NA genes in the majority of
      isolates. The few changes observed were all natural variants. No amino acid
      changes that had previously been identified in vitro as being involved with
      reduced susceptibility to zanamivir were observed. These studies highlighted
      problems associated with monitoring susceptibility to NA inhibitors in the
      clinic, in that no reliable cell-based assay is available. At present the NA
      assay is the best available predictor of susceptibility to NA inhibitors in vivo,
      as measured in the validated ferret model of infection.

PMID- 10602728
TI  - In vitro activity of riboflavin against the human malaria parasite Plasmodium
      falciparum.
AB  - The human malaria parasite Plasmodium falciparum digests hemoglobin and
      polymerizes the released free heme into hemozoin. This activity occurs in an
      acidic organelle called the food vacuole and is essential for survival of the
      parasite in erythrocytes. Since acidic conditions are known to enhance the auto
      oxidation of hemoglobin, we investigated whether hemoglobin ingested by the
      parasite was oxidized and whether the oxidation process could be a target for
      chemotherapy against malaria. We released parasites from their host cells and
      separately analyzed hemoglobin ingested by the parasites from that remaining in
      the erythrocytes. Isolated parasites contained elevated amounts (38.5% +/- 3.5%)
      of oxidized hemoglobin (methemoglobin) compared to levels (0.8% +/- 0.2%) found
      in normal, uninfected erythrocytes. Further, treatment of infected cells with the
      reducing agent riboflavin for 24 h decreased the parasite methemoglobin level by
      55%. It also inhibited hemozoin production by 50% and decreased the average size
      of the food vacuole by 47%. Administration of riboflavin for 48 h resulted in a
      65% decrease in food vacuole size and inhibited asexual parasite growth in
      cultures. High doses of riboflavin are used clinically to treat congenital
      methemoglobinemia without any adverse side effects. This activity, in conjunction
      with its impressive antimalarial activity, makes riboflavin attractive as a safe
      and inexpensive drug for treating malaria caused by P. falciparum.

PMID- 10602729
TI  - Persistence of infectious herpes simplex virus type 2 in the nervous system in
      mice after antiviral chemotherapy.
AB  - Young adult mice were inoculated with herpes simplex virus type 2 (HSV-2) in the
      ear pinna. A relatively severe infection resulted, and 45% of the mice died by 11
      days postinfection. Therapy at 1 mg/ml by means of the drinking water with either
      famciclovir for periods of 5 or 10 days or valaciclovir for 5, 10, 15, or 20 days
      decreased clinical signs and reduced mortality to 15% or less. Throughout a
      period of 27 days, mice were tested daily for the presence of infectious virus in
      the ear pinna, brain stem, and ipsilateral trigeminal ganglia. Virus was cleared
      from these tissues in surviving, untreated animals by 12 days postinfection, and
      no infectious virus was detected subsequently in any tissue. Furthermore, no
      infectious virus was detected after day 9 in mice that had been treated with
      famciclovir. In mice that had received valaciclovir therapy, however, infectious
      virus was repeatedly detected in the trigeminal ganglia and brain stem tissue
      samples up to 7 days after treatment was discontinued. To date, no specific
      mechanism to account for these results has been discovered; however, possible
      mechanisms for the persistence of potentially infectious virus in neural tissue
      of treated mice are discussed.

PMID- 10602730
TI  - Genotypic analysis of Mycobacterium tuberculosis in two distinct populations
      using molecular beacons: implications for rapid susceptibility testing.
AB  - Past genotypic studies of Mycobacterium tuberculosis may have incorrectly
      estimated the importance of specific drug resistance mutations due to a number of
      sampling biases including an overrepresentation of multidrug-resistant (MDR)
      isolates. An accurate assessment of resistance mutations is crucial for
      understanding basic resistance mechanisms and designing genotypic drug resistance
      assays. We developed a rapid closed-tube PCR assay using fluorogenic reporter
      molecules called molecular beacons to detect reportedly common M. tuberculosis
      mutations associated with resistance to isoniazid and rifampin. The assay was
      used in a comparative genotypic investigation of two different study populations
      to determine whether these known mutations account for most cases of clinical
      drug resistance. We analyzed samples from a reference laboratory in Madrid,
      Spain, which receives an overrepresentation of MDR isolates similar to prior
      studies and from a community medical center in New York where almost all of the
      resistant isolates and an equal number of susceptible controls were available.
      The ability of the molecular beacon assay to predict resistance to isoniazid and
      rifampin was also assessed. The overall sensitivity and specificity of the assay
      for isoniazid resistance were 85 and 100%, respectively, and those for rifampin
      resistance were 98 and 100%, respectively. Rifampin resistance mutations were
      detected equally well in isolates from both study populations; however, isoniazid
      resistance mutations were detected in 94% of the isolates from Madrid but in only
      76% of the isolates from New York (P = 0.02). In New York, isoniazid resistance
      mutations were significantly more common in the MDR isolates (94%) than in single
      drug-resistant isolates (44%; P < 0.001). No association between previously
      described mutations in the kasA gene and isoniazid resistance was found. The
      first mutations that cause isoniazid resistance may often occur in sequences that
      have not been commonly associated with isoniazid resistance, possibly in other as
      yet uncharacterized genes. The molecular beacon assay was simple, rapid, and
      highly sensitive for the detection of rifampin-resistant M. tuberculosis isolates
      and for the detection of isoniazid resistance in MDR isolates.

PMID- 10602731
TI  - Characterization of the antiviral effect of 2',3'-dideoxy-2', 3'-didehydro-beta-L
      5-fluorocytidine in the duck hepatitis B virus infection model.
AB  - A novel L-nucleoside analog of deoxycytidine, 2',3'-dideoxy-2', 3'-didehydro-beta
      L-5-fluorocytidine (beta-L-Fd4C), was recently shown to strongly inhibit
      hepatitis B virus (HBV) replication in the 2.2.15 cell line. Therefore, its
      antiviral activity was evaluated in the duck HBV (DHBV) infection model. Using a
      cell-free system for the expression of the DHBV polymerase, beta-L-Fd4C-TP
      exhibited a concentration-dependent inhibition of dCTP incorporation into viral
      minus-strand DNA with a 50% inhibitory concentration of 0.2 microM which was
      lower than that of other tested deoxycytidine analogs, i.e. , lamivudine-TP, ddC
      TP, and beta-L-FddC-TP. Further analysis showed that beta-L-Fd4C-TP is likely to
      be a competitive inhibitor of dCTP incorporation and to cause premature DNA chain
      termination. In primary duck hepatocyte cultures infected in vitro, beta-L-Fd4C
      administration exhibited a long-lasting inhibitory effect on viral DNA synthesis
      but could not clear viral covalently closed circular DNA (CCC DNA). Results of
      short-term antiviral treatment in experimentally infected ducklings showed that
      beta-L-Fd4C exhibited the most potent antiviral effect, followed by beta-L-FddC,
      lamivudine, and ddC. Longer administration of beta-L-Fd4C induced a sustained
      suppression of viremia (>95% of controls) and of viral DNA synthesis within the
      liver. However, the persistence of trace amounts of viral CCC DNA detected only
      by PCR was associated with a recurrence of viral replication after drug
      withdrawal. In parallel, beta-L-Fd4C treatment suppressed viral antigen
      expression within the liver and decreased intrahepatic inflammation and was not
      associated with any sign of toxicity. Our data, therefore, demonstrate that in
      the duck model of HBV infection, beta-L-Fd4C is a potent inhibitor of DHBV
      reverse transcriptase activity in vitro and suppresses viral replication in the
      liver in vivo.

PMID- 10602732
TI  - Safety assessment, in vitro and in vivo, and pharmacokinetics of emivirine, a
      potent and selective nonnucleoside reverse transcriptase inhibitor of human
      immunodeficiency virus type 1.
AB  - Emivirine (EMV), formerly known as MKC-442, is 6-benzyl-1-(ethoxymethyl)-5
      isopropyl-uracil, a novel nonnucleoside reverse transcriptase inhibitor that
      displays potent and selective anti-human immunodeficiency virus type 1 (HIV-1)
      activity in vivo. EMV showed little or no toxicity towards human mitochondria or
      human bone marrow progenitor cells. Pharmacokinetics were linear for both rats
      and monkeys, and oral absorption was 68% in rats. Whole-body autoradiography
      showed widespread distribution in tissue 30 min after rats were given an oral
      dose of [(14)C]EMV at 10 mg/kg of body weight. In rats given an oral dose of 250
      mg/kg, there were equal levels of EMV in the plasma and the brain. In vitro
      experiments using liver microsomes demonstrated that the metabolism of EMV by
      human microsomes is approximately a third of that encountered with rat and monkey
      microsomes. In 1-month, 3-month, and chronic toxicology experiments (6 months
      with rats and 1 year with cynomolgus monkeys), toxicity was limited to readily
      reversible effects on the kidney consisting of vacuolation of kidney tubular
      epithelial cells and mild increases in blood urea nitrogen. Liver weights
      increased at the higher doses in rats and monkeys and were attributed to the
      induction of drug-metabolizing enzymes. EMV tested negative for genotoxic
      activity, and except for decreased feed consumption at the high dose (160
      mg/kg/day), with resultant decreases in maternal and fetal body weights, EMV
      produced no adverse effects in a complete range of reproductive toxicology
      experiments performed on rats and rabbits. These results support the clinical
      development of EMV as a treatment for HIV-1 infection in adult and pediatric
      patient populations.

PMID- 10602733
TI  - Comparison of the effects of liposomal amphotericin B and conventional
      amphotericin B on propafenone metabolism and hepatic cytochrome P-450 in rats.
AB  - The effects of conventional amphotericin B (AmB) dissolved in sodium deoxycholate
      on microsomal cytochrome P-450 concentrations and propafenone metabolism to 5
      hydroxy-propafenone and N-desalkyl-propafenone were compared with those of
      liposomal AMB (Li-AMB) in rats. AmB (3 mg/kg/day, intravenously [i.v.]) given for
      4 days caused a significant decrease in the concentration of hepatic microsomal
      cytochrome P-450 (0.43 +/- 0.06 nmol/mg versus 0.62 +/- 0. 05 nmol/mg for the
      control [P < 0.05]). Following the application of Li-AMB (15 mg/kg/day, i.v.),
      hepatic microsomal cytochrome P-450 concentrations were unchanged at 0.64 +/-
      0.08 nmol/mg. AmB decreased ex vivo propafenone metabolism to 5-hydroxy
      propafenone and N-desalkyl-propafenone significantly. Sodium deoxycholate (the
      vehicle of AmB) by itself induced a significant decline of 5-hydroxy-propafenone
      and N-desalkyl-propafenone production, while microsomal cytochrome P-450
      concentrations remained unchanged. In contrast, Li-AMB did not change the levels
      of production of 5-hydroxy-propafenone or of N-desalkyl-propafenone at either
      substrate concentration tested (50 micromol and 200 micromol). Microsomal AmB
      concentrations were significantly higher following Li-AMB application (21.1 +/-
      6.2 microg/g versus 3.7 +/- 1.4 microg/g for AmB [P < 0.05]). We conclude that Li
      AMB, in contrast to AmB, decreases neither hepatic microsomal cytochrome P-450
      nor hepatic propafenone metabolism in rats ex vivo. Sodium deoxycholate alone
      decreases propafenone metabolism in a similar way to AmB, suggesting that it
      participates in AmB-induced disturbance of hepatic metabolic function.

PMID- 10602734
TI  - Chemical specificity of the PDR5 multidrug resistance gene product of
      Saccharomyces cerevisiae based on studies with tri-n-alkyltin chlorides.
AB  - To understand the chemical basis of action for the PDR5-encoded multidrug
      resistance transporter of Saccharomyces cerevisiae, we compared the relative
      hypersensitivities of the wild-type (RW2802) and null mutant strains toward a
      series of tri-n-alkyltin compounds. These compounds differ from each other in a
      systematic fashion-either by hydrocarbon chain length or by anion composition.
      Using zone-of-inhibition and fixed-concentration assays, we found that the ethyl,
      propyl, and butyl compounds are strong PDR5 substrates, whereas the methyl and
      pentyl compounds are weak. We conclude that hydrophobicity and anion makeup are
      relatively unimportant factors in determining whether a tri-n-alkyltin compound
      is a good PDR5 substrate but that the dissociation of the compound and the
      molecular size are significant.

PMID- 10602735
TI  - Effect of zinc-reversible growth-inhibitory activity in human empyema fluid on
      antibiotic microbicidal activity.
AB  - Abscess fluid supernatants have zinc-reversible microbial growth-inhibitory
      activity that is mediated by calprotectin, a zinc-binding protein. Because it
      inhibits microbial growth, this activity might interfere with killing by
      antibiotics that require their target organisms to be proliferating. In the
      present study, we cultured bacteria in human empyema fluid and used zinc to
      overcome the growth-inhibitory effect of calprotectin. We then compared the
      effect of zinc on killing by the beta-lactams ampicillin and cefazolin with that
      of the fluoroquinolone trovafloxacin, since the latter may be better able to kill
      nonproliferating organisms. In empyema fluid diluted 1:5 in normal saline,
      addition of zinc (30 microM) increased growth of two strains of Staphyloccocus
      aureus and two strains of Escherichia coli but did not affect the MICs or MBCs of
      the three antibiotics in Mueller-Hinton broth. For one strain of S. aureus, no
      effect of zinc was found on killing by either ampicillin or cefazolin. However,
      with the other strain of S. aureus and both strains of E. coli, significant
      enhancement of killing by both drugs was observed with zinc addition. On the
      other hand, no effect on the killing of any of the organisms was observed for
      trovafloxacin when zinc was added. These results suggest that the zinc-reversible
      growth-inhibitory activity of abscess fluid may interfere with the microbicidal
      activity of antibiotics requiring proliferating target organisms, although
      antibiotics better able to kill nonproliferating organisms may be less affected
      by this phenomenon.

PMID- 10602736
TI  - Immunosuppressive and nonimmunosuppressive cyclosporine analogs are toxic to the
      opportunistic fungal pathogen Cryptococcus neoformans via cyclophilin-dependent
      inhibition of calcineurin.
AB  - Cyclosporine (CsA) is an immunosuppressive and antimicrobial drug which, in
      complex with cyclophilin A, inhibits the protein phosphatase calcineurin. We
      recently found that Cryptococcus neoformans growth is resistant to CsA at 24
      degrees C but sensitive at 37 degrees C and that calcineurin is required for
      growth at 37 degrees C and pathogenicity. Here CsA analogs were screened for
      toxicity against C. neoformans in vitro. In most cases, antifungal activity was
      correlated with cyclophilin A binding in vitro and inhibition of the mixed
      lymphocyte reaction and interleukin 2 production in cell culture. Two unusual
      nonimmunosuppressive CsA derivatives, (gamma-OH) MeLeu(4)-Cs (211-810) and D-Sar
      (alpha-SMe)(3) Val(2)-DH-Cs (209-825), which are also toxic to C. neoformans were
      identified. These CsA analogs inhibit C. neoformans via fungal cyclophilin A and
      calcineurin homologs. Our findings identify calcineurin as a novel antifungal
      drug target and suggest nonimmunosuppressive CsA analogs warrant investigation as
      antifungal agents.

PMID- 10602737
TI  - Activities of the triazole derivative SCH 56592 (posaconazole) against drug
      resistant strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi in
      immunocompetent and immunosuppressed murine hosts.
AB  - We have studied the in vivo activity of the new experimental triazole derivative
      SCH 56592 (posaconazole) against a variety of strains of the protozoan parasite
      Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas' disease, in
      both immunocompetent and immunosuppressed murine hosts. The T. cruzi strains used
      in the study were previously characterized as susceptible (CL), partially
      resistant (Y), or highly resistant (Colombiana, SC-28, and VL-10) to the drugs
      currently in clinical use, nifurtimox and benznidazole. Furthermore, all strains
      are completely resistant to conventional antifungal azoles, such as ketoconazole.
      In the first study, acute infections with the CL, Y, and Colombiana strains in
      both normal and cyclophosphamide-immunosuppressed mice were treated orally,
      starting 4 days postinfection (p.i.), for 20 consecutive daily doses. The results
      indicated that in immunocompetent animals SCH 56592 at 20 mg/kg of body
      weight/day provided protection (80 to 90%) against death caused by all strains, a
      level comparable or superior to that provided by the optimal dose of benznidazole
      (100 mg/kg/day). Evaluation of parasitological cure revealed that SCH 56592 was
      able to cure 90 to 100% of the surviving animals infected with the CL and Y
      strains and 50% of those which received the benznidazole- and nifurtimox
      resistant Colombiana strain. Immunosuppression markedly reduced the mean survival
      time of untreated mice infected with any of the strains, but this was not
      observed for the groups which received SCH 56592 at 20 mg/kg/day or benznidazole
      at 100 mg/kg/day. However, the overall cure rates were higher for animals treated
      with SCH 56592 than among those treated with benznidazole. The results were
      confirmed in a second study, using the same model but a longer (43-dose)
      treatment period. Finally, a model for the chronic disease in which oral
      treatment was started 120 days p.i. and consisted of 20 daily consecutive doses
      was investigated. The results showed that SCH 56592 at 20 mg/kg/day was able to
      induce a statistically significant increase in survival of animals infected with
      all strains, while benznidazole at 100 mg/kg/day was able to increase survival
      only in animals infected with the Colombiana strain. Moreover, the triazole was
      able to induce parasitological cures in 50 to 60% of surviving animals,
      irrespective of the infecting strain, while no cures were obtained with
      benznidazole. Taken together, the results demonstrate that SCH 56592 has in vivo
      trypanocidal activity, even against T. cruzi strains naturally resistant to
      nitrofurans, nitroimidazoles, and conventional antifungal azoles, and that this
      activity is retained to a large extent in immunosuppressed hosts.

PMID- 10602738
TI  - Development of a long-term ascending urinary tract infection mouse model for
      antibiotic treatment studies.
AB  - A model of ascending unobstructed urinary tract infection (UTI) in mice was
      developed to study the significance of the antibiotic concentration in urine,
      serum, and kidney tissue for efficacy of treatment of UTI in general and
      pyelonephritis in particular. Outbred Ssc-CF1 female mice were used throughout
      the study, and Escherichia coli was used as the pathogen. The virulence of 11
      uropathogenic E. coli isolates and 1 nonpathogenic laboratory E. coli strain was
      examined. Strain C175-94 achieved the highest counts in the kidneys, and this
      strain was subsequently used as the infecting organism. The model gave
      reproducible bladder infections, i.e., bacteria were recovered from 22 of 23
      control mice after 3 days, and histological examination of kidney tissue showed
      that of 14 infected kidneys, 7 (50%) showed major histological changes, whereas 3
      of 36 uninfected kidneys showed major histological changes (P = 0.018). Once the
      model was established, the efficacies of different doses of cefuroxime and
      gentamicin, corresponding to active concentrations in urine only or in urine,
      serum, and kidney tissue simultaneously, were examined. All cefuroxime doses
      resulted in significantly lower counts in urine than control treatments, but the
      dose which produced concentrations of cefuroxime only in urine and not in serum
      or kidney tissue had no effect on kidney infection. Even low doses of gentamicin
      (0.05 mg/mouse) resulted in concentrations in renal tissue for prolonged times
      due to accumulation. All gentamicin doses had a significant effect (compared to
      the effect of the control treatment) on bacterial counts in urine and kidneys.
      The antibiotic effect on bacterial counts in bladders was negligible for unknown
      reasons. Use of the mouse UTI model is feasible for study of the effect of an
      antibiotic in the urinary system, although the missing antibacterial effect in
      the bladder needs further evaluation.

PMID- 10602739
TI  - Ciprofloxacin, lomefloxacin, or levofloxacin as treatment for chronic
      osteomyelitis.
AB  - The efficacy and safety of three oral fluoroquinolones (lomefloxacin,
      levofloxacin, and ciprofloxacin) for the treatment of chronic osteomyelitis were
      analyzed. Twenty-seven patients had documented infections with quinolone
      sensitive organisms and received either lomefloxacin, levofloxacin, or
      ciprofloxacin. Levofloxacin was effective therapy for 9 of 15 (60%) patients.
      Lomefloxacin was effective therapy for five of seven (71%) patients, and
      ciprofloxacin was effective therapy for two of five patients (40%). Average
      follow-up was 11.8 months for patients who completed the course of therapy, and
      the average duration of therapy was 60.6 days. Gram-positive bacteria were
      isolated from 18 patients, and 11 patients were cured. Oral fluoroquinolones can
      be safe, effective therapy if they are given for a prolonged course as treatment
      for infections caused by susceptible gram-positive as well as gram-negative
      organisms and in combination with adequate surgical debridement.

PMID- 10602740
TI  - Successful treatment with nitazoxanide of Enterocytozoon bieneusi
      microsporidiosis in a patient with AIDS.
AB  - A patient with AIDS and chronic diarrhea caused by Enterocytozoon bieneusi was
      successfully treated with nitazoxanide, producing a complete clinical and
      parasitological response, while off of antiviral therapy. This suggests that
      nitazoxanide may be effective in treating microsporidiosis caused by E. bieneusi,
      a disease for which there is no established treatment.

PMID- 10602741
TI  - Role of penicillin-binding proteins in the initiation of the AmpC beta-lactamase
      expression in Enterobacter cloacae.
AB  - Penicillin-binding proteins (PBPs) are involved in the regulation of beta
      lactamase expression by determining the level of anhydromuramylpeptides in the
      periplasmatic space. It was hypothesized that one or more PBPs act as a sensor in
      the beta-lactamase induction pathway. We have performed induction studies with
      Escherichia coli mutants lacking one to four PBPs with DD-carboxypeptidase
      activity. Therefore, we conclude that a strong beta-lactamase inducer must
      inhibit all DD-carboxypeptidases as well as the essential PBPs 1a, 1b, and/or 2.

PMID- 10602742
TI  - Activities of masked 2',3'-dideoxynucleoside monophosphate derivatives against
      human immunodeficiency virus in resting macrophages.
AB  - The anti-human immunodeficiency virus (HIV) activity of aryloxyphosphoramidate
      protides of a number of anti-HIV nucleoside analogues was assessed in resting
      primary monocyte-macrophages (M/M). While 2',3'-dideoxythymidine (d4T), 2',3'
      dideoxyadenosine (ddA), and 2',3'-dideoxy-2',3'-didehydroadenosine (d4A) protides
      showed an anti-HIV activity that was 25- to 625-fold greater than the parent
      nucleotides d4T, ddA, and d4A, respectively, other aryloxyphosphoramidate
      protides showed similar or even lower anti-HIV activities than their parent
      compounds. This variable anti-HIV effect is most likely related to the different
      dynamics of intracellular nucleoside monophosphate release from the protides. Our
      results indicate the potential advantage of therapeutic use of this approach for
      some nucleotide analogues to affect HIV replication in M/M, one of the major
      reservoirs of HIV in vivo.

PMID- 10602743
TI  - Trovafloxacin concentrations in airway fluids of patients with severe community
      acquired pneumonia.
AB  - The penetration of trovafloxacin (TVA), 200 mg once daily, into the airways of 17
      patients with severe pneumonia was studied. The mean (standard deviations are
      given in parentheses) steady-state TVA concentrations, 2 h after the last intake,
      were 3.1 (0.3) mg/liter in induced sputum (n = 8), 3.2 (1.1) mg/liter in
      bronchial secretions (n = 9), 3.2 (0.9) mg/liter in bronchoalveolar lavage fluid
      (n = 10), and 4.9 (1.4) mg/liter in epithelial lining fluid (n = 11).

PMID- 10602744
TI  - In vitro susceptibilities of rapidly growing mycobacteria to telithromycin (HMR
      3647) and seven other antimicrobials.
AB  - The antimicrobial activities of telithromycin (HMR 3647) and seven other
      antimicrobials against 94 strains of rapidly growing mycobacteria were
      determined. Telithromycin at a concentration of 1 microg/ml inhibited
      Mycobacterium peregrinum (100%), Mycobacterium chelonae (80%), Mycobacterium
      abscessus-Mycobacterium mucogenicum (44.4%), and Mycobacterium fortuitum (2.1%).
      All or most strains of M. peregrinum, M. fortuitum, and M. mucogenicum were
      inhibited by 2 microg of quinolones per ml.

PMID- 10602745
TI  - A nine-codon deletion mutation in the cytomegalovirus UL97 phosphotransferase
      gene confers resistance to ganciclovir.
AB  - A deletion mutation (codons 595 to 603) in the cytomegalovirus (CMV) UL97 gene
      was recently reported after sequence analysis of leukocyte DNA from a patient
      receiving ganciclovir. The corresponding viral phenotype was examined by transfer
      of this mutation to a laboratory CMV strain (strain Towne). The recombinant virus
      was resistant to ganciclovir (8.4-fold increase in the 50% inhibitory
      concentration), was sensitive to foscarnet, and replicated normally in cell
      culture.

PMID- 10602746
TI  - Postantibiotic effects of grepafloxacin compared to those of five other agents
      against 12 gram-positive and -negative bacteria.
AB  - The postantibiotic effect (PAE) (10x the MIC) and the postantibiotic sub-MIC
      effects (0.125, 0.25, and 0.5x the MIC) were determined for six compounds against
      12 strains. Measurable PAEs ranged between 0 and 1.8 h for grepafloxacin, 0 and
      2.2 h for ciprofloxacin, 0 and 3. 1 h for levofloxacin, 0 and 2.2 h for
      sparfloxacin, 0 and 2.4 h for amoxicillin-clavulanate and 0 and 4.8 h for
      clarithromycin. Reexposure to subinhibitory concentrations increased the PAEs
      against some strains.

PMID- 10602747
TI  - satG, conferring resistance to streptogramin A, is widely distributed in
      Enterococcus faecium strains but not in staphylococci.
AB  - A gene almost identical to satG was isolated from an Enterococcus faecium strain.
      This gene was transferred to a Staphylococcus aureus recipient strain where it
      conferred resistance to streptogramin A. satG was found to be widely distributed
      among E. faecium strains but not detected among staphylococci.

PMID- 10602748
TI  - Susceptibilities of Neisseria gonorrhoeae isolates containing amino acid
      substitutions in GyrA, with or without substitutions in ParC, to newer
      fluoroquinolones and other antibiotics.
AB  - We examined the antimicrobial susceptibilities of 85 Neisseria gonorrhoeae
      isolates, classified according to the presence of amino acid substitutions in the
      GyrA and ParC proteins, to 12 fluoroquinolones and 7 other antibiotics.
      Sitafloxacin and HSR-903 showed excellent activity against N. gonorrhoeae,
      including strains with both GyrA and ParC substitutions. Among the strains with
      various GyrA substitutions, strains with a serine-91-to-phenylalanine mutation
      required the highest MICs of all of the fluoroquinolones tested and were cross
      resistant to structurally unrelated beta-lactams.

PMID- 10602749
TI  - Sequence analysis of ARI-1, a novel OXA beta-lactamase, responsible for imipenem
      resistance in Acinetobacter baumannii 6B92.
AB  - The sequence of the bla(ARI-1) gene from imipenem-resistant Acinetobacter
      baumannii 6B92 has been determined. The structural gene encodes a 273-amino-acid
      protein which is most related to the OXA class D beta-lactamases. The conserved S
      T-F-K and K-T-G motifs were identified in the ARI-1 protein sequence, also named
      OXA-23, but significantly, a point mutation (Y-->F) was identified in the Y-G-N
      conserved motif, also known to function in the active site.

PMID- 10602750
TI  - Delta(12)-prostaglandin J(2) is a potent inhibitor of influenza A virus
      replication.
AB  - 9-Deoxy-Delta(9),Delta(12)-13,14-dihydro-prostaglandin D(2) (Delta(12)-PGJ(2)), a
      natural cyclopentenone metabolite of prostaglandin D(2), is shown to possess
      therapeutic efficacy against influenza A virus A/PR8/34 (H1N1) infection in vitro
      and in vivo. The results indicate that the antiviral activity is associated with
      induction of cytoprotective heat shock proteins and suggest novel strategies for
      treatment of influenza virus infection.

PMID- 10602751
TI  - Morphological change in Pseudomonas aeruginosa following antibiotic treatment of
      experimental infection in mice and its relation to susceptibility to phagocytosis
      and to release of endotoxin.
AB  - The relationship between morphological changes in Pseudomonas aeruginosa
      following antibiotic treatment of experimental infection in mice, susceptibility
      to phagocytosis, and release of endotoxin was studied. The intraperitoneal
      administration of P. aeruginosa with imipenem or ceftazidime into mice induced
      morphological changes in the cells 2 h after injection. Round P. aeruginosa cells
      with imipenem treatment became susceptible to phagocytosis by peritoneal cells,
      whereas long filamentous cells with ceftazidime treatment were hardly
      phagocytized by peritoneal cells. The morphological changes also affected the
      plasma endotoxin level in the circulation.

PMID- 10602752
TI  - Bioavailability of aciclovir after oral administration of aciclovir and its
      prodrug valaciclovir to patients with leukopenia after chemotherapy.
AB  - The median bioavailabilities of aciclovir after administration of aciclovir and
      its prodrug valaciclovir were 21.5 and 70.1%, respectively, in 12 patients with
      malignant hematological diseases with leukopenia after chemotherapy. The
      interindividual variations of the bioavailability were 48.5 and 21.0% after
      administration of aciclovir and valaciclovir, respectively. Neither the
      bioavailability nor the interindividual variation of area under the concentration
      time curve of oral aciclovir or valaciclovir differed from that reported in
      healthy volunteers.

PMID- 10602753
TI  - Complete sequence of a beta-lactamase-encoding plasmid in Neisseria meningitidis.
AB  - Identical beta-lactamase-encoding (TEM-1) plasmids were found in two different
      clinical Neisseria meningitidis strains. They were completely sequenced (5,597
      bp) and designated pAB6. The plasmid is almost identical to Neisseria gonorrhoeae
      plasmid pJD5 (5,599 kb) and may have been picked up from a gonococcus in vivo.

PMID- 10602754
TI  - Production of a TEM-24 plasmid-mediated extended-spectrum beta-lactamase by a
      clinical isolate of Pseudomonas aeruginosa.
AB  - Several Pseudomonas aeruginosa strains, including one urinary isolate producing
      an extended-spectrum beta-lactamase TEM-24, were isolated from a long-term
      hospitalized woman. Three TEM-24-producing enterobacterial species (Enterobacter
      aerogenes, Escherichia coli, and Proteus mirabilis) were isolated from the same
      patient. TEM-24 and the resistance markers for aminoglycosides, chloramphenicol,
      and sulfonamide were encoded by a 180-kb plasmid transferred by conjugation into
      E. coli HB101.

PMID- 10602755
TI  - Mechanism of inhibition of the human immunodeficiency virus type 1 reverse
      transcriptase by d4TTP: an equivalent incorporation efficiency relative to the
      natural substrate dTTP.
AB  - Among the clinically used nucleoside analogue inhibitors that target human
      immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), there is little
      detailed mechanistic information on the interactions of 2',3'-didehydro-2', 3'
      dideoxythymidine-5'-triphosphate (d4TTP) with the enzyme. primer-template complex
      and how these interactions compare with those of the natural substrate, dTTP.
      Using a pre-steady-state kinetic analysis, we found that d4TTP was incorporated
      by HIV-1 RT just as efficiently as dTTP during both DNA- and RNA-dependent DNA
      synthesis. To our knowledge, these results represent the first observation of a
      3'-modified nucleoside triphosphate analogue that has an incorporation efficiency
      comparable to that observed for the natural substrate during DNA synthesis by HIV
      1 RT. This information provides a mechanistic basis for understanding the
      inhibition of HIV-1 RT by d4TTP as well as insight into the clinically observed
      lack of d4T resistance mutations in HIV-1 RT isolated from AIDS patients.

PMID- 10602756
TI  - A novel integron in Salmonella enterica serovar Enteritidis, carrying the bla(DHA
      1) gene and its regulator gene ampR, originated from Morganella morganii.
AB  - The genetic organization of the gene coding for DHA-1 and the corresponding ampR
      gene was determined by PCR mapping. These genes have been mobilized from the
      Morganella morganii chromosome and inserted into a complex sulI-type integron,
      similar to In6 and In7. However, they are not themselves mobile cassettes. This
      integron probably includes a specific site for recombination allowing the
      mobilization of diverse resistance genes, as observed for bla(CMY-1) and bla(MOX
      1).

PMID- 10602757
TI  - In vitro activities of the new antifungal triazole SCH 56592 against common and
      emerging yeast pathogens.
AB  - A broth microdilution method performed in accordance with the National Committee
      for Clinical Laboratory Standards guidelines was used to compare the in vitro
      activity of the new antifungal triazole SCH 56592 (SCH) to that of fluconazole
      (FLC), itraconazole (ITC), and ketoconazole (KETO) against 257 clinical yeast
      isolates. They included 220 isolates belonging to 12 different species of
      Candida, 15 isolates each of Cryptococcus neoformans and Saccharomyces
      cerevisiae, and seven isolates of Rhodotorula rubra. The MICs of SCH at which 50%
      (MIC(50)) and 90% (MIC(90)) of the isolates were inhibited were 0.06 and 2.0
      microg/ml, respectively. In general, SCH was considerably more active than FLC
      (MIC(50) and MIC(90) of 1.0 and 64 microg/ml, respectively) and slightly more
      active than either ITC (MIC(50) and MIC(90) of 0.25 and 2.0 microg/ml,
      respectively) and KETO (MIC(50) and MIC(90) of 0.125 and 4.0 microg/ml,
      respectively). Our in vitro data suggest that SCH has significant potential for
      clinical development.

PMID- 10602758
TI  - Fire and resprouting in Mediterranean ecosystems: insights from an external
      biogeographical region, the mexical shrubland.
AB  - We investigated modes of regeneration of dominant species of the mexical
      vegetation after fire. The mexical shrubland shows a remarkable structural,
      morphological, and floristic similarity to Mediterranean-type vegetation and is
      considered a relict of the Madro-Tertiary Geoflora under a non-Mediterranean
      climate. This vegetation provides an ideal scenario to test the role of fire in
      Mediterranean ecosystems because historical fire occurrence is absent and the
      species assembly is constituted mostly by Madro-Tertiary elements and Neotropical
      species (some of them, endemic species from Mexico). The existence of congeneric
      species of the California chaparral allows us to determine the regeneration
      ability of these communities after fire in relation to resprouting and seeding
      strategies, which are widespread modes reported in the Mediterranean-type
      vegetation. By the experimental application of fire in the two biogeographical
      groups of species, we tested the hypothesis that low resprouting ability of
      California congeneric species (Madro-Tertiary species) after fire would indicate
      that fire has played an important selective force in the resprouting habit. A low
      resprouting ability in the Neotropical group of species would suggest that fire
      has molded the set of species dominating fire-prone environments.Our results
      indicated that resprouting is a widespread trait in the mexical species
      characterized by the presence of lignotubers and burls. Resprouting can be
      considered an ancient trait, probably linked to losses of aboveground biomass,
      that became a pre-adaptation in Mediterranean fire-prone communities. The
      Neotropical group of species showed less ability to regenerate after fire, and
      small plants were more likely to die after disturbance in this group than in the
      Madro-Tertiary group. The resprouting feature and the seeder strategy of other
      species after a fire in the mexical shrubland are similar to Mediterranean-type
      ecosystems, emphasizing their common origin and the relevance of phylogenetic and
      biogeographical studies to explain current patterns of vegetation.

PMID- 10602759
TI  - Pollen and anther development in Nelumbo (Nelumbonaceae).
AB  - The Nelumbonaceae are a small family of aquatic angiosperms comprising Nelumbo
      nucifera and Nelumbo lutea. Historically, the genus has been considered to be
      closely related to Nymphaeales, however new systematic work has allied Nelumbo
      with lower eudicots, particularly Platanus. In recent years, studies of pollen
      development have contributed greatly to the understanding of phylogenetic
      relationships, but little has been known about these events in Nelumbo. In this
      paper, pollen and anther development are morphologically described for the first
      time in N. lutea. A comprehensive ontogenetic sequence is documented, including
      the sporogenous tissue, microspore mother cell, tetrad, free spore, and mature
      pollen grain stages. The deposition of a microspore mother cell coat and callose
      wall, the co-occurrence of both tetrahedral and tetragonal tetrads, the formation
      of a primexine in tetrads, and primexine persistence into the late free spore
      stage are shown. The majority of exine development occurs during the free spore
      stage with the deposition of a tectate-columellate ectexine, a lamellate
      endexine, and an unusual granular layer below and intermixed with the endexine
      lamellae. A two-layered intine forms rapidly during the earliest mature pollen
      stage. Major events of anther development documented include the degradation of a
      secretory-type tapetum during the free spore stage and the rapid formation of U
      shaped endothecial thickenings in the mature pollen grain stage. The majority of
      mature pollen grains are tricolpate, however less common monosulcate and
      diaperturate grains also develop. Co-occurring aperture types in Nelumbo have
      been suggested to be an important transition in angiosperm aperture number.
      However, aperture variability in Nelumbo may be correlated with the lateness of
      aperture ontogeny in the genus, which occurs in the early free spore stage. This
      character, as well as other details of pollen and anther ontogeny in Nelumbo, are
      compared to those of Nymphaeales and Platanus in an effort to provide additional
      insight into systematic and phylogenetic relationships. Although Nelumbo is
      similar to both groups in several characters, the ontogenetic sequence of the
      genus is different in many ways.

PMID- 10602760
TI  - Biomechanical properties of the trunk of the devil's walking stick (Aralia
      spinosa; Araliaceae) during the crown-building phase: implications for tree
      architecture.
AB  - During the crown-building phase, the mechanical architecture of the trunk of
      Aralia spinosa exhibits considerable ontogenetic variation. All trunks were
      tapered along their length, and taper was dependent on both ramet size and age;
      older, larger trunks were more tapered than younger, smaller trunks. Trunk
      specific gravity, % bark, wood, and pith exhibited considerable inter- and intra
      ramet variation. Specific gravity increased with both increasing ramet size and
      age, and declined acropetally in the majority of ramets sampled. Wood specific
      gravity was generally unrelated to ramet size, age, or position along the length
      of the trunk. Percent wood increased while % pith decreased with increasing ramet
      size and age. There was no relationship between % bark and either ramet size or
      age. Both % bark and % wood tended to decline acropetally, while % pith increased
      acropetally. On average, 47% of the variation in specific gravity could be
      attributed to % wood, while 77% could be attributed to % pith. Percent bark
      accounted for only 14% of the variation in specific gravity. We suggest that the
      relatively pithy trunk of Aralia spinosa (average range: 4-15%) allows for rapid
      height growth, but imposes severe constraints on crown architecture and the
      maximum size attainable by this species.

PMID- 10602761
TI  - Developmental instability in hybrids between Lychnis viscaria and Lychnis alpina
      (Caryophyllaceae).
AB  - Developmental instability shown by increased fluctuating asymmetry can be caused
      by either genetic or environmental stress. Genomic coadaptation and
      heterozygosity are the genetic factors that are commonly assumed to increase the
      level of developmental stability. Therefore, in hybrid populations the level of
      fluctuating asymmetry (FA) can be lower due to higher heterozygosity or higher
      due to disruption of coadapted gene complexes, depending on the degree of
      divergence between hybridizing taxa. Here I present data on FA in petals from
      hybrids between Lychnis viscaria (Caryophyllaceae) and Lychnis alpina and from
      parental species grown in a common garden environment. Petal asymmetry of hybrids
      was clearly higher than that of either parental species grown in common
      environment. Between the two parental species petal asymmetry did not differ. The
      mean size of the petals in hybrids was about the same as in L. viscaria, thus
      indicating no heterotic effect. Therefore, it seems that hybrids between L.
      viscaria and L. alpina do suffer from the disruption of coadapted gene complexes
      as indicated by higher developmental instability.

PMID- 10602762
TI  - Habitat-specific genetic effects on growth rate and morphology across pH and
      water-level gradients within a population of the moss Sphagnum angustifolium
      (Sphagnaceae).
AB  - To study genetic adaptations in bryophytes on small ecological and spatial scales
      and to assess the adaptive significance of morphological trait variation,
      genotypes of Sphagnum angustifolium originating from habitats characterized by
      different pH and height above water table were clonally propagated and grown
      along the same gradients that exist in the field. Clones from ombrotrophic
      habitats grew consistently better ombrotrophically than clones from minerotrophic
      habitats and vice versa, suggesting that the genotypes were adapted to different
      pH levels. Genetic variation was found in several morphological traits, but
      habitat-specific genetic effects were detected only in length of spreading
      branches. Covariation between morphology and growth was generally environmentally
      induced. Positive and negative cross-environment genetic correlations suggested
      the presence of constraints on adaptive reaction norm evolution. The indications
      of small-scale genetic adaptations suggest either selective establishment of
      genotypes adapted to specific habitats, strong selective forces operating at the
      later stages of the life cycle, restricted gene flow over short distances, or a
      combination of these. In contrast to prevailing views, these results indicate
      that bryophytes are likely to respond genetically to small-scale environmental
      gradients.

PMID- 10602763
TI  - Trade-offs between flower number and investment to a flower in selfing and
      outcrossing varieties of Impatiens hypophylla (Balsaminaceae).
AB  - Floral resource allocation was compared on a whole-plant basis between two
      varieties of Impatiens hypophylla that differ in flower size. There were
      significant negative correlations between flower number and investments to a
      flower at both the within-population and between-variety levels. In individual
      flowers, var. hypophylla with larger flowers invested significantly more
      resources to male and pollinator-attractive functions, whereas investments to
      female function did not differ between the varieties. In experimental populations
      placed in the field, pollinators preferred the larger flowers of var. hypophylla
      even within the same habitat of var. microhypophylla, which has smaller flowers.
      There was a significant lack of observed heterozygosity only in var.
      microhypophylla. Thus, the outcrossing variety had more attractive but fewer
      flowers, while the selfing variety had less attractive but more abundant flowers.

PMID- 10602764
TI  - Apical pattern of fruit production in the racemes of Ceratonia siliqua
      (Leguminosae: Caesalpinioideae): role of pollinators.
AB  - Fruit production and arrangement within the raceme were studied in two dioecious
      populations of Ceratonia siliqua (Leguminosae: Caesalpinioideae), an arboreal
      species that produces caulogenous racemes (emerging only from the old branches)
      with numerous flowers. Fruit production per raceme was low and similar between
      years and populations and even between individuals. During flowering, there were
      considerable flower losses from predation and lack of pollination. A mean of nine
      flowers per raceme began the transformation into fruits, of which 77% aborted.
      The final fruit production per raceme increased significantly following hand
      pollination, but was always very much lower than the availability of flowers in
      the raceme. The results suggest that fruit production of each raceme is limited
      by both availability of resources and a deficient pollination. In racemes setting
      fruit arrangement follows a definite pattern that remains constant between years
      and populations: fruit production was significantly higher in the apical zone of
      the raceme and lower in the basal zone. The pollinators of C. siliqua (flies and
      wasps) showed a clear preference for beginning their visits at the apex of a
      raceme. As a result, the pollen load deposited on the stigmas decreased from apex
      to base of the raceme. In most of the flowers situated in the central and basal
      zone of the raceme, the number of pollen grains deposited on their stigmas was
      lower than the number of their ovules. The high number of seeds in developed
      fruits suggests that the plant selectively aborts flowers that receive a smaller
      pollen load. The results indicate that the final pattern of fruit arrangement
      within the raceme is a direct result of pollinator activity.

PMID- 10602765
TI  - Reproductive and vegetative organs with affinities to Haloragaceae from the Upper
      Cretaceous Huepac Chert Locality of Sonora, Mexico.
AB  - From the Upper Cretaceous (Maastrichtian-Campanian) Huepac Chert Locality of the
      Tarahumara Formation, a new extinct aquatic plant of the Haloragaceae (Subclass:
      Rosidae), Tarahumara sophiae Hernandez-Castillo and Cevallos-Ferriz, is
      presented. It is reconstructed on the basis of both reproductive and vegetative
      organs preserved in chert. Its description and comparison with extant plants are
      based on the analysis of 350 permanent slides made with thin section and peel
      techniques. A mosaic of anatomical and morphological characters found in the
      extant Myriophyllum, Meziella, and Haloragodendron is used to characterize the
      new taxon. The development from flower to fruit in the fossil plant follows
      similar stages found in some extant species of Myriophyllum. However, a floral
      cup is reported for the first time in the family, and it is compared to the
      persistent fused sepals (terminal corona) of Meziella. This plant reconstruction
      increases the morphological diversity of the Haloragaceae, demonstrates the
      presence of a new dispersal mechanism compared with those known for the family,
      suggests that this lineage had originated by at least the Upper Cretaceous, and
      refutes the interpretation of several haloragacean Tertiary reports as
      representing genera of extant plants.

PMID- 10602766
TI  - Evolutionary implications of matK indels in Poaceae.
AB  - Insertion/deletion events (indels) and nucleotide substitutions at the extreme 3'
      end of the chloroplast gene matK have been identified that distinguish certain
      major lineages of grasses. A 1-bp (base pair) deletion creating a shift in the
      open reading frame (ORF) and a point mutation support the positions of
      Streptochaeta and Anomochloa as the two most basal lineages in Poaceae. Another 1
      bp deletion resulting in early termination of the ORF is unique to Ehrharta, a
      member of the taxonomically disputable tribe Ehrharteae. A 6-bp insertion
      supports monophyly of subfamilies Panicoideae, Arundinoideae, Centothecoideae,
      and Chloridoideae (PACC). This marker appears useful in defining PACC clade
      members and may have potential in providing insight into the sister-group
      relationship between PACC and other lineages. Alignment of deduced amino acid
      sequences from bryophytes, gymnosperms, and angiosperms shows that this region is
      relatively conserved, but variation is notably higher in Poaceae. The
      evolutionary implications of these changes in grasses and other plant families
      are addressed.

PMID- 10602767
TI  - Phylogenetic relationships of Eurasian pines (Pinus, Pinaceae) based on
      chloroplast rbcL, MATK, RPL20-RPS18 spacer, and TRNV intron sequences.
AB  - The sequence divergence of chloroplast rbcL, matK, trnV intron, and rpl20-rps18
      spacer regions was analyzed among 32 Pinus species and representatives of six
      other genera in Pinaceae. The total aligned sequence length is 3570 bp. Of the
      four sequences examined, matK evolved much faster than rbcL in Pinus and in other
      Pinaceae genera. The two noncoding regions did not show more divergence than the
      two coding regions, especially within each Pinus subgenus. Phylogenetic analyses
      based on these four sequences gave consistent results and strongly supported the
      monophyly hypothesis for the genus Pinus and its two recognized subgenera. Pinus
      krempfii, the two-flat-needle pine endemic to Vietnam, was placed in subgen.
      Strobus and showed closer affinity to subsect. Gerardianae. The ancient character
      of sect. Parrya is further confirmed. However, monophyly of the sect. Parrya is
      not supported by our data. Among the Eurasian pines of subgen. Pinus,
      Mediterranean pines formed one clade and the Asian members of subsect. Sylvestres
      formed another. The Himalayan P. roxburghii showed considerable divergence from
      all the other hard pines from both regions. Pinus merkusii was distinctly
      separated from all the Asian members of subsect. Sylvestres. The implications of
      our results for Pinus classification are discussed.

PMID- 10602768
TI  - Cytogeography and chromosome evolution of subgenus Tridentatae of Artemisia
      (Asteraceae).
AB  - The subgenus Tridentatae of Artemisia (Asteraceae: Anthemideae) is composed of 11
      species of various taxonomic and geographic complexities. It is centered on
      Artemisia tridentata with its three widespread common subspecies and two more
      geographically confined ones. Meiotic chromosome counts on pollen mother cells
      and mitotic chromosome counts on root tips were made on 364 populations ( = 3.1
      plants per population). These population counts are ~60% of all Tridentatae
      counts. Some are first records for taxa. The Tridentatae are a polyploid complex
      (x = 9) with ploidy levels from 2x to 8x, but mostly 2x (48%) and 4x (46%).
      Polyploidy occurs in nine of the 11 species and in many subspecies as well.
      Supernumerary or b chromosomes are present only at a low frequency. In the
      principal species, A. tridentata, 2x plants are larger than 4x ones, which are
      adapted to drier conditions, probably in consequence of their slower growth
      rates. Gigas diploidy is a phenomenon shared by some other woody genera, but is
      in contrast to the gigas polyploid nature of many herbaceous genera. Polyploidy
      occurs within populations and is essentially autoploid. Hybridization sometimes
      occurs at taxa interfaces in stable hybrid zones. Stable Tridentatae hybrid zones
      coupled with the group's inherent propensity for polyploidization has led to the
      establishment of a geographically and numerically large and successful complex of
      species.

PMID- 10602769
TI  - Hybridization among sympatric species of Rhododendron (Ericaceae) in Turkey:
      morphological and molecular evidence.
AB  - Rhododendron (Ericaceae) is a large genus in which barriers to hybridization are
      especially weak, but many species are maintained in sympatry. Hybridization among
      four species of Rhododendron subsect. Pontica, which occur in sympatry in Turkey,
      was investigated. Material of R. ponticum, R. smirnovii, R. ungernii, and R.
      caucasicum and their putative hybrids was collected from the wild. Based on
      morphology, chloroplast DNA and nuclear ribosomal DNA restriction fragment length
      polymorphism (RFLP) profiles, each accession was identified as a species or
      hybrid combination. Five of the six possible hybrid combinations among the four
      species were detected. Rhododendron ponticum * R. smirnovii was represented by a
      single individual and R. caucasicum * R. smirnovii by one small group of hybrid
      plants. The combinations R. ponticum * R. ungernii and R. ungernii * R. smirnovii
      showed evidence of frequent backcrossing, while R. ponticum * R. caucasicum
      appeared unusual in that an intermediate hybrid type was abundant, whereas
      hybrids with phenotypes approaching either parent were rare. Possible
      explanations of this latter situation are discussed. The results suggest that
      natural hybridization among Rhododendron species is common and that ecological
      factors are important in maintaining integrity when species occur in sympatry.

PMID- 10602770
TI  - Phenology and fecundity in 11 sympatric pioneer species of Macaranga
      (Euphorbiaceae)in Borneo.
AB  - Reproductive traits of tropical tree species vary predictably in relation to
      successional stage, but this variation may be due to the species' phylogenetic
      histories rather than selective pressures imposed by regeneration requirements.
      Reproductive phenology, tree size at the onset of reproduction, and fecundity of
      11 sympatric, closely related Macaranga species were studied to investigate
      within-species variation in reproductive traits in relation to resource
      availability, and among-species variation in relation to other life-history
      traits (shade tolerance, seed size and maximum tree size, H(max)) and
      consequently the requirements for forest-gap colonization. Nine species
      reproduced in synchronous episodes, and two species reproduced continuously over
      32 mo. Episodic reproduction was most intense in 1992 following a severe drought.
      For several species, reproductive trees had greater light availability, lower
      fecundity in lower light levels, and lower growth rates than nonreproductive
      trees, reflecting resource-limited reproduction. Among species, H(max) was
      negatively correlated with shade tolerance and seed size. Tree size at the onset
      of reproduction and fecundity was strongly linked to this axis of life-history
      variation, but phenological pattern was not. Absolute tree size at the onset of
      reproduction was positively correlated with H(max) and negatively correlated with
      shade tolerance. Relative size at reproductive onset was not correlated with
      shade tolerance or H(max). Fecundity ranged four orders of magnitude among
      species and was correlated positively with H(max) and negatively with seed size
      and shade tolerance. The interrelationships among these reproductive and other
      life-history traits are strongly correlated with the species' requirements for
      gap colonization.

PMID- 10602771
TI  - Dominant Wilty mutants of Zea mays (Poaceae) are not impaired in abscisic
      acidperception or metabolism.
AB  - Abscisic acid (ABA) is a plant hormone involved in growth, development, and
      stress adaptation. It acts via multiple pathways including rapid closure of
      stomatal pores by ion efflux from guard cells (thereby decreasing water loss) and
      by slower changes in gene expression. The Wilty2, Wilty3, and Wilty-2445 mutants
      are nonallelic members of a class of dominant mutants whose top leaves wilt when
      plants are subjected to drought conditions. We investigated the ABA responses of
      the Wi2 mutant by analysis of leaf transpiration rates and RAB17 (Responsive to
      ABA) gene expression. Wi2 leaves transpired less than those of wild-type
      siblings, but the slopes of Wi2 and wild-type ABA dose-leaf transpiration curves
      were identical, suggesting that Wi2 guard cell sensitivity to ABA is normal.
      Based on total RNA blot analysis, RAB17 transcripts in unstressed and drought
      stressed Wi2 leaves were elevated relative to wild-type tissue. Wi2 ABA
      concentrations were also elevated relative to wild type in both unstressed and
      drought-stressed leaves. Similar to the Wi2 phenotype, Wilty3 and Wi-2445 mutants
      transpired less than their wild-type siblings and had normal ABA and ABA
      conjugate levels, as measured by gas chromatography-mass spectrometry. Despite
      lower leaf transpiration rates, Wi2 mutants lost a greater percentage of fresh
      mass over time compared to the wild type. The previously characterized recessive
      mutant wilty1, which has a defect in vascular element development, also had
      reduced transpiration rates. It is concluded that the dominant Wi2, Wi3, and Wi
      2445 mutants are not impaired in ABA metabolism or signaling. It is hypothesized,
      based on preliminary data, that the dominant mutants described here are impaired
      in vascular element development, analogous to the wilty1 mutant.

PMID- 10602772
TI  - Aab Institute of Biomedical Sciences.

PMID- 10602774
TI  - Heme oxygenase-2 is neuroprotective in cerebral ischemia.
AB  - Heme oxygenase (HO) is believed to be a potent antioxidant enzyme in the nervous
      system; it degrades heme from heme-containing proteins, giving rise to carbon
      monoxide, iron, and biliverdin, which is rapidly reduced to bilirubin. The first
      identified isoform of the enzyme, HO1, is an inducible heat-shock protein
      expressed in high levels in peripheral organs and barely detectable under normal
      conditions in the brain, whereas HO2 is constitutive and most highly concentrated
      in the brain. Interestingly, although HO2 is constitutively expressed, its
      activity can be modulated by phosphorylation. We demonstrated that bilirubin,
      formed from HO2, is neuroprotectant, as neurotoxicity is augmented in neuronal
      cultures from mice with targeted deletion of HO2 (HO2(-/-)) and reversed by low
      concentrations of bilirubin. We now show that neural damage following middle
      cerebral artery occlusion (MCAO) and reperfusion, a model of focal ischemia of
      vascular stroke, is substantially worsened in HO2(-/-) animals. By contrast,
      stroke damage is not significantly altered in HO1(-/-) mice, despite their
      greater debility. Neural damage following intracranial injections of N-methyl-d
      aspartate (NMDA) is also accentuated in HO2(-/-) animals. These findings
      establish HO2 as an endogenous neuroprotective system in the brain whose
      pharmacologic manipulation may have therapeutic relevance.

PMID- 10602775
TI  - Identification and expression of mutations in the hydroxymethylbilane synthase
      gene causing acute intermittent porphyria (AIP).
AB  - BACKGROUND: Acute intermittent porphyria (AIP), an autosomal dominant inborn
      error, results from the half-normal activity of the heme biosynthetic enzyme
      hydroxymethylbilane synthase (EC 4.3.1.8; HMB-synthase). This disease is
      characterized by acute, life-threatening neurologic attacks that are precipitated
      by various drugs, hormones, and other factors. The enzymatic and/or biochemical
      diagnosis of AIP heterozygotes is problematic; therefore, efforts have focused on
      the identification of HMB-synthase mutations so that heterozygotes can be
      identified and educated to avoid the precipitating factors. In Spain, the
      occurrence of AIP has been reported, but the nature of the HMB-synthase mutations
      causing AIP in Spanish families has not been investigated. Molecular analysis was
      therefore undertaken in nine unrelated Spanish AIP patients. MATERIALS AND
      METHODS: Genomic DNA was isolated from affected probands and family members of
      nine unrelated Spanish families with AIP. The HMB-synthase gene was amplified by
      long-range PCR and the nucleotide sequence of each exon was determined by cycle
      sequencing. RESULTS: Three new mutations, a missense, M212V; a single base
      insertion, g4715insT; and a deletion/insertion, g7902ACT-->G, as well as five
      previously reported mutations (G111R, R116W, R149X R167W, and R173W) were
      detected in the Spanish probands. Expression of the novel missense mutation M212V
      in E. coli revealed that the mutation was causative, having <2% residual
      activity. CONCLUSIONS: These studies identified the first mutations in the HMB
      synthase gene causing AIP in Spanish patients. Three of the mutations were novel,
      while five previously reported lesions were found in six Spanish families. These
      findings enable accurate identification and counseling of presymptomatic carriers
      in these nine unrelated Spanish AIP families and further demonstrate the genetic
      heterogeneity of mutations causing AIP.

PMID- 10602776
TI  - NO-Evoked macrophage apoptosis is attenuated by cAMP-induced gene expression.
AB  - BACKGROUND: Previous work has suggested that an increase in expression of
      cyclooxygenase-2, concomitant formation of E-type prostanoids, and in turn
      intracellular cAMP conveys macrophage resistance against apoptosis. MATERIALS AND
      METHODS: We analyzed the effects of lipophilic cAMP analogs on nitric oxide (NO)
      induced apoptosis in RAW 264.7 macrophages and human primary monocyte-derived
      macrophages. Parameters comprised DNA fragmentation (diphenylamine assay),
      annexin V staining of phosphatidylserine, caspase activity (quantitated by the
      cleavage of a fluorogenic caspase-3-like substrate Ac-DEVD-AMC), and
      mitochondrial membrane depolarization (DeltaPsi), analyzed using DiOC(6)(3).
      Western blots detected accumulation of the tumor suppressor protein p53,
      relocation of cytochrome c, and expression of the antiapoptotic protein Bcl-X(L).
      A cAMP response-element decoy approach confirmed cAMP-dependent gene induction.
      RESULTS: We verified resistance of murine and human macrophages against NO donors
      such as S-nitrosoglutathione or spermine-NO by pre-exposing cells to lipophilic
      cAMP analogs or by pretreatment with lipopolysaccaride, interferon-gamma, and
      N(G)-nitroarginine-methylester for 15 hr. Cellular prestimulation decreased NO
      evoked apoptosis, as apoptotic parameters were basically absent. Macrophage
      protection was not achieved during a short period of preexposure, i.e., 1 hr. To
      verify gene induction as the underlying protective principle, we treated RAW
      cells with oligonucleotides containing a cAMP-responsive element in order to
      scavenge cAMP response element-binding protein prior to its promoter-activating
      ability. Decoy oligonucleotides, but not an unrelated control oligonucleotide,
      weakened cAMP-evoked protection and re-established a p53 response following NO
      addition. CONCLUSION: Gene induction by cAMP protects macrophages against
      apoptosis that occurs as a result of excessive NO formation. Decreasing
      programmed cell death of macrophages may perpetuate inflammatory conditions in
      humans when macrophages become activated in close association with innate immune
      responses.

PMID- 10602777
TI  - Cysteinyl leukotrienes mediate histamine hypersensitivity ex vivo by increasing
      histamine receptor numbers.
AB  - BACKGROUND: Hyperresponsiveness to histamine is a key feature of a variety of
      pathological conditions, including bronchial asthma, food allergy, colitis
      ulcerosa, and topical allergic disorders. Cells isolated from hyperresponsive
      individuals do not display exaggerated histamine responses ex vivo and thus the
      molecular mechanisms underlying histamine responsiveness remain obscure.
      Importantly, several in vivo observations implicate cysteinyl leukotrienes as
      possible mediators of increased histamine responses. We decided to investigate
      whether cysteinyl leukotrienes enhance the cellular reaction to histamine in cell
      types involved in pathological and immunological histamine hyperresponsiveness,
      as this might provide an in vitro system for studying histamine responsiveness
      and could shed light on the underlying molecular mechanisms. MATERIALS AND
      METHODS: Histamine responsiveness was determined by measuring histamine-induced
      prostaglandin E(2) production. Scatchard analysis was performed to determine the
      number of histamine H(1) receptors. Mouse macrophages, primary isolated human
      peripheral blood monocytes, and human umbilical smooth muscle cells were
      investigated before and after cysteinyl leukotriene stimulation. RESULTS: In all
      three cell types tested, cysteinyl leukotrienes instantaneously enhanced
      histamine-induced prostaglandin E(2) production. This increase in prostaglandin
      E(2) production coincided with the immediate and transient appearance of
      additional H(1) receptors on the plasma membrane. CONCLUSIONS: Cysteinyl
      leukotrienes prime histamine responses by recruiting additional histamine
      receptors in immunologically relevant cell types in vitro.

PMID- 10602778
TI  - Circular antisense oligonucleotides inhibit growth of chronic myeloid leukemia
      cells.
AB  - BACKGROUND: Antisense represents a conceptually powerful method for regulating
      gene expression. However, antisense oligonucleotides developed to date manifest
      two serious limitations-nuclease susceptibility and nonspecific hybridization.
      Circular oligonucleotides may be superior to conventional linear oligonucleotides
      in both respects. First, circular agents, having no ends, are exonuclease
      resistant. Second, they bind to complementary strands of RNA and DNA with a
      higher affinity than corresponding linear agents. METHODS AND RESULTS: We
      assessed the activity of circular phosphodiester deoxynucleotides using chronic
      myeloid cell lines by targeting polypurine sequences. To represent cells having a
      bcr3/abl2-type junction, we used K562 cells. A circle targeting a bcr polypurine
      sequence 385 nucleotides 5' to the junction decreased the cell number by day 5
      with an IC(50) of 9 microM. To represent cells having a bcr2/abl2-type junction,
      we used BV173 cells. A circle targeting the bcr-abl junction itself decreased the
      cell number by day 7 with an IC(50) of 8 microM. Control oligonucleotides,
      whether the same sequence uncircularized or circles with the same nucleotide
      composition but in scrambled sequence, had little effect. Unlike linear agents,
      circles were stable when incubated in 10% serum. The amount of bcr-abl protein
      detected by Western blotting using a specific anti-bcr-abl antibody at 24 hr in
      antisense-treated BV173 cells was only 10% of that of cells treated with control
      circles, which demonstrates an antisense mechanism of action. CONCLUSIONS:
      Circular oligodeoxyribonucleotides (1) inhibit the accumulation of CML cells, (2)
      decrease the amount of bcr-abl protein per cell, (3) have sequence-selective
      activity, and (4) are more active than linear oligonucleotides containing only
      the base-pairing region.

PMID- 10602779
TI  - Infectivity of scrapie prions.

PMID- 10602781
TI  - [Effect of preoperative tracheotomy in transglottic T3 laryngeal carcinoma].

PMID- 10602782
TI  - [Preventing misuse of antibiotics].

PMID- 10602783
TI  - [Expert-assessment of suitability for a driving license in otorhinolaryngology].
AB  - An absolute requirement for acquiring a driving license according to German law
      consists in the suitability for driving a motor vehicle. The "driving license
      decree" defines these requirements; in case of doubt the administrative authority
      may demand a medical certificate. According to law (enactment: 1.1.99) these
      medical certificates must be refunded by either appropriate medical specialists,
      company doctors or public health officers. The criterions for appraisal are set
      down in the guidelines for driving ability which are edited by the advisory board
      for traffic medicine; a new edition will be published soon. Concerning
      otorhinolaryngology hearing impairment and dizziness are the most relevant
      diseases. Bilateral deafness is no general exception for conferring a driving
      license for the classes A and B; for classes C and DE hearing loss, established
      from the pure tone audiogram must not exceed 60%; an exceptional case is a three
      year demonstration of reliability in class B. Permanent dizziness or vertigo
      attacks are in most cases incompatible with conferring driving licenses. The most
      important issue for medical appraisal is to determine the amount of compensation
      of the impaired sense organ. Therefore in cases of multiple disabilities more
      stringent criterions must be established.

PMID- 10602784
TI  - [Stenoses of the upper airways. Lung function, local resistance and load
      compensation. A review].
AB  - In benign laryngotracheal stenosis the amount of respiratory deterioration rather
      than the crude morphologic appearance will determine whether or not surgical
      measures such as dilatation or resection should be applied. This review focuses
      on currently available and newly developed diagnostic tools to assess the
      functional importance of central airway obstruction. After an outline of upper
      airway physiology is formulated, spirometric measurements at rest are collected.
      Among these, Peak Expiratory Flow Rate (PEF) proved to be the simplest and most
      reliable parameter to monitor an obstructing lesion of the upper airways. A novel
      technique for fibrobronchoscopic assessment of glottic and tracheal resistance is
      presented in detail. In contrast to usual tests of total airflow resistance which
      cannot distinguish between central and peripheral contributions, this test
      identifies the pressure-flow-relationship created exclusively by the local
      lesion. In serial stenoses, it indicates which is of higher clinical impact.
      Patients with upper airway obstruction complain of impaired exercise capacity.
      They tend to hypoventilate with imminent respiratory muscle fatigue. Therefore,
      spiroergometry may play a role in defining the point of incomplete compensation
      of a central load. The decision to operate will depend upon up the degree of
      physical capacity required to compensate for the stenosis.

PMID- 10602785
TI  - [Evaluation of the "new" TNM classification of head and neck tumors in 3247
      patients].
AB  - The 5th edition of the TNM classification entails a number of changes concerning
      head and neck tumors. The division of stage IV tumors into three subcategories
      marks a significant expansion of the stage grouping procedure. METHODS: In a
      retrospective study the clinical course of 3247 patients with head and neck
      carcinomas were comparatively evaluated according to the 4th and 5th editions of
      the new TNM classification. In particular it was the aim of the study to test the
      prognostic relevance of the subdivision of stage IV especially in mucosal cancer.
      RESULTS: In classifying the primary tumor the most extensive changes were noted
      for supraglottic and salivary gland tumors. On the basis of the 4th edition of
      the TNM classification the following recurrence-free 5-year survival rates for
      3033 cases of mucosal cancer were calculated: stage I 91,0%, stage II 78.6%,
      stage III 61.4%, stage IV 31.0%. The calculations based on the 5th edition
      yielded: stage I 91.0%, stage II 77.2%, stage III 61.2%, stage IVA 32.4%, stage
      IVB 25.3%, stage IVC 3.6%. CONCLUSIONS: The adequacy of the revised stage
      classification in establishing a prognostic hierarchy was confirmed. However, a
      significant prognostic distinction between N2- (stage IVA) and N3-metastasis
      (stage IVB) could not be found.

PMID- 10602786
TI  - [Clinical and diagnostic findings of sialolithiasis].
AB  - INTRODUCTION: Sialolithiasis is one of the most common diseases of the salivary
      glands. Within the scope of a retrospective analysis we report on our clinical
      and diagnostic findings in the largest patient group suffering from
      sialolithiasis reported in literature. MATERIAL AND METHODS: Between 1987 and
      1997, data from 635 patient histories and follow-up examinations were
      systematically collected and analysed to look for typical symptoms of
      sialolithiasis, locations of stones and possible risk factors. RESULTS:
      Sialoliths predominated among patients aged 30 and 70 years, with no male/female
      predilection. A total of 78.9% of all calculi were detected in the submandibular
      ducts and 21.1% in the ducts of the parotid glands. The sublingual gland and the
      smaller salivary glands were not affected. A simultaneous stone disease of the
      urinary tract or the bile duct system occurred by chance (4.3%). Even regular
      medication in cases of other systemic diseases cannot be considered cofactors in
      pathogenesis. CONCLUSION: Diagnosis of sialolithiasis is the result of careful
      consideration of patient histories demonstrating typical symptoms and clinical
      examination. Sonography is the first choice of imaging. Pathogenesis of
      sialolithiasis seems to be based on local factors within the salivary ducts and
      glands.

PMID- 10602787
TI  - [The usefulness of intraoperatively registered, electrically evoked stapedius
      reflex for the programming of cochlear implants in children].
AB  - The programming of a cochlear implant speech processor used by young children is
      often difficult, especially when the stimulus level associated with maximum
      auditory loudness (MAL) needs to be determined. Excessively high stimulation
      should be avoided as this can have a traumatic effect. The aim of this study was
      to determine if a relationship exists between the intraoperatively determined
      electrical stapedius reflex threshold (ESRT) and the postoperatively determined
      MAL and hearing threshold for 27 patients, each having one of three implant
      types. The question of whether the ESRT provides a practical technique to
      simplify, improve and accelerate speech processor programming was investigated.
      For the monopolar stimulation mode used for the Med-El and Clarion implant
      systems, the average MAL and threshold was expressed as a percentage of the
      average ESRT across all electrodes. For the "common ground" stimulation mode used
      for the Nucleus implant system, a parabolic transformation was used to relate MAL
      and ESRT to one another. These transformations between MAL values calculated from
      the ESRT and the actual MAL values, determined psychoacoustically, diverged
      considerably from one another. Therefore, it was not possible to determine the
      MAL from the ESRT with certainty. The ESRT does, however, provide a means to
      estimate an approximate upper boundary for the MAL, apart from its use to control
      implant function. The determination of the exact MAL will still need to be
      determined using behavioural techniques.

PMID- 10602788
TI  - [Prospective investigations on the spontaneous healing of intraoperative lesions
      of the mucosa of the nasal septum].
AB  - Mucosal lesions of the nasal septum during septal surgery are frequent, but there
      is scarce information in the literature about their outcome. In 283 operations of
      the nasal septum, 92 (32.5%) mucosal lesions occurred, 67 of these could be
      documented and classified 1, 3 and 6 months postoperatively. Although there was
      no therapy in 93% (74 cases) of the one-sided lesions, no permanent septal
      perforation was seen. A total of 7% (six cases) were treated by suture or
      lyophilised dura combined with tissue adhesive. On the other hand, double-sided
      and correspondent lesions (12 cases: six without therapy, four sutures, one
      lyophilised fascia, one tissue adhesive) showed a perforation in five cases
      without any symptoms. This represents 1.7% of all operations of the nasal septum
      and 7.4% of all recorded mucosal lesions of the nasal septum. Although the number
      of examinations are still few, it might be justifiable to conclude that one-sided
      lesions of the nasal septum need no specific therapy. All bilateral corresponding
      lesions, even those smaller than 5 mm, should be treated by one-sided suture in
      the anterior septum and with tissue adhesive in the posterior septum. The use of
      cartilage, bone or fascia alone is insufficient. Large defects of the mucosa
      should be treated by maximal therapy, i.e. covering with lyophilised fascia or
      dura, underlaying of cartilage or bone and using tissue adhesive.

PMID- 10602789
TI  - [Phoniatric studies in myasthenia gravis patients].
AB  - The authors have for the first time evaluated the basic parameters of the voice
      using computed voice analysis in patients with myasthenia gravis (MG). The aim of
      the study was to introduce an objective method suitable for the assessment of
      dysphonic symptoms, which predominate in bulbar, oculobulbar and generalized MG.
      Voice profile studies included the evaluation of the singing voice range, voice
      dynamics, maximum phonation time, and mean fundamental frequency and intensity
      during speech. The characteristic of the stroboscopic picture was also
      determined. Investigations were carried out before and after the intake of
      Mestinon, a reversible cholinesterase inhibitor, and healthy subjects were used
      as a control group. In MG, the voice range and dynamics are badly impaired,
      maximum phonation time is shortened, the mean fundamental frequency during speech
      is increased, while the intensity is decreased. Mestinon resulted in an
      improvement in all these parameters, however, they were still impaired in
      comparison to the control subjects. Most changes were found to be statistically
      significant. The authors emphasize the role of the otolaryngologist and objective
      phoniatric methods in the evaluation of MG and other myasthenia-like neurological
      diseases. The use of these methods for the assessment of phoniatric symptoms in
      neurological diseases is highly recommended.

PMID- 10602790
TI  - [An aberrant course of the internal carotid artery through the middle ear].
AB  - The presence of the internal carotid artery in the middle ear is a rare but known
      vascular anomaly. A blue-reddish mass behind the tympanic membrane, hearing loss
      and a tinnitus that is synchronous with the pulse are the typical symptoms and
      should lead to a correct diagnosis. The diagnostic procedure includes high
      resolution CT scans with or without contrast or MRI. Possible methods of therapy
      include embolization, stent implantation or balloon occlusion of the internal
      carotid artery but are seldom indicated clinically because of the high rate of
      side-effects. However, regular followup examinations must be performed.

PMID- 10602791
TI  - [Temporal bone fracture after head trauma causing rhinoliquorrhea and
      meningitis].
AB  - We report our experience in managing a temporal bone fracture after head trauma
      that had no apparent clinical signs. Recurrent CSF rhinorrhea and meningitis lead
      to extensive diagnostic procedures. Operative exploration of the temporal bone
      demonstrated a fracture line along the horizontal part of the carotid artery. The
      location of the fracture did not cause such typical symptoms as hearing
      impairment, facial paralysis, vertigo or tinnitus. Only CSF liquorrhea through
      the Eustachian tube indicated a fracture at the lateral skull base.

PMID- 10602792
TI  - [Slowly growing space-occupying lesion of uncertain origin in the left jaw angle.
      Bilateral carotid body tumor].

PMID- 10602793
TI  - [Recurrent inflammation of cartilaginous structures. Relapsing polychondritis].

PMID- 10602794
TI  - [Adverse effects of cytostatic chemotherapy in patients with head and neck
      carcinomas. Prevention and therapy].

PMID- 10602795
TI  - [Dear readers, ladies and gentlemen].

PMID- 10602796
TI  - [The technical bases and uses of multi-slice CT].
AB  - In this review the technical principles and applications of multi-slice CT are
      discussed. Multi-slice CT systems allow simultaneous acquisition of up to 4
      slices by using multi-row detector systems. Intuitive geometrical arguments are
      used to establish the limitation to a maximum of 4 slices which is kept by all
      currently existing multi-slice CT systems. Two different construction principles
      of the detector are discussed, the "Fixed Array" detector and the "Adaptive
      Array" detector. The extension of conventional 360 LI and 180 LI spiral
      interpolation techniques to multi-slice spiral CT is explained as well as a new
      generalized multi-slice spiral weighting concept, the so-called "Adaptive Axial
      Interpolation". Several techniques to improve multi-slice spiral image quality
      are discussed. Finally, some examples for clinical applications are given, and
      the principle of ECG triggered and ECG gated cardiac examinations with optimized
      temporal resolution is presented. Multi-slice CT systems are a milestone with
      respect to increased volume coverage, shorter scan times, improved axial
      (longitudinal) resolution and better use of the X-ray tube output. Additionally,
      new clinical applications are possible such as Cardiac CT.

PMID- 10602797
TI  - [The morphological and functional diagnosis of the head-neck area with
      multiplanar spiral CT].
AB  - PURPOSE: To evaluate the improvement of multislice-spiral CT in the assessment of
      head and neck tumors. MATERIAL AND METHODS: 80 patients with suspected tumor in
      the head and neck region were examined with MSCT (Somatom Plus 4 VZ) after the
      administration of i.v. contrast material. Slice collimation was 4 x 1 mm with a
      pitch factor of 6. Additional multiplanar reformations were calculated in each
      case. RESULTS: The specific anatomy and pathways of tumor spread is difficult to
      demonstrate in cross-sectional imaging. Tumor infiltration of the base of the
      skull or the palate could be depicted or excluded on coronal MPR, additional
      coronal scanning was not necessary. The detection of pathologic lymph nodes was
      improved with MPR in 7 patients. DISCUSSION: The exact determination of tumor
      margins is mandatory for modern therapy concepts of limited surgery. High
      resolution datasets are basis for reformations in arbitrary planes, making
      additional coronal scanning not necessary. Functional imaging of the larynx and
      hypopharynx improve the diagnostic accuracy of CT, a short scan time is necessary
      to reduce motion artifacts. Conclusive assessment of tumor infiltration,
      lymphatic spread and functional alterations is improved with MSCT.

PMID- 10602798
TI  - [The diagnosis of stages T1 and T2 in laryngeal carcinoma with multislice spiral
      CT].
AB  - The purpose of the study was to preoperatively investigate small laryngeal
      carcinomas using multi-slice spiral CT (MSCT) and subsequent multiplanar
      reconstructions (MPR) and to compare the results to the detailed spread found at
      surgery and histology. Nine patients with small (T1, T2) laryngeal cancer were
      investigated on a MSCT scanner (Siemens plus 4 Volume Zoom, Siemens). A 4 x 1 mm
      collimation, 120 kV, 200 mAs and a 0.5 seconds rotation time were used, allowing
      a coverage of the entire larynx in approximately 10 seconds within a single
      breathhold. Multiplanar reconstruction's (MPR) in sagittal and coronal plane were
      reconstructed in all patients and rated in consensus reading. In 8 of nine
      patients, the glottic spread was detected by MSCT, in one cause of a supraglottic
      tumor a glottic invasion was excluded. The infiltration of the anterior
      commissure, the infiltration into the subglottic space and the extension into the
      hypopharynx was correctly assessed in all patients. MSCT was not able to predict
      infiltration of the arythnoids in two patients. The use of multi-slice spiral CT
      for the preoperative assessment of small laryngeal tumors shows great promise.
      The detection or exclusion of subtle spread of these tumors into the supra- or
      subglottic space and along the glottic level was possible with high accuracy. As
      the examination time is short, artifacts are rare and multiplanar reconstructions
      gain in clinical importance.

PMID- 10602799
TI  - [Imaging of the thorax with multislice spiral CT].
AB  - With multislice spiral computed tomography (MSCT), existing indications for
      performing CT of the chest are strengthened and new applications are emerging.
      The high speed of MSCT improves efficiency, image quality and patient comfort of
      "routine" imaging of the chest. The ability to cover large volumes with thin
      slices improves the evaluation of mediastinal lymph nodes and pulmonary nodules
      and allows for high-quality secondary reconstruction. If a comprehensive
      diagnosis of the mediastinal structures and the pulmonary parenchyma is desired,
      MSCT for the first time allows reconstruction of contiguous and high-resolution
      (HRCT) sections from the same set of thin-collimation raw data. This way,
      contiguous chest images of superior and HRCT sections of equal image quality
      compared to conventional CT scanning can be obtained. Vascular protocols greatly
      benefit from the high speed of MSCT: For imaging the thoracic aorta or pulmonary
      emboli (PE), the amount of contrast material can be substantially reduced. Owing
      to thin collimation, the detection rate of small peripheral emboli can be
      significantly increased. If indicated, the entire subphrenic venous system can be
      evaluated during the same session, without additional contrast material.

PMID- 10602800
TI  - [Image analysis in multislice spiral CT of the lung with MPR and MIP
      reconstructions].
AB  - PURPOSE: To test, whether axial, coronal and sagittal MIP and MPR reconstructions
      of diagnostic quality can be obtained from 1-mm collimation MSCT data of the
      chest for the evaluation of thoracic anatomy and pathology. MATERIALS AND
      METHODS: 1-mm collimation MSCT scans were obtained with a pitch of 6 in an
      acrylic phantom and in 20 patients. Axial images were reconstructed with 0.6-mm
      increment. Multiplanar reformations (MPRs) and sliding thin-slab maximum
      intensity projections (STS-MIPs) were reconstructed in axial, coronal and
      sagittal planes. Images were printed in lung windows and evaluated by three
      readers by using a standardized evaluation scheme. RESULTS: Overall, both methods
      allowed good visualization of anatomic structures. MIP was superior for
      visualization of the pulmonary arteries (p < 0.05) while central and peripheral
      bronchi and the lung parenchyma were better depicted on multiplanar
      reconstructions. A confident diagnosis of thoracic pathology was feasible using
      both modalities, however MIPs appeared less usefull for evaluation of gross
      parenchymal abnormalities, such as pneumonic infiltrates or fibrotic changes. No
      significant difference in the degree of motion artifacts were detected between
      both modalities. CONCLUSION: MSCT data sets are ideally suited for generating MPR
      and MIP reconstructions. While MIPs are superior for the evaluation of thoracic
      vessels, MPR is advantageous for visualizing central and peripheral bronchi and
      the pulmonary parenchyma.

PMID- 10602801
TI  - [Multiplanar spiral CT in the diagnosis of pancreatic tumors].
AB  - PURPOSE: Investigation of the capabilities of MSCT and its value for the staging
      of pancreatic carcinomas. METHODS: 50 Patients with suspected pancreatic
      carcinoma were examined with a biphasic multislice-spiral-CT protocol: slice
      collimation 4 x 1 mm, Pitch 3.5-4 mm. After administration of 120 ml contrast
      medium and 50 ml NaCl with a flow rate of 3.0 ml/s the examination was started
      with a delay of 40 s (pancreatic phase) and 80 s (portal venous phase). RESULTS:
      Multislice spiral CT allows the examination of the whole upper abdomen with
      nearly isotropic data sets. This is the premise for the optimal assessment of the
      tumor extent in all planes, excellent demarcation of the tumor against the
      adjacent vessels and organs and the demarcation of small peripancreatic lymph
      nodes. CONCLUSIONS: Multislice spiral CT and the use of interactive multiplanar
      reconstructions improve the staging of pancreatic cancer.

PMID- 10602802
TI  - [Multislice computed tomography of the small intestine. Preliminary results].
AB  - SUBJECT: Spiral computer tomography (SCT) became an important supplement to the
      Sellink examination. Multi slice computer tomography (MSCT) achieves a z-axis
      resolution of 1-2 mm without considerable increase in the acquisition time. In
      this paper, examination technique in first clinical results of CT-Sellink
      examination with MSCT, including the 3D-reconstruction are presented. MATERIALS
      AND METHODS: The investigations were carried out with the Somatom Plus 4 Volume
      Zoom (Siemens, Forchheim) scanner. The following parameters were employed: 4
      parallel detector ledges, collimation 4 x 1 mm, tube power 140 mA, tube voltage
      120 kV, pitch 5 up to 6 mm, slice thickness 1 mm and 2 mm, reconstruction with
      50% overlap. Via a duodenal tube, the small intestine was distended by means of
      1.5 up to 2.5 l methyl-cellulose suspension. The data were acquired 35 s after
      injection of 120 ml contrast media (Ultravist). Various methods of postprocessing
      were applied on a workstation. RESULTS: As of yet, 16 patients were examined with
      MSCT-Sellink. In 4 cases pathological findings were detected with MSCT-Sellink,
      which were not recognized with X-ray Sellink. CONCLUSION: Due to high z-axis
      resolution and short acquisition time, the morphological details of the small
      intestine can be visualized utilizing MSCT-Sellink. The data set is well suited
      for 3D postprocessing. Improvement of diagnostic accuracy can be anticipated.

PMID- 10602803
TI  - [Biphasic liver diagnosis with multiplanar-detector spiral CT].
AB  - PURPOSE: Scan protocol optimization and value of a multi-row-detector helical CT
      (MS-CT) in comparison to a single-row-detector spiral CT (SS-CT) for imaging of
      focal liver lesions. MATERIALS AND METHODS: The ability of a MS-CT with different
      scan parameters (slice thickness, scan mode, table-speed, reconstruction
      interval) for the detection of low-contrast objects was evaluated with a liver
      phantom and compared to a SS-CT. The clinical value (detection and
      characterization) of MS-CT with various slice thicknesses (3.75, 5, 7.5 mm) was
      compared intraindividually in 20 patients with a total of 43 benign and malignant
      lesions. RESULTS: In the experimental study the MS-CT reached the same detection
      rates for low-contrast objects despite a three-times faster scan-time compared to
      a SS-CT. The slice thicknesses of 3.75 and 5 mm proved to be optimal and were
      superior to a thickness of 7.5 mm for the detection and characterization of liver
      lesions. A distinct separation between arterial and portal venous phase was
      achieved by this protocol. CONCLUSION: The MS-CT allows a reliable acquisition of
      the entire liver parenchyma in defined perfusion phases. It improves the
      detection and characterization of focal liver lesions with optimized scan
      parameters with a significantly faster scan time than with the SS-CT.

PMID- 10602804
TI  - [The diagnosis of acute aortic diseases with multiplanar-detector CT using the
      spiral technic].
AB  - Acute diseases of the central arteries require an immediate investigation. An
      efficient, fast and reliable diagnosis is necessary because of the high
      mortality, if the patient remains untreated. These requirements are perfectly
      fulfilled by the new CT-techniques. METHODS: Suspected aortic diseases were
      examined with a new multi-slice helical CT. The thoracic or the abdominal aorta
      as well as the entire vascular tree from the supra-aortic branches to the
      inguinal arteries were investigated with different CT protocols. The slice
      thickness and the scan mode were changed while the total examination time was
      kept constant for the first two groups. In the third group a monophasic
      examination was compared to a biphasic one. RESULTS: In the diagnosis of acute
      aortic diseases multi-slice helical CT proved to be a fast and reliable method
      with all scan protocols. The objective measurements of contrast homogeneity and
      image quality were comparable in the first two groups. The monophasic contrast
      medium injection protocol was superior to the biphasic administration mode.
      CONCLUSIONS: Multi-slice helical CT appears to be a very effective approach for
      the diagnosis of acute aortic diseases and seems to be the new gold standard.

PMID- 10602805
TI  - [Brain tumor resections in an open 0.5-T MRT. 2 years' experiences from the
      neuroradiological viewpoint].
AB  - After two years clinical experience using an open 0.5 T-MRI, which make it
      possible to control all steps of a brain tumor resection, the high expense in
      relation to the effect is proofed. In 80 MRI-guided brain tumor resections the
      indication, the degree of resection, the appearance of operative induced changes,
      complications and clinical state are analysed. The advantage of the method
      consists in safety of localisation and detection especially of intra-axial
      cerebral tumors, recording of intraoperative invisible tumor parts and saving
      eloquent areas during tumor resection. To have optimal results, all over the
      operation time, the participation of a special experienced radiologist is
      necessary. The best results are shown in treatment of low grade gliomas and
      tumors near eloquent areas.

PMID- 10602806
TI  - [Routine skull CT in psychiatric diagnosis].
AB  - PURPOSE: To prospectively assess the spectrum of brain CT findings in psychiatric
      patients and to determine the number of patients that had an underlying cause for
      the symptoms. PATIENTS AND METHODS: Over a period of six months, 142 patients (78
      males, 64 females; median age 61 [18-91] years) were referred for CT brain scans.
      Their scans were reviewed, along with the clinical information that was provided
      in the request form. All the hard copies were reviewed to assess areas of
      ischaemia, infarction, atrophy, tumours, and haematomas. The majority of requests
      were to exclude vascular event or space-occupying lesions. Clinical indications
      included mood disorders (depression, mania), schizophrenic disorders, dementia,
      personality and behavioural disorders. RESULTS: 31 (22%) were normal. 111 (78%)
      had varying degrees of ischaemia, infarction and cerebral/cerebellar atrophy. 7
      (4.9%) had space-occupying lesions which included two gliomas and five
      meningiomas. There were two chronic subdural haematomas and one arteriovenous
      malformation. CONCLUSION: 1. In our series, pathologic findings in "routine"
      brain CT's were encountered in 78%. 2. The incidence of brain tumours was 4.9%,
      compared with 0.00005% of the general population. 3. CT scanning in psychiatric
      patients is cost-effective and especially indicated when there is an atypical
      presentation, or inadequate response to standard treatment.

PMID- 10602807
TI  - [An asymptomatic retroperitoneal space-occupying lesion. Retroperitoneal
      extrarenal angiomyolipoma].

PMID- 10602809
TI  - ?

PMID- 10602808
TI  - [Pneumonias in childhood. Their age dependence, forms and therapeutic
      consequences].

PMID- 10602811
TI  - ?

PMID- 10602810
TI  - [In Process Citation]

PMID- 10602812
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PMID- 10602813
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PMID- 10602815
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PMID- 10602816
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PMID- 10602817
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PMID- 10602818
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PMID- 10602819
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PMID- 10602820
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PMID- 10602821
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PMID- 10602823
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PMID- 10602822
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PMID- 10602824
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PMID- 10602825
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PMID- 10602826
TI  - [The low back problem].

PMID- 10602827
TI  - [Lumbago and radicular complaints: not always a herniated disk or degenerative
      stenosis of the spinal canal. A differential diagnosis of infrequent diseases].
AB  - Low back ache and pain in the legs are not always due to disc displacement and
      lumbar spinal degenerative changes. Some infrequent, but really not very rare
      diseases are presented in order to avoid mistakes which can have serious
      consequences for the patients. Degenerative changes of the lumbar spine are very
      common, not only in aged people. A superficial examination of the patient with
      back ache and/or pain in the legs can lead to a fallacious tie-up between such
      lesions and disturbances and complaints which are not connected to them.

PMID- 10602828
TI  - [Injection therapy in lumbar syndromes].
AB  - Injection therapy as part of orthopaedic pain treatment is of major importance in
      sciatica. It helps to differentiate unclear complaints and allows a break through
      of the vicious circle of pain and muscle spasm. Pharmacological principles and
      possible complications have to be observed. The different techniques need
      experience and manual training. The paper describes the various injection
      techniques in detail.

PMID- 10602829
TI  - [Medical training therapy in lumbar syndromes].
AB  - Chronic low back pain can be considered to be one of the most frequently treated
      and most costly diseases in modern industrial societies. Dysfunctions and
      imbalances of the spine-supporting muscles increase the risk of low back pain.
      Consequently preventive treatment and rehabilitation have to aim at preserving
      and restoring the full capacity of the spine-supporting muscles as well as
      training coordination and spine-friendly behaviour. In addition to various
      measures of pain therapy, physiotherapeutic treatment including neuro
      physiotherapy, physical treatment (eg electrotherapy), balneotherapy and
      supportive behavioural training, medical rehabilitation therapy (MRT) ranks among
      the most effective ways of treating low back pain. MRT applies guidelines and
      methods of exercise methodology within medically indicated programmes of
      preventive treatment and rehabilitation. Various objectives of MRT are outlined
      with special regard to the stages of MRT treatment, emphasizing positive
      adaptation of the neuro-muscular system in the course of rehabilitation.
      Physicians are responsible for MRT diagnosis and control. Taking into account the
      base disorder and the progress of therapy physiotherapists and the physicians in
      charge determine MRT objectives and treatment strategies.

PMID- 10602830
TI  - [Manual therapy in lumbo-vertebral syndromes].
AB  - Based upon the shortly presented survey among the members of the Swiss Medical
      Association for Manual Medicine, the low back pain problems are approached by the
      means of manual therapy on average 805 times per year and physician. On average
      each case with low back pain is treated 1,4 times by a general practitioner with
      experience in manual medicine while specialists who are dealing with more complex
      cases on average 4 to 5 times. The functional disorders of the lumbar spine
      treated by manual therapy are superior to the physiotherapy approach or in
      comparison with a "placebo group" (information by general practitioner about low
      back pain and application of medication). An appropriate indication for manual
      therapy is relevant to avoid or reduce the possible risk of the treatment
      procedure. The physician who performs the manual therapy has to know the limits
      of the method. Also the knowledge of contraindications for manual therapy will
      reduce the incidence of possible complication. However based upon the survey
      among the swiss association the side effects and complications due to manual
      therapy of the lumbal spine are extremely seldom.

PMID- 10602831
TI  - [The multimodal interdisciplinary therapeutic program in chronic back pain. A new
      treatment strategy].
AB  - The epidemic-like rise in chronic low back pain in western industrial nations is
      less an expression of a medical than a psychosocial phenomenon. Differentiation
      between acute, chronic or chronifying pain is of crucial importance for
      therapeutic procedures. Pain syndromes in the muscular-skeletal system tend to
      become chronic to a far larger extent than expected. More than 80 % of low back
      pain represents a functional pain syndrome and does not show any pathoanatomical
      correlate. Pain existing independently seems to be predestined by a somatic and
      psychosocial deconditioning syndrome. Those at risk of chronifying pain or those
      whose pain is already chronic should be given an interdisciplinary, multimodal
      therapeutic program. A pilot study was carried out in our clinic:
      multidisciplinary treatment was given to our patients (of which over 90 %
      belonged to stages II and III on the Gerbershagen scale) and the result was
      significant improvement in the measurements of pain intensity, sensoric and
      affective pain perception, their list of complaints, the common scale of
      depression and the pain disability index. Taking previously published studies
      into consideration, it is safe to say that a multidisciplinary, multimodal
      program of therapy even after stay in hospital results in considerable relief of
      pain and improvement in the ability to cope with the pain for patients with
      chronified pain syndromes in the muscular-skeletal system which are resistant to
      treatment on an outpatient basis.

PMID- 10602832
TI  - [Effectiveness of the back school. A review of the results of evidence-based
      evaluation].
AB  - Back schools are high frequency-low cost interventions. Their effectiveness has
      lately been regarded with skepticism. The variety of back school programs makes
      an over-all evaluation difficult. The number of evaluative publications has
      increased dramatically during the last 10 years, including 18 randomized
      controlled trials. Results of these studies have been contradictory. The results
      of two lately published randomized controlled trials, of 18 randomized controlled
      trials, of five systematic reviews, two publications conducting metaanalyses, and
      five task forces presenting guidelines for clinical practice are reported.
      According to the conclusions of the reviews there is limited to strong evidence
      for the effectiveness of back schools for chronic back pain. The metaanalyses
      show clear effects for knowledge and behavior change up to 6 months. Three of
      five task forces recommend back schools for acute pain respectively at worksite.
      Summarizing the results of the given evidence based recommendations it is
      concluded that back schools at work sites and back schools with intensive
      training is effective. There is still need to prove the effectiveness of single
      elements of the back school programs, of strategies to increase long term
      effects, the effectiveness for subtypes of patients and the effectiveness of back
      schools as part of a comprehensive orthopedic pain therapy.

PMID- 10602833
TI  - [Aspects of conservative sciatic pain therapy].
AB  - Successful multimodal conservative treatment of sciatic pain will prevent
      unfavorable results of life discectomy and accelerates the natural course. In
      assessment of modalities of conservative treatment of sciatic pain, somatic and
      psychosomatic aspects have to be considered. Severe neurological deficits caused
      by lumbar disc herniation have to be treated surgically. Conservative treatment
      of sciatic pain follows the etiopathogenetic hypothesis of a centrally triggered
      and radicularly terminated inflammation; it reflects the biopsychosocial
      paradigm. Inflammatory alterations in the disc and psychosocial peculiarities of
      the patients prove this disease model. Conservative treatment of sciatic pain
      does not determine its, but works by the combined operation of different but
      etiopathogenetic or scientifically efficient means. Somatic therapy aims at
      blocking the inflammatory cascade by peridural and systemic antiphlogistic drugs,
      sufficiently applied analgesics and temporally limited bedrest. Physiotherapy and
      sports therapy for remobilization will follow. Psychosomatic therapy works
      through relaxation, support and interpretation. Physiotherapy, relaxation and
      verbal intervention work prophylactically, too. The patient-doctor relationship
      plays a crucial role in conservative treatment of sciatic pain.

PMID- 10602834
TI  - [Allo-arthroplasty of the knee joint].

PMID- 10602835
TI  - Pre-Conference Satellite Symposium on Biomechanics.Sponsored by Stratec.

PMID- 10602836
TI  - The relationship between phalangeal bone density and vertebral deformities.
AB  - Radiographic absorptiometry (RA) of the phalanges is a convenient and reliable
      technique for measuring bone mineral density (BMD). It needs only a radiograph of
      the hand, which can be sent for evaluation to a central facility, whereas other
      techniques require specialized equipment. We assessed the relationship between RA
      measurements and the presence of vertebral deformities in a population-based
      cohort of postmenopausal women, and to compare the results with simultaneously
      obtained BMD of the hip by dual-energy X-ray absorptiometry (DXA). A total of 389
      women aged 55-84 (mean age 67.2 years, SD 8.7) were randomly selected from a
      large general practice. RA, DXA of the hip, and vertebral deformities in the
      lateral spine X-rays by vertebral morphometry were assessed. Thirty-eight women
      (9.8%) had severe (grade II) vertebral deformities, and their BMD at the
      phalanges and femoral neck was significantly lower than that of women without
      severe vertebral deformities. Odds ratios for the presence of severe vertebral
      deformities of 1.5 (95% CI: 1.1-2.1) for RA and 1.3 (95% CI: 0.9-1. 9) for DXA,
      together with similar receiver operating characteristics curves, were found using
      age-adjusted logistic regression. Phalangeal BMD is related to vertebral
      deformities at least as closely as BMD of the femoral neck BMD. RA may therefore
      help to evaluate fracture risk, especially if no DXA equipment is available.

PMID- 10602837
TI  - Influence of body composition on quantitative ultrasound parameters of the os
      calcis in a population-based sample of pre- and postmenopausal women.
AB  - Body mass is known to be related to measures of bone mineral density (BMD) as
      well as to parameters of quantitative ultrasound (US). To examine the effect of
      the body compartment's fat mass and lean body mass on quantitative ultrasonic
      bone parameters, data from a sample of 3241 German women were analyzed.
      Anthropometric measures, including skinfold thickness, were obtained from
      standardized measurements, and fat and lean body mass were derived from classical
      regression formulas based on skinfold measurements. Ultrasonic bone measurements
      were performed on the right os calcis, and speed of sound (SOS) and broadband
      ultrasound attenuation (BUA) were determined. Women were grouped into pre- and
      postmenopausal status; postmenopausal women were further stratified into ever and
      never hormone-replacement user. Correlation analysis indicated lean body mass to
      be stronger correlated with BUA than fat mass in both pre- (r = 0.23; P = 0.0001)
      and postmenopausal women with (r = 0.19; P = 0.0001) and without hormone
      replacement therapy (HRT) (r = 0.26; p = 0.0001). SOS demonstrated very small or
      no associations with body mass or its components. Multiple linear regression
      models were used to describe the relationship among body weight, fat mass, and
      lean body mass on BUA after adjustment for confounding variables. Both in pre-
      and postmenopausal women lean body mass was more strongly related to BUA than fat
      mass. However, body mass measures explained only small amounts of the overall
      variance in BUA (R(2) = 1-3% in premenopausal women; R(2) = 1% postmenopausal
      with HRT; R(2) = 4-5% in postmenopausal women without HRT). In conclusion, the
      strong influence of body mass and its components previously reported for BMD was
      not observed for quantitative ultrasonic bone parameters.

PMID- 10602838
TI  - Bone ultrasonometry and turnover markers in primary hyperparathyroidism.
AB  - Quantitative ultrasound (QUS) of bone and new markers of bone remodeling have
      been poorly investigated in mild primary hyperparathyroidism (PHPT). In this
      study 26 patients (20 females and 6 males) were evaluated. BUA and SOS were
      measured by QUS at the heel. Markers of bone remodeling assessed were bone
      alkaline phosphatase (BAP), osteocalcin (OC), procollagen type I N- and C
      terminal propeptides (PINP et PICP), and procollagen type I C-terminal
      telopeptide in blood and urine (ICTP and CTX). Bone mineral density (BMD) was
      measured at the lumbar spine (LS), femoral neck (FN), and Ward's triangle (WT).
      The control group comprised 35 sex- and age-matched subjects. The statistically
      significant variables between the two groups were (P < 0.05) BUA, BMD(LS),
      BMD(FN), BMD(WT), BAP, and OC. Corresponding z-scores were -0.55 +/- 0.75, -0.66
      +/- 0.77, -0.66 +/- 0.71, -0.67 +/- 0.52, 1.87 +/- 3.87, and 1.93 +/- 3.53,
      respectively. Although PICP and PINP levels were higher in PHPT patients as
      compared with controls, the difference was not significant. Several markers of
      bone turnover were moderately correlated with both QUS (r = -0.39 to -0.55) and
      BMD (r = -0.48 to 0.63). In conclusion QUS seems to be a relevant tool in the
      assessment of bone status for patients with mild PHPT.

PMID- 10602839
TI  - Quantitative ultrasound imaging of the calcaneus: precision and variations during
      a 120-Day bed rest.
AB  - This study reports on the precision and variation of quantitative ultrasound (US)
      parameters [broadband ultrasonic attenuation (BUA) or slope of the frequency
      dependent attenuation in dB/MHz and speed of sound (SOS m/second)] after 120 days
      of continuous bed rest in six normal male volunteers. Quantitative US was
      measured at the calcaneus using a new US bone imaging scanner. The measurements
      were carried out on both heels at approximately 2-week intervals. The short-term
      precision was 0.31% for SOS and 2.8% for BUA. The long-term precision was 0.58%
      for SOS, 4.7% for BUA. A significant decrease of SOS values of -26 m/second (P <
      0.0001) for the right heel and -17 m/second (P < 0.05) for the left heel was
      found at the group level. In terms of percentage change this represents -1.7% for
      the right heel and -1.1% for the left heel. These percentage decrements were 3.5
      5.5 times that of the short-term precision and 2-3 times that of the long-term
      precision of the technique. At the individual level, the decrease of SOS was
      statistically significant (P < 0.05) or marginally significant (P < 0.1) for four
      out of 6 subjects. For 2 other subjects, similar trends were observed, but
      without reaching statistical significance. BUA did not change significantly
      during follow-up. These results are consistent with previous findings on changes
      of ultrasonic properties from the calcaneus during aging, pregnancy, or therapy,
      showing that calcaneus SOS is a valuable index of bone loss. These preliminary
      data suggest that prolonged exposure to simulated weightlessness may lead to a
      lower SOS, which then could be used for the follow-up of bone demineralization
      occurring during long-term space flights.

PMID- 10602840
TI  - Activity increase after extraction of alkaline phosphatase from human
      osteoblastic membranes by nonionic detergents: influence of age and sex.
AB  - The solubilization of alkaline phosphatase (AP) from osteoblastic cell membranes
      obtained from human primary bone cell cultures was studied according to the age
      and sex of the donors (17 females, 11 males; age range: 2-77 years). Cell
      membranes were treated by non-ionic (n-octyl beta-D-glucopyranoside, OG), ionic
      or zwitterionic detergents, then centrifuged. When OG was used almost all the AP
      was solubilized. AP activity in supernatant of solubilization was compared to the
      activity of the suspension before centrifugation. The activity ratio (AR)
      increased in function of age for subjects between 65 and 74. Neither total nor
      specific AP activities were influenced by age or sex. Electrophoresis studies
      showed that the AP released was a GPI (glycosyl phosphatidylinositol)-anchored
      protein, amphipathic form, with 140 kDa as apparent molecular mass. The activity
      change of AP in the presence of OG may result from age-related modifications
      either in the AP structure or in the constituents of the plasma membranes
      (proteins or phospholipids).

PMID- 10602841
TI  - Osteoblast numbers after calcitonin therapy: a retrospective study of paired
      biopsies obtained during long-term calcitonin therapy in postmenopausal
      osteoporosis.
AB  - The present study is a retrospective examination of osteoblast indices in human
      iliac crest bone biopsies from a study on the long-term efficacy of calcitonin.
      Paired baseline and 2-year biopsies were examined from eight control subjects and
      10 treated subjects; treated subjects received 100 MRC units synthetic salmon
      calcitonin (Calcimar, Armour Pharmaceutical Co, Scottsdale, AZ) injected i.m. sub
      Q at bedtime. Control patients did not receive a placebo injection. All subjects
      received 400 units vitamin D(2) p.o. q.d. and 1200 mg CaCO(3) p.o. q.d. When the
      differences in baseline and 2-year values were analyzed, subjects receiving
      calcitonin showed no decrease compared with control subjects for the fraction of
      osteoid surface lined by osteoblasts (ObS/OS) (but were in fact significantly
      greater, P = 0.04). There was no difference from control subjects in the number
      of osteoblasts/mm bone surface (NOb/BPm), or mean mineral apposition rate (MAR).
      Since calcitonin is receiving renewed interest for osteoporosis therapy, these
      data (derived from paired human biopsies) are valuable since they show that no
      decrease in osteoblast cell number resulted from long-term calcitonin therapy.
      Results point to the need for renewed investigation concerning the effect of
      calcitonin on osteoblast-osteoclast interactions.

PMID- 10602842
TI  - Mineralization and alkaline phosphatase activity in collagen lattices populated
      by human osteoblasts.
AB  - Adult human osteoblastic cells were grown in a native type I collagen gel.
      Proliferation and viability analyses showed that cells rapidly stopped dividing
      and became blocked in the G0G1 phase (91% on day 13). Carboxyfluorescein
      diacetate cell staining and flow cytometry showed that osteoblasts were viable
      for the first 16 days and then viability decreased (58% viable cells on day 22).
      Osteoblasts were able to retract the matrix. Betaglycerophosphate (betaGP)
      stimulated the deposition of mineral particles in the collagen network, and
      electron probe microanalysis showed that they were principally calcium and
      phosphorus, with a Ca/P ratio of about 1.7. Various times of betaGP supply were
      tested. We compared 10 mM betaGP added only once at day 0, or continuously from
      day 0, day 8, or day 21. Mineralization was observed in conditions where betaGP
      was added at day 0. Furthermore, 10 mM betaGP added once during gel preparation
      was sufficient to induce mineralization with mineral accumulation up to day 15
      whereas the speed of the gel contraction decreased. In every condition, cultures
      expressed high alkaline phosphatase (ALP) levels as early as day 3, which
      decreased afterwards. These kinetics might explain why the other conditions did
      not prove favorable to the mineralization process. The model was used to study
      the influence of blocking gel retraction. Blocking retraction delayed the ALP
      activity decrease, but had no effect on mineralization. In conclusion, human
      adult osteoblasts cultured in native collagen gel stopped proliferation and
      underwent mineralization very early. This model should be used to investigate the
      influence of effectors on the early stages of culture.

PMID- 10602843
TI  - Lifestyle factors affecting bone ultrasonometry of the calcaneus in Japanese
      women.
AB  - Ultrasonometry is increasingly used to assess bone characteristics. A group of
      1412 women with a mean age of 57 years attended a screening examination in a
      Japanese city. Seventy-four percent of participants were postmenopausal.
      Broadband ultrasound attenuation (BUA), speed of sound (SOS), and Stiffness index
      (SI) of the calcaneus were measured; subjects also completed a questionnaire
      examining lifestyle factors; anthropometric data were recorded. Analysis showed
      that the strongest predictors of decreased BUA, SOS, and SI were increased age
      and menopausal status. Higher body mass index and current participation in
      exercise or sports were significant predictors of increased BUA, SOS, and SI in a
      multivariate model. Higher calcium intake predicted increased BUA (P = 0.004) and
      missing meals predicted a lower SOS (P = 0.019). This study suggests that dietary
      factors as well as physical activity influence bone characteristics assessed by
      QUS. QUS may be a suitable technique to assess the effect of lifestyle changes on
      bone.

PMID- 10602844
TI  - Vertebral deformity in chinese men: prevalence, risk factors, bone mineral
      density, and body composition measurements.
AB  - The prevalence and risk factors for vertebral deformity were studied in 396
      community-dwelling Chinese men aged 70-79 years. Anterior to posterior
      (H(a)/H(p)), middle to posterior (H(m)/H(p)) and posterior to posterior (H(p)/H(p
      - 1) or H(p)/H(p + 1)) ratios from T5 to L5 were derived from lateral spine X-ray
      films, using standardized digitization methods. Using values of 3 standard
      deviations (SD) or more below the mean and 4 SD or more below the mean as the
      cutoff, 16% and 7% of these men, respectively, were deemed to have one or more
      deformed vertebra. Heavy cigarette smoking, heavy alcohol consumption, and
      working as a heavy manual worker were risk factors for vertebral deformity. Men
      with severe vertebral deformity (VHR < mean - 4 SD below mean) had much lower
      body weight, fat mass, and bone mineral density (BMD) than controls. The odds
      ratios for severe vertebral deformity was 9.9 (95% CI 2.1-45.7) in the lowest
      quartile of femoral neck BMD.

PMID- 10602845
TI  - Effect of silicon supplement on osteopenia induced by ovariectomy in rats.
AB  - The effect of silicon (Si) supplement on preventing bone mass loss induced by
      ovariectomy (OVX) in rats was investigated. Three groups of 15, 100-day-old
      female Wistar rats each, with a mean initial weight of approximately 260 g per
      animal, were selected for the present study. One of the experimental group
      consisting of 15 OVX rats was fed a diet supplemented with 500 mg of Si per kg of
      feed (Si + OVX). The other two groups consisting of 15 OVX and 15 sham-OVX rats
      did not receive these supplements. Morphometric (weight and length) and
      densitometric studies with dual-energy X-ray absorptiometry were performed on the
      whole femur and 5th lumbar vertebra of each animal 30 days after the experiment.
      The Si + OVX rats did not show a loss of bone mass induced by OVX at axial level
      (5th lumbar vertebra) or periphery (femur). Nonetheless, a significant increase
      (ANOVA with Bonferroni/Dunn post hocs test) of longitudinal development of the
      femur (P < 0.0001) was patent. These results, obtained through the measurements
      of axial and peripheral bones, warrant closer scrutiny in connection with the Si
      inhibitory effect on bone mass loss as well as the stimulatory effect on bone
      formation. Both actions, namely, inhibition of resorption and stimulation of
      formation, infer that Si may have a potential therapeutic application in the
      treatment of involutive osteoporosis.

PMID- 10602846
TI  - Restoration of ovariectomy-induced osteopenia by nitroglycerin.
AB  - Nitric oxide (NO) is known to inhibit osteoclastic bone resorption. Previously,
      we demonstrated that the NO donor nitroglycerin (NG) prevented ovariectomy (OVX)
      induced bone loss. The current study shows that NG restores ovariectomy-induced
      osteopenia. Twenty-four female Sprague-Dawley rats, 36 weeks of age, underwent
      OVX, and a further six rats were sham-operated. Bone mineral density (BMD) was
      measured by dual-energy X-ray absorptiometric (DXA) scanning prior to OVX, at 6
      weeks postsurgery, and at 6 weeks posttreatment. OVX rats were then assigned to
      four groups and treated with either (1) vehicle, (2) 17-beta-estradiol, (3) NG
      (0.2 mg/kg/day), or (4) a combination of estrogen and NG (n = 6/group). During
      the first 6-week post-OVX period, there was a significant decrease in the BMD in
      all ovariectomized (OVXed) rats (-11.0%, P < 0.001). There were no significant
      changes in BMD during the entire 12-week period in sham-operated rats. During the
      second 6-week period (after developing bone loss), there was no further
      significant loss of BMD in OVXed controls. BMD loss and loss of femur weight
      produced by OVXed were restored by treatment with estrogen, NG, or the two agents
      together during the second 6-week period (P < 0.01). The effects of estrogen and
      NG together, however, were not additive. The BMD of rats treated with NG alone,
      at 12 weeks, was similar to that of animals treated with estrogen alone or with
      estrogen and NG, and was comparable to that of sham-operated rats. The increased
      urinary excretion of deoxypyridinolines caused by OVX was negated by estrogen,
      NG, and estrogen together with NG (P < 0.01). In contrast to estrogen, NG did not
      decrease the post-OVX-induced increase of serum osteocalcin levels, suggesting
      that NG may also have a positive effect on bone formation. In summary, the
      results suggest that the NO donor, NG, reverses the OVX-induced bone loss in
      rats, and these effects are likely due to decreased bone resorption and, perhaps,
      increased bone formation.

PMID- 10602847
TI  - The synthetic phytoestrogen, ipriflavone, and estrogen prevent bone loss by
      different mechanisms.
AB  - Ipriflavone (IP), a synthetic isoflavone has been reported to prevent bone loss
      in both postmenopausal women and ovariectomized (ovx) rats. The purpose of this
      study was to compare and contrast some of the bone protective mechanisms of IP to
      those of 17beta-estradiol (E(2)) in ovarian hormone deficiency. Forty-eight 95
      day-old Sprague-Dawley rats were assigned to four groups: sham, ovx, ovx+IP, and
      ovx+E(2). The doses of IP and E(2) were 100 mg and 10 microg/kg body weight per
      day, respectively. Rats were fed a diet that contained 0.4% calcium, 0.3%
      phosphorus, and 0.195 nmol vitamin D(3)/g diet. After sacrifice, left femoral
      bone densities were measured and bone histomorphometry was performed on the
      proximal tibial metaphysis. Ipriflavone as well as E(2) treatment completely
      prevented the ovx-induced femoral bone density loss. However, in contrast to
      E(2), IP did not lower the ovx-induced rise in serum alkaline phosphatase (ALP)
      activity or insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3
      concentrations. On histomorphometry analysis, the ovariectomy-induced increase (P
      < 0. 09) in bone formation rate (BFR) was significantly (P < 0.05) suppressed by
      E(2) treatment, whereas this higher BFR was maintained in IP-treated animals.
      These findings indicate that IP is effective in preventing the ovx-associated
      bone loss. The bone protective mechanisms of IP in ovarian hormone deficiency may
      be different from those of E(2) and may involve increased rates of bone
      formation.

PMID- 10602848
TI  - Development of mineralized nodules in fetal rat mandibular osteogenic precursor
      cells: requirement for dexamethasone but not for beta-glycerophosphate.
AB  - We have reported that a cell population obtained from fetal rat mandible with
      neutral protease (Pro I) has a unique differentiation sequence in which the
      elevation of alkaline phosphatase (ALPase), calcium accumulation, and collagen
      synthesis occurs simultaneously. In this report, we further characterized Pro I
      released population of cells by studying the effect of dexamethasone (Dex) or
      beta-glycerophosphate (beta-GP) on the formation of bone nodules. The formation
      of bone nodules in Pro I-released population of cells (ProIRPC) was augmented by
      the addition of Dex (10(-7) M) from days 3 to 14, suggesting that Pro IRPC
      contained osteoprogenitor (OP) cells. A 24-hour pulse treatment of ProIRPC
      released population of cells with Dex on days 9 and 12 resulted in an increase in
      the number of nodules but treatment on days 3, 6, or 15 did not. The number of
      bone nodules formed in Pro IRPC pulse treated with Dex on day 9 was comparable
      with that in Pro IRPC treated with Dex from days 3 to 14. Dex caused an earlier
      elevation of ALPase, in which maximal expression was observed on day 10. beta-GP
      caused a prolonged elevation of ALPase, but did not affect the formation of bone
      nodules. Unlike Pro I-released population of cells, rat calvarial cells did not
      form mineralized nodules without beta-GP, and showed that a Dex-responsive period
      on bone nodule formation in rat calvarial cells was at preconfluency (days 0 and
      1). Thus, it appeared that the Dex-induced differentiation of early OP cells in
      Pro IRPCs occurred during the limited period from day 9 to day 12. Pro IRPC was
      found to have an unique characteristic that bone nodule formation was not
      affected by beta-GP.

PMID- 10602849
TI  - Accuracy and precision of in vivo bone mineral measurements in sheep using dual
      energy X-ray absorptiometry.
AB  - We evaluated the precision and accuracy of in vivo measurements of spine bone
      mineral density (BMD) and bone mineral content (BMC) in five ewes using dual
      energy X-ray absorptiometry (DXA, Lunar DPX-L). The short-term in vivo
      reproducibility expressed as the coefficient of variation (CV) varied from 0.9 to
      1.6% for spine BMD and from 1 to 3.1% for spine BMC. The ex vivo measurements,
      performed in 20 cm of water to simulate soft tissue thickness, correlated closely
      with the in vivo measurements, yielding an r value of 0.98 and 0.97 for spine BMD
      and BMC, respectively. The accuracy was determined by comparing the total BMC of
      each vertebra measured in vivo with the corresponding ash weight. The correlation
      coefficient between the two measurements was r = 0.98, with an accuracy error of
      5.6%. We concluded that the DXA allows a precise and accurate measurement of
      spine bone mineral in live ewes using the methodology designed for humans.

PMID- 10602850
TI  - Magnetic resonance imaging measurements of bone density and cross-sectional
      geometry.
AB  - Magnetic resonance imaging (MRI) is commonly used in the assessment of the
      musculoskeletal system and associated pathology. The ability of MRI to measure
      the signals from water and lipid protons enables quantitative measurements of
      bone porosity. The goal of this investigation was to demonstrate that the density
      and cross-sectional geometry of whole bones can be noninvasively measured using
      MRI. Ten trabecular specimens cored from whale vertebrae were used to compare
      apparent bone density measured directly, and using a quantitative MRI algorithm.
      Bone density and several cross-sectional geometric properties were also measured
      using MRI in the distal tibia of 14 volunteers. The MRI measurements were
      compared with measurements made using quantitative-computed tomography (QCT). A
      proton density sequence was used for all MRI studies. A porosity phantom was
      included in the MRI examinations and used to convert the MRI signal intensity to
      bone volume fraction. Bone density and cross-sectional bone geometry were
      calculated from the bone volume fractions by assuming constant tissue properties.
      The apparent density of trabecular bone cores measured directly and using
      quantitative MRI were linearly related (r(2) = 0.959; P < 0. 01). A strong linear
      relation also existed between MRI and QCT measurements of ash density (r(2) =
      0.923; P < 0.01) and cross-sectional geometric properties (r(2) = 0.976-0.992; P
      < 0.01). MRI data can be used to measure bone density and cross-sectional
      geometry of whole bones if a proton density sequence is used to homogenize
      differences in marrow composition and a porosity phantom is used for slice
      specific volume fraction calibration.

PMID- 10602851
TI  - In memoriam

PMID- 10602852
TI  - Intracranial dural arteriovenous fistulae with perimedullary venous drainage.
      Anatomical, clinical and therapeutic considerations.
AB  - We report five cases of intracranial dural arteriovenous fistula (DAVF) with
      perimedullary venous drainage. All the patients presented with rapidly
      progressive myelopathy and three had autonomic disorders. The DAVF were on the
      tentorium cerebelli (two cases), sigmoid (one), superior petrosal (one), and
      cavernous sinus (one). Slow venous drainage was directed through dilated
      perimedullary cervical veins. The transverse sinus was occluded in two cases.
      MRI, performed in four cases, demonstrated high signal on T2-weighted spin-echo
      sequences in the medulla oblongata and upper cervical spinal cord consistent with
      oedema, which signal resolved after complete cure of the DAVF in three cases.
      Embolisation was performed in all cases. It was followed by clinical
      deterioration in two cases and in the dramatic improvement in the other three,
      with complete clinical cure in two. Extensive venous thrombosis may explain the
      deterioration observed in one case.

PMID- 10602853
TI  - Changes in visibility of intracranial arteries on MRA with normal ageing.
AB  - We investigated age-related changes in the visibility of intracranial arteries on
      magnetic resonance angiography (MRA) and the influence of risk factors for
      stroke. We studied 230 adult patients without specific neurological deficits. MRA
      was performed using the three-dimensional time-of-flight technique with a spoiled
      gradient-recalled acquisition sequence. We classified internal carotid artery
      (IC) and the horizontal (M1) and distal (beyond M2) middle cerebral segments into
      4 grades. Linear regression revealed a significant negative relation between age
      and the quality of demonstration on MRA. For IC and M1, the score was
      significantly lower in subjects with risk factors than in those without. The
      distal MCA was poorly seen in patients without a history of hypertension or
      lacunar infarcts. A marked correlation was observed between visibility and age
      patients with no history of hypertension, diabetes mellitus and hyperlipidaemia.
      We suggest that atherosclerotic change and decline in flow velocity with normal
      ageing are factors leading to decreased visibility on MRA.

PMID- 10602854
TI  - Correlation between the degree of contrast enhancement and the volume of
      peritumoral edema in meningiomas and malignant gliomas.
AB  - Peritumoral edema and contrast enhancement of brain tumors are both thought to be
      due to breakdown of the blood-brain barrier (BBB); however, the exact mechanism
      by which these two phenomena occur and whether there is a quantitative or
      etiological relationship is not known. Our purpose was to determine whether the
      relationship between the breakdown of the BBB, defined radiologically as the
      degree of contrast enhancement, and the volume of surrounding edema is different
      for high-grade gliomas and meningiomas. We analyzed 13 meningiomas and 23
      gliomas. A direct linear relationship between the degree of contrast enhancement
      (dC) and volume of peritumoral edema (V) with a high correlation coefficient (R =
      0.66, P = 0.0006) was established for gliomas. A mathematical relationship
      between dC and V could not be established for meningioma. The findings for
      gliomas offer indirect radiological evidence that the defect in the BBB which
      causes edema is quantitatively and etiologically related to the defect in the BBB
      responsible for contrast enhancement. For meningiomas, the lack of a relationship
      between dC and V implies either that the mechanisms responsible for formation of
      edema and contrast enhancement are fundamentally different or that a physical
      barrier in certain meningiomas limits propagation of edema into the adjacent
      white matter.

PMID- 10602855
TI  - Giant-cell tumour involving the cranial vault: imaging and treatment.
AB  - A giant-cell tumour involving the cranial vault was diagnosed in a 37-year-old
      man who presented with a large swelling at the vertex. The role of imaging in the
      diagnosis and treatment of this tumour is described. On CT and MRI the
      appearances were nonspecific and the diagnosis was established by histological
      examination after removal of the tumour. A preoperative angiogram showed a tumour
      blush and before surgery, embolisation was performed via the percutaneous and
      transarterial routes.

PMID- 10602856
TI  - Diffusion-weighted MRI postoperative assessment of an epidermoid tumour in the
      cerebellopontine angle.
AB  - Cerebellopontine angle epidermoid tumour generally has a typical appearance with
      conventional MRI sequences. The lesion is irregular in shape and gives slightly
      higher signal than cerebrospinal fluid on T1- and T2-weighted images, with a
      characteristic marbled inner pattern on T1-weighted images. Diffusion-weighted
      imaging (DWI) can be useful for the diagnosis of an atypical epidermoid tumour.
      Our case report illustrates the usefulness of DWI for postoperative assessment of
      residual foci of tumour. The specific appearance of an epidermoid tumour is
      illustrated, with emphasis on apparent diffusion coefficient (ADC) measurements.

PMID- 10602857
TI  - Rathke's cleft cyst with pituitary apoplexy: case report.
AB  - We report a Rathke's cleft cyst which presented as pituitary apoplexy, a rare
      presentation. A 46-year-old woman suffered sudden headache and visual loss. T1
      weighted MRI 3 weeks after this apoplectic episode demonstrated a cystic lesion
      between the anterior and posterior lobes of the pituitary, with some high-signal
      material layering in it. The mass showed spontaneous regression on an image 3
      weeks later. Trans-sphenoidal surgery confirmed the diagnosis of a Rathke's cleft
      cyst with a haematoma within it.

PMID- 10602858
TI  - Acute intermittent porphyria with central pontine myelinolysis and cortical
      laminar necrosis.
AB  - Acute intermittent porphyria (AIP) is an autosomal-dominant disease caused by a
      deficiency of porphobilinogen (PBG) deaminase. Patients with AIP present with
      neurological syndromes such as autonomic neuropathy, peripheral axonal neuropathy
      or central nervous system dysfunction. We report serial MRI of a patient with AIP
      who had cortical and subcortical cerebral changes. A 29-year-old woman with a 6
      month history of AIP had an attack with severe hyponatraemia and generalised
      convulsions, treated with haem arginate and supportive therapy. MRI showed
      central pontine and extrapontine myelinolysis and cortical laminar necrosis.
      These are not common in AIP, but are likely to have been caused by rapid
      correction of hyponatraemia and by vasospasm, which could be induced by AIP.

PMID- 10602859
TI  - Proteus syndrome: craniofacial and cerebral MRI.
AB  - The Proteus syndrome is a rare hamartoneoplastic syndrome that may affect the
      brain, skull, and extracranial head and neck. We present a case with severe,
      characteristic findings. Brain abnormalities are not common in Proteus syndrome;
      when present, hemimegalencephaly and migrational disorders are typically seen,
      commonly with an associated seizure disorder. Maxillary and mandibular
      dysmorphism may occur, including unilateral condylar hyperplasia. Subcutaneous
      fatty, fibrous, lymphangiomatous masses commonly seen in this syndrome may
      involve the neck and face, leading to disfigurement and potential airway
      compromise.

PMID- 10602860
TI  - MRI of cerebral alveolar echinococcosis.
AB  - Cerebral alveolar echinococcosis is rare. We report a case with multiple
      intracranial masses which show cauliflower-like contrast enhancement pattern on
      MRI. The lesions originated from hepatic involvement with invasion of the
      inferior vena cava.

PMID- 10602861
TI  - Pial involvement in Wegener's granulomatosis shown on MRI.
AB  - Involvement of the brain and meninges is rare in Wegener's granulomatosis (WG);
      it has been reported in 1.2-8 % of patients. Meningeal involvement in WG has been
      reported in imaging as being confined to the dura mater, and is thought to
      represent granulomatous infiltration. We present a case of WG with abnormal pial
      enhancement and involvement of the perivascular spaces on MRI, pathologically
      proven to represent granulomatous infiltration due to the primary disease rather
      than to infection.

PMID- 10602862
TI  - Widening of the spinal canal and dural ectasia in Marfan's syndrome: assessment
      by CT.
AB  - We describe a method for diagnosing dural ectasia (DE) and spinal canal widening
      (SCW) using CT. We examined 23 patients with Marfan's syndrome (MFS), 17 with
      Ehlers-Danlos syndrome (EDS) and 29 normal subjects, using six axial slices at
      the level of the L1-S1 pedicles. Transverse diameters of the vertebral bodies,
      spinal canal and dural sac were measured and indices were defined to
      differentiate patients with DE and SCW from normal. Statistical significance was
      assessed using Student's t -test, chi (2)-test and Pearson's correlation
      coefficient. DE and SCW occurred in 69.6 % and 60.9 % of cases of MFS and in 23.5
      % and 35.3 % of EDS respectively. In MFS, prevalence was significantly higher
      than in the control group. DE was significantly more frequent in MFS than in EDS.
      A strong correlation existed between DE and SCW in MFS and the control group, but
      not in EDS. Our system enables quantitative assessment of SCW and DE. The latter
      is particularly important in subjects suspected of having MFS, in whom it is a
      common and characteristic sign.

PMID- 10602863
TI  - MRI in recurrent nasopharyngeal carcinoma.
AB  - In this study, we retrospectively reviewed the MRI features of recurrent
      nasopharyngeal carcinoma (NPC) in 72 patients who underwent MRI before and after
      gadolinium injection. Recurrent NPC exhibited a high degree of regional spread
      and a variety of signal intensities and contours. MRI showed a nasopharyngeal
      mass in 50 patients (69.4 %); other sites of involvement included the
      parapharyngeal space (44.4 %), nasal cavity (12.5 %), paranasal sinuses (27.8 %),
      oropharynx (4.2 %), orbit (8.3 %), infratemporal fossa (18.1 %), skull base (59.8
      %), intracranial area (51.4 %) and regional lymph nodes (15.3 %). On T2-weighted
      images, the nasopharyngeal mass gave high signal in 9 of 50 cases (18 %),
      intermediate in 27 (54 %), mixed in 8 (16 %) and low signal in 6 (12 %). Contrast
      enhancement was strong in 12 cases (24 %), moderate in 29 (58 %) and
      heterogeneous in 9 (18 %). The lesion was convex in 31 cases (62 %) and concave
      or straight in 19 (38 %). Recognition of the distribution and the appearance of
      recurrent NPC on MRI is essential for timely diagnosis and appropriate treatment.

PMID- 10602864
TI  - Imaging and therapeutic approach of hemangiomas and vascular malformations in the
      pediatric age group.
AB  - Terminology regarding the vascular lesions of the soft tissues remains confusing.
      A single classification is necessary in order to decide on the proper
      investigation and the best treatment. At the Workshop on Vascular Anomalies in
      Rome in June 1996, the membership accepted the Mulliken and Glowacki
      classification, which differentiates vascular lesions into vascular tumors,
      including hemangiomas and vascular malformations. At Sainte-Justine, we have set
      up a multidisciplinary clinic for the discussion of problem patients with
      vascular anomalies, both in terms of diagnosis and treatment. In this review, we
      present our experience regarding the classification, the imaging modalities and
      the treatment of vascular anomalies. In our experience, Doppler ultrasound should
      be the initial imaging modality for recognizing vascular tumors from vascular
      malformations. CT scan or magnetic resonance imaging is best to evaluate the
      extent of the lesions prior to treatment. A multidisciplinary approach is
      essential to establish a correct diagnosis and define accordingly the appropriate
      treatment and follow-up.

PMID- 10602865
TI  - Feeding difficulties in the first days of life: findings on upper
      gastrointestinal series and the role of the videofluoroscopic swallowing study.
AB  - BACKGROUND: Feeding difficulties in the newborn period are a common indication
      for an upper gastrointestinal (UGI) series. OBJECTIVE: To review the radiological
      findings in infants with feeding-related difficulties, with no other medical
      problems, and to evaluate the role, if any, of the videofluoroscopic swallowing
      study (modified barium swallow, MBSW). MATERIALS AND METHODS: We retrospectively
      reviewed all the UGI and MBSW studies performed at our institution over a 5-year
      period in infants under 1 month of age. We found a total of 77 patients referred
      for feeding-related problems. RESULTS: All patients had at least one UGI study
      performed at our institution, and 17 patients had at least one additional MBSW.
      The most frequently found abnormality that could directly account for the
      patients' symptoms was swallowing dysfunction. This was detected in 19 patients;
      in 10 of these patients the swallowing dysfunction was seen only on the MBSW.
      CONCLUSION: Swallowing dysfunction with aspiration is a common cause of feeding
      related difficulties in childhood. In infants with feeding difficulties, a MBSW
      may demonstrate aspiration when the UGI is negative.

PMID- 10602866
TI  - The diagnostic value of intrarenal colour duplex Doppler ultrasonography in
      children with lower urinary tract infection.
AB  - BACKGROUND: The diagnostic value of Doppler US in infectious disease of the
      kidney is well documented. Previous studies have demonstrated high resistive
      indices, especially in tubulo-interstitial diseases. OBJECTIVE: To evaluate the
      role of intrarenal colour duplex Doppler US in lower urinary tract infections
      (UTI). MATERIALS AND METHODS: This prospective study was carried out in 111
      children (222 kidneys) (age range 1-180 months). Of the children, 78 were healthy
      while 33 presented with lower UTI. The resistive indices (RI) were measured from
      the spectral waveforms obtained from interlobar arteries. RESULTS: No
      statistically significant difference was found between RI of right and left
      kidneys in both groups. The mean RI was 0.75 +/- 0.07 in patients with lower UTI
      and 0.71 +/- 0.1 in the control group (P < 0.05). In the control group there was
      an inverse correlation between age and RI (P < 0.05). CONCLUSIONS: High RI may be
      found in lower UTI.

PMID- 10602867
TI  - Pleuropulmonary blastoma and ovarian teratoma.
AB  - We report a patient with pleuropulmonary blastoma who had a benign teratoma as a
      second primary tumor. The radiology, clinical course, and the biological
      importance of this rare neoplasm are discussed.

PMID- 10602868
TI  - The thymus in Langerhans' cell histiocytosis.
AB  - OBJECTIVE: To determine the frequency of thymic involvement in Langerhans' cell
      histiocytosis and describe its imaging appearance before and after treatment.
      MATERIALS AND METHODS: A retrospective review of the radiology and clinical
      records of all patients diagnosed with Langerhans' cell histiocytosis at DeVos
      Children's Hospital between 1992 and 1998. RESULTS: Of the 14 patients diagnosed
      with Langerhans' cell histiocytosis, 7 demonstrated multisystem involvement. The
      thymus was involved in 5 of 7 patients. The thymus was enlarged in 5; thymic
      contours were nodular/lobulated in 2; cystic changes were noted in 4; and
      dystrophic vascular-appearing calcifications were seen in 1. In all cases,
      findings regressed or resolved following chemotherapy. CONCLUSION: The thymus is
      commonly involved in Langerhans' cell histiocytosis, especially in multisystem
      disease. Radiologically, the thymus is enlarged and may be smooth or
      lobulated/nodular in contour, possibly containing cysts and calcifications.

PMID- 10602869
TI  - Budd-Chiari syndrome caused by Gaucher's disease.
AB  - We present a unique case of Budd-Chiari syndrome caused by Gaucher's disease. The
      diagnosis was based on Doppler sonography, magnetic resonance imaging, contrast
      enhanced three-dimensional magnetic resonance angiography, standard venography,
      and venous pressure measurements and was confirmed histologically.

PMID- 10602870
TI  - Reinsertion of accidentally removed tunneled central venous catheter via the
      existing subcutaneous tract.
AB  - BACKGROUND: A technique for reinsertion of an inadvertently removed tunneled
      central venous catheter is presented. A 6-year-old boy with short-gut syndrome
      caused by necrotizing enterocolitis accidentally removed his tunneled central
      venous catheter. MATERIALS AND METHODS: The existing subcutaneous catheter tract
      was recanalized using a hydrophilic guidewire and 5-French end-hole catheter with
      the child unter conscious sedation, and a new catheter was placed over a
      guidewire. RESULTS: This obviated the need for a new venipuncture and creation of
      a new subcutaneous tunnel, which are performed under general anesthesia in our
      hospital.

PMID- 10602871
TI  - Progressive bone resorption after pathological fracture of the femoral neck in
      Hunter's syndrome.
AB  - We report a case of Hunter's syndrome associated with a transverse fracture of
      the left femoral neck after minor trauma, followed by progressive resorption of
      the femoral head at 12 years of age and a stress fracture of the right femoral
      neck at 16 years of age. MRI performed at 15 years of age revealed intra
      articular low intensity on T1-weighted and T2-weighted images of both hip joints.
      The MR finding may represent fibrous synovial thickening, which caused pressure
      erosion of the femoral neck, resultant pathological and/or stress fractures, and
      subsequent osteonecrosis with rapid absorption of the femoral head.

PMID- 10602872
TI  - Immunogenetics: in the forefront.

PMID- 10602873
TI  - Self-nonself discrimination, histoincompatibility, and the concept of immunology.

PMID- 10602874
TI  - Expanding our understanding of immunoglobulin, T-cell antigen receptor, and novel
      immune-type receptor genes: a subset of the immunoglobulin gene superfamily.
AB  - The immunoglobulin superfamily (IgSF) is an extensively diversified multigene
      family whose members share a common structural feature, the Ig fold. Members of
      the Ig/T-cell antigen receptor (TCR) subset of the IgSF mediate antigen-specific
      recognition in adaptive immune responses. Antigen-binding receptors belonging to
      this subset are present in all species of jawed vertebrates. To explore whether
      there are additional structurally related but otherwise distinct members of this
      subset, we have developed a technique termed the short-primer polymerase chain
      reaction (PCR) that targets structurally conserved short motifs in the Ig fold.
      Large-scale sequencing efforts and recent advances in information biotechnology,
      including "electronic PCR," provide additional computational means to implement
      similarly directed searches within databases. The use of these approaches has led
      to the discoveries of Ig/TCR homologues in a variety of phylogenetically diverse
      organisms, a diversified family of novel immune-type receptor genes, as well as a
      novel human IgSF member. The potential of random sequencing efforts and virtual
      screening of databases is described in the context of two novel genes in bony
      fish. The various methodologies that are discussed and the examples shown provide
      means for further investigating, and/or elucidating novel, IgSF receptors as well
      as components of pathways that are involved in immune responses in both
      traditional and nontraditional model systems.

PMID- 10602875
TI  - Genome dynamics of the major histocompatibility complex: insights from genome
      paralogy.
AB  - It has recently become apparent that the human genome contains at least three
      regions that are paralogous to the major histocompatibility complex (MHC). The
      number of gene families with copies in the MHC and these paralogous regions is
      increasing steadily as genome analysis progresses. This review presents the
      updated listing of the human gene families that constitute the MHC paralogous
      group. When genes with multiple copies within the MHC, such as class I and class
      II genes, are counted as single entities, nearly one-third of the genes residing
      in the HLA complex have paralogous copies in at least one of the three paralogous
      regions. The review also discusses the long-term genome dynamics of the MHC,
      taking into account the rapidly accumulating information on the genomic
      organizations of the MHCs in various model organisms.

PMID- 10602876
TI  - Highly conserved antigen-presenting function of CD1d molecules.
AB  - The lack of polymorphism of nonclassical antigen-presenting molecules has led to
      the proposal that they may carry out some conserved and essential antigen
      presenting function. Although this is a plausible hypothesis, the major
      histocompatibility complex has undergone dramatic expansions and contractions
      through evolution, and there is surprisingly little evidence for interspecies
      conservation of nonclassical class I molecules. The CD1d molecule, by contrast,
      shows an extremely high degree of functional conservation between mice and
      humans, with regard to its interaction with the relatively invariant TCRs that
      are expressed by NK T cells. This conservation for CD1d recognition is observed
      either in the absence of exogenous Ag or together with a lipoglycan antigen. The
      close functional and phenotypic conservation of NK T cells, in mammalian species
      separated by approximately 50 million years, suggests an essential role in the
      immune system for CD1d recognition by NK T cells.

PMID- 10602877
TI  - The MHC quarterly report.

PMID- 10602878
TI  - The major histocompatibility complex class II region of the chimpanzee: towards a
      molecular map.

PMID- 10602879
TI  - The gene conversion hypothesis of MHC evolution: a review.
AB  - Gene conversion is often invoked to explain the evolution of sequence patterns
      observed in major histocompatibility complex (MHC) genes and their alleles. This
      is the gene conversion hypothesis of MHC sequence evolution. These observations
      and their interpretation probably belong in a larger theoretical framework,
      namely the evolution of systems of resistance to rapidly evolving pathogens. This
      review looks critically at the evidence in favor of the gene conversion
      hypothesis in this context. We conclude that the case for the existence of an
      adaptive mechanism in the MHC favoring gene conversion mutations is not proven.

PMID- 10602880
TI  - Nine major HLA class I supertypes account for the vast preponderance of HLA-A and
      -B polymorphism.
AB  - Herein, we review the epitope approach to vaccine development, and discuss how
      knowledge of HLA supertypes might be used as a tool in the development of such
      vaccines. After reviewing the main structural features of the A2-, A3-, B7-, and
      B44- supertype alleles, and biological data demonstrating their immunological
      relevance, we analyze the frequency at which these supertype alleles are
      expressed in various ethnicities and discuss the relevance of those observations
      to vaccine development. Next, the existence of five new supertypes (A1, A24, B27,
      B58, and B62) is reported. As a result, it is possible to account for the
      predominance of all known HLA class I with only nine main functional binding
      specificities. The practical implications of this finding, as well as its
      relevance to understanding the functional implication of MHC polymorphism in
      humans, are discussed.

PMID- 10602881
TI  - SYFPEITHI: database for MHC ligands and peptide motifs.
AB  - The first version of the major histocompatibility complex (MHC) databank
      SYFPEITHI: database for MHC ligands and peptide motifs, is now available to the
      general public. It contains a collection of MHC class I and class II ligands and
      peptide motifs of humans and other species, such as apes, cattle, chicken, and
      mouse, for example, and is continuously updated. All motifs currently available
      are accessible as individual entries. Searches for MHC alleles, MHC motifs,
      natural ligands, T-cell epitopes, source proteins/organisms and references are
      possible. Hyperlinks to the EMBL and PubMed databases are included. In addition,
      ligand predictions are available for a number of MHC allelic products. The
      database content is restricted to published data only.

PMID- 10602882
TI  - The role of HLA-B27 in spondyloarthritis.
AB  - The human major histocompatibility complex (MHC) class I allele HLA-B27 bears a
      striking association with the spondylolarthritic group of inflammatory
      arthritides, yet despite extensive studies its role in the disease process
      remains obscure. As an MHC class I protein, the primary function of HLA-B27 is to
      complex with beta(2)-microglobulin forming a structure that presents short
      antigenic peptides for recognition by cytotoxic T lymphocytes (CTL). It has been
      proposed that the role of HLA-B27 in spondyloarthropathy involves this process of
      antigen presentation, and of the numerous theories proposed to explain the
      association, the most popular have involved the binding and presentation of
      "arthritogenic" peptides. Transgenic rodent studies directly implicate HLA-B27
      heavy chains in disease pathogenesis, but suggest that the mechanism may be
      distinct from their primary function. The recent demonstration that HLA-B27 heavy
      chains can form stable homodimers may thus be of relevance. This review
      summarizes the evidence supporting current theories of disease association and
      proposes an alternative model of disease based on recent findings.

PMID- 10602883
TI  - Co-evolving genes in MHC haplotypes: the "rule" for nonmammalian vertebrates?

PMID- 10602884
TI  - Houdini's box: towards an understanding of AIDS virus escape from the cytotoxic T
      lymphocyte response.

PMID- 10602885
TI  - Immunization of mice with fucosyl-GM1 conjugated with keyhole limpet hemocyanin
      results in antibodies against human small-cell lung cancer cells.
AB  - Fucosyl-GM1 (Fuc-GM1) [Fucalpha1 --> 2Galbeta1 --> 3GalNAcbeta1 --> 4(NeuAcalpha2
      3)Galbeta1 --> 4Glcbeta1 --> O-Cer] is a small-cell-lung-cancer (SCLC)-associated
      ganglioside initially defined by the murine monoclonal antibody F12. On the basis
      of its known distribution, Fuc-GM1 is a potential target for active immunotherapy
      in SCLC patients. Fuc-GM1 has been extracted and purified from bovine thyroid.
      The immunogenicity of Fuc-GM1 was tested in mice either alone, mixed with carrier
      protein keyhole limpet hemocyanin (KLH) or covalently linked with KLH, plus
      immunological adjuvant QS-21. The Fuc-GM1-KLH conjugate plus QS-21 adjuvant was
      found to be optimal. It induced consistent IgM and IgG enzyme-linked
      immunosorbent assay (ELISA) titers against Fuc-GM1. These antibodies were
      strongly reactive with the strongly Fuc-GM1-positive rat hepatoma cell line H4-II
      E, and they were moderately reactive with the moderately positive human SCLC cell
      line H146 by flow cytometry and complement-mediated lysis. Both ELISA and
      fluorescence-activated cell sorting (FACS) reactions were inhibited with Fuc
      GM1or H4-II-E but not with the structurally related ganglioside GM1 or Fuc-GM1
      negative colon cancer cell line LS-C. On the basis of these results, a vaccine
      comprising Fuc-GM1-KLH plus QS-21 is being prepared for testing in patients with
      SCLC.

PMID- 10602886
TI  - Sialoadhesin expression by bone marrow macrophages derived from Ehrlich-tumor
      bearing mice.
AB  - Sialoadhesin (sheep erythrocyte receptor, SER) is a macrophage-restricted
      adhesion molecule that binds certain sialylated ligands. It is borne by bone
      marrow stromal macrophages, promoting the interaction with developing myeloid
      cells, and by a subset of tissue macrophages involved in antigen presentation and
      activation of tumor-reactive T cells. The expression of sialoadhesin on SER+
      macrophages is not constitutive but requires the continuous supply of a
      sialoadhesin-inducing serum factor. Tumor growth is often associated with marked
      alterations of myelopoiesis and impairment of T cell activation; yet the
      expression of sialoadhesin in macrophages derived from tumor bearers has not been
      addressed. The aim of this study was to assess whether Ehrlich tumor (ET) - a
      murine mammary carcinoma - growth may modify the sialoadhesin expression by bone
      marrow macrophages and/or sialoadhesin-inducing activity in ET-bearing sera.
      Moreover, putative functional sialoadhesin inhibitors produced by ET cells were
      tested. The results indicate that bone marrow cells from ET bearers show a seven-
      to eight-fold decrease in SER+ cells as detected by flow cytometry. This is
      accompanied by an overall decrease in sheep erythrocyte binding to tumor-bearer
      derived bone marrow cells, but also by lower numbers of plastic-adherent cells.
      Functional sialoadhesin expression is preserved at the single-cell level and no
      inhibitors are found in ET-bearing sera or ET cell culture supernatants. Tumor
      progression does not impair the sialoadhesin-inducing activity of ET-bearing
      sera, or the ability of SER- macrophages (e.g. peritoneal macrophages) to respond
      to such an induction. In conclusion, while SER+ macrophages are greatly decreased
      in bone marrow from ET bearers, this is not due to a down-regulation of
      sialoadhesin expression, nor to an impairment of sialoadhesin-inducing factor or
      to the presence of sialoadhesin-binding moieties of tumor origin, but, more
      likely, to a decrease of fully mature macrophages.

PMID- 10602887
TI  - Cancer immunotherapy by antisense suppression of Ii protein in MHC-class-II
      positive tumor cells.
AB  - This study was aimed at creating a more effective tumor cell vaccine by
      suppressing Ii protein in the presence of MHC class II molecules within a cancer
      cell. Absence of the Ii protein, which normally blocks the antigenic-peptide
      binding site of MHC class II molecules at synthesis in the endoplasmic reticulum,
      presumably increases the range of cancer-related epitopes presented to CD4+
      helper T cells. Effective suppression of Ii protein was achieved with an
      antisense, phosphorothioate oligonucleotide, which was selected on the basis of
      (1) the RNase H activation assay, (2) an assay for Ii protein suppression, and
      (3) a test for potency with respect to the extent of base sequence ("sequence
      walking"). The SaI murine sarcoma, which is MHC-class-I+ and MHC-class-II-, Ii
      protein-, upon transfection with genes for either interferon gamma or the MHC
      class II transactivator, came to express MHC class II molecules and Ii protein.
      In each line of transfected tumor cells, the antisense oligonucleotide profoundly
      suppressed Ii protein in 35%-55% cells, without affecting expression of MHC class
      II molecules. Inoculation of mice with such Ii-protein-suppressed tumor vaccine
      cells, after either formaldehyde fixation or X-irradiation, led to much greater
      protection against challenge with the parental SaI sarcoma than did inoculation
      with untreated cells. This approach to cancer cell vaccination can be applied in
      a wide range of human tumors.

PMID- 10602888
TI  - Sensitization of resting T cells to autologous natural-killer-cell-mediated lysis
      by phytohemagglutinin.
AB  - Natural killer (NK) cells are non-T, non-B cell lymphocytes that lyse a variety
      of tumor and virus-infected cells. In this study, we demonstrated that
      phytohemagglutinin (PHA) rendered resistant autologous T cells extremely
      sensitive to natural-killer(NK)-cell-mediated lysis. The sensitization was very
      rapid and concentration-dependent (0.01-1 microg/ml); 62% and 95% of autologous T
      cells were lysed by interleukin-2-activated NK cells 5 min and 18 h respectively
      after treatment with PHA (1 microg/ml). The maximal decrease in the level of MHC
      class I molecules observed on T cells was 22%. Induction of susceptibility to NK
      mediated lysis was correlated with the expression of activation markers on T
      cells treated for relatively long intervals (more than 18 h) with high
      concentrations of PHA (more than 0.1 microg/ml). Sensitization of T cells
      required RNA and protein synthesis, although DNA synthesis was not essential. We
      propose that this unique system is suitable for studying the mechanisms involved
      in recognition and killing of target cells by NK cells.

PMID- 10602889
TI  - The role of monocytes and natural killer cells in mediating antibody-dependent
      lysis of colorectal tumour cells.
AB  - Monocytes and natural killer (NK) cells are known to be important effector cell
      populations in mediating antibody-dependent cell-mediated cytotoxicity (ADCC).
      Purified monocyte and NK effector cell populations, from normal and colorectal
      cancer (CRC) patients, together with a number of murine (17-1A and 323/A3) and
      their chimaeric (c17-1A) or humanised (3622W94) equivalents, and chimaeric (c)
      SF25 were compared for their ability to mediate ADCC of colorectal tumour cells.
      The chimaeric and humanised antibodies were significantly better at mediating
      tumour lysis than their murine equivalents with all-effector populations. When
      effector cells from CRC patients were used the cSF25 antibody was significantly
      better than 3622W94 (P < 0.02) which, in turn, was significantly better than c17
      1A (P < 0.03). Depletion of NK cells produced a decrease in specific tumour lysis
      with all antibodies. In addition a higher rate of NK cell death was observed in
      CRC patients during the assay than in normal controls. The chimaeric and
      humanised antibodies stained a similar percentage of the HT-29 target cells
      (>80%), but 3622W94 bound to significantly more cells from primary tumour
      biopsies than cSF-25 (P = 0.001). Together, the results suggest that NK cells are
      the most important effector cell type mediating ADCC in vitro, that there is some
      impairment of NK function in CRC patients, and that cSF25 is the most potent
      antibody. For use in vivo the anti-Ep-CAM antibody 3622W94 would appear to be the
      most suitable reagent for further study.

PMID- 10602890
TI  - Modulation of CD4 cell cytokine production by colon cancer-associated mucin.
AB  - PURPOSE: Mucins have been implicated in tumor-associated immunosuppression. The
      possibility that colon cancer mucin (CCM) may modulate T-helper 1 (TH1) activity
      was evaluated by investigating its effect on the production of interleukin-2 (IL
      2) by CD4+ cells, a process that requires antigen-specific and costimulatory
      signals. METHODS: CCM was purified from human colorectal cancer cells by gel
      exclusion fast-pressure liquid chromatography. Cytokine production of purified
      CD4+ cells was evaluated at the protein and gene level in the presence of a
      phorbol ester or an anti-CD3 monoclonal antibody (mAb) plus mAb against the CD28
      costimulatory receptor to mimic two-signal activation. RESULTS: Soluble CCM,
      which contains mucins MUC2 as well as MUC1, inhibited IL-2 mRNA expression and
      secretion of CD4+ stimulated with a phorbol ester or an anti-CD3 mAb plus anti
      CD28 mAb. Pretreatment of CD4+ cells with anti-CD28 mAb abrogated the suppressive
      effects of CCM on IL-2 production, and flow cytometry showed decreased binding of
      anti-CD28 mAb to its receptor in the presence of mucin. In addition, Ca2+
      mobilization after T cell receptor cross-linking with anti-CD3 mAb was maintained
      in the presence of CCM. Although interferon gamma production was also diminished,
      CCM did not induce a general inhibition of cytokine production, nor did it
      decrease cell viability. Macrophage inflammatory protein 1alpha production was up
      regulated; the production of IL-10 and transforming growth factor beta was
      unchanged. CONCLUSIONS: The results indicate that CCM can alter TH1 activity and
      suggest that the modulation of costimulatory interactions is involved. They
      provide another mechanism of immunosuppression mediated by these highly expressed
      tumor products.

PMID- 10602891
TI  - Association of immune parameters with clinical outcome in stage III colon cancer:
      results of Southwest Oncology Group Protocol 9009.
AB  - Levamisole (LMS), utilized in the adjuvant treatment of patients with stage III
      colon cancer, is immunomodulatory. To determine whether alterations in immune
      parameters before, during and after 12 months of 5FU/LMS therapy correlate with
      disease-free survival, 38 patients enrolled on Southwest Oncology Group (SWOG)
      protocol 8899 received extensive lymphocyte phenotypic analysis prior to therapy
      and 3, 6, 12 and 15 months after treatment initiation. The median follow-up of
      patients is 41 months. Significant increases in the proportion and total number
      of CD56+ natural killer cells were seen, starting at 3 months and continuing
      until 15 months (P < 0. 001). Increases in the total numbers of cells expressing
      CD25 (interleukin-2 receptor), VLA4 and the combinations of CD4: CD45RA and
      CD4:CDw29 were not evident during therapy but were seen at 15 months (P < 0.05:
      CD25, CD4:CDw29, CD4:CD45RA; P < 0.001: VLA4). Low levels of CD8+ cells prior to
      treatment initiation and after 3 months of therapy correlated with early relapse
      within the first year of 5FU/LMS treatment. Patients who have remained disease
      free (n = 22, median follow-up 45 months) demonstrated increases in the total
      numbers of CD8+, CD25+, CD56+, VLA4+, CD4: CDw29 and CD4:CD45RA cells, primarily
      at 15 months. In contrast, patients who relapsed had decreased numbers of CD8+,
      CD4:CDw29, CD4: CD45RA and VLA4+ cells and minimal increases in CD56+ and CD25+
      cells. Statistically significant differences between the late-relapse group and
      the group remaining disease-free were seen for CD25+, CD4: CD45RA and CD4:CDw29
      cells at the 15-month assay time (P = 0.0276, P = 0.0349, P = 0.0178
      respectively). In conclusion, multiple alterations in lymphocyte phenotype, with
      increases in the proportion and total number of cells involved in cell-mediated
      immune responses, were seen during and especially following completion of therapy
      with 5FU/LMS. Many of these changes are significantly associated with clinical
      outcome and may be useful for risk stratification of stage III colon cancer
      patients following completion of adjuvant therapy.

PMID- 10602892
TI  - Management of mantle cell lymphoma.

PMID- 10602893
TI  - Histochemistry and morphometry on bone marrow biopsies in chronic
      myeloproliferative disorders - aids to diagnosis and classification.
AB  - The aim of this review is to evaluate morphological characteristics of the
      different subtypes of chronic myeloproliferative disorders (MPDs) derived by
      applying immunohistochemical and morphometric techniques to bone marrow biopsies
      and to combine these results with relevant clinical parameters. In comparison to
      control specimens, a significant decrease in erythroid precursors is determinable
      in chronic myeloid leukemia (CML), while this cell lineage is most prominent in
      polycythemia vera (PV) and moderately to markedly reduced in idiopathic
      myelofibrosis (IMF). On the other hand, neutrophilic granulopoiesis shows a
      predominance in CML and a relevant increase in PV, but no conspicuous changes are
      detectable in essential thrombocythemia (ET). CML is characterized by a prevalent
      growth of dwarflike micromegakaryocytes, occurring in particular in the so-called
      megakaryocyte-rich subtypes (about 30%). This finding differs significantly from
      the pleomorphous aspect, i.e. , clusters of small to giant-sized megakaryocytes
      in PV and the grossly abnormal (dysplastic) appearance of this cell lineage in
      patients with IMF. Similar cytological abnormalities of megakaryopoiesis
      consistent with maturation defects are never encountered in ET. The incidence of
      mature (resident) macrophages (phagocytic reticular cells) is significantly
      enhanced in IMF in comparison to the other MPDs and controls. Moreover, there is
      a striking difference in the density of reticulin-collagen fibers, ranging from
      normal (ET) to extreme values (IMF). In IMF more than 80% of the patients present
      with some degree of myelofibrosis-osteosclerosis at diagnosis, while the rest
      show an initial prefibrotic, hypercellular stage. This feature deserves special
      attention since, when accompanied by thrombocythemia, it may simulate ET.
      Sequential bone marrow biopsies in patients with IMF disclose that evolution of
      myelofibrosis is progressive, but occurs at a variable and unpredictable speed. A
      synoptical approach regarding clinical diagnosis and histological subtyping of
      MPDs is explicitly recommended and demonstrated by sets of diagnostic criteria.
      This rationale requires equal consideration of laboratory data and morphology by
      clinicians to include well-defined subtypes of MPDs into prospective management
      studies. Furthermore, it may even warrant follow-up studies and repeated bone
      marrow examinations in initially unclassifiable cases.

PMID- 10602894
TI  - Long-term follow-up of patients after related- and unrelated-donor bone marrow
      transplantation for chronic myelogenous leukemia.
AB  - Between January 1983 and December 1997, 88 patients (36 female, 52 male, median
      age 37 years, range 19-57) with chronic myelogenous leukemia (CML) underwent
      allogeneic bone marrow transplantation (BMT) at the University Hospital of
      Vienna. Sixty patients were in chronic phase, 18 in accelerated phase, and ten in
      blast crisis. Marrow donors were HLA-identical siblings for 64 patients (BM 58,
      PBSC 6), 2-antigen-mismatched related donors (RD) for two, HLA-identical
      unrelated donors (URD) for 17, and 1-antigen-mismatched URD for five. The median
      time from diagnosis to BMT was 22 months (range 2-91), and 63 patients had
      received prior interferon (IFN)-alpha therapy, 46 (73%) for more than 6 months.
      Conditioning therapy consisted of cyclophosphamide (CY) and total body
      irradiation (TBI) in 71 patients and CY and busulfan (BU) in 16. One patient
      received etoposide and TBI. For graft-versus-host disease (GVHD) prophylaxis
      methotrexate (MTX) was given to 12 patients, MTX and cyclosporin A (CSA) to 67,
      CSA alone to four, and CSA and methylprednisolone to five. Durable engraftment
      was documented in 80 of 82 patients (98%). As of December 31, 1997, 52 patients
      (59%) were alive, 38 (58%) after sibling transplantation with a median
      observation time of 73 months and 14 (64%) after URD transplantation with a
      median observation time of 12 months. Probability of overall survival is 59%, for
      patients undergoing transplantation in chronic phase and 44% for patients
      undergoing transplantation in advanced stage CML. Probability of disease-free
      survival (DFS) after sibling and URD BMT is 55% and 59%, respectively. Ten
      patients (12%) experienced relapse of CML. Transplant-related mortality was 32%
      both after RD and after URD transplantation. Acute GVHD occurred in 53 of 80
      evaluable patients (66%), consisting of grade III or IV in 14 patients (18%).
      Chronic GVHD developed in 40 of 63 eligible patients (63%), including extensive
      disease in 26 patients (41%). Thus, sibling and URD BMT offer high cure rates
      with acceptable toxicity to patients with CML.

PMID- 10602895
TI  - Cytidine deaminase - the methodological relevance of AraC deamination for ex vivo
      experiments using cultured cell lines, fresh leukemic blasts, and normal bone
      marrow cells.
AB  - The clinical effects of cytosine arabinoside (AraC) are highly dependent on
      schedule and dose. Many regimens administered to patients are derived from
      artificial model systems involving permanent leukemic cell lines. The differences
      in pharmacokinetics between the in vivo situation and such cell lines are largely
      neglected. However, cytidine deaminase activity in particular has a major impact
      on AraC pharmacokinetics by degrading AraC to its inactive metabolite AraU, and
      it has been shown to be of prognostic relevance in the treatment of acute myeloid
      leukemia. This study therefore investigated cytidine deaminase activities and
      AraC deamination in a variety of the most commonly used leukemic cell lines and
      fresh blasts and their impact on the results of an in vitro model system. It was
      found that cells from different cell lines (BLIN, CEM, HL60, K562, RAJI, REH,
      U937) vary greatly in cytidine deaminase activity (e.g., 1.89 nmol per min/mg in
      K562 versus 0.01 in BLIN cells) and degrade between 18.5 (BLIN) and 96.5% (REH)
      of AraC to AraU in the incubation medium. This degradation results in highly
      different AraC exposures for different cells (e.g., AUC of 960 ng per h/ml in REH
      versus 4048 ng per h/ml in BLIN cells) in spite of identical starting
      concentrations of the drug. Formation of AraCTP as the main cytotoxic metabolite
      of AraC is significantly influenced by the differences in cell type-dependent
      cytidine deaminase activity (e.g., 35.6 ng/10(7) cells in REH versus 180.2
      ng/10(7) cells in BLIN cells). In contrast to permanent cell lines, fresh
      leukemic blasts and normal bone marrow mononuclear cells featured low AraC
      degradation in the model system.

PMID- 10602896
TI  - Vincristine as salvage treatment for refractory thrombotic thrombocytopenic
      purpura.
AB  - Vincristine (1.4 mg/m(2) on day 1, followed by 1 mg on days 4 and 7) was given to
      eight patients with thrombotic thrombocytopenic purpura (TTP) who were refractory
      to plasma exchange (n=4) or plasma infusion (n=4). Seven of eight patients (87%)
      achieved a complete response; one was refractory to treatment and died within a
      few weeks. After a median follow-up of 50 months, all responding patients are
      alive and well. Two patients relapsed and were successfully retreated with
      vincristine. Toxicity was mild, consisting of two episodes of leukopenia and one
      of autonomic neuropathy leading to paralytic ileus in a patient aged 70 years. We
      conclude that vincristine is highly effective in the treatment of patients
      suffering from refractory TTP, with negligible toxicity.

PMID- 10602897
TI  - Frequency of very late fatal sepsis after splenectomy for hereditary
      spherocytosis: impact of insufficient antibody response to pneumococcal
      infection.
AB  - Very late sepsis in splenectomized patients with hereditary spherocytosis has
      been seen rarely up to now; the frequency and the immunodeficiency causing it are
      largely unknown. Within the past 7 years we have learned of four cases of sepsis
      or meningitis (three fatal) in adult patients with hereditary spherocytosis who
      had been splenectomized years earlier. The estimated frequency of very late
      postsplenectomy infections is 0.69 cases of sepsis or meningitis in 1000 patient
      years (0.46 deaths in 1000 patient-years). Pneumococci were proven in two
      patients. The surviving patient showed low antibody titers against pneumococcal
      serotypes even after pneumococcal meningitis and subsequent vaccination. There
      have been several reports of an insufficient response to pneumococcal vaccination
      in patients with severe infections. We recommend determination of pneumococcal
      antibody titers after immunization in every splenectomized patient: Nonresponders
      to vaccination may be at high risk for overwhelming postsplenectomy infection.
      Our data demonstrate that there is a lifelong risk for severe postsplenectomy
      infections and therefore the lasting need for immediate antibiotic therapy in any
      case with sudden onset of high fever.

PMID- 10602898
TI  - Aspergillus osteoarthritis in acute lymphoblastic leukemia.
AB  - We report an unusual case of arthritis of the right wrist due to Aspergillus
      fumigatus without evidence for a generalized infection, following chemotherapy
      for acute lymphoblastic leukemia. The diagnosis was made by surgical biopsy.
      Amphotericin-B (Am-B) was not tolerated by the patient. Liposomal preparations of
      Am-B penetrate poorly into bone and cartilage. Therefore, oral itraconazole was
      given; the arthritis improved and chemotherapy was continued without infectious
      complications. Two weeks after complete hematopoietic recovery, an intracranial
      hemorrhage from a mycotic aneurysm of a brain vessel occurred, although the
      patient was still receiving itraconazole. We emphasize the importance of prompt
      and thorough efforts to identify the causative agent in immunocompromised
      patients with a joint infection. Itraconazole is effective in Aspergillus
      osteoarthritis but, due to its poor penetration into the brain, the combination
      with a liposomal formulation of Am-B is recommended.

PMID- 10602899
TI  - Simultaneous occurrence of hepatocellular carcinoma and low grade non-Hodgkin's
      lymphoma in a chronic hepatitis B surface antigen carrier.

PMID- 10602901
TI  - Ifosfamide given by continuous-intravenous infusion in association with
      vinorelbine in patients with anthracycline-resistant metastatic breast cancer: A
      phase I-II clinical trial.
AB  - BACKGROUND: Vinorelbine (VNR) is highly active in metastatic breast cancer (MBC)
      and has shown an overall response rate of 40%-50% as first-line treatment. In
      vitro, a synergy has been observed between this drug and ifosfamide (IFX). In
      addition, the pharmacokinetics of IFX suggest that it may have greater activity
      when given by continuous-intravenous infusion (C.I.V.I.). The aim of this study
      was therefore to assess the antitumor efficacy and toxicity of the combination of
      bolus VNR and C.I.V.I. IFX as second-line therapy in anthracycline-resistant
      breast cancer patients. PATIENTS AND METHODS: Forty-two patients with MBC who had
      already received anthracycline-based chemotherapy were treated with a regimen
      consisting of IFX, by C.I.V.I. for 72 hours and bolus VNR. The courses were
      repeated every three weeks for a maximum of eight cycles. Four dose
      intensification steps were planned. IFX, 1.5 g/m(2) on days 1-3 + VNR, 30 mg/m(2)
      on day 1 (six patients); IFX, 2 g/m(2) on days 1-3 + VNR, 25 mg/m(2) on day 1
      (six patients); IFX, 1.8 g/m(2) on days 1-3 + VNR, 25 mg/m(2) on days 1 and 8
      (six patients); IFX, 2 g/m(2) on days 1-3 + VNR, 25 mg/m(2) on days 1 and 8 (24
      patients). Sodium-2-mercaptoethane sulfonate (mesna) was associated with IFX at
      an infusion ratio of 1:1 and, once the infusion was completed, per os every four
      hours for three times. RESULTS: All of the 42 patients entered were assessable
      for toxicity, and 41 of them for response. Neutropenia was the most frequently
      occurring toxicity, but only five patients at the highest dose level (11.9%)
      presented grade 4, and none of those at the first three steps. Other significant
      toxic effects were mild (only grade I-II). The median relative dose intensity was
      95% at the highest dose level and all the treatments were administered on an out
      patient basis. The overall response rate was 36.5% with a CR rate of 4.8% (two of
      41 patients, all at the highest dose level) and a PR rate of 31.7% (13 of 41
      patients). The median response duration was 7.0 months (range 2-13 months).
      CONCLUSIONS: The present phase I-II study shows that the IFX and VNR combination
      is an active and well-tolerated treatment in MBC and provides an alternative to
      taxanes for patients previously treated with anthracyclines.

PMID- 10602902
TI  - Phase II study of ifosfamide plus vinorelbine in metastatic breast cancer
      patients previously treated with combination chemotherapy.
AB  - Forty-six patients were included in a phase II study to evaluate the response
      rate and toxicity of a combination of ifosfamide and vinorelbine in metastatic
      breast cancer patients previously treated with one or more regimens of
      chemotherapy. Treatment consisted of ifosfamide 1.6 g/m(2) IV days 1-3 (with
      mesna) and vinorelbine 25 mg/m(2) IV days 1 and 8, every 3 weeks up to 6 cycles.
      The median age was 55 years (range 40-76), the World Health Organization (WHO)
      performance status was 0-1 in 93% of the patients and 2 in the remaining 7%. In
      all, 43% had received two or more previous lines of chemotherapy, and 91% had
      been treated with anthracyclines. Forty-four patients were evaluable for
      response, and all patients for toxicity. The overall response rate was 36.4% [95%
      confidence interval (CI) 22.4-52.2]. Stabilization was observed in 20.4% and
      progression in 43.2%. The median time to progression was 25 weeks (95% CI 14-36).
      Median relative dose intensity (=actual received dose intensity/planned dose
      intensity) was 0.99 for ifosfamide and 0. 80 for vinorelbine. The main toxicity
      was hematological, with 63% of the patients experiencing grade 3-4 neutropenia.
      With a moderate toxicity, this is an active regimen that may be taken into
      consideration in pretreated metastatic breast cancer patients when further
      chemotherapy is indicated.

PMID- 10602903
TI  - Ifosfamide and vinorelbine in metastatic breast cancer in patients with prior
      anthracycline therapy.
AB  - OBJECTIVE: A prospective trial to evaluate the efficacy and toxicity of
      ifosfamide (IFX) and vinorelbine (VNB) in patients with prior anthracycline
      therapy for metastatic breast cancer (MBC) was conducted. At the same time, the
      scheduling of VNB in order to minimize toxicity of the combination was also
      evaluated. PATIENTS AND METHODS: Twenty-three patients with MBC who had already
      received initial chemotherapy with doxorubicin-containing regimens either as
      adjuvant or as first-line treatment in MBC were entered into the study. IFX 3
      g/m(2) and mesna 3 g/m(2) were given in divided doses over 2 days. In 4 patients,
      VNB was given 25 g/m(2) on days 1 and 3 in 3-h infusion. In 8 patients, VNB was
      given on days 1 and 8 and in 5 patients VNB was given on days 1 and 15. Thirteen
      patients had received doxorubicin in adjuvant setting, while 10 patients received
      doxorubicin as first-line treatment in metastatic disease. Dominant disease sites
      were soft tissues in 7 patients, visceral in 12 patients, and bone in 4 patients.
      The median age was 47 years. RESULTS: Overall objective response was seen in
      12/23 patients (52.2%). Four patients achieved complete remission (CR), 8
      patients achieved partial remission (PR). The median duration of response was 9
      months in responding patients, and the median overall survival duration was 15
      months. The major dose-limiting toxicities were neutropenia grade III and IV in
      8/17 patients and asthenia grade III and IV in 4 patients. CONCLUSION: IFX and
      VNB is an active combination. Neutropenia and asthenia were most significant when
      VNB was given on days 1 and 3. In the best-tolerated regimen, VNB was given on
      days 1 and 8.

PMID- 10602904
TI  - Adjuvant high-dose therapy with peripheral blood stem cell support for patients
      with high-risk breast cancer.
AB  - We report on the efficacy and toxicity of a sequential high-dose therapy with
      peripheral blood stem cell (PBSC) support in 107 patients with high-risk stage
      II/III breast cancer. There were 90 patients with more than 9 tumour-positive
      axillary lymph nodes. An induction therapy of two cycles of ifosfamide (total
      dose, 7,500 mg/m(2)) and epirubicin (120 mg/m(2)) was given, and PBSC were
      harvested during granulocyte colony-stimulating factor (G-CSF)-supported
      leukocyte recovery following the second cycle. The PBSC-supported high-dose
      chemotherapy consisted of two cycles of ifosfamide (total dose 12,000 mg/m(2)),
      carboplatin (900 mg/m(2)) and epirubicin (180 mg/m(2)). Patients were autografted
      with a median number of 4.1 x 10(6) CD34+ cells/kg (range 1.9-26.5 x 10(6)),
      resulting in haematological reconstitution within approximately 2 weeks following
      high-dose therapy. The toxicity was moderate in general, and there was no
      treatment-related toxic death. Twenty-nine patients (27.1% of all patients)
      relapsed between 3 and 46 months following the last cycle of high-dose therapy
      (median 15 months). The probability of disease-free and overall survival at 3
      years was 56% and 83%, respectively. A multivariate analysis showed that patients
      with stage II disease had a significantly better probability of disease-free
      survival (71%) in comparison with patients with stage III disease (30%). The
      probability of disease-free survival was also significantly better for patients
      with oestrogen receptor-positive tumours (62%) compared with patients with
      receptor-negative ones (40%). In conclusion, sequential high-dose chemotherapy
      with PBSC support can be safely administered to patients with high-risk stage
      II/III breast cancer. Further intensification of the therapy including the
      addition of non-cross-resistant drugs or immunological approaches may be
      envisaged for patients with stage III disease and hormone receptor-negative
      tumours.

PMID- 10602905
TI  - FILM (5-fluorouracil, ifosfamide, leucovorin and mitomycin C), an alternative
      chemotherapy regimen suitable for the treatment of advanced breast cancer in the
      'out-patient' setting.
AB  - FILM, a combination of 5-fluorouracil (5-FU) 750 mg/m(2), ifosfamide 1 g/m(2),
      leucovorin 200 mg/m(2) and mitomycin C 6 mg/m(2) (alternate cycles), was
      administered to 24 chemo-naive patients with inoperable disease, locally advanced
      or metastatic. Up to 6 x 3-weekly cycles of FILM were administered on an out
      patient basis. Responses included 8 patients in complete remission (CR) and 12
      showing a partial response (PR) (83%). Following analysis of these results, the
      FILM regimen was introduced as a standard out-patient protocol at the North
      Middlesex Hospital, United Kingdom. A further 66 patients have been treated in
      this setting. Retrospective analysis of these data confirm the trial results and
      allow conclusions regarding tolerability, toxicity, duration of response and
      survival to be drawn from a total cohort of 90 patients. A total of 524 cycles
      have been administered. Nineteen cycles (4%) were delayed owing to slow recovery
      of white blood cells (WBC), but no dose reductions were necessary. Five blood
      transfusions were required for anaemia. The most frequent non-haematological
      toxicities included nausea, vomiting and fatigue. Of 80 patients treated for
      inoperable or locally advanced disease, 56 (70%) remain in remission, and 69
      (86%) remain alive after 5 years.

PMID- 10602906
TI  - Dose-intense salvage therapy after neoadjuvant chemotherapy: feasibility and
      preliminary results.
AB  - Breast cancer patients who, following treatment with primary chemotherapy (FAC
      50) present an axillary node involvement of more than 4 nodes together with
      clinically palpable residual disease (minor response to chemotherapy) and the
      presence of tumour cell emboli in lymphatics have a very poor outcome. DFS rates
      of 50 patients treated between 1990 and 1994 were 31% at 5 years. Our aim was
      therefore to evaluate an entirely different therapeutic regime in these very high
      risk patients. 32 patients selected for these criteria entered a pilot study
      consisting in treatment with 3 four weekly cycles of vinorelbine, ifosfamide,
      cisplatinum followed by a high dose chemotherapy (HDCT) course and rescue by
      peripheral hematopoietic stem cells which had been collected by cytapheresis
      after the second course of chemotherapy. HDCT consisted of thiotepa, L-Pam, CBDCA
      (800 mg/m(2) d1), ifosfamide and mesna. Following primary chemotherapy, 14
      patients had breast conservation and 18 had a modified mastectomy. Median number
      of involved lymph nodes was 11 (range 4-26). 29 patients received the complete
      HDCT course. Median age was 40 (range 24-59). Engraftment was prompt with a
      median of 10 days to leucocyte recovery to 1,000/microl and 9 days to platelet
      recovery. One patient developed reversible renal failure, and subsequently died
      of Gram-septicemia. To date, with a median follow up of 20 months (range 14-36),
      6 patients have relapsed and 2 patients have died. It is too early to make any
      firm conclusions, but we feel that this alternative regime is feasible and may
      prove superior to the classical optimal dose anthracycline-containing regimes in
      patients who have a tendency to rapidly develop resistance to anthracyclines.

PMID- 10602907
TI  - Ifosfamide, carboplatin and etoposide (ICE) in metastatic and refractory breast
      cancer.
AB  - Twenty-five patients with metastatic breast cancer were treated with ICE after
      failure of previous chemotherapy. Their median age was 50 years (range 36-73).
      All but 1 patient had multiple sites of metastases. Nineteen (76%) patients had
      undergone two or more chemotherapy regimens for metastatic disease prior to ICE.
      The performance status (PS) of the patients was Eastern Cooperative Oncology
      Group (ECOG) 0:6; 1:12; 2:5; 3:2. Ifosfamide 1.25 g/m(2) over 3 h D1-3 along with
      mesna, etoposide 80 mg/m(2) D1-3 and carboplatin 300 mg/m(2) D1 were given every
      3 weeks. We observed a partial response in 10 patients (40%, 95% confidence
      interval 21-62%). The response duration ranged from 1 to 15 months with a median
      duration of 4.5 months. The survival of all 25 patients ranged from 10 days to 25
      months, with a median of 9 months. All 25 patients were evaluable for toxicity.
      Thirteen patients (52%) experienced grade 4 hematological toxicity, which
      improved after growth factor support. Four patients had leukopenic fever, 1 had
      gram-negative sepsis, while 2 had Clostridium difficile enterocolitis and another
      had herpes zoster reactivation. Four patients (16%) experienced grade 3-4
      gastrointestinal (G-I) toxicity. No hepatic or renal toxicity was observed (1
      patient had microscopic hematuria). One patient died of G-I bleed, and another
      patient died at home of undetermined cause. We conclude that ICE is an effective
      salvage regimen in metastatic and refractory breast cancer, even in heavily
      pretreated patients, and is a tolerable treatment when used with growth factor.

PMID- 10602908
TI  - Miltefosine as a topical treatment for cutaneous metastases in breast carcinoma.
AB  - BACKGROUND: Recurrent cutaneous breast cancer is difficult to manage, with
      surgery, radiotherapy and systemic therapy all having their limitations.
      Miltefosine is a topical cytostatic agent which may provide an alternative
      approach in its treatment. PATIENTS AND METHODS: Patients with previously treated
      progressive cutaneous lesions from breast cancer were treated with miltefosine on
      a named-patient compassionate supply basis. Miltefosine was applied topically to
      the skin at a dose of 2 drops/10 cm(2) skin area. RESULTS: Twenty-five patients
      were treated, most of whom had been heavily pre-treated. Treatment was continued
      for a median of 14 weeks (range 2-164). In 7 patients grade I skin toxicities
      were observed, and in 4 patients grade 3 local toxicities necessitated dose
      adjustments. A response was seen in 9 patients (1 complete response, 2 partial
      responses, 6 minor responses) giving a total response rate of 36%, with stable
      disease in 11 patients (44%) and progressive disease in 5 (20%). Those lesions
      which were superficial or < 2 cm in diameter were most likely to respond.
      CONCLUSIONS: Miltefosine, either used alone or in conjunction with other
      therapies for distant metastases, is an effective and tolerable local treatment
      for cutaneous breast cancer.

PMID- 10602909
TI  - Treatment of skin metastases of breast cancer.

PMID- 10602910
TI  - Excitability of an age-structured plankton ecosystem.
AB  - We adapt a simple two-component model of a plankton ecosystem to account for the
      life spans of individual predatory organisms. We investigate the system's short
      term dynamics, in particular its excitability, and its long-term dynamics, and
      show how both can be highly sensitive to initial conditions. We discover that
      this effect is enhanced by imposing age structure on the system.

PMID- 10602911
TI  - No BLUE among phylogenetic estimators.
AB  - Multivariate analysis is a branch of statistics that successfully exploits the
      powerful tools of linear algebra to obtain a fairly comprehensive theory of
      estimation. The purpose of this paper is to explore to what extent a linear
      theory of estimation can be developed in the context of coalescent models used in
      the analysis of DNA polymorphism. We consider a large class of coalescent models,
      of which the neutral infinite sites model is one example. In the process, we
      discover several limitations of linear estimators that are quite distinct from
      those in the classical theory. In particular, we prove that there does not exist
      a uniformly BLUE (best linear unbiased estimator) for the scaled mutation
      parameter, under the assumptions of the neutral model of evolution. In fact, we
      show that no linear estimator performs uniformly better than the Watterson (1975)
      method based on the total number of segregating sites. For certain coalescent
      models, the segregating-sites estimator is actually optimal.The general
      conclusion is the following. If genealogical information is useful for estimating
      the rate of evolution, then there is no optimal linear method. If there is an
      optimal linear method, then no information other than the total number of
      segregating sites is needed.

PMID- 10602912
TI  - The rainbow bridge: Hamiltonian limits and resonance in predator-prey dynamics.
AB  - In the presence of seasonal forcing, the intricate topology of non-integrable
      Hamiltonian predator-prey models is shown to exercise profound effects on the
      dynamics and bifurcation structure of more realistic schemes which do not admit a
      Hamiltonian formulation. The demonstration of this fact is accomplished by
      writing the more general models as perturbations of a Hamiltonian limit, &Hscr;,
      in which are contained infinite numbers of periodic, quasiperiodic and chaotic
      motions. From &Hscr;, there emanates a surface, Gamma, of Nejmark-Sacker
      bifurcations whereby the annual oscillations induced by seasonality are
      destabilized. Connecting Gamma and &Hscr; is a bridge of resonance horns within
      which invariant motions of the Hamiltonian case persist. The boundaries of the
      resonance horns are curves of tangent (saddle-node) bifurcations corresponding to
      subharmonics of the yearly cycle. Associated with each horn is a rotation number
      which determines the dominant frequency, or "color", of attractors within the
      horn. When viewed through the necessarily coarse filter of ecological data
      acquisition, and regardless of their detailed topology, these attractors are
      often indistinguishable from multi-annual cycles. Because the tips of the horns
      line up monotonically along Gamma, it further follows that the distribution of
      observable periods in systems subject to fluctuating parameter values induced,
      for example, by year-to-year variations in the climate, will often exhibit a
      discernible central tendency. In short, the bifurcation structure is consistent
      with the observation of multi-annual cycles in Nature. Fundamentally, this is a
      consequence of the fact that the bridge between &Hscr; and Gamma is a rainbow
      bridge. While the present analysis is principally concerned with the two species
      case (one predator and one prey), Hamiltonian limits are also observed in other
      ecological contexts: 2n-species (n predators, n prey) systems and periodically
      forced three level food chain models. Hamiltonian limits may thus be common in
      models involving the destruction of one species by another. Given the oft
      commented upon structural instability of Hamiltonian systems and the
      corresponding lack of regard in which they are held as useful caricatures of
      ecological interactions, the pivotal role assigned here to Hamiltonian limits
      constitutes a qualitative break with the conventional wisdom.

PMID- 10602913
TI  - Foreword

PMID- 10602914
TI  - Broadband transducers.

PMID- 10602915
TI  - Evolution of ultrasound transducers: 1.5 and 2D arrays.

PMID- 10602916
TI  - An overview of digital technology in ultrasonic imaging.

PMID- 10602917
TI  - Manufactory development: ATL. Digital ultrasound: from beamforming to PACs.

PMID- 10602918
TI  - Manufactory development: Acuson. Digital technology for solving acoustic
      problems.

PMID- 10602919
TI  - Power doppler.

PMID- 10602920
TI  - Tissue harmonic imaging.

PMID- 10602921
TI  - Ultrasound elasticity imaging: definition and technology.

PMID- 10602922
TI  - 3D ultrasound: a dedicated system.

PMID- 10602923
TI  - System architecture for various image reconstruction and processing techniques.

PMID- 10602924
TI  - Introduction to ultrasound contrast agents: physics overview.

PMID- 10602925
TI  - Preliminary experience with NC100100, a new ultrasound contrast agent for
      intravenous injection.

PMID- 10602926
TI  - SonoVue, a new ultrasound contrast agent.

PMID- 10602927
TI  - Liver-specific imaging with SHU 563A: diagnostic potential of a new class of
      ultrasound contrast media.
AB  - The purpose of this study was to evaluate the imaging properties and diagnostic
      potential of the novel polymeric ultrasound contrast agent SHU 563 A. After i. v.
      injection, the agent circulates in the blood pool for about 10 min and is then
      subsequently sequestered by the RES cells predominantly in the liver. The
      acoustic emission capabilities enable a very sensitive detection during the blood
      pool phase and after uptake in the RES cells, contributing to differential
      diagnosis as well as detection of liver lesions. During a multicenter study, 28
      patients with liver lesions were examined. In all patients the results were
      compared to baseline ultrasound and Contrast enhanced Spiral CT. With respect to
      lesion size and location, very good agreement between SHU 563 A ultrasound and
      Spiral CT was achieved. Additional lesions could be shown in the RES phase by SHU
      563 A enhanced ultrasound. 26 further patients were examined in other
      indications. The results in all 54 patients indicate good safety and tolerance of
      SHU 563 without limitations for diagnostic use. SHU 563 A enhanced ultrasound
      adds significantly to the detection and delineation of focal liver lesions by
      improving conspicuity due to RES based contrast after uptake.

PMID- 10602928
TI  - Contrast-specific imaging and potential vascular applications.

PMID- 10602929
TI  - Parenchymal enhancement on gray-scale in normal and pathologic tissues.

PMID- 10602930
TI  - Wideband harmonic imaging: a novel contrast ultrasound imaging technique.
AB  - A novel ultrasonic imaging method, wideband harmonic imaging, for nonlinear
      imaging of microbubble contrast agents is evaluated. In wideband harmonic mode,
      two pulses of alternate phase are send out. The image is then processed from the
      sum of both pulses, resulting in an image of nonlinear scatterers such as
      microbubbles. A prototype ultrasound system, Siemens Elegra, was evaluated with
      in vitro investigations and animal trials, using conventional, harmonic and
      wideband harmonic settings with the galactose based ultrasound contrast agent
      Levovist. Wideband harmonic imaging offers superior sensitivity for ultrasound
      contrast agents compared to conventional imaging and harmonic imaging. At low
      transmit power settings (MI 0. 1-0.5) the nonlinear response is already
      sufficient to generate a image of the blood pool distribution of Levovist in the
      rabbit kidney including the microvasculature, with clear delineation of vessels
      and perfused parenchyma. At high transmit amplitudes, nonlinear tissue response
      reduced the apparent image contrast between contrast agent and tissue. The
      results suggest that wideband harmonic imaging is currently the most sensitive
      contrast imaging technique, maintaining highest spatial resolution. This may add
      to image quality and offer new clinical potential for the use of ultrasound
      contrast agents such as Levovist.

PMID- 10602931
TI  - Flow quantification.

PMID- 10602932
TI  - Quantitative analysis of contrast enhancement.

PMID- 10602933
TI  - Transit-time studies with levovist in patients with and without hepatic
      cirrhosis: a promising new diagnostic tool.

PMID- 10602934
TI  - Detection of liver metastases with pulse inversion harmonic imaging: preliminary
      results.
AB  - The aim of this study is to evaluate capability of contrast enhanced
      ultrasonography (US) using pulse inversion harmonic imaging (PIHI) to detect
      liver metastases in comparison to fundamental B-mode ultrasound and spiral CT.
      Thirty-six consecutive patients with known malignancies and sonographically
      proved or suspicious liver metastases have been examined with fundamental B-mode
      US, with PIHI 2', 4' and 6' after Levovist injection and with four phase spiral
      CT. Presence, conspicuity and number of lesions have been evaluated comparing
      PIHI with fundamental B-mode US and spiral-CT. A strong grey-scale enhancement of
      the liver parenchyma has been observed 2' and 4' after Levovist injection. The
      optimum parenchymal enhancement and contrast difference between liver and
      metastases was observed during the 2' measurements. PIHI revealed more lesions
      than fundamental B-mode US in 56 % of patients, while in 39 % and in 5 % revealed
      respectively the same number and fewer lesions. PIHI and spiral-CT were in
      agreement in 67 % of patients, while in 22 % and 11 % PIHI revealed respectively
      more and fewer lesions. PIHI accurancy presents restrictions in anterior
      superficial and in deep liver areas, whereas it may be superior to spiral-CT in
      studying sub-diaphragmatic liver regions.

PMID- 10602935
TI  - Improved detection of liver metastases with phase inversion imaging during the
      liver-specific phase of the ultrasound contrast agent levovist.

PMID- 10602936
TI  - Kidney: normal anatomy.

PMID- 10602937
TI  - Contrast-enhanced ultrasonography of native and transplanted kidney diseases.

PMID- 10602938
TI  - The breast.

PMID- 10602939
TI  - Musculoskeletal power doppler.

PMID- 10602940
TI  - Penile sonography.

PMID- 10602941
TI  - Microbubble enhancement of tumour neovascularity.

PMID- 10602942
TI  - Genitourinary MR: kidneys and adrenal glands.
AB  - Due to its high tissue contrast and multiplanar imaging capabilities, MRI
      provides a detailed display of renal and adrenal anatomy. Recent technical
      developments overcoming the problem of respiration induced motion artifacts and
      the use of paramagnetic contrast agents have further improved the performance of
      MRI which has now evolved as an alternative or complementary imaging modality to
      ultrasound, excretory urography and computed tomography. Dynamic contrast
      enhanced studies will usually allow to detect even small enhancing solid areas
      within the cyst wall. Use of a fast (turbo) spoiled gradient echo sequence allows
      for assessment of contrast enhancement dynamics in renal and adrenal masses. For
      tumor staging, the multiplanar imaging capabilities of MRI are advantageous.
      Perinephric extent is best detected using opposed-phase GRE images resulting in
      an artificial accentuation of renal contours. Extension into venous structures is
      best diagnosed by using a GRE sequence allowing for distinction between flowing
      blood and tumor thrombus. Noninvasive differentiation of adrenal lesions can be
      performed with an unprecedented accuracy using chemical-shift imaging.

PMID- 10602943
TI  - Female pelvis.
AB  - Magnetic resonance imaging is gaining increasing importance in imaging of the
      female pelvis. This overview attempts to describe the various imaging strategies
      in the evaluation of gynecologic diseases, as well as the normal MR anatomy of
      the female genital organs. The MR indications for the assessment of various
      pathologic conditions, including characterization and staging of gynecologic
      neoplasms and prenatal diagnosis of fetal malformations, are discussed.

PMID- 10602944
TI  - MR imaging of the male pelvis.
AB  - Prostate and urinary bladder cancer are the most frequently encountered
      malignancies of the urinary tract. Appropriate use of the different imaging
      techniques is crucial for accurate assessment of prognosis and for the
      development of appropriate treatment planning. Especially determination of local
      tumor extension and detection of nodal or bone metastases is extremely important.
      In this regard MR imaging is the most promising imaging technique. Therefore, in
      this review its role in staging these malignancies is evaluated and compared with
      clinical staging, and other imaging techniques. Finally, future developments,
      such as new sequences, new contrast agents, the role of surface coils and MR
      guided biopsy, are considered. Also, the preferred radiological approach is
      discussed.

PMID- 10602945
TI  - MR imaging of the chest: mediastinum and chest wall.
AB  - This review presents the options and limitations of MRI in non-vascular diseases
      of the mediastinum and the chest wall. In numerous thoracic pathologies, MRI is a
      useful supplement to spiral CT. This imaging procedure also allows a contrast
      media-free differentiation of solid tumors and vascular lesions (e. g., aortic
      aneurysms). The advantages of MRI over CT are particularly useful when
      multiplanar tumor imaging is required prior to surgery to establish the exact
      spatial relationship between tumor and the other mediastinal structures. Primary
      indications for MRI in diseases of the mediastinum and chest wall are therefore:
      (a) tumors of the posterior mediastinum for determining their position in
      relation to the neural foramina and the spinal canal; (b) chest wall tumors; (c)
      preoperative multiplanar imaging of primary mediastinal tumors; and (d)
      contraindications against CT exams with iodine contrast media.

PMID- 10602946
TI  - Pulmonary magnetic resonance angiography.
AB  - In the past few years magnetic resonance angiography (MRA) of the pulmonary
      vasculature has advanced from a research tool to a clinically relevant imaging
      modality. Early 2D phase-contrast and time-of-flight (TOF) sequences without the
      use of contrast agents were time-consuming and limited by considerable imaging
      and motion artifacts. Since the introduction of MR scanners with stronger
      gradients (> 20 mT/m) and contrast-enhanced techniques, imaging of the pulmonary
      vasculature with adequate spatial resolution within a single breathhold is now
      possible. In the detection of pulmonary embolism in the lobar or segmental
      arteries, contrast-enhanced MRA is now on the verge of being considered an
      established modality, possibly competing with conventional pulmonary angiography
      and contrast-enhanced helical CT. In the future, utilization of phased-array
      torso coils, the application of navigator pulse sequences, and 3D time-resolved
      ultrafast MRA will overcome the final limitations of current techniques. Blood
      pool MR contrast agents may provide a "one-stop-shopping" approach to the
      investigation of lower extremity veins and pulmonary arteries in venous
      thromboembolism.

PMID- 10602947
TI  - MRI of the pulmonary parenchyma.
AB  - Imaging of the pulmonary parenchyma represents a unique challenge for MRI.
      Limited signal is caused by low proton density, susceptibility artifacts, and
      physiological motion (cardiac pulsation, respiration). Recently, further
      improvements in MRI techniques have widened the potential for investigations of
      pulmonary parenchymal disease. These include very short echo times, ultrafast
      turbo-spin-echo acquisitions, projection reconstruction technique, breathhold
      imaging, ECG triggering, contrast agents (perfusion imaging, aerosols), sodium
      imaging, hyperpolarized noble gas imaging, and oxygen enhancement. By using
      widely available techniques, MRI is helpful in the assessment of (a) acute
      alveolitic processes in chronic infiltrative lung disease, (b) detection and
      characterization of pulmonary nodules, (c) detection, characterization, and
      follow-up of pneumonia, (d) differentiation of obstructive atelectasis from non
      obstructive atelectasis and infarctions, and (e) measurements of lung water
      content. Chronic bronchitis, bronchiectasis, and emphysema are not readily
      assessable by routine MRI techniques. More sophisticated techniques are under
      investigation for MR imaging of pulmonary ventilation and perfusion. They
      represent the beginning of functional MR imaging of the lung which will be
      established in the future.

PMID- 10602948
TI  - Peripheral MR angiography.
AB  - Atherosclerotic disease of the lower extremities is a common disorder in western
      society. Its debilitating nature calls for accurate diagnosis and treatment. The
      gold standard for diagnosing this disease by depiction of vessel morphology is X
      ray angiography (either conventional or digital subtraction angiography).
      However, the invasive nature of this technique and the possible harmful effects
      of iodinated contrast agents have led to the idea that non-invasive MR
      angiography might be a good alternative for acquiring information about vessel
      morphology. Most extensively studied was time-of-flight MR angiography. Although
      first results with this technique were encouraging, it is now apparent that time
      of-flight MR angiography is hampered by the virtue of which it exists, since
      blood flow not only generates vessel-to-background contrast, but is also the
      cause of disturbing artifacts. However, with the introduction of minimally
      invasive contrast-enhanced MR angiography, using gadolinium chelates to reduce
      the T1 of blood, image quality has improved dramatically. Moreover, using
      contrast-enhanced MR angiography, high-resolution three-dimensional data about
      the entire peripheral vascular tree can be obtained within several minutes, which
      might make MR angiography a true competitor of X-ray angiography as a diagnostic
      tool in the clinical work-up of a patient with complaints of peripheral
      atherosclerosis. The purpose of this article is to explain working mechanisms and
      usefulness of both time-of-flight and contrast-enhanced MR angiography.

PMID- 10602949
TI  - Three-dimensional MR angiography of a nitinol-based abdominal aortic stent graft:
      assessment of heating and imaging characteristics.
AB  - OBJECTIVE: To assess heating- and 3D MRA imaging characteristics of a commonly
      used aortic stent graft in a 1.5T MR-environment. MATERIALS AND METHODS: A
      bifurcated stent graft (Vanguard; Boston Scientific, Oakland, N. J.) was
      evaluated in vitro regarding localized heating effects as well as imaging
      appearance using fast 3D GRE sequences. To quantitate stent related artifacts,
      stent wall thickness and luminal diameters were measured. Subsequently eight
      patients were imaged three months following placement of an aortic stentgraft
      with 3D MRA. Images were assessed for the presence of stent leaks, luminal
      patency, and stent configuration. RESULTS: There were no temperature changes
      associated with the stent during scanning. Wall thickness measurements
      overestimated true stent thickness, resulting in minimal underestimation of
      luminal diameters on 3D MRA images. In vivo imaging confirmed these results.
      Stent patency was confirmed in all 8 patients. CONCLUSION: Contrast-enhanced 3D
      MRA appears well suited for the evaluation of the abdominal and pelvic
      vasculature following aortic implantation of a Vanguard stent.

PMID- 10602950
TI  - Imaging of trabecular bone structure in osteoporosis.
AB  - Osteoporosis is a metabolic bone disorder that is characterized by reduced bone
      mass and a deterioration of bone structure which results in an increased fracture
      risk. Since the disease is preventable, diagnostic techniques are of major
      importance. Standard techniques determine bone mineral density, whereas some of
      the newer techniques focus on trabecular structure. This article reviews
      structure analysis techniques in the diagnosis of osteoporosis. Imaging
      techniques applied to the assessment of trabecular bone structure include
      conventional radiography, magnification radiography, high-resolution CT (HRCT)
      and high-resolution MR imaging (HRMRI). The best results were obtained using high
      resolution tomographic techniques. The highest spatial resolutions in vivo were
      achieved using HRMRI. The most common texture analysis techniques that have been
      used are morphological parameters (analogous to bone histomorphometry). Fractal
      dimension, co-occurrence matrices, mathematical filter techniques and
      autocorrelation functions are more complex techniques. Most of the studies
      evaluating structure analysis show that texture parameters and bone mineral
      density both predict bone strength and osteoporotic fractures, and that combining
      both techniques yields the best results in the diagnosis of osteoporosis.

PMID- 10602951
TI  - Open MR imaging of the unstable shoulder in the apprehension test position:
      description and evaluation of an alternative MR examination position.
AB  - The aim of this study was to describe and evaluate an alternative MR assessment
      procedure for analysis of unstable shoulders. Twelve patients with unilateral
      recurrent anterior shoulder dislocation had both shoulders examined. Magnetic
      resonance imaging was performed with an open-MR system in the apprehension
      position with the shoulder in 90 degrees of abduction and maximum tolerable
      external rotation. Contrast enhancement was achieved with intravenous gadolinium.
      Correlations were made to the findings at operation. In 10 of 12 unstable
      shoulders the inferior glenohumeral ligament labral complex (IGHLLC) was detached
      from the glenoid as seen on MR and later verified during surgery. In one shoulder
      MR was unable to show a capsulolabral detachment that was verified at surgery,
      whereas in one shoulder both MR and surgical assessment revealed no soft tissue
      detachment (accuracy 92 %). A Hill-Sachs lesion was visualized and verified in
      all unstable shoulders, whereas the stable controls revealed normal IGHLLC and no
      Hill-Sachs lesion. Open-MRI evaluation of the shoulder in the apprehension test
      position may become a useful tool for the evaluation of anterior shoulder
      instability.

PMID- 10602952
TI  - Synovialisation of the torn anterior cruciate ligament of the knee: comparison
      between magnetic resonance and arthroscopy.
AB  - The aim of this study was to assess the accuracy of MR in the diagnosis of
      synovialisation of the anterior cruciate ligament (ACL) compared with
      arthroscopy. One hundred and forty-nine patients were examined with MR imaging
      and arthroscopy of the knee. The MR sign used to consider a synovialised ACL
      consisted of hypointense fibrillar tracts, disrupted and wavily, in its expected
      course. Sensitivity, specificity, positive predictive value (PPV) and negative
      predictive value (NPV), comparison of proportions (McNemar test) and Kappa values
      for agreement between MR imaging and arthroscopy were calculated. Of the 133
      (89.3 %) ligaments without synovialisation at arthroscopy, 130 accorded with the
      MR results. Of the 16 (10.7 %) synovialised ligaments, 13 accorded with the MR
      results. Three false-positive and three false-negative MR diagnoses were
      identified. The agreement between both techniques was excellent (Kappa = 0.79; p
      = 0.000), without differences (McNemar test; p = 1). Sensitivity was 0.81,
      specificity 0.98, PPV 0.98 and NPV 0.81. Magnetic resonance imaging is highly
      reliability for synovialisation diagnosis. The imaging sign used to diagnose
      synovialised ACL (hypointense comma-like tracts in its expected course) is
      reliable. As this reparative process can simulate an intact ligament, knowledge
      of this sign is important in diagnosing synovialisation of ACL tears so as not to
      confuse it with normal ACL.

PMID- 10602953
TI  - Chondromyxoid fibroma of the sacrum.
AB  - A 30-year-old man with a 7-month history of mild sacral pain and intermittant
      left sciatica was found to have an expansile lesion in the sacrum on a plain
      radiograph. Biopsy confirmed a chondromyxoid fibroma which was removed
      surgically. A 1-year follow-up showed no recurrence. The case is the fifth to be
      reported. Plain film and MRI appearances, histology and treatment are described.
      The previously reported cases are reviewed and the current literature is
      discussed.

PMID- 10602954
TI  - Imaging features of thalassemia.
AB  - Thalassemia is a kind of chronic, inherited, microcytic anemia characterized by
      defective hemoglobin synthesis and ineffective erythropoiesis. In all
      thalassemias clinical features that result from anemia, transfusional, and
      absorptive iron overload are similar but vary in severity. The radiographic
      features of beta-thalassemia are due in large part to marrow hyperplasia.
      Markedly expanded marrow space lead to various skeletal manifestations including
      spine, skull, facial bones, and ribs. Extramedullary hematopoiesis (ExmH),
      hemosiderosis, and cholelithiasis are among the non-skeletal manifestations of
      thalassemia. The skeletal X-ray findings show characteristics of chronic
      overactivity of the marrow. In this article both skeletal and non-skeletal
      manifestations of thalassemia are discussed with an overview of X-ray findings,
      including MRI and CT findings.

PMID- 10602955
TI  - Parosteal lipoma with hyperostosis.
AB  - A case of parosteal lipoma of the femur combined with hyperostosis is presented.
      The parosteal lipoma is a rare benign tumor containing adipose tissue and is
      intimately related to the periosteum. We report the MRI features and correlative
      pathologic findings of a parosteal lipoma. The MRI technique is useful for
      evaluating the relationship between the periosteum and the lipoma.

PMID- 10602956
TI  - Linear opacities on HRCT in bronchiolitis obliterans organising pneumonia.
AB  - The aim of this study was to report the high-resolution computed tomography
      (HRCT) appearances of linear opacities that may occur in isolation or in
      combination with other changes in bronchiolitis obliterans organising pneumonia
      (BOOP). Eleven patients with BOOP and linear opacities on HRCT were identified at
      three independent teaching hospitals. The HRCT images and clinical course of each
      patient were reviewed. Two distinct types of linear opacity were identified. The
      type-1 opacity extended in a radial manner along the line of the bronchi towards
      the pleura and was usually intimately related to bronchi. The type-2 opacity
      occurred in a sub-pleural location and bore no relationship to the bronchi. Both
      types occurred most commonly in the lower lobes, frequently were associated with
      multi-focal areas of consolidation and usually completely resolved with
      treatment. There was no associated bronchiectasis, irreversible volume loss or a
      reticular or honeycomb pattern. In 2 patients linear opacities were the sole
      abnormality on HRCT. Bronchiolitis obliterans organising pneumonia may occur in a
      pure "linear form" or HRCT may demonstrate linear opacities in addition to multi
      focal consolidation.

PMID- 10602957
TI  - Small peripheral carcinomas of the lung: thin-section CT and pathologic
      correlation.
AB  - The aim of this study was to clarify the thin-section CT features of small
      peripheral carcinomas of the lung on the basis of pathologic findings of tumor
      growth patterns. Thin-section CT and pathologic correlation was evaluated in 19
      patients with surgically verified small peripheral carcinomas of the lung ( < 20
      mm in size) that had been detected in a screening trial for lung cancer using
      spiral CT. Four thin-section CT types of nodules were observed: (a) type L1 (4 of
      19, 21 %), a fairly well-defined nodule with ground-glass attenuation,
      corresponding to tumor lepidic growth without alveolar collapse; (b) type L2 (4
      of 19, 21 %), a partly lobulated nodule with a low but inhomogeneous attenuation,
      corresponding to tumor lepidic growth with scattered foci of alveolar collapse;
      (c) type L3 (4 of 19, 21 %), an ill-defined nodule with an irregularly shaped
      higher-density central zone in a ground-glass attenuation peripheral zone,
      accompanied by convergence of the bronchovascular structures from the surrounding
      lung parenchyma, which corresponded to desmoplastic response in the central zone
      and to tumor lepidic growth in the peripheral zone; and (d) type H (7 of 19, 37
      %), a well-defined nodule with a solid homogeneous attenuation, corresponding to
      tumor hilic growth. Thin-section CT features of small peripheral carcinomas of
      the lung can be classified into four types, based on the density distribution of
      the tumor, which reflect the histologic findings.

PMID- 10602958
TI  - Image quality for five modern chest radiography techniques: a modified FROC study
      with an anthropomorphic chest phantom.
AB  - The purpose of the study was to compare the image quality for one conventional
      and four digital chest radiography techniques. Three storage phosphor systems,
      one selenium drum system, and one film-screen system were compared using a
      modified receiver-operating-characteristics method. Simulated pathology was
      randomly positioned over the parenchymal regions and the mediastinum of an
      anthropomorphic phantom. Eight observers (four chest radiologists, one specialist
      in general radiology, one hospital physicist, and two radiographers) evaluated 60
      images for each technique. The selenium drum system (Philips, Eindhoven, The
      Netherlands) rated best for the detection of parenchymal nodules. Together with
      the storage phosphor system of generation IIIN (Philips/Fuji), the selenium drum
      system also rated best for detection of thin linear structures. The storage
      phosphor system of generation V (Fuji) rated best for the detection of
      mediastinal nodules. The first generation of the storage phosphor system from
      Agfa (Mortsel, Belgium) rated worst for the detection of parenchymal nodules and
      thin linear structures. These differences were significant (p < 0.0001).
      Averaging the results for all test objects, the selenium drum system and the
      storage phosphor system of generation V were significantly better than the other
      systems tested. The film/screen system performed significantly better than the
      first-generation storage phosphor system from Agfa, equal to the generation IIIN
      storage phosphor system (Philips/Fuji) and significantly worse than the selenium
      drum system (Philips) and the generation-V storage phosphor system (Fuji). The
      conclusion is therefore that the image quality of selenium-based digital
      technique and of the more recent generations of storage phosphor systems is
      superior to both conventional technique and storage phosphor systems using image
      plates of older types.

PMID- 10602959
TI  - Aberrant left brachiocephalic vein: CT imaging findings and embryologic
      correlation.
AB  - Computed tomography was utilized to evaluate aberrant left brachiocephalic vein
      (ALBCV), an infrequently discussed congenital vascular anomaly among Chinese
      people. Associated vascular variation and possible embryonic correlation are
      discussed. Since 1990, a total of 14 cases of ALBCV have been reported in
      patients receiving CT scan of chest, and was mainly an incidental diagnosis. One
      case was confirmed angiographically and two others were confirmed by magnetic
      resonance imaging. Emphasis was placed on the entry of the azygos vein into the
      superior vena cava (SVC), the length of the SVC, and the presence of other
      cardiovascular abnormalities. Of the 14 cases of ALBCV, the level of azygos vein
      entry was higher than the origin of the SVC in 7 cases: 4 were approximately the
      same level and 3 were lower. The average length of the SVC was approximately 5. 6
      cm shorter than that of the general population, which is approximately 7.0 cm.
      Three cases had associated vascular anomaly. Most cases of ALBCV had azygos vein
      drainage level higher than or equal to the origin of the SVC. Right-sided aorta
      is one of the causes giving rise to the ALBCV during embryonic development. The
      CT scan remains a definitive diagnostic modality for ALBCV.

PMID- 10602960
TI  - Hilar lymphocele following blunt trauma.

PMID- 10602961
TI  - Current value of double-contrast pharyngography and of computed tomography for
      the detection and for staging of hypopharyngeal, oropharyngeal and supraglottic
      tumors.
AB  - In light of recent endoscopic techniques the current value of double-contrast
      pharyngography (DCP) and of CT for detection and staging of hypo-, oropharyngeal,
      and supraglottic tumors is evaluated. The DCP of 151 patients and CT obtained
      from 99 of these patients were retrospectively analyzed in a double-blinded
      manner. We used a standard protocol which comprised all relevant anatomical
      subregions. Results were compared with direct microlaryngoscopy (DL), indirect
      laryngoscopy (IL), and post-operative histopathological findings. Sensitivity and
      specificity of DCP was 75.0 % and 86.7 %, respectively. The DCP and IL techniques
      together yielded a higher sensitivity (96.7 %) than each method separately.
      Sensitivity and specificity of CT was 87.5 and 100 %, respectively. In 74.7 % CT
      provided correct staging. Subregional analysis revealed that the results of DCP
      and CT depend highly on the localization of the tumor. Our results indicate that
      DCP represents an important screening method for diagnosing hypo-, oropharyngeal,
      and supraglottic tumors to complete IL and DL. We show that CT is a reliable
      method for preoperative staging, although small superficial tumors may
      occasionally be missed by this method.

PMID- 10602962
TI  - Evaluation of the middle and inner ear structures: comparison of hybrid
      rendering, virtual endoscopy and axial 2D source images.
AB  - Recent developments in 3D reconstructions can enhance the quality and diagnostic
      value of axial 2D image data sets with direct benefits for clinical practice. To
      show the possible advantages of a hybrid rendering method [color-coded 3D shaded
      surface display (SSD)- and volume rendering method] with the possibility of
      virtual endoscopy we have specifically highlighted the use in relation to the
      middle and inner ear structures. We examined 12 patients with both normal
      findings and postoperative changes, using image data sets from high-resolution
      spiral computed tomography (HRSCT). The middle and inner ear was segmented using
      an interactive threshold interval density volume-growing method and visualized
      with a color-coded SSD rendering method. The temporal bone was visualized using a
      transparent volume rendering method. The 3D- and virtual reconstructions were
      compared with the axial 2D source images. The evaluated middle and inner ear
      structures could be seen in their complete form and correct topographical
      relationship, and the 3D- and virtual reconstructions indicated an improved
      representation and spatial orientation of these structures. A hybrid and virtual
      endoscopic method could add information and improve the value of imaging in the
      diagnosis and management of patients with middle or inner ear diseases making the
      understanding and interpretation of axial 2D CT image data sets easier. The
      introduction of an improved rendering algorithm aids radiological diagnostics,
      medical education, surgical planning, surgical training, and postoperative
      assessment.

PMID- 10602963
TI  - Wegener's granulomatosis with unusual cavernous sinus and sella turcica
      extension.
AB  - Intracerebral extension of Wegener's granulomatosis (WG) is rare. We present a
      patient with oculomotor and trochlear nerve palsy with histologically proved WG.
      An MR examination revealed granulomatous tissue in nasal cavity, paranasal
      sinuses with meningeal infiltration, and uncommon penetration into cavernous
      sinus and sella turcica. The MR images before and during pharmacological therapy
      are presented.

PMID- 10602964
TI  - Tubular ectasia of the rete testis: a potential pitfall in scrotal imaging.
AB  - Tubular ectasia of the rete testis (TERT) is a benign entity due to dilation of
      the tubules of the rete testis. Most of the time it is discovered incidentally on
      scrotal sonograms and may be misinterpreted as malignant. This article outlines
      the diagnostic criteria of TERT, its possible causes, its incidence and its
      potential evolution. Recognizing this entity owing to its characteristic
      clinical, sonographic and, if necessary, MRI features is important to avoid
      unnecessary surgery or biopsies.

PMID- 10602965
TI  - Misleading diagnosis of retroperitoneal actinomycosis.
AB  - A 34-year-old woman presented with a left-sided suprarenal space-occupying lesion
      on sonography. Culture of material obtained during sonographic-guided puncture of
      the retroperitoneal lesion yielded a mixed flora of Actinomyces and
      Peptostreptococcus. Initially, a misleading diagnosis of an adrenal
      pheochromocytoma was initiated by highly positive metaiodobenzylguanidine
      scintigraphy after chemical chemistry vanillylmandelic acid (VMA) test showed
      elevated values for adrenaline and its derivatives. Retroperitoneal actinomycosis
      with yet unproven spread into thoracic and cervical compartments is a particular
      unusual presentation of an infection with these organisms. Because it may mimic
      subacute infections or malignant masses in terms of clinical and laboratory
      findings, radiological diagnosis of this entity may be difficult. The diagnosis
      was based on results of culture and the response of the patient to long-term
      penicillin-derivate therapy after surgical drainage of the suprarenal abscess
      formation.

PMID- 10602966
TI  - A case of totally cystic fibroepithelial polyp of the renal pelvis.
AB  - Fibroepithelial polyps are the most frequently observed mesenchymal tumors of the
      renal pelvis. We report on one case of fibroepithelial polyp of the renal pelvis
      with unusual CT findings of totally cystic structure with septations.

PMID- 10602967
TI  - Vesicouterine fistula: MRI diagnosis.
AB  - A case of vesicouterine fistula in a young woman following caesarean section is
      presented. The diagnosis was established successfully using heavily T2-weighted
      MRI which clearly demonstrated fluid within the fistula, obviating the need for
      conventional radiographic contrast examination.

PMID- 10602968
TI  - Tibial and fibular developmental fields defects.
AB  - Malformations of the lower limbs are rare and heterogeneous anomalies. To explain
      the diversity and complexity of these abnormalities, authors introduced the
      concept of tibial and fibular developmental fields. Defects in these fields are
      responsible for different malformations, which have been described, to our
      knowledge, in only one report in the radiology literature. We present a case of a
      newborn with femoral bifurcation, absent fibulae and talar bones, ankle and foot
      malformations, and associated atrial septal defect. Our case is an example of
      defects in both fibular and tibial developmental fields.

PMID- 10602969
TI  - Diagnosis of neonatal hemochromatosis with MR imaging and duplex Doppler
      sonography.
AB  - Neonatal hemochromatosis is a rare congenital disorder which affects both fetuses
      and newborns. It is characterized by hepatocellular failure, often appearing on
      the first day of life in the form of coagulopathy, hypoalbuminemia, hypoglycemia,
      and jaundice. Most of the affected infants die early in life, and definitive
      diagnosis has often been made only by post-mortem evaluation. With the help of
      MRI, plus increasing awareness of the disorder, diagnosis is now often made
      early, even in utero. Duplex Doppler sonography does not provide information on
      siderosis but shows abnormalities in the liver or blood-flow patterns associated
      with liver disease.

PMID- 10602970
TI  - Infarction of omentum and epiploic appendage: diagnosis, epidemiology and natural
      history.
AB  - Epiploic appendicitis and segmental omentum infarction are considered to be rare
      conditions, which may mimic an abdominal surgical emergency. The purpose of our
      study was to describe clinical findings, US and CT appearance of infarction of an
      epiploic appendage and omentum, and to determine their epidemiological
      characteristics and natural history. We retrospectively studied clinical, US and
      CT findings at hospital admission and follow-up of all patients who were
      diagnosed at our institution with epiploic appendicitis or omentum infarction
      between June 1988 and November 1997. We found a relatively high incidence of 40
      cases: 20 patients with epiploic appendicitis, 11 with omentum infarction, and 9
      in whom it was not possible to discriminate between the both. All 40 patients
      recovered under conservative treatment without complications. We conclude that US
      and CT features allow a reliable diagnosis, thereby obviating unnecessary
      surgery. Discriminating between both conditions is of no practical relevance
      since treatment and prognosis are identical.

PMID- 10602971
TI  - Self-expanding oesophageal metal stents for the palliation of dysphagia due to
      extrinsic compression.
AB  - The role of self-expanding metallic stents is well established in the palliation
      of oesophageal stenosis and dysphagia due to primary oesophageal malignancy.
      However, their role in palliation of dysphagia due to external compressive
      mediastinal malignancies is not well established. The purpose of this study was
      to assess the efficacy of self-expanding metallic stents in the palliation of
      dysphagia due to extrinsic oesophageal compression by mediastinal malignancy.
      Between January 1995 and January 1998, 21 patients with oesophageal compression
      due to malignant mediastinal tumours underwent oesophageal stent placement for
      palliation of dysphagia. Complete data were available in 17 patients (10 men and
      7 women). The mean age was 63.5 years (range 46-89 years). A total of 19 stents
      were placed successfully. The dysphagia grade prior to and after oesophageal
      stent placement was assessed and the complications documented. Of the 17
      patients, 16 reported an improvement in dysphagia. The mean dysphagia score
      improved from 3.1 prior to treatment to 1.3 after treatment. In 1 patient the
      stent slipped during placement and another stent was placed satisfactorily. Early
      complications (within 48 h) in the form of mild to moderate retrosternal chest
      pain occurred in 5 patients. This was treated symptomatically. Late complications
      (after 48 h) in the form of bolus impaction occurred in 2 patients. This was
      successfully treated with oesophagoscopy and removal of bolus. In 2 patients the
      stent was overgrown by tumour and in one of these an additional stent was placed.
      In 1 patient incomplete closure of a tracheo-oesophageal fistula was observed.
      There was no procedure- or stent-related mortality. The mean survival time of
      this group was 2. 1 months. Self-expanding metallic stents can be safely and
      effectively used in the palliation of dysphagia due to external mediastinal
      malignancies.

PMID- 10602972
TI  - Intraluminal duodenal diverticulum: radiological and endoscopic ultrasonography
      findings of an unusual cause of acute pancreatitis.
AB  - Intraluminal duodenal diverticulum is a rare congenital web of membrane which may
      be symptomatic when it becomes distended. This report describes a case revealed
      by presenting as an acute pancreatitis. The radiological findings are reported.
      The findings at CT, upper gastro-intestinal series, endoscopic ultrasound and
      endoscopic retrograde cholangiopancreatography are described and differential
      diagnostic features from choledochocele and duodenal duplication are discussed.
      By endoscopic ultrasonography, observation of a thin wall, without different
      layers such as choledochocele or duodenal duplication, may be useful for
      diagnosis.

PMID- 10602973
TI  - A double-blind, prospective, randomized, multicenter group comparison study of
      iopromide 240 vs iohexol 240 in myelography.
AB  - The aim of this study was to evaluate the safety and efficacy of iopromide 240
      mgI/ml in comparison with iohexol 240 mgI/ml in myelography. A total of 421
      patients in seven centers and four countries received an average of 11.9 ml of
      either iopromide 240 (278 patients) or iohexol 240 (143 patients) for X-ray
      and/or CT myelography in a randomized (2:1), prospective, double-blind study. All
      patients were followed up 3-4 h after the procedure, and 327 patients remained
      hospitalized for 24 h. In 82 patients an EEG was recorded prior to as well as 3-4
      h and 24 h after myelography. Physical examinations, including measurement of
      vital signs, were performed in all patients at these time points. The results
      were subject to statistical analysis with the primary variable being the
      incidence of adverse events. Both contrast media (CM) were equally effective in
      terms of opacification. The rating for opacity was "good" or "excellent" in 88 %
      for both CM. Four patients (iopromide group: n = 3; iohexol group: n = 1) had
      transient EEG changes but did not show clinical symptomatology. The overall rate
      of patients experiencing any adverse event (AE) was 16.9 % for iopromide 240 and
      14.0 % for iohexol 240. Equivalence testing was inconclusive; however, the
      results indicated equivalence. The rate for AEs considered as study-drug related
      was slightly lower with iopromide 240 than with iohexol 240 (7.2 vs 7.7 %,
      respectively). Neither unknown nor unexpected AEs known for myelographic X-ray CM
      nor serious adverse events were observed. Iopromide 240 and iohexol 240 are
      equally safe and effective and can be recommended for myelography.

PMID- 10602974
TI  - Dynamic contrast-enhanced subtraction MR angiography in intracranial vascular
      abnormalities.
AB  - We present our clinical experience with dynamic contrast-enhanced MR angiography
      (MRA) with subtraction for assessing intracranial vascular abnormalities. Ten
      patients with various cerebrovascular disorders underwent dynamic contrast
      enhanced MRA on a 1.0-T system. Thirty sections (2 mm) were acquired in 29-30 s.
      Maximum intensity projection images and subtracted source images were compared
      with those obtained by conventional angiography. In all cases, the presence or
      absence of abnormalities in the targeted vessels, as well as the morphology of
      the sagittal sinuses, was clearly visualized as in conventional angiography,
      without any obstructions such as hyperintense hematomas or thrombi, or
      intraluminal turbulence. Although the temporal and spatial resolutions with
      current hardware are insufficient, these preliminary results suggest that dynamic
      contrast-enhanced MRA with subtraction may be useful for assessing vascular
      lesions with hemorrhage or thrombus, and the dural sinuses.

PMID- 10602975
TI  - MR findings in a patient with Kernicterus.
AB  - We report on a 2.5-year-old boy with severe mental retardation, choreoathetosis,
      dystonia, muscle rigidity, opisthotonus and severe hearing impairment. He had
      history of severe hyperbilirubinaemia immediately after birth presumably due to
      ABO incompatibility. The history and the clinical picture suggested the diagnosis
      of Kernicterus. The MR imaging examination upon admission revealed bilateral
      signal intensity increase in the globus pallidum on T2-weighted sequences.
      Additionally, our patient showed signal intensity changes within the subthalamic
      nuclei, which is known to be another characteristic area of bilirubin deposition
      in Kernicterus.

PMID- 10602976
TI  - Diffusion-weighted MRI in cyclosporin A neurotoxicity for the classification of
      cerebral edema.
AB  - Cyclosporin A, an immunosuppressive agent, is known to have neurotoxic effects,
      but until now, there has not been agreement on the underlying mechanism. Our
      report suggests, by using diffusion-weighted MRI, that the brain lesions caused
      by cyclosporin A, are probably related to vasogenic edema. This may explain the
      complete recovery of the lesions on imaging when cyclosporine therapy is stopped.

PMID- 10602977
TI  - Radiation doses delivered to radiologists during contrast-enhanced helical-CT
      examinations.
AB  - This work monitors the radiation doses to a radiologist during supervision of
      automatic contrast media injections during helical-CT examinations of the chest
      and abdomen. Forty consecutive standard helical-CT examinations of adult's chest
      and/or abdomen were monitored with five dosimeters worn by the radiologist
      supervising the entire injection with the hand on the injection site. Mean doses
      per examination measured at chest, thyroid gland, and hand levels were 11, 16,
      and 130 microGy, respectively, during chest examinations, and 5, 7, and 55
      microGy during abdominal examinations. According to the high number of CT
      examinations performed, wearing lead apron, special lead glove protection, and
      thyroid shield is highly recommended.

PMID- 10602978
TI  - Erbium filtration: a cost-effective, dose-reducing filter which maintains
      abdominal image quality.
AB  - The current study investigated the effect of erbium filtration on an
      anteroposterior abdominal image. The radiation dose reductions achievable and the
      cost effectiveness of this filter were also evaluated. An assessment of the
      radiation dose delivered employing either the standard total filtration (3 mm Al
      equivalent) or 0.1 mm of erbium filtration added to the standard filtration was
      undertaken on 21 patients. Image quality was assessed using the Commission of
      European Communities (CEC) criteria. Significant reductions of 64.6 % in entrance
      surface (p = 0.0001) and 23.4 % in effective dose (p = 0.0099) were recorded with
      erbium filtration. Image quality was maintained and the cost per man saved was
      pound 128. More widespread use of this dose reducing filter is advocated.

PMID- 10602979
TI  - International differences in health care costs in Europe and the United States:
      Do these affect the cost-effectiveness of diagnostic strategies for pulmonary
      embolism?
AB  - The aim of this study was to assess whether potential differences in costs for
      diagnostic procedures and treatment of pulmonary embolism (PE) among European and
      U. S. hospitals alter the optimal cost-effective diagnostic strategy for PE. A
      standardized questionnaire was used to obtain cost data for the diagnosis and
      treatment of PE in participating European and U. S. hospitals. Costs for
      diagnostic tests and treatment of PE were then calculated in a standardized
      manner for all participating hospitals, from the hospital perspective. Costs were
      used in an existing cost-effectiveness analysis (CEA) model to determine the most
      cost-effective diagnostic strategy in participating hospitals. There were
      considerable differences in costs for diagnostic and therapeutic procedures for
      PE among the participating centers. These differences, however, did not affect
      the most cost-effective strategy based on incremental cost-effectiveness. In all
      hospitals the most cost-effective strategy appeared to be ultrasound followed by
      helical CT. International differences in cost of diagnostic and therapeutic
      procedures certainly exist and should be considered before applying a published
      CEA. Nevertheless, despite these cost differences, the diagnostic strategy for PE
      of ultrasound followed by helical CT appears most cost-effective.

PMID- 10602980
TI  - Camurati-Engelmann disease. A case report.

PMID- 10602981
TI  - Miliary lung disease induced by intravesical Bacillus Calmette-Guerin treatment.

PMID- 10602982
TI  - Bilateral Sertoli cell tumor of the testis: MRI and sonographic appearance.

PMID- 10602983
TI  - Quiz case of the month. Diagnosis: clear-cell renal cell carcinoma (RCC) with
      metastasis to lung, mediastinal and abdominal lymph nodes and bones.

PMID- 10602985
TI  - Mapping of obesity QTLs in a cross between mouse lines divergently selected on
      fat content.
AB  - A genome-wide quantitative trait locus (QTL) analysis was performed in a
      polygenic obesity mouse model resulting from a long-term selection experiment.
      The parental lines were outbred lines divergently selected for 53 generations for
      high-fat (fat, F line) or low-fat (lean, L line) percentage (fat%) that differed
      fivefold in fat% at 14 weeks of age. An F2 population of 436 mice was used for
      the QTL analysis with 71 markers distributed across the genome. The analysis
      revealed significant QTLs Fob1 (for F-line obesity QTL 1), Fob2, Fob3, and Fob4,
      on Chromosomes (Chrs) 2, 12, 15, and X, respectively. None of these QTLs map to
      regions of known single gene obesity mutations (Lepob, Leprdb, Cpefat, Ay, tub),
      though they map to regions of previously described obesity QTLs and candidate
      genes. The effects of Fob1, Fob3, Fob4 were additive, and that of Fob2 was
      dominant. Fob2 also showed a significant female-specific effect. Fob1, Fob2,
      Fob3, and Fob4 explained 4.9%, 19.5%, 14.4%, and 7.3% of the F2 phenotypic
      variance for fat%, respectively. This study identified four loci that contributed
      to the response to divergent selection and control a significant proportion of
      the difference in obesity between the F and L lines.

PMID- 10602986
TI  - An axonemal dynein at the Hybrid Sterility 6 locus: implications for t haplotype
      specific male sterility and the evolution of species barriers.
AB  - Poor sperm motility characterized by a distinct aberration in flagellar waveform
      known as "curlicue" is a hallmark of t haplotype (t) homozygous male sterility.
      Previous studies have localized "curlicue" and a flagellar developmental defect,
      "whipless", to the Hybrid Sterility 6 locus (Hst6), between the markers Pim1 and
      Crya1. More recent heterospecific breeding experiments between Mus spretus
      (Spretus) and Mus musculus domesticus (Domesticus) have mapped the primary
      source(s) of both "curlicue" and "whipless" to a small sub-locus of Hst6,
      Curlicue a (Ccua). Here we report the complete physical isolation of the Ccua
      locus and the identification of a candidate gene for expression of both
      "whipless" and "curlicue" at its proximal end, an axonemal dynein heavy chain
      gene, Dnahc8, formerly mapped by interspecific backcross analysis near Pim1.
      Dnahc8 mRNA expression commences in the Domesticus wild-type testis just prior to
      flagellar assembly and is testis-specific in the adult male. However, expression
      of Dnahc8 is not readily evident in the testis of either Spretus or "whipless"
      animals (Domesticus males homozygous for the Spretus allele of Dnahc8). Our
      results argue that Dnahc8 is fundamental to flagellar organization and function
      in Domesticus, but not Spretus, and suggest that Dnahc8 is integral to both Hst6-
      and t-specific male infertility.

PMID- 10602987
TI  - The mouse adducin gene family: alternative splicing and chromosomal localization.
AB  - Mouse cDNA sequences encoding alpha, beta, and gamma adducins were cloned from a
      mouse reticulocyte cDNA library. The purified clones contain alternatively
      spliced exons from all three adducin genes. In the case of alpha and beta, the
      inclusion of the alternatively spliced exons results in truncated polypeptide
      isoforms (called alpha-2 and beta-2). The mouse predicted amino acid sequences
      are compared with published rat and human sequences. For completion of this
      comparison, cDNA encoding the rat beta-1 carboxy terminus was cloned by PCR. The
      carboxy terminal region containing MARCKS homology, calmodulin-binding region-2,
      and spectrin-actin-binding site, is conserved among alpha-1, beta-1, and gamma-1
      isoforms in mouse, rat, and humans. We also report here the localization of the
      gene encoding gamma adducin (Add3) to murine Chr 19, in a region that shows
      conserved synteny with human Chr 10.

PMID- 10602988
TI  - Melanocortin 1 receptor variation in the domestic dog.
AB  - The melanocortin 1 receptor (Mc1r) is encoded by the Extension locus in many
      different mammals, where a loss-of-function causes exclusive production of
      red/yellow pheomelanin, and a constitutively activating mutation causes exclusive
      production of black/brown eumelanin. In the domestic dog, breeds with a wild-type
      E allele, e. g., the Doberman, can produce either pigment type, whereas breeds
      with the e allele, e.g., the Golden Retriever, produce exclusively yellow
      pigment. However, a black coat color in the Newfoundland and similar breeds is
      thought to be caused by an unusual allele of Agouti, which encodes the
      physiologic ligand for the Mc1r. Here we report that the predicted dog Mc1r is
      317 residues in length and 96% identical to the fox Mc1r. Comparison of the
      Doberman, Newfoundland, Black Labrador, Yellow Labrador, Flat-coated Retriever,
      Irish Setter, and Golden Retriever revealed six sequence variants, of which two,
      S90G and R306ter, partially correlated with a black/brown coat and red/yellow
      coat, respectively. R306ter was found in the Yellow Labrador, Golden Retriever,
      and Irish Setter; the latter two had identical haplotypes but differed from the
      Yellow Labrador at three positions other than R306ter. In a larger survey of 194
      dogs and 19 breeds, R306ter and a red/yellow coat were completely concordant
      except for the Red Chow. These results indicate that the e allele is caused by a
      common Mc1r loss-of-function mutation that either reoccurred or was subject to
      gene conversion during recent evolutionary history, and suggest that the allelic
      and locus relationships for dog coat color genes may be more analogous to those
      found in other mammals than previously thought.

PMID- 10602989
TI  - Cloning of the canine gene encoding transcription factor Pit-1 and its exclusion
      as candidate gene in a canine model of pituitary dwarfism.
AB  - Combined pituitary hormone deficiency (CPHD) is an autosomal recessive inherited
      disease of German shepherd dogs characterized primarily by dwarfism. In mice and
      humans a similar genetic disorder has been described that results from an
      alteration in the gene encoding the transcription factor Pit-1. In this study we
      characterized the canine Pit-1 gene, determined the chromosomal localization of
      the Pit-1 gene, and screened dwarf German shepherd dogs for the presence of
      mutations in this gene. The full-length canine Pit-1 cDNA contained an open
      reading frame encoding 291 amino acids, 92 bp of 5'-untranslated region, and 1959
      bp of 3'-untranslated region. The deduced amino acid sequence was highly
      homologous with Pit-1 of other mammalian species. Using a Pit-1 BAC clone as
      probe, the Pit-1 gene was mapped by FISH to canine Chromosome (Chr) 31. In dwarf
      German shepherd dogs a C to A transversion was detected, causing a Phe (TTC) to
      Leu (TTA) substitution at codon 81. This alteration was present neither in other
      canine breeds analyzed nor in other mammalian species. However, healthy German
      shepherd dogs were also homozygous for the mutant allele, indicating that it is
      not the primary disease-causing mutation. In addition, linkage analysis of
      polymorphic DNA markers flanking the Pit-1 gene, 41K19 and 52L05, revealed no co
      segregation between the Pit-1 locus and the CPHD phenotype. These findings
      suggest that a gene other than Pit-1 is responsible for the pituitary anomaly in
      dwarf German shepherd dogs.

PMID- 10602990
TI  - Regional characterization of a hamster-sheep somatic cell hybrid panel.
AB  - The regional characterization of a previously obtained hamster-sheep hybrid panel
      is reported. Using data available from ruminant maps (sheep, cattle, and goat),
      we have selected a set of 300 markers and have analyzed them by PCR in this
      hybrid panel. Results obtained for 204 markers show the presence of all sheep
      chromosomes (including gonosomes) in entire or fragmented form. Analysis of
      syntenies has given 130 types of answer defining segments of variable sizes. This
      study has led to the regional characterization of this panel and provides
      comparative data on a set of bovine and caprine markers. With the level of
      characterization now achieved for this hybrid panel, the regional assignment of
      new genes or markers to sheep chromosomes can be rapidly obtained. Finally, this
      panel will help to collect new data for comparative mapping of domestic animals
      and to highlight the conservation of syntenic groups between closely related
      species, that is, sheep, cattle, and goat.

PMID- 10602991
TI  - Physical mapping and promoter structure of the murine cAMP-specific
      phosphodiesterase pde4a gene.
AB  - The Pde4a gene is a mammalian homolog of the dunce learning and memory gene of
      Drosophila melanogaster and encodes cAMP-specific phosphodiesterases, targets for
      drugs with antidepressant and anti-inflammatory actions in humans. We have
      analyzed the intron/exon and promoter structure of the murine Pde4a gene. Pde4a
      encodes at least two different transcripts, each generated by alternative mRNA
      splicing and the use of alternative promoters. The majority of Pde4a exons are
      tightly clustered at the 3' end of the gene. The 5' region of the gene contains
      at least one widely separated exon, which encodes the 5' end of a distinct mRNA
      transcript and contains a separate promoter and transcriptional start site.
      Analysis of YAC clones determined that the Pde4a gene maps to the 4-cM region of
      Chromosome (Chr) 9, close to Ldlr and Epor, in a region syntenic to human PDE4A.

PMID- 10602992
TI  - The human polycystic kidney disease 2-like (PKDL) gene: exon/intron structure and
      evidence for a novel splicing mechanism.
AB  - Polycystin-L is a member of the expanding family of polycystins. Mutations in
      polycystin-1 or -2 cause human autosomal dominant polycystic kidney disease
      (ADPKD). The mouse ortholog of PKDL, Pkdl, is deleted in a mouse line with renal
      and retinal defects. We recently have shown that polycystin-L has calcium channel
      properties. In the current study, we determined the exon/intron organization of
      the PKDL gene and its alternative splicing. We show that PKDL has 16 exons. All
      splice acceptor/donor sites for these exons conform to the GT-AG rule. The
      positions of introns and the sizes of exons in the PKDL gene are very similar to
      those of PKD2, except for the last two 3' end exons. RT-PCR demonstrates the
      existence of at least three polycystin-L splice variants: PKDL(Delta5),
      PKDL(Delta456), and PKDL(Delta15) that are expressed in a tissue-specific manner.
      In addition, we have localized polymorphic marker D10S603 to intron 4 and exon 5
      of PKDL. Elucidation of the gene structure, exact location, and alternative
      splicing patterns of PKDL will facilitate its evaluation as a candidate gene in
      cystic or other genetic disorders.

PMID- 10602993
TI  - A deletion on chromosome 4 cosegregates with the whirler deafness mutation:
      exclusion of Orm1 as a candidate.
AB  - Whirler (wi) mice display profound deafness and a head-tossing and circling
      phenotype, showing an autosomal recessive mode of inheritance. The wi mutation
      has been shown to map close to the Orm gene cluster on mouse Chromosome (Chr) 4.
      We have, therefore, investigated the Orm loci as candidates for the whirler gene.
      Detailed mapping and analysis of the Orm gene cluster in both normal and whirler
      mice indicates the presence of a <48-kb deletion in whirler mice that disrupts
      the Orm1 locus. The Orm1 locus is also deleted in the CE/J mouse strain, and we
      discuss the candidature of Orm1 for the whirler gene.

PMID- 10602994
TI  - A comparative transcript map and candidates for mutant phenotypes in the Tyrp1
      (brown) deletion complex homologous to human 9p21-23.
AB  - The mouse Tyrp1 deletion complex is a valuable resource for high-resolution
      mapping of genes and phenotypes to the central region of Chromosome (Chr) 4. The
      distal part of the complex is homologous to human Chr 9p21-23, and we have used
      the available radiation hybrid maps to identify human transcripts in the region.
      We localize seven genes to a human YAC contig that spans the full extent of the
      distal deletion complex and show that the mouse homologs of four of these,
      including Cer1, map within the complex. On the basis of location and/or
      expression, we exclude genes as candidates for several known phenotypes in the
      region and identify a candidate transcript for the neonatal lethal phenotype
      l(4)Rn2.

PMID- 10602995
TI  - Genomic cloning, chromosomal mapping, and expression analysis of msal-2.
AB  - Mutations of SALL1 related to spalt of Drosophila have been found to cause Townes
      Brocks syndrome, suggesting a function of SALL1 for the development of anus,
      limbs, ears, and kidneys. No function is yet known for SALL2, another human spalt
      like gene. The structure of SALL2 is different from SALL1 and all other
      vertebrate spalt-like genes described in mouse, Xenopus, and Medaka, suggesting
      that SALL2-like genes might also exist in other vertebrates. Consistent with this
      hypothesis, we isolated and characterized a SALL2 homologous mouse gene, Msal-2.
      In contrast to other vertebrate spalt-like genes both SALL2 and Msal-2 encode
      only three double zinc finger domains, the most carboxyterminal of which only
      distantly resembles spalt-like zinc fingers. The evolutionary conservation of
      SALL2/Msal-2 suggests that two lines of sal-like genes with presumably different
      functions arose from an early evolutionary duplication of a common ancestor gene.
      Msal-2 is expressed throughout embryonic development but also in adult tissues,
      predominantly in brain. However, the function of SALL2/Msal-2 still needs to be
      determined.

PMID- 10602996
TI  - A modifier of Niemann Pick C 1 maps to mouse chromosome 19.

PMID- 10602997
TI  - Structure and expression of two members of the d4 gene family in mouse.

PMID- 10602998
TI  - Investigation of the retinol-binding protein 4 (RBP4) gene as a candidate gene
      for increased litter size in pigs.

PMID- 10602999
TI  - Molecular characterization of human and murine C11orf5, a new member of the FAUNA
      gene cluster.

PMID- 10603000
TI  - Cloning, mapping, and expression of a novel brain-specific transcript in the
      familial dysautonomia candidate region on chromosome 9q31.

PMID- 10603001
TI  - From conception to the child.
AB  - An attempt to present all the data that account for the progressive
      transformation of a fertilized zygote into a child at birth is obviously a
      herculean work. In this review, I focus on four aspects of central nervous system
      development in which our understanding has considerably been enhanced during the
      last century. The first part concerns the phenomenon of neural induction, a
      process devoted to the acquisition of neural identity. It was classically
      considered that active molecules were secreted by the organizer (the dorsal lip
      of the blastopore in amphibians and the node in amniotes) and that these
      molecules induced the neural induction. Nowadays, the model is much more complex,
      based upon both positive and negative regulatory mechanisms. The positive
      inductor is BMP4, and this induces the epidermal induction. The organizer
      secretes negative signals that can bind BMP4 and prevent its action. The second
      part is devoted to the morphogenetic movements that allow formation of the neural
      tube. Classically, primary and secondary neurulations are opposed. It is now well
      established that the two modes of neurulation obey the same basic rules. The
      problem of segmentation of the central nervous system during embryogenesis could
      be easily studied for the rhombencephalon. This structure is formed by repetitive
      subunits called rhombomeres. Each rhombomere corresponds to a compartment
      separated from the others. In addition, each rhombomere expresses specific genes,
      and the invalidation of some of them leads to the absence of these rhombomeres.
      However, the situation is much more complex with regions specified very early
      during development and acting on adjacent regions to induce a specific pattern.
      The last part of my paper concerns the development of the cortex. During the last
      50 years, all the classic concepts have been challenged. The fixed law of radial
      migration has been extensively discussed, and it is now admitted that other kinds
      of migration do take place during corticogenesis. These results force us to
      reconsider the interpretations of some cortical malformations. It seems
      reasonable to adopt descriptive terms for a malformative syndrome instead of
      terms based on putative mechanisms.

PMID- 10603002
TI  - From child to adult.
AB  - This essay discusses a number of aspects of the neurosurgical problems that occur
      as a child progresses into adulthood. Some typical disorders may not present
      until a patient reaches adulthood ("pediatric" brain tumors, hydrocephalus,
      Arnold-Chiari malformation). The neurosurgeon will be confronted with disorders
      of maturation - children who are prematurely adult and adults who remain
      childlike. A variety of neurological disorders may present with these disorders
      of maturation; and they are discussed. Finally, the neurosurgeon must be prepared
      to follow-through for adults who have been treated for neurological problems when
      they were children. These include patients with shunts for hydrocephalus,
      patients with spinal deformities, and patients with secondary effects of
      adjunctive therapy.

PMID- 10603003
TI  - Past, present and future of pediatric neuroradiology.
AB  - The last century has seen the evolution of neuroimaging from nonexistent to a
      group of techniques that, in our eyes, appears to be highly sophisticated. The
      rapidity of advancement in imaging has been concentrated in the last quarter
      century. There is no reason to expect this continual forward expansion of
      neuroradiology to abate; rather it seems likely that it will continue to increase
      at an even faster rate. The near future is one of refinement in imaging, faster
      and higher resolution as well as a much greater emphasis on physiology and
      biochemistry.

PMID- 10603004
TI  - Congenital malformations of the brain--a neurosurgical perspective at the close
      of the twentieth century.
AB  - Current classifications, indications for surgery, operative options and outcome
      statistics available to neurosurgeons for the management of congenital
      encephaloceles, arachnoid cysts and the Dandy-Walker complex are reviewed.

PMID- 10603005
TI  - The molecular genetics of holoprosencephaly: a model of brain development for the
      next century.
AB  - The recent identification of some of the human holoprosencephaly genes is
      beginning to elucidate the intricate developmental programs that pattern normal
      and abnormal brain development. Here we present some of these advances in the
      context of our present understanding and conclude with some speculations
      regarding the direction for future investigations. We are living in a
      tremendously exciting time in medicine with the rapid application of molecular
      genetic approaches to the understanding of human disease. It is the purpose of
      this review to stress the underlying principals of our approach at a level that
      can be readily appreciated by colleagues who themselves are experts in brain
      anatomy but not necessarily the molecular genetics of brain development.

PMID- 10603006
TI  - Intraventricular hemorrhage: past, present and future, focusing on
      classification, pathogenesis and prevention.
AB  - The improvement in the survival rate of infants born at the limit of viability,
      i.e. < 26 weeks of gestational age, raises concern about the risk of
      neurodevelopmental disabilities. The relevance of intraventricular hemorrhage
      (IVH), which is the most frequent cerebral lesion diagnosed in extremely low
      birth weight neonates, cannot then be underestimated. Pharmacological
      interventions designed to prevent the occurrence of IVH and its complications
      have not been entirely conclusive. The understanding of pathogenetic factors
      involved in the genesis of IVH is the key to planning of new strategies and
      meanwhile of implementing care guidelines aimed at its prevention.

PMID- 10603007
TI  - Hypothalamic-pituitary function and growth in children with intracranial lesions.
AB  - Intracranial lesions may affect hypothalamic-pituitary (HP) function and growth
      in several ways, depending on the location of the lesion within this area, the
      presence or absence of secondary hydrocephalus, and/or treatment of the lesion by
      surgery and/or radiotherapy. The lesion may cause a deficiency of HP hormones or,
      conversely, activation of the HP-gonadal axis leading to precocious puberty.
      Growth hormone (GH) deficiency is the most frequent endocrine abnormality that
      results from the lesions of the HP area. There has been progress in diagnosis,
      patterns of replacement therapy and the administration of biosynthetic GH in
      association with gonadotropin-releasing hormone analogues in precocious puberty.
      The major problem in these patients is the dramatic increase in their weight,
      which frequently occurs after surgery and increases their psychosocial and
      physical disabilities. It may be due to the hyperinsulinism caused by the lesion.
      This hyperinsulinism may be the factor that replaces GH in stimulating growth
      factor production and leads to normal growth in some of the patients.

PMID- 10603008
TI  - Mechanisms of premature closure of cranial sutures.
AB  - Craniosynostosis is defined as premature closure of the sutures of the skull,
      resulting in cranial deformity. Since Virchow's original paper describing the
      relationship between premature suture closure and skull morphology, we have
      learned much about the underlying mechanisms and consequences of premature suture
      closure. In this paper we will describe the biology of suture closure, the rules
      governing the resulting phenotypes seen clinically, and a prospective study of
      skull growth during the 1st year of life.

PMID- 10603009
TI  - Craniosynostosis: from a clinical description to an understanding of bone
      formation of the skull.
AB  - The genetic studies of syndromic craniosynostoses lead to the characterisation of
      genes that regulate the correct development of the bones of the skull. From these
      studies, it appears that FGF/FGFR signalling has a crucial role in this problem.
      Numerous mutations affecting the genes coding for FGFR1, 2 or 3 are responsible
      for these syndromes. It is interesting to note that some identical mutations
      produced various different phenotypes, suggesting that other genes modulate the
      phenotypic expressivity. The other involved genes in these syndromes code for
      such proteins as Msx2 or Twist that interact in the cellular pathways responsible
      for FGF action. From these genetic studies, it is now important to establish the
      role of these proteins during the development of the skull. Msx2 plays a
      repressive role in osteogenesis, whereas FGFRs act as promoting proteins. In the
      near future, it will be very important to improve our understanding of these
      phenomena in order to test specific treatments to prevent the development of such
      syndromes.

PMID- 10603010
TI  - Midface surgery from Tessier to distraction.
AB  - The wall separating the face and the cranium was broken by Paul Tessier and
      Gerard Guiot in the 1960s, making it possible to perform a combined operation
      around the orbits and forehead, and opening up close cooperation between plastic
      surgeons and neurosurgeons, especially for treatment of the major malformations
      such as hypertelorism of major facial retrusions. The principles of mobilization
      of the orbits to correct teleorbitism or orbital dystopia are recalled with
      reference to the different variations and with clinical examples. Facial
      advancement to correct the retrusions created by faciocraniosynostosis is
      explained with the many possible variants, combined with a intracranial approach
      or not, with or without a bipartition. The indications are discussed as is the
      risk linked to combined advancement of face and forehead. The progressive bone
      elongation principle introduced by Ilizarov for the limbs has been applied to the
      face at the mandibular level by McCarthy, with great success. The distraction of
      bone structures is now also applied at the level of the midface and makes it
      possible to overcome the retraction of soft tissues and lower the risk of relapse
      of facial retrusion. Many technical problems have still to be solved, but the
      results are already very promising. Many other applications of the distraction
      principle will be developed for the midface level, with other technical
      improvements such as the use of absorbable mini-plates and screws.

PMID- 10603011
TI  - Blood salvage in craniosynostosis surgery.
AB  - In the history of surgery, every single step forward in the development of
      complex surgical techniques has been sustained by the acquisition of more
      reliable and effective methods for controlling hemostasis. For many years, in
      fact, uncontrolled hemorrhages, together with infections, represented the most
      deadly hazard of surgical procedures. In the last century, technical advances in
      surgical hardware and homologous blood transfusions have been utilized to
      counteract operative and postoperative anemia and hypovolemia. At the end of this
      millennium, however, new revelations about the infective and noninfective risks
      of allogeneic blood transfusions have led to a new acceleration in patients' and
      physicians' demands for autologous transfusions and more efficient blood
      conservation techniques. Specific surgical protocols, based on the preoperative
      administration of r-HuEPO, preoperative autologous blood donation, acute
      preoperative normovolemic hemodilution and intraoperative blood salvage
      techniques, have been designed by pediatric neurosurgeons to minimize the
      exposure of patients affected by craniosynostoses to allogeneic blood and blood
      components even when the surgical procedure is to be realized at an early age. In
      spite of the evolution expected in this area in the immediate future, the
      implementation of these blood concentration methodologies may prove to be highly
      effective only when associated with a concerned attitude of the surgeon toward
      blood-sparing intraoperative strategies.

PMID- 10603012
TI  - Long-term follow-up of shunting therapy.
AB  - Ventricular CSF shunting surgery has changed the overall outcome figures for
      hydrocephalic patients over the past three decades. The factors that have
      improved the outcome are evolution of the shunt systems, improvement of the
      surgical environment and use of potent antibiotics, technological advances in
      brain imaging, and refinements in the assessment of cognitive and functional
      outcomes and of actuarial statistical techniques. But the recent large studies
      revealed that nearly half of all shunt placements were for revision, and there is
      a low but real percentage of cases in which death and neurological impairment are
      related to shunt surgery. The most frequent complication was shunt obstruction,
      followed by infection, disconnection, hematoma and slit ventricle syndrome. This
      clearly means that the shunt systems and the techniques in current use involve
      many problems that have yet to be solved. To solve these problems, new shunt
      systems should be developed and continuous efforts at reducing shunt infection
      should be made. The overall complication rate in the authors' series was 31.7%,
      but we have been able to reduce the complication rate from 37% to 25% by
      exercising special care focused on the surgical environment and techniques.
      Careful, long-term follow-up using various parameters and proper statistical
      analysis is another important factor in improving surgical outcome. Multicenter
      and international studies will be easier with the development of a network, and
      it will give us a strong background to treat hydrocephalus.

PMID- 10603013
TI  - Alternatives to shunting.
AB  - The growing awareness of mechanical and infectious complications related to the
      implantation of extracranial CSF shunts and the rapid developments in
      neuroendoscopic surgery have given pediatric neurosurgeons the possibility of
      choosing between the two types of treatment. The decision will depend on a number
      of factors, such as whether it is possible to identify the etiology of the
      hydrocephalus on the preoperative examinations, the surgeon's familiarity with
      the endoscopic technique, and his or her personal opinions about the efficacy of
      the alternative techniques to shunt implantation. The history and the state of
      the art of the alternatives to shunting are briefly reviewed for each of the main
      pathophysiological groups of pediatric hydrocephalus: aqueductal stenosis,
      posterior fossa tumors, meningomyelocele, Dandy-Walker malformation,
      posthemorrhagic hydrocephalus and others.

PMID- 10603014
TI  - Critical care management of neurotrauma in children: new trends and perspectives.
AB  - Secondary brain lesions resulting from cerebral metabolic and hemodynamic
      reactions can be prevented by neurocritical care management. It must be initiated
      as soon as possible, ideally in a prehospital setting. Tracheal intubation,
      controlled ventilation and hemodynamic stabilization are the prerequisites.
      Beside intracranial and cerebral perfusion pressure, monitoring must evaluate the
      coupling between cerebral metabolic demand and blood flow. Jugular bulb oximetry
      is the most reliable approach to global cerebral coupling. Transcranial Doppler
      evaluates cerebral blood flow indirectly and noninvasively. Technological
      developments have led to local metabolic evaluation that does not yet have any
      clinical relevance. Therapeutic developments are more a new approach to the use
      of old drugs. Controlled hyperventilation, mannitol and, more recently,
      hypertonic saline solutions, used for restoring cerebral metabolic coupling, are
      the foundations of treatment. Thiopental, revisited as a vasoconstrictive agent,
      the "Lund" vasoconstrictive approach with anti-hypertensive drugs and cerebral
      vasoconstrictors, must be further evaluated in children, as must therapeutic
      hypothermia. Finally, what we probably need for the immediate future is a
      noninvasive and easily reproducible method of monitoring cerebral metabolic
      coupling that will allow precise therapeutic adaptation of multimodal therapy to
      the individual needs of the child.

PMID- 10603015
TI  - The role of ultrasonography in imaging of paediatric head trauma.
AB  - Ultrasound appears to be a promising tool for assessment of the state of the dura
      in patients suffering from a diastatic skull fracture. Our goal is to identify
      patients who are at a high risk of developing the complications associated with
      this type of fracture as early as possible in order to keep the neurosurgical
      repair as simple as possible.

PMID- 10603016
TI  - Pediatric spine and spinal cord trauma. State of the art for the third
      millennium.
AB  - The purpose of this work was to analyze the literature published in English and
      to review the experience of the Barrow Neurological Institute (BNI) with spine
      and spinal cord injury (SCI) in children. Standard computerized data bases were
      queried for information regarding SCI, spinal injury, spinal instability, and
      spinal cord regeneration to produce a review of the epidemiology, diagnosis,
      treatment, outcome and directions for future research. We also reviewed our
      experiences in the management of infants and children with spine injuries and
      SCIs and with spinal instability from all causes. A total of 132 articles were
      identified and obtained from the Medical Library at St. Joseph's Hospital and
      Medical Center in Phoenix, Ariz. and through interlibrary loan. All these
      articles were read, although not all were used in the final review. A review of
      all children with SCIs revealed that fractures treated over the past 20 years at
      the BNI were very rare in preadolescent children, who suffered mostly from
      ligamentous injury or SCI without radiographic abnormality. A total of 68
      children aged 16 years or younger who had been treated over the past 15 years and
      who had undergone spinal fusions for trauma, congenital anomalies, or tumor
      resection were identified. Occipitocervical fusion is well tolerated in children
      as young as 11 months when internal stabilization with a threaded titanium rod is
      used. Posterior instrumentation, including pedicle screw fixation, is feasible in
      children as young as 4 years. Fusion techniques derived from the adult spinal
      instrumentation experience were found appropriate except for the youngest
      patients. Fusion in the newborn period was futile in our experience. The
      adolescent spine does not differ from the adult spine in terms of sensitivity or
      response to fixation. Children past the neonatal period can be successfully
      instrumented for spinal stability without apparent long-term sequelae. Related
      advances are needed in the area of prevention. Long-term advances in spinal cord
      regeneration can be expected from ongoing basic science investigations.

PMID- 10603017
TI  - Neurointerventional procedures in the pediatric age group.
AB  - Over the past 15 years there have been significant changes in the field of
      interventional neuroradiology, which have led to the inclusion of this specialty
      in the management of pediatric patients with vascular disorders of the central
      nervous system. Miniaturization of the devices and improvements in the embolic
      materials used have made it possible to perform endovascular therapy safely on
      neonates, infants and children. The role of endovascular therapy in the
      management of patients presenting with vein of Galen malformations and dural
      arteriovenous shunts has become clearly established. Endovascular therapists have
      also become important members of multidisciplinary teams managing patients with
      arteriovenous malformations of the brain and spinal cord. The role of
      endovascular therapy in the management of children with intracranial aneurysms is
      rapidly evolving, and experience with thrombolytic intra-arterial therapy for
      acute ischemic stroke is just gaining momentum. It is anticipated that in the
      future the role of endovascular therapy will continue to grow as part of the
      multidisciplinary team approach to the management of children presenting with
      complex vascular diseases of the central nervous system.

PMID- 10603018
TI  - Neuronavigation.
AB  - The fact that the visualization process has been deferred since MRI and CT
      scanning have become the imaging standards for today's neurosurgeons has led to
      the importance of developing a tool for testing and teaching young pediatric
      neurosurgeons in the future. Navigation and teaching in a virtual reality model
      seems a sound solution.

PMID- 10603019
TI  - Epidemiologic impact of children with brain tumors.
AB  - The impact of CNS tumors during childhood and adolescence has been steadily
      increasing. In many countries, brain and spinal cord tumors are now second in
      frequency only to leukemia as a cancer affecting children, and the most common
      cause of cancer mortality in the young. In the United States, brain tumors are
      now more common than acute lymphoblastic leukemia, and the proportion of cancer
      deaths due to CNS tumors has nearly doubled during the past 25 years. Worldwide,
      approximately 30,000-40,000 children develop CNS tumors each year, and the
      majority do not survive. Compared with most other malignancies that occur during
      childhood, CNS tumors have not been treated with comparable success in treatment
      outcome. Also, no specific risk factor, or set of risk factors, has been
      identified to explain a substantial proportion of CNS tumor occurrence. In many
      countries, CNS tumors are now the greatest challenge in pediatric oncology.

PMID- 10603020
TI  - The present and future management of childhood craniopharyngioma.
AB  - Childhood craniopharyngiomas are rare tumours that present formidable
      difficulties in their treatment if cure is to be achieved without producing
      severe hypothalamic damage. Experience with our own cases suggests that the
      morbidity from an attempted radical removal can be predicted - allowing a
      treatment algorithm to be devised that combines both surgery (radical and
      "conservative") and radiotherapy (both external fractionated and intra-cyst
      instillations) in order to achieve long-term tumour control that is not at the
      expense of a severe functional disability.

PMID- 10603021
TI  - Surgery in the management of primary intracranial germ cell tumors.
AB  - Surgery plays an important part in the overall management of primary central
      nervous system (CNS) germ cell tumors. While the general surgical objectives in
      patients with these neoplasms are similar to those with other types of CNS
      tumors, to obtain an accurate histopathologic diagnosis and to contribute towards
      improving patient survival the unique features of germ cell tumors have
      necessitated novel treatment strategies. Pure germinomas are exquisitely
      radiosensitive, and prior studies have shown no survival benefit from radical
      resection of such lesions. However, a significant proportion of CNS GCTs contain
      admixtures of nongerminomatous GCT (NGGCT) elements and are less responsive to
      aggressive chemotherapy and irradiation. Biopsy of these malignant GCTs carries
      the risk of histologic sampling error. Nevertheless, a proportion of NGGCTs
      produce tumor markers detectable in serum or CSF and may be accurately diagnosed
      without surgical intervention. Although the role of radical surgical resection
      has not been definitively demonstrated in the literature, recent data from an
      international cooperative trial suggest a survival benefit from radical resection
      of localized NGGCTs. Lastly, increasing experience has supported the role of
      delayed resective ("second-look") surgery for patients with negative tumor
      markers but residual radiographic abnormalities after initial chemotherapy.
      Resection of such lesions has typically yielded necrosis or teratoma, which may
      be cured by surgical resection, and obviated the need for additional chemotherapy
      or irradiation.

PMID- 10603022
TI  - Lateral ventricle tumors in children: a series of 54 cases.
AB  - A series of 54 patients with lateral ventricle tumors diagnosed and surgically
      treated from 1988 to 1998 was reviewed. Neoplasms invading ventricles and
      originating beyond their walls were excluded. There were 35 male and 19 female
      patients. Their ages ranged from 15 days to 20 years, and two frequency peaks
      were observed, one at 2 and one at 11 years. The most frequent signs and symptoms
      were attributed to increased intracranial pressure. The 54 patients included 41
      who developed hydrocephalus, but only 15 of these required shunting. The trigonal
      region and frontal horn were the most common sites of origin. Surgery was planned
      with due consideration for the localization of the tumor, its presumptive
      histology, its main feeding vessels, the parenchymal functionality, and the
      presence or absence of hydrocephalus. The most frequent tumor types were
      subependymal giant cell astrocytoma, choroid plexus tumors, ependymoma, and
      astrocytoma. The most common complications were intraventricular hemorrhage,
      cortical collapse, subdural collection and seizures. To conclude, tumors located
      within the lateral ventricles are often very voluminous and are predominantly
      benign, and the treatment of choice is total resection. In the case of
      malignancy, postsurgical radiotherapy and/or chemotherapy should be given.

PMID- 10603023
TI  - The impact of extent of resection in the management of malignant gliomas of
      childhood.
AB  - Radical surgical resection of newly diagnosed glioblastoma multiforme (GBM) and
      anaplastic astrocytoma (AA) in children is the most powerful favorable predictor
      of outcome when followed by radiation therapy and chemotherapy. In the largest
      study of childhood malignant gliomas (Children's Cancer Group Study, CCG-945),
      which was conducted between 1985 and 1992, a radical surgical resection was
      defined as greater than 90% resection of tumor as seen on imaging studies,
      predominantly using MRI. Of note is that the training of the neurosurgeon (i.e.
      in pediatric versus adult neurosurgery) had a significant impact on the extent of
      surgical resection in patients enrolled on this study. In children with recurrent
      malignant glial tumors, radical surgical resection has been shown to predict a
      more favorable survival for children, both with GBM and AA, undergoing high-dose
      (marrow-ablative) chemotherapy with hematopoietic stem cell rescue. In these
      studies, radical surgical resection was defined as resection leaving less than 3
      cm maximal diameter of enhancing tumor mass in place.

PMID- 10603024
TI  - Alternative treatments for childhood brain tumors.
AB  - The treatment options for children with brain tumors are quite limited. Advances
      in tumor biology and neuroscience have opened new avenues of treatment. New
      approaches include gene therapy, agents designed to interfere with signal
      transduction, antiangiogenesis drugs, maturation agents, immunotherapy, and
      immunoconjugates. New means of drug/agent delivery, including drugs that
      selectively open the tumor-blood barrier and convection-infusional approaches,
      are under study. Such innovative treatments will be more widely employed in the
      years ahead and may improve outcome for children with brain tumors.

PMID- 10603025
TI  - Comparison between pediatric and adult neurosurgery: management and future
      perspectives. Tethered cord syndrome, hydrocephalus, craniosynostosis.
AB  - With creation of the many subdivisions within the field of neurosurgery,
      neurosurgeons have taken on different roles. It is important for neurosurgeons to
      understand all the different subjects involved to enable them to build up long
      term goals in patient management and research. As pediatric neurosurgeons, the
      authors give accounts of three characteristic diseases encountered in pediatric
      patients: spinal dysraphism with tethered cord syndrome, hydrocephalus, and
      craniosynostosis. Drawing on their personal experience of tethered cord syndrome,
      the authors stress the pathophysiological mechanisms, clinical characteristics
      and proper management of the pediatric disease. Because pediatric neurosurgeons
      cover the whole range of neurosurgical diseases of infancy and childhood, the
      authors emphasize that their actions can be the basis for the management of
      general neurosurgical patients. A comparison between pediatric and adult
      neurosurgery is also drawn, with special reference to the interaction between
      pediatric and adult neurosurgeons.

PMID- 10603026
TI  - The present and future state of pediatric neurosurgery in Latin America.
AB  - After a previous review of the paper presented during the Pediatric Neurosurgery
      Symposium held in New York during the XV Meeting of ISPN on the situation of
      pediatric neurosurgery in Latin America, the present situation will be reviewed
      with special emphasis on economic factors, the technical gap between Latin
      American and First World countries, manpower, the impact of private health
      organization and the inclusion of pediatric neurology courses in university
      curricula.

PMID- 10603027
TI  - Paediatric neurosurgery in India.
AB  - In a vast country like India, with children constituting 40% of a total
      population of 900 million people, the need and scope for paediatric neurosurgery
      is enormous. Initial organised attempts to focus attention on the need for
      paediatric neurosurgery as a subspecialty were made in 1983 and 1987,
      respectively, by holding symposia on infections and tumours in children. However,
      when the Annual Conference of ISPN was held in Bombay this served as a great
      impetus to the development of paediatric neurosurgery as a subspecialty in this
      country. It led to the formation of the Indian Society for Paediatric
      Neurosurgery in the following year, which now has 90 neurosurgeons in full
      membership. It has held annual meetings ever since its inception and has held CME
      programmes with international faculty in 1992, 1994, 1996, 1997 and 1998. Half a
      dozen neurosurgeons have already devoted themselves mainly to the practice of
      paediatric neurosurgery. Paediatric neurosurgery is best developed in a large
      multi-disciplinary paediatric institute. We have been able to establish a
      neurosurgical service at Jerbai Wadia Hospital for Children, a paediatric
      institute of repute in Mumbai, and hope to have training programmes and
      fellowships in the near future for both general and paediatric neurosurgeons, as
      they will have to continue treating cases of spina bifida and hydrocephalus for
      several years to come.

PMID- 10603028
TI  - Pediatric neurosurgery--a golden decade.
AB  - Pediatric neurosurgery, once an annex of general neurosurgery, has evolved into a
      well-defined and complex medical specialty. The last 10 years have witnessed
      major advances in documentation of the minute details of CNS diseases of
      childhood, refinement of the specific means of action and better adaptation of
      therapeutic efforts to the requirements of a developing organism. Pediatric
      neurosurgeons are now increasingly involved in beneficial cooperation within
      complex medical teams. This fact has by no means diminished the importance of
      pediatric neurosurgery; rather, in such settings it has proved to have better
      effects in the struggle for stable long-lasting good results of multi-modal
      treatments covering all pathological entities. Progress in neurological surgery
      for patients in the pediatric age group has emerged from the development of
      supranational scientific structures and from that of specific concepts exchanging
      channels, so that today pediatric neurosurgeons belong to an extremely
      specialized medical corps, working in harmony across geographical and socio
      economic national features in the interests of humankind's young generation's
      health.

PMID- 10603029
TI  - Pediatric neurosurgery in the Middle East: present and future.
AB  - The Middle East is the term used for more than ten countries with populations
      characterized by different ethnic roots and religions and with diverse political
      and economic power. It is probably the most unstable part of the whole world,
      having spent centuries struggling for a settled situation. Reflecting this
      political turmoil, the health problems and priorities in these countries are very
      different than in western countries. Medical associations, including
      neurosurgical associations, in most of these countries have very little
      communication with international societies compared with such associations in
      other parts of the world. Although one or two neurosurgeons in almost every
      country in the region enjoy some prominence in the international neurosurgical
      arena, almost no society-based relationships have been established among Middle
      East countries. Pediatric neurosurgery has been regarded as a subspecialty in the
      Middle East countries for the last two decades. Although it is not well organized
      except in Turkey and Israel, most of the countries in this region now have
      neurosurgeons who give special attention to pediatric neurosurgery within their
      general neurosurgical practice. Practicing neurosurgeons are few and and far
      between; there are certainly not enough of them to allow specialization in
      specific fields of neurosurgery in most countries in the Middle East. Moreover,
      owing to political and economic problems, most countries in the region are behind
      the standard neurosurgical agenda. Nonetheless, the flow rate of papers submitted
      to Child's Nervous System from several countries in the region has been slowly
      but progressively increasing. Hopefully, political stabilization in the near
      future will activate progress in pediatric neurosurgery along with neurosurgery
      in this region.

PMID- 10603030
TI  - In memoriam henry M. Wisniewski, M.D., ph.D

PMID- 10603031
TI  - Neuropathology and prognosis of foetal brain tumours.
AB  - A survey of brain tumours that had been diagnosed prenatally by foetal sonography
      yielded 89 cases. The most commonly found tumour entities were teratomas (53.9%),
      glioblastomas (14.6%), lipomas (9. 0%), plexus papillomas (7.9%) and
      craniopharyngiomas (5.6%). The mean gestational age at ultrasound diagnosis was
      30.0 weeks, ranging between 25.4 weeks in craniopharyngiomas and 35.3 weeks in
      lipomas. Girls were more frequently affected (57.4%; P < 0.05). The average
      maximum tumour size at diagnosis was 6.5 cm, ranging between 1.6 cm in lipomas
      and 8.2 cm in teratomas. Tumours diagnosed between 1979- 1988 accounted for 29.2%
      of all cases and were larger when identified than the ones reported between 1989-
      1998 (5.9 vs 8.4 cm; P = 0.08). Of all patients, only 18.8% were alive after the
      first week and 10.5% after the 1st year of life. Prognosis was particularly poor
      among foetuses with brain tumours detected before 30 weeks' gestation of which
      96.9% died. Significantly longer survival was found for lipomas (12.0 vs 3.8
      months), tumour detection after gestational age of 30 weeks (6.3 vs 1.2 months)
      and in cases reported after 1988 (5.3 vs 2.9 months, all P < 0.05). Cytogenetic
      data was given for eight teratomas of which three showed a pathological and five
      cases a normal karyotype for both foetus and tumour. In conclusion, foetal brain
      tumours are rare neoplasms of whose cytogenetics little is known. They are mainly
      detected at the beginning of the third trimester of pregnancy with teratomas
      being the most common entity. Foetal brain tumours have a mainly unfavourable
      clinical outcome. However, their prognosis has improved in the last decade.

PMID- 10603032
TI  - Ultrastructural evidence of early non-fibrillar Abeta42 in the capillary basement
      membrane of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch
      type.
AB  - The C-terminal profile and ultrastructure of small and presumably early capillary
      amyloid beta protein (Abeta) deposits were investigated in four patients with
      hereditary cerebral hemorrhage with amyloidosis, Dutch type. The C terminus of
      the 40 (Abeta40) or the 42 (Abeta42) amino acid form of Abeta was gold labeled in
      serial, ultrathin sections on glass slides for reflection contrast microscopy and
      on grids for electron microscopy. In all studied subjects, reflection contrast
      microscopy revealed capillaries with focal Abeta42 immunolabeling in the absence
      of Abeta40 labeling. In the adjacent electron microscopic section, Abeta42
      labeling was confined to the capillary basement membrane. The majority of
      Abeta42(+)40(-) deposits showed no amyloid fibrils. Abeta42(+)40(-) deposits were
      sometimes observed in an unremarkable basement membrane but usually showed
      increased electron density and reticular structures. A small subset of
      Abeta42(+)40(-) deposits with basement membrane changes showed few amyloid
      fibrils. Abeta42(+)40(+) capillary deposits always showed definite fibrils and
      were larger than Abeta42(+)40(-) capillary deposits. The present findings suggest
      that in capillaries the accumulation and subsequent polymerization of Abeta42,
      possibly in conjunction with basement membrane changes, precedes the definite
      fibril formation with Abeta40.

PMID- 10603033
TI  - Increased lipocortin-1 (annexin-1) expression in the sciatic nerve of Lewis rats
      with experimental autoimmune neuritis.
AB  - Lipocortin-1 exerts a potent immunosuppressive effect on pathogenic T cells. In
      multiple sclerosis and experimental autoimmune encephalomyelitis levels of
      lipocortins are raised, suggesting their involvement in the recovery from an
      immunological insult or in neural regeneration. To further understand the role of
      lipocortins in the peripheral nervous system we have characterized lipocortin-1
      levels and cellular distribution of lipocortin-1 immunoreactivity in sciatic
      nerves of rats with experimental autoimmune neuritis (EAN), a model of human
      Guillain-Barre syndrome. EAN was induced actively by immunization with bovine
      peripheral myelin (active EAN) or by adoptive-transfer (AT-EAN) of P2-specific T
      cells. Cellular infiltrates in serial and semithin cryosections were
      characterized by immunohistochemistry. In parallel, lipocortin-1 levels in tissue
      extracts were quantified by a sandwich-ELISA. Only weak lipocortin-1
      immunoreactivity was found in nerves of control animals injected with non
      pathogenic T cells. The majority of macrophages and lymphocytes in EAN lesions
      exhibited lipocortin-1 immunoreactivity. Some very heavily stained cells showed a
      distribution and morphology similar to ED-2-positive macrophages which were
      abundant during early stages of EAN. Lipocortin-1 expression in T cells and
      macrophages was proven by immunocytochemical studies in semithin serial sections.
      In tissue extracts, lipocortin-1 levels increased from 0.24 +/- 0.14
      micrograms/mg protein in controls receiving non-pathogenic T cells to a maximum
      of 0.55 +/- 0.1 micrograms/mg protein in AT-EAN at the peak of disease, and then
      slowly decreased during clinical recovery but still remained elevated. In dose
      response studies in AT-EAN, highest values of lipocortin-1 (0. 71 +/- 0.23
      micrograms/mg protein) were recorded after transfer of 2 x 10(7) T cells.
      Increased levels of lipocortin-1 were also measured in active EAN but occurred
      during the recovery phase (0.65 +/- 0.27 micrograms/mg protein). By analogy with
      other immune-mediated disorders, increased lipocortin-1 expression in the
      inflamed sciatic nerve in EAN may exert immunoregulatory functions in-situ and
      contribute to the termination of the autoimmune response.

PMID- 10603034
TI  - Migration of virus-infected neuronal cells in cerebral slice cultures of
      developing mouse brains after in vitro infection with murine cytomegalovirus.
AB  - To investigate the effect of murine cytomegalovirus (MCMV) infection on the
      developing mouse brain in vitro, we developed an infection system using cerebral
      slice cultures. Using a micromanipulator, the cerebral slices from mouse embryos
      on day 18.5 of gestation were injected in the subventricular zone with
      recombinant MCMV in which the lacZ gene was inserted into a late gene, and were
      cultured for 7 days. Viral infection, detected by beta-galactosidase reaction,
      was developed at the injection sites of the slices. The virus-infected spots in
      the slices were enhanced by adding tumor necrosis factor-alpha to the medium and
      inhibited by adding phosphonoacetic acid or ganciclovir. Sections from paraffin
      embedded slices were subjected to immunohistochemical analyses. Neuronal cells,
      labeled with 5-bromo-2-deoxyuridine 24 h before cutting the slices, migrated to
      the cerebral cortex in the slices. Virus-infected neuronal cells expressing only
      the early viral antigen migrated to the cortex, whereas glial cells expressing
      the immediate early and late antigens tended to remain at the injected sites. The
      neuronal migration of infected cells was not observed in the cerebral slices from
      7-day-old mice and viral infection was not detected after injection in the
      cerebral slices from 14- and 21-day-old mice. These results from these cerebral
      slices may reflect the infectious dynamics in vivo, and this system may provide a
      useful model for analysis of disorders of brain development caused by CMV.

PMID- 10603035
TI  - Deposition of the prion protein (PrP) during the evolution of experimental
      Creutzfeldt-Jakob disease.
AB  - We studied the immunocytochemical distribution of the prion or proteinase
      resistant protein (PrP) during the evolution of experimental Creutzfeldt-Jakob
      disease (CJD) in mice. Fifty-one brains were collected up to 22 weeks following
      intracerebral inoculation with the Fujisaki strain of the CJD agent. Slides were
      also immunostained for apolipoprotein E (apoE) and glial fibrillary acidic
      protein. Vacuolar changes with focal astrocytosis first occurred around the
      needle track at week 2 and later spread along white matter tracks. Until week 12,
      changes were asymmetrical, affecting more the side of inoculation. Spongiform
      change and astrogliosis spread subsequently to the gray matter. Time course and
      intensity of spongiform change and immunocytochemistry for PrP were discrepant:
      in most brain regions, severe vacuolation preceded immunocytochemically
      detectable PrP accumulation. PrP deposits in form of small dots were first
      detectable at week 6 in the area surrounding the needle track. After week 7,
      plaque-like amorphous PrP deposits were observed in white matter pathways.
      Finally, PrP was detectable also in basal ganglia and in the dorsal hippocampus
      (week 13) and in the neocortex (week 17), as the synaptic type of PrP
      immunopositivity. In the hippocampus, diffuse PrP deposits paralleled spongiform
      change, while in the cortex severe vacuolation was accompanied only by weak
      synaptic PrP deposits. Immunocytochemically detectable apoE was restricted to
      compact plaque-type PrP deposits after week 15. We conclude that disease-specific
      neuropathology spreads from the needle track along white matter pathways towards
      the gray matter; in this model, there is some discrepancy between development of
      tissue pathology and immunocytochemically detectable deposition of PrP.
      Immunocytochemically detectable apoE deposition follows PrP accumulation.

PMID- 10603036
TI  - Changes in guanylate cyclase activity in arteriolar smooth muscle cells and
      hemodynamics after ischemia-reperfusion in rats.
AB  - Participation of nitric oxide (NO) and hydroxyl radicals in the pathogenesis of
      hemodynamic alterations after postischemic recirculation were examined by
      measuring cerebral blood flow (CBF) and estimating guanylate cyclase activities
      in arteriolar smooth muscle cells using a reversible 2-h thread occlusion model
      in rats and an electron microhistochemical technique. In the reversible 2-h
      ischemia model, guanylate cyclase activity in the arteriolar smooth muscle cells
      increased at the peak of hyperemia and decreased during postischemic
      hypoperfusion. Administration of N(omega)-nitro-l-arginine (L-NNA), a NO synthase
      inhibitor, in this model decreased infarct volume and completely inhibited both
      hyperemia and guanylate cyclase activation at hyperemia. Administration of 1,2
      bis(nicotinamido)-propane (AVS), a free radical scavenger, affected neither CBF
      nor guanylate cyclase activity during hyperemia despite a significant reduction
      in infarct volume. Administration of L-NNA and AVS significantly suppressed the
      decrease in CBF during postischemic hypoperfusion and the effect of AVS was
      greater than that of L-NNA. Although continuous infusion of sodium nitroprusside
      (SNP) following postischemic hypoperfusion in the reversible 2-h ischemia rats
      without treatment with L-NNA and AVS did not alter either CBF or guanylate
      cyclase activity, it significantly elevated both CBF and guanylate cyclase
      activities in rats administered L-NNA and AVS. The responses of CBF and guanylate
      cyclase to SNP were also greater in AVS- than L-NNA-treated rats. These results
      suggest that a physiological vasodilative mechanism is involved in the induction
      of postischemic hyperemia through the NO-guanylate cyclase pathway in arteriolar
      smooth muscle cells. Both NO-related and non-related radicals are involved in the
      pathogenesis of postischemic delayed hypoperfusion through the loss of arteriolar
      smooth muscle relaxation capability.

PMID- 10603037
TI  - Changes in serotonergic neurons in the brain of pyrithiamine-induced acute
      thiamine-deficient mice.
AB  - We examined changes in 5-hydroxytriptamine (5-HT, serotonin) neurons in
      pyrithiamine-induced thiamine deficiency in mice immunohistochemically. Extensive
      decreases in the densities of 5-HT-immunoreactive fibers were detected in the
      lateral septal nucleus, the thalamus, the medial mammillary nucleus, the dorsal
      and the median raphe nuclei, the raphe obscurus nucleus, the tegmental area, the
      cerebellum and the vestibular nucleus, though only a small decrease was detected
      in the inferior colliculus. Most remarkably, degenerative winding fibers were
      detected between the deep mesencephalic nucleus and the ventral tegmental area.
      Increases in intensity of 5-HT immunoreactivity in the dorsal raphe nucleus and
      decreases in the number of 5-HT-immunoreactive cell bodies in the dorsal and the
      median raphe nuclei were detected. These results demonstrated the differential
      vulnerability of 5-HT neurons in thiamine-deficient mice. This is the first
      report to demonstrate changes in 5-HT neurons immunohistochemically throughout
      the brain of pyrithiamine-induced thiamine deficient mouse.

PMID- 10603038
TI  - Corticotropin-releasing factor--immunolabeled fibers in brain regions with
      localized kainate neurotoxicity.
AB  - Rats treated with the neuroepileptic drug, kainic acid, exhibit a specific
      regional pattern of neurodegeneration 24 h following onset of acute limbic status
      epilepticus. At 24 h post-seizure, the areas undergoing neurodegeneration also
      exhibit substantial amounts of the neuropeptide corticotropin-releasing factor
      (CRF) which is not present under normal conditions. In experimental brains, CRF
      is localized immunocytochemically to cells and densely labeled fibers in areas
      with neurodegeneration. Networks of CRF fibers closely surround moribund neurons
      staining intensely for acid fuchsin. Acid fuchsin, an acidophilic dye, is used
      routinely as a marker for irreversible neuronal injury, and acid fuchsin-positive
      neurons are identified in specific areas affected by kainic neurotoxicity.
      Evidence exists in the literature that CRF functions in brain as a excitatory
      neurotransmitter/neuromodulator. Under certain pathological conditions (i.e.,
      seizures, brain trauma, ischemia), it has been postulated that CRF could act as
      an neurotoxic agent. This study provides anatomical evidence that CRF may
      function following seizures as an neurotoxin because of the close proximity of
      CRF-labeled fibers to degenerating neurons.

PMID- 10603039
TI  - p27/kip1 expression in oligodendrogliomas and its possible prognostic role.
AB  - p27/kip1 regulates the G1-S transition of the cell cycle by inhibiting cyclinD
      CDK4, cyclinE-CDK2 and cyclinA-CDK2 complexes. Regulation of p27 levels occurs
      mainly post-translationally by ubiquitin-mediated proteasomal proteolysis.
      Although genetic changes of p27/kip1 are extremely rare, in many human carcinomas
      p27 levels are reduced, correlate with histological malignancy, and are
      associated with poor prognosis. In astrocytic gliomas, p27 decreases with
      anaplasia and is almost absent in glioblastomas. p27/kip1 was
      immunohistochemically studied in 37 oligodendrogliomas, categorized according to
      WHO classification. In this series, the immunohistochemical reaction for p27 was
      confined to nuclei. p27 score showed a tendency to decrease with malignancy. When
      the p27 score was considered as high versus low expression (cut-off of p27
      labeling index, LI, at 25%), it represented an independent prognostic factor in
      univariate (P = 0.02) and in multivariate analysis (P = 0.04). The risk ratio
      suggested that the p27 low expression group had a threefold increased possibility
      to show a reduced survival. Moreover, p27 levels did not correlate with MIB-1 LI,
      suggesting that p27 is not merely associated with the control of proliferation.

PMID- 10603040
TI  - Pursuit of the origin of the large myelinated fibers of the anterolateral
      funiculus in the spinal cord in humans in relation to the pathomechanism in
      amyotrophic lateral sclerosis.
AB  - To determine the origin of the large myelinated fibers in the anterolateral
      funiculus (ALF) in the spinal cord of humans, myelinated fibers in the ALF of the
      mid-cervical spinal cord were examined quantitatively. Five groups of subjects
      were examined, consisting of control subjects, patients with cerebral lesions and
      showing complete degeneration of the unilateral/bilateral pyramis of the medulla
      oblongata, those with lesions of the pontine tegmentum, those with lesions of the
      lower cervical spinal cord, and those with thoracic/lumbar lesions. The results
      indicate that the large myelinated fibers in the ALF of the mid-cervical spinal
      cord of humans originate from the tegmentum of the brain stem and the lower
      cervical spinal cord, and not from the cerebrum, or the thoracic or lumbar spinal
      cord. Thus, they are descending fibers from the brain stem tegmentum and
      ascending fibers from the lower cervical cord, and not corticospinal tracts or
      long-ascending fibers from the thoracic or lumbar spinal cord. The origin of the
      large myelinated fibers in the ALF of the spinal cord in humans, the number of
      which was severely decreased in patients with amyotrophic lateral sclerosis, is
      considered to be the long-descending neurons in the brain stem tegmentum and the
      propriospinal neurons in the spinal cord.

PMID- 10603041
TI  - Experimental rabies virus infection of p75 neurotrophin receptor-deficient mice.
AB  - The low-affinity neurotrophin (NT) receptor, p75(NTR), has complex biologic
      functions. A recent report provided evidence that the p75(NTR) is a rabies virus
      receptor in cultured BSR cells. We studied the experimental infection of 6-day
      old p75(NTR)-deficient mice with the challenge virus standard strain of fixed
      rabies virus inoculated intracerebrally. The mice developed a fatal encephalitis.
      There were morphologic changes of apoptotic cell death involving neurons in
      widespread areas of the brain, which were associated with in situ evidence of
      oligonucleosomal DNA fragmentation. The findings were very similar to those that
      we previously reported in wild-type ICR mice of the same age. If the p75(NTR) is
      an important receptor of rabies virus in animal hosts, then a greater effect on
      the clinical and pathologic features of rabies virus-infected p75(NTR)-deficient
      mice would have been expected.

PMID- 10603042
TI  - Motor neuron disease with predominantly upper extremity involvement: a
      clinicopathological study.
AB  - We report two autopsy cases of motor neuron disease (MND) patients with an
      unusual type of muscular atrophy predominantly affecting the shoulder girdle and
      the upper extremities with proximal dominance. Both patients are considered to be
      clinically categorized into the El Escorial suspected form of amyotrophic lateral
      sclerosis (ALS). At autopsy, they showed marked loss of spinal anterior horn
      cells accompanied by astrogliosis positively immunostained with anti-glial
      fibrillary acidic protein antibody at the cervical level. At the lumbosacral
      level, anterior horn neurons were relatively well preserved and Bunina bodies,
      ubiquitin-positive skein-like inclusions and Lewy body-like inclusions were
      observed in the remaining neurons. In one patient, brain stem motor neurons
      (nerves V, VII, XII) and motor cortex, including Betz cells, were also affected
      and the corticospinal tracts were degenerated at the level of the thoracic and
      lumbar spinal cord. Pathological findings of this patient are consistent with
      those of ALS. In the other patient, the motor cortex, brain stem motor nuclei and
      the corticospinal tracts were well preserved, which is pathologically compatible
      with progressive spinal muscular atrophy. These patients with such a peculiar
      pattern of progressive muscular atrophy should be placed in a subgroup of ALS.

PMID- 10603043
TI  - Docetaxel neuropathy: a distal axonopathy.
AB  - Docetaxel has been implicated as a causative agent in peripheral neuropathy, but
      pathological changes in peripheral nerve have not been described. During
      docetaxel treatment a 54-year-old man developed a sensorimotor polyneuropathy
      when the overall docetaxel dosage was 540 mg/m(2). Neurophysiological
      investigation revealed a sensorimotor axonal neuropathy. Fascicular sural nerve
      biopsy showed an axonal neuropathy with a preferentially loss of large myelinated
      fibers. There was evidence of considerable fiber regeneration. Sensory and motor
      symptoms progressively improved after docetaxel withdrawal.

PMID- 10603070
TI  - Benefit-risk evaluation of olanzapine, risperidone and sertindole in the
      treatment of schizophrenia.

PMID- 10603071
TI  - CGRP immunohistochemistry in wound healing and dentin bridge formation following
      rat molar pulpotomy.
AB  - The aim of the present study was to investigate the neuropeptide CGRP in order to
      determine the effect on dentin bridge formation during the healing process after
      pulpotomy. First maxillary molars in 56-day-old Wistar rats (n=60) were used. The
      rats were killed for a neurohistopathological examination at 1, 3, 7, 14, and 28
      days postoperatively. Neuronal changes in the residual pulp were studied using
      CGRP immunohistochemistry. By 1-3 days postoperatively, the CGRP-IR nerve fibers
      with abnormal beaded or knob-like structures were found to be more swollen than
      in the control and the leakage of a CGRP-IR-positive substance from the involved
      end of the nerve fibers was seen. At 7 days postoperatively, a vast number of
      newly sprouted CGRP-IR nerve fibers appeared in the residual pulp and some of
      them terminated in the differentiating odontoblast layer and the initial matrix
      layer of the dentin bridge. By 14-28 days, the nerve density had become
      progressively lower in the residual pulp. Regenerated axons also terminated in
      the odontoblast layer and the fibrous matrix layer of the calcified dentin
      bridge. These findings suggest that such sensory neuropeptides as CGRP may,
      therefore, play a role in dentin bridge formation in the rat molar.

PMID- 10603072
TI  - Epipodite and fat cells as sites of hemoglobin synthesis in the branchiopod
      crustacean Daphnia magna.
AB  - In contrast to the malacostracan crustaceans that use hemocyanin as the oxygen
      carrier, a number of branchiopod crustaceans, such as the water flea Daphnia
      magna, utilize hemoglobin (Hb) as the respiratory protein. By means of in situ
      hybridization (ISH) techniques with subsequent signal amplification using
      catalyzed reporter deposition, sites of Hb synthesis were localized in Daphnia
      magna. Based on a previously reported Hb-cDNA sequence, a specific ISH probe was
      designed and hybridized with the Hb-mRNA in histological sections of adult D.
      magna. The detection of Hb-mRNA was tissue specific and revealed that Hb is
      synthesized in fat cells, which play a role in fat and glycogen metabolism, and
      in epithelial cells of the epipodites, which are involved in osmoregulation.
      Sites of Hb synthesis have been identified in several invertebrate phyla,
      including Annelida and Nematoda. However, this is the first example in the class
      Crustacea, and only the second in the phylum Arthropoda.

PMID- 10603073
TI  - Rearrangement of the F-actin cytoskeleton in estradiol-treated MCF-7 breast
      carcinoma cells.
AB  - In response to treatment with 17beta-estradiol, MCF-7 human breast carcinoma
      cells undergo a marked rearrangement of the F-actin cytoskeleton. The most
      conspicuous aspect of this rearrangement is the formation of an extensive array
      of lamellipodial structures which are situated beneath cell clusters. Treatment
      of cells with 17beta-estradiol in the presence of the anti-estrogen ICI182,780
      suppressed the development of the lamellipodial structures, indicating that this
      cytoskeletal rearrangement is mediated by the estrogen receptor. Time-lapse,
      video-enhanced, differential interference contrast microscopy reveals that the
      lamellipodial structures are actively motile beneath cell clusters. Furthermore,
      the lamellipodial structures form few focal contacts with the underlying
      substrate of the coverslip, as evidenced by either interference reflection
      microscopy or staining for the focal contact protein talin, indicating that these
      structures are not strongly adhered to the substratum. Immunofluorescence
      localization of E-cadherin indicates that this cell-cell adhesion receptor is
      present within these structures as either adhesion plaque- or point contact-like
      depositions. These findings implicate the cadherin-based cell-cell adhesion
      system in supporting tumor cell motility over adjacent cell surfaces via discrete
      adhesive structures which are associated with motile lamellipodia.

PMID- 10603074
TI  - Tubular invaginations with caveolae and coated pits in the sinus endothelial
      cells of the rat spleen.
AB  - The fine structure of plasmalemmal tubular invaginations with caveolae and coated
      pits in the sinus endothelial cells of the rat spleen has been demonstrated by
      scanning and transmission electron microscopy. In addition, the three-dimensional
      structure of the tubular invagination has been revealed by computer-aided
      reconstruction. The tubular invaginations of the plasma membrane plunged into the
      cytoplasm everywhere from the apical, lateral, and basal surfaces of the plasma
      membrane. The invaginations were tubular and branched away, and their plasma
      membranes were reinvaginated to form numerous caveolae and occasional coated
      pits. Numerous caveolae were found in clusters that looked similar to a bunch of
      grapes and the coated pits were present at the base of the clusters. The caveolae
      and coated pits derived from the tubular invaginations were almost
      ultrastructurally identical to those derived from the surface plasma membrane.
      From examination of the fractured surfaces of the endothelial cells treated with
      the aldehyde prefix osmium-dimethyl sulfoxide-osmium method and of ultrathin
      sections of those infiltrated by lanthanum nitrate, the tubular invaginations
      were found to not penetrate any endothelial cells. A computer-aided
      reconstruction revealed that the caveolae derived from the tubular invaginations
      were in close apposition to the surface-connected canaliculi. The reaction
      product of Concanavalin A conjugated to horseradish peroxidase was present on the
      outer leaflet of the membranes of the coated pits and coated vesicles and also in
      the contents of the endosomes, but it was absent from any caveolae. Based on our
      observations, the functional significance of the tubular invaginations in sinus
      endothelial cells is discussed.

PMID- 10603075
TI  - Hexokinase I expression and activity in embryonic mouse heart during early and
      late organogenesis.
AB  - Hexokinase (HK) catalyzes the first step in glucose metabolism, that is, the
      conversion of glucose to glucose-6-phosphate (G6P). Four HK isoforms have been
      identified, of which HK-I is predominant in embryonic and fetal tissues. HK-I has
      been studied in preimplantation embryos and in fetal stages, but little is known
      about its activity or expression in the early postimplantation embryo. We
      evaluated HK-I expression, HK-I activity, and glycolytic metabolism in the
      embryonic mouse heart during early [gestational day (gd) 9.5] and late (gd 13.5)
      organogenesis. Immunohistochemistry demonstrated that HK-I is localized mainly in
      the heart at both stages, with stronger expression on gd 13.5. Densitometry after
      SDS-PAGE/western analysis confirmed higher immunodetectable HK-I protein levels
      in hearts on gd 13.5 vs gd 9.5. By contrast, RT-PCR demonstrated higher HK-I mRNA
      expression on gd 9.5 vs gd 13.5. Similarly, cardiac HK-I activity (conversion of
      glucose to G6P) and glycolysis (conversion of glucose to lactate) were higher on
      gd 9.5 than on gd 13.5. These results suggest a complex regulation of HK-I
      expression and activity in the embryonic heart during organogenesis, involving a
      change in the intrinsic activity of the enzyme with development. HK-I appears to
      play an important role in glucose metabolism during this critical stage of
      cardiogenesis.

PMID- 10603076
TI  - Changes in calcium concentrations in subcellular compartments of rat
      submandibular gland acinar cells induced by cholinergic stimulation.
AB  - The effects of cholinergic and alpha-adrenergic stimulation on calcium
      concentrations in rat submandibular gland acinar cells were evaluated at the
      subcellular level by electron probe X-ray microanalysis, and the subcellular
      distribution of receptors for inositol 1,4,5-trisphosphate (IP(3)Rs) was
      investigated by electron microscopic immunohistochemistry. For measurement of
      calcium concentrations, experiments were carried out both in vivo and in vitro.
      In in vivo experiments, fragments of glands were removed and slam-frozen 3 min
      after intraperitoneal injection of an agonist. In in vitro experiments, the gland
      tissue was enzymatically dispersed, treated with an agonist in the presence or
      absence of extracellular Ca(2+), and slam-frozen. The frozen specimens were cut
      into ultrathin cryosections, which were then freeze dried. Spectra were collected
      from secretory granules, the perinuclear cytoplasm containing endoplasmic
      reticulum (ER), and the nucleus of the acinar cells. A clear decrease in calcium
      content in secretory granules was observed after cholinergic stimulation both in
      vivo and in vitro in the presence or absence of extracellular Ca(2+). In the
      presence of extracellular Ca(2+), cholinergic stimulation following alpha
      adrenergic stimulation reduced the calcium content in secretory granules to the
      same extent as cholinergic stimulation alone. No significant changes in the
      calcium content of the perinuclear cytoplasm and the nucleus were noticed after
      cholinergic stimulation. alpha-adrenergic stimulation did not significantly
      affect the calcium concentrations in any of the three compartments studied.
      IP(3)Rs were localized to ER lamellae, but not to secretory granule membranes or
      to nuclear membranes. Our findings suggest that: (1) in rat submandibular acini,
      Ca(2+) can be released from secretory granules by exposure to cholinergic, but
      not alpha-adrenergic, stimuli, (2) there are, however, no IP(3)Rs present in the
      granular membrane and the trigger for the Ca(2+) release remains under study, and
      (3) the response to either type of stimulus does not involve changes in the
      Ca(2+) content of the nucleus or of the perinuclear cytoplasm/ER, despite the
      presence of IP(3)Rs in the latter structure. This may be the result of limitation
      in the technique used, which cannot measure changes in the proper compartment of
      the ER.

PMID- 10603077
TI  - Actin filaments during terminal differentiation of urothelial cells in the rat
      urinary bladder.
AB  - The localisation of actin filaments was studied in rat urothelial cells during
      differentiation which accompanied regeneration after cell damage induced by
      cyclophosphamide (CP). By immunofluorescence it was established that actin
      filaments equally stained along the cell circumference in basal and intermediate
      cells, while basolateral cell membrane expression was found in terminally
      differentiated superficial cells. During regeneration, after CP treatment, simple
      urothelial hyperplasia developed with smaller cuboidal superficial cells, in
      which actin filaments were equally distributed under the apical and basolateral
      plasma membranes. As demonstrated by immunoelectron microscopy, the apical
      surface of these superficial cells was covered with microvilli containing bundles
      of actin filaments. Within 1 week, the urothelium reverted to its normal three
      layer thickness. Superficial cells became larger and flattened and the
      unthickened apical plasma membrane matured into a thick asymmetric unit membrane.
      Concomitantly actin filaments disappeared from apical areas of superficial cells
      while remaining abundant at basolateral areas. Our results indicate that in the
      urothelium subcellular distribution of actin filaments can be considered as a
      marker of cell differentiation.

PMID- 10603078
TI  - Mast cell heterogeneity in the human uvea.
AB  - To identify chymase- and tryptase-positive mast cells in the human uvea, and to
      study their associations with different types of resident uveal cells, uveal
      specimens from 24 human donor eyes were cryosectioned in sagittal and tangential
      planes. Enzyme histochemical staining of chymase was combined with
      immunohistochemical staining for tryptase, detected with the APAAP method.
      Fluorescence immunohistochemistry was performed with antibodies against c-kit,
      alpha smooth muscle actin, protein gene product (PGP) 9.5, CD45, and HLA-DR. In
      different uveal compartments, the total amounts of mast cells were calculated and
      the distributions of chymase and tryptase were quantified. All uveal mast cells
      were c-kit and CD45 positive and HLA-DR negative. No association existed between
      mast cells and actin-containing cells. Only a few mast cells were in close
      association with PGP 9.5-labeled nerve fibers. In the choroid, most mast cells
      were located in the inner central part (mean density = 48.9/mm(2)), and contained
      both chymase and tryptase (96%). The ciliary muscle contained numerous mast cells
      (mean density = 33.7/mm(2)), many of them tryptase positive but chymase negative
      (63%). In the pars plana, a high number of chymase-positive, tryptase-negative
      mast cells were found (20%). In the iris only a few mast cells were present.
      Although the choroid contains the most common subtype of mast cells, a unique
      situation concerning the distribution of chymase and tryptase is present in the
      anterior uveal tissues. A possible role for these cells in the special
      immunological situation of the anterior eye chamber merits further investigation.

PMID- 10603079
TI  - Localization of liver myofibroblasts and hepatic stellate cells in normal and
      diseased rat livers: distinct roles of (myo-)fibroblast subpopulations in hepatic
      tissue repair.
AB  - Previous in vitro studies indicated that hepatic stellate cells (HSC) and rat
      liver myofibroblasts (rMF) have to be regarded as different cell populations of
      the myofibroblastic lineage with fibrogenic potential. Employing the
      discrimination features defined by these studies the localization of HSC and rMF
      was analyzed in diseased livers. Normal and acutely as well as chronically carbon
      tetrachloride-injured livers were analyzed by immunohistochemistry and by in situ
      hybridization. In normal livers HSC [desmin/glial fibrillary acid protein (GFAP)
      positive cells] were distributed in the hepatic parenchyma, while rMF
      (desmin/smooth muscle alpha actin-positive, GFAP-negative cells colocalized with
      fibulin-2) were located in the portal field, the walls of central veins, and only
      occasionally in the parenchyma. Acute liver injury was characterized almost
      exclusively by an increase in the number of HSC, while the amount of rMF was
      nearly unchanged. In early stages of fibrosis, HSC and rMF were detected within
      the developing scars. In advanced stages of fibrosis, HSC were mainly present at
      the scar-parenchymal interface, while rMF accounted for the majority of the cells
      located within the scar. At every stage of fibrogenesis, rMF, in contrast to HSC,
      were only occasionally detected in the hepatic parenchyma. HSC and rMF are
      present in normal and diseased livers in distinct compartments and respond
      differentially to tissue injury. Acute liver injury is followed by an almost
      exclusive increase in the number of HSC, while in chronically injured livers not
      only HSC but also rMF are involved in scar formation.

PMID- 10603080
TI  - Conservation of the WD-repeat, microtubule-binding protein, EMAP, in sea urchins,
      humans, and the nematode C. elegans.
AB  - The echinoderm microtubule-associated protein (EMAP) is the most abundant
      microtubule-binding protein in the first cleavage mitotic apparatus in sea urchin
      embryos. The first goal of this study was to determine whether there is
      sufficient EMAP in the egg and embryo to modify microtubule dynamics during the
      early cleavages divisions and whether EMAP functions at a specific time or place
      in the embryo. To accomplish this goal, we examined the relative abundance,
      tissue distribution, and temporal pattern of EMAP expression during embryonic
      development. The second goal of this study was to identify important functional
      domains within the EMAP coding sequence. A conserved sequence might reveal a
      potential microtubule-binding domain. We cloned, sequenced and compared
      overlapping EMAP cDNAs from two different sea urchin species that diverged
      approximately 80 million years ago, and compared these with cDNA sequences from a
      vertebrate and nematode species. From quantitative immunoblots, we determined the
      EMAP concentration in eggs to be 4 microM. The steady-state levels of EMAP mRNA
      and protein accumulated during development, and all three germ layers expressed
      EMAP. During the early stages of development, EMAP and tubulin were both abundant
      in the ectoderm, mesoderm and endoderm. However, during late gastrulation and the
      formation of the early pluteus larvae, EMAP was enriched in the mesoderm, while
      tubulin staining was most abundant in the archenteron. These results indicate
      that EMAP may have tissue-specific functions in the late stage embryo. To
      identify conserved functional domains, we compared the predicted amino acid
      sequence encoded by Strongylocentrotus purpuratus and Lytechinus variegatus EMAP
      cDNAs, and determined that these two sea urchin EMAPs were 95% conserved and
      shared an identical domain organization. A parsimonious analysis of these sea
      urchin protein sequences, as well as human and C. elegans EMAP sequences was used
      to construct a gene tree. Together these results suggest that EMAP is an
      important microtubule protein required at all developmental stages of sea
      urchins, and whose cellular function may be conserved amongst metazoans.

PMID- 10603081
TI  - Characterization of a hemichordate fork head/HNF-3 gene expression.
AB  - Based on anatomical and developmental similarities, hemichordates are thought to
      be most closely related to chordates. However, so far very few developmental
      genes have been characterized from hemichordates. To gain molecular insight into
      the developmental mechanisms involved in the origin and evolution of chordates,
      we investigated the expression of a fork head/HNF-3 (PfHNF3) gene in the acorn
      worm embryo. Chordate fork head genes are implicated in the formation of
      endoderm, notochord and floor plate. We found that a PfHNF3 transcript was first
      detected at the early blastula stage; the signal of in situ hybridization was
      found in the vegetal plate cells, invaginating endoderm and then in the
      archenteron. By the late gastrula and into the early tornaria larva stages, an
      intense signal remained in the anterior region of the archenteron, while the
      expression in the other regions of archenteron decreased. The intense signal was
      retained in the pharynx of the tornaria larva. A comparison of the pattern of
      PfHNF3 with that of HNF-3 genes of sea urchin, ascidian, amphioxus and vertebrate
      suggests a possible acquisition of new functions of the gene during deuterostome
      evolution.

PMID- 10603082
TI  - Allelic expression of IGF2 in marsupials and birds.
AB  - Genomic imprinting, the parent-of-origin- specific expression of genes, has been
      observed in a variety of eutherian mammals. One gene that has been shown to be
      imprinted in all eutherians examined is the IGF2 gene. This gene encodes a potent
      fetal-specific growth factor that is expressed almost exclusively from the
      paternal chromosome. Several other imprinted genes in the IGF2 pathway are
      imprinted as well, suggesting that IGF2 is a focal point for the selective
      pressure leading to imprinted gene expression. This observation is in keeping
      with a proposal that imprinting arose as the result of a genetic conflict between
      parents over the allocation of maternal resources to the embryo. One prediction
      of this model is that imprinting exists in species in which there is at least
      some contribution of maternal resources to the embryo, and in which polyandry is
      observed. To test this prediction the allelic expression of the IGF2 gene was
      examined in two noneutherian species. The IGF2 gene was shown to be expressed in
      a paternal-specific manner identical to that in eutherians in Monodelphis
      domestica, a placental South American opossum. In contrast, the IGF2 gene is
      biallelic in expression in chickens, which are oviparous, and make no
      postfertilization contribution of maternal resources to the offspring.

PMID- 10603083
TI  - Ectopic expression of Xenopus noggin RNA induces complete secondary body axes in
      embryos of the direct developing frog Eleutherodactylus coqui.
AB  - We tested the effects of noggin RNA from Xenopus laevis on axis induction in
      embryos of a direct developing frog, Eleutherodactylus coqui. We microinjected
      noggin RNA into one blastomere of 4-cell embryos at the site close to the animal
      pole, and found that overexpression of noggin RNA is not only sufficient to
      induce additional axes but also induces heads with eyes. We also injected noggin
      RNA into 8-cell or 16-cell embryos in various sites, including the marginal zone,
      above the marginal zone, and the vegetal pole, and found the formation of a
      complete secondary axis in all three types of injection. These effects of X.
      laevis noggin RNA on the E. coqui embryo are remarkably different from those
      found in the X. laevis embryo itself. It has been shown previously that
      overexpression of noggin RNA on the ventral side of the normal X. laevis embryo
      induces only a partial axis, with no head structures. We show here that the
      failure of noggin induction of a complete axis when overexpressed on the ventral
      side of the X. laevis embryos is not due to an insufficient amount of RNA
      injected. Also, the failure is unlikely due to inhibition from the primary axis
      since noggin RNA can induce duplicated head structures on opposite sides of UV
      irradiated X. laevis embryos. There appear to be fundamental differences in the
      responses of E. coqui and X. laevis embryos to exogenous noggin RNA. We propose
      that these differences stem from an alteration in cytoplasmic arrangements that
      occurred during evolution of this large egg.

PMID- 10603084
TI  - An in situ hybridization screen for the rapid isolation of differentially
      expressed genes.
AB  - To rapidly isolate genes specifically expressed during medaka development we
      generated a cDNA library enriched for genes expressed in the head region of the
      developing embryo. Clones were spotted on filters automatically and preselected
      for abundantly expressed genes by hybridizing them with a probe derived from RNA
      of undifferentiated totipotent cells. Of the nonhybridizing clones 153 were
      chosen randomly and further analyzed by whole-mount in situ hybridization. There
      were 67 selected clones differentially expressed in the developing embryos, and
      48 of these were expressed in the developing head. Differentially expressed genes
      were either of novel type or showed homology to known genes containing DNA
      binding motifs or to putative housekeeping genes.

PMID- 10603085
TI  - Restricted expression of a truncated adenylyl cyclase in the cephalic furrow of
      Drosophila melanogaster.
AB  - We have identified a novel isoform of adenylyl cyclase, DAC78C, in Drosophila
      melanogaster that encodes two structurally distinct proteins in a developmentally
      restricted manner. The protein corresponding to one transcript is potently
      activated by G protein and protein kinase C and is expressed ubiquitously. The
      protein corresponding to the second transcript is expressed in a dynamic pattern
      in gastrulation stage embryos; it is restricted to the cephalic furrow and dorsal
      transverse folds, active regions of cell movement of unknown function in the
      Drosophila embryo. We propose that DAC78C and the cAMP pathway play an important
      role in directing these morphogenetic movements, and that this gene may provide
      clues to the functional significance of these structures in gastrulation.

PMID- 10603086
TI  - Identification and spatial distribution of the mRNA encoding an egg envelope
      component of the Cyprinid zebrafish, Danio rerio, homologous to the mammalian ZP3
      (ZPC).
AB  - Using degenerate reverse transcription polymerase chain reaction (RT-PCR)
      techniques we have isolated a cDNA encoding a putative component of the zebrafish
      Danio rerio egg chorion, homologous to the mammalian ZP3 (ZPC). The predicted
      protein (zfZPC) has a calculated molecular mass of 58.4 kDa and contains a signal
      peptide (located in the N-terminal region) composed of 11 hydrophobic amino acid
      residues followed by a signal peptide cleavage site. The zfZPC contains the ZP
      domain, a characteristic amino acid sequence shared by all ZP proteins of the
      mammalian zona pellucida and of both amphibian and bird egg envelope components.
      The zfZPC also exhibits certain unique features including five N-terminal Q-rich
      tandem repeats presumably involved in the hardening of the chorion after the
      fertilization of the egg and a long C-terminal tail containing two potential
      sites of N-linked type glycosylation. RT-PCR and in situ hybridization revealed a
      restricted pattern of tissue distribution: the gene encoding zfZPC is transcribed
      only in the growing oocyte of sexually mature female fish.

PMID- 10603087
TI  - NKX2 gene expression in neuroectoderm but not in mesendodermally derived
      structures depends on sonic hedgehog in mouse embryos.
AB  - NKX2 genes in vertebrates encode a sub- family of homeodomain-containing
      transcription factors which regulate morphogenetic events and cell
      differentiation during embryogenesis. In mouse embryos several NKX2 genes are
      expressed in the ventral midline domains of the neuroectoderm, while other NKX2
      genes are primarily expressed in the mesendoderm and mesendodermally derived
      organs, such as heart and gut. Within several patterning centers for tissue
      organization sonic hedgehog (Shh) is an important signal in the formation of
      ventral midline structures in vertebrate embryos. Here, we investigated the role
      of Shh in the embryonic expression of six different but closely related NKX2
      genes in Shh null mutant mice. We found that expression of NKX2.1, NKX2.2, and
      NKX2.9 in neural domains requires Shh signaling, whereas NKX2.3, NKX2.5 and
      NKX2.6 expression in endoderm and mesoderm is independent of Shh.

PMID- 10603088
TI  - Expression of chLIS1, a chicken homolog of LIS1.
AB  - We have isolated the chicken LIS1 homolog, chLIS1, with DNA sequence similarity
      of over 68% to the human cDNA and 99% amino acid identity. Additionally, we
      describe the pattern of chLIS1 expression in the chicken embryo. The early
      embryonic expression is highly specific to the developing nervous system, whereas
      later the expression is more widespread.

PMID- 10603089
TI  - Immunocytochemical distribution of the GABA(B) receptor splice variants GABA(B)
      R1a and R1b in the rat CNS and dorsal root ganglia.
AB  - The anatomical distribution of the GABA(B) receptor (GBR) splice variants GBR1a
      and 1b in the CNS has not previously been studied. In the present study,
      distribution of the splice variants was mapped using immunohistochemistry.
      Polyclonal antibodies against splice variant unique epitopes were raised in
      rabbits. Affinity purified antibodies were used according to routine
      immunohistochemical procedures in sections from the rat CNS or dorsal root
      ganglia (DRG). The staining intensity was high in the cerebral cortex but lower
      in basal ganglia and the hippocampus. In the cerebellum, there was a marked
      difference in the distribution of GBR1a- and 1b-like immunoreactivity (LI). GBR1a
      LI was preferentially localised in the granule cell layer whilst GBR1b-LI was
      mostly found in Purkinje cells and in the molecular layer. Cell bodies of the
      deep cerebellar nuclei stained for the GBR1a antibody while terminals surrounding
      the cell bodies were strongly labelled with the GBR1b antibody. A similar pre- vs
      postsynaptic pattern was seen in several nuclei ventral or caudal to the
      cerebellum (e.g. the cochlear nucleus, the facial nucleus, the spinal cord) but
      not in regions rostral to the cerebellum. In the spinal cord, strong labelling
      for both antibodies was seen in the dorsal horn. The GBR1b but not the GBR1a
      antibody stained tanycytes in the epithelium of the 3rd ventricle and in the
      central canal at the brain stem level. DRG neurons were positive for both the
      GBR1a and 1b antibody, but the former stained the cells much more intensely.
      Satellite cells were labelled with the GBR1b antibody. The most important aspect
      of these findings is that in some nuclei, GBR1b may mediate inhibition of
      transmitter release while in the same regions, GBR1a may mediate postsynaptic
      inhibition. Further, the observations support previous findings that GBR1b is the
      predominant splice variant in Purkinje cells.

PMID- 10603090
TI  - The limbic zone of the rabbit and rat claustrum: a study of the claustrocingulate
      connections based on the retrograde axonal transport of fluorescent tracers.
AB  - The claustrum is a subcortical structure lying under the insular and piriform
      cortices, whose function is still not clear. Although data exist on connections
      of the claustrum and the limbic cortex, the topography of the limbic zone in the
      rabbit and rat claustrum has not been studied extensively. The study was
      performed on 17 adult Wistar rats and 12 New Zealand rabbits. Two percent water
      solutions of fluorescent retrograde tracers fast blue and nuclear yellow were
      injected into the various regions of the limbic cortex. The limbic zone is
      localized throughout the whole rostrocaudal extent of the claustrum, mainly in
      its ventromedial portion lying close to the external capsule. Although this zone
      of the claustrum is localized similarly in both rat and rabbit, some differences
      between these two species exist. In the rat, neurons projecting to all limbic
      areas are localized mainly in the anterior and central parts of the claustrum,
      whereas in the rabbit, the majority of the neurons projecting to the cingulate
      cortex are present in the anterior and central parts of this structure, while
      neurons sending axons to the retrosplenial cortex are localized in the central
      and posterior parts. In both species, double-labeling study showed that neurons
      projecting to various limbic regions are intermingled and that neurons sending
      axons into two different limbic regions are seen only occasionally. Our findings
      give support to the role of the claustrum in integrating information between
      different areas of the cerebral cortex and the limbic system.

PMID- 10603091
TI  - Induction of cellular contractions in the human melanoma cell line SK-mel 28
      after muscarinic cholinergic stimulation.
AB  - In a previous immunohistochemical study we observed muscarinic acetylcholine
      receptors in primary and metastatic human melanomas, which were not present in
      normal skin melanocytes. In the present study we demonstrated the endogenous
      expression of muscarinic receptors, of choline acetyltransferase and of
      cholinesterase activity in the human melanoma cell line SK-mel 28. We tested the
      effect of muscarinic agonists on cellular movements of the melanoma cells in a
      perfusion chamber by digital video time-lapse microscopy. Within 3 to 10 min
      after onset of muscarinic perfusion cell body contractions and retraction of cell
      processes of more than 5 micrometer occurred in about 30% of the melanoma cells.
      The effect disappeared after addition of atropine. The proportion of reacting
      cells corresponded to the endogenous expression of muscarinic receptors revealed
      by immunocytochemistry with the monoclonal antibody M35. The experiments indicate
      the presence of an autocrine muscarinic cholinergic system in the melanoma cells
      and demonstrate a direct link between muscarinic receptors and the contractile
      apparatus. Melanocytes are derived from neural crest cells that express
      cholinesterase activity and muscarinic receptors during their migratory phase in
      the embryo. Therefore, re-expression of the muscarinic cholinergic system in
      tumour cells may be involved in invasive growth.

PMID- 10603092
TI  - HNK-1 expression patterns in the embryonic rat heart distinguish between
      sinuatrial tissues and atrial myocardium.
AB  - HNK-1 expression was studied by immunohistochemistry in serial sections of
      embryonic and fetal rat hearts from 11.5 to 16.5 embryonic days. Graphic
      reconstructions were made to obtain detailed 3D information on the localization
      of immunoreactive tissues. The antibody used appeared to stain most parts of the
      venous sinus and the sinuatrial transitional zone as well as the atrioventricular
      transitional zone, but the patterns varied through the different developmental
      stages. At 11.5 days, positive myocardium was found in the right atrium and on
      top of the ventricular septal primordium. At 13.5 days, the left venous valve and
      the posterior atrial wall containing the orifice of the pulmonary vein were
      immunoreactive, and so were the right venous valve, the septum spurium and the
      superior, right-lateral and inferior parts of the atrioventricular canal. From
      the latter, immunoreactivity continued onto the crest of the ventricular septum.
      At 15.5 days, HNK-1 positivity in the two venous valves had become continuous,
      whereas the right-lateral part of the atrioventricular canal had lost its
      positivity, thus making the positive areas in the superior and inferior parts of
      this canal discontinuous. From the venous valves immunoreaction continued into
      the venous sinus septum but this area remained discontinuous with the inferior
      part of the atrioventricular canal. It is concluded that the entirety of venous
      sinus and sinuatrial transitional zone expresses the HNK-1 antigen and that the
      orifice of the pulmonary vein belongs to this complex, rather than to the
      embryonic atrium proper, which is HNK-1 negative. Extrapolation of these data to
      the adult human atrium leads to the conclusion hat most "atrial septal
      structures" are of sinuatrial origin, leaving the flap valve of the oval fossa
      (atrial septum primum) as the only really atrial structure. It is suggested that
      the atrioventricular node is derived from the inferior portion of the
      atrioventricular canal, and that two expansions of sinuatrial tissue form the
      substrate for anterior and posterior atrionodal inputs which in the literature
      have been described as internodal tracts.

PMID- 10603093
TI  - Ultrastructure of the normal adult human female prostate gland (Skene's gland).
AB  - The predominant cells of female prostatic glands lining their lumen were found to
      be tall cylindrical secretory cells with short stubby microvilli, protuberances
      of the apical cytoplasm, and with bleb formation. Abundant secretory vacuoles and
      granules, rough endoplasmic reticulum, developed Golgi complexes and numerous
      mitochondria are characteristic of their active secretory configuration with
      apocrine (apical blebs) and merocrine (secretory vacuoles and granules) type of
      secretion. Basal (reserve) cells were seen to be located between the secretory
      (luminal) cells and the basement membrane. Their ground cytoplasm is dense with
      rough endoplasmic reticulum and mitochondria. Their nuclei, unlike those of
      secretory cells, possess more peripheral condensed chromatin, denser dispersed
      chromatin and sporadic nucleoli. Besides the two basic types of mature prostatic
      cells intermediary cells were also seen, located between the basal and secretory
      cells or in their close vicinity. Their cytoplasm exhibits numerous profiles of
      rough endoplasmic reticulum and free ribosomes. Secretory vacuoles and granules
      were mostly practically absent (type 1 intermediary cells) so that they resembled
      basal (reserve) cells. In some of them, however, as in secretory cells, such
      secretory elements do gradually appear (type 2 intermediary cells). The finding
      of intermediary cells in the lining of prostatic glands supports the role of
      basal (reserve) cells in the renewal of cells in glands of the female prostate.
      The first ultrastructural analysis of the normal female prostate performed by
      transmission electron microscopy showed that, as in the postpubertal male, the
      prostatic glands in the adult female display mature secretory and basal cells.
      The results of the presented study further corroborate the contemporary concept
      of the female prostate as a functional genitourinary organ.

PMID- 10603094
TI  - Localization of motoneurons innervating the extraocular muscles in the chameleon
      (Chamaeleo chameleon).
AB  - The topography and localization of motoneurons innervating the six extraocular
      muscles in the chameleon (Chamaeleo chameleon) was studied following HRP
      injection in each of these individual muscles. Four muscles were innervated
      ipsilaterally: medial rectus, inferior rectus, inferior oblique and lateral
      rectus. The medial rectus muscle was innervated by the dorsomedial part of the
      oculomotor nucleus. The innervation to the inferior rectus muscle arose from the
      lateral part of the intermediate oculomotor subnucleus, which extended to the
      lateral part of the dorsal subdivision. The lateral rectus muscle was innervated
      by the abducens nucleus, which was composed by two subgroups of labeled cells,
      respectively observed in the principal and accessory abducens subnuclei, whereas
      efferents to the inferior oblique muscle originated from both the ventral and
      intermediate oculomotor subnuclei. The contralateral pattern consisted of
      motoneurons innervating the superior rectus and the superior oblique that were
      located respectively in the caudal portion of the ventral oculomotor nucleus and
      in the trochlear nucleus. These results confirmed data reported in most
      vertebrate species, and were discussed from a comparative and functional point of
      view.

PMID- 10603096
TI  - Preface

PMID- 10603095
TI  - Organisation of the amygdalo-thalamic pathways in rats.
AB  - This study examines the organisation of the pathways from the amygdala to the
      thalamus. Amygdaloid nuclei (medial, central, basolateral and olfactory groups)
      of Sprague-Dawley rats were injected with biotinylated dextran using stereotaxic
      coordinates and their brains were then aldehyde-fixed and processed using
      standard methods. We have three major findings. First, the amygdala has a
      distinct set of projections to particular nuclei of the thalamus. The thalamic
      nuclei with the heaviest amygdaloid terminations include the zona incerta, the
      mediodorsal and the midline nuclei. Second, nuclei of different amygdaloid groups
      project to the thalamus in slightly different patterns. For example, some groups
      of nuclei project to the thalamic reticular nucleus (e.g. medial, olfactory)
      whilst others do not (e.g. central, basolateral). Thus, there is a certain amount
      of heterogeneity within the amygdaloid projections to the thalamus. Third, when
      we compare our results on the amygdalo-thalamic pathways to the many previous
      descriptions of the thalamo-amygdaloid pathways, we note that they are largely
      out of register. In other words, some of the thalamic nuclei that project to a
      given group of amygdaloid nuclei do not necessarily receive a projection back
      from that same amygdaloid nucleus. Hence, there is no substrate for a strong feed
      back relationship between the thalamus and the amygdala, as there has been shown
      for other centres of the brain (e.g. between the thalamus and neocortex).

PMID- 10603097
TI  - Liver transplantation in children: long-term outcome and quality of life.
AB  - Liver transplantation has become a standard therapy in acute and chronic liver
      failure. Since 1968, 2554 paediatric patients receiving a liver transplant have
      been registered in the European Liver Transplant Registry (ELTR). Compared with
      22,600 total transplants registered in the ELTR over the same period of time this
      means that about 10% of all liver transplants performed in Europe concern
      paediatric recipients, aged from 0 to 15 years. The indications in the paediatric
      population differ significantly from those of adult patients: More than 50% of
      patients suffer from cholestatic disorders, followed by hepatic based metabolic
      disorders, acute liver failure, non-cholestatic cirrhosis and liver tumours. The
      results of liver transplantation in paediatric patients have improved remarkably
      since the early 1980s. In 1997 a survival rate of 80% is almost the international
      standard. This improvement is due to the use of better immunosuppressive agents
      such as cyclosporin A and tacrolimus, followed by improvement in surgical
      techniques and finally by improvement in intensive care, better diagnostic tools
      for viral, bacterial and fungal infections and corresponding appropriate
      therapies. Quality of life as a measure of transplant results has not been
      sufficiently studied. The majority of paediatric liver transplant recipients has
      a good quality of life; only 10% suffer from significant morbidity. The impact of
      pretransplant damage to other organs such as brain, kidneys, bone and lungs and
      the influence of immunosuppression on somatic growth, neurological development,
      infection and metabolic balance are subjects of increasing concern. CONCLUSION:
      The results available today show convincing evidence that liver transplantation
      is a therapeutic option in otherwise fatal hepatic disorders. Much effort,
      however, has to be made in order to achieve further improvements by increasing
      our knowledge of the pathophysiology of both pre- and posttransplant conditions.

PMID- 10603098
TI  - Liver transplantation for glycogen storage disease types I, III, and IV.
AB  - Glycogen storage disease (GSD) types I, III, and IV can be associated with severe
      liver disease. The possible development of hepatocellular carcinoma and/or
      hepatic failure make these GSDs potential candidates for liver transplantation.
      Early diagnosis and initiation of effective dietary therapy have dramatically
      improved the outcome of GSD type I by reducing the incidence of liver adenoma and
      renal insufficiency. Nine type I and 3 type III patients have received liver
      transplants because of poor metabolic control, multiple liver adenomas, or
      progressive liver failure. Metabolic abnormalities were corrected in all GSD type
      I and type III patients, while catch-up growth was reported only in two patients.
      Whether liver transplantation results in reversal and/or prevention of renal
      disease remains unclear. Neutropenia persisted in both GSDIb patients post liver
      transplantation necessitating continuous granulocyte colony stimulating factor
      treatment. Thirteen GSD type IV patients were liver transplanted because of
      progressive liver cirrhosis and failure. All but one patient have not had
      neuromuscular or cardiac complications during follow-up periods for as long as 13
      years. Four have died within a week and 5 years after transplantation. Caution
      should be taken in selecting GSD type IV candidates for liver transplantation
      because of the variable phenotype, which may include life-limiting extrahepatic
      manifestations. It remains to be evaluated, whether a genotype-phenotype
      correlation exists for GSD type IV, which may aid in the decision making.
      CONCLUSION: Liver transplantation should be considered for patients with glycogen
      storage disease who have developed liver malignancy or hepatic failure, and for
      type IV patients with the classical and progressive hepatic form.

PMID- 10603099
TI  - Indications and outcome of liver transplantation in tyrosinaemia type 1.
AB  - A retrospective analysis was performed on 17 patients presenting with
      tyrosinaemia type 1 (TT1) between 1989-1997; 7 pre 1992 prior to the introduction
      of 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC) therapy and
      10 post 1992. During this time, eight children (5 males) underwent orthotopic
      liver transplantation (OLT); six prior to the introduction of NTBC in 1992 and
      two on NTBC therapy. The primary indications for OLT pre-1992 were risk of
      hepatocellular carcinoma with evidence of hepatic dysplasia in all, associated
      with liver failure in two, and rise in alpha-fetoprotein (AFP) in four. Two of
      the ten treated with NTBC required OLT. The indications were non-response to NTBC
      in one child and development of hepatic dysplasia associated with poor quality of
      life in the second patient. Median age for OLT was 64 months (range 5-127 months)
      with a median weight of 24 kg (range 6-25 kg). The histology of hepatectomy
      specimens at transplantation showed: cirrhosis in 8, hepatic dysplasia in 6 and
      hepatocellular carcinoma in 1. Plasma tyrosine and AFP returned to normal in all
      cases. Urinary succinylacetone reduced but persisted in small amounts (median 7.7
      micromol/mmol creatinine). Hypertrophic cardiomyopathy resolved in 3/3 patients.
      Hypoglycaemia, not responding to dietary therapy or NTBC treatment, resolved post
      transplant in one patient. There were two deaths, one from primary non-function
      and one from chronic rejection. Late complications in survivors (n=6) include
      post-transplant lymphoproliferative disease of the iris in one child which
      resolved and renal dysfunction with a fall in glomerular filtration rate in three
      (50%). Median follow up post OLT is 6.7 years (range 1-7 years). Quality of life
      post-transplant in survivors is good with unrestricted diet in all. CONCLUSION:
      Liver transplantation is an effective treatment for TT1 with good quality of
      life. The current indications of OLT in TT1 are non-response to NTBC, risk of
      malignancy and poor quality of life related to dietary restriction and frequency
      of blood sampling.

PMID- 10603100
TI  - Liver transplantation in urea cycle disorders.
AB  - We report here our experience in the long-term management of 28 patients with
      citrullinaemia, 13 patients with carbamoyl phosphate synthase deficiency and 15
      patients with argininosuccinic aciduria. In addition, we report a national French
      survey of 119 patients with ornithine transcarbamylase (OTC) deficiency
      enzymatically characterized in our laboratory. We also include in this report
      four personal patients (two with OTC and two with citrullinaemia) who were liver
      transplanted, and one OTC patient from the National French survey. Although this
      retrospective series is not really representative of the modern treatment
      combining low protein diet and arginine, sodium benzoate and sodium
      phenylbutyrate, it is obvious that the long-term outcome of all urea cycle
      disorders remains very guarded. We highlight the severity of the neonatal forms
      of such disorders, and mostly for OTC-deficient males. According to this
      evidence, our policy is not to treat such severely affected patients in the
      neonatal period who die anyway spontaneously within 2 to 3 days. At the present
      time, we only have three patients with neonatal citrullinaemia, aged 1, 6 and 10
      years respectively, who are still doing well. One of them has been successfully
      liver transplanted at 5 years. Another transplanted patient died in the post
      surgical phase. We emphasize the unexpected severity of argininosuccinic aciduria
      in which there is no one patient doing well. This is a rather surprising finding
      as this disorder is easy to manage and rarely presents with recurrent attacks of
      hyperammonaemia when it is treated by arginine supplementation. This
      consideration would suggest to extend the indication of orthotopic liver
      transplantation in this disorder. Finally, the most difficult indication is in
      the late onset symptomatic female OTC group. In this last group, despite a
      significant residual activity due to heterozygote status, even with a variable
      lyonisation, only seven girls are still mentally and neurologically normal.
      Interestingly, three of these seven were liver-transplanted before the
      constitution of irreversible neurological damage. These three girls and their
      family declare their well-being, their feeling to be cured and enjoy their normal
      life.

PMID- 10603101
TI  - Liver transplantation in maple syrup urine disease.
AB  - Maple syrup urine disease (MSUD) is an autosomal recessive disorder. Impaired
      activity of the branched-chain 2-oxoacid dehydrogenase complex (BCOA-DH) causes
      accumulation of branched-chain L-amino (BCAA) and 2-oxoacids (BCOA) which may
      exert neurotoxic effects. Treatment comprises dietary management with strictly
      reduced quantities of protein and BCAA as well as aggressive intervention during
      acute neonatal and subsequent metabolic complications. MSUD is regarded as a
      metabolic disorder with potentially favourable outcome when the patients are kept
      on a carefully supervised long-term therapy. Up to now, three MSUD patients,
      exhibiting the classical form of the disease, have received orthotopic whole
      liver transplantation (OLT). Liver replacement resulted in a clear increase in
      whole body BCOA-DH activity to at least the level of very mild MSUD variants.
      These patients no longer require protein restricted diets and the risk of
      metabolic decompensation during catabolic events is apparently abolished.
      CONCLUSION: Considering the overall expenses, risks, and outcome, however, the
      benefit of OLT, even in the most severe form of MSUD, may not be significantly
      different from that of a classical strict dietary management. Thus, OLT appears
      not to represent a specific option in the treatment in MSUD.

PMID- 10603102
TI  - Liver transplantation in propionic acidaemia.
AB  - Despite the improvement in dietary therapy during the past 20 years, the overall
      outcome of severe forms of propionic acidaemia (PA) remains often disappointing.
      Good results can be obtained at a very high price in terms of medical attention,
      family burden and high cost. In most early onset forms of PA, the intake of
      natural protein must be rigidly restricted to 8-12 g/day for the first 3 years of
      life, and then slowly increased to 15-20 g/day by the age of 6-8 years.
      Supplementation with a precursor-free aminoacid mixture to provide 1.5 g/kg
      protein per day is generally recommended, although remains controversial. From
      the age of 1 year onward, these children are often severely anorectic and most of
      the diet must be delivered by nocturnal gastric drip feeding or gastrostomy.
      Metronidazole is very effective in reducing the excretion of propionate
      metabolites derived from the gut. L-carnitine (50 to 100 mg/kg) is systematically
      given to promote propionylcarnitine synthesis and excretion. We report here a
      retrospective study of 33 patients with PA diagnosed during the last 20 years in
      our hospital. Of them, 2 have been liver transplanted. In these two patients who
      presented frequent severe and unexpected metabolic decompensations despite good
      compliance with the dietary therapy, orthotopic liver transplantation (OLT) was
      done at 7 and 9 years respectively. One child died 15 months after
      transplantation due to a severe lymphoproliferative disorder; the other child now
      aged 13.5 years is doing well. Despite a persistent methylcitrate excretion, she
      is under normal moderate daily protein intake (40-50 g/day) and still on
      carnitine supplementation. Interestingly, another patient who filled the criteria
      for OLT (very frequent and severe decompensations leading to frequent admissions
      to the intensive care unit despite excellent dietary management) was also placed
      on the list for OLT. From the time he was registered onward, he experienced no
      further episodes of metabolic decompensation, there was almost no interruption in
      his daily intake and he gained height and weight and developed well. He was
      finally removed from the list and is still doing very well 2 years thereafter.
      Correction of propionylCoA carboxylase deficiency restricted to hepatic tissues
      seems to induce a change towards clinical normalisation and a milder biochemical
      phenotype. Liver transplanted PA patients still require slight protein
      restriction and carnitine treatment. We consider that at the moment OLT should
      only be performed in severe forms of PA, mostly characterised by frequent and
      unexpected episodes of metabolic decompensation despite good dietary therapy.
      However, a strict appreciation of these criteria is difficult. A more generalised
      indication for OLT in PA will require more information about the long-term
      outcome of transplanted patients. We should also await other alternatives like
      auxiliary partial OLT from living donors or transplantation of isolated allogenic
      hepatocytes, genetically modified or not.

PMID- 10603103
TI  - Liver transplantation for methylmalonic acidaemia.
AB  - The outcome for children with severe forms of methylmalonic acidaemia remains
      poor. Patients have recurrent episodes of metabolic decompensation; many have
      neurodevelopmental complications and the mortality is high. Long-term survivors
      develop chronic renal failure. Because of the poor prognosis, transplantation has
      been considered. In young patients with early onset disease, liver
      transplantation might prevent complications and, for those in end-stage renal
      failure, kidney transplantation could be combined with that of the liver. The
      results of liver transplantation in the early onset patients have generally been
      disappointing. In particular there appears to be a high risk of neurological
      complications. The optimal management of those in end-stage renal failure has not
      yet been determined although combined liver and kidney transplantation has been
      successful. CONCLUSION: The role of transplantation in methylmalonic acidaemia
      has yet to be established and follow up of all patients who are considered for
      transplantation is essential.

PMID- 10603104
TI  - Combined liver-kidney transplantation in primary hyperoxaluria type 1.
AB  - Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder
      characterised by an increased urinary excretion of calcium oxalate, leading to
      recurrent urolithiasis, nephrocalcinosis and accumulation of insoluble oxalate
      throughout the body (oxalosis) when the glomerular filtration rate falls to below
      40-20 mL/min per 1.73 m(2). The disease is due to a functional defect of the
      liver-specific peroxisomal enzyme alanine: glyoxylate aminotransferase (AGT), the
      gene of which is located on chromosome 2q37.3. The diagnosis is based on
      increased urinary oxalate and glycollate, increased plasma oxalate and AGT
      measurement in a liver biopsy. AGT mistargeting may be investigated by immuno
      electron microscopy and DNA analysis. End-stage renal failure is reached by the
      age of 15 years in 50% of PH1 patients and the overall death rate approximates
      30%. The conservative treatment includes high fluid intake, pyridoxine and
      crystallisation inhibitors. Since the kidney is the main target of the disease,
      isolated kidney transplantation (Tx) has been proposed in association with
      vigorous peri-operative haemodialysis in an attempt to clear plasma oxalate at
      the time of Tx. However, because of a 100% recurrence rate, the average 3-year
      graft survival is 15%-25% in Europe, with a 5-10-year patient survival rate
      ranging from 10% to 50%. Since the liver is the only organ responsible for the
      detoxification of glyoxylate by AGT, deficient host liver removal is the first
      rationale for enzyme replacement therapy. Subsequent orthotopic liver Tx aims to
      supply the missing enzyme in its normal cellular and subcellular location and
      thus can be regarded as a form of gene therapy. Because of the usual spectrum of
      the disease, isolated liver Tx is limited to selected patients prior to having
      reached an advanced stage of chronic renal failure. Combined liver-kidney Tx has
      therefore become a conventional treatment for most PH1 patients: according to the
      European experience, patient survival approximates 80% at 5 years and 70% at 10
      years. In addition, the renal function of survivors remains stable over time,
      between 40 and 60 mL/min per 1.73 m(2) after 5 to 10 years. In addition, liver Tx
      may allow the reversal of systemic storage disease (i.e. bone, heart, vessels,
      nerves) and provide valuable quality of life. Whatever the transplant strategy,
      the outcome is improved when patients are transplanted early in order to limit
      systemic oxalosis. According to the European experience, it appears that combined
      liver-kidney Tx is performed in PH1 patients with encouraging results, renal Tx
      alone has little role in the treatment of this disease, and liver Tx reverses the
      underlying metabolic defect and its clinical consequences.

PMID- 10603105
TI  - Liver transplantation in mitochondrial respiratory chain disorders.
AB  - Mitochondrial respiratory chain disease may lead to neonatal or late onset liver
      failure, requiring liver transplantation. In rare cases, the disease is
      restricted to the liver and the patient is cured after surgery. More frequently,
      other organs are simultaneously involved and neuromuscular or other extra-hepatic
      symptoms may pre-exist, or appear in the post-transplant follow up. Pre
      transplant evaluation should aim to rule out neurological disease, which may be
      difficult to differentiate from signs accompanying liver insufficiency.
      Cerebrospinal fluid lactic acid levels, compared to blood lactate, may be
      suggestive of central nervous system involvement. Of 11 cases with respiratory
      chain disorders who had liver transplantation in various centres, 4 are alive and
      well on follow up, and 6 died, three of them having developed neurological
      disease post orthotopic liver transplantation. All three patients with initial
      liver and gastro-intestinal disease died early after transplantation, indicating
      that these may be poor candidates for this procedure. CONCLUSION: Liver
      transplantation is feasible in hepatic respiratory chain disorders, but extra
      hepatic disease should be ruled out before transplantation. Extra-hepatic
      manifestations may, however, appear and cause patient death despite successful
      transplantation.

PMID- 10603106
TI  - Liver transplantation in alpha(1)-antitrypsin deficiency.
AB  - Only a minority of infants born with alpha(1)-antitrypsin deficiency will develop
      serious liver disease during childhood, mostly but not always after neonatal
      cholestasis. Early prognosis is difficult and all children have to be followed up
      carefully. The liver disease progresses with varying speed and it lacks specific
      features. At the time of liver transplantation the young patients have no
      pulmonary disease induced by the deficiency and in those with renal involvement,
      the kidney problems can mostly be dealt with by conservative therapy. The peri-
      and postoperative care of the patients who undergo liver transplantation does not
      differ from the usual routines.

PMID- 10603107
TI  - Diagnosis and management of Crigler-Najjar syndrome.
AB  - Crigler-Najjar syndrome (CNS) results from a mutation in one of the five exons of
      the gene coding for the enzyme bilirubin-UDP-glucuronosyltransferase by exon 1*1
      and exons 2-5 of the UDP-glucuronosyltransferase 1 locus, the bilirubin
      glucuronidating isoform of UDP-glucuronosyltransferase. CNS type 2 is caused by a
      single base pair mutation leading to a decreased but not totally absent enzyme
      activity. In these patients the enzyme remains responsive to phenobarbital
      induction therapy and their bile contains low amounts of bilirubin mono- and
      diglucuronides. In CNS type 1 the enzyme activity is completely absent. CNS type
      1 patients do not respond to phenobarbital and their bile does not contain more
      than traces of bilirubin conjugates. In 1997 we reported a World Registry on the
      treatment of patients with CNS type 1. Data were collected on 57 patients, of
      whom 21 (37%) had been transplanted at the time of data collection. Some 15
      patients (26%) had brain damage, in 7 of whom the brain damage was mild and they
      received a liver transplant. Patients with brain damage at transplantation were
      significantly older than those without brain damage (14.3 vs 5.9 years). Before
      transplantation the serum bilirubin level of CNS type 1 patients should be kept
      below 350 micromol/l with daily phototherapy. Oral calcium supplementation makes
      phototherapy more efficient. Gene therapy has been performed successfully in the
      Gunn rat, an animal model for this disease. Liver cell transplantation has
      recently been done in a child with CNS type 1.

PMID- 10603108
TI  - Liver transplantation in metabolic disorders: summary of the general discussion.

PMID- 10603109
TI  - Post graft development of short children treated with growth hormone before
      kidney graft.
AB  - Sixteen prepubertal patients with chronic renal failure (CRF) were given daily
      recombinant human growth hormone (rhGH) treatment (1.2 IU/kg per week) for 2.6+/
      1.6 years until kidney transplant. Therapy was then discontinued and the patients
      followed for a further 3. 5+/-1.4 years. During treatment, mean height increased
      from -3.0+/-0. 9 standard deviation score (SDS) to -1.9+/-1.4 SDS (P<0.001) at
      the time of transplantation, corresponding to a mean height gain of +1. 2+/-0.9
      SDS. After discontinuation of rhGH therapy, prepubertal children continued a
      partial catch-up growth with a height gain of +0.5+/-0.8 SDS for the follow-up
      period. Conversely, negative changes of height were observed in pubertal
      transplanted children: -0.5+/-0.4 SDS in patients grafted at early stages of
      puberty (P2-P3) and -0.15+/-0.9 SDS in patients grafted at late stages of puberty
      (P4-P5). These data confirmed the benefit of rhGH therapy in CRF patients.
      Nevertheless, only early initiation of rhGH treatment led some of these patients
      to their target height at transplantation, thus preserving their potential
      growth. Reinitiation of rhGH therapy after transplantation should be considered
      in order to complete catch-up growth to target height in prepubertal children.

PMID- 10603110
TI  - Renal transplantation in children under 5 years of age.
AB  - Between March 1987 and December 1997, 59 renal transplants [49 cadaveric, 10 live
      related (LRD)], were performed in 54 children aged 5 years and younger. Six
      children required a second transplant. The median (range) age of the recipients
      was 2.9 (1.4-5.0) years; mean weight was 12.6 kg (7.4-23) and donor age 11 (2-50)
      years. Immunosuppression was cyclosporin or FK506, prednisolone, and
      azathioprine. Antithymocyte globulin was given as induction therapy for second
      transplants. Patient survival was 98.3%; 1 patient died from upper
      gastrointestinal haemorrhage. Graft survival was 67.7% at 1 year, 57.4% at 5
      years, and 45.2% at 10 years. No LRD graft was lost during 7 years of follow-up.
      Thrombosis was the main cause of graft loss (10 cases) followed by vascular
      rejection (2 cases). There was no significant difference in graft survival
      between recipients aged less than 2, 2-3, and 3-5 years. The height standard
      deviation score (+/-SD) improved from -2.1+/-1.3 at transplantation to -1.0+/-1.3
      at 1 year, -1.1+/-1.5 at 5 years, and to -0.14+/-1.1 at 10 years.

PMID- 10603111
TI  - Serial estimation of glomerular filtration rate in children after renal
      transplant.
AB  - Evaluation of serial monthly estimated glomerular filtration rate (eGFR) may be
      useful for studying pediatric renal allograft outcome. To determine the validity
      of this approach, we reviewed our single-center experience in pediatric renal
      transplant recipients to determine the effect of risk factors for renal allograft
      failure on eGFR. Clinical parameters recorded monthly through 5 years post
      transplant allowed serial assessment of eGFR. Monthly clinical data included
      height, weight, serum creatinine, cumulative number of acute rejection episodes,
      cyclosporine dose, and cyclosporine trough levels. From these data, eGFR was
      calculated monthly for each patient using the Schwartz formula. Time post
      transplant was grouped in 6-month intervals and plotted against mean eGFR to
      compare eGFR in patients grouped by demographic and clinical factors; 1,786
      monthly data sets from 6 months post transplant (n=76 patients) to 5 years post
      transplant (n=25 patients) were analyzed. Overall mean eGFR from 6 months to 1
      year was 75 ml/min per 1.73 m(2) and from 4. 5 to 5 years 46 ml/min per 1.73
      m(2). eGFR was lower at all time intervals for recipients of cadaver versus
      living-related donor grafts, and patients with >/=1 versus 0 acute rejections
      (P<0.01). After 1 year, eGFR was lower in black patients compared with white or
      Hispanic patients (P<0.01). Cyclosporine dose greater than 5 mg/kg per day was
      associated with better early and worse late graft function. These results are
      similar to those reported in multi-center studies using the outcome variable of
      graft failure and suggest that serial eGFR may be valid as an outcome variable to
      study chronic renal allograft dysfunction in children.

PMID- 10603112
TI  - A limited sampling strategy for the estimation of Neoral AUCs in pediatric
      patients.
AB  - The improved pharmacokinetics of Neoral allows the development of an accurate
      estimate of the full area under the concentration time curve (AUC) from a limited
      sampling strategy. As no such strategy has been derived from pharmacokinetic data
      obtained from children on 12-hourly dosing, and as patient convenience demands
      shorter sampling times, we derived a limited sampling strategy from 45 AUCs
      obtained from 19 pediatric renal transplant patients by stepwise forward multiple
      regression, and prospectively tested them on a separate group of 49 AUCs obtained
      from 18 pediatric renal transplant patients. Full cyclosporine (CsA) AUCs were
      obtained from samples drawn pre dose (C0) and at 2, 4, 6, 8 and 12 h post dose
      (C2, C4, C6, C8, and C12). High-precision predictions of full AUC were obtained
      based on the formula: AUC = 444 + 3.69 x C0 + 1.77 x C2 + 4. 1 x C4 (mean
      prediction error +/- SD = 0.3 +/- 6.4%, 95% confidence interval=-1.7% to 1.9%.)
      In conclusion, CsA exposure in pediatric renal transplant patients on 12-hourly
      Neoral dosing can be reliably predicted by an early time point-based limited
      sampling strategy in children. This formula has the advantage of obtaining trough
      as well as AUC from one brief, convenient sampling period.

PMID- 10603113
TI  - Posttransplant lymphoproliferative disorder in pediatric renal transplantation.
AB  - Of 84 renal transplants performed in our center since 1986, six recipients (7.1%)
      developed posttransplant lymphoproliferative disorder (PTLD). All received
      quadruple immunosuppression with Minnesota anti-lymphoblastic globulin or anti
      thymocyte globulin, methylprednisolone, cyclosporine, and azathioprine or
      mycophenolate mofetil. Five were seronegative for Epstein-Barr virus (EBV) when
      they received their renal transplant. All patients received prophylactic
      acyclovir treatment postrenal transplant and none developed a cytomegalovirus
      (CMV) infection. All patients were positive for EBV by serology and polymerase
      chain reaction at the time of diagnosis of PTLD. Clinical features at
      presentation included fever (6/6), adenopathy (4/6), hypertrophied adenoids
      (4/6), liver involvement (2/6), and allograft involvement (2/6), 2-78 months
      (4/6<6 months) postrenal transplant. Histopathology of PTLD tissue revealed T
      cell rich/ Hodgkin disease-like B cell PTLD in one patient, polymorphic PTLD in
      four, and monomorphic (large B cell lymphoma) PTLD in one. Immunophenotyping of
      the PTLD biopsy specimen revealed predominant T cells in three, mixed B and T
      cells in two patients, and B cell in one. No aneuploid populations were
      identified by flow cytometric DNA ploidy assay. DNA from the PTLD tissue revealed
      weak to moderate IgH gene rearrangement in four of six patients but no T cell
      receptor beta-chain or c-myc gene rearrangement on Southern blot analysis. The
      child with monomorphic (large B cell lymphoma) PTLD was clonal with lambda light
      chain restriction on immunophenotyping. Treatment consisted of reduced
      immunosuppression and ganciclovir/ acyclovir in all patients. CMV hyperimmune
      globulin was used as an adjunctive therapy in two patients. Chemotherapy was
      needed in only one patient. A single rejection episode occurred in two children
      following reduction in immunosuppression, which reversed following intravenous
      methylprednisolone therapy. PTLD resolved in all patients and at present all
      patients are alive with functional grafts 2-54 months post diagnosis. Our
      experience suggests that reduced immunosuppression and anti-viral treatment is
      adequate in most cases of PTLD, but chemotherapy and hyperimmune globulin therapy
      may be beneficial in cases resistant to first-line therapy. Since all but one of
      our patients were EBV seronegative at the time of transplant, vigilance is
      especially important for early detection of PTLD in this group of the pediatric
      renal transplant population.

PMID- 10603114
TI  - Possible association of retinoic acid with bone marrow transplant nephropathy.
AB  - Bone marrow transplant (BMT) nephropathy is characterized by the acute onset of
      nephritis more than 100 days after BMT. The renal lesion in BMT nephropathy is
      similar to radiation nephritis, but BMT nephropathy occurs earlier and with lower
      radiation doses than radiation nephritis. The combined effects of
      chemotherapeutic agents and nephrotoxic drugs given before and after BMT appear
      to sensitize or unmask radiation nephritis. Reporting of drugs that may
      contribute to BMT nephropathy is critical for the development of optimal
      treatment regimens. Herein, we report two cases of BMT nephropathy that developed
      coincident with retinoic acid therapy. Both patients received autologous BMT for
      neuroblastoma after preparative therapy with total body
      irradiation/melphalan/carboplatin/etoposide. They were randomized to receive cis
      retinoic acid as part of a clinical trial. Both patients developed acute
      nephritis during their second 2-week course of retinoic acid on post-BMT days 105
      and day 139. The nephritis was associated with hypertension, anemia,
      thrombocytopenia, azotemia, hematuria, and proteinuria. Clinical features,
      laboratory evaluation, and renal biopsy indicated that these two patients
      developed radiation-induced BMT nephropathy. The fact that both patients
      developed nephritis concurrent with retinoic acid therapy raises a concern that
      retinoic acid may have unmasked radiation injury and triggered BMT nephropathy.

PMID- 10603115
TI  - Neurodevelopmental outcome of children initiating peritoneal dialysis in early
      infancy.
AB  - A retrospective review of 34 infants who started long-term peritoneal dialysis at
      </=3 months of age was conducted. Six of the patients died during infancy,
      leaving 28 infants who survived >1 year and who underwent a formal
      neurodevelopmental evaluation. In addition to dialysis, treatment of the patients
      included the use of calcium carbonate as the sole phosphate binder in all
      patients and supplemental nasogastric tube feeding in 27. At 1 year of age, the
      28 patients had a mean head circumference standard deviation score of -0.96+/
      1.2. The mental developmental score of 22 (79%) patients fell in the average
      range, while only 1 (4%) child was significantly delayed. Of 19 children retested
      at >/=4 years of age, 15 (79%) performed in the average range and 1 (5%)
      performed in the impaired range. Of 16 patients >/=5 years of age, 15 (94%)
      attended school full time and in age-appropriate classrooms. Twenty-four patients
      received their initial kidney transplant at a mean age of 2.1+/-0.8 years. This
      experience provides evidence that the combination of aggressive nutrition, the
      elimination of aluminum as a phosphate binder, the provision of dialysis, and
      subsequent transplantation all contribute to a favorable developmental outcome in
      infants who develop end-stage renal disease in early infancy.

PMID- 10603116
TI  - Factors related to psychosocial adjustment in children with end-stage renal
      failure.
AB  - Psychological functioning and adjustment to dialysis were assessed in the
      families of 60 children and adolescents undergoing chronic dialysis.
      Sociodemographic factors, treatment variables, health status and satisfaction
      with health care provision were also measured. Correlation analyses identified a
      number of important factors associated with poor adjustment to dialysis and/or
      anxiety and depression in children and parents. Particularly at risk are parents
      in lower socioeconomic status households, parents with large families, parents
      with limited support and parents of young children. Children were more at risk
      where there was greater functional impairment caused by illness.

PMID- 10603117
TI  - Penicillium peritonitis in an adolescent receiving chronic peritoneal dialysis.
AB  - A 19-year-old female on chronic peritoneal dialysis developed acute peritonitis;
      multiple peritoneal fluid and catheter tip cultures yielded Penicillium species.
      She promptly responded to catheter removal and intravenous amphotericin B,
      followed by oral fluconazole, without further recurrences 1 year later. This is
      the first reported case of Penicillium peritonitis in the pediatric population.
      We review the microbiology and clinical spectrum of this disease, as well as the
      few previous reported cases in adults.

PMID- 10603118
TI  - Treatment of vancomycin overdose using high-efficiency dialysis membranes.
AB  - Two children underwent acute hemodialysis using high-efficiency dialysis
      membranes for vancomycin intoxication (plasma levels 238 microg/ml and 182
      microg/ml). During a 3-h treatment, plasma vancomycin removal was on average 60%,
      with a calculated vancomycin half-life (t(1/2)) of 2 h. This is in contrast to a
      recent report using charcoal hemoperfusion for vancomycin intoxication (plasma
      level of 137 microg/ml), which resulted in a 40% relative plasma clearance and a
      calculated vancomycin t(1/2) of 12.5 h for a 4-h treatment. The choice of optimal
      modality for clearing a toxin should take into account the availability of
      equipment, protein or lipid binding of the toxin, and inherent risks of charcoal
      hemofiltration (large extracorporeal circuit, reversible hypocalcemia, heat loss,
      reversible coagulation defects) versus risks of high-efficiency hemodialysis
      (large extracorporeal circuit).

PMID- 10603119
TI  - Repeat charcoal hemoperfusion treatments in life threatening carbamazepine
      overdose.
AB  - A 16-month-old female experienced a massive carbamazepine ingestion resulting in
      a peak serum carbamazepine concentration of 55 microg/ml. Clinical manifestations
      included generalized seizures, coma, shock, and gastrointestinal hypomotility.
      Gut decontamination was attempted using multiple-dose activated charcoal and
      cathartics. Because of the severity of illness, charcoal hemoperfusion was
      initiated. The patient underwent three sessions of charcoal hemoperfusion, each
      utilizing a fresh cartridge, with one session immediately following the other.
      Serum carbamazepine and carbamazepine-10,11-epoxide concentrations decreased from
      54 microg/ml to 23 microg/ml, and 30 microg/ml to 17 microg/ml, respectively,
      during charcoal hemoperfusion. There were no complications. The patient recovered
      completely and was discharged on the 4th hospital day. Charcoal hemoperfusion
      should be considered for life-threatening carbamazepine intoxication, especially
      when drug-induced gastrointestinal hypomotility prevents elimination via the gut.

PMID- 10603120
TI  - Coexistence of thin membrane and alport nephropathies in families with
      haematuria.
AB  - The finding of familial haematuria without a history of deafness or renal
      impairment is often assumed to indicate a benign prognosis. However, we describe
      three families in whom Alport and thin basement membrane nephropathy were
      separately identified within the same pedigree. Our findings illustrate the
      importance of fully investigating families with haematuria, even if thin basement
      nephropathy has been diagnosed in one member.

PMID- 10603121
TI  - End-stage renal disease in two pediatric patients with Fechtner syndrome.
AB  - Fechtner syndrome, a disease in the spectrum of the hereditary nephridites, is a
      macrothrombocytopenia associated with sensorineural hearing loss, cataracts,
      nephritis, and characteristic leukocyte inclusions. Renal biopsy findings are
      consistent with those of Alport syndrome, and the associated renal disease is
      said to be unusual before mid to late adulthood. Here, we review the available
      literature on this disease and report two African-American pediatric patients
      with Fechtner syndrome who rapidly progressed to end-stage renal disease during
      adolescence. We conclude that chronic renal failure can occur at a young age in
      patients with Fechtner syndrome, with a possible relation to race/ethnicity.
      Fechtner syndrome, or other variants of Alport syndrome, need to be considered in
      patients presenting with proteinuria and thrombocytopenia.

PMID- 10603122
TI  - Renal vascular abnormalities in Bardet-Biedl syndrome.
AB  - Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder. Specific
      diagnostic criteria for BBS have now been defined. At least four of the five
      cardinal signs of mental retardation, obesity, hypogenitalism in men, distal limb
      anomalies, and progressive tapetoretinal degeneration of the retina are required
      for the diagnosis. Renal involvement has been described as a sixth cardinal
      feature. Chronic renal failure occurs in 30%-60% of patients. Hypertension has
      been noted in 50%-66% of cases. Renal abnormalities reflect a defect in
      maturation of the kidneys. We present a patient with BBS who had bilateral
      microaneurysms and occlusions in renal arterioles.

PMID- 10603123
TI  - Nephrotic syndrome and end-stage renal disease with WT1 mutation detected at 3
      years.
AB  - We report a boy who presented at 3 years with nephrotic syndrome and end-stage
      renal failure. Although histopathological findings showed end-stage kidney,
      isolated diffuse mesangial sclerosis (IDMS) was suspected because of his clinical
      course, and was confirmed by the presence of WT1 (Wilms tumor suppressor gene)
      mutation. He did not have ambiguous genitalia or Wilms tumor. The karyotype was
      46:XY. A constitutional mutation in exon 7 (953G-->A, 312Arg-->Gin) was detected.
      A few cases of male IDMS, associated with WT1 mutations, have been reported. We
      believe that investigation for the WT1 mutation should be performed not only in
      Denys-Drash syndrome and IDMS, but also in end-stage renal disease with
      unexplained nephrotic syndrome of early onset. WT1 mutation-associated nephrotic
      syndrome has an increased risk of Wilms tumor. Careful ultrasound evaluations or
      bilateral nephrectomies are indicated.

PMID- 10603124
TI  - Developmental stage-specific involvement of angiotensin in murine nephrogenesis.
AB  - Angiotensinogen-deleted mice (Agt-KO) show phenotypes of hypotension and renal
      atrophy. To investigate whether an alternative pathway other than angiotensin II
      (AII), i.e., processed angiotensin fragments, may play a biological role in
      nephrogenesis, we analyzed a congenic line of Agt-KO fetuses and neonates derived
      from two sources: one (Agt-KO/He) from mating with heterozygous angiotensinogen
      deleted mice and the other (Agt-KO/Ho) from mating homozygous angiotensinogen
      deleted mice. Although Agt-KO/He did not show a typical phenotype at birth, these
      mice showed papillary atrophy 2 weeks later and thereafter, a marked increase in
      renal size, i.e., pelvic dilatation. In contrast, Agt-KO/Ho showed renal
      abnormalities at birth and subsequently died. TUNEL staining and electron
      microscopy revealed that accelerated papillary apoptosis was present at birth in
      Agt-KO/Ho and caused abnormal papillary development; however, apoptosis was not
      detected in Agt-KO/He, suggesting that different mechanisms for the abnormal
      renal development exist in Agt-KO/He and Agt-KO/Ho. Two-week administration of an
      angiotensin fragment (3-8), angiotensin IV (AIV), to Agt-KO/He markedly
      attenuated the renal atrophy, decreasing the incidence from 81% to 14%. However,
      administration of AIV to fetal Agt-KO/Ho through the mother did not decrease the
      incidence. This is marked contrast to AII, which prevented renal atrophy in both
      fetal and neonatal periods. It is therefore suggested that AIV is involved in
      nephrogenesis in a developmental stage-specific manner.

PMID- 10603125
TI  - Age-dependent expression of protein phosphatase 2A in the developing rat kidney.
AB  - Several lines of evidence suggest that the serine/threonine protein phosphatase
      (PP)2A is of vital importance for cell cycle regulation, cell differentiation,
      and signal transduction. This prompted us to study the expression of the mRNA for
      PP2A catalytic isoforms alpha and beta in the developing rat kidney using in situ
      hybridization histochemistry. The expression patterns of the two isoforms were
      strikingly similar. Both were ubiquitously expressed in early metanephric
      kidneys. Later in gestation they were expressed in the nephrogenic zone. Strong
      expression was observed on postnatal day (PN) 10. This was followed by a
      downregulation at PN20, i.e., when nephrogenesis is completed. The expression in
      the adult kidney was very weak and mainly confined to the medulla. In a
      phosphatase activity assay, PP2A accounted for 78% of the total serine/threonine
      phosphatase activity in embryonic day 15 rat kidneys. PP1 was the main
      contributor to the remaining activity. In conclusion, PP2A is the major
      serine/threonine phosphatase in fetal kidneys. The age-dependent expression
      pattern supports the concept that this enzyme is of particular importance during
      renal morphogenesis and development.

PMID- 10603126
TI  - Ontogeny of renal sulfate transporters: postnatal mRNA and protein expression.
AB  - Renal reabsorption of inorganic sulfate changes during growth and development. We
      have studied the expression of two proximal tubular sulfate transporters, NaS(i)
      1 and sat-1, during postnatal maturation. Both NaS(i)-1 and sat-1 mRNA levels
      increase postnatally, peaking at day 14, with a maximal tenfold increase in
      NaS(i)-1 and sat-1 mRNA levels compared with day 1. A similar age-dependent
      increase was observed for sodium-dependent and sodium-independent sulfate uptakes
      by injection of rat kidney mRNA into Xenopus oocytes. Western blot analysis of
      renal membranes from rats aged day 1 to day 77 showed no significant changes for
      NaS(i)-1 protein, whereas sat-1 protein levels paralleled mRNA expression,
      increasing from day 1 to day 14, followed by a decrease in protein levels
      thereafter. For NaSi-1 protein expression, translational or posttranslational
      mechanisms may maintain equal numbers of sulfate proteins on proximal tubular
      membranes during maturation, whereas sat-1 protein levels are in close agreement
      with mRNA changes. This is the first study to look at the ontogeny of renal
      sulfate transporter (NaS(i)-1 and sat-1) expression during postnatal maturation.

PMID- 10603127
TI  - Effects of pre- and postnatal cysteamine exposure on renal function in the rat.
AB  - The safety of cysteamine after renal transplantation and during pregnancy is an
      important issue, since girls with cystinosis are in better health on cysteamine
      therapy and thus more likely to become pregnant. In the first study, cysteamine
      was given to pregnant rats on days 6.5-18.5 post conception in oral doses of 0,
      37.5, 75, 100, and 150 mg/kg per day. The dams were sacrificed on day 20.5, the
      fetal kidneys removed and prepared for histological examination. In the second
      study, cysteamine was given to dams on days 6.5-19.5 post conception in oral
      doses of 0, 37.5, 50, and 75 mg/kg per day. Dams were allowed to give birth
      naturally and pups were given cysteamine on days 4-21 to yield the same oral
      doses of cysteamine given to the dam. Renal function was evaluated on day 35.
      Histological examination of fetal kidneys revealed no changes even in kidneys
      from fetuses with growth retardation and malformations. Furthermore, there were
      no alterations in renal function in offspring on day 35. These findings
      demonstrate that cysteamine therapy does not affect renal development in the rat.
      Further investigations will be required to prove whether cysteamine therapy has
      the potential to affect renal development in the human.

PMID- 10603128
TI  - Clinical outcome of Schonlein-Henoch purpura nephritis in children.
AB  - We studied the long-term outcome of 64 children with biopsy-proven Schonlein
      Henoch purpura (SHP) nephritis over 1-23 years of follow-up. Overall renal
      survival 10 years after onset was 73%. Multivariate logistic regression analysis
      identified initial renal insufficiency (P=0.004), nephrotic syndrome (P=0.037),
      and the severity of histological alterations, as defined by the proportion of
      glomerular crescents (P=0.051), as significant independent predictors of
      progressive renal failure. Four patients followed for more than 19 years showed
      glomerular damage after transient recovery. Eight children with crescentic
      nephritis associated with a rapidly progressive course and/or persistent
      nephrotic syndrome were treated by at least seven sessions of plasma exchange
      (PE) within 16 weeks of onset of purpura. During treatment serum creatinine
      levels dropped in each patient from a mean of 2.3 to 1.1 mg/dl, followed by a
      rebound increase. Repeated courses of PE in 5 patients produced comparable
      responses. Four patients undergoing PE reached end-stage renal disease at 1.2.
      3.7 years after onset, whilst 3 finally were in preterminal renal failure
      (creatinine 3.2-6.1 mg/dl after 7-13.5 years), and 1 patient reached a normal
      glomerular filtration rate. Our experience suggests that initial renal
      insufficiency is the best single predictor of the further clinical course in
      children with SHP nephritis. Early PE appears to delay the progression in some
      patients with severe, rapidly progressive forms of the disease.

PMID- 10603129
TI  - Prolonged versus standard prednisolone therapy for initial episode of nephrotic
      syndrome.
AB  - We have examined, in a prospective randomized controlled trial, the effect of 8-
      and 16-week initial steroid treatment on the course of idiopathic nephrotic
      syndrome (INS). Patients with a first episode of INS were randomized to receive
      standard 8-week prednisolone (2 mg/kg daily for 4 weeks, then 1.5 mg/kg on
      alternate days for 4 weeks) or prolonged 16-week prednisolone treatment (2 and
      1.5 mg/kg daily each for 4 weeks, then 1.5 and 1 mg/kg on alternate days each for
      4 weeks). Relapses were treated with prednisolone, 2 mg/kg daily for 2 weeks,
      then 1.5 mg/kg on alternate days for 4 weeks. Of 45 patients, 23 received
      standard therapy and 22 prolonged therapy. The mean duration of follow-up was
      29.2 and 27.3 months in the standard and prolonged treatment groups,
      respectively. The time to first relapse was longer in the prolonged treatment
      (mean 222.2 days, median 120.0 days) than the standard group (mean 134.3 days,
      median 96.5 days). The percentage of patients with no relapse at 6 and 12 months
      after prednisolone withdrawal was 40.9% and 27.3% in the prolonged treatment and
      21.7% and 8.7% in the standard groups, respectively. The inability to show
      statistically significant differences between the two groups was probably related
      to the small number of patients studied. Prolonged therapy did not affect the
      subsequent relapse rates and proportion of patients with frequent relapses and
      steroid dependence. The mean dose of prednisolone received, for the initial
      episode and relapses during the next year, was higher and associated with
      significant steroid toxicity in the prolonged treatment group. Our findings
      suggest that 16-week prednisolone treatment for the initial episode of INS may
      delay occurrence of the first relapse, but results in significant side effects.
      Prolongation of initial therapy may be useful in developing countries where
      frequent infections often induce early relapses.

PMID- 10603130
TI  - Body growth of children with steroid-resistant nephrotic syndrome.
AB  - Whilst it is assumed that body growth is retarded in children with steroid
      resistant nephrotic syndrome (NS), the degree of growth failure and the
      pathomechanisms involved are poorly understood. We collected serial growth data
      in 45 children (24 males) with steroid-resistant NS usually from onset to end
      stage renal disease (ESRD) during childhood (n=10) or until final height was
      attained (n=27). Mean follow-up time was 9 (2-19) years. Mean initial
      standardized height was -0.3+/-1.2 standard deviation scores (SDS). Mean final
      height was +0.4 SDS in males and -1.0 SDS in females (sex difference not
      significant). In 16 patients with serum creatinine levels consistently <1.2
      mg/dl, mean final height SDS was 0.3 SDS higher than that obtained within 6
      months of onset. In contrast, 9 children who entered ESRD lost an average of 1.3
      SDS from the initial record to ESRD (P=0.017). In prepubertal patients without
      renal insufficiency, mean height SDS decreased during corticosteroid treatment by
      0.3 SDS, followed by a partial catch-up after discontinuation of treatment; the
      change from initial to final height SDS was inversely correlated with the total
      prednisone dose given (r=-0.50, P=0.03). In 16 prepubertal children with serial
      height and serum protein measurements who were off steroids and maintained normal
      creatinine levels, mean individual albumin concentrations correlated with the
      change in height SDS per year (r=0.65, P=0.0006) and in boys with final height
      (r=0.73, P=0.03). In conclusion, growth in steroid-resistant NS depends on the
      preservation of renal function, the cumulative dose of steroids applied, and the
      severity of hypoproteinemia.

PMID- 10603131
TI  - Microbiological spectrum of septicemia and peritonitis in nephrotic children.
AB  - From April 1993 to December 1997, 452 admissions of 231 children with nephrotic
      syndrome to Chang Gung Children's Hospital were retrospectively reviewed. There
      were 10 episodes of sepsis and 8 episodes of peritonitis in 18 children, and 14
      microorganisms were cultured. Two children died due to Streptococcus pneumoniae
      sepsis. Gram-positive microorganisms (n=7) and Gram-negative microorganisms (n=7)
      were found in equal numbers. Enterococcus (1), Streptococcus pneumoniae (4),
      group D streptococcus (1), and Streptococcus viridans (1) were the Gram-positive
      microorganisms cultured. Two of 4 cases of Streptococcus pneumoniae sepsis were
      penicillin resistant. Gram-negative microorganisms included Enterobacter cloacae
      (1), Klebsiella pneumoniae (1), Escherichia coli (2), Acinetobacter baumannii
      (1), Neisseria meningitidis (1), and group B salmonella (1). The last three
      microorganisms have not been previously associated with nephrotic children.
      Vancomycin therapy to cover penicillin-resistant Streptococcus pneumoniae and a
      third-generation cephalosporin therapy to cover rare Gram-negative microorganisms
      should be considered in serious infections of nephrotic children.

PMID- 10603132
TI  - A case of Fournier gangrene complicating idiopathic nephrotic syndrome of
      childhood.
AB  - A 10-year-old boy presenting with steroid resistant nephrotic syndrome developed
      Fournier gangrene of the scrotum. Antimicrobial drug therapy, intravenous
      albumin, excision of necrotic scrotum and left orchidectomy followed by skin
      grafting 3 weeks later led to an excellent cosmetic and medical result. Six
      months later he remains nephrotic on diuretic and angiotensin converting enzyme
      inhibitor medication.

PMID- 10603133
TI  - Circulating inflammatory cytokine levels in hemolytic uremic syndrome.
AB  - Experimental data suggest that the host's inflammatory response is involved in
      the pathophysiology of verotoxin-producing Escherichia coli (VTEC)-associated
      hemolytic uremic syndrome (HUS). We compared the circulating levels of pro-
      [interleukin (IL)-6, IL-8] and anti-inflammatory [IL-10 and IL-1 receptor
      antagonist (Ra)] mediators on enrollment among children with HUS due to E. coli
      O157:H7, according to the severity of renal dysfunction. The latter was evaluated
      by the occurrence of oligoanuria, the requirement for dialysis, and a glomerular
      filtration rate (GFR) </=80 ml/min per 1. 73 m(2) measured 1 year later.
      Increased levels of IL-6 (P<0.0001), IL-10 (P<0.0001), and IL-1Ra (P<0.07) were
      found among patients with HUS compared with normal controls. Children with severe
      renal dysfunction also had tenfold increased levels of IL-6 and higher
      concentrations of IL-10 and IL-1Ra. Both the IL-6/IL-10 (4.9+/-8.3 vs. 0.5+/-0.4,
      P=0.01) and the IL-6/IL-1Ra ratios (0.10+/-0.20 vs. 0. 01+/-0.01, P=0.04) were
      significantly increased. GFR correlated well with IL-6 levels, IL-6/IL-10 and IL
      6/IL-1Ra ratios. Our data demonstrate that the inflammatory response of the host
      is associated with the severity of renal dysfunction during classic HUS. An
      imbalance between the pro- and the anti-inflammatory responses may be involved in
      the pathophysiology of VTEC-associated HUS.

PMID- 10603134
TI  - Distal tubular dysfunction in lupus nephritis of childhood and adolescence.
AB  - We describe a girl with lupus nephritis who presented with distal renal tubular
      acidosis and hyporeninemic hypoaldosteronism. While distal tubular dysfunction is
      well recognized in adult systemic lupus erythematosus (SLE), only a few pediatric
      patients have been reported. Evaluation of five pediatric patients with SLE
      revealed that distal tubular dysfunction in childhood and adolescence is rare.

PMID- 10603135
TI  - Glomerulonephritis in a neonate with atypical congenital lupus and toxoplasmosis.
AB  - The development of glomerulonephritis as a complication of neonatal lupus or
      congenital toxoplasmosis is extremely rare. We report a case of membranous
      glomerulonephritis occurring in a neonate with toxoplasmosis and atypical
      congenital lupus, including high-titer antinuclear antibodies and
      hypocomplementemia. This case illustrates that glomerulonephritis in the neonate
      may be induced by passively transferred maternal antibodies.

PMID- 10603136
TI  - Renal hemodynamic changes in children with liver cirrhosis.
AB  - To assess the sensitivity of duplex Doppler ultrasonography in detecting early
      impairment of renal function in childhood cirrhosis, intrarenal arterial
      pulsatility index (PI) and resistive index (RI) were measured in 10 ascitic and
      11 non-ascitic children with liver cirrhosis and normal creatinine clearance and
      10 age- and sex-matched controls. PI and RI were higher in ascitic than non
      ascitic children [PI 1.54+/-0.4 vs. 1.1+/-0.2 (mean +/- SD), P=0. 006; RI 0.76+/
      0.07 vs. 0.68+/-0.07, P=0.03). Non-ascitic patients had higher PI and RI than
      controls (P=0.002 and 0.0001, respectively). PI was inversely correlated with
      creatinine clearance (r=-0.54, P=0.01). A significant positive relationship was
      observed between both PI and RI and Child score (r=0.47, P=0.009; r=0.45, P=0.
      01, respectively). However, no significant correlation was observed between PI
      and RI and portal hypertension. We conclude that renal vascular resistance
      indexes evaluated by duplex Doppler ultrasonography are increased in the non
      ascitic phase of cirrhosis. Development of ascites is associated with a further
      increase in these indexes. The resistance indexes are best correlated with
      severity of hepatocellular dysfunction, assessed by Child score, but not with
      portal hypertension. Hence, monitoring these indexes, especially PI, is a non
      invasive means of studying early renal hemodynamic alteration in childhood
      cirrhosis.

PMID- 10603137
TI  - Prognostic factors in fetal hydronephrosis: a multivariate analysis.
AB  - With the increasing use of obstetric echography fetal hydronephrosis has been
      reported more frequently. The purpose of this study was to identify prognostic
      factors associated with adverse outcome, such as renal failure and death, in
      fetal hydronephrosis. One hundred and forty-eight children with fetal
      hydronephrosis were admitted, submitted to a systematic protocol, and
      prospectively followed. Prognostic factors associated with fetal echography and
      clinical and laboratory findings on admission were studied. The median follow-up
      was 39 months. The analysis was conducted in two steps. In a univariate analysis,
      variables associated with adverse outcome were identified by the Kaplan-Meier
      method. The variables that were significantly associated with adverse outcome
      were then included in a multivariate analysis. This analysis, using the
      multivariate Cox's model, was performed to identify variables that were
      independently associated with a worse prognosis. Only variables that remained
      independently associated with adverse outcome were included in the final model.
      After final adjustment by Cox's multivariate model, three variables were
      identified as independent predictors of adverse outcome: oligohydramnios,
      prematurity, and glomerular filtration rate lower than 20 ml/min. Thus, in the
      presence of oligohydramnios, prematurity, and abnormal renal function, the
      medical team must plan appropriate follow-up for infants at health centers
      prepared to investigate and treat uropathies in newborns.

PMID- 10603138
TI  - Conservative treatment for chronic renal failure from birth: a 3-year follow-up
      study.
AB  - Fifteen children with chronic renal failure from early infancy who did not
      require renal replacement therapy were followed for 3 years. Chronic renal
      failure was defined as a serum creatinine at or above 1 mg/dl for the entire 1st
      year of life. These patients were treated conservatively with diet and
      supplements of sodium bicarbonate and sodium chloride, calcium and vitamin D.
      Erythropoietin was given to 5 patients. Neither nasogastric nor gastrostomy tube
      feeding was used, and none of the patients received recombinant human growth
      hormone. We analyzed length, weight, and head circumference at 3, 12, 24, and 36
      months of age. All three variables displayed a significant drop in the first 3
      months, but remained stable for the whole observation period thereafter. At the
      age of 3 years, the patients' mean values of length, weight, and head
      circumference standard deviation score were -1.96, -1.37, and -1.07,
      respectively. Height velocity during the 1st, 2nd, and 3rd year was 22.2, 10.9,
      and 7.6 cm per year, respectively. The first two figures and the cumulative
      height velocity are significantly better than those from a large cohort of
      chronic renal failure patients collected by the European Study Group for
      Nutritional Treatment of Chronic Renal Failure in Childhood; here the
      corresponding figures of height velocity were 12.3, 8.3, and 7.6 cm per year.
      Median serum calcium, phosphate, parathyroid hormone, and albumin levels remained
      within normal limits for the entire study period. Therapy-resistant
      hyperparathyroidism occurred in 1 patient and radiological signs of renal
      osteodystrophy in 4 patients. Kidney length, as measured by ultrasonography,
      showed almost no growth.

PMID- 10603139
TI  - Long-term enteral nutrition in infants and young children with chronic renal
      failure.
AB  - An inadequate nutritional intake is common in infants and young children with
      chronic and end-stage renal failure (CRF/ESRF), causing poor weight gain and
      growth retardation. In a programme of enteral feeding (EF), growth, nutritional
      intake and outcome for oral feeding were evaluated in 35 children with CRF/ESRF,
      mean (range) age 1.6 (0-4.9) years at start of EF for 30 (12-60) months. Twenty
      nine had a glomerular filtration rate of 12.1 (6-26) ml/min per 1.73 m(2) and 6
      were on peritoneal dialysis. Mean (SD) weight standard deviation scores (SDSs) in
      the 0 to 2-year age group (n=26) were -3.3 (1.0) 6 months before EF, -3.1 (1.3)
      at the start, -1.7 (1. 4) at 1 year, (P=0.0003) and -1.4 (1.8) at 2 years,
      (P=0.0008). Height SDSs were -2.9 (0.7), -2.9 (1.2), -2.2 (1.2) (P=0.008) and -2.
      1 (1.3) (P=0.004). Weight SDSs in the 2 to 5-year age group (n=9) were -2.3
      (1.2), -2.0 (1.1), -1.1 (1.3) (P=0.002) and -0.9 (1.0) (P=0.04). Height SDSs were
      -2.8 (0.6), -2.3 (0.7), -2.0 (0.7) and -2. 0 (0.8). There was no change in energy
      intake as a percentage of the estimated average requirement, nor was this
      exceeded. Percentage energy from the EF in the 0 to 2 year age group remained
      unchanged despite an absolute increase in energy intake with age. Twenty-one have
      had renal transplants, of whom 86% eat and drink normally. Long-term EF prevents
      or reverses weight loss and growth retardation in children with CRF/ESRF, with
      the achievement of significant catch-up growth if started before age 2 years.

PMID- 10603140
TI  - Body growth in early diagnosed vesicoureteric reflux.
AB  - Body growth was studied in 32 subjects with vesicoureteric reflux (VUR),
      diagnosed following the prenatal finding of urinary tract dilatation, who had
      normal renal filtration function and who received antibacterial prophylaxis by
      the first few days of life. They were followed for 1-5 years (mean 2.3 years).
      Most had persistent VUR during the 1st year of life. Body growth performance was
      compared with that of 94 subjects with VUR diagnosed and treated by us after the
      neonatal period. During the follow-up period, none of the patients with
      prenatally detected VUR had a height Z score below -2, nor a weight-for-height
      index below 90%, and 1 had variations in height Z score >/=1. The difference in
      the percentage of patients with prenatally detected VUR (1/32) and those with VUR
      diagnosed and treated after the neonatal period (20/94) who had variations in
      height Z score >/=1 was significant (P=0.035). Patients with prenatally detected
      VUR and normal renal filtration function, given antibacterial prophylaxis by the
      first few days of life, have normal body growth, although VUR still persists.

PMID- 10603141
TI  - Transtubular potassium concentration gradient in preterm neonates.
AB  - To determine the postnatal changes in mineralocorticoid action on the cortical
      distal nephron in preterm neonates, we evaluated the transtubular potassium
      gradient (TTKG) and its relationship to other renal and non-renal parameters in
      16 preterm neonates during the first 5 weeks of life. Preterm neonates were
      divided into two groups according to their gestational age: the first group
      (group A, n=9) had a gestational age less than 30 weeks and the second group
      (group B, n=7) had a gestational age over 30 weeks. TTKG in both groups increased
      significantly with postnatal age, and TTKG in group A was significantly lower
      than that in group B (P=0.0003; two-way repeated analysis of variance). TTKG in
      group A was significantly lower during the 2 weeks of postnatal life than that in
      full-term neonates [TTKG during 1st week (mean+/-SD) 3.73+/-1.32, P<0.00001;
      during 2nd week 7.77+/-3.60, P=0.0096 versus full-term neonates (n=19); 11.56+/
      3.23]. TTKG in group B was significantly lower only during the 1st week of life
      (6.55+/-2.71, P=0.0013) compared with full-term neonates. Plasma aldosterone
      concentration did not correlate with TTKG value. Stepwise regression analysis
      showed that postnatal age, cortical lumen sodium concentration (CLNa), and
      clinical condition requiring the use of mechanical ventilation were independent
      variables that correlated significantly with TTKG. We postulate that the low TTKG
      level in preterm neonates might reflect the prematurity of renal function (early
      postnatal age, CLNa) and the condition(s), relating to immaturity, such as the
      use of mechanical ventilation.

PMID- 10603142
TI  - Prematurity-associated nephrocalcinosis and kidney function in early childhood.
AB  - To assess the impact of prematurity-associated nephrocalcinosis on kidney
      function later in life, 20 premature children with neonatal nephrocalcinosis and
      20 controls, matched for birth weight and postnatal age but without
      nephrocalcinosis, were examined (birth weight 905+/-209 vs. 957+/-226 g; study
      age 4.7+/-1.1 vs. 4.6+/-0.9 years). Distal tubular acidification capacity was
      measured with the oral acetazolamide test, in which the response was abnormal in
      1 out of the 20 children with a history of nephrocalcinosis, but in none of the
      controls. Urinary calcium and beta(2)-microglobulin excretion were higher in the
      children with nephrocalcinosis, but no differences were found in fractional
      excretion of sodium and potassium or tubular reabsorption of phosphate. Estimated
      creatinine clearance was not different between the groups. Of the 6 children with
      nephrocalcinosis lasting beyond 2 years of age, 5 had had chronic lung disease
      neonatally and exhibited a tendency for compensated respiratory acidosis at the
      time of the examination. Neonatal nephrocalcinosis seems to lead to some signs of
      renal tubular dysfunction in early childhood of preterm infants. Glomerular
      function, however, appears not to be specifically disturbed by nephrocalcinosis.

PMID- 10603143
TI  - Effect of metabolic acidosis on hyperlipidemia in uremia.
AB  - Nine patients (aged 18+/-1 years) on maintenance hemodialysis with metabolic
      acidosis and hyperlipidemia were studied before and after 2 weeks of oral sodium
      bicarbonate (NaHCO(3)) treatment to correct the acidosis. To control for the
      effect of additional sodium, they were also studied after 2 weeks of an
      equivalent amount of oral sodium chloride (NaCl). Oral NaHCO(3 )treatment led to
      significant increases in venous pH, serum bicarbonate, and serum 1, 25
      dihydroxyvitamin D(3) concentrations, but no significant change in total and
      ionized calcium, phosphate, sodium, potassium, creatinine, blood urea nitrogen,
      and intact parathyroid hormone concentrations. Oral NaCl did not change any of
      the biochemical parameters. Before treatment of acidosis, these uremic patients
      had high serum triglycerides, low serum high-density lipoprotein (HDL)
      cholesterol, but normal total cholesterol compared with controls. Following 2
      weeks of NaHCO(3) treatment, there was a significant decrease in the serum
      concentrations of triglycerides (P<0.01). HDL and total cholesterol did not
      change. There were no changes in triglycerides, HDL or total cholesterol from
      baseline values following 2 weeks of NaCl. Thus treatment of metabolic acidosis
      ameliorated hypertriglyceridemia but had no effect on HDL and total cholesterol
      in patients with uremia on hemodialysis. The underlying mechanism may involve
      1,25-dihydroxyvitamin D3.

PMID- 10603144
TI  - Urinary calcium excretion in healthy children and adolescents.
AB  - Urinary calcium (Ca) excretion was determined in 1,578 24-h urine samples from
      507 healthy children and adolescents (252 boys, 255 girls; 2.8-18.4 years)
      participating in the DONALD Study and is presented for 32 different age and sex
      groups. Calciuria values related to body weight (mg/kg per day) were relatively
      constant except for a transient decrease during puberty in all centiles, with a
      later onset in boys than girls. Distribution of calciuria (mg/kg per day) was
      best normalized by log transformation, with an almost constant standard deviation
      of the log-transformed values. Ca excretion was >/=4 mg/kg per day in 8.6% and
      >/=6 mg/kg per day in 1. 5% of the urine samples. Based on Ca excretion rates of
      1,080 pairs of 24-h urine samples from 364 children and adolescents, sensitivity,
      specificity, and the predictive value for hypercalciuria (>/=4 mg/kg per day) in
      the next urine sample were calculated at three test levels classifying calciuria
      of the initial urine sample. In summary, this study presents normal values of
      urinary Ca excretion related to age and sex in a population of healthy German
      children and adolescents consuming a typical western-style diet. A high level of
      calciuria in a random urine sample is important in the diagnosis of
      hypercalciuria.

PMID- 10603145
TI  - Evaluation of pediatric nephropathies by a computerized Urine Protein Expert
      System (UPES).
AB  - A computerized Urine Protein Expert System (UPES) measuring creatinine, total
      protein, albumin, IgG, alpha(1)-microglobulin, alpha(2)-macroglobulin, and N
      acetyl-beta-D-glucosaminidase, together with urine dipstick testing for
      granulocyte esterase and hemoglobin pseudoperoxidase, and measurement of serum
      creatinine had been found to be useful in adults for differentiating between
      renal disorders. The objective of this study was to investigate UPES for
      identifying the different types of proteinuria and their underlying prerenal,
      glomerular, tubular, and postrenal causes in 146 children characterized by
      routine and invasive nephrological investigations. UPES proved to be a useful
      tool in pediatric renal patients after refinements were implemented in the
      program. Comparing UPES with the pediatric nephrologist's interpretation of all
      available clinical and laboratory data, UPES diagnosed glomerulopathies in 46
      (75%) of 61 patients. In a further 23% it suggested glomerular involvement by
      indicating either a disturbed glomerular permeability or increased excretion of
      albumin. Tubular proteinuria was correctly described by UPES in 23 (100%)
      patients with different tubulopathies. UPES revealed normal kidney function in
      all healthy children and all children with remission of renal disorders.
      Therefore, UPES can be regarded as a useful tool in the automated differentiation
      of renal diseases in children.

PMID- 10603146
TI  - Renal function during and after childhood acute poststreptococcal
      glomerulonephritis.
AB  - It is still debatable whether acute poststreptococcal glomerulonephritis (APSGN)
      can lead to permanent renal impairment. The clinical, immunological, and
      histological findings during the acute disease have been described thoroughly,
      however, the hemodynamic events are still poorly understood. In this
      retrospective study, the inulin and p-aminohippurate clearances were measured to
      evaluate glomerular filtration rate (GFR) and effective renal plasma flow (ERPF)
      within a month of onset of the disease (acute stage) in 26 children, and 2-12
      months after onset (follow-up) in 22 children with APSGN. During the acute stage,
      the mean GFR was 77+/-23 (SD) ml/min per 1.73 m(2), the mean ERPF 537+/-138
      ml/min per 1.73 m(2), and the filtration fraction (FF) 14%+/-3%, compared with
      values for controls of 115+/-11 ml/min per 1. 73 m(2), 607+/-72 ml/min per 1.73
      m(2), and 19%+/-2%, respectively (n=42). At follow-up, GFR was 114+/-15 ml/min
      per 1.73 m(2), ERPF 600+/-68 ml/min per 1.73 m(2), and FF 19%+/-3%. Thus, during
      the disease both GFR and ERPF fell below values for controls, but later were
      restored. The GFR, however, was more reduced than the ERPF, as indicated by the
      reduced FF. This might reflect a relative hyperperfusion of individual nephrons,
      which might start processes later deleterious to the nephrons. This finding,
      however, needs to be further investigated and we have therefore started a long
      term follow-up of these patients.

PMID- 10603147
TI  - Plasma concentrations and renal clearance of orotic acid in argininosuccinic acid
      synthetase deficiency.
AB  - Argininosuccinic acid synthetase deficiency (ASD) is a rare disorder of urea
      cycle metabolism, with pronounced citrullinemia and orotic aciduria being
      characteristic biochemical features. To further investigate the role of plasma
      orotic acid and its possible use for monitoring the metabolic status in ASD, we
      determined plasma orotic acid, amino acid, and ammonium levels in plasma samples
      collected over a period of 3 years from a patient who is now 8 years of age.
      Orotic acid plasma concentrations varied widely from less than 1 micromol/l to
      more than 60 micromol/l. The renal clearance of orotic acid was eightfold the
      glomerular filtration rate, thus supporting an active mechanism underlying the
      excretion of this pyrimidine. Data obtained during a metabolic crisis yielded a
      statistically significant linear correlation of orotic acid plasma levels with
      those of glutamine and ammonium, which are generally accepted for assessment of
      the successful treatment of this disorder. Our data revealed no advantage of
      plasma orotic acid concentrations over the established amino acids (glutamine and
      arginine) and ammonium for determining acute treatment responses. Since several
      effects of high levels of orotic acid have been described in mammals, further
      research is necessary to assess a possible contribution of orotic acid to the
      pathogenesis of ASD and the use of plasma orotic acid levels in the long-term
      monitoring of these patients.

PMID- 10603148
TI  - Angiotensin converting enzyme inhibitor-induced angioedema: a report of two
      cases.
AB  - Angioedema is a rare but potentially fatal side effect of angiotensin converting
      enzyme (ACE) inhibitors. We report for the first time, two children with systemic
      lupus erythematosus who developed acute angioedema after the long-term use of
      enalapril. Prompt recognition and appropriate management of ACE-induced
      angioedema prevented life-threatening complications. This report highlights the
      potential risks of angioedema associated with the use of ACE inhibitors in
      children. Patients should be advised to seek medical treatment immediately if
      they experience swelling of the face, neck, or tongue, and especially if they
      have trouble breathing, speaking, or swallowing.

PMID- 10603149
TI  - Urolithiasis in Tunisian children: a study of 120 cases based on stone
      composition.
AB  - The composition of urinary stones in children depends on socioeconomic conditions
      and hygiene, geographical area, and dietary habits. We analyzed urinary stones
      from 120 consecutive Tunisian children (81 males, 39 females) aged 5 months to 15
      years. The stone was located in the upper urinary tract in 91 cases (76%). Stone
      analysis included both a morphological examination and an infrared analysis of
      the nucleus and the inner and peripheral layers. The main components of bladder
      calculi were whewellite (69%) and struvite (22%), whereas the main component of
      upper urinary tract calculi was whewellite (67%). The nucleus of bladder stones
      was composed of ammonium urate (45%), struvite (28%), cystine (10%), and
      carbapatite (7%). The nucleus of kidney and ureteral calculi was mainly composed
      of ammonium urate (38%), whewellite (24%), carbapatite (13%), or struvite (11%).
      Based on stone composition, urinary tract infection was involved in the
      nucleation or growth of a third of calculi. Endemic urolithiasis involving
      simultaneous nutritional, metabolic, and infectious factors, and defined by its
      nucleus composed of ammonium urate without struvite, represented 40% of cases.
      Exclusive metabolic factors - including genetic diseases such as primary
      hyperoxaluria, cystinuria, and hypercalciuria - were responsible for less than
      25% of cases.

PMID- 10603150
TI  - Commentary on the article by A. Kamoun Et al

PMID- 10603151
TI  - 46,XY gonadal dysgenesis associated with congenital nephrotic syndrome and
      sepsis.
AB  - The occurrence of nephrosis in the first 3 months of life is rare and is termed
      'congenital nephrotic syndrome.' The congenital nephrotic syndrome is a group of
      heterogeneous diseases with a clinical course that differs markedly from the
      childhood nephrotic syndrome. The coexistence of a congenital nephrotic syndrome
      and gonadal dysgenesis in a 46,XY karyotype with normal female external genitalia
      is extremely rare. Frequent severe infections are often seen in the Finnish type,
      but sepsis leading to death is rare in the neonatal onset of gonadal dysgenesis.
      This report describes an unusual case of complete XY gonadal dysgenesis in a
      46,XY female neonate with the congenital nephrotic syndrome and overwhelming
      sepsis.

PMID- 10603152
TI  - Mumps interstitial nephritis: a case report.
AB  - Mumps is still a common childhood disease in rural areas where mumps vaccination
      is not widespread. A 14-year-old girl with fatal interstitial nephritis as a
      complication of mumps is reported. The patient had not been vaccinated with mumps
      vaccine and had contracted mumps during a village epidemic. The illness began
      with parotitis, and renal insufficiency developed within a week. The patient's
      renal function rapidly deteriorated and the outcome was fatal. The postmortem
      renal necropsy sample demonstrated interstitial mononuclear cell infiltration,
      edema, and focal tubular epithelial cell damage, confirming the clinical
      diagnosis. In developing countries routine mumps vaccination may help to prevent
      possible fatal complications of mumps. Furthermore, patients with mumps,
      especially complicated cases, should be followed closely.

PMID- 10603153
TI  - Septic arthritis secondary to vesicoureteral reflux into single ectopic ureter.
AB  - A 3-week-old male infant, born full term without complication, developed septic
      arthritis of his left shoulder. His joint fluid, blood, and bone marrow were all
      positive for Escherichia coli. Urinalysis demonstrated pyuria. Urine culture
      obtained after one dose of ceftriaxone and several doses of nafcillin was
      negative. Work-up revealed a refluxing, right single ectopic ureter with severe
      hydroureteronephrosis and a non-functioning ipsilateral kidney. After appropriate
      management of the musculoskeletal infection, he underwent a right
      nephroureterectomy. Coliform septic arthritis is exceedingly rare in children,
      with only a few cases reported. We report the first case of septic arthritis with
      anomalous genitourinary tract development as the source of bacterial seeding.
      This report re-emphasizes the need to screen the urinary tract in all cases of
      pediatric gram-negative sepsis.

PMID- 10603154
TI  - Chronic renal failure after Puumala virus infection.
AB  - Chronic renal failure has never been described after Puumala hantavirus
      infection, which usually causes acute renal failure with spontaneous full
      recovery. We report a 15-year-old boy who presented with Puumala hantavirus
      infection and initial severe acute renal failure. His renal function gradually
      improved, but more than 2 years after the acute episode it was still moderately
      impaired, with a creatinine clearance of about 60 ml/min per 1.73 m(2)

PMID- 10603155
TI  - Transient acute renal failure due to nitrofurantoin poisoning.
AB  - A 3-year-old girl developed acute oliguric renal failure after accidental
      ingestion of nitrofurantoin (190 mg/kg body weight). The time interval between
      poisoning and the onset of renal failure was 9 days. She later recovered with
      symptomatic management.

PMID- 10603156
TI  - Antenatal and perinatal uro-nephrology: current questions and dilemmas.
AB  - The development of antenatal ultrasonography and the detection of fetal
      uropathies has created a new field for paediatric urologists. The embryology and
      physiology of the fetal renal tract is still poorly understood. It is, however,
      recognised that delays in the maturation of the renal system can lead to
      transient dilatation of the urinary tract. Structural and functional anomalies
      can also result in dilatation, but these are permanent. The ability to
      distinguish between the transient and permanent impairments to urine flow
      represents a diagnostic challenge. This review article discusses the
      pathophysiology of urine flow impairment, antenatal detection and the postnatal
      management of the common congenital uropathies.

PMID- 10603157
TI  - Treatment of cystinuria.
AB  - Cystine urolithiasis is the only clinical expression of cystinuria, an autosomal
      recessive genetic defect of the transepithelial transport of cystine and other
      dibasic amino acids in the kidney. Stones form due to the increased excretion of
      cystine, which is poorly soluble at normal urine pH. Cystine stones are often
      resistant to extracorporeal shock wave lithotripsy, so that percutaneous surgery
      or ureteroscopy are the preferred techniques of stone extraction. Medical
      preventative treatment is based on high diuresis (>/=1.5 l/m(2) per day) well
      distributed throughout the day and night, and urine alkalinization up to pH 7.5
      by means of sodium bicarbonate and/or potassium citrate. When these basal
      measures are ineffective at preventing stone recurrence or dissolving pre
      existing stones, sulfhydryl agents such as D-penicillamine or tiopronin, which
      form highly soluble mixed disulfides with cystine moieties, are to be added to
      urine dilution and alkalinization, especially when cystine excretion is in excess
      of 750 mg/day (3 mmol/day). Frequent clinical and ultrasound follow-up is needed
      to encourage patient compliance and assess efficacy and tolerance of treatment.

PMID- 10603158
TI  - Cardiac function and structure in patients with chronic renal failure.
AB  - The long-term consequences of cardiac alterations in children with chronic renal
      failure (CRF) and after renal transplantation (TX) are largely unknown. Studies
      in adults with end-stage renal disease (ESRD) assume that the fate of many
      pediatric patients is determined by a high cardiovascular morbidity and
      mortality. This review describes clinical manifestations, pathophysiology,
      cardiac function and structure, and management of heart disease in children with
      CRF and post transplant. Echocardiography and Doppler ultrasonography allow
      differentiation of three functional disturbances: hypercirculation, systolic left
      ventricular (LV) dysfunction, and diastolic LV dysfunction, in addition to
      analysis of LV size and myocardial mass. From adult studies LV hypertrophy is
      recognized as an early prognostic marker of cardiovascular disease. It is present
      in about half of children with ESRD and after TX. It may regress, at least in
      part, by control of hypertension, hypervolemia, and anemia. Experimental studies
      have shown that, independent of these hemodynamic complications, uremia is
      associated with structural abnormalities of the heart, which were also described
      in adult patients with ESRD. These lesions consist mainly of hypertrophy of
      cardiomyocytes, interstitial fibrosis, and vascular changes (rarefied
      capillaries, thickened arteriolar walls). Cardiac complications in children with
      CRF and after TX deserve regular clinical and echocardiographic monitoring in
      order to minimize later cardiovascular morbidity by appropriate treatment.

PMID- 10603159
TI  - Xenotransplantation of the kidney: a pediatric perspective.
AB  - The major factor limiting the application of allotransplantation for the
      treatment of renal failure is a severe shortage of donor organs. One approach to
      overcoming this limitation is the use of kidneys from animals for clinical
      transplantation, that is xenotransplantation. Although of interest for many
      years, the application of xenotransplantation has been prevented because of the
      devastating immune responses of the recipient against the graft. Research
      conducted in recent years has elucidated the immune mechanisms underlying the
      rejection of xenografts and has led to the development of incisive therapeutic
      strategies, including the genetic engineering of donor animals. Success in
      dealing with the xenogeneic immune response has encouraged the view that
      xenotransplantation might be feasible in the near future. It also raises
      consideration of two additional hurdles, the potential limitations of xenogeneic
      kidneys as physiological replacement for human kidneys and the possibility that
      the animal organ might transfer infectious organisms to the recipient and to the
      wider population. This paper reviews recent progress in the field of
      xenotransplantation of the kidney and offers a perspective on the hurdles to
      clinical application that remain.

PMID- 10603160
TI  - Modulation of the immune response by fetal kidney allografts.
AB  - Fetal kidneys modulate the allogeneic immune response by a synergistic effect:
      first, fetal kidney tissue tropism is abrogated by the initial relative lack of
      adhesion molecules. Second, the reduced expression of major histocompatibility
      complex (MHC) determinants is less effective in inducing the alloantigen-primed T
      cell response, which in turn induces the downregulation of Th1 cytokines, beta
      chemokines, and Fas ligand, but spares protective Th2 cytokines, and leads to
      minimal induction of MHC and adhesion molecules on immature renal parenchymal
      elements. Thus, at the onset and during this altered rejection process, cellular
      recruitment to the fetal renal site is less prominent than to the adult renal
      tissue, and effector cells in the fetal graft are less activated.

PMID- 10603161
TI  - Drug secretion systems in renal tubular cells: functional models and molecular
      identity.
AB  - For the last several decades, functional characterization of renal drug handling
      has provided the conceptual framework of drug transport, especially drug
      secretion by the renal tubular cells. Functional models have been postulated for
      the two distinct groups of drugs with regard to their ionization characteristics
      at physiological pH (i.e., organic cations and organic anions). Organic cations
      are predicted to cross the basolateral membranes through a potential-sensitive
      uptake system along an inside-negative potential gradient, with secretion of
      organic cations into urine across apical membranes appearing to occur via a
      proton-organic cation antiport system. Organic anions are predicted to enter the
      cells against an electrical-potential gradient through basal membranes via an
      organic anion-dicarboxylic acid exchanger. Secretion of organic anions into urine
      across apical membranes is less well characterized, but the presence of an
      organic anion exchanger and a potential-driven transporter is hypothesized.
      Recent data obtained using molecular biology techniques have helped to elucidate
      molecular identity of each system postulated in these models. Novel drug
      transport proteins have also been discovered that were not part of the original
      organic cation/anion model, such as P-glycoprotein for hydrophobic neutral and
      cationic compounds. Moreover, the search for homologous genes of these
      transporters has led to the discovery of previously unknown transporter proteins,
      whose function has yet to be identified. Integral roles of these transport
      proteins in overall tubular handling of drugs remain to be determined.

PMID- 10603162
TI  - Extracellular fluid and its proteins: dehydration, shock, and recovery.
AB  - This review highlights characteristics of extracellular fluid (ECF) that are
      often overlooked. ECF has, in addition to plasma and interstitial fluid (ISF)
      surrounding cells, a third large compartment, the ISF of skin and connective
      tissue. This acts as a reservoir that gives up ECF to plasma volume (PV) in order
      to sustain circulation in the event of either shock or dehydration. While
      Starling forces drive filtration, ECF is returned to PV more by lymph and less by
      Starling forces than previously appreciated. Lymph return to PV is dependent on
      physical activity and muscle contraction to overcome gravity. Regional change in
      metabolic rate alters the need for oxygen and nutrients that is met by a regional
      increase in capillary blood flow. Blood flow is controlled by vasoactive
      compounds released in response to a drop in PO(2); these relax capillary smooth
      muscle to increase blood flow and delivery of oxygen and nutrients. Plasma
      proteins, including albumin, are filtered into the interstitium through larger
      pores than those filtering ECF. The rate of protein filtration is set by size and
      charge of these larger endothelial pores and by size and charge of proteins.
      Charge of these pores, hence albumin permeability, is regulated by many of the
      same vasoactive compounds that control capillary flow. As a consequence, in
      response to gravitational stress and other forms of shock that reduce effective
      circulation, albumin as well as ECF is rapidly shifted from plasma and
      sequestered in ISF. When this has occurred, as in burn shock, restoration is
      better effected by generous expansion of ECF with Ringer's solution alone, rather
      than with Ringer's solution supplemented with human serum albumin or other
      colloid. Restoring both PV and ISF volume restores lymph circulation and returns
      sequestered albumin to PV.

PMID- 10603163
TI  - Rupestris stem pitting associated virus-1 consists of a family of sequence
      variants.
AB  - Rupestris stem pitting (RSP) seems to be one of the most widespread virus
      diseases of grapevines. A virus, designated as rupestris stem pitting associated
      virus-1 (RSPaV-1), is consistently associated with, and likely to be the
      causative agent of RSP. Sequence analyses of cDNA clones derived from several RSP
      affected grapevines suggested that a family of sequence variants of RSPaV-1 was
      associated with RSP. The genome structure of the sequence variants is identical
      to that of RSPaV-1 in that they had five open reading frames (ORF) and sequence
      identities ranging from 75 to 93% in nucleotide sequence and from 80 to 99% in
      amino acid sequence. ORF5 (coat protein) and the carboxyl-terminal portion of
      ORF1 (replicase) appeared to be the most conserved regions. The coat proteins of
      the sequence variants exhibited highly similar antigenic indices, suggesting
      serological relatedness among them. The cDNA clones obtained through reverse
      transcription-polymerase chain reaction from RSP-infected grapevines were
      heterogeneous in nt sequence with identities of 77-99% relative to RSPaV-1.
      Furthermore, a number of sequence variants were identified in several grapevines
      infected with RSP. Baselines for defining RSPaV-1 and possible mechanisms
      accounting for infection of grapevines with multiple sequence variants of RSPaV-1
      are proposed. Findings from this study should have practical applications toward
      understanding the etiology of RSP and developing reliable assays to rapidly
      detect the disease.

PMID- 10603164
TI  - Two novel genetic groups (VIIb and VIII) responsible for recent Newcastle disease
      outbreaks in Southern Africa, one (VIIb) of which reached Southern Europe.
AB  - 34 strains of Newcastle disease virus (NDV) isolated during epizootics in the
      Republic of South Africa and in Mozambique between 1990 and 1995, and in Bulgaria
      and Turkey in 1995-1997 were identified by restriction enzyme and partial
      sequence analysis of the fusion (F) protein gene. The majority of isolates in
      southern Africa and those from Bulgaria and Turkey were placed into a novel group
      which has been termed VIIb. Group VIIb is part of a larger genetic cluster (VII)
      that also includes NDV strains from the Far East and some western European
      countries (VIIa). The genetic distance of 7-8, 5% between genotype VIIa and VIIb
      viruses excludes the existence of a direct epidemiological link between recent
      southern African epizootics and outbreaks in either western Europe in the 1990's
      or those of the Far East. Another hitherto unrecorded genotype (VIII) was also
      found in South Africa with descendants of putative ancestral members isolated in
      the 1960's. The genetic distance of recent group VIII strains from the major
      epizootic genotype (VIIb) is over 11%, therefore outbreaks caused by them were
      epidemiologically unrelated. Genotype VIII viruses must have been maintained in
      South Africa by endemic infections during the past decades while group VIIb
      appears to be introduced more recently.

PMID- 10603165
TI  - Detection and differentiation of Aino and Akabane Simbu serogroup bunyaviruses by
      nested polymerase chain reaction.
AB  - Reverse transcription-polymerase chain reaction (RT-PCR) and nested PCR were
      developed to detect and differentiate Aino (AINO) and Akabane (AKA) virus S RNA.
      Two pairs of AINO- and AKA-specific primers for nested PCR were synthesized and
      examined for their capacity to amplify PCR products using 7 Simbu serogroup
      viruses isolated in Japan and Australia. RT- and nested PCR using AKA-specific
      primers amplified cDNA from Tinaroo virus RNA as well as homologous RNA. Nested
      PCR products were differentiated by Hph I and Bst EII digestion. Peaton (PEA)
      virus S cDNA was also amplified using AINO- specific primers. The nested PCR
      products of PEA virus were not digested by 3 restriction enzymes (Ava II, Eco RI
      and Hae II), whereras those of AINO virus were digested as expected. Using this
      technique, AINO and AKA viruses were detected at concentrations as low as 10(-3)
      plaque-forming units (PFU) and 10(-5) PFU, respectively, in a supernatant of
      virus-infected cells. It was possible to detect AINO and AKA genome from various
      tissues of experimentally infected mice, and also the AKA nested PCR products
      from serum samples from sentinel cattle naturally infected with AKA virus. The
      present nested PCR appears a simple, rapid and valuable method for diagnosing
      AINO and AKA infection.

PMID- 10603166
TI  - Genome organization and mRNA structure of Periplaneta fuliginosa densovirus imply
      alternative splicing involvement in viral gene expression.
AB  - We determined the complete nucleotide sequence of an infectious clone of the
      cockroach small spherical virus (CSSV) genome. Analysis of the genome
      organization and the predicted viral protein sequences showed clearly that this
      virus should be classified as a new member of the subfamily Densovirinae, genus
      Densovirus, and should be designated as PfDNV. However, our data revealed some
      differences between the gene expression strategies used by PfDNV and other DNVs.
      An internal promoter, in addition to the promoter (p3) at the genome terminus,
      was observed at map unit 18 (p18), implying transcriptional regulation of
      generation of the nonstructural proteins of PfDNV. Furthermore, the structural
      analysis of cDNAs complementary to mRNAs from the region coding for structural
      proteins suggested alternative splicing and polyadenylation as means for
      generation of the structural proteins of PfDNV.

PMID- 10603167
TI  - Molecular characterization of a new furovirus mainly infecting rye.
AB  - The complete or almost complete nucleotide sequences were determined for the two
      RNAs of three different sources of a new furovirus which mainly infects rye and
      for which the name Soil-borne rye mosaic furovirus (SBRMV) is proposed. The
      genome organization of this virus is virtually identical to that of Soil-borne
      wheat mosaic furovirus (SBWMV). However, SBRMV and SBWMV differ considerably in
      the nucleotide sequences of their genomes and in the derived amino acid sequences
      of their putative gene products. The sequences of the three sources of SBRMV (two
      from rye and one from wheat) differ between each other in various parts of their
      genomes by 1% to 10%. Larger differences were found in the readthrough part of
      the coat protein readthrough protein. There are no indications that the
      relationship of the C source from wheat to the other two sources from rye is more
      distant than the relationship between the two sources from rye. The 3'UTRs of
      both SBRMV RNAs are remarkable in having a predicted upstream pseudoknot domain
      (UPD) with seven pseudoknots. The same number was also predicted for the UPD of
      SBWMV RNA 1 whereas the much shorter UDP of SBWMV RNA 2 may form only four
      pseudoknots.

PMID- 10603168
TI  - Mutations designed to alter the stability of a putative RNA duplex in the HIV-1
      pol gene.
AB  - In the HIV-1 integrase coding region there is a polypurine tract (PPT) involved
      in the initiation of provirus plus-strand synthesis. Upstream of this PPT there
      is a 15-nucleotide inverted repeat (IR) complementary to most of the PPT. We have
      constructed one mutant with five amino acid-neutral U to C and A to G changes in
      the IR and one mutant with corresponding amino acid-neutral changes in the PPT.
      Each set of changes abolished the complementarity and suppressed the replication
      of HIV-1 slightly. The combination of these ten changes restored the
      complementarity, and doubled the calculated free energy of the putative duplex
      between the IR and the PPT. This double mutant did not replicate under normal
      conditions, possibly because the reverse transcriptase was unable to penetrate
      the duplex. However, when high loads of the double mutant were added to
      permissive cells, replicative HIV did occasionally appear. The resurrected virus
      harvested from these cells replicated consistently, even though the ten
      nucleotide changes were left unchanged. There were no compensatory mutations in
      the vicinity of the IR/PPT or in the reverse transcriptase gene.

PMID- 10603169
TI  - Comparison of the effect of FK506 and cyclosporin A on virus production in H9
      cells chronically and newly infected by HIV-1.
AB  - The presence of FK506-binding protein-12 was demonstrated in virions of HIV-1,
      although its concentration was lower than that of cyclophilin A. The effect of
      two inhibitors of the peptidyl-prolyl cis-trans isomerases FK506 and cyclosporin
      A (CsA) was studied in H9 cells that were chronically infected by HIV-1. Both
      drugs inhibited virus production in the infected cells in a concentration
      dependent manner, by decreasing the number of the producing cells. FK506 did not
      have an effect on Gag processing, based on the p24 antigen content of virions
      produced in the presence of this drug. Furthermore, FK506 treatment of uninfected
      H9 cells did not diminish their susceptibility toward HIV-1 infection, whereas
      CsA treatment decreased the degree of HIV-1 infection with an IC(50) of 1-2
      microg/ml. Also, pretreatment of the virus with CsA decreased its infectivity in
      HeLaCD4-LTR/beta-gal cells; in contrast, at concentrations up to 10 microg/ml,
      FK506 did not have an effect. Our findings on the antiviral activity of FK506 and
      CsA suggest that FK506 is effective only in chronically infected cells, by
      selectively inhibiting the growth of HIV-1 infected cells, whereas CsA has a
      specific effect on virus replication.

PMID- 10603170
TI  - Identification and characterization of the simian varicella virus uracil DNA
      glycosylase.
AB  - Simian varicella virus (SVV) infection of non-human primates is used as a model
      to study the pathogenesis and latency of varicella-zoster virus (VZV), the
      etiological agent of chickenpox and shingles. Uracil DNA glycosylase (UDG) is a
      DNA repair enzyme responsible for excision of uracil residues misincorporated
      into DNA. UDG is conserved throughout the herpesvirus family and may play an
      important role in viral pathogenesis. This study identified a 300 amino acid SVV
      UDG that shares 53.9% amino acid identity with the VZV UDG. The SVV UDG is
      expressed in infected Vero cells as determined by reverse transcriptase
      polymerase chain reaction (RT-PCR) and Northern blot analysis. The SVV UDG is
      encoded on a 2.0 kb transcript which also appears to encode the SVV glycoprotein
      L (gL) and the VZV gene 58 homolog. The SVV UDG is enzymatically active as
      determined by the ability of a SVV UDG-maltose binding protein fusion construct
      to remove [(3)H]-uracil incorporated into DNA.

PMID- 10603171
TI  - Liver and peripheral blood mononuclear cells are not major sites for GB virus
      C/hepatitis G virus replication.
AB  - The pathogenesis and replication sites of GB virus-C/hepatitis G virus (GBV
      C/HGV) in humans remain unclear. The presence of GBV-C/HGV and hepatitis C virus
      (HCV) RNA sequences in matched serum, peripheral blood mononuclear cells (PBMC)
      and liver samples in 10 patients with GBV-C/HGV infection, 8 of whom were
      coinfected with HCV was explored. Positive- and negative-strand GBV-C/HGV and HCV
      RNA were detected by strand-specific reverse-transcription polymerase chain
      reaction (RT-PCR), and virus titers were quantified by competitive PCRs. Positive
      strand GBV-C/HGV RNA was detected in 7 of 10 PBMC samples of the patients with
      serum GBV-C/HGV RNA, but negative-strand GBV-C/HGV RNA was not found in these
      cells. Positive-strand GBV-C/HGV RNA was found in 9 liver samples, and 2 (22%) of
      them also had negative strand. In contrast, negative-strand HCV RNA was
      frequently found in PBMC and liver samples. A positive correlation between the
      titer of viral RNA in liver tissue and that in serum sample was demonstrated in
      HCV infection, but not in GBV-C/HGV infection. These findings suggest that liver
      and PBMC are not the major replication sites for GBV-C/HGV and that GBV-C/HGV is
      not a primary hepatotropic virus.

PMID- 10603172
TI  - Sequence and comparative structural analysis of the murine leukaemia virus
      amphotropic strain 4070A RNase H domain.
AB  - The sequence of a 900-nucleotide segment (encoding part of the reverse
      transcriptase, including the entire RNase H domain) of the pol gene of the murine
      leukaemia virus (MLV) amphotropic strain 4070A is presented. Alignment of the
      inferred 4070A RNase H amino acid sequence (157 residues) with other MLV RNase H
      sequences revealed only minor differences compared with the divergence between
      other retroviral and prokaryotic or eukaryotic RNase H sequences. Only 10
      residues were invariant across the entire sample set, but secondary structure
      predictions for the enzymes from E. coli, yeast, human liver and diverse
      retroviruses (HIV, Rous sarcoma virus, foamy viruses) supported, in every case,
      the five beta-strands (1 to 5) and four or five alpha-helices (A, B/C, D, E) that
      have been identified by crystallography in the RNase H domain of HIV-1 reverse
      transcriptase and in E. coli RNase H. In the case of MLV, analysis of the RNase H
      domain sequences inferred from 10 different strains (including the amphotropic
      4070A) predicted all five alpha-helices (A-E), as well as beta-strands 4 and 5.
      However, the N-terminal segment (residues 1-40) was predicted, without exception
      and with high probability, to fold uniquely into one (or two adjacent) alpha
      helix(es) encompassing residues 13-37, instead of the three beta-strands known to
      exist in the HIV-1 and E. coli enzymes. The unerring consistency between the
      known and predicted structures of the HIV-1 and E. coli enzymes, and the
      prediction of the same structural elements (including beta-strands 1-3 within the
      N-terminal segment) for all other (non-MLV) RNase H proteins examined in this
      study, suggests that the N-terminal segment of the MLV RNase H domain assumes a
      conformation distinct from that of other retroviral and cellular RNase H
      molecules. An additional (sixth) beta-strand was also predicted uniquely within
      the C-terminal region of foamy virus RNase H domains.

PMID- 10603173
TI  - The nucleotide sequence of a chinese isolate of wheat yellow mosaic virus and its
      comparison with a Japanese isolate. Brief report.
AB  - The nucleotide sequences of wheat yellow mosaic virus isolated in China were
      determined and compared with a Japanese isolate of the same virus. Results showed
      that the viral genome had 7629 nucleotides for RNA1 and 3639 nucleotides for
      RNA2, which shared 97. 1% and 94.6% of identities to the RNAs of Japanese
      isolate. The single open reading frames in RNA1 and RNA2 encoded polyproteins
      with 2407 amino acids and 903 amino acids respectively, from which ten proteins
      may be produced by autolytic cleavage processing as the Japanese isolate. Since
      the sequence of WYMV RNA1 showed identity of less than 70% with that of WSSMV, it
      is further confirmed that WYMV is a distinct species within Bymovirus.

PMID- 10603174
TI  - The nucleotide sequence of the high-leukemogenic murine retrovirus SL3-3 reveals
      a patch of mink cell focus forming-like sequences upstream of the ecotropic
      envelope gene. Brief report.
AB  - We report the complete nucleotide sequence of the potent T-lymphomagenic murine
      retrovirus SL3-3. The non-LTR regions of the virus show 98% sequence identity to
      the endogenous ecotropic Akv murine leukemia virus. While the region encoding the
      surface envelope protein is completely identical to that of Akv, a approximately
      200 nucleotide stretch in the integrase encoding region upstream of env is
      similar to the sequence of mink cell focus forming (MCF) viruses and shows a
      complete match with the mouse retrovirus 10A1. The history of SL3-3 may therefore
      include recombination involving an Akv-like virus and a virus with MCF-like
      sequences.

PMID- 10603175
TI  - Reciprocal assistance for aphid transmission between non-transmissible strains of
      zucchini yellow mosaic potyvirus in mixed infections. Brief report.
AB  - Several aphid non-transmissible strains of zucchini yellow mosaic potyvirus
      (ZYMV) have been described, in relation with mutations in the two viral proteins
      required for transmissibility, coat protein and helper component. Assistance
      mechanisms were previously shown to allow transmission of such strains when
      functional proteins are provided in trans. In this paper, we used monoclonal
      antibodies to allow a specific detection of two aphid non-transmissible strains
      of ZYMV and we revealed that reciprocal assistance mechanisms can mediate
      simultaneous aphid transmission of these deficient strains. Potential
      epidemiological and evolutive consequences of such assistance mechanisms between
      variants in complex virus populations are discussed.

PMID- 10603176
TI  - Demethylation of the Epstein-barr virus origin of lytic replication and of the
      immediate early gene BZLF1 is DNA replication independent. Brief report.
AB  - Epstein-Barr virus (EBV) episomal DNA is extensively methylated in Burkitt
      lymphoma derived cell lines. In this study we examined whether lytic viral cycle
      reactivation is dependent on demethylation of critical viral genes. Viral
      replication was induced in the Burkitt's lymphoma cell line Daudi by the
      combination of 12-O-tetradecanoylphorbol-13-acetate (TPA) and sodium-butyrate.
      Two regions necessary for EBV replication, the BZLF1 immediate early region and
      the origin of lytic cycle replication (ori Lyt) were demethylated during the
      early phase of the lytic virus cycle. Demethylation was observed while production
      of new (unmethylated) viral DNA was blocked by phosphonoformic acid (PFA). This
      suggests that demethylation, which may be instrumental for the onset of the lytic
      cycle, is an active process independent of viral DNA replication

PMID- 10603177
TI  - Anti-CD8 treatment alters interleukin-4 but not interferon-gamma mRNA levels in
      murine sensory ganglia during herpes simplex virus infection. Brief report.
AB  - Clearance of herpes simplex virus (HSV) from sensory ganglia of infected mice is
      dependent on CD8(+) cells but not on the death of infected neurons. The mechanism
      of action of CD8(+) cells in HSV infected ganglia is therefore unknown. The
      determine which cytokines might be involved in the CD8(+) cell dependent response
      to ganglionic HSV infection, IL-2, IL-4, IL-6, IL-10, and IFN-gamma mRNA levels
      were measured in infected ganglia from immunocompetent and anti-CD8 treated mice.
      Anti-CD8 treatment increased the abundance of mRNA encoding IL-4, and, to a
      lesser extent, IL-2, and IL-6. Significantly, IFN-gamma mRNA was not affected.

PMID- 10603178
TI  - Persistence of coxsackievirus B4 infection in rhabdomyosarcoma cells for 30
      months. Brief report.
AB  - A persistent infection of rhabdomyosarcoma (RD) cells by Coxsackie B4 virus (CBV
      4) was established. The persistently infected RD (piRD) cells have been
      maintained for over 130 passages (30 months) and have released virus continuously
      without cellular destruction. The production of infectious virus declined three
      times during the study. After the first decline (third week post infection) a
      viral variant with a littered cytopathic effect (CPE) and a marked delayed
      replication cycle on Green Monkey Kidney (GMK) cells, replaced the original viral
      population. 100-fold diluted cell cultures were recovered from the piRD cells at
      the 48(th) and 104(th) passage. All 96 cultures from the former whereas 72% from
      the second dilution showed virus production when tested on GMK cells. Using a
      streptavidin/biotin immune-staining assay all piRD cells were positively stained.
      Test for ts mutants showed that the persistence of the CBV-4 strain was not
      dependent upon incubation temperature and addition of the antiviral compound
      disoxaril did not cure the piRD cells.

PMID- 10603179
TI  - Infection of barley protoplasts with rice hoja blanca tenuivirus. Brief report.
AB  - A barley protoplast system has been established that supports replication of Rice
      hoja blanca tenuivirus (RHBV). Following polyethylene glycol-mediated RHBV
      inoculation of barley protoplasts, newly synthesized viral RNAs and proteins
      could be detected. Time course analyses revealed de novo synthesis of genome
      length viral RNA4, as well as subgenomic-sized RNA4 molecules of both polarities.
      Two proteins, N and NS4, encoded by viral complementary RNA3 and viral RNA4
      respectively, were detected by Western immunoblot analysis. The barley protoplast
      system thus constitutes a promising tool for in vivo studies of the sequential
      steps involved in the multiplication cycle of RHBV.

PMID- 10603180
TI  - Characterization of echovirus 25 (ECV 25) in the VP1/2A gene junction region.
      Brief report.
AB  - Genetic relationships among echovirus type 25 (ECV 25) isolates associated with
      aseptic meningitis in Germany 1997/98 and a 40-year-old ECV 25 prototype strain
      were investigated using RT-PCR and direct sequencing the VP1/2A gene junction
      region. Sequences were compared to each other and to non-polio enterovirus
      representatives (phylogenetic analysis). The analysis indicated that the
      sequences of recent isolates have drifted over time distinctly away from the
      prototype strain sequence. Genetic drift may change biological features of
      isolates possibly leading to new antigenic variants.

PMID- 10603181
TI  - Taxonomic implications for Fijiviruses based on the terminal sequences of Fiji
      disease fijivirus. Brief report.
AB  - The 5' and 3' terminal sequences of the plus strand of Fiji disease fijivirus
      (FDV) segments 2, 3, 9 and 10 possess the conserved terminal sequences,
      5'AAGUUUUU.....CAGCAGAUGUC 3'. The 5' sequence is identical to that of maize
      rough dwarf fijivirus (MRDV) and rice black-streaked dwarf fijivirus (RBSDV),
      whereas the FDV 3' sequence shares the consensus, CAGCNNNNGUC, with MRDV and
      RBSDV. The FDV terminal sequences, and the amino acid sequences from FDV segment
      9, are more closely related to those from MRDV and RBSDV than to those from oat
      sterile dwarf fijivirus (OSDV) and Nilaparvata lugens reovirus (NLRV; a putative
      Fijivirus).

PMID- 10603182
TI  - Abbreviations for invertebrate virus species names.

PMID- 10603184
TI  - ASCUS! ASCUS! down the rabbit hole.

PMID- 10603185
TI  - Aspiration cytopathology of malignant lymphoma: coming of age.

PMID- 10603186
TI  - Diagnosis of lymphoma by fine-needle aspiration cytology using the revised
      European-American classification of lymphoid neoplasms.
AB  - BACKGROUND: Recent changes in the classification of non-Hodgkin lymphoma (NHL)
      emphasize the diagnostic importance of cytomorphology, immunophenotyping, and
      molecular findings in addition to histology. These changes have allowed for a
      greater role of fine-needle aspiration cytology (FNA) in the diagnosis of NHL.
      METHODS: A review of the English language literature regarding the use of FNA in
      the cytodiagnosis of lymphoma was performed. The revised European-American
      classification of lymphoid neoplasms (REAL) was reviewed in the context of its
      adaptability to the cytologic diagnosis of lymphoid neoplasms. RESULTS: FNA is
      being used more frequently in the diagnosis, staging, and follow-up of lymphoma
      whenever supportive studies are readily available. Cytomorphologic,
      immunophenotypic, and molecular criteria as well as pitfalls in the diagnosis of
      lymphoma by FNA have been delineated. Information was compiled into tables to
      facilitate correlation of criteria with the proposed REAL system. CONCLUSIONS:
      Many cases of NHL can be diagnosed and subclassified by FNA when there is
      adequate immunophenotypic information. Cancer (Cancer Cytopathol)

PMID- 10603187
TI  - Reclassification of negative smears as atypical squamous cells of undetermined
      significance in quality assurance reviews: implications and limitations.

PMID- 10603188
TI  - A practical problem with calculating the false-negative rate of Papanicolaou
      smear interpretation by rescreening negative cases alone.
AB  - BACKGROUND: Rescreening negative Papanicolaou (Pap) smears alone is the most
      commonly employed method of determining the false-negative rate (FNR) or the
      false-negative proportion for a laboratory. Acceptable FNRs have been proposed,
      and the number of slides needed to be rescreened to demonstrate a statistically
      significant difference in FNRs has been determined. The authors sought to
      determine the range of FNRs this method can measure and, by implication, the
      value of this method. METHODS: A literature review and an analysis of the FNRs
      this method can generate was performed. RESULTS: If one assumes that the FNR of
      review is the same as that of initial screening, the maximum measured FNR is only
      25%, even with a true FNR of anywhere from 0-100%. In fact, as a laboratory's FNR
      increases over 50%, the measured FNR decreases back to zero. This range of FNRs
      corresponds very closely to the published range of FNRs of 1.6-28%. Because many
      authorities believe that 5% may be the lowest achievable FNR, the entire possible
      range of measured FNRs is only 5-25%. In this setting, a statistically
      significant difference of 20% is meaningless, and a statistically significant
      difference of 10% can only be achieved by laboratories with an initial FNR of
      less than 15%, and actual changes in FNR that are much greater than 10%.
      CONCLUSIONS: FNRs determined by review of negative smears without abnormal smears
      generate unreliable and potentially seriously misleading results. Current
      methodologies exist for more accurately determining the FNR of Pap smear
      screening by incorporating abnormal smears into the review process. There is
      little justification for further review of negative Pap smears alone as a method
      for determining the FNR of a laboratory. Cancer (Cancer Cytopathol)

PMID- 10603189
TI  - Detection of high grade squamous intraepithelial lesions and tumors using the
      AutoPap System: results of a primary screening clinical trial.
AB  - BACKGROUND: The AutoPap System for the initial screening and quality control of
      conventional cervical cytology slides previously has shown superior performance
      for the detection of abnormal slides of low grade squamous intraepithelial
      lesions and above. This report presents data regarding the important category of
      high grade squamous intraepithelial lesions and above (HSIL+). METHODS: All
      slides were run through a Current Practice (CP) arm of manual screening with 10%
      random quality control followed by an AutoPap (AP) arm of device initial
      screening with approximately 25% of slides receiving no further review; 75%
      received a manual rescreen with AP ranking and QC rescreening of 15% of the top
      ranking negative manual screen slides was performed. Detection performance for
      truth-determined HSIL+ cases was compared between the two study arms. Available
      follow-up biopsy results were correlated for cases determined to be HSIL+.
      RESULTS: Of 25,124 analyzed slides, 70 slides had truth-determination at the
      HSIL+ level (67 HSILs, 1 adenocarcinoma in situ, and 2 invasive tumors). The AP
      arm identified 68 of 70 cases (including both invasive tumors). Neither false
      negative HSIL+ was found in the 25% "No Further Review" population. The CP arm
      identified 65 of 70 cases (missing both invasive tumors). The results showed
      statistical equivalence between the two arms (P = 0.0129). Biopsy follow-up was
      available in 27 of 70 HSIL+ cases identified by AP and showed abnormality at some
      level in 100% of cases. CONCLUSIONS: The AP arm was statistically equivalent and
      showed numeric superiority to the CP arm for the category of HSIL+. Follow-up
      data confirmed the true-positive nature of these findings. These results are
      significant because any overall improvement in the performance of an initial
      screening device must be paralleled by at least equivalence in the clinically
      important subset category of HSIL+. Cancer (Cancer Cytopathol)

PMID- 10603190
TI  - Fine-needle aspiration cytology of spindle cell lesions of the breast.
AB  - BACKGROUND: Fine-needle aspiration biopsy (FNA) has been successful in diagnosing
      epithelial lesions of the breast. Its role in the evaluation of spindle cell and
      mesenchymal lesions of the breast, which include a variety of benign and
      malignant conditions, is less clear. This article discusses the cytologic
      features and differential diagnosis of these lesions, as well as the potential
      diagnostic pitfalls associated with them. METHODS: FNAs of the breast, in which a
      spindle cell or mesenchymal component was a key or dominant feature, were
      retrieved. Fibroadenomas without cellular stroma and typical lipomas were
      excluded. RESULTS: Forty-six aspirates (0.87%) in a series of 5306 breast FNAs
      contained a significant spindle cell or mesenchymal component. The aspirates were
      classified into 4 categories: 1) reactive conditions, including 2 diabetic
      mastopathies, 3 granulation tissue specimens, and 7 granulomatous lesions; 2)
      benign neoplastic conditions, including 1 mammary hamartoma, 1 dermatofibroma, 1
      fibromatosis, 2 granular cell tumors, 2 angiolipomas, and 7 cellular
      fibroadenomas; 3) low grade malignant neoplastic lesions, including 10 low grade
      phyllodes tumors; and 4) high grade malignant neoplastic lesions, including 1
      metaplastic carcinoma with chondroid stroma, 1 pleomorphic liposarcoma, 2
      malignant fibrous histiocytomas, 2 osteosarcomas, and 4 metastatic melanomas. A
      specific diagnosis was rendered in 38 cases (82.6%). The mammary hamartoma was
      diagnosed as fibrocystic changes; the dermatofibroma as benign spindle cell
      lesion, not otherwise specified (NOS); and the primary osteosarcoma as an
      atypical spindle cell proliferation, NOS. The reactive ductal epithelial cells in
      one of the granulomatous mastitis specimens, as well as the hyperplastic ductal
      epithelial cells in one of the phyllodes tumors, were interpreted as atypical
      ductal proliferation. The marked cytologic atypia displayed by one granular cell
      tumor was interpreted as low grade adenocarcinoma and the primary liposarcoma as
      poorly differentiated carcinoma. CONCLUSIONS: Breast lesions with a significant
      spindle cell or mesenchymal component are rarely encountered in FNA and
      constitute a heterogeneous group that may pose a diagnostic dilemma. FNA should
      be the initial diagnostic procedure for investigating these lesions, as a
      specific diagnosis was rendered in the majority of cases. Cancer (Cancer
      Cytopathol)

PMID- 10603191
TI  - Use of archival fine-needle aspirates for the allelotyping of tumors.
AB  - BACKGROUND: Loss of heterozygosity (LOH) analysis (allelotyping) based on
      polymorphic microsatellite DNA is one of the most powerful molecular tools
      currently available for studying carcinogenesis. However, allelotyping studies
      that require archival paraffin embedded tissues are often hampered by technical
      difficulties related to microdissection and poor DNA quality. METHODS: The
      authors compared allelotyping results from 12 paraffin embedded breast carcinoma
      cases with those from matching alcohol fixed fine-needle aspiration (FNA)
      cytology slides obtained for routine diagnostic purposes, using 30 polymorphic
      microsatellite markers at chromosomes 3p, 4p, 4q, 5q, 6p, 8p, 9p, 11q, 17p, and
      17q. Cells from the alcohol fixed FNA slides were dissected and processed in
      three different ways, and DNA dilution experiments were performed to determine
      the minimum number of cells required for accurate allelotyping. RESULTS: LOH
      results were identical for paraffin embedded and alcohol fixed tumors for 97% of
      114 polymerase chain reactions (PCR) when 1000-2000 cells were dissected from
      each FNA slide and DNA from 100 cells was used for each multiplex PCR. However,
      with lower cell numbers, the discordance rate increased and artifactual LOH was
      observed. Intratumor allelotype heterogeneity could not be documented.
      CONCLUSIONS: The use of alcohol fixed cytology preparations improves the ease of
      PCR-based allelotyping and greatly expands the range of archival materials
      available for study. The allelotyping is accurate and reproducible when DNA from
      >/=25 cells is used in the initial multiplex PCR. Cancer (Cancer Cytopathol)

PMID- 10603192
TI  - The role of fine-needle aspiration cytology in the evaluation of metastatic clear
      cell tumors.
AB  - BACKGROUND: Clear cell tumors (CCTs) occur as primary neoplasms in a number of
      anatomic sites. Due to their overlapping morphologic features, these tumors can
      be challenging for the cytologist, particularly when they present as metastatic
      lesions. METHODS: Forty-nine fine-needle aspirations (FNA) of metastatic CCTs
      from 46 patients (age range, 29-87 years; mean, 64 years) were reviewed
      retrospectively. In addition to the routine smears and cell block preparations,
      ancillary studies were performed in selected cases. Clinical and/or histologic
      follow-up was obtained for all patients. RESULTS: The sites of the 49 FNAs were
      the lung (12 cases), lymph nodes (9 cases), liver (7 cases), bone (7 cases), soft
      tissue (4 cases), pelvis (2 cases), adrenal gland (2 cases), pancreas (1 case),
      thyroid (2 cases), peritoneum (2 cases), and vagina (1 case). Twenty-seven
      patients had a previous history of a CCT and the FNA material in these cases was
      consistent with a metastasis. The primary anatomic sites in these cases were the
      kidney (20 cases), ovary (2 cases), salivary gland (1 case), and cervix (1 case).
      On light microscopy, these tumors had a similar appearance and often were
      indistinguishable. Nineteen patients did not have a prior history of malignancy;
      12 of these patients had a concurrent renal mass and the diagnosis of metastatic
      renal cell carcinoma was made. The anatomic site of origin of seven of the ten
      remaining tumors (kidney [2 cases], lung [2 cases], ovary [1 case], germ cell [1
      case], and endometrium [1 case]) was established through immunocytochemical
      studies of cytologic material and clinical follow-up. CONCLUSIONS: FNA plays an
      important role in the diagnosis of metastatic CCT. Cytologic examination,
      ancillary studies, and clinical information can establish the anatomic site of
      origin in the majority (95%) of cases, precluding the necessity of obtaining
      additional tissue. Cancer (Cancer Cytopathol)

PMID- 10603193
TI  - MOC-31 aids in the differentiation between adenocarcinoma and reactive
      mesothelial cells.
AB  - BACKGROUND: Evaluation of effusion specimens for the presence of adenocarcinoma
      often is complicated by the presence of reactive mesothelial cells that can mimic
      adenocarcinoma. Ancillary studies, in particular immunohistochemistry, can be
      helpful in making this distinction. MOC-31 is an antibody that recently was
      reported to be useful in distinguishing adenocarcinoma from mesothelioma in
      tissue specimens. In this study we examined the utility of this antibody in
      pleural effusions. METHODS: Eighty-nine archival, formalin fixed, paraffin
      embedded cell blocks representing 59 adenocarcinomas, 12 other neoplasms
      (including 6 mesotheliomas), and 18 reactive effusions were retrieved. After
      protease digestion, recut slides were immunostained with the MOC-31 antibody
      utilizing a modified avidin-biotin complex technique. Only membrane-based
      reactivity was considered as positive. RESULTS: In two adenocarcinomas there was
      insufficient material remaining in the cell block. Among the 57 remaining cases,
      reactivity was observed in 54 cases. Reactivity also was observed in one of six
      mesotheliomas and one small cell carcinoma. The remaining cases, including all 18
      reactive effusions, were nonreactive. In distinguishing adenocarcinoma from
      reactive mesothelial cells, the presence of MOC-31 reactivity was found to be 95%
      sensitive and 100% specific with a positive predictive value of 100% and a
      negative predictive value of 95%. CONCLUSIONS: MOC-31 is useful in
      differentiating between adenocarcinoma and reactive mesothelial cells in pleural
      effusion specimens. Cancer (Cancer Cytopathol)

PMID- 10603195
TI  - Introduction: birth defect surveillance in the United States.

PMID- 10603196
TI  - Integrating birth defects surveillance in maternal and child health at the state
      level.

PMID- 10603197
TI  - Analytical resources for assessment of clinical genetics services in public
      health: current status and future prospects.
AB  - CONTEXT: Genetics services are not well integrated into the public health
      programs of most states, nor has there been effective use of clinical and program
      databases in the design, evaluation, and monitoring of public health genetics
      services at the state level. OBJECTIVE: To evaluate the availability and current
      use of population-based clinical genetics databases, including birth defects
      surveillance programs, in state-level public health genetics programs. DESIGN:
      Mail survey to state genetics coordinators in 50 states and 3 territories during
      1996 with an update in 1997. RESULTS: Thirty states had birth defects
      surveillance programs; data from these resources were used in public health
      genetics program planning and management in only 15 states. Thirty states or
      territories had clinical genetics services databases. Most states had newborn
      screening program databases; few linked these records to vital statistics for
      programmatic purposes. Only 24 states had individual record databases for the
      Children with Special Health Care Needs program; 8 states had databases for
      maternal serum alpha-fetoprotein screening, and 7 had statewide cytogenetics
      registries. CONCLUSION: Population-based databases concerning aspects of public
      health genetics are largely unavailable at the state level. Where these databases
      exist, they are poorly integrated into state public health genetics program
      activities. More attention should be paid to the development and use of clinical
      data programs for the assessment, monitoring, and assurance of genetics issues
      with relevance to population health.

PMID- 10603198
TI  - Genetic susceptibility to birth defects in humans: from gene discovery to public
      health action.

PMID- 10603199
TI  - Collecting and interpreting birth defects surveillance data by hispanic
      ethnicity: a comparative study. The Hispanic Ethnicity Birth Defects Workgroup.

PMID- 10603200
TI  - Neural tube defects surveillance: a national survey.

PMID- 10603201
TI  - State birth defects surveillance programs directory.

PMID- 10603202
TI  - Birth defect surveillance data from selected states, 1989 - 1996.

PMID- 10603203
TI  - Appendix A

PMID- 10603204
TI  - Synthesis, pharmacological and biophysical characterization, and membrane
      interaction QSAR analysis of cationic amphiphilic model compounds

PMID- 10603205
TI  - Discovery and structure-activity relationships of imidazole-containing
      tetrahydrobenzodiazepine inhibitors of farnesyltransferase

PMID- 10603206
TI  - Emerging infectious diseases and amphibian population declines.
AB  - We review recent research on the pathology, ecology, and biogeography of two
      emerging infectious wildlife diseases, chytridiomycosis and ranaviral disease, in
      the context of host-parasite population biology. We examine the role of these
      diseases in the global decline of amphibian populations and propose hypotheses
      for the origins and impact of these panzootics. Finally, we discuss emerging
      infectious diseases as a global threat to wildlife populations.

PMID- 10603207
TI  - Development of orphan vaccines: an industry perspective.
AB  - The development of vaccines against rare emerging infectious diseases is hampered
      by many disincentives. In the face of growing in-house expenditures associated
      with research and development projects in a complex legal and regulatory
      environment, most pharmaceutical companies prioritize their projects and
      streamline their product portfolio. Nevertheless, for humanitarian reasons, there
      is a need to develop niche vaccines for rare diseases not preventable or curable
      by other means. The U.S. Orphan Drug Act of 1983 and a similar proposal from the
      European Commission (currently under legislative approval) provide financial and
      practical incentives for the research and development of drugs to treat rare
      diseases. In addition, updated epidemiologic information from experts in the
      field of emerging diseases; increased disease awareness among health
      professionals, patients, and the general public; a list of priority vaccines;
      emergence of a dedicated organization with strong leadership; and the long-term
      pharmacoeconomic viability of orphan products will be key factors in overcoming
      the complexity of orphan status and the limited need for vaccine.

PMID- 10603208
TI  - Antimicrobial resistance with Streptococcus pneumoniae in the United States, 1997
      98.
AB  - From November 1997 to April 1998, 1,601 clinical isolates of Streptococcus
      pneumoniae were obtained from 34 U.S. medical centers. The overall rate of
      strains showing resistance to penicillin was 29. 5%, with 17.4% having
      intermediate resistance. Multidrug resistance, defined as lack of susceptibility
      to penicillin and at least two other non-ss-lactam classes of antimicrobial
      drugs, was observed in 16.0% of isolates. Resistance to all 10 ss-lactam drugs
      examined in this study was directly related to the level of penicillin
      resistance. Penicillin resistance rates were highest in isolates from middle ear
      fluid and sinus aspirates of children ambulatory-care settings. Twenty-four of
      the 34 medical centers in this study had participated in a similar study 3 years
      before. In 19 of these 24 centers, penicillin resistance rates increased 2.9% to
      39.2%. Similar increases were observed with rates of resistance to other
      antimicrobial drugs.

PMID- 10603210
TI  - Serologic evidence of human monocytic and granulocytic ehrlichiosis in Israel.
AB  - We conducted a retrospective serosurvey of 1,000 persons in Israel who had fever
      of undetermined cause to look for Ehrlichia chaffeensis antibodies. Four of five
      cases with antibodies reactive to E. chaffeensis were diagnosed in the summer,
      when ticks are more active. All patients had influenzalike symptoms with high
      fever. None of the cases was fatal. Three serum samples were also seroreactive
      for antibodies to E. canis, and one was also reactive to the human granulocytic
      ehrlichiosis (HGE) agent. The titer to the HGE agent in this patient was higher
      than the serum titer to E. chaffeensis, and the Western blot analysis also
      indicated that the HGE agent was the primary cause of infection. We present the
      first serologic evidence that the agents of human monocytic ehrlichiosis (HME)
      and HGE are present in Israel. Therefore, human ehrlichiosis should be included
      in the differential diagnoses for persons in Israel who have been exposed to
      ticks and have influenzalike symptoms.

PMID- 10603209
TI  - Epidemiologic studies of Cyclospora cayetanensis in Guatemala.
AB  - In 1996 and 1997, cyclosporiasis outbreaks in North America were linked to eating
      Guatemalan raspberries. We conducted a study in health-care facilities and among
      raspberry farm workers, as well as a case-control study, to assess risk factors
      for the disease in Guatemala. From April 6, 1997, to March 19, 1998, 126 (2.3%)
      of 5, 552 surveillance specimens tested positive for Cyclospora; prevalence
      peaked in June (6.7%). Infection was most common among children 1.5 to 9 years
      old and among persons with gastroenteritis. Among 182 raspberry farm workers and
      family members monitored from April 6 to May 29, six had Cyclospora infection. In
      the case-control analysis, 62 (91%) of 68 persons with Cyclospora infection
      reported drinking untreated water in the 2 weeks before illness, compared with 88
      (73%) of 120 controls (odds ratio [OR] 3.8, 95% confidence interval [CI] 1.4,
      10.8 by univariate analysis). Other risk factors included water source, type of
      sewage drainage, ownership of chickens or other fowl, and contact with soil
      (among children younger than 2 years).

PMID- 10603211
TI  - Supplementing tuberculosis surveillance with automated data from health
      maintenance organizations.
AB  - Data collected by health maintenance organizations (HMOs), which provide care for
      an increasing number of persons with tuberculosis (TB), may be used to complement
      traditional TB surveillance. We evaluated the ability of HMO-based surveillance
      to contribute to overall TB reporting through the use of routinely collected
      automated data for approximately 350,000 HMO members. During approximately 1.5
      million person-years, 45 incident cases were identified in either HMO or public
      health department records. Eight (18%) confirmed cases had not been identified by
      the public health department. The most useful screening criterion (sensitivity of
      89% and predictive value positive of 30%) was dispensing of two or more TB drugs.
      Pharmacy dispensing information routinely collected by many HMOs appears to be a
      useful adjunct to traditional TB surveillance, particularly for identifying cases
      without positive microbiologic results that may be missed by traditional public
      health surveillance methods.

PMID- 10603212
TI  - Using automated pharmacy records to assess the management of tuberculosis.
AB  - We used automated pharmacy dispensing data to characterize tuberculosis (TB)
      management for 45 health maintenance organization (HMO) members. Pharmacy records
      distinguished patients treated in HMOs from those treated elsewhere. For cases
      treated in HMOs, they provided useful information about appropriateness of
      prescribed regimens and adherence to therapy.

PMID- 10603213
TI  - Hantavirus reservoir hosts associated with peridomestic habitats in Argentina.
AB  - Five species of sigmodontine rodents have been identified in Argentina as the
      putative reservoirs of six circulating hantavirus genotypes. Two species of
      Oligoryzomys are associated with the genotypes causing hantavirus pulmonary
      syndrome, Oligoryzomys flavescens for Lechiguanas and O. longicaudatus for Andes
      and Oran genotypes. Reports of human cases of hantavirus pulmonary syndrome
      prompted rodent trapping (2,299 rodents of 32 species during 27,780 trap nights)
      at potential exposure sites in three disease-endemic areas. Antibody reactive to
      Sin Nombre virus was found in six species, including the known hantavirus
      reservoir species. Risk for peridomestic exposure to host species that carry
      recognized human pathogens was high in all three major disease-endemic areas.

PMID- 10603214
TI  - Large, persistent epidemic of adenovirus type 4-associated acute respiratory
      disease in U.S. army trainees.
AB  - In May 1997, a large, persistent epidemic of adenovirus type 4-associated acute
      respiratory disease began at Fort Jackson, South Carolina, the largest army basic
      training center. The epidemic lasted until December and declined when vaccine
      administration resumed. More than 1,000 male and female trainees were
      hospitalized; 66.1% of those hospitalized had an adenovirus type 4 isolate.

PMID- 10603215
TI  - Changes in antimicrobial resistance among Salmonella enterica Serovar typhimurium
      isolates from humans and cattle in the Northwestern United States, 1982-1997.
AB  - We compared antimicrobial resistance patterns of Salmonella enterica serovar
      Typhimurium (ST) of isolates from humans (n = 715) and cattle (n = 378) in the
      Pacific Northwest from 1982 through 1997. The major changes in antimicrobial
      resistance can be attributed to the widespread clonal dissemination of multidrug
      resistant definitive phage type 104 ST.

PMID- 10603216
TI  - Toxic shock syndrome in the United States: surveillance update, 1979 1996.
AB  - Menstrual toxic shock syndrome (TSS) emerged as a public health threat to women
      of reproductive age in 1979 80. We reviewed surveillance data for the period 1979
      to 1996, when 5,296 cases were reported, and discuss changes in the epidemiologic
      features of TSS.

PMID- 10603217
TI  - New Rickettsiae in ticks collected in territories of the former soviet union.
AB  - Dermacentor nuttallii from Siberia, Rhipicephalus sanguineus from Crimea, and Rh.
      pumilio from the Astrakhan region were infected with Rickettsia sibirica (12%),
      R. conorii (8%), and the Astrakhan fever agent (3%), respectively. Three new
      Rickettsiae of the R. massiliae genogroup were identified in ticks by 16S rDNA,
      gltA, and ompA sequencing.

PMID- 10603218
TI  - Computer-generated dot maps as an epidemiologic tool: investigating an outbreak
      of toxoplasmosis.
AB  - We used computer-generated dot maps to examine the spatial distribution of 94
      Toxoplasma gondii infections associated with an outbreak in British Columbia,
      Canada. The incidence among patients served by one water distribution system was
      3.52 times that of patients served by other sources. Acute T. gondii infection
      among 3, 812 pregnant women was associated with the incriminated distribution
      system.

PMID- 10603219
TI  - HIV infection as a risk factor for shigellosis.
AB  - We investigated cases of shigellosis in San Francisco and Alameda Counties
      identified during 1996 by active laboratory surveillance to assess the role of
      HIV infection as a risk factor for shigellosis. Dramatically elevated rates of
      shigellosis in HIV-infected persons implicate HIV infection as an important risk
      factor for shigellosis in San Francisco.

PMID- 10603220
TI  - Dengue seroconversion among Israeli travelers to tropical countries.
AB  - We tested for dengue seroconversion among 104 Israeli young adults who traveled
      to tropical countries for at least 3 months. Seven (6. 7%) seroconverted during
      travel; four (3.8%) had immunoglobulin (Ig) M antibodies; one was symptomatic
      with borderline IgM and a rise in IgG; two others (1.9%) had a rise in IgG
      titers, without detectable IgM. All four IgM-positive patients had traveled to
      Southeast Asia.

PMID- 10603221
TI  - Effectiveness of pneumococcal polysaccharide vaccine for preschool-age children
      with chronic disease.
AB  - To estimate the effectiveness of pneumococcal polysaccharide vaccine, we
      serotyped isolates submitted to the Pneumococcal Sentinel Surveillance System
      from 1984 to 1996 from 48 vaccinated and 125 unvaccinated children 2 to 5 years
      of age. Effectiveness against invasive disease caused by serotypes included in
      the vaccine was 63%. Effectiveness against serotypes in the polysaccharide
      vaccine but not in a proposed seven-valent protein conjugate vaccine was 94%.

PMID- 10603222
TI  - Stimulating the development of orphan (and other) vaccines.

PMID- 10603223
TI  - Swine as a potential reservoir of shiga toxin-producing Escherichia coli O157:H7
      in Japan.

PMID- 10603224
TI  - Hospitalizations for rotavirus gastroenteritis in Gipuzkoa (Basque country),
      Spain.

PMID- 10603225
TI  - Israeli spotted fever rickettsia (Rickettsia conorii complex) associated with
      human disease in Portugal.

PMID- 10603226
TI  - Avoiding misdiagnosis of malaria: a novel automated method allows specific
      diagnosis, even in the absence of clinical suspicion.

PMID- 10603227
TI  - The first reported case of Aerococcus bacteremia in a patient with HIV infection.

PMID- 10603228
TI  - Proficiency in detecting vancomycin resistance in enterococci among clinical
      laboratories in Santiago, Chile.

PMID- 10603229
TI  - Food-related illness and death in the United States.

PMID- 10603231
TI  - Specimen collection for electron microscopy.

PMID- 10603232
TI  - Editor's note

PMID- 10603233
TI  - Advances in radiation target analysis.

PMID- 10603234
TI  - Simultaneous determination of N-acetylaspartic acid, N-acetylglutamic acid, and N
      acetylaspartylglutamic acid in whole brain of 3-mercaptopropionic acid-treated
      rats using liquid chromatography-atmospheric pressure chemical ionization mass
      spectrometry.
AB  - The measurement of N-acetylaspartic acid (NAA), N-acetylglutamic acid (NAG), and
      N-acetylaspartylglutamic acid (NAAG) in the whole brain of 3-mercaptopropionic
      acid (3-MPA)-treated rats has been developed using liquid chromatography-mass
      spectrometry with an atmospheric pressure ionization interface system. The
      recoveries of these compounds were 90.85 +/- 3.43% for NAA, 91.62 +/- 5.47% for
      NAG, and 92.29 +/- 4.44% for NAAG. The detection limits for NAA, NAG, and NAAG
      were 12, 15, and 20 microg/ml, respectively. After administration of 3-MPA, the
      concentrations of NAA, NAG, and NAAG in the whole brain over 10 min increased
      177.25, 134.23, and 127.70%, respectively. These concentrations then decreased
      over the next 60 min. The simultaneous determination of NAA, NAG, and NAAG using
      this method was found to be very useful for studies of metabolism of NAA, NAG,
      and NAAG in biological samples.

PMID- 10603235
TI  - A luminescent ruthenium complex for ultrasensitive detection of proteins
      immobilized on membrane supports.
AB  - SYPRO Ruby protein blot stain provides a sensitive, gentle, fluorescence-based
      method for detecting proteins on nitrocellulose or polyvinylidene difluoride
      (PVDF) membranes. SYPRO Ruby dye is a permanent stain composed of ruthenium as
      part of an organic complex that interacts noncovalently with proteins. Stained
      proteins can be excited by ultraviolet light of about 302 nm or with visible
      light of about 470 nm. Fluorescence emission of the dye is approximately 618 nm.
      The stain can be visualized using a wide range of excitation sources utilized in
      image analysis systems including a UV-B transilluminator, 488-nm argon-ion laser,
      532-nm yttrium-aluminum-garnet (YAG) laser, blue fluorescent light bulb, or blue
      light-emitting diode (LED). The detection sensitivity of SYPRO Ruby protein blot
      stain (0.25-1 ng protein/mm(2)) is superior to that of amido black, Coomassie
      blue, and india ink staining and nearly matches colloidal gold staining. SYPRO
      Ruby protein blot stain visualizes proteins more rapidly than colloidal gold
      stain and the linear dynamic range is more extensive. Unlike colloidal gold
      stain, SYPRO Ruby protein blot stain is fully compatible with subsequent
      biochemical applications including colorimetric and chemiluminescent
      immunoblotting, Edman-based sequencing and mass spectrometry.

PMID- 10603236
TI  - Measurement of trimethylamine and trimethylamine N-oxide independently in urine
      by fast atom bombardment mass spectrometry.
AB  - We report a method based upon fast atom bombardment mass spectrometry (FAB-MS)
      and stable isotope dilution techniques for the measurement of urinary
      trimethylamine (TMA) and trimethylamine N-oxide (TMAOx). TMA is extracted from
      urine that was spiked with (15)N-labeled TMA. The extracted TMA isotopomers are
      quaternized with trideuteromethyl iodide and analyzed in FAB-MS with hexaethylene
      glycol as matrix. TMAOx is measured by evaporation of another sample of the urine
      spiked with (15)N-labeled TMAOx on the FAB probe and analyzed as for the TMA. The
      method allows the ready and simple distinguishing of controls and patients with
      TMAuria, and is useful in monitoring patients with the disorder. We give examples
      of its use in determining normal control ranges for these metabolites and in
      evaluating patients.

PMID- 10603237
TI  - Rate and equilibrium constants for protein unfolding and refolding determined by
      hydrogen exchange-mass spectrometry.
AB  - Studies of protein unfolding and refolding may help us understand the more
      general problem of protein folding. Recent studies from this laboratory
      demonstrated that the unfolding and refolding of a large protein, rabbit muscle
      aldolase (M(r) 157 kDa), can be studied by combining amide hydrogen exchange and
      mass spectrometry. Results of these studies indicated that aldolase has three
      unfolding domains which likely unfold sequentially. Urea was used to increase the
      populations of partially unfolded states which were labeled with deuterium
      following a brief exposure to D(2)O. Electrospray ionization mass spectra of both
      the intact protein and its peptic fragments had multiple envelopes of isotope
      peaks from which the populations of unfolded forms were determined. The present
      study extends the previous investigations to include different urea
      concentrations and kinetic modeling of data taken as the system approaches
      equilibrium. Analysis of these results gives rate and equilibrium constants
      describing the unfolding and refolding processes characteristic of aldolase
      destabilized in urea. The change in solvent-accessible surface, which has been
      used as a reaction coordinate for protein folding, is estimated from the
      dependence of the equilibrium and rate constants on the concentration of urea.

PMID- 10603238
TI  - A spectrophotometric assay for the transphosphatidylation activity of
      phospholipase D enzyme.
AB  - We developed a specific spectrophotometric assay for the quantitative
      determination of phospholipase D-catalyzed transphosphatidylation activity. The
      assay measures p-nitrophenol liberated by phospholipase D-catalyzed reaction of
      phosphatidyl-p-nitrophenol and ethanol in an aqueous-organic emulsion system. The
      release of p-nitrophenol was linear to reaction time at an early stage of the
      reaction with phospholipase D from Streptomyces sp. In the spectrophotometric
      assay for the reaction with phospholipase D from Streptomyces chromofuscus, which
      has higher hydrolytic activity than transphosphatidylation activity, p
      nitrophenol was not found. The advantages of this novel method for measuring the
      transphosphatidylation activity of phospholipase D are that (i) it does not use
      radioactive compounds, (ii) it can measure the initial velocity of the reaction,
      and (iii) it is rapid, easy, and accurate to perform.

PMID- 10603239
TI  - High-pressure liquid chromatography quantitation of cytochrome c using 393 nm
      detection.
AB  - The release of cytochrome c from the mitochondrial intermembrane space can induce
      apoptotic cell death. Previous methods to detect cytochrome c release from
      mitochondria have relied upon immunoblotting, a procedure that can be limited by
      nonlinearity of signal, epitope masking, and impracticality for large numbers of
      samples. In order to circumvent these limitations, we have developed a reverse
      phase high-pressure liquid chromatography method for cytochrome c detection and
      quantitation by taking advantage of a novel acid-induced absorbance maximum at
      393 nm for cytochrome c in buffer containing 0.1% trifluoroacetic acid. Using a
      C4 reverse-phase analytical column, this assay had a quantitation limit of 10 ng
      (0.8 pmol) of cytochrome c. We demonstrated the detection and quantitation of
      cytochrome c from isolated mitochondria. This method of cytochrome c analysis may
      be useful for the study of agents that cause mitochondrial dysfunction and
      apoptotic cell death.

PMID- 10603240
TI  - Time-resolved fluorescence immunoassay of thyroxine in serum: immobilized antigen
      approach.
AB  - With T(4)-bovine IgG as a solid-phase antigen, we have developed a direct
      competitive-type immunoassay for serum total thyroxine (TT(4)), which depends on
      the competitive distribution of europium-labeled anti-T(4) monoclonal antibody
      between solid-phase-bound T(4) and the T(4) in the sample or standard. The
      captured fraction of the tracer was measured after a dissociation-enhancement
      step. Four different T(4) protein conjugates were synthesized, of which T(4)
      bovine IgG was selected as the most favorable for the preparation of solid-phase
      antigen. The sensitivity was 3.5 ng/ml with a sample volume of 20 microl. T(4)
      values obtained by this procedure agreed well with those obtained by RIA (r =
      0.967, n = 38) and EG&G Wallac TRFIA (r = 0.926, n = 64). All other quality
      criteria was also fulfilled with respect to precision, accuracy, and dynamic
      range.

PMID- 10603241
TI  - Real-time, sequence-specific detection of nucleic acids during strand
      displacement amplification.
AB  - Strand displacement amplification (SDA) is an isothermal nucleic acid
      amplification method based on the primer-directed nicking activity of a
      restriction enzyme and the strand displacement activity of an exonuclease
      deficient polymerase. Here we describe fluorogenic reporter probes that permit
      real-time, sequence-specific detection of targets amplified during SDA. The new
      probes possess the single-strand half of a BsoBI recognition sequence flanked on
      opposite sides by a fluorophore and a quencher. The probes also contain target
      binding sequences located 3' to the BsoBI site. Fluorophore and quencher are
      maintained in sufficiently close proximity that fluorescence is quenched in the
      intact single-stranded probe. If target is present during SDA, the probe is
      converted into a fully double-stranded form and is cleaved by the restriction
      enzyme BsoBI, which also serves as the nicking agent for SDA. Fluorophore and
      quencher diffuse apart upon probe cleavage, causing increased fluorescence.
      Target replication may thus be followed in real time during the SDA reaction.
      Probe performance may be enhanced by embedding the fluorogenic BsoBI site within
      the loop of a folded hairpin structure. The new probe designs permit detection of
      as few as 10 target copies within 30 min in a closed-tube, real-time format,
      eliminating the possibility of carry-over contamination. The probes may be used
      to detect RNA targets in SDA mixtures containing reverse transcriptase.
      Furthermore, a two-color competitive SDA format permits accurate quantification
      of target levels from the real-time fluorescence data.

PMID- 10603242
TI  - Applications of short-chain polydimethylacrylamide as sieving medium for the
      electrophoretic separation of DNA fragments and mutation analysis in uncoated
      capillaries.
AB  - In capillary electrophoresis (CE), separation of DNA fragments is usually
      performed in covalently coated capillaries. Recent studies have demonstrated that
      certain polymers form a dynamic coating on the inner surface of the capillary,
      thereby suppressing the electroosmotic flow and DNA-capillary wall interactions.
      We developed a simple method for the synthesis of short-chain
      polydimethylacrylamide (PDMA) using isopropanol as a chain transfer agent.
      Capillary (<75 microm internal diameter) filling and replacement of this low
      viscosity (14 cP at 4% PDMA) self-coating medium were easily carried out by
      commercial CE instruments. Using PDMA and uncoated capillaries, we first examined
      the separation of phi X174 HaeIII DNA digests and observed that the stability of
      the dynamic coating was markedly better at pH 7.8 than at pH 8.3. At this lower
      pH and nondenaturing conditions, high resolution of the phi X174 HaeIII DNA
      digests was obtained for more than 850 injections in the same capillary. We then
      exploited this sieving medium in CE using multiple approaches for mutation
      analysis of clinical DNA samples including separation of restriction enzyme
      cleavage products, analysis of single strand conformation polymorphisms, and
      simultaneous detection of several mutations using multiplex allele-specific PCR
      amplification. Our results demonstrate that CE in uncoated capillaries using PDMA
      as sieving medium is a simple, versatile, and reliable strategy for separation
      and mutation analysis of clinical DNA samples.

PMID- 10603243
TI  - Gas chromatographic-tandem mass spectrometric quantification of free 3
      nitrotyrosine in human plasma at the basal state.
AB  - A fully validated gas chromatographic-tandem mass spectrometric (GC-tandem MS)
      method for the accurate and precise quantification of free 3-nitrotyrosine in
      human plasma at the basal state is described. In the plasma of 11 healthy humans
      a mean concentration of 2.8 nM (range 1.4-4.2 nM) for free 3-nitrotyrosine was
      determined by this method. This is the lowest concentration reported for free 3
      nitrotyrosine in plasma of healthy humans. The presence of endogenous free 3
      nitrotyrosine in human plasma was unequivocally shown by generating a daughter
      mass spectrum. Various precautions had to be taken to avoid artifactual formation
      of 3-nitrotyrosine from nitrate during sample treatment. Endogenous plasma 3
      nitrotyrosine and 3-nitro-l-[(2)H(3)]tyrosine added for use as internal standard
      were isolated by high-performance liquid chromatographic (HPLC) analysis of 200
      microl aliquots of plasma ultrafiltrate samples (20 kDa cut-off), extracted from
      a single HPLC fraction by solid-phase extraction, derivatized to their n-propyl
      ester-pentafluoropropionyl amide-trimethylsilyl ether derivatives, and quantified
      by GC-tandem MS. Overall recovery was determined as 50 +/- 5% using 3-nitro-l
      [(14)C(9)]tyrosine. The limit of detection of the method was 4 amol of 3
      nitrotyrosine, while the limit of quantitation was 125 pM using 3-nitro-l
      [(14)C(9)]tyrosine. 3-Nitrotyrosine added to human plasma at 1 nM was quantitated
      with an accuracy of > or = 80% and a precision of > or = 94%. The method should
      be useful to investigate the utility of plasma free 3-nitrotyrosine as an
      indicator of nitric oxide ((.)NO)-associated oxidative stress in vivo in humans.

PMID- 10603244
TI  - Real-time measurements of DNA hybridization on microparticles with fluorescence
      resonance energy transfer.
AB  - When capture oligonucleotides are tethered on planar surfaces, mass transport
      limitations influence the kinetics of solid-phase nucleic acid hybridizations. By
      diffusion theory, however, hybridization of oligonucleotides on microparticles
      should be reaction-rate limited. In an initial effort to understand the kinetics
      of microparticle hybridization reactions, we developed a fluorescence resonance
      energy transfer method for monitoring oligonucleotide hybridization on
      microparticles. Microparticles were coated with a fluoresceinated oligomer at
      surface densities of 20, 40, and 80% saturation, hybridized to a complementary
      oligonucleotide labeled with tetramethylrhodamine, and monitored over time for
      quenching of the fluorescein signal as hybridization occurred on the particle
      surface. Association rate constants were compared for microparticle-based
      hybridization and solution-phase hybridization. Rate constants for hybridizations
      on the particle surface were about an order of magnitude less than those for
      hybridization in solution, but decreasing the surface density of the capture
      oligonucleotide to 20% saturation improved particle hybridization rates. Although
      a bimolecular reaction model adequately described solution-phase hybridization
      kinetics, oligonucleotide hybridization on microparticles did not fit this model
      but exhibited biphasic reaction kinetics. Based on two different lines of
      reasoning, we argue that microparticle-based oligonucleotide hybridization was
      indeed reaction-rate limited in our system and not diffusion-rate limited.

PMID- 10603245
TI  - Description of a 96-well plate assay to measure cytochrome P4503A inhibition in
      human liver microsomes using a selective fluorescent probe.
AB  - The standard method to evaluate CYP3A inhibition is to study the conversion of
      the specific CYP3A probe testosterone to its 6 beta-hydroxy metabolite in human
      liver microsomes, in the absence and presence of potential inhibitors.
      Quantification of the 6 beta-hydroxy metabolite is achieved by HPLC resulting in
      a tedious and time-consuming assay. In order to increase the P450 inhibition
      throughput, efforts were made to find a CYP3A probe that would produce a
      fluorescent metabolite. This paper reports the discovery of DFB as a potential
      CYP3A fluorescent probe. DFB was significantly metabolized in human microsomes
      (approximately 1-2 nmol/(min. mg protein)) to give the fluorescent compound DFH.
      The involvement of CYP3A in the metabolism of DFB was determined using multiple
      approaches. First, incubations conducted with microsomes made from cell lines
      expressing single CYPs (Gentest Supersomes) indicated that CYP3A played a major
      role in the metabolism of DFB. Secondly, immunoinhibition studies conducted with
      CYP3A antibody resulted in >95% inhibition of DFB metabolism in HLM. Thirdly,
      inhibition studies with specific CYP1A1, 1A2, 2C8/9, 2C19, 2D6, and 2E1 chemical
      inhibitors did not suppress DFB activity in HLM. However, ketoconazole,
      miconazole, nicardipine, and nifedipine, all known CYP3A inhibitors, completely
      abolished the formation of DFH in HLM. The potency of several inhibitors
      determined using DFB and testosterone as CYP3A probes was consistent (R = 0.98).
      Finally, a good agreement was obtained for the formation of DFH and production of
      6 beta-hydroxytestosterone when DFB and testosterone were incubated separately
      with various human liver microsome preparations (R = 0.94, N = 11). In order to
      use DFH as a fluorescent CYP3A marker in a 96-well plate format, it was important
      to remove the excess of NADPH at the end of the incubation because the
      fluorescence of NADPH interferes with DFH detection. This was achieved by adding
      oxidized glutathione and glutathione reductase to convert NADPH to NADP(+) which
      is not fluorescent. The liquid-handling steps were fully automated in a 96-well
      plate format and a template was designed to generate IC(50) curves and to address
      potential fluorescent interferences from the test compounds. The assay was found
      to be reproducible (intraday variability <10% and interday variability indicated
      less than a 2-fold variation in the IC(50) values) and is now routinely used in
      our laboratory to evaluate CYP3A inhibition of NCEs.

PMID- 10603246
TI  - Method for determining protein kinase substrate specificities by the
      phosphorylation of peptide libraries on beads, phosphate-specific staining,
      automated sorting, and sequencing.
AB  - A method is described for the elucidation of the peptide substrate
      phosphorylation specificity of a protein kinase. Peptide libraries with two to
      six degenerate positions and a length of seven or nine amino acids were generated
      directly on Sepharose beads by solid-phase peptide synthesis according to the
      split-and-mix procedure. The immobilized peptides were incubated with the
      catalytic subunit of the cyclic AMP-dependent protein kinase (PKA) as a model
      enzyme resulting in the phosphorylation of the beads that contain the recognition
      motif of the kinase. The beads were then stained with a new phosphate-monoester
      specific fluorescent dye consisting of a complex of iron(III) with fluorescein
      coupled iminodiacetic acid. A flow cytometer was used to analyze the
      phosphorylation efficiency and the beads with the highest phosphorylation degree
      were isolated by the use of a fluorescence-activated cell sorter. Pool sequencing
      of those beads revealed the preferred kinase motif. The results are in good
      agreement with data from the literature. The method lends itself to the rapid
      elucidation of the specificity of uncharacterized protein kinases.

PMID- 10603247
TI  - The separation and direct detection of ceramides and sphingoid bases by normal
      phase high-performance liquid chromatography and evaporative light-scattering
      detection.
AB  - Sphingolipids are an important class of lipids due to their role as biologically
      active molecules and as intracellular second messengers. Sphingolipid metabolites
      are involved in a wide variety of important biological processes including signal
      transduction and growth regulation. Simple, quantitative analytical methods are
      needed to assay these complex lipids, in order to study their biological
      functions. The current methods used to quantify ceramides and long-chain
      sphingoid bases are primarily based on derivatization with uv or fluorescent tags
      and with radioactive-based enzymatic assays. A method was developed to separate
      ceramides and sphingoid bases by normal-phase high-performance liquid
      chromatography and detect them directly with evaporative light-scattering
      detection. Ceramides and the sphingoid bases phytosphingosine,
      dihydrosphingosine, sphingosine, and sphingosine 1-phosphate were resolved with a
      rapid and quantitative assay in the nanomole range. Yeast extracts grown to
      various time points were assayed for ceramide and sphingoid bases using a simple,
      isocratic HPLC system. Both ceramide and phytosphingosine, the primary sphingoid
      base present in yeast cell extracts, were detected in yeast cell extracts.
      Phytosphingosine was resolved as a sharp peak with the addition of triethylamine
      and formic acid modifiers to a chloroform/ethanol mobile phase. This method
      demonstrates the first direct assay of both ceramides and sphingoid bases.

PMID- 10603248
TI  - A new chromophoric assay for arginase activity.

PMID- 10603249
TI  - Immunoblotting with antiphosphoamino acid antibodies: importance of the blocking
      solution.

PMID- 10603250
TI  - A quantitative method to detect RNA editing events.

PMID- 10603251
TI  - Gas-liquid chromatographic determination of total glycerophosphate in an aqueous
      solution.

PMID- 10603252
TI  - Initial results on the molecular phylogeny of the Nudibranchia (Gastropoda,
      Opisthobranchia) based on 18S rDNA data.
AB  - This study investigated nudibranch phylogeny on the basis of 18S rDNA sequence
      data. 18S rDNA sequence data of 19 taxa representing the major living orders and
      families of the Nudibranchia were analyzed. Representatives of the Cephalaspidea,
      Anaspidea, Gymnomorpha, Prosobranchia, and Pulmonata were also sequenced and used
      as outgroups. An additional 28 gastropod sequences taken from GenBank were also
      included in our analyses. Phylogenetic analyses of these more than 50 gastropod
      taxa provide strong evidence for support of the monophyly of the Nudibranchia.
      The monophyly of the Doridoidea, Cladobranchia, and Aeolidoidea within the
      Nudibranchia are also strongly supported. Phylogenetic utility and information
      content of the 18S rDNA sequences for Nudibranchia, and Opisthobranchia in
      general, are examined using the program SplitsTree as well as phylogenetic
      reconstructions using distance and parsimony approaches. 0Results based on these
      molecular data are compared with hypotheses about nudibranch phylogeny inferred
      from morphological data.

PMID- 10603253
TI  - The tribal radiation of the family Bovidae (Artiodactyla) and the evolution of
      the mitochondrial cytochrome b gene.
AB  - The nucleotide sequence of the complete mitochondrial cytochrome b gene has been
      determined and compared for 51 species of the family Bovidae and 10 potential
      pecoran and tragulid outgroups. A detailed saturation analysis at each codon
      position relative to the maximum parsimony procedure indicates that all
      transitions on third codon positions do not accumulate in a similar fashion: C-T
      are more saturated than A-G substitutions. The same trend is observed for second
      positions but not for first positions where A-G and C-T transitions exhibit
      roughly the same levels of saturation. Maximum parsimony reconstructions were
      weighted according to these observations. Maximum parsimony, maximum likelihood,
      and distance phylogenetic reconstructions all depict a major split within
      Bovidae. The subfamily Bovinae includes four multifurcating tribes and subtribes:
      Boselaphini, Tragelaphini, cattle-Bovini (Bos and Bison), and buffalo-Bovini
      (Bubalus and Syncerus). Its sister group is the subfamily Antilopinae, i.e., all
      non-Bovinae taxa, represented by seven lineages: Antilopini (including Saiga),
      Caprini sensu lato (i. e., Caprinae including Pantholops), Hippotragini,
      Alcelaphini, Reduncini (including Pelea), Aepyceros possibly linked to Neotragus,
      and Cephalophini possibly linked to Oreotragus (the suni and the klipspringer
      being members of a polyphyletic Neotragini). These various tribes and major
      lineages were produced by two noteworthy explosive radiations, which occurred
      simultaneously between 12.0 and 15.3 MY (Middle Miocene) in the subfamilies
      Bovinae and Antilopinae.

PMID- 10603254
TI  - Miocene radiation of deep-sea hydrothermal vent shrimp (Caridea: Bresiliidae):
      evidence from mitochondrial cytochrome oxidase subunit I.
AB  - The evolutionary history of deep-sea shrimp (Caridea: Bresiliidae) inhabiting
      deep-sea hydrothermal vent and hydrocarbon seep environments was assessed using
      the mitochondrial Cytochrome c Oxidase subunit I (COI) gene (600 bp).
      Phylogenetic analyses (parsimony, likelihood, and neighbor-joining) recovered
      three distinct clades (A, Rimicaris/Chorocaris/Opaepele; B, Alvinocaris; and C,
      Mirocaris) consistent with higher level taxonomy based on morphology. However,
      robust phylogenetic results suggested that Chorocaris is paraphyletic and that
      Mirocaris fortunata and M. keldyshi may not be genetically distinct. A Kishino
      Hasegawa likelihood approach was used to test alternative phylogenetic hypotheses
      based on biogeography and morphology. Evolutionary relationships of vent-endemic
      shrimp species did not appear to be correlated either with their extant
      biogeographic distribution or with the history of sea floor spreading.
      Additionally, COI data suggested that these vent-endemic organisms are not
      remnants of a Mesozoic vent assemblage; instead, they radiated in the Miocene.

PMID- 10603255
TI  - Partial 28S rDNA sequences and the antiquity of hydrothermal vent endemic
      gastropods.
AB  - A molecular phylogenetic investigation of the hypothesized antiquity of the
      hydrothermal vent endemic Neomphalina (Mollusca; Gastropoda) is reported.
      Sequences of two domains of the gene encoding for 28S ribosomal RNA were acquired
      for 3 outgroup and 32 gastropod genera. Use of the likelihood ratio test
      indicated complex substitution patterns for these domains and taxa, corresponding
      to a general time-reversible model with among-site rate variation. Phylogenetic
      analyses were performed using this model under maximum likelihood criteria. The
      data lacked resolution of gastropod radiations of the Paleozoic and all three of
      the outgroup sequences were randomized relative to the ingroup. Acceleration of
      evolutionary rates had additionally randomized the sequences of the
      Patellogastropoda relative to the other Gastropoda. The data resolved radiations
      of the Mesozoic and supported monophyly of the sampled Neritopsina,
      Vetigastropoda, Neomphalina, Caenogastropoda (including Campanile and the
      Architaenioglossa), and Heterobranchia (Valvata + Euthyneura), although several
      results were not significantly different from nonmonophyletic alternatives.
      Mesozoic origins of the hydrothermal vent endemic Neomphalina are preliminarily
      supported and implications for the hydrothermal vent refugia hypothesis
      discussed. Issues related to phylogenetic resolution of the Gastropoda are
      additionally discussed.

PMID- 10603256
TI  - Molecular phylogenetics and the evolution of labral spines among eastern Pacific
      ocenebrine gastropods.
AB  - Labral spines are sharp projections of the apertural lip found in some marine
      gastropods that are used to penetrate hard-shelled prey. The majority of
      gastropod genera that contain labral spine-bearing species are found in the
      subfamily Ocenebrinae (Gastropoda: Muricidae). To reconstruct the evolutionary
      history of labral spine-bearing and labral spine-lacking gastropods in the
      eastern Pacific (EP) Ocean, partial sequences of two mitochondrial genes
      (cytochrome oxidase I and 12S rRNA) were obtained from representative taxa.
      Despite high nucleotide bias, a variety of phylogenetic reconstruction methods
      produced the same tree topology. The traditional taxonomic view that all "Nucella
      like" spine-bearing taxa in the EP belong to a monophyletic "Acanthina" is
      rejected due to nonmonophyly of this group. The more recently recognized
      "Acanthinucella" is also not monophyletic, and we therefore propose the new genus
      Mexacanthina for two Mexican species formerly assigned to Acanthinucella. The
      genus Ocinebrina, which first appears in the middle Eocene, is not a stem EP
      ocenebrine lineage and may also not be a monophyletic clade. Tracing the
      evolutionary history of labral spines among extant lineages indicates that the
      absence of a labral spine is ancestral for all EP ocenebrines. Ancestral
      conditions could not be resolved unambiguously for all nodes of the phylogeny
      based on extant taxa. However, by jointly considering both molecular phylogenetic
      relationships and the phylogenetic affinities of several extinct taxa, all
      remaining character state transformation can be inferred unambiguously. Based on
      this analysis, a labral spine likely evolved independently in at least four
      lineages of EP ocenebrines. Although homoplasy appears to characterize labral
      spine evolution among ocenebrine gastropods, the structural position of a labral
      spine was evolutionarily altered in one lineage, indicating that different types
      of labral spines do not necessarily reflect convergent evolution.

PMID- 10603257
TI  - Phylogeny of the Neotropical killifish family Rivulidae (Cyprinodontiformes,
      Aplocheiloidei) inferred from mitochondrial DNA sequences.
AB  - Phylogenetic relationships of 70 taxa representing 68 species of the Neotropical
      killifish family Rivulidae were derived from analysis of 1516 nucleotides sampled
      from four different segments of the mitochondrial genome: 12S rRNA, 16S rRNA,
      cytochrome oxidase I, and cytochrome b. The basal bifurcation of Cynolebiatinae
      and Rivulinae (Costa, 1990a,b) is supported; however, Terranatos, Maratecoara,
      and Plesiolebias are rivulins, not cynolebiatins. These three genera, along with
      the other recognized annual rivulin genera, form a monophyletic clade.
      Austrofundulus, Rachovia, Renova, Terranatos, and 3 species of the genus
      Pterolebias, all from northeastern South America, form a monophyletic clade
      excluding other species of Pterolebias. Pterolebias as presently understood is
      clearly polyphyletic. Trigonectes and Moema are supported as sister groups but do
      not form a monophyletic group with the genera Neofundulus and Renova as
      previously proposed. The suite of adaptations necessary for an annual life
      history has clearly been lost several times in the course of rivulid evolution.
      Also revealed is a considerable increase in substitution rate in most annual
      lineages relative to the nonannual Rivulus species. The widespread and speciose
      genus Rivulus is paraphyletic, representing both basal and terminal clades within
      the Rivulidae. Previous hypotheses regarding the vicariant origin of Greater
      Antillean Rivulus species are supported. Most rivulid clades show considerable
      endemism; thus, detailed analysis of rivulid phylogeny and distribution will
      contribute robust hypotheses to the clarification of Neotropical biogeography.

PMID- 10603258
TI  - Dynamically heterogenous partitions and phylogenetic inference: an evaluation of
      analytical strategies with cytochrome b and ND6 gene sequences in cranes.
AB  - ki ctes over whether molecular sequence data should be partitioned for
      phylogenetic analysis often confound two types of heterogeneity among partitions.
      We distinguish historical heterogeneity (i.e., different partitions have
      different evolutionary relationships) from dynamic heterogeneity (i.e., different
      partitions show different patterns of sequence evolution) and explore the impact
      of the latter on phylogenetic accuracy and precision with a two-gene,
      mitochondrial data set for cranes. The well-established phylogeny of cranes
      allows us to contrast tree-based estimates of relevant parameter values with
      estimates based on pairwise comparisons and to ascertain the effects of
      incorporating different amounts of process information into phylogenetic
      estimates. We show that codon positions in the cytochrome b and NADH
      dehydrogenase subunit 6 genes are dynamically heterogenous under both Poisson and
      invariable-sites + gamma-rates versions of the F84 model and that heterogeneity
      includes variation in base composition and transition bias as well as
      substitution rate. Estimates of transition-bias and relative-rate parameters from
      pairwise sequence comparisons were comparable to those obtained as tree-based
      maximum likelihood estimates. Neither rate-category nor mixed-model partitioning
      strategies resulted in a loss of phylogenetic precision relative to unpartitioned
      analyses. We suggest that weighted-average distances provide a computationally
      feasible alternative to direct maximum likelihood estimates of phylogeny for
      mixed-model analyses of large, dynamically heterogenous data sets.

PMID- 10603259
TI  - Novelty in phylogeny of gastrotricha: evidence from 18S rRNA gene.
AB  - Gastrotricha form a phylum which is crucial for defining the origin of
      pseudocoelomates, in that they share a number of characters with Rotifera and
      Nematoda but also with acoelomates, and even the evolutionary relationships
      within the phylum are anything but defined. For this reason the first extensive
      molecular data on Gastrotricha from the 18S rRNA sequences of both orders have
      been obtained and analyzed. Sequence analyses show that the phylum Gastrotricha
      is strictly monophyletic along an evolutionary line quite distinct from that of
      both Rotifera and Nematoda. A new view of the evolutionary history of the phylum
      Gastrotricha is put forward, in which Chaetonotida, and not Macrodasyida, are the
      most primitive forms of the group, contrary to the commonly held view. A
      polyphyletic origin of aschelminthes is supported, and the misleading term
      pseudocoelomates should be discarded.

PMID- 10603260
TI  - Phylogeny of Drosophila and related genera: conflict between molecular and
      anatomical analyses.
AB  - Drosophila species are extensively used in biological research; yet, important
      phylogenetic relationships within the genus and with related genera remain
      unresolved. The combined data for three genes (Adh, Sod, and Gpdh) statistically
      resolves outstanding issues. We define the genus Drosophila inclusively so as to
      include Scaptomyza and Zaprionus (considered distinct genera in the taxonomy of
      Wheeler, 1981) but excluding Scaptodrosophila. The genus Drosophila so defined is
      monophyletic. The subgenus Sophophora (including the melanogaster, obscura, and
      willistoni groups) is monophyletic and the sister clade to all other Drosophila
      subgenera. The Hawaiian Drosophila (including Scaptomyza) is a monophyletic
      group, but the subgenus Drosophila is not monophyletic, because the immigrans
      group is more closely related to the subgenus Hirtodrosophila than to other
      species of the subgenus Drosophila, such as the virilis and repleta groups.

PMID- 10603261
TI  - A method for evaluating phylogenetic relationship of alpha-satellite DNA
      suprachromosomal family by nucleotide frequency calculation.
AB  - The sequence similarity among chromosome-specific alpha-satellite DNA was
      quantitatively evaluated by a novel procedure: nucleotide frequency calculation.
      Tandem-arrayed repetitive DNA segments were aligned with unit length repeat, and
      the nucleotide frequency at each position was used to estimate the phylogenetic
      distance between repetitive DNA segments. The calculations for human and
      chimpanzee X chromosome alpha-satellites showed that the results were consistent
      with the known relationships of primates, indicating that the nucleotide
      frequency calculation worked effectively to estimate the distances between
      satellite arrays. Human chromosome-specific alpha-satellites had been grouped
      into three suprachromosomal families (I, II, and III), and in the current work
      the nucleotide frequency analysis has defined the quantitative distances between
      the chromosome-specific alpha-satellite DNA.

PMID- 10603262
TI  - Different models, different trees: the geographic origin of PTLV-I.
AB  - Using nucleotide sequences from three genomic regions of the human and simian T
      cell lymphotropic virus type I (HTLV-I/STLV-I)-consisting of 69 sequences from a
      140-bp segment of the pol region, 98 sequences from a 503-bp segment of the LTR,
      and 154 sequences from a 386-bp segment of the env region-we tested two
      hypotheses concerning the geographic origin and evolution of STLV-I and HTLV-I.
      First, we tested the assumption of equal rates of evolution along STLV-I and HTLV
      I lineages using a likelihood ratio test to ascertain whether current levels of
      genomic diversity can be used to determine ancestry. We demonstrated that unequal
      rates of evolution along HTLV-I and STLV-I lineages have occurred throughout
      evolutionary time, thus calling into question the use of pairwise distances to
      assign ancestry. Second, we constructed phylogenetic trees using multiple
      phylogenetic techniques to test for the geographic origin of STLV-I and HTLV-I.
      Using the principle of likelihood, we chose a statistically justified model of
      evolution for each data set. We demonstrated the utility of the likelihood ratio
      test to determine which model of evolution should be chosen for phylogenetic
      analyses, revealing that using different models of evolution produces conflicting
      results, and neither the hypothesis of an African origin nor the hypothesis of an
      Asian origin can be rejected statistically. Our best estimates of phylogenetic
      relationships, however, support an African origin of PTLV for each gene region.

PMID- 10603263
TI  - Molecular phylogeny of Old World monkeys (Cercopithecidae) as inferred from gamma
      globin DNA sequences.
AB  - DNA sequence data of the nuclear-encoded gamma1-gamma2-globin duplication region
      were used to examine the phylogenetic relationships of 16 cercopithecid (Old
      World monkey) species representing 12 extant genera. Morphology- and molecular
      based hypotheses of Old World monkey branching patterns are generally congruent,
      except for generic relationships within the subtribe Papionina. The
      cercopithecids divide into colobines (leaf-eating monkeys) and cercopithecines
      (cheek-pouched monkeys). The colobines examined by the DNA data divide into an
      Asian clade (Nasalis, proboscis monkeys; Trachypithecus, langurs) and an African
      clade (Colobus, colobus monkeys). The cercopithecines divide into tribes
      Cercopithecini (Erythrocebus, patas monkey; Chlorocebus, green monkeys;
      Cercopithecus, guenons) and Papionini. Papionins divide into subtribes Macacina
      (Macaca, macaques) and Papionina (Papio, hamadryas baboons; Mandrillus, drills
      and mandrills; Theropithecus, gelada baboons; Lophocebus, arboreal mangabeys;
      Cercocebus, terrestrial mangabeys). In a morphologically based classification,
      Mandrillus is a subgenus of Papio, whereas Lophocebus is a subgenus of
      Cercocebus. In contrast, the molecular evidence treats Mandrillus as a subgenus
      of Cercocebus, and treats both Theropithecus and Lophocebus as subgenera of
      Papio. Local molecular clock divergence time estimates were used as a yardstick
      in a "rank equals age" system to propose a reduction in taxonomic rank for most
      clades within Cercopithecidae.

PMID- 10603264
TI  - Molecular phylogeny and geographic distribution of wood-feeding cockroaches in
      East Asian Islands.
AB  - Molecular phylogenetic relationships of the wood-feeding cockroach genera
      Salganea and Panesthia (Blaberidae; Panesthiinae) in East Asian Islands (Ryukyu
      archipelago and Taiwan Island) were analyzed based on the DNA sequence of the
      complete mitochondrial cytochrome oxidase II gene. Unweighted parsimony analysis
      resulted in high bootstrap support for relationships within Panesthia taxa;
      however, some nodes were unresolved between members of Salganea. Comparison of
      the number of transitions and transversions with genetic distance at each codon
      position suggested that saturation of third-codon substitutions has occurred
      between certain pairs of taxa. Consequently, differential weighting of
      substitutions at these sites was performed, which resulted in a substantial
      increase in resolution of Salganea relationships. The inferred phylogenies for
      both genera displayed good correspondence to the geographical locations of
      populations but however did not agree with previous subspecies designations based
      on morphological characters. It appears that both cockroach genera invaded the
      Ryukyu archipelago from the Taiwan region via a land-bridge present in the
      Miocene period. Invasion of the main islands of Japan by these cockroaches most
      likely occurred before the formation of the Tokara Tectonic Strait. Our study
      suggests that several barriers to gene flow have arisen and persisted over the
      past approximately 10 million years, which have caused segregation and vicariant
      speciation of the cockroach taxa of this region.

PMID- 10603265
TI  - Phylogenetic relationships within the aquatic snail genus Tryonia: implications
      for biogeography of the North American Southwest.
AB  - We examined the phylogenetic relationships among 23 species of the North American
      aquatic snail genus Tryonia (Hydrobiidae), 10 additional representatives of the
      subfamily Cochliopinae, and two outgroups. Maximum parsimony analysis of a 601
      base-pair sequence from the mitochondrial COI gene did not support monophyly of
      the genus nor its subgenus Paupertryonia. A clade composed of the type species of
      Tryonia and 16 congeners was strongly supported by the COI data and congruent
      with recently discovered variation in female genitalic morphology. This "true
      Tryonia" clade included two large western subclades having a sister-group
      relationship. The phylogenetic structure of one of these subclades is congruent
      with vicariant events associated with late Neogene history of the lower Colorado
      River drainage. The other subclade mirrors development of the modern Rio Grande
      rift and inception of modern topography in the southwestern Great Basin during
      the late Neogene. Both subclades are represented in the composite Tryonia fauna
      of the Amargosa River basin, whose assembly is attributed to the complex
      geological history of the Death Valley region.

PMID- 10603266
TI  - The place of Callimico goeldii in the Callitrichine phylogenetic tree: evidence
      from von Willebrand factor gene intron II sequences.
AB  - Sequences of a 0.9-kb DNA segment spanning intron 11 of the von Willebrand Factor
      gene (vWF) were determined for 21 individuals of 19 primate species. The results
      of maximum parsimony and maximum likelihood analyses of these vWF sequences are
      congruent with previous molecular findings from other nonlinked nuclear genomic
      loci which divide the platyrrhine superfamily Ceboidea into three monophyletic
      families: Cebidae, Atelidae, and Pitheciidae. The vWF results strongly support
      the taxon Callitrichinae as a monophyletic subfamily within Cebidae. The four
      extant callitrichine genera constitute tribe Callitrichini, and the basal
      branchings within this tribe first separate out Saguinus (tamarins), next
      Leontopithecus (lion tamarins), and last the sister genera Callimico (Goeldi's
      monkeys) and Callithrix (marmosets). Callithrix divides into three subclades,
      with pygmy marmosets (C. pygmaea) as sister of the C. argentata species group and
      with the C. jacchus species group as their sister. Fossil and DNA evidence place
      the emergence of the callitrichine clade in the basal cebid radiation at about 20
      Ma (million years ago) and the three basal branchings in the callitrichin
      radiation at about 13 to 11 Ma. In turn, the branchings separating the three
      subclades of Callithrix are placed at about 5 to 4 Ma.

PMID- 10603267
TI  - The long and short of it: branch lengths and the problem of placing the New
      Zealand short-tailed bat, Mystacina.
AB  - The taxonomic position of the endemic New Zealand bat genus Mystacina has vexed
      systematists ever since its erection in 1843. Over the years the genus has been
      linked with many microchiropteran families and superfamilies. Most recent
      classifications place it in the Vespertilionoidea, although some immunological
      evidence links it with the Noctilionoidea (=Phyllostomoidea). We have sequenced
      402 bp of the mitochondrial cytochrome b gene for M. tuberculata (Gray in
      Dieffenbach, 1843), and using both our own and published DNA sequences for taxa
      in both superfamilies, we applied different tree reconstruction methods to find
      the appropriate phylogeny and different methods of estimating confidence in the
      parts of the tree. All methods strongly support the classification of Mystacina
      in the Noctilionoidea. Spectral analysis suggests that parsimony analysis may be
      misleading for Mystacina's precise placement within the Noctilionoidea because of
      its long terminal branch. Analyses not susceptible to long-branch attraction
      suggest that the Mystacinidae is a sister family to the Phyllostomidae. Dating
      the divergence times between the different taxa suggests that the extant
      chiropteran families radiated around and shortly after the Cretaceous-Tertiary
      boundary. We discuss the biogeographical implications of classifying Mystacina
      within the Noctilionoidea and contrast our result with those classifications
      placing Mystacina in the Vespertilionoidea, concluding that evidence for the
      latter is weak.

PMID- 10603268
TI  - Phylogenetic relationships within the class Anthozoa (phylum Cnidaria) based on
      nuclear 18S rDNA sequences.
AB  - Taxonomic relationships within the corals and anemones (Phylum Cnidaria: Class
      Anthozoa) are based upon few morphological characters. The significance of any
      given character is debatable, and there is little fossil record available for
      deriving evolutionary relationships. We analyzed complete 18S ribosomal sequences
      to examine subclass-level and ordinal-level organization within the Anthozoa. We
      suggest that the Subclass Ceriantipatharia is not an evolutionarily relevant
      grouping. The Order Corallimorpharia appears paraphyletic and closely related to
      the Order Scleractinia. The 18S rRNA gene may be insufficient for establishing
      robust phylogenetic hypotheses concerning the specific relationships of the
      Corallimorpharia and the Ceriantharia and the branching sequence for the orders
      within the Hexacorallia. The 18S rRNA gene has sufficient phylogenetic signal,
      however, to distinguish among the major groupings within the Class Anthozoa, and
      we use this information to suggest relationships for the enigmatic taxa
      Dactylanthus and Dendrobrachia.

PMID- 10603269
TI  - The Tarsius gamma-globin gene: pseudogene or active gene?
AB  - We sequenced the approximately 5-kb long gamma-globin gene locus from Tarsius
      bancanus and compared it to the published gamma-globin gene sequence from the
      related species Tarsius syrichta. The T. syrichta gene's promoter lacks the
      distal CCAAT box and has a point mutation in the functionally important proximal
      CCAAT box (CCgAT). This previous finding had suggested that in tarsiers the gamma
      globin gene might be a nonexpressed pseudogene. The two tarsier species show the
      same point mutation at the third nucleotide of the proximal CCAAT element and
      absence of the distal CCAAT element. Nevertheless, our results indicate that in
      tarsiers the gamma-globin gene is active, since all three coding regions show
      only synonymous substitutions and a much lower level of divergence than the
      noncoding regions. This is significantly different from what would be expected
      for a silent gene evading stabilizing selection. Thus, we hypothesize that the
      tarsier's gamma-globin gene locus is expressed even with the mutation in the
      proximal CCAAT box.

PMID- 10603270
TI  - Re: Origin and diversification of Euleptocarabus porrecticollis (Coleoptera,
      Carabidae) in the Japanese islands inferred from mitochondrial ND5 gene
      sequences.

PMID- 10603271
TI  - Ontogenetic and phylogenetic development of the endocrine pancreas (islet organ)
      in fish.
AB  - The morphology of the gastroenteropancreatic (GEP) system of fish was reviewed
      with the objective of providing the phylogenetic and ontogenetic development of
      the system in this vertebrate group, which includes agnathans and gnathostome
      cartilaginous, actinoptyerygian, and sarcopterygian fish. Particular emphasis is
      placed on the fish homolog of the endocrine pancreas of other vertebrates, which
      is referred to as the islet organ. The one-hormone islet organ (B cells) of
      larval lampreys is the most basic pattern seen among a free-living vertebrate,
      with the two-hormone islet organ (B and D cells) of hagfish and the three-hormone
      islet organ (B, D, and F cells) of adult lampreys implying a phylogenetic trend
      toward the classic four-hormone islet tissue (B, D, F, and A cells) in most other
      fish. An earlier stage in the development of this phylogenetic sequence in
      vertebrates may have been the restriction of islet-type hormones to the
      alimentary canal, like that seen in protochordates. The relationship of the islet
      organ to exocrine pancreatic tissue, or its equivalent, is variable among bony,
      cartilaginous, and agnathan fishes and is likely a manifestation of the early
      divergence of these piscine groups. Variations in pancreatic morphology between
      individuals of subgroups within both the lamprey and chondrichthyan taxa are
      consistent with their evolutionary distance. A comparison of the distribution and
      degree of concentration of the components of the islet organ among teleosts
      indicates a diffuse distribution of relatively small islets in the generalized
      euteleosts and the tendency for the concentration into Brockmann bodies of large
      (principal) islets (with or without secondary islets) in the more derived forms.
      The holostean actinopterygians (Amiiformes and Semiontiformes) share with the
      basal teleosts (osteoglossomorphs, elopomorphs) the diffuse arrangement of the
      components of the islet organ that is seen in generalized euteleosts. Since
      principal islets are also present in adult lampreys the question arises whether
      principal islets are a derived or a generalized feature among teleosts. There is
      a paucity of studies on the ontogeny of the GEP system in fish but it has been
      noted that the timing of the appearance of the islet cell types parallels the
      time that they appear during phylogeny; the theory of recapitulation has been
      revisited. It is stressed that the lamprey life cycle provides a good opportunity
      for studying the development of the GEP system. There are now several markers of
      cell differentiation in the mammalian endocrine pancreas which would be useful
      for investigating the development of the islet organ and cells of the remaining
      GEP system in fish.

PMID- 10603272
TI  - Developmental expression of steroidogenic factor 1 in a turtle with temperature
      dependent sex determination.
AB  - A variety of reptiles possess temperature-dependent sex determination (TSD) in
      which the incubation temperature of a developing egg determines the gonadal sex.
      Current evidence suggests that temperature signals may be transduced into steroid
      hormone signals with estrogens directing ovarian differentiation. Steroidogenic
      factor 1 (SF-1) is one component of interest because it regulates the expression
      of steroidogenic enzymes in mammals and is differentially expressed during
      development of testis and ovary. Northern blot analysis of SF-1 in developing
      tissues of the red-eared slider turtle (Trachemys scripta), a TSD species,
      detected a single primary SF-1 transcript of approximately 5.8 kb across all
      stages of development examined. Analysis by in situ hybridization indicated
      nearly equivalent SF-1 expression in early, bipotential gonads at male (26
      degrees C)- and female (31 degrees C)-producing incubation temperatures. In
      subsequent stages, as gonadal sex first becomes histologically distinguishable
      during the temperature-sensitive period, SF-1 expression increased in gonads at a
      male-producing temperature and decreased at a female-producing temperature,
      suggesting a role for SF-1 in the sex differentiation pathway. SF-1 message was
      also found in adrenal and in the periventricular region of the preoptic area and
      diencephalon, but there was no apparent sex bias in these tissues at any stage
      examined. The overall developmental pattern of SF-1 mRNA expression in T. scripta
      appears to parallel that found in mammals, indicating possible homologous
      functions.

PMID- 10603273
TI  - Actions of two forms of gonadotropin releasing hormone and a GnRH antagonist on
      spawning behavior of the goldfish Carassius auratus.
AB  - The central effects of two native forms of gonadotropin-releasing hormone (GnRH),
      salmon GnRH (sGnRH) and chicken GnRH-II (cGnRH-II), and a GnRH antagonist, ?Ac
      delta 3-Pro(1), 4FD-Phe(2), D-Trp(3, 6)mGnRH (analog E), on the spawning behavior
      of sexually recrudescent female goldfish were investigated. The effects of analog
      E were also observed in mature males. Female spawning behavior was induced by
      intramuscular injection of females with prostaglandin F(2alpha) and placing them
      in the presence of mature males. Behavioral responses were quantified by
      recording the numbers of spawning acts performed by each pair of fish for 2 h
      following brain intracerebroventricular (icv) injection of different dosages of
      peptide or saline as control. For males, the time spent courting the female was
      recorded. Each pair of fish was pretested to determine their level of spawning
      behavior, for comparison to spawning behavior following icv treatment. Icv
      injection of analog E caused a significant decrease in the number of spawning
      acts performed by females, suggesting a role of endogenous GnRH in modulating
      female spawning behavior. icv injection of 0.5 ng/g of sGnRH or cGnRH-II
      significantly stimulated female spawning behavior, whereas doses of 1 ng/g and
      higher resulted in an almost complete inhibition of spawning, reflecting a down
      regulation as a result of the excessive dosages. Analog E suppressed the actions
      of exogenous sGnRH and cGnRH-II on spawning behavior, as both the sGnRH- and
      cGnRH-II-induced increases in the number of spawning acts were inhibited by
      concomitant treatment with analog E. Analog E-injected males showed no alteration
      in courtship behavior. These results indicate that GnRH peptides play a major
      role in the control of female reproductive behavior in goldfish, but have little
      or no role in the control of male behavior.

PMID- 10603274
TI  - Plasma steroid concentrations and male phallus size in juvenile alligators from
      seven Florida lakes.
AB  - Neonatal and juvenile alligators from contaminated Lake Apopka in central Florida
      exhibit abnormal plasma sex steroid concentrations as well as morphological
      abnormalities of the gonad and phallus. This study addresses whether similar
      abnormalities occur in juvenile alligators inhabiting six other lakes in Florida.
      For analysis, animals were partitioned into two subsets, animals 40-79 cm total
      length (1-3 years old) and juveniles 80-130 cm total length (3-7 years old).
      Plasma testosterone (T) concentrations were lower in small males from lakes
      Apopka, Griffin, and Jessup than from Lake Woodruff National Wildlife Refuge
      (NWR). Similar differences were observed in the larger juveniles, with males from
      lakes Jessup, Apopka, and Okeechobee having lower plasma T concentrations than
      Lake Woodruff males. Plasma estradiol-17beta (E(2)) concentrations were
      significantly elevated in larger juvenile males from Lake Apopka compared to Lake
      Woodruff NWR. When compared to small juvenile females from Lake Woodruff NWR,
      females from lakes Griffin, Apopka, Orange, and Okeechobee had elevated plasma
      E(2) concentrations. Phallus size was significantly smaller in males from lakes
      Griffin and Apopka when compared to males from Lake Woodruff NWR. An association
      existed between body size and phallus size on all lakes except Lake Apopka and
      between phallus size and plasma T concentration on all lakes except lakes Apopka
      and Orange. Multiple regression analysis, with body size and plasma T
      concentration as independent covariables, explained the majority of the variation
      in phallus size on all lakes. These data suggest that the differences in sex
      steroids and phallus size observed in alligators from Lake Apopka are not limited
      to that lake, nor to one with a history of a major pesticide spill. Further work
      examining the relationship of sex steroids and phallus size with specific biotic
      and abiotic factors, such as antiandrogenic or estrogenic contaminants, is
      needed.

PMID- 10603275
TI  - Effect of octopamine on the activity of juvenile-hormone esterase in the silkworm
      Bombyx mori and the red flour beetle Tribolium freemani.
AB  - This study focuses on the effect of octopamine (OA) on metamorphosis of the
      silkworm Bombyx mori and the red flour beetle Tribolium freemani Hinton. Titers
      of OA and juvenile-hormone esterase (JHE) were measured at various larval and
      pupal stadia of both insects. Effects of OA, OA agonists, and antagonists on
      metamorphosis and JHE activity were also examined. At day 2, peaks of OA and JHE
      activity were observed in third instars, and at day 3, a sharp peak of OA was
      observed, followed by a large peak of JHE activity at day 4 in last instars of B.
      mori. However, no peaks of OA and JHE activity were observed in fourth instars. A
      high titer of OA appeared at days 2-4, followed by a peak of JHE activity at day
      7 and the second OA peak at day 9 after the start of assay of T. freemani. At
      pupation, a small peak of OA and the highest activity of JHE were observed. The
      effects of OA on JHE activity were examined in vitro, because the relationship
      could be responsible for triggering pupation in B. mori and T. freemani larvae.
      Exogeneous OA (0.1-10 mM) stimulated the JHE activity of final instars (day 2) of
      B. mori in vitro. Similarly, the presence of OA (10 mM) activated the JHE
      activity of newly ecdysed T. freemani pupae in vitro. OA antagonists
      chlorpromazine and gramine delayed the start of spinning and reduced the JHE
      activity of B. mori, when applied in diet at 10-100 ppm. Some OA agonists
      stimulated the pupation and JHE activity of T. freemani larvae reared under
      crowded conditions, when topically applied. Thus, OA may contribute to activation
      of the events preparatory to a pupal molt, i.e., the secretion of OA increases
      JHE activity followed by stimulation of pupation.

PMID- 10603276
TI  - Ecdysone has an effect on the regeneration of midgut epithelial cells that is
      distinct from 20-hydroxyecdysone in the silkworm Bombyx mori.
AB  - We investigated the effects of two ecdysteroids, ecdysone (E) and 20
      hydroxyecdysone (20E), on silkworm larval development. Silkworm larvae, Bombyx
      mori, were fed an artificial diet supplemented with 20E during the fourth instar
      to promote premature molting. At the onset of the fifth instar, these precocious
      fifth-instar larvae were fed diets supplemented with either E or 20E to determine
      the effects of the two ecdysteroids on the morphology of midgut epithelial cells.
      Regeneration of midgut epithelial cells normally occurs only during the molting
      period. However, in larvae fed E, complete replacement of midgut epithelial cells
      was observed 24 h before the larvae entered apolysis. In larvae fed 20E, the
      morphology of midgut epithelial cells was disrupted, leading to death of the
      larvae during the fifth instar. We also observed similar differences in the
      effects of the two ecdysteroids in an in vitro experiment. These results suggest
      that E has a specific effect on the morphological change of midgut epithelial
      cells in precocious fifth-instar larvae that is distinct from 20E.

PMID- 10603277
TI  - Potassium-induced secretion of melanocyte-stimulating hormone from the
      melanotrophs of the neurointermediate lobe of the lizard Anolis carolinensis.
AB  - Secretion of melanocyte-stimulating hormone (MSH) from the melanotrophs of the
      neurointermediate lobe (NIL) of the lizard Anolis carolinensis was studied to
      investigate the role of membrane potential and extracellular calcium ions in the
      control of secretion in this species. MSH secretion was monitored from perifused
      NILs which had been in organ culture for 7-14 days prior to experiment to allow
      the nerve terminals present in the tissue to degenerate. Elevation of the K(+)
      concentration in the perifusate induced a marked increase in MSH secretion.
      Perifusion of the cultured NILs with a nominally Ca-free solution did not reduce
      basal MSH secretion but blocked K-induced secretion. Moreover, nimodipine, an
      antagonist of voltage-gated Ca(2+) channels, inhibited K-induced secretion,
      whereas BAY K 8644, a Ca(2+) channel agonist, potentiated it; but neither drug
      affected basal secretion. High ?K(+) perifusate also stimulated MSH secretion
      from freshly excised (acute) NILs. Furthermore, in these preparations nominally
      Ca-free solution reduced basal secretion by 40% in addition to blocking K-induced
      secretion. As in the cultured NILs, nimodipine blocked and BAY K 8644 potentiated
      K-induced secretion in the acute NILs while not affecting basal secretion. The
      results from the cultured NILs are consistent with the hypothesis that stimulated
      MSH secretion from the melanotrophs of the anole is dependent upon Ca(2+) influx
      through voltage-gated calcium channels. The qualitatively similar results
      obtained from the acute NILs in response to high ?K(+), nimodipine, and BAY K
      8644 suggest that, for the most part, what is being observed are the direct
      effects of these substances on the melanotrophs. Basal secretion of MSH in
      cultured NILs is significantly less than that in the acute preparations. The
      calcium-sensitive fraction of basal secretion present in acute NILs may require
      the presence of nerve terminals.

PMID- 10603278
TI  - Developmental changes and among-sibling variation of corticosterone levels in an
      altricial avian species.
AB  - The postnatal development of the activity of the brain-pituitary-adrenal axis was
      investigated in an altricial bird species by measurements of plasma
      corticosterone levels in nestling and fledgling canaries, Serinus canaria.
      Corticosterone was detectable (>2.6 ng/ml) in 30% of 5-day-old, 67% of 10-day
      old, 72% of 15-day-old, and 88% of 23-day-old birds. When detectable, the
      corticosterone levels of 5-day-old nestlings were comparable to the baseline
      levels of adult birds. Levels were higher in 10- and 15- than in 5-day-old
      nestlings. The levels of 23-day-old fledglings (about 6 to 7 days after
      fledgling) were significantly higher than those of 15-day-old nestlings. They
      were intermediate between adult baseline and stress-induced levels. Sex did not
      influence this general profile, but levels varied with the order of hatching
      within broods. At the age of 15 and 23 days first hatched chicks had higher
      corticosterone levels than last hatched chicks, while second hatched chicks had
      intermediate levels. These differences were not correlated with body mass. The
      results suggest that (1) the brain-pituitary-adrenal axis of this altricial bird
      becomes fully functional after hatching and (2) birth order within broods
      influences corticosterone secretion during subsequent stages of development. It
      is unlikely that the brain-pituitary-adrenal axis matures at different rates in
      first and later hatched chicks or that the different levels of first and later
      hatched chicks were caused by capture and handling stress. Rather, they may
      result from such maternal effects as hatching asynchrony or differential
      concentrations of yolk steroids among the eggs in a clutch. Further studies will
      have to show whether this systematic variation of corticosterone levels among
      siblings during early life persists into adulthood and how it is related to
      behavior and fitness.

PMID- 10603279
TI  - Ultrastructure and immunocytochemistry of the islet organ of osteoglossomorpha
      (Teleostei).
AB  - Both routine electron microscopy and immunocytochemistry with protein A-gold were
      used to identify the cell types within the islet organs of four species of
      teleosts (Osteoglossum bicirrhosum, Pantodon buchholzi, Notopterus chitala, and
      Gnathonemus petersii) within Osteoglossomorpha, a subdivision with an ancient
      lineage. Four primary endocrine cell types, A, B, D, and F, were identified
      within the islets of the four species examined. The B- and D-cells were located
      mainly in the central core of the islet in the four species. In general, the A
      cells were located at the islet periphery in all of the four species but in P.
      buchholzi and N. chitala they were also differently distributed toward the islet
      core. F-cells were present only at the islet periphery. Granules of B-cells in
      three species had a relatively homogeneous shape of the matrix core, but in O.
      bicirrhosum, the shape varied greatly. Variation in matrix shape of B-cell
      granules may indicate a different conformation of insulin molecules among at
      least some species of osteoglossomorphs, and this observation may have some
      taxonomic significance. Two somatostatin-containing (SST) D-cell types (D1 and
      DX) with granules of different shape were observed in all four species of
      osteoglossomorphs. The granules of the two D-cells immunostained either with anti
      SST-25 and anti-SST-14 (D1-cells) or with anti-SST-34 (DX-cells).
      Immunocytochemistry confirmed that A-cells, containing glucagon-family peptides,
      and F-cells, containing peptides of the pancreatic polypeptide family, had
      granules of different shape. The cells of the islet organs of these
      osteoglossomorphs are more similar to those in more derived teleosts than they
      are to those of nonteleost actinopterygians.

PMID- 10603280
TI  - Behavioral and hormonal basis of polygynous breeding in male bush warblers
      (Cettia diphone).
AB  - Plasma levels of testosterone and corticosterone were measured in free-living
      male bush warblers captured on their breeding ground at different times of the
      breeding season. Their territoriality was also estimated from their singing
      response to song playbacks. The pattern of change detected in the levels of
      plasma testosterone was different from that of "typical" monogamous species but
      similar to that of polygynous species. In "typical" monogamous species, plasma
      testosterone levels elevated during territory settlement and courtship behavior
      and then declined to low, stable levels during incubation. In bush warblers,
      plasma levels of testosterone were already high (1-2 ng/ml) upon arrival in late
      March and peaked (2. 5-4 ng/ml) in early June. They then decreased but relatively
      high levels were maintained until early August. In late August the testosterone
      concentration was 0.03 ng/ml or less. Plasma levels of corticosterone also showed
      a seasonal change, being highest in May to July and declining in late August.
      Territoriality showed clear seasonality, reflecting the levels of circulating
      testosterone. Upon arrival, latency periods for responses to song playback were
      long and singing activity was rather low but this behavior was soon stabilized
      and a high degree of territoriality was maintained to late August. These results
      suggest that high levels of circulating testosterone and corticosterone allow
      males to pursue a polygynous breeding strategy, to hold a territory, and to
      maintain breeding activity for a prolonged period, characteristics which are
      likely to be adaptations to dense bushes with high rates of predation and brood
      parasitism of this species.

PMID- 10603281
TI  - Cloning of a proopiomelanocortin cDNA from the pituitary of the Australian
      lungfish, Neoceratodus forsteri: analyzing trends in the organization of this
      prohormone precursor.
AB  - The polypeptide hormone precursor, proopiomelanocortin (POMC), was cloned and
      sequenced from the pituitary of the Australian lungfish, Neoceratodus forsteri,
      the only surviving species of the oldest extant lineage of lungfish. The
      Australian lungfish POMC cDNA had an open reading frame that coded for a 255
      amino acid precursor. A comparison of POMC sequences from the Australian lungfish
      and the African lungfish indicated that the deduced amino acid sequences for
      ACTH, beta-MSH, and beta-endorphin were over 90% identical. Furthermore, within
      the open reading frames of the two lungfish POMCs, there was 84% identity at the
      nucleotide level. Although a gamma-MSH-like region was detected in the Australian
      lungfish POMC cDNA, this sequence contained mutations that have been detected in
      the gamma-MSH sequences of some ray-finned fish and are not found in the gamma
      MSH sequence of the African lungfish or those of tetrapods. In addition, the
      sequence of beta-endorphin in the two species of lungfish has amino acid motifs
      that are found in the beta-endorphin sequences of cartilaginous fish and ray
      finned fish but not in tetrapods. However, maximum parsimony analysis of the
      entire POMC open reading indicated that the lungfish POMC sequences form a clade
      with two amphibian POMC sequences rather than with POMC sequences from ray-finned
      fish. This result is consistent with the accepted view that the sarcopterygians
      (lungfishes and tetrapods) are a monophyletic assemblage. Analysis of rates of
      divergence for various POMC sequences indicate that point mutations are
      accumulating in the lungfish POMC sequences at a slower rate than in either
      amphibian or mammalian POMC sequences. The phylogenetic implications of these
      observations are discussed.

PMID- 10603282
TI  - Ontogeny of the insulin-like growth factor system (IGF-I, IGF-II, and IGF-1R) in
      gilthead seabream (Sparus aurata): expression and cellular localization.
AB  - There is evidence for the presence of an insulin-like growth factor (IGF) system
      during fish development. The pattern of gene expression of IGF-I, IGF-II, and
      their cognate receptors during early development of gilthead seabream (Sparus
      aurata) was studied by reverse transcription-polymerase chain reaction (RT-PCR).
      Transcripts for IGF-I, IGF-II, and IGF-1R were detected throughout development in
      unfertilized eggs, embryos, and larvae, suggesting that these mRNAs are products
      of both the maternal and the embryonic genomes. Analysis of IGF-1R mRNA in
      various adult tissues using RT-PCR revealed expression in all tissues studied,
      with the highest levels in gill cartilage, skin, kidney, heart, pyloric caeca,
      and brain. The distribution of the two types of IGF-1R and IGF-I in gilthead
      seabream larvae was studied by immunohistochemistry and found to be tissue
      specific and age-dependent. IGF-I and its receptors are widely distributed and
      appear in various tissues of seabream larvae. IGF-I immunoreactivity was highest
      in skeletal muscle and pancreas. The general distribution of the two types of IGF
      receptors in larval tissues appeared similar except for the muscle and the corpus
      cerebelli, in which IGF-1R was detected only by SpIR6 antisera. Both IGF-I and
      IGF-II may thus play a role during early development of teleosts, as in other
      vertebrates.

PMID- 10603283
TI  - Differential expression of corticotropin-releasing factor (CRF) and urotensin I
      precursor genes, and evidence of CRF gene expression regulated by cortisol in
      goldfish brain.
AB  - Corticotropin-releasing factor (CRF) and urotensin I (UI) precursor cDNAs were
      cloned and sequenced from a goldfish brain cDNA library in order to investigate
      the distribution of CRF and UI mRNAs in goldfish brain and the regulation of CRF
      and UI gene expression. The CRF (966-bp) and UI (769-bp) cDNAs encode 163- and
      146-amino acid precursors, respectively, and consist of a signal peptide
      sequence, a cryptic region, and a 41-amino acid mature peptide at the carboxy
      terminal. The deduced amino acid sequences of the CRF and UI peptides exhibit a
      sequence identity of 54%. Northern blot analysis revealed a single size of CRF
      (1.3 kb) and UI (2.0 kb) mRNAs, which are expressed in the telencephalon
      preoptic, hypothalamic, optic tectum-thalamus, and posterior brain regions, but
      not in the pituitary. In addition, while the CRF gene is strongly expressed in
      the olfactory bulbs, the UI gene is not. In brain regions in which both genes are
      expressed, the mRNA levels of CRF were three- to sevenfold higher that those of
      UI. While the low expression levels of the UI gene prevented further analysis of
      its regulation, the regulation of CRF gene expression by cortisol was examined.
      In response to intraperitoneal implants of cortisol (300 microg/g BW) the level
      of CRF mRNA in the telencephalon-preoptic region decreased to 69% of control
      values at 6 and 24 h posttreatment. In sham-treated fish, in parallel with a
      transient injection stress-elicited increase in plasma cortisol, CRF mRNA levels
      declined to 72% of control value at 6 h postinjection and recovered after 24 h.
      Injection of the glucocorticoid antagonist, RU-486 (100 microg/g BW), prevented
      the reduction in CRF gene expression associated with the injection stress at 6 h
      and increased CRF mRNA levels to 145% of control value after 24 h. In contrast,
      the various implants had no effect on CRF mRNA levels in either the hypothalamus
      or the optic tectum-thalamus region. These results provide evidence of
      differential expression of the CRF and UI genes in hypothalamic and
      extrahypothalamic regions of goldfish brain. Furthermore, they demonstrate that
      stress levels of plasma cortisol can lead to a decrease in CRF gene expression
      that is mediated by glucocorticoid receptors in the telencephalon-preoptic region
      and give an indication of the regional specificity of the regulation of CRF gene
      expression by cortisol.

PMID- 10603284
TI  - Cumulative animal index volumes 113-116

PMID- 10603285
TI  - Frank A. Beach Award. Oxytocin and vasopressin receptors and species-typical
      social behaviors.

PMID- 10603286
TI  - Estrogen replacement enhances acquisition of a spatial memory task and reduces
      deficits associated with hippocampal muscarinic receptor inhibition.
AB  - A delayed matching-to-position (DMP) T-maze task was used to examine the effects
      of estrogen replacement on spatial learning and memory, as well as the ability of
      estrogen replacement to reduce performance deficits produced by acute systemic
      and intrahippocampal muscarinic cholinergic inhibition. Two experiments were
      performed. In Experiment 1, ovariectomized animals were trained to criterion on
      the DMP task and then tested with increased intertrial delays and following
      systemic scopolamine administration. The animals then received either continuous
      estrogen replacement or sham surgery and were retested beginning 10 days later.
      In Experiment 2, ovariectomized animals received guide cannulae implanted
      bilaterally into the hippocampus. Half of these animals also began receiving
      continuous estrogen replacement. Two months later, the animals were trained on
      the DMP task and then tested with increased intertrial delays and following
      systemic as well as intrahippocampal scopolamine administration. Animals received
      the same test battery 8 months later and were then immediately trained on a
      reversal task. The results indicate that estrogen-treated animals acquired the
      DMP task at a significantly faster rate than the ovariectomized, non-estrogen
      treated controls. In addition, estrogen replacement significantly reduced
      deficits in DMP performance produced by intrahippocampal, but not systemic,
      scopolamine administration. This occurred when animals were tested after 3.5
      months, as well as after 12 months, of continuous estrogen replacement. No
      evidence for an effect of estrogen replacement on spatial working memory or
      reversal learning was detected. These findings demonstrate that estrogen
      replacement can enhance acquisition of a spatial memory task and reduce
      performance deficits associated with hippocampal cholinergic impairment.

PMID- 10603287
TI  - Implicit power motivation moderates men's testosterone responses to imagined and
      real dominance success.
AB  - This study tested the hypothesis that implicit power motivation moderates
      individuals' testosterone responses to the anticipated success in and actual
      outcome of a dominance contest. Salivary testosterone levels were assessed in 42
      male students at the beginning of the study, after they had imagined a success in
      an ensuing power contest, and immediately after the contest had taken place.
      Contest outcome (winning or losing against a competitor on a speed-based task)
      was varied experimentally. Participants' power motive was assessed with a picture
      story exercise, in which an assertive, personalized (p Power) component was
      distinguished from an altruistic, socialized (s Power) component. In contrast to
      all other participants, individuals high only in p Power (a) had elevated
      testosterone after imagining a success in a subsequent dominance contest and (b)
      continued to have high testosterone levels after actually winning, but not after
      losing, the contest.

PMID- 10603288
TI  - Comparison of the "nursing" and other parental behaviors of nulliparous and
      lactating female rats.
AB  - Virgin female rats display maternal behaviors after continuous exposure to pups
      (sensitization) that are in some respects similar to those of postpartum females.
      We herein provide a detailed comparison of the "nursing" and other parental
      behaviors of maternally sensitized virgin females and postpartum lactating dams.
      Ovariectomized and intact virgin females were exposed to pups until displaying
      maternal behavior. On the females' fourth day of maternal responsiveness, the
      pups were removed for 3 h and then returned, and subject-litter interactions were
      observed for 45 min. Behavior of maternal virgins was compared with that of
      lactating dams observed on day 4 postpartum interacting with either suckling pups
      or pups unable to suckle due to perioral anesthesia. Ovariectomy had no effect on
      behavior of virgins. Retrieval and licking of pups were deficient in virgins
      compared with lactating dams. Suckled dams showed prolonged kyphosis (upright
      crouched nursing), whereas nonsuckled dams displayed little kyphosis but rather
      were often in a hunched position over pups. Some aspects of quiescent "nursing"
      behaviors of virgins were surprisingly similar to those of suckled dams,
      including the latency to and duration of quiescence. Nonsuckling pup stimulation
      elicited more kyphosis in virgins than in lactating dams, which was still much
      less than in suckled dams. Virgins also "nursed" pups in hunched and prone
      postures. Differences between sensitized and postpartum females in their maternal
      behaviors likely reflect differences in motivation as well as sensory inputs they
      receive from pups. In particular, sensory regulation of "nursing" behaviors is
      influenced by reproductive state because nonsuckling pups elicit different
      postural responses in sensitized and lactating mothers.

PMID- 10603289
TI  - Display of proceptive behaviors in relation to urinary and fecal progestin levels
      over the ovarian cycle in female tufted capuchin monkeys.
AB  - In many primates species, female sexual attractivity is influenced by behavioral
      cues as well as by nonbehavioral cues (i.e., visual-morphological or chemical
      signals). Both kinds of cues are usually related to the ovarian cycle and female
      hormonal state. Female tufted capuchins (Cebus apella) lack any external
      morphological change in relation to the ovarian cycle and evidence of scent
      marking behavior has never been reported. In addition, tufted capuchin males do
      not routinely investigate the female's body or urine. Instead, capuchin females
      are extremely active in sexually soliciting the male(s) and their courtship
      toward them involves a rich behavioral repertoire. In the present study we
      defined female tufted capuchin proceptivity and investigated its relationship
      with female reproductive state. Ovarian hormones were measured in urine and fecal
      samples from four captive females in order to (a) assess their reliability for
      monitoring female ovarian function and (b) provide information on the timing of
      the component cycle phases and in particular the periovulatory phase.
      Measurements of urinary and fecal progestin metabolites provided the best
      indicator of ovarian cyclicity and for timing of the periovulatory phase. Through
      a multivariate analysis of the behavioral data set we distinguished four
      behaviors (eyebrow raising with vocalization, touching-and-running, nuzzling and
      head cocking) which showed a marked cyclicity (21.3 days) that matched that of
      urinary progesterone (21.9 days). Data showed that each period of proceptive
      behaviors was 2.7 +/- 0.8 days long and the day of a defined luteal phase rise in
      urinary progesterone levels was markedly shifted toward the end of this period.
      Furthermore, the ejaculations observed always occurred within proceptive periods.
      The results clearly indicate that female behavior is a good indicator of the
      periovulatory phase and can enhance female attractivity.

PMID- 10603290
TI  - Postnatal experiences and genetic effects on squirrel monkey social affinities
      and emotional distress.
AB  - Most nonhuman primate research on risk factors underlying vulnerability to stress
      has focused on early psychosocial experiences in various species of macaques. To
      test for genetic and experiential effects on emotional vulnerability in randomly
      bred squirrel monkeys, here we combined a paternal half-sibling analysis with
      three postnatal rearing protocols that altered aspects of maternal availability.
      In one condition offspring were periodically removed from natal groups, whereas
      differences in maternal availability were produced in two other conditions by
      manipulating the effort required of lactating mothers to successfully locate
      food. After completion of these protocols at 21 weeks of age, social affinities,
      maternal separation induced peep-calls, and plasma levels of cortisol were
      assessed from 29 to 37 weeks of age. Significant postnatal rearing effects and
      the lowest heritabilities were detected in peak elevations of cortisol measured 1
      day after the removal of mothers from otherwise undisturbed groups. Individual
      differences in cortisol 3-7 days later revealed negligible postnatal rearing
      effects and the highest heritabilities (h(2) approximately. 70), as offspring
      sired by certain fathers failed to return to the preseparation level found in
      undisturbed natal groups. Paternal half-siblings that responded with long lasting
      increases in cortisol spent more time near their mother in undisturbed groups and
      exhibited long-lasting increases in separation induced peep-calls. These findings
      concur with human twin studies that suggest genetic and experiential factors
      contribute to individual differences in vulnerability to emotional distress.

PMID- 10603291
TI  - Lesions to the medial preoptic area affect singing in the male European starling
      (Sturnus vulgaris).
AB  - The aromatization of testosterone (T) in the medial preoptic nucleus (POM) is
      known to regulate male courtship and sexual behaviors expressed prior to, and in
      anticipation of, copulation. Singing in male European starlings is used to
      attract mates prior to physical sexual contact, suggesting that the POM might be
      involved. The present study was performed to examine the effects of lesions
      targeting the POM on singing and courtship behavior in reproductively active male
      starlings. A significant decrease in song output and the gathering of green nest
      materials was observed in males with lesions to the POM compared to males with
      damage to brain areas outside of the POM. Lesions did not affect a male's
      tendency to remain near a female or to occupy a nestbox, suggesting that the
      effects of POM lesions were specific to courtship behaviors. Behavioral
      differences were not related to testis mass or volume, and GnRH immunoreactivity
      was observed within the hypothalamus and median eminence for each male,
      suggesting that the effects of POM lesions were related specifically to POM
      involvement in song expression rather than to a disruption of the GnRH axis.
      These results suggest a general role for the POM in the expression of behaviors
      related to sexual arousal or anticipation, including song.

PMID- 10603292
TI  - Estradiol accelerates extinction of lithium chloride-induced conditioned taste
      aversions through its illness-associated properties.
AB  - Estradiol accelerates extinction of LiCl-induced conditioned taste aversions when
      it is present during a period that starts 2-3 days after acquisition and extends
      throughout extinction (before and during extinction). It has been suggested that
      estradiol acts before, not during, extinction and that its effect on extinction
      is associated with its illness-inducing properties. This hypothesis is based on
      previous work which shows an attenuation of conditioned taste aversion learning
      when rats are exposed to illness-inducing agents during a period that starts 2
      days after acquisition and ends 2 days before extinction trials are initiated.
      Four experiments were designed to test elements of this hypothesis. The first two
      experiments demonstrated that if an estradiol-filled Silastic capsule is
      implanted before extinction of a LiCl-induced aversion, when the conditioned
      taste is not present, it accelerates extinction, but if it is implanted during
      extinction, when the conditioned taste is present, it prolongs extinction. The
      third experiment showed that the same dose of estradiol that accelerates
      extinction of a LiCl-induced aversion was effective in producing a conditioned
      taste aversion when it was present for 18 h after consumption of a novel sucrose
      solution. The fourth experiment indicated that serum levels of estradiol were
      elevated during the 18 h. These results are consistent with the hypothesis that
      the acceleration of extinction by estradiol is associated with its illness
      inducing properties. It is suggested that estradiol acts on neural areas that
      mediate illness information and that one of these areas, the area postrema is
      necessary for estradiol to accelerate extinction of a LiCl-induced aversion.

PMID- 10603293
TI  - A collection of remembrances of the life and career of Robert W. Goy (January 25,
      1924-January 14, 1999).

PMID- 10603299
TI  - Calcium controls the transcription of its own transporters and channels in
      developing neurons.
AB  - Calcium has now become important as a regulator of gene expression. Cerebellar
      granule cells developing in culture undergo early apoptosis unless their calcium
      is permitted to increase, e.g., by depolarizing their plasma membrane. The
      increase is kept within controlled limits by changing the pattern of
      transcription of calcium transporters: The IP(3) channel (but not the ryanodine
      channel) becomes strongly up-regulated after some days in culture in a reaction
      which is controlled by calcineurin. Two plasma membrane calcium pumps (isoforms
      PMCA2 and PMCA3) also become strongly up-regulated after some days; one (PMCA1)
      experiences instead a splicing switch which up-regulates a truncated variant of
      the isoform. By contrast, one splicing variant of the isoform PMCA4 and one of
      the Na/Ca exchangers of the plasma membrane (NCX2) become very rapidly down
      regulated: Their down-regulation is also controlled by calcineurin. The altered
      pattern of Ca(2+) transporter expression is likely to reflect development-linked
      changes in the demands for calcium signaling in different domains of the neuronal
      cell.

PMID- 10603300
TI  - Deubiquitinating enzymes: their diversity and emerging roles.
AB  - A growing number of important regulatory proteins within cells are modified by
      conjugation of ubiquitin, a well-conserved 76-amino-acid polypeptide. The
      ubiquitinated proteins are targeted to proteasome for degradation or alternative
      metabolic fates, such as triggering of plasma membrane endocytosis and
      trafficking to vacuoles or lysosomes. Deubiquitination, reversal of this
      modification, is being recognized as an important regulatory step.
      Deubiquitinating enzymes are cysteine proteases that specifically cleave off
      ubiquitin from ubiquitin-conjugated protein substrates as well as from its
      precursor proteins. Genome sequencing projects have identified more than 90
      deubiquitinating enzymes, making them the largest family of enzymes in the
      ubiquitin system. This review will concentrate on recent important findings as
      well as new insights into the diversity and emerging roles of deubiquitinating
      enzymes in the ubiquitin-dependent pathway.

PMID- 10603301
TI  - Enhancement of lipocalin-type prostaglandin D synthase enzyme activity by
      guanidine hydrochloride.
AB  - The characterization of unfolding of mouse recombinant lipocalin-type
      prostaglandin D synthase (L-PGDS) by guanidine hydrochloride (GdnHCl) was carried
      out. In the presence of low concentrations of GdnHCl (up to 0.75 M), enhancement
      of the enzyme activity was observed. However, above a 1 M concentration of
      GdnHCl, the enzyme activity was reduced in a concentration-dependent manner. The
      maximum enzyme activity induced by GdnHCl was approximately 1. 5-fold compared
      with the activity under physiological conditions without GdnHCl. The ellipticity
      in circular dichroism (CD) spectrum of the L-PGDS at 218 nm, reflecting the beta
      sheet content, was decreased by GdnHCl (up to 0.75 M), and the minimum
      ellipticity was observed at 0.5 M GdnHCl. The fluorescence quenching of the
      intrinsic tryptophan of L-PGDS due to the binding of bilirubin in the presence or
      absence of GdnHCl was measured. The K(d) values obtained in the presence and
      absence of 0.5 M GdnHCl were 447 and 115 nM, respectively, indicating lower
      affinity of the L-PGDS for bilirubin with GdnHCl than without it. Further, an NMR
      study revealed that the reorganization of hydrogen-bond network in the L-PGDS was
      observed in the presence of 0.5 M GdnHCl. These results, taken together, indicate
      that the enzyme activity of L-PGDS is enhanced by the conformational change,
      especially by the change in the secondary structure.

PMID- 10603302
TI  - BCA, HGF, and proteasomes.
AB  - This is my reminiscent essay of my research life, but not a review article of
      specific subject. We found in the 1960s that BCAs (the branched chain amino
      acids, valine, leucine, and isoleucine) are unique in being the least metabolized
      amino acids in liver due to low activity of their transaminase. Later it was
      found clinically that BCAs are quite effective for recovery from hepatic
      encephalopathy. Furthermore, they could restore protein metabolism by stimulating
      synthesis and inhibiting degradation of body proteins under stress conditions.
      The signal of BCAs seems to be mediated by the amino acid sensor, Ssyl, which
      induces the amino acid permease AGP1. After liver injury, hepatocytes regenerate
      actively. In the 1980s, to study the molecular mechanism involved, we used
      primary cultured rat hepatocytes, the gene expressions of which respond very well
      to nutrients and hormones in the medium and to cell density. We identified HGF
      (hepatocyte growth factor) as a potent mitogen. The HGF receptor is cMet, an
      oncogene, and it initiates tyrosine phosphorylation in cellular signal
      transduction. The proteasome is a unique protease consisting of a very large
      multisubunit complex, which shows energy- and ubiquitin-dependent activity. In
      the 1990s we characterized the molecular structures of its subunits. Recently,
      proteasomes were found to degrade the HGF receptor, cMet. Furthermore, the Grrlp
      transcription factor, which is stimulated by Ssyl described above, has been
      identified as a ubiquitin-protein ligase. These studies on BCA, HGF, and
      proteasomes seemed to be unrelated to each other when I was working, but recent
      studies have shown that they are very closely related. So I would like to discuss
      the relations of my old work to recent findings.

PMID- 10603303
TI  - Role of actin in regulated exocytosis and compensatory membrane retrieval:
      insights from an old acquaintance.
AB  - This review summarizes new insights into the role of the actin cytoskeleton in
      exocytosis and compensatory membrane retrieval from mammalian regulated secretory
      cells. Data from our lab and others now indicate that the actin cytoskeleton is
      involved in exocytosis both as a negative regulator of membrane fusion under
      resting conditions and as a facilitator of movement of secretory granules to
      their site of fusion with the apical plasmalemma. Coating of docked secretory
      granules with actin filaments correlates with the dissociation of secretory
      granule-associated rab3D, pointing out a novel role for rab proteins in
      modulating the actin cytoskeleton during regulated exocytosis. Compensatory
      membrane retrieval following regulated exocytosis is also critically dependent on
      the actin cytoskeleton both in initiating the formation of clathrin-coated
      retrieval vesicles and subsequent trafficking back into the cell. We propose that
      insertion of secretory granule membrane into the plasmalemma initiates a trigger
      for membrane retrieval, possibly by exposing sites where proteins involved in
      compensatory membrane retrieval are assembled. The results summarized in this
      review were derived primarily from investigations on the pancreatic acinar cell,
      an old friend who is providing modern wisdom not attainable in other simpler
      systems.

PMID- 10603304
TI  - Regulation of energy metabolism in human cells in aging and diabetes: FoF(1),
      mtDNA, UCP, and ROS.
AB  - Recent advances in bioenergetics consist of discoveries related to rotational
      coupling in ATP synthase (FoF(1)), uncoupling proteins (UCP), reactive oxygen
      species (ROS) and mitochondrial DNA (mtDNA). As shown in cloned sheep, mammalian
      genomes are composed of both nuclear DNA (nDNA) and maternal mtDNA. Oxidative
      phosphorylation (oxphos) varies greatly depending on cellular activities, and is
      regulated by both gene expression and the electrochemical potential difference of
      H(+) (Delta muH(+)). The expression of both mtDNA (by mtTFA) and nDNA for oxphos
      and UCP (by NRFs, etc.) is coordinated by a factor called PGC-1. The Delta muH(+)
      rotates an axis in FoF(1) that is regulated by inhibitors and ATP-sensitive K(+)
      channels. We cultured human rho(o) cells (cells without mtDNA) in synthetic media
      and elucidated relationships among mtDNA, nDNA, Delta muH(+), UCPs, ROS, and
      apoptosis. These cells lack oxphos-dependent ROS formation and survive under
      conditions of high O(2). Cells cultured in the absence of ROS scavengers have
      proliferated for 40 years. UCPs lower Delta muH(+) and prevent ROS formation and
      resulting apoptosis. These results were applied to diabetology and gerontology.
      The pancreatic rho(o) cells did not secrete insulin, and mtDNA mutations caused
      diabetes, owing to the deficient Delta muH(+). Insulin resistance was closely
      related to UCPs and other energy regulators. The resulting high-glucose
      environment caused glycation of proteins and ROS-mediated apoptosis in vascular
      cells involved in diabetic complications. Telomeres, oxphos, and ROS are
      determinants in cellular aging. Cell division and ROS shortened telomeres and
      accelerated aging. In aged cells, Delta muH(+) was reduced by the slow
      respiration, and this change induced apoptosis. Cybrids made from aged cytoplasts
      and rho(o) cells showed that both decreased expression of nDNA, and somatic
      mutations of mtDNA are involved in the slowing of respiration in aged cells.

PMID- 10603305
TI  - Role of the CCAAT enhancer binding proteins (C/EBPs) in adipocyte
      differentiation.
AB  - Members of the C/EBP family of transcription factors play essential roles in the
      adipocyte differentiation program. Treatment of growth-arrested 3T3-L1
      preadipocytes with appropriate hormonal agents causes the cells to synchronously
      reenter the cell cycle and to undergo mitotic clonal expansion. Expression of
      C/EBPbeta and delta occur early in clonal expansion, later followed by C/EBPalpha
      (which is anti-mitotic) as the cells exit the cell cycle begin to express
      adipocyte genes. C/EBPalpha serves as transcriptional activator of many adipocyte
      genes whose expression produce the adipocyte phenotype. Recent work in this
      laboratory has focussed on the roles of C/EBPbeta and delta in the
      differentiation program, in particular the mechanisms by which they activate
      transcription of the C/EBPalpha gene. Several regulatory elements, both
      repressive and activating, in proximal promoter of the gene have been identified.
      The cognate transacting factors that interact with these elements have been
      characterized and their functions elucidated. These factors have been
      incorporated into a model for a cascade that leads to transcriptional activation
      of the C/EBPalpha gene and the terminal steps in the differentiation program.

PMID- 10603306
TI  - Oligosaccharyltransferase: a complex multisubunit enzyme of the endoplasmic
      reticulum.
AB  - The attachment of N-linked oligosaccharide chains to proteins is an important
      cotranslational process. These chains can, in some cases, serve to stabilize the
      protein, while in other cases they function as recognition elements. A key enzyme
      in the N-glycosylation process is oligosaccharyltransferase (OT). In yeast this
      enzyme, which is found in the endoplasmic reticulum, consists of nine different
      transmembrane protein subunits. Our general aim is to learn more about the
      functions of the multiple subunits of yeast OT and their mode of interaction with
      each other. Using a combination of biochemical and genetic techniques the subunit
      Ost1p has been shown to recognize Asn-X-Ser/Thr glycosylation sites. The
      principle tool used in the identification process was a benzophenone-based
      glycosylation site peptide that was shown to be crosslinked to Ost1p. Our current
      objective is to identify the domain in the primary structure that is involved in
      recognition of the glycosylation site sequence. By use of bifunctional
      crosslinkers, the possible interaction of Ost1p with other subunits of OT will be
      studied. This work and other studies on the OT subunits are concisely summarized.

PMID- 10603307
TI  - Forty years of cytochrome P450.
AB  - The term "cytochrome P450" first appeared in literature in 1962. It was a
      microsomal membrane-bound hemoprotein without known physiological functions at
      that time and was characterized by a unique 450-nm optical absorption peak of its
      carbon monoxide-bound form, which was originally reported as the spectrum of a
      novel "microsomal carbon monoxide-binding pigment" in 1958. Elucidation of its
      function as the oxygenase in 1963 triggered a rapid expansion of research on this
      hemoprotein. Annual numbers of the published papers dealing with cytochrome P450,
      which were listed in Biological Abstracts, increased from 60 in 1970 to 500 in
      1980, 900 in 1990, and 1500 in 1997. Cytochrome P450 is now regarded as the
      collective name of a large family of hemoproteins, "cytochrome P450 superfamily,
      "which seems to have diversified from a single ancestral protein to many forms
      during the course of biological evolution and is distributed widely among various
      forms of life from animals and plants to fungi and bacteria. Multicellular
      eukaryotic organisms including animals and plants have about 100 or more P450
      genes in their genomes, and those many P450 genes are expressed tissue
      specifically and developmental stage specifically, indicating their diverse
      physiological functions. In mammals, various P450s participate in the
      biosynthesis and metabolism of sterols and steroid hormones and the metabolism of
      various lipid biofactors including eicosanoids, vitamin D3, and retinoids.
      Oxidative metabolism of foreign hydrophobic compounds as the first step of their
      excretion from the animal body is apparently another major function of cytochrome
      P450, which protects animals from noxious foreign compounds, man-created and
      natural.

PMID- 10603308
TI  - Apoptosis in human disease: a new skin for the old ceremony?
AB  - Naturally occurring cell death or apoptosis is essential for the maintenance of
      tissue homeostasis and serves to remove extraneous or dangerous cells in a swift
      and unobtrusive manner. Recent studies have indicated a role for apoptosis in a
      plethora of human diseases. Hence, dysregulation of apoptosis has been implicated
      in autoimmune disease, acquired immune deficiency syndrome, and other viral (and
      bacterial) infections, as well as in neurodegenerative disorders and cancer.
      Furthermore, dysregulated apoptosis signaling may impinge on other age-related
      disorders such as osteoporosis and atherosclerosis and perhaps on the process of
      aging itself. The present review provides an overview of human diseases, which
      are associated with defective or inadvertent apoptosis, with examples of
      pathological conditions in which putative apoptosis defects have been elucidated
      at the molecular level. Novel apoptosis-modulating therapeutic strategies are
      also discussed.

PMID- 10603309
TI  - Angiogenesis: how a tumor adapts to hypoxia.
AB  - The growth of new blood vessels from the preexisting vascular tree, also known as
      angiogenesis, occurs in situations such as wound and fracture healing, arthritis,
      cardiovascular and cerebral ischemia, and nearly every type of cancer known.
      Vascular endothelial growth factor (VEGF) has been shown to play a crucial role
      in these events. Hypoxia-dependent VEGF induction is mediated by hypoxia
      inducible factor-1 (HIF-1). HIF-1 is a heterodimeric transcription factor tightly
      regulated by oxygen concentration. In this short review, we summarize recent data
      concerning the control of HIF-1 activity and notably the regulation of HIF-1alpha
      subunit by phosphorylation and the ubiquitin proteasomal degradation system. A
      complete knowledge of this mechanism could, by the design of new antiangiogenic
      strategies, have a strong impact in clinical oncology.

PMID- 10603310
TI  - Of mice and men: from early NMR studies of the heart to physiological genomics.
AB  - Just before I became an editor of Biochemical and Biophysical Research
      Communications in 1977 we published our first paper in this same journal on the
      study of tiny perfused rat hearts by (31)P NMR. In this article I trace the
      development of this in vivo NMR approach from the study of small rat and mouse
      hearts to human investigations. With the advent of molecular genetics the mouse
      became a key model organism for understanding and characterizing the function of
      human genes. I illustrate this by some of our recent work on Duchenne and Becker
      muscular dystrophy where the in vivo biochemical abnormalities observed in the
      human can be better understood from investigations of the muscle and heart of the
      murine model for muscular dystrophy, the mdx mouse. In particular, the mdx mouse
      heart exhibits ECG (conduction) abnormalities similar to that in the human which
      we associate with the reduction of the neuronal nitric oxide synthase activity
      compared to controls. We have also demonstrated in the mouse model that the
      increased sensitivity of the heart to ischemia is associated with a decrease in
      the insulin-stimulated glucose transport. Imaging techniques involving NMR,
      visible light, and others will play an increasingly important role in linking
      genomics to functional "molecular physiology."

PMID- 10603311
TI  - Tn5: A molecular window on transposition.
AB  - DNA transposition is an underlying process involved in the remodeling of genomes
      in all types of organisms. We analyze the multiple steps in cut-and-paste
      transposition using the bacterial transposon Tn5 as a model. This system is
      particularly illuminating because of the existence of structural, genetic, and
      biochemical information regarding the two participating specific macromolecules:
      the transposase and the 19-bp sequences that define the ends of the transposon.
      However, most of the insights should be of general interest because of
      similarities to other transposition-like systems such as HIV-1 DNA integration
      into the host genome.

PMID- 10603312
TI  - Development of bivalent (B/E) vaccines able to neutralize CCR5-dependent viruses
      from the United States and Thailand.
AB  - Recombinant envelope glycoproteins prepared from a subtype B (MN) strain and a
      subtype E (CM244) strain of HIV-1 were combined to create a bivalent vaccine
      (B/E) effective against viruses circulating in the United States and Asia.
      Combining the two antigens resulted in formulations that increased the breadth
      and potency of the inter-subtype neutralizing response. Antibodies to the
      bivalent vaccine formulation neutralized viruses possessing diverse phenotypes,
      including syncytia-inducing and non-syncytia-inducing primary isolates, viruses
      using either the CCR5 or the CXCR4 chemokine receptors, and viruses differing in
      their sensitivity to soluble CD4. These studies demonstrate for the first time
      that the magnitude and quality of the immune response to HIV-1 can be improved by
      combining recombinant envelope glycoproteins from different genetic subtypes.

PMID- 10603313
TI  - Properties of the adenovirus type 40 E1B promoter that contribute to its low
      transcriptional activity.
AB  - The adenovirus type 5 (Ad5) E1B promoter contains two elements essential for
      maximal activity, a TATA box and a GC box. The enteric adenovirus type 40 (Ad40)
      E1B promoter has a TATA box sequence identical to that of Ad5 and a GC box that
      fits the Sp1 binding site consensus. Nevertheless, Ad40 E1B RNA synthesis is
      severely impaired in HeLa cells, attributable in part at least to the weak
      transactivating activity of Ad40 E1A. However, the responsiveness of Ad40 early
      promoters to E1A transactivation has not been directly demonstrated. Using a
      transient expression assay with a chloramphenicol acetyl transferase (CAT)
      reporter gene, the Ad40 E1B promoter was very poorly transactivated by E1A of
      both Ad40 and Ad5 and showed only a limited response to the promiscuous varicella
      zoster virus transactivator p140. Construction of Ad5 recombinant viruses
      expressing the CAT gene under the control of the Ad5 or Ad40 E1B promoter allowed
      detection and measurement of expression from the Ad40 E1B promoter in a well
      defined background and showed that overall activity is some 100-fold lower than
      for the Ad5 E1B promoter. Deletion analysis revealed that sequences upstream of
      the Sp1 binding site down-modulated Ad40 E1B promoter responsiveness, and two
      protein binding sites, identified by DNase footprinting and gel retardation
      assay, may be implicated in this effect. Gel shift analysis also showed that the
      Ad40 Sp1 binding site had a reduced affinity for Sp1 protein, relative to the Ad5
      site, and that the context as well as the core sequence had an influence on Sp1
      recognition.

PMID- 10603314
TI  - The refined crystal structure of cowpea mosaic virus at 2.8 A resolution.
AB  - Comoviruses are a group of plant viruses in the picornavirus superfamily. The
      type member of comoviruses, cowpea mosaic virus (CPMV), was crystallized in the
      cubic space group I23, a = 317 A and the hexagonal space group P6(1)22, a = 451
      A, c = 1038 A. Structures of three closely similar nucleoprotein particles were
      determined in the cubic form. The roughly 300-A capsid was similar to the
      picornavirus capsid displaying a pseudo T = 3 (P = 3) surface lattice. The three
      beta-sandwich domains adopt two orientations, one with the long axis radial and
      the other two with the long axes tangential in reference to the capsid sphere. T
      = 3 viruses display one or the other of these two orientations. The CPMV capsid
      was permeable to cesium ions, leading to a disturbance of the beta-annulus inside
      a channel-like structure, suggesting an ion channel. The hexagonal crystal form
      diffracted X rays to 3 A resolution, despite the large unit cell. The large (
      approximately 200 A) solvent channels in the lattice allow exchange of CPMV
      cognate Fab fragments. As an initial step in the structure determination of the
      CPMV/Fab complex, the P6(1)22 crystal structure was solved by molecular
      replacement with the CPMV model determined in the cubic cell.

PMID- 10603315
TI  - Recombinant hepatitis E capsid protein self-assembles into a dual-domain T = 1
      particle presenting native virus epitopes.
AB  - The three-dimensional structure of a self-assembled, recombinant hepatitis E
      virus particle has been solved to 22-A resolution by cryo-electron microscopy and
      three-dimensional image reconstruction. The single subunit of 50 kDa is derived
      from a truncated version of the open reading frame-2 gene of the virus expressed
      in a baculovirus system. This is the first structure of a T = 1 particle with
      protruding dimers at the icosahedral two-fold axes solved by cryo-electron
      microscopy. The protein shell of these hollow particles extends from a radius of
      50 A outward to a radius of 135 A. In the reconstruction, the capsid is dominated
      by dimers that define the 30 morphological units. The outer domain of the
      homodimer forms a protrusion, which corresponds to the spike-like density seen in
      the cryo-electron micrograph. This particle retains native virus epitopes,
      suggesting its potential value as a vaccine.

PMID- 10603316
TI  - Particle-mediated DNA immunization of cattle confers long-lasting immunity
      against bovine herpesvirus-1.
AB  - Particle-mediated delivery was used as a method to vaccinate ruminants with a DNA
      vaccine. The optimal conditions for gene gun-based delivery of gold particles
      into the epidermal layer of the skin were determined. After delivery of the gold
      particles, an inflammatory response was observed. This response occurred
      regardless of the presence of plasmid and therefore was a result of the physical
      disturbance of the skin by the gold particles. To identify transfected cells, a
      plasmid expressing a green fluorescent protein was delivered into the skin.
      Fluorescent cells were located primarily in the outermost layers of the epidermis
      and outside the core of gold particles deposited by the gene gun. Cattle were
      immunized by gene gun with a plasmid expressing a truncated, secreted form of
      bovine herpesvirus-1 glycoprotein D. Serum antibody responses, antigen-specific
      proliferation, and interferon-gamma secretion by peripheral blood lymphocytes
      were demonstrated. These immune responses were found to be of long duration and
      sufficient magnitude to protect cattle against challenge with bovine herpesvirus
      1, which demonstrates the efficacy of gene gun-based delivery of DNA vaccines to
      target species.

PMID- 10603317
TI  - The use of a quantitative fusion assay to evaluate HN-receptor interaction for
      human parainfluenza virus type 3.
AB  - Sialic acid is the receptor determinant for the human parainfluenza virus type 3
      (HPF3) hemagglutinin-neuraminidase (HN) glycoprotein, the molecule responsible
      for binding of the virus to cell surfaces. In order for the fusion protein (F) of
      HPF3 to promote membrane fusion, HN must interact with its receptor. In addition
      to its role in receptor binding and fusion promotion, the HPF3 HN molecule
      contains receptor-destroying (sialidase) activity. The putative active sites are
      in the extracellular domain of this type II integral membrane protein. However,
      HN is not available in crystalline form; the exact locations of these sites, and
      the structural requirements for binding to the cellular receptor, which has not
      yet been isolated, are unknown. Nor have small molecular synthetic inhibitors of
      attachment or fusion that would provide insight into these processes been
      identified. The strategy in the present study was to develop an assay system that
      would provide a measure of a specific step in the viral cycle-functional
      interaction between viral glycoproteins and the cell during attachment and fusion
      and serve to screen a variety of substances for inhibitory potential. The assay
      is based on our previous finding that CV-1 cells persistently infected (p.i.)
      with HPF3 do not fuse with one another but that the addition of uninfected CV-1
      cells, supplying the critical sialic acid containing receptor molecules that bind
      HN, results in rapid fusion. In the present assay two HeLa cell types were used:
      we persistently infected HeLa-LTR-betagal cells, assessed their fusion with
      uninfected HeLa-tat cells, and then quantitated the beta-galactosidase (betagal)
      produced as a result of this fusion. The analog alpha-2-S-methyl-5-N
      thioacetylneuraminic acid (alpha-Neu5thioAc2SMe) interfered with fusion,
      decreasing betagal production by 84% at 50 mM and by 24% at 25 mM. In beginning
      to extend our studies to different types of molecules, we tested an unsaturated
      derivative of sialic acid, 2,3-dehydro-2-deoxy-n-acetyl neuraminic acid (DANA),
      which is known to inhibit influenza neuraminidase by virtue of being a transition
      state analog. We found that 10 mM DANA inhibited neuraminidase activity in HPF3
      viral preparations. More significantly, this compound was active in our assay of
      HN-receptor interaction; 10 mM DANA completely blocked fusion and betagal
      production, and hemadsorption inhibition by DANA suggested that DANA blocks
      attachment. In plaque reduction assays performed with the compounds, the active
      analog alpha-Neu5thioAc2SMe reduced plaque formation by 50% at a 50 mM
      concentration; DANA caused a 90% inhibition in the plaque reduction assay at a
      concentration of 25 mM. Our results indicate that specific sialic acid analogs
      that mimic the cellular receptor determinant of HPF3 can block virus cell
      interaction and that an unsaturated n-acetyl-neuraminic acid derivative with
      affinity to the HN site responsible for neuraminidase activity also interferes
      with HN-receptor binding. Strategies suggested by these findings are now being
      pursued to obtain information regarding the relative locations of the active
      sites of HN and to further elucidate the relationship between the receptor
      binding and receptor-destroying activities of HN during the viral life cycle. The
      quantitative assay that we describe is of immediate applicability to large-scale
      screening for potential inhibitors of HPF3 infection in vivo.

PMID- 10603318
TI  - Cryphonectria hypovirus 3, a virus species in the family hypoviridae with a
      single open reading frame.
AB  - Isolate Grand Haven (GH) 2 is a naturally occurring isolate of the chestnut
      blight fungus, Cryphonectria parasitica, that is greatly reduced in virulence due
      to the presence of a double-stranded RNA virus. Unlike many other virus-infected,
      hypovirulent isolates, GH2 is not substantially reduced in pigmentation,
      conidiation, or laccase expression compared to its virus-free counterpart. The
      dsRNA genome of the GH2 virus was cloned, sequenced, and compared to
      hypovirulence-associated viruses of the family Hypoviridae. GH2 dsRNA is
      considerably smaller than previously characterized members of the family, 9.8 kb
      compared to 12.5-12.7 kb for other members. The genome organization of GH2 dsRNA
      reflected the substantial difference in genome size. Like other members of the
      family, one strand contained a poly(A)(+) tail at the 3' end and a long sequence
      with several minicistrons at the 5' end of the same strand. Only a single open
      reading frame (ORF) of 8622 nucleotides was predicted from deduced translations
      of the poly(A)(+)-containing strand, however. This contrasts with the two-ORF
      structures of previously characterized members. Analysis of the deduced ORF of
      GH2 dsRNA revealed putative proteinase, RNA polymerase, and helicase domains
      similar to those previously identified in confirmed members of the virus family
      Hypoviridae. GH2 dsRNA was more distantly related to Cryphonectria hypovirus
      (CHV) 1-EP713 and CHV2-NB58 than the latter two were to each other but has
      features in common with each of those viruses. We propose that the GH2 virus be
      included in this taxon as a member of the genus Hypovirus, representing a strain
      of a new species, CHV3.

PMID- 10603319
TI  - The hypersensitive response to cucumber mosaic virus in Chenopodium amaranticolor
      requires virus movement outside the initially infected cell.
AB  - Cucumber mosaic virus (CMV) expressing the green fluorescent protein (GFP), and
      lacking either the 3a movement protein or the coat protein (CP), failed to induce
      a hypersensitive response producing local lesions in inoculated leaves of
      Chenopodium amaranticolor. Cytological analysis showed that both viral-encoded
      proteins are required for cell-to-cell movement of the virus and the simultaneous
      appearance of cellular necrosis. In the absence of either or both proteins,
      infection was confined to single, non-necrotized, epidermal cells. CMV with a
      mutation in the 3a protein (M8 CMV) could infect tobacco systemically but did not
      induce necrotic lesions in C. amaranticolor. In this host, the mutated 3a protein
      was unable to promote viral movement out of the initially infected epidermal
      cell. Movement-deficient CMV expressing wild-type (WT) 3a protein as a fusion to
      the GFP, as well as WT CP, also failed to induce necrosis. Finally, single
      epidermal cells infected with a movement-deficient CMV expressing WT 3a protein,
      WT CP, and free GFP did not show necrosis. These data indicate that viral
      movement out of the initially infected epidermal cell, and not the simultaneous
      expression in this cell of the 3a protein and the CP, is required for the
      induction of cell death.

PMID- 10603320
TI  - Mutagenesis of the RGD motif in the yellow fever virus 17D envelope protein.
AB  - The envelope protein of yellow fever virus 17D (YFV-17D) contains a solvent
      exposed RGD motif, which has led to the suggestion that integrins may function as
      cellular receptors for YFV-17D. We found that mutating the RGD motif to RGE had
      no effect on viral titers, whereas changing RGD to TGD, TGE, TAD, TAE, or RGS led
      to reduced titers. Substitution of RGD by RAD or RAE yielded RNA genomes that
      replicated in mammalian cells but could not spread to neighboring cells at 37
      degrees C. These mutants did spread through the cell monolayer at 30 degrees C
      (both in mosquito cells and in SW13 cells) and viruses grown at this temperature
      were capable of infecting mammalian cells at 37 degrees C. These results strongly
      suggest that RGD-mediated integrin binding does not play a major role in YFV-17D
      entry, since the RGD to RAD mutation, as well as many or all of the other
      mutations studied, should disrupt all RGD-dependent integrin binding. However,
      the RGD to RAD or RAE mutations (as well as TAD and TAE) severely destabilized
      the envelope protein at 37 degrees C, providing an explanation for the observed
      phenotype. Implications of these findings are discussed in light of the fact that
      mutations that alter tropism or virulence in different flaviviruses are often
      found within the loop containing the RGD motif.

PMID- 10603321
TI  - The nucleocapsid protein of coronavirus mouse hepatitis virus interacts with the
      cellular heterogeneous nuclear ribonucleoprotein A1 in vitro and in vivo.
AB  - The nucleocapsid (N) protein of mouse hepatitis virus (MHV) and the cellular
      heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1) are RNA-binding proteins,
      binding to the leader RNA and the intergenic sequence of MHV negative-strand
      template RNAs, respectively. Previous studies have suggested a role for both N
      and hnRNP-A1 proteins in MHV RNA synthesis. However, it is not known whether the
      two proteins can interact with each other. Here we employed a series of methods
      to determine their interactions both in vitro and in vivo. Both N and hnRNP-A1
      genes were cloned and expressed in Escherichia coli as glutathione S-transferase
      (GST) fusion proteins, and their interactions were determined with a GST-binding
      assay. Results showed that N protein directly and specifically interacted with
      hnRNP-A1 in vitro. To dissect the protein-binding domain on the N protein, 15
      deletion constructs were made by PCR and expressed as GST fusion proteins. Two
      hnRNP-A1-binding sites were identified on N protein: site A is located at amino
      acids 1 to 292 and site B at amino acids 392 to 455. In addition, we found that N
      protein interacted with itself and that the self-interacting domain coincided
      with site A but not with site B. Using a fluorescence double-staining technique,
      we showed that N protein colocalized with hnRNP-A1 in the cytoplasm, particularly
      in the perinuclear region, of MHV-infected cells, where viral RNA
      replication/transcription occurs. The N protein and hnRNP-A1 were
      coimmunoprecipitated from the lysates of MHV-infected cells either by an N- or by
      an hnRNP-A1-specific monoclonal antibody, indicating a physical interaction
      between N and hnRNP-A1 proteins. Furthermore, using the yeast two-hybrid system,
      we showed that N protein interacted with hnRNP-A1 in vivo. These results thus
      establish that MHV N protein interacts with hnRNP-A1 both in vitro and in vivo.

PMID- 10603322
TI  - Localization of rubella virus core particles in vero cells.
AB  - Rubella virus (RV) infection induces a variety of morphological changes in the
      host cell including the modification of lysosomes to produce "replication
      complexes" and the alteration of mitochondrial morphology and distribution. The
      morphogenesis of RV was further characterized with particular emphasis on the
      localization of RV core particles. Thin-section electron microscopy (TSEM)
      studies indicated that RV core-like particles, measuring approximately 33 nm in
      diameter, were found associated with RV replication complexes. Immunogold
      labeling electron microscopy (EM) using monoclonal antibodies to RV capsid
      proteins confirmed that these particles were viral cores. RV core particles were
      also detected in association with mitochondria as observed by TSEM and immunogold
      labeling EM using monoclonal antibodies to capsid or polyclonal antibodies to RV
      virions. The results of this study indicate that the localization of RV core
      particles in relation to replication complexes is similar to that found for the
      alphaviruses. However, the association of RV core particles with mitochondria
      appears unique within the family Togaviridae.

PMID- 10603323
TI  - Rotavirus open cores catalyze 5'-capping and methylation of exogenous RNA:
      evidence that VP3 is a methyltransferase.
AB  - Rotavirus open cores prepared from purified virions consist of three proteins:
      the RNA-dependent RNA polymerase, VP1; the core shell protein, VP2; and the
      guanylyltransferase, VP3. In addition to RNA polymerase activity, open cores have
      been shown to contain a nonspecific guanylyltransferase activity that caps viral
      and nonviral RNAs in vitro. In this study, we examined the structure of RNA caps
      made by open cores and have analyzed open cores for other capping-related
      enzymatic activities. Utilizing RNase digestion and thin-layer chromatography, we
      found that the majority ( approximately 70%) of caps made by open cores contain
      the tetraphosphate linkage, GppppG, rather than the triphosphate linkage, GpppG,
      found on mRNAs made by rotavirus double-layered particles. Enzymatic analysis
      indicated that the GppppG caps resulted from the lack of a functional RNA 5'
      triphosphatase in open cores, to remove the gamma-phosphate from the RNA prior to
      capping. RNA 5'-triphosphatases commonly exhibit an associated nucleoside
      triphosphatase activity, and this too was not detected in open cores. Caps of
      some RNAs contained an extra GMP moiety (underlined) and had the structure 3'
      GpGp(p)ppGpGpC-RNA-3'. The origin of the extra GMP is not known but may reflect
      the cap serving as a primer for RNA synthesis. Methylated caps were produced in
      the presence of the substrate, S-adenosyl-l-methionine (SAM), indicating that
      open cores contain methyltransferase activity. UV cross-linking showed that VP3
      specifically binds SAM. Combined with the results of earlier studies, our results
      suggest that the viral guanylyltransferase and methyltransferase are both
      components of VP3 and, therefore, that VP3 is a multifunctional capping enzyme.

PMID- 10603324
TI  - The effects of targeting the vaccinia virus B5R protein to the endoplasmic
      reticulum on virus morphogenesis and dissemination.
AB  - The consequence of redirecting the vaccinia virus (VV) B5R protein to the
      endoplasmic reticulum (ER) has been investigated by the addition of an ER
      retrieval signal KKSL (K(2)X(2)) to the B5R C-terminus. This mutant B5R gene and
      a version of the gene with the inactive ER retrieval sequence KKSLAL (K(2)X(4))
      were inserted into the thymidine kinase locus of a VV mutant lacking the B5R
      gene, vDeltaB5R. Similar levels of B5R protein were made by each virus, but the
      B5R-K(2)X(2) protein remained sensitive to endoglycosidase H and colocalised with
      protein disulphide isomerase in the ER. In contrast, the B5R-K(2)X(4) protein
      colocalised with 1, 4-galactosyltransferase in the trans-Golgi network. Electron
      microscopy revealed that even when the B5R protein was redirected to the ER,
      intracellular mature virus particles were wrapped by cellular membranes to form
      intracellular enveloped virus particles, although more incompletely wrapped
      particles were evident compared with wild type. These intracellular enveloped
      virus particles were, however, unable to efficiently induce the polymerisation of
      actin and the plaque size formed by vB5R-K(2)X(2) was small. Nevertheless, the
      amount and specific infectivity of EEV produced by vB5R-K(2)X(2) were similar to
      those of wild type, despite the dramatic reduction in the amount of B5R protein
      present in vB5R-K(2)X(2) EEV.

PMID- 10603325
TI  - Restoration of the 3' end of potyvirus RNA derived from Poly(A)-deficient
      infectious cDNA clones.
AB  - Poly(A)-deficient full-length cDNA clones of clover yellow vein virus (ClYVV), a
      member of the genus Potyvirus, were found to be infectious when expressed from
      the CaMV 35S promoter. The poly(A) tail was replaced with different short
      sequences and the infectivities of the cDNA constructs were examined. Although
      the infectivity of the plasmid varied depending on the sequences introduced, all
      the constructs were infectious. In all cases, progeny viral RNAs from the cDNA
      clones had an authentic viral sequence at their 3' regions with poly(A) tails and
      the downstream nonviral sequences were completely lost. However, two minor
      mutations, a two-nucleotide deletion at the 3' end and a single-nucleotide
      addition at the second nucleotide position downstream of the poly(A) site, were
      also observed. The clones of the viral (-) strand RNAs had poly(U) tracts at
      their 5' ends, suggesting that their synthesis is primed by the poly(U) sequence.
      It furthermore suggests that the mutations were introduced during or after
      primary transcription from the cDNA and were maintained during authentic viral
      replication. Although the mechanism involved is not known, recovery of the
      poly(A) tail is an essential step for maintaining the infectivity of the viral
      cDNAs.

PMID- 10603326
TI  - Crystal structure of an inhibitor complex of the 3C proteinase from hepatitis A
      virus (HAV) and implications for the polyprotein processing in HAV.
AB  - The proteolytic processing of the viral polyprotein is an essential step during
      the life cycle of hepatitis A virus (HAV), as it is in all positive-sense, single
      stranded RNA viruses of animals. In HAV the 3C proteinase is the only proteolytic
      activity involved in the polyprotein processing. The specific recognition of the
      cleavage sites by the 3C proteinase depends on the amino acid sequence of the
      cleavage site. The structure of the complex of the HAV 3C proteinase and a
      dipeptide inhibitor has been determined by X-ray crystallography. The double
      mutant of HAV 3C (C24S, F82A) was inhibited with the specific inhibitor
      iodoacetyl-valyl-phenylalanyl-amide. The resulting complex had an acetyl-Val-Phe
      amide group covalently attached to the S(gamma) atom of the nucleophilic Cys 172
      of the enzyme. Crystals of the complex of HAV 3C (C24S, F82A) acetyl-Val-Phe
      amide were found to be monoclinic, space group P2(1), having 4 molecules in the
      asymmetric unit and diffracting to 1.9-A resolution. The final refined structure
      consists of 4 molecules of HAV 3C (C24S,F82A) acetyl-Val-Phe-amide, 1 molecule of
      DMSO, 1 molecule of glycerol, and 514 water molecules. There are considerable
      conformational differences among the four molecules in the asymmetric unit. The
      final R-factor is 20.4% for all observed reflections between 15.0- and 1.9-A
      resolution and the corresponding R(free) is 29.8%. The dipeptide inhibitor is
      bound to the S(1)(') and S(2)(') specificity subsites of the proteinase. The
      crystal structure reveals that the HAV 3C proteinase possesses a well-defined
      S(2)(') specificity pocket and suggests that the P(2)(') residue could be an
      important determinant for the selection of the primary cleavage site during the
      polyprotein processing in HAV.

PMID- 10603327
TI  - Delta-peptide is the carboxy-terminal cleavage fragment of the nonstructural
      small glycoprotein sGP of Ebola virus.
AB  - In the present study we have investigated processing and maturation of the
      nonstructural small glycoprotein (sGP) of Ebola virus. When sGP expressed from
      vaccinia virus vectors was analyzed by pulse-chase experiments using SDS-PAGE
      under reducing conditions, the mature form and two different precursors have been
      identified. First, the endoplasmic reticulum form sGP(er), full-length sGP with
      oligomannosidic N-glycans, was detected, sGP(er) was then replaced by the Golgi
      specific precursor pre-sGP, full-length sGP containing complex N-glycans. This
      precursor was finally converted by proteolysis into mature sGP and a smaller
      cleavage fragment, Delta-peptide. Studies employing site-directed mutagenesis
      revealed that sGP was cleaved at a multibasic amino acid motif at positions 321
      to 324 of the open reading frame. Cleavage was blocked by RVKR-chloromethyl
      ketone. Uncleaved pre-sGP forms a disulfide-linked homodimer and is secreted into
      the culture medium in the presence of the inhibitor as efficiently as
      proteolytically processed sGP. In vitro treatment of pre-sGP by purified
      recombinant furin resulted in efficient cleavage, confirming the importance of
      this proprotein convertase for the processing and maturation of sGP. Delta
      peptide is also secreted into the culture medium and therefore represents a novel
      nonstructural expression product of the GP gene of Ebola virus. Both cleavage
      fragments contain sialic acid, but only Delta-peptide is highly O-glycosylated.

PMID- 10603328
TI  - Determinants of embryonic stage at oviposition in the lizard Urosaurus ornatus.
AB  - Relatively few squamate reptiles oviposit eggs with embryos at developmental
      stages greater than stage 30. To investigate potential proximate and ultimate
      bases of this phenomenon, we experimentally induced females of the lizard
      Urosaurus ornatus to retain their eggs past the normal time of oviposition (NTO).
      This procedure allowed us to determine whether the length of egg retention is
      fixed or facultative and to evaluate the effects of retention on embryos,
      hatchlings, and females. Females were able to retain eggs facultatively for at
      least 29 d past the NTO. However, retention resulted in arrested development of
      embryos; arrest occurred at stages 30-30.5, which is only slightly more advanced
      than that at the NTO (stage 29.5). Embryogenesis was reinitiated when eggs were
      removed from females and placed in incubation media. Hatching success of these
      eggs was high (87%), and incubation time was not affected by the number of days
      that development had been arrested. However, the snout-vent length and water
      content of hatchlings were negatively related to the length of retention, and
      they ran slower than hatchlings from control eggs obtained at the NTO. Retention
      of eggs past the NTO had no detectable effect on the body condition or running
      speeds of females. Developmental arrest and the adverse effects of retention on
      hatchling phenotype, if widespread among squamates, would account for the limited
      range of embryo stages at oviposition and act as major constraints on the
      evolution of viviparity.

PMID- 10603329
TI  - Metabolic response to air temperature and wind in day-old mallards and a standard
      operative temperature scale.
AB  - Most duckling mortality occurs during the week following hatching and is often
      associated with cold, windy, wet weather and scattering of the brood. We
      estimated the thermoregulatory demands imposed by cold, windy weather on isolated
      1-d-old mallard (Anas platyrhynchos) ducklings resting in cover. We measured O2
      consumption and evaporative water loss at air temperatures from 5 degrees to 25
      degrees C and wind speeds of 0.1, 0.2, 0.5, and 1.0 m/s. Metabolic heat
      production increased as wind increased or temperature decreased but was less
      sensitive to wind than that of either adult passerines or small mammals.
      Evaporative heat loss ranged from 5% to 17% of heat production. Evaporative heat
      loss and the ratio of evaporative heat loss to metabolic heat production was
      significantly lower in rest phase. These data were used to define a standard
      operative temperature (Tes) scale for night or heavy overcast conditions. An
      increase of wind speed from 0.1 to 1 m/s decreased Tes by 3 degrees -5 degrees C.

PMID- 10603330
TI  - Individual variation in morphological, physiological, and biochemical features
      associated with calling in spring peepers (Pseudacris crucifer).
AB  - In an eastern North American tree frog, the spring peeper (Pseudacris crucifer),
      calling rate has been correlated with reproductive success in the field. To
      determine the sources of individual variation in calling rate in this species, I
      analyzed males calling at rates greater than and less than the chorus average
      throughout one breeding season. Compared to low-rate callers, high-rate callers
      were relatively larger, heavier, older, and in better body condition, and their
      muscles used in calling had higher activities of the enzymes citrate synthase and
      beta-hydroxyacyl-CoA dehydrogenase. This muscle profile is functionally matched
      by cardiovascular correlates, as indicated by the larger ventricles and higher
      blood hemoglobin concentrations in high-calling rate males. These cardiovascular
      features are much less developed in females and may result from the fact that
      females do not engage in vigorous calling behavior. In P. crucifier, a male's
      calling rate may function as an indicator of the presence of a suite of
      functionally interrelated traits responsible for the maintenance of this sexually
      selected display behavior.

PMID- 10603331
TI  - Variation in milk production and lactation performance in grey seals and
      consequences for pup growth and weaning characteristics.
AB  - Phocid seals are one of the few groups of mammals capable of sustaining the
      energetic demands of lactation entirely through body nutrient stores while
      fasting. Lactation performance of the female in turn influences the rate and
      pattern of pup growth. We examined variation in and patterns of milk composition
      and production, maternal energy output, and pup growth and energy deposition over
      the entire lactation period in 18 grey seal mother-pup pairs using hydrogen
      isotope (3H2O and D2O) dilution. Milk composition was independent of maternal
      mass and nutrient stores, indicating dependence on other physiological and
      genetic factors. Heavier females lactated longer (r2=0.653, P<0.001), had higher
      total milk outputs (r2=0.652, P<0.001), and produced larger pups at weaning
      (r2=0.417, P=0.005). While fatter females lactated for longer periods of time
      (r2=0.595, P<0.001), females with a larger lean body mass at parturition produced
      more milk (r2=0.579, P<0.001). Total milk energy output was the strongest
      predictor of pup weaning mass, which, along with the pup's efficiency of energy
      storage, accounted for 91% of the variation in weaning mass. Nevertheless, there
      was sufficient plasticity in milk composition and energy output that some smaller
      females produced relatively large pups. Few females appeared to deplete body
      nutrients to the point where it might limit the duration of lactation.

PMID- 10603332
TI  - Surfactant in the gas mantle of the snail Helix aspersa.
AB  - Surfactant occurs in cyclically inflating and deflating, gas-holding structures
      of vertebrates to reduce the surface tension of the inner fluid lining, thereby
      preventing collapse and decreasing the work of inflation. Here we determined the
      presence of surfactant in material lavaged from the airspace in the gas mantle of
      the pulmonate snail Helix aspersa. Surfactant is characterized by the presence of
      disaturated phospholipid (DSP), especially disaturated phosphatidylcholine (PC),
      lavaged from the airspace, by the presence of lamellated osmiophilic bodies (LBs)
      in the airspaces and epithelial tissue, and by the ability of the lavage to
      reduce surface tension of fluid in a surface balance. Lavage had a
      DSP/phospholipid (PL) ratio of 0.085, compared to 0.011 in membranes, with the
      major PL being PC (45.3%). Cholesterol, the primary fluidizer for pulmonary
      surfactant, was similar in lavage and in lipids extracted from cell homogenates
      (cholesterol/PL: 0.04 and 0. 03, respectively). LBs were found in the tissues and
      airspaces. The surface activity of the lavage material is defined as the ability
      to reduce surface tension under compression to values much lower than that of
      water. In addition, surface-active lipids will vary surface tension, increasing
      it upon inspiration as the surface area expands. By these criteria, the surface
      activity of lavaged material was poor and most similar to that shown by pulmonary
      lavage of fish and toads. Snail surfactant displays structures, a biochemical PL
      profile, and biophysical properties similar to surfactant obtained from primitive
      fish, teleost swim bladders, the lung of the Dipnoan Neoceratodus forsteri, and
      the amphibian Bufo marinus. However, the cholesterol/PL and cholesterol/DSP
      ratios are more similar to the amphibian B. marinus than to the fish, and this
      similarity may indicate a crucial physicochemical relationship for these lipids.

PMID- 10603333
TI  - Nonshivering thermogenesis in a marsupial (the tasmanian bettong Bettongia
      gaimardi) is not attributable to brown adipose tissue.
AB  - The Tasmanian bettong (Bettongia gaimardi, a marsupial) is a rat-kangaroo that
      increases nonshivering thermogenesis (NST) in response to norepinephrine (NE).
      This study attempted to assess whether brown adipose tissue (BAT), a specialized
      thermogenic effector, is involved in NST in the bettong. Regulatory NST,
      indicated by resting oxygen consumption (Vo2) of the whole body, was measured
      under conscious conditions at 20 degrees C with various stimuli: cold (4 degrees 
      5 degrees C) or warm (25 degrees C) acclimation, NE injection, and the beta3
      adrenoceptor agonist (BRL) 37344. In line with the functional studies in vivo,
      the presence of BAT was evaluated by examining the expression of the uncoupling
      protein 1 (UCP1) with both rat cDNA and oligonucleotide probes. Both NE and BRL
      37344 significantly stimulated NST in the bettong. After cold acclimation of the
      animals (at 4 degrees -5 degrees C for 2 wk), the resting Vo2 was increased by
      15% and the thermogenic effect of NE was enhanced; warm-acclimated animals showed
      a slightly depressed response. However, no expression of UCP1 was detected in
      bettongs either before or after cold exposure (2 wk). These data suggest that the
      observed NST in the marsupial bettong is not attributable to BAT.

PMID- 10603334
TI  - Physiological components of growth differences between individual oysters
      (Crassostrea gigas) and a comparison with Saccostrea commercialis.
AB  - Pacific oysters (Crassostrea gigas) of identical age from two genetically
      distinct lines, one fast growing and the other slow growing, were held at three
      levels of ration and analysed for physiological traits to explain differences in
      their rates of growth. The data supported three hypotheses; faster growth was
      associated with faster rates of consumption of food, reduced metabolic rate at
      maintenance (i.e., at zero growth), and reduced metabolic costs of growth. A
      comparison with the Sydney rock oyster, Saccostrea commercialis, based on similar
      experiments on the two species, indicated that faster growth of Pacific oysters
      depended on similar physiological differences; the mean metabolic costs of
      growth, however, were similar in the two species. It is suggested that a general
      model for genetically linked differences in the growth rate of bivalve molluscs
      will need to include the processes of metabolic control rather than relying
      solely on an analysis of the individual components of the energetics of growth.

PMID- 10603335
TI  - Influence of water availability during incubation on hatchling size, body
      composition, desiccation tolerance, and terrestrial locomotor performance in the
      snapping turtle Chelydra serpentina.
AB  - The effects of water availability during incubation on the water contents of
      neonatal snapping turtles at hatching were examined, along with the influence of
      hatchling water content on desiccation tolerance and terrestrial locomotor
      performance. The water contents of hatchlings from eggs incubated on wet
      substrates were both absolutely and proportionally greater than were those of
      hatchlings from eggs incubated on dry substrates. Hatchlings with greater water
      contents at hatching were able to survive longer and to lose more water before
      physiological performance was adversely affected by desiccation. Increased water
      contents in hatchlings with greater water availability during incubation may
      enhance survival by increasing the amount of water the animal can afford to lose
      before dehydration begins to adversely affect whole animal performance.

PMID- 10603336
TI  - Metabolic effects of low-energy diet on steller sea lions, Eumetopias jubatus.
AB  - Diets of six Steller sea lions (Eumetopias jubatus) were switched between a high
      (herring) and a low (squid) energy density food for 14 d to determine the effects
      on ingested prey mass, body mass, resting metabolic rate, and the heat increment
      of feeding. Body mass was measured daily, and resting metabolism was measured
      weekly by gas respirometry. Ingested food mass did not differ significantly
      between the squid diet and the control or the recovery herring diet periods. As a
      result of differences in energy density, gross energy intake was significantly
      lower during the squid diet phase than during either the control or recovery
      periods. As a result, sea lions lost an average of 1.1 kg/d, totaling 12.2% of
      their initial body mass by the end of the experimental period. The heat increment
      of feeding for a 4-kg squid meal was significantly lower than for a similarly
      sized meal of herring. Decreases in both absolute (24.0 to 18.0 MJ/d, -24%) and
      mass-corrected (903 to 697 kJ/d/kg0.67, -20%) metabolism were observed by the end
      of the squid feedings. This study suggests that sea lions can depress their
      resting metabolism in response to decreases in energy intake or body mass,
      regardless of satiation level.

PMID- 10603337
TI  - Intermittent locomotion increases endurance in a gecko.
AB  - Nocturnal geckos can actively forage at low temperatures. A low minimum cost of
      locomotion allows greater sustainable speeds by partially offsetting the decrease
      in maximal oxygen consumption (VO2max) associated with low nocturnal
      temperatures. The nocturnality hypothesis (Autumn et al. 1997) proposes that the
      reduced cost of continuous locomotion is a shared, derived characteristic that
      increases the capacity to sustain locomotion at low temperatures. Yet many
      lizards move intermittently at speeds exceeding those that elicit VO2max. We
      exercised the frog-eyed gecko, Teratoscincus przewalskii, continuously and
      intermittently on a treadmill. At an exercise speed of 0.90 km h-1 (270% maximum
      aerobic speed), lizards alternating a 15-s exercise period with a 30-s pause
      period exhibited a 1.7-fold increase in distance capacity (total distance
      traveled before fatigue) compared with lizards exercised continuously at the same
      average speed (0.30 km h-1). The average aerobic cost of intermittent exercise
      was not significantly different from VO2max. Locomoting intermittently could
      augment the increase in endurance resulting from the low minimum cost of
      continuous locomotion in nocturnal geckos. Intermittent behavior could increase
      the endurance of lizard movement in general.

PMID- 10603338
TI  - Validation of the doubly labeled water method in growing precocial birds: the
      importance of assumptions concerning evaporative water loss.
AB  - The doubly labeled water (DLW) method was validated against respiration gas
      analysis in growing precocial chicks of the black-tailed godwit (Limosa limosa)
      and the northern lapwing (Vanellus vanellus). To calculate the rate of CO2
      production from DLW measurements, Lifson and McClintock's equations (6) and (35)
      were employed, as well as Speakman's equation (7.17) (all single-pool models).
      The average errors obtained with the first two equations (+7.2% and -11.6%,
      respectively) differed significantly from zero but not the error obtained with
      Speakman's equation (average: -2.9%). The latter error could be reduced by taking
      a fractional evaporative water loss of 0.13, instead of the value of 0. 25
      recommended by Speakman. Application of different two-pool models resulted in
      relative errors of the DLW method of -15.9% or more. After employing the single
      pool model with a fractional evaporative water loss value of 0.13, it was found
      that there was no relationship between the relative growth rate of the chick and
      the relative error of the DLW method. Recalculation of previously published
      results on Arctic tern (Sterna paradisaea) chicks revealed that the fit of the
      validation experiment could be considerably improved by employing a single-pool
      model and assuming a fractional evaporative water loss of 0.20 instead of the
      value of 0.50 taken originally. After employing the value of 0.20, it was found
      that there was no relationship between the relative growth rate of the chick and
      the relative error of the DLW method. This suggests that isotope incorporation
      into new body substances does not cause a detectable error. Thus, the DLW method
      seems to be applicable in young birds growing as fast as 20% d-1, after making
      adjustments for the fractional evaporative water loss. We recommend Speakman's
      equation (7.17) for general use in growing birds when evaporation is unknown.

PMID- 10603339
TI  - Coexpression of the homeobox genes Distal-less and homothorax determines
      Drosophila antennal identity.
AB  - The Distal-less gene is known for its role in proximodistal patterning of
      Drosophila limbs. However, Distal-less has a second critical function during
      Drosophila limb development, that of distinguishing the antenna from the leg. The
      antenna-specifying activity of Distal-less is genetically separable from the
      proximodistal patterning function in that certain Distal-less allelic
      combinations exhibit antenna-to-leg transformations without proximodistal
      truncations. Here, we show that Distal-less acts in parallel with homothorax, a
      previously identified antennal selector gene, to induce antennal differentiation.
      While mutations in either Distal-less or homothorax cause antenna-to-leg
      transformations, neither gene is required for the others expression, and both
      genes are required for antennal expression of spalt. Coexpression of Distal-less
      and homothorax activates ectopic spalt expression and can induce the formation of
      ectopic antennae at novel locations in the body, including the head, the legs,
      the wings and the genital disc derivatives. Ectopic expression of homothorax
      alone is insufficient to induce antennal differentiation from most limb fields,
      including that of the wing. Distal-less therefore is required for more than
      induction of a proximodistal axis upon which homothorax superimposes antennal
      identity. Based on their genetic and biochemical properties, we propose that
      Homothorax and Extradenticle may serve as antenna-specific cofactors for Distal
      less.

PMID- 10603340
TI  - Independent regulation of Dlx2 expression in the epithelium and mesenchyme of the
      first branchial arch.
AB  - Dlx2, a member of the distal-less gene family, is expressed in the first
      branchial arch, prior to the initiation of tooth development, in distinct, non
      overlapping domains in the mesenchyme and the epithelium. In the mesenchyme Dlx2
      is expressed proximally, whereas in oral epithelium it is expressed distally.
      Dlx2 has been shown to be involved in the patterning of the murine dentition,
      since loss of function of Dlx1 and Dlx2 results in early failure of development
      of upper molar teeth. We have investigated the regulation of Dlx2 expression to
      determine how the early epithelial and mesenchymal expression boundaries are
      maintained, to help to understand the role of these distinct expression domains
      in patterning of the dentition. Transgenic mice produced with a lacZ reporter
      construct, containing 3.8 kb upstream sequence of Dlx2, led to the mapping of
      regulatory regions driving epithelial but not mesenchymal expression in the first
      branchial arch. We show that the epithelial expression of Dlx2 is regulated by
      planar signalling by BMP4, which is coexpressed in distal oral epithelium.
      Mesenchymal expression is regulated by a different mechanism involving FGF8,
      which is expressed in the overlying epithelium. FGF8 also inhibits expression of
      Dlx2 in the epithelium by a signalling pathway that requires the mesenchyme.
      Thus, the signalling molecules BMP4 and FGF8 provide the mechanism for
      maintaining the strict epithelial and mesenchymal expression domains of Dlx2 in
      the first arch.

PMID- 10603341
TI  - Induction and differentiation of the zebrafish heart requires fibroblast growth
      factor 8 (fgf8/acerebellar).
AB  - Vertebrate heart development is initiated from bilateral lateral plate mesoderm
      that expresses the Nkx2.5 and GATA4 transcription factors, but the extracellular
      signals specifying heart precursor gene expression are not known. We describe
      here that the secreted signaling factor Fgf8 is expressed in and required for
      development of the zebrafish heart precursors, particularly during initiation of
      cardiac gene expression. fgf8 is mutated in acerebellar (ace) mutants, and
      homozygous mutant embryos do not establish normal circulation, although vessel
      formation is only mildly affected. In contrast, heart development, in particular
      of the ventricle, is severely abnormal in acerebellar mutants. Several findings
      argue that Fgf8 has a direct function in development of cardiac precursor cells:
      fgf8 is expressed in cardiac precursors and later in the heart ventricle. Fgf8 is
      required for the earliest stages of nkx2.5 and gata4, but not gata6, expression
      in cardiac precursors. Cardiac gene expression is restored in acerebellar mutant
      embryos by injecting fgf8 RNA, or by implanting a Fgf8-coated bead into the heart
      primordium. Pharmacological inhibition of Fgf signalling during formation of the
      heart primordium phenocopies the acerebellar heart phenotype, confirming that Fgf
      signaling is required independently of earlier functions during gastrulation.
      These findings show that fgf8/acerebellar is required for induction and
      patterning of myocardial precursors.

PMID- 10603342
TI  - Glia maintain follower neuron survival during Drosophila CNS development.
AB  - While survival of CNS neurons appears to depend on multiple neuronal and non
      neuronal factors, it remains largely unknown how neuronal survival is controlled
      during development. Here we show that glia regulate neuronal survival during
      formation of the Drosophila embryonic CNS. When glial function is impaired either
      by mutation of the glial cells missing gene, which transforms glia toward a
      neuronal fate, or by targeted genetic glial ablation, neuronal death is induced
      non-autonomously. Pioneer neurons, which establish the first longitudinal axon
      fascicles, are insensitive to glial depletion whereas the later extending
      follower neurons die. This differential requirement of neurons for glia is
      instructive in patterning and links control of cell number with axon guidance
      during CNS development.

PMID- 10603343
TI  - Tissue-specific requirements for the proprotein convertase furin/SPC1 during
      embryonic turning and heart looping.
AB  - Furin, the mammalian prototype of a family of serine proteases, is required for
      ventral closure and axial rotation, and formation of the yolk sac vasculature.
      Here we show additionally that left-sided expression of pitx2 and lefty-2 are
      also perturbed in Furin-deficient embryos. These tissue abnormalities are
      preceded by a marked delay in the expansion of the definitive endoderm during
      gastrulation. Using a chimera approach, we show that Furin activity is required
      in epiblast derivatives, including the primitive heart, gut and extraembryonic
      mesoderm, whereas it is nonessential in the visceral endoderm. Thus, chimeric
      embryos, derived by injecting wild-type embryonic stem (ES) cells into fur(-/-)
      blastocysts, develop normally until at least 9.5 d.p.c. In contrast, Furin
      deficient chimeras developing in the context of wild-type visceral endoderm fail
      to undergo ventral closure, axial rotation and yolk sac vascularization. Fur(-/-)
      cells are recruited into all tissues examined, including the yolk sac vasculature
      and the midgut, even though these structures fail to form in fur mutants. The
      presence of wild-type cells in the gut strikingly correlates with the ability of
      chimeric embryos to undergo turning. Overall, we conclude that Furin activity is
      essential in both extraembryonic and precardiac mesoderm, and in definitive
      endoderm derivatives.

PMID- 10603344
TI  - The fate of cells in the tailbud of Xenopus laevis.
AB  - The vertebrate tailbud and trunk form very similar tissues. It has been a
      controversial question for decades whether cell determination in the developing
      tail proceeds as part of early axial development or whether it proceeds by a
      different mechanism. To examine this question more closely, we have used
      photoactivation of fluorescence to mark small neighborhoods of cells in the
      developing tailbud of Xenopus laevis. We show that, in one region of the tailbud,
      very small groups of adjacent cells can contribute progeny to the neural tube,
      notochord and somitic muscle, as well as other identified cell types within a
      single embryo. Groups averaging three adjacent cells at a later stage can
      contribute progeny with a similar distribution. Our data suggest that the tailbud
      contains multipotent cells that make very late germ-layer decisions.

PMID- 10603345
TI  - The receptor tyrosine kinase EphB4 and ephrin-B ligands restrict angiogenic
      growth of embryonic veins in Xenopus laevis.
AB  - The cues and signaling systems that guide the formation of embryonic blood
      vessels in tissues and organs are poorly understood. Members of the Eph family of
      receptor tyrosine kinases and their cell membrane-anchored ligands, the ephrins,
      have been assigned important roles in the control of cell migration during
      embryogenesis, particularly in axon guidance and neural crest migration. Here we
      investigated the role of EphB receptors and their ligands during embryonic blood
      vessel development in Xenopus laevis. In a survey of tadpole-stage Xenopus
      embryos for EphB receptor expression, we detected expression of EphB4 receptors
      in the posterior cardinal veins and their derivatives, the intersomitic veins.
      Vascular expression of other EphB receptors, including EphB1, EphB2 or EphB3,
      could however not be observed, suggesting that EphB4 is the principal EphB
      receptor of the early embryonic vasculature of Xenopus. Furthermore, we found
      that ephrin-B ligands are expressed complementary to EphB4 in the somites
      adjacent to the migratory pathways taken by intersomitic veins during angiogenic
      growth. We performed RNA injection experiments to study the function of EphB4 and
      its ligands in intersomitic vein development. Disruption of EphB4 signaling by
      dominant negative EphB4 receptors or misexpression of ephrin-B ligands in Xenopus
      embryos resulted in intersomitic veins growing abnormally into the adjacent
      somitic tissue. Our findings demonstrate that EphB4 and B-class ephrins act as
      regulators of angiogenesis possibly by mediating repulsive guidance cues to
      migrating endothelial cells.

PMID- 10603346
TI  - Phosphorylation of bicoid on MAP-kinase sites: contribution to its interaction
      with the torso pathway.
AB  - The Torso signal transduction pathway exhibits two opposite effects on the
      activity of the Bicoid (Bcd) morphogen: (i) Bcd function is repressed by Torso
      (Tor) at the anterior pole of the embryo leading to a retraction of the
      expression of many Bcd targets from the most anterior region of the embryo, where
      the Tor tyrosine kinase receptor is activated, and (ii) Bcd function is
      strengthened by Tor in a broader anterior region, as indicated by a shift of the
      posterior border of Bcd targets towards the anterior pole in embryos deprived
      from Tor activity. Anterior repression of Bcd targets was not observed in embryos
      lacking maternal contribution of D-sor, which acts downstream of Tor and encodes
      a MAP-kinase kinase. This indicates that the Ras signalling cascade is directly
      involved in this process, although the known transcriptional effectors of the Tor
      pathway, tll and hkb, are not (Ronchi, E., Treisman, J., Dostatni, N., Struhl, G.
      and Desplan, C. (1993) Cell 74, 347-355). Bcd is a good in vitro substrate for
      phosphorylation by MAP-kinase and phosphorylation of the protein occur in vivo on
      MAP-kinase sites. In the presence of a Bcd mutant that could no longer be
      phosphorylated by MAP-kinase, expression of Bcd targets remained repressed by Tor
      at the pole while strengthening of Bcd activity was reduced. These experiments
      indicate that phosphorylation of Bcd by MAP-kinase is likely to be required for
      the Tor pathway to induce its full positive effect on Bcd. This suggests that Tor
      signalling acts at a distance from the anterior pole by direct modification of
      the diffusing Bcd morphogen.

PMID- 10603347
TI  - Antagonism of notch signaling activity by members of a novel protein family
      encoded by the bearded and enhancer of split gene complexes.
AB  - Cell-cell signaling through the Notch receptor is a principal mechanism
      underlying cell fate specification in a variety of developmental processes in
      metazoans, such as neurogenesis. In this report we describe our investigation of
      seven members of a novel gene family in Drosophila with important connections to
      Notch signaling. These genes all encode small proteins containing predicted basic
      amphipathic (&agr;)-helical domains in their amino-terminal regions, as described
      originally for Bearded; accordingly, we refer to them as Bearded family genes.
      Five members of the Bearded family are located in a newly discovered gene
      complex, the Bearded Complex; two others reside in the previously identified
      Enhancer of split Complex. All members of this family contain, in their proximal
      upstream regions, at least one high-affinity binding site for the Notch-activated
      transcription factor Suppressor of Hairless, suggesting that all are directly
      regulated by the Notch pathway. Consistent with this, we show that Bearded family
      genes are expressed in a variety of territories in imaginal tissue that
      correspond to sites of active Notch signaling. We demonstrate that overexpression
      of any family member antagonizes the activity of the Notch pathway in multiple
      cell fate decisions during adult sensory organ development. These results suggest
      that Bearded family genes encode a novel class of effectors or modulators of
      Notch signaling.

PMID- 10603348
TI  - Regulation of mouse lens fiber cell development and differentiation by the Maf
      gene.
AB  - Maf is a basic domain/leucine zipper domain protein originally identified as a
      proto-oncogene whose consensus target site in vitro, the T-MARE, is an extended
      version of an AP-1 site normally recognized by Fos and Jun. Maf and the closely
      related family members Neural retina leucine zipper (Nrl), L-Maf, and Krml1/MafB
      have been implicated in a wide variety of developmental and physiologic roles;
      however, mutations in vivo have been described only for Krml1/MafB, in which a
      loss-of-function causes abnormalities in hindbrain development due to failure to
      activate the Hoxa3 and Hoxb3 genes. We have used gene targeting to replace Maf
      coding sequences with those of lacZ, and have carried out a comprehensive
      analysis of embryonic expression and the homozygous mutant phenotype in the eye.
      Maf is expressed in the lens vesicle after invagination, and becomes highly
      upregulated in the equatorial zone, the site at which self-renewing anterior
      epithelial cells withdraw from the cell cycle and terminally differentiate into
      posterior fiber cells. Posterior lens cells in Maf(lacZ) mutant mice exhibit
      failure of elongation at embryonic day 11.5, do not express (&agr;)A- and all of
      the (beta)-crystallin genes, and display inappropriately high levels of DNA
      synthesis. This phenotype partially overlaps with those reported for gene
      targeting of Prox1 and Sox1; however, expression of these genes is grossly
      normal, as is expression of Eya1, Eya2, Pax6, and Sox2. Recombinant Maf protein
      binds to T-MARE sites in the (alpha)A-, (beta)B2-, and (beta)A4-crystallin
      promoters but fails to bind to a point mutation in the (alpha)A-crystallin
      promoter that has been shown previously to be required for promoter function. Our
      results indicate that Maf directly activates many if not all of the (beta)
      crystallin genes, and suggest a model for coordinating cell cycle withdrawal with
      terminal differentiation.

PMID- 10603349
TI  - Myf5 is a novel early axonal marker in the mouse brain and is subjected to post
      transcriptional regulation in neurons.
AB  - Myf5 is a key basic Helix-Loop-Helix transcription factor capable of converting
      many non-muscle cells into muscle. Together with MyoD it is essential for
      initiating the skeletal muscle programme in the embryo. We previously identified
      unexpected restricted domains of Myf5 transcription in the embryonic mouse brain,
      first revealed by Myf5-nlacZ(+/)(-) embryos (Tajbakhsh, S. and Buckingham, M.
      (1995) Development 121, 4077-4083). We have now further characterized these Myf5
      expressing neurons. Retrograde labeling with diI, and the use of a transgenic
      mouse line expressing lacZ under the control of Myf5 regulatory sequences, show
      that Myf5 transcription provides a novel axonal marker of the medial longitudinal
      fasciculus (mlf) and the mammillotegmental tract (mtt), the earliest longitudinal
      tracts to be established in the embryonic mouse brain. Tracts projecting caudally
      from the developing olfactory system are also labelled. nlacZ and lacZ expression
      persist in the adult brain, in a few ventral domains such as the mammillary
      bodies of the hypothalamus and the interpeduncular nucleus, potentially derived
      from the embryonic structures where the Myf5 gene is transcribed. To investigate
      the role of Myf5 in the brain, we monitored Myf5 protein accumulation by
      immunofluorescence and immunoblotting in neurons transcribing the gene. Although
      Myf5 was detected in muscle myotomal cells, it was absent in neurons. This would
      account for the lack of myogenic conversion in brain structures and the absence
      of a neural phenotype in homozygous null mutants. RT-PCR experiments show that
      the splicing of Myf5 primary transcripts occurs correctly in neurons, suggesting
      that the lack of Myf5 protein accumulation is due to regulation at the level of
      mRNA translation or protein stability. In the embryonic neuroepithelium, Myf5 is
      transcribed in differentiated neurons after the expression of neural basic Helix
      Loop-Helix transcription factors. The signalling molecules Wnt1 and Sonic
      hedgehog, implicated in the activation of Myf5 in myogenic progenitor cells in
      the somite, are also produced in the viscinity of the Myf5 expression domain in
      the mesencephalon. We show that cells expressing Wnt1 can activate neuronal Myf5
      nlacZ gene expression in dissected head explants isolated from E9.5 embryos.
      Furthermore, the gene encoding the basic Helix-Loop-Helix transcription factor
      mSim1 is expressed in adjacent cells in both the somite and the brain, suggesting
      that signalling molecules necessary for the activation of mSim1 as well as Myf5
      are present at these different sites in the embryo. This phenomenon may be
      widespread and it remains to be seen how many other potentially potent regulatory
      genes, in addition to Myf5, when activated do not accumulate protein at
      inappropriate sites in the embryo.

PMID- 10603350
TI  - Sonic hedgehog synergizes with the extracellular matrix protein vitronectin to
      induce spinal motor neuron differentiation.
AB  - Patterning of the vertebrate neural tube depends on intercellular signals
      emanating from sources such as the notochord and the floor plate. The secreted
      protein Sonic hedgehog and the extracellular matrix protein Vitronectin are both
      expressed in these signalling centres and have both been implicated in the
      generation of ventral neurons. The proteolytic processing of Sonic hedgehog is
      fundamental for its signalling properties. This processing generates two secreted
      peptides with all the inducing activity of Shh residing in the highly conserved
      19 kDa amino-terminal peptide (N-Shh). Here we show that Vitronectin is also
      proteolitically processed in the embryonic chick notochord, floor plate and
      ventral neural tube and that this processing is spatiotemporally correlated with
      the generation of motor neurons. The processing of Vitronectin produces two
      fragments of 54 kDa and 45 kDa, as previously described for Vitronectin isolated
      from chick yolk. The 45 kDa fragment lacks the heparin-binding domain and the
      integrin-binding domain, RGD, present in the non-processed Vitronectin
      glycoprotein. Here we show that N-Shh binds to the three forms of Vitronectin
      (70, 54 and 45 kDa) isolated from embryonic tissue, although is preferentially
      associated with the 45 kDa form. Furthermore, in cultures of dissociated
      neuroepithelial cells, the combined addition of N-Shh and Vitronectin
      significantly increases the extent of motor neuron differentiation, as compared
      to the low or absent inducing capabilities of either N-Shh or Vitronectin alone.
      Thus, we conclude that the differentiation of motor neurons is enhanced by the
      synergistic action of N-Shh and Vitronectin, and that Vitronectin may be
      necessary for the proper presentation of the morphogen N-Shh to one of its target
      cells, the differentiating motor neurons.

PMID- 10603351
TI  - Essential role of Bmp7 (snailhouse) and its prodomain in dorsoventral patterning
      of the zebrafish embryo.
AB  - Bone morphogenetic proteins (Bmps) are signaling molecules that have been
      implicated in a variety of inductive processes. We report here that zebrafish
      Bmp7 is disrupted in snailhouse (snh) mutants. The allele snh(st1) is a
      translocation deleting the bmp7 gene, while snh(ty68) displays a Val->Gly exhange
      in a conserved motif of the Bmp7 prodomain. The snh(ty68) mutation is temperature
      sensitive, leading to severalfold reduced activity of mutant Bmp7 at 28 degrees C
      and non-detectable activity at 33 degrees C. This prodomain lesion affects
      secretion and/or stability of secreted mature Bmp7 after processing has occurred.
      Both snh(st1) and snh(ty68) mutant zebrafish embryos are strongly dorsalized,
      indicating that bmp7 is required for the specification of ventral cell fates
      during early dorsoventral patterning. At higher temperature, the phenotype of
      snh(ty68) mutant embryos is identical to that caused by the amorphic bmp2b
      mutation swirl swr(ta72) and similar to that caused by the smad5 mutation
      somitabun sbn(dtc24). mRNA injection studies and double mutant analyses indicate
      that Bmp2b and Bmp7 closely cooperate and that Bmp2b/Bmp7 signaling is transduced
      by Smad5 and antagonized by Chordino.

PMID- 10603352
TI  - Anucleate Caenorhabditis elegans sperm can crawl, fertilize oocytes and direct
      anterior-posterior polarization of the 1-cell embryo.
AB  - It has long been appreciated that spermiogenesis, the cellular transformation of
      sessile spermatids into motile spermatozoa, occurs in the absence of new DNA
      transcription. However, few studies have addressed whether the physical presence
      of a sperm nucleus is required either during spermiogenesis or for subsequent
      sperm functions during egg activation and early zygotic development. To determine
      the role of the sperm nucleus in these processes, we analyzed two C. elegans
      mutants whose spermatids lack DNA. Here we show that these anucleate sperm not
      only differentiate into mature functional spermatozoa, but they also crawl toward
      and fertilize oocytes. Furthermore, we show that these anucleate sperm induce
      both normal egg activation and anterior-posterior polarity in the 1-cell C.
      elegans embryo. The latter finding demonstrates for the first time that although
      the anterior-posterior embryonic axis in C. elegans is specified by sperm, the
      sperm pronucleus itself is not required. Also unaffected is the completion of
      oocyte meiosis, formation of an impermeable eggshell, migration of the oocyte
      pronucleus, and the separation and expansion of the sperm-contributed
      centrosomes. Our investigation of these mutants confirms that, in C. elegans,
      neither the sperm chromatin mass nor a sperm pronucleus is required for
      spermiogenesis, proper egg activation, or the induction of anterior-posterior
      polarity.

PMID- 10603353
TI  - Suppression of the rbf null mutants by a de2f1 allele that lacks transactivation
      domain.
AB  - In mammals, a large number of proteins including E2F transcription factors have
      been shown to interact with the tumor suppressor gene product pRB, but it is not
      clear to what extend the function of pRB is mediated by E2F. In addition, E2F was
      shown to mediate both transcription activation and repression; it remains to be
      tested which function of E2F is critical for normal development. Drosophila
      homologs of the RB and E2F family of proteins RBF and dE2F1 have been identified.
      The genetic interactions between rbf and de2f1 were analyzed during Drosophila
      development, and the results presented here showed that RBF is required at
      multiple stages of development. Unexpectedly, rbf null mutants can develop until
      late pupae stage when the activity of dE2F1 is reduced, and can develop into
      viable adults with normal adult appendages in the presence of a de2f1 mutation
      that retains the DNA binding domain but lacks the transactivation domain. These
      results indicate that most, if not all, of the function of RBF during development
      is mediated through E2F. In turn, the genetic interactions shown here also
      suggest that dE2F1 functions primarily as a transcription activator rather than a
      co-repressor of RBF during Drosophila development. Analysis of the expression of
      an E2F target gene PCNA in eye discs showed that the expression of PCNA is
      activated by dE2F1 in the second mitotic wave and repressed in the morphogenetic
      furrow and posterior to the second mitotic wave by RBF. Interestingly, reducing
      the level of RBF restored the normal pattern of cell proliferation in de2f1
      mutant eye discs but not the expression of E2F target genes, suggesting that the
      coordinated transcription of E2F target genes does not significantly affect the
      pattern of cell proliferation.

PMID- 10603354
TI  - The Xenopus tadpole gut: fate maps and morphogenetic movements.
AB  - We have produced a comprehensive fate map showing where the organs of the gut and
      respiratory system are derived from in the early Xenopus laevis endoderm. We also
      show the origin of the associated smooth muscle layer on a separate fate map.
      Comparison of the two maps shows that for most organs of the gut the prospective
      epithelium and smooth muscle do not overlie each other in the early embryo but
      come together at a later stage. These fate maps should be useful for future
      studies into endoderm specification. It was not previously known how the
      elongation of the endoderm occurs, how the single-layered dorsal and many-layered
      ventral endoderm gives rise to the single layered epithelium, and whether or not
      the archenteron cavity actually gives rise to the gut lumen. Using a variety of
      labelling procedures we show firstly, that radial intercalation occurs in the gut
      transforming a short thick tube into a long thin tube; secondly, that the
      archenteron lining does not become the definitive gut lumen. Instead the
      archenteron cavity almost closes at tailbud stages before providing a nucleus for
      the definitive gut cavity, which opens up during elongation. Based on this work
      we present a model explaining the morphogenesis of the gut.

PMID- 10603355
TI  - Glia dictate pioneer axon trajectories in the Drosophila embryonic CNS.
AB  - Whereas considerable progress has been made in understanding the molecular
      mechanisms of axon guidance across the midline, it is still unclear how the
      axonal trajectories of longitudinal pioneer neurons, which never cross the
      midline, are established. Here we show that longitudinal glia of the embryonic
      Drosophila CNS direct formation of pioneer axon pathways. By ablation and
      analysis of glial cells missing mutants, we demonstrate that glia are required
      for two kinds of processes. Firstly, glia are required for growth cone guidance,
      although this requirement is not absolute. We show that the route of extending
      growth cones is rich in neuronal cell bodies and glia, and also in long processes
      from both these cell types. Interactions between neurons, glia and their long
      processes orient extending growth cones. Secondly, glia direct the fasciculation
      and defasciculation of axons, which pattern the pioneer pathways. Together these
      events are essential for the selective fasciculation of follower axons along the
      longitudinal pathways.

PMID- 10603356
TI  - Temporospatial cell interactions regulating mandibular and maxillary arch
      patterning.
AB  - The cellular origin of the instructive information for hard tissue patterning of
      the jaws has been the subject of a long-standing controversy. Are the cranial
      neural crest cells prepatterned or does the epithelium pattern a developmentally
      uncommitted population of ectomesenchymal cells? In order to understand more
      about how orofacial patterning is controlled we have investigated the temporal
      signalling interactions and responses between epithelium and mesenchymal cells in
      the mandibular and maxillary primordia. We show that within the mandibular arch,
      homeobox genes that are expressed in different proximodistal spatial domains
      corresponding to presumptive molar and incisor ectomesenchymal cells are induced
      by signals from the oral epithelium. In mouse, prior to E10, all ectomesenchyme
      cells in the mandibular arch are equally responsive to epithelial signals such as
      Fgf8, indicating that there is no pre-specification of these cells into different
      populations and suggesting that patterning of the hard tissues of the mandible is
      instructed by the epithelium. By E10.5, ectomesenchymal cell gene expression
      domains are still dependent on epithelial signals but have become fixed and
      ectopic expression cannot be induced. At E11 expression becomes independent of
      epithelial signals such that removal of the epithelium does not affect spatial
      ectomesenchymal expression. Significantly, however, the response of
      ectomesenchyme cells to epithelial regulatory signals was found to be different
      in the mandibular and maxillary primordium. Thus, whereas both mandibular and
      maxillary arch epithelia could induce Dlx2 and Dlx5 expression in the mandible
      and Dlx2 expression in the maxilla, neither could induce Dlx5 expression in the
      maxilla. Reciprocal cell transplantations between mandibular and maxillary arch
      ectomesenchymal cells revealed intrinsic differences between these populations of
      cranial neural crest-derived cells. Research in odontogenesis has shown that the
      oral epithelium of the mandibular and maxillary primordia has unique instructive
      signaling properties required to direct odontogenesis, which are not found in
      other branchial arch epithelia. As a consequence, development of jaw-specific
      skeletal structures may require some prespecification of maxillary ectomesenchyme
      to restrict the instructive influence of the epithelial signals and allow
      development of maxillary structures distinct from mandibular structures.

PMID- 10603357
TI  - Lbx1 is required for muscle precursor migration along a lateral pathway into the
      limb.
AB  - In mammalian embryos, myogenic precursor cells emigrate from the ventral lip of
      the dermomyotome and colonize the limbs, tongue and diaphragm where they
      differentiate and form skeletal muscle. Previous studies have shown that Pax3,
      together with the c-Met receptor tyrosine kinase and its ligand Scatter Factor
      (SF) are necessary for the migration of hypaxial muscle precursors in mice. Lbx1
      and Pax3 are co-expressed in all migrating hypaxial muscle precursors, raising
      the possibility that Lbx1 regulates their migration. To examine the function of
      Lbx1 in muscle development, we inactivated the Lbx1 gene by homologous
      recombination. Mice lacking Lbx1 exhibit an extensive loss of limb muscles,
      although some forelimb and hindlimb muscles are still present. The pattern of
      muscle loss suggests that Lbx1 is not required for the specification of
      particular limb muscles, and the muscle defects that occur in Lbx1(-/-) mice can
      be solely attributed to changes in muscle precursor migration. c-Met is expressed
      in Lbx1 mutant mice and limb muscle precursors delaminate from the ventral
      dermomyotome but fail to migrate laterally into the limb. Muscle precursors still
      migrate ventrally and give rise to tongue, diaphragm and some limb muscles,
      demonstrating Lbx1 is necessary for the lateral, but not ventral, migration of
      hypaxial muscle precursors. These results suggest that Lbx1 regulates
      responsiveness to a lateral migration signal which emanates from the developing
      limb.

PMID- 10603358
TI  - Regulation of neurogenesis by interactions between HEN1 and neuronal LMO
      proteins.
AB  - Basic-helix-loop-helix transcription factors regulate neurogenesis and neuronal
      differentiation by as yet unknown mechanisms. We show that an embryonic neuronal
      specific basic-helix-loop-helix protein, HEN1 (also known as NSCL1 or NHLH),
      interacts with 'LIM only' proteins. Examination of the expression patterns of
      XHEN1 and XLMO-3, the Xenopus homologues of these human genes, reveals extensive
      overlap during early neurogenesis: at the onset of gastrulation on the dorsal
      side of the blastopore lip and, subsequently, in the prospective neural plate.
      Binding of XLMO-3 increases the transcriptional activity of XHEN1 in vivo. Co
      expression of these two genes in Xenopus embryos induces a cascade of expression
      of neuronal-specific basic-helix-loop-helix proteins that leads to neuronal
      differentiation. We propose that XHEN1, in concert with XLMO-3, is a critical
      regulator of neurogenesis.

PMID- 10603359
TI  - The role of Lbx1 in migration of muscle precursor cells.
AB  - The homeobox gene Lbx1 is expressed in migrating hypaxial muscle precursor cells
      during development. These precursors delaminate from the lateral edge of the
      dermomyotome and form distinct streams that migrate over large distances, using
      characteristic paths. The targets of migration are limbs, septum transversum and
      the floor of the first branchial arch where the cells form skeletal muscle of
      limbs and shoulders, diaphragm and hypoglossal cord, respectively. We used gene
      targeting to analyse the function of Lbx1 in the mouse. Myogenic precursor cells
      delaminate from the dermomyotome in Lbx1 mutants, but migrate in an aberrant
      manner. Most critically affected are migrating cells that move to the limbs.
      Precursor cells that reach the dorsal limb field are absent. In the ventral limb,
      precursors are present but distributed in an abnormal manner. As a consequence,
      at birth some muscles in the forelimbs are completely lacking (extensor muscles)
      or reduced in size (flexor muscles). Hindlimb muscles are affected strongly, and
      distal limb muscles are more affected than proximal ones. Other migrating
      precursor cells heading towards the floor of the first branchial arch move along
      the appropriate path in Lbx1 mutants. However, these cells migrate less
      efficiently and reduced numbers of precursors reach their distal target. At
      birth, the internal lingual muscle is therefore reduced in size. We suggest that
      Lbx1 controls the expression of genes that are essential for the recognition or
      interpretation of cues that guide migrating muscle precursors and maintain their
      migratory potential.

PMID- 10603360
TI  - Lipopolysaccharide-induced biliary factors enhance invasion of Salmonella
      enteritidis in a rat model.
AB  - In this study, the role of the hepatobiliary system in the early pathogenesis of
      Salmonella enteritidis infection was investigated in a rat model. Intravenous
      (i.v.) challenge with lipopolysaccharide (LPS) has previously been shown to
      enhance the translocation of normal gut flora. We first confirmed that LPS can
      similarly promote the invasion of S. enteritidis. Oral infection of outbred
      Australian Albino Wistar rats with 10(6) to 10(7) CFU of S. enteritidis led to
      widespread tissue invasion after days. If animals were similarly challenged after
      intravenous administration of S. enteritidis LPS (3 to 900 microg/kg of body
      weight), significant invasion of the livers and mesenteric lymph nodes (MLN)
      occurred within 24 h, with invasion of the liver increasing in a dose-dependent
      fashion (P < 0.01). If bile was prevented from reaching the intestine by bile
      duct ligation or cannulation, bacterial invasion of the liver and MLN was almost
      totally abrogated (P < 0.001). As i.v. challenge with LPS could induce the
      delivery of inflammatory mediators into the bile, biliary tumor necrosis factor
      alpha (TNF-alpha) concentrations were measured by bioassay. Biliary
      concentrations of TNF-alpha rose shortly after LPS challenge, peaked with a mean
      concentration of 27.0 ng/ml at around 1 h postchallenge, and returned to baseline
      levels (3.1 ng/ml) after 2.5 h. Although TNF-alpha cannot be directly implicated
      in the invasion process, we conclude that the invasiveness of the enteric
      pathogen S. enteritidis is enhanced by the presence of LPS in the blood and that
      this enhanced invasion is at least in part a consequence of the delivery of
      inflammatory mediators to the gastrointestinal tract by the hepatobiliary system.

PMID- 10603361
TI  - Characterization of PaxA and its operon: a cohemolytic RTX toxin determinant from
      pathogenic Pasteurella aerogenes.
AB  - Pasteurella aerogenes is known as a commensal bacterium or as an opportunistic
      pathogen, as well as a primary pathogen found to be involved in abortion cases of
      humans, swine, and other mammals. Using broad-range DNA probes for bacterial RTX
      toxin genes, we cloned and subsequently sequenced a new operon named paxCABD
      encoding the RTX toxin PaxA in P. aerogenes. The pax operon is organized
      analogous to the classical RTX operons containing the activator gene paxC
      upstream of the structural toxin gene paxA, which is followed by the secretion
      protein genes paxB and paxD. The highest sequence similarity of paxA with known
      RTX toxin genes is found with apxIIIA (82%). PaxA is structurally similar to
      ApxIIIA and also shows functional analogy to ApxIIIA, since it shows cohemolytic
      activity with the sphingomyelinase of Staphylococcus aureus, known as the CAMP
      effect, but is devoid of direct hemolytic activity. In addition, it shows to some
      extent immunological cross-reactions with ApxIIIA. P. aerogenes isolated from
      various specimens showed that the pax operon was present in about one-third of
      the strains. All of the pax-positive strains were specifically related to swine
      abortion cases or septicemia of newborn piglets. These strains were also shown to
      produce the PaxA toxin as determined by the CAMP phenomenon, whereas none of the
      pax-negative strains did. This indicated that the PaxA toxin is involved in the
      pathogenic potential of P. aerogenes. The examined P. aerogenes isolates were
      phylogenetically analyzed by 16S rRNA gene (rrs) sequencing in order to confirm
      their species. Only a small heterogeneity (<0.5%) was observed between the rrs
      genes of the strains originating from geographically distant farms and isolated
      at different times.

PMID- 10603362
TI  - Glycosylation of homologous immunodominant proteins of Ehrlichia chaffeensis and
      Ehrlichia canis.
AB  - The glycoprotein genes of Ehrlichia chaffeensis (1,644 bp) and Ehrlichia canis
      (2,064 bp) encode proteins of 548 to 688 amino acids with predicted molecular
      masses of only 61 and 73 kDa but with electrophoretic mobilities of 120 kDa
      (P120) and 140 kDa (P140), respectively. The 120-kDa protein gene of E.
      chaffeensis contains four identical 240-bp tandem repeat units, and the 140-kDa
      protein gene of E. canis has 14 nearly identical, tandemly arranged 108-bp repeat
      units. Conserved serine-rich motifs identified in the repeat units of P120 and
      P140 were also found in the repeat units of the human granulocytotropic
      ehrlichiosis agent 130-kDa protein and of the fimbria-associated adhesin protein
      Fap1 of Streptococcus parasanguis. Nearly the entire (99%) E. chaffeensis P120
      gene (1,616 bp), the 14-repeat region (78%) of the E. canis P140 gene (1,620 bp),
      and a 2-repeat region from the E. chaffeensis P120 gene (520 bp) were expressed
      in Escherichia coli. The recombinant proteins exhibited molecular masses ranging
      from 1.6 to 2 times larger than those predicted by the amino acid sequences.
      Antibodies against the recombinant proteins reacted with E. chaffeensis P120 and
      E. canis P140, respectively. Carbohydrate was detected on the E. chaffeensis and
      E. canis recombinant proteins, including the two-repeat polypeptide region of E.
      chaffeensis P120. A carbohydrate compositional analysis identified glucose,
      galactose, and xylose on the recombinant proteins. The presence of only one site
      for N-linked (Asn-Xaa-Ser/Thr) glycosylation, a lack of effect of N-glycosidase
      F, the presence of 70 and 126 Ser/Thr glycosylation sites in the repeat regions
      of P120 and P140, respectively, and a high molar ratio of carbohydrate to protein
      suggest that the glycans may be O linked.

PMID- 10603363
TI  - Differences in resistance of C57BL/6 and C57BL/10 mice to infection by
      Mycobacterium avium are independent of gamma interferon.
AB  - After infection with a low-virulence strain of Mycobacterium avium, C57BL/6 and
      C57BL/10 mice had clear differences in the control of the infection in their
      livers and spleens. This difference in susceptibility was not associated with
      differences in the H-2 complex. It was dependent on the activity of CD4(+) T
      cells but unrelated to the ability of these cells to secrete gamma interferon or
      to the development of delayed-type hypersensitivity responses at 3 weeks of
      infection. It was associated with lower total numbers of CD4(+) cells present in
      infected spleens and was related to an earlier induction of protective T cells,
      as measured by adoptive-transfer assays. These data further strengthen the notion
      of gamma-interferon-independent mechanisms of protection against mycobacteria.

PMID- 10603364
TI  - Invasion and intracellular survival of Burkholderia cepacia.
AB  - Burkholderia cepacia has emerged as an important pulmonary pathogen in
      immunocompromised patients and in patients with cystic fibrosis (CF). Little is
      known about the virulence factors and pathogenesis of B. cepacia, although the
      persistent and sometimes invasive infections caused by B. cepacia suggest that
      the organism possesses mechanisms for both cellular invasion and evasion of the
      host immune response. In this study, cultured human cells were used to analyze
      the invasion and intracellular survival of B. cepacia J2315, a highly
      transmissible clinical isolate responsible for morbidity and mortality in CF
      patients. Quantitative invasion and intracellular growth assays demonstrated that
      B. cepacia J2315 was able to enter, survive, and replicate intracellularly in
      U937-derived macrophages and A549 pulmonary epithelial cells. Transmission
      electron microscopy of infected macrophages confirmed the presence of
      intracellular B. cepacia and showed that intracellular bacteria were contained
      within membrane-bound vacuoles. An environmental isolate of B. cepacia, strain
      J2540, was also examined for its ability to invade and survive intracellularly in
      cultured human cells. J2540 entered cultured macrophages with an invasion
      frequency similar to that of the clinical strain, but it was less invasive than
      the clinical strain in epithelial cells. In marked contrast to the clinical
      strain, the environmental isolate was unable to survive or replicate
      intracellularly in either cultured macrophages or epithelial cells. Invasion and
      intracellular survival may play important roles in the ability of virulent
      strains of B. cepacia to evade the host immune response and cause persistent
      infections in CF patients.

PMID- 10603365
TI  - Increased expression of periplasmic Cu,Zn superoxide dismutase enhances survival
      of Escherichia coli invasive strains within nonphagocytic cells.
AB  - We have studied the influence of periplasmic Cu,Zn superoxide dismutase on the
      intracellular survival of Escherichia coli strains able to invade epithelial
      cells by the expression of the inv gene from Yersinia pseudotuberculosis but
      unable to multiply intracellularly. Intracellular viability assays, confirmed by
      electron microscopy observations, showed that invasive strains of E. coli
      engineered to increase Cu,Zn superoxide dismutase production are much more
      resistant to intracellular killing than strains containing only the chromosomal
      sodC copy. However, we have found only a slight difference in survival within
      HeLa cells between a sodC-null mutant and its isogenic wild-type strain. Such a
      small difference in survival correlates with the very low expression of this
      enzyme in the wild-type strain. We have also observed that acid- and oxidative
      stress-sensitive E. coli HB101(pRI203) is more rapidly killed in epithelial cells
      than E. coli GC4468(pRI203). The high mortality of E. coli HB101(pRI203),
      independent of the acidification of the endosome, is abolished by the
      overexpression of sodC. Our data suggest that oxyradicals are involved in the
      mechanisms of bacterial killing within epithelial cells and that high-level
      production of periplasmic Cu,Zn superoxide dismutase provides bacteria with an
      effective protection against oxidative damage. We propose that Cu,Zn superoxide
      dismutase could offer an important selective advantage in survival within host
      cells to bacteria expressing high levels of this enzyme.

PMID- 10603366
TI  - DNA vaccination with genes encoding Toxoplasma gondii antigens GRA1, GRA7, and
      ROP2 induces partially protective immunity against lethal challenge in mice.
AB  - C57BL/6, C3H, and BALB/c mice were vaccinated with plasmids encoding Toxoplasma
      gondii antigens GRA1, GRA7, and ROP2, previously described as strong inducers of
      immunity. Seroconversion for the relevant antigen was obtained in the majority of
      the animals. T. gondii lysate stimulated specific T-cell proliferation and
      secretion of gamma interferon (IFN-gamma) in spleen cell cultures from vaccinated
      BALB/c and C3H mice but not in those from control mice. Although not
      proliferating, stimulated splenocytes from DNA-vaccinated C57BL/6 mice also
      produced IFN-gamma. No interleukin-4 was detected in the supernatants of lysate
      stimulated splenocytes from DNA-vaccinated mice in any of the mouse strains
      evaluated. As in infected animals, a high ratio of specific immunoglobulin G2a
      (IgG2a) to IgG1 antibodies was found in DNA-vaccinated C3H mice, suggesting that
      a Th1-type response had been induced. For BALB/c mice, the isotype ratio of the
      antibody response to DNA vaccination was less polarized. The protective potential
      of DNA vaccination was demonstrated in C3H mice. C3H mice vaccinated with plasmid
      encoding GRA1, GRA7, or ROP2 were partially protected against a lethal oral
      challenge with cysts of two different T. gondii strains: survival rates increased
      from 10% in controls to at least 70% after vaccination in one case and from 50%
      to at least 90% in the other. In vaccinated C3H mice challenged with a nonlethal
      T. gondii dose, the number of brain cysts was significantly lower than in
      controls. DNA vaccination did not protect BALB/c or C57BL/6 mice. Our results
      demonstrate for the first time in an animal model a partially protective effect
      of DNA vaccination against T. gondii.

PMID- 10603367
TI  - Igh-6(-/-) (B-cell-deficient) mice fail to mount solid acquired resistance to
      oral challenge with virulent Salmonella enterica serovar typhimurium and show
      impaired Th1 T-cell responses to Salmonella antigens.
AB  - In the present study we evaluated the role of B cells in acquired immunity to
      Salmonella infection by using gene-targeted B-cell-deficient innately susceptible
      mice on a C57BL/6 background (Igh-6(-/-)). Igh-6(-/-) mice immunized with a live,
      attenuated aroA Salmonella enterica serovar Typhimurium vaccine strain showed
      impaired long-term acquired resistance against the virulent serovar Typhimurium
      strain C5. Igh-6(-/-) mice were able to control a primary infection and to clear
      the inoculum from the reticuloendothelial system. However, Igh-6(-/-) mice,
      unlike Igh-6(+/+) C57BL/6 controls, did not survive an oral challenge with strain
      C5 at 4 months after vaccination. Transfer of immune serum did not restore
      resistance in Igh-6(-/-) mice. Total splenocytes and purified CD4(+) T cells
      obtained from Igh-6(-/-) mice 4 months after vaccination showed reduced ability
      to release Th1-type cytokines (interleukin 2 and gamma interferon) upon in vitro
      restimulation with serovar Typhimurium soluble cell extracts compared to cells
      obtained from Igh-6(+/+) C57BL/6 control mice. Therefore, the impaired resistance
      to oral challenge with virulent serovar Typhimurium observed in B-cell-deficient
      mice, which cannot be restored by passive transfer of Salmonella-immune serum,
      may be in part due to a reduced serovar Typhimurium-specific T-cell response
      following primary immunization.

PMID- 10603368
TI  - Archaeosome vaccine adjuvants induce strong humoral, cell-mediated, and memory
      responses: comparison to conventional liposomes and alum.
AB  - Ether glycerolipids extracted from various archaeobacteria were formulated into
      liposomes (archaeosomes) possessing strong adjuvant properties. Mice of varying
      genetic backgrounds, immunized by different parenteral routes with bovine serum
      albumin (BSA) entrapped in archaeosomes ( approximately 200-nm vesicles),
      demonstrated markedly enhanced serum anti-BSA antibody titers. These titers were
      often comparable to those achieved with Freund's adjuvant and considerably more
      than those with alum or conventional liposomes (phosphatidylcholine
      phosphatidylglycerol-cholesterol, 1. 8:0.2:1.5 molar ratio). Furthermore, antigen
      specific immunoglobulin G1 (IgG1), IgG2a, and IgG2b isotype antibodies were all
      induced. Association of BSA with the lipid vesicles was required for induction of
      a strong response, and >80% of the protein was internalized within most
      archaeosome types, suggesting efficient release of antigen in vivo. Encapsulation
      of ovalbumin and hen egg lysozyme within archaeosomes showed similar immune
      responses. Antigen-archaeosome immunizations also induced a strong cell-mediated
      immune response: antigen-dependent proliferation and substantial production of
      cytokines gamma interferon (Th1) and interleukin-4 (IL-4) (Th2) by spleen cells
      in vitro. In contrast, conventional liposomes induced little cell-mediated
      immunity, whereas alum stimulated only an IL-4 response. In contrast to alum and
      Freund's adjuvant, archaeosomes composed of Thermoplasma acidophilum lipids
      evoked a dramatic memory antibody response to the encapsulated protein (at
      approximately 300 days) after only two initial immunizations (days 0 and 14).
      This correlated with increased antigen-specific cell cycling of CD4(+) T cells:
      increase in synthetic (S) and mitotic (G(2)/M) and decrease in resting (G(1))
      phases. Thus, archaeosomes may be potent vaccine carriers capable of facilitating
      strong primary and memory humoral, and cell-mediated immune responses to the
      entrapped antigen.

PMID- 10603369
TI  - Typing of intimin genes in human and animal enterohemorrhagic and
      enteropathogenic Escherichia coli: characterization of a new intimin variant.
AB  - Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC)
      produce the characteristic "attaching and effacing" (A/E) lesion of the brush
      border. Intimin, an outer membrane protein encoded by eae, is responsible for the
      tight association of both pathogens with the host cell. Several eae have been
      cloned from different EPEC and EHEC strains isolated from humans and animals.
      These sequences are conserved in the N-terminal region but highly variable in the
      last C-terminal 280 amino acids (aa), where the cell binding activity is
      localized. Based on these considerations, we developed a panel of specific
      primers to investigate the eae heterogeneity of the variable 3' region by using
      PCR amplification. We then investigated the distribution of the known intimin
      types in a large collection of EPEC and EHEC strains isolated from humans and
      different animal species. The existence of a yet-unknown family of intimin was
      suspected because several EHEC strains, isolated from human and cattle, did not
      react with any of the specific primer pairs, although these strains were eae
      positive when primers amplifying the conserved 5' end were used. We then cloned
      and sequenced the eae present in one of these strains (EHEC of serotype O103:H2)
      and subsequently designed a PCR primer that recognizes in a specific manner the
      variable 3' region of this new intimin type. This intimin, referred to as
      "epsilon," was present in human and bovine EHEC strains of serogroups O8, O11,
      O45, O103, O121, and O165. Intimin epsilon is the largest intimin cloned to date
      (948 aa) and shares the greatest overall sequence identity with intimin beta,
      although analysis of the last C-terminal 280 aa suggests a greater similarity
      with intimins alpha and gamma.

PMID- 10603370
TI  - Lymphocyte function-associated antigen 1 is a receptor for Pasteurella
      haemolytica leukotoxin in bovine leukocytes.
AB  - Pasteurella (Mannheimia) haemolytica leukotoxin (Lkt) causes cell type- and
      species-specific effects in ruminant leukocytes. Recent studies indicate that P.
      haemolytica Lkt binds to bovine CD18, the common subunit of all beta2 integrins.
      We designed experiments with the following objectives: to identify which member
      of the beta2 integrins is a receptor for Lkt; to determine whether Lkt binding to
      the receptor is target cell (bovine leukocytes) specific; to define the
      relationships between Lkt binding to the receptor, calcium elevation, and
      cytolysis; and to determine whether a correlation exists between Lkt receptor
      expression and the magnitude of target cell cytolysis. We compared Lkt-induced
      cytolysis in neutrophils from control calves and from calves with bovine
      leukocyte adhesion deficiency (BLAD), because neutrophils from BLAD-homozygous
      calves exhibit reduced beta2 integrin expression. The results demonstrate for the
      first time that Lkt binds to bovine CD11a and CD18 (lymphocyte function
      associated antigen 1 [LFA-1]). The binding was abolished by anti-CD11a or anti
      CD18 monoclonal antibody (MAb). Lkt-induced calcium elevation in bovine alveolar
      macrophages (BAMs) was inhibited by anti-CD11a or anti-CD18 MAb (65 to 94% and 37
      to 98%, respectively, at 5 and 50 Lkt units per ml; P < 0.05). Lkt-induced
      cytolysis in neutrophils and BAMs was also inhibited by anti-CD11a or anti-CD18
      MAb in a concentration-dependent manner. Lkt bound to porcine LFA-1 but did not
      induce calcium elevation or cytolysis. In neutrophils from BLAD calves, Lkt
      induced cytolysis was decreased by 44% compared to that of neutrophils from
      control calves (P < 0.05). These results indicate that LFA-1 is a Lkt receptor,
      Lkt binding to LFA-1 is not target cell specific, Lkt binding to bovine LFA-1
      correlates with calcium elevation and cytolysis, and bovine LFA-1 expression
      correlates with the magnitude of Lkt-induced target cell cytolysis.

PMID- 10603371
TI  - Episomal expression of specific sense and antisense mRNAs in Leishmania
      amazonensis: modulation of gp63 level in promastigotes and their infection of
      macrophages in vitro.
AB  - The major surface glycoprotein (gp63) of Leishmania amazonensis is a
      metalloprotease implicated in the infection of mammalian macrophages. The
      expression of gp63 and its participation in this infection were further examined
      by modulating the level of this molecule in a virulent gp63-abundant wild-type
      clone. Promastigotes were transfected with gp63 genes cloned into a Leishmania
      specific vector in two different orientations, leading to the expression of gp63
      sense and antisense RNAs. With increasing selective pressure, cell surface gp63
      was increasingly augmented in the transfectants with sense transcripts and
      suppressed to a very low level in those with antisense transcripts. Thus, the
      expression of gp63 from chromosomal, repetitive genes is not stringently
      regulated at the protein level and can be substantially reduced by episomal
      antisense transcription of a single copy. The transfectants differed
      significantly only in the level of gp63, thereby allowing specific evaluation of
      this molecule in leishmanial infection of macrophages in vitro. Kinetic studies
      of infection in vitro indicate that gp63 plays a role not only in the binding of
      this parasite to these macrophages but also in its intramacrophage survival and
      replication.

PMID- 10603372
TI  - Resistance of transgenic mice expressing human group II phospholipase A2 to
      Escherichia coli infection.
AB  - Group II phospholipase A2 (PLA2) is a newly recognized antibacterial acute-phase
      protein. Recently we observed that transgenic mice expressing group II PLA2
      (PLA2(+) mice) were able to resist experimental Staphylococcus aureus infection
      by killing the bacteria, as indicated by improved survival and by the small
      numbers of live bacteria in their tissues (V. J. O. Laine, D. S. Grass, and T. J.
      Nevalainen, J. Immunol. 162:7402-7408, 1999). To establish the role of group II
      PLA2 in Escherichia coli infection, the host responses of PLA2(+) mice and their
      PLA2-deficient C57BL/6J littermates (PLA2(-) mice) were studied after
      intraperitoneal administration of E. coli. The levels of group II PLA2 in sera of
      PLA2(+) mice increased after the administration of E. coli, and the concentration
      of group II PLA2 correlated significantly with the catalytic activity of PLA2 in
      serum. PLA2(+) mice showed lower rates of mortality and less bacterial growth in
      peritoneal lavage fluid, blood, and spleen and liver tissues than PLA2(-) mice.
      Unlike the observations with staphylococcal infection, serum and peritoneal
      lavage fluid did not inhibit the growth of E. coli in vitro. The results indicate
      that expression of the group II PLA2 transgene improves the host defense of mice
      against E. coli infection.

PMID- 10603373
TI  - Perturbations in eosinophil homeostasis following treatment of lymphatic
      filariasis.
AB  - Treatment of patients with patent Wuchereria bancrofti infection results in an
      acute clinical reaction and peripheral eosinophilia. To investigate the dynamics
      of the eosinophil response, changes in eosinophil activation and degranulation
      and plasma levels of eosinophil-active chemokines and cytokines were studied in
      15 microfilaremic individuals in south India by sequential blood sampling before
      and after administration of 300 mg of diethylcarbamazine (DEC). Clinical symptoms
      occurred within 24 h. Plasma interleukin-5 (IL-5) and RANTES levels peaked 1 to 2
      days posttreatment, preceding a peak peripheral eosinophil count at day 4. Major
      basic protein secretion from eosinophils paralleled IL-5 secretion, while levels
      of eosinophil-derived neurotoxin peaked at day 13 after treatment. Expression of
      the activation markers HLA-DR and CD25 on eosinophils rose markedly immediately
      after treatment, while expression of VLA-4 and alpha4beta7 showed an early peak
      within 24 h and a second peak at day 13. Thus, the posttreatment reactions seen
      in filarial infections can be divided into an early phase with killing of
      microfilariae, clinical symptomatology, increases in plasma IL-5 and RANTES
      levels, and eosinophil activation and degranulation and a later phase with
      expression of surface integrins on eosinophils, recruitment of eosinophils from
      the bone marrow to tissues, and clearance of parasite antigen.

PMID- 10603374
TI  - Induction of follicular gastritis following postthymectomy autoimmune gastritis
      in Helicobacter pylori-infected BALB/c mice.
AB  - Helicobacter pylori is the major causative agent of chronic antral gastritis and
      is thought to be involved in the pathogenesis of mucosa-associated lymphoid
      tissue lymphoma (MALToma) developing in the human stomach. The aim of this study
      was to clarify whether corporal autoimmune gastritis (AIG), which is known to
      decrease acidity due to destruction of parietal cells, predisposes mice to H.
      pylori infection, thereby leading to MALToma-like pathology. BALB/c mice in which
      AIG had been induced by thymectomy 3 days after birth (AIG mice) were used. The
      AIG mice were orally administered mouse-adapted H. pylori at the age of 6 weeks
      and were examined histologically and serologically after 2 to 12 months. The
      results were compared with those obtained from uninfected AIG mice and infected
      normal mice. Germinal centers were induced in the corpus in 57% of the H. pylori
      infected AIG mice, which elicited anti-H. pylori antibody responses in
      association with upregulation of interleukin-4 (IL-4) mRNA. In these mice,
      parietal cells remained in the corpus mucosa. These findings were in contrast to
      those with the uninfected AIG mice: fundic gland atrophy due to disappearance of
      parietal cells associated with upregulation of gamma interferon, but not IL-4,
      mRNA and no germinal center formation in the corpus. These observations suggest
      that AIG alters the infectivity of H. pylori, leading to MALToma-like follicular
      gastritis, at an early stage after H. pylori infection.

PMID- 10603375
TI  - Strain-specific restriction of the antiphagocytic property of group A
      streptococcal M proteins.
AB  - Group A streptococcal M proteins are type-specific virulence factors that inhibit
      phagocytosis. We used two M proteins, M5 and Emm22, to analyze the influence of
      genetic background on the properties of M proteins. Mutant strains, engineered to
      lack these M proteins, were complemented with genes encoding the homologous or
      heterologous M protein, and the complemented strains were analyzed for
      phagocytosis resistance. Neither the M5 nor the Emm22 protein conferred
      phagocytosis resistance in the heterologous background, but they did do so in the
      homologous background. This was not due to lack of surface expression in the
      heterologous background. Moreover, the M5 and Emm22 proteins expressed in
      heterologous background appeared to have normal structure, since they were not
      affected in their ability to bind different human plasma proteins. In particular,
      M5 or Emm22 had normal ability to bind human complement inhibitors, a property
      that has been implicated in phagocytosis resistance. Results similar to those
      obtained with M5 and Emm22 were obtained in experiments with the M6 and Emm4
      proteins. Together, these data suggest that the surface expression of M protein
      alone may not be sufficient to confer phagocytosis resistance and consequently
      that strain-specific factors other than M and Emm proteins may contribute to the
      ability of group A streptococci to resist phagocytosis.

PMID- 10603376
TI  - Transcriptional regulation of beta-defensin gene expression in tracheal
      epithelial cells.
AB  - Innate immunity provides an ever-present or rapidly inducible initial defense
      against microbial infection. Among the effector molecules of this defense in many
      species are broad-spectrum antimicrobial peptides. Tracheal antimicrobial peptide
      (TAP) was the first discovered member of the beta-defensin family of mammalian
      antimicrobial peptides. TAP is expressed in the ciliated epithelium of the bovine
      trachea, and its mRNA levels are dramatically increased upon stimulation with
      bacteria or bacterial lipopolysaccharide (LPS). We report here that this
      induction by LPS is regulated at the level of transcription. Furthermore, the
      transfection of reporter gene constructs into tracheal epithelial cells indicates
      that DNA sequences in the 5' flanking region of the TAP gene, within 324
      nucleotides of the transcription start site, are responsible in part for
      mediating gene induction. This region includes consensus binding sites for NF
      kappaB and nuclear factor interleukin-6 (NF IL-6) transcription factors. Gel
      mobility shift assays indicate that LPS induces NF-kappaB binding activity in the
      nuclei of these cells, while NF IL-6 binding activity is constitutively present.
      The gene encoding human beta-defensin 2, a human homologue of TAP with similar
      inducible expression patterns in the airway, was cloned and found to have
      conserved NF-kappaB and NF IL-6 consensus binding sites in its 5' flanking
      region. Previous studies of antimicrobial peptides from insects indicated that
      their induction by infectious microbes and microbial products also occurs via
      activation of NF-kappaB-like and NF IL-6-like transcription factors. Together,
      these observations indicate that a strategy for the induction of peptide-based
      antimicrobial innate immunity is conserved among evolutionarily diverse
      organisms.

PMID- 10603377
TI  - Induction of tumor necrosis factor alpha and interleukin-8 gene expression in
      bronchial epithelial cells by toxic shock syndrome toxin 1.
AB  - Major histocompatibility complex (MHC) class II engagement by toxic shock
      syndrome toxin 1 (TSST-1) transduces signals leading to proinflammatory cytokine
      gene expression (tumor necrosis factor alpha [TNF-alpha]) in human monocytes. To
      study the proinflammatory role of MHC class II molecules expressed by bronchial
      epithelial cells (BEC), primary human BEC were isolated from surgical bronchial
      samples, expanded in vitro, and cultured in the presence or absence of gamma
      interferon (IFN-gamma) for 48 h. (125)I-TSST-1 binding to BEC pretreated with IFN
      gamma was inhibited up to 97% by anti-MHC class II monoclonal antibody 3B12,
      indicating that in BEC also MHC class II molecules were targets for the
      staphylococcal exotoxin. As analyzed by a quantitative reverse transcriptase PCR,
      a 1-h stimulation of BEC with TSST-1 resulted in a vigorous expression of TNF
      alpha and interleukin-8 (IL-8) genes. TNF-alpha and IL-8 expression was optimal
      in BEC pretreated with 50 IU of IFN-gamma/ml, whereas TSST-1 stimulation of BEC
      pretreated with 200 IU of IFN-gamma/ml failed to enhance either TNF-alpha or IL-8
      transcripts. In a time course study, peak expression of TNF-alpha and IL-8 mRNA
      was reached 6 h after TSST-1 stimulation. These results demonstrate that
      bacterial superantigen TSST-1 binds to MHC molecules on BEC and induces TNF-alpha
      and IL-8 gene expression upon engagement of MHC class II molecules on BEC, thus
      contributing to the perpetuation of bronchial mucosa inflammation via chemokine
      or cytokine gene expression.

PMID- 10603378
TI  - Host and bacterial factors involved in the innate ability of mouse macrophages to
      eliminate internalized unopsonized Escherichia coli.
AB  - In an effort to better understand genetic and cellular factors that influence
      innate immunity, we examined host and bacterial factors involved in the
      nonopsonic phagocytosis and killing of Escherichia coli K-12 by mouse
      macrophages. Unelicited (resident) peritoneal macrophages from five different
      mouse strains, BALB/c, C57BL/6, CD-1, C3H/HeJ, and C3H/HeN, were employed.
      Additional macrophage populations were obtained from CD-1 mice (bone marrow
      derived macrophages). Also, for BALB/c and C57BL/6 mice, peritoneal macrophages
      elicited with either thioglycolate or proteose peptone, bone marrow-derived
      macrophages, and macrophage-like cell lines derived from the two strains were
      employed. Two E. coli K-12 strains that differed specifically in their abilities
      to produce type 1 pili containing the adhesive protein FimH were examined. The
      parameters used to assess macrophage bacteriocidal activity were (i) the killing
      of internalized (gentamicin-protected) E. coli during the approximately 4-h assay
      and (ii) the initial rate at which internalized E. coli were eliminated. Data on
      these parameters allowed the following conclusions: (i) unelicited or proteose
      peptone-elicited peritoneal macrophages were significantly better at eliminating
      internalized bacteria than thioglycolate-elicited peritoneal macrophages, bone
      marrow-derived macrophages, or macrophage cell lines; (ii) the host genetic
      background had no significant effect upon the ability of unelicited peritoneal
      macrophages to kill E. coli (even though the mouse strains differ widely in their
      in vivo susceptibilities to bacterial infection); and (iii) the FimH phenotype
      had no significant effect upon E. coli survival once the bacterium was inside a
      macrophage. Additionally, there was no correlation between the bacteriocidal
      effectiveness of a macrophage population and the number of bacteria bound per
      macrophage. However, macrophage populations that were the least bacteriocidal
      tended to bind higher ratios of FimH(+) to FimH(-) E. coli. The effect of gamma
      interferon, fetal calf serum, and the recombination proficiency of E. coli were
      examined as factors predicted to influence intracellular bacterial killing. These
      had no effect upon the rate of E. coli elimination by unelicited peritoneal
      macrophages.

PMID- 10603379
TI  - Additive attenuation of virulence of Streptococcus pneumoniae by mutation of the
      genes encoding pneumolysin and other putative pneumococcal virulence proteins.
AB  - Although the polysaccharide capsule of Streptococcus pneumoniae has been
      recognized as a sine qua non of virulence, much recent attention has focused on
      the role of pneumococcal proteins in pathogenesis, particularly in view of their
      potential as vaccine antigens. The individual contributions of pneumolysin (Ply),
      the major neuraminidase (NanA), autolysin (LytA), hyaluronidase (Hyl),
      pneumococcal surface protein A (PspA), and choline-binding protein A (CbpA) have
      been examined by specifically mutagenizing the respective genes in the
      pneumococcal chromosome and comparing the impact on virulence in a mouse
      intraperitoneal challenge model. Mutagenesis of either the ply, lytA, or pspA
      gene in S. pneumoniae D39 significantly reduced virulence, relative to that of
      the wild-type strain, indicating that the respective gene products contribute to
      pathogenesis. On the other hand, mutations in nanA, hyl, or cbpA had no
      significant impact. The virulence of D39 derivatives carrying a ply deletion
      mutation as well as an insertion-duplication mutation in one of the other genes
      was also examined. Mutagenesis of either nanA or lytA did not result in an
      additional attenuation of virulence in the ply deletion background. However,
      significant additive attenuation in virulence was observed for the strains with
      ply-hyl, ply-pspA, and ply-cbpA double mutations.

PMID- 10603380
TI  - Analysis of immune responses against T- and B-cell epitopes from Plasmodium
      falciparum liver-stage antigen 1 in rodent malaria models and malaria-exposed
      human subjects in India.
AB  - Liver-stage antigen 1 (LSA-1) is a potential vaccine candidate against
      preerythrocytic stages of malaria. We report here the immunogenicity of linear
      synthetic constructs delineated as T(H)-cell determinants from the nonrepeat
      regions of Plasmodium falciparum LSA-1 in murine models and human subjects from
      areas where malaria is endemic in Rajasthan State, India. Seven peptide
      constructs (LS1.1 to LS1.7) corresponding to predicted T-cell sites from both the
      N- and C-terminal regions and peptide LS1R from a repeat region of PfLSA-1 were
      synthesized to analyze the cellular immune responses. These linear peptides were
      also tested for humoral responses in order to determine if there were any
      overlapping B-cell epitopes in the predicted T-cell sites. Most peptides induced
      cellular responses in peptide-immunized BALB/c and C57BL/6 mice as measured by
      proliferation and cytokine analysis. Cross-reactive T-cell recognition of P.
      falciparum-based peptides in Plasmodium berghei-immune animals was evaluated, but
      only one peptide, LS1.2 (amino acids 1742 to 1760) triggered T-cell proliferation
      and interleukin-2 and gamma interferon secretion in P. berghei-immune splenocytes
      of BALB/c and C57BL/6 mice as well as in Thamnomys gazellae (natural host of P.
      berghei ANKA). In an enzyme-linked immunosorbent assay with the peptides, only
      one peptide, LS1.1, was recognized by anti-P. berghei liver-stage serum. Three
      peptides (LS1. 1, LS1.2, and LS1.3) of the eight peptides tested in this study
      were recognized by a relatively large percentage of P. falciparum-exposed human
      subjects; the reactivities ranged from approximately 45% for LS1.3 to
      approximately 60% for LS1.1 and LS1.2. Interestingly, all of the eight putative T
      cell determinants were also recognized by the sera collected from malaria
      patients, although the response was variable in nature. These T(H)- and B-cell
      epitopes may be of potential value for preerythrocytic antigen-based malaria
      subunit vaccine formulations.

PMID- 10603381
TI  - Two distinct antigenic types of the polysaccharide chains of Helicobacter pylori
      lipopolysaccharides characterized by reactivity with sera from humans with
      natural infection.
AB  - We have purified lipopolysaccharides (LPS) from 10 Helicobacter pylori clinical
      isolates which were selected on the basis of chemotype and antigenic variation.
      Data from immunoblotting of the purified LPS with sera from humans with H. pylori
      infection and from absorption of the sera with LPS indicated the presence of two
      distinct epitopes, termed the highly antigenic and the weakly antigenic epitopes,
      on the polysaccharide chains. Among 68 H. pylori clinical isolates, all smooth
      strains possessed either epitope; the epitopes were each carried by about 50% of
      the smooth strains. Thus, H. pylori strains can be classified into three types on
      the basis of their antigenicity in humans: those with smooth LPS carrying the
      highly antigenic epitope, those with smooth LPS carrying the weakly antigenic
      epitope, and those with rough LPS. Sera from humans with H. pylori infection
      could be grouped into three categories: those containing immunoglobulin G (IgG)
      antibodies against the highly antigenic epitope, those containing IgG against the
      weakly antigenic epitope, and those containing both specific IgGs; these groups
      made up about 50%, less than 10%, and about 40%, respectively, of all infected
      sera tested. In other words, IgG against the highly antigenic epitope were
      detected in more than 90% of H. pylori-infected individuals with high titers. IgG
      against the weakly antigenic epitope were detected in about 50% of the sera
      tested; however, the antibody titers were low. The two human epitopes existed
      independently from the mimic structures of Lewis antigens, which are known to be
      an important epitope of H. pylori LPS. No significant relationship between the
      reactivities toward purified LPS of human sera and a panel of anti-Lewis antigen
      antibodies was found. Moreover, the reactivities of the anti-Lewis antigen
      antibodies, but not human sera, were sensitive to particular alpha-L-fucosidases.
      The human epitopes appeared to be located on O-polysaccharide chains containing
      endo-beta-galactosidase-sensitive galactose residues as the backbone. Data from
      chemical analyses indicated that all LPS commonly contained galactose,
      glucosamine, glucose, and fucose (except one rough strain) as probable
      polysaccharide components, together with typical components of inner core and
      lipid A. We were not able to distinguish between the differences of antigenicity
      in humans by on the basis of the chemical composition of the LPS.

PMID- 10603382
TI  - Coxiella burnetii survives in monocytes from patients with Q fever endocarditis:
      involvement of tumor necrosis factor.
AB  - Endocarditis is the most frequent form of chronic Q fever, an infectious disease
      caused by Coxiella burnetii. As this obligate intracellular bacterium inhabits
      monocytes and macrophages, we wondered if pathogenesis of Q fever endocarditis is
      related to defective intracellular killing of C. burnetii by monocytes. Monocytes
      from healthy controls eliminated virulent C. burnetii within 3 days. In contrast,
      monocytes from patients with ongoing Q fever endocarditis were unable to
      eliminate bacteria even after 6 days. In patients who were cured of endocarditis,
      the monocyte infection was close to that of control monocytes. This killing
      deficiency was not the consequence of generalized functional impairment, since
      patient monocytes eliminated avirulent C. burnetii as did control cells. The
      addition of supernatants of C. burnetii-stimulated monocytes from patients with
      ongoing endocarditis to control monocytes enabled them to support C. burnetii
      survival, suggesting that some soluble factor is responsible for bacterial
      survival. This factor was related to tumor necrosis factor (TNF): expression of
      TNF mRNA and TNF release were increased in response to C. burnetii in patients
      with ongoing endocarditis compared to cured patients and healthy controls. In
      addition, neutralizing anti-TNF antibodies decreased C. burnetii internalization,
      an early step of bacterial killing, in monocytes from patients with ongoing
      endocarditis but did not affect delayed steps of intracellular killing. We
      suggest that Q fever-associated activation of monocytes allows the survival of C.
      burnetii by modulating early phases of microbial killing.

PMID- 10603383
TI  - Inhibition of human NK cell function by valinomycin, a toxin from Streptomyces
      griseus in indoor air.
AB  - Streptomyces griseus strains isolated from indoor dust have been shown to
      synthesize valinomycin. In this report, we show that human peripheral blood
      lymphocytes treated with small doses (30 ng ml(-1)) of pure valinomycin or high
      pressure liquid chromatography-pure valinomycin from S. griseus quickly show
      mitochondrial swelling and reduced NK cell activity. Larger doses (>100 ng/ml(
      1)) induced NK cell apoptosis within 2 days. Within 2 h, the toxin at 100 ng ml(
      1) dramatically inhibited interleukin-15 (IL-15)- and IL-18-induced granulocyte
      macrophage colony-stimulating factor and gamma interferon (IFN-gamma) production
      by NK cells. However, IFN-gamma production induced by a combination of IL-15 and
      IL-18 was somewhat less sensitive to valinomycin, suggesting a protective effect
      of the cytokine combination against valinomycin. Thus, valinomycin in very small
      doses may profoundly alter the immune response by reducing NK cell cytotoxicity
      and cytokine production.

PMID- 10603384
TI  - T-cell-dependent control of acute Giardia lamblia infections in mice.
AB  - We have studied immune mechanisms responsible for control of acute Giardia
      lamblia and Giardia muris infections in adult mice. Association of chronic G.
      lamblia infection with hypogammaglobulinemia and experimental infections of mice
      with G. muris have led to the hypothesis that antibodies are required to control
      these infections. We directly tested this hypothesis by infecting B-cell
      deficient mice with either G. lamblia or G. muris. Both wild-type mice and B-cell
      deficient mice eliminated the vast majority of parasites between 1 and 2 weeks
      postinfection with G. lamblia. G. muris was also eliminated in both wild-type and
      B-cell-deficient mice. In contrast, T-cell-deficient and scid mice failed to
      control G. lamblia infections, as has been shown previously for G. muris.
      Treatment of wild-type or B-cell-deficient mice with antibodies to CD4 also
      prevented elimination of G. lamblia, confirming a role for T cells in controlling
      infections. By infecting mice deficient in either alphabeta- or gammadelta-T-cell
      receptor (TCR)-expressing T cells, we show that the alphabeta-TCR-expressing T
      cells are required to control parasites but that the gammadelta-TCR-expressing T
      cells are not. Finally, infections in mice deficient in production of gamma
      interferon or interleukin 4 (IL-4) and mice deficient in responding to IL-4 and
      IL-13 revealed that neither the Th1 nor the Th2 subset is absolutely required for
      protection from G. lamblia. We conclude that a T-cell-dependent mechanism is
      essential for controlling acute Giardia infections and that this mechanism is
      independent of antibody and B cells.

PMID- 10603385
TI  - Contribution of Escherichia coli alpha-hemolysin to bacterial virulence and to
      intraperitoneal alterations in peritonitis.
AB  - Alpha-hemolysin (Hly) is a common exotoxin produced by Escherichia coli that
      enhances virulence in a number of clinical infections. The addition of hemolysin
      production to laboratory bacterial strains is known to increase the lethality of
      E. coli peritonitis. However, the mechanisms involved have not been determined
      and the contribution of hemolysin to the alterations in the host intraperitoneal
      environment and the leukocyte response is not known. Utilizing a rat peritonitis
      model, we show that wild-type hemolytic E. coli strains have a significant
      competitive advantage over nonhemolytic strains within the peritoneum. To examine
      the specific contribution of Hly to E. coli-induced virulence and alterations
      within the peritoneum, a mixed peritonitis model of E. coli, Bacteroides
      fragilis, and sterile fecal adjuvant was used. Three transformed E. coli strains
      were utilized: one strongly secretes active hemolysin (WAF 270), a second
      secretes active hemolysin but a reduced amount (WAF 260), and the third does not
      produce hemolysin (WAF 108). After an equal inoculum of each of the three
      strains, WAF 270 produced a markedly increased lethality and an increased
      recovery of both E. coli and B. fragilis from the host relative to the other
      strains. Changes in the intraperitoneal pH, degree of erythrocyte lysis, and
      recruitment and viability of leukocytes within the peritoneum following the
      induction of peritonitis differed significantly between the strongly hemolytic
      and nonhemolytic strains. Induction of peritonitis with WAF 270 caused a
      pronounced decrease in intraperitoneal pH, lysis of most of the intraperitoneal
      erythrocytes, and a marked decrease in recoverable viable leukocytes compared to
      WAF 108. Thus, hemolysin production by E. coli within the peritoneum may alter
      not only the host's ability to control the hemolytic strain itself but also other
      organisms.

PMID- 10603386
TI  - Cytolethal distending toxin sequence and activity in the enterohepatic pathogen
      Helicobacter hepaticus.
AB  - Little is known about the molecular pathogenesis of hepatitis and enterocolitis
      caused by enterohepatic Helicobacter species. Sonicates of the murine pathogen
      Helicobacter hepaticus were found to cause progressive cell distension,
      accumulation of filamentous actin, and G(2)/M cell cycle arrest in HeLa cell
      monolayers. The genes encoding this cytotoxic activity were cloned from H.
      hepaticus. Three open reading frames with closest homology to cdtA, cdtB, and
      cdtC from Campylobacter jejuni were identified. Sonicates of a laboratory strain
      of Escherichia coli carrying the cloned cdtABC gene cluster from H. hepaticus
      reproduced the cytotoxic activities seen with sonicates of H. hepaticus.
      Cytolethal distending toxin activity is a potential virulence determinant of H.
      hepaticus that may play a role in the pathogenesis of Helicobacter-associated
      hepatitis and enterocolitis.

PMID- 10603387
TI  - Subclinical chlamydial infection of the female mouse genital tract generates a
      potent protective immune response: implications for development of live
      attenuated chlamydial vaccine strains.
AB  - Chlamydia trachomatis is a major cause of sexually transmitted disease (STD) for
      which a vaccine is needed. CD4(+) T-helper type 1 (Th1) cell-mediated immunity is
      an important component of protective immunity against murine chlamydial genital
      infection. Conventional vaccine approaches have not proven effective in eliciting
      chlamydial-specific CD4 Th1 immunity at the genital mucosa. Thus, it is possible
      that the development of a highly efficacious vaccine against genital infection
      will depend on the generation of a live attenuated C. trachomatis vaccine.
      Attenuated strains of C. trachomatis do not exist, so their potential utility as
      vaccines cannot be tested in animal models of infection. We have developed a
      surrogate model to study the effect of chlamydial attenuation on infection and
      immunity of the female genital tract by treating mice with a subchlamydiacidal
      concentration of oxytetracycline following vaginal infection. Compared to
      untreated control mice, antibiotic-treated mice shed significantly fewer
      infectious organisms (3 log(10)) from the cervico-vagina, produced a minimal
      inflammatory response in urogenital tissue, and did not experience infection
      related sequelae. Antibiotic-treated mice generated levels of chlamydia-specific
      antibody and cell-mediated immunity equivalent to those of control mice.
      Importantly, antibiotic-treated mice were found to be as immune as control
      untreated mice when rechallenged vaginally. These findings demonstrate that
      subclinical chlamydial infection of the murine female genital tract is sufficient
      to stimulate a potent protective immune response. They also present indirect
      evidence supporting the possible use of live attenuated chlamydial organisms in
      the development of vaccines against chlamydial STDs.

PMID- 10603388
TI  - Involvement of CD4(+) Th1 cells in systemic immunity protective against primary
      and secondary challenges with Trypanosoma cruzi.
AB  - In general, gamma interferon (IFN-gamma)-producing CD4(+) Th1 cells are important
      for the immunological control of intracellular pathogens. We previously
      demonstrated an association between parasite-specific induction of IFN-gamma
      responses and resistance to the intracellular protozoan Trypanosoma cruzi. To
      investigate a potential causal relationship between Th1 responses and T. cruzi
      resistance, we studied the ability of Th1 cells to protect susceptible BALB/c
      mice against virulent parasite challenges. We developed immunization protocols
      capable of inducing polarized Th1 and Th2 responses in vivo. Induction of
      parasite-specific Th1 responses, but not Th2 responses, protected BALB/c mice
      against virulent T. cruzi challenges. We generated T. cruzi-specific CD4(+) Th1
      and Th2 cell lines from BALB/c mice that were activated by infected macrophages
      to produce their corresponding cytokine response profiles. Th1 cells, but not Th2
      cells, induced nitric oxide production and inhibited intracellular parasite
      replication in T. cruzi-infected macrophages. Despite the ability to inhibit
      parasite replication in vitro, Th1 cells alone could not adoptively transfer
      protection against T. cruzi to SCID mice. In addition, despite the fact that the
      adoptive transfer of CD4(+) T lymphocytes was shown to be necessary for the
      development of immunity protective against primary T. cruzi infection in our SCID
      mouse model, protective secondary effector functions could be transferred to SCID
      mice from memory-immune BALB/c mice in the absence of CD4(+) T lymphocytes. These
      results indicate that, although CD4(+) Th1 cells can directly inhibit
      intracellular parasite replication, a more important role for these cells in T.
      cruzi systemic immunity may be to provide helper activity for the development of
      other effector functions protective in vivo.

PMID- 10603389
TI  - In vivo characterization of the murine intranasal model for assessing the
      immunogenicity of attenuated Salmonella enterica serovar Typhi strains as live
      mucosal vaccines and as live vectors.
AB  - Attenuated Salmonella enterica serovar Typhi live vector vaccine strains are
      highly immunogenic in mice following intranasal but not orogastric inoculation.
      To elucidate the relationship between organs within which vaccine organisms are
      found and the induction of specific serum immunoglobulin G (IgG) antibodies, we
      examined the in vivo distribution of serovar Typhi vaccine strain CVD 908-htrA
      following intranasal administration. Vaccine organisms were cultured from the
      nasal lymphoid tissue (NALT), lungs, and Peyer's patches 2 min after intranasal
      inoculation. Vaccine organisms persisted longer in NALT than in other organs. By
      decreasing the volume of intranasal inoculum containing 10(9) CFU (from a single
      30- or 10-microl dose to four 2.5-microl doses given over the course of 1 h), we
      were able to significantly reduce the number of vaccine organisms isolated from
      the lungs (P < 0.05) without reducing the number of vaccine organisms in NALT.
      Reducing the number of vaccine organisms in the lungs resulted in a significant
      decrease in the serum tetanus antitoxin response elicited by CVD 908-htrA
      expressing tetanus toxin fragment C under the control of the redox-responsive
      nir15 promoter. In contrast, a similar construct expressing tetanus toxin
      fragment C under control of the constitutive lpp promoter stimulated a strong
      serum IgG tetanus antitoxin response with both inoculation regimens. The data
      suggest that following intranasal inoculation, NALT is a sufficient inductive
      site for elicitation of an immune response against both the live vector and
      heterologous antigen and, as occurs following oral inoculation of humans,
      attenuated serovar Typhi vaccine organisms elicit serum IgG responses.

PMID- 10603390
TI  - Comparative evaluation of low-molecular-mass proteins from Mycobacterium
      tuberculosis identifies members of the ESAT-6 family as immunodominant T-cell
      antigens.
AB  - Culture filtrate from Mycobacterium tuberculosis contains protective antigens of
      relevance for the generation of a new antituberculosis vaccine. We have
      identified two previously uncharacterized M. tuberculosis proteins (TB7.3 and
      TB10.4) from the highly active low-mass fraction of culture filtrate. The
      molecules were characterized, mapped in a two-dimensional electrophoresis
      reference map of short-term culture filtrate, and compared with another recently
      identified low-mass protein, CFP10 (F. X. Berthet, P. B. Rasmussen, I.
      Rosenkrands, P. Andersen, and B. Gicquel. Microbiology 144:3195-3203, 1998), and
      the well-described ESAT-6 antigen. Genetic analyses demonstrated that TB10.4 as
      well as CFP10 belongs to the ESAT-6 family of low-mass proteins, whereas TB7.3 is
      a low-molecular-mass protein outside this family. The proteins were expressed in
      Escherichia coli, and their immunogenicity was tested in cultures of peripheral
      blood mononuclear cells from human tuberculosis (TB) patients, Mycobacterium
      bovis BCG-vaccinated donors, and nonvaccinated donors. The two ESAT-6 family
      members, TB10.4 and CFP10, were very strongly recognized and induced gamma
      interferon release at the same level (CFP10) as or at an even higher level
      (TB10.4) than ESAT-6. The non-ESAT-6 family member, TB7.3, for comparison, was
      recognized at a much lower level. CFP10 was found to distinguish TB patients from
      BCG-vaccinated donors and is, together with ESAT-6, an interesting candidate for
      the diagnosis of TB. The striking immunodominance of antigens within the ESAT-6
      family is discussed, and hypotheses are presented to explain this targeting of
      the immune response during TB infection.

PMID- 10603391
TI  - Development of a DeltaglnA balanced lethal plasmid system for expression of
      heterologous antigens by attenuated vaccine vector strains of Vibrio cholerae.
AB  - We have previously shown that more prominent immune responses are induced to
      antigens expressed from multicopy plasmids in live attenuated vaccine vector
      strains of Vibrio cholerae than to antigens expressed from single-copy genes on
      the V. cholerae chromosome. Here, we report the construction of a DeltaglnA
      derivative of V. cholerae vaccine strain Peru2. This mutant strain,
      Peru2DeltaglnA, is unable to grow on medium that does not contain glutamine; this
      growth deficiency is complemented by pKEK71-NotI, a plasmid containing a complete
      copy of the Salmonella typhimurium glnA gene, or by pTIC5, a derivative of pKEK71
      NotI containing a 1. 8-kbp fragment that directs expression of CtxB with a 12
      amino-acid epitope of the serine-rich Entamoeba histolytica protein fused to the
      amino terminus. Strain Peru2DeltaglnA(pTIC5) produced 10-fold more SREHP-12-CtxB
      in supernatants than did ETR3, a Peru2-derivative strain containing the same
      fragment inserted on the chromosome. To assess immune responses to antigens
      expressed by this balanced lethal system in vivo, we inoculated germfree mice on
      days 0, 14, 28, and 42 with Peru2DeltaglnA, Peru2DeltaglnA(pKEK71-NotI),
      Peru2(pTIC5), Peru2DeltaglnA(pTIC5), or ETR3. All V. cholerae strains were
      recoverable from stool for 8 to 12 days after primary inoculation, including
      Peru2DeltaglnA; strains containing plasmids continued to harbor pKEK71-NotI or
      pTIC5 for 8 to 10 days after primary inoculation. Animals were sacrificed on day
      56, and serum, stool and biliary samples were analyzed for immune responses.
      Vibriocidal antibody responses, reflective of in vivo colonization, were
      equivalent in all groups of animals. However, specific anti-CtxB immune responses
      in serum (P </= 0.05) and bile (P </= 0. 001) were significantly higher in
      animals that received Peru2DeltaglnA(pTIC5) than in those that received ETR3,
      confirming the advantage of higher-level antigen expression in vivo. The
      development of this balanced lethal system thus permits construction and
      maintenance of vaccine and vector strains of V. cholerae that express high levels
      of immunogenic antigens from plasmid vectors without the need for antibiotic
      selection pressure.

PMID- 10603392
TI  - Cytotoxic T-lymphocyte epitopes for HLA-B53 and other HLA types in the malaria
      vaccine candidate liver-stage antigen 3.
AB  - The development of an effective preerythrocytic vaccine against Plasmodium
      falciparum malaria is likely to require inclusion of components from several
      preerythrocytic antigens. The association of HLA-B53 with resistance to severe
      malaria in West Africa provided evidence that HLA class I-restricted CD8(+) T
      cell responses play a role in protective immunity in African children, supporting
      data from rodent models of malaria. Previously, a single epitope from liver-stage
      specific antigen 1 (LSA-1) has been shown to be recognized by HLA-B53-specific
      cytotoxic T lymphocytes (CTL), but HLA-B53 epitopes were not found in four other
      antigens. In this study we measured CTL responses to peptides from the recently
      sequenced antigen liver-stage antigen 3 (LSA-3) and identified in it a new
      epitope restricted by HLA-B53. Several CTL epitopes restricted by other class I
      types were also identified within LSA-3 in studies in The Gambia and Tanzania.
      CTL were also identified to an additional P. falciparum antigen, exported protein
      1 (Exp-1), the homologue of which is a protective antigen in a rodent model of
      malaria. These findings emphasize the diversity of P. falciparum antigens
      recognized by CD8(+) T cells in humans and support the inclusion of components
      from several antigens in new CTL-inducing vaccines against malaria.

PMID- 10603393
TI  - Enhanced production of recombinant Mycobacterium tuberculosis antigens in
      Escherichia coli by replacement of low-usage codons.
AB  - A major obstacle to development of subunit vaccines and diagnostic reagents for
      tuberculosis is the inability to produce large quantities of these proteins. To
      test the hypothesis that poor expression of some mycobacterial genes in
      Escherichia coli is due, in part, to the presence of low-usage E. coli codons, we
      used site-directed mutagenesis to convert low-usage codons to high-usage codons
      for the same amino acid in the Mycobacterium tuberculosis genes for antigens 85A
      and 85B and superoxide dismutase. Replacement of five codons in the wild-type
      gene for antigen 85B increased recombinant protein production in E. coli 54-fold.
      The recombinant antigen elicited proliferation and gamma interferon production by
      lymphocytes from healthy tuberculin reactors and was recognized by monoclonal
      antibodies to native antigen 85, indicating that the recombinant antigen
      contained T-cell and B-cell epitopes. Northern blotting demonstrated only a 1.7-
      to 2.5-fold increase in antigen 85B mRNA, suggesting that the enhanced protein
      production was due primarily to enhanced efficiency of translation. Codon
      replacement in the genes encoding antigen 85A and superoxide dismutase yielded
      four- to sixfold increases in recombinant protein production, suggesting that
      this strategy may be generally applicable to overexpression of mycobacterial
      genes in E. coli.

PMID- 10603394
TI  - Murine immune response to Neisseria meningitidis group C capsular polysaccharide:
      analysis of monoclonal antibodies generated in response to a thymus-independent
      antigen and a thymus-dependent toxoid conjugate vaccine.
AB  - Antibody (Ab) responses to polysaccharides (PSs) such as Neisseria meningitidis
      group C PS (MCPS) are characterized as being thymus independent (TI) and are
      restricted with regard to clonotype and isotype expression. PS conjugated to
      proteins, e.g., MCPS coupled to tetanus toxoid (MCPS-TT), elicits a thymus
      dependent (TD) response. In order to understand the influence of the form of a
      vaccine (TI versus TD) on the Ab repertoire, we generated monoclonal antibody
      (MAb) panels from mice immunized and boosted with MCPS or MCPS-TT in different
      ways. The panels of MAbs were examined for isotype, fine specificity, affinity,
      and V(H) gene family usage. The use of MCPS-TT resulted in a shift in the isotype
      from immunoglobulin M (IgM) and IgG3 elicited in response to the MCPS to
      primarily IgG1. This isotype shift was accompanied by a change in the fine
      specificity of the response to the conjugate compared to that of PS. New fine
      specificities and increased affinity were observed in response to the TD antigen
      (Ag). Dot blot and Northern analyses of MCPS MAbs revealed that V(H) gene family
      usage is dominated by V(H)J558, used by 23 of 39 MAbs. V(H)3609 was seen in three
      MAbs of restricted fine specificity. V(H)Q52, V(H)7183, and V(H)VGAM3-8 were seen
      in more than one MAb across these panels, while V(H)10 and V(H)X24 were detected
      only once in response to the TI-2 Ag. All MAbs in the panels utilized kappa light
      chains, and all functional J(kappa) genes were expressed.

PMID- 10603395
TI  - Delivery of CD8(+) T-cell epitopes into major histocompatibility complex class I
      antigen presentation pathway by Bordetella pertussis adenylate cyclase:
      delineation of cell invasive structures and permissive insertion sites.
AB  - Bordetella pertussis adenylate cyclase (AC) toxin-hemolysin (ACT-Hly) can
      penetrate a variety of eukaryotic cells. Recombinant AC toxoids have therefore
      been recently used for delivery of CD8(+) T-cell epitopes into antigen-presenting
      cells in vivo and for induction of protective antiviral, as well as therapeutic
      antitumor cytotoxic T-cell responses. We have explored the carrier potential of
      the ACT molecule by insertional mutagenesis scanning for new permissive sites, at
      which integration of two- to nine-residue-long peptides does not interfere with
      membrane interaction and translocation of ACT. A model CD8(+) T-cell epitope of
      ovalbumin was incorporated at 10 of these permissive sites along the toxin
      molecule, and the capacity of ACT constructs to penetrate into cell cytosol and
      deliver the epitope into the major histocompatibility complex (MHC) class I
      antigen processing and presentation pathway was examined. While all six
      constructs bearing the epitope within the Hly portion of ACT failed to deliver
      the epitope to the MHC class I molecules, all four toxoids with inserts within
      different permissive sites in the AC domain efficiently delivered the epitope
      into this cytosolic pathway, giving rise to stimulation of a specific CD8(+) T
      cell hybridoma. The results suggest that, in contrast to the AC domain, the
      hemolysin moiety of ACT does not reach the cytosolic entry of the MHC class I
      pathway.

PMID- 10603396
TI  - Effects of opsonization and gamma interferon on growth of Brucella melitensis 16M
      in mouse peritoneal macrophages in vitro.
AB  - Entry of opsonized pathogens into phagocytes may benefit or, paradoxically, harm
      the host. Opsonization may trigger antimicrobial mechanisms such as reactive
      oxygen or nitric oxide (NO) production but may also provide a safe haven for
      intracellular replication. Brucellae are natural intramacrophage pathogens of
      rodents, ruminants, dogs, marine mammals, and humans. We evaluated the role of
      opsonins in Brucella-macrophage interactions by challenging cultured murine
      peritoneal macrophages with Brucella melitensis 16M treated with complement-
      and/or antibody-rich serum. Mouse serum rich in antibody against Brucella
      lipopolysaccharide (LPS) (aLPS) and human complement-rich serum (HCS) each
      enhanced the macrophage uptake of brucellae. Combinations of suboptimal levels of
      aLPS (0. 01%) and HCS (2%) synergistically enhanced uptake. The intracellular
      fate of ingested bacteria was evaluated with an optimal concentration of
      gentamicin (2 microg/ml) to control extracellular growth but not kill
      intracellular bacteria. Bacteria opsonized with aLPS and/or HCS grew equally well
      inside macrophages in the absence of gamma interferon (IFN-gamma). Macrophage
      activation with IFN-gamma inhibited replication of both opsonized and
      nonopsonized brucellae but was less effective in inhibiting replication of
      nonopsonized bacteria. IFN-gamma treatment of macrophages with opsonized or
      nonopsonized bacteria enhanced NO production, which was blocked by N(G)
      monomethyl L-arginine (MMLA), an NO synthesis inhibitor. MMLA also partially
      blocked IFN-gamma-mediated bacterial growth inhibition. These studies suggest
      that primary murine macrophages have limited ability to control infection with B.
      melitensis, even when activated by IFN-gamma in the presence of highly opsonic
      concentrations of antibody and complement. Additional cellular immune responses,
      e.g., those mediated by cytotoxic T cells, may play more important roles in the
      control of murine brucellosis.

PMID- 10603397
TI  - Differential binding of clonal variants of Plasmodium falciparum to allelic forms
      of intracellular adhesion molecule 1 determined by flow adhesion assay.
AB  - Adhesion of Plasmodium falciparum-infected erythrocytes to the endothelial ligand
      intercellular adhesion molecule 1 (ICAM-1) has been implicated in the
      pathogenesis of cerebral malaria. Recently, a high-frequency coding polymorphism
      in the N-terminal domain of ICAM-1 (ICAM-1(Kilifi)) that is associated with
      susceptibility to cerebral disease in Kenya has been described. Preliminary
      static adhesion assays suggested that two different selected P. falciparum lines,
      ITO4-A4 (A4) and ItG-ICAM (ItG), have different properties of binding to the
      natural variant proteins ICAM-1 and ICAM-1(Kilifi). Using a flow adhesion assay
      system, we have confirmed differences between the two lines in binding of
      parasitized erythrocytes to the variant ICAM-1 proteins. Total adhesion of ItG
      infected erythrocytes to ICAM-1 and ICAM-1(Kilifi) is greater than that of A4
      infected erythrocytes, and erythrocytes infected by both parasite strains show
      reduced binding to ICAM-1(Kilifi). However, under these physiologically relevant
      flow conditions, we have shown differences between A4 and ItG strains in dynamic
      rolling behavior on ICAM-1(Kilifi). The percentage of erythrocytes infected with
      A4 that roll on both ICAM-1 and ICAM-1(Kilifi) is greater than that of those
      infected with ItG. Also, the rolling velocity of A4-infected erythrocytes on ICAM
      1(Kilifi) is markedly increased compared to that on ICAM-1, in contrast to the
      rolling velocity of ItG-infected erythrocytes, which is similar on both proteins.
      These findings suggest that different parasite lines can vary in their avidity
      for the same host ligand, which may have important consequences for the
      pathophysiology of P. falciparum malaria.

PMID- 10603398
TI  - Interleukin-12 as an adjuvant promotes immunoglobulin G and type 1 cytokine
      recall responses to major surface protein 2 of the ehrlichial pathogen Anaplasma
      marginale.
AB  - Anaplasma marginale is a tick-transmitted pathogen of cattle closely related to
      the human ehrlichiae, Ehrlichia chaffeensis and the agent of human granulocytic
      ehrlichiosis (HGE). These pathogens have in common a structurally conserved outer
      membrane protein (OMP) designated the major surface protein 2 (MSP-2) in A.
      marginale and HGE and OMP-1 in E. chaffeensis. Protective immunity against
      ehrlichial pathogens is believed to require induction of gamma interferon (IFN
      gamma) and opsonizing immunoglobulin (Ig) subclasses directed against OMP
      epitopes that, in concert, activate macrophages for phagocytosis and killing.
      Because interleukin-12 (IL-12) acts as an adjuvant for protein immunization to
      induce IFN-gamma and protective immunity against intracellular pathogens, we
      hypothesized that as an adjuvant with MSP-2, IL-12 would augment type 1 recall
      responses to A. marginale. IL-12 was coadsorbed with MSP-2 to alum and shown to
      significantly enhance IFN-gamma production by lymph node cells (LNC) and LNC
      derived CD4(+) T-cell lines from immunized calves following recall stimulation
      with A. marginale. LNC proliferation and IL-2 production were also enhanced in IL
      12-treated calves. Elevated recall proliferative responses by peripheral blood
      mononuclear cells were still evident 9 months after immunization. Serum IgG
      levels were consistently increased in IL-12 immunized calves, predominantly due
      to higher IgG1 responses. The results support the use of IL-12 coadsorbed with
      OMP of ehrlichial pathogens in alum to amplify both antibody and type-1 cytokine
      responses important for protective immunity.

PMID- 10603399
TI  - Comparative analysis of the mucosal adjuvanticity of the type II heat-labile
      enterotoxins LT-IIa and LT-IIb.
AB  - Cholera toxin (CT) and the heat-labile enterotoxin of Escherichia coli (LT-I) are
      members of the serogroup I heat-labile enterotoxins (HLT) and can serve as
      systemic and mucosal adjuvants. However, information is lacking with respect to
      the structurally related but antigenically distinct serogroup II HLT, LT-IIa and
      LT-IIb, which have different binding specificities for ganglioside receptors. The
      purpose of this study was to assess the effectiveness of LT-IIa and LT-IIb as
      mucosal adjuvants in comparison to the prototypical type I HLT, CT. BALB/c mice
      were immunized by the intranasal (i.n.) route with the surface protein adhesin
      AgI/II of Streptococcus mutans alone or supplemented with an adjuvant amount of
      CT, LT-IIa, or LT-IIb. Antigen-specific antibody responses in saliva, vaginal
      wash, and plasma were assayed by enzyme-linked immunosorbent assay. Mice given
      AgI/II with LT-IIa or LT-IIb by the i.n. route had significantly higher mucosal
      and systemic antibody responses than mice immunized with AgI/II alone. Anti
      AgI/II immunoglobulin A (IgA) antibody activity in saliva and vaginal secretions
      of mice given AgI/II with LT-IIa or LT-IIb was statistically similar in magnitude
      to that seen in mice given AgI/II and CT. LT-IIb significantly enhanced the
      number of AgI/II-specific antibody-secreting cells in the draining superficial
      cervical lymph nodes compared to LT-IIa and CT. LT-IIb and CT induced
      significantly higher plasma anti-AgI/II IgG titers compared to LT-IIa. When LT
      IIb was used as adjuvant, the proportion of plasma IgG2a relative to IgG1 anti
      AgI/II antibody was elevated in contrast to the predominance of IgG1 antibodies
      promoted by AgI/II alone or when CT or LT-IIa was used. In vitro stimulation of
      AgI/II-specific cells from the superficial lymph nodes and spleen revealed that
      LT-IIa and LT-IIb induced secretion of interleukin-4 and significantly higher
      levels of gamma interferon compared to CT. These results demonstrate that the
      type II HLT LT-IIa and LT-IIb exhibit potent and distinct adjuvant properties for
      stimulating immune responses to a noncoupled protein immunogen after mucosal
      immunization.

PMID- 10603400
TI  - Roles of endogenous gamma interferon and macrophage microbicidal mechanisms in
      host response to chemotherapy in experimental visceral leishmaniasis.
AB  - In experimental visceral leishmaniasis, in which the tissue macrophage is the
      target, in vivo responsiveness to conventional chemotherapy (pentavalent antimony
      [Sb]) requires a T-cell-dependent mechanism. To determine if this mechanism
      involves gamma interferon (IFN-gamma)-induced activation and/or specific IFN
      gamma-regulated macrophage leishmanicidal mechanisms (generation of reactive
      nitrogen or oxygen intermediates, we treated gene-deficient mice infected with
      Leishmania donovani. In IFN-gamma gene knockout (GKO) mice, Sb inhibited but did
      not kill intracellular L. donovani (2% killing versus 76% in controls). Sb was
      active (>94% killing), however, in both inducible nitric oxide synthase (iNOS)
      knockout (KO) and respiratory burst (phagocyte oxidase)-deficient chronic
      granulomatous disease (X-CGD) mice. Sb's efficacy was also maintained in doubly
      deficient animals (X-CGD mice treated with an iNOS inhibitor). In contrast to Sb,
      amphotericin B (AmB) induced high-level killing in GKO mice; AmB was also fully
      active in iNOS KO and X-CGD animals. Although resolution of L. donovani infection
      requires iNOS, residual visceral infection remained largely suppressed in iNOS KO
      mice treated with Sb or AmB. These results indicate that endogenous IFN-gamma
      regulates the leishmanicidal response to Sb and achieves this effect via a
      pathway unrelated to the macrophage's primary microbicidal mechanisms. The role
      of IFN-gamma is selective, since it is not a cofactor in the response to AmB.
      Treatment with either Sb or AmB permits an iNOS-independent mechanism to emerge
      and control residual intracellular L. donovani infection.

PMID- 10603401
TI  - M-like proteins of Streptococcus dysgalactiae.
AB  - Streptococcus dysgalactiae is one of the most important bacterial species
      isolated from bovine mastitis. To identify potential virulence factors of this
      species we prepared chromosomal DNA from strain 8215 and constructed a phage
      display library. By affinity selection of the library against fibrinogen (Fg), we
      isolated and characterized a gene, called demA, encoding a protein with the
      molecular mass of approximately 58 kDa, called DemA, displaying both plasma
      protein binding properties and sequence similarities with the M and M-like
      proteins of other streptococcal species. Purified recombinant DemA protein was
      found to completely inhibit Fg-binding to cells of S. dysgalactiae. A continued
      sequence analysis revealed that the demA gene was preceded by an open reading
      frame (dmgA) coding for a putative protein, called DmgA, with high similarities
      to the Mga proteins of Streptococcus pyogenes. By additional cloning, the
      corresponding dmgA and demA genes from another strain, called Epi9, were isolated
      and analyzed. These genes, called dmgB and demB, respectively, revealed a high
      degree of similarity to the corresponding genes in strain 8215. Increased binding
      of Fg by cells of strain Epi9, grown in an atmosphere with 10% CO(2), was
      correlated to an enhanced transcription of the demB gene as shown in a Northern
      blot. Strain 8215 did not respond to CO(2), which could be explained by a
      nonfunctional dmgA gene due to insertion of an insertion sequence element. Based
      on sequence similarities of the described proteins to Mga, M, and M-like proteins
      and the response to elevated level of CO(2), we suggest that the dmg and dem
      genes are members of a regulon similar to the described mga regulon in S.
      pyogenes, which encodes several virulence factors in this species.

PMID- 10603402
TI  - Seroreactivity to Chlamydia trachomatis Hsp10 correlates with severity of human
      genital tract disease.
AB  - We have identified the chlamydial heat shock protein Hsp10 as a potential
      correlate to the immunopathogenic process in women with tubal factor infertility
      (TFI). The human serologic response to chlamydial Hsp10, Hsp60, and major outer
      membrane protein (MOMP) was measured by enzyme-linked immunosorbent assay. Three
      populations of women were studied: uninfected controls (CU), acutely infected
      (AI) women, and women with TFI. Sera from women in the AI and TFI groups both
      recognized Hsp10 more frequently and at a higher overall level than sera from
      healthy uninfected controls. Moreover, the infertile women had significantly
      greater Hsp10 seroreactivity than acutely infected women, indicating a
      concomitant increase of Hsp10 recognition in populations with increasing levels
      of disease severity. Hsp60 reactivity showed a similar correlation in these
      populations, while MOMP reactivity peaked at the same level in both AI and TFI
      populations but did not increase with disease severity. Test populations were
      standardized by level of reactivity to formalin-fixed Chlamydia trachomatis
      elementary bodies (EBs) to address whether these associations were reflections of
      increased overall chlamydial exposure rather than a property specific to Hsp10.
      Associations between Hsp10 seropositivity and TFI were greater in the EB(+)
      subgroup while associations among the EB(-) subgroup were diminished. When
      restricted to the EB(+) subgroups, Hsp60 and MOMP responses in the TFI population
      did not increase significantly over the level of AI group responses. Thus, among
      women with similar exposure to chlamydiae, the serologic response to Hsp10
      exhibited a stronger correlation with TFI than did the response to Hsp60 or MOMP.
      These findings support the hypothesis that the serological response to C.
      trachomatis heat shock proteins is associated with the severity of disease and
      identifies Hsp10 as an antigen recognized by a significant proportion of women
      with TFI.

PMID- 10603403
TI  - Molecular cloning and mutagenesis of a DNA locus involved in lipooligosaccharide
      biosynthesis in Haemophilus somnus.
AB  - Haemophilus somnus undergoes antigenic and structural phase variation in its
      lipooligosaccharide (LOS). A gene (lob-1) containing repetitive 5'-CAAT-3'
      sequences that may, in part, contribute to phase variation was cloned and
      sequenced (T. J. Inzana et al., Infect. Immun. 65:4675-4681, 1997). We have now
      identified another putative gene (lob-2A) immediately upstream from lob-1. Lob-2A
      contained homology to several LOS biosynthesis proteins of the family
      Pasteurellaceae and the LgtB and LgtE galactosyltransferases of Neisseria
      meningitidis and N. gonorrhoeae. Unlike lob-1, lob-2A contained 18 to 20 5'-GA-3'
      repeats 141 bp upstream of the termination codon as determined by PCR
      amplification of DNA from individual colonies. Twenty repeats were most common,
      but when 19 5'-GA-3' repeats were present a stop codon would occur 1 bp after the
      last 5'-GA-3' repeat. A 630-bp SalI-BsgI fragment within lob-2A was deleted, and
      a kanamycin resistance (Km(r)) gene was inserted into this site to create
      pCAATDeltalob2A. Following electroporation of pCAATDeltalob2A into H. somnus 738,
      several allelic exchange mutants were isolated. The LOS electrophoretic profile
      of one mutant, strain 738-lob2A1::Km, was altered, and the phase variation rate
      was reduced but phase variation was not eliminated. A variant with 19 5'-GA-3'
      repeats in lob-2A had an LOS profile similar to that of 738-lob2A1::Km,
      suggesting that lob-2A was turned off in this phase. Nanoelectrospray mass
      spectrometry (nES-MS) and nuclear magnetic resonance spectroscopy showed that 738
      lob2A1::Km was deficient in the terminal betaGal(1-3)betaGlcNAc residue present
      in parent strain 738. Mutant 738-lob2A1::Km was significantly more sensitive to
      the bactericidal action of normal bovine serum and was less virulent in mice than
      was parent strain 738. When H. somnus 129Pt was electrotransformed with shuttle
      vector pLS88 containing lob-2A, its LOS electrophoretic profile was modified and
      additional N-acetylhexosamine residues were present, as determined by nES-MS
      analysis. These results indicated that lob-2A may be an N-acetylglucosamine
      transferase involved in LOS biosynthesis and phase variation and that LOS
      structure is important to H. somnus virulence.

PMID- 10603404
TI  - Intracellular and extracellular cytokine production by human mixed mononuclear
      cells in response to group B streptococci.
AB  - Group B streptococci (GBS) are a major cause of severe infection in newborns,
      pregnant females, and other immunocompromised hosts. Infection often includes
      septicemia, shock, pneumonia, and respiratory failure. In previous studies, we
      have reported that GBS induce marked production of tumor necrosis factor alpha
      (TNF-alpha) by human mononuclear cells. The present study was designed to measure
      the production of TNF-alpha as well as additional cytokines, including
      interleukin 1beta (IL-1beta), IL-6, IL-8, IL-12, and gamma interferon (IFN-gamma)
      but also to determine from what cells and at what time point during incubation
      with GBS that these cytokines are produced. Mixed mononuclear cells were
      incubated with heat-killed GBS, media alone, or 1 microg of Escherichia coli
      lipopolysaccharide (LPS). Brefeldin A was added to each sample prior to staining,
      which prevented the export of cytokines by the Golgi apparatus. The cells were
      then stained with the appropriate conjugated antibodies and analyzed by using a
      flow cytometer. Results indicate that intracellular cytokines appear, in almost
      all cases, simultaneous to or before secreted proteins are detected. In contrast
      to the response to LPS, where TNF-alpha, IL-1beta, IL-6, and IL-8 appear almost
      simultaneously, the human monocyte response to GBS results in the production of
      TNF-alpha but delayed appearance of IL-1beta, IL-6, and IL-8. The lymphocyte
      response to GBS was also strikingly different from that to LPS in that both
      secreted IFN-gamma and IL-12 was detected, while LPS failed to induce production
      of these critical cytokines. This suggests an important role for TNF-alpha, IFN
      gamma, and IL-12 in GBS pathogenesis and/or immunity.

PMID- 10603405
TI  - Interleukin-8 secretion of cortical tubular epithelial cells is directed to the
      basolateral environment and is not enhanced by apical exposure to Escherichia
      coli.
AB  - In upper urinary tract infections, tubular epithelial cells (TEC) may play a
      pivotal role in the initiation of the renal inflammatory response. They exert
      crucial immunological functions such as processing and presentation of foreign
      antigen, secretion of proinflammatory cytokines (interleukin-6 [IL-6] and tumor
      necrosis factor alpha) and chemokines (IL-8, MCP-1, ENA-78, and RANTES). Since
      monolayer cultures are a limited model for polarized tubular epithelial cells, we
      studied the side-dependent IL-8 secretion of TEC by using cell culture inserts as
      a basement membrane imitation. Primary cultures of proximal TEC were stimulated
      with differently fimbriated mutants of Escherichia coli, E. coli LPS, S-fimbria
      isolates, and IL-1alpha. IL-8 protein was measured by enzyme-linked immunosorbent
      assay, and IL-8-like biological activity was tested by measuring elastase release
      from polymorphonuclear cells in supernatants of the upper and lower compartments.
      IL-8 mRNA was compared by competitive PCR. IL-8 secretion by TEC into the
      basolateral environment was significantly higher than secretion into the apical
      compartment, representing the tubular lumen. However, stimulation of IL-8
      secretion by TEC was restricted to IL-1alpha and was not inducible by E. coli
      mutants, S fimbriae, or lipopolysaccharide. With this in vitro model of polarized
      TEC, we show that luminal contact of TEC with uropathogenic E. coli does not
      result in enhanced IL-8 secretion. The basolaterally directed production of the
      neutrophil chemotactic factor IL-8 by TEC after stimulation with IL-1alpha might
      play an important role in the initiation of inflammatory cell influx into the
      renal parenchyma.

PMID- 10603406
TI  - Clearance and organ distribution of Mycobacterium tuberculosis lipoarabinomannan
      (LAM) in the presence and absence of LAM-binding immunoglobulin M.
AB  - Lipoarabinomannan (LAM) is a component of the mycobacterial surface which has
      been associated with a variety of deleterious effects on immune system function.
      Despite the importance of LAM to the pathogenesis of mycobacterial infection,
      there is no information available on its fate in vivo. In this study, we
      determined the pharmacokinetics and tissue distribution of exogenously
      administered LAM in mice. For measurements of serum and tissue LAM
      concentrations, we developed an enzyme-linked immunosorbent assay which used
      monoclonal antibodies of different isotypes to capture and detect LAM at
      concentrations of >/=0.4 microg/ml. Intravenous administration of LAM to mice
      resulted in transient serum levels with organ deposition in the spleen and in the
      liver. Immunohistochemical studies localized LAM to the spleen marginal zone
      macrophages and, to a lesser degree, to liver macrophages. When LAM was
      administered to mice previously given a LAM-binding immunoglobulin M (IgM), LAM
      was very rapidly cleared from circulation. In those mice, deposition of LAM in
      the spleen was significantly reduced while LAM deposition in the liver increased.
      Administration of LAM-binding IgM resulted in significant levels of IgM to LAM in
      bile consistent with an increased hepatobiliary excretion of LAM in the presence
      of specific antibody. Bile, liver extracts, and bile salts were found to rapidly
      inactivate the immunoreactivity of LAM. The results indicate that serum clearance
      and organ deposition of LAM in mice are affected by the presence of LAM-binding
      antibody and suggest a mechanism by which antibody could modify the course of
      mycobacterial infection.

PMID- 10603407
TI  - In vitro Brucella suis infection prevents the programmed cell death of human
      monocytic cells.
AB  - During the complex interaction between an infectious agent and a host organism,
      the pathogen can interfere with the host cell's programmed death to its own
      benefit. Induction or prevention of host cell apoptosis appears to be a critical
      step for determining the infection outcome. Members of the gram-negative
      bacterial genus Brucella are intracellular pathogens which preferentially invade
      monocytic cells and develop within these cells. We investigated the effect of
      Brucella suis infection on apoptosis of human monocytic phagocytes. The present
      study provides evidence that Brucella infection inhibited spontaneously occurring
      apoptosis in human monocytes. Prevention of monocyte apoptosis was not mediated
      by Brucella lipopolysaccharide and required bacterial survival within infected
      cells. Both invaded and noninvaded cells were protected, indicating that soluble
      mediators released during infection were involved in the phenomenon. Analysis of
      Brucella-infected monocytes revealed specific overexpression of the A1 gene, a
      member of the bcl-2 family implicated in the survival of hematopoietic cells.
      Brucella infection also rendered macrophage-like cells resistant to Fas ligand-
      or gamma interferon-induced apoptosis, suggesting that Brucella infection
      protected host cells from several cytotoxic processes occurring at different
      steps of the immune response. The present data clearly show that Brucella suis
      modulated the monocyte/macrophage's apoptotic response to the advantage of the
      pathogen, thus preventing host cell elimination. This might represent a strategy
      for Brucella development in infected hosts.

PMID- 10603408
TI  - Depletion of CD8(+) T cells in vivo impairs host defense of mice resistant and
      susceptible to pulmonary paracoccidioidomycosis.
AB  - Using a pulmonary model of infection, we demonstrated previously that A/Sn and
      B10.A mice are, respectively, resistant and susceptible to Paracoccidioides
      brasiliensis infection. Employing the same experimental model, we examined herein
      the role of CD8(+) T cells in the course of paracoccidioidomycosis. Treatment
      with anti-CD8 monoclonal antibodies caused a selective depletion of pulmonary and
      splenic CD8(+) T cells in both mouse strains. The number of pulmonary CD4(+) T
      cells and immunoglobulin-positive cells was independent of the number of CD8(+) T
      cells. In susceptible mice, the loss of CD8(+) T cells by in vivo treatment with
      anti-CD8 monoclonal antibodies impaired the clearance of yeasts from the lungs
      and increased the fungal dissemination to the liver and spleen. The same
      treatment in resistant mice increased fungal dissemination to extrapulmonary
      tissues but did not alter the pulmonary fungal load. Furthermore, CD8(+) T-cell
      depletion did not modify delayed-type hypersensitivity reactions of A/Sn mice but
      increased these reactions in B10.A mice. The production of P. brasiliensis
      specific antibodies by resistant and susceptible mice depleted of CD8(+) T cells
      was similar to that of mice given control antibody. Histopathologically,
      depletion of CD8(+) T cells did not disorganize the focal granulomatous lesions
      developed by both mouse strains. These results indicate that CD8(+) T cells are
      necessary for optimal clearance of the fungus from tissues of mice infected with
      P. brasiliensis and demonstrate more prominent protective activity by those cells
      in the immune responses mounted by susceptible animals.

PMID- 10603409
TI  - Isolates of Chlamydia trachomatis that occupy nonfusogenic inclusions lack IncA,
      a protein localized to the inclusion membrane.
AB  - The chlamydiae are obligate intracellular pathogens that occupy a nonacidified
      vacuole, termed an inclusion, throughout their developmenal cycle. When an
      epithelial cell is infected with multiple Chlamydia trachomatis elementary
      bodies, they are internalized by endocytosis into individual phagosomal vacuoles
      that eventually fuse to form a single inclusion. In the course of large-scale
      serotyping studies in which fluorescent antibody staining of infected cells was
      used, a minority of strains that had an alternate inclusion morphology were
      identified. These variants formed multiple nonfusogenic inclusions in infected
      cells, with the number of independent inclusions per cell varying directly with
      the multiplicity of infection. Overall the nonfusogenic phenotype was found in
      1.5% (176 of 11,440) of independent isolates. Nonfusing variants were seen in C.
      trachomatis serovars B, D, D-, E, F, G, H, Ia, J, and K. The nonfusing phenotype
      persisted through repeated serial passage, and the phenotype was consistent in
      four mammalian host cell lines. Fluorescence microscopy and immunoblotting with
      antisera directed at proteins in the C. trachomatis inclusion membrane revealed
      that one such protein, IncA, was not detected in the inclusion membrane in each
      tested nonfusogenic strain. The distributions of other chlamydial proteins,
      including one additional Inc protein, were similar in wild-type and variant
      strains. The incA coding and upstream regions were amplified and sequenced from
      the prototype serovar D and two nonfusing serovar D((s)) strains. Three
      nucleotide changes were discovered in the D((s)) incA gene, leading to two amino
      acid changes within the predicted D((s)) IncA sequence. These studies demonstrate
      a subgroup of variant C. trachomatis isolates that form nonfusing inclusions; the
      variant phenotype is associated with the absence of detectable IncA and with an
      altered incA sequence that modifies the characteristic hydrophobic domain of the
      IncA protein.

PMID- 10603410
TI  - Characterization of a macrophage-specific infectivity locus (milA) of Legionella
      pneumophila.
AB  - Legionella pneumophila has been shown to possess multiple genetic loci that play
      roles in its ability to survive within host cells. The mil (macrophage-specific
      infectivity loci) mutants of L. pneumophila exhibit a spectrum of defects in
      intracellular survival in and cytopathogenicity to macrophages and alveolar
      epithelial cells. This study characterizes one of the mil mutants (GB111).
      Intracellular growth of GB111 in macrophages was approximately 100- to 1,000-fold
      less than that of AA100, the parental strain, at 24 and 48 h postinfection. This
      defect in turn corresponded to a defect in cytopathogenicity. Sequence analysis
      of the affected GB111 open reading frame (ORF) revealed it to encode a putative
      transport protein, and the ORF was designated milA. The phenotypic defect of the
      milA mutant was complemented with a PCR fragment containing only milA, indicating
      that the defect in GB111 was due to the disruption of milA. Intracellular
      trafficking of the mutant was examined by laser scanning confocal microscopy. The
      data showed that 50% of the GB111 phagosomes colocalized with the late
      endosomal/lysosomal marker LAMP-2 (2 and 4 h postinfection), while less than 10%
      of the AA100 phagosomes colocalized with this marker. On the other hand, over 80%
      of the GB111 phagosomes were similar to the AA100 phagosome in that they were
      devoid of LAMP-1 and cathepsin D, and they were colocalized with the endoplasmic
      reticulum (ER) marker BiP. However, the number of GB111 phagosomes that
      colocalized with BiP decreased to 50% 6 h postinfection compared to that of
      AA100, which remained constant (80% colocalization). Thus, compared to AA100, the
      milA mutation caused a defect in intracellular replication, which was associated
      with colocalization of the phagosome with LAMP-2 and BiP, while colocalization
      with LAMP-1 and cathepsin D was not affected.

PMID- 10603411
TI  - A P5 peptide that is homologous to peptide 10 of OprF from Pseudomonas aeruginosa
      enhances clearance of nontypeable Haemophilus influenzae from acutely infected
      rat lung in the absence of detectable peptide-specific antibody.
AB  - Nontypeable Haemophilus influenzae (NTHi) is an opportunistic pathogen associated
      with otitis media and the exacerbation of chronic bronchitis. This study reports
      the vaccine potential of three peptides representing conserved regions of the
      NTHi P5 outer membrane protein which have been fused to a promiscuous measles
      virus F protein T-cell eptitope (MVF). The peptides correspond to a region in
      surface loop one (MVF/L1A), the central region of loop four (MVF/L4), and a C
      terminal region homologous to peptide 10 of OprF from Pseudomonas aeruginosa
      (MVF/H3). Immunization of rats with MVF/H3 was the most efficacious in
      significantly reducing the number of viable NTHi in both the broncho-alveolar
      lavage fluid (74%) and lung homogenates (70%), compared to control rats.
      Importantly, despite significantly increased rates of clearance, immunization
      with MVF/H3 elicited poor antibody responses, suggesting that cell-mediated
      rather than humoral responses play an important role in the enhanced clearance of
      NTHi in this model.

PMID- 10603412
TI  - Interaction of enteropathogenic or enterohemorrhagic Escherichia coli with HeLa
      cells results in translocation of cortactin to the bacterial adherence site.
AB  - Infection of cultured HeLa epithelial cells with enteropathogenic Escherichia
      coli (EPEC) or enterohemorrhagic E. coli (EHEC) O157:H7 results in accumulation
      of cortactin under the adherent bacteria. Tyrosine phosphorylation of cortactin
      is not induced following HeLa cell infection with EHEC or EPEC, contrary to what
      has been reported to occur with Shigella flexneri.

PMID- 10603413
TI  - Evaluation of Mycobacterium tuberculosis genes involved in resistance to killing
      by human macrophages.
AB  - A coinfection assay was developed to examine Mycobacterium tuberculosis genes
      suspected to be involved in resistance to killing by human macrophages. THP-1
      macrophages were infected with a mixture of equal numbers of recombinant
      Mycobacterium smegmatis LR222 bacteria expressing an M. tuberculosis gene and
      wild-type M. smegmatis LR222 bacteria expressing the xylE gene. At various times
      after infection, the infected macrophages were lysed and the bacteria were
      plated. The resulting colonies were sprayed with catechol to determine the number
      of recombinant colonies and the number of xylE-expressing colonies. M. smegmatis
      bacteria expressing the M. tuberculosis glutamine synthetase A (glnA) gene or
      open reading frame Rv2962c or Rv2958c demonstrated significantly increased
      survival rates in THP-1 macrophages relative to those of xylE-expressing
      bacteria. M. smegmatis bacteria expressing M. tuberculosis genes for
      phospholipase C (plcA and plcB) or for high temperature requirement A (htrA) did
      not.

PMID- 10603414
TI  - Plasmodium falciparum rosette formation is uncommon in isolates from pregnant
      women.
AB  - We examined the formation of Plasmodium falciparum erythrocyte rosettes using
      parasite isolates from placental or peripheral blood of pregnant Malawian women
      and from peripheral blood of children. Five of 23 placental isolates, 23 of 38
      maternal peripheral isolates, and 136 of 139 child peripheral isolates formed
      rosettes. Placental isolates formed fewer rosettes than maternal isolates (range,
      0 to 7. 5% versus 0 to 33.5%; P = 0.002), and both formed fewer rosettes than
      isolates cultured from children (range, 0 to 56%; P < 0.0001). Rosette formation
      is common in infections of children but uncommon in pregnancy and rarely detected
      in placental isolates.

PMID- 10603415
TI  - High levels of inducible nitric oxide synthase mRNA are associated with increased
      monocyte counts in blood and have a beneficial role in Plasmodium falciparum
      malaria.
AB  - To date, there have been conflicting reports concerning the clinical significance
      of nitric oxide (NO) in Plasmodium falciparum malaria. Some authors have proposed
      that NO contributes to the development of severe and complicated malaria, while
      others have argued that NO has a protective role. To investigate these apparently
      contradictory reports, reverse transcription-coupled PCR was used to study
      inducible NO synthase (iNOS) in whole-blood RNA samples from patients with severe
      and complicated malaria or uncomplicated malaria and from healthy donors. This
      work produced three principal findings. First, samples of patients with severe
      and complicated malaria were variably positive, with weak to moderate intensity.
      Markedly higher iNOS RNA levels were observed in samples of patients with
      uncomplicated malaria than in patients with severe and complicated malaria.
      Samples of healthy donors were uniformly negative. Second, since we initially
      demonstrated iNOS expression in whole-blood RNA samples, we extended our
      investigations to individual blood cells such as monocytes, lymphocytes,
      neutrophils, and platelets to identify the cellular source of iNOS. We found that
      iNOS was expressed predominantly in monocytes. Third, retrospective statistical
      analysis of monocyte counts clearly demonstrated that patients with uncomplicated
      malaria had higher monocyte counts at the time of presentation than patients with
      severe and complicated malaria. Taken together, our findings give room to the
      interpretation that NO may have a beneficial rather than a deleterious role in
      falciparum malaria.

PMID- 10603416
TI  - Innate immunity to amebic liver abscess is dependent on gamma interferon and
      nitric oxide in a murine model of disease.
AB  - Evidence from in vitro studies suggests that gamma interferon (IFN-gamma) and
      nitric oxide (NO) are important in host defense against the protozoan parasite
      Entamoeba histolytica. We used SCID mice with targeted disruption of the IFN
      gamma receptor gene and mice with targeted disruption of the gene encoding
      inducible NO synthase to show that IFN-gamma plays a role in the innate immunity
      to amebic liver abscess seen in SCID mice while NO is required for control of
      amebic liver abscess in immunocompetent mice.

PMID- 10603417
TI  - ExoT of cytotoxic Pseudomonas aeruginosa prevents uptake by corneal epithelial
      cells.
AB  - The presence of invasion-inhibitory activity that is regulated by the
      transcriptional activator ExsA of cytotoxic Pseudomonas aeruginosa has previously
      been proposed. The results of this study show that both ExoT and ExoS, known type
      III secreted effector proteins of P. aeruginosa that are regulated by ExsA,
      possess this activity. Invasion was reduced 94.4% by ExoT and 96.0% by ExoS.
      Invasion-inhibitory activity is not linked to ADP-ribosylation activity, at least
      for ExoS, since a noncatalytic mutant also inhibits uptake by an epithelial cell
      line (invasion was reduced 96. 0% by ExoSE381A).

PMID- 10603418
TI  - Toxoplasma gondii infection induces gene expression and secretion of interleukin
      1 (IL-1), IL-6, granulocyte-macrophage colony-stimulating factor, and
      intercellular adhesion molecule 1 by human retinal pigment epithelial cells.
AB  - We have used human retinal pigment epithelial (HRPE) cultures to investigate the
      primary cellular responses of retinal resident cells to intracellular Toxoplasma
      gondii replication. At 4 days postinoculation, when all of the cells were
      infected, the secretion of interleukin 1beta (IL-1beta), IL-6, granulocyte
      macrophage colony-stimulating factor (GM-CSF), and intercellular adhesion
      molecule 1 (ICAM-1) was augmented by 23-, 10-, 8-, and 5-fold, respectively, over
      the control. Northern and reverse transcriptase PCR analyses showed significant
      upregulation of steady-state levels of mRNA for IL-1beta, IL-6, GM-CSF, and ICAM
      1. The secretion of these molecules by HRPE cells may play a critical
      immunoregulatory role in the pathophysiological processes associated with T.
      gondii-induced retinochoroiditis.

PMID- 10603419
TI  - Inhibition of Borrelia burgdorferi migration from the midgut to the salivary
      glands following feeding by ticks on OspC-immunized mice.
AB  - Borrelia burgdorferi-infected ticks were fed on either OspC-immunized mice or
      normal, nonimmunized mice. After 72 h, the ticks were detached, followed by
      dissection and subsequent culturing in Barbour-Stoenner-Kelley II medium of the
      salivary glands from each tick to determine the presence of borreliae. Forty
      percent (10 of 25) of salivary glands from ticks that had fed on nonimmunized
      mice were culture positive, while only 7.4% (2 of 27) of salivary glands from
      ticks that had fed on OspC-immunized mice were culture positive, thus indicating
      a much reduced borrelial migration from the midgut when the bloodmeal contained
      anti-OspC antibodies. Fluorescent antibody staining of the corresponding midguts
      from ticks that had fed on the OspC-immunized mice showed that borreliae were
      present but did not produce OspC. In contrast, borreliae in midguts from ticks
      that had fed on normal mice demonstrated substantial ospC expression. This study
      provides evidence that, during tick feeding on an OspC-immunized host,
      transmission of borreliae from the tick is prevented; it also suggests that OspC
      functions in a tick-to-host transmission mechanism.

PMID- 10603420
TI  - Isolation of Bacteroides fragilis mutants with in vivo growth defects by using
      Tn4400', a modified Tn4400 transposition system, and a new screening method.
AB  - A modified version of the Bacteroides fragilis transposon Tn4400, designated
      Tn4400', enabling rapid isolation and analysis of B. fragilis mutants has been
      constructed. To identify potential virulence factors, Tn4400'-generated mutants
      were screened by a new method; this resulted in the isolation of 21 mutant
      strains with impaired growth characteristics on tissue culture monolayers but
      normal growth in rich medium anaerobically.

PMID- 10603421
TI  - Identification and cloning of genes from Porphyromonas gingivalis after
      mutagenesis with a modified Tn4400 transposon from Bacteroides fragilis.
AB  - Porphyromonas gingivalis is a gram-negative, black-pigmented, oral anaerobe
      strongly associated with adult periodontitis. Previous transposon mutagenesis
      studies with this organism were based on the Bacteroides transposon Tn4351.
      Characterization of Tn4351-disrupted genes by cloning has not been an efficient
      way to analyze large numbers of mutants and is further complicated by the high
      rate of cointegration of the suicide delivery vector containing Tn4351. In this
      study, we mutagenized P. gingivalis with a modified version of the Bacteroides
      fragilis transposon Tn4400. Plasmid pYT646B carrying the transposon was mobilized
      from Escherichia coli to P. gingivalis ATCC 33277 by conjugation. Both normal and
      inverse transposition frequencies were similar (3 x 10(-8)). However, the inverse
      transposon (Tn4400') contains a pBR322 replicon and a beta-lactamase gene; thus,
      the cloning of disrupted genomic DNAs from inverse transposition mutants was
      easily accomplished after ligation of genomic fragments and transformation into
      E. coli. Thousands of transconjugants could be obtained in a single mating
      experiment, and inverse transposition was random as demonstrated by Southern
      hybridization. By this procedure the disrupted genes from P. gingivalis
      pleiotropic mutants were quickly cloned, sequenced, and identified.

PMID- 10603423
TI  - Effects of maximal interval training on arterial oxygen desaturation and
      ventilation during heavy exercise.
AB  - The purpose of the present study was to clarify longitudinally the effects of
      exercise training on arterial O(2) saturation (Sa(O(2))) and ventilation during
      heavy exercise. A group of six subjects (training group) volunteered to train
      four times a week for 12 weeks. Each training session consisted of five 3-min
      periods of exercise on a cycle ergometer at a power output of 100% maximal O(2)
      uptake (V(.)(O(2 max))), interspersed with 2-min recovery period cycling at 50%
      V(.)(O(2 max)). During the training, V(.)(O(2 max)), Sa(O(2)), the ventilatory
      equivalent for oxygen (V(.)E/V(.)(O(2))), and the end-tidal partial pressure of
      O(2) (PET(O(2))) during heavy exercise were measured periodically. The same
      parameters were measured simultaneously in another group of five subjects
      (control group) who led normal lives. Maximal interval training increases
      V(.)(O(2 max)), with little change in V(.)E(max) and pulmonary functions at rest.
      The training decreased PET(O(2)), V(.)E/V(.)(O(2)), and Sa(O(2)) during heavy
      exercise. Sa(O(2)) is significantly related to V(.)E/V(. )(O(2)) (r(2) = 0.49).
      These results suggest that less hyperventilatory response to exercise occurs with
      progress in physical training because the adaptability of ventilatory capacity is
      less than that of aerobic work capacity, which half induces arterial O(2)
      desaturation during heavy exercise. PET(O(2)) as well as V(.)E/V(.)(O(2)) and
      V(.)(O(2 max)) did not change anymore after the 6th week, nevertheless Sa(O(2))
      kept decreasing up to the last 2 weeks. In addition, when the Sa(O(2))
      V(.)E/V(.)(O(2)) plot was compared between the two groups, the regression line of
      the training group was steeper than that of the control groups; i.e., compared at
      a lower level of V(.)E/V(.)(O(2)) ( approximately 30 ml.ml(-1)), the Sa(O(2)) of
      the trained subjects exercising at a higher V(.)(O(2)) level was lower than that
      of the control subjects. Predominance of less hyperventilation and another
      factor, increased A-aDO(2), in the genesis of arterial hypoxemia and O(2)
      desaturation may be dependent upon V(.)(O(2)) levels in heavy exercise and the
      state of training.

PMID- 10603424
TI  - Protein kinase C inhibitors abolish the increased resistance of diabetic rat
      heart to ischemia-reperfusion injury.
AB  - Protein kinase C (PKC) has been implicated in ischemic preconditioning, but
      whether it plays a role in the cardioprotection observed in the diabetic heart is
      not known. We assessed the possible role of PKC by investigating whether the
      inhibition of PKC with staurosporine (Stau, 0.01 microM) or chelerythrine (Chel,
      1 microM) can abolish the increased resistance to ischemia (25 min)-reperfusion
      (30 min) injury in Langendorff perfused hearts from streptozotocin-induced 4-week
      diabetic rats. In the diabetic heart, pre-ischemic left ventricular developed
      pressure (LVDP), double product (DP: LVDPxheart rate/1,000), +/- dP/dt(max) and
      coronary flow rate (CFR) were all reduced compared to the control. The
      pretreatment with Stau or Chel significantly improved these parameters. The post
      ischemic contractile function was recovered to a greater extent in the diabetic
      heart (116.9 +/- 20.5% of pre-ischemic DP) than in the control (23.3 +/- 2.3% of
      pre-ischemic DP), indicating the increased resistance of the diabetic heart to
      ischemia-reperfusion injury. The treatment with Stau or Chel abolished the
      enhanced recovery in the diabetic heart (36.0 +/- 14.6 and 54.1 +/- 12.8% of pre
      ischemic DP, respectively). The reduction in post-ischemic end diastolic pressure
      (EDP) and lactate dehydrogenase (LDH) release in diabetes (13.5 +/- 2.5 mmHg and
      27.2 +/- 6.2 U/g heart) compared to the control (55.8 +/- 2.9 mmHg and 60. 3 +/-
      5.7 U/g heart) was significantly (p<0.05) increased by pretreatment with Stau
      (39.0 +/- 4.9 mmHg and 53.1 +/- 7.6 U/g heart) or Chel (36.2 +/- 3.0 mmHg and
      48.8 +/- 4.3 U/g heart). Neither Stau nor Chel had any influence on the post
      ischemic values of LVDP, DP, +/- dP/dt(max), EDP and LDH release in the control
      heart. In the conclusion, the present results suggest that PKC activation may, at
      least in part, contribute to the increased resistance of the diabetic heart to
      ischemia-reperfusion injury.

PMID- 10603425
TI  - Postural adjustment response to depth direction moving patterns produced by
      virtual reality graphics.
AB  - PURPOSE: Human posture is controlled by a combination of vestibular,
      somatosensory and visual information. This paper is concerned with postural
      readjustment responses induced by vection. In the visual control of posture,
      visually-induced perception of self-motion plays an important role and is called
      vection. Vection is difficult to measure quantitatively because it is a highly
      subjective phenomenon. HYPOTHESIS: An optokinetic stimulus that moves in depth
      induces vection. We hypothesize that the magnitude of the visually-induced body
      sway is correlated with the degree of vection. METHODS: A depth optokinetic
      stimulus (DOKS) was projected onto a head-mounted display (HMD) worn by standing
      subjects. The DOKS consisted of a random dot pattern that was perceived three
      dimensionally and moved in depth sinusoidally. Vection was estimated in two ways,
      a verbal assessment and a joystick maneuver. In addition, visually-induced body
      sway was measured by monitoring five reference points on the body by two video
      motion analyzers. RESULTS: The magnitude of the subjective vection was highly
      correlated with visually-induced body sway and was strongly dependent on the
      velocity of the visual stimulus. The ankle joint was pivoted during visually
      induced body sway and acted as a motion initiator. When the magnitude of body
      sway was large, the body movement was adjusted at the hip and head-neck joints.
      CONCLUSIONS: The high correlation between vection and body sway suggests that
      vection can be estimated quantitatively by measuring visually-induced body sway.

PMID- 10603426
TI  - After-effect of entrainment on the period of human circadian system.
AB  - The purpose of the present study is to examine changes of the circadian period in
      humans during temporal isolation, where the circadian rhythm is free-running.
      Twelve young males each spent 22 d alone in a temporal isolation room. Rectal
      temperature was continuously recorded and plasma melatonin was measured on day 3
      (D3) and from days 10 to 13 (D10-D13). The light intensity in the room was less
      than 100 lx during the waking period. The free-run period of temperature rhythm
      from D3 to D10 (24.75 h) was not significantly different from those of the plasma
      melatonin rhythm (24.63 h) and sleep-wake cycle (24.69 h). The free-run period of
      temperature rhythm was 24.58 h in S-1 (D2-D6), which was gradually and
      significantly lengthened to 24.84 h in S-2 (D6-D10), 25.16 h in S-3 (D12-D16),
      and 25.18 h in S-4 (D18-D22). The free-run period of rectal temperature rhythm
      was steadily lengthened throughout the isolation period, which was probably due
      to the after-effect of previous entrainment to 24-h time cues.

PMID- 10603427
TI  - Effects of ionophores on the phospholipid flippase activity of gastric vesicles.
AB  - Recently, a gastric Mg(2+)-ATP-dependent phospholipid flippase was found. Here,
      the effects of ionophores and monovalent cations on the gastric flippase were
      examined. We found that translocation of the fluorescent analogue of
      phosphatidylcholine was inhibited by valinomycin in the presence of K(+). The
      inhibition depended on both the concentrations of valinomycin and K(+).
      Valinomycin did not inhibit translocation in the absence of K(+). Protonophores,
      carbonylcyanide-m-chlorophenylhydrazone (CCCP) and carbonylcyanide-p
      (trifluoromethoxy)phenylhydrazone (FCCP), accelerated translocation by 190-270%.
      These increases were completely abolished by 2-methyl-8-(phenylmethoxy)imidazo
      [1, 2-a]pyridine-3-acetonitrile (SCH 28080), a gastric flippase inhibitor. Since
      these protonophores did not affect the Mg(2+)-dependent ATPase activity that is
      responsible for phospholipid translocation by the flippase, the coupling ratio of
      the amount of transported phospholipids/the amount of hydrolyzed ATP was variable
      and seemed to depend on the state of the membrane bilayer, for example fluidity.
      Inhibition by the valinomycin-K(+) complex was abolished in the presence of CCCP
      or FCCP, indicating the valinomycin-K(+)-CCCP(FCCF) ternary complex did not
      inhibit the flippase.

PMID- 10603428
TI  - Involvement of superoxide in acute reaction of angiotensin II in mesenteric
      microcirculation.
AB  - Superfusion of angiotensin II (Ang II) ceased blood flow in rat mesenteric
      microcirculation, however, successive reflow occurred. When nitric oxide synthase
      inhibitor was present, the stoppage of flow occurred by the lower concentration
      of Ang II. Superoxide dismutase (SOD) significantly delayed the stoppage by Ang
      II and restored the successive reflow earlier. The acute reaction between Ang II
      and mesenteric artery induced immediate superoxide (O(2)(-)) production when
      observed by a chemiluminescence method using the Cypridina luciferin analog. The
      acute vascular O(2)(-) production on the addition of Ang II contributed to in
      vitro vascular contraction as it was significantly attenuated by SOD. The acute
      superoxide-producing effect is likely to be specific to Ang II because such
      significant modification by SOD was not observed for norepinephrine.

PMID- 10603429
TI  - Spatiotemporal properties of neural activity propagation from the subicular
      complex to the posterior cingulate cortex in rat brain slices detected by the
      optical recording technique.
AB  - Using the optical technique, we investigated the functional neural circuits from
      the subicular complex to the posterior cingulate cortex in rat brain slices. In
      11 out of 98 slices, an electrical stimulation to the subicular complex induced
      an excitation wave that spread into the posterior cingulate cortex (PCC) and
      propagated along its superficial layer. The process of this propagation was
      clearly divided into three steps. The first step was a fast conduction process in
      the superficial layers of the subiculum, which might arise from propagation of
      action potentials directly evoked by the stimulation. The second one was a slow
      process around the boundary between the subiculum and PCC, during which
      significant signal enhancement was observed via a pathway in the middle to deep
      layers. The third step was a slow propagating process along the superficial
      layers of PCC. Application of the non-NMDA receptor antagonist, CNQX, restricted
      propagation in the first step, suggesting that a synaptic relay exists between
      the first and second steps. In the rest of the slices (87 out of 98), signal
      propagation showed only the first step in response to electrical stimulation.
      However, when bicuculline, a GABA(A) receptor antagonist, was applied to these
      slices, the signal propagation spread into PCC in a manner indistinguishable from
      the one characterized above. It is therefore plausible that, under the conditions
      we adopted for the silces, the propagation pathway to PCC usually remains
      suppressed by GABAergic synaptic mechanisms.

PMID- 10603430
TI  - Point-mutations related to the loss of batrachotoxin binding abolish the
      grayanotoxin effect in Na(+) channel isoforms.
AB  - The effect of grayanotoxin (GTX) on site-specific mutants of the alpha-subunit of
      rat skeletal muscle Na(+) channels (micro1) (micro1-I433K, micro1-N434K and
      micro1-L437K), which are resistant to batrachotoxin (BTX) (Wang and Wang (1998)
      Proc Natl Acad Sci USA, 95, 2653-2658) was studied using a whole-cell patch-clamp
      method. The GTX modification of the Na(+) channels was detected as a
      characteristic-sustained Na(+) current flow with repetitive pulses. We also
      studied the GTX action on mutants of the alpha-subunit of rat heart Na(+)
      channels (RH1) (RH1-V406K and RH1-L410K) which match with micro1-I433 and micro1
      L437. All the mutants lost their sensitivity to GTX. This finding indicates that
      GTX may share a binding site with BTX in transmembrane segment I-S6 of two
      different Na(+) channel isoforms, micro1 and RH1.

PMID- 10603431
TI  - The activation of the tissue plasminogen activator-plasmin system induced in the
      mouse hippocampus after injection of trimethyltin: possible proteolysis of highly
      polysialylated NCAM.
AB  - Trimethyltin (TMT) is a neurotoxicant that causes the death of granule cells and
      degrades highly polysialylated NCAM (PSA-NCAM) in the dentate gyrus. To
      investigate the role of the tPA-plasmin system in the degradation of PSA-NCAM, we
      injected trimethyltin (TMT) into mice. As a result, tPA activity was
      significantly increased in CA1-CA4 and the dentate gyrus after TMT injection.
      These results suggest that up-regulated tPA may contribute to the degradation of
      PSA-NCAM.

PMID- 10603432
TI  - Central control mechanisms of circulation in the medulla oblongata by nitric
      oxide.
AB  - Nitric oxide (NO) is involved in numerous physiological functions. Besides its
      role as an endothelium-dependent relaxing factor (EDRF), NO inhibits platelet
      aggregation, contributes to cytotoxicity against bacteria, is active in synaptic
      transmission within the brain, etc. NO synthase (NOS) is distributed in brain
      regions related to the regulation of cardiovascular functions. NO has been
      inferred not only to act directly on vascular vessels, but also to regulate
      circulation within the brain. In this review paper, we mainly consider the
      functions of NO in the cardiovascular center of the medulla oblongata. That is,
      we describe the anatomical distribution of NOS in the brain, effects of
      intravenous and intracerebroventricular administration of NOS inhibitors on the
      circulation, effects of microinjection of NO donors and NOS inhibitors into the
      nucleus tractus solitarius (NTS) and ventrolateral medulla (VLM), the results of
      electrophysiological studies on these areas, and finally, the data obtained by
      new molecular biological techniques.

PMID- 10603433
TI  - Haloperidol prolongs diastolic phase of Ca(2+) transient in cardiac myocytes.
AB  - Haloperidol (HPL), a widely used antipsychotic drug, is known to induce serious
      ventricular arrhythmias. However, the mechanism underlying their induction is not
      clear. We therefore examined the effects of HPL on the intracellular Ca(2+)
      ([Ca(2+)](i)) transient and on cell motion in cultured cardiac myocytes, as well
      as the pathways involving the HPL-induced abnormality of Ca(2+) homeostasis. HPL
      prolonged the diastolic phase of the Ca(2+) transient, with a mid-diastolic re
      elevation of [Ca(2+)](i). The re-elevation of [Ca(2+)](i) was shown to be
      provoked by Ca(2+) release from sarcoplasmic reticulum (SR), which can trigger
      delayed afterdepolarization, the major arrhythmogenic factor. The re-elevation of
      [Ca(2+)](i) coincided with cell re-contraction during diastole. The induction of
      this abnormality by HPL appears to be independent of the mechanisms of the
      antipsychotic action.

PMID- 10603434
TI  - Effects of conditioning stimulation of the central amygdaloid nucleus on tooth
      pulp-driven neurons in the cat somatosensory cortex (SI).
AB  - To study the limbic control of nociception, we examined the effect of
      conditioning stimulation of the central amygdaloid nucleus (ACE) on tooth pulp
      driven (TPD) neurons in the first somatosensory cortex (SI). Cats were
      anesthetized with N(2)O-O(2) (2:1) and 0.5% halothane, and immobilized with
      tubocurarine chloride. The tooth pulp test stimulus was applied by a single
      rectangular pulse (0.5 ms in duration and 3-5 times the threshold intensity for
      the jaw-opening reflex). Conditioning stimuli to the ACE consisted of trains of
      33 pulses (300 microA) delivered at 330 Hz at intervals of 8-10 s. In 35 out of
      61 of the slow (S)-type TPD neurons with latencies of more than 20 ms,
      conditioning stimulation in the ACE, especially in the medial division, markedly
      reduced the firing response to the pulpal stimulation. The inhibition of the
      firing rate in the S-type neurons was 74% of the control. In these S-type
      neurons, the neurons that were inhibited had significantly longer latencies
      compared to the non-inhibited neurons (45.0 +/- 17.6 ms, n = 32 vs. 34.8 +/- 10.5
      ms, n = 26). In contrast, the ACE conditioning stimulation affected only one out
      of 18 fast-type TPD neurons with latencies of less than 20 ms. In addition, ACE
      stimulation had no effect on the spontaneous discharges of either S-type or F
      type neurons. The ACE inhibitory effect on S-type neurons was not diminished by
      naloxone administration (1 mg/kg, I.V. ), while the blockade of histamine H(1)
      receptor by diphenhydramine hydrochloride (0.5 mg/kg, I.V.) partially reversed
      the inhibitory effect. These results suggest that the ACE inhibits ascending
      nociceptive information to the SI and that this inhibition is mediated in part by
      histamine (H(1)) receptors. It seems likely that the antinociceptive effect is a
      neurophysiological basis for stress-induced analgesia (SIA).

PMID- 10603435
TI  - The effects of tetrandrine on the contractile function and microvascular
      permeability in the stunned myocardium of rats.
AB  - The effects of tetrandrine (Tet) on the contractile function and microvascular
      permeability in stunned rat myocardium in vivo were studied. Stunned myocardium
      was induced by 15 (MS(15) group) or 20 (MS(20) group) min of myocardial ischemia
      plus 60 min of reperfusion. The following was shown. (1) FITC-BSA concentration
      was 166.0 +/- 7. 9 microg/g myocardium in the control group. The concentrations
      in ischemic myocardium increased by 35.4 and 45.6% in MS(15) and MS(20) groups
      respectively (p<0.05). (2) Administration of Tet (64.2 and 96. 3 micromol/kg,
      I.P.) 20 min before ischemia not only ameliorated the contractile function, but
      also reduced the FITC-BSA concentrations in ischemic myocardium. At 60 min after
      reperfusion, the contractile function parameters in Tet-treated groups were
      significantly superior to those in corresponding stunning groups. FITC-BSA
      concentrations in Tet-treated groups were lower than those in stunning groups.
      Then, there was already no significant difference in FITC-BSA concentrations
      between Tet-treated groups and the control group. The FITC-BSA concentrations at
      the end of experiments were correlated negatively with dp/dt(max) (r = -0.83,
      p<0.01). (3) Tet inhibited KCl-induced calcium influx in isolated cardiomyocytes.
      The results suggest that Tet given before ischemia may be involved in the
      reduction of microvascular permeability in stunned myocardium, which might be
      associated with its calcium channel blocking effect.

PMID- 10603436
TI  - Relationship between parotid amylase secretion and osmolality in the gastric
      contents of rats fed a pelleted or liquid diet.
AB  - The relationship between parotid amylase secretion and the osmolality in the
      gastric contents of rats fed a pelleted or liquid diet was investigated. In sham
      operated rats fed a pelleted diet, amylase activity in the parotid glands
      decreased, amylase activity in the plasma increased, and there was strong amylase
      activity in the gastric contents. As a result, both reducing sugar concentration
      and osmolality in the gastric contents increased. In parotid duct-ligated rats,
      the feeding of a pelleted diet affected neither parotid nor plasma amylase
      activity and there was little amylase activity in the gastric contents; this
      resulted in decreased starch digestion. The amylase activity in the gastric
      contents of rats fed a liquid diet was lower than that of rats fed the pelleted
      diet. Both the reducing sugar concentration and osmolality in the gastric
      contents of rats fed the liquid diet were lower than those of rats fed the
      pelleted diet. However, both the reducing sugar concentration and osmolality in
      the gastric contents of rats fed the liquid diet were higher than those in the
      liquid diet itself. A small quantity of parotid amylase seems to effectively
      digest a large part of the starch in the stomaches of rats fed the liquid diet.
      These findings suggest that amylase secreted from parotid glands increases
      osmolality in the gastric contents via the production of reducing sugars from
      starch in rats when fed either pelleted or liquid diets.

PMID- 10603437
TI  - New index for oxygen cost of contractility from curved end-systolic pressure
      volume relations in cross-circulated rat hearts.
AB  - We have already reported the linear oxygen consumption per beat (VO(2))-systolic
      pressure-volume area (PVA) relation from the curved left ventricular (LV) end
      systolic pressure-volume relation (ESPVR) in the cross-circulated rat heart. The
      VO(2) intercept (PVA-independent VO(2)) is primarily composed of VO(2) for Ca(2+)
      handling in excitation-contraction (E-C) coupling and basal metabolism. The aim
      of the present study was to obtain the oxygen cost of LV contractility that
      indicates VO(2) for Ca(2+) handling in E-C coupling per unit LV contractility
      change in the rat heart. Oxygen cost of LV contractility is obtainable as a slope
      of a linear relation between PVA-independent VO(2) and LV contractility. We
      obtained a composite VO(2)-PVA relation line at a mid-range LV volume (mLVV)
      under gradually enhanced LV contractility by stepwise increased Ca(2+) infusion
      and thus the gradually increased PVA-independent VO(2) values. As a LV
      contractility index, we could not use E(max) (ESP-V ratio; ESP/ESV) for the
      linear ESPVR because of the curved ESPVR in the rat LV. A PVA at a mLVV
      (PVA(mLVV)) has been proposed as a good index for assessing rat LV
      mechanoenergetics. Since the experimentally obtained PVA(mLVV) was not triangular
      due to the curved ESPVR, we propose an equivalent ESP-V ratio at a mLVV,
      (eESP/ESV)(mLVV), as a LV contractility index. This index was calculated as an
      ESP-V ratio of the specific virtual triangular PVA(mLVV) that is energetically
      equivalent to the real PVA(mLVV). The present approach enabled us to obtain a
      linear relation between PVA-independent VO(2) and (eESP/ESV)(mLVV) and the oxygen
      cost of LV contractility as the slope of this relation.

PMID- 10603438
TI  - Effects of iodoacetate on spontaneous electrical activity, slow wave, in the
      circular muscle of the guinea-pig gastric antrum.
AB  - In the circular muscle of the guinea-pig gastric antrum, the contribution of
      glycolysis to spontaneous electrical activity, slow wave, was studied. The slow
      wave could be maintained without a marked change in glucose-free solution for
      more than 1 h even when treated with iodoacetic acid (IAA, 0.1-0.5 mM). However,
      reapplication of glucose following the IAA treatment produced clear inhibitory
      effects on the slow wave. Lactate release from the tissue was reduced to about
      10% of the control by IAA (0.1 mM) in the absence of glucose and there was very
      slow recovery on glucose reapplication. This suggests that IAA did not block
      glycolysis completely and that the inhibition of slow wave was mainly due to the
      accumulation of some metabolites. Small electrical activity often remained during
      the inhibition by IAA and glucose. When the excitability of the smooth muscle was
      increased by Co(2+) application or Na(+) removal, slow wave-like activity could
      be generated under the condition in which the slow wave was strongly inhibited by
      IAA and glucose. These results may be explained by assuming that the accumulation
      of glycolytic metabolites decreases the excitability of smooth muscle cells and
      also reduces the driving potential generated in the interstitial cells of Cajal
      to a subthreshold level for the slow wave in the smooth muscle cells.

PMID- 10603439
TI  - Fibronectin induces pseudopod formation and cell migration by mobilizing internal
      Ca(2+) in blastoderm cells from medaka embryos.
AB  - During vertebrate embryogenesis, blastoderm cells at the gastrula stage migrate
      to new locations for subsequent development. The cellular mechanism of migration
      was studied in medaka (Oryzias latipes) embryos at the early gastrula stage. When
      fibronectin was applied iontophoretically or by the puff method, cell surface
      protrusion known as pseudopods and a local [Ca(2+)](i) rise at the site of
      application were observed in approximately half of the isolated blastoderm cells.
      When the pseudopod adhered to the substrate, the cell body moved toward the
      direction of the pseudopod as [Ca(2+)](i) declined and the pseudopod was
      withdrawn. Local puff application of ionomycin, a Ca(2+) ionophore, in the
      presence of external Ca(2+) induced protrusions of the plasma membrane similar to
      pseudopods, suggesting that the [Ca(2+)](i) rise itself is causing pseudopod
      formation. On the other hand, fibronectin induced pseudopods even in the absence
      of external Ca(2+), suggesting the mobilization of Ca(2+) from internal stores.
      In accordance with this interpretation, fibronectin failed to induce [Ca(2+)](i)
      rises after pretreatment with thapsigargin, a blocker of Ca(2+)-ATPase in the
      endoplasmic reticulum. Furthermore, chelating internal Ca(2+) with BAPTA
      prevented fibronectin from inducing pseudopods. U-73122, a blocker of
      phospholipase C, completely suppressed both the [Ca(2+)](i) rise and
      morphological changes accompanied with fibronectin application, suggesting
      involvement of the inositol phosphate pathway. On the other hand, caffeine evoked
      a [Ca(2+)](i) rise in a great majority of the fibronectin-responsive cells and
      the percentage of fibronectin-responsive cells was greatly reduced by a blocking
      dose of ryanodine. These results suggest that fibronectin activates phospholipase
      C and the initial [Ca(2+)](i) rise through IP(3) receptors further activates
      ryanodine receptors, achieving the local [Ca(2+)](i) rise. The decay time course
      of [Ca(2+)](i) after fibronectin application was prolonged in the absence of
      external Na(+). DCB, an inhibitor of Na(+)/Ca(2+) exchangers, also prolonged the
      time course of the [Ca(2+)](i) decay, suggesting the contribution of Na(+)/Ca(2+)
      exchangers. Cytochalasin D, an inhibitor of actin polymerization by binding to
      the barbed end of F-actin, induced swelling in fibronectin-responsive cells and
      prevented fibronectin from inducing pseudopod formation without suppressing the
      [Ca(2+)](i) rise. These results support the hypothesis that fibronectin
      facilitates cell migration via pseudopod formation during gastrulation.

PMID- 10603440
TI  - Decreased exhaled nitric oxide in mild persistent asthma patients treated with a
      leukotriene receptor antagonist, pranlukast.
AB  - Exhaled nitric oxide (NO) level decreases after corticosteroid treatment in
      asthmatics, but the effect of a leukotriene receptor antagonist, pranlukast, on
      exhaled NO has not been elucidated. Pranlukast treatment in mild persistent
      asthmatics for 4 weeks decreased the exhaled NO level, which did not differ from
      the levels in healthy subjects.

PMID- 10603441
TI  - Inhibition of Ca(2+) entry caused by depolarization in acetylcholine-stimulated
      antral mucous cells of guinea pig: G protein regulation of Ca(2+) permeable
      channels.
AB  - The effects of depolarizing conditions resulting from increasing extracellular
      K(+) concentration or nystatin treatment on intracellular Ca(2+) concentration
      ([Ca(2+)](i)) were studied in guinea pig antral mucous cells following
      acetylcholine (ACh) stimulation. ACh stimulation evoked a biphasic increase in
      [Ca(2+)](i), that is, an initial transient increase followed by a plateau.
      Depolarizing conditions reduced the [Ca(2+)](i) in the plateau phase during ACh
      stimulation. However, pertussis toxin (PTX, a G protein inhibitor) treatment
      caused [Ca(2+)](i) in the ACh-evoked plateau phase to increase under depolarizing
      conditions, while it had no effect on [Ca(2+)](i) under hyperpolarized
      conditions. Based on these observations, Ca(2+) permeable channels are regulated
      by a G protein which is activated by depolarized conditions and inhibited by
      hyperpolarized conditions and PTX; activation of the G protein (depolarization)
      causes Ca(2+) permeable channels to inhibit, and in turn, inhibition of the G
      protein (hyperpolarization) causes them to activate.

PMID- 10603442
TI  - The salivary amylase, lactate and electromyographic response to exercise.
AB  - Twelve trained young males (age: 24 +/- 5 years) performed an incremental test to
      exhaustion during which capillary blood and saliva samples were obtained to
      determine the blood lactate (LT) and salivary amylase (T(sa)) thresholds. The
      root mean-square voltage of electromyographic activity (rms-EMG) of the vastus
      lateralis muscle was also recorded to detect the electromyographic threshold
      (EMG(T)). No significant difference was found between the exercise intensity
      corresponding to the LT, T(sa) or EMG(T).

PMID- 10603443
TI  - Extracellular matrix of the human aortic media: an ultrastructural histochemical
      and immunohistochemical study of the adult aortic media.
AB  - Aortic distensability is the key to normal aortic function and relates to the
      lamellar unit in the media. However, the organization of the extracellular matrix
      components in these lamellar units, which are largely responsible for the
      distensability, is insufficiently known, especially in the human. We therefore
      performed a detailed ultrastructural analysis of these components. Thoracic
      aortas of 56 individuals (age 45-74 years), none of whom suffered from aortic
      disease, were studied by immunoelectron microscopy of elastin, collagen types I,
      III, IV, V, and VI, fibronectin, and fibrillin-1, and by ultrastructural
      histochemistry of proteoglycans, which were further characterized by enzymatic
      digestion. The elastic lamellae were closely associated with thick collagen
      fibers containing types I, III, and V collagen. Between these collagen fibers,
      numerous complex, circumferentially oriented streaks of elastin protruded from
      the lamellae. In contrast to what is usually reported in the aortas of
      experimental animals, the smooth muscle cells preferentially adhered to these ill
      defined streaks rather than directly to the solid lamellae. Fibrillin-1- and type
      VI collagen-containing bundles of microfibrils (oxytalan fibers) were also
      involved in the smooth muscle cell-elastin contact. The smooth muscle cells were
      invested by basal lamina-like layers connecting them to each other as well as to
      the oxytalan fibers. Unexpectedly, these layers were abundantly labeled by anti
      fibronectin, whereas type IV collagen, a specific basement membrane component,
      was mainly found in larger, flocculent deposits. The proteoglycans present were
      collagen-associated dermatan sulfate proteoglycan, cell-associated heparan
      sulfate proteoglycan, and interstitial chondroitin sulfate proteoglycan. Our
      observations demonstrate that the extracellular matrix in the human aorta is
      extremely complex and therefore differs from most descriptions based on
      experimental animals. They serve as reference for future studies on aortic
      diseases, such as aneurysmas and dissections.

PMID- 10603444
TI  - Scanning EM of resting gastric parietal cells reveals a network of cytoplasmic
      tubules and cisternae connected to the intracellular canaliculus.
AB  - Using a recently developed fixation technique for parietal cells (Sugai et al.,
      Acta Anat Nippon 1995:70:S79, 1999:74:S101), we have reinvestigated the
      organization of the cytoplasmic membrane system in the resting stomach by ultra
      high-resolution scanning electron microscopy (SEM). Rat gastric mucosae were
      microwave-fixed in cacodylate buffer [334 milliosmoles/kg H(2)O (mOsm)], to which
      1.0% glutaraldehyde and 0.5% formaldehyde were added. Specimens examined by
      transmission electron microscopy (TEM) of thin sections revealed cytoplasm packed
      with tubular membranes similar to images detected by rapid-freeze/freeze
      substitution fixation which is generally considered to cause minimal structural
      alterations. To render the cytoplasmic membranes visible by SEM, fixed mucosae
      were frozen, fractured, and the exposed cytoplasm of parietal cells was macerated
      by the aldehyde-osmium-DMSO-osmium procedure. With much of the cell matrix and
      filaments removed, SEM revealed numerous 30-60 nm tubules which formed a meshwork
      and also small cisternae. The cytoplasmic surface of the tubules was smooth while
      some cisternal areas had attached polyribosomes. Vesicles or isolated tubules
      were not found in appropriately macerated parietal cells. The cytoplasmic surface
      of the intracellular canaliculus was smooth except for round openings
      representing the bases of macerated microvilli. In favorable sites connections of
      the tubular membranes to the canaliculi were clearly visible. Stereo pair views
      were particularly useful to demonstrate these continuities. Connections between
      these two membrane compartments suggest the probability of rapid membrane
      transposition.

PMID- 10603445
TI  - Up-regulation of novel intermediate filament proteins in primary fiber cells: an
      indicator of all vertebrate lens fiber differentiation?
AB  - The early embryonic development and expression patterns of the eye lens specific
      cytoskeletal proteins, CP49 and CP95, were determined for the chick and were
      found to be similar in both human and mouse. These proteins, as well as their
      homologs in other species, are obligate polymerization partners which form unique
      filamentous structures termed "beaded filaments." CP49 and CP95 appeared as
      protein products after 3 days of embryonic development in the chick during the
      elongation of primary fiber cells. Although limited data were obtained for human
      embryos at these early developmental timepoints, they were consistent with the
      interpretation that the up-regulation of these lens specific proteins began only
      after the initiation of lens vesicle closure. In situ hybridization with the
      mouse lens confirmed that message levels for beaded filament proteins were
      greatly elevated in differentiating primary fiber cells. Nuclease protection
      assays established that mRNA levels for CP49 remained relatively constant while
      CP95 mRNA levels increased once the process of secondary fiber formation was
      under way. Although present in relatively low abundance, the mRNA for a unique
      splice variant of CP49, CP49(INS), was also detected early in embryonic
      development and into adulthood. Peptide-specific antibodies directed against
      unique predicted sequences were able to confirm the protein expression of
      CP49(INS) in both embryonic and adult chick lens cells. These data present the
      first detailed study of the expression of CP49 and CP95 during early lens
      development. They suggest that the up-regulated expression of CP49 and CP95 could
      serve as pan-specific markers for all vertebrate lens fiber development.

PMID- 10603446
TI  - Type II pneumocytes are preferentially located along thick elastic fibers forming
      the framework of human alveoli.
AB  - Type II pneumocytes were found to be preferentially located on thick elastic
      fibers which formed the main structural framework of the alveoli in humans. Eight
      lobes resected from eight patients with adenocarcinoma or atypical adenomatous
      hyperplasia and two lobes from two necropsies were examined. Four small specimens
      of normal lung tissue were obtained from each lobe fixed in a buffered formalin.
      Thick sections (200-300 microm) were stained with hematoxylin to contrast nuclei
      or with elastica staining to demonstrate elastic fibers and immunostained with an
      antibody against Thomsen-Friedenreich antigen after pretreatment with sialidase
      to visualize type II pneumocytes. Alveolar structure and the distribution of type
      II pneumocytes were examined in 3D reconstructions generated using a standard
      microscope, a personal computer and NIH-Image software. Nuclei including those of
      type I and type II pneumocytes and endothelial cells were distributed diffusely
      throughout the alveolar wall. Thick elastic fibers constructed the main
      structural framework of the alveoli and formed the sides of the polygonal
      alveoli. Type II pneumocytes were found to be linearly located along these thick
      elastic fibers. This previously undisclosed distribution of type II pneumocytes
      may be concerned with alveolar rapid movement.

PMID- 10603447
TI  - Expression of adhesion molecules relevant to leukocyte migration on the
      microvilli of liver peritoneal mesothelial cells.
AB  - To help assess the immunological functions of the liver peritoneum, expression
      and 3D-microlocalization of adhesion molecules were studied by immuno-SEM and 
      TEM. The peritoneal tissues of the liver obtained from lipopolysaccharide (LPS,
      1.5 microg/g BW for 24 hr)-stimulated (n = 18 including nine controls) and non
      stimulated mice (n = 6 including three controls) were analyzed by immunolabeling
      with 15 nm gold particle single-labeling analysis of ICAM-1, ICAM-2, VCAM-1,
      MAdCAM-1, PECAM-1, ELAM-1, and CD105 expression. In addition, 10 and 20 nm gold
      particle double-labeling analysis of ICAM-1 and VCAM-1 was carried out with
      conventional TEM and BSE (backscatter electron) imaging. Gold particles detected
      in the peritoneal mesothelial cells were quantified using a computer analyzer,
      LUZEX III. Only ICAM-1 in non-stimulated mice and both ICAM-1 and VCAM-1 in LPS
      stimulated mice were expressed on the mesothelium, but no other adhesion
      molecules were detected in either condition. Expression of ICAM-1 was
      consistently about four times greater than that of VCAM-1. Each adhesion molecule
      was restricted to the microvilli. ICAM-1 was expressed on all microvilli and
      tended to form clusters of three or four molecules. On the other hand, about 24%
      of the microvilli expressed VCAM-1 and less clustering was seen. Double-labeling
      techniques disclosed that VCAM-1 and ICAM-1 were rarely closely associated,
      usually spaced by about 40 nm. These results suggest that microvilli of the
      mesothelial cell play a significant role in leukocyte migration in the peritoneal
      cavity, by providing the important substrates for adhesion, ICAM-1 and VCAM-1.

PMID- 10603448
TI  - Intimal thickening involves transdifferentiation of embryonic endothelial cells.
AB  - Morphological studies have hypothesized different origins for the precursors of
      the vascular smooth muscle cells (SMCs). The intriguing possibility that intimal
      SMCs may arise from the endothelium has newly emerged. As a first step towards
      understanding of the possible mechanisms involved in the transdifferentiation of
      endothelium into smooth muscle cells, we characterized the in vivo phenotype of
      the cells located in the aortic wall (distal to the aortic arches). This was
      accomplished using advanced stages of chicken embryo development. Furthermore, we
      investigated whether the cells present at the intimal thickening derive from the
      endothelial cell transdifferentiation. Immunolabeling of serial cryosections
      suggested that mesenchymal cells observed in the intimal thickening may arise
      from the endothelium. These cells may persist either as non-muscle throughout the
      development or possibly convert to cells expressing smooth muscle alpha-actin (SM
      alpha-actin). To determine whether endothelial cells may actually
      transdifferentiate into mesenchymal cells, aortic explants from 14-day-old
      chicken embryos (stage 40) were used. We found that explanted endothelial cells
      lose their cobblestone-appearance and migrate toward cell-free area. Some of
      these cells maintain the vWf immunoreactivity, whereas other cells coordinately
      lose vWf and gain SM alpha-actin expression (transitional cells). Taken together
      these findings strongly support the possibility that embryonic aortic endothelial
      transdifferentiate into mesenchymal cells, some of which express SM alpha-actin.
      Since TGFbeta-3 is considered an essential factor during epithelial to
      mesenchymal transitions in earlier chicken heart development, we also
      investigated the distribution of this growth factor at day 14. Our observations
      indicated that the immunoreactivity for TGFbeta-3 in this stage may be associated
      with migrating mesenchymal cells and that this immunoreactivity appears to
      decrease as cell differentiation advances. Therefore, the present study provides
      evidence that could help to explain 1) the presence of cells displaying a
      phenotype reminiscent of fetal-like cells in the normal chicken aorta and in the
      intimal region of the human aorta; 2) the SM lineage diversity in the chicken
      embryo reported by others; 3) a subpopulation of immature cells in the
      subendothelial region of the main pulmonary arteries of fetal, neonatal and adult
      bovines; and 4) the presence of intimal cushions, intimal pads, eccentric and
      diffuse intimal thickening that are observed in mammalian and avian vessels at
      birth.

PMID- 10603449
TI  - Histomorphometry of dominant and subordinate bovine ovarian follicles.
AB  - The study was designed to quantitatively characterize the histomorphological
      attributes of dominant and subordinate follicles in relation to follicular wave
      dynamics. Heifers (n = 27) were examined daily using ultrasonography to record
      the growth of individual follicles from 2 days before ovulation until the day of
      ovariectomy to obtain growing (n = 7), early static (n = 6), late static (n = 6)
      and regressing (n = 5) phase anovulatory dominant follicles of Wave 1, as well as
      preovulatory (n = 6) and subordinate (n = 42) follicles. The wall thickness of
      Wave 1 dominant follicles decreased dramatically (P < 0.01) during the late
      static (60.2 +/- 4. 3 microm) and regressing (41.8 +/- 4.3 microm) phases
      compared to earlier phases. Cells of the granulosa layer of the dominant follicle
      of Wave 1 became loose during the late-static phase, with an increase (P < 0.001)
      in number of degenerating cells. Dominant follicles of Wave 1 were lined by
      fibroblast-like flattened cells during the regressing phase. One day after wave
      emergence (i.e., before selection), the three largest follicles of the wave were
      histomorphologically indistinguishable. The wall of the preovulatory follicle
      close to the medulla of the ovary was thicker (P < 0.01) than the wall facing the
      ovarian surface. The wall of subordinate follicles was thinner (P < 0.01) and had
      a lower mitotic index (P < 0.01) than that of their dominant counterparts 3 days
      and 6 days after wave emergence. In summary, follicular status, ascribed by
      ultrasonography, was associated with quantitatively distinct histomorphological
      characteristics. Morphometric changes in the dominant follicle during immature,
      mature, and post-mature phases were similar to, but occurred later than, those of
      subordinate follicle. The dominant follicles of Wave 1 entered histological
      atresia at the time of emergence of Wave 2.

PMID- 10603450
TI  - Ultrastructural and three dimensional aspects of the lymphatic vessels of the
      absorbing peripheral lymphatic apparatus in Peyer's patches of the rabbit.
AB  - We studied the absorbing lymphatic peripheral vessels of the Peyer's patches of
      the small and large intestine of the rabbit by means of light microscopy after
      injection of Neoprene latex and transmission electron microscopy in order to
      highlight their topographical distributions to blood vessels as well as the
      morphologic mechanism of transendothelial passage of the lymphocytes to the
      lymph. The distribution of absorbing lymphatic vessels originates from the
      lacteal vessels and the subepithelial mucosal lymphatic network, which continue
      without interruptions and dilations into the vessels of the interfollicular area
      which are woven into basket-like networks entwining the medio-basal portion of
      each lymphoid follicle. The interfollicular area vessels then drain into the
      large vessels of the tunica submucosa, which in turn drain into the valved
      precollector vessels of the subserosa by way of intramuscular vessels. TEM
      revealed the absorbing lymphatic vessels to have a continuous endothelial wall
      without open junctions, fenestrations, and continuous basal lamina. We observed
      many lymphocytes wedged in the lymphatic endothelial wall. This underlines the
      different phases of their migration from the lymphoid tissue in the lumen of the
      lymphatic vessel. Results of ultrathin serial sections and three dimensional
      reconstruction of lymphatic vessel segments with included lymphocyte showed the
      transendothelial passage of lymphocyte, through the "intraendothelial channels."

PMID- 10603451
TI  - Blood cells of sea bass (Dicentrarchus labrax L.). Flow cytometric and
      microscopic studies.
AB  - Studies of fish blood cells made to date presented numerous problems derived from
      both the nomenclature and the techniques used. A combination of quantitative and
      morphological methods is needed if the classification of fish blood cells is to
      advance from it present provisional state. The aim of the present paper was first
      to isolate sea bass blood cell populations by flow cytometry and second to
      characterize then microscopically. Blood cell populations from sea bass
      (Dicentrarchus labrax L.) were isolated according to their FSC (size) and SSC
      (granularity) properties by flow cytometry. The isolated populations were then
      processed for light and transmission and scanning electron microscopic
      characterization. Sea bass blood leukocytes isolated by flow cytometry consisted
      of two main cell subpopulations. Subsequent microscopic study of these cells
      revealed that the first subpopulation was composed of small cells (3-5 microm) of
      low granularity and consisted of thrombocytes and lymphocytes whereas, the second
      subpopulation was formed of 6-9 microm sized cells of high granularity consisting
      of granulocytes and monocyte/macrophages. The combined use of flow cytometry and
      electron microscopy makes it possible to characterize the different cell types
      present in sea bass peripheral blood with a high degree of certainty. Although
      sea bass basically follows the common vertebrate hematological pattern,
      significant modifications such as the presence of circulating immature
      erythrocytes, plasma cells and monocyte/macrophages and different forms of
      thrombocytes can be established with respect to this pattern.

PMID- 10603452
TI  - Ultrastructural characterization of maturation, platelet release, and senescence
      of human cultured megakaryocytes.
AB  - The aim of this study was to evaluate the ultrastructural features of human
      megakaryocytes cultured in vitro. For this purpose, pluripotent CD34(+) (cluster
      of differentiation 34) hematopoietic progenitor cells, obtained from the
      peripheral blood of healthy adult donors, were differentiated along the
      megakaryocytic lineage in liquid cultures by the addition of the megakaryocyte
      specific growth factor thrombopoietin (TPO, 100 ng/ml). After only 6-8 days,
      virtually all of the CD34-derived cells expressed the early megakaryocytic CD61
      antigen, while, after 15-16 days, most cells also expressed the late
      megakaryocytic CD42a antigen. Ultrastructural analysis of cells obtained after 7
      days of culture showed aspects typical of developing megakaryocytes (MK), such as
      formation of platelet territories and cytoplasmic fragmentation. At later (15-16
      day) culture times, two distinct cell populations were observed: fully developed
      megakaryocytes releasing platelets into the culture medium and senescent
      megakaryocytes, characterized by morphological features of apoptosis. Analysis of
      DNA fragmentation in these cells revealed that apoptosis in megakaryocytes
      occurred in the absence of the internucleosomic cleavage, which is characteristic
      of most, but not all, types of apoptosis in cells of hematopoietic origin. On the
      other hand, flow cytometry of the DNA content of senescent megakaryocytes showed
      a subdiploid peak that was likely due to a loss of micronuclei during processing.

PMID- 10603453
TI  - Extracellular matrix environment influences chondrogenic pattern formation in
      limb bud micromass culture: experimental verification of theoretical models.
AB  - Various theoretical models have been proposed to explain the periodicity in the
      pattern of limb chondrogenesis, but experimental comparison of these models have
      seldom been performed properly. In the present study, micromass culture of limb
      bud mesenchyme cells was undertaken to test the validity of three theoretical
      models: the reaction-diffusion model, the cell sorting model, and the
      mechanochemical model. Computer simulations were undertaken to predict the
      factors that can affect the coarseness of the chondrogenic pattern. According to
      the predictions, we performed micromass culture of limb mesenchyme in collagen
      and agarose gel. Then we carried out time-lapse observation to analyze the cell
      movement during pattern formation. From computer simulations it was theoretically
      predicted that changes in the surrounding extracellular matrix should alter the
      periodicity of the chondrogenic pattern in vitro, and we found that pattern
      changes actually occurred under different culture conditions. When compared with
      the culture in a liquid medium, the chondrogenic pattern became less coarse when
      the cells were cultured in collagen or agarose gel, and the pattern change
      appeared to be independent of the cell differentiation. Time-lapse observation
      revealed a decrease in cell motility when the cells were cultured in gel. It was
      found that both the reaction-diffusion and cell sorting models fit the pattern
      change produced and that the mechanochemical model is not primarily important in
      the chondrogenic pattern formation in vitro.

PMID- 10603454
TI  - Uptake of cationized ferritin by the epithelium of the main excretory duct of the
      rat submandibular gland.
AB  - Previous studies demonstrated that the main excretory duct (MED) of the rat
      submandibular gland can internalize exogenous protein in addition to reabsorbing
      and secreting electrolytes. However, more precise studies have not been
      conducted. The aim of this study was to elucidate the cell types responsible for
      endocytosis of an exogenous protein (ferritin) and to follow the movements of the
      endocytosed protein in the ductal epithelial cells. The MEDs of the right
      submandibular gland of male Wistar rats were exposed near the glands proper and
      cationized ferritin solution was injected into each MED through a fine glass
      cannula. The MEDs were removed at intervals after ferritin injection, fixed and
      examined by transmission electron microscopy. The epithelium of the MED of the
      rat submandibular gland was pseudostratified and consisted of light (types I and
      II), dark, tuft and basal cells. Uptake of ferritin by the light (types I and II)
      and dark cells occurred frequently. Small vesicles and multivesicular bodies
      containing ferritin particles were observed in the supra-nuclear and lateral
      nuclear cytoplasm. Endocytosis of tracers by tuft cells was rare. Some of the
      small vesicles and the multivesicular bodies were acid phosphatase-positive. By
      60 min after treatment, ferritin-containing small vesicles and multivesicular
      bodies appeared in the basal cytoplasm. Ferritin particles were also observed in
      basal extracellular spaces. The light (types I and II), dark and tuft cells
      (latter rarely) participated in endocytosis of exogenous proteins in the
      epithelium of the MED of the rat submandibular gland. Almost all of the
      internalized proteins appeared to be processed by the lysosomal system, and some
      proteins were released into the extracellular spaces.

PMID- 10603455
TI  - Toward guidelines for pedigree selection in genetic studies of attention deficit
      hyperactivity disorder.
AB  - Converging evidence from family, twin, and adoption studies points to a
      substantial genetic component of the etiology of attention deficit hyperactivity
      disorder (ADHD). These data about ADHD have motivated molecular genetic studies
      of the disorder, which have produced intriguing but somewhat conflicting results.
      Some studies have reported associations with candidate genes and others not. Our
      review of the literature shows that one problem facing molecular genetic studies
      of ADHD is that its recurrence risk to first-degree relatives is only about five
      times higher than the population prevalence. This suggests that, to produce
      consistently replicated results, molecular genetic studies should either use much
      larger samples or should select those families in which genes exert the largest
      effect. Risch [(1990a) Am J Hum Genet 46:222-228; (1990b) Am J Hum Genet 46:229
      241] proved that the statistical power of a linkage study increases with the
      magnitude of risk ratios (lambda's) computed by dividing the affection rate among
      each relative type to the rate of affection in the population. Our prior work
      suggests two dimensions of genetic heterogeneity that might be useful for
      selecting ADHD subjects for molecular genetic studies: comorbidity with conduct
      disorder and persistence of ADHD into adolescence. This paper shows that these
      sub-phenotypes are useful for molecular genetic studies because (1) they have
      much higher empirical lambda values and (2) they affect a substantial minority of
      ADHD patients.

PMID- 10603456
TI  - Assessing changes in ages at onset over successive generation: an application to
      breast cancer.
AB  - Decreased age at onset in successive generations has been observed for a number
      of diseases. Two nonparametric matched and unmatched test statistics are
      proposed, taking into account not only current age or age at death for unaffected
      individuals and age at disease onset for affected individuals, but also possible
      correlations among family members. Both are asymptotically normal with readily
      estimated variances from the data. A simulation study is conducted to compare the
      proposed tests with the commonly used paired t-test and log-rank test. It has
      been shown that the proposed test statistics yield valid conclusions in assessing
      genetic anticipation under all situations considered. However, the paired t-test
      is valid only when the censoring distributions are comparable between two
      generations, whereas the log-rank test is valid when the correlation among family
      members is weak. As expected, the matched test is most powerful when the data are
      heterogeneous, and the unmatched and the log-rank tests are most powerful when
      the data are homogeneous and the correlation is weak. Lastly, a population-based
      family study of breast cancer conducted at the Fred Hutchinson Cancer Research
      Center is used for illustration of the proposed and the log-rank tests. The
      preliminary analysis suggests that there appears a decreased age at onset over
      the successive generations in breast cancer.

PMID- 10603457
TI  - Complex segregation analysis of families ascertained through Gilles de la
      Tourette syndrome.
AB  - Although family and twin studies suggest that genetic factors are involved in the
      etiology of Tourette syndrome and other related tic disorders, further evidence
      is needed to demonstrate that the familial transmission is consistent with known
      genetic factors. We performed a complex segregation analysis that allowed for a
      variable age of onset of Gilles de la Tourette, other tic disorders and obsessive
      compulsive phenotype information on 108 extended families, each ascertained
      through one Tourette proband by using regressive models that are able to
      incorporate additional explanatory variables and major gene effects. A special
      version of the S.A.G.E. program, REGTLhunt, was used to explore the likelihood
      surface of all examined models. Results indicated that the pattern of Tourette
      and other related tic disorders in our data sample is not consistent with
      Mendelian inheritance even after modelling explanatory variables such as
      obsessive compulsive symptomatology.

PMID- 10603458
TI  - A Monte Carlo procedure for two-stage tests with correlated data.
AB  - One strategy for mapping disease loci using marker-disease associations is to
      test for association with case-control samples and follow up a positive result
      with a family-based test. Using a family-based test in the second stage can help
      provide protection against false-positive results that can result from use of
      inappropriate controls and provides assurance that association identified in the
      first stage is occurring between linked loci. It is crucial for this two-stage
      strategy that the first stage be as powerful as possible to detect association
      since only positive results are tested in the second stage. In certain
      situations, the power of the first-stage test can be increased by combining the
      case-control and family data. However, this introduces correlation between the
      first- and second-stage tests, and treating them as independent tests causes a
      bias. Here we propose a Monte Carlo method that accounts for the correlation and
      provides the correct significance level for the second-stage test. We also
      discuss the use of a two-stage procedure when doing a genome scan for the data
      presented in the Genetic Analysis Workshop 9 study.

PMID- 10603459
TI  - Potential gain in efficiency and power to detect gene-environment interactions by
      matching in case-control studies.
AB  - BACKGROUND: There is growing interest in interactions between genetic and
      environmental risk factors of disease, but adequate power to detect such
      interactions in epidemiologic studies is of concern. The aim of this paper is to
      quantify the effect of matching on the efficiency of estimation and power to
      detect gene-environment interactions in case-control studies. METHODS: Starting
      from an empirical example in cancer epidemiology, we simulated frequency matched
      and unmatched case-control studies for a wide range of assumptions regarding the
      prevalence and the effects of an environmental and a genetic factor on disease
      risk as well as the quality and quantity of the interaction between these
      factors. Simulated studies were analyzed with multivariable logistic regression.
      RESULTS: Matching increased the efficiency and power in most scenarios. The gain
      was most pronounced in scenarios assuming a low prevalence of the environmental
      exposure. In such scenarios, equivalent power was only obtained with more than
      twice as many unmatched than matched controls. CONCLUSIONS: Frequency matching
      for known environmental risk factors with a low prevalence in the population may
      increase the efficiency of estimation and power of case-control studies to detect
      gene-environment interactions considerably. Investigators should weigh the gain
      in efficiency and power against known potential disadvantages of matching.

PMID- 10603460
TI  - Genetic epidemiology of breast cancer: segregation analysis of 389 Icelandic
      pedigrees.
AB  - A genetic epidemiologic investigation of breast cancer involving 389 breast
      cancer pedigrees including information on 14,721 individuals from the Icelandic
      population-based cancer registry is presented. Probands were women born in or
      after 1920 and reported to have breast cancer in the cancer registry. The average
      age of the 389 probands was 45.5 years (SD 8.92). Segregation analyses was
      performed evaluating residual maternal effects, a dichotomous cohort effect, and
      assuming the age at diagnosis followed a logistic distribution after log
      transformation. Familial aggregation could be best explained by the inheritance
      of a high-risk allele leading to early onset breast cancer among the homozygotes,
      which represent approximately 2.6% of the population. A Mendelian codominant
      model was selected as the best fitting model, with an estimated age at diagnosis
      of 51.8 years among these high-risk homozygotes, 64.0 years for heterozygotes and
      76.3 years for the low-risk genotype. The predicted cumulative risk for
      homozygote carriers of the high-risk allele is 32.2% by age 60, compared to 16.4%
      for heterozygotes and 5.0% for non-carriers of the same age. These predicted age
      profiles in the current study complement recent reports from Iceland of a
      majority of BRCA2 mutation carriers being diagnosed with breast cancer below the
      age of 50 years, and 60 years being the mean age at diagnosis for non-carriers.
      This model also predicted a high background risk of breast cancer for women in
      this population (estimated susceptibility gamma = 0.44 +/- 0.08). This implies
      that if carriers and non-carriers did not die of competing causes, the estimated
      risk of being diagnosed with breast cancer by age 80 years irrespective of
      carrier status is 11.4%.

PMID- 10603461
TI  - Pet theories - the misappliance of science.

PMID- 10603462
TI  - FDA approval provides new option against breast cancer.

PMID- 10603463
TI  - FDA approves new immunosuppressants.

PMID- 10603464
TI  - Pegylated liposomal adriamycin: a review of current and future applications.
AB  - Anthracyclines such as adriamycin have a broad spectrum of activity in human
      tumours, but are limited, to an extent, by their non-selective delivery to a host
      of normal tissues and hence, subsequent toxicity. The development of liposomes
      has offered a drug delivery system with significant potential to target tumours
      whilst sparing normal tissues. A significant breakthrough has been achieved by
      coating the liposome with polyethylene glycol (pegylation), and thus altering the
      pharmacokinetics of the drug considerably. In this review, the authors discuss
      the promising data now emerging with pegylated liposomal adriamycin, and also
      describe possible future applications.

PMID- 10603465
TI  - Aging processes in pharmaceutical polymers.
AB  - In the practical field of solid pharmaceutical formulations, studies of the
      physical aging of polymers and the stability of dosage forms are of great
      importance. Polymers are the additives used to convert pharmacologically active
      compounds into pharmaceutical dosage forms suitable for administration to
      patients, and thus a knowledge of the physical aging effects on the stability of
      final products is essential. In this review, the author attempts to elucidate the
      fundamental concepts of physical aging in polymers, and correlate the effects of
      physical aging on the properties with changes in solid dosage form stability.

PMID- 10603466
TI  - Synthesis and applications of novel, highly efficient HPLC chiral stationary
      phases: a chiral dimension in drug research analysis.
AB  - This review provides an overview of the synthesis and application of stable and
      versatile HPLC chiral stationary phases (CSPs), with emphasis placed on the
      binding strategies developed to anchor several structurally different chiral
      selectors to silica-gel microparticles. In addition, selected applications
      relating to the use of these CSPs for the direct resolution of racemates of
      biological and pharmaceutical relevance will be described. This review discusses
      enantioselective molecular recognition and dynamic stereochemistry of
      stereolabile compounds with reference to receptor-based chiral stationary phases
      (CSPs) and dynamic HPLC on CSPs, respectively.

PMID- 10603467
TI  - Monitor: progress and profiles.
AB  - Monitor provides an insight into the latest developments in pharmaceutical
      science and technology through brief synopses of recent presentations,
      publications and patents, and expert commentaries on the latest technologies.
      There are two sections: Progress summarizes the latest developments in
      pharmaceutical process technology, formulation, analytical technology,
      sterilization, controlled drug delivery systems and regulatory issues; Profiles
      offers expert commentary on emerging technologies, novel processes and strategic,
      organizational and logistic issues underlying pharmaceutical R&D.

PMID- 10603468
TI  - Neuro-fuzzy logic in tablet film coating formulation.

PMID- 10603469
TI  - Spindles get the ran around.
AB  - Despite its fundamental role in cell division, the mitotic spindle remains an
      enigmatic figure in cell biology. This is due to the complex dynamic behaviour of
      microtubules, which form the spindle fibres responsible for segregating
      chromosomes to opposite ends of the cell during mitosis. Recent reports indicate
      that the small GTPase Ran, which plays a key role in nuclear transport, also has
      a role in mitosis by regulating microtubule nucleation and/or growth. The race is
      now on to determine how Ran exerts its effects on spindle assembly.

PMID- 10603470
TI  - Sorting nuclear membrane proteins at mitosis.
AB  - The nuclear envelope (NE) breaks down reversibly and reassembles at mitosis. Two
      models of mitotic nuclear membrane disassembly and reformation have emerged from
      studies of NE dynamics in somatic cells and egg extracts. One model suggests that
      nuclear membranes fragment reversibly by vesiculation, producing NE-derived
      vesicles separate from the endoplasmic reticulum. The second model proposes that
      nuclear membranes vanish by diffusion of their integral proteins through a
      continuous endoplasmic reticulum. Here, we discuss critically the grounds for the
      elaboration of these apparently mutually exclusive views. Our conclusions favour
      a model in which nuclear membranes do not vesiculate during mitosis.

PMID- 10603471
TI  - Wnt signalling in Caenorhabditis elegans: regulating repressors and polarizing
      the cytoskeleton.
AB  - Wnt proteins are secreted, cysteine-rich glycoprotein ligands with numerous roles
      during animal development. Recent studies of endoderm induction during
      embryogenesis in the nematode Caenorhabditis elegans challenge the prevailing
      view that Wnt signalling specifies cell fate by converting transcriptional
      repressors into activators. Instead, a mitogen-activated protein kinase (MAPK)
      related pathway converges with Wnt signalling in C. elegans to relieve
      transcriptional repression. Furthermore, Wnt signalling induces endoderm in part
      by aligning the mitotic spindle in a responding cell along the anterior-posterior
      body axis. To orient mitotic spindles, Wnt signalling might directly target the
      cytoskeleton, prior to any regulation of gene transcription in responding cells.

PMID- 10603472
TI  - The kelch repeat superfamily of proteins: propellers of cell function.
AB  - The kelch motif was discovered as a sixfold tandem element in the sequence of the
      Drosophila kelch ORF1 protein. The repeated kelch motifs predict a conserved
      tertiary structure, a beta-propeller. This module appears in many different
      polypeptide contexts and contains multiple potential protein-protein contact
      sites. Members of this growing superfamily are present throughout the cell and
      extracellularly and have diverse activities. In this review, we discuss current
      information concerning the structural organization of kelch repeat proteins,
      their biological roles and the molecular basis of their action.

PMID- 10603473
TI  - Protein translocation into mitochondria: the role of TIM complexes.
AB  - Import of nuclear-encoded mitochondrial preproteins is mediated by a general
      translocase in the outer membrane, the TOM complex, and by two distinct
      translocases in the mitochondrial inner membrane, the TIM23 complex and the TIM22
      complex. Both TIM complexes cooperate with the TOM complex but facilitate import
      of different classes of precursor proteins. Precursors with an N-terminal
      presequence are imported via the TIM23 complex, whereas mitochondrial carrier
      proteins require the TIM22 complex for insertion into the inner membrane. This
      review discusses recent advances in understanding the structure and function of
      the translocases of the inner membrane and the possible role of Tim proteins in
      the development of the Mohr-Tranebjaerg syndrome, a mitochondrial disorder
      leading to neurodegeneration.

PMID- 10603474
TI  - No longer an exclusive club: eukaryotic signalling domains in bacteria.
AB  - Reversible phosphorylation of serine, threonine and tyrosine residues by the
      interplay of protein kinases and phosphatases plays a key role in regulating many
      different cellular processes in eukaryotic organisms. A diversity of control
      mechanisms exists to influence the activity of these enzymes and choreograph the
      correct concert of protein modifications to achieve distinct biological
      responses. Such enzymes and their adaptor molecules were long thought to be
      specific to eukaryotic cellular processes. However, there is increasing evidence
      that many prokaryotes achieve regulation of key components of cellular function
      through similar mechanisms.

PMID- 10603475
TI  - Understanding transmission of the prion diseases.

PMID- 10603476
TI  - Pathogenic interference with host vacuolar trafficking.

PMID- 10603477
TI  - A drug resistance determinant in Trypanosoma brucei.

PMID- 10603478
TI  - Applying antisense technology to the study of Entamoeba histolytica pathogenesis.

PMID- 10603479
TI  - Applying antisense technology to the study of entamoeba histolytica pathogenesis:
      response

PMID- 10603480
TI  - Towards controlling mycobacterial infections.

PMID- 10603482
TI  - Response from murray

PMID- 10603481
TI  - Why is IFN-gamma insufficient to control tuberculosis?

PMID- 10603483
TI  - Multilocus sequence typing.
AB  - Multilocus sequence typing (MLST) provides a new approach to molecular
      epidemiology that can identify and track the global spread of virulent or
      antibiotic-resistant isolates of bacterial pathogens using the Internet. MLST
      databases, together with interrogation software, are available for Neisseria
      meningitidis and Streptococcus pneumoniae and databases for Streptococcus
      pyogenes and Staphylococcus aureus will be released shortly.

PMID- 10603484
TI  - Mutation as an origin of genetic variability in Helicobacter pylori.
AB  - The availability of two complete Helicobacter pylori genome sequences and recent
      studies of its population genetics have provided a detailed picture of genetic
      diversity in this important human gastric pathogen. It is believed that, in
      addition to genetic recombination, de novo mutation could have a role in
      generating the high level of genetic variation in H. pylori.

PMID- 10603485
TI  - Interactions between mycoplasma lipoproteins and the host immune system.
AB  - Mycoplasmas typically have a number of distinct lipoproteins anchored on the
      outer face of the plasma membrane. These surface antigens have a potent modulin
      activity and are preferential targets of the host immune response. However, the
      variation of some of these lipoproteins provides mycoplasmas with an effective
      means of evading the host immune defence system.

PMID- 10603486
TI  - Pipes and wiring: the regulation of copper uptake and distribution in yeast.
AB  - Copper is required for processes as conserved as respiration and as specialized
      as protein modification. Recent exciting findings from studies in yeast cells
      have revealed the presence of specific pathways for copper transport, trafficking
      and signal transduction that maintain the delicate balance of this essential yet
      toxic metal ion.

PMID- 10603487
TI  - Life on the edg.

PMID- 10603488
TI  - TinyGRAP database: a bioinformatics tool to mine G-protein-coupled receptor
      mutant data.

PMID- 10603489
TI  - Kinetics versus equilibrium: the importance of GTP in GPCR activation.
AB  - Agonist-bound G-protein-coupled receptors (GPCRs) facilitate GDP-GTP exchange on
      their cognate G proteins. The binding properties of GPCRs are adequately
      described by the ternary complex model. However, in this article a more realistic
      (steady-state) model, which is necessary to describe the catalytic effect of
      agonist-bound receptors on G-protein activation, will be discussed. This model
      predicts that agonist potency and efficacy might vary from tissue to tissue,
      depending on the G-protein concentration and can be extended to explain why an
      agonist's ability to increase the receptor's affinity for empty G proteins (in
      the absence of GTP) is related to the agonist's efficacy.

PMID- 10603490
TI  - Traditional African medicine: theory and pharmacology explored.
AB  - Traditional African medicine (TAM) is a shorthand reference to indigenous forms
      of healing that are practiced all over Africa. Although TAM is based on the
      accumulated experience of ancient Africans, its mode of transmission by word-of
      mouth has hindered emergence of a generally accepted theory and hence of the
      systematic development of TAM as a self-regulating profession. A major
      therapeutic objective in the treatment of illness in TAM is diffusion of
      emotional stress. This article summarizes the argument for such a therapy, and
      suggests that TAM is a distinct system of health care and not a rudimentary form
      of modern Western medicine.

PMID- 10603491
TI  - Pulmonary hypertension, anorexigens and 5-HT: pharmacological synergism in
      action?
AB  - In pulmonary hypertension (PHT), pulmonary vascular resistance is elevated as a
      result of increased pulmonary vascular tone and pulmonary vascular remodelling.
      Certain diet pills, such as the fenfluramines, have been associated with the
      development of PHT. This class of drugs act as indirect 5-HT receptor agonists
      and can inhibit 5-HT reuptake and cause the release of 5-HT from platelets. Many
      pulmonary vasoconstrictors, including 5-HT, activate both Gi- and Gq-linked
      receptors. Increasing evidence suggests that Gq activation might amplify Gi
      linked intracellular pathways to 'uncover' or potentiate vasoconstrictor
      responses - a phenomenon known as pharmacological synergism, which occurs in the
      pulmonary circulation. In this review the evidence that 5-HT plays a role in PHT
      and that pharmacological synergism might contribute to its pathology is
      discussed.

PMID- 10603492
TI  - General anaesthetic action at transmitter-gated inhibitory amino acid receptors.
AB  - Research within the past decade has provided compelling evidence that
      anaesthetics can act directly as allosteric modulators of transmitter-gated ion
      channels. Recent comparative studies of the effects of general anaesthetics
      across a structurally homologous family of inhibitory amino acid receptors that
      includes mammalian GABAA, glycine and Drosophila RDL GABA receptors have provided
      new insights into the structural basis of anaesthetic action at transmitter-gated
      channels. In this article, the differential effects of general anaesthetics
      across inhibitory amino acid receptors and the potential relevance of such
      actions to general anaesthesia will be discussed.

PMID- 10603493
TI  - Pharmacological manipulation of granulocyte apoptosis: potential therapeutic
      targets.
AB  - Resolution of inflammation involves the clearance of excess or effete
      inflammatory cells by a process of physiological programmed cell death
      (apoptosis) and the subsequent recognition and removal of apoptotic cells by
      phagocytes. The therapeutic induction of apoptosis for the resolution of chronic
      inflammation and the general pharmacology of apoptosis have become subjects of
      increasing interest. In this article, some of the unique and important
      differences in the control of apoptosis of various inflammatory cells
      (particularly neutrophil and eosinophil granulocytes) are highlighted. It is
      suggested that apoptosis can be specifically regulated pharmacologically and
      could be exploited to develop new drug therapies.

PMID- 10603494
TI  - New insights on how temporal variation in predation risk shapes prey behavior.

PMID- 10603495
TI  - Evolving dispersal: where to go next?

PMID- 10603496
TI  - Adaptive cycles: parasites selectively reduce inbreeding in Soay sheep.

PMID- 10603497
TI  - How severe is sperm limitation in natural populations of marine free-spawners?
AB  - Successful fertilization in marine organisms that release sperm into seawater is
      potentially limited by the rapid dilution of gametes; cases of severe sperm
      limitation have been demonstrated in nature. However, recent surveys of naturally
      spawning populations indicate fairly high fertilization levels in many taxa. The
      extreme selection exerted by sperm limitation has resulted in numerous
      adaptations to reduce sperm limitation and enhance fertilization. Thus, most taxa
      show indications of the evolutionary consequences of sperm limitation even when
      population level, ecological effects are minimal.

PMID- 10603499
TI  - Erratum.

PMID- 10603498
TI  - Genetically modified plants - the debate continues.
AB  - The debate about the potential risks and benefits of genetically modified
      organisms (GMOs) has hit the headlines over the past few months. The polarization
      of much of the debate obscures what really constitutes ecological risk, and what
      methods we can apply to identify and quantify those risks. Ecological science has
      much to offer in this respect, including ecological theory, manipulative
      experiments, the application of molecular tools and the interpretation of
      observational data from conventional agriculture. In the current heated debate,
      it is perhaps belief in the scientific method, above all else, that needs to be
      promoted and discussed.

PMID- 10603500
TI  - Allochthonous inputs: integrating population changes and food-web dynamics.
AB  - Most ecosystems are recipients of allochthonous materials that enhance in situ
      productivity. Recent theoretical and empirical studies suggest that low to
      moderate inputs can stabilize food webs. However, depending on the trophic levels
      that use the resource, food webs can become unstable as inputs increase. Where
      large amounts of agricultural resources are transferred to natural habitats,
      trophic dynamics change: trophic cascades can occur and rare or uncommon species
      can become invasive. Rates of change in species abundances can also be amplified
      by the effects of changes in legislation and management practices on subsidized
      consumers.

PMID- 10603502
TI  - Brood parasitism: ducks can be cuckoos too.

PMID- 10603501
TI  - Cognitive ecology: a field of substance?
AB  - In 1993, Les Real invented the label 'cognitive ecology'. This label was intended
      for work that brought cognitive science and behavioural ecology together. Real's
      article stressed the importance of such an approach to the understanding of
      behaviour. At the end of a decade in which more interdisciplinary work on
      behaviour has been seen than for many years, it is time to assess whether
      cognitive ecology is a label describing an active field.

PMID- 10603503
TI  - Reply from R. Winfree.

PMID- 10603504
TI  - Towards a new evolutionary synthesis.
AB  - New concepts and information from molecular developmental biology, systematics,
      geology and the fossil record of all groups of organisms, need to be integrated
      into an expanded evolutionary synthesis. These fields of study show that large
      scale evolutionary phenomena cannot be understood solely on the basis of
      extrapolation from processes observed at the level of modern populations and
      species. Patterns and rates of evolution are much more varied than had been
      conceived by Darwin or the evolutionary synthesis, and physical factors of the
      earth's history have had a significant, but extremely varied, impact on the
      evolution of life.

PMID- 10603505
TI  - Laboratory selection experiments using Drosophila: what do they really tell us?
AB  - Laboratory selection experiments using Drosophila, and other organisms, are
      widely used in experimental biology. In particular, such experiments on D.
      melanogaster life history and stress-related traits have been instrumental in
      developing the emerging field of experimental evolution. However, similar
      selection experiments often produce inconsistent correlated responses to
      selection. Unfortunately, selection experiments are vulnerable to artifacts that
      are difficult to control. In spite of these problems, selection experiments are a
      valuable research tool and can contribute to our understanding of evolution in
      natural populations.

PMID- 10603506
TI  - Hirudin: Its Biology and Clinical Use.
AB  - Over a century has passed since the anticoagulant properties of hirudin were
      identified. Our understanding of this unique and promising 65 amino acid
      polypeptide has grown steadily, allowing clinical experience to be gained. In
      acute myocardial infarction, hirudin has been associated with a higher incidence
      of early and sustained TIMI grade 3 flow, a higher rate of infarct-related artery
      patency at 18-36 hours with a decreased rate of reocclusion, and a lower
      incidence of in-hospital death and reinfarction as compared with heparin. hirudin
      has also been associated with a stable level of articoagulation and an acceptable
      hemorrhagic complication rate when given in carefully chosen doses. In acute
      coronary syndromes, the initial results indicate that hirudin can improve the
      resolution of coronary thrombus and reduce the incidence of recurrent ischemic
      events. Similarly impressive reductions in thrombotic complications and ischemia
      have been observed in the early balloon angioplasty experience. Promising results
      have also been seen with hirudin in preventing deep venous thrombosis following
      orthopedic surgery. The favorable effects of hirudin as compared with heparin in
      phase II clinical trials have prompted further investigation in two large phase
      III trials, TIMI 9 and GUSTO 2. It is hoped that these initial results can be
      confirmed and that hirudin can be proved to be a safe and effective treatment for
      thrombotic syndromes of the venous and arterial circulatory systems.

PMID- 10603507
TI  - Bleeding Complications to Long-Term Oral Anticoagulant Therapy.
AB  - Objective: To evaluate the incidence of bleeding complications in recent
      randomized trials on oral anticoagetlant treatment for prevention of arterial
      thromboembolism. Data sources: International publications on studies of
      prevention. of arterial thromboembolism by oral anticoagulant therapy. Study
      selection and data extraction: Randomized trials an oral anticoagulant therapy in
      patients with atrial fibrillation, recent myocardial infarction, and prosthetic
      heart valves were selected. For comparison older nonrandomized studies were
      studied. Background: Oral anticoagulant drugs are recommended for primary
      prevention of thromboembolic events in patients with chronic atrial fibrillation,
      recent myocardial infarction, and prosthetic heart valves. Still many physicians
      hesitate to prescribe anticoagulant drugs, presumably for fear of bleeding
      complications. Results: In six recent trials of warfarin in patients with atrial
      fibrillation, the highest annual incidence of fatal and major bleeding was 0.8%
      and 2.0%, respectively. In patients treated with warfarin after a recent
      myocardial infarction, the incidence of fatal and major bleeding was 0.2% and
      0.5% per year, respectively. The annual incidence of fatal and major bleeding in
      patients with prosthetic heart valves on warfarin treatment was found to be 1.4%
      and 5.2%, respectively. The mean incidence of fatal and major bleeding in
      patients on warfarin in these eight trials was 0.5% and 1.7% per year,
      respectively. The mean incidence of fatal and major bleeds in patients on placebo
      was 0.1% and 0.7% per year, respectively. In three randomized trials evaluating
      aspirin versus warfarin, the respective mean incidences of fatal and major
      bleeding during aspirin treatment were 0.2% and 0.8% per year. A remarkable
      decrease in the incidence of major bleeding complications to oral anticoagulant
      therapy is revealed by these trials as compared to previous studies. Reasons for
      this decline may be less intensive anticoagulant regimes, better control of
      anticoagulant therapy due to the introduction of the international normalized
      ratio, and careful pretreatment evaluation of risk factors for bleeding. In alI
      prospective trials of oral anticoagulation, the risk of bleeding was more than
      over-weighed by the beneficial effect on the incidence of stroke and peripheral
      thromboemboli.

PMID- 10603508
TI  - Time as an Adjunctive Agent to Thrombolytic Therapy.
AB  - Thrombolytic therapy has dramatically reduced mortality following acute
      myocardial infarction (MI) with the major effect coming from early achievement of
      infarct-related artery patency. A major factor in achieving rapid reperfusion is
      early treatment with thrombolytic therapy. Recent trials have shown that
      mortality can be reduced if time to treatment is shortened: In the Thrombolysis
      in Myocardial Infarction (TIMI) 2 trial, for each hour earlier that thrombolytic
      therapy was started, approximately 10 lives were saved per 1000 patients treated.
      Thus, one must consider time as an adjunctive agent to thrombolytic therapy.
      There are four components of the time delay between the onset of MI and
      achievement of reperfusion: (1) patient delays in seeking medical attention; (2)
      transport delays; (3) the so-called door to needle time, the interval between the
      patient's arrival at the medical facility and the initiation of thrombolytic
      therapy; and (4) thrombolytic reperfusion time, the time between the
      administration of thrombolytic therapy and the achievement of roperfusion,
      Efforts to reduce each of these components will lead to additive benefits in
      improving time to reperfusion and survival of patients with acute MI.

PMID- 10603509
TI  - Plasma Concentration of Endogenous Tissue Plasminogen Activator and the
      Occurrence of Future Cardiovascular Events.
AB  - Data from recent prospective studies of hemostasis and thrombosis indicate that
      the plasma concentration of endogenous tissue-type plasminogen activator (tPA) is
      often elevated years in advance of a first arterial occlusion. Specifically,
      among healthy subjects with no prior cardiovasacular disease, the risk of future
      myocardial infarction and stroke appears to be three to four times higher among
      subjects with high baseline levels of tPA antigen as compared to subjects with
      lower levels. Whether this relationship represents activation of the endogenous
      fibrinolytic system in response to the presence of preclinical atherosclerosis or
      is a reflection of elevated concentrations of local plasminogen activator
      inhibitors is currently unresolved. However, cross-sectional data indicate that
      the plasma concentration of IPA antigen is related to several traditional
      atherosclerotic risk factors, including HDL cholesterol, findings that further
      support a direct relationship between endogenous IPA and vascular risk. In
      concert with data concerning the primary inhibitors of plasminogen activation, it
      has been hypothesizd that the endogenous fibrinolytic system varies within the
      general population such that certain individuals are prone to thrombosis, whereas
      others may be prone to hemorrhage. Thus, observations regarding fibrinolytic
      activation and inhibition raise the possibility that assessment of the intrinsic
      fibrinolytic system may prove useful in identifying individuals at increased risk
      for vascular thrombosis. In addition, available findings suggest that therapeutic
      agents capable of favorably shifting the net filerinolytic balance may provide a
      new strategy for cardiovascular disease prevention.

PMID- 10603510
TI  - The Emergence of Thrombocardiology.

PMID- 10603511
TI  - Discrepant In Vivo Recovery of Factor VIII:C Following Infusion of Two Different
      Monoclonal Factor VIII Preparations.
AB  - Background: We experienced decreased recovery of factor VIII:C after commercial
      monoclonal factor VIII infusions. We report the recovery data obtained from
      infusing two brands of monoclonal factor VIII. Methods: Factor VIII:C activity
      was measured before and after an infusion of one of two monoclonal factor VIII
      preparations. The increments were calculated and expressed as a function of units
      of factor VIII administered per kilogram. Results: Monoclate increments averaged
      2.3% (range: 1.6-3.2%). Antihemophilic factor (human) method M (AHFM) yielded an
      average increment of 1.4% (range: 1-1.7%). Conclusions: The two monoclonal factor
      VIII preparations used are not equivalent in activity. In switching brands, one
      must recalculate the prescribed dose based on the institution's experience in
      recovery of VIII:C from the particular brand to be prescribed. Cost calculations
      and comparisons should be based on the recovered factor VIII:C increments rather
      the unit purchase price.

PMID- 10603512
TI  - Heparin Binding Sites Are Located in a 40-kD gamma-Chain and a 36-kD beta-Chain
      Fragment Isolated from Human Fibrinogen.
AB  - Objective: We have previously shown that (125)I-fibrinogen binds to heparin
      sepharose CL-6B. To identify the localization of the heparin binding domain in
      human fibrinogen, reduced and alkylated fibrinogen was digested by limited
      Staphylococcus aureus V8 protease. Methods/Results: Two fragments have now been
      isolated and purified to apparent homogeneity by heparin-affinity chromatography.
      These fragments, denoted the 40-kD and 36-kD fragments, contain NH(2)-terminal
      sequences of Ala-Ser-Ile-Leu-Thr-Hb;-Asp and Thr-Val-Asn-Ser-Asn-Ile-Pro,
      respectively. These fragments established the positions of these peptides within
      the gamma chain of fibrinogen as beginning with the residue tentatively
      designated 124 and within the beta chain as beginning with the residue designated
      186. Binding of (125)I-fibrinogen to heparin-sepharose CL-6B was completely
      inhibited by a mixture of these fragments, with an IC(50) of 3.2 uM. The
      synthetic peptide of the gamma chain carboxy-terminal 15 residues
      (GQQHHLGGAKQAGDV;G15) partially inhibited fibrinogen binding. The mixture of
      these fragments partially inhibited the ADP-induced aggregation of platelets.
      Conclusions: These data indicate that the domains for heparin binding may be
      present on both the gamma chain and the beta chain of fibrinogen, and that the
      domain on the gamma chain may be close to the binding domain on the carboxy
      terminus of the fibrinogen gamma chain to glycoprotein IIb-IIIa.

PMID- 10603513
TI  - Effects of Late Coronary Artery Reperfusion on Left Ventricular Remodeling
      Persist for 10 Weeks After Experimental Rat Myocardial Infarction and Are
      Associated with Improved Survival.
AB  - Objective: To test the hypothesis that coronary artery reperfusion performed too
      late to reduce infarct size improves survival by altering left ventricular
      remodeling and preventing progressive left ventricular dilation. Background:
      Several clinical trials have suggested that late coronary artery reperfusion
      without infaret size reduction is associated with a survival benefit. Although
      the mechanism is not known, survival benefits could be related to decreased
      infarct expansion associated with late coronary artery reperfusion. Decreased
      infarct expansion results in decreased left ventricular volume, and the resulting
      decreased wall stress could prevent or attenuate progressive left ventricular
      dilation and improve survival. Methods: Rats (n = 84) were randomized to undergo
      sham operation, permanent left coronary artery ligation, or 2 hours of left
      coronary artery ligation followed by reperfusion. Ten weeks later, hemodynandic
      measurements were made before and after volume loading. The rats were killed, the
      hearts were removed, and passive pressure-volume curves were obtained. The hearts
      were fixed at a constant pressure and analyzed morphometrically. Results: When
      examined 10 weeks after experimental myocardial infarction late eperfusion's
      effects on left ventricular remodeling resulted in reduced left ventricular
      volume when compared to hearts with infarcts supplied by a permanently occluded
      coronary artery (1.9 +/- 0.1 ml/kg vs. 2.1 +/- 0.2 ml/kg; p < 0.01). Although
      there was a trend toward less thinning along (0.95 +/- 0.13 mm vs. 1.00 +/- 0.10
      mm; p = NS) and less expansion (2.3 +/- 0.4 vs. 2.8 +/- 0.9; p = NS) in
      reperfused hearts compared to hearts with a permanently occluded coronary artery,
      changes in infarct shape 10 weeks after infarction were not significantly
      different. Reperfusion's beneficial effects on remodeling of noninfarcted
      myocardiurn were associated with improved survival. Mortality was higher in the
      permanently occluded rats than in the reperfused rats (35% vs. 12%; p < 0.05).
      Conclusion: Late coronary artery reperfusion has a beneficial effect on
      remodeling of noninfarcted myocardum that results in reduced left ventricular
      volume in rat hearts examined 10 weeks after infarction. These beneficial effects
      on left ventricular remodeling are associated with improved survival.

PMID- 10603514
TI  - Pathology of Unstable Angina: Analysis of Biopsies Obtained by Directional
      Coronary Atherectomy.
AB  - Background: The transient and generally nonfatal nature of unstable angina has
      impaired the accumulation of pathologic data and the definition of the
      pathoanatomy of this syndrome. Methods: Atherectomy specimens from patients
      enrolled in CAVEAT were examined for the presence of thrombus, foam cells,
      cholesterol clefts, media, and adventitia. Comparison of the pathologic findings
      was made according to clinical presentation in the following categories: stable
      angina, unstable angina, and recent myocardial infarction. Results: Patients with
      unstable angina had. a slightly higher incidence of thrombus when compared with
      patients presenting with stable angina (36% vs. 26%, p =.14). Within the unstable
      angina population some subgroups demonstrated a greater incidence of thrombus,
      including those whose pain was associated with ECG changes (43%, p =.07). The
      incidence of thrombus was highest among patients who had a myocardial infarction
      within 30 days (53%, p =.004) or within 14 days (58%, p =.003). No difference
      between the patient groups was detected with respect to the other histologic
      findings. Conclusions: Atherectomy specimens from patients with unstable angina
      demonstrated a trend toward increasing incidence of thrombus, but this trend did
      not achieve statistical significance. Specimens from patients with a recent
      myocardial infarction did not demonstrate a significant increase in the presence
      of thrombus. While thrombus is a component of the pathophysiology of unstable
      angina in a significant number of patients, continued study is required to
      determine the other factors that are responsible.

PMID- 10603515
TI  - Percutaneous Transluminal Coronary Angioplasty for Unstable Angina: Predictors of
      Outcome in a Multicenter Study.
AB  - Background: Angiographic and clinical studies have demonstrated that coronary
      artery plaque rupture with thrombus formation, spasm, or both are frequently
      responsible for the syndrome of unstable angina. Percutaneous transluminal
      coronary angioplasty (PTCA) is commonly used in the treatment of patients with
      coronary artery disease and unstable angina. A number of studies have shown,
      however, that intracoronary thrombus increases the risk of abrupt vessel closure.
      The purpose of this study was to define preprocedural variables predictive of the
      outcome of PTCA performed on patients with unstable angina in a prospective
      multicenter study using a core angiographic laboratory. Methods and Results: A
      total of 386 patients with unstable angina underwent coronary angioplasty of 487
      lesions treated with balloon PTCA at 9 medical centers. Multivessel or left main
      coronary artery diseasewas present in 55% and recent myocardial infarction in
      22%. Clinical success was achieved in 317 of 386 patients (82.1%), as defined by
      <50% residual stenosis at every target lesion evaluated in the core angiographic
      laboratory and no major complication during hospitalization. Major complications
      (death, Q-wave or non-Q-wave myocardial infarction, or emergency coronary artery
      bypass surgery) occurred in 36 patients (9.3%), and abrupt vessel closure
      occurred in 50 (13.0%). Logistic regression analysis identified preprocedural
      variables that were predictive of outcome of angioplasty. Strong predictors of
      any complication (major complication or abrupt vessel closure) included age [odds
      ratio (OR) = 1.04; 95% confidence interval [CII 1.02. 1.071) for each additional
      year of age; p < 0.001), number of diseased vessels (OR = 1.58; 95% Cl = 1.16,
      2.15 per additional vessel; is = 0.012), the number of le~ions treated at
      angioplasty (OR) = 1.04%; 95% confidence interval [CI] 1.02, 1.07]) for each
      additional year of age; p < 0.001), number of diseased vessels (OR = 1.58%; 95%
      CI = 1.16, 2.15 per additional vessel; p = 0.012), the number of lesions treated
      at angioplasty (OR = 1.72%; 95% CI = 1.11, 2.66;; p = 0.014), and angiographic
      evidence of filling defect preceding angioplasty (OR = 3.30; 95% CI = 1.11, 9.75;
      p < 0.001). Conclusions: The outcome of PTCA performed for unstable angina is
      influenced by a combination of clinical, angiographic, and procedural variables.
      This study suggests that PTCA performed on lesions associated with filling
      defects or on more than one lesion at the time of the procedure carries an
      increased risk of complication. The outcome of PTCA for unstable angina may be
      improved by identifying new strategies for the treatment of lesions associated
      with filling defects and by using more accurate methods to identify and treat the
      culprit lesion responsible for unstable angina.

PMID- 10603516
TI  - Association Between Serial Measures of Systemic Blood Pressure and Early Coronary
      Arterial Perfusion Status Following Intravenous Thrombolytic Therapy.
AB  - Background: Systemic hypotension, at times transient while in other instances
      more prolonged, is common among patients with myocardial infarction (MI). It also
      is a characteristic feature for patients experiencing either advanced congestive
      heart failure or cardiogenic shock. In this group of patients, thrombolytic
      therapy has failed to exert. favorable impact on their high in-hospital
      mortality. Although it has been postulated that the success of thrombolytic
      therapy is directly linked to systemic blood pressure' there is little
      information available in human subjects. Methods and Results: In a University of
      Massachusetts Thrombolysis Data Bank Study, 127 patients with MI who were given
      intravenous thrombolytic therapy (tPA or streptokinase) within 6 hours from
      symptom onset (4.2 +/- 1.5 hours) had serial systemic blood pressure measurements
      (at the time of hospital arrival, treatment initiation, and every 30 minutes
      during the thrombolytic infusion) and underwent coronary angiography within 120
      minutes of treatment initiation. All patients received intravenous heparin and
      oral aspirin. By univariate analysis, disastolic blood pressure below 80 mmHg at
      the time of treatment initiation was associated with a reduced angiographic
      coronary perfusion grade [Thrombolysis in Myocardial Infarction (TIMI) flow
      grade; p + 0.02]. A correlation analysis of tPA-treated patients indicated that a
      greater maximum change in diastolic blood pressure during treatment correlated
      inversely with coronary perfusion (r +.24, p < 0.05). By multivariate regression
      analysis, however, only shorter time to treatment (p + 0.001) and thrombolysis
      with tPA (p + 0.02) were independent predictors of coronary arterial perfusion
      grade. Conclusion: Systemic blood pressure (and presumably proximal coronary
      arterial perfusion pressure) in the ranges investigated in this study is not an
      independent predictor of coronary reperfusion following intravenous thrombolytic
      therapy with either tPA or streptokinase. It seems likely, therefore, that
      properties intrinsic to the ruptured plaque and occlusive thrombus, and
      potentially the local metabolic environment, either alone or acting
      synergistically with perfusion pressure, are determinants of thrombolytic
      success. Further investigation of factors influencing the efficacy of
      thrombolysis should be undertaken.

PMID- 10603517
TI  - Characteristics of Myocardial Infarction Episodes in Two Distant Communities:
      From the REGICOR Registry in Girona, Spain and the MITI Registry in Greater
      Seattle, USA.
AB  - Background: The objective of the study is to compare patient characteristics and
      outcome after myocardial infarction (MI) between two geographically and socially
      different communities. Methods/Results: The study was designed as an ecological
      comparison between a 1-year hospital registry of consecutive MIs in Seattle
      (1,400,000 inhabitants and a predominantly urban and suburban distribution) and
      nine hospitals in Giroma (500,000 inhabitants in a predominantly rural
      distribution). Hospitalization rates for MI are higher in Seattle (standardized
      rates of 2.5/1000 for men and 0.8/1000 for women) than in Girona (1.5/1000 for
      men and 0.2/1000 for women). In both registries men under age 60 accounted for
      45.5% of cases. Women accounted for 25% of all MI episodes in Seattle and for
      only 16% in Giromi. Treatment with thrombolytic and beta-blocking drugs was twice
      as common in Seattle hospitals as in Girona. Hospital mortality in tertiary care
      hospitals was similar in both registries, but mortality in local hospitals
      (having no coronary care unit) in Giroma was significantly higher than other
      hospital mortality rates for MI. Conclusions: The higher in-hospital mortality
      rate may in large part be explained by the absence of a coronary care unit.
      However, the dispersion of Girona's population and the lack of specific programs
      to provide emergent specialized care to possible MI patients may also contribute
      to the higher in-hospital mortality rate in Girona.

PMID- 10603518
TI  - Platelet Activation Determined by Flow Cytometry Persists Despite Antithrombotic
      Therapy in Patients with Unstable Angina and Non-Q-Wave Myocardial Infarction.
AB  - Background: Current strategies in the treatment of patients with acute coronary
      syndromes include antiplatelet agents and thrombin antagonists, most commonly
      aspirin and heparin, respectively. Cardiac events, however, occur despite what is
      considered to be maximal medical treatment. Methods: We determined the percentage
      of activated platelets in whole blood samples taken from 22 patients with
      unstable angina and non-Q-wave myocardial infarection participating in the TIMI
      III B trial. Platelet activation was assessed using a monoclonal antibody to the
      surface-expressed alpha-granule protein, P-selectin, and flow cytometry. All
      patients received a full complement of antiischemic medications as well as
      intravenous heparin and oral aspirin, and were then randomized to tissue
      plasminogen activator or placebo. Results: Platelet activation prior to
      randomization was increased threefold to fourfold compared with healthy
      volunteers (11.4 +/- 11.4% vs. 2.0%; p < 0.01). Serial measurements performed 12,
      24, 48, and 96 hours after treatment initiation revealed that platelet activation
      persisted. No differences in patients experiencing recurrent ischomic events (n =
      9) or those randomized to a 90-minute, accelerated infusion of tissue plasminogen
      activator (n = 12) were observed. Conclusions: A modest degree of platelet
      activation is seen for at least 96 hours and possibly longer in patients with
      unstable angina and non-Q-wave myocardial infarction, despite being treated with
      intravenous heparin and oral aspirin. These findings support current efforts to
      identify more potent and selective antithrombotic treatment strategies.

PMID- 10603519
TI  - Surface 12-Lead Electrocardiographic Findings and Plasma Markers of Thrombin
      Activity and Generation in Patients with Myocardial Ischemia at Rest.
AB  - Background: Myocardial ischemia at rest is typically associated with
      atherosclerotic coronary artery disease, atherommous plaque rupture, and
      intracoronary thrombosis. In areas of advanced disease and vascular injury, the
      extent of thrombus is influenced largely by a delicate balance of procoagulant
      factors, favoring thrombus initiation, growth, and development, and anticoagulant
      factors, attempting to limit potentially flow-limiting coronary thrombosis.
      Thrombin, a 308 amino acid serine pretense, is considered the most patent
      procoagulant factor in the setting of acute vessel wall injury, playing an
      essential role in the conversion of fibrinogen to fibrin, accelerating the
      prothrombinase complex, activating platelets, and stabilizing fibrin polymers.
      The purpose of this study was to determine the relationship between
      electrocardiographic abnormalities and markers of thrombin activity and
      generation among patients with unstable angina and non-Q.wave myocardial
      infarction. Mehtods and Results: In a study of 36 patients (59.1+/- 11.0 years)
      with myocardial ischemia at rest participating in the Thrombolysis in Myocardial
      Ischemia (TIMI) IIIB trial, thrombin activity in plasma, as determined by
      fibrinopeptide A (FPA), prothrombin fragment 1.2 (F 1.2), and thrombin
      antithrombin III complexes (TAT) concentrations, were found to be increased
      significantly when compared with healthy volunteers (p < 0.004). Thrombin
      generation was also increased modestly compared with age-matched patients with
      stable coronary artery disease undergoing elective cardiac catheterization. Given
      that,he surface 12-lead electrocardiogram (ECG) is frequently abnormal in
      patients with ischemic chest pain at rest and represents a readily available,
      first-line diagnostic test for assessing disease activity and treatment response,
      we investigated whether ECG abnormalities and thrombin activity/generation in
      plasma were correlated. Twenty-six patients (72%) had ECG changes compatible with
      myocardial ischemia at the time of study entry, including 18 (50%) with newly
      inverted T waves (or pseudonormalization), 14 (39%) with reversible ST-segment
      depression, and 4 (11%) with transient (<30 minutes) ST-segment elevation. Within
      the predefined ECG groups there were no differences in plasma thrombin activity
      between patients with and those without confirmed abnormalities. Similarly, there
      were no differences in either plasma thrombin activity or generation between the
      predefined ECG groups. Conclusion: Although ECG abnormalities supporting the
      presence of myocardial ischemia occur commonly in patients with chest pain at
      rest, they do not correlate closely with markers of thrombin activity and
      generation in plasma. The diagnostic and prognostic capabilities of these
      diagnostic tools, considered either alone or together, require further
      investigation.

PMID- 10603520
TI  - Direct Comparison of Aspirin Plus Hirudin, Aspirin Plus Heparin, and Aspirin
      Alone Among 12,000 Patients with Acute Myocardial Infarction Not Receiving
      Thrombolysis: Rationale and Design of the First American Study of Infarct
      Survival (ASIS-1).
AB  - While antithrombotic therapy of acute myocardial infarction is clearly
      beneficial, substantial controversy exists regarding the optimal regimen. In
      particular, while aspirin alone has proven highly effective in reducing rates of
      reinfarction, stroke, and death following acute coronary occlusion, heparin has
      not clearly been shown to have additional benefit when added to aspirin but is
      associated with increased rates of hemorrhagic stroke and major bleeding. At the
      same time, available data for newer specific thrombin inhibitors such as hirudin
      suggest greater benefits than aspirin alone or aspirin plus heparin in terms of
      maintaining coronary flow, but possibly higher risks of hemorrhagic stroke and
      major bleeding. Since no completed or ongoing large-scale clinical trial has
      directly compared aspirin plus hirudin, aspirin plus heparin, and aspirin alone,
      it is not currently possible to decide which of these three antithrombotic
      regimens provides the optimal bmefit-to-risk ratio. The First American Study of
      Infarct Survival (ASIS-1) is directly comparing aspirin alone, aspirin plus
      heparin, and aspirin plus hirudin among 12,000 patients presenting with signs and
      symptoms of acute myocardial infarction who are not felt by their responsible
      physicians to be appropriate candidates for thrombolytic therapy. Such patients
      comprise almost two thirds of all U.S. subjects presenting with acute myocardial
      infarction and are a group at substantial risk of death, reinfarction, and
      stroke. Thus, the ASIS-I trial will provide importantly relevant data regarding
      the optimal antithrombotic regimen for the majority of patients presenting with
      acute myocardial infarction. In this manuscript we provide the rationale and
      design for the First American Study of Infarct Survival (ASIS-1), a randomized,
      double-blind, placebo-controlled trial directly comparing aspirin alone, aspirin
      plus intravenous heparin, and aspirin plus intravenous hirudin in the treatment
      of acute myocardial infarction patients not receiving thrombolytic therapy.

PMID- 10603521
TI  - Hemostatic Factors and Ischemic Heart Disease Risk Among Postmenopausal Women.
AB  - The following is a review of (largely) epidemiologic evidence on whether changes
      in plasma hemostatic concentrations occur with menopause and with postmenopausal
      hormone therapy which may have an impact on risk of ischemic heart disease. To
      date, only plasma fibrinogen has been positively associated with long-term risk
      of disease among women; however, data are sparse. Taken together, the evidence
      supports an impact of endogenous sex hormone levels on thrombotic potential and
      points to a modest increase in a number of plasma hemostatic factor levels at
      menopause. Results of studies of estrogen therapy are somewhat conflicting.
      Observational findings suggest that, except for possibly the Factor VII level,
      estrogen therapy may prevent the menopause-related rise in plasma hemostatic
      factors. In contrast, controlled experiments have found increased markers of
      thrombin generation with use of common formulations of estrogen therapy. The
      hemostatic effects found with oral preparations do not appear to occur with
      transdermal forms of estrogen although data are limited. Overall, the evidence
      shows menopause to have an impact on plasma levels of hemostatic factors which
      appears to be modified by use of oral estrogen. Whether these alterations in
      plasma levels have an impact on risk of ischemic heart disease among
      postmenopausal women remains to be demonstrated.

PMID- 10603522
TI  - Improving the Efficacy and Stability of Coronary Reperfusion Following
      Thrombolysis: Exploring the Thrombin Hypothesis.
AB  - A major assumption in the treatment of patients with acute myocardial infarction
      (MI) implies that the speed of coronary arterial reperfusion correlates directly
      with the overall extent of myocardial salvage, and that the extent of mycardial
      salvage, in turn, determines the absolute reduction in patient mortality. While a
      growing experience has made it clear that myocardial salvage-independent (time
      independent) mechanisms of benefit also exist, few would argue with the
      hypothesis that the greatest benefit derived from coronary thrombolysis occurs
      with early (time-dependent) treatment. Thus, improvements in the efficacy of
      reperfusion and the stability of reperfusion are likely to have considerable
      impact on patient outcome.

PMID- 10603523
TI  - Novel and Innovative Dosing Regimens in Thrombolytic Therapy for Acute Myocardial
      Infarction.

PMID- 10603524
TI  - The National Heart Attack Alert Program: A Review.

PMID- 10603525
TI  - The Heparin Rebound Phenomenon-Does It Offer Insights Toward Understanding the
      Pathobiology of Coronary Thrombosis and Its Treatment?

PMID- 10603526
TI  - Effects of a Novel Leumedin NPC 15669 on Myocardial Stunning and Preconditioned
      Infarction Size in Swine.
AB  - Background: NPC is a member of the leumedins and is an inhibitor of leukocyte
      adhesion to endothelium via blockage of integrin binding. NPC 15669 also may have
      antiplatelet effects. We tested the efficacy of the novel leukocyte recruitment
      inhibitor NPC 15669 on myocardial stunning (MS) and preconditioned myocardial
      infarction (MI). Methods and Results: In an open-chested swine model, NPC 15669
      (10 rng NPC/kg loading dose followed by constant infusion at 6 mg/kg/hr) was
      administered in six animals. Myocardial thickening (MT) was determined by
      epicardial ultrasound. The left anterior descending artery was occluded for 8
      minutes followed by 90 minutes of reperfusion, during which myocardial MT was
      recorded at regular intervals. We have found that treatment with NPC 15669
      increases myocardial contractility and significantly decreases MS time compared
      to controls (26.7 +/- 4.0 minutes vs. 50.0 +/- 4.3 minutes, p =.0026). In NPC
      15669-treated animals we observed a reduction of MI size (23.4 +/- 6.7% of tissue
      at risk became necrotic compared to 53.0 +/- 6.6% in controls, p =.0102).
      Conclusions: Our data suggest that NPC 15669 significantly reduces myocardial
      injury in both the stunning and infarction models.

PMID- 10603527
TI  - NPC 15669, an Antiinflammatory Leucine Derivative, Reduces In Vitro Platelet
      Aggregability in Both Swine and Human Plasma.
AB  - Background: Leumedins inhibit cell adhesion to endothelium via blockage of
      integrin binding. We tested a hypothesis that the novel leucine derivate NPC
      15669 will affect in vitro platelet aggregability (PA) in both human and swine
      plasma. Methods and Results: Platelet-rich plasma (PRP) was incubated with 200 u
      g and 400 u g of NPC 15669. Then PA was induced by ADP, collagen, thrombin, and
      ristocetin in the PRP without NPC 15669 and in NPC 15669-treated samples. We have
      found that PRP incubation with 200 u g of NPC 15669 significantly decreases PA
      compared to baseline in all three experimental groups in response to all agonists
      tested. When PRP was treated with 400 u g of NPC 15669, dose-dependent reduction
      of PA was observed only in the human control and swine groups, but not in
      patients with coronary atherosclerosis. Conclusions: Leumedins, known for their
      antiinflammatory properties, may have clinical applications related to their
      effect on platelet function. The mechanism of these effects is unknown, but may
      be related to the inhibition of platelet-endothelial binding.

PMID- 10603528
TI  - Neutrophil and Platelet Activity and Quantification Following Delayed tPA Therapy
      in a Rabbit Model of Thromboembolic Stroke.
AB  - Although there is considerable interest in the role of neutrophils and platelets
      in acute cerebral ischemia-reperfusion, there are very little data related to the
      effect of systemic thrombolytic therapy on these blood elements. In the present
      study a rabbit model was used to examine the effects of cerebral ischemia, tissue
      plasminogen activator therapy, or both on neutrophil and platelet peripheral
      counts and activity, the latter studied by stimulated neutrophil and platelet
      impedance aggregation and neutrophil oxygen-free radical chemiluminescence. New
      Zealand white rabbits (n = 25) were randomized to receive either tissue
      plasminogen activator (6.3 mg/kg IV; 20% bolus, remainder as a 2-hour infusion)
      or vehicle (0.9% saline) 3 hours following either autologous clot embolization or
      sham carotid artery isolation. Thus, four groups were examined: sham (n = 4), tPA
      only (n = 4), stroke only (n = 8), and stroke plus tPA (n = 9). Two hours after
      completion of thrombolytic therapy or vehicle infusion, the experiments were
      terminated, that is, 7 hours following autologous clot embolization or sham
      instrumentation. Blood was sampled from the thoracic aorta, and neutrophil and
      platelet peripheral counts and activity were determined prior to embolization and
      0.5, 2.0, 4.0, and 7.0 hours following autologous clot embolization. No
      significant difference in platelet counts, either over time or between groups,
      was noted. In contrast to the platelet counts, the neutruphil count significantly
      increased over time, rising approximately 2.5-fold from baseline in all four
      groups (p < 0.001). No significant increase in neutrophil accumulation
      (myeloperoxidase assay; 10 (7) PMNs/g tissue; mean +/- SEM) was noted within
      infarcted regions of either the stroke (1.26 +/- 0.07; n = 5) or stroke plus
      tissue-plasminogen activator (1.26 +/- 0.09; n = 5) groups when compared to
      either viable brain regions within the ischemic hemisphere (1.29 +/- 0.03; n = 4)
      or in sham controls (1.36 +/- 0.35; n = 4). Neutrophil activity (aggregation,
      oxygen-free radical release) in both groups undergoing autologous clot
      embolization demonstrated a trend toward higher values when compared to the two
      sham-operated groups. Tissue-plasrninogen activator administration did not
      significantly affect ex vivo neutrophil activity. In contrast, platelet
      aggregation was significantly reduced by the administration of tPA with (p =
      0.001) or without (p < 0.01) autologous clot embolization. Thus, in the present
      rabbit model platelet but not neutrophil activity is modulated by the
      administration of tissue-plasminogen activator, while autologous clot
      embolization results in a trend toward acute neutrophil activation.

PMID- 10603529
TI  - Regional and Systemic Platelet Function Is Altered by Myocardial Ischemia
      Reperfusion.
AB  - Background: Myocardial reperfusion after short durations of ischemia causes
      prolonged contractile dysfunction (myocardial stunning). Recently it has also
      been suggested that ischemia-reperfusion results in impaired coronary endothelial
      function. Since platelet function is, in part, regulated by an intact functioning
      endothelium, platelet function could be expected to change during ischemia
      reperfusion. However, the effect of ischemia and reperfusion on regional and
      systemic platelet function is unknown. The purpose of this study was to determine
      the effect of a brief period of myocardial ischemia followed by reperfusion on
      regional and systemic platelet function. Methods: Fourteen swine in an open-chest
      model underwent left anterior descending coronary artery (LAD) occlusion for 15
      minutes followed by 120 minutes of reperfusion. Platelet aggregability in
      response to 5 uM ADP was determined simultaneously in the femoral (systemic; N =
      14) and great cardiac (regional; N = 9) venous blood at baseline, during
      occlusion, and at 40 and 90 minutes after reperfusion. LAD blood flow and
      regional myocardial function were determined by standard methods. Results:
      Hemodynamics remained stable in all animals. During LAD occlusion platelet
      aggregability, increased only in the regional coronary circulation (126% of
      baseline, p =.0001). At 40 minutes of reperfusion systemic platelet aggregahility
      decreased (86% of baseline, p =.0001) and subsequently increased at 90 minutes at
      reperfusion in both the systemic (127% of baseline, p =.0001) and regional
      circula. tions (156% of baseline, p =.0001). Ischemia was evident by the absence
      ofdistal LAD flow during occlusion that returned during reperfusion and a typical
      response ofmyocardial stunning in each animal (stunning time = 47.7 +/- 5.2
      minutes). Conclusions: This study demonstrates that platelet function is not
      static during ischemia-reperfusion. Instead, during ischemia regional platelet
      aggregability is increased. Systemic and regional platelet aggregability also
      increase during myocardial reperfusion. The mechanism of these responses is
      unknown but may be related to regional endathelial dysfunction created by
      ischernia. The response observed could also be explained by the release of
      proaggregatory mediators in the connary and/or systemic circulation during
      ischemia-reperfusion. The relative hyeraggregability observed following
      reperfusion may be relevant for further investigations of coronary artery
      reocclusion occurring after the relief of myocardial ischemia.

PMID- 10603530
TI  - Changes in the Use of Thrombolytic Therapy in Seattle Area Hospitals from 1988 to
      1992: Results from the Myocardial Infarction Triage and Intervention Registry.
AB  - Background: Thrombolytic therapy has been shown to reduce mortality in select
      patients with acute myocardial infarction (AMI). The determinants of eligibility
      for therapy are changing as more information about the safety and efficacy of
      thrombolytic therapy is obtained. In the United States, there is some concern
      that thrombolytic therapy is underutilized, particularly in women and older
      patients. The purpose of this investigation is to examine change in the use of
      thrombolytic therapy in a single community from the years 1988 to 1992.
      Particular attention was paid to women and older patients. Methods: From January
      1988 through December 1992, 9154 patients who developed AMI were admitted to
      coronary care units in 19 hospitals in the metropolitan Seattle area. The
      hospital records of each consecutive patient were reviewed, and key information
      was entered into the Myocardial Infarction Triage and Intervention database.
      Patients who developed AMI after hospital admission for another medical condition
      were excluded, as were the small numbers of patients with AMI complicated by
      cardiac arrest and resuscitation prior to hospital admission. This population
      based study contains first admissions for AMI during the 5 year period of the
      registry. Results: The use of thrombolytic therapy in all patients increased from
      18% to 24% (p <.0001) during the 5 year period; women (10-16%) and patients 75
      years and older (3-10%) had proportionately greater increases in utilization.
      Despite widespread awareness of its importance, the median time from symptom
      onset to hospital arrival did not change during the 5 years, although there was a
      slight decrease in the time from hospital arrival to treatment with thrombolytic
      therapy. Conclusions: The change in use of thrombolytic therapy indicates that
      age and gender are less often used as exclusions for receiving thrombolytic
      therapy. It is possible that exclusionary criteria are being modified, with the
      result that this important treatment is being received by more people. The
      finding that there was no change in the time from acute symptom onset to hospital
      arrival requires intensive study. In particular, more needs to be known about
      patient decisionmaking, and innovative community interventions to reduce delay
      times must be evaluated.

PMID- 10603531
TI  - Clinical Experience with Routine Activated Coagulation Time Monitoring During
      Elective PTCA.
AB  - Background: Intracoronary thrombosis is an important factor in the pathogenesis
      of acute complications during percutaneous coronary interventions. The activated
      coagulation time (ACT) is a simple, reproducible bedside test that has become
      standard as the means of monitoring the anticoagulant effect of heparin during
      these procedures. To determine if ACT-adjusted heparin dosing reduces the
      procedure-related complications of elective PTCA, 1200 patients who underwent
      nomemergent percutancous transluminal coronary angioplasty (PTCA) between January
      1, 1988 and February 26, 1992 were studied. MethodslResults: Two groups were
      identified based on the use of empirical heparin dosage (group 1, before July 1,
      1990) vs. ACT-guided heparin administration strategies (group 2, after July 1,
      1990). Group 2 patients were older, had worse left ventricular function, and were
      more likely to have experienced a prior myocardial infarction than patients in
      group 1. Patients in group 1 were more likely to have chronic stable angina and a
      positive exercise test, while group 2 patients were more likely to be undergoing
      PTCA for post-myocardial infarction (MI) angina. Angiographic characteristics
      were also consistent with a higher risk profile in group 2 than in group 1 (92.7%
      vs. 83.4%, p < 0.001). Postprocedural complications, including abrupt closure and
      late closure, were lower in group 2 patients. The incidence of abrupt vessel
      closure was decreased by approximately 50% (6.9% vs. 3.5%, p < 0.025), and
      delayed vessel closure was significantly reduced by over 6017,(3.2% vs. 1.0%, p <
      0.05). There were no differences in femoral artery complications between the two
      specified groups. Conclusion: ACT-guided heparin therapy during percutaneous
      coronary interventions decreases acute and delayed vessel closure, even in the
      presence of clinical and angiographic characteristics that would predict a higher
      incidence of these events.

PMID- 10603533
TI  - Key References: Antiplatelet Therapy as an Adjunct to Thrombolysis and Coronary
      Angioplasty.

PMID- 10603532
TI  - Key References: Coronary Arterial Blood Flow.

PMID- 10603534
TI  - Work Content and Eye Discomfort in VDT Work.
AB  - A questionnaire study of Swedish public employees with frequent and different
      types of VDT work (n = 2,025) was conducted. Eight different kinds of eye
      discomfort were examined, and an additive index was constructed. Eye discomfort
      was statistically related to aspects of work organization. The highest levels of
      discomfort were reported by computer-aided design (CAD), data entry, and word
      processing groups; groups with mixed VDT tasks displayed the lowest level of
      symptoms. Time spent at a VDT, low degree of work control, time pressure, and
      high pace of work were all associated with relatively high levels of eye
      discomfort. There was significant interaction between experience of stress and
      time spent at a VDT with respect to both the eye discomfort index and three
      specific symptoms (itching, gritty feeling, and dryness). Whereas dryness,
      smarting, and itching of the eyes seem most strongly related to work conditions,
      redness and watery eyes seem most weakly related.

PMID- 10603535
TI  - Protection Against Dust by Respirators.
AB  - This article is a brief review of the mechanism of action of fibrous filters and
      of the performance of respirators; it neglects many of the complications
      discussed in longer and more detailed articles. An expression is given for the
      pressure drop across a filter in terms of fibre diameter and filtration velocity.
      The particle capture mechanisms of interception and diffusional deposition are
      introduced and the way in which filtration efficiency varies with particle size
      is discussed. Filters with fibres of small diameter are shown to be the most
      efficient, but their use can cause problems. Electrically charged materials are
      widely used in respirators because of their high efficiency and low pressure
      drop. Types of material, their means of charging, and their method of action are
      described. An account is given of respirator leakage, the protection factor, and
      of the way that these may vary in a period of use. The leakage of air and
      particles through face seal leaks and leaky valves is discussed. The frequent
      discrepancy in the protection given by respirators in the workplace, on the one
      hand, and that suggested by laboratory measurements, on the other, is reviewed,
      and the article ends with an account of the combined effect of aerosol
      penetration through a filter and through a leak.

PMID- 10603536
TI  - Dimensions of Job Control in Computerized and Traditional Office Work and Its
      Health Effects.
AB  - This study investigates whether a consistent relationship exists between
      computerization and job control. It also examines the role of job control as a
      predictor of stress symptoms typical for data entry and word processing (VDU)
      work. Two groups of VDU users and two comparable non-VDU-user groups took part in
      this study. A special questionnaire made it possible to assess global job control
      and four indexes of control related to specific aspects of work (control over
      choice of tasks and methods, control over time frame, control related to one's
      skill, and control related to participation in the decision-making process).
      Results did not show an unequivocal relation between computerization and the
      latitude of control. The latitude of control depends on the task performed and
      the aspect of control we are considering. Regression analyses showed that global
      control is a good predictor of job satisfaction, some mood disturbances, and
      visual complaints. The other aspects of control are related in a variety of ways
      to stress symptoms. The role of a Type A behavior pattern in the relationship
      between job control and stress symptoms varies depending on which aspect of
      control is being considered. It was concluded that because of the high functional
      differences between various aspects of control, it is better to avoid using the
      concept of global control and, when possible, apply specific indexes of control.

PMID- 10603537
TI  - Repetitive Strain in Nonrepetitive Work: A Case Study.
AB  - In a Quebec factory, a woman in a nontraditional job suffered from epicondylitis
      whereas her male coworkers were unaffected. A study was undertaken in order to
      enumerate the operations at risk for epicondylitis. Workers were interviewed in
      order to identify difficult operations and systematic observations were done over
      4 work days. Although tasks were extremely varied, certain movements at risk for
      epicondylitis were repeated many times. Fifty-three valves were turned against
      resistance as part of this job, and one valve requiring a particularly difficult
      movement was turned 20 times in one day. There were at least 61 operations at
      risk for epicondylitis per day over a 4-day period. Strain on the elbow joint was
      particularly intense for the woman worker because the design of the workplace
      gave an advantage to taller workers with larger hands. Although this case study
      does not permit us to conclude that the worker's epicondylitis was due to her
      job, it enables us to suggest that it would be wise to adapt the dimensions of
      relevant equipment and worksites to a wider range of potential worker sizes. We
      also raise some questions about the definition of repetitive strain in
      epidemiological studies. We suggest that it may be necessary to consider not only
      the cycle time but also the total of forces exerted on a joint in order to study
      workplace injuries to the musculoskeletal system.

PMID- 10603538
TI  - Development of Micropore Mufflers.
AB  - Research on micropore mufflers was started in the middle of the 1970s. In this
      article we have summarized and systematized what has been done in the past 20
      years. Some expressions, derivations, and calculation curves have been formally
      modified to make them easier to understand and apply. Some new considerations
      have been added. The main purpose of this article is to introduce the
      fundamentals, theories, and calculations that are useful for the design of a
      micropore muffler. Therefore, we have not included any experiments. Direct and
      indirect experimental proofs can be found in the given relevant references.
      Micropore mufflers are grouped into two classes, simple micropore mufflers and
      expansion micropore mufflers. The latter have additional noise reduction due to
      flow expansion. Noise reduction and flow are two important aspects that have been
      discussed in detail.

PMID- 10603539
TI  - Predictive Models of Lumbar Loadings When Handling Boxes.
AB  - Back problems resulting from the compression forces on the intervertebral disks
      during manual material-handling tasks are an important problem affecting workers
      in various industries. The quantification of these forces using intradiscal
      pressure or biomechanical modeling is complex, time consuming, and costly, and
      these methods cannot be readily used in the workplace to estimate loadings on the
      lower back. The objective of this study was to develop a predictive model that
      would allow the estimation of lumbar loadings for lifting and lowering boxes
      using easily measured anthropometric variables and variables related to the task.
      A dynamic and planar segmental model and a model of internal forces at L5/S1 were
      used to determine the compression forces on the lower back. Two predictive
      models, a field model and a laboratory model, were developed to estimate the
      compression forces when lifting or lowering 3.3 kg to 22.0 kg boxes between
      heights of 15 cm and 185 cm. Both models were validated by an examination of the
      residuals. Their predictive performance was also compared, with the laboratory
      model offering a slightly better prediction than the field model. Thus, these
      equations represent a practical tool for a better planning of handling tasks in
      the working environment with the purpose of reducing the back injuries of
      workers.

PMID- 10603540
TI  - Musculoskeletal Symptoms in Two Plants in the Electrical Sector.
AB  - The study consisted of describing, using a questionnaire, the musculoskeletal
      symptoms in two industries in the electrical sector. The questionnaire was
      distributed to more than 600 workers in the two industries. The questionnaire
      described four types of variables: usual population data (age, gender,
      experience, etc.), certain work variables, the regions of the body affected in
      the past 12 months and in the past 7 days, and the severity of the symptoms. Ten
      variables were used to provide a symptom severity index. In the two plants, the
      women reported more frequent and more serious problems than the men and the least
      experienced workers were the most affected. In Plant 1, the questionnaire
      pinpointed two work sectors, whereas in Plant 2, the problems were found not to
      be concentrated in a few sectors, but distributed among different jobs throughout
      the entire plant.

PMID- 10603541
TI  - CEN Standards for Testing and Certifying Personal Protective Equipment-Status Quo
      and Deficiencies: Examples.
AB  - By establishing the internal market, the European Union intended to create an
      area in which safety and health at work are guaranteed. For this purpose, a
      series of directives was passed. The EC Directive 89/686/EEC "Approximation of
      the laws of the Member States relating to personal protective equipment" is of
      particular interest to the manufacturers of personal protective equipment (PPE).
      On the European level, harmonized standards, that put these basic health and
      safety requirements into more concrete terms have to be available. The European
      Standardizing Committee (CEN) is charged with the elaboration of European
      standards. A total of 176 standards relating to personal protective equipment
      have to be setup; 57 of them are available at present. All CEN members are
      obliged to transpose them without modification into national standards. Formerly
      existing national standards have to be withdrawn. Existing European standards
      sometimes show deficiencies regarding the specification of requirements according
      to Directive 89/686/EEC: the standardization of PPE for special fields of
      application and insufficient harmonization of provisions for different PPE
      serving the same protective purpose. Test methods are not always described
      precisely enough.

PMID- 10603542
TI  - The Subjective Rating Scales for Measurement of Mental Workload-Thurstonian
      Scaling.
AB  - Subjective rating scales for measuring work demands and individual capabilities
      to cope with work requirements were developed using the Thurstonian procedure.
      The scales measure six dimensions of mental workload: mental difficulties,
      feeling of responsibility, awareness of risk, interpersonal conflicts, monotony,
      and time pressure. Individual scale results make it possible to assess the level
      of mental workload understood as a relation between the subjective rating of work
      demands and individual capabilities in each of the six dimensions. Two versions
      of scales were prepared: classic and modified ones. To assess the level of
      reliability of the particular scales, 481 participants were examined twice at a 1
      month interval. A procedure to prepare scales for the measurement of other
      dimensions of mental workload is also presented.

PMID- 10603543
TI  - Mental Workload and Health: A Latent Threat.
AB  - The aim of this study is to investigate changes in cardiovascular activity
      associated with a high mental workload. The reported experiments, carried out in
      naturalistic settings, point to information load and information processing under
      time pressure as main risk factors. This kind of occupational stress had to be
      dealt with by two of the three groups under investigation: brokers and
      simultaneous interpreters; it was not experienced by lecturing university
      professors. The pattern of cardiovascular activity of the two former groups
      consisted of overmobilization of cardiovascular activity at the beginning of
      work, and only partial normalization of task-evoked changes in cardiovascular
      activity at the end of work. Substantial elevations of diastolic blood pressure
      and tachycardia, which followed earlier overmobilization, resemble a miniature
      copy of changes seen in the development of cardiovascular diseases.

PMID- 10603544
TI  - Workplace Design for Manual Assembly Tasks: Effect of Spatial Arrangement on Work
      Cycle Time.
AB  - This article reports the results of an experimental study undertaken to
      investigate the effect of spatial arrangement of assembly board and parts bin in
      the normal work area on work-cycle time in manual assembly tasks. Operator
      performance was measured in terms of average work-cycle time taken to complete a
      laboratory-simulated manual assembly task. Results showed that both location and
      distance factors had significant effects on work-cycle time. Effect of the size
      of parts was also investigated in the study. Average observed work-cycle times
      were compared with the methods-time measurement (MTM) values. Repetitive manual
      assembly tasks are common in industry and are thought to lead to musculoskeletal
      disorders. The results of this research are important for ergonomic design of the
      workplace for assembly tasks, which would help to enhance operators' efficiency.

PMID- 10603545
TI  - Assessment of Physical Load at Work Sites: A Finnish-German Concept.
AB  - The aim of this article is to introduce a set of work physiology methods for the
      assessment of physical load at the work site and to consider (a) their relevance
      for different types of muscular work, and (b) their feasibility for occupational
      health and safety practitioners. The results of an ergonomic intervention study
      for the reduction of workload associated with various manual materials handling
      tasks were used for the evaluation of the feasibility and sensitivity of the
      measurements of heart rate, the Edholm and OWAS methods, and the ratings of
      overall and local perceived exertion. The methods proved feasible, although time
      consuming, and their sensitivity for the quantification of small changes in
      physical workload was limited. Despite these shortcomings, these methods can be
      used by occupational health and safety practitioners when their strategy and data
      collection techniques are developed further. In conclusion, there are relevant
      and feasible methods fora reliable work-site assessment of cardiorespiratory and
      postural load related to the activation of large muscle masses. On the other
      hand, field methods for the quantification of local static workload and
      repetitive type of workload with small muscle masses are scarce.

PMID- 10603546
TI  - Most Comfortable Listening Level and Speech Attenuation by Hearing Protectors.
AB  - Hearing protectors attenuate both the background noise and the useful sounds
      embedded in noise such as the sounds of speech and warning signals. An effective
      hearing protector is one that attenuates background noise while leaving
      sufficient energy of speech and warning signals to reach the ear of the worker.
      At present, however, there are no established criteria for assessing effective
      change in speech-to-noise ratio caused by hearing protection devices (HPDs). One
      such criterion could be a change in most comfortable (listening) level (MCL) for
      speech caused by the presence of HPDs. In this study the HPD-related shift in MCL
      for speech presented in quiet was measured and compared with two measures of
      noise attenuation: Noise Reduction Rating (NRR) and high-medium-low (H-M-L). The
      results indicate that the MCL shift may be a sensitive measure of speech
      attenuation by HPDs, which together with the appropriate H-M-L may describe
      technical properties of HPDs.

PMID- 10603547
TI  - Flicker Test as a Load Measurement During the Combined Effect of Heat and Noise.
AB  - This study was a joint physiological and psychological experiment undertaken to
      determine changes in physiological and psychological human functions under the
      combined influence of heat, noise, and physical activity. Seven experimental
      situations were simulated in a climatic chamber with different configurations of
      three independent variables: heat (40  degrees C), noise (98 dB), and physical
      effort (30% of maximum volume of oxygen uptake-V02 max). Five psychological
      variables (critical flicker fusion-CFF, hand tremor, reaction time, subjective
      climate evaluation, and subjective evaluation of the given condition load) and
      two physiological variables (heart rate and rectal temperature) were monitored.
      Results indicate that CFF changed (increased) significantly when more than one
      experimental variable was applied. These changes coincided with significant
      changes in both subjective climate evaluation and subjective evaluation of a
      given condition load. There were no significant changes in psychomotor functions
      (hand tremor and reaction time). None of the observed physiological parameters
      were above the critical value. The results suggest that CFF can be treated as a
      psychophysical load indicator.

PMID- 10603548
TI  - Chlorfenvinphos Dermal Absorption in Rats: Histological and Ultrastructural
      Changes in the Skin and Internal Organs.
AB  - We studied the effect of chlorfenvinphos dermal absorption on the morphological
      picture of blood, on the histological and fine structure of tail skin, and on the
      histological structure of internal organs (lungs, heart, liver, spleen, and
      kidney) of rats. This study was conducted on 25 white Wistar rats, the tail skin
      of which was-or was not-hydrated before exposure. Rat tails were soaked in 0.5%
      or 0.05% chlorfenvinphos for 1 hr day for 3 months. Evident tendencies for a
      decrease in the absolute level of leukocytes and for an increase in the absolute
      level of erythrocytes in all experimental animals were observed.
      Histopathological changes in the internal organs were mildly manifested in only a
      few rats, mainly as liver and pulmonary hyperaemia. Rat tail skin at the direct
      exposure site showed hyperceratosis, intensive desquamation, and compensatory
      hyperplasia.

PMID- 10603549
TI  - The European Conformity Assessment Procedures and the Quality Assurance
      Instruments for Personal Protective Equipment in the Internal Market.
AB  - Conformity assessment procedures prescribed by European legislation are presented
      and their concrete implementation is illustrated by the example of personal
      protective equipment (PPE). The different categories of PPE defined by Council
      Directive 89/686/EEC are explained with reference to the applicable conformity
      assessment elements. Quality assurance of production is presented as the central
      element of the conformity assessment procedure for complex PPE. Special emphasis
      is put on the necessity of having a regular exchange of views and information
      among notified bodies in Europe. Ways in which third countries can eventually
      carry out conformity assessment on the basis of a contract with the European
      Community Commission are explained.

PMID- 10603550
TI  - A Digital Filter for the State Estimation of Impulsive Noise Under the Existence
      of a Background Noise and its Experiment in the Work Environment.
AB  - In the actual work environment, a specific objective noise, like machine and
      industrial noises, shows impulsive fluctuation form. Furthermore, it often occurs
      that a specific noise is partially or completely contaminated by background
      noise. In that case, the fluctuation wave form of the specific noise has to be
      estimated moment by moment in order to evaluate and/or improve the work
      environment. In this study, a digital filter for estimating an impulsively
      fluctuating specific noise is proposed. More specifically, after introducing a
      generalized time series regressive model of the specific noise, a method for
      estimating the impulsive noise based on an observation contaminated by the
      background noise is theoretically derived. Furthermore, the proposed method is
      applied to the actual task of estimating an industrial impact noise.

PMID- 10603551
TI  - Arm and Leg Girths of Industrial Workers During a Workday.
AB  - The aim of this study was to characterize changes in the limb perimeters of
      workers in various widespread occupations in Estonian industry. Investigations
      were carried out using special measuring instruments designed at Tallinn
      Technical University. The subjects under investigation consisted of 202 workers:
      garment workers, tailoring cutters, shoe factory operators, weavers, press
      operators, fitters, and drivers. Investigations in the workshops showed that
      during the initial part of a work-shift perimeters often decreased. By the end of
      the shift, girths increased markedly (up to 1.6%), depending on the properties of
      the external load. There are many reasons for this change, with fatigue often
      playing an important role. The exact measurement of the girths of human limbs is
      of great importance for collecting information in the field of ergonomics. It is
      possible to find effective preventive measures against fatigue and occupational
      diseases.

PMID- 10603552
TI  - Biomechanical Consequences of the Hand's Action on Unstable Handle.
AB  - The concept of muscular stabilization refers to imposing active muscular
      constraints on the joint degrees of freedom that are not used in a given motor
      task and the stabilization of unstable working objects. The human organism bears
      considerable cost due to the realization of this process, which in the case of
      muscular static force developed in relation to an unstable working object reaches
      approximately 24%. The aim of this article is twofold: (a) to determine the
      useful efficiency of the hand-working object system with an unstable handle in
      relation to the released muscular force and power dynamics and (b) to identify
      the relative contribution of the upper extremity muscles engaged in the
      realization of motor or stabilizing functions in the electromyography (EMG)
      sphere.

PMID- 10603553
TI  - Perceived Discomfort and Electromyographic Activity of the Upper Trapezius While
      Working at a VDT Station.
AB  - Ten female participants performed work at a video display terminal (VDT) station
      over a whole working day. Subjective local muscular fatigue was evaluated by
      means of the Category Ratio 10 scale. Electromyographic activity of the upper
      right and left trapezius was measured. A comparison was made between 5
      participants who had previous complaints and 5 participants who reported no
      musculoskeletal problems in the shoulder-neck region. The subjective scores for
      the shoulder differed significantly between the two groups, being higher for the
      group with complaints. Both groups showed a decrease in discomfort after the
      lunch break. The activity of the trapezius increased significantly for both
      groups, in a more pronounced way for the group with disorders. Although it is
      found in literature that VDT work is a task with very low static loads, it seems
      from this study that the EMG activity increase can be an indication of muscle
      fatigue: More effort was required to accomplish the same VDT task at the end of
      the day.

PMID- 10603554
TI  - A Distributed Signal Detection Theory Model: Implications for the Design of
      Warnings.
AB  - A distributed signal detection theory model is employed to analyze the
      effectiveness of warnings under different operating conditions. In particular,
      the following two cases are examined: (a) the warning on a product is always
      present and (b) the warning on a product is administered selectively. The
      comparative effects of warning versus no warning are described. It is established
      that selectivity always increases effectiveness. The implications to optimal
      warning design of intermittent hazard versus continuous hazard are discussed.
      Furthermore, a series of experiments is conducted to compare the behavior of
      human participants with the prescriptive behavior of the normative model. The
      changes in the behavior of the human participants response to changes in the
      warning levels are consistent with the predictions of the model. These changes
      should be taken into consideration in the design of warnings.

PMID- 10603555
TI  - Physiological Method of Evaluating Protective Clothing for Work in a Cold
      Environment.
AB  - The purpose of this study was to determine the usefulness of physiological
      studies in the evaluation of protective clothing for work in a cold environment.
      The study included the examination of the dynamics of changes in chosen
      physiological parameters (core and skin temperatures, heart rate, pulmonary
      minute ventilation) as well as physical ones (the temperature and relative
      humidity under the clothes) during work in protective clothing with unknown
      thermal insulation. The experiment was conducted in extreme environmental
      conditions (-10 and -15 degrees C) at a work load defined by the clothing
      manufacturer as moderate. Results show that thermal equilibrium was achieved and
      maintained throughout the investigated work time (60 min) and that the protective
      clothing ensures safety on the time scale of a regular 8-hour work day. It was
      also shown that the dynamics of thermal stress physiological parameters can be
      used to determine the maximum duration of exposure for cold protective clothing
      with unknown thermal insulation.

PMID- 10603556
TI  - Some Aspects of Vehicle Active Safety.
AB  - Three selected aspects of vehicle active safety are presented in this article:
      (a) modeling the driver and the driver-vehicle environment system, (b) the
      dynamic aspects of vehicle rollover, and (c) an analysis of the process of
      passing. Sample solutions and results show the need for further research in the
      field of vehicle safety in order to lower the probability of drivers, passengers,
      and other road users being involved in road accidents.

PMID- 10603557
TI  - Role Stress, Job Anxiety, Job Involvement, and Job Satisfaction Among Three
      Groups of Organizational Employees: A Factor Analytic Study.
AB  - This study is an attempt to compare organizational role stress, job involvement,
      job anxiety, and job satisfaction among three groups of employees in a private
      sector organization. The sample consisted of 50 top managers, 50 middle managers,
      and 50 workers. The Organizational Role Stress developed by Pareek (1983), the
      Job Involvement scale by Lodhal and Kejner (1965), the Job Anxiety scale by
      Srivastava and Sinha (1977), and the Job Descriptive Index developed by Smith,
      Yulin, and Kendall (1969) were administered to all three groups of employees. The
      results were analyzed both by the factor analytic technique and by discriminant
      function analysis. The factor analysis yielded three important factors that are
      discussed. The discriminant function analysis separated the three groups on 10
      out of the 23 variables considered in the study. The findings are discussed in
      the light of other relevant studies.

PMID- 10603558
TI  - Handling Techniques: The Influence of Weight and Height for Experts and Novices.
AB  - The purpose of this study was to evaluate the influence of the weight of the load
      (12 kg, 22 kg) and of the height of the grasp (high: 126 cm; middle: 64 cm and 95
      cm; low: 33 cm) on the handling techniques adopted by six experienced handlers
      and six novices having only limited handling experience during a free box
      handling task. Each subject had to transfer two sets of 16 boxes from a platform
      to a four-wheel cart. The observations dealt with the position of the subject at
      the beginning of transfer and at deposit (position of the back, knees and feet,
      pelvic orientation, position of the hands), his way of moving during the transfer
      (position of the feet), and his way of positioning and moving the box during
      handling (tilt of the box, impulse given to the box, grip change). The results
      show that the weight and the height of grasp/deposit had an influence on the
      techniques adopted by expert handlers and novices. Some of these variations are
      common to both groups but many of them are not, such as the position of the
      knees, the grips and the position of the box. This study suggests that there is
      not one method that is suitable for all situations, and that expert handlers may
      have learned how to adjust their methods to the working environment. A better
      understanding of the experts' techniques could help in redesigning efficient
      training programs.

PMID- 10603559
TI  - Issues of the Human Reliability Analysis in the Context of Probabilistic Safety
      Studies.
AB  - This article addresses methodological issues of the human reliability analysis
      (HRA) in the context of probabilistic safety studies. Several conventional HRA
      techniques, more often used for the evaluation of the human error probabilities
      (HEPs), have been classified. A taxonomy of human actions, failure events, and
      related factors is outlined in order to distinguish action phases, human behavior
      types and incorrect outputs (errors of omission or commission), error types
      (slips, lapses, and mistakes), and performance-shaping factors (PSFs) influencing
      the human performance. A tree is proposed to facilitate the selection of a
      specific method for the evaluation of human reliability with regard to attributes
      of the situation analyzed. A software system based on the expert system
      technology to facilitate and document PSA and HRA is outlined. At the end of the
      article some research challenges in the domain are discussed.

PMID- 10603561
TI  - The Influence of Alcohol on Industrial Accidents in the Czech Republic.

PMID- 10603560
TI  - Lifting Belts: A Review.
AB  - This article reviews and evaluates the literature related to the effectiveness of
      protective restraints on abdominal strength, lower back injuries, and workers'
      discomfort. The studies indicate that back belts have potential disadvantages as
      well as advantages. Belts seem to reduce lifting stress. They may, however, lead
      to a false sense of security while being worn and may also weaken the body, so
      injury occurs when they are not being worn. There also seems to be comfort
      problems with some belts. More scientific research is needed before any
      conclusions can be drawn about positive, negative, or long-term effects of
      lifting belts.

PMID- 10603562
TI  - The Organisation of the WASP Scheme in the U.K.

PMID- 10603563
TI  - Regulation of the immune response in experimental and human schistosomiasis: the
      limits of an attractive paradigm.

PMID- 10603564
TI  - Immunoregulation within the granulomas of murine schistosomiasis mansoni.

PMID- 10603565
TI  - The schistosome granuloma: an immunoregulatory organelle.

PMID- 10603566
TI  - The development of granulomas in schistosomiasis: genetic backgrounds, regulatory
      pathways, and specific egg antigen responses that influence the magnitude of
      disease.

PMID- 10603567
TI  - T helper cell populations, cytokine dynamics, and pathology of the schistosome
      egg granuloma.

PMID- 10603568
TI  - Infection-stimulated or perinatally initiated idiotypic interactions can direct
      differential morbidity and mortality in schistosomiasis.

PMID- 10603569
TI  - Immune deviation as a strategy for schistosomiasis vaccines designed to prevent
      infection and egg-induced immunopathology.

PMID- 10603570
TI  - Strategies for a schistosome vaccine: can we manipulate the immune response
      effectively?

PMID- 10603571
TI  - Role of interleukin-7 in the relation between Schistosoma mansoni and its
      definitive vertebrate host.

PMID- 10603572
TI  - Immunology of hepatosplenic schistosomiasis mansoni: a human perspective.

PMID- 10603573
TI  - Infection and disease in human schistosomiasis mansoni are under distinct major
      gene control.

PMID- 10603574
TI  - Paternal contributions to the mammalian zygote: fertilization after sperm-egg
      fusion.
AB  - Mammalian fertilization has traditionally been regarded as a simple blending of
      two gametes, during which the haploid genome of the fertilizing spermatozoon
      constitutes the primary paternal contribution to the resulting embryo. In
      contrast to this view, new research provides evidence of important cytoplasmic
      contributions made by the fertilizing spermatozoon to the zygotic makeup, to the
      organization of preimplantation development, and even reproductive success of new
      forms of assisted fertilization. The central role of the sperm-contributed
      centriole in the reconstitution of zygotic centrosome has been established in
      most mammalian species and is put in contrast with strictly maternal centrosomal
      inheritance in rodents. The complementary reduction or multiplication of sperm
      and oocyte organelles during gametogenesis, exemplified by the differences in the
      biogenesis of centrosome in sperm and oocytes, represents an intriguing mechanism
      for avoiding their redundancy during early embryogenesis. New studies on
      perinuclear theca of sperm revealed its importance for both spermatogenesis and
      fertilization. Remodeling of the sperm chromatin into a male pronucleus is guided
      by oocyte-produced, reducing peptide glutathione and a number of molecules
      required for the reconstitution of the functional nuclear envelope and nuclear
      skeleton. Although some of the sperm structures are transformed into zygotic
      components, the elimination of others is vital to early stages of embryonic
      development. Sperm mitochondria, carrying potentially harmful paternal mtDNA,
      appear to be eliminated by a ubiquitin-dependent mechanism. Other accessory
      structures of the sperm axoneme, including fibrous sheath, microtubule doublets,
      outer dense fibers, and the striated columns of connecting piece, are discarded
      in an orderly fashion. The new methods of assisted fertilization, represented by
      intracytoplasmic sperm injection and round spermatid injection, bypass multiple
      steps of natural fertilization by introducing an intact spermatozoon or
      spermatogenic cell into oocyte cytoplasm. Consequently, the carryover of sperm
      accessory structures that would normally be eliminated before or during the entry
      of sperm into oocyte cytoplasm persist therein and may interfere with early
      embryonic development, thus decreasing the success rate of assisted fertilization
      and possibly causing severe embryonic anomalies. Similarly, foreign organelles,
      proteins, messenger RNAs, and mitochondrial DNAs, which may have a profound
      impact on the embryonic development, are propagated by the nuclear transfer of
      embryonic blastomeres and somatic cell nuclei. This aspect of assisted
      fertilization is yet to be explored by a focused effort.

PMID- 10603575
TI  - Coat proteins regulating membrane traffic.
AB  - This review focuses on the roles of coat proteins in regulating the membrane
      traffic of eukaryotic cells. Coat proteins are recruited to the donor organelle
      membrane from a cytosolic pool by specific small GTP-binding proteins and are
      required for the budding of coated vesicles. This review first describes the four
      types of coat complexes that have been characterized so far: clathrin and its
      adaptors, the adaptor-related AP-3 complex, COPI, and COPII. It then discusses
      the ascribed functions of coat proteins in vesicular transport, including the
      physical deformation of the membrane into a bud, the selection of cargo, and the
      targeting of the budded vesicle. It also mentions how the coat proteins may
      function in an alternative model for transport, namely via tubular connections,
      and how traffic is regulated. Finally, this review outlines the evidence that
      related coat proteins may regulate other steps of membrane traffic.

PMID- 10603576
TI  - Regulation of monoamine receptors in the brain: dynamic changes during stress.
AB  - Monoamine receptors are membrane-bound receptors that are coupled to G-proteins.
      Upon stimulation by agonists, they initiate a cascade of intracellular events
      that guide biochemical reactions of the cell. In the central nervous system, they
      undergo diverse regulatory processes, among which are receptor desensitization,
      internalization into the cell, and downregulation. These processes vary among
      different types of monoamine receptors. alpha 2-Adrenoceptors are often
      downregulated by agonists, and beta-adrenoceptors are internalized rapidly.
      Others, such as serotonin1A-receptors, are controlled tightly by steroid
      hormones. Expression of these receptors is reduced by the "stress hormones"
      glucocorticoids, whereas gonadal hormones such as testosterone can counterbalance
      the glucocorticoid effects. Because of this, the pattern of monoamine receptors
      in certain brain regions undergoes dynamic changes when there are elevated
      concentrations of agonists or when the hormonal milieu changes. Stress is a
      physiological situation accompanied by the high activity of brain monoaminergic
      systems and dramatic changes in peripheral hormones. Resulting alterations in
      monoamine receptors are considered to be in part responsible for changes in the
      behavior of an individual.

PMID- 10603577
TI  - Rhodopsin trafficking and its role in retinal dystrophies.
AB  - We review the sorting/targeting steps involved in the delivery of rhodopsin to
      the outer segment compartment of highly polarized photoreceptor cells. The
      transport of rhodopsin includes (1) the sorting/budding of rhodopsin-containing
      vesicles at the trans-Golgi network, (2) the directional translocation of
      rhodopsin-bearing vesicles through the inner segment, and (3) the delivery of
      rhodopsin across the connecting cilium to the outer segment. Several independent
      lines of evidence suggest that the carboxyl-terminal, cytoplasmic tail of
      rhodopsin is involved in the post-Golgi trafficking of rhodopsin. Inappropriate
      subcellular targeting of naturally occurring rhodopsin mutants in vivo leads to
      photoreceptor cell death. Thus, the genes encoding mutations in the cellular
      components involved in photoreceptor protein transport are likely candidate genes
      for retinal dystrophies.

PMID- 10603578
TI  - Calcium signaling during abiotic stress in plants.
AB  - Plants experience a wide array of environmental stimuli, not all of which are
      favorable, and, unlike animals, are unable to move away from stressful
      environments. They therefore require a mechanism with which to recognize and
      respond to abiotic stresses of many different types. Frequently this mechanism
      involves intracellular calcium. Stress-induced changes in the cytosolic
      concentration of Ca2+ ([Ca2+]cyt) occur as a result of influx of Ca2+ from
      outside the cell, or release of Ca2+ from intracellular stores. These alterations
      in [Ca2+]cyt constitute a signal that is transduced via calmodulin, calcium
      dependent protein kinases, and other Ca(2+)-controlled proteins to effect a wide
      array of downstream responses involved in the protection of the plant and
      adjustment to the new environmental conditions. Ca2+ signaling has been
      implicated in plant responses to a number of abiotic stresses including low
      temperature, osmotic stress, heat, oxidative stress, anoxia, and mechanical
      perturbation, which are reviewed in this article.

PMID- 10603579
TI  - [Lymphoscintigraphy in the study of lymphatic drainage patterns in patients with
      melanoma].
AB  - BACKGROUND: In order to plan the pertinent surgical technique for each patient
      with melanoma or other skin malignancies, it is mandatory to identify those
      lymphatic basins at risk for metastases. The advent of radiotracers for
      functional studies of the cutaneous lymphatic system during the last decade has
      resulted in the disclosure of an unexpected interindividual variability of the
      lymphatic drainage in both head and neck and trunk. OBJECTIVE: To ascertain the
      usefulness of lymphoscintigraphy for depicting the cutaneous lymphatic draining
      basins in patients with primary melanoma of the head, trunk and limbs, and to
      compare the observed lymphatic drain with the expected pattern of lymph flow
      according to the classical anatomical studies. MATERIAL AND METHODS: Prospective
      study in a university hospital (Barcelones Nord area). Consecutive patients with
      the diagnosis of cutaneous melanoma were recruited after excisional biopsy of the
      primary tumor. Every patient was intradermally injected with rhenium-sulfide
      colloids or colloidal technetium labelled with Tc-99m in four quadrant doses of
      0.3 ml around the lesions or its excisional scar. Scintigraphic imaging of the
      migrating radiotracer resulted in a flow pattern that was compared with its
      "classical" expected counterpart. RESULTS: Altogether, 55 lesions were studied,
      including 9 in the head, 21 in the trunk and 25 in the limbs (7 upper and 18
      lower). The scintigraphic drain pattern did not match the expected classical
      pattern in 37.0% of the lesions overall (14% upper limbs, 42% truncal lesions out
      from an area 2.5 cm at both sides of Sapey's line or the midline, 16.6% lower
      limbs and 89% head and neck). CONCLUSIONS: Lymphatic drain of the skin shows a
      very high intrapersonal variability leading to the need for an individual work-up
      in order to know the lymphatic basins at risk for metastases. The high rate of
      unexpected or non-matching patterns casts some doubts over those previous studies
      that did not include lymphoscintigraphy on a patient-basis.

PMID- 10603580
TI  - [Bone ultrasound in healthy women and bone mass related factors].
AB  - BACKGROUND: Bone mineral density (BMD) has been related with age, hormonal
      status, body mass index (BMI) and life style. We have evaluated the influence of
      these factors on BMD in healthy women, without risk factors for osteoporosis,
      using ultrasound measures. PATIENTS AND METHODS: We have selected 255 women (136
      premenopausal and 119 postmenopausal). We measured the weight and height. Other
      factors related to BMD were assessed with a clinical questionnaire. With an
      ultrasonic bone contact analyser broadband ultrasonic attenuation (BUA) and speed
      of sound (VS) were obtained. RESULTS: Premenopausal women had mean (SD) BUA and
      VS values (73.4 [13.1] and 1,617.2 [30.4], respectively) significantly higher
      than postmenopausal women (BDA 64.1 [14.9] and VS 1,601.1 [34.5]; p < 0.001). No
      relationship between BUA, VS and the style of life related variables was found.
      Age and weight were significant predictors of BUA in all women in multiple
      regression model, and the length of lactation in premenopausal women. The
      association of BUA with age were significantly stronger (p < 0.05) in
      postmenopausal women. CONCLUSIONS: Age and body weight were the factors more
      strongly associated with ultrasonic measures in healthy women. The effect of age
      was different depending on menopausal status. No relation has been found between
      life habits and bone mass.

PMID- 10603581
TI  - [Lipoprotein (a) and the evaluation of low density cholesterol by the Friedewald
      formula: a new problem for an old equation].
AB  - BACKGROUND: To evaluate the influence of lipoprotein(a) [Lp(a)] concentration on
      the LDL-cholesterol calculated by the Friedewald formula. MATERIAL AND METHODS:
      Lp(a) was determined to a worker population of 947 subject in order to perform a
      correction of LDL-cholesterol obtained by the Friedewald formula. RESULTS: In
      subjects in whom Lp(a) was > 30 mg/dl (12.9%) LDL-cholesterol levels were
      overestimated 10 mg/dl at least. CONCLUSION: Lp(a) should be considered in order
      to reduce Friedewald's formula error on the estimation of LDL-cholesterol.

PMID- 10603582
TI  - [New approaches to the role of estrogens in bone metabolism].

PMID- 10603583
TI  - [An update of treatment of acute coronary syndromes].

PMID- 10603584
TI  - [86-year-old woman with malaise, fever, bilateral alveolar congestion and
      abnormal liver function tests].

PMID- 10603585
TI  - [Familial papillary thyroid carcinoma].

PMID- 10603586
TI  - [Intravenous immunoglobulins commercialized in Spain and potential risk of acute
      renal failure].

PMID- 10603587
TI  - [Medical and legal questions about medical record].

PMID- 10603588
TI  - [Treatment of urinary tract infections in patients with risk factors].

PMID- 10603589
TI  - [Genetics of schizophrenic disorders. New concepts and findings].
AB  - Schizophrenia is a genetic complex disease as it does not follow monogenic
      transmission while non-familial environmental factors have a strong additional
      impact. A heterogeneous, continuous phenotype is transmitted in families which
      can now be more precisely characterized. Genes coding for proteins with presumed
      pathophysiological relevance are apparently not playing a major causal role.
      However, in the last three years several (currently seven) candidate regions have
      been identified in a replicable manner by linkage studies. These regions are
      likely to host susceptibility genes for schizophrenia, but none of them has been
      identified up to now. Given these findings, polygenic transmission has now become
      very likely. The candidate regions are currently being narrowed down by various
      promising techniques.

PMID- 10603590
TI  - [Socioeconomic status and gender. Manifestations of social inequality in
      psychiatric diseases].
AB  - This paper is concerned with the relationship between social inequality and
      psychiatric disorders, an issue being neglected in German psychiatry for a long
      time. Social inequality will be discussed in it's dimensions "socioeconomic
      status" and "sex" referring to the present state of epidemiological and
      sociological knowledge. Because such macro-social factors offer little
      explanation for the association with psychiatric disorders by themselves micro
      social concepts of burden and resources are necessary to link the structural and
      the individual level. These concepts are considered to be one pathway by which
      the mechanisms to disease may occur. A short review of empirical findings and
      analytic approaches show the complexity of these mechanisms requiring further
      research not only because of analytic deficiencies but also because of social
      change. Further research will concern in general the explanation of social
      patterns of diseases, in detail the link between individual stress and coping
      with the social structure, and last but not least a gender-sensitive approach to
      psychiatric disorders which is more differentiated.

PMID- 10603591
TI  - [How is delusion possible in psychopathologic terms?].
AB  - Delusion is understood to mean inter-subjectively disconcerting convictions with
      a tendency toward subjective certainty that lose their disconcerting character
      when made the object of psychiatric analysis in the knowledge of their
      independence from mental disorder. The perceptions from which delusions arise are
      dynamically charged according to their role in the structural context. The
      realization pressure that burdens the perceptions and is intensified in psychotic
      constitutions is a precondition for the delusion. The failure of derealization
      brought about by the psychotic disorganisation of the structure is also a
      requirement. Based on a case study, considerations arising out of the initial
      stages of schizophrenic delusion are extended to other forms of delusion and to
      the conditions for chronification.

PMID- 10603592
TI  - [Decision-making and delusion. A study on decision-making in delusional,
      depressive and healthy subjects].
AB  - Delusion as a phenomenon was always in the focus of psychiatric interest.
      Explanations for its origin reach from disturbed perception or affect to deficits
      in cognition. In our study we investigated 20 deluded, 20 depressive and 20
      healthy subjects in order to find out differences in decision making, while a
      neutral test situation. Our hypothesis was that deluded subjects need less
      information for decision making and tend less to change their decision, made
      before, than both control groups will do this. For examination our hypothesis a
      modified version of "Probabilistic Inference Task" by Philips and Edwards was
      performed. In summary we found that deluded subjects need less information for
      decisions making than the control groups. Furthermore, decision making of deluded
      subjects seems more impulsive and less referring to formal logical criteria than
      it was found in depressed and healthy volunteers.

PMID- 10603593
TI  - [Repetition and iteration. From psychoanalysis to systems theory].
AB  - Starting with Freud's presentation in "Beyond the Pleasure Principle", the
      conception of the repetition compulsion is introduced. Freud gave a teleological
      interpretation of the psychological phenomenon of repetition. On one hand, he
      considered it as an attempt of the psyche to get delayed control over a
      penetrating amount of traumatic stimuli, on the other hand, he interpreted it
      within his conception of death instinct as an expression of a destructive
      impulse. From systems theory, especially from chaos theory originates the
      conception of iteration. It is used to describe systems characterized by
      repeatedly performed operations representing simultaneously an important model of
      homeostatic regulation in living systems. The applicability of the iteration
      conception on repetition phenomena in the psychic field is being discussed. With
      reference to Luhmann's systems theory, repetition can be considered as an
      iterative phenomenon within the selfreferencing organization of the psyche.
      However the connection between physiological processes in the nervous system and
      psychological phenomena is not ascertainable, especially not from the point of
      view of systems theory. Conceptions of systems theory being transferred to the
      psychic field represent a hermeneutic approach to the matter.

PMID- 10603594
TI  - [Temperament- and character traits as well as trait patterns in alcoholic men and
      controls].
AB  - This study is on the personality of alcoholics, an empirical investigation based
      on Cloninger's biopsychological temperament- and character-traits. His
      Temperament and Character Inventory (TCI) was applied to 94 detoxified men
      suffering from primary alcohol dependence as well as to controls matched for sex
      and sociodemographic data. The following questions were the matter of interest:
      (1) Do alcoholics and controls differ in their personality as reflected by the
      TCI and (2) are there indicators based on personality with potential relevance
      for differential therapies? A multiple univariate statistical comparison yielded
      significant differences between alcoholics and controls on only 2 subscales
      (Sentimentality, Resourcefulness). A multivariate analysis of the TCI temperament
      traits using two-sample configural frequency analysis revealed no statistically
      significant difference between the two groups. Temperament patterns associated
      with Cloninger's Type-I/Type-II alcoholics could not be demonstrated. Analyzing
      the temperament and character traits of the alcohol dependent subjects with a log
      linear model revealed two bivariate temperament-/character classifications on the
      scales "Harm Avoidance" and "Self-Directedness" as well as "Reward Dependence"
      and "Self Transcendence"-both making it possible to define subgroups which may be
      relevant for different therapeutical approaches. Taken together, the results of
      this study suggest that it may be useful to closer investigate the personality of
      alcoholics even if it is not principally different from that of control subjects.

PMID- 10603595
TI  - [Diagnostic, forensic and therapeutic-ethical aspects of false memory of sexual
      abuse induced by psychotherapy].
AB  - This article examines the risk of false memories induced by psychotherapy with
      special regard to sexual abuse. Current psychological constructs based on depth
      psychology are reviewed critically. The multitude of psychological disorders
      connected with sexual abuse in recent time and a subjectivistic misunderstanding
      of empathy frequently lead sometimes to uncritical acceptance of anamnestic
      reports about sexual abuse. Thus, the question of what really happened often is
      risen not before forensic appraisals. It can be shown that the descriptive
      psychiatric view and depth psychological oriented constructs tend to compete with
      each other with the consequence of different results in therapeutic practise and
      forensic appraisal if inappropriately applied. The author shows how to distinct
      between induced delusional symptoms and dissociative phenomena. Furthermore he
      draws attention on the ethically doubtful long-term results of a not correctly
      indicated use of psychological constructs based on depth psychology about extreme
      traumatization in the psychotherapy of strongly suggestible patients.

PMID- 10603596
TI  - [Assisted suicide and psychiatric disorders].
AB  - In the region of Basel in Switzerland 43 assisted suicides were registered
      between 1992 and 1997, eight percent of all suicides in the region. Assisted
      suicide was administered by the help-to-die society Exit. There was a psychiatric
      history in six of the suicides. Four of them suffered of serious physical illness
      as well. The analyses of these six suicides focuses on the conditions of assisted
      suicide in people with mental illness and the ethical problems arising.

PMID- 10603597
TI  - [Pierre Janet (1859-1947). "Physician-philosopher, psychologist and
      psychotherapist].
AB  - Today's efforts at the foundation of psychotherapy by psychology should consider
      the work of the French philosopher, physician and psychologist Pierre Janet. The
      article sketches some aspects of Janet's biography, work and influence and refers
      to a few of his progressive ideas about an empirically based psychotherapy.

PMID- 10603598
TI  - [Psychopharmacological therapy of self-injurious behavior in mentally retarded
      individuals].
AB  - Neurobiological research has implicated the dopamine and serotonin system in the
      pathogenesis of self-injurious behavior. The efficacy of antipsychotic drugs has
      been questioned. Opened and controlled investigations have shown risperidone is
      effective for reducing self-injurious behaviour in mentally retardation. We
      report about 3 mentally retarded patients which were given open-label risperidone
      for 12 weeks. They participated in a detailed assessment of behaviour symptoms at
      baseline and the repetitive behaviour was weekly rated with the disability
      assessment schedule (DAS). All three patients responded.

PMID- 10603599
TI  - [Biological hallucinogens. New patterns of substance abuse in young addicts?].
AB  - Among young patients with multiple substance abuse, a high level of abuse of
      natural products was noticed. In a rehabilitation clinic for young addicts 180
      patients filled out a questionnaire regarding drugs they regularly consumed. It
      was discovered that the patients consumed high levels of Psilocybe, Amanita and
      Datura. The natural drugs of the 70's, Ayahuasco and Cactus, are now rarely seen.
      The toxicological basis of the frequently used biological drugs is discussed. The
      results imply that a specific exploration of patients with multiple substance
      abuse in regard to the use of biological drugs is necessary.

PMID- 10603600
TI  - [Supplementary remarks and commentary on the article by M.M. Weber et al.
      Disability evaluation of posttraumatic stress disorder. Nervenarzt 1998:811-814].

PMID- 10603601
TI  - [Interferon beta-1b in multiple sclerosis. Basic therapy in intermittent and
      secondary progressive course].

PMID- 10603602
TI  - [Therapy of schizophrenia with high compliance. Ziprasidon increases
      pharmaceutical options].

PMID- 10603603
TI  - Prevention of isoimmunization in pregnancy developed by Freda and Gorman.

PMID- 10603604
TI  - Focus on primary care female population with migraine.

PMID- 10603605
TI  - Synthesis and chemistry of fluorine containing bioactive 1,2,4-triazines--an
      overview. Chemistry of uncondensed 1,2,4-triazines, Part III.
AB  - Studies on the chemical reactivity of fluorine containing bioactive 1,2,4
      triazines are reviewed. The synthesis, unique features and biological
      significance of these constituents are discussed.

PMID- 10603606
TI  - Quinoxaline derivatives. Part II: Synthesis and antimicrobial testing of 1,2,4
      triazolo[4,3-a]quinoxalines, 1,2,4-triazino[4,3-a]quinoxalines and 2
      pyrazolylquinoxalines.
AB  - Three main classes of quinoxaline derivatives have been synthesized. The first
      class comprises the synthesis of three novel series of 1,2,4-triazolo[4,3
      a]quinoxalines; namely 1-substituted-1,2,4-triazolo[4,3-a]quinoxalines 3a-f, 1
      substituted aminomethyl-1,2,4-triazolo[4,3-a]quinoxalines 14a-d and 1-cyano or
      ethoxycarbonylmethyl-1,2,4-triazolo[4,3-a]quinoxalines 6, 12. The second class
      involves the synthesis of 2-substituted-1 H-1,2,4-triazino[4,3-a]quinoxalines 4a
      d. The third class deals with the synthesis of a variety of 2
      pyrazolylquinoxalines, namely 2-(5-amino-3-arylpyrazol-1-yl)-3-phenylquinoxalines
      5a-d, 2-[5-hydroxy-3-phenyl-4-(4-substituted sulfamoylphenyl)azopyrazol-1-yl]-3
      phenylquinoxalines 15a, b, and 2-(5-hydroxy-4-nitroso-3-phenylpyrazol-1-yl)-3
      phenylquinoxalin e (16). The prepared compounds were tested in vitro for their
      antimicrobial activity. Compounds 13 and 14b exhibited promising antifungal
      activity against C. albicans (MIC 25, 50 mu/ml respectively). Compound 13 was as
      active as the antibiotic nystatin.

PMID- 10603607
TI  - [Five-ring analogs of nifedipine. 3. Synthesis and reactions of 1,4
      dihydropyridines with 4-(4-nitro-5-imidazolyl)-substituents].
AB  - In the Hantzsch pyridine synthesis the 4-nitro-5-imidazolylcarbaldehydes 4 react
      with methyl 3-aminocrotonate or 3-aminocrotononitrile in acetic acid to yield the
      1,4-dihydropyridines (DHP) 5 and 6. The corresponding pyridines 7 and 8 are
      obtained by oxidation with cerium(IV) or chromium(VI), respectively. Reduction of
      the nitro group in 7 with iron in acetic acid leads to the lactames 9, while from
      8a the imidazolylamine 10 is isolated. Compound 8a reacts with dithionite to
      yield the cyclic amidine 11. Irradiation of the DHP 5 and 6b with UV-A light
      affords the 4-nitroso-5-imidazolyl-pyridines 12 and 13. The half wave potentials
      E1/2 of the DHP 5 were determined by anodic oxidation using difference pulse
      voltammetry (DPV); nifedipine was used as reference substance. The DHP 5 inhibit
      the growth of Staphylococcus aureus in the platelet diffusion test.

PMID- 10603608
TI  - 1,2,3,4-tetrahydroisoquinoline derivatives; lipophilicity evaluation vs. 5-HT1A
      receptor affinity.
AB  - Retention parameters (log k') of 1,2,3,4-tetrahydroisoquinoline derivatives--a
      new class of 5-HT1A receptor ligands--were determined on the basis of reversed
      phase HPLC experiments. Good correlations were found between the log k' values
      and the calculated log Pc, van der Waals volume of the R substituent (VR) as well
      as the 5-HT1A receptor affinity (Ki) of the investigated compounds. It was
      demonstrated that hydrophobic forces played a pivotal role in stabilizing the
      ligand-receptor bioactive complex for that group of compounds.

PMID- 10603609
TI  - Diacyl glyceryl ester prodrugs for slow release in the skin: synthesis and in
      vitro degradation and absorption studies for naproxen derivatives.
AB  - Diacyl glyceryl ester derivatives of naproxen were synthesized and tested for
      transdermal and dermal administration. Diacyl derivatives of aliphatic acids of
      various chain length were compared. The pharmaceutical properties of these
      compounds, such as lipophilicity, hydrolysis in a buffer solution at various pH
      values and degradation in human serum and hairless mouse skin homogenate, were
      investigated. All the diacyl derivatives were relatively stable in a neutral
      buffer solution, but were rapidly degraded to release naproxen in human serum and
      hairless mouse skin homogenate. The diacyl compounds could not penetrate hairless
      mouse skin in vitro. However, significant absorption into the skin could be
      measured, and this increased with increasing lipophilicity. A more than 100-fold
      difference in absorption was observed. The prodrugs were slowly hydrolyzed to
      naproxen inside the skin. The release of naproxen to the receptor compartment of
      diffusion cells showed that this type of prodrug could be used for controlled
      drug delivery.

PMID- 10603610
TI  - Evaluation of in vitro toxicity of N,N-dimethyl-2-propen-1-amines isomers.
AB  - The trypanocidal activities of cis-3-(4'-bromo[1,1'-biphenyl]-4-yl)- 3-(phenyl)
      N,N-dimethyl-2-propen-1-amine (Vb) and cis-3-(4'-bromo[1,1'-biphenyl]-4-yl)-3-(4
      bromophenyl)-N,N-dimethyl-2- propen-1-anine (Vg) appeared 6.3 and 3.5 fold more
      active than the trans-isomers, respectively. Multi-endpoints for toxicity were
      also applied. Neutral red uptake (NRU), tetrazolium salt reduction (MTT), DNA
      content on V79 fibroblast cell culture and acute toxicity von E. coli were
      measured. The IC50 through DNA contents was lower for the cis-isomers in both
      series of compounds 5b: 7.8 microM and 5g: 5.2 microM). NRU values for derivative
      5b in isomeric mixture shows the same value as the isolated isomers however, in
      the case of 5g a more significant toxicity of the cis-isomer was found. MTT
      values show that 5g is more toxic than 5b. In both cases, the acute toxicity of
      the trans-isomers was higher than that of the cis-isomers.

PMID- 10603611
TI  - Ampicillin prodrugs: amide conjugates from aminoacids, peptide and ampicillin.

PMID- 10603612
TI  - Over-the-counter melatonin--quality or quackery?

PMID- 10603613
TI  - Immunomodulatory activity of the saponin-rich fraction from roots of Silene
      vulgaris Garcke: initial study.

PMID- 10603614
TI  - Multiple sclerosis: the disease and its manifestations.
AB  - Multiple sclerosis is an immune-mediated inflammatory demyelinating disease of
      the central nervous system clinically characterized by relapses and remissions of
      neurological disturbance. A typical relapse, exemplified by optic neuritis,
      increases in severity over a week or two and after approximately one month begins
      to remit. Resolution takes place over the course of two to three months. In the
      early stages, clinical recovery is virtually complete, though persistent
      abnormalities of conduction can usually be detected by evoked potential
      techniques and persistent structural abnormalities can be detected by magnetic
      resonance imaging (MRI). These techniques, together with cerebrospinal fluid
      examination for oligoclonal IgG, provide supporting evidence for the diagnosis
      which, in the absence of a specific test, nevertheless remains primarily
      clinical. The course of the disease is very variable, but after a number of years
      neurological deficit begins to accumulate after each relapse. In most patients,
      the relapsing and remitting phase of the disease is followed by a phase of
      continuous progression of disability. Cognitive disturbances can be detected in
      many patients even quite early in the course of the illness. Deficits in
      attention, memory and executive skills may be prominent and tend to become
      increasingly prominent as neurological deficit increases, although this is not
      always the case. There is some correlation between the extent of MRI
      abnormalities in the cerebral white matter and the severity of cognitive deficit.
      Depression and anxiety are commonly experienced but are poorly correlated to the
      lesion load seen on MRI. In contrast, the much rarer psychotic symptoms, euphoria
      and emotional lability are closely linked to the severity of white matter
      disease.

PMID- 10603615
TI  - The genetic epidemiology of multiple sclerosis.
AB  - Epidemiological studies have implicated an interplay between genetic and
      environmental factors in the aetiology of multiple sclerosis (MS). There is a
      familial recurrence rate of approximately 15%. Meta-analysis of the recurrence
      risk shows that the rate is highest overall for siblings, then parents and
      children, with lower rates in second- and third-degree relatives. Recurrence is
      highest for monozygotic twins. Conversely, the frequency in adoptees is similar
      to the population lifetime risk. The age-adjusted risk for half siblings is also
      less than for full siblings. Recurrence is higher in the children of conjugal
      pairs with MS than the offspring of single affected. These classical genetic
      observations suggest that MS is a complex trait in which susceptibility is
      determined by several genes acting independently or epistatically. Comparisons
      between co-affected sibling pairs provide no evidence for correlation with age or
      year at onset and mode of presentation or disability. Thus far, the
      identification of susceptibility genes has proved elusive but genetic strategies
      are now in place which should illuminate the problem. The main dividend will be
      an improved understanding of the pathogenesis. To date, population studies have
      demonstrated an association between the class II major histocompatibility complex
      (MHC) alleles DR15 and DQ6 and their corresponding genotypes. An association with
      DR4, with or without the primary DR15 link, is seen in some Mediterranean
      populations. Candidate gene approaches have otherwise proved unrewarding. Four
      groups of investigators have undertaken a systematic search of the genome. In
      common with most other complex traits, no major susceptibility gene has been
      identified but regions of interest have been provisionally identified. These
      genetic analyses are predicated on the assumption that MS is one disease.
      Genotypic and phenotypic analyses are beginning to question this assumption. A
      major part of future studies in the genetics of MS will be to resolve the
      question of disease heterogeneity.

PMID- 10603616
TI  - The pathology of multiple sclerosis and its evolution.
AB  - The pathology of multiple sclerosis (MS) was defined more than a century ago as a
      chronic inflammatory process which is associated with widespread primary
      demyelination and glial scarring. In this short review we discuss controversial
      issues on (i) the relationship between inflammation and demyelination, (ii) the
      various possible mechanisms of myelin destruction, and (iii) axonal involvement
      in this disease. We suggest that the disease process of MS is more complex that
      previously believed.

PMID- 10603617
TI  - Axon damage and repair in multiple sclerosis.
AB  - It is well known that within long-standing multiple sclerosis (MS) lesions there
      is axonal loss but whether it is an early or late event has been more difficult
      to establish. The use of immunocytochemical methods that reveal axonal end-bulbs
      is a valuable approach to investigating acute axonal injury in human pathological
      material. The application of these techniques to multiple sclerosis tissue
      reveals evidence of axonal injury in acute lesions; the distribution of the end
      bulbs in acute and active-chronic lesions is associated with regions of maximal
      density of infiltrating macrophages. Axon injury within the MS lesion will result
      in both Wallerian degeneration of the axon and also retrograde degeneration of
      the cell body. The functional consequences of the axon injury will depend upon
      numbers of axons injured and the topographical organization of the fibres
      coursing through the lesion. The molecular mechanisms by which the recruited
      leucocytes damage or transect the axons are not known. However, investigations in
      the Wld mutant mouse with very slow Wallerian degeneration demonstrate that axon
      degeneration is not simply a passive disintegration of the axon but has clear
      parallels with the active processes of programmed cell death. The presence of
      early axon injury and the consequences of an ever increasing load of neuronal
      damage has important implications not only for when therapy should be initiated
      in MS but also the therapeutic target.

PMID- 10603619
TI  - Characterization of tissue damage in multiple sclerosis by nuclear magnetic
      resonance.
AB  - Nuclear magnetic resonance (NMR) imaging is an established diagnostic medium to
      diagnose multiple sclerosis (MS). In clinically stable MS patients, NMR detects
      silent disease activity, which is the reason why it is being used to monitor
      treatment trials, in which it serves as a secondary outcome parameter. The
      absence of a clear correlation with clinical disability, the so-called 'clinico
      radiological' paradox, and the poor predictive value of NMR prohibit the use of
      NMR as a primary outcome parameter in clinical trials. This is--among others--a
      result of the limited histopathological specificity of conventional, or 'T2
      weighted' imaging, the most commonly used NMR technique. In this paper we review
      additional NMR techniques with higher tissue specificity, most of which show
      marked heterogeneity within NMR-visible lesions, reflecting histopathological
      heterogeneity. Gadolinium enhancement identifies the early inflammatory phase of
      lesion development, with active phagocytosis by macrophages. Persistently
      hypointense lesions on T1-weighted images ('black holes') relate to axonal loss
      and matrix destruction, and show a better correlation with clinical disability.
      Marked prolongation of T1 relaxation time correlates with enlargement of the
      extracellular space, which occurs as a result of axonal loss or oedema. Axonal
      viability can also be measured using the concentration of N-acetyl aspartate
      (NAA) using NMR spectroscopy; this technique is also capable of showing lactate
      and mobile lipids in lesions with active macrophages. The multi-exponential
      behaviour of T2 relaxation time in brain white matter provides a tool to monitor
      the myelin water component in MS lesions (short T2 component) as well as the
      expansion of the extracellular space (long T2 component). Chemical exchange with
      macromolecules (e.g. myelin) can be measured using magnetization transfer
      imaging, and correlates with demyelination, axonal loss and matrix destruction.
      Increased water diffusion has been found in MS lesions (relating to oedema and an
      expanded extracellular space) and a loss of anisotropy may indicate a loss of
      fibre orientation (compatible with demyelination). Apart from the
      histopathological heterogeneity within focal MS lesions, the normal-appearing
      white matter shows definite abnormalities with all quantifiable NMR techniques. A
      decrease in the concentration of NAA, decreased magnetization transfer values and
      prolonged T1 relaxation time values are probably all related to microscopic
      abnormalities, including axonal damage. This 'invisible' lesion load may
      constitute a significant proportion of the total lesion load but is not visible
      on conventional NMR. Similarly, mechanisms for clinical recovery exist, which are
      not distinguished using MR imaging. Therefore, it is highly unlikely that the
      clinico-radiological paradox will ever be solved completely. However, NMR
      provides an opportunity to sequentially measure tissue changes in vivo. Using MR
      parameters with (presumed) histopathological specificity, the development of
      (irreversible) tissue damage can be monitored, which perhaps allows the
      identification of factors that determine lesional outcome in MS. Since the
      absence of severe tissue destruction is prognostically favourable, NMR monitoring
      of the extent to which such changes can be prevented by treatment will ultimately
      benefit the selection of future treatment strategies.

PMID- 10603618
TI  - The pathophysiology of multiple sclerosis: the mechanisms underlying the
      production of symptoms and the natural history of the disease.
AB  - The pathophysiology of multiple sclerosis is reviewed, with emphasis on the
      axonal conduction properties underlying the production of symptoms, and the
      course of the disease. The major cause of the negative symptoms during relapses
      (e.g. paralysis, blindness and numbness) is conduction block, caused largely by
      demyelination and inflammation, and possibly by defects in synaptic transmission
      and putative circulating blocking factors. Recovery from symptoms during
      remissions is due mainly to the restoration of axonal function, either by
      remyelination, the resolution of inflammation, or the restoration of conduction
      to axons which persist in the demyelinated state. Conduction in the latter axons
      shows a number of deficits, particularly with regard to the conduction of trains
      of impulses and these contribute to weakness and sensory problems. The mechanisms
      underlying the sensitivity of symptoms to changes in body temperature (Uhthoff's
      phenomenon) are discussed. The origin of 'positive' symptoms, such as tingling
      sensations, are described, including the generation of ectopic trains and bursts
      of impulses, ephaptic interactions between axons and/or neurons, the triggering
      of additional, spurious impulses by the transmission of normal impulses, the
      mechanosensitivity of axons underlying movement-induced sensations (e.g.
      Lhermitte's phenomenon) and pain. The clinical course of the disease is
      discussed, together with its relationship to the evolution of lesions as revealed
      by magnetic resonance imaging and spectroscopy. The earliest detectable event in
      the development of most new lesions is a breakdown of the blood-brain barrier in
      association with inflammation. Inflammation resolves after approximately one
      month, at which time there is an improvement in the symptoms. Demyelination
      occurs during the inflammatory phase of the lesion. An important mechanism
      determining persistent neurological deficit is axonal degeneration, although
      persistent conduction block arising from the failure of repair mechanisms
      probably also contributes.

PMID- 10603620
TI  - Nuclear magnetic resonance monitoring of treatment and prediction of outcome in
      multiple sclerosis.
AB  - Magnetic resonance (MR) techniques provide an objective, sensitive and
      quantitative assessment of the evolving pathology in multiple sclerosis. There is
      an increasing definition of the pathological specificity of newer techniques, and
      more robust correlations with clinical evolution are emerging. As the
      pathophysiological basis of in vivo nuclear MR signal abnormalities is further
      elucidated, it is likely that the importance of MR as a tool to monitor new
      therapies will increase.

PMID- 10603621
TI  - Therapeutic strategies in multiple sclerosis. I. Immunotherapy.
AB  - This review first addresses several general aspects of the immunotherapy of
      multiple sclerosis. Next, two approved immunomodulatory treatments, interferon
      beta and copolymer-1 (glatiramer acetate), are reviewed in more detail. Finally,
      other immunosuppressive therapies and experimental strategies are briefly
      discussed.

PMID- 10603623
TI  - Directly observed therapy for the treatment of tuberculosis--evidence based
      dosage guidelines.
AB  - Tuberculosis is a communicable disease with public health implications and
      effective treatment is essential for control of the disease and prevention of the
      emergence of drug resistant strains. Drug therapy for this disease is well
      established and discussion now surrounds frequency of administration, duration of
      treatment and methods of improving compliance. Directly observed intermittent
      therapy of tuberculosis is supported by the World Health Authority and has become
      the standard of care in the U.S.A. Available dosage guidelines for directly
      observed therapy are only supported by limited data. A literature review of
      recent studies with clinical outcome measures was conducted. Following this
      review evidence based guidelines have been produced.

PMID- 10603622
TI  - Therapeutic strategies in multiple sclerosis. II. Long-term repair.
AB  - Spontaneous myelin repair in multiple sclerosis (MS) provides a striking example
      of the brain's inherent capacity for sustained and stable regenerative tissue
      repair--but also clearly emphasizes the limitations of this capacity;
      remyelination ultimately fails widely in many patients, and disability and
      handicap accumulate. The observation of endogenous partial myelin repair has
      raised the possibility that therapeutic interventions designed to supplement or
      promote remyelination might have a useful and significant impact both in the
      short term, in restoring conduction, and in the long term, in safeguarding axons.
      Therapeutic remyelination interventions must involve manipulations to either the
      molecular or the cellular environment within lesions; both depend crucially on a
      detailed understanding of the biology of the repair process and of those glia
      implicated in spontaneous repair, or capable of contributing to exogenous repair.
      Here we explore the biology of myelin repair in MS, examining the glia
      responsible for successful remyelination, oligodendrocytes and Schwann cells,
      their 'target' cells, neurons and the roles of astrocytes. Options for
      therapeutic remyelinating strategies are reviewed, including glial cell
      transplantation and treatment with growth factors or other soluble molecules.
      Clinical aspects of remyelination therapies are considered--which patients, which
      lesions, which stage of the disease, and how to monitor an intervention--and the
      remaining obstacles and hazards to these approaches are discussed.

PMID- 10603624
TI  - Compliance in asthma.
AB  - Low rates of compliance with medication pose a major challenge to the effective
      management of most chronic diseases, including asthma. The high medical and
      social costs of non-compliance, and the apparent lack of effective methods for
      dealing with it, has stimulated renewed interest in this complex issue. Two broad
      categories of non-compliance have been identified, namely unintentional (or
      'accidental') and intentional (or 'deliberate'). Unintentional non-compliance may
      result from poor doctor-patient communication or a lack of ability to follow
      advice. Intentional non-compliance occurs when the patient knows what is required
      but decides not to follow this to some degree. Healthcare professionals need to
      be aware of the various issues affecting compliance in all patients. The reasons
      for non-compliance are many and varied, and include factors such as complexity of
      the treatment regimen, administration route, patient beliefs about therapy and
      other psychological factors. Improvement in patient compliance with therapy will
      require better doctor-patient communication, improved patient education, the
      tailoring of therapy to the individual and possible novel strategies such as
      offering feedback to the patients on their level of compliance.

PMID- 10603625
TI  - Intra-tracheal delivery strategy of gentamicin with partial liquid ventilation.
AB  - Patients with pulmonary infection often present with ventilation and perfusion
      abnormalities, which can impair intravenous antibiotic therapy. Intra-tracheal
      (i.t.) administration has met with obstacles, such as inadequate delivery to
      affected lung regions and the disruption of gas exchange. We hypothesized that
      i.t. administration of a gentamicin (G)/perfluorochemical (PFC) suspension
      (G/PFC) would effectively deliver and distribute gentamicin to the lung, while
      maintaining gas exchange and non-toxic serum levels. In addition, we sought to
      compare serum G and lung levels and distribution of G when G/PFC is administered
      at the initiation of partial liquid ventilation (PLV) vs. during PLV. To test
      this hypothesis, 17 newborn lambs were ventilated by PLV with perflubron
      (LiquiVent) for 4 h using three different G (5 mg kg-1) administration
      techniques: i.t. slow-fill (SF) (n = 6; G/PFC over 15 min at start of PLV), i.t.
      top-fill (TF) (n = 6; G/PFC 10-65 min after start of PLV), intravenous (i.v.) (n
      = 5, aqueous injection at start of PLV). Serum levels of gentamicin were obtained
      1, 15, 30 and 60 min after administration, and hourly there after for the
      remainder of the protocol (4 h). Arterial blood gas and pulmonary function
      measurements were obtained throughout the protocol. At the conclusion of the
      protocol, representative samples from each lung lobe, the brain and kidney were
      homogenized and assayed for gentamicin. All results are presented as the mean +/-
      SEM; P < 0.05. Over time, serum gentamicin levels were greatest (P < 0.05) in
      i.v. (11.0 +/- 2.3 micrograms ml-1), followed by TF (2.3 +/- 0.1 micrograms ml-1)
      and SF (0.8 +/- 0.1 microgram ml-1). The percentage of the administered dose
      remaining in the lungs after 4 h was greater (P < 0.05) following i.t. delivery
      (SF 23.8 +/- 4.3%, TF 13.7 +/- 2.5%) as compared to i.v. (3.7 +/- 0.5%). These
      findings suggest that for a given dose of G, both SF and TF delivery methods of
      G/PFC can enhance pulmonary, relative to systemic, antibiotic coverage.

PMID- 10603626
TI  - Current and future medical costs of asthma and chronic obstructive pulmonary
      disease in The Netherlands.
AB  - The aim of this study was to estimate the healthcare costs of asthma and chronic
      obstructive pulmonary disease (COPD), in the Netherlands, in 1993. Also studied
      was the future development of these costs, as a result of ageing and possible
      changes in smoking behavior. A prevalence-based cost-of-illness approach was used
      to estimate direct medical costs. Age- and gender-specific data were obtained
      from representative national registries and large, representative surveys. To
      model future costs, cost estimates were linked to an epidemiological model based
      on a dynamic multi-state lifetable. It describes 1 yr changes, from one state to
      another, that result from ageing, birth, migration, incidence, recovery from
      asthma and death due to asthma, COPD or other causes, and starting or quitting
      smoking. Three different scenarios were modelled: 1) a reference scenario which
      primarily predicts the impact of ageing. 2) an 'attainable' smoking reduction
      scenario and 3) an 'extreme' smoking reduction scenario. Direct medical costs
      were estimated to be $US 346 million in 1993. With increasing age, the relative
      importance of asthma in total asthma and COPD costs decreased from 91% to less
      than 4%. Annual costs per patient were estimated to be $US 499 for asthma and $US
      876 for COPD. The breakdown of costs differed considerably between asthma and
      COPD. The reference scenario predicted the costs to increase by 60% to reach $US
      555 million by 2010, COPD prevention as modelled in the second and the third
      scenario reduced the projected cost increase from 60%, to 57% and 48%,
      respectively. Together, the direct costs of asthma and COPD represent 1.3% of the
      Dutch health care budget. The breakdown of the costs shows different patterns for
      asthma and COPD. The costs of these diseases are expected to increase by 60% in
      the near future. In the short run the impact of smoking reduction on reducing
      this increase is relatively small, but it will be greater in the long run.

PMID- 10603627
TI  - Pharmaceutically-based severity stratification of an asthmatic population.
AB  - Algorithms designed to precisely identify disease severity for a given patient
      within a managed care population are helpful in organizing targeted
      interventions. These algorithms are also attracting considerable attention within
      the medical research community. Several health risk screening instruments have
      been developed; however, these involve survey methodologies and have several
      shortcomings. We present a valid and efficient method for predicting healthcare
      resource utilization among asthmatics in an Health Maintenance Organization (HMO)
      population. First, various diagnosis, procedure and pharmacy billing codes were
      used to identify the asthmatics within the database. The screening algorithm
      awards points each time one of these codes is identified for an HMO member. By
      varying the number of points necessary to consider a patient asthmatic, the
      sensitivity, specificity, positive and negative predictive values of the
      algorithm can be adjusted. Once identified as asthmatic, subjects were then
      stratified into severity levels based on pharmacy data. Severity stratification
      was validated directly by measuring asthma-related bed days utilized during the
      12 months following the date of stratification. Our identification algorithm
      estimated an asthma prevalence of 3.84% within the studied population, with age
      specific prevalence estimates that closely mirrored previously published survey
      data. There was a monotonic relationship between pharmacy severity levels and
      inpatient resource utilization. For example, asthmatics in severity level 1 used
      only 92 hospital days per 1000 asthmatics in the year following characterization,
      while those in levels 2-5 used 133, 156, 277 and 1168 hospital days (P < 0.001),
      respectively. Results from this model can be used as adjusters in other
      predictive models or stand alone to represent a patient's severity of illness.

PMID- 10603628
TI  - The effects of time delay and temperature on capillary blood gas measurements.
AB  - Monitoring of blood gas measurements is an important part of the assessment of
      patients with chronic lung disease. Increasingly, this is being done in the
      patients' homes by specialist nurses. This makes it important to know the effect
      of time delay and storage temperature on the reliability of capillary blood gas
      analysis results. In this study, the effect of a delay of 1 and 2 h and of
      storage at both room temperature and in ice, on blood stored in glass capillary
      tubes was investigated. Samples, initially taken from the earlobes, were
      transferred to glass capillary tubes and used to provide duplicate initial
      samples for immediate analysis, and then single samples at 1 and 2 h stored at
      room temperature or in ice. The duplicate baseline measurements showed good
      reproducibility. There was a small, but statistically significant, increase in
      PCO2 when samples were stored in capillaries at room temperature, or in ice, both
      at 1 and 2 h. Small changes in PO2 were not statistically significant, either in
      ice or at room temperature. None of the changes was considered to be sufficient
      to be of clinical significance, thus supporting the use of capillary blood
      sampling even when there might be a delay of 1-2 h and transport is at room
      temperature, as might be the case when taking domiciliary samples.

PMID- 10603629
TI  - Increasing prevalence of asthma but not of chronic bronchitis in Finland? Report
      from the FinEsS-Helsinki Study.
AB  - To assess the prevalence of asthma, chronic bronchitis and respiratory symptoms,
      and to calculate risk factors for them, we performed a postal survey in Helsinki,
      the capital of Finland. During the spring of 1996, questionnaires were mailed to
      a random sample of 8000 individuals aged 20-69. The total response rate was 76%,
      with 6062 complete answers. The prevalence of having ever had asthma was 7.2%,
      physician-diagnosed asthma was 6.6% and physician-diagnosed chronic bronchitis
      was 3.7%. Asthma was significantly more common among women than men, but no
      gender differences existed in prevalence of chronic bronchitis. The most common
      respiratory symptom was sputum production when coughing, reported by 27%. During
      the previous 12 months, wheezing had occurred in 20% and attacks of shortness of
      breath in 13% of subjects. Generally, the prevalence of different respiratory
      symptoms were significantly higher among smokers. The most important risk factor
      for asthma was a family history of asthma (Odds ratio:OR 3.3). Multivariate
      analysis revealed that being a member of the socioeconomic group, manual workers,
      was associated with a significantly increased risk for chronic productive cough
      (OR 1.7), and for wheezing during the previous 12 months (OR 1.7). Manual workers
      of both genders had the highest prevalence of asthma, chronic productive cough
      and wheezing during the previous 12 months. The prevalence of asthma in Helsinki
      was higher than previously found in Finland, and was at a similar level to that
      of other Nordic countries. In contrast, prevalence of chronic bronchitis was
      lower than previously shown in Finland.

PMID- 10603630
TI  - Does the 'oxygen cost diagram' reflect changes in six minute walking distance in
      follow up studies?
AB  - The oxygen cost diagram (OCD) is a simple scale for quantifying a patient's
      evaluation of his tolerance to exercise frequently used in clinical trials; it
      has been shown to be well correlated with objective measures of capacity of
      ambulation such as the 6 min walk test (6' W). This study aimed to determine
      whether the OCD accurately depicts changes in capacity of ambulation either
      quantitatively or qualitatively. OCD ratings were analysed at baseline and after
      a 1 yr follow-up, in patients treated by non-invasive home mechanical
      ventilation, as well as objective measurements of pulmonary function [forced
      expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), arterial blood
      gases], physical autonomy (6' W), resting dyspnoea (Borg scale) and scores for
      anxiety or depressive disorders (HAD). Forty-five patients (24 male, 21 female,
      aged 62 +/- 16 years, mean FEV1: 38 +/- 17% of predicted) were evaluated at
      baseline. OCD ratings were significantly correlated with 6 min walking distance
      (P < 0.0001)--although with a large variability around the regression line--but
      not with resting dyspnoea (Borg). Patients were re-evaluated after 352 +/- 90
      days. Changes in OCD ratings were not significantly correlated with changes in
      FFV1 FVC, PaO2, PaCO2, 6' W, HAD scores or resting dyspnoea; furthermore--albeit
      for Borg scores--changes in OCD did not reflect the trend of changes in these
      parameters. These results show that although OCD ratings are well correlated with
      results of a 6' W test, they cannot be used to extrapolate individual
      performances, because of a large variability around the regression line,
      furthermore, changes in the OCD over 1 yr did not depict objective changes in 6'
      W test results, either quantitatively or qualitatively. The use of the OCD in
      clinical trials should be limited to the description of the patient's perception
      of exercise tolerance, as a component of health-related quality of life, with the
      awareness of possible discrepancies between changes in objective performances and
      changes in OCD ratings.

PMID- 10603631
TI  - ADA1/ADAp ratio in pleural tuberculosis: an excellent diagnostic parameter in
      pleural fluid.
AB  - We analysed the efficacy of pleural adenosine deaminase (ADAp) and the ADA1/ADAp
      ratio in the diagnosis of pleural tuberculosis in 103 pleural effusions, 27 of
      which were tuberculosis (TB) and 76 other diagnoses (non-TB). Smears, cultures
      and pleural biopsies were carried out in all cases, and were used for final
      diagnosis. The diagnostic yield of the parameters under study were as follows:
      smears/cultures of mycobacteria in fluid 11.1%/33.3%; biopsy 33.3%/51.8% and
      tuberculosis granulomas 85.1%. The levels of ADAp and ADA1/ADAp ratio in TB and
      non-TB groups showed very significant differences (P < 0.00001); in the TB group:
      ADAp 54.7 +/- 23.5 IU and ADA1/ADAp 0.27 +/- 0.08; in the non-TB group: ADAp 18.3
      +/- 43.2 IU and ADA1/ADAp 0.64 +/- 0.14. The assay established ADA levels in
      pleural fluid > or = 40 IU and an ADA1/ADAp ratio < or = 0.42 as cut-off levels
      to identify individuals in the TB group, with a sensitivity of 88.8%/100%, a
      specificity of 92%/98.6%, a positive predictive value (PPV) of 80%/96.4%, a
      negative predictive value (NPV) of 95.8%/100% and an accuracy of 91.2%/99.02%.
      The ADAp levels in 27 patients with TB, showed close correlation with the number
      of monocyte macrophages (P = 0.001), but not with the number of lymphocytes (P =
      n.s.). The ADA1/ADAp ratio overcomes the limitations of ADAp (false positives and
      negatives), and is the most useful parameter for diagnosis on account of a high
      diagnostic yield, low cost and speed of the assay for identifying a pleural
      tuberculosis diagnosis, when compared with traditional methods.

PMID- 10603632
TI  - Differences in mortality between patients attending the emergency room services
      for asthma and chronic obstructive pulmonary disease.
AB  - Asthma has a more favourable prognosis than chronic obstructive pulmonary disease
      (COPD), based on studies including few asthmatics and few women with COPD. We
      assessed differences in mortality between people attending the emergency room for
      asthma and for COPD in a population-based cohort. We recruited all the men and
      women, who were residents of Barcelona (Spain) over 14 years of age, who attended
      emergency room services for an obstructive lung disease during the period 1985
      1989. Vital status was followed up to the end of 1995. A total of 15,517
      individuals (including 4555 asthmatics and 2194 females with COPD) were studied.
      Mortality was ascertained using a record linkage with the regional Mortality
      Registry. Overall, 43.6% people died during the follow-up period. Mortality was
      higher among individuals with COPD than with asthma, in males and females, for
      all causes of death, as well as for cancer, cardiovascular and respiratory
      causes. After adjusting for age, the relative risk (RR) of dying of a male
      attending for COPD and discharged home was 1.50 (1.29-1.74) in comparison with a
      male attending for asthma, and 3.06 (2.66-3.51) for a male attending for COPD and
      admitted into the hospital. Similar figures were found for females. The increased
      risk for patients with COPD was significantly higher than for asthma in all age
      groups. Both males and females with asthma have a more favourable prognosis than
      patients with COPD, for all age groups.

PMID- 10603633
TI  - Induced sputum compared to bronchoalveolar lavage for evaluating patients with
      sarcoidosis and non-granulomatous interstitial lung disease.
AB  - Bronchoalveolar lavage (BAL), an important tool for evaluating interstitial lung
      diseases (ILDs), has limited utility due to its invasiveness and the difficulty
      of performing it in clinically contraindicated patients. We compared BAL with the
      induced sputum (IS) technique to analyse cells and T lymphocytes in patients with
      sarcoidosis (SA) and non-granulomatous ILD (NG-ILD). Pulmonary function tests and
      BAL were performed by conventional methods. IS induction was done 20 sec after
      inhalation of 3.5% saline with an ultrasonic nebulizer. Giemsa-stained cytopreps
      were differentially counted. T lymphocyte subsets were analysed by flow activated
      cell sorter (FACS). Patients with NG-ILD had impaired total lung capacity (TLC).
      Transbronchial biopsy demonstrated lung fibrosis in NG-ILD and non-caseating
      granuloma in SA. The differential cell count in both groups demonstrated a
      significantly lower percentage of neutrophils and a significantly higher
      percentage of macrophages in BAL than in IS. The IS samples of patients with SA
      were significantly richer in metachromatic cells and eosinophils, but had a lower
      percentage of lymphocytes, compared to the BAL samples. The profiles of T cell
      subsets showed the same pattern, in both samples, in both groups. A CD4/CD8 ratio
      of 2.5 or greater had a sensitivity of 100% and a specificity of 81.2%, with a
      positive predictive value of 81.2% to distinguish SA from NG-ILD. IS is an
      effective non-invasive technique to identify CD4+ inflammation which
      distinguishes sarcoidosis from other NG-ILDs.

PMID- 10603634
TI  - Prophylactic antibiotic therapy is associated with an increased prevalence of
      Aspergillus colonization in adult cystic fibrosis patients.
AB  - Aspergillus colonization is a common phenomenon in adult cystic fibrosis (CF)
      patients. The clinical significance of Aspergillus for the pathogenesis of CF
      lung disease remains unclear and factors predisposing to such colonization are
      still completely unknown. We investigated the prevalence of Aspergillus
      colonization in 104 adult CF patients who attended our outpatient clinic in 1997.
      With respect to demographic and clinical data, and antibiotic therapy received,
      we further examined which factors were associated with Aspergillus colonization
      in these patients. Repeated investigations of CF sputum samples revealed
      Aspergillus species in 43/104 (41.3%; 95% confidence interval 30.2-52.5%) of the
      patients. We found no significant relationship between Aspergillus colonization
      and age (P > 0.4), gender (P = 0.4), colonization with pseudomonas species (P >
      0.6), lower lung function values (P > 0.9), or worse chest radiography (P > 0.1).
      Surprisingly, the prevalence of Aspergillus colonization was higher in CF
      patients receiving prophylactic antibiotic therapy (oral antibiotics: P = 0.05;
      inhalative antibiotics: P = 0.035; both antibiotics: P = 0.048). Prophylactic
      antibiotics are widely used to eradicate or decrease chronic bronchopulmonary
      infection in CF. Our results indicate that long-term antibiotic therapy may
      predispose CF patients to Aspergillus colonization.

PMID- 10603635
TI  - Demonstration of tracheal stenosis by computed tomography of different modalities
      and their comparisons: report of one child with congenital stridor and wheezing.

PMID- 10603636
TI  - [Proton magnetic resonance spectrometry for the non-invasive exploration of human
      brain metabolism: current and future clinical applications].
AB  - Magnetic resonance spectrometry (MRS) is now a routine investigation method in
      neurology. In some situations, its diagnostic sensitivity is better than MRI. In
      this review, we propose a critical analysis of the large body of literature on
      brain MRS concerning a wide range of pathologies and many different protocols.
      The diagnostic value of MRS is not fully determined in all neurological diseases,
      but the specific properties of MRS (detection of neuron-specific and glial
      specific metabolites, quantitative data, reversibility of metabolic lesions) make
      it a high-performance tool for quantifying neuron, glial and membrane
      abnormalities. After reviewing the methodological advances in MRS and discussing
      restrictions on interpretation of spectral data, we describe variations in
      metabolic patterns detected by MRS in different groups of diseases. The currently
      reasonable indications for MRS exploration are presented as well as new avenues
      for research. Based on MRS data, we propose a metabolic definition of
      encephalopathy which could be useful in better understanding the role of MRS in
      modern neurology.

PMID- 10603637
TI  - [Four "alien" hands for two hands after a lesion in corpus callosum].
AB  - Callosal lesions, associated or not to internal frontal lesions, may produce
      different types of complex gestural behaviors. Four signs can be identified, each
      of which has been generally reported separately: the "alien hand" sign, the
      "diagnostic apraxia", the "wayward hand" and the "callosal apraxia". Some authors
      justify considering these signs as different entities, while others propose
      regrouping them either in an unique syndrome--the "alien hand"--or as two
      syndromes--the "frontal alien hand" and the "callosal alien hand". We present the
      observation of a patient who presented with the four mentioned syndromes in
      association. In this context, we review the clinical features of each of the four
      signs and the arguments supporting their individualization.

PMID- 10603638
TI  - [Difficulties in face identification after lesion in the left hemisphere].
AB  - A 82 year-old right-handed man, without any intellectual impairment, suffered
      from an acute neurological deficit consisting in letter-by-letter reading, right
      superior quadrant hemianopia with achromatopia in the lower quadrant, and anomia.
      Cerebral MRI showed an infarct involving the ventral structures of the left
      hemisphere sparing the splenium of the corpus callosum and the thalamus.
      Neuropsychological examination revealed that the patient easily identified the
      objects, the animals and the famous places he could not name: his comments
      attested normal visual recognition. Conversely, when he was presented with famous
      faces, he always had a strong feeling of familiarity, but could not provide
      accurate information about the corresponding individual. Biographic information
      about personalities was not impaired in the semantic-biographic store, because it
      could be accessed from the names. Activation of face recognition units (where the
      visual description provided by the structural encoding and the stored sets of
      descriptions of familiar faces are compared), was effective, since the patient
      could distinguish famous faces from unknown ones. In a modular-sequential model
      of face recognition, this deficit is interpreted as a disconnection between face
      recognition units and person identity nodes (which are considered to contain
      semantic-biographic information about individuals). This kind of disturbance
      differs from classic prosopagnosia in which, characteristically, the patients are
      unable to experience a feeling of familiarity when viewing famous faces, and to
      perform a categorization between famous and unknown faces. Right hemisphere has a
      preponderant role in structural analysis of faces and in activation of face
      recognition units. The integrity of this hemisphere in this patient could explain
      the preservation of these two steps of processing. Left-hemisphere specific
      function in facial recognition enabled access to semantic-biographic store in a
      conscious, verbal and explicit way, after the right hemisphere had achieved basic
      visual analysis and activation of facial representation in memory. We compare the
      cognitive impairment in our patient to those encountered in classical
      prosopagnosic patients. This case illustrates the validity of the modular
      sequential model considered. In addition it throws a light on the poor-known role
      of the left hemisphere in face recognition.

PMID- 10603639
TI  - [Tuberculous meningitis in an immunocompetent adult: contribution of cerebral
      imaging techniques to the diagnosis and follow-up].
AB  - We have studied 5 men, mean age 47 years, affected by tuberculous meningitis (TM)
      without documented immunodepression. The diagnosis of TM was supported by
      clinical and biological investigations and confirmed by the cultures of CSF. All
      the patients received a four-drug combination therapy and steroids. No drug
      resistance of the bacilli was observed. Cerebral imaging by CT and MRI was rarely
      diagnostic but most useful during the follow-up. All the patients developed
      complications including tuberculomas (5), hydrocephalus (4), ischemic lesions
      (2), arachnoiditis (1) and abscess of spinal cord (1). Four patients recovered
      and one died. The mean duration of the follow-up was 16 months. MRI was more
      sensitive than CT scan to identify inflammatory lesions such as granulomas,
      angeitis or arachnoiditis and to follow their outcome. Tuberculomas and
      hydrocephalus were easily diagnosed by CT scan with contrast enhancement.
      Recommendations of sequential imaging are suggested to identify unexpected or
      asymptomatic complications of TM during therapy and evaluate the outcome.

PMID- 10603640
TI  - [Rett's syndrome: report of 5 cases in Tunisia].
AB  - We report 5 girls presenting Rett syndrome. All of them were from south Tunisia.
      They fulfilled the Rett syndrome diagnosis criteria (The Rett syndrome diagnosis
      criteria work group, 1988). Pregnancy, birth and psychomotor development during
      the first year of live were normal. The mean age at the onset was 19.8 +/- 2.5
      months. The two revealing symptoms were psychomotor regression (3 cases) and
      epilepsy (2 cases). They were admitted to our ward at a mean age of 4.7 +/- 1.5
      years. Clinical presentation was typical of Rett syndrome. Mental retardation,
      stereotypic hand movement (hand washing/wringing or clapping/tapping) and loss of
      purposeful manual skills were noted in all cases. Gait was apraxic and increase
      of head circumference was slowed. Additional features included, respiratory
      dysfunction (episodic hyperventilation and breath-holding), epilepsy, scoliosis
      (4 cases), growth retardation and spasticity (3 cases). Electroencephalography
      showed slow activity with multifocal epileptiform abnormalities. Sleep enhanced
      these EEG abnormalities. MRI and CT-scan disclosed non specific cortical and sub
      cortical atrophy. All cases were isolated and parents were consanguineous in 3
      cases. Rett syndrome is relatively frequent in Europe, but in Tunisia this
      disease remains rare and certainly underdiagnosed.

PMID- 10603641
TI  - [JC virus infection and lympho-plasmocytic infiltration of the central nervous
      system revealed by a cerebellar syndrome].
AB  - We report the case of a 74 year-old woman who had been treated since 8 years for
      a Waldenstrom's disease. She also was affected by a progressive multi-focal
      leukoencephalopathy. The interest of this case lies in two principal features. On
      the one hand, the clinical and radiological signs were restricted to the
      cerebellum and to the brainstem, on the other hand, brain examination revealed
      lymphocytes and plasma cells infiltration suggestive of an associated Bing and
      Neel syndrome.

PMID- 10603642
TI  - [Epilepsy in an adult with chromosome 22q11 micro-deletion].
AB  - Chromosome 22q11 deletion is a frequent genetic anomaly, recently discovered,
      responsible for DiGeorge syndrome and velo-cardio-facial syndrome. The spectrum
      of clinical features is large: dysmorphic syndrome, mental delay, conotroncal
      cardiopathy; neurologic manifestations are not rare. Case report is a 28 year old
      man who presented a symptomatic epilepsy caused by stroke, associated with
      conotroncal cardiopathy, mental delay, hypocalcemia and facial dysmorphy. A
      cytogenetic study confirmed the chromosome 22q11 deletion.

PMID- 10603643
TI  - [To Caesar Caesar's...].

PMID- 10603644
TI  - [From cellular pathology to molecular pathology: a paradigm change].

PMID- 10603645
TI  - In utero stem cell transplantation for the treatment of genetic diseases.
AB  - In utero haematopoietic cell transplantation is currently in its embryonic stage
      of development, but holds considerable developmental promise as a therapeutic
      approach for the treatment of a large number of congenital haematological
      diseases. Despite, until recently, limited evidence of clinical efficacy,
      interest in the field has been gaining momentum, and clinical application is
      likely to increase. Parallel advances in prenatal diagnosis, fetal intervention,
      and haematopoietic stem cell technology have removed many of the practical,
      technical, and ethical obstacles to clinical application. With this progress,
      there has been a significant increase in the number of centers around the world
      with both the stated interest and perceived expertise to develop clinical
      programs. At this point in the evolution of in utero haematopoietic stem cell
      transplantation there are more questions than answers. Widespread clinical
      applications are premature based on the extremely limited clinical success, which
      has been achieved. The biology of each disease is unique and expectations of
      success or failure can only be based upon sound clinical investigation guided by
      an understanding of the relevant issues and careful selection and evaluation of
      patients. Clinical centers should be associated with an active research effort to
      solve the remaining problems with this potentially valuable therapeutic approach.
      In the near future, advances in our understanding of stem cell biology,
      developmental ontogeny, and gene therapy may allow prenatal stem cell and gene
      therapy to achieve their full potential.

PMID- 10603646
TI  - [Fetal cells in maternal blood--their significance in non-invasive prenatal
      diagnosis and in etiologically determined diseases].
AB  - The first report of the occurrence of fetal cells in maternal circulation dates
      back to 1893 when the German pathologist Schmorl identified trophoblast cells in
      the lungs of women who had died from eclampsia. Till recently, however, the
      existence of fetal cells in maternal blood was a matter of considerable debate.
      The main reason for this dispute was the inability to successfully and reliably
      enrich for these cells, which has also hindered their clinical use. In the
      meantime, this issue has been addressed and the both fetal aneuploidies and
      single gene defects can now be detected in a non-invasive manner using fetal
      cells enriched from maternal blood.

PMID- 10603647
TI  - Molecular approaches for safer and stronger vaccines.
AB  - Progress in molecular biology and biotechnology is making possible the
      development of new vaccines or the improvement of already existing ones.
      Recombinant DNA technology, genetic attenuation of bacterial and viral pathogens
      and their use as vectors for heterologous proteins, expression of microbial
      antigens in transgenic edible plants, and naked nucleic acid technology represent
      the most popular approaches hitherto adopted. A successful biotechnological
      approach to the development of new and improved vaccines has been based on
      genetic detoxification of bacterial toxins, such as the toxin of Bordetella
      pertussis, the heat-labile enterotoxin of Escherichia coli, and the toxin of
      Vibrio cholerae. Genetically detoxified Bordetella pertussis is now included in a
      commercially available acellular vaccine against pertussis. Genetically
      detoxified Escherichia coli and Vibrio cholerae have been shown to behave as very
      strong and safe mucosal adjuvants and are now entering the clinical stage. These
      results demonstrate that a rational molecular approach to the development of
      safer and stronger vaccines is feasible.

PMID- 10603648
TI  - Molecular pathology of breast cancer and its impact on clinical practice.
AB  - Molecular studies in breast cancer are in their infancy but infants mature very
      quickly nowadays. The impact of new technologies on medical practice is already
      becoming evident and will transform the entire scene within a generation. The
      most rapidly moving part of the field at present is familial breast cancer.
      Molecular data are available for only a minority of affected families today and
      this is reflected in a great deal of imprecision in selection of family members
      for special surveillance and in decisions about management. Nevertheless, it is
      important to be systematic in setting up and auditing services for breast cancer
      families so that these can evolve effectively in parallel with developments in
      molecular technology. Our limited experience of these services so far does at
      least suggest they are doing more good than harm!

PMID- 10603649
TI  - [Molecular therapy in malignant tumors].
AB  - Gene therapy encompasses deliberate alteration of the genetic material of cancer
      cells. Somatic-cell therapy involves the administration to cancer patients of
      living cells that have been genetically manipulated or processed to change their
      biological characteristics. Gene therapy of cancer, although much hyped, is still
      in its very early infancy. Current approaches to delivering genes into cells
      include physico-chemical methods, viral vectors and direct DNA injection. None of
      these strategies is in any way perfect and their efficacy leaves much to be
      desired. Based on the somatic mutation theory of carcinogenesis, it would be
      attractive to repair genetic alterations responsible for neoplastic
      transformation and clonal evolution of cancer cells. Attempts have been made to
      replace inactivated tumour suppressor genes in cancer cells through intact wild
      type gene copies, or to suppress the leukaemogenic effects of chromosomal fusion
      genes in leukaemia through antisense oligonucleotides. One of the snags of these
      concepts is that cancer cells harbour several if not myriads of mutated genes,
      and clonal tumour heterogeneity seems to be the rule rather than the exception.
      It is at present impossible to repair all gene mutations in cancer lesions of a
      given patient if such were to be the aim of therapy. Nevertheless, some
      interesting clinical data have been reported. These include the local injection
      via bronchoscopy of p53 wild type gene copies into p53-deficient lung cancer
      lesions and other tumours. Somatic-cell therapy includes a considerable spectrum
      of interventions. Tumour cells may be transduced with genes which upon their
      expression will render the tumour cells more immunogenic. Tumour-infiltrating
      lymphocytes may be harvested, transduced with a gene of interest and re-injected.
      Since they recognise tumours specifically, they will serve as vehicles to carry
      therapeutic genes into cancer lesions where the gene product can exert an anti
      cancer effect. Such attempts might increase the immunogenicity of tumours
      considerably. Examples are the transduction of tumour-infiltrating lymphocytes
      with a gene for tumour necrosis factor alpha or the transduction of tumour cells
      with the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) in
      patients with metastatic renal cell carcinoma. Protocols on gene therapy and
      somatic-cell therapy seem to be a worthy goal of cancer research. However, it
      seems unlikely that gene therapy will provide magic anti-cancer bullets in the
      near future or the definitive cancer cure, although this is often promised in the
      media. Careful clinical and laboratory research will pave the way towards
      stepwise improvement of cancer patient care.

PMID- 10603650
TI  - [Multiple sclerosis: epidemiology, molecular pathology and therapy].
AB  - Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central
      nervous system. It results from an autoimmune response against one of several
      antigens of cerebral white matter tissue. The pathogenesis of MS lesions consists
      in migration of auto-reactive T-cells and disruption of the blood-brain-barrier.
      B-cells and their products are, however, also important for demyelination
      together with various cytotoxic or pro-inflammatory cytokines. Recent advances in
      immunology and biotechnology and protein engineering techniques have opened the
      door for novel immunotherapies. Immune modulation with beta-interferon has shown
      beneficial effect, both in relapsing remitting and secondary progressive multiple
      sclerosis.

PMID- 10603651
TI  - Gene therapy in the world and in Switzerland.
AB  - Until the mid-seventies, biology used to be taught as an interesting, yet rather
      "useless" discipline in our high schools. The advent of molecular biology has
      drastically changed this image. Now, applied molecular genetics has been shown to
      have the potential to revolutionize many aspects of our life, including the
      paradigms of medicine. In a first phase, gene knowledge has allowed medical
      diagnosis with previously unimaginable precision. In a second wave, gene transfer
      in micro-organisms has produced a plethora of biopharmaceuticals. This decade has
      seen the third era of molecular medicine, in which direct gene transfer into
      humans is being developed. This article comments on the most recent developments
      and concepts in the field of human gene transfer (also called "gene therapy").
      Some essential methods are briefly presented and a great deal of attention is
      devoted to the technical hurdles still to be overcome in achieving efficient and
      safe gene therapy protocols. The final paragraph attempts to clear up some myths
      and misunderstandings that are commonly propagated when people talk or think
      about gene therapy. The purpose of this article will be fulfilled if at the end
      the reader is convinced that gene therapy is not necessarily dedicated
      exclusively to hereditary disorders, that Switzerland undertaken an intensive and
      competitive experimental effort in this direction, that gene therapy has already
      proven its efficacy and has great potential, but that it will take a couple of
      decades before some applications are routinely used in the clinic.

PMID- 10603652
TI  - [Gene therapy of cystic fibrosis].
AB  - Cystic fibrosis represents a paradigm for gene therapy of hereditary disorders.
      Because it is a monogenic disease, it was believed that it would be relatively
      simple to approach by gene therapy. In fact, it turned out that the apical side
      of the respiratory epithelium is resistant to transduction by various gene
      vectors, including recombinant adenoviruses. In addition, the relationship
      between the genetic defect (the mutated CFTR gene) and the pathogenesis of the
      disease is more complex than was thought at first. So far, the results of gene
      therapy trials in patients with cystic fibrosis have been disappointing in terms
      of efficacy. However, they have brought a fair amount of new information about
      the basic mechanism of this disease.

PMID- 10603653
TI  - [Gene therapy in heart diseases].
AB  - Cardiovascular diseases are the most important cause of death and hospitalisation
      in industrialised countries. Although pharmacological, interventional and
      surgical therapy has achieved major progress during the past 25 years, most
      therapeutic measures are only transiently effective or require life-long
      medication. Molecular cardiology aims at applying molecular biological methods
      for both diagnosis and treatment of cardiovascular disease. With respect to
      diagnosis of cardiac diseases such as hypertrophic cardiomyopathy or the long QT
      syndrome, it has become possible to characterise mutations in the genome
      responsible for the disease process. It is interesting that different mutations
      inducing hypertrophic cardiomyopathy are associated with a different prognosis
      and survival time. This example demonstrates that molecular biological analysis
      allows a better estimation of the individual risk in patients with a monogenetic
      disease. Such diseases are an important target for genetic therapies, as
      transfection of normal copies of the diseased gene would potentially cure the
      patient. Clinical experience has so far only been obtained in patients with
      familial hypercholesterolaemia and mutations in the LDL receptor. Molecular
      biology also permits a better understanding of the pathogenesis of
      atherosclerosis, which is responsible for most cardiovascular disease.
      Atherosclerosis is a disease of conduit arteries such as the aorta and the
      coronary arteries. In recent years it has become possible to characterise better
      the molecular and cellular changes leading to endothelial dysfunction, coronary
      vasospasm, adhesion of monocytes and lymphocytes, proliferation and migration of
      vascular smooth muscle cells, and formation of extracellular matrix. This
      improved understanding has led to new therapeutic approaches, although a genetic
      intervention is not probable for the moment due to the complexity of the disease
      process. Balloon dilatation of coronary arteries has generated a new disease,
      namely restenosis. Vascular remodelling and proliferation are of major importance
      for this disease. Many cellular mechanisms have been characterised, and gene
      therapeutic strategies including signal transduction and cell cycle regulation
      have already been investigated experimentally. Coronary bypass graft disease
      represents another target for gene therapy in the vascular system. Many
      experimental and a few clinical protocols have been performed with the saphenous
      vein. Yet another strategy for gene therapy is the endogenous formation of new
      vessels due to the effect of vascular endothelial growth factor. Molecular
      cardiology is a new and promising approach to a better understanding of
      cardiovascular disease. Genetic analysis is already established for the diagnosis
      of single gene disorders and, in addition, allows a more precise prognostic
      evaluation. Cardiovascular gene therapy has been focussing mainly on
      angiogenesis; other strategies, however, are under investigation mainly in an
      experimental setting.

PMID- 10603654
TI  - [The new molecular physician: engineer, soothsayer or health advisor?].
AB  - The label of molecular medicine stands for a variety of scientific, diagnostic
      and therapeutic developments. While these aspects of modern medicine have
      relatively little in common in terms of the ethical tissues they raise, they
      change the overall philosophy of medicine in characteristic ways. These changes
      are analysed in terms of three somewhat non-traditional dimensions of medical
      practice: the engineering's deal, the predictive dimension, and the role of the
      doctor as personal health advisor.

PMID- 10603656
TI  - Medical-ethical guidelines for somatic gene therapy in humans. Swiss Academy of
      Medical Sciences (SAMS).

PMID- 10603655
TI  - [Transition of molecular medicine from research to practice: tasks of the Swiss
      Academy of Medical Sciences (SAMW)].
AB  - During the symposium discussions were held in workshops on how the SAMS can
      support the transition of "molecular medicine" from research into practice. This
      transition is currently happening in prenatal diagnostics. With the help of
      molecular medicine doctors are at an early stage able to diagnose a variety of
      diseases, preliminary stages and dispositions of diseases--even with the unborn.
      Gene-diagnostics stands as a promising method of investigation, with no
      therapeutic equivalent yet. Here the SAMS should as soon as possible develop
      guidelines for the responsible use of gene-diagnostic methods; besides, the
      Academy should work towards connecting the use of gene-diagnostic methods to
      certain professional requirements. Furthermore, the SAMS is expected to ensure
      good basic and further training in the field of "molecular medicine" and to
      support "evidence-based medicine".

PMID- 10603657
TI  - [Therapy edema: secondary effect without effect!].

PMID- 10603658
TI  - Intracellular bacteria of Acanthamoebae resembling Legionella spp. turned out to
      be Cytophaga sp.
AB  - Acanthamoeba sp. isolated from the drinking water system of a hospital harboured
      gram-negative bacteria multiplying inside phagosomes and within the cytoplasm of
      their host cells. According to their morphology demonstrated by electron
      microscopy they resembled Llaps (Legionella-like amoebal pathogens) but turned
      out to be Cytophaga sp. as shown by a typical profile of cellular fatty acids
      obtained by means of gas-liquid chromatography.

PMID- 10603659
TI  - Clonal relationship of Salmonella enterica serovar typhimurium phage type DT104
      in Germany and Austria.
AB  - A new epidemic clone of Salmonella enterica serovar Typhimurium designated
      definitive phage type (DT) 104 has been emerging since 1990 to become most common
      type among S. Typhimurium isolates in Germany and Austria. Molecular
      fingerprinting (PFGE-pattern, plasmid profiles, IS200 pattern, ribotype, ERIC
      type, OMP and MLE patterns) revealed the majority of the DT104 isolates to have
      clonal identity; they were designated as type 1 (about 95%). Moreover, clonal
      type 1 of DT104 was found to occur in sensitive as well as in a range of multiply
      drug-resistant variants and in a variety of plasmid profile types (in particular
      with small cryptic plasmids in the range of 1.0 to 5.0 Md). Since the clonal type
      1 of DT104 has been identified among isolates from other countries, too,
      including such from the United Kingdom, the United Arab Emirates, the
      Philippines, and the Netherlands, its pandemic spread in man indicates that the
      import/export of this pathogen continues. About 5% of the DT104 isolates have
      been identified as genetically diverse indicating the independent appearance of
      the same multiple drug resistance and phage pattern phenotype among different
      Salmonella ancestor strains.

PMID- 10603660
TI  - An effective, rapid and simple method for isolation of Shiga toxin-producing
      Escherichia coli O26, O111 and O157 from faeces and food samples.
AB  - An effective, rapid and simple method was developed for isolating Shiga toxin
      producing Escherichia coli (STEC) O26:H11, O111:H- and O157:H7 from faeces and
      food in less than 24 h. The procedure involves enrichment of these samples in
      Trypticase soy broth (TSB) at 42 degrees C for 6 h. The enrichment culture is
      exposed to 1/8N HCl +0.5% NaCl solution (1 + 1) for 30 sec, then plated onto
      MacConkey agar containing sorbitol, tellurite and cefixime (CT-SMAC) following
      culture at 37 degrees C for 18 h. The findings were compared with conventional
      enrichment methods for efficiency in recovering STEC from bovine faeces. The new
      method increased the sensitivity for isolation of < 10(2) STEC O26:H11, O111:HUT
      and O157:H7 CFU/g of bovine faeces and decreased the growth of other gram
      negative microorganisms. This procedure is readily implemented for use in
      laboratories doing routine microbiological testing.

PMID- 10603661
TI  - Detection of antibodies against Campylobacter jejuni serogroup PEN O:19 purified
      flagellar protein in a patient with Guillain-Barre syndrome.
AB  - C. jejuni serogroup PEN O:19 was isolated from a stool specimen from a patient
      with Guillain-Barre syndrome (GBS). Flagellar protein was isolated and purified
      from reference strain C. jejuni PEN O:19, ATCC 43,446, as well as from a
      homologous patient strain. Antibodies against flagellar protein were detected by
      means of immunoblotting, enzyme-linked immunosorbent assay (ELISA) and tube
      agglutination test. The antibody titres were found to be directly correlated at
      the beginning and in the recovery phase of GBS. Antibodies of IgG and IgA classes
      were present from the very onset of the disease as well as 5 months later, but
      with a lower titre population. However, antibodies of the IgM class were
      persistent only at the onset of the infection and disappeared during the
      following 5 months. Our results strongly support the hypothesis that in GBS
      patients, antiflagellar antibodies are induced during C. jejuni infection and can
      be used in the diagnosis of C. jejuni-associated GBS.

PMID- 10603662
TI  - In-vitro and in-vivo efficacy of zinc acetate against propionibacteria alone and
      in combination with erythromycin.
AB  - Some studies have been published about the in vitro activity of zinc acetate
      (ZA), erythromycin (E) and their combination (ZA/E) against Propionibacterium
      spp., especially erythromycin resistant strains. The efficacy of topical ZA/E
      combination has been reported as well, but a comparison to ZA monotherapy is
      missing. Therefore, the MIC values of ZA, E and the ZA/E combination were
      determined for 15 erythromycin-resistant and 12 erythromycin-sensitive
      Propionibacterium strains using the agar dilution method and the checkerboard
      technique. Furthermore, the antimicrobial efficacy of ZA (1.2%) vs. the ZA/E
      (1.2%/4%) combination in an alcoholic solution was tested in a 7-day treatment
      administered to 32 acne patients. The MIC 100 for ZA was 1024 micrograms ZA/ml
      for both, erythromycin resistant and erythromycin sensitive Propionibacterium
      strains. The ZA, as well as the ZA/E solution showed efficacy reducing both the
      Propionibacterium spp., and the Micrococcaceae in the sebaceous gland infundibula
      of acne patients. There was no significant difference between the two treatments.
      As the MIC 100 of ZA/E was equal to the MIC 100 of ZA, the decrease of the
      erythromycin MIC of the ZA/E combination in erythromycin-resistant strains may be
      partly attributed to the addition of ZA to E. The in vivo antibacterial efficacy
      on 32 acne patients supports the hypothesis that the antibacterial effect of ZA/E
      in short-term treatment can be mostly attributed to ZA.

PMID- 10603663
TI  - Isolation and characterisation of four distinct cytotoxic factors of Salmonella
      Weltevreden.
AB  - Four distinct cytotoxins with different biological, physico-chemical and
      antigenic characteristics were isolated from a single Salmonella Weltevreden
      strain recovered from buffalo meat. The toxins were purified by means of salt
      precipitation, dialysis, gel filtration and ion-exchange chromatographic methods.
      Cytotoxin I was dermonecrotic, verocytotoxic and lethal for the mouse (LD50 120
      micrograms). It induced accumulation of serosanguinous fluid in the rabbit
      ligated ileal loop (RLIL) and mucinous fluid in the stomach. It was active within
      a narrow pH range (5.0-8.0) and lost its activity on autoclaving for 1 min.
      Cytotoxin II was verocytotoxic, enterotoxic and lethal to for the mouse (LD50, 1
      mg). It induced delayed vasopermeability in rabbit skin, was active at between pH
      5.6 and 8.4 only and heat-sensitive (100 degrees C, 30 min). Cytotoxin III was
      neither dermatotoxic nor enterotoxic. It induced vacuolation, multinucleation and
      formation of syncytia in Vero cells. It was pH-sensitive beyond the range of 4.8
      to 8.2. It was completely inactivated on boiling for 30 min. Cytotoxin IV was
      intensely necrotizing to rabbit skin within 6 h of inoculation and lysed Vero
      cells. It also possessed haemolytic and lecithinase/phospholipase-C activities.
      The cytotoxin lost its activity on heating at 90 degrees C (30 min) but remained
      active between pH 2.5 and 7.5. The PIs of the cytotoxins were estimated to be
      9.0, 7.0, 5.6 and 3.0, respectively. All the four cytotoxins were immunogenic in
      rabbits but antigenically unrelated as the anticytotoxin neutralized only the
      homologous cytotoxin and did not cross-react with heterologous cytotoxins.

PMID- 10603664
TI  - Epidemiological analysis of immunity to poliovirus after termination of an era of
      vaccination with OPV in Germany. An analysis of the German Association Against
      Viral Diseases (DVV).
AB  - The global eradication of poliomyelitis by the year 2000 is an objective of the
      World Health Organization (WHO). Since 1998, after a period of 37 years of
      vaccination using live oral poliovirus vaccine (OPV), single use of inactivated
      poliovirus vaccine (IPV) has been recommended in Germany. The present
      epidemiological analysis shows the immunity of 3474 patients to poliovirus types
      1, 2 and 3 by using a microneutralization assay. A non-age-specific evaluation of
      antibodies seroprevalence to poliovirus type 1 remained 81% and similarly, for
      poliovirus type 2 86% while the poliovirus type 3 decreased from 78% in 1990-1992
      to 68% in 1997. In the important group of children aged 5-14 years, the
      prevalence of antibodies to type 3 decreased clearly from 74% in 1990 to 47% in
      1997. The relatively favorable level of seroprevalence of antibody to type 2 in
      children aged 1-4 years (89%) indicates a good acceptance of vaccination
      programs. However, a good immunity to all 3 serotypes was not achieved by primary
      vaccination. The objective of a global eradication of poliomyelitis has not yet
      been be achieved. Great problems still exist, especially in Africa and Asia.

PMID- 10603665
TI  - [New central agents in the treatment of arterial hypertension].

PMID- 10603666
TI  - [Clinical characteristics and follow-up of patients attending a hospital
      hypertension clinic. 10-year experience].
AB  - OBJECTIVE: To analyze the characteristics and control of hypertensive patients
      visited in a hospital hypertension clinic, dependent of the internal medicine
      department. METHODS: The study included 597 hypertensive patients, mean age 51.9
      years (range 14-85), visited consecutively during the period 1989-1998. We
      applied the following initial protocol: Usual and orientated HBP anamnesis and
      physical examination, routine blood and urine test, standard electrocardiography
      and abdominal echocardiography. If necessary, we indicated other test or special
      explorations. After every visit, the data were stored into an electronic
      database, which we analyzed retrospectively to obtain the data of this study.
      RESULTS: Initial and final BP were: systolic BP 154 +/- 25 vs 141 +/- 21 mmHg,
      Dif. -12.9 (95% CI -14.8 a -11.0), and diastolic BP 96 +/- 12 vs 88 +/- 19 mmHg,
      Dif. -7.6 (95% CI -8.6 a -6.6). Four hundred and five patients (79.5%) presented
      I-II OMS stage and 121 (20.2%) III stage. One hundred and seventy-four
      cardiovascular events were registered. Hypercholesterolemia and obesity were
      present in 32% of the patients. Seventy-four (10.7%) had secondary HBP. ECA
      inhibitors were the antihypertensive drugs more used, either associated (58.9%)
      or as monotherapy (37%). Nine hundred patients (31.8%) presented optimal BP
      control (< 140/90 mmHg), and 27 (4.5%) refractory HBP. Weight and laboratory
      values (but uric acid) did not change significantly during the follow-up period.
      CONCLUSIONS: The patients showed a high prevalence of severe cardiovascular
      events, and associated risk factors. The 10% presented secondary HBP. About 31%
      of the patients reached optimal BP control.

PMID- 10603667
TI  - [Short-stay units depending on Internal Medicine].
AB  - BACKGROUND: Wetry to establish the utility that a Short Stay Unit depending on
      Internal Medicine has for a third level hospital. This unit manages the patients
      under the "appropriate stay" concept. METHODS: Several clinical and epidemic
      variables and sanitary indicators were studied in 867 patients. Cost was measured
      as the origin by average stays, explorations and readmission. Effectiveness was
      considered as the percentage of discharges that stay in the hospital for three
      days or less. RESULTS: The average age of the patients was 65.05 years. 55% were
      males. 82.24% had any previous disease. The most common diagnosis (ICD-9) were
      respiratory diseases, nervous system diseases and digestive diseases. The average
      stay of the patients was 57 hours, 2,259 explorations were ordered, it supposes
      an average of 0.328 urgent explorations and 2,276 UCE explorations. 310
      explorations were no received when the patient was sent home. 36.56% of the
      patients required no explorations. 62.4% of the patients were sent home.
      Explorations not received had a bad influence in the average stay and in the
      discharges. Readmissions were 9.36%. CONCLUSIONS: We got hay 62.4% of the
      patients had a stay of 2,375 days in the hospital, With a reasonably low cost in
      readmissions and explorations. However it wasn't possible to establish which
      patient coming to the Emergency Service is appropriate for this Short Stay Unit.

PMID- 10603668
TI  - [Usefulness of troponin T and troponin I in the diagnosis and prognostic
      stratification of patients with ischemic cardiopathy attending an emergency
      service].
AB  - BACKGROUND: Diagnostic of chest pain in the emergency services supposes a serious
      problem. This study wants objective if the new non enzymatic markers of
      myocardial necrosis (T troponin and I troponin) may be an aid for the diagnostic
      and prognostic stratification of patients with myocardial ischemia. PATIENTS AND
      METHODS: 82 successive patients who went to the emergency room for chest pain
      were studied. Electrocardiogram and blood samples were obtained at 0,4, and 12
      house of admission. A clinic-evolutive study was performed at discharge, and they
      were classified in 3 categories: a) myocardial infarction, b) unstable angina
      (Braunwald classification) and no coronary pains. RESULTS: In the 27 patients
      with myocardial infarction the markers of troponin group were more sensitive than
      creatinine kinase to determine myocardial necrosis at 4 hours of admission. Of 41
      patients with unstable angina, 34% were of Braunwald III-B class. Troponin group
      markers discriminate a group of high risk patients, 70% of the patients that need
      an emergency coronarography for bad clinical evolution were troponin group marker
      positive. CONCLUSIONS: The use in the emergency room of troponin necrosis markers
      (T and I troponin) allows to optimize the sanitary resources, detecting quickly
      the patients with acute myocardial infarction and discriminate a group of high
      risk of patients with angina.

PMID- 10603669
TI  - [Real clinical medicine and evidence-based medicine: evaluative clinical
      research].
AB  - BACKGROUND: The clinical view is essential in the application of a new paradigm
      on "evidence based medicine". Also, we hardly haven't studies that had been made
      with patients in real time and place. We analyzed the rate of evidence that found
      our clinical praxis. METHODS: A randomized observational epidemiological study
      was made over 689 clinical decisions in relation with 167 pathological processes,
      considered in 36 patients. Age (65.9, SD 2.1), sex (23 F, 13 M), comorbidity
      (4.6, SD 2.1), poly-pharmacy (8.8, SD 3.3). Case-mix of GRDs (infections--even
      HIV-, chronic respiratory affections, neurologic, cardiovascular diseases,
      diabetes and its complications ..., in decreased order. We used the D.L.
      Sackett's criterium (evidence level one "experimental", level two "no
      experimental but convincing-rational", level three "without any scientific base".
      A progressive internal control was used in order to adjust the "arbitrariness in
      the assignation". RESULTS: 60% of the decisions provided elevated care evidence
      level; 24.5% in level number two, and 15.5% without any foundation. The
      proceedings reasonably founded were 84.5%. The pharmacological treatment had more
      evidence. The diagnosticum was more empiric. The primary illness and its
      treatment concentrated more evidence that the enclosed conditions (65% level one
      and 50% respectively). The prediction is still unknown (null evidence).
      CONCLUSIONS: More than a half of the patients were benefited of a clinical
      praxis, tested in effectiveness and safety. 15.5% of the decisions had an
      uncertain effect (favourable, newer or damaging). Nowadays, the complex clinical
      praxis, despite of exceeding the paradigm of "evidence based medicine", should
      tend toward scientific foundation as much as possible.

PMID- 10603670
TI  - [Renal failure secondary to granulomatous interstitial nephritis as initial
      manifestation of sarcoidosis].
AB  - Sarcoidosis is a rare cause of renal failure and it has been associated with a
      wide spectrum of renal manifestations, including granulomatous interstitial
      nephritis. We present the case of a 48-year old male patient with rapidly
      progressive renal insufficiency due to sarcoid normocalcemic granulomatous
      interstitial nephritis who lacked the pulmonary signs of sarcoidosis. Prednisone
      therapy yielded a favorable outcome with fall in serum creatinine level and
      resolution of abnormalities of the urinary sediment.

PMID- 10603671
TI  - [Pulmonary sarcoidosis with testicular and epididymal disease].
AB  - We expose a case of sarcoidosis with pulmonary and intrathoracic ganglion
      infection added to an infrequent testicular and epididymal affection
      simultaneously. We only have found this association in six cases in the revised
      literature, but we didn't found the affection of Morgagni's hydatid by
      sarcoidosis. The presence of testicular mass and hilar adenopathies in young
      patients make us to think about a diagnostic threat. The inguinal treatment with
      testicular biopsy has been chosen like the diagnostic management in this case.

PMID- 10603672
TI  - [Disseminated extrapulmonary tuberculosis with skin, lymph node and bone
      involvement].
AB  - Disseminated extrapulmonary tuberculosis is uncommon in no immunocompromised
      hosts. We described the case of a 68-year-old HIV seronegative man, who presented
      with a 5 months history of constitutional symptoms, generalized lymphadenopathy,
      evening fever, osteomyelitis of the left fibula and cutaneous lesions (papules
      and pustules). There was neither clinical nor radiological evidence of pulmonary
      involvement. On the basis of bacteriological and pathological findings the
      diagnosis of disseminated extrapulmonary tuberculous was made.

PMID- 10603673
TI  - [Leptospirosis. Review of 5 cases].
AB  - Five cases of leptospirosis diagnosed from 1978 to 1996 were retrospectively
      reviewed. The five patients were male and their mean age was 34.2 years.
      Epidemiologic factors were found in the 5 patients. The 3 common clinical
      findings: fever, myalgia and jaundice were found in the 5 patients. Hepatorenal
      involvement was observed in 4 cases (80%), bleeding episodes in 4 patients (80%),
      cardiac involvement in 4 (80%); in none case was observed central nervous system
      involvement. In one case (20%) was observed septic shock with acute respiratory
      failure. The Leptospira serogroups identified were icterohaemorrhagiae in 3 cases
      and could not be determined in 2. All the patients were amelioration with
      antibiotic therapeutic. The epidemiologic, clinical, analytical and therapeutic
      aspects are discussed.

PMID- 10603674
TI  - [Leptin in the endocrinology of obesity].
AB  - The article summarizes the endocrinology axis in relation to leptin in the
      obesity. There is a glucocorticoid hypothesis in the obesity origin. Human plasma
      leptin levels are elevated in Cushing's syndrome and there is a robust leptin
      secretory responses to dexamethasone. Obesity impacts on reproductive function in
      man and women. Leptin levels are higher in women than in men and a critical blood
      leptin level is necessary to trigger reproductive ability in women. The
      relationship between body mass index and circulating leptin varies during the
      course of spontaneous cycles in women, the best correlation occurring during the
      luteal phase when progesterone and leptin concentrations are highest. Obesity is
      associated with a decrease in growth hormone (GH) and reversible with weight
      loss. The influence of body composition on GH secretion in the obesity may be
      mediated through leptin, acting as a peripheral signal from adipose tissue.
      Thyroid dysfunction appear not associated with alterations in serum leptin
      levels. There is a significant relationship between insulin and leptin, but it is
      not immediate, since type 2 diabetics show similar leptin levels to those of
      nondiabetic humans of the same body mass index.

PMID- 10603675
TI  - [Small cell lung carcinoma in a 20-year-old patient].

PMID- 10603676
TI  - [Changes in the criteria of patient selection in clinical trials].

PMID- 10603677
TI  - [Erythrocytic glucose-6-phosphate dehydrogenase deficiency, hemolysis and
      diabetic ketoacidosis].

PMID- 10603678
TI  - [Usefulness of percutaneous hepatic biopsy in patients with HIV infections].

PMID- 10603679
TI  - [Posologic factors of digoxin in Catalonia].

PMID- 10603680
TI  - [Acute intermittent porphyria with neurologic manifestations].

PMID- 10603681
TI  - [Association of hepatocarcinoma and non-Hodgkin's lymphoma in a patient with
      hepatitis C virus infection].

PMID- 10603682
TI  - [Severe hyponatremia secondary to panhypopituitarism in a patient with primary
      empty sella turcica syndrome].

PMID- 10603683
TI  - [Severe thrombocytopenia secondary to cytomegalovirus infection in an
      immunocompetent adult].

PMID- 10603684
TI  - [Endoscopy in celiac disease].

PMID- 10603685
TI  - [Psoas abscess: percutaneous or surgical drainage?].

PMID- 10603686
TI  - Pain in adult recipients of blood or marrow transplant.
AB  - Severe pain is a problem for most bone marrow transplant (BMT) recipients. The
      purpose of this descriptive study was to describe the pain experience of adults
      undergoing autologous BMT, allogeneic BMT, or peripheral blood stem cell
      transplant. The sample consisted of 20 adults, 21 to 54 years of age. Using
      investigator-developed structured interview guides, investigators interviewed
      each participant four times: on the day of transplant, then at 3-weekly
      intervals. Investigators used a content analysis approach when analyzing data.
      During the first interview, 18 participants said that they were told to expect
      mouth sores during BMT, yet only six said that they actually expected to
      experience mouth sores during BMT. During successive interviews, 13 reported
      mouth sores. Eight other pain sites were reported. Participants reported that
      their tolerance of mild, moderate, and severe pain decreased over 2 weeks, and
      they named a wide variety of factors that caused or relieved pain. Ten said that
      they used nonpharmacologic techniques to feel more comfortable. Seven said that
      their BMT pain was worse or more difficult than they had expected. Overall pain
      ratings ranged from 0 to 8 on a 0 to 10 scale, M = 4.5. Five said the side
      effects of analgesics bothered them more than their pain. Most of them said a
      pain-rating scale was useful. Three weeks post-BMT, seven said they still
      experienced pain. Implications for clinical practice, research, and education are
      discussed.

PMID- 10603687
TI  - Concerns and misconceptions about pain among Hong Kong Chinese patients with
      cancer.
AB  - It is estimated that approximately 50% of patients with cancer experience pain,
      and this percentage increases to 80% in patients with terminal cancer.
      Misconceptions and concerns of patients with cancer regarding the use of opioid
      analgesics have been identified as one of the major barriers to achieving optimal
      pain control. Misconceptions and concerns regarding addiction and tolerance to
      opioid analgesics and patients' desire to be "good" have been reported in the
      United States. The aim of this survey was to determine if similar misconceptions
      and concerns exist in Hong Kong Chinese patients with cancer. The results
      indicate that Hong Kong Chinese patients have the same concerns regarding the use
      of opioid analgesics. The respondents' fatalistic beliefs are a major hindrance
      to optimizing pain control, with 79% indicating that pain is an inevitable aspect
      of hospitalization because they believe that cancer pain cannot be relieved by
      medications. Fear of addiction was a major concern for 52% of the respondents,
      and about the same number of respondents believed that opioid analgesics should
      be administered only as a last resort. Regarding a desire to be "good," more
      patients reported that they would prefer to disturb nurses rather than
      physicians. It is desirable that culturally specific education programs be
      provided to dispel patient misconceptions and concerns regarding the use of
      opioid analgesics.

PMID- 10603688
TI  - Caring for and about cancer patients: identifying the meaning of the phenomenon
      "caring" through narratives.
AB  - For several decades nurses have been using the terms "caring" and "nursing."
      Caring, considered to be a universal phenomenon, has been seen as a nursing term,
      including all aspects of delivering nursing care to patients. Ten registered
      nurses selected from hematologic, oncologic, and lung medicine wards were asked
      to narrate one situation in which they had been able to supply good caring and
      one situation wherein they had not been able to provide good caring for the
      patient. To identify the meaning of the caring phenomenon as experienced and
      expressed by nurses working with patients who have cancer, a qualitative analysis
      using phenomenologic hermeneutics was used. The narrated interviews, tape
      recorded and transcribed verbatim, were analyzed, and a theme was interpreted:
      developing and maintaining a helping-trusting interpersonal relationship. Five
      subthemes also were identified: creating an interaction with the patient and the
      next of kin, acting to satisfy the needs of the patient and next of kin, feeling
      frustration in the role of caring, being affected by time aspects, and developing
      self and acquiring insight. It is in caring that nurses and patients connect with
      one another, are fulfilled, and experience growth. If they work actively with
      this perspective, nurses will feel fulfilled, not frustrated.

PMID- 10603689
TI  - Body image, decision making, and breast cancer treatment.
AB  - This study was performed to describe women's satisfaction with body image before
      and 8 weeks after the surgical treatment of breast cancer compared with women
      without breast cancer. Additional aims were to describe women's perceived
      participation in decisions regarding choice of surgical procedure to treat their
      breast cancer, and postoperative satisfaction with their breast cancer treatment,
      as well as to explore factors influencing women's decisions regarding choice of
      surgical procedure. The design was prospective with a descriptive, comparative
      design. The convenience sample included 31 women with breast cancer from an urban
      breast health center, and 30 women without breast cancer from the community. The
      majority were college educated, white, ranging in age from 29-82 years. Women
      with breast cancer completed instruments before and 8 weeks after surgery. Women
      without breast cancer completed the instruments two times 8 weeks apart. Three
      instruments measuring body image satisfaction were used. Participation in
      treatment decision-making, having a treatment choice, and posttreatment
      satisfaction, along with a description of important factors in decision making,
      were measured with open and closed-ended questions. During the study period,
      women with breast cancer experienced a significant decrease in satisfaction with
      body image after surgery (p < .004). Satisfaction with body image remained
      constant in the women without breast cancer. Most (94%) of the women with breast
      cancer reported participating in treatment decisions about the type of surgical
      procedure used to treat their breast cancer, had a treatment choice (77%), and
      were moderately to very satisfied with the outcome of their surgeries (94%).
      Qualitative data results suggest that women's treatment decisions were based on
      their perceptions of "survival," that is, which type of surgery offered the best
      chance for long-term survival. These data suggest that satisfaction with body
      image is disturbed by surgery for breast cancer despite active participation in
      decisions regarding selection of treatment or postoperative satisfaction with
      type of surgical treatment received. These outcomes suggest that women need
      assistance in adjusting to alterations in body image from nurses and the need for
      research to describe effective interventions. Future studies of body image and
      breast cancer treatment should be conducted with larger samples, and at different
      points after surgery to determine the effects of mastectomy and breast-conserving
      surgery on the body image of breast cancer survivors over time.

PMID- 10603690
TI  - Student nurses' breast self-examination health beliefs, attitudes, knowledge, and
      performance during the first year of a preregistration degree program.
AB  - Very little information is available about young women's breast self-examination
      (BSE) health beliefs and practice. The purpose of this descriptive survey was to
      determine if changes occurred in young women's BSE health beliefs, attitudes,
      knowledge, and performance over the first year of a registered nursing degree
      program. The convenience sample consisted of female students ages 40 years or
      younger who were surveyed at the beginning (n = 105) and end (n = 71) of the
      first year of the course. The Health Belief Model was used as the conceptual
      model in the study to measure the students' health beliefs and to calculate mean
      health belief scores. Data were collected using self-administered questionnaires
      and analyzed using descriptive and inferential statistics. Results found
      students' BSE health belief scores to be high for perceived seriousness and
      benefits; moderate for susceptibility, control, and health motivation; and low
      for perceived barriers. These beliefs were not found significantly to predict or
      increase student's attitudes, knowledge, or performance of BSE, even though
      significant associations were identified between individual health beliefs.
      Students consistently reported positive attitudes toward the importance of BSE
      and in learning more about the procedure. Approximately one-third of students
      reported performing BSE monthly. No significant differences were identified in
      their BSE knowledge or performance over the year. Positive correlations were
      found between students' BSE frequency and their nursing experience as well as BSE
      instruction gained outside the course. In summary, no statistically significant
      differences were found between students' pretest and posttest BSE variables.

PMID- 10603691
TI  - Assessing women's sexuality after cancer therapy: checking assumptions with the
      focus group technique.
AB  - Cancer and cancer therapies impair sexual health in a multitude of ways. The
      promotion of sexual health is therefore vital for preserving quality of life and
      is an integral part of total or holistic cancer management. Nursing, to provide
      holistic care, requires research that is meaningful to patients as well as the
      profession to develop educational and interventional studies to promote sexual
      health and coping. To obtain meaningful research data instruments that are
      reliable, valid, and pertinent to patients' needs are required. Several sexual
      functioning instruments were reviewed for this study and found to be lacking in
      either a conceptual foundation or psychometric validation. Without a defined
      conceptual framework, authors of the instruments must have made certain
      assumptions regarding what women undergoing cancer therapy experience and what
      they perceive as important. To check these assumptions before assessing women's
      sexuality after cancer therapies in a larger study, a pilot study was designed to
      compare what women experience and perceive as important regarding their sexuality
      with what is assessed in several currently available research instruments, using
      the focus group technique. Based on the focus group findings, current sexual
      functioning questionnaires may be lacking in pertinent areas of concern for women
      treated for breast or gynecologic malignancies. Better conceptual foundations may
      help future questionnaire design. Self-regulation theory may provide an
      acceptable conceptual framework from which to develop a sexual functioning
      questionnaire.

PMID- 10603692
TI  - Attendance at cancer follow-up clinic: does it increase anxiety or provide
      reassurance for men successfully treated for testicular cancer?
AB  - This cross-sectional descriptive study examined the meaning of the cancer follow
      up clinic for men who have been successfully treated for testicular cancer. The
      sample of 62 men were selected using a nonprobability quota sampling method
      before attendance at a routine testicular cancer follow-up clinic within the
      Directorate of Clinical Oncology, Western General Hospitals NHS Trust, Edinburgh,
      Scotland. Subjects were given four instruments to complete immediately before
      seeing the doctor in the clinic, and two instruments to complete on day 8 after
      the clinic appointment. Instruments included the State-Trait Anxiety Inventory
      (STAI), a demographic questionnaire, and two Likert scales adapted for use in the
      study: the Common Concerns about Testicular Cancer questionnaire and the
      Psychological Consequences of Screening questionnaire (PCQ). Results demonstrated
      that men attending the clinic exhibit low levels of anxiety at the points
      measured, but gain a great deal of reassurance from the clinic visit. Results
      also demonstrated the areas of concern about testicular cancer and its management
      that influence anxiety in the follow-up clinic.

PMID- 10603693
TI  - The relationship of rural persons' multidimensional health locus of control to
      knowledge of cancer, cancer myths, and cancer danger signs.
AB  - The purpose of the study was to determine if a relationship exists between
      multidimensional health locus of control and knowledge of breast cancer, prostate
      cancer, cancer myths, and danger signs. A descriptive correlational design was
      used. A convenience sample of 78 rural men and 79 rural women participated in the
      study. Participants completed three questionnaires: (a) the Cancer Danger Signs
      Questionnaire, (b) the Cancer Myths Questionnaire, (c) the Prostate Cancer
      Knowledge Test (completed by the men) and the Breast Cancer Knowledge Test
      (completed by the women). Results indicated that an internal score on the
      Multidimensional Health Locus of Control (MHLOC) scale did not predict knowledge
      of breast cancer in women, prostate cancer in men, cancer myths, or danger signs.
      Women who scored high on the Powerful Others subscale of the MHLOC had
      statistically significant high scores on knowledge of breast cancer, but not on
      cancer myths and danger signs. The MHLOC and its subscales did not predict
      knowledge of prostate cancer, cancer myths, or cancer danger signs for the male
      participants. The implications of these results for rural nursing practice and
      their relationship to previous research are discussed.

PMID- 10603694
TI  - Effects of semantic predictability on children's preservation of a phonemic voice
      contrast.
AB  - We investigated the effects of semantic predictability on children's preservation
      of the /t/-/d/ phonemic voice contrast in American English. In Experiment 1, a
      total of 36 seven-, nine-, and twelve-year-olds produced minimal pairs differing
      in intervocalic /t/ and /d/ in semantically biasing and semantically neutral
      passages. The seven-year-olds preserved the phonemic contrast in both passage
      types. However, for the nine- and twelve-year-olds, total word duration and
      preceding vowel duration preserved the /t/-/d/ contrast, but this interacted with
      semantic predictability. The contrast was preserved in the biasing and not in the
      neutral passages. The production results from the older children replicated
      previous findings from adults, demonstrating that semantic predictability
      influences speech production at both a lexical and a segmental level. In
      Experiment 2, listeners identified the tokens produced in Experiment 1. The
      identification results suggested that differences produced by speakers may not
      necessarily have a functional role for listeners. An interactive activation
      framework is proposed to account for the semantic effects on older children's and
      adults' production. For the youngest children, however, we suggest that pragmatic
      compensation and task demands interact with the effects of interactive
      activation.

PMID- 10603695
TI  - Some differences between English plural noun inflections and third singular verb
      inflections in the input: the contributions of frequency, sentence position, and
      duration.
AB  - Grammatical inflections such as the English plural noun -s and third person
      singular verb -s are acquired at different points in time by young children. This
      finding is typically attributed to factors such as relative semantic salience or
      the distinction between lexical and functional categories. In this study input
      frequency, sentence position, and duration were examined as possible contributing
      factors. In both conversations with and stories aimed at young children, noun
      plural inflections were found to be more frequent than third singular verb
      inflections, especially in sentence-final position. Analysis of the speech of
      four mothers reading stories to their two-year-old children confirmed that
      duration differences also exist in the input. Because fricatives were lengthened
      in sentence-final position and plural nouns were much more likely to appear in
      these positions than were third singular verb forms, plural nouns were
      significantly longer than third singular inflections on average. The possible
      implications of these findings for language learnability theories and accounts of
      grammatical deficits in specific language impairment are discussed.

PMID- 10603696
TI  - The learning of first and second person pronouns in English: network models and
      analysis.
AB  - Although most English-speaking children master the correct use of first and
      second person pronouns by three years, some children show persistent reversal
      errors in which they refer to themselves as you and to others as me. Recently,
      such differences have been attributed to the relative availability of overheard
      speech during the learning process. The present study tested this proposal with
      feed-forward neural networks learning these pronouns. Network learning speed and
      analysis of their knowledge representations confirmed the importance of exposure
      to shifting reference provided by overheard speech. Errorless pronoun learning
      was linked to the amount of overheard speech, interactions with a greater number
      of speakers, and prior knowledge of the basic-level kind PERSON.

PMID- 10603697
TI  - The acquisition of past tense morphology in Icelandic and Norwegian children: an
      experimental study.
AB  - Icelandic and Norwegian past tense morphology contain strong patterns of
      inflection and two weak patterns of inflection. We report the results of an
      elicitation task that tests Icelandic and Norwegian children's knowledge of the
      past tense forms of a representative sample of verbs. This cross-sectional study
      of four-, six- and eight-year-old Icelandic (n = 92) and Norwegian (n = 96)
      children systematically manipulates verb characteristics such as type frequency,
      token frequency and phonological coherence--factors that are generally considered
      to have an important impact on the acquisition of inflectional morphology in
      other languages. Our findings confirm that these factors play an important role
      in the acquisition of Icelandic and Norwegian. In addition, the results indicate
      that the predominant source of errors in children shifts during the later stages
      of development from one weak verb class to the other. We conclude that these
      findings are consistent with the view that exemplar-based learning, whereby
      patterns of categorization and generalization are driven by similarity to known
      forms, appropriately characterizes the acquisition of inflectional systems by
      Icelandic and Norwegian children.

PMID- 10603698
TI  - Pathbreaking verbs in syntactic development and the question of prototypical
      transitivity.
AB  - The first verbs to participate in VO and SVO combinations, and the temporal
      parameters of the spread of these combinatory patterns over different verbs were
      investigated. The longitudinal language observations of 16 children, one
      acquiring English, the others Hebrew, were examined. The children were observed
      once a week for 3-12 months, the observations starting when the children were
      still in the single-word stage (1.1-2.1) and ending when they were well into
      multiword speech (1.8-2.7). The results indicate that the more verbs children
      already know to combine in a certain pattern, the faster they learn new ones.
      Apparently children induce from individual word-combinations some general
      principles that facilitate further learning. The 'pathbreaking verbs' that begin
      the acquisition of a novel syntactic rule tend to be generic verbs expressing the
      relevant combinatorial property in a relatively pure fashion: the same verbs that
      children first combine with direct objects, are typical grammaticalized markers
      of transitivity in many languages. These verbs do not have HIGH TRANSITIVITY as
      defined by Hopper & Thompson (1980). Rather, they express fundamental 'object
      relations' of incorporation into, and ejection from the personal. Crosslinguistic
      evidence indicates that this may be the basic transitivity construct in
      languages. The results raise the possibility that lexical-specific learning of
      positional patterns is sufficient to account for the formation of syntactic
      abstractions.

PMID- 10603699
TI  - Deixis, personal reference, and the use of pronouns by blind children.
AB  - Blind children are considered to use personal reference terms late and with a
      great deal of reversal errors. However, in previous research, there has been a
      dearth of both quantitative and qualitative data on their use of pronouns. In the
      present paper data from a longitudinal study of five children (three totally
      blind, one partially sighted, and one sighted) is presented. The children had
      different ages at the beginning of the study, ranging from 0.9 to 2.5, and were
      followed for a time span of over 12 months. Every spatial deictic term and
      personal reference term used by the children was analysed. Special attention was
      given to the analysis of the reversal errors. The data obtained clearly showed
      that the blind children began to use personal reference terms as early as the
      sighted children, and that the use of reversals was not a general characteristic
      of the language of the blind children, since only one of the four blind or
      partially sighted children produced a noticeable percentage of reversals. The
      analysis of the contexts in which reversal errors were produced showed that
      imitation does not fully explain them, and some proposals for a multiplex
      explanation of reversals are offered. Thus, the data do not give support to the
      idea that blind children in general show problems with pronouns, nor to those
      claims that link blind children with autistic children in this regard.

PMID- 10603700
TI  - Personal pronouns and perspective taking in toddlers.
AB  - This study examined the evolution of visual perspective-taking skills in relation
      to the comprehension and production of first, second and third person pronouns.
      Twelve French-speaking and 12 English-speaking children were observed
      longitudinally from 1.6 until they had acquired all pronouns and succeeded on all
      tasks. Free-play sessions and three tasks were used to test pronominal
      competence. Four other tasks assessed Level-1 perspective-taking skills: two of
      these tasks required the capacity to consider two visual perspectives, and two
      others tested the capacity to coordinate three such perspectives. The results
      indicated that children's performance on perspective-taking tasks was correlated
      with full pronoun acquisition. Moreover, competence at coordinating two visual
      perspectives preceded the full mastery of first and second person pronouns, and
      competence at coordinating three perspectives preceded the full mastery of third
      person pronouns when a strict criterion was adopted. However, with less stringent
      criteria, the sequence from perspective taking to pronoun acquisition varied
      either slightly or considerably. These findings are discussed in the light of the
      'specificity hypothesis' concerning the links between cognition and language, and
      also in the context of the recent body of research on the child's developing
      theory of mind.

PMID- 10603701
TI  - Evaluative explanations in children's narratives of a video sequence without
      dialogue.
AB  - Children's narratives consist of event clauses and contextualizing or
      'evaluative' clauses. Bamberg & Damrad-Frye (1991) and Bamberg (1994) claimed
      that young children make limited use of evaluative clauses because they are less
      able to adopt a global perspective on the narrative. In an earlier study,
      Karmiloff-Smith (1985) demonstrated that the narratives of younger children have
      coherence only at a local level. However, Wellman & Bartsch (1988) showed that
      young children could produce evaluative-like causal explanations if given a
      specific prompt. The present study on 160 young children aged five, seven, nine
      and eleven years examined their production of evaluatives in narratives of a
      story presented as a video sequence with no spoken dialogue, to ensure that the
      children's production was not simply a re-working of verbal input. Results
      indicated that prompts greatly facilitated children's production of evaluatives
      and that they could adopt a global perspective on the story when formulating
      evaluatives. These results indicate that limitations in the narratives of young
      children are more plausibly explained by contextual factors influencing language
      production and by constraints on working memory than by children's presumed lack
      of understanding of the structure of events or their inferences about the minds
      of the characters.

PMID- 10603702
TI  - When and how peers give reasons: justifications in the talk of middle school
      children.
AB  - The ability to justify one's beliefs or actions requires linguistic, social, and
      cognitive skills, including an understanding of the psychological states of
      others and the negotiation of a socially-sensitive discourse. The production of
      verbal justifications was examined both quantitatively and qualitatively in eight
      pairs of eight- to eleven-year-old children whose natural discourse was
      videotaped, transcribed and coded for justifications. Previous research has
      frequently studied justifications in conflicts; children in this study produced
      most of their justifications both in the context of elaborating on a previously
      asserted claim and in conflicts. The statement justified and the justifications
      themselves most frequently focused on facts, evaluations, actions, and habitual
      characteristics or occurrences. A majority of the justifications were produced to
      support a statement which had some negative valence to it. Although causal
      connectives have previously been often used as the means for determining
      justifications, the children in this study rarely used causal connectives and
      mental verbs in statements with justifications. A qualitative analysis of the
      discourse of the dyads revealed differences in conversational styles which
      produced very different types of justifications. Some dyads made frequent use of
      narratives and co-constructed justifications; other dyads generally produced very
      short, often isolated justifications.

PMID- 10603703
TI  - Different rates of pronoun case error: comments on Rispoli (1998)
AB  - Rispoli (1998) presents data to motivate a model of pronoun case errors in child
      English. His data consist of relative rates of occurrence of errors involving
      particular forms in the study of twenty-seven English children between the ages
      of 2.6 and 4.0. I show that his claim that overextensions of he and him are
      antagonistic cannot be maintained. I argue that his explanation for why her
      subjects are more frequent than other errors is insufficient, and suggest an
      account in terms of relative input frequencies. Finally, I demonstrate that the
      fundamental assumption underlying Rispoli's model is untenable, and that his
      findings are not counterevidence for developmental syntax models such as that of
      Schutze (1997).

PMID- 10603704
TI  - Previous hyperthermic treatment increases mitochondria oxidative enzyme activity
      and exercise capacity in rats.
AB  - The study was designed to investigate the role of hyperthermia in the tolerance
      of exercise in rats and the possible mechanism was examined. The hyperthermic
      pretreatment was performed using an electric pad on the anesthesized rats 24
      hours before exercise. Rats were exercised passively in a motor-controlled round
      treadmill in high temperature environment (36-37 degrees C) until exhaustion. The
      capacity of tolerance was calculated. Lymphocytes and gastrocnemius muscle were
      collected from both groups. The changes in muscular morphology, mitochondria
      oxidative enzyme activity and induction of Hsp72 were investigated. The results
      revealed that experimental rats were more tolerant to exercise at high
      temperature than the control group; the duration time were 89 +/- 17.8 min and
      63.1 +/- 7.3 min, respectively. Hsp72 was induced markedly in the experimental
      group, both in muscle and lymphocytes, indicating a heat shock response. There
      was no significant change in morphology of the mitochondria, 24 hours after
      hyperthermic treatment, as shown by histopathological and electromicroscopic
      investigation. However, the activity of mitochondrial enzymes increased
      significantly in experimental group before exercise: 84.6 +/- 6.3 and 345 +/-
      15.4 (nmole cytochrome c/min/mg total protein) respectively of NADH-cytochome c
      reductase and succinate-cytochome c reductase activity in experimental group
      compared to 58.9 +/- 4.7 and 269.0 +/- 24.0 in control group (p < 0.05, by
      student t-test). It is concluded that hyperthermic treatment enhances muscular
      mitochondrial oxidative enzyme activity in rats, and results in increasing
      tolerance to exercise at high temperature. The heat shock response, most probably
      the inducible Hsp72, is a crucial factor in this effect.